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

Phenylalkyloxirane carboxylic acids, preparation and therapeutical use Download PDF

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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
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group
denotes
methyl
hydrogen atom
lower alkyl
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PCT/EP1982/000156
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French (fr)
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Gulden Lomberg Chemische Fabrik Gesellschaft ... Byk
Gerhard Ludwig
Horst Wolf
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Kohl, Bernhard
Eistetter, Klaus
Amschler, Hermann
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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 DK133083A priority patent/DK133083A/en

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    • 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.

Abstract

Phenylalkyloxirane carboxylic acids of the general formula I $(8,)$wherein 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)-CH(R?7)-CH(R?8)-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 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 are new compounds having a hypoglycaemic action. A process for their preparation and a new process for the preparation of the intermediate products is described.

Description

PHENYLALKYLOXIRANE CARBOXYLIC ACIDS, PREPARATION AND THERAPEURICAL USE
The invention relates to phenyIaIkyIoxirane carboxylic acids, a process for their preparation, their use, and medicaments containing them.
In the context of an investigation into the ability of substituted three-membered ring compounds to be used as a substrate or inhibitor for guinea pig liver microsome epαxyhydrase, phenyIoxiranecarboxyIic acid esters, inter alia, for example 2-phenyl-oxirane-2-car boxylic acid ethyl ester, were employed |F. Oesch et aI., Biochem. 10(1971) No. 26, 4858-66|. In the course of the clarification of the structure of isamic acid |P. de Mayo and J.J. Ryan, Can. J. Chem. 45(1967) 2177-2190 |, methyl 2- (o-a cetarai nobenzyl ) -glycidate was obtained by reacting methyl N-acetylisatinate with excess diazomethane Substituted oxiranecarboxyIic acids are described in German offenlegungsschrift 3,032,669. The condensation of benza Idehydes with ethyIidene-malonate in the preparation of cannabinoids is reported by L. Crombie et al. (Tetrahedron Letters 1979, 49, 4773-76).
The invention relates to phenylaIkyIoxirane- carboxylic acids of the general formula I
Figure imgf000003_0001
wherein
R1 denotes a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a trifluoromethyl group,
R2 has one of the meanings of R1,
A denotes a single bond, a -CH(R6)-CH(R7)- group, a -CH(R6)-(H(R7)-CH(R8)- group or a
-CH(R6)-CH(R7)-CH(R8)-CH(R9)- group,
R5 denotes a hydrogen atom or a lower alkyl group and one of the substituents R3, R4, R6, R7, R8 or R9 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. Examples of 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. Examples of 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 R1 and R2 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.
PhenylalkyloxiranecarboxyIic acids of the general formula I wherein R1 and R2 are meta- or para-substituents and R1 denotes a hydrogen atom, a chlorine atom, a methyl group or a trifluoromethyl group and R2 denotes a hydrogen atom or a chlorine atom, A denotes a single bond, a -CH(R6)- CH(R7)-group or a -CH(R6)-CH (R7)-CH(R8)-group, R5 denotes a hydrogen atom or a lower alkyl group and one of the sub stituents R3, R4, R6, R7 or R8 represents a methyl or ethyl group and the others denote hydrogen atoms, and the salts of the carboxylic acids, form an embodiment of the invention.
Phenylal kyloxiranecarboxyl ic acids of the general formula I wherein R1 and R2 are meta- or para-substituents and R1 denotes a hydrogen atom, a chlorine atom or a trifluoromethyl group and R2 denotes a hydrogen atom, A denotes a single bond or a -CH(R6)-CH(R7)-group, R5 denotes a hydrogen atom, a methyl group or an ethyl group and one of the substituents R3, R4, R6 or R7 represents a methyl group and the others denote hydrogen atoms, and the pharmacologically acceptable salts of the carboxylic acids with inorganic and organic bases, form a further embodiment of the invention.
Preferred compounds of the general formula I are those, wherein R1 and R2 are meta- or para-substituents, R1 denotes a hydrogen atom, a chlorine atom or a trifluoromethyl group,
R2 denotes a hydrogen atom, A denotes a single bond, a -CH(R6)-CH(R7)-group or a -CH (R6) -CH(R7) -CH (R8) -CH(R9)-group,
R5 denotes a hydrogen atom or a lower alkyl group with 1 to 4 carbon atoms, one of the substituents R3, R4, R6 , R7, R8 or R9 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, R2 denotes a hydrogen atom, A denotes a -CH(R6)-CH(R7)-group or a -CH(R6)-CH(R7)-CH(R8)-CH(R9)-group, R5 denotes a hydrogen atom, a methyl group or an ethyl group, R4 denotes a hydrogen atom, R8 denotes a hydrogen atom, one of the substituents R3, R6, R7 or R9 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|-oxirane-2- carboxylic acid methyl ester, 2-|2-methyl-3-(3-trifluoromethyIphenyl)-propyI|-oxirane-2-carboxylic acid ethyl ester, 2-|3-(4-bromophenyl)-2-propyl-propyl)-oxirane-2- carboxylic acid ethyl ester, 2-|5-(4-fluorophenyl)-1- methyIpentyI|-oxirane-2-carboxylic acid isopropyl ester, 2-| 5-(3-chlorophenyl)-2-methyIpentyl|-oxirane-2-carboxylic acid ethyl ester, 2-|4-ethyl-5-(4-methyIphenyl)- pentyl|-oxirane-2-carboxylic acid ethyl ester, 2- |4- methyl-5- (3-trifluoromethyIpheny 10-pentyI|-oxirane-2- carboxylic acid n-butyl ester, 2-(2-butyl-5-phenyIpentyl)- oxirane-2-carboxylic acid ethyl ester, 2-|2-isobutyl-5-(4- methoxyphenyl)- pentyl|- oxirane-2- carboxylic acid isopropyl ester, 2-(2-methyl-6-phenyIhexyl)-oxirane-2-carboxylic acid ethyl ester, 2-|6-(3-chlorophenyl)-2-methyIhexyI|- oxirane-2-carboxylic acid ethyl ester, 2-|7-(3,4-dichlorophenyl)-5-methyIheptyI|-oxirane-2-carboxylic acid methyl ester, 2-|2-ethyl-7-(3-trifluoromethyIphenyI)-heptyI|- oxirane-2-carboxyIic acid n-propyl ester, 2-│7- (4 -chIoro phenyI)-4-methyIheptyI│-oxirane-2-carboxyIic acid ethyl ester, 2-(2-methyl-3-phenylpropyl)-oxirane-2-carboxylic acid n-propyl ester, 2-│2-ethyl-3-(4-fIuorophenyI)-propyI│- oxirane-2-carboxylic acid ethyl ester, 2-│3-(4-bromophenyI)-
1-methyIpropyl│-oxirane-2-carboxyIic acid ethyl ester, 2- │3- (2-chlorophenyI)-1-methyIpropyI│-oxirane-2-carboxylic acid ethyl ester, 2-|2-n-butyl-3-(4-chlorophenyI)-propyI│- oxirane-2-carboxyIic acid ethyl ester, 2-│5-(2-chloro phenyI)-5-ethyIpentyI│-oxirane-2-carboxyIic acid ethyl ester, 2-│5-(3,4-dichlorophenyl)-5-methylpentyl│-oxirane- 2-carboxylic acid ethyl ester, 2-│5-(2,4-dichIorophenyI)- 4-methyIpentyI|-oxirane-2-carboxyIic acid propyl ester, 2-│5-(3,4-dichlorophenyl)-4-methylpentyl│-oxirane-2- carboxylic acid n-butyl ester, 2-│5- (2,4-dichlorophenyI)- 4-methyIpentyI│-oxirane-2-carboxylic acid sec-butyl ester, 2-|5-(4-chlorophenyl)-2-propylpentyl│-oxirane-2-carboxylic acid methyl ester, 2-│5-(4-fluorophenyI)-2-isopropyl pentyI│-oxirane-2-carboxylic acid ethyl ester, 2-│5-(4- chloro-2-methyIphenyl)-5-ethylpentyl|-oxirane-2-carboxyIic acid ethyl ester and 2-│5-(4-methoxyphenyI)-4-methyI pentyl│-oxirane-2-carboxylic acid n-propyl ester, and the corresponding phenylaIkyloxirane-2-carboxylic acids and salts thereof with inorganic and organic bases. 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 diastereomers, the racemates and the enantiomers as well as mixtures thereof.
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.
On the basis of their advantageous activity, 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. Examples of 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. As medicaments, the new compounds can be employed as such or, if appropriate, in combination with suitable pharmaceutical excipients. If 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.
In accordance with the invention, 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.
When in the form of unit doses and intended, for example, for administration to humans, 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.
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.
In the case of long-term medication, 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. In acute cases, medication takes place at varying points in time. Under certain circumstances, it may be necessary to deviate from the dosages mentioned, and in particular to do so in accordance with the nature, body weight and age of the patient to be treated, the nature and severity of the illness, the nature of. the formutation and of the administration of the medicament, and the time or interval over which administration takes place. Thus, it may in some cases be sufficient to manage with less than the abovementioned amount of active compound, whilst in other cases the abovementioned amount of active compound must be exceeded. 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 . Examples of 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 .
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.
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 In addition to the phenylalkyloxiranecarboxylic acids according to the invention, in which the substituents have the abovement ioned meaning, and/or their salts, 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. 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
Figure imgf000013_0001
wherein R1, R2, R3, R4, R5, 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 α-methylenecarboxylic acids II are oxidised under conditions known to the expert for oxidation of carbon-carbon double bonds to give epoxides. Examples of possible 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.
The 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.
The carboxylic acids of the general formuta I (R5 = -H) can be converted into salts by direct alkaline hydrolysis of the acid derivatives I (R5 = lower alkyl). The inorganic or organic base of which the salt is desired is used as the alkaline reactant. However, the salts are also obtained by reacting the carboxylic acids I (R5 = -H) with the stoichiometric equivalent of a corresponding base, for example sodium hydroxide or sodium ethanolate, or by converting readily soluble salts into sparingly soluble salts by double decomposition, or by converting any desired salt into pharmacologically acceptable salts.
The phenylal kyloxiranecarboxyl ic acids of the general formula I (R5 = -H) are converted into the lower alkyl esters
(R5 = lower alkyl) in the customary manner. For example, 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.
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. Racemic mixtures can also be resolved into the optical isomers by chromato graphy over optically active sorbents. Alternatively, the α,-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.
The phenylalkyl -α-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.
The phenylalkyl-α-methylenecarboxyIic acids II are prepared, for example, by a process analogous to that of H. Stetter and H. Kuhlmann |Synthesis 1979, 29 |, by reacting malonic acid half-esters of the general formula
Figure imgf000015_0001
wherein R1, R2, R3, R4, and A have the - abovementioned meaning and
R10 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
Figure imgf000016_0001
wherein R1, R2, R3, R4 and R10 have the abovementioned meanings and
B denotes a single bond, a -CH(R6)-CH(R7)- group, a -C(R6)=C(R7)- group, a -CH (R6)-CH (R7)-CH (R8)- group, a -CH(R6)-CH (R73-CH (R8) -CH (R9) - group or a -C(R6)=C(R7)-C(R8)=C(R9)- group. The oxo compounds IV are condensed with the alkylidene-malonates V under mild conditions and in very good yield. It is particularly surprising that 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'
Figure imgf000017_0001
which is characterised in that oxo compounds of the general formula IV'
Figure imgf000017_0002
are subjected to condensation with alkyIidene-maIonates of the general formula V
Figure imgf000017_0003
wherein
R 1' and R 2' have the meanings of and R2 ,
B' denotes a -CH (R6')-CH(R 7')- group, a
-C(R6')=C(R7')- group, a -CH( R6')-CH(R 7' )-CH(R8')- group, a -CH(R6')-CH(R7')-CH(R8')-CH(R9')- group or a -C(R6')=C(R7')-C(R8')=C(R9')-group. R3', R4', R6', R7', R8' and R9' denote hydrogen atoms or one of the substituents denotes a lower alkyl group and the others denote hydrogen atoms and R10' has the meanings of R10
The condensation of the oxo compounds IV or IV' is preferably carried out in alkanols, in particular inR10-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. Alternatively, for 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. For example, 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, R10 -OH.
The examples which follow serve to illustrate the invention in more detail. "M.p." denotes "melting point"; "B.p." denotes boiling point. The temperature data are in °C.
Exa m p I e s
E x ampl e 1 2-(4-Methyl-5-phenylpentyl)-oxirane-2-carboxylic acid ethyl ester a) 2-(4-Methyl-5-phenylpentyl)-oxirane-2-carboxylic acid ethyl ester
7.80 g of 6-methyl-2-methyIene-7-phenyIheptanoic acid ethyl ester and 12.9 g of m-chloroperbenzoic acid (85% strength) are boiled under reflux in 110 ml of methylene chloride for 40 hours. The mixture is allowed to cool, the m-chloroperbenzoic acid which has separated out is filtered off, the filtrate is concentrated, the residue is taken up in 30 ml of acetone, 20 ml of saturated sodium carbonate solution are added and the mixture is stirred at 0º for 1 hour. The mixtrure is diluted with 100 ml of water and extracted 3 times with 50 ml of methylene chloride each time, the organic phase is concentrated and the residue is distilled. This gives 4.80 g of the titIe compound of b.p. 142-144º under 0.008 mm Hg (1.06 Pa). b) 6-MethyI-2-methylene-7-phenyIheptanoic acid ethyl ester
13.1 g of 4-methyl-5-phenyl-pentylmalonic acid monoethyl ester, 1.26 g of paraformaldehyde, 8.2 ml of pyridine and 0.5 ml of piperidine are stirred at 50º for 5 hours. After the reaction mixture has been cooled, 100 ml of water are added and the mixture is extracted 3 times with 50 ml of hexane each time. The organic phase is washed with 1 N hydrochloric acid, water and sodium bicarbonate solution and concentrated and the residue is distilled. This gives 8.3 g of 6-methyl-2- methylene-7-phenylheptanoic acid ethyl ester of b.p. 110- 114° under 0.008 mm Hg (1.06 Pa). c) 4-MethyI-5-phenyIpentylmaIonic acid monoethyl ester 18.6 g of 5-methyl-6-phenyl-1,3,5-hexatriene-1,1- dicarboxylic acid monoethyl ester and 1.9 g of palladiumon-charcoal (5% strength) are suspended in 300 ml of ethanol in a circulatory hydrogenation apparatus and hydrogenation is carried out at 20º. After 4.5 I of hydrogen have been taken up, a sudden decrease in the uptake of hydrogen is observed. For working up, the catalyst is filtered off, the residue on the filter is washed with 50 ml of ethanol and the filtrate is evaporated completely at 40-50º on a rotary evaporator. This gives 17.5 g of 4-methyl-5-phenyIpentylmalonic acid monoethyl ester as a viscous oil. d) 5-Methyl-6-phenyl-1,3,5-hexatriene-1,1-dicarboxylic acid monoethyl ester
34.5 g of benzyItriethylammonium hydroxide, dissolved in 140 ml of ethanol, are added dropwise, with ice cooling, to 21 -9 g of 2-methyl-cinnamaldehyde and 30.0 g of ethylidenemalonic acid diethyl ester in a manner such that the internal temperature does not exceed 20º. The mixture is then stirred for a further 20 hours at 20º.
For working up, 80 ml of ethanol are distiIled off under a waterpump vacuum at 40º, 800 ml of water are added to the residue and the mixture is extracted twice with 150 ml of diisopropyl ether each time and twice with ,
100 ml of cyclohexane. The product is then precipitated by acidification of the aqueous phase to pH 3 with 1 N hydrochloric acid, whilst stirring vigorously, and is filtered off with suction, washed with water and dried to constant weight. This gives 29.4 g of 5-methyl-6- phenyl-1,3,5-hexatriene-1,1-dicarboxyIic acid monoethyl ester as a yellow solid of m.p. 132°. Example 2 2-(2-Ethyl-5-phenylpentyl-)oxirane-2-carboxylic acid ethyl ester a) 2- (2-Ethyl-5-phenyIpentyl)-oxirane-2-carboxylic acid ethyl ester
4.5 g of the title compound of b.p. 138-141º under 0.005 mm Hg (0.66 Pa) are obtained from 6.9 g of 4-ethyl 2-methylene-7-phenyIheptanoic acid ethyl ester and 12 g of m-chloroperbenzoic acid in 80 ml of methylene chloride by the procedure described in Example 1 a). b) 4-Ethyl-2-methylene-7-phenyIheptanoic acid ethyl ester 8.9g of 4-ethyl-2-methylene-7-phenyheptanoic acid ethyl ester of b.p. 125-128º under 0-1 mm, Hg (13.3 Pa ) are obtained from 16.0 g of 2-ethyI-5-phenyIpentyl malonic acid monoethyl ester, 1.35 g of paraformaldehyde, 9.1 ml of pyridine and 0.6 ml of piperidine by the proce dure described in Example 1 b). c) 2-Ethyl-5-phenylpentyImalonic acid monoethyl ester
21 g of 2-ethyl-5-ρhenylpentyImalonic acid monoethyl ester are obtained as a viscous oil from 21.3 g of 3-ethyl-6-phenyl-1,3,5-hexatriene-1,1-dicarboxylic acid monoethyl ester with hydrogen in 280 ml of ethanol, with the addition of 2.1 g of paIladium-on-charcoal (5% strength), by the procedure described in Example 1 c). A sample is chromatographed on silica gel under neutral conditions. The Rf value in chIoroform/methanol (19:1. is 0.58. d) 3-Ethyl-6-phenyl-1,3,5-hexatriene-1,1-dicarboxylic acid monoethyl ester
53 g of 3-ethyl-6-ρhenyl-1,3,5-hexatriene-1,1- dicarboxylic acid monoethyl ester are obtained as a mix ture of oil and solid from 26.4 g of cinnama ldehyde; 50 g of n-butylidenemalonic acid dϊethyl ester and 46 g of benzyltriethy lammohium hydroxide in 180 ml of ethanol by the procedure described in Example 1 d). Recrystal lisation from ethanol gives a product of m.p. 95-96 (lemon-yeIlow needles). Example 3 2-│5-(4-Chlorophenyl)-2-ethylpentyl│-oxirane-2-carboxylic acid ethyl ester a) 2-│5- (4-Chlorophenyl)-2-ethylpentyI│-oxirane-2- carboxylic acid ethyl ester
11 g of the title compound of b.p. 150-155º under 0.005 mm Hg (0.66 Pa) are obtained from 15.4 g of 7-(4- chlorophenyl)-4-ethyl-2-methylene-heptanoic acid ethyl ester and 22 g of m-chIoroperbenzoic acid in 600 ml of methylene chloride by the procedure described in Example 1a). b) 7-(4-ChlorophenyI)-4-ethyl-2-methyteneheptanoic acid ethyl ester
13 g of 7-(4-chlorophenyI)-4-ethyl-2-methylene- heptanoic acid ethyl ester of b.p. 130-135 under 0.01 mm Hg (1.33 Pa) a re obtained from 20 g of 5-(4-chlorophenyl)- 2-ethylpentyImaIonic acid monoethyl ester, 1.70 g of para formaldehyde, 8 ml of pyridine and 0.9 ml of piperidine by the procedure described in Example 1 b). c) 5-(4-Chlorophenyl)-2-ethyIpentyImalonic acid monoethyl ester
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 Rf value of 0.30. d) 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. 112-113º from 19.2 g of p- chlorocinnamaldehyde, 3.0 g of n-butylidenemalonic acid diethyl ester and 26 g of benzyItriethylammonium hydroxide in 150 ml of ethanol by the procedure described in Example 1 d). Example 4 2-(5-Methyl-5-phenylpentyl)-oxirane-2-carboxylic acid ethyl ester a) 2-(5-Methyl-5-phenylpentyl)-oxirane-2-carboxylic acid ethyl ester
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°. After the mixture has been stirred in an ice-bath for one hour, 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.
For working up, 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 ) . b) 7-MethyI-2-methylene-7-phenyI-heptanoic acid ethyl ester
9.0 g of 7-methyl-2-methylene-7-phenyIheptanoic acid ethyl eiter of b.p. 118-120º under 0.1 mm Hg (13 Pa) are obtained from 14.6 g of 5-methyI-5-phenylpentyI malonic acid monoethyl ester, 1.45. g of paraformaIdehyde, 9 ml of pyridine and 0.6 ml of piperidine by the procedure described in Example 1 b). c) 5-Methyl-5-phenylpentyImaIonic acid monoethyl ester
25.5 g of 5-methyl-5-phenyIpentyImalonic acid monoethyl ester are obtained as a viscous oil from 25.74 g of 6-methyI-6-phenyl-1,3,5-hexatriene-1,1-dicarboxylic acid monoethyl ester with hydrogen in 500 ml of ethanol, with the addition of 1.3 g of palladium-on-charcoaI (5% strength), by the procedure described in Example 1 c).
Chromatography on silica gel under neutral conditions in chloroform/methanol (19:1) gives an Rf value of 0.35. d) 6-HethyI-6-phenyI-1,3,5-hexatriene-1,1-dicarboxylic acid monoethyl ester
39 g of 6-methyl-6-phenyl-1,3,5-hexatriene-1,1- dicarboxylic acid monoethyl ester are obtained as a glassy solid from 29.2 g of 3-methyI-cinnamaIdehyde, 41 g of ethylidenemaIonic acid diethyl ester and 44.1 g of benzyltriethyIammonium hydroxide in 180 ml of ethanol by the procedure described in Example 1 d). A sample is chromatographed on silica gel under neutral conditions T h e R f v a l u e i n c h l o r o f o r m / m e t h a n o l ( 1 9 : 1 ) i s 0 . 5 . E x a mpl e 5 2-(1 -Methyl-5-phenylpentyl)-oxirane-2-carboxylic acid ethyl ester a) 2-(1-Methyl-5-phenyIpentyl)-oxirane-2-carboxyIic acid ethyI ester
10.8 g of the title compound of b.p. 135-138° under 0.005 mm Hg (0.66 Pa) are obtained from 18.7.g of 3-methyl-2-methylene-7-phenylheptanoic acid ethyl ester and 31 g of m-chloroperbenzoic acid in 260 ml of methylene chloride by the procedure described in Example 1 a). b) 3-Methyl-2-methylene-7-phenyIheptanoic acid ethyl ester
22 g of 3-methyl-2-methylene-7-phenyIheptanoic acid ethyl ester of b.p. 95-100° under 0.008 mm Hg (1.06 pa) are obtained from 39 g of 1 -methyl-5-phenylpentyl malonic acid monoethyl ester, 3.8 g of paraformaldehyde, 25 ml of pyridine and 1.6 ml of piperidine by a procedure analogous to that described in Example 1 b). c) 1-Methyl-5-phenylpentyImalonic acid monoethyl ester 25-8 g of 1-methyl-5-phenyIpentyImalonic acid monoethyl ester are obtained as a viscous oil from 26 g of 2-methyl-6-phenyl-1,3,5-hexatriene-1,1-dicarboxylic acid monoethyl ester with hydrogen in the presence of 2.7g of palladium-on-charcoal (5% strength) in 450 ml of ethanol by a procedure analogous to that described in Example 1 c). d) 2-Methyl-6-phenyI-1,3,5-hexatriene-1,1-dicarboxylic acid monoethyl ester
51 g of 2-methyl-6-phenyI-1,3,5-hexatriene-1,1- dicarboxylic acid monoethyl ester are obtained as a glassy solid from 36 g of cinnama ldehyde, 50 g of 2-propylidenemalonic acid diethyl ester and 57 g of benzyItriethyl ammonium hydroxide in 230 ml of ethanol by a procedure analogous to that described in Example 1 d). Example 6 2 -(4-MethyI-5-phenylpentyl)-oxirane-2-carboxylic acid
2.8 g of 2- (4-methyl-5-phenyIpentyI)-oxirane-2- carboxylic acid ethyl ester are stirred with 10 ml of 1 N sodium hydroxide solution in 10 ml of tetrahydrofuran at room temperature for 2 hours. The mixture is concentrated to half, the concentrate is extracted twice with 10 ml of diethyl ether, the product phase is acidified to pH 3 with 2 N hydrochloric acid and extracted twice with 20 ml of diethyl ether and the product phase is dried over sodium sulphate and concentrated completely. This gives 2.3 g of the title compound as a colourless oil. Example 7
Sodium 2- (4-methyl-5-phenylpentyl)-oxirane-2-carboxylate 2.8 g of 2- (4-methyl-5-phenyIpentyl)-oxirane-2- carboxylic acid ethyl ester are stirred with 10 ml of 1 N sodium hydroxide solution and 10 ml of ethanol at room temperature for 1 hour. The mixture is concentrated in vacuo, whereupon the title compound remains as a colourless, glassy powder; yield: 2.75 g. Exapgle 8 2-│3-(4-Chlorophenyl)-2-ethylpropyl│-oxirane-2-carboxylic acid ethyl ester a) 2-│3-(4-Chlorophenyl)-2-ethyIpropyl│-oxirane-2- carboxylic acid ethyl ester
9 g of the title compound of b.p. 115-120º under
0.005 mm Hg (0.66 Pa) are obtained from 13.5 g of 5-(4- chlorophenyl)-4-ethyl-2-methylenevaleric acid ethyl ester,
4.6 g of 85% strength hydrogen peroxide and 13.8 g of maleic anhydride in 70 ml of methylene chloride by the procedure described in Example 4 a). b) 5-(4-ChlorophenyI)-4-ethyI-2-methylenevaleric acid ethyl ester
16 g of 5-(4-chlorophenyl)-4-ethyl-2-methylenevaleric acid ethyl ester of b.p. 135-137° under 0.05 mm Hg (6.65 Pa) are obtained from 21 g of 3-(4-chlorophenyI)-2- ethyIpropylmalonic acid monoethyl ester, 2-05 g of paraformaldehyde, 13 ml of pyridine and 1 ml of piperidine by the procedure described in Example 1 b). c) 3-(4-Chlorophenyl)-2-ethyIpropyImalonic acid monoethyl ester
30 g of 3-(4-chIorophenyl)-2-ethyIpropyImalonic acid monoethyl ester are obtained as a viscous oil from 30 g of 4-(4-chlorophenyl)-3-ethyl-1,3-butadiene-1,1- dicarboxylic acid monoethyl ester with hydrogen in the presence of 1.5 g of platinum-on-charcoal (5% strength) in 300 ml of ethanol by the procedure described in Exarmpl e 1 c). d) 4- (4-ChlorophenyI)-3-ethyl-1,3-butadiene-1,1-dicarboxylic acid monoethyl ester
73 g of 4-(4-chlorophenyl)-3-ethyl-1,3-butadiene- 1,1-dicarboxylic acid monoethyl ester are obtained as a highly viscous, yellow oil from 44 g of 4-chIorobenzaIdehyde, 65 g of butyIidenemaIonic acid diethyl ester and 68 g of benzyItriethylammonium hydroxide in 400 ml of ethanol by the procedure described in Example 1 d). Examgle 9 2-│1-Methyl-3-(3-trifluoromethylphenyl)-propyl│-oxirane- 2-carboxylic acid ethyl ester a) 2-│1-M ethyl-3-(3-trifluoromethyIphenyl)-propyl│-oxirane- 2-carboxylic acid ethyl ester
9.4 g of the title compound of b.p. 111-112 under 0.05 mm Hg (6.65 Pa) are obtained from 16 g of 3-methyl- 2-methylene-5-(3-trifluoromethyIphenyl)-valeric acid ethyl ester and 21.5 g of m-chloroperbenzoic acid in 160 ml of methylene chloride by the procedure described in Example 1 a). b) 3-Methyl-2-methylene-5-(3-trifluoromethyIphenyI)- valeric -acid ethyl ester
20.1 g of 3-methyI-2-methyIene-5- (3-trifluoromethyIphenyl)-valeric acid ethyl ester of b.p. 100-104º under 0.05 mm Hg (6.65 Pa) are obtained from 25-5 g of 1- methyl-3-(3-trifluoromethylphenyl)-propylmalonic acid monoethyl ester, 2.95 g of paraformaldehyde, 25 ml of pyridine and 1.6 ml of piperidine by the procedure described in Example 1 b). c) 1-Methyl-3-(3-trifluoromethylphenyl)-propyImalonic acid monoethyl ester 51 g of 1-methyl-3-(3-trifIuoromethyIphenyI)- propyImaIonic acid monoethyl ester are obtained as a viscous oil from 52 g of 2-methyl-4-(3-trifIuoromethylphenyl)-1,3-butadiene-1,1-dicarboxylic acid monoethyl ester with hydrogen in the presence of 2.6 g of palladium on-charcoal (5% strength) in 400 ml of ethanol by the procedure described in Example 1 c). d) 2-Methyl-4-(3-trif luoromethylphenyl)-1,3-butadiene- 1,1-dicarboxyIic acid monoethyl ester 62 g of 2-methyl-4-(3-trif luoromethyIphenyl)-1,3- butadiene-1,1-dicarboxyIic acid monoethyl ester are obtained from 52.2 g of 3-trifIuoromethyIbenzaIdehyde, 66 g of 2-propyIidenemaIonic acid diethyl ester and 64 g of benzyltrimethylammonium hydroxide in 700 ml of ethanol by the procedure described in Example 1 d). Example 10 6-(4-Chlorophenyl)-1,3,5-hexatriene-1,1-dicarboxylic acid monoethyl ester a) 400 ml of a 1.1 molar solution (0.44 mol) of benzyItriethylammonium hydroxide (= 92.4 g) in ethanol are added dropwise, with ice-cooling and whilst stirring, to 66.65 g (0.4 mol) of 4-chlorocinnamaIdehyde and 76.5 g (0.42 mol) of ethylidenemalonic acid diethyl ester in a manner such that the internal temperature does not exceed 20º. The mixture is then subsequently stirred at 20º for 20 hours.
For working μp, 200 ml of ethanol are distilled off under a waterpump vacuum at 40º, 2 I of water are added to the residue and the mixture is extracted twice with 400 ml of diisopropyl ether each time and twice with 200 ml of cyclohexane. The product is then precipitated as a yellow-red solid by acidifying the aqueous phase to pH 3 with 1 N hydrochloric acid, whilst stirring vigorously, and is filtered off with suction, washed with water and dried to constant weight. The resulting crude product (103 g, 84% of theory) is subsequently used according to Example 10 d) without further purification.
Reprecipitation from 600 g of ethanol with 1,200 g of water gives 91 g of the title compound of m .p. 138-145º (yellow solid).
Chromatography on silica gel with chloroform/ methanol (19:1) gives an Rf value of 0.33. b) Alternatively, the title compound is obtained as follows:
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). This gives 23.1 g (75% of theory) of 6- (4-chlorophenyI)-1,3,5-hexatriene-1,1-dicarboxyIic acid monoethyl ester. c) Alternatively, the title compound is obtained as follows:
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). This gives 20-7 g (68% of theory) of 6-(4- chlorophenyl)-1,3,5-hexatriene-1,1-dicarboxylic acid mono ethyl ester.
d) 2.81 of a 1 molar solution of tetramethylammonium hydroxide in ethanol [prepared according to the method described for the preparation of benzyltrimethylammonium ethoxide in Organic Synthesis IV (1963), 98] are added dropwise at a temperature of -5 to +3ºC in the course of 7 hours to a solution of 400 g (2.4 moles) of 4-chlorocinnamaldehyde and 465 g (2.5 moles) of ethyl i denema! onic. acid diethyl ester in 0.41 of dry ethanol. The mixture is then stirred for a further
20 hours. 21 of ethanol are distilled off under a waterpump vacuum. The residue is worked up according to Example 10a.588 g of the title compound of m.p. 136 - 138° are obtained. e) 103 g of 6- (4-chlorophenyl)-1,3,5-hexatriene-1,1- dicarboxylic acid monoethyl ester and 5 g of platinum-on- charcoal (5% strength) are suspended in 1.2 l of ethanol in a circulatory hydrogenation apparatus, and hydrogena tion is carried out at 20°. After 23 I of hydrogen have been taken up, a sudden drop in the uptake of hydrogen is observed. For working up, 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
(19:1). The Rf value is 0.30. 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). b) 50.5 g of 5-phenylpentylmalonic acid monoethyl ester are obtained as a viscous oil by hydrogenating 50 g of 6-phenyl-1,3,5-hexatriene-1,1-dicarboxylic acid monoethyl ester over 2.5 g of palladium-on-charcoaI (5% strength) in 600 ml of ethanol by the procedure described in Example 10 c).
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). b) 9.9 g of 5-phenyIpentyImalonic acid monoethyl ester are obtained as a viscous oil from 10 g of 6-phenyl- 1,3-hexadi ene-1,1-dicarboxyIic acid monoethyl ester with hydrogen in the presence of 0.5 g of paIladium-on-charcoaI (5% strength) in 80 ml of ethanol by the procedure described in Example 10c). According to thin layer chromatography and NMR and IR spect roscopy, the compound is identical to the compound obtained according to
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
14 g of the title compound of b.p. 110-112º under 0.005 mm Hg (0.66 Pa) are obtained from 18.5 g of 4-ethyl
5-phenyI-2-methylenevaleric acid ethyl ester, 7.5 g of 852 strength hyd r ogen peroxide and 22.5 g of maleic anhydride in 100 ml of methylene chloride by the procedure described in Example 4 a). b) 4-Ethyl-5-phenyl-2-methylenevaleric acid ethyl ester
42 g of 4-ethyl-5-phenyl-2-methylenevaleric acid ethyl ester of b.p. 95-98° under 0.05 mm Hg (6.65 Pa) are obtained from 55.6 g of 2-ethyI-3-phenyIpropyImalonic acid monoethyl ester, 6.0 g of paraformaldehyde, 37 ml of pyridine and 2 ml of piperidine by the procedure described in Example 1 b). c) 2-Ethyl-3-phenyIpropyImalonic acid monoethyl ester
70 g of 2-ethyl-3-phenyIpropylmalonic acid monoethyl ester are obtained as a viscous oil from 69 g of 3- ethyl-4-phenyl-1,3-butadiene-1,1-dicarboxylie acid monoethyl ester with hydrogen in the presence of 3.5 g of palladium-on-charcoal (5% strength) in 700 ml of ethanol by the procedure described in Example 1 c). d) 3-EthyI-4-phenyl-1,3-butadiene-1,1-dicarboxyIic acid monoethyl ester
93 g of 3-ethyl-4-phenyl-1,3-butadiene-1,1-di carboxylic acid monoethyl ester (orange-yellow viscous oil) are obtained from 53 g of benzaIdehyde, 107 g of n butylidenemalonic acid diethyl ester, 11.4 g of benzyltriethylammonium chloride and 20 g of sodium hydroxide in 600 ml of ethanol by the procedure described in Example 10 b). Example 14 2-(4-Methyl-7-phenylheptyl)-oxirane-2-carboxylic acid ethyl ester a) 2- (4-Methyl-7-phenylheptyl)-oxirane-2-carboxylic acid ethyl ester 1.5 g of the title compound of b.p. 150° under
0.01 mm Hg (1.3 Pa) are obtained from 8.0 g of 6-methyl-9- phenyl-2-methylenenonanoic acid ethyl ester, 2.78 g of 85% strength hydrogen peroxide and 8.15 g of maleic anhydride in 60 ml of methylene chloride by the procedure described in Example 4a). b) 6-Methyl-9-phenyl-2-methyl enenonanoic acid ethyl ester
9.4 g of 6-methyl-9-phenyl-2-methylenenonanoic acid ethyl ester are obtained from 25 g of 4-methyl-7-phenyl heptylmalonic acid monoethyl ester, 2.34 g of paraformaldehyde, 14.3 ml of pyridine and 0.8 ml of piperidine by the procedure described in Example 1 b). c) 4-Methyl-7-phenylheptylmalonic acid monoethyl 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). d) 5-Methyl-8-phenyl-1,3,5,7-octatetraen-1,1-dicarboxylic acid monoethyl ester 28 g of 5-methyl-8-phenyl-1,3,5,7-octatetraen-1,1-di carboxylic monoethyl ester are obtained from 24.0 g of 2-methyl- 5-phenyl-2,4-pentadienal, 31.1 g of ethylidenemalonic acid diethyl ester and 365 ml of a 0.5 molar solution (0.182 mol) of benzyl trimethyl ammonium hydroxide in ethanol. The product is precipitated as a yellow-red oil by acidifying with hydrochloric acid. e) 2-Methyl-5-phenyl-2,4-pentadienal
250 ml of a 15% strength sodium hydroxide solution are added under a nitrogen atmosphere whilst stirring to a solution of 132.16 g of cinπamic aldehyde in 400 ml of ethanol. 50 g of propional dehyde are then added dropwise, with ice cooling, within three hours. The mixture is then allowed to come to room temperature in the course of 16 hours. It is neutralised with hydrochloric acid, concentrated and extracted 3 times with di ethyl ether. The organic phase is dried and distilled under a high vacuum. The product is brought to crystallisation by dissolution in hot ethanol and subsequent cooling in an ice bath.
25.6 g of yellow crystal of m.p. 59.5-60.5° are obtained.
Example 15 2-[5-(4-Chlorophenyl)-4-methylpentyl]-oxirane-2-carboxylic acid ethyl ester a) 2-[5-(4-Chiorophenyl)-4-methylpentyl]-oxirane-2-carboxylic acid ethyl ester
10.9 g of the title compound of b.p. 200-202° under
0.01 mm Hg (1.3 Pa) are obtained from 12.3 g of 7-(4-chlorophenyl)-6-methyl-2-methyleneheptanoic acid ethyl ester,
4.17 g of 85% strength hydrogen peroxide and 12.27 g of maleic anhydride in 70 ml of methylene chloride by the procedure described in Example 4 a). b) 7-(4-Chlorophenyl)-6-methyl-2-methyleneheptanoic acid ethyl ester 15.5 g of 7-(4-chlorophenyl)-6-methyl-2-methylene heptanoic acid ethyl ester are obtained from 21.45 g of 5-(4-chlorophenyl )-4-methylpentylmalonic acid monoethyl ester, 1.82 g of paraformaldehyde, 12.74 ml of pyridine and 0.96 ml of piperidine as a clear yellow oil by the procedure described in Example 1 b). c) 5-(4-Chlorophenyl )-4-methylpentylmalonic acid monoethyl ester
25.0 g of 5-(4-chlorophenyl )-4-methylpentylmalonic acid monoethyl ester are obtained as a colourless oil from 23.0 g of 6-(4-chlorophenyl)-5-methyl -1,3,5-hexatriene-1,1- dicarboxylic acid monoethyl ester with hydrogen in the presence of 1.2 g of platinum-on-charcoal (5% strength) in 400 ml of ethyl acetate by the procedure described in Example 1 c). d) 6-(4-Chloropbenyl)-5-methyl-1,3,5-hexatriene-1 ,1-dicarboxylic acid monoethyl ester
53.8 g of 6-(4-chlorophenyl)-5-methyl -1 ,3,5-hexatriene- 1,1-dicarboxylic acid monoethyl ester are obtained as an orange-red solid of m.p. 151-153° from 47 g of 3-(4-chloro phenyl)-2-methyl-propenal , 51.9 g of ethylidenemalonic acid diethyl ester and 48.2 g of benzyltrimethylammonium hydroxide in 400 ml of ethanol by the procedure described in Example
1 d).
Example 16 2-(6-Methyl-7-phenylheptyl)-oxirane-2-carboxylic acid ethyl ester a) 2-(6-Methyl-7-phenylheptyl)-oxirane-2-carboxylic acid ethyl ester
8.7 g of the title compound of b.p. 135-144° under 0.01 mm Hg (1.3 Pa) are obtained from 15 g of 8-methyl-9- phenyl-2-methylenenonanoic acid ethyl ester, 4.42 g of 85% strength hydrogen peroxide and 15.3 g of male.ic anhydride in 130 ml of methylene chloride by the procedure described in Example 4 a). b) 8-Methyl-9-phenyl-2-methylenenonanoic acid ethyl ester
19.1 g of 8-methyl-9-phenyl-2-methylenenonanoic acid ethyl ester of b.p. 140° under 0.01 mm Hg (1.3 Pa) are obtained from 29.5 g of 6-methyl-7-phenylheptylmalonic acid monoethyl ester, 3.46 g of paraformal dehyde, 60 ml of pyridine and 5 ml of piperidine by the procedure described in Example 1 b). c) 6-Methyl-7-phenylheptylmalonic acid monoethyl ester
30.5 g of 6-methyl-7-phenylheptylmalonic acid monoethyl ester are obtained from 31.6 g of 7-methyl-8-phenyl- 1,3,5,7-octatetraene-1,1-dicarboxylic acid monoethyl ester with hydrogen in the presence of 3.0 g of pal ladium-on- charcoal (5% strength) in 300 ml of ethyl acetate by the procedure described in Example 1 c). d) 7-Methyl-8-phenyl-1,3,5,7-octatetraene-1,1-dicarboxylic acid monoethyl ester
10.1 g of 7-methyl-8-phenyl-1,3,5,7-octatetraene- 1,1-dicarboxylic acid monoethyl ester of m.p. 137-144º are obtained from 8.6 g of 4-methyl-5-phenyl-2,4-pentadienal, 10.2 g of ethyl idenemalonic acid diethyl ester and 78 ml of a 0.8 molar solution of tetramethyl ammonium hydroxide in 30 ml of ethanol. e) 4-Rethyl-5-phenyl-2,4-pentadienal
80.4 g of 2-methyl-cinnamal dehyde are added under a nitrogen atmosphere to a mixture of 96.33 g of ethyl orthoformate and 0.5 ml of orthophosphoric acid. The mixture is stirred for 4 hours at 50° and then cooled to -15°. After the addition of 1.5 g of zinc chloride in 10 ml of ethyl acetate, 41 ml of ethyl vinyl ether are added dropwise at a temperature of -10 in the course of 3 hours. The mixture is then allowed to stand at room temperature over night. Ethanol is distilled off, 40 ml of formic acid, 30 g of sodium formate and 10 ml of water are added and the mixture is then boϋed under reflux for 40 hours. The mixture is then evaporated on a rotary evaporator and the remaining residue is recrystallized from diisopropyl ether and petroleum ether. Yield: 45.6 g. Galenical Examples
Example 1 Mixture for ampoules
100 g of 2-(4-methyl-5-ρhenylpentyl)-oxirane-2- carboxylic acid are dissolved in approx. 8 litres of twice distilled water with the addition of an equivalent amount of sodium hydroxide solution. The pH of the solution is adjusted to 7.0 + 0.5 and the solution is made up to 10 litres with twice-distilled water. It is then filtered under sterile conditions and filled into 2 ml ampoules under aseptic conditions. Example 2
10.000 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
Tablets containing 25 mg of active compound are prepared as follows: 1.0 kg of sodium 2-(4-methyl-5-phenylpentyl)-oxirane-2-carboxylate, 4.5 kg of xylitol and 3.0 kg of calcium phosphate, are granulated with 0.25 kg of polyvinylpyrrolidone (MW 25.000; MW = molecular weight) in approximately 0.5 1 of water. The granules are sieved through a screen with a mesh width of 1.25 mm and, after drying,
0.9 kg of carboxymethylcellulose, 0.25 kg of talc and 0.1 kg of magnesium stearate are added. The dry granules are compressed to give tablets with a diameter of 8 mm, a weight of 250 mg and a hardness of 5-6 kg. Pharmacology
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. They are superior to commercial preparations (for example Buformin and Phenformin) having an extra-pancreatic action. In addition, they are distinguished by their long-term action.
In the following Table the investigated compounds are characterized by a serial number, which is allocated as follows:
Serial No. Name of Compound
1 Buformin 2 Phenformin
3 2-(4-Methyl-5-phenylpentyl)-oxirane-2-carbo xylic acid ethyl ester 4 2-(2-Ethyl-5-phenylpentyl)-oxirane-2- carboxylic acid ethyl ester
5 2-[5-(4-Chlorophenyl)-4-methylpentyl ] - oxirane-2-carboxylic acid ethyl ester
6 2-(4-Methyl-7-phenylheptyl)-oxirane-2- carboxylic acid ethyl ester
7 2-(5-Methyl-5-phenylpentyl)-oxirane-2- carboxylic acid ethyl ester
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 (LD50; mice, peroral administration).
Figure imgf000037_0001
Re Table I:
* Cited according to Blickens, D.A.; Riggi, S.J.: Toxicol. Appl. Pharmacol., 14(1969)393-400.
The pharmacological properties were determined by the follo wing methods:
1. Determination of glucose in the blood after a single oral administration. Young male Sprague-Dawley rats (body weight 150 to 200 g) are used. The animals (6 animals per dose) are kept in Makrolon cages with up to 4 animals per cage (ambient temperature: 23°C, relative atmosperic humidity: 55% fixed day/night rhytm [12/12 hours], standard diet: Altromin®). The rats are deprived of the feed 18 hours before the first sample of blood is taken. Water is available ad libitum. Samples of blood are taken from the postorbital plexus by puncture immediately before and 2, 4 and 6 hours after administration of the substance.
After deproteinization with perchloric acid, 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.
2. Determination of the toxicity.
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 LD50, that is to say the dose at which 50 % of the animals die, is determined graphically from the dose-/response curve.

Claims

Patent Claims
1. PhenyIaIkyIoxiranecarboxylic acids of the general formula I
Figure imgf000039_0001
wherein
R1 denotes a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a trifluoromethyl group,
R2 has one of the meanings of R1,
A denotes a single bond, a -CH(R6)-CH(R7)- group, a -CH(R6)-CH(R7)-CH(R8)- group or a
-CH(R6)-CH(R7)-CH(R8)-CH(R9)- group, R5 denotes a hydrogen atom or a lower alkyl group and one of the substituents R3, R4, R6, R7, R8 or R9 represents a Lower alkyl group and the others denote hydrogen atoms, and the salts of the carboxylic acids.
2. Phenylalkyloxiranecarboxylic acids of the general formula I according to claim 1, wherein R1 and R2 are meta or para-substituents and R1 denotes a hydrogen atom, a chlorine atom, a methyl group or a trifluoromethyl group and
R2 denotes a hydrogen atom or a chlorine atom, A denotes a single bond, a -CH(R6)-CH(R7)-group or a -CH(R6)-CH(R7)-CH(R8)- group, R5 denotes a hydrogen atom or a lower alkyl group and one of the substituents R3, R4, R6, R7, or R8 represents a methyl or ethyl group and the others denote hydrogen atoms, and the salts of the carboxylic acids.
3. Phenylalkyloxiranecarboxylic acids of the general formula I according to claim 1, wherein R1 and R2 are metaor para-substituents and R1 denotes a hydrogen atom, a chlorine atom or a trifluoromethyl group and R2 denotes a hydrogen atom,
A denotes a single bond or a -CH(R6)-CH(R7)-group, R5 denotes a hydrogen atom, a methyl group or an ethyl group and one of the substituents R3, R4, R6 or R7 represents a methyl group. and the others denote hydrogen atoms, and the pharmacologically acceptable salts of the carboxylic acids.
4. Phenylalkyloxiranecarboxylic acids of the general formula I according to claim 1, wherein R1 and R2 are metaor para-substituents, R1 denotes a hydrogen atom, a chlorine atom or a trifluoromethyl group, R2 denotes a hydrogen atom, A denotes a single bond, a -CH(R6)-CH(R7)-group or a -CH(R6)- CH(R7)-CH(R8)-CH(R9)-group, R5 denotes a hydrogen atom or a lower alkyl group with 1 to 4 carbon atoms, one of the substituents R3, R4, R6, R7, R8 or R9 represents a methyl or ethyl group and the others denotes hydrogen atoms, and the salts of the carboxylic acids.
5. Phenylalkyloxiranecarboxylic acids of the general formula I according to claim 1, wherein R1 is a para-sub stituent and denotes a hydrogen atom or a chlorine atom, R2 denotes a hydrogen atom, A denotes a -CH(R6)-CH(R7)- or a
-CH(R6)-CH(R7)-CH(R8)-CH(R9)-group, R5 denotes a hydrogen atom, a methyl group or an ethyl group, R4 denotes a hydrogen atom, R8 denotes a hydrogen atom, one of the substituents R3, R6, R7 or R9 represents a methyl or ethyl group and the others denote hydrogen atoms, and the pharmacologically acceptable salts of the carboxylic acids.
6. Process for the preparation of compounds according to Claim 1, characterised in that phenylalkyl-2-methylene- carboxylic acids of the general formula II
Figure imgf000040_0001
wherein
R1, R2, R3, R4, R5 and A have the meanings given in Claim 1, 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
7. Process for the preparation of phenyIaIkylidene malonic acid half-esters VI'
(VI')
Figure imgf000041_0001
characterised in that oxo compounds of the general formul IV'
(IV')
Figure imgf000041_0002
are subjected to a condensation reaction with alkylidene malonates of the general formula V
(V')
Figure imgf000041_0003
wherein
R1' denotes a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a tri fluoromethyl group,
R2' has one of the meanings of R1',
B' denotes a -CH(R6')-CH(R7')- group, a
-C(R6')=C(R1')- group, a -CH(R6')-CH(R7')-CH(R8')- group, a -CH (R6')-CH(R7')-CH(R8')-CH(R9')- group or a -C(R6')=C(R7')-C(R8')=C(R9')- group,
R3', R4', R6', R7', R8' and R9' denote hydrogen atoms or one of the substituents denotes a lower alkyl group and the others denote hydrogen atoms and R10' denotes a lower alkyl group.
8. Medicaments containing one or more compounds according to one or more of claims 1 to 5.
9. Compounds according to one or more of Claims 1 to 5 for use in the treatment and prophylaxis of illnesses based on disorders in glucose metabolism and lipid metabolism.
10. A process for the preparation of phenylalkyloxiranecarboxylic acids of the general formula I according to claim 1 substantially as described with reference to the specific examples hereinbefore set forth.
PCT/EP1982/000156 1981-07-24 1982-07-21 Phenylalkyloxirane carboxylic acids, preparation and therapeutical use WO1983000334A1 (en)

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US4750952A (en) * 1984-07-17 1988-06-14 Kawasaki Steel Corporation Cold-rolled steel sheets
WO1998035952A1 (en) * 1997-02-14 1998-08-20 Wolf Horst P O Oxiran carboxylic acids for the treatment of diabetes

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DE3680507D1 (en) * 1985-08-02 1991-08-29 Byk Gulden Lomberg Chem Fab USE OF OXIRANCARBONIC ACIDS FOR TREATING HYPERLIPAEMIA.
EP0283168A3 (en) * 1987-03-16 1989-06-14 American Home Products Corporation Fluorooxirane carboxylates
CN111613407B (en) * 2020-06-03 2022-05-03 福建省长汀金龙稀土有限公司 R-T-B series permanent magnet material, raw material composition, preparation method and application thereof

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EP0025192A2 (en) * 1979-09-07 1981-03-18 Byk Gulden Lomberg Chemische Fabrik GmbH Substituted oxirane carboxylic acids, process for their preparation, their use and medicines containing them

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0025192A2 (en) * 1979-09-07 1981-03-18 Byk Gulden Lomberg Chemische Fabrik GmbH Substituted oxirane carboxylic acids, process for their preparation, their use and medicines containing them

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* 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 (en) * 1997-02-14 1998-08-20 Wolf Horst P O Oxiran carboxylic acids for the treatment of 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

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