Certain cyclic thio substituted acylaminoacid amide derivatives

Details Certain cyclic thio substituted acylaminoacid amide derivatives Certain cyclic thio substituted acylaminoacid amide derivatives

1999-11-08

2001-03-13

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C544S168000, C546S224000, C546S245000, C546S309000, C548S537000, C548S557000, C548S966000, C549S009000, C549S072000, C549S088000, C549S346000, C549S425000, C549S487000, C549S512000, C564S153000, C564S154000

Reexamination Certificate

active

06201133

ABSTRACT:

SUMMARY OF THE INVENTION
The present invention relates to novel thio substituted cyclic acylaminoacid amide derivatives described below, as inhibitors of matrix-degrading metalloproteinases and TNF alpha (tissue necrosis factor alpha) activity, methods for preparation thereof, pharmaceutical compositions comprising said compounds, a method of inhibiting TNF alpha and matrix degrading metalloproteinase activity and a method of treating TNF alpha and matrix metalloproteinase dependent diseases or conditions in mammals which are responsive to matrix metalloprotease and TNF alpha inhibition, using such compounds or pharmaceutical compositions comprising such compounds of the invention.
The compounds of the invention inhibit matrix degrading metalloproteinases such as gelatinase, stromelysin, collagenase, macrophage metalloelastase, and also membrane-type matrix metallo-proteinases such as MT-MMP 1 and 2. They are particularly useful as collagenase-3 inhibitors. Compounds of the invention are also inhibitors of TNF-alpha converting enzyme (TNF-alpha convertase) and thus inhibit TNF alpha activity, e.g. suppress the production and/or release of TNF alpha, an important mediator of inflammation and tissue growth.
Thus the compounds of the invention inhibit matrix degradation and are useful for the treatment of gelatinase-, stromelysin-, collagenase-, TNF alpha-, MT-MMP-1 and 2-, and macrophage metalloelastase-dependent pathological conditions in mammals. Such conditions include malignant and non-malignant tumors (by inhibiting tumor growth, tumor metastasis, tumor progression or invasion and/or tumor angiogenesis), such tumors including e.g. breast, lung, bladder, colon, ovarian and skin cancer. Other conditions to be treated with the compounds of the invention include rheumatoid arthritis, osteoarthritis, bronchial disorders (such as asthma by inhibiting the degradation of elastin), atherosclerotic conditions (by e.g. inhibiting rupture of atherosclerotic plaques), as well as acute coronary syndrome, heart attacks (cardiac ischemia), strokes (cerebral ischemias), restenosis after angioplasty, and also vascular ulcerations, ectasia and aneurysms.
Further conditions to be treated with the compounds of the invention are inflammatory demyelinating disorders of the nervous system in which myelin destruction or loss is involved (such as multiple sclerosis), optic neuritis, neuromyelitis optica (Devic's disease), diffuse and transitional sclerosis (Schilder's disease) and acute disseminated encephalomyelitis, also demyelinating peripheral neuropathies, such as Landry-Guillain-Barre-Strohl syndrome for motor defects; also tissue ulceration (e.g. epidermal and gastric ulceration), abnormal wound healing, periodental disease, bone disease (e.g. Paget's disease and osteoporosis), also endometriosis, septic shock, inflammatory bowel disease, Crohn's disease and the like.
Ocular applications of the compounds of the invention include the treatment of ocular inflammation, corneal ulcerations, pterygium, keratitis, keratoconus, open angle glaucoma, retinopathies, and also their use in conjunction with refractive surgery (laser or incisional) to minimize adverse effects.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the cyclic thio substituted acylaminoacid amide derivatives of formula I
wherein
R represents hydrogen, lower alkyl, cycloalkyl, bicycloalkyl, adamantyl, aryl, biaryl, or mono- or di-(cycloalkyl, aryl or biaryl)-lower alkyl, di-(lower alkyl or aryl-lower alkyl)-amino-lower alkyl, or (piperidino, morpholino, pyrrolidino)-lower alkyl;
R
1
represents hydrogen, lower alkyl, cycloalkyl, aryl, biaryl, or (cycloalkyl, aryl or biaryl)-lower alkyl;
R
2
represents hydrogen, lower alkyl, lower alkoxy, aryl-lower alkyl, aryl-lower alkoxy, amino, mono- or di-(lower alkyl or aryl-lower alkyl)-amino, acylamino, or (lower alkyl or aryl-lower alkyl)-(thio, sulfinyl or sulfonyl);
R
3
represents hydrogen, lower alkyl, cycloalkyl, aryl-lower alkyl, cycloalkyl-lower alkyl, or C
2
-C
7
-alkyl interrupted by S, SO, SO
2
, O or N—R
5
;
R
4
represents hydrogen or acyl;
R
5
represents hydrogen, lower alkyl, aryl-lower alkyl, acyl, or (lower alkyl, aryl or aryl-lower alkyl)-sulfonyl;
A together with the carbon to which it is attached forms a ring and represents a bivalent radical of the formula (CH
2
)
P
which may be interrupted by S, SO, SO
2
, O, or N—R
5
;
n represents zero or an integer from one to four;
p represents an integer from 2 to 6;
any pharmaceutically acceptable salts thereof; and disulfides corresponding to said compounds of formula I wherein R
4
is hydrogen.
The compounds of the invention depending on the nature of the substituents, possess one or more asymmetric carbon atoms. Also the A-containing ring substituent R
2
is either cis or trans to the amide grouping. The resulting diastereoisomers, enantiomers and geometric isomers are encompassed by the instant invention.
Preferred are the compounds of the invention wherein the configuration of the asymmetric carbon atom of the terminal amino acid amide moiety corresponds to that of an L-amino acid precursor and is assigned the (S)-configuration.
Further preferred are the compounds of formula I in which the A-containing ring is e.g. cyclohexane in which the substituent R
2
is at the 4-position and is preferably cis to the amide grouping.
Compounds in which R
4
is acyl represent prodrug acyl derivatives and are preferably those derived from an organic carbonic acid, an organic carboxylic acid or a carbamic acid.
An acyl derivative which is derived from an organic carboxylic acid is, for example, lower alkanoyl, phenyl-lower alkanoyl or unsubstituted or substituted aroyl, such as benzoyl.
An acyl derivative which is derived from an organic carbonic acid is, for example, alkoxycarbonyl, especially lower alkoxycarbonyl, which is unsubstituted or substituted by carbocyclic or heterocyclic aryl or is cycloalkoxycarbonyl, especially C
3
-C
7
-cycloalkyloxycarbonyl, which is unsubstituted or substituted by lower alkyl.
An acyl derivative which is derived from a carbamic acid is, for example, aminocarbonyl which is substituted by lower alkyl, carbocyclic or heterocyclic aryl-lower alkyl, carbocyclic or heterocyclic aryl, lower alkylene or lower alkylene interrupted by O or S.
Pharmaceutically acceptable salts of any acidic compounds of the invention are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethylammonium, diethylammonium, and tris-(hydroxymethyl)-methylammonium salts.
Similarly acid addition salts, such as of mineral acids, organic carboxylic, and organic sulfonic acids e.g. hydrochloric acid, methanesulfonic acid, maleic acid, are possible provided a basic group, such as pyridyl, constitutes part of the structure.
The general definitions used herein have the following meaning within the scope of the present invention, unless otherwise specified.
The term “lower” referred to above and hereinafter in connection with organic radicals or compounds respectively defines such as branched or unbranched with up to and including 7, preferably up to and including 4 and advantageously one or two carbon atoms.
A lower alkyl group is branched or unbranched and contains 1 to 7 carbon atoms, preferably 1-4 carbon atoms, and represents for example methyl, ethyl, propyl, butyl, isopropyl or isobutyl. Lower alkyl for R
1
is preferably C
2
-C
5
-alkyl, advantageously C
2
-C
4
-alkyl.
Lower alkylene in general represents either straight chain or branched alkylene of 1 to 7 carbon atoms and represents preferably straight chain alkylene of 1 to 4 carbon atoms, e.g. a methylene, ethylene, propylene or butylene chain, or said methylene, ethylene, propylene or butylene chain mono-substituted by C
1
-C
3
-alkyl (advantageously methyl) or disubstituted on the same or different carbon atoms by C
1
-C
3
-alkyl (advantageously methyl), the total number of carbon atoms being

Affiliated with

Also associated with

Rating

Certain cyclic thio substituted acylaminoacid amide derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Certain cyclic thio substituted acylaminoacid amide derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Certain cyclic thio substituted acylaminoacid amide derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2453279