NO814097L - PROCEDURE FOR THE PREPARATION OF 3,4-DISUBSTITUTED 1,2,5-OCSADIAZOL-2-OXYDS - Google Patents

Abstract

1. Claims for the contracting States : BE, CH, DE, FR, GB, IT, LI, NL, SE 3,4-Disubstituted 1,2,5-oxadiazole-2-oxides of the formula I see diagramm : EP0054873,P10,F11 wherein one of the radicals R**1 and R**2 denotes -CH3 and the other denotes -CONHR**3 N(R**4 )2 , see diagramm : EP0054873,P10,F13 see diagramm : EP0054873,P10,F1 see diagramm : EP0054873,P10,F3 -CONHR**3 OR**6 , -CONHR**7 , -CONR**4 R**8 , see diagramm : EP0054873,P10,F5 see diagramm : EP0054873,P10,F6 wherein R**3 denotes an alkylene radical -Cn H2n -, wherein n = 2, 3 or 4, R**4 and R**8 denote -CH3 or - C2 H5 , R**5 denotes -OCH3 or -Cl, R**6 denotes -H or -CH3 , R**7 denotes alkyl having 1 to 4 atoms, cycloalkyl having 5 to 7 C atoms, allyl, or pyridyl methyl, and X denotes -(CH2 )2 -O-(CH2 )2 -, see diagramm : EP0054873,P10,F8 -CH2 CH2 CH2 CH2 - or -CH2 CH2 CH2 CH2 CH2 - and pharmacologically acceptable acid addition compounds thereof. 1. Claims for the contracting State : AT Process for the preparation of 3,4-disubstituted 1,2,5-oxadiazole-2-oxides of the formula I see diagramm : EP0054873,P11,F2 wherein one of the radicals R**1 and R**2 denotes -CH3 and the other denotes -CONHR**3 N(R**4 )2 , see diagramm : EP0054873,P11,F3 see diagramm : EP0054873,P11,F4 see diagramm : EP0054873,P11,F5 -CONHR**3 OR**6 , -CONHR**7 , -CONR**4 R**8 , see diagramm : EP0054873,P11,F7 see diagramm : EP0054873,P11,F8 wherein R**3 denotes an alkylene radical -Cn H2n -, wherein n = 2, 3 or 4, R**4 and R**8 denote -CH3 or -C2 H5 , R**5 denotes -OCH3 or -Cl, R**6 denotes -H or -CH3 , R**7 denotes alkyl having 1 to 4 C atoms, cycloalkyl having 5 to 7 C atoms, allyl, or pyridyl methyl, and X denotes -(CH2 )2 -O-(CH2 )2 -, see diagramm : EP0054873,P11,F11 -CH2 CH2 CH2 CH2 - or -CH2 CH2 CH2 CH2 CH2 - as well as pharmacologically acceptable acid addition compounds thereof, characterised in that for the preparation of compounds of the formula Ia see diagramm : EP0054873,P11,F11 a 3-methyl-1,2,5-oxadiazole-2-oxide-4-carboxylic acid ester of the formula II see diagramm : EP0054873,P12,F1 wherein R**9 denotes alkyl having 1 to 6 C atoms, is reacted with an amine HZ and the amine employed here is selected in such a way that the radical Z, together with the carbonyl group of the ester II, forms the radical R**1 , and the resulting compound is, if appropriate, converted into an acid addition compound or, if appropriate, for the preparation of the compounds of the formula Ib see diagramm : EP0054873,P12,F4 is heated to temperatures from 150 to 220 degrees C, preferably 180 to 200 degrees C, and the resulting compound is, if appropriate, converted into an acid addition compound.

Description

The invention relates to a process for the production of 3,4-disubstituted 1,2,5-oxadiazole-2-oxides with. formula I

and their pharmacologically acceptable acid addition compounds.

In formula I, the residues have the following meaning:

R<1>means in the event that R<2>means -CH3:

dfe o3r ovdeent fotr ilffeor lle R 1 aat ngR i2ttee r bfeotrysdknjeinlgeig r, fbra ety-Cr HR -J, l and -CHha7r, one of R means an alkylene residue -C H„ -, where n means 2, 3 or 4,48n 2n ' n 2, 4, R and R mean -CH3, ~C2H5,

R 5 means -OCH-,, -Cl,

R means -H, -CH-./

7

R means alkyl with 1-4 C atoms, cycloalkyl with 5-7 C atoms, allyl, pyridylmethyl,

X means -(CH2)2~0-(CH2)2~,

—CH 2 CH 2 CH 2 CH 2

or -CH2CH2CH2CH2CH2~,

R<2> means 1-CH-. and for - the case that R<1>means -CH-., R<2> has the meaning for R indicated except for -CH.,.

12 From the above definitions of the residues R and R

appears that with the compounds of formula I always means one

1 2 1

and 2 only one of the residues R or R -CH.,, i.e. the residues R and R in a compound cannot simultaneously mean -CH^, one of them must, however, mean -CH-..

7 8

The alkyl residues specified for R (and the ones for the below-mentioned R ) and the alkylene residue specified for R 3 can be linear or branched. R 3 preferably means -CH 2 CH 2 -or -CH-CH-CH»-. Of the compounds of formula I, the preferred ones are those where R means -CH 2 , further those in which the residue R has an -NH grouping.

2

The compounds of formula I with R equal to -CH^ can, according to the invention, be prepared by reacting 3-methyl-1,2,5-oxadiazole-2-oxide-4-carboxylic acid esters of formula II with an amine HZ

R g thereby means an alkyl radical with 1-6 C atoms, especially 1-4 C atoms, preferably methyl or ethyl. The amine HZ is thereby chosen so that the residue Z together with the carbonyl group of the ester II in the compound Ia forms the residue R''". Z thereby has the following meanings:

The reaction of the compound II with the amine HZ is conveniently carried out in a suitable solvent or dispersant. As such solvents or dispersants, alcohols such as methanol, ethanol, i-propanol, further ethers such as diethyl ether, dioxane, tetrahydrofuran, ketones such as acetone, hydrocarbons such as toluene, xylenes, petroleum ether, halogenated hydrocarbons such as chloroform, chlorobenzene, polar aprotic solvents such as acetonitrile, dimethylformamide or aqueous solutions of the amine HZ. The reaction is usually carried out at temperatures from 15 - 25°C'. However, it can also be carried out at temperatures of 0°C up to the reflux temperature of the solvent or dispersant.

g

The compound of formula II where R is ethyl is described in Berichte der deutschen chemischen.Gesellschaft 28, 2681 (1895) as ester of peroxydiisonitros butyric acid. Compounds of formula II with other R g residues can be prepared analogously by choosing suitable starting products.

The compounds with R"<*>" = CH^, which belong to formula Ib

is produced from the compounds Ia by thermal rearrangement. The thermal rearrangement is conveniently carried out without a solvent or dispersant by heating the substance to temperatures of 150 - 220°C, preferably 180 - 200°C. The thermal rearrangement is usually finished after 15 - 120 minutes, in most cases after 30 - 60 minutes. The progress of the rearrangement can be followed by thin-layer chromatography.

The compounds I which have a basic side chain form salts with inorganic or organic acids. Such acids are, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, lactic acid, tartaric acid, acetic acid, salicylic acid, benzoic acid, citric acid, ascorbic acid, adipic acid and naphthalene disulfonic acid. The acid addition compounds are obtained in a known manner by combining the components in a suitable solvent or dispersant.

The compounds of formula I and wherein pharmacologically acceptable acid addition compounds have valuable pharmacological properties. Their effect on the cardiac circulatory system is particularly pronounced. In low doses, they lower the blood pressure, lower the peripheral resistance and lead to a reduction in the pulmonary artery pressure at a slightly affected heart rate to a reduction in the heart's work.

The compounds of formula I and their pharmacologically acceptable acid addition salts can therefore be administered to humans as healing agents alone, in admixture with each other or in the form of pharmaceutical preparations which enable an enteral or parenteral application and as active ingredient contain an effective dose of at least one compound with formula I or an acid addition salt thereof in addition to usual pharmaceutically harmless carriers and additives.

The drugs can be administered orally, e.g. in shape

of pills, tablets, varnish tablets, dragees, hard and soft gelatin capsules, solutions, syrups, emulsions or suspensions or aerosol mixtures. However, the administration can also take place rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions or percutaneously, e.g. in the form of ointments or tinctures.

Pharmaceutically inert inorganic or organic carriers are used for the production of pharmaceutical preparations. For the production of pills, tablets, dragees and hard gelatin capsules, e.g. lactose, corn starch or derivatives thereof, talc, stearic acid or their salts etc. Carriers for soft gelatin capsules and suppositories are e.g. fat, wax, semi-solid and liquid polyols, natural or hardened oils, etc. Suitable carriers for the production of solutions and syrups are e.g. water, sucrose, invert sugar, glucose, polyols etc. Suitable carriers for the production of injection solutions are e.g. water, alcohols, glycerol, polyols, vegetable oils, etc.

In addition to active substances and carriers, the pharmaceutical preparations may also contain additives such as e.g. fillers, thickeners, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, dyes, flavorings or flavoring agents, thickeners, diluents, buffering agents, further solvents or dissolution mediators or agents for achieving a depot effect, such as salts to change the osmotic pressure, coating agents or antioxidants. They may also contain two or more compounds of formula I or their pharmacologically acceptable acid addition salts and, moreover, other therapeutically active substances.

Such other therapeutically active substances are, for example: β-receptor blockers such as e.g. propranolol, pindolol, metoprolol, vasodilators such as carbochromes, gelling agents such as e.g. barbituric acid derivatives, 1,4-benzodiazepines and meprobamate, diuretics such as chlorothiazide, cardiac tonics such as e.g. digitalis preparations, blood pressure-lowering agents such as hydralazine, dihydralazine, prazosin, clonidine, Rauwolfia alkaloids, agents that lower the fatty acid level in the blood such as e.g. bezafibrate, fenofibrate, agents for thrombosis prophylaxis such as phenprocoumon.

The compounds of formula I, their pharmacologically acceptable acid addition salts and pharmaceutical preparations containing the compounds of formula I or their pharmacologically acceptable acid addition salts as active substances, can be used on humans by combating resp. prevention of diseases in the cardiovascular system, for example as an anti-hypertensive healing agent for the most diverse forms of high blood pressure, by combating resp. prevention of angina pectoris etc. The dosage can vary within wide limits and must be adapted to the individual condition in each case. Usually it is by oral administration per human individual to measure a daily dose from approx. 0.2 - 150 mg, preferably 1 - 30 mg. Also with other forms of application, due to the good absorption of the active substances, the daily dose is in similar quantity ranges, i.e. usually likewise at 0.2 - 150 mg per human. The daily dose is normally divided into several, e.g. 2-4 partial administrations.

The pharmaceutical preparations contain of the active substances of formula I and their pharmacologically acceptable acid addition salts usually 0.1 - 50 mg, preferably 0.5 - 10 mg per dose.

The investigation into the antianginous and antihypertensive effect of the compounds of formula I was carried out on bastard dogs of both sexes in pentobarbital anesthesia (30 - 40 mg/kg i.v.) or in urethane-chloralose anesthesia (3 ml/kg urethane-chloralose mixture i.v. = 20 mg/kg chloralose and 250 mg/kg urethane). The animals' breathing took place with a Bird-Mark-7 respirator. The end-expiratory carbonic acid content (measured with uras) was between 4.5 and 5% by volume. During the combined experiment, the animals with pentobarbital anesthesia received a permanent infusion of pentobarbital i.v. = 4 mg/kg/6 ml/h to ensure a constant depth of anesthesia. The animals with urethane-chloralose anesthesia received no permanent infusion. The infusion was given through the vena cephalica. After the preparation of the experimental animal, approx. 1 hour until all hemodynamic parameters had adjusted (steady state). Then the actual experiment began.

The systolic and diastolic blood pressure was measured peripherally in the femoral artery over a Statham pressure recorder.

A Miller-Tip catheter pushed over the carotid artery in the left ventricle provides the signal for LVEDP (left ventricular end-diastolic pressure) and heart rate. With another Tip catheter inserted above the jugular vein, mean blood pressure in the pulmonary artery was determined. The results obtained are listed in the following table.

In the table means:

LVEDP = left ventricular end-diastolic pressure

PAP = mean pulmonary artery pressure

BDm = mean peripheral blood pressure

HF = heart rate

ISDN = isosorbide dinitrate (reference substance)

A = 1,2,5-oxadiazole-2-oxide-4-methyl-3-carboxylic acid methylamide

B = 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid methoxyethylamide

C = 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid (pyrid-3-yl-methylamide).

The invention will be explained in more detail with the help of some examples.

Example 1

1,2,5-oxadiazole-2-oxide-3-methyl-4-(carboxylic acid-2-hydroxy-ethylamide)

19.2 g of 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid ethyl ester was dissolved in 50 ml of ethanol. At 20°C, a solution of 6.1 g of ethanolamine in 40 ml of ethanol is added drop by drop. The mixture is stirred for 4 hours at 20°C and cooled to 0°C. The solid is suctioned off, washed with a little cold ethanol and recrystallized from isopropanol: colorless crystals of melting point 107 - 108°C.

Analogous to this method, the following compounds can be prepared in the indicated solvents at the indicated reaction temperatures: 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid allylamide (oil) in methanol at 15°C.

1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid methylamide (melting point 89 - 91°C) in water at 0°G.

1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid ethylamide (melting point 80 - 82°C) in i-propanol at 20°C. 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid isopropyl-amide (melting point 94 - 95°C) in toluene at 50°C. 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid (2-diethyl-

in

in

aminoethylamide) (m.p. 216°C, NDS salt) in diethyl ether at reflux temperature.

1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid-(3-diethylaminopropylamide) (oil) in diethyl ether at reflux temperature.

1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid-[3-(4-o-methoxyphenylpiperazin-1-yl)-propylamide7 (m.p. 232°C, NDS salt) in toluene at 110 °C.

1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid-(4-o-methoxy-cyphenylpiperazinide) (m.p. 152 - 153°C) in chlorobenzene at 100°C.

1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid-[3-(4-o-chlorophenylpiperazin-1-yl)-propylamide? (melting point 205 - 206°C decomposition NDS salt) in toluene at 110°C.

1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid-/3-(4-o-methoxyphenylpiperazin-1-yl)-2-methyl-propylamide7 (melting point 114 - 115°C) in toluene at 10°C.

1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid cyclopentyl amide (melting point 104 - 106°C) in ethanol at 40°C. 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid cyclohexyl-amide (melting point 95 - 96.5°C) in ethanol at 60°C. 1> 2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid (2-m-toxyethylamide) (melting point 69 - 70°C) in ethanol at 20°C. 1,2-bis-[1,2,5-oxadiazole-2-oxide-3-methyl-4-carbonylamine7-ethane (melting point 195 - 200°C decomposition) in ethanol at 25°C. 1,3-bis-[1,2,5-oxadiazole-2-oxide-3-methyl-4-carbonylamino-7-propane (melting point 183 - 186°C) in ethanol at 25°C. 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid morpholide (melting point 75 - 78°C) in acetonitrile at 40°C. 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid benzylamide (melting point 91 - 93°C) in petroleum ether at 20°C.

1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid pyrrolidide (melting point 65 - 67°C) in ethanol at 15°C.

1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid (4-methyl-piperazide) hydrochloride (melting point 278 - 280°C decomposition) in methylene chloride at 25°C.

1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid dimethylamide

(melting point 70 - 72°C) in dimethylformamide/water at 30°C. 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid (pyrid-3-yl-methylamide) (m.p. 127 - 129°C) in ethanol at 25°C. Example 2

1, 2, 5- oxadiazole- 2- oxide- 4- methyl- 3- carboxylic acid methylamide

5 g of 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid methylamide is heated without solvent for 30 minutes at 190°C. After the melt has cooled, the product mixture is separated by column chromatography (eluent: methylene chloride, column filling: silica gel). The faster-flowing fraction is evaporated and stirred with naphtha. The white solid is filtered off and analyzed after drying in vacuum: melting point 57 - 59°C.

Analogous to this method, the following compounds can be prepared at the reaction temperatures indicated after the compounds: 1,2,5-oxadiazole-2-oxide-4-methyl-3-carboxylic acid ethylamide (oil) 150°C,

1,2,5-oxadiazole-2-oxide-4-methyl-3-carboxylic acid-(2-methoxyethylamide) (oil) at 220°C,

1,2,5-oxadiazole-2-oxide-4-methyl-3-carboxylic acid isopropyl-amide (melting point 65 - 68°C) at 200°C,

1,2,5-oxadiazole-2-oxide-4-methyl-3-carboxylic acid-(2-diethyl-aminoethylamide) (melting point 200 - 202°C NDS salt) at 190°C, 1,2,5-oxadiazole -2-oxide-4-methyl-3-carboxylic acid-(4-o-methoxyphenylpiperazinide) (melting point 129 - 131°C) at 200°C, 1,2,5-oxadiazole-2-oxide-4-methyl -3-carboxylic acid cyclopentyl amide (melting point 91 - 94°C) at 190°C,

1,2,5-oxadiazole-2-oxide-4-methyl-3-carboxylic acid morpholide (melting point 45 - 46°C) at 185°C,

1,2,5-oxadiazole-2-oxide-4-methyl-3-carboxylic acid pyrrolidide (oil) at 180°C,

1,2,5-oxadiazole-2-oxide-4-methyl-3-carboxylic acid-(4-methyl-piperazide (melting point of the hydrochloride 250 - 252°C decomposition) at 195°C.

The indication "NDS salt" in connection with the melting point of any of the above-mentioned compounds means that it is about the melting point of the addition compound with naphthalene-1,5-disulfoic acid.

The structures of the synthesized compounds could be confirmed by elemental analysis and by IR and NMR spectra.

Claims (3)

1. Process for the preparation of 3,4-disubstituted 1,2,5-oxadiazole-2-oxides of formula I in which R <1> in the event that R <2> means -CH3 = and in the case that R 2 is different from -CH, and has one of the meanings given above for R, R means -CH-,, 3 R means an alkylene residue -CH»-, where n means 2, 3 or 4, 4 8 n R and R° = -CH3 ," C2 H5 , R5 R = —H, —CH_, 7 R means alkyl with 1-4 C atoms, cycloalkyl with 5 - 7 C atoms, allyl, pyridylmethyl X means -(CH2 )2~ 0-(CH2 )2~ , -, -CH2 CH2 CH2 CH2 -or -CH2 CH2 CH2 CH2 CH2~ R <2> means -CH 2 1 and R means, in the event that R means -CH., one of the meanings given for R 1 with the exception of -CH^ as well as their pharmacologically acceptable acid addition compounds, characterized in that a 3-methyl-1,2,5-oxadiazole-2 -oxide-4-carboxylic acid ester of formula II in which R g means alkyl with 1-6 C atoms is reacted with an amine HZ and thereby the amine is selected such that the residue Z with the carbonyl group of the ester II forms the residue R and the compound formed is optionally transferred into an acid addition compound or optionally to produce compounds with formula Ib is heated to temperatures of 150 - 220°C, preferably 180 - 200°C and the compound formed is optionally transferred to an acid addition compound. 2. Method according to claim 1, characterized in that the reaction of the ester of formula II with the amine HZ is carried out in a solvent or dispersant at temperatures of 0°C up to the reflux temperature of the solvent or dispersant. 3. Process according to claim 1 or 2, characterized in that R g means alkyl with 1-4 C atoms, preferably methyl or ethyl.