# US 5,705,505 A · Cyclic amide derivatives for treating asthma

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- Number: US 5,705,505 A
- Document ID: US5705505A
- Status: Granted
- Kind: A
- Application number: 08/717,999
- Filed: 1996-09-26
- Granted: 1998-01-06
- Earliest claimed: 1993-12-15
- Assignees: Zeneca Limited
- Inventors: Ashokkumar Bhikkappa Shenvi; Robert Toms Jacobs; Scott Carson Miller; Cyrus John Ohnmacht, Jr.; Chris Allan Veale
- Web page: https://patentgrep.com/patent/US5705505A

## CPC

- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- A61P 11/00: Drugs for disorders of the respiratory system
- C07D 401/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds of formula I ##STR1## wherein Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 have any of the meanings given in the specification, their N-oxides, and their pharmaceutically acceptable salts are nonpeptide antagonists of neurokinin A and useful for the treatment of asthma, etc. Also disclosed are pharmaceutical compositions, processes for preparing the compounds of formula I and intermediates.

## Claims

### Claim 1

A compound of Formula:
Z.sup.b is a disubstituted methylene group R.sup.bb (CH.sub.2).sub.p --C--R.sup.bc in which R.sup.bb is Ar; p is the integer 0 or 1; and R.sup.bc is hydrogen, hydroxy, (1-4C)alkoxy, (1-4C)alkanoyloxy, COOR.sup.bd (wherein R.sup.bd is hydrogen or (1-3C)alkyl), cyano, NR.sup.be R.sup.bf or SR.sup.bg in which R.sup.be and R.sup.bf are independently hydrogen, (1-4C)alkyl, (1-4C)hydroxyalkyl or (1-4C)alkanoyl: and R.sup.bg is hydrogen or (1-4C)alkyl; or R.sup.bc forms a double bond with the carbon atom to which it is bonded and with the adjacent carbon atom in the piperidine ring;
Ar is a phenyl radical or an ortho-fused bicyclic carbocyclic radical of nine of ten ring atoms in which at least one ring is aromatic, which radical Ar may be unsubstituted or may bear one or more substituents selected from halo, cyano, trifluoromethyl, (1-4C)alkyl, (1-4C)alkoxy, methylenedioxy, hydroxy, mercapto, --S(O).sub.n R.sup.xa, (1-5C)alkanoyl, (1-5C)alkanoyloxy, nitro, NR.sup.xb R.sup.xc, NR.sup.xd R.sup.xc,C(.dbd.NR.sup.xf)NR.sup.xg R.sup.xh, CONR.sup.xb R.sup.xc and COOR.sup.xj wherein n is the integer 0, 1, or 2; R.sup.xa is (1-6C)alkyl, (3-6C)cycloalkyl or phenyl (which phenyl may bear a halo, trifluoromethyl, (1-3C)alkyl or (1-3C)alkoxy substituent); the radical NR.sup.xb R.sup.xc contains zero to seven carbons and each of R.sup.xb and R.sup.xc is independently hydrogen, (1-5C)alkyl or (3-6C)cycloalkyl; and wherein R.sup.xd is hydrogen or (1-4C)alkyl and R.sup.xe is (1-5C)alkanoyl, benzoyl; or a group of formula C(.dbd.J.sup.x)NR.sup.xg R.sup.xh in which J.sup.x is oxygen, sulfur, NR.sup.xf or CHR.sup.xi,R.sup.zf is hydrogen, (1-5)alkyl; the radical NR.sup.xg R.sup.xh contains zero to 7 carbons and each of R.sup.xg and R.sup.xh is independently hydrogen, (1-5C)alkyl or (3-6C)cycloalkyl and R.sup.xh is hydrogen or (1-5C)alkyl; R.sup.xi is cyano, nitro, (1-5C)alkylsulfonyl or phenylsulfonyl; and R.sup.xj is hydrogen, (1-5C)alkyl or benzyl;
J is oxygen or sulfur; M.sup.1 is CR.sup.F ; R.sup.A is hydrogen or (1-3C)alkyl; the radicals R.sup.B, R.sup.C, R.sup.D and R.sup.E are each hydrogen; or one or more of R.sup.B, R.sup.C, R.sup.D and R.sup.E is a substituent independently selected from halo, trifluoromethyl, hydroxy, (1-3C)alkoxy, (1-3C)alkyl, (1-3C)alkylthio, (1-3C)alkylsulfinyl and (1-3C)alkylsulfonyl, and the others of R.sup.B, R.sup.C, R.sup.D and R.sup.E are each hydrogen; or two adjacent radicals of R.sup.B, R.sup.C, R.sup.D and R.sup.E form a methylenedioxy substituent and the others of R.sup.B, R.sup.C, R.sup.D and R.sup.E are hydrogen; R.sup.F is hydrogen, hydroxy, (1-3C)alkoxy or (1-3C)alkyl;
Q.sup.3 is hydrogen or (1-3C)alkyl; and
Q.sup.4 is phenyl which may bear one or two substituents independently selected from halo, trifluoromethyl, hydroxy, (1-3C)alkoxy, (1-3C)alkyl and methylenedioxy (1-3C)alkoxycarbonyl and (1-3C)alkylthio; or Q.sup.4 is thienyl, imidazolyl, benzo›b!thiophenyl or naphthyl any of which may bear a halo substituent; or Q.sup.4 is biphenylyl; or Q.sup.4 is carbon-linked indolyl which may bear a benzyl substituent at the 1-position;
or the N-oxide of a piperidino nitrogen indicated by .DELTA.;
or a pharmaceutically acceptable salt thereof:
or a quaternary ammonium salt thereof in which the piperidino nitrogen indicated by .DELTA. is a quadricovalent ammonium nitrogen wherein the fourth radical on the nitrogen R.sup.1 is (1-4C)alkyl or benzyl and the associated counterion A is a pharmaceutically acceptable anion.

### Claim 2 (depends on 1)

A compound as claimed in claim 1, wherein:
Q.sup.4 is phenyl which may bear one or two substituents independently selected from halo, trifluoromethyl, hydroxy, (1-3C)alkoxy, (1-3C)alkyl and methylenedioxy; or Q.sup.4 is thienyl, imidazolyl, benzo›b!thiophenyl or naphthyl any of which may bear a halo substituent; or Q.sup.4 is biphenylyl; or Q.sup.4 is carbon-linked indolyl which may bear a benzyl substituent at the 1-position:
or the N-oxide of a piperidino nitrogen indicated .DELTA.;
or a pharmaceutically acceptable salt thereof;
or a quaternary ammonium salt thereof in which the piperidino nitrogen indicated by .DELTA. is a quadricovalent ammonium nitrogen wherein the fourth radical on the nitrogen R.sup.1 is (1-4C)alkyl or benzyl and the associated counterion A is a pharmaceutically acceptable anion.

### Claim 3 (depends on 1)

A compound as claimed in claim 1 wherein Q.sup.3 is H; and Q.sup.4 is 3,4-dichlorophenyl;
or the N-oxide of a piperidino nitrogen indicated by .DELTA.;
or a pharmaceutically acceptable salt thereof;
or a quaternary ammonium salt thereof in which the piperidino nitrogen indicated by .DELTA. is a quadricovalent ammonium nitrogen wherein the fourth radical on the nitrogen R.sup.1 is (1-4C)alkyl or benzyl and the associated counterion A is a pharmaceutically acceptable anion.

### Claim 4 (depends on 1, 2)

A compound as claimed in any one of claims 1, 2, or 3 wherein ##STR3## is 4-benzylpiperidino, 4-(3-methoxyphenyl)piperidino, 4-(2-methylsulfinylphenyl)piperidino, 4-hydroxy-4-phenylpiperidino, or 4-acetamido-4-phenylpiperidino;
or the N-oxide of a piperidino nitrogen indicated by .DELTA.;
or a pharmaceutically acceptable salt thereof;
or a quaternary ammonium salt thereof in which the piperidino nitrogen indicated by .DELTA. is a quadricovalent ammonium nitrogen wherein the fourth radical on the nitrogen R.sup.1 is (1-4C)alkyl or benzyl and the associated counterion A is a pharmaceutically acceptable anion.

### Claim 5 (depends on 4)

A compound as claimed in claim 4, wherein J is oxygen; M.sup.1 is CH; R.sup.A is (1-3C)alkyl; R.sup.B, R.sup.C, R.sup.D and R.sup.E are each hydrogen or R.sup.C is methoxy and R.sup.B, R.sup.C and R.sup.D are hydrogen;
Q.sup.3 is hydrogen; and
Q.sup.4 is 3,4-dichlorophenyl;
or the N-oxide of a piperidino nitrogen indicated by .DELTA.;
or a pharmaceutically acceptable salt thereof:
or a quaternary ammonium salt thereof in which the piperidino nitrogen indicated by .DELTA. is a quadricovalent ammonium nitrogen wherein the fourth radical on the nitrogen R.sup.1 is (1-4C)alkyl or benzyl and the associated counterion A is a pharmaceutically acceptable anion.

### Claim 6 (depends on 1)

A compound as claimed in claim 1 which is: 3-›1-(3,4-dichlorophenyl)-3-(4-hydroxy-4-phenylpiperidino)propyl!-2-methyl -2H-isoquinolin-1-one;
or the N-oxide of a piperidino nitrogen indicated by .DELTA.:
or a pharmaceutically acceptable salt thereof:
or a quaternary ammonium salt thereof in which the piperidino nitrogen indicated by .DELTA. is a quadricovalent ammonium nitrogen wherein the fourth radical on the nitrogen R.sup.1 is (1-4C)alkyl or benzyl and the associated counterion A is a pharmaceutically acceptable anion.

### Claim 7 (depends on 1)

A compound as claimed in claim 1 which is: 3-›(1S*)-1-(3,4-dichlorophenyl)-3-(4-hydroxy-4-phenylpiperidino)propyl!-2- methyl-2H-isoquinolin-1-one;
or the N-oxide of a piperidino nitrogen indicated by .DELTA.;
or a pharmaceutically acceptable salt thereof:
or a quaternary ammonium salt thereof in which the piperidino nitrogen indicated by .DELTA. is a quadricovalent ammonium nitrogen wherein the fourth radical on the nitrogen R.sup.1 is (1-4C)alkyl or benzyl and the associated counterion A is a pharmaceutically acceptable anion.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising a compound as defined in claim 1; or the N-oxide of a piperidino nitrogen indicated by .DELTA.;
or a pharmaceutically acceptable salt thereof;
or a quaternary ammonium salt thereof in which the piperidino nitrogen indicated by .DELTA. is a quadricovalent ammonium nitrogen wherein the fourth radical on the nitrogen R.sup.1 is (1-4C)alkyl or benzyl and the associated counterion A is a pharmaceutically acceptable anion.

### Claim 9 (depends on 1)

A method of treating asthma in a human or other mammal in need thereof, comprising: administering an effective mount of a compound as defined in claim 1:
or the N-oxide of a piperidino nitrogen indicated by .DELTA.;
or a pharmaceutically acceptable salt thereof;
or a quaternary ammonium salt thereof in which the piperidino nitrogen indicated by .DELTA. is a quadricovalent ammonium nitrogen wherein the fourth radical on the nitrogen R.sup.1 is (1-4C)alkyl or benzyl and the associated counterion A is a pharmaceutically acceptable anion.