Phenalkoxyalkyl- and phenoxyalkyl-substituted oxiranecarboxylic acids, their use and medicaments containing them

Phenalkoxyalky- and phenoxyalkyl-substituted oxiranecarboxylic acids of the formula ##STR1## wherein R.sup.1 denotes a hydrogen atom (--H), a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro 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, PA1 Y denotes --O--(CH.sub.2).sub.m --, PA1 m denotes O or an integer from 1 to 4, and PA1 n denotes an integer from 2 to 8, with the proviso that the sum of m and n is an integer from 2 to 8, 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 phenalkoxyalkyl- and phenoxyalkyl-substituted 
oxiranecarboxylic acids, processes for their preparation, their use and 
medicaments containing them. 
BACKGROUND 
Phenoxymethyloxiranes, for example 2-(4-nitrophenoxymethyl)-oxirane, and 
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]. Phenalkoxyalkyl- and 
phenoxyalkyl-substituted oxiranecarboxylic acids have now been found to be 
pharmaceutically-active compounds with a specific action. 
SUMMARY OF THE INVENTION 
Pharmaceutically-active phenalkoxyalkyl- and phenoxyalkyl-substituted 
oxiranecarboxylic 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 or 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 the compound aspect of 
this invention; corresponding salts and lower alkyl esters are readily 
appreciated by any man skilled in the art: 
2-[.omega.-phenoxy(C.sub.2-8)alkylene]oxirane-2-carboxylic acid, 
2-[.omega.-(monosubstituted)phenoxy(C.sub.2-8)alkylene]oxirane-2-carboxylic 
acid, 
2-[.omega.-(disubstituted)phenoxy(C.sub.2-8)alkylene]oxirane-2-carboxylic 
acid, 
2-[.omega.-benzyloxy(C.sub.2-7)alkylene]oxirane-2-carboxylic acid, 
2-[.omega.-(monosubstituted)benzyloxy(C.sub.2-7)alkylene]oxirane-2-carboxyl 
ic acid, 
2-[.omega.-(disubstituted)benzyloxy(C.sub.2-7)alkylene]oxirane-2-carboxylic 
acid, 
2-[.omega.-(2-phenylethoxy) (C.sub.2-6)alkylene]oxirane-2-carboxylic acid, 
2-{.omega.-[2-(monosubstituted)phenylethoxy(C.sub.2-6)alkylene}oxirane-2-ca 
rboxylic acid, 
2-{.omega.-[2-(disubstituted)phenylethoxy](C.sub.2-6)alkylene}oxirane-2-car 
boxylic acid, 
2[.omega.-(3-phenylpropoxy) (C.sub.2-5)alkylene]oxirane-2-carboxylic acid, 
2-{.omega.-[3-(monosubstituted)phenylpropoxy](C.sub.2-5)alkylene}oxirane-2- 
carboxylic acid, 
2-{.omega.-[3-(disubstituted)phenylpropoxy](C.sub.2-5)alkylene}oxirane-2-ca 
rboxylic acid, 
2-[.omega.-(4-phenylbutoxy) (C.sub.2-4)alkylene]oxirane-2-carboxylic acid, 
2-{.omega.-[4-(monosubstituted)phenylbutoxy](C.sub.2-4)alkylene}oxirane-2-c 
arboxylic acid, and 
2-{.omega.-[4-(disubstituted)phenylbutoxy](C.sub.2-4)alkylene}oxirane-2-car 
boxylic 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 lower 
alkyl group, a lower alkoxy group, a nitro 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, 
Y denotes --O--(CH.sub.2).sub.m --, 
m denotes O or an integer from 1 to 4 and 
n denotes an integer from 2 to 8, with the proviso that the sum of m and n 
is an integer from 2 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 meta-position or 
para-position of the phenyl ring. 
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, aminosugars 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. 
Phenalkoxyalkyl- and phenoxyalkyl-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, a nitro 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, 
Y denotes --O--(CH.sub.2).sub.m --, 
m denotes 0 or 1 and 
n denotes an integer from 3 to 7, with the proviso that the sum of m and n 
is an integer from 3 to 7, and salts of the carboxylic acids form an 
embodiment of the invention. 
Phenoxyalkyl-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, 
Y denotes --O-- and 
n denotes 4 to 6, and pharmacologically-acceptable salts of the carboxylic 
acids with an inorganic or organic base form a preferred embodiment of the 
invention. 
Examples of compounds according to the invention are: 
2-[2-(4-chlorobenzyloxy)ethyl]oxirane-2-carboxylic acid ethyl ester, 
2-[3-(3-chlorobenzyloxy)propyl]oxirane-2-carboxylic acid methyl ester, 
2-[4-(4-fluorobenzyloxy)butyl]oxirane-2-carboxylic acid isopropyl ester, 
2-[2-(4-bromophenoxy)ethyl]oxirane-2-carboxylic acid propyl ester, 
2-[2-(4-methoxyphenoxy)ethyl]oxirane-2-carboxylic acid ethyl ester, 
2-[2-(4-nitrophenoxy)ethyl]oxirane-2-carboxylic acid methyl ester, 
2-[2-(4-chlorophenoxy)ethyl]oxirane-2-carboxylic acid n-butyl ester, 
2-[2-(4-methoxyphenoxy)ethyl]oxirane-2-carboxylic acid methyl ester, 
2-[2-(3-trifluoromethylphenoxy)ethyl]oxirane-2-carboxylic acid ethyl ester, 
2-[3-(3-fluorophenoxy)propyl]oxirane-2-carboxylic acid ethyl ester, 
2-[3-(4-bromophenoxy)propyl]oxirane-2-carboxylic acid methyl ester, 
2-[3-(3-methylphenoxy)propyl]oxirane-2-carboxylic acid sec.-butyl ester, 
2-[3-{4-(n-butoxy)phenoxy}propyl]oxirane-2-carboxylic acid ethyl ester, 
2-[3-(2-isopropylphenoxy)propyl]oxirane-2-carboxylic acid isopropyl ester, 
2-[3-(4-chlorophenoxy)propyl]oxirane-2-carboxylic acid methyl ester, 
2-[3-(3-trifluoromethylphenoxy)propyl]oxirane-2-carboxylic acid n-butyl 
ester, 
2-[4-(4-bromophenoxy)butyl]oxirane-2-carboxylic acid ethyl ester, 
2-[4-(4-chlorophenoxy)butyl]oxirane-2-carboxylic acid n-propyl ester, 
2-[4-(3,4-dichlorophenoxy)butyl]oxirane-2-carboxylic acid ethyl ester, 
2-[4-(3-chloro-4-methylphenoxy)butyl]oxirane-2-carboxylic acid methyl 
ester, 
2-[4-(3-methylphenoxy)butyl]oxirane-2-carboxylic acid ethyl ester, 
2-[5-(2,5-dimethoxyphenoxy)pentyl]oxirane-2-carboxylic acid ethyl ester, 
2-[5-(3-trifluoromethylphenoxy)pentyl]oxirane-2-carboxylic acid n-butyl 
ester, 
2-[5-(4-methylphenoxy)pentyl]oxirane-2-carboxylic acid methyl ester, 
2-[5-(3-chlorophenoxy)pentyl]oxirane-2-carboxylic acid isobutyl ester, 
2-[5-(4-nitrophenoxy)pentyl]oxirane-2-carboxylic acid ethyl ester, 
2-[6-(4-fluorophenoxy)hexyl]oxirane-2-carboxylic acid ethyl ester, 
2-[6-(4-trifluoromethylphenoxy)hexyl]oxirane-2-carboxylic acid methyl 
ester, 
2-[6-(3,4-dichlorophenoxy)hexyl]oxirane-2-carboxylic acid n-butyl ester, 
2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylic acid isopropyl ester, 
2-[7-(3-fluorophenoxy)heptyl]oxirane-2-carboxylic acid ethyl ester, 
2-[7-(4-trifluoromethylphenoxy)heptyl]oxirane-2-carboxylic acid ethyl 
ester, 
2[7-(3-chloro-4-methylphenoxy)heptyl]oxirane-2-carboxylic acid methyl 
ester, 
2[7-(3-chlorophenoxy)heptyl]oxirane-2-carboxylic acid n-propyl ester, 
2-[8-(4-fluorophenoxy)octyl]oxirane-2-carboxylic acid ethyl ester, 
2-[8-(3-trifluoromethylphenoxy)octyl]oxirane-2-carboxylic methyl ester, 
2-[8-(3,4-dichlorophenoxy)octyl]oxirane-2-carboxylic acid ethyl ester, 
2-[8-(4-chlorophenoxy)octyl]oxirane-2-carboxylic acid isobutyl ester, 
2-[2-(2-phenylethoxy)ethyl]oxirane-2-carboxylic acid ethyl ester, 
2-{2-[2-(4-chlorophenyl)ethoxy]ethyl}oxirane-2-carboxylic acid isopropyl 
ester, 
2-{2-[2-(4-fluorophenyl)ethoxy]ethyl}oxirane-2-carboxylic acid methyl 
ester, 
2-{2-[2-(3-trifluoromethylphenyl)ethoxy]ethyl}oxirane-2-carboxylic acid 
sec.-butyl ester, 
2-{2-[3-(3-chlorophenyl)propoxy]ethyl}oxirane-2-carboxylic acid ethyl 
ester, 
2-{2-[3-(4-nitrophenyl)propoxy]ethyl}oxirane-2-carboxylic acid methyl 
ester, 
2-{2-[4-(3-trifluoromethylphenyl)butoxy]ethyl}oxirane-2-carboxylic acid 
n-butyl ester, 
2-{2-[4-(4-chlorophenyl)butoxy]ethyl}oxirane-2-carboxylic acid n-propyl 
ester, 
2-{2-[4-(4-bromophenyl)butoxy]ethyl}oxirane-2-carboxylic acid ethyl ester, 
2-[2-(3-phenylpropoxy)ethyl]oxirane-2-carboxylic acid ethyl ester, 
-carboxylic acid ethyl ester, 
2-[2-(4-phenylbutoxy)ethyl]oxirane-2-carboxylic acid ethyl ester, 
2-[3-(2-phenylethoxy)propyl]oxirane-2-carboxylic acid methyl ester, 
2-[3-(3-phenylpropoxy)propyl]oxirane-2-carboxylic acid ethyl ester, 
2-[3-(4-phenylbutoxy)propyl]oxirane-2-carboxylic acid n-propyl ester, 
2-[4-(4-phenylbutoxy)butyl]oxirane-2-carboxylic acid ethyl ester, 
2-{3-[2-(4-chlorophenyl)ethoxy]propyl}oxirane-2-carboxylic acid ethyl 
ester, 
2-{3-[2-(3-trifluoromethylphenyl)ethoxy]propyl}oxirane-2-carboxylic acid 
methyl ester, 
2-{3-[3-(4-nitrophenyl)propoxy]propyl}oxirane-2-carboxylic acid n-propyl 
ester, 
2-{3-[4-(3-trifluoromethylphenyl)butoxy]propyl}oxirane-2-carboxylic acid 
isopropyl ester, 
2-{3-[4-(4-chlorophenyl)butoxy]propyl}oxirane-2-carboxylic acid ethyl 
ester, 
2-{4-[2-(4-chlorophenyl)ethoxy]butyl}oxirane-2-carboxylic acid n-butyl 
ester, 
2-{4-[2-(4-fluorophenyl)ethoxy]butyl}oxirane-2-carboxylic acid methyl 
ester, 
2-{4-[2-(3-trifluoromethylphenyl)ethoxy]butyl}oxirane-2-carboxylic acid 
ethyl ester, 
2-{4-[3-(4-nitrophenyl)propoxy]butyl}oxirane-2-carboxylic acid ethyl ester, 
2-{4-[4-(3-trifluoromethylphenyl)butoxy]butyl}oxirane-2-carboxylic acid 
ethyl ester, 
2-{4-[4-(4-chlorophenyl)butoxy]butyl}oxirane-2-carboxylic acid ethyl ester, 
2-{5-[2-(4-chlorophenyl)ethoxy]pentyl}oxirane-2-carboxylic acid methyl 
ester, 
2-{5-[2-(3-trifluoromethylphenyl)ethoxy]pentyl}oxirane-2-carboxylic acid 
ethyl ester, 
2-{5-[3-(4-nitrophenyl)propoxy]pentyl}oxirane-2-carboxylic acid ethyl 
ester, 
2-{5-[3-(3-chlorphenyl)propoxy]pentyl}oxirane-2-carboxylic acid ethyl 
ester, 
2-[5-(2-phenylethoxy)pentyl]oxirane-2-carboxylic acid n-butyl ester, 
2[6-(2-phenylethoxy)hexyl]oxirane-2-carboxylic acid ethyl ester, 
2-{6-[2-(4-chlorophenyl)ethoxy]hexyl}oxirane-2-carboxylic acid n-propyl 
ester, 
2-{6-[2-(4-fluorophenyl)ethoxy]hexyl}oxirane-2-carboxylic acid methyl 
ester, and 
2-{6-[2-(3-trifluoromethylphenyl)ethoxy]hexyl}oxirane-2-carboxylic acid 
ethyl ester, the corresponding oxirane-2-carboxylic acids and salts 
thereof with inorganic and organic bases. 
Preferred representatives are 
2-[4-(3-chlorophenoxy)butyl]-oxirane-2-carboxylic acid ethyl ester, 
2-[4-(3-trifluoromethylphenoxy)butyl]oxirane-2-carboxylic acid ethyl 
ester, 2-[5-(4-chlorophenoxy)pentyl]oxirane-2-carboxylic acid ethyl ester 
and 2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylic acid ethyl ester, the 
corresponding oxirane-2-carboxylic acids and pharmacologically-acceptable 
salts thereof. 
The phenalkoxyalkyl- and phenoxyalkyl-substituted oxiranecarboxylic acids 
of formula I and of embodiments 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* 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 accompanied 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 lower 
alkyl group, a lower alkoxy group, a nitro 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, 
Y denotes --O--(CH.sub.2).sub.m --, 
m denotes O or an integer from 1 to 4 and 
n denotes an integer from 2 to 8, with the proviso that the sum of m and n 
is an integer from 2 to 8, 
and/or pharmacologically-acceptable salts of the acids with inorganic or 
organic bases. 
Medicament embodiments include those which contain phenalkoxyalkyl- and 
phenoxyalkyl-substituted oxiranecarboxylic acids 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 illness. 
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 are 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 phenalkoxyalkyl- and phenoxyalkyl-substituted 
oxiranecarboxylic acids according to the invention 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 phenalkoxyalkyl- and 
phenoxyalkyl-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, Y 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* 
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* 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 
benezene, 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-l-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, Y and n have their respective meanings for embodiments I* and 
I**, are employed for preparing the substituted oxiranecarboxylic acids of 
embodiments I* and I**. 
The .alpha.-methylenecarboxylic acids of formula II are prepared by 
conventional methods from known starting materials. They are valuable 
intermediate products for the synthesis of the oxiranecarboyxlic acids I, 
I* and I**. 
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, Y 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. 
The malonic half-esters III are prepared by methods with which those 
skilled in the art are familiar, for example by reacting dialkyl malonates 
IV with phenalkoxyalky or phenoxyalkyl 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, Y 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* or III**; IV* or IV**; V* or V**; and 
VI* or VI** (in which R.sup.1, R.sup.2, Y and n have the meanings 
corresponding to those for embodiments I* and I**, respectively, and 
R.sup.4* denotes a lower alkyl group, and R.sup.4** denotes a methyl or 
ethyl group, and 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* and II**. 
The phenalkoxyalkyl and phenoxyalkyl compounds V and their embodiments V* 
and V**, respectively, are prepared by methods known to the artisan, e.g. 
in analogy to J. Augstein et al., [J. Med. Chem., 8 (1965) 356 to 367] or 
J. D. Genzer et al., [J. Amer. Chem. Soc., 73 (1951) 3159 to 3162] or Sh. 
Mamedov et al. [Chem. Abstr., 59 (1963) 4401e and Chem. Abstr., 60 (1964) 
5321c]. 
The phenalkoxyalkyl and phenoxyalkyl compounds V are prepared, for example, 
analogously to Genzer et al. by reacting alkanediols VII with phenalkyl 
chlorides VIII and reacting the resulting phenalkoxy alkanols IX with 
thionyl halides or sulfonic acid halides, according to the following 
reaction scheme: 
##STR6## 
wherein R.sup.1, R.sup.2 and n have their previously-noted meanings and m 
denotes an integer from 1 to 4. 
The phenalkyl chlorides VIII are prepared by methods with which those 
skilled in the art are familiar, by reducing carboxylic acids X and 
reacting the resulting alkanols XI with thionyl chloride, according to the 
following reaction scheme: 
##STR7## 
wherein R.sup.1 and R.sup.2 have their previously-noted meanings and m 
denotes an integer from 1 to 4. 
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-(4-Phenoxybutyl)oxirane-2-carboxylic acid ethyl ester 
(a) 2-(4-Phenoxybutyl)oxirane-2-carboxylic acid ether ester - 
32 g of 2-methylene-6-phenoxyhexanoic acid ethyl ester and 78.5 g of 
m-chloroperbenzoic acid (85% pure) are boiled under reflux in 200 ml of 
methylene chloride for 24 hours. The mixture is allowed to cool, the 
m-chloroperbenzoic acid which has separated out is filtered off and washed 
thoroughly with petroleum ether. The combined filtrates are concentrated, 
the oily reddish-brown residue is taken up in 150 ml of acetone, 100 ml of 
saturated sodium bicarbonate solution and 100 ml of water are added, and 
the mixture is stirred for 30 minutes. The mixture is then extracted 3 
times with 500 ml of petroleum ether each time, the organic phase is 
concentrated, and the reddish-brown residue is distilled. The fraction 
boiling between 113.degree. and 140.degree. C. (0.008 mm Hg=1.06 Pa) is 
chromatographed on silica gel (eluant: petroleum ether/ethyl acetate 9:1) 
and distilled again. 6.15 g of the title compound [b.p. 125.degree. under 
0.07 mm Hg (9.3 Pa)] are obtained. 
(b) 2-Methylene-6-phenoxyhexanoic acid ethyl ester- 
66.45 g of 4-phenoxybutylmalonic acid ethyl ester, 45 ml of pyridine, 3 ml 
of piperidine and 9.9 g of paraformaldehyde are stirred together at 
50.degree. C. for 4 hours. After cooling, 400 ml of water are added to the 
reaction mixture which is then acidified with half-concentrated 
hydrochloric acid, while cooling with ice. The reaction mixture is then 
extracted 3 times with 200 ml of diethyl ether each time, the combined 
organic phases are concentrated and distilled in vacuo. 43.6 g 
2-methylene-6-phenoxyhexanoic acid ethyl ester are obtained as a colorless 
liquid of b.p. 140.degree. C. under 0.06 mm Hg (9 Pa). 
(c) 4-Phenoxybutylmalonic acid ethyl ester - 
A solution of 16.1 g of potassium hydroxide in 250 ml of ethanol is added 
dropwise to 87 g of 4-phenoxybutylmalonic acid diethyl ester in 250 ml of 
ethanol at room temperature. 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 with 200 ml of diethyl ether. 
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. 
66.45 g of 4-phenoxybutylmalonic acid ethyl ester of m.p. 69.degree. to 
72.degree. C. are obtained. 
EXAMPLE 2 
2-[4-(4-Methylphenoxy)butyl]oxirane-2-carboxylic acid ethyl ester 
(a) 2-[4-(4-Methylphenoxy)butyl]oxirane-2-carboxylic acid ethyl ester - 
23.3 g of the title compound [pale yellow oil which is purified by 
chromatography on silica gel (eluant: petroleum ether/methylene chloride 
1:1)] are obtained from 116.6 g of 6-(4-methylphenoxy)-2-methylenehexanoic 
acid ethyl ester and 152.2 g of m-chloroperbenzoic acid by the procedure 
described in Example 1a), 41.8 g of the starting compound are regained. 
(b) 6-(4-Methylphenoxy)-2-methylenehexanoic acid ethyl ester - 
166.6 g of 6-(4-methylphenoxy-2-methylenehexanoic acid ethyl ester [b.p. 
132.degree. to 134.degree. C. under 0.1 mm Hg (13.3 Pa)] are obtained from 
254 g of 4-(4-methylphenoxy)butylmalonic acid ethyl ester, 27.2 g of 
paraformaldehyde, 260 ml of pyridine and 9 ml of piperidine by the 
procedure described in Example 1b). 
(c) 4-(4-Methylphenoxy)butylmalonic acid ethyl ester - 
254.2 of 4-(4-methylphenoxy)butylmalonic acid ethyl ester (pale yellow oil) 
are obtained from 303.7 g 44-methylphenoxy)butylmalonic acid diethyl ester 
and 60.8 g of potassium hydroxide in 1.5 l of ethanol by the procedure 
described in Example 1c). 
(d) 4-(4-Methylphenoxy)butylmalonic acid diethyl ester - 
176.2 g of malonic acid diethyl ester are added dropwise at 50.degree. C. 
to a sodium ethylate solution freshly prepared from 23 g of sodium and 500 
ml of ethanol. The mixture is kept at this temperature for 2 hours, and 
243.2 g of 4-(4-methylphenoxy)butyl bromide are then added dropwise. When 
the addition is complete, the obtained mixture is stirred at 60.degree. C. 
for 3 hours, and substantially concentrated; 1 l of ice-water is then 
added and the mixture is extracted 3 times with a total of 1 liter of 
methylene chloride. The combined organic phases are dried over sodium 
sulfate, and the solvent and the excess malonic acid diethyl ester is 
distilled off in vacuo. 303.9 g of 4-(4-methylphenoxy)butylmalonic acid 
diethyl ester are obtained as pale yellow, oily residue. 
EXAMPLE 3 
2-[4-(3-Trifluoromethylphenoxy)butyl]oxirane-2-carboxylic acid ethyl ester 
(a) 2-[4-(3-Trifluoromethylphenoxy)butyl]oxirane-2-carboxylic acid ethyl 
ester - 
46.9 g of the title compound [colorless oil, purified by chromatography on 
silica gel (eluant: petroleum ether/methylene chloride 1:1] are obtained 
from 48.3 g of 2-methylene-6-(3-trifluoromethylphenoxy)hexanoic acid ethyl 
ester and 62 g of m-chloroperbenzoic acid in 950 ml of methylene chloride 
by the procedure described in Example 1a). 
(b) 2-Methylene-6-(3-trifluoromethylphenoxy)hexanoic acid ethyl ester - 
58.7 g of 2-methylene-6-(3-trifluoromethylphenoxy)hexanoic acid ethyl ester 
[colorless oil, purified by chromatography on silica gel (eluant: 
petroleum ether/methylene chloride 1:1] are obtained from 90.7 g of 
4-(3-trifluoromethylphenoxy)butylmalonic acid ethyl ester, 8.3 g of 
paraformaldehyde, 95 ml of pyridine and 2.5 ml of piperidine by the 
procedure described in Example 1b). 
(c) 4-(3-Trifluoromethylphenoxy)butylmalonic acid ethyl ester - 
90.7 g of 4-(3-trifluoromethylphenoxy)butylmalonic acid ethyl ester 
(yellowish, viscous oil) are obtained from 117 g of 
4-(3-trifluoromethylphenoxy)butylmalonic acid diethyl ester and 20.5 g of 
potassium hydroxide in 650 ml of ethanol by the procedure described in 
Example 1c). 
(d) 4-(3-Trifluoromethylphenoxy)butylmalonic acid diethyl ester - 
117.4 g of 4-(3-trifluoromethylphenoxy)butylmalonic acid diethyl ester 
(light oil) are obtained from 102.4 g of 4-(3-trifluoromethylphenoxy)butyl 
bromide, 58 g of malonic acid diethyl ester and a solution of 8 g sodium 
in 280 ml of ethanol by the procedure described in Example 2d). 
(e) 4-(3-Trifluoromethylphenoxy)butyl bromide - 
267 ml of 1.6 N sodium hydroxide solution are added dropwise with stirring 
at 100.degree. C. within 90 minutes to a mixture of 69.3 g of 
3-hydroxybenzotrifluoride and 119 g of 1,4-dibromobutane. The mixture is 
stirred at this temperature for a further 5 hours and is then allowed to 
cool. 200 ml of methylene chloride are added, the organic phase is 
separated off, washed with dilute sodium hydroxide solution, dried over 
sodium sulfate and concentrated. The residue is distilled in vacuo. 102.6 
g of 4-(3-trifluoromethylphenoxy)butyl bromide of b.p. 143.degree. to 
144.degree. C. (13 mm Hg=1730 Pa) are obtained. 
EXAMPLE 4 
2-[4-(3-Chlorophenoxy)butyl]oxirane-2-carboxylic acid ethyl ester 
(a) 2-[4-(3-Chlorophenoxy)butyl]oxirane-2-carboxylic acid ethyl ester - 
50.7 g of the title compound [colorless oil of b.p. 135.degree. to 
136.degree. C. at 0 .05 mm Hg (6.7 Pa)] are obtained from 110.2 g of 
6-(3-chlorophenoxy)-2-methylenehexanoic acid ethyl ester and 135.5 g of 
m-chloroperbenzoic acid in 1.4 l of methylene chloride by the procedure 
described in Example 1a). 
(b) 6-(3-Chlorophenoxy)-2-methylenehexanoic acid ethyl ester - 
110.6 g of 6-(3-chlorophenoxy)-2-methylenehexanoic acid ethyl ester [b.p. 
131.degree. to 134.degree. C. at 0.1 mm Hg (13.3 Pa)] are obtained from 
178 g of 4-(3-chlorophenoxy)butylmalonic acid ethyl ester, 17.8 g of 
paraformaldehyde, 180 ml of pyridine and 5.6 ml of piperidine by the 
procedure described in Example 1b). 
(c) 4-(3-Chlorophenoxy)butylmalonic acid ethyl ester - 
178.2 g of 4-(3-chlorophenoxy)butylmalonic acid ethyl ester (pale yellow 
oil) are obtained from 231.5 g of 4-(3-chlorophenoxy)butylmalonic acid 
diethyl ester and 43.6 g of potassium hydroxide in 1.05 l of ethanol by 
the procedure described in Example 1c). 
(d) 4-(3-Chlorophenoxy)butylmalonic acid diethyl ester - 
231.7 g of 4-(3-chlorophenoxy)butylmalonic acid diethyl ester (pale yellow 
oil) are obtained from 186.9 g of 4-(3-chlorophenoxy)butyl bromide, b 
124.9 g of malonic acid diethyl ester and a solution of 16.3 g sodium in 
650 ml of ethanol by the procedure described in Example 2d). 
EXAMPLE 5 
2-(2-Phenoxyethyl)oxirane-2-carboxylic acid ethyl ester 
(a) 2(2-Phenoxyethyl)oxirane-2-carboxylic acid ethyl ester - 
9.3 g of the title compound [almost colorless oil, purified by 
chromatography on silica gel (eluant: methylene chloride] are obtained 
from 25.4 g of 2-methylene-4-phenoxybutyric acid ethyl ester and 43.7 g of 
m-chloroperbenzoic acid in 500 ml of methylene chloride by the procedure 
described in Example 1a). 
(b) 2- Methylene-4-phenoxybutyric acid ethyl ester - 
62.5 g of 2-methylene-4-phenoxybutyric acid ethyl ester [colorless oil of 
b.p. 97.degree. to 100.degree. C. at 0.01 mm Hg (1.3 Pa)] are obtained 
from 94.5 g of 2-phenoxyethylmalonic acid ethyl ester, 11.8 g of 
paraformaldehyde, 95 ml of pyridine and 3.8 ml of piperidine by the 
procedure described in Example 1b). 
(c) 2-Phenoxyethylmalonic acid ethyl ester - 
94.5 g of 2-Phenoxyethylmalonic acid ethyl ester are obtained from 147 g of 
2-phenoxyethylmalonic acid diethyl ester and 28.1 g of potassium hydroxide 
in 800 ml of ethanol by the procedure described in Example 1c). 
EXAMPLE 6 
2-(3-Phenoxypropyl)oxirane-2-carboxylic acid ethyl ester 
(a) 2-(3-Phenoxypropyl)oxirane-2-carboxylic acid ethyl ester - 
14.0 g of the title compound [almost colorless oil, purified by 
chromatography on silica gel (eluant: methylene chloride)] are obtained 
from 70.3 g of 2-methylene-5-phenoxyvaleric acid ethyl ester and 124.3 g 
of m-chloroperbenzoic acid in 900 ml of methylene chloride by the 
procedure described in Example 1a). 
(b) 2-Methylene-5-phenoxyvaleric acid ethyl ester - 
142.4 g of 2-methylene-5-phenoxyvaleric acid ethyl ester [b.p. 108.degree. 
to 111.degree. C. at 0.01 mm Hg (1.3 Pa)] are obtained from 200.6 g of 
2-phenoxypropylmalonic acid ethyl ester, 23.8 g of paraformaldehyde, 200 
ml of pyridine and 7.6 ml of piperidine by the procedure described in 
Example 1b). 
(c) 3-Phenoxypropylmalonic acid ethyl ester - 
200.6 g of 3-phenoxypropylmalonic acid ethyl ester (yellow oil) are 
obtained from 302 g of 3-phenoxypropylmalonic acid diethyl ester and 52.2 
g of potassium hydroxide in 1.2 of ethanol by the procedure described in 
Example 1c). 
EXAMPLE 7 
2-[6-(4-Chlorophenoxy)hexyl]oxirane-2-carboxylic acid ethyl ester 
(a) 2-[6-(4-Chlorophenoxy)hexyl]oxirane-2-carboxylic acid ethyl ester - 
5.5 g of the title compound [colorless oil of b.p. 164.degree. C. at 0.2 mm 
Hg (26.6 Pa)] are obtained from 15.0 g of 
8-(4-chlorophenoxy)-2-methyleneoctanoic acid ethyl ester and 14.72 g 
m-chloroperbenzoic acid in 50 ml of methylene chloride by the procedure 
described in Example 1a). 
(b) 8-(4-Chlorophenoxy)-2-methyleneoctanoic acid ethyl ester - 
52.1 g of 8-(4-chlorophenoxy)-2-methyleneoctanoic acid ethyl ester [b.p. 
171.degree. C. at 0.1 mm Hg (13.3 Pa)] are obtained from 74 g of 
6-(4-chlorophenoxy)hexylmalonic acid ethyl ester, 8.2 g of 
paraformaldehyde, 41 ml of pyridine and 2.8 ml of piperidine by the 
procedure described in Example 1b). 
(c) 6-(4-chlorophenoxy)hexylmalonic acid ethyl ester (yellowish viscous 
oil) are obtained from 83.5 g of 6-(4-chlorophenoxy)hexylmalonic acid 
diethyl ester and 14.4 g of potassium hydroxide in 500 ml of ethanol by 
the procedure described in Example 1c). 
(d) 6-(4-Chlorophenoxy)hexylmalonic acid diethyl ester - 
87 g of 6-(4-chlorophenoxy)hexylmalonic acid diethyl ester [b.p. 
173.degree. C. at 0.1 mm Hg (13.3 Pa)] are obtained from 106.7 g of 
6-(4-chlorophenoxy)hexyl bromide, 53.8 g of malonic acid diethyl ester and 
a solution of 8.4 g of sodium in 350 ml of ethanol by the procedure 
described in Example 2d). 
EXAMPLE 8 
2-[3-(4-Nitrophenoxy)propyl]oxirane-2-carboxylic acid ethyl ester 
(a) 2-[3-(4-Nitrophenoxy)propyl]oxirane-2-carboxylic acid ethyl ester - 
3.8 g of the title compound (yellow oil) are obtained from 10.0 g of 
2-methylene-5-(4-nitrophenoxy)valeric acid ethyl ester and 10.5 g of 
m-chloroperbenzoic acid in 50 ml of methylene chloride by the procedure 
described in Example 1a). 
(b) 2-Methylene-5-(4-nitrophenoxy)valeric acid ethyl ester - 
61 g of 2-methylene-5-(4-nitrophenoxy)valeric acid ethyl ester [yellow oil 
of b.p. 167.degree. to 170.degree. C. at 0.005 mm Hg (0.7 Pa)] are 
obtained from 89 g of 3-(4-nitrophenoxy)propylmalonic acid ethyl ester, 
10.8 g of paraformaldehyde, 54 ml of pyridine and 4 ml of piperidine by 
the procedure described in Example 1b). 
(c) 3-(4-Nitrophenoxy)propylmalonic acid ethyl ester - 
90 g of 3-(4-nitrophenoxy)propylmalonic acid ethyl ester (yellow oil) are 
obtained from 116.5 g of 3-(4-nitrophenoxy)propylmalonic acid diethyl 
ester and 21.7 g of potassium hydroxide in 500 ml of ethanol by the 
procedure described in Example b 1c). 
(d) 3-(4-Nitrophenoxy)propylmalonic acid diethyl ester - 
119.5 g of 4-(4-nitrophenoxy)propylmalonic acid diethyl ester (yellowish 
oil) are obtained from 110.5 g of 3-(4-nitrophenoxy)propyl bromide, 101 g 
of malonic acid diethyl ester and a solution of 9.7 g of sodium in 1.1 l 
of ethanol by the procedure described in Example 2d). 
EXAMPLE 9 
2-(5-Phenoxypentyl)oxirane-2-carboxylic acid ethyl ester 
(a) 2-(5-Phenoxypentyl)oxirane-2-carboxylic acid ethyl ester - 
2.15 g of the title compound [colorless oil, purified by chromatography on 
silica gel (eluant: petroleum ether/ethyl acetate 9:1] are obtained from 
10 g of 2-methylene-7-phenoxyheptanoic acid ethyl ester and 11.6 g of 
m-chloroperbenzoic acid in 50 ml of methylene chloride by the procedure 
described in Example 1a). 4.7 g of the starting compound are regained. 
(b) 2-Methylene-7-phenoxyheptanoic acid ethyl ester - 
58 g of 2-methylene-7-phenoxyheptanoic acid ethyl ester [b.p. 118.degree. 
C. at 0.001 mm Hg (0.13 Pa)] are obtained from 143.7 g of 
5-phenoxypentylmalonic acid ethyl ester, 18.3 g of paraformaldehyde, 92 ml 
of pyridine and 6 ml of piperidine by the procedure describe in Example 
1b). 
(c) 5-Phenoxypentylmalonic acid ethyl ester - 
143.7 g of 5-phenoxypentylmalonic acid ethyl ester (yellowish oil) are 
obtained from 174.4 g of 5-phenoxypentylmalonic acid diethyl ester and 
34.4 g of potassium hydroxide in 500 ml of ethanol by the procedure 
described in Example 1c). 
EXAMPLE 10 
2-[5-(4-Chlorophenoxy)pentyl]oxirane-2-carboxylic acid ethyl ester 
(a) 2-[5-(4-Chlorophenoxy)pentyl]oxirane-2-carboxylic acid ethyl ester- 
6.6 g of the title compound [b.p. 176.degree. to 178.degree. C. at 0.005 mm 
Hg (0.7 Pa)] are obtained from 10 g of 
7-(4-chlorophenoxy)-2-methyleneheptanoic acid ethyl ester and 10.9 g of 
m-chloroperbenzoic acid in 50 ml of methylene chloride by the procedure 
described in Example 1a). 
(b) 7-(4-Chlorophenoxy)-2-methyleneheptanoic acid ethyl ester- 
88.6 g of 7-(4-chlorophenoxy)-2-methyleneheptanoic acid ethyl ester [b.p. 
154.degree. C. at 0.01 mm Hg (1.3 Pa)] are obtained from 202.5 g of 
5-(4-chlorophenoxy)pentylmalonic acid ethyl ester, 23.4 g of 
paraformaldehyde, 116 ml of pyridine and 7.9 ml of piperidine by the 
procedure described in Example 1b). 
(c) 5-(4-Chlorophenoxy)pentylmalonic acid ethyl ester- 
202.5 g of 5-(4-chlorophenoxy)pentylmalonic acid ethyl ester (viscous oil) 
are obtained from 250.6 g of 5-(4-chlorophenoxy)pentylmalonic acid diethyl 
ester and 44.6 g of potassium hydroxide in 500 ml of ethanol by the 
procedure described in Example 1c). 
(d) 5-(4-Chlorophenoxy)pentylmalonic acid diethyl ester- 
265 g of 5-(4-chlorophenoxy)pentylmalonic acid diethyl ester [of b.p. 
160.degree. to 161.degree. C. at 0.01 mm Hg (1.3 Pa)] are obtained from 
212.6 g of 5-(4-chlorophenoxy)pentyl bromide, 185.8 g of malonic acid 
diethyl ester and a solution of 17.7 g of sodium in 1.25 1 of ethanol by 
the procedure described in Example 2d). 
EXAMPLE 11 
2-(3-Benzyloxypropyl)oxirane-2-carboxylic acid ethyl ester 
(a) 2-(3-Benzyloxypropyl)oxirane-2-carboxylic acid ethyl ester- 
7.2 g of the title compound [almost colorless oil, purified by 
chromatography on silica gel (eluant: petroleum ether/ethyl acetate 9:1)] 
are obtained from 26 g of 5-benzyloxy-2-methylenevaleric acid ethyl ester 
and 48 g of m-chloroperbenzoic acid in 200 ml of methylene chloride by the 
procedure described in Example 1a). 
(b) 5-Benzyloxy-2-methylenevaleric acid ethyl ester- 
30.1 g of 5-benzyloxy-2-methylenevaleric acid ethyl ester [yellowish oil, 
purified by chromatography on silica gel (eluant: petroleum ether/ethyl 
acetate 9:1)] are obtained from 44 g of 3-benzyloxypropylmalonic acid 
ethyl ester, 30 ml of pyridine, 2 ml of piperidine and 6.6 g of 
paraformaldehyde by the procedure described in Example 1b). 
(c) 3-Benzyloxypropylmalonic acid ethyl ester- 
44.5 g of 3-benzyloxypropylmalonic acid ethyl ester (tough, yellowish oil) 
are obtained from 67 g of 3-benzyloxypropylmalonic acid diethyl ester and 
12.4 g of potassium hydroxide in 200 ml of ethanol by the procedure 
described in Example 1c). 
(d) 3-Benzyloxypropylmalonic acid diethyl ester- 
67.4 g of 3-benzyloxypropylmalonic acid diethyl ester (yellowish oil) are 
obtained from 86 g of 3-benzyloxypropyl bromide, 78 g of malonic acid 
diethyl ester and a solution of 9 g of sodium in 600 ml of ethanol by the 
procedure described in Example 2d). 
EXAMPLE 12 
2-[5-(4-Chlorophenoxy)pentyl]oxirane-2-carboxylic acid 
2.0 g of 2-[5-(4-chlorophenoxy)pentyl]oxirane-2-carboxylic acid ethyl 
ester, 6.4 ml of 1 N sodium hydroxide solution and 6.4 ml of 
tetrahydrofuran are stirred at room temperature until a clear solution has 
formed (after about one hour). The solution is concentrated to one half of 
its volume in vacuo and 6.5 ml of 1 N hydrochloric acid are added while 
cooling with ice. The resulting mixture is extracted 3 times with 20 ml of 
diethyl ether each time. After drying the combined organic phases over 
sodium sulfate and evaporating off the solvent 1.65 g of the title 
compound as a viscous oil are obtained. 
EXAMPLE 13 
Sodium 2-[4-(3-trifluoromethylphenoxy)butyl]oxirane-2-carboxylate 
4.0 g of 2-[4-(3-trifluoromethylphenoxy)butyl]oxirane-2-carboxylic acid 
ethyl ester, 12 ml of 1 N sodium hydroxide solution and 16 ml of 
tetrahydrofuran are stirred for 2 hours at room temperature. The solution 
which has formed is concentrated to one half of its volume in vacuo and is 
then extracted 2 times with 50 ml of diethyl ether each time. On standing 
a precipitate crystallizes out of the aqueous solution, which is filtered 
off and washed with little water and diethyl ether. 2.44 g of the title 
compound of m.p. 94.degree. to 97.degree. C. are obtained by gradual 
concentration of the filtrates to a small volume. 
EXAMPLE 14 
Sodium 2-[4-(3-chlorophenoxy)butyl]oxirane-2-carboxylate 
11.4 g of the title compound of m.p. 102.degree. to 106.degree. C. are 
obtained analogously to Example 13 from 13.1 g of 
2-[4-(3-chlorophenoxy)butyl]oxirane-2-carboxylic acid ethyl ester and 43.8 
ml of 1 N sodium hydroxide solution in 50 ml of tetrahydrofuran. 
EXAMPLE 15 
Calcium 2-[4-(3-chlorophenoxy)butyl]oxirane-2-carboxylate 
400 mg of calcium chloride in 5 ml of water are added to a solution of 1 g 
of sodium 2-[4-(3-chlorophenoxy)butyl]oxirane-2-carboxylate in 10 ml of 
water. The greasy residue which has formed is separated off by 
decantation, and the sediment is washed by two decantations with little 
water. The residue is dried over phosphorus pentoxide. 840 mg of the title 
compound are obtained. Decomposition (without melting) at 225.degree. C. 
EXAMPLE 16 
2-[4-(3-Trifluoromethylphenoxy)butyl]oxirane-2-carboxylic acid methyl ester 
5.4 g of the title compound [colorless oil, purified by chromatography on 
silica gel (eluant: petroleum ether/methylene chloride 1:1)] are obtained 
from 7.8 g of 2-methylene-6-(3-trifluoromethylphenoxy)hexanoic acid methyl 
ester and 11.0 g of m-chloroperbenzoic acid by the procedure described in 
Example 3a). 
8.0 g of the starting compound 
2-methylene-6-(3-trifluoromethylphenoxy)hexanoic acid methyl ester are 
obtained from 17.5 g of 4-(3-trifluoromethylphenoxy)butylmalonic acid 
dimethyl ester by the procedure described in Example 3b) and 3c). 
EXAMPLE 17 
2-[2-(3-Phenylpropyloxy)ethyl]oxirane-2-carboxylic acid ethyl ester 
(a) 2-[2-(3-Phenylpropyloxy)ethyl]oxirane-2-carboxylic acid ethyl ester- 
6.6 g of the title compound [colorless oil, purified by chromatography on 
silica gel (eluant: petroleum ether/ethyl acetate 9:1]are obtained from 
18.0 g of 2-methylene-4-(3-phenylpropyloxy)butyric acid ethyl ester and 22 
g of m-chloroperbenzoic acid in 150 ml of methylene chloride by the 
procedure described in Example 1a). 
(b) 2-methylene-4-(3-phenylpropyloxy)butyric acid ethyl ester- 
27 g of 2-methylene-4-(3-phenylpropyloxy)butyric acid ethyl ester 
[colorless oil of b.p. 140.degree. C. at 0.1 mm Hg (13 Pa)] are obtained 
from 45 g of 2-(3-phenylpropyloxy)ethylmalonic acid ethyl ester, 28.5 ml 
of pyridine, 1.9 ml of piperidine and 5.74 g of paraformaldehyde by the 
procedure described in Example 1b). 
(c) 2-(3-Phenylpropyloxy)ethylmalonic acid ethyl ester- 
46.6 g of 2-(3-phenylpropyloxy)ethylmalonic acid ethyl ester (yellowish 
oil) are obtained from 54 g of 2-(3-phenylpropyloxy)-ethylmalonic acid 
diethyl ester and 10.68 g of potassium hydroxide in 120 ml of ethanol by 
the procedure described in Example 1c). 
(d) 2-(3-Phenylpropyloxy)ethylmalonic acid diethyl ester- 
54 g of 2-(3-phenylpropyloxy)ethylmalonic acid diethyl ester ]b.p. 
168.degree. to 171.degree. C. at 0.2 mm Hg (27 Pa)] are obtained from 72.7 
g of 2-(3-phenylpropyloxy)ethyl chloride, 87.9 g of malonic acid diethyl 
ester, 3 g of potassium iodide and a solution of 12.6 g of sodium in 300 
ml of ethanol by the procedure described in Example 2d). 
EXAMPLE 18 
2-[2-(4-Chlorobenzyloxy)ethyl]oxirane-2-carboxylic acid ethyl ester 
(a) 2-[2-(4-chlorobenzyloxy)ethyl]oxirane-2-carboxylic acid ethyl ester- 
6.2 g of the title compound [b.p. 130.degree. to 135.degree. C. at 0.05 mm 
Hg (7 Pa)] are obtained from 10.3 g of 
4-(4-chlorobenzyloxy)-2-methylenebutyric acid ethyl ester and 13 g of 
m-chloroperbenzoic acid in 100 ml of methylene chloride by the procedure 
described in Example 1a). 
(b) 4-(4-Chlorobenzyloxy)-2-methylenebutyric acid ethyl ester- 
14.0 g of 4-(4-chlorobenzyloxy)-2-methylenebutyric acid ethyl ester [b.p. 
125.degree. to 130.degree. C. at 0.1 mm Hg (13.3 Pa)] are obtained from 
19.0 g of 2-(4-chlorobenzyloxy)ethylmalonic acid ethyl ester, 12 ml of 
pyridine, 0.8 ml of piperidine and 2.0 g of paraformaldehyde by the 
procedure described in Example 1b). 
(c) 2-(4-Chlorobenzyloxy)ethylmalonic acid ethyl ester- 19.5 g of 
2-(4-chlorobenzyloxy)ethylmalonic acid ethyl ester are obtained from 26.0 
g of 2-(4-chlorobenzyloxy)ethylmalonic acid diethyl ester and 5.05 g of 
potassium hydroxide in 100 ml of ethanol by the procedure described in 
Example 1c). 
(d) 2-(4-Chlorobenzyloxy)ethylmalonic acid diethyl ester- 
60.3 g of 2-(4-chlorobenzyloxy)ethylmalonic acid diethyl ester [b.p. 
168.degree. C. at 0.2 mm Hg (27 Pa)] are obtained from 87 g of 
2-(4-chlorobenzyloxy)ethyl chloride, 102 g of malonic acid diethyl ester, 
3 g of potassium iodide and a solution of 14.6 g of sodium in 300 ml of 
ethanol by the procedure described in Example 2d). 
EXAMPLE 19 
Batch for ampoules 
100 g of 2-[5-(4-Chlorophenoxy)pentyl]oxirane-2-carboxylic acid are 
dissolved in about 8 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 10 liters with doubly-distilled water. It 
is then filtered under sterile conditions and filled into 2 ml ampoules 
under germ-free conditions. 
EXAMPLE 20 
10,000 capsules with an active compound content of 30 mg are prepared from 
the following constitutents: 
300 g of 2-(5-phenoxypentyl)oxirane-2-carboxylic acid ethyl ester are mixed 
with 500 g of neutral oil, and the mixture is filled into soft gelatin 
capsules. 
EXAMPLE 21 
1,000 capsules with an active compound content of 25 mg are prepared as 
follows: 
25 g of 2-[4-(3-chlorophenoxy)butyl]oxirane-2-carboxylic acid ethyl ester 
are dissolved in 100 ml of methylene chloride The solution is mixed 
thoroughly with 75 g of micronized silicic acid. The mixture is evaporated 
to dryness and then filled into hard gelatin capsules. 
EXAMPLE 22 
10,000 capsules with an active compound content of 20 mg are prepared as 
follows: 
200 g of 2-[4-(3-trifluoromethylphenoxy)butyl]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 23 
10,000 capsules with an active compound content of 25 mg are prepared as 
follows: 
250 g of 2-[6-(4-chlorophenoxy)hexyl]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 24 
Tablets containing 25 mg of active compound are prepared as follows: 
1 kg of sodium 2-[4-(3-trifluoromethylphenoxy)butyl]-oxirane-2-carboxylate, 
4.5 kg of xylit, 3.0 kg of calcium phosphate and 0.25 kg of 
polyvinylpyrrolidone (MG 25,000; MG = molecular weight) are moistened with 
approx. 0.5 liter of water and granulated through a sieve with a mesh 
width of 1.25 mm. The granules are dried and 0.9 kg of 
carboxymethylcellulose, 0.25 kg of talc and 0.1 kg of magnesium stearate 
are then added. The dry granules are compressed to give tablets weighing 
250 mg, having a diameter of 8 mm and a hardness of 5 to 6 kg. 
EXAMPLE 25 
10,000 capsules with an active compound content of 20 mg are prepared as 
follows: 
200 g of 2-[5-(4-chlorophenoxy)pentyl]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. 
The following Examples describe the preparation of starting materials which 
are reacted analogously to the process of Genzer et al. 
EXAMPLE A 
2-[3-(5-Chloro-2-methoxyphenyl)propyloxy]ethyl chloride- 
11.2 g of 2-[3-(5-chloro-2-methoxyphenyl)propyloxy]-ethanol and 20 ml 
thionyl chloride are stirred at 50.degree. C. for 3 hours; the excess 
thionyl chloride is distilled off in vacuo. 11.3 g of 
2[3-(5-chloro-2-methoxyphenyl)propyloxy]ethyl chloride are obtained as a 
brown oil. 
(b) 2-[3-(5-Chloro-2-methoxyphenyl)propyloxy]ethanol- 
10 ml of xylene are added to a solution of 1.6 g of sodium in 20 g of 
ethyleneglycol. A solution of 21.9 g of 2-(5-chloro-2-methoxyphenyl)propyl 
chloride in 10 ml of xylene are then successively added dropwise. The 
resulting mixture is boiled for one hour under reflux, allowed to cool, 
mixed with 100 ml of water and extracted three times with 100 ml of 
diethyl ether each time. The united organic phases are dried over sodium 
sulfate and concentrated. 11.2 g of 
2-[3-(5-chloro-2-methoxyphenyl)propyloxy]ethanol are obtained as a brown 
oil. 
(c) 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. C. for 8 hours; the excess thionyl chloride is 
distilled off in vacuo and the residue is distilled under a high vacuo. 
50.9 g of 3-(5-chloro-2-methoxyphenyl)propyl chloride of b.p. 87.degree. 
to 95.degree. C. under 0.005 mm Hg are obtained. 
(d) 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. C. 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 
Bd). 
(e) 3-(5-Chloro-2-methoxyphenyl)propionic acid- 
63.2 g of 3-(5-chloro-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 B(e). 
EXAMPLE B 
(a) 3-[3-(4-Fluorophenyl)propyloxy]propyl chloride- 
10.0 g of 3-[3-(4-fluorophenyl)propyloxy]propyl chloride are obtained from 
9.9 g of 3-[3-(4-fluorophenyl)propyloxy]propanol-1 and 20 ml thionyl 
chloride by the procedure described in Example A(a). 
(b) 3-[3-(4-Fluorophenyl)propyloxy]propanol-1- 
9.9 g of 3-[3-(4-fluorophenyl)propyloxy]propanol-1 (brown oil) are obtained 
from a solution of 1.6 g of sodium in 25 g of 1,3-propanediol, 20 ml of 
xylene and 17.2 g of 3-(4-fluorophenyl)propyl chloride by the procedure 
described in Example A(b). 
(c) 3-(4-Fluorophenyl)propyl chloride- 
30.2 g of 3-(4-fluorophenyl)propyl chloride (oil) are obtained from 35 g of 
3-(4-fluorophenyl)propanol-1 and 30 ml of thionyl chloride by the 
procedure described in Example A(c). 
(d) 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 has ended, 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 
colorless oil. 
(e) 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-fluorobenzylmalonic 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. C. 
for 1.5 hours. After cooling, the reaction product is stirred with a 
little diethyl ether. 41.6 of 3-(4-fluorophenyl)propionic acid of m.p. 
85.degree. to 88.degree. C. [from ethyl acetate/petroleum ether (1:4)] 
thereby crystallize out. 
EXAMPLE C 
(a) 3-(3-Trifluoromethylphenyl)propyl chloride- 
10.3 g 3-(3-trifluoromethylphenyl)propyl chloride (oil) are obtained from 
12 g of 3-(3-trifluoromethylphenyl)propanol-1 and 10 g of thionyl chloride 
by the procedure described in Example A(a). 
(b) 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 of b.p. 85.degree. to 95.degree. C. 
under 0.02 mm Hg are obtained. 
Pharmacology 
The substituted oxiranecarboxylic acids of 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 (for 
example sulfonyl-ureas) which have an action on the pancreas, and their 
mode of action differs fundamentally 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 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-(3-Chlorophenoxy)butyl]oxirane-2-carboxylic 
acid ethyl ester 
4 2-[4-(3-Trifluoromethylphenoxy)butyl]oxirane-2-car- 
boxylic acid ethyl ester 
5 2-[6-(4-Chlorophenoxy)hexyl]oxirane-2-carboxylic 
acid ethyl ester 
6 2-[5-(4-Chlorophenoxy)pentyl]oxirane-2-carboxylic 
acid ethyl ester 
7 2-[4-(4-Methylphenoxy)butyl]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, 
metabolically healthy rats which are observed for 6 hours after a single 
oral administration of from 0.01 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 a 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 24 3 390 
4 13 .about.7 460 
5 7 &lt;7 300 
6 6 5 310 
7 19 8 
______________________________________ 
Re Table I: 
*Cited according to Blickens, D.A.; Riggi, S.J.: Toxicol. Appl. 
Pharmacol., 14 (1969)393-400 
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 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 to 200 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 
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 3 and 6 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. 
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.