2-THIOMETHYL-SUBSTITUTED-PYRIDINES, A METHOD FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract: Pyridines of formula I wherein R₁ is acetyl, benzoyl, cyano, nitro, alko­ xycarbonyl or aminocarbonyl groups; R₂ is an optionally substituted aryl or a heterocyclic group; and Ø is a sulphurated residue such as alkylthio, cycloakylthio, arylthio, heteroarylthio, aminoalkylthio. Compounds I are useful in therapy in cardiovascular field.

Description: The present invention refers to 2-thiomethyl-substituted pyridines, a method for their preparation and pharmaceutical compositions containing them. The compounds of the invention have the following formula I wherein: R₁ is a CO₂R₅ group; cyano or nitro; R₂ is a phenyl ring selected in the group of m-nitrophenyl, phenyl, p-fluorophenyl, m-chlorophenyl, o-chlorophenyl, m-cyanophenyl, o-methylthiophenyl or m-trifluoromethylphenyl; R₃ is a CO₂R₅ group;  is a thioether -S(O) n -R₄ residue wherein n is 0, 1 or 2 and R₄ is a group of formula wherein P is hydrogen, C₁-C₈-alkyl or phenyl; NP₁P₂ is a primary, secondary or tertiary amino group, an amido or imido residue wherein P₁ and P₂ that can be the same or different are hydrogen, C₁-C₆-alkyl or benzyl, C₁-C₆-acyl groups or a benzoyl group; R₅ is hydrogen; an ammonium or an alkaline metal cation; a C₁-C₆-alkyl group; m is an integer from 1 to 3. The pharmaceutically acceptable salts, optical antipodes, i.e. the single enantiomers; racemic mixtures of optical antipodes, diasteroisomers of compounds I and mixtures of thereof are also included in the scope of the invention. According to the invention, alkyl, alkenyl, alkoxy and groups may have both a linear or branched chain. A C₁-C₆-alkyl group is preferably methyl, ethyl, isopropyl or t-butyl. A C₁-C₆-alkoxycarbonyl is preferably a methoxy, ethoxy or terbutoxy-carbonyl. R₅ is preferably methyl, ethyl or isopropyl; When one of P₁ and P₂ is an acyl group, it is preferably a C₁-C₄-acyl, or benzoyl, optionally substituted by amino or methoxy groups. When NP₁P₂ is a cyclic imide, it is preferably obtained starting from succinic, glutaric, maleic, 2,3-diphenylmaleic, phthalic, hexahydro- or tetrahydrophtalic acid. Particularly preferred compounds of the present invention are those wherein R₄ is a group of formula The non toxic pharmaceutically acceptable salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphates, alkyl and arylsulphonates, phosphates, sulphates, maleates, fumarates, succinates, tartrates, citrates as well as other salts normally used in the art. Salts obtained by variation of the acid employed in some case have special advantages due to an increased stability, increased or lowered solubility, ease of crystallization, absence of disgusting taste, etc., but these are all secondary in comparison to the main physiological action of the free base, that does not depend on the kind of acid used in the preparation of the salt. Specific examples of preferred compounds of the invention are shown in Table 1: The compounds of the invention are obtained by means of a process including: a) aromatization of a compound of formula II wherein R₁, R₂, R₃ and  are as above defined, to give a compound of general formula I. The aromatization reaction is carried out by oxidation of a compound II with an oxidizing agent such as potassium or sodium permanganate, nitrous, nitric, chromic acids, palladium on charcoal, sulphur, potassium hexacyanoferrate, chloranyl or 2,3-dicyano-5,6-dichloroquinone (DDQ). These high potential quinones are preferred oxidizing agents. The reaction is carried out in an inert solvent; e.g. benzene, toluene, xylene; methanol, ethanol, isopropanol; methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride; acetone, methylethylketone or in mixtures thereof using a slight molar excess of quinone with respect to compounds II, at a temperature ranging from 0°C to the solvent's reflux temperature, for times ranging from few minutes to 24 hours; b) By reaction of a compound of formula III wherein R₁, R₂, R₃ are as above defined and Hal is chlorine, bromine or iodine, with a thiol of formula IV R'₄SH (IV) wherein R'₄ is hydrogen, C₁-C₁₂-alkanoyl, -C(=NR₈)NR₉R₁₀ , being R₈, R₉ and R₁₀ that can be the same or different, are hydrogen or a C₁-C₄-alkyl group obtaining a compound of formula I wherein  is a thiol or its C₁-C₁₂ alkanoyl-ester, a thiouronium salt -S-C(N=R₈)NR₉R₁₀ (+) Hal(-) or -S(O) n R₄ (R₄, R₈, R₉, R₁₀, Hal (-) are as above defined and n is zero) that can optionally be oxidized to give a compound of formula I wherein n is 1 or 2 and, if desired, after removal of known protecting groups optionally present in R₄, converting a compound of formula I, in another compound of formula I and/or if desired, salifying a compound of formula I and/or if desired, obtaining a free compound of formula I from a salt thereof and/or if desired separating a mixture of isomers into the single isomers. The reaction is carried out using equimolecular quantities of a compound III with a compound IV in an inert solvent such as alcohol (for instance methanol, ethanol, isopropanol), an ether (for instance tetrahydrofurane, 1,2-dimethoxyethane, dioxane); a dipolar aprotic solvent (for ex. dimethylsulphoxide, dimethylformamide, 1-methyl-2-pyrrolidinone); aromatic solvents (for ex. benzene, toluene, pyridine), chlorinated solvents (for ex. methylene chloride, 1,2-dichloroethane) and mixtures thereof, in the presence of an equimolecular quantity or an excess of a base selected in the group of NaOH, K₂CO₃ , Na₂CO₃ , LiCO₃, KHCO₃, MeONa, EtONa, T-BuOK, (EtO)₂Mg, CaH₂ , NaH, NaNH₂, isopropylamine, triethylamine, N-methyl-piperidine, 4-dimethylamino-pyridine, etc., at a temperature ranging from -30°C to the solvent's reflux temperature, for reaction periods ranging from a few minutes to 48 hours. When R'₄ is -C(=NR₈)NR₉R₁₀ the reaction is carried out in the above specified conditions, but preferably in the absence of a base, at a temperature ranging from the room temperature to the solvent's reflux temperature, for times ranging from 1 to 48 hours. Compounds of formula II, are claimed and described in WO 87/00836: the compounds of formula III are obtained starting from their 1,4-dihydropyridine analogues of formula V described in EP-A-0212340 in Applicant's name submitting these halo-methyl compounds to the aromatization process above described in the conversion of a compound of formula II in a compound of formula I. The thiols of formula IV are known compounds or are prepared according to WO 87/00836. In EP-A-0 088 940 structurally related pyridines with a CH₂OH-group in position 2 of the pyridine ring are described. Such compounds are useful against diseases caused by hypoxia and/or ischemia excluding an influence on the blood pressure. The compounds of the invention show a long lasting antihypertensive effect when administered by oral route to spontaneously hypertensive rats. The antihypertensive effect has a slow onset and the decrease of the mean blood pressure is reached 4-6 hours after the administration; for ex. 3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-pyridine derivatives: 2-aminoethylthiomethyl 2-aminoethylsulphinylmethyl 2-aminoethylsulphonylmethyl induce a lowering of mean blood pressure of 10-20% when administered by the oral route at dosages of 3 mg/kg. The compounds of the invention show moreover a low acute toxicity when administered to rats by the oral and intraperitoneal route. The clear antihypertensive effect of the compounds of the invention is not due or related to putative Ca⁺⁺ antagonist properties: infact compounds I are totally unable to inhibit calcium induced contraction of K-depolarized rat aorta and do not displace or reduce binding of 3H-nitrendipine from Ca⁺⁺ antagonist receptor. Due to their particular pharmacological characteristics, the compounds of the invention are useful in human therapy for treating cardiovascular pathologies, particularly hypertensive forms. In order to achieve the desired effects in human and veterinary therapy, the compounds may be administered by parenteral route (by intravenous, hypodermic or intramuscular injections) infusional, rectal or oral route. The compounds may be administered to the patient in pure form or formulated into pharmaceutical compositions. Suitable pharmaceutical compositions may be prepared in accordance with known techniques, such as described for example in "Remington's Pharmaceutical Sciences Handbook", Hack Publishing Co., U.S.A. When the compounds of the invention are used as antihypertensives, the dosage will vary according to the seriousness of hypertension and administration route. The amount of active principle administered by the oral route may range from 1 γ/Kg/die to 1 mg/Kg/die and preferably from 5 γ/mg/Kg/die to 0.1 mg/Kg/die. The amount of active principle administered by the parenteral route may vary from 0.1 γ/Kg/die to 0.5 mg/Kg/die, preferably from 0.5 γ/Kg/die to 0.2 mg/Kg/die. A unit dose may contain, for instance, from 50 γ to 70 mg of active principle. The compounds of the invention may be administered even once a day, but more spaced and/or repeated administrations may be convenient at least in some cases and may vary according to the patient's conditions and to the admnistration route and dosage. In the present case the word "patient" means hot-blooded animal, man included. For the oral administration the compounds may be given in solid or liquid preparations, in form of capsules, pills, tablets, powders, solutions, suspensions or emulsions. The unit solid dosage can be a hard or soft gelatine capsule, containing lubricants and inert excipients such as lactose, saccharose and starch. The compounds of the invention may be also formulated into tablets, using conventional excipients such as lactose, saccharose, starch, gelatine, alginic acid, stearic acid, magnesium stearate, etc. For the parenteral administration, the compounds may be prepared as injectable formulations dissolved or suspended in physiologically acceptable diluents, with a sterile vehicle (water or an oil), with our without addition of other excipients. Oils may be of vegetal, animal or synthetic origin, such as peanut oil, soya or mineral oil. Generally, as a vehicle for injectable solutions, it is possible to use water, aqueous solutions of mineral salts, aqueous solutions of dextrose or other sugars, ethanol, glycols such as propylene or polyethylene glycol. The compounds may also be administered by the rectal route in form of suppositories, mixtures with conventional vehicles, such as cocoa butter, wax, polyvinylpyrrolidone, polyoxyethylenglycol or derivatives thereof. The compounds of the invention are preferably administered by the oral route. The following examples illustrate the invention without limiting it. Preparation 1 2,3-dicyano-5,6-dichloroquinone (DDQ, 3 g) is added to a chloroform solution (50 ml) of 2-chloromethyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (5 g). After 30 minutes the suspension is filtered on a celite panel, the solvent is evaporated under vacuum, the residue is diluted with ethyl ether (100 ml), washed with water (2 x 20 ml), with a NaHCO₃ saturated solution (3 x 10 ml) and water (3 x 10 ml), dried on Na₂SO₄ and the ether is evaporated under vacuum. The residue is filtered on a silica gel column (30 g, eluent 1,2-dichloroethane), the solvent is evaporated under vacuum and the residue is crystallized from isopropyl alcohol. 3,5 g of 2-chloromethyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methylpyridine, m.p. 76-78°C are obtained. In the same way the following compounds were prepared: 2-chloromethyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methylpyridine, m.p. 93-94°C; 2-chloromethyl-3-carboethoxy-5-cyano-4-(m-nitrophenyl)-6-methylpyridine; 2-chloromethyl-3,5-dicarboethoxy-4-(m-trifluoromethylphenyl)-6-methylpyridine; 2-chloromethyl-3,5-dicarboethoxy-4-(o-methylthiophenyl)-6-methylpyridine; 2-chloromethyl-3,5-dicarboethoxy-4-(m-chlorophenyl)-6-methylpyridine; 2-chloromethyl-3-carboethoxy-5-carbomethoxy-4-(m-methoxyphenyl)-6-methylpiridine. EXAMPLE 1 DDQ (0,25 g) is added at room temperature to a chloroform solution (4,5 ml) of 2-(2-formamidoethylthio) methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (0,43 g) (this product having a m.p. 109-111°C, obtained according to P.C.T. EP 86/00445). After 15 minutes it is filtered on celite, the chloroform is evaporated under vacuum, the residue is dissolved in ethyl acetate (10 ml), the organic phase is washed with NaOH (0.3 N; 4 x 5 ml) and with water (3 x 10 ml, dried (Na₂SO₄) and evaporated under vacuum. 400 mg of 2-(2-formamidoethylthio)methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-pyridine are obtained as an amorphous solid. ¹H-NMR (CDCl₃)δ (TMS): 0.8-1.1 (3H, t); 2.5-2.9 (5H; s + m); 3.1-3.7 (5H; S + m); 3.8-4.20 (4H, m); 6.0-6.8 (1H, m); 7.1-8.2 (5H, m). Likewise, for oxidation with DDQ of a 2-(2-acetamidoethylthio)-methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine, 2-(2-formamidoethylthio)-methyl-3-carbomethoxy-5-carbomethoxy-4-(2-methylthiophenyl)-6-methyl-1,4-dihydropyridine, 2-(2-benzamidoethylthio)methyl-3,5-dicarboethoxy-4-(m-chlorophenyl)-6-methyl-1,4-dihydropyridine, 2-(2-furylmethylthio)methyl-3-carboethoxy-5-carbomethoxy-4-(m-methoxyphenyl)-6-methyl-1,4-dihydropyridine, the following 6-methylpyridines were obtained: 2-(2-formamidoethylthio)methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl); 2-(2-formamidoethylthio)methyl-3-carboethoxy-5-carbomethoxy-4-(2-methylthiophenyl)-; amorphous solid ¹H-NMR (CDCl₃)δ (TMS): 1.0-1.3 (3H, t); 2.10-3 (8H, s + s + m); 3.1-3.7 (5H; s + m); 3.8-4.2 (4H, m); 6.5-6.8 (1H, m); 6.9-7.5 (4H, m); 8.1 (1H, s). 2-(2-benzamidoethylthio)methyl-3,5-dicarboethoxy-4-(m-chlorophenyl). 2-(2-furylmethylthio)methyl-3-carboethoxy-5-carbomethoxy-4-(m-methoxyphenyl). EXAMPLE 2 A solution of 2-chloromethyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methylpyridine (8.5 g) in ethanol (20 ml) is added dropwise to a solution at -10°C of cysteamine hydrochloride (2.6 g) and NaOH (solution 20% p/p; ml 7.3) in ethanol (50 ml). After 15 minutes the solution is warmed to room temperature, acidified with acetic acid (final pH 3.5-4) and evaporated to a small volume. The residue is partitioned between water (100 ml) and ethyl ether (50 ml), the ether phase is eliminated, the aqueous phase is made basic with a NaHCO₃ saturated solution and extracted with ethyl ether (3 x 50 ml). The organic phase is dried on Na₂SO₄, then it is evaporated under vacuum to give 9 g of an oil. A solution of fumaric acid (2.5 g) in ethanol (25 ml) is added dropwise to a solution, kept at reflux, of the above oil (9 g) in ethyl acetate (180 ml). The suspension is refluxed for 30 minutes, then it is cooled at room temperature, stirred for one hour, the solid is filtered, and dried at 50°C under vacuum. 8.5 g of 2-(2-aminoethylthio)-methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methylpyridine fumarate C₂₀H₂₃N₃O₆S.C₄H₄O₄, m.p. 145-147°C, are obtained. Using in the conditions above described a thiol selected in the group of cysteamine, 2-amino-2-methylethanthiol, 2-amino-2-phenylethanthiol, 2-N-isopropylamino-ethanthiol, 2-N-butylaminoethanthiol and 2-N-benzylaminoethanthiol and a pyridine selected in the group of 2-chloromethyl-3,5-dicarboethoxy-4-(m-trifluoromethyl-phenyl)-6-methylpyridine, 2-chloromethyl-3,5-dicarboethoxy-4-(o-methylthiophenyl)-6-methylpyridine, 2-chloromethyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methylpyridine, 2-chloromethyl-3,5-dicarboethoxy-4-(m-chlorophenyl)-6-methylpyridine, 2-chloromethyl-3,5-dicarbomethoxy-4-(m-nitrophenyl)-6-methylpyridine and 2-chloromethyl-3-carbomethoxy-5-carboisopropoxy-4-(p-fluorophenyl)-6-methylpyridine, the following compounds were obtained: 2-(2-aminoethylthio)-methyl-3,5-dicarboethoxy-4-(m-trifluoromethylphenyl)-6-methylpyridine; 2-(2-aminoethylthio)-methyl-3,5-dicarboethoxy-4-(o-methylthiophenyl)-6-methylpyridine; 2-(2-aminopropylthio)-methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methylpyridine; 2-(2-amino-2-phenylethylthio)-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methylpyridine; 2-(2-N-isopropylaminoethylthio)-methyl-3,5-dicarboethoxy-4-(m-chlorophenyl)-6-methylpyridine; 2-(2-N-n-butylaminoethylthio)-methyl-3,5-dicarbomethoxy-4-(m-nitrophenyl)-6-methylpyridine; 2-(2-N-benzylaminoethylthio)-methyl-3-carbomethoxy-5-carboisopropoxy-4-(p-fluorophenyl)-6-methylpyridine. EXAMPLE 3 A solution of m-chloroperbenzoic acid (85%, 1.2 g, one molar equivalent) in 1,2-dichloroethane (13 ml) is dropped in a solution at -10°C of 2-(2-aminoethylthio)-methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methylpyridine hydrochloride (2.5 g) in 1,2-dichloroethane (25 ml). The mixture is warmed to 0°C and the precipitate is filtered (and then eliminated). The organic phase is washed with an Na₂S₂O₃ aqueous solution (5%, 2 x 10 ml) and with water (3 x 10 ml). The dried organic phase is evaporated on Na₂SO₄ and the residue is dissolved in ethyl ether (50 ml). The organic phase is eliminated, the aqueous phase is made basic with a NaHCO₃ saturated solution, and extracted with methylene chloride (2 x 50 ml), dried (Na₂SO₄) and evaporated under vacuum. 2 g of 2-(2-aminoethylsulphinyl)-methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methylpyridine are obtained. Salification with fumaric acid (0.7 g), according to the method described in Example 2, gives 2.6 g of the corresponding fumarate C₁₀H₁₃N₃O₇S.C₄H₄O₄, m.p. 170-172°C. EXAMPLE 4 A solution of m-chloro-perbenzoic acid (85%, 2.05 g; 2 molar equivalents) in methanol (15 ml) is dropped in a solution at -10°C of 2-(2-aminoethylthio)methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methylpyridine fumarate (2.85 g) in methanol (28 ml). The solution is warmed at +15°C stirred for 30', then the solvent is evaporated at reduced pressure, (paying attention that the warming bath does not exceed 35°C). The residue is dissolved in methylene chloride and treated as described in the Example 3. 1.83 g of 2-(2-aminoethylsulphonyl)-methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methypyridine fumarate are obtained C₂₀H₂₄N₃O₈S.C₄H₄O₄, m.p. 157-158°C.

Claims: Compounds of formula I wherein: R₁ is a CO₂R₅ group, cyano or nitro; R₂ is a phenyl ring selected in the group of m-nitrophenyl, phenyl, p-fluorophenyl, m-chlorophenyl, o-chlorophenyl, m-cyanophenyl, o-methylthiophenyl or m-trifluoromethylphenyl; R₃ is a CO₂R₅ group;  is a thioether -S(O) n -R₄ residue wherein n is 0, 1 or 2 and R₄ is a group of formula wherein P is hydrogen, C₁-C₈-alkyl or phenyl; NP₁P₂ is a primary, secondary or tertiary amino group, an amido or imido residue wherein P₁ and P₂ that can be the same or different are hydrogen, C₁-C₆-alkyl or benzyl, C₁-C₆-acyl groups or a benzoyl group; R₅ is hydrogen; an ammonium or an alkaline metal cation; a C₁-C₆-alkyl group; m is an integer from 1 to 3, their salts, enantiomers or diastereoisomers. A compound according to claim 1 wherein R₁ and R₃ are alkoxycarbonyl groups wherein the alkoxy portions have from 1 to 3 carbon atoms. A compound according to any one of the preceding claims wherein  is a group of formula -S(O) n -R₄ wherein n is zero or 1 and R₄ is a group of formula wherein m, P, P₁ and P₂ have the same meaning as in claim 1. A compound according to claim 3, wherein m is 1, P is hydrogen, methyl or phenyl, P₁ and P₂ are both hydrogen, or one of them is hydrogen and the other is a C₁-C₄-alkyl, benzyl, acetyl, benzoyl or formyl group. The compound 2-(2-furylmethylthio)methyl-3-carbethoxy-5-carbomethoxy-4-(m-methoxyphenyl)-6-methylpyridine and 2-(pyrimidin-2-yl-thio)-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methylpyridine. A process for preparation of compounds of formula I according to claims 1 to 5 characterized by the fact a compound of formula II wherein R₁, R₂, R₃ and  are as above defined, is subjected to an aromatizing reaction with an oxidizing agent. A process according to claim 6 wherein the oxidizing agent is selected in the group of potassium or sodium permanganate, nitrous, nitric, chromic acid, carbon palladium on charcoal/sulphur, potassium hexacyanopherrate, chloranyl and 3,3-dicyano-5,6-dichloroquinone (DDQ). A process for preparation of compounds of formula I according to claims 1 to 5 characterized in that a compound of formula III wherein R₁, R₂, R₃ are as above defined and Hal is chlorine, bromine or iodine, is reacted with a thiol of formula IV R'₄SH (IV) wherein R'₄ is hydrogen, C₁-C₁₂-alkanoyl, or -C(=NR₈)NR₉R₁₀, being R₈, R₉ and R₁₀ that can be the same or different, are hydrogen or a C₁-C₄-alkyl group and that the compound obtained is then optionally submitted to oxidation reactions, displacement of protecting groups, salification, separation of isomers. Compounds of claims 1 to 5 for use as medical agents. Pharmaceutical compositions containing as an active principle a compound of claims 1 to 5 in admixture with an acceptable vehicle.

Inventors: FRIGERIO, MARCO, GANDOLFI, CARMELO A., TOFANETTI, ODOARDO, TOGNELLA, SERGIO
Applicants: BOEHRINGER MANNHEIM ITALIA S.P.A.
Application year: 1988
Main classification: C07D213
IPC codes: A61K31, C07D405, C07D213, A61P9, C07D401