Substituted pyrido-or pyrimido-containing 6,6- or...

Details Substituted pyrido-or pyrimido-containing 6,6- or... Substituted pyrido-or pyrimido-containing 6,6- or...

1999-05-24

2002-12-10

Shah, Mukund J. (Department: 1611)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S123000, C514S300000

Reexamination Certificate

active

06492520

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to certain pharmaceutically active substituted pyrido- or pyrimido-containing 6,6- or 6,7-bicyclic derivatives, pharmaceutical compositions containing them and methods of administering them to subjects in need of their corticotropin releasing factor antagonist activity.
The substituted heterocyclic derivatives claimed in this case exhibit activity as corticotropin releasing factor (hormone) CRF (CRH) antagonists.
CRF antagonists are mentioned in U.S. Pat. Nos. 4,605,642 and 5,063,245 referring to peptides and pyrazolinones, respectively. They are also referred to in the following: PCT Patent Application PCT/IB95/00439, which designates the United States and was filed on Jun. 6, 1995 and published on Dec. 14, 1995; PCT patent application PCT/IB95/00373, which designates the United States and was filed on May 18, 1995 and published on Dec. 21, 1995; U.S. patent application Ser. No. 08/448,539, which was filed in the PCT on Nov. 12, 1993 and entered the U.S. national phase on Jun. 14, 1995; PCT patent application WO 95/10506, which was filed on Oct. 12, 1993 and published on Apr. 20, 1995, and U.S. patent application 08/481,413, which was filed in the PCT on Nov. 26, 1993 and entered the U.S. national phase on Jul. 24, 1995; U.S. patent application Ser. No. 08/254,820, which was filed on Apr. 19, 1995; Provisional U.S. patent application Ser. No. 60/008,396, which was filed on Dec. 8, 1995; and Provisional U.S. patent application Ser. No. 60/006,333, which was filed on Nov. 8, 1995. All the foregoing patent applications are incorporated herein by reference in their entireties.
The importance of CRF antagonists is set out in the literature, e.g., P. Black,
Scientific American SCIENCE & MEDICINE
, 1995, p. 16-25; T. Lovenberg, et al.,
Current Pharmaceutical Design
, 1995, 1, 305-316; and U.S. Pat. No. 5,063,245, which is referred to above. 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. Based on the research described in these two and other references, CRF antagonists are effective in the treatment of a wide range of stress-related Illnesses, mood disorders such as depression, major depressive disorder, single episode depression, recurrent depression, child abuse induced depression, postpartum depression, dysthemia, bipolar disorders and cyclothymia; chronic fatigue syndrome; eating disorders such as anorexia and bulimia nervosa; generalized anxiety disorder; panic disorder; phobias; obsessive-compulsive disorder, post-traumatic stress disorder, pain perception such as fibromyalgia; headache; gastrointestinal diseases; hemorrhagic stress; ulcers; stress-induced psychotic episodes; fever; diarrhea; post-operative ileus, colonic hypersensitivity; irritable bowel syndrome; Crohn's disease; spastic colon; inflammatory disorders such as rheumatoid arthritis and osteoarthritis; pain; asthma; psoriasis; allergies; osteoporosis; premature birth; hypertension, congestive heart failure; sleep disorders; neurodegenerative diseases such as Alzheimers disease, senile dementia of the Alzheimer's type, multiinfarct dementia, Parkinson's disease, and Huntington's disease; head trauma; ischemic neuronal damage; excitotoxic neuronal damage; epilepsy; stroke; spinal cord trauma; psychosocial dwarfism; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone; obesity; chemical dependencies and addictions; drug and alcohol withdrawal symptoms; infertility, cancer; infertility; muscular spasms; urinary incontinence; hypoglycemia and immune dysfunctions including stress induced immune dysfunctions, immune suppression and human immunodeficiency virus infections; and stress-induced infections in humans and animals.
The compounds of this invention are also believed to be inhibitors of CRH binding protein and therefore useful in the treatment of disorders the treatment of which can be effected or facilitated by inhibiting such protein. Example of such disorders are Alheimer's disease and obesity.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
the dashed lines represent optional double bonds;
A is nitrogen or CR
7
:
B is —NR
1
R
2
, —CR
1
R
2
R
10
, —C(═CR
2
R
11
)R
1
, —NHCR
1
R
2
R
10
, —OCR
1
R
2
R
10
, —SCR
1
R
2
R
10
, —CR
2
R
10
NHR
1
, —CR
2
R
10
OR
1
, —CR
2
R
10
SR
1
or —COR
2
, and is single bonded to D; or B is —CR
1
R
2
, and is double bonded to D and D is carbon;
D is nitrogen or CR
4
and is single bonded to all atoms to which it is attached, or D is carbon and is double bonded to E or double bonded to B;
E is oxygen, nitrogen, sulfur, C═O, C═S, CR
6
R
12
, NR
6
or CR
6
; or E is a two atom spacer, wherein one of the atoms is oxygen, nitrogen, sulfur, C═O, C═S, CR
6
R
12
, NR
6
or CR
6
, and the other is CR
6
R
12
or CR
9
;
K and G are each, independently, C═O, C═S, sulfur, oxygen, CHR
8
or NR
8
when single bonded to both adjacent ring atoms, or nitrogen or CR
8
when it is double bonded to an adjacent ring atom;
the 6- or 7-membered ring that contains D, E, K and G may contain from one to three double bonds, from zero to two heteroatoms selected from oxygen, nitrogen and sulfur, and from zero to two C═O or C═S groups, wherein the carbon atoms of such groups are part of the ring and the oxygen and sulfur atoms are substituents on the ring;
R
1
is C
1
-C
6
alkyl optionally substituted with from one or two substituents independently selected from hydroxy, fluoro, chloro, bromo, iodo, C
1
-C
4
alkoxy, CF
3
, —C(═O)(C
1
-C
4
alkyl), —C(═O)—O—(C
1
-C
4
)alkyl, —OC(═O)(C
1
-C
4
alkyl), —OC(═O)N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), —NHCO(C
1
-C
4
alkyl), —COOH, —COO(C
1
-C
4
alkyl), —CONH(C
1
-C
4
alkyl), —CON(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), —S(C
1
-C
4
alkyl), —CN, —NO
2
, —SO(C
1
-C
4
alkyl), —SO
2
(C
4
alkyl), —SO
2
NH(C
1
-C
4
alkyl) and —SO
2
N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), wherein each of the C
1
-C
4
alkyl groups in the foregoing R
1
groups may optionally contain one or two double or triple bonds;
R
2
is C
1
-C
12
alkyl which may optionally contain from one to three double or triple bonds, aryl or (C
1
-C
4
alkylene)aryl, wherein said aryl and the aryl moiety of said (C
1
-C
4
alkylene)aryl is selected from phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidinyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, indolyl, pyrrolopyridyl, oxazolyl and benzoxazolyl; C
3
-C
8
cycloalkyl or (C
1
-C
6
alkylene)(C
3
-C
8
cycloalkyl), wherein one or two of the carbon atoms of said cycloalkyl and the 5 to 8 membered cycloalkyl moieties of said (C
1
-C
6
alkylene)(C
3
-C
8
cycloalkyl may optionally and independently be replaced by an oxygen or sulfur and wherein each of the foregoing R
2
groups may optionally be substituted with from one to three substituents independently selected from chloro, fluoro, hydroxy and C
1
-C
4
alkyl, or with one substituent selected from C
1
-C
6
alkoxy, —OC(═O)(C
1
-C
6
alkyl), —OC(═O)N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), —S(C
1
-C
6
alkyl), amino, —NH(C
1
-C
2
alkyl), —N(C
1
-C
2
alkyl)(C
1
-C
4
alkyl), —N(C
1
-C
4
alkyl)—CO—(C
1
-C
4
alkyl), —NHCO(C
1
-C
4
alkyl), —COOH, —COO(C
1
-C
4
alkyl), —CONH(C
1
-C
4
alkyl), —CON(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), —SH, —CN, —NO
2
, —SO(C
1
-C
4
alkyl), —SO
2
(C
1
-C
4
alkyl), —SO
2
NH(C
1
-C
4
alkyl) and —SO
2
N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl);
—NR
1
R
2
or CR
1
R
2
R
10
may form a ring selected from saturated 3 to 8 membered rings, the 5 to 8 membered rings of which may optionally contain one or two double bonds, and wherein one or two of the ring carbon atoms of such 5 to 8 membered rings may optionally and independently be replaced by an oxygen or sulfur atom or by NZ
3
wherein Z
3
is hydrogen or C
1
-C
4
alkyl;
R
3
is hydrogen, C
1
-C
4
alkyl, —O(C
1
-C
4
alkyl)

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