GB2146987A - Azole derivatives process for their production compositions containing them and their use - Google Patents

Azole derivatives process for their production compositions containing them and their use Download PDF

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GB2146987A
GB2146987A GB08423710A GB8423710A GB2146987A GB 2146987 A GB2146987 A GB 2146987A GB 08423710 A GB08423710 A GB 08423710A GB 8423710 A GB8423710 A GB 8423710A GB 2146987 A GB2146987 A GB 2146987A
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chlorophenyl
hydrogen
hydroxy
cyclopropane
ethyl
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Helmut Egger
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Sandoz AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/50—1,3-Diazoles; Hydrogenated 1,3-diazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
    • A01N43/647—Triazoles; Hydrogenated triazoles
    • A01N43/653—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/004—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with organometalhalides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
    • C07C49/813—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/08—Compounds containing oxirane rings with hydrocarbon radicals, substituted by halogen atoms, nitro radicals or nitroso radicals

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Abstract

A compound of formula I <IMAGE> wherein R1 and R2, independently, are hydrogen, halogen, nitro; or unsubstituted or mono- or poly-halogen substituted lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy or lower alkylthio; or unsubstituted or substituted phenyl or phenoxy, R3 is hydrogen or lower alkyl, R4 and R5, independently, are hydrogen or halogen, Y is CH or N, A is a C2-7methylene bridge and n is 0 or 1, in free base form or in the form of an acid addition salt or a physiologically-hydrolysable and -acceptable derivative, which compounds are indicated for use as chemotherapeutic agents e.g. as anti-mycotics and in addition as fungicides.

Description

SPECIFICATION Azole derivatives, process for their production compositions containing them and their use The present invention concerns azole derivatives, a process for their production, pharmaceutical compositions containing them and their use as pharmaceuticals, e.g. as anti-mycotics and as agrochemicals e.g. as fungicides.
In particularthe invention concerns compounds of formula I
wherein R1 and R2, independently, are hydrogen, halogen, nitro or unsubstituted or mono- or poly-halogen substituted lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy or lower alkylthio or unsubstituted or substituted phenyl or phenoxy, R3 is hydrogen or lower alkyl, R4 and R5, independently, are hydrogen or halogen, Y is CH or N, A is a C2-7 alkylene bridge and nisOori, in free base form or in the form of an acid addition salt or a physiologically-hydrolysable and acceptable derivative.
By the term "physiologically-hydrolysable and -acceptable derivative" is meant e.g. an ester of a compound in accordance with the invention in which the hydroxy moiety is esterified, and which is hydrolysable under physiological conditions to yield in the case of an ester, an acid which is itself physiologically acceptable, e.g. non-toxic at desired dosage levels.
Lower alkyl moieties appearing in or as substituents preferably contain 1 to 5, especially 1 to 3 carbon atoms, lower alkenyl and alkynl preferably 2 to 5 especially 2 or 3. Halogen stands for F, Cl, Br or I. Examples of halogenated groups as R1 and R2 are mono-, di- ortri-substituted groups such as CF3, CH2CI, C2H5CI, CBr=CH2; OCHF2, SCF3, CCBr, CIC6H4, Cl2C6H30. Examples of suitable unsubstituted groups as R1 and R2 are H, halogen, CH3, C2H5, CH=CH2, C-CH, OCH3, SCH3, C6H5, C6H50, NO2.
The compounds of formula I and their acid addition and physiologically-hydrolysable and -acceptable derivatives may be prepared according to the invention by reacting a compound of formula II
with a compound of formula Ill
wherein R1 to R5, Y, m and n are as defined above and M is hydrogen, a metal, or a trialkylsilyl group, and isolating the compound thus obtained in free base form or in the form of an acid addition salt or physiologically-hydrolysable and -acceptable derivative.The reaction may be carried out in conventional manner for example by treating a compound of formula lli wherein M is hydrogen dissolved in a solvent inert under the reaction conditions e.g. dimethylsulfoxide, with sodium hydride and then adding the oxirane of formula II preferably dissolved in the same solvent and stirring the mixture at room temperature.
Examples of metals as M are alkali metals such as sodium, trialkylsilyl is for example trimethylsilyl.
The desired end product can be isolated and purified in conventional Manner and recovered in free base form or in the form of an acid addition salt or physiologically-hydrolysabie and -acceptable derivative.
SCHEME I SCHEME III SCHEME II
Free base forms and other forms such as salt and e.g. ester forms can also be interconverted in conventional manner The starting materials of formula II are new and can be prepared for example according to the reaction schemes 1,2 and 3 which are carried out in conventional manner e.g. as described in the examples. The products may be isolated and purified in conventional manner or directly further reacted, as appropriate.
Remaining intermediates are either known or may be prepared analogously to known methods and/or analogously to the examples hereinafter.
The compounds of formula I exhibit chemotherapeutic, in particular local and peroral anti-mycotic activity as indicated in vitro on families and species of mycetes e.g. Trichophyton, Aspergillus, Microsporium, Sporothrix and Candida in serial dilution tests and in the germ tube inhibition test (C. albicans) at concentrations of 1.5 to 100 Fg/ml and 0.05 Fg/ml respectively and in vivo in the experimental genital mycosis model in mouse and rat e.g. on peroral administration at between ca. 3 and 25 mg/kg animal body weight The compounds are therefore indicated for use as pharmaceuticals particularly an anti-mycotics.
An indicated suitable daily dosage for use as an anti-mycotic is from about 20 to 1500 mg. If desired this may be administered in divided doses 2 to 4times a day in unit dosage form containing from about 5 to 750 mg of the compound or in sustained release form.
The compounds may be used in free base form or in the form of chemotherapeutically acceptable acid addition salts e.g. as the hydrochloride, hydrogen fumarate or naphthalin-1 ,5-disulphonate or in the form of a physiologically-hydrolysable and -acceptable derivative preferably an ester. Such forms exhibit the same order of activity as the free base forms.
The compounds may be admixed with conventional chemotherapeutically acceptable diluents and carriers, and, optionally other excipients and administered orally, topically, i.v. or parenterally in such forms as tablets, capsules, creams, tinctures or injectable preparations.
Such compositions also form part of the invention.
The invention therefore also concerns a method of combatting infections and diseases caused by mycetes comprising administering to a subject in need of such treatment an effective amount of a compound of formula I in free base form or in the form of a chemotherapeutically acceptable acid addition salt or physiologically-hydrolysable and -acceptable derivative thereof, and such compounds for use as chemotherapeutic agents, in particular as anti-mycotic agents.
The compounds of the invention in free form or in agriculturally acceptable salt or metal complex form are also suitable for combatting phytopathogenic fungi. This fungicidal activity can be demonstrated i.a. in in vivo tests against Uromyces appendiculatus (bean rust) on runner beans as well as against other rust fungi (e.g. Hemileia, Puccinia) on coffeee, wheat, flax and ornamentals (e.g. pelargonium, snapdragon); and against Erysiphe cichoracearum on cucumber as well as against other powdery mildews (e.g. E. Graminis f.
sp. tritici. E. gram. f. sp. hordei, Podosphaera leucotricha, Uncinula recator) on wheat, barley, apple and vines.
Preferred substituent meanings are R1 and R2, independently, = a) hydrogen b) halogen especially for Cl or c) one hydrogen the other halogen especially F or Cl, R3 = a) hydrogen b) alkyl, R4 and R5, independently, a) hydrogen b) halogen especially F or Cl or c) one hydrogen the other halogen especially F or Cl, Y = a)N b) CH A = a) a C2, 4 or 6 alkylene bridge b) ethylene or butylene n = a)O b) 1.
Free base and acid addition salt forms are preferred.
Especially preferred are combinations of the above mentioned substituent meanings.
A particular compound group is that comprising compounds of formula I wherein R1 and R2, independently, are hydrogen, halogen, nitro or optionally halogenated lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy or lower alkylthio or optionally substituted phenyl or phenoxy, R3 is hydrogen or alkyl, R4 is hydrogen or halogen, R5 is halogen, Y is CH or N A is a C27 alkylene bridge and n is O or 1, in free base form or in the form of an acid addition salt.
Another compound group is that wherein R1 and R2 are hydrogen or halogen, B3 is hydrogen, R4 and R5 are hydrogen or halogen andY, A and n are as defined above.
Within this group halogen is preferably F or Cl and one each of R1 and R2, and R4 and R5 is hydrogen.
In this case halogen is preferably para-positioned.
A preferred compound is I-[l-(4-chlorophenyl)-l-hydroxy-2-(IH-l ,2,4-triazol-l-yl)ethyl]-l-(4- fluorophenyl)cyclopropane in free base form or in the form of an acid addition salt or physiologicallyhydrolysable and -acceptable derivative.
The following examples illustrate the invention, tempeatures being in degrees centigrade.
EXAMPLE 1 1-Ji (4-Chiorophenyl)- 1-hydroxy-2-( 1K- 1,2,4triazol- 1-yI)ethyli- 1 (4-chlorophenyl)cyclopropane A solution of 1.81 g of 1,2,4-triazole in 20 ml of abs. dimethylsulfoxide is mixed, under argon atmosphere with stirring and ice-cooling, with 0.63 g of sodium hydride (ca. 50% dispersion in mineral oil) and then allowed to warm up to RT within 1 hour. To this is added a solution of 0.8 g of 2-[l-(4 chlorophenyl)]cyclopropyl-2-(4-chlorophenyl)oxirane in 5 ml of abs. dimethylsulfoxide and stirred for 24 hours at RT. For working-up the reaction mixture is poured into saturated sodium chloride solution and extracted with ethylacetate and the organic phase dried over sodium sulphate and evaporated.The crude product is dissolved in a little dichloromethane and diluted with ether to obtain colourless crystals m.p.
103-106 .
The following compounds may be prepared analogously to Example 1 or as otherwise hereinbefore described.: Ex. R1 R2 R3 R4 R5 Y A=(CH2)m n physico-chemical m characteristics 2 4-CI H - H 4-CI CH 2 0 mp.194-198 3 4-CI H - H 4-CI N 4 0 mp.127-135 4 4-CI H - 4-CI CH 4 0 mp.155-160 5 4-CI H H H 4-CI N 2 1 mp.140-150 6 4-CI H H H 4-CI CH 2 1 mp.183-185 7 4-CI H H H 4-CI CH 4 1 mp.169-172 8 4-CI H - H 2-F N 2 0 mp.12 9 4-F H - H 4-F N 2 0 mp.103-105 10 4-CI H - H 4-F N 2 0 mp.125 11 H H - H H N 2 0 mp.185-187 The required starting materials may be prepared as follows:: A) 2-f l-(4- Chlorophenyl)Jcycloprop yl-2-(4-chlorophen yl)oxfrane (for examples 1and2) a) 1-(4-Chlorophenyl)cyclopropane nitrile 30 g of 4-Chlorobenzylcyanide are dissolved in 300 ml of a mixture of dry tetrahydrofurane and dimethylsulfoxide (111) cooled to 10 and reacted with stirring with 79 g of dry pulverised (ball-mill) sodium hydroxide. 37.1 g of 1,2-dibromoethane are added dropwise to this mixture with thorough stirring in such a way that the temperature does not exceed 15 . On completion the mixture is stirred for 45 minutes at RT and then poured into saturated sodium chloride solution and extracted with ethylacetate. The combined ethylacetate phases are washed with NaCI solution, dried over sodium sulphate and concentrated under vacuum.The residue is vacuum destilled, b.p.92-94 /1.33 Pascal. The product commences to crystalise in the cooler m.p.42-45 .
b) 1-(4-Chlorobenzoyl)-1-(4-chlorophenyl)cyclopropane A Grignard solution is prepared in conventional manner from 54.9 g of 4-bromochlorobenzene and 7.5 g of magnesium turnings in abs. ether. To this are added dropwise 17 g of 1-(4-chlorophenyl)cyclopropannitrile and the mixture then refluxed for 2 hours. The reaction mixture is carefully mixed under cooling with half its volume of 6N HCI and refluxed for 3 hrs. to hydrolyse the ketimine formed. Working-up is carried out by dilution with NaCI solution, extraction with ethylacetate, evaporation and chromatography on silica gel 60 (petroleum ether/ether:10/1). A colourless oil results which according to TLC and NMR is uniform.
NMR (CDCl3): 1.25 and 1.68 (each 2H, m, CH2); 7.18 (4H, m); 7.25 (2H, m); 7.70 (2H,m).
c) l-(4-Chlorophenyl)- l-fl-(4-chlorophenyl)- 1-hydroxy-2-phenylthio]ethyl-cyclopropane A solution of 7.46 g of thioanisole and 6.74 g of 1 ,4-diazabicyclo-[2,2,2]octane ("DABCO") in 40 ml of dry tetrahydrofuran is cooled to 0 and under argon atmosphere slowly mixed with a solution of 3.85 g of n-butyllithium in n-hexane. The mixture is allowed to warm to RT and stirring continued for 40 mins. The mixture is again cooled to 0 , a solution of 7 g of 1-(4-chlorobenzoyl)-1-(4-chlorophenyl)cyclopropane in 40 ml drytetrahydrofuran added dropwise with stirring and after removal of the cooler stirring continued for 45 mins.Working-up is carried out by pouring in ice-cold NaCI solution, extraction with ethylacetate, evaporation and chromatography on silica gel 60 (toluene/petroleum ether:1/1). A colourless oil results which according to TLC and NMR is uniform.
NMR (CDCl3): 0.63 and 1.30 (each 2H, m, cyclopropane-CH2); 3.04 (1H, s, OH); 3.42 and 3.83 (each 1 H, AB-q, J = 13, 1Hz, -SCH2); 6.8-7.4 (13H, m, aromatics).
d) 2-[1-4-chlorophenyl) cyclopropyl]-2-(4-chlorophenyl)oxirane 8 g of 1-(4-chlorophenyl)-1-[1-(4-chlorophenyl)-1-hydroxy-2-phenylthio] ethylcyclopropane are dissolved in 30 ml of dry dichloromethane and reacted with 9.1 g of triethyloxonium fluoroborate by stirring at RTfor 3 hours. Then an equal volume of 0.5N sodium hydroxide was added and the mixture stirred overnight.
Working-up is carried out by separating phases, removal of solvent and the residue chromatographed on silica gel 60 (toluene/petroleum ether:1/1). A colourless, viscous mass results which according to TLC and NMR is uniform.
NMR (CDCl3): 0.7-1.25 (4H, m, cyclopropane); 2.92 and 3.10 (each 1H,AB-a,J=5.4Hz, -CH2O); 7.0-7.3 (8H, m, aromatics).
B) 2-Ji- (4-Fluorophen yl)cycloprop yl]-2- (4-chlorophen yl)oxfrane (for example 10) a) 1-(4-Chlorobenzoyl)-1-(4-fluorophenyl)cyclopropane A Grignard solution is prepared in conventional manner from 45.2 g 4-bromochlorobenzene and 6 g of magnesium turnings in abs. ether. Upon completion of the reaction by 1/2 hr. refluxing 6 g of abs. pyridine and then 12.7 g of 1-84-fluorophenyl)cyclopropannitrile are added dropwise with stirring. The mixture is refluxed for 2 hours, carefully mixed under ice cooling with 250 ml of 6N HCI and refluxed for 3 hours to hydrolyse the ketimine formed. Working-up is carried out by dilution with NaCI solution, extraction with ethylacetate, evaporation and chromatography on silica gel 60 (toluene/petroleum ether: 60-80 1/1). A colourless oil results which according to TLC and NMR is uniform.
NMR (CDCl3): 1.33 and 1.66 (each 2H, m, cyclopropane); 6.85-7.35 (6H, m, aromatics); 7.60-7.75 (2H, m, aromatics).
b) l-(4-Fluorophenyl)- l-fl-(4-chlorophenyl)- 1-hydroxy-2-phenylthio]ethyl-cyclopropane Analogously to A). The compound is employed in next step without further purification.
c) 2-Jl-(4-Fluorophenyl)cyclopropylj-2-(4-chlorophenyl)oxirane Analogously to A).
NMR (CDCl3): 0.6-1.2 (4H, m, cyclopropane); 2.88 (1 H, d, J=5,4 Hz) and 3.08 (1 H, d, J=5,4 Hz, -CH2O); 6.8-7.3 (8H, m, aromatics).
C) 2-[1-(4-Chlorophenyl)cyclopentyl]-2-(4-chlorophenyl)oxirane (for Examples 3 and 4) Analogous to A) or B).
a) 1-(4-Chlorophenyl)cyclopentanenitrile Colourless oil bp: 6'/1 .33 Pascal (purity HPLC 99%).
NMR (CDCl3): 1.8-2.6 (8H, m); 7.3-7.5 (4H, m).
b) 1-(4-Chlorobenzoyl)-1-(4-chlorophenyl)cyclopentane NMR (CDCI3): 1.6-2.6 (8H, m); 7.15-7.40 and 7.52-7.65 (together8H, m).
c) l-(4-Chlorophenyl)- l-[l-(4-chlorophenyl)- 1-hydroxy-2-phenylthio]ethyl-cyclopentane NMR(CDCl3(: 1.2-2.3 (18H, m); 3.22(1 H, s, OH); 3.28 and 3.83 (each I H, AB-q, J--13Hz); 6.9-7.3 (13H, m).
d) 2-[1-(4-Chlorophenyl)cyclopentyl]-2-(4-chlorophenyl)oxirane NMR (CDCl3): 1.5-2.05 (8H, m); 2.74 and 3.27 (each 1H,AB-q,J=5Hz); 6.746.79 (2H, m); 7.06-7.27 (6H, m).
D) 2-[1-(4-Chlorophenyl)cyclopropyl]-2-(4-Chlorobenzyl)oxirane(for Exs.5 and 6) a) 1-(4-Chlorobenzoyl)-1-(4-chlorophenyl)cyclopropane A Grignard solution is prepared in conventional manner from 14.4 g of 4-bromochlorobenzene and 2 g of magnesium turnings in 100 ml of abs. ether. 6.9 g of pulverised cadmium chloride are added and the mixture refluxed for 1 hour. The ether is replaced by 100 ml of dry benzene and a solution of 15 g of 1-(4-chlorobenzyl)cyclopropane-carboxylic acid chloride in 20 ml of benzene is added in one lot at 60. The resulting mixture is refluxed for one hour, poured into ice-cold ammonium chloride solution and extracted with ethylacetate. The organic phase is washed successively with 2N HCI and saturated sodium hydrocarbonate solution, dried over sodium sulphate and evaporated.Chromatography on silica gel 60 (toluene) yields colourless crystals of the title compound m.p. 92.93 .
Steps b) and c) are carried out analogously to A) or B).
b) 1-(4-Chlorophenyl)- l-[l-(4-chlorobenzyl)- 1-hydroxy-2-phenylthio]ethyl-cyclopropane cJ 2-[ l-(4-Chlorophen yl)cycloprop ylJ-2- (4-chlorobenzyl)oxfrane Colourless oil.
E) 2-[1- (4- Chlorophen yl)cyclop entylj-2- (4-chlorobenzyl)oxfrane (for Example 7) a) 1-(4-Chlorobenzoyl)-1-(4-chlorobenzyl)cyclopentane 5 g of 4-Chloro-3-(4-chlorophenyl)propiophenone are dissolved in 50 ml of a mixture of dry tetrahydrofuran and dimethylsulphoxide (1/1) cooled to 0 and mixed with stirring with 7 g of pulverised (ball-mill) sodium hydroxide. 3.86 g of 1.4-dibromobutane in 5 ml of dry tetrahydrofuran are added with thorough stirring at 09.
After removal of the cooling bath the mixture is stirred for a further 40 minutes, then poured into sat. NaCI solution and extracted with ethylacetate. The combined organic phases are washed with sodium chloride dried over sodium sulphate and concentrated under vacuum. The residue is chromatographed on silica gel 60 (toluene/petroleum ether: 4/1). The title compound is isolated from the second main fraction as a colourless oil.
NMR (CDCl3): 1.6-2.4 (8H, m); 3.15 (2H, s); 6.8-7.8 (8H, m).
Steps b) and c) are carried out analogously to A) or B).
b) 1-(4-Chlorophenyl)-1-[1-(4chlorobenzyl)-1-hydroxy-2-phenylthio]ethyl-cyclopentane Colourless oil c) 2-fl-(4-Chlorophen yl)cycloprop ylj-2-(4-chlorobenzyl)oxfrane The oily crude product is reacted without further purification.
F) 2-[1-(4-Chlorophenyl)cyclopropyl]-2-(2-fluorophenyl)oxirane (for Example 8) Analogously to A) or B).
a) 1-(2-Fluorophenyl)cyclopropanenitrile bp: 66 /13.33 Pascal NMR (CDCl3):1.40 and 1.69 (each 2H, m, cyclopropane); 7.05-7.4 (4H, m, aromatics).
b) 1-(4-Chlorobenzoyl)-1-(2-fluorophenyl)cyclopropane NMR (CDCl3): 1.35 and 1.80 (each 2H, m, cyclopropane); 6.8-7.6(8 H, m, aromatics).
c) 1-(2-Fluorophenyl)-1-[1-(4-chlorophenyl)-1-hydroxy-2-phenylthio]ethyl-cyclopropane NMR(CDCl3): 0.50-0.85 (2H, m. cyclopropane); 1.34 (2H, m, cyclopropane); 3.10(1H,s,-OH); 3.50 and 3.96 (each 1H,dq,J=13.5 Hz and 1.8 Hz, -SCH2); 6.8-7.3(13H, m, aromatics).
d) 2-[1-(4-Chlorophenyl)cyclopropyl]-2-(2-fluorophenyl)oxirane NMR (CDCl3): 0.55-1.15 (4H, m, cyclopropane); 2.93 (1H, d, J =5.4 Hz); 3.14(1 H, dd, J =5.4 and 2.0 Hz, -CH20); 6.9-7.2 (8H, m, aromatics).
G) 2-[1-(4-Fluorophenyl)cyclopropyl]-2-(4-fluorophenyl)oxirane (for Example 9) Analogously to A) or B).
a) 1-(4-Fluorophenyl)cyclopropannitrile bp: 66 /13.33 Pascal NMR (CDCl3): 1.35 and 1.70 (each 2H, m, cyclopropane); 7.0-7.4 (4H, m, aromatics).
b) 1-(4-Fluorobenzoyl)-1-(4-fluorophenyl)cyclopropane NMR (CDCl3): 1.30 and 1.66 (each 2H, m, cyclopropane); 6.8-7.85 (8H, m, aromatics).
c) 1-(4-Fluorophenyl)-1-[1-(4-fluorophenyl)-1-hydroxy-2-phenylthio]ethyl-cyclopropane NMR (CDC13): 0.48-0.85 (2H, m, cyclopropane); 1.32 (2H, m, cyclopropane); 3.07 (1 H, s, -OH); 3.43 and 3.86 (each 1H,AB-q,J=13.1 Hz, -SCH2); 6.8 - 7.3 (13H, m, aromatics).
d) 2-Ji-(Fluorophen yl)cycloprop ylj-2-(4-fluorophen yl)oxfrane NMR (CDCl3): 0.6-1.2 (4H, m, cyclopropane); 2.90 (1 H, d, J=5.4 Hz); 3.08 (1 H, d, J=5.4 Hz, -CH2O); 6.8-7.3 (8H, m, aromatics).

Claims (17)

1. A compound of formula I
wherein R1 and R2, independently, are hydrogen, halogen, nitro or unsubstituted or mono- or polyl-halogen substituted lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy or lower alkylthio or unsubstituted or substituted phenyl or phenoxy, R3 is hydrogen or lower alkyl, R4 and R5, independently, are hydrogen or halogen, YisCH or N, A is a C2-7 alkylene bridge and n is 0 or 1.
2. A compound according to Claim 1 wherein R1 and R2, independently, are hydrogen, halogen, nitro or optionally halogenated lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy or lower alkylthio or optionally substituted phenyl or phenoxy, R3 is hydrogen or alkyl, R4 is hydrogen or halogen, R5 is halogen, Y is CH or N A is a C2-7 alkylene bridge and n is 0 or 1.
3. A compound according to Claim 1 wherein R1, R2, R4 and R5, independently, are hydrogen or halogen, R3 is hydrogen.
4. A compound according to Claim 3 wherein R1 and R4 are hydrogen.
5. A compound according to Claim 4 wherein R2 and R5 independently are F or Cl.
6. A compound according to Claim 5 wherein R2 and R5 are in para-position.
7. A compound selected from 1-[1(4-chlorophenyl)-1-hydroxy-2-(1H-1,2,4-triazol-1-yl)ethyl]-1-(4-chlorophenyl)cyclopropane; 1-[1(4-chlorophenyl)-1-hydroxy-2-(1H-1,3-imidazol-1-yl)ethyl]-1-(4-chlorophenyl)cyclopropane; 1-[1(4-chlorophenyl)-1-hydroxy-2-(1H-1,2,4-triazol-1-yl)ethyl]-1-(4-chlorophenyl)cyclopentane; 1-[1(4-chlorophenyl)-1-hydroxy-2-(1H-1,3-imidazol-1-yl)ethyl]-1-(4-chlorophenyl)cyclopentane; 1-[1(4-chlorophenyl)-1-hydroxy-2-(1H-1,2,4-triazol-1-yl)ethyl]-1-(4-chlorobenzyl)cyclopropane; 1-[1(4-chlorophenyl)-1-hydroxy-2-(1H-1,3-imidazol-1-yl)ethyl]-1-(4-chlorobenzyl)cyclopropane; 1-[1(4-chlorophenyl)-1-hydroxy-2-(1H-1,3-imidazol-1-yl)ethyl]-1-(4-chlorobenzyl)cyclopentane; 1-[1(4-chlorophenyl)-1-hydroxy-2(1H-1,2,4-triazol-1-yl)ethyl]-1-(2-fluorophenyl)cyclopropane; 1-[1(4-fluorophenyl-1-hydroxy-2-(1H-1,2,4-triazol-1-yl)ethyl]-1-(4-fluorophenyl)cyclopropane.
8. 1 -[1 -(4-chlorophenyl)-1-hydroxy-2-(1H-1,2,4-triazol-1-yl)ethyl]-1-(4-fluorophenyl)cyclopropane.
9. 1-[1-(4-chlorophenyl)-1-1 hydroxy-2-(1H-1,2,4-triazol-1-yl)ethyl]-1-phenyl-cyclopropane.
10. A compound according to any one of Claims 1 to 9 in free base form.
11. A compound according to any one of Claims 1 to 9 in the form of an acid addition salt.
12. A compound according to any one of Claims 1 to 9 in the form of a physiologically-hydrolysable and -acceptable derivative.
13. A chemotherapeutical composition containing a compound according to any one of Claims 1 to 9 in free base form or in the form of a chemotherapeutically acceptable acid addition salt or physiologicallyhydrolysable and -acceptable derivative thereof.
14. A compound according to any one of Claims 1 to 9 in free base form or in the form of a chemotherapeutically acceptable acid addition salt or physiologically-hydrolysable and -acceptable derivative thereof, for use as a chemotherapeutic agent.
15. A compound according to any one of Claims 1 to 9 in free base form or in the form of a chemotherapeutically acceptable acid addition salt or physiologically-hydrolysable and -acceptable derivative thereof, for use as an anti-mycotic.
16. A process for preparing a compound according to Claim 1 acid addition and physiologicallyhydrolysable and -acceptable derivatives thereof which comprises reacting a compound of formula 11
with a compound of formula Ill
wherein R1 to R, Y, A and n are as defined above and M is hydrogen, a metal, or a trialkylsilyl group, and isolating the compound thus obtained in free base form or in the form of an acid addition salt or physiologically-hydrolysable and -acceptable derivative.
17. A compound of formula II according to Claim 16.
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US4767777A (en) * 1984-11-27 1988-08-30 Pfizer Inc. Triazole antifungal agents
WO1989005581A1 (en) * 1987-12-17 1989-06-29 E.I. Du Pont De Nemours And Company Antifungal carbinols
US4965280A (en) * 1986-06-23 1990-10-23 E. I. Du Pont De Nemours And Company Antifungal carbinols
US4965281A (en) * 1986-06-23 1990-10-23 E. I. Du Pont De Nemours And Cmopany Antifungal carbinols
US4980367A (en) * 1987-12-17 1990-12-25 E. I. Du Pont De Nemours And Company Antifungal carbinols
EP0409049A2 (en) * 1989-07-18 1991-01-23 BASF Aktiengesellschaft Method for the stereoselective production of Z-1,2-diaryl-alkyl-chlorides and their conversion to azolylmethyloxiranes as well as intermediates
US5084465A (en) * 1986-06-23 1992-01-28 Du Pont Merck Pharmaceutical Company Antifungal carbinols
US5268517A (en) * 1989-07-14 1993-12-07 Basf Aktiengesellschaft Stereoselective preparation of Z-1,2-diarylallyl chlorides and the conversion thereof into azolylmethyloxiranes, and novel intermediates
US6858627B2 (en) 2002-08-21 2005-02-22 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US6903215B2 (en) 2002-03-26 2005-06-07 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US6960581B2 (en) 2002-01-14 2005-11-01 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical formulations, and uses thereof
US7074806B2 (en) 2002-06-06 2006-07-11 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7186864B2 (en) 2002-05-29 2007-03-06 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7268152B2 (en) 2002-03-26 2007-09-11 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7507843B2 (en) 2003-10-16 2009-03-24 Boehringer Ingelheim Pharmaceuticals, Inc. Stereoselective synthesis of certain trifluoromethyl-substituted alcohols
US7579469B2 (en) 2003-01-03 2009-08-25 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
WO2009150660A1 (en) * 2008-06-13 2009-12-17 Reliance Life Sciences Pvt. Ltd. A process for the preparation of arylcyclopropane carboxylic carbonitriles, and compounds derived therefrom
US7635711B2 (en) 2004-12-27 2009-12-22 Boehringer-Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
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US8741897B2 (en) 2003-09-24 2014-06-03 Boehringer Ingelheim Pharmaceuticals Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof

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DE3644615A1 (en) * 1986-12-29 1988-07-07 Lentia Gmbh IMIDAZOLE AND TRIAZOLE DERIVATIVES FOR USE AS AN ANTIMYCOTIC AGENTS

Cited By (29)

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US4767777A (en) * 1984-11-27 1988-08-30 Pfizer Inc. Triazole antifungal agents
US5084465A (en) * 1986-06-23 1992-01-28 Du Pont Merck Pharmaceutical Company Antifungal carbinols
US4965280A (en) * 1986-06-23 1990-10-23 E. I. Du Pont De Nemours And Company Antifungal carbinols
US4965281A (en) * 1986-06-23 1990-10-23 E. I. Du Pont De Nemours And Cmopany Antifungal carbinols
US4952232A (en) * 1987-04-29 1990-08-28 E. I. Du Pont De Nemours And Company Antifungal carbinols
US4980367A (en) * 1987-12-17 1990-12-25 E. I. Du Pont De Nemours And Company Antifungal carbinols
WO1989005581A1 (en) * 1987-12-17 1989-06-29 E.I. Du Pont De Nemours And Company Antifungal carbinols
US5268517A (en) * 1989-07-14 1993-12-07 Basf Aktiengesellschaft Stereoselective preparation of Z-1,2-diarylallyl chlorides and the conversion thereof into azolylmethyloxiranes, and novel intermediates
EP0409049A3 (en) * 1989-07-18 1991-10-30 Basf Aktiengesellschaft Method for the stereoselective production of z-1,2-diaryl-alkyl-chlorides and their conversion to azolylmethyloxiranes as well as intermediates
EP0409049A2 (en) * 1989-07-18 1991-01-23 BASF Aktiengesellschaft Method for the stereoselective production of Z-1,2-diaryl-alkyl-chlorides and their conversion to azolylmethyloxiranes as well as intermediates
US6960581B2 (en) 2002-01-14 2005-11-01 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical formulations, and uses thereof
US7189758B2 (en) 2002-01-14 2007-03-13 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical formulations, and uses thereof
US7553966B2 (en) 2002-03-26 2009-06-30 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US8212040B2 (en) 2002-03-26 2012-07-03 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and thereof
US6903215B2 (en) 2002-03-26 2005-06-07 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7932392B2 (en) 2002-03-26 2011-04-26 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7268152B2 (en) 2002-03-26 2007-09-11 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7186864B2 (en) 2002-05-29 2007-03-06 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7074806B2 (en) 2002-06-06 2006-07-11 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US6858627B2 (en) 2002-08-21 2005-02-22 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7579469B2 (en) 2003-01-03 2009-08-25 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US8741897B2 (en) 2003-09-24 2014-06-03 Boehringer Ingelheim Pharmaceuticals Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
US7507843B2 (en) 2003-10-16 2009-03-24 Boehringer Ingelheim Pharmaceuticals, Inc. Stereoselective synthesis of certain trifluoromethyl-substituted alcohols
US7795272B2 (en) 2004-03-13 2010-09-14 Boehringer Ingelheim Pharmaceutical, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
US7635711B2 (en) 2004-12-27 2009-12-22 Boehringer-Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7741361B2 (en) 2004-12-27 2010-06-22 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US8658637B2 (en) 2006-12-06 2014-02-25 Boehringer Ingelheim International Gmbh Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
US8268859B2 (en) 2008-06-06 2012-09-18 Boehringer Ingelheim International Gmbh Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
WO2009150660A1 (en) * 2008-06-13 2009-12-17 Reliance Life Sciences Pvt. Ltd. A process for the preparation of arylcyclopropane carboxylic carbonitriles, and compounds derived therefrom

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