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Details for Patent: 5,049,679
| Title: | Carboxamide derivatives |
| Abstract: | This invention provides a series of novel heterocyclic amides of formula I in which the group >X--Y--Z< is selected from >C.dbd.CH--N<, >C.dbd.N--N<, >N--(CH.sub.2)--N<, >CH--CH.sub.2 --N< and <N--N.dbd.C< and the other radicals have the meanings defined in the following specification. The compounds of formula I are leukotriene antagonists. The invention also provides pharmaceutically acceptable salts of the formula I compounds; pharmaceutical compositions containing the formula I compounds, or their salts, for use in the treatment of, for example, allergic or inflammatory diseases, or endotoxic or traumatic shock conditions; and processes for the manufacture of the formula I compounds, as well as intermediates for use in such manufacture. |
| Inventor(s): | Bernstein; Peter R. (Wallingford, PA) |
| Assignee: | ICI Americas Inc. (Wilmington, DE) |
| Filing Date: | Dec 29, 1989 |
| Application Number: | 07/458,868 |
| Claims: | 1. A carboxylic acid of formula IV, or a lower alkyl ester or acid halide thereof, wherein the group >X--Y--Z< is selected from a group consisting of >C.dbd.CH--N< and >CH--CH.sub.2 --N< wherein: A is a direct link; Rc is selected from a group consisting of hydrogen and (1-4C)alkoxy; Rd is hydrogen, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-4C)alkyl or (1-10C)alkyl optionally containing one or two double or triple bonds, said (1-10C)alkyl additionally optionally bearing a substituent P selected from a group consisting of cyano, carboxy, 1H-tetrazol-5.yl, (1-4C)alkoxycarbonyl, carbamoyl of formula CONR.sup.2 R.sup.3, ureido of formula NR.sup.4 CONR.sup.2 R.sup.3, carbamoyloxy of formula OCONR.sup.2 R.sup.3, a carbamate of formula NR.sup.4 COOR.sup.5, acylamino of formula NR.sup.4 COR.sup.5, acyloxy of formula OCOR.sup.5, and an (optionally oxidized) thio group of formula S(O).sub.n R.sup.5 in which (1) R.sup.2 is selected from a group consisting of hydrogen, (1-6C)alkyl, and phenyl, the phenyl moiety of which may optionally bear 1 or 2 substituents selected from a group consisting of halogeno, (1-4C)alkyl, (1-4C)alkoxy and trifluoromethyl, and R.sup.3 and R.sup.4 are independently chosen from a group consisting of hydrogen and (1-6C)alkyl; or (2) R.sup.2 and R.sup.3 together with the adjacent nitrogen form a pyrrole, pyrrolidine, piperidine, morpholine, piperazine or N-(1-6C)alkylpiperazine ring; and R.sup.4 is hydrogen or (1-6C)alkyl; R.sup.5 is selected from a group consisting of (1-4C)alkyl and pheny wherein the phenyl moiety may optionally bear 1 or 2 substituents selected from a group consisting of halogen, (1-4C)alkyl, (1-4C)alkoxy and trifluoromethyl; and n is the integer 0, 1 or 2; and T is an acidic group selected from a group consisting of carboxy, an acylsulphonamide residue of formula --CO.NH.SO.sub.2 R.sup.6 and 1H-tetrazol-5-yl in which R.sup.6 is selected from a group consisting of (1-6C)alkyl, (3-8C)cycloalkyl, (6-2C)aryl, heteroaryl selected from a group consisting of furyl, thienyl and pyridyl, and (6-2C)aryl-(1-4C)alkyl, in which any of the aromatic or heteroaromatic moieties may bear 1 or 2 substituents selected from a group consisting of halogeno, amino, (1-4C)alkyl, (1-4C)alkoxy, and trifluoromethyl; or a salt thereof. 2. A compound as claimed in claim 1 wherein: Rd is hydrogen, (3-6C)cycloalkyl, (3-6C)-cycloalkyl-(1-2C)alkyl or (1-5C)alkyl optionally containing one double or triple bond, said (1-5C)alky additionally optionally bearing a substituent P selected from a group consisting of cyano, carboxy, 1H,tetrazol-5-yl, (1-2C)alkoxycarbonyl, carbamoyl of formula CONR.sup.2 R.sup.3, and an oxidized thio group of formula S(O).sub.n R.sup.5 in which (1) R.sup.2 is selected from a group consisting of hydrogen, (1-4C)alkyl, and phenyl, the phenyl moiety of which may optionally bear 1 or 2 substituents selected from a group consisting of halogeno, (1-4C)alkyl, (1-4C)alkoxy and trifluoromethyl, and R.sup.3 is chosen from a group consisting of hydrogen and (1-4C)alkyl; or (2) R.sup.2 and R.sup.3 together with the adjacent nitrogen form a piperidine, morpholine, piperazine or N-(1-2C)alkylpiperazine ring; R.sup.5 is selected from a group consisting of (1-4C)alkyl and phenyl wherein the phenyl moiety may optionally bear 1 or 2 substituents selected from a group consisting of halogen, (1-4C)alkyl, (1-4C)alkoxy and trifluoromethyl; and n is the integer 1 or 2; and T is an acidic group selected from a group consisting of carboxy, an acylsulphonamide residue of formula --CO.NH.SO.sub.2 R.sup.6 and 1H-tetrazol-5-yl in which R.sup.6 is selected from a group consisting of (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, and heteroaryl, in which any of the aromatic or heteroaromatic moieties may bear 1 or 2 substituents selected from a group consisting of halogeno, amino, (1-4C)alkyl, (1-4C)alkoxy, and trifluoromethy. 3. A compound as claimed in claim 2 wherein: R.sup.2 and R.sup.3 are independently selected from a group consisting of hydrogen and (1-4C)alkyl; R.sup.5 is (1,4C)alkyl; n is the integer 1 or 2; and R.sup.6 is selected from a group consisting of (1-4C)alkyl, phenyl, and heteroaryl, in which any of the aromatic or heteroaromatic moieties may bear 1 or 2 substituents selected from a group consisting of halogeno, amino, (1-4C)alkyl, (1-4C)alkoxy, and trifluoromethyl. 4. A compound as claimed in claim 1 wherein T is carboxy, 1H-tetrazol-5-yl or a radical of formula --CO.NH.SO.sub.2 R.sup.6 wherein R.sup.6 is phenyl, optionally substituted as defined in claim 1. 5. A compound as claimed in claim 1 wherein Rc is methoxy or ethoxy; Rd is selected from a group consisting of cyclopropyl, cyclopentyl or cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, 3-methylbutyl, pentyl, hexyl, vinyl, allyl, 1-propenyl, 2-methylallyl, 3-methylbut-2-enyl, 1,3-butadienyl, 1,3-pentadienyl, 2-propynyl, and 3-butynyl, each of said alkyl groups additionally optionally bearing the substituents P; R.sup.2, R.sup.3, R.sup.4, and the N-substituent of a piperazine when the particular group is (1-6C)alkyl are independently selected from a group consisting of methyl, ethyl, propyl, isopropyl, butyl, t-butyl and pentyl; R.sup.5 is methyl, ethyl, propyl or isopropyl; R.sup.6 is methyl, ethyl, propyl isopropyl, butyl, cyclopentyl, cyclohexyl, phenyl, 1-naphthyl, 2-naphthyl, furyl, thienyl, pyridyl, benzyl, 1-naphthylmethyl or 2-naphthylmethyl wherein each aromatic or heteroaromatic moiety may be optionally substituted by a member selected from a group consisting of fluoro, chloro, bromo, methyl, ethyl, methoxy and ethoxy. 6. A compound as claimed in claim 1 wherein Rc is methoxy; Rd is methyl, 2-carbamoylethyl or 1-(N,N-dimethylcarbamoyl)ethyl; and T is carboxy or an acylsulfonamide residue of formula --CO.NH.SO.sub.2 R.sup.6 in which R.sup.6 is 2-methylphenyl. 7. A compound as claimed in claim 1 wherein: Rc is hydrogen or methoxy; Rd is methyl, ethyl, propyl, butyl, vinyl, allyl, 1-propenyl, 1,3-butadienyl or 2-propynyl, said group additionally optionally bearing the substituent P; R.sup.2, R.sup.3 and R.sup.4 are selected from a group consisting of (a) R.sup.2 is hydrogen, methyl, ethyl, propyl, isopropyl, t-butyl, phenyl, 2-methylphenyl or 4-chlorophenyl and R.sup.3 and R.sup.4 are each independently selected to be hydrogen, methyl or ethyl; and (b) R.sup.3 and R.sup.3 together with the adjacent nitrogen form a piperidine, morpholine or N.methylpiperazine ring and R.sup.4 is hydrogen, methyl or ethyl; R.sup.5 is methyl ethyl, propyl, isopropyl, phenyl, 2-methylphenyl or 4-chlorophenyl; and R.sup.6 is methyl, isopropyl, butyl, cyclopentyl, phenyl, 4-chlorophenyl, 4-methylphenyl, 2 chlorophenyl, 2-aminophenyl, 2-methylphenyl, 2-methoxyphen 2-naphthyl, thien 2-yl or 6-chloropyrid-3-yl. 8. A compound as claimed in claim 7 wherein Rc is methoxy; and R.sup.6 is phenyl, 2-aminophenyl, 2-methylphenyl, 2-methoxyphenyl or 2-chlorophenyl. 9. A compound as claimed in claim 1, 2, 3, 4, 5, 6, 7 or 8 wherein >X--Y--Z< has the value >C.dbd.CH--N<. 10. A compound as claimed in claim 1 wherein <X--Y--Z< has the value (d) >CH--CH.sub.2 --N<. 11. N-2-methylbenzenesulfonamide. |
