NZ207958A - Dihydropyridine derivatives and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £07958 2 07958 Priority Date(s): J^TpQjktiy. l^Tj/A/^, I?)'.']*?*. £l/'Ms&. sty*?#*;....

Complete Specification Filed: Class: Ph' Mwm./. f R&J&3tjit }&>£?$'.

Publication Date: P£9. !§§(>... j P.O. Journal. No: I NO DRAW^SS new zealand patents act, 1953 No.: Date: COMPLETK SPECIFIC ATI0 "DIHYDROPYRIDINES" )4/We, FISONS pic, a British Company, of Fison House, Princes Street, Ipswich, England, n,z.patento^SL 26APRW84 BEC pJV'P hereby declare the invention for which £ / we pray that a patent may be granted to xw«/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- . i . (followed by Daqe la) lcx~ 83/11519 This invention relates to new compounds, methods for their preparation and compositions containing them.

A wide variety of dihydropyridines have been described as being useful as pharmaceuticals and some, notably nifedipine, have been sold for this use.

We have now found a new group of pyridine derivatives which have pharmacological activity.

According to the invention we provide compounds of formula I, in which represents benzofurazanyl, pyridyl or phenyl, the pyridyl or phenyl being substituted by one or more of the groups halogen, nitro, -CN, -OR^, -S (0}prg, or alkyl CI to 6 optionally substituted by halogen, p is 0, lor 2, R2 and R-j, which may be the same or different, each represent hydrogen; alkyl CI to 6 optionally substituted by one or more of the groups halogen, cyano, ~^R5R6 or phenyl; cycloalkyl C3 to 8 7 8 I h ? o~*~ ~ -2 - ' ' ^ 51 optionally substituted by alkyl CI to 6; a 4, 5 or 6 membered oxygen or nitrogen containing heterocyclic ring which is optionally substituted by alkyl CI to 6 the alkyl in turn optionally being substituted by one or more phenyl 5 groups; and Rg, which may be the same or different, each represent alkyl CI to 6 optionally substituted by phenyl, Y and Z together form a bond, and additionally, when 10 Rg is an electron withdrawing group Y may be hydrogen and Z may be hydroxy, one of Rj and Rg represents alkyl CI to 6 and the other represents -CONR^r^; -CSNH2; -C(=NH)SRg; -S(0)mRg; phenyl optionally substituted by one or more 15 of alkyl CI to 6, halogen, alkoxy CI to 6 or nitro; alkyl CI to 6 substituted by halogen; or furanyl, or R^ and Rg may be the same or different and each represents phenyl optionally substituted by one or more of alkyl CI to 6, halogen, alkoxy CI to 6 or nitro; amino; alkyl CI to 6 substituted by halogen; -CN; -CH2OH; -CHO or -CH(ORg)2, X is 0 or S, m is 0 or 1, R 4 is alkyl CI to 6 or phenyl, ^ R^ is alkyl CI to 6, 207958 o o R10 and R-^ each independently represent hydrogen or alkyl CI to 6, or together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclic ring, provided that A) when R7 is alkyl CI to 6, Y and Z together form a bond, and i) when represents benzofurazanyl then Rg does not represent -CF^, or ii) when R^ represents 2-nitrophenyl, or 2-chlorophenyl and R2 and are both ethyl, then Rg does not represent mono-chloromethyl, or iii) when represents 3-nitrophenyl and R2 and are both ethyl, then Rg does not represent unsubstituted phenyl, B) when neither of R-, and Rg is alkyl CI to 6, Y and Z together form a bond and iv) when and are both ethyl then R^ and Rg are not both -CF^, or v) when one of or Rg is amino then the other is not phenyl or amino, or N p vi )■ when one of R? or Rg is -CN, -CH2OH, -CHO or -CH(0R9)2 then the other is not -CN, -CH2OH, -CHO or -CH(ORg)2, and C) both of R_ and Rg are not optionally substituted phenyl, lr \ rt6SEPW86 •; 1 M>/' I and pharmaceutically acceptable acid addition salts of those compounds containing a basic nitrogen atom.

According to the invention we also provide the compounds of formula I without proviso ii) for use as pharmaceuticals.

According to the invention we further provide a process for the production of a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, which comprises a) reaction of a compound of formula II, R^CHO ii with compounds of formulae III and IV, R2OOCCH=C(R7)NH2 III R3OOCCH2CORg IV in which formulae R^, R2, R^, R^ and Rg are as defined above, b) reaction of a compound of formula V, R1CH=C(COOR3)CORg V in which R^, and Rg are as defined above, with a compound of formula III, c) production of a compound of formula I in which Y and Z together form a bond by dehydration of a compound of formula VII, 2 0795 8 R2OOC VII o in which , R2 ^ R3, R-j 3nd Rg 3 r6 ss defined above, d) production of a compound of formula I in which m is 1 or p is 1 or 2 by selective oxidation of a corresponding compound of formula I in which m is 0, or p is 0 or 1 respectively, e) production of a compound of formula I in which one of R7 and Rg is -CONR^qR^ by reaction of an acid halide, imidazole or a mixed anhydride of a corresponding compound of formula I in which one of R^ and Rg is -COOH with a compound HNR^qR-^ in which R-^q and R^2 are as defined above, or, when the group -NR10ri:l in the product represents an imidazole, reacting the free carboxylic acid of formula I with N,N'-carbonyldiimidazole, f) production of a compound of formula I in which one of and Rg is -CSNH2 by reaction of a corresponding compound of formula I in which one of R^ and Rg is -CN with hydrogen sulphide, g) isomerising a 3,4-dihydropyridine to a corresponding compound of formula I, 207958 h) production of a compound of formula I in which one of and Rg is -C(=NH)SRg by reaction of a corresponding compound of formula I in which one of R7 and Rg is -CSNH2 with a compound R^-hal, in which 5 Rg is as defined above and hal is a halogen atom, i) reaction of a compound of formula IV with ammonia and a compound of formula VI, R1CH=C (C00R2)C0R7 VI or reaction of a compound of formula V with ammonia and a compound of formula VIII", r2oocch2cor7 VIII or reaction of compounds of formulae II, IV and VIII with ammonia, in which formulae R^, R2, R^, R? and Rg are ^ as defined above, j) production of a compound of formula I in which Y and Z together form a bond and one or both of R7 and Rg is -CHF2 or -CH2F by reaction of a corresponding compound of formula I in which Y and Z together form a bond and one or both of R7 and Rg is -CHO or -CH2L, where L is -OH or a good leaving group, respectively with a fluorinating agent, k) production of a compound of formula I in which one of R7 and Rg is -CHO by selective hydrolysis of a corresponding compound of formula I in which one of R7 W' I " ' - . * .v. ' .... 2079 5 3 and Rg is -CH(ORg)2, 1) production of a compound of formula I in which one of R^ and Rg is -CH2OH by selective reduction of a corresponding compound of formula I in which one of R^ and Rg is -CHO, m) production of a compound of formula I in which one of R^ and Rg is -CN by elimination of ROH from a corresponding compound of formula I in which one of R? and Rg is -CH=NOR, and -OR is a good leaving group, n) production of a compound of formula I in which at least one of R2 and R^ is hydrogen by reductive cleavage or hydrolysis of a corresponding compound of formula I in which at least one of R2 and R^ is other than hydrogen, o) production of a compound of formula I in which at least one of R2 and R^ is other than hydrogen by ester ification or transesterification of a corresponding compound of formula I in which at least one of R2 and R^ is hydrogen or is a group R2 or R^ other than that desired in the end product, or p) production of an optical isomer of a compound of formula I by resolution of a mixture of optical isomers of the compound, and where desired or necessary converting the resulting compound of formula I to a pharmaceutically G acceptable acid addition salt thereof or vice versa.

The reaction of process a) may be carried out by subjecting the compounds of formulae II, III and IV to an elevated temperature, eg of from about 20° to 140°C in the presence or absence of a suitable solvent, eg a lower alkanol.

Processes b) and i) may be carried out under similar conditions to process a). In processes a), b) and i) when Y and Z in the final product are together to form a bond dehydration is generally required as a separate process step when Rg is an electron withdrawing group, eg —CF^, perhaloalkyl-, nitro- or mono- or di-chlorophenyl or unsubstituted phenyl. The presence of a base, eg diethylamine or ammonia, tends to inhibit dehydration in these processes. We prefer not to use process a), b) or i) when R? or Rg is -C(=NH)SR9, -CN, -CH2OH or -CHO, or when R^ or R^ is hydrogen.

Process c) may be carried out in a solvent which is inert under the reaction conditions, eg methylene chloride, and in the presence of a dehydrating agent, eg trifluoracetic anhydride, and a base, eg pyridine. The dehydration may also be effected using diethylaminosulphur trifluoride. The reaction may be carried out at from about 0° to 40°C. The compounds of formula VII may be formed as intermediates, which may 2 07953 or may not be isolated, in processes a), b) and i).

Under certain circumstances, eg when Rg is not an electron withdrawing group, the compound of formula VII may dehydrate spontaneously to yield the compound of 5 formula I in which Y and 2 together form a bond. When diethylaminosulphur trifluoride is used in this process and Rg is Cf^OH or CHO in the starting material the -CH20H or -CHO will, as in process j), be converted to -CH2F and -CHF2 respectively. ^ 10 Process d) may be carried out using a suitable oxidising agent, eg peracetic acid. The reaction may be carried out in a suitable solvent, eg a mixture of methanol and acetic acid. We prefer not to use this process when R? or Rg is -C(=NH)SR9.

Process e) may be carried out by treating the acid halide, imidazole or the mixed anhydride (which compounds may be prepared by conventional processes known per se), with aqueous ammonia or the amine HNR^o^ll at a temperature of from 0° to 30°C. When Z is -OH, or 20 R^ or Rg is -CH2OH, we prefer to use the imidazole or a mixed anhydride. We prefer not to use this process when R2 or R^ is hydrogen.

Process f) may be carried out by treating the nitrile starting material with hydrogen sulphide gas in a suitable W •><; solvent, eg pyridine. The reaction is preferably carried * - 5 8 out in the presence of a base, eg triethylamine, and may conveniently be carried out at a temperature of from 10 to 30°C.

Process g) may be carried out under basic conditions, eg in the presence of an alkylamine such as triethylamine. This process is particularly applicable when Rg is both electron withdrawing and bulky.

Process h) may be carried out in a solvent which is inert under the reaction conditions, eg diethyl ether. We prefer hal to be iodine.

Process j) is preferably carried out at a temperature of from about -70° to 100°C, and in a solvent which is inert under the reaction conditions, e.g. a halogenated hydrocarbon and preferably methylene chloride. The fluorinating agent is preferably a dialkylaminosulphur trifluoride, e.g. diethylaminosulphur trifluoride, or (2-chloro-l,1,2-trifluoroethyl)diethylamine. The group L may be, for example, -OSC^Rx, where Rx is alkyl CI to 6, e.g. methyl, or aryl, e.g. p-tolyl.

The hydrolysis of process k) may be carried out using an aqueous acid, for example hydrochloric acid (eg 0.5 to 2.5 molar) in a water miscible organic solvent, eg acetone or tetrahydrofuran. The reaction may be carried out at a temperature of from about -10 to 50°C.

The reduction of process 1) may be carried out either O , - r,,.y yfjtStwy.trj\■■,—;y :.f--,' 2 07958 chemically or catalytically, eg by use of sodium borohydride in an alcoholic solvent, eg methanol or ethanol, at a temperature of from about 0 to 50°C.

The elimination of process m) may be carried out using a variety of dehydrating agents which will not adversely effect the other substituents in the molecule, e.g., an excess of acetic anhydride, thionyl chloride in ether or N,N'-dicylohexylcarbodiimide in pyridine. The group -OR may be, for example, a 2,4-dinitrophenoxy group. The reaction may be carried out at a temperature of from about 0° to 150^C depending on the reagent and solvent used. The oxime may, if desired, be formed in situ from the corresponding formyl compound using conventional methods known per se.

The reductive cleavage of process n) may be carried out chemically, eg using zinc and formic acid. The reaction may conveniently be carried out in a solvent which is inert under the reaction conditions, eg acetonitrile. When process n) involves a hydrolysis the hydrolysis may be carried out using conventional techniques known per se.

Process o) may, when it involves an esterfication, be carried out using the appropriate alcohol, preferably in excess and in the presence of a dehydrating agent, eg dicyclohexylcarbodiimide, or under similar conditions to ?9 era - 12 - ^ ® process e). The reaction may conveniently be carried out in a solvent which is inert under the reaction conditions, eg ethyl acetate. When a transesterification is involved the process may be carried out by treating the starting ester with the sodium alcoholate corresponding to the desired ester moiety.

The resolution of process p) may be carried out by means of conversion of the mixture to, when R2 or is H, a salt with an optically active base or an ester with an optically active alcohol (eg CCl^(CgH^)CHOH or CgH5(OCH3)CHCH2OH), or, when R2 or R3 is aminoalkyl, a salt with an optically active acid and separation of the product by selective crystallisation, or, preferably, by means of high performance liquid chromatography (HPLC). The separated product may then be converted to the desired optically active acid or ester by, for example, process n) or o).

The starting materials for the above processes are either known, or if they are not specifically known they may be made by processes described in the Examples, or they may be made from known compounds using one or more process steps which are known per se or are analogous to those described in the Examples.

Certain of the compounds of formula II are novel and the invention therefore also provides those compounds of . .. 2 07958 • formula II in which is 2-chloro-3-trifluoromethyl phenyl or phenyl substituted by three substituents selected from chloro-, fluoro- and -CF^. Specifically we provide 2,3-dichloro-6-fluorobenzaldehyde, 3-chloro-6-5 fluoro-2-(trifluoromethyl)benzaldehyde and 2-chloro-3-(trifluoromethyl)benzaldehyde.

The compounds of formula I and the intermediates therefor may be isolated from their reaction mixtures using conventional processes, eg crystallisation or chromatography.

The compounds of formula I, and the pharmaceutically acceptable salts thereof, are useful because they exhibit pharmacological properties in animals. More particularly they block the entry of calcium into vascular and cardiac muscle leading to falls 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, 7jJ, Supplement, 157-165, 1980. (b) Reduction of inotropy and chronotropy of isolated atria. Henry, Excerpta Med. Int. Congr. Ser., 474, 14-23, 1979. (c) Reduction of blood pressure and increase cardiac output in anaesthetised dogs. Hirakawa, Ito, Kondo, Watanbe, Hiei, Banno & Hyase, Arzneim-Forsch, 22, • - \. - . -14 - '2' 0? 9 r c- 344-349, 1972. (d) Reduction of blood pressure 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 renovascular, malignant or essential hypertension (including hypertensive emergencies), pulmonary hypertension, vasospastic angina, chronic stable angina and congestive heart failure. Other indications are the treatment of renal failure, cardiac arrhythmias, hypertrophic cardiomyopathy, cerebrovascular diseases (including cerebral haemorrhage, ischaemia and vasospasm, migraine, altitude sickness and hearing loss), peripheral vascular diseases (including Raynauds syndrome, intermittent claudication and digital ulceration); use as a cardioplegic agent during surgery eg in cardiopulmonary bypass, and for the treatment of, and protection against, myocardial infarction and ischaemia.

By virtue of their ability to inhibit calcium entry into other cells and tissues the compounds are also indicated in the treatment of thrombosis, atherosclerosis, respiratory diseases (including asthma and bronchitis) glaucoma, aldosteronism, uterine hypermoti' ity and for the relief of oesophageal and skeletal muscle spasm. r> 2 07958 o 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 O.l-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 lOOmg, which may be administered preferably once daily, or in divided doses of about l-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 hypotensive and direct negative chronotropic effects), 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 readily absorbed or less readily metabolised, are more easily formulated, possess less, or less undesirable, side effects, are more stable 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, the eye or ?079 5 8 to other available surfaces of the body; by injection, eg intravenously, intramuscularly, intraperitoneally, or by surgical implant.

When R2 and/or R^ represents a 4, 5 or 6 membered oxygen or nitrogen containing heterocyclic ring that ring may be an oxetanyl, azetidinyl, piperidinyl or tetrahydropyranyl ring. R2 and/or may also represent -(CH2)nXR4, -(CH2)nCN, -CH(C6H5) CCl^ or - (CH2) j^R^Rg in which n is 4, 3 or preferably 2.

When R^q and R^ together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclic ring we prefer that ring to be a morpholino or imidazolyl ring.

We prefer compounds of formula I in which Y and Z together form a bond. We also prefer those compounds in which one of R^ and Rg is alkyl CI to 6, eg methyl. We further prefer those compounds in which one of R^ and Rg is mono-, di- or tri- fluoromethyl. We particularly prefer one of R^ and Rg to be mono- fluoromethyl.

Groups Rg which are electron withdrawing include alkyl CI to 6 substituted by 2 or more halogen atoms; furanyl and phenyl optionally substituted by one or more of alkyl CI to 6, halogen, alkoxy CI to 6 or nitro.

V."'' / 0 AJ1. /<r, . jti 2079 58 Preferred electron withdrawing significances of Rg are -CCl^, -CF^, -CF2 CF^, phenyl, 4-nitrophenyl, 3,4-dichlorophenyl, 4-chlorophenyl and 3-chlorophenyl.

Values for R-^ include nitrophenyl; 5 (trifluoromethyl)phenyl; mono- or poly-fluorophenyl; mono-or poly-chlorophenyl; chloro- and/or fluoro-(trifluoromethyl)phenyl; (alkylthio)pyridyl; alkyl-and/or chloro- and/or alkoxy-nitrophenyl; mixed chloro-and fluoro-phenyl; mono- or poly- alkoxy-phenyl; 10 alkylphenyl; (alkylthio)phenyl; (alkylsulphonyl)phenyl; and 4-benzofurazanyl. Values for R^ and R3 are alkyl CI to 4, 2-alkoxy CI to 3 - ethyl, 2-phenoxy- ethyl, cycloalkyl C4 to 6 optionally substituted by methyl, the saturated 4, 5 or 6 membered heterocyclic groups as 15 defined inunediately above and optionally substituted by phenylmethyl or diphenylmethyl, alkyl CI to 4 -(phenylmethyl)aminoethyl, cyano- or alkyl CI to 4 - thio-alkyl CI to 4; phenyl alkyl CI to 4 or -CH(CgH^)CCl^. Values of Rg are chloro- or 20 fluoro- alkyl CI or 2, -CsNH2, -CON (alkyl C 1 to 4)2, -COmorpholino, -COimidazolyl, -C(=NH)S-alkyl CI to 4, -S-alkyl CI to 4, -S(0)-alkyl CI to 4, or phenyl substituted by one or two chlorine, nitro, methoxy or methyl groups, e.g. in the 4- and/or 3- positions. Ry 25 may be methyl. When R^ is not alkyl R7 and Rg are I \ u ? 58 preferably selected from a fluoromethyl group, e.g. -CH2F, -CHF2 or -CF3; -CHO; -CH(0C2H5)2; phenyl and -CH20H. The Examples illustrate various permutations of substituents. The individual substituents exemplified may also be permutated in other combinations.

As a preferred group of compounds of formula I we provide those in which R^ is phenyl carrying a 2-nitro or a 2-CF3 group or at least two substituents selected from chloro; fluoro; alkyl CI to 6, eg methyl; ~CF3 and nitro; R2 is alkyl CI to 6, eg isopropyl, cyclopentyl or cyclobutyl or is oxetan-3-yl; R3 is alkyl CI to 6, eg methyl; R^ is alkyl CI to 6, eg methyl; Rg is fluoromethyl, eg mono-, di- or tri-fluoromethyl; and Y and Z together form a bond.

As a most preferred group of compounds of formula I we provide those in which R^ is phenyl carrying at least two substituents selected from chloro, fluoro, -CF-j, methyl and nitro, R3 and are both methyl, Rg is -CH2F, R2 is isopropyl or cyclopentyl and Y and Z together form a bond.

A specific group of compounds of formula I are those in which R^ represents benzofurazanyl, pyridyl or phenyl, the pyridyl or phenyl being substituted by one or more of the groups halogen, nitro, trihalomethyl or -SRg; R2 and R3 each represent alkyl CI to 6, 2 07958 "{CH2)n R4' ~(CH2)nCN, -CH (CgH5) CCI3 or ~^H2^n ^R5R6; ^ anc^ 2 together form a bond; one of R7 and Rg represents alkyl CI to 6 and the other represents -CONR^R^; -CSNH2; -C( = NH)SRg; -StOJ^Rg; phenyl substituted by one or more of alkyl CI to 6, halogen, alkoxy CI to 6 or nitro; or alkyl CI to 6 substituted by halogen; R4 and Rg are each alkyl CI to 6; and R^0 and R^ each represent hydrogen or alkyl CI to 6, and provisos i) and ii) apply.

According to our invention we also provide a pharmaceutical composition comprising preferably less than 80%, more preferably less than 50%, eg 1 to 20%, by weight of a compound of formula I, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

Thus the compound may be put up as a tablet, capsule, dragee, suppository, suspension, solution, injection, implant, a topical, eg transdermal, preparation such as a gel, cream, ointment, aerosol or a polymer system, or an inhalation form, e.g. an aerosol or a powder formulation.

We prefer compositions which are designed to be taken oesophageally and to release their contents in the gastrointestinal tract. Thus we prefer tablets which may, for example, be made by direct compression. In such a process the active ingredient is mixed with one or more of •y n ■> ts SB modified forms of starch, calcium phosphate, a sugar eg lactose, microcrystalline cellulose and/or other directly compressible excipients, together with lubricant(s), eg stearic acid or magnesium stearate, flow aid(s), eg talc 5 or colloidal silicon dioxide, and disintegrant(s), eg starch, substituted sodium carboxymethyl cellulose, cross linked sodium carboxy methyl cellulose, carboxy methyl starch and cross linked polyvinylpyrrolidone. Tablets are then formed by direct compression, and may be sugar or 10 film coated e.g. with hydroxypropylmethylcellulose.

Alternatively the active ingredient may be granulated before tabletting. In such case? the active ingredient is mixed with one or more of starch, calcium phosphate, a sugar eg lactose, microcrystalline cellulose or other suitable excipients and granulated with a binder such as starch, pregelled starch, polyvinylpyrrolidone, gelatine, a modified gelatine, or a cellulose derivative, eg hydroxypropylmethylcellulose. The mass is then dried, sieved and mixed with lubricant(s), flow aid (s) and 20 disintegrant(s), such as described in the previous paragraph. Tablets are then formed by compression of the granules, and may be sugar or film coated, eg with hydroxypropylmethylcellulose.

As a further alternative a powder, blend or granules, ^5 such as are described above as intermediates in 2 07958 tabletting, may be filled into a suitable, eg gelatine, capsule.

In order to improve the bioavailability, or decrease variability of availability, of the active ingredient the 5 compound may be:- a) dissolved in a suitable solvent, eg polyethylene glycol, Gelucaire, arachis oil, a (hydrogenated) vegetable oil or beeswax and the solution is then filled into a gelatine capsule, 0 b) produced as a spray-dried or freeze-dried form prior to mixing with other excipients, c) milled and/or micronised to produce a powder with a large surface area prior to mixing with other excipients, d) made into a solution and distributed over an inert 5 excipient having a large surface area, eg colloidal silicon dioxide. The solvent is evaporated and further excipients added, e) formed into a complex with cyclodextrin prior to mixing with other excipients. This complex also assists '0 in increasing light stability, or f) made into a solid solution or co-precipitated, eg with polyvinylpyrrolidone, polyethyleneglycol, modified cellulose, hydroxypropylmethylcellulose, urea or a sugar prior to mixing with further excipients.

The compounds, either in their normal form or in a ? 07 9 58' modified form, eg as described immediately above, may be formulated in a controlled release form. Thus the compound may be dispersed, or contained in, a polymer matrix formed from, for example, ethylcellulose, hydroxypropylmethylcellulose or an acrylate/methacrylate polymer. Alternatively the compound may be formulated as a tablet or beads which are surrounded by a semi-permeable membrane, eg shellac, ethylcellulose or an acrylate/methacrylate polymer.

The compounds of this invention may be given in combination with other pharmaceutically active compounds, eg diuretics, beta-blockers, antihypertensives or inotropic agents. The dosage of the other pharmaceutically active compound can be that conventionally used when the compound is administered on its own, but is preferably somewhat lower. To illustrate these combinations, a compound of this invention effective in the range, eg 5-100 milligrams per day, can be combined at levels ranging, eg from 1-200 milligrams per day with the following beta-blockers, antihypertensives and diuretics in dose ranges per day as indicated: hydrochlorothiazide (15-200mg), chlorothiazide (125-2000mg), ethacrynic acid (15-100mg), amiloride (5-20mg), furosemide (5-80mg) , propanolol (20-480mg) , timolol (5-50mg), captopril (10-500mg), methyldopa 2 07958 (65-2000mg) or digoxin (0.1-0.5mg). In addition, the triple drug combinations of hydrochlorothiazide (15-200mg) plus amiloride (5-20mg) plus a compound of this invention (3-200mg) and hydrochlorothiazide (15-200mg) plus timolol (5-50mg) plus a compound of this invention (3-200mg), are provided. The above dose ranges may be adjusted on a unit basis as necessary to permit divided daily dosage. Also, the dose may vary depending on the severity of the disease, weight of patient and other factors which a person skilled in the art will recognise.

Certain of the compounds of formula I are assymetric and exhibit optical isomerism. Such compounds may be separated into their optical isomers using process p) or may be made by stereospecific syntheses using conventional techniques know per se.

The invention therefore provides the compounds as their individual optical isomers (we prefer the (+) isomers), and racemic or other mixtures of the individual isomers.

In those compounds in which Y is hydrogen and Z is -OH there will be at least 3 assymetric carbon atoms and the corresponding number of isomers is provided.

Certain of the compounds of the invention can form solvates, eg hydrates or alcoholates, and certain of the compounds are light sensitive and should therefore be i 24 produced, handled, stored and formulated in such a manner that they are not subjected to degrading amounts of light of the appropriate wavelengths.

The invention is illustrated, but in no way limited by the following Examples in which temperatures are in degress centigrade. o "T" TT 2 07958 Example 1 3-(Methyl) 5-(1-methylethyl) 4-(2,3-dichlorophenyl)-2-- (fluoromethyl)-l,4 -di hydro-6-met hyl-3 , 5-pyridinedicarboxylate 2,3-Dichlorobenzaldehyde [1.75g, lOmnioles), methyl 4-fluoro-3-oxobutanoate (1.34g, lOmmoles) and 1-methylethyl 3-amino-2-butenoate (1.43g, lOmmoles) were heated with stirring at 90° for 2.5 hours. The reaction mixture was dissolved in ethyl acetate and chromatographed on silica eluting with petroleum ether (60-80°)/ethyl acetate mixtures. Pure fractions were combined and evaporated to dryness. The title compound (1.6g) was obtained by crystallisation from 2-propanol. mp 148-9°. Example 2 3-Methyl 5-(1-methylethyl) 2- (fluoromethyl)-1,4-di hydro-6-methyl-4-(2-methyl-3-nitrophenyl)-3,5 -pyridinedicarboxylate 2-Methyl-3-nitrobenzaldehyde (1.23g, 7.5mmoles), methyl 4-fluoro-3-oxobutanoate (l.Og, 7.5mmoles) and 1-methylethyl 3-amino-2-butenoate (1.07g, 7.5mmoles) were heated with stirring at 80° for 2.5 hours. The cooled residue was chromatographed twice on silica eluting first with ethyl acetate/petroleum ether (60-80°) and then with ethyl acetate/methylene chloride. The title compound (0.61g) was obtained by crystallisation from a mixture of "*> n-7<y 5 petroleum ether (60-80°) and 2-propanol rap 132-133°. Example 3 -Cyclopentyl 3-methyl 4-(2,3-dichlorophenyl)-2-(f luoromethyl) -1,4-dihydro-6-methyl-3 , 5-pyridinedicarboxylate 2,3-Dichlorobenzaldehyde (1.31g, 7.5mmoles), methyl 4-fluoro-3-oxobutanoate (l.Og, 7.5mmoles) and cyclopentyl 3-amino-2-butenoate (1.26g, 7.5mmoles) were heated at 90° with stirring under nitrogen for 2.5 hours. The reaction mixture was dissolved in ethyl acetate, dried (MgSO^) and the solvent was removed in vacuo. The residue was chromatographed on silica eluting with ethyl acetate/methylene chloride mixtures. The title compound (0.95g) was obtained after crystallisation from petroleum ether (60-80°) mp 148-50°.

Example 4 3-Methyl 5-(1-methylethyl) 4-(3-chloro-6-fluoro-2-(tr ifluoromethyl)phenyl)-2-(fluoromethyl)-1, 4-dihydro-6-methy1-3,5-pyridinedicarboxylate 3-Chloro-6-fluoro-2-(trifluoromethyl)benzaldehyde (1.3g, 5.7mmoles), methyl 4-fluoro-3-oxobutanoate (0.77g, 5.7mmoles) and 1-methylethyl 3-amino-2-butenoate (0.82g, 5.7mmoles) were heated under nitrogen with stirring for 1.5 hours at 90°, followed by 1.5 hours at 100° and then 1 hour at 110°. The cooled reaction mixture was 2 07958 chromatographed twice on silica first using methylene chloride as eluent and then toluene/ethyl acetate mixtures. The title compound (0.2g) was obtained after crystallisation from petroleum ether (60-80°) mp 142-3°.

Example 5 3-Methyl 5-(1-methylethyl) 4-(2-chloro-3-nitrophenyl)-2- (fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate 2-Chloro-3-nitrobenzaldehyde (1.38g, 7.5mmoles), methyl 4-fluoro-3-oxobutanoate (l.Og, 7.5mmoles) and 1-methylethyl 3-amino-2-butenoate (1.06g, 7.5mmoles) were heated at 90° for 2.5 hours. The reaction mixture was chromatographed on silica eluting with petroleum ether (60-80°)/ethyl acetate mixtures. The title compound (1.35g) was obtained after crystallisation from petroleum ether (60-80°)/2-propanol. mp 156-7°.

Example 6 3-Methyl 5-(1-methylethyl) 2-(fluoromethyl)-4-(2-fluoro-6-(tr ifluoromethyl)phenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate 2-Fluoro-6-(trifluoromethyl)benzaldehyde (1.51g, 7.8mmoles), methyl 4-fluoro-3-oxobutanoate (1.06g, 7.8mmoles) and 1-methylethyl 3-amino-2-butenoate (1.13g, 7.8mmoles) were heated at 90° under nitrogen with \ ~" i .. ...,V 70>9 5 3 stirring for 2 hours. The cooled reaction mixture was chromatographed twice; first eluting with toluene/ethyl acetate mixtures and then with ethyl acetate/petroleum ether (60-80°) mixtures. The title compound (O.lg) was obtained on evaporation of the pure fractions mp 82-4°. Example 7 3-Methyl 5-(1-methylethyl) 4-(2,3-dichloro-6-fluorophenyl)-2-(fluoromethyl)-1, 4-dihydro-6-methyl-3,5-pyridinedicarboxylate 2,3-Dichloro-6-fluorobenzaldehyde (1.44g, 7.5mmoles)r methyl 4-fluoro-3-oxobutanoate (l.Og, 7.5mmoles) and 1-methylethyl 3-amino-2-butenoate (1.06g, 7.5mmoles) were heated at 90° under nitrogen with stirring for 2.5 hours. The cooled reaction mixture was chromatographed on silica eluting with ethyl acetate/methylene chloride mixtures. The title compound (l.lg) was obtained by crystallisation from a petroleum ether (60-80°)/2-propanol mixture mp 129-31°.

The compounds of Examples 8 to 49 were prepared using appropriate starting materials and the method described in Examples 1-7.

Example 8 -Ethyl 3-methyl 2-(fluoromethyl)-1,4-dihvdro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate Recrystallised from 2-propanol. mp 127-9°. 2 079 5 8 Example 9 3-Methyl 5-(1-methylethyl) 2- (fluoromethyl)-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate Recrystallized from 2-propanol/cyclohexane. mp 107-9°.

Example 10 3-Methyl 5-(2-methylpropyl) 2- (fluoromethyl)-1,4-di hydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate Recrystallized from 2-propanol/cyclohexane. mp 101-2°.

Example 11 3-Ethyl 5-methyl 2-(fluoromethyl)-1,4-dihydro -6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate Recrystallised from 2-propanol. mp 137-8°.

Example 12 Diethyl 2-(fluoromethyl)-1,4-dihydro-6-methyl-4-(2-(trifluoromethyl)phenyl)-3, 5-pyridinedicarboxylate Crystallised from hexane. mp 84-6°.

Example 13 Diethyl 4-(4-benzofurazanyl)-2-(fluormethyl)-1,4-dihydro-6-methyl-3,5-pyr idinedicarboxylate Recrystallised from methylene chloride/cyclohexane. mp 125-7°. ni* " - 30 - •- •? ■ f Example 14 Dimethyl 2-(fluoromethyl)-1,4-dihydro-6-methyl-4--(2,3,4,5,6-pentafluorophenyl) - 3,5-pyridinedicarboxylate Crystallised from cyclohexane. mp 148-50°. 5 Example 15 -Methyl 3-(1-methylethyl) 2- (fluoromethyl)-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate Recrystallised from methylene chloride/cyclohexane. 10 mp 122-4°.

Example 16 -Ethyl 3-methyl 4-(2,3-dichlorophenyl)-2-(fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyridined icarboxylate Recrystallised from methylene chloride/cyclohexane. mp 124-5°.

Example 17 Diethyl 2-(fluoromethyl)-1,4-dihydro-6-methyl-4-(2-(methylthio)-3-pyridyl)-3,5-pyridinedicarboxylate 20 Recrystallised from cyclohexane/petroleum ether (60-80°) . mp 92-4°.

Example 18 3-Methyl 5-(2-(methyl(phenylmethyl)amino)ethyl) 2-(fluoromethyl)-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5- pyndmedicarboxylate oxalate hemihydrate • - ••-•V 207958 The purified free base was converted into the oxalate which was obtained as a yellow solid after trituration with ether, mp 95° with decomposition, softens at about 70°.

Example 19 . 5-(2-Methoxyethyl) 3-(1-methylethyl) 4-(2,3- dichlorophenyl)-2- ( fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyridined icarboxylate Recrystallised from cyclohexane/petroleum ether O 10 (60-80°). mp 88-9°.

Example 20 -(2-Cyanoethyl) 3-(1-methylethyl) 2-(fluoromethyl) -1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate Recrystallised from 2-propanol. mp 231-232.5°. Example 21 3-(1-Methylethyl) 5- (2-(methylthio)ethyl) 2-(fluoromethyl)-1,4-di hydro-6-methyl-4-(3-ni trophenyl)-3,5-pyridinedicarboxylate Recrystallised from 2-propanol/petroleum ether (60-80°). mp 109-111°.

Example 22 3-Methyl 5-(1-methylethyl) 4-(2-chloro-5-nitrophenyl) -2-(fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyr idine-dicarboxylate \ i V >0"r^5 8 Recrystallised from 2-propanol/petroleum ether (60-80°). mp. 131-133°.

Example 23 3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-2-5 (fluoromethyl)-1,4-di hydro-6-methyl-3,5-pyridinedicarboxylate Obtained as a solid by trituration with petroleum ether (60-80°). mp 99-101°.

Example 24 I® 3-Methyl 5-(1-methylethyl) 2- (fluoromethyl)-1,4- di hydro-6-methy1-4-(2-methyl-5-n i trophenyl)-3,5-pyridine-dicarboxylate Recrystallised from 2-propanol/petroleum ether (60-80°), mp 100-1°.

Example 25 3-(2-Methoxyethyl) 5-(1-methylethyl) 2-(fluoromethyl) -1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate Recrystallised from cyclohexane as yellow crystals mp 112-4°.

Example 26 -(2-Methoxyethyl) 3-(1-methylethyl) 2-(fluoromethyl) -1,4-di hydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate Recrystallised from cyclohexane-isopropanol as a I ft -33- 207958 yellow solid mp 95-6°.

Example 27 3-Methyl 5-(1-methylethyl) 4-(2-chloro-3-(tri-fluoromethyl)phenyl)-2-(fluoromethyl)-l,4-dihydro-6-methyl-5 3,5-pyridined icarboxylate Recrystallised from petroleum ether (60-80°) mp 145-7°.

Example 28 -(1-Methylethyl) 3- (tetrahydro-4H-pyran-4-yl) 2- (fluoromethyl)-1,4-dihydro-6-methyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate Recrystallised from petroleum ether (60-80°) ./acetone , mp 128-30°.

Example 29 5-(1-Methylethyl) 3-(2-phenoxyethyl) 2-(fluoromethyl) -l,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate M+ 498; nmr (CDC13) £ 6.6(d,NH) , 5.1(s,H).

Example 30 5-Methyl 3-(tetrahydro-4H-pyran-4-yl) 2-(fluoromethyl) 1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate Yellow prisms (acetone/petroleum ether 60-80°) mp 152-4°.

Example 31 - 34 - ' v ; > 5 8 -Cyclohexyl 3-methyl 4-(2,3-dichlorophenyl)-2-(fluoromethyl)-l,4-dihydro-6-methyl-3,5-pyr idinedicarboxylate Orange prisms (petroleum ether 60-80°) mp 121-3°.

Example 32 -Cyclopentyl 3-methyl 2-(fluoromethyl)-1,4-dihydro-6-methyl-4-(2-methy1-3-n itrophenyl) - 3,5-pyr idinedicarboxylate mp 167-8°. (2-Propanol).

Example 33 3-Methyl 5-(1-methylethyl) 4-(2,3-dimethoxyphenyl)-2-(fluoromethyl)-1,4-di hydro-6-methyl-3,5-pyridinedicarboxylate mp 89-91°. (Petroleum ether 60-80°/2-propanol). Example 34 3-Methyl 5-(tetrahydro-4H-pyran-4-yl) 4-(2,3- - dichlorophenyl)-2-(fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate Orange prisms (acetone/petroleum ether 60-80°) mp 143-5°.

Example 3 5 -Cyclopentyl 3-methyl 2- (fluoromethyl)-1,4-dihydro-6-methyl-4-(2-(trifluoromethyl)phenyl)-3,5-pyridinedicarboxylate Yellow crystals (petroleum ether 40-60°) mp 122-3°. 2 07958 Example 36 -Cyclopentyl 3-methyl 4-(3-chloro-6-fluoro-2-(tr ifluoromethyl)phenyl)-2-(fluoromethyl) -1,4-dihydro-erne thy 1-3 ,5-pyridinedicarboxylate 5 mp 184-6°. (2-Propanol/petroleum ether 60-80°).

Example 37 -(1-Ethylpropyl) 3-methyl 4-(2,3-dichlorophenyl)-2-(fluoromethyl)-1,4-dihydro-6-methyl-3, 5-pyridinedicarboxylate 10 Pale yellow prisms (petroleum ether 40-60°) mp 118-9°.

Example 38 3-Methyl 5-(1-methylethyl) 2- (fluoromethyl)-1,4-dihydro-4-(2-methoxy-3-nitrophenyl)-6-methyl-3,5-15 pyridinedicarboxylate mp 105-6°. (2-Propanol/petroleum ether 60-80°). Example 39 3-Methyl 5-(1-methylethyl) 2-(fluoromethyl)-1,4-dihydro-6-methyl-4-(2-(trifluoromethyl)phenyl)-3,5-20 pyridinedicarboxylate Pale yellow crystals (hexane) mp 71-2°.

Example 40 3-Methyl 5-(1-methylethyl) 2-(fluoromethyl)-1,4-dihydro-6-methyl-4-(2-nitrophenyl)-3,5- pyridinedicarboxylate o 207958 Yellow crystals (petroleum ether 60-80°) mp 142-3°.

Example 41 3-Methyl 5-(l-methvlethyl) 2-(fluoromethyl)-4-(2-5 fluorophenyl)-1,4-di hvdro-6-methyl-3,5-pvr idi ned icarboxylate Yellow crystals (petroleum ether 60-80°) mp 129-31°.

Example 42 3-Methyl 5-(1-methylethyl) 2-(fluoromethyl)-1,4-dihydro-6-methyl-4- (2-methylphenyl)-3,5-pyridinedicarboxylate Pale yellow crystals (petroleum ether 60-80°) mp 94-5°.

Example 43 3-Methyl 5-(l-methvlethyl) 4-(2-chlorophenyl)-2-(fluoromethyl) -1,4 -di hvdro-6-niethyl-3, 5-pyridinedeica rboxyl ate Yellow crystals (petroleum ether 60-80°) mp 137-9°. c- v Example 44 _ " 16 SEP 1986 ~j 3-Methyl 5-(1-methvlethvl) 2- (fluoromethvl)-1,4- o./ dihydro-6-methyl-4-(2- (methylthio)phenyl)-3,5- pyridinedicarboxylate Example 45 I '<57958 3-Methyl 5-(1-methylethyl) 2-(fluoromethyl)-1,4-d ihydro-6-ine thyl-4-(2-(me thylsulphonyl) phenyl) -3 , 5-py r id ined ica r boxy la te Example 4 6 3-Methyl 5-(1-methylethyl) 4-(3-chloro-2-methylphenyl) -2-(fluoromethyl)-1,4-d ihydro-6-me thy1-3,5-pyrid inedicarboxyla te mp 73-5° (cyclohexane).

Example 47 3-Methyl 5-(1-methylethyl) 4-(2,3-dimethylphenyl)-2- (fluoromethyl)-1, 4-dihydro-6-methyl-3,5-pyridinedicarboxylate Example 48 3-Methyl 5-(1-methylethyl) 4-(3-cyanophenyl)-2- (fluoromethyl)-1,4-d ihydro-6-methyl-3,5-pyridinedicarboxylate Pale yellow crystals (2-propanol/petroleum ether 60-80°) mp 117-8°.

Example 49 3-Methyl 5-(1-methylethyl) 4-(3-chlorophenyl) -2- (fluoromethyl) -1, 4-difiydro-6-methyl-3 , 5-pyridined icarboxylate Pale yellow crystals (petroleum ether 60-80°) mp 107-9°.

Example 50 w ■,.> h • Diethyl 1,2,3,4-tetrahydro-2-hydroxy-6-methyl -4- (3-ni trophenyl)-2-(tri fluoromethyl)-3,5-pyridine-dicarboxylate 3-Nitrobenzaldehyde (3.0g, 20 mmoles), ethyl 5 3-amino-2-butenoate (2.6g, 20 mmoles) and ethyl 4,4,4-trifluoro-3-oxobutanoate (2.92ml, 20 mmoles) were heated at reflux in ethanol (25ml) for 6 hours. The solvent was removed i_n vacuo and the residue crystallised by the addition of ether/petroleum ether (60-80°). The 10 resulting solid was recrystallised from ether/petroleum ether (60-80°) to give the title compound as colourless crystals (1.9g) mp 120-1°.

Example 51 3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-1,2,3,4-15 tetrahydro-2-hydroxy-6-methyl-2-(tr ifluoromethyl)-3,5-pyridinedicarb6xylate Prepared by the method of Example 50. Two isomeric compounds were obtained. Isomer 1 recrystallised from cyclohexane mp 140-1°. Isomer 2 recrystallised from 20 cyclohexane mp 118-9.5°.

Example 52 Diethyl 1,2,3,4-te trahydro-2-hydroxy-6-methyl-4-(3-n itrophenyl)-2-(pentafluoroethyl)-3,5-pyridined icarboxylate Prepared by the method of Example 50. Two isomeric 2079s . compounds were obtained. Isomer 1 recrystallised from 2-propanol mp 103-4°. Isomer 2 recrystallised from 2-propanol mp 121-2°.

Example 53 5-Cyclopentyl 3-methyl 4-(2,3-dichlorophenyl)-2- (fluoromethyl)-1,4-dihydro-6-methyl-3, 5-pyridinedicarboxylate a) Cyclopentyl 2- (2,3-dichlorophenylmethylene)-3-oxobu tanoa te A solution of 2,3-dichlorobenzaldehyde (2.5g, 14.3mmoles), cyclopentyl 3-oxobutanoate (2.42g, 14.3mmoles), piperidine (8 drops) and hexanoic acid (11 drops) in dry benzene (80ml) was heated at reflux for 4 hours using a Dean and Stark apparatus. The solution was 15 allowed to cool to room temperature and the solvent removed in vacuo to leave the sub-title compound as an oil 5. lg. b) A solution of the product of step a) (5.1g, 14.3mmoles) and methyl 3-amino-4-fluoro-2-butenoate (1.9g, 14.3mmoles) in dry tert-butanol (25ml) was heated to 60° (oil bath temperature) for 108 hours. The solution was allowed to cool to room temperature and the solvent removed in vacuo. Chromatography on silica eluting with dichloromethane afforded the title compound as a yellow 25 oil which crystallises on addition of petroleum ether o -f- A e 0- - 40 - ,„, ,.* . (60-80°) to afford the title compound 1.5g mp 148-9°. (Identical with the product of Example 3).

Example 54 -Cyclobutyl 3-methyl 4-(2,3-dichlorophenyl)-2-5 (fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate a) Cyclobutyl 2-(2,3-dichlorophenylmethylene)-3-oxobutanoate A solution of 2,3-dichlorobenzaldehyde (1.57g, 8.9mmoles), cyclobutyl 3-oxobutanoate (1.4g, 8.9mmoles), piperidine (8 drops) and hexanoic acid (11 drops) in dry benzene (100ml) was heated at reflux for 12 hours using a Dean and Stark apparatus. The solution was allowed to cool to room temperature and the solvent removed in vacuo 15 to leave the crude sub-title compound as an oil 3.5g. Chromatography on silica eluting with petroleum ether (60-80°)/ethyl acetate mixtures afforded the sub-title compound as an oil, 1.7g. b) The product of step a) (1.7g, 5.4mmoles) and methyl 3-amino-4-fluoro-2-butenoate (0.72g, 5.4mmoles) were mixed and heated to 95° (oil bath temperature) under an atmosphere of nitrogen for 6 hours. The oil was allowed to cool to room temperature. Chromatography on silica eluting with petroleum ether (60-80°)/ethyl acetate mixtures, afforded the title compound as a yellow solid, 2 0795 which was recrystallised from petroleum ether (60-80°) to afford the title compound 0.37g, mp 148-9°.

Example 55 3-Methyl 5-(3-oxetanyl) 4-(2,3-dichlorophenyl)-2-(fluoromethyl)-1,4-dihydro-6-methyl-3, 5-pyridinedicarboxylate a) (3-Oxetanyl) 2-(2,3-dichlorophenylmethylene)-3-oxobutanoate A solution of 2,3-dichlorobenzaldehyde (1.33g, 7.6mmoles), 3-oxetanyl 3-oxobutanoate (1.2g, 7.6mmoles), piperidine (6 drops) and hexanoic acid (8 drops) in dry benzene (80ml) was heated at reflux using a Dean and Stark apparatus. The solution was allowed to cool to room temperature and the solvent removed in vacuo to leave the sub-title compound as an oil 2.9g. b) A solution of the product of step a) (2.9g, 7.6mmoles) and methyl 3-amino-4-fluoro-2-butenoate (lg, 7.6mmole5) in dry tert-butanol (20ml) was heated to 60° (oil bath temperature) for 16 hours. The solution was allowed to cool to room temperature and the solvent removed in vacuo. Chromatography on silica, eluting with dichloromethane/ethyl acetate mixtures afforded the title compound as an oil which crystallised on addition of petroleum ether (60-80°). The solid was recrystallised from petroleum ether (60-80°)/acetone to afford the ? °"T9 5 8 • title compound 1.03g, mp 155-6°.

Example 56 Diethyl It 2,3,4-tetrahydro-2-hydroxy-6-roethyl-4-(3-nitrophenyl)-2-{tr ichloromethyl)-3,5-5 pyridinedicarboxylate a) Ethyl 4,4,4-trichloro-2-(3-ni trophenylmethylene)--3-oxobutanoate 3-Nitrobenzaldehyde (7.55g, 50mmoles), ethyl 4,4,4-trichloro-3-oxobutanoate (18.33g, 59.5mmoles), piperidine I® (0.66ml) and hexanoic acid (0.33ml) were heated at reflux in toluene (130ml) for 48 hours using a Dean and Stark apparatus. The mixture was cooled, evaporated to dryness in vacuo and crystallised by trituration with ethyl acetate/petroleum ether (60-80°). Recrystallisation 15 from 2-propanol gave the sub-title compound (5.3g) mp 105.5-7°. b) Diethyl 1,2,3,4-tetrahydro-2-hydroxy-6-methyl-4-(3-nitrophenyl)-2-(tr ichloromethyl)-3,5- pyridinedicarboxylate Ethyl 4,4,4-trichloro-2-(3-nitrophenylmethylene)-v-' 3-oxobutanoate (7.19g, 0.02mmoles) and ethyl 3-amino-2- butenoate (2.53g) were heated at 60° for 24 hours in tert-butanol (60ml). The solvent was evaporated and the residue chromatographed on silica eluting with ether/petroleum ether (60-80°) mixtures to give the 2 07958 title compound (4.04g). Recrystallised from 2-propanol. mp 125-6.5°.

Example 57 3-Methyl 5- ((5)-2,2,2-trichloro-l-phenylethyl) 4-(2,3-5 dichlorophenyl)-2-(fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate a) (S)-2,2,2-Trichloro-l-phenylethyl 2-f2,3-dichlorophenylmethylene)-3-oxobutanoate (S)-2,2,2-Trichloro-l-phenylethyl 3-oxobutanoate 10 (8.6g, 27.5mmoles) and 2,3-dichlorobenzaldehyde (4.82g, 27.5mmoles) in dry benzene (100ml) were heated at reflux for 5 hours with hexanoic acid (25 drops) and piperidine (8 drops) in a Dean and Stark apparatus. The solvent was evaporated and the residue dissolved in ethyl acetate (200ml), washed with saturated sodium bicarbonate, 2% aqueous sodium bisulphite solution and brine, dried (MgSO^) and the solvent removed in vacuo. The sub-title compound was obtained as a yellow oil. HPLC and nmr indicate 2:1 mixture of geometric isomers. 20 b) 3-Methyl 5-((S)-2,2,2-trichloro-l-phenylethyl) 4-(2,3-dichlorophenyl)-2-(fluoromethyl)-l,4-dihydro-6-methyl-3,5-pyridinedicarboxylate Single diastereomers A and B (S)-2,2,2-Trichloro-l-phenylethyl 2- (2,3-dichlorophenylmethylene)-3-oxobutanoate (10.8g, 23mmoles) 25 and methyl 3-amino-4-fluoro-2-butenoate (3.7g, 28mmoles) 2°7 9 sg . were heated at 55° in dry tert- butanol (50ml) for 68 hours- The solvent was removed and the residue purified and separated into single diastereomers by HPLC eluting with methylene chloride/petroleum ether (60-80°) 5 mixtures.

First eluted: diastereomer A, recrystallised from cyclohexane/petroleum ether (60-80°) mp 167.5-8° [°<]p5 +17.5° (c, 0.1 in ethanol).

Second eluted: diastereomer B, recrystallised from 10 petroleum ether (60-80°) mp 141-3° -150.1° (c, 0.1 in ethanol).

Example 58 3-Methyl 5- (2,2,2-trichloro-l-phenylethyl) 4-(2,3-dichlorophenyl)-2-(fluoromethyl)-1,4-dihydro-6-methyl-3,5-15 pyridinedicarboxylate Diastereomeric pairs A and B Prepared by the method of Example 57 and separated by HPLC using methylene chloride/petroleum ether (60-80°) mixtures.

First eluted: diastereomeric pair A. Recrystallised 20 from cyclohexane/petroleum ether (60-80°) mp 203-4°.

Second eluted: diastereomeric pair B.

Recrystallised from cyclohexane/petroleum ether (60-80°) mp 176-176.5°.

The compounds of Examples 59 to 73 were prepared using appropriate starting materials and the method 207958 . described in Examples 53-58.

Example 59 Diethyl 2- (difluoromethyl)-1,4-dihydro-6-methyl-4-(3-n itrophenyl)-3,5-pyr idi nedicarboxylate 5 mp 148°-9° (2-propanol).

Example 60 Diethyl 1,4-dihydro-2-methy1-6-methylthio-4-(3-ni trophenyl )-3,5-pyr idi ned icarboxyla te mp 123-5° (2-propanol).

Example 61 Diethyl 1, 4-dihydro-2-(4-methoxyphenvl)-6-methy1-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate mp 166-7° (2-Propanol).

Example 62 Diethyl 2-(dichloromethyl)-1,4-dihydro-6-methyl-4- (3-nitrophenyl)-3,5-pyridinedicarboxylate Recrystallised from isopropanol as yellow crystals mp 139-141°.

Example 63 Diethyl 1,4-dihydro-2-methyl-6-phenyl-4-(2-(trifluoromethyl) phenyl)-3,5-pyridinedicarboxylate Recrystallisation from 2-propanol gave the title compound (3.7g) mp 149-150°.

Example 64 5-Methyl 3-(1-methylethyl) 4-(4-benzofurazanyl)-1,4- "* o ■ sr *s< ^ 3 • di hydro-2-methy1-6-phenyl-3,5-pyridinedicarboxylate Recrystallised from 2-propanol to give the title compound mp 198-200°.

Example 65 5-Methyl 3-(1-methylethyl) 1, 4-dihydro-2-methyl-6- phenyl-4-(2-(tr ifluoromethyl)phenyl)-3,5-pyr idinedicar boxylate Recrystallised from petroleum ether (60-80°) mp 111-2°.

Example 66 -Ethyl 3-methyl 4-(2,3-dichlorophenyl)-1,2,3,4-tetrahydro-2-hydroxy-6-methyl-2-phenyl-3,5-pyrid ined icarboxylate The title compound was obtained as a white solid. 15 Nmr (Dg-DMSO) £ 6.0(S,1H), 4 . 9 (d , 1H, J=llHz) , 0.7(t,3H, J = 7Hz) .

Example 67 Diethyl 4- (4-benzofurazanyl)-2-diethoxymethyl-l, 4,5,6-tetrahydro-6-hydroxy-6-(tr i fluromethyl)-3,5-20 pyridinedicarboxylate The title product was obtained as an oil. M+ 531. Example 68 -(1-(Diphenylmethyl)-3-azetidinyl) 3-methyl 4-(2,3-dichlorophenyl)-2-(fluoromethyl)-1,4-dihydro-6-methyl-3,5- pyridinedicarboxylate 2 0795 Pale yellow solid (petroleum ether 60-80°) mp 163-5°.

Example 69 3-Methyl 5-(1- (phenylmethyl)-4-piperidinyl) 4-(2,3-dichlorophenyl)-2-(fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate Pale yellow solid. mp 118-20°.

Example 70 -(1,l-Diroethylethyl) 3-methyl 4-(2,3-dichlorophenyl) -2-(fluoromethyl)-1,4-dihydro-6-methyl-3, 5-pyridinedicarboxylate Pale yellow solid (petroleum ether 60-80°) mp 141°.

Example 71 3-Methyl 5-(1-methyl-1-phenylethyl) 4-(2,3- dichlorophenyl)-2-(fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate Colourless solid (acetone-petroleum ether 60-80°). mp 173-5°.

Example 72 3-Methyl 5-(1-methylcyclopentyl) 4-(2,3-dichlorophenyl)-2- (fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate Colourless solid (petroleum ether 60-80°). 25 mp 111°. 0*^9 g Example 73 3-Methyl 5- (2,2,2-trichloro-l-phenylethyl) 2-(fluoromethyl)-1,4-dihydro-6-methyl-4-(3-nitrophenyl) -3, 5-pyridinedicarboxylate Diastereomers obtained as yellow foam.

M+ 562/560/558/556. Nmr (CDC13) £ 5.24 and 5.26 (2xs,lH), 6.32 and 6.34 (2xs,lH).

Example 74 Diethyl 2-(fluoromethyl)-6-formyl-l,4-dihydro-4-10 (3-nitrophenyl)-3/5-pyridinedicarboxylate Ethyl 4,4-diethoxy-2-(3-ni trophenylmethylene)-3-oxobutanoate (21.75g, 62mmoles) and ethyl 3-amino-4-fluoro-2-butenoate (9.17g, 68mmoles) were heated at 125° for 1.5 hours. The reaction mixture was dissolved in ethyl acetate (150ml), washed with water and saturated brine, dried (MgS04) and the solvent was removed in vacuo. The residue was dissolved in tetrahydrofuran (195ml) and 50% aqueous hydrochloric acid (292ml) was added slowly. After 30 minutes the reaction 20 mixture was extracted with ethyl acetate and the organic extract washed with saturated aqueous sodium bicarbonate, water, dried (MgSO^) and the solvent was removed in vacuo. The residue was chromatographed on silica eluting with ethyl acetate/petroleum ether (60-80°) mixtures. 25 Crystallisation from 2-propanol gave the title compound 207958 (4.6g) , mp 88-90°.

Example 75 3-Methyl 5-(1-methylethyl) 4-(4-benzofurazanyl)-1,2,3,4-tetrahydro-2-hydroxy-6-methyl-2-phenyl-3,5-pyridined icarboxylate 4-Benzofurazancarboxaldehyde (2.96g, 20mmoles), methyl beta-oxobenzenepropanoate (3.56g, 20mmoles), piperidine (0.05ml) and hexanoic acid (0.13ml) were heated at reflux for 3 hours in benzene (50ml) using a Dean and Stark apparatus. The reaction was cooled, diluted with ethyl acetate and washed in turn with water, brine and saturated sodium bicarbonate and dried (Na2S04). The solvent was removed iji vacuo and the residue dissolved in ethanol (6ml). 1-Methylethyl 3-amino-2-butenoate (3.0g) and diethylamine (0.6ml) were added and the mixture heated at 60° for 34 hours. The reaction mixture was cooled, evaporated to dryness jj} vacuo and the residue was dissolved in 2-propanol and treated with charcoal. The charcoal was filtered off and the title compound (l.lg) was obtained on addition of cyclohexane mp 132-4°.

Example 76 Diethyl 2-amino-6-(fluoromethyl)-1,4-dihydro-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate Ethyl 4-fluoro-2-(3-ni trophenylmethylene)-3-oxobutanoate (0.6g, 2.1mmoles) and ethyl 3,3-diamino-2- r> 2 07958 , propenoate hydrochloride (0.34g, 12.0mmoles) were heated at reflux in ethanol (10ml) and a solution of sodium (0.05g) in ethanol (5ml) was added over one hour. The resulting solution was heated at reflux for a further 10 5 minutes and then filtered hot. The ethanolic solution was evaporated to dryness in vacuo and the resulting solid triturated with 2-propanol. The resulting solid was chromatographed on silica eluting with ether/petroleum ether (60-80°) mixtures to give pure title compound, mp 10 177-8°.

Example 77 Diethyl 2- (fluoromethyl)-1,4,5,6-tetrahydro-6-hydroxy-4-(3-nitrophenyl)-6-phenyl-3,5-pyr idinedicarboxylate and Diethyl 2-(fluoromethyl)-1,4-dihydro-4-15 (3-nitrophenyl)-6-phenyl-3,5-pyridinedicarboxylate Ethyl alpha-(3-nitrophenylmethylene)-beta-oxobenzenepropanoate (1.66g, 16.3mmoles), ethyl 3-amino-4-fluoro-2-butenoate (0.75g, 15.6mmoles) and piperidine (0.06ml) were heated at 60° in ethanol (1ml) 20 for 72 hours. The reaction mixture was cooled and diluted with ethanol. The solid was filtered off, dried and then chromatographed on silica eluting with ethyl acetate/petroleum ether (60-80°) mixtures to give the hydroxy compound (0.43g) mp 188-90° (dec). 25 The ethanolic mother liquors were evaporated to • -V 107958 dryness in vacuo, dissolved in methylene chloride and pyridine (0.58ml), and trifluoroacetic anhydride (0.48ml) was added with stirring. After 16 hours, the solution was washed with 5% aqueous acetic acid (3 x 10ml), and saturated sodium bicarbonate, dried (Na-SO„) and the 2. 4 solvent was removed in vacuo. The residue was chromatographed on silica eluting with ethyl acetate/petroleum ether (60-80°) mixtures.

Recrystallisation from 2-propanol gave the dihydropyridine 10 (0.31g), mp 151-2°.

Example 78 3-Ethyl 5-methyl 4-(2 , 3-dichlorophenyl)-1,4-dihydro-2-methvl-6-phenyl-3,5-pyridinedicarboxylate Ammonia (0.5ml, d =0.88) was added to a solution of 15 methyl alpha-(2,3-dichlorophenylmethylene)-beta-oxobenzenepropanoate (2g, 7.3mmoles) and ethyl 3-amino-2-butenoate (0.77g, 6.0mmoles) in tert. butanol (8ml) at 60°. The reaction was maintained at this temperature for 16 hours. The solvent was removed in vacuo and the residue was chromatographed on silica eluting with ethyl acetate/petroleum ether (60-80°) mixtures. The title compound (0.25g) was obtained after crystallisation from 2-propanol mp 185-6°.

Example 79 Diethyl 1,4-dihydro-2-methyl-4-(3-ni trophenyl)-6- S-i/ i^7 9 5Q . (4-nitrophenyl)-3,5-pyridinedicarboxylate Trifluoroacetic anhydride (0.65ml, 4.63mmoles) was added with stirring to pyridine (0.75ml, 9.26mmoles) and diethyl 1,2,3,4-tetrahydro-2-hydroxy-6-methyl-4-(3-5 nitrophenyl)-2-(4-nitrophenyl)-3,5-pyridinedicarboxylate (2.31g, 4.63mmoles) in methylene chloride (60ml). After stirring for 2.5 hours, the solution was washed with water, dilute hydrochloric acid (x3), water, saturated sodium bicarbonate solution, water and dried 10 (NajSO^). The solvent was removed in vacuo and the residue recrystallised from ethanol to give the title compound (1.77g) as a yellow solid, mp 176-7°.

The compounds of Examples 80 to 86 were prepared using appropriate starting materials and the method of 15 Example 79.

Example 80 Diethyl 2-(3,4-dichlorophenyl)-1,4-dihydro-6-methyl -4-(3-nitrophenyl)-3,5-pyridinedicarboxylate Yellow solid mp 153-6° (ethanol).

Example 81 Diethyl 2-(4-chlorophenyl)-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyr idinedicarboxylate Yellow solid mp 158-60° (ethanol).

Example 82 Diethyl 1,4-dihydro-2-methyl-4-(3-nitrophenyl)-6- ft 207958 (trifluoromethyl)-3,5-pyridinedicarboxylate Yellow solid mp 93-5° (ether-petroleum ether 60-80°).

Example 83 Diethyl 2-(3-chlorophenyl)-1,4-dihydro-6-methyl- 4-(3-nitrophenyl)-3,5-pyr idinedicarboxylate Recrystallised from 2-propanol. mp 160-1°.

Example 84 Diethyl 1,4-dihydro-2-methyl-4-(3-ni trophenyl)-6-(pentafluoroethyl)-3,5-pyridinedicarboxylate Obtained pure after chromatography, mp 88-9°. Example 85 -Ethyl 3-methyl 4- (2,3-dichlorophenyl)-1,4- # di hydro-2-methy1-6-(tr i fluoromethyl)-3,5-15 pyridinedicarboxylate Recrystallised from cyclohexane, mp 101-2°.

Example 86 Diethyl 4- (4-benzofurazanyl)-2-(diethoxymethyl)-l,4-dihydro-6-(trifluoromethyl)-3,5-pyridinedicarboxylate Obtained as an oil. Nmr (CDCl^) & 6.1 (s,H), .6(s,H) .

Example 87 Diethyl 1,4-dihydro-2-methyl-4-(3-ni trophenyl)-6-(trichloromethyl)-3,5-pyridinedicarboxylate a) Diethyl 3,4-dihydro-2-roethyl-4-(3-nitrophenyl)-6- • • i " " *" - ' «^wwwwwsii>»>iii«r ^ o ^ • (trichloromethyl)-3,5-pyr idi nedicar boxylate Diethyl 1,2,3, 4-tetrahydro-2-hydroxy-6-methyl-4-(3-n i trophenyl)-2-(tri chloromethyl)-3,5- pyridinedicarboxylate (3.0g, 6.05mmoles) was dissolved in 5 dry methylene chloride (150ml) and diethylaminosulphur trifluoride (1.5ml) was added. After 1 hour the solution was diluted with methylene chloride and washed in turn with dilute hydrochloric acid and saturated sodium bicarbonate solution. After drying (MgSC>4), the solvent was removed in vacuo to give the sub-title compound (2.82g) as an oil. Nmr (Dg-DMS0)£ 4.8 (s,H), 4.4 (s,H). b) Diethyl 1,4-dihydro-2-methyl-4-(3-nitrophenyl)-6- (trichloromethyl)-3,5-pyridinedicarboxylate * The product of step a) (2.67g) was dissolved in 15 methylene chloride (20ml) and triethylamine (0.5ml) was added. After 18 days at room temperature, the solvent was evaporated and the residue chromatographed on silica eluting with methylene chloride. The title compound (0.65g) was obtained after crystallisation from 2-propanol 20 mp 113-5°. Nmr (Dg-DMS0) <f 9.0 (s,H), 4.9 (srH).

Example 88 Diethyl 1,4-dihydro-2-methyl-6-(methylsulphinyl)-4- (3-nitrophenyl)-3,5-pyridinedicarboxylate Isomers I and II Peracetic acid (6.8ml of 1M solution in methanol) was added to a solution of diethyl 1,4-dihydro-2-methyl-6- 2 0795 . (methylthio)-4-(3-n i trophenyl)-3,5-pyridi nedicarboxylate (2.77g 6.8mmoles) in methylene chloride (150ml) at -78°. The reaction mixture was allowed to reach room temperature and was then stirred for 30 minutes.

Saturated aqueous sodium bicarbonate (150ml) was added and the organic layer separated, dried (Na2S04) and the solvent removed iji vacuo. The residue was chromatographed on silica, eluting with ether/petroleum ether (60-80°) mixtures. The two isomers were separated and 10 recrystallised from 2-propanol.

Diastereomer I yellow crystals mp 143-4° (0.84g).

Diastereomer II yellow crystals mp 133-5° (1.25g). Example 89 Diethyl 2-aminocarbonyl-1,4-dihydro-6-methyl-4-(3-15 nitrophenyl)-3,5-pyr idinedicar boxylate A solution of 3,5-diethyl 1,4-dihydro-6-methyl-4-(3-nitrophenyl)-2,3,5-pyridinetricarboxylate (4.Og; 10. 3nunoles) , 1,1' -carbonyldi imidazole (1.75g; 10. 8mmoles) in dry dichloromethane (180ml) was stirred at room 20 temperature under an atmosphere of dry nitrogen. After 2 hours a yellow suspension had formed, ammonia solution (20ml, d=0.88) was added and the 2-phase mixture left stirring for 16 hours.

Saturated brine (100ml) was added, the organic 25 solution was separated, washed with 15% aq. sodium ■>(•^9 58 hydroxide solution, saturated brine, water and dried (MgS04) .

Evaporation of the solvent was followed by chromatography on silica (150g) using ethyl acetate/petroleum ether (60-80°) as eluent.

The title compound was obtained as a white solid which was recrystallised from 2-propanol to give a white powder (0.8g) mp 166-8°.

Example 90 Diethyl 2-(dimethylaminocarbonyl)-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyr idinedicarboxylate Thionyl chloride (0.05ml) was added to a solution of 3,5-diethyl 1,4-dihydro-6-methyl-4-(3-nitrophenyl)-2,3,5-pyridinetricarboxylate (0.25g, 0.62mmoles) in methylene chloride (10ml) containing dimethylformamide (1 drop). After 2 hours at room temperature further thionyl chloride (0.05ml) was added and the solution was refluxed for 30 mins. After cooling to room temperature 10% dimethylamine in benzene (1 ml) was added and the mixture stirred for 30 mins. The solvent was evaporated and the residue dissolved in dilute hydrochloric acid and ether. The organic extract was washed with brine, dried (Na2S04) and the solvent removed _in vacuo to leave the title compound (0.2g). M+ 431; nmr (CDC13) 5 .12 (s,H), 3.05 (s,3H), 2.95 (S,3H). -57- 2 079 5 8 . Example 91 Diethyl 1,4-dihydro-2-(lH-imidazol-1-ylcarbonyl)-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate and Diethyl 1,4 -di hydro-2-methyl-6- (4-inorphol inylcar bonyl) -5 4-(3-nitrophenyl)-3,5-pyridinedicarboxylate A solution of 3,5-diethyl 1,4-dihydro-6-methyl-4-(3-nitrophenyl)-2, 3 , 5-pyridinetricarboxylate (2.5g , 6.2mmoles) and 1,1 1 -carbonyldi imidazole (1.2g, 7.4mmoles) in methylene chloride (100ml) was stirred at room 10 temperature for 4 hours. Morpholine (1.08ml, 12.4mmoles) was added, the mixture stirred overnight and then poured onto 10% hydrochloric acid. The organic layer was separated, washed with 10% hydrochloric acid, brine, saturated sodium bicarbonate, brine and dried 15 (Na2S04). The solvent was evaporated and the residue chromatographed on silica eluting with ethyl acetate/petroleum ether (60-80°) mixtures. The imidazolyl-carbonyl (0.24g) compound was eluted first (M+ 454) .

Further elution afforded the morpholinylcarbonyl compound (0.4g) (M+ 4 73).

Example 92 Diethyl 2-(aminothioxomethyl)-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate 25 Hydrogen sulphide was bubbled through a solution of "**V lT\ WB»« -t> - 53 - >• 5 Q diethyl 2-cyano-l,4-dihydro-6-methyl-4-(3-nitrophenyl)-3, 5-pyridinedicarboxylate (lg, 2.6nunoles) in triethylamine (0.36ml, 2.6mmoles) and pyridine (20ml) at room temperature for 2 hours. The solution was degassed with nitrogen and poured into water (300ml). After stirring for 2 hours, the precipitate was filtered off, dissolved in methylene chloride and dried (Na2S04). The solvent was removed in vacuo and the residue triturated with CCl^ and filtered to give the title compound 10 (0.5g) . M+ 419; (CDC1,) £ 9.3 (s,NH,), 5.2 (s,H).

Example 9 3 Diethyl l,4-dihydro-2-(imino(methylthio)methyl)-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate hydroiodide Methyl iodide (0.06ml, 0.96mmoles) was added to a solution of diethyl 2- (aminothioxomethyl)-1,4-dihydro -6-methyl-4- (3-nitrophenyl)-3,5-pyridinedicarboxylate (0.2g, 0.48mmoles) in methanol (10ml). After stirring for 16 hours at room temperature methyl iodide (0.1ml) was 20 added and the stirring continued for 1 day. The solvent was evaporated and the residue crystallised on addition of ether. The hydroscopic solid was filtered and dried in vacuo to give the title compound (0.17g).

Nmr (CDC13) & 5.9 (s,H), 2.9 (s,SMe).

Example 94 2 07958 Di ethyl 2-(fluoromethyl)-1,4-dihydro-6-methy1-4-(3-ni trophenyl)-3,5-pyridinedicarboxylate Ethyl 4-fluoro-3-oxobutanoate (1.45g, lOmmoles), ethyl 2-(3-nitrophenylmethylene)-3-oxobutanoate (2.63g, lOmmoles) and aqueous ammonia (1.1ml, d 0.88) were heated at reflux in ethanol (15ml) for 6 hours. The solvent was removed in vacuo and the residue purified by chromatography on silica eluting with petroleum ether (60-80°)/ether mixtures. Recrystallisation from ether/petroleum ether (60-80°) gave the title compound (l.lg) as yellow crystals mp 139-41°.

The compounds of Examples 95 to 104 were prepared using appropriate starting materials and the method of Example 94.

Example 95 Di-(2-propoxyethyl) 2-(fluoromethyl)-l,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate Recrystallised from ether-hexane as a yellow solid mp 52-3°.

Example 96 Diethyl 1,2,3,4-tetrahydro-2-hydroxy-6-methyl-4 -(3-nitrophenyl)-2-(4-nitrophenyl)-3,5-pyridinedicarboxylate Recrystallised from ethanol as yellow needles mp 196-7°.

Example 97 2 0 7' 9 5 g -Methyl 3-(1-methylethyl) 1, 4-dihydro-2-methyl-4-(3-ni trophenyl)-6-phenyl-3, 5-pyr idi ned icar boxylate mp 184.5-185.5° (2-propanol).

Example 98 Diethyl 1,2,3,4-tetrahydro-2-hydroxy-6-methyl-4-(3- - ni trophenyl)-2-phenyl-3,5-pyridinedicarboxylate m.p. 213-5°. (Ethanol).

Example 99 Diethyl 2- (3,4-dichlorophenyl)-1,2, 3, 4-10 tetrahydro-2-hydroxy-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate White solid mp 188-9°. (Ethanol).

Example 100 * Diethyl 2- (4-chlorophenyl)-1,2,3,4-15 tetrahydro-2-hydroxy-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate Yellow solid mp 175-8°. (Ethanol).

Example 101 Diethyl 1,4-dihydro-2-methyl-6-(4-methylphenyl)-4-20 (3-n itrophenyl)-3,5-pyridinedicarboxylate mp 149-50°. (Ethanol).

Example 102 3-Methyl 5-(1-methylethyl) 1,2,3,4-tetrahydro-V 2-hydroxy-6-methyl-4-(3-nitrophenyl)-2-phenyl-3,5- pyridinedicarboxylate 2 07958 Cj , mp 134-5°. (2-Propanol).

Example 103 Diethyl 2-(3-chlorophenyl)-1,2,3,4-tetrahydro^-hydroxy-S-methyl^- (3 — n itrophenyl)-3,5-5 pyridinedicarboxylate mp 212-4°. (Ethanol).

Example 104 Diethyl 2-(2-furanyl)-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate 10 mp 130-1° (2-propanol).

Example 105 3-Methyl 5-(1-methylethyl) 2- (difluoromethyl)-1,4-di-hydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate Diethylaminosulphur trifluo'ride (0.64ml, 5.1mmoles) 15 was added to a stirred solution at -10° of 3-methyl 5- (1-methylethyl) 2-formyl-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (2g, 5. 2iranoles) in dry methylene chloride (20ml). After stirring for 2 hours at -10° and 1 hr at room temperature, 20 diethylaminosulphur trifluoride (0.2ml) was added and the stirring continued for a further hour. The reaction mixture was poured into aqueous sodium bicarbonate (100ml) and extracted with methylene chloride (2 x 100ml). The organic extracts were washed with water (2x) and brine, 25 dried (MgSO^) and the solvent was evaporated.

S.JL: »-r, ? 0">Q s . Chromatography on silica eluting with ethyl acetate/petroleum ether (60-80°) mixtures, followed by crystallisation from 2-propanol gave the title compound (0.57g). mp 140-1°.

Example 106 -Cyclopentyl 3-methyl 2- (difluoromethyl)-1,4-dihydro-6-methyl-4-(2-methyl-3-nitrophenyl)-3,5-pyridinedicarboxylate -Cyclopentyl 3-methyl 2-formyl-l,4-dihydro-6-methyl 10 -4-(2-methyl-3-nitrophenyl)-3,5-pyridinedicarboxylate (0.62g, 1.45mmoles) was dissolved in dry methylene chloride (6ml) and then cooled to 0°.

Diethylaminosulphur trifluoride (180jj1, 1.45mmoles) was * added and the reaction mixture stirred at room temperature 15 for 4 hours. The solvent was removed in vacuo and the residue chromatographed on silica eluting with ether/petroleum ether (60-80°) mixtures. The title compound (0.22g) was obtained on evaporation of pure fractions mp 154-6°.

Example 107 3-Methyl 5-(1-methylethyl) 4-(2,3-dichlorophenyl)-2-(d i fluoromethyl)-1,4-di hydro-6-methyl-3,5-pyridinedicarboxylate 3-Methyl 5-(1-methylethyl) 4-(2,3-dichlorophenyl)-2-25 formyl-1,4-di hydro-6-methyl-3,5-pyridinedicarboxylate 2 07 958 (1.5g, 3.6mmoles) was dissolved in dry methylene chloride (20ml) and cooled to -60°. Diethylaminosulphur trifluoride (0.59g, 3.6mmoles) was added and the stirred mixture was allowed to reach room temperature. After 2 hours, the solvent was removed in vacuo and the residue chromatographed on silica eluting with methylene chloride/ethyl acetate mixtures. The title compound (0.6g) was obtained, after crystallisation from 2-propanol. mp 156-7°.

Example 108 Diethyl 2-(fluoromethyl)-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridined.icarboxylate Diethyl 1, 4-dihydro-2-(hydroxymethyl)-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (0.lg , 0.25mmoles) in dry methylene chloride (5ml) was added to a stirred solution at -60° of diethylaminosulphur trifluoride (0.068ml, 0.55mmoles) in dry methylene chloride (10ml) over 10 minutes. The reaction mixture was allowed to reach room temperature over 2.5 hours, poured into aqeuous sodium bicarbonate (15ml) and the aqueous layer extracted with methylene chloride (2x). The organic extracts were washed with water, dried (MgSO^) and the solvent was evaporated. The residue was chromatographed on silica eluting with ethyl acetate/methylene chloride mixtures to give the title 70'9 58 compound (0.015g); identical with that prepared in Example 94 .

The compounds of Examples 109 and 110 were prepared using appropriate starting materials and the method described in Examples 105-107.

Example 109 3-(2-Methoxyethyl) 5-(1-methylethyl) 4-(2,3-dichlorophenyl)-2-(di fluoromethyl)-1,4-dihydro-6-methyl-3, 5-pyridinedicarboxylate mp. 127-128°. (2-Propanol).

Example 110 3-(2-Methoxyethyl) 5-(1-methylethyl) 2-(difluoromethyl)-1,4-dihydro-6-methyl-4-(3-nitrophenyl) -3,5-pyr idi nedicarboxylate mp 146-7°. (2-Propanol).

Example 111 Diethyl 4-(4-benzofurazanyl)-2-formyl-l, 4-dihydro-6-(tr ifluoromethyl)-3,5-pyridinedicarboxylate To a solution of diethyl 4-(4-benzofurazanyl)-2-(diethoxymethyl)-1,4-dihydro-6-(trifluoromethyl)-3,5-pyridinedicarboxylate (7.6g, 14.5mmoles) in tetrahydrofuran (100ml) was added 25% aqueous hydrochloric acid solution (100ml) and the resulting solution heated at reflux. After 1.5 hours the cooled solution was poured into ethyl acetate (200ml). The organic phase was 207958 separated and washed with water, saturated aqueous sodium bicarbonate solution, brine and dried (MgSO^).

Evaporation of the solvent left an oil (7.5g) which was purified by chromatography on silica f30Og) using ether-petroleum ether (60-80°) as eluent. The major component was obtained as an oil which gave a solid on trituration with 2-propanol. Recrystallisation from 2-propanol gave the title compound (0.45g) as yellow crystals mp 94-5°.

Example 112 Diethyl 4- (4-benzofurazanyl)-l,4-dihydro-2-(hydroxymethyl)-6-tr ifluoromethyl-3,5-pyr idi nedicarboxylate A solution of diethyl 4-(4-benzofurazanyl)-2-formyl-1,4-di hydro-6-(tr i fluoromethyl)-3,5~pyridinedicarboxylate (l.lg; 2.5mmoles) in dry ethanol (90ml) was cooled to 0° and sodium borohydride (0.14g; 3.7mmoles) was added portionwise over 3 minutes. After 10 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 ether (50ml) and saturated aqueous sodium bicarbonate was added to pH9. The organic solution was separated, washed with saturated aqueous sodium bicarbonate solution, water, brine and dried (MgSO^). Evaporation of the solvent left a yellow oil which was crystallised from 2-propanol to give the ? 0 ? 9 5 g title compound (0.5g) mp 110-11°.

The compound of Example 113 was prepared using appropriate starting materials and the method of Example 112.

Example 113 Diethyl 2-(fluoromethyl)-1,4-dihydro-6-hydroxymethyl -4-(3-nitrophenyl)-3,5-pyridinedicarboxylate mp 149-50°. (2-Propanol).

Example 114 Diethyl 2-cvano-6-(fluoromethyl)-l,4-dihydro-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (a) Diethyl 2-(2,4-dinitrophenoxyiminomethyl)-6-(fluoromethyl)-1,4-dihydro-4-(3-nitrophenyl)-3, 5- pyridinedicarboxylate The compound of Example 74 (0.2g, 10.5mmoles) and 0-(2,4-dinitrophenyl)hydroxylamine (0 . lg , 10.5mmoles) were dissolved in warm ethanol (5ml) and c.hydrochloric acid (1 drop) was added. The reaction mixture was allowed to cool to room temperature, and then in ice, and the resulting solid filtered off (0.157g), mp 150-2°. (b) Diethyl 2-cyano-6- (fluoromethyl)-1,4-dihydro-4-(3-nitrophenyl)-3, 5-pyridinedicarboxylate The product of step (a) (0.45g, 0.8mmoles) was dissolved in 95% aqueous ethanol (20ml) by heating, and then potassium hydroxide (10.16ml of 0.2M in 95% aqueous i 2 07953 ethanol) was added dropwise. The solution was heated at reflux for 3 hours and then the ethanol removed in vacuo. The residue was dissolved in water (75ml), 5% aqueous sodium hydroxide ( 6ml) and chloroform (100ml). The 5 aqueous layer was separated and extracted several times with chloroform. The combined extracts were washed with water, dried (MgSO^) and the solvent was removed in vacuo. The residue was crystallised from 2-propanol to give the title compound (0.19g ) mp 147-8° (dec.) . ^ 10 Example 115 Diethyl 2,6-di-(fluoromethyl)-1,4-dihydro-4-(3-ni trophenyl) -3,5-pyridinedicarboxylate 3-Nitrobenzaldehyde (1.51g, lOmmoles), ethyl ♦ 4-fluoro-3-oxo-butanoate (3g, 20mmoles) and aqueous ammonia (1.1ml, d=0.88) in ethanol (15ml) were heated at reflux for 14 hours; more aqueous ammonia (0.55ml) was added after 6 hours. The solvent was removed in vacuo and the residue was chromatographed on silica eluting with ether/petroleum ether (60-80°) mixtures and the product 20 obtained was recrystallised from 2-propanol to give the title compound as yellow crystals (0.4g) mp 113-4°.

Example 116 ( + ) 3-Methyl 5-(1-methylethyl) 4-(2,3-dichlorophenyl)- . 2-(fluoromethyl)-1,4-dihydro-6-methyl-3,5- pyridinedicarboxylate - -l,-. . "» " I . " . "... , 11 '• ? -. '-J •" v " . Diastereomer A (0.58g, from Example 57) was dissolved in acetonitrile (6ml) and formic acid (0.19ml) and zinc dust (0.6g) were added in turn. The reaction mixture was stirred for 2.5 hours and then cooled in ice while 5 chloroform (20ml) and water (20rnl) were added. The aqueous layer was acidified with dilute hydrochloric acid; the organic layer was separated and the aqueous layer re-extracted with chloroform. The combined organic extracts were dried (Na2S04) and the solvent removed in vacuo to afford 3-methyl 4-(2,3-dichlorophenyl)-2-(fluoromethyl)-1,4-di hydro-6-methyl-3,5-pyridinedicarboxylate.

The mono-acid was azeotroped once with carbon tetrachloride and then dissolved in ethyl acetate (10ml). 15 2-Propanol (0.7ml) and dicyclohexylcarbodiimide (1.75g) were added and the mixture stirred at room temperature overnight and then heated at 60° for 2 hours. The solvent was removed in vacuo and the residue chromatographed on silica eluting with methylene chloride, 20 followed by recrystallisation from hexane, to give the title compound (0.2g) mp 124-5° +38.2° (c 0.1 in ethanol).

Example 117 ^ (-) 3-Methyl 5-(1-methylethyl) 4-(2,3-dichlorophenyl) -2- (fluoromethyl)-1,4-dihydro-6-methyl-3,5- S679 58 • pyridinedicarboxylate Prepared as in Example 116, using diastereomer B from Example 57. Recrystallised from methanol/hexane mp 124-5° t°<]04 -42.3° (c 0.11 in ethanol).

Example 118 ( + ) 5-Cyclopentyl 3-methyl 4-(2, 3-dichlorophenyl)-2-(fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate Prepared as in Example 116, using diastereomer A from 10 Example 57 and esterifying with cyclopentanol. Recrystallised from hexane mp 89-91°, [°<]^*^ +62.9° (c 0.1 in ethanol).

Example 119 (-) 5-Cyclopentyl 3-methyl 4-(2,3-dichlorophenyl)-2-15 (fluoromethyl)-1,4-di hydro-6-methyl-3,5-pyridinedicarboxylate Prepared as in Example 118, using diastereomer B from Example 57 and esterifying with cyclopentanol. . ■; —- '' • ,.u . . i ^ Pi ~r < * / / VJ * 5 8 70 • Examples of Intermediates Example A Methyl 4-fluoro-3-oxo-butanoate Fluoroacetyl chloride (7.1g, 73mmoles) was added 5 dropwise to a stirred solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (10.65g, 74mmoles) and pyridine (16.85ml, 210mmoles) in methylene chloride (75ml) keeping the temperature below 10°. After stirring for 16 hours at room temperature the solution was diluted with methylene 10 chloride (100ml) and then washed with IN hydrochloric acid (200ml) and water (100ml). The organic extract was dried (Na2S04) and the solvent removed _in vacuo. The residue was dissolved in methanol (150ml) and the solution heated at reflux for 2.5 hours. Removal of the solvent 15 followed by distillation at 60-80° (bath temp)/14mm Hg gave methyl 4-fluoro-3-oxobutanoate (6.4g).

The compounds of Examples B and C were prepared using appropriate starting materials and the method of Example A. Example B 1-Methylethyl 4-fluoro-3-oxobutanoate Colourless oil, bp 100-120° (bath temp)/12nun Hg. Example C Tetrahydro-4H-pyran-4-yl 4-fluoro-3-oxobutanoate Nmr (CDC13) £ 5.0(m,H), 4.9(d,2H,J=48Hz).

Example D 2079 . 2-Methoxyethyl 4-fluoro-3-oxobutanoate Ethyl 4-fluoro-3-oxobutanoate (2.1g) was heated at reflux in 2-methoxyethanol (10ml) for 3 hours. The solvent was removed j_n vacuo and the residue distilled to 5 give the title compound as a colourless oil (1.75g). Nmr (CDC13)£4.9 (d, 2H, J-48Hz) , 3.4 (s,3H).

The compounds of Examples E and F were prepared using appropriate starting materials and the method of Example D Example E 2-Propoxyethyl 4-fluoro-3-oxobutanoate Nmr (CDC13)&4.9 (d , 2H, J=4 7Hz) , 0.9 (t, 3H, J=7Hz) . Example F 2-Phenoxyethyl 4-fluoro-3-oxobutanoate Nmr (CDC13) £ 7.5-6.9 (m,5H), (4.9 dr2H,J=48Hz). 15 Example G Methyl 3-amino-4-fluoro-2-butenoate Ammonia was bubbled through a solution of methyl 4-fluoro-3-oxobutanoate (2.6g) in methanol (26ml) at 0° for 3 hours. After stirring overnight at room 20 temperature the solvent was removed in vacuo and the residue distilled (bp 100° at 20 mm Hg) to give the title compound (1.3g) Nmr (CDC13)^4.9 (d , 2H, J=48Hz) , 4.6 (s,H) , (3.7 s,3H).

The compounds of Examples H to J were prepared using 25 appropriate starting materials and the method of Example G ? 0 ?9 58 Example H Ethyl 3-amino-4-fluoro-2-butenoate M+ 147; nmr (Dg -DMSO) & 4. 9 (d,2H,J=46Hz), 4.5 (s,H) .

Example I Tetrahydro-4H-pyran-4-yl 3-amino-2-butenoate Colourless crystals mp 88-90°.

Example J 1-Ethylpropyl 3-amino-2-butenoate Pale yellow oil, bp 143-8°/12mm Hg.

Example K (S)-2, 2,2-Trichloro-l-phenylethyl 3-oxobutanoate Diketene (3.7ml, 47mmoles) was added slowly to a stirred mixture of (S)-alpha-(trichloromethyl) phenylmethanol (9.2g, 41mmoles) and triethylamine (0.05ml) kept at 80-90°. The mixture was maintained for 5 hours at 90°. The cooled reaction mixture was purified using HPLC eluting with methylene chloride/petroleum ether 60-80° to give the title compound (llg) as an oil. Nmr (CDC13)^6.39 (s,H), 3.61 (s,2H), 2.31 (s,3H).

The compound of Example L was obtained by the same method.

Example L 2,2,2-Trichloro-l-phenylethyl 3-oxobutanoate Colourless solid, nmr (CDC13)^6.39 (s,H), 3.61 - -v I (s , 2H), 2.31 (S,3H).

Example M Tetrahydro-4H-pyran-4-yl 3-oxobutanoate A solution of tetrahydro-4H-pyran-4-ol (1.6ml, 16.8mmoles) and 5-acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione (3.0g, 16. lnunoles) in dry benzene (50ml) was heated under reflux for 4 hours. The solvent was removed in vacuo and the residue distilled at 146-151°/l4mm Hg to afford the title product as a colourless oil, 2.84g. Nmr (CDC13)<$5.1 (m,H) , 3.5 (s,3H).

The esters of Examples N to R were prepared using appropriate starting materials and the method of Example M. Example N 1-Ethylpropyl 3-oxobutanoate ^ Colourless oil, bp 128-38° (bath temp)/14mm Hg.

Example O 1-Methyl-1-phenyl ethyl 3-oxobutanoate Colourless oil, bp 108-110° (bath temp)/0.03mm Hg. Example P 1-Methylcyclopentyl 3-oxobutanoate Colourless oil, bp 134-145° (bath temp)/14nun Hg. Example Q 4- (1-Diphenylmethylazetidinyl) 3-oxobutanoate Pale yellow oil. M+ 323.

, „ Example R 20795* . 3-Oxetanyl 3-oxobutanoate Pale yellow oil 165-70° (bath temp)/12mm Hg.

Example S 1-Chipro-4-fluoro-2-(t ri fluoromethyl)benzene 4-Chloro-3-(trifluoromethyl)benzenamine (19.5g, lOOmmoles), water (40ml) and c.hydrochloric acid (40ml) were heated with stirring on a steam bath until a white solid formed. The mixture was cooled (ice-salt bath) and a solution of sodium nitrite (7g, lOlmmoles) in water 10 (15ml) was added over 15 mins. After stirring for a further hour at 0°, tetrafluoroboric acid (30g of 40% aqueous solution) was added dropwise over 15 minutes.

After one hour the solid was filtered off, washed with water (10ml), methanol (30ml) and ether (30ml) and then 15 dried in vacuo. The dry compound was heated at 140°-180° until no more fumes were observed. The cooled residue was dissolved in ethyl acetate, washed with 5% aqueous sodium hydroxide, dried (Na2S04) and the solvent was removed in vacuo. The residue was distilled 20 in vacuo (12mmHg, oven temperature 50°-55°) to give the sub-title compound as a colourless oil (7.5g). M+ 200/198; nmr (CDC13) & 7. 8-7 . 2 (m) .

Example T 2-Chloro-5-fluoro-3-(trifluoromethyl)benzaldehyde and 25 3-Chloro-6-fluoro-2- (trifluoromethyl)benzaldehyde r^ 0 7 9 5 q , Butyl lithium (60.4ml of 1.6M in hexane, 97mmoles) was added with stirring over 1.5 hours under nitrogen to a solution of l-chloro-4-fluoro-2- (trifluoromethyl)benzene (17.8g , 91mmoles) in dry tetrahydrofuran (150ml) at 5 -73°. After a further 1.5 hours at this temperature, N-methyl-N-phenylformamide (10.86ml, 90mmoles) in dry tetrahydrofuran (20ml) was added over 0.5 hours. After 15 minutes the reaction mixture was poured onto 10% aqueous sulphuric acid. The ethereal layer was separated, washed 10 with saturated sodium bicarbonate, dried (Na2S04) and the solvent evaporated. The residue was purified by HPLC eluting with ethyl acetate/petroleum ether 60-80° mixtures. 2-Chloro-5-fluoro-3- (trifluoromethyl) benzaldehyde (0.5g) was eluted first.

M+ 226/228; nmr (CDCl3)£l0.5 (s,H).

Further elution afforded 3-chloro-6-fluoro-2-(trifluoromethyl)benzaldehyde (8.35g).

M+ 226/228; nmr (CDC13)&10.5 (q,H) .

Example U 2-Chloro-3-(trifluoromethyl) benzaldehyde Butyl lithium (36.4ml of 1.6M in hexane) was added to a stirred solution at -65° of l-chloro-2-(trifluoromethyl)-benzene (lOg) in dry tetrahydrofuran (100ml) over 20 mins. After stirring for 1.5 hours at 25 -65°, a solution of N-methyl-N-phenylformamide (6.85ml) -"5QL.V 2 079 J a* 76 in tetrahydrofuran (30ml) was added over 1 hour. The reaction mixture was left at this temperature for 1.5 hours and then allowed to reach room temperature. It was then poured onto 10% sulphuric acid, extracted with ether and the organic extract was washed with brine, dried (Na2S04) and the solvent removed in vacuo. The residue was distilled (20mmHg, oven temperature 100-125°); the distillate was cooled, filtered and the solid washed with petroleum ether (60-80°) to give the desired aldehyde (3.5g) as a colourless solid.

M+ 210/208, nmr (CDCl-j) £ 10. 75 (s,H).

Example V 2,3-D ichloro-6-fluoroben zaldehyde Butyl lithium (48ml of 1.6M in hexane, 52.3mmoles) was added with stirring over 1.5 hours under nitrogen to a solution of 1,2-dichloro-4-fluorobenzene (7.85g, 47.6mmoles) in dry tetrahydrofuran (120ml) at -68°. The solution was stirred at -68° for 2 hours and then N-methyl-N-phenylformamide (6.48ml) in dry tetrahydrofuran (15ml) was added over 1.5 hours. After a further 1.5 hours at -68°, the reaction mixture was poured into 10% aqueous sulphuric acid and ether. The ethereal layer was separated, washed with brine, dried (Na2S04) and evaporated to give the desired aldehyde (8g).

M+ 196/194/192, nmr (CDC13)&10.5 (s,H). 2 07 9 58 Example W % w/w Range % w/w Compound of formula I 5 1-20 Microcystalline cellulose 50 10-80 spray dried lactose 37.75 10-80 Magnesium stearate 1 0.25-2 Colloidal silicon dioxide 0.25 0.1-1 Cross linked sodium carboxy methyl cellulose 3 1-5 Hydroxypropylmethylcellulose (coating) 3 1-5 This formulation is made up as a direct compression tablet, or without compression or coating, may be filled into a gelatine capsule.

Example X % w/w Range % w/w Compound of formula I 5 1-20 Microcystalline cellulose 50 10-80 Lactose 35.75 10-80 Polyvinylpyrrolidone 2 1-5 Magnesium stearate 1 0.25-2 Colloidal silicon dioxide 0.25 0.1-1 o Cross linked sodium carboxy methyl cellulose 3 1-5 Hydroxypropyl methyl cellulose

Claims (14)

- 78 - 2 07958 (coating) 3 1-5 This formulation is made up as a granulate and then compressed into a tablet. Alternatively the granules may be filled into a gelatine capsule. <pn 5 10 15 CJ 20 t - 79 - 207958 • What we claim is:-

1. A compound of formula I, r2ooc coor. a o 10 in which R^ represents benzofurazanyl, pyridyl or phenyl, the pyridyl or phenyl being substituted by one or more of the groups halogen, nitro, -CN, -ORg( -S(0)pRg, or alkyl CI to 6 optionally substituted by halogen, p is 0, 1 or 2, R2 and R^, which may be the same or different, each represent hydrogen; alkyl Cl to 6 optionally substituted by one or more of the groups halogen, cyano, -xr^, -nr-rg or phenyl; cvcloalkvl C3 to 8 optionally substituted by alkyl Cl to 6; a 4, 5 or 6 membered oxygen or nitrogen containing heterocyclic ring which is optionally substituted by alkyl Cl to 6 the alkyl in turn optionally being substituted by one or more pheg' groups; / R5 and Rg, which may be the same or different, each represent alkyl Cl to 6 optionally substituted by 20 25 phenyl, - 80 - Y and Z together form a bond, and additionally, when Rg is an electron withdrawing group Y may be hydrogen and Z may be hydroxy, one of R7 and Rg represents alkyl Cl to 6 and the other represents -CONR^R^j -CSNH2; -C(=NH)SRg,--S(0)mR9; phenyl optionally substituted by one or more of alkyl Cl to 6, halogen, alkoxy Cl to 6 or nitro; alkyl Cl to 6 substituted by halogen; or furanyl, or R7 and Rg may be the same or different and each represents phenyl optionally substituted by one or more of alkyl Cl to 6, halogen, alkoxy Cl to 6 or nitro; amino; alkyl Cl to 6 substituted by halogen; -CN; -CH2OH; -CHO or -CH(ORg)2, X is 0 or S, m is 0 or 1, R4 is alkyl Cl to 6 or phenyl, Rg is alkyl Cl to 6, R10 and R^ each independently represent hydrogen or alkyl Cl to 6, or together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclic ring, provided that A) when R? is alkyl Cl to 6, Y and Z together form a bond, and i) when R1 represents be.nzofurazanyl then Rg does not represent -CF^, or f ....... . i - 81 - ii) when R1 represents 2-nitrophenyl, or 2-chlorophenyl and R2 and R3 are both ethyl, then Rg does not represent mono-chloromethyl, iii) when represents 3-nitrophenyl and R2 and 5 R^ are both ethyl, then Rg does not represent unsubstituted phenyl, B) when neither of R? and R0 is alkyl Cl to 6, Y and Z together form a bond and iv) when and FU are both ethyl then R^ and Rg 10 are not both "CF^, or v) when nne of or Rg is amino then the other is not phenyl or amino, or vi) when one of R? or Rg is -CN, -CHjOH, -CHO or -CH(ORg)2 then the other is not -CN, -CH2OH, -CHO or 15 -CH(OR9)2, and C) both of R7 and Rg are not optionally substituted phenyl, and pharmaceutically acceptable acid addition salts of those compounds containing a basic nitrogen atom. 20 2. A compound according to Claim 1, wherein R^ is nitrophenyl; (trifluoromethyl)phenyl; mono-or poly-fluorophenyl; mono- or poly-chlorophenyl; chioro-and/or fluoro-(trifluoromethyl)phenyl; (alkylthio)pyridyl; alkyl- and/or chloro- and/or alkoxv-nitrophenyl; mixed 25 chloro- and fluoro-phenyl; mono- or poly- alkoxy-phenyl; ? " ,'958 - 82 - alkylphenyl; (alkylthio)phenyl; (alkylsulphonyl)phenyl, or 4-benzofurazany1, 1*2 and are selected from alkyl Cl to 4;

2-alkoxy Cl to 3 - ethyl; 2-phenoxy- ethyl; cycloalkyl C4 5 to 6 optionally substituted by methyl; an oxetanyl, azetidinyl, piperidinyl or tetrahydropyranyl ring optionally substituted by phenylmethyl or diphenylmethyl; alkyl Cl to 4 - (phenylmethyl)aminoethyl; cyano- or alkyl Cl to 4 - thio- alkyl Cl to 4; phenyl alkyl Cl to 4 or 10 -CH(C6H5)CC13, R^ is methyl, and 20 R 8 is chloro- or fluoro- alkyl Cl or 2, -CsNf^/ -CON (alkyl C 1 to 4)2, -COmor pholino, -COimidazolyl, -C(=NH)S-alkyl Cl to 4, -S-alkyl Cl to 4, -S(0)-alkyl Cl 15 to 4, or phenyl substituted by one or two chlorine, nitro, methoxy or methyl groups.

3. A compound according to Claim 1, wherein R^ is phenyl carrying a 2-nitro or a 2-CF3 group or at least two substituents selected from chloro, fluoro, alkyl Cl to 6, -CF3 and nitro; R2 is alkyl Cl to 6, or is oxetan ~3-yl, r3 is alkyl Cl to 6, Ry is alkyl Cl to 6, Rg is fluoromethyl, and Y and Z together form a bond.

4. A compound according to Claim 1, wherein R^ is phenyl carrying at least two substituents selected from chloro, fluoro, -CF3, methyl and nitro, R3 and R-j are both methyl, Rg is -CH2F, R2 is isopropyl or 25 2079 - 83 - cyclopentyl and Y and Z together form a bond.

5. A compound according to Claim 1, wherein represents benzofurazanyl, pyridyl or phenyl, the pyridyl or phenyl being substituted by one or more of the groups halogen, nitro, trihalomethyl or -SRg; R2 and R^ each represent alkyl Cl to 6, "(CHjJh R4, - (CH2) nCN , -CH (CgH5)CCl3 or -(CH2)n NR5R6; Y and Z to9et^er form a bond; one of R^ and Rg represents alkyl Cl to 6 and the other represents -CONR10Rn; -CSNH2; -C(=NH)SRg; "S(0)mR9; phenyl substituted by one or more of alkyl Cl to 6, halogen, alkoxy Cl to 6 or nitro; or alkyl Cl to 6 substituted by halogen; r4 and Rg are each alkyl Cl to 6; R^q and R^ each represent hydrogen or alkyl Cl to 6, n is 2, 3 or 4 and provisos i) and ii) apply.

6. 3-Methyl 5-(1-methylethyl) 4-(3-chloro-6-fluoro-2- (tr i fluoromethyl)phenyl)-2-(fluoromethyl)-1,4-dihydro-6-methy1-3,5-pyridinedicarboxylate.

7. 3-Methyl 5-(1-methylethyl) 4-(2,3-dichlorophenyl)-2- - (fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyr idinedica rboxyla te, 3-Methyl 5-(1-methylethyl) 2-(fluoromethyl)-1,4-dihydro-6-methyl-4-(2-methyl-3-n itrophenyl)-3,5-pyridinedicarboxylate, 5-Cyclopentyl 3-methyl 4-(2,3-dichlorophenyl)-2- 2 °7958 (fluoromethyl)-1,4-dihydro-6-methy1-3,5-pyridinedicarboxylate, 3-Methyl 5-(1-methylethyl) 4-(2-chloro-3-nitrophenyl)-2-(fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, 3-Methyl 5-(1-methylethyl) 2-( fluoromethyl)-4-(2-fluoro-6-(tr ifluoromethyl)phenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, 3-Methyl 5-(1-methylethyl) 4-(2,3-dichloro-6-fluorophenyl)-2-(fluoromethyl)-1,4-d ihydro-6-me thyl-3,5-pyr idinedicarboxylate, 5-Ethyl 3-methyl 2-(fluoromethyl)-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyr idinedicarboxylate, 3-Methyl 5-(1-methylethyl) 2-( fluoromethyl) -1,4-dihydro-6-methyl-4-(3-n itrophenyl)-3,5-pyridined icarboxyla te, 3-Methyl 5-(2-methylpropyl) 2-(fluoromethyl)-1,4-dihydro-6-methyl-4-(3-n itrophenyl)-3,5-pyridinedicarboxylate, 3-Ethyl 5-methyl 2-(fluoromethyl)-1,4-dihydro -6-methyl-4-(3-n itrophenyl)-3,5-pyr idinedicarboxylate, Diethyl 2-(fluoromethyl)-1,4-dihydro-6-methyl-4-(2-(tr ifluoromethyl)phenyl)-3, 5-pyr idinedicarboxylate, Diethyl 4-(4-benzofurazanyl)-2-(fluormethyl)-1,4-dihydro-6-methyl-3,5-pyr idinedica rboxylate, Dimethyl 2- (fluoromethyl)-1,4-dihydro-6-methyl-4--(2,3,4,5,6-pentafluorophenyl)-3,5-pyr idined icarboxylate, 5-Methyl 3-(1-methylethyl) 2-(fluoromethyl)-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyr idinedicarboxylate, 5-Ethyl 3-methyl 4-(2,3-dichlorophenyl)-2-(fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyridined icarboxylate, Diethyl 2-(fluoromethyl)-1,4-dihydro-6-me thyl-4-(2-(methylthio)-3-pyr idyl)-3,5-pyr idinedicarboxylate, 3-Methyl 5-(2-(methyl(phenylmethyl)amino)ethyl) 2-(fluoromethyl)-1,4-d ihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate oxalate, 5-(2-Methoxyethyl) 3-(1-methylethyl) 4-(2,3-dichlorophenyl)-2-(fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, 5-(2-Cyanoethyl) 3-(1-me thyle thyl) 2-( fluoromethyl) -1,4-dihydro-6-methyl-4-(3-n itrophenyl)-3,5-pyridinedicarboxylate, 3-(1-Methylethyl) 5-(2-(methylthio) ethyl) 2-(fluoromethyl)-1,4-dihydro-6-methyl-4-(3-n itrophenyl)-3,5-pyridinedicarboxylate, 3-Methyl 5-(1-methylethyl) 4-(2-chloro-5-nitrophenyl) -2-(fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyr idinedicarboxylate , i 2 07958 - 86 - 3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-2-(fluoromethyl)-1p 4-dihydro-6-me thy1-3,5-pyr idined ica rboxyla te, 3-Methyl 5-(1-methylethyl) 2-(fluoromethyl)-1,4-5 dihydro-6-methyl-4- (2-methyl-5-n itrophenyl)-3,5-pyr idinedicarboxylate , 3-(2-Methoxyethyl) 5-(1-me thylethyl) 2-(fluoromethyl) -1,4-d ihydro-6-methy1-4-(3-n itrophenyl)-3,5-pyridinedicarboxylate, 10 5-(2-Methoxyethyl) 3-(1-methylethyl) 2-(fluoromethyl) -1,4-dihydro-6-methyl-4-(3-n itrophenyl)-3,5-pyridined icarboxyla te, 3-Methyl 5-(1-methylethyl) 4-(2-chloro-3-(tr i-fluoromethyl)phenyl)-2-(fluoromethyl)-1,4-dihydro-6-methyl-15 3,5-pyridinedicarboxylate, 5-(1-Methylethyl) 3-(tetrahydro-4H-pyran-4-yl) 2-(fluoromethyl)-1,4-dihydro-6-methyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate, 5-(1-Methylethyl) 3-(2-phenoxyethyl) 2-(fluoromethyl) 20 -1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate, 5-Methyl 3-(tetrahydro-4H-pyran-4-yl) 2-(fluoromethyl) 1,4-dihydro-6-methyl-4-(3-nitrophenyl) - 3,5-pyrid ined icarboxylate, 25 5-Cyclohexyl 3-methyl 4-(2,3-dichlorophenyl)-2- - 87 - ' "7958 (fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyridined icarboxylate, 5-Cyclopentyl 3-methyl 2-( fluoromethyl)-1,4-dihydro-6-methyl-4 - (2-methyl-3-n itrophenyl)-3,5-pyridined icarboxylate, 3-Methyl 5-(1-methylethyl) 4-(2,3-dimethoxyphenyl)-2-(fluoromethyl)-1,4-di hyd ro-6-methyl-3 , 5-pyridinedicarboxylate, 3-Methyl 5-(tetrahydro-4H-pyran-4-yl) 4-(2,3-dichlorophenyl)-2-(fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, 5-Cyclopentyl 3-methyl 2-(fluoromethyl)-1,4-dihydro-6-methyl-4-(2-(tr ifluoromethyl)phenyl)-3,5-pyridined icarboxylate, 5-Cyclopentyl 3-methyl 4-(3-chloro-6-fluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-1,4-dihydro-6-methy1-3,5-pyridinedicarboxylate, 5-(1-Ethylpropyl) 3-methyl 4-(2,3-dichlorophenyl)-2-(fluoromethyl)-1,4-d ihydro-6-methyl-3,5-pyridinedicarboxylate, 3-Methyl 5-(1-methylethyl) 2-( fluoromethyl)-1,4-dihydro-4- (2-methoxy-3-nitrophenyl)-6-methyl-3,5-pyridinedicarboxylate, 3-Methyl 5-(1-methylethyl) 2-(fluoromethyl)-1,4-dihydro-6-methyl-4-(2-(tr ifluoromethyl)phenyl)-3,5- - 88 - 207958 10 pyr idined icarboxyla te, 3-Methyl 5-(1-methylethyl) 2-(fluoromethyl)-1,4-dihydro-6-methyl-4- (2-nitrophenyl)-3,5-pyr idined icarboxylate, 3-Methyl 5-(1-methylethyl) 2-(fluoromethyl)-4-(2-fluorophenyl)-1,4-dihydro-6-methyl-3 , 5-pyr idined icarboxylate, 3-Methyl 5-(l-methvlethyl) 2-(fluoromethyl)-1,4-dihydro-6-methyl-4- (2-methylphenyl)-3,5-pyridined icarboxyla te, 3-Methyl 5-(1-me thyle thyl) 4-(2-chlorophenyl)-2-(fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyridine.deicarboxylate, 3-Methyl 5-(1-methylethyl) 2-( fluorome thyl) -1,4-dihydro-6-methy1-4- (2- (methylthio)phenyl)-3,5-pyridined icarboxylate, 3-Methyl 5-(1-methylethyl) 2-(fluoromethyl)-1,4-dihydro-6-methyl-4- (2- (methylsulphonyl)phenyl)-3,5-pyridinedicarboxylate, 20 3-Methyl 5-(1-methylethyl) 4-(3-chloro-2-methylphfenyl) 15 -2-(fluoromethyl)-1, 4-dihydro-6-methyl-3,5- u>SEP 1986 pyrid ined icarboxylate, 3-Methyl 5-(1-methylethyl) 4-(2,3-dimethylphenyl)-2-(fluoromethyl)-1,4-dihydro-6-methy1-3 , 5- 25 pyridined icarboxylate, - 89 - "2. 0 7 9 • 3-Methyl 5-(1-methylethyl) 4-(3-cyanophenyl)-2- (fluoromethyl)-1,4-d ihydro-6-methyl-3,5-pyr idinedicarboxylate, 3-Methyl 5-(1-methylethyl) 4-(3-chlorophenyl)-2-5 (fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, Diethyl 1,2,3,4-tetrahydro-2-hydroxy-6-methyl -4-(3-nitrophenyl)-2-(trifluoromethyl)-3,5-pyr idinedicarboxylate, 3-Ethyl 5-methyl 4-(2 , 3-dichlorophenyl)-1, 2,3 , 4-v. tetrahydro-2-hydroxy-6-methyl-2-(tr i fluoromethyl)-3,5-pyridinedicarboxylate, Diethyl 1,2,3,4-tetrahydro-2-hydroxy-6-methyl-4-(3-n itrophenyl)-2-(pentafluoroethyl)-3,5-15 pyridinedicarboxylate, 5-Cyclobutyl 3-methyl 4-(2,3-dichlorophenyl)-2-(fluoromethyl)-1,4-dihydro-6-methy1-3, 5-pyridinedicarboxylate, 3-Methyl 5-(3-oxetanyl) 4-(2,3-dichlorophenyl)-2-(f luoromethyl) -1, 4-dihydro-6-inethyl-3 , 5-pyridinedicarboxylate, Diethyl 1,2,3,4-tetrahydro-2-hydroxy-6-methyl-4-(3-n itrophenyl)-2-(tr ichloromethyl)-3,5-pyridinedicarboxylate, 3-Methyl 5-((S)-2,2,2-trichloro-l-phenylethyl) 4-(2,3- 20 25 - 90 - 2 079.5 8 dichlorophenyl)-2-(fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, 3-Methyl 5-(2,2,2-trichloro-l-phenylethyl) 4-(2,3-d ichlorophenyl)-2-(fluoromethyl)-1,4-dihydro-6-methy1-3,5-pyr id ined icarboxylate, Diethyl 2-(difluoromethyl)-1,4-dihydro-6-methyl-4-(3-n itrophenyl)-3,5-pyr idinedicarboxylate, Diethyl 1,4-dihydro-2-methyl-6-methylthio-4-(3-nitrophenyl) -3 , 5-pyr idinedica rboxylate, Diethyl 1,4-dihydro-2-(4-methoxyphenyl)-6-methyl-4-(3-n itrophenyl)-3,5-pyr idined icarboxylate, Diethyl 2-(dichloromethyl)-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5rpyridinedicarboxylate, Die thyl 1,4-d ihydro-2-me thyl-6-phenyl-4- (2-(tr i fluoromethyl) phenyl)-3,5-pyr idinedicarboxylate, 5-Methyl 3-(1-methylethyl) 4-(4-benzofurazanyl)-1,4-dihydro-2-methyl-6-phenyl-3,5-pyr idinedicarboxyla te, 5-Methyl 3-(1-methylethyl) 1,4-dihydro-2-methy1-6-phenyl-4- (2-(tr ifluoromethyl)phenyl)-3,5-pyr idinedicarboxylate , 5-Ethyl 3-methyl 4-(2,3-dichlorophenyl)-1,2,3,4-tetrahydro-2-hydroxy-6-methyl-2-phenyl-3,5-pyridinedicarboxylate, Diethyl 4-(4-benzofurazanyl)-2-diethoxymethy1-1,4,5,6-tetrahydro-6-hydroxy-6-(trifluromethyl)-3,5- -■■■I- t .. .... ' - »■ V - 9i - ^ 9 58 pyr idinedicarboxylate, 5- (1-(Diphenylmethyl)-3-azetidinyl) 3-methyl 4-(2,3-dichlorophenyl)-2-(fluoromethyl)-1, 4-d ihydro-6-methy1-3,5-pyrid ined icarboxylate, 3-Methyl 5-(1-(phenylmethyl)-4-piperidinyl) 4-(2,3-d ichlorophenyl)-2-(fluoromethyl)-1,4-d ihydro-6-me thyl-3,5-pyridinedicarboxylate, 5-(1,1-Dimethylethyl) 3-methyl 4-(2,3-dichlorophenyl) -2- (fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyr idinedicarboxylate, 3-Methyl 5-(1-methyl-l-phenylethyl) 4 — (2,3— dichlorophenyl)-2-(fluoromethyl)-1,4-d ihydro-6-methyl-3,5-pyridinedicarboxylate, 3-Methyl 5- (1-methylcyclopentyl) 4-(2,3-d ichlor ophenyl) -2 - ( fluoromethyl) -1, 4-d i hydro-6-me thyl-3 ,5-pyridinedicarboxylate, 3-Methyl 5-(2,2,2-trichloro-l-phenylethyl) 2-(fluoromethyl)-1,4-dihydro-6-methyl-4-(3-n itrophenyl) -3,5-pyrid ined icarboxylate, Die thyl 2-(fluoromethyl)-6-formy1-1,4-d ihydro-4-( 3-n itrophenyl)-3,5-pyr idinedicarboxylate, 3-Methyl 5-(1-methylethyl) 4-(4-benzofurazanyl)-1,2,3,4-tetrahydro-2-hydroxy-6-methyl-2-phenyl-3,5-pyridined icarboxylate, Diethyl 2-amino-6-(fluoromethyl)-1,4-dihydro-4- 2 07 95 - 92 - (3-n itrophenyl)-3,5-pyr idined icarboxylate, Diethyl 2- (fluoromethyl)-1,4,5,6-tetrahydro-6-hydroxy 4-(3-n itrophenyl)-6-phenyl-3,5-pyr idinedicarboxylate, Diethyl 2- (fluoromethyl)-1,4-dihydro-4-(3-n itrophenyl)-6-phenyl-3,5-pyr idined icarboxylate, 3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-1,4-dihydro-2 methyl-6-phenyl-3,5-pyr idinedicarboxylate, Diethyl 1,4-dihydro-2-methyl-4-(3-nitrophenyl)-6-(4-n itrophenyl)-3,5-pyr idinedica rboxylate, Diethyl 2-(3,4-dichlorophenyl)-1,4-dihydro-6-methyl -4-(3-n itrophenyl)-3,5-pyr idined icarboxyla te, Diethyl 2-(4-chlorophenyl)-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyr idinedicarboxylate, Diethyl 1,4-dihydro-2-methyl-4-(3-nitrophenyl)-6-(trifluoromethyl)-3,5-pyr idinedicarboxylate, Diethyl 2-(3-chlorophenyl)-l,4-dihydro-6-methyl-4-(3-n itrophenyl)-3,5-pyr idinedicarboxylate, Diethyl 1,4-dihydro-2-methyl-4-(3-nitrophenyl)-6-(pentafluoroethyl)-3,5-pyr idinedicarboxylate, 5-Ethyl 3-methyl 4-(2,3-dichlorophenyl)-1,4-dihydro-2-methyl-6-(tr ifluoromethyl)-3,5-pyridinedica rbox yla te, Diethyl 4-(4-benzofurazanyl)-2-(diethoxymethyl)-1,4-dihydro-6-(tr ifluoromethyl)-3,5-pyr idined icarboxyla te, Diethyl l,4-dihydro-2-methyl-4-(3-nitrophenyl)-6- ? 0 7 9 ^ js _ 93 _ , w-* <i ,4' . (tr ichloromethyl)-3,5-pyr idined icarboxyla te, Diethyl 1,4-dihydro-2-methyl-6-(methylsulphinyl)-4- (3-nitrophenyl)-3,5-pyr idinedicarboxylate, Diethyl 2-aminocarbonyl-l,4-dihydro-6-methyl-4-(3-5 nitrophenyl)-3,5-pyridinedicarboxylate, Diethyl 2-(dimethylaminocarbonyl)-1,4-dihydro-6-methyl-4-(3-n itrophenyl)-3,5-pyr idinedicarboxylate, Diethyl 1,4-d ihydro-2-(lH-imidazol-l-yIcarbonyl)-6-methyl-4-(3-n itrophenyl)-3,5-pyr idined ica rboxylate, 10 Diethyl l,4-dihydro-2-methyl-6- (4-morpholinyIcarbonyl)-4-(3-nitrophenyl)-3,5-pyridined icarboxyla te, Diethyl 2-(aminothioxomethyl)-1,4-dihydro-6-methy1-4-(3-n itrophenyl)-3,5-pyr idinedicarboxyla te, 15 Diethyl 1,4-dihydro-2-(imino(methy1thio)methyl)-6- methyl-4-(3-n itrophenyl)-3,5-pyr idinedicarboxyla te hydroiod ide, Diethyl 2-(fluoromethyl)-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate, 20 Di-(2-propoxyethyl) 2-(fluoromethyl)-1,4-dihydro-6- methyl-4-(3-nitrophenyl)-3,5-pyr id inedicarboxylate, Diethyl 1,2,3,4-tetrahydro-2-hydroxy-6-methyl-4- (3-n itrophenyl)-2-(4-n itrophenyl)-3,5-pyr idinedicarboxylate, 5-Methyl 3-(1-methylethyl) 1,4-dihydro-2-methyl-4-25 (3-nitrophenyl)-6-phenyl-3,5-pyr idinedicarboxylate, 2 °7 9.58 Diethyl 1,2,3,4-te trahydro-2-hydroxy-6-methy1-4-(3-nitrophenyl)-2-phenyl-3,5-pyr id ined icarboxylate, Diethyl 2-(3,4-dichlorophenyl)-1,2,3,4-te trahydro-2-hydroxy-6-methyl-4-(3-ni t rophenyl)-3,5-pyr idinedicarboxylate, Diethyl 2-(4-chlorophenyl)-1,2,3,4-tetrahydro-2-hydroxy-6-methyl-4-(3-nitrophenyl)-3,5-pyr idined icarboxylate, Diethyl 1,4-d ihydro-2-me thy1-6-(4-me thylphenyl)-4-(3-n itrophenyl)-3 , 5-pyr idined icarboxyla te, 3-Methyl 5-(1-methylethyl) 1,2,3,4-tetrahydro-2-hydroxy-6-methyl-4-(3-n itrophenyl)-2-phenyl-3,5-py ridined icarboxylate, Diethyl 2-(3-chlorophenyl)-1,2,3,4-tetrahydro-2-hydroxy-6-methyl-4-(3-n itrophenyl)-3,5-pyrid ined icarboxylate, Diethyl 2-(2-furanyl)-1,4-dihydro-6-methy1-4-(3-n itrophenyl)-3,5-pyr idinedicarboxylate, 3-Methyl 5-(1-methylethyl) 2-(difluoromethyl)-1,4-di-hydro-6-methyl-4-(3-n itrophenyl)-3,5-pyr idinedica rboxylate, 5-Cyclopentyl 3-methyl 2-(difluoromethyl)-1,4-dihydro-6-methyl-4-(2-methyl-3-n itrophenyl)-3 , 5-pyridinedicarboxylate, 3-Methyl 5-(1-methylethyl) 4-(2,3-dichlorophenyl)-2-(d ifluoromethyl)-1,4-dihydro-6-methyl-3,5- ^7=158 pyr idinedicarboxylate, Diethyl 2-(fluoromethyl)-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyr idinedicarboxylate, 3-(2-Methoxyethyl) 5-(1-methylethyl) 4 —(2,3— dichlorophenyl)-2-(d i fluoromethyl)-1,4-d ihydro-6-methy1-3,5-pyr id ined icarboxyla te, 3-(2-Methoxyethyl) 5-(1-methylethyl) 2-(difluoromethyl)-l,4-dihydro-6-methyl-4-(3-nitrophenyl) -3,5-pyr idinedicarboxyla te, Diethyl 4-(4-benzofurazanyl)-2-formyl-l,4-dihydro-6-(tr i fluoromethyl)-3,5-pyr idined icarboxylate, Diethyl 4-(4-benzofurazanyl)-1,4-dihydro-2-(hydroxymethyl)-6-tr ifluoromethyl-3,5-pyr idinedica rboxyla te, Diethyl 2- (fluoromethyl)-1,4-dihydro-6-hydroxymethyl -4-(3-n itrophenyl)-3,5-pyr idinedica rboxyla te, Die thyl 2-cyano-6-(fluoromethyl)-1,4-d ihydro-4-(3-n itrophenyl)-3,5-pyr idinedicarboxylate, Diethyl 2,6-di-(fluoromethyl)-1,4-dihydro-4-(3-nitrophenyl) -3,5-pyr idinedicarboxylate, (+) 3-Methyl 5-(1-methylethyl) 4-(2,3-dichlorophenyl)-2-(fluoromethyl)-1,4-di hydro-6-methyl-3,5-pyr idined icarboxyla te, 3-methyl 4-(2,3-dichlorophenyl)-2-(fluoromethyl)-l,4-dihydro-o-methyl-3,5-pyridinedicarboxylate, (-) 3-Methyl 5-(1-methylethyl) 4-(2,3-dichlorophenyl)-2-(fluoromethyl) -l,4-dihydro-6-methyl-3,5- - \'7 ^"TO^PICE ? 96 207958 » pyr idinedicarboxyla te, ( + ) 5-Cyclopentyl 3-methyl 4-(2,3-dichlorophenyl)-2-(fluoromethyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, or (fluoromethyl) -1,4-dihydro-6-methyl-3,5-pyr id ined icarboxylate.

8. A pharmaceutical formulation containing a compound according to any one of the preceding claims in admixture 10 with a pharmaceutically acceptable adjuvant, diluent or carr ier.

9. A process for the production of a compound of formula 15 I, as defined in Claim 1, or a pharmaceutically acceptable acid addition salt thereof, which comprises a) reaction of a compound of formula II, 5 (-) 5-Cyclopentyl 3-methyl 4-(2,3-dichlorophenyl)-2- R]lCHO with compounds of formulae III and IV, II 20 R2OOCCH=C(R?)NH2 R3OOCCH2CORg in which formulae R-^, R2, R3, R7 and Rg are III o as defined in Claim 1, b) reaction of a compound of formula V, 25 R1CH=C(COOR3)CORg V 97 in which R^, R^ and Rg are as defined in Claim 1, with a compound of formula III, c) production of a compound of formula I in which Y and Z together form a bond by dehydration of a compound of formula VII, in which R-^, R2, R3, R*^ and Rg are as defined in Claim 1, d) production of a compound of formula I in which m is 1 or p is 1 or 2 by selective oxidation of a corresponding compound of formula I in which m is 0, or p is 0 or 1 respect ively, e) production of a compound of formula I in which one of R7 and Rg is -CONR^gR^ by reaction of an acid halide, imidazole or a mixed anhydride of a corresponding compound of formula I in which one of R7 and Rg is -COOH with a compound HNR^R^ in which R10 and R-q are as defined in Claim 1, or, when the group -NR10R11 in the product represents an imidazole, reacting the free carboxylic acid of formula I with N,N'-carbonyIdiimidazole, VII h - 98 - 207958 . f) production of a compound of formula I in which one of R7 and Rg is -CSNH-, by reaction of a corresponding compound of formula I in which one of R^ and Rg is -CN with hydrogen sulphide, 5 g) isorae r is ing a 3,4-dihydropvridine to a corresponding compound of formula I, h) production of a compound of formula I in which one of R7 and Rg is -C(=NH)SRg b^ reaction of a corresponding compound of formula I in which one of R^

10 and Rg is -CSNH- with a compound Rg-hal, in which Rg is as defined in Claim 1 and hal is a halogen atom, i) reaction of a compound of formula IV with ammonia and a compound of formula VI, R1CH=C(COOR2)COR7 VI 15 or reaction of a compound of formula V with ammonia and a compound of formula VIII r2oocch2cor7 VIII or reaction of compounds of formulae II, IV and ; > 1 ( with ammonia, ' < 20 in which formulae R^, R2, R^, R7 and Rg are 16SEPI986' as defined in Claim 1, <. j) production of a compound of formula I in which Y and z together form a bond and one or both of R-, and rg is -CHF2 or -CH2F by reaction of a corresponding compound 25 of formula I in which Y and z together form a bond and one ~..I. .. v. ■- - . 207152 - 99 - . or both of R-j and Rg is -CHO or -CH2L, where L is -OH or a good leaving group, respectively with a fluorinating agent, k) production of a compound of formula I in which 5 R-j and Rg is -CHO by selective hydrolysis of a corresponding compound of formula I in which one of and Rg is -CH(OR9)2, 1) production of a compound of formula I in which R"7 and Rg is -CH2OH by selective reduction of a 10 corresponding compound of formula I in which one of and Rg is -CHO, m) production of a compound of formula I in which R7 and Rg is -CN by elimination of ROH from a corresponding compound of formula I in which one of 15 and Rg is -CH=NOR, and -OR is a good leaving group, n) production of a compound of formula I in which least one of R2 and R3 is hydrogen by reductive cleavage or hydrolysis of a corresponding compound of formula I in which at least one of R2 and R3 is other 20 than hydrogen, o) production of a compound of formula I in which at least one of R2 and R3 is other than hydrogen by ester ification or transesterification of a corresponding compound of formula I in which at least one of R2 and 25 R3 is hydrogen or is a group R2 or R3 other than one of R7 one of R7 one of R7 at - 100 - 20795® that desired in the end product, or p) production of an optical isomer of a compound of formula I by resolution of a mixture of optical isomers of the compound, and where desired or necessary converting the resulting compound of formula I to a pharmaceutically acceptable acid addition salt thereof or vice versa. 10. A compound of formula VII as defined in Claim 9.

11. A compound as claimed in any one of claims 1 to 7 and 10 substantially as hereinbefore described with reference to any example thereof.

12. A formulation as claimed in claim 8 substantially as hereinbefore described.

13. A process as claimed in claim 9- when performed substantially as hereinbefore described with reference to any example thereof.

14. A compound of formula I when prepared by a process as claimed in claim 9 or 13. A. J. PARK & SON PER AGENTS FOR TH" AFFt!CANTS