Title of Invention	ANTHRANILIC ACID DERIVATIVES
Abstract	Compounds of formula (I), for clinical treatment of autoimmune diseases, inflammatory diseases, organ transplant rejection and malignant neoplasia. A pharmaceutical composition comprising a compound of formula (I) in an amount giving a daily dosage of from 0.005 mg/kg to 10 mg/kg body weight, in particular from 0.025 mg/kg to 2 mg/kg body weight.

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FIELD OF THE INVENTION The present invention relates to novel anthranilic acid derivatives, which are potent inhibitors of dihydroorotate dehydrogenase (DHODH), to be used for clinical treatment of autoimmune diseases, inflammtatory diseases, organ transplant rejection and malignant neoplasia. These compounds and pharmaceutical compositions of this invention are particularly useful for preventing and treating acute and chronic inflammation, rheumatoid arthritis, multiple sclerosis, type-1 diabetes, inflammatory bowel disease, psoriasis, transplant rejection and malignant neoplastic disease, More particularly, the present invention relates to novel derivatives suitable for the treatment of rheumatoid arthritis and transplant rejection. BACKGROUND OF THE INVENTION Rheumatoid arthritis (RA) is a chronic inflammatory and destructive joint disease that affects 0.5-1.0% of the population in the industrialised world. RA is a polyarthritis and in the disease virtually all peripheral joints might be affected. Furthermore, extra-articular involvement is another hallmark of RA and this ranges from rheumatoid nodules to life threatening vasculitis. Although the cause of RA remains unknown, autoimmunity plays a pivotal role in its chronicity and progression (Breedveld, 1998). Many pathways involved in the generation of the disease have been recognised and some of these have been unequivocally identified as important by therapeutic proof of principle studies. Management of R A is a major problem since there is no cure available. Drug therapy for RA rests on two principal approaches: symptomatic treatment with non-steroidal antiinflammatory drugs (NSAIDs) and disease-modifying antirheumatic drags (DMARDs). NSAIDs only interfere with a small segment of the inflammatory cascade (prostaglandin generation) but do not interfere with the underlying immuno-inflammatory events. By contrast, DMARDs modify the disease process in all these respects. DMARDs can be divided into small molecules and biological agents. A number of biologicals have recently been approved for clinical treatment of RA. These drugs (proteins, e.g., monoclonal antibodies) prevent in general pro-inflammatory cytokines, in particular TNF-α and IL-1, from interacting with their receptors. A number of small-molecule DMARDs are used today in RA therapy. In feet methotrexate is still the most commonly used DMARD and sulphasalazine was the second most common DMARD used in Europe during the 1990s. Thus, a number of drugs have been developed and used in RA therapy each targeting a specific pathway of importance to the generation of the disease. The latest addition to the group of small chemical DMARDs is leflunomide (Merck Index 13th ed. No. 5451). OH A771726 Leflunomide is in vivo rapidly metabolised to the active metabolite A771726, which inhibits dihydroorotate-dehydrogenase (DHODH), an enzyme that is pivotally involved in de novo pyrimidine synthesis. Inhibition of this enzyme inhibits the growth of (pathologically) fast proliferating cells. The most important cell types for the immune response, the lymphocytes, use exclusively the synthesis of pyrimidines for their growth and react particularly to DHODH inhibition (Batt, 1.9-99; Cherwinski et al., 1995). Substances that inhibit growth of lymphocytes are important medicaments for the treatment of autoimmune diseases including RA. The DHODH inhibiting leflunomide is the first medication of this class of compounds for the treatment of RA. The efficacy of leflunomide in the treatment of RA has been investigated in numerous Phase n and m clinical studies. Leflunomide has provided clinical proof of concept for the mechanism, but due to its side effects, e.g., liver abnormalities and influence on fertility, it is far from optimal for treatment of RA. EP0497740 discloses benzyloxyphenyl derivatives of general formula (A) Said patent concerns compounds possessing antihyperproliferative/antiinflammatory and anticancer activity, in a preferred group of compounds RI and R3 are methoxy, and the benzyloxy moiety is in meta-position in respect to R«. R$ is carboxy or an ester group, RS is hydtoxy or acetylamino, especially hydroxy. EPOS 15087 discloses trisubstituted phenyl derivatives of general formula (B) Said patent concerns compounds for the treatment of inflammatory and proliferative skin diseases and cancer. The compounds are to be administered topically or in divided doses up to four times a day. In the most preferred compounds R1and R2 are methoxy, W is CH2CH2, and R3 and R4 together with the phenyl ring form a condensed ring system. Research Disclosure, 1998,409(May), PS61-PS62 (No. 40953) discloses synthetic analogues of the natural product lavendustin A, of general formula (C) Compounds are disclosed wherein R1and R2 are the same or different and represent alkoxy, alkyl or alkenyloxy, R3 is La. alkoxy and R4 is i.a. acylamino. Gennari et al, (1994) reported an anaerobic degradation in soil of 2-nitrophenoxy acids used as herbicides, e.g., acifluorfen, (Merck Index 13 ed. No. Ill) that gives compound There is no teaching in the literature disclosing the use of compound D as a pharmaceutical agent Symmetrical anthranilic acids of the general formula (E) (E) have been reported in the literature to be used, for example, as high temperature resistant polyheterocycles. The synthesis of the anthranilic acid of formula (F) has been reported by Sevbo et al. (1976). Compound F is used as a synthetic intermediate in the preparation of 2-amino-3-phenothiazone derivatives. There is no teaching in the literature disclosing the use of such intermediate as a pharmaceutical agent DESCRIPTION OF THE INVENTION A primary objective of the present invention is to provide structurally novel anthranilic acid derivatives, which by virtue of their pharmacological profile, with high potency in experimental models and low level of side effects, are considered to be of value in the treatment of autoimmune disease, inflammatory diseases, organ transplant rejection and malignant neoplasia. In particular, the invention refers to novel compounds, which inhibit DHODH, to a process for their manufacture and pharmaceutical compositions containing them, and to their use for the treatment and prevention of diseases, in particular their use in diseases where there is an advantage in inhibiting DHODH. The compounds may be used for preventing and treating, but not restricted to, acute and chronic inflammation, rheumatoid arthritis, multiple sclerosis, type-1 diabetes, inflammatory bowel disease, psoriasis, transplant rejection and malignant neoplastic disease. More particularly, the present invention relates to novel derivatives suitable for the treatment of rheumatoid arthritis and transplant rejection. The present invention is directed to compounds of formula (I) wherein X is GHz, NH, 0, S, CH=CH, OC, NHCH2 or OCH2, wherein the nitrogen or oxygen atom is bound to ring A; CH2O or CH2S, wherein the oxygen or sulphur atom is bound to ring B; Y is hydrogen, straight or branched C1-C4 alkyl or a pharmaceutically acceptable inorganic cation; RI is ethyl or cyplopropyl; RZ and Ra are the same or different and represent hydrogen, straight or branched C1-C4 alkylthio, NHR4, NR4R5, trifluoromethyl, trifiuoromethoxy, NHCOR6, phenyl, phenoxy, phenylthio or phenylamino; wherein the phenyl moiety optionally is monosubstituted with fluoro; wherein R4 and R5 independently are hydrogen or straight or branched C1-C4 alkyl; or R4 and R5together with the nitrogen to which they are bound, form a 5- or 6-membered ring wherein Z is CH2,0, NH or NCH3; R« is C1-C3 alkyl, phenylamino, or phenyl optionally mono-substituted with C1-C2 alkoxy or fluoro; and with the proviso that R2 and RS are not both hydrogen when X is OCH2; which are unexpectedly effective as inhibitors of DHODH and lymphocyte dell proliferation. When Y is a pharmaceutically acceptable cation it may be selected from e.g. Li+, Na+, K+, Mg2*, Ca2+ and Zn2+. In case Y is a divalent cation, it is to be understood that the salt may contain two anthranilic acid derivative moieties for each cation. In a preferred embodiment of the invention X is CH2,0, S, CH=CH, OCH2) CH2O or CH2S; Y is hydrogen, straight or branched C1-C4 alkyl or a pharmaceutically acceptable inorganic cation; R2 and Rj are the same or different and represent hydrogen or substituents in; the 2-, 3- or 5- positions, selected from NHR4, NR4Rs, trifluoromethyl, trifhioromethoxy, phenyl, phenoxy, phenylthio or phenylamino; wherein the phenyl moiety optionally is monosubstituted with fluoro; and R4 and RS independently are hydrogen or straight or branched C1-C4 alkyl. In a more preferred embodiment of the invention X is O, S, OCH2, CH2O or CH2S; Y is hydrogen, or a pharmaceutically acceptable inorganic cation; Ra is a substituent in the 2- or 3-position and is NHR4, NR4R5, trifluoromethyl, or trifluoromethoxy; R3 is hydrogen; and R4 and RS independently are hydrogen or straight or branched C1-C4alkyl. In another more preferred embodiment of the invention X is O, S, OCH2,CH2O or CH2S; Y is hydrogen, or aphannaceutically acceptable inorganic cation; R2 is a substituent in the 2-position and is n-propylamino, di-(n-propyl)amino, trifluoromethyl or trifluoromethoxy; and R3 is hydrogen. In a still more preferred embodiment of the invention X is OCH2; Y is hydrogen oif a pharmaceutically acceptable inorganic cation; Ra is a substituent in the 2-position and is trifluoromethyl; and Ra is hydrogen. In a further preferred embodiment of the invention XisO; Y is hydrogen or a pharmaceutically acceptable inorganic cation; and R2 and R3 are substituents in the 3- and S-positions, and are trifluoromethyl. Among the most preferred compounds of formula (I) are: 5-benzyl-2-propionylamino-benzoic aci3; 2-(cyclopropanecarbonyl-amino)-5-(2-trifluoromethyl-benzyloxy)-benzoicacid; 5-phenylethynyl-2-propionylamino-benzoic acid; 2-propionylamino-5-(2-trifluoromelhoxy-phenoxymethyl)-benzoicacid; 2-propionylamino-5-(2-trifluoromethyl-ben2yloxy)-benzoicacid; 2-propionylamimo-5-(2-trifluoromethyl-phenylsulfanymiethyl)-benzoicacid; 2-propionylamino-5-(2-propylamino-benzyloxy)-benzoicacid; 2-propionylamino-5-(2-propylamino-phenoxy)-benzoicacid; 2-propionylamino-S-(2-propylamino-phenylsulfanyl)-benzoicacid; 2-propionylamino-5-[(E)-22-trifluoromethyl-phenyl-vinyl]-benzoicacid; 5-(2-phenoxy-phenoxy)-2-propionylamino-benzoicacid; 5-(3,5-bis-trifluoromethyl-phenoxy)-2^yclopropanecarbonylamino-benzoicacid; 5-(3,5-bis-trifluoromethyl-phenoxy)-2-propionylamino-benzoic acid; and 5-(2-dipropylamino-phenoxy)-2-propionylamino-benzoic acid. The compounds of formula (I) unexpectedly displayed potent inhibition of the enzyme DHODH. The results surprisingly demonstrated an unexpected structure-activity relationship reflecting a specific interaction with the enzyme. Compounds of formula (I) wherein the acylamino group adjacent to the carboxylic acid group was replaced by a hydroxy group demonstrated no DHODH inhibition. Exchanging in a compound wherein the acylamino moiety is acetylamino, the acetylamino moiety for propionylamino or cyclopropylcarbonylamino increased fee inhibitory effect up to a 10-fold. Further addition of bulk, however, strongly reduced the DHODH inhibition, reflecting a specific interaction with a size dependent enzyme pocket Compounds wherein X represents O, S, CH=CH, OCHj, CH2O or CH2S demonstrated particularly high potency as inhibitors of DHODH. The type and position of the R2/R3 substitution was found to be crucial for a strong DHODH inhibition. Compounds wherein R2 /Rs are lipophilic substituents with high it-values in the range 0.5 to 2 (Kubinyi, 1990) displayed maximal inhibition. Moreover, monosubstitution, i.e., R3 is hydrogen, was superior to disubstitution. The position of the monosubstitution was important for the effect, i.e., the orthosubstitution was superior to mew-substitution, and far superior to substitution in the paraposition. The type and position of the R2/Ra substitution did also affect the pharmacokinetic profile. SYNTHETIC PROCEDURES The compounds of formula (I) may be prepared by the following methods: Method A The compounds of formula (I) may be prepared by known methods, for example, by aromatic nucleophilic substitution of nitro-activated fluoro derivatives (II) in a suitable solvent such as acetonitrile or abolar aptotic solvent, e.g., DMP. Suitable reactants (TO) are for example, aryl thiols and phenols (W = OH or SH) in the presence of an alkaline salt such as potassium or cesium carbonate. The reduction of the resultant nitro derivative to corresponding amino derivative may be accomplished by use of anhydrous copper(II)acetate activated sodium borohydride in ethanlol at room temperature. This reduction agent is particularly useful for reduction of sulphur containing nitro derivatives as described by Mathis et al. (2003). The resultant amino derivative may be readily transformed to target compound (I) by acylation. Suitable acylating reagecjts are for example anhydrides and acyl chlorides (Method f). Simple alkaline hydrolysis of the ester functionality provides the acidic function. MethodB The compoundslof formula (I) may also be prepared by N- and O-arylation of substituted anilines or phenols (W = NH2 or OH) with a phenylboronic acid (V) for example using the procedure described by Chan et al. (1998). The yields are generally in the range of 5-80 %, with lower yields for p/t/w-substituted aryl compounds. Simple alkaline hydrolysis of the ester functionality provides the acidic function. Method C Aromatic nucleophilic substitution may also be applied in the preparation of 2-substituted amino derivatives. The reaction conditions are similar to the conditions in method A, with a good yield of the intermediate nitro derivative. This may then be reduced to the corresponding amino derivative, which may be reacted with phenylboronic acid derivatives as described in Method B, or alkylated via reductive alkylation as described in Method D. The compound of formula (I) wherein R2 is NJfc may be further transformed by acylation thereof. Suitable acylating reagents are for example anhydrides and acyl chlorides (Method J). Simple alkaline hydrolysis of the ester functionality provides the acidic function. Method D Compounds with X = NHCH2 may be prepared by reacting a compound of formula (IV) (W = NH2) with an aromatic aldehyde under reductive conditions. Simple alkaline hydrolysis of the ester functionality provides the acidic function. Method E Compounds witiji X = CHa (formula (I)) may be prepared according to the method described by Freitag (1970). Thus, methyl anthranilate may be condensed with the appropriate benzyl alcohol under heating. The yields are generally low. The formed 5-substituted anthranilic ester may then be acylated and the ester optionally hydrolysed. The compounds [of formula (I), may also be prepared by reacting a compound of formula (TV) or corresponding acid, wherein W is a nucleophilic group, with abenzylic reagent wherein A is a leaving group, e.g., bromide, chloride, mesyloxy or tosyloxy. The substitution may be carried out in a suitable solvent such as a polar aprotic solvent, e.g., acetone or DMF, in the presence of an alkali metal carbonate, e.g., potassium carbonate. Simple alkaline hydrolysis of the ester functionality provides the acidic function. Compounds with X = CH=CH or C=C may be prepared by reacting a compound of formula (IV) (W = Br) with a styrene (Heck-reaction) or a phenyl acetylene (Steven-Castro-coupling) with palladium catalysis. Simple alkaline hydrolysis of the ester functionality provides the acidic function. The compounds of fbnnula (I) may also be prepared by reacting a compound «f formula (IV) (W = CHaBr) with a phenol or thiophenol (A = OH or SH). Simple alkaline tyydrolysis of the ester functionality provides the acidic function. The compounds of formula (I) may also be prepared by N-alkylation of anilines with an difiinctionalized alkyl-moiety (Z = CH2 when n - 1,2; or Z=NH, NCH3,0 when n = 2) wherein A is a leaving group, e.g., bromide, chloride, mesyloxy or tosyloxy as described by Hutchinson et all 1996. Simple alkaline hydrolysis of the ester functionality provides the acidic function. The N-acylanthranilic ester (TV) may be prepared from commercially available isatoic anhydrides or by reacting commercially available 5-substituted anthranilic acids with phosgene to provide isatoic anhydrides. The reaction of an isatoic anhydride with anhydrous alcohols, in the presence of small quantities of sodium methoxide provides the corresponding anthranilic ester in a good yield (Staiger and Miller, 1959). Suitable acylating reagents to transform the anthranilic ester to the amide (IV) are for example acid anhydrides and acyl chlorides (A is a leaving group). Method K Compounds of formula (IV) may also be prepared from commercially available 5-substituted anthranilic acids. Reaction of such an acid with anhydrous alcohols in the presence of thionyl chloride provides the anthranilic ester which men can give amides IV according to method J. Method L (IV) Compounds of formula (IV) (W = CH3) may be transformed to the corresponding S-benzyl bromide with l,3-dibromo-5,5-dimethyl hydantoin (Patil et al. 1989). The following examples illustrate the present invention, but are not to be construed as limiting the scope of the invention. In the Examples below AutoNom Standard was used to generate the compound names. In general, nuclear magnetic resonance data were recorded at 400 MHz using a Broker ARX 400 spectrometer. The spectra were obtained in CDC13, CD3OD and DMSO-de and the shift scale was referenced to TMS, defined as 0.00 ppm. Abbreviations used in the description of NMR spectra were: s = singlet, d = doublet, t = triplet, q = quartet, m = multijplet, b = broad, bs - broad singlet, dd = double doublet and dt=double triplet EXAMPLE 1 2-Propionylamino-5-(2-trifluoromethyl-phenylsulfanyl)-benzoicacid A mixture of 5-fluoro-2-nitrobenzoic acid (1.9 g, 10 mmol), 2-(trifluoromethyl)thiophenol (2.0, 1 1 mmol), potassium iodide (0.8 g, 5 mmol) and cesium carbonate (6.5 g, 20 mmol) was heated at reflux in acetonitrile (60 mL) for 10 minutes. The reaction mixture was then cooled and the precipitate collected by filtration. This material was worked up with 1 M HC1 (20 mL) and CH2C12 (SO mL), the organic layer was washed with brine solution (20 mL), dried over MgSO4 and evaporated to dryness, leaving a yellow solid (3.0 g, 8.7 mmol) of 2-nitro-5-(2- trifiuoromethyl)-phenylsulfanyl-benzoic acid. This crude product was dissolved together with anhydrous copper(II)acetate (1.7 g, 8.7 mmol) in ethanol (SO inL). Sodium borohydride (3.4 g, 87 mmol) was then added in portions over 10 min. After 1 h, the solvent was evaporated, the residue was {treated with cold O.S M HC1 and the mixture was extracted with ethyl acetate. The collected black organic phase was dried, filtered through a short column of silica gel and the solvent was evaporated to afford a yellow solid (2.1 g, 6.8 mmol) of 2-amino-5-(2- trifluoromethyl)-phenylsulfanyl-benzoic acid. This was treated with propionic anhydride (20 mL), gently warmed and after 1 h treated with hot water (100 mL) under maintained stirring. Upon chilling, the title compound precipitated as greyish crystals 2.S g (total yield 67 %). 'H NMR (CDCk) 8 1.30 (t, 3H), 2.53 (q, 2H), 7.13 (d, 1H), 7.29 (t, 1 H), 7.36 (t, 1H), 7.64 (d, 1H), 7.70 (d, 1H), 8.27 (s, 1H), 8.80 (d, 1H), 11.9 (bs, 1H). In essentially the same manner the following compounds were obtained from the corresponding starting materials: 2-Propionylamino-5-(3-trifluoromethyl-phenylsulfanyl)-benzoicacid 'H NMR (CDCl^) 6 1.30 (t, 3H), 2.53 (q, 2H), 7.43 (m, 4H), 7.66 (d, 1H), 8.27 (s, 1H), 8.82 2-(Cyclopropariecarbonyl-amino)-5-(3-trifluoromethyl-ph(!nylsulfanyl)-benzoicacid JH NMR (CD3OD) 8 0.99 (m, 4H), 1.75 (m, 1H), 7.24 (d, 1H), 7.41 (t, 1H), 7.49 (t, 1H), 7.61 (dd, 1H), 7.77 (d, 1H), 8.16 (d, 1H), 8.66 (d, 1H). 5-(2-Isopropyl-phenylsulfanyl)-2-propionylamino-benzoicacid 'H NMR (CDClb) 5 1.24 (d, 6H), 1.28 (t, 3H), 2.50 (q, 2H), 3.53 (m, 1H), 7.13 (t, 1H), 7.22 (d, 1H), 7.30 (ml 1H), 7.36 (d, 1H), 7.45 (d, 1H), 8.07 (s, 1H), 8.72 (d, 1H), 10.87 (bs, 1H). 2-(Cyclopropanecarbonyl-amino)-5-(2-isopropyl-phenylsulfanyl)-benzoilcacid 'HNMR (CDG13) 8 0.87 (m, 2H), 1.08 (m, 2H), 1.22 (d, 6H), 1.62 (m, IH), 3.51 (m, 1H), 7.09 (t, 1H), 7.15 (d, 1H), 7.25 (m, IH), 7.33 (d, 1H), 7.41 (dd, 1H), 8.06 (d, IH), 8.64 (d, 1H), 11.42 (bs,lH). 2-Propionylamino-5-(2-trifluoromethoxy-phenylsulfany1)-benzoic acid 'H NMR (CDC13) 6 1.30 (t, 3H), 2.54 (q, 2H), 7.04 (d, IH), 7.16 (t, IH), 7.25 (m, 2H), 7.67 (dd, IH), 8.29 (d, IH), 8.82 (d, IH), 11.01 (bs, IH). EXAMPLE 2 2-Propionylamino-5-(2-propylamino-phenoxy)-benzoicacid A mixture of 5-hydroxy-2-piopionylamino-benzoic acid methyl ester (1.0 g, 4.5 ramol) and potassium carbonate (0.62 g, 45 mmol) was stirred in DMF (5 mL) for 10 ihinutes. 2- fluoronitrobenzene (0.63 g, 4.5 mmol) was then added and stirring was continued at room temperature overnight Water (10 mL) was added and the resulting precipitate was collected by filtration, washed with water and dried under vacuum to give pure 2-propionylamino-5-(2- nitro-phenoxy)-benzoic methyl ester (1.16 g, 3.4 mmol). 'HNMR (CDC13) 8 1.30 (t, 3H), 2.50 (q, 2H), 3.92 (s, 3H), 6.97 (dd, IH), 7.22 (dt, IH), 7.28, (dd, IH), 7.52 (dt, IH), 7.75 (d, IH), 7.97 (dd, IH), 8.80 (d, IH), 10.99 (bs, IH). This material was dissolved in methanol (50 mL) and 10% Pd/C (116 mg) was added. The flask was then flushed with HZ and stirred at room temperature and at 1 atm. After 5 h of reduction, the catalyst was removed by filtration through Celite. The catalyst was carefully washed and the combined filtrate was evaporated to dryness to give pure 2-propionylamino- (2-amino-phenoxy)-benzoic methyl ester compound as a grey solid (0.97 g, 3.1 mmol). 'HNMR (CDC13) 8 1.29 (t, 3H), 2.48 (q, 2H), 3.89 (s, 3H), 6.72 (dt, IH), 6.80 (dd, IH), 6.84 (dd, IH), 6.99 (dt, IH), 7.21 ( This (200 mg, 0.636 mmol), propionaldehyde (33.3 mg, 0.572 mmol) and acetic acid (1 mL) were stirred together with methanol (20 mL) for 0.5 h. Then, sodium cyanoborohydride (94.3 mg, 0.954 mmol) was added and the mixture was stirred overnight at room temperature. Aqueous saturated sodium bicarbonate (2 mL) was added to the reaction mixture and the methanol was evaporated. The aqueous phase was extracted with ether, and the ether phase was washed with aqueous saturated sodium bicarbonate, dried over sodium sulphate, filtered and evaporated \/o dryness. Chromatography using silica gel 60 and heptane/ethyl acetate (3:1) as eluent afforded the pure ester product (110 mg). This was liydrolysed in methanol (3 mL) and 1M NaOH (11 .5 mL) overnight, acidified with 0.5 M HG1 sand the product was collected by filtration (90 mg, total yield 54 %). H NMR (CDClb) 6 0.98 (t, 3H), 1.28 (t, 3H), 1.66 (m, 2H), 2,,48 (q, 2H), 3.14 (t, 2H), 6.67 (t, 1H), 6.79 (m, 21), 7.07 (t, 1H), 7.26 (m, 1H), 7.67 (d, 1H), 10.78 (bs, 1H). The following compounds were obtained by reacting the intermediate 2-propionylamino-5-(2- amino-phenoxy i-benzoic methyl ester or 5-(2-amino-phenylsulfanyl)-2-propionylaminobenzoic acid methyl ester (EXAMPLE 17) with boronic acids according to EXAMPLE 6 or with aldehydes as described above. 5-(2-Phenylami|no-phenoxy)-2-propionylamino-benzoicaciid 'H NMR (CDC1&) 5 1.28 (t, 3H), 2.49 (q, 2H), 6.8-6.9 (m, 2H), 6,99 (t, 1H), 7.06 (m, 1H), 7.16 (m, 2H), 7.&J-7.33 (m, 3H), 7.40 (dd, 1H), 7.75 (d, 1H), i8.75 (d, 1H), 10.77 (bs, 1H). 5-[2-(4-Fluoro-phenylamino)-phenoxy]-2-propionylamino-benzoicacid !H NMR (CDaOD) 5 1.24 (t, 3H), 2.45 (q, 2H), 6.87 (m, 1H), 6.92-6.99 (m, 3H), 7.02-7.09 (m, 3H), 7.14 (dd, 1H), 7.22 (dd, 1H), 7.60 (d, 1H), 8.48 (d, 1H). 5-(2-Ethylamino phenoxy)-2-propionylamino-benzoic acid JH NMR (CD30D) 8 1.23 (m, 6H), 2.43 (q, 2H), 3.19 (q, 2H), 6.61 (dt, 1H), 6.78 (m, 2H), 7.02 (m, 2H), 7.65 (d, 1H), 8.47 (d, 1H). 5-(2-Dipropylamino-phenoxy)-2-propionylamino-benzoic acid 'H NMR (CDCU) 5 0.81 (t, 6H), 1.27 (t, 3H), 1.46 (q, 4H), 2.48 (q, 2H), 3.18 (t, 4H), 6.91 (d, 1H), 7.03 (t, IHj, 7.11 (m, 2H), 7.18 (d, 1H), 7.80 (d, 1H), 8.68 (d, 1H), 11.29 (bs, 1H). 2-Pr opionylamilno-5-(2-pr opylamino-phenylsulfanyl)-benzioic acid 'H NMR (DMSO-de) 5 0.78 (t, 3H), 1.10 (t, 3H), 1.46 (m, 2HX 2.36 (q, 2H), 3.06 (bt, 2H), 5.33 (bs, 1H), 6.&2 (t, 1H), 7.71 (d, 1H), 7.29 (dt, 1H), 7.35 (dd, 1H), 7.40 (dd, 1H), 7.65 (d, 1H), 8.38 (d, IHfr, 11.01 (bs, 1H). EXAMPLE 3 5-(2-Butyrylamino-phenoxy)-2-(cyclopropanecarbonyl-amino)-benzoicaicid A mixture of 5-(2-amino-phencixy)-2-(cyclopropanecafbonyl-amino).-benzoic acid methyl ester (50.0 mg, 0.1 S3 mmol, pnjpared according to EXAMPLE 2) and butyiyl chloride (23.3 rag, 0.184 mmol) in CH2C12 (1.5 mL) was heated in a microwave oven at 110°C for 10 minutes. The reaction mixture was allowed to reach room temperature and the solvent was removed by evaporation. The crude ester product was hydrolysed in methanol (2 mL) and 1M NaOH (1 mL) over night, acidified with 1M HC1 and the product was isolated by filtration (18 mg, total yield: 31%). 'HNMR (CDC13) 8 0.91 (m, 2H), 0.99 ft 3H), 1.12 (m, 2H), 1.64 (m, 1H), 11.75 (m, 2H), 2.38 ft 2H), 6.79 (d, 1H), 7.01 (t, 1H), 7.13 (t, 1H), 7.29 (dd, 1H), 7.70 (d, 1H), 7L73 (bs, 1H), 8.42 (d, 1H), 8.76 (d, 1H), 11.09 (bs, 1H). In essentially the same manner the following compounds were obtained from the corresponding starting materials: 2-Propionylamino-5-(2-propionylamino-phenoxy)-benzoicacid 'HNMR (CDC13) 8 1.26 (m, 611), 2.47 (m, 4H), 6.79 (d, 1H), 7.02 (t, 1H), 7,14 (t, 1H), 7.31 (dd, 1H), 7.33 (m, 2H), 8.45 (d, 1H), 8.80 (d, 1H), 10.86 (bs, 1H). 5-(2-Benzoylamino-phenoxy)"2-propionylamino-benzoic acid 'H NMR (CDC13) 8 1.28 (t, 3H), 2.50 (q, 2H), 6.84 (d, 1H), 7.07 (t, 1H), 7.20 ft 1H), 7.37 (dd, 1H), 7.49 (t, 2H), 7.56 ft 1H), 7.77 (d, 1H), 7.86 (d, 1H), 8.51 (bs, 1H), 8.62 (d, 1H), 8.82 (d,lH), 10.84 (bs, 1H). '2-(Cyclopropanecarbonyl-amino)-5-[2-(4-methoxy-benzoylamino)-phenoxy]-benzoic acid 'HNMR (CDC13) 8 0.86 (m, 2H), 1.05 (m, 2H), 1.60 (m, 1H), 3.79 (s, 3H), 6.85 (dd, 1H), 6.98 (dd, 1H), 7.01 (dt, 1H), 7.11 (dt, 1H), 7.15 (dt, 1H), 7.27 (dd, 1H), 7.46!(dt, 1H), 7.71 (d, 1H), 8.24 (dd, 1H), 8.66 (dd, 1H), 8.68 (d, 1H), 10.70 (bs, 1H), 11.43 (bs, IF). 2-(Cyclopropartecarbonyl-amino)-5-[2-(3-methoxy-bcnzo)rlamino)-phenoxy]-benzoic acid 'HNMR (CDCfe) 5 0.91 (m, 2H), 1.12 (m, 2H), 1.63 (m, IH), 3.86 (s, 3H), 6.84 (dd, IH), 7.07 (m, 2H), 7.J19 (dt, IH), 7.38 (m, 3H), 7.44 (bs, IH), 7.76 (d, IH), 8.49 (bs, IH), 8.59 (dd, IH), 8.78 (d, IF}), 11.05 (bs, IH). 2-(Cyclopropai?ecarbonyl-amino)-5-(2-phenylacetylamino-phenoxy)-benzoic acid 'H NMR (CDCfe) 6 0.87 (m, 2H), 1.11 (m, 2H), 1.62 (m, IH), 3.70 (s, 2H), 6.84 (d, IH), 7.02 (m, 2H), 7.12 (t 1H), 7.17 (m, 2H), 7.25 (m, 3H), 7.40 (d, IH), 7.66 (bs, IH), 8.27 (d, IH), 8.67(d,lH),1133(bs,lH). EXAMPLE4 5-[2-(3-Phenyl-iureido)-phenoxy]-2-propionylamino-benzoicacid A mixture of 2-propionylamino-5-(2-amino-phenoxy)-benzoic acid methyl ester (50.0 mg, 0.153 mmoL, prepared as described in EXAMPLE 2) and phenyl isocyanate (21.0 mg, 0.175 mmol) in CH2CJ2 (10 mL) was stirred at room temperature for 2 hours. The solvent was removed by evaporation and the crude ester product was hydrolysed in methanol (1 mL) and IM NaOH (1 mL) over night. The reaction mixture was acidified with IM HCI and the product was collected by filtration (54 mg, total yield 80%). 'H NMR (CDClb) 8 1.40 (t, 3H), 2.66 (q, 2H), 6.67 (d, 1^0^6,94 (m, 2H), 7.05 (t, IH), 7.17 (t, IH), 7.29 (t, 2H), 7.43 (d, 2H), 7.68 (bs, IH), 7.95 (bs, IH), 8.42 (bd, IH), 8.52 (d, IH), 10.94 (bs, IH). EXAMPLES 5-(2-Piperidin-l-yl-phenoxy)-2-propionylamino-benzoicacid This compound was prepared essentially as described by Hutchinson et al. 1996. A mixture of 5-(2-amino-phenoxy)-2-propionylamino-benzoic acid methyl ester (1.26 g, 5.00 mmol), 1,5- dibromo-pentane (1.38 g, 6.00 mmol) and ethyl-diisopropyl-amine (2.60 mL, 6.00 mmol) in DMF (30 mL) was stirred at 100°C for 16 hours. The reaction, mixture was allowed to reach room temperature and ethyl acetate (100 mL) was added The organic layer was washed with aqueous saturated NaHCO3 and brine and was then dried over MgSO^ filtered and evaporated to dryness. Chrqmatography using silica gel 60 and heptane/ethyl acetate (4:1 -> 1:1) as eluent afforded a crude product that was again subjected to chrornatography using heptane/ethyl acetate (19:1 - 4:1) as eluent, yielding the pure ester product (304 mg). This was hydrolysed in ethanol (2 mL) and 1M NaOH (2mL) over night, acidified with 1M HC1 and the product was isolated by filtration (132 rag, total yield: 7%). 'HNMR (CDC13) 8 1.29 (t, 3H), 1.53 (bd, 1H), 1.94 (bd, 2H),2.01 (bd, 1H) 2.50 (q, 2H), 2.79 (bd, 2H), 3.83 (bs, 2H), 3.88 (bd, 2H), 6.83 (d, 1H), 7.16 (t, 1H), 7.33 (m, 2H), 7.82 (d, 1H), 8.55 (d, 1H), 8.86 (d, 1H),, 11.08 (s, 1H), 12.99 (bs, 1H). In essentially the same manner the following compounds were obtained from the corresponding starting materials: 5-(2-Piper idin -1 -yl-ben zyloxy)-2-pr opionylamin o-benzoic acid 5-(2-Piperidin-l-yl-phenoxymethyl)-2-propionylamino-benzoicacid 5-(2-Piperidin-l-yl-phenylsulfanylmethyl)-2-propionylamino-benzoic acid 5-[(E)-2-(2-Piperidin-l-yl-phcnyl)-vinyl]-2-propionylamino-benzoic acid 5-(2-Piperidin-l-yl-phenylsulfanyl)-2-propionylamino-benzoic acid 5-(2-Morpholin-4-yl-benzyloxy)-2-propionylamino-benzoic acid 5-(2-Morpholm-4-yl-phenoxymethyl)-2-propionylamino-benzoic acid 5-(2-Morpholin-4-yl-phenylsiLlfanylmethyl)-2-propionylamino-benzoic acid 5-(2-Morpholin-4-yl-phenoxy)-2-propionylamino-benzoicacid 1HNMR (CDC13) 5 1.29 (t, 3IQ, 2.49 (q, 2H), 3.17 (bs, 4H), 3.88 (bs, 4H), 6.94 (d, 1H), 7.06 (t, 1H), 7.11 (d, 1H), 7.18 (m, 2H), 7.67 (d, 1H), 8.71 (d, 1H), 10.08 (bs, 1H), 5-(2-Morpholin-4-yl-phenylsnlfanyl)-2-propionylamino-benzoic acid 5-[(E)-2-(2-Morpholin-4-yl-phenyl)-vinyl]-2-propionylamino-benzoic acid 5-{(E)-2-[2-(4-Methyl-pipera2in-l-yl)-phenyl]-vinyl}-2-pr opionylamin o-benzoic acid 5-[2-(4-Methyl-piperazin-l-yl)-benzyloxy]-2-propionylamino-benzoicacid 5-t2-(4-Methyl-piperazin-l-yl)-phenoxymcthyl]-2-propionylamino-benzoicacid 5-[2-(4-Methy1-piper azin-1 -yl)-phenylsulfanylmethyl]-2-pr opionylamino-benzoic acid 5-[2-(4-Methyl-piperazin-l-yl)-phenoxy]-2-propiony1arnino-benzoicacid 5- [2-(4-M ethyl-piper azin-1 -yl)-phenylsu Ifanyl] -2-pr opiony lamin o-benzoic acid EXAMPLE 6 5-(2-PheQoxy-pftenoxy)-2-propionylamino-benzoic acid A mixture of 5-hydroxy-2-propionylamino-benzoic acid methyl ester (2.2 g, 10 mmol), (2- phenoxy)phenylboronic acid (4.3 g, 20 mmol), anhydrous copper(II) acetate (1.8 g, 10 mmol) and pyridine (4.o g, 50 mmol) in CHjCfe (50 mL) was stirred at room temperature for 72 h in the presence of ? A powdered molecular sieves. The reaction -mixture was then filtered through Celite and chromatographed on silica gel (Rf = 0.11, CHzCk) to give the intermediate methyl ester. This was dissolved in a mixture of methanol (5 mL) and 1M NaOH (5 mL), wanned at 60 °C for 1 h, and then acidified to pH 3 with 1 M HC1. After cooling, the pure title compound was collected by filtration, dried, and obtained as a grey solid (0.34 g,'^% yield). 'H NMR (CDCla; 8 1.27 (t, 3H), 2.4$ (q, 2H), 6.90 (d, 2 H), 7.03-7.10 (m, 3H), 7.11-7.19 (m, 3H), 7.28 (t, 2H), 7.64 (d, 1H) 8.69 (d, 1H), 10.7 (bs, 1H). In essentially the same manner the following compounds wen; obtained from the corresponding starting materials: 2-Pr op ion ylamin o-5- (3-tr ifluor omethyl-phenoxy )-benzoic acid JH NMR (CCbOp) 8 1.25 (t, 3H), 2.48 (q, 2H), 7.22 (d, 1 H), 7.26 (s, 1H), 7.30 (dd, 1H), 7.42 (d, 1H), 7.56 (t, JH), 7.72 (d, 1H), 8.63 (d, 1H). 2-Propionylamino-5-(2-trifluoromethyl-phenylamino)-benzoic acid 'HNMR (CDC13) 6 1.29 (t, 3H), 2.50 (q, 2H), 6.04 (bs, 1 H), 6.96 (t, 1H), 7 19 (d, 1H), 7.38 (t, 1H), 7.41 (dd, 1H), 7.58 (d, 1H), 7.85 (d, 1H), 8.74 (d, 1H), 10.8 (bs, 1H), 2-Propionylamino-5-(2-trifluijromethyl-phenoxy)-benzoic acid 'HNMR (CDC13) 8 1.28 (t, 3J[), 2.50 (q, 2H), 6.89 (d, 1 H), 7.19 (t, 1H), 7.30 (dd, 1H), 7.47 (t, 1H), 7.69 (d, 1H), 7.79 (d, 1H), 8.78 (d, 1H), 10.8 (bs, 1H). 5-{Biphenyl-2-yloxy)-2-propionylamino-benzoicacid 'H NMR (CDC13) 3 1.27 (t, 3H), 2.48 (q, 2H), 6.98 (d, 1H), 7.18 (dd, 1H), 7, Z2-7.40 (m, 5H), 7.47 (dd, 1H), 7.53(d, 2H), 7.6(5 (d, 1H), 8.67 (d, 1H), 10.8 (bs, 1H). 2-(Cyclopropanecarbonyl-amino)-5-(2-trifluoromethyl-pheaoxy)-benzoicacid 'H NMR (CDC13) 5 0.87 (m, 2]3), 1.09 (m, 2H), 1.62 (m, 1H), 6.86 (d, 1 H), 7.15 (t, 1H), 7.23 (dd, 1H), 7.44 (t, 1H), 7.67 (d, 1H), 7.76 (d, 1H), 8.70 (d, 1H), 11.3 (bs, 1H) 5-(3,5-Bis-trifluoromcthyl-phenoxy)-2-(cyclopropanecarbonyl-amino)-bcnzoic acid JH NMR (CDC13) 8 0.88 (m, 21RQ, 1.08 (m, 2H), 1.63 (m, 1H), 7.24 (dd, lH)i 7.32 (s, 2H), 7.54 (s, 1H), 7.78 (d, 1H), 8.76 (d, 1H), 11.4 (bs, 1H). 2-Propionylamino-5-(2-trifluoromethoxy-phenoxy)-benzoicacid JH NMR (DMSO-dfi) 81.13 (t, 3H), 2.41 (q, 2H), 7.14 (d, 1 H), 7.30 (t, 1H), 7.34 (dd, 1H), 7.42 (t, 1H), 7.48 (d, 1H), 7.55 (d, 1H), 8.50 (d, 1H), 11.0 (bs, 1H). 5-(3,5-Bis-trifluoromethyl-phenoxy)-2-propionylamino-benzoicacid 'H NMR (DMSO-ds) S 1.12 (t, 3H), 2.41 (q, 2H), 7.47 (dd, 1H), 7.63 (s, 2H), 7.68 (d, 1H), 7.85 (s, 1H), 8.55 (d, 1H), 11.05 (bs, 1H). 2-Propionylamino-5-(2-triflu promethoxy-phenylamino)-benzoicacid !H NMR (CDC13) 8 1.30 (t, 3JO, 2.50 (q, 2H), 5.89 (bs, 1H), 6.86 (m, 1H), 7.15 (d, 2KQ, 7.25 (d, 1H), 7.38 (dd, 1H), 7.82 (d, 1H), 8.72 (d, 1H), 10.93 (bs, 1H). EXAMPLE 7 2-(Cyclopropanecarbonyl-amino)-5-(2-trifluoromethyl-be!nzyloxy)-benzoicacid. A mixture of 2-(cyclopropanecarbonyl-amino)-5-hydroxy-benzoic acid (7.0 g, 32 mmol) and 2-(trifluoromethyl)-benzyl bromide (9.09 g, 38 mmol) in 0.5 M KOH (158 mL, 79 mmol) and acetone (200 mL) was heated to reflux. After 4 hours, acetone was evaporated and the resulting mixture was diluted with more water and washed with CHaCU- The water phase was acidified with 1 M HC1 and the resulting solid was collected by filtration. Recrystallisation in methanol gave the product as an off-white powder (6.0 g, yield 50%). 'H NMR (DMSO-dg) S.0.80-0.87 (m, 4H), 1.66-1.74 (m, 1H), 5.30 (s, 2H), 7.27 (dd, 1 H), 7.52 (d, 1H), 7.59 (t, 1H), 7.73 (t, 1H), 7.77 (d, 1H), 7.81 (d, 1H), 8.33 (d, 1H), 11.1 (bs, 1H). 13C NMR (DMSO-dg) 5 7.4 (2 x CH2), 15.6 (CH), 66.5 (CH2), 115.6 (CH), 118.3 (C), 120.7 (CH), 122.2 (CH), 124.2 (CF3, q, JCF=273.9 Hz), 126.1 (CH, q, JCF= 5.5 Hz), 126.8 (C, q, JCF=30.4 Hz), 128.7 (CH), 130.3 (CH), 132.8 (CH), 134.6 (C), 134.7 (C), 152.7 (C), 168.9 (COOH), 171.2 (CO). MS-ESI: m/z 380 [MH]+. In essentially tile same manner the following compounds were obtained from the corresponding starting materials: 2-(Cyclopropanecarbonyl-amino)-5-(3-trifluoromethyl-benzyloxy)-benzoicacid 'H NMR (DMSO-de) 8 0.84 (m, 4H), 1.70 (m, 2H), 5.23 (s, 2H), 7.29 (dd, 1H), 7.56 (d, 1H), 7.65 (t, 1H), 7.71 (4 3H), 7.78 (d, 1H), 7.82 (s, 1H), 8.31 (d, 1H), 10.98 (bs, 1H), 13.62 (bs, 1H). 2-Propionylammo-5-(2-trifluoromethyl-benzyloxy)-benzoicacid. 'HNMR (DMSO-d6) S 1.08 (t, 3H), 2.33 (q, 2H), 5.22 (s, 2H), 7.23 (dd, 1H), 7.48 (s, 1H), 7.53 (t, 1H), 7.74 (m, 3H), 8.35 (d, 1H), 10.8 (bs, 1H), 14.1 (le, 1H). 5-(Biphenyl-2-ylmethoxy)-2-propionylamino-benzoicacid !H NMR (DMSO-ds) 8 1.08 (t, 3H), 2.20 (q, 2H), 4.92 (s, 2H), 7.10 (dd, 1H), 7.36 (m, 9H), 7.57 (dd, 1H), 8L25 (d, 1H), 10.76 (bs, 1H). 2-Propionylamino-5-(2-trifluoromethoxy-benzyloxy)-benzoicacid 1HNMR(DMSO-d6)5 1.12ft 3H), 2.37 (q, 2H), 5.16 (s, 2H), 7.29(dd, 1H), 7.44 (t,2H), 7.52 (dt, 2H), 7.66 (d, 1H), 8.37 (d, 1H), 10.79 (s, 1H). EXAMPLES 2-Propionylamino-5-(3-propylamino-benzyloxy)-benzoicacid A mixture of 5-(3-nitro-benzylOxy)-2-propionylamino-benzoic acid methyl ester (196 mg, 0.54 mmol, prepared according to EXAMPLE 7) and hydrazine hydrate (0.81 mL, 1.62 mmol) in 1,2-dichloroethane (15 mL) was cooled to 5°C. Raney-nickel (50 mg) was added carefully in small portions. After the adclition the reaction mixture was allowed to reach room temperature and was left with stirring ibr 2 hours. The catalyst was removed by filtration and the organic phase was washed with water, dried over Na2SO4, filtered and evaporated to dryness. The crude amine, triacetoxy sodium borohydride (241 mg, 1.10 mmol), propiionaldehyde (0.54 mL of a 1M solution in 1,2-dichloroethane, 540 mmol) and acetic acid (0.43 mL) were allowed to react in 1,2-dichloroethane at room temperature for 10 minutes. The reaction mixture was filtered through silica gel 60, which was then washed with CHCb. the solvents were removed by evaporation, which afforded the pure ester product This was hydrolysed in ethanol (3 mL) and 1M NaOH (ImL) over night, acidified with 1M HC1 until pH 6 and the product was collected by filtration (83 mg, total yield 43%). 'H NMR (DMSO-ds) 6 0.92 (t, 3H), 1.11 (t, 3H), 1.54 (m, 2H), 2.37 (q, 2H), 2.9$.(t, 2H), 4.99 (s, 2H), 6.50 (dd, 1H), 6.57 (d, 1H), 6.62 (s, 1H), 7.06 (t, 1H), 7.25 (dd, 1H), 7.51 (d, 1H), 8.36 (d, 1H), 10.83 (s, 1H). In essentially the same manner lite following compound was obtained from the corresponding starting materials: 2-Pr opionylamino-5-(2-pr opylamino-benzyloxy)-benzoic acid 'HNMR (DMSO-dc) 6 0.94 (t, 3H), 1.12 (t, 3H), 1.56 (m, 2H), 2.37 (q, 2H), 3.07 (t, 2H), 5.03 (s, 2H), 5.08 (bs, 1H), 6.58 (t, 1H), 6.62 (d, 1H), 7.15 (dt, 1H), 7.22 (dd 1H), 7.29 (dd, 1H), 7.56 (d, 1H), 8.36 (d, 1H), 10.82 (s, 1H), 13.61 (bs, 1H). EXAMPLE 9 2-Propionylaniino-5-(2-trifluoromethyl-benzylamino)-ben;zoic acid A mixture of 5-amino-2-propionylamino-benzoic acid methyl ester (100 mg, 1.12 mmol), 2- irifluoromethyl benzaldehyde (196 mg, 1.12 mmol), sodium iicetate trihydrate (305 mg, 2.24 mmol) and acetic acid (2.7 mL) was stirred at room temperature for 10 minutes in a mixture of methanol (9 mL) and water (7 mL). Sodium cyanoborohydlride (98 mg, 1.57 mmol) was added in small portions whereafter the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured onto water (50 :mL) and the aqueous solution was brought to basic pH with 2M NaOH. Cooling the mixture in an ice-bath afforded the pure ester product, Which was collected by filtration (330 mg). The ester was hydrolysed in methanol (19 mL) and 5M NaOH (0.5 mL) over night, acidified wiilh 2M HC1 and the product was collected by filtration (265 mg, total yield 64%). 'H NMR (DMSO-dfi) 8 1.09 (t, 3H), 2.30 (q, 2H), 4.42 (s, 2H), 6.44 (bs, 1H), 6.74 (dd, 1H), 7.12 (d, 1H), 7.37 (t, 1H), 7.62 (m, 2H), 7.77 (d, 1H), 8.11 (d,f 1H), 10.54 (bs, 1H), 13.21 (bs, 1H). In essentially the same manner the following compound was obtained from the corresponding starting materials: 2-Propionylam!ino-5-(3-trifluoromethyl-benzylamioo)-benzoicacid 'H NMR (DMSQ-dg) 5 1.09 (t, 3H), 2.30 (q, 2H), 4.36 (s, 2H), 6.41 (bs, 1H), 6.80 (d, 1H), 7.17 (s, 1H), 7.59 (m, 2H), 7.66 (d, 1H), 7.73 (s, 1H), 8.09 (d, 1H), 10.48 (bs, 1H), 13.26 (bs, 1H). EXAMPLE 10 2-Pr opion ylamin o-5- (3-tr ifluor omethyl-phcn oxymethyl)-b en zoic acid A mixture of 5-broniomethyl-2-propionylamino-benzoic acid methyl ester (250 mg, 0.83 mmol), 3-trifluoromethyl phenol (149 mg, 0.92 mmol) and potassium carbonate (173 mg, 1.25 mmol) was heated at reflux in acetone (6 mL) for 18 hours. The reaction mixture was allowed to reach room temperature and was then poured into water (20 mL) under vigorous stirring. The aqueous mixture was extracted with CKQ3 (40 naL) and the organic layer was dried over Na2SO4, filtered and evaporated to dryness. Chromatography using silica gel 60 and heptane/ethyl acetate (4:1) as eluent afforded the pure ester product (239 mg). This was hydrolysed in ethanol (10 mL) and 1M NaOH (10 mL) over night, acidified with 1M HC1 and the product was collected by filtration (215 mg, total yield 71%). ]H NMR (DMSO-ds) S 1.13 ft 3H), 2.42 (q, 2H), 5.19 (s, 2H), 7.32 (m, 3H), 7.54 (t, 1H), 7.68 (d, 1H), 8.08 (s, 1H), 8.53 (d, 1H), 11.18 (bs, 1H). In essentially the same manner the following compounds were obtained frond the corresponding starting materials: 5-Phenoxymethyl-2-propionylamino-benzoicacid 'H NMR (DMSO-ds) 8 1.11 (t, 3H), 2.42 (q, 2H), 5.06 (s, 2H), 6.94 (t, 1H), 7.00 (d, 2H), 7.29 (t, 2H), 7.65 (d, 1H), 8.05 (s, 1;H), 8.52 (d, 1H), 11.10 (s, 1H), 13.63 (bs, 1H). 2-Propionylammo-5-(2-trifluoromethyl-phenoxymethyl)-benzoicacid ]HNMR (DMSO-de) 5 1.12 (t, 3H), 2.42 (q, 2H), 5.25 (s, 2H), 7.10 (t, 1H), 7.33 (d, 1H), 7.62 (m, 3H), 8.10 (d, 1H), 8.51 (d, 1H), 11.12(s, 1H), 13.64 (bs, 1H). 2-Propioflylamino-5-(2-trifluoromethoxy-phenoxymethyl)-benzoicacid 'HNMR (DMSO-dfi) S 1.13 (t, 3H), 2.42 (q, 2H), 5.21 (s, 2H), 7.04 (t, 1H), 17.31 (d, 1H), 7.36 (m, 2H), 7.63 (d, 1H), 8.09 (s, 1H), 8.52 (d, 1H), 11.22 (bs, 1H). 2-Propionylamino-5-(2%ifluoromethyl-phenylsulfanylmethyl)-benzoic4cid 'HNMR (DMSO-de) 5 1.12 (t, 3H), 2.40 (q, 2H), 4.31 (s, 2H), 7.19 (t, 1H)5 7.30 (t, 1H), 7.43 (d, 1H), 7.45 (d, 1H), 8,01 (s, 1H), 8.44 (d, 1H), 11.15 (bs, 1H). 2-Propionylamino-5-(2-trifluoroniethoxy-phenylsulfanylmethyl)-benzoicacid 2-Propionylamino-5-(2-propylamino-phenoxymethyl)-benzoicacid 5-(2-Dipropylamino-phenoxymethyl)-2-propionylamino-benzoicacid 2-Propionylamino-5-(3-prop)'lamino-phenoxymethyl)-benzoicacid 5-(3-Dipropylamino-phenoxymethyl)-2-propionylamino-benzoicacid 2-Propionylamino-5-(2-propylamino-phenylsulfanylmethyl)-benzoic acid 5-(2-Dipropylamino-phenylsulfanylmethyl)-2-propionylamino-benzoicacid 2-Propionylamino-5-(3-propylamino-phenylsulfanylmethyl)-benzoicacid 5-(3-Dipropylamino-phenylsulfany]methyl)-2-propionylamino-benzoicacid EXAMPLE 5-[(E)-2-(2-Fluoro-phenyl)-vinyl]-2-propionylamino-benzioic acid (not included in the claims) To a mixture of 5-bromo-2-propionylamino-benzoic acid methyl ester (1.0 g, 3.50 mmol), potassium carbbnate (532 mg, 3.85 mmol), tri-n-butyl amine (0.917 mL, 3.85 mmol) and PdCl2(PPh3)2 (35 mg, 0.05 mmol) in DMF (20 mL) was added 2-fluoro-styrene (0.50 mL, 4.2 mmol). The reaction mixture was heated to 150°C and left at this temperature for 18 hours after which it was allowed to reach room temperature. Water (10 mL) and 5M NaOH (2 mL) were added and the temperature was once again raised to 150°C. After one hour at mis temperature the reaction mixture was allowed to reach room temjjerature. Water (50 mL) was added and the mixture was filtered by suction through Celite. The filtrate was acidified with 5M HC1, the product collected by filtration and re-crystallised from ethanol (5J1 mg, 47%). 'H NMR (DMSO-dfi) 8 1.13 (t, 3H), 2.42 (q, 2H), 7.26 (m, 5H), 7.79 (t, 1H), 7.89 (d, 1H), 8,14 (s, 1H), 8.53 (d, 1H), 11.18 (bs, 1H). In essentially the same manner the following compounds were obtained from the corresponding starting materials: 2-Pr opionylamin o-5-((E)-styr yl)-benzoic acid ]HNMR (DMSO-d«) 8 1.12 (t, 3H), 2.38 (q, 2H), 7.28 (m, 3H), 7.36 (t, 2H), 7.59 (d, 2H), 7.85 (d, 2H), 8-14 (s, 1H), 8.52 (d, 1H), 11.13 (s, 1H). 2-Propionylaniino-5-[(E)-2-(2-trifluoromethyI-phenyl)-vinyl]-benzoicacid ]H NMR (DMfiO-de) 8 1.11 (t, 3H), 2.43 (q, 2H), 7.32 (m, 210, ?-48 (t, 1H), 7.70 (t, 1H), 7.75 (d, 1H), 7.85 (dd, 1H), 8.00 (d, 1H), 8.18 (d, 1H), 8.58 (d, 1H), 11.16 (bs, 1H). 2-Propionylamino-5-[(E)-2-C)-trifluoromethyl-phenyl)-vinyl]-benzoicadd 'H NMR (DMSO-de) 8 1.12 (t, 3H), 2.41 (q, 2H), 7.32 (d, 1H), 7.46 (d, 1H), 7.59 (d, 2H), 7.87 (m, 2H), 7.96 (s, 1H), 8.22 (d, 1H), 8.54 (d, 1H), 11.21 (bs, 1H). 2-Propionylamino-5-[(E)-2-( trifluoromethoxy-phenyl)-vinyl]-benzoic acid 2-Propionylamino-5-[(E)-2-CJ-trifluoromethoxy-phenyl)-vinyl]-benzoicacid EXAMPLE 12 5-Phenylethynyl-2-prdpionyiamino-benzoic acid To a solution of 5-bromo-2-prtjpionylamino-benzoic acid methyl ester (2.0 e. 7.0 mmol) in diethyl amine (55 mL) was added PdCl2(PPh3)2 (708 mg, 0.49 mmol), phenol acetylene (2.2 ImL, 20.1 mmol) and copj>er (I) iodide (109 mg, 0.27 mmol). The reaction mixture was heated to 50°C and was left with stirring at this temperature for 18 hours. After having been allowed to reach room tempeniture the reaction mixture was divided between ethyl acetate and water. The organic layer ^fes washed with brine, dried over MgSO4, filtered and evaporated to dryness. Chromatograjphy using silica gel 60 and heptane/ethyl acetate (3:1) as eluent afforded an orange-coloured cmde product to which was added ethanol (50 mL). The suspension was brought to boiling, filtered hot and the-filtrate was allowed to slowly reach room temperature. The precipitated jgrey material was collected by filtration and washed with ethanol to yield the pure ester product (1.20 g). A portion of this (400 mg) was hydroh/sed in ethanol (10 mL) and 1M NaOH (10 mL) over night, acidified with 1M HO and the product was collected by filtration (362 mg, total yield 53%). MHNMR (DMSO-de) 6 1.12 (t, 3H), 2.45 (q, 2H), 7.44 (m, 3H), 7.58 (m, 2H), 7.76 (dd, 1H), 8.12 (d, 1H), 8.60 (d, 1H), 11.34 (bs, 1H), 13.96 (bs, 1H). In essentially the same manner the following compounds were obtained from the corresponding starting materials: 2-Propionylamino-5-(2-trifluoromethoxy-phenylethynyl)-benzoicacid 2-Propionylamino-5-(3-trifluoromethoxy-phenylethynyl)-benzoic acid 2-PropionylaDiino-5-(2-trifluoromethyl-phenylethynyl)-b«nzoicacid 2-Propionylammo-5-(3-trifluoromethyl-phenylethynyl)-b«nzoicacid EXAMPLE 13 5-Benzyl-2-propionylamino-benzoicacid Methyl anlhraiiilate (30.9 g; 205 mmols) and benzyl alcohol (4.43 g; 40,9 mmols) were dissolved in 50 mL of p-xylene. Montmorillonite (1.3 g), activaled with hydrochloric acid, was added to the reaction mixture, which was then heated to boiling. The water produced during the reaction was collected using a Dean-Starck-apparatus. After three hours the solvent and the excess of methyl anthranilate were distilled off at reduced pressure. Chromatograpby using silica gel 60 and heptane/ethyl acetate (1 9/1 -> 9/1) as eluent afforded 430 mg (4.4%) of the desired methyl 5-benzylanthranilate. Methyl 5-benzylanthranilate (300 mg; 1.24 mmols) was dissolved in 7 mL of chloroform and propionyl chloride (344mg; 3.72 mmols) was added and the leaction mixture was left at room temperature fbir 18 hours. Aqueous saturated sodium bicarbonate (5 mL) was added to the reaction mixture whereafter the organic phase was separated, dried over magnesium sulphate, filtered and evaporated to dryness. The resulting yellow oil was dissolved in 5 mL of methanol and aqueous sodium hydroxide (1M, 5 mL) was added. The reaction mixtu^g was then heated to 60°C for two hours. After cooling to room-temperature the reaction mixture was acidified with 20 mL of hydrochloric acid (1M). The white precipitate was filtered with suction, washed twice with water and dried under vacuum yielding the title compound quantitatively. 'H NMR (DMSO-dj) 6 1.09 (t, 3H, J=7.4, -CH3), 2.37 (q, 2H, J=7.5, -CH2-CH3), 3.92 (s, 2H, -C#2-Ph), 7.13-7.45 (m, 5H, -Ph\ 7.44 (d, 1H, J=8.6, H4), 7.79 (s, 1H, H6), 8.39 (d, 1H, J=8.5, H3\ 1 1 .01 (s, 1H, >NH), 13.54 (bs, 1H, -COOH). EXAMPLE 14 5-Hydroxy-2-propionylamino-benzoic acid methyl ester 5-Hydroxy isatoic anhydride (17.9 g, 0.1 mol) was heated to reflux with sodium methoxide (0.5 g, O.Olmol) in methanol (600 mL) for 1 h. The reaction taixture was cooled on icebath, propionic anhydride (15.0 g, 0.1 15 mol) was added and men the mixture was heated to reflux for 0.5 h. The mixture was then concentrated under reduced pressure to app. one-half of its original and left over night in a refrigerator. The resulting precipitate was collected, washed with methanol and to give die title compound as pure white crystals (15.2 g, 0.068 mol). 'H NMR (DMSO-ds) 6 1.08 (t, 3H), 2.31 (q, 2H), 3.80 (s, 3 H), 6.98 (dd, 1H), 7.25 (d, 1H), 7.93 (d, 1H), 9.6 (bs, 1H), 10.1 (bs, 1H). EXAMPLE 15 5-Amino-2-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester 5-nitroisatoic anhydride (20.8 g, 0.1 mol)) was heated to reflux with sodium methoxide (0.5 g, O.Olmol) in methanol (600 mL). After 1 h, the solvent was evaporated under vacuum and the residue dissolved in 1,2-dichloroethane (400 mL), washed with cold water and dried over MgSO4. Cyclopropanecarbonyl chloride (20.9 g, 0.2 mol) was added to the solution and then heated at 80 °C for 4.5 h. The :mixture was allowed to cool and water (200 mL) was added under vigorous stirring. After 0.5 h, the stirring was interrupted and the phases separated, the CzHUCfe layer washed with sodium bicarbonate solution and dried over MgSO4. Evaporation of the solvent afforded 2-(cyclopropanecarbonyl-amino)-5-nitro-benzoic acid methyl ester (21.7 g, 0.082 mmol). This material was dissolved in methanol (500 mL) and 10% Pd/C (2.2 g) was added. The flask was then flushed with H2 and stirred at room temperature and at 1 atm. After 5 h reduction, the catalyst was removed by filtration through Celite. The catalyst was carefully washed and the mbined filtrate evaporated to dryness to give the pure title compound as a grey solid (18.0 g, 0.077 mo1) 'H NMR (CDC13 + CD3OD) 6 0.84 (m, 2H), 1.06 (m, 2H), 1.60 (m, 1H), 3.91 (s, 3H), 6.89 (dd, 1H), 7.33 (d, 1H), 8.47 (d, 1H), 10.9 (bs, 1H). In essentially the same manner the following compound was obtained from the corresponding starting materials: 5-Amino-2-propionylamino-benzoic acid methyl ester JH NMR (CDC13) 5 1.27 (t, 3FQ, 2.45 (q, 2H), 3.64 (bs, 2H), 3.91 (s, 3H), 6.92 (dd, 1H), 7.34 (d, 1H), 8.53 (d, 1H), 10.7 (bs, 1H). EXAMPLE 16 2-(Cyclopropanecarbonyl-amino)-5-hydroxy-benzoicacid 2-Airimo-5-hydroxy-benzoic acid (15.3 g, 0.1 mol) was dissolved in 0.5 M NaOH (650 mL, 0.325 mol). Toluene (300 mL) was added and the mixture wan cooled to 4°C. Cyclopropanecarbonyl chloride (26.1 g, 0.25 mol) was added in portions under vigorous stirring and the stirring continued for about 10 minutes. The partly diacylated product precipitated on addition of 5 M HC1 and was collected by filtration. Hydrolysis by stirring in 5 M NaOH (150 mL) for 1 hour at room temperature, cooling to 4°C and acidification with 2.5 M HC1 gave after filtration and drying a light purpur solid (19 g, yield 86%). JH NMR (DMSO-de) 5 0.73-0.79 (m, 4H), 1.59-1.64 (m, IW), 6.90 (dd, 1H), 7.31 (d, 1H), 8.12 (d, 1H), 9.5 (bs, 1H), 10.9 (bs, 1H). EXAMPLE 17 5-(2-Amino-phenylsulfanyl)-2-propionylamino-benzoic acid methyl ester A mixture of 5-(2-nitro-phenylsulianyl)-2-propicmylamino-benzoic acid methyl ester (110 mg, 0.31 mmol prepared according to Sevbo et al. 1976) andpalladium-on-charcoal (10%, 25 mg) in ethyl acetate (5 mL) was stirred in an atmosphere of hydrogen (1 atm) at room temperature for 2 hours. The catalyst was filtered off and the solvent was removed by evaporation to yield the tide compound quantitatively. 'H NMR (CEXBte) 8 1.28 (t, 3H), 2.47 (q, 2H), 3.93 (s, 3H), 4.28 (bs, 2H), 6.80 (m2H), 7.25 (m, 2H), 7.45 (d, 1H), 7.90 (d, 1H), 9.24 (d, 1H), 10.97 (bs, 113). EXAMPLE 18 5-Bromomethyl-2-propionylamino-benzoic acid methyl ester 2-Amino-5-methyl-benzoic acid (23,58 g, 156 mmol) was dissolved in methanol. The solution was brought to 0°C on an ice-bath and thionyl chloride (46.3 mL, 636 mmol) was added dropwise during 30 minutes. After the addition the reaction mixture was refluxed for 18 hours and was then allowed to reach room temperature. The solvent was evaporated and the remainder was divided between CTfeCk (500 mL) and aqueous saturated NaHCOa (500 mL). The organic layer was washed with an additional 500 mL of aqueous saturated NaHCCh, dried over MgSO4 and evaporated to dryness (16.59 g, 64%). 2-Amino-5-rnethyl-benzoic acid methyl ester (8.00 g, 48.4 mrnol) was dissolved in CHCla (275 mL) andpropionyl chloride (12.6 mL, 145 mmol) was added dropwise during 10 minutes after which the reaction mixture was left with stirring at room temperature for 72 hours. Aqueous saturated NaHCOs (400 mL) was carefully added under vigorous stirring and when no more gas evolved the organic layer was separated, dried over MgSO.*, filtered and evaporated to dryness (10.06 g, 94%). The radical bromination was performed as described by Patil et al. 1989: 5-Methyl-2- propionylamino-benzoic acid methyl ester (8.85 g, 40 mmol) and l,3-dibromo-5,5-dimethyl hydantohi (DDH) (5,72 g, 20 iimiol) ma mixture of CHC13 (500 mL) and CCU (500 mL) was heated to reflux. Every 60 minutes SO mg of dibenzoyl peroxide was added tor six hours and then the reaction mixture was left at reflux over night It was then allowed to reach room temperature and the solvents were removed by evaporation. Chromatography using silica gel 60 and heptane/ethyl acetate (18:2 -> 17:3 -> 16:4) as eluent afforded the pure title compound (6.40 g, 53%). H NMR (CDC13) 6 1.26 (t, 3EE), 2.48 (q, 2H), 3.95 (s, 3H), 4.47 (s, 2H), 7.55 (dd, 1H), 8.04 (d, 1H), 8.72 (d, 1H), 11.06 (fas, 1H). EXAMPLE 19 5-Bromo-2-propionylamino-benzoic acid methyl ester 2-Amino-5-bromo-benzoic acid methyl ester (6.37 g, 27.7 mmol) was dissolved in CHCU (140 mL) and propionyl chloride (4.81 mL, 55.4 mmol) was added dropwise during 10 minutes and the reaction mixture was left at room temperature over night Aqueous saturated Na- HCOs (150 mL) was added carefully and the mixture was left with vigorous stirring for 2 hours. The organic layer was separated, dried over MgSO filtered and evaporated to dryness (7.54 g, 95%). H NMR (CDCla) 5 1.26 (t, 3EI), 2.42 (q, 2H), 3.91 (s, 3H), 7.62 (dd, 1H), 8.13 (d, 1H), 8.67 (d,lH),11.02(bs,lH). PHARMACOLOGICAL METHODS Inhibition assay ofDHODH activity Inhibition of recombinant human DHODH was assayed by the dihydroorotate (DHO) driven reduction of dichloroindophenol (DCIP), (Bruneau et al., 1998). The standard assay mixture contained 0.4 ug/mL recombinant protein, 50 mM Tris pH8,100 pM decylubiquinone, 1 mM KCN, 200 uM DCIP and 0.1% Triton X-100. Inhibitory compounds were added at 10 different concentrations and the enzyme reaction initiated by the addition of 500 (aM DHO. The reaction was allowed to continue for 10 minutes before the reduction of DCIP was measured in a microtiterrilate reader as a decrease in absorbance at 650 nm. The ICso values (concentration of inhibitor required for 50% inhibition) for each compound were calculated fiom the obtained dose response curves. Inhibition of cell proliferation Inhibition of T cell proliferation was studied in a functional assay. A human T lymphoblast cell line (Jurkai) was cultured in the presence and absence of DHODH inhibiting compounds. Jurkat cells were seeded in microtiterplates at a concentration of 5 x 105 / mL in RPMI1640 growth media supplemented with ultraglutamin, 10% fetal calf serum, 1 mM sodium pyruvat, 10 mM HEPES and 0.1 mg/mL gentamycin. A dilution series often different concentrations of inhibitor was added to the wells and the plates were kept in a cell incubator for 3 days. At the beginning of me last 4 hours period, the cultures were pulsed with 10 ul/well O.lCi/mmol 3H-TdR and then harvested on filter papers and counted with a p-counter. The ICso values for each compound were calculated from the obtained dose response curves. Adding 50 |iM undine to the wells monitored the specificity for the mechanism. This reverses the antiproliferative effect by bypassing the DHODH enzyme using {in external source of pyrimidine. Inhibition of transplant rejection in the rat. Inbred rat strains, male PVG (RT16) (100-149 g) and DA (RTlwl) (180-240 g) rats were used as donors and recipients, respectively. Heterotopic cardiac transplantation was performed with a non-suture cuff technique. The donor heart was transplanted! to the recipient's right vessels of the neck, the aortic root being anastomosed to the common carotid artery and the pulmonary artery to the jugular vein. The graft veins were ligated. Graft survival was monitored twice daily and rejection was defined as cessation of palpable cardiac graft beats. Parallel subgroups of recipients were treated orally with a gastric feeding catheter once daily for ten consecutive days. First day of treatment was the day of transplantation and the rats were treated a few minutes before transplantation. Determination of pharmacokinetic properties in the mouse. Female mice (SJL/N Tac) were given a single intravenous or oral dose of a mixture of 4 or 6 compounds per cassette (nominal dose: 1 mg/kg/compound). The test items were formulated in physiological saline/5% Cremophor to a final concentration of each 0.1 mg/mL. Blood samples were collected from vena cava (terminal bleed) into sodium heparinised tubes. The dose formulations and plasma concentrations of each compound were determined by LCMS/ MS. The pharmacokinetic parameters were determined by non-compartmental analysis using WinNonlin Professional (version 4.0.1). EP0497740 discloses compounds that are stated to be useful as antihyperproliferative/ antiinflammatory and anticancer agents. The compound disclosed as most preferred is S-(2,Sdimethoxy- benzyloxy)-2-hydri3xy-benzoic acid methyl ester. The present inventors found 5- (2,5-dimethoxy-benzyloxy)-2-hydroxy-benzoic acid to be inactive as a DHdDH inhibitor. EP0497740 also discloses the impound 2-acetylamino-5-(2)5-dimethoxy-benzyloxy)- benzoic acid methyl ester. The compound 2-acetylamino-5-(2,5-dimethoxy-t>enzyloxy)- benzoic acid (hereinafter called compound G) has been tested and found to display only a weak inhibitory effect on T-cell proliferation, see Table 1. EPOS 15087 discloses compounds structurally related to compounds of formula (I) that are stated to be useful for the treatment of proliferative and/or inflammatory disorders and cancer, e.g., 2-acetylamino-5-[2-(:2J5-dimethoxy-phenyl)-ethyl]-benzoic acid methyl ester. 2- Acetylarnino-5-[2-(2,S-dimeuioxy-pheny])-ethyl]-benzoic acid (hereinafter called compound H) been tested and found to display a very weak inhibitory effect on T-cell proliferation, see Table 1. The.fompound 2-prqHonylamino-5-[2-(2-trifluoromethyl-phenyl)-ethyl>benzoic acid (hereinafter called compound J) is included as a reference compound. Compound J displayed a weak antiproliferatroi effect, see Table 1. The following compounds are intended to illustrate the DHODH inhibitory effect of the compounds of the present invention: compound K ' 2-propionyhimino-5-(2-trifluoromethyl-benzylamino)-benzoic acid compound L 2-propionyhimino-5-(2-trifluoromethyl-phenoxy)-benzoic acid compound M 2-propionyl£imino-5-(2-trifluoromethyl-benzyloxy)-benzoic acid compound N 2-propionyUimino-5-(2-trifluoromethyl-phenoxymethyl)-benzoic acid compound O 2-propionyl£imino-5-(2-trifluoromethyl-phenylsulfiinyl)-benzoic acid compound P 2-propionykirnmo-S-(2-trifluorome1hyl-phenylsulianyhnethyl)-benzoic acid compound Q 2-propionyUimino-5-[(E)-2-(2-trifluoromethyl-phenyl-vinyl]-benzoic acid compound R 2-propionyltimino-S-[(E)-2-(3-trifluoromethyl-phenyl-vuiyl]-benzoic acid compound S 5-(3,5-bis-taifluoromefliyl-phenoxy)-2-propioTiylamino-benzoic acid compound U compound AA compound AB compound AC compound AD compound AE 2-propionylamino-5-(2-propylamino-phencxy)-benzoic acid 2-propionylamino-5-(2-propylamino-benzyloxy)-benzoicacid 2-propiony]amino-5-(2-propylamino-phenj'lsuHanyl)-benzoicacid 5-(2propylamino-phenoxy)-2-propionyl{imino-benzoicacid 2-propionylamino-5-(2-trifluoromethoxy-bsnzyloxy)-benzoic acid 2-propionylamino-5-(2-trifluoromethoxy-phienoxymetiiyl)-benzoicacid 2-propionyJamino-5-(2-trifluoromethoxy-phienylsulianyl)-benzoicacid Inhibition of T cell proliferation was studied in a functional assay. Table 1 exemplifies the invention, without limiting the scope thereof A human T lymphoblast cell line (Jurkat) was cultured hi the presence of the compound to be screened The IQo value for each compound was calculated from the dose response curve. Adding undine was used to monitor the specificity of the DEtODH mechanism. (Table Removed) In comparison with prior art arid reference (not according to the invention) compounds, the compounds of the present invention possess advantageous pharmacokinetic properties and high oral bioavailability. The clearance (CL) and half-life of representative compounds in the mouse following i.v. administration are shown in Table 2. Table 2 exemplifies the invention, without limiting the scope: thereof. (Table Removed) b) 2-Propionylamino-5-[(E)-s1yryl]-lbenzoic acid c) 5-Benzyl-2-propionylamino-benzoic acid In a heart transplantation model in the rat, hearts were rejected in the control group (N=6) on day 6.5 after transplantation. Following daily treatment for 10 days with 2-((yclopropanfecaibonyl-ammo)-5-(2-trifluoromemyl-benzyiloxy)-benzoic acid (invention) (N=6) or compound S (N=6) the grafts were accepted and there was a tolerance induced as measured as a median graft survival of more than 100 days. Pharmaceuticallv acceptable salts of the compounds of formula (I) can be prepared by reacting the free acid with a base in water or in an organic solvent Lists of suitable; salts are found in Remington's Fnarmaceutical Sciences, 17.th edition, Macl: Publishing; Company, Easton, PA, 1985, p. 1418. Effective quantities of the compounds of this invention are preferably administered to a patient in need of such treatment according to usual routes 01 administration and formulated in usual pharmaceutical compositions comprising an effective amount of the active ingredieqt and a suitable pharmaceutically acceptable carrier. Such compositions may take a variety of forms, e.g., solutions, suspensions, emulsions, tablets, capsules, and powders prepared for oral administration, sterile solutions for parental administration, and suppositories for rectal administration or suitable topical formulations. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Design", M.B. Aulton, Churchill Livingstone, 1988. A suitable daily dose for use in the treatment of a disease selected from autoimmune diseases, inflammatory diseases, organ transplant rejection and malignant'neoplasia isitcontemplated to vary between 0.005 mg/kg to about 10 mg/kg body weight, in particular between 0.025 mg/kg to 2 mg/kg body weight, depending upon the specific condition to be treated the age and weight of the specific patient, amd the specific patient's response to the medication. The exact individual dosage, as well as the daily dosage, will be determined according to standard medical principles under the direction of a physician. REFERENCES Bait, DG, Inhibitors of dihydroorotate dehydrogenase. Exp. (Dpin. Ther. Patents, 1999, 9 (l):41-54. BreedveldFC, New insights in the pathogenesis of rheumatoid arthritis. J. Rheumatol. SuppL, 1998,53:3r7. Review. Bruneau JM, Yea CM, Spinella-Jaegle S, Fudali C, Woodward K, Robson PA, Sautes C, Westwood R, KUO EA, Williamson RA, Ruuth E, Purification of human dihydro-orotate dehydrogenase and its inhibition by A77 1726, the active metalxlite of leflunomide. Biochem. J., 1998,336 (Pt2):299-303. Chan DM T, Monaco KL, Wang Ru-Ping, Winters MP, New N- and O-arylation with phenylboronic acids and cupric acetate, Tetrahedron Letters, 1998,39(19):2933-2936. Cherwinski HM, Cohn RG, Cheung P, Webster DJ, Xu YZ, Caulfield JP, Young JM, Nakano G, Ransom JT, The immunosuppressant leflunomide inhibits lymphocyte proliferation by inhibiting pyrimidine biosynthesis, J. Pharmacol. Exp. Ther., 1995,275(2): 1043-9. Freitag, D., DE 2064305(A1) 1970. Gennari M, Negre M, Ambrosoli R, Andreoni V, Vincenti M, Acquati A, Anaerobic Degradation of Acifluorfen by Different Enrichment Cultures. J. Agricultural and Food Chemistry, 1994,42(5):1232-6. Hutchinson JH, Cook JT, Brashear KM, Bieslin MJ, Glass JD, Gould RJ, Halczenko W, Holahan MA, Lynch RJ, Sitko GR, Stranieri MT, Hartman GD. Non-Peptide Glycoprotein Ilb/IIIa Antagonists. 11. Design and in Vivo Evaluation of 3,^i-Dihydro-l(lH)risoquinolmone- Based Antagonists and Ethyl Ester Prodrugs. J. Med. Chenx, 1996,39:4583-91. Kubinyi, H. Chapter 3. Parameters. In Methods and Principles in Medicinal Chemistry Vol. 1, QSAR: Hanscri Analysis and Related Approaches; Mannholii, R., Kroogsgard-Larsen, P.,Timmermann, H, Eds.; VCH: Weinherm, 1993; pp 21-27. Mathis CA, Wang Y, Holt DP, Huang GF, Debnath ML, Hunk WE, Synthesis and evaluation of 1 1C-labeled 6-substituted 2 -aiylbenzothiazoles as amyloid imaging agents. J. Med Chem., 2003,46(13): 2740-54. Patil SD, Jones C, Nair MG, Galivan J, Maley F, Kisliuk RL, Gaumont Y, Duch D, Ferone R, Folate Analogues. 32. Synthesis and Biological Evaluation of 2-Desamino-2-methyl-N10- propargyl-5,8-dideazafolic Aciid and Related Compounds. J. Med. Chem., 1989,32:1284-89. Research Disclosure, 1998,409(May), P561-P562 (No. 40953) Sevbo DP, Ginzburg OF, 2-Annino-3-phenothiazone derivatives. III. Methyl 2-amino-3- phenothiazone-1-catboxylate. Zhumal Organicheskoi KMmii, 1976,12(8):1819-25. Staiger RP and Miller EB, Isatoic anhydride. IV. Reactions with various nucleophiles J. Org. Chem., 1959,24:1214-1219. We Claim: 1. An anthranilic acid derivative of formula (1), wherein: X is CH2, NH, O, S, CH=CH. C=C, NHCH2 or OCH2 wherein the nitrogen or oxygen atom is bound to ring A; CH2O or CH2S wherein the oxygen or sulphur atom is bound to ring B; Y is hydrogen, straight or branched C1-C4 alkyl or a pharmaceutically acceptable inorganic cation; R1 is ethyl or cyclopropyl; R2 and R3 are the same or different and represent hydrogen, straight or branched C1-C4 alkylthio, NHR4, NR4R5, trifluoromethyl trifluoromethoxy, NHCOR6, phenyl, phenoxy. phenylthio or phenylamino; wherein the phenyl moiety optionally is monosubstituted with fluoro; R4 and R5 independently are hydrogen or straight or branched C1-C4 alkyl: or R4 and R5 together with the nitrogen to which they are bound, form a 5-or 6-membered ring Z is CH2, O,NH or NCH3;and R6 is C1-C3 alkyl, phenylamino, or phenyl optionally mono-substituted with C|-C2 alkoxy or fluoro; with the proviso that R2 and R.3 are not both hydrogen when X is OCH2. 2. The anthranilic acid derivative as claimed in claim 1, wherein; X is CH2, O, S, CH=CH, OCH2, CH2O or CH2S: Y is hydrogen, straight or branched C1-C4 alkyl or a pharmaceutically acceptable inorganic cation; R2 and R3 are the same or different and represent hydrogen or subslituents in the 2-, 3-or 5- positions, selected from NHR4. NR4R5, trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, phenylthio and phenylamino; wherein the phenyl moiety optionally is monosubstituted with fluoro; and R4 and R5 independently are hydrogen or straight or branched C1-C4 alkyl. 3. The anthranilic acid derivative as claimed in claim 1, wherein: X is O, S, OCH2, CH2O or CH2S; Y is hydrogen or a pharmaceutically acceptable inorganic cation; R2 is a substituent in the 2-or 3-position and is NHR4, NR4R5, trifluoromethyl or trifluor- methoxy; R3 is hydrogen; and R4 and R5 independently are hydrogen or straight or branched C1-C4 alkyl. 4. The anthranilic acid derivative as claimed in claim 1, wherein: X is O. S, OCH2, CH2O or CH2S; Y is hydrogen or a pharmaceutically acceptable inorganic cation: R2 is a substituent in the 2-position and is n-propylamino, di-(n-propyl)amino, trifluoromethyl or trifluoromethoxy; and R3 is hydrogen. 5. The anthranilic acid derivative as claimed in claim 1, wherein: X is OCH2; Y is hydrogen or a pharmaceutically acceptable inorganic cation; R2 is a substituent in the 2-position and is trifluoromethyl; and R3 is hydrogen. 6. The anthranilic acid derivative as claimed in claim 1, wherein: X is O: Y is hydrogen or a pharmaceutically acceptable inorganic cation; and R2 and R3 are substituents in the 3-and 5-positions, and are trifluoromethyl. 7. The anthranilic acid derivative as claimed in claim 1, wherein: X is O, OCH2 or CH2O; Y is hydrogen or a pharmaceutically acceptable inorganic cation; and R2 and R3 are the same or different and represent hydrogen, trifluoromethyl or trifluoromethoxy, 8. The anthranilic acid derivative as claimed in claim 1. wherein: X is O, S, OCH2, NHCH2 or CH2; Y is hydrogen or a pharmaceutically acceptable inorganic cation; and R2 and R3 are the same or different and represent hydrogen, trifluoromethyl, NHR4. NHC0R6 or phenoxy; R4 is straight or branched C1-C4 alkyl; and R6 is phenyl. 9. The anthranilic acid derivative as claimed in claim 7 or claim 8, wherein R2 nd R3 are not both hydrogen. 10. The anthranilic acid derivative as claimed in claim 1 selected from 2-(cyclopropanecarbonyl-amino)-5-(2-trifluoromethyl-benzyloxy)-benzoic acid; 2-propionylamino-5-(2-trifluoromethyl-benzyloxy)-benzoic acid; 5-(3, 5-bis-trifluoromethyl-phenoxy)-2-cyclopropanecarbonylamino-benzoic acid; 5-(3, 5-bis-trifluoromethyl-phenoxy)-2-propionylamino-benzoic acid: and salts thereof with a pharmaceuticaliy acceptable inorganic cation. 11. The anthranilic acid derivative as claimed in claim 1 selected from 5-benzyl-2- propionylamino-benzoic acid; 5-(2 phenoxy-phenoxy)-2-propionylamino-benzoic acid; 2-propionylamino-5-(2-trifluoromethyI-phenyisulfanyl)-benzoic acid; 2-propionylaraino-5-(2-propylamino-phenoxy)-benzoic acid; 2-(cycIopropanecarbonyl-amino)-5-(2-trifluoromethyi-phenoxy)-benzoic acid; 5-(2-benzoylamino-phenoxy)-2- propionylamino-benzoic acid; 2-(cyclopropanecarbonyl-amino)-5-(3-trifluoromethyl-benzyloxy)-benzoic acid; 2-propionylamino-5-(2-trifluoromethyl-benzylamino)-benzoic acid; and salts thereof with a pharmaceutically acceptable inorganic cation, 12. The anthranilic acid derivative as claimed in claim 1 selected from 5-phenylethynyl-2-propionylamino-benzoicacid; 2-propionylamino-5-(2-trifIuoromethoxy-phenylethynyl)-benzoic acid; 2-propionylamino-5-(3-trifluoromethoxy-phenylethynyl)-benzoic acid; 2-propionylamino-5-(2-trifluoromethyl-phenylethynyl)-benzoic acid; 2-propiotiylamino-5-(3-trifluoromethyl-phenylethynyl)-benzoic acid; 2-propionylamino-5-(2-trifluoromethoxy-phenoxymethyl)-benzoic acid; 2-propionylamino-5-(2-trifluoromethyl-phenylsulfanyImethyl)-benzoic acid; 2-propionylamino-5-(2-propylamino-benzyloxy)-benzoic acid; 2-propionylamino-5-(2-propylamino-phenylsulfanyl)-benzoic acid; 5-(2-dipropylamino-phenoxy)-2-propionylamino-benzoic acid; 2-propionylamino-5-(2-trifluoromethyl-benzylamino)-benzoic acid; 2-propionylamino-5-(2-trifluoromethyl-phenoxy)-benzoic acid; 2 propionylamino-5-(2-trifluoromethyl-phenoxymethyl)-benzoic acid; 2-propionylamino-5- [(E)-2-(2-trifluoromethylphenyl)-vinyl]-benzoic acid; 2-propionylamino-5-[(E)-2-(3-trifluoromethyl-phenyl-vinyl]-benzoic acid; 2-propionylamino-5-(2-trifluormethoxy-benzyloxy)-benzoic acid; 2-propionylamino-5-(2-trifluoromethyl-phenylsulfanyl)-benzoic acid; 2-propionylamino-5-(3-trifluoromethyl-phenylsulfanyl)-benzoic acid; 2-propionylamino-5-(3-trifluoromethyl-phenoxy)-benzoic acid; 2-propionylamino-5-(2-trifluoromethyl-phenyIamino)-benzoic acid; 2-(cyclopropanecarbonyI-amino)-5-(3-trif[uoromethyl-phenyIsulfanyl)-benzoic acid; 5-(2-phnyIamino-phenoxy)-2-propionyiaimno-benzoic acid; 5-[2-(4-fluoro-phenyIamino)-phenoxyI]-2-propionyIamino-benzoic acid; 5-(2-ethylamino-phenoxy)-2-propionylamino-benzoic acid; 5-(2-butyrylamino-phenoxy)-2-(cyclopropanecarbonyI-amino)-benzoic acid; 2-propionylamino-5-(2-propionylamino-phenoxy)-benzoic acid; 2-(cyclopropanecarbonyl-amino)-5-[2-(4-methoxy-benzoylamino)-phenoxy]-benzoic acid; 2-(cyclopropanecarbonyl-amino)-5-[2-(3-methoxy-benzoylamino)-phenoxy)-benzoic acid; 2-propionylamino-5-(3-propylamino-benzyloxy)-benzoic acid; 2-propionylamino-5-(3-trifluoromethyl-benzylamino)-benzoic acid; 2-propionyIamino-5-(3-trifluoromethyl-phenoxymethyl)-benzoic acid; 2-phenoxymethyl-2-propionylamino-benzoic acid; 2-propionylamino-5-((E)-styryi)-benzoic acid; 5-{biphenyl-2-yloxy)-2-propionylamino-benzoic acid; 5-(biphenyl-2-ylmethoxy)-2-propionylamino-benzoic acid; 5-[2-(3 -phenyl-urcido)-phenoxy]-2-propionyl amino-benzoic; acid; 5-(2-piperidin-l-yl-phenoxy)-2-propionylamino-benzoic acid; 5-(2-piperidin-l-yl-benzyloxy)-2-propionylamino-benzoic acid; 5-(2-piperidin-l -yl-phenoxymethyl)-2-propionylamino-benzoic acid; 5-(2-piperidin-l-yl-phenylsulfanylmethyl)-2-propionylamino-benzoic acid; 5-[(E)-2-(2-piperidin-l -yl-phenyl)-vinyl]-2-propionyIamino-benzoic acid; 5-(2-pipendin-1-yl-phenylsulfanyl)-2-propionylamino-benzoic acid; 5-(2-morpholin-4-yl-benzyloxy)-2-propionylamino-benzoic acid; 5-(2-morpholin-4-yl-phenoxymethyl)-2-propionylamino-benzoic acid; 5-(2 -morpholin-4-yl-phenylsulfanylmethyl)-2-propionylamino-benzoic acid; 5-(2-morphoIin-4-yl-phenoxy)-2-propionyIamino-benzoic acid; 5-(2-morpholin-4-yl-phenylsulfanyl)-2-propionylamino-benzoic acid; 5-[(E)-2-(2-morpholin-4-yl-phenyl)-vinyl]-2-propionyIamino-benzoic acid; 5-{(E)-2 -[2-(4-methyl-piperazin-l-yl)-phenyl]-vinyl}-2-propionylamino- benzoic acid; 5-[2-(4-methyl-piperazin-l-yI)-benzyloxy]-2-propionylamino-benzoic acid; 5-[2-(4-methyi-piperazin-I-yl)-phenoxymethyl]-2-propionylamino-benzoic acid, 5-[2-(4-methyl-piperazin-l-yl)-phenylsulfanylmethyl]-2-propionylamino-benzoic acid; 5-[2-(4-methyl-piperazin-l-yl)-phenoxy]-2-propionylamino-benzoic acid; 5-[2-(4-methyl-piperazin-l-yl)-phenylsulfanyl)-2-propiony!amino-benzoic acid; 5-(2-amino-phenylsulfanyl)-2-propionylamino-benzoic acid methyl ester; and salts thereof with a pharmaceutically acceptable inorganic cation. 13. A pharmaceutical composition comprising a compound as claimed in any of the preceding claims as an active ingredient, in association with pharmaceutically acceptable excipients, wherein the composition is in the form of a solution, suspension emulsions, tablet, capsule, or powder for oral administration, a sterile solution for parental administration, a suppository for rectal administration or a topical formulation. 14. The compound as claimed in any of claims 1-12 for treating a condition responsive to inhibition of dihydroorotate-dehydrogenase, wherein the condition is selected from acute and chronic inflammation, rheumatoid arthritis, multiple sclerosis, type-1 diabetes, inflammatory bowel disease, psoriasis, transplant rejection, and malignant neoplastic disease.

Documents:

4289-delnp-2006-Abstract-(05-07-2011).pdf

4289-delnp-2006-abstract.pdf

4289-delnp-2006-assignment-(23-12-2008).pdf

4289-delnp-2006-Claims (24-10-2011).pdf

4289-delnp-2006-Claims-(05-07-2011).pdf

4289-DELNP-2006-Claims-(23-12-2008).pdf

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4289-DELNP-2006-Correspondence Others-(03-05-2011).pdf

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4289-delnp-2006-correspondence-others-1.pdf

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4289-delnp-2006-description (complete).pdf

4289-delnp-2006-Form-1-(05-07-2011).pdf

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4289-delnp-2006-form-13-(23-12-2008).pdf

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4289-delnp-2006-Form-2-(05-07-2011).pdf

4289-DELNP-2006-Form-2-(23-12-2008).pdf

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4289-DELNP-2006-Form-3-(03-05-2011).pdf

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