DK146762B - ANALOGY PROCEDURE FOR THE PREPARATION OF 2,6-DIMETHYL-3-METHOXYCARBONYL-4- (2'-NITROPHENYL) -1,4-DIHYDROPYRIDINE-5-CARBOXYLIC ACID ISOBUTYL ESTER - Google Patents

Description

(19) DENMARK (w) \ Ray

(12) PUBLICATION (s) 146762 B

DIRECTORATE OF

THE PATENT AND TRADEMARKET SYSTEM

(21) Patent Application No: 4984/76 (51) IntCI.3: C 07 D 211/90 (22) Filing Date: 04 Nov 1976 (41) Aim. available: 06 May] 1977 (44) Submitted: 27 Dec 1983 (86) International Application No: - (30) Priority: 05 Nov 1975 DE 2549568 (71) Applicant: * BAYER AKTIENGESELLSCHAFT; 509 Leverkusen, DE.

(72) Inventor: Egbert * Wehlnger; DE, Friedrich * Bossert; DE, Eagle * Health; DE, Stanislav * Ka2da; DE, Kurt 'Stoepel; DE, Wulf * Father; THE.

(74) Plenipotentiary: Engineer Budde, Schou & Co (54) Analogous Process for Preparation of 2,6-Dimethyl-3-Methoxycarbonyl-4- (2'-Nitrophenyl) ~ 1,4-Dihydropyridine-5-Carboxylic Acidobutyl Ester

The present invention relates to an analogous process for the preparation of 2,6-dimethyl-3-methoxycarbonyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-5-carboxylic acid isobutyl ester.

It is already known that by reaction of benzylidene-acetic acid ethyl ester with iso-amino-crotonic acid ethyl ester or acet-acetic acid ethyl ester and ammonia, 2,6-dimethyl-4-phenyl-1,4-dihydropyridine ~ 3,5-dicarboxylic acid diethyl ester ( cf. Knoevenagel, Ber.

DQ dtsch.chem.Ges. 3JL, 743 (1898). Furthermore, it is known that certain 1,4-dihydropyridines have interesting pharmacological properties (cf. F. Bossert, W. Vater, die Naturwissenschaften 5J3, 578 (1971)).

'ί Furthermore, it is from the applicant's older German publication letters *

Q

2 146762 Nos. 2,117,571 and 2,117,573, cf. Danish submission no.

134,600, known that similar dihydropyridines can be used as coronary agents. However, this compound is characterized by a novel strong and long-lasting coronary action and a surprisingly high therapeutic index (toxicity-therapeutic effect ratio) relative to these known compounds.

The method of preparing the novel

2,6-Dimethyl-3-methoxycarbonyl-4- (2'-nitrophenyl) -1,4-dihydro-pyridine-5-carboxylic acid isobutyl ester of formula I

Q *.

3 \

HC-H, C-OOC in COOCH, I

v 'xj: h, c ^^ ch, ό E ά is peculiar in that one

a) Reacts with 21-nitrobenzylidene acetacetic acid oreobutyl ester of formula II

H, C O S ^ "02

3 \ li I

HC-H0C .C. JZ. II

„/ 2 ^

H3C I

/ 'V

H3C 0

with β-aminocrotonic acid methyl ester of formula III

EU COOCH, -3 | l m H2W \ Ch3 optionally in the presence of water or inert organic solvents, or

b) reacting 21-nitrobenzylideneacetic acetic acidobutyl ester of formula II with acetic acetic acid methyl ester of formula IV

146762 3 o

✓ IV

H-C-C

3 \ CH 2 -COOCH 3 and ammonia optionally in the presence of water or inert organic solvents, or

c) reacting 2'-nitrobenzylideneacetic acetic acid methyl ester of formula V

kXuo2

o V

/ HN. .COOCH-H 3 0 ^ XCH3

with β-aminocrotonic acid isobutyl ester of formula VI

H, C 3 \ HC-H-C-00C .H / 2 H3c f vi H3C xnh2 optionally in the presence of water or inert solvents, or

d) reacting 2'-nitrobenzylideneacetic acetic acid methyl ester of formula V with acetic acid oreobutyl ester of formula VII

H-C-C ^ CH-VI1

'• ^ CH ^ -COO-CHO CH

Δ Δ \ ch3 and ammonia optionally in the presence of water or inert organic solvents, or e) reacting β-aminocrotonic acid isobutyl ester of formula VI with 2-nitrobenzaldehyde of formula VIII and acetic acid methyl ester Π

M02 VIII

(c) optionally in the presence of water or inert organic solvents; or f) reacting β-aminocrotonic acid methyl ester of formula XII with 2-nitrobenzaldehyde of formula VIII and acetic acetic acid isobutyl ester of formula VII with each other as such water or in inert organic solvents.

As mentioned, the compound of formula I produced has a very strong coronary effect.

Among the prior art, similar 1,4-dihydropyridine derivatives known, such a strong and long-lasting coronary effect, especially after enteral administration, has not been detected so far. In addition, the compound of this invention is less lysstable than similar known dihydropyridines. Thus, with regard to these special properties, it offers an advance in pharmacy.

The compound produced is chiral and may be present in stereoisomeric forms such as image and mirror image (enantiomers, antipodes). These can again occur in different conformations. Both the racemic form and the antipodes are encompassed by the present invention.

Depending on the nature of the starting materials used, the synthesis of the present compound can be represented by the following formula:

CiL fX

a) H3CS TN02 H3C \> ^ N ° 2 HC-H2C-00Cx ^ Cn HC-H2COOCv ^ n ^ COOCH, H3C 'f H H3C / [I IT 3 hn „cooch3 h3ct n ch3

H3C o + £ --- ► H

n h2n ch3

III

(file b) h3Cx ύ ^ νο H3 c> \ no «HC-H2C00Cx ^ Cn HC-H2COOC -v ^ S ^ COOCH3

E ^ C 'C H ✓ COOCH3 E ^ C7 I II

£ H? C w h3c ^ n ^ ch,

H3c o + #cx H

nh3 o ch3

II IV

O) HjCs CjX &, c, Y ~ no2 HC-CHo -OOCv, H T N02 HC-H2C00C vAyCOOCIIj H3Cy C ^ X ^ p ^ C00CH3 H3C> Il 1. Å + H Y _► h3c ^ nach3

h3c nh2 ^ N

o ch3

WE V

d) H3Cn Q ^ N ° 2 HC-CH2-00Cn ^ Ck ^ gooch3

Hg O 'CHa + H C

C C ► i 's.

H3 c O ΝΙΪ3 o xch3

VII V

& ·) HsC, HC-CH2 -OOC v, / Η 0 "υ H„ r ^ C00CH3 lp · τΐ2 o ^ h3c S + „£ ► '/ Cv 0 * υ> Όί3 H3 C nh2 H3 C \ V ^ n ° 2 HC-H2 C00 ^ XvC00CH3 h3c / il \] h3c h ch3 f) H3 C \ ζ ^ Ν02 HC-H2C00C., Cx h3c / Sch2 * h _ ✓c * + Hs sC00CH3 h3c oc 11 h2n ch3 h3cs χ ^ 2 ° 2 HC-H2C00C vXv ^ COOCHa

H3G 'Y | T

h3c h ch3 6 146762

The starting compounds of formulas II · VIII are known or can be prepared by known methods (Lit .: Org. Reactions XV, 204 ff (1967), AC COPE J. Amer. Chem. Soc. 67, 1017 (1945) and Houben-Weyl, The Method of Organ Chemistry VII / 4, 230 ff (1968)).

In carrying out the process variants (a) to (f), the substances involved in the reaction are each used in approximately molar amounts. The ammonia used is suitably added in excess.

Water and all inert organic solvents can be used as diluents. Preferably include alcohols such as ethanol and methanol, ethers such as dioxane, diethyl ether or glacial acetic acid, pyridine, dimethylformamide, dimethylsulfoxide or acetonitrile.

The reaction temperatures can be varied within a larger range. Usually between approx. 20 and 200 ° C, preferably at 50-120 ° C and especially at the boiling point of the solvent.

The reaction can be carried out at normal pressure, but also at elevated pressure. Normal work is usually done.

The compound prepared is a substance useful as a drug. With enteral or parenteral use, it causes a strong and prolonged increase in myocardial blood flow and can therefore be used for the prophylaxis and treatment of ischemic heart disease, especially when combined with hypertension.

This active ingredient can be converted in known manner to the usual formulations such as tablets, capsules, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable carriers or solvents. In this case, the therapeutically active compound must be present in a concentration of approx. 0.5-90% by weight of the total mixture, ie in amounts sufficient to reach the specified dosage clearance.

In the case of intravenous administration, it has usually proved advantageous to administer amounts of approx. 0.0001-1 mg / kg, preferably approx. 0.0005-0.01 mg / kg body weight per per day to achieve effective results, and on enteral administration the dosage is approx. 0.0005-10 mg / kg, preferably 0.001-0.1 mg / kg body weight per day. day.

7 146762

To detect the blood flow promoting effect in the heart muscle, the drug is administered to dogs and the neocardial blood flow is measured by an electromagnetic flow meter.

The drug increases blood flow to the heart after intravenous and enteral administration. Particularly advantageous is its rapid and complete resorption after perlingual administration, so that in this mode of application it is also strong and long-lasting in very low doses.

The results of the studies on dogs after sublingual administration are shown in the following Table I.

Table I

} - 'r I - -

Dose mg / kg Increase in blood flow- Blood pressure reduction sublingual flow in the heart in% Half-life of in% duration of action ___ duration in minutes__ 0.003 23 100 0 0.01 46 133 5 0.1 142 184 13

It is seen that the compound of the invention, depending on the dose, increases blood flow in the heart muscle, whereby it has surprisingly been found that the effective doses are very low. The effect of the substance begins after sublingual administration within a few minutes and lasts depending on the dose for 2-6 hours (the table shows, as a more accurate measure of the duration of action, the half-life of the effect). At the same time, it induces a slight and equally prolonged lowering of blood pressure, which is usually a further benefit of the treatment of coronary disease.

The strong efficacy of the compound of the invention and beneficial therapeutic indices in relation to closely related compounds are shown in the following Table II.

8 146762 Λ 3 to

• 3 -H

+ J 3 O O

3 0 0 O.

α) ω> 6 o o ΒιΒ o g 3 Φ ο · m o) 3 Ό in m n 0) a Q in Λ

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+ J X

Φ · \ + J - 0 O

• Η (I) · £ Ο O

o 3 ft Ο O

-η s tn o ch

ra o -3 H

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Ό 3 s 3 o O 'Ή Λ -P β 3 P -3 O' “3 ti

H '-'tigS

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IH 3 Μ · O O O O

• 3 β 0) P 3 3 O O '

β 0 Ό 44 Φ * 3 - O O

οιμβαιρω o o • 3 0 3 p “3 0

m o Λ ω S Q

η ΰ ti ϋΤ ύ a ό o) ο

O ω ω tN O η P

CN O η> P o o a ή o o a o) auu-3 syypO / \ / 3) - = r \ p -3 / - \ / - \ 01 O '

/ \ / · - P Ή / V— {S tti 3 P

{y \ jω p § \ -fyJ s p / \ g {D Ο Ο Φ ft

CJ O Φ O 'Q O O' S

O m 3 p O Β θ 'φ 0 aw e. ^ Y- ^ s) 3 1 m u- ^ a ^ yp 44 O φ -3 η n S Φ φ cn 3 aa φ 3 ap fi 3 * · H i φ Φ ΜΗ ο Φ xy \ Ό Ό t Ο ό υ a -y β »3 λ ο β η η -3 g ω · -3 aa λ 3 β ό · Λ 3 θ '3 0 3 Ο β Q ρ Ο Ή 3 ^ ft ^ O '9 146762

The compound prepared is therefore suitable for the prophylaxis and therapy of acute and chronic, ischemic heart disease in the broadest sense. The compound can be used as a means for the prevention and therapy of pectanginous disorders and seizures and for the therapy of conditions after myocardial infarction. It is particularly suitable for treating cases where one of the above heart diseases is combined with hypertension.

Preparation Examples 2,6-Dimethyl-3-methoxycarbonyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-5-carboxylic acid isobutyl ester

ISLAND

A) 14.6 g (50 mmol) of 21-nitrobenzylideneacetic acetic acid isobutyl ester are heated at reflux for 20 hours with 5.8 g (50 mmol) β-Aminocrotonic acid methyl ester in 80 ml of ethanol. After cooling the reaction mixture, the solvent is distilled off in vacuo and the oily residue is mixed with a little ethanol. The product crystallizes after a short time, is separated by suction and recrystallized from ethanol. Mp: 141-142 ° C, yield: 15.2 g (78%).

b) 14.6 g (50 mmol) of 21-nitrobenzylideneacetic acetic acid isobutyl ester are heated under reflux for 24 hours, together with 5.8 g (50 mmol) of acetic acid methyl ester and 6 ml (88 mmol) of a 25% aqueous ammonia solution in 80 ml methanol. The solvent is then distilled off in vacuo and the oily residue mixed with a little ethanol. The product crystallizes after a short time, is separated by suction and recrystallized from ethanol. Mp: 140-142 ° C, yield: 11.9 g (61%).

c) 12.5 g (50 mmol) of 2'-nitrobenzylideneacetic acetic acid methyl ester are heated at reflux for 20 hours together with 7.85 g (50 mmol) of β-aminocrotonic acid isobutyl ester in 80 ml of ethanol. After cooling the reaction mixture, the solvent is distilled off in vacuo, the solid residue is triturated with ether, separated by suction and recrystallized from ethanol. Mp: 140-142 ° C, yield: 14.5 g (74%).

D) 12.5 g (50 mmol) of 21-nitrobenzylideneacetic acetic acid methyl ester are heated under reflux for 15 hours, together with 7.85 g (50 mmol) of acetic acid isobutyl ester and 6 ml (88 mmol) of a 25% aqueous ammonia solution in 80 ml of isobutanol. After cooling the reaction mixture, the solvent is distilled off in vacuo. The oily residue crystallizes out over night, triturates with ether, is separated by suction and recrystallized from ethanol. Mp: 140-142 ° C, yield: 10.9 g (56%).

e) 7.85 g (50 mmol) of β-aminocrotonic acid isobutyl ester is heated at reflux for 24 hours with 7.6 g (50 mmol) of 2-nitrobenz aldehyde and 5.8 g (50 mmol) of acetic acid methyl ester in 80 ml of ethanol. After cooling the reaction mixture, the solvent is evaporated in vacuo, the solid residue is triturated with ether, separated by suction and recrystallized from ethanol. Mp: 141-142 ° C, yield: 14.5 g (75%).

f) 5.8 g (50 mmol) of β-aminocrotonic acid methyl ester is heated for 24 hours to the boiling point, along with 7.6 g (50 mmol) of 2-nitrobenzaldehyde and 7.85 g (50 mmol) of acetic acid isobutyl ester in 80 ml of ethanol. The solvent is then distilled off in vacuo and the solid residue is recrystallized from ethanol. Mp: 141-142 ° C, yield: 13.6 g (70%).

b

Claims (2)

Analogous Process for Preparation of 2,6-Dimethyl-3-methoxycarbonyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-5-carboxylic acid isobutyl ester of Formula I nHIHC 3HC-H2C-OOC \ JLxC00CH3 h3c / TT / VN ^ CH, h3c characterized by a) reacting 2'-nitrobenzylideneacetacetic acid oreobutyl ester of formula II Η3 <\ o UAno2 HC-H0C JZ I TT / 2 VC ^ H 11 H3C N> with β-aminocrotonic acid methyl ester of formula III H. COOCH ™> Q / II m .c. Optionally in the presence of water or inert organic solvents, or b) reacting 21-nitrobenzylideneacetic acetic acidobutyl ester of formula II with acetic acid methyl ester of formula IV H-CC IV XCH2-COOCH3 and ammonia optionally in the presence of water or inert agents, or c) reacting 2'-nitrobenzylideneacetic acetic acid methyl ester of formula V