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Details for Patent: 5,338,734

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Details for Patent: 5,338,734

Title: Heterocyclic amide derivatives and pharmaceutical use thereof
Abstract:The invention concerns novel, pharmaceutically useful, amide derivatives of certain benzoheterocyclylalkanoic acids (and related tetrazoles and acylsulphonamides) of the formula I and salts thereof, wherein the radicals R.sup.1, R.sup.2, L, X, Y, Z, A.sup.1, Q, A.sup.2 and M have the meanings set out in the specification. The invention also includes pharmaceutical compositions incorporating a formula I compound or a salt thereof, a process for the manufacture of the said compound, together with intermediates for use in the latter process. ##STR1##
Inventor(s): Bernstein; Peter R. (Wallingford, PA), Brown; Frederick J. (Newark, DE), Matassa; Victor G. (Wilmington, DE), Yee; Ying K. (Square, PA)
Assignee: Zeneca Inc. (Wilmington, DE)
Filing Date:Nov 25, 1992
Application Number:07/981,718
Claims:1. A compound of formula I ##STR38## wherein the group >X--Y--Z-- is >N--CRbRe--CRcRf--Zb--

wherein

Rb and Rc are each hydrogen or, together with the existing carbon to carbon bond, form an unsaturated linkage;

Re and Rf are independently hydrogen or (1-4C)alkyl;

Zb is oxy or thio;

the group R.sup.1.L-- stands for amidic radicals of the formula: R.sup.1.W.CO.NH-- or R.sup.1.W.CS.NH--, in which R.sup.1 is selected from the group consisting of (a) (2-10C)alkyl optionally containing 1 or more fluorine substituents; (b) phenyl-(1-6C)alkyl in which the (1-6C)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 the group consisting of halogeno, (1-4C)alkyl, (1-4C)alkoxy and trifluoromethyl; and (c) (3-8C)cycloalkyl or (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;

W is oxy, thio, imino or a direct link to R.sup.1 ;

R.sup.2 is hydrogen, halogeno, (1-4C)alkyl or (1-4C)alkoxy;

Q is phenylene optionally bearing 1 or more substituents independently selected from the group consisting of halogeno, hydroxy, (1-4C)alkyl, (1-4C) alkoxy and trifluoromethyl;

A.sup.1 is (1-2C)alkylene or vinylene;

A.sup.2 is methylene, vinylene or a direct link to M; and

M is an acidic group selected from the group consisting of carboxy, 1H-tetrazol-5-yl and an acylsulphonamide residue of the formula --CO.NH.SO.sub.m R.sup.3 in which m is the integer 1 or 2 and R.sup.3 is selected from the group consisting of (1-6C)alkyl, (3-8C)cycloalkyl, (6-12C)aryl, heteroaryl comprising 5-12 atoms at least one of which is carbon and at least one of which is selected from a group consisting of oxygen, sulfur and nitrogen, and (6-12C)aryl-(1-4C)alkyl, in any of which the aromatic or heteroaromatic moiety may bear 1 or 2 substituents selected from the group consisting of halogeno, (1-4C)alkyl, (1-4C)alkoxy, trifluoromethyl, nitro and amino;

or a pharmaceutically acceptable salt thereof.

2. A compound as claimed in claim 1 wherein

R.sup.1 is selected from the group consisting of ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 1-ethylpropyl, hexyl, heptyl, 1-ethylpentyl, nonyl, heptafluoropropyl, benzyl, 4-chlorobenzyl, 4-trifluoromethylbenzyl, 4-methylbenzyl, 1-phenylethyl, 2-phenylethyl, 1-methyl-1-phenylethyl, 1-phenylpropyl, 1-phenylpentyl, alpha-fluorobenzyl, alpha-methoxybenzyl, cyclobutyl, cyclopentyl, cyclcohexyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentylethyl, 1-cyclopentylbutyl, 1-cyclohexylpropyl, 1-cyclohexylbutyl, 5-methyl-2-(1-methylethyl)cyclohexyl, and 1-cyclohexen-4-yl;

R.sup.2 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl and methoxy;

R.sup.3 is selected from the group consisting of methyl, isopropyl, butyl, cyclopentyl, phenyl, 4-chlorophenyl, 4-methylphenyl, 2-methylphenyl, naphthyl, thien-2-yl and 6-chloropyrid-3-yl;

Rb and Rc are selected to each be hydrogen or Rb and Rc are taken together and form an unsaturated linkage with the existing carbon to carbon bond;

Rd and Rf are each independently selected from the group consisting of hydrogen, methyl and ethyl;

A.sup.1 is selected from methylene and ethylene;

A.sup.2 is selected from a direct linkage and methylene;

Q is selected from the group consisting of meta-phenylene and para-phenylene, each of which optionally may bear a fluoro, chloro, hydroxy, methyl, methoxy or trifluoromethyl substituent; and

W is selected from the group consisting of oxy, imino, thio and a direct linkage.

3. A compound as claimed in claim 2 wherein

R.sup.1 is selected from the group consisting of butyl, pentyl, 1-ethylpentyl, 1-phenylpropyl, alpha-fluorobenzyl, alpha-methoxybenzyl, cyclopentyl, and cyclopentylmethyl;

R.sup.2 is hydrogen;

R.sup.3 is phenyl or 2-methylphenyl;

Rb and Rc are selected to each be hydrogen or Rb and Rc are taken together and form an unsaturated linkage with the existing carbon to carbon bond;

Re and Rf are each hydrogen;

A.sup.1 is methylene;

A.sup.2 is a direct link;

Q is selected from the group consisting of meta-phenylene and para-phenylene, each of which may optionally be substituted by a hydroxy or methoxy; and

W is selected from the group consisting of oxy, imino and a direct linkage.

4. A compound as claimed in claim 1 wherein Zb is oxy.

5. A compound as claimed in claim 1 wherein Zb is oxy or thio and Rb and Rc are each hydrogen.

6. A compound as claimed in claim 1 which is a 2,3-dihydrobenz-1,4-oxazine derivative of formula IIe, ##STR39## or a pharmaceutically acceptable salt thereof.

7. A compound as claimed in any one of claims 1, 2, 3, 4 or 5 wherein

A.sup.1 is methylene;

A.sup.2 is a direct link to M;

Q is p-phenylene optionally substituted by methoxy;

M is selected from the group consisting of carboxy, 1H-tetrazol-5-yl, and a radical of the formula --CO.NH.SO.sub.2 R.sup.4 wherein R.sup.4 is phenyl, optionally substituted as defined for R.sup.3.

8. A compound as claimed in any one of claims 1-3, wherein R.sup.1.L-- is attached to the benzene moiety of formula I in such a way that it bears a meta-relationship to the group X but does not bear an ortho-relationship to the group Z.

9. A salt of a compound as claimed in claim 1.

10. A compound as claimed in claim 1 wherein said compound is selected from the group consisting of

(1) N-[4-[6-(cyclopentyloxycarbonyl)amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethy l]-3-methoxybenzoyl]benzenesulphonamide,

(2) N-[4-[6-(2-cyclopentylacetamido)-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl]-3- methoxybenzoyl]benzenesulphonamide, and

(3) N-[4-[6-(2-cyclopentylacetamido)-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl]-3- methoxybenzoyl]-2-methylbenzenesulphonamide; and wherein each of these compounds may be in the form of a free acid or as its corresponding pharmaceutically acceptable salt.

11. A pharmaceutical composition having leukotriene antagonist properties comprising a pharmaceutically effective amount of a compound as claimed in claim 1 and a non-toxic pharmaceutically-acceptable diluent or carrier.

12. A composition as claimed in claim 11 wherein said composition is in the form of a liquid or powdered aerosol.

13. A method for antagonizing one or more of the actions of leukotrienes in a living mammal comprising administering to said mammal an effective amount of a compound claimed in claim 1.

14. A compound of formula III ##STR40## wherein Rh is selected from the group consisting of (a) (1-6C)alkyl optionally bearing an acetoxy, (1-4C)alkoxy or (1-4C)alkylthio group; (b) phenyl; and (c) benzyl; and wherein the other groups and substituents have the meaning as defined in claim 1.

15. A compound of formula VII ##STR41## wherein the groups and substituents have the meanings as defined in claim 1.
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