Arylpiperidinol and arylpiperidine derivatives and drugs containing the same

• US 6,455,549 B1
• Filed: 03/20/1998
• Issued: 09/24/2002
• Est. Priority Date: 07/22/1996
• Status: Expired due to Fees

• Current Assignee: Asubio Pharma Co., Ltd. (Daiichi Sankyo Company Limited)
• Original Assignee: Suntory Ltd (Kotobuki Realty Co., Ltd.)
• Inventors: Tamura, Shigeki, Annoura, Hirokazu, Nakanishi, Kyoko
• Primary Examiner(s): Rotman, Alan L.
• Assistant Examiner(s): DESAI, RITA J
• Application Number:
  US09/043,563
• Time in Patent Office: 1,649 Days
• Field of Search: 546/192, 546/194, 546/217, 546/233, 546/234, 546/240, 546/241, 514/331, 514/327, 514/330
• US Class Current: 514/327
• 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 the alleviation or treatment of symptoms due to ischemic diseases or symptoms derived from migraine containing, as an effective ingredient, a compound having the formula (I) or its pharmaceutically acceptable salt:

wherein, R is a hydrogen atom, an optionally substituted phenyl group, an optionally substituted phenoxy group, or 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 interger of 1 to 5, E is a connecting bond, an oxygen atom, or a methylene group, X is a hydroxyl group or a hydrogen atom, provided that, when E is an oxygen atom or a methylene group, X is not a hydrogen atom, and 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 akyl group optionally substituted with a halogen atom; and

also provided that, when X is a hydroxyl group, and R is a hydrogen atom or an optionally substituted phenyl group, and A is a connecting bond or a cycloalkylene group, then B is not a group —

NHCO(CH₂)_n—

, where n is an integer of 1 to 5.

2. A pharmaceutical composition 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 alkyl group, and X is a hydroxyl group.

3. A pharmaceutical composition 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 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 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.

11. A method for the alleviation or treatment of symptoms due to ischemic diseases or symptoms derived from migraine, comprising administering to a patient in need of such treatment a pharmaceutical composition as recited in claim 1 in an amount effective for the alleviation or treatment of said symptoms.

6. A Ca⁺ overload suppressant comprising a compound having the formula (I) or its pharmaceutically acceptable salt:

wherein, R is a hydrogen atom, an optionally substituted phenyl group, an optionally substituted phenoxy group, or 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 interger of 1 to 5, E is a connecting bond, an oxygen atom, or a methylene group, X is a hydroxyl group or a hydrogen atom, provided that, when E is an oxygen atom or a methylene group, X is not a hydrogen atom, and 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 akyl group optionally substituted with a halogen atom; and

also provided that, when X is a hydroxyl group, and R is a hydrogen atom or an optionally substituted phenyl group, and A is a connecting bond or a cycloalkylene group, then B is not a group —

NHCO(CH₂)_n—

, where n is an integer of 1 to 5.

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.

12. A pharmaceutical composition for the alleviation or treatment of symptoms due to ischemic diseases or symptoms derived from migraine containing, as an effective ingredient, a compound having the formula (I) or its pharmaceutically acceptable salt:

wherein, R is a hydrogen atom, an optionally substituted phenyl group, an optionally substituted phenoxy group, or 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, E is a connecting bond, an oxygen atom, or a methylene group, X is a hydroxyl group or a hydrogen atom, provided that, when E is an oxygen atom or a methylene group, X is not a hydrogen atom, and 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 akyl group optionally substituted with a halogen atom.