MXPA00008762A - Cytostatic agents - Google Patents

Abstract

2(R or S)-[2R-(S-Hydroxy-hydroxycarbamoyl- methyl)-4-methyl-pentanoylamine]-2- phenyl-ethanoic acid cyclopentyl ester;2(R or S)-(3S-Hydroxycarbamoyl-2R-isobutyl- hex-5-enoylamino)-2-phenylethanoic acid isopropyl ester;2(R or S)-[2R-(S-Hydroxycarbamoyl-methoxy- methyl)-4-methyl-pentanoylamino]-3- phenylethanoic acid cyclopentyl ester;2(R or S)-(3S-Hydroxycarbamoyl-2R-isobutyl-hex- 5-enoylamino)-2-(4- methoxyphenyl)ethanoic acid cyclopentyl ester;2(R or S)-(3S-Hydroxycarbamoyl-2R-isobutyl- hex-5-enoylamino)-2- (thien-2-yl)ethanoic acid cyclopentyl ester;and 2(R or S)-(3S-Hydroxycarbamoyl- 2R-isobutyl-hex- 5-enoylamino)-2-(thien-3-yl)ethanoic acid cyclopentyl ester are cytostatic agents.

Description

CITOSTATIC AGENTS Field of the Invention The present invention relates to therapeutically active esters and thioesters, to processes for their preparation, to pharmaceutical compositions containing them, and to the use of such compounds in medicine. In particular, the compounds are inhibitors of the proliferation of a range of rapidly dividing tumorigenic cells, for example melanoma cells and / or lymphoma.

Background of the Invention International patent application No. PCT / GB97 / 02398 of the same applicant describes and claims a method for the inhibition of the proliferation of tumorigenic cells in mammals, which comprises administering to the mammal suffering such proliferation an amount of a compound of the general formula (I) or a hydrate or solvate of the pharmaceutically acceptable salt thereof, sufficient to inhibit such proliferation: Ref. 122859 where R is hydrogen or alkyl with (C? -C6); Ri is hydrogen; alkyl with (Ci-Ce); alkenyl with (C2-C6); phenyl or substituted phenyl; phenyl alkyl with (C? -C6) or phenyl alkyl with (C? -C6) substituted; phenyl alkenyl with (C2-C6) or alkenyl with (C2-C6) substituted; heterocyclyl or substituted heterocyclyl; heterocyclyl alkyl with (C? -C6) or heterocyclyl alkyl with (Ci-Ce) substituted; a group BSOrA- wherein is O, lo 2 and B is hydrogen or an alkyl with (C? -C6), phenyl, substituted phenyl, heterocyclyl, substituted heterocyclyl, acyl with (C? -C6), phenacyl or a phenacyl group substituted, and A represents alkenyl with (Ci-Cß); hydroxy or alkoxy with (Ci-Cß) amino, protected amino, acylamino, alkylamino with (Ci-Cß) or dialkylamino with (Ci-Cß); mercapto or alkylthio with (C? -C6); amino-alkyl with (C? -C6), alkylamino with (Ci-C?) alkyl with (C? -C6), dialkylamino with (Ci-Ce) alkyl with (Ci-C?), hydroxy alkyl with (Ci-C?), mercapto alkyl with (C? -C6) or carboxy alkyl with (Ci-Cß) wherein the amino, hydroxy, mercapto or carboxyl group is protected or the carboxyl group amidated; lower alkyl substituted by carbamoyl, mono (lower alkyl) carbamoyl, di (lower alkyl) carbamoyl, di (lower alkyl) amino, or carboxy-lower alkanoylamino; or a cycloalkyl, cycloalkenyl or a non-aromatic heterocyclic ring containing up to 3 heteroatoms, any of which may be (i) substituted by one or more substituents selected from alkyl with (Ci-Ce), alkenyl with (C2-Ce), halo , cyano (-CN), -C02H, -C02R, -CONH2, -COHNR, -CON (R) 2, -OH, -OR, oxo-, -SH, -SR, -NHCOR, and -NHC02R wherein R is alkyl with (Ci-Ce) or benzyl and / or (ii) fused to a cycloalkyl or heterocyclic ring; is an alkyl with (C? -C? 2), alkenyl with (C2-C2), alkynyl with (C2-C? 2), phenyl (alkyl with (C? -C6)) -, heteroaryl (alkyl with (Ci -Cß)) -, phenyl (alkenyl with (C2-C6)) -, heteroaryl (alkenyl with (C2-C6)) -, phenyl (alkynyl with (C2-C6)) -, heteroaryl (alkynyl with (C2-C6) )) -, cycloalkyl (alkyl with (C? -C6)) -, cycloalkyl (alkenyl with (C2-C6)) -, cycloalkyl (alkynyl with (C2-C6)) -, cycloalkenyl (alkyl with (Ci-Cß) ) -, cycloalkenyl (alkenyl with (C2-C6)) -, cycloalkenyl (alkynyl with (C2-C6)) -, phenyl (alkyl with (C? -C6)) O (alkyl with (C? -C6)) - , or a heteroaryl group (alkyl with (Ci-Ce)) 0 (alkyl with any of which may be optionally substituted by alkyl with (C? -C6), alkoxy with (Ci-C?), halo, cyano (-CN) ), phenyl, or phenyl substituted by alkyl with (C? -C6), alkoxy with (C? -C6), halo, or cyano (-CN); R3 is the characterization group of a natural or non-natural amino acid in which any functional groups can be protected; Y R 4 is an ester or thioester group, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Brief Description of the Invention This invention relates to certain specific compounds which are inhibitors of the proliferation of tumorigenic cells in mammals. The compounds in question are not specifically described in PCT / GB97 / 02398, and have valuable pharmacokinetic and pharmacological properties such as inhibitors of tumorigenic cells.

Detailed description of the invention _ _ , According to the present invention there is provided a compound selected from the group consisting of: cyclopentyl ester of acid 2 (R or S) - [2R- (S-hydroxy-hydroxycarbamoyl-methyl) -4-methyl-pentanoylamine] -2-phenyl-ethanoic acid, 2 (R or S) - (3S-hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino) -2-phenylethanoic acid isopropyl ester, cyclopentyl ester of acid 2 (R or S) - [2R- (S-hydroxycarbamoyl- methoxy-methyl) -4-methyl-pentanoylamino] -3-phenylethanoic, 2 (R or S) - (3S-hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino) -2- (4-methoxyphenyl) ethanoic acid cyclopentyl ester, 2 (R or S) - (3S-hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino) -2- (thien-2-yl) ethanoic acid cyclopentyl ester, 2 (R or S) - (3S-hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino) -2- (thien-3-yl) ethanoic acid cyclopentyl ester, and the salts, hydrates or solvates thereof pharmaceutically or veterinarily acceptable.

The 2-S diastereomers of the above compounds are preferred. The salts of the compounds of the invention include the physiologically acceptable acid addition salts, for example hydrochlorides, hydrobromides, sulfates, methane sulfonates, p-toluenesulfonates, phosphates, acetates, citrates, succinates, lactates, tartrates, fumarates and maleates. The salts can also be formed with bases, for example the sodium, potassium, magnesium, and calcium salts. In another of its aspects, the invention comprises a method for inhibiting the proliferation of tumorigenic cells in mammals, which comprises administering to the mem- orient suffering from such proliferation an amount of a compound specified above or a pharmaceutically acceptable salt, hydrate or solvate thereof. or veterinary entity, sufficient to inhibit such proliferation. In another aspect, the invention comprises the use of a compound specified above or a pharmaceutically or veterinarily acceptable salt, hydrate or solvate thereof, in the manufacture of a composition for inhibiting the proliferation of tumorigenic cells in mammals. The compounds of the invention are useful in human or veterinary medicine since they are active as inhibitors of the proliferation of cancer cells. The utility of the invention therefore lies in the treatment of cancers, such as those caused by the overproliferation of lymphoma cells, leukemia, myeloma, adenocarcinoma, carcinoma, mesothelioma, teratocarcinoma, choriocarcinoma, small cell carcinoma, large cell carcinoma, melanoma, retinoblastoma, fibrosarcoma, leiomyosarcoma, glioblastoma or endothelioma. It will be understood that different compounds of the invention will have different potencies as inhibitors of proliferation depending on the type of cancer being treated. The activity of any particular compound of the invention in inhibiting the proliferation of any particular cell type can be routinely determined by standard methods, for example analogous to those described in the Biological Example here. In a further aspect of the invention there is provided a pharmaceutical or veterinary composition comprising a compound of the invention, together with a pharmaceutically or veterinarily acceptable excipient or carrier. One or more compounds of the invention may be present in the composition together with one or more excipients or carriers. Orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in the unit dosage form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; a lubricant for tableting, for example magnesium stearate, talc, polyethylene glycol or silica, disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulfate. The tablets can be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooletate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerin, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional coloring or flavoring agents. . For topical application to the skin, the drug may be composed of a cream, lotion or ointment. The cream or ointment formulations which can be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutical substances such as the British Pharmacopoeia. The active ingredients can also be administered parenterally in a sterile medium. Depending on the vehicle and the concentration used, the drug can be either suspended or dissolved in the vehicle. Advantageously, adjuvants such as a local anesthetic, preservatives and buffering agents can be dissolved in the vehicle. 'It will be understood that the level of the specific dose for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, the route of administration, the rate of excretion, the combination of drugs and the severity of the particular disease that the therapy is experiencing.

The compounds of the invention (Examples 1-6) were prepared using procedures similar to those described in Examples 8, 16, 3, and 41 of the international patent application PCT / GB97 / 02398 of the same applicant. These Examples are reproduced below as Preparative Examples A-D respectively. The products obtained as mixtures of the diastereoisomers were separated by reverse phase HPLC. In the Examples, the following abbreviations have been used: DCM - Dichloromethane DMF - N, N - Dimethylformamide NMM - N - Methylmorpholine TFA - Trifluoroacetic acid HOBT - 1 - Hydroxybenzotriazole The column chromatography was carried out with silica gel of instantaneous degree of operation. The 1 H-NMR and 13 C-NMR were recorded on a Bruker AC 250E spectrometer at 250.1 and 62.9 MHz respectively. CDC13 methanol-d4 and dimethylsulfoxide-d6 (DMSO-de) were used as solvents and internal reference and spectra are reported as d ppm from TMS.

Preparatory Example A 2S- [2R- (S-hydroxy-hydroxycarbamoyl-methyl) -4-methyl-pentanoylamine] -3-phenylpropionic acid isopropyl ester [a) 2S- [2R- (2, 2-Dimethyl-5-oxo- [1,3] -dioxolan-4S-yl) -4-methyl-pentanoylamino] -3-phenylpropionic acid isopropyl ester.

A solution of 2-p- (2,2-dimethyl-5-oxo- [1,3-dioxolan-4S-yl) -4-methyl-pentanoic acid pentafluorophenyl ester (WO 95/19956) (2.87 g, 7.3 mmol) and isopropyl ester of L-phenylalanine (1.5 g, 7.3 mmol) in DCM was allowed to stand at room temperature for 96 hours. The reaction mixture is diluted with DCM and washed with aqueous sodium carbonate, IM hydrochloric acid and brine before drying over magnesium sulfate, filtering and concentration under reduced pressure. The product was recrystallized from ethyl acetate / hexane to give the isopropyl ester of 2S- [2R- (2, 2-Dimethyl-5-oxo- [1, 3] -dioxolan-4S-yl) -4- methyl-pentanoylamino] -3-phenylpropionic acid as fine white needles (810 mg, 29%). (b) 2S- [2R- (S-hydroxy-hydroxycarbamoyl-methyl) -4-methyl-pentanoylamine] -3-phenylpropionic acid isopropyl ester A solution of the sodium methoxide (325 mg, 6.1 mmol) and hydroxylamine hydrochloride (396 mg, 6.1 mmol) in methanol (15 mL) is stirred at room temperature for 2 hours. The solution is then filtered into a solution of 2S- [2R- (2, 2-dimethyl-5-oxo- [1, 3] -dioxolan-4S-yl) -4-methyl-pentanoylamino] -3 isopropyl ester. phenylpropionic acid (800 mg, 2.1 mmol) in methanol (10 ml). The reaction is allowed to stand at room temperature for 18 hours. The reaction mixture is concentrated under reduced pressure and the residue is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Recrystallization from ethyl acetate gave the 2S- [2R- (S-hydroxy-hydroxycarbamoyl-methyl) -4-methyl-pentanoylamine] -3-phenylpropionic acid isopropyl ester as a white crystalline material which was dried under vacuum (465 mg, 58%).

Preparatory Example B 2S- [2R- (S-hydroxycarbamoyl-methoxy-methyl) -4-methylpentamoylamino] -3-phenylpropionic acid isopropyl ester. (a) 2R- (S-Benzoyloxycarbamoyl-methoxy-methyl) -4-methylpentanoic acid.

A solution of 3R-isobutyl-4S-methoxy-dihydrofuran-2,5-dione (WO 97/02239) (609 mg, 3.27 mmole), and O-benzylhydroxylamine (403 mg, 3.27 mmole) in ethyl acetate (5%). mi) is stirred at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure to provide 2R- (S-benzoyloxycarbamoyl-methoxy-methyl) -4-methyl-pentanoic acid as a white foam (1.01 g, 100%). b) 2S- [2R- (S-benzoyloxycarbamoyl-methoxy-methyl) -4-methyl-pentanoylamino] -3-phenyl-propionic acid isopropyl ester.

A solution of 2R- (S-benzoyloxycarbamoyl-methoxy-methyl) -4-methyl-pentanoic acid (1.01 g, 3.3 mmol) in tetrahydrofuran (15 ml) at 0 ° C is treated with the isopropyl ester of L-phenylalanine ( 810 mg3.9 mmoles) and N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (750 mg, 3.9 mmol). The reaction mixture is allowed to warm to room temperature and is stirred for 18 hours. The solution is concentrated under reduced pressure and the residue is received in DCM. This solution is washed with 1M hydrochloric acid, saturated sodium hydrogen carbonate and brine. The organic phase is dried with sodium sulfate, filtered and concentrated under reduced pressure. The product is purified by column chromatography, eluting with 2% methanol / DCM. The fractions containing the product were combined and concentrated under reduced pressure to provide the isopropyl ester of 2S- [2R- (S-benzoyloxycarbamoyl-methoxy-methyl) -4-methyl-pentanoylamino] -3-phenyl-propionic ester as a solid. white (1.39 g, 85%). (c) 2S- [2R- (S-Hydroxycarbamoyl-methoxy-methyl) -4-methyl-pentanoylamino] -3-phenyl-propionic acid isopropyl ester A solution of the isopropyl ester of 2S- [2R- (S-benzoyloxycarbamoyl-methoxy-methyl) -4-methyl-pentanoylamino] -3-phenyl-propionic acid (1.37 g, 2.8 mmol) in ethanol (30 ml) is treated with a palladium catalyst (274 mg, 10% Pd / carbon) as a suspension in ethyl acetate (5 ml). The hydrogen gas is passed through the suspension for 2 hours. The reaction mixture is filtered and concentrated under reduced pressure. The product was recrystallized from ethyl acetate / hexane to give the isopropyl ester of 2S- [2R- (S-hydroxycarbamoyl-methoxy-methyl) -4-methyl-pentanoylamino] -3-phenyl-propionic acid (778 mg, 70%).

Preparatory Example C 2S- (3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino) -3-phenylpropionic acid isopropyl ester (a) 2S- (3S-tert-Butoxycarbonyl-2R-isobutyl-hex-5-enoylamino) -3-phenylpropionic acid isopropyl ester.

A solution of the isopropyl ester of L-phenylalanine (3.9 g, 18.8 mmol) in DMF (15 ml) is cooled in an ice-water bath and treated with the pentafluorophenyl ester of 3S-tert-butoxycarbonyl-2R-isobutyl -hex-5-enóico (9.03 g, 20.7 'mmoles). The reaction is allowed to warm to room temperature and is stirred overnight. The reaction mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate and washed with 1M hydrochloric acid, sodium carbonate and brine. The solution is dried over sodium sulfate, filtered and concentrated under reduced pressure. The product is purified by column chromatography using gradient elution of 100% DCM 10% methanol / DCM. The fractions containing the product were combined and the solvent removed to give the isopropyl ester of 2S- (3S-tert-butoxycarbonyl-2R-isobutyl-hex-5-enoylamino) -3-phenylpropionic acid as a yellow solid (3.5 g, 41%). (b) 2S- (3S-Hydroxycarbonyl-2R-isobutyl-hex-5-enoylamino) -3-phenylpropionic acid isopropyl ester A solution of the isopropyl ester of 2S- (3S-tert-butoxycarbonyl-2R-is-butyl-hex-5-enoylamino) -3-phenylpropionic acid ester (3.5 g, 7.6 mmol) in a mixture of TFA and DCM (1: 1, 10 mi) is allowed to sit at 5 ° C overnight. The reaction mixture is concentrated under reduced pressure. Addition of the ether to the residue gave the isopropyl ester of 2S- (3S-hydroxycarbonyl-2R-isobutyl-hex-5-enoylannino) -3-phenylpropionic acid as a white solid (261 mg, 8%). (c) 2S- (3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino) -3-phenylpropionic acid isopropyl ester A solution of 2S- (3S-hydroxycarbonyl-2R-isobutyl-hex-5-enoylamino) -3-phenylpropionic acid isopropyl ester (260 mg, 0.64 mmol) in DMF (10 ml) is cooled in an ice water bath . The N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (148 mg, 0.77 mmol) and HOBT (104 mg, 0.77 mmol) are added with stirring. The reaction is allowed to warm to room temperature and after 2 hours a solution of hydroxylamine hydrochloride (67 mg, 0.96 mmol) and NMM (0.1 mL, 0.96 mmol) in DMF (5 mL) is added. After stirring overnight the reaction mixture is concentrated under reduced pressure and the product is purified by chromatography on acid washed silica using 5-10% methanol in DCM. Recrystallization from ethyl acetate / hexane gave the isopropyl ester of 2S- (3S-hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino) -3-phen-1-propionic acid as a white solid (12 mg, 4%) .

Preparatory Example D 2S- (3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino) -2-phenylethanoic acid cyclopentyl ester The title compound was prepared using a route analogous to that described for Preparative Example C using the cyclopentyl ester of L-phenylglycine in place of the isopropyl ester of L-phenylalanine.

Example 1 2- [2R- (S-hydroxy-hydroxycarbamoyl-methyl) -4-methyl-pentanoylamine] -2-phenyl-ethanoic acid cyclopentyl ester Prepared using procedures similar to those described in Preparative Example A using the cyclopentyl ester of phenylglycine.

Diastereoisomer A: Hí-NMR; d (MeOD), 7.4-7.29 (5H, m), 5.43 (1H, s), 5.2-5.14 (1H, m), 4.02 (1H, d, J = 6.9Hz), 2.94-2.85 (1H, m) , 1.91-1.34 (10H, ma), 1.25-1.14 (1H, m) and 0.86 (6H, dd, J = 6.5, 11.5Hz). 13C- EMN; 5 (MeOD). 175.6, 171.8, 171.4. 137.8, 129.8, 129.4. 128.6. 80.0, 73.2. 58. 5, 49.2, 39.1, 33.3. 33.3, 26.8, 24.5, 24.4, 23.7 and 22.1.

Diastereoisomer B XH-NMR; d (MeOD), 7.33-7.19 (5H, m), 5.3 (1H, s), 5.11-5.06 (1H, m), 3.81 (1H, d, J = 7.3Hz), 2.83-2.74 (1H, m) , 1.83-1.45 (1OH, ma), 1.12-1.03 (1H, m) and 0.88-0.81 (6H, dd, J = 6.4, 12.3Hz). 3C- NMR; d (MeOD), 175.8, 171.8.171.5.137.3, 129.8, 129.5, 128.8, 79.9, 73.3.58.7, 48.9, 39.2, 33.3, 33.3, 26.7, 24.5, 24.5, 24.0 7 22.2.

Example 2 2- (3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino) -2-phenylethanoic acid isopropyl ester Prepared using methods similar to those described in Preparative Example D, using the isopropyl ester of phenylglycine.

Diastereoisó ero A -H-RMN; d (MeOD), 7.34-7.24 (5H, m), 5.59-5.42 (1H, m), 5.36 (1H, s), 5.02-4.77 (3H, m), 2.63-2.53 (1H, m), 2.17- 2.02 (2H, m), 1.89-1.78 (1H, m), 1.63-1.45 (2H, m), 1.18 (3H, d, J = 6.3Hz), 1.05 (3H, d, J = 6.2Hz), 1.00 -0.93 (1H, m), 0.88 (3H, d, J = 6.5Hz) and 0.81 (3H, D.J = 6.5Hz). 13C- NMR; d (MeOD), 176.2, 172.4, 171.3. 137.6, 136.0, 129.9, 129.6, 129.0.117.4.70.5.58.7.47.4, 41.5, 36.0. 26.7.24.5. 21.9.21.7 and 21.7.

Diastereoisomer B ^ -RMN; d (MeOD), 7.4-7.34 (5H, m), 5.77-5.61 (1H, m), 5.42 (1H, s), 5.1-4.98 (3H.m), 2.7-2.6 (1H, m), 2.44- 2.17 (3H, m), 1.61-1.5 (1H, m), 1.42-1.29 (1H, m), 1.25 (3H, d, J = 6.3Hz), 1.13 (3H, d, J = 6.2Hz), 1.09 -1.00 (1H, m) and 0.81 (6H, d.J = 6.4H?). 13C-NMR; d (MeOD), 176.4, 172.5, 171.5.137.2, 136.4, 129.9, 129.6, 129.0, 117.5.70.5, 58.8.48.4.47.4.41.3.36.0.27.1,24.3.21.9.21.8 and 21.6.

Example 3 Cyclopentyl ester of 2- [2R- (S-hydroxycarbamoyl-methoxy-methyl) -4-methyl-pentanoylamino] -3-phenylethanoic acid ester Prepared using methods similar to those described in Preparative Example B, using the cyclopentyl ester of phenylglycine.

Diastereoisomer A ^ -RMN; d (MeOD), 8.83 (1H, d, J = 6.6Hz), 7.48-7.29 (5H, m), 5.44-5.42 (1H, m), 5.20-5.16 (1H, m), 3.53 (1H, d, J = 9.7Hz), 3.17 (3H, s), 2.89-2.79 (1H, m), 1.90-1.54 (1 OH,? A), 1.06-0.99 (1 H, m), 0.95 (3H, d, J = 6.5Hz) and 0.90 (3H, d, J = 6.4Hz). 13C- NMR; d (MeOD), 175.3, 171.6, 169.4, 137.5, 129.7, 129.4.128.7, 83.1, 79.9, 58.7.58.1,48.5,38.4,33.4.33.3,26,7,24,6,24,5,24.3 and 21.8.

Diastereoisomer B ^ H-NMR; d (MeOD), 7.39-7.30 (5H.m), 5.45 (1H, s) .5.21-5.15 (1H.m), 3.59 (1H. d, J = 9.4Hz), 3.29 (3H.s), 2.89 -2.79 (1H, m) .1.93-1.49 (9H, ma), 1.42-1.21 (1H.m), 1.01 (1H, ddd.J = 3.7, 9.9, 13.3Hz) .0.83 (3H, d, J = 6.5Hz) and 0.79 (3H.D, J = 6.6Hz), 3C- NMR; d (MeOD), 175.1, 171.5, 169.5, 137.9, 129.7, 129.4, 128.7, 83.0.79.8. 58.5.58.3,48.6,38.5,33.3,27.8,24.5.24.4.24.1 and 21.7.

Example 4 Cyclopentyl ester of 2- (3S-hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino) -2- (4-methoxyphenyl) ethanoic acid Prepared using methods similar to those described in Preparative Example D, using the cyclopentyl ester of 4-methoxyphenylglycine.

Diastereoisomer A i H-NMR; d (MeOD), 8.94 (1H, d, J = 6.4Hz), 7.32 (2H, d, J = 8.7Hz), 6.93 (2H, d, J = 8.7Hz), 5.67-5.50 (1H, m), 5.36-5.33 (1H,), 5.20-5.14 (1H, m), 4.93 ^ .87 (2H, m), 3.79 (3H, s), 2.68-2.59 (1H, m), 2.24-2.09 (2H, m ), 1.97-1.55 (11H, ma), 1.11-1.00 (1H, m), 0.95 (3H.dJ = 6.5Hz) and 0.88 (3H.d, J = 6.5Hz). , 3C-RN; d (MeOD), 176.2, 172.4.171.9, 161.4.136.0, 130.2.129.4.117.4.115.2, 79.7, 58.2, 55.8.48.3,47.3, 41.5,36.0,33.4,33.3,26,7,24.6, 24.5 and 21.7.

Diastereoisomer B XH-NMR; d (MeOD), 8.96 (1H, d, J = 6.7Hz), 7.29 (2H.D.J = 8.7Hz), 6.93 (2H.D.J = 8.7Hz), 5.77-5.61 (1H, m), 5.32 (1H. S) .5.20-5.15 (1H. Rp) .5.09-4.97 (2H, m). 3.80 (3H. S), 2.64 (1H, di, J = 3.3, 1.4.13.5Hz), 2.43-2.16 (3H, m), 1.91-1.49 (9H, ma), 1.42-1.29 (1H, m), 1.05 (1H, ddd, J = 3.3, 10.1.13.2Hz) and 0.81 (6H, d, J = 65Hz), 3C- NMR; d (MeOD), 176.3, 172.5, 172.0, 161.4, 136.4, 130.2, 129.0, 117.5, 115.2, 79.8, 58.2, 55.8, 48.4, 47.4, 41.3, 36.1, 33.4, 27.1, 24.5, 24.3 and 21.6.

Example 5 Cyclopentyl ester of 2- (3S-hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino) -2- (thien-2-yl) ethanolic acid Prepared using methods similar to those described in Preparative Example D, using the thien-2-ylglycine cyclopentyl ester.

Diastereoisomer A ^ -RMN; d (MeOD), 7.41 (1H, dd, J = 5.1, 1.2Hz). 7.12 (1H, d = 3.5Hz), 7.01 (1H, dd, J = 5.1, 3.5Hz), 5.72 (1H, s), 5.69-5.52 (1H, m), 5.26-5.18 (1H, m ), 5.00-4.89 (2H, m), 2.70-2.59 (1 H, m), 2.28-2.13 (2H, m), 2.09-1.50 (11 H, m), 1.05 (1 H, ddd, J = 13.8, 11.0, 2.9Hz), 0.93 (3H, d, J = 6.4Hz) and 0.87 (3H, d, J = 6.5Hz). 13C- NMR; d (MeOD), 176.5, 172.7, 171.1, 139.5. 136.4, 128.4, 128.3, 127.7, 117.9, 80.7, 54.1, 48. 7, 47.7, 41.9, 36.5, 33.8, 33.7, 27.2, 25.1, 25.0, 24.9, and 22.1.

Diastereoisomer B ^ -RMN; d (MeOD) .7.42 (1H, dd, J = 5.0, 0.7Hz), 7.10 (1H, d.J = 3.6Hz), 7.01 (1H, dd, J = 5.0, 3.6Hz), 5.79-5.59 (2H , m), 5.28-5.19 (1H, m), 5.10-4.94 (2H, m). 2.71-2.59 (1H.m), 2.36-2.16 (3H.m) .1.97-1.34 (10H, m), 1.13-1.00 (1H, m), 0.86 (3H, d, J = 6.2Hz) and 0.84 ( 3H, d.J = 6.3Hz). 3C- NMR; d (MeOD), 176.7, 172.8, 171.2, 139.3, 136.7, 128.3.128.2, 127.6, 117.9.80.7.54.2.48.8,47.8,41.7,36.4, 33.8.27.5,25.1,25.0,24.8 and 22.1.

Example 6 Cyclopentyl ester of 2- (3S-hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino) -2- (thien-3-yl) ethanoic acid Prepared using methods similar to those described in Preparative Example D, using the cyclopentyl ester of thien-3-ylglycine.

Diastereoisomer A XH-NMR; d (MeOD), 7.48-7.42 (2H, m), 7.13 (1H, dd, J = 4.2, 2.0Hz) .5.69-5.52 (2H, m), 5.21-5.16 (1H, m), 4.98-4.90 ( 2H, m), 2.71-2.59 (1H, m), 2.28-2.11 (2H.m), 2.00-1.50 (11H, m), 1.12-0.98 (1H, m), 0.94 (3H, d, J = 6.4 Hz) and 0.88 (3H.D. J = 6.5Hz). 13C- NMR; d (MeOD), 176.6.172.8.171.8, 137.8, 136.4.128.3, 128.0, 125.2,117.9,80.3,54.6,41.9,36.5,33.8, 33.8,27.1,25.0,24.9 and 22.1.

Diastereoisomer B XH-NMR; d (MeOD), 7.45 (1H, dd, J = 4.9, 3.0Hz), 7.43-7.40 (1H, m), 7.12 (1H, dd, J = 5.0, 1.3Hz), 5.68 (1H, ddt, J = 17.0, 10.1, 6.8Hz), 5.53 (1H, s), 5.23-5.17 (1H, m), 5.10-4.96 (2H, m), 2.70-2.60 (1H, m), 2.41-2.16 (3H, m) , 1.94-1.49 (9H, m), 1.44-1.29 (1H, m) .1.05 (1H, ddd, J = 12.9.10.3, 3.3Hz), 0.84 (3H, d, J = 6.5Hz) and 0.83 (3H , d, J = 6.5Hz).

Biological Example . The compounds of Examples 1-6 were tested in the following cell proliferation assay, to determine their respective abilities to inhibit proliferation of the cell type in question.

A human cell line, especially a histiocytic lymphoma (U937), was seeded in 30 mm2 of tissue culture cavities, in the appropriate culture medium supplemented with 10% fetal bovine serum at a density of 250 cells / m2. Six hours later the test compounds were added in the same culture medium to the cells to give a final concentration of 6 μM. The control-cavities contained cells supplemented with the same culture medium containing the equivalent amount of the drug vehicle, which in this case was the DMSO at a final concentration of 0.08%. After 72 hours in the culture the cells were subjected to pulsations for 3 hours with [methyl-3 [H] thymidine] (2μCi / ml) and then they were collected on filter mats and the radioactivity associated with the DNA was counted. The results were expressed as percentage of incorporation of the control 3 [H] Thymidine (n = 6 + 1 standard deviation). Inhibition of proliferation was observed with all test compounds.

It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the contents of the following are claimed as property or property.

Claims (6)

1. A compound, characterized in that it is selected from the group consisting of: cyclopentyl ester of acid 2 (R or S) - [2R- (S-hydroxy-hydroxycarbamoyl-methyl) -4-methyl-pentanoylamine] -2-phenyl-ethanoic acid, 2 (R or S) - (3S-hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino) -2-phenylethanoic acid isopropyl ester, cyclopentyl ester of acid 2 (R or S) - [2R- (S-hydroxycarbamoyl-methoxy-methyl) -4-methyl-pentanoylamino] -3-phenylethanoic acid, 2 (R or S) - (3S-hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino) -2- (4-methoxyphenyl) ethanoic acid cyclopentyl ester, 2 (R or S) - (3S-hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino) -2- (thien-2-yl) ethanoic acid cyclopentyl ester, 2 (R or S) - (3S-hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino) -2- (thien-3-yl) ethanoic acid cyclopentyl ester, and the salts, hydrates or solvates thereof pharmaceutically or veterinarily acceptable.

2. A compound according to claim 1, characterized in that it is the 2-S diastereoisomer.

3. A pharmaceutical or veterinary composition, characterized in that it comprises a compound according to claim 1 or claim 2, together with a pharmaceutically or veterinarily acceptable carrier or excipient.

4. A method of inhibiting the proliferation of tumorigenic cells in mammals, characterized in that it comprises administering to the mammal suffering from such proliferation an amount of a compound as claimed in claim 1 or claim 2, sufficient to inhibit such proliferation.

5. A method according to claim 4, characterized in that the cell proliferation treated is the overproliferation of lymphoma cells, leukemia, myeloma, adenocarcinoma, carcinoma, mesothelioma, teratocarcinoma, choriocarcinoma, small cell carcinoma, large cell carcinoma, melanoma. , retinoblastoma, fibrosarcoma, leiomyosarcoma, glioblastoma or endothelioma.

6. The use of a compound according to claim 1 or claim 2 in the manufacture of a composition for inhibiting the proliferation of tumorigenic cells in mammals.