US2004157851A1PendingUtilityA1
CRF receptor antagonists and methods relating thereto
Est. expiryNov 12, 2018(expired)· nominal 20-yr term from priority
A61P 25/22C07D 487/16C07D 471/16
53
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Claims
Abstract
CRF receptor antagonists are disclosed which have utility in the treatment of a variety of disorders, including the treatment of disorders manifesting hypersecretion of CRF in a warm-blooded animals, such as stroke. The CRF receptor antagonists of this invention have the following structure: including stereoisomers and pharmaceutically acceptable salts thereof, wherein n, m, A, B, C, R, R 1 , R 2 and Ar are as defined herein. Compositions containing a CRF receptor antagonist in combination with a pharmaceutically acceptable carrier are also disclosed, as well as methods for use of the same
Claims
exact text as granted — not AI-modified1 . A compound having the following structure:
including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof,
wherein:
n is 1 or 2;
A and C are each independently nitrogen, carbon or CH;
B is nitrogen or CR 3 ;
with the provisos that at least one of A, B and C is nitrogen; A, B and C are not all nitrogen; and either A-B or B-C is a double bond;
X is nitrogen or CR q ;
R q is hydrogen, alkyl or halo;
Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R is an optional substituent which, at each occurrence, is independently alkyl, alkylidenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, wherein m is 0, 1, 2 or 3 and represents the number of R substituents;
R 1 is —C(H) 0,1 (R 4 )(R 5 ) or —SO 2 R 5 ;
R 2 is hydrogen, alkyl, haloalkyl or cyano
R 3 is hydrogen, alkyl or haloalkyl;
R 4 is hydrogen, oxo, alkyl, substituted alkyl, alkylidenyl or halo; and
R 5 is a radical of the formula —Y-Z-R 6 , wherein
Y is an alkanediyl, substituted alkanediyl, or a direct bond,
Z is NH, —N(R 7 ), O, S, SO 2 , C(═O), C(═O)O, OC(═O), NHC(═O), C(═O)NH, NH(SO 2 ), (SO 2 )NH, NR 8 C(═O)O, or a direct bond;
R 6 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyle, substituted heterocycle, heterocyclealkyl, or substituted heterocylcealkyl; w
R 7 and R 8 are alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyle, substituted heterocycle, heterocyclealkyl, or substituted heterocylcealkyl; or
R 6 and R 7 taken together with the nitrogen atom to which they are attached form a heterocyle ring or substituted heterocyle ring;
or R 4 and R 5 taken together with the carbon atom to which they are attached form cycloalkyl, substituted cycloalkyl, cycloalkylcycloalkyl, substituted cycloalkylcycloalkyl, cycloalkylaryl, substituted cycloalkyaryl, cycloalkylheterocycle, or substituted cycloalkylheterocycle.
2 . The compound of claim 1 wherein n is 1 and having one of the following structures:
3 . The compound of claim 1 wherein n is 2 and having one of the following structures:
4 . The compound of claim 1 having one of the following structures:
5 . The compound of claim 4 wherein X is CR q and having one of the following structures:
6 . The compound of claim 4 wherein X is nitrogen and having one of the following structures:
7 . The compound of claim 1 wherein Ar is phenyl or substituted phenyl.
8 . The compound of claim 7 wherein substituted phenyl is 2,4-dichlorophenyl, 2-chloro-4-methyl-phenyl, 2-methyl-4-chloro-phenyl, 2,4,6-trimethyl-phenyl, 2-chloro-4-methoxy-phenyl, 2-methyl-4-methoxy-phenyl, or 2,4-dimethoxy-phenyl.
9 . The compound of claim 1 wherein Ar is heteroaryl or substituted heteroaryl.
10 . The compound of claim 9 wherein heteroaryl is pyridinyl.
11 . The compound of claim 9 wherein substituted heteroaryl is 4-methyl-6-dimethylamino-pyridin-3-yl, 4-dimethylamino-6-methyl-pyridin-3-yl or 6-dimethylamino-pyridin-3-yl.
12 . The compound of claim 1 wherein m is zero.
13 . The compound of claim 1 wherein R is alkyl.
14 . The compound of claim 1 wherein R is arylalkyl.
15 . The compound of claim 1 wherein R 1 is —CH(n-propyl) 2 , —CH(n-propyl)(CH 2 OCH 3 ), —CH(phenyl)(CH 2 OCH 3 ), —CH(CH 2 OR′) 2 , —CH(CH 2 OR′)(ethyl), —CH(CH 2 OR′)(n-butyl), —CH(CH 2 OR′)(tert-butyl), —CH(CH 2 OR′)(4-chloro-phenyl), —CH(CH 2 OR)(CH 2 CH 2 SCH 3 ), —CH(CH 2 CH 3 )(CH 2 O phenyl), where each occurrence of R′ is independently selected from C 1-6 alkyl.
16 . The compound of claim 1 wherein R 1 is —SO 2 R 5 .
17 . The compound of claim 1 wherein R 1 is —C(H) 0,1 (R 4 )(R 5 ).
18 . The compound of claim 17 wherein R 1 is —CH 2 R 5 .
19 . The compound of claim 17 wherein R 1 is —C(═O)R 5 .
20 . The compound of claim 17 wherein R 1 is —CH(R 4 )(R 5 ).
21 . The compound of claim 1 wherein R 4 is hydrogen.
22 . The compound of claim 1 wherein R 4 is alkyl.
23 . The compound of claim 1 wherein R 4 is keto.
24 . The compound of claim 1 wherein Y is alkanediyl or substituted alkanediyl.
25 . The compound of claim 1 wherein Y is a direct bond.
26 . The compound of claim 1 wherein Z is NH, —N(R 7 ), O, S, SO 2 , C(═O), C(═O)O, OC(═O), NHC(═O), C(═O)NH, NH(SO 2 ), (SO 2 )NH or NR 8 C(═O)O.
27 . The compound of claim 1 wherein Z is a direct bond.
28 . The compound of claim 1 wherein R6 is hydrogen, alkyl or substituted alkyl.
29 . The compound of claim 1 wherein R 6 is aryl, substituted aryl, arylalkyl or substituted arylalkyl.
30 . The compound of claim 1 wherein R 6 is heterocyle, substituted heterocycle, heterocyclealkyl or substituted heterocylcealkyl.
31 . The compound of claim 1 wherein R 2 is methyl.
32 . The compound of claim 1 wherein R 2 is ethyl.
33 . The compound of claim 1 having the structure:
34 . The compound of claim 33 wherein Ar is 2,4-dichlorophenyl, 2-chloro-4-methylphenyl, 2-trifluorometyl-4-chlorophenyl, or 2-methoxy-4-trifluoromethyl.
35 . The compound of claim 33 wherein m is 0.
36 . The compound of claim 33 wherein R 1 is CH(alkyl)(alkyl).
37 . The compound of claim 36 wherein R 1 is CH(n-propyl) 2 .
38 . The compound of claim 36 wherein R 1 is CH(n-butyl) 2 .
39 . The compound of claim 33 wherein m is 1 and R is alkyl.
40 . The compound of claim 39 wherein R is methyl, ethyl or n-propyl.
41 . The compound of claim 40 wherein R 1 is —CH 2 (cycloalkyl).
42 . The compound of claim 41 wherein R 1 is —CH 2 (cyclopropyl).
43 . The compound of claim 40 wherein R 1 is CH(alkyl)(alkyl).
44 . The compound of claim 43 wherein R 1 is CH(n-propyl) 2 or CH(n-butyl) 2 .
45 . A composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier or diluent.
46 . A method for treating a disorder manifesting hypersecretion of CRF in a warm-blooded animal, comprising administering to the animal an effective amount of the pharmaceutical composition of claim 45 .
47 . The method of claim 46 wherein the disorder is stroke.
48 . The method of claim 46 wherein the disorder is depression.
49 . The method of claim 46 wherein the disorder is anxiety.Join the waitlist — get patent alerts
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