DIHYDROPYRIDINES, METHODS FOR THEIR PRODUCTION AND THEIR FORMULATION AND USE AS PHARMACEUTICALS

Abstract: There are described compounds of formula I, in which X is oxygen or sulphur, R₁ and R₂, which may be the same or different, each re­ present alkyl C 1 to 6, -(CH₂) n OR₅, or -(CH₂) n NR₆R₇, and in addition R₂ may represent hydrogen, n is a whole number from 2 to 4 inclusive, R₃ represents -CH₂OH, -CN, -CH(OR₄)₂, -CHO, -CH=NOH, -CF₃, or, together with R₂ forms a chain -CHOH-, R₄ represents alkyl C 1 to 6, R₅ represents alkyl C 1 to 6 or phenyl, R₆ and R₇, which may be the same or different, each re­ present alkyl C 1 to 6 optionally substituted by phenyl, and R₈ is alkyl C 1 to 6, and pharmaceutically acceptable acid addition salts of those compounds containing a basic nitrogen atom. There are also described methods for making the com­ pounds and pharmaceutical, e.g. cardiac, compositions con­ taining them.

Description: DIHYDROPYRIDINES, METHODS FOR THEIR PRODUCTION AND THEIR FORMULATION AND USE AS PHARMACEUTICALS This invention relates to new compounds, methods for their preparation and compositions containing them. According to the invention we provide compounds of formula I, EMI1.1 in which X is oxygen or sulphur, R1 and R2, which may be the same or different, each represent alkyl C 1 to 6, -(CH2)n OR5, or -(CH2)n NR6R7, and in addition R2 may represent hydrogen, n is a whole number from 2 to 4 inclusive, R3 represents -CH20H, -CN, -CH(OR4)2, -CHO, -CH=NOH, -CF3, or, together with R2 forms a chain -CHOR-, R4 represents alkyl C 1 to 6, R5 represents alkyl C1 to 6 or phenyl, R6 and R7, which may be the same or different, each represent alkyl C1 to 6 optionally substituted by phenyl, and R8 is alkyl C1 to 6, and pharmaceutically acceptable acid addition salts of those compounds containing a basic nitrogen atom. According to the invention we also provided a process for the production of a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, which comprises a) production of a compound of formula I in which R3 is -CH(OR4)2 by i) reaction of a compound of formula II, EMI2.1 in which Rg is a group -CF3 or -CH(OR4)2, X, R2 and R4 are as defined above, with a compound of formula III, R1OOCCH=C(R8)NH2 III in which R1 and R8 are as defined above, or ii) reaction of a corresponding compound of formula I in which R3 is -CHO with an alcohol R4OH, b) production of a compound of formula I in which R3 is -CHO by selective hydrolysis of a corresponding compound of formula I in which R3 is -CH(OR4)2, c) production of a compound of formula I in which R3 is -CH=NOH by reaction of a corresponding compound of formula I in which R3 is -CHO with hydroxylamine, or a salt thereof, d) production of a compound of formula I in which R3 is -CN by dehydration of a corresponding compound of formula I in which R3 is -CH=NOH, e) production of a compound of formula I in which R3 is -CH2OH by selective reduction of a corresponding compound of formula I in which R3 is -CHO, f) production of a compound of formula I in which R2 is hydrogen, by selective hydrolysis of a corresponding compound of formula I in which -COOR2 is an ester group, g) production of a compound of formula I in which R2 is other than hydrogen by esterification, with a compound R2L in which L is a leaving group, of a corresponding compound of formula I in which R2 is hydrogen, or R2 together with R3 forms a chain -CHOH-, or h) selective reduction of a corresponding pyridine, and where desired or necessary converting the resulting compound of formula I to a pharmaceutically acceptable acid addition salt thereof, or vice versa. Process a) i) may be carried out at a temperature of from about 50 to 150 0C. The reaction may be carried out in an excess of the compound of formula III, or, less preferably, in a solvent which is inert under the reaction conditions, e.g. a polar solvent such as methanol, ethanol, dioxan or dimethylformamide. We prefer R2 to be methyl or ethyl. Process a) ii) may be carried out in the presence of an excess of the alcohol and preferably in the presence of an acidic catalyst. The reaction may be carried out at a temperature of from about 50 to 1500C. In processes a) i) and a) ii) we prefer R2 not to be hydrogen. The hydrolysis of process b) may be carried out using an aqueous acid, for example hydrochloric acid (e.g. 0.5 to 2.5 molar), in a water miscible organic solvent, e.g. acetone or tetrahydrofuran. The reaction may be carried out at a temperature of from about 20 to 500C. The reaction is preferably not carried out for more than about 6 hours. Process c) may be carried out in a suitable solvent, e.g. acetic acid or ethanol, and in the presence of a basic catalyst, e.g. sodium acetate or sodium carbonate. The reaction may be carried out at a temperature of from about 20 to 1200C. The dehydration of process d) may be carried out using a variety of dehydrating agents, e.g. an excess of acetic anhydride, thionyl chloride in ether or N,N'-dicyclohexylcarbodiimide in pyridine. The reaction may be carried out at a temperature of from about 0 to 1500C depending on the reagent and solvent used. The reduction of process e) may be carried out either chemically or catalytically, e.g. by use of sodium borohydride in an alcoholic solvent, e.g. methanol or ethanol at a temperature of from about 0 to 500C. Process f) may be carried out under similar, but comparatively more forcing, conditions to process b) above, e.g. temperature of up to 1000C, reaction time of 24 to 72 hours and stronger acid, e.g. 2.5 to 5 molar HCl. We prefer the process to be carried out using a starting material in which R3 is -CHO. Processes b) and f) may be carried out simultaneously under the more forcing conditions of process f). In process g) the leaving group is preferably an anion forming group, e.g. chlorine, bromine, iodine, methanesulphonate or p-toluenesulphonate. The reaction may be carried out at a temperature of from about 20 to 100 0C and in a polar solvent which is inert under the reaction conditions, e.g. acetone, acetonitrile or dimethylformamide and in the presence of a base, e.g. sodium or potassium carbonate. The reduction of process h) may be carried out using an appropriate reducing agent, eg a dithionate such as sodium dithionate, in an aqueous organic solvent, for example aqueous ethanol or aqueous dioxan. The reaction may be carried out at a temperature of from about 200 to 800C. In the above processes where R2 is (CH2)nNR6R7 the reaction may be carried out using, and may, where appropriate produce, a compound in the form of an acid addition salt thereof. Such processes are included within the scope of the invention. Compounds of formula II may be made by the reaction of a compound of formula IV, EMI6.1 in which X is as defined above, with a compound of formula V, R2OOCCH2COR9 V in which R2 and Rg are as defined above. The reaction may be carried out in refluxing benzene or toluene in the presence of an organic base or an anhydrous acid, the water produced being removed by azeotropic distillation. Alternatively compounds of formula II may be made by reaction of a compound of formula V with a compound of. formula VI, EMI7.1 in which X is as defined above, in the presence of a basic catalyst. Compounds of formulae III, IV, V, and VI and the pyridine starting materials for process h) are either known or may be made fran known compounds using conventional techniques known per se. The pyridine starting materials for process h) may also be made by selective oxidation, e.g. using dichlorodicyano-benzoquinone in an organic solvent such as chloroform, of the corresponding dihydropyridine of formula I. The compounds of formula I, and the intermediates therefor, may be isolated from their reaction mixtures using conventional processes known per se. The compounds of formula I possess an asymetric carbon atom and the invention provides the compounds in optically active form or as racemic or other mixtures. The optical isomers may be separated by conventional procedures which are known per se. We prefer X to be oxygen. We also prefer R1, R2 and R4 to be selected from methyl, and, more preferably, ethyl and isopropyl. In particular R1 and R2 can both be ethyl or methyl, or one can be methyl or ethyl and the other isopropyl. n is preferably 2. R3 is preferably -CH20H or especially -CHO or -CN. We also prefer the benzofurazanyl or benzothiadiazolyl group to be attached to the tetrahydropyridine moiety through its 4-position. R8 is preferably C1 to 4 and most preferably is methyl. Compounds of formula I containing a basic nitrogen atom include those in which R2 is -(CH2)NR6R7. We prefer the compounds of Examples 3, 4 ii), 7, 10 ii), 10 iii), 12 ii), 12 iii) and particularly 11. The compounds of formula I, and the pharmaceutically acceptable salts thereof, are useful because they possess pharmacological properties in animals. More particularly they block the entry of calcium into vascular and cardiac muscle leading to a fall in blood pressure, inotropy and heart rate. They are active in the following systems: (a) Relaxation of contracted vascular smooth muscle. Van Breemen, Aaronson, Loutzenhiser and Meisheri, Chest, 78, Supplement, 157-165, 1980. (b) Reduce inotropy and chronotropy of isolated atria. Henry, Excerpta Med. Int. Congr. Ser., 474, 14-23, 1979. (c) Reduce blood pressure and increase cardiac output in anaesthetised dogs. Hirakawa, Ito, Kondo, Watanbe, Hiei, Banno & Hyase, Arzneim-Forsch, 22, 344-349, 1972. (d) Reduce blood pressure with small rises in heart rate in conscious dogs when given by the intravenous and oral routes. Newman, Bishop, Peterson, Leroux & Horowitz, J Pharm. Exp. Ther. 201, 723-730, 1977. The compounds are thus indicated for use in the treatment of hypertension, angina pectoris, variant angina, congestive heart failure, myocardial infarction, cerebrovascular disorders, vascular disease and in asthmatic conditions. For the above uses the dosage will depend upon the compound used, the route of administration and the effect desired, but in general will be in the range of 0.1-lOmg per kilogram body weight per day. For man the indicated total daily dose will be from about 5-500mg, preferably from 5 to 200mg and more preferably from 5 to 100mg, which may be administered in divided doses of about 1-200mg, preferably 2 to 25mg, e.g. 2 to 4 times per day. The compounds of formula I are advantageous in that they possess greater potency (e.g. with respect to direct negative chronotropic effect), produce a lower level of reflex tachycardia, are more selective (e.g. for vascular smooth muscle vs cardiac muscle), produce less depression of cardiac contractility, are longer acting, are more easily formulated, possess less, or less undesirable, side effects or have other more beneficial properties than known compounds of similar structure. The compounds of the invention may be administered by a wide variety of routes and may act systemically or locally. Thus the compounds may be administered by oral or nasal inhalation to the lung, to the buccal cavity, oesophageally, rectally, topically to the skin or to other available surfaces of the body; by injection, eg intravenously, intramuscularly, intraperitoneally, or by surgical implant. According to our invention we also provide a pharmaceutical composition comprising preferably less than 80% and more preferably less than 50* by weight of a compound of formula I, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Examples of suitable adjuvants, diluents or carriers are: for tablets, capsules and dragees; microcrystalline cellulose, polyethylene glycol, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin; for suppositories; natural or hardened oil or waxes; and for inhalation compositions, coarse lactose. The compounds may also be formulated in controlled release form, e.g. in the form of a matrix out of which the compound is slowly leached. The compounds may also, if desired, be used in admixture with other pharmaceutically active compounds, e.g. a beta blocker. Compounds of formula I in which R2 is hydrogen and R3 is -CHO may exist in the tautomeric form Ia, EMI11.1 i.e. a form in which R3 together with R2 forms a chain -CHOH-. The invention is illustrated, but in no way limited by the following Examples in which temperatures are indegrees centigrade. Example 1 Diethyl 4- (4-benzofurazanyl)-2- (diethoxymethyl) -1,4-dihydro -6-methylpyridine-3,5-dicarboxylate A solution of 4-benzofurazancarboxaldehyde (6.0g, 40 moles), ethyl 4,4-diethoxy-3-oxobutyrate (8.0g, 37 mmoles) and piperidine (0.5ml) in dry benzene (150ml) was heated at reflux using a Dean and Stark water separator for 3 hours. The cooled solution was added to ether (200ml) and the organic solution washed with water and brine, and then dried (MgSO4). Evaporation of the solvents left crude ethyl 2-(4-benzofurazanmethylidene) -4,4-diethoxy-3-oxobutanoate (mixture of E- and Z-isomers) as a brown oil (13.5g). The foregoing oil (13.5g, 37 mmoles) and ethyl 3-amino-2-butenoate (4.76g, 37mmoles) were mixed and heated at 1000C for 16 hours. The resulting dark oil was dissolved in ether (200ml) and the organic solution washed with water and brine, and then dried (MgSO4). Evaoration of the solvent left the title compound as an oil (18.8g) M+ 459. Example 2 By the method of Example 1 were also prepared i) Dimethyl 4-(4-benzofurazanyl)-1,4-dihydro-2 (dimethoxymethyl)-6-methylpyridine-3, 5-dicarboxylate (Oil, M+403) ii) 3-Ethyl 5- (l-methylethyl)-4- (4-benzofurazanyl)-2- (diethoxymethyl-1,4-dihydro-6-methylpyridine-3,5- dicarboxylate (Oil, M+473) iii) Diethyl 4-[4-(2,1,3-benzothiadiazolyl)]-2 (diethoxymethyl)-1,4-dihydro-6-methylpyridine-3,5- dicarboxylate (Oil, M+475) Example 3 Diethyl 4-(4-benzofurazanyl)1,4-dihydro-2-formyl-6methylpyridine-3, 5-dicarboxylate The product of Example 1 above (18.8g) in tetrahydrofuran (100ml) was treated with 50% hydrochloric acid (25ml). After 4 hours at room temperature the solvent was removed by evaporation to leave a brown gum which was dissolved in ethyl acetate (150ml) and treated with saturated aqueous sodium bicarbonate until pH9. The organic solution was separated and washed with sodium bicarbonate solution, water and brine, and then dried (MgSO4). Evaporation of the solvent left a brown oil (16.lg), which gave a solid on trituration with 2-propanol. Recrystallisation from 2-propanol gave the title compound (6.lg) as an orange solid m.p. l3ll320. Example 4 By the method of Example 3 were also prepared i) Dimethyl 4-(4-benzofurazanyl)-1,4-dihydro-2-formyl -6-methylpvridine-3,5-dicarboxylate m.p. 166.5-167.5 ii) 3-Ethyl 5-(1-methylethyl)4-(4-benzofurazanyl)-1,4dihydro-2-formyl-6-methylpyridine-3,5-dicarboxylate m.p. 115-116 iii) Diethyl 4-[4-(2,1,3-benzothiadiazolyl) 0-1,4-dihydro -2-formyl-6-methylpyridine-3, 5-dicarboxylate m.p. 122.5-124 iv) 3-Ethyl 5-(2-methylpropyl)4-(4-benzofurazanyl)1,4dihydro-2-formyl-6-methylpyridine-3,5-dicarboxylate. m.p. 97-98 v) 3-Ethyl 5-(2-(N-methyl-N-(phenylmethyl)amino)ethyl)4-(4-benzofurazanyl)-1,4-dihydro-2-formyl-6 methylpyridine-3,5-dicarboxylate hydrochloride m.p 1150. Example 5 3-Ethyl 5-(1-methylethyl) 4-(4-benzofurazanyl)-1,4-dihydro -6-methyl-2-tbis(l-methylethoxy)-methyllpyridine-3,5- dicarboxylate The product of Example 4 (ii) above (5.0g, 12.5 mmoles) in 2-propanol (100 ml) was heated at reflux for 45 minutes. The solvent was removed by evaporation and the resulting yellow solid separated on silica (200g) using ether-petroleum ether mixtures as eluent. The first eluted band, after removal of solvent and recrystallisation from 2-propanol, gave the title compound as a yellow solid (2.2g) m.p. 103-104.5 . Example 6 4-(4-Benzofurazanyl)-1,4-dihydro-2-formyl-6-methylpyridine -3,5-dicarboxylic acid, 5-methyl ester A solution of the product of Example 4 (i) (5.0g, 12.4 mmoles) in tetrahydrofuran (50ml) was treated with 50% hydrochloric acid (25ml). After 72 hours at room temperature the solvent was removed by evaporation to leave a gum which was dissolved in ethyl acetate, and neutralised with sodium bicarbonate. The organic solution was separated and washed with water and brine, and then dried (MgSO4). Evaporation of the solvent gave a yellow solid (3.2g) m.p. 224.5O225.5O (decompn.) NMR analysis indicates that this compound exists almost entirely in the cyclised pseudo-acid form, viz: Methyl 4-(4-benzofurazanyl)-1,4,5,7-tetrahydro-7-hydroxy 5-oxo-2-methylfuro[3,4-bpyridine-3-carboxylate, when in solution. Example 7 5-Methyl 3- (1-methylethyl) 4- (4-benzofurazanyl) -1,4-dihydro-2-formyl-6-methylpyridine-3,5-dicarboxylate The product of Example 6 above (2.22g, 6.4 mmoles), anhydrous potassium carbonate (1.78g, 12.8 mmoles) and 2-iodopropane (0.8ml 8 mmoles) in acetonitrile (looms) were heated at reflux for 3 hours. The cooled mixture was filtered, the solid washed with ethyl acetate and the combined filtrates concentrated in vacuo. The resulting oil was dissolved in ethyl acetate (looms) and the solution washed with water and brine, and then dried (MgSO4). Evaporation of the solvent left a brown oil which was separated by chromatography on silica (lOOg) using ether-petroleum ether mixtures as eluent. The title compound (0.9g) was obtained as an orange solid m.p. 166-167 after trituration with petroleum ether (b.p. 40-60 ). Example 8 By the method described in Example 7 above was also prepared: i) 5-Methyl 3-(2-phenoxyethyl)4-(4-benzofurazanyl)1,4-dihydro-2-formyl-6-methylpyridine-3,5-dicarboxylate m.p. 121-122 ii) 3-(2-Ethoxyethyl) 5-methyl 4-(4-benzofurazanyl)-1,4dihydro-2-formyl-6-methylpyridine-3,5-dicarboxylate m.p. 1420. iii) 3-(2-(N,N-dimethylamino)ethyl)5-methyl 4-(4 benzofurazanyl) -1, 4-dihydro-2-formyl-6-methylpyridine -3,5-dicarboxylate hydrochloride m.p. 1300. Example 9 Diethyl 4-(4-benzofurazanyl)-1,4-dihydro-2-(hydroxymethyl) -6-methylpyridine-3,5-dicarboxylate A solution of the product of Example 3 above (3.6g, 9.3 mmoles) in dry ethanol (l00ml) was cooled to 00 and sodium borohydride (0.42g, 11 mmoles) was added portionwise over 3 minutes. After 30 minutes 10% aqueous hydrochloric acid was added dropwise to pH3, and the mixture concentrated in vacuo at room temperature. The resulting yellow oil was dissolved in ethyl acetate (100ml) and saturated aqueous sodium bicarbonate was added to pH9. The organic solution was separated, washed with sodium bicarbonate solution, water and brine, and then dried (MgS04). Evaporation of the solvent left a yellow brown solid which was recrystallised from a mixture of ethyl acetate, ether and petroleum ether (b.p. 60-80 ) to give the title compound as a yellow powder (1.47g) m.p. 128-129 . Example 10 By the method described in Example 9 above were also prepared i) Dimethyl 4-(4-benzofurazanyl)-l,4-dihydro-2- (hydroxymethyl) -6-methylpyridine-3, 5-dicarboxylate m.p. 182-1840 ii) 3-Ethyl 5- (1-methylethyl) 4- (4-benzofurazanyl) -1,4-dihydro-2-(hydroxymethyl)-6-methylpyridine -3,5-dicarboxylate m.p. 118-119 iii) Diethyl 4-[4-(2,1,3-benzothiadiazolyl)]-1,4-dihidro-2 (hydroxymethyl)-6-methylpyridine-3,5-dicarboxylate m.p. 133.5-135 iv) 3-Ethyl 5-(2-methylpropyl) 4- (4-benzofurazanyl)- 1,4-dihydro-2-(hydromethyl)-6-methylpyridine-3,5dicarboxylate m.p. 99-101 Example 11 Diethyl 4-(4-benzofurazanyl)-2-cyano-1,4-dihydro-6methylpyridine-3, 5-dicarboxylate A mixture of the product of Example 3 above (5.0g, 13 mmoles), sodium acetate (2.13g, 26 mmoles), hydroxylamine hydrochloride (1.13g, 16.2 mmoles) and acetic acid was stirred at room temperature for 2 hours. Acetic anhydride (2.5ml, 28.6 moles) was then added and the resulting mixture heated at reflux for 2 hours and then concentrated in vacuo. The yellow semi-solid residue was dissolved in ethyl acetate, and sodium bicarbonate added to pH9. The organic solution was separated and washed with aqueous sodium bicarbonate, water and brine, and then dried (MgSO4). Evaporation of solvent left a brown oil which was purified by chromatography on silica (200 g) using ether petroleum ether mixtures as eluent. The title compound was thus obtained as a yellow solid (1.12g) m.p. 157-158 after recrystallisation from cyclohexane-ether. Example 12 By the method of Example 11 above were also prepared: i) Dimethyl 4-(4-benzofurazanyl)-2-cyano-1,4-dihydro -6-methylpyridine-3,5-dicarboxylate m.p. 2310 ii) 3-Ethyl 5- (1-methylethyl) 4- (4-benzofurazanyl)-2-cyano -1,4-dihydro-6-methylpyridine-3,5-dicarboxylate m.p. 185-186.50 iii) Diethyl 4-[4-(2,1,3-benzothiadiazolyl)] -2-cyano-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate m.p. 137-1380 iv) 3-Ethyl 5-(2-methylpropyl) 4- (4-benzofurazanyl)- 2-cyano-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate m.p. 134-1350 Example 13 3-Ethyl 5-(2-methylpropyl)4-(4-benzofurazanyl)-1,4-dihydro -2- (hydroxyiminomethyl) -6-methylpyridine-3,5-dicarboxylate The product of Example 4(iv) (5.4g, 0.013 moles), hydroxylamine hydrochloride (1.18g, 0.016 mole) and sodium acetate (2.15g, 0.026 moles) in acetic acid were stirred at 200 for 2 hours. The solvent was evaporated, the residue taken up in ethyl acetate, and sodium bicarbonate added to pH8. The organic phase was separated, washed with water, dried and evaporated. The residue was recrystallised from 2-propanol/petroleum ether and then from pure 2-propanol to give the title oxime as yellow crystals m.p. 167-8 . Example 14 Diethyl 4-(4-benzofurazanyl)-1,4-dihydro-2-methyl-6 (trifluoromethyl) -pyridine-3,5-dicarboxylate A solution of 4-benzofurazancarboxaldehyde (l.0g. 6.75m moles), ethyl 4,4,4-trifluoro-3-oxybutyrate (l.Oml., 6.75m moles) and piperidine (0.lml) in benzene (50ml) was heated at reflux under a Dean-Stark water separator for 2 hours. The solution was cooled, ether (50ml) added, and the mixture washed with water and brine and dried. Evaporation gave crude ethyl 2-(4-benzofurazanmethylidene)4,4,4-trifluoromethyl-3-oxobutanoate (mixture of E- and Zisomers) as a brown oil (2.2g). Ethyl 3-amino-2-butenoate (0.87g., 6.75m moles) was added to the foregoing oil and the mixture heated on a steam bath for 72 hours. The mixture was cooled, dissolved in dichloromethane (50ml) and trifluoroacetic anhydride (2.6ml., 18.4m moles) and pyridine (1.6 ml., 18.4m moles) added. The solution was kept at 200 for 16 hours, then washed with water, aqueous hydrochloric acid, and brine. Evaporation of the organic phase afforded a brown oil (2.6g), which was dissolved in ether and petroleum ether was added until precipitation of dark impurities was complete. The mixture was filtered and the filtrate cooled at 00 overnight to afford yellow crystals (0.5g) of the title compound m.p. 1000.

Claims: What we claim is: 1. A compound of formula I, EMI22.1 in which X is oxygen or sulphur, R1 and R2, which may be the same or different, each represent alkyl C 1 to 6, -(CH2)n OR5, or (CH2)n NR6R7, and in addition R2 may represent hydrogen, n is a whole number from 2 to 4 inclusive, R3 represents -CH2OH, -CN, -CH(OR4)2, -CHO, -CH=NOH, -CF3, or, together with R2 forms a chain -CHOH-, R4 represents alkyl C 1 to 6, R5 represents alkyl C1 to 6 or phenyl, R6 and R7, which may be the same or different, each represent alkyl C1 to 6 optionally substituted by phenyl, and R8 is alkyl C1 to 6, and pharmaceutically acceptable acid addition salts of those compounds containing a basic nitrogen atom. 2. A compound according to Claim 1 in which X is oxygen and the benzofurazanyl group is attached through its 4-position to the tetrahydropyridine ring. 3. A compound according to Claim 1 or 2, wherein R and R2 are selected from ethyl and isopropyl. 4. A compound according to any one of the preceding claims, wherein R3 is -CH2OH, -CHO or -CN. 5. A compound according to Claim 4, wherein R3 is -CHO or -CN. 6. A compound according to any one of the preceding claims, wherein R8 is methyl. 7. Diethyl 4-(4-benzofurazanyl)-2-(diethoxymethyl) 1, 4-dihydro-6-methylpyridine-3, 5-dicarboxylate, Dimethyl 4-(4-benzofurazanyl)-1,4-dihydro-2 (dimethoxymethyl)-6-methylpyridine-3, 5-dicarboxylate, 3-Ethyl 5-(1-methylethyl)-4-(4-benzofurazanyl)-2 (diethoxymethyl-1,4-dihydro-6-methylpyridine-3,5- dicarboxylate, Diethyl 4-[4-(2,1,3-benzothiadiazolyl)]-2 (diethoxymethyl)-1,4-dihydro-6-methylpyridine-3,5- dicarboxylate, Diethyl 4-(4-benzofurazanyl)1,4-dihydro-2-formyl-6- methylpyridine-3, 5-dicarboxylate, Dimethyl 4-(4-benzofurazanyl)-1,4-dihydro-2-formyl -6-methylpyridine-3,5-dicarboxylate, 3-Ethyl 5-(1-methylethyl)4-(4-benzofurazanyl)-1,4dihydro-2-formyl-6-methylpyridine-3,5-dicarboxylate, Diethyl 4-[4-(2,1,3-benzothiadiazolyl)]-1,4-dihydro -2-formyl-6-methylpyridine-3, 5-dicarboxylate, 3-Ethyl 5-(2-methylpropyl) 4- (4-benzofurazany) 1,4- dihydro-2-formyl-6-methylpyridine-3,5-dicarboxylate, 3-Ethyl 5-(2-(N-methyl-N-(phenylmethyl)amino)ethyl)4-(4-benzofurazanyl)-1,4-dihydro-2-formyl-6methylpyridine-3, 5-dicarboxylate hydrochloride, 3-Ethyl 5-(1-methylethyl)4-(4-benzofurazanyl) -1, 4-dihydro-6 -methyl- 2- (bis (1-methylethoxy) -methyl]pyridine -3,5-dicarboxylate, 4-(4-Benzofurazanyl)-1,4-dihydro-2-formyl-6methylpyridine-3,5-dicarboxylic acid, 5-methyl ester, Methyl 4-(4-benzofurazanyl)-1,4,5,7-tetrahydro-7hydroxy 5-oxo-2-methylfuro[3,4-b]pyridine-3-carboxylate, 5-Methyl 3-(1-methylethyl) 4-(4-benzofurazanyl) -1,4-dihydro-2-formyl-6-methylpyridine-3,5-dicarboxylate, 5-Methyl 3-(2-phenoxyethyl)4-(4-benzofurazanyl)1,4-dihydro-2-formyl-6-methylpyridine-3,5-dicarboxylate, 3- (2-Ethoxyethyl) 5-methyl 4-(4-benzofurazanyl)-1,4dihydro-2-formyl-6-methylpyridine-3,5-dicarboxylate, 3-(2-(N,N-diethylamino)ethyl)5-methyl 4-84 benzofurazanyl) -1,4-dihydro-2-formyl-6-methylpyridine -3,5-dicarboxylate hydrochloride, Diethyl 4-(4-benzofurazanyl)-1,4-dihydro-2- (hydroxymethyl)-6-methylpyridine-3,5-dicarboxylate, Dimethyl 4-(4-benzofurazanyl)-1,4-dihydro-2 (hydroxymethyl)-6-methylpyridine-3,5-dicarboxylate, 3-Ethyl 5-(1-methylethyl) 4-(4-benzofurazanyl) -1,4-dihydro-2-(hydroxymethyl)-6-methylpyridine -3, 5-dicarboxylate, Diethyl 4-[4-(2,1,3-benzothiadiazolyl)]-1,4-dihydro-2 (hydroxymethyl)-6-methylpyridine-3,5-dicarboxylate, 3-Ethyl 5-(2-methylpropyl) 4-(4-benzofurazanyl)1,4-dihydro-2-(hydroxymethyl)-6-methylpyridine-3,5dicarboxylate, Diethyl 4-(4-benzofurazanyl)-2-cyano-1,4-dihydro-6methylpyridine-3, 5-dicarboxylate, Dimethyl 4- (4-benzofurazanyl)-2-cyano-l,4-dihydro -6-methylpyridine-3,5-dicarboxylate, 3-Ethyl 5- (1-methylethyl) 4-(4-benzofurazanyl)-2-cyano -l,4-dihydro-6-methylpyridine-3,5-dicarboxylate, Diethyl 4-[4-(2,l,3-benzothiadiazolyl)] -2-cyano-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate, 3-Ethyl 5-(2-methylpropyl) 4-(4-benzofurazanyl)2-cyano-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate, 3-Ethyl 5-(2-methylpropyl)4-(4-benzofurazanyl) -1,4-dihydro-2-(hydroxyiminomethyl)-6-methylpyridine-3, 5-dicarboxylate, or Diethyl 4-(4-benzofurazanyl)-1,4-dihydro-2-methyl-6- (trifluoromethyl)-pyridine-3,5-dicarboxylate 8. A pharmaceutical formulation comprising a compound according to any one of the preceding claims in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. 9. A process for the production of a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, which comprises a) production of a compound of formula I in which R3 is -CH(OR4)2 by i) reaction of a compound of formula II, EMI26.1 in which Rg is a group -CF3 or CH(OR4)2, and X, R2 and Rq are as defined above, with a compound of formula III, R1OOCCH=C (R8) NH2 III in which R1 and R8 are as defined above, or ii) reaction of a corresponding compound of formula I in which R3 is -CHO with an alcohol R4OH, b) production of a compound of formula I in which R3 is -CHO by selective hydrolysis of a corresponding compound of formula I in which R3 is KH(OR4)2, c) production of a compound of formula I in which R3 is -CH=NOH by reaction of a corresponding compound of formula I in which R3 is -CHO with hydroxylamine, or a salt thereof, d) production of a compound of formula I in which R3 is -CN by dehydration of a corresponding compound of formula I in which R3 is -CH=NOH, e) production of a compound of formula I in which R3 is -CH2OH by selective reduction of a corresponding compound of formula I in which R3 is -CHO, f) production of a compound of formula I in which R2 is hydrogen, by selective hydrolysis of a corresponding compound of formula I in which -COOR2 is an ester group, g) production of a compound of formula I in which R2 is other than hydrogen by esterification, with a compound R2L in which L is a leaving group, of a corresponding compound of formula I in which R2 is hydrogen, or R2 together with R3 forms a chain -CHOH-, or h) selective reduction of a corresponding pyridine, and where desired or necessary converting the resulting compound of formula I to a pharmaceutically acceptable acid addition salt thereof, or vice versa. 10. Use of a compound according to any one of Claims 1 to 7 as a pharmaceutical. CLAIMS FOR AUSTRIA What we claim is:1. A process for the production of a compound of formula I, EMI29.1 in which X is oxygen or sulphur, R1 and R2, which may be the same or different, each represent alkyl C 1 to 6, -(CH2)n OR5, or -(CH2)n NR6R7, and in addition R2 may represent hydrogen, n is a whole number from 2 to 4 inclusive, R3 represents -CH2OH, -CN, -CH(OR4)2, -CHO, -CH=NOH, -CF3, or, together with R2 forms a chain -CHOH-, R4 represents alkyl C 1 to 6, R5 represents alkyl C1 to 6 or phenyl, R6 and R7, which may be the same or different, each represent alkyl C1 to 6 optionally substituted by phenyl, and R8 is alkyl C1 to 6, or pharmaceutically acceptable acid addition salt of those compounds containing a basic nitrogen atom, which comprises a) production of a compound of formula I in which R3 is -CH(OR4)2 by i) reaction of a compound of formula II, EMI30.1 in which Rg is a group -CF3 or -CH(OR4)2, and X, R2 and R4 are as defined above, with a compound of formula III, R1OOCCH=C(R8)NH2 III in which R1 and R8 are as defined above, or ii) reaction of a corresponding compound of formula I in which R3 is -CHO with an alcohol R40H, b) production of a compound of formula I in which R3 is -CHO by selective hydrolysis of a corresponding compound of formula I in which R3 is -CH(OR4)2, c) production of a compound of formula I in which R3 is -CH=NOH by reaction of a corresponding compound of formula I in which R3 is -CHO with hydroxylamine, or a salt thereof, d) production of a compound of formula I in which R3 is -CN by dehydration of a corresponding compound of formula I in which R3 is -CH=NOH, e) production of a compound of formula I in which R3 is -CH2OH by selective reduction of a corresponding compound of formula I in which R3 is -CHO, f) production of a compound of formula I in which R2 is hydrogen, by selective hydrolysis of a corresponding compound of formula I in which -COOR2 is an ester group, g) production of a compound of formula I in which R2 is other than hydrogen by esterification, with a compound R2L in which L is a leaving group, of a corresponding compound of formula I in which R2 is hydrogen, or R2 together with R3 forms a chain -CHOH-, or h) selective reduction of a corresponding pyridine, and where desired or necessary converting the resulting compound of formula I to a pharmaceutically acceptable acid addition salt thereof, or vice versa. 2. A process according to Claim 1 in which X is oxygen and the benzofurazanyl group is attached through its 4-position to the tetrahydropyridine ring. 3. A process according to Claim 1 or 2, wherein R1 and R2 are selected from ethyl and isopropyl. 4. A process according to any one of the preceding claims, wherein R3 is -CH20H, -CHO or -CN. 5. A process according to Claim 4, wherein R3 is -CHO or -CN. 6. A process according to any one of the preceding claims, wherein R8 is methyl. 7. A process according to any one of the preceding claims, wherein the compound of formula I is Diethyl 4-(4-benzofurazanyl)-2-(diethoxymethyl) l,4-dihydro-6-methylpyridine-3, 5-dicarboxylate, Dimethyl 4- (4-benzofurazanyl) -l,4-dihydro-2- (dimethoxymethyl)-6-methylpyridine-3,5-dicarboxylate, 3-Ethyl 5-(1-methylethyl)-4-(4-benzofurazanyl)-2 (diethoxymethyl-1,4-dihydro-6-methylpyridine-3,5- dicarboxylate, Diethyl 4-[4-(2,1,3-benzofurazanyl)]-2 (diethoxymethyl)-1,4-dihydro-6-methylpyridine-3,5- dicarboxylate, Diethyl 4-(4-benzofurazanyl)1,4-dihydro-2-formyl-6methylpyridine-3 , 5-dicarboxylate, Dimethyl 4-(4-benzofurazanyl)-1,4-dihydro-2-formyl -6-methylpyridine-3,5-dicarboxylate, 3-Ethyl 5-(1-methylethyl) 4- (4-benzofurazanyl) -1,4- dihydro-2-formyl-6-methylpyridine-3,5-dicarboxylate, Diethyl 4-[4-(2,1,3-benzothiadiazolyl)]-1,4-dihydro -2-formyl-6-methylpyridine-3,5-dicarboxylate, 3-Ethyl 5-(2-methylpropyl)4-(4-benzofurazanyl)1,4dihydro-2-formyl-6-methylpyridine-3,5-dicarboxylate, 3-Ethyl 5-(2-(N-methyl-N-(phenylmethyl)amino)ethyl)4-(4-benzofurazanyl)-1,4-dihydro-2-formyl-6methylpyridine-3,5-dicarboxylate hydrochloride, 3-Ethyl 5-(1-methylethyl) 4-(4-benzofurazanyl) -1,4-dihydro-6-methyl-2-[bis(l-methylethoxy)-methyl3pyridine -3,5-dicarboxylate, 4-(4-Benzofurazanyl)-1,4-dihydro-2-formyl-6methylpyridine-3,5-dicarboxylic acid, 5-methyl ester, Methyl 4-(4-benzofurazanyl)-1,4,5,7-tetrahydro-7- hydroxy 5-oxo-2-methylfuro[3,4-b3pyridine-3-carboxylate, 5-Methyl 3-(1-methylethyl) 4-(4-benzofurazanyl) -1,4-dihydro-2-formyl-6-methylpyridine-3,5-dicarboxylate, 5-Methyl 3-(2-phenoxyethyl)4-(4-benzofurazanyl)1,4-dihydro-2-formyl-6-methylpyridine-3,5-dicarboxylate, 3-(2-Ethoxyethyl) 5-methyl 4-(4-benzofurazanyl)-1,4dihydro-2-formyl-6-methylpyridine-3,5-dicarboxylate, 3-(2-(N,N-diethylamino)ethyl)5-methyl 4-(4benzofurazanyl)-1,4-dihydro-2-formyl-6-methylpyridine -3,5-dicarboxylate hydrochloride, Diethyl 4-(4-benzofurazanyl)-1,4-dihydro-2 (hydromethyl)-6-methylpyridine-3,5-dicarboxylate, Dimethyl 4-(4-benzofurazanyl)-1,4-dihydro-2 (hydromethyl)-6-methylpyridine-3,5-dicarboxylate, 3-Ethyl 5- (1-methylethyl) 4- (4-benzofurazanyl) -1,4-dihydro-2-(hydroxymethyl)-6-methylpyridine -3,5-dicarboxylate, Diethyl 4-[4-(2,1,3-benzothiadiazolyl)]-1,4-dihydro-2 (hydroxymethyl)-6-methylpyridine-3,5-dicarboxylate, 3-Ethyl 5-(2-methylpropyl) 4-(4-benzofurazanyl)1,4-dihydro-2-(hydroxymethyl)-6-methylpyridine-3,5dicarboxylate, Diethyl 4- (4-benzofurazanyl) -2-cyano-l,4-dihydro-6- methylpyridine-3, 5-dicarboxylate, Dimethyl 4-(4-benzofurazanyl)-2-cyano-1,4-dihydro -6-methylpyridine-3,5-dicarboxylate, 3-Ethyl 5- (1-methylethyl) 4-(4-benzofurazanyl)-2-cyano -1,4-dihydro-6-methylpyridine-3,5-dicarboxylate, Diethyl 4-[4-(2,1,3-benzothiadiazolyl)] -2-cyano-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate, 3-Ethyl 5-(2-methylpropyl) 4-(4-benzofuranyl)2-cyano-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate, 3-Ethyl 5-(2-methylpropyl) 4-(4-benzofurazanyl) -1,4-dihydro-2-(hydroxyiminomethyl)-6-methylpyridine-3, 5-dicarboxylate, or Diethyl 4- (4-benzofurazanyl) -1,4-dihydro-2-methyl-6- (trifluoromethyl) -pyridine-3, 5-dicarboxylate.

Inventors: DIXON, JOHN, TINKER, ALAN CHARLES
Applicants: FISONS PLC
Application year: 1982
Main classification: C07D413
IPC codes: C07D491, C07D417, C07D413, C07D271