DD298913A5 - PROCESS FOR PREPARING N-SUBSTITUTED 3-AMINO-PRYROLES - Google Patents

Abstract

The invention relates to a process for the preparation of N-substituted 3-aminopyrroles of the general formula I, which are largely new and have previously unknown pharmacological properties in this class of substances, in particular anticonvulsive or analgesic action. The aim of the invention is to develop new N-substituted 3-aminopyrroles, in particular those having anticonvulsant or analgesic properties hitherto unknown in this class of substances. According to the invention, N-substituted 3-aminopyrroles of general formula I are obtained by cyclization of trimethinium salts. The compounds have pronounced anticonvulsive and analgesic effects. Formula I {anticonvulsant; Analgesic; Drug; CNS effectiveness; 3-aminopyrroles; manufacture; cyclization; Trimethiniumsalze; Starting materials}

Description

US 4,198,502). Six representatives of S-morpholino-arylpyrrolecarboxylic acid esters having a highly confined substituent pattern have been prepared by cyclization of 3-alkoxycarbonyl-methylamino-2-arylthioacryic acid morpholides (A. Knoll, J. Liebscher: Khim Geterotsikl Soedin 1985, 628). About a pharmacological effect of such compounds is not yet known. However, З-Атіпо-4-arylpyrroles, whose amino group is unsubstituted, were obtained by reduction of related 3-nitropyrroles (J.M. Tedder, B. Webster: J. Chem. Soc. 1960, 3270).

3-Amino-2,4-diphenylpyrrole is formed in the condensation of phenacylamine with itself (S.Gabriel: Ber. Dtsch. Chem. Ges.

41 [1908] 1127).

The known processes do not describe any amino-substituted З-Атіпо-4-arylpyrroles possessing an anticonvulsant activity. The substituent variability of the known processes is severely limited.

The known anticonvulsants have the disadvantage of undesired side effects (eg neurotoxicity).

Object of the invention

The object of the invention is to develop a process which makes it possible to make available N-substituted 3-aminopyrroles having pharmacological properties hitherto unknown in this class of substances.

Explanation of the essence of the invention

The object of the invention is the development of a process for the preparation of N-substituted 3-aminopyrroles with pharmacological properties not previously known in this class of substances, in particular with anticonvulsive or analgesic action. The aim is to reduce side effects, eg. As a lower neurotoxicity, to achieve than in the current conventional anticonvulsants

 According to the invention, this object is achieved in that N-substituted 3-aminopyrroles of the general formula I,

R ³ R ⁴

in the

R ^{1 is} hydrogen, an unsubstituted or substituted alkyl, an unsubstituted or substituted cycloalkyl, aralkyl, an unsubstituted or substituted aryl or hetaryl, an acyl, alkoxycarbonyl, an N-ung, N-mono- or N, N-disubstituted aminocarbonyl or an aminothiocarbonyl,

R ^{2 represents} hydrogen, formyl, acyl, oxycarbonyl, alkoxycarbonyl, aryloxycarbonyl, an N-unsaturated, N-mono or N, N-disubstituted aminocarbonyl or aminothiocarbonyl, an unsubstituted or substituted aryl or hetaryl radical, a cyano or nitro group,

R ^{3 is} hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aralkyl, an unsubstituted or substituted aryl or hetaryl radical

R ^{4 is} identical or different from R ³ for substituted or unsubstituted alkyl, cycloalkyl, aralkyl, an unsubstituted or substituted aryl or hetaryl radical or R ³ and R ⁴ together for an alkyl bridge, which may also contain oxygen, sulfur or nitrogen as ring atoms,

R ^{5 is} an unsubstituted or substituted aryl or hetaryl radical

or R ⁵ and R ⁶ together represent an alkyl bridge and R ^{6 represents} hydrogen, an alkyl or aryl radical or a halogen, are prepared by reacting an enamine of the general formula II,

R ⁶

R ¹ NC = CH-R ⁶ II

CH ₂ R ²

with the meaning explained for R ¹ , R ² , R ⁸ and R ⁶ or R ⁵ / R ⁶ with an iminium salt of the general formula III

Y ³ -C = N ⁺ R ³ R ⁴ Y "III

Y '

with the meaning explained for R ³ and R ⁴ or R ³ / R ⁴ and in Y ³ and Y ^{4 are the} same or different leaving groups, such as chlorine, amino groups, Alkylmercapto, trifloxy or alkoxy groups, and Y ~ an acid residue anion, for example a halide, a sulfonate, a sulfate or a triflate, and optionally reacted with a base, for example an amine, an alkali or alkaline earth metal hydroxide or hydride, an alkali metal carbonate or a metaHamide.

The compounds according to the invention are methyl 4- (p-chlorophenyl) -3-morpholinopyrrole-2-carboxylate, methyl S-morpholino-phenylpyrrole-1-carboxylate and ethyl ester, 3-morpholino-4- (p-tolyl) - pyrrole-2-carboxylic acid methyl and ethyl ester and the 4- (p-anisyl) -3-morpholinopyrrol-2-carboxylic acid methyl ester new. The

Compounds according to the invention exhibit a high anticonvulsant effect in various spasmodic models and are distinguished by low toxicity and, above all, a significantly higher protective index than currently known commercial anticonvulsants. The anticonvulsant effect is surprising, since hitherto no such effect has generally been described for 3-aminopyrroles. The new active compounds can be converted in a known manner into the customary formulations, such as, for example, tablets, capsules, dragees, granules or solutions using inert, non-toxic pharmaceutically suitable excipients or solvents.

Enamines of the general formula II can be prepared in a known manner from corresponding carbonyl compounds and amines.

The invention will be explained below in some embodiments.

embodiments

example 1

Synthesis of N-substituted 3-aminopyrroles of the general formula I

The N-substituted 3-aminopyrroles of general formula I prepared according to the various variants are compiled in Table 1.

option A

A mixture of 10 mmol enamine of the general formula II, 12 mmol iminium salt of the general formula limit Y ³ = Y ⁴ = Y = Cl and 20 ml methylene chloride is refluxed for 2 hours. Then 4 ml of triethylamine are added. After heating for a further 2 hours under reflux, the cooled mixture is poured onto ice. The end product is filtered off and recrystallized.

Variant B

A mixture of 10 mmol of enamine of the general formula II, 12 mmol of iminium salt of the general formula III (Y ³ = ethylmercapto, Y ⁴ = methylmercaptone Y "= methoxyolate), 15 ml of acetonitrile and 4 ml of α, S-diazabicycloSAOJ-undecene is heated under reflux for 5 hours. After cooling, the solution is concentrated to half the volume and mixed with a little water. The 3-aminopyrrole of general formula I is filtered off, washed with a little water and recrystallized.

Variant C

A solution of 10 mmol of enamine of general formula II, 10 mmol of iminium salt of general formula III with Y ³ = morpholine and Y ⁴ = Cl, and Y "= chloride in 10 ml of acetonitrile is heated under reflux for 3 hours After adding one of 0.5 g of sodium and The sodium carbonate solution is refluxed for a further 10 minutes and the cooled reaction mixture is poured onto ice, neutralized and the final product is filtered off with suction and recrystallized.

TABLE 1 The 3-aminopyrroles of the general formula I prepared according to the different variants

Ser. R ¹ R ² R ³ R ⁴ R ⁵ R ^s Mp. Ausb./ No. variant ° C % 1-1 H CO ₂ CH ₃ CH ₃ CH ₃ C ₆ H ₅ H 136-137 38 / B (Methanol) 1-2 H CO ₂ CH ₃ (CH ₂ I ₂ O (CH ₂ I ₂ C ₆ H ₅ H 179-181 47 / A (Methanol) 1-3 H CO ₂ CH ₃ (CH ₂ I ₄ C ₆ H ₅ H oil 45 / A 1-4 CH ₃ CO ₂ CH ₃ (CH ₂ J ₂ O (CHj) ₂ C ₆ H ₅ H 86-88 34 / C (Methanol) 1-5 CH ₂ CO ₂ CH ₂ CH ₃ CO ₂ CH ₃ (CH ₂ I ₂ O (CH ₂ I ₂ C ₆ H ₅ H 97-98 32 / A (Methanol) 1-6 H CO ₂ CH ₃ (CH ₂ ) ₂ O (CH ₂ ) ₂ 4-CIC ₆ H ₄ H 192-193 41 / C (Methanol) 1-7 H COCH ₃ (CH ₂ I ₂ O (CH ₂ I ₂ 4-CIC ₆ H ₄ H 172-173 29 / B (Methanol) 1-8 H CO ₂ CH ₂ CH ₃ HC ₆ H ₅ (CH ₂ I ₄ 192-194 26 / B (Ethanol) 1-9 H CHO (CH ₂ I ₂ O (CH ₂ ), 4-CIC ₆ H ₄ H 208-210 29 / A (Methanol) 1-10 H CO ₂ CH ₃ (CH ₂ CHjbNCO-fur-2-yl 4-CIC ₆ H ₄ H 234-236 / A (Acetonitrile)

Example 2

Determination of protection against maximal electroconvulsive (MEK)

By electrical stimulation of the front paws with a TUR stimulation current device, type RS 12 (pulse frequency 35Hz, pulse width 20 ms, duty cycle 1: 1, group duration between 400 and 600 ms, current strength of the square pulses 5OmA) becomes in mice with a weight of 18-22g KM triggered a stretch cramp of the hind limbs.

Anticonvulsants protect the animals from the maximum electro convulsions.

Results:

Compound I-6: ip administration: Eo ₅₀ = 3.9 10 ~ ⁵ mol / kg po: E ₀₅₀ = 4.5 10 ~ ⁵ mol / kg

Compound I-3: ip administration: 5 10 ~ ⁴ mol / kg: 70%

Comparative values: "Carbamazepine": ip administration: _Low = 4.3 · 10 ~ ⁵ mol / kg

Example 3 Determination of the effect in the pentetrazole-induced spasm

Intravenous injection into the tail vein of mice (18-22g BM) immediately causes a spasm of the hind limbs. The suppression of this spasm image is considered a criterion for an anticonvulsive effect of the tested substances.

Results:

Compound I-6: For IP administration: E o = _D6 4,5-10 ~ ^Б mol / kg for po administration: Edm = 1.5 10 ^-4 mol / kg

Example 4 Determination of the seizure threshold

By infusion of 100mg / kg pentetrazole (infusion rate of 36ml / h) via the tail vein the first clonic convulsions (myoclonic convulsions) occur in mice (18-22g BM). Prolongation of the duration of infusion (in s) to the onset of convulsions compared to control animals is considered to increase the pentetrazole seizure threshold and thus as an anticonvulsant effect of the tested substances.

Results:

Compound I-5: ip at 5 x 10 ~ ⁴ mol / kg: 20.4% increase in seizure threshold Compound 1-4: ip at 5 x 10 ~ ⁴ mol / kg: 19.4% increase

Example 5 Determination of the orienting lethal dose

Mice (18-22g KM) receive the substances to be tested in doses of 5 x 10 ^"4, 10" ^3, and 5 × 10 ^-3 mol / kg BW. 24 hours post applicationem the lethality of the animals is determined.

Results:

Compound 1-6: oLD greater than 5 x 10 ^-3 mol / kg

Example 6 Determination of the analgesic effect with the Hot Plate Test

Mice (18-22 g BM) are placed on the hot plate at 56 ° C 30 minutes after administration of the test substances, and the reaction time to this thermal pain stimulus is determined. An extension of the reaction time of substance-treated animals compared to control animals is considered as an analgesic effect.

Results:

Compound I-2: po at 10 ~ ³ mol / kg: 90% inhibition (30 min pa)

Analgin 55% inhibition

Example 7 Determination of the analgesic effect with the acetic acid writhing test

By i. p. Administration of 0.6% acetic acid in mice (18-22g KM) causes writhing. A measure of the potency of a substance is the reduction in the number of writhing reactions of treated animals compared to the control group. In addition to analgesic compounds also various CNS-effective compounds lower the writhings.

Results:

Compound I-2: po at 10 ~ ³ mol / kg 71.3% inhibition

Analgin: po at 10 " ⁴ mol / kg 50% inhibition

Example 8 Determination of neurotoxicity with the torsion bar model

Trained mice (18-22g KM) are placed after substance application for 1 min on the torsion bar (5 revolutions / min). As a measure of a substance effect is the premature dropping of the torsion bar. The protective index is the quotient of TD ₆₀ ZED ₅₀ MEK.

Result:

Compound I-6: TD _S0 = 1.4 × 1 (Γ ³ mol / kg, protective index = comparative value:

Carbamazapin: TD ₆₀ 2.2 x 10 ^-4 mol / kg Protective Index = 5.1

Example 9 Application Forms The following recipes are suggested for the application, among others:

Capsules 3-Aminopyrrole of the general formula I is suspended in the required amount in polyethylene glycol and in a gelatin mixture of the composition

Gelatin 1 part by weight

Glycerol 5 parts by weight

Water 2 parts by weight

incorporated.

capsules

A mixture is made with the following components:

Lactose 5 parts by weight

Potato starch 5 parts by weight

Magnesium stearate 1 part by weight

The appropriate amount of the substance of general formula I is added to this mixture.

The above examples are intended to illustrate the invention without limiting it. Other preparations are possible as dragees, tablets, lozenges, granules, powders, aqueous suspension, syrup and the like.

Claims (1)

1. A process for the preparation of N-substituted S-aminopyrroles of the general formula I, R ⁵ NR ³ R ⁴ R ¹ in the R ^{1 represents} hydrogen, an unsubstituted or substituted alkyl, an unsubstituted or substituted cycloalkyl, aralkyl, an unsubstituted or substituted aryl or hetaryl radical, an acyl, alkoxycarbonyl, an N-unsaturated, N-mono- or Ν, Ν-disubstituted aminocarbonyl or an aminothiocarbonyl, R ^{2 is} hydrogen, formyl, acyl, oxycarbonyl, alkoxycarbonyl, aryloxycarbonyl, an N -un, N-mono or Ν, Ν-disubstituted aminocarbonyl or aminothiocarbonyl, an unsubstituted or substituted aryl or hetaryl radical, a cyano or nitro group, R ^{3 is} hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aralkyl, an unsubstituted or substituted aryl or hetarryl radical R ^{4 is} identical or different from R ³ for substituted or unsubstituted alkyl, cycloalkyl, aralkyl, an unsubstituted or substituted aryl or hetaryl radical or R ³ and R ⁴ together represent an alkyl bridge which may also contain oxygen, sulfur or nitrogen as ring atoms, R ^{5 represents} an unsubstituted or substituted aryl or hetaryl radical or R ⁵ and R ⁶ together represent an alkyl bridge and R ^{6 represents} hydrogen, an alkyl or aryl radical or a halogen, characterized in that an enamine of the general formula II Ψ
R ¹ NC = CH-R ⁵ II CH ₂ R ² with the meaning explained for R ¹ , R ² , R ⁵ and R ⁶ or R ⁵ / R ⁶ with an iminium salt of the general formula III Y ³ -C = N ⁺ R ³ R ⁴ Υ "III γ4 with the meaning explained for R ³ and R ⁴ or R ³ / R ⁴ and Y ³ and Y ^{4 are the} same or different leaving groups, such as, for example, chlorine, amino groups, alkylmercapto, trifloxy or alkoxy groups, and Y "is an acid residue anion, for example A process according to claim 1, characterized in that the base is, for example, an amine, an alkali metal or alkaline earth metal hydroxide or hydride, an alkali metal carbonate or a metal amide is used. Field of application of the invention The invention relates to a process for the preparation of N-substituted 3-aminopyrroles. The invention can be used in the pharmaceutical and chemical industries as well as in human medicine. Characteristic of the known state of the art An anticonvulsant effect on 3-aminopyrroles is not yet known. It is described that 3-aminopyrroles carrying aminocarbonyl (DE 2605419) or carbonyl groups (US Pat. No. 4,198,502) in the 4-position have been classified as CNS-active substances. This effect is specifically called as sedative and analgesic but not proven by any test results. The synthesis of these compounds was carried out by modifying aminopyrrole derivatives, which in turn were obtained from α-aminonitriles and β-dicarbonyl compounds (DE 2605419, DE 2439284, DE 2462967, DE 2462966, DE 2462963, GB 1 492663,