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US 6,787,560 B2Granted
Serotonin reuptake inhibitor
AssigneeSumitomo Pharmaceuticals Company, Limited
InventorsToru Kodo, Shuji Masumoto, Koji Koyama, Naoya Kinomura
Life of this patent
Estimating the term…
Abstract
A serotonin reuptake inhibitor containing a cyclic amine represented by the following formula, a prodrug thereof, or a pharmaceutically acceptable salt of said cyclic amine or prodrug as an active ingredient: wherein R0 is a hydrogen atom, a halogen atom, an alkyl group, a substituted alkyl group, a hydroxyl group, an alkoxy group or the like, R3 is a hydrogen atom or the like, Y is an alkylene group or the like, Z is a hydrogen atom, a cycloalkyl group, an aryl group or the like, n is 1, 2 or 3, and m is 2, 3, 4, 5 or 6.
Claims47
A method of treating depression comprising administering an effective amount of a cyclic amine represented by the formula:
- wherein R1 is a halogen atom, an alkyl group or a substituted alkyl group;
- R2 is a hydrogen atom, a hydroxyl group, an alkoxy group, a substituted alkoxy group, an alkylthio group, a substituted alkylthio group or a halogen atom, provided that R1 is a bromine atom in the case of R2 being a hydrogen atom;
- R4 is a hydrogen atom, a halogen atom or an alkoxy group, or R4 may be taken together with R2 form a ring;
- and
- R3 is a hydrogen atom or a substituent;
- Y is a group represented by the formula:
- Z is a hydrogen atom, a cycloalkyl group, an aryl group, a substituted aryl group, an aromatic heterocyclic group, a substituted aromatic heterocyclic group, or an aliphatic heterocyclic group having an amide linkage (CO—N) or an imide linkage (CO—N—CO) in the ring;
- n is an integer of 1, 2 or 3;
- m is an integer of 2, 3, 4, 5 or 6;
- R5s are independently a hydrogen atom or a substituent;
- and
- R6s are independently a hydrogen atom or a substituent,
- or a pharmaceutically acceptable salt of said cyclic amine to a patient in need thereof, wherein
- the substituent(s) of each of the substituted alkyl group and the substituted lower alkyl group is/are halogen atom(s), hydroxyl group(s), alkoxy group(s), aryl group(s), substituted aryl group(s), phenoxy group(s) and/or cycloalkyl group(s);
- the substituent(s) of each of the substituted alkoxy group, the substituted lower alkoxy group and the substituted alkylthio group is/are halogen atom(s), hydroxyl group(s), alkoxy group(s), aryl group(s), substituted aryl group(s) and/or cycloalkyl group(s);
- as the substituent(s) of the substituted aryl group as
- 1) the substituent of the substituted alkyl group,
- 2) the substituent of the substituted lower alkyl group,
- 3) the substituent of the substituted alkoxy group,
- 4) the substituent of the substituted lower alkoxy group, and
- 5) the substituent of the substituted alkylthio group,
- is/are lower alkyl group(s);
- substituted lower alkyl group(s) (whose substituent(s) is/are selected from halogen atom(s), hydroxyl group(s), alkoxy group(s), phenoxy group(s) and cycloalkyl group(s));
- halogen atom(s), hydroxyl group(s) and/or lower alkoxy group(s);
- the substituent(s) R3 is/are lower alkyl group(s) and/or halogen atom(s);
- each of the substituents R5 and R6 are lower alkyl group(s), hydroxyl group(s), acyloxy group(s), alkoxy group(s) and/or halogen atom(s);
- alternatively, R5 and R6 may bind to each other to form a 3- to 8-membered cycloalkane ring together with the carbon atom to which they are bonded;
- the aromatic heterocyclic group is a 5- or 6-membered aromatic heterocyclic group containing 1 to 3 heteroatom(s) selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom;
- the aliphatic heterocyclic ring is a 5- or 6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom;
- as
- 1) the substituent(s) of the substituted aryl group for Z, and
- 2) the substituent(s) of the substituted aromatic heterocyclic group,
- is/are lower alkyl group(s), substituted lower alkyl group(s), lower alkoxy group(s), substituted lower alkoxy group(s), carbamoyl group, N-substituted carbamoyl group(s), N,N-di-substituted carbamoyl group(s), alkoxycarbonyl group(s), formyl group, acyl group(s), cyano group, halogen atom(s), lower alkylthio group(s), lower alkanesulfonyl group(s), lower alkanesulfonyl amide group(s), lower alkylureide group(s), phenylureide group(s), benzylureide group(s), amino group, lower alkylamino group(s), lower alkanoylamino group(s), aroylamino group(s), hydroxyl group, lower alkanesulfonyloxy group(s), oxime group(s), oxime ether group(s), cycloalkyl group(s), aryl group(s), substituted aryl group(s), aromatic heterocyclic group(s), substituted aromatic heterocyclic group(s), aminosulfonyl group and/or lower alkylaminosulfonyl group(s);
- the two adjacent substituents of the substituted aryl group or substituted aromatic heterocyclic group may bind to each other to form a ring;
- the substituent(s) of each of the N-substituted carbamoyl group and the N,N-di-substituted carbamoyl group is/are lower alkyl group(s), substituted lower alkyl group(s), aryl group(s), hydroxyl group(s) and/or lower alkoxy group(s);
- alternatively, the two substituents of the N,N-di-substituted carbamoyl group may bind to each other to form a cyclic group;
- as the substituent(s) of each of
- 1) the substituted aryl group as
- i) the substituent(s) of the substituted aryl group for Z, and
- ii) the substituent(s) of the substituted aromatic heterocyclic group;
- and
- 2) the substituted aromatic heterocyclic group as
- i) the substituent(s) of the substituted aryl group for Z, and
- ii) the substituent(s) of the substituted aromatic heterocyclic group,
- is/are lower alkyl group(s), substituted lower alkyl group(s), halogen atom(s), hydroxyl group(s)and/or lower alkoxy group(s),
- with the proviso that when n is 2 and the aliphatic heterocyclic group is a ring fused with another ring, the aliphatic heterocyclic group is selected from the group consisting of the following formulas:
- wherein R is a hydrogen atom, a lower alkyl group, a benzyl group, a protective group for the nitrogen atom, or the substituted lower alkyl group defined above.
44 more elements
A cyclic amine represented by the formula:
- wherein R1 is a halogen atom or a lower alkyl group;
- R2 is a hydroxyl group, a lower alkoxy group, a substituted lower alkoxy group or a halogen atom, provided that R1 and R2 are not the same;
- R3 is a hydrogen atom or a lower alkyl group;
- R4 is a hydrogen atom, a halogen atom or a lower alkoxy group, R4 or may be taken together with R2 to form a ring;
- n is an integer of 1 or 2;
- and
- Y is a group represented by the formula:
- Z is a hydrogen atom, a cycloalkyl group, an aryl group, a substituted aryl group, an aromatic heterocyclic group, a substituted aromatic heterocyclic group, or an aliphatic heterocyclic group having an amide linkage (CO—N) or an imide linkage (CO—N—CO) in the ring;
- m is an integer of 2, 3, 4, 5 or 6;
- R5s are independently a hydrogen atom or a substituent;
- and
- R6s are independently a hydrogen atom or a substituent,
- or a pharmaceutically acceptable salt of said cyclic amine, wherein
- the substituent(s) of the substituted lower alkyl group is/are halogen atom(s), hydroxyl group(s), alkoxy group(s), aryl group(s), substituted aryl group(s), phenoxy group(s) and/or cycloalkyl group(s);
- the substituent(s) of the substituted lower alkoxy group is/are halogen atom(s), hydroxyl group(s), alkoxy group(s), aryl group(s), substituted aryl group(s) and/or cycloalkyl group(s);
- as the substituent(s) of the substituted aryl group as
- 1) the substituent of the substituted lower alkyl group, and
- 2) the substituent of the substituted lower alkoxy group,
- is/are lower alkyl group(s);
- substituted lower alkyl group(s) (whose substituent(s) is/are selected from halogen atom(s), hydroxyl group(s), alkoxy group(s), phenoxy group(s) and cycloalkyl group(s));
- halogen atom(s), hydroxyl group(s) and/or lower alkoxy group(s);
- each of the substituents R5 and R6 are lower alkyl group(s), hydroxyl group(s), acyloxy group(s), alkoxy group(s) and/or halogen atom(s);
- alternatively, R5 and R6 may bind to each other to form a 3- to 8-membered cycloalkane ring together with the carbon atom to which they are bonded;
- the aromatic heterocyclic group is a 5- or 6-membered aromatic heterocyclic group containing 1 to 3 heteroatom(s) selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom;
- the aliphatic heterocyclic ring is a 5- or 6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom;
- as
- 1) the substituent(s) of the substituted aryl group for Z, and
- 2) the substituent(s) of the substituted aromatic heterocyclic group,
- is/are lower alkyl group(s), substituted lower alkyl group(s), lower alkoxy group(s), substituted lower alkoxy group(s), carbamoyl group, N-substituted carbamoyl group(s), N,N-di-substituted carbamoyl group(s), alkoxycarbonyl group(s), formyl group, acyl group(s), cyano group, halogen atom(s), lower alkylthio group(s), lower alkanesulfonyl group(s), lower alkanesulfonyl amide group(s), lower alkylureide group(s), phenylureide group(s), benzylureide group(s), amino group, lower alkylamino group(s), lower alkanoylamino group(s), aroylamino group(s), hydroxyl group, lower alkanesulfonyloxy group(s), oxime group(s), oxime ether groups, cycloalkyl group(s), aryl group(s), substituted aryl group(s), aromatic heterocyclic group(s), substituted aromatic heterocyclic group(s), aminosulfonyl group and/or lower alkylaminosulfonyl group(s);
- the two adjacent substituents of the substituted aryl group or substituted aromatic heterocyclic group may bind to each other to form a ring;
- the substituent(s) of each of the N-substituted carbamoyl group and the N,N-di-substituted carbamoyl group is/are lower alkyl group(s), substituted lower alkyl group(s), aryl group(s), hydroxyl group(s) and/or lower alkoxy group(s);
- alternatively, the two substituents of the N,N-di-substituted carbamoyl group may bind to each other to form a cyclic group;
- as the substituent(s) of each of
- 1) the substituted aryl group as
- i) the substituent(s) of the substituted aryl group for Z, and
- ii) the substituent(s) of the substituted aromatic heterocyclic group;
- and
- 2) the substituted aromatic heterocyclic group as
- i) the substituent(s) of the substituted aryl group for Z, and
- ii) the substituent(s) of the substituted aromatic heterocyclic group,
- is/are lower alkyl group(s), substituted lower alkyl group(s), halogen atom(s), hydroxyl group(s)and/or lower alkoxy group(s).
38 more elements
A cyclic amine represented by the formula:
- wherein R1 is a halogen atom or a lower alkyl group;
- R2 is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a substituted lower alkoxy group or a halogen atom, provided that R1 is a bromine atom in the case of R2 being a hydrogen atom;
- R3 is a hydrogen atom or a lower alkyl group;
- R4 is a hydrogen atom, a halogen atom or a lower alkoxy group, or R4 may be taken together with R2 to form a ring;
- n is an integer of 1 or 2;
- and
- Y is a group represented by the formula:
- Z is a hydrogen atom, a cycloalkyl group, an aryl group, a substituted aryl group, an aromatic heterocyclic group, a substituted aromatic heterocyclic group, or an aliphatic heterocyclic group having an amide linkage (CO—N) or an imide linkage (CO—N—CO) in the ring;
- m is an integer of 2, 3, 4, 5 or 6;
- R5s are independently a hydrogen atom or a substituent;
- and
- R6s are independently a hydrogen atom or a substituent,
- or a pharmaceutically acceptable salt of said cyclic amine, wherein
- the substituent(s) of the substituted lower alkyl group is/are halogen atom(s), hydroxyl group(s), alkoxy group(s), aryl group(s), substituted aryl group(s), phenoxy group(s) and/or cycloalkyl group(s);
- the substituent(s) of the substituted lower alkoxy group is/are halogen atom(s), hydroxyl group(s), alkoxy group(s), aryl group(s), substituted aryl group(s) and/or cycloalkyl group(s);
- as the substituent(s) of the substituted aryl group as
- 1) the substituent of the substituted lower alkyl group, and
- 2) the substituent of the substituted lower alkoxy group,
- is/are lower alkyl group(s);
- substituted lower alkyl group(s) (whose substituent(s) is/are selected from halogen atom(s), hydroxyl group(s), alkoxy group(s), phenoxy group(s) and cycloalkyl group(s));
- halogen atom(s), hydroxyl group(s) and/or lower alkoxy group(s);
- the substituent(s) R3 is/are lower alkyl group(s) and/or halogen atom(s);
- each of the substituents R5 and R6 are lower alkyl group(s), hydroxyl group(s), acyloxy group(s), alkoxy group(s) and/or halogen atom(s);
- alternatively, R5 and R6 may bind to each other to form a 3- to 8-membered cycloalkane ring together with the carbon atom to which they are bonded;
- the aromatic heterocyclic group is a 5- or 6-membered aromatic heterocyclic group containing 1 to 3 heteroatom(s) selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom;
- the aliphatic heterocyclic ring is a 5- or 6-membered heterocyclic ring containing 1 to 3 heteroatom(s) selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom;
- as
- 1) the substituent(s) of the substituted aryl group for Z, and
- 2) the substituent(s) of the substituted aromatic heterocyclic group,
- is/are lower alkyl group(s), substituted lower alkyl group(s), lower alkoxy group(s), substituted lower alkoxy group(s), carbamoyl group, N-substituted carbamoyl group(s), N,N-di-substituted carbamoyl group(s), alkoxycarbonyl group(s), formyl group, acyl group(s), cyano group, halogen atom(s), lower alkylthio group(s), lower alkanesulfonyl group(s), lower alkanesulfonyl amide group(s), lower alkylureide group(s), phenylureide group(s), benzylureide group(s), amino group, lower alkylamino group(s), lower alkanoylamino group(s), aroylamino group(s), hydroxyl group, lower alkanesulfonyloxy group(s), oxime group(s), oxime ether group(s), cycloalkyl group(s), aryl groups, substituted aryl group(s), aromatic heterocyclic group(s), substituted aromatic heterocyclic group(s), aminosulfonyl group and/or lower alkylaminosulfonyl group(s);
- the two adjacent substituents of the substituted aryl group or substituted aromatic heterocyclic group may bind to each other to form a ring;
- the substituent(s) of each of the N-substituted carbamoyl group and the N,N-di-substituted carbamoyl group is/are lower alkyl group(s), substituted lower alkyl group(s), aryl group(s), hydroxyl group(s) and/or lower alkoxy group(s);
- alternatively, the two substituents of the N,N-di-substituted carbamoyl group may bind to each other to form a cyclic group;
- as the substituent(s) of each of
- 1) the substituted aryl group as
- i) the substituent(s) of the substituted aryl group for Z, and
- ii) the substituent(s) of the substituted aromatic heterocyclic group;
- and
- 2) the substituted aromatic heterocyclic group as
- i) the substituent(s) of the substituted aryl group for Z, and
- ii) the substituent(s) of the substituted aromatic heterocyclic group,
- is/are lower alkyl group(s), substituted lower alkyl group(s), halogen atom(s), hydroxyl group(s)and/or lower alkoxy group(s).
39 more elements
A compound selected from the group consisting of the following compounds (1) to (42), a pharmacologically acceptable salt thereof, or a solvate of said compound or salt:
- (1) N-benzyl-3-{2-[4-(2-bromo-5-methoxybenzyl)-1-piperidinyl]ethyl}benzamide,
- (2) 3-{2-[4-(2-bromo-5-methoxybenzyl)-1-piperidinyl]ethyl}benzamide,
- (3) 3-{2-[4-(2-bromo-5-ethoxybenzyl)-1-piperidinyl]ethyl }benzamide,
- (4) 3-{2-[4-(2-bromo-5-isopropoxybenzyl)-1-piperidinyl]ethyl }benzamide,
- (5) 3-{2-[4-(2-bromo-5-methoxybenzyl)-1-piperidinyl]ethyl}-N,N-dimethylbenzamide,
- (6) 3-{2-[4-(2-bromo-5-ethoxybenzyl)-1-piperidinyl]ethyl}-N,N-dimethylbenzamide,
- (7) 3-{2-[4-(2-bromo-5-isopropoxybenzyl)-1-piperidinyl]ethyl}-N,N-dimethylbenzamide,
- (8) 3-{2-[4-(2-bromo-5-chlorobenzyl)-1-piperidinyl]ethyl}-N,N-dimethylbenzamide,
- (9) 3-{2-[4-(2-bromo-5-fluorobenzyl)-1-piperidinyl]ethyl}-N,N-dimethylbenzamide,
- (10) 4-(2-bromo-5-methoxybenzyl)-1-[2-(2-chlorophenyl)ethyl]piperidine,
- (11) 4-(2-bromo-5-ethoxybenzyl)-1-[2-(2-chlorophenyl)ethyl]piperidine,
- (12) 4-(2-bromo-5-isopropoxybenzyl)-1-[2-(2-chlorophenyl)ethyl]piperidine,
- (13) 4-(2-bromo-5-methoxybenzyl)-1-[2-(2-methoxyphenyl)ethyl]piperidine,
- (14) 4-(2-bromo-5-methoxybenzyl)-1-[2-(2-ethoxyphenyl)ethyl]piperidine,
- (15) 4-(2-bromo-5-methoxybenzyl)-1-[2-(3-methoxyphenyl)ethyl]piperidine,
- (16) 4-(2-bromo-5-methoxybenzyl)-1-[2-(3-isopropoxyphenyl)ethyl]piperidine,
- (17) 4-(2-bromo-5-chlorobenzyl)-1-[2-(3-methoxyphenyl)ethyl]piperidine,
- (18) 4-(2-bromo-5-chlorobenzyl)-1-[2-(3-ethoxyphenyl)ethyl]piperidine,
- (19) 4-(2-bromo-5-chlorobenzyl)-1-[2-(3isopropoxyphenyl)ethyl]piperidine,
- (20) 4-(2-bromo-5-fluorobenzyl)-1-[2-(3-methoxyphenyl)ethyl]piperidine,
- (21) 4-(2-bromo-5-fluorobenzyl)-1-[2-(3-ethoxyphenyl)ethyl]piperidine,
- (22) 4-(2-bromo-5-fluorobenzyl)-1-[2-(3-isopropoxyphenyl)ethyl]piperidine,
- (23) 4-(2-bromo-5-methoxybenzyl)-1-[2-(2-chloro-6-fluorophenyl)ethyl]piperidine,
- (24) 1-[2-(1,3-benzodioxol-5-yl)ethyl]-4-(2-bromo-5-methoxybenzyl)piperidine,
- (25) 1-[2-(1,3-benzodioxol-5-yl)ethyl]-4-(2-bromo-5-ethoxybenzyl)piperidine,
- (26) 1-[2-(1,3-benzodioxol-5-yl)ethyl]-4-(2-bromo-5-isopropoxybenzyl)piperidine,
- (27) 1-[2-(1,3-benzodioxol-5-yl)ethyl]-4-(2-bromo-5-fluorobenzyl)piperidine,
- (28) 1-[2-(1,3-benzodioxol-5-yl)ethyl]-4-(2-bromo-5-chlorobenzyl)piperidine,
- (29) 4-(2-bromo-5-methoxybenzyl)-1-[2-(6-chloro-1,3-benzodioxol-5-yl)ethyl]piperidine,
- (30) 4-(2-bromo-5-ethoxybenzyl)-1-[2-(6-chloro-1,3-benzodioxol-5-yl)ethyl]piperidine,
- (31) 4-(2-bromo-5-isopropoxybenzyl)-1-[2-(6-chloro-1,3-benzodioxol-5-yl)ethyl]piperidine,
- (32) 4-(2-bromo-5-chlorobenzyl)-1-[2-(6-chloro-1,3-benzodioxol-5-yl)ethyl]piperidine,
- (33) 4-(2-bromo-5-fluorobenzyl)-1-[2-(6-chloro-1,3-benzodioxol-5-yl)ethyl]piperidine,
- (34) 4-(2-bromo-5-methoxybenzyl)-1-[2-(2-chloro-3-methoxyphenyl)ethyl]piperidine,
- (35) 4-(2-bromo-5-fluorobenzyl)-1-[2-(2-chloro4-methoxyphenyl)ethyl]piperidine,
- (36) 4-(2-bromo-5-methoxybenzyl)-1-[2-(2-naphthyl)ethyl]piperidine,
- (37) 4-(2-bromo-5-methoxybenzyl)-1-[2-(4-fluorophenyl)ethyl]piperidine,
- (38) 4-benzyl-2-{4-[4-(5-methoxy-2-methylbenzyl)-1-piperidinyl]butyl}-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one,
- (39) 4-benzyl-2-{4-[4-(2-bromo-5-methoxybenzyl)-1-piperidinyl]butyl}-1,2,4-triazine-3,5(2H,4H)-dione,
- (40) 2-{3-[4-(2-bromo-5-methoxybenzyl)-1-piperidinyl]propyl}-1H-isoindole-1,3(2H)-dione,
- (41) 4-(2-bromo-5-methoxyethoxybenzyl)-1-[2-(7-chloro-1,4-benzodioxan-6-yl)ethyl]piperidine, and
- (42) 4-(2-chloro-5-methoxyethoxybenzyl)-1-[2-(7-chloro-1,4-benzodioxan-6-yl)ethyl]piperidine.
39 more elements
A cyclic amine represented by the formula:
- wherein R1 is a bromine atom, a chlorine atom or a lower alkyl group;
- R2 is a substituted lower alkoxy group;
- R3 is a hydrogen atom or a lower alkyl group;
- R4 is a hydrogen atom, a halogen atom or an alkoxy group, or R4 may be taken together with R2 to form a ring;
- and
- n is an integer of 1 or 2, or
- a salt of said cyclic amine.
4 more elements
A compound selected from the group consisting of the following compounds (1) to (4), a salt thereof, or a solvate of said compound or salt:
- (1) 4-[2-bromo-5-(difluoromethoxy)benzyl]piperidine,
- (2) 4-[2-chloro-5-(difluoromethoxy)benzyl]piperidine,
- (3) 4-(2-bromo-5-methoxyethoxybenzyl)piperidine, and
- (4) 4-(2-chloro-5-methoxyethoxybenzyl)piperidine.
1 more element
A process for producing a compound represented by the formula:
- which comprises 1) reacting a compound represented by the formula:
- with a compound represented by the formula (3):
- X—Y—Z;
- or
- 2) reacting the former compound with a carboxylic acid compound represented by the formula (4):
- HOOC—Y1—Z, and then reducing the amide linkage;
- or
- 3) reacting the former compound with an aldehyde compound represented by the formula (6):
- OHC—Y1—Z under reductive amination conditions wherein R1 is a halogen atom or a lower alkyl group;
- R2 is a hydroxyl group, a lower alkoxy group, a substituted lower alkoxy group or a halogen atom, provided that R1 and R2 are not the same;
- R3 is a hydrogen atom or a lower alkyl group;
- R4 is a hydrogen atom, a halogen atom or a lower alkoxy group, or R4 may be taken together with R2 to form a ring;
- n is an integer of 1 or 2 and
- Y is a group represented by the formula:
- Z is a hydrogen atom, a cycloalkyl group, an aryl group, a substituted aryl group, an aromatic heterocyclic group, a substituted aromatic heterocyclic group, or an aliphatic heterocyclic group having an amide linkage (CO—N) or an imide linkage (CO—N—CO) in the ring, X is a leaving group, Y1 is a substituted or unsubstituted alkylene group having a carbon atom(s) in a number smaller by one than the number of carbon atoms of Y, and —CH2—Y1— corresponds to Y.
12 more elements
Dependencies are inferred from the claim text.