WO1983000334A1 - Phenylalkyloxirane carboxylic acids, preparation and therapeutical use - Google Patents

Phenylalkyloxirane carboxylic acids, preparation and therapeutical use Download PDF

Info

Publication number
WO1983000334A1
WO1983000334A1 PCT/EP1982/000156 EP8200156W WO8300334A1 WO 1983000334 A1 WO1983000334 A1 WO 1983000334A1 EP 8200156 W EP8200156 W EP 8200156W WO 8300334 A1 WO8300334 A1 WO 8300334A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
denotes
methyl
hydrogen atom
lower alkyl
Prior art date
Application number
PCT/EP1982/000156
Other languages
English (en)
French (fr)
Inventor
Gulden Lomberg Chemische Fabrik Gesellschaft ... Byk
Gerhard Ludwig
Horst Wolf
Original Assignee
Kohl, Bernhard
Eistetter, Klaus
Amschler, Hermann
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 Kohl, Bernhard, Eistetter, Klaus, Amschler, Hermann filed Critical Kohl, Bernhard
Priority to AU86836/82A priority Critical patent/AU8683682A/en
Publication of WO1983000334A1 publication Critical patent/WO1983000334A1/en
Priority to DK1330/83A priority patent/DK133083D0/da

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals

Definitions

  • the invention relates to phenyIaIkyIoxirane carboxylic acids, a process for their preparation, their use, and medicaments containing them.
  • the invention relates to phenylaIkyIoxirane- carboxylic acids of the general formula I
  • R 1 denotes a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a trifluoromethyl group
  • R 2 has one of the meanings of R 1 ,
  • A denotes a single bond, a -CH(R 6 )-CH(R 7 )- group, a -CH(R 6 )-(H(R 7 )-CH(R 8 )- group or a
  • R 5 denotes a hydrogen atom or a lower alkyl group and one of the substituents R 3 , R 4 , R 6 , R 7 , R 8 or R 9 represents a lower alkyl group and the others denote hydrogen atoms, and the salts of the carboxylic acids.
  • Possible lower alkyl groups are straight-chain or branched alkyl radicals with 1 to 4 carbon atoms.
  • straight-chain alkyl radicals are the methyl, ethyl, n-propyl and n-butyl radical, of which those with 1 and 2 carbon atoms are preferred.
  • branched alkyl radicals are the isopropyl, isobutyl and sec-butyl radicals, of which that with 3 carbon atoms is preferred.
  • Possible alkyl radicals in lower alkoxy groups are both straight-chain and branched lower alkyl groups The methoxy group is the preferred lower alkoxy group.
  • Halogen atorcs are fluorine, chlorine or bromine atoms, of which fluorine and, in particular, chlorine are preferred.
  • the substituents R 1 and R 2 are preferably in the meta- or para-position relative to the aIkyleneoxiranecarboxylic acid radical.
  • Possible salts are salts with inorganic and organic bases. Pharmacologically unacceptable salts are converted into pharmacologicaIly, that is to say biologically, acceptable salts, which are preferred amongst the salts according to the invention, in a manner which is in itself known.
  • Cations which are used for salt formation are, above all, the cations of the alkali metals, alkaline earth metals or earth metals, but the corresponding cations of organic nitrogen bases, such as amine , aminoalkanols, amino sugars, basic aninoacids and the like can also be used.
  • Examples which may be mentioned are the salts of lithium, sodium, potassium, magnesium, calcium, aluminum, ethylenediamine, dimethyIamine, diethyIamine, morphotine, piperidine, piperazine, N-lower aIkyIpiperazines (for example N-methyIpiperazine), methyIeyeIohexyIamine, benzylamine, ethanoIamine, diethanoIamine, triethanol amine, tris- (hydroxymethyI)-aminomethane, 2-amino-2- methylpropanol, 2-amino-2-methyl-1,3-propanedioI, gluc amine, N-methyIglucamine, glucosamine, N-methyIglucos amine, lysine, ornithine, arginine and quinoline.
  • N-lower aIkyIpiperazines for example N-methyIpiperazine
  • A denotes a single bond, a -CH(R 6 )- CH(R 7 )-group or a -CH(R 6 )-CH (R 7 )-CH(R 8 )-group
  • R 5 denotes a hydrogen atom or a lower alkyl group and one of the sub stituents
  • R 3 , R 4 , R 6 , R 7 or R 8 represents a methyl or ethyl group and the others denote hydrogen atoms
  • the salts of the carboxylic acids form an embodiment of the invention.
  • Preferred compounds of the general formula I are those, wherein R 1 and R 2 are meta- or para-substituents, R 1 denotes a hydrogen atom, a chlorine atom or a trifluoromethyl group,
  • R 2 denotes a hydrogen atom
  • A denotes a single bond, a -CH(R 6 )-CH(R 7 )-group or a -CH (R 6 ) -CH(R 7 ) -CH (R 8 ) -CH(R 9 )-group,
  • R 5 denotes a hydrogen atom or a lower alkyl group with 1 to 4 carbon atoms
  • one of the substituents R 3 , R 4 , R 6 , R 7 , R 8 or R 9 represents a methyl or ethyl group and the others denote hydrogen atoms, and the salts of the carboxylic acids.
  • Particularly preferred compounds of the general formula I are those, wherein R is a para-substi tuent and denotes a hydrogen atom or a chlorine atom, R 2 denotes a hydrogen atom, A denotes a -CH(R 6 )-CH(R 7 )-group or a -CH(R 6 )-CH(R 7 )-CH(R 8 )-CH(R 9 )-group, R 5 denotes a hydrogen atom, a methyl group or an ethyl group, R 4 denotes a hydrogen atom, R 8 denotes a hydrogen atom, one of the substituents R 3 , R 6 , R 7 or R 9 represents a methyl or ethyl group and the others denote hydrogen atoms, and the pharmacologically acceptable salts of the carboxylic acids.
  • Examples of representatives of the compounds according to the invention which may be mentioned are 2- (2-ethyI-3- phenyIpropyl)-oxirane-2-carboxylic acid ethyl ester, 2- ⁇ 3-(3-chlorophenyl)-1-methyIpropyI
  • Preferred representatives are 2-(4-methyl-5-phenylpentyl)-oxirane-2-carboxylic acid ethyl ester, 2-(2-ethyl- 5-phenylpentyl)-oxirane-2-carboxylic acid ethyl ester, 2-[5-(4-chlorophenyl)-4-methylpentyl]-oxirane-2-carboxylic- acid ethyl ester, 2-(4-methyl-7-phenylheptyl)-oxirane-2- carboxylic acid ethyl ester and 2- (5-methyl-5-phenylpentyl)- oxirane-2-carboxylic acid ethyl ester, and the corresponding phenylalkyloxirane-2-carboxylic acids and pharmacologically acceptable salts thereof.
  • the phenylalkyloxiranecarboxylic acids of the general formula I have two centers of chirality. The invention thus includes the diastere
  • the compounds according to the invention have valuable pharmacological properties which render them commercially useful. They lower the blood glucose level and the level of ketone substances in the blood, and they differ fundamentally from beta-cytotropic substances which act on the pancreas (for example sulphony lureas) in their chemical structure and their activity by their extrapancreatic action, and they have proved superior to commercial products with an extrapancreatic action. In addition, they are distinguished by their long-term action.
  • the substituted oxiranecarboxylic acids of the general- formula I according to the invention and their pharmacologically acceptable salts are suitable for the treatment and prophylaxis, in human and veterinary medicine, of illnesses which are based on disorders of glucose metabolism and lipid metabolism.
  • diseases which are based on disorders of glucose metabolism and lipid metabolism.
  • conditions which are treated are prediabetic conditions for preventing manifestation of diabetes, manifest diabetes for example adult diabetes. labile diabetes in juveniles and all morbid conditions accompanied by a pathologically increased production of ketone substances.
  • the invention thus also relates to a method for combating the illnesses mentioned by administration of the compounds according to the invention.
  • the invention furthermore relates to the use of the compounds according to the invention in combating the illnesses mentioned.
  • the invention also relates to medicaments which contain one or more of the phenylaIkyloxiranecarboxylic acids of the general formula I and/or the pharmacologically acceptable salts of the acids with inorganic or organic bases.
  • the invention furthermore relates to the use of the compounds according to the invention for the preparation of medicaments for combating the illnesses mentioned.
  • the medicaments are prepared by processes which are in themselves known.
  • the new compounds can be employed as such or, if appropriate, in combination with suitable pharmaceutical excipients.
  • the new pharmaceutical formulations contain pharmaceuti cal excipients in addition to the active compounds, the content of active compound in these mixtures is 1 to 95, preferably 15 to 85, per cent by weight of the total mixture.
  • the active compounds can be used, in the field of human medicine, in any desired form, for example systemicaIly, provided that the establishment and maintenance of sufficient levels of active compounds ia the blood or tissue are ensured. This can be achieved, for example, by oral or parenteral administration in suitable doses.
  • the pharmaceutical formulation of the active compound is advantageously in the form of unit doses appropriate for the desired adminis tration.
  • a unit dose can be, for example, a tablet, a dragee, a capsule, a suppository or a measured volume of a powder, of granules, of a solution, of an emulsion or of a suspension.
  • Unit dose for the purpose of the present invention means a physically discrete unit which contains an individual amount of the active ingredient in combination with a pharmaceutical excipient, the content of active compound in the unit dose corresponding to a fraction or multiple of a therapeutic individual dose.
  • An individual dose preferably contains the amount of active compound which is given in one administration and usually corresponds to a whole daily dose or a half, one-third or one- quarter of the daily dose. If only a fraction, such as a half or one-quarter, of the unit dose is required for an individual therapeutic administration, the unit dose is advantageously divisible, for example in the form of a tablet with a breaking groove.
  • the pharmaceutical formulations according to the invention contain about 2 to 200 mg, advantageously 10 to 100 mg and in particular 20 to 60 mg, of active compound.
  • the active compound or compounds in general, it has proved advantageous in human medicine to administer the active compound or compounds, when these are given orally, in a daily dose of about 0.1 to about 30, preferably 0.3 to 15 and in particular 0.6 to 3, mg/kg of body weight, if appropriate in the form of several, preferably 1 to 3, individual administrations to achieve the desired result.
  • An individual administration contains the active compound or compounds in amounts of about 0.05 to about 10, preferably 0.1 to 5 and in particular 0.3 to 1, mg/kg of. body weight.
  • Similar dosages can be used for parenteral treatment, for example intravenous or intramuscular administra tion. In this therapy, about 0.3 to 1 mg of active compound/kg of body weight is administered.
  • the pharmaceutical formulation is in general administered, for therapeutic purposes, at fixed points in time, such as 1 to 4 times daily, for example after each meal and/or in the evening.
  • medication takes place at varying points in time.
  • the optimum dosage and administration of the active compounds required in each particular case can be determined by the expert in accord ance with his expert knowledge.
  • the pharmaceutical formulations as a rule consist of the active compounds according to the invention and non-toxic, pharmaceutically acceptable medicinal excipients, which are used as an admixture or diluent in solid, semi-solid or liquid form, or as a means of encasing, for example in the form of a capsule, a tablet coating, a sachet or some other container for the therapeuticaIly active ingredient.
  • An excipient can, for example, serve as a promoter of the absorption of the medicament by the body, as a formulating auxiliary, as a sweetener, as a flavour correcter, as a colorant or as a preservative .
  • forms which may be used orally are tablets, dragees, hard and soft capsules, for example made of gelatine, dispersible powders, granules and aqueous and oily suspensions, emulsions and solutions.
  • Tablets may contain inert diluents, for example calcium carbonate, calcium phosphate, sodium phosphate or xylitol; granulating agents and dispersing agents, for example calcium phosphate or alginates; binders, for example starch, gelatine or gum acacia; and lubricants, for example aluminium stearate or magnesium stearate, talc or silicone oil.
  • the tablets may additionally be provided with a coating, which can also be such that delayed dissolution and absorption of the medicament in the gastrointestinal tract and hence, for example, better toleration, a protracted effect or a retarded effect are achieved.
  • Gelatine capsules may contain the medicament mixed with a solid diluent, for example calcium carbonate or kaolin, or an oily diluent, for example paraffin oil.
  • Aqueous suspensions may contain suspending agents, for example sodium carboxymethyIcetIulose, methyIceIlu lose, hydroxypropyIceIIulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth or gum acacia; dispersing agents and wetting agents, for example polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethyIene sorbitol monooleate, polyoxyethylene sorbitan monooleate or lecithin; preservatives, for example methyl hydroxybenzoate or propyl hydroxybenzoate; flavouring agents; and sweeteners, for example saccharin or sodium cyclamate .
  • suspending agents for example sodium carboxymethyIcetIulose
  • Oily suspensions may contain, for example, paraffin oil and thickeners, such as beeswax, hard paraffin or cetyl alcohol; and furthermore sweeteners, flavouring agents and antioxidants.
  • Water-dispersible powders and granules may contain the medicaments mixed with dispersing agents, wetting agents and suspending agents, for example those mentioned above, as well as with sweeteners, flavouring agents and colorants.
  • Emulsions may contain, for example, paraffin oil, in addition to emulsifying agents, such as, for example, gum acacia, gum tragacanth, phosphatides, sorbitan monooleate or polyoxyethylene sorbitan monooleate, and sweeteners and flavouring agents.
  • emulsifying agents such as, for example, gum acacia, gum tragacanth, phosphatides, sorbitan monooleate or polyoxyethylene sorbitan monooleate, and sweeteners and flavouring agents.
  • sterile injectable aqueous suspensions for parenteral administration of the medicaments, sterile injectable aqueous suspensions, isotonic salt solutions or other solutions which contain dispersing agents or wetting agents and/or pharmacologically acceptable diluents, for example propylene glycol or butylene glycol, are used.
  • the active compound or compounds can also be used in a microencapsulated form, if appropriate together with one or more of the abovementioned excipients or auxili
  • the pharmaceutical formulations can also contain one or more pharmacologically active ingredients from other groups of medicaments, such as antidiabetics (suIphonamides, sul phonylureas and the like), for example carbutamide, tol butamide, chlorproparaide, glibenclamide, glibornuride, glisoxepide, gliquidone and glymidine, or hypolipaemic agents, such as nicotinic acid and derivatives and salts thereof.
  • antidiabetics suIphonamides, sul phonylureas and the like
  • carbutamide tol butamide
  • chlorproparaide glibenclamide
  • glibornuride glisoxepide
  • gliquidone and glymidine or hypolipaemic agents
  • the invention furthermore relates to a process for the preparation of phenylaIkyloxiranecarboxyIic acids of the general formula I and the salts of the carboxylic acids, which is characterised in that phenylalkyl-2-methylenecarbo xylic acids of the general formula II
  • R 1 , R 2 , R 3 , R 4 , R 5 , and A have the abovementioned meanings, are oxidised and, if appropriate, the resulting lower alkyl esters are then hydrolysed, or the resulting acids are then converted into salts or lower alkyl esters.
  • the ⁇ -methylenecarboxylic acids II are oxidised under conditions known to the expert for oxidation of carbon-carbon double bonds to give epoxides.
  • oxidising agents are peroxo compounds, such as hydrogen peroxide, peracetic acid, trifluoroperacetic acid, 3,5-dinitroperbenzoic acid and, preferably, m chloroperbenzoic acid and permaleic acid.
  • the reaction is advantageously carried out in inert solvents, for example aromatic or chlorinated hydrocarbons, such as benzene, toluene, methylene chloride and chloroform.
  • reaction temperatures are between 0o and the boiling point of the solvent, preferably between 20o and 70oC.
  • the Lower alkyl esters are hydrolysed in a manner which is in itself known.
  • the hydrolysis is carried out, for example, with an aqueous or alcoholic (for example ethanolic) alkali metal hydroxide (for example potassium hydroxide) solution at room temperature, if appropriate with the addition of an inert diluent, such as dioxane or toluene.
  • an aqueous or alcoholic (for example ethanolic) alkali metal hydroxide (for example potassium hydroxide) solution at room temperature, if appropriate with the addition of an inert diluent, such as dioxane or toluene.
  • the inorganic or organic base of which the salt is desired is used as the alkaline reactant.
  • R 5 lower alkyl
  • they are esterified with lower alkanols in the presence of strong acids, such as sulphuric acid or p- toluenesulphonic acid, or acid ion exchangers under conditions under which no decarboxy lation takes place, or with dialkyl sulphates or alkyl halides in the presence of diazabicycloundecene or diazabicy clononene in inert solvents, such as benzene, toluene or acetone.
  • strong acids such as sulphuric acid or p- toluenesulphonic acid, or acid ion exchangers under conditions under which no decarboxy lation takes place
  • dialkyl sulphates or alkyl halides in the presence of diazabicycloundecene or diazabicy clononene in inert solvents, such as benzene, toluene or acetone.
  • the compounds of the general formula I are usually obtained in the form of diastereomers or racemates, which can be separated into the enantiomers by means of known processes.
  • the diastereomers are separated, for example, on the basis of their different physicochemical properties, such as melting point or solubility;
  • the racemates are separated into the optically active isomers with the aid of optically active resolving agents, for example optically active bases, such as I- and d-1-phenyl ethylamine, cinchonidine or d-ephedrine, from which salts of the acids of the general formula I are prepared, or with the aid of optically active alcohols, such as borneol or menthol, from which esters of the carboxylic acids of the general formula I are prepared.
  • optically active resolving agents for example optically active bases, such as I- and d-1-phenyl ethylamine, cinchonidine or d-ephedrine, from which salt
  • Racemic mixtures can also be resolved into the optical isomers by chromato graphy over optically active sorbents.
  • the ⁇ ,-methylenecarboxyIic acids II are first reacted with an optically active resolving agent, for example borneol or menthol, and the resulting products are oxidised to the corresponding diastereomer mixtures of the phenyl alkyloxiranecarboxylic acid esters, from which the optical isomers of the acids I can be obtained in the customary manner.
  • an optically active resolving agent for example borneol or menthol
  • phenylalkyl - ⁇ -methylenecarboxylic acids of the general formula II can be prepared by methods which are in themselves known. They are valuable intermediate products for the synthesis of the oxiranecarboxylic acids I.
  • phenylalkyl- ⁇ -methylenecarboxyIic acids II are prepared, for example, by a process analogous to that of H. Stetter and H. Kuhlmann
  • R 1 , R 2 , R 3 , R 4 , and A have the - abovementioned meaning and
  • R 10 denotes a lower alkyl group, with formaldehyde in pyridine in the presence of secondary amines, preferably piperidine, and, if appropriate, then hydrolysing the resulting lower alkyl esters.
  • the malonic acid half-esters III are prepared by condensation of oxo compounds IV with aIkylidene-malonates V and hydrogenation of the resulting phenylaIkyIidene malonic acid half-esters VI in accordance with the follow ing equation
  • R 1 , R 2 , R 3 , R 4 and R 10 have the abovementioned meanings and
  • the oxo compounds IV are condensed with the alkylidene-malonates V under mild conditions and in very good yield.
  • oxo compounds IV in which 8 does not represent a single bond undergo condensation without further reaction or sidereactions.
  • the invention thus also relates to a process for the preparation of phenylaIkyIidene-malonic acid half-esters VI' which is characterised in that oxo compounds of the general formula IV'
  • R 1' and R 2' have the meanings of and R 2 ,
  • B' denotes a -CH (R 6' )-CH(R 7' )- group, a
  • R 3' , R 4' , R 6' , R 7' , R 8' and R 9' denote hydrogen atoms or one of the substituents denotes a lower alkyl group and the others denote hydrogen atoms and R 10' has the meanings of R 10
  • the condensation of the oxo compounds IV or IV' is preferably carried out in alkanols, in particular inR 10 -OH, at room temperature in the presence of molaramounts of benzyltrialkylammonium hydroxides, wherein alkyl has 1 to 11 carbon atoms and is preferably an ethyl or methyl group, or tetraalkylammonium hydroxides, wherein alkyl has 1 to 11 carbon atoms and is preferably a cetyl, ethyl or methyl group.
  • condensation with yields which are not substantially lower it is also possible to use molar amounts of ethanolic sodium or potassium hydroxide in the presence of catalytic amounts of benzyltriaIkylammonium halides, the corresponding benzyItriaIkyIammonium hydroxide being intermediately formed. Even in the absence of catalytic amounts of benzyItriaIkylammonium halide, the condensation proceeds smoothly and with reasonable yields. Working up in aqueous solution then gives, after acidification, the corresponding compounds VI.
  • the phenylalkylidenemaIonic acid half-esters VI a re hydrogenated by methods such as are in themselves known to the expert.
  • the hydrogenation is carried out with hydrogen on palladium, platinum, rhodium or ruthenium, at 0o to 60oC, preferably at room temperature, under a pressure of 1-200 bar, preferably 1- 10 bar, in an inert solvent, such as ethanol, ethyl acetate or, preferably, R 10 -OH.
  • 29 g of 5-(4-chlorophenyl)-2-ethyIpentyImalonic acid monoethyl ester are obtained as a viscous oil from 30 g of 6-(4-chlorophenyI)-3-ethyl-1,3,5-hexatriene-1,1- dicarboxylic acid monoethyl ester with hydrogen in the presence of 1.5 g of platinum-on-charcoal (5% strength) in 400 ml of ethanol by the procedure described in Example 1 c). Chromatography on silica gel under neutral conditions in chloroform/methanol (19:1) gives an R f value of 0.30.
  • 6-(4-ChlorophenyI)-3-ethyl-1,3,5-hexatriene-1,1- dicarboxylic acid monoethyl ester 32 g of 6-(4-chlorophenyl)-3-ethyl-1,3,5-hexatriene-1,1-dicarboxyIic acid monoethyl ester are obtained as a pale yellow solid of m.p.
  • 17.6 g of freshly ground maleic anhydride are added all at once to a solution, prepared at 0o, of 6.0 g of 85% strength hydrogen peroxide in 100 ml of methylene chloride, whereupon the temperature drops from 0 to -5°.
  • 17.6 g of 7-methyI-2-methylene-7-phenyIheptanoic acid ethyl ester in 50 ml of methylene chloride a re added to the solution of permaleic acid and the mixture is then healed at the boiling point under reflux for 16 hours.
  • the maleic acid which has separa ted out is filtered off, the filtrate is stirred with 150 ml of saturated sodium bicarbonate solution for two hours, first whilst cooling with ice and then at room temperature, the organic phase is separated off and the extractive stirring is repeated again. After the phases have been separated again, the organic phase is stirred with 30 g of solid sodium bisulphite (1 hour) (test for peroxide: negative) and filtered, the fil trate is concentrated completely and the residue is dis tilled. - This gives 10.5 g of the title compound of b.p. 134-138° under 0.005 mm Hg (0.66 Pa ) .
  • a solution of 4.0 g (0.1 mol) of sodium hydroxide in 100 ml of ethanol is added drop wise to a solution of 16.6 g (0.1 mol) of chlorocinnam aldehyde, 20 g (0.11 mol) of ethyIidenemaIonic acid diethyl ester and 4.5 g (0.02 mol) of benzyItriethyIammonium chloride in 100 ml of ethanol, whilst cooling with ice, and the mixture is subsequently stirred for 24 hours and worked up analogously to Example 10a).
  • a solution of 4.0 g (0.1 mol) of sodium hydroxide in 100 ml of ethanol is added dropwise to a solution of 16.6 g (0.1 mol) of 4-chlorocinnamaldehyde and 20 g (0.1 mol) of ethylidenemalonic acid diethyl ester in 100 ml of ethanol, whilst cooling with ice, and the mixture is stirred for 24 hours and worked up analogously to Example 10 a).
  • the catalyst is filtered off, the residue on the filter is washed with 100 m of ethanol and the filtrate is concentrated completely at 40-50o on a rotary evaporator. This gives 103 g of 5- (4-chlorophenyl)-pentyImalonic acid monoethyl ester as a viscous oil. A sample is chromatographed on silica gel under neutral conditions with chloroform/methanol
  • Example 11 6-Phenyl-1,3,5-hexatriene-1,1-dicarboxylic acid monoethyl ester a) 38.8 g of 6-phenyl-1,3,5-hexatriene-1,1-dicarboxy lic acid monoethyl ester of m.p. 139-142o (orange-yellow needles) are obtained from 34 g of cinnamaIdehyde, 52.3 g of ethylidenemalonic acid diethyl ester and 63 g of benzyItriethylammonium hydroxide in 300 ml of ethanol by the procedure described in Example 10 a).
  • Example 12 6-Phenyl-1,3-hexadiene-1,1-dicarboxylic acid monoethyl ester a) 15.8 g of the title compound are obtained as a yellow viscous oil from 13.4 g of 3-phenylpropionaldehyde, 20 g of ethy lidenemalonic acid diethyl ester and 16.5 g of tetraethylammonium hydroxide in 190 ml of ethanol by the procedure described in Example 10 a).
  • Example 11b Example 13 2-(2-Ethyl-3-phenylpropyl)-oxirane-2-carboxylic acid ethyl ester a) 2- (2-Ethyl-3-phenyIpropyl)-oxirane-2-carboxyIic acid ethyl ester
  • 25 g of 4-methyl-7-phenyl heptylmalonic acid monoethyl ester are obtained as a yellow oil from 28 g of 5-methyl-8- phenyl-1,3,5,7-octatetraene-1,1-dicarboxylic acid monoethyl ester with hydrogen in the presence of 3.0 g of palladium-on- charcoal (5% strength) in 400 ml of ethyl acetate by the procedure described in Example 1 c).
  • capsules each containing 30 mg of active compound are prepared from the following ingredients: 300 g of 2-[5-(4-chlorophenyl)-4-methylpentyl]-oxirane-2-carboxylic acid ethyl ester are mixed with 500 g of neutral oil and the mixture is filled into soft gelatine capsules.
  • Example 3
  • the phenylalkyloxiranecarboxylic acids of formula I lower the level of glucose and of ketones in the blood.
  • Their chemical structure differs from that of beta-cytotropic substances (for example sulfonylureas) which have an action on the pancreas, and their mode of action differs fundamen tally from that of these substances in that .they have an extra-pancreatic action.
  • beta-cytotropic substances for example sulfonylureas
  • They are superior to commercial preparations (for example Buformin and Phenformin) having an extra-pancreatic action.
  • they are distinguished by their long-term action.
  • Table I reflects investigations of the effect of representative compounds according to the invention on the blood glucose concentration of fasting, metabol ically healthy rats.
  • Column A in each case gives the maximum lowering of the blood glucose concentration of rats which have been fasted (in %, relative to the control group) which is observed in the course of 6 hours after single oral administration of 0.6 mmole of substance/kg of body weight.
  • Column B provides data relating to acute toxicity (LD 50 ; mice, peroral administration).
  • the pharmacological properties were determined by the follo wing methods:
  • the glucose in the blood is determined by means of the glucose dehydrogenase method [Banauch et al, J. Clin. Chem. Clin. Biochem. 13, 101(1975)] by using commercially available reagents.
  • a control group (10 animals, treated with pure solvent) is also investigated in each case for comparison.
  • the toxicity investigations are carried out on female NMRI mice (body weight: 22 to 26 g). 18 hours before the treatment, the feed (Altromin ® ) for the animals (5 animals per dose) is reduced to 50 g/50 animals and water is available ad libitum. Various doses of the substances (volume: 10 ml/kg) are administered orally by means of a stomach tube. The observation time is 7 days.
  • the LD 50 that is to say the dose at which 50 % of the animals die, is determined graphically from the dose-/response curve.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Epoxy Compounds (AREA)
  • Polyesters Or Polycarbonates (AREA)
  • Pyrane Compounds (AREA)
PCT/EP1982/000156 1981-07-24 1982-07-21 Phenylalkyloxirane carboxylic acids, preparation and therapeutical use WO1983000334A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU86836/82A AU8683682A (en) 1981-07-24 1982-07-21 Phenylalkyloxiranecarboxylic acids, a process for their preparation, their use, and medicaments containing them
DK1330/83A DK133083D0 (da) 1981-07-24 1983-03-23 Fremgangsmade til fremstilling af phenylalkyloxirancarboxylsyrer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH4838/81-1810724 1981-07-24
CH483881 1981-07-24

Publications (1)

Publication Number Publication Date
WO1983000334A1 true WO1983000334A1 (en) 1983-02-03

Family

ID=4283438

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1982/000156 WO1983000334A1 (en) 1981-07-24 1982-07-21 Phenylalkyloxirane carboxylic acids, preparation and therapeutical use

Country Status (11)

Country Link
EP (1) EP0071175B1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
JP (1) JPS58501124A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
AT (1) ATE18556T1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
DE (1) DE3269811D1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
DK (1) DK133083D0 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
ES (1) ES514235A0 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
GR (1) GR76871B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
IL (1) IL66365A0 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
PT (1) PT75311B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
WO (1) WO1983000334A1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
ZA (1) ZA825291B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4750952A (en) * 1984-07-17 1988-06-14 Kawasaki Steel Corporation Cold-rolled steel sheets
WO1998035952A1 (de) * 1997-02-14 1998-08-20 Wolf Horst P O Oxirancarbonsäuren für die behandlung von diabetes

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2556496B2 (ja) * 1985-08-02 1996-11-20 ホルスト パウル オットー ヴォルフ 高脂血症の治療のための薬剤
EP0283168A3 (en) * 1987-03-16 1989-06-14 American Home Products Corporation Fluorooxirane carboxylates
CN111613407B (zh) * 2020-06-03 2022-05-03 福建省长汀金龙稀土有限公司 一种r-t-b系永磁材料、原料组合物及其制备方法和应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0025192A2 (de) * 1979-09-07 1981-03-18 Byk Gulden Lomberg Chemische Fabrik GmbH Substituierte Oxirancarbonsäuren, Verfahren zu ihrer Herstellung, ihre Verwendung und sie enthaltende Arzneimittel

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0025192A2 (de) * 1979-09-07 1981-03-18 Byk Gulden Lomberg Chemische Fabrik GmbH Substituierte Oxirancarbonsäuren, Verfahren zu ihrer Herstellung, ihre Verwendung und sie enthaltende Arzneimittel

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4750952A (en) * 1984-07-17 1988-06-14 Kawasaki Steel Corporation Cold-rolled steel sheets
WO1998035952A1 (de) * 1997-02-14 1998-08-20 Wolf Horst P O Oxirancarbonsäuren für die behandlung von diabetes
US6479676B1 (en) 1997-02-14 2002-11-12 Medigene Ag Gesellschaft Fur Molekularbiologische Kardiologie Und Onkologie OxiranEcarboxylic acids for the treatment of diabetes
US6670481B2 (en) 1997-02-14 2003-12-30 Medicone Ag Gesellschaft Fur Molekularbiologische Kardiologie Oxiranecarboxylic acids for the treatment of diabetes

Also Published As

Publication number Publication date
DK133083A (da) 1983-03-23
IL66365A0 (en) 1982-11-30
ES8307780A1 (es) 1983-08-01
PT75311A (en) 1982-08-01
PT75311B (en) 1985-01-11
ZA825291B (en) 1983-05-25
EP0071175A2 (de) 1983-02-09
ES514235A0 (es) 1983-08-01
DK133083D0 (da) 1983-03-23
JPS58501124A (ja) 1983-07-14
EP0071175A3 (en) 1983-04-13
ATE18556T1 (de) 1986-03-15
DE3269811D1 (en) 1986-04-17
EP0071175B1 (de) 1986-03-12
GR76871B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 1984-09-04

Similar Documents

Publication Publication Date Title
DK171890B1 (da) Analogifremgangsmåde til fremstilling af phen(alk)oxyalkyl-substituerede oxirancarboxylsyrer eller derivater deraf og mellemprodukter til anvendelse som udgangsmaterialer ved fremgangsmåden
EP0202164B1 (fr) Dérivés de (benzoyl-4 pipéridino)-2 phenyl-1 alcanols, leur préparation et leur application en thérapeutique
CA1149404A (en) Substituted oxiranecarboxylic acids, processes for their preparation, their use and medicaments containing them
US4430339A (en) Substituted oxiranecarboxylic acids, their preparation and their use as medicaments
CA1176273A (en) Substituted oxocarboxylic acids, processes for their preparation, their use and medicaments containing them
WO1983000334A1 (en) Phenylalkyloxirane carboxylic acids, preparation and therapeutical use
JPH01106839A (ja) アルカジエン誘導体類、それらの製造、およびそれらを含有している薬学的組成物
FR2662442A1 (fr) Trifluoromethylphenyltetrahydropyridines n-substituees procede pour leur preparation, intermediaires du procede et compositions pharmaceutiques les contenant.
EP0061380A1 (fr) Dérivés d'imidazo (1,2-a) pyrimidines, leur préparation et leur application en thérapeutique
EP0074873B1 (fr) Dérivés de phénoxy-3 propanol-2, leur préparation et leur application en thérapeutique
FR2480286A1 (fr) Nouveaux derives de theophyllinylmethyldioxolane, leurs procedes de preparation et leur application en therapeutique
HU211554A9 (en) Circulation-active dibenzo/1,5/dioxocin-5-ones
GB2171997A (en) 4-Amino-6,7-dimethoxy-2-Piperazin-1-ylquinazoline derivatives
EP0005091B1 (fr) Nouvelles pipérazines monosubstituées, leurs procédés de préparation et les compositions pharmaceutiques les renfermant
JP2001503753A (ja) アリールオキシプロパノールアミン誘導体、その製造方法及びその用途
EP0266246A1 (fr) Dérivés d'imidazo[4,5-b]pyridinone-2, leur préparation et leur application en thérapeutique
EP0061379B1 (fr) Dérivés de pyridine, leur préparation et leur application en thérapeutique
CA1163644A (en) Process for the preparation of epoxycycloalkylalkanecarboxylic acids
US4146728A (en) Esters of 2-[4-(4-chlorobenzoyl)-phenoxy-2-methyl-propionic acid with bis-(hydroxyalkylthio)-alkanes
EP0013726B1 (en) Indanyloxamic derivatives, their preparation and pharmaceutical compositions containing them
EP0100257A2 (fr) Nouveaux dérivés aminoalkyl naphtaléniques, leurs sels d'addition d'acide et le procédé de préparation ainsi que l'application en thérapeutique de ces dérivés et sels
EP0179009A1 (fr) Nouvelles n1-(aminoalcoxy)-4 isopropyl-5 phénoxy)-2 éthyl n4-phényl pipérazines, leur méthode de préparation et leur application thérapeutique
NZ199837A (en) Epoxycycloalkylalkanecarboxylic acids and pharmaceutical compositions
JPH05194316A (ja) ｐ−オキシ安息香酸誘導体、およびその製造方法ならびにｐ−オキシ安息香酸誘導体を有効成分とする低脂肪血剤
FR2461497A1 (fr) Nouvelles compositions therapeutiques a base de certains derives de l'isoquinoleine

Legal Events

Date Code Title Description
AK Designated states

Designated state(s): AU DK JP US