DK158983B - Analogifremgangsmaade til fremstilling af benzoylpiperazinestre eller syreadditionssalte deraf - Google Patents

Analogifremgangsmaade til fremstilling af benzoylpiperazinestre eller syreadditionssalte deraf Download PDF

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DK158983B
DK158983B DK290583A DK290583A DK158983B DK 158983 B DK158983 B DK 158983B DK 290583 A DK290583 A DK 290583A DK 290583 A DK290583 A DK 290583A DK 158983 B DK158983 B DK 158983B
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compound
acid
acid addition
preparation
addition salts
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DK290583A (da
DK158983C (da
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Setsuo Fujii
Eizuo Hattori
Mitsuteru Hirata
Koichiro Watanabe
Kazuhiro Onogi
Masahiko Nagakura
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Kowa Co
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Priority claimed from JP58075868A external-priority patent/JPS59204173A/ja
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Description

DK 158983 B
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte benzoylpi-perazinestre med den almene formel
5 CON
eller farmaceutisk acceptable syreadditionssalte deraf, 10 hvor er hydrogen eller en methoxygruppe, og R2er en ligekædet eller forgrenet (C^-Cg)alkylgruppe eller en cyclohexyl-, cyclohexylmethyl- eller benzylgruppe, med undtagelse af den forbindelse, hvor er H, og R2 er CHg, hvilken fremgangsmåde er ejendommelig ved det i 15 kravets kendetegnende del anførte.
Opfinderne af den foreliggende opfindelse har tidligere fundet, at forskellige phenylestre har udmærkede chymotryps i n-hæmmende virkninger (se offentliggjort japansk patentansøgning nr. 158737/1981 og europæisk pa-20 tentpublikation nr. EP-A1-71433).
Endvidere har opfinderne syntetiseret analoge forbindelser med henblik på undersøgelse af deres farmakologiske virkninger. I de undersøgelser, der ligger til grund for den foreliggende opfindelse, har det, som ne-25 denfor dokumenteret, vist sig, at de hidtil ukendte ben-zoylpiperazinestre med ovenstående formel (I) og syreadditionssalte deraf udmærker sig i forhold til de kendte forbindelser ved deres enzymhsatimende aktivitet, navnlig chymotrypsin-haanmende aktivitet, samt ved deres mindre toxicitet. Forbindelserne 30 Kan finde vid anvendelse for eksempel som medicinske produkter, såsom til behandling af pancreatopati.
Den omhandlede fremgangsmåde til fremstilling af forbindelserne med ovenstående formel (I) eller deres syreadditionssalte er ejendommelig ved, at en carboxyl-35 syre med den almene formel
COOH
n,~€i0 (II)
DK 158983 B
2 hvor R.j er som ovenfor defineret, eller et reaktivt derivat deraf, omsættes med en substitueret phenol med den almene formel 5 :HO-^-CONJ.-fl2 (III) hvor R2 er som ovenfor defineret, eller et reaktivt derivat deraf, og at en opnået forbindelse med formlen (I), 10 om ønsket, overføres i et farmaceutisk acceptabelt syreadditionssalt deraf.
Esterificeringsreaktionen mellem forbindelserne med formlerne (II) og (III) kan gennemføres ved anvendelse af konventionel teknik. Egnede former for teknik om-15 fatter en fremgangsmåde, hvor forbindelsen med formlen (II) eller et reaktivt derivat deraf, for eksempel et syrehalogenid, et syreanhydrid, et blandet syreanhydrid, en aktiv ester eller et aktivt azid omsættes med forbindelsen (III) eller et reaktivt derivat deraf, og en frem-20 gangsmåde, hvor forbindelserne (II) og (III) omsættes i nærværelse af et dehydrationsmiddel, såsom dicyclohexyl-carbodiimid.
Den på denne måde opnåede forbindelse (I) kan yderligere ved en konventionel metode omdannes til et 25 uorganisk syreadditionssalt, f.eks. med saltsyre, svovlsyre, phosphorsyre eller hydrogenbromidsyre, eller en organisk syre, for eksempel eddikesyre, propionsyre, male-insyre, fumarsyre, vinsyre, citronsyre, methansulfonsyre, benzensulfonsyre eller toluensulfonsyre.
30 Farmakologiske tests
Den chymotrypsin-hæmmende aktivitet af de omhandlede forbindelser vil fremgå af følgende forsøgsresultater.
35 Målemetode
En opløsning, der var fremstillet ved at blande 0,1 ml af en dimethylsulfoxidopløsning indeholdende en testforhindelse, 0,1 ml vand og 0,1 ml af en puffer-
DK 158983 B
3 opløsning indeholdende lOy^g/ml chymotrypsin (0,lM trissal tsyrepufferopløsning, pH 8,01 blev inkuberet 10 minutter ved metoden ifølge Muramatsu et al. [se The Journal of Biochemistry, 62_, 408 (1967) ] . Af en pufferopløs-5 ning indeholdende 25 mM af en acetyl-L-tyrosinethylester blev 0,2 ml blandet med den ovenfor fremstillede opløsning og omsat ved 30°C i 30 minutter. Mængden af tilbageværende substrat bestemtes ved at bringe det til at fremkalde farve ved Hestrin-metoden og måle absorptionsevnen 10 ved 530 nm. Til sammenligning anvendtes tosylphenylala-ninchlormethylketon, der er en kendt chymotrypsin-inhi-bitor (Sammenligningsforbindelse 1).
Resultaterne er anført i Tabel I.
15
Tabel I
Chymotrypsin-hæmmende
Testforbindelser aktivitet [50% hæmnings- koncentration (M) ] 20 . -------
Omhandlede forbindelser ^ 3 x ]_q”7 2 9 x 10"7 3 8 x 10~7 25 -7 4 9 x 10
Sammenlignings- τ 5 χ 10-4 forbindelse
Bern.: Nummeret for hver testforbindelse opnået 3q ifølge opfindelsen angiver det tilsvarende eksempel blandt de nedenfor anførte.
Endvidere er følgende testforbindelser: (1) (Forbindelse fremstillet i eksempel 3) 35 .C00-^""Vc0-N ^tf-CH'CH3 o5 w ^ 4
DK 158983 B
(2) (Forbindelse fremstillet i eksempel 4) οοο-^Λ-co-n N-CH2CH3 5 · Qu w sammenlignet med følgende sammenligningsforbindelse (3) (Forbindelse fremstillet i eksempel 80 i oven nævnte japanske patentpublikation nr. 56-158737 (A2) ) 10
COO-/”VcO-N N-CEU
00 15 ved følgende farmakologiske tests.
Test A: Enzym-hæmmende aktivitet.
Ved metoden beskrevet i US patentskrift nr. 4.443.603 blev hver af forbindelserne (1)f (2) og (3) underkastet bestemmelse af deres hæmmende aktivite-20 ter over for chymotrypsin, trypsin og. thrombin.
Nedenstående tabel II viser de enzymhæmmende aktiviteter.
Tabel II 25 50% Inhibitionskoncentration: IC5Q (M) Forbindelse Chymotrypsin Trypsin Thrombin —6 -4 _«
Sammenlignings- 1 χ 10 1 X 10 8 x 10 ° 30 forbindelse (3) >7 -4 _c
Omhandlet for- 8 X 10 * 5 X 10 1 x 10 bindelse (1)
Omhandlet for- 9 x 10 ^ 8 x 10 ^ 2 x 10 ^ bindelse (2)___^ 4
DK 158983 B
5
Test B; Akut toxicitet (LD5Q).
Forbindelsen (1) og sammenligningsforbindelsen (3) blev indgivet intravenøst på ddY-hanmus (én gruppe: 10 5 mus) gennem deres haler. Observation blev fortsat i to uger, og LD,-g-værdi en for hver testforbindelse blev beregnet ud fra musenes dødsrate.
Nedenstående tabel III viser LD^g-værdierne.
10 Tabel III
Forbindelse LDg^ (mg/kg)
Sammenligningsforbindelse (3) 70
Omhandlet forbindelse (1) 95 15__
Test C: Toxicitet ved kontinuert anvendelse.
Forbindelserne (1) og (2) og sammenligningsforbindelsen (3) blev anvendt i vandig opløsning til ddY-hanmus (én gruppe: 5 mus). Anvendelsen foregik i en dosis 20 på 2.000 mg/kg/dag ad en oral tvangsvej i 7 på hinanden følgende dage. Renset vand anvendtes til en kontrolgruppe af mus. Daglige vægtændringer blev observeret tillige med fraværelse eller tilstedeværelse af enhver form for symptomer. Dagen efter den sidste anvendelse blev alle 25 de således behandlede dyr dissekeret for visuelt at bestemme ethvert unormalt tegn i de intestinale organer.
Hvert dyr fik vægten bestemt for et område strækkende sig fra maven til rectum, fordi det viste sig, at gas havde samlet sig i fordøjelseskanalen.
30 Nedenstående tabel IV viser de opnåede resultater i henseende til død, gasansamling og intestinalt volumen.
DK 158983 B
6
Tabel IV
Forbindelse Døde. Gas- Intestinalt volumen ansamling (ml/10 g legemsvægt) 5 Kontrol 0/5 0/5 1, 24
Sammenlignings- 2/5 4/5 2,45 forbindelse (3)
Omhandlet forbin- 2/5 2/5 1,39 delse (1) 10
Omhandlet forbin- 2/5 2/5 1,40 del se_{2)__________
Bem.: Det anførte intestinale volumen er gennemsnits-15 værdien beregnet for 5 mus.
Sammenligningsforbindelse (3) inducerede gasansamling i det væsentlige i hele regionen af fordøjelseskanalen, mens forbindelserne (1) og (2) kun medførte lille og lokal gasansamling.
20 Fremgangsmåden ifølge opfindelsen beskrives nær mere gennem følgende eksempler.
Eksempel 1 l-Methyl-4-[4-(7-methoxy-l,2,3,4-tetrahydro-l-naphthoyl-25 oxy)benzoyl]piperazin-methansulfonat.
Til 100 ml af en opløsning af acetonitril indeholdende 4,4 g l-methyl-4-(4-hydroxybenzoyl)piperazin og 4,94 g 7-methoxy-l,2,3,4-tetrahydro-l-naphthylcarboxyl-syre blev der sat 4,94 g dicyclohexylcarbodiimid, og 30 blandingen blev omrørt natten over ved rumtemperatur.
Efter frafiltrering af uopløseligt materiale blev filtratet koncentreret ved reduceret tryk, og der blev inkorporeret 50 ml 0,5N saltsyre og vasket med ethylacetat.
Efter neutralisation med en mættet natriumbicarbonatop-35 løsning blev den vandige fase ekstraheret med ethylacetat. Ekstrakten blev vasket med vand og tørret, efterfulgt af afdestillation af opløsningsmidlet, hvorved opnåedes et olieagtigt råprodukt. Rensning af produktet 7
DK 158983B
ved silicagelsøjlechromatografi (elueringsopløsning: chloroform/methanol 30:1) gav 7,57 g af et olieagtigt produkt. Dette produkt blev på konventionel måde omdannet videre til methansulfonat, hvorved opnåedes 6,2 g nålelig-5 nende, bleggule krystaller med smp. 150-151°C (udbytte 61,6%).
Eksempler 2-9
Ved samme fremgangsmåde som i Eksempel 1 blev der op-10 nået de i Tabel V anførte forbindelser.
15 ' 20
DK 158983B
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Claims (1)

  1. DK 158983 B Analogifremgangsmåde til fremstilling af benzoyl-piperazinestre med den almene formel c°o-Q-°oQ^ Β,-Θ0 10 eller farmaceutisk acceptable syreadditionssalte deraf, hvor er hydrogen eller en methoxygruppe, og R2 er en ligekædet eller forgrenet (C^-Cg)alkylgruppe eller en cyclohexyl-, cyclohexylmethy-1-- e-l-l-er benzylgruppe, med undtagelse af den forbindelse, hvor R^ er H, og R2 er 15 CH^, kendetegnet ved, at en carboxylsyre med den almene formel COOH --60 20 ^ hvor R^ er som ovenfor defineret, eller et reaktivt derivat deraf, omsættes med en substitueret phenol med den almene formel 25 = Ηθ-Q- cc{3-r2 (iii) hvor R2 er som ovenfor defineret, eller et reaktivt derivat deraf, og at en opnået forbindelse med formlen (I), 30 om ønsket, overføres i et farmaceutisk acceptabelt syreadditionssalt deraf. 35
DK290583A 1982-06-25 1983-06-23 Analogifremgangsmaade til fremstilling af benzoylpiperazinestre eller syreadditionssalte deraf DK158983C (da)

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JP57109192A JPS58225080A (ja) 1982-06-25 1982-06-25 ベンゾイルピペラジン誘導体
JP10919282 1982-06-25
JP7586883 1983-04-28
JP58075868A JPS59204173A (ja) 1983-04-28 1983-04-28 ベンゾイルピペラジンエステル類

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JPS59212471A (ja) * 1983-05-19 1984-12-01 Kowa Co インド−ルカルボン酸ベンゾイルエステル
JPS59222484A (ja) * 1983-06-02 1984-12-14 Kowa Co テトラヒドロナフチルカルボン酸フエニルエステル誘導体
JPS608225A (ja) * 1983-06-29 1985-01-17 Kowa Co 腸管吸収医薬組成物
MY102447A (en) * 1986-06-16 1992-06-30 Ciba Geigy Ag Disubtituted piperazines
EP0385043A1 (en) * 1989-02-28 1990-09-05 Fabrica Espanola De Productos Quimicos Y Farmaceuticos, S.A. (Faes) New derivatives of 4-substituted piperazines
JP2773897B2 (ja) * 1989-05-19 1998-07-09 サンアプロ株式会社 アミン化合物、製造法およびウレタン化反応用触媒
US5240956A (en) * 1990-11-07 1993-08-31 Cortech, Inc. Ester inhibitors
DE4443891A1 (de) * 1994-12-09 1996-06-13 Bayer Ag Heterocyclisch substituierte Oxy-phenyl-(phenyl)glycinolamide
DE60131967D1 (de) * 2001-08-13 2008-01-31 Phenex Pharmaceuticals Ag Nr1h4-kern-rezeptor-bindende verbindungen
KR100578484B1 (ko) * 2003-12-04 2006-05-10 씨제이 주식회사 쌀을 이용한 무균화 즉석 포장죽의 제조 방법
WO2008080092A2 (en) 2006-12-22 2008-07-03 Ironwood Pharmaceuticals, Inc. Compositions comprising bile acid sequestrants for treating esophageal disorders
WO2012027331A1 (en) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders
EA201591338A1 (ru) 2013-01-15 2016-01-29 Айронвуд Фармасьютикалз, Инк. Гастроретентивная лекарственная форма секвестранта желчных кислот с замедленным высвобождением для перорального применения
CN106798743B (zh) * 2017-01-23 2019-05-03 南阳师范学院 (n-异丙基哌嗪基)-2-羟基苯甲酰胺化合物在制备治疗神经退行性疾病药物中的用途

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US620005A (en) * 1899-02-21 Loom-temple
JPS56158737A (en) * 1980-05-07 1981-12-07 Kowa Co Phenyl ester
JPS57203060A (en) * 1981-06-05 1982-12-13 Kowa Co Piperazine derivative
EP0071433A1 (en) * 1981-07-28 1983-02-09 Kowa Company, Ltd. Medicine for the treatment of diabetes
JPS5821622A (ja) * 1981-07-28 1983-02-08 Kowa Co 糖尿病治療用薬剤

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DE3372966D1 (en) 1987-09-17
EP0098713A2 (en) 1984-01-18
DK290583A (da) 1983-12-26
AU545463B2 (en) 1985-07-18
ES523561A0 (es) 1985-03-16
EP0098713A3 (en) 1984-12-27
US4898876A (en) 1990-02-06
DK158983C (da) 1991-01-07
ES8503678A1 (es) 1985-03-16
CA1210005A (en) 1986-08-19
KR840005120A (ko) 1984-11-03
KR900003278B1 (ko) 1990-05-12
DK290583D0 (da) 1983-06-23
AU1593183A (en) 1984-01-05
EP0098713B1 (en) 1987-08-12

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