WO1988009785A1 - Amides a base d'acide butenoique, leurs sels, compositions pharmaceutiques contenant ces amides et procede pour leur preparation - Google Patents

Amides a base d'acide butenoique, leurs sels, compositions pharmaceutiques contenant ces amides et procede pour leur preparation Download PDF

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Publication number
WO1988009785A1
WO1988009785A1 PCT/HU1988/000041 HU8800041W WO8809785A1 WO 1988009785 A1 WO1988009785 A1 WO 1988009785A1 HU 8800041 W HU8800041 W HU 8800041W WO 8809785 A1 WO8809785 A1 WO 8809785A1
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WO
WIPO (PCT)
Prior art keywords
substituted
group
phenyl
halogen
general formula
Prior art date
Application number
PCT/HU1988/000041
Other languages
English (en)
Inventor
János Fischer
László Dobay
György FEKETE
Elemér Ezer
Judit Matuz
László Szporny
Original Assignee
Richter Gedeon Vegyészeti Gyár RT
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Richter Gedeon Vegyészeti Gyár RT filed Critical Richter Gedeon Vegyészeti Gyár RT
Publication of WO1988009785A1 publication Critical patent/WO1988009785A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups

Definitions

  • the invention relates to novel 4-oxo-4-
  • R stands for hydrogen, halogen, C 1-4 alkyl, C 1-4 - alkoxy or (C 1-4 acyl)amino group
  • R 1 means straight or branched chain C 1-6 alkylene group optionally substituted by a mercapto, hydroxyl, C 1-3 alkylthio or phenyl or indolyl group, wherein the phenyl group optionally may in itself be substituted by halogen or hydroxyl group and the indolyl group optionally may in itself be substituted by halogen; and
  • R 2 stands for hydrogen or C 1-4 alkyl group of E and/or Z configuration as well as their salts and pharmaceutical compositions containing these compounds
  • the compounds of the general formula (I) contain a double bond thus, they can exist in the form of the E or Z geometrical isomer.
  • the general formula (I) may represent any of the enantiomers or a mixture containing these enantiomers in an optional ratio.
  • R stands for hydrogen, halogen, C 1-4 alkyl, C 1-4 - alkoxy or (C 1-4 acyl)amino group
  • R 1 means straight or branched chain C 1-6 alkylene group optionally substituted by a mercapto, hydroxyl, C 1-3 alkylthio or phenyl or indolyl group, wherein. the phenyl group optionally may in itself be substituted by halogen or hydroxyl group and the indolyl group optionally may in itself be substituted by halogen
  • R 2 stands for hydrogen or C 1-4 alkyl group and salts thereof, which comprises reacting a compound of the general formula (II)
  • R is as defined above, or with a carboxylic group-activated derivative thereof and, if desired, removing any optionally present protective group in a known manner and/or, if desired, changing in the obtained compound of the general formula (I) the configuration, determined by the double bond, in a known way.
  • a substituted butenoic acid of the general formula (III) or a carboxylic group-activated derivative thereof, which may have E or Z configuration on basis of the geometry of the double bond is reacted with an amino acid derivative of the general formula (II) in an inert organic solvent.
  • Activated derivatives of the compounds of general formula (III) are their esters, acid halides or acid anhydrides or a derivative formed with an activating reagent each of which can be prepared in a manner known per se.
  • Carbodiimides such as dicyclohexylcarbodiimide may preferably be used as activating reagents.
  • the reaction is preferably carried out in anhydrous dichloromethane as inert organic solvent at a temperature between 0 °C and 20 °C.
  • Diphenylphospinyl chloride may also be employed as activating agent preferably in ethyl acetate as an inert organic solvent at -10 °C as described in the literature (Houben-Weyl as cited above, Vol. E5, p. 949, 1985) by adding a stoichiometric amount of a base, preferably triethylamine or N-methylmorpholine to the reaction mixture for binding the hydrogen chloride formed.
  • the E and Z isomers of the compounds of the general formula (I) can be converted into each other under the effect of e.g. UV light in the presence of an inert organic solvent.
  • the compounds of the general formula (I) contain ing hydrogen as R 2 are prepared in such a way that any group, which is bound in the carboxylic group and is different from hydrogen, is removed in a known way, e.g. by using trifluorocacetic acid.
  • ethyl N-(4-oxo-4-phenyl-2(E)-butenoyl)- ⁇ -alaninate and related compounds proved to possess cytoprotective action which could be demonstrated by using the method of A. Robert [Gastroenterology 77, 761 ( 1919)] as follows.
  • ED 50 values of the compounds according to the invention proved to be 2 to 3 mg/kg.
  • their toxicity values were also very favourable since no toxic symptoms were observed after the single oral administration of 1000 mg/kg of body-weight.
  • Example 1 The invention is illustrated in detail by the following non-limiting Examples.
  • Example 1 The invention is illustrated in detail by the following non-limiting Examples.
  • a suspension containing 3.0 g (17 mmol) of 4- -oxo-4-phenyl-2(E)-butenoic acid and 2.85 g (17 mmol) of ethyl ⁇ -aminobutyrate hydrochloride in 50 ml of dichloromethane is cooled to 0 °C, 1.72 g (17 mmol) of N-methylmorpholine are added and after stirring for 5 minutes a solution of 3.50 g (17 mmol) of dicyclohexyl carbodlimide in 10 ml of dichloromethane is added to the reaction mixture.
  • the precipitated dicyclohexylurea is filtered and the filtrate is extracted twice with 15 ml of 1N hydrochloric acid each, with 15 ml of water, then twice with 15 ml of saturated aqueous sodium carbonate solution each and finally with 15 ml of water.
  • the organic phase is dried over anhydrous magnesium sulfate. then the solvent is evaporated.
  • the residue is crystallized from ethyl ether to give 2.05 g (42%) of the title compound, m.p.: 56-57 oC.
  • the filtrate is extracted twice with 15 ml of IN hydrochloric acid each, then with 15 ml of water, twice with 15 ml of saturated aqueous sodium carbonate solution each and finally with 15 ml of water.
  • the organic phase is dried over anhydrous magnesium sulfate and the solvent is evaporated.
  • the oily residue is dissolved in 20 ml of dichloromethane and 20 ml of trifluoroacetic acid are added dropwise to the solution while cooling.
  • the filtrate is extracted twice with 15 ml of 1N hydrochloric acid each, then with 15 ml of water, twice with 15 ml of 10% aqueous sodium carbonate solution each and finally with 15 ml of water.
  • a suspension of 3.80 g (20 mmol) of 4-(4-methyl- phenyl)-4-oxo-2(E)-butenoic acid and 3.07 g (20 mmol) of ethyl (S)-alaninate hydrochloride in 60 ml of dichloromethane is cooled to 0 oC and first 2 .02 g (20 mmol) of N-methylmorpholine and then 4.12 g (20 mmol) of dicyclohexylcarbodiimide are added.
  • the filtrate is extracted twice with 15 ml of 1N hydrochloric acid each, then with 15 ml of water, twice with 15 ml of saturated aqueous sodium carbonate solution each and finally with 15 ml of water.
  • the precipitated dicyclohexylurea is filtered and the filtrate is extracted twice with 15 ml of IN hydrochloric acid each, then with 15 ml of water, twice with 15 ml of saturated aqueous sodium carbonate solution each and finally with 15 ml of water.
  • the residue is crystallized from ethyl ether to give 3.30 g (64%) of the title compound, m.p.: 86-88 °C.
  • the precipitated dicyclohexylurea is filtered and the filtrate is extracted twice with 15 ml of 1N hydrochloric acid each, then with 15 ml of water, twice with 15 ml of 10% aqueous sodium carbonate solution each and finally with 15 ml of water.
  • the oily residue is crystalized by using ethyl ether to give 3.10 g (50%) of the title compound, m.p.: 112-114 °C.
  • the filtrate is extracted twice with 20 ml of IN hydrochloric acid each, then with 20 ml of water, twice with 20 ml of saturated aqueous sodium carbonate solution each and finally with 20 ml of water.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention se rapporte à de nouveaux composés représentés par la formule générale (I), où R représente un groupe hydrogène, halogène, C1-4alkyle, C1-4alkoxy ou (C1-4acyl)amino; R1 représente un groupe alkylène C1-6 à chaîne droite ou ramifiée éventuellement substitué par un groupe mercapto, hydroxyle, C1-3 alkythio, phényle ou indolyle, où le groupe phényle peut éventuellement en lui-même être substitué par un groupe halogène ou hydroxyle et le groupe indolyle peut éventuellement en lui-même être substitué par un halogène; et R2 représente un groupe hydrogène ou C1-4 alkyle à configuration en E et/ou en Z. La présente invention se rapporte également aux sels de ces nouveaux composés. Lesdits composés présentent un effet cytoprotecteur et leur toxicité est faible.
PCT/HU1988/000041 1987-06-10 1988-06-10 Amides a base d'acide butenoique, leurs sels, compositions pharmaceutiques contenant ces amides et procede pour leur preparation WO1988009785A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU2637/87 1987-06-10
HU263787A HU198294B (en) 1987-06-10 1987-06-10 Process for producing butenoic acid amides and pharmaceutical compositions comprising such active ingredient

Publications (1)

Publication Number Publication Date
WO1988009785A1 true WO1988009785A1 (fr) 1988-12-15

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU1988/000041 WO1988009785A1 (fr) 1987-06-10 1988-06-10 Amides a base d'acide butenoique, leurs sels, compositions pharmaceutiques contenant ces amides et procede pour leur preparation

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Country Link
CN (1) CN1030229A (fr)
HU (1) HU198294B (fr)
WO (1) WO1988009785A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0309261A2 (fr) * 1987-09-25 1989-03-29 Richter Gedeon Vegyeszeti Gyar R.T. Amides d'acide buténoique, leur sels, compositions pharmaceutiques les contenant et leur procédé de préparation
WO1993012070A1 (fr) * 1991-12-19 1993-06-24 Richter Gedeon Vegyszeti Gyár Rt. Nouveaux derives de tetrahydronaphtalene

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1064400C (zh) * 1997-05-09 2001-04-11 司纪圣 添加蝎、蚁活性有效成分的保健酒及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2454094A1 (de) * 1973-11-15 1975-05-22 Merck & Co Inc Substituierte benzoylacrylanilide
DE3214082A1 (de) * 1981-04-17 1982-11-04 Roussel-Uclaf, 75007 Paris Neue derivate von phenyl-aliphatischen carbonsaeuren, deren herstellung, deren verwendung als arzneimittel und die sie enthaltenden zusammensetzungen

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2454094A1 (de) * 1973-11-15 1975-05-22 Merck & Co Inc Substituierte benzoylacrylanilide
DE3214082A1 (de) * 1981-04-17 1982-11-04 Roussel-Uclaf, 75007 Paris Neue derivate von phenyl-aliphatischen carbonsaeuren, deren herstellung, deren verwendung als arzneimittel und die sie enthaltenden zusammensetzungen

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0309261A2 (fr) * 1987-09-25 1989-03-29 Richter Gedeon Vegyeszeti Gyar R.T. Amides d'acide buténoique, leur sels, compositions pharmaceutiques les contenant et leur procédé de préparation
EP0309261A3 (en) * 1987-09-25 1990-06-13 Richter Gedeon Vegyeszeti Gyar R.T. Butenoic acid amides, their salts, pharmaceutical compositions containing them and process for preparing same
WO1993012070A1 (fr) * 1991-12-19 1993-06-24 Richter Gedeon Vegyszeti Gyár Rt. Nouveaux derives de tetrahydronaphtalene

Also Published As

Publication number Publication date
CN1030229A (zh) 1989-01-11
HU198294B (en) 1989-09-28
HUT47899A (en) 1989-04-28

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