Arylpiperidinol and arylpiperidine derivatives and pharmaceuticals containing the same

• US 20040186138A1
• Filed: 03/15/2004
• Published: 09/23/2004
• Est. Priority Date: 07/22/1996
• Status: Active Grant

• Current Assignee: Asubio Pharma Co., Ltd. (Daiichi Sankyo Company Limited)
• Original Assignee: Daiichi Suntory Pharma Co. Ltd. (Daiichi Sankyo Company Limited)
• Inventors: Nakanishi, Kyoko, Tamura, Shigeki, Annoura, Hirokazu
• Granted Patent: US 7,498,344 B2
• Time in Patent Office: Days
• US Class Current: 514/317
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 211/12 with only hydrogen atoms attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/14 with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/18 with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 211/44 attached in position 4
• CPC Class Codes: C07D 211/52 having an aryl radical as the second substituent in position 4
• CPC Class Codes: C07D 211/70 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Abstract

A pharmaceutical composition, especially a pharmaceutical composition for the alleviation or treatment of symptoms due to ischemic diseases and symptoms derived from seizures, epilepsy, and migraine, and a Ca²⁺ overload suppressant, containing an arylpiperidinol or arylpiperidine derivative having the formula (I):

wherein, R is H, an optionally substituted phenyl, an optionally substituted phenoxy, or an optionally substituted benzoyl, A is a connecting bond, a cycloalkylene, or an alkenylene optionally substituted with a lower alkyl, B is an alkylene optionally substituted with OH or an alkoxy or —NHCO(CH₂)_n— where n is an integer of 1 to 5, E is a connecting bond, O, or a methylene, X is OH or H provided that when E is O or a methylene, X is not H, and Y and Z are independently H, a halogen, an alkoxy, or an alkyl optionally substituted with a halogen.

Claims

1. A pharmaceutical composition for thee alleviation or treatment of symptoms due to ischemic diseases or symptoms derived from seizures, epilepsy, and migraine containing, as an effective ingredient, a compound having the formula (I):

2. A pharmaceutical composition for the alleviation or treatment of symptoms due to ischemic diseases and symptoms derived from seizures, epilepsy, and migraine containing, as an effective ingredient, a compound as claimed in claim 1, or its pharmaceutically acceptable salt, wherein, in the formula (I), R is an optionally substituted phenyl group, A is an alkenylene group optionally substituted with a lower alkyt group, and X is a hydroxyl group.

3. A pharmaceutical composition for the alleviation or treatment of symptoms due to ischemic diseases or symptoms derived from seizures, epilepsy, and migraine, as claimed in claim 1, wherein, in the formula (I), R is an optionally substituted benzoyl group, A is a connecting bond, and X is a hydroxyl group.

4. A pharmaceutical composition for the alleviation or treatment of symptoms due to ischemic diseases or symptoms derived from seizures, epilepsy, and migraine, as claimed in claim 1, wherein, in the formula (I), R is an optionally substituted phenyl group, A is a connecting bond, B is a dimethylene group substituted with a hydroxyl group, and X is a hydroxyl group.

5. A pharmaceutical composition for the alleviation or treatment of symptoms due to ischemic diseases or symptoms derived from seizures, epilepsy, and migraine, as claimed in claim 1, wherein, in the formula (I), R is an optionally substituted phenoxy group, A is a connecting bond, B is a trimethylene group substituted with a hydroxy group, and X is a hydroxyl group.

6. A Ca²⁺ overload suppressant containing, as an effective ingredient, a compound having the formula (I):

7. A Ca²⁺ overload suppressant as claimed in claim 6, wherein, in the formula (I), R is an optionally substituted phenyl group, A is an alkenylene group optionally substituted with a lower alkyl group, and X is a hydroxyl group.

8. A Ca²⁺ overload suppressant as claimed in claim 6, wherein, in the formula (I), R is an optionally substituted benzoyl group, A is a connecting bond, and X is a hydroxyl group.

9. A Ca²⁺ overload suppressant as claimed in claim 6, wherein, in the formula (I), R is an optionally substituted phenyl group, A is a connecting bond, B is a dimethylene group substituted with a hydroxyl group, and X is a hydroxyl group.

10. A Ca²⁺ overload suppressant as claimed in claim 6, wherein, in the formula (I), R is an optionally substituted phenoxy group, A is a connecting bond, B is a trimethylene group substituted with a hydroxyl group, and X is a hydroxyl group.

11. A compound having the formula (I′

);

12. A compound and its pharmaceutically acceptable salt as claimed in claim 11, wherein, in the formula (I′

), R′

, A, B, and X are selected from the group consisting of;

1) R′

is an optionally substituted phenyl group, A is an alkenylene group optionally substituted with a lower alkyl group, B is an alkylene group optionally substituted with a hydroxyl group or an alkoxy group or a group —

NHCO(CH₂)_n—

, where n is an integer of 1 to 5, and X is a hydroxyl group;

2) R′

is an optionally substituted phenyl group, A is a connecting bond or a cycloalkylene group, B is an alkylene group substituted with a hydroxyl group, and X is a hydroxyl group;

3) R′

is an optionally substituted phenyl group, A is a connecting bond or a cycloalkylene group, B is a group —

NHCO(CH₂)_n—

, where n is an integer of 1 to 5, and X is a hydroxyl group or a hydrogen atom;

4) R′

is an optionally substituted phenoxy group, A is a connecting bond, a cycloalkylene group, or an alkenylene group optionally substituted with a lower alkyl group, B is an alkylene group substituted with a hydroxyl group, and X is a hydroxyl group; and

5) R′

is an optionally substituted benzoyl group, A is a connecting bond, a cycloalkylene group, or an alkenylene group optionally substituted with a lower alkyl group, B is an alkylene group optionally substituted with a hydroxyl group or an alkoxy group or a group —

NHCO(CH₂)_n—

, where n is an integer of 1 to 5, and X is a hydroxyl group or a hydrogen atom where further E is a connecting bond, an oxygen atom, or a methylene group, Y and Z may be the same or different from each other and represent a hydrogen atom, a halogen atom, an alkoxy group, or an alkyl group optionally substituted with a halogen atom.

13. A compound and its pharmaceutically acceptable salt as claimed in claim 11 or claim 12, wherein, in the formula (I′

), R′

is an optionally substituted phenyl group, A is an alkenylene group optionally substituted with a lower alkyl group, and X is a hydroxyl group.

14. A compound and its pharmaceutically acceptable salt as claimed in claim 11 or claim 12, wherein, in the formula (I′

), R′

is an optionally substituted benzoyl group, A is a connecting bond, and X is a hydroxyl group.

15. A compound and its pharmaceutically acceptable salt as claimed in claim 11 or claim 12, wherein, in the formula (I′

), R′

is an optionally substituted phenyl group, A is a connecting bond, B is a dimethylene group substituted with a hydroxyl group, and X is a hydroxyl group.

16. A compound and its pharmaceutically acceptable salt as claimed in claim 11 or claim 12, wherein, in the formula (I′

), R′

is an optionally substituted phenoxy group, A is a connecting bond, B is a trimethylene group substituted with a hydroxyl group, and X is a hydroxyl group.

17. A compound and its pharmaceutically acceptable salt as claimed in claim 11 or claim 12, wherein, in the formula (I′

), R′

is an optionally substituted phenyl group, A is a connecting bond or a cycloalkylene group, B is a group —

NHCO(CH₂)_n—

, wherein n is an integer of 1 to 5, and X is a hydroxyl group or a hydrogen atom.

18. A compound and its pharmaceutically acceptable salt as claimed in claim 11 or claim 12, wherein, in the formula (I′

), R′

is an optionally substituted benzoyl group and A and E are connecting bonds.

19. A pharmaceutical composition containing as an effective ingredient, the compound having the formula (I′

) according to claim 11 and its pharmaceutically acceptable salt.

20. A compound having the formula (II):