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Details for Patent: 5,440,035

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Details for Patent: 5,440,035

Title: Heterocyclic amide derivatives
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. (Kennett Square, PA)
Assignee: Zeneca Inc. (London, GB)
Filing Date:Oct 25, 1994
Application Number:08/328,469
Claims:1. A compound of formula IV ##STR38## wherein the group >X--Y--Z-- is selected from the group consisting of (b) >C.dbd.N--Za--

(c) >C.dbd.CRa--Zb--

(d) >N--CRa.dbd.N--

(e) >N--CRbRe--CRcRf--Zb--

(f) >N--N.dbd.N--

(g) >N--NRg--CO--

(h) >N--N.dbd.C.ORd--

wherein

Ra is hydrogen or (1-4C)alkyl;

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

Rd is hydrogen or (1-10C)alkyl optionally containing one or two double or triple bonds and in which a carbon atom may optionally be replaced by oxygen or sulphur, said (1-10C)alkyl additionally optionally bearing a substituent selected from the group consisting of (1-4C)alkoxy, cyano, carboxy, H-tetrazol-5-yl, carbamoyl, N-(1-4C)carbamoyl, N,N-di[(1-4C)alkyl]carbamoyl, and (1-4C)alkoxycarbonyl, or Rd is selected from the group consisting of (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-4C)alkyl, (2-6C)alkanoyl and phenyl-(1-4C)alkyl, the phenyl moiety of which may optionally bear a substituent selected from the group consisting of cyano, halogeno, (1-4C)alkyl, (1-4C)alkoxy and trifluoromethyl;

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

Rg is (1-4C)alkyl;

Za is oxy, thio, or substituted imino of the formula --N(Rd)-- in which Rd has any of the meanings defined above;

Zb is oxy or thio;

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 T; and

T is an acidic group selected from the group consisting of carboxy, 1H-tetrazol-5-yl and an acyl-sulphonamide 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.

2. A compound of the formula IVa ##STR39## wherein the group >X--Y--Z-- is selected from the group consisting of (b) >C.dbd.N--Za--

(c) >C.dbd.CRa--Zb--

(d) >N--CRa.dbd.N--

(e) >N--CRbRe--CrcRf--Zb--

(f) >N--N.dbd.N--

(g) }N--NRg--CO--

(h) >N--N.dbd.C.ORd--

wherein

Ra is hydrogen or (1-4C)alkyl;

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

Rd is hydrogen or (1-10C)alkyl optionally containing one or two double or triple bonds and in which a carbon atom may optionally be replaced by oxygen or sulphur, said (1-10C) alkyl additionally optionally bearing a substituent selected from the group consisting of (1-4C)alkoxy, cyano, carboxy, 1H-tetrazol-5-yl, carbamoyl, N-(1-4C)carbamoyl, N,N-di[(1-4C)alkyl]carbamoyl, and (1-4C)alkoxycarbonyl, or Rd is selected from the group consisting of (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-4C)alkyl, (2-6C)alkanoyl and phenyl-(1-4C)alkyl, the phenyl moiety of which may optionally bear a substituent selected from the group consisting of cyano, halogeno, (1-4C)alkyl, (1-4C)alkoxy and trifluoromethyl;

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

Rg is (1-4C)alkyl;

Za is oxy, thio, or substituted imino of the formula --N(Rd)-- in which Rd has any of the meanings defined above;

Zb is oxy or thio;

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 T; and

T is an acidic group selected from the group consisting of carboxy, 1H-tetrazol-5-yl and an acyl-sulphonamide residue of the formula --CO.NHSO.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.

3. A compound as claimed in claim 1 or 2 wherein

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

Zb is oxy or thio and Rb and Rc are each hydrogen;

A.sup.1 is methylene;

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

Q is p-phenylene optionally substituted by methoxy;

T 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.

4. A compound as claimed in claim 1 or 2 selected from the group consisting of

(a) compounds wherein T is carboxy and Rd is selected from the group consisting of methyl, propyl, 2-methoxyethyl, N-ethylcarbamoylmethyl and cyclopentyl;

(b) compounds wherein T is a radical of the formula --CO.NH.SO.sub.2 R.sup.4 wherein is phenyl and Rd is selected from the group consisting of hydrogen, methyl, 2-methoxyethyl and N-ethylcarbamoylmethyl; and

(c) compounds wherein T is a radical of the formula --CO.NH.SO.sub.2 R.sup.4 wherein is 2-methylphenyl and Rd is selected from the group consisting of methyl and N,N-dimethylcarbamoylmethyl.

5. A compound as claimed in claim 1 wherein

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;

Ra is selected from hydrogen and methyl;

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 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, allyl, propargyl, 3-methylbutyl, 3-methylbut-2-enyl, 2-carbamoylethyl, carboxymethyl, carboxyethyl, N-ethylcarbamoylmethyl, N,N-dimethylcarbamoylmethyl, 2-carboxyvinyl, 2-(methoxycarbonyl)vinyl, 2-methoxyethyl, 3-methoxypropyl, cyclopentyl, cyclopropylmethyl, acetyl, benzyl, 3-cyanobenzyl and 4-chlorobenzyl;

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

Rg is selected from the group consisting of methyl, ethyl, and propyl;

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

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

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

6. A compound as claimed in claim 1 wherein

R.sup.2 is hydrogen;

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

Ra is hydrogen;

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 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, hexyl, allyl, propargyl, 3-methylbutyl, 3-methylbut-2-enyl, carboxymethyl, carboxyethyl, N-ethylcarbamoylmethyl, N,N-dimethylcarbamoylmethyl, 2-methoxyethyl, cyclopentyl, cyclopropylmethyl, acetyl, benzyl, and 3-cyanobenzyl;

Re and Rf are each hydrogen;

Rg is propyl;

A.sup.1 is methylene;

A.sup.2 is a direct link; and

Q is selected from The group consisting of m-phenylene and p-phenylene, each of which may optionally be substituted by a hydroxy or methoxy.
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