Substituted heterocyclic derivatives

Details Substituted heterocyclic derivatives Substituted heterocyclic derivatives

2000-11-08

2003-02-25

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S314000, C514S266210, C514S256000, C514S249000, C514S255050, C544S284000, C544S333000, C544S353000, C544S405000, C546S173000, C546S176000

Reexamination Certificate

active

06525067

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to certain pharmaceutically active substituted heterocyclic derivatives, pharmaceutical compositions containing them and methods of administering them to subjects in need of their corticotropin releasing factor antagonist activity.
CRF antagonists are referred to in U.S. Pat. No. 4,605,642 (issued Aug. 12, 1986) and U.S. Pat. No. 5,063,245 (issued Nov. 5, 1991) and in International patent publications WO 95/33750 (published Dec. 14, 1995); WO 95/34563 (published Dec. 21, 1995); WO 94/13676 (published Jun. 23, 1994); WO 94/13677 (published Jun. 23, 1994); WO 95/33727 (published Dec. 14, 1995); WO 98/05661 (published Feb. 12, 1998); WO 98/08847 (published Mar. 5, 1998); and WO 98/08846 (published Mar. 5, 1998) and European patent publications EP 778277 (published Jun. 11, 1997) and EP 773023 (published May 14, 1997). CRF antagonists are also referred to in the following patent publications: EP 576350; WO 95/10506 (published Apr. 20, 1995); WO 96/35689 (published Nov. 14, 1996); WO 96/39400 (published Dec. 12, 1996); WO 97/00868 (published Jan. 9, 1997); WO 97/14684 (published Apr. 24, 1997); WO 97/29109 (published Aug. 14, 1997); WO 97/29110 (published Aug. 14, 1997); WO 97/35580 (published Oct. 2, 1997); WO 97/35846 (published Oct. 2, 1997); WO 97/44038 (published Nov. 27, 1997); WO 98/03510 (published Jan. 29, 1998); WO 98/08821 (published Mar. 5, 1998); WO 98/11075 (published Mar. 19, 1998); WO 98/15543 (published Apr. 16, 1998); WO 98/21200 (published May 22, 1998); WO 98/27066 (published Jun. 25, 1998); WO 98/29397 (published Jul. 9, 1998); WO 98/29413 (published Jul. 9, 1998); WO 98/42699 (published Oct. 1, 1998); WO 98/35967 (published Aug. 20, 1998); WO 98/45295 (published Oct. 15, 1998); WO 98/47874 (published Oct. 29, 1998); WO 98/47903 (published Oct. 29, 1998); WO 99/01454 (published Jan. 14, 1999); WO 99/01439 (published Jan. 14, 1999); WO 99/10350 (published Mar. 4, 1999); WO 99/12908 (published Mar. 18, 1999); WO 99/00373 (published Jan. 7, 1999); and WO 99/38868 (published Aug. 5, 1999).
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. An outline of activities possessed by CRF antagonists is found in M. J. Owens et al., Pharm. Rev., 1991, 43:425-473. CRF antagonists have been referred to as effective in the treatment 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; schizophrenia; 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 Alzheimer's 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 antidiuretic hormone; obesity; chemical dependencies and addictions; drug and alcohol withdrawal symptoms; 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.
SUMMARY OF THE INVENTION
The present invention relates to a compound selected from Formulas I to V:
wherein:
the dashed lines in the figures represent optional double bonds;
n is 0 or 1;
A is nitrogen or CR
7
;
B is —C(R
2
)(═NY
1
R
1
), —(Y
3
)—C(R
2
)(═NY
1
R
1
), —NR
16
R
2
, —NHCR
16
R
2
, —SCHR
16
R
2
, —CHR
16
R
2
, —C(OH)R
16
R
2
, —CHR
16
(OR
12
), —C(F)R
16
R
2
, —C(OMe)R
16
R
2
, —CR
16
(═CR
2
R
1
), —CHR
16
(NR
1
), ═C(R
2
)(R
16
), —C(N(C
0
-C
4
alky)R
2
)(═NY
1
R
1
), —Y
3
C(Y
2
R
2
)(═NY
1
R
1
), —C(R
2
)(NR
14
C(═X
2
)NR
1
R
15
), —C(R
2
)(OC(═X
2
)NR
1
R
15
), —C(R
2
)(NR
14
C(═X
2
)R
15
), or —V
1
—V
2
, provided that B may be ═C(R
2
)(R
16
) only in the compounds of Formulas IV and V and only where G is carbon in the compounds of Formulas IV and V;
J
1
and J
2
are independently nitrogen or CR
5
; or J
1
or J
2
optionally connects to Z
1
to form a compound of Formula VI to IX;
Q and U are independently nitrogen or carbon provided that Q and U are not both nitrogen;
V
1
is (C
0
-C
1
alkylene), O, S, NH, or —N(C
1
-C
4
alkylene);
V
2
is a five to eight membered carbocyclic ring wherein one or two of the carbocyclic ring carbons may optionally and independently be replaced by O, S, N, or NZ
3
, and the ring optionally contains one to three double bonds, further wherein the ring is optionally substituted with from one to two R
22
substituents and wherein the ring or R
22
comprises the moiety C═N—Y
1
—(C
1
-C
4
alkylene);
X
1
is O, S, ═NOH, ═NO(C
1
-C
4
alkyl), or ═C(H)(R
5
), ═C(C
1
-C
4
alkyl)(R
5
), wherein said C
1
-C
4
alkyl in said X
1
group is optionally substituted with F, —O(C
1
-C
4
alkyl), —OCF
3
, —OCHF
2
, or OH; or X
1
may bond to Z
1
to form a compound of Formula X or XI:
X
2
is S or O;
Y
1
, Y
2
, and Y
3
are each independently O, S, NH, or —N(C
1
-C
4
alkyl);
Z
1
is O, S, NH, —N(C
1
-C
2
alkyl), NCOCF
3
, NCO(C
1
-C
2
alkyl), or —C(R
11
)(R
12
), or Z
1
may bond to J
1
, J
2
, or X
1
to form said compounds of Formulas VI to XI, or Z
1
may bond to Ar at the ortho position of Ar to form a five or six membered fused ring in the compounds of Formulas XII to XV:
 wherein:
D and E are independently selected from nitrogen and CR
4
when double bonded to any adjacent ring atom, or are independently selected from C═O, C═S, sulfur, oxygen, C(R
4
)(R
6
), and NR
8
when single bonded to both adjacent ring atoms;
F, M, and L are independently nitrogen or carbon, wherein the ring containing F, M, and L is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl;
K is selected from nitrogen and CR
6
when it is double bonded to any adjacent ring atom, or K is selected from oxygen, sulfur, C═O, C═S, CR
6
R
12
, and NR
8
when it is single bonded to both adjacent atoms, or K is two bonded atoms, wherein one of the atoms is oxygen, sulfur, nitrogen, CR
6
, C═O, C═S, CR
6
R
12
, or NR
8
, and the other is CR
9
or CR
6
R
12
;
G is nitrogen or carbon, provided that when G is nitrogen it is single bonded to the adjacent E or K and when G is carbon it is double bonded to the adjacent E or K, further provided that G may be a double bonded to B only where G is carbon, and that where G is double bonded to B, it is single bonded to E in Formulas IV and XIII and single bonded to K in Formulas V and XIV and further where G is double bonded to B, B is C(R
2
)(R
16
);
wherein the ring containing D, E, K, G, in Formula VII, VIII, or XI optionally has from one to three double bonds, from zero to two heteroatoms, and from zero to two C═O or C═S groups;
and wherein the ring containing D, E, G atoms in Formula VI, IX, or X
optionally has one to two double bonds;
further wherein when Z
1
connects to the ortho position of Ar to form a five or six membered ring of a compound of Formulas XII to XV, the ring optionally contains from one to two doub

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