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Details for Patent: 5,391,758

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Details for Patent: 5,391,758

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. (Wilmington, DE)
Filing Date:Jun 06, 1994
Application Number:08/254,350
Claims:1. A compound of formula III ##STR37## 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 group >X--Y--Z-- is (a) >CRc-CRaRb--NRd-- 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; and

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;

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; and

A.sup.2 is methylene, vinylene or a direct link to the CO.sub.2 Rh radical.

2. A compound as claimed in claim 1 wherein

Rh is methyl, ethyl, propyl, t-butyl, acetoxymethyl, methoxymethyl, 2-methoxyethyl, methylthiomethyl, phenyl or benzyl;

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, cyclohexyl, 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;

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;

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 m-phenylene and p-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;

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;

A.sup.1 is methylene;

A.sup.2 is a direct link;

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; and

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

4. A compound as claimed in claim 3 wherein Rh is methyl, t-butyl or benzyl.

5. A compound as claimed in claim 1, 2, 3 or 4 wherein

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

the group R.sup.1.L-- stands for an amidic radical of the formula R.sup.1.W.CO.NH-- which is attached to the benzene moiety of formula III in such a way that it bears a para-relationship to the group --NRd--;

A.sup.1 is methylene;

A.sup.2 is a direct link; and

Q is p-phenylene optionally substituted by methoxy.

6. A compound as claimed in claim 1 which is an ester of an alcohol of formula HORh and 4-[5-(cyclopentyloxycarbonyl)amino-1-methylindol-3-ylmethyl]-3-methoxybenz oic acid.

7. A compound of formula VII ##STR38## wherein the group >X--Y--Z-- is (a) >CRc--CRaRb--NRd-- 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; and

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;

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; and

A.sup.2 is methylene, vinylene or a direct link to the CN radical.

8. A compound of formula IV ##STR39## wherein T is chosen from the values defined for M;

and wherein

the group >X--Y--Z-- is (a) >CRc-CRaRb--NRd-- 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; and

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;

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 the radical T; 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 R3 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.

9. A compound as claimed in claim 8 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;

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.

10. A compound as claimed in claim 9 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;

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.

11. A compound as claimed in claim 8, 9 or 10 wherein Rb and Rc, together with the existing carbon to carbon bond, form an unsaturated linkage;

the radical H.sub.2 N-- is attached to the benzene moiety of formula IV in such a way that it bears a para-relationship to the group --NRd--;

A.sup.1 is methylene;

A.sup.2 is a direct link;

Q is p-phenylene optionally substituted by methoxy; and

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.

12. A compound as claimed in claim 11 selected from the group consisting of

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

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

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

13. A compound of formula IV ##STR40## wherein T is COORh or CN 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 group >X--Y--Z-- is (a) >CRc-CRaRb--NRd-- 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; and

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;

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; and

A.sup.2 is methylene, vinylene or a direct link to the radical T.

14. A compound as claimed in claim 13 wherein

Rh is methyl, ethyl, propyl, t-butyl, acetoxymethyl, methoxymethyl, 2-methoxyethyl, methylthiomethyl, phenyl or benzyl;

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

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;

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.

15. A compound as claimed in claim 14 wherein

R.sup.2 is hydrogen;

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;

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.

16. A compound as claimed in claim 15 wherein T is COOR; and Rh is methyl, t-butyl or benzyl.

17. A compound as claimed in claim 13, 14, 15 or 16 wherein

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

the radical H.sub.2 N-- is attached to the benzene moiety of formula IV in such a way that it bears a para-relationship to the group --NRd--;

A.sup.1 is methylene;

A.sup.2 is a direct link; and

Q is p-phenylene optionally substituted by methoxy.

18. A compound as claimed in claim 13 which is an ester of an alcohol of formula HORh and 4-(5-amino-1-methylindol-3-ylmethyl)-3-methoxybenzoic acid.

19. A compound of formula IVa ##STR41## wherein T is chosen from the values defined for M; and wherein

the group >X--Y--Z-- is (a) >CRc-CRaRb--NRd-- 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; and

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;

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 the radical T; 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 R3 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.

20. A compound as claimed in claim 19 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;

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.

21. A compound as claimed in claim 20 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;

A.sup.1 is methylene;

A.sup.2 is a direct link;

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.

22. A compound as claimed in claim 19, 20 or 21 wherein

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

the radical O.sub.2 N-- is attached to the benzene moiety of formula IV in such a way that it bears a para-relationship to the group --NRd--;

A.sup.1 is methylene;

A.sup.2 is a direct link;

Q is p-phenylene optionally substituted by methoxy; and

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.

23. A compound as claimed in claim 22 selected from the group consisting of

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

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

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

24. A compound of formula IVa ##STR42## wherein T is COORh or CN 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 group >X--Y--Z-- is (a) >CRc-CRaRb--NRd-- 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; and

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;

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; and

A.sup.2 is methylene, vinylene or a direct link to the radical T.

25. A compound as claimed in claim 24 wherein

Rh is methyl, ethyl, propyl, t-butyl, acetoxymethyl, methoxymethyl, 2-methoxyethyl, methylthiomethyl, phenyl or benzyl;

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

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;

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.

26. A compound as claimed in claim 25 wherein

R.sup.2 is hydrogen;

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;

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.

27. A compound as claimed in claim 26 wherein T is COOR; and Rh is methyl, t-butyl or benzyl.

28. A compound as claimed in claim 24, 25, 26 or 27 wherein

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

the radical O.sub.2 N-- is attached to the benzene moiety of formula IV in such a way that it bears a para-relationship to the group --NRd--;

A.sup.1 is methylene;

A.sup.2 is a direct link; and

Q is p-phenylene optionally substituted by methoxy.

29. A compound as claimed in claim 24 which is an ester of an alcohol of formula HORh and 4-(5-nitro-1-methylindol-3-ylmethyl)-3-methoxybenzoic acid.
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