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US 6,552,015 B2Granted
Azabicycloalkane derivatives and therapeutic uses thereof
AssigneePfizer Inc.
InventorsAnton Franz Joseph Fliri, Todd William Butler, Randall James Gallaschun
Life of this patent
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Abstract
The present invention is directed to a compound of the formula (I): and pharmaceutically acceptable salts thereof, wherein R1, R2, Y, U, W, k, A, E, V, R4 and R5 are as defined herein, pharmaceutical compositions thereof, and methods of use thereof in the inhibition of serotonin reuptake, the inhibition of the binding of 5-HT2A serotonin receptors and the treatment of diseases, conditions or disorders of the central nervous system. Further, the present invention is also directed to methods for the preparation of compounds of formula (I) and intermediates useful therefor.
Claims17
A compound of formula (I):
- or pharmaceutically acceptable salts thereof, wherein the group
- wherein, for each,
- A is (CH2)n where n is 1 or 2;
- E is selected from the group consisting of N, CH, C—OH, C—CN, C—O—(C1-C6)alkyl, and C—(C1-C6)alkyl;
- U is NH or NR3, where R3 is selected from the group consisting of (C1-C6)alkyl and C(═O)—(C1-C6)alkyl;
- k is 1 or 2;
- R1 and R2 are selected independently from H, (C1-C6)alkyl, halo, CN, nitro, CF3, —NHC(O)R6 and —OR7, where R6 and R7 are selected independently from H, (C1-C6)alkyl, a 5- to 7-membered aryl ring, and a 5- to 7-membered heteroaryl ring;
- or R1 and R2, if on adjacent carbon atoms, together with the atoms to which they are attached, if adjacent, form a carbocyclic or heterocyclic five- or six-membered ring;
- R4 and R5 are selected from H, (C1-C6)alkyl, halo, —CF3, nitro, —CN, —NHC(═O)R6, —OR7, a 5- to 7-membered aryl ring, and a 5- to 7-membered heteroaryl ring;
- where R6 and R7 are as defined above;
- V is CH, CR8, or N, where R8 is H, (C1-C6)alkyl, halo, —CF3, nitro, —CN, —NHC(═O)R6, —OR7, a 5- to 7-membered aryl ring, or a 5- to 7-membered heteroaryl ring;
- wherein R6 and R7 are as defined above;
- W is C(O);
- and
- Y is CH, CR1 or CR2, where R1 and R2 are as defined above.
12 more elements
A process for preparing a compound of formula (I):
- or pharmaceutically acceptable salts thereof, wherein the group
- wherein, for each,
- A is (CH2)n where n is 1 or 2;
- E is selected from the group consisting of N, CH, C—OH, C—CN, C—O—(C1-C6)alkyl, and C—(C1-C6)alkyl;
- U is NH or NR3, where R3 is selected from the group consisting of (C1-C6)alkyl and C(═O)—(C1-C6)alkyl;
- k is 1 or 2;
- R1 and R2 are selected independently from H, (C1-C6)alkyl, halo, CN, nitro, CF3, —NHC(O)R6 and —OR7, where R6 and R7 are selected independently from H, (C1-C6)alkyl, a 5- to 7-membered aryl ring, and a 5- to 7-membered heteroaryl ring;
- or R1 and R2, if on adjacent carbon atoms, together with the atoms to which they are attached, if adjacent, form a carbocyclic or heterocyclic five- or six-membered ring;
- R4 and R5 are selected from H, (C1-C6)alkyl, halo, —CF3, nitro, —CN, —NHC(═O)R6, —OR7, a 5- to 7-membered aryl ring, and a 5- to 7-membered heteroaryl ring;
- where R6 and R7 are as defined above;
- V is CH, CR8, or N, where R8 is H, (C1-C6)alkyl, halo, —CF3, nitro, —CN, —NHC(═O)R6, —OR7, a 5- to 7-membered aryl ring, or a 5- to 7-membered heteroaryl ring;
- wherein R6 and R7 are as defined above;
- W is C(O);
- and
- Y is CH, CR1 or CR2;
- comprising the step of allowing a compound of formula (AII)
- wherein
- k is 1 or 2;
- U is NH, or NR3, where R3 is selected from the group consisting of (C1-C6)alkyl, and C(═O)—(C1-C6)alkyl;
- W is C(O);
- Y is CH, CR1 or CR2, where R1 and R2 are as defined above
- R1 and R2 are selected independently from H, (C1-C6)alkyl, halo, CN, nitro, CF3, —NHC(O)R6 and —OR7, where R6 and R7 are selected independently from H, (C1-C6)alkyl, a 5- to 7-membered aryl ring, and a 5- to 7-membered heteroaryl ring, or
- R1 and R2, together with the atoms to which they are attached, if adjacent to one another, form a carbocyclic or heterocyclic five- or six-membered ring;
- to react with a compound of formula (BI)
- wherein, for each,
- A is (CH2)n where n is 1 or 2;
- E is selected from the group consisting of N, CH, C—OH, C—CN, C—O—(C1-C6)alkyl, and C—(C1-C6)alkyl;
- R4 and R5 are selected from H, (C1-C6)alkyl, halo, —CF3, nitro, —CN, —NHC(═O)R6, —OR7, a 5- to 7-membered aryl ring, and a 5- to 7-membered heteroaryl ring;
- where R6 and R7 are as defined above;
- V is CH, CR8, or N, where R8 is H, (C1-C6)alkyl, halo, —CF3, nitro, —CN, —NHC(═O)R6, —OR7, a 5- to 7-membered aryl ring, or a 5- to 7-membered heteroaryl ring;
- wherein R6 and R7 are as defined above.
28 more elements
A process for the preparation of a compound of formula (I):
- or pharmaceutically acceptable salts thereof, wherein the group
- wherein, for each,
- A is (CH2)n where n is 1 or 2;
- E is selected from the group consisting of N, CH, C—OH, C—CN, C—O—(C1-C6)alkyl, and C—(C1-C6)alkyl;
- U is NH;
- k is 1 or 2;
- R1 and R2 are selected independently from H, (C1-C6)alkyl, halo, CN, nitro, CF3, —NHC(O)R6 and —OR7, where R6 and R7 are selected independently from H, (C1-C6)alkyl, a 5- to 7-membered aryl ring, and a 5- to 7-membered heteroaryl ring;
- or R1 and R2, if on adjacent carbon atoms, together with the atoms to which they are attached, if adjacent, form a carbocyclic or heterocyclic five- or six-membered ring;
- R4 and R5 are selected from H, (C1-C6)alkyl, halo, —CF3, nitro, —CN, —NHC(═O)R6, —OR7, a 5- to 7-membered aryl ring, and a 5- to 7-membered heteroaryl ring;
- where R6 and R7 are as defined above;
- V is CH, CR8, or N, where R8 is H, (C1-C6)alkyl, halo, —CF3, nitro, —CN, —NHC(═O)R6, —OR7, a 5- to 7-membered aryl ring, or a 5- to 7-membered heteroaryl ring;
- wherein R6 and R7 are as defined above;
- W is C(O);
- and
- Y is CH, CR1 or CR2;
- comprising the steps of
- (a) allowing a compound of formula (AIII)
- wherein W′ is C(O);
- Y is CH, CR1 or CR2, and R1 and R2 are selected independently from H, (C1-C6)alkyl, halo, CN, nitro, CF3, —NHC(O)R6 and —OR7, where R6 and R7 are selected independently from H, (C1-C6)alkyl, a 5- to 7-membered aryl ring and a 5- to 7-membered heteroaryl ring, or R1 and R2, together with the atoms to which they are attached, if adjacent, form a carbocyclic or heterocyclic five- or six-membered ring;
- to react with a compound of formula (BII)
- wherein
- A is (CH2)n where n is 1 or 2;
- k is 1 or 2;
- E is selected from the group consisting of N, CH, C—OH, C—CN, C—O—(C1-C6)alkyl, and C—(C1-C6)alkyl;
- V is CH, CR3, or N, where R3 is as defined above;
- and
- R4 and R5 are selected from H, (C1-C6)alkyl, halo, —CF3, —CN, —NHC(═O)R6, —OR7, a 5- to 7-membered aryl ring, and a 5- to 7-membered heteroaryl ring, where R6 and R7 are as defined above;
- to form a compound of formula (CI)
- k, R1, R2, Y, W′, A, E, V, R4, and R5 are as defined above;
- and
- (b) allowing the compound of formula (CI) to undergo a ring closure reaction.
28 more elements
A process for the preparation of compounds of formula (I):
- or pharmaceutically acceptable salts thereof, wherein the group
- wherein, for each,
- A is (CH2)n where n is 1 or 2;
- E is selected from the group consisting of N, CH, C—OH, C—CN, C—O—(C1-C6)alkyl, and C—(C1-C6)alkyl;
- U is NH;
- k is 1 or 2;
- R1 and R2 are selected independently from H, (C1-C6)alkyl, halo, CN, nitro, CF3, —NHC(O)R6 and —OR7, where R6 and R7 are selected independently from H, (C1-C6)alkyl, a 5- to 7-membered aryl ring, and a 5- to 7-membered heteroaryl ring;
- or R1 and R2, if on adjacent carbon atoms, together with the atoms to which they are attached, if adjacent, form a carbocyclic or heterocyclic five- or six-membered ring;
- R4 and R5 are selected from H, (C1-C6)alkyl, halo, —CF3, nitro, —CN, —NHC(═O)R6, —OR7, a 5- to 7-membered aryl ring, and a 5- to 7-membered heteroaryl ring;
- where R6 and R7 are as defined above;
- V is CH, CR8, or N, where R8 is H, (C1-C6)alkyl, halo, —CF3, nitro, —CN, —NHC(═O)R6, —OR7, a 5- to 7-membered aryl ring, or a 5- to 7-membered heteroaryl ring;
- wherein R6 and R7 are as defined above;
- W is C(O);
- and
- Y is CH, CR1 or CR2;
- comprising the steps of
- (a) allowing a compound of formula (DIII)
- wherein Y, R1 and R2 are as defined above;
- to react with a halo(C3-C4)alkylisocyanate of the formula X—(CH2)k+2NCO, wherein k is 1 or 2, and X is halo, to form a compound of formula (GI)
- wherein Y, R1, R2 and k are as defined above;
- (b) allowing the compound of formula (GI) to undergo a double ring closure reaction to form a tricyclic compound of formula (FI)
- wherein R1, R2 and Y are as defined above;
- and
- (c) further permitting (FI) to react with a compound of formula (BI)
- and E, V and R4 and R5 are as defined above, or a salt thereof.
22 more elements
Dependencies are inferred from the claim text.