DD298918A5 - PROCESS FOR THE PREPARATION OF 3-AMINOPYRROL DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of 3-aminopyrrole derivatives of general formula I, which are largely new and have previously unknown in this class of pharmacological properties, especially anticonvulsive or analgesic effect. The invention pursues the goal, Grosztenteils new 3-aminopyrrole derivatives to produce previously unknown in this class of pharmacological properties, in particular with anticonvulsive or analgesic effect. According to the invention, 3-aminopyrrole derivatives of general formula I are obtained by reacting a 3-substituted pyrrole with an amine. The compounds have markedly anticonvulsive and also analgesic properties. Formula I {3-aminopyrrole derivatives; Synthesis; CNS-active compounds; anticonvulsants; analgesics; 3-substituted pyrroles}

Description

R ¹

with the meaning explained for R ¹ , R ² , R ⁵ and R ⁶ or R ⁵ / R ⁶ and in the X for a leaving group such as a halogen, a hydroxy, an alkoxy, a mercapto, alkylthio, a Sulfonyloxy, an alkyl sulfate or a diazonium group, with an amine of general formula III

HNR ³ R ⁴ III

with the meaning explained for R ³ and R ⁴ or R ³ / R ^{4 is} implemented.

Field of application of the invention

The invention relates to a process for the preparation of 3-Aminopyrrolderivaten with pharmacological activity. 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 named 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 2 605 419, DE 2 439 284, DE 2462 967, DE 2 462 966, DE 2462 963, GB 1 492 663 , US 4,198,502). Six members of З-МогрпоІіпо-4-arylpyrrolecarboxylic acid esters having a highly limited substituent pattern have been prepared by cyclization of S-alkoxycarbonylmethylamino-arylthioacrylic acid morpholides (A. Knoll, J. Liebscher: Khim, Geterotsikl, Soedin, 1985, 628). About a pharmacological effect of such compounds is not yet known. 3-Amino-4-arylpyrroles, the amino group of which is unsubstituted, were obtained by reduction of associated 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 [19081 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 undesirable side effects (e.g., neurotoxicity).

Object of the invention

The object of the invention is to develop a process which makes it possible to make available 3-aminopyrrole derivatives 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 3-aminopyrrole derivatives with previously unknown in this class of pharmacological properties, in particular with anticonvulsive or analgesic effect. 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 3-aminopyrrole derivatives of the general formula I,

R ³ NR ³ R ⁴

R ¹

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 is} hydrogen, formyl, acyl, oxycarbonyl, alkoxycarbonyl, aryloxycarbonyl, an N -un, 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 a 3-substituted pyrrole of general formula II,

R ⁵

with the meaning explained for R ¹ , R ² , R ⁵ and R ⁶ or R ⁵ / R ⁶ and in the X for a leaving group, for example a halogen, a hydroxy, an alkoxy, an acyloxy, a mercapto, an alkylthio, a sulphonyloxy, an alkylsulfate or a diazonium group, with an amine of general formula III

HNR ³ R ⁴ III

with the meaning explained for R ³ and R ⁴ or R ³ / R ⁴ .

The compounds according to the invention are, apart from methyl (p-chlorophenyl-S-morpholinopyrrolecarboxylate), methyl S-morpholino-phenylpyrrole-1-carboxylate and ethylester, 3-morpholino-4- (p-tolyl) pyrrole 2-carboxylic acid methyl ester and ethyl ester and the 4- (p-anisyl) -3-morpholinopyrrol-2-carboxylic acid methyl ester new. The compounds according to the invention show in the test a high anticonvulsant effect in various spasmodic models, are characterized by low toxicity and above all a significantly higher protective index than currently known commercially available 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.

The invention will be explained below in some embodiments.

embodiments example 1 Synthesis of 3-aminopyrrole derivatives of general formula I. The 3-aminopyrrole derivatives of the general formula I prepared according to the various variants are shown in Table

compiled.

Variant A mixture of 0.01 mol of 3-substituted pyrrole of the general formula II (X =SH) in 15 ml of acetonitrile is mixed with 0.01 mol of amine of the general formula III and heated under reflux for 3 hours. After cooling, dilute with a little water. The end product of general formula I is filtered off and recrystallized.

Variant B

Analog variant A, but a 3-substituted pyrrole of the general formula II (X = SMethyl) is used.

Variant C

Analog variant A, but a 3-substituted pyrrole of the general formula II (X = chlorine) is used.

Variant D

Analog variant A, but dimethylformamide is used as solvent. TABLE 1 The 3-aminopyrrole derivatives of general formula I prepared according to the different variants

Ser. R ' R ² R ³ R ⁴ R ⁵ R ⁶ Mp. Ausb./ No. variant ⁰ C % 1-1 H CO ₂ CH ₃ CH ₃ CH ₃ C ₆ H ₆ H 136-137 67 / A (Methanol) I-2 H CO ₂ CH ₃ (CH ₂ ) ₂ O (CH ₂ ) ₂ СеНб H 179-181 73 / B (Methanol) I-3 H CONHC ₆ H ₆ (CH ₂ J ₂ O (CH ₂ J ₂ C ₆ H ₅ H 269-270 78 / C (Acetonitrile) I-4 H CO ₂ CH ₃ (CH ₂ I ₄ C ₆ H ₆ H oil 66 / B I-5 CH ₃ CO ₂ CH ₃ (CH ₂ I ₂ O (CH ₂ J ₂ C ₆ H ₅ H 86-88 71 / D (Methanol) I-6 H CO ₂ CH ₃ (CH ₂ J ₂ O (CH ₂ J ₂ 4-CIC ₆ H ₄ H 192-193 81 / D (Methanol) I-7 H CO ₂ CH ₂ CH ₃ HC ₆ H ₆ (CH ₂ J ₄ 192-194 75 / B (Ethanol) I-8 H CO ₂ CH ₃ (CH ₂ CH ₂ ) ₂ NCO-fur-2-yl 4-CIC ₆ H ₄ H 234-236 79 / B (Acetonitrile)

Example 2 Determination of protection against maximal electroconvulsions, (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 of rectangular pulses 5OmA) in mice with a weight of 18-22 g BM, a spasm of the hind limbs is triggered. Anticonvulsants protect the animals from the maximum electro convulsions.

Results:

Compound I-6: For IP administration: E o = _D6 3.9 10 ^"5 mol / kg for po administration: E ₀₅₀ = 4.5 x 10 ^-5 mol / kg

Compound I-4: For IP administration: 5 x 10 ~ ⁴ mol / kg: 70% Comparative values: "Carbamazepine": ip administration: E _D50 = 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 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: ₀₅ E o = 4.5 x 10 ~ ^s mol / kg for po administration: E _D6 o = 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: 19.4% increase

Example 5 Determination of the orienting lethal dose

Mice (18-22g KM) receive the substances to be tested in dosages of 5 1 Г ⁴ , 1 Г ³ and 5 10 10 ^-3 mol / kg KM. 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 KM) are placed on the hot plate of 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. The administration of 0.6% acetic acid in mice (18-22 g) causes a reduction in the number of derwriting reactions of treated animals compared to the control group Also various CNS-active 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

Results:

Compound I-6: TD ₆₀ = 1.4 × 10 ^-3 mol / kg; Protective index = comparison value:

Carbamazapin: TD ₅₀ 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 gelatine 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

To this mixture, the appropriate amount of the substance of general formula I is added.

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)

Process for the preparation of 3-aminopyrrole derivatives of general formula I, R * NR 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 is} hydrogen, formyl, acyl, oxycarbonyl, alkoxycarbonyl, aryloxycarbonyl, an N -un, N-mono- or N, N-disubstituted aminocarbonyl or aminotharbonyl, 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 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 a 3-substituted pyrrole is the general formula II, w ^x