Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-01
2002-10-29
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C544S126000
Reexamination Certificate
active
06472530
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel benzo-fused 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 the 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 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. However, the compounds disclosed in this patent are not taught to be calcium channel blockers. Finally, 10-Phenyl-2H-thiopyranol[3,2-b]quinolines are disclosed in Pagani, G. P. A., J. Chem. Soc. Perkin Trans. 2,1392 (1974).
“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 benzo-fused 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 still 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.
DETAILED DESCRIPTION OF THE INVENTION
This invention provides a compound of Formula I,
or a pharmaceutically acceptable salt thereof, wherein
(a) R
1
, R
2
, R
3
, R
4
and R
5
are independently selected from the group consisting of H, OH, halogen, cyano, NO
2
, alkyl, C
1-8
alkoxy, C
1-8
alkylsulfonyl, C
1-4
carboalkoxy, C
1-8
alkylthio, difluoromethoxy, difluoromethylthio, trifluoromethyl and oxadiazole (formed by R
1
and R
2
);
(b) R
6
is selected from the group consisting of H, C
1-5
straight or branched alkyl, aryl, 3-piperidyl, N-substituted 3-piperidyl, N-substituted 2-pyrrolidinyl methylene and substituted alkyl, wherein
said N-substituted 3-piperidyl and said N-substituted 2-pyrrolidinyl methylene may be substituted with C
1-8
straight or branched chain alkyl or benzyl, and said substituted alkyl may be substituted with C
1-8
alkoxy, C
2-8
alkanoyloxy, phenylacetyloxy, benzoyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, carboalkoxy or NR′R″, wherein
(i) R′ and R″ are independently selected from the group consisting of H, C
1-8
straight or branched alkyl, C
3-7
cycloalkyl, phenyl, benzyl and phenethyl, or (ii) R′ and R″ together form a heterocyclic ring selected from the group consisting of piperidino, pyrrolidino, morpholino, thiomorpholino, piperazino, 2-thieno, 3-thieno and an N-substituted derivative of said heterocyclic rings, said N-substituted derivative being substituted with H, C
1-8
straight or branched alkyl, benzyl, benzhydryl, phenyl and/or substituted phenyl (substituted with NO
2
, halogen, C
1-8
straight or branched chain alkyl, C
1-8
alkoxy and/or trifluoromethyl);
(c) R
7
is selected from the group consisting of H, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno; and
(d) R is SO or SO
2
.
In one embodiment of Formula I, R
6
is —(CH
2
)
2
N(CH
3
)CH
2
PH. In another embodiment, R
6
is methyl. In a further embodiment R
4
and R
5
are Cl, R
7
is methyl, and R is SO. In yet a further embodiment, R
5
is Cl, R
7
is methyl, and R is SO
2
.
The following compounds are preferred embodiments of the present invention:
1H-[1,5]Benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2-chlorophenyl)-4,11-dihydro-2-methyl, methyl ester, 5,5,10-trioxide;
1H-[1,5]Benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2,3-dichlorophenyl)-4,11-dihydro-2-methyl, 2-[methyl(phenylmethyl)amino]ethyl ester, 5,5,10,10-tetraoxide;
1H-[1,5]Benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4,11-dihydro-2-methyl-4-(2-nitrophenyl), 2-[methyl(phenylmethyl)amino]ethyl ester, 5,5,10,10-tetraoxide;
1H-[1,5]Benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(3-chlorophenyl)-4,11-dihydro-2-methyl, 2-[methyl(phenylmethyl)amino]ethyl ester, 5,5,10,10-tetraoxide;
1H-[1,5]Benzodithiepino[3,2-b]pyridine-3-carboxylic acid, 4-(2-chlorophenyl)-
Bullington James L.
Hall Daniel A.
Desai Rita
Rotman Alan L.
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