Heterocyclic amide derivatives and pharmaceutical use

• US 4,859,692 A
• Filed: 04/16/1986
• Issued: 08/22/1989
• Est. Priority Date: 04/17/1985
• Status: Expired due to Term

• Current Assignee: Astrazeneca Pharmaceuticals LP (Astrazeneca PLC)
• Original Assignee: ICI Americas Inc (Astrazeneca PLC)
• Inventors: Yee, Ying Kwong, Matassa, Victor G., Brown, Frederick J., Bernstein, Peter R.
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US06/852,798
• Time in Patent Office: 1,224 Days
• Field of Search: 548/490, 548/491, 548/505, 548/510, 548/253, 514/381, 514/415
• US Class Current: 514/381
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/14 Antitussive agents
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 209/18 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 231/56 Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 235/04 Benzimidazoles; Hydrogenated benzimidazoles
• CPC Class Codes: C07D 249/18 Benzotriazoles
• CPC Class Codes: C07D 265/36 condensed with one six-membered ring
• CPC Class Codes: C07D 333/60 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 403/10 linked by a carbon chain containing aromatic rings

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 R¹, R², L, X, Y, Z, A¹, Q, A² 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##

Claims

1. A compound of formula Ia ##STR37## 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 a group consisting of (1-4C)alkoxy, cyano, carboxy, 1H-tetrazol-5-yl, carbamoyl, N-(1-4C)carbamoyl, N,N-dicarbamoyl, and (1-4C)alkoxycarbonyl, or Rd is selected from a 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 a grou consisting of cyano, halogeno, (1-4C)alkyl, (1-4C)alkoxy and trifluoromethyl;

the group R¹.L-- stands for amidic radicals of the formula;

R¹.W.CO.-- NH-- or R¹.W.CS.NH--, in which R¹ is selected from a 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 a 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 R¹ ;

R² is hydrogen, halogeno, (1-4C)alkyl or (1-4C)alkoxy;

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

A¹ is (1-2C)alkylene or vinylene;

A² is methylene, vinylene or a direct link to M; and

M is an acidic group selected from a group consisting of carboxy, 1H-tetrazol-5-yl and an acylsulphonamide residue of the formula --CO.NH.SO_m R³ in which m is the integer 1 or 2 and R³ is selected from a 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 a 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

R¹ 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;

R² is selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl and methoxy;

R³ is selected from the group consisting of methyl, isopropyl, butyl, cyclopentyl, phenyl, 4-chlorophenyl, 4-methylphenyl, 2-methylphenyl, natphthyl, 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-methylbutyl-2-enyl, 2-carbamoylethyl, carboxymethyl, carboxyethyl, N-ethylcarbamoylmethyl, N,N-dimethylcarbamoylmethyl, 2-carboxyvinyl, 2-(methoxycarbonyl)vinyl, 2-methoxyethyl, 3-methoxypropyl, cyclopentyl, cyclopropylmethyl, acetl, benzyl, 3-cyanobenzyl and 4-chlorobenzyl;

A¹ is selected from methylene and ethylene;

A² 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

R¹ is selected from the group consisting of butyl, pentyl, 1-ethylpentyl, 1-phenylpropyl, alpha-fluorobenzyl, alpha-methoxybenzyl, cyclopentyl and cyclopentylmethyl;

R² is hydrogen;

R³ 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-methylbutyl-2-enyl, carboxymethyl, carboxyethyl, N-ethylcarbamoylmethyl, N,N-dimethylcarbamoylmethyl, methoxyethyl, cyclopentyl, cyclopropylmethyl, acetyl, benzyl, and 3-cyanobenzyl;

A¹ is methylene;

A² 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 1 wherein Rb and Rc, together with the existing carbon to carbon bond, form an unsaturated linkage.

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

A¹ is methylene;

A² 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.SO₂ R⁴ is phenyl, optionally substituted as defined for R³.

6. A compound as claimed in claim 1, 2, 3 or 4 wherein R¹.L-- is attached to the benzene moiety of formula Ia in such a way that it bears a para-relationship to the group --NRd--.

7. A compound as claimed in claim 4 consisting of an indole derivative of formula IIa. ##STR38##

8. A compound as claimed in claim 7 selected from the group consisting of

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

(b) compounds of formula IIa wherein M is a radical of the formula --CO.NH.SO₂ R⁴ wherein R⁴ is phenyl and Rd is selected from the group consisting of hydrogen, methyl, 2-methoxyethyl and N-ethylcarbamoylmethyl; and

(c) compounds of formula IIa wherein M is a radical of the formula --CO.NH.SO₂ R⁴ wherein R⁴ is 2-methylphenyl and Rd is selected from the group consisting of methyl and N,N-dimethylcarbamoylmethyl.

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

(a) N-[4-[5-(cyclopentyloxycarbonyl)amino-1-methylindol-3-ylmethyl]-3-methoxybenzoyl]benzenesulphonamide,

(b) N-[4-[5-(cyclopentyloxycarbonyl)amino-1-(N-ethylcarbamoylmethyl)indol-3-ylmethyl]-3-methoxybenzoyl]benzenesulphonamide,

(c) N-[4-[5-(cyclopentyloxycarbonyl)amino-1-methylindol-3-ylmethyl]-3-methoxybenzoyl]-2-methylbenzenesulphonamide,

(d) N-[4-[5-(2-cyclopentylacetamido)-1-(N,N-dimethylcarbamoylmethyl)indo-3-ylmethyl]-3-methoxybenzoyl]-2-methylbenzenesulphonamide,

(e) N-[4-[5-(N'"'"'-cyclopentylureido)-1-methylindol-3-ylmethyl]-3-methoxybenzoyl]-2-methylbenzenesulphonamide,

(f) N-[4-[5-(cyclopentyloxycarbonyl)aminoindol-3-ylmethyl]-3-methoxybenzoyl]benzenesulphonamide,

(g) N-[4-[5-(cyclopentyloxycarbonyl)amino-1-(2-methoxyethyl)indol-3-ylmethyl]-3-methoxybenzoyl]benzenesulphonamide, and

(h) N-[4-[5-(2-cyclopentylacetamido)-1-methylindol-3-ylmethyl]-3-methoxybenzoyl]benzenesulphonamide,

wherein each of these compounds may be in the form of a free acid or as its corresponding pharmaceutically acceptable salt.

10. A compound as claimed in claim 9 wherein said compound is N-[4-[5-(2-cyclopentylacetamido)-1-methylindo-3-ylmethyl -3-methoxybenzoyl]-benzenesulphonamide.

11. A compound as claimed in claim 9 wherein said compound is N-[4-[5-(cyclopentyloxycarbonyl)amino-1-methylindol-3-ylmethyl]-3-methoxybenzoyl]-2-methylbenzenesulphonamide.

12. 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.

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

14. 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.

15. A method as claimed in claim 14 for the treatment of allergic diseases, inflammatory diseases, endotoxic conditions or traumatic shock conditions.

16. A method as claimed in claim 15 for the treatment of allergic asthma.

17. A salt of a compound claimed in any of claims 1-4 and 7-10.