CA1117117A - 2-methyl-dihydropyridine compound, processes for preparation thereof and pharmaceutical composition comprising the same - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

New 2-methyl-dihydropyridines are provided of the formula:

Description

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2-METHYL-DIHYDROPYRIDINE COMPOUND, PROCESSES
FOR PREPARATION THER~OF AND PHARMACEUTICAL
COMPOSITION COMPRISING THE SAME

This invention relates to 2:-methyl-dihydropyridine :~: compound and a salt thereof. More particularly, it relates to a new~2-methyl-dihydropyridine compound and a pharmaceutically acceptable salt thereo~ which haYe vasodilating and anti-hypertensive activi:ties, to processes for the preparation thereof,:and to a pharmaceutical composition compris~ng the same ~or ` therapeutical trea~men~ of cardiovascular disorder : and hypertension in human being.
With regard to the states of the arts in this ~ield, for example, the following dihydropyridine : ~ ~
~: ~ compounds are known.

:: : ~ ' '~ ~ .
~ , ~ , I~L N02 A-lCH300C~ COQCH3 ~U.S.P. 3,485,847) (Ni fe dip ine ) ~ 2 ~1 A-2 C2H5OOC\ ~ COOCzH5 (German Offenlegungsschrift 26 29 892) ~13 H -\CN

A-3 C~H500C ~ OOC2H5 (Ger29n892)enlegungsschri~t One object of this invention:is to provide the new and useful 2-methyl-dihydropyridine compound and ~, :~ a pharmaceutically acceptable salt thereof, which are structurally characterized in the substituent at the third position of the dihydropyridine nucleus and have stronger activity as compa~ed with the known compounds, for example, as shown above, : Another object of this in~ention is to provide processes for the preparation of said 2-methyl-dihydropyridine compound and the salt thereof.
~: 35 A furtber object of this invention lS to pro~ide ~ .

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-3-a useful pharmaceutical composition comprising, as an active ingredient, said 2-methyl dihydropyridine compound or the pharmaceutical:Ly acceptable salt thereof, which is useful, as a vasodilator and anti-hypertensive.agents~

Still ~urther object of this invention is toprovide a therapeutical method for treatment of cardiovascular disorder such as coronary insufficiency~
angina pectoris or myocardial :infarction and hyper-tension.
The 2-methyl-dihydropyridine compound o this invention can be represented by the following formula:

Rl ~ (I) wherein Rl is phenyl, 3-nitrophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, : ~ 2-allyloxyphenyl, 2,4-dichlorophenyl, 3 9 4-dichlorophenyl, 3,4-dimethoxyphenyl, : 25 2-tolyl, 4-pyridyl or 2-thienyl, : R2 is propyl, isopropyl, 2-chloroethyl, 2-- hydroxyethyl, 2-ethoxyethyl, 2-phenoxyethyl, 2-benzyloxyethyl or 2-(N-benzyl-N-methyl-amino)ethyl, ~:~ 30 R3 is lower alkyl, and R4 is di~lower)alkoxymethyl~ formyl, hydroxy-methyl or cyano, pro~ided that, when Rl is 3-nitrophenyl, ~hen R is 2-hydroxyethyl and R is cyano or formyl, or R is propyl or isopropyl.
With regard to ~he object compound o the above formula (I), it is to be undeTstood that theTe can 5 be a pair of two optical isomers due to the asymmetric carbon atom at the ~ourth pos:ition o the dihydro-pyridine nucleus; and accordingly, this type of isomers are to be included within the scope of this invention and r~presented by the same formula (I), inclusively~
According to this invent:ion, the object compound (I) can be prepared by the processes as illustrated by the ~ollowing schemes.
[I] Construction o~ ~undamental structure:-(1) Process 1:
Rl Rl~CH=C-C~Ra + CH3-1C=CH CRa~ Ra ~ ooR3 (II-l) (m -1) (I-l') wherein Rl and R3 are each as defined befoTe, R2 is propyl9 isopropyl, 2-chlo~oethyl, 2-ethoxyethyl, 2-phenoxyethyl, 2-benzyl-oxyethyl or 2- (N-benzyl-N-methylamino) -

4 ethyl ana : Ra is di(lowe~)alkoxymethyl, : ~ provided that - when R' is 3-nitrophenyl, : ~ then R2 is propyl or is opropyl .
(2) Process 2 Rl Rl-CH=C-COCH3 ~ R4-C=CH-CoOR3~R2OOC~:ooR3 ~OORa ~H2 CH ~ ~ 4 3S (~ -2) ~m -2) 3 H a (I-2) :

~ .

'7 -s-wherein Rl, R2, R3 and R4 are each as defined before, provided that, when Rl is 3-nitrophenyl, then Ra is propyl or isopropy:l.
[II~ Transformations of a f~lctional group:-~3) Process 3-R2OOC ~ ~ CooR3 Hydrolysis R2OOC ~ CoOR3 (I-l) (I-3) wherein Rl, R2) R3 and R4a are each as defined beforQ, provided that, when Rl is 3-nitrophenyl, then R2 is propyl, isopropyl or 2-`hydroxyethyl.

~4) Process 4:
.
Rl' Rl `
: R2OOC ~ CoOR3 ReductionR2OOC ~ CoOR3 , ~I-3) ~I-4) wherein Rl, R2 and R3 are each as defined before, provided that, when Rl is 3-nitrophenyl, then R is propyl or isopropyl.

3a ~5) Process 5:

Rl ~i) Hydroxylamine Rl RbOOC ~ CoOR3 or a salt thereof RbOOC ~ CoOR3 ~ N ~) ~hydrating t CH 3 H CHO agent CH ~ 'CN

~I-3') (I-S~

wherein Rl and R3 are each as defined before, and Rb is propyl, isopropyl, 2-hydroxyethyl, Z~ethoxyethyl, Z-phenoxyethyl, 2-benzyloxy-ethyl or 2-(N-benzyl-N-methylamino)ethyl, provided that, when Rl is 3-nitrophenyl, then Rb is propyl, isopropyl or 2-hydroxyethyl.

~6) Process 6:
._ Rl Rl Re20CH2CH200C~COOR HydTOlysi5 HOCH2~H200C~cooR3 . CH3 H CN 3 H
~IIc) ~I-6) . wneréin Rl and R3 are each as defined before, and Re is acyl.
) ProCess-?

~1 ~;~ ClC~z~HzOOC ~ C6H5CHz S ~ CH2CH ~ ~ COC 3 : ~ 35 ~ IId~ 7) '' , .

7~

, wh-~re~n Rl, R3 and R4 are each as defined before, provided that, when Rl is 3-nitrophenyl) then R is propyl OT isopropyl.
, .
"Lower alkylt' for R3 includes Cl-C6alkyl, pre-ferably Cl-C3alkyl and more preferably normal straight ones such as methyl, ethyl, propyl or the like.
"Di(lower)alkoxymethyl" ~or R4 and Ra includes di(Cl-C6 straight and branchecl chain lower alkoxy)-methyl, preferably Cl-C3 ones such as dimethoxymethyl, diethoxyme~hyl, dipropoxymethyl or the like.
"Acyl" for Re includes a conventional one, pre-ferably alkanoyl, and more preferably lower alkanoyl such as Cl-C6alkanoyl (e.g. formyl, acetyl, propiollyl~
butyryl, isobutyryl, valeryl, etc.~, or the like.
The starting compounds (II-l) and ~ 2) used in Processes 1 and 2 include new and known ones and new ones can be prepared by reacting 4-substituted aceto-acetate (IIA) or (IIA') and aldehyde (IIB) as shown inthe following reaction schemes according to a conven-tional manner.

) R~ 10 + R4-CoCH;~CooR3--,~ Rl-CH=C-CO-Ra 2~
COOR

wherein Rl, R3 and R4 are each as defined before.

~) Rl-CHO + CH3COCHzCOOR2 `-- > Rl-CH=C-COCH3 :~ ~OORa ) (IIAI) (II-2) wherein Rl and R2 are each as defined before.
~`~ a ~ ' . ., ~ .

1~7~:~'7 The other starting compounds (III-l) and ~III-2) used in Processes 1 and 2 can be prepared from a 4-substituted acetoacetate compound (IIIA) or ~IIIA') and ammonia or a salt thereof as shown in the following reaction schemes.

3-~-CH2CRa + NH3 --~ CH3-C=CH-COORa (IIIA) (III-l) wherein Ra is as defined before.

~ Ra-S-CH2CooR3 ~ NH3 __~ Ra- ~ CH-CooR3 ~IIIA'~ (III-2) 2~ wherein R3 and R4 are each as defined before.
a Fur~her, the starting compound (IIC) used in Process 6 can be pTepared by the method as shown in the following reaction scheme, and the compound (I-8) 2~ can be prepared according to the similar manner to ~, those of Process 2 and ~ollowed by the Process 3 as :~ . mentioned above.
Rl (i) Hyd~oxyl~ne Rl HOaH2CH200C I ~ R3hydrochlri~ R2.0CH2CH200C ~ ~ R3 30 C~31N~O e 2 CH3~NJlCN
H H
(I-8) (IIc) wherein Rl, R3 and Re a~ each aS ~fmed before.

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Processes for preparation of the 2-methyl-dihydropyrldine compound ~I) will be explained in details below.

~1) Process 1 This process relates to a method for pre-paring a compound tI-l') by reacting a compound (II-l) with an amino compound (III-l).
Each of the starting compounds ~II-l) and (III-l) includes cis and trans geometrical isomers due to the double bond in their molecules, and according to this process, the compound (I-ll) can be prepared by any sequence of the reaction of either geometrical isomers of compound _- 15 (II-l) with either on0s of the compound (III-l), and accordingly all isomers and optional mixtures of the isomers of these starting compounds tII-l) and (III-l) are to be included within the scope of this process.
The reaction can be carried oùt at ambient temperature or under warming or heating. The re-action can preferably be conducted in the absence of a solvent, but may be conducted in a suitable solvent such as benzene, toluene, xylene, chloroform, ;~5 carbon tetrachloride, methylene chloride, ethylene .
chloride, or other conventional solvents. The re-action can preferably~be accelerated in the pre-sence of an agent such as an acid (e.g. acetic acid), a base (e~.g. pyridine or picoline) or in a conven-tional buffer solution. These agents act as a reac-tion accelerator and may also be used as a solvent in case that they~are in liquid. The reaction can also be accelerated by warming or heating. The reaction condition may vary according to the kind of the reactants, solvent and/or other agent as mentioned above to be used -As to the reaction mode of this Process, it .

'3L7 ....

is to be noted that it can alternatively be conducted, for example, by reacting the 4-substitu~0d acetoacetate compound (IIA~, with the aldehyde (IIB) in the presence of the amino compound (III-l).
(2) Process 2:
This process relates to a method for pre-paring a compound (I-2) by reacting a compound (II-Z) with an amino compound (III-2).
This process is substantially the same as Process 1, and accordingly can be conducted by reacting the compound (II-2) with (III-2) in the same manner as those for the Proc~ss 1. That is, the same reaction conditions (e.g. reaction tem-perature, solvent, accelerator, etc.) and the same alternative reac~ion procedure as mentioned in the Process 1 are also applied to this process, provided that the compound (II-2) or alternative reactànts (IIA') and ~IIB), and the compound (III-2) are used in ~his process instead of using the compound ~II-l) or alternative reactants (IIA) and ~IIB), and th~ compound (III-l) in the Process 1, respectirely.
(3) Process 3: ~, This process relates to a me~hod for pre-paring a compound (I-3) by hydrolysing a compound The compound (I-l} can be prepared by the method as illustrated in the above (Processes 1 and ~).
In this process, the di~lower)alkoxymethyl group for Ra of the compound (I 1~ is ~ransforme~
into a formyl group.
Hydrolysis may be carried out in a conven-tional m~ner which is applicable to cleavage F

-.~ .

~ 7 so~called acetal function into the correspond-ing carbonyl ~unctionJ and preferably, for example, an acidic hydrolysis, i.e. in the presence of an acid such as an inorganic acid (e.g. hydrochloric acid, sulfuric acid, etc.) or an o~ganic acid ~e~g~ formic acid, acetic acid, trifluoroacetic acid, p-toluenesulonic acid, etc.), or an acidic ion-exchange resin.
This hydrolysis may be carried out in a sui~able conventional solvent such as water, acetone, methyl ethyl ketone, dioxane, ethanol, methanol, N,N-dimethylformamide, or dimethyl-suloxide, an optional mixture thereof or a buffer solution thereof. The reaction tempe-rature is not restrictive, and the reaction is usually conducted under cooling, at room tem-perature or under somewhat elevated temperature.
(4) Process 4:
This process relates to a method for pre-~0 paring a compound (I-4) by reducing the compound ~I-3).
;~; The reduction can be carried out in a con-ventianal manner which can be~ applied to reduction of a formyl group into a hydroxymethyl : 25 group ,: and particularly, ~he reduction is con-ducted by using a reducing agent such as an alkali metal borohydride ~e.g;. lithium borohydride, sodium borohydride, potassium borohydTide, sodium cyanoborohydride, etc.) or by catalytic reduction for which preferable catalyst may be palladium carbon, palladium chloride OT rhodium carbon and he like. The reduction is usually carried out in a conven~ional solvent such as water, methanol, ethanol, isopropanol, dimethylformamide, tetra-hydTofuran, etc., and *he like. The ~eaction ' ~7 ~7 temperature is not restrictive J and the react-ion is usually carried out undar cooling, at room temperature or at somewhat eleva~ed tem-perature. And, the method of reduction may optionally be selected according to the kind of the compound (I-3).

(5) Process 5:
This process relates to a me~hod ~or pre-paring a compound (I 5) by reacting a compound ~I-3') with hydroxylamine or a salt thereof, and then reacting the res.ultant product with a dehydrating agent.
According to this process, the formyl group of the starting compound (I-3') may be transformed into the hydroxyiminomethyl group (the first step~, and in succession said group is transformed into the cyano group (the second step).
Preferable salt o hydroxylamine may be a salt with an acid such as an inorganic acid (e.g.
hydrochloric acid, sulfuric acid, etc.) or an organic acid (e.g. acetic acid, etc.).
(i) The irst step:-The reaction of this step is carried out in a usual manner as so-called oximation ~eaction, for ~ ~ 25 example, in the presencs of an acid (e.g. hydTochloric `~ acid, hydrobromic acid, sulfuric~acid, formic acid, acetic acid, p-toluenesulonic acid, boron trifluoride, silicon tetrachloride or ~itanium tetrachloride); in a basic condition brought abou~ by a base, for example free hydroxylamine; or in an acidic or basic conven-tional buffer s~olution. The reaction is usually con-ducted in a suitable conventional solvent such as water, dioxane, ethanol, methanol, dimethylformamide or an optional mixture thereof, and in case that the above acid is in li.quid, it can also be used as a solvent.

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7~7 The reaction temperature is not restrictive, and the reaction is usually carried out under cooling, at room temperature or under somewhat elevated tem-perature The reaction product of the ~irst step is subjected to the ollowing second step with or without isolation and/or p~rification.

~ii) The second step:-Suitable dehydrating agent used in this step includes conventional organic or inorganic ones such as inorgani~ acid (e.g. sulfuric acid, phosphoric acid, polyphosphoric acid, etc.), an organic acid (e.g. formic acid, ^ 15 acetic acid, trifluoroacetic acid, ethanesul~onic . .
acid, p-toluenesulfonic acid, etc.), an organic acid anhydride (e.g acetic anhydride, benzoic anhydride, phthalic anhydride, etc.), an organic acid halide (e.g. acetyl chloride, benzoyl chloride, trichloro-acetyl chloride, mesyl chloride, tosyl chloride, ethyl chloroformate, phenylchlorofoTmate, etc.);
an inorganic halogen compound (e.g. thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, stannic chloride, titanium tetrachloride, etc.); a carbodiimide ~e.g. N,N'- ., dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholino-ethylcarbodiimide, etc.), N,N'-carbonyldiimidazole, pentamethyleneketene-N-cyclohexylimine; ethoxyacetylene;
2-ethyl-7-hydroxyisoxazolium salt; other phosphorus compound (e.g. phosphorus pentoxide, polyphosphoric acid ethyl ester, triethylphosphate or phenylphosphate) and the like or an optional mixture thereof. When an acid is used as the dehydrating agent~ the reaction can also be conducted in the presence of its salt such as an alkali metal salt (e.g. sodium salt or potassium salt), or the like.

, '7 14~

This reaction is usually carried out in a conventional solvent such as diethyl ether, dimethylformamide, pyridine, acetic acid, ~ormic acid, benzene, carbon tetrachLoride, chloroform, methylene chloride, tetrahydrofuran, dioxane, and the like, and usually carried out at room temperature OT under heating, but the reac~ion ~emperature is not restrictive to the above.

~6~ Process 6:
This process relates to a method for preparing a compound ~I-6) by hydrolysing a compound (IIc).
In this process, the acyl group for Re f the compound ~IIc) is eliminated by hydrolysis to give the 2-hydroxyethyl compound (I-6).
Hydrolysis is carried out in a con~entional manner which is conventionally applied to a cleavage of a so-called ester bond into the hydroxy function, and is preferably carried out 9 for example, by a basic hydrolysis, i.e. in the presence of a base such as an alkali metal hydroxide, carbonate or bicarbonate, ~e.g. sodium hydroxide, potassium hydroxideJ sodium carbonate, potassium carbonate, sodium bicarbonate, etc.~ or by an acidic hyarolysis in the presence of an organic or inorganic acid, suitable examples thereof include those given in the above-mentioned Process 3.
This hydrolysis may preferably be caTried out in a conventional solvent such as water, acetone, dioxane, me~hanol, e~hanol, dimethylfoTmamide~
dime*hylsulfoxide, or an optional mixture thereof.
The reaction temperature is not restrictive, and the reaction is usually conducted at room temperature or under heating.

t7) Process 7:
This process relates to a method for pre-paring a compound ~I-7) by reacting a compound ~IID) with N-methyl benzylamine.
The reaction is usually carried out in a suitable solvent such as chloroform, methylene chloride,benzene, acetone, diethyl ether, tetrahydrofuran, dimethylformamide, methanol, ethanol~propanol, isopropanol,water and other conventional solvent or an optional mixture ~hereof.
This reaction can also be carried out in the presence of a base, suitable examples of which include an inorganic base such as an alkali metal hydroxide, carbonate bicar-bonate, hydride or amide (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydride, sodium amide, etc.) or an organic base such as an alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium ethoxide, lithium methoxide, etc.), a salt of an organic acid (e.g. sodium acetate, potassium acetate, etc.), a tertiary amine or imine base (e.g. trie~hylamine, pyridine, picoline, N,N-dime~hylaniline, N-methylpyrolidine,N-methylmorpholine, etc~) and the like.
Furthar, this reac~ion is preferably carried out in the presence of an alkali metal iodide such as lithium iodidQ, sodium iodide or the like in addition ~o the base.
The reaction temperature is not restrictive, and the reaction is usually carried ou~ at room temperature, or under warming or hea~ing.
According to this invention, the object reaction product can be separated and isolated from the reaction mixture and purified by methods commonly used for this purpose, for instance, extraction with suitable sol~ent, chromatography, precipitation, recrystalliæation and so on.
Suitable examples of a salt of the ~9 7 ~ ~'7 ;~`

2-methyl-dihydropyridine compound ~I) include a pharmaceutically aoceptable salt such as an inorganic acid salt (e.g. hydrochloride, hydrobromide, phosphate, sulfate, etc.) and an organic acid salt (e.g. ~ormate, acetate J fumara~e, maleate, aspartate, glutamate, etc.).
The compound (I) thus obtained frequently includes at leas~ one pair of optical isomers due to the presencP of an asymmetric carbon atom of the fourth position of the 1,4-dihydropyridine nucleus and can exist as each optical isomer or a mixture thereof.
A racemic compound can be resolved into each optlcal isomer by a conven~ional method for racemic resolution, such as a chemical resolution of the salts of the diastereomer with a conventional optically active acid te.g. tartaric acid or camphor sulfonic acid, etc.).
It is to be noted that the compound tI) and a pharmaceutically acceptable salt thereo~ possess a strong vasodilating and anti-hypertensive activities and useful for therapeu~ical treatment in cardiovascular disorder and hypertension such as coronary insufficiency, angina pectoris or myocardial infarction, and hyperten-sion.
Particularly, the strong pharmacological activi~ies of ~he compound (I) according to this inven- ~, tion is structurally characterized by the radical R2, specifically selected rom the group consisting of propyl, isopropyl, 2-chloroe~hyl, 2-hydroxyethyl, 2-ethoxyethyl, 2-phenoxyethyl, 2-benzyloxyethyl and 2-~N-benzyl-N-methylamino)ethyl.
More particularly, the compound (I), wherein3 for example, i) Rl is 3-nitrophenyl or 2-chlorophenyl, R2 is isopropyl, R3 is methyl and R4 is cyano, and-ii) Rl is 2-trifluoromethylphenyl, R is isopropyl or 2-phenoxyethyl, R3 is methyl and R4 is hydroxymethyl .
.

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1~7~

or cyano, possesses stronger therapeutical ef~ects as mentioned abo~e, as compared with -the known compound as mentioned hereinbefore.

Further, the compound (I), wherein, or example, iii) Rl is 3-nitrophenyl or 2-chlorophenyl, R2 is isopropyl, R3 is methyl and R4 is dimethoxymethyl or formyl, and i~) Rl is 2-trifluoromethylphenyl, R2 is isopropyl or 2-phenoxyethyl, R3 is methyl or ethyl and R is dimethoxymethyl, diethoxymethyl or formyl, is useful not only as vasodilating and anti-hypertensive agents but also as an intermediate ~or preparing the more preferable vasodilating and anti-hypertensive agents of this invention as illustrated hereinabove.
For therapeutical purpose 9 the 2-methyl-dihydropyridine compound (I) is administered in daily dose of 0.1 to 500 mg3 preferably 1 to 50 mg.
The pharmaceutical compositions of this invention comprise, as an active ingredient, the 2-methyl-dihydropyridine compound (I) or pharmaceuti-cally acceptable salt thereof in an amount of about 0.01 mg. to about 500 mg., preferabIy about 0.1 mg.
to about 250 mg. per dosage unit for oral and paren-teral use. ~' One skilled in the ar~ will recognize that the amount-of the active ingredient in the dosage unit form may be determined by considering the activity of the ingredient as well as the size of the host human being. The active ingredient may usually be formulaked in a solid form such as tablet, granule, powder, capsule, troche, lozenge or suppo-~- sitory, or a suspension or solution form such as syrup, injection, emulsion, lemonade, etc and ~he like.
A pharmaceutical carrier or diluent includes solid or '' . ., ' ~ .
: ~ ~

73L~'7 liquid non-toxic pharmaceutically acceptable sub-stances. Examples of solid or liquid carriers or diluents are lactose, magnesium stearate; terra alba, sucrose, corn starch, talc, stearic acid, gelatin, agar, pectin, acacia, peanut oil, olive oil or sesame oil, cacao butter, ethyleneglycol or the other conventional ones. Similarly, the carrier or diluent may include a time delay material such as glyceryl monostearate, glyceryl distearat~, a wax and the like.
~or the purpose of showing the utility of the compound [I), the pharmacological test results o~
some represented compounds will be shown as follows.
HYpotensive effect:
Test Method;
Five Wistar rats were used per group. Each animal was immobilized in a cage sized to the body. Blood pre-ssure was measured at the femoral artery by means o a pressure transducer and recorded as electrically integrated values of mean arterial pressure, and heart rate was determined by a pulse wave detector.
Opera~ion for the catheterization was performed under light ~nesthesia with ether. The test compound was administered orally 3 hours after completion of the operation.
Test Compound;
Compound A-l : Nifedipine (reference compound) Compound B : Isopropyl ester o 6-cyano-5-methoxy-carbonyl-2-methyl-4-t3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid.

Compound C : Isopropyl ester of 4-(2-chlorophenyl)- `

6 - cyano-5-methoxycarbonyl-2-methyl-1~4-dihydropyridine-3-carboxylic acid.-

7~

.

Compound D : Isopropyl ester o 6-cyano-4-~2-trifluoromethylphenyl)-5-methoxy-carbonyl-2-methyl-l,4-dihydropyridine-3-carboxylic acid.
S , .
Compound E : 2-Phenox~ethyl ester of 6-cyano-4-(.2-tri~luoromethylphenyl)-5-ethoxy-carbonyl-2-methyl-l,4-dihydropyridine-3~carboxylic acid.
Compound F : Isopropyl ester of 4-~2-trifluoromethyl-phenyl~-6-hydroxymethyl-5-methoxy-carbonyl-2-methyl-l,4-dihydropyridine-3-carboxylic acid.
Compound G : 2-Phenoxyethyl ester of 4-(2-trifluoro-methylphenyl)-5-ethoxycarbonyl-6-: hydroxymethyl-2-methyl-l,4-dihydropyridine-3-carboxylic acid.
Test Results;
,~ ~
Mean values of ~ Maximum Decrease of blood pressure mmHg) were shown in the following table.
~, (continued to the next page) ~: ~ 30 -:

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Tabl_ 1 , \ose ¦1 mg/kg 10 mg/kg S Compound I _ .
A-l -25.6 ~ 1.5 -44.6 + 1.2 ~ . _ ~ , -44.6 ~ 1.7 -5~.0 ~ 1. 3 C -29.2 + 3.0 40.6 + Z,~
_ D -34.6 i o.g 47,4 i 1.3 _ . .
E ~-22.8 + 2.1 -44.2 + 1.5 . ... ~._ .... , _ F -18.0 +1.9 -46.6 ~ 2.1 . . _~ ~
G -13,2 +3,3 -47.8 + 2.4 . ~ _ ~:: --'-"
Effect of Coronary Blood Flow :
~; 25 Test Method:
Mongrel dogs, weighing 8-15 kg, were anesthetized with an intrapectoneal dose of pentobarbital sodium 35 mg/kg. After the thorax was opened under artificial ; 30 respiration, a flow-meter probe was fitted to the left circumflex branch of the coronary artery. The blood pressure was measured in the femoral artery, and the object compound of this invention were injected intravenously. The values at peak blood flow were ; 35 measured.

:
:' ' Test Results;
Table 2. Increase of coronary blood flow (~) The value indicate percentages compared to control.

~~~ose _ ~ugtkg :L O 10 0 Test Compound ~ _ _ _ _ 181 219 The following examples are given for the purpose of illustrating this invention.

(continued to the next page) :; , .

~: 30 : :
:

~ 35 ~ .

Preparation of the starting compounds ~or Processes l and 2 S ~ _.
.

1) To a solution of 3-nitrobenzaldehyde ~7 56 g~
and methyl 4,4-dimethoxyacetoacjetate ~7.93 g~ in dried benzene t30 ml~ were added acetic acid (0.18 g) and piperidine (0.17 g), and the mixture was heated under reflux for 3,5 hours, while azeotropically removing the water formed therefrom.
After adding benzene to the reaction mixture 9 the solution was washed successively with water, diluted aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride, in turn and then dried. Removal o~ the solvent under reduced pressure gave an oily residue ~15.74 g), which was chromatographed ove~ silica gel (470 g) with a mixture of benzene and ethyl acetate ~25:1 by volume as an eluent to give a yellow oil (8.06 g) of methyl 4,4-dime~hoxy-2-~3-nitTobenzylidene)-acetoaceta~e (a mixture of cis and trans isomers).

25N.M.R. ~ppm (CDC~3) : 3.45 (s)} ~6H) 3.48 (s) ~ 3-8~ ~5)} ~3H) 4- (S) }(lH), :~ 3.91 (s) 5.08 (s) 7.2S - 8.4 ~5H, m).

The ~ollowing compounds were obtained in sub-stan~ially the same manner as that of prepaTation 1 .

~; 35 :

, , ' ~ ' ' 2) Methyl 4,4-dimethoxy-2-(2-me~hylbenzylidene)-- acetoacetate ~a mixture of cis and trans isomers), N.M.R. ~ppm (CDC~3) : 2.33 (3M, s), 3.Z3 tS) 3,42 ~s) 3.64 (s)}~3H) 4-53 (s)}~lH), 3.79 (s) 5.04 (5) 6.8-7.4 ~4H, m), 7-97 ts)}(lH) ' 8.09 ts) 3) Methyl 2-(2-chlorobenæyiidine)-4,4-dimethoxy-acetoacetate ~a mixture of cis and trans isomers).
N.M.R. ~ppm (CDC~3) : 3.28 ~s) 3.41 (s) 3,71 ts)}t3H) 4.68 tS) ~lH), 3.81 (s) 5.~ ~s) 7 7,5 ~4H, m), 8-02 (s) }~lH).

8.12 (s) 4) Methyl 4,4-dimethoxy-2-~4-pyridylmethylene)-acetoacetate ~a mix~ure of cis and trans isomers~.
20N.M.R. ~ppm (CDCQ3) : 3~41 ~s)}(6H) 3.48 ~s) 3.82 ts)}(3H)~ 4-82 (s)}~lHj, 3.89 (s~ 5.06 ~s) ; 7.1-7.4 t2H~ m), 7.73 (s3 7.83 (s) 8.5-8.8 (2H, m).
5) Methyl 2-(2-trifluoromethylbenzylidene)-4,4-dimethoxyacetoace~ate (a mixture of cis and ~ans isome~s), N.M.R. ~ppm ~CDCQ3) : 3.Z8 (s) 3.42 (s) 3.61 ts))~3H)~ 4-62 ~s)}tlH)9 3.84 ts) 5.~6 (s) 7.2-~7.8 t4H, m) 7 8.0-8,14 tlH, m).
6) ~ Methyl 4,4-dimethoxy-2-~2-methoxybenzylidene)-- : :

~7 1~7 -.

acetoacetate (a mixture of cis and trans isomers).
N.M.R. ~ppm (CDCQ3) : 3-39 (s)}(6H) 3.47 (s) 3.78 (s)}(6H) 4-77 (9)}~lH), 3.88 (s) 5.16 (s) 6.7-7.2 tm~ } (4H) 8-15 (s) } (lH) 7.3-7.9 (~) 8.23 ts) 7) Methyl 2-(2-allyloxyb~nzylidine)-4,4-dimethoxy-~
acetoacetate (a mixture of cis;and trans isomers).
N.M.R. ~ppm ~CDCQ3) : 3-3 (s)}(6H), 3,4 (s) 3.73 ~5) } ~3H), 4.54 t2H~ m), 3,78 (s) 4,71 (53 } (lH), 5.1-5,5 ~2H, m), 5.07 (s) 5.8-6.22 ~lH, m), 6.7-7.0 ~m) } (4H
7.2-7.4 ~m) 8.14 (5) }(lH).
8.23 ts) 8) Methyl 4,4-dimethoxy-2-(2-thenylidene)acetoacetate ~a mixture of cis and trans isomers).
N.M.R. ~ppm ~CD~Q3) : 3.45 (6H, s), 3.88 ~s) ~: ~: 3.9S ~s) S.ll ~s)}~lH~ 7-7.8 ~3H, m), 5.17 ~s) 7.93 ~s) 8.06 (s)

9~: Methyl 2-~2,4-dichlorobenzylidine)-4,4-dimethoxy-acetoacetate ~a mixture of cis and trans isomers?.
: 30 ~N.M.R. : ~ppm ~CDC~3) : 3.39 ~s)}~6~) :
:: 3.47 ~s) 3.77 tS)}(3~) 4-77 ~s)}~lH),~
3.88 (s) 5.01 ~s) .2-~:.5 ~3H, m), 7.97 (s)} ~j~H).
8.08 (s) E - 3:

~ ~: ' ' :

lO) ~lethyl 2-(3,4-dichlorobenzylidene)-4,4-dimethoxyacetoacetate (one of cis and trans isomers), mp 86.5 - 87.5C.
11) Methyl 4,4-dimethoxy-2-(3,4-dimethoxybenzylidene)-acetoacetate (a mixture of cis and trans isomers).
N.M.R. ~ppm (CDCQ3) : 3.43 (s) }~6H
3 49 (s) 3-923 (5)~ (9H), i S 10 (s) 3.97 (s) 6 6 - 7.4 (3H, m) J 7.80 ~5) ~tlH)~
7 89 (s) , (12) 2-Phenoxyethylester of 2-(2-trifluoromethyl-benzylidene)acetoacetic acid (a mixture of cis and trans isomers).
N.M.R. ~ppm (CDCQ3) : 2-18 (5) }(3H), 2.47 (s) 3. 9-4 . 9 (4H, m), 6.8-8.2 (lOH, m).
(13) 2-ChloroethyI ester of Z-(2-trifluoro-methylbenzylidene)acetoacetic acid (a mixture of cis and trans isomers).
N.M.R. ~ppm (CDCQ3) : 2.18 (5) } (3H~
2.46 (s) ~` 25 3 SO ~t, J-6Hz) } (2H), 3.76 (t~ J~6Hz) 4.34 (t, J=6Hz) } ~2H) 7 3-7 9 (4~, m), ` 4.51 tt, J=6Hz) 7 95 (q, J'2-2HZ) } tlH).
8.04 (q, J=2.2Hz) - .
(14) 2-Ethoxyethyl ester of 2-(2-trifluoromethyl-benzylidene~acetoacetic acid (a mixture of cis and trans isomers).
~ i .
.

7 ~' N-M-R- ~ppm (CCQ4) : l.10 (t, J=7Hz) }~3~) 1.18 (t, J~7Hz) 2.11 (5) }(3H) 3.1-3.8 t4H, m), 2.38 (s) 4,1-4.5 ~2H, m), 7.3-8.0 (5H~ m~.
~15) 2-Benzyloxyethyl ester of 2-(2 trifluoro-methylbe~zylidene)acetoacetic acid (a mixture of cis and trans isomers).
N.M.R~ ~ppm (CC~4) : 2-10 (5) }~3H), 1~ 2.37 (s) 4.1-4.7 (m~ 7,2-8.0 tlOH, m) 4,37 (s) ~ (4H), 4.53 ~s) J

lS (continued to the next page) ~ ~ ' ,:
~ 25 :
.~
: ~ . : . , ~ ; 30 ! , ~ . ; :
~ E - 5 :
, ~: .

. . , 7~17 `.

Preparation of the object compounds ~or this invention:

Exam~e 1 1) A mixture of methyl 4,4-dimethoxy-2-t3-nitrobenzylidene)acetoacetate (8.0 g) and isopropyl 3-aminocrotona~e ~4.07 g) was Xeated at 70C for an hour with stirring, and the sti~ring was continued at 100C for an h~ur and at 120C for additional 2.5 hours. After dissolving the reaction mix~ure in ethyl acetate, the solution was washed with wate~ and an aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated to dryness under reduced pressure to give a yellow-orange oil (11.0~ g) of isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-t3-: nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid.

~: N.M.R. ~ppm (CDCQ~3) : 1.13 (d, J=7.0HZ) 1.27 (d, J-7.GHz) 2.40 (3H7 s), 3.47 (s) }(6H)~
: . 3.50 ~s) :~ 25 3.69 ~3H, s), 5.0 ~lHJ heptet, J=7.0Hz), 5.17 (lH9 s), 6.04 ~lH, s), : . 6.92 (lH, broad s), 7.2-8.2 (4H, m).

2) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxy-methyl-2-methyl-4-phenyl-1~4-dihydropyridine-3-carboxylic acid was prepared by reacting methyl 2-benzylidene-4,4-dime~hoxyacetoacetate, whichiwas 1~ ~7 ~ ~'7 Z~
obtained from benzaldehyde and methyl 4,4-dimethoxyacetoacetate according to the same manner as that of Preparation l, with isopropyl 3-amino-crotonate in substantially the same manner as that of Example l-l).
N.M.R ~ppm (CDCQ3) : l.ll t3H, d, J~6.5Hz)7 1.23 (3H, d~ J=6.5Hz), 2 37 (3H, s~, 3.42 t3H, s3, 3.46 (3H, s), 4.96 (lH, hep~et, J=6.5Hz), 5,03 (lH, s), 6,03 (lH, s)~ 6.73 (lH, s), 7.0-7.4 (SH, m).
The following examples are prepared in substan-tially the same manner as that of Example l-l).
3) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxy-methyl-2-methyl-4-(2-tolyl)-1,4-dihydropyridine-3-carboxylic acid.
N.M.R. ~ppm (CDCQ3) : 1.07 ~ 3H, d~ J=6.~5Hz), l.21 ~3H, d, J=6.SHz), 2.32 (3H, s), 2.55 ~3H, s), 3.41 (3H~ s), 3.44 (3H, s), 3.62 (3H, s), 4.96 (lH, hep~et, : J~6.5Hz), 5.20 (lH, 5)7 5.97 (lH, s), 6.65 ~lH, s), 6.9-7.4 ~4H, m~.
. 4) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(4-pyridyl)-l, 4-dihydro-::~ 25 pyridine-3-carboxylic acid, mp 115-117C.
S) Isopropyl ester of 4- t2-chlorophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-Z-methyl-1,4-~ ~ dihydropyridine-3-carboxylic acid, mp 86-87.5C.
:~ 6) Isopropyl esteT of 4-~2-trifluoromethylphenyl)-` 30 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-l,4-dihydropyridin~-3-carboxylic acid, mp 9~-94C.
7) Isopropyl~ester of 5-methoxycarbonyl-6-dimethoXymethyl-4-(2-methoxyphenyl)-2-methyl-l,4-~:: dihydropyridine-3-carboxylic acid, mp llO-l~I.5C.
:~ ~ 35 8) Isopropyl es~er of 4-(2-allyloxyphenyli)-S-~ E - 7 1~ 7 methoxyoarbo~yl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
N.M.R. ~ppm (CDC~3) : l.01 (3H, d, J=6,5Hz3, 1.21 ~3H, d, J~6.5Hz3, 2.33 (3H, s), 3.46 (6H, s), 3.63 (3H, s), 4.4-6.3 (8H, m), 6.60 (lH~ broad s)~
6.7-7.5 (4H, m), 9) Isopropyl ester of 5-methoxycarbonyl-6-dime thoxymethyl-2-methyl-4-(Z-thienyl)-1,4-dihydro-

10 pyridi~e-3-carboxylic acid.
N.M.R. ~ppm ~CDCQ3) : 1.22 (3H, d, J=6.5Hz), 1.28 (3H, d, J=6.5Hz), 2.37 (3H, s), 3,43 (3H, s), 3.49 (3H, s), 3.76 (3H, s), 5.07 (lH, heptet, J=6.5Hz), 5.38 ~lH, s3, lS . 6,04 (lH, s), 6,65-7.45 (4H, m).
10) Isopropyl ester of 4- (2,4-dichlorop~enyl) -5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-: dihydropyridine-3-carbo~xylic acid.
: N.M.R. ~ppm ~CDC~3) : 1.07 ~3H, d, J=6.5Hz), 1.21 (3H, d, J-6.5Hz), ~.34 ~3H, s), :~ 3.42 (3H, s), 3.46 ~3H, s), 3.64 (3H, s)~
4.97 (lH, heptet, J-6.5Hz), 5.39 (lH9 s~, S,g6 ~lH, s), 6.65 ~lH, s), 7.0-7.4 (3H, ~).

11) Isopropyl este~ o~ 4- t3,4-dichlorophenyl) -5-: methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
N.M.R. ~ppm (CDCQ3) : 1.18 ~d, J=6.5Hz) } t6H) 5 (d, J=6~5Hz) : 30 2.39 (3H~ s), 3.46 (3H, s), 3~50 (3H, s),:
3.70 ~3H, s:), 5.00 ~lH, s3, S.00 (lH, hept~t, J=6.5Hz), 6.03 ~l~, s), 6.75 (lH, s), 7.0-7.5 ~3H, m).

12) Isopropyl ester of 5-methoxycarbonyl-6-i dimethoxymethyl 4-(3,4-dimethoxyphenyl)-2-me!thyl-1,4-~ .
' E - 8 1~7~17 f. ?

dihydropyridine-3-carboxylic acid.
N.M.R. ~ppm ~CDCQ3) : 1.16 (3H, d, J-6.5Hz), 1.25 t3H, d, J=6.SHz), 2,37 (3H, s), 3 41 (s)~
3;43 (S)J(6H), 3.4~ (5) 3.79 (3H, s), 3.84 (6H, s), 4.99 (lH, s), 4.99 (lH9 heptet, J~6.5Hz), 6.03 ~lH, s), 6.6-7.3 (4H, m~.

13) Dipropyl ester o 2-met~yl-4-(3-nitrophenyl)-6 dipropoxym~thyl-1,4-dihydropyridine-3,5-dicarboxylic acid.
N.M.R. ~ppm ~CDCQ3) : 2.37 (3H, s), 5.02 (lH, s~, 6.21 ~lH, s), 6.88 (lH, broad s).

14) 2-~N-Benzyl-N-methylamino)ethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4-~2-trifluoromethyl-phenyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid, N.M.R, ~ppm (CDCS3) ~ 1.3 (9H, m), 2017 :~ (3H~ s), 2.33 t3H, s), 2.60 ~2H, t, J-6Hz), 3.48 (2H, s), 3.4-4.4 (8H, m), :~ 5.63 (lH, s), 6.13 ~lH, s), 6.71 (lH, s), 7.1-7.6 (9H, m).
. lS) 2-Phenoxyethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4-(2~trifluoromethylphenyl~-2-methyl-1,4-dihydropyridine-3-carboxylic ~cid.
N.M.R. ~ppm (CDCQ3) : 1.0 ~o 1.5 (9H, m), 2.37 (3H, s), 3.5-4.~ (lOH, m), 5.67 ~ (lH, s~, 7.12 (lH, s), 6.7-7.8 tlOH, m) A
:~ 16) 2-Chloroethyl ester o~ 5-ethoxycarbonyl-6' : 30 diethoxymethyl-4-~2-tri~luoromethylp~enyl)-2-methyl-: 1,4-dihydropyridine-3-carboxylic acid.
:~ N.M.R. ~ppm ~CCQ~) : 1.0-1.5 (6H, m~,`2.39 3H, s)~ 3.4-4.5 ~lOH, m)~ 5~5-5.7 ~ (lH, m), 6,10 (lH, s), 6.55 (lH,-s), ;~ 35 7-7.6 (4H, m). i/
~ ~ E - g ' :: .

~17~17 17) 2-~thoxyethyl ester o 5-ethoxycarbonyl-6-diethoxymethyl-4-~2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxy.lic acid.
N.M.R. ~ppm ~CCQ~ L.0-1.4 (12H~ m), S ~.38 (3H, s), 3.3-4.3 ~12H, m), 5-5-5.7 tlH, m), 6.10 (lH, s), 6.47 (lH, s~, 7.2-7.7 (4H, m~.
18) 2-Benzyloxyethyl ester of 5-ethoxycarbonyl-6-diethoxyme~hyl-4-(2-trifluorométhylphenyl~-2-me~hyl-1,4-dihydropyridine-3-carboxylic acid.
N.M.R. ~ppm ~CDCQ3) : 1.0-1.6 t9H, m), 2.32 t3H~ s), 3.4-4.4 (lOH, m), 4.47 ~2H, s), 5.6-S, 7 (lH, m), 6.11 (lH, s), 6.6-6.8 ~lH, broad s), lS 7.2-7.7 ~9H, m).

(continued to the next page) .
~. ~, :~
~ .
~ ~ 30 -~ 35 .
E ~ 10 .

7~17 Example 2 1) A mixture of 2-phenoxyethyl ester of 2-(2-trifluoromethylbenzylidene)acetoacetate (19.62 g~ and ethyl 2-amino-4,4-diethoxycrotonate (ll.9S g) was heated for 20 hours at 100 to 110C and for additional 12 hours à~ 120 to 130~C. The resultant mixture was dissolved in ethyl acetate and washed with water and then dried over anhydrous magnesium sulfate. The sol~ent was removed by distil:la~ti~n to give a crude oil (27.7 g), which was chromatographed o~er silica gel with a mixture of benzene and ethyl acetate ~50:1 by volume) as an eluent to gi~e 2-phenoxyethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoro-methylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid (19.34 g~.
N.M.R. ~ppm (CDCQ3) : 1.0 to 1.5 (9H, m), 2.37 (3H, s), 3.5-4.6 (lOH, m), 5.67 (lH, s) 9 7.12 (lH, s), 6,7-7.8 (lOH, m).
The following compounds were obtained in substan-tially the same manner as that of Example 2-1).
2~ 2-Chloroethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethylphenyl)-2-~ethyl-1,4-dihydropyridine-3-carboxylic acid.
N.M.R. ~ppm (CCQ4) : 1.0-1.5 (6H, m), 2.39 t3H,.
s3, 3.4-4.5 (lOH, m), 5.5-5.7 (lH, m), : 6.10 (lH, s), 6.55 (lH, s), 7-7.6 ~4H, m)- .
~ 3) 2-E*hoxyethyl ester o 5-ethoxycarbonyl-6-:~ 30 diethoxymethyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid. :
N.M.R. ~ppm (CCQ4) : 1.0-1.4 (12H, m), 2.38 (3H, s), 3.3-4.3 (12H, m), -. 505-5.7 (lH, m), 6.10 (lH, s), 35. 6.47 (lH, s), 7.2-7.7 (4H, ~.
~ E - 11 4) 2-Benzyloxyethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4-(2-tri~luoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
N.M.R. ~ppm ~CDCQ3) : 1.0-1.6 (9H, m~, 5 ~- 2.32 (3H, s), 3.4-4.4 (lOH, m), 4.47 (2H, s), 5.6-5.7 (lH, m) 7 6.11 (lH, s), 6.6-6.8 (lH, broad s~, 7.2-7.7 ~9H, m), S) 2-(N-Benzyl-N-methylamino)ethyl ester of 5-ethoxycarbonyl-6-dicthoxymethyl-4-~2-trifluoromethyl-phenyl)-2-methyl-1,4-dihydropyridine-3 carboxylic acid.
N.M.R. ~ppm (CDCQ3) ~ 1.3 (9H, m), 2,17 t3H, s), 2.33 (3HJ s), 2.60 (2H, t, J=6Hz), 3.48 (2H, s), 3,4-4.4 (8H, m), 5.63 (lH, s~, 6.13 (lH, s), 6.71 (lH, s), 7.1-7.6 (9H, m).
6) Isopropyl ester o 5-methoxycarbonyl-6-dimethoxy-methyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-: 3-carboxylic acid.
N.M.R. ~ppm (CDCQ3) : 1.13 (d, J=7.0Hz) }(6H
1.27 ~d, J=7.OHz) 2.40 ~3H, 5), 3 47 ~5) }(6H), ~ 3.50 (s) :~ 3,69 (3H, s), 5.0 (lH, hep~et, J-7.0Hz), ;:~ 25 5.17 (lH, s), 6~04 (lH, s), 6.92 (lH, broad s)~ 7.2-8.2 ~4H, m).
:~ 7) Isop~opyl ester of 5-methoxycarbonyl-6-dimethoxy-methyl-~-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylic acid.
~ 30 N.M.R. ~ppm (CDCQ3) : 1.11 (3H, d, J=6.5Hz), : 1.23 (3H, d, J=6.5Hz)~ 2.37 ~3H, s), ::: 3.42 (3H, s)~ 3.46 (3H, s), 4.96 (lH, ~- heptet, Ja6.5Hz~, 5.03 (lH, s3, 6.03 (lH, s), 6.73 (lH, s), ,7.0-7.4 (5H, m).
~ ~ E - 12 : ~ .

7~7 -`:

3~
8) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(2-tolyl)-1, 4 - dihydro -pyridine-3-carboxylic acid.
N~M.R. ~ppm ~CDCQ3) : 1.07 (3H, d9 J-6.5Hz), S 1.21 ~3H, d, J=6.SHz~, 2,32 (3H, s), .SS (3H, s), 3.41 t3H, s~, 3.44 (3H, s), 3.62 (3H, s), 4,96 ~lH, heptet, J-6..5Hz), 5.20 (lH~ s~, 5.97 (lH, s), 6.65 (lH, s), 6.9-7.4 (4H,.m).
9) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxy-methyl-2-methyl-4-(4-pyridyl)-1,4-dihydropyridine-3-carboxylic acid.

I.R. v NUa~ol : 3300, 3200, 3070, 1710 (shoulder), lS 1700~ 1650, 1603, 1518, 1278, 1269, 1190, 1090, 960, 782 cm 1 10) Isopropyl ester of 4-(2-chlorophenyl)-5-methoxy-: carbonyl-6-dime thoxyme thyl - 2 -me thyl -1, 4 - dihydropyridine-3-carboxylic acid~ mp 86-87.5C.
Isopropyl ester of 4-(2-trifluoromethylphenyl)-: 5 -me thoxy carbonyl-6-dime~hoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.

: : 25 I.R. ~ ma~ : 3400- 1720, 1690, 1653, 1493, : 1319, 1310? 1278, 12067 lO9S, 1035, 951, 768 cm :~ 12) Isopropyl ester of 5-methoxycarbonyl-6-dimethoxy ~: methyl-4-(2-methoxyphenyl)-2-methyl-1,4-dihydropyridine-3-c~rboxylic:acid, mp 110-111.5C.
13) Isopropyl ester of 4-(2-allyloxyphenyl)-5-: methoxycarbonyl-6-dimethoxyme~hyl-2-methyl-1,4 dihydropyridine-3-carboxylic acid.
N.M.R. ~ppm ~CDCQ3) : 1.01 (3H~ d, ~;=6.SHz)~
: 35 1.21 (3H, d, J=6.5Hz), 2.33 (3H, s), -'"`' ` ;:

' 7~7 i -`

3.46 (6H, s), 3.63 ~3H, s~, 4.4-6.3 (8H, m), 6.60 (lH, broad s), 6.7-7.5 (4H, m) 14) Isopropyl ester of S-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(~ hienyl~1,4-dihydro- --pyridine-3-carboxylic acid.
N.M.R. ~ppm (CDC~3) : 1.22 (3H, d, J=6.5Hz), 1.28 (3H, d, J36.5Hz) 7 2.37 (3H, s), 3.43 (3H, s)~ 3.49 (3H, s)~ 3.76 (3H, s~, 5.07 (lH~ heptet, J~6.5Hz~, 5.3B (lH, s ), 6.04 (lH, s), 6.65-7 45 (4H7 m).

15) Isopropyl es~er of 4-(2,4-dichlorophenyl~-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-15 dihydropyridine-3-carboxylic acid.
N.M.R. ~ppm (CDCQ3) : 1 07 ~3H, d, J=6,5Hz), 1.21 (3H~ d~ J=6 5HZ) ~ 2.34 (3HJ S~
3.42 (3H, s), 3.46 (3H~. S), 3t64 (3H, s), 4.97 (lH, heptet, J=6.5H7),5.39 (lH, s), 5.96 (lH, sj, 6.65 (lH, s~, 7.0-7.4 (3H, m)

16) Isopropyl ester of 4-(3,4-dichlorophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
N.M.R. ~ppm (CDCQ3) : 1.18 (d, J-6.5Hz) } ~6H
1.25 (d9 J=6.5Hz) 2.39 (3H~ S), 3.46 (3H, S), 3.50 (3H~ S), 3.70 (3H, s), 5.00 (lH, s), 5.00 (lH, heptet, J=6.SHz~, 6.03 (lH, s), 6~75 ~lH, s), 7.0-7.5 (3H, m).

17~ Isopropyl ester of 5-me~hoxycarbonyl-6-dimethoxymethyl-4-(3,4-dimethoxyphenyl)-2-methyl-1,4 dihydropyrid1ne-3-carboxylic acid.
N.M.R. ~ppm ~CDCQ3) : 1.16 (3H, d, J-6.5Hz), 1.25 (3H~ d, J=6.5Hz), 2.37 ~3H, s), . ~ .

. ' ' ' ' l7 0 3~3 3.41 ~S) 3 43 ~S) (6 3.49 ~S) 3.79 (3H, S)V 3.84 (6H, S~J 4.99 (1H, S)7 4 . 99 (1H~ hePtet, J36 . SHZ) ~ 6 . 03 ~1H, S~
6,6-7.3 (4H~ m).

18) Dip~opyl ester of 2-methyl-4-(3-nitrophenyl) -6-dipropoxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid.
N.M.R. ~ ppm ~CDC Q3) : 2.37 ~3H~ S~ ~ 5 ~ 02 ~1H, S) 6,21 ~lH, s) J 6.88 (lH, broad s).
(continued to the next page) .

, .
~ ~ ~30 3 s .
: ': , ,:

: ~ , ~7 Example 3 1) To a solution of ~-phenoxyethyl ester of 5-ethoxycarbonyl-6-diethoxymethyl-4-(2-trifluoromethyl-phenyl)-2-methyl 1,4-dihydropyridine 3-carboxylic acid ~15.85 g) in acetone (159 ml) was added 6N
hydrochloric acid.(15.85 ml) at ambient temperature with stirring and the stirring was continued for 1.5 hours, The reaction mixture wa~ neutralized with a saturated aqueous solution of sodium bicarbonate, and the acetone was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water and then dried. Removal of the solvent gave an oil (13.56 g) of 2-phenoxyethyl ester of 5-ethoxycarbonyl-4-(2-trifluoromethylphenyl)-6-formyl-2-methyl 1,4-dihydropyridine-3-carboxylic acid.
N.M.R. ~ppm (CDCQ3) : 1.22 (3H~ t, J~7,5Hz), 2.40 (3H, s~, 4.0-4.6 ~6H, m), 5.71 (lH9 s), 6.7-7.7 (lOH, m), 10.26 (lH, s).
The following compounds were prepared in substan-tially the same manner as that o~ Example 3-1).
2) Isopropyl ester of 6-formyl-5-meth.o.xycarbonyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxyli~. acidO
3) Isopropyl ester of 6-formyl-5-me~hoxycarbonyl~
2-methyl-4-(2-tolyl)-1,4-dihydropyridine-3-carboxylic : acid, mp 143-144C.
4) Isopropyl ester o 6-formyl-5-methoxycarbonyl-2-methyl-4-(4-pyridyl)-1,4-dihydropyridine-3-carboxylic acid, mp 143-145C.
5) Isopropyl ester of 4-~2-chlorophenyl)-6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp 102-103C.
6) Isop~opyl ester of 4-(2-trifluoromethylphenyl)-6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydro/pyridine-3-carboxylic acid, mp 83-85C.

......... ~ ,.. ... ... ...

7~L~7 3~3 7) Isopr~pyl ester of 6-~ormyl-5-m~thoxycarbonyl-4 - ( 2 -methoxyphenyl ) - 2 -me thyl -1, 4 - dihyclropyridine - 3 -carboxylic acid, mp 142-143C.
8) Isopropyl ester of 4-(2-allyloxyphenyl)-6-formyl-5-methoxyfarbonyl-~-methyl-1,4-dihydropyridine-3-carboxylic acidt mp 103-104 . 5C.
9) Isopropyl ester of 6-formyl- 5-methoxycarbonyl- ~
2-methyl-4-~2-thienyl)-1,4-dihy~ropyridine-3-carboxylic acid, mp 114-116C.
10) Isopropyl ester o 4-(2,4-dichlorophenyl)-6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
N.M.R. ~ppm (CDCQ3) : 1.07 ~3H, d, J=6.5Hz), 1.24 ~3H, d, J=6.5Hz), 2,39 (3H, s), lS 3.71 (3H, s), 4.98 ~lH, heptet, J~6.5Hz)9 5.Sl ~lH, s), 6.93 ~lH, s), 7.0-7.4 (3H, m), 10 34 ~lH, s).
ll) Isopropyl ester of 4-(3,4-dichlorophenyl)-6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp 95-96C.
12) Isopropyl ester of 6-formyl-5-methoxycarbonyl-4-~3,4-dimethoxyphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
N.M.R. ~ppm (CDC~3) : 1.14 ~3H, d~ J=6.5Hz), 1 26 (3H, d, J=6.5Hz), 2.40 ~3H, s), 3.78 ~3H, s), 3.84 ~6H~ s), 4.98 (lH, ` heptet, J-6.5Hz), 5.05 ~lH, s), 6.5-7.3 ~4H, m), 10.44 (lH, s~.
13) Dipropyl ester of 6-formyl-2-methyl-4-~3-nitrophenyl)-1,4-dihydropyridine-395-dicarboxylic acid.
N.M.R. ~ppm (CDCQ3) : 0.87 ~3H~ t, J=7.5Hz), 0.90 (3H, t, J=7.5Hz), 1.55 (2H, sixtet, J~7.5Hz), 1.61 (2H, six~et, J=7.5Hz), 2.44 (3H, s), 4.02 ~2H, t, J=7.5Hz), 4.13 (2H, t, J=7.5Hz~, 5.28 (lH, s), 7.11 ~lH, broad s~, 7.4-8.2 (4H, m), 10.56 ~lH, s).
14) 2-HydToxrethyl ester of 5-ethoxycarbonyl-6-formyl-2-me~hyl-4-~3-nitroph~yl)-1,4-dihydrapyridine-3-carboxylic aîcd.
N.M.R. ~ppm ~CDC~3) : .5.25 (lH, s), 10.50 ~lH, s).
) 2-~thaxyethyl est~r of 5-ethoxycarbonyl-6-~ formyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
. 10 N_~.R. ~ppm tCDCQ3) : 1.14 (t, J-7Hz) } (6H~
1 . Z 6 (t, J~ 7Hz) 2.43 (3H, s), 3.3-3.8 ~4H, m) 9 4,0-4.5 (4H, m~, 5.7-5.8 (lH, m), 6.~-7.0 (lH, m), 7.1-7.8 (4H, m), li 10.27 (lH, s).
16~ 2-Benzyloxye~hyl ester o 5-ethoxycarbonyl-6-~ormyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
N.M.R. ~ppm ~CCQ4) : 1.23 (3H) t, J-7.5Hz)~
2.40 (3H, s), 3.4-4.5 (6H, m), 4.41 (2H, s), 5.7-5.8 ~lH, m), 6.8-6.9 (lH, m), 7.2-7.8 (9H, m)~
10.28 (lH, s).
17) 2- ~N-Benzyl-N-methylamirlo~ethyl es~er of S-25 . ethoxycarbonyl-6 -formyl- 4- (2 -trifluoromethylphenyl)-~ 2-methyl-1,4-dihydropyridi~e-3-carboxylic acid.
: : N.M.~. ~ppm (CDCQ3) : 1.23 ~3H9 t, J~7Hz), Z.19`(3H, s), 2.41 (3H, s), 2.63 (2H, t, 3=7Hz), 3.51 (2H, s), :~ 30 . 4-4.4 ~4H, m), 5.71 ~lH, broad~s)~
. 6 .91 (lH, broad s), 7.2-7.7 (~H, m~, 10.28 (lH, s~.

(continued to the ne,xt page) `~ 35 1~:L7 Example 4 A mixture of isopropyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl~4-~3-nitrophenyl)-1,4-dihydropyridin-3-carboxylic acid ~11.0 g.) acid (11.0 g.) and 6N hydrochloric acid (11 ml.) in ace-tone ~110 ml.) was stirred at ambient temperature for 4 hours. ~fter removal of the acetone, water ~as added to the reaction mixture and adjusted to pH 7.~
with a saturated aqueous solution of sodium bicarbonate The resultant aqueous solution was e~tracted with ethyl acetate, and the extract was washed with water and dried over anhydrous magnesium sulfate. The removal of the _. solvent gave an oily residue, which was immediately solidified to provide crude yellow-orange crystals of isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4-~3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid.

N~ppm(CDC13) : 1.13(3H, d, J=7H~), 1.28(3H, d, J=7Hz), 1.79(3H, s), 3.80(3H, s), 5.02(1H, heptet, J=7Hz), 5.27(1H, s), 7.11(1H, broad s), 7.4-8.2(4H, m), 10.60 (lE~, 5) `
(continued to the next page) !

- 19 ' : :

1~7~7 _"

a~l Example 5 1) To a solution of isopropyl ester of 6~formyl-5-methoxycarbonyl-2-me~hyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate (4.2 g) in e~hanol ~85 ml) was gradually added portionwise sodium borohydride (0.409 g) ~VeT a period of 35 minutes under cooling below 0C with stirring. After the reaction mixture was acidified;with 50~ aqueous solution o~ acetic acid, ~he ethanol was removed under reduced pressure. To the resultant aqueous suspension was diluted with water and th~ precipitated pale-yellowish powder was collected by filtration, washed with water and dried. This powder t3-89 g~ was recrystallized with ethanol to give a yellow powder lS t3.05 g) of isopropyl ester of 6-hydroxymethyl-S-methoxycarbonyl-2-methyl-4-(3-nitrophenyl~ 1,4-dihydropyridine-3-carboxylic acid, mp 164-166C.
The following compounds were prepared in substan-~ially the same manner as that of Bxample 5-1).
2) Isopropyl ester of 6-hydroxymethyl-5-methoxy-carbonyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylic acid, mp 132-133C.
3) Isopropyl ester of 6-hydroxymethyl-5-methoxy-carbonyl-2-methyl-4-(2-tolyl~-1,4-dihydropyridine-3-carboxylic acid, mp 134-135.5C.
: 4) Isopropyl ester of 6-hydroxymethyl-S-methoxy-~: carbonyl-2-methyl-4-(4-pyridyl)-1,4-dihydropyridine-3-carboxylic acid, mp 182-183C ~dec.).
5) Isopropyl ester of 4-(2-chlorophenyl)-6-hydroxymethyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp 122-123C.
~: 6) Isopropyl ester o~ 4-(2-tri~luoromethylphenyl)-6-hydroxymethyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp lZ3-125, DC.
7) Isopropyl ester of 6-hydroxymethyl-5-methoxy-~ E - 20 7~
~ _J

carbonyl-4-~2-methoxyphenyl~-2-methyl-1~4-dihydro-pyridine-3-carboxylic acid, mp 142-143C.
8) Isop~opyl ester of 4-(2-allyloxyphenyl)-6-hydroxymethyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp 124-125~C.
9) Isopropyl ester of 6-hydroxymethyl-5-methoxy-carbonyl-2-methyl-4-(2-thienyl~-1,4-dihydropyridine-3-carboxylic acid, mp 124.5-126~C.
10) Isopropyl ester of 4-~2,4-dichlorophenyl)-6-hydroxymethyl-5-methoxycarbonyl-2-methyl-1,4-dihydro-pyridine-3-carboxylic acid, mp 150-151C.
11) Isopropyl es~er of 4 (3,4-dichlorophenyl~-6-hydroxymethyl-5-methoxycarbonyl-2-methyl-1,4-dihydro-pyridine-3-carboxylic acid, mp 122-123C.
12) Isopropyl ester of 6-hydroxymethyl-5-me~hoxy-carbonyl-4-(3 7 4-dimethoxyphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp 123-124C.
13~ Dipropyl ester o 6-hydroxymethyl-2-methyl-4-~3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid, mp 118-120C.
14) 2-Phenoxyethyl ester of 5-èthoxycarbonyl-4-~2-trifluoromethylphenyl)-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp 148-149C.
15) 2-Ethoxyethyl ester of 5-e~hoxycarbonyl-4-~2-trifluoromethylphenyl)-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp 65-66.5~C.
16) 2-Benzyloxyethyl ester of 5-ethoxycarbonyl-4-~2-trifluoromethylphenyl)-6~hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp 104-106C.
~ 30 ; ~ (continued to t~e next page) ~ ~ .

Example_ 6 1) To a solutiDn of isopropyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1~4-dihydropyridine-3-carboxylic acid (4.5 g) in acetic acid t35 ml) were added hydroxylamine hydrochloride ~0.97 g) and sodium acetate (:L.43 g), and the mixture was stirred at ambient temperature ~or 2.5 hours.
After acetic anhydride (4.14 g~ was added to this reaction mixture, the mixture was stirred at ambient temperature for 1.5 hours and at 95-lOO~C for additional 4 hours. The acetic acid and the excess of acetic anhydride were removed in vacuo, followed by adding water to the residue and it was neutralized with a saturated aqueous solution of sodium bicarbonate.
This aqueous suspension was extracted twice with ethyl acetate, and the combined extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to gi~e a redaish-bro~n oil (4.88 g), which was chromatographed o~er silica gel ~150 g) with a mixture of benzene and ethyl acetate (10:1 by volume) as an eluen~ to give a crude crystals (2.99 g). These were recrystallized from ethanol to gi~e yellow prisms (1.89 g) of isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4-t3-ni~rophenyl)-1,4-dihydropyridine-3-carboxylic acid, mp 148-150C.
The following compounds were prepared in substan-tially the same manner as that of Example 6-1).
2) Isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylic acid, mp 130-131C.
3) Isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4-(2-tolyl)-1,4-dihydropyridi~e-3-carboxylic arid, mp 147-149C.
4) IsopropyI ester of 6-cyano-5-methoxycarbonyl-2-..
~ ~ - E - 22 ,: ' : ~17~;17 4a~
methyl-4-(4-pyridyl)-1,4-dihydropyridine-3-carboxylic acid, mp 192-195C ~dec.).
5) Isopropyl ester of 4-(2-chlorophenyl)-6-cyano-S-methoxycarbonyl-2-me~hyl-1,4-dihydropyridine-3-carboxylic acid~ mp 176-177C~
6) Isopropyl ester of 6-cyano-4-(2-trifluoromethyl-phenyl)-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp 172-173"C.
7) Isopropyl ester of 6-cyano-5-methoxycarbonyl-4-~2-methoxypheny~-2-methyl-1,4 dihydropyridine-3-carboxylic acid, mp 139-140C.
8) Isopropyl es~er of 4-(2-allyloxyphenyl)-6-cyano-S-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp 115 116C.
9) Isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4-(2-thienyl)-1,4-dihydropyridine-3-carboxylic acid, mp 129-131C.
10) Isopropyl ester of 4-(2,4-dichlorophenyl)-6-cyano-S-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid~ mp 141-142C.
11) Isopropyl ester o 4-~3j4-dichlorophenyl)-6-cyano-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp 159-160C.
12) Isopropyl ester of 6-cyano-5-methoxycarbonyl-4-(3,4-dimethoxyphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp 124.5-125.5C.
13) Dipropyl ester of 6-cyano-2-meth~1-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid, mp 138-1409C.
14) 2-Phenoxyethy} ester of 6-cyano-5-ethoxycarbonyl-4-(2-trifluoromethylphenyl)-2-methyl-1,4-dihydro-pyridine-3-carboxylic acid, mp 118-119C.
15) 2-Hydroxyethyl ester of 6-cyano-5-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridi~e-3-carboxylic acid, mp 150.5-152C. ' .

L1'7 '_ a~s 16) 2-E~hoxyethyl ester of 6-cyano-5-ethoxycarbonyl-4-(2-trifluorome~hylphenyl)-~-methyl-1,4-dihydro-pyridine-3-carboxylic acid, mp 104-105C.
17) 2-Benzyloxyethyl ester o~E 6-cyano-5-ethoxy-S carbonyl-4~2-trifluoromethylph~nyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid, mp 146-147.5C.
18) 2-(N-Benzyl-N-methylamino3ethyl ester of 6-cyano-S-ethoxycarbonyl-4-(2-trifluo~omethylphenyl)-2-methyl-1,4-dihydropyridine-3-c~boxylic acid hydro-chloride, mp 203-204C (dec.) (continued to th~ next page) ~, .

~ 25 ~ .
,.

~ .

' ~ 117~L~L 7 ~6 Example 7 To a solution of 2-acetoxyethyl ester o 6-cyano-S-ethoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid ~1.119 g) in ethanol (20 ml) was added dropwise an aqueaus solution (5 ml~
of potassium carbonate (0.346 g) under refluxing and stirring for 2 hours.
After cooling, the ethanol was removed in vacuo from the reaction mixture, followed by neutralizing with acetic acid and extracted twice with ethyl acetate. The combined extract was washed with diluted aqueous solution o sodi~m bicarbonate and an aqueous solution of sodium chloride~ and then dried.
The solven~ was removed in vacuo to gi~e an oil, which was spontaneously crystallized to obtain crystals (0.94 g) of 2-hydroxyethyl ester of 6-cyano-5-ethoxycarbonyl-2-methyl-4-(3-ni~rophenyl)-1,4-dihydropyridine-3-carboxylic acid, mp 150.5-152C.

Exa~E~_~8 A mixture of 2-chloroethyl ester of S-ethoxy-carbonyl-6 diethoxymethyl-4-~2-trifluoromethylphenyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid ~5.20 g), N-methyl benzylamine ~3.63 g) and sodium iodide (0.2 g) in propyl~alcohol (10 ml) was heated under ~eflux for 4.5 hours. A~ter the solven~ was removed in vacuo from the reaction mixture, water and ethyl acetate were added to the residue. The ethyl acetate layer was separated, washed with water and ~hen dried.
Removal of the solvent gave a residual oil (6.98 g)~
which was chromatographed over silica gel (210 g) with a mix~ure of benze~e and e~hyl aceta~e (5:1 by .
volume) as an e~uent;to give an oil ~3.67 g) of 2-~N-benzyl-N-methylamino)e~hyl ester of 5-etho~ycarbonyl-6-diethoxymethyl-4-t2-trifluoromethylphenyl)-2-mechyl-E ^ 25~

.

r~ 7 ~
` 47 , 1,4~dihydropyridine-3-carboxylic acid.
N.M.R. ~ ppm~CDC13)~ 1.3 t9H,m), 2.17(3H,s), 2.33(3H,s), 2.60(2H,t,J=6Hz), 3.48 (2H,s), 3.4-4.4(8H,m), 5.63 (lH,s),6.13(1H,s), 6.71(lH,s), 7.1 - 7.6 (9H,m).

In this specification the expression "such as" means "for example" and is not in-tended to be construed as limiting.

: .
~: .

.

:~
: : E - 26.
.

. . . ' .. ~
' .
.

Claims (90)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a compound of the formula:

(I) wherein R1 is phenyl, 3-nitrophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-allyloxyphenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 2-tolyl, 4-pyridyl or 2-thienyl, R2 is propyl, isopropyl, 2-chloroethyl, 2-hydroxyethyl, 2-ethoxyethyl, 2-phenoxyethyl, 2-benzyloxyethyl or 2-(N-benzyl-N-methyl-amino)ethyl, R3 is lower alkyl, and R4 is di(lower)alkoxymethyl, formyl, hydroxy-methyl or cyano, provided that, when R1 is 3-nitrophenyl, then R2 is 2-hydroxyethyl and R4 is cyano or formyl, or R2 is propyl or isopropyl, and pharmaceutically acceptable salts thereof, which comprises (1) reacting a compound of the formula:

(II-1) wherein R1 and R3 are each as defined above and R? is di(lower)alkoxymethyl, with an amino compound of the formula:

(III-1) wherein R? is as defined below, to give a compound of the formula:

(I-1') wherein R1, R3 and R? are each as defined above, and R? is ispropyl, isopropyl, 2-chloroethyl, 2-ethoxyethyl, 2-phenoxyethyl, 2-benzyloxyethyl or 2-(N-benzyl-N-methylamino)ethyl, provided that when R1 is 3-nitrophenyl, then R?
is propyl or isopropyl; or (2) reacting a compound of the formula:

(II-2) wherein R1 and R2 are each as defined above, with an amino compound of the formula:

(III-2) wherein R3 and R? are each as defined above, to give a compound of the formula:

(I-2) wherein R1, R?, R3 and R? are each as defined above, provided that when R1 is 3-nitrophenyl, then R? is propyl or isopropyl; or (3) hydrolysing a compound of the formula:

(I-1) wherein R1, R2, R3 and R? are each as defined above, provided that when R1 is 3-nitrophenyl, then R2 is propyl, isopropyl or 2-hydroxyethyl, to give a compound of the formula:

(I-3) wherein R1, R2 and R3 are each as defined above, provided that when R1 is 3-nitrophenyl, then R2 is propyl, isopropyl or 2-hydroxyethyl; or (4) reducing a compound of the formula:

(I-3) wherein R1, R2 and R3 are each as defined above, provided that when R1 is 3-nitrophenyl, then R2 is propyl or isopropyl, to give a compound of the formula:

(I-4) wherein R1, R2 and R3 are each as defined above, provided that when R1 is 3-nitrophenyl, then R2 is propyl or isopropyl; or (5) reacting a compound of the formula:

(I-3') wherein R1 and R3 are each as defined above, and R? is propyl, isopropyl, 2-hydroxyethyl, 2-ethoxyethyl, 2-phenoxyethyl, 2-benzyloxyethyl or 2-(N-benzyl-N-methylamino)ethyl, provided that when R1 is 3-nitrophenyl, then R? is propyl, isopropyl or 2-hydroxyethyl, with hydroxylamine or a salt thereof, and then reacting the resultant product with a dehydrating agent to give a compound of the formula:

(I-5) wherein R1, R? and R3 are each as defined above, provided that when R1 is 3-nitrophenyl, then R? is propyl, isopropyl or 2-hydroxyethyl; or (6) hydrolysing a compound of the formula:

(IIc) wherein R1 and R3 are each as defined above, and R? is acyl, to give a compound of the formula:

(I-6) wherein R1 and R3 are each as defined above; or (7) reacting a compound of the formula:

(IId) wherein R1, R3 and R? are each as defined above, with N-methyl benzylamine to give a compound of the formula:

(I-7) wherein R1, R3 and R? are each as defined above.

2. A process according to claim 1, which comprises reacting a compound of the formula:

(II-1) wherein R1 is as defined in claim 1, R3 is methyl, ethyl or propyl, and R? is dimethoxymethyl, diethoxymethyl or dipropoxymethyl, with an amino compound of the formula:

(III-1) wherein R? is as defined in claim 1 to give a compound of the formula:

(I-1') wherein R1 and R? are each as defined in claim 1, and R3 and R? are each as defined above.

3. A process according to claim 2, wherein R1 is 3-nitrophenyl, R? is isopropyl, R3 is methyl and R? is dimethoxymethyl.

4. A process according to claim 1, which comprises reacting a compound of the formula:

(II-2) wherein R1 and R? are each as defined in claim 1, with an amino compound of the formula:

(III-2) wherein R3 is methyl, ethyl or propyl, and R? is dimethoxymethyl, diethoxymethyl or dipropoxymethyl, to give a compound of the formula:

(I-2) wherein R1 and R2 are each as defined in claim 1, and R3 and R? are each as defined above.

5. A process according to claim 4, wherein R1 is 3-nitrophenyl, R? is isopropyl, R3 is methyl and R? is dimethoxymethyl.

6. A process according to claim 1, which comprises hydrolysing a compound of the formula:

(I-1) wherein R1 and R2 are each as defined in claim 1, R3 is methyl, ethyl or propyl, and R? is dimethoxymethyl, diethoxymethyl or dipropoxymethyl, to give a compound of the formula:

(I-3) wherein R1 and R2 are each as defined in claim 1, and R3 is as defined above.

7. A process according to claim 6, wherein R1 is 3-nitrophenyl, R2 is isopropyl, R3 is methyl and R? is dimethoxymethyl.

8. A process according to claim 1, which comprises reacting a compound of the formula:

(I-3') wherein R1 and R? are each as defined in claim 1, and R3 is methyl, ethyl or propyl, with hydroxylamine or a salt thereof, and then react-ing the resultant product with a dehydrating agent to give a compound of the formula:

(I-5) wherein R1 and R? are each as defined in claim 1, and R3 is as defined above.

9. A process according to claim 8, wherein R1 is 3-nitrophenyl, R? is isopropyl and R3 is methyl.

10. A compound of the formula (I) as defined in claim 1, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

11. A compound of the formula (I-1') as defined in claim 2, whenever prepared by the process of claim 2 or by an obvious chemical equivalent thereof.

12. A compound of the formula (I-1') as defined in claim 3, whenever prepared by the process of claim 3 or by an obvious chemical equivalent thereof.

13. A compound of the formula (I-2) as defined in claim 4, whenever prepared by the process of claim 4 or by an obvious chemical equivalent thereof.

14. A compound of the formula (I-2) as defined in claim 5, whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.

15. A compound of the formula (I-3) as defined in claim 6, whenever prepared by the process of claim 6 or by an obvious chemical equivalent thereof.

16. A compound of the formula (I-3) as defined in claim 7, whenever prepared by the process of claim 7 or by an obvious chemical equivalent thereof.

17. A compound of the formula (I-5) as defined in claim 8, whenever prepared by the process of claim 8 or by an obvious chemical equivalent thereof.

18. A compound of the formula (I-5) as defined in claim 9, whenever prepared by the process of claim 9 or by an obvious chemical equivalent thereof.

19. A process according to claim 8, wherein R1 is phenyl, R? is isopropyl and R3 is methyl.

20. A process according to claim 8, wherein R1 is 2-tolyl, R? is isopropyl and R3 is methyl.

21. A process according to claim 8, wherein R1 is 4-pyridyl, R? is isopropyl and R3 is methyl.

22. A process according to claim 8, wherein R1 is 2-chlorophenyl, R? is isopropyl and R3 is methyl.

23. A process according to claim 8, wherein R1 is 2-trifluoromethylphenyl, R? is isopropyl and R3 is methyl.

24. A process according to claim 8, wherein R1 is 2-methoxyphenyl, R? is isopropyl and R3 is methyl.

25. A process according to claim 8, wherein R1 is 2-allyloxyphenyl, R? is isopropyl and R3 is methyl.

26. A process according to claim 8, wherein R1 is 2-thienyl, R? is isopropyl and R3 is methyl.

27. A process according to claim 8, wherein R1 is 2,4-dichlorophenyl, R? is isopropyl and R3 is methyl.

28. A process according to claim 8, wherein R1 is 3,4-dichlorophenyl, R? is isopropyl and R3 is methyl.

29. A process according to claim 8, wherein R1 is 3,4-dimethoxyphenyl, R? is isopropyl and R3 is methyl.

30. A process according to claim 8, wherein R1 is 3-nitrophenyl, and R? and R3 are each propyl.

31. A process according to claim 8, wherein R1 is 2-trifluoromethylphenyl, R? is 2-phenoxyethyl and R3 is ethyl.

32. A process according to claim 8, wherein R1 is 3-nitrophenyl, R? is 2-hydroxyethyl and R3 is ethyl.

33. A process according to claim 8, wherein R1 is 2-trifluoromethylphenyl, R? is 2-ethoxyethyl and R3 is ethyl.

34. A process according to claim 8, wherein R1 is trifluoromethylphenyl, R? is 2-benzyloxyethyl and R3 is ethyl.

35. A process according to claim 8, wherein R1 is 2-trifluoromethylphenyl, R? is 2-(N-benzyl-N-methylamino)ethyl and R3 is ethyl.

36. A process according to claim 1,which comprises reducing a compound of the formula:

(I-3) wherein R1, R2 and R3 are each as defined in claim 1, provided that when R1 is 3-nitrophenyl, R2 is propyl or isopropyl, to give a compound of the formula:

(I-4) wherein R1, R2 and R3 are each as defined above.

37. A process according to claim 36, wherein R1 is 3-nitrophenyl, R? is isopropyl and R3 is methyl.

38. A process according to claim 36, wherein R1 is phenyl, R? is isopropyl and R3 is methyl.

39. A process according to claim 36, wherein R1 is 2-tolyl, R? is isopropyl and R3 is methyl.

40. A process according to claim 36, wherein R1 is 4-pyridyl, R? is isopropyl and R3 is methyl.

41. A process according to claim 36, wherein R1 is 2-chlorophenyl, R? is isopropyl and R3 is methyl.

42. A process according to claim 36, wherein R1 is 2-trifluoromethylphenyl, R? is isopropyl and R3 is methyl.

43. A process according to claim 36, wherein R1 is 2-methoxyphenyl, R? is isopropyl and R3 is methyl.

44. A process according to claim 36, wherein R1 is 2-allyloxyphenyl, R? is isopropyl and R3 is methyl.

45. A process according to claim 36, wherein R1 is 2-thienyl, R? is isopropyl and R3 is methyl.

46. A process according to claim 36, wherein R1 is 2,4-dichlorophenyl, R? is isopropyl and R3 is methyl.

47. A process according to claim 36, wherein R1 is 3,4-dichlorophenyl, R? is isopropyl and R3 is methyl.

48. A process according to claim 36, wherein R1 is 3,4-dimethoxyphenyl, R? is isopropyl and R3 is methyl.

49. A process according to claim 36, wherein R1 is 3-nitrophenyl, and R? and R3 are each propyl.

50. A process according to claim 36, wherein R1 is 2-trifluoromethylphenyl, R? is 2-phenoxyethyl and R3 is ethyl.

51. A process according to claim 36, wherein R1 is 2-trifluoromethylphenyl, R? is 2-ethoxyethyl and R3 is ethyl.

52. A process according to claim 36, wherein R1 is 2-trifluoromethylphenyl, R? is 2-benzyloxyethyl and R3 is ethyl.

53. A process according to claim 1, which comprises hydrolysing a compound of the formula:

(IIc) wherein R1, R? and R3 are each as defined in claim 1, to give a compound of the formula:

(I-6) wherein R1 and R3 are each as defined in claim 1.

54. A process according to claim 53, wherein R1 is 3-nitrophenyl, R? is acetyl and R3 is ethyl.

55. A compound of the formula (I-5) as defined in claim 19, whenever prepared by the process of claim 19 or by an obvious chemical equivalent thereof.

56. A compound of the formula (I-5) as defined in claim 20, whenever prepared by the process of claim 20 or by an obvious chemical equivalent thereof.

57. A compound of the formula (I-5) as defined in claim 21, whenever prepared by the process of claim 21 or by an obvious chemical equivalent thereof.

58. A compound of the formula (I-5) as defined in claim 22, whenever prepared by the process of claim 22 or by an obvious chemical equivalent thereof.

59. A compound of the formula (I-5) as defined in claim 23, whenever prepared by the process of claim 23 or by an obvious chemical equivalent thereof.

60. A compound of the formula (I-5) as defined in claim 24, whenever prepared by the process of claim 24 or by an obvious chemical equivalent thereof.

61. A compound of the formula (I-5) as defined in claim 25, whenever prepared by the process of claim 25 or by an obvious chemical equivalent thereof.

62. A compound of the formula (I-5) as defined in claim 26, whenever prepared by the process of claim 26 or by an obvious chemical equivalent thereof.

63. A compound of the formula (I-5) as defined in claim 27, whenever prepared by the process of claim 27 or by an obvious chemical equivalent thereof.

64. A compound of the formula (I-5) as defined in claim 28, whenever prepared by the process of claim 28 or by an obvious chemical equivalent thereof.

65. A compound of the formula (I-5) as defined in claim 29, whenever prepared by the process of claim 29 or by an obvious chemical equivalent thereof.

66. A compound of the formula (I-5) as defined in claim 30, whenever prepared by the process of claim 30 or by an obvious chemical equivalent thereof.

67. A compound of the formula (I-5) as defined in claim 31, whenever prepared by the process of claim 31 or by an obvious chemical equivalent thereof.

68. A compound of the formula (I-5) as defined in claim 32, whenever prepared by the process of claim 32 or by an obvious chemical equivalent thereof.

69. A compound of the formula (I-5) as defined in claim 33, whenever prepared by the process of claim 33 or by an obvious chemical equivalent thereof.

70. A compound of the formula (I-5) as defined in claim 34, whenever prepared by the process of claim 34 or by an obvious chemical equivalent thereof.

71. A compound of the formula (I-5) as defined in claim 35, whenever prepared by the process of claim 35 or by an obvious chemical equivalent thereof.

72. A compound of the formula (I-4) as defined in claim 36, whenever prepared by the process of claim 36 or by an obvious chemical equivalent thereof.

73. A compound of the formula (I-4) as defined in claim 37, whenever prepared by the process of claim 37 or by an obvious chemical equivalent thereof.

74. A compound of the formula (I-4) as defined in claim 38, whenever prepared by the process of claim 38 or by an obvious chemical equivalent thereof.

75. A compound of the formula (I-4) as defined in claim 39, whenever prepared by the process of claim 39 or by an obvious chemical equivalent thereof.

76. A compound of the formula (I-4) as defined in claim 40, whenever prepared by the process of claim 40 or by an obvious chemical equivalent thereof.

77. A compound of the formula (I-4) as defined in claim 41, whenever prepared by the process of claim 41 or by an obvious chemical equivalent thereof.

78. A compound of the formula (I-4) as defined in claim 42, whenever prepared by the process of claim 42 or by an obvious chemical equivalent thereof.

79. A compound of the formula (I-4) as defined in claim 43, whenever prepared by the process of claim 43 or by an obvious chemical equivalent thereof.

80. A compound of the formula (I-4) as defined in claim 44, whenever prepared by the process of claim 44 or by an obvious chemical equivalent thereof.

81. A compound of the formula (I-4) as defined in claim 45, whenever prepared by the process of claim 45 or by an obvious chemical equivalent thereof.

82. A compound of the formula (I-4) as defined in claim 46, whenever prepared by the process of claim 46 or by an obvious chemical equivalent thereof.

83. A compound of the formula (I-4) as defined in claim 47, whenever prepared by the process of claim 47 or by an obvious chemical equivalent thereof.

84. A compound of the formula (I-4) as defined in claim 48, whenever prepared by the process of claim 48 or by an obvious chemical equivalent thereof.

85. A compound of the formula (I-4) as defined in claim 49, whenever prepared by the process of claim 49 or by an obvious chemical equivalent thereof.

86. A compound of the formula (I-4) as defined in claim 50, whenever prepared by the process of claim 50 or by an obvious chemical equivalent thereof.

87. A compound of the formula (I-4) as defined in claim 51, whenever prepared by the process of claim 51 or by an obvious chemical equivalent thereof.

88. A compound of the formula (I-4) as defined in claim 52, whenever prepared by the process of claim 52 or by an obvious chemical equivalent thereof.

89. A compound of the formula (I-6) as defined in claim 53, whenever prepared by the process of claim 53 or by an obvious chemical equivalent thereof.

90. A compound of the formula (I-6) as defined in claim 54, whenever prepared by the process of claim 54 or by an obvious chemical equivalent thereof.