RU2000124933A - MATRIX METALLOPROTEINASE INHIBITORS - Google Patents

Claims (14)

1. The compound of General formula (I)

where X denotes the group -CO ₂ N or -CONHOH;
Y and Z are independently sulfur or oxygen, with at least one being sulfur
R ₁ is hydrogen, hydroxy, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl or (C ₃ -C ₈ ) cycloalkyl;
R ₂ is (C ₁ -C ₂₄ ) alkyl, phenyl (C ₁ -C ₆ ) alkyl or phenyl (C ₀ -C ₆ alkyl) O- (C ₁ -C ₆ ) alkyl, each of which can be independently substituted ( C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, halogen or cyano (CN);
R ₃ denotes the determining side chain of the natural α-amino acid, in which any functional groups can be protected, (C ₁ -C ₆ ) alkyl, which can optionally be substituted, or cycloaclyl (C ₁ -C ₆ ) alkyl;
R ₄ denotes hydrogen, (C ₁ -C ₆ ) alkyl, phenyl (C ₁ -C ₆ ) alkyl, optionally substituted phenyl or heteroaryl, or a group of the formula - (QO) _n -Q,
where Q denotes (C ₁ -C ₆ ) alkyl, where n denotes an integer> 1, and a non-continuous linear sequence of atoms in the group R ₄ is>12; any of the above alkyl or alkenyl groups is linear or branched;
or its salts, hydrates or solvates.  2. The diastereoisomer of a compound according to claim 1 in pure form or a mixture of the stereoisomers of the compound according to claim 1. 3. The compound according to any one of the preceding paragraphs, wherein R ₁ is hydrogen, hydroxyl, allyl, or propyl. 4. A compound according to any one of the preceding claims, wherein R ₂ is isobutyl, phenylpropyl, (4-chlorophenyl) propyl, (4-methylphenoxy) ethyl or (C ₆ -C ₁₆ ) alkyl. 5. A compound according to any one of the preceding claims, wherein R ₃ is benzyl, t-butyl, cyclohexylmethyl, 4-methoxybenzyl, indolmethyl, isobutyl, or isopropyl. 6. The compound according to any one of the preceding claims, wherein R ₄ is methyl, phenylpropyl, 2- (2-methoxyethoxy) ethyl, 2- (2-methoxyethoxymethoxy) ethyl, or 2- (ethoxyethoxymethoxy) ethyl. 7. A compound according to any one of the preceding claims, wherein R ₁ is hydrogen, hydroxyl, allyl, or propyl; R ₂ is isobutyl, phenylpropyl, (4-chlorophenyl) propyl, (4-methylphenoxy) ethyl or (C ₆ -C ₁₆ ) alkyl; R ₃ is benzyl, t-butyl, cyclohexylmethyl, 4-methoxybenzyl, indolmethyl, isobutyl, or isopropyl; R ₄ is methyl, phenylpropyl, 2- (2-methoxyethoxy) ethyl, 2- (2-methoxyethoxymethoxy) ethyl, or 2- (ethoxyethoxymethoxy) ethyl. 8. The compound according to any one of the preceding paragraphs, which is selected from the group including: a) N ⁴ -Hydroxy-2 (R) -phenylethyl-N ¹ - [1 (S) - (3-phenylpropylthiocarbamoyl) -2-phenylethyl] succinamide , b) N ⁴ -Hydroxy-2 (R) -isobutyl-N ¹ - [1 (S) - (3-phenylpropylthiocarbamoyl) -2-phenylethyl] succinamide, c) N ⁴ -Hydroxy-2 (R) -isobutyl- N ¹ - [1 (S) - (methylthiocarbamoyl) -2-phenylethyl] succinamide, d) N ⁴ -Hydroxy- [1 (S) - (methylthiocarbamoyl) -2-phenylethyl] -2 (R) -phenylpropyl] succinamide, e) N ⁴ -Hydroxy-2 (R) -phenylpropyl-N ¹ - [1 (S) - (3-phenylpropylthiocarbamoyl) -2-phenylethyl] succinamide, f) N ⁴ -Hydroxy-2 (R) -phenylpropyl-N ¹ - [1 (S) - (3-phenylpropyl okarbamoyl) -2-cyclohexylethyl] succinamide, g) N ⁴ -Hydroxy-N ¹ - [1 (S) - (methylthiocarbamoyl) -2-cyclohexylethyl] -2 (R) -phenylpropylsuccinamide, h) N ⁴ -Hydroxy-2 ( R) -isobuty-N ¹ -thion-N ¹ - [1 (S) - (methylcarbamoyl) -2-phenylethyl] succinamide, i) 3 (S), N ⁴ -Dyhydroxy-2 (R) -isobutyl-N ¹ - [1 (S) - (methylthiocarbamoyl) -2-cyclohexylethyl] succinamide, j) 3 (S), N ⁴ -Dyhydroxy-2 (R) -isobutyl-N ¹ - [1 (S) - (methylthiocarbamoyl) -2 -phenylethyl] succinamide, k) N ⁴ -Hydroxy-2 (R) -isobutyl-N ¹ - [1 (S) - (3-phenylpropylthiocarbamoyl) -2-cyclohexylethyl] succinamide, l) N ⁴ -Hydroxy-2 (R ) -isobutyl-N ¹ - [1 (S) - (3-methylthiocarbamoyl) -2-cyclohexylethyl] succinamide, m) N ⁴ -Hydroxy-2 (R) -isobutyl-N ¹ - [1 (S) - (3-methylthiocarbamoyl) -2- (1H-indole-3-yl) ethyl] succinamide, n) N ⁴ -Hydroxy-N ¹ - {1 (S) - [2- (2-methoxyethoxymethoxy) ethylthiocarbamoyl] -2-phenylethyl} -2 (R) -phenylpropylsuccinamide, o) 3 (S), N ^4- Dihydroxy-2 (R) -isobutyl-N ¹ - [1 (S) - (methylthiocarbamoyl) -2,2-dimethylpropyl] succinamide, p) 3 (S) -Allyl-N ⁴ -hydroxy-2 (R) -isobuty-N ¹ - {1 (S) - [ 2- (2-methoxyethoxy) ethylthiocarbamoyl] -2,2-dimethylpropyl} succinamide, q) 3 (S) -Allyl-N ⁴ -hydroxy-2 (R) -isobutyl-N ¹ - {1 (S) - [2 - (2-methoxyethoxy) etiltiokarbamoil] -2- (4-methoxyphenyl) ethyl} -succinamide, r) N ⁴ -Gidpokci-2 (R) -izobutil-N ¹ - [1 (S) - (methylthiocarbamoyl) -2-metilp sawdust] -3 (S) -propilsuktsinamid, s) N ⁴ -Gidpokci-2 (R) -izobutil-N ¹ - (1 (S) - {2- [2- ( 2-methoxyethoxy) ethoxy]} -3 etiltiokarbamoil -methylbutyl) -3 (S) -propylsuccinamide, t) 2 (R) -Dodecyl-N ⁴ -hydroxy-N ¹ - [1 (S) - (methylthiocarbamoyl) -3-methylbutyl] succinamide, u) 2 (R) -Dodecyl-N ⁴ -hydroxy-N ¹ - [1 (S) - (phenylethylthiocarbamoyl) -2-methylbutyl] succinamide, v) 2 (R) -Hexadecyl-N ⁴ -hydroxy-N ¹ - [1 (S) - (Phenylthiocarbamoyl) ethyl] succinamide, w) 2 (R) -hexadecyl-N ⁴ -hydroxy-N ¹ - [1 (S) - (methylthiocarbamoyl) -2,2-dimethylpropyl] succinamide, x) 3 (S), N ^4- Dihydroxy-N ¹ - {1 (S) - [2- (2-methoxyethoxy) ethylthiocarbamoyl] -2- (4-methoxyphenyl) ethyl} -2 (R) -phenylpropyl uccinamide, y) 3 (S), N ⁴ -Hydroxy-N ¹ - {1 (S) - [2- (2-methoxyethoxymethoxy) ethylthiocarbamoyl] -2-methylpropyl} -2 (R) -phenylpropylsuccinamide, z) N ⁴ -Hydroxy-2 (R) - (4-chlorophenyl) propyl-N ¹ {1 (S) - [2- (2-methoxyethoxy) ethylthiocarbamoyl] -2- (4-methoxyphenyl) ethyl} succinamide, aa) N ⁴ - Hydroxy-2 (R) - (4-chlorophenyl) propyl-N ¹ - (1 (S) - {2- [2- (2-methoxyethoxy) ethoxy] ethylthiocarbamoyl} -3-methylbutyl) succinamide, bb) N ⁴ - Hydroxy-2 (R) - (4-chlorophenyl) propyl-N ¹ - {1 (S) - [2- (2-methoxyethoxymethoxy) ethylthiocarbamoyl] -2-methylpropyl} succinamide, cc) N ⁴ -Hydroxy-2 (R ) - (4-chlorophenyl) propyl-N ¹ - [1 (S) - (methylthiocarbamoyl) -2- (1H-indole-3-yl) ethyl] with uccinamide, dd) N ⁴ -Hydroxy-N ¹ - {1 (S) - [2- (2-methoxyethoxymethoxy) ethylthiocarbamoyl] -2-methylpropyl} -2 (R) - (4-methylphenoxy) ethyl} succinamide, it) N ⁴ -Hydroxy-N ¹ - (1 (S) - {2- [2- (2-methoxyethoxy) ethoxy] ethylthiocarbamoyl} - (4-methoxyphenyl) ethyl) -2 (R) - (4-methylphenoxy) ethylsuccinamide, ff) N ⁴ -Hydroxy-N ¹ - [1 (S) - (methylthiocarbamoyl) -2- (1H-indol-3-yl) ethyl] -2 (R) - (4-methylphenoxy) ethylsuccinamide,
a diastereoisomer of any of said compounds, a mixture of stereoisomers of any of said compounds, and pharmaceutically acceptable salts, hydrates or solvates of said compounds. 9. The method of obtaining the compounds of formula I under item 1, characterized in that the acid of General formula (II)

is reacted with hydroxylamine, O-protected hydroxylamine or N, O-de-protected hydroxylamine, the acid of formula (II) possibly being protected in this reaction, followed by removal of any protecting groups from the resulting part of the hydroxamic acid and from any protected substituents in R ₁ , R ₂ , R ₃ and R ₄ .  10. Pharmaceutical composition comprising an effective amount of one or more compounds according to claims. 1-8 as an active ingredient together with pharmaceutically acceptable carriers and / or additional substances.  11. The pharmaceutical composition according to claim 10 in a standard dosage form for systemic treatment, containing from 0.07 mg to 1 g. One or more compounds according to claims. 1-8 as an active ingredient.  12. The pharmaceutical composition according to claim 10 in a standard dosage form for systemic treatment, containing from 0.5 mg to 500 mg of one or more compounds according to claims. 1-8 as an active ingredient.  13. A method of treating or preventing conditions including tissue rejection and inflammatory processes, such as rheumatoid arthritis, osteoarthritis, osteogenic disorders such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulcers and metastases, invasions and tumor growth, and treatment of neuro- inflammatory disorders, including disorders causing myelin cleavage, for example, multiple sclerosis, as well as in the treatment of diseases caused by the development of blood vessels, including arthritis and ost solid tumors, as well as psoriasis, proliferative retinopathies, neovascular glaucoma, ocular tumors, angiofibromas and hemangiomas, comprising administering to a patient in a pharmaceutical composition of the claim. 10-12.  14. The compound according to any one of paragraphs. 1-8, suitable for obtaining a drug for the treatment or prevention of conditions, including tissue rejection and inflammatory processes, such as rheumatoid arthritis, osteoarthritis, osteogenesis disorders such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulcers and metastases, invasions and tumor growth, and the treatment of neuro-inflammatory disorders, including disorders causing myelin cleavage, such as multiple sclerosis, as well as in the treatment of diseases caused by the development of vascular vessels, including arthritis and solid growth, as well as psoriasis, proliferative retinopathy, neovascular glaucoma, eye tumors, angiofibromas and hemangiomas.