# US 5,703,239 A · Indanylpiperidines as melatonergic agents

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- Number: US 5,703,239 A
- Document ID: US5703239A
- Status: Granted
- Kind: A
- Application number: 08/633,362
- Filed: 1996-04-16
- Granted: 1997-12-30
- Earliest claimed: 1995-06-02
- Assignees: Bristol-Myers Squibb Company
- Inventors: Ronald J. Mattson; John D. Catt
- Web page: https://patentgrep.com/patent/US5703239A

## CPC

- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/24: Antidepressants
- A61P 25/26: Psychostimulants, e.g. nicotine, cocaine
- C07D 211/18: with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D 211/22: by oxygen atoms
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 409/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Certain indanyl piperidines are useful as melatonergic agents and can treat various CNS disorders. They are useful in treating sleep disorders and other conditions related to circadian rhythms.

## Claims

### Claim 1

A compound of Formula I: ##STR14## wherein: R is H, C.sub.1-7 alkoxy, halogen, hydroxyl, C.sub.1-4 haloalkoxy or C.sub.1-4 alkoxyphenyl C.sub.1-7 alkoxy;
Y is hydrogen or halogen;
Z is O or S;
m is 1 or 2; and
R.sup.1 is hydrogen, C.sub.1-6 straight or branched alkyl, C.sub.1-6 straight or branched haloalkyl, C.sub.2-8 alkylthioalkyl, C.sub.2-8 alkyloxyalkyl, C.sub.2-6 straight or branched alkenyl, C.sub.3-5 cycloalkyl, C.sub.3-5 cycloalkenyl, thienyl, furanyl, thiadiazolyl, pyrrolyl, C.sub.1-6 alkylthio or NR.sup.2 R.sup.3, in which R.sup.2 and R.sup.3 are independently hydrogen or C.sub.1-4 alkyl.

### Claim 2 (depends on 1)

The compound of claim 1 wherein R is methoxy.

### Claim 3 (depends on 2)

The compound of claim 2 wherein m is 1 and R.sup.1 is C.sub.3-5 cycloalkyl, thienyl or furanyl.

### Claim 4 (depends on 3)

The compound of claim 3 selected from the group consisting of:
1-(Cyclopropylcarbonyl)-4-(6-methoxy-indan-1-yl)piperidine;
4-(6-Methoxy-indan-1-yl)-1-›(2-thienyl)carbonyl!piperidine;
(-)-1-(Cyclopropylcarbonyl)-4-(6-methoxy-indan-1-yl)piperidine;
(+)-1-(Cyclopropylcarbonyl)-4-(6-methoxy-indan-1-yl)piperidine;
1-(Cyclopropylcarbonyl)-4-(5-fluoro-6-methoxy-indan-1-yl)piperidine; and
1-(Cyclopropylcarbonyl)-4-(6-hydroxy-indan-1-yl)piperidine.

### Claim 5 (depends on 2)

The compound of claim 2 wherein R.sup.1 is NR.sup.2 R.sup.3.

### Claim 6 (depends on 5)

The compound of claim 5 selected from the group consisting of:
N-Ethyl-4-(6-methoxy-indan-1-yl)piperidine-1-carboxamide;
N-Methyl-4-(6-methoxy-indan-1-yl)piperidine-1-carboxamide;
(-)-N-Ethyl-4-(6-methoxy-indan-1-yl)piperidine-1-carboxamide;
(-)-N-Methyl-4-(6-methoxy-indan-1-yl)piperidine-1-carboxamide;
N-Ethyl-4-(5-fluoro-6-methoxy-indan-1-yl)piperidine-1-carboxamide;
(-)-N,N-Dimethyl-4-(6-methoxy-indan-1-yl)piperidine-1-carboxamide;
N-Methyl-4-(5-fluoro-6-methoxy-indan-1-yl)piperidine-1-carboxamide;
N-Ethyl-4-(7-methoxy-tetralin-1-yl)piperidine-1-carboxamide; and
N-Ethyl-4-(6-fluoro-indan-1-yl)piperidine-1-carboxamide.

### Claim 7 (depends on 2)

The compound of claim 2 wherein R.sup.1 is C.sub.1-4 alkyl or C.sub.1-4 haloalkyl.

### Claim 8 (depends on 7)

The compound of claim 7 selected from the group consisting of:
4-(6-Methoxy-indan-1-yl)-1-(2-methylpropanoyl)piperidine;
(-)-4-(6-Methoxy-indan-1-yl)-1-(trifluoroacetyl)piperidine;
4-(6-Methoxy-indan-1-yl)-1-(trifluoroacetyl)piperidine;
(-)-4-(6-Methoxy-indan-1-yl)-1-(2-methylpropanoyl)piperidine;
4-(5-Fluoro-6-methoxy-indan-1-yl)l-(2-methylpropanoyl)piperidine;
(-)-4-(6-Methoxy-indan-1-yl)-1-pentanoylpiperidine;
(-)-1-Butanoyl-4-(6-methoxy-indan-1-yl)piperidine;
(-)-4-(6-Methoxy-indan-1-yl)-1-propanoylpiperidine;
(-)-1-Acetyl-4-(6-methoxy-indan-1-yl)piperidine;
1-Butanoyl-4-(5-fluoro-6-methoxy-indan-1-yl)piperidine;
4-(5-Fluoro-6-methoxy-indan-1-yl)-1-propanoylpiperidine; and
1-Acetyl-4-(5-fluoro-6-methoxy-indan-1-yl)piperidine.

### Claim 9 (depends on 2)

The compound of claim 2 wherein R.sup.1 hydrogen.

### Claim 10 (depends on 9)

The compound of claim 9 selected from the group consisting of:
(-)-1-Formyl-4-(6-methoxy-indan-1-yl)piperidine; and
1-Formyl-4-(6-methoxy-indan-1-yl)piperidine.

### Claim 11 (depends on 2)

The compound of claim 2 wherein m=2.

### Claim 12 (depends on 11)

The compound of claim 11 selected from the group consisting of:
N-Ethyl-4-(7-methoxy-tetralin-1-yl)piperidine-1-carboxamide; and
1-(Cyclopropylcarbonyl)-4-(7-methoxy-tetralin-1-yl)piperidine.

### Claim 13 (depends on 2)

The compound of claim 2 selected from the group consisting of:
1-›(2-Furanyl)carbonyl!-4-(6-methoxy-indan-1-yl)-piperidine;
4-(6-Methoxy-indan-1-yl)-1-›(1H-pyrrol-2-yl)carbonyl!piperidine;
4-(6-Methoxy-indan-1-yl)-1-›(3-methyl-furan-2-yl)carbonyl!piperidine;
1-›(3-Furanyl)carbonyl!4-(6-methoxy-indan-1-yl)-piperidine;
4-(6-Methoxy-indan-1-yl)-1-›(1-methyl-pyrrol-2-yl)carbonyl!piperidine;
4-(6-Methoxy-indan-1-yl)-1-›(3-methyl-thien-2-yl)carbonyl!piperidine;
4-(6-Methoxy-indan-1-yl)-1-›(3-thienyl)carbonyl!piperidine;
1-›(3-Chloro-thien-2-yl)carbonyl!-4-(6-methoxy-indan-1-yl)piperidine;
4-(6-Methoxy-indan-1-yl)-1-›(1,2,3-thiadiazol-4-yl)carbonyl!piperidine;
4-(6-Methoxy-indan-1-yl)-1-(2-methylbutanoyl)piperidine;
4-(6-Methoxy-indan-1-yl)-1-(2-methylthioacetyl)piperidine;
1-›(Cyclopent-1-en-1-yl)carbonyl!-4-(6-methoxy-indan-1-yl)piperidine;
(-)-4-(6-Methoxy-indan-1-yl)-1-(2-methoxyacetyl)piperidine; and
N-Methyl-4-(6-methoxy-indan-1-yl)-piperidine-1-thiocarboxamide.

### Claim 14 (depends on 1)

The compound of claim 1 selected from the group consisting of:
1-(Cyclopropylcarbonyl)-4-(6-fluoro-indan-1-yl)piperidine;
4-(6-Fluoro-indan-1-yl)-1-(2-methylpropanoyl)piperidine;
1-Butanoyl-4-(6-fluoro-indan-1-yl)piperidine;
4-(6-Ethyl-indan-1-yl)-1-(2-methylpropanoyl)piperidine;
1-(Cyclopropylcarbonyl)4-(6-ethyl-indan-1-yl)piperidine;
N-Ethyl-4-(6-fluoro-indan-1-yl)piperidine-1-carboxamide;
N-Ethyl-4-(6-ethyl-indan-1-yl)piperidine-1-carboxamide;
N-Ethyl-4-›6-(n-heptyloxy)-indan-1-yl!piperidine-1-carboxamide;
1-(Cyclopropylcarbonyl)-4-(indan-1-yl)piperidine; and
N-Methyl-4-(indan-1-yl)-piperidine-1-carboxamide.

### Claim 15 (depends on 1)

The compound of claim 1, (-)-1-(Cyclopropylcarbonyl)-4-(6-methoxy-indan-1-yl)piperidine.

### Claim 16 (depends on 1)

The compound of claim 1, (-)-4-(6-Methoxy-indan-1-yl)-1-(2-methylpropanoyl)piperidine.

### Claim 17 (depends on 1)

The compound of claim 1, 1-(Cyclopropylcarbonyl)-4-(5-fluoro-6-methoxy-indan-1-yl)piperidine.

### Claim 18 (depends on 1)

The compound of claim 1, (-)-N-Methyl-4-(6-methoxy-indan-1-yl)piperidine-1-carboxamide.

### Claim 19 (depends on 2)

The compound of claim 2 wherein m is 1 and R.sup.1 is methylfuranyl, methylthienyl, halothienyl, thiadiazolyl or pyrrolyl.

### Claim 20 (depends on 19)

The compound of claim 19 selected from:
4-(6-Methoxy-indan-1-yl)-1-›(1H-pyrrol-2-yl)carbonyl!piperidine;
4-(6-Methoxy-indan-1-yl)-1-›(3-methyl-furan-2-yl)carbonyl!piperidine;
4-(6-Methoxy-indan-1-yl)-1-›(3-methyl-thien-2-yl)carbonyl!piperidine;
1-›(3-Chloro-thien-2-yl)carbonyl!-4-(6-methoxy-indan-1-yl)piperidine; and
4-(6-Methoxy-indan-1-yl)-1-›(1,2,3-thiadiazol-4-yl)carbonyl!piperidine.

### Claim 21 (depends on 1)

A pharmaceutical composition for treating a sleep or circadian rhythm disorder in a patient in need of such treatment comprising an effective amount of a compound of claim 1 and a suitable amount of a pharmaceutically acceptable carrier.

### Claim 22 (depends on 1)

A method of treating a sleep disorder in a patient in need of such treatment comprising the administration to said patent of an effective amount of a compound of claim 1.

### Claim 23 (depends on 1)

A pharmaceutical composition for treating depression in a patient in need of such treatment comprising an effective amount of a compound of claim 1 and a suitable amount of a pharmaceutically acceptable carrier.

### Claim 24 (depends on 1)

A method of treating depression in a patient in need of such treatment comprising the administration to said patient of an effective amount of a compound of claim 1.