Dihydropyridine alkanol amines, process for their preparation and pharmaceutical compositions containing them

Claim 2

A dihydropyridine of the formula:- wherein R l and R 2 , which may be the same or different, each is alkyl or alkoxyalkyl each of up to 6 carbon atoms: wherein R 3 and R 4 , which may be the same or different, each is alkyl of up to 6 carbon atoms; wherein R 5 is alpha-branched-chain alkyl or alkoxyalkyl each of up to 6 carbon atoms, or alpha-branched-chain arylalkyl or aryloxyalkyl each of up to 12 carbon atoms or acylaminoalkyl wherein the acyl is of up to 10 carbon atoms and the alkyl is of up to 6 carbon atoms; wherein benzene ring A bears one or more additional substituents selected from halogeno, cyano, nitro, trifluoromethyl and alkyl of up to 6 carbon atoms or bears the substituent attached to the 5- and 6-positions (that is, to form a benzo-2,1,3-oxadiazole nucleus); wherein Ar is phenylene, naphthylene, tetrahydronaphthylene, indanylene or pyridylene which is unsubstituted or which bears one or more substituents selected from halogeno, trifluoromethyl, hydroxy, amino, nitro, carbamoyl and cyano, and alkyl, alkenyl, alkoxy, alkenyloxy, alkoxyalkoxy, alkylthio, alkanoyl, carbamoylalkyl and alkanoylamino each of up to 6 carbon atoms; wherein p is 0 or 1; wherein X is -O- or -S-; wherein X 1 is a direct link or is -O-, -S-, -NH- or -NHS 0 2 -; and wherein Y is straight-or branched-chain alkylene of 1 to 12 carbon atoms which may optionally be interrupted by one or two groups selected from oxygen (-0-), sulphur (-S-), imino and substituted imino (-NR 6 wherein R 6 is hydrogen, alkyl or alkanoyl each of up to 10 carbon atoms, phenyl or aralkyl of up to 12 carbon atoms), phenylene, substituted phenylene, pyridylene, cycloalkylene of up to 6 carbon atoms, 1,4-piperazinediyl, 1,4-piperidinediyl and amido (-CONH- or -NHCO-) groups; or an acid-addition salt thereof.

Claim 3

A dihydropyridine as claimed in claim 1 which has the formula:- wherein R l and R 2 are either both methyl or both ethyl, wherein R 5 is isopropyl or t-butyl and wherein -Y-X 1 - is either - (CH 2 )m-NHCOCH 2 - or -(CH 2 ) n -O- wherein m and n each is 3,4,5 or 6, or an acid-addition salt thereof.

Claim 4

A dihydropyridine as claimed in claim 2 wherein R 5 is isopropyl and m is 3 or 4 or n is 5 or 6.

Claim 5

The compound dimethyl 4-{2-(4-(2-hydroxy-3-isopropylaminopropoxy)phenylacetamidobutoxy]-5-nitrophenyl}-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate.

Claim 6

The compound dimethyl 4-{2-(4-(2-hydroxy-3-isopropylaminopropoxy)phenylacetamidobutoxy]-5-nitrophenyl}-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate.

Claim 7

A process for the manufacture of a dihydropyridine, claimed in any of claims 1 to 4,which comprises (a) the reaction of an epoxide of the formula:- wherein A, R 1 , R 2 , R 3 , R 4 , X, X 1 , Y, A r and p have the meanings stated in any of claims 1 to 3, with an amine of the formula:- wherein R 5 has the meanings stated in any of claims 1 to 3, or when p is 0, the reaction of said amine with a haloketone of the formula:- wherein R 1 , R 2 , R 3 , R 4 , X, X 1 , Y and Ar have the meanings stated above and wherein Hal stands for a halogen group, followed by reduction of the aminoketone thus obtained; or (b) for the manufacture of a dihydropyridine wherein the group -Y- is alkylene interrupted by an amido group -NHCO-, the reaction of an amine of the formula:- wherein A, R 1 , R 2 , R 3 , R 4 and X have the meanings stated above, with an acid of the formula:- wherein R 5 , X 1 , Ar and p have the meanings stated above, or with an activated derivative thereof, and wherein Y 1 and Y 2 are such that -Y 1 -NHCO-Y 2 - has the same meaning as stated above for Y; or (c) for the manufacture of a dihydropyridine wherein X 1 is other than a direct link, the reaction of a compound of the formula:- wherein A, R l , R 2 , R 3 , R 4 , X and Y have the meanings stated above and wherein Z stands for a displaceable group, with a compound of the formula:- wherein R 5 , X 1 , A r, and p have the meanings stated above; or (d) the reaction of an aldehyde of the formula wherein A, X, X l , Y, Ar, p and R 5 have the meanings stated above, an aminocrotonate of the formula wherein R 1 and R 3 have the meanings stated above and a ketoacid derivative of the formula wherein R 2 and R 4 have the meanings stated above.

Claim 8

A pharmaceutical composition comprising as active ingredient at least one dihydropyridine, claimed in any of claims 1 to 4, or an acid-addition salt thereof, in association with a pharmaceutically-acceptable diluent or carrier therefor.

Claim 9

A composition as claimed in claim 6 which is a tablet, capsule, aqueous or oily solution or suspension, dispersible powder, spray or aerosol formulation.

Claim 10

A composition as claimed in claim 6 or 7 which contains, in addition to the dihydropyridine, one or more drugs selected from sedatives, vasodilators, diuretics, other antihypertensive agents, cardiac membrane stabilising agents, agents used in the treatment of Parkinson's disease and other tremors, cardiotonic agents, and alpha-adrenergic blocking agents.

Claim 11

The use of a compound, claimed in any of claims 1 to 4, for the manufacture of a medicament for producing an antihypertensive effect in a warm-blooded animal.

Claim 12

A method for the treatment of heart disease or hypertension in a warm-blooded animal which comprises administering to said animal an effective amount of a compound claimed in claim 1.

Claim 13

CLAIMS FOR AUSTRIA

Claim 14

What we claim is:

Claim 15

A process for the manufacture of a dihydropyridine of the formula:- wherein R 1 and R 2 , which may be the same or different, each is alkyl or alkoxyalkyl each of up to 6 carbon atoms: wherein R 3 and R 4 , which may be the same or different, each is alkyl of up to 6 carbon atoms; wherein R 5 is alpha-branched-chain alkyl or alkoxyalkyl each of up to 6 carbon atoms, or alpha-branched-chain arylalkyl or aryloxyalkyl each of up to 12 carbon atoms or acylaminoalkyl wherein the acyl is of up to 10 carbon atoms and the alkyl is of up to 6 carbon atoms; wherein benzene ring A bears one or more additional substituents selected from halogeno, cyano, nitro, trifluoromethyl and alkyl of up to 6 carbon atoms or bears the substituent attached to the 5- and 6-positions (that is, to form a benzo-2,l,3-oxadiazole nucleus); wherein Ar is phenylene, naphthylene, tetrahydronaphthylene, indanylene or pyridylene which is unsubstituted or which bears one or more substituents selected from halogeno, trifluoromethyl, hydroxy, amino, nitro, carbamoyl and cyano, and alkyl, alkenyl, alkoxy, alkenyloxy, alkoxyalkoxy, alkylthio, alkanoyl, carbamoylalkyl and alkanoylamino each of up to 6 carbon atoms; wherein p is O or 1; wherein X is -O- or -S-; wherein X l is a direct link or is -O-, -S-, -NH- or -NHS 0 2 -; and wherein Y is straight-or branched-chain alkylene of 1 to 12 carbon atoms which may optionally be interrupted by one or two groups selected from oxygen (-0-), sulphur (-S-), imino and substituted imino (-NR 6 wherein R 6 is hydrogen, alkyl or alkanoyl each of up to 10 carbon atoms, phenyl or aralkyl of up to 12 carbon atoms), phenylene, substituted phenylene, pyridylene, cycloalkylene of up to 6 carbon atoms, 1,4-piperazinediyl, 1,4-piperidinediyl and amido (-CONH- or -NHCO-) groups; or an acid-addition salt thereof, characterised by:-(a) the reaction of an epoxide of the formula:- wherein A, R 1 , R 2 , R 3 , R 4 , X, X 1 , Y, Ar and p have the meanings stated above, with an amine of the formula:- wherein R 5 has the meanings stated above or when p is 0, the reaction of said amine with a haloketone of the formula:- wherein R l, R 2, R 3 , R 4 , X , X 1 , Y and Ar have the meanings stated above and wherein Hal stands for a halogen group, followed by reduction of the aminoketone thus obtained; or (b) for the manufacture of a dihydropyridine wherein the group -Y- is alkylene interrupted by an amido group -NHCO-, the reaction of an amine of the formula:- wherein A, R 1 , R 2 , R 3 , R 4 and X have the meanings stated above, with an acid of the formula:- wherein R 5 , X l , Ar and p have the meanings stated above, or with an activated derivative thereof, and wherein Y 1 and Y 2 are such that -Y 1 -NHCO-Y 2 - has the same meaning as stated above for Y; or (c) for the manufacture of a dihydropyridine wherein X 1 is other than a direct link, the reaction of a compound of the formula:- wherein A, R l , R 2 , R 3 , R 4 , X and Y have the meanings stated above and wherein Z stands for a displaceable group, with a compound of the formula:- wherein R 5 , X 1 , Ar, and p have the meanings stated above; or (d) the reaction of an aldehyae of the formula wherein A, X, X l , Y, Ar, p and R 5 have the meanings stated above, an aminocrotonate of the formula wherein R 1 and R 3 have the meanings stated above and a ketoacid derivative of the formula wherein R 2 and R 4 have the meanings stated above.

Claim 16

A process for the manufacture of a dihydropyridine of the formula:- wherein R 1 and R 2 , which may be the same or different, each is alkyl or alkoxyalkyl each of up to 6 carbon atoms: wherein R 3 and R 4 , which may be the same or different, each is alkyl of up to 6 carbon atoms; wherein R 5 is alpha-branched-chain alkyl or alkoxyalkyl each of up to 6 carbon atoms, or alpha-branched-chain arylalkyl or aryloxyalkyl each of up to 12 carbon atoms or acylaminoalkyl wherein the acyl is of up to 10 carbon atoms and the alkyl is of up to 6 carbon atoms; wherein benzene ring A bears one or more additional substituents selected from halogeno, cyano, nitro, trifluoromethyl and alkyl of up to 6 carbon atoms or bears the substituent attached to the 5- and 6-positions (that is, to form a benzo-2,l,3-oxadiazole nucleus); wherein Ar is phenylene, naphthylene, tetrahydronaphthylene, indanylene or pyridylene which is unsubstituted or which bears one or more substituents selected from halogeno, trifluoromethyl, hydroxy, amino, nitro, carbamoyl and cyano, and alkyl, alkenyl, alkoxy, alkenyloxy, alkoxyalkoxy, alkylthio, alkanoyl, carbamoylalkyl and alkanoylamino each of up to 6 carbon atoms; wherein p is O or 1; wherein X is -O- or -S-; wherein X l is a direct link or is -O-, -S-, -NH- or -NHS 0 2 -; and wherein Y is straight-or branched-chain alkylene of 1 to 12 carbon atoms which may optionally be interrupted by one or two groups selected from oxygen (-0-), sulphur (-S-), imino and substituted imino (-NR 6 wherein R 6 is hydrogen, alkyl or alkanoyl each of up to 10 carbon atoms, phenyl or aralkyl of up to 12 carbon atoms), phenylene, substituted phenylene, pyridylene, cycloalkylene of up to 6 carbon atoms, 1,4-piperazinediyl, 1,4-piperidinediyl and amido (-CONH- or -NHCO-) groups; or an acid-addition salt thereof, characterised by:-(a) the reaction of an epoxide of the formula:- wherein A, R 1 , R 2 , R 3 , R 4 , X, X 1 , Y, Ar and p have the meanings stated above, with an amine of the formula:- wherein R 5 has the meanings stated above or when p is 0, the reaction of said amine with a haloketone of the formula:- wherein R l, R 2, R 3 , R 4 , X , X 1 , Y and Ar have the meanings stated above and wherein Hal stands for a halogen group, followed by reduction of the aminoketone thus obtained; or (b) for the manufacture of a dihydropyridine wherein the group -Y- is alkylene interrupted by an amido group -NHCO-, the reaction of an amine of the formula:- wherein A, R 1 , R 2 , R 3 , R 4 and X have the meanings stated above, with an acid of the formula:- wherein R 5 , X l , Ar and p have the meanings stated above, or with an activated derivative thereof, and wherein Y 1 and Y 2 are such that -Y 1 -NHCO-Y 2 - has the same meaning as stated above for Y; or (c) for the manufacture of a dihydropyridine wherein X 1 is other than a direct link, the reaction of a compound of the formula:- wherein A, R l , R 2 , R 3 , R 4 , X and Y have the meanings stated above and wherein Z stands for a displaceable group, with a compound of the formula:- wherein R 5 , X 1 , Ar, and p have the meanings stated above; or (d) the reaction of an aldehyae of the formula wherein A, X, X l , Y, Ar, p and R 5 have the meanings stated above, an aminocrotonate of the formula wherein R 1 and R 3 have the meanings stated above and a ketoacid derivative of the formula wherein R 2 and R 4 have the meanings stated above.

Claim 17

A process as claimed in claim 1 for the manufacture of a compound of the formula:- wherein R 1 and R 2 are either both methy or both ethyl, wherein R 5 is isopropyl or t-butyl and wherein -Y-X 1 is either -(CH 2 ) m -NHCOCH 2 - or -(CH 2 ) n -0- wherein m and n each is 3,4,5 or 6, or an acid-addition salt thereof.

Claim 18

A process as claimed in claim 2 wherein R 5 is isopropyl and m is 3 or 4 or n is 5 or 6.