U.S. patent application number 09/751005 was filed with the patent office on 2002-04-25 for benzosulfones and related compositions and methods.
Invention is credited to Bullington, James L., Dodd, John H., Hall, Daniel A., Rupert, Kenneth C..
Application Number | 20020049326 09/751005 |
Document ID | / |
Family ID | 22641084 |
Filed Date | 2002-04-25 |
United States Patent
Application |
20020049326 |
Kind Code |
A1 |
Dodd, John H. ; et
al. |
April 25, 2002 |
Benzosulfones and related compositions and methods
Abstract
This invention provides novel benzosulfones of the following
formulae: 1 These compounds are useful as calcium channel
antagonists with cardiovascular, antiasthmatic and
antibronchoconstriction activity. Thus, this invention also
provides pharmaceutical compositions, as well as methods, for
preventing and treating disorders such as hypersensitivity,
allergy, asthma, bronchospasm, dysmenorrhea, esophageal spasm,
glaucoma, premature labor, urinary tract disorders,
gastrointestinal motility disorders and cardiovascular
disorders.
Inventors: |
Dodd, John H.; (Stochton,
NJ) ; Rupert, Kenneth C.; (South Orange, NJ) ;
Bullington, James L.; (Hamilton Square, NJ) ; Hall,
Daniel A.; (Somerset, NJ) |
Correspondence
Address: |
Philip S. Johnson, Esq.
Johnson & Johnson
One Johnson & Johnson Plaza
New Brunswick
NJ
08933-7003
US
|
Family ID: |
22641084 |
Appl. No.: |
09/751005 |
Filed: |
December 28, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60175650 |
Jan 12, 2000 |
|
|
|
Current U.S.
Class: |
546/80 |
Current CPC
Class: |
A61P 37/02 20180101;
A61P 37/08 20180101; A61P 11/00 20180101; A61P 9/10 20180101; A61P
27/06 20180101; A61P 1/00 20180101; A61P 15/08 20180101; A61P 9/00
20180101; A61P 9/02 20180101; A61P 11/08 20180101; A61P 9/12
20180101; C07D 495/04 20130101; A61P 15/06 20180101; A61P 5/30
20180101; A61P 11/06 20180101; A61P 43/00 20180101 |
Class at
Publication: |
546/80 |
International
Class: |
C07D 495/04 |
Claims
What is claimed is:
1. A compound of Formula I, 13or a pharmaceutically acceptable salt
thereof, wherein (a) R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5
are independently selected from the group consisting of H, OH,
halogen, cyano, NO.sub.2, alkyl, C.sub.1-8 alkoxy, C.sub.1-8
alkylsulfonyl, C.sub.1-4 carboalkoxy, C.sub.1-8 alkylthio,
difluoromethoxy, difluoromethylthio, trifluoromethyl, and
oxadiazole (formed by R.sub.1 and R.sub.2); (b) R.sub.6 is selected
from the group consisting of H, C.sub.1-5 straight or branched
alkyl, alkylamine, aryl, 3-piperidyl, N-substituted 3-piperidyl,
and N-substituted 2-pyrrolidinyl methylene, wherein said
N-substituted 3-piperidyl and said N-substituted 2-pyrrolidinyl
methylene may be substituted with C.sub.1-8 straight or branched
chain alkyl or benzyl, and said substituted alkyl may be
substituted with C.sub.1-8 alkoxy, C.sub.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.sub.1-8
straight or branched alkyl, C.sub.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.sub.1-8
straight or branched alkyl, benzyl, benzhydryl, phenyl and/or
substituted phenyl (substituted with NO.sub.2, halogen, C.sub.1-8
straight or branched chain alkyl, C.sub.1-8 alkoxy and/or
trifluoromethyl); and (c) R.sub.7 is selected from the group
consisting of H, amino, alkyl, aryl, trifluoromethyl, alkoxymethyl,
2-thieno and 3-thieno.
2. The compound of claim 1 wherein R.sub.6 is selected from methyl,
--(CH.sub.2).sub.2N(CH.sub.3)CH.sub.2PH and 14
3. The compound of claim 2, wherein R.sub.4 is NO.sub.2and R.sub.7
is methyl.
4. The compound of claim 2, wherein R.sub.4 and R.sub.5 are Cl, and
R.sub.7 is methyl.
5. The compound of claim 1 wherein R.sub.7 is methyl.
6. The compound of claim 1 which is
[3]Benzothiepino[1,2-b]pyridine-3-carb- oxylic acid,
4-(2-chlorophenyl)-1,4,6,7-tetrahydro-2-methyl-, methyl ester,
5,5-dioxide.
7. The compound of claim 1 which is
[3]Benzothiepino[1,2-b]pyridine-3-carb- oxylic acid, 4-(2
,3-dichlorophenyl)-1,4,6,7-tetrahydro-2-methyl-,
2-[methyl(phenylmethyl)amino]ethyl ester, 5,5-dioxide.
8. The compound of claim 1 which is
[3]Benzothiepino[1,2-b]pyridine-3-carb- oxylic acid,
4-(2,3-dichlorophenyl)-1,4,6,7-tetrahydro-2-methyl-, methyl ester,
5,5-dioxide.
9. The compound of claim 1 which is
[3]Benzothiepino[1,2-b]pyridine-3-carb- oxylic acid,
1,4,6,7-tetrahydro-2-methyl-4-(pentafluorophenyl)-, methyl ester,
5,5-dioxide.
10. The compound of claim 1 which is
[3]Benzothiepino[1,2-b]pyridine-3-car- boxylic acid,
1,4,6,7-tetrahydro-2-methyl-4-(2-nitrophenyl)-, methyl ester,
5,5-dioxide.
11. The compound of claim 1 which is
[3]Benzothiepino[1,2-b]pyridine-3-car- boxylic acid,
4-(3-chlorophenyl)-1,4,6 ,7-tetrahydro-2-methyl-, methyl ester,
5,5-dioxide.
12. The compound of claim 1 which is
[3]Benzothiepino[1,2-b]pyridine-3-car- boxylic acid,
4-(2,3-dichlorophenyl)-I ,4,6,7-tetrahydro-2-methyl-, 2-[methyl
(2-thienylmethyl)amino]ethyl ester, 5,5-dioxide.
13. The compound of claim 1 which is
[3]Benzothiepino[1,2-b]pyridine-3-car- boxylic acid,
1,4,6,7-tetrahydro-2-methyl-4-(3-nitrophenyl)-, methyl ester,
5,5-dioxide.
14. The compound of claim 1 which is
[3]Benzothiepino[1,2-b]pyridine-3-car- boxylic acid,
4-(2-chloro-6-hydroxyphenyl)-1,4,6,7-tetrahydro-2-methyl-, methyl
ester, 5,5-dioxide.
15. The compound of claim 1 which is
[3]Benzothiepino[1,2-b]pyridine-3-car- boxylic acid, 4-(2-chloro
phenyl)-1,4,6, 7-tetrahydro-2-methyl-, 2-[methyl
(2-thienylmethyl)amino]ethyl ester, 5,5-dioxide.
16. The compound of claim 1 which is
[3]Benzothiepino[1,2-b]pyridine-3-car- boxylic acid,
4-(2-chlorophenyl)-1,4,6,7-tetrahydro-2-methyl-,
2-[methyl(phenylmethyl)amino]ethyl ester, 5,5-dioxide.
17. A compound of Formula II, 15or a pharmaceutically acceptable
salt thereof, wherein (a) R.sub.1, R.sub.2, R.sub.3, R.sub.4 and
R.sub.5 are independently selected from the group consisting of H,
OH, halogen, cyano, NO.sub.2, alkyl, C.sub.1-8 alkoxy, C.sub.1-8
alkylsulfonyl, C.sub.1-4 carboalkoxy, C.sub.1-8 alkylthio,
difluoromethoxy, difluoromethylthio, trifluoromethyl, and
oxadiazole (formed by R.sub.1 and R.sub.2); (b) R.sub.7 is selected
from the group consisting of H, amino, alkyl, aryl,
trifluoromethyl, alkoxymethyl, 2-thieno and 3-thieno; and (c)
R.sub.8 is selected from the group consisting of-alkyl-OH,
alkylamine, lactone, cyclic carbonate, alkyl-substituted cyclic
carbonate, aryl-substituted cyclic carbonate, -aryl-C(O)OR'",
-alkyl-aryl-C(O)OR'", -alkyl-OC(O)R'", -alkyl-C(O)R'",
-alkyl-C(O)OR'", -alkyl-N(R")C(O)R'", and -alkyl-N(R"")C(O)OR'",
wherein R'" and R"" are independently selected from the group
consisting of hydrogen, amino, alkyl, aryl, aryl-fused cycloalkyl
and heterocyclyl, the amino, alkyl, aryl, aryl-fused cycloalkyl and
heterocyclyl being optionally substituted with halogen, cyano,
NO.sub.2, lactone, amino, alkylamino, aryl-substituted alkylamino,
amide, carbamate, carbamoyl, cyclic carbonate, alkyl,
halogen-substituted alkyl, arylalkyl, alkoxy, heterocyclyl and/or
aryl (the aryl being optionally substituted with OH, halogen,
cyano, NO.sub.2, alkyl, amino, dimethylamino, alkoxy,
alkylsulfonyl, C.sub.1-4 carboalkoxy, alkylthio and/or
trifluoromethyl).
18. The compound of claim 17 wherein R.sub.7 is methyl and R.sub.1,
R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are independently selected
from hydrogen, halogen, trifluoromethyl and NO.sub.2.
19. The compound of claim 17 wherein R.sub.8 is selected from the
group consisting of -alkyl-OH, alkylamine, lactone, cyclic
carbonate, alkyl-substituted cyclic carbonate, aryl-substituted
cyclic carbonate, -aryl-C(O)OR'", -alkyl-aryl-C(O)OR'",
-alkyl-C(O)R'", -alkyl-N(R")C(O)R'", and -alkyl-N(R"")C(O)OR'".
20. The compound of claim 17 wherein R.sub.8 is selected from the
group consisting of
--(CH.sub.2).sub.2OC(O)CH(CH.sub.2CH.sub.3).sub.2,
--(CH.sub.2).sub.2OC(O)CH(CH.sub.3).sub.2,
--(CH.sub.2).sub.2OC(O)PH--OCH- (CH.sub.3).sub.2,
--CH.sub.2OC(O)CH.sub.2N(CH.sub.3)CH.sub.2PH,
--CH.sub.2OC(O)CH.sub.2--PH--N(CH.sub.3).sub.2, and
--CH.sub.2OC(O)CH(CH.sub.2).sub.6.
21. A pharmaceutical composition comprising the compound of claim 1
or 17 and a pharmaceutically acceptable carrier.
22. 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 pharmaceutical composition of claim 21.
23. The method of claim 22, wherein the subject has normal or low
blood pressure.
24. The method of claim 22, wherein the disorder is selected from
the group consisting of hypersensitivity, allergy, asthma,
bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature
labor, a urinary tract disorder, a gastrointestinal motility
disorder and a cardiovascular disorder.
25. The method of claim 24, wherein the disorder is asthma.
26. The method of claim 24, wherein the cardiovascular disorder is
selected from the group consisting of hypertension, ischemia,
angina, congestive heart failure, myocardial infarction and
stroke.
27. 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 pharmaceutical composition of claim 21.
28. The method of claim 27, wherein the subject has normal or low
blood pressure.
29. The method of claim 27, wherein the disorder is selected from
the group consisting of hypersensitivity, allergy, asthma,
bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature
labor, a urinary tract disorder, a gastrointestinal motility
disorder and a cardiovascular disorder.
30. The method of claim 29, wherein the disorder is asthma.
31. The method of claim 29, wherein the cardiovascular disorder is
selected from the group consisting of hypertension, ischemia,
angina, congestive heart failure, myocardial infarction and
stroke.
32. An apparatus for administering to a subject the pharmaceutical
composition of claim 21, 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.
33. A process for preparing the compound of Formula I 16which
comprises reacting compound 1a with compounds of Formulae 1b and 1c
to form compound 1d. 17
Description
FIELD OF THE INVENTION
[0001] This invention relates to novel benzosulfones 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
[0002] 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.
[0003] 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.
[0004] 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.sub.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).
[0005] 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, each 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 this
entire genus. However, these compounds are not 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).
[0006] "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
[0007] This invention provides novel benzosulfones 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.
[0008] 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.
[0009] 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.
[0010] 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
[0011] This invention provides a compound of Formula I, 2
[0012] or a pharmaceutically acceptable salt thereof, wherein
[0013] (a) R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are
independently selected from the group consisting of H, OH, halogen,
cyano, NO.sub.2, alkyl, C.sub.1-8 alkoxy, C.sub.1-8 alkylsulfonyl,
C.sub.1-4 carboalkoxy, C.sub.1-8 alkylthio, difluoromethoxy,
difluoromethylthio, trifluoromethyl, and oxadiazole (formed by
R.sub.1 and R.sub.2);
[0014] (b) R.sub.6 is selected from the group consisting of H,
C.sub.1-5 straight or branched alkyl, alkylamine, aryl,
3-piperidyl, N-substituted 3-piperidyl, and N-substituted
2-pyrrolidinyl methylene, wherein
[0015] said N-substituted 3-piperidyl and said N-substituted
2-pyrrolidinyl methylene may be substituted with C.sub.1-8 straight
or branched chain alkyl or benzyl, and said substituted alkyl may
be substituted with C.sub.1-8 alkoxy, C.sub.2-8 alkanoyloxy,
phenylacetyloxy, benzoyloxy, hydroxy, halogen, p-tosyloxy,
mesyloxy, amino, carboalkoxy or NR'R", wherein
[0016] (i) R' and R" are independently selected from the group
consisting of H, C.sub.1-8 straight or branched alkyl, C.sub.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.sub.1-8 straight or branched alkyl, benzyl,
benzhydryl, phenyl and/or substituted phenyl (substituted with
NO.sub.2, halogen, C.sub.1-8 straight or branched chain alkyl,
C.sub.1-8 alkoxy and/or trifluoromethyl); and
[0017] (c) R.sub.7 is selected from the group consisting of H,
amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and
3-thieno.
[0018] The following compounds are embodiments of the present
invention:
[0019] [3]Benzothiepino[1,2-b]pyridine-3-carboxylic acid,
4-(2-chlorophenyl)-1,4,6,7-tetrahydro-2-methyl-, methyl ester,
5,5-dioxide;
[0020] [3]Benzothiepino[1,2-b]pyridine-3-carboxylic acid,
4-(2,3-dichloro-phenyl)-1,4,6,7-tetrahydro-2-methyl-,
2-[methyl(phenylmethyl)amino]ethyl ester, 5,5-dioxide;
[0021] [3]Benzothiepino[1,2-b]pyridine-3-carboxylic acid,
4-(2,3-dichloro-phenyl)-1,4,6,7-tetrahydro-2-methyl-, methyl ester,
5,5-dioxide;
[0022] [3]Benzothiepino[1,2-b]pyridine-3-carboxylic acid,
1,4,6,7-tetrahydro-2-methyl-4-(pentafluorophenyl)-, methyl ester,
5,5-dioxide;
[0023] [3]Benzothiepino[1,2-b]pyridine-3-carboxylic acid,
1,4,6,7-tetrahydro-2-methyl-4-(2-nitrophenyl)-, methyl ester,
5,5-dioxide;
[0024] [3]Benzothiepino[1,2-b]pyridine-3-carboxylic acid,
4-(3-chlorophenyl)-1,4,6,7-tetrahydro-2-methyl-, methyl ester,
5,5-dioxide;
[0025] [3]Benzothiepino[1,2-b]pyridine-3-carboxylic acid,
4-(2,3-dichloro-phenyl)-1,4,6,7-tetrahydro-2-methyl-,
2-[methyl(2-thienylmethyl)amino]ethyl ester, 5,5-dioxide;
[0026] [3]Benzothiepino[1,2-b]pyridine-3-carboxylic acid,
1,4,6,7-tetrahydro-2-methyl-4-(3-nitrophenyl)-, methyl ester,
5,5-dioxide;
[0027] [3]Benzothiepino[1,2-b]pyridine-3-carboxylic acid,
4-(2-chloro-6-hydroxyphenyl )-1,4,6,7-tetrahydro-2-methyl-, methyl
ester, 5,5-dioxide;
[0028] [3]Benzothiepino[1,2-b]pyridine-3-carboxylic acid,
4-(2-chlorophenyl)-1,4,6,7-tetrahydro-2-methyl-,
2-[methyl(2-thienylmethy- l)amino]ethyl ester, 5,5-dioxide; and
[0029] [3]Benzothiepino[1,2-b]pyridine-3-carboxylic acid,
4-(2-chlorophenyl)-1,4,6,7-tetrahydro-2-methyl-, 2-[methyl(phenyl
methyl)amino]ethyl ester, 5,5-dioxide.
[0030] This invention also provides soft drug analogs of the
compounds of Formula I. These soft drugs are characterized by a
chemically labile moiety bound to the ester group in turn bound to
the dihydropyridine ring structure. The soft drugs permit the
instant drugs to exert their effect locally, and to subsequently be
metabolized in the blood stream, thereby reducing unwanted systemic
effects (e.g. low blood pressure). Use of such soft drug analogs
permits the administration of greater doses of the claimed
dihydropyridine compounds without subjecting the subject to
intolerable levels of unwanted systemic effects.
[0031] Specifically, this invention provides compounds of Formula
II, 3
[0032] or a pharmaceutically acceptable salt thereof, wherein
[0033] (a) R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are
independently selected from the group consisting of H, OH, halogen,
cyano, NO.sub.2, alkyl, C.sub.1-8 alkoxy, C.sub.1-8 alkylsulfonyl,
C.sub.1-4 carboalkoxy, C.sub.1-8 alkylthio, difluoromethoxy,
difluoromethylthio, trifluoromethyl, and oxadiazole (formed by
R.sub.1 and R.sub.2);
[0034] (b) R.sub.7 is selected from the group consisting of H,
amino, alkyl, aryl, trifluoromethyl, alkoxymethyl, 2-thieno and
3-thieno; and
[0035] (c) R.sub.8 is selected from the group consisting
of-alkyl-OH, alkylamine, lactone, cyclic carbonate,
alkyl-substituted cyclic carbonate, aryl-substituted cyclic
carbonate, -aryl-C(O)OR'", -alkyl-aryl-C(O)OR'", -alkyl-OC(O)R'",
-alkyl-C(O)R'", -alkyl-C(O)OR'", -alkyl-N(R")C(O)R'", and
-alkyl-N(R'")C(O)OR'", wherein
[0036] R'" and R'" are independently selected from the group
consisting of hydrogen, amino, alkyl, aryl, aryl-fused cycloalkyl
and heterocyclyl, the amino, alkyl, aryl, aryl-fused cycloalkyl and
heterocyclyl being optionally substituted with halogen, cyano,
NO.sub.2, lactone, amino, alkylamino, aryl-substituted alkylamino,
amide, carbamate, carbamoyl, cyclic carbonate, alkyl,
halogen-substituted alkyl, arylalkyl, alkoxy, heterocyclyl and/or
aryl (the aryl being optionally substituted with OH, halogen,
cyano, NO.sub.2, alkyl, amino, dimethylamino, alkoxy,
alkylsulfonyl, C.sub.1-4 carboalkoxy, alkylthio and/or
trifluoromethyl).
[0037] Each of the embodiments of the compound of Formula I set
forth above is also contemplated as an embodiment of the compound
of Formula II. In addition, in one embodiment of Formula II,
R.sub.7 is methyl and R.sub.1, R.sub.2, R.sub.3, R.sub.4, and
R.sub.5 are independently selected from hydrogen, halogen,
trifluoromethyl and NO.sub.2. In another embodiment of Formula II,
R.sub.8 is selected from the group consisting of -alkyl-OH,
alkylamine, lactone, cyclic carbonate, alkyl-substituted cyclic
carbonate, aryl-substituted cyclic carbonate, -aryl-C(O)OR'",
-alkyl-aryl-C(O)OR'", -alkyl-C(O)R'", -alkyl-N(R")C(O)R'", and
-alkyl-N(R'")C(O)OR'". More particularly, R.sub.8 is selected from
the group consisting of
--(CH.sub.2).sub.2OC(O)CH(CH.sub.2CH.sub.3).sub.2,
--(CH.sub.2).sub.2OC(O)CH(CH.sub.3).sub.2,
--(CH.sub.2).sub.2OC(O)PH--OCH- (CH.sub.3).sub.2,
--CH.sub.2OC(O)CH.sub.2N(CH.sub.3)CH.sub.2PH,
--CH.sub.2OC(O)CH.sub.2--PH--N(CH.sub.3).sub.2 and
CH.sub.2OC(O)CH(CH.sub.2).sub.6.
[0038] Unless specified otherwise, the term "alkyl" refers to a
straight, branched or cyclic substituent consisting solely of
carbon and H with no unsaturation. Alkyl may be substituted by, for
example, OH, halogen, cyano, NO.sub.2, alkyl, C.sub.1-8 alkoxy,
C.sub.1-8 alkylsulfonyl, C.sub.1-4 carboalkoxy, and C.sub.1-8
alkylthio. The term "alkoxy" refers to 0-alkyl where alkyl is as
defined. Aryl substituents include, for example, phenyl, naphthyl,
diphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl,
carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl,
hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl,
methoxyethylphenyl, acetamidophenyl, tolyl, xylyl,
dimethylcarbamylphenyl and the like. "Ar" may be aryl or
heteroaryl. The term "heterocyclyl", "heterocycle" or "heterocyclic
residue" represents a single or fused ring or rings having at least
one atom other than carbon as ring member, e.g. pyridine,
pyrimidine, oxazoline, pyrrole, imidazole, morpholine, furan,
indole, benzofuran, pyrazole, pyrrolidine, piperidine, thiophene,
and benzimidazole. Illustrative alkylamines include
--(CH.sub.2).sub.2N(Me)CH- .sub.2(Ar) such as
--(CH.sub.2).sub.2N(Me)CH.sub.2 (PH),
--CH.sub.2CH.sub.2--N(Me)--CH.sub.2(heteroaryl) and 4
[0039] The symbol "Ph" or "PH" refers to phenyl. The term "halo"
means fluoro, chloro, bromo or iodo. A "dehydrating agent," which
is used in a solvent such as CH.sub.2Cl.sub.2 or toluene, includes
but is not limited to sulfuric acid and acetic anhydride.
"Independently" means that when there are more than one
substituent, the substitutents may be different.
[0040] The compounds of the instant invention are asymmetric in the
dihydropyridine ring at the 4-position and thus exist as optical
antipodes. As such, all possible optical isomers, antipodes,
enantiomers, and diastereomers resulting from additional asymmetric
centers that may exist in optical antipodes, racemates and racemic
mixtures thereof are also part of this invention. The antipodes can
be separated by methods known to those skilled in the art such as,
for example, fractional recrystallization of diastereomeric salts
of enantiomerically pure acids. Alternatively, the antipodes can be
separated by chromatography in a Pirkle-type column.
[0041] As used herein, the phrase "pharmaceutically acceptable
salt" means a salt of the free base which possesses the desired
pharmacological activity of the free base and which is neither
biologically nor otherwise undesirable. These salts may be derived
from inorganic or organic acids. Examples of inorganic acids are
hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid,
and phosphoric acid. Examples of organic acids are acetic acid,
propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic
acid, succinic acid, malic acid, maleic acid, fumaric acid,
tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic
acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic
acid, methyl sulfonic acid, salicyclic acid and the like.
[0042] The instant compounds can be prepared using readily
available starting materials and reaction steps well known in the
art (Edema et al. J. Org. Chem. 58: 5624-7, 1993; Howard et al., J.
Amer. Chem. Soc. 82:158-64, 1960).
[0043] This invention also provides a pharmaceutical composition
comprising the instant compound and a pharmaceutically acceptable
carrier.
[0044] Pharmaceutical compositions containing a compound of the
present invention as the active ingredient in intimate admixture
with a pharmaceutical carrier can be prepared according to
conventional pharmaceutical techniques. The carrier may take a wide
variety of forms depending on the form of preparation desired for
administration, such as systemic administration including but not
limited to intravenous, oral, nasal or parenteral. In preparing the
compositions in oral dosage form, any of the usual pharmaceutical
carriers may be employed, such as water, glycols, oils, alcohols,
flavoring agents, preservatives, coloring agents, syrup and the
like in the case of oral liquid preparations (for example,
suspensions, elixirs and solutions), and carriers such as starches,
sugars, diluents, granulating agents, lubricants, binders,
disintegrating agents and the like in the case of oral solid
preparations (for example, powders, capsules and tablets).
[0045] In one embodiment, the compounds of the instant invention
are administered by inhalation. For inhalation administration, the
compounds can be in a solution intended for administration by
metered dose inhalers, or in a form intended for a dry powder
inhaler or insufflator. More particularly, the instant compounds
can be conveniently delivered in the form of an aerosol spray from
a pressurized container, a pack or a nebuliser with the use of a
suitable propellant, e.g., dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethan- e, carbon dioxide
or other suitable gas. The dosage unit may be determined by
providing a valve to deliver a metered amount. Capsules and
cartridges made of a pharmaceutically acceptable material such as
gelatin for use in an inhaler or insufflator can be formulated to
contain a powder mix of the compound and a suitable powder base
such as lactose or starch.
[0046] Because of their ease of administration, tablets and
capsules represent an advantageous oral dosage unit form wherein
solid pharmaceutical carriers are employed. If desired, tablets can
be sugar-coated or enteric-coated by standard techniques. For
parenterals, the carrier will usually comprise sterile water,
though other ingredients to aid solubility or to act as
preservatives can be included. Injectable suspensions can also be
prepared, wherein appropriate liquid carriers, suspending agents
and the like are employed. The instant compounds can also be
administered in the form of an aerosol, as discussed above.
[0047] The instant pharmaceutical composition can contain a per
dosage unit (e.g., tablet, capsule, powder, injection, teaspoonful
and the like) from about 0.001 to about 100 mg/kg, and preferably
from about 0.01 to about 20 mg/kg of the instant compound.
[0048] The compounds of the present invention inhibit the uptake of
calcium ions into smooth muscle cells, and therefore act to relax
or prevent calcium ion-mediated contraction of smooth muscle
tissue.
[0049] Thus, 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. By way of example, in a subject
suffering from asthma, the subject's airways are constricted due to
inflammation of airway smooth muscle cells ("SMC's"). Reducing the
calcium influx into the SMC's, whose action (i.e., inflammation)
contributes to the disorder, would be expected to alleviate the
disorder.
[0050] 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.
[0051] In one embodiment, the disorder is selected from the group
consisting of hypersensitivity, allergy, asthma, bronchospasm,
dysmenorrhea, esophageal spasm, glaucoma, premature labor, a
urinary tract disorder, a gastrointestinal motility disorder and a
cardiovascular disorder. In the preferred embodiment, the disorder
is asthma. The cardiovascular disorder can be, for example,
hypertension, ischemia, angina, congestive heart failure,
myocardial infarction or stroke.
[0052] As used herein, "treating" a disorder means eliminating or
otherwise ameliorating the cause and/or effects thereof.
"Inhibiting" the onset of a disorder means preventing, delaying or
reducing the likelihood of such onset.
[0053] The term "subject" includes, without limitation, any animal
or artificially modified animal. In the preferred embodiment, the
subject is a human.
[0054] Methods are known in the art for determining therapeutically
and prophylactically effective doses for the instant pharmaceutical
composition. The effective dose for administering the
pharmaceutical composition to a human, for example, can be
determined mathematically from the results of animal studies.
[0055] This invention further 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. In the preferred embodiment, the apparatus is an
aerosol spray device for treating and/or preventing asthma via
topical respiratory administration.
[0056] Finally, this invention provides a process for preparing the
compound of Formula I 5
[0057] which process comprises reacting compound 1a with compounds
of Formulae 1b and 1c to form the corresponding compound of Formula
1d. 6
[0058] This invention will be better understood by reference to the
Experimental Details that follow, but those skilled in the art will
readily appreciate that these are only illustrative of the
invention as described more fully in the claims which follow
thereafter. Additionally, throughout this application, various
publications are cited. The disclosure of these publications is
hereby incorporated by reference into this application to describe
more fully the state of the art to which this invention
pertains.
[0059] Experimental Details
[0060] A. Schemes and Syntheses
[0061] The compounds of Formula I can be prepared in accordance
with the following general procedures outlined in Scheme I. The
starting materials are all well known and readily available in the
art (Synthesis of 1,3,5,6-tetrahydro-2H-4,1-benzothiazocin-2-one,
Nair et al., Indian J. Chem., Sect. B (1980), 19B(9), 765-6. CODEN:
IJSBDB, ISSN: 0376-4699. CAN 94:121488 AN 1981:121488 CAPLUS).
7
[0062] Procedures for making dihydropyrides are well documented in
the art as shown in Eistert et al. (Chem. Ber. 110,1069-1085,1977),
G. A. Pagani (J. Chem. Soc., Perkin Trans. 2, 1392-7, 1974), Mason
et al. (J. Chem. Soc. (C) 2171-76, 1967), E. A. Fehnel (J. Amer.
Chem. Soc. 74, 1569-74, 1952), and M. Seiyaku (Japan Patent
Application No. 58201764, 1984).
[0063] The compounds of Formula II can be made in accordance with
Scheme II, wherein R.sub.1-8 are as described above, preferably in
the presence of K.sub.2CO.sub.3 or CsCO.sub.3 in an organic solvent
such as dimethylformamide (DMF). 8
[0064] The compounds of Formula II may also be made in accordance
with Scheme III, wherein R.sub.1-8 are as described above,
preferably in the presence of formic acid or NaOH (aq),
respectively. 9
[0065] The Examples below describe in greater detail the chemical
syntheses of representative compounds of the present invention. The
rest of the compounds disclosed herein can be prepared similarly in
accordance with one or more of these methods. No attempt has been
made to optimize the yields obtained in these syntheses, and it
would be clear to one skilled in the art that variations in
reaction times, temperatures, solvents, and/or reagents could be
used to increase such yields.
[0066] Table 1 below sets forth the mass spectra data, the
inhibition of nitrendipine binding and inhibition of
calcium-dependent smooth muscle contraction for the instant
compounds tested.
1TABLE 1 Molecular Weight, Mass Spectra Data and Calcium Channel
Antagonist Activity for Compounds 1-11 Formula Ia 10 Nitrendi pine
Com- Mass Binding pound Mol. Spectro- Assay No. R.sub.1 R.sub.2
R.sub.3 R.sub.4 R.sub.5 R.sub.6 Wt. scopy IC.sub.50nM 1 H H H H Cl
Me 429.92 M + H = 430 612 2 H H H Cl Cl
(CH.sub.2).sub.2N(CH.sub.3)CH.sub.2Ph 597.56 M + H = 597 118 3 H H
H Cl Cl Me 464.37 M + H = 464 38 4 F F F F F Me 485.43 M + H = 486
261 5 H H H H NO.sub.2 Me 440.47 M + Na = 463 1900 6 H H H Cl H Me
429.92 M + H = 430 337 7 H H H Cl CI 11 603.59 M + H = 603 38 8 H H
H NO.sub.2 H Me 440.47 M + Na = 463 261 9 Cl H H H OH Me 445.92 M +
Na = 468 1300 10 H H H H Cl (CH.sub.2).sub.2N(CH.sub.3)CH.sub.2Ph
569.14 M + H = 569 99 11 Cl H H H H
(CH.sub.2).sub.2N(CH.sub.3)CH.sub.2Ph 563.1169 M + H = 563 453
EXAMPLE 1
[3]Benzothiepino[1,2-b]pyridine-3-carboxylic acid,
4-(2,3-dichlorophenyl)-- 1,4,6,7-tetrahydro-2-methyl-,
2-[methyl(phenylmethyl)amino]ethyl ester, 5,5-dioxide
[0067] 12
[0068] Compound 2 was prepared following Scheme II above. The
details of the preparation are as follows:
[0069] A solution of 0.37 g (1.76 mmoles) of the benzoketosulfone,
0.31 g (1.76 mmoles) of 2,3-dichlorobenzaldehyde and 0.44 g (1.76
mmoles) of 2-(N-Benzyl-N-methylamino)ethyl-3-aminocrotonate in 5 ml
of dioxane was refluxed 18 hours. The reaction was cooled to room
temperature, diluted with 100 ml of ethyl acetate and washed
2.times.60 ml water, dried over MgSO.sub.4, filtered, and
concentrated in vacuo to give a yellow oil that solidified from
diethyl ether to give 0.4224 g of the dihydropyridine as an
off-white solid.
[0070] B. Assays
EXAMPLE 2
Assay for Inhibition of Nitrendipine Binding
[0071] Female, New Zealand white rabbits (1-2 kg) are sacrificed by
cervical dislocation, and the heart is immediately removed, cleaned
and chopped into small pieces. The tissue is homogenized in
5.times.times volume of 0.05M Hepes buffer, pH 7.4. The homogenate
is centrifuged at 4000 g for 10 minutes, and the supernatant is
re-centrifuged at 42,000.times.g for 90 minutes. The resulting
membrane pellet is resuspended (0.7 ml/g weight) in 0.05M Hepes, pH
7.4 and stored at 70.degree. C. until used. Each tube of the
binding assay contains .sup.3H-nitrendipine (0.05-0.50 nM), buffer,
membranes (0.10 ml), and test compound in a total volume of 1.0 ml.
After 90 minutes at 4.degree. C., the bound nitrendipine is
separated from the unbound by filtration on Whatman GF/C filters.
After rinsing, the filters are dried and counted in a liquid
scintillation counter.
[0072] Non-specific binding of .sup.3H-nitrendipine (that amount
bound in the presence of excess unlabelled nitrendipine) is
subtracted from the total bound to obtain specifically bound
radiolabeled nitrendipine. The amount of specifically bound
nitrendipine in the presence of a test compound is compared to that
amount bound in the absence of a compound. A percent displacement
(or inhibition) can then be calculated.
EXAMPLE 3
Test for Inhibition of Calcium-Dependent Smooth Muscle
Contraction
[0073] The trachea and the aorta from dogs sacrificed by excess KCl
injection are stored overnight at 4.degree. C. in oxygenated
Krebs-Henseleit buffer. Tracheal rings, one cartilage segment wide
(5-10 mm), are cut starting from the bronchial end. Rings of aorta
tissue of the same width are also prepared. After cutting the
cartilage, the trachealis muscle tissue and the aorta tissue are
suspended in oxygenated Krebs-Henseleit buffer at 37.degree. C. in
a 25 ml tissue bath. After a 60-minute equilibration period, the
tissues are challenged with 10 .mu.M carbachol. After 5 minutes,
the tissues are rinsed and allowed to rest 50 minutes. The tissues
are then challenged with 50 mM KCl and, after 30 minutes, the
contractions are quantitated. The tissues are then rinsed and
re-equilibrated for 50 minutes. Test compounds are then added for
10 minutes, and the tissue is rechallenged with 50 mM KCl. After 30
minutes, the contraction is recorded. A percent inhibition of
smooth muscle contraction can then be calculated.
* * * * *