# US 5,708,008 A · 5-Substituted-3-(1,2,3,6-tetrahydropyridin-4-yl)-and 3-(piperidin-4-yl)-1H-indoles: new 5-HT.sub.1F agonists

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- Number: US 5,708,008 A
- Document ID: US5708008A
- Status: Granted
- Kind: A
- Application number: 08/619,783
- Filed: 1996-03-20
- Granted: 1998-01-13
- Earliest claimed: 1995-03-20
- Assignees: Eli Lilly and Company
- Inventors: James Edmund Audia; Bruce Anthony Dressman; James Joseph Droste; James Erwin Fritz; Stephen Warren Kaldor; Daniel James Koch; Joseph Herman Krushinski, Jr.; Jeffrey Scott Nissen; Vincent Patrick Rocco; John Mehnert Schaus; Dennis Charles Thompson
- Web page: https://patentgrep.com/patent/US5708008A

## CPC

- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/14: containing three or more hetero rings
- C07D 407/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- Y02P 20/582: Recycling of unreacted starting or intermediate materials
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

This invention provides novel 5-HT.sub.1F agonists of Formula I ##STR1## where A--B, R, R.sup.1 and X are as defined in the specification, which are useful for the treatment of migraine and associated disorders.

## Claims

### Claim 1

A compound of Formula I: ##STR13## in which A--B is --CH--CH.sub.2 -- or --C.dbd.CH--;
R is H or C.sub.1 -C.sub.6 alkyl;
R.sup.1 is H or C.sub.1 -C.sub.4 alkyl;
X is --C(O)NR.sup.4 R.sup.15, --NR.sup.5 R.sup.6, --NR.sup.7 SO.sub.2 R.sup.8, --NHC(Q)NR.sup.10 R.sup.11, --NHC(O)OR.sup.12 or --NR.sup.13 C(O)R.sup.14 ;
where
Q is O, or S;
R.sup.4 is heteroaryl, substituted heteroaryl, heteroaryl(C.sub.1 -C.sub.4 alkyl), or substituted heteroaryl(C.sub.1 -C.sub.4 alkyl);
R.sup.4 and R.sup.15 taken together with the nitrogen atom form a pyrrolidine, piperidine, substituted piperidine, piperazine, 4-substituted piperazine, morpholine or thiomorpholine ring;
R.sup.5 and R.sup.6 are both trifluoromethanesulfonyl;
R.sup.7 is H or C.sub.1 -C.sub.4 alkyl;
R.sup.8 is phenyl, substituted phenyl, or di(C.sub.1 -C.sub.4 alkyl)amino;
R.sup.10 and R.sup.11 are independently selected from the group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 alkenyl, C.sub.3 -C.sub.8 cycloalkyl, phenyl, substituted phenyl, phenyl(C.sub.1 -C.sub.4 alkylene), phenyl(C.sub.1 -C.sub.4 alkylene) substituted in the phenyl ring, ((C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxycarbonyl substituted)C.sub.1 -C.sub.4 alkyl)phenyl, C.sub.1 -C.sub.4 alkyl .alpha.-substituted with C.sub.1 -C.sub.4 alkoxycarbonyl; or
R.sup.10 and R.sup.11 taken together with the nitrogen atom form a pyrrolidine, piperidine, piperazine, 4-substituted piperazine, morpholine or thiomorpholine ring;
R.sup.12 is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 alkenyl, phenyl, substituted phenyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.1 -C.sub.4 alkyl .omega.-substituted with C.sub.1 -C.sub.4 alkoxy;
R.sup.13 is H or C.sub.1 -C.sub.4 alkyl;
R.sup.14 is C.sub.1 -C.sub.10 alkyl substituted with from one to three substituents selected from the group consisting of hydroxy, C.sub.1 -C.sub.4 alkoxy, halo, aryloxy, C.sub.1 -C.sub.4 alkoxycarbonyl and heteroaryloxy, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, phenyl, substituted phenyl, naphthyl, phenyl(C.sub.1 -C.sub.4 alkylene), phenyl(C.sub.1 -C.sub.4 alkylene) substituted on the phenyl ring, 2-phenylethylen-1yl, diphenylmethyl, benzofused C.sub.4 -C.sub.8 cycloalkyl, C.sub.1 -C.sub.4 alkylene w-substituted with C.sub.3 -C.sub.6 cycloalkyl, or a heterocycle;
R.sup.15 is H or C.sub.1 -C.sub.6 alkyl;
and pharmaceutically acceptable acid addition salts and solvates thereof.

### Claim 2 (depends on 1)

A compound of claim 1, in which A--B is --C.dbd.CH--.

### Claim 3 (depends on 1)

A compound of claim 1, in which A--B is --CH--CH.sub.2 --.

### Claim 4 (depends on 1)

A compound of claim 1, in which R.sup.1 is H.

### Claim 5 (depends on 1)

A pharmaceutical formulation which comprises, in association with a pharmaceutically acceptable carrier, diluent or excipient, a compound of claim 1.

### Claim 6 (depends on 5)

A pharmaceutical formulation of claim 5, in which A--B is --C.dbd.CH--.

### Claim 7 (depends on 5)

A pharmaceutical formulation of claim 5, in which A--B is --CH--CH.sub.2 --.

### Claim 8 (depends on 5)

A pharmaceutical formulation of claim 5, in which R is H.

### Claim 9 (depends on 1)

A method for the activation of 5-HT.sub.1F receptors in mammals, comprising administering to a mammal in need of such activation an effective amount of a compound of claim 1.

### Claim 10 (depends on 9)

A method of claim 9 where the mammal is a human.

### Claim 11 (depends on 1)

A method for the inhibition of neuronal protein extravasation, comprising administering to a mammal in need thereof an effective amount of a compound of claim 1.

### Claim 12 (depends on 11)

A method of claim 11 where the mammal is a human.

### Claim 13 (depends on 1)

A compound of claim 1, in which X is --NR.sup.13 C(O)R.sup.14.

### Claim 14 (depends on 13)

A compound of claim 13 which is 5-(4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole and pharmaceutically acceptable acid addition salts and solvates thereof.

### Claim 15 (depends on 14)

A compound of claim 14 which is 5-(4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole hydrochloride.

### Claim 16 (depends on 5)

A pharmaceutical formulation of claim 5, in which X is --NR.sup.13 C(O)R.sup.14.

### Claim 17 (depends on 16)

A pharmaceutical formulation of claim 16, in which the compound is 5-(4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole and pharmaceutically acceptable acid addition salts and solvates thereof.

### Claim 18 (depends on 16)

A pharmaceutical formulation of claim 16, in which the compound is 5-(4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole hydrochloride.

### Claim 19 (depends on 1)

A method for the treatment of migraine, comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 1.

### Claim 20 (depends on 19)

A method of claim 19 where the mammal is human.

### Claim 21 (depends on 19)

A method of claim 19, in which X is --NR.sup.13 C(O)R.sup.14.

### Claim 22 (depends on 21)

A method of claim 21 where the compound is 5-(4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole and pharmaceutically acceptable acid addition salts and solvates thereof.

### Claim 23 (depends on 21)

A method of claim 21 where the compound is 5-(4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole hydrochloride.

### Claim 24 (depends on 1)

A method for the prevention of migraine, comprising administering prophylactically to a mammal subject to a migraine, an effective amount of a compound of claim 1.

### Claim 25 (depends on 24)

A method of claim 24 where the mammal is human.

### Claim 26 (depends on 24)

A method of claim 24, in which X is --NR.sup.13 C(O)R.sup.14.

### Claim 27 (depends on 26)

A method of claim 26 where the compound is 5-(4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole and pharmaceutically acceptable acid addition salts and solvates thereof.

### Claim 28 (depends on 26)

A method of claim 26 where the compound is 5-(4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole hydrochloride.