Substituted oxiranecarboxylic acids, their use and medicaments containing them

Substituted oxiranecarboxylic acids of the formula ##STR1## wherein R.sup.1 denotes a hydrogen atom (--H), a halogen atom, a hydroxyl roup, a lower alkyl group, a lower alkoxy group or a trifluoromethyl group, PA1 R.sup.2 has one of the meanings of R.sup.1, PA1 R.sup.3 denotes a hydrogen atom (--H) or a lower alkyl group and PA1 n denotes an integer from 1 to 5, and the salts of the acids are new compounds. They display a hypoglycaemic action in warm-blooded animals. Processes for the preparation of the new compounds and of the intermediate products required for their preparation are described.

TECHNICAL FIELD 
The invention relates to substituted oxiranecarboxylic acids, processes for 
their preparation, their use and medicaments containing them. 
BACKGROUND 
Phenyloxiranecarboxylic acid esters, for example 
2-phenyloxirane-2-carboxylic acid ethyl ester, inter alia, are within the 
scope of an investigation into the ability of substituted cyclic compounds 
(with a three-membered ring) to serve as a substrate or inhibitor for 
epoxide hydrase from guinea pig liver microsomes [F. Oesch et al., 
Biochem. 10 (1971) No. 26, 4,858-66]. Reaction of methyl N-acetyl isatoate 
with an excess of diazomethane yielded methyl 
2-(o-acetamidobenzyl)glycidate in the course of the elucidation of the 
constitution of isamic acid [P. de Mayo and J. J. Ryan, Can.J.Chem. 45 
(1967) 2177-2190]. Certain substituted oxiranecarboxylic acids have now 
been found to be pharmaceutically-active compounds with a specific action. 
SUMMARY OF THE INVENTION 
Pharmaceutically-active substituted oxiranecarboxylic acids, 
.omega.-(optionally substituted)phenylalkylene-.alpha.-methylenecarboxylic 
acids, their pharmacologically-acceptable salts and their lower alkyl 
esters have a hypoglycemic and hypoketonemic activity which makes them 
useful for the prophylaxis and treatment of disorders, such as diabetes, 
based on glucose and fat metabolism. The compounds are administered 
enterally or parenterally in conventional dosage forms to those subject to 
or afflicted with such disorders. The dosage forms ordinarily comprise 
compositions in which the active ingredient is in admixture with a 
suitable excipient or carrier. 
The following types of acids are illustrative of that part of the compound 
aspect of this invention; corresponding salts and lower alkyl esters are 
readily appreciated by any artisan: 
2-[.omega.-phenyl(C.sub.1-8)alkylene]oxirane-2-carboxylic acid, 
2-[.omega.-(monosubstituted)phenyl(C.sub.1-8)alkylene]oxirane-2-carboxylic 
acid, 
2-[.omega.-(disubstituted)phenyl(C.sub.1-8)alkylene]oxirane-2-carboxylic 
acid, 
.alpha.-methylene-.omega.-phenylheptanoic acid, 
.omega.-(m- or 
p-chloro)phenyl(C.sub.4-6)alkylene-.alpha.-methylenecarboxylic acid and 
.alpha.-methylene-.omega.-(m- or p-trifluoromethyl)phenylheptanoic acid. 
DETAILS 
More particularly, the invention relates to substituted oxiranecarboxylic 
acids of the formula 
##STR2## 
wherein R.sup.1 denotes a hydrogen atom (--H), a halogen atom, a hydroxyl 
group, a lower alkyl group, a lower alkoxy group or a trifluoromethyl 
group, 
R.sup.2 has one of the meanings of R.sup.1, 
R.sup.3 denotes a hydrogen atom (--H) or a lower alkyl group and 
n denotes an integer from 1 to 8, and 
salts of the carboxylic acids. 
The lower alkyl groups include straight-chain and branched alkyl radicals 
with from 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 
or 2 carbon atoms are preferred. Examples of branched alkyl radicals are 
the isopropyl, isobutyl and sec.-butyl radical, of which that with 3 
carbon atoms is preferred. Alkyl radicals in lower alkoxy groups are 
similarly both straight-chain and branched lower alkyl groups. The methoxy 
group is the preferred lower alkoxy group. 
Halogen atoms are fluorine, chlorine and bromine atoms, of which fluorine 
and, in particular, chlorine are preferred. 
Substituents R.sup.1 and R.sup.2 are preferably in the metaposition or 
para-position. 
Salts include those with either an inorganic or an organic base. 
Pharmacologically-unacceptable salts are readily converted into 
pharmacologically-, that is to say biologically-, acceptable salts (which 
are preferred salts according to the invention) by conventional methods. 
Cations used for salt formation are, advantageously, those of alkali 
metals, alkaline-earth metals or earth metals, but cations corresponding 
to organic nitrogen bases, such as amines, aminoalkanols, amino-sugars and 
basic aminoacids, are optionally used. 
Exemplary salts are those of lithium, sodium, potassium, magnesium, 
calcium, aluminum, ethylenediamine, dimethylamine, diethylamine, 
morpholine, piperidine, piperazine, N-(lower alkyl)piperazine (for example 
N-methylpiperazine), methylcyclohexylamine, benzylamine, ethanolamine, 
diethanolamine, triethanolamine, tris-(hydroxymethyl)aminomethane, 
2-amino-2-methylpropanol, 2-amino-2-methyl-1,3-propanediol, glucamine, 
N-methylglucamine, glucosamine, N-methylglucosamine, lysine, ornithine, 
arginine and quinoline. 
Substituted oxiranecarboxylic acids I* of formula I, wherein 
R.sup.1 and R.sup.2 are in the meta-position or para-position and 
R.sup.1 denotes a hydrogen atom (--H), a chlorine atom, a methyl group, a 
methoxy group or a trifluoromethyl group, 
R.sup.2 denotes a hydrogen atom (--H) or a chlorine atom, 
R.sup.3 denotes a hydrogen atom (--H) or a lower alkyl group and 
n denotes an integer from 3 to 7, and 
salts of the carboxylic acids form an embodiment of the invention. 
Substituted oxiranecarboxylic acids I** of formula I, wherein 
R.sup.1 and R.sup.2 are in the meta-position or para-position and 
R.sup.1 denotes a hydrogen atom (--H), a chlorine atom or a trifluoromethyl 
group, 
R.sup.2 denotes a hydrogen atom (--H), 
R.sup.3 denotes a hydrogen atom (--H), a methyl group or an ethyl group and 
n denotes 3 or 4, and 
pharmacologically-acceptable salts of the carboxylic acids with an 
inorganic or organic base form a preferred embodiment of the invention. 
Substituted oxiranecarboxylic acids I*** (wherein R.sup.1, R.sup.2 and 
R.sup.3 have the same meanings as for embodiment I**, but n denotes 5) and 
the pharmacologically-acceptable salts of these carboxylic acids form a 
particularly preferred embodiment of the invention. 
Examples of compounds according to the invention are: 
2-(4-chlorobenzyl)oxirane-2-carboxylic acid ethyl ester, 
2-(3-chlorobenzyl)oxirane-2-carboxylic acid methyl ester, 
2-(4-fluorobenzyl)oxirane-2-carboxylic acid isopropyl ester, 
2-[2-(4-chlorophenyl)ethyl]oxirane-2-carboxylic acid n-butyl ester, 
2-[2-(4-methoxyphenyl)ethyl]oxirane-2-carboxylic acid methyl ester, 
2-[2-(3-trifluoromethylphenyl)ethyl]oxirane-2-carboxylic acid ethyl ester, 
2-[3-(3-fluorophenyl)propyl]oxirane-2-carboxylic acid ethyl ester, 
2-[3-(4-bromophenyl)propyl]oxirane-2-carboxylic acid methyl ester, 
2-[3-(3-methoxyphenyl)propyl]oxirane-2-carboxylic acid sec.-butyl ester, 
2-{3-[4-(n-butoxy)phenyl]propyl}oxirane-2-carboxylic acid ethyl ester, 
2-[3-(3-isopropoxyphenyl)propyl]oxirane-2-carboxylic acid isopropyl ester, 
2-[4-(3-fluorophenyl)butyl]oxirane-2-carboxylic acid methyl ester, 
2-[4-(3-trifluoromethylphenyl)butyl]oxirane-2-carboxylic acid n-butyl 
ester, 
2-[4-(3-bromophenyl)butyl]oxirane-2-carboxylic acid ethyl ester, 
2-[4-(4-chlorophenyl)butyl]oxirane-2-carboxylic acid n-propyl ester, 
2-[4-(3,4-dichlorophenyl)butyl]oxirane-2-carboxylic acid ethyl ester, 
2-[4-(3-chloro-4-methylphenyl)butyl]oxirane-2-carboxylic acid methyl ester, 
2-[4-(4-ethoxyphenyl)butyl]oxirane-2-carboxylic acid ethyl ester, 
2-[5-(4-methoxyphenyl)pentyl]oxirane-2-carboxylic acid ethyl ester, 
2-[5-(3-trifluoromethylphenyl)pentyl]oxirane-2-carboxylic acid n-butyl 
ester, 
2-[5-(4-methylphenyl)pentyl]oxirane-2-carboxylic acid methyl ester, 
2-[5-(3-chlorophenyl)pentyl]oxirane-2-carboxylic acid isobutyl ester, 
2-[5-(4-methoxyphenyl)pentyl]oxirane-2-carboxylic acid ethyl ester, 
2-[6-(4-fluorophenyl)hexyl]oxirane-2-carboxylic acid ethyl ester, 
2-[6-(3-trifluoromethylphenyl)hexyl]oxirane-2-carboxylic acid methyl ester, 
2-[6-(3,4-dichlorophenyl)hexyl]oxirane-2-carboxylic acid n-butyl ester, 
2-[6-(4-chlorophenyl)hexyl]oxirane-2-carboxylic acid isopropyl ester, 
2-[7-(3-fluorophenyl)heptyl]oxirane-2-carboxylic acid ethyl ester, 
2-[7-(4-trifluoromethylphenyl)heptyl]oxirane-2-carboxylic acid ethyl ester, 
2-[7-(3-chloro-4-methylphenyl)heptyl]oxirane-2-carboxylic acid methyl 
ester, 
2-[7-(3-chlorophenyl)heptyl]oxirane-2-carboxylic acid n-propyl ester, 
2-[8-(4-fluorophenyl)octyl]oxirane-2-carboxylic acid ethyl ester, 
2-[8-(3-trifluoromethylphenyl)octyl]oxirane-2-carboxylic acid methyl ester, 
2-[8-(3,4-dichlorophenyl)octyl]oxirane-2-carboxylic acid ethyl ester and 
2-[8-(4-chlorophenyl)octyl]oxirane-2-carboxylic acid isobutyl ester, 
the corresponding oxirane-2-carboxylic acids and salts thereof with 
inorganic and organic bases. 
Preferred representatives are: 
2-[3-(3-chlorophenyl)propyl]oxirane-2-carboxylic acid ethyl ester, 
2-[3-(4-chlorophenyl)propyl]oxirane-2-carboxylic acid ethyl ester, 
2-[3-(3-trifluoromethyl-phenyl)propyl]oxirane-2-carboxylic acid ethyl 
ester, 
2-(5-phenylpentyl)oxirane-2-carboxylic acid ethyl ester, 
2-[5-(4-chlorophenyl)pentyl]oxirane-2-carboxylic acid ethyl ester, the 
corresponding oxirane-2-carboxylic acids and pharmacologically acceptable 
salts thereof. 
The substituted oxiranecarboxylic acids of formula I and of embodiments I*, 
I** and I*** have a chirality center. The invention includes the 
racemates, the enantiomers and mixtures thereof. 
The compounds according to the invention have valuable pharmacological 
properties which render them commercially valuable. They have a 
hypoglycemic and hypoketonemic action. 
Because of their advantageous activity, the substituted oxiranecarboxylic 
acids of formula I (including embodiments I*, I** and I***) and their 
pharmacologically-acceptable salts, are suitable in human and veterinary 
medicine for the treatment and prophylaxis of illnesses based on glucose 
and fat metabolism disorders. Prediabetic conditions are treated for 
prevention of the manifestation of diabetes; manifest diabetes, for 
example diabetes in adults, and labile diabetes in young persons and 
diseases which are accompagnied by an increased production of ketones are 
treated for control and symptom alleviation. 
The invention thus also relates to a method for combating such illnesses by 
administration of compounds according to the invention to those subject to 
or afflicted with disorders of the indicated type. The invention 
furthermore relates to the use of compounds according to the invention in 
combating these illnesses. 
Moreover, the invention relates to medicaments which contain one or more 
substituted oxiranecarboxylic acids of formula I, 
wherein 
R.sup.1 denotes a hydrogen atom (--H), a halogen atom, a hydroxyl group, a 
lower alkyl group, a lower alkoxy group or a trifluoromethyl group, 
R.sup.2 has one of the meanings of R.sup.1, 
R.sup.3 denotes a hydrogen atom or a lower alkyl group and 
n denotes an integer from 1 to 8, and/or 
pharmacologically-acceptable salts of the acids with inorganic or organic 
bases. 
Medicament embodiments include those which contain substituted 
oxiranecarboxylic acids I*, I** and I*** and/or 
pharmacologically-acceptable salts of such acids with inorganic or organic 
bases. 
The invention also encompasses the use of the compounds according to the 
invention for preparing medicaments for combating the noted illnesses. 
The medicaments are conventionally prepared by known processes. As 
medicaments, the new compounds are employed as such or in combination with 
suitable pharmaceutical excipients. When the new pharmaceutical 
formulations contain pharmaceutical excipients in admixture with or in 
addition to one or more active compounds, the content of active compound 
is from 1 to 95, preferably from 15 to 85, percent by weight of the total. 
According to the invention, the active compounds are used in the field of 
human medicine in any desired form, for example systemically, provided 
that sufficient levels of active compound are established and maintained 
in the blood or tissue. This is 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 mode of administration. A unit dose is, 
for example, in the form of a tablet, a dragee, a capsule, a suppository 
or a measured volume of a powder, of a granular material, of a solution, 
of an emulsion or of a suspension. 
"Unit dose" for the purpose of the present invention means a 
physically-determined unit which contains an individual amount of 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 from about 2 to 200 mg, advantageously from 10 to 100 mg 
and, in particular, from 20 to 60 mg of active compound. 
In general, it is advantageous in human medicine to administer the active 
compound or compounds, when these are given orally, in a daily dose of 
from about 0.1 to about 30, preferably from 0.3 to 15 and, in particular, 
from 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 
results. An individual administration contains the active compound or 
compounds in amounts of from about 0.05 to about 10, preferably from 0.1 
to 5 and, in particular, from 0.3 to 1 mg/kg of body weight. 
Similar dosages are used in parenteral treatment, for example intravenous 
or intramuscular administration. From about 0.3 to 1 mg of active 
compound/kg of body weight is administered for this therapy. 
For long-term medication, the pharmaceutical formulation is generally 
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 mentioned 
dosages and, in particular, to do so in accordance with the nature, body 
weight and age of the patient being treated, the nature and severity of 
the illness, the frequency of administration, the nature of the 
formulation and of the mode of administration of the medicament, and the 
time or interval over which administration takes place. Thus, in some 
cases it may be sufficient to manage with less than the indicated amount 
of active compound, while such amount of active compound must be exceeded 
in other cases. The optimum dosage and method of administration of the 
active compounds required in each particular case are readily determined 
by the expert in accordance with his expert knowledge. 
The pharmaceutical formulations ordinarily comprise one or more active 
compounds according to the invention and nontoxic, 
pharmaceutically-acceptable medicinal excipient. Excipients are used, 
e.g., 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 therapeutically-active 
ingredient. An excipient serves, for example, as a promoter of the 
resorption of the medicament by the body, as a formulating auxiliary, as a 
sweetener, as a flavor correctant, as a colorant or as a preservative. 
Examples of oral dosage forms are tablets, dragees, hard and soft capsules 
(for example, made of gelatin), dispersible powders, granules, aqueous and 
oily suspensions, emulsions or solutions. 
Tablets contain, e.g., inert diluents, such as calcium carbonate, calcium 
phosphate, sodium phosphate or xylitol; granulating agents and dispersing 
agents, such as calcium phosphate or alginates; binders, such as starch, 
gelatin or gum acacia; and lubricants, such as aluminum or magnesium 
stearate, talc or silicone oil. The tablets are optionally provided with a 
coating, such as one which brings about delayed dissolution and resorption 
of the medicament in the gastrointestinal tract and hence, for example, 
better toleration, a protracted effect or a retarded effect. Gelatin 
capsules optionally contain the medicament mixed with a solid diluent, for 
example calcium carbonate or kaolin, or an oily diluent, for example 
paraffin oil. 
Aqueous suspensions contain, e.g., suspending agents, such as sodium 
carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, sodium 
alginate, polyvinylpyrrolidone, gum tragacanth or gum acacia; dispersing 
agents and wetting agents, such as polyoxyethylene stearate, 
heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, 
polyoxyethylene sorbitan monooleate or lecithin; preservatives, such as 
methyl hydroxybenzoate or propyl hydroxybenzoate; flavoring agents; and 
sweeteners, such as saccharin or sodium cyclamate. 
Oily suspensions contain, for example, paraffin oil, and thickeners, such 
as beeswax, hard paraffin or cetyl alcohol; and furthermore sweeteners, 
flavoring agents and antioxidants. 
Water dispersible powders and granules contain the medicaments mixed, e.g., 
with dispersing agents, wetting agents and suspending agents, for example 
those previously mentioned, as well as sweeteners, flavoring agents and 
colorants. 
Emulsions contain, for example, paraffin oil in addition to emulsifying 
agents, such as gum acacia, gum tragacanth, phosphatides, sorbitan 
monooleate or polyoxyethylene sorbitan monooleate, and sweeteners and 
flavoring agents. 
For parenteral administration of the medicaments, sterile injectable 
aqueous suspensions, isotonic salt solutions or other solutions, which 
optionally 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 is also optionally prepared in a 
micro-encapsulated form, if appropriate together with one or more of the 
noted excipients or additives. 
In addition to the substituted oxiranecarboxylic acids according to the 
invention, in which the substituents have their previously-ascribed 
meanings, and/or their salts, the pharmaceutical formulations 
alternatively contain one or more pharmacologically-active ingredients 
from other groups of medicaments, such as antidiabetic agents 
(sulfonamides and sulfonylureas), for example carbutamide, tolbutamide, 
clorpropamide, glibenclamide, glibornuride, glisoxepide, gliquidone and 
glymidine, or hypolipidaemic agents, such as nicotinic acid and 
derivatives and salts thereof. 
The invention also relates to a process for preparing substituted 
oxiranecarboxylic acids of formula I and salts of the acids, characterized 
by oxidizing substituted .alpha.-methylenecarboxylic acids of the formula 
##STR3## 
wherein R.sup.1, R.sup.2, R.sup.3 and n have their previously-ascribed 
meanings, and optionally saponifying the resulting lower alkyl esters or 
optionally converting the resulting acids into salts or lower alkyl 
esters. 
The oxidation of the .alpha.-methylenecarboxylic acids II is effected under 
known and well-established conditions for oxidation of carbon-carbon 
double bonds to obtain epoxides. Suitable oxidizing agents include peroxo 
compounds, such as hydrogen peroxide, peracetic acid, trifluoroperacetic 
acid, 3,5-dinitroperbenzoic acid and, preferably m-chloroperbenzoic acid. 
The reaction is appropriately carried out in inert solvent, for example an 
aromatic or chlorinated hydrocarbon, such as benzene, toluene, methylene 
chloride or chloroform. The reaction temperature is between 0.degree. C. 
and the boiling point of the solvent, preferably between 20.degree. and 
70.degree. C. 
The saponification of lower alkyl esters is also effected conventionally. 
It is carried out, for example, with an aqueous or alcoholic (for example 
ethanolic) alkali-metal hydroxide (for example potassium hydroxide) 
solution at room temperature, optionally with the inclusion of an inert 
diluent, such as dioxane, tetrahydrofurane or toluene. 
The conversion of acids of formula I (R.sup.3 =--H) or of embodiments I*, 
I** and I*** into salts is effected, e.g., by direct alkaline hydrolysis 
of the acid derivatives I (R.sup.3 =lower alkyl). That inorganic or 
organic base of which the salt is desired is used as the alkaline 
reactant. The salts are alternatively obtained by reacting the acids I 
(R.sup.3 =--H) with the stoichiometric equivalent of the corresponding 
base, for example sodium hydroxide or sodium ethanolate, by converting 
readily-soluble salts into sparingly-soluble salts by double decomposition 
or by converting any salt into a pharmacologically-acceptable salt. 
The conversion of oxiranecarboxylic acids of formula I (R.sup.3 =--H) or of 
embodiments I*, I** and I*** into corresponding lower alkyl esters 
(R.sup.3 =lower alkyl) is effected in a well-established manner. For 
example, they are esterified (a) with a lower alkanol in a reaction medium 
comprising strong acid, such as sulfuric acid or p-toluenesulfonic acid, 
or acid ion exchanger under conditions in which no decarboxylation takes 
place or (b) with dialkylsulfate or an alkyl halide in a reaction medium 
comprising diazabicycloundecene or diazabicyclononene in inert solvent, 
such as benzene, toluene or acetone. 
The compounds of the general formula I are normally obtained in the form of 
racemic mixtures which, by means of known processes, are separated into 
the enantiomers. For example, the racemate is converted with an 
optically-active splitting agent into diastereoisomers which subsequently 
are separated by selective crystallization and converted into the 
appropriate optical isomers. Suitable optically-active splitting agents 
include, e.g, optically-active bases, such as l- and d-1-phenylethyl 
amine, cinchonidine or d-ephedrine, from which salts of the acids of 
formula I are prepared, or optically-active alcohols, such as borneol or 
menthol, from which esters of the acids of formula I are prepared. The 
racemic mixtures are also separated by chromatography via optically-active 
sorbing agents. Alternatively, the .alpha.-methylenecarboxylic acids II 
are primarily reacted with an optically-active splitting agent, e.g. 
borneol or menthol; the obtained products are subsequently oxidized to the 
mixtures of the diastereoisomers of the oxiranecarboxylic acid esters, 
from which the optical isomers of the acids I are obtained in a manner 
known to the expert. 
.alpha.-Methylenecarboxylic acids of formula II, wherein R.sup.1, R.sup.2, 
R.sup.3 and n have their respective meanings for embodiments I*, I** and 
I***, are employed for preparing the substituted oxiranecarboxylic acids 
of embodiments I*, I** and I***. 
The .alpha.-methylenecarboxylic acids of formula II are known or are 
prepared by conventional methods from known starting materials. They are 
valuable intermediate products for the synthesis of the oxiranecarboxylic 
acids I, I*, I** and I***. Moreover, the .alpha.-methylenecarboxylic acids 
II** (in which R.sup.1 denotes a chlorine atom and R.sup.2, R.sup.3 and n 
have the meanings indicated for embodiment I**) and the 
.alpha.-methylenecarboxylic acids II*** (in which R.sup.1, R.sup.2, 
R.sup.3 and n have the meanings indicated for embodiment I***) also have 
hypoglycemic activity. 5-(3-Chlorophenyl)-.alpha.-methylenevaleric acid 
ethyl ester, .alpha.-methylene-7-phenylheptanoic acid, 
7-(4-chlorophenyl)-.alpha.-methyleneheptanoic acid and, in particular, 
5-(4-chlorophenyl)-.alpha.-methylenevaleric acid ethyl ester are 
exemplary. Compounds II** (in which R.sup.1 denotes a chlorine atom) and 
II*** are useful both as intermediates and as medicaments. The medicaments 
are formulated in a known manner by previously-described methods. 
The .alpha.-methylenecarboxylic acids II are prepared, for example, by a 
process analogous to that of H. Stetter and H. Kuhlmann [Synthesis 1979, 
29] by reacting a malonic acid half-ester of the formula 
##STR4## 
wherein R.sup.1, R.sup.2 and n have their previously-indicated meanings 
and R.sup.4 denotes a lower alkyl group, with formaldehyde in a reaction 
medium comprising pyridine and secondary amine, preferably piperidine, and 
optionally saponifying the lower alkyl esters obtained. 
Alternatively, the .alpha.-methylenecarboxylic acids II are prepared by 
methods analogous to those described by Ph. E. Pfeffer et al. [J. Org. 
Chem., 37 (1972) 1,256] and W. S. Wadsworth, junior, and W. D. Emmons [J. 
Am. Chem. Soc., 83 (1961) 1,733]. 5-Phenyl-.alpha.-methylenevaleric acid 
and 3-phenyl-.alpha.-methylenepropionic acid are considered by C. Mannich 
and E. Ganz [Ber. Dtsch. Chem. Ges., 55 (1922) 3,486]. 
3-Phenyl-.alpha.-methylenepropionic acid ethyl ester is considered by Y. 
Ueno et al. [Tetrahedron Letters, 1978, 3,753] and 
4-phenyl-.alpha.-methylenebutyric acid ethyl ester is considered by F. 
Hahne and F. Zymalkowski [Arch. Pharm., 312 (1979) 472]. 
The malonic acid half-esters III are prepared by methods with which those 
skilled in the art are familiar, for example by reacting dialkyl malonates 
IV with phenylalkyl compounds V and partially hydrolyzing the resulting 
malonic acid diesters VI, according to the following reaction scheme: 
##STR5## 
wherein R.sup.1, R.sup.2, R.sup.4 and n have their previously-noted 
meanings and 
X denotes a leaving group, for example a chlorine or bromine atom or a 
mesyloxy or p-toluenesulfonyloxy group. 
Appropriate starting compounds III*, III** or III***; IV*, IV** or IV***; 
V*, V** or V***; and VI*, VI** or VI*** (in which R.sup.1, R.sup.2 and n 
have the meanings corresponding to those for embodiments I*, I** and I***, 
respectively, and R.sup.4* denotes a lower alkyl group, R.sup.4** and 
R.sup.4***, respectively, denote a methyl or ethyl group, and X*, X** and 
X***, respectively, denote a chlorine or bromine atom or a mesyloxy- or 
p-toluenesulfonyloxy group) are employed for the preparation of 
.alpha.-methylenecarboxylic acids II*, II** and II***. 
The following Examples, wherein b.p. denotes boiling point and m.p. denotes 
melting point, illustrate the invention without limiting it. The 
temperature data are in .degree.C.

EXAMPLE 1 
2-(3-Phenylpropyl)oxirane-2-carboxylic acid ethyl ester 
(a) 2-(3-Phenylpropyl)oxirane-2-carboxylic acid ethyl ester 
10 g of 5-phenyl-2-methylenevaleric acid ethyl ester and 18.3 g of 
m-chloroperbenzoic acid (85% pure) are boiled under reflux in 180 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 40 ml of acetone; 20 
ml of a saturated sodium carbonate solution are added, and the mixture is 
stirred at 0.degree. C. for 1 hour. It is then 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. 8.3 g of 
the liquid title compound (b.p. 115.degree. under 0.03 mm Hg) are 
obtained. 
(b) 5-Phenyl-2-methylenevaleric acid ethyl ester 
50 g of 3-phenylpropylmalonic acid monoethyl ester, 7.5 g of 
paraformaldehyde, 37.5 ml of pyridine and 2.5 ml of piperidine are stirred 
together at 50.degree. C. for 5 hours. After cooling, 350 ml of water are 
added to the reaction mixture, and the mixture is then extracted 3 times 
with 150 ml of hexane each time. After washing with 1 N hydrochloric acid, 
water and sodium bicarbonate solution, the organic phase is concentrated 
and distilled. 5-Phenyl-2-methylenevaleric acid ethyl ester is obtained as 
a colorless liquid of b.p. 78.degree. to 79.degree. C. under 0.02 mm Hg. 
Alternatively, 5-phenyl-2-methylenevaleric acid ethyl ester is obtained by 
esterifying 5-phenyl-2-methylenevaleric acid with ethanol in the presence 
of p-toluenesulfonic acid. 
EXAMPLE 2 
2-(3-Phenylpropyl)oxirane-2-carboxylic acid 
6.0 g of 2-(3-phenylpropyl)oxirane-2-carboxylic acid ethyl ester, 26 ml of 
1 N sodium hydroxide solution and 60 ml of ethanol are stirred at room 
temperature for 1 hour; 13 ml of 2 N hydrochloric acid are added to the 
solution (while cooling with ice), and the mixture is then concentrated to 
one third of its volume in vacuo. 50 ml of water are added to the 
thus-concentrated solution, and the resulting mixture is extracted 3 times 
with 50 ml of diethyl ether each time. After drying the organic phase over 
sodium sulfate and evaporating off the solvent, 4.3 g of a viscous oil are 
obtained. 
Alternatively, the compound is obtained as follows: a solution of 
trifluoroperacetic acid (prepared from 1.8 ml of 85% strength hydrogen 
peroxide, 17 g of trifluoroacetic anhydride and 15 ml of methylene 
chloride) is added dropwise to a boiling mixture of 9.5 g of 
5-phenyl-2-methylenevaleric acid and 28 g of disodium hydrogen phosphate 
in 50 ml of methylene chloride. The mixture is boiled under reflux for a 
further 30 minutes; 150 ml of ice-water are added; *the organic phase is 
separated off and, after drying over sodium sulfate, is concentrated. The 
title compound remains as a viscous oil. 
FNT *the pH is adjusted to 2 with hydrochloric acid; 
EXAMPLE 3 
2-(4-Phenylbutyl)oxirane-2-carboxylic acid ethyl ester 
(a) 2-(4-Phenylbutyl)oxirane-2-carboxylic acid ethyl ester 
7.6 g of the title compound (b.p. 105.degree. C. under 0.005 mm Hg) are 
obtained from 12 g of 6-phenyl-2-methylenehexanoic acid ethyl ester and 
26.5 g of m-chloroperbenzoic acid in 160 ml of methylene chloride by the 
procedure described in Example 1a. 
(b) 6-Phenyl-2-methylenehexanoic acid ethyl ester 
49 g of 6-phenyl-2-methylenehexanoic acid ethyl ester (b.p. 120.degree. to 
125.degree. C. under 0.005 mm Hg) are obtained from 72 g of 
4-phenylbutylmalonic acid monoethyl ester, 11.3 g of paraformaldehyde, 
51.3 ml of pyridine and 3.4 ml of piperidine by the procedure described in 
Example 1b. 
(c) 4-Phenylbutylmalonic acid monoethyl ester 
A solution of 17.8 g of potassium hydroxide in 200 ml of ethanol is added 
dropwise to 91 g of 4-phenylbutylmalonic acid diethyl ester in 200 ml of 
ethanol at room temperature (20.degree. C.). The mixture is stirred for 24 
hours and substantially concentrated in vacuo; the residue is taken up in 
500 ml of water, and the aqueous mixture is extracted twice with 100 ml of 
diethyl ether each time. The aqueous phase is acidified with concentrated 
hydrochloric acid (while cooling with ice) and extracted 3 times with 200 
ml of diethyl ether each time; after drying over sodium sulfate, the 
organic phase is concentrated. 72.8 g of a viscous oil remain. 
EXAMPLE 4 
2-[3-(2-Chlorophenyl)propyl]oxirane-2-carboxylic acid ethyl ester 
(a) 2-[3-(2-Chlorophenylpropyl]oxirane-2-carboxylic acid ethyl ester 
5.0 g of the title compound (b.p. 110.degree. to 113.degree. C. under 0.007 
mm Hg) are obtained from 14 g of 5-(2-chlorophenyl)-2-methylenevaleric 
acid ethyl ester and 22.5 g of m-chloroperbenzoic acid in 170 ml of 
methylene chloride by the procedure described in Example 1a. 
(b) 5-(2-Chlorophenyl)-2-methylenevaleric acid ethyl ester 
53.3 g of 5-(2-chlorophenyl)-2-methylenevaleric acid ethyl ester (b.p. 
95.degree. to 98.degree. C. under 0.005 mm Hg) are obtained from 71 g of 
3-(2-chlorophenyl)acid monoethyl ester, 10.42 g of paraformaldehyde, 47 ml 
of pyridine and 3.1 ml of piperidine by the procedure described in Example 
1b. 
(c) 3-(2-Chlorophenyl)propylmalonic acid monoethyl ester 
71.8 g of 3-(2-chlorophenyl)propylmalonic acid monoethyl ester are obtained 
as a viscous oil from 92 g of 3-(2-chlorophenyl)propylmalonic acid diethyl 
ester and 16.8 g of potassium hydroxide in 400 ml of ethanol by the 
procedure described in Example 3c. 
EXAMPLE 5 
2-[3-(3-Chlorophenyl)propyl]oxirane-2-carboxylic acid ethyl ester 
(a) 2-[3-(3-Chlorophenyl)propyl]oxirane-2-carboxylic acid ethyl ester 
10.8 g of the title compound (b.p. 135.degree. to 138.degree. C. under 
0.005 mm Hg) are obtained from 14 g of 
5-(3-chlorophenyl)-2-methylenevaleric acid ethyl ester and 22.5 g of 
m-chloroperbenzoic acid in 170 ml of methylene chloride by the procedure 
described in Example 1a. 
(b) 5-(3-Chlorophenyl)-2-methylenevaleric acid ethyl ester 
35.75 g of 5-(3-chlorophenyl)-2-methylenevaleric acid ethyl ester (b.p. 
105.degree. to 110.degree. C. under 0.005 mm Hg) are obtained from 57 g of 
3-(3-chlorophenyl)propylmalonic acid ethyl ester, 8.36 g of 
paraformaldehyde, 37.7 ml of pyridine and 2.5 ml of piperidine by the 
procedure described in Example 1b. 
(c) 3-(3-Chlorophenyl)propylmalonic acid ethyl ester 
57.7 g of 3-(3-chlorophenyl)propylmalonic acid ethyl ester are obtained as 
a viscous oil from 74 g of 3-(3-chlorophenyl)propylmalonic acid diethyl 
ester and 13.5 g of potassium hydroxide in 200 ml of ethanol by the 
procedure described in Example 3c. 
(d) 3-(3-Chlorophenyl)propylmalonic acid diethyl ester 
91.3 g of malonic acid diethyl ester are added dropwise, at 50.degree. C., 
to a sodium ethylate solution freshly prepared from 13.11 g of sodium and 
650 ml of ethanol. The mixture is kept at that temperature for 2.5 hours, 
and 185 g of p-toluenesulfonic acid [3-(3-chlorophenyl)propyl] ester are 
then added dropwise. When the addition is complete, the obtained mixture 
is stirred at 50.degree. C. for 6 hours; 800 ml of water are then added, 
and the mixture is extracted 3 times with a total of 1 liter of diethyl 
ether. The combined organic phases are dried over sodium sulfate; the 
solvent is evaporated off, and the residue is distilled. 74.2 g of 
3-(3-chlorophenyl)propylmalonic acid diethyl ester (b.p. 145.degree. to 
152.degree. C. under 0.01 mm Hg) are obtained. 
(e) p-Toluenesulfonic acid [3-(3-chlorophenyl)propyl] ester 
86 ml of pyridine are added dropwise to 90 g of 
3-(3-chlorophenyl)propan-1-ol and 124 g of p-toluenesulfonic acid chloride 
in 300 ml of chloroform at 0.degree. C. When the addition is complete, the 
mixture is stirred at room temperature for 3 hours, and the solution is 
poured into a mixture of 400 ml of water and 120 ml of concentrated 
hydrochloric acid. The organic phase is separated off, washed 3 times with 
water, dried over sodium sulfate and concentrated to a viscous oil in 
vacuo. 
EXAMPLE 6 
2-[3-(4-Chlorophenyl)propyl]oxirane-2-carboxylic acid ethyl ester 
(a) 2-[3-(4-Chlorophenyl)propyl]oxirane-2-carboxylic acid ethyl ester 
4.3 g of the title compound (b.p. 110.degree. C. under 0.005 mm Hg) are 
obtained from 10.0 g 5-(4-chlorophenyl)-2-methylenevaleric acid ethyl 
ester and 20.3 g of m-chloroperbenzoic acid in 150 ml of methylene 
chloride by the procedure described in Example 1a. 
(b) 5-(4-Chlorophenyl)-2-methylenevaleric acid ethyl ester 
58.8 g of 5-(4-chlorophenyl)-2-methylenevaleric acid ethyl ester (b.p. 
120.degree. to 123.degree. C. under 0.05 mm Hg) are obtained from 91.7 g 
of 3-(4-chlorophenyl)propylmalonic acid ethyl ester, 14.5 g of 
paraformaldehyde, 73.1 ml of pyridine and 4.8 ml of piperidine by the 
procedure described in Example 1b. 
(c) 3-(4-Chlorophenyl)propylmalonic acid ethyl ester 
92.2 g of 3-(4-chlorophenyl)propylmalonic acid ethyl ester are obtained as 
a viscous oil from 125.15 g of 3-(4-chlorophenyl)propylmalonic acid 
diethyl ester and 25.5 g of potassium hydroxide in 500 ml of ethanol by 
the procedure described in Example 3c. 
(d) 3-(4-Chlorophenyl)propylmalonic acid diethyl ester 
105.6 g of 3-(4-chlorophenyl)propylmalonic acid diethyl ester (b.p. 
145.degree. to 155.degree. C. under 0.01 mm Hg) are obtained from 220 g of 
p-toluenesulfonic acid [3-(4-chlorophenyl)propyl] ester, 108.5 g of 
malonic acid diethyl ester and a solution of 15.6 g of sodium in 750 ml of 
ethanol by the procedure described in Example 5d. 
(e) p-Toluenesulfonic acid [3-(4-chlorophenyl)propyl] ester 
285 g of p-toluenesulfonic acid [3-(4-chlorophenyl)propyl] ester are 
obtained as a viscous, yellowish oil from 150 g of 
3-(4-chlorophenyl)propan-1-ol, 206.6 g of p-toluenesulfonic acid chloride 
and 135 ml of pyridine in 300 ml of chloroform by the procedure described 
in Example 5e. 
EXAMPLE 7 
2-[3-(4-Methoxyphenyl)propyl]oxirane-2-carboxylic acid ethyl ester 
(a) 2-[3-(4-Methoxyphenyl)propyl]oxirane-2-carboxylic acid ethyl ester 
5.8 g of the title compound (b.p. 120.degree. to 125.degree. C. under 0.005 
mm Hg) are obtained from 10 g of 5-(4-methoxyphenyl)-2-methylenevaleric 
acid ethyl ester and 20 g of m-chloroperbenzoic acid in 150 ml of 
methylene chloride by the procedure described in Example 1a. 
(b) 5-(4-Methoxyphenyl)-2-methylenevaleric acid ethyl ester 
31.5 g of 5-(4-methoxyphenyl)-2-methylenevaleric acid ethyl ester (b.p. 
134.degree. to 135.degree. C. under 0.05 mm Hg) are obtained from 50 g of 
3-(4-methoxyphenyl)propylmalonic acid ethyl ester, 33.7 ml of pyridine, 
2.2 ml of piperidine and 7.4 g of paraformaldehyde by the procedure 
described in Example 1b. 
(c) 3-(4-Methoxyphenyl)propylmalonic acid ethyl ester 
50.3 g of 3-(4-methoxyphenyl)propylmalonic acid ethyl ester are obtained as 
a viscous oil from 63 g of 3-(4-methoxyphenyl)propylmalonic acid diethyl 
ester and 12.7 g of potassium hydroxide in 250 ml of ethanol by the 
procedure described in Example 3c. 
EXAMPLE 8 
2-[3-(3-Trifluoromethylphenyl)propyl]oxirane-2-carboxylic acid ethyl ester 
(a) 2-[3-(3-Trifluoromethylphenyl)propyl]oxirane-2-carboxylic acid ethyl 
ester 
8.5 g of the title compound (b.p. 110.degree. C. under 0.07 mm Hg) are 
obtained from 15 g of 2-methylene-5-(3-trifluoromethylphenyl)valeric acid 
ethyl ester and 21.27 g of m-chloroperbenzoic acid in 150 ml of methylene 
chloride by the procedure described in Example 1a. 
(b) 2-Methylene-5-(3-trifluoromethylphenyl)valeric acid ethyl ester 
19.53 g of 2-methylene-5-(3-trifluoromethylphenyl)valeric acid ethyl ester 
(b.p. 98.degree. to 110.degree. C. under 0.07 mm Hg) are obtained from 
35.4 g of 3-(3-trifluoromethylphenyl)propylmalonic acid ethyl ester, 4.24 
g of paraformaldehyde, 19.2 ml of pyridine and 1.27 ml of piperidine by 
the procedure described in Example 1b. 
(c) 3-(3-Trifluoromethylphenyl)propylmalonic acid ethyl ester 
36.2 g of 3-(3-trifluoromethylphenyl)propylmalonic acid ethyl ester are 
obtained as a viscous oil from 45.3 g of 
3-(3-trifluoromethylphenyl)propylmalonic acid diethyl ester and 7.5 g of 
potassium hydroxide in 260 ml of ethanol by the procedure described in 
Example 3c. 
(d) 3-(3-Trifluoromethylphenyl)propylmalonic acid diethyl ester 
50.6 g of 3-(3-trifluoromethylphenyl)propylmalonic acid diethyl ester (b.p. 
118.degree. to 120.degree. C. under 0.07 mm Hg) are obtained from 125 g of 
p-toluenesulfonic acid [3-(3-trifluoromethylphenyl)propyl] ester, 58.1 g 
of malonic acid diethyl ester and a solution of 8.5 g of sodium in 400 ml 
of ethanol by the procedure described in Example 5d. 
(e) p-Toluenesulfonic acid [3-(3-trifluoromethylphenyl)propyl] ester 
125 g of p-toluenesulfonic acid [3-(3-trifluoromethylphenyl)propyl] ester 
are obtained as a yellow oil from 71.5 g of 
3-(3-trifluoromethylphenyl)propan-1-ol, 83 g of p-toluenesulfonic acid 
chloride and 54 ml of pyridine in 160 ml of chloroform by the procedure 
described in Example 5e. 
(f) 3-(3-Trifluoromethylphenyl)propan-1-ol 
A solution of 57 g of oxirane in 120 ml of diethyl ether is added dropwise 
(at 0.degree. to 10.degree. C.) to a Grignard solution prepared from 14.8 
g of magnesium and 100 g of 3-(chloromethyl)benzotrifluoride in 450 ml of 
diethyl ether. The mixture is subsequently stirred at room temperature for 
1 hour, and 300 ml of 10% strength sulfuric acid are then added, while 
cooling with ice. The organic phase is collected and extracted twice more 
with diethyl ether, and the combined organic phases are dried over 
magnesium sulfate and distilled. 76.7 g of 
3-(3-trifluoromethylphenyl)propan-1-ol (b.p. 85.degree. to 95.degree. C. 
under 0.02 mm Hg) are thus obtained. 
EXAMPLE 9 
2-[3-(4-Methylphenyl)propyl]oxirane-2-carboxylic acid ethyl ester 
(a) 2-[3-(4-Methylphenyl)propyl]oxirane-2-carboxylic acid ethyl ester 
6.8 g of the title compound (b.p. 110.degree. to 115.degree. C. under 0.005 
mm Hg) are obtained from 10 g of 5-(4-methylphenyl)-2-methylenevaleric 
acid ethyl ester and 11.8 g of 3,5-dinitroperbenzoic acid in 100 ml of 
methylene chloride by the procedure described in Example 1a. 
(b) 5-(4-Methylphenyl)-2-methylenevaleric acid ethyl ester 
46.5 g of 5-(4-methylphenyl)-2-methylenevaleric acid ethyl ester (b.p. 
120.degree. to 128.degree. C. under 0.008 mm Hg) are obtained from 72 g of 
3-(4-methylphenyl)propylmalonic acid ethyl ester, 11.3 g of 
paraformaldehyde, 51 ml of pyridine and 3.4 ml of piperidine by the 
procedure described in Example 1b. 
(c) 3-(4-Methylphenyl)propylmalonic acid ethyl ester 
73.2 g of 3-(4-methylphenyl)propylmalonic acid ethyl ester are obtained 
from 90 g of 3-(4-methylphenyl)propylmalonic acid diethyl ester and 17.6 g 
of potassium hydroxide by the procedure described in Example 3c. 
EXAMPLE 10 
2-(5-Phenylpentyl)oxirane-2-carboxylic acid ethyl ester 
(a) 2-(5-Phenylpentyl)oxirane-2-carboxylic acid ethyl ester 
7.9 g of the title compound (b.p. 115.degree. to 120.degree. C. under 0.005 
mm Hg) are obtained from 13 g of 2-methylene-7-phenylheptanoic acid ethyl 
ester and 21.4 g of m-chloroperbenzoic acid in 160 ml of methylene 
chloride by the procedure described in Example 1a. 
(b) 2-Methylene-7-phenylheptanoic acid ethyl ester 
20.65 g of 2-methylene-7-phenylheptanoic acid ethyl ester are obtained as 
an oil (b.p. 122.degree. to 125.degree. C. under 0.07 mm Hg) from 44 g of 
5-phenylpentylmalonic acid ethyl ester, 6.6 g of paraformaldehyde, 30 ml 
of pyridine and 2 ml of piperidine by the procedure described in Example 
1b. 
(c) Phenylpentylmalonic acid ethyl ester 
44.8 of 5-phenylpentylmalonic acid ethyl ester are obtained as a viscous 
oil from 60 g of 5-phenylpentylmalonic acid diethyl ester and 11.16 g of 
potassium hydroxide in 250 ml of ethanol by the procedure described in 
Example 3c. 
(d) 5-Phenylpentylmalonic acid diethyl ester 
66.8 g of 5-phenylpentylmalonic acid diethyl ester are obtained as an oil 
(b.p. 142.degree. to 148.degree. C. under 0.02 mm Hg) from 80.8 g of 
1-bromo-5-phenylpentane, 64.1 g of malonic acid diethyl ester and a 
solution of 8.2 g of sodium in 400 ml of ethanol by the procedure 
described in Example 5d. 
EXAMPLE 11 
2-[5-(4-Chlorophenyl)pentyl]oxirane-2-carboxylic acid ethyl ester 
(a) 2-[5-(4-Chlorophenyl)pentyl]oxirane-2-carboxylic acid ethyl ester 
8.8 g of the title compound (b.p. 135.degree. to 140.degree. C. under 0.005 
mm Hg) are obtained from 15 g of 7-(4-chlorophenyl)-2-methyleneheptanoic 
acid ethyl ester and 23 g of m-chloroperbenzoic acid in 180 ml of 
methylene chloride by the procedure described in Example 1a. 
(b) 7-(4-Chlorophenyl)-2-methyleneheptanoic acid ethyl ester 
15.5 g of 7-(4-chlorophenyl)-2-methyleneheptanoic acid ethyl ester (b.p. 
140.degree. to 145.degree. C. under 0.008 mm Hg) are obtained from 25 g of 
5-(4-chlorophenyl)pentylmalonic acid ethyl ester, 3.8 g of 
paraformaldehyde, 16 ml of pyridine and 1 ml of piperidine by the 
procedure described in Example 1b. 
(c) 5-(4-Chlorophenyl)pentylmalonic acid ethyl ester 
26.5 g of 5-(4-chlorophenyl)pentylmalonic acid ethyl ester are obtained as 
a viscous oil from 34 g of 5-(4-chlorophenyl)pentylmalonic acid diethyl 
ester and 5.7 g of potassium hydroxide in 150 ml of ethanol by the 
procedure described in Example 3c. 
(d) 5-(4-Chlorophenyl)pentylmalonic acid diethyl ester 
35.5 g of 5-(4-chlorophenyl)pentylmalonic acid diethyl ester are obtained 
as an oil from 70.5 g of p-toluenesulfonic acid [5-(4-chlorophenyl)pentyl] 
ester, 32 g of malonic acid diethyl ester and a solution of 4.6 g of 
sodium in 250 ml of ethanol by the procedure described in Example 5d. 
EXAMPLE 12 
2-[3-(4-Chlorophenyl)propyl]oxirane-2-carboxylic acid 
The title compound is obtained as a viscous oil from 1.0 g of 
2-[3-(4-chlorophenyl)propyl]oxirane-2-carboxylic acid ethyl ester and 3.72 
ml of 1 N sodium hydroxide solution by the procedure described in Example 
2. 
EXAMPLE 13 
2-(3-Phenylpropyl)oxirane-2-carboxylic acid methyl ester 
The title compound is obtained as a colorless oil (b.p. 75.degree. to 
80.degree. C. under 0.01 mm Hg) analogously to Example 3a. 
The starting compound 5-phenyl-2-methylenevaleric acid methyl ester is 
obtained from 3-phenylpropylmalonic acid dimethyl ester analogously to 
Example 3b and 3c. 
EXAMPLE 14 
Sodium 2-(3-phenylpropyl)oxirane-2-carboxylate 
5 g of 2-(3-phenylpropyl)oxirane-2-carboxylic acid is dissolved in the 
equivalent amount of 1 N sodium hydroxide solution, and the resulting 
aqueous solution is washed once with diethyl ether and evaporated to 
dryness. The glassy residue, which is dried at 20.degree. C. in vacuo, 
consists of the pure sodium salt. 
EXAMPLE 15 
2-Benzyloxirane-2-carboxylic acid ethyl ester 
7.6 g of the title compound (b.p. 79.degree. to 80.degree. C. under 0.003 
mm Hg) are obtained from 15.0 g of 2-methylene-3-phenylpropionic acid 
ethyl ester and 32.0 g of m-chloroperbenzoic acid in 300 ml of methylene 
chloride by the procedure described in Example 1a. 
EXAMPLE 16 
2-(2-Phenylmethyl)oxirane-2-carboxylic acid ethyl ester 
9 g of 4-phenyl-2-methylenebutyric acid ethyl ester and 22.3 g of 
m-chloroperbenzoic acid (85% pure) are boiled under reflux in 150 ml of 
methylene chloride for 24 hours. The mixture is allowed to cool; the 
m-chlorobenzoic acid (which has separated out) is filtered off; the 
filtrate is concentrated; the resulting residue is taken up in 30 ml of 
acetone; 15 ml of a saturated sodium carbonate solution are then added, 
and the obtained mixture is stirred at 0.degree. C. for 1 hour. It 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 oily 
residue is distilled. 7.3 g of the title compound (b.p. 110.degree. to 
112.degree. C. under 0.01 mm Hg) are thus obtained. 
EXAMPLE 17 
Sodium 2-[3-(3-chlorophenyl)propyl]oxirane-2-carboxylate 
2.7 g of 2-[3-(3-chlorophenyl)propyl]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, after which the title compound remains as a colorless glassy 
powder. 
EXAMPLE 18 
2-[3-(2-Chlorophenyl)propyl]oxirane-2-carboxylic acid ethyl ester 
A mixture of 104 ml of 15% strength butyl-lithium (in hexane), 19 g of 
diisopropylamine and 400 ml of tetrahydrofuran is stirred together at 
-78.degree.; 39 g of 5-(2-chlorophenyl)-2-acetylvaleric acid ethyl ester 
[prepared from 3-(2-chlorophenyl)propyltosylate and ethyl acetoacetate] 
are added dropwise to the resulting admixture. The mixture thus obtained 
is stirred for a further 20 minutes. After removing the cooling bath, 19.4 
g of paraformaldehyde (anhydrous) are added in portions to the mixture. 
After stirring the mixture for 1 hour, it is heated under reflux for 5 
hours and left to stand overnight. The solid constituents are filtered 
off, and the filtrate is concentrated in a rotary evaporator. 500 ml of 
saturated sodium bicarbonate solution are added to the residue, and the 
mixture is stirred for 30 minutes. Extraction with methylene chloride and 
evaporation of the solvent yield (after purification by distillation) 14 g 
of 5-(2-chlorophenyl)-2-methylenevaleric acid ethyl ester of b.p. 
95.degree. to 98.degree. C. under 0.005 mm Hg. The title compound is 
obtained analogously to Example 4a by oxidation. 
EXAMPLE 19 
Sodium 2-[3-(4-chlorophenyl)propyl]oxirane-2-carboxylate 
A solution of 4.2 g of 2-[3-(4-chlorophenyl)propyl]oxirane 2-carboxylic 
acid ethyl ester is added dropwise to a solution of 0.36 g of sodium in 15 
ml of ethanol, 0.28 g of water is then added and the mixture is stirred at 
room temperature for 1 hour. The precipitate which has separated out is 
filtered off, washed with diethyl ether and recrystallized once from 
ethanol/diethyl ether. 2.0 g of the title compound of m.p. 160.degree. to 
167.degree. C. are obtained. 
EXAMPLE 20 
Sodium 2-[3-(3-trifluoromethylphenyl)propyl]oxirane-2-carboxylate 
A solution of 28 g of 
2-[3-(3-trifluoromethylphenyl)propyl]oxirane-2-carboxylic acid ethyl ester 
in 50 ml of tetrahydrofuran is added dropwise to a solution of 92.6 ml of 
1 N sodium hydroxide solution and 50 ml of tetrahydrofuran at room 
temperature. After a clear solution has formed, the solution is 
concentrated to a viscous mass in vacuo. The mass is dissolved in 70 ml of 
tetrahydrofuran, the small amount of undissolved material is filtered off, 
and 200 ml of methylene chloride are added dropwise to the clear filtrate. 
The voluminous precipitate is filtered off and stirred again with 200 ml 
of diethyl ether, the mixture is filtered and the solid product is dried 
over calcium chloride. The title compound of m.p. 64.degree. to 70.degree. 
C., which contains 2 mols of water of crystallization, is converted into 
the form containing no water of crystallization, of m.p. &gt;170.degree. C., 
when dried over phosphorus pentoxide in vacuo (yield: 22.8 g). 
EXAMPLE 21 
Sodium 2-(5-phenylpentyl)oxirane-2-carboxylate 
A mixture of 166 ml of 1 N sodium hydroxide solution and 90 ml of 
tetrahydrofuran is added dropwise to a solution of 43.6 g of 
2-(5-phenylpentyl)oxirane 2-carboxylic acid ethyl ester in 90 ml of 
tetrahydrofuran. When the addition has ended, the mixture is stirred for 
about 45 minutes, until a clear solution has formed. 1.6 l of acetone are 
now added dropwise in the course of 3 hours, a crystalline precipitate, 
which is filtered off and washed with acetone, separating out. The product 
is recrystallized from water to give 42.9 g of the title compound as the 
dihydrate of m.p. 82.degree. to 86.degree. C. 
EXAMPLE 22 
Sodium 2-[5-(4-chlorophenyl)pentyl]oxirane-2-carboxylate 
A mixture of 8.05 g of 2-[5-(4-chlorophenyl)pentyl]oxirane 2-carboxylic 
acid ethyl ester, 27 ml of tetrahydrofuran and 27 ml of 1 N sodium 
hydroxide solution is stirred for about 1 hour until a clear solution has 
formed. The solution is concentrated and the colorless residue is 
recrystallized from ethanol/diethyl ether. 6.5 g of the title compound of 
m.p. 136.degree. to 142.degree. C. are obtained. 
EXAMPLE 23 
Sodium 2-[3-(4-methylphenyl)propyl]oxirane-2-carboxylate 
2.7 g of the title compound of m.p. &gt;250.degree. C. (from methanol/diethyl 
ether) are obtained from a solution of 0.7 g of sodium in 70 ml of 
ethanol, 0.5 ml of water and 7.0 g of 2-[3-(4-methylphenyl)propyl]oxirane 
2-carboxylic acid ethyl ester by the procedure described in Example 19. 
EXAMPLE 24 
2-[3-(4-Fluorophenyl)propyl]oxirane-2-carboxylic acid ethyl ester 
(a) 2-[3-(4-Fluorophenyl)propyl]oxirane-2-carboxylic acid ethyl ester 
23.8 g of the title compound of b.p. 115.degree. to 117.degree. C. under 
0.02 mm Hg are obtained from 25.4 g of 
5-(4-fluorophenyl)-2-methylenevaleric acid ethyl ester and 32.2 g of 
m-chloroperbenzoic acid in 330 ml of methylene chloride by the procedure 
described in Example 1a. 
(b) 5-(4-Fluorophenyl)-2-methylenevaleric acid ethyl ester 25.7 g of 
5-(4-Fluorophenyl)-2-methylenevaleric acid ethyl ester of b.p. 84.degree. 
to 86.degree. C. under 0.01 mm Hg are obtained from 43.5 g of 
3-(4-fluorophenyl)propylmalonic acid ethyl ester, 5.1 g of 
paraformaldehyde, 50 ml of pyridine and 1.6 ml of piperidine by the 
procedure described in Example 1b. 
(c) 3-(4-Fluorophenyl)propylmalonic acid ethyl ester 
43.5 g of 3-(4-fluorophenyl)propylmalonic acid ethyl ester are obtained as 
a yellowish oil from 80 g of 3-(4-fluorophenyl)propylmalonic acid diethyl 
ester and 16.6 g of potassium hydroxide in 170 ml of ethanol by the 
procedure described in Example 3c. 
(d) 3-(Fluorophenyl)propylmalonic acid diethyl ester 
80 g of 3-(4-fluorophenyl)propylmalonic acid diethyl ester are obtained as 
a yellowish oil from 83 g of p-toluenesulfonic acid 
3-(4-fluorophenyl)propyl ester, 43.3 g of malonic acid diethyl ester and a 
solution of 6.5 g of sodium in 400 ml of ethanol by the procedure 
described in Example 5d. 
(e) p-Toluenesulfonic acid 3-(4-fluorophenyl)propyl ester 
83 g of p-toluenesulfonic acid 3-(4-fluorophenyl)propyl ester are obtained 
as a yellowish oil from 39.7 g of 3-(4-fluorophenyl)propan-1-ol, 54 g of 
p-toluenesulfonic acid chloride and 83 ml of pyridine in 200 ml of 
toluene, after stirring at room temperature for 40 hours, by the procedure 
described in Example 5e. 
(f) 3-(4-Fluorophenyl)propan-1-ol 
A solution of 43.6 g of 3-(4-fluorophenyl)propionic acid in 300 ml of 
tetrahydrofuran is added dropwise to a suspension of 19.7 g of lithium 
aluminum hydride in 300 ml of tetrahydrofuran at a reaction temperature of 
about 45.degree. C., while stirring. When the addition is complete, the 
above temperature is maintained for a further 2.5 hours and 80 ml of water 
and 20 ml of 4 N sodium hydroxide solution are then successively added 
dropwise. The precipitate is filtered off and rinsed several times with 
diethyl ether and the combined solutions are dried over sodium sulfate and 
concentrated. 39.7 g of 3-(4-fluorophenyl)propan-1-ol remain as an almost 
colourless oil. 
(g) 3-(4-Fluorophenyl)propionic acid 
91.6 g of malonic acid diethyl ester are added dropwise to a solution of 
12.6 g of sodium in 300 ml of ethanol, the mixture is subsequently stirred 
for a further 15 minutes and 98.3 g of 4-fluorobenzyl bromide are then 
added dropwise. The mixture is subsequently boiled for a further 3 hours 
under reflux, most of the solvent is distilled off, the residue is taken 
up in ice-water (800 ml) and methylene chloride (600 ml) and the mixture 
is shaken thoroughly. The organic phase is collected and concentrated and 
the oil which remains (4-fluorobenzyl-malonic acid diethyl ester) (137.6 
g) is stirred with a solution of 133 g of potassium hydroxide in 780 ml of 
methanol for 12 hours. The mixture is substantially concentrated in vacuo, 
the residue is dissolved in water/diethyl ether, the solution is shaken 
thoroughly, the organic phase is separated off and the aqueous phase is 
acidified with 10 N sulfuric acid, while cooling with ice. The mixture is 
extracted with methylene chloride, the organic phase is concentrated and 
the oily residue is stirred with petroleum ether/ethyl acetate (3:1), 
whereupon 53.6 g of 4-fluorobenzylmalonic acid crystallize out (m.p. 
134.degree. to 136.degree. C.). 
The 4-fluorobenzylmalonic acid is heated to 170.degree. to 175.degree. for 
1.5 hours. After cooling, the reaction product is stirred with a little 
diethyl ether. 41.6 g of 3-(4-fluorophenyl)propionic acid of m.p. 
85.degree. to 88.degree. [from ethyl acetate/petroleum ether (1:4)] 
thereby crystallize out. 
EXAMPLE 25 
2-(6-Phenylhexyl)oxirane-2-carboxylic acid ethyl ester 
(a) 2-(6-Phenylhexyl)oxirane-2-carboxylic acid ethyl ester 
2.1 g of the title compound are obtained as a colourless oil, which is 
purified by chromatography on a silica gel column [eluant: petroleum 
ether/ethyl acetate (95:5)], from 4 g of 2-methylene-8-phenyloctanoic acid 
ethyl ester and 5.4 g of m-chloroperbenzoic acid in 150 ml of methylene 
chloride by the procedure described in Example 1a. 
(b) 2-Methylene-8-phenyloctanoic acid ethyl ester 
4.0 g of 2-methylene-8-phenyloctanoic acid ethyl ester are obtained as a 
colourless oil, which is purified over a silica gel column (eluant: 
methylene chloride), from 7 g of 6-phenylhexylmalonic acid ethyl ester, 
0.8 g of paraformaldehyde, 10 ml of pyridine and 0.5 ml of piperidine by 
the procedure described in Example 1b. 
(c) 6-Phenylhexylmalonic acid ethyl ester 
14.5 g of 6-phenylhexylmalonic acid ethyl ester are obtained as a viscous 
oil from 20 g of 6-phenylhexylmalonic acid diethyl ester and potassium 
hydroxide by the procedure described in Example 3c. 
(d) 6-Phenylhexylmalonic acid diethyl ester 
22 g of 6-phenylhexylmalonic acid diethyl ester are obtained as a light oil 
from 24 g of 6-phenylhexyl bromide, 24 g of malonic acid diethyl ester and 
a solution of 2.6 g of sodium in 150 ml of ethanol by the procedure 
described in Example 5d. 
EXAMPLE 26 
2-(5-Phenylpentyl)oxirane-2-carboxylic acid 
3 g of sodium 2-(5-phenylpentyl)oxirane-2-carboxylate are thoroughly shaken 
with 70 ml of ice-cold 1 N hydrochloric acid and 50 ml of diethyl ether; 
the organic phase is collected, dried over sodium sulfate and 
concentrated. 1.7 g of the title compound remain as a viscous, colorless 
oil. 
EXAMPLE 27 
2-(7-Phenylheptyl)oxirane-2-carboxylic acid ethyl ester 
(a) 2-(7-Phenylheptyl)oxirane-2-carboxylic acid ethyl ester 
1.7 g of the title compound of b.p. 126.degree. to 132.degree. under 0.15 
mm Hg are obtained from 4.88 g of 2-methylene-9-phenylnonanoic acid ethyl 
ester and 6.2 g of m-chloroperbenzoic acid by the procedure described in 
Example 1a. 
(b) 2-Methylene-9-phenylnonanoic acid ethyl ester 
5.88 g of 2-methylene-9 -phenylnonanoic acid ethyl ester of b.p. 
136.degree. under 0.05 mm Hg are obtained from 7.77 g of 
7-phenylheptylmalonic acid ethyl ester, 1.08 g of paraformaldehyde, 4.8 ml 
of pyridine and 0.32 ml of piperidine by the procedure described in 
Example 1b. 
(c) 7-Phenylheptylmalonic acid ethyl ester 
7.77 g of 7-phenylheptylmalonic acid ethyl ester are obtained as a viscous 
oil from 10.2 g of 7-phenylheptylmalonic acid diethyl ester and 1.71 g of 
potassium hydroxide in 30 ml of ethanol by the procedure described in 
Example 3c. 
(d) 7-Phenylheptylmalonic acid diethyl ester 
12.1 g of 7-phenylheptylmalonic acid diethyl ester are obtained as a 
colorless oil from 17 g of 7-phenylheptyl bromide, 16 g of malonic acid 
diethyl ester and a solution of 2.0 g of sodium in 100 ml of ethanol by 
the procedure described in Example 5d. 
EXAMPLE 28 
2-[(3,4-Dichlorophenyl)propyl]oxirane-2-carboxylic acid ethyl ester 
(a) 2-[3-(3,4-Dichlorophenyl)propyl]oxirane-2-carboxylic acid ethyl ester 
27.0 g of the title compound are obtained as a colorless oil, which is 
purified by chromatography over a silica gel column (eluant: methylene 
chloride), from 33.1 g of 5-(3,4-dichlorophenyl)-2-methylenevaleric acid 
ethyl ester and 45.6 g of m-chloroperbenzoic acid by the procedure 
described in Example 1a. 
(b) 5-(3,4-Dichlorophenyl)-2-methylenevaleric acid ethyl ester 
33.1 g of 5-(3,4-dichlorophenyl)-2-methylenevaleric acid ethyl ester of b.p 
128.degree. to 130.degree. under 0.02 mm Hg are obtained from 53.9 g of 
3-(3,4-dichlorophenyl)propylmalonic acid ethyl ester, 5.4 g of 
paraformaldehyde, 55 ml of pyridine and 1.7 ml of piperidine by the 
procedure described in Example 1b. 
(c) 3-(3,4-Dichlorophenyl)propylmalonic acid ethyl ester 
53.9 g of 3-(3,4-dichlorophenyl)propylmalonic acid ethyl ester are obtained 
as a light oil from 81 g of 3-(3,4-dichlorophenyl)propylmalonic acid 
diethyl ester and 14.8 g of potassium hydroxide in 340 ml of ethanol by 
the procedure described in Example 3c. 
(d) 3-(3,4-Dichlorophenyl)propylmalonic acid diethyl ester 
79 g of 3-(3,4-dichlorophenyl)propylmalonic acid diethyl ester are obtained 
as a yellowish oil from 82.1 g of p-toluenesulfonic acid 
3-(3,4-dichlorophenyl)-propyl ester, 38.4 g of malonic acid diethyl ester 
and a solution of 5.3 g of sodium in 400 ml of ethanol by the procedure 
described in Example 5d. 
(e) p-Toluenesulfonic acid 3-(3,4-dichlorophenyl)propyl ester 
175.4 g of p-toluenesulfonic acid 3-(3,4-dichlorophenyl)propyl ester are 
obtained as a viscous oil from 125 g of 3-(3,4-dichlorophenyl)propan-1-ol. 
117.4 g of p-toluenesulfonic acid chloride and 200 ml of pyridine in 600 
ml of toluene by the procedure described in Example 5e. 
EXAMPLE 29 
2-[3-(3,4-Dichlorophenyl)propyl]oxirane-2-carboxylic acid methyl ester 
8.0 g of the title compound are obtained as a colorless oil, which is 
purified by chromatography on silica gel [eluant: methylene 
chloride/petroleum ether (1:1)], from 19.2 g of 
5-(3,4-dichlorophenyl)-2-methylenevaleric acid methyl ester and 27.5 g of 
m-chloroperbenzoic acid analogously to Example 1a. 
The starting compound 5-(3,4-dichlorophenyl)-2-methylenevaleric acid methyl 
ester (oil) is obtained from 3-(3,4-dichlorophenyl)propylmalonic acid 
dimethyl ester analogously to Example 3b and 3c. 
EXAMPLE 30 
2-[3-(5-Chloro-2-methoxyphenyl)propyl]oxirane-2-carboxylic acid ethyl ester 
(a) 2-[3-(5-Chloro-2-methoxyphenyl)propyl]oxirane-2-carboxylic acid ethyl 
ester 
8.8 g of the title compound are obtained as a colorless oil of b.p. 
150.degree. under 0.005 mm Hg from 19.5 g of 
5-(5-chloro-2-methoxyphenyl)-2-methylenevaleric acid ethyl ester and 28 g 
of m-chloroperbenzoic acid in 250 ml of methylene chloride by the 
procedure described in Example 1a. 
(b) 5-(5-Chloro-2-methoxyphenyl)-2-methylenevaleric acid ethyl ester 
20.3 g of 5-(5-chloro-2-methoxyphenyl)-2-methylenevaleric acid ethyl ester 
of b.p. 136.degree. to 140.degree. under 0.01 mm Hg are obtained from 28.5 
g of 3-(5-chloro-2-methoxyphenyl)propylmalonic acid ethyl ester. 3.2 g of 
paraformaldehyde, 16.3 ml of pyridine and 1.1 ml of piperidine by the 
procedure described in Example 1b. 
(c) 3-(5-Chloro-2-methoxyphenyl)propylmalonic acid ethyl ester 
28.5 g of 3(5-chloro-2-methoxyphenyl)propylmalonic acid ethyl ester are 
obtained as a viscous oil from 34.8 g of 
3-(5-chloro-2-methoxyphenyl)propylmalonic acid diethyl ester and 6.4 g of 
potassium hydroxide in 400 ml of ethanol by the procedure described in 
Example 3c. 
(d) 3-(5-Chloro-2-methoxyphenyl)propylmalonic acid diethyl ester 
19.1 g of 3-(5-chloro-2-methoxyphenyl)propylmalonic acid diethyl ester of 
b.p. 136.degree. to 145.degree. under 0.01 mm Hg are obtained from 38 g of 
3-(5-chloro-2-methoxyphenyl)propyl chloride, 44 g of malonic acid diethyl 
ester and a solution of 3.9 g of sodium in 150 ml of ethanol by the 
procedure described in Example 5d. 
(e) 3-(5-Chloro-2-methoxyphenyl)propyl chloride 
58.2 g of 3-(5-chloro-2-methoxyphenyl)propan-1-ol and 50 ml of thionyl 
chloride are stirred at 50.degree. for 8 hours; the excess thionyl 
chloride is distilled off in vacuo and the residue is distilled under a 
high vacuum. 50.9 g of 3-(5-chloro-2-methoxyphenyl)propyl chloride of b.p. 
87.degree. to 95.degree. under 0.005 mm Hg are obtained. 
(f) 3-(5-Chloro-2-methoxyphenyl)propan-1-ol 
66.7 g of 3-(5-chloro-2-methoxyphenyl)propan-1-ol of b.p. 94.degree. to 
97.degree. under 0.001 mm Hg are obtained from 96.6 g of 
3-(5-chloro-2-methoxyphenyl)propionic acid and 14 g of lithium aluminum 
hydride in 900 ml of diethyl ether by the procedure described in Example 
24f. 
(g) 3-(5-Chloro-2-methoxyphenyl)propionic acid 
63.2 g of 3-(5-2-methoxyphenyl)propionic acid of m.p. 91.degree. to 
92.degree. C. are obtained by saponifying 124 g of 
5-chloro-2-methoxybenzylmalonic acid diethyl ester with potassium 
hydroxide and heating the resulting 5-chloro-2-methoxybenzylmalonic acid 
to 160.degree. to 170.degree. C. 5-Chloro-2-methoxybenzylmalonic acid 
diethyl ester is obtained from 100 g of 5-chloro-2-methoxybenzyl chloride, 
120 ml of malonic acid diethyl ester and a solution of 12.07 g of sodium 
in 1.1 l of ethanol by the procedure described in Example 24 g. 
EXAMPLE 31 
2-(8-Phenyloctyl)oxirane 2-carboxylic acid ethyl ester 
(a) 2-(8-Phenyloctyl)oxirane 2-carboxylic acid ethyl ester 
10.4 g of the title compound are obtained as a colorless oil, which is 
purified by chromatography on silica gel (eluant: methylene chloride), 
from 11.3 g of 2-methylene-10-phenyldecanoic acid ethyl ester and 16 g of 
m-chloroperbenzoic acid in 300 ml of methylene chloride by the procedure 
described in Example 1a. 
(b) 2-Methylene-10-phenyldecanoic acid ethyl ester 
11.4 g of 2-methylene-10-phenyldecanoic acid ethyl ester are obtained as a 
colorless oil, which is purified by chromatography on silica gel (eluant: 
chloroform), from 16.5 g of 8-phenyloctylmalonic acid ethyl ester, 1.65 g 
of paraformaldehyde, 20 ml of pyridine and 0.5 ml of piperidine by the 
procedure described in Example 1b. 
(c) 8-Phenyloctylmalonic acid ethyl ester 
16.7 g of 8-phenyloctylmalonic acid ethyl ester are obtained as a viscous 
oil from 25.3 g of 8-phenyloctylmalonic acid diethyl ester and 4.6 g of 
potassium hydroxide in 150 ml of ethanol by the procedure described in 
Example 3c. 
(d) 8-Phenyloctylmalonic acid diethyl ester 
25.3 g of 8-phenyloctylmalonic acid diethyl ester are obtained as a 
yellowish oil from 17.4 g of 8-phenyloctyl chloride, 13 g of malonic acid 
diethyl ester, a solution of 1.8 g of sodium in 70 ml of ethanol and a 
pinch of potassium iodide by the procedure described in Example 5d. 
(e) 8-Phenyloctyl chloride 
17.4 g of 8-phenyloctyl chloride are obtained as a light oil from 16.35 g 
of 8-phenyloctan-1-ol and 16 ml of thionyl chloride by the procedure 
described in Example 30e. 
EXAMPLE 32 
2-[3-(4-tert.-Butylphenyl)propyl]oxirane-2-carboxylic acid methyl ester 
(a) 2-[3-(4-tert.-Butylphenyl)propyl]oxirane-2-carboxylic acid methyl ester 
10.7 g of the title compound are obtained as a colorless oil, which is 
purified by chromatography on silica gel [eluant: petroleum ether/ethyl 
acetate (90:10)], from 13 g of 5-(4-tert.-butylphenyl)-2-methylenevaleric 
acid methyl ester and 17.7 g of m-chloroperbenzoic acid in 300 ml of 
methylene chloride by the procedure described in Example 1a. 
(b) 5-(4-tert.-Butylphenyl)-2-methylenevaleric acid methyl ester 
13.1 g of 5-(4-tert.-butylphenyl)-2-methylenevaleric acid methyl ester are 
obtained as a colorless oil, which is purified by chromatography on silica 
gel (eluant: methylene chloride) from 18 g of 
3-(4-tert.-butylphenyl)propylmalonic acid methyl ester, 1.94 g of 
paraformaldehyde, 20 ml of pyridine and 0.5 ml of piperidine by the 
procedure described in Example 1b. 
(c) 3-(4-tert.-Butylphenyl)propylmalonic acid methyl ester 
18.0 g of 3-(4-tert.-butylphenyl)propylmalonic acid methyl ester are 
obtained as a viscous oil from 20.9 g of 
3-(4-tert.-butylphenyl)propylmalonic acid dimethyl ester and 4.5 g of 
potassium hydroxide in 140 ml of methanol by the procedure described in 
Example 3c. 
(d) 3-(4-tert.-Butylphenyl)propylmalonic acid dimethyl ester 
51.8 g of 3-(4-tert.-butylphenyl)propylmalonic acid dimethyl ester are 
obtained as a yellowish oil from 64.9 g of p-toluenesulfonic acid 
3-(4-tert.-butylphenyl)propyl ester, 26 g of malonic acid dimethyl ester 
and a solution of 4.74 g of sodium in 250 ml of methanol by the procedure 
described in Example 5d. 
(e) p-Toluenesulfonic acid 3-(4-tert.-butylphenyl)propyl ester 
64.9 g of p-toluenesulfonic acid 3-(4-tert.-butylphenyl)propyl ester are 
obtained as a light yellow oil from 33 g of 
3-(4-tert.-butylphenyl)propan-1-ol, 38.5 g of p-toluenesulfonic acid 
chloride and 65 ml of pyridine in 200 ml of toluene by the procedure 
described in Example 5e. 
EXAMPLE 33 
2-[7-(4-Chlorophenyl)heptyl]oxirane-2-carboxylic acid ethyl ester 
(a) 2-[7-(4-Chlorophenyl)heptyl]oxirane-2-carboxylic acid ethyl ester 
6.13 g of the title compound of b.p. 140.degree. to 148.degree. under 0.005 
mm Hg are obtained from 10.0 of 9-(4-chlorophenyl)-2-methylenenonanoic 
acid ethyl ester and 13.15 g of m-chloroperbenzoic acid in 50 ml of 
methylene chloride by the procedure described in Example 1a. 
(b) 9-(4-Chlorophenyl)-2-methylenenonanoic acid ethyl ester 
15.9 g of 9-(4-chlorophenyl)-2-methylenenonanoic acid ethyl ester are 
obtained as a colorless oil of b.p. 134.degree. to 136.degree. under 0.005 
mm Hg from 33 g of 7-(4-chlorophenyl)heptylmalonic acid ethyl ester, 4.1 g 
of paraformaldehyde, 17.8 ml of pyridine and 1.2 ml of piperidine by the 
procedure described in Example 1b. 
(c) 7-(4-Chlorophenyl)heptylmalonic acid ethyl ester 
33.62 g of 7-(4-chlorophenyl)heptylmalonic acid ethyl ester are obtained as 
a viscous oil from 37.37 g of 7-(4-chlorophenyl)heptylmalonic acid diethyl 
ester and 6.56 g of potassium hydroxide in 100 ml of ethanol by the 
procedure described in Example 3c. 
(d) 7-(4-Chlorophenyl)heptylmalonic acid diethyl ester 
37.37 g of 7-(4-chlorophenyl)heptylmalonic acid diethyl ester of b.p. 
160.degree. to 165.degree. under 0.005 mm Hg are obtained from 33.0 g of 
7-(4-chlorophenyl)heptyl bromide, 27.36 g of malonic acid diethyl ester 
and a solution of 2.62 g of sodium in 200 ml of ethanol by the procedure 
described in Example 5d. 
(e) 7-(4-Chlorophenyl)heptyl bromide 
30 g of 7-(4-chlorophenyl)heptan-1-ol, 0.13 g of red phosphorus and 37 ml 
of 62% strength hydrogen bromide are boiled for 6 hours, 8 ml of 
concentrated sulfuric acid are then added dropwise and the mixture is 
boiled again for 6 hours. The reaction mixture is poured into 100 ml of 
ice-water and is extracted twice with diethyl ether; the ether extracts 
are concentrated and the residue is distilled. 33.5 g of 
7-(4-chlorophenyl)heptyl bromide of b.p. 125.degree. to 127.degree. under 
0.1 mm Hg are obtained. 
(f) 7-(4-Chlorophenyl)heptanol 
31.2 g of 7-(4-chlorophenyl)heptanol of b.p. 140.degree. under 0.3 mm Hg 
are obtained from 51 g of 7-(4-chlorophenyl)heptanoic acid and 8.0 g of 
lithium aluminum hydride in 500 ml of diethyl ether by the procedure 
described in Example 24f. 
(g) 7-(4-Chlorophenyl)heptanoic acid 
80 g of 5-(4-chlorophenyl)pentylmalonic acid ethyl ester are boiled under 
reflux with 45 g of potassium hydroxide in 230 ml of water and 100 ml of 
ethanol for 5 hours; after cooling, the mixture is adjusted to pH 1-2 with 
concentrated hydrochloric acid and is extracted 3 times with diethyl 
ether. The combined organic solutions are concentrated and the residue 
[5-(4-chlorophenyl)pentylmalonic acid] is heated to 160.degree. for 3.5 
hours. The residue consists of 51 g of 7-(4-chlorophenyl)heptanoic acid of 
m.p. 75.degree. to 78.degree.. 
EXAMPLE 34 
Calcium-2-(5-phenylpentyl)oxirane-2-carboxylate 
A solution of 400 mg calcium chloride in 5 ml of water is added dropwise to 
a solution of 1.0 g of sodium 2-(5-phenylpentyl)oxirane-2-carboxylate in 
30 ml of water. The mixture is stirred thoroughly. The solution is 
decanted from the viscous precipitate which has separated out. The 
precipitate is stirred again with water and decanted. After drying over 
phosphorus pentoxide 820 mg of the title compound (softening at 
270.degree. C. and melting at about 300.degree. C. under decomposition) 
are obtained. 
EXAMPLE 35 
2-(3-Phenylpropyl)oxirane-2-carboxylic acid sec.-butyl ester 
(a) 2-(3-Phenylpropyl)oxirane-2-carboxylic acid sec.-butyl ester 
6.1 g of the title compound [almost colorless oil; purified by 
chromatography on a silica gel column (eluant: petroleum ether/ethyl 
acetate 9:1)] are obtained from 10 g of 2-methylene-5-phenylvaleric acid 
sec.-butyl ester and 18 g of m-chloroperbenzoic acid in 200 ml of 
methylene chloride by the procedure described in Example 1a. 
(b) 2-Methylene-5-phenylvaleric acid sec.-butyl ester 
27 g of 2-methylene-5-phenylvaleric acid chloride are added dropwise to a 
solution of 100 ml of sec.-butanol and 20 ml of triethylamine in 300 ml of 
diethyl ether at 25.degree. to 30.degree.. When the addition is complete, 
the obtained mixture is stirred at room temperature for another hour; 500 
ml of ice water are then added and the mixture is shaken thoroughly. The 
organic phase is collected, dried over sodium sulfate and concentrated. 
19.5 g of 2-methylene-5-phenylvaleric acid sec.-butyl ester (b.p. 
115.degree. to 126.degree. under 0.01 mm Hg) are obtained. 
(c) 2-Methylene-5-phenylvaleric acid chloride 
25 g of 2-Methylene-5-phenylvaleric acid and 20 ml of thionyl chloride 
(freshly distilled) are stirred at 50.degree. for 6 hours. Subsequently, 
excess thionyl chloride is distilled off in vacuo. 27 g of 
2-methylene-5-phenylvaleric acid chloride remain as a brown liquid which 
is used without further purification. 
EXAMPLE 36 
2-[3-(4-Chlorophenyl)propyl]oxirane-2-carboxylic acid isopropyl ester 
(a) 2-[3-(4-Chlorophenyl)propyl]oxirane-2-carboxylic acid isopropyl ester 
5.4 g of the title compound [yellowish oil; purified by chromatography on a 
silica gel colunm (eluant: petroleum ether/ethyl acetate 9:1)] are 
obtained from 12 g of 5-(4-chlorophenyl)-2-methylenevaleric acid isopropyl 
ester and 20 g of m-chloroperbenzoic acid in 150 ml of methylene chloride 
by the procedure described in Example 1a. 
(b) 5-(4-Chlorophenyl)-2-methylenevaleric acid isopropyl ester 
12.2 g of 5-(4-chlorophenyl)-2-methylenevaleric acid isopropyl ester (b.p. 
128.degree. to 134.degree. under 0.01 mm Hg) are obtained from 21.5 g of 
5-(4-chlorophenyl)-2-methylenevaleric acid chloride, 100 ml of isopropanol 
and 18 ml of triethylamine in 300 ml of diethyl ether by the procedure 
described in Example 35b. 
(c) 5-(4-Chlorophenyl)-2-methylenevaleric acid chloride 
21.5 g of 5-(4-chlorophenyl)-2-methylenevaleric acid chloride (brown oil) 
are obtained from 20.5 g of 5-(4-chlorophenyl)-2-methylenevaleric acid and 
20 ml of thionyl chloride by the procedure described in Example 35c. 
(d) 5-(4-Chlorophenyl)-2-methylenevaleric acid 
25 g of 5-(4-chlorophenyl)-2-methylenevaleric acid ethyl ester, 100 ml of a 
2 N sodium hydroxide solution and 50 ml of ethanol are stirred at 
50.degree. for 3 hours. After cooling, 100 ml of 2 N hydrochloric acid are 
added slowly, while cooling with ice, to the reaction mixture which is 
then extracted 4 times, with 50 ml of diethyl ether each time. The united 
organic phases are washed with water, dried over sodium sulfate and 
concentrated. 20.5 g of 5-(4-chlorophenyl)-2-methylenevaleric acid remain 
as a brown oil. 
EXAMPLE 37 
Batch for ampoules 
1,000 g of 2-[3-(4-chlorophenyl)propyl]oxirane-2-carboxylic acid are 
dissolved in about 80 liters of doubly-distilled water, the equivalent 
amount of sodium hydroxide solution being added. The solution is adjusted 
to pH 7.0.+-.0.5 and made up to 100 liters with doubly-distilled water. It 
is then filtered under sterile conditions and filled into 2 ml ampoules 
under germ-free conditions. 
EXAMPLE 38 
100,000 capsules with an active compound content of 30 mg are prepared from 
the following constituents: 
3,000 g of 2-(4-phenylbutyl)oxirane-2-carboxylic acid ethyl ester are mixed 
with 5,000 g of neutral oil, and the mixture is filled into soft gelatin 
capsules. 
EXAMPLE 39 
10,000 capsules with an active compound content of 25 mg are prepared as 
follows: 
250 g of 2-[3-(3-chlorophenyl)propyl]oxiranecarboxylic acid ethyl ester are 
dissolved in 1,000 ml of methylene chloride. The solution is mixed 
thoroughly with 750 g of micronized silicic acid. The mixture is 
evaporated to dryness and then filled into hard gelatin capsules. 
EXAMPLE 40 
10,000 capsules with an active compound content of 20 mg are prepared from 
the following constituents: 
200 g of 2-[3-(3-trifluoromethylphenyl)propyl]oxirane-2-carboxylic acid 
ethyl ester are dissolved in 1,000 ml of methylene chloride. The solution 
is mixed thoroughly with 800 g of micronized silicic acid. The mixture is 
evaporated to dryness and then filled into hard gelatin capsules. 
EXAMPLE 41 
10,000 capsules with an active compound content of 25 mg are prepared as 
follows: 
250 g of 2-[5-(4-chlorophenyl)pentyl]oxirane-2-carboxylic acid ethyl ester 
are dissolved in 1,000 ml of methylene chloride. The solution is mixed 
thoroughly with 750 g of micronized silicic acid. The mixture is 
evaporated to dryness and then filled into hard gelatin capsules. 
EXAMPLE 42 
Tablets with an active compound content of 25 mg are prepared as follows: 
10 kg of sodium 2-[5-(4-chlorophenyl)pentyl]oxirane-2-carboxylate, 45 kg of 
xylit and 30 kg of calcium phosphate are granulated with 2.5 kg of 
polyvinylpyrrolidone (molecular weight .about.25,000) in approximately 6 
liters of water. The granulate is sieved through a sieve of 1.25 mm mesh 
size and, after drying, 9 kg of carboxymethylcellulose, 2.5 kg of talc and 
1 kg of magnesium stearate are added. The dry granulate is compressed into 
tablets of 8 mm diameter, 250 mg weight and a hardness of 5-6 kg. 
PHARMACOLOGY 
The substituted oxiranecarboxylic acids of the general formula I according 
to the invention lower the level of glucose and of ketones in the blood, 
their chemical structure differs from that of beta-cytotropic substances 
which have an action on the pancreas (for example sulfonylureas), and 
their mode of action differs fundamentally from that of these substances 
in that they have an extra-pancreatic action, and they prove to be 
superior to commercial preparations having an extra-pancreatic action (for 
example Buformin and Phenformin). 
In the Tables below, the compounds investigated are characterized by a 
serial number, which is allocated as follows: 
______________________________________ 
Serial No. 
Name of compound 
______________________________________ 
1 Buformin 
2 Phenformin 
3 2-[3-(4-Chlorophenyl)-propyl]oxirane-2-carbo- 
xylic acid ethyl ester 
4 2-[3-(4-Chlorophenyl)-propyl]oxirane-2-carbo- 
xylic acid (sodium salt) 
5 2-[3-(3-Trifluoromethylphenyl)-propyl]oxirane- 
2-carboxylic acid ethyl ester 
6 2-[3-(3-Trifluoromethylphenyl)-propyl]oxirane- 
2-carboxylic acid (sodium salt) 
7 2-(5-Phenyl-pentyl)oxirane-2-carboxylic acid 
ethyl ester 
8 2-(5-Phenyl-pentyl)oxirane-2-carboxylic acid 
(sodium salt) 
9 2-[5-(4-Chlorophenyl)-pentyl]oxirane-2-carbo- 
xylic acid ethyl ester 
10 2-[5-(4-Chlorophenyl)-pentyl]oxirane-2-carbo- 
xylic acid (sodium salt) 
11 2-(4-Phenylbutyl)oxirane-2-carboxylic acid 
ethyl ester 
12 2-[3-(3-Chlorophenyl)-propyl]oxirane-2-carbo- 
xylic acid ethyl ester 
13 5-(4-Chlorophenyl)-2-methylenevaleric acid 
ethyl ester 
14 5-(3-Chlorophenyl)-2-methylenevaleric acid ethyl 
ester 
15 2-Methylene-7-phenylheptanoic acid ethyl ester 
______________________________________ 
Table I reflects investigations of the effect of representative compounds 
according to the invention on the blood glucose concentration of fasting, 
metabolically healthy rats which is observed in the course of 5 hours 
after single oral administration of 0.056 to 0.6 mmol of substance/kg of 
body weight. 
Column A states the dose of active compound (mg/kg) which effects in 50% of 
the animals a lowering of the blood glucose concentration by at least 25% 
with reference to the control group. Column B states the dose of active 
compound (mg/kg) which effects in 50% of the animals a lowering of the 
blood glucose concentration by at least 15% with reference to the control 
group. Column C provides data relating to acute toxicity (LD.sub.50 ; 
mice, peroral administration). 
TABLE I 
______________________________________ 
A B 
ED.sub.50 (25%) 
ED.sub.50 (15%) 
C 
[mg/kg] [mg/kg] LD.sub.50 [mg/kg] 
Serial No. 
rats p.o. rats p.o. mice p.o. 
______________________________________ 
1 194 &gt;100 475 
2 &gt;343 &gt;150 410* 
3 54 40 730 
4 41 20 
5 24 6 .about.300 
6 23 14 
7 21** 10 230 
8 12 2 
9 24 3 275 
10 16 5 
11 67 
12 59 
______________________________________ 
Re Table I: 
*Cited according to Blickens, D. A.; Riggi, S. J.: Toxicol.Appl.Pharmacol 
14(1969)393-400 
**ED.sub.50 (23%) 
Column A = dose, which effects a lowering of the blood glucose 
concentration by 25% in 50% of the animals 
Column B = dose, which effects a lowering of the blood glucose 
concentration by 15% in 50% of the animals 
Column C = acute toxicity (LD.sub.50 in mg/kg; mice, peroral 
administration) 
The .alpha.-methylenecarboxylic acids, appearing as intermediates within 
the scope of the invention, also reveal in vivo a hypoglycemic action as 
follows from Table II. 
TABLE II 
______________________________________ 
B 
ED.sub.50 (15%) [mg/kg] 
Serial No. rats p.o. 
______________________________________ 
13 252 
14 &gt;253 
15 80 
______________________________________ 
Re Table II: 
Column B = dose, which effects a lowering of the blood glucose 
concentration by 15% in 50% of the animals. 
Table III reflects investigations of the effect of representative compounds 
according to the invention on the blood glucose concentration of fasting, 
metabolically healthy guinea pigs which is observed in the course of 5 
hours after single oral administration of 0.056 to 0.6 mmol of 
substance/kg of body weight. 
Column A states the dose of active substance (mg/kg) which effects in 50% 
of the animals a lowering of the blood glucose concentration by at least 
25% with reference to the control group. Column B states the dose of 
active substance (mg/kg) which effects in 50% of the animals a lowering of 
the blood glucose concentration by at least 15% with reference to the 
control group. Column C provides data relating to acute toxicity 
(LD.sub.50 ; guinea pig, peroral administration). 
TABLE III 
______________________________________ 
A B 
ED.sub.50 (25%) 
ED.sub.50 (15%) 
C 
[mg/kg] [mg/kg] LD.sub.50 [mg/kg] 
Serial No. 
guinea pig p.o. 
guinea pig p.o. 
guinea pig p.o. 
______________________________________ 
1 40-50** -- 58* 
2 20-25*** -- 47* 
3 22 11 -- 
4 26 12 500-600 
5 &lt;24 3 -- 
6 11 6 300-400 
7 21 11 -- 
8 7 3 500-600 
9 &lt;24 5 -- 
10 8 3 300-400 
______________________________________ 
Re Table III: 
*cited according to Proske, G.; Osterloh, G.; Beckmann, R. Lagler, F.; 
Michael, G.; Muckter, H.: Arzneim.Forsch. 12(1962)314-318. 
**cited according to Beckmann, R.: unpublished studies 1960 in 
Hdb.exp.Pharmakol. XXIX, p.477, Springer, Berlin 1971. 
***cited according to Ungar, G.; Freeman, L.; Schapiro, S. L. 
Proc.Soc.exp.Biol. (N.Y.) 95(1957)190-192. 
Column A = dose, which effects a lowering of the blood glucose 
concentration by 25% in 50% of the animals 
Column B = dose, which effects a lowering of the blood glucose 
concentration by 15% in 50% of the animals 
Column C = acute toxicity (LD.sub.50 in mg/kg; guinea pig, peroral 
administration, preliminary results). 
In relation to the comparison compounds, the compounds according to the 
invention are distinguished by a lower toxicity or better therapeutic 
breadth and by a more powerful hypoglycemic action. 
The pharmacological properties were determined by the following methods: 
1. Determination of glucose in the blood after a single oral administration 
Young male Sprague-Dawley rats (body weight: 150-200 g) and young 
cross-bred male guinea pigs (body weight: 250-300 g) are used. The animals 
are kept in Makrolon cages with up to 4 animals per cage (ambient 
temperature: 23.degree. C., relative atmospheric humidity: 55%, fixed 
day/night rhythm [12/12 hours], standard diet: Altromin.RTM.). The rats 
(guinea pigs) are deprived of the feed 18 (42) 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 3 and 
5 hours after administration of the substance. 
After deproteinization with perchloric acid, the glucose in the blood is 
determined by means of the enzymatic HK/G-6-PDH method of R. Richterich 
[Klinische Chemie, Theorie und praxis, (Clinical Chemistry, Theory and 
Practice), 3rd edition, 1971, S. Karger Verlag, Zurich-Basle, page 275]. A 
control group (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.RTM.) 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.sub.50, that is to say the dose at 
which 50% of the animals die, is determined graphically from the 
dose/response curve. 
Attention is drawn to the fact that the toxicity data determined are 
influenced by the state of nourishment of the animals used, e.g. the 
LD.sub.50 p.o. of rats, which are deprived of the feed only 4 hours, is 
above 1 g/kg of body weight. 
The invention and its advantages are readily understood from the preceding 
description. Various changes may be made in the synthesis, the 
intermediates, the pharmacologically-active final products, the dosage 
forms, the medicament compositions, the mode of administration and 
treatment regimes without departing from the spirit and scope of the 
invention or sacrificing its material advantages. The hereinbefore 
described aspects of the subject invention are merely illustrative of 
preferred embodiments.