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Details for Patent: 4,918,094

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Details for Patent: 4,918,094

Title: Carboxamide derivatives of indoles and leucotriene antagonizing use thereof
Abstract:This invention provides a series of novel heterocyclic amides of formula I in which the group >X-Y-Z< is selected from >C.dbd.CH--N<, >C.dbd.N--N<, >N--(CH.sub.2)--N<, >CH--CH.sub.2 --N< and >N--N.dbd.C< and the other radicals have the meanings defined in the following specification. The compounds of formula I are leukotriene antagonists. The invention also provides pharmaceutically acceptable salts of the formula I compounds: pharmaceutical compositions containing the formula I compounds, or their salts, for use in the treatment of, for example, allergic or inflammatory diseases, or endotoxic or traumatic shock conditions; and processes for the manufacture of the formula I compounds, as well as intermediates for use in such manufacture.
Inventor(s): Bernstein; Peter R. (Wallingford, PA), Brown; Frederick J. (Newark, DE), Matassa; Victor G. (Wilmington, DE), Yee; Ying K. (Kennett Square, PA)
Assignee: ICI Americas Inc. (Wilmington, DE)
Filing Date:Oct 16, 1986
Application Number:06/919,845
Claims:1. A compound of formula Ia

wherein

R.sup.1 is selected from a group consisting of (2-10C)alkyl optionally containing 1 or more fluorine substituents; phenyl-(1-6C)alkyl in which the (1-6C)alkyl may optionally bear a fluoro or (1-4 C)alkoxy substituent and in which the phenyl moiety may optionally bear a substituent selected from a group consisting of halogeno, (1-4C)alkyl, (1-4C)alkoxy and trifluoromethyl; (3-8C)cycloalkyl-(1-6C)alkyl, the cyclic moiety of any of which optionally may contain one unsaturated linkage and may optionally bear 1 or 2 (1-4C)alkyl substituents;

Ra is hydrogen or methyl;

Rc is selected from a group consisting of hydrogen and (1-4C)alkoxy;

Rd is hydrogen, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-4C)alkyl or (1-10C)alkyl optionally containing one or two double or triple bonds, said (1-10C)alkyl additionally optionally bearing a substituent P selected from a group consisting of cyano, carboxy, (1-4C)alkoxycarbonyl, carbamoyl of formula CONR.sup.2 R.sup.3, ureido of formula NR.sup.4 CONR.sup.2 R.sup.3, carbamoyloxy of formula OCONR.sup.2 R.sup.3, a carbamate of formula NR.sup.4 COOR.sup.5, acylamino of formula NR.sup.4 COR.sup.5, acyloxy of formula OCOR.sup.5, and an (optionally oxidized) thio group of formula S(O).sub.n R.sup.5 in which

R.sup.2 is selected from a group consisting of hydrogen, (1-6C)alkyl, and phenyl, the phenyl moiety of which may optionally bear 1 or 2 substituents selected from a group consisting of halogeno, (1-4C)alkyl, (1-4C)alkyoxy and trifluoromethyl, and

R.sup.3 and R.sup.4 are independently chosen from a group consisting of hydrogen and (1-6C)alkyl;

R.sup.5 is selected from a group consisting of (1-4C)alkyl and phenyl wherein the phenyl moiety may optionally bear 1 to 2 substituents selected from a group consisting of halogen, (1-4C)alkyl, (1-4C)alkoxy and trifluoromethyl; and n is the integer 0, 1 or 2; and

M is an acidic group selected from a group consisting of carboxy and and acylsulphonamide residue of formula -CO.NH.SO.sub.2 R.sup.6 in which

R.sup.6 is selected from a group consisting of (1-6C)alkyl, (3-8C)cycloalkyl, (6-12C)aryl, and (6-12C)aryl-(1-4C)alkyl, in which any of the aromatic moieties may bear 1 or 2 substituents selected from a group consisting of halogeno, amino, (1-4C)alkyl, (1-4C)alkoxy, and trifluoromethyl;

or a pharmaceutically acceptable salt thereof.

2. A compound as claimed in claim 1 wherein:)

R.sup.1 is selected from a group consisting of (3-7C)alkyl optionally containing 1 or more fluorine substituents; phenyl-(1-4C)alkyl in which the (1-4C)alkyl moiety may optionally bear a fluoro or (1-4C)alkoxy substituent and in which the phenyl moiety may optionally bear a substituent selected from a group consisting of halogeno, (1-4C)alkyl, (1-4C)alkoxy and trifluoromethyl; (3-6C)cycloalkyl and (3-6C)cycloalkyl-(1-4C)alkyl, the cyclic moiety of any of which optionally may contain one unsaturated linkage and may optionally bear 1 or 2 (1-4C)alkyl substituents;

Ra is hydrogen;

Rd is hydrogen, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-2C)alkyl or (1-5C)alkyl optionally containing one double or triple bond, said (1-5C)alkyl additionally optionally bearing a substituent P selected from a group consisting of cyano, carboxy, [1H-tetrazol-5-yl,] (1-2C)alkoxycarbonyl, carbamoyl of formula CONR.sup.2 R.sup.3, and an oxidized thio group of formula S(O).sub.n R.sup.5 in which R.sup.2 is selected from a group consisting of hydrogen, (1-4C)alkyl, and phenyl, the phenyl moiety of which may optionally bear 1 or 2 substituents selected from a group consisting of halogen, (1-4C)alkyl, (1-4C)alkoxy and trifluoromethyl, and R.sup.3 is chosen from a group consisting of hydrogen and (1-4C)alkyl;

R.sup.5 is selected from a group consisting of (1-4C)alkyl and phenyl wherein the phenyl moiety may optionally bear 1 or 2 substituents selected from a group consisting of halogen, (1-4C)alkyl, (1-4C)alkoxy and trifluoromethyl; and n is the integer 1 or 2; and

M is an acidic group selected from a group consisting of carboxy, and an acylsulphonamide residue of formula -CO.NH.SO.sub.2 R.sup.6 in which

R.sup.6 is selected from a group consisting of (1-4C)alkyl, (3-6C)cycloalkyl, and phenyl, in which the phenyl may bear 1 or 2 substituents selected from a group consisting of halogen, amino, (1-4C)alkyl, (1-4C)alkoxy, and trifluoromethyl.

3. A compound as claimed in claim 2 wherein:

R.sup.2 and R.sup.3 are independently selected from a group consisting of hydrogen and (1-4C)alkyl;

R.sup.5 is (1-4C)alkyl;

n is the integer 1 or 2; and

R.sup.6 is selected from a group consisting of (1-4C)alkyl, and phenyl, in which the phenyl may bear 1 or 2 substituents selected from a group consisting of halogeno, amino, (1-4C)alkyl, (1-4C)alkoxy, and trifluoromethyl.

4. A compound as claimed in claim 1 wherein M is carboxy or a radical of formula -CO.NH.SO.sub.2 R.sup.6 wherein R.sup.6 is phenyl, optionally substituted as defined in claim 1.

5. A compound as claimed in claim 1 wherein R.sup.1 is selected from a group consisting of

(a) ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 3-methylbutyl, 1-ethylpropyl, hexyl, heptyl, 1-ethylpenytl, and nonyl, each of which may optionally be substituted by 1 or more fluorine substituents;

(b) benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-methyl-1-phenylethyl, 1-phenylpropyl, 1-phenylbutyl, amd 1-phenylpentyl, each of which optionally may be substituted on the alkyl portion by methoxy or ethoxy and each of which may optionally be substituted on the phenyl moity by a member selected from a group consisting of fluoro, chloro, bromo, methyl, ethyl, methoxy and ethoxy;

(c) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopentylethyl, 2-cyclopentyl-ethyl, 1-cyclopentylpropyl, 1-cyclopentylbutyl, and 1-cyclohexylbutyl wherein each of the cyclic moieties may optionally be substituted by methyl, ethyl or isopropyl; and

(d) cyclopentenyl, cyclohexenyl, cyclopentenyl-(1-6C)alkyl, and cyclohexen-yl-(1-6C)alkyl wherein each of the cyclic moieties may optionally be substituted by methyl, ethyl or isopropyl;

Rc is methoxy or ethoxy;

Rd is selected from a group consisting of cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, 3-methylbutyl, pentyl, hexyl, vinyl, allyl, 1-propenyl, 2-melthylallyl, 3-methylbut-2-enyl, 1,3-butadientyl, 1,3-pentadienyl, 2-propynyl, and 3-butynyl, each of said alkyl groups additionally optionally bearing the substituent P;

R.sup.2, R.sup.3, and R.sup.4, when the particular group is (1-6C)alkyl are independently selected from a group consisting of methyl, ethyl, propyl, isopropyl, butyl, t-butyl and pentyl;

R.sup.5 is methyl, ethyl, propyl or isopropyl;

R.sup.6 is methyl, ethyl, propyl, isopropyl, butyl, cyclopentyl, cyclohexyl, phenyl, 1-naphthyl, 2-naphthyl, benzyl, 1-naphthylmelthyl or 2-naphthylmethyl wherein each aromatic moiety may be optionally substituted as defined in R.sup.1 for a phenyl moiety.

6. A compound as claimed in claim 1 wherein R.sup.1 is 3-methylbutyl or cyclopentylmethyl, Ra is hydrogen or methyl; Rc is methoxy; Rd is methyl, 2-carbamoylethyl or 1-(N,N-dimethylcarbamoyl)ethyl; and M is carboxy or an acylsulfonamide residue of formula -CO.NH.SO.sub.2 R.sup.6 in which R.sup.6 is 2-methylphenyl.

7. A compound as claimed in claim 1 wherein:

R.sup.1 is ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 3-methylbutyl, 1-ethylpropyl, hexyl, heptyl, 1-ethylpentyl, nonyl, benzyl, 4-chlorobenzyl, 4-trifluoromethylbenzyl, 4-methylbenzyl, 1-phenylethyl, 2-phenylethyl, 1-methyl-1-phenylethyl, 1-phenylpropyl, 1-phenylpentyl, cyclopentyl, cyclohexyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentylethyl, 1-cyclopentylbutyl, 1-cyclohexylpropyl, 1-cyclohexylbutyl, cyclopentenylmethyl, or 1-cyclohexen-4-ylmethyl;

Rc is hydrogen or methoxy;

Rd is methyl, ethyl, propyl, butyl, vinyl, allyl, 1-propenyl, 1,3-butadienyl or 2-propynyl, said group additionally optionally bearing the substituent P;

R.sup.2 is hydrogen, methyl, ethyl, propyl, isopropyl, t-butyl, phenyl, 2-methylphenyl or 4-chlorophenyl and R.sup.3 and R.sup.4 are each independently selected to be hydrogen, methyl or ethyl;

R.sup.5 is methyl, ethyl, propyl, isopropyl, phenyl, 2-melthylphenyl or 4-chlorophenyl; and

R.sup.6 is methyl, isopropyl, butyl, cyclopentyl, phenyl, 4-chlorophenyl, 4-methylphenyl, 2-chlorophenyl, 2-aminophenyl, 2-melthylphenyl, 2-methoxyphenyl, or 2-naphthyl.

8. A compound as claimed in claim 7 wherein R.sup.1 is cyclopentylmethyl; Rc is methoxy; and R.sup.6 is phenyl, 2-aminophenyl, 2-methylphenyl, 2-methoxyphenyl or 2-chlorophenyl.

9. A compound is claimed in claim 1 selected from a group consisting of N-2-methylbenzenesulphonamide and N-2-methylbenzenesulphonamide or a pharmaceutically acceptable salt thereof.

10. A salt as claimed in claim 1 wherein said salt is made with a base forming a physiologically acceptable cation.

11. A pharmaceutical composition comprising a leukotriene antagonizing amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof and a non-toxic pharmaceutically acceptable diluent or carrier.

12. A composition as claimed in claim 1 wherein said composition is in the form of a liquid or powdered aerosol.

13. A method of antagonizing the action of at least one type of leukotriene in a mammal comprising administering to the mammal a pharmaceutically effective amount of a compound of claim 1.

14. A method for the treatment of a selected allergic or inflammatory disorder in a mammal comprising administering a pharmaceutically

15. A compound as claimed in claim 1 wherein Rd is (1-3C)alkyl optionally containing one double bond, said alkyl additionally optionally bearing a substituent P selected to be carbamoyl of formula CONR.sup.2 R.sup.3, and M is an acylsulphonamide residue of formula -CO.NH.SO.sub.2 R.sup.6.

16. A compound as claimed in claim 1 selected to be N-[4-[5-(N-cyclopentylmethylcarbamoyl)-1-methylindol-3-ylmethyl]-3-methoxy benzoyl]-2-methylbenzenesulphonamide.

17. A compound as claimed in claim 1, 2, 3, 4, 5, 7 or 15 wherein Rc is methoxy.
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