# US 5,346,908 A · Nitrogen-containing cyclohetero cycloheteroaminoaryl derivatives for CNS disorders

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- Number: US 5,346,908 A
- Document ID: US5346908A
- Status: Granted
- Kind: A
- Application number: 07/904,354
- Filed: 1992-06-25
- Granted: 1994-09-13
- Earliest claimed: 1992-06-25
- Assignees: National Institutes of Health; Brown University
- Inventors: Wayne Bowen; Brian R. de Costa; Celia Dominguez; Xiao-Shu He; Kenner C. Rice
- Web page: https://patentgrep.com/patent/US5346908A

## CPC

- C07D 409/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 207/14: Nitrogen atoms not forming part of a nitro radical
- C07D 211/56: Nitrogen atoms (nitro radicals C07D211/38)
- C07D 223/12: Nitrogen atoms not forming part of a nitro radical
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Certain nitrogen-containing cyclohetero cycloalkylaminoaryl compounds are described for treatment of CNS disorders such as cerebral ischemia, psychoses and convulsions. Compounds of particular interest are of the formula: ##STR1## wherein each of R.sup.1, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 is independently selected from hydrido, lower alkyl, benzyl, and haloloweralkyl; wherein each of R.sup.2, R.sup.3 and R.sup.8 through R.sup.11 is independently selected from hydrido, hydroxy, loweralkyl, benzyl, phenoxy, benzyloxy and haloloweralkyl; wherein n is an integer of from four to six; wherein m is an integer of from two to four; wherein A is selected from phenyl, naphthyl, benzothienyl, benzofuranyl and thienyl; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy, loweralkyl, loweralkoxy, halo, haloloweralkyl, amino, monoloweralkylamino and diloweralkylamino; or a pharmaceutically acceptable salt thereof.

## Claims

### Claim 1

A compound of the formula ##STR18## or a pharmaceutically acceptable salt thereof, wherein each of R.sup.1, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 is independently selected from the group consisting of methyl, ethyl, propyl, benzyl, and haloloweralkyl of one to five carbon atoms;
wherein each of R.sup.2, R.sup.3 and R.sup.8 through R.sup.11 is independently selected from hydrido, hydroxy, methyl, ethyl, propyl, benzyl, phenoxy, benzyloxy and haloloweralkyl of one to five carbon atoms;
wherein n is four or five and m is two or three, with the proviso that when n is four, m is three; and
wherein A is phenyl, naphthyl, benzothienyl, benzofuranyl or thienyl; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, methylenedioxy, halo, trifluoromethyl, amino, methylamino and dimethylamino.

### Claim 2 (depends on 1)

The compound of claim 1 selected from the group consisting of
3-(1-pyrrolidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)piperidine;
3-(1-piperidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)piperidine;
3-(1-piperidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)pyrrolidine;
3-(1-piperidinyl)-N-(2-[3-benzo[b]thienyl]ethyl)piperidine;
3-(1-pyrrolidinyl)-N-(2-[3-benzo[b]thienyl]ethyl)piperidine; and
3-(1-piperidinyl)-N-(2-[3-benzo[b]thienyl]ethyl)pyrrolidine.

### Claim 3 (depends on 2)

The compound of claim 2 which is 3-(1-pyrrolidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)piperidine.

### Claim 4 (depends on 2)

The compound of claim 2 which is 3-(1-piperidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)piperidine.

### Claim 5

A pharmaceutical composition comprising a pharmaceutically-acceptable carrier or diluent and a therapeutically-effective amount of an active compound for preventing neurotoxic damage or treating or preventing cerebral ischemia, psychotic disorder or convulsive disorder, wherein said active compound is a compound of formula ##STR19## or a pharmaceutically acceptable salt thereof, wherein each of R.sup.1, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 is independently selected from the group consisting of methyl, ethyl, propyl, benzyl, and haloloweralkyl of one to five carbon atoms;
wherein each of R.sup.2, R.sup.3 and R.sup.8 through R.sup.11 is independently selected from hydrido, hydroxy, methyl, ethyl, propyl, benzyl, phenoxy, benzyloxy and haloloweralkyl of one to five carbon atoms;
wherein n is four or five and m is two or three, with the proviso that when n is four, m is three; and
wherein A is phenyl, naphthyl, benzothienyl, benzofuranyl or thienyl; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, methylenedioxy, halo, trifluoromethyl, amino, methylamino and dimethylamino.

### Claim 6 (depends on 5)

The composition of claim 5 wherein the active compound is selected from the group consisting of
3-(1-pyrrolidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)piperidine;
3-(1-piperidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)piperidine;
3-(1-piperidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)pyrrolidine;
3-(1-piperidinyl)-N-(2-[3-benzo [b]thienyl]ethyl)piperidine;
3-(1-pyrrolidinyl)-N-(2-[3-benzo[b]thienyl]ethyl)piperidine; and
3-(1-piperidinyl)-N-(2-[3-benzo[b]thienyl]ethyl)pyrrolidine.

### Claim 7 (depends on 6)

The composition of claim 6 wherein the active compound is 3-(1-pyrrolidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)piperidine.

### Claim 8 (depends on 6)

The composition of claim 6 wherein the active compound is 3-(1-piperidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)piperidine.

### Claim 9

A method for treating a patient afflicted with or susceptible to neurotoxic damage, cerebral ischemia, psychotic disorder or convulsive disorder, which method comprises administering to the patient a therapeutically-effective amount of a compound of the formula ##STR20## or a pharmaceutically acceptable salt thereof, wherein each of R.sup.1, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 is independently selected from the group consisting of methyl, ethyl, propyl, benzyl, and haloloweralkyl of one to five carbon atoms;
wherein each of R.sup.2, R.sup.3 and R.sup.8 through R.sup.11 is independently selected from hydrido, hydroxy, methyl, ethyl, propyl, benzyl, phenoxy, benzyloxy and haloloweralkyl of one to five carbon atoms:
wherein n is four or five and m is two or three, with the proviso that when n is four, m is three; and
wherein A is phenyl, naphthyl, benzothienyl, benzofuranyl or thienyl; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, methylenedioxy, halo, trifluoromethyl, amino, methylamino and dimethylamino.

### Claim 10 (depends on 9)

The method of claim 9 wherein the compound is selected from the group consisting of
3-(1-pyrrolidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)piperidine;
3-(1-piperidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)piperidine;
3-(1-piperidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)pyrrolidine;
3-(1-piperidinyl)-N-(2-[3-benzo [b]thienyl]ethyl)piperidine;
3-(1-pyrrolidinyl)-N-(2-[3-benzo [b]thienyl]ethyl)piperidine; and
3-(1-piperidinyl)-N-(2-[3-benzo[b]thienyl]ethyl)pyrrolidine.

### Claim 11 (depends on 10)

The method of claim 10 wherein the compound is 3-(1-pyrrolidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)piperidine.

### Claim 12 (depends on 10)

The method of claim 10 wherein the compound is 3-(1-piperidinyl)-N-(2-[3,4-dichlorophenyl]ethyl)piperidine.