Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-12-02
1995-10-17
Fan, Jane
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514339, 5142332, 514 33, 514256, 546270, 546273, 546256, 544131, 544333, C07D51304, A61K 3144
Patent
active
054591520
DESCRIPTION:
BRIEF SUMMARY
This application is A 371 of PCT/US92/05890 Jul. 14, 1992 now WO/93-01813 Feb. 4, 1993. This application is a continuation of Ser. No. 07/731,681 Jul. 1, 1991 now abandoned.
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 indolecarbonyl pyridylpyrrolothiazole 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 inflammation and may play a physiological or pathobiological role in a variety of clinical conditions, such as asthma and pulmonary dysfunction, acute inflammation, transplanted organ rejection, shock, thrombosis, 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, orally active antagonists of PAF.
SUMMARY OF THE INVENTION
The present invention provides, in its principal aspect, compounds having PAF antagonsist activity of the formula: ##STR2## or a pharmaceutically acceptable salt thereof.
In the formula given above, R.sup.1 is one or more groups 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 six carbon atoms; (E) alkoxy of from one to seven carbon atoms; (F) phenyl, optionally substituted by (1) alkyl of from one to six carbon atoms, (2) alkoxy of from one to six carbon atoms, or (3) halogen; (G) NR.sup.7 R.sup.8 where R.sup.7 and R.sup.8 are independently selected from (1) hydrogen, and (2) alkyl of from one to six carbon atoms, or (3) taken together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered nitrogen-containing ring; (H)-COOR.sup.9 where R.sup.9 is independently selected from (1) hydrogen, and (2) alkyl of from one to six carbon atoms, (I)-CONR.sup.7 R.sup.8 were R.sup.7 and R.sup.8 are as defined above; (J) -SO.sub.2 NR.sup.7 R.sup.8 where R.sup.7 and R.sup.8 are as defined above; (K) 2- or 3-furyl, (L) 2- or 3-thienyl, (M) 2-, 4-, or 5-thiazolyl, (N) 2-, 3-, or 4-pyridyl, (O) 2-, or 4-pyrimdyl, (P) benzoyl, wherein the phenyl moiety is optionally substituted by (1) halogen, (2) alkyl of from one to six carbon atoms, or (3) alkoxy of from one to six carbon atoms; (Q) phenoxy optionally substituted by (1) halogen, (2) alkyl of from one to six carbon atoms, or (3) alkoxy of from one to six carbon atoms; (R) phenylalkyloxy in which the alkyl portion contains from one to six carbon atoms and the phenyl is optionally substituted with (1) halogen, (2) alkyl of from one to six carbon atoms, or (3) alkoxy of from one to six carbon atoms, and (S) phenylalkoyl in which the alkoyl portion contains from one to seven carbon atoms and the phenyl moiety is optionally substituted by; (1) halogen; ( 2) alkyl of from one to six carbon atoms, or (3) alkoxy of from one to six carbon atoms.
The substituent group R.sup.2 is selected from the group consisting of (A) hydrogen, (B) alkyl of from one to six carbon atoms; (C)-(CH.sub.2).sub.p COOR.sup.9, where p is 0 or an integer of from 1 to 4 and R.sup.9 is as de
REFERENCES:
Chem. Abstr., 1156: 280013z (1991).
Chem. Abstr., 116: 255603e (1992).
D. Lave, et al., Drigs of the Future, 14(9): 891-898 (1989).
D. Lave, et al., J. Pharm. Belg., 45(3) 219-223 (1990).
F. Soler, Drugs of the Future, 17(3): 207-213 (1992).
Carrera, Jr. George M.
Davidsen Steven K.
Heyman H. Robin
Holms James H.
Martin Michael B.
Abbott Laboratories
Fan Jane
Janssen Jerry F.
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