Arylpiperidinopropanol and arylpiprazinopropanol derivatives and pharmaceuticals containing the same

• US 6,838,470 B2
• Filed: 12/31/2002
• Issued: 01/04/2005
• Est. Priority Date: 10/31/1997
• Status: Expired due to Fees

• Current Assignee: Asubio Pharma Co., Ltd. (Daiichi Sankyo Company Limited)
• Original Assignee: Daiichi Suntory Pharma Co. Ltd. (Daiichi Sankyo Company Limited)
• Inventors: Tamura, Shigeki, Annoura, Hirokazu, Nakanishi, Kyoko
• Primary Examiner(s): BERNHARDT, EMILY B
• Application Number:
  US10/331,508
• Publication Number:
  US 20030236269A1
• Time in Patent Office: 735 Days
• Field of Search: 546/217, 546/232, 546/240, 541/327, 541/331, 541/317
• US Class Current: 514/327
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• 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: C07C 217/84 the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
• CPC Class Codes: C07C 271/28 to a carbon atom of a non-condensed six-membered aromatic ring
• CPC Class Codes: C07D 211/22 by oxygen atoms
• CPC Class Codes: C07D 211/52 having an aryl radical as the second substituent in position 4
• CPC Class Codes: C07D 295/088 to an acyclic saturated chain
• CPC Class Codes: C07D 295/13 to an acyclic saturated chain
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

A compound having the formula (I) or its salt, hydrate, hydrate salt or solvate:
wherein R¹ to R⁴ independently represent H, halogen, OH, alkoxy, optionally substituted alkyl, aryl, or aralkyl group, R⁵ represents H, optionally substituted alkyl, aryl, or aralkyl group, E¹ represents O, S, or —NR⁶, where R⁶ represents H, an optionally substituted alkyl, aryl, or aralkyl group, E² represents O, S, or —NR⁷, where R⁷ represents H, an optionally substituted alkyl, aryl, or aralkyl group, A represents CH, C(OH), or N, X represents H, halogen, alkoxy, or an optionally substituted alkyl group, and Q represents an optionally substituted phenyl group, phenoxy, phenylmethyl, or cycloalkyloxy group, where when E¹ represents O or S, E² does not represent O or S, which has an action of suppressing the cytotoxic Ca²⁺ overload and lipid peroxidation and effective for pharmaceutical preparation for the alleviation and treatment of symptoms due to ischemic diseases, etc.

Claims

1. A compound having the formula (I) or its salt, hydrate, or hydrate salt:

wherein R¹ to R⁴ each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group, an alkyl group, or an alkyl group substituted with a halogen atom,

R⁵ represents a hydrogen atom, an alkyl group, or an alkyl group substituted with a halogen atom,

E¹ represents an oxygen atom, a sulfur atom, or a group —

NR⁶, where, R⁶ represents a hydrogen atom, an alkyl group or an alkyl group substituted with a halogen atom,

E² represents an oxygen atom, a sulfur atom, or a group —

NR⁷, wherein R⁷ represents a hydrogen atom, an alkyl group or an alkyl group substituted with a halogen atom,

A represents CH or C(OH),

X represents a hydrogen atom, a halogen atom, an alkoxy group, an alkyl group, or an alkyl group substituted with a halogen atom, and

Q represents

a phenyl group,

a phenyl group substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C₁ to C₅ linear or branched alkoxy group, a C₁ to C₅ linear or branched alkyl group and a C₁ to C₅ linear or branched alkyl group substituted with a halogen atom,

a phenoxy group,

a phenoxy group substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C₁ to C₅ linear or branched alkoxy group, a C₁ to C₅ linear or branched alkyl group and a C₁ to C₅ linear or branched alkyl group substituted with a halogen atom,

a phenylmethyl group,

a phenylmethyl group substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C₁ to C₅ linear or branched alkoxy group, a C₁ to C₅ linear or branched alkyl group and a C₁ to C₅ linear or branched alkyl group substituted with a halogen atom,

a cycloalkyloxy group, or

a cycoalkyloxy group substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C₁ to C₅ linear or branched alkoxy group, a C₁ to C₅ linear or branched alkyl group and a C₁ to C₅ linear or branched alkyl group substituted with a halogen atom; and

,

wherein, when E¹ represents an oxygen atom or sulfur atom, E² does not represent an oxygen atom or a sulfur atom.

2. A compound or its salt, hydrate or hydrate salt as claimed in claim 1, wherein, in the formula (I), R¹ to R⁴ each independently represent a hydrogen atom, a halogen atom, an alkoxy group, an alkyl group, or an alkyl group substituted with a halogen atom, R⁵ represents a hydrogen atom, an alkyl group, or an alkyl group substituted with a halogen atom, E⁵ represents NH, and E² represents an oxygen atom.

3. A compound or its salt, hydrate or hydrate salt as claimed in claim 1, wherein, in the formula (I), R¹ to R⁴ each independently represent a hydrogen atom, a halogen atom, an alkoxy group, an alkyl group, or an alkyl group substituted with a halogen atom, R⁵ represents a hydrogen atom, an alkyl group, or an alkyl group substituted with a halogen atom, E¹ represents an oxygen atom, and E² represents NH.

4. A compound or its salt, hydrate or hydrate salt as claimed in claim 1, wherein, in the formula (I), one of R¹ to R⁴ is a hydrogen atom and the others each independently represent a halogen atom, an alkoxy group, an alkyl group, or an alkyl group substituted with a halogen atom.

5. A compound or its salt, hydrate or hydrate salt as claimed in claim 1, wherein the formula (I), Q represents a phenoxy group, a phenoxy group substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C₁ to C₅ linear or branched alkoxy group, a C₁ to C₅ linear or branched alkyl group, a C₁ to C₅ linear and branched alkyl group optionally substituted with a halogen atom, a phenylmethyl group, or a phenylmethyl group substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C₁ to C₅ linear or branched alkoxy group, a C₁ to C₅ linear or branched alkyl group and a C₁ to C₅ linear or branched alkyl group optionally substituted with a halogen atom.

6. A pharmaceutical composition containing, as an effective ingredient, a compound having the formula (I) or its pharmaceutically acceptable salt, hydrate or hydrate salt:

wherein R¹ to R⁴ each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group, an alkyl group, or an alkyl group substituted with a halogen atom,

R⁵ represents a hydrogen atom, an alkyl group, or an alkyl group substituted with a halogen atom,

E¹ represents an oxygen atom, a sulfur atom, or a group —

NR⁶, where, R⁶ represents a hydrogen atom, an alkyl group or an alkyl group substitute with a halogen atom,

E² represents an oxygen atom, a sulfur atom, or a group —

NR⁷, where R⁷ represents a hydrogen atom, an alkyl group or an alkyl group substituted with a halogen atom,

A represents CH or C(OH),

X represents a hydrogen atom, a halogen atom, an alkoxy group, an alkyl group, or an alkyl group substituted with a halogen atom, and

Q represents

a phenyl group,

a phenyl group substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C₁ to C₅ linear or branched alkoxy group, a C₁ to C₅ linear or branched alkyl group and a C₁ to C₅ linear or branched alkyl group substituted with a halogen atom,

a phenoxy group,

a phenoxy group substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C₁ to C₅ linear or branched alkoxy group, a C₁ to C₅ linear or branched alkyl group and a C₁ to C₅ linear or branched alkyl group substituted with a halogen atom,

a phenylmethyl group,

a phenylmethyl group substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C₁ to C₅ linear or branched alkoxy group, a C₁ to C₅ linear or branched alkyl group and a C₁ to C₅ linear or branched alkyl group substituted with a halogen atom,

a cycloalkyloxy group, or

a cycoalkyloxy group substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C₁ to C₅ linear or branched alkoxy group, a C₁ to C₅ linear or branched alkyl group and a C₁ to C₅ linear or branched alkyl group substituted with a halogen atom; and

,

wherein, when E¹ represents an oxygen atom or sulfur atom, E² does not represent an oxygen atom or a sulfur atom.

7. A pharmaceutical composition as claimed in claim 6, wherein, in the formula (I), R¹ to R⁴ each independently represent a hydrogen atom, a halogen atom, an alkoxy group, an alkyl group, or an alkyl group substituted with a halogen atom, R⁵ represents a hydrogen atom, an alkyl group, or an alkyl group substituted with a halogen atom, E¹ represents NH, and E² represents an oxygen atom.

8. A pharmaceutical composition as claimed in claim 6, wherein, in the formula (I), R¹ to R⁴ each independently represent a hydrogen atom, a halogen atom, an alkoxy group, an alkyl group, or an alkyl group substituted with a halogen atom, R⁵ represents a hydrogen atom, an alkyl group, or an alkyl group substituted with a halogen atom, E¹ represents an oxygen atom, and E² represents NH.

9. A pharmaceutical composition a claimed in claim 6, wherein, in the formula (I), one of R¹ to R⁴ is a hydrogen atom and the others each independently represent a halogen atom, an alkoxy group, an alkyl group, or an alkyl group substituted with a halogen atom.

10. A pharmaceutical composition as claimed in claim 6, wherein, in the formula (I), Q represents a phenoxy group, a phenoxy group substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C₁ to C₅ linear or branched alkoxy group, a C₁ to C₅ linear or branched alkyl group, a C₁ to C₅ linear or branched alkyl group substituted with a halogen atom, a phenylmethyl group, or a phenylmethyl group substitute with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C₁ to C₅ linear or branched alkoxy group, a C₁ to C₅ linear or branched alkyl group, a C₁ to C₅ linear or branched alkyl group substituted with a halogen atom.

12. A method for alleviating or treating symptoms due to ischemic diseases, comprising administering to a patient in need of such alleviation or treatment an effective amount of a pharmaceutical composition of claim 6.

13. A method as claimed in claim 12, wherein said pharmaceutical composition is orally or non-orally administered.

14. A method for alleviating or treating symptoms derived from seizures or epilepsy comprising administering to a patient in need of such alleviation or treatment an effective amount of a pharmaceutical composition of claim 6.

11. A process for producing a compound having the formula (I):

wherein R¹ to R⁴ each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group, an alkyl group, or an alkyl group substituted with a halogen atom,

R⁵ represents a hydrogen atom, an alkyl group, or an alkyl group substituted with a halogen atom,

E¹ represents an oxygen atom, a sulfur atom, or a group —

NR⁶, where, R⁶ represents a hydrogen atom, an alkyl group or an alkyl group substituted with a halogen atom,

E² represents an oxygen atom, a sulfur atom, or a group —

NR⁷, where R⁷ represents a hydrogen atom, an alkyl group or an alkyl group substituted with a halogen atom,

A represents CH or C(OH),

X represents a hydrogen atom, a halogen atom, an alkoxy group, an alkyl group, or an alkyl group substituted with a halogen atom, and

Q represents

a phenyl group,

a phenyl group substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C₁ to C₅ linear or branched alkoxy group, a C₁ to C₅ linear or branched alkyl group and a Cto C₅ linear or branched alkyl group substituted with a halogen atom,

a phenoxy group,

a phenoxy group substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C₁ to C₅ linear or branched alkoxy group, a C₁ to C₅ linear or branched alkyl group and a C₁ to C₅ linear or branched alkyl group substituted with a halogen atom,

a phenylmethyl group,

a phenylmethyl group substituted with a substituent select from the group consisting of a halogen atom, a hydroxy group, a C₁ to C₅ linear or branched alkoxy group, a C₁ to C₅ linear or branched alkyl group and a C₁ to C₅ linear or branched alkyl group substituted with a halogen atom,

a cycloalkyloxy group, or

a cycoalkyloxy group substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C₁ to C₅ linear or branched alkoxy group, a C₁ to C₅ linear or branched alkyl group and a C₁ to C₅ linear or branched alkyl group substituted with a halogen atom, and

wherein, when E¹ represents an oxygen atom or sulfur atom, E² does not represent an oxygen atom or a sulfur atom,

which process comprises reacting a compound having the formula (IV);

wherein X and Q are the same as defined above, or a compound having the formula (X);

wherein X and Q are the same as defined above,

with a compound having the formula (VIIa);

wherein R¹ to R⁴, E¹ and E² are the same as defined above and R⁸ represents an alkyl group, an alkyl group substituted with a halogen atom, a benzyl group, a p-methoxybenzyl group, a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, a tert-butoxycarbonyl group, an ethoxycarbonyl group, an acetyl group or a formyl group, or a compound having the formula (VIIb);

wherein R¹ to R⁴, R⁸, E¹ and E² are the same as defined above, L represents a group which can be easily exchanged with an amino group, or a compound having the formula (VIIc);

wherein R¹ to R⁴, R⁸, E¹ and E² are the same as defined above, and deprotecting the compound obtained by the above reaction, having the formula (VIII′

);

wherein R¹ to R⁴, R⁸, E¹, E², A, X and Q are the same as defined above, to give products having the above formula (I).