CA1085406A

CA1085406A - Isobutyl methyl-1,4-dihydro-2,6-dimethyl-4-(2- nitrophenyl)-3,5-pyridindicarboxylate

Info

Publication number: CA1085406A
Application number: CA264,921A
Authority: CA
Inventors: Egbert Wehinger; Friedrich Bossert; Arend Heise; Stanislav Kazda; Kurt Stoepel; Wulf Vater
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1975-11-05
Filing date: 1976-11-04
Publication date: 1980-09-09
Also published as: DK146762B; LU88275I2; NL175915C; CS200499B2; AU498964B2; ZA766622B; IL50817A0; PT65797A; GR61241B; DK498476A; CH623038A5; NL930035I2; DK146762C; ES452986A1; CH622779A5; BG25079A3; AU1935876A; BG25078A3; FR2330395B1; DE2549568A1

Abstract

A 1,4-dihydropyridine-3,5-dicarboxylic acid di-ester derivative, several processes for its preparation and its use as a coronary therapeutic agent.

Abstract of the disclosure The present invention relates to the new isobutyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridine-dicarboxylate several processes for its preparation and its use as a coronary therapeutic agent. The compound according to the invention is chiral and can exist in stereoisomeric forms which have a mirror image relationship to each other (enantiomers, antipodes). These can, in turn, again occur in different confor-mations. Both the racemic form and the antipodes are included within the present invention.

Description

1~85~i The present invention relates to the new isobutyl methyl 1,4-dihydro-2.6-dimethyl-4-(2-nitrophenyl)-~.5-pyridine-dicarboxylate several processes for its preparation and its use as a coronary therapeutic agent.
It has already been disclosed that diethyl-1,4-~ihydro-

2.6-dimethyl-4-phenyl-3.5-pyridinedicarboxylate is obtained when benæylideneacetoacetic acid ethyl ester is reacted with ~-aminocro~onic acid ethyl ester or acetoacetic acid ethyl ester and ammonia (Knoevenagel, ~er.
dtsch. chem. Ges. 31, 743 (1898)). Further, it is known that certain 1,4-dihydropyridines exhibit interesting pharmacological properties (F. Bo~sert and W. Vater, Naturwissenschaften 58, 578 (1971)).
~urther, it has been disclosed, in the applicant 1 9 earlier German Of~enlegungsschriften (German Published Specifications) 2,117,571 and 2,117,573 that similar dihydro-pyridine~ can be used as coronary agents.
According to the present invention, we now provide ~sobutyl-methyl 1.4-dihydro-2.6-dimethyl-4-(2-nitrophenyl)-

3.5-pyridine dicarboxylate of the formula (I).

H3C~ ~ N02 H cH,C-H2C-ooC ~ COOCH3 (I

The compound of the invention exhibits a very powerful and long-lasting coronary action.
Further, the new active compound of the formula (1) is obtained when A) 2'-nitrobenzylideneacetoacetic acid isobutyl ester (formula (II)) Le A 16 774 - 2 -.
: ~ , 1085~

HC-HzC ~ , C ~ 5 r NO

H~C O

is reacted with R-aminocrotonic acid methyl ester (forr~ula III)) H \ COOCH3 C
~ C (III) if appropriate in the presence of water or inert organic solvents, or B) 2'-nitrobenzylideneacetoacetic acid isobutyl ester (formula (II)) is reacted with acetoacetic acid methyl ester (:~`or~ula (IV)) O
C-C (IV) and ammonia, if appropriate in the presence of water or inert organic solvents, or ! ~ ' C) 2'-nitrobenzylideneacetoacetic acid methyl ester ~ :.
(formula (V)) ~
~ NOg H ~ ~COOCH3 (V) ~ C
O CH~
is reacted with ~-aminocrotonic acid isobutyl ester (formula (VI)) Le A 16 774 - 3 -.

1085~V6 H3 \
HC - H2C-OOC\ / H
H3~ C (VI) / C\

if appropriate in the presence of water or inert ~olvents, or D) 2'-nitrobenzylideneacetoacetic acid methyl e~ter (formula (V)) is reacted with acetoacetic acid isobutyl ester (formula (VII)) o CH2-C00-CH2-CH (VII) and ammonia, if appropriate in the pre~ence of water or inert organic ~olvents, or E) ~-aminocrotonic acid i~obutyl ester (Formula (VI)) is reacted with 2-nitrobenzaldehyde (formula (VIII)) N02 (VIII) ~ C ~

and acetoacetic acid methyl ester (formula (IV)), if appropri-ate in the pre~ence of water or inert organic solvent~, or F) ~-aminocrotonic acid methyl ester (formula (III)) is reacted with 2-nitrobenzaldehyde (formula (VIII)) and aceto-acetic acid isobutyl ester (formula (VII)) a~ ~uch or in water or in inert organic solvent~.
Surprisingly, the ~ubstance accordin g to the invention, of the formula (I), has a particularly str ~ coronary action.
Amongst the series of the similar 1,4-dihydropyridine ~e A 16 774 _ 4 _ .:

1~85~6 derivatives known from the state of the art, such a strong and long-lasting coronary action, especially after enteral administration, has hitherto not been demon~trated. In addition, the compound according to the invention i~ less un~table to light than corresponding dihydropyridine~ which are known from the state of the art. It thus represents in respect of these specia~ properties, an enrichment of pharmacy.
The compound according to the invention is chiral and can exist in stereoisomeric forms which have an image/
relationsip to each other (enantiomers, antipodes). These can, in turn again occur in different conformations. Both the racemic form and the antipodes are included within the present invention.
Depending on the nature of the starting materials used, the synthesis of the compound according to the invention can be represented by the ~llowing equation~:

~e A 16 774 _ 5 _ 1~)85406 C~
o o o ~ ~ o D ~ ~:Z; ~C ~5 O ~ ~) V V V
v 8 ~ 8 ~
~ V ~, C) ~ V ~ 5 ~ ~ t ~ ~ v c~ .
5~ t~o o o ~ o~\ /
V ~ ~ , O + ~ H ~ ) O _~

g 5' 0 ~ o V ~ o ~
~ H ~ H ~ H
V ~ V V ~ V V

~q V

Le A 16 774 - 6 -o~ o ~ Z ~, V ~) o o ,~

V ~ C~
_~ ~ ~ ` ~ ~ .
H
~ ,.' ~ t~ Yu ~

~
+ ~ ~ ~o ~ "o V ~, oo ~ , ~V~
æ ~ ~ O
V H ~_ ~
V

~e A 16 774 - 7 -1~85~6 The substances of the formulae (II) - ~VIII) used as starting materials are known ~rom the l~terature or can be prepared in accordance with methode known from the literature ~literature: Org. Reactions XV, 204 et seq. (1967); A.C.COPE, J. Amer. chem. 30c. 67, 1,017 (1945); and Houben-Weyl, Methoden der Organ, Chemie (Method3 of Organic Chemi~try) VII/4, 230 et seq. (1968)).
In carrying out processes A-F accordin,s to the invention the compounds particlpating in the reaction are in each ca~e employed approximately in equimolar~amount~. The a~onia ueed is advantageouely added ln exce~s.
Dlluents which can be used are water and all lnert organi¢ eolvent~. These prefersntlally inolude alcohole 3uch ae athanol and methanol, ethers such ae dic~xane or dl-ethyl ether, or glacial acetic acid, pyridine, dimethyl-formamide, dimethylsulphoxide or acetonitrile.
~he reaction temperatures can be varied within a ~ubstantial range. In general, the reaction is carried out at a temperature o~ rom 20 to 200C, preferably at 50 to 120C and e~pecially at the boiling point of the solvent.
The reaction can be carried out under normal preesure but also under elevated pressure. In general, norm;~l pressure is used.
The preceding processes of preparation are gi~ren solely for clarification and the preparation of the compound (I) is not re~tricted to these processes; in~tead, any mod-ification of these proces~es can be used in the same manner for the preparation of the compound (I).
The compound according to the invention is a substance ~0 which can be used a~ a medicament. When used enterally or parenterally it produce~ a powerful and long-lasting increase ~e A 16 774 - 8 -. . .

in myocardial perfusion and can therefore be employed for the prophylaxis and treatment of ischaemic heart disease~, especially if they are combined with hyperten~ion.
~he present inventlon provide~ a pharmaceuti¢al compo~ition containing as actlve ingredient the compound of the invention in admixture with a solid or liquefied gaseou~ diluent, or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 (preferably le~s than 350) except in the presence of a surface active agent.
The invention further provides a pharmaceutical composition containing as active ingredient ths compound o~
the invention in the form of a sterile or ieotonic aqueous ~olution.
The invention also provides a medi¢ament in dosage unit form comprisine the compound of the invention.
The i~vention al~o provides a medicament in the form of tablets (including lozenges and granules), dragees, cap-sules, pills, ampoule~ or suppositories comprising the compound of the invention. I
"Medicament" as used in thi~ Specif~cation means physically discrete ooherent portions suitable for medical administration. "Medicament in dosage unit form" as used in this Specification means physioally discrete coherent units suitable for medical administration each ¢ontaining a daily dose or a multiple (up to four times) or sub-multiple (down to a fortieth) of a daily dose of the compou~d of the invention in association with a carrier and/or enclosed within an envelope. Whether the medicament contains a daily dose or, for example, a half, a third, or a quarter of a daily dose will depend on whether the medicament is to be ~e A 16 774 _ 9 _ 1085~06 administered once or, for example, twice, three times or four times a day respectively.
The pharmaceutical compositions according to the invention may, for example, take the form of ointments, gels pastes, crea~s, sprays (including aerosols), lotions, ~uspensions, solutions and emul~ions of the aotive ingredlent in aqueous or non-aqueous diluents, syrups, granules or powders.
The diluents to be used in pharmaceutical oompo~itions (e.g. granulates) adapted to be formed into tablets, dragees, capsules and pill~ include the following:
(a) ~iller~ and extenders, e.g. ~tarch, sugars,m~nnitol, and ~ilicic acid; (b) binding ~gents, e.g. carboxymethyl cellulose and other cellulose derivative~, alginates, gelatine and polyvinyl pyrrolidone; (c) moisturizing agent~, e.g. glycerol; (d) disintegrating agents, e.g. agar-agar, calcium carbonate and sodium bicarbonate; (e) agents for retarding dissolution e.g. paraffin; (f) resorption aGcelerator~, e.g. quaternary ammonium compound~; (g) sur-face active agents, e.g. cetyl alcohol, glycerol monostearate;
(h) adsorptive carriers, e.g. kaolin and bentonite; (i) lubri-cant3, e.g. talc, calcium and magne~ium stearate and solid polyethylene glycols.
The tablets, dragees, capsules and pills formed from the pharmaceutical composition6 of the invention can have the cu~tomary coatings, envelopes and protec~ive matrice~, which may contain opacifiers. They can be 80 conQtituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, poQsibly over a period of time. The 0atings, envelopes and protective matrices may be made, for example, of polymeric substances ~e A 16 774 _ 10 _ . .

:108540t;

waxe~.
The ingredient can also be made up in microencap-sulated ~orm together with one or ~everal of the above-mentioned diluent 8 .
The diluents to be u~ed in pharmaceutical compo~itions adapted to be formed into suppositories can, for example, be the u~ual water-soluble or water-insoluble diluent~, such as poly~hylene glycols and ~ats (e.g. cocoa oil and high esters [e.g. C14-alcohol with C16-fatty acid]) or mi~ture of these diluents.
The pharmaceutical compositions which are ointments, pastes, creams and gels can, for example, contain the usual diluents, e.g. animal and vegetable fats, waxes, parafYins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.
The pharmaceutical compositions which are powders and ~prays can, for example, contain the usual diluents, e.g.
lactose, talc, silicic acid, aluminium hydroxide, calcium silicate, and polyamide powder or mixtures of these sub-stances. ~erosol sprays can, for example, contain the usual propellants, e.g. chloro~luorohydrocarbons.
The pharmaceutical compositions which are solutions and emulsions can, for example, contain the customary diluents (with, of course, the above-mentioned exclusion of solvents having a molecular weight below 200 except in the presence of a surface-active agent), such as solvents, -^
dissolving agents and emulsifiers; specific~examples of such diluents are water, ethyl alcohol, isoprnpyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl bensoate, propylene glycol, 1,~-butylene glycol, dimethylformamide, oils ~for example ground nut oil], glycerol, tetrahydrofur-~e A 16 774 - 11 -,, .~ , . , 1085~

furyl alcohol, polyethylene glycols and fatty acid e~ters of sorbitol or mixtures thereof.
For parenteral administration, the solutions and emulsions should be sterile, and, if appropriate, blood-isotonic.
The pharmaceutical composition~ which are ~uspensions can contain the usual diluents, such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, ~ur~ace-active agents (e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbite and sorbitane esters), microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth or mixtures thereo~.
All the pharmaceutical compositions according to the invention can also contain colouring agents and preservatives as well as perfumes and flavouring additions (e.g. peppermint oil and eucalyptus oil) and sweetening agents (e.g. saccharin).
The pharmaceutical compositions according to the invention in general contain from 0. 1 to 99.5, more usually from 0.5 to 95% o~ the active ingredient by weight o~ the total composition.
In addition to a compound of the invention, the pharmaceutical compositions and medicaments according to the invention can also contain other pharmaceutically active compounds .
Any diluent in the medicaments o~ the present invention may be any of those mentioned above in relation to the pharmaceutical compo~itions of the present invention. Such medicaments may include solvents oi molecular weight less than 200 as sole diluent.
The discrete coherent portios constituting the medica ment according to the invention will generally be adapted, ~e A 16 774 - 12 -10854~6 by virtue of their shape or packaging, for medical ad-ministration, and may be, for example, any of the following:
tablet~,(including lozenges and granules), pilla, dragees, capsules, ~uppositories and ampoules. ~ome of these forms may be made up for delayed release of the active ingredient.
~ome, such as capsules, include a protective envelope which rendere the portions of the medicament physically discrste and coherent.
r~he preferred daily dose for administration of the medicaments of the inven~ion ia 0.005 mg to 1 g of active ingredient.
The production of the above-mentioned pharmaceutical composition~ and medicaments is carried out by any method known in the art, for example, by mixing the active ingredient(s) with the diluent(s) to form a pharmaceutical composition (e.g. a granulate) and then ~orming the compo3-ition into the medicament (e.g. tablets).
This invention further provides a method of combating (including prevention, relief and cure of) the above-mentioned diseases in human and non-human animals, which comprises administering to the animals a compound of the invention alone or in admixture with a diluent or in the form of a medicament according to the invention.
It is envisaged that these active compounds will be administered perorally, enterally, parenterally (~or example intramuscularly, intraperitoneally or intravenously), rectally or locally, preferably enterally or parenterally, especially perlingually or intravenously. Preferred pharmaceutical compositions and medicaments are therefore those adapted for enteral or parenteral administr~tion.
In general it has proved advantageous, in the case of ~e ~ 16 774 - 13 -lntravenou~ administration, to admini~ter amount~ o~ about O.OOOl to l mg/kg, preferably about 0.0005 to 0.01 mg/kg of body weight daily to achie~e effeotive results, whil~t in the ca~e of enteral admini~tration the do~age is about 0.0005 to lO mg/kg, preferably 0.001 to O.l mg/kg of bod~
weight daily.
Neverthele~s it can at tlmes be necessary to deviate from the amounts mentioned and in particular to do 90 as a function of the body weight of the test animals or of the nature of the administration route, but also because of the specie~ of animal and its individual behaviour towards the medicine or interval at which it is administered. Thus it may suffice, in some cases, to manage with less than the above-mentioned minimum amount whilst in other cases the upper limit mentioned must be exceeded. Where ma~or amounts are administered it can be advisable to divide these into several individual administrations over the course of the day. The same dosage range is envisaged for administration in human medicine. Here, again, the general sense of the above comments applies.
~o demonstrate the perfusion-assisting actio~ in heart muscle, the substance was administered to dogs and the myo-cardial perfusion was measured with the aid of an electro-magnetic flow meter.
The substance increases the perfusion of the heart, after intravenous and enteral administration. A particular advantage is its rapid and complete resorption after perlingual administration, 80 that the substance ha~ a strong and long-lasting action even when used in this way, in very low do~es.
~he results of the investigations on dogs after sub-~e A 16 774 - 14 -i(~854~6 lingual administration are shown in the table which ~ollows.

Do~e, mg/k~, Increase in heart~owering administered perfusion of blood sublingually by jO half-life ofpre~ure the durationin %
of action, in minutes 0.003 23 100 0.01 46 133 5 0,1 142 184 1~

It can be seen that the compound according to the invention increases the perfusion of the heart muscle, as a ~uncti3n of the dose, and, surprisingly, the effective doses are very low. The action of the substance start~
a few minutes after sublingual administration and lasts, depending on the dose, for 2 to 6 hours (in the table, the half-life of the action is given as a more accurate yard-stick of the duration of action). At the same time, it cau~es a slight and equally long-lasting lowering of the blood pressure, which as a rule represents an additional advantage in the therapy of coronary illnesses.
The compound according to the invention is therefore suitable for the prophylaxis and therapy of acute and chronic ischaemic heart diseases in the broadest senseO The sub-stance can be u~ed as an agent for the prophylaxis and therapy of angina pectoris complaints and attacks, and for the therapy of conditions after a heart infarct. It is particularly suitable for the therapy of cases in which one of the abovementioned heart diseases is combined with hypertension.
The following Examples i~ustrate the alternative methods ~e A 16 774 _ 15 ~

~ ~ 8 5'~C~6 of preparation of isobutyl methyl 1.4-dihydro-2.6-dl-methyl-4-(2-nitrophenyl)-3.5-pyridine dicarboxylate in accordance with the invention.

H~C\ (~ NO2 HC-H2C-OOC ~ COOCH~
H,C' N CH~

Exam~le 1 (Process A) 14.6 g (50 mmol5 ) of 2'-nitrobenzylideneacetoacetic acid isobutyl e~ter together with 5.8 g (50 mmol~) of ~-aminocrotonic acid methyl ester, in 80 ml of ethanol, ~rere heated for 20 hours under reflux. After the reaction mixture had cooled, the solvent was disti1led off in vacuo and the oily residue was mixed with a little ethanol. The product cry~tallised completely after a short time and was filtered off and recrystallised from ethanol. Melting point:
151-152C yield: 15.2 g (78%).
ExamPle 2 (Process B) 14.6 g (50 mmol~) of 2'-nitrobenzylideneacetoacetic acid isobutyl ester together with 5.8 g (50 mmols) of acetoacet acid methyl ester and 6 ml (88 mmols) of a 25 per cent strength aqueous ammonia solution, in 80 ml of methanol, were heated for 24 hours under reflux. The solvent was then distilled off in vacuo and the oily residue wa~ mixed with a little ~hanol. The product crystallised completely after a short time and was filtered off and recrystallised from ethanol.
Melting point:150-152 C, yield: 11.9 g (61%).
xamPle 3 (Process C) 12.5 g (50 mmols) of 2'-nitrobenzylideneacetoacetic a~id methyl ester together with 7.85 g (50 mmols) of ~-~e .~ 6 ,74 - 16 -.

1085~06 aminocrotonic acid isobutyl ester in 80 ml of ethanol were heated for 20 hours under reflux. After the reaction mixture had cooled, the solvent wa~ distilled off in ~acuo and the solid residue was triturated with ether, filtered off and recrystallised from ethanol.
Melting point: 150-152C, yield: 14.5 g (74%).
Exam~le 4 (P;~o¢e~ D) 12.5 g (50 mmols) of 2'-nitrobenzylideneacetoacetic acid methyl ester together with 7.85 g (50 mmol~) o~ aceto-acetic acid isobutyl e~ter and 6 ml (88 mmols) oi a 25 per cent ~trength aqueous ammonia solutlon, in 80 ml of isobutan-ol, were heated for 15 hour~ under reflux. After the reaotlon mi~ture had ¢ooled, the solvent wa~ di~tllled off in vacuo. The oily re~ldue crystallised completely over-night and was triturated with ether, filtered off and recrystallised from ethanol.
Melting point: 150-152C, yield: 10.9 g (56%).
Exam~le 5 (Process ~) 7.85 g (50 mmols) of ~-aminocrotonic acid isobutyl ester together with 7.6 g (50 mmols) of 2-nitrobenzaldehyde and 5.8 g (50 mmols) of acetoacetic acid methyl ester in 80 ml of ethanol were heated ~or 24 hours under reflux.
After the reaction mixture had cooled, the solvent was con-centrated in vacuo and the solid residue was triturated with ether, filtered off and recrystallised from ethanol.
Melting point: 151-152C, yield: 14.5 g (75%).
E~am~le 6(Process Fl 5.8 g (50 mmols) of ~-aminocrotonic acid methyl ester together with 7.6 g (50 mmols) of 2-nitroben~aldehyde and 7.85 g (50 mmols) of acetoacetic acid isobutyl ester, in 80 ml of ethanol, were heated to the boil for 24 hours. The ~e A 16 774 _ 17 _ .. . . , .. .. . _ .. .. .. . . . . . ... . .
' '.

io85,4~6 solvent was then di~ti~led off in vacuo and the solid residue was recrystall.ised from ethanol.
Melting point: 151-152C,yield: 13.6 g (70~o).

Le A 16 774 - 18 -

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing isobutyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinecarboxylate of formula I

which comprises (a) reacting 2'-nitrobenzylideneaceloacetic acid isobutyl ester of formula II

II

with .beta.-aminocrotonic acid methyl ester of formula III

III

(b) reacting 2'-nitrobenzylideneacetoacetic acid isobutyl ester of formula II above with acetoacetic acid methyl ester of formula IV

IV

and ammonia (c) reacting 2'-nitrobenzylideneacetoacetic acid methyl ester of formula V

V

with .beta.-aminocrotonic acid isobutyl ester of formula VI

VI
(d) reacting 2'-nitrobenzylideneacetoacetic acid methyl ester of formula V above with acetoacetic acid isobutyl ester of formula VII

VII

and ammonia (e) reacting .beta.-aminocrotonic acid isobutyl ester of formula VI
above with 2-nitrobenzaldehyde of formula VIII

VIII
and acetoacetic acid methyl ester of formula IV above or (f) reacting .beta.-aminocrotonic acid methyl ester of formula III
above with 2-nitrobenzaldehyde of formula VIII above and acetoacetic acid isobutyl ester of formula VII above.

2. A process according to claim 1 wherein the reaction is carried out in the presence of water or an inert organic solvent.

3. A process according to claim 1 or 2 wherein the reaction is carried out at a temperature of from 20 to 200°C.

4. Isobutyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate when prepared by a process according to claim 1, 2 or 3 or an obvious chemical equivalent thereof.

5. A process for preparing isobutyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate which comprises refluxing sub-stantially equimolar quantities of 2'-nitrobenzylideneacetoacetic acid iso-butyl ester and .beta.-aminocrotonic acid methyl ester in ethanol.

6. A process for preparing isobutyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate which comprises refluxing sub-stantially equimolar quantities of 2'-nitrobenzylideneacetoacetic acid iso-butyl ester and acetoacetic acid methyl ester and a molar excess of ammonia in methanol.

7. A process for preparing isobutyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate which comprises refluxing sub-stantially equimolar quantities of 2'-nitrobenzylideneacetoacetic acid methyl ester and .beta.-aminocrotonic acid isobutyl ester in ethanol.

8. A process for preparing isobutyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate which comprises refluxing sub-stantially equimolar quantities of 2'-nitrobenzylideneacetoacetic acid methyl ester and acetoacetic acid isobutyl ester and a molar excess of ammonia in isobutanol.

9. A process for preparing isobutyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate which comprises refluxing sub-stantially equimolar quantities of .beta.-aminocrotonic acid isobutyl ester, 2-nitrobenzaldehyde and acetoacetic acid methyl ester in ethanol.

10. A process for preparing isobutyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate which comprises refluxing sub-stantially equimolar quantities of .beta.-aminocrotonic acid methyl ester, 2-nitrobenzaldehyde and acetoacetic acid isobutyl ester in ethanol.

11. Isobutyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate when prepared by a process according to claim 5, 6 or 7 or an obvious chemical equivalent thereof.

12. Isobutyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate when prepared by a process according to claim 8, 9 or 10 or an obvious chemical equivalent thereof.