Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1996-10-30
2002-06-11
Criares, Theodore J. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S272000, C514S275000, C514S381000, C514S415000
Reexamination Certificate
active
06403599
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to the treatment of certain conditions using a compound of formula I or II, or a pharmaceutically acceptable salt thereof, as defined below. Specifically, the compounds of formulas I and II, and their pharmaceutically acceptable salts, as defined below, exhibit corticotropin-releasing factor (CRF) antagonist activity and are useful in the treatment of cardiovascular or heart related diseases such as hypertension, tachycardia, and congestive heart failure, stroke, osteoporosis, premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus, and colonic hypersensitivity associated with psychopathological disturbance and stress.
The compounds of formulas I and II, their pharmaceutically acceptable salts, and methods of preparing such compounds and salts are referred to in copending PCT international patent application numbers PCT/IB95/00373 (filed May 18, 1995) and PCT/IB95/00439 (filed Jun. 6, 1995), both of which designate the United States, and in copending U.S. patent applications Ser. No. 08/448,539 (filed Jun. 14, 1995) and Ser. No. 08/481,413 (filed Jun. 15, 1995). PCT international patent application numbers PCT/IB95/00373 and PCT/IB95/00439, and U.S. patent application Ser. Nos. 08/448,539 and 08/481,413, referred to above, are incorporated herein by reference in their entirety.
The foregoing PCT international patent applications and United States patent applications refer to the use of the compounds of formulas I and II in the treatment of illnesses induced or facilitated by corticotropin releasing factor and in the treatment of anxiety, depression, fatigue syndrome, gastrointestinal diseases, headache, pain, cancer, immune dysfunction, hemorrhagic stress, drug addiction, drug and alcohol withdrawal symptoms, fertility problems, stress-induced psychotic episodes, neurodegenerative diseases such as Alzheimer's disease; irritable bowel syndrome including Crohn's disease, spastic colon and irritable colon; eating disorders such as anorexia nervosa; and inflammatory disorders such as arthritis, asthma and allergies.
Other CRF antagonists that can be used to treat the disorders recited in the method of this invention are referred to in copending PCT international patent application number PCT/IB95/00318 (filed May 4, 1995), which designates the United States, and in copending U.S. patent application Ser. No. 08/448,534 (filed Jun. 14, 1995) and Ser. No. 08/448,529 (filed Jun. 14, 1995). PCT international patent application number PCT/IB95/00318, and U.S. patent application Ser. Nos. 08/448,534 and 08/448,529, referred to above, are incorporated herein by reference in their entirety.
CRF antagonists are mentioned in U.S. Pat. Nos 4,605,642 and 5,063,245 referring to peptides and pyrazolinones, respectively. The importance of CRF antagonists is set out in the literature, e.g., as discussed in U.S. Pat. No. 5,063,245, which is incorporated herein by reference. A recent outline of the different activities possessed by CRF antagonists is found in M. J. Owens et al.,
Pharm. Rev., Vol.
43, pages 425 to 473 (1991), also incorporated herein by reference.
SUMMARY OF THE INVENTION
This invention relates to a method of treating a disorder selected from cardiovascular or heart related diseases such as hypertension, tachycardia, and congestive heart failure, osteoporosis, premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus, and colonic hypersensitivity associated with psychopathological disturbance and stress, by administering to a mammal, including a human, In need of such treatment a therapeutically effective amount of a compound of the formula
or a pharmaceutically acceptable salt thereof, wherein
the dashed line represents an optional double bond;
A is —CR
7
or N;
B is —NR
1
R
2
, —CR
1
R
2
R
11
, —C(═CR
1
R
12
)R
2
, —NHCR
11
R
1
R
2
, —OCR
11
R
1
R
2
, —SCR
11
R
1
R
2
, —CR
11
R
2
OR
1
, —CR
11
R
2
SR
1
, —C(S)R
2
, —NHNR
1
R
2
, —CR
2
R
11
NHR
1
or —C(O)R
2
;
D is: (i) N or —CR
10
when a double bond connects E and D and E is —CR
4
; (ii) —CR
10
when a double bond connects E and D and E is N; (iii) —CR
8
R
9
, —CHR
10
, —C═O, —C═S, —C═NH, or —C═NCH
3
when a single bond connects E and D;
E is —CR
4
or N when a double bond connects E and D, and E is —CR
4
R
6
or —NR
6
when a single bond connects E and D;
Y is N or —CH;
Z is NH, O, S, —N(C
1
-C
2
alkyl) or —CR
12
R
13
, wherein R
12
and R
13
are each, independently, hydrogen, trifluoromethyl or methyl, or one of R
12
and R
13
is cyano and the other is hydrogen or methyl;
R
1
is hydrogen or C
1
-C
6
alkyl which is optionally substituted with one or two substituents independently selected from hydroxy, cyano, nitro, fluoro, chloro, bromo, iodo, CF
3
, C
1
-C
4
alkoxy, —O—CO—(C
1
-C
4
alkyl), —O—CO—NH(C
1
-C
4
alkyl), —O—CO—N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), —NH(C
1
-C
4
alkyl), —N(C
1
-C
2
alkyl)(C
1
-C
4
alkyl), —S(C
1
-C
4
alkyl), —N(C
1
-C
4
alkyl)CO(C
1
-C
4
alkyl), —NHCO(C
1
-C
4
alkyl), —CO
2
(C
1
-C
4
alkyl), —CONH(C
1
-C
4
alkyl), —CON(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), (C
1
-C
4
alkyl)sulfinyl, (C
1
-C
4
alkyl)sulfonyl, and (C
1
-C
4
alkyl)sulfanyl, and wherein said C
1
-C
6
alkyl, C
1
-C
4
alkoxy and the C
1
-C
4
alkyl moieties in the foregoing R
1
groups optionally contain one double or triple bond;
R
2
is C
1
-C
6
alkyl, aryl or (aryl)C
1
-C
4
alkyl wherein said aryl and the aryl moiety of said (aryl)C
1
-C
4
alkyl are selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl, and benzoxazolyl; or R
2
is C
3
-C
8
cycloalkyl or (C
3
-C
8
cycloalkyl)C
1
-C
6
alkyl, wherein one or two of the ring carbons of said cycloalkyl having at least 4 ring members and the cycloalkyl moiety of said (C
3
-C
8
cycloalkyl)C
1
-C
6
alkyl having at least 4 ring members is optionally replaced by an oxygen or sulfur atom or by —NR
14
wherein R
14
is hydrogen or C
1
-C
4
alkyl; and wherein each of the foregoing R
2
groups is optionally substituted by from one to three substituents independently selected from chloro, fluoro and C
1
-C
4
alkyl, or by one substituent selected from bromo, iodo, cyano, nitro, C
1
-C
6
alkoxy, —O—CO—(C
1
-C
4
alkyl), —O—CO—N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), —CO
2
(C
1
-C
4
alkyl), (C
1
-C
4
alkyl)sulfanyl, (C
1
-C
4
alkyl)sulfinyl, and (C
1
-C
4
alkyl)sulfonyl, and wherein said C
1
-C
6
alkyl and the C
1
-C
4
alkyl and C
1
-C
6
alkyl moieties of the foregoing R
2
groups optionally contain one carbon-carbon double or triple bond;
or R
1
and R
2
of said —NR
1
R
2
and said —CR
1
R
2
R
11
are taken together to form a saturated 5 to 8 member ring, wherein said ring optionally contains one or two carbon-carbon double bonds, and wherein one or two of the ring carbons is optionally replaced by an oxygen or sulfur atom;
R
3
is hydrogen, C
1
-C
6
alkyl, fluoro, chloro, bromo, iodo, hydroxy, amino, SH, —NH(C
1
-C
4
alkyl), —N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), —CH
2
OH, —CH
2
OCH
3
, —O(C
1
-C
4
alkyl), (C
1
-C
4
alkyl)sulfanyl, (C
1
-C
4
alkyl)sulfonyl, or (C
1
-C
4
alkyl)sulfinyl, wherein said C
1
-C
6
alkyl and the C
1
-C
4
alkyl moieties of the foregoing R
3
groups optionally contain one double or triple bond and are optionally substituted by from one to three substituents independently selected from hydroxy, amino, C
1
-C
3
alkoxy, —NH(C
1
-C
2
alkyl), —N(C
1
-C
2
)
2
, —NHCOCH
3
, fluoro, chloro and C
1
-C
3
thioalkyl;
R
4
is hydrogen, C
1
-C
6
alkyl, fluoro, chloro, bromo, iodo, C
1
-C
6
alkoxy, formyl, trifluoromethoxy, —CH
2
OCH
3
, —CH
2
OCH
2
CH
3
, —CH
2
CH
2
OCH
3
, —CH
2
CF
3
, CF
3
, amino, nitro, —NH(C
1
-C
4
alkyl), —N(CH
3
)
2
, —NHCOCH
3
, —NHCONHCH
3
, (C
1
-C
4
alkyl)sulfanyl, (C
1
-C
4
alkyl)sulfinyl, (C
1
-C
4
alkyl)sulfonyl, cyano, hydroxy, —CO(C
1
-C
4
alkyl), —
Chen Yuhpyng L.
Fossa Anthony A.
Criares Theodore J.
Ginsburg Paul H.
Pfizer Inc
Richardson Peter C.
Zielinski Bryan C.
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