MXPA00001686A - 3-aryl-succinamido-hydroxamic acids, methods for producing said acids and medicaments containing the same - Google Patents

Abstract

The invention relates to compounds of formula (I), wherein R, R1, R5 and R6 have the meanings given in the Claims, their pharmaceutically suitable salts, esters, and derivatives which can be metabolised in vivo into compounds of formula (I), as well as the use of these compounds for producingmedicaments.

Description

ACIDS 3-ARIL-SUCCINAMIDO-HIDRQXAMICOS, PROCESSES FOR YOUR PRODUCTION AND PHARMACEUTICAL PREPARATIONS CONTAINING THOSE SUBSTANCES DESCRIPTION OF THE INVENTION The present application relates to inhibitors of the matrix metalloproteases. In particular it is related to 3-aryl-succinamido-hydroxamic acids. In the living tissue there is a balance between the synthesis and degradation of the extracellular matrix. The extracellular matrix is degraded mainly by proteases of the matrix metalloprotease family (MMP). Examples of members of this family are collagenases, stromelysins and gelatinases. In living tissue, this degradation is regulated by inhibition with TIMP (tissue inhibitor of metalloproteases). This balance between matrix metalloproteases and TIMP is distributed several diseases such as rheumatoid arthritis and osteoarthritis, multiple sclerosis, metastasis and tumor invasion, corneal ulcer, meningitis, cardiovascular diseases such as restenosis and arteriosclerosis, as well as the bones and the fools. Many examples show that an inhibition of these enzymes can have a positive influence on the clinical picture of these diseases (Beckett et al., 1996). REF .: 32774 The two gelatinases A (MMP-2) and B (MMP-9) seem to be the most important MMPs for metastasis and invasion. Selective inhibition of these two enzymes is desirable. The most developed active substance so far in this one, Marimastat, which is in clinical phase III, is active but exhibits important side effects, such as muscle pain. Marimastat in its current form is an inhibitor of broad spectrum MMP and consequently of MMPs such as MMP1, which are absolutely essential for tissue metabolism, are also inhibited. It is generally assumed that side effects are due to lack of specificity. It has now been found, surprisingly, that the new 3-aryl-succinamido-propionhydroxamic acids have a more favorable pharmacological profile than Marimastat. These substances differ inter alia from Marimastat by the substitution of an aryl at position 3 of the succinyl residue. The specificity with respect to gelatinases is considerably improved in the new compounds or, in addition, is now present for the first time, that is, it is possible to avoid the inhibition of MMP1 and other important enzymes. The present application relates to substances of general formula I To give an optimal inhibition of the gelatinases, the residues R and Rl of the compounds of the general formula I have a certain hydrophobicity. A suitable parameter for this is the clogP which can be determined with the "PCModels clogp3" of Daylight Chemical Information Systems Inc. (1993). The coefficients are based on Hansch, C. & Leo, A: Substituent Constants for Correlatiori Analysis in Chemistry and Biology. Wiley Interscience New York (1979), while the algorithm is based on the following quote: Chou, J. & Jurs, P., J. Chem. Inf. Comput. Sci. 19, 172 (1979). The fragments are introduced as complete molecules for calculation, that is, not as radicals or ions. To obtain the informative values of the clogP values for R are determined together with the neighboring phenyl ring (Ph-R fragments). The clogP values for the residue Rl are determined together with the carbonyl group and neighboring amino acids such as (CH) (NH2) CHR1 (fragments of a -carbonyl-RI).

Examples for Ph-R clogP = 4,030 3,648 4,240 And emplos for am ± nocarbonil-Rl: clogP = 0.370 -0.844 0.461 1.164 The clogP values for R in the form of Ph-R fragments in the compounds of the present invention are 2.0 to 6.0, preferably 2.5 to 5.0, particularly preferably 3.0 to 4.5. The values of clogP for Rl in the form of aminocarbonyl-Rl fragments in the compounds of the present invention are between -1.5 and 2.0, preferably between -1.2 and 1.5, particularly preferably between -1.0 and 1.2. The present application, therefore, relates to substances of general formula I wherein R is a Ph-R fragment having a clogP value between 2.0 and 6.0, preferably between 2.5 and 5.0 and particularly preferably between 3.0 and 4.5, Rl is an aminocarbonyl-RI fragment having a value of clogP between -1.5 and 2.0, preferably between -1.2 and 1.5 and particularly preferably between -1.0 and 1.2 and R5 denotes hydrogen or an alkyl residue of C? ~ C8 / R6 denotes hydrogen, a C alkyl? Optionally substituted C8 or a cycloalkyl, aryl, heteroaryl, aralkyl or optionally substituted monocyclic or bicyclic alkylheteroaryl residue, R5 and R6 together with the N atom denote a saturated or saturated 5-membered or 6-membered ring, which contains at least one additional heteroatom, the salts, esters and pharmacologically compatible derivatives thereof, which are metabolized in vivo to the compounds of the general formula I, as well as for the use of these compounds for the production of pharmaceutical preparations . The alternative subject matter of the present application can be represented as the compounds of the general formula I: wherein R denotes an optionally substituted C? -C8 alkyl, or a cycloalkyl, aryl, heteroaryl, aryolyl, heteroaryloxy, aralkyl, monocyclic or optionally substituted bicyclic residue, RI denotes an optionally substituted C? -C8 alkyl or an optionally substituted monocyclic or bicyclic alkyl cycloalkyl, aryl, heteroaryl, aralkyl or alkylheteroaryl residue, R5 denotes hydrogen or an alkyl residue of C? -C8 R6 denotes hydrogen, an optionally substituted C?-C8 alkyl or a cycloalkyl, aryl, heteroaryl, aralkyl or optionally substituted monocyclic or bicyclic alkylheteroaryl residue, or R5 and R6 together with the N atom denote a 5-membered or 6-membered ring. members, saturated, which contains at least one additional heteroatom, pharmaceutically compatible salts, esters and derivatives thereof which are metabolized in vivo in the compounds of the general formula I as well as the use of those compounds for the production of preparations Pharmaceutical The residues listed under R, Rl and R6 can, independently of one another, be optionally substituted once, twice or three times by halogen, hydroxy, thio, alkyl, C? -C8 cycloalkyl, cycloalkenyl, hydroxyalkyl, alkoxy, hydroxyalkoxy , chloroalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, nitro, carboxyl, carboxamido, alkoxycarbonyl, alkoxycarbonylalkyl, perfluoroalkyl or amino or aminocarbonyl optionally substituted once or twice by lower alkyl, nitrile, oxo or acyl. In this context halogen, hydroxy, oxo, thio, alkoxy, β-hydroxyalkoxy, β-chloroalkoxy, alkylthio, amino, aminocarbonyl, carboxyl and acyl groups are preferred. Particularly preferred are methyl, halogen and hydroxyl. If they are substituted, a single substitution is preferred. If not otherwise stated cycloalkyl denotes carbocycle or mono or polyunsaturated saturated heterocycle containing 3 to 8 structural atoms, preferably 5-7 structural atoms, which may be optionally interrupted once or several times by heteroatoms such as nitrogen, oxygen or sulfur and in particular denotes a residue of cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, thiamorpholinyl, piperidinyl, piperazinyl, tetrahydrofuryl or tetrahydropyranyl.

The alkyl residue in the aralkyl and the heteroalkyl in R, Rl, and R6 denotes independently of another, Ci or C2 alkyl. Acyl in the residues R, R1 and R6 denotes all the above acetyl groups. If not otherwise stated in the residues R, Rl and R6 alkyl alone or in combination, for example with alkoxy, alkylthio, arylsulfonyl, alkylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, alkylamino, alkoxycarbonyl, aryloxycarbonyl, alkylaminthiocarbonyl, arylaminothiocarbonyl, denotes a linear or branched chain, a saturated or unsaturated residue with 1-3 carbon atoms such as methyl, ethyl, propyl, isopropyl, allyl or propinyl. Alkyl of Ci-Cß in the residues R, Rl and R5 denotes independently of another, a linear, branched chain, the saturated or unsaturated residue containing 1 to 8 carbon atoms, which may be interrupted by 1 or 2 heteroatoms such as O, N or S, where an absence of interruption or interruption by oxygen is preferred and in the case of an interruption by oxygen, C?-C alkoxy is particularly preferred. Examples of C.sub.1 -C.sub.8 alkyl residues are methyl, ethyl, propyl, pentyl, octyl, allyl, propargyl, 2,4-pentadienyl, isopropyl, sec. butyl, ter. butyl, 3-methyl-butyl, 2-hydroxy-hexyl, n-butoxy, hexyloxy, C (CH 3) 2) OMe in particular ter. Butyl, n-butoxy, hexyloxy, C (CM3) 2OMe. By "aryl" is meant a phenyl or naphthyl residue which may optionally be especially substituted by halogen, alkyl or alkoxy. A phenyl residue is preferred. By halogen is meant chlorine, bromine or iodine, preferably chlorine. Structural atoms are understood as C, N, O and S and heteroatoms are understood as N, O and S. The heteroaryl residues listed for R, Rl, and R6 independently denote a ring of pyridine, pyrimidine, pyridazine, pyrazine. , piperazine, imidazole, furan, oxazole, isothiazole, isooxazole, 1, 2, 3-triazole or 1,2,4-triazole, thiazole, thiophene or indole, preferably a pyridine, imidazole or thiophene ring. The bicycles listed under R, Rl and R6 are preferably residues such as the naphthyl, tetrahydronaphthyl, decalinyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, benzimidazolyl, indazolyl, oxindolyl, benzofuranyl, benzothienyl, benzthiazolyl, benzoxazolyl or purinyl residue, in particular a naphthyl, quinolyl, isoquinolyl, tetrahydroquinolyl, indolyl or benzimidazolyl residue.

The preferred residues for R are from 4 to 7 structural atoms for the alkyl and the cycloalkyl, and the aryl, bicyclic and heteroaryl residues are preferred from 5 to 10 and particularly from 6 to 8 structural atoms. The preferred residues for R1 are from 1 to 12 structural atoms, particularly preferably from 3 to 10 structural atoms. The especially preferred residues for R are: -O-phenyl (p-R2), phenyl (p-R2), n-butoxy, hexyloxy in which R2 represents a small substituent such as hydrogen, halogen, methyl or hydroxyl; the especially preferred residues for R are -0-phenyl, phenyl and n-butoxy. The residues which are especially preferred for R 1 are benzyl, phenyl, ter. butyl or C (CH3) 2OMe and in particular ter. butyl. The preferred residues for R5 are hydrogen, methyl and ethyl; hydrogen is particularly preferred. The preferred residues for R6 are methyl and ethyl, phenyl and pyridyl; Methyl is particularly preferred. If R5 and R6 form a ring it preferably contains oxygen and morpholino is particularly preferable. The invention also relates to all optical isomers and racemates. The following optical isomers are preferred: C2 of succinylhydroxamic acid and Ca of amino acid amide in the S and C3 configuration of the original substance of succinic acid in the R configuration.

The compounds of the invention of the general formula I can be synthesized by the known processes. The optical isomers can be separated by known methods. However, the appropriate processes related to the separation of the final products and / or precursors are described. The diastomeric salts are formed from racemic mixtures by reaction with an optically active acid such as D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid or- with an optically active amine such as D- or La-phenylethylamine, ephedrine, quinidine or cinchonidine which can be separated by crystallization, or the optical isomers are separated by CLAP. Another method for separating the optical isomers is an enzymatic separation during the synthesis and / or synthesis of intermediates. The compounds of the general formula I are obtained by (a) reacting a carboxylic acid of the general formula II in which R, R1, R5 and R6 have the meanings mentioned above and in which the alcoholic hydroxy group can be present free or protected for example by the formation of ester with acetic acid, with hydroxylamine or with an O-protected or hydroxylamine protected with N, O and subsequently cleaving the protecting group. For these reactions the carboxylic acids can be activated by methods known in peptide chemistry. For example, the carboxylic acids can be activated directly by the reaction with chloroformic esters, carbodiimides, N, N '-carbonyl-diimidazole, 2-chloro-N-methylpyridinium iodide or a reaction intermediate which can be carried out to form active esters such such as pentafluorophenyl, N-hydroxysuccinimide, N-hydroxybenzotriazole, esters which can be reacted with hydroxylamine or a protected hydroxylamine. After completion of the reaction of a protected hydroxylamine derivative, the protecting groups can be cleaved by known methods. Examples of the protected hydroxylamines are 0-benzylhydroxylamine, O-p-methoxybenzylhydroxylamine, 0-trimethylsilylhydroxylamine, and O-tert-butyl-hydroxylamine, N, 0-dibenzylhydroxylamine and N, O-bis-p-methoxybenzylhydroxylamine. The protecting groups can be cleaved in the case of benzyl or p-methoxybenzyl groups by hydrogenolysis or in the latter case or in the case of the O-tert-butyl group by acid hydrolysis. A trimethylsilyl group can be hydrolyzed with water. (b) As an alternative to (a), the compounds of formula I can be prepared by reacting a 1,3-dioxolan-4-one of the general formula III in which R3 and R4 represent hydrogen, lower alkyl or phenyl and preferably methyl with hydroxylamine.

The compounds of the general structure II can be prepared by alkaline hydrolysis from compounds of structure III. The compounds of the general structure III "are obtained by coupling a 2-aryl-3-hydroxy-succinic acid of the general structure IVa in which R, R3 and R4 have the above-mentioned meaning and that hydroxy group and the neighboring COOH group are protect with the formation of a 1,3-dioxolan-4-one structure, with racemic or optically homogeneous amino acids, for example (R) or (S) -tert-butyl-glycine-N-methylamide by the known methods of peptide chemistry. For example, active esters such as N-hydroxysuccinimide, 1-hydroxy-benzotriazole or pentafluorophenyl esters can be prepared by activating the COOH group in IVa with carbodiimides such as dicyclohexylcarbodiimide or diisopropylcarbodiimide, which can then be reacted with the free amino group of an amide of a-amino acid substituted in the amide group. These esters can also be prepared without isolation and further reacted. Other activation methods include the preparation of mixed anhydrides, by reacting the carboxylic acids with esters of chloroformic acid or condensation reagents such as uronium salts for example 2H- (lH-benzotriazol-1-yl) -1, 1, 3 , 3-tetramethyl uronium-tetrafluoroborate. The carboxylic acids of formula IVa can be prepared by reacting -formylacetic acids of general formula V (VI) in which R has the above-mentioned meaning with alkali cyanides or of trimethylsilyl cyanide / zinc iodide, acid saponification of the cyanohydrins of the general structure VI, which is obtained as intermediates and subsequently the hydroxy groups are protected and COOH by an acid catalysis reaction with acetals or ketals, for example 2,2-dimethoxypropane. The cyanohydrins can also be prepared as optically active molecules by the enzymatic reaction of the compound of general structure V catalysed by (R) - or (S) -oxinitrilases, which give, respectively, the stereospecific R or S compound. Alternate compounds of formula IVa can be prepared by reducing oxalo-aryl acetic esters with sodium borohydride, acid saponification of the esters and subsequent protection of the neighboring hydroxy COOH groups by an acid-catalyzed reaction with acetals or ketals for example, 2, 2 -methoxypropane. The alkali salts, ammonium salts, acetates or hydrochlorides are used primarily as pharmacologically compatible salts, which are prepared in the usual manner, for example, by treating the compounds with inorganic or organic bases or inorganic acids such as sodium hydroxide, potassium, aqueous ammonia, amines such as triethylamine or hydrochloric acid. The salts are usually purified by reprecipitation of water / acetone. The new substances of formula I and salts thereof according to the invention can be administered enterally or parenterally in liquid or solid form. All usual administration forms are taken into consideration such as tablets, capsules, dragees, syrups, solutions, suspensions, etc. Water is preferably used as the injection medium, which contains the usual additives in injection solutions such as stabilizers, solubilizers or buffers. Such additives are for example tartrate and citrate buffer, ethanol, complexing agents (such as ethylene diamine tetraacetic acid and non-toxic salts thereof), high molecular weight polymers (such as liquid polyethylene oxide) to regulate the viscosity. The liquid carriers for the injection solutions can be sterile and are preferably filled in ampoules. The solid carriers are for example starch, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, fats. plants and animals, high molecular weight solid polymers (such as polyethylene glycols); Formulations suitable for oral administration may, if desired, contain flavoring and sweetening agents. The dose may depend on several factors such as the form of administration, species, age and / or individual status. The daily dose to be administered is approximately 10-1000 mg / person, preferably 100-500 mg / person and may be taken once or divided into several applications. Apart from the state of the compounds in the examples and the compounds that can be derived by combining all the meanings of the substituents mentioned in the examples, the following acid derivatives are preferred 3-aryl-succinamido-hydroxamic in the sense of the present invention: 1. 2- (Biphenyl-4-ylamino) -NI- (2, 2-dimethyl-l-methyl-carbamoyl-propyl) -3, N4-dihydroxy -succinamide 2. 2- (Biphenyl-4-ylamino) -NI- [2, 2-dimethyl-l- (morpholin-4-ylcarbamoyl) -propyl) -3, N4-dihydroxy-succinamide 3. 2- (biphenyl- 4-ylamino) -NI- [2, 2-dimethyl-l- (pyridin-2-ylcarbamoyl) -propyl) -3, N4-dihydroxy-succinamide 4. 2- (Biphenyl-4-ylamino) -3, N4- dihydroxy- I- (1-methyl-carbamoyl-2-phenyl-ethyl) -succinamide 5. NI- (l-Benzyl-2-morpholin-4-yl-2-oxo-ethyl) -2- (biphenyl-4-) ilamino) -3, N4-dihydroxy-succinamide 6. 2- (Biphenyl-4-ylamino) -3, N4-dihydroxy-Nl- [2-phenyl-1- (pyridin-2-ylcarbamoyl) -ethyl] -succinamide 7 2- (Biphenyl-4-ylamino) -3, N4-dihydroxy-Nl- [2-methoxy-2-methyl-l-methylcarbamoyl-propyl] -succinamide 8. 2- (Biphenyl-4-ylamino) -3, N4-dihydroxy-Nl- [2-methoxy-2-methyl-l- (morpholin-4-carbamoyl) -propyl] -succinamide 9. 2- (Biphenyl-4-ylamino) -3, N4-dihydroxy-Nl- [2-methoxy-2-methyl-1- (pyridin-2-ylcarbamoyl) -propyl] -succinamide . N4- (2,2-Dimethyl-l-methylcarbamoyl-propyl) -2N1-dihydroxy-3- (4-phenoxy-phenylamino) -succinamide 11. N-4- (2,2-Dimethyl-1- (morpholin-4 -carbamoyl) -propyl] -2Nl-dihydroxy-3- (4-phenoxy-phenylamino) -succinamide 12. N4- [2, 2-Dimethyl-1- (pyridin-2-ylcarbamoyl) -propyl] -2Nl-dihydroxy- 3- (4-phenoxy-phenylamino) -succinamide 13. 2, Nl-Dihydroxy-N 4 - (l-methylcarbamoyl-2-phenyl-ethyl) -3- (4-phenoxy-phenylamino) -succinamide 14. N 4 - (l -Benzyl-2-morpholin-4-yl-2-oxo-ethyl) -2N1-dihydroxy-3- (4-phenoxy-phenylamino) -succinamide 15. 2, Nl-Dihydroxy-3- (4-phenoxy-phenylamino) -N4- [2-phenyl-1- (pyridin-2-ylcarbamoyl) -ethyl] -succinamide 16. 2, Nl-Dihydroxy-N4- (2-methoxy-2-methyl-1-methyl-carbamoyl-propyl) - 3- (4-phenoxy-phenylamino) -succinamide 17. 2, Nl-Dihydroxy-N 4 - [2-methoxy-2-methyl-1- (morpholin-4-carbamoyl) -propyl] -3- (4-phenoxy) phenylamino) -succinamide 18. 2, Nl-Dihydroxy-N 4 - [2-methoxy-2-methyl-1- (pyridin-2-ylcarbamoyl) -propyl] -3- (4-phenoxy-phenylamino) -succinamide 19. 2 - (4-Butoxy-phenylamino) -NI- (2, 2-di) methyl-l-methyl-carbamoyl-propyl) -3, N4-dihydroxy-succinamide 20. 2- (4-Butoxy-phenylamino) -NI- [2, 2-dimethyl-l- (morpholin-4-carbamoyl) -propyl ] -3, N4-dihydroxy-succinamide 21. 2- (4-Butoxy-phenylamino) -NI- [2,2-dimethyl-l- (pyridin-2-ylcarbamoyl) -propyl] -3, N4-dihydroxy-succinamide 22. 2- (4-Butoxy-phenylamino) -3, N4-dihydroxy-Nl- (1- (methylcarbamoyl-2-phenyl-ethyl) -succinamide 23. NI- (l-Benzyl-2-morpholin-4-yl) -2-oxo-ethyl) -2- (4-butoxy-phenylamino) -3, N4-dihydroxy-succinamide 24. 2- (4-Butoxy-phenylamino) -3, N4-dihydroxy-Nl- [2-phenyl- 1- (pyridin-2-ylcarbamoyl) -ethyl] -succinamide 25. 2- (4-Butoxy-phenylamino) -3, N4-dihydroxy-Nl- (2-methoxy-2-methyl-1-methyl-1-methylcarbamoyl) -propyl] -succinamide 26. 2- (4-Butoxy-phenylamino) -3, N4-dihydroxy-Nl- [2-methoxy-2-methyl-1- (morpholin-4-carbamoyl) -propyl] -succinamide 27. 2- (4-Butoxy-phenylamino) -3, N4-dihydroxy-Nl- [2-methoxy-2-methyl-1- (pyridin-2-ylcarbamoyl) -propyl] -succinamide 28. NI- (2,2-Dimethyl-l-methylcarbamoyl-propyl) -2- (4-hexyloxy-phenylamino) -3, N4-dihydroxy-succinamide 29. NI- [2, 2-dimethyl-l- (morpholine-4 -carbamoyl) -propyl] -2- (4-hexyloxy-phenylamino) -3, N4-dihydroxy-succinamide 30. NI- [2, 2-Dimethyl-1- (pyridin-2-ylcarbamoyl) -propyl] -2- (4-hexyloxy-phenylamino) -3, N4-dihydroxy-succinamide 31. 2- (4-Hexyloxy-phenylamino) -3, N4-dihydroxy-Nl- (l-methylcarbamoyl-2-phenyl-ethyl) -succinamide 32. NI- (l-Benzyl-2-morpholin-4-yl-2- oxo-ethyl) -2- (4-hexyloxy-phenylamino) -3, N4-dihydroxy-succinamide 33. 2- (4-Hexyloxy-phenylamino) -3, N4-dihydroxy-Nl- [2-phenyl-I- ( pyridin-2-ylcarbamoyl) -ethyl] -succinamide 34. 2- (4-Hexyloxy-phenylamino) -3,4-dihydroxy-N 1 - (2-methoxy-2-methyl-1-methylcarbamoyl-propyl) -succinamide 35. 2- (4-Hexyloxy-phenylamino) -3, N4-dihydroxy-Nl- [2-methoxy-2-methyl-1- (morpholin-4-carbamoyl) -propyl] -succinamide 36. 2- (4-Hexyloxy) phenylamino9) -3, N4-dihydroxy-Nl- [2-methoxy-2-methyl-l- (pyridin-2-ylcarbamoyl) -propyl] -succinamide Example 1 2-Biphenyl-4-yl-Nl- ((SS) -2,2-dimethyl-1-methylcarbamoyl-propyl) 3, N 4 -dihydroxy-succinamide 1. Useful ester of afmyl-biphenylacetic acid A mixture of 24 g of ethyl ester of biphenylacetic acid and 8.2 g of ethyl formate were added, dropwise and while stirring, to a suspension of 2.4 g of sodium hydride in 250 g. ml of ether. The reaction mixture was stirred for 2 hours at room temperature and cold water was added carefully. The aqueous phase was acidified to pH 2 and the product was extracted with ether. The extract was dried and concentrated by evaporation. 1. 2 2-biphenyl-3-hydroxy-succinic acid 2 g of trimethylsilyl cyanide and a catalytic amount of zinc iodide were added to a solution of . 7 g of ethyl ester of a-biphenylacetic acid in 70 ml of dichloromethane. The mixture was stirred overnight at room temperature and concentrated by evaporation. 6 N HCl was added to the residue and boiled under reflux until saponifying the nitrile, trimethylsilyl and ester groups. The product was isolated by extraction with ether. 1. 3 Acid -2, 2-dimethyl-l, 3-dioxolan-4-one-5-yl-bi-e-enyl-acetic 3.14 g of 2-biphenyl-3-hydroxy-succinic acid were dissolved in 100 ml of 2.2 -dimethoxy propane and 30 ml of DMF, a catalytic amount of p-toluenesulfonic acid was added and this was stirred overnight at 30-40 ° C. The solvent was removed by evaporation and the crude product was used in the next step. 1. 4 a-2, 2-Dimethyl-l, 3-dioxolan-4-on-5-yl-biphenyl-acetyl- (S) -ter .butyl-glycine-N'-methylamide 0.6 g of a-2, 2 acid -dimethyl-1, 3-dioxolan-4-on-5-yl-biphenyl-acetic acid and 0.3 g (S) -ter .butyl-glycine-N'-methylamide were dissolved in 30 ml of methylene chloride and 0.2 was added. g of diisopropyl-ethylamine. 0.5 g of 2H- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate was added and the mixture was stirred overnight. Approximately 200 ml of acetic ester were added and the organic phase was washed successively with sodium bicarbonate solution, 0.5 N hydrochloric acid and again with sodium bicarbonate solution. The organic phase was dried and concentrated by evaporation and the residue was triturated with ether. 1. 5 2-Biphenyl-4-yl-Nl- ((SS) -2,2-dimethyl-l-methyl-carbamoyl-propyl) -3, N4-dihydroxy-succinamide 0.14 g of sodium methylate were added to a solution of 0.14 g of hydroxylamine hydrochloride in methanol and the mixture was stirred for two hours at room temperature. The precipitate was removed by filtration and the filtrate was cooled in an ice bath, 0.9 g of R, Sa-2, 2-dimethyl-l, 3-dioxolan-4-one-5-yl-biphenylacety were added in portions. -ter-glycine-N '-methylamide obtained above. The mixture was stirred for 30 minutes at 0 degrees and then overnight at room temperature. The reaction solution was concentrated by evaporation and the residue was purified by chromatography on silica gel using methylene chloride / methanol (3 -10%) as eluent.

Example 2 To determine the inhibitory potential of compounds of general formula I in MMPs such as HNC, the catalytic domain was incubated (for isolation and purification, see Schnierer, S. Kleine, T., Gote, T., Hillemann , A., Knuuper, V., Tschesche, H., Biochem, Biophys, Res. Commun. (1993), 191, 319-326). Subsequently, the initial reaction range of a standard substrate was measured as described in Grams F. et al., FEBS 335 (1993) 76-80). The results were evaluated in the usual manner (see for example Dixon, M., Biochem. J. (1953) 55, 170-202). The synthetic collagenase substrate is a heptapeptide C-terminally coupled with dinitrophenol (DNP). This DNP residue stopped the fluorescence of the Trp from the heptapeptide. After cleavage of a tripeptide containing the DNP residue, the fluorescence was increased medially.

Test buffer: 50 mM Tris / HCl at pH 7.6 (Tris = Tris- (hydroxy ethyl) -aminomethane) 100 mM NaCl / 10 mM CaCl2 / 5% MeOH (if required) enzyme: 8 nM catalytic domain (Met80- Gly242) of human neutrophilic collagenase (MMP8). Substrate: DNP-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH2 10 μM total assay volume: 1 ml An enzyme and inhibitor solution was prepared in assay buffer at 25 ° C. The reaction was initiated by adding the substrate to the solution. The cleavage of the fluorogenic substrate was measured by fluorescence spectroscopy (excitation and emission of the wavelength at 280 and 350 nm respectively). The IC50 value was determined by a concentration of the inhibitor at which the reaction rate is half. The compounds of the general formula I act as inhibitors. The assay was carried out with enzymes MMP2 and MMP1 analogously to the example described above with HNC (MMP8), but at other concentrations and in this case the compound of Example 1.5 was compared with Marimastat. An additional activation is required for MMP2 and MMP3. This shows a clear advantageous selectivity, relative to MMP1.

Table *) N2- [3S-hydroxy-4- (N-hydroxyamino) -2R-isobutyl-succinyl] - L-tert-leucine-N-methylamide While the inhibitors inhibit MMP2 and MMP8 to an almost equal degree, the inhibition of MMP1 by the compound of Example 1.5 according to the invention is substantially poorer than by Marimastat.

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

Claims (10)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. The compounds of the general formula I: characterized in that R denotes an optionally substituted C? -C8 alkyl, or a cycloalkyl, aryl, heteroaryl, aryloxy, heteroaryloxy or aralkyl, optionally substituted monocyclic or bicyclic residue, RI denotes an optionally substituted C? -C8 alkyl or a residue of cycloalkyl, aryl, heteroaryl, aralkyl or alkylheteroaryl, monocyclic or optionally substituted bicyclic, R5 denotes hydrogen or an alkyl residue of C? -C8 R6 denotes hydrogen, an optionally substituted C? -C8 alkyl or a cycloalkyl, aryl, heteroaryl, aralkyl or optionally substituted monocyclic or bicyclic alkylheteroaryl residue, or R5 and R? Together with the N atom denote a 5-membered or 6-membered ring. saturated members which contains at least one additional heteroatom, pharmaceutically compatible salts, esters and derivatives thereof which are metabolized in vivo to the compounds of the general formula I.

2. The compounds of the formula I characterized in that R is a Ph-R fragment having a clogP value between 2.0 and 6.0, Rl is an aminocarbonyl-RI fragment having a clogP value of between -1.5 and 2.0, R5 denotes hydrogen or an alkyl residue of C? ~ C8 / R6 denotes hydrogen, an optionally substituted C? -C8 alkyl or a cycloalkyl, aryl, heteroaryl, aralkyl or alkylheteroaryl-monocyclic or optionally substituted bicyclic residue, or R5 and R6 together with the N atom denote a 5-membered ring or 6 saturated member which contains at least one additional heteroatom, the pharmacologically compatible salts, esters and derivatives thereof which are metabolized in vivo to the compounds of the general formula I.

3. The compounds of the formula I in accordance with one of claims 1 6 2, characterized in that the residue R has from 4 to 7 structural atoms in the case of the alkyl and cycloalkyl or from 5 to 10 structural atoms in the case of the aryl, bicyclic and heteroaryl residues. .

The compounds of formula I according to one of claims 1 to 3, characterized in that the residue R has from 3 to 10 structural atoms.

5. The compounds of formula I according to one of claims 1 to 4, characterized in that the residue R5 denotes hydrogen, methyl and ethyl.

6. The compounds of formula I according to one of claims 1 to 5, characterized in that the residue R6 denotes ethyl, phenyl or pyridyl.

7. The compounds of formula I according to one of claims 1 to 4, characterized in that the residues R5 and R6 denote a ring containing oxygen.

8. The compounds of formula I according to one of claims 1 to 7, characterized in that they are present as optical isomers in the S-configuration of C2 of succinyl-hydroxamic acid and amino acid amide Ca and in the R e C3 configuration of the original substance of succinic acid.

9. The pharmaceutical preparation containing at least one compound of formula I according to one of claims 1 to 8 in addition to the common carrier and auxiliary substances. The use of compounds of formula I as claimed in one of claims 1 to 8 for the production of pharmaceutical preparations having an inhibitory effect on gelatinase. PRODUCTION AND PHARMACEUTICAL PREPARATIONS CONTAINING THOSE SUBSTANCES SUMMARY OF THE INVENTION There are described compounds of formula (I) in which R, Rl, R5 and R6 have the meanings given in the claims, pharmacologically compatible salts, esters and derivatives thereof which are metabolized in vivo to compounds of the general formula (I ) and the use of these compounds to produce pharmaceutical preparations.