DD298917A5 - PROCESS FOR PREPARING 2-SUBSTITUTED 3-AMINOPYRROLES - Google Patents

Abstract

The invention relates to a process for the preparation of 2substituierten 3-aminopyrroles of the general formula I, which are grosztenteils new and previously unknown in this class of pharmacological properties, especially anticonvulsive or analgesic effect. The invention pursues the goal, in large part new, 2-substituted 3-aminopyrroles, with previously unknown in this class of pharmacological properties, especially with anticonvulsive or analgesic effect. According to the invention, 2-substituted 3-aminopyrroles of the general formula I are obtained by cyclization by reactions with electrophilic reagents or heterocumulenes. The compounds have markedly anticonvulsive and also analgesic properties. Formula I {2-substituted 3-aminopyrroles; Synthesis; CNS-active compounds; anticonvulsants; analgesics}

Description

with the meaning explained for R ¹ , R ³ , R ⁴ or R ³ / R ⁴ , R ⁵ and R ^e or R ⁵ / R ⁶ with an electrophilic reagent of the general formula III

R ² -X III

with the meaning explained for R ² and in the X is a leaving group, for example a halogen, a sulfonate or sulfate radical, a hydroxy, acyloxy or a diazo group, or if R ^{2 is} R ⁷ NHC = Z with R ⁷ = Alkyl, aryl, hetaryl or carbonyl and Z = oxygen, sulfur or substituted nitrogen, with a heterocumulen of the general formula IV

R ⁷ N = C = Z IV

is reacted with the meaning explained for R ⁷ and Y and optionally with an acid or base.

2. The method according to claim 1, characterized in that as acid, for example, sulfuric acid, hydrogen chloride, aluminum chloride, boron trifluoride, antimony pentachloride or iron-lll-chloride is used.

3. The method according to claim 1, characterized in that as the base, for example, amine, an alkali or alkaline earth metal hydroxide or hyd id, an alkali metal carbonate or a metal amide is used.

Field of application of the guideline

The invention relates to a process for the preparation of 2-substituted 3-aminopyrrolone with phdrmakologischer effect. The invention can be used in the pharmaceutical and chemical industries.

-2- 298 917 Characteristics of the well-known Stand the technology

Eino nnlikonvulsivo effect on 3-aminopyrrolone is not yet bokonnt. It is Bschschriobon, 3-Amnnopyrrolo, clio in 't-Stollung Amlnocorbonyl · (DE 2605419) or Cnrbonylgruppon HJS Ί198502) trngon, as CNS WirkoumoSubstanzenolngostuit vvurdon. Dioso action is concretely termed sodiorond and analgotic, but is bologt by V- ο i η ο r I ο i Tostorgobnisso. Dio Synthoso diosor Vorbindungen orithero by modification of AminopyrroldonvnOn, dio denorsoits from a-aminonitrile and P-DicarbonylvorbindungongowonnonwurdonlDE 2605419, DE 2439284, DE 2462907, DE 246296G, DE 2462903, GB 1492663, US 4198502). Thus, the pre-rotor of 3-morpholino 4-mylpyrrolocorboxylic acid oostome with oinom stnrk oingogroiizton substituentonmustor have been prepared by cyclization of S-alkoxycarbonylmothylamino ^ -arylthioacrylsiurornorpholidone (A.Knoll, J.Liobschor: Khim, Gotoiotsikl, Soodin, 1985, 628). Uor oino phormokologoj effect clorortljor Vorzubehon is not bokonnt bishor. 3-Amino-4-arylpyrrolo, doron amino unsubstituted, was obtained by reduction of associated 3-nitropyrrologone ammonone (J.M. Toddor, H.Wobstor: J.Chom. Soc., 1960, 3270).

3-Amino-2,4-diphonylpyrrole ontstohl boi dor Condensation of phononylmin with sicli itself (S.Gnbriol: Dor. Dtsch. Chom. Gos.

411190811127).

Dio bocannon Verfahron boschroibon koino on dor amino group substitiorton 3-amino-4-arylpyrrolo, dio oino antikonvulsivo effect bositzon. Dio Substituonton Variability of the Boknnnton Vorithron is severely limited.

Dio bokannton Antikonvuhiva bositzon clon Nachtoil of undesirable Nobon effecton (z.Q, ίJourotoxizitiit).

Aim of the invention

The invention has the advantage of providing an ancestor to the cytokine that is able to form 2-substituted amino-3-aminopyrrolo with not readily available bokanruon phnrmkologischon Eigonschafton in diosor Stoffklasso bishor.

Darling of Wosons dor invention

The object of the invention is the development of oinos precursors for the homologation of 2-substitiortone 3-aminopyrrolone with bishor in the substance class not boknnnton pharmacological Eigonschafton, insbosondoro with anticonvulsivor odor analgotischcr effect. It is angostrobt, goringore Nobonwirkungon, z. B. oino lower Ncurotoxizität to orroichnn as boi (lon currently conventional anticonvulsants

 According to the invention, this object is achieved by substituting 3-aminopyrrolo dor allgomoinone formula I,

R ³ R ⁴

in the dor

R ^{1 is} hydrogen, an unsubstituted or substituted alkyl, an unsubstituted or substituted cycloalkyl, aralkyl, ozone, unsubstituted or substituted aryl oraric aryl orarylaryl, oynyl, alkoxycarbonyl, oyno, N-nione-odor Ν, Ν-disubstituted aminocarbonyl or ooin aminothiocarbonyl,

R ^{2 is} formyl, acyl, oxycarbonyl, alkoxycarbonyl, aryloxycarbonyl, o in N -un, N-mono- odor Ν, Ν-disubstituted aminocarbonyl or aminothiocarbonyl, an unsubstituted or substituted arylorodecarboxylate, a cyano or nitro group,

R ^{3 is} hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aralkyl, ozone, unsubstituted or substituted aryl orararylaryl,

R ^{4 is the} same or different from R ^{3 is} substituted or unsubstituiorto alkyl, cycloalkyl, aralkyl, oinon unsubstituiorton oror substituinrton aryl or hetarylrost or R ¹ and R ⁴ together for oino alkylbrücko, dio may also contain oxygen, sulfur or nitrogen as ring atoms,

R ^{5 is} an unsubstituted or substituted aryl or hotaryl rust

oror R ⁵ and R ^e together are an alkyl bridge and R 'is hydrogen, oynone alkyl or arylrostorodorine halogon, by reversing a 2-unsubstituiorton 3-aminopyrrole dor allgomoinon Formol II,

R ³ NR ³ R ⁴

with the meaning of R ¹ , R ³ , R ⁴ or R ³ / R ⁴ , R ⁵ and R * or R ⁵ / R ^e with an electrophilic reagent of general formula III

R ² -X III

with the meaning explained for R ¹ and in the X for a leaving group, for example a halogen, an acyloxy group, a

Sulfonate odor sulfate rust, Oino hydroxy · odor ELNO Dlaiogruppo, stoht odor, foils R stoht ¹ odor for R ⁷ NHOZ with R ⁷ "is alkyl, aryl, Hoterylodor carbonyl and Z = oxygen, Schwofol substitulortor nitrogen, with oinom Hotorocumulon dor allgomolnon formula IV

R ⁷ NCZ IV

with dor for R ⁷ and Y orklärton meaning and gobobononfalls with oinor acid odor Uneo umgosoUt becomes. For example, SchwofolsHuro, hydrogen chloride, aluminum chloride, boron trifluoride, antimony pontachloride or Eison III chloride and, as Baso boispiolswoiso, an AmIn, an alkali or petroleum hydroxide or -hydld, an alkali carbonate or oor motor oil may have been prewired. The origengedütton compounds are except for the 'i-lp-ChlorphonyO-S-morpholinopyrrol-2-carbonsäurothoth Monster, don S-morpholino-d-plionylpyrrol ^ -carbonstturomothyloster and -othylostor, don 3-morpholino-4- (p-tolyl) pyrrole 2-Carboxynomothylostor and -othylostor; and don 4- (p-anisyl) -3-morpholinopyrrol-2-carbonsturtomo-methylstyrene. Dio orfiiulungsgomüßon Vorbindungon zoigon in Tost in vorschiodonon Krampfmodollon oino hoho ontikonvulsivu effect, are characterized by goringo toxiiity and especially oinon wosontlich liokhoron protoktivon Indox, as dorioit bokannto handolsüblicho anticonvulsivo. Dio antikonvulsivo effect is uborraschond, since bishor gonoroll boi 3-aminopyrrolone koino solcho effect is described. The nutrients can be transferred into bokannlor Woiso in dio formonungon, wio boispiolswoiso tablotton, capsules, dragoos, granules odor solutions or prewarning inortor, non-toxicor pharmaioutic gooignotor carrier or odol solvent. The dioxin derivatives of allgomoinone Formol II are accessible by boilers by decarboxylation. The invention is intended to be repeated at oinigon Ausfülirungsbois | iolon or orally wordon.

Ausführungsbolsplolo

Belspiol 1

Synthesis of 2-Substitulorton 3-An iopyrrolone of allgomolnone Formol I

Horgostollton 2-substitiortone 3-aminopyrrolo dor allgomoinone Formol I, added to don vorjiodonon variants, have been added together in Tabollo.

option A

a mixture of 0.01 mol of 2-unsubstituiortom 3-aminopyrrole of allgomoinone Formol III, 15 ml of acetonitrile and 0.02 mol of electrophilic Roagonz of allgomoinon formula III (X-Cl) is refluxed for 20 minutes. Let cool and pour on ice. The final product of the formula I is fermented and reconstituted.

Variant B

Analogous to variant A, but heating is continued under reflux for 2 minutes until the oloktrophilos Roagonz dor allgomoinon Formol III (X-MothylCOO) is prewired for 30 minutes.

VarlantoC

To ooror solution of 0.2 mol of 2-unsubstuuiortom 3-aminopyrrole dor generalized formol Il in 42 g of dimethylformamide 0.2 mol Phosphoroxychlorid under Rüiiren and cooling so iugotropft that the Temporatur 20 ° C not üborschrnitol. In this case bildot intermediately oin chloromethylon-NN-dimothyiiminiumsalz as oloktrophilos Ronyonz dor Formol III. It is heated to 60 ° C oino hour. It formed oin 2-substitiortO3 3-aminopyrrole of the allgomoinone formula I (R'-CH-N'-Mothylj). After the cooling down, gcgosson is neutralized to 20OmI of ice and sodium hydroxide solution is added with pre-dilution. The initially ontstandono iminium salt is hydrolyzed to 2-substituicrton 3-aminopyrrole dor allgomcinon Formol I (R ² ^ CHO). Diosos is drained off, washed with water and reconstituted.

Variant D

lmmol 2-unsubstituted borane 3-aminopyrrole dor allgomoinone Formula II wordon in 10mi Bonzongolöst. Add 1 mmol of Hotorocumulens to the allgomeinone Formol IV and heat for Ί0 minutes under reflux. The solvent is evaporated and the residue recrystallized.

Variant E

Analog variant A, but the mixture before dom dom heating 1oz wassorfreios zinc chloride zugosotzt.

Tnbollo 1: nor don donothonon Varianton horgoetollton 2-substitulorton 3-aminopyrrolo dor ollgomoinone Formol I

Ser. R ' R ² R ³ R ⁴ R * n · Mp. Ausb./ No. variant • c % I-1 H CO ₁ CM, CH, CH, C ₆ H ₆ H 136-137 54 / A (Methanol) 1-2 H COjCH, (CH,), O (CH,), CH ₄ H 179-181 50 / A (Methanol) 1-3 H CONHCH ₅ (CHj) JO (CH ₁ ), CH, H 2C9-270 61 / D (Acetonitrile) 1-4 H COjCH, (CHj) ₄ CIU H oil 47 / Λ 15 CH, COjCHj (CHj) jO (CH,), C ₈ H ₆ H 86-88 02 / A (Mothanol) 1-6 M COjCH, (CHj) jO (CH,), 4CICH ₄ H 192-193 64 / E (Mothanol) 1-7 H COCH, (CHj) ₁ O (CHj), 4CIC ₈ H ₄ H 172-173 71 / D (Mothanol) 1-8 H COjCH ₂ CH, HC ₆ H ₅ (CHj) ₄ 192-194 36 / Λ (Ethanol) 1-9 H CHO (CHj) jO (CH,), 4-CICeH ₄ H 208-210 73 / C (Mothanol)

Belsplol 2

Determination of protection gogon don maxlmalon elbow spasm (MEK)

By electric Roizung dor Vordorpfoton with oinom TUR-Rolzstromgorät, type RS 12 (pulse frequency 35Hz, Pululsroito 20ms, duty cycle 1: 1, Grupponclnunr zwischon 400 and COOms, Stromsta'rko dor Rochtockimpulso 5OmA) is boi Mäuson with oinom Gowicht of 18-22g KM oin Stlockkrampf dor Hintoroxtromitäton ousgolöst.

Anticonvulsants protect dio Tioro from the maximal eolectomy.

Ergobnisso:

Proliferation I-6: Boi i.p. administration: Edm · »3.9 10" 'mol / kg boi p.o.-Gabo: Edm - 4.5.10 "* mol / kg

Pre-bound M: boii.p.-Gabo; 5 10 ~ ⁴ mol / kg: 70%

Vorgloichsworto: "carbamazopine": i.p.-gift: Eoio "4.3 · 10" "* mol / kg

Bolsplol 3

Determination of effect In ponlotrazollnduzlerton spasm

Intra-osseous inoculation into the tail of mice (18-22g BM) immediately causes stunt spasm of the hindino anomalies. Dio suppression diosos spasms is considered a criterion for oincn anticonvulsivon F.Kokt dor goprüftcn substances.

Results:

Prebinding 1-6: boii.p.-Gabo: E ₀ M - 4.5 x 10 ^"6 mol / kg po boi-Gabo: eow - 1.5 x 10" ⁴ mol / kg

Example 4 Determination of the seizure threshold

By infusion of 100mg / kg pentotrozole (infusion coagulum of 36ml / h) over the tail of dioe trotcn as orstos klonischo Krämpfo (myoclonic twitches) boi mouseon (18-22g KM). Extension of the infusion duration (in s) to mm of the tonicity of the cramp in the course of control is regarded as an increase in the pontotrazole spasm and thus as an anticonvulsant effect of the substance-rich substance.

Results:

Pre-binding I-5: ip boi 5 x 10 ⁴ mol / kg; 19.4% increase

Boisplol 5

Determination of the orienting lethal dose

Mice (18-22g KM) receive the test substances in dosages of 5 x 10 -10 ^-3 and 5 10-mol / kg MK. 24 hours post-application, lethality of the tioro is assessed.

Ergobnisso:

Pre-binding I-6: oLD greater than 5 · 10 ~ ^J mol / kg

Example 6 Determination of analgesic effect with dom Hot Plate Tost

Maused 8-22 g KM) 30 min after Gabo the Testubstanzon on dio plate (hot plate) of 56 ° Cgosutzt, and os the dio reaction time is determined on diosen Tormal Schmerzroiz. An extension of the reaction time of substance-borne animals compared to control animals is considered an analgesic effect.

Results:

Pre-binding I-2: po boi 10 ' ³ mol / kg: 90% inhibition (30 min pa)

Analgin 55% inhibition

Example 7 Treatment of analgotltchon effect with dom Eglaure-wrlthing-Tott By i.p.Gabo of O, G% igor acetic acid wordonboiMHusonl 18-22 g KM) Bouchdockonkrttmpfolwrithingslousgolöst. As a measure

for dioxin substance (Hont clio Roduktion dor number of wrlthlngHoaktionon Bahrenndoltor Tloro In Vorgloich to

Gruppo control. Nobon analgesic compounds sonkon also voischlodono CNS-wlrksomo Vorbindungon dio

writhings.

Ergobnisso: Vorbinduno 1-2: po boi 10 ^"J mol / kg 71.3% inhibition Vorglelchswort: Analgin: p.o. bol 10 'mol / ky 60% Hommung Example 8 Determination of neurotoxicity t with the torsion bar model Trainlorto Mftuso (18-22g KM) was grafted after 1 min of minutrochemil (G umdrohungone / ml) for 1 min Measure of oino substance effect is the premature Horuntorfallon of Orohstab. Dor protoktiv, ndoxorg gives itself as a quotient of

T1) _M / ED _M MEK.

Ergobnis:

Pre-binding Ι · β: TD _M «1.4 · lO'mol / kg; protoktivor Indox> = 36 Vorgleichswort: Carbamazapine: TD _M 2.2-10 ⁴ mol / kg Protoktivor Indox «5.1 _x Example 9 application forms For dio application wordon untor nndorom folyondo Rozopturon vorgoschlagon:

capsules

3-aminopyrrole of ollgomoinone Formol I is in dor orfordoilichon Mongo in polyothylone glycol suspondiort and in oino

Golatin mixture of the composition Golintino 1 Gowichtstoil Glycerol 5% by weight Water 2 Gowiclilstoilo

oingoarboitot.

capsules

Cs ogre oino blend with oudtindtoilon following: Lactose 5 Gowiclilstoilo Kortoffolstärko 5 Gowichtstoilo Magnosium red 1 Gowichtstoil To this Gomisch dio entsprochondo Mongo dor substance of allgcmoinon formula I zugcsotzt.

Dio vorgonannton Boicpiolo solion dio invention niihor oryllorn, ohno sio oinzuschiänkon. There are woitoro preparations as Dragoos, tablets, lozenges, granules, Pulvor, wasserrigo Susponsion, syrup and dorgloichon possible.

Claims (1)

1. ancestor for the preparation of 2-Substltuiorton 3-aminopyrrolone dor general Formol I ₁ R ³ R * in the R ^{1 represents} hydrogen, an unsubstituted or substituted alkyl, or unsubstituted or substituted cycloalkyl, aralkyl, an unsubstituted or substituted aryl orararyl aryl, an acyl, alkoxycarbonyl, an N -un, N-mono- or Ν, Ν-disubstituted aminocarbonyl odor oin aminothiocarbonyl, R ^{2 is} formyl, acyl, oxycarbonyl, alkoxycarbonyl, aryloxycarbonyl, o-N, N-mono- or Ν, Ν-disubstituted aminocirbonyl or aminothiocarbonyl, oinon unsubstituiorton oclor substituted aryl or Hotarylrost, ao cyano-odor nitrogruppo, R ³ for hydrogen, substituted or unsubstituted, alkyl, cycloalkyl, aralkyl, oonon unsubstituiorton or substituted aryl or hotaryl rust, R ' ^{1 is the} same or different from R ³ for substituiortos or unsubstituiortos alkyl, cycloalkyl, aralkyl, an unsubstituiorton odor substituted aryl or Hotarylrost odor R ³ and R ⁴ together for oino alkyl bridge, which may also contain oxygen, sulfur or nitrogen as Ringatomo, R ⁵ for an unsubstituted or si bstituiorton aryl or Hotarylrost odor R ⁵ and R ⁶ together for an alkyl bridge and R ⁶ for hydrogen, an alkyl odor Aryliost or a halogen stoht, characterized in that a 2-unsubstituiortos 3-aminopyrrole of general formula II, NR ³ R ⁴