DD298915A5 - PROCESS FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE 3-AMINOPYRROLOUS - Google Patents

Abstract

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

Description

R ⁶ R ⁵ X ¹ _f

R ¹ NCCC = NR ³ M ⁴ Y II

R ² CH ₂

with the meaning explained for R ¹ , R ² , R ³ , R ⁴ or R ³ / R ⁴ , R ⁵ and R ⁶ or R ⁵ / R ⁶ and in the X ¹ for a leaving group, for example a halogen, the trifloxy group , an alkoxy group, an amino group or, if not, when R ¹ and R ^{6 are} hydrogen and NR ³ R ^{4 is} morpholino, R ² and R ^{5 are} methoxycarbonyl and phenyl, ethoxycarbonyl and phenyl, methoxycarbonyl and p-chlorophenyl, methoxycarbonyl and p-tolyl , Ethoxycarbonyl and p-tolyl, and methoxycarbonyl and p-anisyl, X ^{1 represents a} gine alkylmercapto group and Y "represents an acidurostanion such as a halide, perchlorate, an alkylsulfate, a sulfonate, sulfate, tetrafluoro- or tetraarylborate or picrate, optionally cyclized in the presence of a base.

2. The method according to claim 1, characterized in that as the base, for example, an amine, an alkali 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 oin ancestors for the production of pharmacologically active 3-aminopyrrolone. 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-aminopyrrolo, which in the 4-position aminocarbonyl · (DE 2605419) or Carbonylgruppcn (US 4198502) wear have been classified as ZNF-wirko substances. This effect is concretely named sedative and analgotic abor not proven by any Tostcrgob isso. The synthesis of these compounds takes place by modification of aminopyrrole derivatives, which in turn are obtained from α-Ap-inonitils and P-dicarbonyl compound (DE 2605419, DE 2439284, DE 2462967, DE 2462966, DE 2462963, 492663,

US 4,198,502). Six pre-rotor of 3-morpholino-4-arylpyrrolecarbonic acid η with strongly oingogronzed Substituent patterns are horgostollt by cyclization of 3-alkoxycarbon / lmotliyliii nino ^ -arylthioacrylsäuromorpholidon

wordon (A.Knoll, J.Liobschor: Khim. Goterotsikl. Soodln. 198S, 628). Ul> <olno pharmacological effect dorartigor

Vorbindungon is nothing blahor. S-AminoM-arylpyrrolo, dorone aminogroup unsubstituiort lot, were obtained by reduction

corresponding 3-nitropyrroles (J.M., 'Jddor, O. Wobslor: J. Chom. Soc., 1960, 3270).

3-Amino-2,4-diphonylpyrrole is boride on condyle jtion of phonacyhmine with itself (S. Gabriel: Bor. Dtsch. Chom. Gos.

41 (1908) 1127).

The bokannton ancestors beschroibon koino an dor Aminogruppo substitiorton S-AminoM-orylpyrrolo, dio oino ontikonvulsivo Has effect. Dio Substitutiontonvariobiliti dor bokannton ancestor is heavily oingoschränkt. Dio bokannton anticonvulsants bositzon don Disadvantage of undesirable Nobon effecton (eg Nouiotoxizitttt). Object of the invention

The invention has the aim of providing an ancestral response to the fact that the osteotopic, pharmacologically active, 3-aniinopyrrulo with not yet bokannton properties is available in the diosor class.

Explanation of the essence of the invention The object of the invention is you development oinos Verfahrons for the preparation of pharmacologically active 3-aminopyrrolone

with so far in diosor substance class not bokannton Eigonschafton, insbosondoro with antikonvulsivor odor analgoticor effect.

The aim is to goringoro Nobenwirkungon, z. B. oino goringoro NourotoxizitiJt, to orroichon as boi don dorzoitig usualon Anticonvulsants. Erfindungsgomäß, this Aufgobo is golöst characterized in that pharmacologically wirko 3-Aminopyrrolo dor allgomoinon

Formol I ₁

R ³ R ⁴

in the dor

R ^{1 is} hydrogen, an unsubstituted or substituted alkyl, an unsubstituted or sub-substituted cycloalkyl, aralkyl,

an unsubstituted or substituted aryl-odorarylaryl-rust, an acyl, alkoxycarbonyl, an N-unsaturated, N-mono- or N ₁ N-disubstituted aminocarbonyl or an aminothiocarbonyl,

R ^{2 is} hydrogen, formyl, acyl, oxycarbonyl, alkoxycarbonyl, aryloxycarbonyl, o in N -un, N-mono- or N, N-disubstituted Aminocarbonyl or aminothiocarbonyl, an unsubstituiorton odor substituiorton aryl odor hetarylrost, oino cyano-odor Nitro group, R ^{1 is} hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aralkyl, ozone, unsubstituted or substituted Aryl or hetaryl radical, R ^{4 is the} same or different from R ^{J is} substituted or unsubstituted alkyl, cycloalkyl, aralkyl, an unsubstituted or

substituted aryl or hetaryl radical or R ³ and R ⁴ together for oino alkylbrücko, which may also contain oxygen, sulfur or nitrogen as ring atoms,

R ⁵ for oonon unsubstituiorton odor substituiorton aryl odor hotarylrost

or R ^s and R * together represent an alkyl bridge and R 'is hydrogen, an oyno alkyl or aryl radical or a halogen, are prepared by cyclization of a trimithiniumsal / os dor general formula II,

R ^e R'X <

R ¹ NC = CC = NR ¹ R ⁴ Y "II

R ² CH ₂

with dor for R ', R', R ¹ , R ⁴ or R '/ R ⁴ , R ⁵ and R' or R * / P. ^e orklärton meaning and in the X ¹ for a leaving group, for example for a halogen, the Trifloxygruppo. an alkoxy group, an amino group or, if not, when R 'and R' are hydrogen and NR ¹ R ^{4 is} morpholino, R ² and R ^{s are} methoxycarbonyl and phenyl, ethoxycarbonyl and phenyl, methoxycarbonyl and p-chlorophonyl, methoxycarbonyl and p-tolyl, Ethoxycarbonyl and p-tolyl are, respectively, methoxycarbonyl and p-anisyl, X ^{1 is an} alkylmercapto group and Y "is an acidurostanion such as a halide, perchlorate, an alkylsulfate, a sulfonate, sulfate, total fluorotorodaric tetraarylborate or picrate, preferably in the presence of a base, for example an amine, an alkali metal or alkaline earth metal hydroxide or hydride, an alkali metal carbonate or a metal amide.

The compounds according to the invention are, apart from the methyl 4- {p-chlorophenyl) -3-morpholinopyrrole-2-carboxylic acid ester, the 3-morpholino-4-phenylpyrrole-2-carboxylic acid methyl ester and methylstyrene, the 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. Dio according to the invention compounds show a high anticonvulsant effect in the test in various spasm models, are characterized by low toxicity and above all a much higher protective index than currently known

commercial Antikorwulelva. DIo anticonvulsive effect is surprising, since so far genoroll in 3-Amlnopyrrolon kolno such effect is described. The nouon active ingredients may be used in bocanntor Woiso in clio usual formiorungon wordon, wio boispiolsweiso tablotton, capsule, drngoos, qranulnto odor solution on prewonding inortor, nicrit-toxi, rhor phaimazeutisch gooignetor Trägorstoffo odor solvent.

The starting materials of allgomoinone Formula II can be, for example, prepared from ontsprochondon aminoacrylsuronmidone odor thioamides by alkylation (J.Llobschor, A. Knoll: Z. Chom., 27.8 (1087), Khim Gotorots, S., din, 1985, 628). or Chloriorung (J.Liobscchor: Synthosls 1979,241) Horstollon. The invention will nachstohond to 0InI ₀ . -Operating boise key explains wordon.

Ausführungsbelsplole example 1 Synthesis of pharmacologically active 3-aminopyrroles of the general formula I The pharmacologically active 3-Aminopyrrolo dor allgomoinon Fomiol I produced according to don Variant

are collected in Table 1.

option A

Add lOmmol of trimethinium salt of the allgomoinone Formol II with X '" methylmorcapto and Y" = I "wordon with 10% ethanol and 0% solution of 0.4 g of sodium in 5 ml of ethanol. Heat for 30 minutes on dom slodondon water bath degummed with glacial acetic acid and prediluted with wolf's worm, the final product dorollomoinone Formol I is filtered off with suction and recrystallized

 Formol I is filtered off with suction and recrystallised.

Variant B

A solution of 10 mmol of trimethinium salt dor allgomolnone Formol II with X ¹ = Cl and Y "= chloride in 11 ml of ethanol is pre-treated with 1 ml of ie-diazabicycloSAOj undocon and warmed for 15 minutes to 50 ° C. The boim Abkühlon precipitating 3-aminopyrrole dor allgomoinon Formol I is aspirated, with t: ·· · ·: Vasor gowaschon and recrystallization.

Variant C

A solution of 1 mmol of trimethinium salt dorallgomointi ι ormolll it X ¹ = O ethyl and Y "= BF""in 10 ml of acetonitrile is vorsotzt with 1 g of potassium carbonate and heated under reflux for 20 min. After cooling, dioxygenation is carried out under cooling with pre-hydrochloric acid solution. It is ebgosaugt and recrystallized.

Variant D

A solution of lOmmol Trimothiniumsalz dor allgomoinon formol Il with X '- Cl and Y' = Per · morality in 10ml Pyiidin is orhiüt 15 minutes 100 ⁰ C. After Abkühlon is diluted with water, the final product filtered off with suction dor general formol I and umkristallisiort. ,

Table 1: The different variants of hergostollton 3-aminopyrrolo dor allgomoinone Formol I

Ser. R ¹ R ¹ R ' R " R ' R " Mp. AuFbV No. Voiianto • c %

1-1 H COjCHj CH, CH, 1-2 H CO ₁ CHj (CH ₁ I ₁ O (CH ₁ I ₂ 1-3 M COOH (CH ₁ I ₁ O (CH ₁ ), M H COONd (CH ₁ I ₁ O (CH ₁ I, 1-5 H CONHC ₁ M, (CH ₁ I ₂ O (CM ₁ I ₁ 1-6 1-7 H CHj CO ₂ CH ₃ COiCHj (CH ₁ ), (CH ₁ I ₁ O (CH ₁ ), 1-8 CO _a CH, (CH ₁ I ₁ O (CH ₁ ), 1-9 CH ₂ CO ₂ CH ₂ CH, CO ₁ CH ₁ (CH ₁ I ₂ O (CH ₂ ), i: o H CO ₁ CHiCH ₁ (CH ₂ ), 1-11 H CO ₁ CH, (CH ₂ I ₂ O (CH ₂ ), 1-12 M CO ₁ CHjCH, (CH ₂ I ₁ O (CH ₂ I ₂ 1-13 H CO ₁ CH, (CjHjljOICH,),

CIH, H 136-137 77 / Λ (Methanol) C.H, H 179-101 62 / B (Methanol) C ₆ H ₅ H 130-138 41 / C (ZO (R.) (N-propanol) C.H, H 188-200 48 / D (Zors.) (Wassor) C.H, H 269-270 42 / A (Acetonitrile) C ₄ H, H oil 76 / A C.H, H 86-88 64 / A (Methanol) C.H, H 112-114 6C / A (Methanol) C.H, H 97-98 39 / A methanol) 4-CHjC ₆ H, H 118-120 58 / A (Petrol) 3CHjOC ₆ H ₄ H 159-160 64 / A ! Methanol) 4CHjC ₆ H, H 167-168 59 / A (Ethanol) 4-FC.H, H 181-182 67 / A (Methanol)

By Versouen of the resulting precipitate with ethanol / NaOH.

n ¹ R ¹ R 'R ⁴ R ' R " -4- Mp. 298,915 Continuation of the table ' • c Ami) ./ Ser. H CO ₁ CH, I ₁ I ₁ O (CH ₁ ), 4-CIC ₁ H, H 192-193 variant No. (Methanol) % H COCM) (CH ₁ I ₁ O (CH ₁ ), 4CIC ₆ H, H 172-173 45 / C 1-14 ! Methanol) H COiCH, (CH ₁ ), 4CIC.II, H 122 to 123.6 74 / A 1-15 (Acetonitrile) η CO ₁ CH, (CHj) ₁ O (CHi), 40rC.ll, H 168-169 7 // A 1-16 (Mothenol) M CO ₁ H, (CHj) ₁ O (CH ₁ ), 4OrC (H, H 176-177 70 / A 1-17 (Methanol) H COjCH, (CII ₁ IoO (CH ₁ ), 4CHjCH, H 181-183 64 / A 1-18 (Mothinol) Il COjCH, (CH ₁ ) IO (CH ₁ ), 3.4 (CHjO ₁ CH, H 1Θ2-183 48 / Λ 1-19 (Acetonitrile) H CO ₁ CH ₁ CH, H C (H, (CII ₁ ), 192 194 79 / Λ 1-20 (Ethanol) Il CHO (CH ₁ I ₁ O (CH ₁ I ₁ 4CIC ₁ H, H 208-210 94 / A 1-21 (Methanol) M CO ₁ CH, (CHjCH ₁ I ₁ NCOiIIf- ^ yI 4-CIC (H, H 234-236 73 / A 1-22 (Acetonitrile) 76 / A 1-23

Example 2 Determination of protection against maximum electro-spasm (MEK)

By electric Roizung the Vordorpfoton with einom ΓυΠ-Roizstromgorät, type RS 12 (pulse frequency 35Hz, pulse width 20 ms, duty cycle 1: 1, Gruppondauor between 40 and 600 ms, Stromstilrko dor Rochtockimpulse GOmA) is boi Mäuson with oinom weight of 18-22g KM ooled out in stool spasm of the hindo-rhotomies.

Anticonvulsants protect the tioro from maximal thrombocytopenia.

Results:

Prebinding 1-14: at i, p.-Gabo: E _DM => 3.9 10 'mol / kg boi po gobo: E _O w = 4.5 × 10 -6 mol / kg

Pre-binding I-6: ip-Gabo: 5 10 " ⁴ mol / kg: 70%

Prefix words: "Carbamazopine": For i.multidot.u.s: low = 4.3.times.10.sup.-1 mol / kg

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

Intravenous injection into the tail of mouse Mäuson (18-22 gKM) immediately causes spasm of the Hintoroxtromitäton. Dio suppression diosos spasms ^ is considered a criterion for oinon anticonvulsivon effokt dor goprüfton substances.

Results:

Prebinding 1-14: For IP Gabo: E ₀₅₀ = 4.5 x 10 ^"5 mol / kg po boi-Gabo: E ₀ M = 1.5 x 10" ⁴ mol / kg

Boisplel4

Determination of the seizure threshold

By infusion of 100mg / kg pentetrazole

(Infusiongoschwindigkeit of 36 ml / h) over the tail vein troton as orstes clonischo spasm ο (myoclonic convulsions) in mice 618-22g KM) on. The prolongation of the infusion time (in seconds) until the onset of Krämpfo compared to control is considered an increase in the pentotrazole pomplosole and thus as an anticonvulsant effect of goprüftone substances.

Results:

Compound I 9: ip at 5 10 ^"4 mol / kg: 20.4% increase in Krampfschwollo Compound I-7: 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 Dosiorungen of 5 x 10 "\ 10 ~ ³ and 5 x 10" ¹ mol / kg BW. 24 hours post applicationem determines the lethality of Tiero.

Results:

Pre-binding 1-4: oLD greater than 5 · 10 " ³ mol / kg

Compound I-14: oLDgrößor than 5 x 10 ^"1 mol / kg

Examples Determination of the analgesic effect with the Hot Plate Test

Mice (18-22 g KM) are placed on the hot plate (hot plato) at 56 ° C for 30 minutes after the addition of the minerals, and the reaction time to this thermal pain stimulus is determined. An extension of the reaction time of substance-bred animals compared to control animals is evaluated as an analgesic effect (^).

Results:

Connection Ι · 2: ρ. ο. boi 10 ~ ³ mol / kg: 90% inhibition (30 min p.η.) Preceding Word:

Analgin 55% Honiinuiig

Example 7 Determination of the analgesic effect with the testosterone test

By i. p. Administration of O, 6% of acetic acid, was boosted to Boi mice (18-22g KM) of üniulockonkränipfo (writhings). As a measure of the potency of a substance, the reduction of the ZnIi dor writhlng co-actin bohandoltor Tioro in comparison to the control group. Nobon onolgotic effekton Vorblndungon sonkon also vorschiodono CNS-Wirko Vorbindungon clio writhings.

Results:

Compound 1-2: po boi 10 " ³ mol / kg 71.3% inhibition

Preload 1-4: po boi 10 " ³ mol / kg 84.2% Hommage boi 10 ~ ⁴ mol / kg 50.2% Hommung

Vorgloichswort:

Analgin: p. o. boi 10 ~ 'mol / kg 50% Hommung

Examples Determination of the Nourotoxizlttt with dom torsion bar model

Trainiorto mouse (18-22g KM) wordon after substance application for 1 min on ion dip stick (5 umdrohungon / min) gosotzt. As a measure of olne substance effect the vorzoitigoHoruntorfallon applies from the stick. Oorprotoktivo Indoxor presents itself as a quantitiy of TDm / EDmMEK.

Result:

Compound 1-14: TD ₆₀ ^α 1.4 × 10 ^-3 mol / kg; protoktivor Indox Preface:

Carbamazipine: TD ₆₀ 2.2 · 10 ⁴ mol / kg protoctivor Indox = 5.1

Example 9

Application forms For dio application wordon under andorom following Rozopturon vorgoschlagon:

capsules

3-Amiiopyrrole dor allgomoinon Formol I is dor orfordorlichon Mongo in polyothylone glycol suspension and in oin gelatine mixture of the composition - gelatin 1 Gowichtstoil glycerol 5Gowichtstoilo water 2Gowichtstoilo

eingoarboitet.

Capsules A mixture with following Bostandteilon is horgostollt:

Lactose 5 parts by weight

Potato starch 5Gowichtstoilo

Magnesium Stearate 1 Gowichtstoil

This mixture is the corresponding Mongo dor substance of the general Formol I zugosotzt.

The above examples are intended to explain the invention in more detail without limiting sio. There are woitore preparations as dragees, tablets, lozenges, granules, Pulvor, wasserrigo suspension, syrup and dorgloichon possible.

Claims (1)

1. Process for the preparation of pharmacologically active 3-aminopyrrolone of the general formula I, in the R ^{1 is} hydrogen, an unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, aralkyl, or unsubstituted or substituted aryl or hotaryl, an acyl, alkoxycarbonyl, or N, N-monodooror, Ν-disubstituted borohole Aminocarbonyl or oin aminothiocarbonyl, R ^{2 is} hydrogen, formyl, acyl, oxycarbonyl, alkoxycarbonyl, aryloxycarbonyl, an N -un, N-mono- or N, N-disubstituted aminocarbonyl or aminothiocarbonyl, or an unsubstituted or substituted aryl or hotaryl-rust, a cyano or nitro group, R ^{3 is} hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aralkyl, ozone unsubstituiortone or substituted aryl-odor-hotarylrost, R ' ^{1 is the} same or different from R ³ for substituted or unsubstituiortos alkyl, cycloalkyl, aralkyl, an unsubstituiorten odor substituiott9n aryl odor orharyaryl odor R ³ and R ⁴ together for oino alkyl bridge, which may also contain oxygen, sulfur or nitrogen as ring atoms, R ^{5 is} an unsubstituted or substituted aryl or Hetatylrost or R ⁵ and R ⁶ together is an alkyl bridge and R ^{0 is} hydrogen, oinon alkyl or aryl rust or a halogen, characterized in that oin trimethinium salt dor general Formol II,