FI57944B - PROCEDURE FOR THERAPEUTIC PREPARATION OF THERAPEUTIC 2-AMINO-6-METHYL-4-NITROPHENYL-4H-PYRANER - Google Patents

Description

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Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) P 2235 ^ 06.9 (71) Bayer Aktiengesellschaft, Leverkusen, Federal Republic of Germany-Förbunds-republiken Tyskland (DE) (72) Horst Meyer, Wuppertal, Friedrich Bossert, Wuppertal, Wuppertal, Wulf Vater , Wuppertal, Federal Republic of Germany Förbunds- republiken Tyskland (DE) (7H) Oy Kolster Ab (5Π) Method for the preparation of therapeutically useful 2-amino-6-methyl-U-nitrophenyl 'i + H-pyrans - Förfarande för framställning av terapeu— tiskt anvt 2-Amino-6-methyl-1-nitrophenyl-HH-pyraner (62) Separated from application 2263/73 ~ Avdelad fr & n trap 2263/73

The invention relates to a process for the preparation of therapeutically useful 2-amino-b-methyl-1-nitrophenyl-1 + H-pyrans of the formula I

ςΝ ° 2 J * ^ C00R1 (I)

H3C2H2HH

2 57944 1. ..2 wherein R is lower alkyl and R is lower alkyl or lower alkoxy.

The process according to the invention is characterized in that the unsaturated dicarbonyl compound of the formula II has the formula II: no 2 Ä ~ \ COR2 {'x> -ch = c (ii) \ _ / XCOCH3 2 ...

wherein R is as defined above, is reacted with a cyanoacetic acid ester of formula IV: wherein R 1 is as defined above, in an inert organic solvent and optionally in the presence of a base at a temperature between 10-200 ° C .

It is known that the reaction of d, β-unsaturated carbonyl compounds with enamine yields 2,3-dihydro-1H-pyrans, e.g. as follows:

rs O

r7. O - cf * o .......- n o (cf. I.W. Lewis, P.L. Myers, M.I. Readhead, J, Chem. Soc. C., 19T0, 771).

Inamines react similarly (J. Ficini, A. Krief, Tetrahedron Letters 1969 »1U27) · To date, nothing is known about the possible effect of these UH-pyrans on the bloodstream.

It is further known that the reaction of N-nitrobenzylideneacetylacetone with potassium cyanide in an alkaline medium gives 3-acetyl-5-amino-2-methyl-4- (p-nitrophenyl) furan (see reaction scheme): 3,57944. - i r χί '-γ- CH - CH - COCH - ^ „, X ^ | Γ» ό 0 = C-CH, V 0 ^ c>; h3 o2 »A ^ 3

^ COCH

02N H2N 0 ^ "" * CH

(cf. I.P. Sword, J. Chem. Soc. C, 1970, 1916); The 2-amino-6-methyl-1 + -nitrophenyl-β-H-pyrans prepared according to the invention have a long-lasting, potent vasodilating effect. Such 2-amino-6-methyl-1 + -nitrophenyl-1H-pyrans have not been known to date to have any pharmaceutical effect. The process according to the invention thus provides substances suitable for the treatment of circulatory diseases, and the invention is thus capable of enriching the pharmacy.

If 3'-nitrobenzylideneacetic acid methyl ester and cyanoacetic acid ethyl ester are used as starting materials, the reaction can be represented by the following reaction scheme: f: Y ° 2 H-COOC μ pnpp f 3 .. sj C00C H H C00C / COOC H ,.

Ύ ^ 2 5 V 2

CH XemaaL.) J I

h c ^ ^ CN Λ JK

K "H_C 'NH0 3 2

The β, β-unsaturated dicarbonyl compounds used in the process of the invention are known compounds and can be prepared by known methods (Org. Reactions XV, 20a ff. (1967)).

The cyanoacetic acid esters used according to the invention are known compounds (Inglis, Org. Synth. Coll. Vol. I. 2 ** 9 (1932)).

Suitable diluents are all inert, organic solvents.

These include, for example, alcohols such as methanol, ethanol, propanol, ethers such as dioxane and diethyl ether, hydrocarbons such as cyclohexane, benzene, toluene, xylene; preferably ethanol is used.

, 57944 4

Reaction temperatures can vary within wide limits. The reaction is usually carried out at 10 to 200 ° C, preferably at 20 to 180 ° C, and especially at the boiling point of the solvent.

The reactants according to the invention are always used in molar ratios.

The new compounds can be used as medicaments. Their spectrum of pharmacological action is wide and varied.

Animal experiments have shown that their main modes of action are: 1) when administered parenterally, orally and by tongue absorption, the compounds have a clear and long-lasting coronary vasodilating effect.

This effect on the coronary arteries is enhanced by a concomitant nitrite-type cardioprotective effect. They affect the metabolism of the heart or make it energy-saving.

2) The compounds lower the blood pressure of animals with normal blood pressure and hypertension and thus can be used as antihypertensive agents.

The effect of the new compounds on the coronary artery was tested in anesthetized dogs by measuring the increase in O 2 saturation using a catheter. The results are summarized in the following table.

Table I

Clear increase (20-30%) in coronary oxygen saturation

Example Dose, mg / kg i.v. Duration, min No. 1 1 90 90 2 0.5 30

The effect of some compounds of the invention on blood pressure is shown in Table II. The measurement was performed with a high blood pressure separator (blood pressure at least 15 mmHg).

Table II

Example_Reduction of blood pressure, mg / kg po_ 1 from 1.0 3 from 3.0 U from 3.0 5 57944 3) The irritability of the irritation sites and the irritation conduction system within the heart is reduced, resulting in a ventricular fibrillation that can be demonstrated at therapeutic doses. effect.

b) The tendency of vascular smooth muscles is greatly reduced by the action of the compounds. This vasoconstrictive effect may occur throughout the vascular network or may be more or less isolated in confined vascular areas (such as the central nervous system).

5) The compounds have a strong muscle spasm-triggering effect, which is clearly evident in the smooth musculature of the stomach, intestines, urinary and genital areas, and the respiratory system.

6) The compounds affect blood cholesterol or lipid levels.

The new active ingredients can be prepared in a known manner into conventional pharmaceutical forms, such as tablets, capsules, dragees, pills, granules, aerosol ✓ .... . . ...

cells, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically acceptable carriers or diluents. The amount of therapeutically active compound in the preparations is about 0.5 to 90% by weight, based on the total weight of the mixture, i.e. sufficient to achieve a suitable dose range.

In general, it has been found advantageous to achieve an effective effect by administering 0.005-10 mg / kg, mainly 0.02-5 mg / kg / day, intravenously, and about 0.1-50 mg / kg, mainly 1-30 mg / kg / day orally. .

However, sometimes deviations from said amounts may be necessary, depending not only on the body weight or route of administration of the test animal but also on the species and its individual attitude to the drug, or the nature of the composition and the time or interval of administration. Thus, in some cases it is possible to cope with amounts lower than the above-mentioned minimum amounts, while in other cases the said upper limits have to be exceeded. When administering large amounts, it may be desirable to divide these into several single doses over a day. The dose ranges for human doses are assumed to be the same. In this sense, the above also applies.

Preparation Examples:

Example 1 S-'h H5C2OOC \> C / COOC2H5 T 1 57944 6

A solution of 26.3 g of 3'-nitrobenzylideneacetic acid ethyl ester, 11.3 g of cyanoacetic acid ethyl ester and 2 ml of piperidine in 100 ml of ethanol was heated for 1+ hours. There was obtained 2-amino-6-methyl-1- * (3J-nitrophenyl) -) - * H-pyran-3,5-dicarboxylic acid diethyl ester, m.p. 116 ° C (from ethanol).

Yield: 63% of theory.

Example 2 i i

H3C00C L ^ · 'n COOCgH

H3C

A solution of 2 *, 9 g of 3'-nitrobenzylideneacetic acid methyl ester, 11) 3 g of cyanoacetic acid ethyl ester and 2 ml of piperidine in 100 ml of ethanol was boiled for 1+ hours. There was obtained 2-amino-6-methyl-1 * - (3'-nitrophenyl) -1 + H-pyran-3,5-dicarboxylic acid 3-ethyl ester-5-methyl ester, m.p. was 13 ° C.

Yield 67% of theory.

Example 3 (H3O2HC00C cooc2h5

f T

H 0 NH2

A solution of 27.7 g of 3J-nitrobenzylideneacetic acid isopropyl ester, 11.3 g of cyanoacetic acid ethyl ester and 2 ml of piperidine in 100 ml of ethanol was heated for 1 hour. There was obtained 2-axnino-6-methyl-U- (3'-nitrophenyl) -1 + H-pyran-3,5-dicarboxylic acid 3-ethyl ester-5-isopropyl ester, m.p. was I35 ° C (from ethanol).

Yield 1 * 6% of theory.

T 57944

Example U

r ^ T ° 2

H COCl 3. 1 <H / · COOC H

ί Ϊ

/ \ IS H

Heating a solution of 23.3 g of 3'-nitrobenzylideneacetylacetone, 11.3 g of ethyl cyanoacetate and 2 ml of piperidine in 100 ml of ethanol gave 2-amino-5-acetyl- 6-methyl-N- (3, -nitrophenyl) -1H-pyran-3-carboxylic acid ethyl ester, m.p. was 181 ° C (from ethanol).

Yield: 51% of theory.

«Τ '

Claims (1)

A process for the preparation of therapeutically useful 2-amino-6-methyl-U-nitrophenyl-UH-pyrans of the formula I: NO 2 R0C-JVVCOOH1 γγ m I I H 0 ^ \ NH2. 1. . . 2 '. . wherein R is lower alkyl and R is lower alkyl or lower alkoxy, characterized in that the β-unsaturated dicarbonyl compound of the formula II is 2-λ. / COR2 // Yv CH = C ^ (II) \ / ^ COCH- V - V 3. 2. ... wherein R is as defined above is reacted with a cyanoacetic acid ester of formula IV: wherein R 1 is as defined above, in an inert organic solvent and optionally in the presence of a base at a temperature between 10-200 ° C.