# US 5,352,678 A · Antiischemic piperazinyl- and piperidinyl-cyclohexanes

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- Number: US 5,352,678 A
- Document ID: US5352678A
- Status: Granted
- Kind: A
- Application number: 08/082,587
- Filed: 1993-06-25
- Granted: 1994-10-04
- Earliest claimed: 1992-03-11
- Assignees: Bristol-Myers Squibb Company
- Inventors: Ronald J. Mattson; John D. Catt
- Web page: https://patentgrep.com/patent/US5352678A

## CPC

- C07D 295/03: with the ring nitrogen atoms directly attached to acyclic carbon atoms
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- C07D 209/14: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D 213/38: having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
- C07D 215/20: Oxygen atoms
- C07D 277/64: with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
- C07D 295/073: with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- C07D 295/096: with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- C07D 295/116: with the doubly bound oxygen or sulfur atoms directly attached to a carbocyclic ring
- C07D 317/58: Radicals substituted by nitrogen atoms (nitro radicals C07D317/52)
- C07D 333/20: by nitrogen atoms (nitro, nitroso radicals C07D333/12)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Certain piperazinyl- and piperidinyl-substituted cyclohexanes have anti-ischemic properties.

## Claims

### Claim 1

A dopaminergic compound of Formula I or a pharmaceutically acceptable salt or hydrate thereof: ##STR30## wherein R=R.sub.1 and is independently H or halogen; or R and R.sub.1 may be taken together to form an --O(CH.sub.2).sub.m O-- (m=1 or 2);
X=a phenyl residue;
Y=N;
R.sub.2 =R.sub.3 and is independently H or C.sub.1-4 alkyl; and
R.sub.4 =phenyl or substituted phenyl wherein the phenyl group is mono-, di- or di-substituted with groups selected from: F, Cl, I and C.sub.1-4 alkoxy.

### Claim 2 (depends on 1)

The compound of claim 1 wherein R.sub.2 and R.sub.3 are both H.

### Claim 3 (depends on 2)

The compound of claim 2 wherein R.sub.4 is a mono- or disubstituted phenyl moiety.

### Claim 4 (depends on 3)

The compound of claim 3 selected from the group consisting of:
cis 1-[(2-chlorophenyl)methyl]-4-[4-(4-fluorophenyl)-1-cyclohexyl]piperazine;
trans 1-[(2-chlorophenyl)methyl]-4-[4-(4-fluorophenyl)-1-cyclohexyl]piperazine;
trans 1-[4-(4-fluorophenyl)-1-cyclohexyl]-4-[(2,5-difluorophenyl)methyl]piperazi ne;
trans 1-[4-(1,3-benzodioxol-5-yl)-1-cyclohexyl]-4-[(3-methoxyphenyl)methyl]piper azine;
trans 1-[4-(1,3-benzodioxol-5-yl)-1-cyclohexyl]-4-[(2,5-difluorophenyl) methyl]piperazine;
trans 1-[4-(1,3-benzodioxol-5-yl)-1-cyclohexyl]-4-[(2-chlorophenyl)methyl]pipera zine; and
trans 1-[4-(4-fluorophenyl)-1-cyclohexyl]-4-[(2,5-difluorophenyl)methyl]piperazi ne.

### Claim 5 (depends on 1)

A pharmaceutical composition comprising an effective antiischemia amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 6 (depends on 5)

The composition of claim 5 wherein the compound is one in which R.sub.2 and R.sub.3 are both H.

### Claim 7 (depends on 6)

The composition of claim 6 wherein the compound is one in which R.sub.4 is a mono- or disubstituted phenyl moiety.

### Claim 8 (depends on 5)

The composition of claim 5 wherein the compound is selected from the group consisting of:
cis 1-[(2-chlorophenyl)methyl]-4-[4-(4-fluorophenyl)-1-cyclohexyl]piperazine;
trans 1-[(2-chlorophenyl)methyl]-4-[4-(4-fluorophenyl)-1-cyclohexyl]piperazine;
trans 1-[4-(4-fluorophenyl)-1-cyclohexyl]-4-[(2,5-difluorophenyl)methyl]piperazi ne;
trans 1-[4-(1,3-benzodioxol-5-yl)-1-cyclohexyl]-4-[(3-methoxyphenyl) methyl]piperazine;
trans 1-[4-(1,3-benzodioxol-5-yl)-1-cyclohexyl]-4-[(2,5-difluorophenyl) methyl]piperazine;
trans 1-[4-(1,3-benzodioxol-5-yl )-1-cyclohexyl]-4-[(2-chlorophenyl) methyl]piperazine; and
trans 1-[4-(4-fluorophenyl)-1-cyclohexyl]-4-[(2,5-difluorophenyl)methyl]piperazi ne.

### Claim 9 (depends on 1)

A process for treating ischemia-induced disorders in a mammal in need of such treatment, the treatment comprising administering to the mammal an effective amount of a compound of claim 1.

### Claim 10 (depends on 9)

The process of claim 9 wherein the compound is one in which R.sub.2 and R.sub.3 are both H.

### Claim 11 (depends on 10)

The process of claim 10 wherein the compound is one in which R.sub.4 is a mono- or disubstituted phenyl moiety.

### Claim 12 (depends on 9)

The process of claim 9 wherein the compound is selected from the group consisting of:
cis 1-[(2-chlorophenyl)methyl]-4-[4-(4-fluorophenyl)-1-cyclohexyl]piperazine;
trans 1-[(2-chlorophenyl)methyl]-4-[4-(4-fluorophenyl)-1-cyclohexyl]piperazine;
trans 1-[4-(4-fluorophenyl)-1-cyclohexyl]-4-[(2,5-difluorophenyl)methyl]piperazi ne;
trans 1-[4-(1,3-benzodioxol-5-yl)-1-cyclohexyl]-4-[(3-methoxyphenyl)methyl]piper azine;
trans 1-[4-(1,3-benzodioxol-5-yl)-1-cyclohexyl]-4-[(2,5-difluorophenyl) methyl]piperazine;
trans 1-[4-(1,3-benzodioxol-5-yl)-1-cyclohexyl]-4-[(2-chlorophenyl)methyl]pipera zine; and
trans 1-[4-(4-fluorophenyl)-1-cyclohexyl]-4-[(2,5-difluorophenyl)methyl]piperazi ne.