# US 5,708,005 A · Quinolines, their production and use

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- Number: US 5,708,005 A
- Document ID: US5708005A
- Status: Granted
- Kind: A
- Application number: 08/718,430
- Filed: 1996-12-10
- Granted: 1998-01-13
- Earliest claimed: 1995-06-27
- Assignees: Takeda Chemical Industries, Ltd.
- Inventors: Shigenori Ohkawa; Osamu Uchikawa; Masaomi Miyamoto
- Web page: https://patentgrep.com/patent/US5708005A

## CPC

- C07D 215/227: only one oxygen atom which is attached in position 2
- C07D 215/12: with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D 215/20: Oxygen atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

A compound of the formula: ##STR1## wherein R.sup.1 represents hydrogen or an optionally substituted hydrocarbon group; R.sup.2 represents an optionally substituted hydrocarbon group, an optionally substituted amino group or a substituted hydroxyl group; X represents an optionally halogenated lower alkylene group; Y represents a substituent; n represents an integer of 0 to 6; and m represents 0 or 1; or a salt thereof, a process for producing it, an intermediate for the production, and a pharmaceutical composition containing it are provided.

## Claims

### Claim 1

A di- or tri-cyclic condensed compound of the formula: ##STR14## wherein R.sup.1 represents hydrogen or an optionally substituted hydrocarbon group provided that R.sup.1 is not a cycloalkyl group;
R.sup.2 represents an optionally substituted hydrocarbon group, an optionally substituted amino group or a substituted hydroxy group;
X represents an optionally halogenated C.sub.2-6 alkylene group;
Y represents a substituent;
n represents an integer of 0 to 6; and
m represents 0 or 1;
or a salt thereof.

### Claim 2 (depends on 1)

A compound of claim 1, wherein
R.sup.1 is (i) hydrogen or (ii) a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl or C.sub.6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen, nitro, cyano, hydroxyl, C.sub.1-6 alkoxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, carboxyl, C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkylcarbamoyl, di-C.sub.1-6 alkylcarbamoyl, mono-C.sub.6-10 arylcarbamoyl, di-C.sub.6-10 arylcarbamoyl, C.sub.6-10 aryl and C.sub.6-10 aryloxy;
R.sup.2 is (i) a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl or C.sub.6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen, nitro, cyano, hydroxyl, C.sub.1-6 alkoxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, carboxyl, C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkylcarbamoyl, di-C.sub.1-6 alkylcarbamoyl, mono-C.sub.6-10 arylcarbamoyl, di-C.sub.6-10 arylcarbamoyl, C.sub.6-10 aryl and C.sub.6-10 aryloxy, (ii) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl and C.sub.6-14 aryl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen, nitro, cyano, hydroxyl, C.sub.1-6 alkoxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, carboxyl, C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkylcarbamoyl, di-C.sub.1-6 alkylcarbamoyl, mono-C.sub.6-10 arylcarbamoyl, di-C.sub.6-10 arylcarbamoyl, C.sub.6-10 aryl and C.sub.6-10 aryloxy, or (iii) a hydroxyl group substituted by a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl or C.sub.6-14 aryl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen, nitro, cyano, hydroxyl, C.sub.1-6 alkoxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, carboxyl, C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkylcarbamoyl, di-C.sub.1-6 alkylcarbamoyl, mono-C.sub.6-10 arylcarbamoyl, di-C.sub.6-10 arylcarbamoyl, C.sub.6-10 aryl and C.sub.6-10 aryloxy;
X is a straight or branched C.sub.2-6 alkylene group optionally substituted by 1 to 5 halogens; and
Y is (i) halogen, (ii) a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl or C.sub.6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen, nitro, cyano, hydroxyl, C.sub.1-6 alkoxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, carboxyl, C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkylcarbamoyl, di-C.sub.1-6 alkylcarbamoyl, mono-C.sub.6-10 arylcarbamoyl, di-C.sub.6-10 arylcarbamoyl, C.sub.6-10 aryl and C.sub.6-10 aryloxy; (iii) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl or C.sub.6-14 aryl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen, nitro, cyano, hydroxyl, C.sub.1-6 alkoxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, carboxyl, C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkylcarbamoyl, di-C.sub.1-6 alkylcarbamoyl, mono-C.sub.6-10 arylcarbamoyl, di-C.sub.6-10 arylcarbamoyl, C.sub.6-10 aryl and C.sub.6-10 aryloxy, (iv) a mercapto group which may be substituted by a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl or C.sub.6-14 aryl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen, nitro, cyano, hydroxyl, C.sub.1-6 alkoxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, carboxyl, C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkylcarbamoyl, di-C.sub.1-6 alkylcarbamoyl, mono-C.sub.6-10 arylcarbamoyl, di-C.sub.6-10 arylcarbamoyl, C.sub.6-10 aryl and C.sub.6-10 aryloxy, (v) hydroxy, (vi) C.sub.1-6 alkoxy, (vii) C.sub.1-6 acylamino or (viii) C.sub.1-3 alkylenedioxy.

### Claim 3 (depends on 2)

A compound of claim 2 wherein X is an ethylene group.

### Claim 4 (depends on 2)

A compound of claim 2 wherein R.sup.2 is a C.sub.1-6 alkyl or C.sub.3-6 cycloalkyl group optionally substituted by 1 to 5 halogens.

### Claim 5 (depends on 1)

A compound of claim 1 wherein the 6-position on the quinoline ring is substituted by a C.sub.1-6 alkoxy group.

### Claim 6 (depends on 2)

A compound of claim 2 wherein R.sup.1 is hydrogen or C.sub.1-6 alkyl, R.sup.2 is a C.sub.1-6 alkyl or C.sub.3-6 cycloalkyl group optionally substituted by 1 to 3 halogens, X is an ethylene group, Y is i) halogen, ii) a C.sub.6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen, nitro, cyano, hydroxyl, C.sub.1-6 alkoxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, carboxyl, C.sub.1-6 alkyl-carbonyl, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkylcarbamoyl, di-C.sub.1-6 alkylcarbamoyl, mono-C.sub.6-10 arylcarbamoyl, di-C.sub.6-10 arylcarbamoyl, C.sub.6-10 aryl and C.sub.6-10 aryloxy, iii) a C.sub.1-6 alkoxy group or iv) a C.sub.1-6 alkyl group, n is an integer of 1 to 3 and m is 0.

### Claim 7 (depends on 1)

A compound of claim 1 which is a compound of the formula: ##STR15## wherein R.sup.2 is a C.sub.1-6 alkyl or C.sub.3-6 cycloalkyl group optionally substituted by 1 to 3 halogens, Q is hydrogen, halogen, a C.sub.6-14 aryl group or a C.sub.1-6 alkoxy group and Q' is a C.sub.1-6 alkoxy group, or a salt thereof.

### Claim 8 (depends on 1)

A compound of claim 1 which is
N-›2-(2-chloro-6-methoxyquinolin-4-yl)ethyl!acetamide,
N-›2-(6-methoxyquinolin-4-yl)ethyl!acetamide,
N-›2-(2-chloro-6-methoxyquinolin-4-yl)ethyl!-2,2,2-trifluoroacetamide,
N-›2-(6-methoxyquinolin-4-yl)ethyl!-2,2,2-trifluoroacetamide,
N-›2-(2-chloro-6-methoxyquinolin-4-yl)ethyl!propionamide,
N-›2-(6-methoxyquinolin-4-yl)ethyl!propionamide, or a salt thereof.

### Claim 9 (depends on 1)

A process for producing the compound of claim 1, which comprises subjecting a compound of the formula: ##STR16## wherein all symbols are as defined in claim 1 or a salt thereof to acylation or reaction with an isocyanate, and if necessary, subjecting the resultant compound to oxidation and/or substituent-exchange reaction.

### Claim 10 (depends on 1)

A pharmaceutical composition which comprises a compound of claim 1, if necessary together with a pharmaceutically acceptable carrier.

### Claim 11 (depends on 10)

A composition of claim 10 which has a binding affinity for melatonin receptor.

### Claim 12 (depends on 11)

A composition of claim 11 which is a regulating agent of circadian rhythm.

### Claim 13 (depends on 11)

A composition of claim 11 which is a regulating agent of sleep-awake rhythm.

### Claim 14 (depends on 11)

A composition of claim 11 which is a regulating agent of time zone change syndrome.

### Claim 15 (depends on 10)

A composition of claim 10 which is a therapeutic agent of sleep disorders.

### Claim 16 (depends on 1)

Method for treating disease related to the action of melatonin in mammals which comprises administering to a subject in need a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 17 (depends on 1)

A method for manufacturing a pharmaceutical composition for treating or preventing diseases relating to the action of melatonin in mammals, comprising:
selecting a compound of claim 1; and
admixing said compound with a pharmaceutically acceptable carrier.