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US 6,143,743 AGranted
Imidazopyrimidines and imidazopyridines for the treatment of neurological disorders
AssigneeDuPont Pharmaceuticals Company
InventorsRichard Gerald Wilde, Rajagopal Bakthavatchalam, James Peter Beck, Argyrios Georgious Arvanitis
Life of this patent
Estimating the term…
Abstract
Corticotropin releasing factor (CRF) antagonists of formula (I): ##STR1## and their use in treating 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.
Claims8
A compound of the formula:
- ##STR74## wherein X is selected from the group NR10, O or S(O)n;
- D is an aryl or heteroaryl group attached through an unsaturated carbon atom;
- R.sup.1 is (cyclopropyl)C.sub.1 alkyl or (cyclobutyl)C.sub.1 alkyl;
- R.sup.1 is substituted with 1-2 substituents independently selected at each occurrence from the group R.sup.1a, R.sup.1b, CH.sub.3, CH.sub.2 CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH.sub.3, --(CH.sub.2).sub.3 CH.sub.3, --CH.dbd.CH.sub.2, --CH.dbd.CH(CH.sub.3), --CH.dbd.CH, --CH.dbd.C(CH.sub.3), --CH.sub.2 OCH.sub.3, --CH.sub.2 CH.sub.2 OCH.sub.3, F, CF.sub.3, cyclopropyl, CH.sub.3 --cyclopropyl, cyclobutyl, CH.sub.3 -cyclobutyl, cyclopentyl, CH.sub.3 -cyclopentyl;
- R.sup.1a is phenyl substituted with 0-1 substituents selected from OCH.sub.3, OCH.sub.2 CH.sub.3, and OCF.sub.3, and 0-2 substituents independently selected at each occurrence from the group CH.sub.3, CH.sub.2 CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH.sub.3, Br, Cl, F, CF.sub.3, --CN, and SCH.sub.3 ;
- R.sup.1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, and tetrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH.sub.3, CH.sub.2 CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH.sub.3, OCH.sub.3, OCH.sub.2 CH.sub.3, OCF.sub.3, Br, Cl, F, CF.sub.3, --CN, and SCH.sub.3 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH.sub.3, CO.sub.2 CH.sub.3, COCH.sub.3 and SO.sub.2 CH.sub.3 ;
- R.sup.2 is selected from the group CH.sub.3, CH.sub.2 CH.sub.3, and CH(CH.sub.3).sub.2 ;
- R.sup.3 is selected from the group H and CH.sub.3 ;
- aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH.sub.3, CH.sub.2 CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH.sub.3, cyclopropyl, OCH.sub.3, OCH.sub.2 CH.sub.3, OCH(CH.sub.3).sub.2, OCH.sub.2 CH.sub.2 CH.sub.3, OCF.sub.3, Br, Cl, F, CF.sub.3, --CN, SCH.sub.3, SO.sub.2 CH.sub.3, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2, --C(O)NH.sub.2, --C(O)NHCH.sub.3, and --C(O)N(CH.sub.3).sub.2 ;
- and,
- heteroaryl is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH.sub.3, CH.sub.2 CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH.sub.3, cyclopropyl, OCH.sub.3, OCH.sub.2 CH.sub.3, OCH(CH.sub.3).sub.2, OCH.sub.2 CH.sub.2 CH.sub.3, OCF.sub.3, Br, Cl, F, CF.sub.3, --CN, SCH.sub.3, SO.sub.2 CH.sub.3, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2, --C(O)NH.sub.2, --C(O)NHCH.sub.3, and --C(O)N(CH.sub.3).sub.2.
8 more elements
A compound of the formula:
- ##STR75## wherein, R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3 R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is C.sub.2 H.sub.5 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is C.sub.4 H.sub.9 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is CH.sub.2 OCH.sub.3 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is C.sub.6 H.sub.5 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is c-C.sub.3 H.sub.5 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is C.sub.6 H.sub.13 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is C.sub.3 H.sub.7 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is (CH.sub.2).sub.2 OCH.sub.3 or
- R.sup.5 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is C.sub.2 H, and R.sup.1b is CH.sub.2 CN or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is CH.sub.2 N(CH.sub.3).sub.2 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is c-C.sub.3 H.sub.5 and R.sup.1b is C.sub.4 H.sub.9 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is c-C.sub.3 H.sub.5 and R.sup.1b is CH.sub.2 OCH.sub.3 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is c-C.sub.3 H.sub.5 and R.sup.1b is C.sub.6 H.sub.5 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is c-C.sub.3 H, and R.sup.1b is c-C.sub.3 H.sub.5 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is Cl, R.sup.5 is Cl, R.sup.11 is H, R.sup.6 is H, R.sup.1a is C.sub.2 H.sub.-- and R.sup.1b is C.sub.2 H.sub.5 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is Cl, R.sup.5 is Cl, R.sup.11 is H, R.sup.6 is H, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is CH.sub.2 OCH.sub.3 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is Cl, R.sup.5 is Cl, R.sup.11 is H, R.sup.6 is H, R.sup.1a is C.sub.2 H, and R.sup.1b is C.sub.6 H, or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is Cl, R.sup.5 is Cl, R.sup.11 is H, R.sup.6 is H, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is c-C.sub.3 H, or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is Cl, R.sup.5 is Cl, R.sup.11 is H, R.sup.6 is H, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is C.sub.6 H.sub.13 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is Cl, R.sup.5 is Cl, R.sup.11 is H, R.sup.6 is H, R.sup.1a is c-C.sub.3 H.sub.5 and R.sup.1b is c-C.sub.3 H.sub.5.
17 more elements
A compound selected from the group consisting of:
- 6-(2-chloro-4-methoxyphenyl)-9-(dicyclopropylmethyl)-8-methoxy-9H-purine or
- 6-(2-chloro-4-trifluoromethylphenyl)-9-(dicyclopropylmethyl)-8-methoxy-9H-p urine or
- 6-(2,4-dichlorophenyl)-9-(dicyclopropylmethyl)-8-methoxy-9H-purine or
- 9-(dicyclopropylmethyl)-6-(2,6-dimethoxypyridinyl-3-yl)-8-methoxy-9H-purine
1 more element
A pharmaceutical composition comprising a compound of formula Ic:
- ##STR76## wherein X is selected from the group NR10, O or S(O)n;
- D is an aryl or heteroaryl group attached through an unsaturated carbon atom;
- R.sup.1 is (cyclopropyl)C.sub.1 alkyl or (cyclobutyl)C.sub.1 alkyl;
- R.sup.1 is substituted with 1-2 substituents independently selected at each occurrence from the group R.sup.1a, R.sup.1b, CH.sub.3, CH.sub.2 CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH.sub.3, --(CH.sub.2).sub.3 CH.sub.3, --CH.dbd.CH.sub.2, --CH.dbd.CH(CH.sub.3), --CH.dbd.CH, --CH.dbd.C(CH.sub.3), --CH.sub.2 OCH.sub.3, --CH.sub.2 CH.sub.2 OCH.sub.3, F, CF.sub.3, cyclopropyl, CH.sub.3 -cyclopropyl, cyclobutyl, CH.sub.3 -cyclobutyl, cyclopentyl, CH.sub.3 -cyclopentyl;
- R.sup.1a is phenyl substituted with 0-1 substituents selected from OCH.sub.3, OCH.sub.2 CH.sub.3, and OCF.sub.3, and 0-2 substituents independently selected at each occurrence from the group CH.sub.3, CH.sub.2 CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH.sub.3, Br, Cl, F, CF.sub.3, --CN, and SCH.sub.3 ;
- R.sup.1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, and tetrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH.sub.3, CH.sub.2 CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH.sub.3, OCH.sub.3, OCH.sub.2 CH.sub.3, OCF.sub.3, Br, Cl, F, CF.sub.3, --CN, and SCH.sub.3 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH.sub.3, CO.sub.2 CH.sub.3, COCH.sub.3 and SO.sub.2 CH.sub.3 ;
- R.sup.2 is selected from the group CH.sub.3, CH.sub.2 CH.sub.3, and CH(CH.sub.3)).sub.2 ;
- R.sup.3 is selected from the group H and CH.sub.3 ;
- aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH.sub.3, CH.sub.2 CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH.sub.3, cyclopropyl, OCH.sub.3, OCH.sub.2 CH.sub.3, OCH(CH.sub.3).sub.2, OCH.sub.2 CH.sub.2 CH.sub.3, OCF.sub.3, Br, Cl, F, CF.sub.3, --CN, SCH.sub.3, SO.sub.2 CH.sub.3, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2, --C(O)NH.sub.2, --C(O)NHCH.sub.3, and --C(O)N(CH.sub.3).sub.2 ;
- and,
- heteroaryl is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH.sub.3, CH.sub.2 CH.sub.3, OH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH.sub.3, cyclopropyl, OCH.sub.3, OCH.sub.2 CH.sub.3, OCH(CH.sub.3).sub.2, OCH.sub.2 CH.sub.2 CH.sub.3, OCF.sub.3, Br, Cl, F, CF.sub.3, --CN, SCH.sub.3, SO.sub.2 CH.sub.3, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2, --C(O)NH.sub.2, --C(O)NHCH.sub.3, and --C(O)N(CH.sub.3).sub.2.
8 more elements
A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the formula:
- ##STR77## or a pharmaceutically acceptable salt thereof wherein, R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is C.sub.2 H.sub.5 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is C.sub.4 H.sub.9 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is CH.sub.2 OCH.sub.3 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is C.sub.6 H.sub.5 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is c-C.sub.3 H.sub.5 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is C.sub.6 H.sub.13 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is C.sub.3 H.sub.7 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is (CH.sub.2).sub.2 OCH.sub.3 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is CH.sub.2 CN or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is CH.sub.2 N (CH.sub.3).sub.2 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is c-C.sub.3 H.sub.5 and R.sup.1b is C.sub.4 H.sub.9 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is c-C.sub.3 H.sub.5 and R.sup.1b is CH.sub.2 OCH.sub.3 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is c-C.sub.3 H.sub.5 and R.sup.1b is C.sub.6 H.sub.5 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is CH.sub.3, R.sup.5 is CH.sub.3, R.sup.11 is H, R.sup.6 is CH.sub.3, R.sup.1a is c-C.sub.3 H.sub.5 and R.sup.1b is c-C.sub.3 H.sub.5 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is Cl, R.sup.5 is Cl, R.sup.11 is H, R.sup.6 is H, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is C.sub.2 H.sub.5 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is Cl, R.sup.5 is Cl, R.sup.11 is H, R.sup.6 is H, R.sup.1a is C.sub.2 H.sub..ident. and R.sup.1b is CH.sub.2 OCH.sub.3 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is Cl, R.sup.5 is Cl, R.sup.11 is H, R.sup.6 is H, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is C.sub.6 H.sub.5 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is Cl, R.sup.5 is Cl, R.sup.11 is H, R.sup.6 is H, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is c-C.sub.3 H.sub.5 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is Cl, R.sup.5 is Cl, R.sup.11 is H, R.sup.6 is H, R.sup.1a is C.sub.2 H.sub.5 and R.sup.1b is C.sub.6 H.sub.13 or
- R.sup.2 is selected from CH.sub.3, X is O, R.sup.3 is H, R.sup.4 is Cl, R.sup.5 is Cl, R.sup.11 is H, R.sup.6 is H, R.sup.1a is c-C.sub.3 H.sub.5 and R.sup.1b is c-C.sub.3 H.sub.5.
17 more elements
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound selected from the group consisting of:
- 6-(2-chloro-4-methoxyphenyl)-9-(dicyclopropylmethyl)-8-methoxy-9H-purine or
- 6-(2-chloro-4-trifluoromethylphenyl)-9-(dicyclopropylmethyl)-8-methoxy-9H-p urine or 6-(2,4-dichlorophenyl)-9-(dicyclopropylmethyl)-8-methoxy-9H-purine or
- 9-(dicyclopropylmethyl)-6-(2,6-dimethoxypyridinyl-3-yl)-8-methoxy-9H-purine
- or a pharmaceutically acceptable salt thereof.
1 more element
The compound of the formula 6-(2,4-dichlorophenyl)-9-(dicyclopropylmethyl)-8-methoxy-9H-purine or pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising the compound 6-(2,4-dichlorophenyl)-9-(dicyclopropylmethyl)-8-methoxy-9H-purine and a pharmaceutically acceptable carrier or diluent.
Dependencies are inferred from the claim text.