Claims
- 1. A benzimidazole derivative represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein: R′ represents a group of the formula -(alk)q-R1, in which (alk) represents alkyl, alkenyl, or alkynyl, q is 0 or 1, and R1 represents a group of the formula —CO2R2, wherein R2 represents hydroxy-alkyl, alkoxy-alkyl, or thioalkoxy-alkyl; and R″ represents a group of the formula in which formula “o” is 0 or 1, “n” is 0, 1, or 2, X represents N or CR, Y represents O, NR11, or CHR11, wherein R11 represents hydrogen, alkyl, hydroxyalkyl, alkoxy-alkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p-“Heterocycle”, -(alkyl)p-CO2-“Heterocycle”, or -(alkyl-CO2)p-(alkyl)t-COR5, wherein p, s, and t independently of each another is 0 or 1, “Heterocycle” represents a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxy-alkyl, alkoxy—alkyl, carboxyl, and acyl, R5 represents hydroxy, alkoxy, hydroxy-alkoxy, alkoxy—alkoxy, thioalkoxy-alkoxy, aryl, or aralkyl, or a group of the formula —NR6R7 or -O-alkyl-NR6R7, in which formulas R6 and R7 independently of each another represent hydrogen, alkyl, cycloalkyl, or a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of alkyl and acyl, or R6 and R7 together with the nitrogen to which they are attached form a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of alkyl and acyl, and R14 and R15 independently of each another represent hydrogen, alkyl, hydroxy-alkyl, alkoxy-alkyl, carboxyl, or acyl.
- 2. The benzimidazole derivative of claim 1, wherein R1 represents a group of the formula —CO2—CH2—CH(OH), —CO2(CH2)2OCH3, —CO2(CH2)2SCH3, or —CO2(CH2)2SC2H5.
- 3. The benzimidazole derivative of claim 1, wherein R″ represents 4-(1-methyl-5-tetrazolyl)-methyl-1-piperazinyl; 4-(2-oxazolidinone-5-yl-methyl-1-piperazinyl; 4-(5-methyloxadiazol-3-yl)-methyl-1-piperazinyl; 4-(3,5-dimethylisoxazol-4-yl)-methyl-1--piperazinyl; 4-(2-oxo-tetrahydrofuran-3-yl)-1-piperazinyl; or 4-(2-chloro-5-thienyl)-methyl-1-piperazinyl.
- 4. The benzimidazole derivative of claim 3, which is2-Methoxyethyl 1-(3-(4-(1-methyl-5-tetrazolyl)methyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Methoxyethyl 1-(3-(4-(2-oxazolidinone-5-yl)-methyl)1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Methoxyethyl 1-(3-(4-(5-methyloxadiazol-3-yl)-methyl) 1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Methoxyethyl 1-(3-(4-(3,5-dimethylisoxazol-4-yl)methyl) 1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Methoxyethyl 1-(3-(4-(2-oxo-tetrahydrofuran-3-yl)-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; or 2-Methoxyethyl 1-(3-(4-(2-chloro-5-thienyl)-methyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; or a pharmaceutically acceptable salt thereof.
- 5. The compound according to claim 1, wherein R″ represents 4-methoxycarbonyl-methyl-3,5-dimethyl-1-piperazinyl; 4-ethoxycarbonyl-methyl-3,5-dimethyl-1-piperazinyl; 4-methyl-3,5-dimethyl-1-(piperazinyl; 4-ethyl-3,5-dimethyl-1-piperazinyl; or 3,5-dimethyl-1-piperazinyl.
- 6. The compound according to claim 5, which compound is2-Methoxyethyl 1-(3-(4-ethoxycarbonylmethyl-3,5-dimethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Methoxyethyl 1-(3-(4-ethyl-3,5-dimethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; or 2-Methoxyethyl 1-(3-(3,5-dimethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; or a pharmaceutically acceptable salt thereof.
- 7. The benzimidazole derivative of claim 1, wherein R″ represents a group of the formula in which formula o is 0 or 1, n is 0, 1 or 2, X represents N or CH, and Y represents NR11 or CHR11, wherein R11 represents hydrogen, alkyl, hydroxy-alkyl, carboxy, acyl, or a group of the formula -(alkyl)p—CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)t-COR5 or -(alkyl)t-R5, wherein p and t independently of each another is 0 or 1, and R5 represents hydroxy, alkoxy, NH2, NH(alkyl) or N(alkyl)2.
- 8. The benzimidazole derivative of claim 7, in which R″ represents 4-(methoxy-carbonyl)-1-piperazinylmethyl; 4-(ethoxy-carbonyl)-1-piperazinylmethyl; 4-(methoxy-carbonyl-methyl)-1-piperazinyl; 4-(ethoxy-carbonyl-methyl)-1-piperazinyl; 4-(methoxy-carbonyl-methyl)-1-piperazinylmethyl; 4-(ethoxy-carbonyl-methyl)-1-piperazinylmethyl; 1-piperazinyl; 1-piperazinyl-methyl; 4-acetyl-1-piperazinyl; 4-methyl-1-piperazinyl; 4-ethyl-1-piperazinyl; 1-methyl-4-piperidinyl; 1-acetyl-4-piperidinyl; 1-methyl-4-piperidyl; 1-acetyl-4-piperidyl; 4-tert-butoxycarbonylmethyl-1-piperazinyl; 4-isopropoxycarbonylmethyl-1-piperazinyl; 4-carboxymethyl-1-piperazinyl; 4-benzyl-1-piperazinyl; 4-cyanomethyl-1-piperazinyl; 4-benzyloxy-ethyl-1-piperazinyl; 4-ethyl-1-homopiperazinyl; 4-(2-hydroxy-ethyl)-1-piperazinyl; 4-carbamoylmethyl-1-piperazinyl; 4-dimethylcarbamoylmethyl-1-piperazinyl; or 4-diethylcarbamoylmethyl-1-piperazinyl.
- 9. The compound according to claim 8, which compound is2-Methoxyethyl 1-(3-(4-(ethoxycarbonyl)-1-piperazinylmethyl)-phenyl)-benzimidazole-5-carboxylate; 2-Methoxyethyl 1-(3-(4-(ethoxycarbonylmethyl)-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Methoxyethyl 1-(3-(4-carboxymethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Methoxyethyl 1-(3-(4-methyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Methoxyethyl 1-(3-(4-acetyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Methoxyethyl 1-(3-(1-methyl-4-piperidyl) phenyl) benzimidazole-5-carboxylate; 2-Methoxyethyl 1-(3-(1-acetyl-4-piperidyl)-phenyl)-benzimidazole-5-carboxylate; 2-Methoxyethyl 1-(3-(4-t-butoxycarbonylmethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Methoxyethyl 1-(3-(4-i-propoxycarbonylmethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-(Methylthio)-ethyl 1-(3-(4-methyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Methoxyethyl 1-(3-(4-benzyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Methoxyethyl 1-(3-(4-cyanomethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Methoxyethyl 1-(3-(4-benzyloxyethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Methoxyethyl 1-(3-(4-ethyl-1-homopiperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Methoxyethyl 1-(3-(4-ethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Hydroxyethyl 1-(3-(4-(2-hydroxyethyl)-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Methoxyethyl 1-(3-(1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Hydroxyethyl 1-(3-(4-methyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Hydroxyethyl 1-(3-(4-methoxycarbonylmethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Hydroxyethyl 1-(3-(4-ethoxycarbonylmethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Methoxyethyl 1-(3-(4-diethylcarbamoylmethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Methoxyethyl 1-(3-(4-methoxycarbonylmethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Methoxyethyl 1-(3-(4-carbamoylmethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Hydroxyethyl 1-(3-(4-carbamoylmethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; 2-Hydroxyethyl 1-(3-(4-diethylcarbamoylmethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; or 2-Hydroxyethyl 1-(3-(4-carboxymethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; or a pharmaceutically acceptable salt thereof.
- 10. A pharmaceutical composition containing a therapeutically effective amount of a benzimidazole derivative according to claim 1, or a pharmaceutically acceptable addition salt thereof, together with at least one pharmaceutically acceptable carrier, excipient, or diluent.
- 11. A method for treatment or alleviation of a disease or a disorder or a condition of a living animal body, which disorder, disease, or condition is responsive to modulation of the GABA receptor complex and is selected from the group consisting of pain and muscle spasms, which method comprises the step of administering to such a living animal body in need thereof a therapeutically effective amount of a benzimidazole derivative according to claim 1.
- 12. The method according to claim 11, for the induction or maintenance of anaesthesia or pre-anaesthesia, muscle relaxation, or sedation, or for the treatment or alleviation of fever cramps or status epilepticus.
Priority Claims (1)
Number |
Date |
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Kind |
1999 00888 |
Jun 1999 |
DK |
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Parent Case Info
This is a continuation of PCT/DK00/00333, filed Jun. 22, 2000.
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Continuations (1)
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Number |
Date |
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Parent |
PCT/DK00/00333 |
Jun 2000 |
US |
Child |
10/012490 |
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US |