IE56384B1 - Dihydropyridines - Google Patents

Description

This Invention relates to certain dihydropyridine», specifically to certain 1,4-dihydropyridins* having a heterocyclic group In a side chain attached to the 2-posltlon, which have utility ss anti-ischaemic and antihypertensive agents.

The compounds of the Invention reduce the movement of celclub Into the cell and they are thus able to delay or prevent the cardiac contracture which Is believed to be caused hy an accumulation of Intracellular calciun under ischaemic conditions. Excessive calciun Influx during Ischaemia can have a number of IQ additional adverse effects which would further compromise the lschaealc myocardium. These Include less efficient nee of oxygen for ATP production, activation of mitochondrial fatty acid oxidation and possibly, promotion of cell necrosis. Thus the compounds are useful In the treatment or prevention of a variety of cardiac conditions, such as angina pectoris, cardiac arrythmlaa· heart attacks and cardiac hypertrophy. The compounds also hevs vasodilator activity sines they can Inhibit calcium Influx In cells of vascular tissue and they are thus also useful as antihypertensive agents sad for the treatment of coronary vasospasm. * Patent Specification No. describes aertain dihydrcpyridine calciun antagonists having a secondary or tertiary amino group at the end of a side chain attached to the 2-position.

According Co the present invention there are provided 5 dihydropyrldlnes of the formula:- and their pharmaceutically acceptable acid addition salts; wherein R is a phenyl group optionally substituted by one or two substituents each Independently selected from nitro, halo, C^-C^ alkyl, C^-C^ alkoxy, hydroxy, trifluoromethyl, and cyano; 2 R and R arc each Independently alkyl or 2-tnethoxyethyl; ' Y is -(C«2)2-; R^ Ir attached to the adjacent nitrogen atom by a carbon atom 15 and Is either (a) a monocyclic 5- or 6-membered heterocycle containing at least one N atom and optionally one or two further heteroatoms or groups each independently selected from 0 Φ T · O, S, S, N and N, and ls optionally substituted by Cj-C^ alkyl, Cj-C* alkoxy, halo, hydroxy, oxo, cyano, 3-(Cj-C^ aikyl)ureldo. -44 5 phenyl, phenoxy, pyridyl, acetyl, (Cj-n1koxy)carbonyl, -MR R , -SO2NRAR5 or -CONR'^R5 where either R4 and R5 arc each . independently fl or alkyl or R and R together with the nitrogen atom to which they are attached represent a saturated 5* or 6-membered heterocyclic group optionally containing a further heteroatom or group selected from 0» S, NH, N(Cj-C* alkyl) and ll NCHO; or (b) a bicyclic group which Is an optionally substituted - or 6-membered hcterocycle as defined in (a) fused to an ifoldnzole or benzene ring, said benzene ring being optionally substituted by Cj-Cg alkyl, Cj-C^ alkoxy or halo.

The pharmaceutically acceptable acid addition salts of the conpounds of the formula (1) are those formed from acids which form non-toxic acid addition salts, for example the hydrothloride, hydrobromide, sulphate or bisulphate, phosphate ot acid phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate and tartrate salts.

Halo means F, Cl, Rr or I.

Alkyl and alkoxy groupe having 3 or more carbon atoms can be straight or branched chpin.

R is preferably a phenyl group substituted by 1 or 2 substituents selected from halo and CF^. R Is more preferably 2-chlorophenyl, 2,3-dlchlorophenyl or 2-chloro-3-trlfluoromcthyphcnyl. R is most preferably 2,3-dichlorophenyl.

Preferably either R^ Is Cllj and R^ Is °r ^2^5 4n<^ r2 Is CH^. Most preferably, R^ Is CH^ and is C^H^. * - 5 3 R is preferably a heterocyclic group selected from triuzolyl, oxadiazolylt pyrimidinyl or a partially saturated derivative thereof, purlnyl, qulnazolinyl, Imidazolyl, imldazollnyl, triazinyl, pyridyl, thlazolyl, tlilazollnyl, * 5 benzthlazoly], thladiazolyl, pyrazlnyl, quinoxalinyl and pyrrolinyl, and their N* and S-oxides, R' being optionally V substituted by C^-C^ alkyl, C^-C^ alkoxy, halo, hydroxy, oxo, cyano, 3-methylureido, phenyl, phenoxy, pyridyl, acetyl, carbamoyl, N-methylcarbamoyl, (Cj-C^ alkoxy)carbonyl, -NR Ri , or 4 5 -SOgNR R , where either R and R are each Independently H or • 4 5 Cj-C^ alkyl or R and K together with the nitrogen atom to which they are attached form a piperldino, morpholino, 4-raethylpiperazin-l-yl or 4-formylpiperazin-l-yl group. - 6 l,2,4-Triazol-3-yl, l,2,4-oxadiaxol-3-yl, 1,2,5-thiadiazol3-yl, pyrisiidin-2-yl, pyriaidin-4-yl, iuidazol-2-yl, 1,3,5triazin-2-yl, pyrld-2-yl, thiazol-2-yl, pyrazin-2-yl and pyrrolin-2-yl, optionally substituted as above, represent typical 3 instances of R .

The most preferred individual heterocyclic groups represented 3 by R are as follows :- N — N ΛΛ M NH , B N—0 , a -C t H 0 ' N —rv Ό. .-Z-* -o xnh2 0 -0* · .SH %_/ · w -/% M · 0 0 P-- CHj 0 7Λ · ”^-/V H \ / 0CB3 • oca- o · Cl cc · -Q · 3 <] .-7- ο - 9 In sone of these groups tautomerism may occur, e.g.

In such cases both tautomers are within the scope of this invention.

In the preferred Individual compound, R Is 2,3-dichlorophenyl, R1 is CH^, R2 is C^H^, T is R— N The compounds of the formula (I) containing one or more asymmetric centres will exist as one or more pairs of enantiomers, end such pairs or Individual Isoners may be separable by physical methods, e.g. by fractional crystallisation of the free bases or suitable salts or chromatography of the free bases. The Invention Includes the separated pairs as well as mixtures thereof, as racemic mixtures or as separated optlcally-actlve isomeric forms.

The compounds of the Invention can be prepared by a number of routes, Including the following:-* (1) The compounds of the formula (I) can be prepared via the following route:V' CS.

RXOOC B (XX) COOR23 R . Q cb2owh2 - 10 Q le a facile leaving group, such as -NH.RO^, alkylthio, C^-C* alkoxy, Cl* Br or I. Q la preferably methylthio, methoxy, ethoxy, chloro or nltrosmlno.

The reaction la typically carried out by heating the 5 reactants at 50-^130^0, e.g. under reflux, In a suitable organic solvent until the reaction la substantially complete. Typical organic solvents include methanol, ethanol, w-butanol, acetonitrile, dimethylformamide (DMF), methylene chloride, etc. Whan Q la alkylthio, Cl, Br or 1, tha presence of a base such as triethylamine· sodium carbonate or 4-dlmethylamlnopyrldine Is preferred. The product (I) can then he Isolated aOd purified conventionally The starting materials of the formula (II) are the subject matter of our Patent Specification Ho. ¢.--/,/.

Some typical methods for their preparation are however described In the Preparations hereinafter.

As disclosed In. the said Patent Specification, a typical route to the Intermediates (II) is as follows:20 (a) HO-Y-N3 + ( COOR + R. CHO + 0>) (II) An alternative route to the lntemedlatee (II) ie as follows:(a) V (II) Preparations 16 and 17 describe particularly useful routes to 2,3-dlchlorobenzaldehyde and 2-chloro~3-trlfluoronethylbensaldehyde. 2H3UQro^3“43diluoraiethylbenzald^iyde Is the subject of EP-A-0 145 334. (2) Compounds In which R3 Is N H , ζ ° MB2 ji nh2 H ίι ^V-^AnAh, H X Is -SCH^, -OCH^ or -0.Phenyl.

These reactions are typically carried out In a suitable organic solvent such ae we thanol, ethanol, acetonitrile or tetrahydrofuran, with heating If necessary at up to 130*C and preferably under reflux. Heating is preferred when ethanol is used as the solvent. The reaction is generally conplete ln about 4 hours. The desired product can then be isolated and purified conventionally. - 14 The starting materials of the fomula (III) can he prepared from compounds of the formula (II) [see route (1) above] as follows2/wCH^OYHB^ ,CN X-C-X, (II) N.CH II ^«-CHjO-Y-H-C-X Isopropanol or methanol, room temperature, 4 hours. »· (3) Compounds In which R^ Is can be prepared from the compounds of the fomula (II) ae follows:rcnr-CH2OYNH2 Cl.CH-CH.NCSnr CHj-O-Y-H·^ (II) s The reaction Is typically carried out by stirring the reactants together In a suitable organic solvent, e.g. methylene chloride, for a few hours, and again the product can then he Isolated and purified conventionally. The presence of base la the reaction mixture, e.g. trlethylsmlae, Is preferred. - 15 (4) Compounds In which κ Is COOCC,-C. alkyl) Λ -σ - -0· <1 can he prepared as follows:“ίϊ COGR CHj ' N CS2CS0f-C-MB2 ci.cb2cho H (IV) orsr^ajGasr (iv) BtCHzCrcoQ-CCfS alky1) or CICHjCOCOO.(C1-C4 alkyl) COO(CX-C4 alkyl) (IV) alkyl) or BrCH2CO(C1-C4 alkyl) ch2oyh <1 Cx-C4 alkyl) (IV) BlCa2C0°8t CICHjCOOEt CHjOTOThe reaction le typically carried out hy stirring the reactants together at room temperature In a suitable solvent, e.g. CHCl^/CHgOH, until the reaction is substantially complete. If necessary, the reaction mixture can be heated to accelerate the reaction. The product can be Isolated conventionally. - 16 The. starting materials of the fornula (IV) can be prepared fron the conpounds of the fornula (IX) as follows:rw-CH2OYNH2 S ct-CrSl.

..^—CBjOTK-C-S (II) CaCO^t CH2C12/H2O, roon tenperature NH3/EtOHt heat, 2¼ hours I iwCHjOraCMHj i- _/ Ύ (IT) can he prepared aa (5) Compounds ln which R follows:/v^Hm2oriw4-»Hco2c2H5 ρ ch3i *w*ch2othh-^ T . 11) hydrazine N H hydrate The starting ethozycarhonylthloureldo derivatives can be prepared as follows:rwv-CH2OTNH2 S-C-H-CO^Et^ ctw-CH^OYNH-C-HHCOjC^ - 17 (6) Compounds In which R Is -Q ? '^COCH. and IS can ha prepared by the reaction, of the corresponding amino 3 compound (R H) with 5-acetyl-2-aaino-oxa«ole In aqueous methanol, typically by heating for 24 hours or so. The reaction 3 producea a mixture of two products having R as above. These can be separated by conventional chromatographic procedures. (7) Some of the compounds of the formula (I) can’ be prepared from other compounds of the formula (I), e.g., those where R ls e heterocyclic group substituted by an [C^-C^ alkyl] carbamoyl group can be prepared by the reaction of the corresponding compounds ln which the heterocyclic group Is substituted by (C]~C* alkoxy)carbonyl with a Cj-C* alkylamina. Similarly, compounds ln which R3 is substituted by -Iffig can be prepared by reacting the corresponding methoxy-substltuted derivatives with ammonia, generally ln ethanol, and compounds ln which R^ Is substituted by -NBCONH(C^-C^ alkyl) by reaction of tbe corresponding amino-substituted compound with a C^-C^ elkylleocyanate.

Compounds in which R is a heterocyclic group substituted by an amino or substituted amino group, or a cyclic amino group, e.g. morpholine, piperidino or N-methyl plperazlno, can be prepared by heating the corresponding chloro-substltuted compound with the appropriate amine.

Compounds in which R Is pyrazinyl can be prepared by the reduction of the corresponding compound ln which R ls a pyrazlne-N-oxlde with sodium dlthlonite, e.g. by heating ln aqueous ethanol. - 18 and (8) Acid addition salts can be prepared conventionally, e.g. by reacting a solution of the free base in a suitable organic solvent with a solution of the desired acid in a suitable solvent, and either recovering the salt by filtration when It precipitates from solution, or by evaporation of the solution to dryness.

The ability of the compounds to inhibit the movement of calcium Into the cell la shown by their effectiveness in reducing the response of Isolated heart tissue to an Increase In calcium ion concentration in vitro. The teat ia performed by mounting spirally cut stripe of rat aorta with one end fixed and the other attached to a force transducer. The tissue Is lnswrsed In a hath of physiological saline solution containing potassium lone at a concentration of 45 allllmolar and no calcium. Calcium chloride la added to the bath with a pipette to give a final calcium Ion concentration of 2 mllllmolar. The change In tension caused hy the resulting contraction of the tissue la noted. The hath is drained and replaced with fresh saline solution and, after 45 minutes, the teat la repeated with the particular compound under test present In the saline solution. The concentration of compound required to reduce the response hy SOX (ΙΟ^θ) la recorded.

The antihypertensive activity of the compounds Is also evaluated after oral administration by measuring the fall in blood pressure in spontaneously hypertensive rats or renally hypertensive dogs. - 19 For administration to nan in the curative or prophylactic treatment of cardiac conditions and hypertension· oral dosage· of the compounds will he in the range of from 5-100 mg dally for an average adult patient (70 hg), typically 10-60 ng dally. Thus for a typical adult patient. Individual tablets or capsules will generally contain from 5, 10 or 20 mg of active compound. In a suitable pharmaceutically acceptable vehicle or carrier. Dosages for Intravenous administration will typically be within the range 1 to 10 mg per single dose ss required. In practice the physician will determine the actual dosage which Will be most suitable for en individual patient and It will vary with the age, weight and response of the particular patient. The above dosages ate exemplary of the average case but there can, of course, be Individual Instances where higher or lower dosages ranges are merited, and such are within the scope of this Invention.

For human use, the compounds of the formula (I) can be administered alone, but will generally be administered In admixture with a pharmaceutical carrier selected with regard to the-Intended route of administration and standard pharmaceutical 2(T practice. For example, they may he administered orally ln the form of tablets containing such excipients as starch or lacto··» or ln capsules or ovules either alone or ln admixture with excipients» or In the form of elixirs or suspensions containing flavouring or colouring agents. They may he Injected parenterally, for example. Intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used - 20 ln the fora of a sterile aqueous solution which nay contain other substances, for example, enough salts or glucose to make the . solution Isotonic.

Thus ln a further aspect the Invention provides a 5 pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable diluent or carrier.

The invention also includes a compound of the fornula (I), or a pharmaceutically acceptable acid addition salt thereof, for use In medicine, In particular in the treatment of Ischaemic heart disease, angina, or hypertension in a human being. -21 The following Examples Illustrate the Invention. All temperatures are In *C:EXAMPLE 1 A. H-^2-[ (4-^2-ChloTOphenyl^-3-ethoxycarhonyl-5-nethoxycarhonyl^HMthyl^l^A^diig^drogxrid^gj^JmrthflacyJethg^^jB^ cyano-S-nethyl-iaothiourea MCW W-C-SMe B 2-(2-Arnlnoethoxymethyl]-3-ethoxycarhonyl-4-(2-chlorophenyl}-5-aethoxycarbonyl-6-*«ethyl-l,4-dlfaydropyrldlne (4.3 g) and dimethyl B-cyanolmldodlthlocarbonate (2 g) In isopropanol (15 ml) wdre allowed to stand at room temperature for 4 hours. Ether (30 ul) was then added and the mixture vas stood at room temperature overnight. The crystalline precipitate vas filtered, washed with ether snd dried, yield of the title compound 5.0 g, m.p. 177-179*.

Analysis XsFound: C»54.35; H.5.4; N.11.2 Calculated for C^H^GIB^S: C.54.5; H.5.4; H,11.05. * Β. 2-(2- (3-Amlno-1,2,4-trlaaol-5^ lamino) etbOxymathyl] -4- (2chlorophenyl)-3-athoxy carbony 1-5-methoxy carbony l-6~methyl-1.4dlhydropyrldlne N- £2-1 (4-£ 2~€hlorophe&y 1^ -3-ethoxycarbony 1-5-methoxycarbonyl-6-methyl-l,4-dihydropyrid-2-yl)m6thOxy]ethyl^ -B'-cyaaoS-matfayl-iaothlourea (0.4 g) and hydrazine hydrate (0.15 al) «ere dissolved in ethanol (20 ml) and heated under reflux for 3 hours. The solvent was then evaporated and toluene (10 ml) wee added to the residue, and again the eolation was evaporated to dfyneae.

The residua was chromatographed on Merck Kleselgel 60H (Tirade Mark), eluting with 2X methanol ln methylene chloride, to give a beige solid. The solid waa recrystalllaed froa ethyl acetate plus a trace of ether to give the title Compound, yield 0.1 g, m.p. 137-138°.

Analysis' Z;Foundi C.53.45; H.5.5; 8,17.2 Calculated for C22H27C1N6O5: c>53·8’» H.5.55; 8,17.1. - 23 Part (A) was repeated using (MeO^ON.CN In place of (MeS^ON.CH and using the sane reaction conditions. The resulting Intermediate had -OKe In place of -Site, and this intermediate was converted by the method of part (B), i.e. using hydrazine hydrate, to the title compound of part (B).

* EXAMPLE 2 2-L2-(3-Amlno-lf2,4-Ltiiazol-5-ylainlir>)ethc»cymethyl]-4-(2-chloro·3 - trifluoromethylphenyl)-3-ethozycarbonyl.-5-methoXycarbonyl-6-methy1-1,4-dihydropyridine 2-(2-Amlnoethoxymetfayl)-4-(2-chloro-3-trlfluoroomthyl-phenyl)-3etho^cailxxyl-S-iiBtiwo^carixMiYl-e^inethyl-l ,4-dlhydix^jyridine ¢0.5 g) and dimethyl N-cyanolmldodlthlocarbonate (0.16 g) In 15 Isopropanol (5 ml) were stirred together at room tenperature for 4 hours. Ether (10 ml) was then added and the mixture was stirred for a further 2 hours. The precipitated isothlourea was filtered, washed with dry ether, dried and used directly without further - 24 purification. The solid was dissolved In ethanol (10 al) and heated to reflux while hydrazine hydrate (C.2 ml) vas added ln three portions. After 3 hours at reflux, ths solution vas evaporated to dryness and the residue was crystallised fron ethyl acetate to give the title,conpound, n.p. 144-145*.

Analysis XsFound: C,49.4; H,4.7; N.15.0 Calculated for C23H26C1F3N6O5: C.49.6; H,4.7; N.15.0.

EXAMFLE3 A. The following compound, n.p. 215-217*. was prepared similarly to Example IA, hut starting from the corresponding 4-(2,3-dichloropheny1)-1,4-dlhydropyrldyl derivative: Analysis X:Found: C.50.7; H.5.05; Ν.10.1 Calculated for c23H26CX2N4°5SiC’51.02s H.4.85; Ν,ΙΟ.35. - 25 Β. This conpound was then reacted with hydrazine hydrate according to the procedure of Example IB to produce the following product, m.p. 195-6’:- Analysis X:Found: C.50.2; H.5.35; H.15.6 Calculated for C22H26Cl2M605.l/4 C4H8O2: C.50.45; H.5.15; ».15.35.

EXAMPLE 4 The following conpound, m.p. 110-111*, Was prepared similarly to Example IB, hut using methyl hydraslne:- Analysls X:Found: C.54.1; H.5.8; »,16.3 Calculated for C^^ClN^.MLjOi C,53.7; H.5.9; 16.35. — 26 — EXAMPLE 5 The following compound m.p. 118-120.5’ was prepared similarly to Example 3B. hut .using methyl hydrazine:- Analyeia X;Found: C.50.6; H.5.3; N.15.0 Calculated for G23H28C12N6°5,,aH20: c>50*4· H.5.3; M.15.3.

EXAMPLE 6 2-[ 2- (5-Aalno-l, 2,4-oxadlaaol-3-y lamlno) ethogymethyII-4- ( 2-ghlorophenyl)-3-ethoxycarhonyl-5-methoxycarhonyl-6-mfethyl-l>4-dihydro- < 5 - 27 10 The N'-cyano~S-metfayl-lsothlourea from Example IA (0.4 g) end hydroxylamine (0.2 g) In methanol (20 ml) were heated under reflux for 3 hours. The solvent wee then evaporated, and the residue was chromatographed on Kleselgel 60H (Trade Mark), eluting with chloroform to give a solid which was recrystallised from 1:1 toluene/ether to give the title compound, yield 0.29 g, m.p· 135*.

Analysis,,X:Found: C,53.8; H,5.4; H,14.25 Calculated for C^B^CIM^: C.53.7; H.5.3; 11,14.25.

EXAMPLE 7 The following compound, m.p. 114*, was prepared similarly to the procedure of Example 6 but using the corresponding 2-chloro-3-trifluoromethyl isothiourea Intermediate as prepared In Example 2:- Analyala X;Found: C.49.6; H,4.7; N.12.4 Calculated for C23H25C1F3H5O6: C.49.3; H.4.5; N.12.5.

EXAMPLE 8 4-(2-Chlorophenyl)-3-ethoxy carbony 1-5-scthoxy carbony 1-6-maChy 1-2[ 2- (3,4-dlhydro-4-oxo-pyrlmldln-2-y lamino) athoxynethy1]-1,4-dlhydropyrldlne Η O 2^[2-Amlnoethoxymethyl]-3-ethoxy carbonyl-4-(2-chloropheny 1)S-methoxycarbonyl-6*methy 1-1,4-dlhydropyrldlne (0.75 g) aad 2-eethylthlo-3H-pyrlAid-4-one (0.5 g) were dissolved in ethanol (5 ml) and heated under reflux for 20 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with 28 hydrochloric acid to remove any unreacted amine, and then with dilute sodium hydroxide solution. It was then washed with water, dried, filtered and evaporated to give a yellow gum· Chromatography on silica Kleaelgel 60H (Trade Mark) eluting with ethyl acetate gave the title compound, which was recryetalllsed from ethyl acetate, yield 171 mg, m.p, 148-150*.

Analysis X:Found: C,57.3; H,5.55; 8,11.4 Calculated for C24H27C1H4O6: c»57-35 H»5.4; ».11.15. - 29 EXAMPLES 9-36 The following compounds were prepared similarly co the previous Example, i.e., by the following reaction:- Example Mo. R3 Q Reaction Solvent Base Reaction Time Form Isolated m.p. <*c) Analysis X (Theoretical in brackets) C H N 9 M —- -< N —' H k 0 MeS- EtOH Et3N 4 hrs. Free base 155- 157 55.8 (56.25 5.55 5.55 11.3 11.4) 10 N — Cl CRjCH «a2CO3 6 hrs. Free base 137 59.05 (59.2 5.7 5.6 11.3 11.5) 11 nh2 N HH2 Cl MeOH it3» 12 hrs. Free base . 186- 189 53.25 (53.3 5.5 5.45 18.6 18.9) r r Example Ho. R3 Q Reaction Solvent Base Reaction Tina Form Isolated B.p. CC) Analysis Z (Theoretical in brackets) C H K 12 0 f-t AJ“ ci n-BuOH Bt3M 60 hrs. Free base 225 56.5 (57.35 5.4 5.4 11.05 11.15) . 13 J-C2 Λ_7 Cl n-BuOH Bt3H 60 hrs. Free base 172- 174 57.2 (57.4 5.8 5.6 13.8 13.95) 14 _/*-v -C” Cl n-BuOH Et3N 18 hrs. > Free base 120- 122 56.9 (57.35 5.3 5.4 10.9 11.15) 0 15 J-Λ0 Λ,^Γ* Me ° Cl n-BuOH EtjN IB hre. Free base, h2o 122 55.2 (55.25 5.85 5.9 9.8 9.9) Example No. R3 Q Reaction Solvent Base Reaction Time Form Isolated m.p. CC) Analysis X (Theoretical In brackets) C H N 16 Cl c«3cn Ma2CO3 5 hrs. Free base 153- 155 56.9 (57.0 5.15 5.2 15.9 15.95) N^NH a o Λ-\_ 17 '.-Q·. Cl n-BoOH *t3« 20 hrs. Free base 205- 207 57.35 (58.8 5.3 5.4 8.9 9.15) OMe 18 o Cl Cl MeOH Et3N 2 hrs. Free baae 160 55.35 (55.3 5.2 5.0 10.9 10.75) 19 <0 Cl D.M.F. »a2CO3 5 tors. Free base 176- 177 59.75 (59.8 5.4 5.2 7.55 7.75) Example No. R3 Q ’ Reaction Solvent Base Reaction Time Form Isolated m.p. CC) Analyeia Z (Theoretical In brackets) C Η N 20 -U -OEt EtOH - 3¼ hra. Hydro- chloride 166- 167 56.2 6.15 8.35 (56.25 6.1 8.2) 21 1 1 s s^^se ί L_J 1 !__ -SMe EtOH Et3N 6 hr a. Acetate 164 55.05 6.15 10.45 ¢55.9 6.2 10.45) 22 XT Cl n-BuOH 4- dlmethyl- amlno- pyrldlne 18 hra. Maleate 2.H2° 156- 158 53.9 5.1 8.4 ¢53.85 5.0 8.3) 23 . CH, n-4.cn -g 8 -° -SMe ' EtOH Et3N 1 hr. Free base 226- 228 57.5 6.0 10.8 <57.8 6.0 10.8) Example No. R3 Q ReacClon Solvent Base Reaction Time Form Isolated m.p. CO Analysis X (Theoretical in brackets) C H N 24CH3 -Q -ΝΉΝΟ2 n-BuOH - 18 hrs. Keml-fumarate 197- 199(d) 56.3 (56.4 5.4 5.4 9.8 9.7) • H 25 CONHo o -Cl n-BuOH 4-dlmethyl· amino- pyridine 18 hrs. Maleate 163.5- 164 56.0 ¢56.1 5.1 4.7 8.6 8.7) 26s -Γ’Ό 45 -Cl n-BuOH 4-d lmethyl* amlno- pyrldlne 24 hre. Free base 125 50.1 (50.1 5.1 5.2 9.1 9.3) 27 NIL Y5 Cl n-BuOH Et3H 60 hre. Free baae Heml-etherate 101- 104 57.7 ¢57.9 6.2 6.2 12.9 13.0) Exanple No. R3 Q Reaction Solvent Base Reaction Time Form Isolated m.p. CO Analysis X (Theoretical In brackets) CBN 28 -Q CN -Cl n-BuOB l-dlaethyl- inlno- pyrldlne 20 hre. Free base 133- 134 58.4 5.2 13.3 <58.7 5.1 13.7) 29 45 C0NN2 -Cl n-BuOH b-dlmethyl- ralno- pyrldlne 4 hrs. Free base 211 56.5 5.3 13.0 (56.7 5.3 13.2) 30 V -Cl n-BuOB 4-dimethylamlnopyridIne 18 hrs. Jj. Ethyl acetate 124- 126 57.4 5.8 10.0 (57.8 5.6 10.0) 31 -1 _Ld Cl ch2ci2 EtjN 26 hours Free base 115 55.1 5.1 10.6 (55.3 5.0 10.75) 32 Cl Cl EtOH Et3N 18 hours Free bass 110 55.4 5.35 10.4 (55.3 5.0 10.75) Example Mo. R1 q Reaction Solvent 1 Base I faction Me. I —j Isolated m.p. CP) 1 Analysis Z (Theoretical in brackets) 0 H M 33 Cl EtOH EtgM 18 hours free bee. M2* 144 55.3 (55.3 4.9 5.0 10.6 10.75) 34 Cl BuOH 4-DImethy] amino pyridine 18 hours Free t»«ee 172- 173 58.4 (58.9 5.8 5.6 11.5 11.4) 35 Ο”Λ Cl BuOH . Et3N 48 hours Free f>ase 165- 168 53.5 (53.1 5.25 5.2 9.8 9.9) 36 £^°2{}-CH( 3 Cl EtOH Et3N 60 hours Healhydrate 165- 167 53.9 (53.8 5.5 5.6 10.75 10.45) - 37 EXAMPLES 37-57 The following compounds were prepared similarly to Example 8, I.e. by the following reaction:- NB.R , and were characterised ln the form Indicated: Example No. R3 Q Reaction Solvent Base Reaction Time Form isolated m.p. (°C) Analysis X (Theoretical In brackets) C H . N 37 -Q H -SMe EtOH Et3N 3 hra. Hemlhydrate 218 (d) 51.7 (51.7 5.0 5.1 10.3 10.5) 38 73 γ/-, Η O -SMe EtOH Et3N 22 hrs. Free base 225- 227 53.2 (53.4 5.4 5.6 10.0 10.0) 39 -Q Η O -SMe EtOH Et N 24 hrs. Hemlhydrate 142- 145 52.5 (52.7 4.7 5.0 10.4 10.3) 40 “ . 1 1 1 -Cl n-BuOH Et M 36 hrs. Free base 179 53.5 (53.7 5.2 5.1 13.0 13.1) Example No. R3 Q Reaction Solvent Base Reaction Time Form Isolated m.p. CC) Analysis Z (Theoretical In brackets) C H N y 41 -/1. -Cl n-BuOH l-dlmethyl- aalno- pyrldlne 30 hrs. Free base heml-hydrate 132- 134 52.9 (52.75 4.8 5.0 10.5 10.3) 42 z Η Ό -NHNOg n-BuOH - 18 hrs. Fumarate 144- 146 52.4 (52.2 4.9 4.8 8.6 8.4) 43 Υ» -nhno2 BuOH - 16 hours Free base 201 56.3 (56.0 4.7 4.8 7.7 8.1) 44 l%yN -*A U_ S___ -nhno2 1 V BuOH - 18 hours Free base 205- 206 56.65 (56.7 4.9 4.8 11.0 11.4) Example No. 45 0 Reaction Solvent Base Reaction Time Form Isolated m.p. CC) Analysis Z (Theoretical In brackets) C H N Cl BuOH Et3H L8 hours Free base 177.5- 178.5 51.7 (52.0 5.1 5.1 8.5 8.4) 46 r °D Cl BuOH 4-Dlmethyl amino pyridine 32 hours Sesqul-hydrate 182- 183.5 51.7 (51.9 5.3 5.7 7.9 8.1) 47 O'- Cl EtOH Et3M 66 hours Free base 101- 104 51.55 (51.7 5.3 5.1 9.0 9.0) 48 λ J^2 N Cl BuOH 4-DlmethyL amino pyridine 18 hours Free base 190 55.6 (55.7 5.2 5.15 10.6 10.8) 49 i Cl ( Cl EtOH Et3M 18 hours Free base 101- 103 55.2 (55.5 4.6 5.0 9.00 9.25) * < Example No. R3 Q Reaction Solvent Base Reaction Time Form Isolated m.p. CO • Analysis Z (Theoretical in brackets) C H N 50 o Cl EtOH Et3N 17 hours Free base 148- 150 53.5 (53.6 5.0 4.9 10.4 10.4) 51 'Ό Cl EtOH Et3N 18 hours Free base 111- 112 51.6 (51.9 4.3 4.5 10.2 10.1) 52 XX. Cl EtOH Et3N 18 hours Free base 113- 115 51.8 (51.9 4.6 4.5 10.0 10.1) 53 ύ Cl EtOH Et3R 4 hours Free base 110 51.7 (51.9 4.5 4.5 9.9 10.1) 1- 1 : I . .* I I_1 H^N O^och3 Cl BuOH EtjK 48 hours Free base 162- 164 56.8 (57.0 4.8 5.3 9.2 9.2) Exanple No. 55 R3 Cu5 Q Reaction Solvent Base Reaction Tine Fora Isolated m.p. Cc) Analysis Z (Theoretical In brackets) C H N Cl BuOH Et3N 10 hours Free base 146- 148 58.4 (58.7 5.0 4.9 9.3 9.1) 56 o Cl BuOH Et3N 7 hours Free base 158- 160 55.5 (55.3 5.0 5.0 10.9 10.75) 57 -^NX^OiPr Cl BuOB Et3H 17 hours Free base 137- 139 55.8 (56.0 5.7 5.6 9.8 9.7) - 43 EXAMPLES 58-63 The following compounds were prepared similarly to Example 8, and were characterised In the form Indicated:- Example No. R3 Q Reaction Solvent Base Reaction- Time Form Isolated m.p. . CC) Analysis X (Theoretical In brackets) C H K 58 -O -SMe EtOH ec3n 4 hours fiemlhydrate 206- 208 50.4 (50.75 4.7 4.8 9.7 9.9) 59 73 -SMe EtOH - 24 hours Free Base 139- 140 52.6 (52.6 4.6 4.6 9.85 9.8) 60 7j“ -Cl n-BuOH 4-dimathyl- aalno- pyrldlne 24 hra. Free Base 135- 136 52.3 (52.6 4.6 4.6 9.7 9.8) 61 -NH.N02 n-BuOH - 18 hours Free Base 147- 149 53.5 (53.4 5.2 4.8 9.4 9.6) Example No. R3 Q Reaction Solvent Base Reaction Time Form Isolated m.p· Cc) Analysis Z .(Theoretical la brackets) C H N 62 ύ -SMe n-BuOH - 72 hours Free Base 128- 130 52,2 (52.6 4.7 4.6 9.9 9.8) 63 Ci' -Cl DHF - 24 hours HCl.t^O175 50.4 (50.5 4.5 4.7 8.2 8.7) EXAMPLE 64 3- ^2-((4- ^2,3-Dlchlorophenyl^ -3-ethoxycarbonyl-5rmethoxycarbonyl-6-methyl-l,4-dlhydropyrid*-2-yl)inathoxy] ethylamino^ -4* nethoxy-1,2,5-thladla«ole-l-oxlde O 2-( 2-Amlnoethoxymethyl] -3-ethoxycarbony 1-4- (2,3-dlchloropheay 1) -5-methoxycarbony1-6-netfay 1-1,4-dlhydropyrldlne (0.5 g) and 3,4-dlaMthoxy-l,2,5-thledlazole-l-oxlde (0.2 g) were dissolved ln methanol (15 al) and heated at reflux for 14 hours. The solvent was evaporated end the residue chromatographed on silica Kleselgel 60H (Trade Mark), eluting with ethyl acetate. The product-containing fractions were combined and evaporated to give an oil which waa triturated ln ethyl acetate to give the title compound as a solid, yield 0.14 g, m.p. 183-185°. -t - 47 Analysis X:Found: C,48.1; H,4.6; N,9.4 Calculated for C23H26C12N4°7S5C’48,15; H.4.55; N.9.75.

EXAMPLE 65 The following compound, m.p. 158-160*, was prepared similarly to the previous Example, starting from the corresponding 4-(2chlorophenyl )-1,4 -dihydropyridine and 3,4-dlmethoxy-l .2,5thladlazole-l-oxide. The reaction time was 18 hours, and the solvent methanol:10 Analysis X;Found: C,52.0; H,5.4; Ν,ΙΟ.1; Calculated for C23H27CXH4°7S: C,51.25; H.5.0; N,10.4.

EXAMPLE 66 The following compound, m.p. 139-141°, was prepared similarly to Example 64, starting from the corresponding 4- (2-ctilaro-3trlfluoromethylphenyl)-l,4-dlhydropyrldlne and 3,4-dlmethoxy1,2,5-thladlazole-l-oxlde. The reaction time was 18 hours, and the solvent methanol:-48 - Analysis X:Found: C.47.3; H,4.4; N,9.4 Calculated for C24H26ClF3N407S: c·47·5; H,4.3; N.9.2.

EXAMPLE 67 3-^2- [ (4-fe, 3-Dichlo ropheny 3^-3-ethoxycarbonyl-5-aethoxycarbonyl·· 6-methy 1-1,4-dihydropyrld-2-yl)aethoxy ] ethy lamino^ -4-amino1,2,5-thiadiazole-l-oxide hemlhydrate . ΛΗ2ο - 49 3-J-2-[ (4- &,3-Dichlorophenyl} -3-ethaxycarbonyl-5-sMthoxycarbony 1-6-me thy 1-1 · 4-dihydropyr id-2-yl)methoxy ] ethylamino^ -4-me thoxy-1,2,5-thladlasole-1-oxlde (0.3 g) was dissolved In ethanolic ammonia (10 ml) and stirred at room temperature for 1 hour. The solvent was evaporated and the residue chromatographed on silica ^Kleselgel 60H*· (Trade Mark), «luting with ethyl acetate. The product containing fractions were combined and evaporated to give en oil which wee triturated with ethyl acetate to give the title compound ae a solid, yield 0.15 g, m.p. 135*.

Analysis t:Found: C.46.6; H.4.6; 11,12.1 Calculated for C^^Cl^O^.M^O: C.46.6; H,4.6; N.12.3.

EXAMPLE,68 The foilowing compound, m.p. 130*, was prepared similarly to theprevious Example, starting from the corresponding 2-chlorophenyl compound and amxmla/EtOH. The reaction time wae 1.5 hours:- 2’ - 50 Analysis ZsFound: C.50.4; H.5.3; 11,13.3 Calculated for C^H^ClH^Sr. C.50.4; H.5.0; 11,13.4.

EXAMPLE 69 The following compound, m.p. 142-145°, waa prepared similarly to Example 67, starting from the corresponding 2-chloro*3~ trlfluoromethylphenyl compound and amaonla/ethanol. Tha reaction time waa ona hour:- Analysis XiFound:. C,45.6; H.4.5; N,11.6; Calculated for C^H^ClF^OgSs^O: C.46.0; H.4.4; tf.11.65. - 51 EXAMPLE 70 4“(2-Chlorophenyl)-3-ethoxy carbony 1-5-mathoxycarbony 1-6-nethyl2-[2-<2-thlaaolin-2-ylanlno)ethoxynethyl]-l,4-dlhydropyrldlna , 2-[2-Amlnoethoxymethyl]-3~ethoxycarbonyl-4-(2-chloro* phenyl)-5-methoxycarhonyl-6-methyl-l,4-dihydropyrldlne (0.5 g), triethylamine (0.3 ml) and 2-chloroethylleothlocyanate (0.16 ml) were dissolved in methylene chloride (5 ml) and the mixture was stirred at room temperature for 2 hours. The mixture wae then washed with water (5 ml), dried, filtered and evaporated to give a gum. - Chromatography of the gum oa allies Kleselgel 60H (Trade Mark) eluting Initially with toluene then with chloroform with a trace of methanol gave the title compound, which wae recrystallised from ether, yield 0.102 g, m.p. 145-147*.

Analysis XiFound: C,55.6; H.5.75; 11,8.3 Calculated for C^H^CU^OjS: C,55.6; H.5.75; 11,8.3. - 52 EXAMPLE Μ 4-(2-Chloropheuyl)-3-athoxycarbonyl-5-methosycarbonyl-€-nathyl-2[ 2-( thlasol-2^y laad.no) ethoxy—thy 1] -1,4-dlhydropyrldlne (a) Thlophoegene (0.9 ml) wae added to a stirred mixture of 2-(2-aminoethoxymethyl)-3-ethoxycarbonyl-4-(2-chlorophenyl)-5-SMSthoxycarbonyl^6-emtfayl-l,4-dlhydropyrldlxie (4.08 g) and powdered calcium carbonate (3 g) In methylene chloride (25 al) and water (35 ml). The mixture was stirred overnight at room temperature, filtered,, and partitioned between 2H hydrochloric acid and methylene chloride. The organic layer wee washed with water, dried (NagCOp, filtered end evaporated to give the Intermediate Isothiocyanate as a solid. - 53 This solid was used directly In the next stage of the reaction without further purification. (b) The isothiocyanate from pert (a) (4 g) wee heated in ethanolic ammonia solution for 2¼ hours. The resulting precipitate was filtered and recryetalllsed from ethanol/methylene chloride (5:1) to give the Intermediate thiourea, yield 3.8 g, m.p. 203.5-204.5°.

Analysis ZsFound: C,53.3; H.5.5; 8,8.6 Calculated for Cj^^H^ClO^S: C,53.8; H.5.6; 8,,8.9. (c) The thiourea from pert (h) (0.2 g) and chloroacetaldehyde (0.1 g) were dissolved la a 1:1 mixture of chloro fora/methanol end the mixture waa stirred et room temperature overnight. Removal of the solvent by evaporation left an oil to which toluene (10 ml) wee added. After removal of the toluene by evaporation the residue wee chromatographed on silica (Kleselgel 60H (Trade Mark)]. Elution with toluene, ethyl acetate and finally ethyl acetate/IZ methanol afforded a white solid which was recryetalllsed from ether to give the title compound, yield 0.075 g, m.p. 134*.

Analysis Z:Found; C.56.0; H,5.4; N,8.4 Calculated for C23H26C11I3O55! c·56’15» H,5.3; 8,8.5.

EXAMPLES 72-74 The following conpounds were prepared similarly to the method described ln part (c) of the previous Example, starting from the seme Intermediate thiourea and, respectively, CICH^COCH^, ' BrCHjCOOOOBt and SrCB^COOEt. ca3ooc, Cl coast CB B -a’ Example No. R3 Reaction Solvent Reaction Time m.p. CC) Analysis Z (Theoretical ln brackets) C H N 72 Γ' 5:1:0.5 CH,G17: MeOH: Et3N 3 hre., reflux temp. 147* 56.7 (56.95 5.75 5.6 8.05 8.3) 73 N— Γ 10:1:0.5 CHC1-: MeOHT Bt3N 18 hre., room temp. 129- 131* 55.3 (55.35 5.75 5.35 7.15 7.45) 74 N — 0 r 100:11 12 hrs., room temp. 160- 162* 54.1 (54.4 5.2 5.2 8.1 8.3) EXAMPLE 75 The following compound· m.p. 190-192° waa prepared similarly to Example 7A but starting from the corresponding 4-(2-chloro3H^fluorcmet±ylphenyl)-l,4-dihYdrapyri0ine and without isolation of. the Intermediates. The reaction time waa 20 hours:- Analysis XsFound: C.50.1; H,4.3; H.7.1 Calculated for C24H25Clr3H3°6S: C.50.0; H.4.4; »,7.3« EXAMPLE 76 Preparation of 4-(2,3-Dichlorophanyl)-3-ethoxycarbony 1-5-mathoxy· carbony1-6-methy1-2-12- (4-oxo-2-thiagollP-2-ylami.no) et hoxymethyl]-l,4-dlhydropyridina Cl ^C1 ®3°Λ rl <CO2C2H: II I] CH2o-a - 57 The title compound, m.p. 204-205*, vee prepared by a method similar. to that ln Example 74 hut starting with the corresponding 4-(2, 3-dichloropbenyl)-l, 4*-dlhydropyridine. Ths reaction conditions were the same:Analysis Z:Found: C,51.2; H,4.7; N.7.7 Calculated for C23H25C12H5O6S! C.50.9; H.4.65; H.7.75.

EXAMPLE 77 4-(2-Chlorophenyl)-3-ethoxy carbony 1-5-methoxy carbony l-6-methyl-2[ 2- (4-[H-methylcerbemoyl] -thiazol-2-ylamino) ethoxymethy 11 -1,4-di- The eater product of Example 73 (0.1 g) was dissolved ln s 15 33Z solution of methylamine ln ethanol (10 ml) and the mixture was stood at room temperature overnight and then warmed briefly on a steam bath. The solvent was removed by evaporation and the residue chromatographed on silica Kleselgel 60H (Trade Mark). Elution with toluene and than 1:2 toluene/ethyl acetate afforded a solid which was recrystallised from ether to give the title compound, yield 52 mg, m.p. 120*. - 58 Analyaia Xs-.

Fouad: C,54.35.; 11,5.3; N.10.2 Calculated for C^H^CIB^S: C,54.7; H,5.3; »,10.2.

EXAMPLE 78 2-[ 2- (4,5-Pihydro-5-oxo-l, 2,4-oxadiazol-3-ylamino) ethoxyaethy1J 4-(2,3-dlchlorophenyl)-3-ethoxycarbony 1-5-methoxy carhonyl-6methy1-1,4-dlhydropyrIdine monohydrate 11-^2-(4-^2,3-0ichlorophenylJ-3-ethoxycarbonyl-5«nethoxy10 carbonyl-6-methyl-l,4-dihydropyrid-2-yl)methoxy]ethy^ -M'-cyano-S~methyl-leothlourea (400 ng) waa added to a solution of hydroxylamine hydrochloride (57 mg) and sodium methoxide (44 mg) ln methanol (10 ml) and heated under reflux for 1 hour. The solution was evaporated to dryness end the residue taken up ln ethyl acetate and washed with 2M hydrochloric acid and aqueous sodium carbonate. The organic layer was dried over magnesium - 59 sulphate, filtered and evaporated. The residue was chromatographed on Merck (Trade Mark) J60 silica eluting with ethyl acetate. ’The product containing fractions were combined and evaporated to dryness, trituration with ether giving the title compound (70 mg), m.p. 132*134°.

Analysis S;Found: C,48.45; 0.4,8; 8,10.3 Calculated for ^22^24^2^4^7’®2°S c·**·3· 8,10.5.

EXAMPLE 79 10 2-[2^<2-Methyl-3-/3-msthylureldo^-2H-l,2,4-triaxol-5-ylamino)ethoxymethyl ] -A- ( 2,3-dlchlorophenyl) -3-e thcotycarbonyl-5methoxycarbony1-6-methy1-1,4-dlhydropyrldlne hydrate A solution of (1) (0.2 g; product of Exanple S and methyl 15 isocyanate (0.6 ml) In methylene chloride (50 ml) was stirred at room temperature for 18 hours. The solvent was evaporated to dryness and the residue was chromatographed on Merck (Trade Mark) - 60 J6O silica eluting with 5Z methanol In methylene chloride. The product-containing fractions were combined and evaporated to . dryness, trituration with ethyl acetate giving the title compound, yield 0.04 g; m.p. 110-112°. analysis ZtFound: 0,51.8; H.5.9; 8,16.9 Calculated for ^25^32^7%eH20s C,51.8; H,5.9; 8,17.1.

EXAMPLE 80 4-(2,3-Plchlotfopheay 1) -3-ethoxycarbony1-5-methoxycarbony1-6methyl-[ 2-(6-morphollnopyrlnldln-4-ylanlno) ethoxymethyl] -1,4dlhydropyrldlne - 61 . 4-(2,3-Dlchloropheny 1) -3-ethoxycarbonyl-5-methoxycarbony 1-6methyl-2-[ 2-(6-chloropyrlmldln-4-ylamlno) ethoxymethyl] -1,4dlhydropyrldlne (0.3 g) (Product of Example 53) and morpholine (5 nl) were heated together on a ataam bath for 18 hours. The excess morpholine was then evaporated and the residue was taken up in ethyl acetate, filtered and chromatographed on silica Kleaelgel 60H (Trade Mark) eluting with ethyl acetate. The product-containing fractions were combined and evaporated to dryness, trituration with ether giving the title compound (165 eg), m.p. 163*.

Analysis tsPound: C,55.1; H,5.5; N,11.2 Calculated for C28H33C^‘2S5°6: c,55.45; H,5.5; N, 11.55.

EXAMPLES 81-84 The following compounds were prepared similarly to the previous Example, I.e. by the following.reaction, CH B H H .4 ‘3 and were characterised In the form Indicated:- Reaction Solvent EtOH Reaction Tine hours hours hours . 30 hours Fora Isolated Free bass Free bass Free base Free base n.p. Analysis Z CO (Theoretical ln brackets) 168-170 140-142 158 88-90 56.5 (56.2 .9 13.4 5.9 13.6) 57.9 (57.6 .7 11.2 ;5.8 11.6) 54.2 5.2 12.8 (54.55 5.3 12.7) 54.5 5.55 12.6 (54.55 5.3 12.7) EXAMPLES 85-87 The following compounds were prepared similarly to Example 80, I.e· hy the following reaction Example No. 7 x«5 Reaction Solvent Reaction Time Form Isolated B.p. CC) Analysis X (Theoretical in brackets) C H N 85 N^N ' - 18 hours Hydrate 147 59.4 (59.2 6.4 6.5 11.8 11.9) 86 /Λ rv^ N^N - 20 hours Heai-fumarate Heml-hydrate 171 56.4 (56.3 5.8 5.75 10.95 11.3) 87 -ΓΛ 0 i_____________I - 18 hours Free base 133-154 58.45 (58.8 6.0 6.0 12.4 12.2) - 65 EXAMPLE 88 4-(2-Chloro-3-trifluorottethylpheayl)-3-ethoxycarbonyl-5-mBthoxycarbonyl-6-methyl-[2-(6-morphollnOi>yrlBldln-4-ylamlno)ethoxyethyl1-1.4-dihydropyridlna 4-(2-Chloro-3-trlfluorometfaylphenyl)-3-erthoxycarbony 1-5methoxy carbony 1-6-mathy 1-2-12* (6-chloropy rlmldin-4-y lamino) ethoxymethyl]-!,4-dlhydropyrldlne wae prepared similarly to the procedure of Example 53 from appropriate starting materials end was reacted unpurlfled with morpholine hy a procedure similar to that of Example 80 to give the title compound, m.p. 117-118*.

Analysis E:Found: 0,54.0; H.5.6; 8,10.7 Calculated for C29H33C1?3M5O6: C.54.4; 8,5.2; 8,10.91. - 66 EXAMPLE 89 4-(2,3-Dichlorophenyl)-3--ethoxycarbonyl-5-uethoxycarbopyl-6nethyl-2-[2-(pyragjii-2-ylamlno)ethoxyethyl]-l,4-dlhydropyrldlne The 8-oxlde of 4-(2,3-dlchlorophenyl)-3-ethoxycarbonyl-5uethoxycarbonyl-6-eethyl-2-l2-(pyraxln-2-ylamino)ethoxymethyl]1,4-dlhydropyrldlne (0.35 g) (product of Example 50) vee heated on a eteam bath lm 50X aqueoue ethanol (15 al), to vhich wee added sodium dlthlonite (2 g) portionwise over 1.5 hoars. The reaction mixture wae then heated for a further 1.5 hours before the solvent was evaporated and the residue partitioned between ethyl acetate end water. The organic layer wae separated, dried, filtered and evaporated to give an oil. Chromatography on allies Kieegel 60 H (Trade Mark) eluting with ether gave an oil which afforded the title compound when triturated with dllsopropyl ether, yield 134 mg., m.p. 113*. .- 67 Analysis ZiFound: C.55.2; H.4.9; 8,10.6 Calculated for C^H^ClgS^: 0,55.3; H.5.0; 8,10.75.

EXAMPLE 90 5 (A.) Preparation of 4-(2,3-Plchlorophenyl)-3-ethoxycarbony1-212-(3-othoxycarbonylthioureido) ethoxymethyl] -5-mthoxycarbonyl-6methy1-1,4-dlhydropyrldlae To a suspension of 2-(2-amlnoethoxymethyl)-4-(2,3-dichloropheny 1) -3-ethoxycarbony 1-5-aethoxy carbony 1-6-aethy 1-1,4dlhydropyrldlns (4.43 g) In dry chloroform (50 ml) was added, dropwise, a solution of ethoxy carbonylieothlocyanate (1.31g) la dry chloroform (25 ml). The reaction was stirred for 18 hours at room temperature before. evaporating the solvent and triturating the residue with ether to afford a solid which was recryatalllsed froa diisopropyl ether to give the title compound, yield 2.6 g, m.pt. 144°, - 68 Analysis ΧιFound: C,50.6; H,5.2; 8,7.0 Calculatadfor C^H^Cl^O^:., C.50.2; H.5.1; 8,7.3.

(B.) Preparation of 4-(2,3-Dichlgrophenyl)-3-e thoxy carbony 1-2/2- (5-hydroxy^lH-l, 2,4-triazol-3-ylaalno)ethoxyaft thy V~5msthoxycarhonyl-6-mathyl-l,4-dlhydropyrldlne hydrate To a suspension of 4-(2,3-dlchlorophenyl)-3-ethoxy carbony 110 2~ 12 (3-ethoxycarbonyl thloureldo) ethoxymethy 1] -5-methoxycarbony 16-methy 1-1,4-dlhydropyrldlne (0.25 g) In dry tetrahydrofutan (THF) (5 ml) was added sodium hydride (0.02 g). After stirring for 1 hour at room temperature a solution of methyl Iodide (0.07 g) In dry THF (5 ml) was added dropwise and stirring was continued overnight. After evaporation of the solvent, the residue was taken up in methylene chloride and washed (aqueous 8aCl), dried (MgSO*), filtered and evaporated to give a yellow oil (150 age). - 69 The oil wee dissolved in Isopropanol (5 ml) containing hydrazine hydrate (0.06 g) and heated under reflux for 2 days. The solution was than evaporated and the residue taken up In methylene chloride and washed (aqueous NaHCOj), dried (MgSO*), filtered snd evaporated. The residue was then chromatographed on silica Kleaelgel 60 H (Trade Mark), eluting with ethyl acetate/methanol (1Z Increments up to 20Z methanol). Product-containing fractions were combined, evaporated and recrystalllaed from ethyl acetate to afford the title compound, yield 0.048 g, u.pt. 158*.

Analyels Z:Found: C.48.5; H,4.8; N.13.0 Calculated for C22H25C12H5O6’H2O! C»48’5; Η·5·θ5 »»12.9..

EXAMPLE 91 (A) Preparation of 4-(2,3-dichlorophe«yl)-3-ethoxycarbonyl-2-[215 (5-hydroxy-4-methylpyrfmldln-2^1amlno)ethoxymsthyll-5mathoxycarbony 1-6-methy 1-1.4-dihydropyrldlne - 70 A mixture of 2-(2-amlnoethoxymethyl)-3-ethoxycarbonyl-42,3-dlchloropheny 1) -5-methoxycarbony 1-6-metfayl-l, 4-dihydropyr Idine (3.6 g) end 5-acety 1-2-amlno-oxasole (0.5 g) In methanol (2 ml) and water (3 ml) wae heated on a steam bath for 24 hours. The mixture was then evaporated to dryness and the residue was chromatographed on silica Kleselgel 60H (Trade Mark) eluglng . with ethyl acetate. The product-containing fractions were combined, evaporated and the residue triturated with ether to give the title compound (0.1 g), m.p. 165*.

Analysis Found: C.54.3; H.5.2; 8,10.2 Calculated for C25B28C12N4°6: c»54-*5; H.5.1; N»10.2Z.

(B) Preparation of 2-[2-(4-acatyllmidarol-2-ylanino)ethoxynathyl]-4-(2,3-dichlorophenyl)-3-ethoxycarbony1-5-methoxy15 carbonyl-6-methyl-l,4-dihydropyridlne V - 71 10 Froa the sane reaction described In Fart (A) a second, acre polar product waa subsequently eluted iron the chromatography column using ethyl acetate as tha eluent. The fractions containing this second product were combined, evaporated and the residue waa redlssolved In methylene chloride, washed with dilute hydrochloric acid then with aqueous sodium bicarbonate, dried (MgSOp-, filtered and evaporated. The residue was recryetalllsed from ethyl acetate to give the title compound (0.14 g), m.p. 177°.

Analysis XsFound: C,54.6; 8,5.5; 8,9.9 Calculated for C25H28C12N4°6: C,3A·^5’ 8,5.1; 8,10.21.

EXAMPLES 92-97 The following compounds were prepared similarly to the procedure of Example 8, I.e·, by the following reactlon:C2H500C CH 88. R *2 Example No. R3 Q Reaction Solvent Base Reaction Time Form Isolated Β·Ρ· (•C) Analysis X (Theoretical In brackets) C B N 92 Cl nBuOH 4-dlmethyl- amlno pyridine 24 hrs. Free base he mi -hydrate 139- 141 53.15 (52.75 5.1 5.0 10.6 10.25) 93 -Q 0 Cl nBuOH Et3M 33 hours Hex&i-fuaarate 197- 199 52.4 (52.4 4.9 4.7 9.3 9.4) 94 'Τ' H 0 -NHNO2 EtOH 18 hours Free base sesqui-hydratc 222 51.6 (51.9 5.4 5.4 9.7 9.4) 95 Ώ H 0 -SMe EtOH - 18 hours Hydrochloride 203- 205 50.0 (50.2 4.9 4.7 9.9 9.8) Example No. R3 Q Reaction Solvent Baae Reaction Time Form Isolated m.p. CO Analysis X (Theoretical in brackets) C Η M 96 H -SMe EtOH Et3N 17 hours Hydrochloride hemi-hydrate 195- 198 48.5 (48.3 4.8 9.85 4.9 9.8) 97C1 -Cl EtOH Et3N 50 hours Free base 153 51.8 (51.9 4.6 9.95 4;5 10.1) I -74 EXAMPLES 98-102 The following compounds were prepared similarly to the procedure of the stated Exaaple from appropriate starting materials:- « Example No. Prepared similarly to the procedure of Example no. R3 B.p· CO Form Isolated Analysis X (Theoretical In brackets) C H N 98 74H 0 194- 196 Free base 50. 7 (50.9 4.8 4.65 7.7 7.75)99 80 rrO Ns/H 167- 169 Free base 55.5 (55.45 5.6 5.5 11.4 11.55) 100 1 H 173- 175. Free base heai-hydrate 49.3 (49.4 5.05 5.1 15.5 15.7) ,- J**’ * 101 64 ΊΧ . ft 138- 140 Free base 48.1 (48.2 4.9 4.6 9.7 9.8) , j'™: 102 67 V 142- 144 Free base bemi-hydrate 46.35 (46.6 4.9 4.6 12.3 12.3) . - 76 The following Preparations Illustrate the preparation of certain starting materials· All temperatures ere ln C:- * Preparation 1 Preparation of 2-[(2-aninoethoxy)uathyl]-4-(2-chlorophenyl)-3ethoxycerbonyl-5-methoxycarbonyl-6-aethy1-1,4-dlhydropyridine maleate A suspension of 2->(2-asldoethoxymethyl)-4-(2-chloTOphaixyl)-3ethoxycarbonyl-5-methoxycarbonyl-6-siethyl-l ,4-dlhydropyrldlne (103 g) ln ethanol (2.5 1) was stirred for 16 hours at room temperature under one atmosphere of hydrogen ln the presence of 5X palladium on calcium carbonate (40 g). The reaction mixture was filtered and evaporated and the residue treated with a solution of maleic acid (22 g) in ethanol (100 ml). The reaction mixture vee stirred at room temperature for 2 hours and then the resulting solid collected, washed with ethanol, and dried to give the title compound (100 g), m.p. 169-170.5°. - 77 Analysis X:Found: . C,54.82; H,5.62; 8.5.46 C24H29C1H2O9 Wire8: C,54.91; 8.5.57; 8.5.34.

Preparation 2 2-[ 2-Amlnoethoxymethy 1] -4-[ 2.3-dichlorophenyl] -3-ethoxycarbonyl-5-methoxycarbony 1-6-methy 1-1.4-dlhy dropy rldlne, m.p. 171-3’» waa prepared similarly to the previous Preparation from the appropriate asldo compound» and waa characterised as the hemlfumarate hemlfaydrate.

Analyeia X:Found: 'C.51.7; H.5.3; 8,5.5; Calculated for C20H24C12M2°5’,lC4H4O4‘i5H2O? C>S1.8; H,5.3; 8,5.5.

The hemlfumarate was neutralised to the free base form. m.p. 120-122’.

Preparation 3 2-(2-Aaidoethexymathyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5aethoxycarbony 1-6-msthy 1-1,4-dlhydropyrldine A solution of 2-asldoethanol (160 g) In tetrahydrofuran (300 ml) was added over 40 minutes to a suspension of sodium hydride (114 g; 80Z dispersion In oil) In tetrahydrofuran (500 ml). The mixture was stirred at room temperature for 1 hour and the Ice-cooled solution treated with a solution of ethyl . - 78 4-chloroacetoacetate (276 g) In tetrahydrofuran (250 ml) dropwise over 2 hour a. The mixture was stirred at room temperature for 16 hour a, diluted with ethanol (150 ml)· and the pH adjusted to 6-7 with 4M hydrochloric acid. Sufficient water wae added to dissolve the solid present and the layers were separated. The organic layer was evaporated and the residue diluted with water (600 ml) and evaporated. The residue was partitioned between ethyl acetate and water and the aqueous layer extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO*) and evaporated to give ethyl 4-(2-azidoethoxy)acetoacetate as a brown oil, which was shown by g.l.c. to be 732 pure. A mixture of this crude product and ammonium acetate (92.3 g) in ethanol (600 ml) was bested under reflux for 1 hour, allowed to cool to room temperature, and treated with methyl 2-(2-chlorobenxylldene) acetoacetate (286.6 g). The mixture wae heated under reflux for 5.5 hours and then evaporated. The residue was stirred with methanol (1.5 1) for 16 hours end ths resulting solid collected, washed twice with methanol, dried, and recrystallised from methanol to give the title compound (78 g), m.p. 145-146°.

Analysis 2:Found: 0,55.39; H.5,37; 8,13.01 Calculated for CggH^CUl^: C.55.23; H,5.33; 8,12.88.

Preparation 4 2-(2-Asldoethoxy)methy1-4-(2,3-dlchlorophenyl)-3-ethoxycarbonyl-5-methoKycarbonyl-6-methyl-l,4-dlhydropyrlue vas prepared by the method described ln Preparation 3 using methyl -79 2-(2,3-dichlorobenzylidene)acetoacetate Instead of aethyl 2-(2-chlorobenzylidene)acetoacetate. The product had an m.p. of 141*.

Analysis ts* Found: C,50.88; H.4.78; R.11.73 Calculated for c2oH22C12M4°5! c>51>18« Η·4·735 Η.Π.94.

Preparation 5 ¢1) Preparation of jtthyl-4-(2-phthaliaido To a slurry of sodium hydride (57Z dispersion In oil, 66.1 g; 1.57 M), In tetrahydrofuran (500 al) cooled to 0° under nitrogen uae added 2-phthallaldosthanol (150 g; 0.785 M) followed by ethyl 4-chloroecetoacetate (129 g; 0.785 B) In tetrahydrofuran (250 al) over 1 hour. The mixture was stirred at room temperature overnight then poured Into a mixture of 1M hydrochloric acid (800 al) and ethyl acetate (750 al). The organic phase was separated, and the solvent was evaporated at reduced pressure. The residue separated Into two layers and the upper layer of mineral oil was removed to leave the title compound (243 g) as a crude product which was used without further purification. (ii) Preparation of 4-(2-chlorophenyl)-3-ethoxycarbonyl-5aethoxycarbonyl-6-«ethyl-2-12-phthalimidoathoxymathy 1] -1,4dlhydropyrldlne Methyl 3-amlnocrotonate (72.2 g; 0.627 M) and 2-chlorobenzaldehyde (88.1 g; 0.627 M) were added to a solution of ethyl 4~(2-phthalimidoethoxy)acetoacetate (200 g; 0.627 M) in isopropanol (1 litre) and the mixture waa heated under reflux for X0 20 hours. The iaopropanol was evaporated under reduced pressure and replaced, by acetic acid (1 litre). After granulation at 10* the solid was collected and slurried ln methanol (300 al). The solid was collected hy filtration and dried in vacuo at 50* to afford the title compound, yield 84.4 g, m.p. 146-147*.

Analysis X:Found: C.62.2; H.5.0; N.5.2 Calculated for ^28^7^^2°78 c·^^·^· 8,5.05; N,5.2. - 81 Preparation 6 The following compound, m-,p. 148-150*, was prepared similarly to the previous Preparation hut using the corresponding 2,3-dlchlorobenzaldehyde. Ths reaction time wee ths same:- Analysls 2:Found: C.58.7; H.4.5; 8,5.0 Calculated for C28H26C12M2°7: c·58·6* H.4.6; 8,4.9. - 82 Preparation 7 Preparation of 2-(2-amlnoethoxyms thy 1)-4-(2-chlo ropheny 1)-3ethoxycarbonyl-5-mcthoxycarbonyl-6-nethyl-l, 4-dlhycbMCvriding maleate The intermediate phthallmldo compound from Preparation 5 (400 8) was suspended In ethanol (6 litres) containing hydrazine hydrate (111 g) and heated under reflux for 2 hours. After cooling the reaction mixture wee filtered and -the filtrate wee evaporated to give a yellow oil. The oil was taken up In methylene chloride (6.5 litres)· washed (B20)» dried (MgSO^) and evaporated. The residue wae taken up In hot methylated spirit (1.2 litres) and diluted with hot methylated spirit (400 ml) containing maleic acid (86 g). After cooling the title compound crystallised out as Its maleate salt, yield 303 g, m.p. 169-171°.

Analysis ?sFound: C.54.8; H,5.55; H,5.3 Calculated for c2oH25C11I205’C4H404! C,54.9; H,5.6; H.5.3.

Preparation 8 Tha following compound, m.p. 171-173° waa prepared similarly to tha previous Preparation but starting fron the corresponding 2,3-dlchlorophenyl compound:- Fumarate, h H^O.

Analysis X:Fouad: C,51.55; H,5.3; N,5.4 Calculated for 0*0*0*·Μΐ20: C.51.5; H.5.05; H.5.0.

PREPARATION 9 The following compound· m.p. 179®, was prepared similarly to Preparation 5 but using the corresponding 2-chloro-3-trlf luoromethy lbensaldehyde In stage (11). The reaction. time was the same:- .

Analysis X:Found: C.57.2; H.4.45; 8,4.8 Calculated for . C.57.4; B.4.3; 8,4.6.

PREPARATION 10 * Preparation of 2-(2-Agidoethoxymethyl)-4-(2-chloro-3-trifluoromethylpheny1)-3-ethoxycarbony l-5-nethoxycarbonyl-6-mathy 1-1,4- 4 dihydropyridine The title compound, m.p. 143-145°, was prepared similarly to 10 the method described in Preparation 3 but using the corresponding 2-chloro-3-trlfluorome£bylbensaldehyde. The reaction time wea the same:Analysis XsFound: C.50.2; H,4.4; 8,11.3 Calculated for 0,50.15; H.4.4; 8,11.1. - 85 Preparation 11 Preparation of 2-[2-AaflaoathoxyBathyl1-4-(2-chlorO'-3-trifluoTOmathylphenyl)-3-ethoxycarbonylr5-nethoxycarbonyl-6-mathyl1,4-dlhydropyrldlne The title compound was prepared by the catalytic hydrogenation, of the azido compound of Preparation 10 by the method described In Preparation 1. Thia compound was confirmed by n.m.r. and I.r. analysis to he Identical to the product of Preparation 13.

Preparation 12 Preparation of 2-(2-Azidoethoxyaethyl)-4-(2t3-dlchlorophenyl)-3aathoxycarbonyl-5-ethoxycarbonyl-6-methyl-l,4-dihydropyrldlne The title compound, m.p. 126°, wee prepared similarly to the method described in Preparation 3 but using methyl 4-bromoacetoacetate Instead of ethyl 4-chloroacetoacetate yielding methyl 4-(2*asidoethoxy)acetoacetate instead of ethyl 4-(2~azldoethoxjecetoacetate. The other conditions were the Analysis X:Pound: C,51.3; B,4.7$ Μ,12·1> Calculated for c·51·2’ H'4·7’ N,11.9.

Preparation 13 Preparation of 2-(2-amlnoethoatymethyl)-4-(2-chloro-3-trifluoromethylpbenyD-S-ethoxycarbonyl-S-methoatycerbonyi-S-mBthyl-lfddihydropyrldlna - 87 The Intermediate phthallmldo coepound from Preparation 9 (2.8 g) vaa added to aqueoue methylamine (14 ml of 40Z) end stirred at room temperature for 17 hours. The resultant solid was filtered, redlssolved In chloroform (50 ml), dried (KgSO*), filtered and evaporated to give a yellow solid. Crystallisation from hexane gave the title compound, yield 1.0 g, m.p. 122*.

The title oonpound Is the subject of Patent specification No.; ... φ .

Analysis 2:Fotmd: C.53.25; H.4.9; N.5.75 Calculated for c2iB24C1J3M2O5: C,52.9; H.5.1; N,5.9.

Preparation 14 Preparation of 4-(2,3-dlchlorophenyl)-5-ethoxycarbonyl-3methoxy carbony 1-6-methy l-2-[2-phthallmldoethoxymethyl]-l,4dlhydropyrldlne The title compound, m.p. 165*, vaa prepared similarly to the method described In Preparation 5(11) but using 2,3-dlchlorobenzaldehyde, methyl 4-(2-phthallmldoethoxy)-acetoacetate and ethyl 3-aalnocrotonate. The reaction time was tha same:- 88 Analysis 2:Found: C,58.5; H.4-7; 8,5.0 Calculated forC^H^Cl^O?: C,58.65; H,4.6; 8,4.9.

The starting acetoacetate was prepared similarly to 5 Preparation 5(1).

Preparation 15 Preparation of 2-(2-amlnoethoayBeChyl)-4-(2,3-dlchloropbenyl)-5®£S^2carbonyl^32S»tho2Xcarbon2j£^22Si!fftix£dii2Z3£2E22i^i?^ The title compound· m.p. 131-132°, was prepared similarly to the method described ln Preparation 13 hut using the material from Preparation 14.

Analysis 2:Found: C,53.9; 8,5.5; 8,6.4 Calculated for c2oH24C1AO51 C.54.2; 8,5.5; 8,6.3.

Preparation 16 Preparation of 2-chloro-3-trlfluoromethylbenzaldehyde 2-Chloro-1-trifluoromethyJbensene (54.15 g) wae dissolved In * 5 dry tetrahydrofuran (500 ml) and stirred vhlle cooling to -68” under a stream of dry nitrogen. (The whole reaction ls carried I out under dry nitrogen until the addition of distilled water.) To this was added n-butyl lithium (180 ml of a 1.6 M solution la 10 hexane) dropwlse keeping the temperature below -60°. After stirring at -68° for a further 2 hours, a solution of dlmethylformsmide (22 ml) in dry tetrahydrofuran (100 ml) waa added dropwlse keeping the tenperature below «60°. The reaction mixture was allowed to warm to room temperature slowly over 17 hours and distilled water (200 al) wee then added. The organic 15 phase wae .separated off and the aqueoue liquors were extracted with ether (100 ml). The combined ether extracts plus the organic 20 phase were washed with saturated brine, dried (MgSO*), filtered and evaporated to give 61.5 g of en orange oil, being the crude title compound. This oil was then added to an aqueoue sodium bisulphite solution (65 g ln 600 ml distilled water) and heated et 60° for 25 0.5 hours. The solution was extracted with methylene chloride (3 x 100 ml) and, after acidification of the aqueoue phase with concentrated sulphuric acid to pHl, was heated at 100° for a further 0.5 hours. The resultant aqueous solution was extracted with methylene chloride (3 x 200 ml) and the combined organic extracts were dried (MgSO*), filtered and evaporated to give 42 g of a colourless solid which was crystallised from hexane to give the title compound, m.p. 43-44°.

« Analysis X:Found: C.45.9; H,2.0 Calculated for CgH^F^ClO: C»46.1; H»2.0.

Preparation 17 1 Preparation of 2,3-dichlorohensaldehyde A similar route to that described In the previous y Preparation, starting fron 1,2-dichlorobenzette, proved to be a superior aethod for preparing the title compound, m.p. 62*.

Analysis X:10 Found: C,47.62; H,2.38 Calculated for CyH^ClgO: C,48.04; H,2.30.

Activity Pats Tha molar concentrations of the coapounda required to reduce the response hy 50X In the test specified on pages 16-17 are given below (1M - 1 gm.Mole/lltre). The smaller the concentration the ore active the compound.

Compound · Product of Example IB Product of Example 2 Product of Example 3B Product of Example 4 Product of Exanple 5 i£so x 10-8 M 2.29 x 10M 6.02 x 109 M 8.12 x 10-9 M 3.02 x 10 Compound Product of Exampl· 6 ISso 1.15 X Mf® M Product of Example 7 3.47 X 10~9 11 Product of Example 8 1.05 X io-8 M 5 Product of Example 9 1.26 X IO8 M Product of Example 10 1.9 X !0-’ M Product of Example 11 4.26 X IO’7 M Product of Example 12 2.88 X io-8 M Product of Example 13 6.3 X 10-» 11 10 Product of Example 14 1.0 X 10-8 M Product of Example 15 5.01 X io8 M Product of Example 16 1.00 X 10-7 M Product of Example 17 1.31 X io-8 M Product of Example 18 3.16 X 10-8 11 15 Product of Example 19 1.00 X io-8 M Product of Example 20 1.00 X io-7 11 Product of Example 21 1.00 X io-7 M Product of Example 22 1.82 X 10“® M Product of Example 23 1.00 X io-7 M 20 Product of Example 24 1.00 X io-8 M Product of Example 25 4.57 X 10-8 11 Product of Example 26 3.71 X io-9 K Product of Example 27 3.98 X 10-’ 11 Product of Example 28 1.31 X io-8 M 25 Product of Example 29 1.81 X io-8 K Product of Example 30 2.34 X 10’9 M Product of Example 31 1.77 X 10-8 M Compound Product of Example 32 I£50 1.58 x 108 M Product of Example 33 6.30 X 10’9 M Product of Example 34 1.31 X XO-8 M Product of Example 35 5.75 X 10-9 M Product of Example 36 3.16 X 10-9 M Product of Example 37 1.00 X XO® M Product of Example 38 2.51 X 10-8 M Product of Example 39 2.69 X X0*9 M Product of Example 40 2.23 X 10-9 H Product of Example 41 7.76 X 10-10 M Product of Example 42 4.16 X IO'9 M Product of Example 43 8.31 X XO*9 M Product of Example 44 1.58 X 10-8 M Product of Example 45 1.09 X 109 M Product of Example 46 3.01 X X0*9 M Product of Example 47 1.25 X X0-9 M Product of Example 48 2.95 X XO-8 M Product of Example 49 3.98 X X09 11 Product of Example 50 1.34 X X0-9 M Product of Example 51 2.51 X X0“9 M Product of Example 52 6.02 X X0-9 M Product of Example 53 3.16 X XO-8 M Product of Example 54 1.20 X X0“9 M Product of Example 59 3.72 X X09 M Product of Example 60 4.47 X XO8 M Product of Example 61 2.24 X XO9 M Compound I£ Product of Example 62 1.35 X IO’9 M Product of Example 63 .. 2.95 X IO-9 M Product of Example 64 1.00 X IO8!! 5 Product of Example 65 2.51 X IO”8 M Product of Example 66 2.24 X IO’9 M Product of Example 67 1.99 X 10-8 M Product of Example 68 1.31 X 10-8 M Product of Example 70 9.33 X 10-9 M 10 Product of Example 71 1.00 X 10® M Product of Example 72 3.98 X 108 M Product of Example 73 4.4 X 10-9 M Product of Example 74 2.00 X 10-8 M Product of Example 75 7.08 X 10-9 M 15 Product of Example 77 5.37 X 109 M Product of Example 78 2.29 X .0 10 ’ M Product of Example 79 6.60 X 10-9 M Product of Example 80 1.34 X 10’9 K Product of Example 81 3.16 X 10’9 M 20 Product of Example 82 4.07 X 10~9 M Product of Example 83 3.16 X IO’9 M Product of Example 84 5.01 X .Q 10 * M Product of Example 85 5.01 X -9 10 ’M Product of Example 86 1.58 X -9 10 M 25 Product of Example 87 1.00 X IO-7 M Product of Example 88 1.26 X 10’10 H Compound Product of Product of Product of Product of Example 89 Example 90B Example 91A Example 91B .01 χ 1010 M .1.00 x 10-8 M 1.00 χ 109 M 2.5 χ 10-*9 M t

Claims (20)

1. CIAIMS:
1. • 1. . A dihydropyrldlne of the formula:- or a pharmaceutically acceptable acid addition salt thereof; 5 «diereln R is a phenyl group optionally substituted by one or two substituents each independently selected from nitro, halo, alkyl, C^-C* alkoxy, hydroxy, trifluoromethyl, and cyano; 1 2 R and R are each Independently C^-C* alkyl or 2-methoxyethyl; 10 Y is -(CH 2 ) 2 -; R Is attached to the adjacent nitrogen atom by a carbon atom and Is either (a) a monocyclic 5- or 6-mcmbercd heterocycle containing at least one N atom and optionally one or two further licteroatoms or groups each Independently selected from IC 0 0 15 φ T 0, S, S, N and N, and Is optionally substituted by C^-C* alkyl, C l” C 4 β1Κοχ Χ· halo, hydroxy, oxo, cyano, 3-(C^-C* alkyl)ureido, 4 5 phenyl, phenoxy, pyridyl, acetyl, (Cj-C* alkoxy)carbonyl, -NR R · -SOjNM’^R 3 ·or -CONR^rS where either R^ and R^ are each 20 Independently 11 or (j-C* alkyl or R^ and together with the v nitrogen atom to which they arc attached represent a saturated 5or 6-membered heterocyclic group optionally containing a further heteroatom or group selected from 0, S, NH, M(Cj-C* alkyl) and NCHO; or (b) a bicyclic group which Is an optionally substituted 5- or 6-membered heterocycle as defined in (a) fused to an imidazole or benzene ring, said benzene ring being optionally substituted by C^-C* nlkyJ, C^-C* alkoxy or halo.
2. 2. A compound as claimed in claim 1 wherein R is a phenyl group substituted by 1 or 2 substituents selected from halo and CFy
3. 3. « A compound as claimed ln claim 2, wherein R is 2-chlorophenyl, 2,3-dIchlorophenyl or 2-chloro-3-trifluoromethylpheny1·
4. 4. A compound as claimed ln any one of the preceding claims wherein either (a) is CH^ and Is or (b) R^ is CH^ and R 1 is C 2 H 5 '.
5. 5. A compound as claimed in any one of the preceding claims . 3 wherein R is a heterocyclic group selected from trlazolyl, oxadlazolyl, pyrimldlnyl or a partially saturated derivative thereof, purlnyl, quinazolinyl, imidazolyl, imidazolinyl, triazlnyl, pyridyl, thiazolyl, thlazollnyl, benzthlazolyl, thiadlazolyl, pyrazinyl, quinoxalinyl and pyrrolinyl, and their Nand S-oxldes, R^ being optionally substituted by Cj-C* alkyl, C^-C* alkoxy, halo, hydroxy, oxo, cyano, 3-methylureido, phenyl, phenoxy, pyridyl, acetyl, carbamoyl, N-mcthylcarbamoyl, (Cj-C* 4 5 4 5 4 5 alkoxy)carbonyl, -NR R , or -SOjNR R , where either R and R are * 4 5 each independently II or C^-C* alkyl or R and R together with the •f - 97 nitrogen atom to which they are attached form a piperidino, morpbolino, 4-methylplperazln-l-yl or 4-formylplperazln-l-yl group.
6. 6. , A compound as claimed In claim 5 wherein Is - 98 7. A compound as claimed In claim 5 wherein R Is 99 ηΛ
7. 7. 9. A compound as claimed In claim 5 wherein R la ν—ι N—I F N “k or Ν X 11*0 u λ H COCH.
8. 8. 10. A compound as claimed ln claim 5 wherein R Is Nil.
9. 9. 11. A compound as claimed ln claim 5 wherein R Is
10. 10. 12. A compound as claimed in claim 5 wherein R* Is COOCt -C . YJ . N _z, :ϊ ’ SO^NMo^ 100
11. 11. 13. A compound as claimed In claim 5 wherein It la O t' N N or J-ll— OCIL· O T Λ J_!l— NH. A compound as claimed in claim 5 wherein R la
12. 12. 15. A compound aa claimed In claim 5 wherein ft la 1 2
13. 13. 16. A compound as claimed In claim 1, wherein ft Is CH^, R 3 Is C 2 B 5» R 1* 2,3-dlchlorophenyl, and R la a group of the formula:N-n ; or a pharmaceutically acceptable acid addition salt thereof. 101
14. 14. 17. A compound of the formula (I) as claimed in any one of Che preceding claims, or a pharmaceutically acceptable acid addition salt thereof, for uae as a medicament.
15. 15. 18. A pharmaceutical composition comprising a compound of L, ’ 5 the formula (1) as claimed In any one of claims 1 to 16, or a pharmaceutically acceptable acid addition salt thereof, together ( uith a pharmaceutically acceptable diluent or carrier.
16. 16. 19. The use of a dihydropyridine as claimed In any one of* claims 1 to 16, or pharmaceutically acceptable acid addition salt 10 thereof, for the manufacture of a medicament for treating Ischaemic heart disease, angina or hypertension.
17. 17. 20. A dihydropyridine of the formula (I) given and defined In claim 1 or a pharmaceutically acceptable acid addition salt thereof, which Is any one of those specific15 ally hereinbefore mentioned.
18. 18. 21. A process for preparing a dihydropyridine of the formula (I) given and defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, substantially as hereinbefore described with particular reference to the 20 accompanying Examples.
19. 19. 22. A dihydropyridine of the formula (1) given and defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, whenever.prepared by a process claimed in claim 21.
20. 20. 25 23. A pharmaceutical composition according to claim 18, substantially as hereinbefore described.