# US 6,723,725 B1 · Indole derivatives

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- Number: US 6,723,725 B1
- Document ID: US6723725B1
- Status: Granted
- Kind: B1
- Application number: 10/031,566
- Filed: 2002-01-22
- Granted: 2004-04-20
- Earliest claimed: 1999-07-22
- Assignees: Merck Patent GmbH
- Inventors: Henning Böttcher; Joachim März; Hartmut Greiner; Jürgen Harting; Gerd Bartoszyk; Christoph Seyfried; Christoph van Amsterdam
- Web page: https://patentgrep.com/patent/US6723725B1

## CPC

- C07D 209/12: Radicals substituted by oxygen atoms
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/24: Antidepressants
- 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
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Indole derivatives of formula I, their salts and solvates, have valuable pharmacological properties together with good tolerability, as they have actions on the central nervous system: wherein R1 and R3 are as defined herein. The compounds have a strong affinity for 5-HT2A receptors, and furthermore exhibit 5HT2A receptor-antagonistic properties. These are therefore suitable both in veterinary and in human medicine for the treatment of functional disorders of the central nervous system and also of inflammation.

## Claims

### Claim 1

A compound of formula I
in which
R1 is Het1, or a phenyl radical which is unsubstituted or substituted by R2 and/or R4,
R2, R4,
R5, R6 in each case independently of one another are Hal, A, OA, OH, CN or acyl,
R3 is Het2 or a phenyl radical which is unsubstituted or substituted by R5 and/or R6,
Het1 is a mono- or binuclear unsaturated heterocyclic ring, which contains one, two or three identical or different heteroatoms, and is unsubstituted or mono- or disubstituted by Hal, A, OA or OH,
Het2 is an unsaturated heterocyclic ring which contains one or two identical or different heteroatoms, and is unsubstituted or mono- or disubstituted by Hal, A, or OA
A is alkyl having 1-6 C atoms, and
Hal is F, Cl, Br or I,
or a physiologically acceptable salt or solvate thereof.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein the acyl contains 1-6 C atoms.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein the acyl is formyl, acetyl, propionyl, butyryl, or trifluoroacetyl.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein the heteroatoms are, independently of each other, oxygen, nitrogen or sulfur.

### Claim 5 (depends on 1)

A compound according to claim 1, wherein Het1 is 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4-H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, or 3-, 4-, 5-, 6-, 7- or 8- cinnolinyl, or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl.

### Claim 6 (depends on 1)

A compound according to claim 1, wherein Het2 is 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, or 1-, 2-, 4- or 5-benzimidazolyl.

### Claim 7 (depends on 1)

A compound according to claim 1, wherein Het1 is an unsaturated heterocyclic ring that is unsubstituted or mono- or disubstituted by Hal or A and contains one or two identical or different heteroatoms.

### Claim 8 (depends on 1)

A compound according to claim 1, wherein Het2 is an unsaturated heterocyclic ring that is mono- or disubstituted by Hal or A and contains one heteroatom.

### Claim 9 (depends on 1)

A compound according to claim 1, wherein said compound is selected from:
[3-(4-chlorobenzoyl)-1H-indol-4-yl]-4-phenethylpiperazin-1-ylmethanone, hydrochloride hydrate,
[3-(4-chlorobenzoyl)-1H-indol-4-yl]-[4-(4-fluorophenethyl)piperazin-1-yl]methanone,
[3-(4-chlorobenzoyl)-1H-indol-4-yl]-[4-(thiophen-2-yl)piperazin-1-yl]methanone,
[3-(4-chlorobenzoyl)-1H-indol-4-yl]-[4-(5-chlorothiophen-2-yl)piperazin-1-yl]methanone,
[3-(4-chlorobenzoyl)-1H-indol-4-yl]-[4-(thiophen-3-yl)piperazin-1-yl]methanone,
[3-(4-chlorobenzoyl)-1H-indol-4-yl]-[4-(2,5-dichlorothiophen-3-yl)piperazin-1-yl]methanone,
[3-(4-chlorobenzoyl)-1H-indol-4-yl]-[4-(furan-2-yl)piperazin-1-yl]methanone,
[3-(4-fluorobenzoyl)-1H-indol-4-yl]-(4-phenethylpiperazin-1-yl)methanone, hydrochloride,
[3-(4-fluorobenzoyl)-1H-indol-4-yl]-[4-(4-fluorophenethyl)piperazin-1-yl]methanone,
[3-(4-chlorobenzoyl)-1H-indol-4-yl]-[4-(4-fluorophenethyl)piperazin-1-yl]methanone, hydrochloride, [3-(4-fluorobenzoyl)-1H-indol-4-yl]-[4-(thiophen-2-yl)piperazin-1-yl]methanone,
[3-(4-fluorobenzoyl)-1H-indol-4-yl]-[4-(5-chlorothiophen-2-yl)piperazin-1-yl]methanone,
[3-(4-fluorobenzoyl)-1H-indol-4-yl]-[4-(thiophen-3-yl)piperazin-1-yl]methanone,
[3-(4-fluorobenzoyl)-1H-indol-4-yl]-[4-(2,5-dichlorothiophen-3-yl)piperazin-1-yl]methanone,
[3-(4-fluorobenzoyl)-1H-indol-4-yl]-[4-(furan-2-yl)piperazin-1-yl]methanone,
[3-(4-fluorobenzoyl)-1H-indol-5-yl]-(4-phenethylpiperazin-1-yl)methanone, hydrochloride,
[3-(4-chlorobenzoyl)-1H-indol-5-yl]-(4-phenethylpiperazin-1-yl)methanone,
[3-(4-fluorobenzoyl)-1H-indol-5-yl]-[4-(4-fluorophenethyl)piperazin-1-yl]methanone, hydrochloride,
[3-(4-fluorobenzoyl)-1H-indol-5-yl]-[4-(thiophen-2-yl)piperazin-1-yl]methanone,
[3-(4-fluorobenzoyl)-1H-indol-5-yl]-[4-(5-chlorothiophen-2-yl)piperazin-1-yl]methanone,
[3-(4-fluorobenzoyl)-1H-indol-5-yl]-[4-(thiophen-3-yl)piperazin-1-yl]methanone,
[3-(4-fluorobenzoyl)-1H-indol-5-yl]-[4-(2,5-dichlorothiophen-3-yl)piperazin-1-yl]methanone,
[3-(4-fluorobenzoyl-2-yl)-1H-indol-5-yl]-[4-(furan-2-yl)piperazin-1-yl]methanone,
[3-(furan-2-yl)-1H-indol-4-yl]-(4-phenethylpiperazin-1-yl)methanone,
[3-(furan-2-yl)-1H-indol-4-yl]-[4-(4-fluorophenethyl)piperazin-1-yl]methanone,
[3-(furan-2-yl)-1H-indol-4-yl]-[4-(thiophen-2-yl)piperazin-1-yl]methanone,
[3-(furan-2-yl)-1H-indol-4-yl]-[4-(5-chlorothiophen-2-yl)piperazin-1-yl]methanone,
[3-(furan-2-yl)-1H-indol-4-yl]-[4-(thiophen-3-yl)piperazin-1-yl]methanone,
[3-(furan-2-yl)-1H-indol-4-yl]-[4-(2,5-dichlorothiophen-3-yl)piperazin-1-yl]methanone,
[3-(furan-2-yl)-1H-indol-4-yl]-[4-(furan-2-yl)piperazin-1-yl]methanone,
[3-(furan-2-yl)-1H-indol-5-yl]-(4-phenethylpiperazin-1-yl)methanone, hydrochloride,
[3-(furan-2-yl)-1H-indol-5-yl]-[4-(4-fluorophenethyl)piperazin-1-yl]methanone,
[3-(furan-2-yl)-1H-indol-5-yl]-[4-(thiophen-2-yl)piperazin-1-yl]methanone,
[3-(furan-2-yl)-1H-indol-5-yl]-[4-(5-chlorothiophen-2-yl)piperazin-1-yl]methanone,
[3-(furan-2-yl)-1H-indol-5-yl]-[4-(thiophen-3-yl)piperazin-1-yl]methanone,
[3-(furan-2-yl)-1H-indol-5-yl]-[4-(2,5-dichlorothiophen-3-yl)piperazin-1-yl]methanone,
[3-(furan-2-yl)-1H-indol-5-yl]-[4-(furan-2-yl)piperazin-1-yl]methanone,
[3-(thiophen-2-yl)-1H-indol-4-yl]-(4-phenethylpiperazin-1-yl)methanone,
[3-(thiophen-2-yl)-1H-indol-4-yl]-[4-(4-fluorophenethyl)piperazin-1-yl]methanone,
[3-(thiophen-2-yl)-1H-indol-4-yl]-[4-(thiophen-2-yl)piperazin-1-yl]methanone,
[3-(thiophen-2-yl)-1H-indol-4-yl]-[4-(5-chlorothiophen-2-yl)piperazin-1-yl]methanone,
[3-(thiophen-2-yl)-1H-indol-4-yl]-[4-(thiophen-3-yl)piperazin-1-yl]methanone,
[3-(thiophen-2-yl)-1H-indol-4-yl]-[4-(2,5-dichlorothiophen-3-yl)piperazin-1-yl]methanone,
[3-(thiophen-2-yl)-1H-indol-4-yl]-[4-(furan-2-yl)piperazin-1-yl]methanone,
[3-(thiophen-2-yl)-1H-indol-5-yl]-(4-phenethylpiperazin-1-yl)methanone, hydrochloride,
[3-(thiophen-2-yl)-1H-indol-5-yl]-[4-(4-fluorophenethyl)piperazin-1-yl]methanone,
[3-(thiophen-2-yl)-1H-indol-5-yl]-[4-(thiophen-2-yl)piperazin-1-yl]methanone,
[3-(thiophen-2-yl)-1H-indol-5-yl]-[4-(5-chlorothiophen-2-yl)piperazin-1-yl]methanone,
[3-(thiophen-2-yl)-1H-indol-5-yl]-[4-(thiophen-3-yl)piperazin-1-yl]methanone,
[3-(thiophen-2-yl)-1H-indol-5-yl]-[4-(2,5-dichlorothiophen-3-yl)piperazin-1-yl]methanone,
[3-(thiophen-2-yl)-1H-indol-5-yl]-[4-(furan-2-yl)piperazin-1-yl]methanone, or
[3-benzoyl-1H-indol-4-yl]-[4-(4-fluorophenethyl)piperazin-1-yl]methanone, hydrochloride, and
physiologically acceptable salts and solvates thereof.

### Claim 10 (depends on 1)

A compound according to claim 1, wherein the solvate is a hydrate or alcoholate.

### Claim 11

A compound of formula I
in which
R1 is a phenyl radical which is unsubstituted or substituted by R2 and/or R4,
R2, R4,
R5, R6 in each case independently of one another are Hal, A, OA, OH, CN or acyl having 1 to 6 C atoms,
R3 is a phenyl radical which is unsubstituted or substituted by R5 and/or R6,
A is alkyl having 1-6 C atoms, and
Hal is F, Cl, Br or I,
or a physiologically acceptable salt or solvate thereof.

### Claim 12 (depends on 11)

A compound according to claim 11, wherein the acyl is formyl, acetyl, propionyl, butyryl, or trifluoroacetyl.

### Claim 13 (depends on 11)

A compound according to claim 11, wherein the solvate is a hydrate or alcoholate.

### Claim 14 (depends on 1)

A compound according to claim 1, wherein R1 is phenyl, p-chlorophenyl, p-fluorophenyl, thiophen-2-yl, 5-chlorothiophen-2-yl, 2,5-dichlorothiophen-3-yl or 2- or 3-furyl.

### Claim 15 (depends on 1)

A compound according to claim 1, wherein R3 is phenyl, p-chlorophenyl, p-fluorophenyl, thiophen-2-yl, 5-chlorothiophen-2-yl, 2,5-dichlorothiophen-3-yl or 2- or 3-furyl.

### Claim 16 (depends on 1)

A compound according to claim 1, wherein R2, R4, R5, R6, in each case independently of one another, are H, Hal, alkyl having 1-6 C atoms, alkoxy having 1-6 C atoms or hydroxyl.

### Claim 17 (depends on 1)

A compound according to claim 1, wherein R2, R4, R5, R6, in each case independently of one another, are H, Hal or alkyl having 1-4 C atoms.

### Claim 18 (depends on 1)

A compound according to claim 1, wherein R1 is phenyl.

### Claim 19 (depends on 1)

A compound according to claim 1, wherein R1 is phenyl which is unsubstituted or monosubstituted by Hal.

### Claim 20 (depends on 1)

A compound according to claim 1, wherein R1 is Het1 or phenyl which is monosubstituted by Hal.

### Claim 21 (depends on 1)

A compound according to claim 1, wherein R1 is Het1 or phenyl which is unsubstituted or monosubstituted by Hal.

### Claim 22 (depends on 1)

A compound according to claim 1, wherein R1 is Het1 or phenyl which is unsubstituted or monosubstituted by Hal and Het1 is an unsaturated heterocyclic ring that is unsubstituted or mono- or disubstituted by Hal or A and contains one or two identical or different heteroatoms selected from nitrogen, oxygen and sulfur.

### Claim 23 (depends on 1)

A compound according to claim 1, wherein R1 is Het1 or phenyl which is unsubstituted or monosubstituted by Hal, Het1 is an unsaturated heterocyclic ring that is unsubstituted or mono- or disubstituted by Hal or A and contains one or two identical or different heteroatoms selected from nitrogen, oxygen and sulfur, and R3 is Het2 or phenyl which is unsubstituted or monosubstituted by Hal.

### Claim 24 (depends on 1)

A compound according to claim 1, wherein R1 is Het1 or phenyl which is unsubstituted or monosubstituted by Hal, Het1 is an unsaturated heterocyclic ring that is unsubstituted or mono- or disubstituted by Hal or A and contains one or two identical or different heteroatoms selected from nitrogen, oxygen and sulfur, R3 is Het1 or is phenyl which is unsubstituted or monosubstituted by Hal, and Het2 is an unsaturated heterocyclic ring that is mono- or disubstituted by Hal or A and contains a heteroatom selected from nitrogen, oxygen and sulfur.

### Claim 25 (depends on 1)

A process for preparing a compound according to claim 1 comprising
a) reacting a compound of formula II
wherein L is Cl, Br, I or a free reactively functionally modified OH group, and R3 has the meaning indicated in claim 1, with a compound of formula III
wherein R1 has the meaning indicated in claim 1, or
b) reacting a compound of formula IV
wherein R3 has the meaning indicated in claim 1, with a compound of formula V
L—CH2—CH2—R1 V
wherein L is Cl, Br, I reactively functionally modified OH group, and R1 has the meaning indicated in claim 1, or
c) converting one of the radicals R1 and/or R3 in a compound of claim 1 into another radical R1 and/or R3, and/or converting a base compound of claim 1 into a salt by treatment with an acid, and/or forming a solvate of a compound of formula I by dissolution thereof in a solvent.

### Claim 26 (depends on 25)

A method according to claim 25, wherein converting an R1 and/or R3 radical into another radical R1 and/or R3 comprises cleaving an OA group with formation of an OH group and/or converting a CHO group into a CN group.

### Claim 27 (depends on 1, 11, 22)

A process for preparing a compound to claim 11 comprising
a) reacting a compound of formula II
wherein L is Cl, Br, I or a free or reactively functionally modified OH group, and R3 has the meaning indicated in claim 22, with a compound of formula II
wherein R1 has the meaning indicated in claim 22, or
b) reacting a compound of formula IV
wherein R3 has the meaning indicated in claim 22, with a compound of formula V
L—CH2—CH2—R1 V
wherein L is Cl, Br, I or a free or reactively functionally modified OH group, and R1 has the meaning indicated in claim 1, or
c) converting one of the radicals R1 and/or R3 in a compound of claim 1 into another radical R1 and/or R3, and/or converting a base compound of claim 1 into a salt by treatment with an acid, and/or forming a solvate of a compound of formula I by dissolution thereof in a solvent.

### Claim 28 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, and a physiologically acceptable carrier.

### Claim 29 (depends on 11)

A pharmaceutical composition comprising a compound of claim 11 and a physiologically acceptable carrier.

### Claim 30 (depends on 1)

A method for treating one or more of psychoses, schizophrenia, depression, neurological disorders, memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, eating disorders, premenstrual syndrome or compulsive behavior, comprising administering an effective amount of a compound of claim 1 to a patient in need thereof.

### Claim 31 (depends on 30)

A method according to claim 30, wherein the eating disorder is bulimia, or anorexia nervosa, and the compulsive behavior is obsessive-compulsive disorder.

### Claim 32 (depends on 1)

A method for antagonizing a 5-HT2A receptor, comprising administering to a patient in need thereof a compound according to claim 1.

### Claim 33 (depends on 1)

A method for antagonizing a 5-HT2A receptor in vitro comprising bringing together an effective amount of a compound of claim 1 with material having 5-HT2A receptors.

### Claim 34 (depends on 1)

A method of treating depression comprising administering an effective amount of a compound of claim 1 to a patient in need thereof.

### Claim 35 (depends on 11)

A method for treating one or more of psychoses, schizophrenia, depression, neurological disorders, memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, eating disorders, premenstrual syndrome or compulsive behavior comprising administering a compound of claim 11, to a patient in need thereof.

### Claim 36 (depends on 11)

A method of treating depression, comprising administering a compound of claim 11 to a patient in need thereof.

### Claim 37 (depends on 11)

A method of treating inflammation, comprising administering a compound of claim 11 to a patient in need thereof.

### Claim 38 (depends on 1)

A method of treating inflammation, comprising administering a compound of claim 1 to a patient in need thereof.