CA1146950A - Hydroxybutyl-imidazole derivatives - Google Patents
Hydroxybutyl-imidazole derivativesInfo
- Publication number
- CA1146950A CA1146950A CA000364976A CA364976A CA1146950A CA 1146950 A CA1146950 A CA 1146950A CA 000364976 A CA000364976 A CA 000364976A CA 364976 A CA364976 A CA 364976A CA 1146950 A CA1146950 A CA 1146950A
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- Prior art keywords
- radical
- chlorine
- methyl
- formula
- butyl
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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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- 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
-
- 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
- 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
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
-
- 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
- C07D303/04—Compounds containing oxirane rings containing only hydrogen and carbon atoms in addition to the ring oxygen atoms
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
Abstract of the Disclosure Novel hydroxybutyl-imidazole derivatives represented by the Formula (I) are disclosed.
Description
35~
r ype II (Pha) The present invention relates to the use as anti-microbial agents of certain hydroxybutyl-imidazole derivatives which are novel.
It has already been disclosed that 1-(~-aryl~-ethyl-imidazole derivatives, such as, in particular, 1-[2,4-dichloro-~-(2,4-dichlorobenzyloxy)-phenethyl}-imidazole nitrate ("MICO~IAZOL"(Trade Mark)), have a good antimycotic action (~ee DE-AS (German Published Speci-fication) 1,940,3~8). However, their action in vivo, such as, in particular, againqt Candida, is not always satisfactory.
According to th& present invention there are provided pharmaceutical compositions containing as an active ingredient a cornpound which is a hydroxybutyl-imidazole derivative of the formula ~,~3 OE~ (I) or a phy3iologically acceptable aoid addition ~alt thereof, in which R1 represents Q hydrogen or halogen atom, an alkyl, alkoxy or halogenoalkyl radical or an optionally substituted phenyl or cycloalkyl radical, and R2 represents a hydrogen atom, or R1 and R2 together, in the o-position relative to each other, represent an optionally substi-tuted, multi-membered methylene bridse, or together with the phenyl ring to which they are bonded represent a naphthyl or optionally sub~tituted fluorenyl radical, R3 represents a halogen atom or an alkyl, alkoxy or halogenoalkyl radical, and n is 0, 1,. 2 or 3, Le A 20 002 .. . . . _ , , : : :
5~D
in admixture with an inert pharmaceutical carrier, such as a solid or liquefied gaseous diluent, or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 except in the presence of a surface active agent.
The pharmaceutical compositiQns of the present invention have g~od antimicrobial properties and, especially, good antimycotic properties.
Surprisingly, the hydroxybutyl-imidazole derivatives according to the invention exhibit, in addition to a gocd anti-myootic m vitro activity, a better, therapeutically use~l in vivo activity asainst Candida than
r ype II (Pha) The present invention relates to the use as anti-microbial agents of certain hydroxybutyl-imidazole derivatives which are novel.
It has already been disclosed that 1-(~-aryl~-ethyl-imidazole derivatives, such as, in particular, 1-[2,4-dichloro-~-(2,4-dichlorobenzyloxy)-phenethyl}-imidazole nitrate ("MICO~IAZOL"(Trade Mark)), have a good antimycotic action (~ee DE-AS (German Published Speci-fication) 1,940,3~8). However, their action in vivo, such as, in particular, againqt Candida, is not always satisfactory.
According to th& present invention there are provided pharmaceutical compositions containing as an active ingredient a cornpound which is a hydroxybutyl-imidazole derivative of the formula ~,~3 OE~ (I) or a phy3iologically acceptable aoid addition ~alt thereof, in which R1 represents Q hydrogen or halogen atom, an alkyl, alkoxy or halogenoalkyl radical or an optionally substituted phenyl or cycloalkyl radical, and R2 represents a hydrogen atom, or R1 and R2 together, in the o-position relative to each other, represent an optionally substi-tuted, multi-membered methylene bridse, or together with the phenyl ring to which they are bonded represent a naphthyl or optionally sub~tituted fluorenyl radical, R3 represents a halogen atom or an alkyl, alkoxy or halogenoalkyl radical, and n is 0, 1,. 2 or 3, Le A 20 002 .. . . . _ , , : : :
5~D
in admixture with an inert pharmaceutical carrier, such as a solid or liquefied gaseous diluent, or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 except in the presence of a surface active agent.
The pharmaceutical compositiQns of the present invention have g~od antimicrobial properties and, especially, good antimycotic properties.
Surprisingly, the hydroxybutyl-imidazole derivatives according to the invention exhibit, in addition to a gocd anti-myootic m vitro activity, a better, therapeutically use~l in vivo activity asainst Candida than
2~4-dichloro~-(2,4-dichlorobenzyloxy)-phenethyll-imidazole -nitrate which is known from ~he state of the art and is reco~nised as a good agent of the same type o action.
The active oompounds according to the invention thus repre~lt a valuable enrichment of pharmacy.
Preferred active in~redients in oc~positions of the pre-sent invention are those in which ~ represent a hydrogen ~r halcgen atom (pre~erably a fluorine, chlorine or bromine atom), a straight-chain or branched aIkyl or alkoxy radical with in each case 1 to 4 carbon atcms, a halogenoalkyl radical with 1 to 4 carbon atGms and up bo 5 , ~
, ' . ' ' 511;9 halogen atoms (preferably with l or 2 carbon atoms and up to 3 identical or different (particularly iden~ical) halogen atoms preferably selected from fluorine and chlorine; and trifluoromethyl being mentioned as an exam~le), an optionally substituted phenyl or cycloalkyl radial with 3 to 7 (particularly 5 to 6) carbon atoms, substituents preferably being selected from halogen (preferably f:Luorine, chlorine or bromine), alkyl and alkoxy with l to 4 (preferably with 1 to 2) carbon atoms and nitrc, R2 represents a hydrogen atom, or Rl and R2 together, in the ortho-positlon relative to each other, represent an optionally monosubstituted, disubstituted or polysubstituted methylene bridge with 3 to 5 methylene groups, substituents preferably being selected from halogen (preferably fluorine, chlorine or bromine) and alkyl with 1 to 4 (preferably with 1 or 2) carbon atoms, or 21 and R2, together with the phenyl ring to which they are bonded, respresent a naphthyl radical or a fluorenyl radical which is optionally mono-, di-, tri- or poly-substituted by halo~,en or alkyl with 1 or 2 carbon atoms, R3 represents a halogen atom (preferably a fluorine, chlorine or bromine atom), a straight-chain or branched alkyl or alkoxy radical with in each case l to 4 carbon atoms or a halogenoalkyl Le ~ 20 002 -3-. . ' : -. :
~: ' :......... . .
.' ' :, .
~f~
radical with 1 to 4 carbon atoms (proferably with 1 or 2 carbon atoms) and up to 3 identical or different halogen atoms (halog~ns preferably being fluor.ine and chlorine, and trifluoromethyl being mentioned as an example) and n is 0, 1 or 2.
~ sry particularly preferred compounds of the formula (I) are those in which R1 represents s hydrogen, ~luorine9 chlorine or bromine atom,a methyl, ethyl, methoxy, ethoxy or trifluoromethyl radical or a phenyl, cyclo-pentyl or cyclohexyl radical which i~ optionally mono-substituted or disubstituted by chlorine,- bromine, fluorine, nitro, methyl or methoxy and R2 represents a hydrogen atom, or Rl and R2 together, in the ortho-position relative to each other, represent a tri-, tetra- or penta-methylene bridga which iq optionally substituted by chlorine or methyl, or together with the phe~yl ring to which they sre bonded, repre.~ent a naphthyl radical, or a fluorenyl radical which i~ optionally substituted by chlorine or methyl, R3 represents a chlorine or fluorine atom or a methyl radical snd n is 0 or 1.
The following compounds oF the ~ormula ~I~ can be mentioned specifically, in addition to the compounds mentioned in the preparative Exa~ple~:
R2;~ C -- C(CU ~, (I) ~1 Le A 20 002 -h-~,.
.
~' ~ ' ' ' , ~ ' ' ' R~ R2 R3 Cl~
4-<~ H
Cl~
4-~-Cl H
4~-Cl H
4~-CH~s H
4~0CH3 H
4~>-C ( CH~ )3 H
4-Cl H
The active oompounds according to the invention thus repre~lt a valuable enrichment of pharmacy.
Preferred active in~redients in oc~positions of the pre-sent invention are those in which ~ represent a hydrogen ~r halcgen atom (pre~erably a fluorine, chlorine or bromine atom), a straight-chain or branched aIkyl or alkoxy radical with in each case 1 to 4 carbon atcms, a halogenoalkyl radical with 1 to 4 carbon atGms and up bo 5 , ~
, ' . ' ' 511;9 halogen atoms (preferably with l or 2 carbon atoms and up to 3 identical or different (particularly iden~ical) halogen atoms preferably selected from fluorine and chlorine; and trifluoromethyl being mentioned as an exam~le), an optionally substituted phenyl or cycloalkyl radial with 3 to 7 (particularly 5 to 6) carbon atoms, substituents preferably being selected from halogen (preferably f:Luorine, chlorine or bromine), alkyl and alkoxy with l to 4 (preferably with 1 to 2) carbon atoms and nitrc, R2 represents a hydrogen atom, or Rl and R2 together, in the ortho-positlon relative to each other, represent an optionally monosubstituted, disubstituted or polysubstituted methylene bridge with 3 to 5 methylene groups, substituents preferably being selected from halogen (preferably fluorine, chlorine or bromine) and alkyl with 1 to 4 (preferably with 1 or 2) carbon atoms, or 21 and R2, together with the phenyl ring to which they are bonded, respresent a naphthyl radical or a fluorenyl radical which is optionally mono-, di-, tri- or poly-substituted by halo~,en or alkyl with 1 or 2 carbon atoms, R3 represents a halogen atom (preferably a fluorine, chlorine or bromine atom), a straight-chain or branched alkyl or alkoxy radical with in each case l to 4 carbon atoms or a halogenoalkyl Le ~ 20 002 -3-. . ' : -. :
~: ' :......... . .
.' ' :, .
~f~
radical with 1 to 4 carbon atoms (proferably with 1 or 2 carbon atoms) and up to 3 identical or different halogen atoms (halog~ns preferably being fluor.ine and chlorine, and trifluoromethyl being mentioned as an example) and n is 0, 1 or 2.
~ sry particularly preferred compounds of the formula (I) are those in which R1 represents s hydrogen, ~luorine9 chlorine or bromine atom,a methyl, ethyl, methoxy, ethoxy or trifluoromethyl radical or a phenyl, cyclo-pentyl or cyclohexyl radical which i~ optionally mono-substituted or disubstituted by chlorine,- bromine, fluorine, nitro, methyl or methoxy and R2 represents a hydrogen atom, or Rl and R2 together, in the ortho-position relative to each other, represent a tri-, tetra- or penta-methylene bridga which iq optionally substituted by chlorine or methyl, or together with the phe~yl ring to which they sre bonded, repre.~ent a naphthyl radical, or a fluorenyl radical which i~ optionally substituted by chlorine or methyl, R3 represents a chlorine or fluorine atom or a methyl radical snd n is 0 or 1.
The following compounds oF the ~ormula ~I~ can be mentioned specifically, in addition to the compounds mentioned in the preparative Exa~ple~:
R2;~ C -- C(CU ~, (I) ~1 Le A 20 002 -h-~,.
.
~' ~ ' ' ' , ~ ' ' ' R~ R2 R3 Cl~
4-<~ H
Cl~
4-~-Cl H
4~-Cl H
4~-CH~s H
4~0CH3 H
4~>-C ( CH~ )3 H
4-Cl H
3-Cl H
2-Cl H
2--C1 4-Cl -:~ ~
, ~ :
2-Cl H
2--C1 4-Cl -:~ ~
, ~ :
4~ H
4~ ~ _ Le A 20 00 2 -- .... .... . .
. .
'' :
~: .: .
.
--.
.~ ., - . . .
~ . ~
3~4-(CH2 )y~ ~
~,4-(CE~2 ),,-- _ . Cl ~
[~ ~
2-~1 . 4-Cl.6-Cl The activP campounds to bo uq~d according tD the invcntion and acid addition salt~ thereof are novel~
They can be prepared by reacting oxiranes of the formula C\ - C(CH3~3 (Ir) Rn CH~-O
in which R1, R~ and R3 and n havs th~ m~aning indi~at~d abovc, with imidazole in the presence of an alkali metal alcoholate (preferably an alkali metal Cl-C3-alkanoate), such as sodium methylate, and in the presence of an inert or,,anic solvent, such as, dimethylformamide, at tem?eratures between 30C
and 100C. Isolation of the end products is effected in t~e generally CU9 tomary manner.
The oxiranes of the formula (II) are novel. They are obtained by reacting corresponding ketones of the formula Le A 20 002 -6-, - , . . . - -.: . . . ~ , - ~ .
:, : - . . . :
.
.
. . . . . ~ .
, R- ~CO - C (CH3 )3 ~ I T I ) in which R1, R2 and R3 and n have the meaning indicated above, a) with a dimethyloxosulphonium methylide of the formuls ~CH3)250CH2 (IV) in a manner which is in itself known in the presence of a diluent, such as dimethylsulphoxide,at temperature~
between 20 and ao oc ~in this context, see also JACS 87, 1363-1364 (1965)), or b) with trimethyl~ulphonium methyl-3ulphate of the formula (CH~)35CH3504 ~ (V) . in a manner which is in itself known in the prasence of a two-phase system and if appropriate in thE presence of a phase transfier cataly~t, at temperatures between 0 and 100C (see also the treatment in Hete~ooycles 8, ~97 (1~77)).
The ketones of the formula (III) are generally iO known compounds of organic chemistry.
Dimethyloxasulphonium methylide of the formula (IV) is likewise known and is employed as a product produced ln situ by reacting trimethyloxo.ulphonium iodids with sodium hydride (see also the former above-mentioned literature reference) or sodium amide. Trimethylsul-phonium methyl-sulFhate of the formula (V) is also known and is employed as a product prcduced in situ, by reacting dimethyl sulphide with dimethyl sulphate (see also the letter above-mentioned literature ~eference) Le A 20 002 . _ _ .. . .. .. . .
~' ' .~ .
.. .
.~, . . .
.
'. ~ ' ' , :
.
.
~46~
The oxiranes of the formula (II) obtainab~e by processes (a) and (b) can also be further reacted directly~ that is to say without isolation, to give the end products of the formula ~I).
The compounds of the formula (I) to be used according to the invention can ~lso be obtained if, for example, corresponding imidazolylmethyl phenyl ketones ars reactQd with tert.-butyl-magnesium bromide in a known manner, or if the corresponding l-halogeno-l-hydroxy-2-phenyl-3,3-dimethyl-butane~ are rsacted with imidazole in a known manner.
Any of the physiologically acceptable acids can be used for the preparation of acid addition salts of the compound3 of the formula (I). These acids include, as preference3, hydrogen halide acids (for example, hydrobromic acid and, preferably, hydrochloric acid), phosphoric acid, nitric acid, sulphuric acid, monofunctional and bifunc-tional carboxylic acids and hydroxycarboxylic acids (for example, acatic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citr1c acid7 salicylic acidl sorbic acid p~wic acidc~ld lactic acid) and sulphonic acids (for example, p-toluene-sulphonic acid and 1,5-naphthalenedisulphonic acid).
Th~ salts of the compounds of the formula (I) can be obtained in a simple manner by customary salt Formation methods, for example by dissolving a compound of the formula (I) in a suitable inert solvent and adding the acid, for example hydrochloric acid, and they can be isolated in a known manner, for example by filtration, and if appropriate purified by wa3hing with an inert organic solvent.
The compounds of the formula (I) which can be ussd according to the invention, and their acid addition 3alta and metal salt complexe3, display antimicrobial actions, in particular powerful antimycotic actions.
They po33eqs a very broad antimycotic action spectrum, especially against dermatoph ~es and blastomyces as well as biphase fungi, for example against varieties of Candida, such as Candida albican3! varieties of Le A 20 002 . .: . _ . . --.-- . . .
-: - . - . . , - -, ~ . ~ . .: . . - .
-~: '. ' . , . ,. , . , : , .
: . :
Epid~r~ophyton, such as Epidermophytan floccosum, va~ie-ties of Asp~rgillus, such as Aspergillus niqer and Aspergillus fumigatus, varieties ~f Trichophyton, such as Trichophyton mentagrophytes, varieties of Microsporon, such as Microsporon fe].ineum an~ va~ieties of Penicilli~m, 3uch as Penicillium co~mune. Th~
liYting of the3e micro-organisms in no way implies a limit~tion of the g~rms which can be combat~d but i9 only illustrative.
Examples which may be men~ioned of fields of indicati~n in human medicine are: dermatomycoses ~nd systemic mycoses caused by Trichophyt~n mentagr3phytes and other varieti~s of Trichophyton, varieties oF
Microsporon, Epidermophyton floccosum, blastomyces and biphase fungi as wull as moulds.
As stated above, the invention also relates to the use in medicine of the compounds of the invention.
The present invention provides pharmaceutical compositions containing as active ingredient a compound o~
the invention in admixture with an inert pharmaceutical carrier, such as a solid or liquefied gaseous diluent, or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 (preferably less than 350) except in the presence of a surface active agent.
The invention further provides pharmaceutical compositions containing as active ingredient a compound of the invention in the form of a sterile and/or hysiologically isotonic aqueous solution.
The invention also provides medicamentsin dosage unit form comprising a compound ofthe invention.
; Le A 20 002 -9-_._. . . ___ ,, , `-^
; ~ , .
.
s~
The invention also provides medicaments in the form of tablets (including lozen~es and granules), dragees, capsules, pills, ampoules or suppositories conprisin~
a compound of the invention.
"Medicament" as used in this Specification means physically discrete coherent portions suitable for medical administration. "Medicament in dosage unit form" as used in this Specification means physically discrete co~erent units suitable for medical administration each 1n containing a daily dose or a multiple (up to rour ti~es) or submultiple (down to a fcrtieth) of a daily dose of the co~,pound of the invention in association with a carrier and/or enclosed within an envelope. Whether the medicament contains a daily dose or, for example, a half, a third or a quarter of a daily dose will depend on whether the medicament is to be administered once or, for example, twice, three times or four times a day respectively.
The pharmaceutical co~.position according to the invention may, for example, take the ~orm of ointments, gels, pastes, creams, sprays (including aerosols), lotions, suspensionsl solutions and e~ulsions of the active in~redient in aqueous or non-aqueous diluents, syrups~
granulates or powders.
The diluents to be used in pharmaceutical co~.positions (e.~. ~ranulates) adapted to he formed into tablets~
dragees, capsules and pills include the following:
(a) fillers and extenders, e-.g. starch, su~ars, mannitol, and silicic acid; (b) binding agents, e.g. carboxymethyl cellulose and other cellulose derivatives, al~inates, ~elatine and polyvinyl pyrrolidone; (c) moisturi~ing agents, e.g. ~lycerol; (d) disintegrating agents, e.g.
agar-agar, calcium carbonate and sodium bicarbonate;
(e) agents for retarding dissolution e.~. paraffin; (f) resorp5ion accelerators, e.g. quaternary ammonium compounds;
(g) surface active a~ents, e.~. cetyl alcohol, glycerol monostearate; (h) adsorptive carriers, e.g. kaolin and Le A 20 002 . . ~
,,.,. :~ . :
~ .
bentonite; (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethyl glycols.
The tablets, dragees~ capsules and pills formed from the pharmaceutical compositions of the invention can have the customary coatings, envelopes and protective matrices, which nay contain opasifiers. They can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period cr time. The coatings,, envelopes and pro-10 tective matrices may be made, for exan.ple, of polymericsubstances or waxes.
The ingredient can also be made up in microencapsulated form together with one or several of the above-mentioned dilue~ts.
The diluents to be used in pharmaceutical compositions adapted to be formed into suppositories can, for exa~ple, be the usual water-soluble diluents, such as polyethylene glycols and fats (e.g. cocoa oil and high esters (e.g.
C14-alcohol with C16-fatty acid)) or mixtures of these diluents.
The pharmaceutical compositions which are oint~lents, pastes, creams and gels can, for exanple, contain the usual diluents~ e.g. aninal and ve~etable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene 25 glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures cr these substances.
The pharmaceutical compositions which are po~lders and sprays can, for example, contain the usual diluents, e.g. lactose, talc, silicic acid, aluminiunm hydroxide, 30 calcium silicate, and polyamide powder or mi~tures of these substa~ces. Aerosol sprays can, for example, contain the usual propellants~ e.g. chlorofluorohydrocarbons.
The pharmaceutical compositions which are solutions and emulsions can, for example, contain the customary 35 diluents (with, of course, the above-n-.entioned exclusion of solvents having a molecular weight below 200 except Le A 20 002 -11-.
, . - :
in the presence of a surface-active agent), such as solvents, dissolving agents and emulsifiers; specific examples of sueh diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl ben~oate, propylene glycol, 1~3-butylene glycol, dimethylformamide, oils (for e~ample ground nut oil), ~lyeerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitol or mixtures thereof.
For parenteral administration, solutions and emulsions should be sterile, and, if appropriate, blood-isotonic.
The pharmaeeutical compositions whieh are suspensions ean contain the usual diluents~ such as liquid diluents, e.g. water~ ethyl aleohol, propylene glycol, surface-active agents (e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbite and sorbitane esters), micro-erystalline eellulose, aluminium metahydroxide, bentonite, agar-a~ar and tragaeanth or mixtures thereof.
A11 the pharmaeeutieal eompositions aeeordin~ to the in~ention ean also contain colouring agents ~ncl preser~atives as well as perfumes and flavourin additions (e.g. peppermint oil and euealyptus oil) and sweetening agents te.g. saeeharin).
The pharmaeeutieal eompositions aeeordin~ to the invention generally eontain from 0.1 to 99.5% usually from ~.5 to ~5~ of the aetive ingredient by weight of the total eomposition.
In addition to a compound of the invention, the pharmaceutical compositions and medicaments accordin~
to the invention can also contain other pharmaeeutieally ~o aetive eompounds. They may also eontain a plurality of eo~pounds of the invention.
Any diluent in the medieaments of the present invention may be any of those mentioned above in relation to the pharmaeeutieal eompositions of the present invention.
Sueh medieaments may inelude solvents of moleeular weight less than 200 as sole diluent.
The diserete eoherent portions eonstitutin~ the Le A 20 002 ._ .
- -.
:: :
medicament accordin~ to the invention will ~enerally be adapted by virtue of their shape or packaging for me~ical administration and may be, for example, any of the following: tablets (including lozenges and granulates), pills, dragees, capsules, suppositories and ampoules.
Some of these forms may be made up for delayed release of the active ingredient. ~ome, such as capsules, include a protective envelope which renders the portions of the medicament physically discrete and coherent.
The preferred daily dose for administration of the medicaments of the invention is 2.5 to lOg of active ingredient.
The production of the above mentioned phar~aceutical compositions and medicaments is carried out by any method known in the art, for example, by mixing the active ingredient(s) with the diluent(s) to form a pharmaceutical ccmposition (e.g. a granulate) and then forming the composition into the medicament (e.g. tablets).
This invention further provides a method of combatin~
the above-mentioned diseases in warm-blooded animals, which comprises adminis~ering to the animals a compound o~
the invention alone or in admixture with a diluent or in the fo~m o~ a medicamen~ accordin~ to the invention.
It is envisaged that these active compounds will be administered perorally, parenterally (for example intramuscularly, intraperitoneally, subcutaneously and intravenously), rectally or locally, prelerably parenterally, and especially intravenously. Preferred pharmaceutical co~.positions and medicaments are therefore those adapted for administration such as parenteral administration. Administration in the method of the invention is preferably parenteral administration.
In general it has proved advantageous to administer a~.ounts of from lO m6 to 300 mg/kg, preferably 50 mg to 200 mg/kg of bcdy wei~ht per day to achieve effective results. Nevertheless, it can at times be necessary Le A 20 002 .. . . .
' - ~
~L~LfiL4~9S~
to deviate from those dosage rates, and in partic~lar to do so as a function of the nature and body weight of the subject to be treated the individual reaction of this subject to the treatment, ths type ot Formulation in which the active ingredient is administered and the mode in which the administration is carried out and the point in the progress oF the disease or interval at which it is to be administered. Thus it may in some case suffice to use less than the above-mentioned minimum dosage rate, whilst other cases the upper limit mentioned must be exceeded to achieve the deqired results. Where larg~r amounts are adminjstared it can be advisable to divide the-qe into several individual administrations over the course of the day.
The following Examples A and a illustrate the in vitro and in vivo activity of compounds oF the present invention.
Example A
Antimycot/c in vitro activity Description o~ the experiment The in vitro test is carriad out in a serie~
dilution test using germ inocula of on average 5 x 10 germs/ml of substrate. Tha nutriant medium used was a) for dermatophytes and moulds: Sabouraud'~ milieu d'epreuve and b) for yeasts- Isotonic 5ensitest Proth from Oxoid.
The incubation temperature is 28C; the incubation time is 24 hours in the case of yeasts and 96 hours in the case of dermatophytes and moulds.
In this test, the compounds according to the 3U invention exhibit good minimum inhibitory cqncentration values against numerouQ dermatophy~es~ moulds and ye a3 t q .
Fxample B
~ .
Antimicrobial in vivo activitv (oral~ in candidosis of .
mlce Description oF the axperiment:
Mice of the SPF-CF1 type are .nfected intravenously with 1 - 2 x 106 logarithmically growing Candi~a cells, Le A 20 002 -14-:
:: :
: -~ :
which are su3pended in physiological sodium chloride solution. The animals are treated orally with in each case 50 ~102 mg of the preparation/kg of body weight one hour before and ssven hours after the inFection.
Result:
Untrezt~d animals die 3 to 6 days after infec-tion. The survival rate on the 6th day after infec-tion is about 5O in the case of the untreated control animals.
In this test, the compound according to the pre~ent invention prepared as described in Example 2 exhibit a Yery good action, whilst "Miconazol" (Trade Mark), which iq known, exhibits no action.
The following Examples illustrate processes for the production of compounds of the present invention.
Exampl~ 1 OH
- C - G(CH,)3 ~ .
A solution of 22.2 9 (0.08B mole) of 2-(4-biphenylyl)-2-(tert.-butyl)-oxirans in 150 ml of dimethylformamide is added dropwise to a solution of 6.4 9 (0.117 mole) of sodium methylate and 13.2 9 ~0.2 mole) of imidazole in 40 ml of methyl alcohol. After warming the mixture to 80C for 6 hour3, it is concentrated ln vacuo, the residue is introducad into 3,000 ml of water, the mass of crystals which has separated out is dissolved in mrthylene chloride and ths solution is washed with water.
Ths ~olution is dried over sodium sulphate and evaporated _ vacuo. The crystals are stirred with ether.
20.5 9 (73~ of theory) of 1-(4-biphenylyl)-1-(tert.butyl)-2-(imidazol-1-yl)-~than-1-ol oF melting point l84C are Le A 20 002 -15-.:
4~ ~ _ Le A 20 00 2 -- .... .... . .
. .
'' :
~: .: .
.
--.
.~ ., - . . .
~ . ~
3~4-(CH2 )y~ ~
~,4-(CE~2 ),,-- _ . Cl ~
[~ ~
2-~1 . 4-Cl.6-Cl The activP campounds to bo uq~d according tD the invcntion and acid addition salt~ thereof are novel~
They can be prepared by reacting oxiranes of the formula C\ - C(CH3~3 (Ir) Rn CH~-O
in which R1, R~ and R3 and n havs th~ m~aning indi~at~d abovc, with imidazole in the presence of an alkali metal alcoholate (preferably an alkali metal Cl-C3-alkanoate), such as sodium methylate, and in the presence of an inert or,,anic solvent, such as, dimethylformamide, at tem?eratures between 30C
and 100C. Isolation of the end products is effected in t~e generally CU9 tomary manner.
The oxiranes of the formula (II) are novel. They are obtained by reacting corresponding ketones of the formula Le A 20 002 -6-, - , . . . - -.: . . . ~ , - ~ .
:, : - . . . :
.
.
. . . . . ~ .
, R- ~CO - C (CH3 )3 ~ I T I ) in which R1, R2 and R3 and n have the meaning indicated above, a) with a dimethyloxosulphonium methylide of the formuls ~CH3)250CH2 (IV) in a manner which is in itself known in the presence of a diluent, such as dimethylsulphoxide,at temperature~
between 20 and ao oc ~in this context, see also JACS 87, 1363-1364 (1965)), or b) with trimethyl~ulphonium methyl-3ulphate of the formula (CH~)35CH3504 ~ (V) . in a manner which is in itself known in the prasence of a two-phase system and if appropriate in thE presence of a phase transfier cataly~t, at temperatures between 0 and 100C (see also the treatment in Hete~ooycles 8, ~97 (1~77)).
The ketones of the formula (III) are generally iO known compounds of organic chemistry.
Dimethyloxasulphonium methylide of the formula (IV) is likewise known and is employed as a product produced ln situ by reacting trimethyloxo.ulphonium iodids with sodium hydride (see also the former above-mentioned literature reference) or sodium amide. Trimethylsul-phonium methyl-sulFhate of the formula (V) is also known and is employed as a product prcduced in situ, by reacting dimethyl sulphide with dimethyl sulphate (see also the letter above-mentioned literature ~eference) Le A 20 002 . _ _ .. . .. .. . .
~' ' .~ .
.. .
.~, . . .
.
'. ~ ' ' , :
.
.
~46~
The oxiranes of the formula (II) obtainab~e by processes (a) and (b) can also be further reacted directly~ that is to say without isolation, to give the end products of the formula ~I).
The compounds of the formula (I) to be used according to the invention can ~lso be obtained if, for example, corresponding imidazolylmethyl phenyl ketones ars reactQd with tert.-butyl-magnesium bromide in a known manner, or if the corresponding l-halogeno-l-hydroxy-2-phenyl-3,3-dimethyl-butane~ are rsacted with imidazole in a known manner.
Any of the physiologically acceptable acids can be used for the preparation of acid addition salts of the compound3 of the formula (I). These acids include, as preference3, hydrogen halide acids (for example, hydrobromic acid and, preferably, hydrochloric acid), phosphoric acid, nitric acid, sulphuric acid, monofunctional and bifunc-tional carboxylic acids and hydroxycarboxylic acids (for example, acatic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citr1c acid7 salicylic acidl sorbic acid p~wic acidc~ld lactic acid) and sulphonic acids (for example, p-toluene-sulphonic acid and 1,5-naphthalenedisulphonic acid).
Th~ salts of the compounds of the formula (I) can be obtained in a simple manner by customary salt Formation methods, for example by dissolving a compound of the formula (I) in a suitable inert solvent and adding the acid, for example hydrochloric acid, and they can be isolated in a known manner, for example by filtration, and if appropriate purified by wa3hing with an inert organic solvent.
The compounds of the formula (I) which can be ussd according to the invention, and their acid addition 3alta and metal salt complexe3, display antimicrobial actions, in particular powerful antimycotic actions.
They po33eqs a very broad antimycotic action spectrum, especially against dermatoph ~es and blastomyces as well as biphase fungi, for example against varieties of Candida, such as Candida albican3! varieties of Le A 20 002 . .: . _ . . --.-- . . .
-: - . - . . , - -, ~ . ~ . .: . . - .
-~: '. ' . , . ,. , . , : , .
: . :
Epid~r~ophyton, such as Epidermophytan floccosum, va~ie-ties of Asp~rgillus, such as Aspergillus niqer and Aspergillus fumigatus, varieties ~f Trichophyton, such as Trichophyton mentagrophytes, varieties of Microsporon, such as Microsporon fe].ineum an~ va~ieties of Penicilli~m, 3uch as Penicillium co~mune. Th~
liYting of the3e micro-organisms in no way implies a limit~tion of the g~rms which can be combat~d but i9 only illustrative.
Examples which may be men~ioned of fields of indicati~n in human medicine are: dermatomycoses ~nd systemic mycoses caused by Trichophyt~n mentagr3phytes and other varieti~s of Trichophyton, varieties oF
Microsporon, Epidermophyton floccosum, blastomyces and biphase fungi as wull as moulds.
As stated above, the invention also relates to the use in medicine of the compounds of the invention.
The present invention provides pharmaceutical compositions containing as active ingredient a compound o~
the invention in admixture with an inert pharmaceutical carrier, such as a solid or liquefied gaseous diluent, or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 (preferably less than 350) except in the presence of a surface active agent.
The invention further provides pharmaceutical compositions containing as active ingredient a compound of the invention in the form of a sterile and/or hysiologically isotonic aqueous solution.
The invention also provides medicamentsin dosage unit form comprising a compound ofthe invention.
; Le A 20 002 -9-_._. . . ___ ,, , `-^
; ~ , .
.
s~
The invention also provides medicaments in the form of tablets (including lozen~es and granules), dragees, capsules, pills, ampoules or suppositories conprisin~
a compound of the invention.
"Medicament" as used in this Specification means physically discrete coherent portions suitable for medical administration. "Medicament in dosage unit form" as used in this Specification means physically discrete co~erent units suitable for medical administration each 1n containing a daily dose or a multiple (up to rour ti~es) or submultiple (down to a fcrtieth) of a daily dose of the co~,pound of the invention in association with a carrier and/or enclosed within an envelope. Whether the medicament contains a daily dose or, for example, a half, a third or a quarter of a daily dose will depend on whether the medicament is to be administered once or, for example, twice, three times or four times a day respectively.
The pharmaceutical co~.position according to the invention may, for example, take the ~orm of ointments, gels, pastes, creams, sprays (including aerosols), lotions, suspensionsl solutions and e~ulsions of the active in~redient in aqueous or non-aqueous diluents, syrups~
granulates or powders.
The diluents to be used in pharmaceutical co~.positions (e.~. ~ranulates) adapted to he formed into tablets~
dragees, capsules and pills include the following:
(a) fillers and extenders, e-.g. starch, su~ars, mannitol, and silicic acid; (b) binding agents, e.g. carboxymethyl cellulose and other cellulose derivatives, al~inates, ~elatine and polyvinyl pyrrolidone; (c) moisturi~ing agents, e.g. ~lycerol; (d) disintegrating agents, e.g.
agar-agar, calcium carbonate and sodium bicarbonate;
(e) agents for retarding dissolution e.~. paraffin; (f) resorp5ion accelerators, e.g. quaternary ammonium compounds;
(g) surface active a~ents, e.~. cetyl alcohol, glycerol monostearate; (h) adsorptive carriers, e.g. kaolin and Le A 20 002 . . ~
,,.,. :~ . :
~ .
bentonite; (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethyl glycols.
The tablets, dragees~ capsules and pills formed from the pharmaceutical compositions of the invention can have the customary coatings, envelopes and protective matrices, which nay contain opasifiers. They can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period cr time. The coatings,, envelopes and pro-10 tective matrices may be made, for exan.ple, of polymericsubstances or waxes.
The ingredient can also be made up in microencapsulated form together with one or several of the above-mentioned dilue~ts.
The diluents to be used in pharmaceutical compositions adapted to be formed into suppositories can, for exa~ple, be the usual water-soluble diluents, such as polyethylene glycols and fats (e.g. cocoa oil and high esters (e.g.
C14-alcohol with C16-fatty acid)) or mixtures of these diluents.
The pharmaceutical compositions which are oint~lents, pastes, creams and gels can, for exanple, contain the usual diluents~ e.g. aninal and ve~etable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene 25 glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures cr these substances.
The pharmaceutical compositions which are po~lders and sprays can, for example, contain the usual diluents, e.g. lactose, talc, silicic acid, aluminiunm hydroxide, 30 calcium silicate, and polyamide powder or mi~tures of these substa~ces. Aerosol sprays can, for example, contain the usual propellants~ e.g. chlorofluorohydrocarbons.
The pharmaceutical compositions which are solutions and emulsions can, for example, contain the customary 35 diluents (with, of course, the above-n-.entioned exclusion of solvents having a molecular weight below 200 except Le A 20 002 -11-.
, . - :
in the presence of a surface-active agent), such as solvents, dissolving agents and emulsifiers; specific examples of sueh diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl ben~oate, propylene glycol, 1~3-butylene glycol, dimethylformamide, oils (for e~ample ground nut oil), ~lyeerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitol or mixtures thereof.
For parenteral administration, solutions and emulsions should be sterile, and, if appropriate, blood-isotonic.
The pharmaeeutical compositions whieh are suspensions ean contain the usual diluents~ such as liquid diluents, e.g. water~ ethyl aleohol, propylene glycol, surface-active agents (e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbite and sorbitane esters), micro-erystalline eellulose, aluminium metahydroxide, bentonite, agar-a~ar and tragaeanth or mixtures thereof.
A11 the pharmaeeutieal eompositions aeeordin~ to the in~ention ean also contain colouring agents ~ncl preser~atives as well as perfumes and flavourin additions (e.g. peppermint oil and euealyptus oil) and sweetening agents te.g. saeeharin).
The pharmaeeutieal eompositions aeeordin~ to the invention generally eontain from 0.1 to 99.5% usually from ~.5 to ~5~ of the aetive ingredient by weight of the total eomposition.
In addition to a compound of the invention, the pharmaceutical compositions and medicaments accordin~
to the invention can also contain other pharmaeeutieally ~o aetive eompounds. They may also eontain a plurality of eo~pounds of the invention.
Any diluent in the medieaments of the present invention may be any of those mentioned above in relation to the pharmaeeutieal eompositions of the present invention.
Sueh medieaments may inelude solvents of moleeular weight less than 200 as sole diluent.
The diserete eoherent portions eonstitutin~ the Le A 20 002 ._ .
- -.
:: :
medicament accordin~ to the invention will ~enerally be adapted by virtue of their shape or packaging for me~ical administration and may be, for example, any of the following: tablets (including lozenges and granulates), pills, dragees, capsules, suppositories and ampoules.
Some of these forms may be made up for delayed release of the active ingredient. ~ome, such as capsules, include a protective envelope which renders the portions of the medicament physically discrete and coherent.
The preferred daily dose for administration of the medicaments of the invention is 2.5 to lOg of active ingredient.
The production of the above mentioned phar~aceutical compositions and medicaments is carried out by any method known in the art, for example, by mixing the active ingredient(s) with the diluent(s) to form a pharmaceutical ccmposition (e.g. a granulate) and then forming the composition into the medicament (e.g. tablets).
This invention further provides a method of combatin~
the above-mentioned diseases in warm-blooded animals, which comprises adminis~ering to the animals a compound o~
the invention alone or in admixture with a diluent or in the fo~m o~ a medicamen~ accordin~ to the invention.
It is envisaged that these active compounds will be administered perorally, parenterally (for example intramuscularly, intraperitoneally, subcutaneously and intravenously), rectally or locally, prelerably parenterally, and especially intravenously. Preferred pharmaceutical co~.positions and medicaments are therefore those adapted for administration such as parenteral administration. Administration in the method of the invention is preferably parenteral administration.
In general it has proved advantageous to administer a~.ounts of from lO m6 to 300 mg/kg, preferably 50 mg to 200 mg/kg of bcdy wei~ht per day to achieve effective results. Nevertheless, it can at times be necessary Le A 20 002 .. . . .
' - ~
~L~LfiL4~9S~
to deviate from those dosage rates, and in partic~lar to do so as a function of the nature and body weight of the subject to be treated the individual reaction of this subject to the treatment, ths type ot Formulation in which the active ingredient is administered and the mode in which the administration is carried out and the point in the progress oF the disease or interval at which it is to be administered. Thus it may in some case suffice to use less than the above-mentioned minimum dosage rate, whilst other cases the upper limit mentioned must be exceeded to achieve the deqired results. Where larg~r amounts are adminjstared it can be advisable to divide the-qe into several individual administrations over the course of the day.
The following Examples A and a illustrate the in vitro and in vivo activity of compounds oF the present invention.
Example A
Antimycot/c in vitro activity Description o~ the experiment The in vitro test is carriad out in a serie~
dilution test using germ inocula of on average 5 x 10 germs/ml of substrate. Tha nutriant medium used was a) for dermatophytes and moulds: Sabouraud'~ milieu d'epreuve and b) for yeasts- Isotonic 5ensitest Proth from Oxoid.
The incubation temperature is 28C; the incubation time is 24 hours in the case of yeasts and 96 hours in the case of dermatophytes and moulds.
In this test, the compounds according to the 3U invention exhibit good minimum inhibitory cqncentration values against numerouQ dermatophy~es~ moulds and ye a3 t q .
Fxample B
~ .
Antimicrobial in vivo activitv (oral~ in candidosis of .
mlce Description oF the axperiment:
Mice of the SPF-CF1 type are .nfected intravenously with 1 - 2 x 106 logarithmically growing Candi~a cells, Le A 20 002 -14-:
:: :
: -~ :
which are su3pended in physiological sodium chloride solution. The animals are treated orally with in each case 50 ~102 mg of the preparation/kg of body weight one hour before and ssven hours after the inFection.
Result:
Untrezt~d animals die 3 to 6 days after infec-tion. The survival rate on the 6th day after infec-tion is about 5O in the case of the untreated control animals.
In this test, the compound according to the pre~ent invention prepared as described in Example 2 exhibit a Yery good action, whilst "Miconazol" (Trade Mark), which iq known, exhibits no action.
The following Examples illustrate processes for the production of compounds of the present invention.
Exampl~ 1 OH
- C - G(CH,)3 ~ .
A solution of 22.2 9 (0.08B mole) of 2-(4-biphenylyl)-2-(tert.-butyl)-oxirans in 150 ml of dimethylformamide is added dropwise to a solution of 6.4 9 (0.117 mole) of sodium methylate and 13.2 9 ~0.2 mole) of imidazole in 40 ml of methyl alcohol. After warming the mixture to 80C for 6 hour3, it is concentrated ln vacuo, the residue is introducad into 3,000 ml of water, the mass of crystals which has separated out is dissolved in mrthylene chloride and ths solution is washed with water.
Ths ~olution is dried over sodium sulphate and evaporated _ vacuo. The crystals are stirred with ether.
20.5 9 (73~ of theory) of 1-(4-biphenylyl)-1-(tert.butyl)-2-(imidazol-1-yl)-~than-1-ol oF melting point l84C are Le A 20 002 -15-.:
5~D
obtained.
Preparatinn of the startinc materia-l .
(new intermediate product of the formula (II) (II-1) ~C\-- C (C~ )3 CH;! -120 ml of dimethylsulphoxide are added dropwise to 3.6 9 (0.12 mole) of 80o pure sodium hydride an~ 26.4 9 (0.12 mole) of trimethylo~osulphonium iodide, whilst /tirring. A solution of 23.8 9 (0.1 mole) of 4-biphenylyl tert.-butyl ketone in 150 ml of dimethyl-sulphoxide is then added dropwise, whilst stirring.
~; The mixture is warmed to 50C for ~ hours and 500 ml of water are than added dropwise at 20C, whilst cooling.
The crystals which haveseparated out are dissolved in chloroform and the chloroform solution is washed with water, driad over sodium sulphate and evaporated in a . rutary evaporator. The mass of crystals is stirred with petroleum ether and filterad off. 22.3 9 (88~
of theory~ of 2-(4-biphenylyl)-2-(tert.-butyl)-oxirane of m~ltir.~! D~int ?8C are obtained.
~ G0 - C(CHs~
obtained.
Preparatinn of the startinc materia-l .
(new intermediate product of the formula (II) (II-1) ~C\-- C (C~ )3 CH;! -120 ml of dimethylsulphoxide are added dropwise to 3.6 9 (0.12 mole) of 80o pure sodium hydride an~ 26.4 9 (0.12 mole) of trimethylo~osulphonium iodide, whilst /tirring. A solution of 23.8 9 (0.1 mole) of 4-biphenylyl tert.-butyl ketone in 150 ml of dimethyl-sulphoxide is then added dropwise, whilst stirring.
~; The mixture is warmed to 50C for ~ hours and 500 ml of water are than added dropwise at 20C, whilst cooling.
The crystals which haveseparated out are dissolved in chloroform and the chloroform solution is washed with water, driad over sodium sulphate and evaporated in a . rutary evaporator. The mass of crystals is stirred with petroleum ether and filterad off. 22.3 9 (88~
of theory~ of 2-(4-biphenylyl)-2-(tert.-butyl)-oxirane of m~ltir.~! D~int ?8C are obtained.
~ G0 - C(CHs~
6 9 (0.2 mole) of 80~ pure sodium hydride are initially introduced into 100 ml of tetrahydrofurane.
44.4 9 to.2 nole) of 4-biphenylyl isopropyl ketone are introduced, whi}st stirring. When the evolution of gas has subsided, the mixture is warmed to 40C for 3 hnur3 and 29.9 9 (0.2 mole) of methyl iodide are then added dropwise. After 48 hours, the solution is filtered , Le A 20 002 . .
' : ' '' :' ~, ~ .' :
:. ~ ': ., -' : :, ' ~: ~ ' ~' , ' ' ' ' ' ,, ' ' ' .~ . ', ..
and the filtrate is evaporated in va-cuo-; the resi~ue is dissol~ed in ethyl acetate and the solution is washed ~ith water, dried over sodium sulphate and evaporatcd again in Vacuo. After stirring the mass of crystals with wash benzine, 40.5 9 (85o oF theory) of 4-biphenylyl tert~-butyl ketone of melting point 98C are obtained.
Example 2 -OH
Cl ~ ~ - I - C(CH3 )j CHz 23.5 9 (83o of theory) of 1-(4-chlGrobiphenylyl)-1-(tert.-butyl)-2-(imidazol-1-yl)-ethan-1-al of melting point 164C are obtained as described in Example 1 from 5.6 9 (0.104 mole) of sodium methylate, 40 ml of methyl alcohol, 12.2 9 (0.19 mole) of imidazole, 22.8 9 (O.oa mole) of 2-(4-p-chlorobiphenylyl)-2-(tert.-butyl)-oxirane . and 1S0 ml of dimethylformamide.
of the starting material _ Cl- ~ ~ /C \ - C(CHs~s ~7.3 9 (60~ of theory) of 2-(4-p-chlorobiphenylyl)-2-(tert.-butyl)-oxirane of melting point 118~C are obtained ns describsd in Example 1 from 3.6 9 (0.12 mole) of sodium hydride (B0~o pura), 26.4 9 (0.12 mole) of trimethyloxo-sulphonium iodide, 27.3 9 (0.1 mole) of 4-(p-chloro-biphenylyl) tert.-butyl ketone and 220 ml of dimethyl-sulphoxide, after stirring the crude product with diiso-Le A 20 002 - _ : . ~
~. . :
''; ~ ~ ' ~ ' :
S~
propyl ether.
Cl~ 0 - C (C~3 )~
4-p-Chlorobiphenylyl tert.-butyl ketone of melt-ing point 99C is obt~ined in 70~ yield according to Example 1 by reaction oF 4-p-chlorobiphenylyl isopropyl ketone with methyl iodide.
.~ .
:
' . .
Le A 20 002 -18-,~ .
' : .
' ~ ,
44.4 9 to.2 nole) of 4-biphenylyl isopropyl ketone are introduced, whi}st stirring. When the evolution of gas has subsided, the mixture is warmed to 40C for 3 hnur3 and 29.9 9 (0.2 mole) of methyl iodide are then added dropwise. After 48 hours, the solution is filtered , Le A 20 002 . .
' : ' '' :' ~, ~ .' :
:. ~ ': ., -' : :, ' ~: ~ ' ~' , ' ' ' ' ' ,, ' ' ' .~ . ', ..
and the filtrate is evaporated in va-cuo-; the resi~ue is dissol~ed in ethyl acetate and the solution is washed ~ith water, dried over sodium sulphate and evaporatcd again in Vacuo. After stirring the mass of crystals with wash benzine, 40.5 9 (85o oF theory) of 4-biphenylyl tert~-butyl ketone of melting point 98C are obtained.
Example 2 -OH
Cl ~ ~ - I - C(CH3 )j CHz 23.5 9 (83o of theory) of 1-(4-chlGrobiphenylyl)-1-(tert.-butyl)-2-(imidazol-1-yl)-ethan-1-al of melting point 164C are obtained as described in Example 1 from 5.6 9 (0.104 mole) of sodium methylate, 40 ml of methyl alcohol, 12.2 9 (0.19 mole) of imidazole, 22.8 9 (O.oa mole) of 2-(4-p-chlorobiphenylyl)-2-(tert.-butyl)-oxirane . and 1S0 ml of dimethylformamide.
of the starting material _ Cl- ~ ~ /C \ - C(CHs~s ~7.3 9 (60~ of theory) of 2-(4-p-chlorobiphenylyl)-2-(tert.-butyl)-oxirane of melting point 118~C are obtained ns describsd in Example 1 from 3.6 9 (0.12 mole) of sodium hydride (B0~o pura), 26.4 9 (0.12 mole) of trimethyloxo-sulphonium iodide, 27.3 9 (0.1 mole) of 4-(p-chloro-biphenylyl) tert.-butyl ketone and 220 ml of dimethyl-sulphoxide, after stirring the crude product with diiso-Le A 20 002 - _ : . ~
~. . :
''; ~ ~ ' ~ ' :
S~
propyl ether.
Cl~ 0 - C (C~3 )~
4-p-Chlorobiphenylyl tert.-butyl ketone of melt-ing point 99C is obt~ined in 70~ yield according to Example 1 by reaction oF 4-p-chlorobiphenylyl isopropyl ketone with methyl iodide.
.~ .
:
' . .
Le A 20 002 -18-,~ .
' : .
' ~ ,
Claims (9)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a hydroxybutyl-imidazole derivative of the formula (I) or a pharmaceutically acceptable acid addition salt thereof, in which R1 represents a hydrogen or halogen atom, an alkyl, alkoxy, halogeno-alkyl radical or a phenyl or cycloalkyl radical, the phenyl and cycloalkyl radical being unsubstituted, mono-substituted or di-substituted by chlorine, bromine, fluorine, nitro, methyl or methoxy, and R2 represents a hydrogen atom, or R1 and R2 together, in the o-position relative to each other, re-present a multi-memberd methylene bridge which is unsubstituted or substituted by chlorine or methyl, or together with the phenyl ring to which they are bonded represent a naphthyl or fluorenyl radical which is unsubstituted or substituted by chlorine or methyl, R represents a halogen atom or an alkyl, alkoxy or halogenoalkyl radical and, n is O, 1, 2 or 3, which comprises;
(a) reacting a corresponding oxirane of the formula (II) in which R1, R2 and R3 and n have the meaning indicated above, with imidazole in the presence of an alkali metal alcoholate; or (b) reacting a corresponding ketone of the formula with a tertiary butyl magnesium halide in a Grignard reaction, followed by hydrolysis of the product; or (c) reacting a corresponding alcohol of the formula with imidazole;
and where required converting any free base of formula (I) into a pharmaceuti-cally acceptable acid addition salt thereof.
(a) reacting a corresponding oxirane of the formula (II) in which R1, R2 and R3 and n have the meaning indicated above, with imidazole in the presence of an alkali metal alcoholate; or (b) reacting a corresponding ketone of the formula with a tertiary butyl magnesium halide in a Grignard reaction, followed by hydrolysis of the product; or (c) reacting a corresponding alcohol of the formula with imidazole;
and where required converting any free base of formula (I) into a pharmaceuti-cally acceptable acid addition salt thereof.
2. A process according to claim 1 in which in the starting materials R1 represents a hydrogen, fluorine, chlorine or bromine atom or a methyl, ethyl, methoxy or trifluoromethyl radical, or a phenyl, cyclopentyl or cyclohexyl radical which is optionally mono-substituted or disubstituted by chlorine, bromine, fluorine, nitro, methyl or methoxy, and R2 represents a hydrogen atom, or R1 and R2 together, in the ortho-position relative to each other, represent a tri-, tetra- or penta-methylene bridge which is optionally substituted by chlorine or methyl, or together with the phenyl ring to which they are bonded represent a naphthyl radical, or a fluorenyl radical which is optionally sub-stituted by chlorine or methyl, R3 represents a chlorine or fluorine atom or a methyl radical and n is 0 or 1.
3. A process according to claim 1 wherein in the starting materials R1 is phenyl in the 4-position, R2 is hydrogen and n is zero.
4. A process for the preparation of 1-(4-biphenylyl)-1-(tert.-butyl)-2-(imidazol-1-yl)-ethan-1-ol, which comprises reacting 2-(4-biphenylyl)-2-(tert.-butyl)-oxirane with imidazole in the presence of an alkali metal alcoholate, and in the presence of an inert organic solvent.
5. A process according to claim 1 wherein in the starting materials R1 is p-chlorophenyl in the 4-position, R2 is hydrogen and n is zero.
6. A process for the preparation of 1-(4-p-chlorobiphenylyl)-1-(tert.-butyl)-2-(imidazol-1-yl)-ethan-1-ol, which comprises reacting 2-(4-p-chlorobi-phenylyl)-2-(tert.-butyl)-oxirane with imidazole in the presence of an alkali metal alcoholate, and in the presence of an inert organic solvent.
7. Compounds of formula (I) defined in claim 1 and their pharmaceuti-cally acceptable acid addition salts, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
8. 1-(4-Biphenylyl)-1-(tert.-butyl)-2-imidazol-1-yl)-ethan-1-ol, when prepared by the process of claim 4 or by an obvious chemical equivalent there-of.
9. 1-(4-p-Chlorobiphenylyl)-1-(tert.-butyl)-2-imidazol-1-yl)-ethan-1-ol, when prepared by the process of claim 6 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19792946957 DE2946957A1 (en) | 1979-11-21 | 1979-11-21 | ANTIMICROBIAL AGENTS |
| DEP2946957.6 | 1979-11-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1146950A true CA1146950A (en) | 1983-05-24 |
Family
ID=6086561
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000364976A Expired CA1146950A (en) | 1979-11-21 | 1980-11-19 | Hydroxybutyl-imidazole derivatives |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0031883B1 (en) |
| JP (1) | JPS5686168A (en) |
| CA (1) | CA1146950A (en) |
| DE (2) | DE2946957A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3042303A1 (en) * | 1979-11-13 | 1981-08-27 | Sandoz-Patent-GmbH, 7850 Lörrach | ORGANIC COMPOUNDS, THEIR PRODUCTION AND USE |
| DE2946956A1 (en) * | 1979-11-21 | 1981-06-19 | Bayer Ag, 5090 Leverkusen | HYDROXYBUTYL-IMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS FUNGICIDES |
| JPS5815909A (en) * | 1981-07-22 | 1983-01-29 | Toko Yakuhin Kogyo Kk | Antimycotic agent for external use |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU557755A3 (en) * | 1968-08-19 | 1977-05-05 | Янссен Фармасьютика Н.В. (Фирма) | Method for preparing imidazole derivatives |
| DE2623129C3 (en) * | 1976-05-22 | 1980-04-10 | Nordmark-Werke Gmbh, 2000 Hamburg | U-Diphenyl-3- (imidazol-1-yl) -propan-2-ols, process for their preparation and pharmaceuticals containing them |
| DE2736122A1 (en) * | 1977-08-11 | 1979-02-22 | Basf Ag | FUNGICIDES |
| IL60470A0 (en) * | 1979-07-04 | 1980-09-16 | Pfizer | Imidazole derivatives,their preparation and pharmaceutical compositions containing them |
-
1979
- 1979-11-21 DE DE19792946957 patent/DE2946957A1/en not_active Withdrawn
-
1980
- 1980-11-08 EP EP80106908A patent/EP0031883B1/en not_active Expired
- 1980-11-08 DE DE8080106908T patent/DE3062229D1/en not_active Expired
- 1980-11-18 JP JP16148580A patent/JPS5686168A/en active Pending
- 1980-11-19 CA CA000364976A patent/CA1146950A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| DE3062229D1 (en) | 1983-04-07 |
| JPS5686168A (en) | 1981-07-13 |
| DE2946957A1 (en) | 1981-06-04 |
| EP0031883B1 (en) | 1983-03-02 |
| EP0031883A1 (en) | 1981-07-15 |
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