Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-30
2001-09-18
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252130, C514S301000, C514S231500, C546S114000, C544S061000, C544S127000, C544S362000
Reexamination Certificate
active
06291454
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel dithiepino[6,5-b]pyridines useful as calcium channel blockers. These compounds, and related pharmaceutical compositions, are useful for treating and preventing a number of disorders such as hypersensitivity, allergy, asthma, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature labor, urinary tract disorders, gastrointestinal motility disorders and cardiovascular disorders.
BACKGROUND OF THE INVENTION
Thiacycloalkeno[3,2-b]pyridines are inhibitors of calcium ion uptake into smooth muscle tissue. They act to relax or prevent contraction of tissue mediated by calcium mechanisms (Dodd et al., Drug Des. Discov. 1997 15:135-48). These compounds are active antihypertensives and bronchodilators.
Thiacycloalkeno[3,2-b]pyridines are also useful for the treatment of cardiovascular disorders, including hypertension, ischemia, angina, congestive heart failure, migraines, myocardial infarction and stroke. Such compounds are also useful for the treatment of other disorders such as hypersensitivity, allergy, asthma, dysmenorrhea, esophageal spasm, gastrointestinal motility disorders, glaucoma, premature labor and urinary tract disorders.
Dodd et al. evaluated a series of thiacycloalkeno[3,2-b]pyridines ranging in sulfone ring size from five to nine members for calcium antagonist activity. It was found that increasing the sulfone ring size from 5 to 8 members results in an in vitro potency increase of two orders of magnitude. Aromatic substitution patterns which favor tracheal effects over aortic effects were found to be 2—NO
2
and 2—Cl, 6—F. The ester side chain which was found to maximize in vivo activity was the N-benzyl-N-methyl aminoethyl moiety (Dodd et al., Drug Des. Discov. 1997, 15:135-48, and Drug Des. Discov. 1993, 10:65-75).
Numerous compounds related to thiacycloalkeno[3,2-b]pyridines are known, as exemplified by the following publications. U.S. Pat. No. 5,708,177 to Straub discloses a process for the preparation of optically active ortho-substituted 4-aryl- or heteroaryl-1,4-dihydropyridines by oxidation and subsequent reduction from their opposite enantiomers. U.S. Pat. No. 5,075,440 to Wustrow et al. discloses pyrido[2,3-f] [1,4]thiazepines and pyrido[3,2-b] [1,5]benzothiazepines which are useful as calcium channel antagonists with cardiovascular, antiasthmatic and antibronchoconstriction activity. U.S. Pat. Nos. 4,879,384 and 4,845,225, both to Schwender and Dodd, disclose substituted thiacycloalkeno [3,2-b] pyridines which are also useful as calcium channel antagonists with cardiovascular, antiasthmatic and antibronchoconstrictor activity. U.S. Pat. Nos. 4,285,955 and 4,483,985 disclose acyclic sulfone (substitution on simple dihydropyridines which possess calcium channel antagonist activity. U.S. Pat. No. 4,532,248 discloses a broad genus of dihydropyridines, including cyclic sulfones fused to a dihydropyridine nucleus. Cardiotonic activity is disclosed for the entire genus. Finally, 10-Phenyl-2H-thiopyranol[3,2-b]quinolines are disclosed in Pagani, G.P.A., J. Chem. Soc. Perkin Trans. 2, 1392 (1974). However, these compounds are not calcium channel antagonists. “Soft drugs” (also known as “antedrugs”) are biologically active drugs which are metabolically inactivated after they achieve their therapeutic role at their designed site of action. The use of soft drugs, instead of their non-inactivatable analogs, avoids unwanted side effects. Soft drugs are known generally (see, for example, Biggadike et al., 2000, J. Med. Chem. 43:19-21; Lee et al., 1998, Curr. Opin. Drug Disc. Dev. 1: 235-44). However, no dihydropyridine soft drugs are known.
SUMMARY OF THE INVENTION
This invention provides novel dithiepino[6,5-b]pyridines as defined hereinbelow, as well as methods for making same. This invention also provides a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.
This invention further provides a method of treating a subject suffering from a disorder whose alleviation is mediated by the reduction of calcium ion influx into cells whose actions contribute to the disorder, which method comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.
This invention slill further provides a method of inhibiting in a subject the onset of a disorder whose alleviation is mediated by the reduction of calcium ion influx into cells whose actions contribute to the disorder, which method comprises administering to the subject a prophylactically effective dose of the instant pharmaceutical composition.
Finally, this invention provides an apparatus for administering to a subject the instant pharmaceutical composition, comprising a container and the pharmaceutical composition therein, whereby the container has a means for delivering to the subject a therapeutic and/or prophylactic dose of the pharmaceutical composition.
REFERENCES:
patent: 4285955 (1981-08-01), Wehinger et al.
patent: 4483985 (1984-11-01), Wehinger et al.
patent: 4532248 (1985-07-01), Franckowiak et al.
patent: 4845225 (1989-07-01), Schwender et al.
patent: 4879384 (1989-11-01), Schwender et al.
patent: 4889866 (1989-12-01), Pfister et al.
patent: 4918087 (1990-04-01), Gandolfi et al.
patent: 5075440 (1991-12-01), Wustrow et al.
patent: 5708177 (1998-01-01), Straub
patent: 462696 (1991-12-01), None
patent: 2 178 738 (1986-06-01), None
patent: 58201764 (1983-11-01), None
Dodd et al., Drug Des. Discov. 1997 15:135-48.
Dodd et al., Drug Des. Discov. 1993, 10:65-75.
Pagani, G.P.A., J. Chem. Soc. Perkin Trans. 2, 1392 (1974).
Biggadike et al., 2000, J. Med. Chem. 43:19-21.
Lee et al., 1998, Curr. Opin. Drug Disc. Dev. 1: 235-44.
Edema et al., J. Org. Chem. 58: 5624-7, 1993.
Howard et al., J. Amer. Chem. Soc. 82:158-64, 1960).
Eistert et al. (Chem. Ber. 110, 1069-1085, 1977).
Mason et al. (J. Chem. Soc. (C) 2171-76, 1967.)
E. A. Fehnel (J. Amer. Chem. Soc. 74, 1569-74, 1952).
Bullington James L.
Dodd John H.
Hall Daniel A.
Dow Kenneth J.
Ortho-McNeil Pharmaceutical , Inc.
Robinson Binta
Rotman Alan L.
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