DD209195A5 - PROCESS FOR THE PREPARATION OF 1,2,5-OXADIAZOLE-3,4-DICARBONE-SAE DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of 1,2,5-oxadiazole-3,4-dicarboxylic acid derivatives for use as medicaments, for example for the treatment of hypertension and angina pectoris. The aim of the invention is the provision of new compounds with effect on the cardiovascular system. According to the invention, 1,2,5-oxadiazole-3,4-dicarboxylic acid derivatives of the formula I in which R 1 and R 2 are hydroxyl, alkoxyl, amino or substituted amino are prepared in such a way that a 1,2,5-oxadiazol-3, 4-bis-carboxylic acid ester is reacted or that from a 1,2,5-oxadiazole-2-oxide-3,4- (carboxylic acid amide), the oxide oxygen is removed by reduction.

Description

-ι-

Berlin, 15.2.1983

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Process for the preparation of 1 ^, S-acid derivatives

Field of application of the invention

The invention relates to a process for the preparation of 1 ^, S-oxadiazole-S ^ -dicarbonsäurederivaten with valuable pharmacological properties »in particular with effect on the cardiovascular system. _y

The compounds according to the invention are used as medicaments, for example for the treatment of high blood pressure and angina pectoris.

Characteristic of the known technical solutions

There is no information on which compounds have been used to treat high blood pressure and angina pectoris ♦

There are also no details of processes for the preparation of l, 2 _i 5-oxadiazole-3,4-dicarboxylic acid derivatives known »

Object of the invention

The aim of the invention is the provision of new compounds with effect on the cardiovascular system _? System.

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

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Erfindungsgefflaß be l, 2,5-0xadiazol-3,4 ~ dicarboxylic acid derivatives of the general formula I.

P5 »oq» - «rCO-R

/ η (Χ)

and their pharmacologically acceptable acid addition compounds »

In formula I mean:

R ^{1 is} the group -OH, -OR ³ , -NH ₂ , -NHR ⁴ or -NR ⁵ R ⁵ , R ^{2 is} the group -NHR ⁴ or -NR ⁰ R ⁵ , R is an alkyl group having 1 to 4 C atoms, R is an alkyl group having 1 to 6 C atoms, a cycloalkyl group having 5 or 6 C atoms, an aralkyl group which may optionally be substituted by 1 or 2 methoxy groups, or a Beteroarylalkylgruppe, a -CH ₂ -CH ₂ - (CH ₂ ) 0CH ₃ group, wherein ra represents O or 1 * a 2-hydroxyethyl group or a basic substituted alkyl group, and R and R independently have one of the meanings

R or together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocyclic ring which may also be substituted *

3 4 Dia for R and R-standing alkyl groups may be straight-chain or branched * For R, the ethyl radical is preferred «As for R standing alkyl radicals are those having 1 to 4 carbon atoms are preferred. As cycloalkyl groups for R are cyclo-

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to call pentyl and especially cyclohexyl. For the aralkyl group standing for R, the benzyl and phenethyl groups are preferred, both of which may also be substituted in their phenyl nuclei by one or two methoxy groups. For example, suitable heteroarylalkyl groups include pyridyl-ethyl, in particular pyridyl-metbyl groups · representing R *: basically substituted alkyl groups have z * B, the radical R ⁷ R ⁸ N-CH ₀ - (CH-CH ₀ J ₀ -,

7 8 α α · Π &

in which R and R independently of one another denote straight-chain or branched alkyl radicals having 1 to 4 C atoms "preferably methyl or ethyl, and η O or preferably 1»

7 S '' ''

The radicals R and R can also, together with the nitrogen atom to which they are bonded, form a heterocyclic radical, preferably a 5- or a S-linked radical, which may also be substituted.

The radicals R and R are in particular straight-chain or branched alkyl radicals having 1 to 4 C atoms, preferably methyl or ethyl. The radicals R and R may also be

7 8

as well as the radicals R and R, together with the nitrogen atom to which they are attached, one, preferably 5 or 6-membered, optionally substituted heterocyclic

5 S ring form »For example, the radicals R and R or 7 8

R and R together with the nitrogen atom to which they are attached, a morpholino, a 1-piperazinyl, piperidino or a I-pyrrolidinyl radical "These heterocyclic residues may e.g." B ₀ by alkyl having 1 to 4 C Atoms, in particular methyl or ethyl, be substituted by phenyl, tolyl, methoxyphenyl, diinethoxyphenyl,

1 2

The novel compounds of the formula I which are identically substituted in the R and R positions and correspond to the formulas Ia and, respectively,

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Ib correspond

R ⁴ HN-OC-,.-CO-NHR ⁴ R ⁵ R ⁶ N-OC- __-- CO-NR ⁵ R ⁶

(Ia) (Ib)

can be prepared in a simple manner by reacting a l _# 2y5-oxadiazole-3,4-bis-carboxylic acid ester of the formula

R ³ O-OC-, -CO-OR ³

N N (II),

wherein R is preferably ethyl, with at least 2 moles of the amine R NH ₂ or * RR NH reacts. In general, not more than 2.5 moles of the amine need to be used. This reaction can be done by combining the components. Normally, however, it is desirable to dissolve or disperse a starting component, but preferably both, starting components in a suitable inert solvent or dispersant and to slowly, by dropping, combine the components in this form. The reaction temperatures are depending on the reactivity of the amine used -10 ⁰ C to 120 ⁰ C, in particular O ⁰ C to 120 ⁰ C, In many cases, temperatures of O to 30 C are sufficient. Suitable solvents or dispersants are z, 3, alcohols, especially those

* LV II I

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with 1 to 6 C atoms, such as ζ, B. methanol, ethanol, i- and n-propanol ,. i-, see- and tert-butanol, n- _# , i-, iso-, sec-, tert-pentanol, n-hexanol, cyclopentanols cyclohexanol; Ethers, in particular those having 2 to 8 carbon atoms in the molecule, such as diethyl ether # ,, methyl ethyl ether, di-n-propyl ether, di-isopropyl ether, methyl n-butyl ether ⁼ Ethyl propyl ether, di-butyl ether, tetrahydrofuran; 1,4-oioxane, 1,2-dimethoxyethane, bis-S-methoxyethyl ether; Polyether such _# B _# polyethylene glycols having a molecular weight up to about "600; Oligoethylene glycol diniethyl ether, such as Z ₀ 3 »pentaglyme; Crown ether, h. cyclic polymers of ethylene glycol of the formula (-OCH ₂ CHg), wherein ρ is a number ζ «Β * of 4 to 10, wherein one or more senzol rings may be fused to the ring; Aza and thiacrown ethers (coronandamines and coronand sulfides); Glycols and partially etherified glycols, such as. B "ethylene glycol, propylene glycol, Trirnethylenglykol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, Diethylenglykolraonoethyl ether; Ketones, in particular those having 3 to 10 C atoms in the molecule, such as * B * acetone, methyl ethyl ketone, methyl n-propyl ketone, diethyl katon, 2-hexanone, 3-hexanone di-n-propyl ketone, diisopropyl ketone, Di-iso-butyl ketone, cyclopentanone, cyclohexanone, benzophenone, acetophenone; aliphatic hydrocarbons, such as Z * B »low and high boiling petroleum ethers; aromatic hydrocarbons such as * B, benzene, toluene, o-, m- and p-xylene; halogenated aliphatic or aromatic hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, ethylene chloride, chlorobenzene, dichlorobenzene; Nitrites · such, B _# acetonitrile; Amides, such as 3. diroethylformamide, N-methyl

L "* L. * t Il 1

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pyrrolidone; Sulfoxides such as "B, diraethyl sulfoxide; Water. Mixtures of different solvents or dispersants can also be used »

The preparation of the bis-ester of formula II with R-C ₂ H _1. -S Z "-B" in C, Grundmannr, Chenw Ber * 9T _t (1964)> 575-578. Other bis-esters of the formula II can be prepared analogously.

The novel compounds of the formula I in which R is the group -OR, preferably -OC ₂ H-, means »and which accordingly correspond to the formula Ic,

R ³ O-OC -, -. -CO-R ²

I \

be prepared by reacting the bis-ester of formula II with less than 2 Hol »preferably with 1 to 1.1 mol, one

4 5 p

Amines of Fortsei R NH ₂ or, RR NH prepared. The reaction conditions with respect to temperature and the preferred use of a solvent or dispersing agent and the solvents and dispersants in question are the same as in the reaction of the bis-ester of formula II with 2 moles of amine. "Monoamide formation is favored by the lowest possible reactivity.

The novel compounds of the formula I in which R "denotes the hydroxyl group and which accordingly corresponds to the formula Id

L 4 L OIII:

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speak,

HO-OC

NN '< ^Id >

X ₀ /

become known from the compounds of formula Ic by per se

provides.

known hydrolytic cleavage of the R O radical.

This hydrolytic cleavage is carried out with ca, 10% sodium hydroxide dissolution.

hydroxide solution at 40 to 80 ^° C., preferably 45 to 55 ^° C.,

Novel compounds of formula I in which R ₄ means the -NbU pe and accordingly represents correspond formula Ie

-CO-R ²

N N

(Ie)

Are prepared from compounds of formula Ic by reaction with ammonia. For this purpose, the compounds of the formula Ic are dissolved or suspended in one of the abovementioned solvents or dispersants and ammonia is introduced into the solution or suspension at temperatures of from 0.degree. C. to 30.degree.

1 2

Novel compounds of the formula I in which R and R represent different amino radicals are prepared from compounds of the formula Ic by reaction with amines H ₂ NR or HNR R.

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posed. The temperatures used in this reaction and the preferably used solvents or dispersants correspond to the temperatures and solvents which are used in the preparation of the compounds Ia and Ib by reacting the bis-ester II rait least 2 moles of Arain. In the present reaction of the compound Ic, such amines are used whose amine radical -NHR or -NR R is different from the radical R. In the

1 Preparation of compounds of formula I, in which R and

2 R different amino radicals, the sis-ester II is first reacted with the less reactive, more selective amine to the compound Ic »

If the compounds of formula Ic occur only as intermediates, they need not be isolated. The bis-estrene of formula II may thus be, for example, one mole of a less reactive more selective amine NH-R or HNR R to a compound of formula Ic and immediately without isolation of the compound Ic with the second amine NH ₂ R ' ⁴ or NHR. ' Be turned over ⁵ R * ⁶ * The R ^'4, R' ⁵ and R * have eliminated the defined for R and R and R here.

but R and R ⁵ and R are compounds of the formula I in which R and R are identical, ie compounds of the formulas Ia and Ib can also be prepared from 1,2,5-oxadiazole-2-oxide 3,4-bis- (carboxamides) of the formula III

L ⁴ KO I ί ί

15 .2 * 1983 (III) AP C 07 D / 242 977/7 - 9 - 61 227/11 R ² -QC-, _Λ -CO-R ² H NN ₀ ' V

by reduction. Suitable reducing agents are based on the C of Grundmann loc. cit. method described, preferably lower trialkyl phosphites, d. h, those whose alkyl radicals have 1 to 4 carbon atoms, in an inert solvent at elevated temperature »As a reducing agent, lower trialkyl phasphines and triphenylphosphine are also suitable. Suitable solvents are z, B, aliphatic or aromatic hydrocarbons, such as z, B, low and high boiling petroleum ethers, benzene, toluene or a xylene, or halogenated hydrocarbons, such as "suitable. B. chlorobenzene" The reaction temperatures are 50 to 150 ⁰ C. , preferably 100 to 140 ^° C. * Depending on the required reaction temperature, a solvent with a corresponding boiling point must be selected »

The required starting compounds of the formula III can be prepared from hydroxamoyl chlorides of the formula IV by HCl elimination followed by dimerization:

2R ² -CO-C-C1 base y (III) NOH -2HC1 (IV)

The reaction is carried out in a suitable solvent or dispersant, such as, for example, dimethylformamide, dimethyl sulphoxide,

ί ι

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N-methylpyrrolidone, lower alcohol such as methanol, ethanol, but preferably in water. Also, mixtures of different solvents or dispersants, in particular homogeneous, but also heterogeneous mixtures with water, such as. S. water / ethanol or water / diethyl ether, can be used. The reaction is generally carried out at 0 to 50 ^° C., preferably at 10 to 25 ^° C.

After the introduction of the compound IV in the solvent or dispersant, the reaction often proceeds by itself. However, it can be significantly accelerated by the addition of a base which binds the split-off hydrogen chloride. As such a base z. B. be used: primary, secondary or tertiary organic amines, such as. B ^ methylamine, dimethylamine trimethylamine, ethylamine, diethylamine ,. triethylamine; pyridine; Alkali hydroxides, such as, for example, sodium or potassium hydroxide; Alkaline carbonates and alkali bicarbonates, such as. B, potash, soda and sodium bicarbonate; Alkaliacetates, such as, for example, sodium acetate * soda and sodium bicarbonate are preferred. The base may also be added in the form of a solution (eg, an aqueous solution as in the case of lower organic amines) or a dispersion of the solution or dispersion of compound IV. Because of the incoming reaction, gradual or portionwise addition of the base and stirring of the reaction mixture are desirable. The base is preferably added in normal amount (to 2 moles of the compound IV 2 moles of base) ,, optionally with an up to 20% excess. After completion of the reaction, the formed compound of formula III is separated.

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The compounds of the formula IV can be prepared by various methods known per se, for example by first reacting diketene V with an Arain VI to give an acetoacetamide VII (cf. Z, 8, US Pat. No. 2,174,239):

CH _p = C - O '

^ I I +

CH ₂ -C = 0

(V) (VI) (VII)

The reaction between the compounds V and VI is carried out in a suitable solvent such. B »water, or an alcohol, usually at temperatures of 10 to 50 C, preferably at room temperatures, carried out» The acetoacetamide VII is oxidized by in situ generated nitrous acid in a suitable solvent, such as water, glacial acetic acid or an alcohol, wherein the 0x ± m VIII arises:

COR ²

~ ENT _p t

H ₃ CCOCH ₂ COR ^> H CCO-C = NQH

(VII) (VIII)

This reaction is z. , At a pH value of not 'Veniger than 4.0 and at temperatures of 10 to 50 ⁰ C, preferably at room temperature ,, performed "The nitrous acid is most readily produced from sodium nitrite and hydrochloric acid. The oxime VIII is then dissolved in a suitable solvent.

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such as water or an alcohol z. Example, at Tern- "temperatures of +10 ⁰ C to +70 ⁰ C, preferably 30 to 50 ⁰ C, chlorinated, wherein the hydroxamoyl ehlorid IV formed.

The hydroxanioyl chloride IV can be prepared from the Acetessigaraid VII auh by reversing the order of oximation and chlorination. During chlorination, the acetoacetamide VII first forms the chlorine

compound IX; CH_COCHClCOR, which is then converted by reaction with nitrous acid in the compound IV.

The top management of aceto-oligomers VII in compounds of formula IV according to the abovementioned possibilities is z, B, described in OE-AS 19 63 061, starting from Diksten V and the amine VI, the starting compounds III according to the above-mentioned synthetic steps without isolation of Intermediates are prepared in a single reaction vessel,

The compounds I which have a basic side chain form salts or acid addition compounds with inorganic or organic acids. Examples of such acids are: hydrochloric, hydrobromic, phosphoric, sulfuric, oxalic, lactic, tartaric, acetic, Salicylic, Benzoic, Lemonic, Ascorbic, Adipic and Naphthalenedisulfonic Acid The acid addition compounds are obtained in a known manner by combining the components in a suitable solvent or dispersant »

The compounds of the formula I and their phannacologically

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ingestible acid addition compounds have valuable pharmacological properties is particularly pronounced effect on the cardiovascular system, lower low-dose blood pressure, reduce peripheral resistance and cause a reduction dss Pulroonalarteriendrucks unchanged heart rate to a decrease in cardiac work, Compounds of the formula I and their pharmacologically acceptable acid addition salt can therefore be administered in humans as a cure for high blood pressure and angina pectoris and for the prophylaxis of anginal attack by itself, in mixtures with each other or in the form of pharmaceutical preparations containing an enteral or permit parenteral administration and which contain as active ingredient an effective dose of at least one compound of formula I or of an acid addition salt thereof, in addition to customary pharmaceutically acceptable excipients and additives,

Remedies can be administered orally, z, B, in the form of pills, tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, syrups, emulsions or suspensions or aerosol mixtures. However, the administration may also be rectal, z, B, in the form of suppositories, or parenterally, z, B, in the form of injection solutions, or percutaneously, z, 8, in the form of ointments or tinctures.

For the preparation of the pharmaceutical preparations, pharmaceutically inert inorganic or organic carriers can be used. For the production of pills, tablets, dragées and hard gelatine capsules, it is possible to use, for example, lactose,

i II

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Maize starch or derivatives thereof, TaIk ₄ stearic acid or its salts etc "use" carriers for soft gelatin capsules and suppositories are z. B, fats, waxes, semi-solid and liquid polyols, natural or hydrogenated oils etc. Suitable carriers for the preparation of solutions and syrups are, for example, water * sucrose, invert sugar, glucose, polyol etc. * As carriers for the preparation of injection solutions z, B ₀ are suitable . Water, alcohols, glycerin, polyols, vegetable oils etc.

In addition to the excipients and carriers, the pharmaceutical preparations may also contain additives such as, for example, fillers, extenders, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, Flavoring or flavoring, thickening, diluting agents, buffering agents, further solvents or solubilizers or agents for obtaining a depot effect, as well as salts for varying 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 other therapeutically active substances »

Such other therapeutically active substances are, for example: β-receptor blockers, such as, for example, "propranolol ₄ pindolol, metoprolol" vasodilators, such as, for example, B. Carbochroraen; Sedatives such as barbituric acid derivatives ₃ 1,4-benzodiazepines and meprobate; Diuretics, such as chlorothiazide; the heart ionizing agent, such as B. Digitalis preparations; hypotensive agents, such as. 8th"

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Hydralazine, dihydralazine, prazosin, clonidine, Rauwolfia alkaloids; Agents that lowered the level of fatty acid in the blood, such as, for example, bezafibrate, fenofibrate; Antithrombotic agents, such as phenprocoumon B ₉ .

The dosage may vary within wide limits and must be adapted to individual circumstances in each individual case. "In general, when administered orally per person per day, a daily dose of active substance of about 0.4 to 100 mg, preferably 1 to 20 mg, is appropriate other application forages, the daily dose is because of the good absorption of the active ingredients in similar amounts ranges, d * h * in general also at 0.4 to 100 mg / human (per kg of body weight, this corresponds to a daily dose of about 0.005 mg to 1.4 mg, preferably from 0.013 mg to 0.28 mg). The daily dose is normally "divided B _# 2 to 4, part administrations" into several, for the pharmaceutical preparations contain the active ingredients per dose are generally from 0.1 to 50 mg, preferably 0.5 to 10 rag.

Investigations on the antianginal and antihypertensive effects of the compounds of formula I have been made on bastard dogs of both sexes in pentobarbital anesthesia (30 to 40 mg / kg i, v.) Or in urethane-chloralose anesthesia (3 ml / kg urethane-chloralose- Geraisch i. V "= 20 mg / kg chloralose and 250 rag / kg urethane) carried out, The respiration of the animals was carried out with a Bird-Mark-7, Respirator. The end-expiratory carbon dioxide content (measured with an ultra-absorption recorder) was between

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see 4.5 and 5%, -% " During the entire experiment, the animals with pentobarbital anesthesia received a continuous infusion of pentobarbital i, v. = 4 rags (in 6 ml) / kg / h to ensure a constant depth of anesthesia; the animals with urethane-chloralose anesthesia received no continuous infusion. The infusion was given through the cephalic vein. After preparation of the test animal, it was waited for approximately 1 hour until all hemodynamic parameters had set (steady state). After that, the actual attempt was started.

To determine the mean blood pressure (= BD), the systolic and diastolic blood pressures were measured peripherally in the arteria feraoralis via a Statham pressure transducer. A Millartip catheter pushed over the arteria ca red into the left ventricle provided the signal for the left ventricular end-diastolic pressure (= LVEDP) and the heart rate (= HF). With a second, inserted via the jugular vein tip catheter, the mean blood pressure (= PAP) was detected in the pulmonary artery. The results obtained are given in the following table:

CO-R ²

τ-τ

NN

cn

04

K) Q H H

NUlM

ΙΩ CL Ti H <O

C • Η

U. JQ

C5

CS

ο ε

• Η -i £

ο o

Q 2

CN i

 f

in

ro

ro I

ro J

in

tn +

in

CM i

in

- m

co

Ti

in

in in in in ro ro i t t

OJ I

in

CM 1

CM 2

Ti I

O O

ro ro

i i

Ti I

CM I

ro H I OJ OJ OJ K) co vi i XXX X d α o-o-o .O J I O I X j X 1 HT j. ! K) 1 _0J  Σ. O X X Ö ti t CM o-o OJ X ί X O K) O to X O O τ; O I χ ci X Z CM * £ "7 ™" -r " O ö J Oil UO O H Ü CM 5 ro O O χ- ο

L -r L ₁ υ ι J

15 · 2 "in 1983

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In the table mean:

LVEDP = left ventricular end-diastolic pressure PAP = mean pulmonary artery pressure BD = mean peripheral blood pressure HR = heart rate

ISDN = isosorbide dinitrate (reference substance)

embodiment

The following examples serve to further illustrate the invention, wherein percentages are by weight, Zers. means decomposition,

Example 1 l _j? 2 ₁ 5-oxadiazol-3 _> 4-bis * »{carboxylic acid methylamide}

8.0 g 1.2 _# 5-0xadiazol-2-oxide-3,4-bis- (carbonsäuremethylaraid) and 7.0 g of triethyl phosphite are dissolved in 100 ml of toluene and 24 hours refluxed · Dia still hot solution is filtered and the filtrate is cooled to room temperature to precipitate a colorless precipitate which is recrystallized from 60 ml of isopropanol: 5.3 g (72 % of theory), m.p. = 161-163 ⁰ C _1. Prepared according to the yield the reducing agent used, the solvent and the reaction temperatures are given in% "The following abbreviations are used for the reducing agents:

TBP = tributyl phosphite, TEP = triethyl phosphite, TMP = trimethyl phosphite, TIP = triisopropyl phosphite, TPP = triphenyl phosphine:

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l _f 2 _J 5-Oxadiazole-3,4-bis (carboxylic acid isopropylamine), mp = 169 to 173 ⁰ C (87 % of theory), TBP, chlorobenzene, 130 ⁰ C; 1,2,5-0xadiazol _J-3 4-bis (carboxylic acid propylamide), mp = 127 to 129 ⁰ C (71% of theory), T3P, chlorobenzene, 130 ⁰ C; l, 2,5-0xadiazol-3,4-bis (carboxylic acid morpholide), mp = 112 to 114 ⁰ C (30% of theory), TEP, toluene, 110 ⁰ C; l, 2,5-0xadiazol-3,4-bis- (carbonsäurepiperidid), mp = 79-30 ⁰ C (77% of theory), TEP, toluene, 110 ⁰ C; l, 2,5-0xadiazol-3,4-bis (carboxylic acid-cyclohexyla nid!), mp = 151 to 153 ⁰ C (62% of theory), TBP, o-dichlorobenzene, 150 ⁰ C;

1, 2.5 ~ oxadiazole-3,4-bis (carboxylic acid dimethylamide), mp = 128 to 130 ^° C (75 % of theory), TMP, petroleum ether, 50 ^° C; l, 2,5> Gxadiazol-3,4-bis (carboxylic acid diethylamide), mp = 116 to 118 ⁰ C (78% of theory), TMP, toluene, 80 ⁰ C; l, 2,5-0xadiazol-3,4-bis (carboxylic acid butylamide), Fp 112 to 114 ⁰ C (80% of theory), TEP, toluene, 110 ⁰ C; l, 2,5-0xadiazcl-3 ₄ 4-bis (carboxylic acid ethylamide), mp = 124-125 ⁰ C (76% of theory), TPP, toluene, 110 ⁰ C; ' 1,2,5-Qxadiazoi-3,4-bis (carboxylic acid 2-methoxyethylamide), mp = 74 to 75 ⁰ C (70% of theory), TPP, toluene, 110 ⁰ C; l, .2,5-0xadiazol-3,4-bis- (carbonsäurs ~ teri _{<-butylainid)} · mp 136 to 138 ⁰ C (85% of theory), TBP, xylene, 140 ⁰ C; l, 2,5-0xadiazol-3 .4-bis (carboxylic acid sec-butylamide), mp = 129-130 ⁰ C (72% of theory) /.TBP, xylene, 150. ⁰ C; l, 2,5-oxadiazole-3,4-bis- {carbonsäurecyclopentylamid), mp = 163-165 ⁰ C (73% of theory), TIP, xylene, 120 ⁰ C; l, 2,5 ~ oxadiazole-3,4-bis- (carbonsäurepyrroiidid), mp = 87-88 ⁰ C (71% of theory), TEP, toluene, 110 ⁰ C;

(68% of theory), TBP, Llgroin, 90 ⁰ C.

Ltlti 1 1 I

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The required starting compound!, ^, S 3 »4-bis (carboxylic acid inethylaraid) can be prepared as follows:

12.5 g of methylamine are dissolved in 400 ml of water, 34 g of diketene are slowly added dropwise at room temperature (20 C), whereby a stable pH of 7 is established. In the resulting solution then 28 g of sodium nitrate are dissolved. Concentrated hydrochloric acid (40 g is then added dropwise so that the pH of the solution does not fall below 4. Then 30 min, stirred for a long time and then introduced 30 g of chlorine at 20 to 40 ^° C. After cooling the solution to -10 It is cooled to ⁰ C and the solid is filtered off with suction, it is slurried in 100 ml of water and cautiously added portionwise with 33.6 g of sodium bicarbonate at 20 ^° C. The solution now has a pH of 7.5 to 8 Cooled OC and the precipitated solid is filtered off and recrystallized from isopropanol. Colorless crystals of mp, 164-165 C,

In a corresponding manner, the following ^{1,2,5-oxadiazole-2-oxide-3:} manufactured 4 ~ bis-carbonsäureamlde:

? Up-dia ethylamide (mp 127 to 129 ⁰ C.), Bis-diethylamide (oil)> Up-roorpholid (mp, 137 to 139 ⁰ C) -, bis-butylamide (mp, to 92 ⁰ C), bis pyrrolidide (Fp, 106 to 108 ⁰ C), bis-e.thylamid (m.p., 116-117 ⁰ C), bis-isopropylamide (m.p. * 128-131 ° C), bis ~ (2-methoxyethyl) amide (Fp, 94-95 ⁰ C), Bispiperidid (m.p., 115-116 ⁰ C), bis-tert, -butylatnid (mp. 167 ° C) _r bis-cyclohexylaraid (m.p. 137 to 139 ⁰ C _t),

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8IS-sec »butylamide (oil), bis-cyclopentylamid (m.p. * 144 to 146 ⁰ C), bis-propylamide (m.p., 117-118 ⁰ C), 3is- (3-methoxypropyl) amide (oil).

The structures of the synthesized compounds are confirmed by elemental analysis and by the IR and NMR spectra *

Example 2

1.2 ₁ 5-Qxadiazol-3,4-bis ~ icarbonsäure-C2-pyridyl roethyl) -atnid * |

10.7 ggl _# 2, 5-oxadiazole-3 _# 4-bis (carboxylic acid ethyl ester) are initially charged in 100 ml of ethanol. The solution of 10.8 g (2-pyridylmethyl) -amine in 50 ml of ethanol is slowly added dropwise at room temperature and allowed to stand for 4 hours at 20 ⁰ C »After concentration is recrystallized from isopropanol (100 ml): 14.8 g colorless needles (86 % of theory), mp = 108 to 110 ⁰ C * are prepared analogously to this example: l, 2,5-oxadiazole-3,4-bis (carbic acid tert-butylamide), Fp, = 135 to 138 ^° C (71 % of theory); 1,2,5-oxadiazol-3,4-bis carboxylic acid (2- {3, 4 ~ j diinethoxyphenyl ethyl) -amide J, mp = 105 to 107 ⁰ C (87% of theory). 1,2,5-oxadiazole-3,4-bis (carboxylic acid uriethoxyethyl amide), mp, = 74 to 75 C (82 % of theory); 1,2,5-oxadiazole-3,4-bis-carboxylic acid- (4-fethethoxybenzyl) -raathylamide3 _t Fp, = 115 to 117 C (89% of theory); l _# 2 _J 5-oxadiazole-3,4-bis (carboxylic acid ethanolamide), mp, = 93 to 96 ⁰ C (78 % of theory),

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AP C 07 D / 242 977/7 - 22 - 51 227/11

Example 3

1 2 _t 5-oxadiazole »3'Carbonsaureethvle ⁱ art" 4 * "carboxylic acid" · isopropylamide

10.7 g of 1 _J 2 _i 5-oxad.tazol-3,4-bis-carboxylic acid Ethyl3Ster be presented in 100 ml of ethanol and the mixture was cooled to 0 ⁰ C »This is now slowly the solution of 3.0 g of isopropylamine in 50 ml ethanol dripped "The reaction mixture is kept for 2 hours at 0 ⁰ G and then allowed to stand at 20 ⁰ C overnight and then concentrated on a rotary evaporator. The preparation is carried out via a chromatographic Saulentrennung (silica gel Methylsnchlorid _r) "The second fraction is collected * and after evaporation of the solvent, the oily residue from toluene / petroleum ether umkristallisii (23% of theory) *

recrystallized ether "Fp, = 70 to 72 ⁰ Cy Yield: 2 _ä 5 g

Analogously to this example can be prepared:! ^, S-Qxadiazol-S-carbonsäureeihylester ^ -carboxylic acid -S - fN ^ -raethoxyphenyl-piperazinol-propylamide, Fp * (HCl-SaIz) = 191 to 195 ⁰ C (46 % of Theory); £ i _t 2.5 Qxadiazol-3-carboxylate-4-carbonsäureji-N-methylpiperazide, m.p. _# (HCl salt) = 131 to 133 ⁰ C (33% of theory),

Example 4

1 ^, S-oxadiazole-S-carboxylic acidisop.propylamid - ^ - carboxamide

2.0 g of 1 _J 2 _, 5-oxadiazole-3-carboxylic acid ethyl ester-4-carboxylic acid isopropylamide are dissolved in 50% ethanol. Araraia gas is added to this solution while cooling to saturation.

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AP C 07 D / 242 977/7 -23- Sl 227/11

passes ♦ The mixture is allowed to stand for 2 hours at room temperature, concentrated and the remaining solid recrystallized as isopropanol. 1.1 g _t Fp ₉ = 173 to 176 ⁰ C,

Example 5

Sugar-coated pills can be prepared according to the following recipe:

l, 2,5-oxadiazole-3- _i- 4-bis (carboxylic acid cyclohexylaraid) 1 rag

Grain starch '100 mg

Lactose 50 rag

Secondary Ca.leiumphosph.at. ... 30 mg

Soluble starch 3 mg

Magnesium stearate 2 mg

Colloidal silica. 4 rag

200 rag

Example 6

Tablets can be prepared according to the following recipe:

1,2,5-oxadiazole-3- _i- 4-bis (carboxylic acid diiaethylamide) 2 mg

Lactose SO rag

Grain starch 30 mg

Soluble. Starch 4 mg

Magnesium stearate. 4 mg

100 mg

Claims (6)

Erfindunpsanspruch 1. A process for the preparation of 1,2 _# 5-oxadiazole-3,4-dicarboxylic acid derivatives of the formula I. R ¹ - OC -, - CO-R ² NN wherein R * -the group -OH, -OR ³ , -NH ₂ , -NHR ⁴ or -NR ⁵ R ⁶ , R ^{2 is} the group -NHR ⁴ or -NR ^ R ⁶ , R is an alkyl group with 1 to 4 C atoraene, 2. The method according to item 1, characterized in that the Starting compounds are selected so that for 3. The method according to item 1, characterized in that & Starting compounds are selected so that dia for 4. The method according to item 1, characterized in that the starting compounds are selected so that the for 15,2.1983 AP C 07 D / 242 977/7 - 25 - 51 227/11 R standing basically substituted alkyl group, a R Fl N-CH ₀ - (CH ₀₎ -CH _O moiety where Ra O or 1 j 2 ^x ο - --- --- --- - - · · ' and R and R represent alkyl radicals having 1 to 4 carbon atoms or together with the nitrogen atom to which they are attached denote a 5- or 5-membered heterocyclic radical which may also be substituted. , 4
R standing heteroarylalkyl group is a Py-ridylnethylgruppe. 4
R standing aralkyl group is a senzyl or phenethyl group, which is optionally substituted in * core with a methoxy or with 2 methoxy substituted. 4 5 6 or another Arain R NH ₉ or RR NH implemented or hydrolyzed to cleave the R O group or that of a 1,2,5-oxadiazole-2-oxide ~ 3,4-bis ~ (carboxylic acid) of the formula III N N the oxide oxygen is removed by reduction and the resulting compound of the formula I is converted optionally in a conventional manner into an acid addition compound, Own or 4 -from R together with the nitrogen atom to which they are attached form a saturated heterocyclic ring which may be substituted, or its pharmacologically acceptable acid addition compounds, characterized in _t that a l, 2,5-oxadiazol-3, 4-bis-carboxylic acid esters of the formula II R ³ O-OC--. -CO-OR ³ NN i ¹¹ ) "I am f. 02/15/1933 AP C 07 D / 242 977/7 - 25 - 61 227/11 is reacted with at least 2 moles of an amine R NH- or RR NH, or with less than 2 moles, in particular 1 to 1.1 moles, of a Aaiins R ⁴ NH ₂ or R ⁵ R ⁶ NH is reacted and optionally subsequently with NH . 4
R is an alkyl group having 1 to 6 C atoms, a cycloalkyl group having 5 or 6 C atoms, an aralkyl group which may optionally be substituted by 1 or 2 methoxy groups, or a heteroarylalkyl group _{t is} a -CH ₂ -CH ₂ - (CH ₂ ) -OCH group, wherein ra represents 0 or 1, a 2-hydroxyethyl group or a basic substituted alkyl group, and R and R independently of one another are one of the meanings 5. The method according to item 1, characterized in that the Aüsgangsverbindungen are selected so that the 1,2,5-oxadiazole-3 _# 4-bis (carboxylic acid diraethylamid) is formed, 6 "method according to item 1", characterized in that the starting compounds are selected so that the 1 _J 2 "-, _# 5-oxadiazole-3 _i 4-bis (carboxylic acid cyclohexylamide) is formed,