CA1253865A - 1,4-dihydro having a basic amino-containing group attached to the 2-position as anti-ischaemic and antihypertensive agents - Google Patents

1,4-dihydro having a basic amino-containing group attached to the 2-position as anti-ischaemic and antihypertensive agents

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Publication number
CA1253865A
CA1253865A CA000423148A CA423148A CA1253865A CA 1253865 A CA1253865 A CA 1253865A CA 000423148 A CA000423148 A CA 000423148A CA 423148 A CA423148 A CA 423148A CA 1253865 A CA1253865 A CA 1253865A
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Prior art keywords
formula
compound
methyl
alkyl
chlorophenyl
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French (fr)
Inventor
Simon F. Campbell
Peter E. Cross
John K. Stubbs
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Pfizer Corp
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Pfizer Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

ABSTRACT OF THE DISCLOSURE
Novel dihydropyridines of the formula:- (I) and their pharmaceutically acceptable acid addition salts wherein Y is -(CH2)2-, -(CH2)3-, -CH2CH(CH3)- or -CH2C(CH3)2-; R is aryl or heteroaryl; R1 and R2 are each independently C1-C4 alkyl or 2-methoxyethyl; and R3 is hydrogen, C1-C4 alkyl, 2-(C1-C4 alkoxy)ethyl, cyclopropylmethyl, benzyl, or -(CH2)mCOR4 where m is 1, 2 or 3 and R4 is hydroxy, C1-C4 alkoxy or -NR5R6 where R5 and R6 are each independently hydrogen or C1-C4 alkyl, pharmaceutical compositions containing them, and processes for their production. The compounds are particularly useful in the treatment or prevention of a variety of cardiac conditions, e.g.
angina pectoris.

Description

~JZ ~ 5 Ihis invention relates to certain dihydropyridines, specifically to certain 1,4-dihydropyrldines having a basic amino_containing group attached to the 2-posltion, which have utility as anti-ischaemic and antihypertensive agents.
The compounds of the invention reduce the movement 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 accumula~ion of intracellular calcium under ischaemic conditions.
E~:cessive calcium influx during ischaemia can have a number of additional adverse effects which ~ould further compromise the ischaemic myocardium. These include less efficient use of oxygen for ATP production, activation of mitochondrial fatty acid oxida~ion and possibly, promotion of cell necrosis. Thus the compounds are useful in the treatment or prevention of a variety of cardiac conditions, such as an~ina pectoris, cardiac arrythmias, heart attacks and cardiac hypert.ophy. The con~pounds also have vasodilator activity since they can inhibit calcium i lnflux in cel]s oE vascular tissue and they are thus also useful as antihypertensive agents and for the treatment of coronarv vasospasm.
According to the ;nvention, there are provided novel 1,4-dihydropyridine derivatives of the formula:-H R
R OOC ~ COOR2 ll 11 CH~ ~N ~ Ch~-0-Y-NHR ___ (I

Pl.C 33 - ~Z~3~

wherein Y is -(CH2)2-, -(CH2)3-, -CH2CH(CH3)- or -CH2C(C113)2-;
R is a phenyl group unsubstituted or substituted by one or two substituents selected from nitro, halo, Cl-C4 alkyl, Cl-C4 alkoxy, hydroxy, trifluoromethyl and cyano, or is a 1- or 2-naphthyl group, or is benzofuranyl, benzothienyl, pyridyl unsubstituted or monosubstituted by methyl or cyano, quinolyl, benzoxazolyl, benzthia~olyl, furyl, pyrimidinyl, thiazolyl, 2,1,3-benzoxadiazol-4-yl, 2,1,3-benzthiadiazol-4-yl, or thienyl unsubstituted or monosubstituted by halo or Cl-C4 alkyl;
Rl and R2 are each independently Cl-C4 alkyl or
2-methoxyethyl; and R3 is hydrogen, Cl-C4 alkyl, 2-(Cl-C4 alkoxy)ethyl, cyclopropylmethyl, benzyl, or -(CH2)mCoR4 where m is 1, 2 or 3 and R is hydroxy, Cl-C4 alkoxy or -NR5R6 where R5 and R6 are each independently hydrogen or C1-C4 alkyl;
and their pharmaceutically acceptable salts.
The compounds of the formula (I) containing one or more asymmetric centres will exis-t as one or more pairs of enan-tiomers, and such pairs or individual isomers may be separable by physical methods, e.~. by fractional crystallization 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 d- and l-optically-active iso-meric forms.
The pharmaceutically acceptable salts of the compounds of the formula (I)are preferably formed from acids which form non-toxic acid addi-tion salts containing pharmaceuti-
3~6~

cally acceptable anions, such as the hydrochloride, hydrobromide, sulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate and gluconate salts. The preferred salts are maleates.
"Halo" means fluoro, chloro, bromo or iodo.
C3 and C4 alkyl and alkoxy groups can be straight or branched chain.
R3 is preferably H, CH3, benzyl, 2-methoxyethyl, -CH2COOCH3, -CH2COOC2H5, -CH2CONH2, -CH2CONHCH3, or -CH2COOH.
R3 is most preferably H or CH3.
R is preferably 2-chlorophenyl, 2-fluoxophenyl, 2-methoxyphenyl, 3-chlorophenyl, 2-chloro-3-hydroxyphenyl, 2-chloro-6-fluorophenyl, unsubstituted phenyl or 2,3-dichlorophenyl.
Rl is preferably CH3.
R2 is preferably C2H5.
Y is preferably -(CH2)2- or -CH2CH(CH3)-.
"m" is preferably 1.
Most preferably, R is 2-chlorophenyl.
Most preferably, Y is -(CH2)2.
The most preferred compounds have the formula (I) wherein R is 2-chlorophenyl, R is CH3, R is C2H5, R3 is H or CH3, and Y is -(CH2)2-.

` ~Z~i31~6~i The compounds of the formula (I) are primary or secondary amines and in one method they can be prepared by the removal o-E
the amino-protecting group from the corresponding amino-protected dihydropyridines.
This general method can be illustrated in more detail as follows:-R OOC ~ COOR
I Removal of proteeting group l ~ Compound (I).
CH3 ~ ~ N ~ ` CH2-o-Y-NR3 (II) .

(Q = an amino-protecting group and R, Rl, R , P~3 and Y are as defined for forn~ula [I]);

R OOC . ~ COOR2 CH ~ ~ CH2-O-Y-N ~ Removal of protecting Co~pound (I) 3 H O ~ group ~ [R = H].

[R, R , R and Y are Afi defined for formula ~
Olle preferred amino-protecting group is ben~.y]. ~t is tvpic.llly removed by ~aydrogena~lon, using e.g. H2/Pd on cnarcoai under ac~dic cond~tinns in a suitable organic 301vent, e.g.
~I.l' 338 methanol. The acidic conditions are preferably obtained by using compound (II) in the form of an organic acid addition qalt, e.g.
as an oxalate or acetate salt.
A typical procedure involving the removal of a benzyl group is as follows. Compound (II) as an oxalate salt in methanol is added to a suspension of 10% pre-hydrogenated palladium on charcoal in methanol, and the mixture is then stirred under hydrogen at 50 p.s.i. for up to abou~ 18 hours, e.g. overnight, and at room temperature. If necessary, heating at up to about 60C can be provided. The product can then be isolated and purified by conventional procedures.
When both Q and R3 are benzyi, hydrogenation under the above conditions normally only removes one of the benzyl groups.
Further hydrogenation of the resulting monobenzyl product under the above conditions with fresh catalyst càn then be used to remove the remaining benzyl group.
Many of the starting materials of the formula (II) in which 0~
is benzyl are described and claimed in our European patent application publication no. 0060674. Typical methods to the N-benzyl starting materials of the formula (II) are as follows:-(a) The benzyl-protected intermediates (II) can be prepared by the Han.zsch synthesis, as follows:-Pl,~ 33;3 ~2S3865 P~ OOC COOR

I + RCHO
3 N 2 o~'~ ~ CH -o-Y-NR3 (III) (IV) CH~Ph R OOC ~ COOR
J~
H3C N CH2-o-Y-N-R3 H cH~ph In a typical procedure, the ketoester (IV) and aldehyde are heated under reflux in a suitable organic solvent, e.g. a Cl-C4 alkanol solvent such as ethanol, for about 15 minutes, and then the aminocrotonate (III) is added. Alternatively the aminocrotonate (III), ketGester (IV) and aldehyde can be heated together in the solvent. Pre~erably ~ small amount of a lo~er alkanoic acid such as acetic acid is added to neutralise the solution. The resulting solution can then be heated at 60-130C, preferably under reflux, ~ntil the reaction is essentially complete, typicai]y in 24 hours or less. The product of the formula (Il) can then be isolated and ~urified by conventional procedures .

-- ~A~5 3 ~ 6 5 The ketoesters (IV) are either known compounds or can be prepared by methods analogous to those of the prior art, such as the method illustrated in the Preparations hereinafter, which are essentially the method of Troostwijk and Kellogg, J. C. S. Chem.
Comm., 1977, page 932. Similarly the amino-crotonates (III) are either known compounds or can be prepared by conventional procedures. Also the aldehydes are either known or can be prepared by known methods.
(b) The benzyl-containing intermediates (II) can also ~e prepared by the following process:-R OOC CH
X ~ CH ~ Compound CH3 N ~ \ CH -o-Y~NR3 (V) (VI ) C~E2P~

The crotonate (VI) is typically prepared in situ by reaction of the corresponding acetoacetate (IV):-/ COOR
lc~l2 o ~ CH -o-Y-~R3 CH2P~
(IV) with ammoninm acetate, e.g. by refl~lxing in a suitable organic solvent, e.g~ a Cl-C~ al'~anol sueh as ethanol, for, say, up to an ~'1( 338 ~2~3~

hour. The crotonate (Vl) is then reacted with compound (V), typically by heating in the solvent for Up to about 5 hours at 60C-130C, e.g. under reflux. The product (II) can then be isolated and purified by conventional procedures.
The starting materials (V) are either known compounds or may be prepared by methods analogous to those of the prior art, see e.g. Can. J. Chem., 1967, 45, 1001.
The compounds of the formula (I) in which R is H can be prepared frcm the corresponding phthalimido derivatives according to conventional procedures, e.g.:-H R
RlCOC ~ COOR2 CH~ ~ ~ CH2-O-Y-N

(a) a primary amine ~ CH20YNH2 or (b) hydrazine hydrate or (c) an alkali metal hydroxide followed by HCl or H2SO4.

The prefered primary amine is methylamine. The preferred alkali metal hydrvxide is potassium hydroxide.
The reaction using methylamine is typically carried out in ethanol at roo~ temperature, with heating if necessary. The reaction using hydrazine hydrate is typically carried out in ethanol at the reflux temperature or below. The reaction using potassium hydro~ide is Lypical]y carried out ~t rvom temperature P~,C 33~

386~;
.

(although with heating if necessary) in tetrahydrofuran, following by the addition of the acid and heating at the reflux tPmperature or below. In all cases the product can be isolated conventionally.
The phthalimido starting materials can again be obtained conventionally, e.g.:-(a) ~ N-Y-OH ~ ClCH2COCHzCOORZ

O NaH
O ~ ~

~N-Y-O-CH2COCH2COOR2 .

RlOOC ` 2 COOR
(b) CljH + RCHO + 1 2 CH3 ~ ~ NH2 ¦ O ~ C \ CH2-O-Y-N

H
R100C ~>~COOR2 CU3~ ~ N ~ CH20YN ~

This is again the '~ant~sch reaction.

?l,C 333 ~2~5~36~
.

Compounds of the ~ormula (I) in which R3 is H can also be purified to ~ery high le~els by reacting them with phthalic ; anhydride to form the phthalimido derivatives which can.then be converted back to the compounds in which R3 ~s H by the methods previously described.
To prepare compounds in which R is Cl-C4 alkyl, -COOCH2CC13 can be used as the amino-protecting group. This can be removed in a conventional manner using zinc and either formic or acetic acid. The N-protected starting materials necessary for this process can be prepared as follows:--~--CH2-0-Y-N(Cl-C4 alkyl)2 Cl.COOCa2CC13_~ CH2-0-Y-IN-(Cl-C4 alkyl) COOCH2CCl3 or H2-o-y-Nl-(cl-c4 alkyl) Cl-CCH2CCl3 ~ ~-~C~I2--Y-N-(Cl-C4 alkyl) benzyl COOC~2CC13 Typically the reaction with 2,2,2-trichloroethyl chloroformate is carried by heating the reactants at up to reflux temperature in e.g. toluene. Many of the dialkylamino and N-alkyl-N-benzylamino starting materials needed to prepared these N-protected intermediates are described and claimed in our corresponding European patent application publicat on no. 0060674, and others can be prepared analogous]y.

PI~C 338 8~i The compounds of the formula (I~ where R3 = H can also be obtained frGm the corresponding azido compounds, the aæido group being convertable to -NH~ by reduction, e.g. with triphenyl-phosphine, or zinc and hydrochloric acid, or H2/Pd, under conventional conditions.

KlOOC ~ cooR2 RlOOC ~ cooR2 ~I Jl~ reduetin ~
3 ~ CH2~~Y~N3 CH3 NH CH -O-Y-NH2 In a typical procedure using zinc dust, the reaction is carried out in methanol/aqueous hydrochloric acid. Heating is possible but is not generally necessary. Similarly hydrogenation can be carried out in e.g. methanol or ethanol in the presence of a catalyst such as Pd/CaC03 at room temperature.
Again the azido starting materials c2n be prepared by the Hantzsch synthesis under conditions similar to those previously described:-Pl.C 338 ~253~

C / COOR

+ RCHO ~ Cl 2 CH3 ~ ~ NH2 O ~ ~ CH~-O-Y-N3 \~

RlOOC .~ ~ ~ COOR2 The azido-containing acetoacetates can also be obtained by ; conventional procedures:-1~0-Y-~3 + Cl.cH2cocH2cooR ~ C~2 ~ \
O CH 2 -O-~-N 3 .

Similarly the azido starting materials can also be prepared analogously to route (b) above for preparing the N-benzyl searting materials.
Some of the compounds of the invention can be prepared from other compounds of the invention by cenventional techniques, e.g.:-531~

R ooC X COOR R OOC E~ COO~.
Hal.(CH2~mCOO(Cl-C4 alkyl), -~ Base. I
CH3 2 2 (T~al=Cl or sr) CH3~ N~ ~ cH2oyNH(cH2)mcoo(cl 4 .~ /alkyl) 66~

NH(cH2)mcooH 5 6 V~ NH(CH2)mCONE~

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 in 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 immersed in a bath of physiological saline solution containing potassium ions at a concentration of 45 millimolar and no calcium. Calcium chloride is added to ths bath with a pipette to give a final calcium lon 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 min~tes, the test is repeated wit~ the particular compound under Pl~C 338 i386~

test present in the saline solution. The concentration of compound required to reduce the response by 50% is 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.
For administra~ion to man in the curative or prophylactic treatment of cardlac conditions and hypertension, oral dosages of the compounds will be in the range Gf from 2-50 mg daily for an average adult patient (70 kg). Thus for a typical adult patient, individual tablets or capsules are likely to contain from 1 to 10 mg of active compound, in a suitable pharmaceucicaliy acceptable vehicle or carrier. Dosages for incravenous administration would be within the range 1 to 10 mg per single dose as required.
In a further aspect the invention provides a pharmaceu~ical 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 inven~ion also provides a compound of the fonnula (I), or a pharmaceutically acceptable acid addition salt thereof, for use in treating ischaemic heart disease, especially angina, or hypertension, in a human being.
The following Examples illustrate the invention: all temperatures are in C:-Pl(` 338 - ~2~;;386~

EXAMP~E 1 Preparation of 4-(2-c lorophenyl -2-[2-(methylamino)et~y~--h ~ _ 3-ethoxycarbonyl-5-metho~ycarbony1-6-methy_=1,4- ihydropyridine, oxalate salt C~300C ~ H2C~I ~ CH300C ~ H~CH3 CH2Ph H

A solution of 2-[2-(N-benzyl-N-methylamino)ethoxymethyl]-4-~2-chlorophenyl]-3-ethoxycarbonyl-5-methoxyc~rbonyl-6-methyl-1,4-dihydropyridine, oxalate salt (4.3 g) in methanol (220 ml) was added to a suspension of 10% (by weight) palladium on charcoal (0.4 g) pre-hydrogenated in methanol (50 ml). Stirring lmder hydrogen at 50 p.s.i. and room temperature ove-night resuleed in complete removal of the benzyl group. After removal of the catalyst by filtration, the methanol was removed ~y evaporation and the residue crystallised from a little methanol to give the title compound (2.4 g), m.p. 211.

Analysis ~/O -Calculated for C21H27ClN25 C2 2 4 C,53.85; H,5.70; N~5.46;
Found C,53.99; H,5.76; N,5.60.

The free base had a m r of 88-90 (from ether).

` . ~L2~86~;;

EXAMPLES ~ _ 10 The following compounds were prepared similarly to the method described in Example 1 and were characterised in the form indicated, starting from the appropriate N-substituted dihydropyridine oxalate arld H2/Pd. It should be noted that hydrogenation of the N,N-dibenzyl starting material in Example 8 produced the monobenzyl product which was in turn used as the startlng material in Example 9.

H R
COOCH~CH3 ~ ~ HC~NHR3 PT,C 338 ~1~2~865 o~ ~- ~- ~ o,, S I ~ O ~ j--i OCO C~
r~ n u~n 'i o I o r S~ ; S~

X Z ' I I j U~
r~

~25~36~

C ~1 0 i U~ ~I a~
~U~

o o i ~

i3 ~ o 0,~ 1 ~ t I i r L ~

. ~

" ~Z~;38~5 EXAMPI.E I1 Preparation o _2 _(2-aminoethoxy me hyl]-4-(2-chlorophenyl)-3 ethoxycarbonyl-5-methoxycarbonyl-6-methyl 1,4-dihydropyridine maleate C~ 00 ~ C~ OOC ~
3 COOC2H5 3 ~ ~ COOCH2CH3 ~ l~ Zn~acid ~ , ! 1~
CH3 N CH20CH2CH2 3 CH3 ~ N ~ CH2CH2CH2NH2 2-Azidoethanol (3 g) was converted to ethyl 4-(2-azido-ethoxy)acetoacetate similarly to the method described in Preparation 3 hereinafter u~ing ethyl 4-chloroacetoacetate, and the crude ketoester (not characterised) was used in the ~antzsch reaction using the method described in Preparation 9, i.e. by reacting it with methyl 3~aminocrotonate and 2-chlorobenzaldehyde.
The crude Hantzsch product (not characterised) dissolved in methanol (250 ml) and 3N hydrochloric acid (200 ml) was stirred on a water bath at room temperature while zinc dust (15 g) was added portionwise over 10 minutes. After stirring a further 10 minutes the solution was decanted from excess zinc, the methanol evaporated and the aqueous acid residue washed with toluene (100 ml), basified with concentrated ammonia and extracted with methylene chlcride (2 x 100 ml). The extracts were dried (Na2C03), filtered and evaporated to dryness. The residue in toluene was chromatographed on a medium p.essure column Ot silica 3~36~;

(T.L.C. grade, Merck "Kieselgel" [Trade Mark] 60H, 7 g) eluting initially with toluene, changing ,gradually to meehylene chloride and then to methylene chloride plus 3% methanol. Appropriate fractions were combined and converted to the maleate salt in ethyl acetate. Recrystallisation from acetone and ethyl acetate (1:1) gave the titie compound (maleate salt) (l90 mg, lZ yield from 2-azido ethanol) as a white solid, m.p. 169 , identical by t.l.c. with the product obtained in Example 9.

Preparation of 2-[2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbon 1-5-methoxycarbonyl=6= e~hy~ L~LI~Le~L~LC~
maleate , C33OOC ~ COOC2d5 I:2/Pd C33OO ~ 32c33 CH3 N~ CH2OCH2CH2N3 3 H CH2CCH CH2NH2.

A suspension of 2-(2-azidoethoxy)methyl-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-174-dihydropyridine (103 g) in ethanol ~2.5 1) was stirred for 16 hours at room temperature under an atmosphere of hydrogen in the presence of 5% palladium on calcium carbonate (40 g). The reaction mixture was filtered and evaporated and the residue treated with a solution of maleic Pl.C 338 -~ ~z~

acid (22 g) in ethanol (100 ml). The reaction mixture was stirred at room temperature for two hours and then the resulting solid collected, washed with ethanol, and dried to give the tltle compound (100 g), m.p. 169-170.5.

Analysis %:-Found: C,54.82; ~,5.62; N,5.46 C20H25ClN205.C4H404 requires: C,S4.91; H,5.57; N,5-34-The following compounds were prepared similarly to Example 12 from the appropriate azide and H2/Pd:-CH300C ~ C00C2H5 : CH3 N CH20CH2CH2NH2 ___ ___ _ Exampl~ Form ~.p. Analysis %
; No. characterised (C) (Theoretical in brac~ets) 13 ~ Cl L fumara~e 171- 51.7 5 3 5.5 Cl ~ hydrate 173 (51.8 5.3 5.5) 14 11 ~ fumarate 158- 57.6 6.2 5.8 ~ ~ hydrate 168 (57.7 6.3 5.6) ----_ . ... _____ .___. __________ _ ~ fumarate 152 56.95 6.02 5.93 _ _ I (56.68 5.755,5) ____ _______ . . ._______ .__.~_____ ___._ _ __._ ._ -i3~il65 E ~MPLE 16 Methy1 N-(2-S[4-(2,3-dichlorophenyl)-3-ethoxycarbony1-5-methoxy-carbonyl-6-methyl-1,4-dihydropyrid-2-yl~methoxy~ethyl)aminoacetate l BrCH2CO
COC ~

CH3 C~2OC~2CH2~2 Cl 3 ~ COOC2H5 C~3 H CH2CCH2CH2NHCH2COOCH3 ; 5 A solution of methyl bromoacetate (1.53 g) in acetonitrile (20 ml) was added dropwise over 30 minutes to a stirred, refluxing mixture of 2-[(2-aminoethoxy)methyl]-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5- methoxycarbonyl-6-methyl-1~4-dihydropyridine (5.01 g) and potassium carbonate (2.76 ~) in acetonitrile (60 ml).
The mixture was then heated under reflux for 3 hours, filtered, and evaporated. The residue was partitioned between ethyl acetate and water and the organic layer washed with water, dried (Na2S04), and evaporated. The residue was chromatographed on silica (t.l.c.
grade Merck Kieselgel 60H, [Trade Mark] 40 g) elutiDg with dichloromethane plus 0-3~ methanol. Appropriate fractions were combined and evaporated to give the title compound (2.10 g), m.p.
95--98.

~ 38~ -Analysis %:-Found: C,53.25; H,5.49; N,5.48;
C23H28C12N207 requires: C,53.60; H,5.48; N,5.44.

The followlng compounds were prepared by the method described in Example 16 using appropriate starting materials.

~ Cl C~3O2C ~ - N ~

Example R3 m.p. Analysis % or n.m.r.
No. tC) (Theoretical in brackets) __ _ 17 CH2C 2 2 378-80 58.26 6.30 5.65 _____ _ _ ____ _ (58.24 6.31 5.66) 18 -CH C02CH3 oil n.m.r. (CDC13).~ values:
2 7.72 (lH, broad s);
6.96-7.51 (4H, m);
5.43 (lH, s);
4.78 (2H, s);
4.10 (2H, q);
3.78 (3H, 5);
3.63 (3H, s);
3.3-3.7 (6H, m);
2.38 (3H, s);
________ ____ ____ _ ___ _ _____ ____ 1.20 (3~, t);

~53~
,.

~ MPLE 19 2-(2-~[4-(2-Chlorophcnyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2- ~ methoxy~ ethylamino)acetamide ~ '.
~ Cl NH3 CH300C ~ CC2HS

CH3 N CH20cH2cH2N~cH2cooc2H5 H

~ Cl CH300C ~ COOC2H5 Ethyl N-( 2--~[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxy-carbonyl-6-metkyl-1,4-dihydropyrid-2-yl]methoxy~ethyl)aminoacetate (2.50 g) in a mixture of ethanol (40 ml) and 0.880 aqueous ammonia (30 ml) was stirred at room temperature for four days and then evaporated. The residue was partitioned between ethyl acetate and water and the organic layer washed with water, dried (MgS04~, and evaporated. The residue was chromatographed on silica (t.l.c.
grade Merck Kieselgel 60H, [Trade Mark] 30 g) eluting with dichloromethane plus 0-5Y methanol. Appropriate fractions were combined and evaporated. The residue was triturated with ethyl acetate and the resulting solid collected, washed with ethyl acetate, and dried to give the title compound (1.23 g), m.p.
126-]29.

i ~,~'538ÇiS;

Analysis ~:-Found: C,56.78; H,6.06; N,8.68;
C22H28ClN306 requires:C,56.71; H,6.06; N,9.02.

The following compound was prepared by the method described in Example 19 using the same dihydropyridine and methylamine.
¢q . .
~ Cl CE~302'~C2H5 CH3 ~_" ~ Nr~R
H H
_ _ _ .
Example R3 m.p.Analysis % or n.m.r.
No. (C)(Theoretical in brackets) ___ _ _ -CH CONHCH 123-57.80 6.558.73 2 3 124(57.56 6.308.76) ________ __ ~2531365 N-(2-~[4-(2-Chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy~ethyl)aminoacetic acid hemihydrate ~ ' ~Cl aq. NaOH
CE~300C ~C0~2~5 C~13 N C~l2ocH2cH2NHcH2coo~- 3 ~ Cl CH300C ~ COOC2H5 CH3 N CH2ocH2c~2NHcI~2cooH

A solution of methyl N-(2-~[4-(2-chlorophenyl)-3-ethoxy-carbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid--2-yl]me~hox~
ethyl) aminoacetate (2.40 g) in dioxane (80 ml) was treated with lM

aqueous sodium hydroxide solution (10 ml) and the mixture stirred at room temperature for 2 hours and then evaporated. The residue was purified by ion exchange chromatography (Bio-Rad AG 50W-X8, ~Trade Mark], 200-400 mesh, cation form, 40 g) eluting with dioxane initially followed by 2% pyridine in water. Appropriate fractions were combined and evaporated to give the title compound as a hemihydrate (0.56 g)~ mOp. 140-150 (decomp.).

Analysis %:-Found: C,55.52; H,5.95; N,5.92;
C22H27ClN207.l~H20 requires: C,55.52; H,5.93; N,5.~9.

Preparation Of 2-~.(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-etho carbonyl-a-methoxycarbonyl-6-methyl-1,4-dl-nydropyridine maleate ~ Cl 3 2 ~ C020 2 30 Ethanolic methylamine, ~
~ ~ `Cl or hydrazine hydrate, CH302C ~ ~ C02CH2C~3 or KOH ~ollowed by HCl. ~ ~

COOH
H ~
~ Il "'COOH
Method A (using ethanolic methylamine) -4-(2-Chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-(2-phthalimidoethoxy)methyl-1,4-dihydropyridine (80 g) was stirred in 33% ethanolic methylamine solution (1067 ml) at room temperature for three hours. The solvent was then evaporated and the residue was slurried in industrial methylated spirits (300 ml) then filtered. To the filtrate was added maleic acid (17.4 g) and after stirring a precipitate was produced. This was collected by filtration and was washed with industrial methylated spiri~s.
The solid was crystallised from industrial methyla~ed spirits (430 S38~5 ml) and dried at 55 to give the title compound (38.4 g) as a white solid confirmed spectroscopically to be identical with ~he products of Examples 9 and 12.

Method B (using hydrazine hydrate) 4-(2-Chloropheny ~3-ethoxycarbonyl-5-methoxycarbGnyl-6-methyl-2-(2-phthalimidoethoxy)methyl-1,4-d hydropyridine (383 g) was stirred in refluxlng ethanol containing hydrazine hydrate (106.7 g). After two hours~ the reaction mixture was cooled and filtered. The filtrate was evaporated and the residue was dissolved in methylene chloride (2000 ml) and the solution was washed with water (2000 ml). The organic solution was evaporated and ~he residual oil was dissolved in industrial methylated spirit (1120 ml). To this solution was added maleic acid (82.5 g) and the resulting precipitate was collected, washed with induætrial methylated spirit and dried at 55 to give the title compound (304 ; g) as a white solid, again ccnfirmed spectroscopically to be the desired product.

Method C (using ~OH followed by HCl).
4-(2-Chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-(2-phthalimidoethoxy)methyl-1,4-dihydropyridine (15 g) was dissolved in a mixture of tetrahydrofuran (150 ml) and water (100 ml) containing potassium hydroxide (3.13 g). After stirring a~ room temperature for 1.5 hours 2N hyarochloric acid (100 ml) was added and the resl~lting slurry was refluxed for 2.5 hour~.
The solution was extracted twice with methylene chloride (2 x 100 .
~L;~53865 ml) and the combined extracts were dried (MgS04) and evaporated to leave an oil which was dissolved in industrial methylated spirits (S7 ml). Maleic acid (3.24 g) was added and the resulting precipitate was collected, washed with industrial methylated spirits and dried at 55 to givé the title compound (10.2 g) as an off-white solid, again confirmed spectroscopically to be the desired product.

Preparation of 4-(2-Chlorophenyl)-2-[2~ methylamino)et oxy-methyl]-3-ethoxycarbonyl-5-metho~yc rbonyl-6-methy~ 4 dihydropyridine maleate C ~ i) Cl3CCH202r' Cl Cl 11 ~ I
H ~ ~ ii) Zn/HCOOH
CH O G ~ ,CO CH CH H
3 2~ l , 2 2 3 CH302 ~ C02CH2CH3 CH3 N CH20cH2cH21 3 CH3 ~ N l CH2ocH2cH2NHcH3 A mixture of 2-[2-(~-benzyl-N-methylamino)ethoxymethyll-t~-[2-chlorophenyl]-3-ethoxycarbonyl-5-methoxJcarbonyl-6-methql-ll4 dihydropyridine (4.8 g) and 2,2,2-trichloroethyl chloroformate (2.7 g) was heated in toluene at reflux for 20 hours. After cooling to room temperature, the mixture was stirred with lN
hydrochloric acid (50 ~1) and extracted with ether. The extracts 1;~ ri386 were evaporated to l~ave a crude oil (6.9 g) containing ~he corresponding 2-[2-(N- 2,2,2-trichloroethoxycarbonyl-N-methyl-amino)ethoxymethyl] derivative.
The said oil (3.0 g) was dissolved in dimethylformamide (10.5 ml) and formic acid (0.5 g) and at 5 zinc (0.7 g) was added.
The mixture was allowed to warm to room te~perature and kept for three days at this temperature. The reaction ~ixture was then decanted and poured into water (100 ml) and acidified to pHl with concentrated hydrochloric acid. The aqueous solution was washed with n-hexane (50 ml) then 0.88 ammonia solution was added to give a precipitate. This was collected and dried before dissolving in ethyl acetate. Maleic acid (0.34 g) was added followed by ether.
~fter trituration, the solid was collected and dried to give a solid confirmed by NMR and IR to be (apart from the salt form) identical to the product of Example 1.

Preparation of 4-(2-chlorophenyl)-2-[2-(N-m thylamino)ethoxy-methyl]-3-ethoxyc rbonyl=5-methoxycarbonyl-6-~ y~l,4-dihydropyridine maleate Cl ~ 1) C13CCH202C.Cl ~ ~ 2) Zn/HCOOH Cl ~ "
H ~ ~ ~ Tl `1 CH302C ~ C02CH2CH3 H ~
20 ~ ~ CH302C~ ~ C02CH2CH3 CH3 N CH20CH2cH2l_cH3 ~ ~ ~
H CH3 vH3 N CH20CH2CH2NHCH3 ~L~53~365 . ~. .

4-[2-Chlorophenyl]-2-[2-(N,N-dimethylamino)ethoxymethyl]-3-ethoxycarbonyl-5-methoxycarbonyl-~-methyl-1,4-dihydropyridine (147.6 g) and 2,2,2-trichloroethylchloroformate (98.7 g) were stirred together in refluxing toluene for 20 hours. The reaction mixtur~ was then c0012d to room te~perature and lN hydrochloric acid (1147 ml) was added. The mixture was extracced twice with ether (2 x 1147 ml) and the extracts were bulked and evaporated to leave a crude oil (201.6 g) containing the corresponding 2-[2-(~-2,2,2-trichloroethoxycarbonyI-N-methylamino)ethoxymethyl~
derivative.
This o l (196 g) was dissolved in dimethylformamide (686 ml) and formic acid (35.5 g) and the mixture was cooled to 52. Zinc (50.5 g) was added in portions over 20 minutes and then the mixture was stirred at room temperature for 90 hours. The reaction mixture was decanted, added to water (1500 ml), and then taken to pHl ~ith concentrated hydrochloric acid. The aqueous solut~on was washed with n-hexane (500 ml) and the remaining aqueous phase was adjusted to pH10 with 0.88 ammonia solution.
The resulting ~ixture was granulated and the solid was collected and dried to give the crude product (138 g). This solid was dissolved in hot echyl acetate containing maleic acid (37.1 g) and on cooling the title compound was obtained (82.3 g) as a whitP
solid confirmed spectroscopically to be identical to the product of Example 23.

PlC 338 2531~365 EXAMPL~ 25 Preparation of 2-(2=amino~rop-1-oxymethyl)-4-(2-chlorophenyl) 3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1, -d hydropyridine hemifumarate hemihydrate CH300C H Cl ~ COOC~H5 '1, , H ~ H2/Pd/CaC03 ~
CH300C ~ ~ fH3 3 ~ 2 5 A mixture of ethyl 4-(2-azidoprop-1-oxy)acetoacetate (13.05 g), 2-chlorobenzaidehyde (8.3 g) and methyl 3-aminocrotonate (6,8 g) in methanol (80 ml) was heated under reflux for 19 hours, reduced to half-volume, and then cooled overnight at -20. The resulting precipitate was collected, washed with a little cold methanol, and dried to give 2-(2-azidoprop-1-oxymethyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (4.0 g) as a pale yellow solid, m.p. 115, characterised spectro-scopically.

pT C 338 ;25~365 A suspension of the above product (4.0 g) in methanol (100 ml) was stirred under one atmosphere oE hydrogen at room temperature in the presence of'palladium on calcium carbonate (1~0 g) for 18 hours. The mixture was then filtered through "Solkafloc" (Trademark) and evaporated. The residue was dissolved in methanol (20 ml), treated with a warm solution of fumaric acid (1.00 g) in methanol (10 ml), and stored overnight at 0. The resulting solid was collected, recrystallised from ethanol, and dried to give the title hemifumarate hemihydrate (2.4 g), m.p.

Analysis %:-~ound: C,56.46; H,6.63; N,5.68;

21H27ClN205-~C4H404-~H20 C,56.3S; H~6-17; N 5 72 The following Preparations illustrate the preparation of certain starting materials. All temperatures are in C:-PREPARATION 1_eparation of Ethyl 4-~2-(N-benzyl-N-methylamino-ethoxy3aceto-acetate CH NCH CH OH+ClCH COCH CO C H NaH CH NCH CH OCH COCH CO C H
2 CH2Ph Pl.C 338 - ~2~:i31~365 .

Sodium hydride (60% (by weight) in oil, 8 g) was stirred in dry tetrahydrofuran (THF) (100 ml) under nitrogen while 2-(N-benzyl-N-methylamino)ethanol (17 g) was added slowly. The warm mixture was stirred for 1 hour, then kept cool on a water bath at room temperature (20) while a solution of ethyl 4-chloroacetoacetate (16.5 g) in dry THF (100 ml) was added dropwise over 3.5 hours. The mixture was stirred overnight at room temperature under nitrogen, then quenched with a little ethanol and poured onto ice (ioo g) and concentrated hydrochloric acid (30 ml). The THF was removed by evaporation, and the residue washed with light petroleum (b.p. 60-80) to remove mineral oil.
The residue was basified with solid sodium carbonate and extracted with ethyl acetate (200 ml and 100 ml). The combined extracts were dried (Na2C03), filtered and evaporated to give the title compound as an oil (30 g), sufficiently pure for further use.
N.m.r. spectrum in CDCl , ~ values: 7.27 (5H,s); 4.12 (2H,q);

4.06 (2H,s), 3.45-3.70 (6H,m); 2.61 (2H,t); 2.25 (3H,s); 1.23 (3H,t)-The following acetoacetates were prepared similarly to the above, starting from the appropriate N-substituted 2-aminoethanol and ethyl 4-chloroacetoac~tate, and were used directly without characterisation:-R NCH2CH20CH2COCH2C02C2H5 where R3 = -CY.2Ph or -CH2CH20CTd3-CHzPh ~i3~3~;5 Preparat;.on of 2-~2-(N-benzyl-N-methylamino)ethoxymet.hyl]-4-(2-chloro-phenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-m~yl-1,4-di-hydropyridine, oxalate salt Method (a) COOC H

CU ~ NU ~ O C~l2ocu2c~l2~h3 \

~ Acetic acid H ~ Ci CH300C ~ COOC2H5 CH3 H 2 2 2,CH3 C~2Ph Ethyl 4-[2-(N-benzyl-N-methylamino)ethoxy]acetoacetate (25 g), 2-chlorobenzaldehyde (11 gj, methyl 3-aminocrotonate (9.1 g) and acetic acid (5 ml) in ethanol (100 ml) were mixed and heated under reflux for 3.5 hours. The cooled reaction mixture was then evaporated to dryness and the residue par.itioned between 2N
hydrochloric acid (200 ml) and methylene chloride ~300 ml). The methylene chloride solution was washed with saturated sodium :
53~3~5 carbonate solution (200 ml), dried (MgSO4), filtered and evaporated to dryness. The residue in ether ~as treated with an excess of oxalic acid dis~olved in ether to precipitate the crude product. The precipitate was recrystallised from methanol to give the title compound (6.5 g) as a white solid, m.p. 181.

Anal~sis :-Calculated for C28H33ClN25'C2 2 4 C,59.75; H,5.85; N,4.65 Found : C,59.42; H,5.85; N,4.39.

Method (b) ~C~ ' i C~300C ~ ~CH ~ COOC2H5 Title + I ~ Compo~lnd C (as free base) 3 CH2Ph Ethyl 4-[2-(N-benzyl-N-methylamino)ethoxy]acetoacetate (141 g) and ammonium acetate (37.3 g) in ethanol (280 ml) were heated gently under reflux for 20 minutes. The methyl 2-(2-chloroben~yl-idine) acetoacetate (115 g) was added and heating under reflux continued for 4 hours. The cooled reaction mixture was evaporated to dryness, re-dissol~red in toluene (200 ml), and extracred with 25~65 2N hydrochloric acid (2 x 150 ml). The thick oiiy layer in the aqueou~ phase, and the ~queous phase itself, were extracted with methylene chloride (400 ml and 200 ml), and the combined extracts were washed with excess saturated sodium carbonate solution and dried (Na2C03). The methylene chloride was removed by evaporation and the residue in toluene plus 20% petrol was filtered through a medium pressure column of silica (T.L.C. grade, Merck "-~ieselgel"
[Trade Mar~] 60H, 100 g) eluting with toluene plus 20~ petrol (500 ml) and then toluene (1 litre). The combined eluates were evaporated to dryness to g-~e the crude title compound as the free base, an oil ~177 g), sufficiently pure by t.l.c. for use in the subsequent hqdrogenation step.
The following starting materials were also prepared similarly to (~) above, starting from the appropriate N-substituted acetoacetates and ammonium acetate, and were used directly without characterisation:-~, H ~ Cl CH300C ~ ~ COOC~H5 CH3 N 2 2 2, where R3 = -CH2Ph CH2Ph or -CH2cH20cH3 ~

PLC 33&

~. ~ . . ~
~;3~

2-(2-Azidoethoxy~ 4-(2-chlorophenyl)-3-ethoxycarbonyl-5=
methoxycarbonyl-6-mPthyl-1,4-dihydropyridine ~/lCl ~COOC2EI5 C~300C ~ ~CH ~ c~3COONH4 C1~2 CH3 0 o C~2oCH2CN2N3 ~ Cl c~3cOC~c~ 2~ 5 Jl 11 CH3 N ~--`C~20CH2c~2 3 A solution of 2-azidoethanol (160 g) in tetrahydrofuran (300 ml) was added over 40 minutes to a suspension of sodium hydride (114 g; 80% dispersion in oil) in tetrahydrofuran (500 ml). The mixture was stirred at room temperature for 1 hour, then cooled in ice water and treated dropwise with a solution of ethyl 4-chloro-acetoacetate (276 g) in tetrahydrofuran (250 ml) over 2 hours.
The mixture was stirred at room temperature for 16 hours, diluted with ethanol (150 ml), and the pH adjusted to 6-7 with 4M
hydrochloric acid. Sufficient water was added to dissolve the solid present and the layers were separated. The organlc 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 ext;acted twice with ethyl acetate.
The combined ethyl acetate extracts were dried (MgS04) and evaporated to give ethyl 4-(2-a~idoethoxy)acetoacetate as a brown 2~3~5 oil, which was shown by g.l.c. to be 73% pure. A mixture of this crude product and ammonium acetate (92.3 g) in ethanol ~600 ml) was heated under reflux for l hour, allowed to cool to room temperature, and treated with methyl 2-(2-chlorobenzylidene)-acetoacetate (286.6 g). The mixture was heated under reflux forS.5 hours and then evapGrated. The residue was stirred wi~h methanol (1.5 1) for 16 hours and the resulting solld collected, washed twice wi~h methanol, dried, and recrystallised from methanol to give the title compound (78 g), m.p. i45-146.

Analysis %:-Found: C,55.39; H,5.37; N,13.01 Calculated for C20H23ClN45 C,55.23; H~5-33; N~12-88-__ _ The following azides were prepared similarly to Preparation 3 from appropriate starting materials:-H ~
CH300C ~ CC2HS

~53 !3~5 .~

_ _ Preparation R m.p. Analysis %
No. (C) (Theoretical in brackets) _ _ ._ _~

4 ~ Cl~ 141 50.884.78 11.73 ~ Cll (51.184.73 11.94) _ ._ L _ _ ~ l 124 59.646.11 13.98 ~ I (59 996.04 13.99) ll _ 6 ~ 1 ! 129- n.m.r. ln CDCl : S = 7.14 130 (5H,m); 5.28(1~,s);
4.80(2H,s); 4,04(2H,q);
3.65(4H,m); 3.62(3H, 5 ) , 2.35(3H,s); 1.20(3~1,t).
_ _ . _ Preparation 7 Preparation of ethyl 4-[2-(phthalimido)ethoxy]acetoacetate N CH2 2 ClCH2COCH2C00CH2CH3 O

NaH ~ NcH2cH2ocHzcocH2coocH2cH3 Sodium hydride (57% [by weight] in oil, 66.1 g) was stirred in dry tetrahydrofuran (500 ml) under nitrogen at -10 while N-(2-hydroxyethyl)phthalimide (150 g) was added. To this slurry - ~2531~

was added at -10 a solution of ethyl 4-chloroacetoacetate (129.3 g), in dry tetrahydrofuran1 over 1 hour. The reaction mixture was then allowed to warm to room temperature and stirring was continued for 18 hours. This mixture was poured into 1~
hydrochloric acid ~800 ml~ and ethyl acetate was added (750 ml).
The aqueous layer was washed with ethyl acetate (300 ml) and the organic solutions were combined. After washing with watér (300 ml), the ethyl acetate was evaporated to give the title compound as a crude oil (243 g), sufficiently pure for further use.

N.m.r. spectrum in CDC13, ~ values: 7.80 (4H, m), 4.15 (2H, s);
4.10 (2H, q); 3.92 (2H, t); 3.78 (2H, t); 3.49 (2H, s); 1.22 ~3H, t).

-" ~253~36~

Preparation 8 Preparation of 4-(2-Chlorophenyl)-3-ethoxycarbony -5-methoxy-carbonyl-6-methyl-2-(2-phthalimidoethoxy)methyl-1,4-dihydro-pyridine (A.) From 2-[(2-aminoethoxy)methyl]-4 _2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine ~ O
CU302C ~C02CU2CU3 ~

1~9 ~ -Cl CH302~ C02CH2CH3 C N CH20CH2CH2 ~

2-[2-Aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxy-10 carbonyl-S-methoxycarbonyl-6-methyl-1,4-dihydropyridine (2.0 g) and phthalic anhydride (0.73 g) were stirred in refluxing acetic acid (20 ml) for 2.5 hours. After cooling, the insoluble material was collected and stirred in methanol (10 ml). Filtration gave the title compound (1.0 g) as a white solid, m.p. 146-147.
PLC 33i3 ~L2~38Ç;S;

Analysis %:-Found: C,62.18; H,5.02; N,5.20 Calculated for C28~27ClN2O7 C,62.39; H~5-05; N~5.20-~B.) From ethyl 4-~2-(phthalimido)ethoxy]acetoacetate Cl ~ ~ Cl / C02C12CH3 ¢ ~ Cl CH302C ~ C02C 23 0 O

Ethyl 4-[2-(phthalimido)ethoxy]acetoacetate (200 g) was dissolved in isopropanol (1000 ml) and to thls was added 2-chlorobenzaldehyde (88.1 g) and methyl 3-aminocrotonate (72.2 g). The mixture was refluxed for 21 hours then the methanol was evaporated to leave an oil which was dissolved in acetic acid (1000 ml). After granulating overnight, the precipitate was collected, washed with acetic acid then slurried in methanol (300 ~ ~53~6~i ml). Filtration gave the title compound the n.m.r. and ir of which were identical with those of the material prepared by part (A) above.

Preparatlon 9 Prenaration of 2-(2-AzidoethoxY)methYl-4-(2-chloro~henyl)-3-ethoxycarbonyl-5-met-hoxy rbonyl-6-methyl-1 4-dihydropyridine 3 2 ~ CH

CH3~ ~ NH2 Cl ~ ~ C2C2H5 1, ~ Cl CH302CX~ C02C2H5 3 ~ CH20CH2CH2N3 Ethyl 4-(2-azidoethoxy)acetoacetate (46.4 g), prepared from 2-azidoethanol similarly to the method described in Preparation 3, was reacted with methyl 3-aminocrotonate (24.8 ~) and 2-chlorobenzal~ehyde (30.3 g) in methanol (150 ml) at refl~lx for 18 hours. After cooling to room temperature, the r~sulting solid was collected, washed twice with methanol and dried to gi~ the .

2~3136~i title compound (28 g). The product could be crystallised from methanol, acetone or ethyl acetate. It was used directly.
.
Preparation 10 Preparation of _th ~ p-l-oxy)acetoacetate (a) CH3CH(Br)CH20H ~ NaN3 j~ CH3CH(N3)CH20H

(b) CH3CH(N3)CH20H + ClCH2COCH2COOC2H5 i) NaH
ii) HCl CH3cH(N3)cH2ocH2cocH2cooc2Hs A mixture of 2-bromopropan-1-ol (J. Am. Chem. Soc., 7681, 96, [1974])(19.75 g) and sodium azide (10.0 g) was heated on a steam-bath for four days, allowed to cool to room temperature, and then washed four times with ether. The combined ether washings were filtered and evaporated to give 2-azidopropan-1-ol (12.3 g~
as a pale brown oil which was shown by g.l.c. to be 98% pure.
A soluCion of the 2-azidopropan-1-ol (10.1 g) in tecrahydrofuran (100 ml) was added over two minutes to a stirred, ice-cooled suspension of sodium hydride (6.6 g; 80% dispersion in oil) in tetrahydrofuran (50 ml). The mixture was stirred for 15 minutes with ice-cooling and then treaCed over 20 minutes with a solution of ethyl 4-chloroacetoace~ate (16.4 g) in tetrahydrofur~n (150 ml). The mixture was stirred at room temperature for 16 hours and evaporated. The residue was diluted with water, washed .

3~365 twice wlth ether, acidified with 2M hydrochloric acid, and extracted three times into ether. The combi~ed ether extracts were dried (Na2S04) and evaporated to give crude ethyl 4-(2-azidoprop-1-oxy)acetoacetate (20 g), used directly.

~2'~ 5 Activity Data The molar concentration of the compounds required to reduce the response by 50~ in the test specified on pages 8-9 i.s given below (IC50 values) (lM - 1 gm.mole/litre). The smaller the concentra-tion the more active the compound, i.e., the most active compounds are the products of Examples 1, 9, 11, 12, 22, 23 and 24.

IC5~ Values Compound IC50 Product of Example 13.2 x 10 M
Product of Example 23.2 x 10 M
Product of Example 32 x 10 M
Product of Example 46.3 x 10 M
Product of Example 54 x 10 M
Product of Example 62 x 10 M
Product of Example 71.3 x 10 M
Product of Example 85 x 10 M
Product of Example 93.2 x 10 9 M
Product of Example 102.5 x 10 8 M
Product of Example 113.2 x 10 M
Product of Exampie 123.2 x 10 9 M
Product of Example 136.3 x 10 M
Product of Example 141.6 x 10 M
Product of Example lS1.8 x 10 M
Product of Example 194 x 10 M
Product of E~sample 20 2.2 x 10 M
Product of Example 223.2 x 10 9 M
Product of Example 233.2 x 10 9 M
Product of Example 243.2 x 10 9 M
Pl.C 338

Claims (47)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A 1,4-dihydropyridine of the formula:

( I ) or a pharmaceutically acceptable salt thereof, wherein Y is -(CH2)2-, -(CH2)3-, CH2CH(CH3)- or -CH2C(CH3)2-;
R is a phenyl group unsubstituted or substituted by one or two substituents selected from nitro, halo, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, trifluoromethyl and cyano, or is a 1- or 2-naphthyl group, or is benzofuranyl, benzothienyl, pyridyl unsubsti-tuted or monosubstituted by methyl or cyano, quinolyl, benzoxa-zolyl, benzthiazolyl, furyl, pyrimidinyl, thiazolyl, 2,1,3-benzoxadiazol-4-yl, 2,1,3-benzthiadiazol-4-yl, or thienyl unsub-stituted or monosubstituted by halo or C1-C4 alkyl;
R1 and R2 are each independently C1-C4 alkyl or 2-methoxyethyl; and R3 is hydrogen, C1-C4 alkyl, 2-(C1-C4 alkoxy)ethyl, cyclopropylmethyl, benzyl, or -(CH2)mCOR4 where m is 1, 2 or 3 and R4 is hydroxy, C1-C4 alkoxy or -NR5R6 where R5 and R6 are each independently hydrogen or C1-C4 alkyl.
2. A compound as claimed in claim 1, wherein R is phenyl, 2-chlorophenyl, 2-fluorophenyl, 2-methoxyphenyl, 3-chlorophenyl, 2-chloro-3-hydroxyphenyl, 2-chloro-6-fluorophenyl, or 2,3-dichlorophenyl.
3. A compound as claimed in claim 1, wherein Y is -(CH2)2-or -CH2CH(CH3)-.
4. A compound as claimed in claim 1, wherein R3 is H, CH3, benzyl, 2-methoxyethyl, -CH2COOCH3, -CH2COOC2H5, -CH2CONH2, -CH2CONHCH3 or -CH2COOH
5. A compound as claimed in claim 1, 2 or 3, wherein R3 is H or CH3.
6. A compound as claimed in claim 1, 2 or 3, wherein R1 is CH3 and R2 is C2H5.
7. A compound as claimed in claim 1, 2 or 3, wherein R1 is CH3, R2 is C2H5 and R3 is H or CH3.
8. A compound as claimed in claim 1 wherein R is phenyl, 2-chlorophenyl, 2-fluorophenyl, 2-methoxyphenyl, 3-chlorophenyl, 2-chloro-3-hydroxyphenyl, 2-chloro-6-fluorophenyl or 2,3-dichloro-phenyl, Y is -(CH2)2- or -CH2CH(CH3)-, R1 is CH3, R2 is C2H5 and R3 is H, CH3, benzyl, 2-methoxyethyl, -CH2COOCH3, -CH2COOC2H5, -CH2CONH2, -CH2CONHCH3 or -CH2COOH.
9. A compound as claimed in claim 1, wherein R is 2-chloro-phenyl, R1 is CH3, R2 is C2H5, Y is -(CH2)2- and R3 is H.
10. A compound as claimed in claim 1 wherein R is 2-chloro-phenyl, R1 is CH3, R2 is C2H5, Y is -(CH2)2- and R3 is CH3.
11. A compound as claimed in claim 1, 2 or 3, which is in the form of a maleate salt.
12. The compound 2-[(2-aminoethoxy)methyl]-4-(2-chloro-phenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydro-pyridine or a pharmaceutically acceptable salt thereof.
13. The maleate salt of 2-[(2-aminoethoxy)methyl]-4-(2-chloro-phenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydro-pyridine.
14. The compound 2-[(2-methylamino)ethoxymethyl]-4-(2-chloro-phenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydro-pyridine or a pharmaceutically acceptable salt thereof.
15. The maleate salt of 2-[(2-methylamino)ethoxymethyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine.
16. A process for the preparation of a 1,4-dihydropyridine of the formula (I) or a pharmaceutically acceptable salt thereof, wherein Y is -(CH2)2-, -(CH2)3-, -CH2CH(CH3)- or -CH2C(CH3)2-;
R is a phenyl group unsubstituted or substituted by one or two substituents selected from nitro, halo, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, trifluoromethyl and cyano, or is a 1- or 2-naphthyl group, or is benzofuranyl, benzothienyl, pyridyl unsub-stituted or monosubstituted by methyl or cyano, quinolyl, benzoxa-zolyl, benzthiazolyl, furyl, pyrimidinyl, thiazolyl, 2,1,3-benzoxadiazol-4-yl, 2,1,3-benzthiadiazol-4-yl, or thienyl unsub-stituted or monosubstituted by halo or C1-C4 alkyl;
R1 and R2 are each independently C1-C4 alkyl or 2-methoxy-ethyl; and R3 is hydrogen, C1-C4 alkyl, 2-(C1-C4 alkoxy)ethyl, cyclopropylmethyl, benzyl, or -(CH2)mCOR4 where m is 1, 2 or 3 and R4 is hydroxy, C1-C4 alkoxy or -NR5R6 where R5 and R6 are each independently hydrogen or C1-C4 alkyl, which comprises (i) the removal of the amino protecting group from an amino-protected 1,4-dihydropyridine of the formula:

(IA) where R, R1, R2 and Y are as defined above, and X is, as appropri-ate, a protected primary or secondary amino group, said secondary amino group having the formula -NHR3 where R3 is as defined for formula (I) except for hydrogen, or (ii) to prepare a compound in which R3 is H, reducing an azido compound of the formula:

where R, R1, R2 and Y are as defined for formula (I) so as to produce a compound of the formula (I) in which R3 is H, said process step (i) or (ii) being followed, where required, by one or more of the steps from the group consisting of:
(a) conversion of a compound of the formula (I) in which R3 is H into a compound of the formula (I) in which R3 is -(CH2)mCOO(C1-C4 alkyl) where m is 1, 2 or 3 by reaction with a compound of the formula Hal-(CH2)mCOO(C1-C4 alkyl) where "Hal"
is Cl or Br;
(b) conversion of a compound of the formula (I) in which R3 is -(CH2)mCOO(C1-C4 alkyl) where m is 1, 2 or 3 into a compound of the formula (I) in which R3 is -(CH2)mCOOH or -(CH2)mCONR5R6, m, R5 and R6 being as defined for formula (I), by, respectively, hydrolysis or reaction with an amine of the formula R5R6NH; and (c) conversion of a compound of the formula (I) into a pharmaceutically acceptable salt.
17. A process for the preparation of a 1,4-dihydropyridine of the formula:

( I ) or a pharmaceutically acceptable salt thereof, wherein Y is -(CH2)2, -(CH2)3-' -CH2CH(CH3)- or -CH2C(CH3)2-;
R is a phenyl group unsubstituted or substituted by one or two substituents selected from nitro, halo, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, trifluoromethyl and cyano, or is a 1- or 2-naphthyl group, or is benzofuranyl, benzothienyl, pyridyl unsub-stituted or monosubstituted by methyl or cyano, quinolyl, benzoxa-zolyl, benzthiazolyl, furyl, pyrimidinyl, thiazolyl, 2,1,3-benzoxadiazol-4-yl, 2,1,3-benzthiadiazol-4-yl, or thienyl unsub-stituted or monosubstituted by halo or C1-C4 alkyl;
R1 and R2 are each independently C1-C4 alkyl or 2-methoxyethyl; and R3 is hydrogen, C1-C4 alkyl, 2-(C1-C4 alkoxy)ethyl, cyclopropylmethyl, benzyl, or -(CH2)mCOR4 where m is 1, 2 or 3 and R4 is hydroxy, C1-C4 alkoxy or -NR5R6 where R5 and R6 are each independently hydrogen or C1-C4 alkyl;
characterized by the removal of the amino-protecting group from an amino-protected 1,4-dihydropyridine of the formula:

(IA) where R, R1, R2 and Y are as defined above, and X is, as appropriate, a protected primary or secondary amino group, said secondary amino group having the formula -NHR3 where R3 is as defined for formula (I) except for hydrogen, said process being followed by, optionally, one or more of the following steps:
(a) conversion of a compound of the formula (I) in which R3 is H into a compound of the formula (I) in which R3 is -(CH2)mCOO(C1-C4 alkyl) where m is 1, 2 or 3 by reaction with a compound of the formula Hal-(CH2)mCOO(C1-C4 alkyl) where "Hal" is Cl or Br;
(b) conversion of a compound of the formula (I) in which R3 is -(CH2)mCOO(C1-C4 alkyl) where m is 1, 2 or 3 into a compound of the formula (I) in which R3 is -(CH2)mCOOH or -(CH2)mCONR5R6, m, R5 and R6 being as defined for formula (I), by, respectively, hydrolysis or reaction with an amine of the formula R5R6NH; and (c) conversion of a compound of the formula (I) into a pharmaceutically acceptable salt.
18. A process according to claim 17, wherein X is -NR3-(benzyl) where R3 is as defined for formula (I), -NR3(COOCH2CCl3) where R3 is C1-C4 alkyl, or a group of the formula:

19. A process according to claim 18, wherein X is -NR3(benzyl), and the benzyl group is removed by treating compound (IA) with hydrogen.
20. A process according to claim 19, which is carried out in the presence of a palladium catalyst under acidic conditions.
21. A process according to claim 18, wherein X is -NR3(COOCH2CCl3) and said -COOCH2CCl3 group is removed by treat-ment of the compound (IA) with zinc in formic or acetic acid.
22. A process according to claim 17, wherein X is a group of the formula:

and the phthalimido group is removed by treating compound (IA) with either (a) a primary amine, (b) hydrazine hydrate or (c) an alkali metal hydroxide and then with hydrochloric or sulphuric acid.
23. A process according to claim 22, wherein said primary amine is methylamine, and said alkali metal hydroxide is potassium hydroxide.
24. A process for the preparation of a 1,4-dihydropyridine of the formula:

( I ) or a pharmaceutically acceptable salt thereof, wherein Y is -(CH2)2-, -(CH2)3-' -CH2CH(CH3)- or -CH2C(CH3)2-;
R is a phenyl group unsubstituted or substituted by one or two substituents selected from nitro, halo, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, trifluoromethyl and cyano, or is a 1- or 2-naphthyl group, or is benzofuranyl, benzothienyl, pyridyl unsub-stituted or monosubstituted by methyl or cyano, quinolyl, benzoxazolyl, benzthiazolyl, furyl, pyrimidinyl, thiazolyl, 2,1,3-benzoxadiazol-4-yl, 2,1,3-benzthiadiazol-4-yl, or thienyl unsub-stituted or monosubstituted by halo or C1-C4 alkyl;
R1 and R2 are each independently C1-C4 alkyl or 2-methoxyethyl; and R3 is H or -(CH2)mCOR4 where m is 1, 2 or 3, and R4 is hydroxy, C1-C4 alkoxy or -NR5R6 where R5 and R6 are each independently hydrogen or C1-C4 alkyl;
characterized by reducing an azido compound of the formula:

where R, R1, R2 and Y are as defined for formula (I) so as to produce a compound of the formula (I) in which R3 is H, said process being followed by, optionally, one or more of the following steps:
(a) conversion of a compound of the formula (I) in which R3 is H into a compound of the formula (I) in which R3 is -(CH2)mCOO(C1-C4 alkyl) where m is 1, 2 or 3 by reaction with a compound of the formula Hal-(CH2)mCOO(C1-C4 alkyl) where "Hal" is Cl or Br;
(b) conversion of a compound of the formula (I) in which R3 is -(CH2)mCOO(C1-C4 alkyl) where m is 1, 2 or 3 into a compound of the formula (I) in which R3 is -(CH2)mCOOH or -(CH2)mCONR5R6, m, R5 and R6 being as defined for formula (I), by, respectively, hydrolysis or reaction with an amine of the formula R5R6NH; and (c) conversion of a compound of the formula (I) into a pharmaceutically acceptable salt.
25. A process according to claim 24, wherein the reduction is carried out with hydrogen.
26. A process according to claim 25, wherein the hydrogena-tion is carried out in the presence of a palladium catalyst.
27. A process according to claim 24, wherein the reduction is carried out with zinc and hydrochloric acid.
28. A process according to claim 16, which is used to prepare a compound of the formula (I) in which R is 2-chlorophenyl, R1 is CH3, R2 is C2H5, Y is -(CH2)2- and R3 is H or CH3.
29. A process according to claim 24, which is used to prepare a compound of the formula (I) in which R is 2-chlorophenyl, R1 is CH3, R2 is C2H5, Y is -(CH2)2- and R3 is H.
30. A process according to claim 16, wherein R is phenyl, 2-chlorophenyl, 2-fluorophenyl, 2-methoxyphenyl, 3-chlorophenyl, 2-chloro-3-hydroxyphenyl, 2-chloro-6-fluorophenyl, or 2,3-dichloro-phenyl.
31. A process according to claim 16, wherein Y is -(CH2)2-or -CH2CH(CH3)-.
32. A process according to claim 16, wherein R3 is H, CH3, benzyl, 2-methoxyethyl, -CH2COOCH3, -CH2COOC2H5, -CH2CONH2, -CH2CONHCH3 or -CH2COOH.
33. A process according to claim 16, wherein R3 is H or CH3.
34. A process according to claim 16, wherein R is 2-chloro-phenyl, R1 is CH3, R2 is C2H5, Y is -(CH2)2 and R3 is H or CH3.
35. A process according to claim 16, which includes the step of treating an obtained compound of formula (I) with maleic acid to give the maleate salt thereof.
36. A process according to claim 16, 17 or 28, wherein X is -NR3 (benzyl) and the compound of formula (IA) is obtained by reacting an aminocrotonate ester of formula (III) (III) with an aldehyde of formula RCHO
and a ketoester of formula (IV) IMG> ( IV ) wherein R, R1, R2, R3 and Y are as defined in claim 16, in the Hantzsch synthesis.
37. A process according to claim 16, 17 or 28, wherein X is -NR3(benzyl) and the compound of formula (IA) is obtained by reacting a compound of formula (V) (V) with a compound of formula (VI) (VI) wherein R, R1, R2, R3 and Y are as defined in claim 16.
38. A process for preparing 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine or a pharmaceutically acceptable salt thereof which comprises subjecting 2-[2-(N-benzylamino)ethoxymethyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine or its oxalate salt to hydrogenolysis in the presence of a palladium on charcoal catalyst and, if required, converting the obtained compound into a pharmaceutically accept-able salt thereof.
39. A process according to claim 38 wherein the 2-[2-(N-benzylamino)ethoxymethyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine or its oxalate salt is obtained by subjecting 2-[2-(N,N-dibenzylamino)-ethoxymethyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine or its oxalate salt to hydrogenolysis in the presence of a palladium on charcoal catalyst.
40. A process for preparing 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine or a pharmaceutically acceptable salt thereof which comprises by subjecting 2-(2-azido-methoxy)methyl-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine to reduction and, if required, converting the obtained compound into a pharmaceutically acceptable salt.
41. A process according to claim 40 wherein the reduction is effected by reaction with zinc and hydrochloric acid or by reaction with hydrogen in the presence of a palladium on calcium carbonate catalyst.
42. A process according to claim 40 wherein the 2-(2-azido-methoxy)methyl-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxy-carbonyl-6-methyl-1,4-dihydropyridine is obtained by reacting ethyl 4-(2-azidoethoxy)acetoacetate with methyl 3-aminocrotonate and 2-chlorobenzaldehyde in the Hantzsch synthesis.
43. A process for preparing 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine or a pharmaceutically acceptable salt thereof which comprises removing a phthalimido group from 4-(2-chloro-phenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-(2-phthalimidoethoxy)methyl-1,4-dihydropyridine and, if required converting the obtained compound into a pharmaceutically accept-able salt thereof.
44. A process according to claim 43 wherein the phthalimido group is removed by reaction with ethanolic methylamine, by reaction with hydrazine hydrate or by reaction with potassium hydroxide followed by hydrochloric acid.
45. A pharmaceutical composition which comprises as active ingredient a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof in admixture with a suitable diluent or carrier.
46. A pharmaceutical composition which comprises as active ingredient 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxy-carbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine or a pharmaceutically acceptable salt thereof, in admixture with a suitable diluent or carrier.
47. A pharmaceutical composition which comprises as active ingredient 2-[(2-methylamino)ethoxymethyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine or a pharmaceutically acceptable acld addition salt thereof, in admixture with a suitable diluent or carrier.
CA000423148A 1982-03-11 1983-03-09 1,4-dihydro having a basic amino-containing group attached to the 2-position as anti-ischaemic and antihypertensive agents Expired CA1253865A (en)

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