PHOSPHONOPYRIDINES AND THEIR 1,4-DIHYDRODERIVATIVES

Abstract: 5-Phosphono-1,4-dihydropyridines and pyridines of formula I wherein m is zero or 1, R₁ and R₂ may be hydrogen, alkyl or aryl groups, R₃ is an optionally substituted aryl or hetaryl group, R₄ is a carboxyester, cyano, nitro, acetyl, benzyl or carboxyamido group, R₅ and R are alkyl chains optionally substituted or interrupted by heteroatoms, double or triple bonds, are endowed with a calcium antagonistic effect.

Description: The present invention relates to phosphono-1,4-di­ hydropyridines and phosphonopyridines, to a method for their preparation and to pharmaceutical and veterinary compositions containing them. The invention provides novel compounds of formula I wherein the heterocyclic ring is an aromatic pyridine ring when m is zero and a 1,4-dihydropyridine ring when m is the integer 1; R is a member selected from the group consisting of a) a C₁ -C₁₂ alkyl residue; b) a -(CH₂) n -Y-X-(CH₂) p -R₆ group wherein n is zero or an integer from 1 to 4; p is zero or an integer from 1 to 5; Y represents a single bond or a group CR₇R₈ wherein R₇ and R₈, which may be the same or different, represent hydrogen, C₁ -C₆ alkyl groups or fluorine or R₇ and R₈, taken together with the carbon atom to which they are connected, form the group C=CH₂ or the groups X represents a single bond, a cis or trans double bond, a triple bond, an oxygen or sulfur atom or SO, SO₂, NH, N-(C₁-C₆)-acyl, N-phenyl, N-benzyl groups; R₆ is a member selected from the group consisting of a') hydrogen; b') C₁-C₄ alkyl; c') a C₃-C₉ cycloaliphatic residue, unsubstituted or substituted by one or more C₁-C₆ alkyl or C₁-C₆ alkoxy substituents; d') aryl, unsubstitued or substituted by one or more halo-C₁-C₆ alkyl, C₁-C₆ alkoxy, NO₂, CN, S-C₁-C₆ alkyl, OH, C₁-C₆ acyloxy, unsubstituted or substituted amino substituents; e') a saturated or unsaturated heterocyclic ring, unsubstituted or substituted by one or more halogen, halo-C₁-C₆ alkyl, C₁-C₆ alkyl and C₁-C₆ alkoxy substituents; each or R₁ and R₂, which may be the same or different, are hydrogen, C₁-C₄ alkyl, phenyl, benzyl; R₃ represents: . a phenyl ring unsubstituted or substituted by one or more halogens, NO₂, C≡N, C₁-C₄ alkyl, halo-C₁-C₆ alkyl, C₁-C₄-alkoxy, halo-C₁-C₆ alkoxy, S-C₁-C₆ alkyl, SO-C₁-­ C₆ alkyl substituents; . a pentafluorophenyl; . a five or a six-membered heterocyclic ring; . a bicyclic ring such as α-naphthyl, β-naphthyl, α-benzofuroxanyl, α-benzo[2,3-b]-1,4-dioxanyl; R₄ is selected in the group consisting of COCH₃; COC₆H₅; C≡N; NO₂; -CONR₉R₁₀,wherein R₉ and R₁₀ which may be the same or different, are hydrogen, C₁-C₆ alkyl, phenyl and benzyl; or CO₂R₁₁ wherein R₁₁ is a C₁-C₆ alkyl or C₂-C₆ alkenyl group optionally substituted by one or more phenyl, C₁-C₆ alkoxy, hydroxy, a primary, secondary or tertiary amino group; an optionally substituted phenyl substituent; R₅ is a C₁-C₄ alkyl, phenyl or benzyl group; with the proviso that, when m is 1 and R₄ is a carboxyester group, R is different from C₁-C₁₂ alkyl. Also the pharmaceutically acceptable salts as well as the optical antipodes, i.e. the enantiomers, the racemic mixtures of the optical antipodes, the diastereoisomers and the mixtures of the diasteroisomers of the compounds of formula (I) are included in the scope of the present invention. The alkyl, alkenyl, alkynyl, alkoxy, alkanoyloxy groups may be branched or straight-chain groups. A halo-C₁-C₆ alkyl group is preferably trihalo-­ C₁-C₆ alkyl, in particular trifluoromethyl; a C₁-C₆ or a C₁-C₁₂ alkyl group is preferably methyl, ethyl, isopropyl, propyl, pentyl; a C₁-C₆ alkoxy is preferably methoxy or ethoxy; a C₂-C₆ alkenyl group is preferably allyl; a C₁-C₆ acyloxy group is preferably formyl or acetyl groups; n and p are preferably the integer 1, 2 or zero when Y is a single bond; When R₆ is a C₃-C₉ cycloaliphatic residue, it is preferably cyclopropyl, cyclopentyl, cyclohexyl or a C₃-C₉ cycloalkenyl ring e.g. cyclopentenyl; when R₆ is an aryl ring, it is preferably a phenyl unsub­ stituted or substituted by one or more hydroxy or methoxy groups; when R₆ is a heterocyclic ring, it may be either a hetero­ monocyclic ring or a heterobicyclic ring. Examples of preferred heteromonocyclic residues are furyl, tetrahydrofuryl, thienyl, tetrahydrothienyl, piri­ dyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, 5,6-dihydro-3-oxo-pyridazin-6-yl groups. Preferred secondary amino groups are -NHCH₃,NH-­ C₂H₅ and NH-CH₂-C₆H₅, preferred tertiary amino groups are Examples of pharmaceutically acceptable salts when either R₁ or R₂ are hydrogen, are those with inorganic bases such as, for example, alkaline hydroxides and alka­ line-earth hydroxides, or with organic bases such as for example methylamine, dimethylamine, trimethylamine, ethyl­ diethanolamine, tromethamine, lysine, arginine. When amino groups are present in a compound of formula (I), pharmaceutically acceptable salts are those with inorganic acids such as for example hydrochloric, sulphuric acid or organic acids such as acetic, fumaric, succinic, maleic, malic, tartaric acids. Specific examples of preferred compounds of the invention are those included in Table I and in Table II wherein respectively A and B represent a 1,4-dihydropyri­ dine and a pyridine ring. The compounds of the invention are prepared by reacting a compound of formula II wherein R and R₃ are as defined above and each of R'₁ and R'₂, which may be the same or different, are C₁-C₄ alkyl, benzyl or phenyl group, with a compound of formula III wherein R₄ and R₅ are as defined above, to give a compound of formula Ia wherein R, R'₁, R'₂, R₃, R₄ and R₅ are as defined above and m is 1, which may be subjected to a series of further possible transformation such as oxidation to give a compo­ und wherein m is zero, removal of protective groups, hy­ drolysis of phosphonic ester groups, acylation, salt for­ mation, separation of isomers etc. The cyclization reaction of a compound II with a compound III may be carried out either with a stoichiome­ tric amount of the reagents or with a small excess of the enamine III in an inert solvent, either in the presence or in absence of an acid. Suitable solvents are, for example, aromatic hydro­ carbons such as benzene, toluene; cycloaliphatic hydrocar­ bons such as cyclohexane; cyclic or linear ethers e.g. dioxane, tetrahydrofuran, dimethoxyethane; alcohols such as methanol, ethanol, 2-propanol; or mixtures thereof. Catalytic amounts of an acid such as formic, ace­ tic, trifluoroacetic, p-toluensulphonic acids are prefera­ bly added to accelerate the reaction which is preferably carried out under an inert gas atmosphere at temperatures ranging from 50°C to the solvent reflux temperature. The reaction times range from few minutes to several days, but usually do not exceed 48 hours and often a few hours are sufficient to complete the reaction. When the cyclization reaction of a compound of formula II with a compound of formula III is carried out, in the presence of air, a compound of formula Ia wherein m is zero, is obtained. The optional dehydrogenation of a compound of formula Ia wherein m is 1 may be optionally carried out in an inert solvent by treatment with an ex­ cess of oxydizing reagent such as activated manganese dioxide, a quinone such as tetrachloro-benzo-1,4-quinone or 2,3-dichloro-4,5-dicyano-benzo-1,4-quinone, etc. Preferred solvents are the above mentioned aroma­ tic, cycloaliphatic hydrocarbons, and ethers, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and esters such as ethyl acetate. A large ex­ cess of the oxidizing reagent is used when the reaction is carried out in heterogeneous phase (MnO₂), otherwise a small excess (1.2-2 molar equivalents) is sufficient to complete the reaction in a time range of few hours. The reaction is preferably carried out at room temperature. The starting compounds of formula II are prepared by reacting an aldehyde of formula (IV) R₃-CHO (IV) wherein R₃ is defined above with a phosphonate of formula (V) R-CO-CH₂-PO₃-R'₁R'₂ (V) wherein R, R'₁ and R'₂ are as defined above, in the pre­ sence of a catalyst, such as piperidine acetate, in an inert solvent, according to conventional methods. The aldehydes of formula IV are known compounds; the acyloylphosphonates of formula V are also known com­ pounds, largely used as intermediates (see for example C. Gandolfi et al., U.S.Pat. No. 4,721,184 (2.6.1981) and U.S. Pat. No. 4,328,240 (4.5.1982) and R. Pellegata et al., U.S. Pat. No. 4,338,332 (6.7.1982) or they are prepa­ red according to known methods by reaction of an activated form of acarboxylic acid of formula (VI) R-CO₂H (IV) (e.g. an ester, an imidazolyde and/or an acid chloride) wherein R is as defined above, with a lithium methylpho­ sphonate of formula (VII) Li (+) (-) CH₂PO₃R'₁R'₂ (VII) wherein R'₁ and R'₂ are as defined above (see, for exam­ ple, E.J. Corey, J. Amer. Chem. Soc., 8 8 , 5654, 1966 ; ibidem, 9 0 , 3297, 1968 . The enamine compounds of formula III are commer­ cially available substances or they can readily be prepar­ ed by reacting the corresponding carbonyl compounds R₅COCH₂R₄ with ammonium salts such as ammonium formiate, or acetate in an alcohol solvent such as methanol, etha­ nol, propanol or isopropanol. The compounds of formula III can also be obtained by hydrogenolytic cleavage of the O-N bond of isoxazole compounds of formula (VIII a,c) using conventional techniques. The reaction of ethyl-3-aminocrotonate with die­ thyl-1-phenyl- and diethyl-1-(p-methoxy-phenyl)-methyliden-­ 2-oxo-propyl-phosphonate to give 3-phosphonic ester of 2,6-dimethyl-1,4-dihydropyridines was firstly described by K. Isoleib et al., J. Prakt. Chem., 318, 207, 1976 . They did not succeeded in the preparation of other substituted phenylmethylidenphosphonates; biological data are not reported for these phosphonic-1,4-dihydropyridines. Furthermore, the E.P. Applications No. 121117, 141221 and 141222 disclose a wide range of 2,6-dime­ thyl-5-phosphonate-1,4-dihydropyridine-3-carboxylates, methods for their synthesis and therapeutic uses. The claimed compounds inhibit the contraction of smooth muscle and cardiac muscle as a consequence of a calcium antagonistic effect and are useful as antihyper­ tensive agents and coronary or peripheral vasodilators when administered orally. The compounds of the present invention of formula I, wherein m is the integer 1, are novel 5-phosphonate-­ 1,4-dihydropyridines whose peculiarity, inter alia, is an hindering substituent at the C-6 carbon atom of the dihy­ dropyridine moiety. As a consequence, 2-methyl-5-phosphonate-1,4-dihy­ dropyridine-3-carboxylate derivatives having an hindering substituent in position 6, seem to be particularly useful for achieving gradual onset in action and long lasting activities. This finding is contrary to the known statement pursued in design of effective drugs that the 2,6 substi­ tuents of the 1,4-dihydropyridine ring should be lower alkyl, although one NH₂ group may be present (see for ex. R. A. Janis et al., J. Med. Chem., 26 , 775, 1983). Furthermore, "in vitro" and "in vivo" experiments with the compounds of formula I, wherein m is the integer 1, show their ability to modify the intracellular availa­ bility of calcium ions. For example, a reduced production of malondialdehyde is observed after challenge with hydro­ gen peroxide of rat erythrocyte membranes incubated with compounds of formula I showing a protective effect of the cellular membranes from oxidative challenges. Sudden death, induced by bolus administration of arachidonic acid or of ADP and collagene mixtures, is preven­ ted in a dose related way, in intraperitoneally or orally treated mice and rabbits with the compounds of the inven­ tion. When tested by oral, i.p., and intravenous routes, the compounds of formula I exhibit very low acute toxici­ ty, with LD₅₀ values ranging from 0.7 g and 1.4 g/kg, in rats. The compounds of the invention are therefore useful for the control of calcium-dependent tissutal and enzyma­ tic processes; for medical treatment of the coronary, cerebral diseases or hypertension conditions. The compounds of formula I wherein m is zero are useful for treatment of dislipidemic and atherosclerotic diseases in mammals. To obtain the desired therapeutic effect, the compounds of the invention of the formula I may be administered to the patient in different way, alone or in pharmaceutical preparation by oral or parenteral route, i.e. intravenously or intramuscularly. A pharmaceu­ tical composition suitable to this purpose can be prepared according to the known techniques, as described for in­ stance in "Remington's Pharmaceutical Sciences Handbook", Hack Publishing Company, U.S.A. The administered amounts vary according to gravity of the treated disease and to the administration route. If administered orally, the quantity of the active principle administered varies from 0.01 mg/kg to 10 mg/kg of the patient's body weight pro die. If administered parenteral­ ly, the amount of active principle varies from 0.001 mg/kg to 5 mg/kg of patient's body weight pro die and it is preferably comprised between 0.01 mg/kg and 2 mg/kg of patient's body weight pro die. A single dose for oral administration may contain for example from 0.05 to 100 mg of active principle. A single dose for parenteral administration may contain, for example, from 0.05 to 70 mg of active principle. The compounds of the invention, because of their long lasting effect, may be administered once or twice a day; however repeated daily administrations could be - at least in some cases - desirable and may vary according to the patient's conditions or the administration route. The word "patient" means not only human beings, but generally warm-blooded animals. For the oral administration, the compound may be formulated in solid or liquid preparations such as capsu­ les, pills, tablets, powders, solutions, suspension or emulsions. The unit dosage form may be the hard or soft gelatine capsule containing for instance lubricants and inert excipients such as lactose, saccharose or starch. Alternatively, the compounds of the invention may be admi­ nistered as tablets, on carriers such as lactose, saccha­ rose or starch in combination with binders wuch as starch itself or gelatin, disintegrating agents such as potato starch, or alginic acid, and lubricants such as stearic acid and magnesium stearate. For parenteral administration the compounds of the invention may be administered in injectable forms, dissol­ ved or suspended in pharmaceutically acceptable diluents, with a pharmaceutical carrier such as a sterile liquid such as water or an oil, with or without the addition of other pharmaceutically acceptable excipients. Oils which may be used in said preparations are of mineral, vegetal, animal or synthetic kind. Generally, as a carrier for injectable solutions the following substances may be used: water, salts, aqueous solutions, dextrose or other sugars aqueous solutions, ethanol, glycols such as propylenglycol and polyethylenglycols. For the rectal administration, the compounds may be formulated in forms of suppositories, mixed with conven­ tional vehicles such as, for example, cocoa butter, wax, polyvinylpyrrolidone or polyoxyethyleneglycols, or deriva­ tives thereof. The administration route generally preferred is the oral route, while the preferred pharmaceutical formula­ tions are capsules. The invention is illustrated by the following non-­ limitative examples, wherein the abbreviations AcOH, AcOEt, EtOH, THF and Et₂O refer to acetic acid, ethyl acetate, ethanol, tetrahydrofuran and ethylether, respec­ tively. EXAMPLE 1 A stirred mixture of dimethyl-2-oxo-propyl-phospho­ nate (10 g), m-nitro-benzaldehyde (9.1 g), AcOH (2 ml), piperidine (0.8 ml) and toluene (100 ml) is heated to the reflux temperature with azeotropic removal of the formed water for 6 hours. After cooling at room temperature, the reaction mixture is washed with brine (3 × 15 ml), dried on Na₂SO₄ and the solvents are evaporated to dryness in vacuum. The crude residue is purified by SiO₂ column chro­ matography (SiO₂ 100 g, eluents: hexane/AcOEt (60:40), to give Z,E-dimethyl-1-(m-nitrophenyl)methyliden-2-oxo-pro­ pylphosphonate, as oil H-NMR (CDCl₃), δ (TMS): 2.25 (3H, s); 3.85-3.95 (6H, m); 7.25-8.30 (5H, m). EXAMPLE 2 The use of alternative solvents such as cyclohexa­ ne, benzene, a mixture of o-, m-, p-xylenes and halogenat­ ed hydrocarbons, i.e., chloroform, 1,2-dichloroethane, dichloromethane, does not introduce substantial improve­ ments in the yield of the process. Using in the procedure of the Example 1 an aldehyde selected in the group of o-nitro-, o-methylthio-,o-tri­ fluoromethyl-, m-trifluoromethyl- or 2,3-dichloro-benzal­ dehydes the following Z,E-dimethyl-2-oxo-propyl-phosphona­ tes derivatives are prepared: 1-(o-nitrophenyl)methylidene, oil, 1-(o-methylthiophenyl)methylidene, oil, 1-(o-trifluoromethylphenyl)methylidene, oil, 1-(m-trifluoromethylphenyl)methylidene, oil, 1-(2',3'-dichlorophenyl)methylidene, oil, with overall yields ranging from 50 to 69%. EXAMPLE 3 Z,E-Dimethyl-1-(o-nitrophenyl)methylidene-2-oxo-3-­ phenylthio-propyl-phosphonate (26.4 g, as an yellow oil) is prepared by reaction of o-nitrobenzaldehyde (15.8 g), dimethyl-3-phenylthio-propyl-phosphonate (26 g), AcOH (1.8 ml), piperidine (0.6 ml) and benzene (150 ml), using the procedure of the Example 1. Under nitrogen gas atmosphere, a stirred solution of the methylidene compound (4 g) in EtOH (120 ml) is added with 1-ethoxycarbonyl-2-amino-prop-1-ene (1.3 g) and few drops of 5% HCl acid in EtOH. The mixture is heated for 3 hours at the reflux temperature, and then evaporated to dryness in vacuum. The residue is partitioned between AcOEt (80 ml) and water (20 ml). The organic phase is washed with brine, dried on Na₂SO₄ and the solvent is evaporated in vacuum. The residue is purified by column chromatography on SiO₂ (60 g, CHCl₃/AcOEt (80:20) as eluent) to give, after crystallization from Et₂O, 2-me­ thyl-3-carboethoxy-4-(o-nitrophenyl)-5-dimethylphosphonate-­ 6-phenylthiomethyl-1,4-dihydropyridine, m.p. 128-130°C. EXAMPLE 4 Under a nitrogen gas atmosphere, a stirred solution of dimethyl-1-(m-nitrophenyl)methylidene-2-oxopropyl-pho­ sphonate (8 g) and 1-cyano-2-amino-1-propene (3.2 g) in EtOH (80 ml) is heated to the reflux temperature for 2 hours. After cooling at room temperature, few drops of aqueous 36% HCl are added, the stirring is continued for one additional hour to complete the precipitation of a solid material which is filtered and crystallized from isopropanol to yield 2,6-dimethyl-3-cyano-4-(m-nitrophe­ nyl)-5-dimethylphosphonate-1,4-dihydropyridine (4.8 g), m.p. 232-235°C. Using in the same procedure 1-nitro-2-amino-1-pro­ pene, 1-benzoyl-2-amino-1-propene and 1-acetyl-2-amino-1-­ propene the following compounds are prepared: 2,6-dimethyl-3-nitro-4-(m-nitrophenyl)-5-dimethylphosphona­ te-1,4-dihydropyridine; 2,6-dimethyl-3-benzoyl-4-(m-nitrophenyl)-5-dimethylphospho­ nate-1,4-dihydropyridine; 2,6-dimethyl-3-acetyl-4-(m-nitrophenyl)-5-dimethylphospho­ nate-1,4-dihydropyridine, m.p. 226-229°C. EXAMPLE 5 2,6-Dimethyl-3-carboethoxy-4-(m-nitrophenyl)-5-dime­ thylphosphonate-1,4-dihydropyridine (m.p. 156-157°C) is obtained using, in the procedure of the Example 4, 1-etho­ xycarbonyl-2-amino-1-propene. 2,3-Dichloro-5,6-dicyano-benzoquinone (DDQ, 0.3 g) is added to a solution of this 1,4-dihydropyridine in chloroform. After 30 minutes, the reaction mixture is filtered on celite (R) and the eluate is evaporated to dryness. Following chromatographic purification on SiO₂ (CHCl₃/AcOEt) (1 : 1) as eluent) 0.38 g of 2,6-dimethyl-­ 3-carboethoxy-4-(m-nitrophenyl)-5-dimethylphosphonate-pyri­ dine are obtained. In a similar way, starting from the following 2,6-­ dimethyl-5-dimethylphosphonate-1,4-dihydropyridines deri­ vatives 3-carbomethoxy-4-(m-nitrophenyl), m.p. 218-220°C; 3-carbomethoxy-4-(o-nitrophenyl), m.p. 208-209°C; 3-carbomethoxy-4-(m-trifluoromethylphenyl), m.p. 182-­ 186°C; 3-carbomethoxy-4-(o-methylthiophenyl), m.p. 190-193°C; 3-carbomethoxy-4-(2',3'-dichlorophenyl) the corresponding 2,6-dimethyl-5-dimethylphosphonate-pyri­ dine derivatives are prepared: 3-carbomethoxy-4-(m-nitrophenyl); 3-carbomethoxy-4-(o-nitrophenyl); 3-carbomethoxy-4-(m-trifluoromethylphenyl); 3-carbomethoxy-4-(o-methylthiophenyl); 3-carbomethoxy-4-(2',3'-dichlorophenyl). EXAMPLE 6 Under nitrogen gas atmosphere, a 2.5 M butyl-li-­ thium-hexane solution (14 ml) is added dropwise to a stir­ red solution of a dialkoxymethylphosphonate (for example CH₃PO(OCH₃)₂, 4 ml) in dry THF (30 ml), cooled to -60°C. After 30 minutes, finely powdered cuprous bromide (4.7 g) is added to a cooled mixture which is then warmed at -30°C and maintained at this temperature for two hours. The reaction mixture is then further cooled to -45°C and a solution of 4-phtalimido-2-oxa-butyroyl chlo­ ride (7.4 g) in THF (15 ml) is added dropwise to the mix­ ture so that the inner temperature of the reaction vessel is maintained at around -40 ÷ -35°C. After three hours the reaction mixture is warmed at room temperature, neutraliz­ ed by adding of few drops of AcOH and evaporated to dry­ ness. After the usual work-up the residue is purified by SiO₂ column chromatography to give dimethyl-2-oxo-3-(phta­ limidoethoxy)propylphosphonate. In a similar way dimethyl-2-(5',6'-dihydro-3'-oxo-­ pyridazin-6'-yl)-2-oxo-ethylphosphonate is prepared. EXAMPLE 7 By reaction of a ortho and/or meta substituted benzaldehyde with a dialkyl phosphonate according to the procedure of the Examples 1-3 the following Z,E-methylide­ ne-phosphonates of the general formula II are prepared: EXAMPLE 8 Under a nitrogen inert atmosphere, a solution of dimethyl-1-(3'-nitrophenyl)methylidene-2-oxo-3-(2'-phtali­ mideothoxy)propylphosphonate (4.2 g) EtOH (90 ml) is treated with 1-methoxycarbonyl-2-amino-1-propene (2.1 g) and few drops of AcOH and the mixture is heated to the reflux temperature for 2 hours. After cooling to the room temperature, the solvents are evaporated to dryness under vacuum, and the residue is partitioned between AcOEt and water. After the usual work-up, the obtained crude mate­ rial is purified by SiO₂ column chromatography (cyclohexa­ ne-AcOEt 3:7 as eluent) to yield 2.3 g of 2-methyl-3-car­ bomethoxy-4-(m-nitrophenyl)-5-dimethyl phosphonate-6-phta­ limidoethoxymethyl-1,4-dihydropyridine. A sample of this compound (1.1 g) is treated in EtOH (25 ml) with an excess of 40% aqueous hydrazine hydrate (4 ml) and heated for 20 minutes to 50°C. The cooled mixture is filtered to elimi­ nate 1,2-phtalic hydrazide, the solvent is evaporated in vacuum and the residue is dissolved with 5% aqueous AcOH. After removal of neutral materials from said solution by washing with Et₂O, the aqueous phase is alkalinized to pH 8.5 and extracted with Et₂O, to give, after the usual work-up, 0.49 g of 2-methyl-3-carbomethoxy-4-(m-nitrophe­ nyl)-5-dimethylphosphonate-6-(2'-aminoethoxy)methyl-1,4-di­ hydropyridine, m.p. 84-88°C. Treatment with acetic anhydride in pyridine gives its N-acetylderivative as an oil. EXAMPLE 9 Using in the procedure of the Example 3, 1-amino­ carbonyl-2-amino-1-propene and Z,E-dimethyl-1-(m-nitro­ phenyl)methylidene-2-oxo-3-phenylthiopropyl-phosphonate, 2-methyl-3-aminocarbonyl-4-(m-nitrophenyl)-5-dimethylpho­ sphonate-6-phenylthiomethyl-1,4-dihydropyridine is obtain­ ed. EXAMPLE 10 2-Amino-1-nitro-1-propene (2.6 g) is added to a solution of dimethyl-1-(o-trifluoromethylphenyl)-3-oxo-­ propylphosphonate (8.2 g) in EtOH (80 ml). The mixture is heated at the reflux temperature for 24 hours under an inert gas atmosphere. After the usual work-up and SiO₂ column chromato­ graphic purification, 2,6-dimethyl-3-nitro-4-(o-trifluoro­ methylphenyl)-5-dimethylphosphonate-1,4-dihydropyridine (3.4 g, 38% yield) is obtained as an oil H-NMR (CDCl₃-­ DMSO-d₆): 2.4 (3H, s); 2.8 (3H, s); 3.10-4.20 (6H, m); 5.8-6.1 (1H, d); 7.0-7.4 (4H, m);8.2 (1H, m; exchange with D₂O). EXAMPLE 11 The reaction of a 1-methylidenephosphonate, prepar­ ed according to the procedure of the Examples 1, 2 and 3, with 1-acetyl-2-amino-1-propene and with 1-cyano-2-amino-­ propene yields the following compounds: 2,6-dimethyl-3-acetyl-4-(o-methylthiophenyl)-5-dimethyl­ phosphonate-1,4-dihydropyridine, m.p. 207-209°C; 2,6-dimethyl-3-acetyl-4-(o-nitrophenyl)-5-dimethyl-phospho­ nate-1,4-dihydropyridine; 2,6-dimethyl-3-cyano-4-(m-nitrophenyl)-5-dimethyl-phospho­ nate-1,4-dihydropyridine; 2,6-dimethyl-3-cyano-4-(2',3'-dichlorophenyl)-5-dimethyl­ phosphonate-1,4-dihydropyridine. EXAMPLE 12 2,3-Dichloro-5,6-dicyano-benzoquinone (DDQ) (0.3 g) is added to a stirred solution of 2,6-dimethyl-3-acetyl-4-­ (o-nitrophenyl)-5-dimethylphosphonate-1,4-dihydropyridine (0.5 g) in dimethoxyethane (25 ml). After 30 minutes the reaction mixture is filtered and evaporated to dryness in vacuum; the residue is purified by column chromatography on SiO₂ (25 g, CHCl₃/AcOEt (1 : 1) as eluent) to give 0.38 g of 2,6-dimethyl-3-acetyl-4-(o-nitrophenyl)-5-dimethyl­ phosphonate-pyridine,as a yellow oil, H-NMR(CDCl₃);δ (TMS): 2.0 (3H, s); 2.5 (3H, s); 2.8 (3H, s); 3.3-3.8 (6H, m); 7.4-8.2 (4H, m). In similar way the following compounds are prepar­ ed: 2,6-dimethyl-3-cyano-4-(m-nitrophenyl)-5-dimethylphospho­ nate-pyridine, H-NMR (CDCl₃); δ (TMS): 2.7 (3H, s); 2.9 (3H, s); 3.3-3.6 (6H, m); 7.5-8.2 (4H, m); 2-methyl-3-carbomethoxy-4-(m-nitrophenyl)-5-dimethylpho­ sphonate-6-(2'-phtalimidoethoxy)methyl-pyridine. EXAMPLE 13 By reacting a Z,E-1-methylidenephosphonate prepared according to the procedure of the Example 1-3 and 7 with a suitable 2-amino-1-propene of formula II, the following 2-methyl-1,4-dihydropyridines are prepared: 3-carbomethoxy-4-(o-nitrophenyl)-5-dimethylphosphonate-6-­ cyclohexyl; 3-nitro-4-(o-nitrophenyl)-5-dimethylphosphonate-6-cyclohe­ xyl; 3-carboethoxy-4-(m-nitrophenyl)-5-dimethylphosphonate-6-­ phenyl; 3-cyano-4-(m-nitrophenyl)-5-dimethylphosphonate-6-phenyl; 3-carbomethoxy-4-(o-methylthiophehyl)-5-dimethylphosphona­ te-6-(m-trifluoromethyl)phenoxymethyl; 3-carbomethoxy-4-(o-CF₃-phenyl)-5-dimethylphosphonate-6-­ (β-pyridyl); 3-carbomethoxy-4-(m-CF₃-phenyl)-5-dimethylphosphonate-6-­ (β-pyridyl); 3-carbomethoxy-4-(m-nitrophenyl)-5-dimethylphosphonate-6-­ (β-pyridyl); 3-carbomethoxy-4-(2',3'-dichlorophenyl)-5-dimethylphospho­ nate-6-(phenylthio)methyl; 3-nitro-4-(m-nitrophenyl)-5-dimethylphosphonate-6-(phenyl­ thio)methyl; 3-carbomethoxy-4-(o-nitrophenyl)-5-diethylphosphonate-6-­ phenylethyl; 3-cyano-4-(o-nitrophenyl)-5-diethylphosphonate-6-phenyl­ ethyl; 3-benzoyl-4-(o-nitrophenyl)-5-diethylphosphonate-6-phenyl­ ethyl; 3-carbomethoxy-4-(m-nitrophenyl)-5-dimethylphosphonate-6-­ (2"-cyclohexyl-1'-fluoro)ethyl; 3-carbomethoxy-4-(m-nitrophenyl)-5-dibenzylphosphonate-6-­ cyclopentyl; 3-carbomethoxy-4-(o-nitrophenyl)-5-dimethylphosphonate-6-­ (5',6'-dihydro-3'-oxo-pyridazin-6'-yl); H-NMR (CDCl₃-­ DMSO-d₆), δ (TMS): 2.2 (3H, s); 2.7 (4H, m); 3.2-3.9 (6H, m); 3.7 (3H, s); 5-5.1 (1H, d); 6.9-8.1 (5H, m); 9.4 (1H, m). The following reaction with DDQ yields the corre­ sponding 2-methyl-pyridine derivatives. EXAMPLE 14 A stirred solution of dimethyl-1-(m-nitrophenyl)me­ thylidene-2-oxo-propylphosphonate (2.8 g)and 1-ethoxycarbo­ yl-2-amino-propene (1.3 g) in EtOH (40 ml) is heated to the reflux temperature, with constant bubbling of air through the reaction mixture, for twelve hours. After cooling at room temperature, few drops of aqueous 30% HCl are added, the stirring is continued for one hour at room temperature and for 2 hours at the reflux temperature with continuous air insufflation. The mixture is evaporated to dryness and partitioned between AcOEt and water. After the usual work-up and chromatographic purification on SiO₂, 1.2 g of 2,6-dimethyl-3-carboethoxy-4-(m-nitrophenyl)-5-­ dimethylphosphonate-pyridine is obtained.

Claims: 1. Compounds of formula I wherein the heterocyclic ring is an aromatic pyridine ring when m is zero and a 1,4-dihydropyridine ring when m is the integer 1; R is a member selected from the group consisting of a) a C₁-C₁₂ alkyl residue; b) a-(CH₂)n-Y-X-(CH₂)p-R₆ group wherein n is zero or an integer from 1 to 4; p is zero or an integer from 1 to 5; y represents a single bond or a group CR₇R₈ wherein R₇ and R₈, which may be the same or different, represent hydrogen, C₁-C₆ alkyl groups or fluorine or R₇ and R₈, taken together with the carbon atom to which they are connected, form the group C=CH₂ or the groups X represents a single bond, a cis or trans double bond, a triple bond, an oxygen or sulfur atom or SO, SO₂, NH, N-(C₁-C₆)-acyl, N-phenyl, N-benzyl groups; R₆ is a member selected from the group consisting of a') hydrogen; b') C₁-C₄ alkyl; c') a C₃-C₉ cycloaliphatic residue, unsubstituted or substituted by one or more C₁-C₆ alkyl or C₁-C₆ alkoxy substitutets; d') aryl, unsubstitued or substituted by one or more halo-C₁-C₆ alkyl, C₁-C₆ alkoxy, NO₂, CN, S-C₁-C₆ alkyl, OH, C₁-C₆ acyloxy, unsubstituted or substituted amino substitu­ ents; e') a saturated or unsaturated heterocyclic ring, unsubstituted or substituted by one or more halogen, halo-C₁-C₆ alkyl, C₁-C₆ alkyl and C₁-C₆ alkoxy substitu­ ents; each or R₁ and R₂, which may be the same or different, are hydrogen, C₁-C₄ alkyl, phenyl, benzyl; R₃ represents: . a phenyl ring unsubstituted or substituted by one or more halogens, NO₂, C≡N, C₁-C₄ alkyl, halo-C₁-C₆ alkyl, C₁-C₄-alkoxy, halo-C₁-C₆ alkoxy, S-C₁-C₆ alkyl, SO-C₁-C₆ alkyl substituents; . a pentafluorephenyl; . a five or a six-membered heterocyclic ring; . a bicyclic ring such as α-naphthyl, β-naphthyl, α-benzofuroxanyl, α-benzo [2,3,-b] -1,4-dioxanyl; R₄ is selected in the group consisting of COCH₃; COC₆H₅; C≡N; NO₂; -CONR₉R₁₀, wherein R₉ and R₁₀, which may be the same or different, are hydrogen, C₁-C₆ alkyl, phe­ nyl and benzyl; or CO₂R₁₁ wherein R₁₁ is a C₁-C₆ alkyl or C₂-C₆ alkenyl group optionally substituted by one or more phenyl, C₁-C₆ alkoxy, hydroxy, a primary, seconda­ ry or tertiary amino group; an optionally substituted phenyl substituent; R₅ is a C₁-C₄ alkyl, phenyl or benzyl group; with a proviso that, when m is 1 and R₄ is a carboxy­ ester group, R is different from C₁-C₁₂ alkyl, their salts, enantiomers, diastereoisomers and mixtures thereof. 2. Compounds according to claim 1 ehrein m is 1. 3. Compounds accortding to claim 1 wherein m is zero. 4. Compounds according to any one of claims 1 to 3, wherein R₁ and R₂ are lower C₁-C₄ alkyl groups; R₃ is selected in the group consisting of m-nitrophenyl, o-ni-­ trophenyl, o-methylthiophenyl, o-trifluoromethylphenyl, 2,3-dichlorophenyl; R₄ is selected in the group consisting of C₅-C₆ cycloalkyl, optionally substituted aryl, optio­ nally substituted heterocyclic ring, aralkyl, alkylthio­ aryl or alkoxyaryl groups. 5. Process for the preparation of compounds of formula I, characterized in that a compound of formula II wherein R and R₃ are as above defined and each of R'₁ and R'₂ which may be the same or different, are C₁-C₄ alkyl, benzyl or phenyl group, are reacted with a compound of formula III wherein R₄ and R₅ are as above defined, and that the so obtained dihydropyridine compounds (m = 1) are optionally subjected to further transformations such as oxidation to give compounds wherein m is zero, removal of prospective groups, hydrolysis of phosphonic ester groups, acylation, salt formation and separation of iso­ mers. 6. A process according to claim 5, wherein the oxida­ tion of compounds I wherein m is 1 to compounds I wherein m is zero, is carried out by means of dichlorodicyanoqui­ none, chloranyl or activated manganese dioxide. 7. Pharmaceutical compositiuons containing as the acti­ ve principle at least a compound of claim 1-4, in admix­ ture with a suitable carrier. 8. A compound of claims 1-4 for use as an active thera­ peutic substance. 9. A compound of claims 1-4 for use as calcium antago­ nist, antihypertensive, antihrombotic, antiatherosclerotic, coronary and/or peripheral vasodilator agents. Claims for contracting state: AT 1. Process for the preparation of compounds of formula wherein the heterocyclic ring is an aromatic pyridine ring when m is zero and 1,4-dihydropyridine ring when m is the integer 1; R is a member selected from the group consisting of a) a C₁-C₁₂ alkyl residue; b) a-(CH₂)n-Y-X-(CH₂)p-R₆ group wherein n is zero or an integer from 1 to 4; p is zero or an integer from 1 to 5; y represents a single bond or a group CR₇R₈ wherein R₇ and R₈, which may be the same or different, represent hydrogen, C₁-C₆ alkyl groups or fluorine or R₇ and R₈, taken together with the carbon atom to which they are connected, form the group C=CH₂ or the groups X represents a single bond, a cis or trans double bond, a triple bond, an oxygen or sulfur atom or SO, SO₂, NH, N-(C₁-C₆)-acyl, N-phenyl, N-benzyl groups; R₆ is a member selected from the group consisting of a') hydrogen; b') C₁-C₄ alkyl; c') a C₃-C₉ cycloaliphatic residue, unsubstituted or substituted by one or more C₁-C₆ alkyl or C₁-C₆ alkoxy substituents; d') aryl, unsubstituted or substituted by one or more halo-C₁-C₆ alkyl, C₁-C₆ alkoxy, NO₂, CN, S-C₁-C₆ alkyl, OH, C₁-C₆ acyloxy, unsubstituted or substituted amino substitu­ ents; e') a saturated or unsaturated heterocyclic ring, unsubstituted or substituted by one or more halogen, halo-C₁-C₆ alkyl, C₁-C₆ alkyl and C₁-C₆ alkoxy substitu­ ents; each or R₁ and R₂, which may be the same or different, are hydrogen, C₁-C₄ alkyl, phenyl, benzyl; R₃ represents: . a phenyl ring unsubstituted or substituted by one or more halogens, NO₂, C≡N, C₁-C₄ alkyl, halo-C₁-C₆ alkyl, C₁-C₄-alkoxy, halo-C₁-C₆ alkoxy, S-C₁-C₆ alkyl, SO-C₁-C₆ alkyl substituents; . a pentafluorophenyl; . a five or a six-membered heterocyclic ring; . a bicyclic ring such as α-naphthyl, β-naphthyl, α-benzofuroxanyl, α-benzo[2, 3-b]-1,4-dioxanyl; R₄ is selected in the group consisting of COCH₃; COC₆H₃; C≡N; NO₂; -CONR₉R₁₀, wherein R₉ and R₁₀, which may be the same or different, are hydrogen, C₁-C₆ alkyl, phe­ nyl and benzyl; or CO₂R₁₁ wherein R₁₁ is a C₁-C₆ alkyl or C₂-C₆ alkenyl group optionally substituted by one or more phenyl, C₁-C₆ alkoxy, hydroxy, primary, seconda­ ry or tertiary amino group; an optionally substituted phenyl substituent; R₅ is a C₁-C₄ alkyl, phenyl or benzyl group; with the proviso that, when m is 1 and R₄ is a carboxy­ ester group, R is different from C₁-C₁₂ alkyl, characterized in that a compound of formula II wherein R and R₃ are as above defined and each of R'₁ and R'₂ which may be the same or different, are C₁-C₄ alkyl, benzyl or phenyl group, are reacted with a compound of formula III wherein R₄ and R₅ are as above defined, and that the so obtained dihydropyridine compounds (m = 1) are optionally subjected to further transformations such as oxidation to give compounds wherein m is zero, removal of protective groups, hydrolysis of phosphonic ester groups, acylation, salt formation and separation of iso­ mers. 2. A process according to claim 1, wherein the oxida­ tion of compounds I wherein m is 1 to compounds I wherein m is zero, is carried out by means of dichlorodicyanoqui­ none, chloranyl or activated manganese dioxide.

Inventors: FRIGERIO, MARCO, GANDOLFI, CARMELO A., RIVA, CARLO, SPINELLI, SILVANO, TOFANETTI, ODOARDO, TOGNELLA, SERGIO
Applicants: BOEHRINGER BIOCHEMIA ROBIN S.P.A.
Application year: 1986
Main classification: C07F9
IPC codes: C07F9