Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-10-22
1998-01-06
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546118, A61K 3144, C07D47104
Patent
active
057055041
DESCRIPTION:
BRIEF SUMMARY
This application is the National phase of PCT/EP 95/03487, filed Sep. 9, 1995.
FIELD OF THE INVENTION
The present invention relates to new piperidine derivatives which are potent platelet activating factor (PAF) antagonists. The invention also relates to a process for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of diseases in which PAF is involved.
DESCRIPTION OF THE PRIOR ART
Platelet activating factor (PAF) or (1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine), also called acetyl glyceryl ether phosphorylcholine (AGEPC) or PAF-acether, is a natural phospholipid synthesized by different cells (basophiles, macrophages, neutrophiles, platelets) and tissues (heart, lung and kidney) of the organism.
PAF was described for the first time as a potent platelet aggregating agent. Later on it was demonstrated to have other biological activities in vivo, such as peripheral vasodilatation, increase of the vascular permeability, induction of bronchoconstriction and hyperreactivity of the respiratory tract. PAF also produces immediate hypotension followed by pulmonary and renal hypertension in rats, guinea pigs, rabbits and dogs, and it has been rated as the most potent ulcerogenic agent described until now.
Consequently, PAF is a mediator that is implicated in a large set of pathological processes such as asthma, septic shock, transplant rejection, thrombosis, ulceration, inflammation and renal diseases.
The closest, prior art from the structural point of view is believed to be EP 441226, which discloses pyridylcyanomethylpiperazines and piperidines having PAF antagonistic activity, different from the compounds of the present invention.
DESCRIPTION OF THE INVENTION
The present invention relates to new piperidine derivatives of general formula I ##STR2## wherein: m represents 0, 1 or 2; or C.sub.1-4 alkyl; --SO.sub.2 --, then ##STR3## n represents 0, 1, 2 or 3; one of R.sup.2 or R.sup.3 represents C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl or aryl, and the other represents hydrogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.3-7 cycloalkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, aryl or aryl-C.sub.1-4 alkyl; or --CONR.sup.4 R.sup.5, and when A represents --CO-- or --SO.sub.2 --, then Z can also be hydroxy, --NR.sup.4 R.sup.5, --NR.sup.6 C(.dbd.O)OR.sup.4, --NR.sup.6 C(.dbd.O)R.sup.4, --NR.sup.6 C(.dbd.O)NR.sup.4 R.sup.5, --N(OH)C(.dbd.O)NR.sup.4 R.sup.5 or --NR.sup.6 SO.sub.2 R.sup.4 ; case R.sup.2 represents C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl or aryl; aryl-C.sub.14 alkyl or bisaryl-C.sub.1-4 alkyl; --C(.dbd.O)OR.sup.4, --C(.dbd.O)R.sup.4, --C(.dbd.O)NR.sup.4 R.sup.5, or --SO.sub.2 R.sup.4 ; phenyl substituted with 1, 2, 3 or 4 groups independently selected from halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, cyano, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, C.sub.1-4 alkylcarbonyl, C.sub.1-4 alkylcarbonyloxy, C.sub.1-4 alkoxycarbonyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylthio, C.sub.1-4 alkylcarbonylamino or C.sub.1-4 alkoxycarbonylamino; and their salts and solvates.
The invention also provides a pharmaceutical composition which comprises an effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.
The invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by PAF. Preferred is the use for the manufacture of a medicament for the treatment or prevention of ischemia and shock states such as septic shock, anaphylactic shock, hemorrhagic shock and myocardial ischemia; pancreatitis; and diseases related with allergy and inflammation such as asthma, dermatitis, urticaria, arthritis and psoriasis.
The invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof for the treatment or p
REFERENCES:
patent: 5358953 (1994-10-01), Alker
"Quantitative Investigations into the Aggregation of Blood Platelets", G.V.R. Born, J. Physiol., 1962, 162, pp. 67-68.
Almansa Carmen
Bartroli Javier
Carceller Elena
Jimenez Pere J.
Recasens Nuria
Huang Evelyn
Ivy C. Warren
J. Uriach & Cia S.A.
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