DIHYDROPYRIDINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract: Compound, with hypoglycaemic activity, having for­ mula (II) or a pharmaceutically acceptable quaternary ammonium or acid addition salt thereof: wherein R¹ and R² are substituents attached to any of the carbon atoms of the dihydropyridine ring and represent hydrogen, C₁₋₆ alkyl, halogen, carbo-C₁₋₆ alkoxy or R³ represents hydrogen, C₁₋₆ alkyl, phenyl or benzyl; R⁴ represents hydrogen or C₁₋₆ alkyl; R⁵ represents C₁₋₆ alkyl, phenyl optionally substituted with up to 3 groups selected from halogen, C₁₋₆ alkyl, and C₁₋₆ alkoxy; or benzyl optionally substituted with up to 3 groups selected from halogen, C₁₋₆ alkyl and C₁₋₆ alkoxy; or R⁴ and R⁵ together represent the remaining members of a 5- or 6-

Description: Dihydropyridine derivatives and processes for their preparation This invention relates to a class of novel dihydropyridine derivatives which are useful in the treatment of diabetes. The invention also relates to a process for their preparation and to pharmaceutical compositions containing them. The compound of formula (I): EMI1.1 has been reported to be useful in the treatment of diabetes in Belgian Patent No. 852,565 and in Diabetes, 27, 856 and 868 (1978). We have now found a novel class of dihydropyridylidene compounds which have hypoglycaemic activity. Accordingly the present invention provides a compound of formula (II) or a pharmaceutically acceptable quaternary ammonium or acid addition salt thereof: EMI2.1 wherein R1 and R2 are substituents attached to any of the carbon atoms of the dihydropyridine ring and represent hydrogen, C1-6 alkyl, halogen, carbon-1-6 alkoxy or carboxy. R represents hydrogen, C16 alkyl, phenyl or benzyl; R4 represents hydrogen or C16 alkyl; 5 R represents C16 alkyl, phenyl optionally substituted with up to 3 groups selected from halogen, C16 alkyl, and C16 alkoxy; or benzyl optionally substituted with up to 3 groups selected from halogen, C1-6 alkyl and C16 alkoxy; or R4 and R5 together represent the remaining members of a 5- or 6 membered ring optionally containing an oxygen, sulphur or additional nitrogen atom and being optionally substituted with C1-6 alkyl; and R6 represents C1-6 alkyl, phenyl, optionally substituted with up to 3 groups selected from halogen, nitro-, amino-, or trifluoromethyl, C1-6 alkyl and C16 6 alkoxy; or benzyl optionally substituted with up to 3 groups selected from halogen, C16 alkyl and C16 alkoxy. Suitable acid addition salts of compound (II) include inorganic salts such as the sulphate, nitrate, phosphate and borate, hydrohalides such as the hydro chloride, hydrobromide and hydroiodide, and organic acid addition salts such as acetate, oxalate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesulphonate and p-toluenesulphonate. Preferred salts are hydrohalide salts. Suitable quaternary salts are the C16 alkyl halides, in particular the methylhalide, such as the methyliodide salt. Examples of suitable C16 alkyl groups which R1 to R6 may represent include methyl, ethyl, n- and isopropyl, and n-, sec-, iso- and tert-butyl. Suitable substituents for the phenyl and benzyl groups for R5 and R6 include ortho-, meta- and paramethyl, methoxy, chloro, bromo, fluoro, nitro and amino. Suitably RÚ and Rê represent hydrogen, methyl or halogen particularly hydrogen. Suitably R3 is methyl,-ethyl, n-propyl or phenyl, but preferably R3 is methyl. 4 Suitably R4 is hydrogen, methyl, ethyl or npropyl, and R5 represents methyl, ethyl, n-propyl, phenyl or benzyl. Preferably R4 and R5 are both ethyl. When R4 and R5 complete a ring, suitable such rings include pyrrolidine, piperidine, morpholine, thiamorpholine, piperazine and 4-methylpiperazine. rings. Preferably R4 and R5 complete a morpholine ring. Suitably R6 is methyl, ethyl, n-propyl or phenyl, but preferably R6 is phenyl or substituted phenyl. One sub-group of compounds falling within the scope of this invention comprises compounds of formula (III) and pharmaceutically acceptable quaternary ammonium or acid addition salts thereof: EMI4.1 wherein Ra and Rb are the same as RÚ and Rê respectively as defined in formula (II), R7 represents C1-6 alkyl, preferably methyl, R8 represents hydrogen -or C16 alkyl; R represents C16 alkyl or benzyl; or R and R9 together form the remaining members of a pyrrolidine, thiamorpholine or morpholine ring, and RÚÚ represents phenyl optionally substituted with up to 3 groups selected from C16 alkyl, halogen or nitro. Preferably, R8 and R9 are both ethyl, and when taken together form a morpholine ring. Examples of compounds of formula (II) include the following: N-(1,2-dihydro-1-methyl-2-pyridylidene)-N'-phenyl-l- pyrrolidinecarboxamidine hydroiodide, N-(1,2-dihydro-1- methyl-2-pyridylidene)-N'-phenyl-4-morpholinecarboxamidine hydroiodide, N-(1,2-dihydro-1-methyl-2-pyridylidene)-N'- phenyl-4- (2, 6-dimethylmorpholine)carboxamidine, N-benzyl-N'-(1,2-dihydro-l-methyl-2 pyridylidene) -N" -phenylguanidine, N- (1, 2-dihydro-l- methyl-2-pyridylidene) -N' - (4-methylphenyl) -4-morpholine- carboxamidine hydroiodide, N'-(4-chlorophenyl)-N (1, 2-dihydro-l-methyl-2-pyridylidene) -4-morpholine- carboxamidine hydroiodide, N- (1, 2-dihydro-l-methyl-2- pyridylidene)-N'-(4-fluorophenyl)-4-morpholine- carboxamidine hydroiodide, N,N-diethyl-N'-(1,2 dihydro-l-methyl-2-pyridylidene)-N"-(4-fluorophenyl) guanidine hydroiodide, N-(1,2-dihydro-l-methyl-2- pyridylidene) -N' - (4-nitrophenyl) -4-morpholinecarboxamidine hydroiodide, N,N-diethyl-N'-(1,2-dihydro-1,3-dimethyl 2-pyridylidene)-N"-phenylguanidine hydroiodide, N-(1,2-dihydro-1,4-dimethyl-2-pyridylidene)-N'- phenyl-4-morpholinecarboxamidine hydroiodide, N-(5 bromo-1,2-dihydro-1-methyl-2-pyridylidene)-N'-phenyl- 4-morpholinecarboxamidine hydroiodide, N-(5-carbo methoxy-1,2-dihydro-1-methyl-2-pyridylidene)-N'-phenyl- 4-morpholinecarboxamidine hydroiodide, N-(1,2-dihydro 1, 5-dimethyl-2-pyridylidene) -N' -phenyl-4-morpholine- carboxamidine, N,N-diethyl-N'-(1,2-dihydro-1-methyl- 2-pyridylidene) -N"-phenylguanidine, N-(1,2-dihydro-1- methyl-2-pyridylidene) -N1-phenyl-4-thiamorpholine- carboxamidine, N-(1,2-dihydro-l-methyl-2-pyridylidene)- N'-phenyl-l-pyrrolidinecarboxamidine methiodide. Compounds of formula (II) may be prepared by reacting a compound of formula (IV) or a salt thereof: EMI5.1 wherein R1, R2, R3 and R6 are as defined with respect to formula (II) above, and R10 represents C16 alkyl; with an amine of formula R4R5NH, wherein R4 and R5 are as defined with reference to formula (II) above and thereafter where desired converting a free base of formula (II) so obtained into a pharmaceutically acceptable salt or converting a salt of a compound of formula (II) so obtained into the free base. The reaction is conveniently carried out in polar organic solvent, the choice of which is not critical to the success of the reaction provided that it forms a homogeneous solution of the reagent and is substantially inert to the reagent and product. Convenient solvents include alkanols such as iso-propanol and alkanoic acids such as glacial acetic acid. The reaction is generally carried out at a moderate temperature i.e. greater than room temperature, the reflux temperature of the solvent being selected for convenience. The period for which the reaction is allowed to proceed depends upon the particular starting materials employed. The course of the reaction may be followed by conventional methods such as thin layer chromatography and terminated when an optimum quantity of product is present in the reaction mixture. However, in general we have found that it is convenient to leave the reaction mixture to reflux overnight. Intermediates of general formula (IV) are novel and represent a further aspect of the invention. 10 Examples of C1 6 alkyl groups which R1O may represent include methyl, ethyl, n-propyl, or n-butyl, but preferably R10 represents methyl. The intermediates of formula (IV) may be prepared by the route shown in the following scheme: EMI7.1 Thus, intermediates (IV) are prepared by alkylation of a thiourea (VI) -using an alkylating agent R10.Z wherein R10 is as defined with reference to formula (IV) and Z is a leaving group such as chloride, bromide or iodide. Suitably the reaction is carried out in a polar organic solvent, the choice of which is not critical. Suitable solvents include lower alkanones. The reaction is suitably carried out at the boiling point of the solvent. The thiourea (VI) is in turn prepared by reacting an iso-thiocyanate R6.NCS with a corresponding imino compound (V), where R1, R2, R3 and R6 are as defined with reference to formula (II). This reaction is carried out in a solvent such as ethanol, toluene, benzene, dioxane or tetrahydrofuran. The reaction is carried out at non-extreme temperatures i.e. up to and including the reflux temperature of the solvent. Compounds of formula (II) may also be prepared by reacting a compound of formula (VII). EMI8.1 wherein R4, R5 and R6 are as defined with respect to formula (II) above; with an imino compound (V), where R11 R2 and R3 are as defined with respect to formula (II) above and thereafter where desired converting a free base of formula (II) so obtained into a pharmaceutically acceptable salt or converting a salt of a compound of formula (II) so obtained into the free base. The reaction is conveniently carried out in a non-hydroxylic solvent system such as an ether, chlorinated hydrocarbon or a mixture thereof. Suitable solvent systems include mixtures of diethyl ether.and chloroform. The reaction is suitably carried out at ambient temperature. The period for which the reaction is allowed to proceed may be determined by methods as described hereinbefore; however, we have found it convenient to leave the reaction mixture to stand overnight. The intermediates of formula (VII) may be prepared by reaction of an isocyanide dichloride of R6 6 formula : R6-N=CC12 wherein R6 is as defined with respect to formula (11) above; with an amine of formula R R4R5 NH, wherein R4 and R5 are as defined with reference to formula (II) above. Suitably the reaction is carried out in ethereal solvent such as diethyl ether or tetrahydrofuran. The reaction is suitably carried out at ambient temperature. The -period for which the reaction is allowed to proceed may be determined by methods as described hereinbefore; however, we have found a two hour reaction time to be sufficient. In order to put the compounds (II) to use as medicinal agents for the treatment of diabetes, they are presented as pharmaceutical compositions in a variety of dosage forms. This invention therefore also includes a pharmaceutical composition which comprises a compound of formula (II) together with a pharmaceutically acceptable carrier or excipient. The compositions may be formulated for administration by any route, although an oral administration is preferred. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, or liquid preparations, such as oral or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol, or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups,-or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxy-methyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents. The compound may also if desired be incorporated in a foodstuff, for example in the form of a biscuit. For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a locai anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. The compositions may contain from 0.1% to 99% by weight, preferably from i0-60% by weight, of the active material, depending on the method of administration. The dosage employed for adult treatment will of course depend on the dose-response characteristics of the particular active ingredient but will normally be in the range 0.1 to 150 mg/kg/day. The following Examples illustrate the preparation of a number of compounds of this invention: Example 1 N-(1 2-Dihvdro-l-methyl-2-pvridvlidene)-N'-phenyl-l- pyrrolidinecarboxamidine hydroiodide a) 1- (1 2-Dihvdro-l-inethvl-2-pvridylidene )-3-phenyl- 2-thiourea Sodium methoxide (0.71 g) was added to 1,2dihydro-2-imino-l-methylpyridine hydroiodide (3.1 g) in ethanol (30 ml) and heated to reflux when phenyl isothiocyanate (1.96 g) in ethanol (20 ml) was added over 5 minutes. The resultant mixture was heated under reflux, with stirring, for 50 minutes, cooled in ice, filtered, washed well with ethanol and dried to give the product, mpt 186.5 - 1880, of analytical purity. Recrystallisation from ethanol gave a sample mpt 186 - 1870. b) 3- (1 g 2-Dihvdro-l-methvl-2-pyridylidene )-2-methyl- l-phenyl-2-thiopseudourea hydroiodide A mixture of 1(1, 2-dihydro-1-methyl-2-pyridylidene )3-phenyl-2-thiourea (15.5 g), methyl iodide (11.93 g) and acetone (175 ml) was heated under reflux, with stirring, for 40 minutes, cooled in ice and filtered to give the analytically pure product, mpt 150 - 151 . c) N- (1 g 2-Dihydro-l-methyl-2-pyridylidene )-N' phenyl l-pyrrolidenecarboxamidine hydroiodide A mixture of 3- (1, 2-dihydro-1-methyl-2-pyridylidene )- 2-methyl-1-phenyl-2-thiopseudourea hydroiodide (2.55 g) and pyrrolidine (3.24 g) in dry iso-propanol (60 ml) was heated under reflux, with stirring, for 20 hours, cooled in ice, filtered, washed well with iso-propanol then diethyl ether to give the analytically pure product as its hydroiodide salt, mpt 239 - 2400. Examples 2 - 4 By an analogous procedure to that described in Example l(c), the following products were obtained by reaction of 3-(1,2-dihydro-1-methyl-2-pyridylidene)- 2-methyl-l-phenyl-2-thiopseudourea hydroiodide, described in Example l(b), with the appropriate amine: Example 2 N-(1,2-dihydro-1-methyl-2-pyridylidene)-N'- phenyl-4-morpholinecarboxamidine hydroiodide, mpt 213.5 - 215 . Example 3 N-(1,2-dihydro-1-methyl-2-pyridylidene)-N'- phenyl-4- (2, 6-dimethylmorpholine)-carboxamidine, mpt 142 - 40. Example 4 N-benzyl-N' (1, 2-dihydro-l-methyl-2-pyridylidene) - N"-phenylguanidine as an oil which was purified by column chromatography on silica using 7% of (33% dimethylamine in ethanol) in dichloromethane. Example 5 - 13 The following thioureas were prepared, by an analogous procedure to that described in Example l(a), from the appropriate imine and isothiocyanate: 1-(1,2-dihydro-1-methyl-2-pyridylidene)-3-(4-methylphenyl)- 2-thiourea. 3- (4-chlorophenyl) -1- (1, 2-dihydro-l-methyl-2-pyridylidene) - 2-thiourea, mpt 164 - 60. 1-(1,2-dihydro-1-methyl-2-pyridylidene)-3-(4-fluoro- phenyl)-2-thiourea, mpt 179 - 800. 1-(1,2-dihydro-1-methyl-2-pyridylidene)-3-(4-nitro- phenyl)-2-thiourea, mpt 204 - 80. 1-(1,2-dihydro-1,3-dimethyl-2-pyridylidene)-3-phenyl2-thiourea, mpt 202.5 - 203.50. 1-(1,2-dihydro-1,4-dimethyl-2-pyridylidene)-3-phenyl2-thiourea, mpt 207 - 90. 1-(5-bromo-1,2-dihydro-1-methyl-2-pyridylidene)-3- phenyl-2-thiourea, mpt 183 - 6 (chloroform-diethyl ether). 1- (5-carbomethoxy-l , 2-dihydro-l-methyl-2-pyridylidene) - 3-phenyl-2-thiourea, mpt 176 - 80. Reaction of these thioureas with methyl iodide by an analogous procedure to that described in Example l(b) gave the following 2-methyl-2-thiopseudoureas: 3-(1,2-dihydro-1-methyl-2-pyridylidene)-2-methyl-1 (4-methylphenyl)-2-thiopseudourea hydroiodide, mpt 147 - 500. 1- (4-chlorophenyl) -3- (1, 2-dihydro-l-methyl-2-pyridylidene) - 2-methyl-2-thiopseudourea hydroiodide, mpt 163 - 40 (isopropanol). 3-(1,2-dihydro-1-methyl-2-pyridylidene)-1-(4-fluoro- phenyl)-2-methyl-2-thiopseudourea hydroiodide, mpt 114 3-(1,2-dihydro-1-methyl-2-pyridylidene)-2-methyl-1- (4-nitrophenyl)-2-thiopseudourea hydroiodide, mpt 173 - 60. 3-(1,2-dihydro-1,3-dimethyl-2-pyridylidene)-2-methyl-1- phenyl-2-thiopseudourea hydroiodide. 3-(1,2-dihydro-1,4-dimethyl-2-pyrìdylidene)-2-methyl-1- phenyl-2-thiopseudourea hydroiodide, mpt 168 - 720 (methanol-diethyl ether). 3-(5-bromo-1,2-dihydro-1-methyl-2-pyridylidene)-2- methyl-l-phenyl-2-thiopseudourea hydroiodide, mpt 184 - 60. 3-(5-carbomethoxy-1,2-dihydro-1-methyl-2-pyridylidene)- 2-methyl-l-phenyl-2-thiopseudourea hydroiodide, mpt 168 - 90 Reaction of the appropriate 2-methyl-2-thiopseudourea hydroiodide and amine gave the following guanidines by an analogous procedure to that described in Example l(c): Example 5 N- (1, 2-dihydro-l-methyl-2-pyridylidene) -N' - (4-methylphenyl) -4-morpholinecarboxamidine hydroiodide, mpt 206 - 7 (ethanol-diethyl ether). Example 6 N'-(4-chlorophenyl)-N-(1,2-dihydro-1-methyl-2- pyridylidene)-4-morpholinecarboxamidine hydroiodide, mpt 207 - 9 (methanol-diethyl ether). Example 7 N-(1,2-dihydro-1-methyl-2-pyridylidene)-N'- (4-fluorophenyl)-4-morpholinecarboxamidine hydroiodide, mpt 171 - 30. Example 8 N,N-diethyl-N'-(1,2-dihydro-1-methyl-2-pyridylidene)- N"-(4-fluorophenyl)guanidine hydroiodide, mpt 129.5 130.5 (methanol-diethyl ether). Example 9 N-(1,2-dihydro-1-methyl-2-pyridylidene)-N'- (4-nitrophenyl)-4-morpholinecarboxamidine hydroiodide, mpt 221 - 30 Example 10 N,N-diethyl-N'-(1,2-dihydro-1,3-dimethyl-2- pyridylidene)-N"-phenylguanidine hydroiodide, mpt 215 - 6 , (methanol-diethyl ether). Example 11 N- (1 ,2-dihydro-l, 4-dimethyl-2-pyridylidene) - N' -phenyl-4-morpholinecarboxamidine hydroiodide, mpt 181 - 2 (methanol-diethyl ether). Example 12 N-(5-bromo-1,2-dihydro-1-methyl-2-pyridylidene) N'-phenyl-4-morpholinecarboxamidine hydroiodide, mpt 226 - 80. Example 13 N- (5-carbomethoxy-l, 2-dihydro-l-methyl-2- pyridylidene)-N'-phenyl-4-morpholinecarboxamidine hydroiodide, mpt 214 - 'O (methanol-diethyl ether). Example 14 N-(1,2-Dihydro-1,5-dimethyl-2-pyridylidene)-N'-phenyl 4-morphol inecarboxamidine Morpholine (2.70 g) in tetrahydrofuran (30 ml) was added dropwise, at 0 C, with stirring to a solution of phenylisocyanide dichloride (2.70 g) in tetrahydrofuran (40 ml), stirred for one hour then filtered. The filtrate was added to a mixture of 1,5-dimethyl1,2-dihydro-2-iminopyridine (3.79 g) in tetrahydrofuran (50 ml) methylene chloride (50 ml) and the mixture stirred overnight then filtered. The filtrate was evaporated to dryness, the residue dissolved in dilute hydrochloric acid, washed with diethyl ether (X 1), basified with dilute sodium hydroxide solution and extracted with diethyl ether (X 2). The combined organic extracts were washed with water (X 1), dried over anhydrous magnesium sulphate, filtered and evaporated to dryness. The residue was crystallised from isopropanol to give analytically pure product, mpt 98 - 90. Examples 15 & 16 By use of the appropriate imine and amine, the following compounds have been prepared from phenylisocyanide dichloride by an analogous procedure to that described in Example 14. Example 15 N,N-diethyl-N'-(1,2-dihydro-1-methyl-2-pyridylidene) N"-phenylguanidine, mpt 113 - 40 (petroleum ether, bp 60 - 800). Example 16 N-(1,2-dihydro-1-methyl-2-pyridylidene)-N'- 0 phenyl-4-thiamorpholinecarboxamidine, mpt 208 - 210 Example 17 N- (1 ,2-Dihydro-l-methyl-2-pyridylidene) -N1 -phenyl-l- pyrrolidinecarboxamidine methiodide A mixture of N-(1,2-dihydro-1-methyl-2-pyridylidene)- N'-phenyl-l-pyrrolidinecarboxamidine (1.78 g) and iodomethane (1.30 g) in tetrahydrofuran (25 ml) was allowed to stand for 24 hours. Filtration gave the desired methiodide, mpt 188 - 90, of analytical purity. Biological Data Activity on Glucose Tolerance in Fasted Mice For this assay mice were fasted for 24 hours before the experiment and then randomised so that each treatment group contained 8 mice. The compounds were dosed orally in 1% aqueous carboxymethyl cellulose (10 ml/kg body weight), and 30 minutes later glucose (lg/kg) was administered by the sub-cutaneous route. Blood samples for glucose analysis were taken from the tail 60 minutes after glucose administration; the results are shown in the table below. N.B. A standard system for indicating the significance of results with respect to the controls (dose = zero mmol/kg) which received the 1% aqueous carboxymethyl cellulose vehicle only, is as follows: ** P < 0.05 *** P < 0.01 **** P < 0.001 In the following Table, column A represents the dose of compound (mmol/kg body weight) and column B represents the blood glucose concentration (mmol/litre) 60 minutes after sub-cutaneous glucose load. TABLE EMI20.1 <tb> <SEP> Compound <SEP> A <SEP> B <tb> Example <SEP> 1 <tb> <SEP> Cr) <tb> <SEP> 0 <SEP> 6.10 <tb> <SEP> I!NIN-C=N <tb> <SEP> CH3 <SEP> H1 <SEP> Salt <tb> Example <SEP> 2 <tb> <SEP> tun) <SEP> 0 <SEP> 6.10 <tb> <SEP> 0,25 <SEP> 0.25 <SEP> 3.88 <SEP> **** <tb> <SEP> - <SEP> lir,C=l <tb> <SEP> CH3 <SEP> Hl <SEP> Salt <tb> Example <SEP> 3 <tb> <SEP> CH <SEP> CH3 <tb> <SEP> N <SEP> 0 <SEP> 4.88 <tb> <SEP> i¹NNN%=N <SEP> 0.2 <SEP> 3.48 <tb> <SEP> t <SEP> ,7 <SEP> o <SEP> 0.2 <SEP> 5.36 <SEP> ** <tb> <SEP> CH3 <tb> Example <tb> <SEP> N <SEP> 0 <SEP> 6.18 <tb> <SEP> 1 <SEP> 0,2 <SEP> 4.97 <SEP> ** <tb> <SEP> N1NC=N <SEP> CH3 <tb> <SEP> CH3 <SEP> H1 <SEP> Salt <tb> Cont/d ..... TABLE EMI21.1 <tb> <SEP> Compound <SEP> A <SEP> B <tb> Example <SEP> 6 <tb> <SEP> o <SEP> N-C=N <SEP> o <SEP> C1 <SEP> 0.2 <SEP> 3.36 <SEP> *** <tb> <SEP> N <SEP> Cl <tb> <SEP> H3 <SEP> H1 <SEP> Salt <tb> <SEP> 3 <tb> Example <SEP> 7 <tb> <SEP> I <SEP> 0 <SEP> 5.28 <tb> <SEP> C <SEP> N <SEP> 0.2 <SEP> 2.55 <SEP> *** <tb> <SEP> CH3 <SEP> H1 <SEP> Salt <tb> Example <SEP> 8 <tb> <SEP> Et <SEP> Et <SEP> 0 <SEP> 5.84 <tb> <SEP> 0.2 <SEP> F <SEP> 0.2 <SEP> 3.21 <SEP> *** <tb> <SEP> F <tb> <SEP> CH3 <SEP> Hl <SEP> Salt <tb> Example <SEP> 9 <tb> <SEP> 10I <SEP> 0 <SEP> 6.56 <tb> <SEP> 0.2 <SEP> 3.75 <SEP> *k* <tb> Example <SEP> 10 <tb> <SEP> Et <SEP> Et <tb> <SEP> \/ <SEP> 0 <SEP> 8.45 <tb> <SEP> CH3N <SEP> 0.2 <SEP> 8.45 <SEP> *** <tb> <SEP> N <SEP> N-C=N <SEP> 4 <tb> <SEP> CH3 <SEP> H1 <SEP> Salt <tb> Cont/d ..... TABLE EMI22.1 <tb> <SEP> Compound <SEP> A <SEP> B <tb> . <tb> <SEP> Example <SEP> 11 <tb> <SEP> Cm <SEP> 0 <SEP> 6.12 <tb> <SEP> g <SEP> tI <SEP> 0.2 <SEP> 4 <SEP> 4127 <SEP> ** <tb> <SEP> Ij <SEP> /I\ <tb> <SEP> CH3 <SEP> Hl <SEP> Salt <tb> <SEP> Example <SEP> 12 <tb> <SEP> 0 <tb> <SEP> Br <SEP> N-C=N <SEP> 4 <SEP> 0.2 <SEP> 6.12 <tb> <SEP> 0.2 <SEP> 0.2 <SEP> 3.52 <SEP> """ <tb> <SEP> CH3 <SEP> H1 <SEP> Salt <tb> <SEP> Example <SEP> 13 <tb> <SEP> 0 > <SEP> 0 <SEP> 4.88 <tb> a,o,e <SEP> tp <SEP> 0.2 <SEP> 3.36 <SEP> ** <tb> <SEP> 0.2 <SEP> 3.36 <SEP> ** <tb> <SEP> 1 <tb> <SEP> ¯. <tb> <SEP> I <tb> <SEP> CH3 <SEP> 0.2 <SEP> 2.53 <SEP> *** <tb> <SEP> NN <SEP> I <tb> <SEP> N-C=No <tb> <SEP> CH3 <tb> <SEP> Example <SEP> 15 <tb> <SEP> Et <SEP> Et <SEP> 0 <SEP> 6 <SEP> 52 <SEP> 6.52 <tb> <SEP> N <SEP> N-C-N <SEP> 4 <SEP> 0.2 <SEP> 5 <SEP> 4 <SEP> 4.10 <SEP> i <tb> <SEP> NCI=N <tb> <SEP> CH3 <tb> Cont/d ..... TABLE EMI23.1 <tb> <SEP> Compound <SEP> A <SEP> B <tb> Example <SEP> 16 <tb> <SEP> Cs' <SEP> 0 <SEP> 4.88 <tb> <SEP> \N/' <SEP> -C=N- <SEP> 0.2 <SEP> 3 <SEP> 11 <SEP> *** <tb> <SEP> CH3 <tb> Example <SEP> 17 <tb> <SEP> 4Th <SEP> 0 <SEP> 6.42 <tb> METHIODIDE <SEP> 0.05 <SEP> 1.49 <SEP> **** <tb> <SEP> CH3 <tb>

Claims: CLAIMS: 1. A process for the preparation of a compound of formula (II) or a pharmaceutically acceptable quaternary ammonium or acid addition salt thereof: EMI24.1 wherein R1 and R2 are substituents attached to any of the carbon atbms of the dihydropyridine ring and represent hydrogen, C1-6 alkyl, halogen, carbon, alkoxy or carboxy, R represents hydrogen, C1-6 alkyl, phenyl or benzyl; 4 R represents hydrogen or C16 alkyl; 5 R5 represents C1-6 alkyl, phenyl optionally substituted with up to 3 groups selected from halogen, C16 alkyl, and C16 alkoxy; or benzyl optionally substituted with up to 3 groups selected 4 from halogen, C16 alkyl and C16 alkoxy; or R4 and R5 together represent the remaining members ofa 5- or 6- membered ring optionally containing an oxygen, sulphur or additional nitrogen atom and being optionally substituted with C16 alkyl; and R6 represents C1-6 alkyl, phenyl, optionally substituted with up to 3 groups selected from halogen, nitro-, amino-, or trifluoromethyl, C16 alkyl and C16 alkoxy; or benzyl optionally substituted with up to 3 groups selected from halogen, C16 alkyl and C16 alkoxy, in which either (a) a compound of formula (IV) or a salt thereof: EMI25.1 wherein R1, R2, R3 and R6 are as defined with respect to formula (II) above, and R10 represents C16 alkyl; is reacted with an amine of formula R4R5NH, wherein R4 and R5 are as defined with reference to formula (II) above, and thereafter, where desired, a free base of formula (II) so obtained is converted into a pharmaceutically acceptable salt, or a salt of a compound of formula (II) is converted into the free base, or (b) a compound of formula (VII): EMI25.2 wherein R4, R5 and R6 are as defined with respect. to formula (II) above; is reacted with an imino compound (V): EMI26.1 where R1, R2 and R3 are as defined with respect to formula (II) above, and there after where desired, a free base of formula (II) so obtained is converted into a pharmaceutically acceptable salt, or a salt of a compound of formula (II) is converted into the free base. 2. A process according to claim 1 in which R3 is methyl, ethyl, n-propyl or phenyl. 3. A process according to claim 1 or claim 2, in which R6 represents phenyl optionally substituted with halogen, C16 alkylor nitro. 4. A process according to any one of claims 1 to 3, in which R4 and R5 together represent a pyrrolidine, piperidine, morpholine, thiamorpholine or piper azine ring, optionally substituted with C16 alkyl. 5. A process according to claim 1, in which the compound of general formula (II) has the formula (III): EMI27.1 wherein Ra and Rb are the same as R1 and R2 respectively as defined in formula (II), R7 represents C16 alkyl; R8 represents hydrogen or C16 alkyl; R9 represents C16 alkyl or benzyl; or R8 and R9 together form the remaining members of a pyrrolidine or morpholine ring, and RÚÚ represents phenyl optionally substituted with up to 3 groups selected from C1-6 alkyl, halogen or nitro. 6. A process according to claim 5, in which R8 and R9 are both ethyl. CLAIMS 1. A compound of formula (II) or a pharmaceutically acceptable quaternary ammonium or acid addition salt thereof: EMI28.1 wherein R1 and R2 are substituents attached to any of the carbon atoms of the dihydropyridine ring and represent hydrogen, C1-6 alkyl, halogen, carbo-Cl 6 alkoxy or carboxy. R3 represents hydrogen, C1-6 alkyl, phenyl or benzyl; R4 represents hydrogen or C1-6 alkyl; R5 represents C16 alkyl, phenyl optionally substituted with up to 3 groups selected from halogen, C 1-6 alkyl, and C16 alkoxy; or benzyl optionally substituted with up to 3 groups selected from halogen, C1-6 alkyl and C16 alkoxy; or R4 and R5 together represent the remaining members of a 5- or 6membered ring optionally containing an oxygen, sulphur or additional nitrogen atom and being optionally substituted with C16 alkyl; and R6 represents C16 alkyl, phenyl, optionally substituted with up to 3 groups selected from halogen, nitro-, amino-, or trifluoromethyl, C1-6 alkyl and C 1-6 alkoxy; or benzyl optionally substituted with up to 3 groups selected from halogen, C16 alkyl and C16 alkoxy. 2. A compound according to claim 1 in which R3 is methyl, ethyl, n-propyl or phenyl. 3. A compound according to claim 1 or claim 2, in which R6 represents phenyl optionally substituted with halogen, C16 alkyl or nitro. 4. A compound according to any one of claims 1 to 3, in which R4 and R5 together represent a pyrrolidine, piperidine, morpholine or thiamorpholine ring, optionally substituted with C16 alkyl. 5. A compound according to claim 1, having the formula (III), or a pharmaceutically acceptable quaternary ammonium or acid addition salt thereof: EMI29.1 wherein Ra and Rb are the same as R1 and R2 respectively as defined in formula (II), R7 represents C16 alkyl; R8 represents hydrogen or C16 alkyl; R9 8 represents C1 6 alkyl or benzyl; or R and R9 together form the remaining members of a pyrrolidine or morpholine ring, and RÚÚ represents phenyl optionally substituted with up to 3 groups selected from C16 alkyl, halogen, nitro or amino. 6. A compound according to claim 5, in which R8 9 and R are both ethyl. 7. A compound according to claim 1 selected from the following, or their pharmaceutically acceptable quaternary ammonium or acid addition salts, N-(1,2-dihydro-1-methyl-2-pyridylidene)-N'- phenyl-l-pyrrolidinecarboxamidine, N-(1,2-dihydro l-methyl-2-pyridylidene)-N'-phenyl-4-morpholine carboxamidine, N- (1, 2-dihydro-l-methyl-2-pyridylidene) - N'-phenyl-4-(2,6-dimethylmorpholine)carboxamidine, N-benzyl-N'-(1,2-dihydro-1-methyl-2-pyridylidene)- N"-phenylguanidine, N-(1,2-dihydro-1-methyl-2 pyridylidene) -N' - (4-methylphenyl) -4-morpholine- carboxamidine, N'-(4-chlorophenyl)-N-(1,2 dihydro-l-methyl-2-pyridylidene) -4-morpholine- carboxamidine, N-(1,2-dihydro-1-methyl-2 pyridylidene) -N' - (4-fluorophenyl) - 4-morpholine- carboxamidine, N,N-diethyl-N'-(1,2-dihydro-1- methyl-2-pyridylidene) -N11 - (4-fluorophenyl) guanidine, N-(1,2-dihydro-1-methyl-2-pyridylidene)-N'-(4- nitrophenyl)-4-morpholinecarboxamidine, N,N-diethyl N'-(1,2-dihydro-1,3-dimethyl-2-pyridylidene)-N"- phenylguanidine, N-(1,2-dihydro-1,4-dimethyl-2 pyridylidene) -N' -phenyl-4-morpholinecarboxamidine, N-(5-bromo-1,2-dihydro-1-methyl-2-pyridylidene)- N'-phenyl-4-morpholinecarboxamidine, N-(5-carbo methoxy-1,2-dihydro-1-methyl-2-pyridylidene)-N'- phenyl-4-morpholinecarboxamidine, N-(1,2-dihydro 1, 5-dimethyl-2-pyridylidene) -N' -phenyl-4-morpholine- carboxamidine, N,N-diethyl-N'-(1,2-dihydro-1- methyl-2-pyridylidene) -N" -phenylguanidine, N-(1,2-dihydro-1-methyl-2-pyridylidene)-N'-phenyl 4-thiamorpholinecarboxamidine, N-(1,2-dihydro-l- methyl-2-pyridylidene)-N'-phenyl-1-pyrrolidine- carboxamidine. 8. A process for the preparation of a compound of formula (II) as defined in claim 1, in which a compound of formula (IV) or a salt thereof: EMI31.1 wherein R1, R , R3 and R6 are as defined with R10 respect to formula (II) above, and R10 represents C1-6 alkyl; is reacted with an amine of formula R4R5NH, wherein R4 and R5 are as defined with reference to formula (II) above, and thereafter, where desired, a free base of formula (II) so obtained is converted into a pharmaceutically acceptable salt, or a salt of a compound of formula (II) is converted into the free base. 9. A process for the preparation of a compound of formula (II) as defined in claim 1, in which a compound of formula (VII): EMI31.2 wherein R4, R5 and R6 are as defined with respect to formula (II) above; is reacted with an imino compound (V) EMI31.3 where R1, R2 and R3 are as defined with respect to formula (II) above, and thereafter where desired, a free base of formula (II) so obtained is converted into a pharmaceutically acceptable salt, or a salt of a compound of formula (II) is converted into the free base. 10. A compound according to claim 1 whenever prepared by a process according to claim 8 or claim 9. 11. A pharmaceutical composition which comprises a compound, or a pharmaceutically acceptable quaternary ammonium or acid addition salt thereof, according to any one of claims 1 to 7 or claim 10, together with a pharmaceutical carrier or excipient. 12. A composition according to claim 11 in unit dosage form. 13. An intermediate of formula (IV) or a salt thereof: EMI32.1 wherein R1, R2, R3 and R6 are as defined with respect to formula (II) above, and R10 represents C16 alkyl.

Inventors: CANTELLO, BARRIE CHRISTIAN CHARLES
Applicants: BEECHAM GROUP PLC
Application year: 1980
Main classification: C07D213
IPC codes: A61K31, A61P3, C07D213, C07D413