Title of Invention	SPIROIMIDAZOLIDINE DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL PREPARATION COMPRISING THEM
Abstract	The present invention relates to spiroimidazolidine derivatives of formula (I) in which E, V, W, X, R<sup>1</sup> and R<sup>2</sup> have the meanings indicated in the claims. The compounds of formula (I) are valuable pharmaceutical active compounds which are suitable, for example, for the therapy and prophylaxis of inflammatory disorders, for example of rheumatoid arthritis, or of allergic disorders. The compounds of formula (I) are inhibitors of the adhesion and migration of leukocytes and/or antagonists of the adhesion receptor VLA-4 belonging to the integrins group. They are generally suitable for the therapy and prophylaxis of illnesses which are caused by an undesired extent of leukocyte adhesion and/or leukocyte migration or are associated therewith or in which cell-cell or cell-matrix interactions which are based on interactions of VLA-4 receptors with their ligands play a part. The invention furthermore relates to processes for the preparation of the compounds of formula (I), their use and pharmaceutical preparations which contain compounds of formula (I).

Title of Invention

SPIROIMIDAZOLIDINE DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL PREPARATION COMPRISING THEM

Abstract

The present invention relates to spiroimidazolidine derivatives of formula (I) in which E, V, W, X, R<sup>1</sup> and R<sup>2</sup> have the meanings indicated in the claims. The compounds of formula (I) are valuable pharmaceutical active compounds which are suitable, for example, for the therapy and prophylaxis of inflammatory disorders, for example of rheumatoid arthritis, or of allergic disorders. The compounds of formula (I) are inhibitors of the adhesion and migration of leukocytes and/or antagonists of the adhesion receptor VLA-4 belonging to the integrins group. They are generally suitable for the therapy and prophylaxis of illnesses which are caused by an undesired extent of leukocyte adhesion and/or leukocyte migration or are associated therewith or in which cell-cell or cell-matrix interactions which are based on interactions of VLA-4 receptors with their ligands play a part. The invention furthermore relates to processes for the preparation of the compounds of formula (I), their use and pharmaceutical preparations which contain compounds of formula (I).

Full Text	Spiroimidazolidine derivatives, their preparation, their use and pharmaceutical preparations comprising them in which E, V, W, X, R1 and R2 have the meanings indicated below/. The compounds of the formula I are valuable pharmaceutical active compounds, which are suitable, for example, for the therapy and prophylaxis of inflammatory disorders, for example of rheumatoid arthritis, or of allergic disorders. The compounds of the formula I are inhibitors of the adhesion and migration of leukocytes and/or antagonists of the adhesion receptor VLA-4 belonging to the integrins group. They are generally suitable for the therapy and prophylaxis of illnesses which are caused by an undesired extent of leukocyte adhesion and/or leukocyte migration or are associated therewith or in which cell-cell or cell-matrix interactions which are based on interactions of VLA-4 receptors with their ligands play a part. The invention furthermore relates to processes for the preparation of the compounds of the formula 1, their use and pharmaceutical preparations which contain compounds of the formula 1. The integrins are a group of adhesion receptors which play an important part in cell-cell-binding and cell-extracellular matrix-binding processes. They have an aβ-heterodimeric structure and exhibit a wide cellular distribution and a high extent of evolutive conservation. The integrins include, for example, the fibrinogen receptor on platelets, which interacts especially with the RGD sequence of fibrinogen, or the vitronectin receptor on osteoclasts, which interacts especially with the RGD sequence of vitronectin or of osteopontin. The integrins are divided into three major groups, the p2 subfamily with the representatives LFA-1, Mac-1 and p150/95, which are responsible in particular for cell-cell interactions of the immune system, and the subfamilies β1 and β3, whose representatives mainly mediate cell adhesion to components of the extracellular matrix (Ruoslahti, Annu. Rev. Biochem. 1988, 57, 375). The integrins of the β1 subfamily, also called VLA proteins (very late (activation) antigen), include at least six receptors which interact specifically with fibronectin, collagen and/or laminin as ligands. Within the VLA family, the integrin VLA-4 (a4p1) is atypical, insofar as it is mainly restricted to lymphoid and myeloid cells and is responsible in these for cell-cell interactions with a large number of other cells. For example, \/LA-4 mediates the interaction of T and B lymphocytes with the heparin Il-binding fragment of human plasma fibronectin (FN). The binding of \/LA-4 with the heparin Il-binding fragment of plasma fibronectin is especially based on an interaction with an LDVP sequence. In contrast to the fibrinogen or vitronectin receptor, VLA-4 is not a typical RGD-binding integrin (Kilger and Holzmann, J. Mol. Meth. 1995, 73,347). The leukocytes circulating in the blood normally exhibit only a low affinity for the vascular endothelial cells which line the blood vessels. Cytokines which are released from inflamed tissue cause the activation of endothelial cells and thus the expression of a large number of cell surface antigens. These include, for example, the adhesion molecules ELAM-1 (endothelial cell adhesion molecule-1; also designated as E-selectin), which, inter alia, binds neutrophils, ICAM-1 (intercellular adhesion molecule-1), which interacts with LFA-1 (leukocyte function-associated antigen 1) on leukocytes, and VCAM-1 (vascular cell adhesion molecule-1), which binds various leukocytes, inter alia lymphocytes (Osborn et al., Cell 1989, 59, 1203). VCAM-1, like lCAM-1, is a member of the immunoglobulin gene superfamily. VCAM-1 (first know as INCAM-110) was identified as an adhesion molecule that is induced on endothelial cells by inflammatory cytokines such as TNF and IL-1 and lipopolysaccharides (LPS). Elices et al. (Cell 1990, 60, 577) showed that VLA-4 and VCAM-1 form a receptor-ligand pair which mediates the adhesion of lymphocytes to activated endothelium. The binding of VCAM-1 to VLA-4 does not take place here due to an interaction of the \/LA-4 with an RGD sequence; this sequence is not contained in VCAM-1 (Bergelson et al., Cun-ent Biology 1995, 5, 615), VLA-4, .however, also occurs on other leukocytes, and the adhesion of leukocytes other than lymphocytes is also mediated via the VCAM-1 A/LA-4 adhesion mechanism. VLA-4 thus represents an individual example of a µl integrin receptor which, via the ligands VCAM-1 and fibronectin, plays an important part both in cell-cell interactions and in cell-extracelluiar mathx interactions. The cytokine-induced adhesion molecules play an important part in the recnjitment of leukocytes into extravascular tissue regions. Leukocytes are recruited into inflammatory tissue regions by cell adhesion molecules which are expressed on the surface of endothelial cells and serve as ligands for leukocyte cell surface proteins or protein complexes (receptors) (the terms ligand and receptor can also be used vice versa). Leukocytes from the blood must first adhere to endothelial cells before they can migrate into the synovium. Since VCAM-1 binds to cells which camy the integrin VLA-4 (a4βl), such as eosinophils, T and B lymphocytes, monocytes or neutrophils, it and the VCAM-1 / VL-4 mechanism have the function of recruiting cells of this type from the blood stream into areas of infection and inflammatory foci (Elices et al., Cell 1990, 60, 577; Osborn, Cell 1990, 62, 3; Issekutz et al.. J. Exp. Med. 1996, 183, 2175). The VCAM-1 A/LA-4 adhesion mechanism has been connected with a number of physiological and pathological processes. Apart from by cytokine-induced endothelium, VCAM-1 is additionally expressed, inter alia, by the following cells; myoblasts, lymphoid dendritic cells and tissue macrophages, rheumatoid synovium, cytokine-stimulated neural cells, parietal epithelial cells of the Bowman's capsule, the renal tubular epithelium, inflamed tissue during heart and kidney transplant rejection and by intestinal tissue in graft-versus-host disease. VCAM-1 is also found to be expressed on those tissue areas of the arterial endothelium which correspond to early arteriosclerotic plaques of a rabbit model. Additionally, VCAM-1 is expressed on follicular dendritic cells of human lymph nodes and is found on stroma cells of the bone marrow, for example in the mouse. The latter finding points to a function of VCAM-1 in B-cell development. Apart from on cells of hematopoietic origin, VLA-4 is also found, for example, on melanoma cell lines, and the VCAM-1A/LA-4 adhesion mechanism is connected with the metastasis of such tumors (Rice et al., Science 1989.246, 1303). The main form in which VCAM-I occurs in vivo on endothelial cells and which is the dominant form in vivo is designated as VCAM-7D and carries seven immunoglobulin domains. The domains 4, 5 and 6 are similar in their amino add sequences to the domains 1, 2 and 3. In a further form consisting of six domains, designated here as VCAM-6D, the fourth domain is removed by alternative splicing. VCAM-6D can also bind VLA-4-expressing cells. Further details on VLA-4, VCAM-I, integrins and adhesion proteins are found, for example, in the articles by Kilger and Holzmann, J. Mol. Meth. 1995, 73, 347; Elices, Cell Adhesion in Human Disease, Wiley, Chichester 1995, p. 79; Kuijpers, Springer Semin. Immunopathol. 1995, 15, 379. On account of the role of the VCAM-1 A/LA-4 mechanism in cell adhesion processes, which are of importance, for example, in infections, inflammations or atherosclerosis, it has been attempted by means of interventions into these adhesion processes to control illnesses, in particular, for example, inflammations (Osbom et a!., Cell 1989, 59, 1203). A method of doing this is the use of monoclonal antibodies which are directed against VLA-4. Monoclonal antibodies (mABs) of this type, which as VLA-4 antagonists block the interaction between VCAM-1 and VLA-4, are known. Thus, for example, the anti-VLA-4 mABs HP2/1 and HP1/3 inhibit the adhesion of VLA-4-expressing Ramos cells (B-cell-like cells) to human umbilical cord endothelial cells and to VCAM-1-transfected COS cells. The anti-VCAM-1 mAB 4B9 likewise inhibits the adhesion of Ramos cells, Jurkat cells (T-cell-like cells) and HL60 cells (granulocyte-like cells) to COS cells transfected with genetic constructs which cause synovial endothelial cells is blocked, an adhesion which plays a part in rheumatoid arthritis (van Dinther-Janssen et al., J. Immunol. 1991, 147, 4207). • In vivo experiments have shown that an experimental autoimmune encephalomyelitis } can be inhibited by anti-a4 mAB. The migration of leukocytes into an inflammatory focus is likewise blocked by a monoclonal antibody against the a4 chain of \/LA-4. The influencing of the VLA-4-dependent adhesion mechanism by antibodies was also investigated in an asthma model in order to investigate the role of VLA-4 in the recruitment of leukocytes into inflamed lung tissue (WO-A-93/13798), The I administration of anti-VLA-4 antibodies inhibited the late-phase reaction and airway overreaction in allergic sheep. The VLA-4-dependent cell adhesion mechanism was also investigated in a primate model of inflammatory bowel disease (IBD). In this model, which corresponds to ulcerative colitis in man, the administration of anti-VLA-4 antibodies resulted in a significant reduction in the acute inflammation. Moreover, it was possible to show that VI-A-4-dependent cell adhesion piays a part in the following clinical conditions including the following chronic inflammatory processes: rheumatoid arthritis (Cronstein and Weismann, Arthritis Rheum. 1993, 36, 147; Eiices et al., J. Clin. Invest. 1994, 93, 405), diabetes mellitus (Yang et at., Proc. Natl. Acad. Sci. USA 1993, 90, 10494), systemic lupus erythematosus (Takeuchi et al., J. Clin. Invest. 1993, 92, 3008), allergies of the delayed type (type IV allergy) (Eiices et al., Clin. Exp. Rheumatol. 1993, 11, S77), multiple sclerosis (Yednock et al., Nature 1992, 356, 63), malaria (Ockenhouse et al.. J. Exp. Med. 1992, 176, 1183), arteriosclerosis (O'Brien et al., J. Clin. Invest. 1993, 92, 945), transplantation (Isobe et a!., Transplantation Proceedings 1994, 26, 867), various malignancies, for example melanoma (Renkonen et al.. Am. J. Pathol. 1992, 140, 753), lymphoma (Freedman et al.. Blood 1992, 79, 206) and others (Albelda et al.. J. Cell Biol 1991, 114, 1059). \/LA-4 blocking by suitable antagonists accordingly offers effective therapeutic possibilities, in particular, for example, of treating various inflammatory conditions including asthma and IBD. The particular relevance of VLA-4 antagonists for the treatment of rheumatoid arthritis in this case results, as already stated, from the fact • that leukocytes from the blood must first adhere to endothelial cells before they can migrate into the synovium, and that the VLA-4 receptor plays a part in this adhesion. The fact that VCAM-1 is induced by inflammatory agents on endothelial cells (Osborn, Cell 1990, 62, 3; Stoolman, Cell 1989, 56, 907), and the recruitment of various leukocytes into areas of infection and inflammatory foci has already been discussed above. At the same time, T cells adhere to activated endothelium mainly via the LFA-1/1CAM-1 and VLA-4A/CAM-1 adhesion mechanisms (Springer, Cell V,,, 1994, 76, 301). On most synovial T cells, the binding capacity of VLA-4 for VCAM-1 is increased in rheumatoid arthritis (Postigo et al., J. Clin. Invest. 1992, 89, 1445). Additionally, an increased adhesion of synovial T cells to fibronectin has been obsen/ed (Laffon et al., J. Clin, invest 1991, 88, 546; Morales-Ducret et a!., J. Immunol. 1992, 149, 1424). VLA-4 is upregulated both in the course of its expression and with respect to its function on T lymphocytes of the rheumatoid synovial membrane. The blocking of the binding of VLA-4 to its physiological ligands VCAM-1 and fibronectin makes possible an effective prevention or alleviation of articular inflammatory processes. This is also confirmed by experiments with the antibody HP2/1 on Lewis rats with adjuvant arthritis, in which an effective prevention of illness has been obsen/ed (Barbadillo et al., Springer Semin. Immunopathol. 1995, 16, 427). VLA-4 is thus an important therapeutic target molecule. The abovementioned VLA-4 antibodies and the use of antibodies as VLA-4 antagonists are described in the Patent Applications WO-A-93/13798, WO-A-93/15764. WO-A-94/15094, WO-A-94/17828 and WO-A-95/19790. In the Patent Applications WO-A-94/15958, WO-A-95/15973, WO-A-96/00581, WO-A-96/06108 and WO-A-96/20215, peptide compounds are described as VLA-4 antagonists. The use of antibodies and peptide compounds as pharmaceuticals, however, has some disadvantages, for example lack of oral availability, easy degradabiiity or immunogenic action on longer-term use, and there is thus a need for VLA-4 antagonists having a favorable profile of properties for use in therapy and prophylaxis. WO-A-95/14008, WO-A-93/18057. US-A-5 658 935, US-A-5 686 421, US-A-5 389 614, US-A-5 397 796, US-A-5 424 293 and US-A-5 554 594 describe substituted 5-membered ring heterocycles which have an amino, amidino or guanidino function at the N-terminal end of the molecule and which exhibit platelet aggregation-inhibiting actions. EP-A-796 855 describes further heterocycles which are inhibitors of bone resorption. EP-A-842 943, EP-A-842 945 and EP-A-842 944 describe that compounds from this series and further compounds surprisingly also inhibit leukocyte adhesion and are VLA-4 antagonists. EP-A-903 353, EP-A-905 139 and EP-A-918 059 and WO-A-99/60015 (German patent application 19821483.9) describe further compounds which inhibit leukocyte adhesion and are VLA-4 antagonists. The properties of these compounds, however, are still not satisfactory in various respects and there is a need for compounds having a further improved property profile. EP-A-918 059 describes, inter alia, imidazolidine derivatives which contain a spiro-linked ring system on the imidazolidine ring. Not specifically disclosed, however, are the spiroimidazoiidine derivatives of the present invention, which are distinguished by their advantageous property profile. residues can be replaced by a carbonyl group C=0; W is isopropyl or cyclopropyl; V is hydrogen or methoxy; ■ E is -CO-R3 -CO-H, -CH2-0-R4 -CH2-O-CO-R4. -CHa-O-CO-O-R5 or 5-tetrazolyl; R3 is hydroxy, (Ci-Cio)-alkoxy, phenyl-(C1-C8)-alkoxy-, phenyioxy-, (C1-C8)- alkylcarbonyloxy-{C1-C6)-alkoxy-, phenylcarbonyloxy-(C1-C6)-alkoxy-, pheny!-(C1-C6)- alkylcarbonytoxy-(C1-C6}-alkoxy-, (C1-C8)-alkoxycarbonyloxy-(C1-C6)-alkoxy-, phenyloxycarbonyloxy-{C1-C6)-alkoxy-, phenyl-(C1-C6)-alkoxycarbonyloxy-{C1-C6)- alkoxy-, amino, mono-((Ci-Cio)-alkyl)-amino-, di-((C1-C10)-a!kyl)-amino-or R4R4N-CO-(C1-C6)-alkoxy- in which the residues R4 are independent of one another and can be identical or different; R4 is hydrogen, (C1-C10)-alkyl, phenyl or phenyl-(C1-C8)-aikyl-; R5 has one of the meanings of R4 with the exception of hydrogen; phenyl is an unsubstituted phenyl residue or a phenyl residue which is substituted by one or more identical or different substituents from the group consisting of (C1-C4)-alkyl, {C1-C4)-aIkoxy, methylenedioxy, ethylenedioxy, halogen, trifluoromethyl and trifluoromethoxy; in all their stereoisomeric fomns and mixtures thereof in ail ratios, and their physiologically tolerable salts. If a residue occurs more than once in a compound of the formula I, for example if R2 is phenyl and a further phenyl residue is contained in the group E, the residues are in all cases independent of one another and can be identical or different. Alkyl residues can be straight-chain or branched. This also applies if they carry substituents or occur as substituents of other residues, for example in alkoxy residues, alkoxycarbonyl residues or arylalkyl residues. Examples of suitable alkyl residues are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyi, n-octyl, n-nonyl, n-decyi, isopropyl, isobutyl, isopentyl, isohexyl, 3-methytpenty!, neopentyl, neohexyl, 2,3,5-trimethylhexyl, sec-butyl, tert-butyl, tert-pentyl. Preferred alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. Substituted alkyl residues can be substituted in any desired positions. If the divalent residue X in the formula I is the divalent 1,2-ethyiene residue -CH2-CH2-. that is if X together with the two CH2 groups to which X is bonded forms a tetramethylene residue, the compounds of the formula I contain a spiro-linked cyclopentane nng, and thus compounds of the formula la are present which can be designated as 4,4-tetramethyleneimida2olidine derivatives. forms a pentamethylene residue, the compounds of the formula I contain a spiro-linked cyclohexane ring, and thus compounds of the formula Ic are present which can be designated as 4,4-pentamethyleneimidazolidine derivates. In the compounds of the formulae Id and le, X together with the two CH2 groups in the formula I to which X is bonded forms a 2-oxopentamethylene residue -CH2-CO-CH2-CH2-CH2- or a 3-oxopentamethylene residue -CH2-CH2-CO-CH2-CH2-. The compounds of the formulae Id and le can be designated as 4,4-(2-oxopentamethylene)imidazolidine denvatives and 4,4-(3-oxopentamethylene)- imidazoiidine derivatives. If, in the residue -CH2-CH2-CH2- representing X, a CH2 group is replaced by a carbonyi group, the middle CH2 group is preferably replaced, that is preferably compounds of the formula le are present in this case. Phenyl residues can be unsubstituted or are monosubstituted or polysubstituted. for example monosubstituted, disubstituted, trisubstituted, tetrasubstituted or pentasubstituted, by identical or different residues. If a phenyl residue is substituted, it preferably cam'es one or two identical or different substituents. The same applies, for example, to substituted phenyl residues in groups such as phenylalkyl, phenylcarbonyl, etc. PhenyiaikyI residues are, for example, benzyl, 1-phenylethyl or 2-phenylethyl, in particular benzyl, all of which can also be substituted. In monosubstituted phenyl residues, the substituent can be located in the 2-position, the 3-position or the 4-position. In disubstituted phenyl residues, the substituents can be located in the 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. In trisubstituted phenyl residues, the substituents can be located in the 2,3,4-position, 2,3,5-position, 2,4,5-position, 2,4,6-position, 2,3,6-position or 3,4,5-position, if a phenyl residue carries substituents from the group consisting of methytenedioxy (-O-CH2-O-) and ethylenedioxy {-O-CH2-CH2-O-), it preferably carries only one substituent from this group (optionally in addition to other substituents). Examples of substituted phenyl residues which, for example, can be R2, are 2-methyiphenyl, 3-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl, 2,4-dimethyiphenyl, 2,5-dimethylpheny!, 2,5-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethyiphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, 3,4,5-trimethylphenyl, 2-(n-butyl)phenyl, 3-{n-butyi)phenyi, 4-(n-butyl)phenyl, 2-isobutylphenyl, 3-isobutylphenyl, 4-isobutylphenyl, 3-tert-butylphenyi, 4-tert-butylphenyi, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dtmethoxyphenyl, 3,5-dimethoxyphenyl, 2,4,5-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 3,4,5-tnmethoxyphenyl, 2-(n-butoxy)phenyi, 3-(n-butoxy)phenyl, 4-(n-butoxy)phenyl, 2-isobutoxyphenyl, 3-isobutoxyphenyl 4-isobutoxyphenyl, 2-tert-butoxyphenyt, 3-tert- butoxyphenyl, 4-tert-butoxyphenyl, 2,3-methylenedioxyphenyl, 3,4- methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethyienedioxyphenyl, 2- fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyi, 2,5-difluorophenyt, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,4.5- trifluorophenyl, 2,4,6-trifluorophenyl, 3,4,5-trifluorophenyl, 2,3,5,6-tetrafluorophenyl, 2,3,4,5,6-pentafluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3- dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,5-dichlorophenyl, 3,4- dichlorophenyi, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyi, 3-iodophenyl, 4-iodophenyl, 2-trifluoromethylphenyl, 3-trifluoromethytphenyi, 4-trifluoromethylphenyl, 3.4-bis(trifluoromethyl)phenyl, 3,5-bis(trifiuoromethyl)phenyl, ■.. 2-trifIuoromethoxyphenyi, 3-trifluoromethoxyphenyi, 4-trifIuoromethoxyphenyl, etc. In substituted phenyl residues, however, different substituents can also be contained in any desired combination, such as, for example, in the residues 3-methoxy-4-methylphenyl, 4-f]uoro-3-methoxyphenyi, 3-fluoro-4-methoxyphenyl, 3,5-difIuoro-4-methoxyphenyl, 3-fluoro-4,5-methylenedioxyphenyl, 3-fluoro-4,5--ethylenedioxyphenyi, 2-chloro-3-methylphenyl, 3-chloro-4-methylphenyl, 3-chloro-4-fluorophenyl, etc. Halogen is fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine. Physiologically tolerable salts of the compounds of the formula I are in particular ^"^ nontoxic or pharmaceutically utilizable salts. Salts of this type of compounds of the formula 1 which contain acidic groups, for example a carboxylic add group representing the group E, are, for example, alkali metal salts or alkaline earth metal salts such as, for example, sodium salts, potassium salts, magnesium salts and calcium salts, or ammonium salts such as, for example, salts with physiologically tolerable quaternary ammonium ions and acid addition salts with ammonia and physiologically tolerable organic amines, such as, for example, methylamine, ethylamine, triethylamine, 2-hydroxyethyiamine, tris(2-hydroxyethyl)amine, a,a,a-tris(hydroxymethyl)methylamine (tromethamine) or amino acids, in particular basic amino acids. Salts of an acidic compound of the formula I and an organic amine can contain the two components in the ratio 1:1 {or about 1:1) or in another ratio, for example in a ratio of about 1:0.5 to about 1:4 (1 molecule of the formula I to 0.5 to 4 molecules of the amine), in particular in a ratio of about 1:0.5 to about 1:2 (1 molecule of the formula I to 0.5 to 2 molecules of the amine). Compounds of the formula I which contain basic groups, for example an amino group in the alcohol component of a carboxyiic acid ester group, form salts with inorganic acids such as, for example, hydrochloric acid, sulfuric acid or phosphoric acid, and with organic carboxyiic acids or sulfonic acids such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumahc acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. Compounds which contain both acidic groups and basic groups can also be present in the form of inner salts or betaines or zwitterions, which are likewise included by the present invention. Salts can be obtained from the compounds of the formula I according to customary processes known to the person skilled in the art, for example by combination with an organic or inorganic acid or base in a solvent or diluent, or also from other salts by anion exchange or cation exchange. The compounds of the formula I can be present in stereoisomeric forms. On all asymmetric centers in the compounds of the formula I, independently of one another the S configuration or the R configuration can be present or a R/S mixture can be present. Thus the asymmetric carbon atom to which the residue R2 is bonded can have the R configuration or S configuration or the compound of the formula I can be present, with respect to this carbon atom, as an R/S mixture. Likewise, the asymmetric carbon atom to which the group -CH2-W, which is an isobutyi group (= 2-methylpropyl group) or a cyclopropylmethyi group, and the imidazolidine ring are bonded can have the R configuration or S configuration or the compound of the formula 1 can be present with respect to this carbon atom as an R/S mixture. AH other asymmetric carbon atoms can also have the R configuration or the S configuration or the compound of the formula I can be present with respect to each of these carbon atoms as an R/S mixture. The invention includes all possible stereoisomers of the compounds of the fonnula I, for example pure or largely pure enantiomers and pure or largely pure diastereomers and mixtures of two or more stereoisomeric forms, for example mixtures of • enantiomers and/or diastereomers, in all ratios. Enantiomers are thus a subject of the invention in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. Likewise, diastereomers in diastereomerically pure form and in the form of mixtures in all ratios are a subject of the invention. Examples of individual stereoisomers which are a subject of the invention are the compounds of the formulae If, Ig, Ih and li. The individual stereoisomers can be prepared, if desired, by use of stereochemicaily uniform starting substances in the synthesis, by stereoselective synthesis or by separation of a mixture according to customary methods, for example by chromatography or crystallization, in the case of enantiomers for example by chromatography on chiral phases. Opitionally, before separation of stereoisomers a derivatization can be carried out. The separation of a stereoisomer mixture can take place at the stage of the compounds of the formula 1 or at the stage of a starting substance or of an intermediate in the course of the synthesis. The compounds of the formula I according to the invention can contain mobile hydrogen atoms, that is be present in various tautomeric forms. Al! tautomers of the compounds of the formula I are also a subject of the present invention. The present invention also includes solvates and addition compounds or adducts of compounds of the formula I, for example adducts with water, that is hydrates, or adducts with alcohols or amines. The invention furthermore includes derivatives of compounds of the formula I, for example esters, amides, prodrugs and other physiologically tolerable derivatives, and also active metabolites of compounds of the formula I. The invention in particular also relates to prodrugs of the compounds of the formula I, which can be converted into compounds of the formula I under physiological conditions. Suitable prodrugs of the compounds of the formula I, that is chemically modified derivatives of the compounds of the formula I having desirably improved properties, are known to the person skilled in the art. Details of prodrugs are found, for example, in Fleisher et al.. Advanced Drug Delivery Reviews 19 (1996) 115; Design of Prodrugs, H. Bundgaard, Ed., Elsevier, 1985; H. Bundgaard, Drugs of the Future 16 (1991) 443. Possible prodrugs of the compounds of the formula I are especially ester prodrugs, amide prodrugs, aldehyde prodrugs and alcohol prodrugs of carboxylic acid groups. Examples of ester prodrugs and amide prodrugs which may be mentioned are (C1-C4)-alkyl esters such as methyl esters, ethyl esters, isopropyl esters, isobutyl esters, substituted alkyl esters such as hydroxyalkyi esters, ■ acyloxyalkyl esters, aminoalkyl esters, acylaminoalkyl esters, dialkyiaminoalkyl esters, unsubstituted amides or N-{C1-C4)-alkylamides such as methylamides or ethytamides. With respect to the structural elements V and W, the present invention includes four embodiments each of which expressly is a subject of the present invention. In one of these embodiments, the group W in the formula I is isopropyl, that is the residue -CH(CH3)2, and at the same time V is hydrogen. This embodiment thus includes compounds of the formula Ik and can be identical or different; R4 is hydrogen, (C1-C10)-alkyl, phenyl or phenyl-(C1-C8)-alkyl-; R5 has one of the meanings of R4 with the exception of hydrogen; phenyl is an unsubstituted phenyl residue or a phenyl residue which is substituted by one or more identical or different substituents from the group consisting of (C1-C4)-alkyl, (C1-C4}-alkoxy, methylenedioxy, ethylenedioxy, halogen, trifluoromethyi and tnfluoromethoxy; in all their stereoisomehc forms and mixtures thereof in all ratios, and their physiologically tolerable salts. and at the same time V is hydrogen. A third embodiment relates to compounds of the formula I in which W is isopropyl and at the same time V is methoxy, that is the residue -OCH3. A fourth embodiment relates to compounds of the formula I in which W is cydopropyl and at the same time V is methoxy. A subgroup of the compounds according to the invention includes the compounds of the second, third and fourth embodiment described above, that is compounds of the formula I in which V is hydrogen or methoxy and W is isopropyl or cydopropyl. but in which not at the same time V is hydrogen and W is isopropyl. Also the compounds of the second, third and fourth embodiment of the invention are a subject of the invention in all their stereoisomehc forms and mixtures thereof in all ratios and in the form of their physiologically tolerable salts. The individual structural elements in the formula I preferably have the following meanings, which they can have independently of one another. E is preferably -CO-R3 -CO-H, -CH2-0-R4, -CH2-O-CO-R4 or-CH2-0-C0-0R5, particularly preferably -CO-R3 -CO-H, -CH2-0-R4 or -CH2-0-C0-R4 very particularly preferably -CO-R3 -CH2-0-R4 or -CHa-O-CO-R4 moreover preferably -CO-R3 or -CH2-0-R4, especially preferably -CO-R3. A residue -CH2-O-R4 representing the group E is preferably the hydroxymethyl residue -CH2-OH. Especially preferred meanings of E are -C0-0-(C1-C4)-aikyl, -CO-OH. -CO-NH2 and -CH2-OH, in particular -CO-OH, -CO-NH2 and -CH2-OH, especially -CO-OH. X is preferably -CH2-CH2 or -CH2-CH2-CH2-. in particular -CH2-CH2-CH2-, where none of the CH2 groups is replaced by a carbonyi group. R2 is preferably unsubstituted phenyl, phenyl which is substituted by a methyienedioxy residue or an ethylenedioxy residue, phenyl which is substituted by one or two (C1-C4)-alkQxy groups, in particular by methoxy groups, or (C1-C4)-alkyl, where the (C1-C4)-alkyi group preferably is methyl, ethyl or isobutyl, more preferably methyl or ethyl, particularly preferably methyl. Particularly preferably, R^ is unsubstituted phenyl, phenyl which is substituted by a methyienedioxy residue or an ethylenedioxy residue, phenyl which is substituted by one or two methoxy groups, or methyl. Very particularly preferably, R2 is unsubstituted phenyl, 3,4-methylene-dioxyphenyi, 3,4-ethylenedioxyphenyl, 2-methoxyphenyl, 3-methoxyphenyt, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethQxyphenyl or methyl. R3 is preferably hydroxy, (C1-C6)-alkoxy or amino (-NH2), particularly preferably hydroxy, (C1-C4)-alkoxy or amino, very particularly preferably hydroxy or amino, especially preferably hydroxy. R4 is preferably hydrogen or (C1-C6)-alkyl, particularly preferably hydrogen or (C1-C4)-alkyi. R5 is preferably (C1-C6)-alkyl, particularly preferably (C1-C4)-alkyi. Preferred compounds of the formula I are those which have a uniform configuration on one or on more chiral centers, for example on the carbon atom which carries the residue R2, and/or on the carbon atom which carries the group -CH2-W. That is, compounds are preferred which are present in uniform or in essentially uniform configuration on one or more chiral centers, either in the R configuration or in the S configuration, but not as an R/S mixture. As explained, the individual chirai centers in these compounds of the formula 1, however, can independently of one another have the R configuration or the S configuration and can have identical or different configurations. Particularly preferred compounds of the formula I are those in which the carbon atom which carries the group -CH2-W is present in the S configuration, that is in the configuration with respect to this stereocenter which is shown in the formulae If and Ig. Particularly preferred compounds of the formula I are also those in which the carbon atom which carnes the group R2 is present in the configuration shown in the formulae If and Ih. If R2 is phenyl or substituted phenyl, in these particularly preferred compounds the carbon atom which carries the group R2 has the S configuration, if R2 is, for example, methyl, ethyl or isobutyl, it has the R configuration. Very particularly preferred compounds of the formula 1 are those in which the two abovementioned stereocenters are present in the configurations shown in the formula If. Preferred compounds of the formula I are those compounds in which one or more of the residues have preferred meanings or have a specific meaning from the listed meanings, all combinations of preferred meanings of residues being a subject of the present invention. Particularly preferred compounds are compounds of the formula 1, in which R1 is hydrogen or methyl; R2 is unsubstituted phenyl, phenyl which is substituted by a methylenedioxy residue or an ethylenedioxy residue, phenyl which is substituted by one or two (C1-C4)-alkoxy groups, or (C1-C4)-alkyl; X is -CH2-CH2- or -CH2-CH2-CH2-, where one of the CH2 groups in these two residues can be replaced by a carbonyl group C=0; W is isopropyi or cyclopropyl; V is hydrogen or methoxy; E is -CO-R3 -CO-H, -CH2-0-R4 -CH2-0-C0-R4 or -CH2-O-CO-O-R65; R3 is hydroxy, (C1-C10)-alkoxy, phenyl-(C1-C8}-aikoxy-, phenyioxy-, (C1-C8)-alkylcarbonyloxy-(C1-C6)-alkoxy-, phenylcarbonyloxy-(C1-C6)-alkoxy-, phenyl-(C1-C6)-alkylcarbonyioxy-(C1-C6)-alkoxy-, (Ci-Ca)-alkoxycarbonyloxy-{C1-C6)-alkoxy-, ■ phenyloxycarbonytoxy-(C1-C6)-alkoxy-, phenyl-(C1-C6)-alkoxycarbonytoxy-(Ci-C6)-alkoxy-, amino, mono-{(CrCio)-a!kyl)-amino-, di-((C1-C10)-aikyl)-amino-or R4R4 N-CO-(C1-C6)-alkoxy- in which the residues R4 are independent of one another and can be identical or different; R4 is hydrogen, (C1-C10)-alkyl, phenyl or phenyl-(C1-C8)-alkyl-; R5 has one of the meanings of R4 with the exception of hydrogen; phenyl which is contained in the group E is an unsubstituted phenyl residue or a phenyl residue which is substituted by one or more identical or different substituents from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, methylenedioxy, ethylenedioxy, halogen, trifluoromethyl and trifluoromethoxy; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts. Very particularly preferred compounds are compounds of the formula 1 in which R1 is hydrogen or methyl; R2 is unsubstituted phenyl, phenyl which is substituted by a methylenedioxy residue or an ethylenedioxy residue, phenyl which is substituted by one or two methoxy groups, or (C1-C4)-alkyi; X is "CH2-CH2- or •CH2-CH2-CH2-, where one of the CH2 groups in these two residues can be replaced by a carbonyl group C=0; W is isopropyi or cyclopropyi; V is hydrogen or methoxy; E is -CO-OH, -C0-0-{C1-C4)-alkyl, -CO-NH2 or -CH2-OH; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts. A subgroup of these compounds is formed by the compounds of the formula I in which R1 is hydrogen or methyl; R2 is phenyl which is substituted by a methylenedioxy residue or an ethylenedioxy residue, or phenyl which is substituted by one or two methoxy groups; X is -CH2-CH2- or -CH2-CH2-CH2-. where one of the CH2 groups in these two residues can be replaced by a carbonyl group C=0; W is isopropyl or cyciopropyt; V is hydrogen or methoxy; E is -CO-OH, -C0-0-(CrC4)-alkyl, -CO-NH2 or -CH2-OH; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts. A further subgroup of these compounds is formed by compounds of the formula i in which R1 is hydrogen or methyl; R2 is unsubstituted phenyl; X is -CH2-CH2- or -CH2-CH2-CH2-, where one of the CH2 groups in these two residues can be replaced by a carbonyl group C=0; W is isopropyl or cyclopropyl; V is hydrogen or methoxy; E is -CO-OH, -C0-0-(C1-C4)-alkyl. -CO-NH2 or -CH2-OH; in all their stereoisomeric forms and mixtures thereof in ail ratios. and their physiologically tolerable salts. A further subgroup of these compounds is formed by compounds of the formula I in which R1 is hydrogen or methyl; R2 is (C1-C4)-alkyl, preferably methyl; X is -CH2-CH2- or -CH2-CH2-CH2-, where one of the CH2 groups in these two residues can be replaced by a carbonyl group C=0; W is isopropyl or cyclopropyl; V is hydrogen or methoxy; E is -CO-OH, -C0-0-(C1-C4)-alkyl, -C0-NH2 or -CH2-OH; in all their stereoisomenc forms and mixtures thereof in all ratios, and their physiologically tolerable salts. For the abovementioned embodiment of the invention in which the group V in the • compounds of the formula I is hydrogen and the group W is isopropyi, that is for the compounds of the formula Ik, examples of specific compounds are indicated below each of which expressly is a subject of the present invention. The following abbreviations are used in the names of the compounds. IBU = 2-methylpropyl = isobutyl = -CH-CH2-CH(CH3)2 4PM-3-PUB-DI =4,4-pentamethylene-3-(4-(3-phenyiure(do)benzyl)-2,5-dioxoimid- a2olidin-1-yl 4PM-3-MPUB-DI =4.4-pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2.5- dioxoimidazolidin-l -yl 4TM-3-PUB-DI = 4,4-tetramethylene-3-{4-{3-phenyiureido)ben2yl)-2,5-dioxoimid- a2olidin-1-yl 4TM-3-MPUB-DI = 4.4-tetramethylene-3"(4-{3-{2-methylphenyl)ureido)benzyl)-2,5- dioxoimidazolidin-1 -yl 40PM-3-PUB-DI = 4,4-(3-oxopentamethy!ene)-3-(4-(3-phenylureido)benzyl)-2,5- dioxoimidazolidin-1 -yl 40PM-3-MPUB-DI = 4,4-{3-oxopentamethylene)-3-{4-(3-(2-methylphenyl)ureido)- benzyl)-2,5-diQxoimidazolidin-1-yl 40TM-3-PUB-DI = 4,4-(2-oxotetramethylene)-3-(4-(3-pheny!ureido)benzyl)-2,5- dioxoimidazolidin-1 -yl 40TM-3-MPUB-DI = 4,4-(2-oxotetramethylene)-3-{4-(3-(2-methylphenyl)ureido)- benzyl)-2,5-dioxoimidazolidin-1-yl A name such as, for example, 3-(2"{40PM-3-MPUB-Di)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionamide is thus to be understood as meaning the compound 3-(2-(4,4-(3-oxopentamethylene)-3-(4-(3-(2-methylphenyi)ureido)benzyi)-2,5-dioxo-!midazolidin-1-yl)-2-(2-methylpropyl)acety!amino)-3-(3,4-dimethoxyphenyi)propion-amide of the formula Im. The present invention relates, for example, to the following compounds: 3-(2-(4PM-3-PUB-D()-2-{IBU)-acetylamino)-3-methyipropionic acid 3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methylpropionic acid 3-(2-{4TM-3-PUB-Dl)-2-(IBU)-acetylamino)-3-methylpropionic acid 3-(2-{4TM-3-MPUB-DI)-2-(IBU)-acetylanriino)-3-methylpropionic acid 3-(2-(40PM-3-PUB-DI)-2-(IBU)-acety!amino)-3-methyipropionic acid 3-(2-(40PM-3-MPUB-DI)-2-(IBU)-acetyiamino)-3-methylpropionic acid 3-{2-(40TM-3-PUB-DI)-2-{lBU)-acetylamino)-3-methylpropionic acid 3-(2-(40TM-3-MPUB-Dl)-2-{lBU)-acetylamino)-3-methylpropionic acid 3-(2-{4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-methyipropionamide 3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methytpropionamide 3-(2-(4TM-3-PUB-Dl)-2-(lBU)-acetylamino)-3-methylpropionamide 3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methylpropionamide 3-(2-(40PM-3-PUB-DI)-2-(iBU)-acetylamino)-3-methylpropionamide 3-(2-(40PM-3-MPUB-DI)-2-(!BU)-acetyiamino)-3-methylpropionamide 3-(2-(40TM-3-PUB-Di)-2-{lBU)-acetylamino)-3-methylpropionamide 3-(2-{40TM-3-MPUB-Dl)-2-{lBU)-acetylamino)-3-methylpropionamide 3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-methylpropanol 3-{2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methylpropanol 3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-methylpropanol 3-(2-{4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methyipropanol 3-(2-(40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-methylpropanol 3-(2-(40PM-3-MPUB-Dl)-2-(IBU)-acetylamino)-3-methylpropanol 3-{2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-methylpropanoi 3-(2-{40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methyipropanol 3-(2-{4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(lBU)-propionic acid 3-(2-{4PM-3-MPUB-DI)-2-(IBU)-acetyiamino)-3-(IBU)-propionic acid 3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propionic acid 3-(2-(4TM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-(IBU)-propionic acid :, 3-(2-(40PM-3-PUB-DI)-2-(IBU)-acety!amino)-3-(IBU)-propionic acid 3-(2-{40PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-{lBU)-propionic acid 3-(2-(40TM-3-PUB-Dl)-2-(IBU)-acetylamino)-3-{IBU)-propionic acid 3-(2-(40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propionic acid 3-(2-{4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(lBU)-propionamide 3-(2-(4PM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-{IBU)-propionamide 3-(2-{4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-{IBU)-propionamide 3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-{IBU)-propionamide 3-(2-(40PM-3-PUB-D!)-2-(lBU)-acetylamino)-3-(IBU)-propionamide 3-{2-(40PM-3-MPUB-DI}-2-{lBU)-acetylamino)-3-{lBU)-propionamide 3-(2-(40TM-3-PUB-DI)-2-{IBU)-acetylamino)-3-(IBU)-propionamide 3-(2-(40TM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(!BU)-propionamide 3-{2-(4PM-3-PUB-DI)-2-(lBU)-acetylamino)-3-(IBU)-propanol 3-(2-{4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(lBU)-propanol 3-(2-(4TM-3-PUB-DI)-2-(lBU)-acetylamino)-3-(IBU)-propanol 3-{2-(4TM-3-MPUB-Di)-2-(!BU)-acetylamino)-3-{lBU)-propanol 3-(2-(40PM-3-PUB-Dl)-2-(IBU)-acetylamino)-3-(IBU)-propanol 3-(2-{40PM-3-MPUB-DI)-2-(!BU)-acetylamino)-3-(IBU)-propanol 3-(2-(40TM-3-PUB-DI)-2-{IBU)-ac8tylamino)-3-(lBU)-propanol 3-(2-(40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propanol 3-(2-{4PM-3-PUB-DI)-2-{IBU)-acetylamino)-3-phenyipropionic acid 3-{2-{4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionic acid 3-(2-{4TM-3-PUB-Dl)-2-(lBU)-acetyiamino)-3-phenylpropionic acid i 3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionic acid 3-(2-(40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionic acid 3-(2-{40PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionic acid 3-(2-{40TM-3-PUB-Dl)-2-(lBU)-acetylamino)-3-phenylpropionic acid 3-(2-{40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionic acid 3-(2-(4PM-3-PUB-DI}-2-(!BU)-acetylamino)-3-phenylpropionamide 3-(2-(4PM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-phenylpropionamide 3-(2-{4TM-3-PUB-DI)-2-(IBU)-acetyiamino)-3-phenylpropionamide 3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-pheny(propionamide 3-{2-(40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionamide 3-(2-(40PM-3-MPUB-DI)-2-(IBU)-acetyiamino)-3-phenylpropionamide 3-(2-(40TM-3-PUB-Dl)-2-(IBU)-acetylamino)-3-phenytpropionamide 3-(2-{40TM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-phenylpropionamide 3-(2-(4PM-3-PUB-D!)-2-{!BU)-acetylamino)-3-phenyipropanol 3-(2-{4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropanol 3-(2-{4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-phenylpropanoi 3-(2-{4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropano( 3-(2-(40PM-3-PUB-DI)-2-{IBU)-acetylamino)-3-phenytpropanol 3-(2-(40PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropanol 3-{2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-phenytpropanol 3-(2-(40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenyipropanol 3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propionic acid 3-(2-(4PM-3-MPUB-Dl)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propionic acid 3-(2-(4TM-3-PUB-DI)-2-(lBU)-acetylamino)-3-{2-methoxyphenyl)propionic acid 3-(2-{4TM-3-MPUB-D!)-2-(IBU)-acetylam!no)-3-(2-methoxyphenyi)propionic acid 3-{2-(40PM-3-PUB-DI)-2-(lBU)-acetylamino)-3-{2-methoxyphenyl)propionic acid 3-(2-{40PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propionic acid 3-(2-{40TM-3-PUB-Dl)-2-(IBU)-acetylamino)-3-(2-methQxyphenyl)propionic acid ■3-{2-{40TM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(2-methoxyphenyl)propionic acid 3-(2-(4PM-3-PUB-DI)-2-{IBU)-acetytamino)-3-(2-methoxyphenyl)propionamide 3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetyiamino)-3-(2-methoxyphenyl)propionamide 3-{2-{4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-{2-methoxyphenyl)propionamide 3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetytamino)-3-(2-methoxypheny!)propionamide 3-(2-(40PM-3-PUB-Dl)-2-(IBU)-acetytamino)-3-(2-methoxyphenyi)propionamide 3-(2-{40PM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-{2-methoxyphenyl)propionamide 3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetyiamino}-3-{2-methoxyphenyl)propionamide 3-(2-(40TM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(2-methoxyphenyl)propionannide 3-{2-(4PM-3-PUB-Dl)-2-(lBU)-acetylamino)-3-(2-methoxyphenyl)propanol 3-(2-(4PM-3-MPUB-DI)-2-(!BU)-acetylamino)-3-(2-methoxyphenyl)propanol 3-(2-{4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propanol 3-{2-(4TM-3-MPUB-Dl)-2-(IBU)-acetylamino)-3-{2-methoxyphenyl)propanol 3-(2-(40PM-3-PUB-DI)-2-{IBU)-acetyiamino)-3-(2-methoxyphenyl)propanol 3-{2-{40PM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-(2-methoxyphenyl)propanol 3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propanol 3-(2-(40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-{2-methoxyphenyl)propanol 3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionic acid 3-(2-{4PM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-(3-methoxyphenyl)propionic acid 3-{2-(4TM-3-PUB-DI}-2-{IBU)-acetylamino)-3-(3-methoxyphenyi)propionic acid 3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetytamino)-3-(3-methoxyphenyl)propionic acid 3-(2-(40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionic acid 3-(2-(40PM-3-MPUB-DI)-2-(lBU)-acetyiamino)-3-(3-methoxyphenyl)propionic acid 3-(2-(40TM-3-PUB-DI}-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionic acid 3-(2-{40TIV1-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(3-methoxyphenyl)propionic acid 3-(2-(4PM-3-PUB-DI)-2-(lBU)-acetyiamino)-3-(3-methoxyphenyt)propionamide 3-(2-{4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxypheny()propionamide 3-(2-(4TM-3-PUB-D()-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionamide 3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionamide 3-(2-(40PM-3-PUB-Di)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionamide 3-(2-(40PM-3-MPUB-Dl)-2-{lBU)-acetylamino)-3-(3-methoxyphenyl)propionamide 3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetyiamino)-3-(3-methoxyphenyl)propionamide 3-(2-{40TM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(3-methoxyphenyl)propionamide 3-{2-{4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)prQpanol 3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propanol 3-(2-(4TM-3-PUB-DI)-2-(lBU)-acetylam!no)-3-(3-methoxyphenyl)propanol 3-(2-{4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propanol 3-(2-(40PM-3-PUB-Di)-2-(lBU)-acetylamino)-3-(3-methoxyphenyl)propanol 3-(2-(40PM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-(3-methoxyphenyl)propanol 3-{2-{40TM-3-PUB-DI)-2-{IBU)-acetylamino)-3-(3-methoxyphenyl)propanol 3-(2-(40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propanol 3-(2-(4PM-3-PUB-Dl)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionic acid 3-(2-{4PM-3-MPUB-DI)-2-(IBU)-acetylam!no)-3-{4-methoxyphenyl)propionic acid 3-{2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionicadd 3-(2-(4TM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-{4-methoxyphenyl)propionic acid 3-(2-(40PM-3-PUB-DI)-2-{IBU)-acetylamino)-3-(4-methoxyphenyl)propionic acid 3-(2-{40PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionic acid i 3-(2-(40TM-3-PUB-DI)-2-{IBU)-acetylamino)-3-{4-methoxyphenyl)propionicadd 3-(2-(40TM-3-MPUB-DI)-2-([BU)-acetylam(no)-3-(4-methoxyphenyl)propionic acid 3-(2-(4PM-3-PUB-Dl)-2-(lBU)-acetytamino)-3-(4-methoxyphenyi)propionamide 3-(2-(4PM-3-MPUB-D!)-2-(lBU)-acetylamino)-3-(4-methoxyphenyl)propionamide ) 3-(2-(4TM-3-PUB-DI)-2-((BU)-acetylamino)-3-{4-methoxyphenyi)propionamide 3-(2-(4TM-3-MPUB-Dl)-2-(IBU)-acetylamino)-3-{4-methoxyphenyl)propionamide 3-(2-{40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionamide 3-{2-{40PM-3-MPUB-DI}-2-(iBU)-acety!amino)-3-{4-methoxyphenyl)propionamide 3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetytamino)-3-(4-methoxyphenyl)propionamide 3-(2-(40TM-3-MPU6-DI)-2-{IBU)-acetylamino)-3-(4-methoxyphenyl)propionamide 3-(2-(4PM-3-PUB-DI)-2-(lBU)-acetylamino)-3-(4-methoxyphenyl)propanol 3-(2-{4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propanol 3-(2-(4TM-3-PUB-Dl)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propanol 3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-{4-methoxyphenyl)propanol 3-(2-(40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-{4-methoxyphenyl)propanol 3-{2-(40PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propanol 3-(2-(40TM-3-PUB-DI)-2-{IBU)-acetylamino)-3-{4-methoxyphenyl)propanol 3-{2-(40TM-3-MPUB-Dl)-2-(IBU)-acetylamino)-3-{4-methoxyphenyl)propanol 3-(2-{4PM-3-PUB-Dl)-2-(lBU)-acetyiamino)-3-(2,3-dimethoxyphenyl)propionic acid 3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetyiaminQ)-3-(2,3-dimethoxyphenyl)propionic acid 3-{2-{4TM-3-PUB-Dl)-2-(lBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionic acid 3-(2-{4TM-3-MPUB-DI)-2-(IBU)-acetyiamino)-3-(2,3-dimethoxypheny!)propionic acid 3-(2-(40PM-3-PUB-Dl)-2-(!BU)-acetyiamino)-3-(2,3-dimethoxyphenyl)propionic acid 3-(2-(40PM-3-MPUB-DI)-2-(IBU)-acetytamino)-3-(2,3-dimethoxyphenyi)propionic add 3-{2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionic acid 3-(2-(40TM-3-MPUB-Dl)-2-(iBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionic acid 3-(2-(4PM-3-PUB-Di)-2-(iBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionamide 3-(2-(4PM-3-MPUB-D!)-2-(iBU)-acetytamino)-3-(2,3-dimethoxyphenyi)propionamide 3-(2-(4TM-3-PUB-DI)-2-(lBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionamide 3-{2-(4TM-3-MPUB-DI)-2-(lBU)-acetylannino)-3-(2,3-dimethoxyphenyl)propionamide 3-(2-(40PM-3-PUB-DI)-2-(IBU)-acetyiamino)-3-{2,3-dimethoxyphenyi)propionannide 3-{2-(40PM-3-MPUB-DI)-2-{!BU)-acetylamino)-3-{2,3-dimethoxyphenyl)propionamide 3-(2-{40TM-3-PUB-DI)-2-(IBU)-acetyiamino)-3-{2,3-dimethoxyphenyl)propionamide 3-(2-{40TM-3-MPUB-D!)-2-(iBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionannide 3-(2-{4PM-3-PUB-DI)-2-(lBU)-acetylamino)-3-(2,3-dimethoxypnenyl)propanol 3-(2-(4PM-3-MPUB-Di)-2-(IBU)-acetylamino)-3-(2,3-dimethQxyphenyl)propanol 3-(2-(4TM-3-PUB-DI)-2-(lBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propanol 3-(2-{4TM-3-MPUB-Dl)-2-{lBU)-acetylamtno)-3-(2,3-dimethoxyphenyl)propano( 3-(2-(40PM-3-PUB-DI)-2-(lBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propanol 3-(2-{40PM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propanol 3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)prQpanol 3-{2-{40TM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(2,3-dim6thQxyphenyl)prQpanol 3-(2-{4PM-3-PUB-Dl)-2-(lBU)-acetyiamino)-3-(2,4-dimethoxyphenyl)propionic acid 3-(2-{4PM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid 3-(2-(4TM-3-PUB-Dl)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid 3-{2-(4TM-3-MPUB-Dl)-2-{IBU)-acetylamino)-3-{2,4-dimethoxyphenyl)propionic acid 3-(2-{40PM-3-PUB-Dl)-2-{lBU)-acetylamino)-3-(2,4-dimethoxyphenyi)propionic acid 3-(2-(40PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2.4-dimethoxyphenyl)propionic acid 3-(2-(40TM-3-PUB-Dl)-2-(lBU)-acetyiamino)-3-(2,4-d!methoxyphenyi)propionic acid 3-(2-(40TM-3-MPUB-Dl)-2-(lBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid 3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetyiamino)-3-(2,4-dimethoxyphenyl)propionamide 3-(2-(4PM-3-MPUB-D!)-2-(!BU)-acetylamino)-3-{2,4-ciimethoxyphenyl)propionamide 3-(2-(4TM-3-PUB-D!)-2-(lBU)-acetyiamino)-3-(2,4-dimethoxyphenyl)propionamide 3-(2-(4TM-3-MPUB-Dl)-2-(!BU)-acetyiamino)-3-(2,4-dimethoxyphenyi)propionamide 3-(2-(40PM-3-PUB-DI)-2-(iBU)-acetylami^o)-3-{2,4-dimethoxypi^e^y!)propionamide 3-(2-(40PM-3-MPUB-DI)-2-(iBU)-acety!amino)-3-(2,4-dimethoxypiieny!)propionamide 3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionamide 3-(2-(40TM-3-MPUB-D!)-2-(iBU)-acety(amino)-3-(2,4-dimethoxyphenyl)propionamide 3-(2-(4PM-3-PUB-DI)-2-(IBU)-acety!amino)-3-(2,4-dimethoxyphenyl)propanQl 3-(2-(4PM-3-MPUB-D!)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propanol 3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-{2,4-dimethoxyphenyi)propanol 3-(2-{4TM-3-MPUB-DI)-2-(IBU)-acetytamino)-3-(2,4-dimethoxyphenyl)propanol 3-(2-(40PM-3-PUB-DI)-2-(iBU)-acetylamino)-3-(2,4-dimethoxyphenyl}propanol 3-(2-{40PM-3-MPUB-DI)-2-(IBU}-acetylamino)-3-(2,4-dimethoxyphenyl)propanoi 3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetyiamino)-3-(2,4-dimethoxyphenyi)propanol 3-(2-(40TM-3-MPUB-Dl)-2-(iBU)-acetyiamino)-3-(2,4-dimethoxyphenyl)propanol 3-(2-(4PM-3-PUB-Dl)-2-(lBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionic acid 3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxypheny!)propionic acid 3-(2-(4TM-3-PUB-DI)-2-(lBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionic acid 3-(2-(4TM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionic acid 3-(2-{40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionic acid 3-(2-(40PM-3-MPUB-DI)-2-(IBU)-acetyiamino)-3-(2,5-dimethaxyphenyi)propionic acid 3-(2-{40TM-3-PUB-Dl)-2-(IBU)-acetylannino)-3-(2,5-dimethoxyphenyl)propionic acid 3-(2-{40TM-3-MPUB-DI)-2-(iBU)-acetylamino}-3-(2,5-dimethoxyphenyl)prQpianic acid 3-(2-{4PM-3-PLIB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionamide 3-(2-(4PM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(2,5-dimethoxyphenyi)propionamide 3-(2-(4TM-3-PUB-D!)-2-(!BU)-acetylannino)-3-(2,5-dimethoxyphenyl)propionamide 3-(2-{4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionamide 3-(2-(40PM-3-PUB-DI)-2-{lBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionamlde 3-(2-(40PM-3-MPUB-DI)-2-{IBU)-acetylamino}-3-(2,5-dimethoxyphenyi)propionamide 3-(2-(40TM-3-PUB-DI)-2-{!BU)-acety!amino)-3-(2,5-dimethoxyphenyi)propionamide 3-(2-(40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyi)propionamide 3-(2-(4PM-3-PUB-Di)-2-(iBU)-acetyiamino)-3-(2,5-dimethoxypheny!)propanol 3-(2-(4PM-3-MPUB-Dl)-2-(lBU)-acetylamino)-3-(2,5-dimethoxyphenyi)propanol 3-(2-(4TM-3-PUB-Dl)-2-{lBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propanol 3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylaminQ)-3-(2,5-dimethoxypheny!)propanol 3-(2-(40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxypheny!)propanoi 3-(2-{40PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-{2,5-dinnethoxyphenyl)propanol 3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propanol 3-{2-{40TM-3-MPUB-DI)-2-(iBU)-acetylamino}-3-{2,5-dirnethoxyphenyl)propanol 3-(2-{4PM-3-PUB-DI)-2-{lBU)-acetylamino)-3-{2,6-dimethoxyphenyi)propionic acid 3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino}-3-{2,6-dimethoxyphenyl)propionic acid 3-(2-{4TM-3-PUB-DI)-2-{IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionic acid 3-(2-(4TM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionic acid 3-(2-{40PM-3-PUB-D!)-2-(IBLI)-acetylamino)-3-(2,6-dimethoxyphenyl)propionic acid 3-{2-{40PM-3-MPUB-DI)-2-{IBU)-acetyiamino)-3-(2,6-dimethoxypheny()propionic acid 3-(2-{40TM-3-PUB-DI)-2-{!BU)-acetytamino)-3-{2,6-dimethoxyphenyl)propionic acid 3-(2-(40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionic acid 3-(2-{4PM-3-PUB-DI)-2-(iBU)-acety!amino)-3-(2,6-dimethoxyphenyl)propionamide 3-(2-{4PM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(2,6-dimethoxyphenyi)propionamide 3-(2-{4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionamide 3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetyiarnino)-3-(2,6-dimethoxyphenyl)propionamide 3-{2-(40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyi)propionamide 3-{2-(40PM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-{2,6-dimethoxyphenyl)prGptonamide 3-(2-(40TM-3-PUB-DI)-2-(lBU)-acetylamino)-3-{2,6-dimethGxyphenyl)propionamide 3-(2-{40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionamide 3-(2-{4PM-3-PUB-DI)-2-(lBU)-acetyiamino)-3-{2,6-dimethoxyphenyl)propanol 3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-{2,6-dimethoxyphenyi)propanoi 3-(2-{4TM-3-PUB-Dl)-2-{IBU)-acetylamino)-3-(2,6-dimethoxyphenyi)propanoi 3-(2-(4TM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propanol 3-(2-{40PM-3-PUB-DI)-2-{IBU)-acetytamino)-3-(2,5-dimethoxyphenyl)propanol 3-(2-(40PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propanol 3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propanoi 3-(2-(40TM-3-MPUB-Dl)-2-(IBU)-acetylamio)-3-(2,6-dimethoxyphenyl)propanol 3-(2-{4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid 3-(2-(4PM-3-MPUB-DI)-2-(lBU)-acetylamino}-3-(3,4-dimethoxyphenyl)propionic acid ■ 3-(2-{4TM-3-PUB-Dl)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid 3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid 3-(2-(40PM-3-PUB-Dl)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid 3-(2-(40PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid 3-(2-(40TM-3-PUB-DI)-2-(lBU)-acetylamino)-3-{3,4-dimethoxyphenyl)propionic acid 3-(2-{40TM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-{3,4-dimethoxyphenyl)propionic acid 3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylarnino)-3-(3,4-dimethoxyphenyl)propionamide 3-(2-{4PM-3-MPUB-Dl)-2-(lBU)-acetyiamino)-3-(3,4-dimethoxyphenyl)propionamide 3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamio)-3-(3,4-dimethoxyphenyl)propionamide 3-(2-{4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionamide 3-(2-{40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionamide 3-(2-(40PM-3-MPUB-DI)-2-{IBU)-acetyiamino)-3-(3,4-dimethoxyphenyl)propionamide 3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionamide 3-{2-(40TM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(3,4-dimetlnoxyphenyl)propionamide 3-(2-{4PM-3-PUB-DI)-2-(iBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propanol 3-(2-{4PM-3-MPUB-DI)-2-{lBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propanol 3-(2-{4TM-3-PUB-DI)-2-(!BU)-acetylamino)-3-(3,4-dimethoxyphenyl)propanoi 3-(2-{4TM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propanol 3-(2-{40PM-3-PUB-Dl)-2-(IBU)-acetylamino)-3-(3,4Hdimethoxyphenyl)propanol 3-{2-{40PM-3-MPUB-DI)-2-(IBU)-acetylamino}-3-(3,4-dimethoxyphenyl)propanol 3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetylafnino)-3-(3,4-dimethoxyphenyl)propanol 3-(2-{40TlV1-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dirnethoxyphenyl)propanol 3-(2-(4PM-3-PUB-DI)-2-(lBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionic acid 3-{2-{4PM-3-MPUB-DI)-2-{lBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionic acid 3-{2-(4TM-3-PUB-DI)-2-{lBU)-acetylamino)-3-{3,5-dinnethoxyphenyl)propionic acid 3-(2-(4TM-3-MPUB-DI)-2-{lBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionic acid 3-(2-{40PM-3-PUB-DI)-2-(lBU)-acetylamino)-3-{3,5-dimethoxyphenyl)propionic acid 3-(2-{40PM-3-MPUB-DI)-2-{lBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionic acid 3-(2-(40TM-3-PUB-DI)-2-{IBU)-acetylamino}-3-(3,5-dimethoxyphenyl)propionic acid 3-(2-(40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionic acid 3-(2-(4PM-3-PUB-DI)-2-{lBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionamide 3-(2-{4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionamide 3-(2-(4TM-3-PUB-DI)-2-{lBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionamide 3-{2-(4TM-3-MPUB-DI)-2-(IBU)-acetytamino)-3-(3,5-dimethoxyphenyl)propionamide 3-(2-(40PM-3-PUB-DI)-2-{IBU)-acety!amino)-3-(3,5-dimethoxyphenyt)propianamide 3-(2-(40PM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(3,5-dimethoxypheny!)propionamide 3-(2-(40TM-3-PUB-DI)-2-(lBU)-acetylamino)-3-(3,5-dimethoxyphenyi)propionamide 3-(2-(40TM-3-MPUB-DI)-2-{IBU)-acetyiamino)-3-(3,5-dimethoxyphenyl)propionamide 3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propanol 3-(2-(4PM-3-MPUB-DI)-2-(!BU)-acetylamino)-3-(3,5-dimethoxyphenyl)propanol 3-(2-{4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propanol 3-(2-{4TiV1-3-MPUB-DI)-2-(IBU)-acetyiamino)-3-(3,5-dimethoxyphenyl)propanol 3-(2-{40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propanol 3-(2-(40PM-3-MPUB-DI)-2-(IBU}-acetylamino)-3-(3,5-dimethoxyphenyl)propanol 3-(2-{40TM-3-PUB-D!)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propanol 3-{2-{40TM-3-MPUB-DI)-2-(lBU)-acetyiamino)-3-{3,5-dimethoxyphenyl)propanol 3-(2-(4PM-3-PUB-D!)-2-(!BU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionic acid 3-(2-(4PM-3-MPUB-Dl)-2-(lBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionic acid 3-(2-(4TM-3-PUB-DI)-2-{iBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionic acid 3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methyienedioxyphenyl)propionic acid 3-(2-(40PM-3-PUB-DI)-2-(lBU)-acetyiamino)-3-(3,4-rnethyienediQxyphenyi}propionic acid 3-(2-{40PM-3-MPUB-Di)-2-(IBU)-acetytamino)-3-(3,4-methylenedioxyphenyl)- propionic acid 3-(2-(40TM-3-PUB-Dl)-2-(!BU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionic acid 3-{2-(40TM-3-MPUB-DI)-2-(IBU)-acetytamtno)-3-(3,4-metlnylenedioxyphenyi)- propionic acid 3-(2-{4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-{3,4-methylenedioxyphenyi)- propionamide 3-(2-{4PM-3-MPUB-DI)-2-(IBU)-acetytamino)-3-{3,4-methyienedioxyphenyl)- propionamide 3-(2-(4TM-3-PUB-DI)-2-(lBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)- propionamide 3-(2-(4TM-3-MPUB-DI)-2-{!BU)-acetyiamino)-3-(3,4-methylenedioxyphenyl)- propionamide 3-(2-{40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)- propionamide 3-(2-{40PM-3-MPUB-D!)-2-(!BU)-acetylamino)-3-(3,4-methylenedioxyphenyi)- propionamide 3-(2-(40TM-3-PUB-Di)-2-(IBU)-acetylamino)-3-{3,4-methylenedioxyphenyl)- propionamide 3-(2-(40TM-3-MPUB-Dl)-2-(lBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)- propionamide 3-(2-(4PM-3-PUB-Di)-2-(lBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propanol 3-(2-(4PM-3-MPUB-D!)-2-(lBU)-acetylam!no)-3-(3,4-methylenedioxyphenyl)propanol 3-(2-(4TM-3-PUB-Dl)-2-(IBU)-acetytamino)-3-(3,4-methylenedioxyphenyl)propanol 3-(2-{4TM-3-MPUB-Di)-2-{(BU)-acetyiamino)-3-(3,4-methylenediQxypheny!)propano! 3-(2-(40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propanol 3-(2-{40PM-3-MPUB-Di)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)-propanol . 3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methyienedioxyphenyl)prQpanoi 3-(2-{40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl}-propanol 3-{2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethyienedioxyphenyl)propionic acid 3-(2-(4PM-3-MPUB-D!)-2-(IBU)-acety(amino)-3-(3,4-ethylenedioxyphenyl)propiQnic acid 3-(2-{4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethy!enedioxyphenyl)propionic acid 3-(2-{4TM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-(3,4-ethyienedioxyphenyi)propionic acid 3-(2-{40PM-3-PUB-Dl)-2-(lBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propionic acid 3-(2-(40PM-3-MPUB-DI)-2-{lBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propionic acid 3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetyiamino)-3-(3,4-€thylenedioxyphenyl)propionic acid 3-{2-{40TM-3-MPUB-DI)-2-(lBU)-acetytamino)-3-(3,4-ethylenedioxyphenyl)propionic acid 3-(2-(4PM-3-PUB-DI)-2-(!BU)-acetylamino)-3-(3,4-ethylenedioxyphenyi)propionamide 3-(2-{4PM-3-MPUB-DI)-2-(iBLI)-acetylamino)-3-{3,4-ethylenedioxypheny()- propionamide 3-(2-(4TM-3-PUB-Dl)-2-(lBU)-acetyiamino)-3-(3,4-ethylenedioxyphenyl)propionamide 3-(2-(4TM-3-MPUB-DI)-2-(!BU)-acetylamino)-3-(3,4-ethylenediQxyphenyl)- propionamide 3-(2-(40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-{3,4-ethylenedioxyphenyl)- propionamide 3-(2-(40PM-3-MPUB-DI)-2-(IBU)-ac8tylamino)-3-{3,4- ethylenedioxyphenyl)propionamide 3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)-propionamide .3-(2-(40TM-3-MPUB-DI)-2-(IBU)-acetylaminQ)-3-(3,4-ethyienedioxyphenyl)-propionamide 3-{2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3.4-ethylenedioxyphenyl)propanol 3-(2-(4PM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propanol 3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetytarriino)-3-(3,4-€thylenedioxyphenyl)propanoi 3-{2-{4TM-3-MPUB-DI)-2-(IBU)-acety!amino)-3-(3,4-ethylenedioxyphenyl)propanol 3-(2-(40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyt)propanol 3-(2K40PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-€thylenedioxyphenyl)propanol 3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3.4-ethylenedioxyphenyl)propanol 3-(2-{40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-{3,4-ethyienedioxyphenyl)propanol All abovementioned compounds are a subject of the present invention in all their stereoisomeric forms and in the form of mixtures thereof in all ratios. The compound 3-(2-{4,4-{3-oxopentamethylene)-3-{4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)-propionamide mentioned above as an example is thus a subject of the invention, inter alia, in the form of (RS)-3-((RS)-2-(4,4-(3-oxopentamethylene)-3-(4-{3-(2-methyiphenyl)ureido)ben2yf)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyi)acetyl-amino)-3-(3,4-dimethoxyphenyl)propionamide, in the form of (S)-3-((S)-2-(4,4-(3-oxopentamethylene)-3-(4-(3-(2-methylphenyl)ureido)ben2yl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acety!amino)-3-{3,4-dimethoxyphenyl)propionamide, in the form of (S)-3-((R)-2-(4,4-(3-oxopentamethyiene)-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)-propionamide, in the form of (R)-3-((S)-2-{4,4-(3-oxopentamethylene)"3-(4-(3-(2-methylphenyl)ure(do)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methy!propyl)acetyl-amino)-3-(3,4-dimethoxypheny!)proptonamide, in the form of (R)'3-((R)-2-(4,4-{3-oxopentamethylene)-3-{4-(3-{2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-{3,4-dimethoxyphenyl)propionamide, in the form of (S)-3-((RS)-2-{4,4-(3-oxopentamethylene)-3-(4-(3-(2-methyiphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)"2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)-propionamide, in the form of (R)-3-((RS)-2-{4,4-{3-oxopentamethylene)-3-(4-(3-(2-. methylphenyl)ureido)ben2yl)-2,5-dioxoimida2olidin'1-yi)-2-(2-methylpropyi)acetyi-amino)-3-(3,4-dimethoxyphenyl)propionamide, in the form of (RS)-3-((R)-2-(4,4-(3-oxopentamethylene)-3-(4-{3-(2-methylphenyl)ureido)ben2yl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)propionamide and in the form of (RS)-3-((S)-2-(4,4-(3-oxopentamethylene}-3-{4-{3-(2-methylphenyl)ureido)-benzyl)-2,5-dioxoimida2olidin-1-y!)-2-(2-methyipropyl)acetylamino)-3-(3.4-dimethoxyphenyl)propionamide, and this applies expressly to all compounds mentioned. In another way of looking at the situation, with respect to the individual stereoisomers all compounds mentioned are a subject of the invention in the stereochemical arrangement which is shown in formula If, as well as in the arrangement which is shown in formula Ig, as well as in the arrangement which is shown in formula Ih, as well as in the arrangement which is shown in formula li, in particular in the stereochemical arrangement which is shown in formula If. Also all above-listed compounds are a subject of the invention in the form of their physiologically tolerable salts and in the form of their prodrugs and other physiologically tolerable derivatives, for example their esters. The present invention furthermore expressly relates to all compounds analogous to the listed individual compounds which instead of the isobutyl-substituted acetyiamino group contain a cyclopropyimethyl-substituted acetyiamino group, and to all compounds analogous to the listed individual compounds which instead of the 4-(3-arylureido)ben2yl group contain a 4-(3-aryiureido)-3-methoxybenzyl group, and to all compounds analogous to the listed individual compounds which at the same time instead of the isobutyl-substituted acetyiamino group contain a cyclopropyimethyl-substituted acetyiamino group and instead of the 4-(3-arylureido)benzyl group contain a 4-{3-aryiureido)-3-methoxyben2yl group, where also all these compounds are a subject of the present invention in all their stereoisomehc forms and in the form of mixtures thereof in all ratios and in the form of their physiologically tolerable salts and in the form of their prodrugs. where, in the formulae II and III the groups X, W, V, E, R1 and R2 are defined as indicated above or also functional groups in these groups can be present in protected form or in the fonn of precursors, and where G is hydroxycarbonyl, (C1-C6)-aikoxycarbonyi or an activated carboxylic acid derivative such as an acid chloride or an active ester. In the condensation of the compounds of the formulae II and III, usually it is necessary that a carboxylic acid group which is present but which is not involved in the condensation reaction is protected by a reversible protective group, for example as a suitable (C1-C6)-alkyl ester such as the tert-butyl ester or as a benzyl ester. If compounds of the formula I are to be prepared in which the group E is, for example, hydroxycarbonyl or a group which is to be prepared from a hydroxycarbonyl group, in the compounds of the formula ill, for example, the group E can initially be a hydroxycarbonyl group which is present in protected form and then, after the condensation of the compounds of the formulae II and III in one or more further steps, the hydroxycarbonyl group can be liberated or the desired final group E can be synthesized. Precursors of functional groups are groups which can be converted into the desired . functional group by the customary synthesis processes known to the person skilled in the art. For example, a cyano group which can be converted into an acid amide group or a carboxylic acid group by hydrolysis or can be converted into a tetrazole by reaction with an azide can be designated as a precursor for these groups. An alcohol group which can be oxidized to an aldehyde group can be designated as a precursor for this group. Examples of protective groups which are introduced into a molecule before carrying out a reaction or a reaction sequence and are later removed again have already been mentioned. For the condensation of the compounds of the formulae ll and III, the coupling methods of peptide chemistry which are well-known to the person skilled in the art are advantageously used (see, for example, Houben-Weyl, Methoden der Organischen Chemie, Volume 15/1 and 15/2, Georg Thieme Verlag, Stuttgart, 1974). Suitable condensing agents or coupling reagents are, for example, carbonyldiimidazole, carbodiimides such as dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide, 0-((cyano(ethoxycarbonyl)methylene)amino)-N,N,N',N'-tetramethyiuronium tetrafluoroborate (TOTU) or propylphosphonic anhydride (PPA). The condensations can be carried out under the standard conditions well-known to the person skilled in the art. In general, they are carried out in an inert solvent or diluent, for example in an aprotic solvent such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), tetrahydrofuran (THF) or dimethoxyethane (DME). Depending on the condensation carried out in the individual case, it may be advantageous to add a base such as a tertiary amine or auxiliary reagents, for example an N-hydroxy compound such as l-hydroxybenzotriazole (HOBT). The working-up of the reaction mixture and a purification of the product can be carried out by customary standard processes. After the condensation, the protective groups present are removed in a suitable manner. For example, benzyl groups in benzyl esters can be removed by hydrogenation or protective groups of the tert-butyl type can be removed acidically. The compounds of the formula 1 can also be prepared, for example, by synthesizing the compounds stepwise on a solid phase according to customary methods, it being possible to introduce the individual structural elements of the molecule in different sequences. The amino compounds of the formula III are commercially available or can be synthesized by or analogously to well-known standard processes from starting compounds which are commercially available or, in turn, are obtainable by or analogously to literature procedures. For example, optically active 3-substituted 3-aminopropionic acids of the formula III or their esters, in particular 3-phenyl-3-aminopropionic acid esters, can be prepared from the corresponding 3-substituted acrylic acids, which in turn are obtainable from the corresponding aldehydes. The 3-substituted acrylic acids are converted into the acid chlorides using oxalyl chloride, and the acid chlorides are converted into the esters using an alcohol, for example into the tert-butyl esters using tert-butanol. For the introduction of the amino group, the ester is then reacted with the lithium salt of an optically active amine, for example the lithium salt of (R)-(+)-N-benzyi-N-(1-phenylethyl)amine, and subsequently, in the 3-substituted tert-butyl 3-(N-benzyl-N-(1-phenylethyl)amino)propionate obtained, the benzyl group and the phenylethyl group are removed by catalytic hydrogenation. For the preparation of compounds of the formula III in which E is the hydroxymethyl group CH2OH or an etherified or esterified hydroxymethyl group, 3-substituted 3-aminopropanols or their esters or ethers which are obtainable from the 3-substituted 3-aminopropionic acids or their esters by reduction of the acid group (or of the ester group), for example from the ethyl ester or tert-butyl ester using lithium aluminum hydride or lithium aluminum hydride/aluminum trichloride, can be employed in the condensation reaction. Compounds of the formula II can be prepared, for example, by first reacting compounds of the formula IV in a Bucherer reaction, for example with ammonium carbonate and potassium cyanide, to give compounds of the formula V in which W, X and G are defined as indicated above or functional groups can be present in protected form or in the form of precursors, can then be obtained by reacting the compounds of the formula V, for example, with a first alkylating reagent of the formula LG-CH(G)-CH2-W which introduces the residue -CH(G)-CH2-W into the molecule. The reaction of compounds of the formula VI with a second alkylating reagent of the formula VII compounds of the formula II. The group LG is a nucieophiiically substitutable leaving group, for example halogen such as chlorine or bromine, or sulfonyloxy such as tosyloxy, methylsulfonyloxy or trifluoromethylsulfonyloxy. Compounds of the formula II can also be prepared, for example, by reacting a compound of the formula VI first with a reagent of the formula 4-{PG-NH)-C6VH3-CH2-LG, in which LG in turn is a nucieophiiically substitutable leaving group and the group V in the 3-position is hydrogen or methoxy, to give a compound of the formula VIII where the meanings indicated above apply to G, V, W and X and PG is an amino protective group, for example tert-butoxycarbony! or benzyloxycarbonyl. After removal of the protective group PG, the compounds of the formula II are obtained by reaction of the resulting amino group H2N with phenyl isocyanate or with 2-methylphenyi isocyanate. Like compounds of the formula VllI, also compounds can .r be prepared and employed in which the group PG-NH- in the formula VIH is replaced by a group which is a precursor for an amino group and which is then converted into an amino group in a further reaction step. For example a compound of the formula VI can first be reacted with a nitro compound of the formula 4-O2N-C6VH3-CH2-LG to give a compound corresponding to the compound of the fonmula VIII, then the nitro group can be converted into the amino group, for example by catalytic hydrogenation, and then the amino group can be converted into the desired compound of the formula II using phenyl isocyanate or 2-methylpheny( isocyanate. In case a compound of the formula I is to be prepared in which one of the CH2 groups in the group X in the spiro-linked ring is replaced by a C=0 group, it is expedient first to protect this carbonyl group, for example as a ketal, and to carry out the Bucherer reaction with the protected compound of the formula IV, for example the monoketal of the cycloalkanedione. The aikylations of the protected compound of the formula V to give the compounds of the formulae Vl and VIII are then carried out as explained and thereafter, or otherwise at a later time dunng the synthesis, the carbonyl group in the group X is liberated again. In the case of a ketal protective group, the liberation of the protected carbonyl group can be carried out by treating with an acid analogously to literature processes. In general, the individual steps in the preparation of the compounds of the formula I can be carried out according to or analogously to known methods familiar to the person skilled in the art. As already mentioned and as is known to the person skilled in the art, depending on the individual case it may be appropriate in all steps in the synthesis of the compounds of the formula i temporarily to block functional groups which could lead to side reactions or undesired reactions by a protective group strategy tailored to the synthesis problem. Compounds of the formula 1 can also be obtained as follows. By reaction of N-substituted amino acids obtainable by standard processes or preferably of their esters, for example the methyl esters, ethyl esters, tert-butyl esters or benzyl esters, for example of compounds of the formula !X for which the above definitions apply and which is obtainable according to standard processes from the corresponding compound which instead of the isocyanate group contains an H2N group, urea derivatives, for example of the formula XI for which the definitions indicated above apply, are obtained. The compounds of the formula XI can then be cydized to the compounds of the formula I by heating with acid. The cyclization of the compounds of the formula XI to the compounds of the formula 1 can also be carried out by treatment with bases in inert solvents, for example by treating with sodium hydride in an aprotic solvent such as dimethylformamide. During the reaction, functional groups can be present in protected form. Compounds of the formula I can also be obtained by reacting a compound of the formula IX with an isocyanate of the formula XII in which Q, for example, is an alkoxy group, for example a (C1-C4)-alkoxy group such as methoxy, ethoxy or tert-butoxy, or a (C5-C14)-aryl-(C1-C4)-alkoxy group, for example benzyloxy, and W has the meanings indicated above. In this case, a compound of the formula XIII is obtained in which X, W, V, Q and R1 are defined as indicated above, which is then cyciized under the influence of an acid or of a base, as described above for the cyclization of the compounds of the formula XI, to a compound of the formula XIV in which Q, W, V, X and R1 are defined as indicated above. In the compound of the formula XIV, it is then possible, for example by means of hydrolysis, to convert the group CO-Q into the carboxylic acid group COOH, If the cyclization of the compound of the formula XIII to the compound of the formula XIV is carried out using an acid, the conversion of the group CO-Q into the group COOH can also be carried out simultaneously with the cyclization. By subsequent coupling with a compound of the formula III, as described above for the coupling of the compounds of the formulae II and III, a compound of the formula 1 is then obtained. In this synthesis process too, functional groups can be present in protected form or in the form of precursors. A further method for the preparation of compounds of the formula I is, for example, for which the definitions indicated above apply, with phosgene or corresponding equivalents (analogously to S. Goldschmidt and M. Wick, Liebigs Ann. Chem. 575 (1952), 217 and C. Tropp, Chem. Ber. 61 (1928), 1431). Compounds of the formula I can also be prepared by first coupling a compound of the formula XVI in which Q' is a protected carboxyiic acid hydroxy group, for example an alkoxy group such as tert-butoxy, and W has the meanings indicated above, to give a compound of the formula XVIII in which X, W and Q' have the meanings indicated above. For the introduction of the carbonyl group, it is possible to use, for example, phosgene or a phosgene equivalent (analogously to the reaction of the compounds of the formula XV illustrated above). An intermediate which can occur or can be specifically prepared in the conversion of the compound of the formula XVlll into the compound of the formula XIX is, for example, an isocyanate. The conversion of the compound of the formula XVIII into that of the formula XIX can be carried out in one or more steps. For example, the carbonyl group can first be introduced into the molecule and in a separate step the cycfization can then be carried out in the presence of a base such as sodium hydride, like the cyciizations described above. Compounds of the formula XVlll, in which PG is the benzyloxycarbonyl group, can also be converted directly into compounds of the formula XIX without an additional synthesis component such as phosgene being employed for the introduction of the carbonyl group. If compounds of the formula XVIll in which PG isbenzytoxycarbonyl are treated with a base such as sodium hydride, the compounds of the formula XIX can be obtained directly. The compounds of the formula XIX can then be alkylated on the NH group using a reagent of the formula VII, for example, as illustrated above for the compounds of the formula VI, and after conversion of the protected carboxylic acid group CO-Q' into the carboxylic acid group COOH, the desired compounds of the formula I can be synthesized as described above for the compounds of the formulae VI and II. In this synthesis process too, functional groups can be present in protected fonn or in the form of precursors. Compounds of the formula XXll can also be prepared by first preparing a compound of the formula XVlll in which X, W and Q' have the meanings indicated and PG is an alkoxycarbonyi group such as (C1-C4)-alkoxycarbonyl, an aryialkoxycarbonyl group such as phenyl-(C1-C4)-alkoxycarbonyl, or an aryloxycarbony! group such as phenyloxycarbonyl, converting it by liberating the protected carboxyiic acid group CO-Q' into a compound of the formula XVlll in which CO-Q' is the free carboxyiic acid group CO-OH, PG is alkoxycarbonyi, aryialkoxycarbonyl or aryloxycarbony! and X and W have the meanings indicated, and cyciizing this compound with a base such as, for example, sodium carbonate to the compound of the formula XXII. in which R\ V, W and X have the meanings indicated above, can then be obtained by reacting the compounds of the formula XXll with an alkylating reagent of the formula VlI in the presence of excess base, for example in the presence of an excess of n-butyllithium, and then acidifying. The 4-(3-arylureido)ben2yl group can also be introduced into the compounds of the formula XXll stepwise, analogously to the preparation of the compounds of the formula Vlll and the compounds of the formula II obtained therefrom. If, in the compounds of the formula XXll, a CH2 group in the group X is replaced by a carbonyi group, it is expedient to protect this carbonyl group for the alkylation reactions to give the compounds of the formula lia and to liberate it again after the alkylation, as has been explained above. ' The compounds of the formula I in which E, for example, is hydroxycarbonyl or hydroxymethyl can be converted by standard processes into compounds of the formula I in which E has other meanings, or into other prodrugs or derivatives of the compounds of the formula 1. Thus, for the preparation of esters the compounds of the formula I in which E is hydroxycarbonyl can be esterified with the corresponding alcohols, for example in the presence of a condensing reagent such as DCC, or the compounds of the formula I in which E is hydroxycarbonyl can be alkylated using alkyl halides such as alkyl chlorides or alkyl bromides, for example using chloroalkanamides to give compounds of the fonmula I in which E is R4R4N-CO-alkoxy-CO-, or with acyloxyalkyl halides to give compounds of the formula I in which E is acyloxyalkoxy-CO-. Compounds of the formula 1 in which E is hydroxycarbonyl can be converted into amides using ammonia or organic amines in the presence of a condensing reagent. Compounds of the formula i in which E is CO-NH2 can advantageously also be obtained on the solid phase, by coupling the compound in which E is COOH to Rink amide resin in the presence of a condensing agent such as TOTU and then removing it again from the resin using trifluoroacetic acid. Compounds of the formula I in which E is the hydroxymethyl group CH2OH can be etherified or esterified on the hydroxymethyl group according to standard processes. According to standard processes for the selective oxidation of alcohols to aldehydes, for example using sodium hypochlorite in the presence of 4-acetamido-2,2,6,6-tetramethylpiperidin-1-oxyl (4-acetamido-TEMPO), compounds of the fonnuia I in which E is CH2OH can be converted into compounds of the formula 1 in which E is the aldehyde group CO-H. The compounds of the formula I are valuable pharmaceutical active compounds which are suitable, for example, for the therapy and prophylaxis of inflammatory diseases, allergic diseases or asthma. The compounds of the formula I and their physiologically tolerable salts and derivatives can be administered according to the invention to animals, preferably to mammals, and in particular to humans, as pharmaceuticals for therapy or prophylaxis. They can be administered on their own, in mixtures with one another or in the form of pharmaceutical preparations which allow enteral or parenteral use and which, as active constituent, contain an efficacious dose of at least one compound of the formula I and/or its physiologically tolerable salts and derivatives in addition to pharmaceutically innocuous vehicles and/or additives. The present invention therefore also relates to the compounds of the formula I and/or their physiologically tolerable salts and derivatives for use as pharmaceuticals, the use of the compounds of the formula I and/or their physiologically tolerable salts and derivatives for the production of pharmaceuticals for the therapy and prophylaxis of the illnesses illustrated above and in the following, for example for the therapy and prophylaxis of inflammatory diseases, and the use of the compounds of the formula 1 and/or their physiologically tolerable salts and derivatives in the therapy and prophylaxis of these illnesses. The present invention furthermore relates to pharmaceutical preparations (or pharmaceutical compositions) which contain an efficacious dose of at least one compound of the formula 1 and/or its physiologically tolerable salts and derivatives and a pharmaceutically tolerable carrier, that is one or more pharmaceutically innocuous vehicles and/or additives. The pharmaceuticals can be administered systemically or locally. They can be administered, for example, orally in the form of pills, tablets, film-coated tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, powders, solutions, syrups, emulsions, suspensions and in other pharmaceutical forms. The administration can also be carried out vaginally or rectally, for example in the form of suppositories, or parenterally or by implantation, for example in the form of injection solutions or infusion solutions, microcapsules or rods, or topically or percutaneously, for example in the form of creams, ointments, powders, solutions, emulsions or tinctures, or in other ways, for example in the form of nasal sprays or aerosol mixtures. Parenteral administration of solutions can occur, for example, intravenously, intramuscularly, subcutaneously, intraarticulariy, intrasynovially or in other ways. The pharmaceutical preparations according to the invention are produced in a known manner, the compound or the compounds of the formula I and/or its physiologically ■ tolerable salts and derivatives being mixed with pharmaceutically inert inorganic and/or organic vehicles and/or additives. For the production of pills, tablets, coated tablets and hard gelatin capsules, for example lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, polyethylene glycols, etc. may be used. For soft gelatin capsules and suppositories, for example, fats, waxes, semisolid and liquid polyols, polyethylene glycols, natural or hardened oils etc. may be used. Suitable vehicles for the production of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, alcohols, glycerol, diols, polyols, sucrose, invert sugar, glucose, vegetable oils etc. Suitable vehicles for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. The pharmaceutical preparations normally contain about 0.5 to about 90% by weight of the compounds of the formula I and/or their physiologically tolerable salts and derivatives. The amount of active compound of the formula I and/or its physiologically tolerable salts and derivatives in the pharmaceutical preparations is normally about 0.2 to about 1000 mg, preferably about 1 to about 500 mg, but depending on the nature of the pharmaceutical preparation the amount of the active compound can also be larger. In addition to the active com.pounds and vehicles, the pharmaceutical preparations can additionally contain excipients or additives, for example fillers, disintegrants, binders, lubricants, wetting agents, stabilizing agents, emulsifiers, preservatives, sweeteners, colorants, flavorings, aromatizers, thickening agents, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for changing the osmotic pressure, coating agents or antioxidants. They can also contain two or more compounds of the formula I and/or their physiologically tolerable salts and derivatives. Furthermore, in addition to at least one compound of the formula I and/or its physiologically tolerable salts and derivatives they can contain one or more other pharmaceutical active compounds, for example substances having antiinflammatory action. If the compounds of the formula I or pharmaceutical preparations comprising them are administered as aerosols, for example as nasal aerosols or by inhalation, this can * be carried out, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaler or a dry powder inhaler. Pharmaceutical forms for administration of the compounds of the formula I as an aerosol can be prepared by processes well-known to the person skilled in the art. For their preparation, for example, solutions or dispersions of the compounds of the formula I in water, water/alcohol mixtures or suitable saline solutions can be employed using customary additives, for example benzyl alcohol or other suitable preservatives, absorption enhancers for increasing the bioavailability, solubilizers, dispersants and others, and, if appropriate, customary propellants, for example chlorofluorohydrocarbons and/or fluorohydrocarbons. Suitable other pharmaceutical active compounds which can be contained in addition to compounds of the formula 1 in the pharmaceutical preparations according to the invention, but with which the compounds of the formula I can also be combined in other ways in the context of a combination therapy or combination prophylaxis, are in particular such active compounds which are suitable for the therapy or prophylaxis of the illnesses mentioned above or in the following for whose therapy or prophylaxis the compounds of the formula I are suitable. Examples of classes of active compound of this type which may be mentioned are steroids, nonsteroidal antiinflammatory substances, nonsteroidal antiinflammatory acetic acid derivatives, nonsteroidal antiinflammatory propionic acid derivatives, nonsteroidal antiasthmatics, salicylic acid derivatives, pyrazolones, oxicams, leukotriene antagonists, inhibitors of leukotriene biosynthesis, cyclooxygenase inhibitors, cyclooxygenase-2 inhibitors, (COX-2 inhibitors), antihistamines, H1-histamine antagonists, nonsedating antihistamines, gold compounds, β2 agonists, anticholinergics, muscarine antagonists, antihyperiipidemics, antihypercholesterolemics, HMG-CoA reductase inhibitors, statins, nicotinic acid derivatives, immunosuppressants, cyclosporins, β-interferons, tumor therapeutics, cytostatics, metastasis inhibitors, antimetabolites, 5-aminosalicyiic add derivatives, antidiabetics, insulins, sulfonylureas, biguanides, giitazones, a-glucosidase inhibitors, and others. Examples of suitable active compounds which may be mentioned are acetylsalicylic acid, benorilate, sulfasalazine, phenylbutazone, oxyphenbutazone, metamizole, mofebutazone, ■ feprazone, celecoxib, rofecoxib, diclofenac, fentiazac, sulindac, zomepirac, tolmetin, indometacin, acemetacin, ibuprofen. naproxen, carprofen, fenbufen, indoprofen, ketoprofen, pirprofen, tiaprofenic acid, diflunisal, flufenamic acid, meciofenamic acid, mefenamic acid, niflumic acid, tolfenamic acid, piroxicam, isoxicam, tenoxicam, nicotinic acid, prednisone, dexamethasone, hydrocortisone, methylprednisolone, betamethasone, bedomethasone, budesonide, montekulast, prankulast, zafirkulast, zileutone, cidosporin, rapamycin, tacrolimus, methotrexate, 6-mercaptopurine, azathiopnne, interferon-beta-1a, interferon-beta-1b, 5-aminosalicylic acid, leflunomide, D-peniciilamine, chloroquine, glibendamide. glimepiride. trogiitazone, metformin, acarbose, atorvastatin, fluvastatin, lovastatin, simvastatin, pravastatin, colestipol, colestyramine, probucol, ciofibrate, fenofibrate, bezafibrate, gemfibrozil, ipatropium bromide, clenbuterol, fenoteroi, metaproterenoi, pirbuterol, tulobuterol, salbutamol, salmeterol, terbutalin, isoetarine, ketotifen, ephedrine, oxitropium bromide, atropine, cromoglycic acid, theophylline, fexofenadine, terfenadine, cetirizine, dimetindene, diphenhydramine, diphenylpyraline, pheniramine, bromopheniramine, chloropheniramine, dexchloropheniramine, alimemazine, antazoiine, astemizole, azatadine, clemastine, cyproheptadine, hydroxyzine, loratidine, mepyramine, promethazine, tripelennamine, triprolidine and others. If compounds of the formula 1 and/or their physiologically tolerable salts or prodrugs are to be employed in a combination therapy or combination prophylaxis together with one or more other active compounds, this can be carried out as mentioned by administering all active compounds together in a single pharmaceutical preparation, for example a tablet or capsule. Pharmaceutical preparations of this type, for which all explanations above correspondingly apply, are expressly likewise a subject of the present invention. The amount of the active compounds in these pharmaceutical preparations is in general such that an efficacious amount of each active compound is present. A combination therapy or combination prophylaxis, however, can also be carried out by the active compounds being present in two or more separate pharmaceutical preparations which can be in a single pack or in two or more separate packs. The administration of the compounds of the formula I and/or their physiologically tolerable salts or products and the other active compounds can be . carried out jointly or separately and can be carried out simultaneously or sequentially, i in any order. The administration can also be carried out in different ways, for example one active compound can be administered orally and the other by injection, inhalation or topical application. The compounds of the formula 1 have, for example, the ability to inhibit cell-cell interaction processes and cell-matrix interaction processes in which interactions between VLA-4 and its ligands play a role. The activity of the compounds of the formula I can be demonstrated, for example, in an assay in which the binding of cells which contain the VLA--4 receptor, for example of leukocytes, to ligands of this receptor, for example to VCAM-I which advantageously can also be prepared for this purpose by genetic engineering, is measured. Details of such an assay are described below. In particular, the compounds of the formula I are able to inhibit the adhesion and the migration of leukocytes, for example the adhesion of leukocytes to endothelial cells which - as explained above - is controlled via the VCAM-1A/LA-4 adhesion mechanism. Apart from as antiinflammatory substances, the compounds of the formula I and their physiologically tolerable salts and derivatives are therefore generally suitable for the therapy and prophylaxis of illnesses which are based on the interaction between the VLA-4 receptor and its ligands or can be affected by an inhibition of this interaction, and they are in particular suitable for the therapy and prophylaxis of illnesses which are at least partially caused by an undesired extent of leukocyte adhesion and/or leukocyte migration or are associated therewith, and for whose prevention, alleviation or cure the adhesion and/or migration of leukocytes should be decreased. The present invention therefore also relates to the compounds of the formula I and their physiologically tolerable salts and derivatives for the inhibition of the adhesion and/or migration of leukocytes or for the inhibition of the VLA-4 receptor, and to the use of the compounds of the formula I for the production of pharmaceuticals for this. that is of pharmaceuticais for the therapy or prophylaxis of illnesses in which leukocyte adhesion and/or leukocyte migration exhibits an undesired extent, or for the therapy or prophylaxis of illnesses in which VLA-4-dependent adhesion processes piay a part, and to the use of the compounds of the formula I and/or their physiologically tolerable salts and derivatives in the therapy and prophylaxis of illnesses of this type. The compounds of the formula I can be employed as antiinflammatories in the case of inflammatory symptoms of very different causes in order to prevent, to decrease or to suppress the undesired or harmful consequences of inflammation. They are used, for example, for the therapy or prophylaxis of arthritis, of rheumatoid arthritis, of polyarthritis, of inflammatory bowel disease (ulcerative colitis), of systemic lupus erythematosus, for the therapy or prophylaxis of inflammatory disorders of the central nervous system such as, for example, of multiple sclerosis, or for the therapy or prophylaxis of asthma or of allergies, for example allergies of the delayed type (type IV allergy). They are furthermore suitable for the therapy or prophylaxis of cardiovascular disorders, of arteriosclerosis, of restenoses, of diabetes, of damage to organ transplants, of immune disorders, of autoimmune disorders, of tumor growth or tumor metastasis in various malignancies, of malaria as well as of further illnesses in which blocking of the integrin VLA-4 and/or influencing of the leukocyte activity appears appropriate for prevention, alleviation or cure. The dose when using the compounds of the formula 1 can vary within wide limits, and as is customary and is known to the physician, it is to be tailored to the individual conditions in each individual case. It depends, for example, on the nature and severity of the illness to be treated, on the condition of the patient, on the compound employed or on whether an acute or chronic disease state is treated or prophylaxis is conducted or on whether further active compounds are administered in addition to the compounds of the formula 1. In general, in the case of oral administration, a daily dose of about 0.01 to about 100 mg/kg, preferably about 0.1 to about 10 mg/kg (in each case mg of the compound per kg of body weight) is appropriate in an adult weighing about 75 kg to achieve effective results. In the case of intravenous administration, the daily dose is in general about 0,01 to about 50 mg/kg of body weight, preferably about 0,01 to about 10 mg/kg. The daily dose can be divided, in particular when relatively large amounts are administered, into several, for example ' 2, 3 or 4, part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated. Apart from as pharmaceutical active compounds in human medicine and veterinary medicine, the compounds of the formula I and their salts and derivatives suitable for the use concerned can furthermore be employed for diagnostic purposes, for example in in-vitro diagnoses of cell samples or tissue samples, and as auxiliaries or as a scientific tool in biochemical investigations in which VLA-4 blocking or influencing of cell-cell or cell-matrix interactions is demanded. Furthermore, the compounds of the formula I and their salts can be used as intermediates for the preparation of other compounds, in particular of other pharmaceutical active compounds which are obtainable from compounds of the formula I, for example by modification or introduction of residues or functional groups, for example by esterification, reduction, oxidation or other conversions of functional groups. Examples Example 1 (S)-3-{(S)-2-(4,4-Pentamethylene-3-(4-(3-phenylureido)benzyl)-2,5-dioxoimida2olidin- 1 -yl)-2-{2-methylpropyl)acetylamino)-3-phenylpropionic acid a) 4-(3-Phenylureido)benzyl alcohol 30.6 g (200 mmol) of 4-nitrobenzyl alcohol were hydrogenated over 1.0 g of palladium/carbon (10% strength; 50% water) in 500 ml of methyl tert-butyl ether After the absorption of hydrogen was complete, the catalyst was filtered off. 24 g (200 mmol) of phenyl isocyanate were added to the filtrate at 15°C with stirring in the course of 30 minutes. The precipitated solid was filtered off with suction and washed with methyl tert-butyl ether. Yield: 43 g (89%). b) 4-(3-Phenylureido)ben2yl chloride 42 g (354 mmol) of thionyl chloride were added dropwise at 30^0 to a suspension of ": 42.8 g (177 mmol) of 4-(3-phenyiureido)benzy! alcohol in 500 ml of dichloromethane. The mixture was subsequently stirred at 40'C for 1 hour. After completion of the evolution of gas, the mixture was allowed to cool to room temperature. The precipitated product was filtered off with suction and washed with dichloromethane. Yield: 44.26 g (96%). c) Methyl 1-aminocyclohexane-1-carboxylate 51 ml of thionyl chloride were added in portions at -5°C to 50 g (350 mmol) of 1-aminocyclohexane-1-carboxylic acid in 1.25 I of methanol. The reaction mixture was subsequently stinted at room temperature for 5 hours and allowed to stand overnight at room temperature. The methanol was removed in vacuo, the residue was mixed with water, and the aqueous solution was adjusted to pH 9 using saturated sodium carbonate solution and extracted twice with dichloromethane. The organic phase was dried over sodium sulfate and, after filtration, the solvent was removed in vacuo. Yield: 36.35 g (66%). d) Methyl 1 -(3-((S)-1 -tert-butoxycarbonyl-3-methylbuty!)ureido)cyclo- hexanecarboxylate A solution of 28 g (179 mmol) of methyl 1-aminocyclohexane-1-carboxytate was added to a solution of 38 g (179 mmol) of L-leucine tert-butyl ester isocyanate (prepared analogously to J.S. Nowick et al., J. Org. Chem. 1996, 61, 3929) in 300 ml of absolute DMF. After stirring at room temperature for 2 hours, the reaction mixture was allowed to stand overnight. The solvent was removed in vacuo, the residue was treated with heptane and the mixture was stirred at room temperature for 2 hours. The precipitate was filtered off with suction and washed with heptane. Yield: 45.94 g (69%). e) (S)-2-(4,4-Pentamethylene-2,5-dioxoimidazolidin-1-yl}-2-(2-methylpropyl)acetic acid 11.4 g (30.8 mmol) of methyl 1-(3-{(S)-1-tert-butoxycarbonyl-3-methylbutyl)ureido)-cyciohexanecarboxyiate were heated at 60°C for 8 hours in 200 ml of 6 N hydrochloric acid, and the mixture was allowed to stand at room temperature overnight and then extracted with diethyl ether. The combined extracts were concentrated in vacuo, and the residue was taken up with a little acetonitrile, treated with water and freeze-dried. Yield: 8.28 g (95%). f) (S)-2-(4,4-Pentamethylene-3-(4-{3-phenylureido)benzyl)-2,5-dioxoimidazolidin- 1 -yl)-2-(2-methyipropyi)acetic acid 21 ml of an n-butyllithium solution (2.5 M in hexane) were added at -76°C under argon to a solution of 7.4 g (26.24 mmol) of (S)-2-(4,4-pentamethylene-2,5-dioxoimidazolidin-1-yl)- 2-(2-methylpropyl)acetic acid in 150 ml of absolute THF, After stirring at -76°C for 30 minutes, the reaction mixture was allowed to warm to 0°C and 5.82 g (26,24 mmol) of 4-(3-phenylureido)benzyl chloride were added in portions. After stirring at 0°C for 30 minutes, the mixture was adjusted to pH 1 by addition of 1 N hydrochloric acid, diluted with water and extracted with ethyl acetate. After separating the phases, the organic phase was dried over sodium sulfate and, after filtration, the solvent was removed in vacuo. The residue thus obtained was purified by means of preparative HPLC. Yield: 2.18 g (16%). g) Ethyl (S)-3-((S)-2-(4,4-pentamethylene-3-(4-(3-phenyluretdo)benzyl)-2,5- dioxoimidazolidin-1-yl)-2-(2-methyipropyl)acetylamino)-3-phenylpropionate 525 mg (1.42 mmol) of TOTU and 230 µl (1.35 mmol) of N,N-diisopropylethylamine were added successively with ice-cooling to a solution of 720 mg (1.42 mmol) of (S)-2-(4,4-pentamethylene-3-(4-(3-phenylureido)benzyi)-2,5-diaxoimidazolidin-1-yl)- 2-(2^methylpropyl)acetic acid and 274 mg (1.42 mmol) of ethyt (S)-3-amino-3-phenytpropionate (prepared from the hydrochloride) in 20 ml of absolute DMF. After 1 hour at room temperature, the solvent was removed in vacuo, the residue was dissolved in ethyl acetate and the ethyl acetate solution was successively washed twice in each case with an aqueous KHSO4/K2SO4 solution, a saturated NaHCOa solution and a saturated sodium chloride solution. After drying the organic phase over sodium sulfate and filtering, the solvent was removed in vacuo and the residue was chromatographed on silica gel using ethyl acetate/heptane (1/1). After concentrating the product fractions, 826 mg (85%) of the title compound were obtained. h) (S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-phenylureido)ben2yl)-2,5- dioxoimida20lidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-phenylpropionic acid 3.61 ml of a 1 M lithium hydroxide solution were added to 820 mg (1.2 mmol) of ethyl (S)-3-((S)-2-(4,4-pentamethylene-3-(4-(3-phenylureido)benzyl)-2,5-dioxoimidazolidin- 1-yl)-2-(2-methylpropyl)acetylamino)-3-phenylpropionate in 30 ml of methanol and the mixture was stirred at room temperature overnight. After fresh addition of 10 ml of methanol and 1.2 ml of 1 M lithium hydroxide solution and stirring overnight, 30 ml of water were added and the methanol was largely removed in vacuo. The residual aqueous phase was adjusted to pH 1 by addition of 1 N hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases were washed with ; ^• water, dried over sodium sulfate and concentrated. 760 mg of the crude product obtained were dissolved in acetonitrile/water and freeze dried. 639 mg of the title compound were obtained. ES(+)-MS: 654.4 (M+H)+. Process for the preparation of the starting compound ethyl (S)-3-amino-3-phenylpropionate hydrochloride i) (R)-2-Amino-2-phenylethanol 20 g (920 mmol) of lithium borohydride were dissolved in 420 ml of absolute THF. 233.5 ml (1.84 mol) of trimethylchlorosilane were added dropwise with stirring and 69.5 g (0.46 moi) of (R)-phenylgiycine were then added in portions in the course of 4 hours. The reaction mixture was stirred overnight at room temperature. 690 ml of methanol were then added, and the mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in 690 ml of 20% strength aqueous potassium hydroxide solution with stirnng. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with water, dhed over magnesium sulfate and concentrated in vacuo. Yield: 41.2 g (65.3%). FAB-MS: 138 (M+H+- j) (R)-2-Benzytoxycarbonylamino-2-phenylethanol 40.5 g (295 mol) of (R)-2-amino-2-phenylethanol were dissolved in 385 ml of absolute DMF. 73.5 g of N-(benzyloxycarbonyloxy)succinimide (295 mmol) were added at O°C with stirring and the mixture was stirred at O°C for 1 hour. The ice bath was removed and the batch was allowed to stand at room temperature for 48 hours. The reaction solution was concentrated in vacuo and the residue was then taken up in 500 ml of ethyl acetate. The organic phase was washed twice with 10% strength aqueous citric acid solution and once with water. It was dried over anhydrous sodium sulfate and concentrated. The crystalline crude product obtained (82.3 g) was dissolved again in ethyl acetate. The organic phase was washed twice with 10% strength aqueous citric acid solution and once with water and concentrated. The residue was then recrystallized from ethyl acetate/petroleum ether. Yield: 74.6 g (93.3%). FAB-MS: 272 (M+H)+ k) (R)-2-Benzyloxycarbonylamino-2-phenylethyl 4-methylphenylsulfonate 53-9 g of (R)-2-benzyloxycarbonylamino-2-phenylethanol (198.7 mmol) were dissolved in a mixture of 500 ml of methylene chloride and 80.3 ml (993.5 mmol) of pyridine, 45.5 g (238.4 mmol) of tosyl chloride in 240 ml of methylene chlonde were added at O°C with stirring and the mixture was stirred at room temperature for 7 hours. A further 11.36 g of tosyl chloride (59.61 mmol) were added. The mixture was stirred at 0°C for 5 hours. The batch was then allowed to stand overnight at room temperature and concentrated in vacuo. The residue was taken up in ethyl acetate. The organic phase was washed three times with 1C% strengtr, aqueous citric acid solution and twice with water, dned over magnesium salfare and • concentrated in vacuo. The residue was triturated with diethyl etner, nitered off with suction, washed with diethyl ether and dried over phosphorus pentoxide. Yield: 60.9 g (72%). The mother liquor was concentrated, taken up in n-hepranetethyl acetate (6/4) and chromatographed on silica gel to give an additional yieid of 3.5 g (4.2%). Total yield: 64.4 g (76.2%). FAB-MS: 426 (M+H)'. I) (S)'-3-Benzyloxycarbonylamino-3-phenylpropionitrile 60.5 g of (R)-2-benzyloxycarbonylamino-2-phenylethyl 4-methyiphenylsulfonate (142.2 mmol) were dissolved in 675 ml of DMF. 13.9 g of potassium cyanide (213.3 mmol). 5.64 g of 18-crown-6 (21.33 mmol) and 520 mg of potassium iodide (3.13 mmol) were added and the mixture was stirred at 50°C for 20 hours The reaction solution was poured into 500 ml of ice water and then stirred at 0°C for 5 hours. The precipitate was filtered off with suction and dissolved in ethyl acetate. The organic phase was washed three times with water, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether, filtered off with suction, washed with diethyl ether and dried over phosphorus pentcxide. Yield: 25.3 g (63.5%). FAB-MS: 281 (M+H)+ m) Ethyl (S)-3-benzyloxycarbonyiamino-3-phenyipropionate 15 g of (S)-3-benzyloxycarbonylamino-3-phenylpropionitrile !;53.51 mmol; were suspended in a mixture of 110 ml of absolute ethanoi and 30 rrd of dicxane. HCl gas was passed in at 10-15°C with stirring and cooling. After a shc.^ t:rTie, a clear solution was formed. Further HCl gas was passed in with cooling until staring material was no longer detectable in the thin-layer chromatogram. Nitrogen was men cassed through the reaction solution for 15 minutes and it was then ccncentratad ;n vacuo. The residue was treated with water until turbidity persisted. The mixture was stirred at room temperature for 30 minutes and the aqueous phase was then extracted three times with ethyl acetate. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was taken up in ethyl acetate/petroleum ether (1/1) and chromatographed on silica gei. Yield: 10.55 9(60%). FAB-MS: 328 (M 4- H)+. n) Ethyl (S)-3-amino-3-phenylpropionate hydrochlonde 10.29 g of ethyl (S)-benzyloxycarbonylamino-3-phenytpropionate (31.44 mmol) were dissolved in 125 ml of ethanol and catalyticaily hydrogenated over palladium/carbon at a pH of 4 in an autoburette with addition of 2 N ethanolic HCI. The catalyst was filtered off with suction through kieselguhr and the filtrate was concentrated. The residue was triturated with diethyl ether, filtered off with suction, washed with diethyl ether and dried over phosphorus pentoxide. Yield: 5.05 g (70%). FAB-MS: 194 (M+H)". (S)-3-((S)-2-(4.4-pentamethylene-3-(4-(3-phenyiureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-{2-methylpropyl)acetylam!no)-3-phenylpropionic acid tromethamine salt were obtained, which according to the 1H-NMR spectrum contained 1.3 mol of . tromethamine per moie of (S)-3-{(S)-2-(4,4-pentamethyle^e-3-(4-(3-phenylu^eido)-be^zyl)-2,5-dioxoimida2olidin-1-y()-2-(2-methyip^opyl)acetylami^o)-3-phenylp^opionic acid. ES(+)-MS: 122.0 (a,a,a-ths(hydroxymethyl)methylamine + H))+ 654.4 (3-(2-(4,4- pentamethylene-3-(4-(3-phenylureido)ben2yl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropy()acetylamino)-3-phenyipropionic acid + H)+; 775.4. Example 3 (R)-3-((S)-2-(4.4-Pentamethylene-3-(4-(3-phenylureido)ben2yl)-2,5-dioxoimidazolidin-1 -yl)-2-(2-methylpropyl)acetylamino)-3-methyipropionic acid 132 mg (0.988 mmol) of HOBT and 245 mg (1,18 mmol) of DCC were added with ice cooling to a solution of 500 mg (0.988 mmol) of (S)-2-(4,4-pentamethyle^e-3-(4-(3-phenylu^eido)be^zyl)-2,5-dioxoimidazo!idi^-1-yl)-2-(2-methylp^opyl)acetic acid in 15 ml of absolute DMF. After stirring with ice cooling for 1 hour, 157 mg (0.988 mmol) of tert-butyl (R)-3-aminobutanoate were added. After stirring at room temperature for 3 hours and allowing to stand overnight, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and in each case washed twice with an aqueous'KHSO4/K2SO4 solution and water. After drying the organic phase over sodium sulfate and filtering, the solvent was removed in vacuo. "The residue was taken up in acetonitrile/water and freeze dried. The residue thus obtained was chromatographed on silica gel using ethyl acetate/heptane (1/3 and 1/1). After concentrating the product fractions, the residue was taken up in acetonitrile/water and freeze dried. For the cleavage of the tert-butyl ester, 10 ml of 95% strength trifluoroacetic acid were added and the mixture was allowed to stand at room temperature for 15 minutes. After removal of the volatile components in vacuo, the residue was taken up in acetonitrile/water and freeze dried. Yield; 463 mg (7S%). ES(+)-MS: 592.4 (M+H)+. Example 4 (R)-3-((S)-2-{4,4-Pentamethylene-3-(4-(3-phenylureido)benzyl)-2,5-dioxoimidazolidin- 1-yl)-2-(2-methylpropyl)acetylamino)-3-(2-methylpropyl)propionic acid 132 mg (0.988 mmol) of HOBT and 245 mg (1.18 mmol) of DCC were added with ice cooling to a solution of 500 mg (0.988 mmol) of (S)-2-(4,4-pentamethylene-3-(4-(3-phenylureido)benzyi)-2,5-dioxoimidazolidin-1 -yl)-2-(2-methy!propyl)acetic acid in 15 ml of absolute DMF. After stirring with ice cooling for 1 hour, 199 mg (0.988 mmol) of tert-butyl (R)-3-amino-5-methylhexanoate were added. After stirring at room temperature for 3 hours and allowing to stand overnight, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and washed twice in each case with an aqueous KHSO4/K2SO4 solution and water. After drying the organic phase over sodium sulfate and filtering, the solvent was removed in vacuo. The residue was chromatographed on silica gel using ethyl acetate/heptane (1/3 and 1/1). After concentrating the product fractions, the residue was taken up in acetonitrile/water and freeze dried. For the cleavage of the tert-butyl ester, 10 ml of 95% strength trifluoroacetic acid were added and the mixture was stirred at room temperature for 30 minutes. After removal of the volatile components in vacuo, the residue was taken up in acetonitnle/water and freeze dried. Yield: 447 mg(71%). ES(+)-MS: 634.4 (M+H)Analogously to Examples 1, 3 and 4, the compounds of Examples 5, 6 and 7 can be prepared starting from l-aminocyciopentane-1-carboxylic acid. Example 5 (S)-3-((S)-2-{4,4-Tetramethylene-3-(4-(3-phenylureido)ben2yl)-2,5-dioxoimida2o!idin-1 'yl)-2-(2-methylpropyl)acetyiamino)-3-phenylpropianic acid Example 7 (R)-3-{(S)-2-{4,4-Tetramethylene-3-(4-(3-phenylureido)ben2yl)-2,5-dioxoimida2olidin- 1-yl)-2-(2-methylpropyl)acetylam!no)-3-(2-methylpropyt)propionic acid a) 4-(3-(2-Methylphenyl)ureido)benzyl alcohol 30.6 g (200 mmol) of 4-nitrobenzyl alcohol were hydrogenated with ice cooling over 1.0 g of palladium/carbon (10% strength; 50% water) in 500 ml of methyl tert-butyl ether. After the absorption of hydrogen was complete, the catalyst was filtered off and 24,8 ml (200 mmol) of 2-methylphenyl isocyanate were added to the filtrate at 15°C with stirring in the course of 30 minutes. The precipitated solid was filtered off with suction and washed with methyl tert-butyl ether. Yield: 46.9 g (92%). b) 4-(3-(2-Methylphenyl)ureido)benzyl chloride 5.66 ml (78.12 mmol) of thionyl chloride were added dropwise with ice cooling to a suspension of 10 g (39.06 mmoi) of 4-(3-(2-methylphenyl)ureido)benzyl alcohol in 150 ml of dichloromethane. The reaction mixture was subsequently stirred at room temperature for 1.5 hours and poured onto 200 ml of n-heptane. The heptane was decanted off from the deposited oil and the oil was stirred with diisopropyl ether. The solid obtained was filtered off and washed with diisopropyl ether. Yield: 8.32 g (78%), c) (S)-2-{4,4-Pentamethylene-3-(4-{3-(2-methyiphenyi)ureido)ben2y()-2,5- dioxoimidazolidin-l -yl)-2-{2-methy!propyl)acetic acid 26.6 ml of an n-butyllithium solution (2.5 M in hexane) were added at 76°C under argon to a solution of 9.5 g (33.6 mmol) of (S)-2-(4,4-pentamethyfene-2,5-dioxoimidazolidin-1-yl)- 2-{2-methylpropyl)acetic add in 190 ml of absolute THF. After stirring at -76°C for 30 minutes, the reaction mixture was allowed to warm to 0°C and a solution of 9 g (33.5 mmol) of 4-(3-(2-methylphenyl)ureido)ben2yl chloride in 95 ml of NMP was added. After stirnng at room temperature for 60 minutes, 38 ml of 2 N hydrochloric acid were added and the THF was removed in vacuo. After addition of dichioromethane, the mixture was adjusted to pH 1 using 1 N hydrochloric acid. The phases were separated and the aqueous phase was extracted with dichioromethane. The combined organic phases were dned over sodium sulfate and, after filtration, concentrated in vacuo. The residue was poured into ice water and the precipitate was filtered off with suction. After chromatography on silica gel using dichioromethane/methanol/acetic acid/water (95/5/0.5/0.5), concentration of the product fractions and subsequent freeze drying, 5.05 g (29%) of the title compound were obtained. d) Ethyl (S)-3-((S)-2-(4,4-pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5- dioxoimidazolidin-1'-yl)-2-(2-methyipropyl)acetylamino)-3-phenylpropionate 566 mg (4.26 mmol) of HOBT and 1.05 g (5.11 mmol) of DCC were added with ice cooling to a solution of 2.22 g (4.26 mmol) of (S)-2-(4,4-pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyi)-2,5-dioxoimidazoltdin-1-yl)-2-(2-methy!propyl)acetic acid in 30 ml of absolute DMF. After stirring at O°C for 1 hour, 823 mg (4.26 mmol) of ethyl 3-amino-3-phenyipropionate (prepared from the hydrochloride) were added. After stirring at room temperature for 4 hours, the reaction mixture was allowed to stand overnight. The urea was filtered off with suction and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and the ethyl acetate solution was successively washed twice in each case with an aqueous KHSO4/K2SO4 solution, a saturated NaHCO3 solution and water. After drying the organic phase over sodium sulfate and filtering, the solvent was removed in vacuo and the residue was chromatographed on silica gel using ethyl acetate/heptane (1/3 and 1/1). After concentrating the product fractions, 1.98 g (67%) of the title compound were obtained. e) (S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyi)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-phenylpropionic acid 8.5 ml of a 1 M lithium hydroxide solution were added to 1.97 g (2.83 mmol) of ethyl (S)-3-((S)-2-(4,4-pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methyipropyl)acetylamino)-3-phenylpropionate in 120 ml of methanol and the mixture was allowed to stand at room temperature for 3 days. The methanol was removed in vacuo, and the residual aqueous phase was adjusted to pH 1 by addition of 1 N hydrochloric acid and extracted twice with ethyl acetate. The organic phase was washed with water and dried over sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was taken up in acetonitrile/water and freeze dried. Yield: 1.69 g (89%). ES(+)-MS: 668.4 {M+H)+ with tert-butyl (R)-3'aminobutanoate analogously to Example 3. Example 10 (R)-3-{(S)-2-(4,4-Pentamethylene-3-{4-(3-(2-methylphenyl)ureido)ben2yl)-2,5-diOxoimida2aiidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(2-methytpropyt)propionic acid The compound can be prepared by coupling of (S)-2-(4,4-pentamethyle^e-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylp^opyl)acetic acid with tert-butyl (R)-3-amino-5-methylhexanoate analogously to Example 4, Analogously to Examples 8, 9 and 10, the compounds of Examples 11, 12 and 13 can be prepared starting from 1-aminocydopentane-1-carboxylic acid. Example 11 (S)-3-((S)-2-(4,4-Tetramethylene-3"(4-(3-(2-methyiphenyl)ureido)ben2yi)-2,5-dioxoimida20(idin-1-yi)-2-(2-methylpropyl)acetylamino)-3-phenytpropionic acid Example 12 (R)-3-((S)-2-(4,4-Tetramethylene-3-(4-(3-(2-methylphenyl)ureido)ben2yl)-2,5-dioxoimidazolid!n-1-yl)-2-(2-methyipropyl)acetylamino)-3-methylpropionic acid Example 13 (R)-3-((S)-2-(4,4-Tetramethylene-3-(4-(3-(2-methylphenyl)ureido)ben2yl)-2,5' dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(2-methylprapyl)propionic acid t Example 14 (R)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-phenylureido)benzyl)-2,5-dioxoimida20lidin- 1-yl)-2-(2-methylpropyl)acetylamino)-3-methylpropionamide The compound was prepared from 1.012 g (2 mmol) of (S)-2-{4,4-pentamethyiene-3-(4-(3-phenylureido)benzyl)-2,5-dioxotmidazolidin-1-yl)-2-(2-methylpropyI)aceticacid and 204 mg (2 mmol) of (R)-3-aminobutanamide as described in Example 1. After chromatographic purification of the coupling product, 392 mg (33%) of the title compound were obtained. ES(+)-MS: 591.4(M+H)+ Example 15 (S)-3-((S)-2-{4,4-Pentamethylene-3-(4-(3-phenyiureido)benzyl)-2,5-dioxoimidazoiidin- 1-yl)-2-{2-methylpropyl)acetylamino)-3-phenylpropionamide 271 mg (2.04 mmol) of HOBT and 290 mg (1.4 mmol) of DCC were added with ice cooling to a solution of 800 mg (1.22 mmol) of (S)-3-((S)-2-(4,4-pentamethylene-3-(4-(3-phenylureido)benzyl)-2,5-dioxoimidazoiidin-1-yl)-2-(2-methylpropyl)acetyiamino)-3-phenylpropionic acid (see Example 1) in 10 ml of DMF. After stirring at room temperature for 1 h, 101 \|jl of a 25% strength aqueous ammonia solution were added and the mixture was allowed to stand overnight at room temperature. After filtration, the filtrate was concentrated in vacuo, the residue was dissolved in dichloromethane and the organic phase was washed twice using an aqueous KHSO4/K2SO4 solution, twice using saturated NaHCO3 solution and twice with water. After drying the organic phase over magnesium sulfate, filtration, removal of the solvent in vacuo and chromatographic puhfication of the residue on silica gel (eluent: ethyl acetate/heptane, 9/1), 543 mg (68%) of the title compound were obtained. ES(+)-MS: 653.4 (M+H)+. Example 16 (S)-3-{(S)-2-(4,4-Pentamethylene-3-(4-(3-phenyiureido)benzyl)-2,5-dioxoimidazoiidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(4-methoxyphenyl)propionic acid The compound was prepared analogously to Example 1 from 2.02 g (3.98 mmol) of (S)-2-(4,4-pentamethylene-3-(4-(3-phenylureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyt)acetic acid and 1 g (3.98 mmol) of tert-butyl (S)-3-aminO-3-(4-methoxyphenyl)propionate (for the preparation of this p-amino acid ester and of the other p-amino acid esters employed in the preparation of the example compounds see S.G. Davies et al., Tetrahedron: Asymmetry 2, 183 (1991) and J. Chem. Soc. Perkin Trans 1, 1129 (1994)). After coupling, chromatographic purification of the coupling product, cleavage of the tert-butyl ester and subsequent chromatographic purification, 1.116 g (41%) of the title compound were obtained. ES(+)-MS: 684.4 (M+H)+, Example 17 (S)-3-((S)-2-{4,4-Pentamethylene-3-(4-(3-phenyiureido)ben2yl)-2,5-dioxoimidazoiidin-1-yl)-2-{2-methylpropyl)acetylamino)-3-(4-methoxyphenyl)propionic acid tromethamine salt The compound was prepared analogously to Example 2. Starting from 550 mg of (S)- 3-((S)-2-(4,4-pentamethylene-3-(4-{3-phenytureido)benzyl)-2,5-dioxoimida2olidin-1- yi)-2-(2-methylpropyl)acetyiamino)-3-(4-methoxphenyl)propionic acid, 632 mg of the corresponding tromethamine salt were obtained (stoichiometry; (S)"3-{(S)"2-{4,4- pentamethylene-3-{4-(3-phenylureido)benzyl)-2,5-dioxoimidazoiidin-1-yl}-2-(2- methylpropyl)acetylamino)-3-(4-methoxyphenyl)propionic acid/tromethamine about 1/1.5). ES(+)-MS: 122.0 (a,a,a-tris(hydroxymethyl)methylamine + H)+, 684.5 (S)-3-((S)-2- (4,4-pentamethylene-3-(4-{3-phenylureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-{2- methylpropyl)acetylamino)-3-(4-methoxyphenyl)propionicacid + H)+, 805.5 (M+H)+. Example 18 (S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-phenyturetdo)ben2yl)-2,5-dioxoimidazolidin-1-yl)-2-{2-methylpropyl)acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid yl)-2-{2-methylpropyl)acetylamino)-3"(2,4-dimethoxyphenyi)propionic acid, 188 mg of the corresponding tromethamine salt were obtained (stoichiometry: (S)-3-((S}-2-(4,4- pentamethytene-3-(4-{3-phenylureido)ben2yl)-2,5-dioxoimidazolidin-1-yl)-2-(2- methylpropyl)acetylamino)-3-{2,4-dimethoxyphenyl)propionic acid/tromethamine about 1/2.1). ES(+)-MS: 122.0 (a,a,a-tris(hydroxymethyl)methylamine + H)+, 714.4 (S)-3-{(S)-2" (4,4-pentamethylene-3-(4-(3-phenylureido)benzyl)-2,5-dioxoimida2olidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-{2,4-dimethoxyphenyl)propionic acid + H)+, 835.5 (M+H)+. Example 20 (S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-phenylureido)ben2yl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid The compound was prepared analogously to Example 1 from 1.5 g (2.96 mmol) of (S)-2-(4,4-pentamethylene-3-{4-(3-phenylureido)benzyl)-2,5-dioxoimJdazolidin-1-yl)-2-(2-methylpropyi)acetic acid and 833 mg (2.96 mmol) of tert-butyl (S)-3-amino-3-(3,4-dimethoxyphenyl)propionate. After coupling, chromatographic purification of the coupling product, cleavage of the tert-butyl ester and trituration with water and then pentane, 1.17 g (55%) of the title compound were obtained. ES(+)"MS: 714.4 (M+H)+. Example 21 yl)-2-{2-rnethylpropyl)acetylarnino)-3--(2,4-dimethoxyphenyl)propionic acid, 188 mg of the corresponding tromethamine salt were obtained (stoichiometry: (S)-3-((S)-2-(4,4- pentamethylene-3-(4-{3-phenylureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2- methylpropyl)acetytamino)-3-{2,4-dimethoxyphenyl)propionic acid/tromethamine about 1/2.1). ES(+)-MS: 122.0 (a,a,a-tris(hydroxymethyl)methylamine + H)+, 714.4 (S)-3-{(S)-2- (4,4-pentamethylene-3-{4-{3-phenylureido)benzyl)-2,5-dioxoimida2olidin-1-yl)-2-{2-methylpropyl)acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid + H)+, 835.5 (M+H)+. Example 20 {S)-3-{(S)-2-{4,4-Pentamethytene-3-(4-(3-phenyiureido)ben2yi)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid The compound was prepared analogously to Example 2. Starting from 200 mg of (S)-3-((S)-2-(4,4-pentamethylene-3-(4-{3-phenylureidQ)benzyl)-2,5-dioxoimida2olidin-1-yl}"2-{2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid, 235 mg of the corresponding tromethamine salt were obtained (stoichiometry: (S)-3-({S)-2-(4,4-pentamethyiene-3-{4-(3-phenylureido)ben2yl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyi)acetylamino)-3-(3,4-dimethoxyphenyl)propiQnic acid/tromethamine about 1/1.4). ES(+)-MS: 122.0 (a,a,a-tns(hydroxymethyl)methylamine + H)+ 714.4 (S)-3-{(S)-2- (4,4-pentamethy!ene-3-{4-{3-phenylureido)benzyl)-2,5-d[oxoimida2olidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid + H)+, 835.4 (M+H). Example 22 (S)-3-{(S)-2-{4,4-Pentamethytene-3-{4-(3-phenylureido)benzyi)-2,5-dioxoimidazQlidin- 1-yl)-2-(2-methylpropyi)acetylamino)-3-(3-methoxyphenyl)propionic acid The compound was prepared analogously to Example 1 from 1.5 g (2.96 mmol) of (S)-2-{4,4-pentamethylene-3-(4-{3-phenylureido)ben2yl)-2,5-dioxoimida2olidin-1-yl)-2-(2-methyipropyl)acetic acid and 1.48 g .(2.96 mmol) of tert-butyl (S)-3-amino-3-(3-methoxyphenyl)propionate. After coupling, chromatographic purification of the coupling product, cleavage of the tert-butyl ester and trituration with water and then pentane, 1.01 g (50%) of the title compound were obtained. ES(+)-MS: 684.4 (M+H)+. Example 23 (S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methylpheny!)ureido)ben2yl)-2,5-dioxoimida20iidin-1-yl)-2-(2-methylpropyl)acetyiamino)-3-phenylpropionic acid tromethamine salt (stoichiometry: (S)-3-((S)-2-(4.4-pentamethyiene-3-(4-{3-(2-methylphenyl)-ureido)benzyt}-2,5 ES(+)-MS: 122.0 (a,a,a-tris(hydroxymethyl)methytamine + H)+ 658.4 ((S)-3-((S)-2-(4,4-pentamethylene-3-(4-{3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimida2olidin-1-yl)+2-(2-methylpropyl)acetylarnino)-3-phenylpropionic acid + H)+ 789.5 (M+H+. Example 24 (R)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyi)-2,5-dioxoimidazolidin-1-y!)-2-{2-methylpropyl)acetylamino)-3-methyipropionic acid tromethamine salt The compound was prepared analogously to Example 1 from 1 g (1.92 mmol) of (S)-2-(4,4-pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimid-azolidin-1-yl)-2-(2-methytpropyl)acetic acid (see Example 8) and 963 mg (3.84 mmol) of tert-butyl (S)-3-amino-3-(3-methoxyphenyi)propionate. After coupling, chromatographic purification of the coupling product, cleavage of the tert-butyi ester and trituration with water and then pentane, 555 mg (40%) of the title compound were obtained. ES(+)-MS: 698.4 (M+H)+ Example 26 (S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5- dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino}-3-(4-methoxyphenyl)propionic acid The compound was prepared analogously to Example 1 from 900 mg (1.73 mmo() of (S)-2-(4,4-pentamethylene-3-{4-(3-(2-methylphenyl)ureido)ben2yI)-2,5-dioxoimid-azolidin-1-yl)-2'(2-methytpropyl)acetic acid (see Example 8) and 434 mg (1.73 mmol) of tert-butyl (S)-3-amino-3-(4-methoxyphenyl)propionate. After coupling, chromatographic purification of the coupling product, cleavage of the tert-butyl ester and trituration with water and pentane, 348 mg (29%) of the title compound were obtained. ES(+)-MS: 698.4 (M+H)+. Example 27 (S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)ben2yl)-2,5-dioxoimida2olidin-1-yi)-2-(2-methylpropyl)acetylamino)-3-(4-methoxyphenyl)propionic acid tromethamine salt 3-{(S)-2-{4,4-pentamethylene-3-(4-(3-{2-methylphenyl)ureido)ben2yl)-2,5- dioxoimida2oiidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(4-methoxyphenyl)propionic acid (see Example 26), 173 mg of the corresponding tromethamine salt were obtained {stoichiometry: (S)-3-((S)-2-{4,4-pentamethylene-3-(4-(3-(2-niethylphenyl)- ureido)ben2y!)-2,5-dioxoimida2olidin-1-yl)-2-(2-rnethylpropyl)acetylamino)-3-{4- methoxyphenyl)propionic acid/tromethamine about 1/1.6). ES(+)-MS: 122.0 (a,a,a-tns(hydroxymethyl)methylamine + H)+ 698.4 ((S)-3-{(S)-2- (4,4-pentamethylene-3-(4-{3-(2-methylphenyl)ureido)benzyl)-2,5-dioxo(mida2olidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(4-methoxyphenyl)propionicacid + H), 819.5 (M+H)+. Example 28 (S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-{2-methyphenyl)ureido)ben2yl)-2,5-dioxoimida2olidin-1-yl)-2-{2-methylpropyl)acetylamJno)-3-(2,4-dimethoxyphenyl)propionic acid The compound was prepared analogously to Example 2. Starting from 160 mg of (S)- 3-((S)-2-(4,4-pentamethylene-3-(4-(3-(2-methy!phenyl)ureido)ben2yl)-2,5-dioxoimid- a2olidin-1-yl)-2-(2-methytpropyl)acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid (see Example 28), 82 mg of the corresponding tromethamine salt were obtained (stoichiometry: (S)-3-{(S)-2-(4,4-pentamethylene-3-{4-(3-(2-methylphenyl)- ureido)ben2yl)-2,5-dioxoimidazoiidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(2,4- dimethoxyphenyi)propionic acid/tromethamine about 1/4.2). ES(+)-MS: 122.0 (a,a,a-tris(hydroxymethyl)methylamine + H)+, 728.5 ((S)-3-{(S)-2- (4,4-pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyI)-2,5-dioxoimida20lidin-1- yl)-2-(2-methylpropyi)acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid + H)+, 849.5 (M+H)+ Example 30 (S)-3-{(S)-2-(4,4-Pentamethylene-3-(4-(3-{2-methylphenyl}ureido)ben2yl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyi)acetylamino)-3-(2,4-dimethoxyphenyl)-propionic acid sodium salt 1 mole equivalent of 1 N sodium hydroxide solution was added to a solution of 292 mg of (S)-3-((S)-2-(4.4-pentamethylene-3-{4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropy[)acetylamino)-3-(2,4-dimethoxyphenyl)-propionic acid (see Example 28) in THF, After stirring for 30 minutes, the THF was removed in vacuo and the solution was diluted with water and freeze dried. After purification on Sephadex using water, 216 mg of the title compound were obtained. ES(+)-MS: 728.3 ((S)-3-((S)-2-(4.4-pentamethylene-3-(4-(3-(2-methylphenyl)-ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyi)acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid + H)+, 750.3 (M+H)+. The compound was prepared analogously to Example 1 from 1 g (1.92 mmol) of {S)-2-(4,4-pentamethylene-3-(4-(3-(2-methylphenyl)ureido)ben2yl)-2,5-diGxoimid-azoiidin-1-yl)-2-(2-methyipropyl)acetic acid (see Example 8) and 540 mg (1.92 mmol) of tert-butyl (S)-3-amino-3-(3,4-dimethoxyphenyl)propionate. After coupling, chromatographic purification of the coupling product, cleavage of the tert-butyl ester, chromatographic purification by means of preparative HPLC, concentration of the product fractions, freeze drying and trituration of the product with water and pentane, 480 mg (34%) of the title compound were obtained. ES(+)-MS: 728,4 (M+H)+. Example 32 (S)-3-((S)-2-(4.4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2.5-dioxoimidazolidin-1-yl)-2-(2-methylprapyl)acetytamino)-3-(3,4-dimethoxyphenyl)-propionic acid tromethamine salt ES(+)-MS: 122.0 (a,a,a-tns(hydroxymethyi)methytamine + H); 728.5 ((S)-3-((S)-2-(4,4-pentamethylene-3-(4-(3-(2-methytphenyi)ureido)ben2yi)-2,5-dioxoimidazolidin--1-y!)--2-(2-methylpropyl)acetylarnino)-3-(3,4-dimethoxyphenyi)propionic acid + H)"", 849.6 (M+H)+. Example 33 (S)-3-((S)-2-(4,4-Pentamethylene-3-{4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimida2olidin-1-yl)-2-(2-methylpropyi)acetylarnino)-3'{3,4-dimethoxyphenyl)-propionic acid sodium salt 1 mole equivalent of 1 N sodium hydroxide solution was added to a solution of 300 mg of (S)-3-((S)-2-(4,4-pentamethytene-3-(4-(3-{2-methylphenyl)ureido)benzyl)-2,5-dioxoimida2o!idin-1-yl)-2-{2-methylpropyl)acetyiamino)-3-(3,4-dimethoxyphenyl)-propionic add (see Example 31) in THF. After stirring for 30 minutes, the THF was removed in vacuo and the solution was diluted with water and freeze dried. After purification on Sephadex using water, 154 mg of the title compound were obtained. ES(+)-MS: 728.3 ((S)-3-((S)'2-(4,4-pentamethylene-3-{4-{3-(2-methylphenyl)-ureido)benzyl)-2,5-dioxoimida2olidin-1-yl)-2-{2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)proptonic acid + H)". 750.3 (M+H)^ Example 34 (S)-3-((S)-2-(4,4-Pentamethytene-3-(4-{3-(2-methylphenyi)ureido)benzyl)-2,5- dioxoimidazoiidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4- The compound was prepared analogously to Example 1 from 590 mg (1.1 mmol) of ((S)'2-(4,4-pentamethylene-3-(4-(3-(2-methylphenyl)ure(dQ)benzyl-2,5-dioxoimid-a2olidin-1-yl)-2-(2-methylpropyl)acetic acid (see Example 8) and 475 mg (1.7 mmol) of tert-butyl (S)-3-amino-3-(3,4-ethylenedioxyphenyi)propionate. After coupling, chromatographic purification of the coupling product and cleavage of the tert-butyl ester, 650 mg (81%) of the title compound were obtained. ES(+)-MS: 726.2 (M+H)+. 0.95 mole equivalent of 1 N sodium hydroxide solution was added to a suspension of 500 mg (0.83 mmol) of (S)-3-{(S)-2-{4,4-p€^tamethylene-3-{4-{3-{2-methylphe^yi)-u^eido)benzyl)-2,5-dioxoimidazolidin-1-yl}-2-(2-methytp^opyl)acetylami^o)-3-(3,4-ethylenedioxyphenyl)propionic acid (see Example 34) in water. After stirring for 30 minutes, the mixture was filtered and the filtrate was freeze dried. 610 mg (98%) of the title compound were obtained. ES(+)-MS: 726.2 ((S)-3-((S)-2-(4,4-pentamethylene-3-(4-(3-(2-methylphenyl)ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-ethytene-dioxyphenyl)propionic add + H)+, 748.2 (M+H). Example 36 (R)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5- dioxoimidazolidin-1-yl)-2-(2-methyipropyl)acetylamino)-3-methyipropionamide The compound was prepared analogously to Example 15. Starting from 150 mg (0.247 mmol) of (R)-3-((S)-2-(4,4-pentamethyiene-3-(4-(3-(2-methylphenyl)-ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-methylpropionic acid (see Example 9), after chromatographic purification of the crude product on silica gel using ethyi acetate as eluent, concentration of the product fractions, trituration of the residue with water and then pentane and freeze drying, 74 mg (50%) of the title compound were obtained. ES(+)-MS: 605.4 (M+H)+. Example 37 (S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)-3-methoxybenzyl)- a) 4-(3-(2-Methyiphenyl)ure(do)-3-methoxyben2yl alcohol 15 g (81.8 mmol) of 3-methoxy-4-nitroben2yl alcohol were hydrogenated with ice cooling on 1.3 g of palladium/carbon (10% strength; 50% water) in 500 ml of methyl tert-butyl ether. After the absorption of hydrogen was complete, the catalyst was filtered off and 10.14 ml (81.8 mmol) of 2-methy(phenyl isocyanate were added to the filtrate with stirring in the course of 30 minutes. The reaction mixture was allowed to stand overnight, and the precipitated solid was filtered off with suction and washed with methyl tert-butyl ether. 20.5 g (88%) of 4-(3-(2-methyiphenyl)ureido)-3-methoxybenzyl alcohol were obtained. b) 4-(3-(2-Methylphenyl)ureido)-3-methoxybenzyl chloride 7.65 ml (104.8 mmol) of thionyl chloride were added dropwise with ice cooling to a suspension of 15 g (52.4 mmol) of 4-(3-(2-methylphenyl)ureido)-3-methoxyben2yl alcohol in 300 ml of dichloromethane. The reaction mixture was subsequently stirred at room temperature for 3 hours, allowed to stand overnight and then poured onto 1000 ml of n-heptane. The heptane was decanted off from the deposited oil, the residue was again suspended with n-heptane and the heptane was decanted off. This process was repeated a further two times. The residue was then dissolved in dichloromethane and poured into 800 ml of ice-cold diisopropyi ether. It was subsequently stirred with ice cooling for 2 hours, and the product was filtered off with 6.6 ml of an n-butyllithium solution (2.5 M in hexane) were added at -40'C under argon to a solution of 1.98 g (8,21 mmol) of (S)-2-(4,4-pentamethylene-2,5-dioxoimidazolidin-1-yI)-2-(2-methylpropyl)acetic acid in 40 ml of absolute THF, After stirring at -40°C for 30 minutes, the reaction mixture was allowed to warm to O°C and a solution of 2.5 g (8.21 mmol) of 4-(3-(2-methylphenyl)ureido)-3-methoxybenzyl chloride in 10 ml of NMP was added. The reaction mixture was allowed to warm to 0°C and was subsequently stirred at 0°C for 2 hours. 15 ml of 1 N hydrochlohc acid were added and the THF was removed in vacuo. The residue was poured onto 300 ml of methyl tert-butyl ether. The phases were separated, and the organic phase was washed with water, dried oyer sodium sulfate and, after filtration, concentrated in vacuo. The residue was purified by preparative HPLC. After concentration of the product fractions and subsequent freeze drying, 716 mg (17%) of the title compound were obtained. d) (S)-3-((S)-2-(4,4-Pentamethytene-3-(4-(3-(2-methytphenyl)ureido)-3-methoxybenzy()-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetyiamino)-3-(3,4~ dimethQxyphenyl)propionic acid The compound was prepared analogously to Example 1 from 300 mg (0.55 mmol) of (S)-2-(4,4-pentamethylene-3-(4-(3-(2-methylphenyi)ureido)-3-methoxybenzyl)-2,5- dioxoimida20lidin-1-yl)-2-(2-methylpropyl)acetic acid and 154 mg (0.55 mmol) of tert-butyi (S)-3-amino-3-(3,4-dimethoxyphenyl)propionate. After coupling, chromatographic purification of the coupling product, cleavage of the tert-butyl ester, chromatographic purification by means of preparative HPLC, concentration of the product fractions and freeze drying, 205 mg (49%) of the title compound were obtained. ES(+)-MS; 758.3 (M+H)+. Example 38 (S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)-3-methoxybenzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)-propionic acid tromethamine salt The compound was prepared analogously to Example 2, Starting from 100 mg of (S)-3-((S)-2-(4,4-pentam€thylene-3-(4-(3-(2-methylphenyl)ureido)-3-methoxyben2yl)-2,5-dioxoimida2olidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)-propionic acid (see Example 37), 123 mg of the corresponding tromethamine salt were obtained (stoichiometry: (S)-3-((S)-2-(4.4-pentamethylene-3-(4-(3-(2-methyl-phenyl)ureido)-3-methoxybenzy()-2,5-dioxoimtda2olidin-1-yl)-2-(2-methylpropyl)-acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid/tromethamine about 1/1.3). ES(+)-MS: 122.0 (a,a,a-tris(hydroxymethyl)methylamine + H), 758,3 ((S)-3-((S)-2-(4,4-pentamethyiene-3-(4-(3-(2-methylphenyl)ureido)-3-methoxybenzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamtno)-3-(3,4-dimethoxyphenyl)- The compound was prepared analogously to Example 1 from 257 mg (0.496 mmol) of (S)-2-(4,4-pe^tamethylene-3-(4-(3-(2-methylphenyl)u^eido)benzyl)-2,5-dioxoimid-azolidin•-1-yl)-2-cyciop^opylmethylacetic acid and 140 mg (0.496 mmol) of tert-butyi (S)-3-amino-3-(3,4-dimethoxyphenyl)propionate. After coupling, chromatographic purification of the coupling product, cleavage of the tert-butyl ester and freeze drying, 296 mg (82%) of the title compound were obtained. ES(+)-MS: 726.3 (M+H)+ The (S)-2-(4,4-pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimtdazolidin-1-yl)-2-cyciopropylmethyiacetic acid was prepared analogously to Example 37 from (S)-2-(4,4-pentamethyiene-2,5-dioxoimidazolidin-1-yl)-2-cyclopropylmethylaceiic acid and 4-(3-(2-methylphenyl)ureido)benzyl chloride (see Example 8). The (S)'-2-(4,4-pentamethylene-2,5-dioxoimidazoiidin-1-yl)-2-cyclopropylmethylacetic acid was prepared from (S)-2-amino-3-cyclopropy(propionic acid by the following process. 1 N sodium hydroxide solution was added to a suspension of 10 g (77.5 mmol) of (S)-2-amino-3-cyciopropylpropionic acid in 160 ml of dioxane at O^^C until a pH of 8 to 9 was reached. 16.9 g (77.5 mmol) of di-tert-butyl dicarbonate were then added, the ice bath was removed and the pH was kept at 8 to 9 by further addition of 1 N sodium hydroxide solution. After allowing to stand overnight, the dioxane was removed in vacuo, ethyl acetate was added to the aqueous phase and the phases were separated. The aqueous phase was adjusted to a pH of 4.5 using 1 N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase thus obtained was dried over sodium sulfate, the drying agent was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in 1000 ml of dichloromethane and treated with 53.4 ml of benzyl alcohol, 8.37 g of 4-dimethylaminopyridine and 18.8 g of DCC. After stirring for 6 hours and standing overnight, the mixture was filtered, the filtrate was concentrated and the residue was treated with 300 ml of 90% strength trifluoroacetic acid. After stirring at room temperature for 10 minutes, the trifiuoroacetic acid was removed in vacuo and the residue was chromatographed twice on silica gel (eluent: dichloromethane/methanot, 95/5). 11.48 g (68%) of benzyl (S)-2-amino-3-cyclopropylpropionate were obtained. A suspension of 39.9 g (279 mmoi) of 1-aminocyclohexane-1-carboxylic acid in a mixture of 75 ml of THF and 75 ml of water was treated dropwise with 23.8 ml of methyl chloroformate, dissolved in 40 ml of THF, such that the temperature of the suspension did not rise above 50°C. In the course of this, the pH of the solution was kept between 8.5 and 9.5 by addition of 25% strength sodium hydroxide solution. After stirring at pH 8 for 30 minutes, the mixture was diluted with water, the THF was removed in vacuo and the aqueous phase was washed twice with methyl tert-butyl ether. The aqueous phase was adjusted to pH 2 using 6 N hydrochloric acid and extracted successively with methyl tert-butyl ether and dichioromethane. The combined organic phases were concentrated in vacuo. The residue was triturated with diethyl ether and the product was filtered off. 47.85 g (85%) of 1-methoxy-carbonylaminocyclohexane-1-carboxylic acid were obtained. 216 mg of HOBT and 3.2 g (16 mmol) of DCC were added to a solution of 3.2 g (16 mmol) of 1-methoxycarbonylaminocyciohexane-i-carboxyiic acid and 3.5 g (16 mmol) of benzyl (S)-2-amino-3-cyclopropylpropionate in 40 ml of THF and the mixture was stirred at room temperature for 1 hour. After allowing to stand overnight and filtering, the THF was removed in vacuo, the residue was taken up in methyl tert-butyl ether and the solution was washed twice in each case with saturated NaHCOa solution and with KHSO4/K2SO4 solution. The organic phase was dried over sodium sulfate and, after filtration, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and hydrogenated in the presence of palladium/carbon (10% strength; 50% water). The catalyst was filtered off and the organic phase was treated with 500 ml of water and 4.5 g of NaHCO3. After extraction by shaking and phase separation, the aqueous phase was stirred at 100°C for 2 hours. 3.39 g of Na2C03 were added and the solution was stirred at 100°C for 8 hours. After allowing to stand overnight, 500 ml of 6 N hydrochloric acid were added and the aqueous phase was extracted with methyl tert-butyl ether. The phases were separated and the organic phase was washed with water, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue was triturated with heptane and the product was filtered off. 3.7 g (83%) of (S)-2-(4,4-pentamethylene-2,5-dioxoimida2olidin-1-yl)-2-cyclopropylmethylacetic acid were obtained. Example 40 (S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyl)"2,5-dioxoimidazolidin-1-yl)-2-cydopropylmethylacetylamino)-3-(2,4-dimethoxyphenyl)-propionic acid The compound was prepared analogously to Example 1 from 522 mg (1 mmol) of (S)-2-{4,4-pentamethylene-3-(4-(3-{2-methylphenyl)ureido)benzyl)-2,5-dioxoimid-azoiidin-1-yl)-2-cyc!opropylmethylacetic acid (preparation see Example 39) and 284 mg (1 mmol) of tert-butyl (S)-3-amino-3-(2,4-dimethoxyphenyi)propionate, After coupling, chromatographic purification of the coupling product, cleavage of the tert-butyl ester using 90% strength trifluoroacetic acid, removal of the trifluoroacetic acid in vacuo, taking-up of the residue in dichloromethane, washing the dichloromethane phase three times with water, removal of the dichloromethane in vacuo and subsequent freeze drying, 590 mg (81%) of the title compound were obtained. ES(+)-MS: 725.3 (M+H) 7.07 ml of 0.1 N sodium hydroxide solution were added in portions with stirring to a suspension of 540 mg (0.74 mmol) of (S)-3-((S)-2-{4,4-pentamethylene-3-(4-(3-(2-. methylphenyi)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-cyclopropylmethytacetyl-amino)-3-(2,4-dimethoxyphenyl)propionic acid in 20 ml of water and the mixture was stirred at room temperature for 1 hour. After filtration and freeze drying of the filtrate, 524 mg (95%) of the title compound were obtained. ES(+)-MS; 726.3 ((S)-3-((S)-2-(4,4-pentamethylene-3-(4-(3-(2-methyiphenyl)ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-cyclopropylmethylacetylamino)-3-(2,4-dimethoxyphenyl)propionic acid + H)", 748.3 (M+H)*. Investigation of the biological activity A) U937A/CAM-1 cell adhesion test The test method used for the activity of the compounds of the formula I on the interaction between VCAM-1 and VLA-4 is the assay described below, which is specific for this interaction. The cellular binding components, that is the VLA-4 integrins, are supplied in their natural form as surface molecules on human U937 cells (ATCC CRL 1593), which belong to the leukocytes group. The specific binding components used are genetically engineered recombinant soluble fusion proteins, consisting of the extracytoplasmic domain of human VCAM-1 and the constant region of a human immunoglobulin of the subclass IgGI. Assay for the measurement of the adhesion of U937 cells (ATCC CRL 1593) to hVCAM-1(1-3)-lgG 1, Preparation of human VCAM-1 (1-3)-lgG and human CD4-lgG A genetic construct for the expression of the extracellular domain of human VCAM-1, combined with the genetic sequence of the heavy chain of human immunoglobulin IgGI (hinge, CH2 and CH3 regions) (from Brian Seed, Massachusetts General Hospital, Boston. USA; cf. Damle and Aruffo, Proc. Natl. Acad. Sci. USA 1991, 88, 5403), was employed. The soluble fusion protein hVCAM-1(1-3)-!gG contained the three aminoterminal extracellular immunoglobulin-like domains of human VCAM-1 . (DamIe and Aruffo, Proc. Natl. Acad. Sci. USA 1991, 88, 6403). CD4-lgG (ZettlmeissI et al., DNA and Cell Biology 1990, 9, 347) served as a fusion protein for negative controls. The recombinant proteins were expressed as soluble proteins after DEAE/dextran-mediated DNA transfection in COS cells (ATCC CRL1651) according to standard procedures (Ausubel et a!., Current protocols in molecular biology, John Wiley & Sons. Inc.. 1994). 2. Assay for the measurement of the adhesion of U937 cells to hVCAM-1(1-3)-lgG 2.1 96-well microtiter test plates (Nunc Maxisorb) were incubated at room temperature for 1 hour with 100 µl/well of a goat-anti-human IgG antibody solution (10 µg/ml in 50 mM tris, pH 9.5). After removal of the antibody solution, washing was carried out once with PBS. 2.2 150 µl/well of a blocking buffer (1 % BSA in PBS) were incubated on the plates at room temperature for 0.5 hour. After removal of the blocking buffer, washing was carried out once with PBS. 2.3 100 µl per well of a cell culture supernatant of transfected COS cells were incubated on the plates at room temperature for 1.5 hours. The COS cells were transfected with a plasmid which codes for the three N-termina! immunoglobuiin-like domains of VCAM-1, coupled to the Fc portion of human IgG1 (hVCAM-1(1-3)-lgG)-The content of hVCAM-1(1-3)-lgG was about 0.5 -1 µg/ml. After removing the culture supernatant, washing was carried out once with PBS. 2.4 The plates were incubated at room temperature for 20 minutes with 100 µl/weil of Fc receptor blocking buffer (1 mg/ml of y-globulin, 100 mM NaCl, 100 µM MgCl2, 100 MM MnCl2. 100 µM CaCl2, 1 mg/ml of BSA in 50 mM HEPES, pH 7.5). After removal of the Fc receptor blocking buffer, washing was carried out once with PBS, 2.5 20 ^Jl of binding buffer (100 mM NaCI, 100 [JM MgCb, 100 (JM MnCb, 100 pM CaCb. 1 mg/ml of BSA in 50 mM HEPES, pH 7.5) were initially introduced, and the substances to be tested were added in 10 pi of binding buffer and incubated for 20 minutes. The controls used were antibodies against VCAM-1 (BBT, No. BBA6) and against VLA-4 (Immunotech, No. 0764). 2.6 U937 cells were incubated in Fc receptor blocking buffer for 20 minutes and then pipetted in at a concentration of 1 x 108/ml and in an amount of 100 µl per well (final volume 125 µ/well). 2.7 The plates were slowly immersed at an angle of 45° in stop buffer (100 mM NaC!, 100 \|JM MgCl2, 100 pM MnCb. 100 \|JM CaCis in 25 mM Ths, pH 7.5) and shaken off. The process was repeated. 2.8 50 µl/we!I of a dye solution (16.7 µg/mi of Hoechst Dye 33258, 4% formaldehyde, 0.5% Thton X-100 in PBS) were then incubated on the plates for 15 minutes. 2.9 The plates were shaken off and slowly immersed at an angle of 45° in stop buffer (100 mM NaCI, lOOµM MgCl2. 100µM MnCl2, 100 pM CaCl2 in 25 mM Ths, pH 7.5). The process was repeated. Then, with the liquid (stop buffer) present, the plates were measured in a cytofiuorimeter (Millipore) (sensitivity: 5, filter: excitation wavelength: 360 nm, emission wavelength: 460 nm) with the liquid present (stop buffer). The intensity of the light emitted from the stained U937 ceils is a measure of the number of U937 cells adhered to the hVCAM-1(1-3)-lgG and remaining on the plate and thus a measure of the ability of the added test substance to inhibit this adhesion. From the inhibition of the adhesion at vanous concentrations of the test substance, the concentration IC50 was calculated which leads to an inhibition of adhesion by 50%. • 3. Results The following test results were obtained in the U937A/CAM-1 cell adhesion test (iCso values in nM (nanom l/liter). Compound of IC50 (nM) Example No. 1 3.2 2 4.5 3 17 4 85.4 8 3.2 9 2.2 16 4 17 1.9 18 2.4 19 3 20 1.6 21 3 22 6.7 23 5.5 24 1.7 25 1.1 26 2.6 27 3.4 28 2.1 29 1.9 30 3.6 Compound of IC50 (nM) Example No. 31 0.8 32 0.6 33 1.3 34 1.8 35 3.4 37 1.3 38 1.6 39 0.8 40 2.1 41 2.3 The pharmacological properties of the compounds of the formula I can also be investigated in the following models. B) Leukocyte adhesion in rats In this model of leukocyte adhesion, the effect on the adhesion of leukocytes by the compounds of the fomiula ! in venules of rats is investigated. The leukocyte adhesion to the endothelium of postcapillary venules is regarded as an important step in inflammatory reactions (J. M, Harlan, Blood 1985, 65, 513). In the recruitment of leukocytes from the blood into inflamed areas, a well-coordinated dynamic sequence of events takes place in which chemotactic cytokines and cellular adhesion molecules play an active part. It has been found that VCAM-1A/LA-4 interactions play a crucial role in the adhesion and emigration of leukocytes and the increased permeability of vessels for macromolecules which are induced by various mediator substances and cyctokines (D. Seiffge, Int. J. Microcirc. 1995, 15, 301). In the present model, a generalized inflammation or rheumatoid arthritis which leads to adhesion of the leukocytes and their emigration into diseased areas of the organ, is caused by local or systemic injection of endotoxins, for example zymosan, bacterial toxins such as lipopolysaccharides (LPS) of Freund's adjuvant. The increased adhesion to the endothelium of the venules produced by the endotoxin is determined. For the determination of the leukocyte adhesion, a camera inverted microscope (Zeiss) which is equipped with a video system is used. Male Sprague-Dawley rats (body weight about 250 g) are injected with zymosan or bacterial endotoxin under a slight halothane premedication. The control animals receive an identical volume of 0.9% strength saline solution. The test substance is then administered to the animals subcutaneously or orally as an individual dose or as a multiple dose. For carrying out the measurement, the rats are anesthetized by an intramuscular injection of 1.25 g/kg of urethane. They are allowed to breathe spontaneously through a tracheal tube. The body temperature is kept at 37°C by means of a regulated heating pad. The mesentery is carefully exposed by means of a hypogastric incision on a thermostated (37°'C) window of the microscope stage, and is covered with liquid paraffin at 37°C. The ileocecal area of the mesentery is held in position with three blunt needles and modeling clay. After a 30-minute equilibration time, during which the tissue is allowed to stabilize, the leukocyte adhesion is determined in postcapillary venules of 20-30 µm diameter and about 100 µm length by counting in 2-3 segments of the venules over 1 hour at intervals of 10 minutes. A leukocyte is regarded as adherent to the endothelium if it is stationary for more than 30 seconds. After the experiment, the systemic leukocyte count and the fibrinogen content of the blood is determined. The inhibition of leukocyte adhesion by the test substance is indicated by the decrease (in %) of the number of adherent leukocytes in the treated animals in comparison with the number in the control animals. C) Delayed-type hypersensitivity in mice In the model of delayed-type hypersensitivity (DTH mode!), the antiallergic or antiinflammatory action of the compounds of the formula 1 is investigated. DTH is an inflammatory reaction of the skin which is induced by sensitization with antigenic substances. In order to determine the corresponding inflammatory reaction and the leukocyte recruitment in the inflamed areas in vivo, the substances are tested in the following DTH model in mice (see also T. B. Issekutz, J. Immunol. 1991, 147, 4178). Groups of female BALB/c mice (body weight about 20 g) are sensitized -epicutaneously on a shaved part of the skin with 150 µ\ of a 3% strength solution of oxazolone, which has been known to induce a strong inflammatory DTH reaction. 6 days later, the reaction is challenged by administration of 20 \|JI of a 1% strength oxazolone solution on the right ear of the animals. The test substances are administered subcutaneously or orally in each case 44 hours before the challenge of the reaction, 20 hours before the challenge and 4 hours after the challenge. Directly before the challenge of the reaction and 24 hours after the challenge, the altered ear thickness due to the inflammatory swelling of the ear is measured on the right ear using a Mitutoyo Engineering micrometer. The difference between these two measurements is determined for each animal of the group. The mean values of the differences of an animal group treated with the test substance on the one hand and an untreated control group on the other hand are compared. The percentage inhibition of ear swelling is indicated as a measure of the effect of the substance. D) Anti-asthmatic action in guinea pigs The effects on the lung function and the anti-asthmatic action of the compounds of the formula I can be determined in a model guinea pigs which follows the method described by G. Moacevic, Arch. Toxicol. 1975, 34, 1. For this, the technical preparations for the investigation are carried out corresponding to the details described by Moacevic. Male albino guinea pigs having a body weight of 300 - 500 g are employed. The animals are placed in a plethysmograph (FMI) and three starting values of the parameters respiratory rate and respiratory amplitude are recorded. In this model, an asthmatic respiration is charactenzed by the decrease in the respiratory amplitude (= lowehng of the respiratory volume on account of the bronchoconstriction) and the increase in the respiratory frequency (= reflex reaction). \ This condition is known in asthma patients as dyspnoea. 22 days before the start of the study, the albino guinea pigs are sensitized with 1 ml per animal of a 0.1 % strength ovalbumin solution on two successive days. The expenmental asthma attack is induced by inhalation of a 0.3% strength ovalbumin solution for 1 minute. After a recovery phase of 40-60 minutes, the animals inhale the test substance as an aqueous solution. Immediately afterwards, 0.3% strength ovalbumin solution is administered for 1 minute. In the following recovery phase of 30 minutes, the animals breathe normal air. This process is repeated twice. If the asthma attacks become life-threatening, oxygen is administered to the animals. Patent ctaims in which R1 is hydrogen or methyl; R2 is phenyl or (C1-C4)-alkyl; X is -CH2-CH2- or -CH2-CH2-CH2-, where one of the CH2 groups in these two residues can be replaced by a carbonyl group C=0; W is isopropyl or cyciopropyl; V is hydrogen or methoxy; E is -CO-R3 -CO-H. -CH2-O-R4 -CH2-0-C0-R4 -CH2-O-CO-O-R5 or 5-tetrazolyl; R3 is hydroxy, (C1-C10)-alkoxy, phenyl-{C1-C8)-a!koxy-, phenyloxy-, (C1-C8)- alkylcarbonyloxy-{C1-C6)-alkoxy-, phenylcarbonyloxy-{C1-C6)-alkoxy-, phenyi-{C1-C6)- alkytcarbanytoxy-(C1-C6)-alkoxy-, (C1-C8)-alkoxycarbonyioxy-{C1-C6)-alkoxy- phenyloxycarbonyloxy-{C1-C6)-alkoxy-, phenyl-{C1-C6)-alkoxycarbonyloxy-(Ci- C5}-alkoxy-, amino, mono-((C1-C10)-alkyl)-amino-, di-((C1-C10)-alkyi)-amino-or R4R4N-CO-{C1-C5)-alkoxy- in which the residues R4 are independent of one another and can be identical or different; R4 is hydrogen, (C1-C10)-alkyl, phenyl or phenyl-1(C1-C8)-alkyI-; R5 has one of the meanings of R4 with the exception of hydrogen; phenyl is an unsubstituted phenyl residue or a phenyl residue which is substituted by one or more identical or different substituents from the group consisting of (C1-C4)- alkyi, (C1-C4)-alkoxy, methylenedioxy, ethylenedioxy, halogen, trifluoromethyl and trifluoromethoxy; in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically tolerable salts. 2. A compound of the formula I as claimed in claim 1. in which W is isopropyt and V is hydrogen, in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically tolerable salts. 3. A compound of the formula I as claimed in claim 1 and/or claim 2, in which R^ is unsubstituted phenyl, phenyl which is substituted by a methyienedioxy residue or an ethylenedioxy residue, phenyl which is substituted by one or two (Ci-C4)-aikoxy groups, or (Ci-C4)-alkyl, in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically tolerable salts. 4. A compound of the formula I as claimed in one or more of claims 1 to 3, in which E is -CO-R3 or -CH2-OH and R3 is hydroxy, (C1-C6)-alkoxy or amino, in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically tolerable salts, 5. A compound of the formula I as claimed in one or more of claims 1 to 4, in which R1 is hydrogen or methyl; R2 is unsubstituted phenyl, phenyl which is substituted by a methyienedioxy residue or an ethylenedioxy residue, phenyl which is substituted by one or two methoxy groups, or (C1-C4)-alkyi; X is -CH2-CH2- or -CH2-CHrCH2-, where one of the CH2 groups in these two residues can be replaced by a carbonyl group C=0; W is isopropyl or cyclopropyl; V is hydrogen or methoxy; E is -CO-OH, -C0-0-(C1-C4)-alkyl. -CO-NH2 or -CH2-OH; in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically tolerable salts. 6. A compound of the formula I as claimed in one or more of claims 1 to 5, which is 3-(2-{4,4-pentamethylene-3-(4-(3-phenylureido)ben2yl)-2,5-dioxoimida2olidin-1-yl)-2- (2-methylpropyl)acetylamino)-3-phenylpropionic acid, 3-(2-(4,4-pentamethyiene-3-{4-(3-phenylureido)benzyl)-2,5-dioxoimidazolidin-1-yi)-2-(2-methylpropyl)acetylamino)-3-methylpropionic acid, 3-(2-(4,4-pentamethylene-3-(4-{3-phenytureido)benzyl)-2,5-dioxoimidazo(idin-1-y()-2- (2-methylpropyl)acetyiamino)-3-{2-methylpropyl)propionic acid, 3-(2-(4,4-pentamethylene-3-(4-{3-(2-methylphenyl)ureido)benzyl)-2,5-dicxoimid- azolidin-1-yl)-2-(2-methyipropyl)acetylamino)-3-phenylpropionic acid, 3-(2-(4,4-pentamethylene-3-{4-(3-(2-methylphenyl)ureido)ben2yl)-2,5-dioxoimid- azolidin-1-y!)-2-(2-methylpropyl)acetylarn(no)-3-rnethyipropionic acid, 3-(2-{4,4-pentamethylene-3-{4-{3-{2-methylphenyl)ureido)benzyl)-2,5-dioxoimid- azolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(2-rnethylpropyi)propionic acid, 3-(2-(4,4-Pentamethylene-3-(4-(3-phenylureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2- (2-methy!propyl)acetyiamino)-3-methylpropionamide, 3-(2-(4,4-Pentamethytene-3-(4-{3-phenylureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2- (2-methylpropyl)acetylamino)'-3-phenylpropionannide, 3-{2-(4,4-Pentamethylene-3-(4-{3-phenylureido)benzyl)-2,5-dioxoimidazol(din-1-yl)-2- (2-methylpropyl)acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid, 3-(2-{4,4-Pentamethylene-3-(4-(3-phenylureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2- (2-methylpropyl)acetylamino)-3-{3,4-dimethoxyphenyl)propionic acid, 3-(2-(4,4-Pentamethylene-3-{4-{3-(2-methyphenyl)ureido)benzyl)-2,5-dJoxoimid- azolidin-1-yl)«2-(2-methyiprGpyl)acetylamino)-3-{2,4-dimethoxyphenyl)propionicacid, 3-(2-{4,4-Pentamethylene-3-{4-(3-{2-methylphenyl)ureido)benzyl)-2,5-dioxoJmid- azolidin-1-yl)-2-(2-methytpropyl)acetyiamino)-3-(3,4-dimethoxyphenyl)propionicacid, 3-{2-{4,4-Pentamethylene-3-(4-{3-{2-methylpheny()ureido)benzy!)-2,5-dioxoimid- azoiidin-1-yi)-2-(2-methylpropyl)acetylarnino)-3-methylpropionamide, 3-(2-{4,4-Pentamethylene-3-(4-{3-(2-methylphenyl)ureido)-3-methoxybenzyl)-2,5- dioxoimidazolidin-1-yi)-2-{2-methylpropy!)acetylamino)-3-(3,4-dirnethoxyphenyl)- propionic acid, 3-(2-(4,4-Pentamethylene-3-{4-{3-(2-methylphenyl)ureido)benzyi)-2,5-dioxoirriid- azolidin-1-yl)-2-cyclopropylmethylacetylamino)-3-(3,4-dimethoxyphenyi)propionic acid, or 3-(2-{4,4-Pentamethylene-3-(4-(3-(2-methylphenyi)ureido)benzyl)-2,5-dioxoimid- azolidin-1-yi)-2-cyciopropylmethylacetyiamino)-3-{2,4-dimethoxypheny'l)prapionic acid, in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically ■tolerable salts.- 7. A compound of the formula t as claimed in one or more of claims 1 to 6, which is (S)-3-((S)-2-(4,4-pentamethylene-3-{4-{3-phenyiureido)benzyl)-2,5-dioxoimidazolidin' 1 -yl)-2-'(2-methyipropyl)acetylamino)-3-pheny)propionic acid, (R)-3-((S)-2-(4,4-pentamethylene-3-(4-{3-phenylureido)ben2yl)-2,5-dioxoimida2olidin- 1 -yl)-2-(2-methylpropyl)acetylamino)-3-methytpropiGnic acid, (R)-3-((S)-2-(4,4-pentamethylene-3-(4-(3-phenylureido)ben2yl)-2,5-dioxoimida2oiidin' 1-yl)-2-{2-methy!propyl)acetylamino)-3-(2-methylpropyl)propionic acid, (S)-3-((S)-2-{4,4'pentamethyiene-3-{4-(3-{2-methylphenyl)ureido)ben2yl)-2,5- dioxoimida2olidin-1-yl)-2-(2-methy[prQpyl)acetylamino)-3-phenylpropionic acid, (R)-3-((S)-2-(4,4-pentamethylene-3-(4-(3-(2-methylphenyl)ureido)ben2yl)-2,5- dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino}-3-methylpropionic acid, (R)-3-((S)-2-(4,4-pentamethylene-3-(4-(3-(2-methyipheny!)ureido)benzy!)-2,5- dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylaminG)-3-(2-methylpropyl)propionic acid, (R)-3-((S)-2-(4,4-Pentamethyiene-3-(4-(3-phenyiureido)ben2y!)-2,5-dioxoimidazolidin- 1-yl)-2-(2-methy)propyl)acetylamino)-3-methylpropionamide, (S)-3-{{S)-2-(4,4-Pentamethyiene-3-{4-(3-phenylureido)benzyl)-2,5-dioxoimidazoiidin- 1-yt)-2-(2-methytpropyi)acetylamino)-3-pheny!propionamide, (S)-3-((S)-2-(4,4-Pentamethyiene-3-(4-(3-phenylureido)benzyi)-2,5-dioxoimidazolidin- 1-yl)-2-(2-methylpropyl)acetylamino)-3-{2,4-dimethoxyphenyl)propionic acid, (S)-3-{(S)-2-(4,4-Pentamethylene-3-(4-(3-phenylureido)benzyi)-2,5-dioxoimidazo(idin- 1-yl)-2-(2-methylpropyl)acetyiamino)-3-(3,4-dimethoxyphenyi)propionic acid, (S)-3-((S)-2-(4,4-Pentamethyiene-3-{4-(3~(2-methyphenyl)ureido)ben2yl)-2,5- dioxoimidazolidin-1-y()-2-(2-methy!propyi)ac6tyiamino)-3-(2,4- dimethoxyphenyl)propionic acid, (S)'3-{(S)-2-(4,4-Pentamethy(ene-3-(4-(3-{2-methyiphenyl)ureido)benzyi)-2,5- dioxotmidazolidin-1-yi)-2-(2-methylpropyl)acetyiamino)-3-(3,4- dimethoxyphenyl)propionic acid, (R)-3-((S)-2-(4,4-Pentamethyiene-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methytpropyl)acetylamino)-3-methylprQpionamide, • (S)-3-((S)-2-{4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ijreido)-3-methoxybenzyl)-2,5-dioxoimidazoitdin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)-propionic acid, (S)-3-((S)-2-(4,4-Pentamethylene-3-(4-{3-(2-methy!phenyl)ureido)ben2yl)-2,5-dioxoimida2olidin-1-yl)-2-cydopropylmethyl-acetylamino)-3-{3,4-dimethoxyphenyl)-propionic acid, or (S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)ben2yl)--2,5-dioxoimida2olidin-1-yl)-2-cyclopropylmethyl-acetylamino)-3-(2,4-dirnethoxyphenyl)-propionic acid, and its physiologically tolerable salts. 8. A compound of the formula 1 as claimed in one or more of claims 1 to 7, which is (S)-3-{(S)-2-{4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)ben2yl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-phenylpropionic acid tromethamine salt, (R)-3-((S)-2-(4,4-Pentamethylene-3-{4-(3-{2-methylphenyi)ureido)ben2yl)-2,5-dioxoimida2olidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-methylpropionic acid tromethamine salt, (S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-{2-methylpheny!)ureido)ben2yl-2,5-dioxoimida20lidin-1-yl)-2-(2-methylpropyl)acetyiamino)-3-(2,4-dimethoxyphenyl)- propionic acid tromethamine salt, (S)-3-{{S)-2-(4,4-Pentamethylene-3-(4-{3-{2-methylphenyi)ureido)benzyl)-2,5- dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(2,4-dimethoxyphenyl)- propionic acid sodium salt, (S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5- dioxoimidazoiidin-1-yl)-2-{2-methyipropyl)acetyiamino)-3-(3,4-dimethoxyphenyl)- propionic acid tromethamine salt, (S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methy(phenyt)ureido)benzyl)-2,5- dioxoimida2olidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)- propionic acid sodium salt, (S)-3-((S)-2-{4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)-3-methoxy 2,5-dioxoimida2oiidin-1-yl)-2-(2-methylpropyi)acetytamino)-3-(3,4-dimethoxyphenyl)-■ propionic acid tromethamine salt, or (S)-3-((S)-2-(4,4-Pentamethyiene-3-(4-(3-(2-methylphenyl)ureido)ben2yl)-2,5-dioxoimidazolidin-1-yl)-2-cyclopropylmethylacetylamino)-3-(2,4-dimethoxyphenyl)-propionic acid sodium salt. 9. A process for the preparation of a compound of the formula I as claimed in one or more of claims 1 to 8, which comprises carrying out a condensation of a compound of the formula II with a compound of the formula ill 12. A compound of the formula I as claimed in one or more of claims 1 to 8 and/or its physioiogicaiiy tolerable salts and/or its prodrugs for use as an antiinflammatory. 13. A compound of the formula I as claimed in one or more of claims 1 to 8 and/or its physiologically tolerable salts and/or its prodrugs for use in the therapy or prophylaxis of arthritis, of rheumatoid arthritis, of polyarthritis, of inflammatory bowel disease, of systemic lupus erythematosus, of multiple sclerosis or of inflammatory disorders of the central nervous system. 14. A compound of the formula I as claimed in one or more of claims 1 to 8 and/or its physiologically salts and/or its prodrugs for use in the therapy or prophylaxis of asthma or allergies. 15. A compound of the formula I as claimed in one or more of claims 1 to 8 and/or its physiologically tolerable salts and/or its prodrugs for use in the therapy or prophylaxis of cardiovascular disorders, of arteriosclerosis, of restenoses, of diabetes, of damage to organ transplants, of immune disorders, of autoimmune disorders, of tumor growth or tumor metastasis or of malaria. 16. A compound of the formula I as claimed in one or more of claims 1 to 8 and/or its physiologically tolerable salts and/or its prodrugs for use as an inhibitor of the adhesion and/or migration of leukocytes or for the inhibition of the VLA-4 receptor. 17. A compound substantially as herein described and exemplified. 18. A pharmaceutical preparation substantially as herein described and exemplified.

Full Text

Spiroimidazolidine derivatives, their preparation, their use and pharmaceutical preparations comprising them

in which E, V, W, X, R1 and R2 have the meanings indicated below/. The compounds of the formula I are valuable pharmaceutical active compounds, which are suitable, for example, for the therapy and prophylaxis of inflammatory disorders, for example of rheumatoid arthritis, or of allergic disorders. The compounds of the formula I are inhibitors of the adhesion and migration of leukocytes and/or antagonists of the adhesion receptor VLA-4 belonging to the integrins group. They are generally suitable for the therapy and prophylaxis of illnesses which are caused by an undesired extent of leukocyte adhesion and/or leukocyte migration or are associated therewith or in which cell-cell or cell-matrix interactions which are based on interactions of VLA-4 receptors with their ligands play a part. The invention furthermore relates to processes for the preparation of the compounds of the formula 1, their use and pharmaceutical preparations which contain compounds of the formula 1.
The integrins are a group of adhesion receptors which play an important part in cell-cell-binding and cell-extracellular matrix-binding processes. They have an aβ-heterodimeric structure and exhibit a wide cellular distribution and a high extent of evolutive conservation. The integrins include, for example, the fibrinogen receptor on platelets, which interacts especially with the RGD sequence of fibrinogen, or the vitronectin receptor on osteoclasts, which interacts especially with the RGD

sequence of vitronectin or of osteopontin. The integrins are divided into three major groups, the p2 subfamily with the representatives LFA-1, Mac-1 and p150/95, which are responsible in particular for cell-cell interactions of the immune system, and the subfamilies β1 and β3, whose representatives mainly mediate cell adhesion to components of the extracellular matrix (Ruoslahti, Annu. Rev. Biochem. 1988, 57, 375). The integrins of the β1 subfamily, also called VLA proteins (very late (activation) antigen), include at least six receptors which interact specifically with fibronectin, collagen and/or laminin as ligands. Within the VLA family, the integrin VLA-4 (a4p1) is atypical, insofar as it is mainly restricted to lymphoid and myeloid cells and is responsible in these for cell-cell interactions with a large number of other cells. For example, \/LA-4 mediates the interaction of T and B lymphocytes with the heparin Il-binding fragment of human plasma fibronectin (FN). The binding of \/LA-4 with the heparin Il-binding fragment of plasma fibronectin is especially based on an interaction with an LDVP sequence. In contrast to the fibrinogen or vitronectin receptor, VLA-4 is not a typical RGD-binding integrin (Kilger and Holzmann, J. Mol. Meth. 1995, 73,347).
The leukocytes circulating in the blood normally exhibit only a low affinity for the vascular endothelial cells which line the blood vessels. Cytokines which are released from inflamed tissue cause the activation of endothelial cells and thus the expression of a large number of cell surface antigens. These include, for example, the adhesion molecules ELAM-1 (endothelial cell adhesion molecule-1; also designated as E-selectin), which, inter alia, binds neutrophils, ICAM-1 (intercellular adhesion molecule-1), which interacts with LFA-1 (leukocyte function-associated antigen 1) on leukocytes, and VCAM-1 (vascular cell adhesion molecule-1), which binds various leukocytes, inter alia lymphocytes (Osborn et al., Cell 1989, 59, 1203). VCAM-1, like lCAM-1, is a member of the immunoglobulin gene superfamily. VCAM-1 (first know as INCAM-110) was identified as an adhesion molecule that is induced on endothelial cells by inflammatory cytokines such as TNF and IL-1 and lipopolysaccharides (LPS). Elices et al. (Cell 1990, 60, 577) showed that VLA-4 and VCAM-1 form a receptor-ligand pair which mediates the adhesion of lymphocytes to

activated endothelium. The binding of VCAM-1 to VLA-4 does not take place here due to an interaction of the \/LA-4 with an RGD sequence; this sequence is not contained in VCAM-1 (Bergelson et al., Cun-ent Biology 1995, 5, 615), VLA-4, .however, also occurs on other leukocytes, and the adhesion of leukocytes other than lymphocytes is also mediated via the VCAM-1 A/LA-4 adhesion mechanism. VLA-4 thus represents an individual example of a µl integrin receptor which, via the ligands VCAM-1 and fibronectin, plays an important part both in cell-cell interactions and in cell-extracelluiar mathx interactions.
The cytokine-induced adhesion molecules play an important part in the recnjitment of leukocytes into extravascular tissue regions. Leukocytes are recruited into inflammatory tissue regions by cell adhesion molecules which are expressed on the surface of endothelial cells and serve as ligands for leukocyte cell surface proteins or protein complexes (receptors) (the terms ligand and receptor can also be used vice versa). Leukocytes from the blood must first adhere to endothelial cells before they can migrate into the synovium. Since VCAM-1 binds to cells which camy the integrin VLA-4 (a4βl), such as eosinophils, T and B lymphocytes, monocytes or neutrophils, it and the VCAM-1 / VL-4 mechanism have the function of recruiting cells of this type from the blood stream into areas of infection and inflammatory foci (Elices et al., Cell 1990, 60, 577; Osborn, Cell 1990, 62, 3; Issekutz et al.. J. Exp. Med. 1996, 183, 2175).
The VCAM-1 A/LA-4 adhesion mechanism has been connected with a number of physiological and pathological processes. Apart from by cytokine-induced endothelium, VCAM-1 is additionally expressed, inter alia, by the following cells; myoblasts, lymphoid dendritic cells and tissue macrophages, rheumatoid synovium, cytokine-stimulated neural cells, parietal epithelial cells of the Bowman's capsule, the renal tubular epithelium, inflamed tissue during heart and kidney transplant rejection and by intestinal tissue in graft-versus-host disease. VCAM-1 is also found to be expressed on those tissue areas of the arterial endothelium which correspond to early arteriosclerotic plaques of a rabbit model. Additionally, VCAM-1 is expressed on follicular dendritic cells of human lymph nodes and is found on stroma cells of the

bone marrow, for example in the mouse. The latter finding points to a function of VCAM-1 in B-cell development. Apart from on cells of hematopoietic origin, VLA-4 is also found, for example, on melanoma cell lines, and the VCAM-1A/LA-4 adhesion mechanism is connected with the metastasis of such tumors (Rice et al., Science 1989.246, 1303).
The main form in which VCAM-I occurs in vivo on endothelial cells and which is the dominant form in vivo is designated as VCAM-7D and carries seven immunoglobulin domains. The domains 4, 5 and 6 are similar in their amino add sequences to the domains 1, 2 and 3. In a further form consisting of six domains, designated here as VCAM-6D, the fourth domain is removed by alternative splicing. VCAM-6D can also bind VLA-4-expressing cells.
Further details on VLA-4, VCAM-I, integrins and adhesion proteins are found, for example, in the articles by Kilger and Holzmann, J. Mol. Meth. 1995, 73, 347; Elices, Cell Adhesion in Human Disease, Wiley, Chichester 1995, p. 79; Kuijpers, Springer Semin. Immunopathol. 1995, 15, 379.
On account of the role of the VCAM-1 A/LA-4 mechanism in cell adhesion processes, which are of importance, for example, in infections, inflammations or atherosclerosis, it has been attempted by means of interventions into these adhesion processes to control illnesses, in particular, for example, inflammations (Osbom et a!., Cell 1989, 59, 1203). A method of doing this is the use of monoclonal antibodies which are directed against VLA-4. Monoclonal antibodies (mABs) of this type, which as VLA-4 antagonists block the interaction between VCAM-1 and VLA-4, are known. Thus, for example, the anti-VLA-4 mABs HP2/1 and HP1/3 inhibit the adhesion of VLA-4-expressing Ramos cells (B-cell-like cells) to human umbilical cord endothelial cells and to VCAM-1-transfected COS cells. The anti-VCAM-1 mAB 4B9 likewise inhibits the adhesion of Ramos cells, Jurkat cells (T-cell-like cells) and HL60 cells (granulocyte-like cells) to COS cells transfected with genetic constructs which cause

synovial endothelial cells is blocked, an adhesion which plays a part in rheumatoid arthritis (van Dinther-Janssen et al., J. Immunol. 1991, 147, 4207).
• In vivo experiments have shown that an experimental autoimmune encephalomyelitis } can be inhibited by anti-a4 mAB. The migration of leukocytes into an inflammatory focus is likewise blocked by a monoclonal antibody against the a4 chain of \/LA-4. The influencing of the VLA-4-dependent adhesion mechanism by antibodies was also investigated in an asthma model in order to investigate the role of VLA-4 in the recruitment of leukocytes into inflamed lung tissue (WO-A-93/13798), The I administration of anti-VLA-4 antibodies inhibited the late-phase reaction and airway overreaction in allergic sheep.
The VLA-4-dependent cell adhesion mechanism was also investigated in a primate model of inflammatory bowel disease (IBD). In this model, which corresponds to ulcerative colitis in man, the administration of anti-VLA-4 antibodies resulted in a significant reduction in the acute inflammation.
Moreover, it was possible to show that VI-A-4-dependent cell adhesion piays a part in the following clinical conditions including the following chronic inflammatory processes: rheumatoid arthritis (Cronstein and Weismann, Arthritis Rheum. 1993, 36, 147; Eiices et al., J. Clin. Invest. 1994, 93, 405), diabetes mellitus (Yang et at., Proc. Natl. Acad. Sci. USA 1993, 90, 10494), systemic lupus erythematosus (Takeuchi et al., J. Clin. Invest. 1993, 92, 3008), allergies of the delayed type (type IV allergy) (Eiices et al., Clin. Exp. Rheumatol. 1993, 11, S77), multiple sclerosis (Yednock et al., Nature 1992, 356, 63), malaria (Ockenhouse et al.. J. Exp. Med. 1992, 176, 1183), arteriosclerosis (O'Brien et al., J. Clin. Invest. 1993, 92, 945), transplantation (Isobe et a!., Transplantation Proceedings 1994, 26, 867), various malignancies, for example melanoma (Renkonen et al.. Am. J. Pathol. 1992, 140, 753), lymphoma (Freedman et al.. Blood 1992, 79, 206) and others (Albelda et al.. J. Cell Biol 1991, 114, 1059).
\/LA-4 blocking by suitable antagonists accordingly offers effective therapeutic

possibilities, in particular, for example, of treating various inflammatory conditions
including asthma and IBD. The particular relevance of VLA-4 antagonists for the
treatment of rheumatoid arthritis in this case results, as already stated, from the fact
• that leukocytes from the blood must first adhere to endothelial cells before they can
migrate into the synovium, and that the VLA-4 receptor plays a part in this adhesion.
The fact that VCAM-1 is induced by inflammatory agents on endothelial cells
(Osborn, Cell 1990, 62, 3; Stoolman, Cell 1989, 56, 907), and the recruitment of
various leukocytes into areas of infection and inflammatory foci has already been
discussed above. At the same time, T cells adhere to activated endothelium mainly
via the LFA-1/1CAM-1 and VLA-4A/CAM-1 adhesion mechanisms (Springer, Cell V,,,
1994, 76, 301). On most synovial T cells, the binding capacity of VLA-4 for VCAM-1 is increased in rheumatoid arthritis (Postigo et al., J. Clin. Invest. 1992, 89, 1445). Additionally, an increased adhesion of synovial T cells to fibronectin has been obsen/ed (Laffon et al., J. Clin, invest 1991, 88, 546; Morales-Ducret et a!., J. Immunol. 1992, 149, 1424). VLA-4 is upregulated both in the course of its expression and with respect to its function on T lymphocytes of the rheumatoid synovial membrane. The blocking of the binding of VLA-4 to its physiological ligands VCAM-1 and fibronectin makes possible an effective prevention or alleviation of articular inflammatory processes. This is also confirmed by experiments with the antibody HP2/1 on Lewis rats with adjuvant arthritis, in which an effective prevention of illness has been obsen/ed (Barbadillo et al., Springer Semin. Immunopathol. 1995, 16, 427). VLA-4 is thus an important therapeutic target molecule.
The abovementioned VLA-4 antibodies and the use of antibodies as VLA-4 antagonists are described in the Patent Applications WO-A-93/13798, WO-A-93/15764. WO-A-94/15094, WO-A-94/17828 and WO-A-95/19790. In the Patent Applications WO-A-94/15958, WO-A-95/15973, WO-A-96/00581, WO-A-96/06108 and WO-A-96/20215, peptide compounds are described as VLA-4 antagonists. The use of antibodies and peptide compounds as pharmaceuticals, however, has some disadvantages, for example lack of oral availability, easy degradabiiity or immunogenic action on longer-term use, and there is thus a need for VLA-4 antagonists having a favorable profile of properties for use in therapy and

prophylaxis.
WO-A-95/14008, WO-A-93/18057. US-A-5 658 935, US-A-5 686 421, US-A-5 389 614, US-A-5 397 796, US-A-5 424 293 and US-A-5 554 594 describe substituted 5-membered ring heterocycles which have an amino, amidino or guanidino function at the N-terminal end of the molecule and which exhibit platelet aggregation-inhibiting actions. EP-A-796 855 describes further heterocycles which are inhibitors of bone resorption. EP-A-842 943, EP-A-842 945 and EP-A-842 944 describe that compounds from this series and further compounds surprisingly also inhibit leukocyte adhesion and are VLA-4 antagonists.
EP-A-903 353, EP-A-905 139 and EP-A-918 059 and WO-A-99/60015 (German patent application 19821483.9) describe further compounds which inhibit leukocyte adhesion and are VLA-4 antagonists. The properties of these compounds, however, are still not satisfactory in various respects and there is a need for compounds having a further improved property profile. EP-A-918 059 describes, inter alia, imidazolidine derivatives which contain a spiro-linked ring system on the imidazolidine ring. Not specifically disclosed, however, are the spiroimidazoiidine derivatives of the present invention, which are distinguished by their advantageous property profile.

residues can be replaced by a carbonyl group C=0; W is isopropyl or cyclopropyl; V is hydrogen or methoxy;
■ E is -CO-R3 -CO-H, -CH2-0-R4 -CH2-O-CO-R4. -CHa-O-CO-O-R5 or 5-tetrazolyl;
R3 is hydroxy, (Ci-Cio)-alkoxy, phenyl-(C1-C8)-alkoxy-, phenyioxy-, (C1-C8)-
alkylcarbonyloxy-{C1-C6)-alkoxy-, phenylcarbonyloxy-(C1-C6)-alkoxy-, pheny!-(C1-C6)-
alkylcarbonytoxy-(C1-C6}-alkoxy-, (C1-C8)-alkoxycarbonyloxy-(C1-C6)-alkoxy-,
phenyloxycarbonyloxy-{C1-C6)-alkoxy-, phenyl-(C1-C6)-alkoxycarbonyloxy-{C1-C6)-
alkoxy-, amino, mono-((Ci-Cio)-alkyl)-amino-, di-((C1-C10)-a!kyl)-amino-or
R4R4N-CO-(C1-C6)-alkoxy- in which the residues R4 are independent of one another
and can be identical or different;
R4 is hydrogen, (C1-C10)-alkyl, phenyl or phenyl-(C1-C8)-aikyl-; R5 has one of the meanings of R4 with the exception of hydrogen; phenyl is an unsubstituted phenyl residue or a phenyl residue which is substituted by one or more identical or different substituents from the group consisting of (C1-C4)-alkyl, {C1-C4)-aIkoxy, methylenedioxy, ethylenedioxy, halogen, trifluoromethyl and trifluoromethoxy;
in all their stereoisomeric fomns and mixtures thereof in ail ratios, and their physiologically tolerable salts.
If a residue occurs more than once in a compound of the formula I, for example if R2 is phenyl and a further phenyl residue is contained in the group E, the residues are in all cases independent of one another and can be identical or different.
Alkyl residues can be straight-chain or branched. This also applies if they carry substituents or occur as substituents of other residues, for example in alkoxy residues, alkoxycarbonyl residues or arylalkyl residues. Examples of suitable alkyl residues are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyi, n-octyl, n-nonyl, n-decyi, isopropyl, isobutyl, isopentyl, isohexyl, 3-methytpenty!, neopentyl, neohexyl, 2,3,5-trimethylhexyl, sec-butyl, tert-butyl, tert-pentyl. Preferred alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. Substituted alkyl residues can be

substituted in any desired positions.
If the divalent residue X in the formula I is the divalent 1,2-ethyiene residue -CH2-CH2-. that is if X together with the two CH2 groups to which X is bonded forms a tetramethylene residue, the compounds of the formula I contain a spiro-linked cyclopentane nng, and thus compounds of the formula la are present which can be designated as 4,4-tetramethyleneimida2olidine derivatives.

forms a pentamethylene residue, the compounds of the formula I contain a spiro-linked cyclohexane ring, and thus compounds of the formula Ic are present which can be designated as 4,4-pentamethyleneimidazolidine derivates.

In the compounds of the formulae Id and le, X together with the two CH2 groups in the formula I to which X is bonded forms a 2-oxopentamethylene residue -CH2-CO-CH2-CH2-CH2- or a 3-oxopentamethylene residue -CH2-CH2-CO-CH2-CH2-. The compounds of the formulae Id and le can be designated as 4,4-(2-oxopentamethylene)imidazolidine denvatives and 4,4-(3-oxopentamethylene)-

imidazoiidine derivatives. If, in the residue -CH2-CH2-CH2- representing X, a CH2 group is replaced by a carbonyi group, the middle CH2 group is preferably replaced, that is preferably compounds of the formula le are present in this case.
Phenyl residues can be unsubstituted or are monosubstituted or polysubstituted. for example monosubstituted, disubstituted, trisubstituted, tetrasubstituted or pentasubstituted, by identical or different residues. If a phenyl residue is substituted, it preferably cam'es one or two identical or different substituents. The same applies, for example, to substituted phenyl residues in groups such as phenylalkyl, phenylcarbonyl, etc. PhenyiaikyI residues are, for example, benzyl, 1-phenylethyl or 2-phenylethyl, in particular benzyl, all of which can also be substituted.
In monosubstituted phenyl residues, the substituent can be located in the 2-position, the 3-position or the 4-position. In disubstituted phenyl residues, the substituents can be located in the 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. In trisubstituted phenyl residues, the substituents can be located in the 2,3,4-position, 2,3,5-position, 2,4,5-position, 2,4,6-position, 2,3,6-position or 3,4,5-position, if a phenyl residue carries substituents from the group consisting of methytenedioxy (-O-CH2-O-) and ethylenedioxy {-O-CH2-CH2-O-), it preferably carries only one substituent from this group (optionally in addition to other substituents).
Examples of substituted phenyl residues which, for example, can be R2, are 2-methyiphenyl, 3-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl, 2,4-dimethyiphenyl, 2,5-dimethylpheny!, 2,5-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethyiphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, 3,4,5-trimethylphenyl, 2-(n-butyl)phenyl, 3-{n-butyi)phenyi, 4-(n-butyl)phenyl, 2-isobutylphenyl, 3-isobutylphenyl, 4-isobutylphenyl, 3-tert-butylphenyi, 4-tert-butylphenyi, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dtmethoxyphenyl, 3,5-dimethoxyphenyl, 2,4,5-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 3,4,5-tnmethoxyphenyl, 2-(n-butoxy)phenyi, 3-(n-butoxy)phenyl, 4-(n-butoxy)phenyl, 2-isobutoxyphenyl, 3-isobutoxyphenyl 4-isobutoxyphenyl, 2-tert-butoxyphenyt, 3-tert-

butoxyphenyl, 4-tert-butoxyphenyl, 2,3-methylenedioxyphenyl, 3,4-
methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethyienedioxyphenyl, 2-
fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl,
2,5-difluorophenyi, 2,5-difluorophenyt, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,4.5-
trifluorophenyl, 2,4,6-trifluorophenyl, 3,4,5-trifluorophenyl, 2,3,5,6-tetrafluorophenyl,
2,3,4,5,6-pentafluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-
dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,5-dichlorophenyl, 3,4-
dichlorophenyi, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyi,
3-iodophenyl, 4-iodophenyl, 2-trifluoromethylphenyl, 3-trifluoromethytphenyi,
4-trifluoromethylphenyl, 3.4-bis(trifluoromethyl)phenyl, 3,5-bis(trifiuoromethyl)phenyl, ■..
2-trifIuoromethoxyphenyi, 3-trifluoromethoxyphenyi, 4-trifIuoromethoxyphenyl, etc. In substituted phenyl residues, however, different substituents can also be contained in any desired combination, such as, for example, in the residues 3-methoxy-4-methylphenyl, 4-f]uoro-3-methoxyphenyi, 3-fluoro-4-methoxyphenyl, 3,5-difIuoro-4-methoxyphenyl, 3-fluoro-4,5-methylenedioxyphenyl, 3-fluoro-4,5--ethylenedioxyphenyi, 2-chloro-3-methylphenyl, 3-chloro-4-methylphenyl, 3-chloro-4-fluorophenyl, etc.
Halogen is fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.
Physiologically tolerable salts of the compounds of the formula I are in particular ^"^
nontoxic or pharmaceutically utilizable salts. Salts of this type of compounds of the formula 1 which contain acidic groups, for example a carboxylic add group representing the group E, are, for example, alkali metal salts or alkaline earth metal salts such as, for example, sodium salts, potassium salts, magnesium salts and calcium salts, or ammonium salts such as, for example, salts with physiologically tolerable quaternary ammonium ions and acid addition salts with ammonia and physiologically tolerable organic amines, such as, for example, methylamine, ethylamine, triethylamine, 2-hydroxyethyiamine, tris(2-hydroxyethyl)amine, a,a,a-tris(hydroxymethyl)methylamine (tromethamine) or amino acids, in particular basic amino acids. Salts of an acidic compound of the formula I and an organic amine can contain the two components in the ratio 1:1 {or about 1:1) or in another ratio, for

example in a ratio of about 1:0.5 to about 1:4 (1 molecule of the formula I to 0.5 to 4 molecules of the amine), in particular in a ratio of about 1:0.5 to about 1:2 (1 molecule of the formula I to 0.5 to 2 molecules of the amine).
Compounds of the formula I which contain basic groups, for example an amino group in the alcohol component of a carboxyiic acid ester group, form salts with inorganic acids such as, for example, hydrochloric acid, sulfuric acid or phosphoric acid, and with organic carboxyiic acids or sulfonic acids such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumahc acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. Compounds which contain both acidic groups and basic groups can also be present in the form of inner salts or betaines or zwitterions, which are likewise included by the present invention.
Salts can be obtained from the compounds of the formula I according to customary processes known to the person skilled in the art, for example by combination with an organic or inorganic acid or base in a solvent or diluent, or also from other salts by anion exchange or cation exchange.
The compounds of the formula I can be present in stereoisomeric forms. On all asymmetric centers in the compounds of the formula I, independently of one another the S configuration or the R configuration can be present or a R/S mixture can be present. Thus the asymmetric carbon atom to which the residue R2 is bonded can have the R configuration or S configuration or the compound of the formula I can be present, with respect to this carbon atom, as an R/S mixture. Likewise, the asymmetric carbon atom to which the group -CH2-W, which is an isobutyi group (= 2-methylpropyl group) or a cyclopropylmethyi group, and the imidazolidine ring are bonded can have the R configuration or S configuration or the compound of the formula 1 can be present with respect to this carbon atom as an R/S mixture. AH other asymmetric carbon atoms can also have the R configuration or the S configuration or the compound of the formula I can be present with respect to each of these carbon atoms as an R/S mixture.

The invention includes all possible stereoisomers of the compounds of the fonnula I, for example pure or largely pure enantiomers and pure or largely pure diastereomers and mixtures of two or more stereoisomeric forms, for example mixtures of • enantiomers and/or diastereomers, in all ratios. Enantiomers are thus a subject of the invention in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. Likewise, diastereomers in diastereomerically pure form and in the form of mixtures in all ratios are a subject of the invention. Examples of individual stereoisomers which are a subject of the invention are the compounds of the formulae If, Ig, Ih and li.

The individual stereoisomers can be prepared, if desired, by use of stereochemicaily uniform starting substances in the synthesis, by stereoselective synthesis or by separation of a mixture according to customary methods, for example by chromatography or crystallization, in the case of enantiomers for example by chromatography on chiral phases. Opitionally, before separation of stereoisomers a derivatization can be carried out. The separation of a stereoisomer mixture can take place at the stage of the compounds of the formula 1 or at the stage of a starting substance or of an intermediate in the course of the synthesis.
The compounds of the formula I according to the invention can contain mobile hydrogen atoms, that is be present in various tautomeric forms. Al! tautomers of the compounds of the formula I are also a subject of the present invention. The present invention also includes solvates and addition compounds or adducts of compounds of the formula I, for example adducts with water, that is hydrates, or adducts with alcohols or amines. The invention furthermore includes derivatives of compounds of the formula I, for example esters, amides, prodrugs and other physiologically tolerable derivatives, and also active metabolites of compounds of the formula I. The invention in particular also relates to prodrugs of the compounds of the formula I, which can be converted into compounds of the formula I under physiological conditions. Suitable prodrugs of the compounds of the formula I, that is chemically modified derivatives of the compounds of the formula I having desirably improved properties, are known to the person skilled in the art. Details of prodrugs are found, for example, in Fleisher et al.. Advanced Drug Delivery Reviews 19 (1996) 115; Design of Prodrugs, H. Bundgaard, Ed., Elsevier, 1985; H. Bundgaard, Drugs of the Future 16 (1991) 443. Possible prodrugs of the compounds of the formula I are especially ester prodrugs, amide prodrugs, aldehyde prodrugs and alcohol prodrugs

of carboxylic acid groups. Examples of ester prodrugs and amide prodrugs which may be mentioned are (C1-C4)-alkyl esters such as methyl esters, ethyl esters, isopropyl esters, isobutyl esters, substituted alkyl esters such as hydroxyalkyi esters, ■ acyloxyalkyl esters, aminoalkyl esters, acylaminoalkyl esters, dialkyiaminoalkyl esters, unsubstituted amides or N-{C1-C4)-alkylamides such as methylamides or ethytamides.
With respect to the structural elements V and W, the present invention includes four embodiments each of which expressly is a subject of the present invention. In one of these embodiments, the group W in the formula I is isopropyl, that is the residue -CH(CH3)2, and at the same time V is hydrogen. This embodiment thus includes compounds of the formula Ik

and can be identical or different;
R4 is hydrogen, (C1-C10)-alkyl, phenyl or phenyl-(C1-C8)-alkyl-; R5 has one of the meanings of R4 with the exception of hydrogen; phenyl is an unsubstituted phenyl residue or a phenyl residue which is substituted by one or more identical or different substituents from the group consisting of (C1-C4)-alkyl, (C1-C4}-alkoxy, methylenedioxy, ethylenedioxy, halogen, trifluoromethyi and tnfluoromethoxy;
in all their stereoisomehc forms and mixtures thereof in all ratios, and their physiologically tolerable salts.

and at the same time V is hydrogen. A third embodiment relates to compounds of the formula I in which W is isopropyl and at the same time V is methoxy, that is the residue -OCH3. A fourth embodiment relates to compounds of the formula I in which W is cydopropyl and at the same time V is methoxy. A subgroup of the compounds according to the invention includes the compounds of the second, third and fourth embodiment described above, that is compounds of the formula I in which V is hydrogen or methoxy and W is isopropyl or cydopropyl. but in which not at the same time V is hydrogen and W is isopropyl. Also the compounds of the second, third and fourth embodiment of the invention are a subject of the invention in all their stereoisomehc forms and mixtures thereof in all ratios and in the form of their physiologically tolerable salts.
The individual structural elements in the formula I preferably have the following meanings, which they can have independently of one another.
E is preferably -CO-R3 -CO-H, -CH2-0-R4, -CH2-O-CO-R4 or-CH2-0-C0-0R5,

particularly preferably -CO-R3 -CO-H, -CH2-0-R4 or -CH2-0-C0-R4 very particularly preferably -CO-R3 -CH2-0-R4 or -CHa-O-CO-R4 moreover preferably -CO-R3 or -CH2-0-R4, especially preferably -CO-R3. A residue -CH2-O-R4 representing the group E is preferably the hydroxymethyl residue -CH2-OH. Especially preferred meanings of E are -C0-0-(C1-C4)-aikyl, -CO-OH. -CO-NH2 and -CH2-OH, in particular -CO-OH, -CO-NH2 and -CH2-OH, especially -CO-OH.
X is preferably -CH2-CH2 or -CH2-CH2-CH2-. in particular -CH2-CH2-CH2-, where none of the CH2 groups is replaced by a carbonyi group.
R2 is preferably unsubstituted phenyl, phenyl which is substituted by a methyienedioxy residue or an ethylenedioxy residue, phenyl which is substituted by one or two (C1-C4)-alkQxy groups, in particular by methoxy groups, or (C1-C4)-alkyl, where the (C1-C4)-alkyi group preferably is methyl, ethyl or isobutyl, more preferably methyl or ethyl, particularly preferably methyl. Particularly preferably, R^ is unsubstituted phenyl, phenyl which is substituted by a methyienedioxy residue or an ethylenedioxy residue, phenyl which is substituted by one or two methoxy groups, or methyl. Very particularly preferably, R2 is unsubstituted phenyl, 3,4-methylene-dioxyphenyi, 3,4-ethylenedioxyphenyl, 2-methoxyphenyl, 3-methoxyphenyt, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethQxyphenyl or methyl.
R3 is preferably hydroxy, (C1-C6)-alkoxy or amino (-NH2), particularly preferably hydroxy, (C1-C4)-alkoxy or amino, very particularly preferably hydroxy or amino, especially preferably hydroxy.
R4 is preferably hydrogen or (C1-C6)-alkyl, particularly preferably hydrogen or (C1-C4)-alkyi. R5 is preferably (C1-C6)-alkyl, particularly preferably (C1-C4)-alkyi.
Preferred compounds of the formula I are those which have a uniform configuration on one or on more chiral centers, for example on the carbon atom which carries the residue R2, and/or on the carbon atom which carries the group -CH2-W. That is,

compounds are preferred which are present in uniform or in essentially uniform configuration on one or more chiral centers, either in the R configuration or in the S configuration, but not as an R/S mixture. As explained, the individual chirai centers in these compounds of the formula 1, however, can independently of one another have the R configuration or the S configuration and can have identical or different configurations. Particularly preferred compounds of the formula I are those in which the carbon atom which carries the group -CH2-W is present in the S configuration, that is in the configuration with respect to this stereocenter which is shown in the formulae If and Ig. Particularly preferred compounds of the formula I are also those in which the carbon atom which carnes the group R2 is present in the configuration shown in the formulae If and Ih. If R2 is phenyl or substituted phenyl, in these particularly preferred compounds the carbon atom which carries the group R2 has the S configuration, if R2 is, for example, methyl, ethyl or isobutyl, it has the R configuration. Very particularly preferred compounds of the formula 1 are those in which the two abovementioned stereocenters are present in the configurations shown in the formula If.
Preferred compounds of the formula I are those compounds in which one or more of the residues have preferred meanings or have a specific meaning from the listed meanings, all combinations of preferred meanings of residues being a subject of the present invention.
Particularly preferred compounds are compounds of the formula 1, in which
R1 is hydrogen or methyl;
R2 is unsubstituted phenyl, phenyl which is substituted by a methylenedioxy residue
or an ethylenedioxy residue, phenyl which is substituted by one or two (C1-C4)-alkoxy
groups, or (C1-C4)-alkyl;
X is -CH2-CH2- or -CH2-CH2-CH2-, where one of the CH2 groups in these two
residues can be replaced by a carbonyl group C=0;
W is isopropyi or cyclopropyl;
V is hydrogen or methoxy;
E is -CO-R3 -CO-H, -CH2-0-R4 -CH2-0-C0-R4 or -CH2-O-CO-O-R65;

R3 is hydroxy, (C1-C10)-alkoxy, phenyl-(C1-C8}-aikoxy-, phenyioxy-, (C1-C8)-alkylcarbonyloxy-(C1-C6)-alkoxy-, phenylcarbonyloxy-(C1-C6)-alkoxy-, phenyl-(C1-C6)-alkylcarbonyioxy-(C1-C6)-alkoxy-, (Ci-Ca)-alkoxycarbonyloxy-{C1-C6)-alkoxy-, ■ phenyloxycarbonytoxy-(C1-C6)-alkoxy-, phenyl-(C1-C6)-alkoxycarbonytoxy-(Ci-C6)-alkoxy-, amino, mono-{(CrCio)-a!kyl)-amino-, di-((C1-C10)-aikyl)-amino-or R4R4 N-CO-(C1-C6)-alkoxy- in which the residues R4 are independent of one another and can be identical or different;
R4 is hydrogen, (C1-C10)-alkyl, phenyl or phenyl-(C1-C8)-alkyl-; R5 has one of the meanings of R4 with the exception of hydrogen; phenyl which is contained in the group E is an unsubstituted phenyl residue or a phenyl residue which is substituted by one or more identical or different substituents from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, methylenedioxy, ethylenedioxy, halogen, trifluoromethyl and trifluoromethoxy; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts.
Very particularly preferred compounds are compounds of the formula 1 in which
R1 is hydrogen or methyl;
R2 is unsubstituted phenyl, phenyl which is substituted by a methylenedioxy residue
or an ethylenedioxy residue, phenyl which is substituted by one or two methoxy
groups, or (C1-C4)-alkyi;
X is "CH2-CH2- or •CH2-CH2-CH2-, where one of the CH2 groups in these two
residues can be replaced by a carbonyl group C=0;
W is isopropyi or cyclopropyi;
V is hydrogen or methoxy;
E is -CO-OH, -C0-0-{C1-C4)-alkyl, -CO-NH2 or -CH2-OH;
in all their stereoisomeric forms and mixtures thereof in all ratios,
and their physiologically tolerable salts.
A subgroup of these compounds is formed by the compounds of the formula I in
which
R1 is hydrogen or methyl;

R2 is phenyl which is substituted by a methylenedioxy residue or an ethylenedioxy
residue, or phenyl which is substituted by one or two methoxy groups;
X is -CH2-CH2- or -CH2-CH2-CH2-. where one of the CH2 groups in these two
residues can be replaced by a carbonyl group C=0;
W is isopropyl or cyciopropyt;
V is hydrogen or methoxy;
E is -CO-OH, -C0-0-(CrC4)-alkyl, -CO-NH2 or -CH2-OH;
in all their stereoisomeric forms and mixtures thereof in all ratios,
and their physiologically tolerable salts.
A further subgroup of these compounds is formed by compounds of the formula i in
which
R1 is hydrogen or methyl;
R2 is unsubstituted phenyl;
X is -CH2-CH2- or -CH2-CH2-CH2-, where one of the CH2 groups in these two
residues can be replaced by a carbonyl group C=0;
W is isopropyl or cyclopropyl;
V is hydrogen or methoxy;
E is -CO-OH, -C0-0-(C1-C4)-alkyl. -CO-NH2 or -CH2-OH;
in all their stereoisomeric forms and mixtures thereof in ail ratios.
and their physiologically tolerable salts.
A further subgroup of these compounds is formed by compounds of the formula I in
which
R1 is hydrogen or methyl;
R2 is (C1-C4)-alkyl, preferably methyl;
X is -CH2-CH2- or -CH2-CH2-CH2-, where one of the CH2 groups in these two
residues can be replaced by a carbonyl group C=0;
W is isopropyl or cyclopropyl;
V is hydrogen or methoxy;
E is -CO-OH, -C0-0-(C1-C4)-alkyl, -C0-NH2 or -CH2-OH;
in all their stereoisomenc forms and mixtures thereof in all ratios,

and their physiologically tolerable salts.
For the abovementioned embodiment of the invention in which the group V in the • compounds of the formula I is hydrogen and the group W is isopropyi, that is for the compounds of the formula Ik, examples of specific compounds are indicated below each of which expressly is a subject of the present invention. The following abbreviations are used in the names of the compounds.
IBU = 2-methylpropyl = isobutyl = -CH-CH2-CH(CH3)2
4PM-3-PUB-DI =4,4-pentamethylene-3-(4-(3-phenyiure(do)benzyl)-2,5-dioxoimid-
a2olidin-1-yl
4PM-3-MPUB-DI =4.4-pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2.5-
dioxoimidazolidin-l -yl
4TM-3-PUB-DI = 4,4-tetramethylene-3-{4-{3-phenyiureido)ben2yl)-2,5-dioxoimid-
a2olidin-1-yl
4TM-3-MPUB-DI = 4.4-tetramethylene-3"(4-{3-{2-methylphenyl)ureido)benzyl)-2,5-
dioxoimidazolidin-1 -yl
40PM-3-PUB-DI = 4,4-(3-oxopentamethy!ene)-3-(4-(3-phenylureido)benzyl)-2,5-
dioxoimidazolidin-1 -yl
40PM-3-MPUB-DI = 4,4-{3-oxopentamethylene)-3-{4-(3-(2-methylphenyl)ureido)-
benzyl)-2,5-diQxoimidazolidin-1-yl
40TM-3-PUB-DI = 4,4-(2-oxotetramethylene)-3-(4-(3-pheny!ureido)benzyl)-2,5-
dioxoimidazolidin-1 -yl
40TM-3-MPUB-DI = 4,4-(2-oxotetramethylene)-3-{4-(3-(2-methylphenyl)ureido)-
benzyl)-2,5-dioxoimidazolidin-1-yl
A name such as, for example, 3-(2"{40PM-3-MPUB-Di)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionamide is thus to be understood as meaning the compound 3-(2-(4,4-(3-oxopentamethylene)-3-(4-(3-(2-methylphenyi)ureido)benzyi)-2,5-dioxo-!midazolidin-1-yl)-2-(2-methylpropyl)acety!amino)-3-(3,4-dimethoxyphenyi)propion-amide of the formula Im.

The present invention relates, for example, to the following compounds:
3-(2-(4PM-3-PUB-D()-2-{IBU)-acetylamino)-3-methyipropionic acid
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methylpropionic acid
3-(2-{4TM-3-PUB-Dl)-2-(IBU)-acetylamino)-3-methylpropionic acid
3-(2-{4TM-3-MPUB-DI)-2-(IBU)-acetylanriino)-3-methylpropionic acid
3-(2-(40PM-3-PUB-DI)-2-(IBU)-acety!amino)-3-methyipropionic acid
3-(2-(40PM-3-MPUB-DI)-2-(IBU)-acetyiamino)-3-methylpropionic acid
3-{2-(40TM-3-PUB-DI)-2-{lBU)-acetylamino)-3-methylpropionic acid
3-(2-(40TM-3-MPUB-Dl)-2-{lBU)-acetylamino)-3-methylpropionic acid
3-(2-{4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-methyipropionamide
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methytpropionamide
3-(2-(4TM-3-PUB-Dl)-2-(lBU)-acetylamino)-3-methylpropionamide
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methylpropionamide
3-(2-(40PM-3-PUB-DI)-2-(iBU)-acetylamino)-3-methylpropionamide
3-(2-(40PM-3-MPUB-DI)-2-(!BU)-acetyiamino)-3-methylpropionamide
3-(2-(40TM-3-PUB-Di)-2-{lBU)-acetylamino)-3-methylpropionamide
3-(2-{40TM-3-MPUB-Dl)-2-{lBU)-acetylamino)-3-methylpropionamide
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-methylpropanol
3-{2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methylpropanol
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-methylpropanol

3-(2-{4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methyipropanol 3-(2-(40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-methylpropanol 3-(2-(40PM-3-MPUB-Dl)-2-(IBU)-acetylamino)-3-methylpropanol 3-{2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-methylpropanoi 3-(2-{40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-methyipropanol
3-(2-{4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(lBU)-propionic acid
3-(2-{4PM-3-MPUB-DI)-2-(IBU)-acetyiamino)-3-(IBU)-propionic acid
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propionic acid
3-(2-(4TM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-(IBU)-propionic acid :,
3-(2-(40PM-3-PUB-DI)-2-(IBU)-acety!amino)-3-(IBU)-propionic acid
3-(2-{40PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-{lBU)-propionic acid
3-(2-(40TM-3-PUB-Dl)-2-(IBU)-acetylamino)-3-{IBU)-propionic acid
3-(2-(40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propionic acid
3-(2-{4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(lBU)-propionamide
3-(2-(4PM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-{IBU)-propionamide
3-(2-{4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-{IBU)-propionamide
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-{IBU)-propionamide
3-(2-(40PM-3-PUB-D!)-2-(lBU)-acetylamino)-3-(IBU)-propionamide
3-{2-(40PM-3-MPUB-DI}-2-{lBU)-acetylamino)-3-{lBU)-propionamide
3-(2-(40TM-3-PUB-DI)-2-{IBU)-acetylamino)-3-(IBU)-propionamide
3-(2-(40TM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(!BU)-propionamide
3-{2-(4PM-3-PUB-DI)-2-(lBU)-acetylamino)-3-(IBU)-propanol
3-(2-{4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(lBU)-propanol
3-(2-(4TM-3-PUB-DI)-2-(lBU)-acetylamino)-3-(IBU)-propanol
3-{2-(4TM-3-MPUB-Di)-2-(!BU)-acetylamino)-3-{lBU)-propanol
3-(2-(40PM-3-PUB-Dl)-2-(IBU)-acetylamino)-3-(IBU)-propanol
3-(2-{40PM-3-MPUB-DI)-2-(!BU)-acetylamino)-3-(IBU)-propanol
3-(2-(40TM-3-PUB-DI)-2-{IBU)-ac8tylamino)-3-(lBU)-propanol
3-(2-(40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(IBU)-propanol

3-(2-{4PM-3-PUB-DI)-2-{IBU)-acetylamino)-3-phenyipropionic acid 3-{2-{4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionic acid 3-(2-{4TM-3-PUB-Dl)-2-(lBU)-acetyiamino)-3-phenylpropionic acid i 3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionic acid 3-(2-(40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionic acid 3-(2-{40PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionic acid 3-(2-{40TM-3-PUB-Dl)-2-(lBU)-acetylamino)-3-phenylpropionic acid 3-(2-{40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionic acid
3-(2-(4PM-3-PUB-DI}-2-(!BU)-acetylamino)-3-phenylpropionamide
3-(2-(4PM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-phenylpropionamide
3-(2-{4TM-3-PUB-DI)-2-(IBU)-acetyiamino)-3-phenylpropionamide
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-pheny(propionamide
3-{2-(40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-phenylpropionamide
3-(2-(40PM-3-MPUB-DI)-2-(IBU)-acetyiamino)-3-phenylpropionamide
3-(2-(40TM-3-PUB-Dl)-2-(IBU)-acetylamino)-3-phenytpropionamide
3-(2-{40TM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-phenylpropionamide
3-(2-(4PM-3-PUB-D!)-2-{!BU)-acetylamino)-3-phenyipropanol
3-(2-{4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropanol
3-(2-{4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-phenylpropanoi
3-(2-{4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropano(
3-(2-(40PM-3-PUB-DI)-2-{IBU)-acetylamino)-3-phenytpropanol
3-(2-(40PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenylpropanol
3-{2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-phenytpropanol
3-(2-(40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-phenyipropanol
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propionic acid 3-(2-(4PM-3-MPUB-Dl)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propionic acid 3-(2-(4TM-3-PUB-DI)-2-(lBU)-acetylamino)-3-{2-methoxyphenyl)propionic acid 3-(2-{4TM-3-MPUB-D!)-2-(IBU)-acetylam!no)-3-(2-methoxyphenyi)propionic acid

3-{2-(40PM-3-PUB-DI)-2-(lBU)-acetylamino)-3-{2-methoxyphenyl)propionic acid 3-(2-{40PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propionic acid 3-(2-{40TM-3-PUB-Dl)-2-(IBU)-acetylamino)-3-(2-methQxyphenyl)propionic acid ■3-{2-{40TM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(2-methoxyphenyl)propionic acid
3-(2-(4PM-3-PUB-DI)-2-{IBU)-acetytamino)-3-(2-methoxyphenyl)propionamide
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetyiamino)-3-(2-methoxyphenyl)propionamide
3-{2-{4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-{2-methoxyphenyl)propionamide
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetytamino)-3-(2-methoxypheny!)propionamide
3-(2-(40PM-3-PUB-Dl)-2-(IBU)-acetytamino)-3-(2-methoxyphenyi)propionamide
3-(2-{40PM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-{2-methoxyphenyl)propionamide
3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetyiamino}-3-{2-methoxyphenyl)propionamide
3-(2-(40TM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(2-methoxyphenyl)propionannide
3-{2-(4PM-3-PUB-Dl)-2-(lBU)-acetylamino)-3-(2-methoxyphenyl)propanol
3-(2-(4PM-3-MPUB-DI)-2-(!BU)-acetylamino)-3-(2-methoxyphenyl)propanol
3-(2-{4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propanol
3-{2-(4TM-3-MPUB-Dl)-2-(IBU)-acetylamino)-3-{2-methoxyphenyl)propanol
3-(2-(40PM-3-PUB-DI)-2-{IBU)-acetyiamino)-3-(2-methoxyphenyl)propanol
3-{2-{40PM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-(2-methoxyphenyl)propanol
3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2-methoxyphenyl)propanol
3-(2-(40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-{2-methoxyphenyl)propanol
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionic acid
3-(2-{4PM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-(3-methoxyphenyl)propionic acid
3-{2-(4TM-3-PUB-DI}-2-{IBU)-acetylamino)-3-(3-methoxyphenyi)propionic acid
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetytamino)-3-(3-methoxyphenyl)propionic acid
3-(2-(40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionic acid
3-(2-(40PM-3-MPUB-DI)-2-(lBU)-acetyiamino)-3-(3-methoxyphenyl)propionic acid
3-(2-(40TM-3-PUB-DI}-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionic acid
3-(2-{40TIV1-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(3-methoxyphenyl)propionic acid

3-(2-(4PM-3-PUB-DI)-2-(lBU)-acetyiamino)-3-(3-methoxyphenyt)propionamide
3-(2-{4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxypheny()propionamide
3-(2-(4TM-3-PUB-D()-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionamide
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionamide
3-(2-(40PM-3-PUB-Di)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propionamide
3-(2-(40PM-3-MPUB-Dl)-2-{lBU)-acetylamino)-3-(3-methoxyphenyl)propionamide
3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetyiamino)-3-(3-methoxyphenyl)propionamide
3-(2-{40TM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(3-methoxyphenyl)propionamide
3-{2-{4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)prQpanol
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propanol
3-(2-(4TM-3-PUB-DI)-2-(lBU)-acetylam!no)-3-(3-methoxyphenyl)propanol
3-(2-{4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propanol
3-(2-(40PM-3-PUB-Di)-2-(lBU)-acetylamino)-3-(3-methoxyphenyl)propanol
3-(2-(40PM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-(3-methoxyphenyl)propanol
3-{2-{40TM-3-PUB-DI)-2-{IBU)-acetylamino)-3-(3-methoxyphenyl)propanol
3-(2-(40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3-methoxyphenyl)propanol
3-(2-(4PM-3-PUB-Dl)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionic acid 3-(2-{4PM-3-MPUB-DI)-2-(IBU)-acetylam!no)-3-{4-methoxyphenyl)propionic acid 3-{2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionicadd 3-(2-(4TM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-{4-methoxyphenyl)propionic acid 3-(2-(40PM-3-PUB-DI)-2-{IBU)-acetylamino)-3-(4-methoxyphenyl)propionic acid 3-(2-{40PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionic acid i 3-(2-(40TM-3-PUB-DI)-2-{IBU)-acetylamino)-3-{4-methoxyphenyl)propionicadd 3-(2-(40TM-3-MPUB-DI)-2-([BU)-acetylam(no)-3-(4-methoxyphenyl)propionic acid
3-(2-(4PM-3-PUB-Dl)-2-(lBU)-acetytamino)-3-(4-methoxyphenyi)propionamide 3-(2-(4PM-3-MPUB-D!)-2-(lBU)-acetylamino)-3-(4-methoxyphenyl)propionamide ) 3-(2-(4TM-3-PUB-DI)-2-((BU)-acetylamino)-3-{4-methoxyphenyi)propionamide 3-(2-(4TM-3-MPUB-Dl)-2-(IBU)-acetylamino)-3-{4-methoxyphenyl)propionamide 3-(2-{40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propionamide

3-{2-{40PM-3-MPUB-DI}-2-(iBU)-acety!amino)-3-{4-methoxyphenyl)propionamide
3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetytamino)-3-(4-methoxyphenyl)propionamide
3-(2-(40TM-3-MPU6-DI)-2-{IBU)-acetylamino)-3-(4-methoxyphenyl)propionamide
3-(2-(4PM-3-PUB-DI)-2-(lBU)-acetylamino)-3-(4-methoxyphenyl)propanol
3-(2-{4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propanol
3-(2-(4TM-3-PUB-Dl)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propanol
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-{4-methoxyphenyl)propanol
3-(2-(40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-{4-methoxyphenyl)propanol
3-{2-(40PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(4-methoxyphenyl)propanol
3-(2-(40TM-3-PUB-DI)-2-{IBU)-acetylamino)-3-{4-methoxyphenyl)propanol
3-{2-(40TM-3-MPUB-Dl)-2-(IBU)-acetylamino)-3-{4-methoxyphenyl)propanol
3-(2-{4PM-3-PUB-Dl)-2-(lBU)-acetyiamino)-3-(2,3-dimethoxyphenyl)propionic acid
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetyiaminQ)-3-(2,3-dimethoxyphenyl)propionic acid
3-{2-{4TM-3-PUB-Dl)-2-(lBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionic acid
3-(2-{4TM-3-MPUB-DI)-2-(IBU)-acetyiamino)-3-(2,3-dimethoxypheny!)propionic acid
3-(2-(40PM-3-PUB-Dl)-2-(!BU)-acetyiamino)-3-(2,3-dimethoxyphenyl)propionic acid
3-(2-(40PM-3-MPUB-DI)-2-(IBU)-acetytamino)-3-(2,3-dimethoxyphenyi)propionic
add
3-{2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionic acid
3-(2-(40TM-3-MPUB-Dl)-2-(iBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionic
acid
3-(2-(4PM-3-PUB-Di)-2-(iBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionamide
3-(2-(4PM-3-MPUB-D!)-2-(iBU)-acetytamino)-3-(2,3-dimethoxyphenyi)propionamide
3-(2-(4TM-3-PUB-DI)-2-(lBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionamide
3-{2-(4TM-3-MPUB-DI)-2-(lBU)-acetylannino)-3-(2,3-dimethoxyphenyl)propionamide
3-(2-(40PM-3-PUB-DI)-2-(IBU)-acetyiamino)-3-{2,3-dimethoxyphenyi)propionannide
3-{2-(40PM-3-MPUB-DI)-2-{!BU)-acetylamino)-3-{2,3-dimethoxyphenyl)propionamide
3-(2-{40TM-3-PUB-DI)-2-(IBU)-acetyiamino)-3-{2,3-dimethoxyphenyl)propionamide
3-(2-{40TM-3-MPUB-D!)-2-(iBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propionannide

3-(2-{4PM-3-PUB-DI)-2-(lBU)-acetylamino)-3-(2,3-dimethoxypnenyl)propanol
3-(2-(4PM-3-MPUB-Di)-2-(IBU)-acetylamino)-3-(2,3-dimethQxyphenyl)propanol
3-(2-(4TM-3-PUB-DI)-2-(lBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propanol
3-(2-{4TM-3-MPUB-Dl)-2-{lBU)-acetylamtno)-3-(2,3-dimethoxyphenyl)propano(
3-(2-(40PM-3-PUB-DI)-2-(lBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propanol
3-(2-{40PM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(2,3-dimethoxyphenyl)propanol
3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,3-dimethoxyphenyl)prQpanol
3-{2-{40TM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(2,3-dim6thQxyphenyl)prQpanol
3-(2-{4PM-3-PUB-Dl)-2-(lBU)-acetyiamino)-3-(2,4-dimethoxyphenyl)propionic acid
3-(2-{4PM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid
3-(2-(4TM-3-PUB-Dl)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid
3-{2-(4TM-3-MPUB-Dl)-2-{IBU)-acetylamino)-3-{2,4-dimethoxyphenyl)propionic acid
3-(2-{40PM-3-PUB-Dl)-2-{lBU)-acetylamino)-3-(2,4-dimethoxyphenyi)propionic acid
3-(2-(40PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2.4-dimethoxyphenyl)propionic
acid
3-(2-(40TM-3-PUB-Dl)-2-(lBU)-acetyiamino)-3-(2,4-d!methoxyphenyi)propionic acid
3-(2-(40TM-3-MPUB-Dl)-2-(lBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionic
acid
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetyiamino)-3-(2,4-dimethoxyphenyl)propionamide
3-(2-(4PM-3-MPUB-D!)-2-(!BU)-acetylamino)-3-{2,4-ciimethoxyphenyl)propionamide
3-(2-(4TM-3-PUB-D!)-2-(lBU)-acetyiamino)-3-(2,4-dimethoxyphenyl)propionamide
3-(2-(4TM-3-MPUB-Dl)-2-(!BU)-acetyiamino)-3-(2,4-dimethoxyphenyi)propionamide
3-(2-(40PM-3-PUB-DI)-2-(iBU)-acetylami^o)-3-{2,4-dimethoxypi^e^y!)propionamide
3-(2-(40PM-3-MPUB-DI)-2-(iBU)-acety!amino)-3-(2,4-dimethoxypiieny!)propionamide
3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propionamide
3-(2-(40TM-3-MPUB-D!)-2-(iBU)-acety(amino)-3-(2,4-dimethoxyphenyl)propionamide
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acety!amino)-3-(2,4-dimethoxyphenyl)propanQl 3-(2-(4PM-3-MPUB-D!)-2-(IBU)-acetylamino)-3-(2,4-dimethoxyphenyl)propanol

3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-{2,4-dimethoxyphenyi)propanol
3-(2-{4TM-3-MPUB-DI)-2-(IBU)-acetytamino)-3-(2,4-dimethoxyphenyl)propanol
3-(2-(40PM-3-PUB-DI)-2-(iBU)-acetylamino)-3-(2,4-dimethoxyphenyl}propanol
3-(2-{40PM-3-MPUB-DI)-2-(IBU}-acetylamino)-3-(2,4-dimethoxyphenyl)propanoi
3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetyiamino)-3-(2,4-dimethoxyphenyi)propanol
3-(2-(40TM-3-MPUB-Dl)-2-(iBU)-acetyiamino)-3-(2,4-dimethoxyphenyl)propanol
3-(2-(4PM-3-PUB-Dl)-2-(lBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionic acid
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxypheny!)propionic acid
3-(2-(4TM-3-PUB-DI)-2-(lBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionic acid
3-(2-(4TM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionic acid
3-(2-{40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionic acid
3-(2-(40PM-3-MPUB-DI)-2-(IBU)-acetyiamino)-3-(2,5-dimethaxyphenyi)propionic
acid
3-(2-{40TM-3-PUB-Dl)-2-(IBU)-acetylannino)-3-(2,5-dimethoxyphenyl)propionic acid
3-(2-{40TM-3-MPUB-DI)-2-(iBU)-acetylamino}-3-(2,5-dimethoxyphenyl)prQpianic
acid
3-(2-{4PM-3-PLIB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionamide
3-(2-(4PM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(2,5-dimethoxyphenyi)propionamide
3-(2-(4TM-3-PUB-D!)-2-(!BU)-acetylannino)-3-(2,5-dimethoxyphenyl)propionamide
3-(2-{4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionamide
3-(2-(40PM-3-PUB-DI)-2-{lBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propionamlde
3-(2-(40PM-3-MPUB-DI)-2-{IBU)-acetylamino}-3-(2,5-dimethoxyphenyi)propionamide
3-(2-(40TM-3-PUB-DI)-2-{!BU)-acety!amino)-3-(2,5-dimethoxyphenyi)propionamide
3-(2-(40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyi)propionamide
3-(2-(4PM-3-PUB-Di)-2-(iBU)-acetyiamino)-3-(2,5-dimethoxypheny!)propanol
3-(2-(4PM-3-MPUB-Dl)-2-(lBU)-acetylamino)-3-(2,5-dimethoxyphenyi)propanol
3-(2-(4TM-3-PUB-Dl)-2-{lBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propanol
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylaminQ)-3-(2,5-dimethoxypheny!)propanol
3-(2-(40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxypheny!)propanoi

3-(2-{40PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-{2,5-dinnethoxyphenyl)propanol
3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,5-dimethoxyphenyl)propanol
3-{2-{40TM-3-MPUB-DI)-2-(iBU)-acetylamino}-3-{2,5-dirnethoxyphenyl)propanol
3-(2-{4PM-3-PUB-DI)-2-{lBU)-acetylamino)-3-{2,6-dimethoxyphenyi)propionic acid
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino}-3-{2,6-dimethoxyphenyl)propionic acid
3-(2-{4TM-3-PUB-DI)-2-{IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionic acid
3-(2-(4TM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionic acid
3-(2-{40PM-3-PUB-D!)-2-(IBLI)-acetylamino)-3-(2,6-dimethoxyphenyl)propionic acid
3-{2-{40PM-3-MPUB-DI)-2-{IBU)-acetyiamino)-3-(2,6-dimethoxypheny()propionic
acid
3-(2-{40TM-3-PUB-DI)-2-{!BU)-acetytamino)-3-{2,6-dimethoxyphenyl)propionic acid
3-(2-(40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionic
acid
3-(2-{4PM-3-PUB-DI)-2-(iBU)-acety!amino)-3-(2,6-dimethoxyphenyl)propionamide
3-(2-{4PM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(2,6-dimethoxyphenyi)propionamide
3-(2-{4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionamide
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetyiarnino)-3-(2,6-dimethoxyphenyl)propionamide
3-{2-(40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyi)propionamide
3-{2-(40PM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-{2,6-dimethoxyphenyl)prGptonamide
3-(2-(40TM-3-PUB-DI)-2-(lBU)-acetylamino)-3-{2,6-dimethGxyphenyl)propionamide
3-(2-{40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propionamide
3-(2-{4PM-3-PUB-DI)-2-(lBU)-acetyiamino)-3-{2,6-dimethoxyphenyl)propanol
3-(2-(4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-{2,6-dimethoxyphenyi)propanoi
3-(2-{4TM-3-PUB-Dl)-2-{IBU)-acetylamino)-3-(2,6-dimethoxyphenyi)propanoi
3-(2-(4TM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propanol
3-(2-{40PM-3-PUB-DI)-2-{IBU)-acetytamino)-3-(2,5-dimethoxyphenyl)propanol
3-(2-(40PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propanol
3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(2,6-dimethoxyphenyl)propanoi
3-(2-(40TM-3-MPUB-Dl)-2-(IBU)-acetylamio)-3-(2,6-dimethoxyphenyl)propanol

3-(2-{4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid 3-(2-(4PM-3-MPUB-DI)-2-(lBU)-acetylamino}-3-(3,4-dimethoxyphenyl)propionic acid ■ 3-(2-{4TM-3-PUB-Dl)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid 3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid 3-(2-(40PM-3-PUB-Dl)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid 3-(2-(40PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid
3-(2-(40TM-3-PUB-DI)-2-(lBU)-acetylamino)-3-{3,4-dimethoxyphenyl)propionic acid 3-(2-{40TM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-{3,4-dimethoxyphenyl)propionic acid
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylarnino)-3-(3,4-dimethoxyphenyl)propionamide
3-(2-{4PM-3-MPUB-Dl)-2-(lBU)-acetyiamino)-3-(3,4-dimethoxyphenyl)propionamide
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetylamio)-3-(3,4-dimethoxyphenyl)propionamide
3-(2-{4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionamide
3-(2-{40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionamide
3-(2-(40PM-3-MPUB-DI)-2-{IBU)-acetyiamino)-3-(3,4-dimethoxyphenyl)propionamide
3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propionamide
3-{2-(40TM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(3,4-dimetlnoxyphenyl)propionamide
3-(2-{4PM-3-PUB-DI)-2-(iBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propanol
3-(2-{4PM-3-MPUB-DI)-2-{lBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propanol
3-(2-{4TM-3-PUB-DI)-2-(!BU)-acetylamino)-3-(3,4-dimethoxyphenyl)propanoi
3-(2-{4TM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-(3,4-dimethoxyphenyl)propanol
3-(2-{40PM-3-PUB-Dl)-2-(IBU)-acetylamino)-3-(3,4Hdimethoxyphenyl)propanol
3-{2-{40PM-3-MPUB-DI)-2-(IBU)-acetylamino}-3-(3,4-dimethoxyphenyl)propanol
3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetylafnino)-3-(3,4-dimethoxyphenyl)propanol
3-(2-{40TlV1-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-dirnethoxyphenyl)propanol
3-(2-(4PM-3-PUB-DI)-2-(lBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionic acid 3-{2-{4PM-3-MPUB-DI)-2-{lBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionic acid

3-{2-(4TM-3-PUB-DI)-2-{lBU)-acetylamino)-3-{3,5-dinnethoxyphenyl)propionic acid 3-(2-(4TM-3-MPUB-DI)-2-{lBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionic acid 3-(2-{40PM-3-PUB-DI)-2-(lBU)-acetylamino)-3-{3,5-dimethoxyphenyl)propionic acid 3-(2-{40PM-3-MPUB-DI)-2-{lBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionic
acid
3-(2-(40TM-3-PUB-DI)-2-{IBU)-acetylamino}-3-(3,5-dimethoxyphenyl)propionic acid 3-(2-(40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionic acid
3-(2-(4PM-3-PUB-DI)-2-{lBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionamide
3-(2-{4PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionamide
3-(2-(4TM-3-PUB-DI)-2-{lBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propionamide
3-{2-(4TM-3-MPUB-DI)-2-(IBU)-acetytamino)-3-(3,5-dimethoxyphenyl)propionamide
3-(2-(40PM-3-PUB-DI)-2-{IBU)-acety!amino)-3-(3,5-dimethoxyphenyt)propianamide
3-(2-(40PM-3-MPUB-DI)-2-(lBU)-acetylamino)-3-(3,5-dimethoxypheny!)propionamide
3-(2-(40TM-3-PUB-DI)-2-(lBU)-acetylamino)-3-(3,5-dimethoxyphenyi)propionamide
3-(2-(40TM-3-MPUB-DI)-2-{IBU)-acetyiamino)-3-(3,5-dimethoxyphenyl)propionamide
3-(2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propanol
3-(2-(4PM-3-MPUB-DI)-2-(!BU)-acetylamino)-3-(3,5-dimethoxyphenyl)propanol
3-(2-{4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propanol
3-(2-{4TiV1-3-MPUB-DI)-2-(IBU)-acetyiamino)-3-(3,5-dimethoxyphenyl)propanol
3-(2-{40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propanol
3-(2-(40PM-3-MPUB-DI)-2-(IBU}-acetylamino)-3-(3,5-dimethoxyphenyl)propanol
3-(2-{40TM-3-PUB-D!)-2-(IBU)-acetylamino)-3-(3,5-dimethoxyphenyl)propanol
3-{2-{40TM-3-MPUB-DI)-2-(lBU)-acetyiamino)-3-{3,5-dimethoxyphenyl)propanol
3-(2-(4PM-3-PUB-D!)-2-(!BU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionic
acid
3-(2-(4PM-3-MPUB-Dl)-2-(lBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionic
acid 3-(2-(4TM-3-PUB-DI)-2-{iBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionic

acid
3-(2-(4TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methyienedioxyphenyl)propionic
acid
3-(2-(40PM-3-PUB-DI)-2-(lBU)-acetyiamino)-3-(3,4-rnethyienediQxyphenyi}propionic
acid
3-(2-{40PM-3-MPUB-Di)-2-(IBU)-acetytamino)-3-(3,4-methylenedioxyphenyl)-
propionic acid
3-(2-(40TM-3-PUB-Dl)-2-(!BU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propionic
acid
3-{2-(40TM-3-MPUB-DI)-2-(IBU)-acetytamtno)-3-(3,4-metlnylenedioxyphenyi)-
propionic acid
3-(2-{4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-{3,4-methylenedioxyphenyi)-
propionamide
3-(2-{4PM-3-MPUB-DI)-2-(IBU)-acetytamino)-3-{3,4-methyienedioxyphenyl)-
propionamide
3-(2-(4TM-3-PUB-DI)-2-(lBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)-
propionamide
3-(2-(4TM-3-MPUB-DI)-2-{!BU)-acetyiamino)-3-(3,4-methylenedioxyphenyl)-
propionamide
3-(2-{40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)-
propionamide
3-(2-{40PM-3-MPUB-D!)-2-(!BU)-acetylamino)-3-(3,4-methylenedioxyphenyi)-
propionamide
3-(2-(40TM-3-PUB-Di)-2-(IBU)-acetylamino)-3-{3,4-methylenedioxyphenyl)-
propionamide
3-(2-(40TM-3-MPUB-Dl)-2-(lBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)-
propionamide
3-(2-(4PM-3-PUB-Di)-2-(lBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propanol 3-(2-(4PM-3-MPUB-D!)-2-(lBU)-acetylam!no)-3-(3,4-methylenedioxyphenyl)propanol 3-(2-(4TM-3-PUB-Dl)-2-(IBU)-acetytamino)-3-(3,4-methylenedioxyphenyl)propanol 3-(2-{4TM-3-MPUB-Di)-2-{(BU)-acetyiamino)-3-(3,4-methylenediQxypheny!)propano!

3-(2-(40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)propanol 3-(2-{40PM-3-MPUB-Di)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl)-propanol . 3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methyienedioxyphenyl)prQpanoi 3-(2-{40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-methylenedioxyphenyl}-propanol
3-{2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethyienedioxyphenyl)propionic
acid
3-(2-(4PM-3-MPUB-D!)-2-(IBU)-acety(amino)-3-(3,4-ethylenedioxyphenyl)propiQnic
acid
3-(2-{4TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethy!enedioxyphenyl)propionic acid
3-(2-{4TM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-(3,4-ethyienedioxyphenyi)propionic
acid
3-(2-{40PM-3-PUB-Dl)-2-(lBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propionic
acid
3-(2-(40PM-3-MPUB-DI)-2-{lBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propionic
acid
3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetyiamino)-3-(3,4-€thylenedioxyphenyl)propionic
acid
3-{2-{40TM-3-MPUB-DI)-2-(lBU)-acetytamino)-3-(3,4-ethylenedioxyphenyl)propionic
acid
3-(2-(4PM-3-PUB-DI)-2-(!BU)-acetylamino)-3-(3,4-ethylenedioxyphenyi)propionamide
3-(2-{4PM-3-MPUB-DI)-2-(iBLI)-acetylamino)-3-{3,4-ethylenedioxypheny()-
propionamide
3-(2-(4TM-3-PUB-Dl)-2-(lBU)-acetyiamino)-3-(3,4-ethylenedioxyphenyl)propionamide
3-(2-(4TM-3-MPUB-DI)-2-(!BU)-acetylamino)-3-(3,4-ethylenediQxyphenyl)-
propionamide
3-(2-(40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-{3,4-ethylenedioxyphenyl)-
propionamide
3-(2-(40PM-3-MPUB-DI)-2-(IBU)-ac8tylamino)-3-{3,4-

ethylenedioxyphenyl)propionamide
3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)-propionamide
.3-(2-(40TM-3-MPUB-DI)-2-(IBU)-acetylaminQ)-3-(3,4-ethyienedioxyphenyl)-propionamide
3-{2-(4PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3.4-ethylenedioxyphenyl)propanol
3-(2-(4PM-3-MPUB-DI)-2-{IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyl)propanol
3-(2-(4TM-3-PUB-DI)-2-(IBU)-acetytarriino)-3-(3,4-€thylenedioxyphenyl)propanoi
3-{2-{4TM-3-MPUB-DI)-2-(IBU)-acety!amino)-3-(3,4-ethylenedioxyphenyl)propanol
3-(2-(40PM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3,4-ethylenedioxyphenyt)propanol
3-(2K40PM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-(3,4-€thylenedioxyphenyl)propanol
3-(2-(40TM-3-PUB-DI)-2-(IBU)-acetylamino)-3-(3.4-ethylenedioxyphenyl)propanol
3-(2-{40TM-3-MPUB-DI)-2-(IBU)-acetylamino)-3-{3,4-ethyienedioxyphenyl)propanol
All abovementioned compounds are a subject of the present invention in all their stereoisomeric forms and in the form of mixtures thereof in all ratios. The compound 3-(2-{4,4-{3-oxopentamethylene)-3-{4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)-propionamide mentioned above as an example is thus a subject of the invention, inter alia, in the form of (RS)-3-((RS)-2-(4,4-(3-oxopentamethylene)-3-(4-{3-(2-methyiphenyl)ureido)ben2yf)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyi)acetyl-amino)-3-(3,4-dimethoxyphenyl)propionamide, in the form of (S)-3-((S)-2-(4,4-(3-oxopentamethylene)-3-(4-(3-(2-methylphenyl)ureido)ben2yl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acety!amino)-3-{3,4-dimethoxyphenyl)propionamide, in the form of (S)-3-((R)-2-(4,4-(3-oxopentamethyiene)-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)-propionamide, in the form of (R)-3-((S)-2-{4,4-(3-oxopentamethylene)"3-(4-(3-(2-methylphenyl)ure(do)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methy!propyl)acetyl-amino)-3-(3,4-dimethoxypheny!)proptonamide, in the form of (R)'3-((R)-2-(4,4-{3-oxopentamethylene)-3-{4-(3-{2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-{3,4-dimethoxyphenyl)propionamide, in the form

of (S)-3-((RS)-2-{4,4-(3-oxopentamethylene)-3-(4-(3-(2-methyiphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)"2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)-propionamide, in the form of (R)-3-((RS)-2-{4,4-{3-oxopentamethylene)-3-(4-(3-(2-. methylphenyl)ureido)ben2yl)-2,5-dioxoimida2olidin'1-yi)-2-(2-methylpropyi)acetyi-amino)-3-(3,4-dimethoxyphenyl)propionamide, in the form of (RS)-3-((R)-2-(4,4-(3-oxopentamethylene)-3-(4-{3-(2-methylphenyl)ureido)ben2yl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)propionamide and in the form of (RS)-3-((S)-2-(4,4-(3-oxopentamethylene}-3-{4-{3-(2-methylphenyl)ureido)-benzyl)-2,5-dioxoimida2olidin-1-y!)-2-(2-methyipropyl)acetylamino)-3-(3.4-dimethoxyphenyl)propionamide, and this applies expressly to all compounds mentioned. In another way of looking at the situation, with respect to the individual stereoisomers all compounds mentioned are a subject of the invention in the stereochemical arrangement which is shown in formula If, as well as in the arrangement which is shown in formula Ig, as well as in the arrangement which is shown in formula Ih, as well as in the arrangement which is shown in formula li, in particular in the stereochemical arrangement which is shown in formula If. Also all above-listed compounds are a subject of the invention in the form of their physiologically tolerable salts and in the form of their prodrugs and other physiologically tolerable derivatives, for example their esters.
The present invention furthermore expressly relates to all compounds analogous to the listed individual compounds which instead of the isobutyl-substituted acetyiamino group contain a cyclopropyimethyl-substituted acetyiamino group, and to all compounds analogous to the listed individual compounds which instead of the 4-(3-arylureido)ben2yl group contain a 4-(3-aryiureido)-3-methoxybenzyl group, and to all compounds analogous to the listed individual compounds which at the same time instead of the isobutyl-substituted acetyiamino group contain a cyclopropyimethyl-substituted acetyiamino group and instead of the 4-(3-arylureido)benzyl group contain a 4-{3-aryiureido)-3-methoxyben2yl group, where also all these compounds are a subject of the present invention in all their stereoisomehc forms and in the form of mixtures thereof in all ratios and in the form of their physiologically tolerable salts and in the form of their prodrugs.

where, in the formulae II and III the groups X, W, V, E, R1 and R2 are defined as indicated above or also functional groups in these groups can be present in protected form or in the fonn of precursors, and where G is hydroxycarbonyl, (C1-C6)-aikoxycarbonyi or an activated carboxylic acid derivative such as an acid chloride or an active ester.
In the condensation of the compounds of the formulae II and III, usually it is necessary that a carboxylic acid group which is present but which is not involved in the condensation reaction is protected by a reversible protective group, for example as a suitable (C1-C6)-alkyl ester such as the tert-butyl ester or as a benzyl ester. If compounds of the formula I are to be prepared in which the group E is, for example, hydroxycarbonyl or a group which is to be prepared from a hydroxycarbonyl group, in the compounds of the formula ill, for example, the group E can initially be a hydroxycarbonyl group which is present in protected form and then, after the condensation of the compounds of the formulae II and III in one or more further steps, the hydroxycarbonyl group can be liberated or the desired final group E can be

synthesized.
Precursors of functional groups are groups which can be converted into the desired . functional group by the customary synthesis processes known to the person skilled in the art. For example, a cyano group which can be converted into an acid amide group or a carboxylic acid group by hydrolysis or can be converted into a tetrazole by reaction with an azide can be designated as a precursor for these groups. An alcohol group which can be oxidized to an aldehyde group can be designated as a precursor for this group. Examples of protective groups which are introduced into a molecule before carrying out a reaction or a reaction sequence and are later removed again have already been mentioned.
For the condensation of the compounds of the formulae ll and III, the coupling methods of peptide chemistry which are well-known to the person skilled in the art are advantageously used (see, for example, Houben-Weyl, Methoden der Organischen Chemie, Volume 15/1 and 15/2, Georg Thieme Verlag, Stuttgart, 1974). Suitable condensing agents or coupling reagents are, for example, carbonyldiimidazole, carbodiimides such as dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide, 0-((cyano(ethoxycarbonyl)methylene)amino)-N,N,N',N'-tetramethyiuronium tetrafluoroborate (TOTU) or propylphosphonic anhydride (PPA). The condensations can be carried out under the standard conditions well-known to the person skilled in the art. In general, they are carried out in an inert solvent or diluent, for example in an aprotic solvent such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), tetrahydrofuran (THF) or dimethoxyethane (DME). Depending on the condensation carried out in the individual case, it may be advantageous to add a base such as a tertiary amine or auxiliary reagents, for example an N-hydroxy compound such as l-hydroxybenzotriazole (HOBT). The working-up of the reaction mixture and a purification of the product can be carried out by customary standard processes. After the condensation, the protective groups present are removed in a suitable manner. For example, benzyl groups in benzyl esters can be removed by hydrogenation or protective groups of the tert-butyl type can be removed acidically. The compounds of the formula 1 can also

be prepared, for example, by synthesizing the compounds stepwise on a solid phase according to customary methods, it being possible to introduce the individual structural elements of the molecule in different sequences.
The amino compounds of the formula III are commercially available or can be synthesized by or analogously to well-known standard processes from starting compounds which are commercially available or, in turn, are obtainable by or analogously to literature procedures. For example, optically active 3-substituted 3-aminopropionic acids of the formula III or their esters, in particular 3-phenyl-3-aminopropionic acid esters, can be prepared from the corresponding 3-substituted acrylic acids, which in turn are obtainable from the corresponding aldehydes. The 3-substituted acrylic acids are converted into the acid chlorides using oxalyl chloride, and the acid chlorides are converted into the esters using an alcohol, for example into the tert-butyl esters using tert-butanol. For the introduction of the amino group, the ester is then reacted with the lithium salt of an optically active amine, for example the lithium salt of (R)-(+)-N-benzyi-N-(1-phenylethyl)amine, and subsequently, in the 3-substituted tert-butyl 3-(N-benzyl-N-(1-phenylethyl)amino)propionate obtained, the benzyl group and the phenylethyl group are removed by catalytic hydrogenation. For the preparation of compounds of the formula III in which E is the hydroxymethyl group CH2OH or an etherified or esterified hydroxymethyl group, 3-substituted 3-aminopropanols or their esters or ethers which are obtainable from the 3-substituted 3-aminopropionic acids or their esters by reduction of the acid group (or of the ester group), for example from the ethyl ester or tert-butyl ester using lithium aluminum hydride or lithium aluminum hydride/aluminum trichloride, can be employed in the condensation reaction.
Compounds of the formula II can be prepared, for example, by first reacting compounds of the formula IV

in a Bucherer reaction, for example with ammonium carbonate and potassium cyanide, to give compounds of the formula V

in which W, X and G are defined as indicated above or functional groups can be present in protected form or in the form of precursors, can then be obtained by reacting the compounds of the formula V, for example, with a first alkylating reagent of the formula LG-CH(G)-CH2-W which introduces the residue -CH(G)-CH2-W into the molecule. The reaction of compounds of the formula VI with a second alkylating reagent of the formula VII

compounds of the formula II. The group LG is a nucieophiiically substitutable leaving group, for example halogen such as chlorine or bromine, or sulfonyloxy such as tosyloxy, methylsulfonyloxy or trifluoromethylsulfonyloxy.
Compounds of the formula II can also be prepared, for example, by reacting a compound of the formula VI first with a reagent of the formula 4-{PG-NH)-C6VH3-CH2-LG, in which LG in turn is a nucieophiiically substitutable leaving group and the group V in the 3-position is hydrogen or methoxy, to give a compound of the formula VIII

where the meanings indicated above apply to G, V, W and X and PG is an amino
protective group, for example tert-butoxycarbony! or benzyloxycarbonyl. After
removal of the protective group PG, the compounds of the formula II are obtained by
reaction of the resulting amino group H2N with phenyl isocyanate or with
2-methylphenyi isocyanate. Like compounds of the formula VllI, also compounds can .r
be prepared and employed in which the group PG-NH- in the formula VIH is replaced
by a group which is a precursor for an amino group and which is then converted into
an amino group in a further reaction step. For example a compound of the formula VI
can first be reacted with a nitro compound of the formula 4-O2N-C6VH3-CH2-LG to
give a compound corresponding to the compound of the fonmula VIII, then the nitro
group can be converted into the amino group, for example by catalytic
hydrogenation, and then the amino group can be converted into the desired
compound of the formula II using phenyl isocyanate or 2-methylpheny( isocyanate.
In case a compound of the formula I is to be prepared in which one of the CH2 groups in the group X in the spiro-linked ring is replaced by a C=0 group, it is expedient first

to protect this carbonyl group, for example as a ketal, and to carry out the Bucherer reaction with the protected compound of the formula IV, for example the monoketal of the cycloalkanedione. The aikylations of the protected compound of the formula V to give the compounds of the formulae Vl and VIII are then carried out as explained and thereafter, or otherwise at a later time dunng the synthesis, the carbonyl group in the group X is liberated again. In the case of a ketal protective group, the liberation of the protected carbonyl group can be carried out by treating with an acid analogously to literature processes.
In general, the individual steps in the preparation of the compounds of the formula I can be carried out according to or analogously to known methods familiar to the person skilled in the art. As already mentioned and as is known to the person skilled in the art, depending on the individual case it may be appropriate in all steps in the synthesis of the compounds of the formula i temporarily to block functional groups which could lead to side reactions or undesired reactions by a protective group strategy tailored to the synthesis problem.
Compounds of the formula 1 can also be obtained as follows. By reaction of N-substituted amino acids obtainable by standard processes or preferably of their esters, for example the methyl esters, ethyl esters, tert-butyl esters or benzyl esters, for example of compounds of the formula !X

for which the above definitions apply and which is obtainable according to standard processes from the corresponding compound which instead of the isocyanate group contains an H2N group, urea derivatives, for example of the formula XI

for which the definitions indicated above apply, are obtained. The compounds of the formula XI can then be cydized to the compounds of the formula I by heating with acid. The cyclization of the compounds of the formula XI to the compounds of the formula 1 can also be carried out by treatment with bases in inert solvents, for example by treating with sodium hydride in an aprotic solvent such as dimethylformamide. During the reaction, functional groups can be present in protected form.
Compounds of the formula I can also be obtained by reacting a compound of the formula IX with an isocyanate of the formula XII

in which Q, for example, is an alkoxy group, for example a (C1-C4)-alkoxy group such

as methoxy, ethoxy or tert-butoxy, or a (C5-C14)-aryl-(C1-C4)-alkoxy group, for example benzyloxy, and W has the meanings indicated above. In this case, a compound of the formula XIII is obtained

in which X, W, V, Q and R1 are defined as indicated above, which is then cyciized under the influence of an acid or of a base, as described above for the cyclization of the compounds of the formula XI, to a compound of the formula XIV

in which Q, W, V, X and R1 are defined as indicated above. In the compound of the formula XIV, it is then possible, for example by means of hydrolysis, to convert the group CO-Q into the carboxylic acid group COOH, If the cyclization of the compound of the formula XIII to the compound of the formula XIV is carried out using an acid, the conversion of the group CO-Q into the group COOH can also be carried out simultaneously with the cyclization. By subsequent coupling with a compound of the formula III, as described above for the coupling of the compounds of the formulae II and III, a compound of the formula 1 is then obtained. In this synthesis process too, functional groups can be present in protected form or in the form of precursors.
A further method for the preparation of compounds of the formula I is, for example,

for which the definitions indicated above apply, with phosgene or corresponding equivalents (analogously to S. Goldschmidt and M. Wick, Liebigs Ann. Chem. 575 (1952), 217 and C. Tropp, Chem. Ber. 61 (1928), 1431).
Compounds of the formula I can also be prepared by first coupling a compound of the formula XVI

in which Q' is a protected carboxyiic acid hydroxy group, for example an alkoxy group such as tert-butoxy, and W has the meanings indicated above, to give a compound of the formula XVIII

in which X, W and Q' have the meanings indicated above. For the introduction of the carbonyl group, it is possible to use, for example, phosgene or a phosgene equivalent (analogously to the reaction of the compounds of the formula XV illustrated above). An intermediate which can occur or can be specifically prepared in the conversion of the compound of the formula XVlll into the compound of the formula XIX is, for example, an isocyanate. The conversion of the compound of the formula XVIII into that of the formula XIX can be carried out in one or more steps. For example, the carbonyl group can first be introduced into the molecule and in a separate step the cycfization can then be carried out in the presence of a base such as sodium hydride, like the cyciizations described above. Compounds of the formula XVlll, in which PG is the benzyloxycarbonyl group, can also be converted directly into compounds of the formula XIX without an additional synthesis component such as phosgene being employed for the introduction of the carbonyl group. If compounds of

the formula XVIll in which PG isbenzytoxycarbonyl are treated with a base such as sodium hydride, the compounds of the formula XIX can be obtained directly.
The compounds of the formula XIX can then be alkylated on the NH group using a reagent of the formula VII, for example, as illustrated above for the compounds of the formula VI, and after conversion of the protected carboxylic acid group CO-Q' into the carboxylic acid group COOH, the desired compounds of the formula I can be synthesized as described above for the compounds of the formulae VI and II. In this synthesis process too, functional groups can be present in protected fonn or in the form of precursors.

Compounds of the formula XXll can also be prepared by first preparing a compound of the formula XVlll in which X, W and Q' have the meanings indicated and PG is an alkoxycarbonyi group such as (C1-C4)-alkoxycarbonyl, an aryialkoxycarbonyl group such as phenyl-(C1-C4)-alkoxycarbonyl, or an aryloxycarbony! group such as phenyloxycarbonyl, converting it by liberating the protected carboxyiic acid group CO-Q' into a compound of the formula XVlll in which CO-Q' is the free carboxyiic acid group CO-OH, PG is alkoxycarbonyi, aryialkoxycarbonyl or aryloxycarbony! and X and W have the meanings indicated, and cyciizing this compound with a base such as, for example, sodium carbonate to the compound of the formula XXII.

in which R\ V, W and X have the meanings indicated above, can then be obtained by reacting the compounds of the formula XXll with an alkylating reagent of the formula VlI in the presence of excess base, for example in the presence of an excess of n-butyllithium, and then acidifying. The 4-(3-arylureido)ben2yl group can also be introduced into the compounds of the formula XXll stepwise, analogously to the preparation of the compounds of the formula Vlll and the compounds of the formula II obtained therefrom. If, in the compounds of the formula XXll, a CH2 group in the group X is replaced by a carbonyi group, it is expedient to protect this carbonyl group

for the alkylation reactions to give the compounds of the formula lia and to liberate it again after the alkylation, as has been explained above.
' The compounds of the formula I in which E, for example, is hydroxycarbonyl or hydroxymethyl can be converted by standard processes into compounds of the formula I in which E has other meanings, or into other prodrugs or derivatives of the compounds of the formula 1. Thus, for the preparation of esters the compounds of the formula I in which E is hydroxycarbonyl can be esterified with the corresponding alcohols, for example in the presence of a condensing reagent such as DCC, or the compounds of the formula I in which E is hydroxycarbonyl can be alkylated using alkyl halides such as alkyl chlorides or alkyl bromides, for example using chloroalkanamides to give compounds of the fonmula I in which E is R4R4N-CO-alkoxy-CO-, or with acyloxyalkyl halides to give compounds of the formula I in which E is acyloxyalkoxy-CO-. Compounds of the formula 1 in which E is hydroxycarbonyl can be converted into amides using ammonia or organic amines in the presence of a condensing reagent. Compounds of the formula i in which E is CO-NH2 can advantageously also be obtained on the solid phase, by coupling the compound in which E is COOH to Rink amide resin in the presence of a condensing agent such as TOTU and then removing it again from the resin using trifluoroacetic acid. Compounds of the formula I in which E is the hydroxymethyl group CH2OH can be etherified or esterified on the hydroxymethyl group according to standard processes. According to standard processes for the selective oxidation of alcohols to aldehydes, for example using sodium hypochlorite in the presence of 4-acetamido-2,2,6,6-tetramethylpiperidin-1-oxyl (4-acetamido-TEMPO), compounds of the fonnuia I in which E is CH2OH can be converted into compounds of the formula 1 in which E is the aldehyde group CO-H.
The compounds of the formula I are valuable pharmaceutical active compounds which are suitable, for example, for the therapy and prophylaxis of inflammatory diseases, allergic diseases or asthma. The compounds of the formula I and their physiologically tolerable salts and derivatives can be administered according to the invention to animals, preferably to mammals, and in particular to humans, as

pharmaceuticals for therapy or prophylaxis. They can be administered on their own, in mixtures with one another or in the form of pharmaceutical preparations which allow enteral or parenteral use and which, as active constituent, contain an efficacious dose of at least one compound of the formula I and/or its physiologically tolerable salts and derivatives in addition to pharmaceutically innocuous vehicles and/or additives.
The present invention therefore also relates to the compounds of the formula I and/or their physiologically tolerable salts and derivatives for use as pharmaceuticals, the use of the compounds of the formula I and/or their physiologically tolerable salts and derivatives for the production of pharmaceuticals for the therapy and prophylaxis of the illnesses illustrated above and in the following, for example for the therapy and prophylaxis of inflammatory diseases, and the use of the compounds of the formula 1 and/or their physiologically tolerable salts and derivatives in the therapy and prophylaxis of these illnesses. The present invention furthermore relates to pharmaceutical preparations (or pharmaceutical compositions) which contain an efficacious dose of at least one compound of the formula 1 and/or its physiologically tolerable salts and derivatives and a pharmaceutically tolerable carrier, that is one or more pharmaceutically innocuous vehicles and/or additives.
The pharmaceuticals can be administered systemically or locally. They can be administered, for example, orally in the form of pills, tablets, film-coated tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, powders, solutions, syrups, emulsions, suspensions and in other pharmaceutical forms. The administration can also be carried out vaginally or rectally, for example in the form of suppositories, or parenterally or by implantation, for example in the form of injection solutions or infusion solutions, microcapsules or rods, or topically or percutaneously, for example in the form of creams, ointments, powders, solutions, emulsions or tinctures, or in other ways, for example in the form of nasal sprays or aerosol mixtures. Parenteral administration of solutions can occur, for example, intravenously, intramuscularly, subcutaneously, intraarticulariy, intrasynovially or in other ways.

The pharmaceutical preparations according to the invention are produced in a known manner, the compound or the compounds of the formula I and/or its physiologically ■ tolerable salts and derivatives being mixed with pharmaceutically inert inorganic and/or organic vehicles and/or additives. For the production of pills, tablets, coated tablets and hard gelatin capsules, for example lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, polyethylene glycols, etc. may be used. For soft gelatin capsules and suppositories, for example, fats, waxes, semisolid and liquid polyols, polyethylene glycols, natural or hardened oils etc. may be used. Suitable vehicles for the production of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, alcohols, glycerol, diols, polyols, sucrose, invert sugar, glucose, vegetable oils etc. Suitable vehicles for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. The pharmaceutical preparations normally contain about 0.5 to about 90% by weight of the compounds of the formula I and/or their physiologically tolerable salts and derivatives. The amount of active compound of the formula I and/or its physiologically tolerable salts and derivatives in the pharmaceutical preparations is normally about 0.2 to about 1000 mg, preferably about 1 to about 500 mg, but depending on the nature of the pharmaceutical preparation the amount of the active compound can also be larger.
In addition to the active com.pounds and vehicles, the pharmaceutical preparations can additionally contain excipients or additives, for example fillers, disintegrants, binders, lubricants, wetting agents, stabilizing agents, emulsifiers, preservatives, sweeteners, colorants, flavorings, aromatizers, thickening agents, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for changing the osmotic pressure, coating agents or antioxidants. They can also contain two or more compounds of the formula I and/or their physiologically tolerable salts and derivatives. Furthermore, in addition to at least one compound of the formula I and/or its physiologically tolerable salts and derivatives they can contain one or more other pharmaceutical active compounds, for example substances having antiinflammatory action.

If the compounds of the formula I or pharmaceutical preparations comprising them are administered as aerosols, for example as nasal aerosols or by inhalation, this can * be carried out, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaler or a dry powder inhaler. Pharmaceutical forms for administration of the compounds of the formula I as an aerosol can be prepared by processes well-known to the person skilled in the art. For their preparation, for example, solutions or dispersions of the compounds of the formula I in water, water/alcohol mixtures or suitable saline solutions can be employed using customary additives, for example benzyl alcohol or other suitable preservatives, absorption enhancers for increasing the bioavailability, solubilizers, dispersants and others, and, if appropriate, customary propellants, for example chlorofluorohydrocarbons and/or fluorohydrocarbons.
Suitable other pharmaceutical active compounds which can be contained in addition to compounds of the formula 1 in the pharmaceutical preparations according to the invention, but with which the compounds of the formula I can also be combined in other ways in the context of a combination therapy or combination prophylaxis, are in particular such active compounds which are suitable for the therapy or prophylaxis of the illnesses mentioned above or in the following for whose therapy or prophylaxis the compounds of the formula I are suitable. Examples of classes of active compound of this type which may be mentioned are steroids, nonsteroidal antiinflammatory substances, nonsteroidal antiinflammatory acetic acid derivatives, nonsteroidal antiinflammatory propionic acid derivatives, nonsteroidal antiasthmatics, salicylic acid derivatives, pyrazolones, oxicams, leukotriene antagonists, inhibitors of leukotriene biosynthesis, cyclooxygenase inhibitors, cyclooxygenase-2 inhibitors, (COX-2 inhibitors), antihistamines, H1-histamine antagonists, nonsedating antihistamines, gold compounds, β2 agonists, anticholinergics, muscarine antagonists, antihyperiipidemics, antihypercholesterolemics, HMG-CoA reductase inhibitors, statins, nicotinic acid derivatives, immunosuppressants, cyclosporins, β-interferons, tumor therapeutics, cytostatics, metastasis inhibitors, antimetabolites, 5-aminosalicyiic add derivatives, antidiabetics, insulins, sulfonylureas, biguanides,

giitazones, a-glucosidase inhibitors, and others. Examples of suitable active compounds which may be mentioned are acetylsalicylic acid, benorilate, sulfasalazine, phenylbutazone, oxyphenbutazone, metamizole, mofebutazone, ■ feprazone, celecoxib, rofecoxib, diclofenac, fentiazac, sulindac, zomepirac, tolmetin, indometacin, acemetacin, ibuprofen. naproxen, carprofen, fenbufen, indoprofen, ketoprofen, pirprofen, tiaprofenic acid, diflunisal, flufenamic acid, meciofenamic acid, mefenamic acid, niflumic acid, tolfenamic acid, piroxicam, isoxicam, tenoxicam, nicotinic acid, prednisone, dexamethasone, hydrocortisone, methylprednisolone, betamethasone, bedomethasone, budesonide, montekulast, prankulast, zafirkulast, zileutone, cidosporin, rapamycin, tacrolimus, methotrexate, 6-mercaptopurine, azathiopnne, interferon-beta-1a, interferon-beta-1b, 5-aminosalicylic acid, leflunomide, D-peniciilamine, chloroquine, glibendamide. glimepiride. trogiitazone, metformin, acarbose, atorvastatin, fluvastatin, lovastatin, simvastatin, pravastatin, colestipol, colestyramine, probucol, ciofibrate, fenofibrate, bezafibrate, gemfibrozil, ipatropium bromide, clenbuterol, fenoteroi, metaproterenoi, pirbuterol, tulobuterol, salbutamol, salmeterol, terbutalin, isoetarine, ketotifen, ephedrine, oxitropium bromide, atropine, cromoglycic acid, theophylline, fexofenadine, terfenadine, cetirizine, dimetindene, diphenhydramine, diphenylpyraline, pheniramine, bromopheniramine, chloropheniramine, dexchloropheniramine, alimemazine, antazoiine, astemizole, azatadine, clemastine, cyproheptadine, hydroxyzine, loratidine, mepyramine, promethazine, tripelennamine, triprolidine and others.
If compounds of the formula 1 and/or their physiologically tolerable salts or prodrugs are to be employed in a combination therapy or combination prophylaxis together with one or more other active compounds, this can be carried out as mentioned by administering all active compounds together in a single pharmaceutical preparation, for example a tablet or capsule. Pharmaceutical preparations of this type, for which all explanations above correspondingly apply, are expressly likewise a subject of the present invention. The amount of the active compounds in these pharmaceutical preparations is in general such that an efficacious amount of each active compound is present. A combination therapy or combination prophylaxis, however, can also be carried out by the active compounds being present in two or more separate

pharmaceutical preparations which can be in a single pack or in two or more separate packs. The administration of the compounds of the formula I and/or their physiologically tolerable salts or products and the other active compounds can be . carried out jointly or separately and can be carried out simultaneously or sequentially, i in any order. The administration can also be carried out in different ways, for example one active compound can be administered orally and the other by injection, inhalation or topical application.
The compounds of the formula 1 have, for example, the ability to inhibit cell-cell interaction processes and cell-matrix interaction processes in which interactions between VLA-4 and its ligands play a role. The activity of the compounds of the formula I can be demonstrated, for example, in an assay in which the binding of cells which contain the VLA--4 receptor, for example of leukocytes, to ligands of this receptor, for example to VCAM-I which advantageously can also be prepared for this purpose by genetic engineering, is measured. Details of such an assay are described below. In particular, the compounds of the formula I are able to inhibit the adhesion and the migration of leukocytes, for example the adhesion of leukocytes to endothelial cells which - as explained above - is controlled via the VCAM-1A/LA-4 adhesion mechanism. Apart from as antiinflammatory substances, the compounds of the formula I and their physiologically tolerable salts and derivatives are therefore generally suitable for the therapy and prophylaxis of illnesses which are based on the interaction between the VLA-4 receptor and its ligands or can be affected by an inhibition of this interaction, and they are in particular suitable for the therapy and prophylaxis of illnesses which are at least partially caused by an undesired extent of leukocyte adhesion and/or leukocyte migration or are associated therewith, and for whose prevention, alleviation or cure the adhesion and/or migration of leukocytes should be decreased.
The present invention therefore also relates to the compounds of the formula I and their physiologically tolerable salts and derivatives for the inhibition of the adhesion and/or migration of leukocytes or for the inhibition of the VLA-4 receptor, and to the use of the compounds of the formula I for the production of pharmaceuticals for this.

that is of pharmaceuticais for the therapy or prophylaxis of illnesses in which leukocyte adhesion and/or leukocyte migration exhibits an undesired extent, or for the therapy or prophylaxis of illnesses in which VLA-4-dependent adhesion processes piay a part, and to the use of the compounds of the formula I and/or their physiologically tolerable salts and derivatives in the therapy and prophylaxis of illnesses of this type.
The compounds of the formula I can be employed as antiinflammatories in the case of inflammatory symptoms of very different causes in order to prevent, to decrease or to suppress the undesired or harmful consequences of inflammation. They are used, for example, for the therapy or prophylaxis of arthritis, of rheumatoid arthritis, of polyarthritis, of inflammatory bowel disease (ulcerative colitis), of systemic lupus erythematosus, for the therapy or prophylaxis of inflammatory disorders of the central nervous system such as, for example, of multiple sclerosis, or for the therapy or prophylaxis of asthma or of allergies, for example allergies of the delayed type (type IV allergy). They are furthermore suitable for the therapy or prophylaxis of cardiovascular disorders, of arteriosclerosis, of restenoses, of diabetes, of damage to organ transplants, of immune disorders, of autoimmune disorders, of tumor growth or tumor metastasis in various malignancies, of malaria as well as of further illnesses in which blocking of the integrin VLA-4 and/or influencing of the leukocyte activity appears appropriate for prevention, alleviation or cure.
The dose when using the compounds of the formula 1 can vary within wide limits, and as is customary and is known to the physician, it is to be tailored to the individual conditions in each individual case. It depends, for example, on the nature and severity of the illness to be treated, on the condition of the patient, on the compound employed or on whether an acute or chronic disease state is treated or prophylaxis is conducted or on whether further active compounds are administered in addition to the compounds of the formula 1. In general, in the case of oral administration, a daily dose of about 0.01 to about 100 mg/kg, preferably about 0.1 to about 10 mg/kg (in each case mg of the compound per kg of body weight) is appropriate in an adult weighing about 75 kg to achieve effective results. In the case of intravenous

administration, the daily dose is in general about 0,01 to about 50 mg/kg of body weight, preferably about 0,01 to about 10 mg/kg. The daily dose can be divided, in particular when relatively large amounts are administered, into several, for example ' 2, 3 or 4, part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated.
Apart from as pharmaceutical active compounds in human medicine and veterinary medicine, the compounds of the formula I and their salts and derivatives suitable for the use concerned can furthermore be employed for diagnostic purposes, for example in in-vitro diagnoses of cell samples or tissue samples, and as auxiliaries or as a scientific tool in biochemical investigations in which VLA-4 blocking or influencing of cell-cell or cell-matrix interactions is demanded. Furthermore, the compounds of the formula I and their salts can be used as intermediates for the preparation of other compounds, in particular of other pharmaceutical active compounds which are obtainable from compounds of the formula I, for example by modification or introduction of residues or functional groups, for example by esterification, reduction, oxidation or other conversions of functional groups.
Examples
Example 1 (S)-3-{(S)-2-(4,4-Pentamethylene-3-(4-(3-phenylureido)benzyl)-2,5-dioxoimida2olidin-
1 -yl)-2-{2-methylpropyl)acetylamino)-3-phenylpropionic acid

a) 4-(3-Phenylureido)benzyl alcohol
30.6 g (200 mmol) of 4-nitrobenzyl alcohol were hydrogenated over 1.0 g of palladium/carbon (10% strength; 50% water) in 500 ml of methyl tert-butyl ether After the absorption of hydrogen was complete, the catalyst was filtered off. 24 g (200 mmol) of phenyl isocyanate were added to the filtrate at 15°C with stirring in the course of 30 minutes. The precipitated solid was filtered off with suction and washed with methyl tert-butyl ether. Yield: 43 g (89%).
b) 4-(3-Phenylureido)ben2yl chloride
42 g (354 mmol) of thionyl chloride were added dropwise at 30^*0 to a suspension of ":
42.8 g (177 mmol) of 4-(3-phenyiureido)benzy! alcohol in 500 ml of dichloromethane.
The mixture was subsequently stirred at 40*'C for 1 hour. After completion of the
evolution of gas, the mixture was allowed to cool to room temperature. The
precipitated product was filtered off with suction and washed with dichloromethane.
Yield: 44.26 g (96%).
c) Methyl 1-aminocyclohexane-1-carboxylate
51 ml of thionyl chloride were added in portions at -5°C to 50 g (350 mmol) of 1-aminocyclohexane-1-carboxylic acid in 1.25 I of methanol. The reaction mixture was subsequently stinted at room temperature for 5 hours and allowed to stand overnight at room temperature. The methanol was removed in vacuo, the residue was mixed with water, and the aqueous solution was adjusted to pH 9 using saturated sodium carbonate solution and extracted twice with dichloromethane. The organic phase was dried over sodium sulfate and, after filtration, the solvent was removed in vacuo. Yield: 36.35 g (66%).
d) Methyl 1 -(3-((S)-1 -tert-butoxycarbonyl-3-methylbuty!)ureido)cyclo-
hexanecarboxylate
A solution of 28 g (179 mmol) of methyl 1-aminocyclohexane-1-carboxytate was added to a solution of 38 g (179 mmol) of L-leucine tert-butyl ester isocyanate (prepared analogously to J.S. Nowick et al., J. Org. Chem. 1996, 61, 3929) in 300 ml of absolute DMF. After stirring at room temperature for 2 hours, the reaction mixture

was allowed to stand overnight. The solvent was removed in vacuo, the residue was treated with heptane and the mixture was stirred at room temperature for 2 hours. The precipitate was filtered off with suction and washed with heptane. Yield: 45.94 g (69%).
e) (S)-2-(4,4-Pentamethylene-2,5-dioxoimidazolidin-1-yl}-2-(2-methylpropyl)acetic
acid
11.4 g (30.8 mmol) of methyl 1-(3-{(S)-1-tert-butoxycarbonyl-3-methylbutyl)ureido)-cyciohexanecarboxyiate were heated at 60°C for 8 hours in 200 ml of 6 N hydrochloric acid, and the mixture was allowed to stand at room temperature overnight and then extracted with diethyl ether. The combined extracts were concentrated in vacuo, and the residue was taken up with a little acetonitrile, treated with water and freeze-dried. Yield: 8.28 g (95%).
f) (S)-2-(4,4-Pentamethylene-3-(4-{3-phenylureido)benzyl)-2,5-dioxoimidazolidin-
1 -yl)-2-(2-methyipropyi)acetic acid
21 ml of an n-butyllithium solution (2.5 M in hexane) were added at -76°C under argon to a solution of 7.4 g (26.24 mmol) of (S)-2-(4,4-pentamethylene-2,5-dioxoimidazolidin-1-yl)- 2-(2-methylpropyl)acetic acid in 150 ml of absolute THF, After stirring at -76°C for 30 minutes, the reaction mixture was allowed to warm to 0°C and 5.82 g (26,24 mmol) of 4-(3-phenylureido)benzyl chloride were added in portions. After stirring at 0°C for 30 minutes, the mixture was adjusted to pH 1 by addition of 1 N hydrochloric acid, diluted with water and extracted with ethyl acetate. After separating the phases, the organic phase was dried over sodium sulfate and, after filtration, the solvent was removed in vacuo. The residue thus obtained was purified by means of preparative HPLC. Yield: 2.18 g (16%).
g) Ethyl (S)-3-((S)-2-(4,4-pentamethylene-3-(4-(3-phenyluretdo)benzyl)-2,5-
dioxoimidazolidin-1-yl)-2-(2-methyipropyl)acetylamino)-3-phenylpropionate
525 mg (1.42 mmol) of TOTU and 230 µl (1.35 mmol) of N,N-diisopropylethylamine were added successively with ice-cooling to a solution of 720 mg (1.42 mmol) of (S)-2-(4,4-pentamethylene-3-(4-(3-phenylureido)benzyi)-2,5-diaxoimidazolidin-1-yl)-

2-(2^methylpropyl)acetic acid and 274 mg (1.42 mmol) of ethyt (S)-3-amino-3-phenytpropionate (prepared from the hydrochloride) in 20 ml of absolute DMF. After 1 hour at room temperature, the solvent was removed in vacuo, the residue was dissolved in ethyl acetate and the ethyl acetate solution was successively washed twice in each case with an aqueous KHSO4/K2SO4 solution, a saturated NaHCOa solution and a saturated sodium chloride solution. After drying the organic phase over sodium sulfate and filtering, the solvent was removed in vacuo and the residue was chromatographed on silica gel using ethyl acetate/heptane (1/1). After concentrating the product fractions, 826 mg (85%) of the title compound were obtained.
h) (S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-phenylureido)ben2yl)-2,5-
dioxoimida20lidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-phenylpropionic acid
3.61 ml of a 1 M lithium hydroxide solution were added to 820 mg (1.2 mmol) of ethyl
(S)-3-((S)-2-(4,4-pentamethylene-3-(4-(3-phenylureido)benzyl)-2,5-dioxoimidazolidin-
1-yl)-2-(2-methylpropyl)acetylamino)-3-phenylpropionate in 30 ml of methanol and
the mixture was stirred at room temperature overnight. After fresh addition of 10 ml of
methanol and 1.2 ml of 1 M lithium hydroxide solution and stirring overnight, 30 ml of
water were added and the methanol was largely removed in vacuo. The residual
aqueous phase was adjusted to pH 1 by addition of 1 N hydrochloric acid and
extracted twice with ethyl acetate. The combined organic phases were washed with ; ^•
water, dried over sodium sulfate and concentrated. 760 mg of the crude product
obtained were dissolved in acetonitrile/water and freeze dried. 639 mg of the title
compound were obtained.
ES(+)-MS: 654.4 (M+H)+.
Process for the preparation of the starting compound ethyl (S)-3-amino-3-phenylpropionate hydrochloride
i) (R)-2-Amino-2-phenylethanol
20 g (920 mmol) of lithium borohydride were dissolved in 420 ml of absolute THF.
233.5 ml (1.84 mol) of trimethylchlorosilane were added dropwise with stirring and

69.5 g (0.46 moi) of (R)-phenylgiycine were then added in portions in the course of 4 hours. The reaction mixture was stirred overnight at room temperature. 690 ml of methanol were then added, and the mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in 690 ml of 20% strength aqueous potassium hydroxide solution with stirnng. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with water, dhed over magnesium sulfate and concentrated in vacuo. Yield: 41.2 g (65.3%). FAB-MS: 138 (M+H+-
j) (R)-2-Benzytoxycarbonylamino-2-phenylethanol
40.5 g (295 mol) of (R)-2-amino-2-phenylethanol were dissolved in 385 ml of absolute DMF. 73.5 g of N-(benzyloxycarbonyloxy)succinimide (295 mmol) were added at O°C with stirring and the mixture was stirred at O°C for 1 hour. The ice bath was removed and the batch was allowed to stand at room temperature for 48 hours. The reaction solution was concentrated in vacuo and the residue was then taken up in 500 ml of ethyl acetate. The organic phase was washed twice with 10% strength aqueous citric acid solution and once with water. It was dried over anhydrous sodium sulfate and concentrated. The crystalline crude product obtained (82.3 g) was dissolved again in ethyl acetate. The organic phase was washed twice with 10% strength aqueous citric acid solution and once with water and concentrated. The residue was then recrystallized from ethyl acetate/petroleum ether. Yield: 74.6 g (93.3%). FAB-MS: 272 (M+H)+
k) (R)-2-Benzyloxycarbonylamino-2-phenylethyl 4-methylphenylsulfonate 53-9 g of (R)-2-benzyloxycarbonylamino-2-phenylethanol (198.7 mmol) were dissolved in a mixture of 500 ml of methylene chloride and 80.3 ml (993.5 mmol) of pyridine, 45.5 g (238.4 mmol) of tosyl chloride in 240 ml of methylene chlonde were added at O°C with stirring and the mixture was stirred at room temperature for 7 hours. A further 11.36 g of tosyl chloride (59.61 mmol) were added. The mixture was stirred at 0°C for 5 hours. The batch was then allowed to stand overnight at

room temperature and concentrated in vacuo. The residue was taken up in ethyl acetate. The organic phase was washed three times with 1C% strengtr, aqueous citric acid solution and twice with water, dned over magnesium salfare and
• concentrated in vacuo. The residue was triturated with diethyl etner, nitered off with suction, washed with diethyl ether and dried over phosphorus pentoxide. Yield: 60.9 g (72%). The mother liquor was concentrated, taken up in n-hepranetethyl acetate (6/4) and chromatographed on silica gel to give an additional yieid of 3.5 g (4.2%). Total yield: 64.4 g (76.2%).
FAB-MS: 426 (M+H)'.
I) (S)'-3-Benzyloxycarbonylamino-3-phenylpropionitrile
60.5 g of (R)-2-benzyloxycarbonylamino-2-phenylethyl 4-methyiphenylsulfonate (142.2 mmol) were dissolved in 675 ml of DMF. 13.9 g of potassium cyanide (213.3 mmol). 5.64 g of 18-crown-6 (21.33 mmol) and 520 mg of potassium iodide (3.13 mmol) were added and the mixture was stirred at 50°C for 20 hours The reaction solution was poured into 500 ml of ice water and then stirred at 0°C for 5 hours. The precipitate was filtered off with suction and dissolved in ethyl acetate. The organic phase was washed three times with water, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether, filtered off with suction, washed with diethyl ether and dried over phosphorus pentcxide. Yield: 25.3 g (63.5%). FAB-MS: 281 (M+H)+
m) Ethyl (S)-3-benzyloxycarbonyiamino-3-phenyipropionate 15 g of (S)-3-benzyloxycarbonylamino-3-phenylpropionitrile !;53.51 mmol; were suspended in a mixture of 110 ml of absolute ethanoi and 30 rrd of dicxane. HCl gas was passed in at 10-15°C with stirring and cooling. After a shc.^ t:rTie, a clear solution was formed. Further HCl gas was passed in with cooling until staring material was no longer detectable in the thin-layer chromatogram. Nitrogen was men cassed through the reaction solution for 15 minutes and it was then ccncentratad ;n vacuo. The residue was treated with water until turbidity persisted. The mixture was stirred

at room temperature for 30 minutes and the aqueous phase was then extracted three times with ethyl acetate. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was taken up in ethyl acetate/petroleum ether (1/1) and chromatographed on silica gei. Yield: 10.55 9(60%).
FAB-MS: 328 (M 4- H)+.
n) Ethyl (S)-3-amino-3-phenylpropionate hydrochlonde
10.29 g of ethyl (S)-benzyloxycarbonylamino-3-phenytpropionate (31.44 mmol) were dissolved in 125 ml of ethanol and catalyticaily hydrogenated over palladium/carbon at a pH of 4 in an autoburette with addition of 2 N ethanolic HCI. The catalyst was filtered off with suction through kieselguhr and the filtrate was concentrated. The residue was triturated with diethyl ether, filtered off with suction, washed with diethyl ether and dried over phosphorus pentoxide. Yield: 5.05 g (70%). FAB-MS: 194 (M+H)".

(S)-3-((S)-2-(4.4-pentamethylene-3-(4-(3-phenyiureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-{2-methylpropyl)acetylam!no)-3-phenylpropionic acid tromethamine salt were obtained, which according to the 1H-NMR spectrum contained 1.3 mol of . tromethamine per moie of (S)-3-{(S)-2-(4,4-pentamethyle^e-3-(4-(3-phenylu^eido)-be^zyl)-2,5-dioxoimida2olidin-1-y()-2-(2-methyip^opyl)acetylami^o)-3-phenylp^opionic acid.
ES(+)-MS: 122.0 (a,a,a-ths(hydroxymethyl)methylamine + H))+ 654.4 (3-(2-(4,4-
pentamethylene-3-(4-(3-phenylureido)ben2yl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropy()acetylamino)-3-phenyipropionic acid + H)+; 775.4.
Example 3
(R)-3-((S)-2-(4.4-Pentamethylene-3-(4-(3-phenylureido)ben2yl)-2,5-dioxoimidazolidin-1 -yl)-2-(2-methylpropyl)acetylamino)-3-methyipropionic acid

132 mg (0.988 mmol) of HOBT and 245 mg (1,18 mmol) of DCC were added with ice cooling to a solution of 500 mg (0.988 mmol) of (S)-2-(4,4-pentamethyle^e-3-(4-(3-phenylu^eido)be^zyl)-2,5-dioxoimidazo!idi^-1-yl)-2-(2-methylp^opyl)acetic acid in 15 ml of absolute DMF. After stirring with ice cooling for 1 hour, 157 mg (0.988 mmol) of tert-butyl (R)-3-aminobutanoate were added. After stirring at room temperature for 3 hours and allowing to stand overnight, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and in each case washed twice with an aqueous'KHSO4/K2SO4 solution and water. After drying the organic phase over sodium sulfate and filtering, the solvent was removed in vacuo. "The residue was taken up in acetonitrile/water and freeze dried. The residue thus obtained was chromatographed on silica gel using ethyl acetate/heptane

(1/3 and 1/1). After concentrating the product fractions, the residue was taken up in acetonitrile/water and freeze dried. For the cleavage of the tert-butyl ester, 10 ml of 95% strength trifluoroacetic acid were added and the mixture was allowed to stand at room temperature for 15 minutes. After removal of the volatile components in vacuo, the residue was taken up in acetonitrile/water and freeze dried. Yield; 463 mg (7S%). ES(+)-MS: 592.4 (M+H)+.
Example 4
(R)-3-((S)-2-{4,4-Pentamethylene-3-(4-(3-phenylureido)benzyl)-2,5-dioxoimidazolidin-
1-yl)-2-(2-methylpropyl)acetylamino)-3-(2-methylpropyl)propionic acid

132 mg (0.988 mmol) of HOBT and 245 mg (1.18 mmol) of DCC were added with ice cooling to a solution of 500 mg (0.988 mmol) of (S)-2-(4,4-pentamethylene-3-(4-(3-phenylureido)benzyi)-2,5-dioxoimidazolidin-1 -yl)-2-(2-methy!propyl)acetic acid in 15 ml of absolute DMF. After stirring with ice cooling for 1 hour, 199 mg (0.988 mmol) of tert-butyl (R)-3-amino-5-methylhexanoate were added. After stirring at room temperature for 3 hours and allowing to stand overnight, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and washed twice in each case with an aqueous KHSO4/K2SO4 solution and water. After drying the organic phase over sodium sulfate and filtering, the solvent was removed in vacuo. The residue was chromatographed on silica gel using ethyl acetate/heptane (1/3 and 1/1). After concentrating the product fractions, the residue was taken up in acetonitrile/water and freeze dried. For the cleavage of the tert-butyl ester, 10 ml of 95% strength trifluoroacetic acid were added and the mixture was stirred at room temperature for 30 minutes. After removal of the volatile components

in vacuo, the residue was taken up in acetonitnle/water and freeze dried. Yield: 447
mg(71%).
ES(+)-MS: 634.4 (M+H)Analogously to Examples 1, 3 and 4, the compounds of Examples 5, 6 and 7 can be prepared starting from l-aminocyciopentane-1-carboxylic acid.
Example 5
(S)-3-((S)-2-{4,4-Tetramethylene-3-(4-(3-phenylureido)ben2yl)-2,5-dioxoimida2o!idin-1 'yl)-2-(2-methylpropyl)acetyiamino)-3-phenylpropianic acid

Example 7 (R)-3-{(S)-2-{4,4-Tetramethylene-3-(4-(3-phenylureido)ben2yl)-2,5-dioxoimida2olidin-
1-yl)-2-(2-methylpropyl)acetylam!no)-3-(2-methylpropyt)propionic acid

a) 4-(3-(2-Methylphenyl)ureido)benzyl alcohol
30.6 g (200 mmol) of 4-nitrobenzyl alcohol were hydrogenated with ice cooling over 1.0 g of palladium/carbon (10% strength; 50% water) in 500 ml of methyl tert-butyl ether. After the absorption of hydrogen was complete, the catalyst was filtered off and 24,8 ml (200 mmol) of 2-methylphenyl isocyanate were added to the filtrate at 15°C with stirring in the course of 30 minutes. The precipitated solid was filtered off with suction and washed with methyl tert-butyl ether. Yield: 46.9 g (92%).
b) 4-(3-(2-Methylphenyl)ureido)benzyl chloride
5.66 ml (78.12 mmol) of thionyl chloride were added dropwise with ice cooling to a suspension of 10 g (39.06 mmoi) of 4-(3-(2-methylphenyl)ureido)benzyl alcohol in 150 ml of dichloromethane. The reaction mixture was subsequently stirred at room temperature for 1.5 hours and poured onto 200 ml of n-heptane. The heptane was

decanted off from the deposited oil and the oil was stirred with diisopropyl ether. The solid obtained was filtered off and washed with diisopropyl ether. Yield: 8.32 g (78%),
c) (S)-2-{4,4-Pentamethylene-3-(4-{3-(2-methyiphenyi)ureido)ben2y()-2,5-
dioxoimidazolidin-l -yl)-2-{2-methy!propyl)acetic acid
26.6 ml of an n-butyllithium solution (2.5 M in hexane) were added at 76°C under argon to a solution of 9.5 g (33.6 mmol) of (S)-2-(4,4-pentamethyfene-2,5-dioxoimidazolidin-1-yl)- 2-{2-methylpropyl)acetic add in 190 ml of absolute THF. After stirring at -76°C for 30 minutes, the reaction mixture was allowed to warm to 0°C and a solution of 9 g (33.5 mmol) of 4-(3-(2-methylphenyl)ureido)ben2yl chloride in 95 ml of NMP was added. After stirnng at room temperature for 60 minutes, 38 ml of 2 N hydrochloric acid were added and the THF was removed in vacuo. After addition of dichioromethane, the mixture was adjusted to pH 1 using 1 N hydrochloric acid. The phases were separated and the aqueous phase was extracted with dichioromethane. The combined organic phases were dned over sodium sulfate and, after filtration, concentrated in vacuo. The residue was poured into ice water and the precipitate was filtered off with suction. After chromatography on silica gel using dichioromethane/methanol/acetic acid/water (95/5/0.5/0.5), concentration of the product fractions and subsequent freeze drying, 5.05 g (29%) of the title compound were obtained.
d) Ethyl (S)-3-((S)-2-(4,4-pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-
dioxoimidazolidin-1'-yl)-2-(2-methyipropyl)acetylamino)-3-phenylpropionate
566 mg (4.26 mmol) of HOBT and 1.05 g (5.11 mmol) of DCC were added with ice cooling to a solution of 2.22 g (4.26 mmol) of (S)-2-(4,4-pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyi)-2,5-dioxoimidazoltdin-1-yl)-2-(2-methy!propyl)acetic acid in 30 ml of absolute DMF. After stirring at O°C for 1 hour, 823 mg (4.26 mmol) of ethyl 3-amino-3-phenyipropionate (prepared from the hydrochloride) were added. After stirring at room temperature for 4 hours, the reaction mixture was allowed to stand overnight. The urea was filtered off with suction and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and the ethyl acetate solution was successively washed twice in each case with an aqueous KHSO4/K2SO4 solution, a

saturated NaHCO3 solution and water. After drying the organic phase over sodium sulfate and filtering, the solvent was removed in vacuo and the residue was chromatographed on silica gel using ethyl acetate/heptane (1/3 and 1/1). After concentrating the product fractions, 1.98 g (67%) of the title compound were obtained.
e) (S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyi)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-phenylpropionic acid 8.5 ml of a 1 M lithium hydroxide solution were added to 1.97 g (2.83 mmol) of ethyl (S)-3-((S)-2-(4,4-pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methyipropyl)acetylamino)-3-phenylpropionate in 120 ml of methanol and the mixture was allowed to stand at room temperature for 3 days. The methanol was removed in vacuo, and the residual aqueous phase was adjusted to pH 1 by addition of 1 N hydrochloric acid and extracted twice with ethyl acetate. The organic phase was washed with water and dried over sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was taken up in acetonitrile/water and freeze dried. Yield: 1.69 g (89%). ES(+)-MS: 668.4 {M+H)+

with tert-butyl (R)-3'aminobutanoate analogously to Example 3.
Example 10
(R)-3-{(S)-2-(4,4-Pentamethylene-3-{4-(3-(2-methylphenyl)ureido)ben2yl)-2,5-diOxoimida2aiidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(2-methytpropyt)propionic acid

The compound can be prepared by coupling of (S)-2-(4,4-pentamethyle^e-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylp^opyl)acetic acid with tert-butyl (R)-3-amino-5-methylhexanoate analogously to Example 4,
Analogously to Examples 8, 9 and 10, the compounds of Examples 11, 12 and 13 can be prepared starting from 1-aminocydopentane-1-carboxylic acid.
Example 11
(S)-3-((S)-2-(4,4-Tetramethylene-3"(4-(3-(2-methyiphenyl)ureido)ben2yi)-2,5-dioxoimida20(idin-1-yi)-2-(2-methylpropyl)acetylamino)-3-phenytpropionic acid

Example 12
(R)-3-((S)-2-(4,4-Tetramethylene-3-(4-(3-(2-methylphenyl)ureido)ben2yl)-2,5-dioxoimidazolid!n-1-yl)-2-(2-methyipropyl)acetylamino)-3-methylpropionic acid

Example 13
(R)-3-((S)-2-(4,4-Tetramethylene-3-(4-(3-(2-methylphenyl)ureido)ben2yl)-2,5' dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(2-methylprapyl)propionic acid
t

Example 14
(R)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-phenylureido)benzyl)-2,5-dioxoimida20lidin-
1-yl)-2-(2-methylpropyl)acetylamino)-3-methylpropionamide

The compound was prepared from 1.012 g (2 mmol) of (S)-2-{4,4-pentamethyiene-3-(4-(3-phenylureido)benzyl)-2,5-dioxotmidazolidin-1-yl)-2-(2-methylpropyI)aceticacid and 204 mg (2 mmol) of (R)-3-aminobutanamide as described in Example 1. After chromatographic purification of the coupling product, 392 mg (33%) of the title compound were obtained. ES(+)-MS: 591.4(M+H)+
Example 15
(S)-3-((S)-2-{4,4-Pentamethylene-3-(4-(3-phenyiureido)benzyl)-2,5-dioxoimidazoiidin-
1-yl)-2-{2-methylpropyl)acetylamino)-3-phenylpropionamide

271 mg (2.04 mmol) of HOBT and 290 mg (1.4 mmol) of DCC were added with ice cooling to a solution of 800 mg (1.22 mmol) of (S)-3-((S)-2-(4,4-pentamethylene-3-(4-(3-phenylureido)benzyl)-2,5-dioxoimidazoiidin-1-yl)-2-(2-methylpropyl)acetyiamino)-3-phenylpropionic acid (see Example 1) in 10 ml of DMF. After stirring at room temperature for 1 h, 101 |jl of a 25% strength aqueous ammonia solution were added and the mixture was allowed to stand overnight at room temperature. After filtration, the filtrate was concentrated in vacuo, the residue was dissolved in dichloromethane

and the organic phase was washed twice using an aqueous KHSO4/K2SO4 solution, twice using saturated NaHCO3 solution and twice with water. After drying the organic phase over magnesium sulfate, filtration, removal of the solvent in vacuo and chromatographic puhfication of the residue on silica gel (eluent: ethyl acetate/heptane, 9/1), 543 mg (68%) of the title compound were obtained. ES(+)-MS: 653.4 (M+H)+.
Example 16
(S)-3-{(S)-2-(4,4-Pentamethylene-3-(4-(3-phenyiureido)benzyl)-2,5-dioxoimidazoiidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(4-methoxyphenyl)propionic acid

The compound was prepared analogously to Example 1 from 2.02 g (3.98 mmol) of (S)-2-(4,4-pentamethylene-3-(4-(3-phenylureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyt)acetic acid and 1 g (3.98 mmol) of tert-butyl (S)-3-aminO-3-(4-methoxyphenyl)propionate (for the preparation of this p-amino acid ester and of the other p-amino acid esters employed in the preparation of the example compounds see S.G. Davies et al., Tetrahedron: Asymmetry 2, 183 (1991) and J. Chem. Soc. Perkin Trans 1, 1129 (1994)). After coupling, chromatographic purification of the coupling product, cleavage of the tert-butyl ester and subsequent chromatographic purification, 1.116 g (41%) of the title compound were obtained. ES(+)-MS: 684.4 (M+H)+,
Example 17

(S)-3-((S)-2-{4,4-Pentamethylene-3-(4-(3-phenyiureido)ben2yl)-2,5-dioxoimidazoiidin-1-yl)-2-{2-methylpropyl)acetylamino)-3-(4-methoxyphenyl)propionic acid tromethamine salt

The compound was prepared analogously to Example 2. Starting from 550 mg of (S)-
3-((S)-2-(4,4-pentamethylene-3-(4-{3-phenytureido)benzyl)-2,5-dioxoimida2olidin-1-
yi)-2-(2-methylpropyl)acetyiamino)-3-(4-methoxphenyl)propionic acid, 632 mg of the
corresponding tromethamine salt were obtained (stoichiometry; (S)"3-{(S)"2-{4,4-
pentamethylene-3-{4-(3-phenylureido)benzyl)-2,5-dioxoimidazoiidin-1-yl}-2-(2-
methylpropyl)acetylamino)-3-(4-methoxyphenyl)propionic acid/tromethamine about
1/1.5).
ES(+)-MS: 122.0 (a,a,a-tris(hydroxymethyl)methylamine + H)+, 684.5 (S)-3-((S)-2-
(4,4-pentamethylene-3-(4-{3-phenylureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-{2-
methylpropyl)acetylamino)-3-(4-methoxyphenyl)propionicacid + H)+, 805.5 (M+H)+.
Example 18
(S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-phenyturetdo)ben2yl)-2,5-dioxoimidazolidin-1-yl)-2-{2-methylpropyl)acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid

yl)-2-{2-methylpropyl)acetylamino)-3"(2,4-dimethoxyphenyi)propionic acid, 188 mg of
the corresponding tromethamine salt were obtained (stoichiometry: (S)-3-((S}-2-(4,4-
pentamethytene-3-(4-{3-phenylureido)ben2yl)-2,5-dioxoimidazolidin-1-yl)-2-(2-
methylpropyl)acetylamino)-3-{2,4-dimethoxyphenyl)propionic acid/tromethamine
about 1/2.1).
ES(+)-MS: 122.0 (a,a,a-tris(hydroxymethyl)methylamine + H)+, 714.4 (S)-3-{(S)-2"
(4,4-pentamethylene-3-(4-(3-phenylureido)benzyl)-2,5-dioxoimida2olidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-{2,4-dimethoxyphenyl)propionic acid + H)+, 835.5 (M+H)+.
Example 20
(S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-phenylureido)ben2yl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid

The compound was prepared analogously to Example 1 from 1.5 g (2.96 mmol) of (S)-2-(4,4-pentamethylene-3-{4-(3-phenylureido)benzyl)-2,5-dioxoimJdazolidin-1-yl)-2-(2-methylpropyi)acetic acid and 833 mg (2.96 mmol) of tert-butyl (S)-3-amino-3-(3,4-dimethoxyphenyl)propionate. After coupling, chromatographic purification of the coupling product, cleavage of the tert-butyl ester and trituration with water and then pentane, 1.17 g (55%) of the title compound were obtained. ES(+)"MS: 714.4 (M+H)+.
Example 21

yl)-2-{2-rnethylpropyl)acetylarnino)-3--(2,4-dimethoxyphenyl)propionic acid, 188 mg of
the corresponding tromethamine salt were obtained (stoichiometry: (S)-3-((S)-2-(4,4-
pentamethylene-3-(4-{3-phenylureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-
methylpropyl)acetytamino)-3-{2,4-dimethoxyphenyl)propionic acid/tromethamine
about 1/2.1).
ES(+)-MS: 122.0 (a,a,a-tris(hydroxymethyl)methylamine + H)+, 714.4 (S)-3-{(S)-2-
(4,4-pentamethylene-3-{4-{3-phenylureido)benzyl)-2,5-dioxoimida2olidin-1-yl)-2-{2-methylpropyl)acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid + H)+, 835.5 (M+H)+.
Example 20
{S)-3-{(S)-2-{4,4-Pentamethytene-3-(4-(3-phenyiureido)ben2yi)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid

The compound was prepared analogously to Example 2. Starting from 200 mg of (S)-3-((S)-2-(4,4-pentamethylene-3-(4-{3-phenylureidQ)benzyl)-2,5-dioxoimida2olidin-1-yl}"2-{2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid, 235 mg of
the corresponding tromethamine salt were obtained (stoichiometry: (S)-3-({S)-2-(4,4-pentamethyiene-3-{4-(3-phenylureido)ben2yl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyi)acetylamino)-3-(3,4-dimethoxyphenyl)propiQnic acid/tromethamine about 1/1.4). ES(+)-MS: 122.0 (a,a,a-tns(hydroxymethyl)methylamine + H)+ 714.4 (S)-3-{(S)-2-
(4,4-pentamethy!ene-3-{4-{3-phenylureido)benzyl)-2,5-d[oxoimida2olidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid + H)+, 835.4 (M+H)*.
Example 22 (S)-3-{(S)-2-{4,4-Pentamethytene-3-{4-(3-phenylureido)benzyi)-2,5-dioxoimidazQlidin-
1-yl)-2-(2-methylpropyi)acetylamino)-3-(3-methoxyphenyl)propionic acid

The compound was prepared analogously to Example 1 from 1.5 g (2.96 mmol) of (S)-2-{4,4-pentamethylene-3-(4-{3-phenylureido)ben2yl)-2,5-dioxoimida2olidin-1-yl)-2-(2-methyipropyl)acetic acid and 1.48 g .(2.96 mmol) of tert-butyl (S)-3-amino-3-(3-methoxyphenyl)propionate. After coupling, chromatographic purification of the coupling product, cleavage of the tert-butyl ester and trituration with water and then pentane, 1.01 g (50%) of the title compound were obtained. ES(+)-MS: 684.4 (M+H)+.
Example 23
(S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methylpheny!)ureido)ben2yl)-2,5-dioxoimida20iidin-1-yl)-2-(2-methylpropyl)acetyiamino)-3-phenylpropionic acid tromethamine salt

(stoichiometry: (S)-3-((S)-2-(4.4-pentamethyiene-3-(4-{3-(2-methylphenyl)-ureido)benzyt}-2,5 ES(+)-MS: 122.0 (a,a,a-tris(hydroxymethyl)methytamine + H)+ 658.4 ((S)-3-((S)-2-(4,4-pentamethylene-3-(4-{3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimida2olidin-1-yl)+2-(2-methylpropyl)acetylarnino)-3-phenylpropionic acid + H)+ 789.5 (M+H+.
Example 24
(R)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyi)-2,5-dioxoimidazolidin-1-y!)-2-{2-methylpropyl)acetylamino)-3-methyipropionic acid tromethamine salt

The compound was prepared analogously to Example 1 from 1 g (1.92 mmol) of (S)-2-(4,4-pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimid-azolidin-1-yl)-2-(2-methytpropyl)acetic acid (see Example 8) and 963 mg (3.84 mmol) of tert-butyl (S)-3-amino-3-(3-methoxyphenyi)propionate. After coupling, chromatographic purification of the coupling product, cleavage of the tert-butyi ester and trituration with water and then pentane, 555 mg (40%) of the title compound were obtained. ES(+)-MS: 698.4 (M+H)+
Example 26 (S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-
dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino}-3-(4-methoxyphenyl)propionic acid

The compound was prepared analogously to Example 1 from 900 mg (1.73 mmo() of (S)-2-(4,4-pentamethylene-3-{4-(3-(2-methylphenyl)ureido)ben2yI)-2,5-dioxoimid-azolidin-1-yl)-2'(2-methytpropyl)acetic acid (see Example 8) and 434 mg (1.73 mmol) of tert-butyl (S)-3-amino-3-(4-methoxyphenyl)propionate. After coupling, chromatographic purification of the coupling product, cleavage of the tert-butyl ester and trituration with water and pentane, 348 mg (29%) of the title compound were obtained. ES(+)-MS: 698.4 (M+H)+.
Example 27
(S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)ben2yl)-2,5-dioxoimida2olidin-1-yi)-2-(2-methylpropyl)acetylamino)-3-(4-methoxyphenyl)propionic acid tromethamine salt

3-{(S)-2-{4,4-pentamethylene-3-(4-(3-{2-methylphenyl)ureido)ben2yl)-2,5-
dioxoimida2oiidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(4-methoxyphenyl)propionic
acid (see Example 26), 173 mg of the corresponding tromethamine salt were
obtained {stoichiometry: (S)-3-((S)-2-{4,4-pentamethylene-3-(4-(3-(2-niethylphenyl)-
ureido)ben2y!)-2,5-dioxoimida2olidin-1-yl)-2-(2-rnethylpropyl)acetylamino)-3-{4-
methoxyphenyl)propionic acid/tromethamine about 1/1.6).
ES(+)-MS: 122.0 (a,a,a-tns(hydroxymethyl)methylamine + H)+ 698.4 ((S)-3-{(S)-2-
(4,4-pentamethylene-3-(4-{3-(2-methylphenyl)ureido)benzyl)-2,5-dioxo(mida2olidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(4-methoxyphenyl)propionicacid + H)*, 819.5 (M+H)+.
Example 28
(S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-{2-methyphenyl)ureido)ben2yl)-2,5-dioxoimida2olidin-1-yl)-2-{2-methylpropyl)acetylamJno)-3-(2,4-dimethoxyphenyl)propionic acid

The compound was prepared analogously to Example 2. Starting from 160 mg of (S)-
3-((S)-2-(4,4-pentamethylene-3-(4-(3-(2-methy!phenyl)ureido)ben2yl)-2,5-dioxoimid-
a2olidin-1-yl)-2-(2-methytpropyl)acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid
(see Example 28), 82 mg of the corresponding tromethamine salt were obtained
(stoichiometry: (S)-3-{(S)-2-(4,4-pentamethylene-3-{4-(3-(2-methylphenyl)-
ureido)ben2yl)-2,5-dioxoimidazoiidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(2,4-
dimethoxyphenyi)propionic acid/tromethamine about 1/4.2).
ES(+)-MS: 122.0 (a,a,a-tris(hydroxymethyl)methylamine + H)+, 728.5 ((S)-3-{(S)-2-
(4,4-pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyI)-2,5-dioxoimida20lidin-1-
yl)-2-(2-methylpropyi)acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid + H)+,
849.5 (M+H)+
Example 30
(S)-3-{(S)-2-(4,4-Pentamethylene-3-(4-(3-{2-methylphenyl}ureido)ben2yl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyi)acetylamino)-3-(2,4-dimethoxyphenyl)-propionic acid sodium salt

1 mole equivalent of 1 N sodium hydroxide solution was added to a solution of 292 mg of (S)-3-((S)-2-(4.4-pentamethylene-3-{4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropy[)acetylamino)-3-(2,4-dimethoxyphenyl)-propionic acid (see Example 28) in THF, After stirring for 30 minutes, the THF was removed in vacuo and the solution was diluted with water and freeze dried. After purification on Sephadex using water, 216 mg of the title compound were obtained. ES(+)-MS: 728.3 ((S)-3-((S)-2-(4.4-pentamethylene-3-(4-(3-(2-methylphenyl)-ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyi)acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid + H)+, 750.3 (M+H)+.

The compound was prepared analogously to Example 1 from 1 g (1.92 mmol) of
{S)-2-(4,4-pentamethylene-3-(4-(3-(2-methylphenyl)ureido)ben2yl)-2,5-diGxoimid-azoiidin-1-yl)-2-(2-methyipropyl)acetic acid (see Example 8) and 540 mg (1.92 mmol) of tert-butyl (S)-3-amino-3-(3,4-dimethoxyphenyl)propionate. After coupling, chromatographic purification of the coupling product, cleavage of the tert-butyl ester, chromatographic purification by means of preparative HPLC, concentration of the product fractions, freeze drying and trituration of the product with water and pentane, 480 mg (34%) of the title compound were obtained. ES(+)-MS: 728,4 (M+H)+.
Example 32
(S)-3-((S)-2-(4.4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2.5-dioxoimidazolidin-1-yl)-2-(2-methylprapyl)acetytamino)-3-(3,4-dimethoxyphenyl)-propionic acid tromethamine salt

ES(+)-MS: 122.0 (a,a,a-tns(hydroxymethyi)methytamine + H); 728.5 ((S)-3-((S)-2-(4,4-pentamethylene-3-(4-(3-(2-methytphenyi)ureido)ben2yi)-2,5-dioxoimidazolidin--1-y!)--2-(2-methylpropyl)acetylarnino)-3-(3,4-dimethoxyphenyi)propionic acid + H)"", 849.6 (M+H)+.
Example 33
(S)-3-((S)-2-(4,4-Pentamethylene-3-{4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimida2olidin-1-yl)-2-(2-methylpropyi)acetylarnino)-3'{3,4-dimethoxyphenyl)-propionic acid sodium salt

1 mole equivalent of 1 N sodium hydroxide solution was added to a solution of 300 mg of (S)-3-((S)-2-(4,4-pentamethytene-3-(4-(3-{2-methylphenyl)ureido)benzyl)-2,5-dioxoimida2o!idin-1-yl)-2-{2-methylpropyl)acetyiamino)-3-(3,4-dimethoxyphenyl)-propionic add (see Example 31) in THF. After stirring for 30 minutes, the THF was removed in vacuo and the solution was diluted with water and freeze dried. After purification on Sephadex using water, 154 mg of the title compound were obtained. ES(+)-MS: 728.3 ((S)-3-((S)'2-(4,4-pentamethylene-3-{4-{3-(2-methylphenyl)-ureido)benzyl)-2,5-dioxoimida2olidin-1-yl)-2-{2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)proptonic acid + H)". 750.3 (M+H)^
Example 34
(S)-3-((S)-2-(4,4-Pentamethytene-3-(4-{3-(2-methylphenyi)ureido)benzyl)-2,5-
dioxoimidazoiidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-

The compound was prepared analogously to Example 1 from 590 mg (1.1 mmol) of ((S)'2-(4,4-pentamethylene-3-(4-(3-(2-methylphenyl)ure(dQ)benzyl-2,5-dioxoimid-a2olidin-1-yl)-2-(2-methylpropyl)acetic acid (see Example 8) and 475 mg (1.7 mmol) of tert-butyl (S)-3-amino-3-(3,4-ethylenedioxyphenyi)propionate. After coupling, chromatographic purification of the coupling product and cleavage of the tert-butyl ester, 650 mg (81%) of the title compound were obtained. ES(+)-MS: 726.2 (M+H)+.

0.95 mole equivalent of 1 N sodium hydroxide solution was added to a suspension of 500 mg (0.83 mmol) of (S)-3-{(S)-2-{4,4-p€^tamethylene-3-{4-{3-{2-methylphe^yi)-u^eido)benzyl)-2,5-dioxoimidazolidin-1-yl}-2-(2-methytp^opyl)acetylami^o)-3-(3,4-ethylenedioxyphenyl)propionic acid (see Example 34) in water. After stirring for 30 minutes, the mixture was filtered and the filtrate was freeze dried. 610 mg (98%) of the title compound were obtained.
ES(+)-MS: 726.2 ((S)-3-((S)-2-(4,4-pentamethylene-3-(4-(3-(2-methylphenyl)ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-ethytene-dioxyphenyl)propionic add + H)+, 748.2 (M+H)*.
Example 36
(R)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-
dioxoimidazolidin-1-yl)-2-(2-methyipropyl)acetylamino)-3-methyipropionamide

The compound was prepared analogously to Example 15. Starting from 150 mg (0.247 mmol) of (R)-3-((S)-2-(4,4-pentamethyiene-3-(4-(3-(2-methylphenyl)-ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-methylpropionic acid (see Example 9), after chromatographic purification of the crude product on silica gel using ethyi acetate as eluent, concentration of the product fractions, trituration of the residue with water and then pentane and freeze drying, 74 mg (50%) of the title compound were obtained. ES(+)-MS: 605.4 (M+H)+.
Example 37 (S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)-3-methoxybenzyl)-

a) 4-(3-(2-Methyiphenyl)ure(do)-3-methoxyben2yl alcohol
15 g (81.8 mmol) of 3-methoxy-4-nitroben2yl alcohol were hydrogenated with ice cooling on 1.3 g of palladium/carbon (10% strength; 50% water) in 500 ml of methyl tert-butyl ether. After the absorption of hydrogen was complete, the catalyst was filtered off and 10.14 ml (81.8 mmol) of 2-methy(phenyl isocyanate were added to the filtrate with stirring in the course of 30 minutes. The reaction mixture was allowed to stand overnight, and the precipitated solid was filtered off with suction and washed with methyl tert-butyl ether. 20.5 g (88%) of 4-(3-(2-methyiphenyl)ureido)-3-methoxybenzyl alcohol were obtained.
b) 4-(3-(2-Methylphenyl)ureido)-3-methoxybenzyl chloride
7.65 ml (104.8 mmol) of thionyl chloride were added dropwise with ice cooling to a suspension of 15 g (52.4 mmol) of 4-(3-(2-methylphenyl)ureido)-3-methoxyben2yl alcohol in 300 ml of dichloromethane. The reaction mixture was subsequently stirred at room temperature for 3 hours, allowed to stand overnight and then poured onto 1000 ml of n-heptane. The heptane was decanted off from the deposited oil, the residue was again suspended with n-heptane and the heptane was decanted off. This process was repeated a further two times. The residue was then dissolved in dichloromethane and poured into 800 ml of ice-cold diisopropyi ether. It was subsequently stirred with ice cooling for 2 hours, and the product was filtered off with

6.6 ml of an n-butyllithium solution (2.5 M in hexane) were added at -40'C under argon to a solution of 1.98 g (8,21 mmol) of (S)-2-(4,4-pentamethylene-2,5-dioxoimidazolidin-1-yI)-2-(2-methylpropyl)acetic acid in 40 ml of absolute THF, After stirring at -40°C for 30 minutes, the reaction mixture was allowed to warm to O°C and a solution of 2.5 g (8.21 mmol) of 4-(3-(2-methylphenyl)ureido)-3-methoxybenzyl chloride in 10 ml of NMP was added. The reaction mixture was allowed to warm to 0°C and was subsequently stirred at 0°C for 2 hours. 15 ml of 1 N hydrochlohc acid were added and the THF was removed in vacuo. The residue was poured onto 300 ml of methyl tert-butyl ether. The phases were separated, and the organic phase was washed with water, dried oyer sodium sulfate and, after filtration, concentrated in vacuo. The residue was purified by preparative HPLC. After concentration of the product fractions and subsequent freeze drying, 716 mg (17%) of the title compound were obtained.
d) (S)-3-((S)-2-(4,4-Pentamethytene-3-(4-(3-(2-methytphenyl)ureido)-3-methoxybenzy()-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetyiamino)-3-(3,4~
dimethQxyphenyl)propionic acid
The compound was prepared analogously to Example 1 from 300 mg (0.55 mmol) of
(S)-2-(4,4-pentamethylene-3-(4-(3-(2-methylphenyi)ureido)-3-methoxybenzyl)-2,5-

dioxoimida20lidin-1-yl)-2-(2-methylpropyl)acetic acid and 154 mg (0.55 mmol) of tert-butyi (S)-3-amino-3-(3,4-dimethoxyphenyl)propionate. After coupling, chromatographic purification of the coupling product, cleavage of the tert-butyl ester, chromatographic purification by means of preparative HPLC, concentration of the product fractions and freeze drying, 205 mg (49%) of the title compound were obtained. ES(+)-MS; 758.3 (M+H)+.
Example 38
(S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)-3-methoxybenzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)-propionic acid tromethamine salt

The compound was prepared analogously to Example 2, Starting from 100 mg of (S)-3-((S)-2-(4,4-pentam€thylene-3-(4-(3-(2-methylphenyl)ureido)-3-methoxyben2yl)-2,5-dioxoimida2olidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)-propionic acid (see Example 37), 123 mg of the corresponding tromethamine salt were obtained (stoichiometry: (S)-3-((S)-2-(4.4-pentamethylene-3-(4-(3-(2-methyl-phenyl)ureido)-3-methoxybenzy()-2,5-dioxoimtda2olidin-1-yl)-2-(2-methylpropyl)-acetylamino)-3-(3,4-dimethoxyphenyl)propionic acid/tromethamine about 1/1.3). ES(+)-MS: 122.0 (a,a,a-tris(hydroxymethyl)methylamine + H)*, 758,3 ((S)-3-((S)-2-(4,4-pentamethyiene-3-(4-(3-(2-methylphenyl)ureido)-3-methoxybenzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamtno)-3-(3,4-dimethoxyphenyl)-

The compound was prepared analogously to Example 1 from 257 mg (0.496 mmol) of (S)-2-(4,4-pe^tamethylene-3-(4-(3-(2-methylphenyl)u^eido)benzyl)-2,5-dioxoimid-azolidin•-1-yl)-2-cyciop^opylmethylacetic acid and 140 mg (0.496 mmol) of tert-butyi (S)-3-amino-3-(3,4-dimethoxyphenyl)propionate. After coupling, chromatographic purification of the coupling product, cleavage of the tert-butyl ester and freeze drying, 296 mg (82%) of the title compound were obtained. ES(+)-MS: 726.3 (M+H)+
The (S)-2-(4,4-pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimtdazolidin-1-yl)-2-cyciopropylmethyiacetic acid was prepared analogously to Example 37 from (S)-2-(4,4-pentamethyiene-2,5-dioxoimidazolidin-1-yl)-2-cyclopropylmethylaceiic acid and 4-(3-(2-methylphenyl)ureido)benzyl chloride (see Example 8).
The (S)'-2-(4,4-pentamethylene-2,5-dioxoimidazoiidin-1-yl)-2-cyclopropylmethylacetic acid was prepared from (S)-2-amino-3-cyclopropy(propionic acid by the following

process.
1 N sodium hydroxide solution was added to a suspension of 10 g (77.5 mmol) of (S)-2-amino-3-cyciopropylpropionic acid in 160 ml of dioxane at O^^C until a pH of 8 to 9 was reached. 16.9 g (77.5 mmol) of di-tert-butyl dicarbonate were then added, the ice bath was removed and the pH was kept at 8 to 9 by further addition of 1 N sodium hydroxide solution. After allowing to stand overnight, the dioxane was removed in vacuo, ethyl acetate was added to the aqueous phase and the phases were separated. The aqueous phase was adjusted to a pH of 4.5 using 1 N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase thus obtained was dried over sodium sulfate, the drying agent was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in 1000 ml of dichloromethane and treated with 53.4 ml of benzyl alcohol, 8.37 g of 4-dimethylaminopyridine and 18.8 g of DCC. After stirring for 6 hours and standing overnight, the mixture was filtered, the filtrate was concentrated and the residue was treated with 300 ml of 90% strength trifluoroacetic acid. After stirring at room temperature for 10 minutes, the trifiuoroacetic acid was removed in vacuo and the residue was chromatographed twice on silica gel (eluent: dichloromethane/methanot, 95/5). 11.48 g (68%) of benzyl (S)-2-amino-3-cyclopropylpropionate were obtained.
A suspension of 39.9 g (279 mmoi) of 1-aminocyclohexane-1-carboxylic acid in a mixture of 75 ml of THF and 75 ml of water was treated dropwise with 23.8 ml of methyl chloroformate, dissolved in 40 ml of THF, such that the temperature of the suspension did not rise above 50°C. In the course of this, the pH of the solution was kept between 8.5 and 9.5 by addition of 25% strength sodium hydroxide solution. After stirring at pH 8 for 30 minutes, the mixture was diluted with water, the THF was removed in vacuo and the aqueous phase was washed twice with methyl tert-butyl ether. The aqueous phase was adjusted to pH 2 using 6 N hydrochloric acid and extracted successively with methyl tert-butyl ether and dichioromethane. The combined organic phases were concentrated in vacuo. The residue was triturated with diethyl ether and the product was filtered off. 47.85 g (85%) of 1-methoxy-carbonylaminocyclohexane-1-carboxylic acid were obtained.

216 mg of HOBT and 3.2 g (16 mmol) of DCC were added to a solution of 3.2 g (16 mmol) of 1-methoxycarbonylaminocyciohexane-i-carboxyiic acid and 3.5 g (16 mmol) of benzyl (S)-2-amino-3-cyclopropylpropionate in 40 ml of THF and the mixture was stirred at room temperature for 1 hour. After allowing to stand overnight and filtering, the THF was removed in vacuo, the residue was taken up in methyl tert-butyl ether and the solution was washed twice in each case with saturated NaHCOa solution and with KHSO4/K2SO4 solution. The organic phase was dried over sodium sulfate and, after filtration, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and hydrogenated in the presence of palladium/carbon (10% strength; 50% water). The catalyst was filtered off and the organic phase was treated with 500 ml of water and 4.5 g of NaHCO3. After extraction by shaking and phase separation, the aqueous phase was stirred at 100°C for 2 hours. 3.39 g of Na2C03 were added and the solution was stirred at 100°C for 8 hours. After allowing to stand overnight, 500 ml of 6 N hydrochloric acid were added and the aqueous phase was extracted with methyl tert-butyl ether. The phases were separated and the organic phase was washed with water, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue was triturated with heptane and the product was filtered off. 3.7 g (83%) of (S)-2-(4,4-pentamethylene-2,5-dioxoimida2olidin-1-yl)-2-cyclopropylmethylacetic acid were obtained.
Example 40
(S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyl)"2,5-dioxoimidazolidin-1-yl)-2-cydopropylmethylacetylamino)-3-(2,4-dimethoxyphenyl)-propionic acid

The compound was prepared analogously to Example 1 from 522 mg (1 mmol) of (S)-2-{4,4-pentamethylene-3-(4-(3-{2-methylphenyl)ureido)benzyl)-2,5-dioxoimid-azoiidin-1-yl)-2-cyc!opropylmethylacetic acid (preparation see Example 39) and 284 mg (1 mmol) of tert-butyl (S)-3-amino-3-(2,4-dimethoxyphenyi)propionate, After coupling, chromatographic purification of the coupling product, cleavage of the tert-butyl ester using 90% strength trifluoroacetic acid, removal of the trifluoroacetic acid in vacuo, taking-up of the residue in dichloromethane, washing the dichloromethane phase three times with water, removal of the dichloromethane in vacuo and subsequent freeze drying, 590 mg (81%) of the title compound were obtained. ES(+)-MS: 725.3 (M+H)

7.07 ml of 0.1 N sodium hydroxide solution were added in portions with stirring to a suspension of 540 mg (0.74 mmol) of (S)-3-((S)-2-{4,4-pentamethylene-3-(4-(3-(2-. methylphenyi)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-cyclopropylmethytacetyl-amino)-3-(2,4-dimethoxyphenyl)propionic acid in 20 ml of water and the mixture was stirred at room temperature for 1 hour. After filtration and freeze drying of the filtrate, 524 mg (95%) of the title compound were obtained.
ES(+)-MS; 726.3 ((S)-3-((S)-2-(4,4-pentamethylene-3-(4-(3-(2-methyiphenyl)ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-cyclopropylmethylacetylamino)-3-(2,4-dimethoxyphenyl)propionic acid + H)", 748.3 (M+H)*.
Investigation of the biological activity
A) U937A/CAM-1 cell adhesion test
The test method used for the activity of the compounds of the formula I on the interaction between VCAM-1 and VLA-4 is the assay described below, which is specific for this interaction. The cellular binding components, that is the VLA-4 integrins, are supplied in their natural form as surface molecules on human U937 cells (ATCC CRL 1593), which belong to the leukocytes group. The specific binding components used are genetically engineered recombinant soluble fusion proteins, consisting of the extracytoplasmic domain of human VCAM-1 and the constant region of a human immunoglobulin of the subclass IgGI.
Assay for the measurement of the adhesion of U937 cells (ATCC CRL 1593) to hVCAM-1(1-3)-lgG
1, Preparation of human VCAM-1 (1-3)-lgG and human CD4-lgG
A genetic construct for the expression of the extracellular domain of human VCAM-1, combined with the genetic sequence of the heavy chain of human immunoglobulin IgGI (hinge, CH2 and CH3 regions) (from Brian Seed, Massachusetts General

Hospital, Boston. USA; cf. Damle and Aruffo, Proc. Natl. Acad. Sci. USA 1991, 88, 5403), was employed. The soluble fusion protein hVCAM-1(1-3)-!gG contained the three aminoterminal extracellular immunoglobulin-like domains of human VCAM-1 . (DamIe and Aruffo, Proc. Natl. Acad. Sci. USA 1991, 88, 6403). CD4-lgG (ZettlmeissI et al., DNA and Cell Biology 1990, 9, 347) served as a fusion protein for negative controls. The recombinant proteins were expressed as soluble proteins after DEAE/dextran-mediated DNA transfection in COS cells (ATCC CRL1651) according to standard procedures (Ausubel et a!., Current protocols in molecular biology, John Wiley & Sons. Inc.. 1994).
2. Assay for the measurement of the adhesion of U937 cells to hVCAM-1(1-3)-lgG
2.1 96-well microtiter test plates (Nunc Maxisorb) were incubated at room temperature for 1 hour with 100 µl/well of a goat-anti-human IgG antibody solution (10 µg/ml in 50 mM tris, pH 9.5). After removal of the antibody solution, washing was carried out once with PBS.
2.2 150 µl/well of a blocking buffer (1 % BSA in PBS) were incubated on the plates at room temperature for 0.5 hour. After removal of the blocking buffer, washing was carried out once with PBS.
2.3 100 µl per well of a cell culture supernatant of transfected COS cells were incubated on the plates at room temperature for 1.5 hours. The COS cells were transfected with a plasmid which codes for the three N-termina! immunoglobuiin-like domains of VCAM-1, coupled to the Fc portion of human IgG1 (hVCAM-1(1-3)-lgG)-The content of hVCAM-1(1-3)-lgG was about 0.5 -1 µg/ml. After removing the culture supernatant, washing was carried out once with PBS.
2.4 The plates were incubated at room temperature for 20 minutes with 100 µl/weil of Fc receptor blocking buffer (1 mg/ml of y-globulin, 100 mM NaCl, 100 µM MgCl2, 100 MM MnCl2. 100 µM CaCl2, 1 mg/ml of BSA in 50 mM HEPES, pH 7.5). After

removal of the Fc receptor blocking buffer, washing was carried out once with PBS,
2.5 20 ^Jl of binding buffer (100 mM NaCI, 100 [JM MgCb, 100 (JM MnCb, 100 pM CaCb. 1 mg/ml of BSA in 50 mM HEPES, pH 7.5) were initially introduced, and the substances to be tested were added in 10 pi of binding buffer and incubated for 20 minutes. The controls used were antibodies against VCAM-1 (BBT, No. BBA6) and against VLA-4 (Immunotech, No. 0764).
2.6 U937 cells were incubated in Fc receptor blocking buffer for 20 minutes and then pipetted in at a concentration of 1 x 108/ml and in an amount of 100 µl per well (final volume 125 µ/well).
2.7 The plates were slowly immersed at an angle of 45° in stop buffer (100 mM NaC!, 100 |JM MgCl2, 100 pM MnCb. 100 |JM CaCis in 25 mM Ths, pH 7.5) and shaken off. The process was repeated.
2.8 50 µl/we!I of a dye solution (16.7 µg/mi of Hoechst Dye 33258, 4% formaldehyde, 0.5% Thton X-100 in PBS) were then incubated on the plates for 15 minutes.
2.9 The plates were shaken off and slowly immersed at an angle of 45° in stop buffer (100 mM NaCI, lOOµM MgCl2. 100µM MnCl2, 100 pM CaCl2 in 25 mM Ths, pH 7.5). The process was repeated. Then, with the liquid (stop buffer) present, the plates were measured in a cytofiuorimeter (Millipore) (sensitivity: 5, filter: excitation wavelength: 360 nm, emission wavelength: 460 nm) with the liquid present (stop buffer).
The intensity of the light emitted from the stained U937 ceils is a measure of the number of U937 cells adhered to the hVCAM-1(1-3)-lgG and remaining on the plate and thus a measure of the ability of the added test substance to inhibit this adhesion. From the inhibition of the adhesion at vanous concentrations of the test substance, the concentration IC50 was calculated which leads to an inhibition of adhesion by

50%.
• 3. Results
The following test results were obtained in the U937A/CAM-1 cell adhesion test (iCso values in nM (nanom l/liter).
Compound of IC50 (nM)
Example No.
1 3.2
2 4.5
3 17
4 85.4

8 3.2
9 2.2
16 4
17 1.9
18 2.4
19 3
20 1.6
21 3
22 6.7
23 5.5
24 1.7
25 1.1
26 2.6
27 3.4
28 2.1
29 1.9
30 3.6

Compound of IC50 (nM)
Example No.
31 0.8
32 0.6
33 1.3
34 1.8
35 3.4

37 1.3
38 1.6
39 0.8
40 2.1
41 2.3
The pharmacological properties of the compounds of the formula I can also be investigated in the following models.
B) Leukocyte adhesion in rats
In this model of leukocyte adhesion, the effect on the adhesion of leukocytes by the compounds of the fomiula ! in venules of rats is investigated. The leukocyte adhesion to the endothelium of postcapillary venules is regarded as an important step in inflammatory reactions (J. M, Harlan, Blood 1985, 65, 513). In the recruitment of leukocytes from the blood into inflamed areas, a well-coordinated dynamic sequence of events takes place in which chemotactic cytokines and cellular adhesion molecules play an active part. It has been found that VCAM-1A/LA-4 interactions play a crucial role in the adhesion and emigration of leukocytes and the increased permeability of vessels for macromolecules which are induced by various mediator substances and cyctokines (D. Seiffge, Int. J. Microcirc. 1995, 15, 301). In the present model, a generalized inflammation or rheumatoid arthritis which leads to adhesion of the leukocytes and their emigration into diseased areas of the organ, is caused by local or systemic injection of endotoxins, for example zymosan, bacterial

toxins such as lipopolysaccharides (LPS) of Freund's adjuvant. The increased adhesion to the endothelium of the venules produced by the endotoxin is determined.
For the determination of the leukocyte adhesion, a camera inverted microscope (Zeiss) which is equipped with a video system is used. Male Sprague-Dawley rats (body weight about 250 g) are injected with zymosan or bacterial endotoxin under a slight halothane premedication. The control animals receive an identical volume of 0.9% strength saline solution. The test substance is then administered to the animals subcutaneously or orally as an individual dose or as a multiple dose. For carrying out the measurement, the rats are anesthetized by an intramuscular injection of 1.25 g/kg of urethane. They are allowed to breathe spontaneously through a tracheal tube. The body temperature is kept at 37°C by means of a regulated heating pad. The mesentery is carefully exposed by means of a hypogastric incision on a thermostated (37°'C) window of the microscope stage, and is covered with liquid paraffin at 37°C. The ileocecal area of the mesentery is held in position with three blunt needles and modeling clay. After a 30-minute equilibration time, during which the tissue is allowed to stabilize, the leukocyte adhesion is determined in postcapillary venules of 20-30 µm diameter and about 100 µm length by counting in 2-3 segments of the venules over 1 hour at intervals of 10 minutes. A leukocyte is regarded as adherent to the endothelium if it is stationary for more than 30 seconds. After the experiment, the systemic leukocyte count and the fibrinogen content of the blood is determined. The inhibition of leukocyte adhesion by the test substance is indicated by the decrease (in %) of the number of adherent leukocytes in the treated animals in comparison with the number in the control animals.
C) Delayed-type hypersensitivity in mice
In the model of delayed-type hypersensitivity (DTH mode!), the antiallergic or antiinflammatory action of the compounds of the formula 1 is investigated. DTH is an inflammatory reaction of the skin which is induced by sensitization with antigenic substances. In order to determine the corresponding inflammatory reaction and the leukocyte recruitment in the inflamed areas in vivo, the substances are tested in the

following DTH model in mice (see also T. B. Issekutz, J. Immunol. 1991, 147, 4178).
Groups of female BALB/c mice (body weight about 20 g) are sensitized -epicutaneously on a shaved part of the skin with 150 µ\ of a 3% strength solution of oxazolone, which has been known to induce a strong inflammatory DTH reaction. 6 days later, the reaction is challenged by administration of 20 |JI of a 1% strength oxazolone solution on the right ear of the animals. The test substances are administered subcutaneously or orally in each case 44 hours before the challenge of the reaction, 20 hours before the challenge and 4 hours after the challenge. Directly before the challenge of the reaction and 24 hours after the challenge, the altered ear thickness due to the inflammatory swelling of the ear is measured on the right ear using a Mitutoyo Engineering micrometer. The difference between these two measurements is determined for each animal of the group. The mean values of the differences of an animal group treated with the test substance on the one hand and an untreated control group on the other hand are compared. The percentage inhibition of ear swelling is indicated as a measure of the effect of the substance.
D) Anti-asthmatic action in guinea pigs
The effects on the lung function and the anti-asthmatic action of the compounds of the formula I can be determined in a model guinea pigs which follows the method described by G. Moacevic, Arch. Toxicol. 1975, 34, 1. For this, the technical preparations for the investigation are carried out corresponding to the details described by Moacevic. Male albino guinea pigs having a body weight of 300 - 500 g are employed. The animals are placed in a plethysmograph (FMI) and three starting values of the parameters respiratory rate and respiratory amplitude are recorded. In this model, an asthmatic respiration is charactenzed by the decrease in the respiratory amplitude (= lowehng of the respiratory volume on account of the bronchoconstriction) and the increase in the respiratory frequency (= reflex reaction).
\ This condition is known in asthma patients as dyspnoea.
22 days before the start of the study, the albino guinea pigs are sensitized with 1 ml

per animal of a 0.1 % strength ovalbumin solution on two successive days. The expenmental asthma attack is induced by inhalation of a 0.3% strength ovalbumin solution for 1 minute. After a recovery phase of 40-60 minutes, the animals inhale the test substance as an aqueous solution. Immediately afterwards, 0.3% strength ovalbumin solution is administered for 1 minute. In the following recovery phase of 30 minutes, the animals breathe normal air. This process is repeated twice. If the asthma attacks become life-threatening, oxygen is administered to the animals.

Patent ctaims

in which
R1 is hydrogen or methyl;
R2 is phenyl or (C1-C4)-alkyl;
X is -CH2-CH2- or -CH2-CH2-CH2-, where one of the CH2 groups in these two
residues can be replaced by a carbonyl group C=0;
W is isopropyl or cyciopropyl;
V is hydrogen or methoxy;
E is -CO-R3 -CO-H. -CH2-O-R4 -CH2-0-C0-R4 -CH2-O-CO-O-R5 or 5-tetrazolyl;
R3 is hydroxy, (C1-C10)-alkoxy, phenyl-{C1-C8)-a!koxy-, phenyloxy-, (C1-C8)-
alkylcarbonyloxy-{C1-C6)-alkoxy-, phenylcarbonyloxy-{C1-C6)-alkoxy-, phenyi-{C1-C6)-
alkytcarbanytoxy-(C1-C6)-alkoxy-, (C1-C8)-alkoxycarbonyioxy-{C1-C6)-alkoxy-
phenyloxycarbonyloxy-{C1-C6)-alkoxy-, phenyl-{C1-C6)-alkoxycarbonyloxy-(Ci-
C5}-alkoxy-, amino, mono-((C1-C10)-alkyl)-amino-, di-((C1-C10)-alkyi)-amino-or
R4R4N-CO-{C1-C5)-alkoxy- in which the residues R4 are independent of one another
and can be identical or different;
R4 is hydrogen, (C1-C10)-alkyl, phenyl or phenyl-1(C1-C8)-alkyI-;
R5 has one of the meanings of R4 with the exception of hydrogen;
phenyl is an unsubstituted phenyl residue or a phenyl residue which is substituted by
one or more identical or different substituents from the group consisting of (C1-C4)-
alkyi, (C1-C4)-alkoxy, methylenedioxy, ethylenedioxy, halogen, trifluoromethyl and
trifluoromethoxy;
in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically

tolerable salts.
2. A compound of the formula I as claimed in claim 1. in which W is isopropyt and V is hydrogen, in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically tolerable salts.
3. A compound of the formula I as claimed in claim 1 and/or claim 2, in which R^ is unsubstituted phenyl, phenyl which is substituted by a methyienedioxy residue or an ethylenedioxy residue, phenyl which is substituted by one or two (Ci-C4)-aikoxy groups, or (Ci-C4)-alkyl, in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically tolerable salts.
4. A compound of the formula I as claimed in one or more of claims 1 to 3, in which E is -CO-R3 or -CH2-OH and R3 is hydroxy, (C1-C6)-alkoxy or amino, in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically tolerable salts,
5. A compound of the formula I as claimed in one or more of claims 1 to 4, in which R1 is hydrogen or methyl;
R2 is unsubstituted phenyl, phenyl which is substituted by a methyienedioxy residue
or an ethylenedioxy residue, phenyl which is substituted by one or two methoxy
groups, or (C1-C4)-alkyi;
X is -CH2-CH2- or -CH2-CHrCH2-, where one of the CH2 groups in these two
residues can be replaced by a carbonyl group C=0;
W is isopropyl or cyclopropyl;
V is hydrogen or methoxy;
E is -CO-OH, -C0-0-(C1-C4)-alkyl. -CO-NH2 or -CH2-OH;
in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically
tolerable salts.
6. A compound of the formula I as claimed in one or more of claims 1 to 5, which is
3-(2-{4,4-pentamethylene-3-(4-(3-phenylureido)ben2yl)-2,5-dioxoimida2olidin-1-yl)-2-

(2-methylpropyl)acetylamino)-3-phenylpropionic acid,
3-(2-(4,4-pentamethyiene-3-{4-(3-phenylureido)benzyl)-2,5-dioxoimidazolidin-1-yi)-2-(2-methylpropyl)acetylamino)-3-methylpropionic acid,
3-(2-(4,4-pentamethylene-3-(4-{3-phenytureido)benzyl)-2,5-dioxoimidazo(idin-1-y()-2-
(2-methylpropyl)acetyiamino)-3-{2-methylpropyl)propionic acid,
3-(2-(4,4-pentamethylene-3-(4-{3-(2-methylphenyl)ureido)benzyl)-2,5-dicxoimid-
azolidin-1-yl)-2-(2-methyipropyl)acetylamino)-3-phenylpropionic acid,
3-(2-(4,4-pentamethylene-3-{4-(3-(2-methylphenyl)ureido)ben2yl)-2,5-dioxoimid-
azolidin-1-y!)-2-(2-methylpropyl)acetylarn(no)-3-rnethyipropionic acid,
3-(2-{4,4-pentamethylene-3-{4-{3-{2-methylphenyl)ureido)benzyl)-2,5-dioxoimid-
azolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(2-rnethylpropyi)propionic acid,
3-(2-(4,4-Pentamethylene-3-(4-(3-phenylureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-
(2-methy!propyl)acetyiamino)-3-methylpropionamide,
3-(2-(4,4-Pentamethytene-3-(4-{3-phenylureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-
(2-methylpropyl)acetylamino)'-3-phenylpropionannide,
3-{2-(4,4-Pentamethylene-3-(4-{3-phenylureido)benzyl)-2,5-dioxoimidazol(din-1-yl)-2-
(2-methylpropyl)acetylamino)-3-(2,4-dimethoxyphenyl)propionic acid,
3-(2-{4,4-Pentamethylene-3-(4-(3-phenylureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-
(2-methylpropyl)acetylamino)-3-{3,4-dimethoxyphenyl)propionic acid,
3-(2-(4,4-Pentamethylene-3-{4-{3-(2-methyphenyl)ureido)benzyl)-2,5-dJoxoimid-
azolidin-1-yl)«2-(2-methyiprGpyl)acetylamino)-3-{2,4-dimethoxyphenyl)propionicacid,
3-(2-{4,4-Pentamethylene-3-{4-(3-{2-methylphenyl)ureido)benzyl)-2,5-dioxoJmid-
azolidin-1-yl)-2-(2-methytpropyl)acetyiamino)-3-(3,4-dimethoxyphenyl)propionicacid,
3-{2-{4,4-Pentamethylene-3-(4-{3-{2-methylpheny()ureido)benzy!)-2,5-dioxoimid-
azoiidin-1-yi)-2-(2-methylpropyl)acetylarnino)-3-methylpropionamide,
3-(2-{4,4-Pentamethylene-3-(4-{3-(2-methylphenyl)ureido)-3-methoxybenzyl)-2,5-
dioxoimidazolidin-1-yi)-2-{2-methylpropy!)acetylamino)-3-(3,4-dirnethoxyphenyl)-
propionic acid,
3-(2-(4,4-Pentamethylene-3-{4-{3-(2-methylphenyl)ureido)benzyi)-2,5-dioxoirriid-
azolidin-1-yl)-2-cyclopropylmethylacetylamino)-3-(3,4-dimethoxyphenyi)propionic
acid, or 3-(2-{4,4-Pentamethylene-3-(4-(3-(2-methylphenyi)ureido)benzyl)-2,5-dioxoimid-

azolidin-1-yi)-2-cyciopropylmethylacetyiamino)-3-{2,4-dimethoxypheny'l)prapionic acid,
in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically ■tolerable salts.-
7. A compound of the formula t as claimed in one or more of claims 1 to 6, which is
(S)-3-((S)-2-(4,4-pentamethylene-3-{4-{3-phenyiureido)benzyl)-2,5-dioxoimidazolidin'
1 -yl)-2-'(2-methyipropyl)acetylamino)-3-pheny)propionic acid,
(R)-3-((S)-2-(4,4-pentamethylene-3-(4-{3-phenylureido)ben2yl)-2,5-dioxoimida2olidin-
1 -yl)-2-(2-methylpropyl)acetylamino)-3-methytpropiGnic acid,
(R)-3-((S)-2-(4,4-pentamethylene-3-(4-(3-phenylureido)ben2yl)-2,5-dioxoimida2oiidin'
1-yl)-2-{2-methy!propyl)acetylamino)-3-(2-methylpropyl)propionic acid,
(S)-3-((S)-2-{4,4'pentamethyiene-3-{4-(3-{2-methylphenyl)ureido)ben2yl)-2,5-
dioxoimida2olidin-1-yl)-2-(2-methy[prQpyl)acetylamino)-3-phenylpropionic acid,
(R)-3-((S)-2-(4,4-pentamethylene-3-(4-(3-(2-methylphenyl)ureido)ben2yl)-2,5-
dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino}-3-methylpropionic acid,
(R)-3-((S)-2-(4,4-pentamethylene-3-(4-(3-(2-methyipheny!)ureido)benzy!)-2,5-
dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylaminG)-3-(2-methylpropyl)propionic
acid,
(R)-3-((S)-2-(4,4-Pentamethyiene-3-(4-(3-phenyiureido)ben2y!)-2,5-dioxoimidazolidin-
1-yl)-2-(2-methy)propyl)acetylamino)-3-methylpropionamide,
(S)-3-{{S)-2-(4,4-Pentamethyiene-3-{4-(3-phenylureido)benzyl)-2,5-dioxoimidazoiidin-
1-yt)-2-(2-methytpropyi)acetylamino)-3-pheny!propionamide,
(S)-3-((S)-2-(4,4-Pentamethyiene-3-(4-(3-phenylureido)benzyi)-2,5-dioxoimidazolidin-
1-yl)-2-(2-methylpropyl)acetylamino)-3-{2,4-dimethoxyphenyl)propionic acid,
(S)-3-{(S)-2-(4,4-Pentamethylene-3-(4-(3-phenylureido)benzyi)-2,5-dioxoimidazo(idin-
1-yl)-2-(2-methylpropyl)acetyiamino)-3-(3,4-dimethoxyphenyi)propionic acid,
(S)-3-((S)-2-(4,4-Pentamethyiene-3-{4-(3~(2-methyphenyl)ureido)ben2yl)-2,5-
dioxoimidazolidin-1-y()-2-(2-methy!propyi)ac6tyiamino)-3-(2,4-
dimethoxyphenyl)propionic acid,
(S)'3-{(S)-2-(4,4-Pentamethy(ene-3-(4-(3-{2-methyiphenyl)ureido)benzyi)-2,5-
dioxotmidazolidin-1-yi)-2-(2-methylpropyl)acetyiamino)-3-(3,4-

dimethoxyphenyl)propionic acid,
(R)-3-((S)-2-(4,4-Pentamethyiene-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methytpropyl)acetylamino)-3-methylprQpionamide, • (S)-3-((S)-2-{4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ijreido)-3-methoxybenzyl)-2,5-dioxoimidazoitdin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)-propionic acid,
(S)-3-((S)-2-(4,4-Pentamethylene-3-(4-{3-(2-methy!phenyl)ureido)ben2yl)-2,5-dioxoimida2olidin-1-yl)-2-cydopropylmethyl-acetylamino)-3-{3,4-dimethoxyphenyl)-propionic acid, or
(S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)ben2yl)--2,5-dioxoimida2olidin-1-yl)-2-cyclopropylmethyl-acetylamino)-3-(2,4-dirnethoxyphenyl)-propionic acid, and its physiologically tolerable salts.
8. A compound of the formula 1 as claimed in one or more of claims 1 to 7, which is (S)-3-{(S)-2-{4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)ben2yl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-phenylpropionic acid tromethamine salt,
(R)-3-((S)-2-(4,4-Pentamethylene-3-{4-(3-{2-methylphenyi)ureido)ben2yl)-2,5-dioxoimida2olidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-methylpropionic acid tromethamine salt,
(S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-{2-methylpheny!)ureido)ben2yl-2,5-dioxoimida20lidin-1-yl)-2-(2-methylpropyl)acetyiamino)-3-(2,4-dimethoxyphenyl)-
propionic acid tromethamine salt,
(S)-3-{{S)-2-(4,4-Pentamethylene-3-(4-{3-{2-methylphenyi)ureido)benzyl)-2,5-
dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(2,4-dimethoxyphenyl)-
propionic acid sodium salt,
(S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)benzyl)-2,5-
dioxoimidazoiidin-1-yl)-2-{2-methyipropyl)acetyiamino)-3-(3,4-dimethoxyphenyl)-
propionic acid tromethamine salt,
(S)-3-((S)-2-(4,4-Pentamethylene-3-(4-(3-(2-methy(phenyt)ureido)benzyl)-2,5-
dioxoimida2olidin-1-yl)-2-(2-methylpropyl)acetylamino)-3-(3,4-dimethoxyphenyl)-

propionic acid sodium salt,
(S)-3-((S)-2-{4,4-Pentamethylene-3-(4-(3-(2-methylphenyl)ureido)-3-methoxy 2,5-dioxoimida2oiidin-1-yl)-2-(2-methylpropyi)acetytamino)-3-(3,4-dimethoxyphenyl)-■ propionic acid tromethamine salt, or (S)-3-((S)-2-(4,4-Pentamethyiene-3-(4-(3-(2-methylphenyl)ureido)ben2yl)-2,5-dioxoimidazolidin-1-yl)-2-cyclopropylmethylacetylamino)-3-(2,4-dimethoxyphenyl)-propionic acid sodium salt.
9. A process for the preparation of a compound of the formula I as claimed in one or more of claims 1 to 8, which comprises carrying out a condensation of a compound of the formula II with a compound of the formula ill

12. A compound of the formula I as claimed in one or more of claims 1 to 8 and/or its physioiogicaiiy tolerable salts and/or its prodrugs for use as an antiinflammatory.
13. A compound of the formula I as claimed in one or more of claims 1 to 8 and/or its physiologically tolerable salts and/or its prodrugs for use in the therapy or prophylaxis of arthritis, of rheumatoid arthritis, of polyarthritis, of inflammatory bowel disease, of systemic lupus erythematosus, of multiple sclerosis or of inflammatory disorders of the central nervous system.
14. A compound of the formula I as claimed in one or more of claims 1 to 8 and/or its physiologically salts and/or its prodrugs for use in the therapy or prophylaxis of asthma or allergies.
15. A compound of the formula I as claimed in one or more of claims 1 to 8 and/or its physiologically tolerable salts and/or its prodrugs for use in the therapy or prophylaxis of cardiovascular disorders, of arteriosclerosis, of restenoses, of diabetes, of damage to organ transplants, of immune disorders, of autoimmune disorders, of tumor growth or tumor metastasis or of malaria.
16. A compound of the formula I as claimed in one or more of claims 1 to 8 and/or its physiologically tolerable salts and/or its prodrugs for use as an inhibitor of the adhesion and/or migration of leukocytes or for the inhibition of the VLA-4 receptor.

17. A compound substantially as herein described and exemplified.
18. A pharmaceutical preparation substantially as herein described and exemplified.

Documents:

in-pct-2001-1571-che-abstract.pdf

in-pct-2001-1571-che-claims filed.pdf

in-pct-2001-1571-che-claims granted.pdf

in-pct-2001-1571-che-correspondnece-others.pdf

in-pct-2001-1571-che-correspondnece-po.pdf

in-pct-2001-1571-che-description(complete)filed.pdf

in-pct-2001-1571-che-description(complete)granted.pdf

in-pct-2001-1571-che-form 1.pdf

in-pct-2001-1571-che-form 13.pdf

in-pct-2001-1571-che-form 19.pdf

in-pct-2001-1571-che-form 26.pdf

in-pct-2001-1571-che-form 3.pdf

in-pct-2001-1571-che-form 5.pdf

in-pct-2001-1571-che-other documents.pdf

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Patent Number

211739

Indian Patent Application Number

IN/PCT/2001/1571/CHE

PG Journal Number

52/2007

Publication Date

28-Dec-2007

Grant Date

09-Nov-2007

Date of Filing

12-Nov-2001

Name of Patentee

M/S. SANOFI-AVENTIS DEUTSCHLAND GMBH

Applicant Address

BRUNINGSTRASSE 50, D-65929 FRANKFURT AM MAIN,

Inventors:

#	Inventor's Name	Inventor's Address
1	WEHNER Volkmar	Lindenstrasse 1, D-97657 Sandberg,
2	STILZ, Hans, Ulrich	Johannesallee 18, D-65929 Frankfurt,
3	SCHMIDT, Wolfgang	Johannesallee 14, D-65929 Frankfurt,
4	SEIFFGE, Dirk	Kostheimer Landstrasse 11, D-55246 Mainz-Kostheim,

PCT International Classification Number

C07D 235/02

PCT International Application Number

PCT/EP2000/004090

PCT International Filing date

2000-05-06

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	DE 19922462.5	1999-05-17	Germany