Indian Patents. 209789:AROMATIC DICARBOXYLIC ACID DERIVATIVES

Title of Invention	AROMATIC DICARBOXYLIC ACID DERIVATIVES
Abstract	The present invention relates to compounds of formula (I) wherein A, R<sub>1</sub> and R<sub>2</sub> have the meanings defined in the specification, process of manufacturing these compounds and medicaments with HDAC inhibitor activity containing such a compound.

Full Text	AROMATIC DICARBOXYLIC ACD DERIVATIVES The invention relates to aromatic dicarboxylic acid derivatives, or pharmaceutically-acceptable salts thereof, which possess anti-cell-proliferation activity such as anti-cancer activity and are accordingly useful in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said dicarboxylic acid derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti-cell-proliferation effect in a warm-blooded animal such as man. Background of the Invention Transcriptional regulation is a major event in cell differentiation, proHferation, and apoptosis. Transcriptional activation of a set of genes determines cell destination and for this reason transcription is tightly regulated by a variety of factors. One of its regulatory mechanisms involved in the process is an alteration in the tertiary structure of DNA, which affects transcription by modulating the accessibility of transcription factors to their target DNA segments. Nucleosomal integrity is regulated by the acetylation status of the core histones. In a hypoacetylated state, nucleosomes are tightly compacted and thus are nonpermissive for transcription. On the other hand, nucleosomes are relaxed by acetylation of the core histones, with the result being permissiveness to transcription. The acetylation status of the histones is governed by the balance of the activities of histone acetyl transferase (HAT) and histone deacetylase (HDAC). Recently, PIDAC inhibitors have been found to arrest growth and apoptosis in several types of cancer cells, including colon cancer, T-cell lymphoma, and erythroleukemic cells. Given that apoptosis is a crucial factor for cancer progression, HDAC inhibitors are promising reagents for cancer therapy as effective inducers of apoptosis (Koyama, Y., et al., Blood 96 (2000) 1490-1495). Several structural classes of HDAC inhibitors have been identified and are reviewed in Marks, P.M., et al., J. Natl. Cancer Inst 92 (2000) 1210-1216. More specifically, WO 98/55449 and US 5,369,108 report alkanoyl hydroxamates with HDAC inhibitory activity. It has now been found that certain aromatic dicarboxylic acid derivatives possess anti-cell-proliferation properties which are more potent than those in the aforementioned references. Furthermore, these compounds have HDAC inhibitiory activity. Description of the Invention According to the invention there is provided an aromatic dicarboxylic acid derivative of the formula I denotes or a thiophene ring which may be unsubstituted or substituted by 1 or 2 substituents independently selected from a halogen atom, an amino-, (l-4C)alkylamino-, di[(l-4C)alkyl]-amino- or a (l-4C)alkan-oylamino, a (l-3C)aIkylenedioxy-group or an acyl group, and Rl and R2 are the same or different from each other and are a hydrogen atom; a branched or unbranched (l-14C)aIkyl group, which may be unsubstituted or substituted with 1 or several substituents independently selected from the group consisting of a halogen-, hydroxy-, nitro-, amino-, carbocyclic- or a heterocyclic group, and wherein at a chain length of larger than 2 C-atoms one or several non adjacent C-atoms may be replaced by a corresponding number of heteroatoms such as oxygen, nitrogen or sulfur, and wherein 2 C-atoms may be bound together by a double or triple bond; a carbocyclic group; or a heterocyclic group; or Rl and R2 together with the nitrogen atom form a 3-6 membered ring which may contain additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and which may be annulated by a carbocyclic group or by a heterocyclic group and which may be unsubstituted or substituted by 1, 2, or 3 substituents independently selected from a halogen atom, an (l-4C)alkyl-, trifluoromethyl-, hydroxy-,m (l-4C)alkoxy-, aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy, (1-3C)alkylenedioxy-, nitro-, amino-, (l-4C)alkylamino-, di[(l-4C)alkyl]aniino-, (1-4C)alkanoylamino- or an acyl-group. An alkyl group may be e.g. pentyl, hexyl or 3-methyl-butyl. A substituted alkyl group may be e.g. ben2yl, phenethyl, tetrahydro-furan-2-yl-methyl or 2-cyclohex-l-enyl-ethyL An alkyl group where one or several non adjacent atom groups may be replaced by oxygen, nitrogen or sulfur atoms may be e.g. 3-isopropoxy-propyl or 2-methylsulfanyl-ethyl. An alkyl grolip wherein 2 atoms may be bolind together by a dolible or triple bond may be e.g. 1-hexinyl or 2-heptenyl. A carbocyclic grolip maybe a non-aromatic ring system with 3-7 carbon atoms, for example cyclopentane, cyclohexane, cyclohexene or cyclopropane, which may be linslibstitlited or slibstitlited by 1, 2, or 3 slibstitlients independently selected from a halogen atom, an (l-4C)alkyl-, trifllioro-methyl-, hydroxy-, (l-4C)alkoxy-, aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy, (l-3C)alkylenedioxy-, nitro-, amino-, (1-4C)alkylamino-, di[(l-4C)alkyl]amino-, (l-4C)alkanoylamino- or an acyl - grolip, and which may be annelated by an aryl or hetaryl grolip, to form e.g.an indane or a tetr aline, or it may be an aryl grolip. An aryl grolip is a carbocyclic conjligated ring system, for example phenyl, naphthyl, preferably phenyl, which may be linslibstitlited or slibstitlited by 1,2, or 3 slibstitlients independently selected from a halogen atom, an (l-4C)alkyl-, trifllioromethyl-> hydroxy-, (1 -4C)aIkoxy-, arylalkyloxy-, aryloxy, (1 - 3C)alkylenedioxy-, nitro-, amino-, (l-4C)alkylamino-, di[(l-4C)alkyl]amino-, (1-4C)alkanoylamino-, carboxyl-, carboxyalkyl- or an acyl - grolip. A heterocyclic grolip may be a non-aromatic ring system with 3-7 members and one or two hetero atoms independently chosen from nitrogen, oxygen, and slilflir, for example piperidino, morpholino, pyrrolidino, piperazino, which may be linslibstitlited or slibstitlited by 1, 2, or 3 slibstitlients independently selected from a halogen atom, an (l-4C)alkyl-, trifllioro-methyl-, hydroxy-, (l-4C)alkoxy-, aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy, (l-3C)alkylenedioxy-, nitro-, amino-, (l-4C)alkylamino-, di[(l-4C)alkyl]amino-, (l-4C)alkanoylamino, or an acyl - grolip, and which may be annelated by an aryl or hetaryl grolip, to form e.g. a tetrahydrochinoline, tetrahydroisochinoline or a dihydroindole, or it may be a hetaryl grolip. A hetaryl grolip is either a 5 or 6 membered cyclic conjligated ring system with one or two hetero atoms independently chosen from nitrogen, oxygen, and sulfur, for example pyridinyl, thiophenyl, fliryl or pyrrolyl, or an annlilated bicyclic conjligated ring system like indolyl-, qliinolyl- or isoqliinolyl-, which may be linslibstitlited or slibstitlited by 1, 2, or 3 slibstitlients independently selected from a halogen atom, an (l-4C)alkyl-, trifllioromethyl-, hydroxy-, (l-4C)alkoxy-, arylalkyloxy-, aryloxy, (l-3C)alkylenedioxy-, nitro-, amino-, (l-4C)alkylamino-, di[(l-4C)aIkyl]amino-, (l-4C)aIkanoylainino, or an acyl grolip. When Rl and R2 together with the nitrogen atom form a 3-6 membered ring which may contain additional heteroatoms independendy selected from nitrogen, oxygen and slilflir, it may be e.g. piperidine, piperazine or morpholine. A sliitable vallie for a slibstitlient when it is a halogen atom is, for example, fllioro, chloro, bromo and iodo; when it is (l-4C)alkyl is, for example, methyl, ethyl, propyl, isopropyl, blityl, isoblityl, sec-blityl; when it is (l-4C)alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy or blitoxy; when it is (l-4C)alkylamino is, for example, methylamino, ethylamino or propylamino; when it is di-[(l-4C)alkyl] amino is, for example, dimethylamino, N-ethyl-N-methylamino, diethylamino, N-methyl-N-propylamino or dipropylamino; when it is (1-4C)alkanoylamino is, for example, formylamido, acetamido, propionamido or blityramido; when it is (l-3C)aIkylenedioxy is, for example, methylenedioxy, ethylenedioxy or propylenedioxy; and when it is acyl is, for example, formyl, acetyl, propionyl, benzoyl, or phenylacetyl. In a preferred embodiment, Rl is hydrogen and R2 has one of the above vallies. In a more preferred embodiment, R2 is a (l-14C)alkyl grolip. Most preferrably, R2 is an arylalkyl - radical, for example the benzyl - radical or slibstitlited benzyl - radicals. Preferred are compolinds wherin A denotes a thiophene ring. Even more preferred are compoimds in wherein this thiophene ring is linslibstitlited. Most preferred are compolinds wherin two carboxylic moieties are bond at positions 2 and 5 of a flirther linslibstitlited thiophene ring. Enantiomers, diastereoisomers, racemates and mixtinres thereof and pharmacelitically acceptable salts of aromatic dicarboxylic acid derivatives of the formlila I are also part of the invention. According to a flirther aspect of the invention there is provided a pharmacelitical composition which comprises an aromatic dicarboxylic acid derivative of the formlila I, or a pharmacelitically-acceptable salt thereof, as defined hereinbefore in association with a pharmacelitically-acceptable dillient or carrier. The composition may be in a form sliitable for oral administration, for example as a tablet or capslile, for parenteral injection (inclliding intravenolis, slibclitaneolis, intramlisclilar, intravasclilar or infiision) as a sterile sollition, slispension or emlilsion, for topical administration as an ointment or cream or for rectal administration as a slippository. In general the above compositions may be prepared in a manner lising conventional excipients. The aromatic dicarboxylic acid derivative will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000 mg per sqliare meter body area of the animal, i.e. approximately 0.1-100 mg/kg , and this normally provides a therapelitically-effective dose. A linit dose form slich as a tablet or capslile will lislially contain, for example 1-250 mg of active ingredient. Preferably a daily dose in the range of 1-100 mg/kg is employed. However the daily dose will necessarily be varied depending lipon the host treated, the particlilar rolite of administration, and the severity of the illness being treated. Accordingly the optimlim dosage may be determined by the practitioner who is treating any particlilar patient According to a flirther aspect of the present invention there is provided an aromatic dicarboxylic acid derivative of the formlila I as defined hereinbefore for lise in a method of treatment of the hliman or animal body by therapy. It has now been folind that the compolinds of the present invention possess anti-cell-proliferation properties which are believed to arise from their histone deacetylase inhibitory activity. Accordingly the compolinds of the present invention provide a method for treating the proliferation of malignant cells. Accordingly the compounds of the present invention are expected to be liseful in the treatment of cancer by providing an anti-proliferative effect, particlilarly in the treatment of cancers of the breast, lung, colon, rectlim, stomach, prostate, bladder, pancreas and ovary. It is in addition expected that a derivative of the present invention will possess activity against a range of lelikemias, lymphoid malignancies and solid tlimors slich as carcinomas and sarcomas in tisslies slich as the liver, kidney, prostate and pancreas. Thlis according to this aspect of the invention there is provided the lise of an aromatic dicarboxylic acid derivative of the formlila I, or a pharmacelitically-acceptable salt thereof, as defined herein in the manlifactlire of a medicament for lise in the prodliction of an anti-cell-proliferation effect in a warm-blooded animal slich as a hliman being. According to a flirther featlire of this aspect of the invention there is provided a method for prodlicing an anti-cell-proliferation effect in a warm-blooded animal, slich as man, in need of slich treatment which comprises administering to said animal an effective amolint of an aromatic dicarboxylic add derivative as defined hereinbefore. The anti-cell-proliferation treatment defined hereinbefore may be apphed as a sole therapy or may involve, in addition to the aromatic dicarboxylic acid derivative of the invention, one or more other anti-tlimor slibstances, for example those selected from, for example, mitotic inhibitors, for example vinblastine; alkylating agents, for example cis-platin, carboplatin and cyclophosphamide; inhibitors of microtliblile assembly, like paclitaxel or other taxanes; antimetabolites, for example 5-fllioroliracil, capecitabine, cytosine arabinoside and hydroxylirea, or, for example, intercalating antibiotics, for example adriamycin and bleomycin; immlinostimlilants, for example trastlizlimab; DNA synthesis inhibitors, e.g. gemcitabine; enzymes, for example asparaginase; topoisomerase inhibitors, for example etoposide; biological response modifiers, for example interferon; and anti-hormones, for example antioestrogens slich as tamoxifen or, for example antiandrogens slich as (4'-cyano-3-(4-flliorophenylslilphonyl)-2-hydroxy-2-methyl-3'-(trifllioromethyl)-propionanilide, or other therapelitic agents and principles as described in, for example, Cancer: Principles & Practice of Oncology, Vincent T. DeVita, Jr., Samliel Hellmann, Steven A. Rosenberg; 5th Ed., Lippincott-Raven Pliblishers 1997. Slich conjoint treatment may be achieved by way of the simliltaneolis, seqliential or separate dosing of individlial components of the treatment. According to this aspect of the invention there is provided a pharmacelitical prodlict comprising an aromatic dicarboxylic acid derivative of the formlila I as defined hereinbefore and an additional anti-tlimor slibstance as defined hereinbefore for the conjoint treatment of cancer. Another object of the present invention are pharmacelitical compositions containing a pharmacologically effective amolint of one or more compolinds of formlila I in admixtlire with pharmacelitically acceptable excipients and/or dillients. Examples for physiologically acceptable-salts of compounds of formlila I are salts with physiologically acceptable bases. These salts can be, among others, alkali, earth alkali, ammonilim and alkylammonilim salts, for example sodilim, potassilim, calcilim, tetra-methyl-ammonilim salts. The separation of racemic compolinds into their enantiomers can be performed by chromatography on an analytical, semipreparative or preparative scale lising sliitable optically active stationary phases with sliitable ellients. Sliitable optically active stationary phases incllide, blit are not limited to, silica (e.g. ChiraSper,Merck; Chiralpak OT/OP, Baker), celllilose esters or carbamates (e.g. Chiracel OB/OY, Baker) or others (e.g. Crownpak, Daicel or Chiracel OJ-R, Baker). Other methods for the separation of enantiomers can also be applied, like the formation of diastereomeric compolinds from compolinds of the formlila I together with other optically active compolinds, e.g. camphorslilfonic acid or brlicin, and separation of these diastereomeric compolinds, followed by the liberation from the optically active agent. Enantiomerically enriched or plire compolinds of formlila I are also obtainable by the lisage of optically active starting materials. Preparation of the Compolinds of the Invention An aromatic dicarboxylic acid derivative of the formlila I, or a pharmacelitically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of chemically-related compolinds. Slich processes, when lised to prepare an aromatic dicarboxyhc acid derivative of the formlila I, or a pharmacelitically-acceptable salt thereof, are provided as a flirther featlire of the invention and are illlistrated by the following representative examples in which, linless otherwise stated. A, Rl and R2 have any of the meanings defined hereinbefore. Necessary starting materials may be obtained by standard procedlires of organic chemistry. The preparation of slich starting materials is described within the accompanying non-limiting examples. Alternatively necessary starting materials are obtainable by analogolis procedlires to those illlistrated which are within the ordinary sklil of an organic chemist (a) One preferred method for the prodliction of compolinds of the formlila I involves the reaction of compounds of the formlila 11 wherein A, Rl and R2 have the meaning defined hereinbefore and R3 is a (1-4C)alkyl grolip, preferably a methyl or ethyl grolip, with hydroxylamine in the presence of a sliitable base. The reaction is carried olit in an inert solvent or dillient slich as methanol or ethanol at temperatlires between 0°C and 100°C, conveniently at or near ambient temperatlire, and at a pH between 10 and 12. A sliitable base is, for example, an alcoholate, for example, sodilim methylate. Compolinds of formlila II are prepared firom compolinds of the formlila III wherein A and R3 have the meaning defined hereinbefore. This reaction typically involves a two-step one-pot procedlire. In the first step, the carboxylate of the formlila III becomes activated. This reaction is carried olit in an inert solvent or dillient, for example, in dichloromethane, dioxane, or tetrahydrofliran, in the presence of an activating agent. A sliitable reactive derivative of an acid is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the add and a chloroformate slich as isoblityl chloroformate; an active ester, for example an ester formed by the reaction of the acid and a phenol slich as pentaflliorophenol; an active ester formed by the reaction of the acid and N-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid and an azide slich as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide slich as diethylphosphoryl cyanide; or the prodlict of the reaction of the acid and a carbodiimide slich as dicydohexylcarbodiimide, or the prodlict of the reaction of the acid and bis-(2-oxo-3-oxazolidinyl)-phosphoi7lchloride. The reaction is carried olit between -30*^C and 60°C, conveniently at or below 0°C. In the second step, an amine of the formlila HNR1R2 in which Rl and R2 have the meaning defined hereinbefore is added to the sollition, at the temperatlire lised for the activation, and the temperatlire is slowly adjlisted to ambient temperatlire. An appropriate scavenger base like e.g. triethylamine, or diisopropyethlyamine may be added to the reaction mixtlire. These methods are well known to those skilled in the art. In principle, all methods for the synthesis of amides as lised in peptide chemistry as described in e.g. "Methoden der organischen Chemie (Holiben-Weyl)" Vol. XV/1 and XV/2 are also applicable. There are qliite a few compolinds of formlila III described in the hteratlire. For example, the prototypic terephthalic monomethylester is described by, e.g., Holba, v., et al., Z. Phys. Chem.(Leipzig) 262 (3) (1981) 445-448. It is also commercially available. Thiophene-2,5-dicarboxylic acid monomethyl ester is described in e.g. liS 2,680,731. These monoesters are lislially prepared by selective saponification of the diester, blit other method may be liseflil as well and are well known to those skilled in the art. wherein Y is a sliitable protecting grolip and A, Rl and R2 have the meaning defined hereinbefore. Compolinds of the formlila IV are new and incllided in the present invention. Sliitable protecting grolips may be the benzyl-, p-methoxybenzyl-, tert.blityloxycarbonyl-, trityl-, or silyl grolips slich as the trimethylsilyl- or dimethyl-tert.blitylsilyl-grolip. The reactions carried olit depend on the type of the protecting grolip. When the protecting grolip is a benzyl- or p-methoxybenzyl grolip, the reaction carried olit is a hydrogenolysis in an inert solvent slich as an alcohol like methanol or ethanol, in the presence of a noble metal catalyst slich as palladilim on a sliitable carrier slich as carbon, barilim slilfate, or barilim carbonate, at ambient temperatlire and presslire. When the protecting grolip is the tert.blityloxycarbonyl-, trityl-, or a silyl grolip slich as the trimethylsilyl- or dimethyl-tert.blitylsilyl-grolip, the reaction is carried olit in the presence of acids at a temperatlire between -20°C and 60°C, preferably between 0°C and ambient temperatlire. The acid may be a sollition of hydrochloric acid in an inert solvent slich as diethyl ether or dioxane, or trifllioro acetic add in dichloromethane. When the protecting grolip is a silyl grolip slich as the trimethylsilyl or dimethyl-tert.blitylsilyl grolip, the reaction can also be carried olit in the presence of a fllioride solirce slich as sodilim fllioride or tetrablityl ammoniimi fllioride in an inert solvent slich as dichloromethane. Not necessarily all protecting grolips Y are compatible with all grolips Rl or R2. In cases where the featlires of these grolips do not allow the lisage of a certain protecting grolip, other protecting grolips Y or other methods of preparation need to be applied. wherein Y is a sliitable protecting grolip as described above. This reaction typically involves a two-step one-pot procedlire. In the first step, the carboxylate of the formlila V becomes activated. This reaction is carried olit in an inert solvent or dillient, for example, in dichloromethane, dioxane, or tetrahydrofuran, in the presence of an activating agent A sliitable reactive derivative of an acid is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloroformate slich as isoblityl chloroformate; an active ester, for example an ester formed by the reaction of the acid and a phenol slich as pentaflliorophenol; an active ester formed by the reaction of the acid and N-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid and an azide slich as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide slich as diethylphosphoryl cyanide; or the prodlict of the reaction of the acid and a carbodiimide slich as dicyclohexylcarbodiimide, or the prodlict of the reaction of the add and bis-(2-oxo-3-oxazolidinyl)-phosphorylchloride. The reaction is carried olit between -30°C and 60°C5 conveniently at or below 0°C. In the second step, compolind VI is added to the sollition, at the temperatlire lised for the activation, and the temperatlire is slowly adjlisted to ambient temperatlire. These methods are well known to those skilled in the art. In principle, all methods for the synthesis of amides as lised in peptide chemistry as described in e.g. "Methoden der organischen Chemie (Holiben-Weyl)" Vol. XV/1 and XV/2 are also applicable. Compolinds of the formlila V are prepared from compolinds of the formlila II by hydrolysis. The conditions under which the hydrolysis is carried olit depend on the natlire of the grolip R3. When R3 is a methyl or ethyl grolip, the reaction is carried olit in the presence of a base, for example, lithium hydroxide, sodilim hydroxide, or potassilim hydroxide in an inert solvent or dillient, for example, in methanol or ethanol. When R3 is the tert.blityl grolip, the reaction is carried olit in the presence of an add, for example, a sollition of hydrochloric acid in an inert solvent slich as diethyl ether or dioxane, or trifllioroacetic acid in dichloromethane. When R3 is the benzyl grolip, the reaction is carried olit by hydrogenolysis in the presence of a noble metal catalyst slich as palladilim or platinlim on a sliitable carrier, slich as carbon. Not necessarily all methods of hydrolysis are compatible with all grolips Rl or R2. In cases where the featlires of these grolips do not allow the lisage of a certain method of hydrolysis, other methods of preparation need to be applied. (c) Another preferred method for the preparation of compolinds of the formlila I is the reaction of a compolind of the formlila V with hydroxylamine. This reaction typically involves a two-step one-pot procedlire. In the first step, the carboxylate of the formlila V becomes activated. This reaction is carried olit in an inert solvent or dillient, for example, in dichloromethane, dioxane, or tetrahydrofliran, in the presence of an activating agent. A sliitable reactive derivative of an acid is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloroformate slich as isoblityl chloroformate; an active ester, for example an ester formed by the reaction of the acid and a phenol slich as pentaflliorophenol; an active ester formed by the reaction of the add and N-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid and an azide slich as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide slich as diethylphosphoryl cyanide; or the prodlict of the reaction of the acid and a carbodiimide slich as dicyclohexylcarbodiimide, or the prodlict of the reaction of the acid and bis-(2-oxo-3-oxazolidinyl)-phosphorylchloride. The reaction is carried olit between -30°C and 60°C, conveniently at or below 0°C. In the second step, hydroxylamine is added to the sollition, at the temperatlire lised for the activation, and the temperatlire is slowly adjlisted to ambient temperatlire. These methods are well known to those skilled in the art. In principle, all methods for the synthesis of amides as lised in peptide chemistry as described in e.g. "Methoden der organischen Chemie (Holiben-Weyl)" Vol. XV/1 and XV/2 are also applicable. (d) Compolinds of formlila I can also be prepared with methods of solid phase slipported synthesis. Terephthalic acid or 2,5-thiophenedicarboxylic acid is reacted with a hydroxylamine moiety (-O-NH2) bolind to a resin, e.g. a Wang resin (Wang-O-NH2 resin was slipplied by EMC microcollections, Tlibingen) to form a resin-bolind hydroxamic acid. The second carbonic acid moiety is reacted with an amine by standard methods of amide formation as described in e.g. "Methoden der organischen Chemie (Holiben-Weyl)" Vol. XV/1 and XV/2. After this, the hydroxamic acid is liberated from the solid slipport. This can be done for example with TFA. The crlide prodlict can be plirified by LC-MS, if necessary. The invention will now be illlistrated in the following non-limiting examples in which, linless otherwise stated: (i) evaporations were carried olit by rotary evaporation in vaclio and work-lip procedlires were carried olit after removal of residlial solids slich as drying agents by filtration; (ii) operations were carried olit at ambient temperatlire, that is in the range 18-25°C and linder an atmosphere of an inert gas slich as argon or nitrogen; (iii) collimn chromatography (by the flash procedlire) and high presslire Hqliid chromatography (HPLC) were performed on Merck Kieselgel silica or Merck Lichroprep RP-18 reversed-phase silica obtained from E. Merck, Darmstadt, Germany; (iv) yields are given for illlistration only and are not necessarily the maximlim attainable; (v) melting points were determined lising a Mettler SP62 alitomatic melting point apparatlis, an oli-bath apparatlis or a Kofler hot plate apparatlis. (vi) the strlictlires of the end-prodlicts of the formlila I were confirmed by nliclear (generally proton) magnetic resonance (NMR) and mass spectral techniqlies (Micromass Platform II machine lising APCI or Micromass Platform ZMD lising electrospray); (vii) intermediates were not generally fliliy characterized and plirity was assessed by thin layer chromatography; (viii) the following abbreviations have been lised: DMF, N,N-dimethylformamide; DMSO, dimethylslilphoxide; THF, tetrahydrofliran; MeOH, methanol; HCl, hydrochloric acid; NaH, sodilim hydride CH2CI2, dichloromethane; H2SO4, slilphliric acid sat, satlirated sol., sollition rt, room temperatlire eq, eqliivalent Example 1 Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(naphthalen-l-ylmethyl)- amide] (la) 1.9g Thiophene-2,5-dicarboxylic acid monomethyl ester and 1.2mL N-methylmorpholine is dissolved in 20mL of CH2CI2 at -10°C. To this sollition is added l.5mL isoblityl chloroformate. After lOmin of stirring, 1.7mL 1-(aminomethyl)-naphthalene in 5mL of CH2CI2 is added. The cooling bath is removed and the reaction mixture is allowed to reach rt. After 90min, lOmL of water and 10mL 2N HCl are added. The phases are separated, and the organic phase is washed with water. After evaporation of the solvent there is obtained 4,4g crlide 5-[(naphtalen-l-ylmethyl)-carbamoyl]-thiophene-2-carboxylic acid methyl ester (lb) which is plirified by recrystalisation from ethylacetate, petrol ether, yielding 58%, mp 125°C. To a sollition of 550mg hydroxylamine hydrochloride in 8mL MeOH is added 2/3 of a sollition of 275mg of sodilim in 8mL of MeOH. To this, a sollition of 1.30g 5-[(naphtalen-l-ylmethyl)-carbamoyl]-thiophene-2-carboxylic acid methyl ester (lb) in 30mL MeOH is added, followed by the remaining sodilim methylate sollition. After stirring for 4h at rt the solvent is evaporated. 20mL of water are. added, , acidified with 4mL 50% acetic acid, and the precipitate is collected by filtration. After tritliration with THF there is obtained 0.76g thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(naphthalen-l-ylmethyl)-amide] (la) as a white powder, mp 170°C. Example 2 Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-(4-trifllioromethyl- benzylamide) (2a) 2a is prepared from thiophene-2,5-dicarboxylic add monomethyl ester in an analogolis manner to that described for the preparation of la example 1. The last step yields 40% of thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-(4-trifluoromethyl-benzylamide) (2a), mp. 172-174°C. Example 3 N-hydroxy-N'-naphthalen- 1-ylmethyl-terephthalamide (3a) leq of Wang-0-NH2 is shaken with lleq of terephthalic acid, 5.5eq N,N'-diisopropylcarbodiimide, 5.5eq l-hydroxybenzotriazole and 25eq diisopropylethylamine in DMF for 4h at 25°C. After that, the resin is washed with DMF (5 times), MeOH (3 times), THF (3 times), CH2CI2 (3 times) and diethylether (3 times). The resin is then shaken with 5eq pentaflliorophenyl trifllioroacetate and lOeq pyridine. After that, the resin is washed with DMF (2 times), followed by CH2CI2 (2 times), followed by diethylether (2 times). The resin is then shaken with 5eq of naphtalenemethylamine, lOeq of diisopropylethylamine and leq of 1-hydroxybenzotriazole. It is then shaken with 5eq pentaflliorophenyl trifllioroacetate and lOeq pyridine. After that, the resin is washed with DMF (2 times), followed by CH2CI2 (2 times). To liberate the prodlict from the solid slipport, the resin is shaken with 50% TFA in dry CH2Cl2 with 5% triisopropylsflane added at rt for Ih. The liqliid phase is filtered, the resin washed with CH2CI2 (3 times), and the combined filtrates are evaporated. The crlide prodlict is dissolved in tert-blitanol/H20 (80:20) and freeze-dxied. To nelitralize any remaining TFA, 100\|iL of a 25% NH4OH-S0I is added and freeze-dried, again. The remaining solid is plirified by preparative LC-MS to N-hydroxy-N'-naphthalen-1-ylmethyl-terephthalamide, MS (APCI): 321.1 (M+1) Example 4 Thiophene-2,5-dicarboxylicacid 2-(3-chloro-benzylamide) 5-hydroxyamide (4a) 9.0g Thiophene-2,5-dicarboxylic acid monomethyl ester is refllixed in 30mL of thionylchloride lintil gas evollition has ceased. The mixtlire is evaporated and the residlie is slowly added to a sollition of 10.3g 3-chlorobenzylanline and 20g triethylamine in 180mL CH2CI2 at 0°C. After 15min the cooling bath is removed and the reaction mixtlire is allowed to reach rt After 2h it is qlienched with water, the phases are separated, and the aqlieolis phase is extracted with CH2CI2. The combined organic phases are dried with Na2SO4 and evaporated yielding a crlide prodlict. This is plirified by recrystaliisation from diethylether / heptane yielding 13.9g (93%) crlide 5-[(3-chlorobenzyl)-carbamoyl]-thiophene-2-carboxylic acid methyl ester (4b), mp 91-93°C. To a sollition of 2.9g hydroxylamine hydrochloride in 45mL MeOH is added 25mL of a sollition of L4g sodiima in 40mL of MeOH. To this, a sollition of 6.4g ester 4b in 30mL MeOH is added, followed by the remaining 15mL of the sodilim methylate sollition. After stirring for 3h at rt the sollition is acidified with IN HCl and some ethylacetate is added. Thiophene-2,5-dicarboxylic acid 2-(3-chloro-benzylamide) 5-hydroxyamide (4a) precipitates as a white solid; 4.7g, 73%, mp. 183oC. Example 5 Thiophene-2,5-dicarboxylic acid 2-(3,5"dimethyl-benzylaniide) 5-hydroxyamide (5a) 5a is prepared from thiophene-2,5-dicarboxylic acid monomethyl ester in an analogolis manner to that described for the preparation of 4a example 4, MS (APCI): 305.3 (M+1) Example 6 Thiophene-2,5-dicarboxylic add 2-hexylamide S-hydroxyamide (6a) 6a is prepared from thiophene-2,5-dicarboxylic acid monomethyl ester in an analogolis manner to that described for the preparation of 4a example 4, mpl71-173°C Example 7 Thiophene-2,4-dicarboxylic acid 2-(3,5-dimethyl-benzylamide) 4-hydroxyaniide (7a) 0.5g 2-carboxy-thiophen-4-carboxylic add ethyl ester (Janda, M., et al., Org. Prep, and Proced. Int. 3 (6) (1971) 295-297) and 0,67g N-(3-dimethylaminopropyl)-N-ethylcarbodiimid x HCl are stirred in 50mL DCM for 15min. Then, 0.338g 3,5-dimethylbenzylamin are added and the mixtlire is stirred overnight The sollition is extracted with 2N HCl and water, then evaporated. The residlie is titlirated with isohexan, and the reslilting crystals are filtrated and air-dried, yielding 0.58g (73%) crlide 5-(3,5-Dimetihyl-ben2ylcarbamoyl)-thiophene-3-carboxylic acid ethyl ester (7b). This ester in converted to title compolind by reaction with hydroxylamine hydrochloride in a manner similar to that described for the conversion of 4b into 4a in example 4. After chromatography (silica, ethylacetate), thiophene-2,4-dicarboxylic acid 2-(3,5"dimethyl-benzylaniide) 4-hydroxyamide (7a) is obtained as crystals; 44mg, 9%, mp: 181o C (decomp.). Example 8 Thiophene-2,4-dicarboxylic acid 2-(3-chloro-benzylamide) 4-hydroxyamiide (8a) 8a is prepared from 2-carboxy-thiophen-4-carboxylic add ethyl ester in an analogolis manner to that described for the preparation of 7a example 7; 163mg, 34%, mp: 90oC (decomp.)- Example 9 Thiophene-2,4-dicarboxylic add 4-hydroxyamide 2-(4-trifkuroromethyl- benzylamide) (9a) 9a is prepared from 2-carboxy-thiophen-4"Carboxylic acid ethyl ester in an analogolis manner to that described for the preparation of 7a example 7; 56mg, 10%,mp:174-177°C. Example 10 Thiophene-2,4-dicarboxylic acid 2-[(ben2o[l,3]dioxol-5-ylmethyl)-amide] 4- hydroxyamide (10a) 10a is prepared from 2-carboxy-thiophen-4-carboxylic acid ethyl ester in an analogolis manner to that described for the preparation of 7a example 7; 16mg, 3%, mp: 182°C (decomp.). Example 11 Thiophene-2,4-dicarboxylic add 2-hexylamide 4-hydroxyamide (11a) 11a is prepared from 2-carboxy-thiophen-4-carboxylic acid ethyl ester in an analogolis manner to that described for the preparation of 7a example 7; 92mg, 20%, mp: 150°C (decomp.). Example 12 Thiophene-2,4-dicarboxylic add 4-(3,5-dimethyl-benzylamide) 2- hy droxyamide (12a) 5.0g 2-carboxy-thiophen-4-carboxylic acid ethyl ester (Org, Prep, and Proced. Int. 3 (6) (1971) 295) is dissolved in 50mL THF and 4.5g thionylchloride is added. After refllixing for 4h, the mixtlire is evaporated. The crlide acid chloride is added to a sollition of 3.1g 0-ben2ylhydroxylamine and 3.06g triethylamine in 80mL DCM. After stirring for 4h the sollition is washed with 2N HCI and water, dried and evaporated. After titlirating the residlie with isohexan / diethylether, bright crystalls of 5-benzyloxycarbamoyl-thiophene-3-carboxylic acid ethyl ester (12b) are obtained, which are filtered and air-dried; 3.5g, 46%. 0.46g NaOH are dissolved in 45mL ethanol and 5mL water. The ester 12b is added and the sollition refllixed for 2h. After cooling, the ethanol is evaporated and the aqlieolis phase extracted with diethylether. The aqlieolis phase is acidified with 2N HCl and the precipitate formed is collected by filtration, yielding 2.8g (88%) 5-benzyloxycarbamoyl-thiophene-3-carboxylic acid (12c) as a solid. 0.4g 5-benzyloxycarbamoyl-thiophene-3-carboxylic acid (12c) is dissolved in 50mL DCM, and 0.387g N'-(3-dimethylaminopropyl)-N-ethylcarbodiimid x HCl are added. After stirring for 15min, 0.195g 3,5-dimethylbenzylainine is added, and the mixtlire is stirred overnight. The sollition is extracted with 2N HCl and water, then evaporated. The residlie is titlirated with ether/isohexan, and the reslilting crystals are filtrated and air-dried, yielding 0.44g {77%) of thiophene-2,4-dicarboxylic acid 2-(benzyloxy-aniide) 4-(3,5-dimethyl-benzylanlide) (12d). This is hydrogenated in a 1:1 mixtlire of THF and MeOH lising Pd/CaSo4/C and plirified by preparative HPLC/MS yielding 12a: MS (APCI): 303.1 (M-1). Example 13 In an analogolis manner to that described in the example 12, the following compolinds are prepared: 1. Thiophene-2,4-dicarboxylic acid 4-(3-chloro-benzylamide) 2-hydjoxyamide 2. Thiophene-2,4-dicarboxylic acid 4-hexylamide 2-hydroxyamide Example 14 4-{[(5-Hydroxycarbamoyl-thiophene-2-carbonyl)-amino]-methyl}-benzoic acid methyl ester In an analogolis manner to that described in the example 12, blit lising 2-carboxy-thiophen-5-carboxylic add methyl ester and methyl 4-(aminomethyl)- benzoate as starting material, 4-{ [(5-Hydroxycarbamoyl-thiophene-2-carbonyl)-amino] -methyl}-benzoic add methyl ester is prepared, mp.: 156-166oC. Example 15 In an analogolis manner to that described in the example 1, and lising known methods as described in the literatlire (e.g. in standard works slich as Holiben-Weyl, -Methoden der Organischen Chemie, Georg Thieme Verlag-, Stlittgart; Organic Reactions, John Wiley & Sons, Inc., New York) the following compolinds are prepared and characterized with MS (APCI): L 5-(4-benzhydryl-piperazine-l-carbonyl)-thiophene-2-carboxylic acid hydroxyamide 2. thiophene-2,5-dicarboxylic acid 2-beiizylamide 5-hydroxyamide 3. thiophene-2,5-dicarboxylic acid 2-hydroxyainide 5-[(3-methyl-blityl)-amide] 4. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-(phenethyl-aniide) 5. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-{[2-(4-methoxy-phenyl)-ethyl]-amide} 6. thiophene-2,5-dicarboxylic acid 2-(4-filioro-benzylamide) 5-hydroxyamide 7. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(l,2,3,4-tetrahydro-naphthalen-l-yl)-amide] 8. thiophene-2,5-dicarboxylic acid 2-(2-ethoxy-benzylamide) 5-hydroxyamide 9. thiophene-2,5-dicarboxylic acid 2-(2,4-difkuroro-benzylamide) 5-hydroxyamide 10. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-indan-l-ylamide 11. thiophene-2,5-dicarboxylic acid 2-[(benzo[l,3]dioxol-5-ylmethyl)-amide] 5-hydroxyamide 12. 5-(4-phenyl-pipera2ine-l-carbonyl)-thiophene-2-carboxylic add hydroxyamide 13. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(3-isopropoxy-propyl)-amide] 14. 5-(4-acetyl-piperazme-l-carbonyl)-thiophene-2-Carboxylic add hydroxyamide 15. thiophene-2,5-dicarboxylic acid 2-diblitylainide 5-hydroxyamide 16. 5-(4-benyyl-piperidine-l-carbonyl)-thiophene-2-carbox7lic acid hydroxyamide 17. thiophene-2,5-dicarboxylic acid 2-hydroxyaiiiide 5-[(pyridin-3-ylinethyl)-amide] 18. thiophene-2,5-dicarboxylic acid 2-cyclohexylamide 5-hydroxyainide 19. thiophene-2,5-dicarboxylic acid 2-cyclopropylamide 5-hydroxyamide 20. tliiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-{[2-(l-methyl-pyrrolidin-2-yl)-ethyl]-amide} 21. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-(2-methoxy-benzylamide) 22. thiophene-2,5-dicarboxylic acid 2-[(2-cydohex-l-enyl-ethyl)-amide] 5-hydroxyamide 23. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(2-morpholin-4-yl-ethyl)-amide] 24. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(2-methyIsidfanyl-ethyl)-amide] 25. thiophene-2,5-dicarboxylic acid 2-hydroxyamdde 5-[(tetrahydro-fliran-2-ylmethyl)-amide] 26- thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-phenylamide 27. 5-(morpholine-4-carbonyl)-thiophene-2-carboxyIic acid hydroxyamide 28. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(4-methoxy-phenyl)-amide] 29. 5-(pyrrolidine-l-carbonyl)-thiophene-2-carboxylic acid hydroxyamide 30. thiophene-2,5-dicarboxylic acid 2-[(4-ben2yloxy-phenyl)-amide] 5-hydroxyamide 31. thiophene-2,5-dicarboxylicacid 2 -[(4-chloro-phenyl)-amide] 5-hydroxyamide 32. thiophene-2,5-dicarboxylic acid 2-hydroxyamjde 5-[(4-iodo-phenyl)-amide] 33. thiopheae-2,5-dicarboxylic acid 2-[(3-ethyl-phenyl)-amide] 5-hydroxyamide 34. thiophene-2>5-dicarboxylic acid 2-[(4-ethyl-phenyl)-amide] 5-hydroxyamide 35. thiophene-2,5-dicarboxylic acid 2-[(3-chloro-phenyl)-amide] 5-hydroxyamide 36. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(3-iodo-phenyl)-amide] 37. 5-(l,4-dioxa-8-aza-spiro[4.5]decane-8-carbonyl)-thiophene-2-carboxylicacid hydroxyamide 38. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(3-morpholin-4-yl-propyl)-amide] 39. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-pentylamide 40. thiophene-2,5-dicarboxylic acid 2-[(2-diethylamino-ethyl)-amide] 5-hydroxyamide 41. tliiophene-2,5-dicarboxylic acid 2-heptylamide 5-hydroxyamide 42. tlliophene-2,5-dicarboxylic acid 2-hydroxyamide 5-(isoblityl-amide) 43. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-nonylamide 44. thiophene-2,5-dicarboxylic acid 2-hydroxyainide 5-[(l-phenyl-ethyl)-amide] 45. thiophene-2,5-dicarboxylic acid 2-[2-(4-fllioro-phenyl)-ethyl]-amide 5-hydroxyamide 46. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[2-(5-nitro-pyridin-2-ylamino)-ethyl] -amide 47. thiophene-2,5-dicarboxylic acid 2-hydioxyamide 5-(3-methyI-benzylamide) 48. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(2-p-tolyl-ethyl)-amide] 49. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[3-(2-oxo-pyrrolidin-l-yl)-propyl]-amide 50. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(2-piperidin-l-yl-ethyl)-amide] 51. thiophene-2,5-dicarboxylic acid 2-cycloblitylamide 5-hydroxyamide 52. thiophene-2,5-dicarboxylicacid 2-(2-fllioro-benzylamide) 5-hydroxyamide 53. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(2-phenyl-propyl)-amide] 54. thiophene-2,5-dicarboxylic acid 2-(2,3-dimethoxy-benzylamide) 5-hydroxyamide 55. thiophene-2,5-dicarboxylic acid 2-[(l-benzyl-piperidin-4-yl)-amide] 5-hydroxyamide 56. 4-[(5-hydroxycarbamoyl-thiophene-2-carbonyI)-amino]-piperidine-l-carboxylic acid ethyl ester 57. thiophene-2,5-dicarboxylic acid 2-[(3-dimethylamino-2,2-dimethyl-propyl)-amide] 5-hydroxyamide 58. thiophene-2,5-dicarboxylic acid 2-[(3-ethoxy-propyl)-amide] 5-hydroxyamide 59. thiophene-2,5-dicarboxylic acid 2-[(3-dimethylamino-propyl)-amide] 5-hydroxyamide 60. thiophene-2,5-dicarboxylic acid 2-[2-(2-chloro-phenyl)-ethyI]-amide 5-hydroxyamide 61. thiophene-2,5-dicarboxylic acid 2-hydroxyainide 5-(2-trifkuroromethyl-ben2ylamide) 62. thiophene-2,5-dicarboxylic acid 2-hydroxyainide 5-(3-trifkuroromethyl-benzylamide) 63. thiophene-2,5-dicarboxylic acid 2-(2,5-difkuroro-ben2ylamide) 5-hydroxyamide 64. thiophene-2,5-dicarboxylic acid 2-(2,6-difkuroro-benzylaimde) 5-hydroxyamide 65. thiophene-2,5-dicarboxylic acid 2-(3,4-difkuroro-benzylamide) 5-hydroxyamide 66. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(3-imidazol-l-yl-propyl)-amide] 67. thiophene-2,5-dicarboxylic acid 2-[(l-cyclohexyl-ethyl)-amide] 5-hydroxyamide 68. thiophene-2,5-dicarboxylic acid 2-[2-(3-chloro-phenyl)-ethyl] -amide 5-hydroxyamide 69. thiophene-2,5-dicarboxylic acid 2-[2-(3-fllioro-phenyl)-ethyl]-amide S-hydroxyamide 70. thiophene-2,5-dicarboxyIic acid 2-[2-(2,4-dichloro-phenyl)-ethyl]-amide 5-hydroxyamide 71. thiophene-2,5-dicarboxylic acid 2-cyclopropyhnethyl-amide 5-hydroxyamide 72. thiophene«2,5-dicarboxylic acid 2-[2-(2-fllioro-phenyl)-ethyl]-amide 5-hydroxyamide 73. thiophene-2,5-dicarboxylic acid 2-[(4-diethylainino-l-methyl-blityl)-amide] 5-hydroxyamide 74. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5- [(2-pyridin-2-yl-ethyl)-amide] 75. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(2-pyrrolidin-l-yl-ethyl)-amide] 76. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(l-methyl-hexyl)-amide] 77. thiophene-2,5-dicarboxylic acid 2-cycloheptylamide 5-hydroxyamide 78. thiophene-2,5-dicarboxylic acid 2-cyclopentylamide 5-hydroxyamide 79. thiophene-2,5-dicarboxylic acid 2-(2,4-dichloro-benzylamide) 5-hydroxyamide 80. thiophene-2,5-dicarboxylic acid 2-[(3-diethylamino-propyl)-amide] 5-hydroxyamide 81. thiophene-2,5-dicarboxylic acid 2-[(l,5-dimethyl-hexyl)-axnide] 5-hydtoxyamide 82. thiophene-2,5-dicarboxylic acid 2-[(2,2-diphenyl-ethyl)-amide] 5-hydroxyamide 83.3-[(5-hydroxycarbamoyl-thiophene-2-carbonyl)-amino]-blityric acid ethyl ester 84. thiophene-2,5-dicarboxylic acid 2-[(2-ethyl-hexyl)-amide] 5-hydroxyamide 85. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-(4-methoxy-benzylamide) 86. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-(4-methyl-benzylamide) 87. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(3-phenyl-propyl)-amide] 88. thiophene-2,5-dicarboxylic add 2-[(2-diisopropylamino-ethyl)-amide] 5-hydroxyamide 89. thiophene-2,5-dicarboxylic acid 2-liydroxyamide 5-[2-(4-nitro-phenyl)-ethyl]- amide 90. thiopliene-2,5-dicarboxylic acid 2-[(3,3-diphenyl-propyl)-ainide] 5-hydroxyamide 91. thiopiiene-2,5-dicarboxylic acid2-(2-ainino-benzylamide) 5-hydroxyamide 92. Thiophene-2,5-dicarboxylic acid 2-(4-broino-benzylainide) S-hydroxyamide 93. Thiophene-2,5-dicarboxylic acid 2-(3,5-bis-trifkurorometbyl-benzylainide) S-hydroxyamide 94. Thiophene-2,5-dicarboxylicacid 2-(3-bromo-benzylaxnide) 5-hydroxyamide 95. Thiophene-2,5-dicarboxylicacid 2-(3-fllioro-benzylamide) 5-hydrox)^imide 96. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-(3-methoxy-ben2ylamide) 97. Thiophene-2,5-dicarboxylic acid 2-{2-chloro-6-filioro-beiizylamide) 5-hydroxyamide 98. Thiophene-2,5-dicarboxylicacid2-(4-tert-blityi-benzylamide) 5-hydroxyamide 99. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-{[2-(4-slilfamoyl-phenyl)-ethyl]-amide} 100. Thiophene-2,5-dicarboxylic add 2-[(2-ben2ylslilfanyl-ethyl)-amide] 5-hydroxyamide 101. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-{[2-(4-hydroxy-phenyl)-ethyl]-amide} 102. Thiophene-2,5-dicarboxylic acid 2-{[2-(4-chloro-phenyI)-ethyI]-amide} 5-hydroxyamide 103. Thiophene-2,5-dicarboxylic acid 2-( [2-(3,4-dimethoxy-phenyl)-ethyl] -amide} 5-hydroxyamide 104. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(2-phenoxy-ethyl)-amide] 105. Thiophene-2,5-dicarboxylic acid 2-hydroxyainide 5-[(4-phenyl-blityl)-amide] 106. Thiophene-2,5-dicarboxylic acid 2-[(3,4-dimethyl-phenyl)-amide] 5-hydroxyamide 107. 5-(4-Pyrimidin-2-yl-piperazine-l-carbonyl)-thiophene-2-carboxylic acid hydroxyamide 108. Thiophene-2,5-dicarboxyIic acid 2-[(3,4-dimethoxy-phenyl)-amide] 5-hydroxyamide 109. Thiophene-2,5-dicarboxylic acid 2-[(4-tert-blityl-phenyl)-amide] 5-hydroxyamide 110. Thiophene-2,5-dicarboxylic add 2-hydroxyaimde 5-[(4-methoxy-2-methyl-phenyl)-amide] 111. Thiophene-2,5-dicarboxylic add 2-[(4-dimethylamino-plienyl)-amide] 5-hydroxyamide 112. Tliiophene-2,5-dicarboxylic acid 2-hydroxyainide 5-[(4-plienoxy-phenyl)-amide] 113. Tliiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-p-tolylamide 114. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(4-piperidin-l-yl-phenyl)-amide] 115. l-(5-Hydroxycarbamoyl-tiiiophene-2-carbonyl)-piperidine-4-carboxylic acid methyl ester 116. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[methyl-(l-methyl-piperidin-4-yl)-amide] 117. Thiophene-2,5-dicarboxylic add 2-hydroxyamide 5-{methyl-[2-(4-nitro-phenyl)-ethyl] -amide} 118. Thiophene-2,5-dicarboxylic add 2-(blityl-methyl-araide) 5-hydroxyamide 119. Thiophene-2,5-dicarboxylic acid 2-diethylamide 5-hydroxyamide 120. Thiophene-2,5-dicaxboxylic acid 2-[(4-cydohexyl-phenyl)-amide] 5-hydroxyamide 121. Thiophene-2,5-dicaxboxylic acid 2-hydroxyamide 5-[methyl-(2-methylamino-ethyl)-amide] 122. Thiophene-2,5-dicarboxylic acid 2-[ethyl-(3-ethylamino-propyl)-amide] 5-hydroxyamide 123. 5-[4-(2-Morpholin-4-yl-2-oxo-ethyl)-piperazine-l-carbonyl]-thiophene-2-carboxylic acid hydroxyamide 124. 5-(4-Dimethylcarbamoylmethyl-piperazine-l-carbonyl)-thiophene-2-carboxylic add hydroxyamide 125. 5-[4-(2-Oxo-2-piperidin-l-yl-ethyl)-pipera2ine-l-carbonyl]-thiophene-2-carboxylic add hydroxyamide 126. Thiophene-2,5-dicarboxylic add 2-hydroxyamide 5-(3-trifkuroromethoxy-benzylamide) 127. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-(3-phenoxy-benzylamide) 128. Thiophene-2,5-dicarboxylic add 2-hydroxyamide 5-[(l-methyl-3-phenyl-propyl)-amide] 129. Thiophene-2,5-dicarboxy[ic acid 2-hydroxyamide 5-[(3-methoxy-propyl)- amide] 130. Thiophene-2,5-dicarboxylic acid 2-(4-chloro-benzylainide) 5-hydroxyainide 131. Thiophene-2,5-dicarboxyIic acid 2-[(2-acetylamino-ethyl)-amide] 5-hydroxyamide 132. Thiophene-2,5-dicarboxylic acid 2--hydroxyamide 5-[(l-methyl-heptyl)-amide] 133. Thiophene-2,5-dicaxboxylic acid 2-hydroxyainide 5-[(l-inethyl-blityl)-amide] 134. Tiiiophene-2,5-dicarboxylic acid 2-allylamide 5-hydroxyaniide 135. Thiophene-2,5-dicarboxylic acid 2- [(l,3-dimethyl-blit7l)-amide] 5-hydroxyamide 136. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-propyIamide 137. Thiophene-2,5-dicarboxylic add 2-sec-blitylainide 5-hydroxyamide 138. Thiophene-2,5-dicarboxylic acid 2-blitylamide 5-hydroxyamide 139. Thiophene-2,5-dicarboxylic acid 2-(3,4-dichloro-benzylamide) 5-hydroxyamide 140. Thiophene-2,5-dicarboxylic acid 2-(2,3-dichloro-ben2ylamide) 5-hydroxyamide 141. thiophene-2,5-dicarboxylic acid 2-(2,3-difkuroro-benzylamide) 5-hydroxyamide 142. thiophene-2,5-dicarboxylic acid 2-(2-chloro-ben2ylamide) 5-hydroxyamide 143. thiophene-2,5-dicarboxyIic acid 2-(3,4-dimedioxy-beazylamide) 5-hydroxyamide 144. thiophene-2,5-dicarboxylic acid 2-(3,5-difkuroro-ben2ylamide) 5-hydroxyamide 145. thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-amide] 5-hydroxyamide 146. thiophene-2,5-dicarboxylic acid 2-[4-(2-amino-phenylcarbamoyl)-benzylamide] 5-(benzyloxy-amide) 147. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[methyl-(4- trifkuroromethyl-benzyl)-amide Example 16 In an analogolis manner to that described in the example 3, and lisliag known methods as described in the literatlire (e,g. in standard works slich as Holiben-Weyl, -Methoden der Organischen Chemie, Georg Thieme Verlag-, Stlittgart; Organic Reactions, John Wiley & Sons, Inc., New York) the following compoimds are prepared and characterized with MS (APCI): 148. 4-(4-benzhydryl-pipera2ine-l-carbonyl)-N-hydroxy-benzamide 149. N-hydroxy-N'-pyridin-3-ylmethyl-terephthalamide 150. N-benzyl-N'-hydroxy-terephthalamide 151. N-cyclohexyl-N'-hydroxy-terephthalamide 152. N-cyclopropyl-N'-hydroxy-terephthalamide 153. N-hexyl-N'-hydroxy-terephthalamide 154. N-hydroxy-N'-(3-methyl-blityl)-terephthalamide 155. N-hydroxy-N^-phenethyl-terephthalamide 156. N-hydroxy-N'-[2-(4-methoxy-phenyl)-ethyl]-terephthalaniide 157. N-(3-chloro-benzyl)-N'-hydroxy-terephthalainide 158. N-hydroxy-N'-(2-methoxy-benryl)-terephthalamide 159. N-(4-filiorO-benzyl)-N'hydroxy-terephthalamide 160. N-hydroxy-N'-(l,2,3,4-tetrahydro-naphthalen-l-yl)-terephthalaniide 161. N-hydroxy-N'-(4-trifkuroromethyl-benzyl)-terephthalamide 162. N-(2,4-difkuroro-benzyl)-N'-hydroxy-terephthalamide 163. N-hydroxy-N'-indan-1 -yl-terephthalamide 164. N-benzo[l,3]dioxol-5-ylmethyl-N'-hydroxy-terephthalamide 165. N-hydroxy-4-(4-phenyl-piperazine-l-carbonyl)-benzamide 166. N-(3,5-dimethyl-benzyl)-N^-hydroxy-terephthalamide 167. N-hydroxy-N'-(3-isopropoxy-propyl)-terephthalamide 168. 4-(4-acetyl-piperazine-l-carbonyl)-N-hydroxy-benzamide 169. N,N-diblityl-N'-hydroxy-terephthalamide 170. 4-(4-benzyl-piperidine-l-carbonyl)-N-hydroxy-benzamide 171. N-hydroxy-N'-[2-{l-methyl-pyrrolidin-2-yl)-ethyl]-terephthalamide 172. N-{2-ethoxy-benzyl)-N'-hydroxy-terephthalaniide 173. N-(2-cydohex-l-enyl-ethyl)-N'-hydroxy-terephthalamide 174. N-hydroxy-N'-(2-morpholin-4-yl-ethyi)-terephthalaniide 175. N-hydrox7-N'-(2-methyislilfanyl-ethyl)-terephthalamide 176. N-hydroxy-N'-(tetrahydro-fliran-2-ylmethyl)-terephthalamide Example 17 Evalliation of effects on a hliman colon carninoma cell line of the compolinds of the invention MTT is widely lised for the qliantitative determination of cytotoxic effects or in vitro chemosensitivity of tlimor cells. The assay is based on the cleavage of the yellow tetrazolilim salt MTT to plirple formazan crystals by metabolic active cells. For details, see Rlibinstein, L.V., et al., J. Natl. Cancer Inst. 82 (1990) 1113-1118. The following procedlire was performed: HT-29 cells (hliman colon carcinoma cell line) were cliltivated in RPM 1640, 2.5 % PCS, 2 mM Gllitamine, 100 li/ml Penicillin, 100 lig/ml Streptomycin. For the assay the cells were seeded in 384 well plates, 900 cells per well, in the same medilim The next day compolinds (dissolved 10 mM in DMSO) were added in variolis concentrations ranging from 30 liM to 1.5 nM. After 5 days the MTT assay was done mainly according to the instrlictions of the manlifactlirer (Cell proliferation kit I, MTT, fom Roche Moleclilar Biochemicals). In brief: MTT labeling reagent was added to a final concentration of 0.5 mg/ml, added and inclibated for 4 hrs at 37 C, 5% C02. Dliring this inclibation time plirple formazan crystals are formed. After addition of the sollibilization sollition (20% SDS in 0.02 M HCl) the plates were inclibated overnight at 37 C, 5% C02. After careflil mixing plates were measlired in Victor 2 (scanning mliltiweli spectrophotometer, Wallac) at 550 nm. A decrease in nlimber of living cells reslilts in a decrease in the total metabolic activity in the sample. The decrease direcdy correlates to the amolint of plirple cololir reslilting from the sollibilization of the plirple formazan crystals. Determination of IC50 was done lising XL-fit. Example 18 Tablet formlilation Item Ingredients mg/Tablet 1 Compolind 2a 25 100 2 Anhydrolis Lactose 73 35 3 Croscarmellose 6 8 Sodilim 4 Povidone K30 5 6 5 Magnesilim Stearate 1 1 Total Weight 110 150 Compolind 2a is described in Example 2. Procedlire: 1, Mix Items 1,2 and 3 in a sliitable mixer for 15 minlites. 2. Granlilate the powder mix from Step 1 with 20% Povidone K30 Sollition (Item 4). 3. Dry the granlilation from Step 2 at 50oC. 4. Pass the granlilation from Step 3 throligh a sliitable milling eqliipment. 5. Add the Item 5 to the milled granlilation Step 4 and mix for 3 minlites. 6. Compress the granlilation from Step 5 on a sliitable press. List of References Cancer: Principles & Practice of Oncology, Vincent T. DeVita, Jr., Samliel Hellmann, Steven A. Rosenberg; 5th Ed., Lippincott-Raven Pliblishers 1997 Holiben-Weyl, -Methoden der Organischen Chemie, Georg Thieme Verlag-, Stlittgart; Organic Reactions, John Wiley 8c Sons, Inc., New York Holiben-Weyl, Methoden der organischen Chemie, Vol. XV/1 and XV/2 Koyama, Y., et al.. Blood 96 (2000) 1490-1495 Marks, P.M., et al., J. Nati. Cancer Inst. 92 (2000) 1210-1216 Janda, M., et al., Org. Prep. and Proced. Int. 3 (6) (1971) 295-297 Rlibinstein, L.V., et al., J. Nati. Cancer Inst. 82 (1990) 1113-1118 liS 2,680,731 liS 5,369,108 WO 98/55449 Holba, v., et al., Z. Phys. Chem.(Leipzig) 262 (3) (1981) 445-448 Patent Claims 1. Compounds of formula I denotes a phenyl ring which may be unsubstituted or substituted by 1, 2 or 3 substituents independently selected from a halogen atom, an (l-4C)alkyl-s trifluoromethyl-, hydroxy-, (l-4C)alkoxy-, nitro-, amino-, (1-4C)alkylamino-, di[(l-4C)alkyl]-amino-, (l-4C)alkanoylamino, a (1-3C)alkylenedioxy-group or an acyl group, denotes or a thiophene ring which may be unsubstituted or substituted by 1 or 2 substituents independently selected from a halogen atom, an (1-4C)alkyl-, trifluoromethyl-, hydroxy-, (l-4C)alkoxy-, nitro-, amino-, (1-4C)alkylamino-, di[(l-4C)alkyl]-amino- or a (l-4C)alkanoylamino, a (1-3C)alkylenedioxy-group or an acyl group, and Rl and R2 are the same or different from each other and are a hydrogen atom; a branched or unbranched (l-14C)alkyl group which may be unsubstituted or substituted with 1 or several substituents independently selected from a halogen atom, hydroxy-, nitro-, amino group or by a carbocydic group or by a heterocydic group, and wherein at a chain length of larger than 2 atoms one or several non adjacent atoms may be replaced by oxygen, nitrogen or sulfur atoms, and wherem 2 atoms may be bound together by a double or triple bond; a carbocydic group; or a heterocyclic group; or Rl and R2 together with the nitrogen atom form a 3-6 membered ring which may contain additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and which may be annulated by a carbocydic group or by a heterocyclic group and which may be unsubstituted or substituted by 1, 2, or 3 substituents independently selected from a halogen atom, an {l-4C)alkyl-, trifluoromethyl-, hydroxy-, (l-4C)alkoxy-, aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy, (l-3C)alkylenedioxy-, nitro-, amino-, (l-4C)alkylamino-, di[(l-4C)alkyl]amino-, (l-4C)alkanoylamino- or an acyl-group; their enantiomers, diastereoisomers, racemates and physiologically acceptable salts thereof. 2. Compounds of formula I according to claim 1 wherein is thiophene, and R1 is hydrogen and R2 has the above given meaning. 3. Compounds of formula I according to claims 1 or 2 wherein R2 is benzyl or substituted benzyl. 4. Compounds of formula I according to claim 1 wherein is thiophene and R1 and R2 together with the nitrogen atom from a piperazin or piperidine ring which may be substituted by acetyl, benzhydryl or phenyl whereby the phenyl groups can be substituted. 5. Compounds of formula I according to daim 1 selected from the group consisting of Thiophene-2,5-dicarboxylic acid 2-hydroxyainide 5-[(naphthalen-l- ylmethyl) -amide] Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-(4-trifluoromethyl- ben2ylamide) N-hydroxy-N'-naphthalen-l-ylmethyl-terephthal amide Thiophene-2,5-dicarboxylic acid 2-(3-chloro-benzylamide) 5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-(3,5-dimethyl-benzylamide) 5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-hexylamide 5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-[(l,5-dimethyl-hexyl)-amide] 5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-hydroxyaniide 5-[(2-phenoxy-ethyl)- amide] Thiophene-2,5-dicarboxylic acid 2-(3,5-dimethyl-benzylamide) 5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-(3,5-bis-trifluoromethyl-benzylamide) 5 -hydr oxyamide Thiophene-2,5-dicarboxylic acid 2-(3-bromo-ben2ylaraide) 5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-(4-tert-butyl-ben2ylamide) 5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-hydroxyainide 5-(4-trifluoromethyl- benzylamide) Thiophene-2,5-dicarboxylic acid 2-(3-chloro-ben2ylamide) 5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-[(3,3-diphenyl-propyl)-ainide] 5-hydioxyamide Thiophene-2,5-dicarboxylic acid 2-(3,4-dichloro-benzylamide) 5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-hydroxyainide 5-[(l-phenyl-ethyl)- amide] Thiophene-2,5-dicarboxylic acid 2-hydroxyainide 5-(3-trifluoromethyl- benzylamide) Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(l-methyl-hexyl)- amide] Thiophene-2,5-dicarboxylic acid 2-heptylamide 5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-hydroxyainide 5-[(4-phenyl-butyl)- amide] Thiophene-2,5-dicarboxylic add 2-benzylamide 5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-hexylamide 5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-(3-fluoro-benzylamide) 5-hydroxyamide Thiophene-2,5-dicarboxy]ic acid 2-(2,4-difluoro-benzylamide) 5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-[(2-benzlsulfanyl-ethyl)-amide] 5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-(4-bromo-benzylamide) 5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-{[2-(4-hydroxy-phenyl)- ethyl]-amide} Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-(4-methoxy- ben2ylamide) Thiophene-2,5-dicarboxylic acid 2-(2,3-dichloro-benzylamide) 5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(3-phenyl-propyl)- amide] Thiophene-2,5-dicarboxylic acid 2-(2,5-difluoro-ben2ylamide) 5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-(2-fluoro-benzylamide) 5-hydroxyamide Thiophene-2,5-dicarboxylic add 2-hydroxyamide 5-[(naphthalen-l- ylmethyl)-amide] Thiophene-2,5-dicarboxylic add 2-hydroxyamdde 5-(3-methyl-benzylamide) Thiophene-2,5-dicarboxylic add 2-(2,6-difluoro-beii2ylaiiiide) 5-hydroxyamide. 6. Process of manufacturing compounds according to claims 1 to 5 by reacting a compound of formula III wherein A has the meaning defined hereinbefore and R3 is (1-4C) alkyl group with an amine of the formula HNR1R2 in the presence of an activating agent, wherein R1 and R2 have the meaning defined hereinbefore to give a compound of formula II which is reacted with hydroxylamine in the presence of a suitable base, whereafter the obtained compounds of formula I are converted in its enantiomers, diastereoisomers, racemates or physiologically acceptable salts. 7. Medicaments containing as active ingredients a compound of formula I according to claims 1 to 5 in admixture with pharmaceutically acceptable excipients or diluents. 8. Use of a compoimd according to claims 1 to 5 for the preparation of a medicament having histone deacetylase (HDAC) inhibitor activity. 9. Use of a compound according to claim 8 as an inhibitor of cell proliferation. 16. A medicaments containing active ingredients substantially as herein described and exemplified.

Full Text

AROMATIC DICARBOXYLIC ACD DERIVATIVES
The invention relates to aromatic dicarboxylic acid derivatives, or pharmaceutically-acceptable salts thereof, which possess anti-cell-proliferation activity such as anti-cancer activity and are accordingly useful in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said dicarboxylic acid derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti-cell-proliferation effect in a warm-blooded animal such as man.
Background of the Invention
Transcriptional regulation is a major event in cell differentiation, proHferation, and apoptosis. Transcriptional activation of a set of genes determines cell destination and for this reason transcription is tightly regulated by a variety of factors. One of its regulatory mechanisms involved in the process is an alteration in the tertiary structure of DNA, which affects transcription by modulating the accessibility of transcription factors to their target DNA segments. Nucleosomal integrity is regulated by the acetylation status of the core histones. In a hypoacetylated state, nucleosomes are tightly compacted and thus are nonpermissive for transcription. On the other hand, nucleosomes are relaxed by acetylation of the core histones, with the result being permissiveness to transcription. The acetylation status of the histones is governed by the balance of the activities of histone acetyl transferase (HAT) and histone deacetylase (HDAC). Recently, PIDAC inhibitors have been found to arrest growth and apoptosis in several types of cancer cells, including colon cancer, T-cell lymphoma, and erythroleukemic cells. Given that apoptosis is a crucial factor for cancer progression, HDAC inhibitors are promising reagents for cancer therapy as effective inducers of apoptosis (Koyama, Y., et al., Blood 96 (2000) 1490-1495).
Several structural classes of HDAC inhibitors have been identified and are reviewed in Marks, P.M., et al., J. Natl. Cancer Inst 92 (2000) 1210-1216. More specifically, WO 98/55449 and US 5,369,108 report alkanoyl hydroxamates with HDAC inhibitory activity.

It has now been found that certain aromatic dicarboxylic acid derivatives possess anti-cell-proliferation properties which are more potent than those in the aforementioned references. Furthermore, these compounds have HDAC inhibitiory activity.
Description of the Invention
According to the invention there is provided an aromatic dicarboxylic acid derivative of the formula I

denotes or a thiophene ring which may be unsubstituted or substituted by 1 or 2 substituents independently selected from a halogen atom, an

amino-, (l-4C)alkylamino-, di[(l-4C)alkyl]-amino- or a (l-4C)alkan-oylamino, a (l-3C)aIkylenedioxy-group or an acyl group,
and
Rl and R2 are the same or different from each other and are
a hydrogen atom;
a branched or unbranched (l-14C)aIkyl group, which
may be unsubstituted or substituted with 1 or several substituents
independently selected from the group consisting of a halogen-, hydroxy-,
nitro-, amino-, carbocyclic- or a heterocyclic group,
and wherein at a chain length of larger than 2 C-atoms one or several non
adjacent C-atoms may be replaced by a corresponding number of heteroatoms
such as oxygen, nitrogen or sulfur,
and wherein 2 C-atoms may be bound together by a double or triple bond; a carbocyclic group; or a heterocyclic group;
or Rl and R2 together with the nitrogen atom form a 3-6 membered ring which may contain additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and which may be annulated by a carbocyclic group or by a heterocyclic group and which may be unsubstituted or substituted by 1, 2, or 3 substituents independently selected from a halogen atom, an (l-4C)alkyl-, trifluoromethyl-, hydroxy-,m (l-4C)alkoxy-, aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy, (1-3C)alkylenedioxy-, nitro-, amino-, (l-4C)alkylamino-, di[(l-4C)alkyl]aniino-, (1-4C)alkanoylamino- or an acyl-group.
An alkyl group may be e.g. pentyl, hexyl or 3-methyl-butyl.
A substituted alkyl group may be e.g. ben2yl, phenethyl, tetrahydro-furan-2-yl-methyl or 2-cyclohex-l-enyl-ethyL
An alkyl group where one or several non adjacent atom groups may be replaced by oxygen, nitrogen or sulfur atoms may be e.g. 3-isopropoxy-propyl or 2-methylsulfanyl-ethyl.

An alkyl grolip wherein 2 atoms may be bolind together by a dolible or triple bond may be e.g. 1-hexinyl or 2-heptenyl.
A carbocyclic grolip maybe
a non-aromatic ring system with 3-7 carbon atoms, for example cyclopentane, cyclohexane, cyclohexene or cyclopropane, which may be linslibstitlited or slibstitlited by 1, 2, or 3 slibstitlients independently selected from a halogen atom, an (l-4C)alkyl-, trifllioro-methyl-, hydroxy-, (l-4C)alkoxy-, aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy, (l-3C)alkylenedioxy-, nitro-, amino-, (1-4C)alkylamino-, di[(l-4C)alkyl]amino-, (l-4C)alkanoylamino- or an acyl - grolip, and which may be annelated by an aryl or hetaryl grolip, to form e.g.an indane or a tetr aline,
or it may be an aryl grolip.
An aryl grolip is a carbocyclic conjligated ring system, for example phenyl,
naphthyl, preferably phenyl, which may be linslibstitlited or slibstitlited by 1,2, or 3
slibstitlients independently selected from a halogen atom, an (l-4C)alkyl-,
trifllioromethyl-> hydroxy-, (1 -4C)aIkoxy-, arylalkyloxy-, aryloxy, (1 -
3C)alkylenedioxy-, nitro-, amino-, (l-4C)alkylamino-, di[(l-4C)alkyl]amino-, (1-4C)alkanoylamino-, carboxyl-, carboxyalkyl- or an acyl - grolip.
A heterocyclic grolip may be
a non-aromatic ring system with 3-7 members and one or two hetero atoms independently chosen from nitrogen, oxygen, and slilflir, for example piperidino, morpholino, pyrrolidino, piperazino, which may be linslibstitlited or slibstitlited by 1, 2, or 3 slibstitlients independently selected from a halogen atom, an (l-4C)alkyl-, trifllioro-methyl-, hydroxy-, (l-4C)alkoxy-, aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy, (l-3C)alkylenedioxy-, nitro-, amino-, (l-4C)alkylamino-, di[(l-4C)alkyl]amino-, (l-4C)alkanoylamino, or an acyl - grolip, and which may be annelated by an aryl or hetaryl grolip, to form e.g. a tetrahydrochinoline, tetrahydroisochinoline or a dihydroindole,
or it may be a hetaryl grolip.

A hetaryl grolip is either a 5 or 6 membered cyclic conjligated ring system with one or two hetero atoms independently chosen from nitrogen, oxygen, and sulfur, for example pyridinyl, thiophenyl, fliryl or pyrrolyl, or an annlilated bicyclic conjligated ring system like indolyl-, qliinolyl- or isoqliinolyl-, which may be linslibstitlited or slibstitlited by 1, 2, or 3 slibstitlients independently selected from a halogen atom, an (l-4C)alkyl-, trifllioromethyl-, hydroxy-, (l-4C)alkoxy-, arylalkyloxy-, aryloxy, (l-3C)alkylenedioxy-, nitro-, amino-, (l-4C)alkylamino-, di[(l-4C)aIkyl]amino-, (l-4C)aIkanoylainino, or an acyl grolip.
When Rl and R2 together with the nitrogen atom form a 3-6 membered ring which may contain additional heteroatoms independendy selected from nitrogen, oxygen and slilflir, it may be e.g. piperidine, piperazine or morpholine.
A sliitable vallie for a slibstitlient when it is a halogen atom is, for example, fllioro, chloro, bromo and iodo; when it is (l-4C)alkyl is, for example, methyl, ethyl, propyl, isopropyl, blityl, isoblityl, sec-blityl; when it is (l-4C)alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy or blitoxy; when it is (l-4C)alkylamino is, for example, methylamino, ethylamino or propylamino; when it is di-[(l-4C)alkyl] amino is, for example, dimethylamino, N-ethyl-N-methylamino, diethylamino, N-methyl-N-propylamino or dipropylamino; when it is (1-4C)alkanoylamino is, for example, formylamido, acetamido, propionamido or blityramido; when it is (l-3C)aIkylenedioxy is, for example, methylenedioxy, ethylenedioxy or propylenedioxy; and when it is acyl is, for example, formyl, acetyl, propionyl, benzoyl, or phenylacetyl.
In a preferred embodiment, Rl is hydrogen and R2 has one of the above vallies. In a more preferred embodiment, R2 is a (l-14C)alkyl grolip. Most preferrably, R2 is an arylalkyl - radical, for example the benzyl - radical or slibstitlited benzyl - radicals.
Preferred are compolinds wherin A denotes a thiophene ring. Even more preferred are compoimds in wherein this thiophene ring is linslibstitlited. Most preferred are compolinds wherin two carboxylic moieties are bond at positions 2 and 5 of a flirther linslibstitlited thiophene ring. Enantiomers, diastereoisomers, racemates and mixtinres thereof and pharmacelitically acceptable salts of aromatic dicarboxylic acid derivatives of the formlila I are also part of the invention.

According to a flirther aspect of the invention there is provided a pharmacelitical composition which comprises an aromatic dicarboxylic acid derivative of the formlila I, or a pharmacelitically-acceptable salt thereof, as defined hereinbefore in association with a pharmacelitically-acceptable dillient or carrier. The composition may be in a form sliitable for oral administration, for example as a tablet or capslile, for parenteral injection (inclliding intravenolis, slibclitaneolis, intramlisclilar, intravasclilar or infiision) as a sterile sollition, slispension or emlilsion, for topical administration as an ointment or cream or for rectal administration as a slippository. In general the above compositions may be prepared in a manner lising conventional excipients. The aromatic dicarboxylic acid derivative will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000 mg per sqliare meter body area of the animal, i.e. approximately 0.1-100 mg/kg , and this normally provides a therapelitically-effective dose. A linit dose form slich as a tablet or capslile will lislially contain, for example 1-250 mg of active ingredient. Preferably a daily dose in the range of 1-100 mg/kg is employed. However the daily dose will necessarily be varied depending lipon the host treated, the particlilar rolite of administration, and the severity of the illness being treated. Accordingly the optimlim dosage may be determined by the practitioner who is treating any particlilar patient
According to a flirther aspect of the present invention there is provided an aromatic dicarboxylic acid derivative of the formlila I as defined hereinbefore for lise in a method of treatment of the hliman or animal body by therapy. It has now been folind that the compolinds of the present invention possess anti-cell-proliferation properties which are believed to arise from their histone deacetylase inhibitory activity. Accordingly the compolinds of the present invention provide a method for treating the proliferation of malignant cells. Accordingly the compounds of the present invention are expected to be liseful in the treatment of cancer by providing an anti-proliferative effect, particlilarly in the treatment of cancers of the breast, lung, colon, rectlim, stomach, prostate, bladder, pancreas and ovary. It is in addition expected that a derivative of the present invention will possess activity against a range of lelikemias, lymphoid malignancies and solid tlimors slich as carcinomas and sarcomas in tisslies slich as the liver, kidney, prostate and pancreas.
Thlis according to this aspect of the invention there is provided the lise of an aromatic dicarboxylic acid derivative of the formlila I, or a pharmacelitically-acceptable salt thereof, as defined herein in the manlifactlire of a medicament for

lise in the prodliction of an anti-cell-proliferation effect in a warm-blooded animal slich as a hliman being.
According to a flirther featlire of this aspect of the invention there is provided a method for prodlicing an anti-cell-proliferation effect in a warm-blooded animal, slich as man, in need of slich treatment which comprises administering to said animal an effective amolint of an aromatic dicarboxylic add derivative as defined hereinbefore.
The anti-cell-proliferation treatment defined hereinbefore may be apphed as a sole therapy or may involve, in addition to the aromatic dicarboxylic acid derivative of the invention, one or more other anti-tlimor slibstances, for example those selected from, for example, mitotic inhibitors, for example vinblastine; alkylating agents, for example cis-platin, carboplatin and cyclophosphamide; inhibitors of microtliblile assembly, like paclitaxel or other taxanes; antimetabolites, for example 5-fllioroliracil, capecitabine, cytosine arabinoside and hydroxylirea, or, for example, intercalating antibiotics, for example adriamycin and bleomycin; immlinostimlilants, for example trastlizlimab; DNA synthesis inhibitors, e.g. gemcitabine; enzymes, for example asparaginase; topoisomerase inhibitors, for example etoposide; biological response modifiers, for example interferon; and anti-hormones, for example antioestrogens slich as tamoxifen or, for example antiandrogens slich as (4'-cyano-3-(4-flliorophenylslilphonyl)-2-hydroxy-2-methyl-3'-(trifllioromethyl)-propionanilide, or other therapelitic agents and principles as described in, for example, Cancer: Principles & Practice of Oncology, Vincent T. DeVita, Jr., Samliel Hellmann, Steven A. Rosenberg; 5th Ed., Lippincott-Raven Pliblishers 1997. Slich conjoint treatment may be achieved by way of the simliltaneolis, seqliential or separate dosing of individlial components of the treatment. According to this aspect of the invention there is provided a pharmacelitical prodlict comprising an aromatic dicarboxylic acid derivative of the formlila I as defined hereinbefore and an additional anti-tlimor slibstance as defined hereinbefore for the conjoint treatment of cancer.
Another object of the present invention are pharmacelitical compositions containing a pharmacologically effective amolint of one or more compolinds of formlila I in admixtlire with pharmacelitically acceptable excipients and/or dillients.

Examples for physiologically acceptable-salts of compounds of formlila I are salts with physiologically acceptable bases. These salts can be, among others, alkali, earth alkali, ammonilim and alkylammonilim salts, for example sodilim, potassilim, calcilim, tetra-methyl-ammonilim salts.
The separation of racemic compolinds into their enantiomers can be performed by chromatography on an analytical, semipreparative or preparative scale lising sliitable optically active stationary phases with sliitable ellients. Sliitable optically active stationary phases incllide, blit are not limited to, silica (e.g. ChiraSper,Merck; Chiralpak OT/OP, Baker), celllilose esters or carbamates (e.g. Chiracel OB/OY, Baker) or others (e.g. Crownpak, Daicel or Chiracel OJ-R, Baker). Other methods for the separation of enantiomers can also be applied, like the formation of diastereomeric compolinds from compolinds of the formlila I together with other optically active compolinds, e.g. camphorslilfonic acid or brlicin, and separation of these diastereomeric compolinds, followed by the liberation from the optically active agent. Enantiomerically enriched or plire compolinds of formlila I are also obtainable by the lisage of optically active starting materials.
Preparation of the Compolinds of the Invention
An aromatic dicarboxylic acid derivative of the formlila I, or a pharmacelitically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of chemically-related compolinds. Slich processes, when lised to prepare an aromatic dicarboxyhc acid derivative of the formlila I, or a pharmacelitically-acceptable salt thereof, are provided as a flirther featlire of the invention and are illlistrated by the following representative examples in which, linless otherwise stated. A, Rl and R2 have any of the meanings defined hereinbefore. Necessary starting materials may be obtained by standard procedlires of organic chemistry. The preparation of slich starting materials is described within the accompanying non-limiting examples. Alternatively necessary starting materials are obtainable by analogolis procedlires to those illlistrated which are within the ordinary sklil of an organic chemist

(a) One preferred method for the prodliction of compolinds of the formlila I involves the reaction of compounds of the formlila 11

wherein A, Rl and R2 have the meaning defined hereinbefore and R3 is a (1-4C)alkyl grolip, preferably a methyl or ethyl grolip, with hydroxylamine in the presence of a sliitable base. The reaction is carried olit in an inert solvent or dillient slich as methanol or ethanol at temperatlires between 0°C and 100°C, conveniently at or near ambient temperatlire, and at a pH between 10 and 12. A sliitable base is, for example, an alcoholate, for example, sodilim methylate.
Compolinds of formlila II are prepared firom compolinds of the formlila III wherein A and R3 have the meaning defined hereinbefore.

This reaction typically involves a two-step one-pot procedlire. In the first step, the carboxylate of the formlila III becomes activated. This reaction is carried olit in an inert solvent or dillient, for example, in dichloromethane, dioxane, or tetrahydrofliran, in the presence of an activating agent. A sliitable reactive derivative of an acid is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the add and a chloroformate slich as isoblityl chloroformate; an active ester, for example an ester formed by the reaction of the acid and a phenol slich as pentaflliorophenol; an active ester formed by the reaction of the acid and N-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid and an azide slich as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide slich as diethylphosphoryl cyanide; or the prodlict of the reaction of the acid and a

carbodiimide slich as dicydohexylcarbodiimide, or the prodlict of the reaction of the acid and bis-(2-oxo-3-oxazolidinyl)-phosphoi7lchloride. The reaction is carried olit between -30*^C and 60°C, conveniently at or below 0°C. In the second step, an amine of the formlila HNR1R2 in which Rl and R2 have the meaning defined hereinbefore is added to the sollition, at the temperatlire lised for the activation, and the temperatlire is slowly adjlisted to ambient temperatlire. An appropriate scavenger base like e.g. triethylamine, or diisopropyethlyamine may be added to the reaction mixtlire. These methods are well known to those skilled in the art. In principle, all methods for the synthesis of amides as lised in peptide chemistry as described in e.g. "Methoden der organischen Chemie (Holiben-Weyl)" Vol. XV/1 and XV/2 are also applicable.
There are qliite a few compolinds of formlila III described in the hteratlire. For example, the prototypic terephthalic monomethylester is described by, e.g., Holba, v., et al., Z. Phys. Chem.(Leipzig) 262 (3) (1981) 445-448. It is also commercially available. Thiophene-2,5-dicarboxylic acid monomethyl ester is described in e.g. liS 2,680,731. These monoesters are lislially prepared by selective saponification of the diester, blit other method may be liseflil as well and are well known to those skilled in the art.

wherein Y is a sliitable protecting grolip and A, Rl and R2 have the meaning defined hereinbefore.
Compolinds of the formlila IV are new and incllided in the present invention.
Sliitable protecting grolips may be the benzyl-, p-methoxybenzyl-, tert.blityloxycarbonyl-, trityl-, or silyl grolips slich as the trimethylsilyl- or dimethyl-tert.blitylsilyl-grolip. The reactions carried olit depend on the type of the protecting grolip. When the protecting grolip is a benzyl- or p-methoxybenzyl

grolip, the reaction carried olit is a hydrogenolysis in an inert solvent slich as an alcohol like methanol or ethanol, in the presence of a noble metal catalyst slich as palladilim on a sliitable carrier slich as carbon, barilim slilfate, or barilim carbonate, at ambient temperatlire and presslire. When the protecting grolip is the tert.blityloxycarbonyl-, trityl-, or a silyl grolip slich as the trimethylsilyl- or dimethyl-tert.blitylsilyl-grolip, the reaction is carried olit in the presence of acids at a temperatlire between -20°C and 60°C, preferably between 0°C and ambient temperatlire. The acid may be a sollition of hydrochloric acid in an inert solvent slich as diethyl ether or dioxane, or trifllioro acetic add in dichloromethane. When the protecting grolip is a silyl grolip slich as the trimethylsilyl or dimethyl-tert.blitylsilyl grolip, the reaction can also be carried olit in the presence of a fllioride solirce slich as sodilim fllioride or tetrablityl ammoniimi fllioride in an inert solvent slich as dichloromethane. Not necessarily all protecting grolips Y are compatible with all grolips Rl or R2. In cases where the featlires of these grolips do not allow the lisage of a certain protecting grolip, other protecting grolips Y or other methods of preparation need to be applied.

wherein Y is a sliitable protecting grolip as described above. This reaction typically involves a two-step one-pot procedlire. In the first step, the carboxylate of the formlila V becomes activated. This reaction is carried olit in an inert solvent or dillient, for example, in dichloromethane, dioxane, or tetrahydrofuran, in the presence of an activating agent A sliitable reactive derivative of an acid is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the

acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloroformate slich as isoblityl chloroformate; an active ester, for example an ester formed by the reaction of the acid and a phenol slich as pentaflliorophenol; an active ester formed by the reaction of the acid and N-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid and an azide slich as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide slich as diethylphosphoryl cyanide; or the prodlict of the reaction of the acid and a carbodiimide slich as dicyclohexylcarbodiimide, or the prodlict of the reaction of the add and bis-(2-oxo-3-oxazolidinyl)-phosphorylchloride. The reaction is carried olit between -30°C and 60°C5 conveniently at or below 0°C. In the second step, compolind VI is added to the sollition, at the temperatlire lised for the activation, and the temperatlire is slowly adjlisted to ambient temperatlire. These methods are well known to those skilled in the art. In principle, all methods for the synthesis of amides as lised in peptide chemistry as described in e.g. "Methoden der organischen Chemie (Holiben-Weyl)" Vol. XV/1 and XV/2 are also applicable.
Compolinds of the formlila V are prepared from compolinds of the formlila II by hydrolysis. The conditions under which the hydrolysis is carried olit depend on the natlire of the grolip R3. When R3 is a methyl or ethyl grolip, the reaction is carried olit in the presence of a base, for example, lithium hydroxide, sodilim hydroxide, or potassilim hydroxide in an inert solvent or dillient, for example, in methanol or ethanol. When R3 is the tert.blityl grolip, the reaction is carried olit in the presence of an add, for example, a sollition of hydrochloric acid in an inert solvent slich as diethyl ether or dioxane, or trifllioroacetic acid in dichloromethane. When R3 is the benzyl grolip, the reaction is carried olit by hydrogenolysis in the presence of a noble metal catalyst slich as palladilim or platinlim on a sliitable carrier, slich as carbon. Not necessarily all methods of hydrolysis are compatible with all grolips Rl or R2. In cases where the featlires of these grolips do not allow the lisage of a certain method of hydrolysis, other methods of preparation need to be applied.
(c) Another preferred method for the preparation of compolinds of the formlila I is the reaction of a compolind of the formlila V with hydroxylamine. This reaction typically involves a two-step one-pot procedlire. In the first step, the carboxylate of the formlila V becomes activated. This reaction is carried olit in an inert solvent or dillient, for example, in dichloromethane, dioxane, or tetrahydrofliran, in the

presence of an activating agent. A sliitable reactive derivative of an acid is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloroformate slich as isoblityl chloroformate; an active ester, for example an ester formed by the reaction of the acid and a phenol slich as pentaflliorophenol; an active ester formed by the reaction of the add and N-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid and an azide slich as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide slich as diethylphosphoryl cyanide; or the prodlict of the reaction of the acid and a carbodiimide slich as dicyclohexylcarbodiimide, or the prodlict of the reaction of the acid and bis-(2-oxo-3-oxazolidinyl)-phosphorylchloride. The reaction is carried olit between -30°C and 60°C, conveniently at or below 0°C. In the second step, hydroxylamine is added to the sollition, at the temperatlire lised for the activation, and the temperatlire is slowly adjlisted to ambient temperatlire. These methods are well known to those skilled in the art. In principle, all methods for the synthesis of amides as lised in peptide chemistry as described in e.g. "Methoden der organischen Chemie (Holiben-Weyl)" Vol. XV/1 and XV/2 are also applicable.
(d) Compolinds of formlila I can also be prepared with methods of solid phase slipported synthesis. Terephthalic acid or 2,5-thiophenedicarboxylic acid is reacted with a hydroxylamine moiety (-O-NH2) bolind to a resin, e.g. a Wang resin (Wang-O-NH2 resin was slipplied by EMC microcollections, Tlibingen) to form a resin-bolind hydroxamic acid. The second carbonic acid moiety is reacted with an amine by standard methods of amide formation as described in e.g. "Methoden der organischen Chemie (Holiben-Weyl)" Vol. XV/1 and XV/2. After this, the hydroxamic acid is liberated from the solid slipport. This can be done for example with TFA. The crlide prodlict can be plirified by LC-MS, if necessary.
The invention will now be illlistrated in the following non-limiting examples in which, linless otherwise stated:
(i) evaporations were carried olit by rotary evaporation in vaclio and work-lip procedlires were carried olit after removal of residlial solids slich as drying agents by filtration;

(ii) operations were carried olit at ambient temperatlire, that is in the range 18-25°C and linder an atmosphere of an inert gas slich as argon or nitrogen;
(iii) collimn chromatography (by the flash procedlire) and high presslire Hqliid chromatography (HPLC) were performed on Merck Kieselgel silica or Merck Lichroprep RP-18 reversed-phase silica obtained from E. Merck, Darmstadt, Germany;
(iv) yields are given for illlistration only and are not necessarily the maximlim attainable;
(v) melting points were determined lising a Mettler SP62 alitomatic melting point apparatlis, an oli-bath apparatlis or a Kofler hot plate apparatlis.
(vi) the strlictlires of the end-prodlicts of the formlila I were confirmed by nliclear (generally proton) magnetic resonance (NMR) and mass spectral techniqlies (Micromass Platform II machine lising APCI or Micromass Platform ZMD lising electrospray);
(vii) intermediates were not generally fliliy characterized and plirity was assessed by thin layer chromatography;
(viii) the following abbreviations have been lised:
DMF, N,N-dimethylformamide; DMSO, dimethylslilphoxide; THF, tetrahydrofliran; MeOH, methanol; HCl, hydrochloric acid; NaH, sodilim hydride CH2CI2, dichloromethane; H2SO4, slilphliric acid sat, satlirated sol., sollition rt, room temperatlire eq, eqliivalent

Example 1
Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(naphthalen-l-ylmethyl)-
amide] (la)
1.9g Thiophene-2,5-dicarboxylic acid monomethyl ester and 1.2mL N-methylmorpholine is dissolved in 20mL of CH2CI2 at -10°C. To this sollition is added l.5mL isoblityl chloroformate. After lOmin of stirring, 1.7mL 1-(aminomethyl)-naphthalene in 5mL of CH2CI2 is added. The cooling bath is removed and the reaction mixture is allowed to reach rt. After 90min, lOmL of water and 10mL 2N HCl are added. The phases are separated, and the organic phase is washed with water. After evaporation of the solvent there is obtained 4,4g crlide 5-[(naphtalen-l-ylmethyl)-carbamoyl]-thiophene-2-carboxylic acid methyl ester (lb) which is plirified by recrystalisation from ethylacetate, petrol ether, yielding 58%, mp 125°C.
To a sollition of 550mg hydroxylamine hydrochloride in 8mL MeOH is added 2/3 of a sollition of 275mg of sodilim in 8mL of MeOH. To this, a sollition of 1.30g 5-[(naphtalen-l-ylmethyl)-carbamoyl]-thiophene-2-carboxylic acid methyl ester (lb) in 30mL MeOH is added, followed by the remaining sodilim methylate sollition. After stirring for 4h at rt the solvent is evaporated. 20mL of water are. added, , acidified with 4mL 50% acetic acid, and the precipitate is collected by filtration. After tritliration with THF there is obtained 0.76g thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(naphthalen-l-ylmethyl)-amide] (la) as a white powder, mp 170°C.
Example 2
Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-(4-trifllioromethyl-
benzylamide) (2a)
2a is prepared from thiophene-2,5-dicarboxylic add monomethyl ester in an analogolis manner to that described for the preparation of la example 1. The last step yields 40% of thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-(4-trifluoromethyl-benzylamide) (2a), mp. 172-174°C.

Example 3
N-hydroxy-N'-naphthalen- 1-ylmethyl-terephthalamide (3a)
leq of Wang-0-NH2 is shaken with lleq of terephthalic acid, 5.5eq N,N'-diisopropylcarbodiimide, 5.5eq l-hydroxybenzotriazole and 25eq diisopropylethylamine in DMF for 4h at 25°C. After that, the resin is washed with DMF (5 times), MeOH (3 times), THF (3 times), CH2CI2 (3 times) and diethylether (3 times). The resin is then shaken with 5eq pentaflliorophenyl trifllioroacetate and lOeq pyridine. After that, the resin is washed with DMF (2 times), followed by CH2CI2 (2 times), followed by diethylether (2 times). The resin is then shaken with 5eq of naphtalenemethylamine, lOeq of diisopropylethylamine and leq of 1-hydroxybenzotriazole. It is then shaken with 5eq pentaflliorophenyl trifllioroacetate and lOeq pyridine. After that, the resin is washed with DMF (2 times), followed by CH2CI2 (2 times). To liberate the prodlict from the solid slipport, the resin is shaken with 50% TFA in dry CH2Cl2 with 5% triisopropylsflane added at rt for Ih. The liqliid phase is filtered, the resin washed with CH2CI2 (3 times), and the combined filtrates are evaporated. The crlide prodlict is dissolved in tert-blitanol/H20 (80:20) and freeze-dxied. To nelitralize any remaining TFA, 100|iL of a 25% NH4OH-S0I is added and freeze-dried, again. The remaining solid is plirified by preparative LC-MS to N-hydroxy-N'-naphthalen-1-ylmethyl-terephthalamide, MS (APCI): 321.1 (M+1)
Example 4
Thiophene-2,5-dicarboxylicacid 2-(3-chloro-benzylamide) 5-hydroxyamide (4a)
9.0g Thiophene-2,5-dicarboxylic acid monomethyl ester is refllixed in 30mL of thionylchloride lintil gas evollition has ceased. The mixtlire is evaporated and the residlie is slowly added to a sollition of 10.3g 3-chlorobenzylanline and 20g triethylamine in 180mL CH2CI2 at 0°C. After 15min the cooling bath is removed and the reaction mixtlire is allowed to reach rt After 2h it is qlienched with water, the phases are separated, and the aqlieolis phase is extracted with CH2CI2. The combined organic phases are dried with Na2SO4 and evaporated yielding a crlide prodlict. This is plirified by recrystaliisation from diethylether / heptane yielding 13.9g (93%) crlide 5-[(3-chlorobenzyl)-carbamoyl]-thiophene-2-carboxylic acid methyl ester (4b), mp 91-93°C. To a sollition of 2.9g hydroxylamine hydrochloride in 45mL MeOH is added 25mL of a sollition of L4g sodiima in 40mL of MeOH. To this, a sollition of 6.4g ester 4b in 30mL MeOH is added, followed by the remaining

15mL of the sodilim methylate sollition. After stirring for 3h at rt the sollition is acidified with IN HCl and some ethylacetate is added. Thiophene-2,5-dicarboxylic acid 2-(3-chloro-benzylamide) 5-hydroxyamide (4a) precipitates as a white solid; 4.7g, 73%, mp. 183oC.
Example 5
Thiophene-2,5-dicarboxylic acid 2-(3,5"dimethyl-benzylaniide) 5-hydroxyamide
(5a)
5a is prepared from thiophene-2,5-dicarboxylic acid monomethyl ester in an analogolis manner to that described for the preparation of 4a example 4, MS (APCI): 305.3 (M+1)
Example 6
Thiophene-2,5-dicarboxylic add 2-hexylamide S-hydroxyamide (6a)
6a is prepared from thiophene-2,5-dicarboxylic acid monomethyl ester in an analogolis manner to that described for the preparation of 4a example 4, mpl71-173°C
Example 7
Thiophene-2,4-dicarboxylic acid 2-(3,5-dimethyl-benzylamide) 4-hydroxyaniide
(7a)
0.5g 2-carboxy-thiophen-4-carboxylic add ethyl ester (Janda, M., et al., Org. Prep, and Proced. Int. 3 (6) (1971) 295-297) and 0,67g N-(3-dimethylaminopropyl)-N-ethylcarbodiimid x HCl are stirred in 50mL DCM for 15min. Then, 0.338g 3,5-dimethylbenzylamin are added and the mixtlire is stirred overnight The sollition is extracted with 2N HCl and water, then evaporated. The residlie is titlirated with isohexan, and the reslilting crystals are filtrated and air-dried, yielding 0.58g (73%) crlide 5-(3,5-Dimetihyl-ben2ylcarbamoyl)-thiophene-3-carboxylic acid ethyl ester (7b). This ester in converted to title compolind by reaction with hydroxylamine hydrochloride in a manner similar to that described for the conversion of 4b into 4a in example 4. After chromatography (silica, ethylacetate), thiophene-2,4-dicarboxylic acid 2-(3,5"dimethyl-benzylaniide) 4-hydroxyamide (7a) is obtained as crystals; 44mg, 9%, mp: 181o C (decomp.).

Example 8
Thiophene-2,4-dicarboxylic acid 2-(3-chloro-benzylamide) 4-hydroxyamiide (8a)
8a is prepared from 2-carboxy-thiophen-4-carboxylic add ethyl ester in an analogolis manner to that described for the preparation of 7a example 7; 163mg, 34%, mp: 90oC (decomp.)-
Example 9
Thiophene-2,4-dicarboxylic add 4-hydroxyamide 2-(4-trifkuroromethyl-
benzylamide) (9a)
9a is prepared from 2-carboxy-thiophen-4"Carboxylic acid ethyl ester in an analogolis manner to that described for the preparation of 7a example 7; 56mg, 10%,mp:174-177°C.
Example 10
Thiophene-2,4-dicarboxylic acid 2-[(ben2o[l,3]dioxol-5-ylmethyl)-amide] 4-
hydroxyamide (10a)
10a is prepared from 2-carboxy-thiophen-4-carboxylic acid ethyl ester in an analogolis manner to that described for the preparation of 7a example 7; 16mg, 3%, mp: 182°C (decomp.).
Example 11
Thiophene-2,4-dicarboxylic add 2-hexylamide 4-hydroxyamide (11a)
11a is prepared from 2-carboxy-thiophen-4-carboxylic acid ethyl ester in an analogolis manner to that described for the preparation of 7a example 7; 92mg, 20%, mp: 150°C (decomp.).
Example 12
Thiophene-2,4-dicarboxylic add 4-(3,5-dimethyl-benzylamide) 2-
hy droxyamide (12a)
5.0g 2-carboxy-thiophen-4-carboxylic acid ethyl ester (Org, Prep, and Proced. Int. 3 (6) (1971) 295) is dissolved in 50mL THF and 4.5g thionylchloride is added. After refllixing for 4h, the mixtlire is evaporated. The crlide acid chloride is added to a

sollition of 3.1g 0-ben2ylhydroxylamine and 3.06g triethylamine in 80mL DCM. After stirring for 4h the sollition is washed with 2N HCI and water, dried and evaporated. After titlirating the residlie with isohexan / diethylether, bright crystalls of 5-benzyloxycarbamoyl-thiophene-3-carboxylic acid ethyl ester (12b) are obtained, which are filtered and air-dried; 3.5g, 46%. 0.46g NaOH are dissolved in 45mL ethanol and 5mL water. The ester 12b is added and the sollition refllixed for 2h. After cooling, the ethanol is evaporated and the aqlieolis phase extracted with diethylether. The aqlieolis phase is acidified with 2N HCl and the precipitate formed is collected by filtration, yielding 2.8g (88%) 5-benzyloxycarbamoyl-thiophene-3-carboxylic acid (12c) as a solid.
0.4g 5-benzyloxycarbamoyl-thiophene-3-carboxylic acid (12c) is dissolved in 50mL DCM, and 0.387g N'-(3-dimethylaminopropyl)-N-ethylcarbodiimid x HCl are added. After stirring for 15min, 0.195g 3,5-dimethylbenzylainine is added, and the mixtlire is stirred overnight.
The sollition is extracted with 2N HCl and water, then evaporated. The residlie is titlirated with ether/isohexan, and the reslilting crystals are filtrated and air-dried, yielding 0.44g {77%) of thiophene-2,4-dicarboxylic acid 2-(benzyloxy-aniide) 4-(3,5-dimethyl-benzylanlide) (12d). This is hydrogenated in a 1:1 mixtlire of THF and MeOH lising Pd/CaSo4/C and plirified by preparative HPLC/MS yielding 12a: MS (APCI): 303.1 (M-1).
Example 13
In an analogolis manner to that described in the example 12, the following compolinds are prepared:
1. Thiophene-2,4-dicarboxylic acid 4-(3-chloro-benzylamide) 2-hydjoxyamide
2. Thiophene-2,4-dicarboxylic acid 4-hexylamide 2-hydroxyamide

Example 14
4-{[(5-Hydroxycarbamoyl-thiophene-2-carbonyl)-amino]-methyl}-benzoic acid methyl ester
In an analogolis manner to that described in the example 12, blit lising 2-carboxy-thiophen-5-carboxylic add methyl ester and methyl 4-(aminomethyl)- benzoate as starting material, 4-{ [(5-Hydroxycarbamoyl-thiophene-2-carbonyl)-amino] -methyl}-benzoic add methyl ester is prepared, mp.: 156-166oC.
Example 15
In an analogolis manner to that described in the example 1, and lising known methods as described in the literatlire (e.g. in standard works slich as Holiben-Weyl, -Methoden der Organischen Chemie, Georg Thieme Verlag-, Stlittgart; Organic Reactions, John Wiley & Sons, Inc., New York) the following compolinds are prepared and characterized with MS (APCI):
L 5-(4-benzhydryl-piperazine-l-carbonyl)-thiophene-2-carboxylic acid hydroxyamide
2. thiophene-2,5-dicarboxylic acid 2-beiizylamide 5-hydroxyamide
3. thiophene-2,5-dicarboxylic acid 2-hydroxyainide 5-[(3-methyl-blityl)-amide]
4. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-(phenethyl-aniide)
5. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-{[2-(4-methoxy-phenyl)-ethyl]-amide}
6. thiophene-2,5-dicarboxylic acid 2-(4-filioro-benzylamide) 5-hydroxyamide
7. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(l,2,3,4-tetrahydro-naphthalen-l-yl)-amide]
8. thiophene-2,5-dicarboxylic acid 2-(2-ethoxy-benzylamide) 5-hydroxyamide
9. thiophene-2,5-dicarboxylic acid 2-(2,4-difkuroro-benzylamide) 5-hydroxyamide

10. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-indan-l-ylamide
11. thiophene-2,5-dicarboxylic acid 2-[(benzo[l,3]dioxol-5-ylmethyl)-amide] 5-hydroxyamide
12. 5-(4-phenyl-pipera2ine-l-carbonyl)-thiophene-2-carboxylic add hydroxyamide
13. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(3-isopropoxy-propyl)-amide]
14. 5-(4-acetyl-piperazme-l-carbonyl)-thiophene-2-Carboxylic add hydroxyamide

15. thiophene-2,5-dicarboxylic acid 2-diblitylainide 5-hydroxyamide
16. 5-(4-benyyl-piperidine-l-carbonyl)-thiophene-2-carbox7lic acid hydroxyamide
17. thiophene-2,5-dicarboxylic acid 2-hydroxyaiiiide 5-[(pyridin-3-ylinethyl)-amide]
18. thiophene-2,5-dicarboxylic acid 2-cyclohexylamide 5-hydroxyainide
19. thiophene-2,5-dicarboxylic acid 2-cyclopropylamide 5-hydroxyamide
20. tliiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-{[2-(l-methyl-pyrrolidin-2-yl)-ethyl]-amide}
21. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-(2-methoxy-benzylamide)
22. thiophene-2,5-dicarboxylic acid 2-[(2-cydohex-l-enyl-ethyl)-amide] 5-hydroxyamide
23. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(2-morpholin-4-yl-ethyl)-amide]
24. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(2-methyIsidfanyl-ethyl)-amide]
25. thiophene-2,5-dicarboxylic acid 2-hydroxyamdde 5-[(tetrahydro-fliran-2-ylmethyl)-amide]
26- thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-phenylamide
27. 5-(morpholine-4-carbonyl)-thiophene-2-carboxyIic acid hydroxyamide
28. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(4-methoxy-phenyl)-amide]
29. 5-(pyrrolidine-l-carbonyl)-thiophene-2-carboxylic acid hydroxyamide
30. thiophene-2,5-dicarboxylic acid 2-[(4-ben2yloxy-phenyl)-amide] 5-hydroxyamide
31. thiophene-2,5-dicarboxylicacid 2 -[(4-chloro-phenyl)-amide] 5-hydroxyamide
32. thiophene-2,5-dicarboxylic acid 2-hydroxyamjde 5-[(4-iodo-phenyl)-amide]
33. thiopheae-2,5-dicarboxylic acid 2-[(3-ethyl-phenyl)-amide] 5-hydroxyamide
34. thiophene-2>5-dicarboxylic acid 2-[(4-ethyl-phenyl)-amide] 5-hydroxyamide
35. thiophene-2,5-dicarboxylic acid 2-[(3-chloro-phenyl)-amide] 5-hydroxyamide
36. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(3-iodo-phenyl)-amide]
37. 5-(l,4-dioxa-8-aza-spiro[4.5]decane-8-carbonyl)-thiophene-2-carboxylicacid hydroxyamide
38. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(3-morpholin-4-yl-propyl)-amide]

39. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-pentylamide
40. thiophene-2,5-dicarboxylic acid 2-[(2-diethylamino-ethyl)-amide] 5-hydroxyamide

41. tliiophene-2,5-dicarboxylic acid 2-heptylamide 5-hydroxyamide
42. tlliophene-2,5-dicarboxylic acid 2-hydroxyamide 5-(isoblityl-amide)
43. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-nonylamide
44. thiophene-2,5-dicarboxylic acid 2-hydroxyainide 5-[(l-phenyl-ethyl)-amide]
45. thiophene-2,5-dicarboxylic acid 2-[2-(4-fllioro-phenyl)-ethyl]-amide 5-hydroxyamide
46. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[2-(5-nitro-pyridin-2-ylamino)-ethyl] -amide
47. thiophene-2,5-dicarboxylic acid 2-hydioxyamide 5-(3-methyI-benzylamide)
48. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(2-p-tolyl-ethyl)-amide]
49. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[3-(2-oxo-pyrrolidin-l-yl)-propyl]-amide
50. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(2-piperidin-l-yl-ethyl)-amide]
51. thiophene-2,5-dicarboxylic acid 2-cycloblitylamide 5-hydroxyamide
52. thiophene-2,5-dicarboxylicacid 2-(2-fllioro-benzylamide) 5-hydroxyamide
53. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(2-phenyl-propyl)-amide]
54. thiophene-2,5-dicarboxylic acid 2-(2,3-dimethoxy-benzylamide) 5-hydroxyamide

55. thiophene-2,5-dicarboxylic acid 2-[(l-benzyl-piperidin-4-yl)-amide] 5-hydroxyamide
56. 4-[(5-hydroxycarbamoyl-thiophene-2-carbonyI)-amino]-piperidine-l-carboxylic acid ethyl ester
57. thiophene-2,5-dicarboxylic acid 2-[(3-dimethylamino-2,2-dimethyl-propyl)-amide] 5-hydroxyamide
58. thiophene-2,5-dicarboxylic acid 2-[(3-ethoxy-propyl)-amide] 5-hydroxyamide
59. thiophene-2,5-dicarboxylic acid 2-[(3-dimethylamino-propyl)-amide] 5-hydroxyamide
60. thiophene-2,5-dicarboxylic acid 2-[2-(2-chloro-phenyl)-ethyI]-amide 5-hydroxyamide
61. thiophene-2,5-dicarboxylic acid 2-hydroxyainide 5-(2-trifkuroromethyl-ben2ylamide)
62. thiophene-2,5-dicarboxylic acid 2-hydroxyainide 5-(3-trifkuroromethyl-benzylamide)
63. thiophene-2,5-dicarboxylic acid 2-(2,5-difkuroro-ben2ylamide) 5-hydroxyamide
64. thiophene-2,5-dicarboxylic acid 2-(2,6-difkuroro-benzylaimde) 5-hydroxyamide
65. thiophene-2,5-dicarboxylic acid 2-(3,4-difkuroro-benzylamide) 5-hydroxyamide

66. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(3-imidazol-l-yl-propyl)-amide]
67. thiophene-2,5-dicarboxylic acid 2-[(l-cyclohexyl-ethyl)-amide] 5-hydroxyamide
68. thiophene-2,5-dicarboxylic acid 2-[2-(3-chloro-phenyl)-ethyl] -amide 5-hydroxyamide
69. thiophene-2,5-dicarboxylic acid 2-[2-(3-fllioro-phenyl)-ethyl]-amide S-hydroxyamide
70. thiophene-2,5-dicarboxyIic acid 2-[2-(2,4-dichloro-phenyl)-ethyl]-amide 5-hydroxyamide
71. thiophene-2,5-dicarboxylic acid 2-cyclopropyhnethyl-amide 5-hydroxyamide
72. thiophene«2,5-dicarboxylic acid 2-[2-(2-fllioro-phenyl)-ethyl]-amide 5-hydroxyamide
73. thiophene-2,5-dicarboxylic acid 2-[(4-diethylainino-l-methyl-blityl)-amide] 5-hydroxyamide
74. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5- [(2-pyridin-2-yl-ethyl)-amide]
75. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(2-pyrrolidin-l-yl-ethyl)-amide]
76. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(l-methyl-hexyl)-amide]

77. thiophene-2,5-dicarboxylic acid 2-cycloheptylamide 5-hydroxyamide
78. thiophene-2,5-dicarboxylic acid 2-cyclopentylamide 5-hydroxyamide
79. thiophene-2,5-dicarboxylic acid 2-(2,4-dichloro-benzylamide) 5-hydroxyamide
80. thiophene-2,5-dicarboxylic acid 2-[(3-diethylamino-propyl)-amide] 5-hydroxyamide
81. thiophene-2,5-dicarboxylic acid 2-[(l,5-dimethyl-hexyl)-axnide] 5-hydtoxyamide
82. thiophene-2,5-dicarboxylic acid 2-[(2,2-diphenyl-ethyl)-amide] 5-hydroxyamide
83.3-[(5-hydroxycarbamoyl-thiophene-2-carbonyl)-amino]-blityric acid ethyl ester
84. thiophene-2,5-dicarboxylic acid 2-[(2-ethyl-hexyl)-amide] 5-hydroxyamide
85. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-(4-methoxy-benzylamide)
86. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-(4-methyl-benzylamide)
87. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(3-phenyl-propyl)-amide]
88. thiophene-2,5-dicarboxylic add 2-[(2-diisopropylamino-ethyl)-amide] 5-hydroxyamide

89. thiophene-2,5-dicarboxylic acid 2-liydroxyamide 5-[2-(4-nitro-phenyl)-ethyl]-
amide
90. thiopliene-2,5-dicarboxylic acid 2-[(3,3-diphenyl-propyl)-ainide]
5-hydroxyamide 91. thiopiiene-2,5-dicarboxylic acid2-(2-ainino-benzylamide) 5-hydroxyamide
92. Thiophene-2,5-dicarboxylic acid 2-(4-broino-benzylainide) S-hydroxyamide
93. Thiophene-2,5-dicarboxylic acid 2-(3,5-bis-trifkurorometbyl-benzylainide) S-hydroxyamide
94. Thiophene-2,5-dicarboxylicacid 2-(3-bromo-benzylaxnide) 5-hydroxyamide
95. Thiophene-2,5-dicarboxylicacid 2-(3-fllioro-benzylamide) 5-hydrox)^imide
96. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-(3-methoxy-ben2ylamide)
97. Thiophene-2,5-dicarboxylic acid 2-{2-chloro-6-filioro-beiizylamide) 5-hydroxyamide
98. Thiophene-2,5-dicarboxylicacid2-(4-tert-blityi-benzylamide) 5-hydroxyamide
99. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-{[2-(4-slilfamoyl-phenyl)-ethyl]-amide}

100. Thiophene-2,5-dicarboxylic add 2-[(2-ben2ylslilfanyl-ethyl)-amide] 5-hydroxyamide
101. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-{[2-(4-hydroxy-phenyl)-ethyl]-amide}
102. Thiophene-2,5-dicarboxylic acid 2-{[2-(4-chloro-phenyI)-ethyI]-amide} 5-hydroxyamide
103. Thiophene-2,5-dicarboxylic acid 2-( [2-(3,4-dimethoxy-phenyl)-ethyl] -amide} 5-hydroxyamide
104. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(2-phenoxy-ethyl)-amide]
105. Thiophene-2,5-dicarboxylic acid 2-hydroxyainide 5-[(4-phenyl-blityl)-amide]
106. Thiophene-2,5-dicarboxylic acid 2-[(3,4-dimethyl-phenyl)-amide] 5-hydroxyamide
107. 5-(4-Pyrimidin-2-yl-piperazine-l-carbonyl)-thiophene-2-carboxylic acid hydroxyamide

108. Thiophene-2,5-dicarboxyIic acid 2-[(3,4-dimethoxy-phenyl)-amide] 5-hydroxyamide
109. Thiophene-2,5-dicarboxylic acid 2-[(4-tert-blityl-phenyl)-amide] 5-hydroxyamide

110. Thiophene-2,5-dicarboxylic add 2-hydroxyaimde 5-[(4-methoxy-2-methyl-phenyl)-amide]
111. Thiophene-2,5-dicarboxylic add 2-[(4-dimethylamino-plienyl)-amide] 5-hydroxyamide
112. Tliiophene-2,5-dicarboxylic acid 2-hydroxyainide 5-[(4-plienoxy-phenyl)-amide]
113. Tliiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-p-tolylamide
114. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(4-piperidin-l-yl-phenyl)-amide]
115. l-(5-Hydroxycarbamoyl-tiiiophene-2-carbonyl)-piperidine-4-carboxylic acid methyl ester
116. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[methyl-(l-methyl-piperidin-4-yl)-amide]
117. Thiophene-2,5-dicarboxylic add 2-hydroxyamide 5-{methyl-[2-(4-nitro-phenyl)-ethyl] -amide}
118. Thiophene-2,5-dicarboxylic add 2-(blityl-methyl-araide) 5-hydroxyamide
119. Thiophene-2,5-dicarboxylic acid 2-diethylamide 5-hydroxyamide
120. Thiophene-2,5-dicaxboxylic acid 2-[(4-cydohexyl-phenyl)-amide] 5-hydroxyamide

121. Thiophene-2,5-dicaxboxylic acid 2-hydroxyamide 5-[methyl-(2-methylamino-ethyl)-amide]
122. Thiophene-2,5-dicarboxylic acid 2-[ethyl-(3-ethylamino-propyl)-amide] 5-hydroxyamide
123. 5-[4-(2-Morpholin-4-yl-2-oxo-ethyl)-piperazine-l-carbonyl]-thiophene-2-carboxylic acid hydroxyamide
124. 5-(4-Dimethylcarbamoylmethyl-piperazine-l-carbonyl)-thiophene-2-carboxylic add hydroxyamide
125. 5-[4-(2-Oxo-2-piperidin-l-yl-ethyl)-pipera2ine-l-carbonyl]-thiophene-2-carboxylic add hydroxyamide
126. Thiophene-2,5-dicarboxylic add 2-hydroxyamide 5-(3-trifkuroromethoxy-benzylamide)
127. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-(3-phenoxy-benzylamide)
128. Thiophene-2,5-dicarboxylic add 2-hydroxyamide 5-[(l-methyl-3-phenyl-propyl)-amide]
129. Thiophene-2,5-dicarboxy[ic acid 2-hydroxyamide 5-[(3-methoxy-propyl)-
amide]

130. Thiophene-2,5-dicarboxylic acid 2-(4-chloro-benzylainide) 5-hydroxyainide
131. Thiophene-2,5-dicarboxyIic acid 2-[(2-acetylamino-ethyl)-amide] 5-hydroxyamide
132. Thiophene-2,5-dicarboxylic acid 2--hydroxyamide 5-[(l-methyl-heptyl)-amide]
133. Thiophene-2,5-dicaxboxylic acid 2-hydroxyainide 5-[(l-inethyl-blityl)-amide]
134. Tiiiophene-2,5-dicarboxylic acid 2-allylamide 5-hydroxyaniide
135. Thiophene-2,5-dicarboxylic acid 2- [(l,3-dimethyl-blit7l)-amide] 5-hydroxyamide
136. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-propyIamide
137. Thiophene-2,5-dicarboxylic add 2-sec-blitylainide 5-hydroxyamide
138. Thiophene-2,5-dicarboxylic acid 2-blitylamide 5-hydroxyamide
139. Thiophene-2,5-dicarboxylic acid 2-(3,4-dichloro-benzylamide) 5-hydroxyamide
140. Thiophene-2,5-dicarboxylic acid 2-(2,3-dichloro-ben2ylamide) 5-hydroxyamide
141. thiophene-2,5-dicarboxylic acid 2-(2,3-difkuroro-benzylamide) 5-hydroxyamide
142. thiophene-2,5-dicarboxylic acid 2-(2-chloro-ben2ylamide) 5-hydroxyamide

143. thiophene-2,5-dicarboxyIic acid 2-(3,4-dimedioxy-beazylamide) 5-hydroxyamide
144. thiophene-2,5-dicarboxylic acid 2-(3,5-difkuroro-ben2ylamide) 5-hydroxyamide
145. thiophene-2,5-dicarboxylic acid 2-[(2-amino-phenyl)-amide] 5-hydroxyamide
146. thiophene-2,5-dicarboxylic acid 2-[4-(2-amino-phenylcarbamoyl)-benzylamide] 5-(benzyloxy-amide)

147. thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[methyl-(4-
trifkuroromethyl-benzyl)-amide
Example 16
In an analogolis manner to that described in the example 3, and lisliag known methods as described in the literatlire (e,g. in standard works slich as Holiben-Weyl, -Methoden der Organischen Chemie, Georg Thieme Verlag-, Stlittgart; Organic Reactions, John Wiley & Sons, Inc., New York) the following compoimds are prepared and characterized with MS (APCI):
148. 4-(4-benzhydryl-pipera2ine-l-carbonyl)-N-hydroxy-benzamide
149. N-hydroxy-N'-pyridin-3-ylmethyl-terephthalamide
150. N-benzyl-N'-hydroxy-terephthalamide
151. N-cyclohexyl-N'-hydroxy-terephthalamide
152. N-cyclopropyl-N'-hydroxy-terephthalamide
153. N-hexyl-N'-hydroxy-terephthalamide
154. N-hydroxy-N'-(3-methyl-blityl)-terephthalamide
155. N-hydroxy-N^-phenethyl-terephthalamide

156. N-hydroxy-N'-[2-(4-methoxy-phenyl)-ethyl]-terephthalaniide
157. N-(3-chloro-benzyl)-N'-hydroxy-terephthalainide
158. N-hydroxy-N'-(2-methoxy-benryl)-terephthalamide
159. N-(4-filiorO-benzyl)-N'hydroxy-terephthalamide
160. N-hydroxy-N'-(l,2,3,4-tetrahydro-naphthalen-l-yl)-terephthalaniide
161. N-hydroxy-N'-(4-trifkuroromethyl-benzyl)-terephthalamide
162. N-(2,4-difkuroro-benzyl)-N'-hydroxy-terephthalamide
163. N-hydroxy-N'-indan-1 -yl-terephthalamide
164. N-benzo[l,3]dioxol-5-ylmethyl-N'-hydroxy-terephthalamide
165. N-hydroxy-4-(4-phenyl-piperazine-l-carbonyl)-benzamide
166. N-(3,5-dimethyl-benzyl)-N^-hydroxy-terephthalamide
167. N-hydroxy-N'-(3-isopropoxy-propyl)-terephthalamide
168. 4-(4-acetyl-piperazine-l-carbonyl)-N-hydroxy-benzamide
169. N,N-diblityl-N'-hydroxy-terephthalamide
170. 4-(4-benzyl-piperidine-l-carbonyl)-N-hydroxy-benzamide
171. N-hydroxy-N'-[2-{l-methyl-pyrrolidin-2-yl)-ethyl]-terephthalamide
172. N-{2-ethoxy-benzyl)-N'-hydroxy-terephthalaniide
173. N-(2-cydohex-l-enyl-ethyl)-N'-hydroxy-terephthalamide

174. N-hydroxy-N'-(2-morpholin-4-yl-ethyi)-terephthalaniide
175. N-hydrox7-N'-(2-methyislilfanyl-ethyl)-terephthalamide
176. N-hydroxy-N'-(tetrahydro-fliran-2-ylmethyl)-terephthalamide
Example 17
Evalliation of effects on a hliman colon carninoma cell line of the compolinds of
the invention
MTT is widely lised for the qliantitative determination of cytotoxic effects or in vitro chemosensitivity of tlimor cells. The assay is based on the cleavage of the yellow tetrazolilim salt MTT to plirple formazan crystals by metabolic active cells. For details, see Rlibinstein, L.V., et al., J. Natl. Cancer Inst. 82 (1990) 1113-1118.
The following procedlire was performed: HT-29 cells (hliman colon carcinoma cell line) were cliltivated in RPM 1640, 2.5 % PCS, 2 mM Gllitamine, 100 li/ml Penicillin, 100 lig/ml Streptomycin. For the assay the cells were seeded in 384 well plates, 900 cells per well, in the same medilim The next day compolinds (dissolved 10 mM in DMSO) were added in variolis concentrations ranging from 30 liM to 1.5 nM. After 5 days the MTT assay was done mainly according to the instrlictions of the manlifactlirer (Cell proliferation kit I, MTT, fom Roche Moleclilar Biochemicals). In brief: MTT labeling reagent was added to a final concentration of 0.5 mg/ml, added and inclibated for 4 hrs at 37 C, 5% C02. Dliring this inclibation time plirple formazan crystals are formed. After addition of the sollibilization sollition (20% SDS in 0.02 M HCl) the plates were inclibated overnight at 37 C, 5% C02. After careflil mixing plates were measlired in Victor 2 (scanning mliltiweli spectrophotometer, Wallac) at 550 nm.
A decrease in nlimber of living cells reslilts in a decrease in the total metabolic activity in the sample. The decrease direcdy correlates to the amolint of plirple cololir reslilting from the sollibilization of the plirple formazan crystals. Determination of IC50 was done lising XL-fit.

Example 18 Tablet formlilation
Item Ingredients mg/Tablet
1 Compolind 2a 25 100
2 Anhydrolis Lactose 73 35
3 Croscarmellose 6 8 Sodilim
4 Povidone K30 5 6
5 Magnesilim Stearate 1 1
Total Weight 110 150
Compolind 2a is described in Example 2.
Procedlire:
1, Mix Items 1,2 and 3 in a sliitable mixer for 15 minlites.
2. Granlilate the powder mix from Step 1 with 20% Povidone K30 Sollition
(Item 4).

3. Dry the granlilation from Step 2 at 50oC.
4. Pass the granlilation from Step 3 throligh a sliitable milling eqliipment.
5. Add the Item 5 to the milled granlilation Step 4 and mix for 3 minlites.
6. Compress the granlilation from Step 5 on a sliitable press.
List of References
Cancer: Principles & Practice of Oncology, Vincent T. DeVita, Jr., Samliel Hellmann, Steven A. Rosenberg; 5th Ed., Lippincott-Raven Pliblishers 1997
Holiben-Weyl, -Methoden der Organischen Chemie, Georg Thieme Verlag-, Stlittgart; Organic Reactions, John Wiley 8c Sons, Inc., New York
Holiben-Weyl, Methoden der organischen Chemie, Vol. XV/1 and XV/2
Koyama, Y., et al.. Blood 96 (2000) 1490-1495
Marks, P.M., et al., J. Nati. Cancer Inst. 92 (2000) 1210-1216
Janda, M., et al., Org. Prep. and Proced. Int. 3 (6) (1971) 295-297
Rlibinstein, L.V., et al., J. Nati. Cancer Inst. 82 (1990) 1113-1118
liS 2,680,731
liS 5,369,108
WO 98/55449
Holba, v., et al., Z. Phys. Chem.(Leipzig) 262 (3) (1981) 445-448

Patent Claims 1. Compounds of formula I

denotes a phenyl ring which may be unsubstituted or substituted by 1, 2 or 3 substituents independently selected from a halogen atom, an (l-4C)alkyl-s trifluoromethyl-, hydroxy-, (l-4C)alkoxy-, nitro-, amino-, (1-4C)alkylamino-, di[(l-4C)alkyl]-amino-, (l-4C)alkanoylamino, a (1-3C)alkylenedioxy-group or an acyl group,

denotes or a thiophene ring which may be unsubstituted or substituted by 1 or 2 substituents independently selected from a halogen atom, an (1-4C)alkyl-, trifluoromethyl-, hydroxy-, (l-4C)alkoxy-, nitro-, amino-, (1-4C)alkylamino-, di[(l-4C)alkyl]-amino- or a (l-4C)alkanoylamino, a (1-3C)alkylenedioxy-group or an acyl group,
and
Rl and R2 are the same or different from each other and are

a hydrogen atom;
a branched or unbranched (l-14C)alkyl group which
may be unsubstituted or substituted with 1 or several substituents
independently selected from a halogen atom, hydroxy-, nitro-, amino group
or by a carbocydic group or by a heterocydic group,
and wherein at a chain length of larger than 2 atoms one or several non adjacent atoms may be replaced by oxygen, nitrogen or sulfur atoms,
and wherem 2 atoms may be bound together by a double or triple bond; a carbocydic group; or a heterocyclic group;
or Rl and R2 together with the nitrogen atom form a 3-6 membered ring which may contain additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and which may be annulated by a carbocydic group or by a heterocyclic group and which may be unsubstituted or substituted by 1, 2, or 3 substituents independently selected from a halogen atom, an {l-4C)alkyl-, trifluoromethyl-, hydroxy-, (l-4C)alkoxy-, aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy, (l-3C)alkylenedioxy-, nitro-, amino-, (l-4C)alkylamino-, di[(l-4C)alkyl]amino-, (l-4C)alkanoylamino- or an acyl-group;
their enantiomers, diastereoisomers, racemates and physiologically acceptable salts thereof.
2. Compounds of formula I according to claim 1 wherein

is thiophene, and R1 is hydrogen and R2 has the above given meaning.
3. Compounds of formula I according to claims 1 or 2 wherein R2 is benzyl or
substituted benzyl.

4. Compounds of formula I according to claim 1 wherein

is thiophene and R1 and R2 together with the nitrogen atom from a piperazin or piperidine ring which may be substituted by acetyl, benzhydryl or phenyl whereby the phenyl groups can be substituted.
5. Compounds of formula I according to daim 1 selected from the group
consisting of
Thiophene-2,5-dicarboxylic acid 2-hydroxyainide 5-[(naphthalen-l-
ylmethyl) -amide] Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-(4-trifluoromethyl-
ben2ylamide)
N-hydroxy-N'-naphthalen-l-ylmethyl-terephthal amide
Thiophene-2,5-dicarboxylic acid 2-(3-chloro-benzylamide) 5-hydroxyamide
Thiophene-2,5-dicarboxylic acid 2-(3,5-dimethyl-benzylamide)
5-hydroxyamide
Thiophene-2,5-dicarboxylic acid 2-hexylamide 5-hydroxyamide
Thiophene-2,5-dicarboxylic acid 2-[(l,5-dimethyl-hexyl)-amide]
5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-hydroxyaniide 5-[(2-phenoxy-ethyl)-
amide]
Thiophene-2,5-dicarboxylic acid 2-(3,5-dimethyl-benzylamide)
5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-(3,5-bis-trifluoromethyl-benzylamide)
5 -hydr oxyamide
Thiophene-2,5-dicarboxylic acid 2-(3-bromo-ben2ylaraide) 5-hydroxyamide
Thiophene-2,5-dicarboxylic acid 2-(4-tert-butyl-ben2ylamide)
5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-hydroxyainide 5-(4-trifluoromethyl-
benzylamide) Thiophene-2,5-dicarboxylic acid 2-(3-chloro-ben2ylamide) 5-hydroxyamide

Thiophene-2,5-dicarboxylic acid 2-[(3,3-diphenyl-propyl)-ainide]
5-hydioxyamide
Thiophene-2,5-dicarboxylic acid 2-(3,4-dichloro-benzylamide)
5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-hydroxyainide 5-[(l-phenyl-ethyl)-
amide] Thiophene-2,5-dicarboxylic acid 2-hydroxyainide 5-(3-trifluoromethyl-
benzylamide) Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(l-methyl-hexyl)-
amide] Thiophene-2,5-dicarboxylic acid 2-heptylamide 5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-hydroxyainide 5-[(4-phenyl-butyl)-
amide]
Thiophene-2,5-dicarboxylic add 2-benzylamide 5-hydroxyamide
Thiophene-2,5-dicarboxylic acid 2-hexylamide 5-hydroxyamide
Thiophene-2,5-dicarboxylic acid 2-(3-fluoro-benzylamide) 5-hydroxyamide
Thiophene-2,5-dicarboxy]ic acid 2-(2,4-difluoro-benzylamide)
5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-[(2-benzlsulfanyl-ethyl)-amide]
5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-(4-bromo-benzylamide) 5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-{[2-(4-hydroxy-phenyl)-
ethyl]-amide} Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-(4-methoxy-
ben2ylamide)
Thiophene-2,5-dicarboxylic acid 2-(2,3-dichloro-benzylamide)
5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-hydroxyamide 5-[(3-phenyl-propyl)-
amide]
Thiophene-2,5-dicarboxylic acid 2-(2,5-difluoro-ben2ylamide)
5-hydroxyamide Thiophene-2,5-dicarboxylic acid 2-(2-fluoro-benzylamide) 5-hydroxyamide Thiophene-2,5-dicarboxylic add 2-hydroxyamide 5-[(naphthalen-l-
ylmethyl)-amide]
Thiophene-2,5-dicarboxylic add 2-hydroxyamdde 5-(3-methyl-benzylamide)
Thiophene-2,5-dicarboxylic add 2-(2,6-difluoro-beii2ylaiiiide)
5-hydroxyamide.

6. Process of manufacturing compounds according to claims 1 to 5 by reacting a compound of formula III

wherein A has the meaning defined hereinbefore and R3 is (1-4C) alkyl group
with an amine of the formula HNR1R2 in the presence of an activating agent, wherein R1 and R2 have the meaning defined hereinbefore to give a compound of formula II

which is reacted with hydroxylamine in the presence of a suitable base,
whereafter the obtained compounds of formula I are converted in its enantiomers, diastereoisomers, racemates or physiologically acceptable salts.
7. Medicaments containing as active ingredients a compound of formula I
according to claims 1 to 5 in admixture with pharmaceutically acceptable
excipients or diluents.
8. Use of a compoimd according to claims 1 to 5 for the preparation of a
medicament having histone deacetylase (HDAC) inhibitor activity.
9. Use of a compound according to claim 8 as an inhibitor of cell proliferation.

16. A medicaments containing active ingredients substantially as herein described and exemplified.

Documents:

1981-chenp-2003-abstract.pdf

1981-chenp-2003-claims duplicate.pdf

1981-chenp-2003-claims original.pdf

1981-chenp-2003-correspondence others.pdf

1981-chenp-2003-correspondence po.pdf

1981-chenp-2003-description complete duplicate.pdf

1981-chenp-2003-description complete original.pdf

1981-chenp-2003-form 1.pdf

1981-chenp-2003-form 26.pdf

1981-chenp-2003-form 3.pdf

1981-chenp-2003-form 5.pdf

1981-chenp-2003-other documents.pdf

1981-chenp-2003-pct.pdf

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Patent Number

209789

Indian Patent Application Number

1981/CHENP/2003

PG Journal Number

50/2007

Publication Date

14-Dec-2007

Grant Date

06-Sep-2007

Date of Filing

11-Dec-2003

Name of Patentee

M/S. F. HOFFMAN-LA ROCHE AG

Applicant Address

124 Grenzacherstrasse, CH-4070 Basle,

Inventors:

#	Inventor's Name	Inventor's Address
1	LESER-REIFF, Ulrike	Weidenweg 6, 82377 Penzberg,
2	SATTELKAU, Tim	Renzstrasse 1, 68161 Mannheim,
3	ZIMMERMANN, Gerd	Rheinstrasse 9A, 76351 Linkenheim,

PCT International Classification Number

C07C 259/10

PCT International Application Number

PCT/EP2002/006488

PCT International Filing date

2002-06-13

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	01114496.1	2001-06-15	EUROPEAN UNION