IE833010L - Dihydropyridines - Google Patents

Description

This Invention relates to certain dihydropyrldines, specifically to certain 1,4-dlhydropyridinea having a heterocyclic group In a side chain attached to the 2-position, which have utility as antl-lschaaulc and antihypertensive agents.

The compounds of the Invention reduce the ftsNsnt of calcium into the cell and they are thus able to delay or prevent the cardiac contracture which is believed to be caused by an accumulation of intracellular calcium under ischaemlc conditions. Excessive calcium Influx during lschaemla can have a number of additional adverse effects which would further compromise the ischaemlc myocardium. These include less efficient use of oxygen for ATP productioni 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 arrythmias, heart attacks and cardiac hypertrophy. The compounds also have vasodilator activity since they can inhibit calcium influx in cells of vascular tissue and they are thus also useful as antihypertensive agents and for the treatment of coronary vasospasm. .

Patent Specification No. describes certain dihydrcFyr- idine calciun antagonists having a secondary or tertiary amino group at the end of a side chain attached to the 2-positlon.

According to the present invention there are provided dihydropyrldlnes of the formula:- H ooc — (I) ai3 N CH.-O-Y-NHR3 II * 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, Cj-C^ alkyl, C^-C^ alkoxy, hydroxy, trifluoronetliyl, and cyano; 1 2 R and R arc each independently C^-C^ alkyl or 2-methoxyetliy]; Y is -(CH2)2-; R3 is attached to the adjacent nitrogen atom by a carbon atom 15 and is either (a) a monocyclic 5- or 6-membered hciterocycle containing at least one N atom and optionally one or two.further heteroatoms or groups each independently selected from 0 0 O, S, S, N and N, and is optionally substituted by Cj-C^ alkyl, Cj-C^ alkoxy, halo, hydroxy, oxo, cyano, 3-(Cj-C^ alkyl)ureldo.

A 5 phenyl, phenoxy, pyridyl, nrccyl* (Cj-C^ n1koxy)cArbonyJ, -MR R , -S(>2NRAR5 or -CONR-*R5 when- either R* and R5 arc each 4 5 independently II or .-tlkyJ or R and R together with the nitrogen atom tn 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 NCHO; or (b) a blcycllc 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 Cj-C^ alkyl, Cj—C/( alkoxy or halo.

The pli.irnincciitir.illy acceptable acid addition salts of the compounds of the formula (1) are those formed from acids which form non-toxic acid addition salts, for example the hydrochloride, hydrobromidc, sulphate or bisulphate, phosphate or acid phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate and tartrate salts.

"Halo" meanR F, CI, Br or I.

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

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

Preferably clthor R* Is CIl^ and R^ is C^Hj or R* is C^Hj and R^ is CH.j. Most preferably, R^ is CH^ and R^ Is C^Rj. 3 R Is preferably « heterocyclic group selected from triuzolyl, oxadinziilyl., pyrlmldlnyl or ;i partially saturated derivative thereof, puflnyl, qulnazolinyl, lmldazolyl, imldazollnyl, trlazinyl, pyridyl, thlazolyl, tliiazoXlnyl, benzthinzolyl, thladiazolyl, pyrazlnyl, quinoxalinyl and 3 pyrrolinyl, and their N- .-iud S-oxides, R being optionally substituted by C^-C^ alkyl, C^-C^ alkoxy, halo, hydroxy, oxo, cyano, 3-methylureldo, phenyl, phenoxy, pyridyl, acetyl, 4 S carbamoyl, N-methylcarbamoyl, (Cj-C^ alkoxy)cnrbonyl, -NR R; , or 4 5 4 5 -SOjNR R , where cither 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 ptperldino, morphollno, 4-methylpiperazin-l-yl or 4-formylpiperazin-l-yl group. 1,2,4-Triazol-3-yl, 1,2,4-oxadiaiol-3-y1, 1,2,5-thladlarol-3-yl, pyrimldin-2-yl, pyrimldin-4-y1, lmidazol-2-yl, 1,3,5-trlasin-2-yl, pyrld-2-yl, thlazol-2-yl, pyraiin-2-yl and pyrrolln-2-yl, optionally substituted as above, represent typical 3 Instances of R .

The most preferred l&divldual heterocyclic groups represented 3 by K are as follows:- N—N N— o m—s H -4. JL. -^\ -f ■4 o -Q- ■ -rt,. _n CHj O H. v -Q • <0 J? MOT,' " m7 ' N_^ , N—k H 2 H O H O ' NH IF -* « _/ 2 o J-f _y""< mr # v »-< • -L> • . -O »h2 -K. "'X' O O" X3 • -6 . >> H-CHO \ / <5 if\*3 A ^ W Km/ B.

OH <y N — N B ■ -OL - COCH, O-Ph and I |) J JsAiPr ■ In mm of these groups tautomerisa may occur, e.g.

-Q - "Q H O OH In such cases both taatomera are within the scope of this invention.

In the preferred individual compound, K is 12 3 2,3-dichloroph«rnyl • R Is CH^> R is CgHy T is R NH H 2 The compounds of the formula (I) containing one or sore asymmetric centres will exist as one or more pairs of enantiomers, and such pairs or individual 1Sonera nay 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 racealc mixtures or as separated optically-active isonerlc forma.

The compounds of the invention can be prepared by a number of routes, including the followlng:- (1) The compounds of the formula (I) can be prepared via che following route .2 , H ^ . R 1 H __2 . , H . ^ H CH, ' CB.OKMH, _ ^ COOR2 "3 £ *-2" 2 CH3 N ' CHjOTNH.R3 CBjOKMHJ (ID <« Q la i facile leaving group, such aa -HH.NO^, C^-C^ alkylthio, Cj-C^ alkoxy, cl, Br or I. Q la preferably methylthlo, nethoxy, ethoxy, chloro or nlcroawlno.

The reaction la typically carried out by heating the reactanta at 50-130'C, e.g. under reflox, In a suitable organic aolvent until the reaction la substantially complete. Typical organic aolventa Include methanol, ethanol, n-butanol, acetonltrlle, dlmethylformamld* (OMF), methylene chloride, etc. -When Q la C^-C^ alkylthlo, Cl, Br or I, the presence of a base such as trlethylaaln*, sodium carbonate or 4-dlmetfcylamlnopyridlna la preferred. The product (I) can than be Isolated and purified conventionally.

The starting materials of the formula (II) are the subject matter of our Patent Specification No. v . . . Some typical methods for their preparation are however deacrlbed in the Preparations hereinafter.

Aa disclosed in. the said Patent Specification, a typical route to the Intermediates (II) la as followss- h3<-y-och2coch2coor' ,2 COCR .2 H / C' + R. CHO + 0 CHjOVNj (II) An alternative route to the internedlatas (u) is as followa:- («) ^ COOR2 X * ) CH-C1 COOR' o HO-Y-N v <b) r ooc . h CH. ^00011 IJ + R.CHO + j 0 "v OT2O™^J^| ROOC CH COOR (c) ROOC .COOR" R H R H , 9 hydrazinahydrate/ethanol, . , / .

■■^ • COOR —: -*■ ROOC ^ or aqueous mstbylaaine CH CH, N CH.OYH ' H 2 3 jj ""20YNH2 (II) Preparations 16 and 17 describe particularly useful routes to 2,3-dlchlorobcnzaldehyde and 2-chloro-3-trifluoromethylbenz-aldetayde. 2KMoro-3-tKifluoronethylbenzald^Tyde is the street of BP-A-0 145 334. .3 — (2) Compounds In which R Is N | ~^N HH, H— O 4. A V—CH.OYN H N.CN N CH-O-Y-N-C-X H can be prepared as follovs:- — (Ill) NBjOH/CajOH MBjOB.BCl/Et -~-ch2O-Y m -^nAH, X Is -SCHj, -OCH^ or -0.Phenyl.

These reactions are typically carried out in a suitable organic solvent Such as methanol, ethanol, acetonltrlle 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 In about 4 hours. The desired product can then be Isolated and purified conventionally.

The starting Materials of the foranla (III) can be prepared from compounds of the formula (II) .[see route (1) above] as follows i.CN H.CN II 'WCH20YKH2 X-C-X, .IWCH.O-Y-K-C-X Isopropanol or methanol, root* (II) temperature, ft hours. (3) Compounds In which R la -f S-^ can be ptepared from the compounds of the foranla (II) as follows nJXr-CHjOTNHj Cl. CH-CH^MCS ^ rw CHj-O-Y-N-^ (XI) The reaction la typically carried out by stirring the reactants together is a suitable organic solvent, e.g. methylene 10 chloride, for a few hours, and again the product can then be Isolated and purified conventionally. The presence of base la the reaction mixture, e.g. trlethylsalne. Is preferred. (4) Compounds In which R is (C1-C4 alkyl) <i COOtC^-C^ alkyl) or -< -n <i can be prepared as follows:- "it coca CHj N CHjOYN-C-NHJ B B (IV) C1.CH2CH0 or Sr.ca2flto ,^-CH.OYH <3 (XV) Bgta2COCOO.(C1-C4 alkyl) or CICHjCOCOO.(Cx-C4 alkyl) (XV) Clta2CO(Cl-C4 alkyl) or BrCH2CO(C^-C^ alkyl) CHjOYN -wnj- CH201M' rfl COO(C1-C4 alkyl) (Cx-C4 alkyl) (1T) BrCHjCOOEt or CICHjCOOEt ~rw- CHjOTO-^ S— The reaction Is typically carried oat by stirring the reactancs together ac room temperature In a sulcable solvent, e.g. CHCl^/CH^OH, until the reaction is substantially complete. If 10 necessary, the reaction mixture can be heated to accelerate the reaction. The product can be Isolated conventionally.

The. starting materials of the formula (IV) can be prepared from the compounds of the formula (II) as follows:- S I «W-CH2<J*KH2 Cl-C-Cl ^~-CH-.OYN-OS CaCOj| CH^Cl^/H^O| (II) room temperature NH3/EtOB. heat. 2>5 hours t s ^ I CHjOYBCSHJ ^ NH (IV) (5) Compounds in Which R3 Is | can be prepared follows:- wCH2<mm-l!-»Hco2c2H5 i) CH3I ^CH2OYHH-^ :a*a!j^0H ^ 11) hydrazine 8 H hydrate The starting ethoxycarbonylthioureldo derivatives can be prepared as follows S II rMv-C^OTHHj S-C"N-CO.Et^ njw CH^OTNH-C-NHCO^C^Hj. 3 (6) Compounds in vhich R Is -a " "O"" H 3 CH3 can ba prapared by the reaction of the correapondlng talao 3 compound (R - H) with 5-acetyl-2-amlno-oxasole In aqueoua ■ethanol. typically by heating for 24 houra or so. The reaction 3 S producea a mixture of two products having R aa above. These can be separated by conventional chromatographic procedures. (7) Soma of the conpounda of the formula (I) can' be prepared from 3 other conpounda of the formula (I), e.g., those where R la a heterocyclic group subatltuted by an [C^-C^ alley 1] carbamoyl group can be prepared by the reaction of the correapondlng conpounda In which the heterocyclic group la subatltuted by (Cj-C^ alkoxy)carbonyl with a C^-C4 alkylamina. Similarly, conpounda in which R3 la substituted by -IHj can be prepared by reacting the correapondlng methoxy-substltuted derivatives with ammonia, IS generally in ethanol, and conpounda in which R3 Is substituted by -NHCONM(Cx-C4 alkyl) by reaction of tha corresponding amlno-aubatltuted compound with a C^-C4 alkyllaocyanate. 3 Compounds in which R Is a heterocyclic group subatltuted by an amino or aubatltuted amino group, or a cyclic amino group, e.g. 20 morphollno, plperldlno or N-methyl plperazlno, can be prepared by heating the correapondlng chloro-aubstltutad compound with the appropriate amine. 3 Compounds in which R is pyrazlnyl can be prepared by the 3 reduction of the correapondlng compound In which R is a 25 pyrazlne-N-oxlde with aodlum dlthionlte, e.g. by heating In aqueous ethanol. 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 la 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 is shown by their effectiveness in reducing the response of Isolated heart tissue to an Increase la calcium ion concentration In vitro. The test is performed by mounting spirally cut strips of rat aorta with one end fixed and the other attached to a force transducer, the tissue is lamersed In a bath of physiological saline solution containing potassium ions at a concentration of 45 allllmolar and no calcium. Calcium chloride Is added to the bath with a pipette to give a final calcium ion concentration of 2 millimolar. The change In tension caused by the resulting contraction of the tissue is noted. The bath is drained and replaced with fresh saline solution and, after 45 minutes, the test Is repeated with the particular compound under test.present in the saline solution. The concentration of compound required to reduce the response by 50Z (ICjq) Is recorded.

The antihypertensive activity of the conpounda la also evaluated after oral administration by measuring the fall In blood pressure in spontaneously hypertensive rats or renally hypertensive dogs.

For administration to nan In the curative or prophylactic treatment of cardiac conditions and hypertension, oral dosages of the compounds will be in the range of from 5-100 mg dally for an average adult patient (70 kg), typically 10-60 mg dally. Thus for a typical adult patient, individual tablets or capsules will generally contain from S, 10 or 20 mg of active compound, in a suitable pharaaceutlcally acceptable vehicle or carrier. Dosages for Intravenous administration will typically be within the range 1 to 10 mg per single dose as required. In practice the physician will determine the actual dosage which Will be most suitable for an 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 conpounda 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 practice. For example, they may be administered orally In the form of tablets containing such exclplents as starch or lactose, or in capsules or ovules either alone or in admixture with exclplents, or In the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected parenterally, for example. Intravenously, Intramuscularly or subcutaneously. For parenteral administration, they are best used In the forn of a sterile aqueous solution which nay contain othet substances, for example, enough salts or glucose to make the .. solution Isotonic.

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

The invention also includes a compound of the formula (I), or a pharmaceutical^ acceptable acid addition salt thereof, for use 10 in medicine, In particular in the treatment of iachaemic heart disease, angina, or hypertension in a human being.

The following Examples Illustrate the Invention. All temperatures are In °C:- EXAMPLE 1 A. H- ^2-[ (4-1^2-Chlorophenyl^ -3-ethoXYcarbonvl-S-ttethoxv-carbonyl-6-methyl-l.4-dlhydropyrid-2-vl)aethoxy]ethylj^ -H'-cyano-S-methyl-laothlourea Cu-=i~ xc MaOOC «nr» MeOOC 2-(2-Amlnoethojty«!«thyll-3-ethorycarbonyl-4-(2-chloro-phenyl)-5-BethoxycArbonyl-6-nethyl-l,4-dihydropyridine (4.3 g) and 10 dimethyl N-cyanolmldodithlocarbonate (2 g) In isopropanol (IS ml) were allowed to stand at room temperature for 4 hours. Ether (30 ml) was than added and the mixture was stood at room temperature . overnight. The crystalline precipitate was filtered, washed with ether and dried, yield of the title compound 5.0 g, m.p. 177-179*.

IS Analysis Z:- Found: C,54.35; H.5.4; H.11.2 Calculated for C^HjjCIN^S: C.54.5; H.5.4; H,11.05.

B. 2 - f 2- (3-Aalno-1.2.4--trlarol-5"ylamlno) eth0xvm3thyl] -4-12-chlorophenyl)-3-ethoxTcarbonyl-5-«iethoxycarbonyl-6~aathyl-1.4-dlhydropyrldlne M—X. X : ^ H- ^2-[ (4-^ 2-Chlorcrpheayl^ -3-ethoxycarbony 1-5-oetboxy- carbonyl-6-methyl-l,4-dlhydropyrld-2-yl)methoxy]ethyl^ -a'-cyano-S-sethyl-lsothlourea (0.4 g) and hydrazine hydrate (0.15 al) were dissolved in ethanol (20 al) and heated under reflux for 3 hoars. The solvent was then evaporated and toluene (10 al) was added to 10 the residue, and again the solution was evaporated to dryness. The residue was chroaacographed on Merck "Klaselgel 60H" (Tirade Mark), eluting with 22 aethanol in aethylene chloride, to give a beige solid. The solid was reerystalllaed froa ethyl acetate plus a trace of ether to give the title coapouikd, yield 0.1 g, m.p. 15 137-138*.

Analysis' Found: C.53.45; H.5.5; H.17.2 Calculated for C^H^ClNgOji C.53.8; H.5.55; H.17.1.

Part (A) was repeated using (MeO^ON.CN In place of (MeS)2OH.CN and using the same reaction conditions. The resulting intermediate had -OMe in place of -SMe, 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-[ 2-(3-Amlno-].2.4-tojazol-5-jylan)lno)ethbxvmethvll -4- (2-chlono -3 - trifluoroaethylphei»yl)-3-ethoxycarboayl-5-iiethoXycarbonyl-6-m-ethy1-1.4-dlhydropyridine 2-(2-Aminoethoxymethyl)-4-(2-chloro-3-trlfluoroi»ethyl-pheryl)->3-etto^carixD^l-S-inethcoycarixMyl-e^-inethyl-l ,4-dlliydK^iyridlne (0.5 g) and dimethyl N-cyanolnldodlthiocarbonate (0.16 g) in lsopropanol (5 ml) were stirred together at room temperature for 4 hours. Ether (10 ml) was then added and the mixture was stirred for a further 2 hours. The precipitated lsothiourea was filtered, washed with dry ether, dried and used directly without further purification. The solid was dissolved in ethanol (10 ml) and heated to reflux while hydrazine hydrate (0.2 ml) was added in three portions. After 3 hours at reflux, the solution was evaporated to dryness and the residue was crystallised from ethyl acetate to give the title.compound, m.p. 144-145*.

Anal2sls_Z.:- Found: C.,49.4; H.4.7; N.15.0 Calculated for CjjHjgClFjNgOj: C.49.6; H.4.7; N.15.0.

A. The following compound, a.p. 215-217*, was prepared similarly to Example 1A, but starting from the corresponding 4-(2,3-dichlorophenyl)-1,4-dlhydropyrldyl derivative: EXAMPLE 3 Cl CHjCOC ca. '3 Analysis Z;- Found: C.50.7; H.5.05; N.10.1 Calculated for C^HjgCl^OjSsC,51.02; H.4.85; H.10.35. >. This compound was then reacted with hydrazine hydrate according to the procedure of Exaaple IB to produce the following product, m.p. 195-6*:- N —N ■ AA . 1/4 ethyl acetate Analysis Z:-Found: C.50.2; H.5.35; H.15.6 Calculated for C22H26Cl2M605.l/4 C^gOji C.50.45; H,5.15i N.15.35.

EXAMPLE 4 The following compound, n.p. 110-111*, was prepared similarly to Example IB, but using methyl hydrazine AnalyslB Z:- Found: C.54.1; H.5.8; N.16.3 Calculated for C^H^ClHgOj.JiHjO: C.53.7; H.5.9; 16.35.

EXAMPLE 5 Tha following compound m.p. 118-120.5" was prepared similarly Co Example 3B, but using methyl hydrazine , Me M — N.' .>>b2o Analysis t:- Found: C.50.6; H.5.3; N.IS.O Calculated for c23H28C12N6°5-llH20: c»50'4> H>5-3! H.15.3.

EXAMPLE 6 2-[ 2-(5-Aalno-l, 2.4-oxadla«ol-3-ylamlno)ethoxyethyl1-4-{2-chloro-phenyl)-3-etKoxycarbonyl-5-aethoxycarbonyl-6-eiethyl-1.4-dlhydro-pyrldlne N— O :A.A, nh.

The S'-cyano-S-raethyl-isothiourea froa Example 1A (0.4 g) and hydroxylaaiae (0.2 g) In methanol (20 ml) were heated under reflux for 3 hours. The solvent was then evaporated, and the residue was chromatographed on "Kleselgel 60H" (Trade Mark), elutlng with chloroform to give a solid which was recrystalllsed 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; 8,14.25 Calculated for C^fl^ClHjOg: C.53.7; H.5.3; N.14.25.

The following compound, m.p. 114*, was prepared similarly to 2-chloro-3-trlfluoromethyl isothlourea intermediate as prepared in Example 2:- ' examfle7 the procedure of Example 6 but using the corresponding chjooc ch, 3 Analysis I:-Found: Calculated for jCIFjNjOj: C.49.6; H.4.7; N.12.4 C.49.3; H.4.5; M.12.5. 28 - EXAMPLE 8 4-i2-Chlorophenyl)-3-ethoxycarbopyl-5-«cthoxyc>rbonyl-6-eethyl-2-I2-(3.A-dlhydro-4-oio-pyrlmldln-2-ylanlno)ethoxyacthyll-1,4-dl-hydropyrldlne 2-[2-Aminoethoxyi»atliyl]-3-«thoxycarbonyl-4-(2-chlorophenyl)-5-methoxycarbonyl-6-»ethyl-l,4-dihydTopyridlne (0.7S g) and 2-isethylthi0-3H-pyriald-4-0Q« (0.5 g) were dissolved in ethanol (5 ml) and heated under reflux for 20 hours. The solvent was 10 evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with 2H 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. 15 Chromatography on silica "Kleselgel 60H" (Trade Mark) eluting with ethyl acetate gave the title compound, which was recrystalllsed from ethyl acetate, yield 171 mg, m.p, 148-150".

Analysis X:- Fouttd: C,57.3; H.5.55; H.11.6 Calculated for C^^CWjO^. C.57.3; H,5.4; H,11.15.

H O - 29 -EXAMPLES 9-36 The following compounds were prepared similarly co the previous exaaple. I.e., by Che following reaction and ware characterised la Che form indicated:- Example Mo.

R3 Q Reaction Solvent Base Reaction Time Form Isolated m.p. (•c) Analysis % (Theoretical in brackets) c h n 9 n _ n -1^ b 0 MeS- EtOH Et3N 4 hrs.

Free base 155-157 55.8 5.55 11.3 (56.25 5.55 11.4) n -O C1 chjch Na2C03 6 hrs.

Free base 137 59.05 5.7 11.3 (59.2 5.6 11.5) 11 n=knh2 Cl MeOH EtjH 12 hrs.

Free base . 186-189 53.25 5.5 18.6 (53.3 5.45 18.9) V- 1 Exanple Mo.

R3 Q Reaction Solvent Base Reaction Tine Form Isolated ■.p.

CC) Analysis X (Theoretical in brackets) C R.N 12 -O" Cl n-BuOH EtjH 60 hrs.

Free base 225 56.5 5.4 11.05 (57.35 5.4 11.15) • 13 Cl n-BuOH Kt3H 60 hrs.

Free base 172-174 57.2 5.8 13.8 (57.4 5.6 13.95) _/N=\ —4 NH o Cl n-BuOH EtjM 18 hrs.

Free base 120-122 56.9 5.3 10.9 (57.35 5.4 11.15) _/~c » ■ o Me Cl n-BuOH EtjN 18 hrs.

Free base, H2O 122 55.2 5.85 9.8 (55.25 5.9 9.9) Example No.

R3 Q Reaction Solvent Base Reaction Tine Torn Isolated m.p.

CC) Analysis X (Theoretical in brackets) C H H 16 N"^ :vr N^NH Cl CH3CN H.2C°3 hrs.

Free base 153-155 56.9 5.15 15.9 (57.0 5.2 15.95) 17 OMe Cl n-BuOH EtjM hrs.

Free base 205-207 57.35 5.3 8.9 (58.8 5.4 9.15) 18 Cl Cl MeOH EtjM 2 hrs.

Free base 160 55.35 5.2 10.9 (55.3 5.0 10.75) 19 <0 Cl D.M.F. ».2C03 hrs.

Free base 176-177 59.75 5.4 7.55 (59.8 5.2 7.75) Example No.

R3 Q ! Reaction Solvent Base Reaction Tine Form Isolated n.p.

CC) Analysis Z (Theoretical In brackets) C H N JJ -OEt EtOH ' - 34 hrs.

Hydrochloride 166-167 36.2 6.15 8.35 (56.25 6.1 8.2) 21 N —J H -SMe EtOH Et3N 6 hrs.

Acetate 164 55.03 6.15 10.45 (55.9 6.2 10.45) 22 XT Cl ti-BuOH 4- diuethyl- anlno- pyridlne 18 hrs.

Maleate 2,H2° 156-138 53.9 5.1 8.4 (53.85 5.0 8.3) 23 .

CH, N-4-CH ll -SMe - EtOH Et3N 1 hr.

Free base 226-228 57.5 6.0 10.8 (57.8 6.0 10.8) Exaaple No.

R3 Q ReacCloti Solvent Base Reaction Tine Form Isolated m.p.

(*C> Analysis Z (Theoretical in brackets) CBN 24 CH, -i3 h o -NHN02 n-BuOH - 18 hrs.

Heni-fuaarste 197-199(d) 56.3 5.4 9.8 (56.4 5.4 9.7) CONB, o -Cl n-BuOH 4-dinethyl- snlno- pyridine 18 hrs.

Maleate 163.5-164 56.0 5.1 8.6 (56.1 4.7 8.7) 26 /PH3 S -/A* -O * N -Cl n-BuOH 4-dlnethyl- amino- pyridine 24 hrs.

Free base 125 50.1 5.1 9.1 (50.1 5.2 9.3) 27 NH <s M mJ Cl n-BuOH EtjH 60 hrs.

Tree base Heni-etherate 101-104 57.7 6.2 12.9 (57.9 6.2 13.0) Exaaple Mo.

R3 Q Reaction Solvent Base Reaction Tine Fora Isolated n.p.

CC) Analysis Z (Theoretical in brackets) c h n 28 ■Q cn -cl n-BuOH i-dlnethyl- imlno- pyrldlne hra.

• Free base 133-134 58.4 5.2 13.3 (58.7 5.1 13.7) 29 -{3 cokhj -cl n-BuOH i-dlnethyl- anlno- pyrldlne 4 hrs.

Free base 211 56.5 5.3 13.0 (56.7 5.3 13.2) .N =\ -cl n-BuOH 4-dlnethyl- amlno- pyrldlne 18 hrs.

Ethyl acetate 124-126 57.4 5.8 10.0 (57.8 5.6 10.0) 31 -C$ \-r cl ch2ci2 Et3N 26 hours Free base US 55.1 5.1 10.6 (55.3 5.0 10.75) 32 Cl cl EtOH etjn 18 hours Free base 110 55.4 5.35 10.4 (55.3 S.O 10.75) Exaapla Ho.

R1 q Reaction Solvent Base faction i Tl*fi i— —1 Isolated a.p.

CP) - Analysis I (Theoretical in brackets) CHS 33 Cl EtOH EtjH 18 hour* ftn twi 142-144 55.3 4.9 10.6 (55.3 5.0 10.75) 34 a%C3 '^N'^SXS)CH3 Cl BuOH 4-Dloethyl amino pyridine 18 hours Free base 172-173 58.4 5.8 11.5 (58.9 5.6 11.4) o^' Cl BuOH .

Et3N 48 hours Free ^sse 165-168 53.5 5.25 9.8 (53.1 5.2 9.9) 36 ^^02{J-CH( Cl EtOH EtjH 60 hours Healhydrate 165-167 53.9 5.5 10.75 (53.8 5.6 10.45) EXAMPLES 37-57 The following compounds were prepared similarly to Exaaple 8, i.e. by the following reaction:- and were characterised in the form indicated:- Example No.

R3 Q Reaction Solvent Base Reaction Time Form Isolated m.p. co Analysis Z (Theoretical In brackets) C H . N 37 N -v, H -SMe EtOH EtjN 3 hrs.

Hemlhydrate 218 (d) 51.7 5.0 10.3 (51.7 5.1 10.5) 38 7> -cfr H 0 -SMe EtOH EtjN 22 hrs.

Free base 225-227 53.2 5.4 10.0 (53.4 5.6 10.0) 39 o H 0 -SMe EtOH Et3N 24 hrs.

Hemihydrate 142-145 52.5 4.7 10.4 (52.7 5.0 10.3) 40 -Lj i -Cl n-BuOH Et3N 36 hrs.

Free base 179 53.5 5.2 13.0 (53.7 5.1 13.1) Exaapla Mo.

R3 Q Reaction Solvent Base Reaction Tiae Font Isolated a.p.

CC) Analysis Z (Theoretical in brackets) C H M 41 —4 NB -Cl n-BuOH- l-diaethyl- uaino- pyrldlne hra.

Free base heml-bydrate 132-134 52.9 4.8 10.5 (52.75 5.0 10.3) 42 B O -NHN02 n-BuOH - 18 hra.

Fumarate 144-146 52.4 4.9 8.6 (52.2 4.8 8.4) 43 T° -NHNO2 BuOH - 18 hours Free base 201 56.3 4.7 7.7 (56.0 4.8 8.1) 44 1 ky» V» L_ J -KHNO2 BuOH - 18 hours Free baae 205-206 56.65 4.9 11.0 (56.7 4.8 11.4) Exaaple No.

R3 <1 Reaction Solvent Base Reaction Tine Font Isolated Iftepe CC) Analysis Z (Theoretical In brackets) C H N 45 0""0 Cl BuOH EtjN L8 hours Free base 177.5-178.5 51.7 5.1 8.5 (52.0 5.1 8.4) 46 O"0 Cl BuOH 4-Dimetbyl amino pyridine 32 hours Sesqul-hydrate 182-183.5 51.7 5.3 7.9 (51.9 5.7 8.1) 47 CT" Cl EtOH EtjH 66 hours Free base 101-104 51.55 5.3 9.0 (51.7 5.1 9.0) 48 Cl BuOH 4-Dlaethji amino pyridine 18 hours Free base 190 55.6 5.2 10.6 (55.7 5.15 10.8) 49 clI» Cl EtOH EtjM 18 hours Free base 101-103 55.2 4.6 9.00 (55.5 5.0 9.25) Exaaple Mo.

R3 Q Reaction Solvent Base Reaction Tine Fora Isolated - n.p.

CC) Analysis Z (Theoretical In brackets) C H N 50 O f X) Cl EtOH Et3N 17 hours Free base 148-150 53.5 (53.6 .0 4.9 .4 10.4) 51 'TO Cl EtOH EtjH 18 hours Free base 111-112 51.6 (51.9 4.3 4.5 .2 10.1) 52 XX Cl EtOH Et3N . 18 hours Free base 113-115 51.8 (51.9 4.6 4.5 .0 10.1) 53 £ Cl EtOH EtjH 4 hours Free base 110 51.7 (51.9 4.5 4.5 9.9 10.1) 1 1 ! 1 .

I « 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) Example No.

R3 Q Reaction Solvent Base Reaction Time Fora Isolated m.p. <*C) Analysis X (Theoretical In brackets) C H N 55 N - kjjt 3 Cl BuOH Et3N hours Free base 146-148 58.4 5.0 9.3 (58.7 4.9 9.1) 56 o Cl BuOH Et3H 7 hours Free base 158-160 55.5 5.0 10.9 (55.3 5.0 10.75) 57 JvA OiPr Cl BuOH EtjN 17 hours Free base 137-139 55.8 5.7 9.8 (56.0 5.6 9.7) EXAMPLES 58-63 Tha following conpounda were prepared similarly to Exaaple 8, I.e. by the following reaction:- and were characterised In the form Indicated:" Example No. 58 R3 Q Reaction Solvent Base Reaction. Tine Form Isolated m.p. • CC) Analysis X (Theoretical in brackets) c h H -SMe EtOH Et3N 4 hours Hemlhydrate 206-208 50.4 4.7 9.7 (50.75 4.8 9.9) 59 -Q -SMe EtOH - 24 hours Free Base 139-140 52.6 4.6 9.85 (52.6 4.6 9.8) 60 -& -Cl n-BuOH 4-diaethyl- amino- pyrldlnc 24 hrs.

Free Base 135-136 52.3 4.6 9.7 (52.6 4.6 9.8) 61 <? B 0 -nh.no2 n-BuOH - 18 hours Free Base 147-149 53.5 5.2 9.4 (53.4 4.8 9.6) Example No.

R3 Q Reaction Solvent - Base Rasctlon Time Fora Isolated m.p.

C C) Analysis Z .(Theoretical in brackets) C H H 62 b -Ska n-BuOH - 72 hours.

Free Base 128-130 52.2 (52.6 4.7 4.6 9.9 9.8) 63 jCT -Cl IMF - - 24 hours HCl.ldljO 175 50.4 (50.5 4.5 4.7 8.2 8.7) £ EXAMPLE 64 3- ^2-[(4- ^2,3-DichXorophenvl^ -3-ethoxycarbonyl-5-««thoxy-carbonvl-6-methy 1-1.4-dlhydropTrld-2-yl)methoxy ] ethy laalno^ -ae thory-1. 2.5-thladla«ole-l-oxlde HaOOC 2-[2-ABlnoetlioxyaethyl]-3-ethoxycarbonyl-4-(2,3-dichloro-phenylO-S-wethoxycarbonyl-^-isathyl-l^-dihydropyridirie (0.5 g) and 3,4-dlaathoxy-l,2,5-thladla»ole-l-oxide (0.2 g) were dissolved In 10 methanol (15 al) and heated at reflux for 14 hours. The solvent was evaporated and the residue chrooatographed on silica "Kleaelgel 60H" (Trade Mark), elutlng with ethyl acetate. The product-containing fractions ware combined and evaporated to give an oil which was triturated In ethyl acetate to give the title 15 compound as a solid, yield 0.14 g, m.p. 183-185°.

Analysis I:- Found: 0,48.1; H,4.6; N.9.4 Calculated £or C^H^Cl^OjS:C,48.15; H.4.55; K.9.75.

EXAMPLE 65 The following compound, m.p. 158-160*, was prepared similarly to the previous Example, starting from the corresponding 4— (2— c±aorophenyl )-lf4-dlhydropyrldlne and 3,4-dlmethoxy-l,2,5-thladiazole-l-oxide. The reaction time was 18 hours, and the solvent methanol:- Analysis Zi- Found: C.52.0; H.5.4; N.10.1; Calculated for C23H27C1N407S: 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-chloro-3-trifluoromethylphenyl)-l,4-dlhydropyrldlne and 3,4-dimethoxy-1,2,5-thiadlazole-l-oxide. The reaction time was 18 hours, and the solvent methanol:- chjooc CH, Analysis ?ound! C.47.3; H,4.4; N,9.4 Calculated for C24H26C1F3N407S: C.47.S; H.4.3; N.9.2.

EXAMPLE 67 3-^2-1 (4-fe.3-Dlchlorophenyl^-3-ethoxycarbonyl-5-ii«thoxycarbonyl-6-methyl-1.4-dlhydropyrld-2-yl)«iethoxylethylamlno^ -4-aMino-1.2.5-thladlazole-l-oxld« healhvdrate .

MeOOC 3-^-2-[ (4- £2,3-Dlchlorophenyl$ -3-«thoxycarbonyl-5--m«thoxy- c«rbonyl-6-methyl-l.4-dihydropyrid-2-yl)Bethoxy ]athylaoino^ -4-aethoxy-l,2,5-thladlacola-l-oxlde (0.3 g) vii dissolved la ethanollc ammonia (10 al) and stirred at rooa teaperature for 1 5 hour. The solvent was evaporated and the residue chroaatographed on silica "Kleselgel 60H" (Trade Mark), eluting with ethyl acetate. The product containing fractions were combined and evaporated to give an oil which was triturated with ethyl acetate to give the title compound as a solid, yield 0.15 g. a.p. 135*.

Analysis t:- Found: C.46.6; H.4.6; 11,12.1 Calculated for C22H25C128506S•'4B20: C.46.6; H.4.6; H.12.3.

EXAMPLE,68 The following compound, a.p. 130*. was prepared similarly to 15 the previous Exaaple, starting from the corresponding 2-chloropheoyl coapound and aanonla/EtOH. The reaction tine was 1.5 hours:- B H Analysis I:- Found: C.50.4; H.5.3; H.13.3 Calculated for C22H26C1SS06S: C.50.4; H.5.0; H.13.4.

EXAMPLE 69 3 -The following compound, a.p. 142-145°, was prepared similarly Co Exaaple 67, starting from the corresponding 2-chloro-3-trlfluorapetbylpheayl compound and asaonia/ethanol. The reaction tlae was one hour:- Analysis li-Foimd:.

Calculated for C23H25C^r3lf506S: ^2°: C.45.6; H.4.5; H.11.6; C.46.0; H.4.4; H.11.65. - 51 -EXAMPLE 70 4-(2-Chlorophenyl)-3-atho3cycarbopyl-5-«ethoxyc«rl>oiiyl-6-methyl-2-[2-(2-thlaiolln-2-ylaalno)ethoxymetliyl1-1.4-dlhydroi>yrldlne S 2-[2-AminoethoxyBiethyl]-3-ethoxycarbonyl-4-(2-chloro- phenyl)-5-raethoxycarbonyl-6-methyl-l,4-dihydropyrldine (0.5 g), trlethylamina (0.3 ml) and 2-chloroethyllaothlocyanate (0.16 ml) were dissolved la methylene chloride (5 ml) and the mixture was stirred at room temperature for 2 hours. The mixture was then 10 washed with water (5 ml), dried, filtered and evaporated co give gum. -Chromatography of the gum on silica "Kleselgel 60H" (Trade Mark) elutlng initially with toluene then with chloroform with a trace of methanol gave the title compound, which was recryatalllaad from ether, yield 0.102 g, m.p. 145-147*.

Analysis Z:- Found: C.55.6; H.5.75; K.8.3 Calculated for C23H28C1B305S: C*55*6: H.5.75; H.8.3.

EXAMPLE 11 4-(2-Chlorophenyl)-3—«thoxycarbonyl-5-iiiethoxycarbonyl-6-netbyl-2-[ 2-(thlazol-2-ylamino) ethwcy—thy 11 -1.4-dlhydropyrldlne (a) Thlophosgene (0.9 (1) was added to a stirred mixture of 2-(2-aainoethoxymethyl)-3-ethoxycarbonyl-4-(2-chlorophenyl)-5-«et-hoxycarbony1-6-oethy1-1,4-dlhydropyrldlne (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 ■ethylene chloride. The organic layer was washed with water, dried; (hjCOj), filtered sad evaporated to give the Intermediate lsothlocyanate as a solid.

This solid was used directly In the next stage of tin reaction without further purification. (b) The laothlocyanate from part (a) (4 g) vaa heated In ethenollc ammonia solution for 3h hours. The resulting precipitate was filtered and recrystalllsed from ethanol/methylene : chloride (5:1) to give the Intermediate thiourea, yield 3.8 g, ■.p. 203.5-204.5*.

Analysis I:- Found: C,53.3; H.5.5; R.8.6 Calculated for Cj^gNjClOjS: C.53.8; H.5.6; N.,8.9. (c) The thiourea from part (b) (0.2 g) and chloroacetaldehyde (0.1 g) were dissolved la a 1:1 mixture of chloroform/nethanol and the mixture was stirred st room temperature overnight. Removal of the solvent by evaporation left an oil to Which toluene (10 ml) was added. After removal of the toluene by evaporation the residue was chromatographed on silica ["Kleselgel 6OH" (Trade Mark)]. Elutlon with toluene, ethyl acetate and finally ethyl acetate/IX methanol afforded a white solid which was recrystalllsed from ether to give the title compound, yield 0.075 20 g, m.p. 134*.

Analysis X:- Found: C.56.0; H.5.4; N.8.4 Calculated for C23H26CU,3°5S: c'56al5> H'5-3I M.8.5. 72-74 The following compounds were prepared similarly Co cha oethod described In part (c) of Che previous Exaaple, scarclng from Che same incensedlate thiourea and, respectively, ClCHjCOCB^, BrCHjCGCOOEt and BrCHjCOOEt.

Example No.

R3 Reaction Solvent Reaction Time m.p. (*C) Analysis Z (Theoretical In brackets) C H H 72 ij"3 :1:0.5 CH.G1,: MeuH: Etjti 3 hrs., reflux temp. 147* 56.7 5.75 8.05 (56.95 5.6 8.3) 73 N—^COQEt "< l s JJ :1:0.5 CHC1.: MeOHT Bt3R 18 hrs.. room temp. 129- ■ 131* 55.3 5.75 7.15 (55.35 5.35 7.45) 74 0 100:1-1 12 hrs., room temp. 160-162* 54.1 5.2 8.1 (54.4 5.2 8.3) EXAMPLE 75 Th« following corpound, a.p. 190-192" was prarparad slallarly to Exaapla 74 but starting from the correapondlng 4- (2-chloro-3H^fluoronethylphemyl) -1,4-dihydropyridLrie and without Isolation of tha laternedlatea. the reaction tlae was 20 hourss- chjooc Analysla I;- Found: C.50.1; H.4.3; H.7.1 Calculated for C^HjjClFjHjOgS: C.50.0; H.4.4; H.7.3.

EXAMPLE 76 Preparation of 4-(2.3-PichlorophanTl)-3-ethoxTcarboBYl-5-aathoxy-carbonv1-6-nathy1-2-[2-(4-oxo-2-thlagolln-2-ylari.no)ethoxv-methy11-1,4-dlhydropyrldlna c°2c2h5 0-«2ch2nh-i 1 - The title conpound. m.p. 204-205°, was praparad by a nethod similar, to that In Exaaple 74 but starting with tha eorraspondlng 4-(2, 3-dlehlorqphenyl) -1, 4 <~dihydropyrldlnft. The reaction conditions 5 were tha saate':- Analyals t:- ' Found: C.51.2; H.4.7; H.7.7 Calculated for C^H^Cl^OgS: C.50.9; H.4.65; H.7.75.

EXAMPLE 77 4-(2-Chlorophemrl)-3-ethoKTcarbonyl-5-—thorycarbonyl-6-—thyl-2~ [2-(4-[N-»athylc«rbamoyl]-thlazol-2-ylamino)athoxroethy11-1.4-dl-hydropyrid ina The eater product of Example 73 (0.1 g) was dissolved In a IS 33Z solution of methylamlne In ethanol (10 ml) and the mixture was stood at room temperature overnight and then warmed briefly on a steam bath. Tha solvent was removed by evaporation and the residue chnautographed on silica "Klsaelgel 60H" (Trade Mark). Elution with toluene and then 1:2 toluene/ethyl acetate afforded a solid which was recrystalllaed from ether to give the title compound, yield 52 mg, n.p. 120*.

Analysis Found: Calculated for C^Hj^ClH^OgS: C.54.35; H.5.3; N.10.2 C.54.7; H.5.3; H.10.2.

EXAMPLE 78 2-12-(4.5-DlhTdro-5-oso-l. 2.4-oxadlazol-3-ylaaino) ethoxyaethyll -4-(2.3-dlchlorophenTl)-3-ethoxycarbonyl--5-iaethoxTcarbonyl-6-methyl-1.4-dlhydroi»yrldlne aonohrdrate •h2° H-£2-[4-^2,3-Oichloropheny]J-3-ethoxycarbonyl-5-«ethoxy- : 10 carbonyl-6-methyl-l,4-dihydropyrid-2-yl)i*ethoxy]ethy{| -N'-cyano-S-methy1-1sothiourea (400 mg) was added to a solution of hydroxylaalne hydrochloride (57 «g) and sodium aathoxlde (44 sg) In methanol (10 al) and heated under reflux for 1 hour. The solution was evaporated to dryness and the residue taken up In 15 ethyl acetate and waahed with 2M hydrochloric acid and aqueous sodlua carbonate. The organic layer was dried over magnesium sulphata, filtered and evaporated. Tha residue wa« chrooatographad on "Merck" (Trade Mark) J60 silica slating with ethyl acetate. 'The product containing fractions were combined and evaporated to dryness, trituration with ether giving the title 5 compound (70 ng), m.p. 132-134*.

Analysis 88- Found: 0,48.45; H.4.8; N.10.3 Calculated for C^Hg^CljH^Oj.HjO: C.48.3; H,4.9; N.10.5.

EXAMPLE 79 2- [ 2-(2-Hathyl-3-/3-»»thylureldoV-2H-l. 2.4-tria«ol-5-ylaalno) -ethoxy—thyl ] -4- ( 2.3-dlchlorophenyl) -3-«thMtycarbonyl-5-methoxycarbony1-6-methy1-1.4-dlhydropyridlne hydrate A solution of (1) (0.2 g; product of Example 9 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 chroaatographed on Merck (Trade Mark) J60 silica elutlng with SZ 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 Z;- Found: C.51.8; B.5.9; H.16.9 Calculated for C^H^ClHfOg.BjO: C.51.8; H.5.9; N.17.1.

EXAMPLE 80 4-(2,3-Dlchlorophenyl)-3-ethoxycarbonyl-5-aathoxycarbonyl-6— methyl-f2-(6-«orphollnopTrinidin-4-yl«aino)ethoxvmethy1]-1.4-dlhydrowrridlne 3 b b b B . 4-(2,3-Dlchlorophanyl) -3-ethoxycarbonyl-5-»ethoxycarbonyl-6-aethyl-2-[2-(6-chloropyrinldln-4-ylaalno)•thozyaathyl]-1,4-dlhydropyrldlne (0.3 g) (Product of Exaaple S3) end norpholine (S ■1) ware heated together on a ateaa bath for 18 hours. The.excess 5 aorphollne was then evaporated and the residue was taken up In ethyl acetate, filtered and chronatographed on silica "Kleaelgel 6OH" (Trade Mark) elutlng with ethyl acetate. The product-containing fractions were conbined and evaporated to dryness, trituration with ether giving the title cospound (165 10 ag), a.p. 163*.

Analysis I:- Found: C.55.1; H.5.5; N,11.2 Calculated for CjgH^CljMjOg: C,5S.4S; H.5.5; N,11.55.

EXAMPLES 81-84 The following coapounds were prepared similarly to the previous Exaaple, I.e. by the following.reaction. and were characterised in the fora Indicated:- Exaaple Ho. y ■~y Reaction Solvent Reaction Tlae Form Isolated a.p.

CC) ■ i Analysis X (Theoretical In brackets) C H H 81 . A ^ VcH w 3 - 18 hours Free base 168-170 56.5 5.9 13.4 (56.2 5.9 13.6) 82 - 18 hours Free base 140-142 57.9 5.7 11.2 (57.6 :5.8 11.6) 83 B YY^ EtOH 18 hours Free base 158 54.2 5.2 12.8 (54.55 5.3 12.7) . 84 J5 CH3 EtOH . 30 hours Free base 88-90 54.5 5.55 12.6 (54.55 5.3 12.7) - 63 -EXAMPLES 85-8.7 The foUcwtng conpounda vara prepared similarly to Example 80, i>a. by the following' reaction S and were characterised la the fora Indicated:- Exaaple No. y Reaction Solvent Reaction Time Form Isolated D«p» CC) Analysis X (Theoretical In brackets) C H N 85 N^H ' - 18 hours Hydrate 147 59.4 6.4 11.8 (59.2 6.5 11.9) 86 /""\ Y »v/» - hours Heai-fuaarate Haal-hydrate - 171 56.4 5.8 10.95 (56.3 3.75 U.3) 87 X 0 i i - 18 hours .

Free base 133-134 58.45 6.0 12.4 (58.8 6.0 12.2) - 65 -EXAMPLE 88 4-(2-Chloro-3-trlfluoroaethylph«nyl) -3-ethoxycarbonyl-5-mBthogyca-rbonyl-6-aBthvl-[2-(6-iaorphollno-pyrlBldln-4-ylamlno)ethorymethyl- methoxycarbonyl-6-«athyl-2-[2-(6-chloropyri»idin-4-ylamino)-ethoxynethyl]-l,4-dlhydropyridine was prepared similarly to the procedure of Exaaple 53 from appropriate starting materials and 10 was reacted unpurlfled with aorpholine by a procedure slallar to that of Exaaple 80 to give the title compound, a.p. 117-118*.

Analysis t:-Found: Calculated for C29H33C1?31,5°6: C.54.0; B.5.6; 11,10.7 C.54.4; H.5.2; H.10.9Z. - 66 -EXAMPLE 89 4-( 2.3-Pichloropheny1)-3-ethoxr catbonvl-5-«etho*ycarbowr 1-6-aethy1-2-f2-(pyrazln-2-vlaalno)«thoxy»athyl]-1.4-dlhydropyrldln« ■ethoxycarbtmy 1-6-nethy 1-2- [ 2-(pyra*ln-2-ylamino) athoxystethy 1 ] -1,4-dlhydropyrIdine (0.35 g) (product of Example 50) was haated on a stem bath la 50Z aqueous ethanol (15 ml), to which vaa added 10 sodium dithlonlte (2 g) portlomrlse over 1.5 hours. The reaction mixture was then heated for a further 1.5 hours before the solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic layer was separated, dried, filtered and evaporated to give an oil. Chromatography on silica "Klesgel 60 15 R" (Trade Mark) elutlng with ether gave an oil which afforded the title compound when triturated with dilsopropyl ether, yield 134 sg., a.p. 113*. a The N-oxlde of 4-(2,3-dlchlorophenyl)-3-ethosycarbonyl-5- Analysis Xi- Found: C.55.2; H.4.9; S.10.6 Calculated Cor C^H^Cl-jH^: C.55.3; H.5.0; H.10.75.

EXAMPLE 90 (A.) Preparation of 4-(2,3-Dlchloroph«py1)-3-«thoxycarbony1-2-I2-(3-ethoxycarbonylthloureldo)athoxyaethyl]-5-«ethoxycarbony 1-6-■ethrl-1. 4-dlhvdropyridlne To a suspension of 2-(2-amino«thoxyi*ttay1) -4- (2,3-dichloro-pheny1)-3-ethoxycarbonyl-5-nethoxycarbonyl-6-mathyl-l,4-dlhydropyrldlne (4.43 g) In dry chloroform (50 al) was added, dropwlse, s solution of ethoxycarbonylisothlocyanate (1.31 g) in 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 recrystalllsed from dilsopropyl ether to give the title coapound, yield 2.6 g, m.pt. 144*.

Analysis Found: 0(50.6; H,5.2; 8,7.0 C«lcnl«C*d for C24^9C12H307S:.. C.50.2; H.5.1; K.7.3.

(B.) Preparation of 4-(2.3-Dlchlorophenyl)-3-ethoxycarbony1-2-5 [Z- (5-hydroMr-lHrl. 2.4-triazol- 3-y 1 amino ) athoxyne thy 17-5- tthoxycarbony1-6-methy1-1.4-dlhydropyrldlne hydrate ,ci 1) Mai To a suspension of 4-(2,3-dlchlorophenyl)-3-ethoxycarboiiyl-2-[2-(3-ethoxycarbonylthloureido)ethoxyaetbyX]-5-methoxycarbony1-6-me thy1-1,4-dlhydropyrldlne (0.25 g) In dry tetrahydrofuran (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 THP (5 ml) was sdded dropwlse and stirring was continued overnight. After evaporation of the solvent, the residue was taken up In methylene chloride and washed (aqueous NaCl), dried (MgSO^), filtered and evaporated to give a yellow oil (150 mgs). 69 - Tha oil was dissolved la lsopropanol (5 ml) containing hydrazine hydrate (0.06 g) and heated under reflux for 2 days. Tha solution was than evaporated and tha residue taken up in methylene chloride and washed (aqueous NaHCO^), dried (MgSO^), filtered and 5 evaporated. The residua was then chromatographed on silica "Kleselgel 60 H" (Trade Mark), elutlng with ethyl acetate/methanol (1Z Increments up to 20Z methanol). Product-containing fractions were combined, evaporated and recrystalllsed from ethyl acetate to afford the title compound, yield 0.048 g, m.pt. 158*.

Analysis Zi- Foimd: C.48.5; H.4.8; N.13.0 Calculated for C^H^ClglgOf.HgOt C,48.5; H.5.0; N.12.9., EXAMPLE 91 (A) Preparation of 4-(2.3-dlchloroi>henyl)-3-athoxy carbony l-2-[ 2-15 (5-hrdro»r-4-metlivlpyrlmldin-2-ylamlno)athoxvsthvH-5-methoCTcarbonv1-6-methy1-1.4-dihydropyridlna Ms0H/H20 CH.

H A nlxture of 2-( 2-amino«thoxyiMthyl)-3--«thoxy carbony 1-4-2,3-dichlorophenyl)-5-«athoxycarbony1-6-aethy1-1,4-dihydropyrldine (3.6 g) and 5-acetyl-2-a*ino-oxaxole (0.5 g) in methanol (2 ml) and water (3 nl) was heated on a steam bath for 24 hours. The 5 mixture was then evaporated to dryness and the residue was chroaatographed on silica "Kieselgel 6OH" (Trade Mark) eluging . with ethyl acetate. The product-containing fractions ware combined, evaporated and the residue triturated with ether to give the title compound (0.1 g), m.p. 165*.

Analysis X:- Found: 0,54.3; H.5.2; H.10.2 Calculated for C25H28C12H4°6: c»54-*5! H.5.1; N.10.2Z.

(B) Preparation of 2-[2-(4-acetylimida»ol-2-Tlamlno)ethoxT-aathTll-4-(2.3-dichlorophenyl)-3-ethoxycarbony1-5-methoxv-15 carbonYl-6-nethy1-1.4-dihydropyrIdlne chjojc -Cl: Me0H/Hz0 Froa che same reaction deacrlbad in Part (A) a aecond, aore polar product was subsequently eluted froa tha cbroaatography coluan using echyl acecace as the elueut. The fractions containing chla second produce were combined, evaporated and the S residue waa redlasolved in Methylene chloride, washed with dlluce hydrochloric add than with aqueous sodlua bicarbonate, dried (MgSO^), filtered and evaporated. The realdue waa recryacalllsed froa echyl aceCaCe Co give Che cltle compound (0.14 g), a.p. 177*.

Analyals I:- Founds C.54.6; H.5.5; H.9.9 Calculated for C25H28C12H4°6: c,54-*5» B>s-1> H.1Q.2Z. examples 92-97 The following compounds were prepared similarly to the procedure of Exaaple 8, I.e., by Che following reactIon:- c2h5ooc ch. 3 3 2 -f C2H5OOC ch. 3 m h nh.r 3 H Ex aspic No.

R3 Q Reaction Solvent Base Reactlotk . Tine Fora Isolated D«Pe <*c) Anelysls X (Theoretical in brackets) CBN 92 -fi H\,_r Cl nBuOH 4-dinethyl- amino pyridine 24 hrs.

Free bsse hemi-hydrate 139-141 53.15 5.1 10.6 (52.75 5.0 10.25) 93 -Q 0 Cl nBuOB EtjH 33 hours Hemi-funarate 197-199 52.4 4.9 9.3 (52.4 A.7 9.4) 94 H 0 -NHN02 EtOH 18 hours Free base sesqui-hydratc 222 51.6 5.4 9.7 (51.9 5.4 9.4) 95 <5 H 0 -SMe StOB - 18 hours Hydrochlorid) 203-205 50.0 4.9 9.9 (50.2 4.7 9.8) Exaaple No. 1 I I ! ! 1 n« I : ■ i i i i <2 Reaction Solvent Baae Reaction Tine Fora Isolated a.p. rc> Analysis Z (Theoretical in br'ackata) C H N 96 -CV H -SMe EtOH Et3N 17 hours Hydrochloride head-hydrate 195-198 48.5 4.8 9.85 (48.3 4.9 9.8) 97 ^ Cl -ty -Cl EtOH EtjN 50 hours Free base 153 51.8 4.6 9.95 (51.9 4;5 10.1) EXAMPLES 98-102 Tha following conpounda ware prepared 8lnllarly to the procedure of the stated Example.from appropriate starting materials CjUJOOC Example No.

Prepared slaillarly Co che procedure of Example no. *3 m.p.

(*C) Form Isolated Analysis X (Theoreclcal in brackecs) C H N 98 74 H 0 194-196 Free base 50;7 4.8 7.7 (50.9 4.65 7.75) 99 80 rvO Nn^M 167-169 Free base 55.5 5.6 11.4 (55.45 5.5 11.55) 100 1 XT' h 173- "5 Free baae hemi-hydrate 49.3 5.05 15.5 (49.4 5.1 15.7) 101 64 Tf N Vg-N if n 138-140 Free baae 48.1 4.9 9.7 (48.2 4.6 9.8) 102 67 ^NH_ 142-144 Free baae hemi-hydrace 46.35 4.9 12.3 (46.6 4.6 12.3) .

Tha following Preparations Illustrate the preparation of certain starting materials. All temperatures are In *C:- Prepqratltm 1 Preparation of 2-[(2-amlnoethoxy)nathyl]-4-(2-chlorophauTl)-3-ethoxy carbony l-5-«thoxycarbony 1-6-iMthy 1-1.4-dlhydropyrldlne maleate A suspension of 2-(2-asidoethoxy*ethyl)-4-(2-chloroptaanyl)-3-ethoxycarbony1-5-nethoxycarbony1-6-iwthyl-1,4-dlhydropyrldlne (103 g) In ethanol (2.5 1) was stirred for 16 hours at room temperature under one atmosphere of hydrogen In the presence of 5Z palladium on calcium carbonate (40 g). The reaction mixture was filtered and evaporated and the residue treated with a solution of malelc add (22 g) In ethanol (100 ml). The reaction mixture was stirred at roam temperature for 2 hours and then tha resulting solid collected, washed with ethanol, and dried to give the title compound (100 g), m.p. 169-170.5".

Analysis Z;-Found: .

C24H29C1H209 t*«Ittlt*8S C.S4.82; H.5.62; H.5.46 C.54.91; B.5.S7; H.5.34.

Preparation 2 2- [ 2-Amino«thoxymethyl] -4-[ 2,3-dichlorophenyl] -3-ethoxy- carbonyl-5-«iethoxy carbony l-6-»athy 1-1,4-dihydropyridine, a.p. 171-3", waa prepared similarly co Che previous Preparaclon Croat che appropriate axldo compound, and waa characterised as Che hcalfuaaraCe hemihydrata.

Analysis 8;- Found: 'C.51.7; 11,5.3; H.5.5 Calculated Cor C^H^CljHjOj.Jtf^H^.lsHjO: C.51.8; H.5.3; H.5.5 Tha heaifuaarate was neutralised to the free base Cora, a.p. 120-122*.

Preparation 3 2-(2-Aaldoethoxymathyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbony1-6-methy1-1.4-dlhydropyrldinc . A solution of 2-azldoethanol (160 g) in tetrahydrofuran (300 al) was added over 40 minutes Co a suspenalon of sodlua hydride (114 g; BOX dispersion In oil) in CeCrahydrofuran (500 ml). The alxcure was stirred aC room ceaperature for 1 hour and che Ice-cooled soludon CresCed vlch a solution of ethyl. 4-chloroacetoacetate (276 g) In tetrahydrofuran (250 al) dropwlae ovar 2 hour*. The aixture waa stirred at rooa temperature for 16 hours, diluted with ethanol (150 al), and the pH adjusted to 6-7 with 4M hydrochloric add. Sufficient water was added to dissolve 5 the solid present and the layers were separated. The organic layer was evaporated and the residue diluted with water (600 al) and evaporated. The residue was partitioned between ethyl acetate and water and the aqueous layer extracted twice with ethyl acetate, the conbined ethyl acetate extracts were dried (MgSO^) 10 and evaporated to give ethyl 4-(2-azidoethoxy)acetoacetate as a brown oil. which was shown by g.l.c. to be 73X pure. A aixture of this crude product and aanonlua acetate (92.3 g) in ethanol (600 al) was heated under reflux for 1 hour, allowed to cool to rooa temperature, and treated with methyl 2-(2-chlorobenzylldene) 15 acetoacetate (286.6 g). The atxtur* was heated under reflux for . 5.5 hours and then evaporated. The residue was stirred with aethanol (1.5 1) for 16 hours and the resulting solid collected, washed twice with aethanol, dried, end recrystalllsed froa aethanol to give the title coapound (78. g), a.p. 145-146°.

Analysis X;- Found: C.55.39; H.5.37; 11,13.01 Calculated for C^H^CIN^: C.55.23; H.5.33; N,12.88.

Preparation 4 2-(2-Asidoethoxy)aethy1-4-(2,3-dichlorophenyl)-3-ethoxyr 25 carbonyl-5-*«thoxycarbony1-6-methy1-1,4-dihydropyrine was prepared by the aethod described In Preparation 3 using oethyl 2-(2,3-dlchlorobenzylidene)acetoaeetata Instead of methyl 2-(2-chlorobenzylldene)acetoacetate. The product had an a.p. of 141°.

Analysis Found: C,50.88; H.4.78; 8,11.73 Calculated for c2oH22C12H405: c,51-18; H.4.73; M.11.94.

Preparation 5 (1) Preparation of Bthyl-4-(2-phthallmidoethoxy)acetoacatato j*?'.. -wfjg) o To a slurry of sodlua hydride (57Z dispersion in oil, 66.1 g 1.57 M), In tetrahydrofuran (500 ml) cooled to 0* under nitrogen waa added 2-phthallnldoethanol (150 g; 0.785 M) followed by ethyl 4-chloroacecoacetate (129 g; 0.785 M) 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 ml) and ethyl acetate (750 ml). 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. (11) Preparation of 4-(2-chlorophenyl)-3-gthoxycarbony1-5-methosycarbony1-6-methy1-2-t2-phthallaldoathoxyinathyl] -1,4- Methyl 3-aalnocrotonats (72.2 g; 0.627 M) and 2-chlorobenzaldehyde (88.1 g; 0.627 M) were added co a solution of ethyl 4-(2~phthalimidoethoxy)acetoacetate (200 g; 0.627 M) in lsopropanol (1 litre) and the mixture was heated under reflux for 20 hours. The lsopropanol was evaporated under reduced pressure and replaced by acetic acid (1 litre). After granulation at 10* the solid was collected end slurried In methanol (300 ml). The solid ns collected by filtration and dried In vacuo at 50* to afford the title compound, yield 84.4 g, m.p. 146-147*.

Analysis I:- Found: C.62.2; H.5.0; N,5.2 Calculated for CjgH^ClK^: C.62.4; H.5.05; H,5.2. dlhydropyrldlne o • o Preparation 6 The following conpound, n.p. 148-150*, waa prepared similarly to the previous Freperatlon hut ualng the correapondlng 2,3-dlchlorobenzaldehyde. The reaction time waa the aame:- Analyala Zi- Found: C.58.7; H.4.5; H.5.0 Calculated for C2gH26Cl2N207: C.58.6; H.4.6; N.4.9. - 82 -Preparation 7 Preparation of 2-(2-amlnoethoryaethyl)-4-(2-chlorophenyl)-3-etho3rrcarbonyl-5-«iethoxTcarbonyl-6-methvl-l .4 meojc Tha intermediate phthallaldo compound from Preparation 5 (400 g) waa suspended in ethanol (6 litres) containing hydrazine hydrate (111 g) and heated under reflux for 2 hours. After cooling the reaction mixture was filtered and the filtrate was evaporated to give a yellow oil. The oil was taken up In methylene chloride (6.5 litres)> washed (HjO), dried (MgSO^) and evaporated. The residue waa 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 crystalliaed out as ita maleate aalt, yield 303 g, m.p. 169-171*.

Analysis Z:-Found: Calculated for CjqHjjClUjOj.C^H^O^: C.54.8; H.5.55; N.5.3 C.54.9; H.5.6; H.5.3. - 83 -Preparation 8 The following compound, m.p. 171-173* waa prepared similarly to the previous Preparation but starting froa the corresponding 2,3-dichlorophenyl compound:- NHjr Fuaarate, *i H^O.

Analysis X:- Found: C.51.55; H.5.3; H.5.4 Calculated for c2oH24Cl2H2°5*C4H4°4'l,H20: c'51*5: H.5.05; H.5.O.

PREPARATION 9 The following compound, a.p. 179*, was prepared similarly to Preparation 5 but using the corresponding 2-chloro-3-trifluoromatfaylb«nzaldehyde in stage (ii). The reaction.tine was the same:- .

Anilwtl Xi- Fotmd: C.57.2; H.4.45; H.4.8 CalcuUted for C29H26CUr3N207: . C.57.4; H.4.3; H.4.6.

PKEPABATION 10 Preparation of 2-(2-Azldoethoxymethyl)-4-(2-chloro-3-trl.fluoro-aethylpheny 1) -3-«thoxycarbopyl-5-irathoxycarbonyl-6-iiathyl-l. 4-dihydropyrldine ch302c>s<f^s^c02c2h5 chf^n— ch20ch20h2h3 The title compound, a.p. 143-145*. was prepared similarly to the method described In Preparation 3 but using the corresponding 2-chloro-3-trlfluoromethylbentaldehyde. The reaction time was che same:- .

Analysis X:- Found: C.50.2; H.4.4; N.11.3 CalcuUted for C21H22C1F3H405: C.50.15; H.4.4; H.ll.l. - 85 -Preparation 11 Preparation of 2-f 2-AmlnoathoxYgathyll -4-(2-chloro-3-trlfluoro-awthylphenyl)-3-athoxycarbony1-5-aathoxycarbony1-6-gethyl-1,4-dihydropyrldlne ®302c>;^vc02c2h5 ch2och2ch2nh2 h The title compound was prepared by the catalytic hydrogenatlon of the asldo compound of Preparation 10 by the method described In Preparation 1. This compound was confirmed by n.m.r. and i.r. analysis to be identical to the product of 10 Preparation 13.

Preparation 12 Preparation of 2-(2-A»ldoetho*ymethyl)-4-(2.3-dlchlorophenyl)-3-aethoxycarbonyl-5-ethoxvcarbonyl-6-«ethyl-l.A-dlhydropyrldlne H5C2°2C 2-o-ch2ch2n3 The title compound, a.p. 126°, was 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 5 4-(2-axldoethoxjscetoacatata. The other conditions were the Analysis Xt- Pound: GiH,4»7, Nf12*lt Calculated for c2oH22C121,405: C' 51-2» H'4-7' «.U.9. 1° Preparation 13 Preparation of 2-(2-amlnoethoxymethTl)-4-(2-chloro-3-trifluoro- »ethvlphenv1)-3-«thoxy carbony1-5-gethoxycarbonyj-6-methyl-l. 4-dlhydropyrldlne Aqueous CH^NHj ,cooc2hs The intermediate phthallaido compound froa Freperatlon 9 (2.8 g) was added to aqueous Bethylmnine (14 al of 40Z) end stirred at rooa temperature for 17 hours. The resultant solid was filtered, redlssolved In chloroform (50 al), dried (MgSO^), filtered and evaporated to give a yellow solid. Crystallisation froa hexane gave the title compound, yield 1.0 g, a.p. 122*.

Hie title compound is the subject of Patent Specification NO. ; . .. ; .

Analysis X:- Found: C.53.25; H.4.9; N.5.75 Calculated for Cgji^ClF^Oj: C.52.9; H.S.I; 11,5.9.

Preparation 14 Preparation of 4-(2.3-dlchlorophenTl)-5-ethoacTcarbonyl-3-aethoxvcarbony1-6-aethy 1—2—12-phthaliaidoethoirvaethylI -1.4-15 dihydropyrldlne c^hjooc co2ch3 n'1 ch20ch2ch2h H The title coapound, a.p. 165*, was prepared slalla'rly to the method described in Preparation 5(11) but using 2,3-dichloro-benzaldehyde, methyl 4-(2-phthaliaidoethoxy)-acetoacetate and ethyl 3-aalnocrotonate.' The reaction time was the sane:- Analysis I:- Found: C.58.5; H.4.7; H.5.0 Calculated for. CjgHjjCljH^s C.5&-65; H.4.6; H.4.9.

The starting acetoacetate was prepared similarly to 5 Preparation 3(1).

Preparation 15 Preparation of 7-^7-»iilno«thoxyBBthyl)-4-(2.3-dlchloroph«nyl)-5-ethoxycarbony l-3-«ethoxy carbony 1-6-methyl-l ,4-dUiydropyridine The title compound, a.p. 131-132°, was prepared similarly to the method described In Preparation 13 but using the material from Preparation 14.

Analysis Found: Calculated for C2oH24C12N2°5: C.53.9; H.5.5; H.6.4 C.54.2; H.5.5; H.6.3.

Preparation 16 . Preparation ot 2-chloro-3-trifluoroi»athvlbengaldehyda 2-Chloro-l-trifluoromethyJ.benzene (54.15 g) waa dissolved la dry tetrahydrofuran (500 al) and stirred while cooling to -68* under a strew of dry nitrogen. (The whole reaction Is carried 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 In hexane) dropwlse keeping the temperature below -60*. 'After stirring at -68* for a further 2 hours, a solution of dlmethylfoxmsmlde (22 ml) In dry tetrahydrofuran (100 ml) waa added dropwlse keeping the temperature below -60*. The reaction mixture was allowed to warm to room temperature slowly over 17 hours and distilled water (200 ml) was then added. The organic phase waa .separated off and the aqueous liquors were extracted with ether (100 ml). The combined ether extracts plus the organic phase ware washed with saturated brine, dried (MgSO^), filtered and evaporated to give 61.5 g of an orange oil, being the crude title compound.

This oil was then added to an aqueous sodium bisulphite solution (65 g in 600 ml distilled water) and heated at - 60* for 0.5 hours. The solution was extracted with methylene chloride (3 x 100 ml) and, after acidification of the aqueous 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 Mich was crystallised from hexane to give the title compound, m.p. 43-44*.

Analysis X:- Found: C.45.9; E.2.0 Calculated for CgH^FjClO: C.46.1; H,2.0.

Preparation 17 % Preparation of 2.3-d ichlorobenzaldehyde A similar route to that described In the previous g Preparation, starting from 1.2-dlchlorobenzene, proved to be a superior method for preparing the title compound, m.p. 62*.

Analysis X:- Xo Found: C.47.62; H.2.38 Calculated for CjH^Cl^O: C.48.04; H.2.30.

Activity Data The molar concentrations of the compounds required to reduce the response by SOX In the test specified on pages 16-17 are given below (1M " 1 gm.Kole/Utre). The smaller the concentration the more active the compound.

Compound i£so Product of Example IB 2 X io-8 N Product of Example 2 2.29 X "9 M Product of Example 3B 6.02 X "9 M Product of Example 4 8.12 X ~9 M Product of Example 3.02 X io~9 M f ( Coapound Product of Exaaple 6 Product of Example.7 Product of Example 8 Product of Example 9 Product of Exemple 10 Product of Example 11 Product of Example 12 Product of Example 13 Product of Example 14 Product of Example 15 Product of Example 16 Product of Example 17 Product of Example 18 Product of Example 19 Product of Example 20 Product of Example 21 Product of Example 22 Product of Example 23 Product of Example 24 Product of Example 25 Product of Example 26 Product of Example 27 Product of Example 28 Product of Example 29 Product of Example 30 Product of Example 31 i£so 1.15 X IO-8 M 3.47 X "9 M 1.05 X io"8 M 1.26 X -® M 1.9 X IO"9 M 4.26 X IO"7 M 2.88 X IO"* M 6.3 X IO'9 M _8 1.0 X M .01 X io-® M 1.00 X IO"7 M 1.31 X IO"8 M 3.16 X "8 M 1.00 X IO"8 M 1.00 X IO"7 M 1.00 X IO"7 H 1.82 X IO"8 M 1.00 X ID"7 M 1.00 X IO"8 M 4.57 X IO-8 M 3.71 X io-9 K 3.98 X io-9 M 1.31 X IO-8 M 1.81 X io-8 K 2.34 X "9 M 1.77 X -8 M Compound IC, Product of Exaaple 32 1.58 X "° M Product of Exaaple 33 6.30 X io-9 M Product of Exaaple 34 1.31 X io-8 M Product of Example .75 X IO"9 M Product of Exaaple 36 3.16 X "9 M Product of Exaaple 37 1.00 X IO-8 M Product of Exaaple 38 2.51 X IO-8 M Product of Exaaple 39 2.69 X -9 M Product of Example 40 2.23 X ~9 M Product of Example 41 7.76 X IO"10 M Product of Example 42 4.16 X -9 K Product of Exaaple 43 8.31 X ~9 M Product of Exaaple 44 1.58 X IO"8 M Product of Exaaple 45 1.09 X -9 M Product of Exaaple 46 3.01 X io-9 M Product of Example 47 1.25 X io"9 M Product of Example 48 2.95 X IO-8 M Product of Example 49 3.98 X IO-9 K Product of Example 50 1.34 X io-9 M Product of Example 51 2.51 X IO-9 M Product of Exaaple 52 6.02 X IO-9 M Product of Example 53 3.16 X IO"6 M Product of Example 54 1.20 X io"9 M Product of Example 59 3.72 X IO"9 M Product of Example 60 4.47 X IO"8 M Product of Exemple 61 2.24 X io-9 M "93 Cunuound ^£50 Product of Exaapla 62 1.35 X IO'9 M product of bnflt 63 .. 2.95 X IO-9 M Product of Exaaple 64 1.00 z IO"8 M Product of Exaaple 65 2.51 X IO"8 M product of Exaaple 66 2.24 X -9 M product of Exaaple 67 1.99 X "8 M Product of 68 1.31 X io-8 M Product of Exaaple 70 9.33 X "9 M Product of Exaaple 71 1.00 X "8 M Product of Exaaple 72 3.98 X "® M product of Exaaple 73 4.4 X io"9 M Product of Exaaple 74 2.00 X "8 M Product of Exaaple 75 7.08 X -9 *M product of Exaaple 77 .37 X -9 M Product of Exaaple 78 2.29 X -9 M Product of Exeaple 79 6.60 X -9 M Product of Exaaple 80 1.34 X -9 H Product of Example 81 3.16 X -9 M Product of Exaaple 82 4.07 X -9 M Product of Exaaple 83 3.16 X -9 M Product of Exaaple 84 .01 X -9 M Product of Exaaple 85 .01 X -9 M Product of Exaaple 86 1.58 X -9 M Product of Exaaple 87 1.00 X -7 M Product of Exaaple 88 1.26 X io"10 M Conpound Zko Product of Exaaple 89 5.01 x 10~*" M Product of Exaaple 90B ,1.00 x IO-8 M Product of Exaaple 91A 1.00 x 10-' M Product of Exaaple 9IB 2.5 x M

Claims (23)

claims: 15

1. . A d ihydropyrid J ne of tho formula:- 1 2 r ooc coor I I (I) 3 ci«3 N cii2-o-*-ni« or a pharmaceutlcally acceptable acid addition salt thereof; 5 wherein R is a phenyl group optionally substituted by one or two substltuents each Independently selected from nltro, halo, Cj-C^ . alkyl, Cj-C^ alkoxy, hydroxy, trlfluoromethyl, and cyano; 1 2 R and R are each Independently C^-C^ alkyl or 2-methoxyethy1; 10 Y Is -(CH2)2-; 3 R Is attached to the adjacent nitrogen atom by a carbon atom and Is either (n) » monocyclic 5- or 6-mombcred heterocycle containing at least one N atom and optionally one or two further lieteroatoms or groups each Independently selected from 0 0 * t 0, S, S, N and N, and Is optionally substituted by Cj-C^ alkyl, Cj-C^ alkoxy, halo, hydroxy, oxo, cyano, 3-(Cj-C^ alkyl)ureido, 4 5 phenyl, phenoxy, pyridyl, acetyl, (C^-C^ alkoxy)carbonyl, -NR R , -S02NR4R5 or -CONR^R^ where either R^ and R^ are each 4 5 Independently II or flJkyl or K and K together with the 20 - 96 - nitrogen .-itom to which they nrc nttoclicil represent a saturated 5-or 6-membered heterocyclic group optloually containing a further heteroatom or group selected from 0, S, NH. H(Cj-C^ alkyl) and NCI10; or (b) a blcycllc group which Is an optionally substituted 5 S- or 6-membered heterocycle as defined In (a) fused to an imidazole or benzene ring, said benzene ring being optionally . substituted by Cj-C^ nlkyJ, C^-C^ alkoxy or halo.

2. A compound as claimed in claim 1 wherein R la a phenyl group substituted by 1. or 2 substltuents selected from halo and 10 CFy

3. A compound as claimed In claim 2, wherein R is 2-chlorophenyl, 2,3-dlchloropheny] or 2-chloro-3-trifluoro-metliylplieny I.

4. A compound as claimed In any one of the preceding claims 15 wherein either (a) R1 Is Cllj and R^ Is C^Hj or (b) R^ is CH^ and R1 Is CjHj.

5. A compound as claimed lu any one of the preceding claims . 3 wherein R is a heterocyclic group selected from trlazolyl, oxadi'azoly], pyrimldlnyl or a partially saturated derivative 20 thereof, purlnyl, quinazollnyl, lmldazolyl, imldazollnyl, trlazlnyl, pyridyl, thlazolyl, thlazollnyl, benzthlazolyl, thladlazolyl, pyrazlnyl, qulnoxallnyl and pyrrollnyl, and their N-and S-oxides, r' being optionally substituted by C^-C^ alkyl, C^-C^ alkoxy, halo, hydroxy, oxo, cyano, 3-methylureido, phenyl, 25 phenoxy, pyridyl, acetyl, carbamoyl, N-mcthylcarbamoyl, (Cj-C^ 4 5 4 5 4 5 alkoxy)carbonyl, -NR R , or -SO^NR R , where either R and R .are 4 5 each independently II or C|-(^ alkyl or R and R together with the - 97 - nitrogen aton to which they are attached forn a pipcridlno, morpholino, 4-aethylpiper.izin-l-yl or 4-fornylpiperazin-l-yl group.

6. A compound as claimed in claim S wherein R^ is CH, N—H N— -a.x • -i a N Nil., N NH ii y 1 ^"3 a or -t A nhconikh. . N N Qr N— Nil - 98 -

7. A compound as claimed In claim 5 wherein R Is N O.

8, A compound ns rlnJroed In cJain 5 wherein R is -q ' n mh ' \ CH. Ph ; \n , -Q • <5 ■ ■ Y-ONIU \ ^ _/ /*h <0 / ^ / \ m N-cn, NHCH o~ -fi ' <51 7 M.—' ' N=/ ' N =* > \ K o - OiPr OPh O -O -O"' N—^ ' N H-&

9. A coapound as claimed In claim S wherein R^ in <] -if' ~<1

» N—I . ~X or N—V ii *o h coch 3 lO.A coapound as clalaed in claim 5 wherein R^ Is nll2 3

11. A compound as clalned In claim 5 wherein R Is NIJ .C / \ T" X" ■ JCrXT"^' N N

12. A compound as claimed in claim 5 wherein R"* Is CH .COOEt d . -a . -a. it. .CONHCII, If ■ ~<J • so^nmo^ - 100 -

13. A compound as claimed In claim S wherein R is o t N N or J ll— OCH, o t Jl—y— nh_

14. A compound as claimed in claim 5 wherein R is

15. A compound as claimed in claim 5 wherein R Is -O 1 2

16. A compound as claimed in claim 1, wherein R Is CH^, R 3 is C^Hji R is 2,3-dlchlprophonyl, and R Is a group of the formula n n 10 -A Jk (Clill ! «r a |ih.irm.iccutically acccpcnhlc acid addition salt thereof. - 101 -

17. A compound of the formula (I) as claimed in any one of the preceding claims, or a pharmaceutlcally acceptable acid addition salt thereof, for use as a medicament.

18. A pharmaceutical composition comprising a compound of the formula (I) as claimed in any one of claims 1 to 16, or a pharmaceutlcally acceptable acid addition salt thereof, together with a pharmaceutlcally acceptable diluent or carrier.

19. The use of a dihydropyrldlne as claimed in any one of' claims 1 to 16, or ph.-irnwio-titically acceptable acid addition salt thereof, for the manufacture of a medicament for treating lscliaemlc heart disease, angina or hypertension.

20. A dihydropyrldlne of the formula (I) given and defined In claim 1 or a pharmaceutlcally acceptable acid addition salt thereof, which Is any one of those specifically hereinbefore mentioned.

21. A process for preparing a dihydropyrldlne of the formula (I) given and defined in claim 1 or a pharmaceutlcally acceptable acid addition salt thereof, substantially as hereinbefore described with particular reference to the accompanying Examples.

22. A dihydropyrldlne of the formula (I) given and defined in claim 1 or a pharmaceutlcally acceptable acid addition salt thereof, whenever.prepared by a process claimed in claim 21.

23. A pharmaceutical composition according to claim 18, substantially as hereinbefore described. F. R. KELLY ft CO., AGENTS FOR THE APPLICANTS.