.

Pharmaceutical Business Intelligence

  • Anticipate P&T budget requirements
  • Evaluate market entry opportunities
  • Find generic sources and suppliers
  • Predict branded drug patent expiration

► Plans and Pricing

Upgrade to enjoy subscriber-only features like email alerts and data export. See the Plans and Pricing

DrugPatentWatch Database Preview

Claims for Patent: 4,859,692

« Back to Dashboard

Claims for Patent: 4,859,692

Title: Heterocyclic amide derivatives and pharmaceutical use
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 Kwong (Kennett Square, PA)
Assignee: ICI Americas Inc. (Wilmington, DE)
Application Number:06/852,798
Patent 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 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 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 R.sup.1 ;

R.sup.2 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;

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 a 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 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

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;

R.sup.3 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;

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;

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-methylbutyl-2-enyl, carboxymethyl, carboxyethyl, N-ethylcarbamoylmethyl, N,N-dimethylcarbamoylmethyl, 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 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

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 is phenyl, optionally substituted as defined for R.sup.3.

6. A compound as claimed in claim 1, 2, 3 or 4 wherein R.sup.1.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.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 of formula IIa 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.

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-methoxyb enzoyl]benzenesulphonamide,

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

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

(d) N-[4-[5-(2-cyclopentylacetamido)-1-(N,N-dimethylcarbamoylmethyl)indo-3-ylm ethyl]-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]be nzenesulphonamide,

(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-methoxybenzoy l]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-methoxyb enzoyl]-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.
« Back to Dashboard

For more information try a trial or see the database preview and plans and pricing

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verifification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.

`abc