Indole derivatives, salts thereof, and congestive heart failure therapeutic agents comprising the same

• US 5,510,366 A
• Filed: 10/28/1994
• Issued: 04/23/1996
• Est. Priority Date: 10/29/1993
• Status: Expired due to Fees

• Current Assignee: KOWA Company Limited
• Original Assignee: KOWA Company Limited
• Inventors: Yamaguchi, Takashi, Ohgiya, Tadaaki, Shimizu, Noboru, Fujii, Mikio, Kyotani, Yoshinori, Uchida, Yasumi, Ohta, Tomio, Okuno, Yukihiro, Shibuya, Kimiyuki, Takahashi, Yoshio, Sato, Seiichi, Onogi, Kazuhiro, Oda, Toshiaki, Toma, Tsutomu, Kawamine, Katsumi, Shigyo, Hiromichi
• Primary Examiner(s): Haley, Jacqueline
• Application Number:
  US08/330,670
• Time in Patent Office: 543 Days
• Field of Search: 514/411, 548/431, 548/430
• US Class Current: 514/411
• CPC Class Codes: C07D 491/04 Ortho-condensed systems

Abstract

An indole derivative represented by formula (1), ##STR1## wherein A is a group ##STR2## wherein R¹⁰ is hydrogen or lower alkyl, dotted lines may optionally be present, and R¹ -R⁹ represents various substitutional groups. The compound (1) exhibits a positive inotropic action on cardiac muscle, an anti-arrhythmic action, and a vasodilation action without increasing the heart rate. A heart affection therapeutic agent comprising this compound as an effective component is extremely effective for treating heart failures and arrhythmia.

Claims

1. An indole derivative represented by the following formula (1), ##STR17## wherein at least one of R¹, R², R³, or R⁴ is a lower alkyl or alkenyl group which may have substituents selected from halogen atoms, hydroxy group, alkylsulfonyloxy groups, alkylsilyloxy groups, azido group, cyano group, amino group, alkylamino groups having 1-8 carbon atoms, dialkylamino groups having 2-16 carbon atoms, phenyl alkylamino groups having 7-12 carbon atoms, alkanoylamino groups having 1-6 carbon atoms, alkoxycarbonylamino groups having 2-10 carbon atoms, pyrrole, pyrrolidine, imidazole, imidazoline, oxazole, oxazoline, thiazole, thiazoline, piperidine, piperazine, and morpholine (wherein these cyclic amino groups may further contain substituents selected from alkyl or alkenyl groups having 1-8 carbon atoms, phenyl alkyl groups having 7-15 carbon atoms, alkanoyl groups having 1-6 carbon atoms, benzoyl group, alkoxybenzoyl groups having 1-8 carbon atoms, and di(C_1-8)alkoxybenzoyl groups), and others represent a hydrogen atom or a lower alkyl group;

R⁵ and R⁶ individually represent a hydrogen atom, a halogen atom, a lower alkyl or acyl group, or a lower alkyl group which may have substituents selected from hydroxy group, halogens, cyano group, alkoxycarbonyl groups, and carboxy groups;

R⁷ may either represent a hydrogen atom or a benzyl group, or form a double bond with A; and

R⁸ and R⁹ individually represent a hydrogen atom, a halogen atom, a hydroxy group, or a lower alkyl group which may have substituents selected from hydroxy group, halogens, cyano group, alkoxycarbonyl groups, and carboxy groups, or R⁸ and R⁹ may together represent an oxygen atom, an alkenyl group, or either one of R⁸ and R⁹ may form a double bond with A; and

A represents a group ##STR18## wherein R¹⁰ is a hydrogen atom or a group; and

the dotted line indicates that the bond may be a double bond;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein at least one of R¹, R², R³, or R⁴ is an alkyl or alkenyl group having 1-8 carbon atoms which may have substituents selected from halogen atoms, hydroxy group, alkylsulfonyloxy groups having 1-8 carbon atoms, alkylsilyloxy groups having 1-8 carbon atoms, azido group, cyano group, amino group, alkylamino groups having 1-8 carbon atoms, dialkylamino groups having 2-16 carbon atoms, phenyl alkylamino groups having 7-12 carbon atoms, alkanoylamino groups having 1-6 carbon atoms, alkoxycarbonylamino groups having 2-10 carbon atoms, pyrrole, pyrrolidine, imidazole, imidazoline, oxazole, oxazoline, thiazole, thiazoline, piperidine, piperazine, and morpholine (wherein these cyclic amino groups may further contain substituents selected from alkyl or alkenyl groups having 1-8 carbon atoms, phenyl alkyl groups having 7-15 carbon atoms, alkanoyl groups having 1-6 carbon atoms, benzoyl group, alkoxybenzoyl groups having 1-8 carbon atoms, and di(C_1-8)alkoxybenzoyl groups), and others represent a hydrogen atom or an alkyl group having 1-8 carbon atoms;

R⁵ and R⁶ individually represent a hydrogen atom, a halogen atom, an alkyl group having 1-8 carbon atoms, or an alkanoyl group having 1-6 carbon atoms;

R⁷ is a hydrogen atom or a benzyl group;

R⁸ and R⁹ are a hydrogen atom, a halogen atom, a hydroxy group, or an alkyl group having 1-8 carbon atoms; and

A is a group ##STR19## wherein R¹⁰ is a hydrogen atom or an alkyl group having 1-8 carbon atoms.

3. The compound of claim 1, wherein at least one of R¹, R², R³, or R⁴ is an alkyl group having 1-8 carbon atoms which may have substituents selected from halogen atoms, hydroxy group, alkylsulfonyloxy groups having 1-8 carbon atoms, alkylsilyloxy groups having 1-8 carbon atoms, azido group, cyano group, amino group, alkylamino groups having 1-8 carbon atoms, dialkylamino groups having 2-16 carbon atoms, phenyl alkylamino groups having 7-12 carbon atoms, alkanoylamino groups having 1-6 carbon atoms, alkoxycarbonylamino groups having 2-10 carbon atoms, pyrrole, pyrrolidine, imidazole, imidazoline, oxazole, oxazoline, thiazole, thiazoline, piperidine, piperazine, and morpholine (wherein cyclic amino groups may further contain substituents selected from alkyl or alkenyl groups having 1-8 carbon atoms, phenyl alkyl groups having 7-15 carbon atoms, alkanoyl groups having 1-6 carbon atoms, benzoyl group, alkoxybenzoyl groups having 1-8 carbon atoms, and di(C_1-8)alkoxybenzoyl groups), and others represent a hydrogen atom or an alkyl group having 1-8 carbon atoms;

R⁵ and R⁶ individually represent a hydrogen atom, a halogen atom, an alkyl group having 1-8 carbon atoms, or an alkanoyl group having 1-6 carbon atoms;

Rⁿ is a hydrogen atom or a benzyl group;

R⁸ and R⁹ are a hydrogen atom, a halogen atom, a hydroxy group, or an alkyl group having 1-8 carbon atoms; and

A is a group ##STR20##

4. A pharmaceutical composition, comprising:

(i) an effective amount of the indole derivative of formula (1) ##STR21## wherein at least one of R¹, R², R³, or R⁴ is a lower alkyl or alkenyl group which may have substituents selected from halogen atoms, hydroxy group, alkylsulfonyloxy groups, alkylsilyloxy groups, azido group, cyano group, amino group, alkylamino groups having 1-8 carbon atoms, dialkylamino groups having 2-16 carbon atoms, phenyl alkylamino groups having 7-12 carbon atoms, alkanoylamino groups having 1-6 carbon atoms, alkoxycarbonylamino groups having 2-10 carbon atoms, pyrrole, pyrrolidine, imidazole, imidazoline, oxazole, oxazoline, thiazole, thiazoline, piperidine, piperazine, and morpholine (wherein these cyclic amino groups may further contain substituents selected from alkyl or alkenyl groups having 1-8 carbon atoms, phenyl alkyl groups having 7-15 carbon atoms, alkanoyl groups having 1-6 carbon atoms, benzoyl group, alkoxybenzoyl groups having 1-8 carbon atoms, and di(C_1-8)alkoxybenzoyl groups), and others represent a hydrogen atom or an alkyl group;

R⁵ and R⁶ individually represent a hydrogen atom, a halogen atom, a lower alkyl or acyl group, or a lower alkyl group which may have substituents selected from hydroxy group, halogens, cyano group, alkoxycarbonyl groups, and carboxy groups;

R⁷ may either represent a hydrogen atom or a benzyl group, or form a double bond with A; and

R⁸ and R⁹ individually represent a hydrogen atom, a halogen atom, a hydroxy group, or a lower alkyl group which may have substituents selected from hydroxy group, halogens, cyano group, alkoxycarbonyl groups, and carboxy groups, or R⁸ and R⁹ may together represent an oxygen atom, an alkenyl group, or either one of R⁸ and R⁹ may form a double bond with A; and

A represents a group ##STR22## wherein R¹⁰ is a hydrogen atom or a lower alkyl group; and

the dotted line indicates that the bond may be a double bond;

or a pharmaceutically acceptable salt thereof; and

(ii) a pharmaceutically acceptable carrier.

5. The composition of claim 4, wherein at least one of R¹, R², R³, or R⁴ is an alkyl or alkenyl group having 1-8 carbon atoms which may have substituents selected from halogen atoms, hydroxy group, alkylsulfonyloxy groups having 1-8 carbon atoms, alkylsilyloxy groups having 1-8 carbon atoms, azido group, cyano group, amino group, alkylamino groups having 1-8 carbon atoms, dialkylamino groups having 2-16 carbon atoms, phenyl alkylamino groups having 7-12 carbon atoms, alkanoylamino groups having 1-6 carbon atoms, alkoxycarbonylamino groups having 2-10 carbon atoms, pyrrole, pyrrolidine, imidazole, imidazoline, oxazole, oxazoline, thiazole, thiazoline, piperidine, piperazine, and morpholine (wherein these cyclic amino groups may further contain substituents selected from alkyl or alkenyl groups having 1-8 carbon atoms, phenyl alkyl groups having 7-15 carbon atoms, alkanoyl groups having 1-6 carbon atoms, benzoyl group, alkoxybenzoyl groups having 1-8 carbon atoms, and di(C_1-8)alkoxybenzoyl groups), and others represent a hydrogen atom or an alkyl group having 1-8 carbon atoms;

R⁵ and R⁶ individually represent a hydrogen atom, a halogen atom, an alkyl group having 1-8 carbon atoms, or an alkanoyl group having 1-6 carbon atoms;

R⁷ is a hydrogen atom or a benzyl group;

R⁸ and R⁹ are a hydrogen atom, a halogen atom, a hydroxy group, or an alkyl group having 1-8 carbon atoms; and

A is a group ##STR23## wherein R¹⁰ is a hydrogen atom or an alkyl group having 1-8 carbon atoms.

6. The composition of claim 4, wherein at least one of R¹, R², R³, or R⁴ is an alkyl group having 1-8 carbon atoms which may have substituents selected from halogen atoms, hydroxy group, alkylsulfonyloxy groups having 1-8 carbon atoms, alkylsilyloxy groups having 1-8 carbon atoms, azido group, cyano group, amino group, alkylamino groups having 1-8 carbon atoms, dialkylamino groups having 2-16 carbon atoms, phenyl alkylamino groups having 7-12 carbon atoms, alkanoylamino groups having 1-6 carbon atoms, alkoxycarbonylamino groups having 2-10 carbon atoms, pyrrole, pyrrolidine, imidazole, imidazoline, oxazole, oxazoline, thiazole, thiazoline, piperidine, piperazine, and morpholine (wherein these cyclic amino groups may further contain substitutents selected from alkyl or alkenyl groups having 1-8 carbon atoms, phenyl alkyl groups having 7-15 carbon atoms, alkanoyl groups having 1-6 carbon atoms, benzoyl group, alkoxybenzoyl groups having 1-8 carbon atoms, and di(C_1-8)alkoxybenzoyl groups), and others represent a hydrogen atom or an alkyl group having 1-8 carbon atoms;

R⁵ and R⁶ individually represent a hydrogen atom, a halogen atom, an alkyl group having 1-8 carbon atoms, or an alkanoyl group having 1-6 carbon atoms;

R⁷ is a hydrogen atom or a benzyl group;

R⁸ and R⁹ are a hydrogen atom, a halogen atom, a hydroxy group, or an alkyl group having 1-8 carbon atoms; and

and A is a group ##STR24##

7. A method of treating a patient suffering from congestive heart failure, which comprises administering an effective amount of an indole derivative of formula (1) to said patient ##STR25## wherein at least one of R¹, R², R³, or R⁴ is a lower alkyl or alkenyl group which may have substituents selected from halogen atoms, hydroxy group, alkylsulfonyloxy groups, alkylsilyloxy groups, azido group, cyano group, amino group, alkylamino groups having 1-8 carbon atoms, dialkylamino groups having 2-16 carbon atoms, phenyl alkylamino groups having 7-12 carbon atoms, alkanoylamino groups having 1-6 carbon atoms, alkoxycarbonylamino groups having 2-10 carbon atoms, pyrrole, pyrrolidine, imidazole, imidazoline, oxazole, oxazoline, thiazole, thiazoline, piperidine, piperazine, and morpholine (wherein these cyclic amino groups may further contain substituents selected from alkyl or alkenyl groups having 1-8 carbon atoms, phenyl alkyl groups having 7-15 carbon atoms, alkanoyl groups having 1-6 carbon atoms, benzoyl group, alkoxybenzoyl groups having 1-8 carbon atoms, and di(C_1-8)alkoxybenzoyl groups), and others represent a hydrogen atom or a lower alkyl group;

R⁵ and R⁶ individually represent a hydrogen atom, a halogen atom, a lower alkyl or acyl group, or a lower alkyl group which may have substituents selected from hydroxy group, halogen, cyano group, alkoxycarbonyl groups, and carboxy groups;

R⁷ may either represent a hydrogen atom or a benzyl group, or form a double bond with A; and

R⁸ and R⁹ individually represent a hydrogen atom, a halogen atom, a hydroxy group, or a lower alkyl group which may have substituents selected from hydroxy group, halogens, cyano group, alkoxycarbonyl groups, and carboxy groups, or R⁸ and R⁹ may together represent an oxygen atom, an alkenyl group, or either one of R⁸ and R⁹ may form a double bond with A; and

A represents a group ##STR26## wherein R¹⁰ is a hydrogen atom or a lower alkyl group; and

the dotted line indicates that the bond may be a double bond;

or a pharmaceutically acceptable salt thereof.

8. The method of claim 7, wherein at least one of R¹, R², R³, or R⁴ is an alkyl or alkenyl group having 1-8 carbon atoms which may have substituents selected from halogen atoms, hydroxy group, alkylsulfonyloxy groups having 1-8 carbon atoms, alkylsilyloxy groups having 1-8 carbon atoms, azido group, cyano group, amino group, alkylamino groups having 1-8 carbon atoms, dialkylamino groups having 2-16 carbon atoms, phenyl alkylamino groups having 7-12 carbon atoms, alkanoylamino groups having 1-6 carbon atoms, alkoxycarbonylamino groups having 2-10 carbon atoms, pyrrole, pyrrolidine, imidazole, imidazoline, oxazole, oxazoline, thiazole, thiazoline, piperidine, piperazine, and morpholine (wherein these cyclic amino groups may further contain substituents selected from alkyl or alkenyl groups having 1-8 carbon atoms, phenyl alkyl groups having 7-15 carbon atoms, alkanoyl groups having 1-6 carbon atoms, benzoyl group, alkoxybenzoyl groups having 1-8 carbon atoms, and di(C_1-8)alkoxybenzoyl groups), and others represent a hydrogen atom or an alkyl group having 1-8 carbon atoms;

R⁵ and R⁶ individually represent a hydrogen atom, a halogen atom, an alkyl group having 1-8 carbon atoms, or an alkanoyl group having 1-6 carbon atoms;

R⁷ is a hydrogen atom or a benzyl group;

R⁸ and R⁹ are a hydrogen atom, a halogen atom, a hydroxy group, or an alkyl group having 1-8 carbon atoms; and

A is a group ##STR27## wherein R¹⁰ is a hydrogen atom or an alkyl group having 1-8 carbon atoms.

9. The method of claim 7, wherein at least one of R¹, R², R³, or R⁴ is an alkyl group having 1-8 carbon atoms which may have substituents selected from halogen atoms, hydroxy group, alkylsulfonyloxy groups having 1-8 carbon atoms, alkylsilyloxy groups having 1-8 carbon atoms, azido group, cyano group, amino group, alkylamino groups having 1-8 carbon atoms, dialkylamino groups having 2-16 carbon atoms, phenyl alkylamino groups having 7-12 carbon atoms, alkanoylamino groups having 1-6 carbon atoms, alkoxycarbonylamino groups having 2-10 carbon atoms, pyrrole, pyrrolidine, imidazole, imidazoline, oxazole, oxazoline, thiazole, thiazoline, piperidine, piperazine, and morpholine (wherein these cyclic amino groups may further contain substituents selected from alkyl or alkenyl groups having 1-8 carbon atoms, phenyl alkyl groups having 7-15 carbon atoms, alkanoyl groups having 1-6 carbon atoms, benzoyl group, alkoxybenzoyl groups having 1-8 carbon atoms, and di(C_1-8)alkoxybenzoyl groups), and others represent a hydrogen atom or an alkyl group having 1-8 carbon atoms;

R⁵ and R⁶ individually represent a hydrogen atom, a halogen atom, an alkyl group having 1-8 carbon atoms, or an alkanoyl group having 1-6 carbon atoms;

R⁷ is a hydrogen atom or a benzyl group;

R⁸ and R⁹ are a hydrogen atom, a halogen atom, a hydroxy group, or an alkyl group having 1-8 carbon atoms; and

A is a group ##STR28##