DIHYDROPYRIDINE ALKANOL AMINES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract: A wherein R¹ and R² each is alkyl, alkenyl or alkoxyalkyl, wherein R³ and R⁴ each is alkyl, wherein benzene ring A is unsubstituted or bears one or more additional substituents selected from halogeno, cyano, nitro, trifluoromethyl and alkyl, or bears the substituent =N-O-N= attached to the 5-and 6-positions, wherein Ar is phenyl, naphthyl, tetrahy­ dronaphthyl, 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 hetero­ atoms selected from oxygen, nitrogen and sulphur, which ring is saturated or unsaturated, which ring is unsubstituted or bears one or more substituents and which ring may also be fused to a benzene ring, wherein p is 0 or 1, wherein X is -O- or -S-, and wherein Y is straight-or branched-chain alkylene or alkenylene each of 2 to 12 carbon atoms 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 cal­ cium ion slow channel blocking properties, or both such properties, and may be used in the treatment of hyperten­ sion.

Description: This invention relates to new alkanolamine derivatives and more particularly it relates to new dihydropyridine derivatives which possess antihypertensive properties. Many 2,6-dialkyl-4-aryl-1,4-dihydropyridine-3,5-dicarboxylate derivatives are known which inhibit the movement of calcium ions in the cardiovascular system of warm-blooded animals, and which thereby produce an antihypertensive effect. The most-used of these is nifedipine, which is dimethyl 1,4-dihydro-2,6-dimethyl-4- o -nitrophenylpyridine-3,5-dicarboxylate. Also known are many 1-aryloxy-3-amino-propan-2-ol derivatives which possess beta-adrenergic receptor blocking properties and which also produce an antihypertensive effect. Two of the most-used of these are propranolol and atenolol, which are respectively 1-(naphth-1-yloxy)- and 1- p -carbamoylmethylphenoxy-3-isopropylaminopropan-2-ol. The only described attempt to combine these two types of chemical structure into one molecule is reported by Merck workers in the Journal of Medicinal Chemistry, 1981, Vol. 24, pages 628 to 631, in which a 3-amino-2-hydroxypropoxy substituent was introduced into the 4-aryl substituent of a 4-aryl-1,4-dihydropyridine derivative, without much success in producing a compound with antihypertensive activity of the type sought by the authors. More recently, since the priority date of the present application, US Specification No. 4500527 has been published describing similar compounds in which the 3-amino-2-hydroxypropoxy substituent is linked to the 4-aryl substituent by the group -CH=N-, such compounds being claimed to have antihypertensive and beta-adrenergic blocking properties. We are also now aware of EP-A-0167371 which was published after the priority date of the present application and which claims compounds of similar chemical structure to those claimed herein. We have now found that compounds which do possess useful antihypertensive activity may be obtained by suitably combining a 3-aryloxy-2-hydroxypropylamino moiety with a 1,4-dihydropyridine moiety. According to the present invention there is provided a dihydropyridine of the formula: wherein R¹ and R², which may be the same or different, each is alkyl or alkoxyalkyl each of up to 6 carbon atoms; wherein R³ and R⁴, which may be the same or different, each is alkyl of up to 6 carbon atoms; wherein benzene ring A bears one substituent selected from cyano and nitro; wherein Ar is phenyl which is unsubstituted or which bears one or two substituents selected from halogeno, hydroxy, nitro and cyano, and alkyl, alkenyl, alkoxy, alkenyloxy and alkanoyl each of up to 6 carbon atoms; or Ar is 4-morpholino-1,2,5-thiadiazol-3-yl or 5-benzo[1,4]dioxanyl; wherein p is 0 or 1; wherein X is -O- or -S-; and wherein Y has the formula -(CH₂)m C(CH₃)₂- wherein m is 2,3,4 or 5; or an acid-addition salt thereof. It will be observed that the dihydropyridine derivative of the invention may possess at least two asymmetric carbon atoms, namely the carbon atom of the -CHOH- group in the alkanolamine chain, and, when R¹ and R², or R³ and R⁴, are different, the carbon atom at the 4-position of the dihydropyridine nucleus, and it can therefore exist in racemic and optically-active forms. It is to be understood that this invention encompasses the racemic form of the dihydropyridine derivative and any optically-active form which possesses antihypertensive activity, it being a matter of common general knowledge how a racemic compound may be resolved into optically-active forms, and how the antihypertensive activity of these forms may be determined. It is further to be understood that beta-adrenergic blocking activity usually predominates in that optically-active form which has the "S" absolute configuration of the said -CHOH- group in the alkanolamine chain when p is 1 and the "R" absolute configuration when p is 0. A suitable value for R¹, R², R³, R⁴, R⁵ or a substituent in Ar when it is alkyl is, for example, methyl, ethyl, isopropyl or isobutyl. A suitable value for a substituent in Ar when it is alkenyl is, for example, allyl. A suitable value for R¹ and R² when it is alkoxyalkyl is, for example, methoxyethyl, ethoxyethyl or propoxyethyl. A suitable halogeno substituent in Ar is, for example fluoro, chloro or bromo. A suitable value for the alkoxy or alkenyloxy substituent in Ar is, for example, methoxy, ethoxy, propoxy, isopropoxy or allyloxy. A suitable value for an alkanoyl substituent in Ar is, for example, formyl or acetyl. A suitable acid-addition salt of a dihydropyridine derivative of the invention is, for example, a salt derived from an inorganic acid, for example a hydrochloride, hydrobromide, phosphate or sulphate, or a salt derived from an organic acid, for example an oxalate, lactate, succinate, tartrate, acetate, salicylate, citrate, benzoate, beta-naphthoate or adipate. A preferred dihydropyridine of the invention has the formula stated above wherein R¹ and R², which may be the same or different, each is alkyl of up to 4 carbon atoms, wherein R³ and R⁴ are both methyl, wherein the benzene ring A bears a nitro substituent, wherein Ar is phenyl which is unsubstituted or which bears one or two substituents selected from fluoro, chloro, bromo, hydroxy, nitro, cyano, alkyl, alkenyl, alkoxy, alkenyloxy and alkanoyl each of up to 4 carbon atoms, or Ar is 1,4-benzodioxan-5-yl or 4-morpholino-1,2,5-thiadiazol-3-yl, wherein p is 0 or 1, wherein X is -O- or -S- and wherein Y is as defined above; or is an acid-addition salt thereof. A particularly preferred dihydropyridine of the invention has the formula stated above wherein R¹ and R², which may be the same or different, each is methyl or ethyl, wherein R³ and R⁴ are both methyl, wherein the benzene ring A bears a nitro substituent in the 5-position, wherein Ar is phenyl which is unsubstituted or which bears a single fluoro, chloro, bromo, nitro, cyano, allyl, methoxy, ethoxy, propoxy, isopropoxy, allyloxy or acetyl substituent in the 2-position, or Ar is 1,4-benzodioxan-5-yl, wherein p is 1, wherein X is -O- and wherein Y is as defined above; or is an acid-addition thereof. Specific dihydropyridine derivatives of the invention are hereinafter described in the Examples. Of these a preferred compound is dimethyl 1,4-dihydro-4-{2-[3-(2-hydroxy-3-phenoxypropylamino)-3-methylbutoxy]-5-nitrophenyl}-2,6-dimethylpyridine-3,5-dicarboxylate; and especially the (S)-enantiomer of the above compound in respect of the asymmetrical carbon atom at the 2-position of the (2-hydroxy-3-phenoxypropylamino)- group. The dihydropyridine derivatives of the invention may be manufactured by any chemical process known to be useful for the manufacture of chemically-analogous compounds. One preferred process for the manufacture of a dihydropyridine derivative of the invention comprises the reaction of an amine of the formula:- wherein A, R¹, R², R³, R⁴, X and Y have the meanings stated above, with an epoxide of the formula:- wherein Ar and p have the meanings stated above, or when p is O, with a haloketone of the formula:- HalCH₂CO-Ar wherein Ar has the meaning stated above and where Ha1 stands for a halogeno group, for example bromo, followed by reduction, for example with sodium borohydride, of the aminoketone thus obtained. The reaction may be carried out in an alcoholic diluent or solvent, for example in isopropanol, at a temperature of up to the boiling point of said diluent or solvent. A second process for the manufacture of a dihydropyridine of the invention comprises the reaction of a compound of the formula:- wherein A, R¹, R², R³, R⁴, X and Y have the meanings stated above and wherein Z stands for a displaceable group, with an amine of the formula:- H₂NCH₂CHOH(CH₂O)p-Ar wherein Ar and p have the meanings stated above. A suitable value for Z is, for example, a halogeno group, for example a bromo or chloro group, or a sulphonyloxy group, for example a methanesulphonyloxy or p -toluenesulphonyloxy group. A third process for the manufacture of a dihydropyridine of the invention comprises the reaction of an aldehyde of the formula:- wherein A, X, Y, Ar and p have the meanings stated above, an aminocrotonoate of the formula:- wherein R¹ and R³ have the meanings stated above and a ketoacid derivative of the formula: R⁴COCH₂COOR² wherein R² and R⁴ have the meanings stated above. This process may be carried out in a diluent or solvent at an elevated temperature, conditions conventionally used for the Hantszch synthesis of dihydropyridines. It is to be understood that when R¹ and R² are the same and R³ and R⁴ are the same the aminocrotonate may be replaced by an additional amount of the ketoacid derivative together with an ammonium salt, for example ammonium acetate. As stated above, the dihydropyridine derivatives of the invention possess antihypertensive activity. This may be demonstrated by the ability of the compound to reduce the blood pressure of a spontaneously hypertensive rat, or of a rat made hypertensive by treatment with deoxycorticosterone acetate, or of a dog made hypertensive by the Goldblatt technique of unilateral nephrectomy and clipping of the contralateral kidney. These are all standard tests used to demonstrate antihypertensive effects of medicaments. Some of the dihydropyridine derivatives of the invention possess beta-adrenergic blocking properties, some of them possess calcium ion slow-channel blocking properties and some of them possess both such activities. A preferred dihydropyridine derivative of the invention possesses both such activities. Beta-adrenergic blocking activity may be demonstrated in vivo by the ability of the compound to inhibit isoprenaline-induced tachycardia in a rat or cat, or in vitro by shifting to the right the dose-response curve of a guinea pig atrium to isoprenaline. Calcium ion slow channel blocking activity may be demonstrated in vitro by the ability of the compound to reduce spontaneous contraction in a rat portal vein preparation. These also are all standard tests used to demonstrate the stated activities. Because of the beta-adrenergic blocking and/or calcium slow channel blocking properties a dihydro-pyridine of the invention may also be useful in the treatment of heart diseases such as angina pectoris and cardiac arrhythmias. At doses of a dihydropyridine derivative which produce effective antihypertensive activity in a rat or dog no symptom of toxicity is apparent. The dihydropyridine derivative of the invention may be administered to warm-blooded animals, including man, in the form of a pharmaceutical composition comprising as active ingredient at least one dihydropyridine derivative of the invention, or an acid-addition salt thereof, in association with a pharmaceutically-acceptable diluent or carrier therefor. A suitable composition is, for example, a tablet, capsule, aqueous or oily solution or suspension, dispersible powder, spray or aerosol formulation. The pharmaceutical composition may contain, in addition to the dihydropyridine derivative of the invention, one or more drugs selected from sedatives, for example phenobarbitone, meprobamate, chloropromazine and the benzodiazepine sedative drugs, for example chlordiazepoxide and diazepam; vasodilators, for example glyceryl trinitrate, pentaerythritol tetranitrate, isosorbide dinitrate and hydralazine; diuretics, for example chlorthalidone, bendrofluazide, hydrochlorothiazide and chlorothiazide; other anti-hypertensive agents, for example reserpine, bethanidine and guanethidine; cardiac membrane stabilising agents, for example quinidine; agents used in the treatment of Parkinson's disease and other tremors, for example benzhexol; cardiotonic agents, for example digitalis preparations; and alpha-adrenergic blocking agents, for example phentolamine. When used for the treatment of heart diseases, for example angina pectoris and cardiac arrhythmias, or for the treatment of hypertension in man, it is expected that the dihydropyridine derivative would be given to man at a total oral dose of between 20 mg. and 600 mg daily, or an intravenous dose of between 1 mg. and 20 mg. Preferred oral dosage forms are tablets or capsules containing between 10 and 100 mg., and preferably 10 mg. or 50 mg., of active ingredient. Preferred intravenous dosage forms are sterile solutions of the dihydropyridine derivative or of a non-toxic acid-addition salt thereof, containing between 0.05% and 1% w/v of active ingredient, and more particularly containing 0.1% w/v of active ingredient. The invention is illustrated by the following Examples:- EXAMPLE 1 (Reference Example) A mixture of dimethyl 4-[2-(4-aminobutoxy)-5-nitrophenyl]-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (0.35 g.), phenylglycidyl ether (0.12 g.) and isopropanol (10 ml.) was heated under reflux for 3.5 hours and then evaporated to dryness, and the residue was purified by flash chromatography on a silica gel (Merck 9385) column using an 80:20:3 v/v/v mixture of ethyl acetate, methanol and concentrated aqueous ammonia solution as eluent. The product was crystallised from a mixture of ethyl acetate and petroleum ether (b.p. 60-80°C.) and there was thus obtained dimethyl 1,4-dihydro-4-{2-[4-(2-hydroxy-3-phenoxypropylamino)butoxy]-5-nitrophenyl}-2,6-dimethylpyridine-3,5-dicarboxylate, m.p. 117-120°C. The dimethyl pyridine-3,5-dicarboxylate used as starting material was obtained as follows:- A stirred mixture of 5-nitrosalicylaldehyde (8.36 g.), potassium carbonate (11.04 g.), potassium iodide (0.2 g.), N -(4-bromobutyl)phthalimide (15.6 g.) and dimethylformamide (120 ml.) was heated at 100°C. for 48 hours and then cooled to laboratory temperature. Saturated aqueous sodium chloride solution (1200 ml.) and ethyl acetate (300 ml.) were added and the mixture was shaken and filtered, the solid residue being retained. The layers of the filtrate were separated, the aqueous layer was extracted with ethyl acetate (200 ml.) and the combined ethyl acetate solutions were washed three times with saturated aqueous sodium chloride solution (100 ml. each time), dried over magnesium sulphate and evaporated to dryness. The combined residue and retained solid were crystallised from methanol and there was thus obtained 5-nitro-2-(4-phthalimidobutoxy)benzaldehyde, m.p. 145-148°C. A stirred mixture of the above aldehyde (5.68 g.), methyl 3-aminocrotonate (1.92 g.), methyl acetoacetate (1.79 g.) and isopropanol (30 ml.) was heated under reflux for 40 hours, cooled to laboratory temperature and the liquid was decanted from the precipitated gum. The gum was stirred with diethyl ether and the mixture was filtered, and the liquid was kept at laboratory temperature for 18 hours and then filtered. The combined solid residues were crystallised from isopropanol and there was thus obtained dimethyl 1,4-dihydro-2,6-dimethyl-4-[2-(4-phthalimidobutoxy)-5-nitrophenyl]pyridine-3,5-dicarboxylate, m.p. 119-123°C. A mixture of the above compound (1.8 g.), hydrazine hydrate (1.8 ml.) and ethanol (35 ml.) was heated under reflux for 18 hours, kept at laboratory temperature for 18 hours and then filtered. The filtrate was evaporated to dryness and the residue was crystallised from ethanol. There was thus obtained dimethyl 4-[2-(4-aminobutoxy)-5-nitrophenyl]-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate, m.p. 200-202°C. EXAMPLE 2 The process described in Example 1 was repeated using the appropriate 4-(2-aminohydrocarbyloxyphenyl)pyridine and the appropriate epoxide as starting materials, and there were thus obtained the compounds described in the following table. If the compounds were not crystalline and therefore characterised by melting point, the structures were confirmed by elemental analysis, mass spectrometry and proton magnetic resonance spectroscopy. The pyridinedicarboxylate starting materials were prepared by a similar process to that described in the second part of Example 1. The aldehyde intermediate for the compound wherein -Y- is -CH₂CH₂C(CH₃)₂- was prepared by reacting 3-amino-3-methylbutan-1-ol with phthalic anhydride in refluxing dimethoxyethane, removal of water by heating in toluene in a Dean and Stark apparatus, and reacting the product obtained with 2-chloro-5-nitrobenzaldehyde in dimethylformamide in the presence of sodium hydride. EXAMPLE 3 (Reference Example) A solution of (±)-dimethyl 1,4-dihydro-4-{2-[4-(2-hydroxy-3-phenoxypropylamino)butoxy)-5-nitrophenyl}-2,6-dimethylpyridine-3,5-dicarboxylate (Example 1; 0.01 g.) in methanol (1 ml.) was injected onto a high performance liquid chromatography column (25 cm. x 2.12 cm.) containing silica ('Zorbax' quality) which had previously been equilibrated with a 58:42 v/v mixture of isopropanol and hexane in which were dissolved (+)-tartaric acid (0.01 molar) and pyridine (0.05% by volume). The column was eluted with the equilibrating solvent mixture, the product being detected by ultra-violet absorption at 300 nm. The two separated products from two such elutions were individually combined and partitioned between ethyl acetate (15 ml.) and saturated aqueous sodium bicarbonate solution (20 ml.). The organic layer was separated, washed twice with saturated aqueous sodium chloride solution, dried and evaporated to dryness. There were thus obtained as oils:- (a) as less polar isomer, eluted first, (-)-dimethyl 1,4-dihydro-4-{2-[4-(2-hydroxy-3-phenoxypropylamino)butoxy]-5-nitrophenyl}-2,6-dimethylpyridine-3,5-dicarboxylate, [α]²⁰ D = -11.1° (c, 0.87% in an 0.26N-solution of hydrochloric acid in methanol); and (b) as more polar isomer, eluted second, the corresponding (+)-isomer. [α]²⁰ D = +11.6° (c, 0.47% in an 0.26N solution of hydrochloric acid in methanol). The process described above was repeated to separate the isomers of (±)-dimethyl 1,4-dihydro-4-{2-[4-(2-hydroxy-3- o -methoxyphenoxypropylamino)butoxy]-5-nitrophenyl}-2,6-dimethylpyridine-3,5-dicarboxylate, the (-)-isomer having [α]²⁰ D = -7.2% (c, 0.6% in an 0.26N solution of hydrochloric acid in methanol) and the (+)-isomer having [α]²⁰ D = +6.1° (C, 0.35% in the same solution).

Claims: A dihydropyridine of the formula: wherein R¹ and R², which may be the same of different, each is alkyl or alkoxyalkyl each of up to 6 carbon atoms; wherein R³ and R⁴, which may be the same or different, each is alkyl of up to 6 carbon atoms; wherein benzene ring A bears one substituent selected from cyano and nitro; wherein Ar is phenyl which is unsubstituted or which bears one or two substituents selected from halogeno, hydroxy, nitro and cyano, and alkyl, alkenyl, alkoxy, alkenyloxy and alkanoyl each of up to 6 carbon atoms; or Ar is 1,4-benzodioxan-5-yl or 4-morpholino-1,2,5-thiadazolyl-3-yl; wherein p is 0 or 1; wherein X is -O- or -S-; and wherein Y has the formula -(CH₂) m C(CH₃)₂- wherein m is 2, 3, 4 or 5; or an acid-addition salt thereof. A dihydropyridine as claimed in claim 1 wherein R¹ and R², which may be the same or different, each is alkyl of up to 4 carbon atoms, wherein R³ and R⁴ are both methyl, wherein the benzene ring A bears a nitro substituent, wherein Ar is phenyl which is unsubstituted or which bears one or two substituents selected from fluoro, chloro, bromo, hydroxy, nitro, cyano, alkyl, alkenyl, alkoxy, alkenyloxy and alkanoyl each of up to 4 carbon atoms, or Ar is 1,4-benzodioxan-5-yl or 4-morpholino-1,2,5-thiadiazol-3-yl, wherein p is 0 or 1, wherein X is -O- or -S- and wherein Y is as defined in claim 1; or an acid-addition salt thereof. A dihydropyridine as claimed in claim 2 wherein R¹ and R², which may be the same or different, each is methyl or ethyl, wherein R³ and R⁴ are both methyl, wherein the benzene ring A bears a nitro substituent in the 5-position, wherein Ar is phenyl which is unsubstituted or which bears a single fluoro, chloro, bromo, nitro, cyano, allyl, methoxy, ethoxy, propoxy, isopropoxy, allyloxy or acetyl substituent in the 2-position, or Ar is 1,4-benzodioxan-5-yl, wherein p is 1, wherein X is -O- and wherein Y is as defined in claim 1; or an acid-addition salt thereof. The compound dimethyl 1,4-dihydro-4-{2-[3-(2-hydroxy-3-phenoxypropylamino)-3-methylbutoxy]-5-nitrophenyl}-2,6-dimethylpyridine-3,5-dicarboxylate. An (S)-enantiomer of the compound claimed in claim 4, in respect of the asymmetrical carbon atom at the 2-position of the (2-hydroxy-3-phenoxypropylamino)-group. A process for the manufacture of a dihydropyridine, claimed in any one of claims 1 to 5, which comprises:- (a) the reaction of an amine of the formula:- wherein A, R¹, R², R³, R⁴, X and Y have the meanings stated in claim 1, 2 or 3, with an epoxide of the formula:- wherein Ar and p have the meanings stated in claim 1, 2 or 3, or, when p is 0, with a haloketone of the formula:- HalCH₂CO-Ar wherein Ar has the meaning stated above and where Hal stands for a halogeno group, followed by reduction of the aminoketone thus obtained; or (b) the reaction of a compound of the formula:- wherein A, R¹, R², R³, R⁴, X and Y have the meanings stated above and wherein Z stands for a displaceable group, with an amine of the formula:- H₂NCH₂CHOH(CH₂O) p -Ar wherein Ar and p have the meanings stated above; or (c) the reaction of an aldehyde of the formula:- wherein A, X, Y, Ar and p have the meanings stated above, an aminocrotonate of the formula:- wherein R¹ and R³ have the meanings stated above and a ketoacid derivative of the formula:- R⁴COCH₂COOR₂ wherein R² and R⁴ have the meanings stated above. 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. A composition as claimed in claim 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. 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.

Inventors: HARGREAVES, RODNEY BRIAN, MCLOUGHLIN, BERNARD JOSEPH, MILLS, STUART DENNETT
Applicants: IMPERIAL CHEMICAL INDUSTRIES PLC
Application year: 1986
Main classification: C07D211
IPC codes: A61K31, C07D211, C07D319, C07D401, A61P3, C07D405, C07D417, A61P9, C07D209, A61P25, C07D521, C07D413