FI77660C - FOERFARANDE FOER FRAMSTAELLNING AV NYA, TERAPEUTISKT ANVAENDBARA AZOLYLMETYLOXIRANER. - Google Patents

Description

1 77660

A process for the preparation of novel therapeutically useful azolylmethyloxiranes

The invention relates to a process for the preparation of new therapeutically useful azolylmethyloxiranes of the formula I

i- \ I

.. N-CH - C-CH-B I

10 1, Z \ / N ^ rr- / \ / 0 wherein A and B are the same or different and independently represent an alkyl group having 1 to 4 carbon atoms or a naphthyl, biphenyl or phenyl group, wherein the phenyl group may in each case be 1 Substituted by alkyl, alkoxy and haloalkyl groups having 4 carbon atoms, and substituted by halogen, nitro, and phenylsulfonyl groups, Z represents a CH group or a nitrogen atom, and to prepare physiologically acceptable salts thereof.

Numerous fungicides, e.g. Miconazole (DE-A-1 940 388) are known. Their effects do not always satisfy the literature: Chemothe-25 rapy 22 (1976) 1; Dtsch. Apoth. Ztg. 118 (1978) 1269; Z. Hautkr. 56 (1981) 1109.7. It is further known to use azole compounds, e.g. azolylmethylcarbinol or azolylmethyl ketone (DE-A-2 431 407, FR-A-2 249 616) as fungicides.

It is an object of the present invention to provide new and more effective drugs for fungal diseases.

It has now been found that the compounds of the formula I, as well as their physiologically acceptable acid addition salts, have good antimicrobial, in particular fungicidal and antifouling properties.

2,77660

The new compounds of the formula I have chiral centers and are generally obtained as racemates or as diastereomeric mixtures containing erythro and threo forms. The erythro and threo diastereomers in the compounds according to the invention can be separated from one another, for example, on the basis of their different solubilities or by column chromatography and can be isolated in pure form. From such homogeneous pairs of diastereomers, homogeneous enantiomers can be obtained by known methods. Both homogeneous diastereomers or enantiomers as well as mixtures obtained in their synthesis can be used as microbicides.

A and B denote, for example: methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-15-butyl, tert-butyl, 1-naphthyl, 2-naphthyl, p-biphenyl , phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5- dichlorophenyl, 3-chloro-4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl , 4-tert. butoxyphenyl, 4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-phenoxyphenyl, 3-phenoxyphenyl, 3-nitrophenyl, 4-nitro-phenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl or 4-phenylsulfonylphenyl.

Preferred are: methyl, tert-butyl, phenyl, 4-chlorophenyl, 4-bromophenyl, 2,4-dichlorophenyl and 4-tert-butylphenyl.

Suitable common physiological salt-forming acids are preferably hydrohalic acids, such as hydrochloric acid and hydrobromic acid, especially

II

3,776,60 hydrochloric acid, with which the compounds of the formula I form particularly well crystallizing salts, further phosphoric acid, nitric acid, sulfuric acid, mono- and bi-functional carboxylic and hydroxycarboxylic acids, such as acetic acid, oxalic acid, maleic acid, maleic acid, marine acid, meric acid citric acid, salicylic acid, sorbic acid, lactic acid and sulfonic acids, p-toluenesulfonic acid and 1,5-naphthalenedisulfonic acid.

The process according to the invention for the preparation of the new azolylmethyloxiranes of the formula I is characterized in that the compound of the formula II

A

L-CH0 - (! - CH-B II

2 V

15

wherein A and B have the meanings given above and L represents a nucleophilically displaceable leaving group is reacted with a compound of formula III

20 _.Z

N-Me III

N 1 is wherein Me represents a hydrogen atom or a metal atom and Z is a CH group or a nitrogen atom, and if desired, the compounds thus obtained are converted into their salts with physiologically acceptable acids.

The reaction takes place - if Me represents a hydrogen atom - optionally in the presence of a solvent or diluent, optionally with the addition of an inorganic or organic base and optionally with the addition of a reaction accelerator at temperatures between 10 and 120 ° C. Preferred solvents or diluents include ketones such as acetone, methyl ethyl ketone and cyclohexanone, nitriles such as acetonitrile, esters such as ethyl acetate, ethers such as diethyl ether, dimethyl ether, dimethylformamide and dioxamide and sulfide such as dimethylamide oxide, sulfoxides such as dimethyl N-methyl-pyrrolidone, further sulfolanes and the like.

Suitable bases which may also be used as acid scavengers in the reaction include, for example, alkali hydroxides such as lithium, sodium and potassium hydroxide; alkali carbonates such as sodium and potassium carbonate and sodium and potassium bicarbonate, amounts of 1,2,4-triazole, pyridine and 4-dimethylaminopyridinyl. However, other common bases can also be used.

Suitable reaction accelerators are metal halides such as sodium iodide and potassium iodide, quaternary ammonium salts such as tetrabutylammonium chloride, bromide and iodide, benzyltriethylammonium chloride and bromide or crown ethers such as 12-crown ethers such as 12-crown ethers. -crown-6, dibenzo-18-crown-6 and dicyclohexano-18-crown-6.

The reaction is generally carried out at temperatures between 20 and 150 ° C, under pressure or under pressure, continuously or discontinuously.

If Me is a metal atom, the reaction is optionally carried out in the presence of a solvent or diluent and optionally with the addition of a strong inorganic or organic base at temperatures between -10 and 120 ° C. Preferred solvents or diluents include amides such as dimethylformamide, diethylformamide, dimethylacetamide, diethylacetamide, N-methylpyrrolidone, hexamethylphosphoric triamide, sulfoxides such as dimethylsulfoxide, and finally sulfolane.

Suitable bases, which may also be used in the reaction as acid scavengers, include, for example, alkali metal hydrides such as lithium, sodium and potassium hydride, alkali amides such as sodium and potassium amide, further sodium and potassium tert-butoxide, lithium, sodium and potassium triphenylmethyl and naphthalene lithium, sodium and potassium.

5,77660

The new starting materials of the formula II are obtained by epoxidation of the corresponding olefins of the formula IX

l-ch2-ca = ch-b (IX) 5 (cf. G. Dittus in Houben-Weyl-Muller, Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1965, Volume VI, 3 from page 385).

The compound of formula IX is prepared by halogenation or oxidation of olefins of formula X according to known methods at the al-10 position.

h3c-ca = ch-b (X)

Suitable halogenating reagents include N-chloro and N-bromosuccinimide in halogenated hydrocarbons such as carbon tetrachloride, trichloroethane or methylene chloride at temperatures between 20 and 100 ° C. A perester such as perbenzoic acid tert-butyl ester or peracetic acid tert-butyl ester in the presence of a heavy metal salt such as copper I-chloride or copper-I-20 bromide is used for allyl meat education. Work in inert solvent temperatures between 10 and 100 ° C.

The allyl halides or alcohols IX thus obtained are subsequently converted to the corresponding epoxides II (L = halogen, OH).

Olefins X are oxidized with peroxycarboxylic acids such as perbenzoic acid, 3-chloroperbenzoic acid, 4-nitroperbenzoic acid, monoperphthalic acid, peracetic acid, perpropionic acid, in -disuccinic acid, perforic acid, monoperperic acid, perpelic acid, perpelic acid, perpel are, for example, methylene chloride, chloroform, carbon tetrachloride and dichloroethane, but optionally also in acetic acid, ethyl acetate, acetone or dimethylformamide, optionally in the presence of a buffer 35 such as sodium acetate, sodium carbonate, sodium hydrogen carbonate, disodium hydrogen phosphate or Triton B60. Work between 10 and 100 ° C and optionally catalyze the reaction with, for example, iodine, sodium tungstate or light. Also suitable for oxidation are basic hydrogen peroxide solutions (about 30%) in methanol, ethanol, acetone or acetonitrile at 25-30 ° C as well as alkyl hydroperoxides, e.g. tert-butyl hydroperoxide, catalyst, e.g. or by adding vanadyl acetylacetonate. Said oxidants can be produced in part.

While the epoxy halides II (L-halogen) thus obtained can be immediately reacted with a compound of formula III, the corresponding epoxy alcohols II (L = OH) are converted into reactive esters, which are then reacted with compounds of formula III to give compounds of formula I.

The preparation of the reactive esters to be reacted with the compounds of the formula III takes place according to generally known methods (Houben-Weyl-20 Möller, Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1955, volume 9, pages 388, 663, 671). Such esters include, for example, methanesulfonic acid esters, trifluoromethanesulfonic acid esters, 2,2,2-trifluoromethanesulfonic acid esters, nonafluorobutanesulfonic acid esters, 4-methylbenzenesulfonic acid nitroisestenesulfonic acid esters, 4-bromobenzenesulfonic acid esters, 4-bromobenzenesulfonic acid esters.

Partially unknown compounds X can be prepared according to the generally known olefin synthesis method (Houben-Weyl-Muller, Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1972, Volume V, Ib).

The compounds of formula I obtained are isolated according to customary methods, optionally purified and optionally reacted with acids to give salts.

7 77660

Surprisingly, the azole derivatives of the formula I, in addition to their good in vitro antibacterial and fungicidal activity, have a better, therapeutically useful in vivo activity, in particular against Dermatophytes and Candida, than the known preparations. The compounds of formula I thus enrich the pharmacy in a valuable manner.

The effect of the compounds of the formula I on dermatophytes, bacteria and protozoa can be demonstrated by the Melo methods described, for example, in P. Klein Bacteriologische Grundlagen den chemotherapeutischen Laboratory Spraxis, Springer-Verlag, Berlin, 1957. A surprising effect on yeast was shown Using Candida albivans (cf. DE-ha-15 Chemical Publication 3,010,093). The lowest preventive concentrations (MHK values) achieved in the agar dilution experiment were investigated. The closest prior art is the compounds of formula III of EP-A-23 103. These known compounds have a significantly weaker anti-20 microbial activity than the new compounds of the formula I. In order to demonstrate this, the above experiments were also performed. Compounds (A) and (B) known from the EP patent publication. Table 1 summarizes the results.

25 f "= - I O-- CH0 I I \ / 2 / = \ n ^ n-ch2-c- <A> 30 C1 ^ n-c" 2-c-4J> -C1 (B) d β 77660 m

(OF

o m • · ^ ^ DI g O ^ TVOrHOOOOOVCVOOO Xld rH (N 04 rH rH 04

<C 4-4 CM i-l rH rH

Λ Λ A

3 3

X

• -P

e m ns •> i -n tn top 00.-Η · * ΤΟΓ404νθ04 00νθ o o

3 Λ O ΓΟ rH rH O O

-P <υ «H rH rH

2 AA

-B

td> Λ <0 rH tn vo <ti vo> td ro m m m m m tn (d · O rH 04 O 04 04 H Dl

Ci Ό OOrHOrHrH O (N

CI ^ tl - - ^ ^ ^ td (d OOOOOOrHOOfM | t • P O S v v v v: td

-P

•B

X3 H Λ

rH rH

ai <d c <D Ό

rl c 04 vo rH VO 00 VO (N

CX td ΓΟ rH rHOVJrH O <00 · * Τ O UI

U X rH VO 04 VO LO 04

0 Λ Λ A rH

P -P • H

> -P

0) £ e Ό CX • H O m> 1 XS · 04

rH C> U -P rH VO LO

fl> 0) -H β »- -

O Ό M di H O rH rH O 00 O VO rH 04 00 OO

Λί -H: td E-t £ 04 rH mm X Q)>

3 -P

rH tn 4-S

2 -h: td td t)> eh x: as ex ·> 1 tn tn ov m • h 0 3 cN m C: rdpp vo mm 04 mm tU- ^ OSH 00404rH 04 04 • rl, β -rl φ «. fcWV »*.

tn d) 24Hmoooo (Nooooo4tN ι i 3 3 -P: td C g tl) g «m -p -h · υ 04 m tn e Ό cj ή m« N m rl 0) -H O O- * - * ^

id-iHeXrHmOrHrHO ^ TOVOrHCNOO O 04 Λί CX (¾ 44 rH rH O rH

3 rH

e

B

tl)

C -P

td tn ·> -h g td tj -h o td xjtnpvor ^ tTirHrooorHO-crio «> h (UC rH 04 -vr 04 ro <m 9 77660

C/O

0 Ρ 0 Λ Μ α>

• Ρ O

ιβ e ·

> td -P

-p to

td 0 -H I I I I rH i — I i — I i — I rH i — I

> W .G A Λ A A Λ A

td Λ Λ <0

-P

E

: td O

-Ρ -G

• Ρ o ·: 0 HO 'VOvr> v £) VDVDVDVDVDvX> V £>

H Ρ rö i — li — li — liHrHfHfHfHf — li — I

-H E-l> ΑΑΛΛΑΛΛΑΛΑ d>

G

d)

•B

Oj -h

-— i — I I

td O Otdpoocococococococooooo O P 0-P0cncncncmc \ icnc \ icncn <n

^ -P · P i — I '—I i — I i — I i — I i — I i — I i — I rH i — I »H

• P H WE'PAAAAAAAAAA

(0> -P

• n (1)

-'C/O

• H>, rH> 1 ·

G> -P

O d> d> Λ · X Ό X d) O m X -H: rd pul'fOictDaiooc'iiN'f'ioo

0 0) t> -P td O i — li — I CN (N CN <N

Ή * P CO P CO ιΗ f — I rH rH

0 tfl -P A A

Id -H «e H d> • G d)

> 1 to · rH

H, G iH G: <d (X · m

d) Ai m P VO ^ OOOCOCN ^ OOOOVOCO

ΗΧ34 -> ^ ϋιΗιΗίΜτΗΠ .H C \ l

to d) CO CO CO rH rH

0 A

0 -P

: id G g <u g P -H p to G O · h a) o to

Id -H 0 0

Ai ft s & i ^> ^ (NtNiHiHCOOOfN ^ ROO

0 iH

E

B

0)

G -P

G CD ·

> -PE

td Ό -H O

td Gcop'sOr'O'iHnooHr ^ cTio X> H 0) G H N (N n 10 77660

Also in the guinea pig model (Trichophyton menta-grophytes) compare with Heffter-Heubner; Handbuch d. exp. Pharmakologie, Volume XVI / IIA, the new compounds of the formula I are more potent than the reference substances when applied topically.

The new compounds are also effective orally, as demonstrated by treatment of experimental mouse candidiasis. To this end, groups of 10 mice weighing about 20 g each were pretreated for 2 days with 50 mg / kg hydrocortisone intramuscularly for 2 days to get off the infection well. Mice were then each infected with 500,000 Candida albicans seeds intravenously and then treated orally with 100 mg / kg of the test substances for 4 days.

In addition to the infected group and the untreated control group, one group was each treated with reference substances for comparison. In this case, the compounds of the formula I to be tested showed better DC-g-ar-20 vo than the reference substances.

In Table 2, the DC g values obtained with the compound of Example 3 are compared with the DC g values obtained with Ketoconazole; The DC g value is the dose that leads to improvement in 50% of the experimental animals.

25 Table 2

Candida infection in mice

Compound DC50 (use; * - administrations) DC ^ g (single administration) __mg / kg p.o.__ mg / kg p.o._

Example 3 0.4 1.21 2g Ketoconazole 28.7 176.0

In a model of experimental Candida albicans vaginitis in rats, complete cures from infection could be achieved with the test substances at low therapeutic doses after oral administration or topical treatment.

n 77660

The compounds of formula I are therefore very suitable for the oral and external treatment of fungal infections in humans and animals.

Indications for use in humans and animals include: Superficial mycoses, superficial phytoses and deep mycoses, especially dermatophytes such as yeasts of the genera Epidermophyton, Microsporum or Trichophyton - such as genera of Candida species and Aspergus genus Aspergus Absida species, causing-10 tamat.

The compounds of the formula I can be used alone or in combination with other known active ingredients, in particular antibiotics.

Chemotherapeutic agents or preparations to which ordinary solid, semi-solid or liquid carriers or diluents and conventionally used pharmaceutical excipients can be added according to the desired use are prepared in the customary manner, in particular by stirring (cf. H. Sucker et al., Pharmazeutische 20 Technologie). -Verlag, Stuttgart, 1978).

Suitable dosage forms are, for example, tablets, beads, capsules, pills, aqueous solutions, suspensions and emulsions, optionally sterile injectable solutions, non-aqueous emulsions, suspensions and solutions, ointments, creams, pastes, waters, etc.

The therapeutically active compound is preferably present in the pharmaceutical preparations in a concentration of 0.5 to 90% by weight of the total mixture.

In general, for oral administration in both human and veterinary medicine, the active ingredient or ingredients may be administered in amounts of about 1.0 to about 10.0, preferably 2 to 6 mg / kg of body weight per day, preferably in multiple single doses to achieve the desired results. However, it may be necessary to deviate from said dosage range 35 depending on the nature and severity of the disease, the nature of the preparation and the mode of administration of the medicament, as well as the time interval or period during which the administration takes place. It may i2 7 7 6 6 0 in some cases be sufficient to survive with less than the above-mentioned amount of active substance, while in other cases the amount of active substance indicated above must be exceeded.

The following examples illustrate the invention

I. Preparation of starting materials Example A

To a solution of 229 g of 2,4-diklooribent-syylitrifenyylifosfoniumkloridia in 800 ml of dry melo methanol-was added at 10 ° C, 63.6 g of potassium-tert.butyl-carbonate in 300 ml of dry methanol, and after a half hour was added to 77 , 2 g of 4-chloroacetophenone. The reaction mixture was refluxed for 3 hours, then the separated salt was filtered off at room temperature and the filtrate was evaporated in vacuo. By extraction of the residue with Petro-ether (50-70 ° C), the solution was separated from triphenylphosphine oxide and evaporated in vacuo.

The residue was taken up in 1 L of carbon tetrachloride and refluxed with 81.7 g of N-bromosuccinimide and 4 g of 2,21-azobutyric acid dinitrile. After completion of the reaction, the succinimide was filtered off, the filtrate was evaporated in vacuo and the residue was crystallized from methanol. 73.4 g (38.8%) of z-1- (2,4-dichlorophenyl) -2-25 (4-chlorophenyl) -3-bromopropene-1, m.p. 128 ° C.

Example B

To 14.6 g of magnesium turnings in 400 ml of dry diethyl ether was added dropwise 118 g of 2,4-dichlorobenzyl chloride at the boiling point. After completion of the reaction, 77.3 g of 4-chloroacetophenone in 400 ml of dry diethyl ether were added. Next, it was decomposed with aqueous ammonium chloride solution, the organic phase was separated, washed until neutral and dried over sodium sulfate. After evaporation in vacuo, the residue was taken up in 1 l of toluene and heated to reflux with 4 g of 4-methylbenzenesulphonic acid with a water separator. After completion of the dehydration, the toluene phase was washed with sodium carbonate solution and water, dried over sodium sulfate and the solvent was evaporated.

II

77660 13 off. The residue afforded 107 g (71.9%) of E-1- (2,4-dichlorophenyl) -2- (4-chlorophenyl) propene-1 from methanol, m.p. = 84-85 ° C.

Example C

5,104 g of E1- (2,4-dichlorophenyl) -2- (4-chlorophenyl) propene-1 were refluxed with 62.3 g of N-bromosuccinimide and 5 g of 2,2'-azobutyric acid dinitrile. in carbon tetrachloride under reflux, the separated succinic acid amide was filtered off and the filtrate was evaporated in vacuo.

Treatment of the residue with methanol afforded 91.5 g (69.4%) of Z-1- (2,4-dichlorophenyl) -2- (4-chlorophenyl) -3-bromopropene-1, m.p. = 128 C.

Example D

58.9 g of Z1- (2,4-dichlorophenyl) -2- (4-chlorophenyl) -3-bromopropene-1 (cf. Example A) were boiled with 52.3 g of 3-chloroperoxybenzoic acid in 590 ml chloroform at reflux. After completion of the reaction, the chloroform phase was washed with aqueous sodium hydrogencarbonate solution and acidified with water, dried over sodium sulfate and evaporated in vacuo. Two crystalline fractions were obtained from the residue with methanol: 1. 41.3 g (70.2%) of 2-bromomethyl-2- (4-chlorophenyl) -3- (2,4-dichlorophenyl) oxirane (isomer A), m.p. = 25-99 ° C and 2. 12 g (20.4%) of 2-bromomethyl-2- (4-chlorophenyl) -3- (2,4-dichlorophenyl) oxirane (isomer B), m.p.

= 93-95 ° C

II. Preparation of final products 30 Example 1

Solution containing 10 g of 2-bromomethyl-2- (4-chlorophenyl) -3- (2,4-dichlorophenyl) oxirane (isomer A) (cf. Example D) in 50 ml of N, N-dimethylformamide , was dropped at 100 ° C into a melt containing 15.6 g of imidazole with 1.37 g of sodium methylate, from which the liberated methanol h 77660 was first allowed to distill off. After 8 hours, the reaction solution was added to water and extracted with ethyl acetate; the organic phase was washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on a silica gel column with methylene chloride / methanol (100: 2). The purified fractions were evaporated and crystallized from diisopropyl ether. 4.6 g (47.5%) of 2- (1H-imidazol-1-ylmethyl) -2- (4-chlorophenyl) -3- (2,4-dichlorophenyl) oxirane (isomer A) were obtained, m.p. . = 10 102-103 ° C.

Example 2 6.2 g of imidazole and 1.3 g of sodium hydride (50% dispersion in mineral oil) were added to 50 ml of Ν, Ν-dimethylformamide, and to this was added, at room temperature, a solution containing 12 g of 2-bromomethyl-2- ( 4-chlorophenyl) -3- (2,4-dichlorophenyl) oxirane (isomer B) (cf. Example D) and 5 g of potassium iodide in 50 ml of Ν, Ν-dimethylformamide. After 8 h, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and the solvent was evaporated in vacuo.

The residue was recrystallized from diisopropyl ether to give 9.4 g (82.5%) of 2- (1H-imidazol-1-ylmethyl) -2- (4-chlorophenyl) -3- (2,4- dichloro-phenyl) oxirane (isomer B), m.p. = 109 ° C.

Example 3 20.9 g of 1,2,4-triazole and 4.4 g of sodium hydride (50% dispersion in mineral oil) were added to 150 ml of Ν, Ν-dimethylformamide, and to this was added at room temperature a solution containing 39 , 2 g of 2-bromomethyl-2- (4-chlorophenyl) -3- (2,4-dichlorophenyl) oxirane (isomer A) (cf. Example D) and 16.6 g of potassium iodide in 150 ml of Ν, Ν- dimethylformamide. After 8 hours, work as in Example 2 to give 31 g (81.9%) of 2- (1,2,4-triazol-1-ylmethyl) -2- (4-chlorophenyl) -3 - (2,4-dichlorophenyl) oxy

II

is 7 7 6 6 0 roman (isomer A)), m.p. = 119 ° C.

According to Examples 1 and 2, the compounds shown in Table III were prepared or can be prepared.

16 77660 LP *

Cp - o tL p- cvi t «-

Ul ~ 1 2 m ^ 5 O h vo t- 10 77 7 -I -H O oo ru \ l J _ 2 · I (H | Il

& 1- = 3-00 sr o VO

w r-lZ (22! I?! 7fn, ~ <ooc ^ '~ i' = rLnru m vo tv.

•B

n —I r — i (D o o m = = $ kk

W KK

• S <3: ‘: C <<’ = £ <c <cm «a: << c << i <« xca <i; o X ίΕ ^ K ϋΠ X 2 2 * £ ^ * T «-r · N 00000020020202 OO 2

M

M

H ^ - = r J3- 0 2 ^ 2 °° ro m ~ vo ’^ vo * Ä S 2 2 0 0

x> ° VO VO VO vO VO I I

3 s: 2 2 nf3- 2 2 0 “00 ro ro _j« i- II EC III = = I 1 __ 3 7 ° O- 'O r -i ° pj pj cm vo vo pjpjmm ni ι772 ΓίΓ ^^ 00 r -ι rH = rc e-ι ._ 'i2 00011 0000 m - ^ 7 iip -F' 1 1 I Ή .H ΙΛ IA II w

® ~ 7 - = 3 - = - 00 = = ^^ - OO

-; -. O ^ ww ^ otMtMNcjuo c \ J pj rrjs- m

VO

= ^ = r - = ro = 5- ix _ _ 2 2 '* 2 1 2 2 1 7 »tT ^ r- ^ 0 ^ mmmmmm ^ vo ~ vo 1,' -J1> —I oo -— *, - -, —v. .___ Cj q <u ί ^ ^ l = ^ = ^ = ^: 70 ^ -00 i '7 7 ^ 7 7 7 = ^ = °°° u O ooooo - ^^ ro- ^ roj ^^ rooocjoooo = r ^ r ε tn i-ι ^ rinvot ^ ooc7 \ 0 ^ pjm = TLr \ vot— cocpo

WC —If — I t— (r-t p-l r-H 1 — t r- <1— <· - <(\ J

17 77660 l 5 S £ 5 5 2 C «

*B

jj r

g ^ Ή rH

ffi o o g

In ® * x • S ä: <!: m <3: <£ <<<< «i'e: <<<« a; rs; <<<<

Q

££ 5 “ίΐί ^ T- W * k - ^ - H, ---, N u ~ zzuzuzozz5z: oz555z * aTaT, I ys ^ vO vo vo cc sc vO - j— - - ^ _f * · J = 3 · Oo vo voo cc sTsc re - __ · _, Ϊ · ^ *** IIOOI vo VO v £> VO -T- * r * t-

-, ™ ™ 00 VO VOfMCMi I CM O O O O sc VO ~ vO

ϋ Π π n I V rl ri ΓΟγΗ I I I I VO O O

1 loo - sco mrnmm ο ι i

Sw '* * * I rH rH I I O O I Cx * [x * Cx * Γχ. t p. \ _,. , 7 ^ "=; ^^^« ^ ooiooou sc1 * "pi. ö x ^ u cc ^ CMrMCMe-irCMOJori ^ CMA ^ rOOOO ^^ r ^ -O0 ^ -

- = y - = y. = r ΠΠ K

Γ ° vo vo vo vo ^ o o o o

r> ° I I I I

<-> mmmm— rr - I ^ —-, ^ C ► £ »y»> -3 "" ", ™, Jri.J ''"> 00 no vo vo vo vo “vo

jH SC Χ CC CC O O OO O

o o O O O I ι || I

= _T, -, TO S 5 s 5 5 a ^ Ö Ö a ^ aTa ^ o rJSSgiiiJ-ii i u ^ u ^ i 5 ° 5 ° 0 °

£ 0 HU

wc ^ n !! Tl? 'l ^ y: 5N®iJ'0H ™ tocir \ voscc is W CMCMCMCMrvJrvjrvirvirvirvirorrvrooommmnn) mo ~, 77660 1.8 —I ΟυΛΟΟΟ— CVVOt-HCTrOOOnO rH LTV LPv LPi f— O <—I VO r — I rH rH CO 00 OJ rH rH OVI CV C 00 t—

O r ~~ ^ 1 “H r-H r-H i ~ H r-H rH r — i rH C \ J Oj r-H 1J" j rH Γΐ | 1tt | 1 "H Oj rH

1—1 lllllll lllllflinljl I II

voonLnLrvojLr \ - = xovLnovOoo "C co hh on - = 3- com Λ O VC <—I rH ι — II I — II — If— 00 ι-HI I-H0 on o—

f — I r-H r-H r-H r-H r-H rH r-H f-H OJ OJ rH X r-H rX «Mr r-H OJ rH rH

• H I

I I

3

tg <<<<<<< CD <CQCD << CCCCC1 <CQ <C

•B

a

CC CD DC X CD XX

IS! XXXXXXOOOXXXOOXX O O XX

• = r - = r - - <· - = 0- = 7-.3-.3- x x -3- x xxx = r x x x x x x

vo VOX VO VO vO VOX VO vO vO vO vO vO

O O VO O O O O VO O O O O O o

I I O I I I I O I I I I I

LTV r-H LISrH IL.S-.OC.IC-C-. in ΙΑ ΙΛ ΙΛ H rH rHrH

xoxot = <cDcQcacQ & - <cacnxxxxo o oo

butter VOI I I I I I I I I vOvCvOvOl I II

CD 0-3-0-3-.3-.3-.3-.3-.3--3-.3-.3-0000-3- = r = r = r = Γ J3- = t - = r

X X X X

vO vO vO vO

O O O O

till on is on is on is mr-.

= r X xxxxXLpvirvLnLO

X VO VO vO vO vO vO X - X X

^ τνΟ- = Γ · = Γ · = Γ · = Γ ^ Τ · 3 · 0 -3- = Γ O O O O O vOvOvO VO

XOXXXXXXIXXI I I I IO o o o VO | VOVOvOVOvOvOOJvOVOOJOjCMOJrvll 1 I I

O LOO OOOOOrHOOrHf — lr — If — IrH OJ OJ OJ OJ

IXIIIIIIOIIOOOOOOOO O

Γ-HVOt-DrH ^ r-lr-llrHr-llllllWCOCO CO

OOCDCQOOOO = xOO = 3 -. = -. 3- = r.3-v- ^ - ^

I I I I I I I I ·> I I ..... I I I I

<HT ^ rHa- ^ T ^ r ^ r ^ r ^ -ojc- ^ roviojoviojOj ^ r = t - = r -3- • 5 § r-HOjon ^ rmvoo-oocT \ OrHOJoncLrNvoo ~ x xv o C ^^ j ^ j - ^^^ jiAiniTiinini ^ iniri u "\ un vo i9 77660 l \ fi *

*B

$ m

Q

to soosozozozSzGzoz 5 2 o 2 on m mm mm K Ä 2 2 2 2

VO VO VO VO vO VO

ην0ηΰην0ην0η '° „Λ CNJCMvOVOCMCMvDvOCMCM vOvO

1.00 1.00 1 I

ΗΙιΗΙ 1 t- E- ι I in in t- t_

2 -L _ _L _L -IJ, "* 11 • '“ It - ^ VO VO I I

^ · = Τ - ~. - = ^ - mmmm - - = r cm cm. = r. = r m cm o o - = t - m m vo vo - = r -3 · 0 0 2 2 sr I I VO VC 2 2

^ ^ O O VO VO

_2 * _ mm Ο ο ι ι o o 2 _ 2 ~ 2 2. = R it ι i m m ι ι ro ° - * -_ vo vo2 2 cm cm.—. . j —f3 "23- 23- 23- oo vo vo 2 2 mm2 2 in m L. V - tE I 1000022 vO VO 2 2

rH ini3 ° r ^ t ^ r ^ CMC ^ IIIIOOOO vOvO

fi .J · ^ S5 ^ -? S * * -? <-t ri mmoo ^ - ^ - 'i ι oo' 1 1 1 oo22w- ^ oo mmi ι -i HH h mini loo ι ι ι 12 2 0 0 - CT> S> (^^> 022mmoo ^ r ^ rooo 0 ^> - <: cm - cm pj io ° o ° mmcMCMmmJ- ^ rJ- ~ ^ - e 0 S «5ϊ2ϊϊϊ £ ϊ2 £ ίίϊί: ίϊ” ί ϊ £ g 2o 776 6 0 7? O cd mo -P oj o · = τ cd o υ ^ · —i · —i <—i cm 1—1 il lii • LPirH in in O N- CM o oo O, ^ '-i O - = ro - = rm σ%

Ui rHr-t —I r-1, H r-1.-H, H, -1

B

$ ω 3 << «t <« a: <cd <<- s 1 -3

- v- O

M 02: 02: 02020202u «3 <d m

P

Q>

-P

a; ai n-00 Γ ° mo o _ a: o Ό

‘IO VO I O

X X O O · = Γ · 5Γ · = τ ^ τοη ^ Γ 3 vo vo il x x χ χ ^ -v χ g

M-3 VJ CMCMt— t— VO VO VO VO m VO

lliHrHXXOOOOXo IÖ r-Pr-PP P ° ° 1 1 <I ° I +>

- ^^^ r ^ roOOOOOOCQD: <N

m Λ 1 '- ~ I I I I I I I I vo -H

X - -ΞΧ CM CM i— (r — 1 ar -ΞΓ j3 * 3 υ 3 03 03

G

3, * ~ Γη „ΡΓ1

MO ~ MO -H

2 = τ · = τ · = Γ · = - O O -, η X a: a: X ι ι x o

C ~ “l MO VO VO MO C— CM CM VO O

= ~ OOOOXXr-lrHO g

OOl I I I OOOOI

in in <-h r-i r-ι rH · - <r- <r-ι.-ι ι I Li cm. X X Ο Ο Ο Ο Ο Ο Ο Ο · = τ - = r CQ \ r-P I I I I I I I I '' • 'I r- <

OocMCM-3--3 -. = R. = Rcii (MCMm. = R - §S '- ^ CMm-TinMOt'-OOCNO'HCMcn

uj G cooocooooooocooooocnoNaNON

Claims (1)

21 77660 Claim A process for the preparation of new therapeutically useful azolylmethyloxiranes having the same or different and wherein A and B are the same or different and mean independently an alkyl group having 1 to 4 carbon atoms or a naphthyl, biphenyl or phenyl group, the phenyl group being in each case a substituent of alkyl, alkoxy and haloalkyl groups having 1 to 4 carbon atoms, and halogen, nitro and phenylsulfonyl groups , Z represents a CH group or a nitrogen atom, and for the preparation of their physiologically tolerable salts, characterized in that the compound of the formula II 20 A L-CH - C-CH-B II 2. i O 25 in which A: 11a and B has the meanings given above and L represents a nucleophilically displaceable leaving group, is reacted with a compound of formula III f == rZ \ I N-Me III wherein Me represents a hydrogen atom or a metal atom and Z is a CH group t ai nitrogen atom, and if desired the compounds thus obtained are converted into their salts with physiologically acceptable acids.