US2004097499A1PendingUtilityA1
Amide, carbamate, and urea derivatives
Priority: Jul 31, 1998Filed: Jul 3, 2003Published: May 20, 2004
Est. expiryJul 31, 2018(expired)· nominal 20-yr term from priority
Inventors:Macklin Brian ArnoldDavid Michael BenderThomas John BleischWinton D. JonesPaul Leslie OrnsteinHamid ZarrinmayehDennis M. Zimmerman
C07C 311/05C07C 233/13C07D 333/20C07C 275/28C07C 255/60C07C 275/24C07C 255/58C07D 333/24C07C 271/14C07C 271/20C07C 233/18
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Claims
Abstract
The present invention provides certain amide, carbamate and urea derivatives useful for potentiating glutamate receptor function in a mammal and therefore, useful for treating a wide variety of conditions, such as psychiatric and neurological disorders.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A compound of the formula:
wherein
B is CONR a , NR a CO, NR a CO 2 or NR a CONR a ;
R a represents hydrogen or (1-6C) alkyl,
q is zero or 1;
R 1 represents a naphthyl group or a phenyl, furyl, thienyl or pyridyl group which is unsubstituted or substituted by one or two substituents selected independently from halogen; nitro; cyano; hydroxyimino; (1-10C)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl; hydroxy(3-8C)cycloalkyl; oxo(3-8C)cycloalkyl; halo(1-10C)alkyl; (CH 2 ) y X 1 R 9 in which y is 0 or an integer of from 1 to 4, X 1 represents O, S, NR 10 , CO, COO, OCO, CONR 11 , NR 12 CO, NR 12 COCOO or OCONR 13 , R 9 represents hydrogen, (1-10C)alkyl, (3-10C)alkenyl, (3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or (3-8C)cycloalkyl and R 10 , R 11 , R 12 and R 13 each independently represents hydrogen or (1-10C)alkyl, or R 9 and R 10 , R 11 , R 12 or R 13 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; N-(1-4C)alkylpiperazinyl; N-phenyl(1-4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl; pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl; dihydro-thienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl; dihydrothiazolyl; (1-4C)alkoxycarbonyldihydrothiazolyl; (1-4C)alkoxycarbonyldimethyldihydrothiazolyl; tetrahydro-thienyl; tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl; benzofuryl; benzothienyl; benzimidazolyl; and a group of formula R 14 -(L a ) n —X 2 -(L b ) m in which X 2 represents a bond, O, NH, S, SO, SO 2 , CO, CH(OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH 2 CONH or CH═CH, L a and L b each represent (1-4C)alkylene, one of n and m is 0 or 1 and the other is 0, and R 14 represents a phenyl or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, nitro, cyano, hydroxyimino, (1-10C) alkyl, (2-10C)alkenyl, (2-10C)alkynyl, (3-8C)-cycloalkyl, 4-(1,1-dioxotetrahydro-1,2-thiazinyl), halo(1-10C)alkyl, cyano(2-10C)alkenyl, phenyl, and (CH 2 ) z X 3 R 15 in which z is 0 or an integer of from 1 to 4, X 3 represents O, S, NR 16 , CO, CH(OH), COO, OCO, CONR 17 , NR 18 CO, NHSO 2 , NHSO 2 NR 17 , NHCONH, OCONR 19 or NR 19 COO, R 15 represents hydrogen, (1-10C)alkyl, phenyl(1-4C)alkyl, halo(1-10C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl, (1-4C)alkylsulfonylamino(1-4C)alkyl, (N-(1-4C)alkoxycarbonyl)(1-4C)alkylsulfonylamino-(1-4C)alkyl, (3-10C)alkenyl, (3-10C)alkynyl, (3-8C)-cycloalkyl, camphoryl or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl, halo(1-4C)alkyl, di(1-4C)alkylamino and (1-4C)alkoxy and R 16 , R 17 , R 18 and R 19 each independently represents hydrogen or (1-10C)alkyl, or R 15 and R 16 R 17 , R 18 or R 19 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group;
R 2 represents hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, fluoro(1-6C)alkyl, chloro(1-6C)alkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylCO 2 (1-4C)alkyl, phenyl(1-6C)alkyl, heteroaromatic, phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or a group of formula R 3 R 4 N in which R 3 and R 4 each independently represents (1-4C)alkyl or, together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group; and
R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, (1-6C)alkyl; aryl(1-6C)alkyl; (2-6C)alkenyl; aryl(2-6C)alkenyl and aryl; or
two of R 5 , R 6 , R 7 and R 8 together with the carbon atom or carbon atoms to which they are attached form a (3-8C) carbocyclic ring; and the remainder of R 5 , R 6 , R 7 and R 8 represent hydrogen; or a pharmaceutically acceptable salt thereof;
with the proviso that when R 2 represents R 3 R 4 N, then B is other than NR a CONR a or CONR a .
2 . A compound according to claim 1 wherein B is CONR a .
3 . A compound according to claim 1 wherein B is NR a CO.
4 . A compound according to claim 1 wherein B is NR a CO 2 .
5 . A compound according to claim 1 wherein B is NR a CONR a .
6 . A compound as claimed in any one of claims 1 to 5 wherein q is 1.
7 . A compound as claimed in any one of claims 1 to 5 wherein R a is hydrogen.
8 . A compound as claimed in any one of claims 1 - 5 wherein R 2 represents hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, fluoro(1-6C)alkyl, chloro(1-6C)alkyl, (2-6C)alkenyl 1-4C)alkoxy(1-4C)alkyl, heteroaromatic, or phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy.
9 . A compound according to claim 8 wherein R 2 represents hydrogen, (1-4C)alkyl; (3-6C)cycloalkyl or heteroaromatic, or phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy.
10 . A compound according to claim 9 wherein R 2 represents methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, isovaleryl, phenyl, benzyl, 2-furyl, 2-thienyl, 5-oxazoyl, 2-pyridyl, 3-pyridyl, 4-pryidyl
11 . A compound as claimed in any one of claims 1 - 5 wherein q is 1 and R 6 and R 7 represent hydrogen.
12 . A compound according to claim 11 wherein R 5 and R 8 are each independently hydrogen or (1-4C)alkyl, or together with the carbon atom to which they are attached form a (3-8C) carbocyclic ring.
13 . A compound as claimed in any one of claims 1 - 12 wherein R 8 represents methyl and R 5 represents hydrogen.
14 . A compound as claimed in claim 1 , which is selected from:
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aaa
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pharmaceutically acceptable salts thereof.
15 . A pharmaceutical composition, which comprises a compound as claimed in claim 1 and a pharmaceutically acceptable diluent or carrier.
16 . A method of potentiating glutamate receptor function in a mammal requiring such treatment, which comprises administering an effective amount of a compound of formula:
wherein
B is CONR a , NR a CO, NR a CO 2 or NR a CONR a ;
R a represents hydrogen or (1-6C) alkyl,
q is zero or 1;
R 1 represents an unsubstituted or substituted aromatic or heteroaromatic group;
R 2 represents hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, fluoro(1-6C)alkyl, chloro(1-6C)alkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylCO 2 (1-4C)alkyl, phenyl(1-6C)alkyl, heteroaromatic, phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or a group of formula R 3 R 4 N in which R 3 and R 4 each independently represents (1-4C)alkyl or, together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group; and
R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, (1-6C)alkyl; aryl(1-6C)alkyl; (2-6C)alkenyl; aryl(2-6C)alkenyl and aryl; or
two of R 5 , R 6 , R 7 and R 8 together with the carbon atom or carbon atoms to which they are attached form a (3-8C) carbocyclic ring; and the remainder of R 5 , R 6 , R 7 and R 8 represent hydrogen; or a pharmaceutically acceptable salt thereof;
with the proviso that when R 2 represents R 3 R 4 N, then B is other than NR a CONR a or CONR a .
17 . A method of potentiating glutamate receptor function in a mammal requiring such treatment, which comprises administering an effective amount of a compound of claim 1 .
18 . A method of treating a cognitive disorder, a neuro-degenerative disorder; age-related dementia; age-induced memory impairment; movement disorder; reversal of a drug-induced state; depression; attention deficit disorder; attention deficit hyperactivity disorder; psychosis; cognitive deficits associated with psychosis; or drug-induced psychosis in a patient, which comprises administering to a patient in need thereof an effective amount of a compound of formula:
wherein
B is CONR a , NR a CO, NR a CO 2 or NR a CONR a ;
R a represents hydrogen or (1-6C) alkyl,
q is zero or 1;
R 1 represents an unsubstituted or substituted aromatic or heteroaromatic group;
R 2 represents hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, fluoro(1-6C)alkyl, chloro(1-6C)alkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylCO 2 (1-4C)alkyl, phenyl(1-6C)alkyl, heteroaromatic, phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or a group of formula R 3 R 4 N in which R 3 and R 4 each independently represents (1-4C)alkyl or, together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group; and
R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, (1-6C)alkyl; aryl(1-6C)alkyl; (2-6C)alkenyl; aryl(2-6C)alkenyl and aryl; or
two of R 5 , R 6 , R 7 and R 8 together with the carbon atom or carbon atoms to which they are attached form a (3-8C) carbocyclic ring; and the remainder of R 5 , R 6 , R 7 and R 8 represent hydrogen; or a pharmaceutically acceptable salt thereof;
with the proviso that when R 2 represents R 3 R 4 N, then B is other than NR a CONR a or CONR a .
19 . A method of treating a cognitive disorder; a neuro-degenerative disorder; age-related dementia; age-induced memory impairment; movement disorder; reversal of a drug-induced state; depression; attention deficit disorder; attention deficit hyperactivity disorder; psychosis; cognitive deficits associated with psychosis; or drug-induced psychosis in a patient, which comprises administering to a patient in need thereof an effective amount of a compound according to claim 1 .
20 . A method for improving memory or learning ability in a patient, which comprises administering to a patient in need thereof an effective amount of a compound of formula:
wherein
B is CONR a , NR a CO, NR a CO 2 or NR a CONR a ,
R a represents hydrogen or (1-6C) alkyl,
q is zero or 1;
R 1 represents an unsubstituted or substituted aromatic or heteroaromatic group;
R 2 represents hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, fluoro(1-6C)alkyl, chloro(1-6C)alkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylCO 2 (1-4C)alkyl, phenyl(1-6C)alkyl, heteroaromatic, phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or a group of formula R 3 R 4 N in which R 3 and R 4 each independently represents (1-4C)alkyl or, together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group; and
R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, (1-6C)alkyl; aryl(1-6C)alkyl; (2-6C)alkenyl; aryl(2-6C)alkenyl and aryl; or
two of R 5 , R 6 , R 7 and R 8 together with the carbon atom or carbon atoms to which they are attached form a (3-8C) carbocyclic ring; and the remainder of R 5 , R 6 , R 7 and R 8 represent hydrogen; or a pharmaceutically acceptable salt thereof;
with the proviso that when R 2 represents R 3 R 4 N, then B is other than NR a CONR a or CONR a .
21 . A method for improving memory or learning ability in a patient, which comprises administering to a patient in need thereof an effective amount of a compound according to claim 1.Join the waitlist — get patent alerts
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