Patent EA-001904-B1 (EA)
Title: Arylsubstituted piperazines useful in the treatment of bening prostatic hyperplasia
Inventor: JOLLIFFE LINDA
IPC: C07D223/10
Filed: 1998-05-08
Abstract: 1. The compound of formula I   wherein: A is (CH2)n where n is 1-6; R1 is C1-6alkyl, phenyl, substituted phenyl where the phenyl substituents are independently selected from one or more of the group consisting of C1-5alkyl, C1-5alkoxy and halogen, phenylC1-5alkyl, or substituted phenylC1-5alkyl, where the phenyl substituents are independently selected from one or more of the group consisting of C1-5alkyl, C1-5alkoxy and halogen; R2 is hydrogen, C1-6alkyl, C2-5alkenyl, C2-5alkynyl, phenylC1-5alkyl, or substituted phenylC1-5alkyl, where the phenyl substituents are independently selected from one or more of the group consisting of C1-5alkyl, C1-5alkoxy and halogen; E is   where: m is 1-5; R3 is hydrogen, C1-6alkyl or oxygen, where if R3 is oxygen, the hashed line represents a bond and if R3 is C1-6 alkyl the hashed line is absent; R4 is oxygen, hydrogen, C1-5alkyl, formyl, carboxy, C1-5alkylcarbonyl, C1-5alkoxycarbonyl, phenylC1-5alkoxy, substituted phenylC1-5alkoxy, where the phenyl substituents are independently selected from one or more of the group consisting of C1-5alkyl, C1-5 alkoxy and halogen, amido, and substituted amido where the nitrogen substituents are independently selected from one or more of the group consisting of hydrogen, C1-5alkyl, C1-5alkoxy and hydroxy, where if R4 is oxygen, the hashed line represents a bond and if R4 is any other substituent, the hashed line is absent; R5 is hydrogen, C1-5alkyl or taken together with R6 to form a cyclohexane, cyclopentane or cyclopropane ring; R6 is hydrogen, C1-5alkyl or taken together with R5 to form a cyclohexane, cyclopentane or cyclopropane ring; and pharmaceutically acceptable salts thereof. 2. The compounds of Claim 1 where R1 is C1-6alkyl, n is 2-4, and R2 is hydrogen or C1-6alkyl, C2-6alkenyl. 3. The compounds of Claim 2 where E is   4. The compounds of Claim 2 where R3 is oxygen and R4 is hydrogen, C1-5alkoxycarbonyl, or oxygen. 5. The compounds of Claim 4 where R4 is hydrogen and E is   6. The compounds of Claim 5 where m is 2 to 5. 7. A compound and pharmaceutically acceptable salts thereof selected from the group consisting of N-[ethyl-2-(2-iso-propyloxyphenyl)piperazin-4-yl)]-[1'-(2-oxy-piperidinyl)]acetamide, N-[ethyl-2-(2-iso-propyloxyphenyl)piperazin-4-yl)]-N-methyl-[1'-(2-oxy-piperidinyl)]acetamide, and N-[propyl-3-(2-iso-propyloxyphenyl)piperazin-4-yl)]-[1'-(2-oxy-piperdinyl)]acetamide. 8. A compound N-[ethyl-2-(2-iso-propyloxyphenyl)piperazin-4-yl)]-[1'-(2-oxy-piperidinyl)]acetamide and pharmaceutically acceptable salts thereof. 9. A pharmaceutical composition comprising a compound according to Claim 1 and a pharmaceutically acceptable carrier or diluent. 10. A pharmaceutical composition comprising a compound according to Claim 6 and a pharmaceutically acceptable carrier or diluent. 11. A pharmaceutical composition comprising a compound according to Claim 8 and a pharmaceutically acceptable carrier or diluent. 12. A method of treating a disease mediated by the α-1a adrenergic receptor comprising administering a compound of Claim 1 to a patient in an effective dose. 13. A method of treating a disease mediated by the α-1a adrenergic receptor comprising administering a composition of Claim 6 to a patient at an effective dose. 14. A method of treating a disease mediated by the α-1a adrenergic receptor comprising administering a composition of Claim 8 to a patient at an effective dose. 15. The method of Claim 13 where the compound is administered orally and an effective dose is 0.01-100 mg/kg daily. 16. The method of Claim 15 where the dose is 0.05-1.0 mg/kg daily. 17. A method of treating benign prostatic hyperplasia comprising administering an effective dose of a compound of Claim 1. 18. A compound of Formula II   wherein: A is (CH2)n where n is 1-6; R1 is branched C2-6alkyl, phenyl, substituted phenyl, where the phenyl substituents are independently selected from one or more of the group consisting of C1-5alkyl, C1-5alkoxy and halogen, phenylC1-5alkyl, or substituted phenylC1-5alkyl, where the phenyl substituents are independently selected from one or more of the group consisting of C1-5alkyl, C1-5alkoxy and halogen; R7 is hydrogen, t-butoxycarbonyl or benzyloxycarbonyl. 19. The compound of Claim 18 where n is 2-4 and R1 is branched C2-6alkyl. 20. The compound of Claim 18 where R7 is hydrogen or t-butoxycarbonyl. 21. A compound selected from the group consisting of 1-(2-aminoethyl)-4-(2-2-isopropyloxyphenyl)piperazine, 1-(3-aminopropyl)-4-(2-2-isopropyloxyphenyl)piperazine, and 1-(4-aminobutyl)-4-(2-2-isopropyloxyphenyl)piperazine. 22. A compound 1-(2-aminoethyl)-4-(2-2-isopropyloxyphenyl)piperazine. 23. A compound of Formula III   wherein: m is 1, 3, 4 or 5. 24. The compound of Claim 23 where m is 3-5. 25. A compound 1-t-butoxycarbonylmethyl-2-piperidone.