CA1160237A - Biphenylyl-azolylethane compounds, their production and their medicinal use - Google Patents
Biphenylyl-azolylethane compounds, their production and their medicinal useInfo
- Publication number
- CA1160237A CA1160237A CA000374351A CA374351A CA1160237A CA 1160237 A CA1160237 A CA 1160237A CA 000374351 A CA000374351 A CA 000374351A CA 374351 A CA374351 A CA 374351A CA 1160237 A CA1160237 A CA 1160237A
- Authority
- CA
- Canada
- Prior art keywords
- chlorophenyl
- process according
- biphenylyl
- imidazol
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- 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
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/08—Compounds containing oxirane rings with hydrocarbon radicals, substituted by halogen atoms, nitro radicals or nitroso radicals
Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to the biphenylylazolylethane compounds of formula I
The invention relates to the biphenylylazolylethane compounds of formula I
Description
~ 6~37 The present invention relates to certain new biphenylylazolyl-ethane compounds, to a process for their production and to their use as antimycotic agents.
It has already been disclosed that biphenylylazolyl-methane derivatives have good antimycotic properties (see DE-OS (German Published Specification)
It has already been disclosed that biphenylylazolyl-methane derivatives have good antimycotic properties (see DE-OS (German Published Specification)
2,461,406 and United States Patent Specification 4,118,487). However, their action is not always completely satisfactory against all species of fungi.
According to the present invention we provide compounds which are biphenylylazolyl-ethanederivatives of the general formula 1 o ~ f ~, I
Xm C~l2 n or a salt thereof, in which A represents the -CH-group or a nitrogen atom; X
represents a halogen atom or an alkyl, halogenoalkyl, alkoxy, alkylthio, nitro or cyano radical; Y represents a halogen atom or an alkyl, halogenoalkyl, alkoxy, alkylthio, nitro, cyano or a phenyl radical which is unsubstituted or is substi-tuted by a halogen atom or an alkyl, halogenoalkyl, alkoxy, alkylthio, nitro or cyano radical; and _ and n are independently 0, 1, 2 or 3.
According to the present invention we further provide a process for the production of a compound of the present invention in which a biphenylylazolyl-ethylene derivative of the general formula ~ ~
m CH n ~ N
N-' i - 1 -in which A, X, Y, m and n have the abovementioned meaning, ' is hydrogenate~ in the presence of a catalyst and optionally in the presence of a diluent.
The new.biphenylyl-azolylethane derivati.ves have .
powerful antimycotic pDope.rties. Surprisingly, the . compounds accordinL to the invention exhibit a more powerful action than the biphenylyl-azolylmethane derivatives which are known from the state of the art and are closely related compounds chemically ~nd from the point o~. view of their action. The substances according to the invention thus represent an enrichment of pha~macy.
Preferred compounds of the presenk invention are those in which X represents a halogen atom, a straight-15 . chain or branched alkyl radical with 1 to 4 carbon atoms,a halogenoalkyl radical with 1 to 4 carbon atoms and 1 to 5 identical or different halo.~en.atoms,. halogens being, preferably, fluorine and chlorine, an alkoxy or alkylthio radical with in each case 1 to 4. carbon atomsg. or a nitro or cyano radical, and Y, independently of X, represents any of the radicals which have been mentioned immediately above for X~ or represents a phenyl radical which is optionally substituted by a radical specified immediately above for X3 and A, m and n have the meanings given in the .25. definition of compounds of formula (I).
Very particularly preferred ccmpounds of the present invelltion are those in which X repre.s.ents a fluorine, chlorine or bromine atom or a methyl, ethyl, isopropyl, tert -butyl, trifluoromethyl, methoxy, ethoxy, methylthio, ethylthio, nitro or cyano radical, Y independ-ently of X represents the radicals mentioned immediately above for X, or represents a phenyl radical which is opticnally substituted by ~.luorine, chlorine, methyl, tert-butyl, trifluoromethyl, nitrc or cyano, and A, n and m have 35. the meanings ~iven in the definition.of compounds of formula (I).
The followin~ comp.ounds of the present inve.n.ti.o~
.. .... .... ....
' L'e 'A''2G''~'30 .
may be mentioned specifically, in addition to the . compounds mentioned in the preparative Exa~.ples:
X '~ CH2 ~ Yn ~ N
N
__ . _ _ 2-Cl ~~~`~~~~ N
According to the present invention we provide compounds which are biphenylylazolyl-ethanederivatives of the general formula 1 o ~ f ~, I
Xm C~l2 n or a salt thereof, in which A represents the -CH-group or a nitrogen atom; X
represents a halogen atom or an alkyl, halogenoalkyl, alkoxy, alkylthio, nitro or cyano radical; Y represents a halogen atom or an alkyl, halogenoalkyl, alkoxy, alkylthio, nitro, cyano or a phenyl radical which is unsubstituted or is substi-tuted by a halogen atom or an alkyl, halogenoalkyl, alkoxy, alkylthio, nitro or cyano radical; and _ and n are independently 0, 1, 2 or 3.
According to the present invention we further provide a process for the production of a compound of the present invention in which a biphenylylazolyl-ethylene derivative of the general formula ~ ~
m CH n ~ N
N-' i - 1 -in which A, X, Y, m and n have the abovementioned meaning, ' is hydrogenate~ in the presence of a catalyst and optionally in the presence of a diluent.
The new.biphenylyl-azolylethane derivati.ves have .
powerful antimycotic pDope.rties. Surprisingly, the . compounds accordinL to the invention exhibit a more powerful action than the biphenylyl-azolylmethane derivatives which are known from the state of the art and are closely related compounds chemically ~nd from the point o~. view of their action. The substances according to the invention thus represent an enrichment of pha~macy.
Preferred compounds of the presenk invention are those in which X represents a halogen atom, a straight-15 . chain or branched alkyl radical with 1 to 4 carbon atoms,a halogenoalkyl radical with 1 to 4 carbon atoms and 1 to 5 identical or different halo.~en.atoms,. halogens being, preferably, fluorine and chlorine, an alkoxy or alkylthio radical with in each case 1 to 4. carbon atomsg. or a nitro or cyano radical, and Y, independently of X, represents any of the radicals which have been mentioned immediately above for X~ or represents a phenyl radical which is optionally substituted by a radical specified immediately above for X3 and A, m and n have the meanings given in the .25. definition of compounds of formula (I).
Very particularly preferred ccmpounds of the present invelltion are those in which X repre.s.ents a fluorine, chlorine or bromine atom or a methyl, ethyl, isopropyl, tert -butyl, trifluoromethyl, methoxy, ethoxy, methylthio, ethylthio, nitro or cyano radical, Y independ-ently of X represents the radicals mentioned immediately above for X, or represents a phenyl radical which is opticnally substituted by ~.luorine, chlorine, methyl, tert-butyl, trifluoromethyl, nitrc or cyano, and A, n and m have 35. the meanings ~iven in the definition.of compounds of formula (I).
The followin~ comp.ounds of the present inve.n.ti.o~
.. .... .... ....
' L'e 'A''2G''~'30 .
may be mentioned specifically, in addition to the . compounds mentioned in the preparative Exa~.ples:
X '~ CH2 ~ Yn ~ N
N
__ . _ _ 2-Cl ~~~`~~~~ N
3-F N
3-Cl N
- CH
3-Cl N
- CH
4-CI CH
4-C(CH3 )3 CH
4-C1 3-Cl CH
4-C1 2-C} CH
2~5-Cl2 CH
44~> CH
4-Br CH
4-Cl, 3-N02 CH
- N
4-Cl N
4-C(CH3 )3 N
:Le A 2 0 2 ~0 ~61~23 X~i ~n . ..
.. . . . .. ..
4-C1 ~-Cl N
4-C1 2-Cl N
~ 3-CF3 N
2,5-Cl2 N
_ 4 ~ N
- 4-Br N
4-Cl,3-N02 N
If, for example 1-(4-biphenylyl)-1-~2-chloro-phenyl-)-2-(imidazol-1-yl)-ethylene and hydrogen are used as starting substances, the course of the reaction according to the present invention is illustrated by the following . equation:
CH ~ C~t~ ~t ~ -C\H
C ~ ~N~
Pre.ferred biphenylyl-azolylethylene derivatives of formula (II) to be used as starting substances for the process according to the invention are those in which A, X~
Y, m and n h.ave those meanings which have already been given in connection with the description of the preferred and particularly preferred compounds of the present invent-ion.
The biphenylyl-azolylethylene derivatives of the formula (Il) are novel. They are obtained by a process in which a hydroxyethyl-azole of the general formula 0~
~ ~ - C ~ (III) Xm CH2 ~n ~ N~
.~ N
. .
.Le ~ 20 230 23~
in which A, X, Y, m and n have the above-mentioned meanlng, is reacted with a water-binding agent, optionally in the presence of a diluent.
Water-binding agents which may be mentioned are, as preferences, acid anhydrides, such as acetic anhydride; halides of oxyacids, such as thionyl chloridei and isocyanates, such as methyl isocyanate.
Preferred diluents Eor this reaction are inert organic solvents. These include, as preferences, chlorinated hydrocarbons, such as chloroform or methylene chloride.
The reaction temperatures can be varied within a substantial range in carrying out this reaction. In general, this reaction is carried out between 0 and 120 C, preferably between 20 and 100 C.
This reaction is preferably carried out in molar amounts or wi-th an excess of water-binding agent. The compounds of the formula II are isolated by customary methods (see also the preparative examples).
The hydroxyethy]azoles of the formula III are likewise novel; however, they are the subject of our earlier copending Application 340,547. They can be obtained by reacting the corresponding hydroxyethyl halides with imidazole or triazole, if appropriate in the presence of an acid-binding agent, such as, preferably, an excess of azole, or in the form of one of their alkali metal salts, such as are obtained, for example, by treatment with sodium methylate in a suitable solvent, and if appropriate in the presence of an inert organic sol-vent, such as, for example, dimethylformamide, at temperatures between 30 and The hydroxyethylazoles of the formula III can also be ob-tained by reacting oxiranes of -the general formula ~:~6~Z37 ~ C ~ ~ IV
Xm 2 n in which X, Y, m and n have the above-men-tioned meaning, with imidazole or tri-azole in the presence of an alkali metal alcoholate, such as sodium methylate, and in the presence of an inert organic solvent, such as, dimethylformamide, at a temperature between 30 and 100 C (see also the preparative examples).
The oxiranes of the formula IV are novel. They can be obtained by reacting appropriate ketones either with dimethyloxosulphonium methylide in a manner which is in itself known in the presence of a diluent, such as dimethyl sulphoxide, at a temperature between 20 and 80 C; or with trimethylsulphonium methyl-sulphate in a manner which is in itself known in the presence of a two-phase system and if appropriate in the presence of a phase transfer catalyst, at a temperature between 0 and 100 C (see also the preparative examples).
The hydrogenation according to the invention is carried out in the presence of a catalyst. Noble metal satalysts, noble metal oxide (or noble metal hydroxide) catalysts or Raney catalysts, such as platinum, platinum oxide, Raney nickel and palladium oxide, are preferably used.
Preferred possible diluents for the hydrogenation according to the invention are inert organic solvents. These include, as preferences, alcohols (such as methanol and ethanol), nitriles (such as acetonitrile), esters (such as ethyl acetate) and glacial acetic acid.
The reaction temperatures can be varied within a substantial range in the hydrogenation according to the . .-. - 6 -, irve.ntion. In general~ the reaction is carried out at a temperature between 20 and 200 C, preferably at a . temperature between 40 and 150C.
The hydrogenation according to the invention is preferably carried out under increased pressure. In general, it is carried out under between l and 200 atmos-p.heres gauge, preferably under l to 150 ~mospheres gauge.
In the hydrogen~tion according to the invention, about l mole of hydrogen and about 0.1 mole of catalyst are preferably employed per mole of the co~pound of the formula (II). The end products of the formula (I) are isolated in the customary manner.
The following acids can pre~erably be used for the preparation of physiologically acceptable acid addition salts of the compounds of the formula (I): hydrogen halide acids (such as hydrobromic acid and, preferably, hydro-chloric acid) phosphoric acid, nitric acid, sulphuric acid,.
monofunctional and bifunctional carboxylic acids and hydroxycarboxylic acids (such as acetic acid, maleic acid~
succinic acid, fumaric acid, tartaric acid, citric acidg salicylic ac.id, sorbic acid and lactic acid), and sulphonic acids (such as p-toluenesulphonlc acld and 1,5-nap~thalene-disulphonic acid).
Amon~ the new.biphenylyl-azolylethane derivative .25. salts of the invention, those salts that are pharmaceut ically acceptable are particularly important and are preferred.
The new free biphenylyl-azolylethane derivatives of the general formula (I) and their salts can be inter-converted in any suitable manner; methods for such inter-conversion are known in the art.
The acid addition salts of the compounds of the formula (I) may be obtained, for example, by dissolving a compound of the formula (I) in a suitable irert solvent and 3~ adding the acid, for example hydrochloric acid, and they can be isolated in a ~.nown manner, for example by filtration~ and if appropriate purified by ~ashin~ with an .. ... .. ..
Le A 20`230 inert organic solvent.
Possible anions o~ the salts are, preferably, those which are derived from the following acids: hydrogen halide acids, such as hydrochIoric acld and hydrobromic acid, and furthermore phosphoric acid, nitric acid and sulphuric acid.
The compounds of the formula (I) according to the invention and their acid addition salts display anti-microbial actions, in particular powerful antim~cotic actions. They have a very broad action spectrum'in itro, which comprises dermatophytes, yeasts,'' o~a~le, moulds and biphase fungi. They can therefore be success~ully employed against fungal infections in humans and animals.
Examples which may be mentioned of fields of indication in human medicine are: dermatomycoses and systemic mycoses caused by Trich'o'ph'y't'on _'n't'a'groph~'t'es and other species o~ ~ichophyt'on, species of'Mi'cr'osp'or'on, Epi~ermophyt~on ~locco9um~ blas~omyces and biphase fungi as well as moulds.
Examples which may be mentioned of fields of indication in veterir.ary medicina are: -all dermatomycoses and systemic mycoses, in particular those caused by the abovementioned pathogens.
The active compounds according to the invention are active against a very broad spectrum o~ micro-organisms.
With their aid, it is possible, for example, for Gram-negative and Gram-positive bacteria and bacteria-like micro-organisms to be combated and for the illnesses caused by these pathogens to ~e prever.ted, alleviated and/or cured.
As stated above, the invention also relates to the use in human and veterinary medicine of the compounds of the invention.
The present invention prcvides a pharmaceutical composition containing as active ingredient a compound of the invention in admixture with a solid or liquefied gaseous diluent, or in admixture with a liquid diluent other than a solvent of a molecular weight less than ' Le' A''?'0''2'30 ~6~237 g 200 (preferably less than 350) except in the presence of a surface active agent.
The invention further provides a pharmaceutical co~osition containing as active ingredient a compound o~ the invention in the form of a sterile and/or physio-logically isotonic aqueous solution.
The invention also provides a medicament in dosage unit form comprising a compound of the invention.
The invention also provides a medicament in the form o~ tablets (including lozenges and granules), dragees, capsules, pills, ampoules or suppositories comprising a compound of the invention.
"Medicament" as used in this Specification means physically discrete coherent portions suitable ~or medical administration. "Medica~.ent in dosage unit form" as used in this Specification means physically discrete coherent units suitable for medical administration each containing a daily dose or a multiple tup to four times) or submultiple (down to a fortieth) of a daily dose of the compound of the invention in association with a carrier and/or enclosed within an envelope. Whether the medicament contains a daily dose or, for exampleg 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 ~our times a day respectively.
The pharmaceutical composition according to the invention may, for exampleg take the form o~ oint~ents, gels, pastes, creams, sprays ~including aerosols)g lotions, suspensions, solutions and emulsions o~ the active ingredient in aqueous or non-aqueous diluents, syrups 3 granulates or powders.
The diluents to be used in pharmaceutical compositions te.g. granulates) adapted to be ~ormed into tablets, dragees? capsules and pills include the following:
(a) fillers and extenders, e.g. starch, sugars, mannitol, and silicic acid; (b) binding agents, e.g. carboxymethyl cellulose and other cellulose derivatives, alg1nates, .. .. .. .... .. ..
~e A 20 230 - 10 - ~l~S~23~
- gelatine and polyvinyl pyrrolidone; (c) moisturizing age~ts, e.g. glycerol; (d) disintegrating agents, e.g.
agar-agar, calcium carbonate and sodium bicarbonate;
(e) agents for retarding dissolution e.g. paraffin;
(f) resorption accelerators3 e.g. quaternary ammonium compounds; (g) surface active agents, e.g. cetyl alcohol~
glycerol monostearate; (h) adsorptive carriers, e.g.
kaolin and bentonite; ~i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethyl glycols or mixtures of these above-mentioned substances.
The tablets, dragees, capsules and pills formed from the pharmaceutical compositions of the invention can have the customary coatings, envelopes and protective matrices, ~hich may contain opacifiers. 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 o~ time. The coatings, envelopes and protective matrices may be made, for example~
of polymeric substances or waxès.
The ingredient can also be made up in microencapsulated form together with one or several of the abo~e-mentioned diluents.
The diluents to be used in pharmaceutical compositions adapted to be formed into suppositories can, for example, be the usual water-soluble or water-insoluble diluents, such as polyethylene glycols and ~ats (e.g.cocoa oil and high esters (e.g. C14-alcohol with C16-fatty acid)) or mixtures o~ these diluents.
The pharmaceutical compositions which are ointments~
pastes, creams and gels can, for example3 contain the usual diluents, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures o~ these substances.
The pharmaceutical compositions which are powders and sprays can, for example, contain the usual diluents, e.g. lactose, talc, silicic acid, aluminium hydroxide, calcium silicate~ and polyamide powder or mixtures o~
these substances. Aerosol sprays can, for example, Le A 20 230 . contain the usual propellants, e.'g. chlorofluorohydro-carbons.
The pharmaceutical compositions which are solutions and emulsicns can, for example,' contain the customary diluerts (with, of course, the above-mentioned exclusion of solvents having a molecular weight below 200 except in the presence o~ a surface-active agent) 3 such as solvents.~ dissolving agents and emulsifiers; specific examples of such diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,. di~ethylformamide, oils (for example ground nut oil), glycerol,. tetrahydro~urfuryl 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 pharmaceutical compositi.ons which are suspensions can co.ntain the usual diluents, such as liquid diluents,.
e.g.. water, ethyl alcohol, propylene glycol, surface-acti.ve agents. (e g. ethoxylated isostearyl alcohols, polyoxyethylene sorbite and sorbitane esters), micro-crystalline cellulose~ aluminium .metahydroxide, bentonite, agar-agar and tragacanth or mixtures thereo~.
All the pharmaceutical compositions according to the invention can also contain colouring agents and preservatives as well as perfumes and flavouring additions (e.g. peppermint oil and eucalyptus cil) and sweetening agents (e.g. saccharin).
~he pharmaceutical compositions according to the invention generall~J contain from 0.1 to 99.5% usually from 0.5 to95% o~ the active ingredient by welght of the total composition.
In addition to a comound of the invention, the pharmaceutical compositions and medicaments according to the invention can also canta.in other pharmaceutically active compo~mds. They may also contain a plurality . of compounds of the lnvention.
.. . .. .... ....
' Le A Z0 230 . . _ .
~ L6~Z37 Any diluent in the medicaments of the presenk invention may be any of those mentioned above in relation to the pharmaceutical compositions of the present invention.
Such medicaments may include solvents of molecular ~Teight less than 200 as sole diluent.
The discrete coherent portions constituting the medicament according to the invention will generally be adapted by virtue of their shape or packa~ing for medical administration and may be, for example, any Of the followin~: tablets (including lozenges and ~ranulates), pills, dragees, capsules, sùppositories and ampoules. Some of these forms may be made up for delayed release of the active ingredient. Some, 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 2.5g to lO g o~ active ingredient.
The production of the above-mentioned pharmaceuticaI
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 composition (e.g. a granulate) and then forming the composition into the medicament (e.g. tablets3.
This invention further provides a method of combating (including prevention, relief and cure of) the above~
mentioned diseases in human and non-human animals, which comprises administering to the animals a compound of the invention alone or in admixture with a diluent or in the form of a medicament according to the invention.
It is envisaged that these active compounds will be administered perorally, parenterally (for example intramuscularly, intraperitoneally, subcutaneously ar.d intravenously), rectally or locally, preferably parenterally, especially intravenously. Preferred pharmaceutical ccmpositions and medicaments are therefore those adapted .. .. .. ..
Le A 20 230 .. . .
1~
.~or administration such as parenteral administration.
Administration in the ~.ethod of the invention is pre.ferably parenteral administration.
In general it has proved advantageous to adminis.ter amounts.of from lOmg to 300mg/kg, preferably from 50mg to 200mg/kg, of body weight per day to achieve effective results. Neverthe.less, it can at times be necessary to deviate from those dosage rates, and in particular to do so as a function of the nature and body weight of the human or animal subject to be treated, the individual reaction of this subje.ct to the treatment, the ty.pe of formulation in which the active ingredient is administered and the mode in which the administration is carried out,. and the point in the progress o~ 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 me.ntioned must.be exce.eded to achi.eve the desired results.. Where larger amounts are administered it can be advisab.le to divide these into several individual .administrations. over the. course of the day.
The following Examples 1 to 8 illustrate processes for the production of compounds of the present invention.
E'ga'mpl'e' 1 Cl ~ ~ IH -. fH2 L~
4.0 g of 1-(4-biphenylyl)-1-(2-chlorophenylj-2-(imidazol-I-yl)-ethylene were dissolved in 100 ml of glacial aceticacid and were hydrogenated at 60C under 40 bars of H2 for ~ hours, using platinum oxide as the catalyst. The solvent was then distilled off and the.
syrupy residue was chromatographed over Merck Silica gel 60 ~mobile phase: chloroform/methanol = 10/0.5).
.... .. .. ..
L'e' A' 2'0' 2'30 .
3~7 3.4 g (85% of theory) of 1-(4-biphenylyl)-1-(2-chloro~
phenyl)-2-(imidazol-1-yl)-ethane of melting point 86C
were. obtained.
Preparat'ion'o'f'th'e pre'curs'o'rs Cl (II-l) ~ e ~
CH
N ~
Il N
1.9 g of 1-(4-biphenylyl)-1-( ~chlorophenyl)-2-timidazol-l-yl)-ethan-l-ol were suspended in 30 ml of . chloroform, and 1.4 ml of thionyl chloride were added.
The mixture was stirred at 60C for 18 hours. The clear .solution was then .evaporated`'in''v'ac'uo, the residue was taken up in 30 ml of chloroform and, after adding another 1.4 ml of thionyl chloride, the mixture was stirred again .at 60C for 18 hours. The crystalline crude product which remained after stripping off the solvent was 1.5 recrystallised from isopropanol. 16 g (89% o~ theory) . of 1-(4-biphenylyl~-1-(2-:chlorophenyl)-2-(imidazol-1-yl)-ethylene of melting point 196C were obtained.
OHcl ._....N
3.5 g (o.o65 mole) of sodium methylate were diss-olved in 20 ml of methanol, and 7.5 ~ (0.11 mole) of imidazole were added. A solution of 15 g (0.05 mole) of 2-(4-biphenylyl)-2-(2-chlorophenyl)-oxirane in 75 ml of dimethylformamide was added dropwise and the reaction mix-. ture was heated to 80C for 1.5 hours. Thereafter, the reaction mixture was poured onto w.ater and the crystals formed were filtered off and dried. 14.7 g (79%. o~
~ Le A'2'0''2'30 .
. theo.ry). of 1-(4-biphenylyl)~1-(2-chlorophenyl)-2-imidazol -l-yl-ethan-l-ol of melting pcint 222C were obtained.
/C\~
90 ml of dimethyl sulphoxide were added to 2.7 g (0.09 mole) of 80% strength sodium hydride and 19.8 g (0.09 mole) of trimethyloxosulphonium iodide in the course of 20 minutes. When the evolution of hydrogen had ended, a solution of 22 g (0.075 mole)' of 2'-chloro-4'-phenyl-. benzophenone in 60 ml of dimethyl sulphoxide was added dropwise and the mixture was sub.sequently stirred at 50C
for 1 hour. 200 ml of water were added to the cooled reaction mi.xture and the mixture was extracted by shaking with ether. The ether solution ~as washed with water, . dri.ed.over s.odium sulphate and. concentrated by distilling off the solvent in''~acuo. The residue was recr~stallised from diisopropyl ether. 15 g (65% of theory) of 2-(4-. biphenylyl)-2-(2-chlorophenyl)-oxirane of melting point '70C were o.btained.
The compounds of the formula (I) listed in Table 1 which follows. c.ould be obtained by the process as described Lxample 1 using corresponding starting materials.
- Ta~le 1 ~ ~ CH
Xm CH2 Yn I
N
N
- Le A 20 230 .
-Ex-. N.o.~.. m .......... Yn - - A Meit n(O
2 4-C1 2-Cl CH 188 3 - 2-F CH resin 4 - 3-Cl CH oil - 2-Cl CH 282(xl/2 NDS).
6 ~ 2-F CH 297(xl/2 NDS) 7 - 3 Cl CH 265(xl/2 N3S.) 8 4-C1 2-Cl N 152 NDS = 1,5-naphthalenedisulphonic acid The starting materials. o~ the ~ormula (II) listed in Table 2 which follows could be obtained by the process described Example 1 for the prepa~ation of precurso:rs using corresponding starting materials for that process.
X~ 11 ~Y
m CH n (II) ~N~A
N_ Ex-ample X Y A Melting . 15 . No... m ........... n................ p.o.in.t. (.C.) (II-2)4-C1 2-Cl CH 174 (II-3) - 2-F CH oil (II~4) - 3-Cl CH 211 (II-5) - 2-F CH 325 (decompo-sition)(xl/2 NDS) (II-6)4-C1 2-C1 N 17Q
(II-7) - 4-Cl CH n20 = 1.6350 Le A 20 230 _ .
~ 3 - 17 - , ... .
' The', following Example illustrates the' in'''i't'ro activity, of compounds of the present invention. In this Example, the compour.ds according to the present invent-ion are each identified by the number ~given in brackets) of the corresponding preparative Example~ which will be found earlier in this specification.
The known comparison compounds are identified as follows:
Cl (A) Cl ~ - ~ - CH
Cl (B) Cl- ~ ~ ~ CH ~
(c) ~-f~
~N~
N
(D) ~ ~ - CH
~ N~N
, I0' Example A
Antimy'c'oti'c'i'n''v'i't'r'o''a'c't'i'v'it'y . .
D'e-sc'rip'ti'on''o'f'the'-e'xpe'ri'men't:
The in ~itro test was carried out as a series dilution test using germ inocula of an average 5 x 10 &erms/ml of substrate, The nutrient medium used was:
Le A 2~ 230 __ a) fcr dermatophytes and moulds: Sabouraud's milieu . d'ep.re.uve, and . b) .for yeasts: isotonic sensi.test broth from Oxid, ~he incubation temperature was 28C; the .5 incubation time was 24 hours in the case of yeasts and 96 hours in the case of dermatophytes and moulds.
In this test, for example, the compounds (5), (6)~ (7) and (8) exhibited a very good action which is superior to. that of the compounds (A), (B), (C) and (D) - lO known from the prior art.
The present invention also comprises pharmaceutic-ally acceptab.Ie bioprecursors of thè active compounds of . the present inventi.on.
For the purposes of this specification the term 'pharmaceutica~ly acceptable bioprecursor' of an active compound of the invention means a compound h.aving a structural formula differe.nt from the active compound but wh.i.ch nonetheless, upon administration to an animal or human being is. converted in the patient's body to the active compound.
Le A 20 2~0 _ _
4-C(CH3 )3 CH
4-C1 3-Cl CH
4-C1 2-C} CH
2~5-Cl2 CH
44~> CH
4-Br CH
4-Cl, 3-N02 CH
- N
4-Cl N
4-C(CH3 )3 N
:Le A 2 0 2 ~0 ~61~23 X~i ~n . ..
.. . . . .. ..
4-C1 ~-Cl N
4-C1 2-Cl N
~ 3-CF3 N
2,5-Cl2 N
_ 4 ~ N
- 4-Br N
4-Cl,3-N02 N
If, for example 1-(4-biphenylyl)-1-~2-chloro-phenyl-)-2-(imidazol-1-yl)-ethylene and hydrogen are used as starting substances, the course of the reaction according to the present invention is illustrated by the following . equation:
CH ~ C~t~ ~t ~ -C\H
C ~ ~N~
Pre.ferred biphenylyl-azolylethylene derivatives of formula (II) to be used as starting substances for the process according to the invention are those in which A, X~
Y, m and n h.ave those meanings which have already been given in connection with the description of the preferred and particularly preferred compounds of the present invent-ion.
The biphenylyl-azolylethylene derivatives of the formula (Il) are novel. They are obtained by a process in which a hydroxyethyl-azole of the general formula 0~
~ ~ - C ~ (III) Xm CH2 ~n ~ N~
.~ N
. .
.Le ~ 20 230 23~
in which A, X, Y, m and n have the above-mentioned meanlng, is reacted with a water-binding agent, optionally in the presence of a diluent.
Water-binding agents which may be mentioned are, as preferences, acid anhydrides, such as acetic anhydride; halides of oxyacids, such as thionyl chloridei and isocyanates, such as methyl isocyanate.
Preferred diluents Eor this reaction are inert organic solvents. These include, as preferences, chlorinated hydrocarbons, such as chloroform or methylene chloride.
The reaction temperatures can be varied within a substantial range in carrying out this reaction. In general, this reaction is carried out between 0 and 120 C, preferably between 20 and 100 C.
This reaction is preferably carried out in molar amounts or wi-th an excess of water-binding agent. The compounds of the formula II are isolated by customary methods (see also the preparative examples).
The hydroxyethy]azoles of the formula III are likewise novel; however, they are the subject of our earlier copending Application 340,547. They can be obtained by reacting the corresponding hydroxyethyl halides with imidazole or triazole, if appropriate in the presence of an acid-binding agent, such as, preferably, an excess of azole, or in the form of one of their alkali metal salts, such as are obtained, for example, by treatment with sodium methylate in a suitable solvent, and if appropriate in the presence of an inert organic sol-vent, such as, for example, dimethylformamide, at temperatures between 30 and The hydroxyethylazoles of the formula III can also be ob-tained by reacting oxiranes of -the general formula ~:~6~Z37 ~ C ~ ~ IV
Xm 2 n in which X, Y, m and n have the above-men-tioned meaning, with imidazole or tri-azole in the presence of an alkali metal alcoholate, such as sodium methylate, and in the presence of an inert organic solvent, such as, dimethylformamide, at a temperature between 30 and 100 C (see also the preparative examples).
The oxiranes of the formula IV are novel. They can be obtained by reacting appropriate ketones either with dimethyloxosulphonium methylide in a manner which is in itself known in the presence of a diluent, such as dimethyl sulphoxide, at a temperature between 20 and 80 C; or with trimethylsulphonium methyl-sulphate in a manner which is in itself known in the presence of a two-phase system and if appropriate in the presence of a phase transfer catalyst, at a temperature between 0 and 100 C (see also the preparative examples).
The hydrogenation according to the invention is carried out in the presence of a catalyst. Noble metal satalysts, noble metal oxide (or noble metal hydroxide) catalysts or Raney catalysts, such as platinum, platinum oxide, Raney nickel and palladium oxide, are preferably used.
Preferred possible diluents for the hydrogenation according to the invention are inert organic solvents. These include, as preferences, alcohols (such as methanol and ethanol), nitriles (such as acetonitrile), esters (such as ethyl acetate) and glacial acetic acid.
The reaction temperatures can be varied within a substantial range in the hydrogenation according to the . .-. - 6 -, irve.ntion. In general~ the reaction is carried out at a temperature between 20 and 200 C, preferably at a . temperature between 40 and 150C.
The hydrogenation according to the invention is preferably carried out under increased pressure. In general, it is carried out under between l and 200 atmos-p.heres gauge, preferably under l to 150 ~mospheres gauge.
In the hydrogen~tion according to the invention, about l mole of hydrogen and about 0.1 mole of catalyst are preferably employed per mole of the co~pound of the formula (II). The end products of the formula (I) are isolated in the customary manner.
The following acids can pre~erably be used for the preparation of physiologically acceptable acid addition salts of the compounds of the formula (I): hydrogen halide acids (such as hydrobromic acid and, preferably, hydro-chloric acid) phosphoric acid, nitric acid, sulphuric acid,.
monofunctional and bifunctional carboxylic acids and hydroxycarboxylic acids (such as acetic acid, maleic acid~
succinic acid, fumaric acid, tartaric acid, citric acidg salicylic ac.id, sorbic acid and lactic acid), and sulphonic acids (such as p-toluenesulphonlc acld and 1,5-nap~thalene-disulphonic acid).
Amon~ the new.biphenylyl-azolylethane derivative .25. salts of the invention, those salts that are pharmaceut ically acceptable are particularly important and are preferred.
The new free biphenylyl-azolylethane derivatives of the general formula (I) and their salts can be inter-converted in any suitable manner; methods for such inter-conversion are known in the art.
The acid addition salts of the compounds of the formula (I) may be obtained, for example, by dissolving a compound of the formula (I) in a suitable irert solvent and 3~ adding the acid, for example hydrochloric acid, and they can be isolated in a ~.nown manner, for example by filtration~ and if appropriate purified by ~ashin~ with an .. ... .. ..
Le A 20`230 inert organic solvent.
Possible anions o~ the salts are, preferably, those which are derived from the following acids: hydrogen halide acids, such as hydrochIoric acld and hydrobromic acid, and furthermore phosphoric acid, nitric acid and sulphuric acid.
The compounds of the formula (I) according to the invention and their acid addition salts display anti-microbial actions, in particular powerful antim~cotic actions. They have a very broad action spectrum'in itro, which comprises dermatophytes, yeasts,'' o~a~le, moulds and biphase fungi. They can therefore be success~ully employed against fungal infections in humans and animals.
Examples which may be mentioned of fields of indication in human medicine are: dermatomycoses and systemic mycoses caused by Trich'o'ph'y't'on _'n't'a'groph~'t'es and other species o~ ~ichophyt'on, species of'Mi'cr'osp'or'on, Epi~ermophyt~on ~locco9um~ blas~omyces and biphase fungi as well as moulds.
Examples which may be mentioned of fields of indication in veterir.ary medicina are: -all dermatomycoses and systemic mycoses, in particular those caused by the abovementioned pathogens.
The active compounds according to the invention are active against a very broad spectrum o~ micro-organisms.
With their aid, it is possible, for example, for Gram-negative and Gram-positive bacteria and bacteria-like micro-organisms to be combated and for the illnesses caused by these pathogens to ~e prever.ted, alleviated and/or cured.
As stated above, the invention also relates to the use in human and veterinary medicine of the compounds of the invention.
The present invention prcvides a pharmaceutical composition containing as active ingredient a compound of the invention in admixture with a solid or liquefied gaseous diluent, or in admixture with a liquid diluent other than a solvent of a molecular weight less than ' Le' A''?'0''2'30 ~6~237 g 200 (preferably less than 350) except in the presence of a surface active agent.
The invention further provides a pharmaceutical co~osition containing as active ingredient a compound o~ the invention in the form of a sterile and/or physio-logically isotonic aqueous solution.
The invention also provides a medicament in dosage unit form comprising a compound of the invention.
The invention also provides a medicament in the form o~ tablets (including lozenges and granules), dragees, capsules, pills, ampoules or suppositories comprising a compound of the invention.
"Medicament" as used in this Specification means physically discrete coherent portions suitable ~or medical administration. "Medica~.ent in dosage unit form" as used in this Specification means physically discrete coherent units suitable for medical administration each containing a daily dose or a multiple tup to four times) or submultiple (down to a fortieth) of a daily dose of the compound of the invention in association with a carrier and/or enclosed within an envelope. Whether the medicament contains a daily dose or, for exampleg 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 ~our times a day respectively.
The pharmaceutical composition according to the invention may, for exampleg take the form o~ oint~ents, gels, pastes, creams, sprays ~including aerosols)g lotions, suspensions, solutions and emulsions o~ the active ingredient in aqueous or non-aqueous diluents, syrups 3 granulates or powders.
The diluents to be used in pharmaceutical compositions te.g. granulates) adapted to be ~ormed into tablets, dragees? capsules and pills include the following:
(a) fillers and extenders, e.g. starch, sugars, mannitol, and silicic acid; (b) binding agents, e.g. carboxymethyl cellulose and other cellulose derivatives, alg1nates, .. .. .. .... .. ..
~e A 20 230 - 10 - ~l~S~23~
- gelatine and polyvinyl pyrrolidone; (c) moisturizing age~ts, e.g. glycerol; (d) disintegrating agents, e.g.
agar-agar, calcium carbonate and sodium bicarbonate;
(e) agents for retarding dissolution e.g. paraffin;
(f) resorption accelerators3 e.g. quaternary ammonium compounds; (g) surface active agents, e.g. cetyl alcohol~
glycerol monostearate; (h) adsorptive carriers, e.g.
kaolin and bentonite; ~i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethyl glycols or mixtures of these above-mentioned substances.
The tablets, dragees, capsules and pills formed from the pharmaceutical compositions of the invention can have the customary coatings, envelopes and protective matrices, ~hich may contain opacifiers. 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 o~ time. The coatings, envelopes and protective matrices may be made, for example~
of polymeric substances or waxès.
The ingredient can also be made up in microencapsulated form together with one or several of the abo~e-mentioned diluents.
The diluents to be used in pharmaceutical compositions adapted to be formed into suppositories can, for example, be the usual water-soluble or water-insoluble diluents, such as polyethylene glycols and ~ats (e.g.cocoa oil and high esters (e.g. C14-alcohol with C16-fatty acid)) or mixtures o~ these diluents.
The pharmaceutical compositions which are ointments~
pastes, creams and gels can, for example3 contain the usual diluents, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures o~ these substances.
The pharmaceutical compositions which are powders and sprays can, for example, contain the usual diluents, e.g. lactose, talc, silicic acid, aluminium hydroxide, calcium silicate~ and polyamide powder or mixtures o~
these substances. Aerosol sprays can, for example, Le A 20 230 . contain the usual propellants, e.'g. chlorofluorohydro-carbons.
The pharmaceutical compositions which are solutions and emulsicns can, for example,' contain the customary diluerts (with, of course, the above-mentioned exclusion of solvents having a molecular weight below 200 except in the presence o~ a surface-active agent) 3 such as solvents.~ dissolving agents and emulsifiers; specific examples of such diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,. di~ethylformamide, oils (for example ground nut oil), glycerol,. tetrahydro~urfuryl 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 pharmaceutical compositi.ons which are suspensions can co.ntain the usual diluents, such as liquid diluents,.
e.g.. water, ethyl alcohol, propylene glycol, surface-acti.ve agents. (e g. ethoxylated isostearyl alcohols, polyoxyethylene sorbite and sorbitane esters), micro-crystalline cellulose~ aluminium .metahydroxide, bentonite, agar-agar and tragacanth or mixtures thereo~.
All the pharmaceutical compositions according to the invention can also contain colouring agents and preservatives as well as perfumes and flavouring additions (e.g. peppermint oil and eucalyptus cil) and sweetening agents (e.g. saccharin).
~he pharmaceutical compositions according to the invention generall~J contain from 0.1 to 99.5% usually from 0.5 to95% o~ the active ingredient by welght of the total composition.
In addition to a comound of the invention, the pharmaceutical compositions and medicaments according to the invention can also canta.in other pharmaceutically active compo~mds. They may also contain a plurality . of compounds of the lnvention.
.. . .. .... ....
' Le A Z0 230 . . _ .
~ L6~Z37 Any diluent in the medicaments of the presenk invention may be any of those mentioned above in relation to the pharmaceutical compositions of the present invention.
Such medicaments may include solvents of molecular ~Teight less than 200 as sole diluent.
The discrete coherent portions constituting the medicament according to the invention will generally be adapted by virtue of their shape or packa~ing for medical administration and may be, for example, any Of the followin~: tablets (including lozenges and ~ranulates), pills, dragees, capsules, sùppositories and ampoules. Some of these forms may be made up for delayed release of the active ingredient. Some, 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 2.5g to lO g o~ active ingredient.
The production of the above-mentioned pharmaceuticaI
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 composition (e.g. a granulate) and then forming the composition into the medicament (e.g. tablets3.
This invention further provides a method of combating (including prevention, relief and cure of) the above~
mentioned diseases in human and non-human animals, which comprises administering to the animals a compound of the invention alone or in admixture with a diluent or in the form of a medicament according to the invention.
It is envisaged that these active compounds will be administered perorally, parenterally (for example intramuscularly, intraperitoneally, subcutaneously ar.d intravenously), rectally or locally, preferably parenterally, especially intravenously. Preferred pharmaceutical ccmpositions and medicaments are therefore those adapted .. .. .. ..
Le A 20 230 .. . .
1~
.~or administration such as parenteral administration.
Administration in the ~.ethod of the invention is pre.ferably parenteral administration.
In general it has proved advantageous to adminis.ter amounts.of from lOmg to 300mg/kg, preferably from 50mg to 200mg/kg, of body weight per day to achieve effective results. Neverthe.less, it can at times be necessary to deviate from those dosage rates, and in particular to do so as a function of the nature and body weight of the human or animal subject to be treated, the individual reaction of this subje.ct to the treatment, the ty.pe of formulation in which the active ingredient is administered and the mode in which the administration is carried out,. and the point in the progress o~ 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 me.ntioned must.be exce.eded to achi.eve the desired results.. Where larger amounts are administered it can be advisab.le to divide these into several individual .administrations. over the. course of the day.
The following Examples 1 to 8 illustrate processes for the production of compounds of the present invention.
E'ga'mpl'e' 1 Cl ~ ~ IH -. fH2 L~
4.0 g of 1-(4-biphenylyl)-1-(2-chlorophenylj-2-(imidazol-I-yl)-ethylene were dissolved in 100 ml of glacial aceticacid and were hydrogenated at 60C under 40 bars of H2 for ~ hours, using platinum oxide as the catalyst. The solvent was then distilled off and the.
syrupy residue was chromatographed over Merck Silica gel 60 ~mobile phase: chloroform/methanol = 10/0.5).
.... .. .. ..
L'e' A' 2'0' 2'30 .
3~7 3.4 g (85% of theory) of 1-(4-biphenylyl)-1-(2-chloro~
phenyl)-2-(imidazol-1-yl)-ethane of melting point 86C
were. obtained.
Preparat'ion'o'f'th'e pre'curs'o'rs Cl (II-l) ~ e ~
CH
N ~
Il N
1.9 g of 1-(4-biphenylyl)-1-( ~chlorophenyl)-2-timidazol-l-yl)-ethan-l-ol were suspended in 30 ml of . chloroform, and 1.4 ml of thionyl chloride were added.
The mixture was stirred at 60C for 18 hours. The clear .solution was then .evaporated`'in''v'ac'uo, the residue was taken up in 30 ml of chloroform and, after adding another 1.4 ml of thionyl chloride, the mixture was stirred again .at 60C for 18 hours. The crystalline crude product which remained after stripping off the solvent was 1.5 recrystallised from isopropanol. 16 g (89% o~ theory) . of 1-(4-biphenylyl~-1-(2-:chlorophenyl)-2-(imidazol-1-yl)-ethylene of melting point 196C were obtained.
OHcl ._....N
3.5 g (o.o65 mole) of sodium methylate were diss-olved in 20 ml of methanol, and 7.5 ~ (0.11 mole) of imidazole were added. A solution of 15 g (0.05 mole) of 2-(4-biphenylyl)-2-(2-chlorophenyl)-oxirane in 75 ml of dimethylformamide was added dropwise and the reaction mix-. ture was heated to 80C for 1.5 hours. Thereafter, the reaction mixture was poured onto w.ater and the crystals formed were filtered off and dried. 14.7 g (79%. o~
~ Le A'2'0''2'30 .
. theo.ry). of 1-(4-biphenylyl)~1-(2-chlorophenyl)-2-imidazol -l-yl-ethan-l-ol of melting pcint 222C were obtained.
/C\~
90 ml of dimethyl sulphoxide were added to 2.7 g (0.09 mole) of 80% strength sodium hydride and 19.8 g (0.09 mole) of trimethyloxosulphonium iodide in the course of 20 minutes. When the evolution of hydrogen had ended, a solution of 22 g (0.075 mole)' of 2'-chloro-4'-phenyl-. benzophenone in 60 ml of dimethyl sulphoxide was added dropwise and the mixture was sub.sequently stirred at 50C
for 1 hour. 200 ml of water were added to the cooled reaction mi.xture and the mixture was extracted by shaking with ether. The ether solution ~as washed with water, . dri.ed.over s.odium sulphate and. concentrated by distilling off the solvent in''~acuo. The residue was recr~stallised from diisopropyl ether. 15 g (65% of theory) of 2-(4-. biphenylyl)-2-(2-chlorophenyl)-oxirane of melting point '70C were o.btained.
The compounds of the formula (I) listed in Table 1 which follows. c.ould be obtained by the process as described Lxample 1 using corresponding starting materials.
- Ta~le 1 ~ ~ CH
Xm CH2 Yn I
N
N
- Le A 20 230 .
-Ex-. N.o.~.. m .......... Yn - - A Meit n(O
2 4-C1 2-Cl CH 188 3 - 2-F CH resin 4 - 3-Cl CH oil - 2-Cl CH 282(xl/2 NDS).
6 ~ 2-F CH 297(xl/2 NDS) 7 - 3 Cl CH 265(xl/2 N3S.) 8 4-C1 2-Cl N 152 NDS = 1,5-naphthalenedisulphonic acid The starting materials. o~ the ~ormula (II) listed in Table 2 which follows could be obtained by the process described Example 1 for the prepa~ation of precurso:rs using corresponding starting materials for that process.
X~ 11 ~Y
m CH n (II) ~N~A
N_ Ex-ample X Y A Melting . 15 . No... m ........... n................ p.o.in.t. (.C.) (II-2)4-C1 2-Cl CH 174 (II-3) - 2-F CH oil (II~4) - 3-Cl CH 211 (II-5) - 2-F CH 325 (decompo-sition)(xl/2 NDS) (II-6)4-C1 2-C1 N 17Q
(II-7) - 4-Cl CH n20 = 1.6350 Le A 20 230 _ .
~ 3 - 17 - , ... .
' The', following Example illustrates the' in'''i't'ro activity, of compounds of the present invention. In this Example, the compour.ds according to the present invent-ion are each identified by the number ~given in brackets) of the corresponding preparative Example~ which will be found earlier in this specification.
The known comparison compounds are identified as follows:
Cl (A) Cl ~ - ~ - CH
Cl (B) Cl- ~ ~ ~ CH ~
(c) ~-f~
~N~
N
(D) ~ ~ - CH
~ N~N
, I0' Example A
Antimy'c'oti'c'i'n''v'i't'r'o''a'c't'i'v'it'y . .
D'e-sc'rip'ti'on''o'f'the'-e'xpe'ri'men't:
The in ~itro test was carried out as a series dilution test using germ inocula of an average 5 x 10 &erms/ml of substrate, The nutrient medium used was:
Le A 2~ 230 __ a) fcr dermatophytes and moulds: Sabouraud's milieu . d'ep.re.uve, and . b) .for yeasts: isotonic sensi.test broth from Oxid, ~he incubation temperature was 28C; the .5 incubation time was 24 hours in the case of yeasts and 96 hours in the case of dermatophytes and moulds.
In this test, for example, the compounds (5), (6)~ (7) and (8) exhibited a very good action which is superior to. that of the compounds (A), (B), (C) and (D) - lO known from the prior art.
The present invention also comprises pharmaceutic-ally acceptab.Ie bioprecursors of thè active compounds of . the present inventi.on.
For the purposes of this specification the term 'pharmaceutica~ly acceptable bioprecursor' of an active compound of the invention means a compound h.aving a structural formula differe.nt from the active compound but wh.i.ch nonetheless, upon administration to an animal or human being is. converted in the patient's body to the active compound.
Le A 20 2~0 _ _
Claims (34)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a biphenylyl-azolylethane compound of the general formula I
or a physiologically acceptable salt thereof, wherein A represents the -CH-group or a nitrogen atom; X represents a halogen atom or an alkyl, halogenoalkyl, alkoxy, alkylthio, nitro or cyano radical; Y represents a halogen atom or an alkyl, halogenoalkyl, alkoxy, alkylthio, nitro, cyano or a phenyl radical which is unsubstituted or is substituted by a halogen atom or an alkyl, halogenoalkyl, alkoxy, alkylthio, nitro or cyano radical; and m and n are independently 0, 1, 2 or 3, which comprises hydrogenating a biphenylyl-azolylethylene compound of the general formula II
wherein A, X, Y, m and n have the above-mentioned meaning, in the presence of a catalyst and, if required, converting the product into a physiologically accept-able salt.
or a physiologically acceptable salt thereof, wherein A represents the -CH-group or a nitrogen atom; X represents a halogen atom or an alkyl, halogenoalkyl, alkoxy, alkylthio, nitro or cyano radical; Y represents a halogen atom or an alkyl, halogenoalkyl, alkoxy, alkylthio, nitro, cyano or a phenyl radical which is unsubstituted or is substituted by a halogen atom or an alkyl, halogenoalkyl, alkoxy, alkylthio, nitro or cyano radical; and m and n are independently 0, 1, 2 or 3, which comprises hydrogenating a biphenylyl-azolylethylene compound of the general formula II
wherein A, X, Y, m and n have the above-mentioned meaning, in the presence of a catalyst and, if required, converting the product into a physiologically accept-able salt.
2. A process according to claim 1 wherein the biphenyl-azolylethylene compound of formula II is obtained by a process in which a hydroxyethyl-azole of formula III
III
wherein A, X, Y, m and n are as defined in claim 1, with a water-binding agent.
III
wherein A, X, Y, m and n are as defined in claim 1, with a water-binding agent.
3. A process according to claim 2 wherein the water-binding agent is an acid anhydride, a halide of an oxyacid or an isocyanate and the reaction is carried out in the presence of a diluent which is a chlorinated hydrocarbon.
4. A process according to claim 2 wherein the compound of formula III is obtained by reacting the corresponding hydroxyethyl halide with imidazole or triazole.
5. A process according to claim 2 wherein the compound of formula III is obtained by reacting an oxirane of formula IV
IV
wherein X, Y, m and n are as defined above, with imidazole or triazole in the presence of an alkali metal alcoholate and in the presence of an inert organic solvent.
IV
wherein X, Y, m and n are as defined above, with imidazole or triazole in the presence of an alkali metal alcoholate and in the presence of an inert organic solvent.
6. A process according to claim 5 wherein the compound of formula IV is obtained by reacting the corresponding ketone with dimethyloxosulphonium methyl-ide in the presence of a diluent or with trimethylsulphonium methyl sulphate in a two-phase system.
7. A process according to claim 1, 2 or 4 in which A, m and n have the same meanings as in claim 1, X represents a halogen atom, a straight-chain or branched alkyl radical with 1 to 4 carbon atoms, a halogenoalkyl radical with 1 to 4 carbon atoms and 1 to 5 identical or different fluorine or chlorine atoms, an alkoxy or alkylthio radical with in each case 1 to 4 carbon atoms, or a nitro or cyano radical and Y, independently of X, has any of the meanings here given for X or a phenyl radical which is substituted by X as here defined.
8. A process according to claim 1, 2 or 4 in which A, m and n have the same meanings as in claim 1, X represents a fluorine, chlorine or bromine atom or a methyl, ethyl, isopropyl, tert.-butyl, trifluoromethyl, methoxy, ethoxy, methylthio, ethylthio, nitro or cyano radical, and Y, independently of X, has any of the meanings here given for X, or represents a phenyl radical which is optionally substituted by fluorine, chlorine, methyl, tert.-butyl, trifluoromethyl, nitro or cyano.
9. A process according to claim 1,2 or 4 wherein n is 1, Y is chlorine in the 3- or 4-position, m is 1 and X is chlorine in the 4-position.
10. A process according to claim 1, 2 or 4 wherein m is zero, n is zero or 1 and when n is 1, Y is chlorine in the 2-, 3- or 4-position, fluorine in the 3-position, methyl in the 3-position, tert.-butyl in the 4-position, tri-fluoromethyl in the 3-position, bromine in the 3-position, phenyl in the 3-position or nitro in the 3-position and A is N.
11. A process according to claim 1, 2 or 4 wherein m is zero, n is zero or 1 and when n is 1, Y is chlorine in the 4-position, methyl in the 3-position, tert.-butyl in the 4-position, trifluoromethyl in the 4-position, phenyl in the 4-position, bromine in the 4-position or nitro in the 3-position and A is -CH-.
12. A process according to claim 1, 2 or 4 wherein m is zero, n is 2, Y is chlorine in the 2- and 5-positions or Y is nitro in the 3-position and chlorine in the 4-position and A is -CH-.
13. A process according to claim 1, 2 or 4 wherein m is zero, n is 2, Y is chlorine in the 2- and 5-positions or Y is nitro in the 3-position and chlorine in the 4-position and A is N.
14. A process according to claim 1, 2 or 4 in which the reaction is carried out in the presence of a diluent.
15. A process according to claim 1, 2 or 4 in which the reaction is carried out in an inert organic solvent as diluent.
16. A process according to claim 1, 2 or 4 in which the catalyst is platinum, platinum oxide, Raney nickel or palladium oxide.
17. A process according to claim 1, 2 or 4 in which the reaction is carried out at a temperature between 40 and 150°C.
18. A compound of formula I as defined in claim 1 or a physiologically acceptable salt thereof when prepared by a process according to claim 1, 2 or 4 or an obvious chemical equivalent thereof.
19. A process for preparing 1-(4-biphenlyl)-1-(2-chlorophenyl)-2-(imidazol-1-yl)-ethane which comprises hydrogenating 1-(4-biphenylyl)-1-(2-chlorophenyl)-2-(imidazol-1-yl)-ethylene in the presence of platinum oxide as catalyst.
20. A process according to claim 19, wherein the 1-(4-biphenylyl)-1-(2-chlorophenyl)-2-(imidazol-1-yl)-etllylene is obtained by reacting 1-(4-biphenylyl)-1-(2-chlorophenyl)-2-(imidazol-1-yl)-ethan?l-ol with thionyl chloride.
21. A process according to claim 20, wherein the 1-(4-biphenylyl)-1-(2-chlorophenyl)-2-(imidazol-1-yl)-ethan-1-ol is obtained by reacting 2'-chloro-4-phenyl-benzophenone with trimethyloxosulphonium iodide in dimethyl sulphoxide, followed by reacting the obtained 2-(4-biphenylyl)-2-(2-chlorophenyl)-oxirane with imidazole in the presence of sodium methylate.
22. The compound 1-(4-biphenylyl)-1-(2-chlorophenyl)-2-(imidazol-1-yl)-ethane when prepared by a process according to claim 19, 20 or 21 or by an ob-vious chemical equivalent thereof.
23. A process for preparing 1-(4-biphenylyl)-1-(2-fluorophenyl)-2-(imidazol-1-yl)-ethane which comprises hydrogenating 1-(4-biphenylyl)-1-(2-fluorophenyl)-2-(imidazol-1-yl)-ethylene in the presence of platinum oxide as catalyst.
24. A process according to claim 23, wherein the 1-(4-biphenylyl)-1-(2-fluorophenyl)-2-(imidazol-1-yl)-ethylene is obtained by reacting 1-(4-biphenylyl)-1-(2-fluorophenyl)-2-(imidazol-1-yl)-ethan-1-ol with thionyl chloride.
25. A process according to claim 24, wherein the 1-(4-biphenylyl)-1-(2-fluorophenyl)-2-(imidazol-1-yl)-ethan-1-ol is obtained by reacting 2'-fluoro-4-phenyl-benzophenone with trimethyloxosulphonium iodide in dimethyl sulphoxide, followed by reacting the obtained 2-(4-biphenylyl)-2-(2-fluorophenyl)-oxirane with imidazole in the presence of sodium methylate.
26. The compound 1-(4-biphenylyl)-1-(2-fluorophenyl)-2-(imidazol-1-yl)-ethane when prepared by a process according to claim 23, 24 or 25 or by an ob-vious chemical equivalent thereof.
27. A process for preparing 1-(4-biphenylyl)-1-(3-chlorophenyl)-2-(imidazol-1-yl)-ethane which comprises hydrogenating 1-(4-biphenylyl)-1-(3-chlorophenyl)-2-(imidazol-1-yl)-ethylene in the presence of platinum oxide as catalyst.
28. A process according to claim 27, wherein the 1-(4-biphenylyl)-1-(3-chlorophenyl)-2-(imidazol-1-yl)-ethylene is obtained by reacting 1(4-biphenylyl)-1-(3-chlorophenyl)-2-(imidazol-1-yl)-ethan-1-ol with thionyl chlo-ride.
29. A process according to claim 28, wherein the 1-(4-biphenylyl)-1-(3-chlorophenyl)-2-(imidazol-1-yl)-ethan-1-ol is obtained by reacting 3'-chloro-4-phenyl-benzophenone with trimethyloxosulphonium iodide in dimethyl sulphoxide, followed by reacting the obtained 2-(4-biphenylyl)-2-(3-chlorophenyl)-oxirane with imidazole in the presence of sodium methylate.
30. The compound 1-(4-biphenylyl)-1-(3-chlorophenyl)-2-(imidazol-1-yl)-ethane when prepared by a process according to claim 27, 28 or 29 or by an ob-vious chemical equivalent thereof.
31. A process for preparing 1-(4'-chlorophenyl-4-phenyl)-1-(2-chlorophenyl)-2-(1,2,4-triazol-1-yl)-ethane which comprises hydrogenating 1-(4'-chlorophenyl-4-phenyl)-1-(2-chlorophenyl)-2-(1,2,4-triazol-1-yl)-ethylene in the presence of platinum oxide as catalyst.
32. A process according to claim 31, wherein the 1 (4'-chlorophenyl-4-phenyl)-1-(2-chlorophenyl)-2-(1,2,4-triazol-1-yl)-ethylene is obtained by react-ing 1-(4'-chlorophenyl-4-phenyl)-1-(2-chlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-1-ol with thionyl chloride.
33. A process according to claim 32, wherein the 1-(4'-chlorophenyl-4-phenyl)-1-(2-chlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-1-ol is obtained by re-acting 2'-chloro-4-(4"-chlorophenyl)-benzophenone with trimethyloxosulphonium iodide in dimethyl sulphoxide, followed by reacting the obtained 2-(4'-chloro-phenyl-4-phenyl)-2-(2-chlorophenyl)-oxirane with 1,2,4-triazole in the presence of sodium methylate.
34. The compound 1-(4'-chlorophenyl-4-phenyl)-1-(2-chlorophenyl)-2-(1,2,4-triazol-1-yl)-ethane when prepared by a process according to claim 31, 32 or 33 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3012770.9 | 1980-04-02 | ||
| DE19803012770 DE3012770A1 (en) | 1980-04-02 | 1980-04-02 | BIPHENYLYL-AZOLYLETHANE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1160237A true CA1160237A (en) | 1984-01-10 |
Family
ID=6099063
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000374351A Expired CA1160237A (en) | 1980-04-02 | 1981-04-01 | Biphenylyl-azolylethane compounds, their production and their medicinal use |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0037049A1 (en) |
| JP (1) | JPS56152466A (en) |
| AU (1) | AU6898281A (en) |
| CA (1) | CA1160237A (en) |
| DE (1) | DE3012770A1 (en) |
| ES (1) | ES500892A0 (en) |
| FI (1) | FI810990L (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA815155B (en) * | 1980-08-26 | 1982-07-28 | Ici Ltd | Heterocyclic compounds |
| DE3121676A1 (en) * | 1981-06-01 | 1982-12-16 | Hoechst Ag, 6000 Frankfurt | "1,1-DIARYL-2-AZOLYL-AETHANE, THEIR PRODUCTION, THEIR USE AND THE PREPARATIONS CONTAINING THESE COMPOUNDS" |
| CA1206970A (en) * | 1981-10-01 | 1986-07-02 | Hak-Foon Chan | Substituted ethylenic imidazoles and triazoles |
| JPS59108468A (en) * | 1982-12-14 | 1984-06-22 | Olympus Optical Co Ltd | Solid-state image pickup device |
| EP0276583A1 (en) * | 1987-01-29 | 1988-08-03 | Instituto de Investigacion Y Desarrollo Quimico Biologico S.A. | Imidazole derivatives, processes for their preparation and their fungicidal properties |
| JP5523076B2 (en) * | 2009-12-11 | 2014-06-18 | 日本合成化学工業株式会社 | Method for producing vinylimidazole compound |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2808086A1 (en) * | 1978-02-24 | 1979-08-30 | Bayer Ag | SUBSTITUTED DIPHENYL-IMIDAZOLYL-METHANES, THE PROCESS FOR THEIR MANUFACTURING AND THEIR USE AS A MEDICINAL PRODUCT |
-
1980
- 1980-04-02 DE DE19803012770 patent/DE3012770A1/en not_active Withdrawn
-
1981
- 1981-03-23 EP EP81102165A patent/EP0037049A1/en not_active Withdrawn
- 1981-03-30 JP JP4569681A patent/JPS56152466A/en active Pending
- 1981-03-31 FI FI810990A patent/FI810990L/en not_active Application Discontinuation
- 1981-03-31 ES ES500892A patent/ES500892A0/en active Granted
- 1981-04-01 AU AU68982/81A patent/AU6898281A/en not_active Abandoned
- 1981-04-01 CA CA000374351A patent/CA1160237A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| DE3012770A1 (en) | 1981-10-08 |
| AU6898281A (en) | 1981-10-08 |
| JPS56152466A (en) | 1981-11-26 |
| ES8201979A1 (en) | 1982-01-16 |
| EP0037049A1 (en) | 1981-10-07 |
| ES500892A0 (en) | 1982-01-16 |
| FI810990L (en) | 1981-10-03 |
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