EP0194752A1
Expired / Lapsed
EP
⏱️ 0.0 years remaining
Dihydropyridine alkanol amines, process for their preparation and pharmaceutical compositions containing them
Assignee: Imperial Chemical Industries Ltd
•
Filing: 1986-02-10
•
Granted: —
•
Expires: 2006-02-10
Abstract
Abstract A dihydropyridine of the formula:- wherein R' and R 2 each is alkyl or alkoxyalkyl, wherein R 3 is alkyl, wherein benzene ring A bears one or more substituents selected from halogeno, cyano, nitro, trifluoromethyl and alkyl or bears the substituent =N-0-N= attached to the 2- and 3-positions; wherein Ar is phenyl, naphthul, tetrahydronaphthyl, indanyl or indenyl which is unsubstituted or which bears one or more substituents or Ar is a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulphur, which ring is saturated or unsaturated, and which ring is unsubstituted or bears one or more substituents, wherein p is 0 or 1; wherein q is 1, 2, 3 or 4; wherein X is -0-, -NH-, -NHCO- or -CONH-; and wherein Y is straight-or branched-chain alkylene which may optionally be interrupted by one or two groups selected from oxygen, sulphur, imino, substituted imino, phenylene, substituted phenylene, pyridylene, cycloalkylene, 1,4-piperazinediyl, 1,4-piperidinediyl and amido groups; or an acid-addition salt thereof, processes for their manufacture and pharmaceutical compositions containing them. The compounds possess either beta-adrenergic blocking or calcium ion slow channel blocking properties or both such properties, and may be used in the treatment of hypertension.
Inventors
- 👤 Rodney Brian Hargreaves
- 👤 Bernard Joseph Mcloughlin
- 👤 Stuart Dennett Mills
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-10-23 20:21
CPC Classifications
C; C07; C07D; C07D401/00; C07D401/02; C07D401/12; A; A61; A61P; A61P25/00; A61P25/02; A61P3/00; A61P9/00; A61P9/06; A61P9/08; A61P9/10; A61P9/12; C07D211/00; C07D211/04; C07D211/80; C07D211/84; C07D211/90; C07D413/00; C07D413/02; C07D413/04
Claims Analysis
Total Claims: 13
Claim 1
Independent Claim
331 words
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 is alkyl of up to 6 carbon atoms; wherein benzene ring A bears one or more substituents selected from halogeno, cyano, nitro, trifluoromethyl and alkyl of up to 6 carbon atoms or bears the substituent =N-0-N = attached to the 2- and 3-positions (that is, to form a benzo-2,1,3-oxadiazole nucleus); wherein Ar is phenyl, naphthyl, tetrahydronaphthyl, indanyl or indenyl 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; or Ar is a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulphur, which ring is saturated or unsaturated, which ring is unsubstituted or bears one or more substituents selected from oxo, halogeno, trifluoromethyl, phenyl and morpholino, and alkyl and alkoxy each of up to 6 carbon atoms, and arylalkyl of up to 12 carbon atoms, and which ring may also be fused to a benzene ring, Ar being joined to the rest of the molecule either from the heterocyclic ring or from the fused benzene ring; wherein p is 0 or 1; wherein q is 1, 2, 3 or 4; wherein X is -O-, -NH-, -NHCO- or -CONH-; and wherein Y is straight-or branched-chain alkylene of 2 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 4 wherein R 4 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 2
Dependent Claim
331 words
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 is alkyl of up to 6 carbon atoms; wherein benzene ring A bears one or more substituents selected from halogeno, cyano, nitro, trifluoromethyl and alkyl of up to 6 carbon atoms or bears the substituent =N-0-N = attached to the 2- and 3-positions (that is, to form a benzo-2,1,3-oxadiazole nucleus); wherein Ar is phenyl, naphthyl, tetrahydronaphthyl, indanyl or indenyl 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; or Ar is a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulphur, which ring is saturated or unsaturated, which ring is unsubstituted or bears one or more substituents selected from oxo, halogeno, trifluoromethyl, phenyl and morpholino, and alkyl and alkoxy each of up to 6 carbon atoms, and arylalkyl of up to 12 carbon atoms, and which ring may also be fused to a benzene ring, Ar being joined to the rest of the molecule either from the heterocyclic ring or from the fused benzene ring; wherein p is 0 or 1; wherein q is 1, 2, 3 or 4; wherein X is -O-, -NH-, -NHCO- or -CONH-; and wherein Y is straight-or branched-chain alkylene of 2 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 4 wherein R 4 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
Dependent Claim
105 words
A dihydropyridine derivative as claimed in claim 1 wherein R 1 and R 2 , which may be the same or different, each is methyl or ethyl, wherein R 3 is methyl, wherein ring A is 2-chlorophenyl or 3-nitrophenyl, wherein Ar is phenyl which is unsubstituted or bears a chloro, cyano, methyl or methoxy substituent at the 2-position, or Ar is unsubstituted 1-naphthyl, 4- indolyl or 4-carbazolyl, wherein p and q are both 1, wherein X is -0-, -NHCO- or -CONH- and wherein Y is alkylene of 2 to 5 carbon atoms which may be interrupted by -0-, -NH-or -CONH-, or an acid-addition salt thereof.
Claim 4
Dependent Claim
37 words
A dihydropyridine as claimed in claim 2 wherein R 1 is methyl or ethyl, R 2 is ethyl, X is -0- and Y is alkylene of 2 to 4 carbon atoms which may be interrupted by -0-.
Claim 5
Dependent Claim
6 words
The compound ethyl 2-[2-(3-o-eyanophanoxy-2-hydroxypropyl amino) ethoxy]methyl-1,4-dihydro-5-methoxycarbonyl-6-methyl-4-m-nitrophenylpyridine-3-carboxylate.
Claim 6
Dependent Claim
6 words
The compound ethyl 2-[2-(3-o-eyanophanoxy-2-hydroxypropyl amino) ethoxy]methyl-1,4-dihydro-5-methoxycarbonyl-6-methyl-4-m-nitrophenylpyridine-3-carboxylate.
Claim 7
Dependent Claim
23 words
The compound ethyl 4-o-chlorophenyl-2-[2-(3-o-cyanophenoxy-2-hydroxypropylamno)ethoxy]methyl-1,4-dihydro-5-methoxycarbonyl-6-methylpyridine-3-carboxylate; ethyl 2-{2-[3-(carbazol-4-yloxy)-2-hydroxypropylamino] ethoxy} methyl-1,4-dihydro-5-methoxycarbonyl-6-methyl-4-m-nitrophenylpyridine-3-carboxylate; diethyl 2-[2-(3-o-cyanophenoxy-2-hydroxypropylamino) ethoxy]methyl-l,4-dihydro-6-methyl-4-m-nitrophenylpyridine-3,5-dicarboxylate; ethyl 2-[3-(3-o-cyanophenoxy-2-hydroxypropylamino)propoxy]methyl-1,4-dihydro-5-methoxycarbonyl-6-methyl-4-m-ni trophenylpyridi ne-3-carboxylate; ethyl 2-[4-(3-o-cyanophenoxy-2-hydroxypropylamino)-butoxy]methyl-1,4-dihydro-5-methoxycarbonyl-6-methyl-4-m-nitrophenylpyridine-3-carboxylate; or ethyl 2-{2-[2-(3-o-cyanophenoxy-2-hydroxypropylami no) - ethoxy]ethoxy}methyl-1,4-dihydro-5-methoxycarbonyl-6-methyl-4-m-nitrophenylpyridine-3-carboxylate.
Claim 8
Dependent Claim
23 words
The compound ethyl 4-o-chlorophenyl-2-[2-(3-o-cyanophenoxy-2-hydroxypropylamno)ethoxy]methyl-1,4-dihydro-5-methoxycarbonyl-6-methylpyridine-3-carboxylate; ethyl 2-{2-[3-(carbazol-4-yloxy)-2-hydroxypropylamino] ethoxy} methyl-1,4-dihydro-5-methoxycarbonyl-6-methyl-4-m-nitrophenylpyridine-3-carboxylate; diethyl 2-[2-(3-o-cyanophenoxy-2-hydroxypropylamino) ethoxy]methyl-l,4-dihydro-6-methyl-4-m-nitrophenylpyridine-3,5-dicarboxylate; ethyl 2-[3-(3-o-cyanophenoxy-2-hydroxypropylamino)propoxy]methyl-1,4-dihydro-5-methoxycarbonyl-6-methyl-4-m-ni trophenylpyridi ne-3-carboxylate; ethyl 2-[4-(3-o-cyanophenoxy-2-hydroxypropylamino)-butoxy]methyl-1,4-dihydro-5-methoxycarbonyl-6-methyl-4-m-nitrophenylpyridine-3-carboxylate; or ethyl 2-{2-[2-(3-o-cyanophenoxy-2-hydroxypropylami no) - ethoxy]ethoxy}methyl-1,4-dihydro-5-methoxycarbonyl-6-methyl-4-m-nitrophenylpyridine-3-carboxylate.
Claim 9
Dependent Claim
305 words
A process for the manufacture of a dihydropyridine, claimed in any of claims 1 to 5, which comprises:- (a) the reaction of an amine of the formula:- wherein A, R 1 , R 2 , R 3 , q, X and Y have the meanings stated in any of claims 1 to 3, with an epoxide of the formula:- wherein Ar and p have the meanings stated in claim 1 or 2, or, when p is 0, with a haloketone of the formula 'wherein Ar has the meaning stated above and wherein Hal stands for a halogeno 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 -CONH-, the reaction of an acid of the formula:- wherei n A, R 1 , R 2 , R 3 , q and X have the meani ngs stated above, or an activated derivative thereof, with an amine of the formula:- wherein Ar and p have the meanings stated above, and wherein Y 1 and Y 2 are such that -Y 1 -CONH-Y 2 - has the same meaning as stated above for Y; or (c) the reaction of a compound of the formula:- wherein A, R 1 , R 2 , R3, q, X and Y have the meanings stated above and wherein Z stands for a displaceable group, with an amine of the formula:- wherein Ar and p have the meanings stated above; or (d) the rection of an aldehyde of the formula wherein A has the meaning stated above, an aminocrotonate of the formula wherein R l and R 3 have the meanings stated above and a ketoacid derivative of the formula wherein Ar, p, q, R 2 , X and Y have the meanings stated above.
Claim 10
Dependent Claim
33 words
A pharmaceutical composition comprising as active ingredient at least one dihydropyridine, claimed in any of claims 1 to 5, or an acid-addition salt thereof, in association with a pharmaceutically-acceptable diluent or carrier therefor.
Claim 11
Dependent Claim
24 words
A composition as claimed in claim 7 which is a tablet, capsule, aqueous or oily solution or suspension, dispersible powder, spray or aerosol formulation.
Claim 12
Dependent Claim
51 words
9 . A composition as claimed in claim 7 or 8 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 13
Dependent Claim
28 words
The use of a compound, claimed in any of claims 1 to 5, for the manufacture of a medicament for producing an antihypertensive effect in a warm-blooded animal.
References Cited (Backward Citations)
USPTO Annuity & Maintenance Windows
Maintenance schedule is calculated for granted US utility patents.