CA1204117A - Azolylmethyloxiranes, their preparation and their use as drugs - Google Patents
Azolylmethyloxiranes, their preparation and their use as drugsInfo
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- CA1204117A CA1204117A CA000426058A CA426058A CA1204117A CA 1204117 A CA1204117 A CA 1204117A CA 000426058 A CA000426058 A CA 000426058A CA 426058 A CA426058 A CA 426058A CA 1204117 A CA1204117 A CA 1204117A
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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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
- C07C17/2635—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions involving a phosphorus compound, e.g. Wittig synthesis
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/08—Compounds containing oxirane rings with hydrocarbon radicals, substituted by halogen atoms, nitro radicals or nitroso radicals
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- Environmental Sciences (AREA)
- Wood Science & Technology (AREA)
- Dentistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Plant Pathology (AREA)
- Pest Control & Pesticides (AREA)
- Agronomy & Crop Science (AREA)
- Veterinary Medicine (AREA)
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- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE:
Compounds of the formula
Compounds of the formula
Description
` ` 12Q4~1~
- 1 - C.Z. 0~50/35922 Azolylmethylox1ranes, their prepara~;on and ~heir use as _ drugs The present invention relates to novel azole compounds, processes for ~heir preparation, therapeu~ic asents ~hich contain these compounds and can be used as ant;mycotics~ and their use in the treatment o~ disorders~
A lar~e number of antimycotic ag2nts, eg. micona-zole (German Laid-Open Application DOS 1,940,3883, is kno~n. Their actions are not always satisfactory tChemo-therapy Z2, ~1976), 1; Dtsch. Apoth. Ztg. 118 (1Ç78)~
1,269; and Z. Hautkr. 5~ t1981), 1,10g). It has also been disclosed that azole compounds, eg. azolylmethyl-carbinols or azolylmethyl ketones ~German La;d-Open Application DOS 2,431,407 and Fren~h Patent 2,249,~16), can be used as fungicides~
It is an object of the present invention to pro-vide novel and more active antimycotics and fungicides.
We have found that this object is ach;eved, and that compounds of the formula I
N~jN-C~2~ H~
where A and B are identica~ or different and are each alkyl of 1 to 4 carbon 3~0~S, naphthyl, biphenyl or phenylO and the pheny~ radical can be substituted by halogen, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, phenoxy or phenylsulfonyl, and Z is CH or a nitrogen atom;
4~17
- 1 - C.Z. 0~50/35922 Azolylmethylox1ranes, their prepara~;on and ~heir use as _ drugs The present invention relates to novel azole compounds, processes for ~heir preparation, therapeu~ic asents ~hich contain these compounds and can be used as ant;mycotics~ and their use in the treatment o~ disorders~
A lar~e number of antimycotic ag2nts, eg. micona-zole (German Laid-Open Application DOS 1,940,3883, is kno~n. Their actions are not always satisfactory tChemo-therapy Z2, ~1976), 1; Dtsch. Apoth. Ztg. 118 (1Ç78)~
1,269; and Z. Hautkr. 5~ t1981), 1,10g). It has also been disclosed that azole compounds, eg. azolylmethyl-carbinols or azolylmethyl ketones ~German La;d-Open Application DOS 2,431,407 and Fren~h Patent 2,249,~16), can be used as fungicides~
It is an object of the present invention to pro-vide novel and more active antimycotics and fungicides.
We have found that this object is ach;eved, and that compounds of the formula I
N~jN-C~2~ H~
where A and B are identica~ or different and are each alkyl of 1 to 4 carbon 3~0~S, naphthyl, biphenyl or phenylO and the pheny~ radical can be substituted by halogen, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, phenoxy or phenylsulfonyl, and Z is CH or a nitrogen atom;
4~17
- 2 - O.Z. ~050/3592~
and kheir physiologically or pharmaceutically acceptable or plant-tolerated add;tion saLts ~;th acids, possess good antimicrobial, in particular antimycotic, properties.
The novel compounds of the formula I cont~in chiral centers, and are obtained in general in the form of racemates or as d;astereomer mixtures of the erythro and threo forms. The erythro and threo diastereomers of the novel compounds can be separated, for example, by utilizing the difference in the;r solubilities, or by column chromatography, and can be ;sol3ted in pure form.
Individual enant;omers can be obt3ined from such pure dia-stereomer pairs by a conventional method. 80th the pure diastereomers or enantiomers and the mixtures thereof ~hich are o~tained in the synthesis can be used as anti-microbial agents.
A and B are each, for example, methyl, ethyl, propyl~ isoprcpyl, butyl, sec~-butyl, ;sobutyl~ tert.
butyl, naphth-1-yl, naphth-2-yl, p-biphenyl~ phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-ch~orophenyl, 4-fluoro-phenyl, 4-bromophenyl~ 204-d;chlorophenyl, 3,4-dichloro phenyl, 3,5-dichlorophenyl, 3-chloro-4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl) 2,4-dimethoxyphenyl~
and kheir physiologically or pharmaceutically acceptable or plant-tolerated add;tion saLts ~;th acids, possess good antimicrobial, in particular antimycotic, properties.
The novel compounds of the formula I cont~in chiral centers, and are obtained in general in the form of racemates or as d;astereomer mixtures of the erythro and threo forms. The erythro and threo diastereomers of the novel compounds can be separated, for example, by utilizing the difference in the;r solubilities, or by column chromatography, and can be ;sol3ted in pure form.
Individual enant;omers can be obt3ined from such pure dia-stereomer pairs by a conventional method. 80th the pure diastereomers or enantiomers and the mixtures thereof ~hich are o~tained in the synthesis can be used as anti-microbial agents.
A and B are each, for example, methyl, ethyl, propyl~ isoprcpyl, butyl, sec~-butyl, ;sobutyl~ tert.
butyl, naphth-1-yl, naphth-2-yl, p-biphenyl~ phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-ch~orophenyl, 4-fluoro-phenyl, 4-bromophenyl~ 204-d;chlorophenyl, 3,4-dichloro phenyl, 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-nitrophenyl, 3-tri-fluoromethylphenyl~ 4-trif~uoromethylphenyl or 4-phenyl~
sulfonylphenyl, preferably methyl~ ~ert~-butylO phenyl, 4-chlorophenyl, 4 bromophenyl, 2,4-dichlorophenyl or 12~117 .
- 3 - Q~Z~ 0050/359Z~
4-tert.-butylphenyl~
Acids which are preferably used for the formation of physiologically tolerated salts include hydrohalic acids, eg. hydrochloric acid and hydrobromic ac;d, ;n part;cular hydrochlor;c ac;d, w;th ~h;ch the novel com-pounds form salts which crystallize particularly readily;
further examples are phosphor;c acid, nitric acid, sul-furic acid, mono,unct;onal and bifunctional carboxyl;c acids and hydroxycarboxylic acids~ eg. acetic acid, oxa-lic acid, maleic acidr succinic acid, ~umaric acid, tar-taric acid, citr;c ac;d, salicyl;c acid, sorbic ac;d and lact;c ac;d, and sulfon;c acids, eg. p-toluenesulfon;c ac;d and naphthalene-1,5-disulfon;c acid.
The novel compounds of the fornula I can be pre-pared by a process wherein a) a compound of the formula II
L-C~2-G-5~
\O (II), where A and B have the above meanings and L is a leav;ng group which can undergo nucleophilic substitution, is reacted with a compound of the formula III
Me ~V (III), Z0 where Me is hydrogen or a metal atom and Z is CH or a ~2~4~
- 4 - 0u~. 0050/35922 nitrogen atom, or b) a compound of the formula II, where A and 8 have the above mean;ngs and L ;s hydroxyl, is reacted ~J;th a com-pound of the formula IV
~_q_~
~ \~N (IV~, where Z has the above mean;ngs and Y is carbon or sulfur, or c) a compound of the formula V
~-CH -C=C~-B
N~ 2 tV), ~here Z, A and B have the above mean;ngs~ is epox;dized, or d) a compound of the formula VI
~-CH2-C0 A
N~J (YI)~
where 2 and A have the above meanings, is reacted with a compound of the general formula VII
R
S( O ) C~-~
z/ n ~YII), where a has the above meanings, R1 and R~ are identical or ~2~
sulfonylphenyl, preferably methyl~ ~ert~-butylO phenyl, 4-chlorophenyl, 4 bromophenyl, 2,4-dichlorophenyl or 12~117 .
- 3 - Q~Z~ 0050/359Z~
4-tert.-butylphenyl~
Acids which are preferably used for the formation of physiologically tolerated salts include hydrohalic acids, eg. hydrochloric acid and hydrobromic ac;d, ;n part;cular hydrochlor;c ac;d, w;th ~h;ch the novel com-pounds form salts which crystallize particularly readily;
further examples are phosphor;c acid, nitric acid, sul-furic acid, mono,unct;onal and bifunctional carboxyl;c acids and hydroxycarboxylic acids~ eg. acetic acid, oxa-lic acid, maleic acidr succinic acid, ~umaric acid, tar-taric acid, citr;c ac;d, salicyl;c acid, sorbic ac;d and lact;c ac;d, and sulfon;c acids, eg. p-toluenesulfon;c ac;d and naphthalene-1,5-disulfon;c acid.
The novel compounds of the fornula I can be pre-pared by a process wherein a) a compound of the formula II
L-C~2-G-5~
\O (II), where A and B have the above meanings and L is a leav;ng group which can undergo nucleophilic substitution, is reacted with a compound of the formula III
Me ~V (III), Z0 where Me is hydrogen or a metal atom and Z is CH or a ~2~4~
- 4 - 0u~. 0050/35922 nitrogen atom, or b) a compound of the formula II, where A and 8 have the above mean;ngs and L ;s hydroxyl, is reacted ~J;th a com-pound of the formula IV
~_q_~
~ \~N (IV~, where Z has the above mean;ngs and Y is carbon or sulfur, or c) a compound of the formula V
~-CH -C=C~-B
N~ 2 tV), ~here Z, A and B have the above mean;ngs~ is epox;dized, or d) a compound of the formula VI
~-CH2-C0 A
N~J (YI)~
where 2 and A have the above meanings, is reacted with a compound of the general formula VII
R
S( O ) C~-~
z/ n ~YII), where a has the above meanings, R1 and R~ are identical or ~2~
- 5 - O.Z. 0050/359Z2 different and are each methyl or phenyl, and n is zero or one, and, if des;red, the resulting compound is con-verted to ;ts salts w;th physiologically tolerated or plant-tolerated ac;ds.
If Me is hydrogen, reaction a) is carried out in the presence or absence of a solvent or diluent, with or without the addition of an inorganic or organic base or of a reaction accelerator, at from 10 to 120C. Pre-ferred solvents or diluents include ketones, eg. acetone, methyl ethyl ketone and cyclohexanone, ni~riles~ eg.
acetonitrile, esters, eg. ethyl acetate, ethers, eg.
diethyl ether, tetrahydrofuran and dioxane, sulfoxides, eg~ dimethylsulfoxide, am;des, eg. dimethylformamide, dimethylacetamide and N-methy!pyrrol;done, and sulfolane~
as well as mixtures of these.
xamples of suitable bases, which, if appropriate, may also be used as acid acceptors ;n the react;on, are alkali metal hydrox;des, such as lithium hydroxide, sodium hydroxide and potassium hydrox;de~ alkali metal carbonates, such as sod;um carbonate~ potassium carbon-ate, sodium bicarbonate and potassium bicarbonate, an excess of the 1,2,4-triazole, pyridine and 4-dimethylamino-pyrid;ne. However, it is also possible to use another conventional base.
Preferred reaction accelerators are metal hal-ides, eg. sodium iodide or potassium iodide, quaternary ammonium salts, eg. tetrabutylammonium chloride, bro-mide or iodide or benzyl triethylammonium chloride or bromide, and crown ethers~ eg. 12-crown-4, 15-crown-5, lZ~?4~17 - g - 0.2. ~Q50~35922 18-crown-~, dibenzo-18-crown-6 or dicyclohexano-18-crown-
If Me is hydrogen, reaction a) is carried out in the presence or absence of a solvent or diluent, with or without the addition of an inorganic or organic base or of a reaction accelerator, at from 10 to 120C. Pre-ferred solvents or diluents include ketones, eg. acetone, methyl ethyl ketone and cyclohexanone, ni~riles~ eg.
acetonitrile, esters, eg. ethyl acetate, ethers, eg.
diethyl ether, tetrahydrofuran and dioxane, sulfoxides, eg~ dimethylsulfoxide, am;des, eg. dimethylformamide, dimethylacetamide and N-methy!pyrrol;done, and sulfolane~
as well as mixtures of these.
xamples of suitable bases, which, if appropriate, may also be used as acid acceptors ;n the react;on, are alkali metal hydrox;des, such as lithium hydroxide, sodium hydroxide and potassium hydrox;de~ alkali metal carbonates, such as sod;um carbonate~ potassium carbon-ate, sodium bicarbonate and potassium bicarbonate, an excess of the 1,2,4-triazole, pyridine and 4-dimethylamino-pyrid;ne. However, it is also possible to use another conventional base.
Preferred reaction accelerators are metal hal-ides, eg. sodium iodide or potassium iodide, quaternary ammonium salts, eg. tetrabutylammonium chloride, bro-mide or iodide or benzyl triethylammonium chloride or bromide, and crown ethers~ eg. 12-crown-4, 15-crown-5, lZ~?4~17 - g - 0.2. ~Q50~35922 18-crown-~, dibenzo-18-crown-6 or dicyclohexano-18-crown-
6.
The reaction is carried out in general at from 20 to 150C, under atmospheric or superatmospheric pres-sure, either cont;nuously or ~atchw;se.
If Me is a metal atom, react;on a) ;s carr;ed out ;n the presence or absence of a solvent or diluent and with or ~ithout the addition of a strong ;norganic or organic base, at from -10 to 120C. Pre,erred solvents or diluents include amides, eg. d;methylformamide, diethylformamide, d;methylacetamide, diethylacetam;de, ~-methylpyrrolidone and hexamethylphosphorotriamide, sul-fox;des, eg. d;methylsulfoxide, and sulfolane.
Examples of suitable bases, wh;ch, if appropri-ate, may also be used as acid acceptors in the react;on, are alkali metal hydrides, such as lith;um hydride, sod-ium hydride and potassium hydride, alkali metal amides, such as sodium amide and potassium amide, and sodium tert.-butoxide~ potass;um tert. butoxide, lithium-tri-phenylmethyl, ~od;um-tr;phenylmethyl, potassium-triphenyl-methyl, naphthalene-lith;um, naphthalene-sodium and naphthalene-potassium.
Suitable diluents for reaction b~ are polar org-anic solvents such as nitr;les, eg. acetonitr;le, sulfox;des, eg. dimethylsulfox;de, formamides, eg. dime-thylformam;de~ ketones, eg. acetone, ethers, eg. d;ethyl ether or tetrahydrofuran, and in particular chlorohydro-carbons, eg. methylene chlor;de or chlorofor~.
The reac~;on is carried out ;n general at from 0 ~2Q~7
The reaction is carried out in general at from 20 to 150C, under atmospheric or superatmospheric pres-sure, either cont;nuously or ~atchw;se.
If Me is a metal atom, react;on a) ;s carr;ed out ;n the presence or absence of a solvent or diluent and with or ~ithout the addition of a strong ;norganic or organic base, at from -10 to 120C. Pre,erred solvents or diluents include amides, eg. d;methylformamide, diethylformamide, d;methylacetamide, diethylacetam;de, ~-methylpyrrolidone and hexamethylphosphorotriamide, sul-fox;des, eg. d;methylsulfoxide, and sulfolane.
Examples of suitable bases, wh;ch, if appropri-ate, may also be used as acid acceptors in the react;on, are alkali metal hydrides, such as lith;um hydride, sod-ium hydride and potassium hydride, alkali metal amides, such as sodium amide and potassium amide, and sodium tert.-butoxide~ potass;um tert. butoxide, lithium-tri-phenylmethyl, ~od;um-tr;phenylmethyl, potassium-triphenyl-methyl, naphthalene-lith;um, naphthalene-sodium and naphthalene-potassium.
Suitable diluents for reaction b~ are polar org-anic solvents such as nitr;les, eg. acetonitr;le, sulfox;des, eg. dimethylsulfox;de, formamides, eg. dime-thylformam;de~ ketones, eg. acetone, ethers, eg. d;ethyl ether or tetrahydrofuran, and in particular chlorohydro-carbons, eg. methylene chlor;de or chlorofor~.
The reac~;on is carried out ;n general at from 0 ~2Q~7
- 7 - O.Z. 0050/35922 to 100C, preferably from 20 to 80C. Where a solvent is usedO the reaction is advantageousLy carried out at the bo;l;ng point of the part;cular solvent~
In carry;ng out process b), about 1 mole of car-bonyl-bis-1-(1,Z,4-triazole) or carbonyl-b;s-1-imidazole, or 1 mole of sulfonyl-bis 1-(1,2,4-triazole) or sulfonyl-b;s 1-imidazole, is preferably employed per mole of the compound oF the formula II where ~ ;s OH, or the sulfo-nyl-bis-1-~1,2~4-triazole) or sulfonyl-bis-1-imidazole ;s produced in s;tu. To isolate the compounds of the formula I, the solvent ;s distilled off, the residue is taken up in an organ;c solvent, and the soluticn is washed with water.
The novel starting compounds II are obtained by epoxid;zing the corresponding olefin~ IX:
~CH2-&A= c~-a ~ IX) (cf. G. Dittus ;n Houben-Weyl-Muller, Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1965, Volume VI, 3, page 385 et seq.).
The compound IX is prepared by halogenating or oxidizing an olefin of the formula X
H3C--CA=C~ (X) at the allyl position, by 3 conventional method.
Suitable halogenat;ng reagents are N-chlorosuc-cinimide and N-bromosuccinimide in halohydrocarbons, such as carbon tetrachloride, trichloroethane or methy-lene chloride, halogenation being carried out at from 20 to 100C. Allyl oxidation is carried out using a per-ester, such as tert.-butyl perbenzoate or tert.-butyl ~2Q~17
In carry;ng out process b), about 1 mole of car-bonyl-bis-1-(1,Z,4-triazole) or carbonyl-b;s-1-imidazole, or 1 mole of sulfonyl-bis 1-(1,2,4-triazole) or sulfonyl-b;s 1-imidazole, is preferably employed per mole of the compound oF the formula II where ~ ;s OH, or the sulfo-nyl-bis-1-~1,2~4-triazole) or sulfonyl-bis-1-imidazole ;s produced in s;tu. To isolate the compounds of the formula I, the solvent ;s distilled off, the residue is taken up in an organ;c solvent, and the soluticn is washed with water.
The novel starting compounds II are obtained by epoxid;zing the corresponding olefin~ IX:
~CH2-&A= c~-a ~ IX) (cf. G. Dittus ;n Houben-Weyl-Muller, Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1965, Volume VI, 3, page 385 et seq.).
The compound IX is prepared by halogenating or oxidizing an olefin of the formula X
H3C--CA=C~ (X) at the allyl position, by 3 conventional method.
Suitable halogenat;ng reagents are N-chlorosuc-cinimide and N-bromosuccinimide in halohydrocarbons, such as carbon tetrachloride, trichloroethane or methy-lene chloride, halogenation being carried out at from 20 to 100C. Allyl oxidation is carried out using a per-ester, such as tert.-butyl perbenzoate or tert.-butyl ~2Q~17
- 8 - O.Z. ~OSOl35922 peracetate~ in the presence of a heavy metal salt, egO
copper(I) chloride or copper~I~ brom;de, ;n an inert soL-vent at from 10 to 100C.
The resulting allyl halide or alcohol IX is then converted to the correspond;ng epoxide II ~here L is halogen or OH. To do this~ IX is oxid;zed with a peroxy-carboxyl;c ac;d, eg. perben~o;c acid, 3-chloroperbenzo;c ac;d, 4-n;troperbenzoic ac;d, monoperphthalic ac;d, per-acet;c ac;d, perpropion;c acid~ permaleic acid, monoper-succ;nic ac;d, perpelargonic ac;d or trifluoroperaceticacid~ in an inert solvent, preferably a chlorohydrocarbon, eg~ methylene chloride, chloroform, carbon tetrachloride or d;chloroethane, or if appropr;ate even in acetic acid, ethy~ acetate, acetone or dimethylformam;de~ in the pre-sence or absence of a buffer, eg. sodium acetate, sodium carbonate, sodium bicarbonate, disod;um hydrogen phos-phate or ~r;ton ~. The reaction is carried out at from 10 to 100C, and, if necessary, ;s catalyzed~ for example with iodine or sodium tungstate or by means of light. Oxidation may a~so be carried out using an alka-l;ne solut;on of hydrogen peroxide tabout 30X strength3 in methanol, ethanol, acetone or acetonitrile at from 25 to 30C~ or an alkyl hydroperoxide, eg. tert.-butyl hydroperoxide, with the addition of a catalyst, eg. sod-ium tungstate, pertungstic acid, molrbdenum hexacarbonyl or vanadyl acetylacetonateO Some Qf the above oxidizing agents can be produced in situ.
While the resu~t;ng epoxy halide II, where L is halogen, can be directly reacted further accord;ng to * Trademark ~2~17
copper(I) chloride or copper~I~ brom;de, ;n an inert soL-vent at from 10 to 100C.
The resulting allyl halide or alcohol IX is then converted to the correspond;ng epoxide II ~here L is halogen or OH. To do this~ IX is oxid;zed with a peroxy-carboxyl;c ac;d, eg. perben~o;c acid, 3-chloroperbenzo;c ac;d, 4-n;troperbenzoic ac;d, monoperphthalic ac;d, per-acet;c ac;d, perpropion;c acid~ permaleic acid, monoper-succ;nic ac;d, perpelargonic ac;d or trifluoroperaceticacid~ in an inert solvent, preferably a chlorohydrocarbon, eg~ methylene chloride, chloroform, carbon tetrachloride or d;chloroethane, or if appropr;ate even in acetic acid, ethy~ acetate, acetone or dimethylformam;de~ in the pre-sence or absence of a buffer, eg. sodium acetate, sodium carbonate, sodium bicarbonate, disod;um hydrogen phos-phate or ~r;ton ~. The reaction is carried out at from 10 to 100C, and, if necessary, ;s catalyzed~ for example with iodine or sodium tungstate or by means of light. Oxidation may a~so be carried out using an alka-l;ne solut;on of hydrogen peroxide tabout 30X strength3 in methanol, ethanol, acetone or acetonitrile at from 25 to 30C~ or an alkyl hydroperoxide, eg. tert.-butyl hydroperoxide, with the addition of a catalyst, eg. sod-ium tungstate, pertungstic acid, molrbdenum hexacarbonyl or vanadyl acetylacetonateO Some Qf the above oxidizing agents can be produced in situ.
While the resu~t;ng epoxy halide II, where L is halogen, can be directly reacted further accord;ng to * Trademark ~2~17
- 9 - O.Z. 0050/35922 process a), ~he correspond;ng epoxy alcohol II, where L
;s OH, is reacted with a compound of the formula IV
accord;ng to process b)~ or ;s converted to a react;ve ester, wh;ch ;s then reacted w;th a compound III accord-;ng to process a)~
The ester which ;s reacted w;th III is prepared by a conventional method ~Houben-Weyl-Muller, Methoden der organ;schen Chemie, Georg Thieme Verlag, Stuttgart, 1955, Volume 9, pages 388~ b~3 and 671). ~xamples of such esters are methanesulfonates, trifluoromethanesul-fonates, 2,2,2-tr;fluoromethanesulfonates, nonafluoro-butanesulfonates, ~-methylbenzenesulfonates, 4-bromoben-zenesulfonates, 4-n;troben2enesulronates and benzene-sulfonates.
The compounds X, some of wh;ch are unknown, can be prepared by a convent;onal olefin- synthesis (Houben-Weyl-Muller, Methoden der organ;schen Chemie, Georg Thieme Verlag, Stutt~art, 1972, Volume V, lb).
Process c) is carried out by a procedure s;m;lar to the epoxidation of the compounds IX.
Some of the starting compounds V are known tGerman Laid Open Appl;cat;on aos 2,549,79B)~ Those which are not known can be prPpared by a method descr;bed in that publ;cation.
In process d)~ according to the invent;on, a known azolyl ketone ~for example, one which is d;sclosed ;n German Laid-dpen Application DOS Z,Ob3,857) of the formula VI is reacted with a sulfur derivative of the formula VII~
~n~7
;s OH, is reacted with a compound of the formula IV
accord;ng to process b)~ or ;s converted to a react;ve ester, wh;ch ;s then reacted w;th a compound III accord-;ng to process a)~
The ester which ;s reacted w;th III is prepared by a conventional method ~Houben-Weyl-Muller, Methoden der organ;schen Chemie, Georg Thieme Verlag, Stuttgart, 1955, Volume 9, pages 388~ b~3 and 671). ~xamples of such esters are methanesulfonates, trifluoromethanesul-fonates, 2,2,2-tr;fluoromethanesulfonates, nonafluoro-butanesulfonates, ~-methylbenzenesulfonates, 4-bromoben-zenesulfonates, 4-n;troben2enesulronates and benzene-sulfonates.
The compounds X, some of wh;ch are unknown, can be prepared by a convent;onal olefin- synthesis (Houben-Weyl-Muller, Methoden der organ;schen Chemie, Georg Thieme Verlag, Stutt~art, 1972, Volume V, lb).
Process c) is carried out by a procedure s;m;lar to the epoxidation of the compounds IX.
Some of the starting compounds V are known tGerman Laid Open Appl;cat;on aos 2,549,79B)~ Those which are not known can be prPpared by a method descr;bed in that publ;cation.
In process d)~ according to the invent;on, a known azolyl ketone ~for example, one which is d;sclosed ;n German Laid-dpen Application DOS Z,Ob3,857) of the formula VI is reacted with a sulfur derivative of the formula VII~
~n~7
- 10 - O.Z. oa50t35522 The alkylidenesulfuranes- VII (where n is O) and the oxysulfuranes VII (where n is 1~ are prepared in s;tu by a convent;onal method (for example as described by H. O. House in Modern Synthetic Reactions, 2nd Edit;on, W. A. Benjamin, Menlo Park 1972, page 71Z et seq.). A
compound VII is reacted with an azolyl ketone VI in an ;nert solvent, preferably an ether, eg. diethyl ether, tetrahydrofuran or a mixture of these, or in a hydrocar-bon~ eg. pentane, hexane or petroleum ether, at from -78 to 30C.
The resulting compound of the formula I is iso-lated ay a conventionaL method, if necessary purified, and if desired reacted with an acid to give a salt.
Surprisingly, the azole derivatives according to the invention exhibit good antibacterial and anti-mycotic in vitro activity, as well as better therapeutic-ally useful in ~ivo activity~ ;n part;cular against der-matophytes and Candida, than conventional formulations.
The active compounds according to the ;nvention thus 20 represent a valuable enrichment of the art.
The action against dermatophytes, bacter1a and protozoa can be demonstrated by a method as described, for example, by P. Klein ;n eakteriologische Grundlagen der chemotherapeutischen Laboratoriumspraxis, Springer-Verlag Berlin, 1957. The action against yeasts, which is surprising, was demonstrated in the pseudomycelium and mycelium phase tests with Candida albicans (cf. German Laid-Open Application DOS 3,010~093)J The minimum inhibitory concentration t~IC) reached in the agar ~2n4;ll7 ~ O.Z. 0050/35922 d;lut;on test was determined. The results are summar;zed in Table 1.
~2~?4~
- 12 - o . Z . 0050/35922 o , , , , A A A A A
O
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Co ~ ~ ~D ~ CO ~ ~ 51 ~D CD
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CS t C~
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a~ c ~J ~ ~
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~ ~ A A A
., ~ Q
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V~ U7 0 ~J Z
~Q~117 - 13 - O~Z. 0050/~59Z2 In the guinea-pig trichophytosis model (Tricho-phyton mentagrophytes; cf. Heffter-Heubner: Handbuch d.
expO Pharmakolog;e, Vol. XVI/IIA), too, the novel com-pounds, when applied externally, exhibit a better action than comparative substances.
The novel substances are also active when admin-istered orally, as can be shown from the treatment of experimental candidosis in the mouse. For this purpose, groups o~ 10 mice weighing about 20 9 each were pre-treated for 2 days, each mouse receiving 50 mglkg ofhydrocortisone intramuscularly, in order to ensure that they had been infected. The mice were then each infected intravenously ~ith 50Q,000 Candida alb;cans germs, after which they each received, t~ice daily, 100 mg/kg of the substances to be tested, this d~se being administered orally over a period of 4 days.
In addition to the infected group and the untreated control group~ further groups ~ere each treated with a reference substance for comparison. As a result, the test substances had bet`ter DCso values than the ref-erence substances.
In the experimental vaginitis model with Candida albicans in the rat, complete elimination of the infec-tion ~as achieved after oral administra~ion or local treatment using low therapeutic doses of the test substances.
The novel compounds are therefore particularly useful for the treatment of fungal infections in humans and animals by oral administration or 2xternal application~
12~4~
- 14 - O.Z. 0050/35922 Examples of fields of indication in humans and animals are dermatomycoses~ dermatophytoses and sys~em-mycoses, ;n particular those caused by dermatophytes, eg.
species of the genera Epidermophyton, M;crosporum ancl Trichophyton, yeasts~ eg. species of the genera Cand;da, and molds, eg. species of the genera Aspergillus, Mucor and Absidia.
The compounds can be used alone or together with other conventional active compounds, in particular antibiot;cs.
The chemotherapeutic a~ents or formulations are prepared ;n a conventional manner~ ;n particular by mix-;ng an appropriate dose with the conventional solid, semi-sol;d or l;quid carriers or diluents and the conven-tional pharmaceutical auxiliaries, in accordance with the desired route OT administration tcf. H. Sucker et al., Pharmazeutische Technologie, Thieme-~erlag, Stuttgart, 1~78).
Examples of suitable formulations are tablets, coa~ed tablets, capsules~ p;lls, aqueous solutions, sus-pensions and emulsions, and, if appropriate, sterile injectable solutions, non-aqueous emulsions~ suspensions and solut;ons, ointments, creams, pastes, lotions, etc.
The therapeutically active compound is preferably present in the pharmaceutical formulation in a concen-trat;on of from C.S to 9n~ by weight, based on the total mixture.
To achieve the desired results in the case of oral administra~ion either in human or in veterinary ~:Q4~
- 15 - O.Z. ~050/3592Z
med;cine, the act;ve compound or compounds can be adm;n-;stered ;n general ;n amounts of from about 1.0 to about 10~0, preferably from Z to 6, mg/kg of body weight per day, preferably in the form of several single doses.
However~ it may be necessary to deviate from the stated doses, and to do th;s as a funct;on of the nature and sever;ty of the disorder, the type of formulation and the route of admin;stration of the drug, as well as the period or interval betueen administrations. Thus, it may be suff;c;ent ;n some cases to use less than the above-ment;oned amount of act;ve compound, while in other cases the above amount of active compound has to be exceeded.
The Examples which follow illustrate the invention.
I. Preparation of the starting materials EXAMPLE A
~ 3.6 9 of potassium tert.-butylate in 300 ml of dry methanol were ;ntroduced ;nto a solut;on of 229 g o~
2,4-dichloroben~yltriphenylphosphonium chloride in 800 ml of dry methanol at 10C, and 77.2 g of 4-chloroaceto-phenone were added after half an hour. The reactionsolut;on was refluxed for 3 hours and then cooled to room temperature, the prec;p;tated salt was f;ltered off, the filtrate was evaporated down under reduced pressure, tr;phenylphosphine ox;de was separated off from the res;-due by digest;ng the latter w;th petroleum ether at from 50 to 70C, and the solution was evaporated down under reduced pressure.
The residue was taken up ;n 1 l;ter of carbon ~Q~L17 ~ 16 - O.Z. 0050/35922 tetrachloride, and the solution was refluxed with 81.7 9 of N-bromosuccinimide and 4 9 of Z,2'-azoisobutyrodinit-rile. When the reaction was complete, the succinim;de was filtered off, the filtrate was evaporated down under reduced pressure and the residue was recrystallized from methanol to give 73.4 g ~38.8%) of Z-1-(2,4-d;chlorophe-nyl)-Z-(4-chlorophenyl)-3-bromoprop-1-ene of melt;ng point 128C.
EXAMPLE B
118 g of 2,4-dichlorobenzyl chlor;de were added dropwise to 14.6 9 of magnesium turnings in 400 ml of dry diethyl ether~ at the boil. When the reaction was com-plete, 77.3 9 of 4-chloroacetophenone in 4n~ ml of dry diethyl ether were added, and decomposition was then effected with aqueous ammonium chloride solution. The organic phase was separated off~ washed neutral, dried over sodium sulfate and evaporated down under reduced pressure, the residue was taken up in 1 liter of toluene and the solution was refluxed with 4 9 of 4-methylben-zenesulfonic acid, in a water separator. When dehydra-tion was complete, the toluene phase was washed with sodium carbonate solution and water and dried over sodium sulfate, the solvent was evaporated off and the residue was recrystallized from methanol to give 107 9 (71.9X) of E-1-(2~4-dichlorophenyl) 2-(4-chlorophenyl)-prop-1-ene of melting point 84 - 85C.
EXAMPLE C
104 g of E-1-(2,4-dichlorophenyl~ (4-chloro-phenyl~-prop-1~ene, 62.3 g of N-bromosucc;nimide and 5 9 ~2Q~
- 17 - O.Z. 0050~35922 of 2,2'-a~oisobutyrodinitrile ;n 1 llter of carbon tetra-chloride were refluxed, the precipitated succ;nim;de was filtered off, the filtrate ~as evaporated down under reduced pressure and the residue ~as treated with metha-nol to give 9105 9 (69.4Z) of I-1 ~2,~-dichlorophenyl)-2-(4-chlorophenyl)-3-bromoprop-1-ene of melting point 1Z8C.
EXAMPLE D
58.9 9 of Z-1-~2,4-dichlorophenyl)-2-t4-chloro-phenyl)-3-bromoprop-1-ene ~c;. Example A) and 52~3 9 of 3-chloroperoxybenzoic acid in 590 ml of chloroform were refluxed. When the reaction ~as complete, the chloroform phase ~as washed acid-free with aqueous sodium bicar-bonate solution and water, dried over sodium sulfate and evaporated down under reduced pressure, and the residue was recrystallized from methanol to give two fractions:
1. 41.3 g (70.2X) of 2-bromomethyl 2-~4-chlorophenyl)-3-~2,4-di~hlorophenyl)-oxirane (isomer h~ of melting poin~ 98 - 9gC and 2. l2 9 ~20.4~) of 2-bromomethyl-2-~4-chlorophenyl)-3-t2,4-dichlorophenyl)-oxirane (isomer B) of melting point 93 - 95C.
II. Preparation of the end products A solution of 10 9 of 2-bromomethyl-2-~4-chloro-phenyl~-3-~Z,4-dichlorophenyl)-oxirane (isomer A, cf.
Example D) in 50 ml of N~N-dimethylformamide was added dropwise, at 100C, to a melt which was obtained from 15~6 9 of imidazole and 1.37 g of sodium methylate and ~2Q4~
- 18 - O.Z. 0050/3i922 from which the l;bera-ted methanol had been d;stilled off beforehand. After 8 hours, the reaction solution was poured onto ~ater, and the mixture was extracted w;th ethyl acetate. The organic phase ~as washed with water, dried over sodium sulfate and evaporated doun under reduced pressure, and the residue was chromatographed over a s;lica gel column with methylene chloride/metha-nol (100 : Z~. The pure fractions were evaporated down, and recrystallized from diisopropyl ether to give 4.6 9 t47.5~) of 2-~1H-imidazol-1-ylmethyl)-2-(4-chlorophenyl)-3-~2,4-dichlorophenyl)-oxirane (isomer A) of melting point 10Z - 103~C.
6.2 9 of imidazole and 1.3 9 of sodium hydride ~as a 50% strength dispersion in mineral oil) in 50 ml of N,N-dimethylformamide were initially taken, and a solution of 12 9 of 2-bromomethyl-2-t4-chlorophenyl)-3-(2~4-dichlorophenyl)-oxirane (isomer 8, cf. Fxample D) and 5 g of potassium iodide in 50 ml of N,N-dimethylfor-mamide was added at room temperature. After 8 hours, the reaction solution was poured onto water, and the mix-ture was extracted with ethyl acetate. The organic phase was washed with water and dried over sodium sulfate, the solvent was evaporated off under reduced pressure and the residue was recrystallized from diisopropyl ether to give 9.4 9 t82.5%) of 2-(1H-imidazol-1-ylmethyl)-2-~4-chlorophenyl)-3-(2~4 dichlorophenyl)-oxirane ~isomer B) of melting point 109C~
~2~
- 19 - O.Z. 0050/3S922 Z0.9 9 of 1,Z,4-triazole and 4.4 g of sod;um 'nyd-ride (as a soæ strength dispersion in mineral oiL) in 15~ ml of N,N-dimethylformamide ~ere initially taken, and a solution of 39.2 9 of 2-bromomethyl-2-~4-chlorophenyl)-3-~2,4-dichlorophenyl)-ox;rane (isomer A, cf. Example D) and 16.~ 9 of potassium iodide ;n 150 ml of N,N-dimethyl-forma~ide was added at room temperature. After 8 hours, the m;xture W2S worked up as described ln Example 2, and the product was recrystallized fro~ diisopropyl ether to give 31 9 (81.9X) of 2-(1,2,4-triazol-1-ylmethyl)-2-~4-chlorophenyl)-3-~2,4-dichlorophenyl)-oxirane (isomer A~
of melting point 119C.
Some of the compounds listed in Table I were prepared by a procedure s;milar to that described in Example 1 or 2. The remaining compounds in the table can also be prepared as descr;bed in these Examples.
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~L2~?4~17 - 22 - O. Z . 0050/35922 ~_ O ~ O O t~ 1 ~ O
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- 25 - O.Z. 0050/35922 Examples of pharmaceutical formulations:
EXAMPLE A
Tablet containing 250 mg of active compound Composition for 1,000 tablets:
Active compound of Example No. 3 250 g Potato starch 100 9 Lactose 50 9 Gelatine solution t4X strength) 45 9 Talc 10 9 Preparation:
1~ ~he finely powdered active compound~ potato starch and lactose are m;xed, the mixture is moistened thoroughly ~ith about 45 9 of 4~ strength gelatine solu-t;on and then granulated to give fine particles, and the granules are dr;ed. The dry granules are sie~ed and then mixed with 1~ 9 of talc, and the mixture is pressed in a rotary tableting machine to give tablees. These are introduced into polypropylene conta;ners ~hich are closed tightly ~XAMPLE 8 Cream containing 1% of act;ve compound 20 Active compound of Example No. 31 0 9 Glycerol monostearate 1000 9 Cetyl alcohol 4 0 9 Polyethylene glycol-400 stearate10.0 g Polyethylene glycol sorbitan monostearate 10 0 9 Propylene glycol ~.0 9 Methyl p-hydroxybenzoate 0.2 g Deioni~ed water, to make up to100.0 9 ~2~17 - 20 - O.Z. 0050/35922 Preparation:
The very finely powdered active compound is sus-pended in propylene glycol, and the suspension is st;rred into a melt, at 65C, comprising glycerol monostearate, cetyl alcohol, polyethylene glyco!-400 stearate and poly-ethylene glycol sorbitan monostearate. A solution, at 70C, of methyl p-hydroxybenzoate in water is emulsi-fied in this mixture, the emulsion is cooled, and the resulting cream is homogeni2ed in a colloid mill and 10 then introduced into tubes.
EXAMPLE C
Powder containing 1X of active compound Active compound of Example No. 31.0 9 Zinc oxide 10.0 9 Magnesium oxide 1~.0 g Finely divided sil;con d;o~ide 2~5 9 Magnesium stearate 1.a 9 Talc 74 5 9 Preparation:
The act;ve compound is micronized in a je~ mill employing air, and ;s then mixed ~ith the other compo-nents to give a homo~eneous mixture. This ;s forced through a s;eve of No. 7 mesh size and then ;n~roduced into polye~hylene con~ainers with a oerforated top.
compound VII is reacted with an azolyl ketone VI in an ;nert solvent, preferably an ether, eg. diethyl ether, tetrahydrofuran or a mixture of these, or in a hydrocar-bon~ eg. pentane, hexane or petroleum ether, at from -78 to 30C.
The resulting compound of the formula I is iso-lated ay a conventionaL method, if necessary purified, and if desired reacted with an acid to give a salt.
Surprisingly, the azole derivatives according to the invention exhibit good antibacterial and anti-mycotic in vitro activity, as well as better therapeutic-ally useful in ~ivo activity~ ;n part;cular against der-matophytes and Candida, than conventional formulations.
The active compounds according to the ;nvention thus 20 represent a valuable enrichment of the art.
The action against dermatophytes, bacter1a and protozoa can be demonstrated by a method as described, for example, by P. Klein ;n eakteriologische Grundlagen der chemotherapeutischen Laboratoriumspraxis, Springer-Verlag Berlin, 1957. The action against yeasts, which is surprising, was demonstrated in the pseudomycelium and mycelium phase tests with Candida albicans (cf. German Laid-Open Application DOS 3,010~093)J The minimum inhibitory concentration t~IC) reached in the agar ~2n4;ll7 ~ O.Z. 0050/35922 d;lut;on test was determined. The results are summar;zed in Table 1.
~2~?4~
- 12 - o . Z . 0050/35922 o , , , , A A A A A
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~Q~117 - 13 - O~Z. 0050/~59Z2 In the guinea-pig trichophytosis model (Tricho-phyton mentagrophytes; cf. Heffter-Heubner: Handbuch d.
expO Pharmakolog;e, Vol. XVI/IIA), too, the novel com-pounds, when applied externally, exhibit a better action than comparative substances.
The novel substances are also active when admin-istered orally, as can be shown from the treatment of experimental candidosis in the mouse. For this purpose, groups o~ 10 mice weighing about 20 9 each were pre-treated for 2 days, each mouse receiving 50 mglkg ofhydrocortisone intramuscularly, in order to ensure that they had been infected. The mice were then each infected intravenously ~ith 50Q,000 Candida alb;cans germs, after which they each received, t~ice daily, 100 mg/kg of the substances to be tested, this d~se being administered orally over a period of 4 days.
In addition to the infected group and the untreated control group~ further groups ~ere each treated with a reference substance for comparison. As a result, the test substances had bet`ter DCso values than the ref-erence substances.
In the experimental vaginitis model with Candida albicans in the rat, complete elimination of the infec-tion ~as achieved after oral administra~ion or local treatment using low therapeutic doses of the test substances.
The novel compounds are therefore particularly useful for the treatment of fungal infections in humans and animals by oral administration or 2xternal application~
12~4~
- 14 - O.Z. 0050/35922 Examples of fields of indication in humans and animals are dermatomycoses~ dermatophytoses and sys~em-mycoses, ;n particular those caused by dermatophytes, eg.
species of the genera Epidermophyton, M;crosporum ancl Trichophyton, yeasts~ eg. species of the genera Cand;da, and molds, eg. species of the genera Aspergillus, Mucor and Absidia.
The compounds can be used alone or together with other conventional active compounds, in particular antibiot;cs.
The chemotherapeutic a~ents or formulations are prepared ;n a conventional manner~ ;n particular by mix-;ng an appropriate dose with the conventional solid, semi-sol;d or l;quid carriers or diluents and the conven-tional pharmaceutical auxiliaries, in accordance with the desired route OT administration tcf. H. Sucker et al., Pharmazeutische Technologie, Thieme-~erlag, Stuttgart, 1~78).
Examples of suitable formulations are tablets, coa~ed tablets, capsules~ p;lls, aqueous solutions, sus-pensions and emulsions, and, if appropriate, sterile injectable solutions, non-aqueous emulsions~ suspensions and solut;ons, ointments, creams, pastes, lotions, etc.
The therapeutically active compound is preferably present in the pharmaceutical formulation in a concen-trat;on of from C.S to 9n~ by weight, based on the total mixture.
To achieve the desired results in the case of oral administra~ion either in human or in veterinary ~:Q4~
- 15 - O.Z. ~050/3592Z
med;cine, the act;ve compound or compounds can be adm;n-;stered ;n general ;n amounts of from about 1.0 to about 10~0, preferably from Z to 6, mg/kg of body weight per day, preferably in the form of several single doses.
However~ it may be necessary to deviate from the stated doses, and to do th;s as a funct;on of the nature and sever;ty of the disorder, the type of formulation and the route of admin;stration of the drug, as well as the period or interval betueen administrations. Thus, it may be suff;c;ent ;n some cases to use less than the above-ment;oned amount of act;ve compound, while in other cases the above amount of active compound has to be exceeded.
The Examples which follow illustrate the invention.
I. Preparation of the starting materials EXAMPLE A
~ 3.6 9 of potassium tert.-butylate in 300 ml of dry methanol were ;ntroduced ;nto a solut;on of 229 g o~
2,4-dichloroben~yltriphenylphosphonium chloride in 800 ml of dry methanol at 10C, and 77.2 g of 4-chloroaceto-phenone were added after half an hour. The reactionsolut;on was refluxed for 3 hours and then cooled to room temperature, the prec;p;tated salt was f;ltered off, the filtrate was evaporated down under reduced pressure, tr;phenylphosphine ox;de was separated off from the res;-due by digest;ng the latter w;th petroleum ether at from 50 to 70C, and the solution was evaporated down under reduced pressure.
The residue was taken up ;n 1 l;ter of carbon ~Q~L17 ~ 16 - O.Z. 0050/35922 tetrachloride, and the solution was refluxed with 81.7 9 of N-bromosuccinimide and 4 9 of Z,2'-azoisobutyrodinit-rile. When the reaction was complete, the succinim;de was filtered off, the filtrate was evaporated down under reduced pressure and the residue was recrystallized from methanol to give 73.4 g ~38.8%) of Z-1-(2,4-d;chlorophe-nyl)-Z-(4-chlorophenyl)-3-bromoprop-1-ene of melt;ng point 128C.
EXAMPLE B
118 g of 2,4-dichlorobenzyl chlor;de were added dropwise to 14.6 9 of magnesium turnings in 400 ml of dry diethyl ether~ at the boil. When the reaction was com-plete, 77.3 9 of 4-chloroacetophenone in 4n~ ml of dry diethyl ether were added, and decomposition was then effected with aqueous ammonium chloride solution. The organic phase was separated off~ washed neutral, dried over sodium sulfate and evaporated down under reduced pressure, the residue was taken up in 1 liter of toluene and the solution was refluxed with 4 9 of 4-methylben-zenesulfonic acid, in a water separator. When dehydra-tion was complete, the toluene phase was washed with sodium carbonate solution and water and dried over sodium sulfate, the solvent was evaporated off and the residue was recrystallized from methanol to give 107 9 (71.9X) of E-1-(2~4-dichlorophenyl) 2-(4-chlorophenyl)-prop-1-ene of melting point 84 - 85C.
EXAMPLE C
104 g of E-1-(2,4-dichlorophenyl~ (4-chloro-phenyl~-prop-1~ene, 62.3 g of N-bromosucc;nimide and 5 9 ~2Q~
- 17 - O.Z. 0050~35922 of 2,2'-a~oisobutyrodinitrile ;n 1 llter of carbon tetra-chloride were refluxed, the precipitated succ;nim;de was filtered off, the filtrate ~as evaporated down under reduced pressure and the residue ~as treated with metha-nol to give 9105 9 (69.4Z) of I-1 ~2,~-dichlorophenyl)-2-(4-chlorophenyl)-3-bromoprop-1-ene of melting point 1Z8C.
EXAMPLE D
58.9 9 of Z-1-~2,4-dichlorophenyl)-2-t4-chloro-phenyl)-3-bromoprop-1-ene ~c;. Example A) and 52~3 9 of 3-chloroperoxybenzoic acid in 590 ml of chloroform were refluxed. When the reaction ~as complete, the chloroform phase ~as washed acid-free with aqueous sodium bicar-bonate solution and water, dried over sodium sulfate and evaporated down under reduced pressure, and the residue was recrystallized from methanol to give two fractions:
1. 41.3 g (70.2X) of 2-bromomethyl 2-~4-chlorophenyl)-3-~2,4-di~hlorophenyl)-oxirane (isomer h~ of melting poin~ 98 - 9gC and 2. l2 9 ~20.4~) of 2-bromomethyl-2-~4-chlorophenyl)-3-t2,4-dichlorophenyl)-oxirane (isomer B) of melting point 93 - 95C.
II. Preparation of the end products A solution of 10 9 of 2-bromomethyl-2-~4-chloro-phenyl~-3-~Z,4-dichlorophenyl)-oxirane (isomer A, cf.
Example D) in 50 ml of N~N-dimethylformamide was added dropwise, at 100C, to a melt which was obtained from 15~6 9 of imidazole and 1.37 g of sodium methylate and ~2Q4~
- 18 - O.Z. 0050/3i922 from which the l;bera-ted methanol had been d;stilled off beforehand. After 8 hours, the reaction solution was poured onto ~ater, and the mixture was extracted w;th ethyl acetate. The organic phase ~as washed with water, dried over sodium sulfate and evaporated doun under reduced pressure, and the residue was chromatographed over a s;lica gel column with methylene chloride/metha-nol (100 : Z~. The pure fractions were evaporated down, and recrystallized from diisopropyl ether to give 4.6 9 t47.5~) of 2-~1H-imidazol-1-ylmethyl)-2-(4-chlorophenyl)-3-~2,4-dichlorophenyl)-oxirane (isomer A) of melting point 10Z - 103~C.
6.2 9 of imidazole and 1.3 9 of sodium hydride ~as a 50% strength dispersion in mineral oil) in 50 ml of N,N-dimethylformamide were initially taken, and a solution of 12 9 of 2-bromomethyl-2-t4-chlorophenyl)-3-(2~4-dichlorophenyl)-oxirane (isomer 8, cf. Fxample D) and 5 g of potassium iodide in 50 ml of N,N-dimethylfor-mamide was added at room temperature. After 8 hours, the reaction solution was poured onto water, and the mix-ture was extracted with ethyl acetate. The organic phase was washed with water and dried over sodium sulfate, the solvent was evaporated off under reduced pressure and the residue was recrystallized from diisopropyl ether to give 9.4 9 t82.5%) of 2-(1H-imidazol-1-ylmethyl)-2-~4-chlorophenyl)-3-(2~4 dichlorophenyl)-oxirane ~isomer B) of melting point 109C~
~2~
- 19 - O.Z. 0050/3S922 Z0.9 9 of 1,Z,4-triazole and 4.4 g of sod;um 'nyd-ride (as a soæ strength dispersion in mineral oiL) in 15~ ml of N,N-dimethylformamide ~ere initially taken, and a solution of 39.2 9 of 2-bromomethyl-2-~4-chlorophenyl)-3-~2,4-dichlorophenyl)-ox;rane (isomer A, cf. Example D) and 16.~ 9 of potassium iodide ;n 150 ml of N,N-dimethyl-forma~ide was added at room temperature. After 8 hours, the m;xture W2S worked up as described ln Example 2, and the product was recrystallized fro~ diisopropyl ether to give 31 9 (81.9X) of 2-(1,2,4-triazol-1-ylmethyl)-2-~4-chlorophenyl)-3-~2,4-dichlorophenyl)-oxirane (isomer A~
of melting point 119C.
Some of the compounds listed in Table I were prepared by a procedure s;milar to that described in Example 1 or 2. The remaining compounds in the table can also be prepared as descr;bed in these Examples.
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- 23 - O.Z. OOSO/35922 ._ a a~
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- 25 - O.Z. 0050/35922 Examples of pharmaceutical formulations:
EXAMPLE A
Tablet containing 250 mg of active compound Composition for 1,000 tablets:
Active compound of Example No. 3 250 g Potato starch 100 9 Lactose 50 9 Gelatine solution t4X strength) 45 9 Talc 10 9 Preparation:
1~ ~he finely powdered active compound~ potato starch and lactose are m;xed, the mixture is moistened thoroughly ~ith about 45 9 of 4~ strength gelatine solu-t;on and then granulated to give fine particles, and the granules are dr;ed. The dry granules are sie~ed and then mixed with 1~ 9 of talc, and the mixture is pressed in a rotary tableting machine to give tablees. These are introduced into polypropylene conta;ners ~hich are closed tightly ~XAMPLE 8 Cream containing 1% of act;ve compound 20 Active compound of Example No. 31 0 9 Glycerol monostearate 1000 9 Cetyl alcohol 4 0 9 Polyethylene glycol-400 stearate10.0 g Polyethylene glycol sorbitan monostearate 10 0 9 Propylene glycol ~.0 9 Methyl p-hydroxybenzoate 0.2 g Deioni~ed water, to make up to100.0 9 ~2~17 - 20 - O.Z. 0050/35922 Preparation:
The very finely powdered active compound is sus-pended in propylene glycol, and the suspension is st;rred into a melt, at 65C, comprising glycerol monostearate, cetyl alcohol, polyethylene glyco!-400 stearate and poly-ethylene glycol sorbitan monostearate. A solution, at 70C, of methyl p-hydroxybenzoate in water is emulsi-fied in this mixture, the emulsion is cooled, and the resulting cream is homogeni2ed in a colloid mill and 10 then introduced into tubes.
EXAMPLE C
Powder containing 1X of active compound Active compound of Example No. 31.0 9 Zinc oxide 10.0 9 Magnesium oxide 1~.0 g Finely divided sil;con d;o~ide 2~5 9 Magnesium stearate 1.a 9 Talc 74 5 9 Preparation:
The act;ve compound is micronized in a je~ mill employing air, and ;s then mixed ~ith the other compo-nents to give a homo~eneous mixture. This ;s forced through a s;eve of No. 7 mesh size and then ;n~roduced into polye~hylene con~ainers with a oerforated top.
Claims (2)
1. A process for the preparation of an azolyl-methyloxirane of the formula I
(I), where A and B are identical or different and independently of one another are each alkyl of 1 to 4 carbon atoms, naphthyl, biphenyl or phenyl, and the phenyl radical can be substituted by halogen, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, phenoxy or phenylsulfonyl, and Z is CH or a nitrogen atom, and pharmaceutically acceptable acid addition salts thereof, wherein a) a compound of the formula II
(II), where A and B have the above meanings and L is a leaving group which can undergo nucleophilic substitution J is reacted with a compound of the formula III
(III), where Me is hydrogen or a metal atom and Z is CH or a nitrogen atom, or b) a compound of the formula II, where A and B have the above meanings and L is hydroxyl, is reacted with a com-pound of the formula IV
(IV), where Z has the above meanings and Y is carbon or sulfur, or c) a compound of the formula V
(V), where Z, A and B have the above meanings, is epoxidized, or d) a compound of the formula VI
(VI), where Z and A have the above meanings, is reacted with a compound of the formula VII
(VII), where B has the above meanings, R1 and R2 are identical or different and are each methyl or phenyl, and n is zero or one, and, if desired, the resulting compound is converted to a pharmaceutically acceptable acid addition salt thereof.
(I), where A and B are identical or different and independently of one another are each alkyl of 1 to 4 carbon atoms, naphthyl, biphenyl or phenyl, and the phenyl radical can be substituted by halogen, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, phenoxy or phenylsulfonyl, and Z is CH or a nitrogen atom, and pharmaceutically acceptable acid addition salts thereof, wherein a) a compound of the formula II
(II), where A and B have the above meanings and L is a leaving group which can undergo nucleophilic substitution J is reacted with a compound of the formula III
(III), where Me is hydrogen or a metal atom and Z is CH or a nitrogen atom, or b) a compound of the formula II, where A and B have the above meanings and L is hydroxyl, is reacted with a com-pound of the formula IV
(IV), where Z has the above meanings and Y is carbon or sulfur, or c) a compound of the formula V
(V), where Z, A and B have the above meanings, is epoxidized, or d) a compound of the formula VI
(VI), where Z and A have the above meanings, is reacted with a compound of the formula VII
(VII), where B has the above meanings, R1 and R2 are identical or different and are each methyl or phenyl, and n is zero or one, and, if desired, the resulting compound is converted to a pharmaceutically acceptable acid addition salt thereof.
2. A compound of the formula I as defined in claim 1 and pharmaceutically acceptable acid addition salts thereof whenever obtained by a process as defined in claim 1 or an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823218129 DE3218129A1 (en) | 1982-05-14 | 1982-05-14 | Azolylmethyloxiranes, their preparation and use as medicaments |
| DEP3218129.9 | 1982-05-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1204117A true CA1204117A (en) | 1986-05-06 |
Family
ID=6163548
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000426058A Expired CA1204117A (en) | 1982-05-14 | 1983-04-18 | Azolylmethyloxiranes, their preparation and their use as drugs |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPS58206585A (en) |
| CA (1) | CA1204117A (en) |
| DE (1) | DE3218129A1 (en) |
| FI (1) | FI77660C (en) |
| ZA (1) | ZA833362B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5057531A (en) * | 1988-02-26 | 1991-10-15 | Basf Aktiengesellschaft | Azolylmethyloxiranes and fungicides containing these compounds |
| 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 |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3511411A1 (en) | 1985-03-29 | 1986-10-02 | Basf Ag, 6700 Ludwigshafen | USE OF AZOLYLMETHYLOXIRANES TO COMBAT VIRAL DISEASES |
| CA1271764A (en) * | 1985-03-29 | 1990-07-17 | Stefan Karbach | Azolylmethyloxiranes, their preparation and their use as crop protection agents |
| DE3907729A1 (en) * | 1989-03-10 | 1990-09-13 | Basf Ag | TRIFLUORMETHYLPHENYLAZOLYLMETHYLOXIRANE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A PLANT PROTECTANT |
| JP2975058B2 (en) * | 1989-07-18 | 1999-11-10 | ビーエーエスエフ アクチェンゲゼルシャフト | Novel Z-1,2-diaryl-allyl chloride, method for its configuration-selective preparation and novel chloromethyl-diaryl-oxirane prepared therefrom |
| EP1899312A2 (en) * | 2005-06-27 | 2008-03-19 | Makhteshim Chemical Works Limited | Improved synthesis of substituted 1-halomethyl-2-phenyl-1-phenyl oxirane |
| UA96450C2 (en) * | 2006-06-21 | 2011-11-10 | Басф Се | Azolylmethyloxiranes, their use for controlling phytopathogenic fungi, a crop protection composition, a method for controlling phytopathogenic fungi and seed |
| US20090305887A1 (en) * | 2006-06-23 | 2009-12-10 | Basf Se | Azolylmethyloxiranes, Their Use for Controlling Phytopathogenic Fungi and Compositions Comprising Them |
| JP2009541250A (en) * | 2006-06-23 | 2009-11-26 | ビーエーエスエフ ソシエタス・ヨーロピア | Azolylmethyloxirane, its use for controlling phytopathogenic fungi, and compositions containing it |
| BRPI0713450A2 (en) * | 2006-07-05 | 2012-01-31 | Basf Se | compounds, use of compounds, crop protection composition, seed, and process to combat phytopathogenic fungi |
| DE502007006380D1 (en) * | 2006-07-05 | 2011-03-10 | Basf Se | AZOLYLMETHYL OXIRANES, THEIR USE IN THE CONTROL OF PLANT PATHOGENIC MUSHROOMS AND THE MEDIUM CONTAINING THEY |
| CN101495473A (en) * | 2006-07-24 | 2009-07-29 | 巴斯夫欧洲公司 | Azolylmethyloxiranes, use thereof for controlling plant pathogenic fungi, and agents containing the same |
| CN101490043A (en) * | 2006-07-25 | 2009-07-22 | 巴斯夫欧洲公司 | Azolylmethyloxiranes, use thereof for controlling plant pathogenic fungi, and agents containing the same |
| WO2008077724A1 (en) * | 2006-12-22 | 2008-07-03 | Basf Se | Azolylmethyloxiranes, their use for controlling phytopathogenic fungi, and compositions comprising them |
| WO2009077471A2 (en) * | 2007-12-19 | 2009-06-25 | Basf Se | Azolylmethyloxiranes, use thereof and agents containing the same |
| JP2011506539A (en) * | 2007-12-19 | 2011-03-03 | ビーエーエスエフ ソシエタス・ヨーロピア | Azolylmethyloxiranes, their use and compositions containing them |
| CN101952279A (en) * | 2007-12-19 | 2011-01-19 | 巴斯夫欧洲公司 | Azolylmethyloxiranes, use thereof and agents containing the same |
| WO2009077497A2 (en) * | 2007-12-19 | 2009-06-25 | Basf Se | Azolyl methyl oxiranes, the use thereof, and agents containing them |
| EP2746276A1 (en) | 2012-12-19 | 2014-06-25 | Basf Se | New substituted triazoles and imidazoles and their use as fungicides |
| WO2014095555A1 (en) | 2012-12-19 | 2014-06-26 | Basf Se | New substituted triazoles and imidazoles and their use as fungicides |
| EP2746275A1 (en) | 2012-12-19 | 2014-06-25 | Basf Se | New substituted triazoles and imidazoles and their use as fungicides |
| CN109996796A (en) | 2016-09-29 | 2019-07-09 | 拜耳作物科学股份公司 | The imidazolyl methyl epoxyethane derivative that 5- as fungicide replaces |
-
1982
- 1982-05-14 DE DE19823218129 patent/DE3218129A1/en not_active Withdrawn
-
1983
- 1983-04-18 CA CA000426058A patent/CA1204117A/en not_active Expired
- 1983-05-09 FI FI831590A patent/FI77660C/en not_active IP Right Cessation
- 1983-05-11 ZA ZA833362A patent/ZA833362B/en unknown
- 1983-05-13 JP JP58082894A patent/JPS58206585A/en active Granted
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5057531A (en) * | 1988-02-26 | 1991-10-15 | Basf Aktiengesellschaft | Azolylmethyloxiranes and fungicides containing these compounds |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| FI831590L (en) | 1983-11-15 |
| JPH0474355B2 (en) | 1992-11-26 |
| FI77660C (en) | 1989-04-10 |
| FI831590A0 (en) | 1983-05-09 |
| FI77660B (en) | 1988-12-30 |
| DE3218129A1 (en) | 1983-11-17 |
| ZA833362B (en) | 1984-02-29 |
| JPS58206585A (en) | 1983-12-01 |
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