Substituted amidino compounds, their manufacture and methods of

Details Substituted amidino compounds, their manufacture and methods of Substituted amidino compounds, their manufacture and methods of

1995-07-25

1997-06-17

Davis, Zinna Northington

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

544162, 546226, 546306, 548539, 560 27, 564 47, 564 48, 564 91, 564 99, 564157, 564165, 5142375, 514330, 514423, 514478, 514595, 514596, 514604, 514605, 514616, 514620, C07C23732, A61K 31165, C07D21381

Patent

active

056397682

DESCRIPTION:

BRIEF SUMMARY
The invention relates to substituted amidinophenoxyalkoxyphenyl derivatives and thio analogs as defined herein which are particularly useful as selective Leukototriene B.sub.4 (LTB.sub.4) receptor antagonists, methods for preparation thereof, pharmaceutical compositions comprising said compounds, and a method of antagonizing LTB-4 and of treating conditions or syndromes in mammals which are responsive to LTB-4 antagonism using said compounds or pharmaceutical compositions comprising said compounds of the invention.
Leukotriene B.sub.4 (LTB.sub.4) is an important inflammatory mediator being a potent chemotactic agent and activator of polymorphonuclear leucocytes (PMN's) and monocytes. It modulates the production and effects of other important inflammatory mediators e.g. Interleukin-1 and gamma interferon. LTB.sub.4 has been implicated in the pathogenesis of a number of inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, non-steroidal-antiinflammatory-drug-induced gastropathy, adult respiratory distress syndrome (ARDS), myocardial infarction, allergic rhinitis, hemodialysis-induced neutropenia, and late phase asthma.
The compounds of the invention are useful for the treatment of the conditions mediated by LTB.sub.4 which are cited above. In addition, the compounds are also useful for the treatment of pain and osteoarthritis, for the treatment of ocular conditions, such as ocular allergy and inflammation, and also for the treatment of dermatitis, such as atopic and contact dermatitis.
There is a strong need in the art in finding potent antagonism of LTB.sub.4 on human PMN's, especially those which are orally active. It has been found that the compounds according to the present invention exhibit significant LTB.sub.4 antagonistic activity on human PMN's and are orally active.
The invention relates to substituted amidinophenoxyalkoxyphenyl derivatives and thio analogs of the formula ##STR2## wherein the C(.dbd.NH)--NHR.sub.3 group may be in tautomeric or isomeric form; and pharmaceutically acceptable salts thereof, in which: from an aliphatic hydrocarbon radical, an araliphatic hydrocarbon radical, an aromatic radical, and a cycloaliphatic hydrocarbon radical, or is amino which is disubstituted by a divalent aliphatic hydrocarbon radical or a said radical interrupted by oxygen; substituted by carboxy, by esterified carboxy or by amidated carboxy; carbonic acid, an organic carboxylic acid, a sulfonic acid, or a carbamic acid; sulphur (--S--); and interrupted by an aromatic radical; further substituted by one or more substituents selected from halogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy, and hydroxy which is etherified by an aliphatic alcohol or which is esterified by an aliphatic or araliphatic carboxylic acid; wherein aryl in the above definitions may be, independently of one another, further substituted by one or more substituents selected from halogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy, and hydroxy which is etherified by an aliphatic alcohol or which is esterified by an aliphatic or araliphatic carboxylic acid; aliphatic radical; which are particularly useful as selective LTB-4 antagonists, methods for preparation thereof, pharmaceutical compositions comprising said compounds, and a method of antagonizing LTB-4 and of treating diseases in mammals which are responsive to LTB-4 antagonism using said compounds or pharmaceutical compositions comprising said compounds of the invention.
The compounds of the invention wherein the C(.dbd.NH)--NHR.sub.3 group is in tautomeric or isomeric form are represented by formula I' ##STR3## wherein R.sub.1, R.sub.2, R.sub.3, X.sub.1, X.sub.2 and X.sub.3 have the meanings as defined for formula I.
As compounds according to the invention have a basic centre, they can thus form acid addition salts, especially pharmaceutically acceptable salts. These are formed, for example, with inorganic acids, such as mineral acids, for example sulfuric acid, a phosphoric or hydrohalic acid, or with organic

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