Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1987-06-29
1988-08-30
Lee, Mary C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546291, 546300, 546301, 546329, 546330, 546333, 546334, 546337, 546339, 546343, 546344, 548337, 548341, C07D21363, C07D21365, C07D23370
Patent
active
047678658
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
Background of the Invention
The present invention relates to novel compositions of matter. More particularly, the present invention relates to pyridyl substituted indenes and indoles. These compounds are potent thromoboxane A.sub.2 inhibitors and as such represent useful pharmacological agents.
Since the discovery that human platelets convert the prostaglandin endoperoxide (PGH.sub.2) into a labile proaggregatory molecule known as thromboxane A.sub.2 (TXA.sub.2), researchers have sought compounds that could selectively inhibit the biological activity of TXA.sub.2. This end may be achieved in two different ways: the synthesis of TXA.sub.2 can be blocked by inhibiting the TXA.sub.2 synthetase, or a compound could be a receptor level antagonist of TXA.sub.2. As therapeutic agents, TXA.sub.2 synthetase inhibitors are more useful. See, e.g., R. Gorman, "Biological and Pharmacological Evaluation of Thomboxane Synthetase Inhibitors," Advances in Prostaglandin and Thromboxane Research, 6: 417 (1980), and references cited therein. Most important are compounds which selectively inhibit TXA.sub.2 synthetase. Id.
A number of TXA.sub.2 synthetase inhibitors are known. See for example the bi-heterocyclic 9,11-trideoxy-PGF-type compounds disclosed in U.S. Pat. No. 4,112,224; SQ 80,388 [1-(3-phenyl-2-propenyl)-1H-imidazole] disclosed in D. Harris, et al., Advances in Prostaglandin and Thromboxane Research 6: 437 (1980); pyridine and its derivatives, disclosed in T. Miyamoto, et al., Advances in Prostaglandin and Thromoboxane Research, 6: 443 (1980), and British patent application No. 2,039,903A (abstracted in Derwent Farmdoc No. 50111C (1980)). See also H. Tai, et al., Advances in Prostaglandin and Thromboxane Research, 6: 447 (1980). Other compounds which have been disclosed as thromboxane synthetase inhibitors, include sodium p-benzyl-4(1-oxo-2-(4-chlorobenzyl)-3-phenylpropyl)phenyl phosphate, imidazoles, nordihydroguaiaretic acid, and 12L-hydroperoxy-5,8,10,14-eicosatetraenoic acid (HETE). As noted in the above named British patent specification, however, the inhibitory activity of these latter compounds on thromboxane synthetase is very weak making them unsatisfactory as practically effective medicines.
INFORMATION DISCLOSURE STATEMENT
U.S. Pat. No. 4,410,539 discloses certain imidazolyl- and pyridinyl-substituted benzofurans, benzothiophenes, and indoles which are stated to be thromboxane synthetase inhibitors. No pyridinyl-substituted indoles are actually named therein. U.S. Pat. Nos. 4,452,986 and 4,447,620 disclose imidazolyl-substituted benzofurans and benzothiophenes, respectively, as thromboxane synthetase inhibitors. U.S. Pat. Nos. 4,495,357; 4,490,531; and 4,455,427 all disclose certain pyridinyl substituted benzofurans as thromboxane synthetase inhibitors. Copending applications Ser. Nos. 715,595 and 715,597, both filed Mar. 25, 1985, disclose pyridinyl-substituted benzothiophenes.
SUMMARY OF THE INVENTION
The present invention particularly provides: acceptable acid addition salts thereof.
The present invention also provides: A compound of the formula II: thereof.
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix (Ci-Cj) indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive. Thus (C1-C3)alkyl refers to alkyl of one to 3 carbon atoms, inclusive, or methyl, ethyl, propyl, and isopropyl.
Examples of alkyl of one to 12 carbon atoms, inclusive, are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and isomeric forms thereof.
The compounds of the present invention may be in the form of pharmacologically acceptable salts. These salts are formed when R.sub.1 is a pharmacologically acceptable cation. Such cations include: pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.
Especially preferred metal cations are those derived from the alkali metals,
REFERENCES:
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Chem Abstracts, vol. 66, No. 25; 115538m (1967).
Johnson Roy A.
Lin Chiu-Hong
Lee Mary C.
Richter J.
The Upjohn Company
Welch Lawrence T.
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