MXPA99010180A - New cysteine derivatives, processes for their production, and pharmaceuticals containing them - Google Patents

Abstract

A compound represented by general formula (I), which binds and inhibits matrix metalloproteinases (MMPs), wherein the cysteine moiety contains an unprotected thiol group, the cysteine moiety is in the L- or D-configuration wherein A denotes -CO-, SO2-, -NH-CO-, or -O-CO-, R1 denotes hydrogen, a linear or branched saturated or unsaturated alkyl group of 1 to 15 carbon atoms or a C1-C15 alkyl group substituted by halogen, mercapto, hydroxy, alkoxy, amino or nitro, or by carbocyclic non aromatic or aromatic ring systems which are optionally substituted once or several times or aromatic or non aromatic heterocycles, optionally substituted, their pharmacologically acceptable salts, or optically active forms thereof. R denotes hydroxy, a linear or branched saturated or unsaturated alkyl group of 1 to 15 carbon atoms or a C1-C15 alkyl group substituted by carbocyclic non aromatic or aromatic ring systems which are optionally substituted once or several times or aromatic or non aromatic heterocycles, optionally substituted, their pharmacologically acceptable salts, or optically active forms thereof, processes for the preparation, pharmaceutical compositions and their use in medicine.

Description

NEW DERIVATIVES OF CISTEINE, PROCEDURE FOR ITS PRODUCTION, AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM "The invention comprises new inhibitors of matrix etaloproteinase which are based on the use of the amino acid L or D-cysteine which is derived in the amino and carboxyl function with groups of the non-peptidic type (formula I.) The invention comprises methods for The production of inhibitors and their use in the therapeutic field The family of matrix metalloproteases (MMPs) has become a major target for drug design, since these enzymes are involved in tissue remodeling and connective tissue disorder, and thus in various diseases where (i) rapid degradation of the extracellular matrix is taking place, for example during heart failure, congestive and extravasation of tumor cells , -highly metastatic, or (ii) slow degradation of the extracellular matrix, for example the formation of atherosclerotic lesions and rupture, is occurring. Loss of the cartilage matrix in osteoarthritis, the degradation of the bone matrix in the REF .: 31957 osteoporosis, gingival degradation in periodontal disease, remodeling of the matrix and deposition in the formation of Alzheimer's plaques and rheumatoid arthritis. The family of MMPs currently includes fourteen members, ten of which are secreted from the cells in a 'soluble' form and box members are enzymes bound to the membrane. MMPs are zinc-dependent enzymes that require calcium which are inhibited by one of the members of the tissue inhibitor of the etaloproteinase family (TIMP). Synthetic inhibitors of this class of enzymes have been developed as hydroxates, N-carboxyalkyl derivatives, phosphonamidates and phosphinates as well as using thiol groups as ligands for the zinc atom of the active site. The three-dimensional structures of the complexes between the catalytic JS domain and several inhibitors have been published, as well as the structure of the MMP-3 proenzyme with. An N-terminal propeptide of approximately 80 residues. The propeptide forms a smaller, separate domain that contains three a-heciless and an extended peptide that occupies the active site. The catalytic domain in all these structures contains two ione Zn- that is, a "structural" zinc ion and a "catalytic" zinc ion. The "catalytic" zinc ion is coordinated by the side chains of three histidyl residues of the consensual sequence HEXXHXXGXXH. The fourth ligand of zinc "catalytic" in the inhibited enzyme is a coordination group of inhibitors similar to hydroxamate or carboxylate; in the propeptid Pro-MMP is the thiol group of the cysteine residue (1). Correspondingly, the thiol-based collagenase inhibitors, proposed hitherto, are generally of peptide structure containing cysteine or cysteine-like amino acids and their design was based on the mode of attachment of the substrate and more recently of the propeptide containing cysteine. . The present invention relates to a new class of inhibitors of the MMPs, which are derived from the cysteine in a non-peptidic manner as shown in the general formula I, the procedures for the preparations and the pharmaceutical compositions containing these compounds and its therapeutic use in medicine, (D wherein A represents -CO-, -S02-, -NH-CO-, or -O-CO-Ri represents hydrogen, a linear or branched, saturated or unsaturated alkyl group of 1 to 15 carbon atoms or a group alkyl of 1 to 15 carbon atoms substituted by halogen, mercapto, hydroxy, alkoxy, amino or nitro, or by aromatic or non-aromatic ring systems, carbocyclic which are optionally substituted once or several times or aromatic or non-aromatic heterocycles, optionally replaced, their pharmacologically acceptable salts, or optically active forms thereof. R represents hydroxy, a linear or branched, saturated or unsaturated alkyl group of 1 to 15 carbon atoms or an alkyl group of 1 to 15 carbon atoms substituted by aromatic or non-aromatic ring systems, carbocyclic which are optionally substituted once or several times or optionally substituted aromatic or non-aromatic heterocycles, pharmacologically acceptable salts thereof, or optically active forms thereof. With respect to formula I, R and / or Ri represent a branched, saturated or unsaturated alkyl group of 1 to 15 carbon atoms selected from methyl, ethyl, propyl, n-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, indecil, dodecyl, etc., vinyl, etc., as well as also the corresponding alkynyl groups, for example acetylene. ~ The carbocyclic, aromatic or non-aromatic substituents for the alkyl groups are selected from cycloalkyls of 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or aromatic substituents, carbocyclics of 6 to 14 carbon atoms such as phenyl, naphthyl or anthranil or heterocyclic, non-aromatic substituents such as pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl Or heterocyclic, aromatic substituents such as pyrrolyl, pyridinyl, furyl, thienyl, thiazolyl, imidazolyl, pyridinyl, purinyl, indolyl, quinolyl, carbazolyl. The aromatic or non-aromatic, carbocyclic or heterocyclic ring systems, respectively, can be optionally substituted once or several times, for example by halogen-, nitro-, hydroxy-, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, amino, ercapto, carboxyl, cyano, or sulfonyl groups.

If A represents -CO-, the RiCO- residue is preferably selected from the residues of the following carboxylic acids: Formic Acid, Acetic acid, Propionic acid, Hexanic acid, Lauric acid, Myristic acid, Palmitic acid, Stearic acid, acid Arachidonic, Behenic acid, Octadecenic acid, Linoleic acid, Lmolénico acid, 3-Mercaptopropiónico acid, Glioxilico acid, Malónico acid, Succínico acid, acid 4-A inobutanoico, acid 6-aminocaproico, acid 3-Nitropropiónico, acid Naftilacético, acid 4- A inophenylacetic acid, Acrylic acid, Cinnamic acid, 4-Amino-cinnamic acid, Aminocrotonic acid, fumaric acid, Maleic acid, Phthalic acid, Benzoic acid, Nitrobenzoic acid, 3-Ammobenzoic acid, 4-A-indobenzoic acid, Anthranilic acid, Salicylic acid , 3-Amino-salicylic acid, 4-Aminosalicylic acid, 5-A? aino-salicylic acid, Naphthoic acid, p-Phenylbenzoic acid, Fenantroic acid or, Nicotinic acid, 3-Aminopyrazin-2-carbonic acid, acid Pyridinecarboxylic acid, Piperazinecarboxylic acid, Piperidinecarboxylic acid. If A represents -S02, the residue R? SO: - is preferably selected from the residues of the following sulphonic acids: Methanesulfonic Acid, Etanesulfonic Acid, Propanesulfonic Acid, 3-Hydroxypropanesulfonic Acid, Ortynyl Acid (Anilin-2-Sulfonic Acid), Naphthalenesulfonic Acid, Naphthylaminosulfonic Acid, Aminomethanesulfonic Acid, 2-Mercaptoethanesulfonic Acid, 2-Chloroethanesulfonic Acid, N, N'- Acid Dimethylsulfamic, Piperidinesulfonic acid, 5- (2-Aminoethylamino) -1-naphthalene sulfonic acid, acid Yodoxiquinolinesulfonic acid, pyridine-3-sulfonic acid, p-Toluenesulfonic acid, 2- (p-Toluidino) naphthalene-6-sulfonic acid, Decyl methanesulfonic acid, 2- [(2-Amino-2-oxyethyl) amino] ethanesulfonic acid, acid 2- (N-Cyclohexylamino) ethanesulfonic acid, 2- [bis (2-hydroxyethyl) amino] ethanesulfonic acid, N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid, N-tris (hydroxymethyl) methyl-2-amino acid -etansulfonic acid, 2- (N-Morpholin) ethanesulfonic acid, Piperazin-N, N'-bis (2-ethanesulfonic acid), 3- (2-pyridyl) -5,6-bis (4-phenylsufonic acid) -1, 2, 4-triazine. If A represents -NHCO-, the residue Ri-NH-CO- is selected preferentially from the residues of the following urea derivatives: n-Butyl-, R- (+) - alpha-Phenylethyl-, R- (- ) -1- (1-Naphthyl) -ethyl-, Ethyl-, Propyl-, Hexyl-, Octyl-, Benzyl-, Chlorobenzyl-, Methylbenzyl-, 3-Picolyl-, 2- (Aminomethyl) -pyridyl urea. If A represents -0-C0-, the residue R? -0-CO- is preferably selected from the residues of the following Carbamates: Methyl carbamate, Ethyl carbamate, 9-Fluorenylmethyl carbamate, 9- (2-Sulfo) fluorenylmethyl carbamate, 9- (2,7-Dibromo) fluorenylmethyl carbamate, 4-methoxyphenacyl carbamate, 2, 2, 2-trichloroethyl carbamate, 2-phenylethyl carbamate, 1- (1-adamantyl) -1-methylethyl carbamate, 1,1- Dimethyl-2-haloethyl carbamate, 1-Methyl-1- (4-biphenyl) -1-methylethyl carbamate, 2- (2'-Pyridyl) ethyl carbamate, 1-Adamantyl carbamate, Vinyl carbamate, Allyl carbamate, 1-Isopropylallyl carbamate , 4-Nitrocinyl carbamate, 8-quinolyl carbamate, Cyclohexyl carbamate, Benzyl carbamate, p-Methoxybenzyl carbamate, p-Nitrobenzyl carbamate, p-Bromobenzyl carbamate, 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylsulonylethyl carbamate, 2- (p- Toluenesulfonyl) ethyl carbamate, 4-methylthiophenyl carbamate.

R is preferably selected from the following residues: Ethyl-, Propyl-, Hexyl-, Octyl-, Benzyl-, 4-Chlorobenzyl-, 4-Methylbenzyl-, 3-Picolyl-, 2- '(methyl) -pyridyl-, 4- (methyl) pyridyl-, 3-phenylpropyl-, 4-phenylbutyl-, 2- (p- ToliDethyl-, 3-Nitrobenzyl- , Benzylethyl-, 2-Phenylethyl-, Adamantyl-, Pyridyl-, Phenyl-, Colestenyl-, Naphthyl-, 4-Phenoxy-phenyl or indolylethyl The preferred compounds according to formula I are the compounds of Example 5-22, and from the following table: The compounds according to formula I consist of three parts which have different structures and different properties. The SH chelation group for the Zn2 + ion of the active site, the hydrophobic groups Ri and R to interact with the hydrophobic protein receptacle Si as well as to contribute to the additional, hydrophobic interactions along the substrate binding fissure P '. The inhibitors of the general formula I allow the development of the selective inhibitors of the different MMPs as required for their differentiated pathological implications, for example rheumatoid arthritis of osteoporosis, periodontal disease, atherosclerosis, heart failure, congestive, tumor invasion and metastasis. and angiogenesis. It is known that there are similar compounds described in the literature. However, these are peptide compounds and these exhibit a longer half-life in human plasma. The chemical structure of the cysteine derivatives is selected in view of the increased metabolic stability. Correspondingly, the amino group was acylated with carboxylic acids to produce amides, but preferentially the known urethanyl derivatives which are more stable to enzymatic metabolism. Similarly, the C-terminal carboxyl function was derivatized as an amide instead of the esterification to avoid fast elimination rates due to the hydrolysis of the esters by the lipases. In addition, N-alkyl and N-aryl amides which are known to be more stable towards peptidases were selected. For the synthesis of the inhibitors, the classical procedures of organic synthesis (2) were applied. The related L- and D-cystine derivatives of formula II were prepared according to the normal procedures of peptide chemistry and then amidated with EDCI / HOBt according to Scheme 1. The subsequent reduction of the compounds of Cystine of formula III to the cysteine derivatives of Formula I was made with mercaptan-like reducing agents or preferentially with tributylphosphine-like phosphines, as shown in scheme 1. n m i Scheme 1. General route for the synthesis of the MMP inhibitors of the present invention.

The compounds of the present invention, which specifically inhibit MMPs, are pharmacologically useful in the treatment of rheumatoid arthritis and related diseases in which collagenolytic activity is a contributing factor, such as, for example, corneal ulceration, osteoporosis, perioditis, Paget's disease, gingivitis, tumor invasion, dystrophic epidermolysis, bullous, systemic ulceration, epidermal ulceration, gastric ulceration and the like. These compounds are particularly useful in the treatment of rheumatoid arthritis (chronic, primary polyarthritis, PCP), systemic lupus erythematosus (SLE), juvenile rheumatoid arthritis, Sjögren's syndrome (RA). + sicca syndrome), polyarteritis nodosa and related vasculitis, eg engener granulomatosis, giant cell arteritis, Goodpasture syndrome, angiitis with hypersensitivity, polymyositis and dermatomyositis, progressive system sclerosis, M. Behcet syndrome, Reiter (arthritis + urethritis + conjunctivitis), mixed connective tissue disease (Sharp syndrome), ankylosing spondylitis (M. Bechterew). The compounds of the present invention can be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted for such a route and in an effective dose for the proposed treatment.The therapeutically effective doses of the compounds of the present invention required to prevent or halt the progress of the medical condition are easily ascertained by one of ordinary skill in the art. Accordingly, the invention provides a class of novel pharmaceutical compositions comprising one or more compounds of the present invention, in association with one or more pharmaceutically acceptable, non-toxic carriers and / or adjuvants (collectively referred to herein as "carrier materials"). ) and, if desired, other active ingredients, the compounds and compositions can, for example, be administered intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically. For all administrations, the pharmaceutical composition may be in the form of, for example, a tablet, a capsule, a suspension or a liquid. The pharmaceutical composition is preferably made in the form of a dosage unit contained in a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. A daily dose, suitable for a mammal can vary widely depending on the condition of the patient and other factors. However, a dose of about 0.1 to 300 mg / kg of body weight, in particular of about 1 to 30 mg / kg of body weight, may be appropriate. The active ingredient can also be administered by injection. The dose regimen for tracing a disease condition with the compounds and / or compositions of this invention is selected according to a variety of factors, including the type, age, weight, sex and medical conditions of the patient. The severity of the infection and the role of the administration and the particular compound employed and in this way can vary widely. For therapeutic purposes, the compounds of the invention are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration, If it is by mouth, the compounds can be mixed with lactose, sucrose, starch powder, esters of cellulose of alkanoic acids, cellulose alkyl ester, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia, sodium alginate, polyvinyl pyrrolidone and / or alcohol poly and in this way make tablets or encapsulate for convenient administration. Alternatively, the compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and / or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. The appropriate dosages in any given example, of course, depend on the nature and severity of the condition being treated, the route of administration and the species of mammal involved, including its size and any individual idiosyncrasies. Carriers, attenuating solutions and representative adjuvants include, for example, water, lactose, gelatin starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, petroleum gelling agent, etc. The pharmaceutical compositions can be made in a solid form, such as granules, powders or suppositories, or in liquid form, such as solutions, suspensions or emulsions. The pharmaceutical compositions can be attached to conventional pharmaceutical adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc. For use in the treatment of rheumatoid arthritis, the compounds of this invention can be administered by any conventional route, preferably in the form of a pharmaceutical composition adapted for such route and in an effective dose for the proposed treatment. In the treatment of arthritis, the administration can conveniently be by the oral route or by intra-articular injection in the affected joint. As indicated, the dose administered and the treatment regimen will be dependent, for example, on the disease, the severity thereof, on the patient being treated and their response to treatment and, therefore, can be widely varied.

Enzyme assay The catalytic domain of MMP8 (Phe79-MMP8) and MMP3 were used for the inhibition experiments. Enzyme assays were performed at 25 ° C in 10 M CaCl2, 100 mM NaCl, 50 mM-Tris / HCl (pH 7.6) using enzyme concentrations of 8 nM and fluorogenic substrates, Dnp-Pro-Leu -Gly-Leu-Trp-Ala-D-Arg-NH2 (Bachem M-1855, 1-10"5 M) for MMP8 and Mca-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg -Lys (Dnp) -NH: (Bachem M-2110, 4.10"6 M) for the MMP3: The measurements were performed essentially as described by Stack et al (3) for the MMP8 and by Nagase et al. (4) for the MMP3. The increase in fluorescence at 350 nm (MMP8) or 390 nm (MMP3) was monitored for a period of 10 sec. to determine the initial rates of hydrolysis. The evaluation of the kinetic data was performed as reported by Copeland et al. (5).

Table I. Examples for the inhibition of MMP8 and MMP3 with the non-peptide L-cysteine derivatives of the general formula I Compound Rr-A R Kil M- Cß K¡; M P3 [μ l [μM] «- - C 1.0 9.7 Synthesis General Methods A) Amidation: 1 mmol of N, N '-uretanyl-cystine, 2 mmol of HOBT (hydroxybenzotriazole) and 2.08 mmol of EDCI (N-ethyl-N '- (3-dimethylaminopropyl) -carbodiimide hydrochloride) are dissolved or suspended in 10 ml of THF.

The amine is added in excess (2.5-5 mmoles) and in the case of the hydrochloride equivalent amounts of N-methylmorpholine are added. The reaction mixture is stirred overnight at room temperature, concentrated to a small volume and partitioned between ethyl acetate and water. The organic layer is washed twice with 5% NaHC03, 5% KHS0 and water and dried over MgSO4. The solvent is evaporated and the residue is precipitated from ethyl acetate with suitable solvents similar to petroleum ether, diisopropyl ether, tert-butyl methyl ether or pentane.

B) Reduction: the cystine compound (1 mmol) is reacted in 10 ml of 95% trifluoroethanol with 1.5 mmoles of tributylphosphine. The reaction mixture is stirred overnight at room temperature, evaporated to a small volume and on dilution with ethyl acetate, the product is precipitated with suitable solvents similar to petroleum ester, diisopropyl ether, tert-butyl methyl ether or pentane 2í, N '-Bi s -benci 1 oxycarboni 1 -L-ci stina -bi s -hi droxama t o (5a) Preparation of? -?' -bis-benzyloxycarbonyl-L-cystine (2) and hydroxylamine according to procedure (A). Yield: 22%; homogeneous in CCD (solvent system: chloroform / methanol; 4: 1, Rf = 0.5).

FAB-MS: m / z = 539.2 [M + H]; Mf = 538.2 calculated for Benzylkoxycarbonyl-L-cysteine-hydroxamate (5) Prepared according to process (B) of 5a. Purified by flash chromatography (eluent: CH2Cl2 / MeOH, 95: 5 followed by 45: 5). Yield: 18%. NMR-1H d6-DMSO): 10.7 (broad s, 1H, NJ? OH); 8.89 (broad s, 1H, OH); 7.50 (d, 1H, NH uret.); 7.38 (m, 5H, H 's arom.); 5.03 (s, 2H, CH2 v. Z), 3.99 (m, 1H, H-C (a)); 2.75 / 2.66 (2xm, 2H, ß-CH2); 2.29 (broad s, 1H, SH).

Bis-tert-butyloxycarbonyl-L-cystine-bis-benzylamide (6a) Prepared from N, N'-bis-tert-butyloxycarbonyl-L-cystine (12) and benzylamine according to (A).

Performance: 77%. Homogeneous in CCD (solvent system: cyclohexane / chloroform / acetic acid, 45:45:10, Rf = 0.7).

L-Cystine-bis-benzylamide hydrochloride (6b) 13.87 g (22.4 mmol) 6a were stirred overnight in 100 ml of 4.6 M HCl in dioxane at room temperature: The precipitate was collected and washed extensively with ether. Yield: 11 (quantitative).

N, N '-Bi s -acetyl-Lc-stine -bi s -benzyl amide (6c) 300 mg (0.61 mmoles) 6b were distributed between ethyl acetate and 40 ml of NaHCO 3 (5%) and then reacted with acetic anhydride (0.27 g, 2.6 mmol). The organic layer was washed with water, dried over MgSO4 and evaporated to dryness. Yield 94%, homogeneous in CCD (solvent system: cyclohexane / chloroform / acetic acid: 45:45:10, Rf = 0.4).

N-Acetyl-L-cysteine-benzyl amide (6) "6c was reduced according to procedure (B) Yield: 65%, homogeneous in CCD (solvent system: CHCl3 / MeOH; 4: 1, Rf = 0.7); p.f. 186-189 ° C, RMN-1 !! (d6-DMS0): 8.56 (t, 1H, NH, amide); 8.23 (d, 1H, NH uret.); 7.32-7.09 (m, 5H, H 's arom.); 4.56, or 4.38 (, 1H, H-Ca); 4.28 (, 2H, CH2-Bn); 3.12 / 2.89, oder 2. 79/269 (2xm, 2H, ß-CH2); 2.30 (broad s, 1H, SH); 1. 87 (d, .3H, CH3). FAB-MS: m / z = 253.1 [M + H]; Mf = 252.1 calculated for C? 2H16N202S N, N '-Bi s -for i 1 -L-cystine -bi s -benz 1 amide (7a) Prepared with 6b and formic acid according to procedure (A). Yield: 59%; homogeneous in CCD (solvent system: cyclohexane / CHCl3 / acetic acid, 45:45:10, Rf = 0.1).

N-Formyl-L-cysteine-benzylamide (7) Reduction of 7a according to procedure (B). Yield: 62%; homogeneous in CCD (solvent system: cyclohexane / CHCl3 / acetic acid; 45:45:10; Rf = 0.45); p.f. 180 - 183 ° C; RM? -aH (d6-DMSO): 8.58 (t, 1H,? H, amide); 8.35 (d, 1H, H uret.); 8.10 (s, 1H, formyl-H); 7.33-7.21 (m, 5H, H 's arom.); 4.49, (, 1H, H-Ca); 4.30 (d, 2H, CH2-Bn); 2.82 / 2.72 (2xm, 2H, ß-CH2); 2.26 (broad s, 1H, SH). FAB-MS: m / z = 239.0 [M + H +]; Mf = 238.3 calculated for CnH? 4? 202S tert-Butyl oxycarbonyl-L-cysteine-benzylamide (8) Reduction of 6a according to procedure (B). Yield: 38%; homogeneous in CCD (solvent system: heptane / t-butanol / acetic acid : 1: 1, R £ = 0.7); p.f. 97 - 100 ° C; RM? -1! (d6-DMSO): 8.38 (m, 1H,? H, amide): 7.32-7.21 (m, 5H, H's arom.); 6.95 (d, 1H,? H-uret.); 4.29 (d, 2H, CH2-Bn); 4.08 (m, 1H, H-C; 2.81 / 2.68 (2xm, 2H, ß-CH2); 2. 29 (broad s, 1H, SH); 1.40 (s, 9H, t-Bu). FAB-MS: m / z 311.1 [M + H +]; Mf = 310.1 calculated for C? 5H22N203S N, N '-Bi s -benzyl oxycarbonyl-L-cis-tine-bis-benzyl amide (9a) of N, N'-bis-benzyloxycarbonyl-cystine and benzylamide according to (A). Performance: 90% N-Benzyloxycarbonyl-L-cysteine-benzylamide (9) Reduction of 9a according to (B). Yield: 41%; homogeneous in CCD (solvent system: cyclohexane / CHCl3 / acetic acid, 45:45:10, Rf = 0.4); p.f. 148 - 152 ° C; RMN-1 !! (d6-DMSO): 8.50 (m, 1H, NH, amide); 7.49 (d, 1H, NH uret.); 7.37-7.23 (m, 10H, H 's arom.); 5.06 (dd, 2H, CH2 v. Z); 4.30 (d, 2H, CH2-Bn); 4.16 (m, 1H, H-Ca); 2.84 / 2.70 (2xm, 2H, ß-CH2); 2.33 (broad s, 1H, SH). FAB-MS: m / z = 345.0 [M + H +]; Mf = 344.4 calculated for C? 8H20N2O3S N ', N' -Bis-benzyloxycarbonyl-L-cystine-bis-4-pyridylmethylamide (10a) of N, N'-bis-benzyloxycarbonyl-L-cystine and 4- (aminomethyl) pyridine according to the procedure (A ). Yield: 59%; homogeneous in CCD (solvent system: CHCl3 / MeOH, 4: 1, Rf = 0.65).

N-Benzyloxycarbonyl-L-cysteine-4-pyridylmethylamide (10) From the 10th according to the procedure (B). Yield: 65%; homogeneous in CCD (solvent system: CHCl3 / MeOH, 4: 1, Rf = 0.8); p-.f. 122-125 ° C; NMR ^ H (d6-DMSO): 8.61 (t, 1H, NH, amide); 8.48 / 7.37 / 7.25 (m, respectively, 9H, H 's arom.); 7.56 (d, 1H, NH-uret.); 5.08 (dd, 2H, CH2, Z); 4.32 (d, 2.H ,. CH2-Bn); 4.18 (, 1H, H-Ca); 2.87 / 2.72 (2xm, 2H, ß-CH2); 2.40 (broad s, 1H, SH). FAB-MS: m / z 346.2 [M + H +]; Mf = 345.1 calculated for N, N '-Bi s -benzyl oxy carbonyl-L-cystine-bis-3-pyridylmethylamide (l a) De?,?' -bis-benzyloxycarbonyl-cystine and 3- (aminomethyl) pyridine according to process (A). Performance: 69%; homogeneous in CCD (solvent system: CHCl3 / MeOH, 4: 1, Rf = 0.2).

N-Benzyl oxycarbonyl-L-cysteine-3-pyridylmethylamide (11) Reduction of lia in accordance with procedure (B). Yield: 14%; homogeneous in CCD (solvent system: CHCl3 / MeOH, 4: 1, Rf = 0.8); p.f. 125-127 ° C; NMR-aH (d6-DMSO); 8.58 (t, 1H, NH, amide); 8.50 / 8.45 / 7.65 / 7.36 (m, respectively, 9H, H 's arom.); 7.52 (d, 1H, NH-uret.); 5.07 (dd, 2H, CH2 v. Z); 4.42 (d, 2H, CH2-Bn); 4.15 (m, 1H, H-Ca); 2.82 / 2.71 (2xm, 2H, ß-CH2); 2.36 (broad s, 1H, SH). FAB-MS: m / z 346. 1 [M + H +]; Mf = 345. 1 calculated for C17H19N3? 3S W, W-Bis-benzyloxycarbonyl-L-cystine-bis-2-pyridylmethylamide (12a) Of N, N'-bis-benzyloxycarbonyl-cystine and 2- (aminomethyl) pyridine according to (A). Yield: 96%; homogeneous in CCD (solvent system: CHCl3 / MeOH, 4: 1, Rf = 0.7).

N-Benzyloxycarbonyl-L-cysteine-2-pyridylmethyl amide (12) Reduction of the 12th according to (B). Yield: 33%: homogeneous in CCD (solvent system: CHCl3 / MeOH, 4: 1, Rf = 0.8); p.f. 129-131 ° C; RMN-1 !! (d6-DMSO): 8.59 (t, 1H, NH, amide); 8. 48 / 7.72 / 7.22 (m, respectively, 9H, H 's arom.); 7.52 (d, 1H, NH-uret.); 5.07 (dd, 2H, CH2 v. Z); 4.49 (d, 2H, CH2-Bn); 4.20 (, 1H, H-Ca); 2.85 / 2.72 (2xm, 2H, ßCH2); 2.42 (broad s, 1H, SH). FAB-MS: m / z 346.1 [M + H +]; Mf = 345.1 calculated for C? 7H? 9N303S N, N '-Bi s-benzoyl-L-cystine -bi s -benzyl amide (13a) From 6b and benzoic acid according to (A).

Yield: 78%; homogeneous in CCD (solvent system: cyclohexane / CHCl3 / acetic acid, 45:45:10, Rf - 0.65).

N-Benzoyl-L-cyanine-benzyl amide (13) By reducing the 13a according to (B), Yield: 57%; homogeneous in CCD (solvent system: cyclohexane / CHCl3 / acetic acid; 45:45:10, Rf = 0. 55); p.f. 174 - 176 ° C; RM? -1! (d6-DMSO): 8.56 (t, 1H,? H, amide); 7.92 (d, 1H, H uret.); 7.57-7.22 (m, 10H, H 's arom.): 4.59, (m, 1H, H-Ca); 4.31 (d, 2H, CH2-Bn); 2.9 / 2.89 (2xm, 2H, ß-CH2); 2. 41 (t, 1H, SH). FAB-EM; m / z = 315. 1 [M + H ~]; Mf = 314. 1 calculated for C? 7H? 8? 202S N, Nr -Bis-tosyl-L-cystine-bis-benzylamide (14a) 390 mg (0.794 mmol) of 6b were reacted with 180 mg (0.952 mmol) of tosyl chloride in 6 ml of pyridine. After 12 hours of stirring at room temperature, the solid was filtered and the filtrate was evaporated to dryness by adding toluene and finally tert-butyl methyl ether. Yield: 81%; homogeneous in CCD (solvent system: CHCl3 / MeOH, 4: 1, Rf = 0.7).

N-tosyl-L-cysteine-benzylamide (14) By reducing the 14a according to (B). Yield: 54%; homogeneous in CCD (solvent system: CHCl3 / MeOH, 4: 1, Rf = 0.6); p.f. 180-182 ° C; RMN-1 !! (d6-DMSO): 8.41 (t, 1H, NH, amide); 7.98 / 7.68 / 7.35-7.14 (m, respectively, and d's, 10H, H 's arom., NH uret.), 4.13 (d, 2H, CH2-Bn); 3.86 (m, 1H, H-Ca); 2.59 (m, 2H, ß-CH2); 2.38 (s, 3H, CH3); 2.17 (t, 1H, SH). FAB-MS: m / z = 365.1 [M + H +]; Mf = 364.1 calculated for N, Nr -Bis-benzyloxycarbonyl-L-cystine-bis-2-phenyl-ethylamide (15a) of N, N'-bis-benzyloxycarbonyl-L-cystine and 2-phenylethylamine according to (A). Yield: 34%; homogeneous in CCD (solvent system: CHCl3 / MeOH, 19: 1, Rf = 0.8).

N-Benzyloxycarbonyl-L-cysteine-2-phenylethylamide (15) Reduction of 15a according to (B). Yield: 61%; homogeneous in CCD (solvent system: cyclohexane / CHCl3 / acetic acid, 45:45:10, Rf = 0.6); p.f. 119-121 ° C; RMN-1 !! (d6-DMSO): 8.02 (t, 1H, NH, amide); 7.39-7.18 (m, 11H, H 's arom., NH uret.); 5.03 (dd, 2H, CH2 v. Z); 4.06 (m, 1H, H-Ca); 2.72 / 2.61 (2xm, 4H, CH2-CH2); 2.22 (broad s, 1H, SH). FAB-MS: m / z-359.1 [M + H +]; Mf = 358.1 calculated for C? 9H22N203S N, N'-Bis-benzyloxycarbonyl-L-cystine-bis-2- (4-hydroxy phenyl) ethylamide (16a) From N, N'-bis-benzyloxycarbonyl-cystine and 2- (4-hydroxyphenyl) ethylamide in accordance with (A), Yield: 71%; homogeneous in CCD (solvent system: cyclohexane / CHCl3 / acetic acid, 45:45:10, Rf = 0.5).

N-Benzylkoxycarbonyl-L-cysteine -2- (4-hydroxyifenyl) ethylamide (16) Reduction of 16a according to (B). Yield: 24%; homogeneous on CCD (solvent system: cyclohexane / CHCl3 / acetic acid, 45:45:10, Rf = 0.6): m.p. 133-135 ° C; 1 H-NMR (d6-DMSO): 9.11 (s, 1H, phenol, OH); 7.98 (t, 1H, NH, amide); 7.38 (m, 6H, arom.V.Z, NH uret.); 6.99 / 6.68 (2xd, 4H, arom.phenol, H's); 5.04 (dd, 2H, CH2 v. Z); 4.05 (m, 1H, H-Ca); 2.73 / 2.60 (2xm, 4H, CH2-CH2); 2.26 (broad s, 1H, SH). FAB-MS: m / z 375.2 [M + H +]; Mf = 374.1 calculated for N, N'-Bis-benzyl oxycarbonyl-1-cystine-bis-4-chlorobenzylamide (17a) From the N, N'-bis-benzyloxycarbonyl-cystine and the 4-chlorobenzylamine according to (A). Yield: 99%; homogeneous in CCD (solvent system: CHCl3 / MeOH, 19: 1, Rf = 0.8) N-Benz i l oxy carbonyl-L-ci stein-4-obencil amide chlorite (1 7) Reduction of 17a according to (B). Yield: 71%; homogeneous in CCD (solvent system: cyclohexane / CHCl3 / acetic acid, 45:45:10, Rf = 0.85); p.f. 137 - 139 ° C; 1 H-NMR (d6-DMSO): 8.53 (t, 1H, NH, amide); 7.51 (d, 1H, NH uret.); 7.38-7.26 (, 9H, H 's arom.); 5.06 (dd, 2H, CH2 v. Z); 4.29 (d, 2H, CH2-Bn); 4.13 (m, 1H, H-Cß); 2.82 / 2.70 (2xm, 2H, ß-CH2); 2.53 (broad s, 1H, SH). FAB-MS: m / z = 379.1 [M + H +]; Mf = 378.1 calculated for C18H19C1N203S N N '-Bis-benzyloxy carbonyl-L-cyti-bis-3-phenylpropylamide (18a) Of the?,?' -bis-benzyloxycarbonyl-cystine and .la 3-phenylpropylamine according to (A). Yield: 94%; homogeneous in CCD (solvent system: cyclohexane / CHCl3 / acetic acid, 45:45:10, Rf = 0.7).

N-Benzyl oxycarbonyl-L-cysteine-3-phenylpropylamide (18) By reducing the 18a according to (B). Yield: 76%; homogeneous in CCD (solvent system: cyclohexane / CHCl3 / acetic acid, 45:45:10, Rf = 0.7); p.f. 104-106 ° C; RM? -1H (d6-DMSO): 8.02 (t, 1H,? H, amide); 7.43 (d, 1H,? H uret.); 7.38-7.15 (m, 10H, H 's arom.); 5.05 (dd, 2H, CH2 v. Z); 4.09 (m, 1H, H-Ca); 3.12 (m, 2H,? -CH2); 2. 70 / 2.69 (2xm, 2H, ß-CH2); 2.58 (t, 2H, CH2-Ph); 2.32 (broad s, 1H, SH); 1.70 (, 2H, CH2. -Cff2-CH2). FAB-MS: m / z = 373.2 [M + H +]; Mf = 372.2 calculated for C2oH24N203S N, N '-Bis-benzyloxycarbonyl-L-cystine-bis-triptamide (19a) Of the?,?' -bis-benzyloxycarbonyl-cystine and tpptamine according to (A). Yield: 75%; homogeneous in CCD (solvent system: cyclohexane / CHCl3 / acetic acid, 45:45:10, Rf = 0.6) Benzyl oxy c arbonyl-L-cysteine -tript amide (19) Reduction of 19a according to (B): Yield: 62%; homogeneous in CCD (solvent system: cyclohexane / CHCl3 / acetic acid, 45:45:10, Rf = 0.7); p.f. 150-152 ° C; RM? -1! (d6-DMS0): 10.80 (s, 1H,? H-tryptamine); 8.09 (t, 1H,? H amide); 7.54-6.96 (m, 11H, H 's arom., Uret.? H); 5.05 (dd, 2H, CH2 v. Z); 4.08 (m, 1H, H-C (a)); 3.32 (m, 2H,? HCiJ2CH2); 2.82 (t, 2H,? HCH2Cif2); 2.77 / 2.65 (2xm, 2H, ß-CH2); 2.26 (m, 1H, SH). FAB-MS: m / z = 398.2 [M + H +]; Mf 397.2 calculated for C2? H23? 303S N, Nr -Bi s -h examoyl -L-cis tina -bi s -benzylamide (2 Oa) Prepared from 6b and hexanoic acid according to procedure (A). Yield: 86%; homogeneous in CCD (solvent system: cyclohexane / chlorofor or acetic acid, 45:45:10, Rf = 0.6). NMR-1H (d6-DMSO): 8.48 (t, 1H, NH, amide); 8.02 - (d, 1H, NH-uret.); 7.3-7.2 (m, 5H, H 's arom.); -4.41 (m, 1H, H-Ca); 4.28 (d, 2H, CH2-Bn); 2.80 / 2.70 (2xm, 2H, ß-CH2); 2.25 (t, 1H, SH); 2.17 (m, 2H, -Ci2-C0-); 1.49-1.21 (m, 10H, alkyl), 0.87 (t, 3H, -CH3).

N-Hexamoyl-L-ci steine-benzylamide (20) Reduction of the -20a according to procedure (B). Performance: 69%; p.f. 141-143 ° C: • NMR-1H (d6-DMSO): NMR-XH (d6-DMSO): 8.48 (t, 1H, NH, amide); 8.02 (d, 1H, NH-uret.); 7.31-7.2 (m, 5H, H 's arom.); 4.40 (m, 1H, H-Ca); 4.22 (d, 2H, CH2-Bn); 2. 80 / 2.70 (2xm, 2H, ß-CH2); 2.3 (broad s, 1H, SH); 2.12 (m, 2H, -Cff2-C0-); 1.50-1.19 (, 6H, alkyl), 0.85 (t, 3H, -CH3). FAB-MS: m / z = 309. 2 [M + H +]; Mf = 308. 2 calculated for C? 6H24N202S N ^ N '-Bis-octamoyl-L-cystine-bis-benzyl amide (21a) Prepared from 6b and octanoic acid according to process (A). Yield: 86%; homogeneous in CCD (solvent system: cyclohexane / chloroform / acetic acid, 45:45:10, Rf = 0.6).

N-Octanoyl-L-cysteine-benzylamide (21) Reduction of 21a according to procedure (B). Performance: 73%; p.f. 137,139 ° C; ? MR-1H (d6-DMSO): RM? -1H (d6-DMS0); 8.48 (t, 1H,? H, amide); 8.02 (d, 1H,? H-uret.); 7.3.7.2 (, 5H, H 's arom.); 4.41 (m, 1H, H-Ca); 4.28 (d, 2H, CH2-Bn); 2. 80 / 2.70 (2xm, 2H, ß-CH2); 2.25 (t, 1H, SH); 2.17 (m, 2H, -CH2-CO-); 1.49-1.21 (m, 10H, alkyl), 0.87 (t, 3H, -CH3) - FAB-MS: m / z = 337.2 [M + H +]; Mf = 336.2 calculated for N, N '-Bis-decanoyl-L-cystine-bis-benzyl amide (22a) Prepared from 6b and decanoic acid according to process (A). Performance: quantitative; homogeneous in CCD (solvent system: cyclohexane / chloroform / acetic acid, 45:45:10, Rf = 0.9).

N-Decanoic-L-cysteine-benzyl amide (22) Reduction of 22a according to procedure (B). Yield: 33%; Rf = 0.7); p.f. 138 - 140 ° C; 1 H-NMR (d6-DMSO): 8.46 (t, 1H, NH, amide); 8.02 (d, 1H, NH-uret.); 7.3-7.2 (m, 5H, H 's arom.); 4.4 (m, 1H, H-Ca); 4.29 (d, 2H, CH2-Bn); 2.80 / 2.70 (2xm, 2H, ß-CH2); 2.25 (t, 1H, SH); 2.18 (m, 2H, -Ceffe-CO-); 1.49-1.19 (, 14H, alkyl), 0.85 (t, 3H, -CH3). FAB-MS: m / z = 365.2 [M + H +]; Mf 364.2 calculated for C2oH32N202S 1. Beckett R. P .; Davidson A. H .; Drummond, A. H .; Huxley, P .; hittaker, M. Drug Disc. Today 1996 2. Wünsch, E. in Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/1, Springer Verlag, Stuttgart, 1974. 3. Stack, M. S .; Gray, R. D. J. Bi ol. Chem. 1989, 264, 4277. 4. Nagase, H .; Fields, C. G .; Fields, G. B. J. Bi ol. Chem:. 1994, 269, 20952.

. Copeland, R. A .; Lombardo, D .; Giannaras, J .; Decicco, C. P. Bi oorg. Med. Chem. Let t. 1995, 5, 1947.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

Having described the invention as above, property is claimed as contained in the following:

Claims (5)

1. A compound represented by general formula I, which binds and inhibits the matrix metalloproteinases (MMPs), wherein the cysteine portion contains an unprotected thiol group, the cysteine portion being in the L or D configuration characterized in that A represents -CO-, -SO; , -NH-CO-, or -0-C0-R: represents hydrogen, a linear or branched, saturated or unsaturated alkyl group of 1 to 15 carbon atoms or an alkyl group of 1 to 15 carbon atoms substituted by halogen, mercapto, hydroxy, alkoxy, amino or nitro, or by aromatic or non-aromatic, carbocyclic ring systems which are optionally substituted once or several times or optionally substituted aromatic or non-aromatic heterocycles, their pharmacologically acceptable salts, or optically active forms thereof. R represents hydroxy, a linear or branched, saturated or unsaturated alkyl group of 1 to 15 carbon atoms or an alkyl group of 1 to 15 carbon atoms substituted by aromatic or non-aromatic, carbocyclic ring systems which are optionally substituted once or several times or optionally substituted aromatic or non-aromatic heterocycles, pharmacologically acceptable salts thereof, or optically active forms thereof.
2. 2. A pharmaceutical composition, characterized in that it contains a compound according to claim 1, or pharmacologically acceptable salts, or optically active forms thereof and pharmaceutically acceptable carriers.
3. 3. A therapeutic composition according to claim 2 for the treatment of rheumatoid arthritis and related diseases in which the collagenolytic activity is a help factor.
4. 4. The use according to claim 3, wherein the dose of the therapeutic agent is 0.1 to 300 mg / kg of body weight.
5. 5. The use according to claim 3 or 4, wherein the therapeutic agent is administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically. SUMMARY OF THE INVENTION A compound represented by the general formula (I), which binds and inhibits matrix metalloproteinases (MMPs), wherein the cysteine portion contains an unprotected thiol group, the cysteine portion being in the L or D configuration in where A represents -CO-, -S02-, -NH-CO-, or -0-C0-, Ri represents hydrogen, a linear or branched, saturated or unsaturated alkyl group of 1 to 15 carbon atoms or an alkyl group of 1 to 15 carbon atoms substituted by halogen, mercapto, hydroxy, alkoxy, amino or nitro, or by aromatic or non-aromatic, carbocyclic ring systems which are optionally substituted once or several times or aromatic or non-aromatic heterocycles, optionally substituted , their pharmacologically acceptable salts, or optically active forms thereof. R represents hydroxy, a linear or branched, saturated or unsaturated alkyl group of 1 to 15 carbon atoms or an alkyl group of 1 to 15 carbon atoms substituted by aromatic or non-aromatic, carbocyclic ring systems which are optionally substituted once or several times or optionally substituted aromatic or non-aromatic heterocycles, pharmacologically acceptable salts thereof, or optically active forms thereof, processes for the preparation, pharmaceutical compositions and their use in medicine. (i)