# US 5,350,754 A · Heterocyclic cycloalkanes

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- Number: US 5,350,754 A
- Document ID: US5350754A
- Status: Granted
- Kind: A
- Application number: 08/024,321
- Filed: 1993-03-01
- Granted: 1994-09-27
- Earliest claimed: 1989-02-28
- Assignees: Zeneca Limited; ICI Pharma
- Inventors: Graham C. Crawley; Jean-Marc M. M. Girodeau
- Web page: https://patentgrep.com/patent/US5350754A

## CPC

- C07D 213/30: Oxygen atoms
- C07D 215/227: only one oxygen atom which is attached in position 2
- C07D 237/08: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 239/26: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 241/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 241/42: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention concerns a heterocyclic cycloalkane of the formula I ##STR1## wherein Q is an optionally substituted 6-membered monocyclic or 10-membered bicyclic heterocyclic moiety containing one or two nitrogen atoms; A is (1-6C)alkylene, (3-6C)alkenylene, (3-6C)alkynylene or cyclo(3-6C)alkylene; X is oxy, thio, sulphinyl, sulphonyl or imino; Ar is phenylene which may optionally bear one or two substituents or Ar is an optionally substituted 6-membered heterocyclene moiety containing up to three nitrogen atoms; R.sup.1 is hydrogen, (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl, cyano-(1-4C)alkyl or (2-4C)alkanoyl, or optionally substituted benzoyl; and R.sup.2 and R.sup.3 together form a (3-6C)alkylene group which, together with the carbon atom to which R.sup.2 and R.sup.3 are attached, defines a ring having 4 to 7 ring atoms, and which ring may bear one or two substituents; or a pharmaceutically-acceptable salt thereof. The compounds of the invention are inhibitors of the enzyme 5-lipoxygenase.

## Claims

### Claim 1

A heterocyclic cycloalkane of the formula I
wherein Q is pyridyl, or a hydrogenated derivative thereof, which may optionally bear one, two or three substituents selected from halogeno, hydroxy, oxo, carboxy, cyano, amino, (1-4C)alkyl, (1-4C)alkoxy, fluoro-(1-4C)alkyl, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, hydroxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl, di[(1-4C)alkyl]amino-(1-4C)alkyl, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy and phenyl-(1-4C)alkyl;
wherein A is (1-6C)alkylene, (3-6C)alkenylene, (3-6C)alkynylene or cyclo (3-6C)alkylene;
wherein X is oxy, thio, sulphinyl, sulphonyl or imino;
wherein Ar is phenylene which may optionally bear one or two substituents selected from halogeno, hydroxy, amino, nitro, cyano, ureido, carbamoyl, (1-4C)alkyl, (3-4C)alkenyloxy, (1-4C)alkoxy, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, fluoro-(1-4C)alkyl, (1-4C)alkoxycarbonyl, N-[(1-4C)alkyl]carbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl, (2-4C)alkanoylamino, cyano-(1-4C)alkoxy, carbamoyl-(1-4C)alkoxy, amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy and (1-4C)alkoxycarbonyl-(1-4C)alkoxy;
wherein R.sup.1 is hydrogen, (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl, cyano-(1-4C)alkyl or (2-4C)alkanoyl, or R.sup.1 is benzoyl which may optionally bear a substituent selected from halogeno, (1-4C)alkyl and (1-4C)alkoxy; and
wherein R.sup.2 and R.sup.3 together form a (3-6C)alkylene group which, together with the carbon atom to which R.sup.2 and R.sup.3 are attached, defines a ring having 4 to 7 ring atoms, and which ring may bear one or two substituents, which may be the same or different, selected from hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylthio, (1-4C)alkylsulphinyl and (1-4C)alkylsulphonyl, or which ring may bear a (1-4C)alkylenedioxy substituent;
or a pharmaceutically-acceptable salt thereof.

### Claim 2 (depends on 1)

A heterocyclic cycloalkane of the formula I as claimed in claim 1 wherein Q is pyridyl, or a hydrogenated derivative thereof, which may optionally bear one, two or three substituents selected from fluoro, chloro, hydroxy, oxo, methyl, ethyl, propyl, trifluoromethyl, 2-fluoromethyl, 2-dimethylaminoethyl and benzyl;
wherein A is methylene, 1-propenylene or 1-propynylene;
wherein X is oxy;
wherein Ar is 1,3-phenylene or 1,4-phenylene which may optionally bear one or two substituents selected from fluoro, chloro, hydroxy, amino, ureido, methoxy and trifluoromethyl;
wherein R.sup.1 is methyl, ethyl, allyl or 2-propynyl;
and
wherein R.sup.2 and R.sup.3 together form a tetramethylene or pentamethylene group which, together with the carbon atom to which R.sup.2 and R.sup.3 are attached, defines a ring having 5 or 6 ring atoms and which ring may bear a substituent selected from hydroxy, methyl, methoxy and ethoxy;
or a pharmaceutically-acceptable salt thereof.

### Claim 3 (depends on 1)

A heterocyclic cycloalkane of the formula I as claimed in claim 1 wherein Q is 2-pyridyl or 3-pyridyl which may optionally bear one substituent selected from chloro, hydroxy, cyano, methyl, methoxy and trifluoromethyl;
A is methylene, ethylene, trimethylene, 1-propenylene, 2-methylprop-1-enylene or 1-propynylene;
X is oxy;
Ar is 1,3-phenylene or 1,4-phenylene which may optionally bear one substituent selected from fluoro, chloro, hydroxy, amino, nitro, methyl, methoxy, methylthio, methylsulphinyl, methylsulphonyl, methylamino, dimethylamino, trifluoromethyl, acetamido, cyanomethoxy and carbamoylmethoxy;
R.sup.1 is methyl, ethyl, allyl or 2-propynyl; and
R.sup.2 and R.sup.3 together form a tetramethylene or pentamethylene group which, together with the carbon atom to which R.sup.2 and R.sup.3 are attached, defines a ring having 5 or 6 ring atoms and which ring may bear a substituent selected from hydroxy, methyl, methoxy, ethoxy, methylthio, methylsulphinyl, methylsulphonyl and methylenedioxy;
or a pharmaceutically-acceptable salt thereof.

### Claim 4 (depends on 1)

A heterocyclic cycloalkane of the formula I as claimed in claim 1 wherein Q is 2-pyridyl or 3-pyridyl, or a hydrogenated derivative thereof, which may optionally bear one or two substituents selected from hydroxy, oxo, methyl, ethyl, propyl, 2-fluoroethyl, 2-dimethylaminoethyl and benzyl;
wherein A is methylene, 1-propenylene or 1-propynylene;
wherein X is oxy;
wherein Ar is 1,3-phenylene or 1,4-phenylene which may optionally bear one to two substituents selected from fluoro, chloro, amino, methoxy and trifluoromethyl;
wherein R.sup.1 is methyl, ethyl or allyl; and
wherein R.sup.2 and R.sup.3 together form a tetramethylene group which, together with the carbon atom to which R.sup.2 and R.sup.3 are attached, defines a ring having 5 ring atoms and which ring may bear a substituent selected from hydroxy and methoxy;
or a pharmaceutically-acceptable salt thereof.

### Claim 5 (depends on 1)

A heterocyclic cycloalkane of the formula I as claimed in claim 1 wherein Q is 2-pyridyl;
A is methylene or 1-propynylene;
Ar is 1,3-phenylene or 5-fluoro-1,3-phenylene;
R.sup.1 is methyl; and
R.sup.2 and R.sup.3 together form a tetramethylene group, which, together with the carbon atom to which R.sup.2 and R.sup.3 are attached, defines a ring having 5 ring atoms and which ring bears a 2-methoxy substituent;
or a pharmaceutically-acceptable salt thereof.

### Claim 6 (depends on 1)

A heterocyclic cycloalkane of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in claim 1 being:
trans-1,2-dimethoxy-1-[3-(3-(2-pyridyl)prop-2-yn-1-yloxy)phenyl]cyclopentan e.

### Claim 7 (depends on 1, 2, 3, 4, 5, 6)

A pharmaceutical composition which comprises a heterocyclic cycloalkane of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 6 in association with a pharmaceutically-acceptable diluent or carrier.

### Claim 8 (depends on 1, 2, 3, 4, 5, 6)

A method of treating a disease or medical condition mediated alone or in part by one or more leukotrienes which comprises administering to a warm-blooded animal requiring such treatment an effective amount of a heterocyclic cycloalkane of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 6.