Substituted tryptophan derivatives

Details Substituted tryptophan derivatives Substituted tryptophan derivatives

2002-07-10

2004-04-27

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S414000, C548S143000, C548S253000, C548S467000

Reexamination Certificate

active

06727266

ABSTRACT:

TECHNICAL FIELD
This invention relates to substituted tryptophane derivatives and metalloproteinase inhibitors containing the same.
BACKGROUND ART
An extracellular matrix, consisting of collagen, fibronectin, laminin, proteoglycan, etc., has a function to support tissues, and plays a role in propagation, differentiation, adhesion, or the like in cells. Metalloproteinases which are protease having a metal ion in the active center, especially matrix metalloproteinases (MMP), are concerned with the degradation of the extracellular matrix. Many types of MMP, from MMP-1 (type-I collagenase) to MMP-18, have been reported as enzymes working for the growth, remodeling of tissues, etc. under usual physiological conditions. It is reported, however, that the progression of various kinds of diseases involving breakdown and fibrosis of tissues (e.g., osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontitis, metastasis and invasion of tumor, and virus infection (HIV infection)) is related with increase of the manifestation or activity of the above-mentioned enzyme.
Substituted tryptophane derivatives having MMP inhibitory activities are described in WO97/27174, WO99/04780, JP11-246527A, EP-0877018A1 and the like.
DISCLOSURE OF INVENTION
The inventors of the present invention have found that certain new substituted tryptophane derivatives have a potent activity to inhibit MMP.
The present invention relates to 1) a compound of the formula (I):
wherein R
2
is hydrogen, optionally substituted lower alkyl, or optionally substituted aralkyl;
R
3
is halogen, hydroxy, lower alkyloxy, or lower alkylthio;
n is an integer from 1 to 3;
R
1
is represented by the formula:
wherein R
4
is hydrogen, halogen, optionally substituted lower alkyl, lower alkyloxy, lower alkylthio, optionally substituted amino, or nitro;
R
5
is hydrogen, halogen, optionally substituted lower alkyl, lower alkyloxy, lower alkylthio, optionally substituted amino, nitro, or a non-aromatic heterocyclic group, provided that when R
5
is amino substituted with two lower alkyls, R
3
is not
6-
methyloxy or 5-fluoro;
R
6
is hydrogen, halogen, optionally substituted lower alkyl, lower alkyloxy, lower alkylthio, optionally substituted amino, or nitro,
provided that when R
6
is lower alkyl, R
3
is not 6-hydroxy or 6-lower alkyloxy;
R
7
is halogen, optionally substituted lower alkyl, lower alkyloxy, lower alkylthio, optionally substituted amino, or nitro;
R
8
is hydrogen, halogen, optionally substituted lower alkyl, lower alkyloxy, lower alkylthio, optionally substituted amino, or nitro; and
Y is —OH or —NHOH,
its optically active substance, its prodrug, its pharmaceutically acceptable salt, or its solvate.
In more detail, the invention relates to the following 2) to 12).
2) A compound of 1), wherein R
1
is a group represented by the formula:
wherein R
4
is halogen,
its optically active substance, its prodrug, its pharmaceutically acceptable salt, or its solvate.
3) A compound of 1), wherein R
1
is a group represented by the formula:
wherein R
5
is optionally substituted amino or a non-aromatic heterocyclic group, provided that when R
5
is amino substituted with two lower alkyls, R
3
is not 6-methyloxy or 5-fluoro;
its optically active substance, its prodrug, its pharmaceutically acceptable salt, or its solvate.
4) A compound of 1), wherein R
1
is a group represented by the formula:
wherein R
6
is lower alkyl,
its optically active substance, its prodrug, its pharmaceutically acceptable salt, or its solvate.
5) A compound of 1), wherein R
1
is a group represented by the formula:
wherein R
7
is lower alkyloxy,
its optically active substance, its prodrug, its pharmaceutically acceptable salt, or its solvate.
6) A compound of 1), wherein R
1
is a group represented by the formula:
wherein R
8
is halogen,
its optically active substance, its prodrug, its pharmaceutically acceptable salt, or its solvate.
7) A compound of any one of 1) to 6), wherein R
2
is hydrogen, its optically active substance, its prodrug, its pharmaceutically acceptable salt, or its solvate.
8) A compound of any one of 1) to 7), wherein R
3
is halogen, hydroxy, or lower alkyloxy and n is 1, its optically active substance, its prodrug, its pharmaceutically acceptable salt, or its solvate.
9) A pharmaceutical composition containing a compound of any one of 1) to 8) as an active ingredient.
10) A composition for inhibiting matrix metalloproteinase containing a compound of any one of 1) to 8) as an active ingredient.
11) Use of a compound of any one of 1) to 8) for preparation of a pharmaceutical composition for treating a disease related with matrix metalloproteinase.
12) A method for treating a disease related with matrix metalloproteinase of a mammal, including a human, which comprises administration to said mammal of a compound of any one of 1) to 8) in a pharmaceutically effective amount.
The term “halogen” herein used means fluoro, chloro, bromo, and iodo. Fluoro, chloro, and bromo are preferred.
In the present specification, the term “lower alkyl” employed alone or in combination with other terms means a straight- or branched chain monovalent hydrocarbon group having 1 to 8 carbon atom(s). Examples of the alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl and the like. C1 to C6 alkyl is preferred. C1 to C3 alkyl is more preferred.
In the present specification, the term “aryl” employed alone or in combination with other terms includes monocyclic or condensed ring aromatic hydrocarbons. Phenyl, 1-naphtyl, 2-naphtyl, anthryl, and the like are exemplified.
The term “aralkyl” herein used means the above mentioned “lower alkyl” substituted with the above mentioned one or more “aryl” at any possible position. Examples of the aralkyl are benzyl, phenethyl (e.g., 2-phenethyl and the like), phenylpropyl (e.g., 3-phenylpropyl and the like), naphthylmethyl (e.g., 1-naphthylmethyl and 2-naphthylmethyl and the like), anthrylmethyl (e.g., 9-anthrylmethyl and the like), and the like. Benzyl and phenylethy are preferred.
In the present specification, the term “non-aromatic heterocyclic group” employed alone or in combination with other terms includes a 5 to 7 membered non-aromatic ring which contains one or more hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen atoms in the ring and a condensed ring which are formed with two or more of the non-aromatic ring. Examples of the non-aromatic heterocyclic group are pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl), imidazolidinyl (e.g., 2-imidazolidinyl), pyrazolidinyl (e.g., 1-pyrazolidinyl, 2-pyrazolidinyl), pyrazolinyl (e.g., pyrazolinyl), piperidyl (piperidino, 2-piperidyl), piperazinyl (e.g., 1-piperazinyl), isoindolynyl (e.g., isoindolynyl), morpholinyl (e.g., morpholino, 3-morpholinyl) and the like.
The term “lower alkyloxy” herein used are methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, and the like. Methyloxy, ethyloxy, n-propyloxy, isopropyloxy and n-butyloxy are preferred.
The term “lower alkylthio” herein used are methylthio, ethylthio, and the like.
In the present specification, the term “acyl” employed alone or in combination with other terms includes alkylcarbonyl in which alkyl group is the above-mentioned “lower alkyl” and arylcarbonyl in which aryl group is the above-mentioned “aryl”. Examples of the acyl are acetyl, propionyl, butyloyl, benzoyl, and the like. “Lower alkyl” and “aryl” may be substituted respectively with substituents mentioned below.
In the present specification, the term “optionally substituted amino” employed alone or in combination with other terms includes amino which may be substituted with one or two of the above mentioned “lower alkyl”, “aryl”, “aralkyl”, or “acyl”. Examples of the optionally substituted amino are amino, methylamino, dimethylamino, ethylmethylamino, diethylamino, ethylmethylamino, benzylamino, acetylamino, benzoylamino and the like. Preferable are a

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