U.S. patent application number 10/228772 was filed with the patent office on 2003-06-05 for aminoalkyl substituted 5,6,7,8-tetrahydro-9h-pyridino[2,3-b]indole and 5,6,7,8-tetrahydro-9h-pyrimidino[4,5-b]indole derivatives: crf1 specific ligands.
This patent application is currently assigned to Neurogen Corporation. Invention is credited to Darrow, James W., Horvath, Raymond F., Maynard, George D..
Application Number | 20030105117 10/228772 |
Document ID | / |
Family ID | 26763477 |
Filed Date | 2003-06-05 |
United States Patent
Application |
20030105117 |
Kind Code |
A1 |
Horvath, Raymond F. ; et
al. |
June 5, 2003 |
Aminoalkyl substituted 5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
and 5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole derivatives: CRF1
specific ligands
Abstract
Disclosed are compounds of the formula: 1 wherein Ar, R.sup.1,
W, X and m are substituents as defined herein. These compounds are
modulators of CRF receptors and are therefore useful for treating
affective disorder, anxiety, depression, headache, irritable bowel
syndrome, post-traumatic stress disorder, supranuclear palsy,
immune suppression, Alzheimer's disease, gastrointestinal diseases,
anorexia nervosa or other feeding disorder, drug addiction, drug or
alcohol withdrawal symptoms, inflammatory diseases, cardiovascular
or heart-related diseases, fertility problems, human
immunodeficiency virus infections, hemorrhagic stress, obesity,
infertility, head and spinal cord traumas, epilepsy, stroke,
ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder
the treatment of which can be effected or facilitated by
antagonizing CRF, including but not limited to disorders induced or
facilitated by CRF, in mammals, comprising: administering to the
mammal a therapeutically effective amount of a compound of Formula
I.
Inventors: |
Horvath, Raymond F.; (North
Branford, CT) ; Darrow, James W.; (Wallingford,
CT) ; Maynard, George D.; (Clinton, CT) |
Correspondence
Address: |
Steven J. Sarussi
McDonnell Boehnen Hulbert & Berghoff
32nd Floor
300 S. Wacker Drive
Chicago
IL
60606
US
|
Assignee: |
Neurogen Corporation
|
Family ID: |
26763477 |
Appl. No.: |
10/228772 |
Filed: |
August 27, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10228772 |
Aug 27, 2002 |
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09408613 |
Sep 30, 1999 |
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6472402 |
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09408613 |
Sep 30, 1999 |
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09283723 |
Apr 1, 1999 |
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6291473 |
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60080410 |
Apr 2, 1998 |
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Current U.S.
Class: |
514/267 ;
514/256; 514/291; 544/250; 544/333; 546/81 |
Current CPC
Class: |
A61P 25/22 20180101;
C07D 471/04 20130101; C07D 487/04 20130101; A61P 3/04 20180101 |
Class at
Publication: |
514/267 ;
514/256; 514/291; 544/333; 544/250; 546/81 |
International
Class: |
C07D 487/02; C07D
471/02; A61K 031/519; A61K 031/506; A61K 031/4745 |
Claims
What is claimed is:
1. A compound of the formula: 50or the pharmaceutically acceptable
salts thereof wherein: Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or
4-pyridyl, 2-, 4- or 5-pyrimidinyl, optionally mono-, di-, or
tri-substituted with halogen, trifluoromethyl, hydroxy, amino,
carboxamido, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, with
the proviso that at least one of the positions ortho or para to the
point of attachment of Ar to the tricyclic ring system is
substituted; R.sup.1 is hydrogen, halogen, trifluoromethyl,
C.sub.1-C.sub.6 alkyl, or (C.sub.1-C.sub.6 alkyl)-G.sup.1-R.sup.2
where G.sup.1 is oxygen or sulfur and R.sup.2 is hydrogen or
C.sub.1-C.sub.6 alkyl; W is N or C--R.sup.3 where R.sup.3 is
hydrogen or C.sub.1-C.sub.6 alkyl; m is 0, 1, or 2; X is 51 wherein
V.sup.1 and V.sup.2 are CH.sub.2, CO, CS, SO.sub.2 or
CH(C.sub.1-C.sub.6 alkyl), with the proviso that both V.sup.1 and
V.sup.2 cannot both be CO, CS or SO.sub.2; Y.sup.1 and Y.sup.2
independently represent a bond or C.sub.1-C.sub.6 alkylene; A.sup.1
is NR.sup.4R.sup.5 wherein R.sup.4 and R.sup.5 are independently
hydrogen or a C.sub.1-C.sub.6 alkyl group which and optionally
forms a heterocycloalkyl group with Y.sup.1; acetyl or sulfonyl
with the proviso that R.sup.4 and R.sup.5 cannot both be acetyl or
sulfonyl; or NR.sup.4R.sup.5 taken together form a C.sub.3-C.sub.6
heterocycloalkyl or a group of the formula: 52wherein e and f are
independently 1, 2, or 3 and the sum of e and f is at least 3; and
G is NR.sup.6 wherein R.sup.6 is hydrogen or C.sub.1-C.sub.6 alkyl,
or CH(C.sub.0-C.sub.6 alkylene)-G.sup.3-R.sup.7 wherein G.sup.3 is
CONH, CONH(C.sub.1-C.sub.6 alkyl), NH, NH(C.sub.1-C.sub.6 alkyl)
and R.sup.7 is hydrogen or C.sub.1-C.sub.6 alkyl; or CONH.sub.2,
CO[N(C.sub.1-C.sub.6 alkyl)R.sup.8] wherein R.sup.8 is hydrogen or
C.sub.1-C.sub.6 alkyl; A.sup.2 is hydrogen, C.sub.1-C.sub.6 alkyl,
(C.sub.1-C.sub.6 alkylene)-G.sup.4-R.sup.9 wherein G.sup.4 is
oxygen or sulfur and R.sup.9 is hydrogen, trifluoromethyl or
C.sub.1-C.sub.6 alkyl; 53wherein heteroaryl is 2-, 3- or 4-pyridyl,
2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or
5-oxazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl,
2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally
mono- or disubstituted with halogen, trifluoromethyl, amino,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, with the proviso
that tetraazolinyl can have at most one substituent; Z is
C.sub.1-C.sub.6 alkyl; and V.sup.2, Y.sup.2 and A.sup.2 are as
defined above; 54 wherein Z.sup.2 is carbon or nitrogen; wherein
when Z.sup.2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R.sup.10
is carboxamido, or (C.sub.1-C.sub.6 alkylene)-G.sup.5-R.sup.11
wherein G.sup.5 is NH, NH(C.sub.1-C.sub.6 alkyl) and R.sup.11 is
hydrogen or C.sub.1-C.sub.6 alkyl; when Z.sup.2 is carbon, n is 1
or 2 and p is 1 or 2, R.sup.10 is amino; or when Z.sup.2 is
nitrogen, n is 1 or 2 and p is 1 or 2, R.sup.10 is hydrogen; or
(iv) a nitrogen heterocycle of the formula: 55 wherein the N-ring
represents triazolyl, tetrazolyl, imidazolyl, pyrazolyl, each of
which is optionally substituted with amino, trifluoromethyl,
carboxamido, or (C.sub.1-C.sub.6 alkylene)-G.sup.6-R.sup.12 wherein
G.sup.6 is NH, NH(C.sub.1-C.sub.6 alkyl) and R.sup.12 is hydrogen
or C.sub.1-C.sub.6 alkyl.
2. A compound according to claim 1, wherein V.sup.1 and V.sup.2
represent methylene; Y.sup.1 is a bond; A.sup.1 represents
pyrrolidinyl, morpholinyl; piperazinyl, or mono- or
di-C.sub.1-C.sub.6 alkyl; Y.sup.2 represents a bond or methylene;
and A.sup.2 represents C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6
alkoxymethyl.
3. A compound according to claim 1, wherein each R.sub.a
independently represents C.sub.1-C.sub.6 alkyl; and A.sup.2 is
C.sub.1-C.sub.6 cycloalkyl.
4. A compound according to claim 1, where A.sup.2 is
(C.sub.3-C.sub.5) cycloalkyl (C.sub.1-C.sub.4) alkyl.
5. A compound according to claim 1, where A.sup.1 is
NR.sup.4R.sup.5 where R.sup.4 and R.sup.5 are independently
hydrogen, C.sub.1-C.sub.6 alkyl; or NR.sup.4R.sup.5 forms a 5 or
6-membered nitrogen heterocycle optionally containing an oxygen or
second nitrogen atom; Y.sup.1 is C.sub.1-C.sub.6 alkylene; Y.sup.2
is a bond or C.sub.1-C.sub.6 alkylene; V.sup.1 is methylene; and
V.sup.2 is methylene.
6. A compound according to claim 5, wherein A.sup.2 is
(C.sub.3-C.sub.5) cycloalkyl.
7. A compound according to claim 6, wherein R.sup.4 and R.sup.5 are
independently C.sub.1-C.sub.6 alkyl.
8. A compound according to claim 5, wherein at least one R.sub.a is
methyl; Y.sup.2 is a bond; and R.sup.4 and R.sup.5 are the same and
represent C.sub.1-C.sub.3 alkyl.
9. A compound according to claim 1, wherein m is 1 and R.sup.1 is
C.sub.1-C.sub.3 alkyl.
10. A compound according to claim 1, which is 56wherein X, m, and
R.sub.1 are as defined in claim 1; and each R.sub.a is halogen,
trifluoromethyl, hydroxy, amino, C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.6 alkoxy.
11. A compound according to claim 10, wherein V.sup.1 and V.sup.2
represent methylene; Y.sup.1 is a bond; Al represents pyrrolidinyl,
morpholinyl; piperazinyl, or mono- or di-C.sub.1-C.sub.6 alkyl;
Y.sup.2 represents a bond or methylene; and A.sup.2 represents
C.sub.1-C.sub.6 alkyl or C.sub.1C.sub.6 alkoxymethyl.
12. A compound according to claim 10, where at least one R.sub.a is
C.sub.1-C.sub.6 alkyl and the other R.sub.a groups are
independently C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6
alkoxy or trifluoromethyl; A.sub.2 is
(C.sub.3-C.sub.5)cycloalkyl(C.sub.1-C.sub.4)a- lkyl or
(C.sub.3-C.sub.4)cycloalkyl; A.sup.1 is NR.sup.4R.sup.5 where
R.sup.4 and R.sup.5 are independently hydrogen, C.sub.1-C.sub.6
alkyl; or NR.sup.4R.sup.5 forms a 5 or 6-membered nitrogen
heterocycle optionally containing an oxygen or second nitrogen
atom; Y.sup.1 is C.sub.1-C.sub.6 alkylene; Y.sup.2 is a bond or
C.sub.1-C.sub.6 alkylene; V.sup.1 is methylene; and V.sup.2 is
methylene.
13. A compound according to claim 10, wherein A.sup.2 is
cyclopropyl(C.sub.1-C.sub.3)alkyl or (C.sub.3-C.sub.5)cycloalkyl;
and R.sup.4 and R.sup.5 are independently C.sub.1-C.sub.6
alkyl.
14. A compound according to claim 12, wherein A.sup.2 is
(C.sub.3-C.sub.5)cycloalkyl; Y.sup.2 is a bond; and R.sup.4 and
R.sup.5 are the same and represent C.sub.1-C.sub.3 alkyl.
15. A compound according to claim 12, where each R.sub.a is methyl;
A.sup.2 is cyclopropyl; Y.sup.2 is a bond; and R.sup.4 and R.sup.5
are the same and represent C.sub.1-C.sub.3 alkyl.
16. A compound according to claim 1, which is 57wherein X, m, and
R.sup.1 are as defined in claim 1; and each R.sub.a is halogen,
trifluoromethyl, hydroxy, amino, C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.6 alkoxy.
17. A compounds according to claim 16, wherein V.sup.1 and V.sup.2
represent methylene; Y.sup.1 is a bond; A.sup.1 represents
pyrrolidinyl, morpholinyl; piperazinyl, or mono- or
di-C.sub.1-C.sub.6 alkyl; Y.sup.2 represents a bond or methylene;
and A.sup.2 represents C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6
alkoxymethyl.
18. A compound according to claim 16, wherein each R.sub.a
independently represents C.sub.1-C.sub.6 alkyl; A.sub.2 is
(C.sub.3-C.sub.5)cycloalkyl(- C.sub.1-C.sub.4)alkyl or
(C.sub.3-C.sub.5)cycloalkyl; A.sup.1 is NR.sup.4R.sup.5 where
R.sup.4 and R.sup.5 are independently hydrogen, C.sub.1-C.sub.6
alkyl; or NR.sup.4R.sup.5 forms a 5 or 6-membered nitrogen
heterocycle optionally containing an oxygen or second nitrogen
atom; Y.sup.1 is C.sub.1-C.sub.6 alkylene; Y.sup.2 is a bond or
C.sub.1-C.sub.6 alkylene; V.sup.1 is methylene; and V.sup.2 is
methylene.
19. A compound according to claim 16, wherein A.sup.2 is
cyclopropyl(C.sub.1-C.sub.3)alkyl or (C.sub.3-C.sub.5)cycloalkyl;
and R.sup.4 and R.sup.5 are independently C.sub.1-C.sub.6
alkyl.
20. A compound according to claim 18, wherein A.sup.2 is
(C.sub.3-C.sub.5)cycloalkyl; Y.sup.2 is a bond; and R.sup.4 and
R.sup.5 are the same and represent C.sub.1-C.sub.3 alkyl.
21. A compound according to claim 18, wherein at least one R.sub.a
is methyl; A.sup.2 is (C.sub.3-C.sub.5) cycloalkyl; Y.sup.2 is a
bond; and R.sup.4 and R.sup.5 are the same and represent
C.sub.1-C.sub.3 alkyl.
22. A compound according to claim 18, wherein each R.sub.a is
methyl; A.sup.2 is cyclopropyl; Y.sup.2 is a bond; and R.sup.4 and
R.sup.5 are the same and represent C.sub.1-C.sub.3 alkyl.
23. A compound according to claim 18, wherein m is 1.
24. A compound according to claim 16, wherein m is 2.
25. A compound according to claim 21, m is 1 and R.sup.1 is
C.sub.1-C.sub.3 alkyl.
26. A compound according to claim 1 which is:
4-(N-(2-Pyrrolidinoethyl)-N--
cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahy-
dro-9H-pyridino[2,3-b]indole;
4-(N-(2-Morpholinoethyl)-N-cyclopropylmethyl-
)amino-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2-
,3-b]indole;
4-(N-2-(4-Methylpiperazinyl)ethyl-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b- ]indole;
4-(N-(2-Dimethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9--
(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole;
4-(N-(2-Pyrrolidinoethyl)-N-2-methylpropyl)amino-2-methyl-9-(2,4,6-trimet-
hylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole;
4-(N-(2-Dimethylaminoethyl)-N-2-methylpropyl)amino-2-methyl-9-(2,4,6-trim-
ethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole;
4-(N-(2-(Ethylmethylamino)ethyl)-N-2-methylpropyl)amino-2-methyl-9-(2,4,6-
-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole;
4-(N-(2-Dimethylaminoethyl)-N-2-methoxyethyl)amino-2-methyl-9-(2,4,6-trim-
ethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole;
4-(N-(2-Dimethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-t-
rimethylphenyl)-5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole; and
4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4-dimet-
hylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole.
27. A compound according to claim 1 which is:
4-(N-(2-Pyrrolidinoethyl)-N--
cyclopropylmethyl)amino-2-methyl-9-(2,6-dimethylphenyl)-5,6,7,8-tetrahydro-
-9H-pyridino[2,3-b]indole;
4-(N-(2-(4-Triazolyl)ethyl)-N-cyclopropylmethyl-
)amino-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2-
,3-b]indole;
4-(N-(2-(2-Methoxyethyl)aminoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b- ]indole;
4-(N-(2-(2-Methylimidazolinyl)ethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b- ]indole;
4-(N-(2-Dimethylaminoethyl)-N-isopropyl)amino-2-methyl-9-(2,4,6-t-
rimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole;
4-(N-(2-(Phenylmethyl)aminoethyl)-N-isopropyl)amino-2-methyl-9-(2,4,6-tri-
methylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole;
4-(N-2-(4-Methylpiperazinyl)ethyl-N-isopropyl)amino-2-methyl-9-(2,4,6-tri-
methylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole;
4-(N-(2-Pyrrolidinoethyl)-N-isopropyl)amino-2-methyl-9-(2,4,6-trimethylph-
enyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole;
4-(N-(2-Diethylaminoeth-
yl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-t-
etrahydro-9H-pyridino[2,3-b]indole; and
4-(N-(2-Diethylaminoethyl)-N-2-met-
hylpropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-p-
yridino[2,3-b]indole.
28. A compound according to claim 1 which is:
4-(N-(2-Aminoethyl)-N-cyclop-
ropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-
-pyridino[2,3-b]indole;
4-(N-(2-Aminoethyl)-N-cyclopropylmethyl)amino-2-me-
thyl-9-(2,6-dimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole;
4-(N-(2-Aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethyl-
phenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole);
4-(N-(2-Aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4-dimethylphe-
nyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole;
4-(N-(2-Dimethylaminoeth-
yl)-N-butyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-
-pyridino[2,3-b]indole; and
4-(N-(2-Dimethylaminoethyl)-N-propyl)amino-2-m-
ethyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indol-
e.
29. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a therapeutically effective amount of a
compound of claim 1.
30. A method for the treatment or prevention of physiological
disorders associated with an excess of CRF, which method comprises
administration to a patient in need thereof a CRF-reducing amount
of a compound according to claim 1.
31. A salt according to claim 1 which is:
4-(N-(2-Morpholinoethyl)-N-cyclo-
propylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9-
H-pyridino[2,3-b]indole citrate;
4-(N-2-(4-Methylpiperazinyl)ethyl-N-cyclo- propylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole phosphate;
4-(N-(2-(2-Methoxyethyl)aminoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b- ]indole citrate;
4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]-
indole dihydrochloride;
4-(N-(2-Dimethylaminoethyl)-N-2-methylpropyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]-
indole citrate;
4-(N-(2-Aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(-
2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
sulfate;
4-(N-(2-(Ethylmethylamino)ethyl)-N-2-methylpropyl)amino-2-methyl-
-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
dihydrochloride;
4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4-dimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]ind-
ole sulfate;
4-(N-(2-(2-Methylimidazolinyl)ethyl)-N-cyclopropylmethyl)amin- o
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-- b]indole fumarate;
4-(N-(2-Dimethylaminoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b- ]indole dihydrochloride; and
4-(N-(2-Dimethylaminoethyl)-N-2-methoxyethyl)- amino
-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2-
,3-b]indole dihydrochloride.
32. A salt according to claim 1 which is:
4-(N-2-(4-Methylpiperazinyl)ethy- l-N-isopropyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-
-9H-pyridino[2,3-b]indole sulfate;
4-(N-(2-Diethylaminoethyl)-N-cyclopropy- lmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl) -5,6,7,8-tetrahydro-9H-p-
yridino[2,3-b]indole sulfate;
4-(N-(2-Dimethylaminoethyl)-N-propyl)amino-2- -methyl
-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]in-
dole maleate; 4-(N-(2-Methylaminoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]-
indole sulfate; 4-(N-(2-(Phenylmethyl)aminoethyl)-N-isopropyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]-
indole phosphate;
4-(N-(2-Diethylaminoethyl)-N-2-methylpropyl)amino-2-meth-
yl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
acetate; 4-(N-(2-(Ethylmethylamino)ethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b- ]indole fumarate;
4-(N-(2-Dimethylaminoethyl)-N-isopropyl)amino-2-methyl-9-
-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
phosphate; 4-(N-(2-Dimethylaminoethyl)-N-ethyl)amino-2-methyl
-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
dihydrochloride; and
4-(N-(2-Dimethylaminoethyl)-N-butyl)amino-2-methyl
-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
dihydrochloride.
33. A salt according to claim 1, which is:
4-(N-(2-Dimethylaminoethyl)-N-c- yclopropyloxomethyl)amino
-2-methyl-10-(2,4,6-trimethylphenyl)-5,6,7,8,9-p-
entahydrocyclohepta[1,2-d]pyridino[2,3-b]pyrrole sulfate;
4-(N-(2-Dimethylaminoethyl)-N-cyclopropylmethyl)amino
-2-methyl-10-(2,4,6-trimethylphenyl)
-5,6,7,8,9-pentahydrocyclohepta[1,2-- d]pyridino[2,3-b]pyrrole
sulfate; 4-(N-(2-Pyrrolidinoethyl)-N-propyl)amino-
-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]i-
ndole sulfate;
4-(N-(2-Dimethylaminoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4-dimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]in- dole sulfate;
4-(N-(2-Pyrrolidinoethyl)-N-(1-oxobutyl))amino-2-methyl-9-(2-
,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
sulfate; 4-(N-- (2-Pyrrolidinoethyl) --N--
(2-methoxy-1-oxoethyl))amino-2-methyl-9-
-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
sulfate;
4-(N-(2-Aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4-di-
methylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole citrate;
4-(N-(2-Pyrrolidinoethyl)-N-ethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl-
)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole sulfate;
4-(N-(2-Dimethylaminoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b- ]indole sulfate;
4-(N-(2-Pyrrolidinoethyl)-N-(2-methoxyethyl))amino
-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]-
indole sulfate; and
4-(N-(2-Pyrrolidinoethyl)-N-butyl)amino-2-methyl-9-(2,-
4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
sulfate.
34. A salt according to claim 1, which is:
4-(N-(2-Dimethylaminoethyl)-N-c- yclopropylmethyl)amino
-2-methyl-9-(2,6-dimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole sulfate;
4-(N-(2-Aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethyl-
phenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
dihydrochloride;
4-(N-(2-Pyrrolidinoethyl)-N-(1-oxopropyl))amino-2-methyl-9-(2,4,6-trimeth-
ylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole sulfate;
4-(N-(2-Pyrrolidinoethyl)-N-(1-oxoethyl))amino-2-methyl-9-(2,4,6-trimethy-
lphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole sulfate;
4-(N-(2-Aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,6-dimethylphe-
nyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole sulfate;
4-(N-(2-Dimethylaminoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyrimidino[4,5- -b]indole mesylate;
4-Piperazinyl-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole tartrate;
4-(N-(2-(Ethylmethylamino)ethyl)-N-2-methylpropyl)amino-2-methyl-9-(2,4,6-
-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
mesylate; 4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4-dimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]ind-
ole dihydrochloride;
4-(N-(2-(2-Methylimidazolinyl)ethyl)-N-cyclopropylmet- hyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl) -5,6,7,8-tetrahydro-9H-pyrid-
ino[2,3-b]indole mesylate; 4-(N-- (2-Pyrrolidinoethyl) --N--
(1-oxopropyl))amino-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-
-9H-pyridino[2,3-b]indole mesylate; and
4-(N-(2-Pyrrolidinoethyl)-N-(1-oxo-
ethyl))amino-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyri-
dino[2,3-b]indole dihydrochloride.
35. A method of treating affective disorder, anxiety, depression,
headache, irritable bowel syndrome, post-traumatic stress disorder,
supranuclear palsy, immune suppression, Alzheimer's disease,
gastrointestinal diseases, anorexia nervosa or other feeding
disorder, drug addiction, drug or alcohol withdrawal symptoms,
inflammatory diseases, cardiovascular or heart-related diseases,
fertility problems, human immunodeficiency virus infections,
hemorrhagic stress, obesity, infertility, head and spinal cord
traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis,
hypoglycemia or a disorder the treatment of which can be effected
or facilitated by antagonizing CRF, including but not limited to
disorders induced or facilitated by CRF, in mammals, comprising:
administering to the mammal a therapeutically effective amount of a
compound of formula in any one of claim 1.
36. The use of a compound for the manufacture of a medicament for
the treatment of affective disorder, anxiety, depression, headache,
irritable bowel syndrome, post-traumatic stress disorder,
supranuclear palsy, immune suppression, Alzheimer's disease,
gastrointestinal diseases, anorexia nervosa or other feeding
disorder, drug addiction, drug or alcohol withdrawal symptoms,
inflammatory diseases, cardiovascular or heart-related diseases,
fertility problems, human immunodeficiency virus infections,
hemorrhagic stress, obesity, infertility, head and spinal cord
traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis,
hypoglycemia or a disorder the treatment of which can be effected
or facilitated by antagonizing CRF, including but not limited to
disorders induced or facilitated by CRF, in mammals, comprising:
administering to the mammal a therapeutically effective amount of a
compound of formula in claim 1.
37. A process for the preparation of a compound as claimed in claim
1.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to aminoalkyl substituted
5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole and
5,6,7,8-tetrahydro-9H-pyr- imidino[4,5-b]indole derivatives,
pharmaceutical compositions containing such compounds and their use
in treating psychiatric disorders, neurological diseases,
immunological, cardiovascular or heart-related diseases and colonic
hypersensitivity associated with psychopathological disturbance and
stress.
[0003] 2. Description of the Related Art
[0004] Corticotropin releasing factor (herein referred to as CRF),
a 41 amino acid peptide, is the primary physiological regulator of
proopiomelanocortin (POMC) derived peptide secretion from the
anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci.
(USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In
addition to its endocrine role at the pituitary gland,
immunohistochemical localization of CRF has demonstrated that the
hormone has a broad extrahypothalamic distribution in the central
nervous system and produces a wide spectrum of autonomic,
electrophysiological and behavioral effects consistent with a
neurotransmitter or neuromodulator role in brain [W. Vale et al.,
Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med.
2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)].
There is also evidence that CRF plays a significant role in
integrating the response of the immune system to physiological,
psychological, and immunological stressors [J. E. Blalock,
Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527
(1987)].
[0005] Clinical data provide evidence that CRF has a role in
psychiatric disorders and neurological diseases including
depression, anxiety-related disorders and feeding disorders. A role
for CRF has also been postulated in the etiology and
pathophysiology of Alzheimer's disease, Parkinson's disease,
Huntington's disease, progressive supranuclear palsy and
amyotrophic lateral sclerosis as they relate to the dysfunction of
CRF neurons in the central nervous system [for review see E. B. De
Souza, Hosp. Practice 23:59 (1988)].
[0006] In affective disorder, or major depression, the
concentration of CRF is significantly increased in the cerebral
spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al.,
Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry
144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988);
M. Arato et al., Biol Psychiatry 25:355 (1989). Furthermore, the
density of CRF receptors is significantly decreased in the frontal
cortex of suicide victims, consistent with a hypersecretion of CRF
[C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In
addition, there is a blunted adrenocorticotropin (ACTH) response to
CRF (i.v. administered) observed in depressed patients [P. W. Gold
et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al.,
Psychoneuroendocrinology 9:147(1984); P. W. Gold et al., New Eng.
J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human
primates provide additional support for the hypothesis that
hypersecretion of CRF may be involved in the symptoms seen in human
depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)].
There is preliminary evidence that tricyclic antidepressants can
alter CRF levels and thus modulate the numbers of CRF receptors in
brain [Grigoriadis et al., Neuropsychopharmacology 2:53
(1989)].
[0007] There has also been a role postulated for CRF in the
etiology of anxiety-related disorders. CRF produces anxiogenic
effects in animals and interactions between
benzodiazepine/non-benzodiazepine anxiolytics and CRF have been
demonstrated in a variety of behavioral anxiety models [D. R.
Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J.
Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the
putative CRF receptor antagonist .alpha.-helical ovine CRF (9-41)
in a variety of behavioral paradigms demonstrate that the
antagonist produces "anxiolytic-like" effects that are
qualitatively similar to the benzodiazepines [C. W Berridge and A.
J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71
(1990)]. Neurochemical, endocrine and receptor binding studies have
all demonstrated interactions between CRF and benzodiazepine
anxiolytics providing further evidence for the involvement of CRF
in these disorders. Chlordiazepoxide attenuates the "anxiogenic"
effects of CRF in both the conflict test [K. T. Britton et al.,
Psychopharmacology 86:170 (1985); K. T. Britton et al.,
Psychopharmacology 94:306 (1988)] and in the acoustic startle test
[N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats.
The benzodiazepine receptor antagonist Ro 15-1788, which was
without behavioral activity alone in the operant conflict test,
reversed the effects of CRF in a dose-dependent manner while the
benzodiazepine inverse agonist FG 7142 enhanced the actions of CRF
[K. T. Britton et al., Psychopharmacology 94:306 (1988)].
[0008] It has been further postulated that CRF has a role in
immunological, cardiovascular or heart-related diseases such as
hypertension, tachycardia and congestive heart failure, stroke and
osteoporosis. CRF has also been implicated in premature birth,
psychosocial dwarfism, stress-induced fever, ulcer, diarrhea,
post-operative ileus and colonic hypersensitivity associated with
psychopathological disturbance and stress.
[0009] The mechanisms and sites of action through which the
standard anxiolytics and antidepressants produce their therapeutic
effects remain to be elucidated. It has been hypothesized however,
that they are involved in the suppression of the CRF hypersecretion
that is observed in these disorders. Of particular interest is that
preliminary studies examining the effects of a CRF receptor
antagonist .alpha.-helical CRF 9-41) in a variety of behavioral
paradigms have demonstrated that the CRF antagonist produces
"anxiolytic-like" effects qualitatively similar to the
benzodiazepines [for review see G. F. Koob and K. T. Britton, In:
Corticotropin-Releasing Factor: Basic and Clinical Studies of a
Neuropeptide, E. B. De Souza and C. B Nemeroff eds., CRC Press p221
(1990)].
SUMMARY OF THE INVENTION
[0010] In one aspect, the present invention provides novel
compounds which bind to corticotropin releasing factor receptors,
thereby altering the anxiogenic effects of CRF secretion. The
compounds of the present invention are useful for the treatment of
psychiatric disorders and neurological diseases, anxiety-related
disorders, post-traumatic stress disorder, supranuclear palsy and
feeding disorders as well as treatment of immunological,
cardiovascular or heart-related diseases and colonic
hypersensitivity associated with psychopathological disturbance and
stress in mammals. In another aspect, the present invention
provides novel compounds of Formula I (described below) which are
useful as antagonists of corticotropin releasing factor. The
compounds of the present invention exhibit activity as
corticotropin releasing factor antagonists and suppress CRF
hypersecretion. The present invention also provides pharmaceutical
compositions containing such compounds of Formula I, and methods of
using such compounds for the suppression of CRF hypersecretion,
and/or for the treatment of anxiogenic disorders.
[0011] According to yet another aspect, the present invention
provides novel compounds, pharmaceutical compositions and methods
for the treatment of affective disorder, anxiety, depression,
irritable bowel syndrome, post-traumatic stress disorder,
supranuclear palsy, immune suppression, Alzheimer's disease,
gastrointestinal disease, anorexia nervosa or other feeding
disorder, drug or alcohol withdrawal symptoms, drug addiction,
inflammatory disorder, fertility problems, disorders, the treatment
of which can be effected or facilitated by antagonizing CRF,
including but not limited to disorders induced or facilitated by
CRF, or a disorder selected from inflammatory disorders such as
rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis
and allergies; generalized anxiety disorder; panic, phobias,
obsessive-compulsive disorder; post-traumatic stress disorder;
sleep disorders induced by stress; pain perception such as
fibromyalgia; mood disorders such as depression, including major
depression, single episode depression, recurrent depression, child
abuse induced depression, and postpartum depression; dysthemia;
bipolar disorders; cyclothymia; fatigue syndrome; stress-induced
headache; cancer, human immunodeficiency virus (HIV) infections;
neurodegenerative diseases such as Alzbeimer's disease, Parkinson's
disease and Huntington's disease; gastrointestinal diseases such as
ulcers, irritable bowel syndrome, Crohn's disease, spastic colon,
diarrhea, and post operative ilius and colonic hypersensitivity
associated by psychopathological disturbances or stress; eating
disorders such as anorexia and bulimia nervosa; hemorrhagic stress;
stress-induced psychotic episodes; euthyroid sick syndrome;
syndrome of inappropriate antidiarrhetic hormone (ADR); obesity;
infertility; head traumas; spinal cord trauma; ischemic neuronal
damage (e.g., cerebral ischemia such as cerebral hippocampal
ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular
and heart related disorders including hypertension, tachycardia and
congestive heart failure; stroke; immune dysfunctions including
stress induced immune dysfunctions (e., stress induced fevers in
humans and the following animal diseases: porcine stress syndrome,
bovine shipping fever, equine paroxysmal fibrillation, and
dysfunctions induced by confinement in chickens. sheering stress in
sheep or human-animal interaction related stress in dogs); muscular
spasms; urinary incontinence; senile dementia of the Alzheimer's
type; multiinfarct dementia; amyotrophic lateral sclerosis;
chemical dependencies and addictions (e.g., dependencies on
alcohol, cocaine, heroin, benzodiazepines, or other drugs); drug
and alcohol withdrawal symptoms; osteoporosis; psychosocial
dwarfism and hypoglycemia in mammals.
[0012] Such methods involve administration to a mammal of a
therapeutically effective amount of a compound of Formula I.
[0013] In yet another aspect of the invention, the compounds
provided the invention (and especially radio-labeled compounds of
this invention) are also useful as standards and reagents in
determining the ability of a potential pharmaceutical to bind to
the CRF receptor.
[0014] The compounds encompassed by the instant invention and
represented by general Formula I: 2
[0015] wherein:
[0016] Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4-
or 5-pyrimidinyl, optionally mono-, di-, or tri-substituted with
halogen, trifluoromethyl, hydroxy, amino, carboxamido,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, with the proviso
that at least one of the positions ortho or para to the point of
attachment of Ar to the tricyclic ring system is substituted;
[0017] R.sup.1 is hydrogen, halogen, trifluoromethyl,
C.sub.1-C.sub.6 alkyl, or (C.sub.1-C.sub.6 alkyl)-G.sup.1-R.sup.2
where G.sup.1 is oxygen or sulfur and R.sup.2 is hydrogen or
C.sub.1-C.sub.6 alkyl;
[0018] W is N or C--R.sup.3 where R.sup.3 is hydrogen or
C.sub.1-C.sub.6 alkyl;
[0019] m is 0, 1, or 2;
[0020] X is 3
[0021] wherein
[0022] V.sup.1 and V.sup.2 are CH.sub.2, CO, CS, SO.sub.2 or
CH(C.sub.1-C.sub.6 alkyl), with the proviso that both V.sup.1 and
V.sup.2 cannot both be CO, CS or SO.sub.2;
[0023] Y.sup.1 and Y.sup.2 independently represent a bond or
C.sub.1-C.sub.6 alkylene;
[0024] A.sup.1 is NR.sup.4R.sup.5 wherein R.sup.4 and R.sup.5 are
independently
[0025] hydrogen or a C.sub.1-C.sub.6 alkyl group which and
optionally forms a heterocycloalkyl group with Y.sup.1;
[0026] acetyl or sulfonyl with the proviso that R.sup.4 and R.sup.5
cannot both be acetyl or sulfonyl; or
[0027] NR.sup.4R.sup.5 taken together form a C.sub.3-C.sub.6
heterocycloalkyl or a group of the formula: 4
[0028] wherein e and f are independently 1, 2, or 3 and the sum of
e and f is at least 3; and
[0029] G.sup.2 is
[0030] NR.sup.6 wherein R.sup.6 is hydrogen or C.sub.1-C.sub.6
alkyl, or
[0031] CH(C.sub.0-C.sub.6 alkylene)-G.sup.3-R.sup.7 wherein G.sup.3
is CONH, CONH(C.sub.1-C.sub.6 alkyl), NH, NH(C.sub.1-C.sub.6 alkyl)
and R.sup.7 is hydrogen or C.sub.1-C.sub.6 alkyl; or
[0032] CONH.sub.2, CO[N(C.sub.1-C.sub.6 alkyl)R.sup.8] wherein
R.sup.8 is hydrogen or C.sub.1-C.sub.6 alkyl;
[0033] A.sup.2 is hydrogen, C.sub.1-C.sub.6 alkyl, (C.sub.1-C.sub.6
alkylene)-G.sup.4-R.sup.9 wherein G is oxygen or sulfur and R is
hydrogen, trifluoromethyl or C.sub.1-C.sub.6 alkyl; 5
[0034] wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or
5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 1-,
3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or
5-tetrazolyl, each of which is optionally mono- or disubstituted
with halogen, trifluoromethyl, amino, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, with the proviso that tetrazolyl can have
at most one substituent;
[0035] Z.sup.1 is C.sub.1-C.sub.6 alkyl; and
[0036] V.sup.2, Y.sup.2 and A.sup.2 are as defined above; 6
[0037] wherein
[0038] Z.sup.2 is carbon or nitrogen;
[0039] where
[0040] when Z.sup.2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3,
R.sup.10 is carboxamido, or (C.sub.1-C.sub.6
alkylene)-G.sup.5-R.sup.11 wherein G.sup.5 is NH,
NH(C.sub.1-C.sub.6 alkyl) and R.sup.11 is hydrogen or
C.sub.1-C.sub.6 alkyl;
[0041] when Z.sup.2 is carbon, n is 1 or 2 and p is 1 or 2,
R.sup.10 is amino; or
[0042] when Z.sup.2 is nitrogen, n is 1 or 2 and p is 1 or 2,
R.sup.10 is hydrogen; or
[0043] (iv) a nitrogen heterocycle of the formula: 7
[0044] wherein the N-ring represents triazolyl, tetrazolyl,
imidazolyl, or pyrazolyl, each of which is optionally substituted
with amino, trifluoromethyl, carboxamido, or (C.sub.1-C.sub.6
alkylene)-G.sup.6-R.sup- .12 wherein G.sup.6 is NH,
NH(C.sub.1-C.sub.6 alkyl) and R.sup.12 is hydrogen or
C.sub.1-C.sub.6 alkyl.
DETAILED DESCRIPTION OF THE INVENTION
[0045] As noted above, the invention provides compounds of Formula
I: 8
[0046] wherein:
[0047] Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4-
or 5-pyrimidinyl, optionally mono-, di-, or tri-substituted with
halogen, trifluoromethyl, hydroxy, amino, carboxamido,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, with the proviso
that at least one of the positions ortho or para to the point of
attachment of Ar to the tricyclic ring system is substituted;
[0048] R.sup.1 is hydrogen, halogen, trifluoromethyl,
C.sub.1-C.sub.6 alkyl, or (C.sub.1-C.sub.6 alkyl)-G.sup.1-R.sup.2
where G.sup.1 is oxygen or sulfur and R.sup.2 is hydrogen or
C.sub.1-C.sub.6 alkyl;
[0049] W is N or C--R.sup.3 where R.sup.3 is hydrogen or
C.sub.1-C.sub.6 alkyl;
[0050] m is 0, 1, or 2;
[0051] X is 9
[0052] wherein
[0053] V.sup.1 and V.sup.2 are CH.sub.2, CO, CS, SO.sub.2 or
CH(C.sub.1-C.sub.6 alkyl), with the proviso that both V.sup.1 and
V.sup.2 cannot both be CO, CS or SO.sub.2;
[0054] Y.sup.1 and Y.sup.2 independently represent a bond or
C.sub.1-C.sub.6 alkylene;
[0055] A.sup.1 is NR.sup.4R.sup.5 wherein R.sup.4 and R.sup.5 are
independently
[0056] hydrogen or a C.sub.1-C.sub.6 alkyl group which and
optionally forms a heterocycloalkyl group with Y.sup.1;
[0057] acetyl or sulfonyl with the proviso that R.sup.4 and R.sup.5
cannot both be acetyl or sulfonyl; or
[0058] NR.sup.4R.sup.5 taken together form a C.sub.3-C.sub.6
heterocycloalkyl or a group of the formula: 10
[0059] wherein e and f are independently 1, 2, or 3 and the sum of
e and f is at least 3; and
[0060] G.sup.2 is
[0061] NR.sup.6 wherein R.sup.6 is hydrogen or C.sub.1-C.sub.6
alkyl, or
[0062] CH(C.sub.0-C.sub.6 alkylene)-G.sup.3-R.sup.7 wherein G is
CONH, CONH(C.sub.1-C.sub.6 alkyl), NH, NH(C.sub.1-C.sub.6 alkyl)
and R.sup.7 is hydrogen or C.sub.1-C.sub.6 alkyl; or
[0063] CONH.sub.2, CO[N(C.sub.1-C.sub.6 alkyl)R.sup.8] wherein
R.sup.8 is hydrogen or C.sub.1-C.sub.6 alkyl;
[0064] A.sup.2 is hydrogen, C.sub.1-C.sub.6 alkyl, (C.sub.1-C.sub.6
alkylene)-G.sup.4 -R.sup.9 wherein G.sup.4 is oxygen or sulfur and
R.sup.9 is hydrogen, trifluoromethyl or C.sub.1-C.sub.6 alkyl;
11
[0065] wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or
5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 1-,
3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or
5-tetrazolyl, each of which is optionally mono- or disubstituted
with halogen, trifluoromethyl, amino, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, with the proviso that tetrazolyl can have
at most one substituent;
[0066] Z.sup.1 is C.sub.1-C.sub.6 alkyl; and
[0067] V.sup.2, Y.sup.2 and A.sup.2 are as defined above; 12
[0068] wherein
[0069] Z.sup.2 is carbon or nitrogen;
[0070] wherein
[0071] when Z.sup.2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3,
R.sup.10 is carboxamido, or (C.sub.1-C.sub.6
alkylene)-G.sup.5-R.sup.11 wherein G.sup.5 is NH,
NH(C.sub.1-C.sub.6 alkyl) and R.sup.11 is hydrogen or
C.sub.1-C.sub.6 alkyl;
[0072] when Z.sup.2 is carbon, n is 1 or 2 and p is 1 or 2,
R.sup.10 is amino; or
[0073] when Z.sup.2 is nitrogen, n is 1 or 2 and p is 1 or 2,
R.sup.10 is hydrogen; or
[0074] (iv) a nitrogen heterocycle of the formula: 13
[0075] wherein the N-ring represents triazolyl, tetrazolyl,
imidazolyl, or pyrazolyl, each of which is optionally substituted
with amino, trifluoromethyl, carboxamido, or (C.sub.1-C.sub.6
alkylene)-G.sup.6-R.sup- .12 wherein G.sup.6 is NH,
NH(C.sub.1-C.sub.6 alkyl) and R.sup.12 is hydrogen or
C.sub.1-C.sub.6 alkyl.
[0076] Preferred compounds of Formula I are those where V.sup.1 and
V.sup.2 represent methylene; Y.sup.1 is a bond; A.sup.1 represents
pyrrolidinyl, morpholinyl; piperazinyl, or mono- or
di-C.sub.1-C.sub.6 alkyl; Y.sup.2 represents a bond or methylene;
and A.sup.2 represents C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6
alkoxymethyl.
[0077] Other preferred compounds of Formula I are those where each
R.sub.a independently represents C.sub.1-C.sub.6 alkyl; and A.sup.2
is C.sub.1-C.sub.6 cycloalkyl. In other preferred compounds of I,
A.sup.2 is (C.sub.3-C.sub.5) cycloalkyl (C.sub.1-C.sub.4)
alkyl.
[0078] Still other preferred compounds of I include are those
where
[0079] A.sup.1 is
[0080] NR.sup.4R.sup.5 where R.sup.4 and R.sup.5 are independently
hydrogen, C.sub.1-C.sub.6 alkyl; or
[0081] NR.sup.4R.sup.5 forms a 5 or 6-membered nitrogen heterocycle
optionally containing an oxygen or second nitrogen atom;
[0082] Y.sup.1 is C.sub.1-C.sub.6 alkylene;
[0083] Y.sup.2 is a bond or C.sub.1-C.sub.6 alkylene;
[0084] V.sup.1 is methylene; and V.sup.2 is methylene.
[0085] More preferably, A.sup.2 is (C.sub.3-C.sub.5) cycloalkyl.
Still more preferably, R.sup.4 and R.sup.5 are independently
C.sub.1-C.sub.6 alkyl. Other particularly preferred compounds of
Formula I are those where each R.sub.a is methyl; Y.sup.2 is a
bond; and R.sup.4 and R.sup.5 are the same and represent
C.sub.1-C.sub.3 alkyl.
[0086] In yet other preferred compounds of Formula I, m is 1 or 2,
more preferably 1. In still other preferred compounds of I, m is 1
and R.sup.1 is C.sub.1-C.sub.3 alkyl, more preferably methyl.
[0087] Preferred compounds of the invention have Formula II: 14
[0088] wherein:
[0089] each R.sub.a independently represents C.sub.1-C.sub.6
alkyl;
[0090] R.sup.1 is hydrogen, halogen, trifluoromethyl,
C.sub.1-C.sub.6 alkyl, or (C.sub.1-C.sub.6 alkyl)-G.sup.1-R.sup.2
where G.sup.1 is oxygen or sulfur and R.sup.2 is hydrogen or
C.sub.1-C.sub.6 alkyl;
[0091] W is N or C--R.sup.3 where R.sup.3 is hydrogen or
C.sub.1-C.sub.6 alkyl;
[0092] m is 0, 1, or 2;
[0093] X is 15
[0094] wherein
[0095] V.sup.1 and V.sup.2 are CH.sub.2, CO, CS, SO.sub.2 or
CH(C.sub.1-C.sub.6 alkyl), with the proviso that both V.sup.1 and
V.sup.2 cannot both be CO, CS or SO.sub.2;
[0096] Y.sup.1 and Y.sup.2 independently represent a bond or
C.sub.1-C.sub.6 alkylene;
[0097] A.sup.1 is NR.sup.4R.sup.5 wherein R.sup.4 and R.sup.5 are
independently
[0098] hydrogen or a C.sub.1-C.sub.6 alkyl group which and
optionally forms a heterocycloalkyl group with Y.sup.1;
[0099] acetyl or sulfonyl with the proviso that R.sup.4 and R.sup.5
cannot both be acetyl or sulfonyl; or
[0100] NR.sup.4R.sup.5 taken together form a C.sub.3-C.sub.6
heterocycloalkyl or a group of the formula: 16
[0101] wherein e and f are independently 1, 2, or 3 and the sum of
e and f is at least 3; and
[0102] G.sup.2 is
[0103] NR.sup.6 wherein R.sup.6 is hydrogen or C.sub.1-C.sub.6
alkyl, or
[0104] CH(C.sub.0-C.sub.6 alkylene)-G.sup.3-R.sup.7 wherein G is
CONH, CONH(C.sub.1-C.sub.6 alkyl), NH, NH(C.sub.1-C.sub.6 alkyl)
and R.sup.7 is hydrogen or C.sub.1-C.sub.6 alkyl; or
[0105] CONH.sub.2, CO[N(C.sub.1-C.sub.6 alkyl)R.sup.8] wherein
R.sup.8 is hydrogen or C.sub.1-C.sub.6 alkyl;
[0106] A.sup.2 is hydrogen, C.sub.1-C.sub.6 alkyl, (C.sub.1-C.sub.6
alkylene)-G.sup.4 -R.sup.9 wherein G.sup.4 is oxygen or sulfur and
R.sup.9 is hydrogen, trifluoromethyl or C.sub.1-C.sub.6 alkyl;
17
[0107] wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or
5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 1-,
3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or
5-tetrazolyl, each of which is optionally mono- or disubstituted
with halogen, trifluoromethyl, amino, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, with the proviso that tetrazolyl can have
at most one substituent;
[0108] Z.sup.1 is C.sub.1-C.sub.6 alkyl; and
[0109] V.sup.2, Y.sup.2 and A.sup.2 are as defined above; 18
[0110] wherein
[0111] Z.sup.2 is carbon or nitrogen;
[0112] wherein
[0113] when Z.sup.2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3,
R.sup.10 is carboxamido, or (C.sub.1-C.sub.6
alkylene)-G.sup.5-R.sup.11 wherein G.sup.5 is NH,
NH(C.sub.1-C.sub.6 alkyl) and R.sup.11 is hydrogen or
C.sub.1-C.sub.6 alkyl;
[0114] when Z.sup.2 is carbon, n is 1 or 2 and p is 1 or 2,
R.sup.10 is amino; or
[0115] when Z.sup.2 is nitrogen, n is 1 or 2 and p is 1 or 2,
R.sup.10 is hydrogen; or
[0116] (iv) a nitrogen heterocycle of the formula: 19
[0117] wherein the N-ring represents triazolyl, tetrazolyl,
imidazolyl, or pyrazolyl, each of which is optionally substituted
with amino, trifluoromethyl, carboxamido, or (C.sub.1-C.sub.6
alkylene)-G.sup.6-R.sup- .12 wherein G.sup.6 is NH,
NH(C.sub.1-C.sub.6 alkyl) and R.sup.12 is hydrogen or
C.sub.1-C.sub.6 alkyl.
[0118] Preferred compounds of Formula II are those where V.sup.1
and V.sup.2 represent methylene; Y.sup.1 is a bond; A.sup.1
represents pyrrolidinyl, morpholinyl; piperazinyl, or mono- or
di-C.sub.1-C.sub.6 alkyl; Y.sup.2 represents a bond or methylene;
and A.sup.2 represents C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6
alkoxymethyl.
[0119] Other preferred compounds of Formula II are those where each
R.sub.a independently represents C.sub.1-C.sub.6 alkyl;
[0120] A.sub.2 is (C.sub.3-C.sub.5)cycloalkyl(C.sub.1-C.sub.4)alkyl
or (C.sub.3-C.sub.5)cycloalkyl;
[0121] A.sup.1 is
[0122] NR.sup.4R.sup.5 where R.sup.4 and Rs are independently
hydrogen, C.sub.1-C.sub.6 alkyl; or
[0123] NR.sup.4R.sup.5 forms a 5 or 6-membered nitrogen heterocycle
optionally containing an oxygen or second nitrogen atom;
[0124] Y.sup.1 is C.sub.1-C.sub.6 alkylene;
[0125] Y.sup.2 is a bond or C.sub.1-C.sub.6 alkylene;
[0126] V.sup.1 is methylene; and V.sup.2 is methylene.
[0127] More preferably, A.sup.2 is
cyclopropyl(C.sub.1-C.sub.3)alkyl or (C.sub.3-C.sub.5)cycloalkyl;
and R.sup.4 and R.sup.5 are independently C.sub.1-C.sub.6 alkyl.
Particularly preferred compounds of Formula II include those where
A.sup.2 is (C.sub.3-C.sub.5) cycloalkyl; Y.sup.2 is a bond; and
R.sup.4 and R.sup.5 are the same and represent C.sub.1-C.sub.3
alkyl. Other particularly preferred compounds of Formula II are
those where each R.sub.a is methyl; A.sup.2 is cyclopropyl; Y.sup.2
is a bond; and R.sup.4 and R.sup.5 are the same and represent
C.sub.1-C.sub.3 alkyl.
[0128] In preferred compounds of Formula II, m is 1 or 2, more
preferably 1. In other preferred compounds of II, m is 1 and
R.sup.1 is C.sub.1-C.sub.3 alkyl, more preferably methyl.
[0129] Other preferred compounds of the invention have Formula III:
20
[0130] wherein:
[0131] each R.sub.a independently represents C.sub.1-C.sub.6
alkyl;
[0132] R.sup.1 is hydrogen, halogen, trifluoromethyl,
C.sub.1-C.sub.6 alkyl, or (C.sub.1-C.sub.6 alkyl)-G.sup.1-R.sup.2
where G.sup.1 is oxygen or sulfur and R.sup.2 is hydrogen or
C.sub.1-C.sub.6 alkyl;
[0133] W is N or C--R.sup.3 where R.sup.3 is hydrogen or
C.sub.1-C.sub.6 alkyl;
[0134] m is 0, 1, or 2;
[0135] X is 21
[0136] wherein
[0137] V.sup.1 and V.sup.2 are CH.sub.2, CO, CS, SO.sub.2 or
CH(C.sub.1-C.sub.6 alkyl), with the proviso that both V and V
cannot both be CO, CS or SO.sub.2;
[0138] Y.sup.1 and Y.sup.2 independently represent a bond or
C.sub.1-C.sub.6 alkylene;
[0139] A.sup.1 is NR.sup.4R.sup.5 wherein R.sup.4 and R.sup.5 are
independently
[0140] hydrogen or a C.sub.1-C.sub.6 alkyl group which and
optionally forms a heterocycloalkyl group with Y.sup.1;
[0141] acetyl or sulfonyl with the proviso that R.sup.4 and R.sup.5
cannot both be acetyl or sulfonyl; or
[0142] NR.sup.4R.sup.5 taken together form a C.sub.3-C.sub.6
heterocycloalkyl or a group of the formula: 22
[0143] wherein e and f are independently 1, 2, or 3 and the sum of
e and f is at least 3; and
[0144] G.sup.2 is
[0145] NR.sup.6 wherein R.sup.6 is hydrogen or C.sub.1-C.sub.6
alkyl, or
[0146] CH(C.sub.0-C.sub.6 alkylene)-G.sup.3-R.sup.7 wherein G.sup.3
is CONH, CONH(C.sub.1-C.sub.6 alkyl), NH, NH(C.sub.1-C.sub.6 alkyl)
and R.sup.7 is hydrogen or C.sub.1-C.sub.6 alkyl; or
[0147] CONH.sub.2, CO[N(C.sub.1-C.sub.6 alkyl)R.sup.8] wherein
R.sup.8 is hydrogen or C.sub.1-C.sub.6 alkyl;
[0148] A.sup.2 is hydrogen, C.sub.1-C.sub.6 alkyl, (C.sub.1-C.sub.6
alkylene)-G.sup.4-R.sup.9 wherein G.sup.4 is oxygen or sulfur and
R.sup.9 is hydrogen, trifluoromethyl or C.sub.1-C.sub.6 alkyl;
23
[0149] wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or
5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 1-,
3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or
5-tetrazolyl, each of which is optionally mono- or disubstituted
with halogen, trifluoromethyl, amino, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, with the proviso that tetrazolyl can have
at most one substituent;
[0150] Z.sup.1 is C.sub.1-C.sub.6 alkyl; and
[0151] V.sup.2, Y.sup.2 and A.sup.2 are as defined above; 24
[0152] wherein
[0153] Z.sup.2 is carbon or nitrogen;
[0154] wherein
[0155] when Z.sup.2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3,
R.sup.10 is carboxamido, or (C.sub.1-C.sub.6
alkylene)-G.sup.5-R.sup.11 wherein G.sup.5 is NH,
NH(C.sub.1-C.sub.6 alkyl) and R.sup.11 is hydrogen or
C.sub.1-C.sub.6 alkyl;
[0156] when Z.sup.2 is carbon, n is 1 or 2 and p is 1 or 2,
R.sup.10 is amino; or
[0157] when Z is nitrogen, n is 1 or 2 and p is 1 or 2, R.sup.10 is
hydrogen; or
[0158] (iv) a nitrogen heterocycle of the formula: 25
[0159] wherein the N-ring represents triazolyl, tetrazolyl,
imidazolyl, or pyrazolyl, each of which is optionally substituted
with amino, trifluoromethyl, carboxamido, or (C.sub.1-C.sub.6
alkylene)-G.sup.6-R.sup- .12 wherein G.sup.6 is NH,
NH(C.sub.1-C.sub.6 alkyl) and R.sup.12 is hydrogen or
C.sub.1-C.sub.6 alkyl.
[0160] Preferred compounds of Formula III are those where V.sup.1
and V.sup.2 represent methylene; Y.sup.1 is a bond; A.sup.1
represents pyrrolidinyl, morpholinyl; piperazinyl, or mono- or
di-C.sub.1-C.sub.6 alkyl; Y.sup.2 represents a bond or methylene;
and A.sup.2 represents C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6
alkoxymethyl.
[0161] Other preferred compounds of Formula III include those where
each R.sub.a is independently halogen, trifluoromethyl, hydroxy,
amino, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy. Specific
preferred compounds of III are those where at least one R.sub.a is
C.sub.1-C.sub.6 alkyl and the other R.sub.a groups are
independently C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6
alkoxy or trifluoromethyl.
[0162] Other preferred compounds of Formula III are those where
each R.sub.a independently represents C.sub.1-C.sub.6 alkyl;
[0163] A.sup.2 is (C.sub.3-C.sub.5)cycloalkyl(C.sub.1-C.sub.4)alkyl
or (C.sub.3-C.sub.5)cycloalkyl;
[0164] A.sup.1 is
[0165] NR.sup.4R.sup.5 where R.sup.4 and R.sup.5 are independently
hydrogen, C.sub.1-C.sub.6 alkyl; or
[0166] NR.sup.4R.sup.5 forms a 5 or 6-membered nitrogen heterocycle
optionally containing an oxygen or second nitrogen atom;
[0167] Y.sup.1 is C.sub.1-C.sub.6 alkylene;
[0168] Y.sup.2 is a bond or C.sub.1-C.sub.6 alkylene;
[0169] V.sup.1 is methylene; and V.sup.2 is methylene.
[0170] More preferably, A.sup.2 is
cyclopropyl(C.sub.1-C.sub.3)alkyl or (C.sub.3-C.sub.5)cycloalkyl;
and R.sup.4 and R.sup.5 are independently C.sub.1-C.sub.6 alkyl.
Particularly preferred compounds of Formula III include those where
A.sup.2 is (C.sub.3-C.sub.5) cycloalkyl; Y.sup.2 is a bond; and
R.sup.4 and R.sup.5 are the same and represent C.sub.1-C.sub.3
alkyl. Other particularly preferred compounds of Formula III
include those where at least one R.sub.a is methyl; A.sup.2 is
(C.sub.3-C.sub.5) cycloalkyl; Y.sup.2 is a bond; and R.sup.4 and
R.sup.5 are the same and represent C.sub.1-C.sub.3 alkyl. Highly
preferred compounds of Formula III are those where each R.sub.a is
methyl; A.sup.2 is cyclopropyl; Y.sup.2 is a bond; and R.sup.4 and
R.sup.5 are the same and represent C.sub.1-C.sub.3 alkyl.
[0171] In preferred compounds of Formula III, m is 1 or 2, more
preferably 1. In other preferred compounds of III, m is 1 and
R.sup.1 is C.sub.1-C.sub.3 alkyl, more preferably methyl.
[0172] In certain situations, the compounds of Formula I may
contain one or more asymmetric carbon atoms, so that the compounds
can exist in different stereoisomeric forms. These compounds can
be, for example, racemates or optically active forms. In these
situations, the single enantiomers, i.e., optically active forms,
can be obtained by asymmetric synthesis or by resolution of the
racemates. Resolution of the racemates can be accomplished, for
example, by conventional methods such as crystallization in the
presence of a resolving agent, or chromatography, using, for
example a chiral HPLC column.
[0173] Representative compounds of the present invention, which are
encompassed by Formula I, include, but are not limited to the
compounds in Table I and their pharmaceutically acceptable acid
addition salts. In addition, if the compound of the invention is
obtained as an acid addition salt, the free base can be obtained by
basifying a solution of the acid salt. Conversely, if the product
is a free base, an addition salt, particularly a pharmaceutically
acceptable addition salt, may be produced by dissolving the free
base in a suitable organic solvent and treating the solution with
an acid, in accordance with conventional procedures for preparing
acid addition salts from base compounds.
[0174] Non-toxic pharmaceutical salts include salts of acids such
as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic,
formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric,
tartaric, maleic, hydroiodic, alkanoic such as acetic,
HOOC--(CH.sub.2)n-ACOOH where n is 0-4, and the like. Those skilled
in the art will recognize a wide variety of non-toxic
pharmaceutically acceptable addition salts.
[0175] The present invention also encompasses the acylated prodrugs
of the compounds of Formula I. Those skilled in the art will
recognize various synthetic methodologies which may be employed to
prepare non-toxic pharmaceutically acceptable addition salts and
acylated prodrugs of the compounds encompassed by Formula I.
[0176] By "alkyl" or "lower alkyl" in the present invention is
meant C.sub.1-C.sub.6 alkyl, i.e., straight or branched chain alkyl
groups having 1-6 carbon atoms, such as, for example, methyl,
ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl,
2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and
3-methylpentyl and straight or branched chain alkyl groups of 1-5
carbon atoms carrying a cyclopropyl, cyclobutyl, or cyclopenlyl
group. Preferred C.sub.1-C.sub.6 alkyl groups are methyl, ethyl,
propyl, butyl, cyclopropyl or cyclopropylmethyl.
[0177] By "CO--C.sub.6 alkylene" is meant a direct bond or a
C.sub.1-C.sub.6 alkylene group.
[0178] By "alkoxy" or "lower alkoxy" in the present invention is
meant C.sub.1-C.sub.6 alkoxy, i.e., straight or branched chain
alkoxy groups having 1-6 carbon atoms, such as, for example,
methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy,
tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy,
2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
[0179] CONH represents an amide functional group, i.e., 26
[0180] The term "heterocycle" or "heterocycloalkyl" means a
monocyclic or bicyclic hydrocarbon group which in which one or more
of the ring carbon atoms has been replaced with a heteroatom, e.g.,
oxygen, sulfur or nitrogen. Such groups preferably have 4 to 10
carbon atoms and 1 to 4 heteroatoms.
[0181] By the term "halogen" in the present invention is meant
fluorine, bromine, chlorine, and iodine.
[0182] Table 1 shows representative aminoalkyl substituted
5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole and
5,6,7,8-tetrahydro-9H-pyr- imidino[4,5-b]indole derivatives of the
present invention. The number under each compound is its compound
number.
1TABLE 1 27 1 28 2 29 3 30 4 31 5 32 6
[0183] The interaction of aminoalkyl substituted
5,6,7,8-tetrahydro-9H-pyr- idino[2,3-b]indole and
5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole derivatives of the
invention with CRF receptors is shown in the examples. This
interaction results in the pharmacological activities of these
compounds as illustrated in relevant animal models.
[0184] The compounds of general Formula I may be administered
orally, topically, parenterally, by inhalation or spray or rectally
in dosage unit formulations containing conventional non-toxic
pharmaceutically acceptable carriers, adjuvants and vehicles. The
term parenteral as used herein includes subcutaneous injections,
intravenous, intramuscular, intrasternal injection or infusion
techniques. In addition, there is provided a pharmaceutical
formulation comprising a compound of general Formula I and a
pharmaceutically acceptable carrier. One or more compounds of
general Formula I may be present in association with one or more
non-toxic pharmaceutically acceptable carriers and/or diluents
and/or adjuvants and if desired other active ingredients. The
pharmaceutical compositions containing compounds of general Formula
I may be in a form suitable for oral use, for example, as tablets,
troches, lozenges, aqueous or oily suspensions, dispersible powders
or granules, emulsion, hard or soft capsules, or syrups or
elixirs.
[0185] Compositions intended for oral use may be prepared according
to any method known to the art for the manufacture of
pharmaceutical compositions and such compositions may contain one
or more agents selected from the group consisting of sweetening
agents, flavoring agents, coloring agents and preserving agents in
order to provide pharmaceutically elegant and palatable
preparations. Tablets contain the active ingredient in admixture
with non-toxic pharmaceutically acceptable excipients which are
suitable for the manufacture of tablets. These excipients may be
for example, inert diluents, such as calcium carbonate, sodium
carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch, or
alginic acid; binding agents, for example starch, gelatin or
acacia, and lubricating agents, for example magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be
coated by known techniques to delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material
such as glyceryl monosterate or glyceryl distearate may be
employed.
[0186] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, for example peanut
oil, liquid paraffin or olive oil.
[0187] Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone,
gum tragacanth and gum acacia; dispersing or wetting agents may be
a naturally-occurring phosphatide, for example, lecithin, or
condensation products of an alkylene oxide with fatty acids, for
example polyoxyethylene stearate, or condensation products of
ethylene oxide with long chain aliphatic alcohols, for example
heptadecaethyleneoxycetanol, or condensation products of ethylene
oxide with partial esters derived from fatty acids and a hexitol
such as polyoxyethylene sorbitol monooleate, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and hexitol anhydrides, for example polyethylene sorbitan
monooleate. The aqueous suspensions may also contain one or more
preservatives, for example ethyl, or n-propyl p-hydroxybenzoate,
one or more coloring agents, one or more flavoring agents, and one
or more sweetening agents, such as sucrose or saccharin.
[0188] Oily suspensions may be formulated by suspending the active
ingredients in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide palatable oral preparations. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0189] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
[0190] Pharmaceutical compositions of the invention may also be in
the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, for example olive oil or arachis oil, or a mineral
oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may be naturally-occurring gums, for example gum
acacia or gum tragacanth, naturally-occurring phosphatides, for
example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol, anhydrides, for example sorbitan
monoleate, and condensation products of the said partial esters
with ethylene oxide, for example polyoxyethylene sorbitan
monoleate. The emulsions may also contain sweetening and flavoring
agents.
[0191] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative and
flavoring and coloring agents. The pharmaceutical compositions may
be in the form of a sterile injectable aqueous or oleaginous
suspension. This suspension may be formulated according to the
known art using those suitable dispersing or wetting agents and
suspending agents which have been mentioned above. The sterile
injectable preparation may also be sterile injectable solution or
suspension in a non-toxic parentally acceptable diluent or solvent,
for example as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's
solution and isotonic sodium chloride solution. In addition,
sterile, fixed oils are conventionally employed as a solvent or
suspending medium. For this purpose any bland fixed oil may be
employed including synthetic mono-or diglycerides. In addition,
fatty acids such as oleic acid find use in the preparation of
injectables.
[0192] The compounds of general Formula I may also be administered
in the form of suppositories for rectal administration of the drug.
These compositions can be prepared by mixing the drug with a
suitable non-irritating excipient which is solid at ordinary
temperatures but liquid at the rectal temperature and will
therefore melt in the rectum to release the drug. Such materials
are cocoa butter and polyethylene glycols.
[0193] Compounds of general Formula I may be administered
parenterally in a sterile medium. The drug, depending on the
vehicle and concentration used, can either be suspended or
dissolved in the vehicle. Advantageously, adjuvants such as local
anesthetics, preservatives and buffering agents can be dissolved in
the vehicle.
[0194] Dosage levels of the order of from about 0.1 mg to about 140
mg per kilogram of body weight per day are useful in the treatment
of the above-indicated conditions (about 0.5 mg to about 7 g per
patient per day). The amount of active ingredient that may be
combined with the carrier materials to produce a single dosage form
will vary depending upon the host treated and the particular mode
of administration. Dosage unit forms will generally contain between
from about 1 mg to about 500 mg of an active ingredient.
[0195] It will be understood, however, that the specific dose level
for any particular patient will depend upon a variety of factors
including the activity of the specific compound employed, the age,
body weight, general health, sex, diet, time of administration,
route of administration, and rate of excretion, drug combination
and the severity of the particular disease undergoing therapy.
[0196] Preparation of Aminoalkyl Substituted
5,6,7,8-Tetrahydro-9H-Pyridin- o[2.3-b]indole and
5,6,7,8-Tetrahydro-9H-Pyrimidino[4,5-b]indole Analogues
[0197] Representative preparations of compounds of the present
invention are shown in Schemes I, II, III and IV. Those having
skill in the art will recognize that the starting materials may be
varied and additional steps employed to produce compounds
encompassed by the present invention. 33
[0198] wherein Ar, R.sup.1 and R.sup.3 are as defined above for
Formula I; and R.sup.14, R.sup.15 and R.sup.16 are encompassed by
the definition of X in Formula I; 34
[0199] wherein Ar, R.sup.1 and R.sup.3 are as defined above for
Formula I; and R.sup.14, R.sup.15 and R.sup.16 are encompassed by
the definition of X in Formula I; 35
[0200] wherein Ar, R.sup.1 and R.sup.3 are as defined above for
Formula I; and R.sup.15 and R.sup.16 are encompassed by the
definition of X in Formula I; 36
[0201] wherein Ar and R.sup.1 are as defined with reference to
Formula I; R.sup.15, R.sup.16 and R.sup.17 are as defined above in
Formula I with respect to the definition of X;
[0202] The preparation of the compounds of the present invention is
illustrated further by the following examples, which are not to be
construed as limiting the invention in scope or spirit to the
specific procedures and compounds described in them.
[0203] The disclosures of all articles and references mentioned in
in this application, including patents, are incorporated herein by
reference.
[0204] Commercial reagents were used without further purification.
THF refers to tetrahydrofuran. LDA refers to lithium
diisopropylamide. Room or ambient temperature refers to 20 to
25.degree. C. Concentration implies the use of a rotary evaporator.
TLC refers to thin layer chromatography. Mass spectral data were
obtained either by CI or APCI methods.
EXAMPLE 1
[0205] A.
2-Amino-4,5,6,7-tetrahydro-1-phenyl-1H-indole-3-carbonitrile 37
[0206] A mixture of 2,4,6-trimethylaniline (500 g) and adipoin (464
g) in toluene (2.5 L) is heated to reflux. A theoretical amount of
water is removed azeotropically over the course of 3 hours. The
mixture is cooled to ambient temperature, then malononitrile (244
g) and ammonium acetate (57 g) are added. The reaction is slowly
reheated back to reflux for about 1 hour with azeotropic removal of
water. After cooling, the precipitate that forms overnight is
collected by filtration. The dark solid is washed with ethanol and
dried to afford 540 g of a white powder: MS 280 (M+H).
[0207] B.
4-Amino-2-methyl-9-(2,4.6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-
-pyridino[2,3-b]indole 38
[0208] To the product of Example 1A (535 g) dissolved in
dichloroethane (4 L) are added 2-methoxypropene (550 mL) and
p-toluenesulfonic acid monohydrate (3.6 g). The mixture is refluxed
for 1 hour then the solvent is removed by distillation. The residue
is dissolved in THF (3 L) and cooled to 0.degree. C. To this
solution, under an atmosphere of nitrogen gas, is added LDA (2.0M,
1.2 L) at a rate to keep the reaction internal temperature below
10.degree. C. After 3 hours the reaction is neutralized with
aqueous HCl. The aqueous layer is extracted with ethyl acetate and
combined with the THF layer. The combined organic phase is
extracted with 3M HCl and the latter is made alkaline (pH=10) with
10N NaOH and ice. The aqueous solution is extracted with
dichloromethane, dried with sodium sulfate, filtered and
concentrated to give a crystaline solid: MS 320 (M+H).
[0209] C.
4-(N-Cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)--
5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole 39
[0210] A solution of dichloroethane (70 mL) containing the product
of Example 1B (11 g) and cyclopropanecarbonyl chloride (3.4 mL) at
reflux is treated with dropwise addition of
N,N-diisopropylethylamine (6.6 mL). After heating for 0.5 hour the
reaction is cooled to ambient temperature and poured into aqueous
potassium carbonate solution. The product is extracted with
dichoromethane, dried over sodium sulfate, filtered and
concentrated to give
4-(N-Cyclopropyloxomethyl)amino-2-methyl-9-(2,4,6-tr-
imethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole. The
latter compound is dissolved in THF (100 mL) and mixed with
borane-methyl sulfide complex (10M, 10.3 mL). The mixture is heated
to reflux for 8 hours and quenched at room temperature with a large
excess of methanol (about 100 mL). Reheat mixture to reflux for 1
hour, then concentrate under reduced pressure. More methanol
(another 50 mL) is added to the gummy residue and the solution is
re-concentrated to yield a white solid: MS 374 (M+H).
[0211] D.
4-(N-(2-Chloroethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-
-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
40
[0212] A solution containing the product from Example 1C (13 g) and
chloroacetyl chloride (3 mL) in dichloroethane (100 mL) is refluxed
for 4 hours. The solvent and excess reagent are removed under
reduced pressure. Aqueous potassium carbonate is added to the
remaining oily residue and extracted with dichloromethane. The
extract is dried with sodium sulfate, filtered and concentrated.
The latter chloroacetyl compound (15 g) is dissolved in THF (100
mL). Add borane-methyl sulfide complex (10M, 3.4 mL) and stir at
ambient temperature for 15 minutes then for 1 hour at reflux
temperature. The solution is cooled back to room temperature,
quenched with a large excess of methanol (50 mL) and reheated to
reflux for 1 hour. The solution is then concentrated: MS 436
(M+H).
[0213] E.
4-(N-(2-Dimethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-
-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
(Compound 1) 41
[0214] A steel bomb containing the product from Example 1D (3.8 g),
dimethylamine (8 mL) and N-methylpyrrolidinone (20 mL) is sealed
and heated to 80.degree. C. for 10 hours. The mixture is poured
into water and extracted with ethyl acetate. The organic layer is
washed with water, dried over sodium sulfate, filtered and
concentrated. The product is purified by crystallization of the
sulfate salt: Concentrated sulfuric acid (0.46 mL) is added to the
isolated amino compound (3.9 g) dissolved in ethanol (5 mL). The
solution is concentrated to dryness and subsequently dissolved in
isopropanol (5 mL). Next ethyl acetate (20 mL) is added and the
solution is allowed to stand at room temperature. The white
crystals of the sulfate salt, i.e.,
4-(N-(2-Dimethylaminoethyl)-N-c-
yclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahyd-
ro-9H-pyridino[2,3-b]indole sulfate, are then collected by
filtration. MS(free base) 445 (M+H).
[0215] Alternatively the above compound can be prepared from
4-(N-Cyclopropyloxomethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,-
8-tetrahydro-9H-pyridino[2,3-b]indole described in Example IC. To a
suspension of the latter amide (20 g, 0.052 mol) and
N,N-dimethylaminoethyl chloride hydrochloride (log, 0.069 mol) in
N,N-dimethylformamide (200 mL) is added sodium hydride (60% in
mineral oil, 6.0 g, 0.15 mol) slowly in portions over a 30-min
period with stirring. After the addition is complete, the mixture
is warmed to 60.degree. C. for 2.5 h, cooled to 0.degree. C.,
diluted by water (100 mL), and acidified by adding 2N HCl (150 mL).
The aqueous solution is washed with hexane to remove mineral oil,
treated with activated carbon (2 g), heated to 80.degree. C. for 30
min, filtered while hot, and allowed to cool to room temperature.
The filtrate is slowly poured into a vigorously stirred, ice-cold
solution of NaOH (40 mL of 10N NaOH in ice-water to make 500 mL).
After 30 min of stirring, the slurry is filtered, air-dried and
recrystallized from hexane to give 15 g of a white solid.
[0216] The latter aminoamide (20.5 q, 44.70 mmol) is dissolved in
100 mL anhydrous THF and added dropwise to an ice-cold, stirring
solution of DIBAL-H (100 mL, 1.5M in toluene, 3 equiv.) in 200 mL
anhydrous toluene under an atmosphere of N.sub.2. The mixture is
allowed to warm to rt over 6 hours. The mixture is cooled again and
carefully quenched with a saturated solution of Na.sub.2SO.sub.4,
diluted with some toluene, and filtered to remove the inorganic
solids. The filtrate is washed with water, brine then dried over
Na.sub.2SO.sub.4 and filtered. The solvent is removed in vacuo to
afford 19.5 g of oil that solidifies upon standing.
[0217] F. 4-Isopropylamino-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole 42
[0218] To a solution containing the product from Example 1B (2 g)
and 2-methoxypropene (10 mL) in dichloroethane (25 mL) are added
acetic acid (0.4 mL) and sodium triacetoxyborohydride (5 g). The
mixture is stirred at room temperature for 24 hours then
concentrated. Dissolve residue in ethyl acetate and wash with
water, followed by 1N sodium hydroxide and brine. Dry extract over
sodium sulfate, filter and concentrate: MS 362 (M+H).
Example 2
[0219] The following compounds are prepared essentially according
to the procedures set forth above for Example 1.
[0220] a) 4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]-
indole: MS 471 (M+H). (Compound 2)
[0221] b) 4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4-dimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]ind-
ole: MS 457 (M+H). (Compound 3)
[0222] c) 4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,6-dimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]ind-
ole: MS 457 (M+H). (Compound 4)
[0223] d)
4-(N-(2-Morpholinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2-
,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole:
MS 487 (M+H). (Compound 5)
[0224] e)
4-(N-2-(4-Methylpiperazinyl)ethyl-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b- ]indole: MS 500 (M+H).
(Compound 6)
[0225] f) 4-(N-(2-(4-Triazolyl)ethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b- ]indole: MS 469 (M+H).
(Compound 7)
[0226] g)
4-(N-(2-(2-Methoxyethyl)aminoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b- ]indole: MS 475 (M+H).
(Compound 8)
[0227] h)
4-(N-(2-(2-Methylimidazolinyl)ethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b- ]indole: MS 484 (M+H).
(Compound 9)
[0228] i)
4-(N-(2-Pyrrolidinoethyl)-N-2-methylpropyl)amino-2-methyl-9-(2,4-
,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole: MS
473 (M+H). (Compound 10)
[0229] j) 4-(N-(2-Dimethylaminoethyl)-N-2-methylpropyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]-
indole: MS 447 (M+H). (Compound 11)
[0230] k)
4-(N-(2-(Ethylmethylamino)ethyl)-N-2-methylpropyl)amino-2-methyl-
-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole:
MS 461 (M+H). (Compound 12)
[0231] l) 4-(N-(2-Dimethylaminoethyl)-N-2-methoxyethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]-
indole: MS 449 (M+H). (Compound 13)
[0232] m)
4-(N-(2-Dimethylaminoethyl)-N-isopropyl)amino-2-methyl-9-(2,4,6--
trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole: MS
433 (M+H). (Compound 14)
[0233] n) 4-(N-(2-(Phenylmethyl)aminoethyl)-N-isopropyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]-
indole: MS 495 (M+H). (Compound 15)
[0234] o) 4-(N-2-(4-Methylpiperazinyl)ethyl-N-isopropyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]-
indole: MS 488 (M+H). (Compound 16)
[0235] p)
4-(N-(2-Pyrrolidinoethyl)-N-isopropyl)amino-2-methyl-9-(2,4,6-tr-
imethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole: MS 459
(M+H). (Compound 17)
[0236] q) 4-(N-(2-Diethylaminoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b- ]indole: MS 473 (M+H).
(Compound 18)
[0237] r)
4-(N-(2-Diethylaminoethyl)-N-2-methylpropyl)amino-2-methyl-9-(2,-
4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole:
MS 475 (M+H). (Compound 19)
[0238] s) 4-(N-(2-Dimethylaminoethyl)-N-ethyl)amino-2-methyl
-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole:
MS 419 (M+H). (Compound 20)
[0239] t) 4-(N-(2-Dimethylaminoethyl)-N-butyl)amino-2-methyl
-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole:
MS 447 (M+H). (Compound 21)
[0240] u) 4-(N-(2-Dimethylaminoethyl)-N-propyl)amino-2-methyl
-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole:
MS 433 (M+H). (Compound 22)
[0241] v) 4-(N-(2-Methylaminoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]-
indole: MS 431 (M+H). (Compound 23)
[0242] w)
4-(N-(2-(Ethylmethylamino)ethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b- ]indole: MS 459 (M+H).
(Compound 24)
[0243] x) 4-(N-(2-Dimethylaminoethyl)-N-cyclopropyloxomethyl)amino
-2-methyl-10-(2,4,6-trimethylphenyl)-5,6,7,8,9-pentahydrocyclohepta[1,2-d-
]pyridino[2,3-b]pyrrole: MS 473 (M+H). (Compound 25)
[0244] y) 4-(N-(2-Dimethylaminoethyl)-N-cyclopropylmethyl)amino
-2-methyl-10-(2,4,6-trimethylphenyl)
-5,6,7,8,9-pentahydrocyclohepta[1,2-- d]pyridino[2,3-b]pyrrole: MS
459 (M+H). (Compound 26)
[0245] z) 4-(N-(2-Dimethylaminoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,6-dimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]in- dole: MS 431 (M+H).
(Compound 27)
[0246] aa) 4-(N-- (2-Pyrrolidinoethyl) --N--
(1-oxoethyl))amino-2-methyl-9-
-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole:
MS 459 (M+H). (Compound 28)
[0247] bb) 4-(N-- (2-Pyrrolidinoethyl) --N--
(1-oxopropyl))amino-2-methyl--
9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole:
MS 473 (M+H). (Compound 29)
[0248] cc) 4-(N-- (2-Dimethylaminoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4-dimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]in- dole: MS 431 (M+H).
(Compound 30)
[0249] dd) 4-(N--
(2-Pyrrolidinoethyl)-N-(1-oxobutyl))amino-2-methyl-9-(2,-
4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole:
MS 487 (M+H). (Compound 31)
[0250] ee) 4-(N--
(2-Pyrrolidinoethyl)-N-(2-methoxy-1-oxoethyl))amino-2-me-
thyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole-
: MS 489 (M+H). (Compound 32)
[0251] ff) 4-(N--
(2-Pyrrolidinoethyl)-N-ethyl)amino-2-methyl-9-(2,4,6-tri-
methylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole: MS 445
(M+H). (Compound 33)
[0252] gg)
4-(N-(2-Pyrrolidinoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trim-
ethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole: MS 459
(M+H). (Compound 34)
[0253] hh)
4-(N-(2-Pyrrolidinoethyl)-N-butyl)amino-2-methyl-9-(2,4,6-trime-
thylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole: MS 473
(M+H). (Compound 35)
[0254] ii) 4-(N-(2-Pyrrolidinoethyl)-N-(2-methoxyethyl))amino
-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]-
indole: MS 475 (M+H). (Compound 36)
Example 3
[0255]
4-(N-(2-Aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-tri-
methylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole (Compound
37) 43
[0256] A solution containing the product from Example 1D (500 mg)
and sodium azide (22 mg) in N-methylpyrrolidinone (5 mL) is heated
to 120.degree. C. for 2 hours. The mixture is poured into water and
extracted with ethyl acetate. The organic layer is washed with
water, dried over sodium sulfate, filtered and concentrated. An
ethanol (10 mL) solution of the crude product and 10% palladium on
carbon (about 200 mg) is hydrogenated for 8 hours at approximately
1 atmosphere pressure. The suspension is filtered over celite and
concentrated. The product is purified by preparative tlc using 20%
ethyl acetate in hexanes as eluant, followed by 10% methanol in
dichloromethane and converted to the hydrochloride salt:
MS(freebase) 417 (M+H).
Example 4
[0257] The following compounds are prepared essentially according
to the procedures set forth above in Example 3.
[0258] a)
4-(N-(2-Aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,6-di-
methylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole: MS 403
(M+H). (Compound 38)
[0259] b)
4-(N-(2-Aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6--
trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole: MS
417 (M+H). (Compound 39)
[0260] c)
4-(N-(2-Aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4-di-
methylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole: MS 403
(M+H). (Compound 40)
Example 5
[0261] A.
4-Chloro-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9-
H-pyridino[2,3-b]indole 44
[0262] Dissolve tert-butylnitrite (0.65 g) in acetonitrile (10 mL)
and add copper(II)chloride (0.68 g). Then the compound from Example
1B (1.33 g) is added portionwise to the greenish-brown solution and
the mixture is stirred for 12 hours. The acetonitrile is removed by
evaporation and the residue is partitioned between water and
dichloromethane. The aqueous layer is extracted with more
dichloromethane and the combined extract is washed with water,
dried over sodium sulfate, filtered and concentrated. The product
is filtered through a plug of silica gel using 20% ethyl acetate in
hexanes as eluant to afford a tan colored solid.
[0263] B. 4-Piperazinyl-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole 45
[0264] Combine the compound from Example 5A (200 mg) and piperazine
(0.58 g) in N-methylpyrrolidinone (2 mL) and heat the solution to
120.degree. C. for 12 hours. Pour mixture into water and extract
with ethyl acetate. Wash extract with aqueous ammonium chloride
then water. Dry extract over sodium sulfate, filter and
concentrate. Purify by preparative tlc using 10% methanol in
dichloromethane as eluant.
Example 6
[0265] A. 4-Hydroxy-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole 46
[0266] A mixture of the compound from Example 1A (5.0 g), acetic
anhydride (1.9 mL) and acetic acid (5 mL) is refluxed for 1 hour
then, concentrated to a solid. Phosphoric acid (5 mL, 85%) is added
to the amide. The mixture is then refluxed for 0.5 hours and cooled
to ambient temperature. The solution is poured onto ice and the
precipitate that forms is collected by filtration: MS 322
(M+H).
[0267] B.
4-Chloro-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9-
H-pyrimidino[4,5-b]indole 47
[0268] The compound from Example 6A (4.4 g) is refluxed in
phosphoryl chloride (35 mL) for 3 hours. The excess phosphoryl
chloride is removed under reduced pressure and the residue is
partitioned between aqueous sodium bicarbonate and dichloromethane.
The aqueous is extracted with more dichloromethane. The combined
extracts are dried over sodium sulfate, filtered and concentrated
to give a tan colored solid: MS 340 (M+H).
[0269] C.
4-Cyclopropylmethylamino-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,-
7,8-tetrahydro-9H-pyrimidino[4,5-b]indole 48
[0270] A mixture containing the compound from Example 6B (1.0 g)
and cyclopropylmethylamine (1.6 g) in N-methylpyrrolidinone (4 mL)
is heated to 100.degree. C. in a sealed tube for 24 hours. Dilute
mixture with ethyl acetate and wash with water, aqueous ammonium
chloride, aqueous sodium bicarbonate, and brine. Dry over sodium
sulfate, filter and concentrate to give a tan colored solid. Purify
by radial chromatography using 30% ethyl acetate in hexanes as
eluant to give 660 mg of product: MS 375 (M+H).
[0271] D. 4-(N-(2-Dimethylaminoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyrimidino[4,5- -b]indole (Compound 41)
49
[0272] To a solution of the compound from Example 6C (650 mg) in
N,N-dimethylformamide (5 mL) at 0 C, under a blanket of nitrogen,
is added sodium hydride (60%, 280 mg). After stirring the solution
for 0.5 hours, 2-dimethylaminoethyl chloride hydrochloride (500 mg)
is added. The mixture is then heated to 40.degree. C. for 2 hours,
then quenched with ice and water. Dilute with ethyl acetate and
wash with water, brine, dry over sodium sulfate, filter and
concentrate. Purify by radial chromatography using 10% methanol and
0.5% ammonium hydroxide in dichloromethane as eluant to obtain 450
mg of product: MS 446 (M+H).
Example 7
[0273] The following salts are prepared essentially according to
the procedures set forth above in Examples 1-6 and, where
necessary, with reference to literature methods for preparing
pharmaceutically acceptable salts.
[0274] a)
4-(N-(2-Morpholinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2-
,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
citrate. (Compound 42)
[0275] b)
4-(N-2-(4-Methylpiperazinyl)ethyl-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b- ]indole phosphate (Compound
43)
[0276] c)
4-(N-(2-(2-Methoxyethyl)aminoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b- ]indole citrate. (Compound
44)
[0277] d) 4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]-
indole dihydrochloride. (Compound 45)
[0278] e) 4-(N-(2-Dimethylaminoethyl)-N-2-methylpropyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]-
indole citrate. (Compound 46)
[0279] f)
4-(N-(2-Aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6--
trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
sulfate. (Compound 47)
[0280] g)
4-(N-(2-(Ethylmethylamino)ethyl)-N-2-methylpropyl)amino-2-methyl-
-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
dihydrochloride. (Compound 48)
[0281] h) 4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4-dimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]ind-
ole sulfate. (Compound 49)
[0282] i)
4-(N-(2-(2-Methylimidazolinyl)ethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b- ]indole fumarate. (Compound
50)
[0283] j) 4-(N-(2-Dimethylaminoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b- ]indole dihydrochloride
(Compound 51)
[0284] k) 4-(N-(2-Dimethylaminoethyl)-N-2-methoxyethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]-
indole dihydrochloride. (Compound 52)
[0285] l) 4-(N-2-(4-Methylpiperazinyl)ethyl-N-isopropyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]-
indole sulfate. (Compound 53)
[0286] m) 4-(N-(2-Diethylaminoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b- ]indole sulfate. (Compound
54)
[0287] n) 4-(N-(2-Dimethylaminoethyl)-N-propyl)amino-2-methyl
-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
maleate. (Compound 55)
[0288] o) 4-(N-(2-Methylaminoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]-
indole sulfate. (Compound 56)
[0289] p) 4-(N-(2-(Phenylmethyl)aminoethyl)-N-isopropyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]-
indole phosphate (Compound 57)
[0290] q)
4-(N-(2-Diethylaminoethyl)-N-2-methylpropyl)amino-2-methyl-9-(2,-
4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
acetate. (Compound 58)
[0291] r)
4-(N-(2-(Ethylmethylamino)ethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b- ]indole fumarate. (Compound
59)
[0292] s)
4-(N-(2-Dimethylaminoethyl)-N-isopropyl)amino-2-methyl-9-(2,4,6--
trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
phosphate. (Compound 60)
[0293] t) 4-(N-(2-Dimethylaminoethyl)-N-ethyl)amino-2-methyl
-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
dihydrochloride. (Compound 61)
[0294] u) 4-(N-(2-Dimethylaminoethyl)-N-butyl)amino-2-methyl
-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
dihydrochloride. (Compound 62)
[0295] v) 4-(N-(2-Dimethylaminoethyl)-N-cyclopropyloxomethyl)amino
-2-methyl-10-(2,4,6-trimethylphenyl)-5,6,7,8,9-pentahydrocyclohepta[1,2-d-
]pyridino[2,3-b]pyrrole sulfate. (Compound 63)
[0296] w) 4-(N-(2-Dimethylaminoethyl)-N-cyclopropylmethyl)
amino-2-methyl-10-(2,4,6-trimethylphenyl)
-5,6,7,8,9-pentahydrocyclohepta- [1,2-d]pyridino[2,3-b]pyrrole
sulfate. (Compound 64)
[0297] x)
4-(N-(2-Pyrrolidinoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trime-
thylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole sulfate.
(Compound 65)
[0298] y) 4-(N-(2-Dimethylaminoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4-dimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]in- dole sulfate. (Compound
66)
[0299] z)
4-(N-(2-Pyrrolidinoethyl)-N-(1-oxobutyl))amino-2-methyl-9-(2,4,6-
-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
sulfate. (Compound 67)
[0300] aa)
4-(N-(2-Pyrrolidinoethyl)-N-(2-methoxy-1-oxoethyl))amino-2-meth-
yl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
sulfate. (Compound 68)
[0301] bb)
4-(N-(2-Aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4-d-
imethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole citrate.
(Compound 69)
[0302] cc)
4-(N-(2-Pyrrolidinoethyl)-N-ethyl)amino-2-methyl-9-(2,4,6-trime-
thylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole sulfate.
(Compound 70)
[0303] dd) 4-(N-(2-Pyrrolidinoethyl)-N-(2-methoxyethyl))amino
-2-methyl-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]-
indole sulfate. (Compound 71)
[0304] ee)
4-(N-(2-Pyrrolidinoethyl)-N-butyl)amino-2-methyl-9-(2,4,6-trime-
thylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole sulfate.
(Compound 72)
[0305] ff) 4-(N-(2-Dimethylaminoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,6-dimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]in- dole sulfate. (Compound
73)
[0306] gg)
4-(N-(2-Aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-
-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
dihydrochloride (Compound 74)
[0307] hh)
4-(N-(2-Pyrrolidinoethyl)-N-(1-oxopropyl))amino-2-methyl-9-(2,4-
,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
sulfate. (Compound 75)
[0308] ii)
4-(N-(2-Pyrrolidinoethyl)-N-(1-oxoethyl))amino-2-methyl-9-(2,4,-
6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
sulfate. (Compound 76)
[0309] jj)
4-(N-(2-Aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,6-d-
imethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole sulfate.
(Compound 77)
[0310] kk) 4-(N-(2-Dimethylaminoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyrimidino[4,5- -b]indole mesylate.
(Compound 78)
[0311] ll) 4-Piperazinyl-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole tartrate (Compound
79)
[0312] mm)
4-(N-(2-(Ethylmethylamino)ethyl)-N-2-methylpropyl)amino-2-methy-
l-9-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
mesylate. (Compound 80)
[0313] nn) 4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4-dimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]ind-
ole dihydrochloride. (Compound 81)
[0314] oo)
4-(N-(2-(2-Methylimidazolinyl)ethyl)-N-cyclopropylmethyl)amino
-2-methyl-9-(2,4,6-trimethylphenyl)
-5,6,7,8-tetrahydro-9H-pyridino[2,3-b- ]indole mesylate. (Compound
82)
[0315] pp)
4-(N-(2-Pyrrolidinoethyl)-N-(1-oxopropyl))amino-2-methyl-9-(2,4-
,6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
mesylate. (Compound 83)
[0316] qq)
4-(N-(2-Pyrrolidinoethyl)-N-(1-oxoethyl))amino-2-methyl-9-(2,4,-
6-trimethylphenyl)-5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole
dihydrochloride. (Compound 84)
Example 8
[0317] The pharmaceutical utility of compounds of this invention is
indicated by the assays shown in the following examples for human
CRF1 receptor activity.
[0318] Assay for CRF Receptor Binding Activity
[0319] CRF receptor binding is performed using a modified version
of the assay described by Grigoriadis and De Souza (Methods in
Neurosciences, Vol. 5, 1991). Membrane pellets containing CRF
receptors are resuspended in 50 mM Tris buffer pH 7.7 containing 10
mM MgCl.sub.2 and 2 mM EDTA and centrifuged for 10 minutes at 48000
g. Membranes are washed again and brought to a final concentration
of 1500 mg/ml in binding buffer (Tris buffer above with 0.1% BSA,
15 mM bacitracin and 0.01 mg/ml aprotinin.). For the binding assay,
100 ml of the membrane preparation is added to 96 well microtube
plates containing 100 ml of 125I--CRF (SA 2200 Ci/mmol, final
concentration of 100 pM) and 50 ml of drug. Binding is carried out
at room temperature for 2 hours. Plates are then harvested on a
Brandel 96 well cell harvester and filters are counted for gamma
emissions on a Wallac 1205 Betaplate liquid scintillation counter.
Non specific binding is defined by 1 mM cold CRF. IC.sub.50 values
are calculated with the non-linear curve fitting program RS/1 (BBN
Software Products Corp., Cambridge, Mass.). The binding affinity
for the compounds of Formula I expressed as IC.sub.50 value,
generally ranges from about 0.5 nanomolar to about 10
micromolar.
[0320] Alternatively, the binding activity of the compounds of
formula I to the human CRF.sub.1 receptor can be measured as
follows:
[0321] Assay for Human CRF Receptor Binding Activity in IMR32
cells
[0322] [.sup.125I]Sauvagine Binding to CRF.sub.1 Receptors
Endogenously Expressed in IMR-32 Cells: IMR-32 human neuroblastoma
cells are grown to 80% confluence in EMEM containing Earle's
Balanced Salts and 2 mM 1-glutamine with 10% FBS, 25 mM HEPES, 1 mM
Sodium Pyruvate, and nonessential amino acids. At this time, flasks
of cells are treated with 2.5 uM 5-bromo-2'-deoxyuridine (Br-dU)
for 10 days. Media is changed every 3-4 days across the 10 day
period. Cells are harvested using No-Zyme (JRH Biosciences) and
rinsed with PBS. For membrane preparation, cells are homogenized in
wash buffer (50 mM Tris HCl, 10 mM MgCl.sub.2, 2 mM EGTA, pH 7.4)
and centrifuged at 48,000.times. g for 10 minutes at 4.degree. C.
Pellets are re-suspended, homogenized and centrifuged two
additional times. The receptor binding assay is performed using
assay buffer (50 mM Tris HCl, 10 mM MgCl.sub.2, 2 mM EGTA, pH 7.4,
0.1% BSA, 0.1 mM bacitracin (22.0 mg/100 mL)), 150 .mu.g
protein/tube, and [.sup.125I]Sauvagine (NEN; 100 pM for competition
analysis and 10 pM-1 nM for saturation analysis) to yield a final
volume of 200 uL. Nonspecific binding is defined using 2 uM r/h CRF
or 9-41 alpha-helical CRF. Cells are incubated for 2 hours at room
temperature. The assay is terminated by rapid vacuum filtration
(Tomtec: Deepwell 3) through GFC filters presoaked in 1% PEI using
ice-cold 50 mM Tris HCl and dry thoroughly by air. Specific
Binding: 70-80%; Kd (nM): 0.30 nM; Bmax (fmole/mg protein): 40-50.
IC.sub.50 values are calculated with the non-linear curve fitting
program RS/1 (BBN Software Products Corp., Cambridge, Mass.).
[0323] The binding affinity for the compounds of Formula I
expressed as IC.sub.50 value, generally ranges from about 0.5
nanomolar to about 10 micromolar.
[0324] The invention and the manner and process of making and using
it, are now described in such full, clear, concise and exact terms
as to enable any person skilled in the art to which it pertains, to
make and use the same. It is to be understood that the foregoing
describes preferred embodiments of the present invention and that
modifications may be made therein without departing from the spirit
or scope of the present invention as set forth in the claims. To
particularly point out and distinctly claim the subject matter
regarded as invention, the following claims conclude this
specification.
* * * * *