1,4-DIHYDROPYRIDINE DERIVATIVES, METHODS FOR THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME

Abstract: 1,4-dihydropyridine derivatives having hypotensive ac­ tion whose time to take effect is long so that blood pressure drops slowly, and whose toxicity is low possess the following general formula wherein specifically R³ is a combined group formed from an unsaturated straight chain hydrocarbon or derivative thereof with (1) an unsaturated hydrocarbyl group or (2) an aryl or hydroaromatic group. A carbon atom of an unsaturated group of the unsaturated hydrocarbon(s) or a ring carbon atom of the aryl or hydroaromatic group is connected to a carbon atom of an unsaturated group of the unsaturated straight chain hydrocarbon or derivative thereof.

Description: This invention relates to novel 1,4-dihydropyridine derivatives having hypotensive action. It is known that some 1,4-dihydropyridine derivatives have hypotensive action. For example, 4-(o-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (US-A-3,644,627; hereinafter referred to as "nifedipine") and 4-(m-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[2-(benzylmethylamino)-ethyl] ester hydrochloride (Japanese Patent Publication No.45075/1980; hereinafter referred to as "nicardipine") have already been utilized in medicine for their hypotensive action and coronary vasodilation effect. Moreover, it is also known that many compounds similar to nifedipine and nicardipine and represented by the following general formula also have hypotensive action (Japanese Patent Publication No.29989/1980, ibid No.29990/1980, Japanese Patent Application Kokai No.64571/l980, etc.). in which R¹ is an alkyl group, for example methyl or ethyl, R² is, inter alia , 3-nitrophenyl, and R⁴ is alkyl, for example ethyl or isopropyl, alkenyl, for example allyl, or alkynyl, for example propargyl. However, these compounds have the disadvantage that the time their effect is maintained (effecting time) is short. For example, it has been reported that when 10 µg/kg of nicardipine whose effecting time is longer than that of nifedipine, were injected into a vein of a dog, the effecting time was only about 30 to 40 minutes (Arzneim-Forsch, vol. 22, p 33 (1976), ibid., vol. 26, p 2172 (1982), Tohoigakkai Zasshi, vol. 26, No.2, p 48 (1972)). Generally, when treating hypertension it is desirable for the effecting time to be long so that the lowering of blood pressure takes place slowly. It is an object of the invention to provide a compound having hypotensive action whose effecting time is long and which only reduces blood pressure slowly. The 1,4-dihydropyridine derivatives of the invention is characterized by the replacement of R⁴ such as ethyl group, isopropyl group, allyl group, propargyl group, etc. in the aforesaid general formula by a combination group of an unsaturated straight chain hydrocarbyl group or derivative thereof and an unsaturated hydrocarbyl group or an aryl or heteroaromatic group linked to an unsaturated carbon chain of the straight chain hydrocarbon.. According to one aspect of this invention, there are provided 1,4-dihydropyridine derivatives represented by the general formula in which R¹ represents a saturated or unsaturated, straight-chain, branched or cyclic hydrocarbyl group containing up to 6 carbon atoms, in which one carbon atom of the carbon skeleton thereof is optionally replaced by an oxygen or sulphur atom and/or in which one or more hydrogen atoms is/are optionally substituted by phenyl, phenoxy or phenylthio; R² represents phenyl, naphthyl or furyl in which one or more hydrogen atoms is/are optionally substituted by a moiety selected from halogen atoms, alkylthio groups, nitro groups and cyano groups, and R³ represents (A), with R² being phenyl or substituted phenyl, a straight-chain or branched hydrocarbyl group containing two double bonds conjugated with each other, or (B) a group which is (a) an unsaturated straight-chain or branched aliphatic hydrocarbyl group containing from 3 to 6 carbon atoms, which group is optionally substituted by phenyl, an unsaturated carbon atom of said hydrocarbyl group having attached thereto a ring carbon atom of (b) a phenyl, naphthyl, furyl, thienyl, N-methyl-1-pyrrolyl or pyridyl group, with a said phenyl group optionally being substituted by a group selected from methyl, nitro and cyano groups, excluding a compound which is cinnamyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate or methyl phenylpropargyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. According to a second aspect of this invention, there are provided 1,4-dihydropyridine derivatives represented by the general formula in which R¹ represents a saturated or unsaturated, straight-chain, branched or cyclic hydrocarbyl group containing up to 6 carbon atoms or an analogue thereof in which one or more carbon atoms of the carbon skeleton thereof is replaced by an oxygen atom or a sulphur atom and/or in which one or more hydrogen atoms is/are substituted by moieties selected from phenyl, phenoxy and phenylthio; R² represents a phenyl, naphthyl, furyl,pyridyl or thienyl group in which one or more hydrogen atoms is/are optionally substituted by a moiety selected from halogen atoms, alkylthio groups, nitro groups and cyano groups, and R³ represents either (A) a group which is (a) an unsaturated straight-chain hydrocarbyl group containing 3 to 6 carbon atoms and in which a carbon atom of an unsaturated group is essentially bound by a direct chemical bond to an unsaturated carbon atom of (b) an unsaturated hydrocarbyl group containing up to 6 carbon atoms such that an unsaturated double bond of (a) is in conjunction with an unsaturated double bond of (b), or (B) a group which is (c) a said unsaturated straight-chain hydrocarbyl group (a) or a said unsaturated straight-chain hydrocarbyl group (a) which is phenyl substituted or in which a hydrogen atom at the 1-position is substituted by C₁₋₄ alkyl or both hydrogen atoms at the 1-position are substituted by methyl groups, an unsaturated carbon atom of said unsaturated straight-chain hydrocarbyl group having attached thereto a ring carbon atom of (d) a phenyl, naphthyl, furyl, thienyl, N-methyl-2-pyrrolyl or pyridyl group, with one or more hydrogen atoms of a said phenyl group being optionally substituted by a moiety selected from methyl, cyano and nitro groups, excluding a compound which is cinnamyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate or methyl phenylpropargyl (or 2-thienylpropargyl or 2-pyridylpropargyl) 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. This invention also includes pharmaceutically acceptable acid addition salts of compounds as aforesaid. EP-A-145434 published on 19 June 1985 disclosed 1,4-dihydropyridine derivatives having, inter alia , hypotensive action. Having regard to Article 54(3) EPC we exclude from our invention various groups of compounds according to the foregoing provisoes. Insofar as the second aspect of the invention is concerned, and also the first aspect of the invention, insofar as the restrictions of the definitions therein permit, the hydrocarbyl group R¹ may be saturated or unsaturated, and may be straight chain, branched or cyclic and contains up to 6 carbon atoms. Such hydrocarbyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.butyl, n-pentyl, n-hexyl, allyl, 3-butenyl, crotyl, 3-butene-2-yl, 2-butynyl, 3-butynyl, cyclohexyl, 2-pentyl, 3-pentyl, 4-penten-1-yl, 3-penten-2-yl, 2-penten-1-yl, 2,4-hexadienyl, 2-hexen-1-yl, 1-hexen-3-yl, propargyl, cyclopropylmethyl, 3-pentynyl, 2-hexen-3-yn-1-yl and 2-cyclohexenyl groups. One or mare carbon atoms of the skeleton of the hydrocarbyl group may be replaced by an oxygen atom or a sulphur atom to produce a hydrocarbyl group analogue. Preferably, one or more carbon atoms of a carbon chain or a carbocyclic ring is/are replaced by oxygen atom(s) and/or one or more hydrogen atoms is/are substituted by phenyl. Such a hydrocarbyl group analogue is exemplified by 2-methoxyethyl, 2-ethoxyethyl, 2-(2-methoxyethoxy)ethyl, 2-butoxyethyl, 2-(2-ethoxyethoxy)ethyl, 3-methoxybutyl, 4-methoxy-3-butene-2-yl, 2-(2-butoxyethoxy)ethyl, 2-cyclohexyloxyethyl, 2-methyithioethyl, 2-ethylthioethyl, 3-methylthiobutyl and 2-cyclohexylthioethyl groups. One or more hydrogen atoms of the hydrocarbon group or its analogue mentioned above may be substituted by phenyl, phenoxy or phenylthio. R² is an aryl or heteroaromatic group, specifically selected from phenyl, thienyl, furyl, pyridyl, and naphthyl groups. One or more hydrogen atoms of the aryl group or the heteroaromatic group may be substituted by halogen, alkylthio, nitro or cyano. The halogen atom may be chlorine, bromine, iodine or fluorine. R³ is a combination of an unsaturated straight chain hydrocarbyl group or derivative thereof and an unsaturated hydrocarbyl group. The unsaturated straight chain hydrocarbyl group is, for example 1-propen-1-yl, 2-butene-2-yl, 1-butene-1-yl, 1-penten-1-yl, 3-penten-3-yl, 2-penten-2-yl, 1-propyn-1-yl, 2-butyn-1-yl, 1,3-hexadienyl-, 1-hexen-1-yl, 3-hexen-3-yl, or 1-hexen-2-yn-1-yl. One or more hydrogen atoms at the 1-position may be substituted by C₁₋₄ alkyl, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl or phenyl. The unsaturated hydrocarbyl group branched off from the unsaturated straight chain hydrocarbyl group is, for example, allyl, 2-butene-1-yl, 3-butene-1-yl, -buten-2-yl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 3-penten-2-yl, propargyl, 3-butyn-1-yl, 2-butyn-1-yl, 2,4-hexadienyl, 2-hexen-3-yl, 3-hexen-1-yl, 3-pentynyl, or 2-hexen-2-yn-1-yl. A carbon atom of an unsaturated group of the above hydrocarbyl group is connected to a carbon atom of an unsaturated group of the above unsaturated straight chain hydrocarbon or derivative thereof, by a direct chemical linkage. As the result, the two unsaturated bonds connected together are conjugated. The term multiple bond as used herein means double, single and (see last paragraph), hybridised bonds of aromatic or heteroaromatic rings. Alternatively, R³ is a combination of an unsaturated straight chain hydrocarbyl group or derivative thereof and a phenyl, naphthyl, cyclohexenyl, furyl, thienyl, N-methylpyrrolyl or pyridyl group in which one or more hydrogen atoms is/are optionally substituted by a moiety selected from methyl, nitro and cyano and in which a ring carbon atom is connected to a carbon atom of an unsaturated group of the unsaturated straight chain hydrocarbon or derivative thereof so as to provide conjugation of multiple bonds. Geometrical isomers of the 1,4-dihydropyridine derivatives which can exist are considered to lie within the ambit of this invention. The 1,4-dihydropyridine derivatives of this invention display hypotensive action. When 1 mg/kg of such a derivative suspended in gum arabic solution in a concentration of 5% by weight is injected into the instinum duodenum of a rat of more than 10 week growth exhibiting spontaneous hypertension, there is a drop in the blood pressure by more than 20 mmHg, usually more than 35 mmHg. The time to reach the lowest blood pressure is more than 20 minutes, usually more than 40 minutes. The half-life period of the activity of the 1,4-dihydropyridine derivative is more than 60 minutes, usually more than 120 minutes. Both the cis isomer and the trans isomer have hypotensive action. This invention also provides methods for the production of the aforesaid 1,4-dihydropyridine derivatives of this invention which may be listed as follows: Method 1 A compound having the following general formula a compound having the following general formula R²-CHO and a compound having the following general formula are mixed with each other in the absence of solvent or in a solvent inert to the reaction, for example methanol, ethanol, propanol, isopropanol, benzene, toluene, dioxane, tetrahydrofuran, dimethyl sulphoxide or dimethylformamide, and the reaction mixture is heated to produce the derivative of the invention. The preferred reaction temperature is from 50 to 150°C, and the reaction time is usually from 0.5 to 15 hours. Method 2 By following a procedure analogous to that used in Method 1, one may react with a compound of general formula a compound having the following general formula R²-CHO and a compound having the following general formula Method 3 Compounds having the general formulae are reacted together under the conditions indicated in Method 1. Method 4 Compounds having the general formulae are reacted together under the conditions indicated in Method 1. Method 5 Ammonia and compounds having the general formulae are reacted together under the conditions indicated in Method 1. Method 6 Ammonia and compounds having the general formulae are reacted together under the conditions indicated in Method 1. Method 7 A compound having the following general formula in which Z represents a hydroxyl group or an acid residue of an active ester, for example a halogen atom, a methylsulphonyloxy group, paratoluenesulphonyloxy group or benzotriazole-1-oxy group and an alcohol having the following formula R³-OH are allowed to react together to produce a 1,4-dihydropyridine derivative of the invention. When Z is a hydroxyl group, the reaction may be carried out in the presence of an acid such as hydrogen chloride, sulphuric acid or boron trifluoride or a dehydrating condensing agent, for example dicyclohexylcarbodiimide, in an inert solvent. A base, for example 4-dimethylaminopyridine may be present in the reaction mixture. When Z is an active ester residue, the reaction may be carried out in an inert solvent, optionally in the presence of a base such as triethylamine, 4-dimethylaminopyridine, pyridine or potassium carbonate. Method 8 A compound of the general formula and an alcohol of the general formula R¹OH are allowed to react in the same manner as in Method 7 to produce a 1,4-dihydropyridine derivative of the invention. The 1,4-dihydropyridine derivatives so produced may be separated from the reaction mixture and purified by conventional procedures. The 1,4-dihydropyridine derivatives of the invention have strongly vasodilative and hypotensive actions. The time to reach the lowest blood pressure is much later than conventionally, and the half-life period of the hypotensive activity of the compounds is sufficiently long. These derivatives are thus useful drugs for the treatment of hypertension. Hence this invention also provides a pharmaceutical composition which comprises a compound of this invention in association with a pharmacologically acceptable adjuvant. The following Examples illustrate the invention: Example 1 3.52 g (10 mM) of 2-(4-methylthiobenzylidene) acetoacetic acid cinnamyl ester were mixed with 1.38 g (12 mM) of 3-aminocrotonic acid methyl ester, and heated at 120°C for 3 hours. The reaction mixture was separated by silica gel column chromatography, and cinnamyl methyl 4-(4-methylthiophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate was obtained in satisfactory yield. This derivative was recrystallized once from methanol. The following 1,4-dihydropyridine derivatives were prepared by following the same procedure as set out in Example 1 but using different starting compounds. When an oily product was produced, recrystallization was not carried out. Example 2 Cinnamyl methyl 4-(2-cyanophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 3 1-tert.butyl-3-phenyl-2-propenyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 4 3-(2-furyl)-2-propenyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 5 1-isopropyl-3-phenyl-2-propenyl methyl 4-(3-nitrophenyl)-2-6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 6 3,3-diphenyl-2-propenyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 7 1-propyl-3-phenyl-2-propenyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 8 4-α-thienyl-3-butenyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 9 4-β-naphthyl-3-butenyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 10 Cinnamyl 2-methoxyethyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 11 4-(4-cyanophenyl)-3-butenyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 12 4-(N-methyl-2-pyrrolyl)-butenyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 13 4-(p-methylphenyl)-3-butenyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 14 4(p-nitropnenyl)-3-butenyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 15 1,1-dimethyl-3-phenyl-2-propenyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 16 1-ethyl-3-phenyl-2-propenyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 17 4-(3-thienyl)-3-butenyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 18 1,3-diphenyl-2-propenyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 19 4-(2-pyridyl)-3-butenyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 20 3-(2-naphthyl)-2-propenyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 21 1-methyl-3-phenyl-2-propenyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 22 1-methyl-3-phenyl-2-propenyl ethyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 23 1-methyl-3-phenyl-2-propenyl isopropyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 24 1-methyl-3-furyl-3-propenyl methyl 4-(3-nitrophenyl)-2-6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 25 1-methyl-3-phenyl-2-propenyl 2-methoxyethyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 26 2,3-diphenyl-2-propenyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 27 1-methyl-3-thienyl-2-propenyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 28 Cinnamyl methyl 4-(2-furyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 29 Cinnamyl methyl 4-(1-naphthyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 30 4,4-diphenyl-3-butenyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 31 Cinnamyl methyl 4-(2-fluorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 32 434 mg (1 mM) of 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid monocinnamyl ester, 226 mg (1.1 mM) of dicyclohexylcarbodiimide, 122 mg (1 mM) of 4-dimethylaminopyridine and 127 mg (1.2 mM) of 2-ethylthioethanol were dissolved in 10 ml of dichloroethene, and refluxed for 2 hours. After the reaction mixture was chilled, insoluble matters were filtered off. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 511 mg of cinnamyl 2-ethylthioethyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (yield 98%). Examples 33-38 The following 1,4-dihydropyridine derivatives were prepared in the same manner as Example 32, except that 2-ethylthioethanol was replaced by the appropriate specified alcohol. Example 33 Cinnamyl 2-phenylthioethyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 34 Cinnamyl 2-phenoxyethyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 35 Dicinnamyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 36 Cinnamyl phenylpropargyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 37 Cinnamyl 1-methyl-3-phenyl-2-propenyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 38 332 mg (1 mM) of 4-(3-nitrophenyl)-2,6-dimethyl-3-methoxycarbonyl-1,4-dihydropyridine-5-carboxylic acid, 226 mg (1.1 mM) of dicyclohexylcarbodiimide, 122 mg (1 mM) of 4-dimethylaminopyridine and 238 mg (1.2 mM) of 4-(1-naphthyl)-3-buten-1-ol were dissolved in 10 ml of dichloroethane, and refluxed for 2 hours. After the reaction mixture was chilled, insoluble matters were filtered off. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain 507 mg of methyl 4-(1-naphthyl)-3-butenyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (yield 99%). Examples 39-44 The following 1,4-dihydropyridine derivatives were prepared in the same manner as Example 38 except that 4-(1-naphthyl)-3-buten-1-ol was changed by the appropriate specific alcohol. Example 39 1,1-dimethyl-4-phenyl-3-butenyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 40 Methyl 5-(2-thienyl)-2,4-pentadienyl 4-(3-nitrophenyl)-2-6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 41 Methyl 5-(2-furyl)-2,4-pentadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 42 Methyl 5-(2-naphthyl)-2,4-pentadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3 , 5-dicarboxylate Example 43 Methyl 5-(1-naphthyl)-2,4-pentadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 44 Methyl (Z)-4-(2-naphthyl)-3-butenyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (cis) Example 45 376 mg (1 mM) of 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid mono 2-methoxyethyl ester, 226 mg (1.1 (mM) of dicyclohexylcarbodiimide, 122 mg (1 mM) of 4-dimethylaminopyridine and 192 mg (1.2 mM) of 5-phenyl-2,4-pentadien-1-ol were dissolved in 10 ml of dichloroethane, and refluxed for 2 hours. Thereafter, the reaction mixture was treated in the same manner as Example 39, and 503 mg of 2-methoxyethyl 5-phenyl-2,4-pentadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate were obtained (yield 97%). Example 46 Bis(5-phenyl-2-4-pentadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(5-phenyl-2,4-pentadienyl) Example 47 Cinnamyl methyl 4-(2-pyridyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate 4-(2-pyridyl)-2,6-dimethyl-3-methoxycarbonyl-1,4-dihydropyridine-5-carboxylic acid Example 48 Cinnamyl methyl 4-(2-thienyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate 4-(2-thienyl)-2,6-dimethyl-3-methoxycarbonyl-1,4-dihydropyridine-5-carboxylic acid Example 49 664 mg (2 mM) of 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester, 206 mg (2.1 mM) of 2,4-hexadien-1-ol, 433 mg (2.1 mM) of dicyclohexylcarbodiimide and 257 mg (2.1 mM) of 4-dimethylaminopyridine were dissolved in 20 ml of dichloroethane, and refluxed for 2 hours. Insoluble matters were filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gal chromatography, and 734 mg of methyl 2,4-hexadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate were obtained (yield 89%). Examples 50-54 The following 1,4-dihydropyridine derivatives were prepared in the same manner as Example 49 except that 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester was replaced by the appropriate ester. Example 50 Ethyl 2,4-hexadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid Example 51 Isopropyl 2,4-hexadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid Example 52 2-methoxyethyl 2,4-hexadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid Example 53 Cyclohexyl 2,4-hexadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid Example 54 Cinnamyl 2,4-hexadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid Example 55 398 mg (1 mM) of 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2,4-hexadienyl) ester, 108 mg (1.1 mM) of 2,4-hexadien-1-ol, 227 mg (1.1 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-dimethylaminopyridine were dissolved in 20 ml of dichloroethane, and refluxed for 2 hours. Insoluble matters were filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and 428 mg (89.4%) of bis(2,4-hexadienyl) 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate were obtained (yield 89.4%). Example 56 332 mg (1 mM) of 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester, 213 mg (1.1 mM) of 4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-ol, 103 mg (1.1 mM) of dicyclohexylcarbodiimide and 124 mg (1.1 mM) of 4-dimethylaminopyridine were dissolved in 20 ml of dichloroethane, and refluxed for 2 hours. Insoluble matters were filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and 468 mg of oily methyl 2-{4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-yl} 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate were obtained (yield 92.1%). Examples 57 199 mg (0.5 mM) of 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid mono (2,4-hexadienyl) ester, 44 mg (0.6 mM) of tert-butanol, 113 mg (0.55 mM) of dicyclohexylcarbodiimide and 61 mg (0.5 mM) of 4-dimethylaminopyridine were dissolved in 5 ml of dichloroethane, and refluxed for 2 hours. After the reaction mixture was chilled, insoluble matters were filtered off. The solvent was evaporated under reduced pressure, and the residue wad purified by silica gel column chromatography to obtain 198 mg of a crude material. This material was recrystallized with methanol, and 166 mg of tert-butyl 2,4-hexadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate were obtained (yield 73%). Examples 58-67 The following 1,4-dihydropyridine derivatives were prepared in the same manner as Example 57 except that tert. butanol was replaced by the appropriate alcohol. Example 58 Isobutyl 2,4-hexadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 59 2-methyl-2-propen-1-yl 2,4-hexadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 60 2-butenyl 2,4-hexadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 61 3-butenyl 2,4-hexadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 62 Allyl 2,4-hexadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 63 Benzyl 2,4-hexadienyl 4-(2-furyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 64 1-methyl-2-propenyl 2,4-hexadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 65 n-butyl 2,4-hexadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 66 n-propyl 2,4-hexadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 67 Cyclopropylmethyl 2,4-hexadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Example 68 Using 235 mg (2.1 mM) of 2,4-heptadien-1-ol instead of 2,4-hexadien-1-ol, methyl 2,4-heptadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate was prepared in the same manner as Example 48. Example 69 Male spontaneously hypertensive rats (SHR) which had mean arterial blood pressures higher than 140 mmHg were used for the experiments. Arterial blood pressure was measured through a catheterized artery with a pressure transducer (MPU-0.5, manufactured by Nihon Kohden Kabushiki Kaisha). The catheter was inserted into the abdominal aorta via the median coccygeal artery of SHR under light ether anesthesia. The recordings were made on a rectigraph (manufactured by Sanei Sokki Kabushiki Kaisha). 1,4-dihydropyridine derivatives prepared in the foregoing examples were administered via a catheter which had been inserted previously into the caudal vein or duodenum at least two hours after the operation. SHR were restrained with wire mesh cage immediately after the operation. Each derivative to be tested was dissolved in 1.5% PVP/ethanol, and then diluted with 0.9% saline for intravenous administration (30 µg/kg), or suspended in 5% gum arabic solution for intraduodenal administration (1 mg/kg). The results of the intravenous administration are shown in the following table. The results of the intraduodenal administration are shown in the following table. Acute toxicity of several derivatives was tested with male ddy mice weighed 15-30 grams by the up and down method. Each derivative was dissolved in 1.5% PVP/ethanol solution, and diluted with a saline solution. Such derivative solution was injected into the caudal vein, and the acute toxicity was determined. The results are shown in the following Table. Example 70 Male SHR which had systolic blood pressure higher than 160 mmHg were used while conscious for the experiments. systolic blood pressure was measured by the tail cuff method with electrophygmomanometer (PE-300, made by Narco Co.). Each derivative (3 mg/kg) was administered orally, suspended in 5% gum arabic solution. The results are shown in the following table. Example 71 Using both trans-form and cis-form of the 1,4-dihydropyridine derivatives prepared in Example 9, the depressor response of the rat was measured in the same manner as Example 69. The results are shown in the following tables.

Claims: 1,4-dihydropyridine derivatives represented by the general formula in which R¹ represents a saturated or unsaturated, straight-chain, branched or cyclic hydrocarbyl group containing up to 6 carbon atoms, in which one carbon atom of the carbon skeleton thereof is optionally replaced by a oxygen or sulphur atom and/or in which one or more hydrogen atoms is/are optionally substituted by phenyl, phenoxy or phenylthio; R² represents phenyl, naphthyl or furyl in which one or more hydrogen atoms is/are optionally substituted by a moiety selected from halogen atoms, alkylthio groups, nitro groups and cyano groups, and R³ represents (A), with R² being phenyl or substituted phenyl, a straight-chain or branched hydrocarbyl group containing two double bonds conjugated with each other, or (B) a group which is (a) an unsaturated straight-chain or branched aliphatic hydrocarbyl group containing from 3 to 6 carbon atoms, which group is optionally substituted by phenyl, an unsaturated carbon atom of said hydrocarbyl group having attached thereto a ring carbon atom of (b) a phenyl, naphthyl, furyl, thienyl, N-methyl-2-pyrrolyl or pyridyl group, with a said phenyl group optionally being substituted by a group selected from methyl, nitro and cyano groups, excluding a compound which is cinnamyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate or methyl phenylpropargyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. 1,4-dihydropyridine derivatives as claimed in claim 1, wherein R³ (B)(a) is an unsaturated straight-chain hydrocarbyl group in which a hydrogen atom at the 1-position is substituted by C₁₋₄ alkyl or both hydrogen atoms at the 1-position are substituted by methyl groups. 1,4-dihydropyridine derivatives as claimed in claim 1, wherein R² represents phenyl substituted by halogen, alkylthio, nitro, or cyano and R³ represents a straight-chain, branched or cyclic hydrocarbon group containing two double bonds conjugated with each other. 1,4-dihydropyridine derivatives represented by the general formula in which R¹ represents a saturated or unsaturated, straight-chain, branched or cyclic hydrocarbyl group containing up to 6 carbon atoms or an analogue thereof in which one or more carbon atoms of the carbon skeleton thereof is replaced by an oxygen atom or a sulphur atom and/or in which one or more hydrogen atoms is/are substituted by moieties selected from phenyl, phenoxy and phenylthio; R² represents a phenyl, naphthyl, furyl, pyridyl or thienyl group in which one or more hydrogen atoms is/are optionally substituted by a moiety selected from halogen atoms, alkylthio groups, nitro groups and cyano groups, and R³ represents either (A) a group which is (a) an unsaturated straight-chain hydrocarbyl group containing 3 to 6 carbon atoms and in which a carbon atom of an unsaturated group is essentially bound by a direct chemical bond to an unsaturated carbon atom of (b) an unsaturated hydrocarbyl group containing up to 6 carbon atoms such that an unsaturated double bond of (a) is in conjunction with an unsaturated double bond of (b), or (B) a group which is (c) a said unsaturated straight-chain hydrocarbyl group (a) or a said unsaturated straight-chain hydrocarbyl group (a) which is phenyl substituted or in which a hydrogen atom at the 1-position is substituted by C₁₋₄ alkyl or both hydrogen atoms at the 1-position are substituted by methyl groups, an unsaturated carbon atom of said unsaturated straight-chain hydrocarbyl group having attached thereto a ring carbon atom of (d) a phenyl, naphthyl, furyl, thienyl, N-methyl-2-pyrrolyl or pyridyl group, with said phenyl group being optionally substituted by a moiety selected from methyl, cyano and nitro groups, excluding a compound which is cinnamyl methyl 4-(3-nitrophenyl)-2, 6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate or methyl phenylpropargyl (or 2-thienylpropargyl or 2-pyridylpropargyl) 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. A pharmacologically acceptable acid addition salt of a compound as claimed in any preceding claim. A 1,4-dihydropyridine derivative as claimed in any preceding claim, which is in the form of a cis- or a trans-isomer. A 1,4-dihydropyridine derivative as claimed in any preceding claim, wherein in R¹, one or more carbon atoms of a carbon chain or carbocyclic ring, is/are replaced by oxygen atom(s) and/or one or more hydrogen atoms is/are substituted by phenyl. The compound methyl 2-{4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-yl}4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. The compound cinnamyl 2-methoxyethyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. The compound 4-β-naphthyl-3-butenyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. (trans or cis). A method for the production of a 1,4-dihydropyridine derivative as claimed in claim 1 or 4, which comprises carrying out a ring closing reaction involving (1) a compound of general formula a compound having the general formula R²-CHO and a compound having the general formula (2) a compound of general formula and a compound of general formula (3) ammonia, a compound of general formula and a compound of general formula wherein R x and R y are R¹ and R³ or R³ and R¹ respectively, R¹, R² and R³ being as defined in claim 1 or 4, reaction being carried out in the absence of a solvent active to the reaction. A method for the production of a 1,4-dihydropyridine compound as claimed in claim 1, which comprises reacting a compound having the general formula in which Z represents a hydroxyl group or an acid residue of an active ester with an alcohol of general formula R y -OH, R x and R y being R¹ and R³ or R³ and R¹ respectively, R¹, R² and R³ being as defined in claim 1. A pharmaceutical composition, which comprises a compound as claimed in any one of claims 1 to 10, in association with a pharmacologically acceptable adjuvant.

Inventors: IKAWA, HIROSHI, KUTSUMA, TERUO, SATO, YOSHIAKI
Applicants: FUJIREBIO KABUSHIKI KAISHA ALSO TRADING AS FUJIREBIO INC.
Application year: 1985
Main classification: C07D211
IPC codes: C07D401, C07D409, C07D405, C07D211