Claims
- 1. A compound of formula (I): or pharmaceutically acceptable salts thereof, wherein the group R1 and R2 are selected independently from H, (C1-C6)alkyl, (C1-C6)fluoroalkyl, F, Cl, W, I, cyano, nitro, O—(C1-C6)alkyl, O—(C1-C6)fluoroalkyl, —NHC(O)R4 and —OR5, where R4 and R5 are selected independently from H, (C1-C6)alkyl, and a 5- to 7-membered aryl or heteroaiyl ring, or R1 and R2 together with the atoms to which they are attached, form a carbocyclic 5- or 6-membered ring or a heterocyclic 5- or 6-membered ring; and R3 is selected from the group consisting of H, (C1-C6)alkyl, (CH2)m-aryl or (CH2)m-heteroaryl, wherein m is an integer from 1 to 4, each aryl or heteroaryl group optionally substituted with Cl, Br, CN, CF3, O—(C1-C6)alkyl, (C1-C6)alkyl, sulfonyl(C1-C6)alkyl, —CO(C1-C6)alkyl, —CONH2, —CONH(C1-C6)alkyl, —CON((C1-C6)alkyl)2, or CH(OH)(C1-C6)alkyl; with the proviso that neither R1 nor R2 can be H or methyl, when R3 is H or —(CH2)m-phenyl and when neither R1 nor R2 can be H or methyl when R3 is methyl.
- 2. A compound according to claim 1 wherein R3 is H or (C1-C6)alkyl; and R1 and R2 are independently chosen from the group consisting of H, halogen, —CF3, (C1-C6)alkyl, —OCH3, and OCF3.
- 3. A compound according to claim 1 wherein R3 is H and R1 and R2 are independently chosen from the group consisting of Cl, —CF3, (C1-C6)alkyl, —OCH3, and OCF3.
- 4. A compound according to claim 1 selected from the group consisting of:3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octane; 3-(3,4-dichlorophenyl)-3,8-diazabicyclo[3.2.1]octane; 3-(2,4-dimethylphenyl)-3,8-diazabicyclo[3.2.1]octane; 3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane; 3-(4-trifluoromethylphenyl)-3,8-diazabicyclo[3.2.1]octane; 3-(3-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane; 8-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]octane; 8-p-tolyl-3,8-diazabicyclo[3.2.1]octane; 3-(p-tolyl)-3,8-diazabicyclo[3.2.1]octane; 8-(3,4-dichlorophenyl)-3,8-diazabicyclo[3.2.1]octane; 8-phenyl-3,8-diazabicyclo[3.2.1]octane; 8-(2,4-dimethylphenyl)-3,8-diazabicyclo[3.2.1]octane; 8-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane; 8-(4-trifluoromethylphenyl)-3,8-diazabicyclo[3.2.1]octane; 8-(3-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane; 8-benzyl-3-(4-fluorophenyl)-3,8-diaza-bicyclo[3.2.1]octane; 2-benzyl-5-(4-fluorophenyl)-2,5-diaza-bicyclo[2.2.2]octane; 8-benzyl-3-(4-chlorophenyl)-3,8-diaza-bicyclo[3.2.2]octane; 2-benzyl-5-(4-chlorophenyl)-2,5-diaza-bicyclo[2.2.2]octane; 8-ethyl-3-(4-chlorophenyl)-3,8-diaza-bicyclo[3.2.1]octane; 2-ethyl-5-(4-chlorophenyl)-2,5-diaza-bicyclo[2.2.2]octane; 8-methyl-3-(4-chlorophenyl)-3,8-diaza-bicyclo[3.2.1]octane; 2-methyl-5-(4-chlorophenyl)-2,5-diaza-bicyclo[2.2.2]octane; 8-ethyl-3-(3,4-dichlorophenyl)-3,8-diaza-bicyclo[3.2.1]octane; 2-ethyl-5-(3,4-dichlorophenyl)-2,5-diaza-bicyclo[2.2.1]octane; 8-methyl-3-(3,4-dichlorophenyl)-3,8-diaza-bicyclo[3.2.1]octane; 2-methyl-5-(3,4-dichlorophenyl)-2,5-diaza-bicyclo[2.2.2]octane; 8-ethyl-3-(4-methylphenyl)-3,8-diaza-bicyclo[3.2.1]octane; 2-ethyl-5-(4-methylphenyl)-2,5-diaza-bicyclo[2.2.2]octane; 8-methyl-3-(4-methylphenyl)-3,8-diaza-bicyclo[3.2.1]octane; 2-methyl-5-(4-methylphenyl)-2,5-diaza-bicyclo[2.2.1]octane; 8-benzyl-8-(4-chlorophenyl)-3,8-diaza-bicyclo[3.2.1]octane; 3-methyl-8-(4-chlorophenyl)-3,8-diaza-bicyclo[3.2.1]octane; 3-propyl-8-(4-chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]octane; 3-(2-naphthyl)-3,8-diazabicyclo[3.2.1]octane; 3-(1-naphthyl)-3,8-diazabicyclo[3.2.1]octane; 3-(2-isoquinolyl)-3,8-diazabicyclo[3.2.1]octane; 8-(2-naphthyl)-3,8-diazabicyclo[3.2.1]octane; 8-(2-naphthyl)-3,8-diazabicyclo[3.2.1]octane; 8-(2-isoquinolyl)-3,8-diazabicyclo[3.2.1]octane; 2-(4-chlorophenyl)-2,5-diaza-bicyclo[2.2.2]octane; 8-methyl-3-(3-trifluoromethylphenyl)-3,8-diazabicyclo[3.2.1]octane; 2-(4-fluorophenyl)-2,5-diazabicyclo[2.2.2]octane; or pharmaceutically acceptable salts thereof.
- 5. A method of treating anxiety or depression in a patient in need thereof comprising administering to the patient an effective amount of a compound of formula (I) according to claim 1.
- 6. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
- 7. A process for the preparation of a compound of formula (I) wherein the group R1 and R2 are selected independently from H, (C1-C6)alkyl, (C1-C6)fluoroalkyl, F, Cl, Br, I, cyano, nitro, O—(C1-C6)alkyl, O—(C1-C6)fluoroalkyl, —NHC(O)R4 and —OR5, where R4 and R5 are selected independently from H, (C1-C6)alkyl, and a 5- to 7-membered aryl or heteroaryl ring, or R1 and R2 together with the atoms to which they are attached, form a carbocyclic 5- or 6-membered ring or a heterocyclic 5- or 6-membered ring; and R3 is selected from the group consisting of H, (C1-C6)alkyl, (CH2)m-aryl or (CH2)m-heteroaryl, wherein m is an integer from 1 to 4, each aryl or heteroaryl group optionally substituted with Cl, Br, CN, CF3, O—(C1-C6)alkyl, (C1-C6)alkyl, sulfonyl(C1-C6)alkyl, —CO(C1-C6)alkyl, —CONH2, —CONH(C1-C6)alkyl, —CON((C1-C6)alkyl)2, or CH(OH)(C1-C6)alkyl; with the proviso that neither R1 nor can be H or methyl, when R3 is H or —(CH2)m-phenyland when neither R1 nor R2 can be H or methyl when R3 is methyl;comprising the steps of (i) reacting a compound of formula (XI) wherein R7 is H, (C1-C6)alkyl, or (C1-C6)alkoxy; X is halo and n is 2; with a compound of formula (IV) wherein R1 and R2 are selected independently from H, (C1-C6)alkyl, (C1-C6)fluoroalkyl, F, Cl, Br, I, cyano, nitro, O—(C1-C6)alkyl, O—(C1-C6)fluoroalkyl, —NHC(O)R4 and —OR5, where R4 and R5 are selected independently from H, (C1-C6)alkyl, and a 5- to 7-membered aryl or heteroaryl ring, or R1 and R2 together with the atoms to which they are attached, form a carbocyclic 5- or 6-membered ring or a heterocyclic 5- or 6-membered ring; in the presence of a base to provide a mixture of compounds of formulae (XII-A) and (XII-B) wherein n, R1 and R2 are as defined above;(ii) separating chromatographically the compounds of formulae (XII-A) and (XII-B); and (iii) subjecting each of the compounds of formulae (XII-A) and (XII-B) independently to hydrogenation of conditions.
- 8. A process according to claim 7 wherein the base in step (i) is triethylamine or potassium carbonate.
- 9. A process according to claim 7 wherein the chromatographic separation of step (ii) is conducted via silica gel flash chromatography using a polar gradient of solvents.
- 10. A process according to claim 7 wherein the hydrogenation step (iii) is conducted in the in presence of a catalyst selected from the group consisting of palladium on carbon and platinum oxide.
- 11. A process according to claim 7 further comprising the step of reacting the product of step (iii) with a compound of formula R3,Y, wherein R3, is selected from (C1-C6)alkyl, (CH2)m-aryl or (CH2)m-heteroaryl, wherein m is an integer from 1 to 4, each aryl or heteroaryl group optionally substituted with Cl, Br, CN, CF3, —O—(C1-C6)alkyl, (C1-C6)alkyl, sulfonyl(C1-C6)alkyl, —CO(C1-C6)alkyl, —CONH2, —CONH(C1-C6)alkyl, —CON((C1-C6)alkyl)2, or CH(OH)(C1-C6)alkyl; and Y is a suitable leaving group.
- 12. A process according to claim 11 wherein the leaving group is selected from a halide tosylate and mesylate.
Parent Case Info
This application claims the benefit of U.S. provisional application Ser. No. 60/222,706, filed Aug. 3, 2000.
US Referenced Citations (1)
Number |
Name |
Date |
Kind |
3951980 |
Henry et al. |
Apr 1976 |
A |
Foreign Referenced Citations (1)
Number |
Date |
Country |
2531709 |
Feb 1984 |
FR |
Provisional Applications (1)
|
Number |
Date |
Country |
|
60/222706 |
Aug 2000 |
US |