Platelet activating factor antagonists

Details Platelet activating factor antagonists Platelet activating factor antagonists

1993-07-07

1995-01-17

Ivy, C. Warren

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

514339, C07D21304, C07D20904, C07D27704

Patent

active

053826701

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to compounds having pharmacological activity, to compositions containing these compounds, and to a medical method of treatment employing the compounds and compositions. More particularly, this invention concerns certain pyridylthiazolidine, pyridyldithiolane, and pyridylpyrrolidine compounds and their salts which have platelet activating factor (PAF antagonist activity, to pharmaceutical compositions containing these compounds, and to a method of treating PAF-mediated disorders.


BACKGROUND OF THE INVENTION

Platelet activating factor (PAF) is a phospholipid released from human and other animal cells and is an acetylglyceryl ether of phosphorylcholine as represented by the following formula: ##STR1## where n is 15 or 17.
PAF is physiologically active and causes contraction of the airway smooth muscle, increased vascular permeability, platelet aggregation, hypotension and the like. It is now recognized as a powerful mediator of intimation and may play a physiological or pathobiologic role in a variety of clinical conditions, such as endotoxin- and IgG-induced shock (septic shock), asthma and pulmonary dysfunction, acute inflammation, transplanted organ rejection, thrombosis, cardiac anaphylaxis, gastrointestinal ulceration, allergic skin diseases, retinal and corneal diseases, chemically induced liver cirrhosis, and ovimplantation in pregnancy.
Several PAF antagonists have been reported (e.g., U.S. Pat. No. 4,948,795, European Patent Application EP 279681, and U.S. Pat. No. 4,786,645) but none have received wide acceptance. Therefore, there is a continuing need for the development of potent antagonists of PAF which have low toxicity.


SUMMARY OF THE INVENTION

The present invention provides, in its principal aspect, compounds having PAF antagonist activity of the formula: ##STR2## where R is B where B is ##STR3## in which A is methylene, hydroxymethyl, or carbonyl, X is sulfur, or NR.sup.5 where R.sup.5 is hydrogen, alkyl of from one to six carbon atoms, formyl, alkoyl of from one to six carbon atoms, alkylsulfonyl of from one to six carbon atoms, trihaloacetyl, or --C(O)NR.sup.6 R.sup.7 where R.sup.6 and R.sup.7 are independently selected from hydrogen and alkyl of from one to six carbon atoms. The group Y is sulfur or methylene.
Alternatively, R is selected from (a) hydrogen; (b) alkyl of from one to six carbon atoms; (c) --(CH.sub.2).sub.n C(O)NR.sup.6 R.sup.7 where R.sup.6 and R.sup.7 are as previously defined and where n is from zero to four, (d) --(CH.sub.2).sub.n C(O)OR.sup.8 where R.sup.8 is alkyl of from one to six carbon atoms, phenyl, optionally substituted with alkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, or halogen; phenylalkyl in which the alkyl portion contains from one to four carbon atoms, alkoxy of from one to six carbon atoms, or halogen, and where n is as previously defined; (e) --(CH.sub.2).sub.n C(O)R.sup.9 where n is as previously defined and R.sup.9 is hydrogen or alkyl of from one to six carbon atoms; (f) --(CH.sub.2).sub.m COOH where m is from one to four, (g) --(CH.sub.2).sub.m NR.sup.6 R.sup.7 where m, R.sup.6, and R.sup.7 are as previously defined; (h) --(CH.sub.2).sub.n SO.sub.2 R.sup.8 where n and R.sup.8 are as previously defined; (i) --(CH.sub.2).sub.n SO.sub.2 NR.sup.6 R.sup.7 where n, R.sup.6, and R.sup.7 are as previously defined; (j) phenylalkyl in which the alkyl portion contains from one to six carbon atoms; and (k) benzoyl, optionally substituted with halogen, alkyl of from one to six carbon atoms, or alkoxy of from one to six carbon atoms.
R.sup.1 is hydrogen or B with the proviso that one of R or R.sup.1 is B, but R and R.sup.1 are not both B.
R.sup.2 is selected from hydrogen or alkyl of from one to six carbon atoms.
R.sup.3 and R.sup.4 are independently selected from the group consisting of (a) hydrogen; (b) halogen; (c) alkyl of from one to six carbon atoms; (d) alkoxy of from one to carbon atoms; (e) alkoyl of from one to six carbon atoms; (f) cyano; (g) phenylalkoxy in which the alkoxy

REFERENCES:
patent: 5120749 (1992-06-01), Summers

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