# US 5,703,083 A · N-aminoalkyl-1-biphenylenyl-2-carboxamides; new dopamine receptor subtype specific ligands

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- Number: US 5,703,083 A
- Document ID: US5703083A
- Status: Granted
- Kind: A
- Application number: 08/631,152
- Filed: 1996-04-15
- Granted: 1997-12-30
- Earliest claimed: 1996-04-15
- Assignees: Neurogen Corporation
- Inventors: Xi Chen; Jun Yuan
- Web page: https://patentgrep.com/patent/US5703083A

## CPC

- C07D 295/13: to an acyclic saturated chain
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- 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 25/30: for treating abuse or dependence
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 217/22: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed are compounds of the formula: ##STR1## or the pharmaceutically acceptable acid addidon salts thereof wherein: R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, and R.sub.7 independently represent hydrogen, halogen, hydroxy, alkyl, alkoxy, amino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, cyano, nitro, trifluoromethyl, or trifluoromethoxy; R.sub.8 is hydrogen or lower alkyl; X represents an optionally substituted alkylene group; and Y represents a mono-, di- or trisubsituted cyclic amino group which compounds are useful in the treatment of affective disorders such as schizophrenia, depression, Alzheimer's disease, movement disorders such as Parldnsonism and dystonia, and other disorders which respond to dopaminergic blockade such as substance abuse and obsessive compulsive disorders. Further, compounds of this invention may be useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents.

## Claims

### Claim 1

A compound of the formula: ##STR20## or the pharmaceutically acceptable acid addition salts thereof wherein: R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are the same or different and represent hydrogen, halogen, hydroxy, amino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, cyano, nitro, trifluoromethyl, trifiuoromethoxy, alkyl or alkoxy;
R.sub.8 is hydrogen or lower alkyl;
X represents an alkylene group of 2 to 6 carbon atoms optionally substituted with one or more alkyl groups having from 1 to 4 carbon atoms;
Y represents a group of the formula: ##STR21## where R.sub.9 and R.sub.10 independently represent alkyl; and
W is
phenyl or 1- or 2-naphthyl each of which is optionally substituted with up to five substituents independently selected from hydrogen, halogen, alkyl, alkoxy, thioalkoxy, hydroxy, amino, alkylamino or dialkylamino;
1-(1,2,3,4-tetrahydro)napthyl or 1-(1,2-dihydro)indenyl;
2-, 3-, or 4-pyddinyl;
2-, 4-, or 5-pyrimidinyl optionally substituted with halogen;
1-, 3-, or 8-isoquinolinyl;
7-benzofuranyl; or
7-benzothienyl.

### Claim 2

A compound of the formula: ##STR22## wherein R.sub.8 is hydrogen or lower alkyl;
X represents an alkylene group of 2 to 6 carbon atoms optionally substituted with one or more alkyl groups having from 1 to 4 carbon atoms;
R.sub.9 and R.sub.10 independently represent alkyl; and
W is
phenyl or 1- or 2-naphthyl each of which is optionally substituted with up to five substituents independently selected from hydrogen, halogen, alkyl, alkoxy, thioalkoxy, hydroxy, amino, alkylamino or dialkylamino;
1-(1,2,3,4-tetrahydro)napthyl or 1-(1,2-dihydro)indenyl;
2-, 3-, or 4-pyridinyl;
2-, 4-, or 5-pyrimidinyl optionally substituted with halogen;
1-, 3-, or 8-isoquinolinyl;
7-benzofuranyl; or
7-benzothienyl.

### Claim 3 (depends on 2)

A compound according to claim 2, wherein R.sub.8 is hydrogen and X is alkylene of 3-5 carbon atoms.

### Claim 4

A compound of the formula: ##STR23## wherein R.sub.8 is hydrogen or lower alkyl;
X represents an alkylene group of 2 to 6 carbon atoms optionally substituted with one or more alkyl groups having fi:om 1 to 4 carbon atoms; and
W is
phenyl or 1- or 2-naphthyl each of which is optionally substituted with up to five substituents independently selected from hydrogen, halogen, alkyl, alkoxy, thioalkoxy, hydroxy, amino, alkylamino or dialkylamino;
1-(1,2,3,4-tetrahydro)napthyl or 1-(1,2-dihydro)indenyl;
2-, 3-, or 4-pyridinyl;
2-, 4-, or 5-pyrimidinyl optionally substituted with halogen;
1-, 3-, or 8-isoquinolinyl;
7-benzofuranyl; or
7-benzothienyl.

### Claim 5 (depends on 4)

A compound according to claim 4, wherein R.sub.8 is hydrogen and X is alkylene of 3-5 carbon atoms.

### Claim 6 (depends on 4)

A compound according to claim 4, wherein R.sub.8 is hydrogen, X is alkylene of 3-5 carbon atoms, and W is dihydroindenyl, quinolinyl, isoquinolinyl, phenyl or naphthyl, each of which is optionally substituted with up to three groups independently selected from halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.4 alkoxy, and hydroxy.

### Claim 7 (depends on 4)

A compound according to claim 4, wherein R.sub.8 is hydrogen, and X is butylene.

### Claim 8

A compound of the formula ##STR24## wherein R.sub.8 is lower alkyl;
X represents an alkylene group of 2 to 6 carbon atoms optionally substituted with one or more alkyl groups having from 1 to 4 carbon atoms; and
W is
phenyl or 1- or 2-naphthyl each of which is optionally substituted with up to five substituents independently selected from hydrogen, halogen, alkyl, alkoxy, thioalkoxy, hydroxy, amino, alkylamino or dialkylamino;
1-(1,2,3,4-tetrahydro)napthyl or 1-(1,2-dihydro)indenyl;
2-, 3-, or 4-pyridinyl;
2-, 4-, or 5-pyrimidinyl optionally substituted with halogen;
1-, 3-, or 8-isoquinolinyl;
7-benzofuranyl; or
7-benzothienyl.

### Claim 9 (depends on 8)

A compound according to claim 8, wherein X is alkylene of 3-5 carbon atoms.

### Claim 10 (depends on 8)

A compound according to claim 8, wherein X is alkylene of 3-5 carbon atoms, and W is dihydroindenyl, quinolinyl, isoquinolinyl, phenyl or naphthyl, each of which is optionally substituted with up to three groups independently selected from halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.4 alkoxy, and hydroxy.

### Claim 11 (depends on 8)

A compound according to claim 8, wherein X is butylene.

### Claim 12 (depends on 1)

A compound according to claim 1, which is 1-(2-methoxyphenyl)-4-{4-›N-(1-biphenylene-2-carboxamido)!butyl}piperazine

### Claim 13 (depends on 1)

A compound according to claim 1, which is 1-(2,3-dimethylphenyl)-4-{4-›N-(1-biphenylene-2-carboxamido)!butyl}piperaz ine dihydrochioride.

### Claim 14 (depends on 1)

A compound according to claim 1, which is 1-(1-napthyl)-4-{4-›N-(1-biphenylene-2-carboxamido)!butyl}piperazine dihydrochloride.

### Claim 15 (depends on 1)

A compound according to claim 1, which is 1-(1-isoquinolyl)-4-{4-›N-(1-biphenylene-2-carboxamido)!butyl}piperazine dihydrochloride.

### Claim 16 (depends on 1)

A compound according to claim 1, which is 1-{1-(1,2-dihydroindenyl)-4-›4-(N-(1-biphenylene-2-carboxamido)!butyl}pipe razine dihydrochloride.

### Claim 17 (depends on 1)

A compound according to claim 1, which is 1-(8-quinolinyl)-4-{4-›N-(1-biphenylene-2-carboxamido)!butyl}piperazine.

### Claim 18 (depends on 1)

A compound according to claim 1, which is 1-(2-chlorophenyl)-4-{4-›N-(1-biphenylene-2-carboxamido)!butyl}piperazine.

### Claim 19 (depends on 1)

A compound according to claim 1, which is 1-(2,3-dichlorophenyl)-4-{4-›N-(1-biphenylene-2-carboxamido)!butyl}piperaz ine.

### Claim 20 (depends on 1)

A compound according to claim 1, which is 1-(2,6-dimethylphenyl)-4-{4-›N-(1-biphenylene-2-carboxamido)!butyl}piperaz ine dihydrochloride.

### Claim 21 (depends on 1)

A compound according to claim 1, which is 1-(2,6-dichlorophenyl)-4-{4-›N-(1-biphenylene-2-carboxamido)!butyl}piperaz ine.

### Claim 22 (depends on 1)

A compound according to claim 1, which is 1-(2-methyl-3-chlorophenyl)-4-{4-›N-(1-biphenylene-2-carboxamido)!butyl}pi perazine.

### Claim 23 (depends on 1)

A compound according to claim 1, which is 1-(2-methylphenyl)-4-{4-›N-(1-biphenylene-2-carboxamido)!pentyl}piperazine dihyctrochloride.