CA1077493A - Derivatives of substituted n-alkyl imidazoles - Google Patents
Derivatives of substituted n-alkyl imidazolesInfo
- Publication number
- CA1077493A CA1077493A CA257,718A CA257718A CA1077493A CA 1077493 A CA1077493 A CA 1077493A CA 257718 A CA257718 A CA 257718A CA 1077493 A CA1077493 A CA 1077493A
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- imidazole
- chloro
- compound
- acid addition
- steps
- Prior art date
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Abstract
ABSTRACT OF THE DISCLOSURE
Compounds of the formula (I) wherein R1 and R2 are each independently phenyl, phenyl straight chain lower alkyl or phenyl straight chain lower alkenyl or one of the above substituted in the phenyl ring with one or more substituents independently selected from the group consisting of lower alkyl of from one to four carbon atoms, halo and trifluoromethyl; X is oxygen or sulfur;
n is an integer of from 1 to 8 with the proviso that n is not 1 when R1 is phenyl or substituted phenyl; and the antimicrobial acid addition salts thereof are useful as antifungal, antibacterial and antiprotozoal agents.
Compounds of the formula (I) wherein R1 and R2 are each independently phenyl, phenyl straight chain lower alkyl or phenyl straight chain lower alkenyl or one of the above substituted in the phenyl ring with one or more substituents independently selected from the group consisting of lower alkyl of from one to four carbon atoms, halo and trifluoromethyl; X is oxygen or sulfur;
n is an integer of from 1 to 8 with the proviso that n is not 1 when R1 is phenyl or substituted phenyl; and the antimicrobial acid addition salts thereof are useful as antifungal, antibacterial and antiprotozoal agents.
Description
` 1077493 Detailed Description of the Invention The present invention relates to novel chemical com- -pounds which are derivatives of substituted N-alkyl imidazoles. More particularly, the compounds of the present invention are represented by the formula:
R -CH-(CH2)n_N
X-R
(I) ~ -wherein R and R are each independently phenyl, phenyl s~raight chain lower alkyl, or phenyl straight chain lower alkenyl; or one of the above substituted in the phenyl ring with one or more substituents independently selected from the group consisting of lower alkyl of from one to four ; carbon atoms, halo and trifluoromethyl; X is oxygen or sul-fur; n is an integer of from 1 to 8 with the proviso that n is not 1 when R is phenyl or substituted phenyl; and the antimicrobial acid addition salts thereof.
In a second aspect the present invention is concerned with a method of combatting fungi, bacteria and protozoa by, administering a compound of the present invention or a compo-sition containing same.
As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated. The term "lower alkyl" refers to a -straight or branched chain monovalent substituent consisting solely of carbon and hydrogen, containing no unsaturation, and having from one to eight carbon atoms. Examples of lower alkyl groups are methyl, ethyl, n-propyl, i-propyl, `:`' 10774g3 n-butyl, t-butyl, pentyl, n-hexyl, and n-octyl. The term "lower alkenyl" refers to a straight or branched chain mono-valent substituent consisting solely of carbon or hydrogen containing mono-olefinic unsaturation, and having from 2 to 8 carbon atoms. Examples of lower alkenyl groups are ethenyl, prop-l-enyl, prop-2-enyl, but-l-enyl, but-2-enyl, pent-l-enyl, pent-3-enyl, hex-l-enyl, hex-3-enyl, hex-5-enyl, hept-l-enyl, hept-4-enyl, hept-6-enyl, oct-l-enyl, oct-5-enyl, and oct-7-enyl. The term "styryl" refers to ~-styryl.
The term "halo" refers to fluoro, chloro and bromo. "Anti-microbial acid addition salts" of the subject bases refers to those salts which retain the antimicrobial properties of the free bases and which are neither biologically or other-wise undesirable, formed with, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; or inorganic acids such as acetic acid, propionic acid, glucolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, siccinic acid, malic acid, ~aleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic aicd, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic ~ , salicyclic - -acid, and the like.
All compounds of formula (I) possess at least one chiral center, i.e., the carbon atom to which are attached the R , X, (CH2) and H moieties. Accordingly, the compounds ~ ~ -of the present invention may be prepared in either optically active form, or as a racemic mixture. Unless otherwise specified, the compounds described herein are all in the ~
racemic form. However, the scope of the subject invention ;
herein is not to be considered limited to the racemic form, ~
. . - :: :, - .
,: . , ~-, - ~. , . , , : ., , , ,' ' - " :
.
.
.
(~ 1077493 . ( .
- ~ ' but to encompass the individual optical isomers of the ' :
. ~ , :
' ', , ~,, . . . , , : ,. . - , . : . :
., ', ,: " . . ' .' . ' ', ::: ,--- ~. , . . : . . : . . -. ' ' '' ' -,: :,' ' ' ,, . ,', - : ' , ,, :.
' ~'': ' : ". ' - : : ' .
.: . - '. ' '' :' .
: ~- ' - . : ' ' . :' . : .
10774~3 subject compounds. Additionally, those compounds posscssing a substituted or unsubstituted phenyl straight chain lower alkenyl group can have geometric (cis and trans) isomers about the double bond. Both isomers as well as mixtures S thereof are intended to be included within the scope of the present invention.
If desired, racemic intermediates or final products prepared herein may be resolved lnto their optical antipodes by conventional resolution means known per se, for example, by the separation (e.g., fractional crystallization) of the : diastereomeric salts formed by reaction of, e.g., racemic compounds of formula ~I) with an optically active acid, or by the separation of the diastereomeric salts or esters formed by reaction of racemic compounds of formula (II), infra, with 15~ an optically active acid. Exemplary of such optically active ¦ acids are the optically active forms of camphor-10-sulfonic acid, -bromo-camphor-~-sulfonic acid, camphoric acid, menthoxy-acetic acid, tartaric acid, malic acid, diacetyl-tartaric acid, pyrrolidone-5-carboxylic acid, and the like.
The separated pure diastereomeric salts or esters may then be cleaved by standard means to afford the respective optical ; isomers of the compounds of formula (I) or (II).
~he subject compounds of formula (I) exhibit anti-fungal, anti-bacterial and anti-protozoal activity. For example, compounds of the present invention exhibit anti-fungal activity against human and animal pathogens such as . .
Microsporum audouini, Microsporum gypseum, .
Microsporum gypseum - canis, ~pldermophyton floccosum, Trichophyton mentagrophytes, Txichophyton rubrum Trichophyton tonsurans Candida albicans, and Cryptococcus neoformans.
The compounds of the present invention also exhibit anti-fungal activity against the following fungi primarily of agricultural significance , , ' ~
~ ~spergillus flavus, Aspergillus niger Cladosporium herbarum, Penicillium oxalicum, ` Fusarium graminearum,- Penicillium spinulosum, .
Penicillium notatum, and Pithomyces chartarum.
In addition, the compounds of the present invention ~ exhibit anti-bacterial activity against human and animalj ':
'~ 15 pathogens, such as Staphylococcus aureus, Streptococcus faecalis, .. , ~ ~ Corynebacterium acnes, i . .
Erysipelothrix insidiosa, Escherichia coli, .1:
~, Proteus vulgaris, -, ~ Salmonella choleraesuis, Pasteurella multocida, and Pseudomonas aeruginosa.
.~ ........ .. .. . .
;1 25 Moreover, the compounds of the present invention exhibit ~ anti-protozoal activity against protozoa such as Trichomonas . . I .
I' ! Vaginalis.
¦ In general, the subject compounds of the instant inven-tion exhibit a low level of toxicity. Moreover, these com-pounds demonstrate good solubility in the stratum corneum.
. ', ' . ~
_ "'''' l ' ' -, , .: - .
~(~77gg3 .
Since d!ermatophyte (i.e., parasitic fungal) infections are usually localized in the dead tissue of the stratum corneum, solubility of anti-fungal agents in this tissue significantly enhances their effectiveness.
S In view of the aforementioned activities, the subject compounds are found to be useful antimicrobials, having not only pharmaceutical but also agricultural and industrial application.
Accordingly,-a further aspect of the present invention relates to compositions for pharmaceutical, agricultural, e~d industrial use, which compositions comprise the subject .~
.
.. .. .
, . . . ., . - - . . - ~ .
.. . : ., - . '- ''' ' : - ... . . . . .
,..... .. . .. .. ~. . : , - . ' - . ' - . , ' ~ ' : : '' ' `~ 1077493 compounds of formula (I) in combination with a suitable carrier. A still further aspect of the present invention relates to methods.of inhibiting the growth of fungi, bacteria and protozoa by applying to a host object containing, or S i subject to attack by, fungi, bacteria or protozoa, an effective amount of a compound of the present invention or ~~ . a suitable composition containing same.
In pharmaceutical applications, compositions may be - solid, semi-solid or liquid in form such as tablets, cap-sules, powders, suppositories, liquid solutions, suspensions, creams, lotions, ointments and the like. Pharmaceutically acceptable non-toxic carriers, or excipients normally employed for solid formulations include tricalcium phosphate, calcium carbonate,.kaolin, bentonite, talcum, gelatin, lactose, starch and the like; for semi-solid formulations ... .
there may be mentioned, for example, poly-alkylene glycols, - vaseline and other cream bases; for liquid formulations there may be mentioned, for example, water, oils of vege-table origin and low boiling solvents such as isopropanol, hydrogenated naphthalenes and the like. The pharmaceutical compositions containing the compounds of the present invention may be subiected to conventional pharmaceutical ~
expedients such as sterilization and can contain conventional pharmaceutical excipients such as preservatives, stabilizing agents, emulsifying agents, salts for the adjustment of osmotic pressure and buffers. The compositions may also contain other therapeutically active materials. In pharma-ceutical applications, the subject compounds and composi-tions may be administered to humans and animals by conven-tional methods, e.g., topically, orally, parentcrally and .
.
" ~077493 . . .
the like. Parenteral administration includes intramuscular as well as subcutaneous and intravenous administration.
Intravenous injection of imidazole-type anti-fungals has been demonstrated to be effective in the treatment of systemic mycoses (see for example, Drugsl 9, pp, 419-420, 1975, which describes the intravenous administration of miconazole, i.e. l-[2,4-dichloro-~-~2',4'-dichlorobenzyloxy)phenethyl]-imidazole nitrate, to patients with systemic candidiasis).
Topical application is the preferred method of administration for pharmaceutical applications. For such treatment, an area having an existing fungal, bacteriaL or protozoal growth, or to be protected against attack by fungi, bacteria or protozoa, may be treated with the subject compounds or compositions by, for example, dusing, sprinkling, spraying, rinsing, brushing, dipping, smearing, coating, impregnating and the like. Topical pharmaceutical compositions containing the compounds of the present invention exhibit anti-fungal anti-bacterial and anti-protozoal activity over a wide range of concentration, for example, from about 0.1 to 10.0%
by weight of the composition, In any event, the composition to be administered will contain a quantity of the subject , compound in an amount effective for relief or prevention of t~e specific condition being treated.
The pharmaceutical compositions hereof typically com-prise one or more subject compounds of Formula (I) and a pharmaceutically acceptable, non-toxic carrier, and are preferably formulated in unit dosage form to facilitate ; administration (unit dosage being the amount of active ingredient administered on one occasion).
In general, for systemic (e.g., oral or parenteral) ' ~ -7-",1 .
- - .
.
1~77493 administration it is expedient to administer the active ingredient in amounts between about 1 and 100 mg./kg- body weight per day, preferably between about 5 and 50 mg./kg. body weight per day; preferably distributed over several applications (e.g., in 3 individual doses) in order to achieve most effective results For localized (e.g. topical) administra-tion, however, proportionately less of the active ingredient is required.
The exact regimen for pharmaceutical administration of the compounds and compositions disclosed herein will necessarily be dependent upon the needs of the individual subject being treated, the type of treatment, e.g., whether preventative or curative, the type of organism involved and, of course, the judgment of the attending practitioner.
... ... .... .. . . .
In agricultural appllcations, the subject compounds may be applied directly to plants (e.g., seeds, foliage) or to soil. For example, compounds of the present invention ¦ may be applied to seeds alone or in admixture with a powdered solid carrier. Typical powdered carriers are the various mineral silicates, e.g., mica, talc, pyrophyllite, and clays. The subject compounds may also be applied to , I the seeds in admixture with a conventional surface-active wetting agent with or without additional solid carrier.
Surface-active wetting agents that can be used are any of :;
:,. . .
'~ , ' . '' ' . . .
. " ' -:
- ~:
. 10774g3 \:
the conventional anionic, non-anionic or cationic types.
As a soil treatment for fungi and the like, the subject compounds can be applied as a dust in admixture with sand, soil or a powdered solid carrier such as a mineral silicate with or without additional surface-active agent, or the subject compounds can be applied as an aqueous spray optionally containing a surface-active dispersing agent and a powdered solid carrier. As a foliage treatment, the sub-ject compounds may be applied to growing ~l,ants as an aqueous spray which contains a surface-active dispersing agent with or without a powdered solid carrier and hydro- -carbon solvents.
In industrial applications, the subject compounds may be used to control bacteria and fungi by contacting the pathogens with the compounds in any known manner. Materials capable of supporting bacteria and fungi may be protected - by contacting, mixing or impregnating these materials with the subject compounds. In order to increase their effect, the subject compounds may be combined with other pesticidal control agents such as fungicides, bactericides, insecti-cides, miticides and the like. A particularly important industrial/agricultural use for the subject compounds of the present invention is as a food preservative against bacteria and fungi which cause deterioration and spoilage of foods.
. .
The compounds of formula (I) may be considered to consist of two subclasses, thos of furmulas (Ia) and (Ib) j shown below.
','~-~ ' ~ 30 8 `
~, R -CH-(CH2)n -N N R -CH-(CH2)n -N N
; O-R S-R
(Ia) (Ib) wherein R , R , and n are as defined above.
Both groups of compounds may be prepared from common intermediates having a free hydroxyl group which is then con- -verted to the ether or thioether, as the case may be, and which may be prepared by a variety of methods, depending upon the length of the (CH2)n chain, i.e. the value of n.
A preferred subgenus of compounds of formula (I) are those wherein n is 1, 2 or 3. When n is 1, a preferred group of compounds are those wherein R is phenethyl, styryl or halo (preferably chloro)-substituted phenethyl or styryl, preferably 4-chloro, 4-bromo, 4-fluoro, 2,4-dichloro or 3,4-dichloro-substituted, and R is independently -.::
l phenyl or benzyl, or halo-substituted derivatives thereof, ,;~
preferably having the halo substituent(s) in the same posi-tions as indicated above for R and, when R is substituted phenylthio, additionally the 2,4,5-trichloro and 2,3,4,5,6-pentachloro-substituted derivatives; or cinnamyl or 4-halocinna-myl.
. ~
When n is 2 or 3 a preferred group of compounds are those wherein R is phenyl or halo-substituted phenyl, preferably .,: .
~`~ 4-chloro, 4-bromo, 4-fluoro, 2,4-dichloro, 2,4-difluoro, or
R -CH-(CH2)n_N
X-R
(I) ~ -wherein R and R are each independently phenyl, phenyl s~raight chain lower alkyl, or phenyl straight chain lower alkenyl; or one of the above substituted in the phenyl ring with one or more substituents independently selected from the group consisting of lower alkyl of from one to four ; carbon atoms, halo and trifluoromethyl; X is oxygen or sul-fur; n is an integer of from 1 to 8 with the proviso that n is not 1 when R is phenyl or substituted phenyl; and the antimicrobial acid addition salts thereof.
In a second aspect the present invention is concerned with a method of combatting fungi, bacteria and protozoa by, administering a compound of the present invention or a compo-sition containing same.
As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated. The term "lower alkyl" refers to a -straight or branched chain monovalent substituent consisting solely of carbon and hydrogen, containing no unsaturation, and having from one to eight carbon atoms. Examples of lower alkyl groups are methyl, ethyl, n-propyl, i-propyl, `:`' 10774g3 n-butyl, t-butyl, pentyl, n-hexyl, and n-octyl. The term "lower alkenyl" refers to a straight or branched chain mono-valent substituent consisting solely of carbon or hydrogen containing mono-olefinic unsaturation, and having from 2 to 8 carbon atoms. Examples of lower alkenyl groups are ethenyl, prop-l-enyl, prop-2-enyl, but-l-enyl, but-2-enyl, pent-l-enyl, pent-3-enyl, hex-l-enyl, hex-3-enyl, hex-5-enyl, hept-l-enyl, hept-4-enyl, hept-6-enyl, oct-l-enyl, oct-5-enyl, and oct-7-enyl. The term "styryl" refers to ~-styryl.
The term "halo" refers to fluoro, chloro and bromo. "Anti-microbial acid addition salts" of the subject bases refers to those salts which retain the antimicrobial properties of the free bases and which are neither biologically or other-wise undesirable, formed with, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; or inorganic acids such as acetic acid, propionic acid, glucolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, siccinic acid, malic acid, ~aleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic aicd, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic ~ , salicyclic - -acid, and the like.
All compounds of formula (I) possess at least one chiral center, i.e., the carbon atom to which are attached the R , X, (CH2) and H moieties. Accordingly, the compounds ~ ~ -of the present invention may be prepared in either optically active form, or as a racemic mixture. Unless otherwise specified, the compounds described herein are all in the ~
racemic form. However, the scope of the subject invention ;
herein is not to be considered limited to the racemic form, ~
. . - :: :, - .
,: . , ~-, - ~. , . , , : ., , , ,' ' - " :
.
.
.
(~ 1077493 . ( .
- ~ ' but to encompass the individual optical isomers of the ' :
. ~ , :
' ', , ~,, . . . , , : ,. . - , . : . :
., ', ,: " . . ' .' . ' ', ::: ,--- ~. , . . : . . : . . -. ' ' '' ' -,: :,' ' ' ,, . ,', - : ' , ,, :.
' ~'': ' : ". ' - : : ' .
.: . - '. ' '' :' .
: ~- ' - . : ' ' . :' . : .
10774~3 subject compounds. Additionally, those compounds posscssing a substituted or unsubstituted phenyl straight chain lower alkenyl group can have geometric (cis and trans) isomers about the double bond. Both isomers as well as mixtures S thereof are intended to be included within the scope of the present invention.
If desired, racemic intermediates or final products prepared herein may be resolved lnto their optical antipodes by conventional resolution means known per se, for example, by the separation (e.g., fractional crystallization) of the : diastereomeric salts formed by reaction of, e.g., racemic compounds of formula ~I) with an optically active acid, or by the separation of the diastereomeric salts or esters formed by reaction of racemic compounds of formula (II), infra, with 15~ an optically active acid. Exemplary of such optically active ¦ acids are the optically active forms of camphor-10-sulfonic acid, -bromo-camphor-~-sulfonic acid, camphoric acid, menthoxy-acetic acid, tartaric acid, malic acid, diacetyl-tartaric acid, pyrrolidone-5-carboxylic acid, and the like.
The separated pure diastereomeric salts or esters may then be cleaved by standard means to afford the respective optical ; isomers of the compounds of formula (I) or (II).
~he subject compounds of formula (I) exhibit anti-fungal, anti-bacterial and anti-protozoal activity. For example, compounds of the present invention exhibit anti-fungal activity against human and animal pathogens such as . .
Microsporum audouini, Microsporum gypseum, .
Microsporum gypseum - canis, ~pldermophyton floccosum, Trichophyton mentagrophytes, Txichophyton rubrum Trichophyton tonsurans Candida albicans, and Cryptococcus neoformans.
The compounds of the present invention also exhibit anti-fungal activity against the following fungi primarily of agricultural significance , , ' ~
~ ~spergillus flavus, Aspergillus niger Cladosporium herbarum, Penicillium oxalicum, ` Fusarium graminearum,- Penicillium spinulosum, .
Penicillium notatum, and Pithomyces chartarum.
In addition, the compounds of the present invention ~ exhibit anti-bacterial activity against human and animalj ':
'~ 15 pathogens, such as Staphylococcus aureus, Streptococcus faecalis, .. , ~ ~ Corynebacterium acnes, i . .
Erysipelothrix insidiosa, Escherichia coli, .1:
~, Proteus vulgaris, -, ~ Salmonella choleraesuis, Pasteurella multocida, and Pseudomonas aeruginosa.
.~ ........ .. .. . .
;1 25 Moreover, the compounds of the present invention exhibit ~ anti-protozoal activity against protozoa such as Trichomonas . . I .
I' ! Vaginalis.
¦ In general, the subject compounds of the instant inven-tion exhibit a low level of toxicity. Moreover, these com-pounds demonstrate good solubility in the stratum corneum.
. ', ' . ~
_ "'''' l ' ' -, , .: - .
~(~77gg3 .
Since d!ermatophyte (i.e., parasitic fungal) infections are usually localized in the dead tissue of the stratum corneum, solubility of anti-fungal agents in this tissue significantly enhances their effectiveness.
S In view of the aforementioned activities, the subject compounds are found to be useful antimicrobials, having not only pharmaceutical but also agricultural and industrial application.
Accordingly,-a further aspect of the present invention relates to compositions for pharmaceutical, agricultural, e~d industrial use, which compositions comprise the subject .~
.
.. .. .
, . . . ., . - - . . - ~ .
.. . : ., - . '- ''' ' : - ... . . . . .
,..... .. . .. .. ~. . : , - . ' - . ' - . , ' ~ ' : : '' ' `~ 1077493 compounds of formula (I) in combination with a suitable carrier. A still further aspect of the present invention relates to methods.of inhibiting the growth of fungi, bacteria and protozoa by applying to a host object containing, or S i subject to attack by, fungi, bacteria or protozoa, an effective amount of a compound of the present invention or ~~ . a suitable composition containing same.
In pharmaceutical applications, compositions may be - solid, semi-solid or liquid in form such as tablets, cap-sules, powders, suppositories, liquid solutions, suspensions, creams, lotions, ointments and the like. Pharmaceutically acceptable non-toxic carriers, or excipients normally employed for solid formulations include tricalcium phosphate, calcium carbonate,.kaolin, bentonite, talcum, gelatin, lactose, starch and the like; for semi-solid formulations ... .
there may be mentioned, for example, poly-alkylene glycols, - vaseline and other cream bases; for liquid formulations there may be mentioned, for example, water, oils of vege-table origin and low boiling solvents such as isopropanol, hydrogenated naphthalenes and the like. The pharmaceutical compositions containing the compounds of the present invention may be subiected to conventional pharmaceutical ~
expedients such as sterilization and can contain conventional pharmaceutical excipients such as preservatives, stabilizing agents, emulsifying agents, salts for the adjustment of osmotic pressure and buffers. The compositions may also contain other therapeutically active materials. In pharma-ceutical applications, the subject compounds and composi-tions may be administered to humans and animals by conven-tional methods, e.g., topically, orally, parentcrally and .
.
" ~077493 . . .
the like. Parenteral administration includes intramuscular as well as subcutaneous and intravenous administration.
Intravenous injection of imidazole-type anti-fungals has been demonstrated to be effective in the treatment of systemic mycoses (see for example, Drugsl 9, pp, 419-420, 1975, which describes the intravenous administration of miconazole, i.e. l-[2,4-dichloro-~-~2',4'-dichlorobenzyloxy)phenethyl]-imidazole nitrate, to patients with systemic candidiasis).
Topical application is the preferred method of administration for pharmaceutical applications. For such treatment, an area having an existing fungal, bacteriaL or protozoal growth, or to be protected against attack by fungi, bacteria or protozoa, may be treated with the subject compounds or compositions by, for example, dusing, sprinkling, spraying, rinsing, brushing, dipping, smearing, coating, impregnating and the like. Topical pharmaceutical compositions containing the compounds of the present invention exhibit anti-fungal anti-bacterial and anti-protozoal activity over a wide range of concentration, for example, from about 0.1 to 10.0%
by weight of the composition, In any event, the composition to be administered will contain a quantity of the subject , compound in an amount effective for relief or prevention of t~e specific condition being treated.
The pharmaceutical compositions hereof typically com-prise one or more subject compounds of Formula (I) and a pharmaceutically acceptable, non-toxic carrier, and are preferably formulated in unit dosage form to facilitate ; administration (unit dosage being the amount of active ingredient administered on one occasion).
In general, for systemic (e.g., oral or parenteral) ' ~ -7-",1 .
- - .
.
1~77493 administration it is expedient to administer the active ingredient in amounts between about 1 and 100 mg./kg- body weight per day, preferably between about 5 and 50 mg./kg. body weight per day; preferably distributed over several applications (e.g., in 3 individual doses) in order to achieve most effective results For localized (e.g. topical) administra-tion, however, proportionately less of the active ingredient is required.
The exact regimen for pharmaceutical administration of the compounds and compositions disclosed herein will necessarily be dependent upon the needs of the individual subject being treated, the type of treatment, e.g., whether preventative or curative, the type of organism involved and, of course, the judgment of the attending practitioner.
... ... .... .. . . .
In agricultural appllcations, the subject compounds may be applied directly to plants (e.g., seeds, foliage) or to soil. For example, compounds of the present invention ¦ may be applied to seeds alone or in admixture with a powdered solid carrier. Typical powdered carriers are the various mineral silicates, e.g., mica, talc, pyrophyllite, and clays. The subject compounds may also be applied to , I the seeds in admixture with a conventional surface-active wetting agent with or without additional solid carrier.
Surface-active wetting agents that can be used are any of :;
:,. . .
'~ , ' . '' ' . . .
. " ' -:
- ~:
. 10774g3 \:
the conventional anionic, non-anionic or cationic types.
As a soil treatment for fungi and the like, the subject compounds can be applied as a dust in admixture with sand, soil or a powdered solid carrier such as a mineral silicate with or without additional surface-active agent, or the subject compounds can be applied as an aqueous spray optionally containing a surface-active dispersing agent and a powdered solid carrier. As a foliage treatment, the sub-ject compounds may be applied to growing ~l,ants as an aqueous spray which contains a surface-active dispersing agent with or without a powdered solid carrier and hydro- -carbon solvents.
In industrial applications, the subject compounds may be used to control bacteria and fungi by contacting the pathogens with the compounds in any known manner. Materials capable of supporting bacteria and fungi may be protected - by contacting, mixing or impregnating these materials with the subject compounds. In order to increase their effect, the subject compounds may be combined with other pesticidal control agents such as fungicides, bactericides, insecti-cides, miticides and the like. A particularly important industrial/agricultural use for the subject compounds of the present invention is as a food preservative against bacteria and fungi which cause deterioration and spoilage of foods.
. .
The compounds of formula (I) may be considered to consist of two subclasses, thos of furmulas (Ia) and (Ib) j shown below.
','~-~ ' ~ 30 8 `
~, R -CH-(CH2)n -N N R -CH-(CH2)n -N N
; O-R S-R
(Ia) (Ib) wherein R , R , and n are as defined above.
Both groups of compounds may be prepared from common intermediates having a free hydroxyl group which is then con- -verted to the ether or thioether, as the case may be, and which may be prepared by a variety of methods, depending upon the length of the (CH2)n chain, i.e. the value of n.
A preferred subgenus of compounds of formula (I) are those wherein n is 1, 2 or 3. When n is 1, a preferred group of compounds are those wherein R is phenethyl, styryl or halo (preferably chloro)-substituted phenethyl or styryl, preferably 4-chloro, 4-bromo, 4-fluoro, 2,4-dichloro or 3,4-dichloro-substituted, and R is independently -.::
l phenyl or benzyl, or halo-substituted derivatives thereof, ,;~
preferably having the halo substituent(s) in the same posi-tions as indicated above for R and, when R is substituted phenylthio, additionally the 2,4,5-trichloro and 2,3,4,5,6-pentachloro-substituted derivatives; or cinnamyl or 4-halocinna-myl.
. ~
When n is 2 or 3 a preferred group of compounds are those wherein R is phenyl or halo-substituted phenyl, preferably .,: .
~`~ 4-chloro, 4-bromo, 4-fluoro, 2,4-dichloro, 2,4-difluoro, or
2,4-dibromo substituted and R is independently phenyl or benzyl, or halo (preferably chloro)-substituted derivatives thereof, preferably having the halo substituents in the same position as indicated for R and, when R is substituted phenylthio, additionally the 2,4,5-trichloro and 2,3,4,5,6-pentachloro-substituted derivatives.
10774~3 : ~
As mentioned above, compounds of formula (I) may be prepared by forming an ether or thioether from a suitable ~ -alcohol of formula (II) ~
~ . -R -CH- (CH2)n- N
wherein R and n are as defined above. Compounds of formula (II) may be prepared by a variety of reaction sequences, depending on the size of n.
For example, when n is 1, certain compounds of formula (IIa) may be prepared by reaction scheme A shown below REACTION SCHEME A
~ ':
: O OH
(IV) /(III) (IIa) .~ / -'.
~ 1 R -CH=CH2 ~ :
" (V) ' ' ; In this reaction scheme the imidazole alcohol of formula ,~ 20 (IIa) is formed by opening of a terminal epoxide of formula (III) with imidazole. This reaction is generally carried out using at least one mole and preferably an excess of ; imidazole relative to epoxide. The reaction may either be ~ -carried out in the absence of solvent or, preferably, in an inert organic solvent, for example, a solvent such as ~ -dimethylformamide, hexamethylphosphoramide, acetoni-trile and the like. The tempetature normally employed for such epoxide opening is in the range of from about -20 to about 100C most preferably from about 20 to ` ~ 74~3 about 60C.
Epoxides of formula (III), insofar as they may not be known or readily available, may be prepared by a variety of well known methods, for example epoxidation of a terminal -olefin (e.g., (V)) with, for example, a peracid, or by - reaction of an aldehyde having one fewer carbon atoms~
(e.g., ~IV)) with the ylide prepared from trimethylsulfox-onium iodide as described, for example, in J. Am. Chem. Soc., ~ 84, p. 867 (1962); ibid, 87, p. 1353 (1965).
Another reaction scheme for preparing certain compounds of formula (IIa) is shown in reaction scheme B presented below Reaction Scheme B
., . . _ .
R COCH2~ ~ CCH2-N~N ~ /~
- - OH
VII ) . (VI ) . . (IIa ) ¦; wherein Y is chloro or bromo.
, ' ' - . . . . . .
In this reaction scheme the hydroxy compound of formula IIa) iS prepared by reduction of the corresponding ketone ~VI), which in turn is prepared by reaction ofan -halo ketone (VII) with imidazole.
-Halo ketones are generally available, or may be readily prepared by, for example, halogenation of the corres-` ~ ponding methyl ketone. When Rl is styryl or substituted styryl, a ; particularly useful method of bromination is described in Tetrahedron, 29, p. 1625 (1973) and Can. J. Chem. 47, p. 706 (1969).
The a-halo ketone is contacted with imidazole in an .
` `` 1~77493 incrt or~anic solvcnt to afford the keto imidazole of formula ~VI). The reaction is carried out utilizing at least a molar amount and, preferably, an excess of imidazole relative to halo ketone. The reaction may be carried out in the absence of solvent or, preferably, in an inert organic solvent such as for example dimethylformamide, hexamethylphosphoramide, acetonitrile, and the like. The reaction is suitably carried out at a temperature initially between about -10 and 100C. most preferably between about 0 and 25C.
In the next step the keto imidazole of formula tVI) is reduced to the hydroxy imidazole of formula(IIa) utilizing a conventional metal hydride reducing agent such as, for example, sodium borohydride. The reaction is suitably 15 ~ carried out in an alcoholic solvent such as, for example, methanol or ethanol at a reduced temperature, for example, between about -10 and +25C., most preferably about 0C.
When n is 2 compounds of formula (IIb) may be prepared , according to a variety of synthetic methods. One convenient method for the preparation of certain compounds of formula (IIb) is shown in reaction scheme C presented below.
Reaction Scheme C
.
Rl-COCH=CH2 ~ > Rl-COCH2CE12-N N
~or Mannich base quaternary salt) (YIII) ~ (IX) . ~ RlCHC112CH2-N N
~ "' I \=~/ .
~ll (lIb) ._ .
`` ~ 1(~77493 This scheme involves the reaction of imidazole with a vinyl ketone of formula (VIII) (or Mannich base quaternary intermediate) followed by reduc~ion of the resulting keto imidazole of formula ~IX) to the hydroxy imidazole of formula ~IIb).
Vinyl ketones of formula ~VIII), insofar as they may not be known or generally available, may be prepared by a variety of methods well known in the synthetic organic chemistry art, for example, by the addition of vinyl lithium to the corresponding c~rboxylic acid; by the addition of - vinyl lithium to the corresponding aldehyde followed by oxiaation of the allylic alcohol thus produced to the vinyl ketone t~.g., J. Chem. Soc. ~C), 1966, p. 1972; J. Chem.
Soc. (London), 1956, p. 3070); or by Mannich reaction of the corresponding methyl ketone, quaternization and elimination.
The first step of the conversion, the reaction of vinyl ketone o formula (VIII) to keto imidazole of formula (IX), '~ ~ is accomplished by contactin~ the vinyl ketone (or a Mannich quaternary base precursor) with imidazole in an inert organic solvent. The reaction is conveniently carried out utilizing at least a molar amount, and preferably an excess, ~; of imidazole relative to vinyl ketone or Mannich quaternary base in an inert organic solvent, for example, diethyl ether, dichloromethane or dimethylformamide, at a tempera-ture between about 0 and 40C. preferably about ambient temperature.
The reduction of the keto imidazole of formula (IX) to the hydroxy imidazole of formula (IIb) is carried out in the same manner as described above ~or the conversion of compound of formula (Vl) to that of formula (IIa).
.
' .
When n is 2 ~or greater) certain compounds of formula ~II) are conveniently prepared as illustrated in reaction scheme D presented below Reaction Scheme D
RlCO~C112)nY ~ RlC~C~2)n~~
~X) ~XI) R IH (C~2~n N~ N
. OH
tII ) .
wherein Y is chloro or bromo.
- . - ,:
In this reaction scheme an ~-halo (preferably chloro) .
: ketone of the formula (X) is converted to the corresponding keto imidazole of formula (XI) and then to the hydroxy imidazole of the formula (II).
, The starting ~-halo ketones,insofar as they may not be known or generally available, may be suitably prepared by the well known Friedel-Crafts reaction involving the aromatic ~ hydrocarbon RlH and an ~-halo acylhalide.
- The conversion from compound (X) to compound (XI) is carried out using imidazole in the same manner as described above for the conversion of (VII) ~ (VI). When n is 3 or greater, the reaction temperature is between about 0 and , .
100C., preferably between 25 and 80C.
The.reduction of the keto imidaæole of formula (XI) to the hydroxy imidazole of formula (II) is carried out as previously described for the conversion of ~ (IIa).
Certain compounds o~ formula (IIc) may also be prepared by an altcrnate procedure dcpicted in reaction scheme E-- , . :
'' -' ' ' .. . ' . , - ~- ,. ...
`- "` . 1077493 .
Reactlon Schemc E
RlCOCH=CH2--~RlCOCH-CH2--~(X) ~ lC (C 2)3 N ~ N
(VIII) (XII) (IIc) involving the conversion of the previously described vinyl ketone of the formula (VIII) to the corresponding cyclo-. propyl ketone of the formula (XII), followed by conversion to the y-halo ketone of formula (X), n=3, and then, as described above, to the hydroxy imidazole of formula (IIc).
The cyclopropanation of the vinyl ketone of formula (VIII) may be accomplished by methods known ~ se, for example as disclosed in J. Am. Chem. Soc., 87, p. 1353 . . (1965). The resulting cyclopropyl ketone is then opened .: 15 to afford the y-halo ketone by treatment with a hydrohalic . acid such as, for-example, hydrobrOmic acid.
: . Certain compounds of formula (II) may also be prepared according to reaction scheme F below.
Reaction Scheme F
RlCBO ~ CH2sCH-(CH2)n_2Y >
. ....... .
. (IV) . ~XI~I) .
. RICO(CH2)nY ~ RlCO(CH2)n-N N
~ .
~X) (XI) . ~ R CH(CII2)n-N N
0~1 .~II) .
wherein Y is chloro or bromo.
, .
` ` ~077493 This reaction scheme is particularly useful for pre-paring compounds wherein n is 4 or greater, but may also be used to prepare compounds where n is 2 or 3. In this scheme, the previously described aldehyde of formula (IV) is reacted with an ~-halo terminal alkene of formula ~XIII), readily prepared, for example, by halogenation of the corresponding alcohol, in a free radical addition reaction to afford the previously described halo ketone of formula (X), which is then converted as previously described through the ~eto imidazole of formula (XI), to the hydroxy imidazole of formula (II). The conversion (IV) ~ (XIII)~ (X) is conveniently carried out using a free radical source such as, for example, diacetyl peroxide, di-tert-butyl peroxide, dibenzoyl peroxide, azobisisobutyronitrile; or photochemi-.: .
i5 cally, at a temperature between about 50 and 150C., most '~ preferably between about 60 and 80C., using an excess of .
~ the aldehyde as a solvent medium.
.; . . . .
Certain compounds of formula (II) may be also prepared as demonstrated below in reaction scheme G
Reaction Scheme G
R COY + C~2=cH-(cH2)n-2-x (XIV) (XIII) .~ I . . .
RlCO (C~2)n~ > XI - ~ IT
ZS ' ~X) wherein Y is chloro or bromo.
This reaction scheme is conveniently utilized where com-pounds having n equal to or greater than 4 are desired~.
In this reaction scheme an acid halide of formula (XIV), -lG-' ,~, `.
readily preparcd from the corrcsponding carboxylic acid, is reacted with the previously described w-halo terminaL
alkene of formula (XIII) to afford the haio ketqne of the formula (X), which is then converted, as shown above, to the hydroxy imidazole of formula (II). The addition reaction between compounds of formulas (XIV) and (XIII) is conven-iently carried out under conditions as described in G. Olah, "Friedel Crafts and Related Reactions", Vol. 3, Part 2, Inter-science Publishers, New York, (1964).
In yet another reaction sequence certain compounds of formula (II) wherein n is 1 or greater may be prepared.
This is illustrated below in reaction scheme H
Reaction Scheme H
R-CH=CH2 + YCO(CH2)nY ~ RlCO~CH2)nY
- ~XV) (XVI) (X) ~
(II) wherein Rl is RCH2CH2 and Y is chloro or bromo.
In this scheme the w-halo ketone of formula (X), described above, is prepared starting with a terminal olefin of formula (XV) and an w-halo acyl halide of formula (XVI), readily prepared, for example, from the corresponding hydroxyacid.
This reaction is carried out under the conditions described above for Reaction Scheme G.
-- - _ .
:
` ^ . 1077493 In reaction scheme I shown below there are illustrated Dlt~rnative methods for preparing certain compounds of ormula ~II) whereln n is 1, Reaction Scheme I
5`
o /~ , R CHO + 03P=CHCOC~ -N N
- (XVII) ~ ~XIX) ~ o ~
¦ R -CH=CH-COCH2-N N i IIa xe tXVIII) ~
R CHO + 03P=CHCOCB2Y > ROCH=C~COCH2y ~XVII) (XXI) - (XXII) Rl is R-CH=CH- or RCH7CH2- and Y is chloro'or bromo.
- 'In this scheme an aldehyde of formula (XVII) is reacted, in' a Wittig reaction, with an ylide of formula (XIX) or (XXI) to afford the corresponding olefin of formula (XX) or (XXII).
.
The ylide ~XXI) is formed, according to methods known ~ se, from the corresponding phosphonium salt (XVIII), prepared in turn from triphenylphosphine and the corresponding dihalo ace-tone. To form the ylide of formula ~XIX) the phosphonium salt is reacted with an excess of imidazole, in an inert organic . solvent such as acetonitrile,'dimethylformamide at a temperature between about 25 and 100C., preferably between about 50 and 80C., thus affording the imidazole substituted ylide of formula ~XIX) which, upon reaction with the aldehyde of formu~a ~XVII) under standard Wittig conditions, (e.g., in ~cetonitrile at 80C.) affords th unsaturated ~eto imida-ole of formula ~XX).
. ' .
. ~"
~lternatively, reaction of the aldchyde of formula ~XVII) with the ylide of formula (XXI), prepared in the normal manner from phos~honium salt ~XVIII) by treatment with a base such as an alkali metal carbonate, affords the : S halo unsaturated ketone of formula (XXII). This compound may then be converted to the corresponding imidazole compound of formula (XX) by treatment with imidazole as described above for the conversion (VII)- > (VI). Reduction of the ~ keto group of compound (XX)affords the hydroxy imidazole of formula tIIa). The double bond adjacent to the hydroxy moiety may be hydrogenated to afford a compound of formula (IIa) having a phenyl lower alkyl or substituted phenyl lower alkyl moiety as ~1. Such hydrogenation may be carried out using standard conditions, for example, using a palladium on charcoal catalyst in a solvent such as methanol. Alter-- natively, hydrogenation may be performed prior to reduction of the ketone. -The compounds of formula (II) are converted to the final products of formula (I) wherein X is O and R2 is 'O substituted or unsubstituted phenyl straight chain lower ~lkyl or phenyl straight chain lower alkenyl, by O-alkylation ~with the appropriate R2Y wherein Y is a leaving group such as halide (chloride, bromide or iodide) or sulfonate ester (e.g., p-toluenesulfonate or methanesulfonate).
'S The alkylation is carried out by converting the hydroxy group of the compound of formula (II) to its alkali metal salt ~y treatment with a strong base such as, for example, an alkali metal hydride such as sodium hydride; and alkali mctal amide such as sodium amide or potassium amide; and the like. This is preferably done in an inert organic solvent such as, for examplc, dimethylformamide, hexamcthyl-phosphoramide~ tc~rahydrofuran, and thc likc. The alkali 19~
. ~
" . 1077493 metal salt is then contacted with the ~2y~ preferably in the same solvent system, at a temperature between about 0 and, 80C., most p~eferably between about 0 and 60C.
', , Compounds of formula (I) wherein R2 is substituted or unsubstituted phenyl ~i.e., phenolic ethers or thioethers) may be prepared from the compounds of formula (II) by a two-step sequence involving conversion of the hydroxy group to a suitable.leaving group such as a halide (e.g., a - ~ chloride or bromide) or a sulfonate ester (e.g., methane-sulfonate or p-toluenesulfonate) which is then reacted with a metal salt of the corresponding phenol R2OH or thiophenol R SH.
.
, The conversion from the alcohol to the halide or sulfonate ester is carried out by means well known in the art. For example, the alcohol may ~e halogenated using a , halogenating agent such as thionyl chloride or thionyl , bromide, either neat, or in an inert organic solvent such as dichloromethane or chloroform, at a temperature between , about 0 and 80C., pref,erably between about 20 and 80C.
' 20 ~he halogenation reaction may be carried out in the presence , of a molar e~uivalent of a base ~e.g., pyridine) if desired.
,Alternate halogenation procedures include, for example, th;
use of triphenylphosphine with either carbon tetrachloride, , carbon tetrabromide, or N-chloro ~or N-bromo) succinimide.
When utilizing thionyl chloride or thionyl bromide without ' the use of added base, the hydrochloride or hydrobromide , 8alt of the corresponding halo compound is produced. This salt may be neutraliz'ed (e.g., with potassium carbonate) ' prior to its use in the alkylation step, or the salt ', 30 may be used dircctly if excess phenol or thiophcnol ., .
- . . .. . . , .:
`1077493 salt is utilized.
Sulfonate esters may be prepared by the standard proce-dure of treating the alcohol with an excess of, for example, methanesulfonyl chloride or p-toluenesulfonyl chloride, in the presence of a base, for example pyridine or triethylamine.
This reaction is carried out at a temperature from about -20 to +50C., preferably between about 0 and 20C.
- The halide or sulfonate ester prepared as described above, is then treated with a metal salt, preferably an alkali metal salt such as the sodium or potassium salt, of the correspon-ding phenol or thiophenol, in the presence of an inert organic solvent such as acetone, methanol, and the like, at a tempe-rature of about 20 to about 80C. If desired, the metal salt of the phenyl or thiophenol may be preformed prior to addition ~ 15 of the halide.
^~ Compounds of formula (I) wherein X is S and R is sub-~ stituted or unsubstituted phenyl straight chain lower alkyl or . .
phenyl straight chain lower alkenyl, may be prepared by react-ing the above~entioned halide or sulfonate ester with the metal salt, preferably an alkali metal salt such as the sodium or . .
potassium salt, of a thiol R SH. This reaction is carried out in an inert organic solvent such as, for example, tetrahydro-furan, diethylether, methanol, and the like. The salt is formed with a strong base such as for example, sodium hydride, sodium amide, sodium methoxide and the like at a temperature between about 20 and 80C.
Compounds of formula (I) wherein n is l, X is S and R is substituted or unsubstituted phenyl straight chain lower alkyl may also be prepared as depicted in reaction scheme J below : .: .. . : :., .: - -: :
- . .. .
1C~77493 Reaction_Schcme J
R1-CH-CH2 I R2Se >
or R SH
(III) Rl-CH-CH2-SR2 ~ Rl-fH-CH2-SR2 and~or Rl-C~-CH2-Y
(XXIII) (XXIV) ~ 10 ,, . .
'' ' ', \ ~
R -CH-CH -N N
S~
(I) wherein Y is a leaving group.
- In this scheme the epoxide of formula (III) described earlier, is opened with a thiol or thiophenol or a metal salt thereof, to afford the compound of formula ~XXIII).
This reaction is carried out utilizing, preferably, an alkali metal salt of the thiol or thiophenol, most preferably the sodium salt, in an inert organic solvent such as, for example, tetrahydrofuran or acetone at a temperature of .
between about 0 and 67C., or using the free thiol or thio-phenol in the presence of an acid catalyst, e.g., perchloric acid, under similar conditions.
In the next step the hydroxy group of the compound of formula (XXIII) is converted to a leaving group such as a . halide ~e.g., chloro or bromo) or sulfonate ester (e.g., l p-toluenesulfonate or methanesulfonate) by treatment with, ~~ .
~22-:
.. __.. _ . . .. ., ... , ........ ,, _.. ~.. . . .. _.. _ ., ~ _.. _ .. ....... .".. _ . _ . .... . . . .... .
` ` iQ77493 e.g., a halogenating agent such as, for example, thionyl chloride, neat, or preferably in an inert solvent such as dichloromethane, or with, for example, p-toluenesulfonyl chloride, in a solvent such as pyridine. The product of formula (XXIV) may exist in either or both forms depicted, and may be interconvertible through an episulfonium inter-mediate.
In the final step, the compound of formu1a (XXIV) is converted to the final product of formula (I) by treatment 10 - with imidazole. This reaction is carried out in an inert organic solvent such as for example acetonitrile, dimethyl-formamide, and the like, at a temperature of about 0 to about 80C.
Alternatively, certain compounds of formula (I) may be formed, in a final step, by hydrogenation of a compound of the formula .. . .
R -fH- (CH2, n~N 1~
' ' ' X R2' or an acid addition salt thereof wherein Rl and R are identical with Rl and R2, respectively, except that Rl and/or R2 contains aliphatic olefinic unsaturation, i.e., wherein Rl and/or R2 is a substituted or unsubstituted phenyl lower alkenyl group. Such hydrogenation may be carried out using conditions well known in the art. ~or D example, the hydrogenation may be carried out at about , atmospheric pressure or at higher pressure, and at tempera-tures from about 0 to about 100C., in the presence of a suitable supported, unsupported or soluble metal catalyst such as palladium, platinum or tris (triphenylphosphine) .. . .
10774~3 : ~
As mentioned above, compounds of formula (I) may be prepared by forming an ether or thioether from a suitable ~ -alcohol of formula (II) ~
~ . -R -CH- (CH2)n- N
wherein R and n are as defined above. Compounds of formula (II) may be prepared by a variety of reaction sequences, depending on the size of n.
For example, when n is 1, certain compounds of formula (IIa) may be prepared by reaction scheme A shown below REACTION SCHEME A
~ ':
: O OH
(IV) /(III) (IIa) .~ / -'.
~ 1 R -CH=CH2 ~ :
" (V) ' ' ; In this reaction scheme the imidazole alcohol of formula ,~ 20 (IIa) is formed by opening of a terminal epoxide of formula (III) with imidazole. This reaction is generally carried out using at least one mole and preferably an excess of ; imidazole relative to epoxide. The reaction may either be ~ -carried out in the absence of solvent or, preferably, in an inert organic solvent, for example, a solvent such as ~ -dimethylformamide, hexamethylphosphoramide, acetoni-trile and the like. The tempetature normally employed for such epoxide opening is in the range of from about -20 to about 100C most preferably from about 20 to ` ~ 74~3 about 60C.
Epoxides of formula (III), insofar as they may not be known or readily available, may be prepared by a variety of well known methods, for example epoxidation of a terminal -olefin (e.g., (V)) with, for example, a peracid, or by - reaction of an aldehyde having one fewer carbon atoms~
(e.g., ~IV)) with the ylide prepared from trimethylsulfox-onium iodide as described, for example, in J. Am. Chem. Soc., ~ 84, p. 867 (1962); ibid, 87, p. 1353 (1965).
Another reaction scheme for preparing certain compounds of formula (IIa) is shown in reaction scheme B presented below Reaction Scheme B
., . . _ .
R COCH2~ ~ CCH2-N~N ~ /~
- - OH
VII ) . (VI ) . . (IIa ) ¦; wherein Y is chloro or bromo.
, ' ' - . . . . . .
In this reaction scheme the hydroxy compound of formula IIa) iS prepared by reduction of the corresponding ketone ~VI), which in turn is prepared by reaction ofan -halo ketone (VII) with imidazole.
-Halo ketones are generally available, or may be readily prepared by, for example, halogenation of the corres-` ~ ponding methyl ketone. When Rl is styryl or substituted styryl, a ; particularly useful method of bromination is described in Tetrahedron, 29, p. 1625 (1973) and Can. J. Chem. 47, p. 706 (1969).
The a-halo ketone is contacted with imidazole in an .
` `` 1~77493 incrt or~anic solvcnt to afford the keto imidazole of formula ~VI). The reaction is carried out utilizing at least a molar amount and, preferably, an excess of imidazole relative to halo ketone. The reaction may be carried out in the absence of solvent or, preferably, in an inert organic solvent such as for example dimethylformamide, hexamethylphosphoramide, acetonitrile, and the like. The reaction is suitably carried out at a temperature initially between about -10 and 100C. most preferably between about 0 and 25C.
In the next step the keto imidazole of formula tVI) is reduced to the hydroxy imidazole of formula(IIa) utilizing a conventional metal hydride reducing agent such as, for example, sodium borohydride. The reaction is suitably 15 ~ carried out in an alcoholic solvent such as, for example, methanol or ethanol at a reduced temperature, for example, between about -10 and +25C., most preferably about 0C.
When n is 2 compounds of formula (IIb) may be prepared , according to a variety of synthetic methods. One convenient method for the preparation of certain compounds of formula (IIb) is shown in reaction scheme C presented below.
Reaction Scheme C
.
Rl-COCH=CH2 ~ > Rl-COCH2CE12-N N
~or Mannich base quaternary salt) (YIII) ~ (IX) . ~ RlCHC112CH2-N N
~ "' I \=~/ .
~ll (lIb) ._ .
`` ~ 1(~77493 This scheme involves the reaction of imidazole with a vinyl ketone of formula (VIII) (or Mannich base quaternary intermediate) followed by reduc~ion of the resulting keto imidazole of formula ~IX) to the hydroxy imidazole of formula ~IIb).
Vinyl ketones of formula ~VIII), insofar as they may not be known or generally available, may be prepared by a variety of methods well known in the synthetic organic chemistry art, for example, by the addition of vinyl lithium to the corresponding c~rboxylic acid; by the addition of - vinyl lithium to the corresponding aldehyde followed by oxiaation of the allylic alcohol thus produced to the vinyl ketone t~.g., J. Chem. Soc. ~C), 1966, p. 1972; J. Chem.
Soc. (London), 1956, p. 3070); or by Mannich reaction of the corresponding methyl ketone, quaternization and elimination.
The first step of the conversion, the reaction of vinyl ketone o formula (VIII) to keto imidazole of formula (IX), '~ ~ is accomplished by contactin~ the vinyl ketone (or a Mannich quaternary base precursor) with imidazole in an inert organic solvent. The reaction is conveniently carried out utilizing at least a molar amount, and preferably an excess, ~; of imidazole relative to vinyl ketone or Mannich quaternary base in an inert organic solvent, for example, diethyl ether, dichloromethane or dimethylformamide, at a tempera-ture between about 0 and 40C. preferably about ambient temperature.
The reduction of the keto imidazole of formula (IX) to the hydroxy imidazole of formula (IIb) is carried out in the same manner as described above ~or the conversion of compound of formula (Vl) to that of formula (IIa).
.
' .
When n is 2 ~or greater) certain compounds of formula ~II) are conveniently prepared as illustrated in reaction scheme D presented below Reaction Scheme D
RlCO~C112)nY ~ RlC~C~2)n~~
~X) ~XI) R IH (C~2~n N~ N
. OH
tII ) .
wherein Y is chloro or bromo.
- . - ,:
In this reaction scheme an ~-halo (preferably chloro) .
: ketone of the formula (X) is converted to the corresponding keto imidazole of formula (XI) and then to the hydroxy imidazole of the formula (II).
, The starting ~-halo ketones,insofar as they may not be known or generally available, may be suitably prepared by the well known Friedel-Crafts reaction involving the aromatic ~ hydrocarbon RlH and an ~-halo acylhalide.
- The conversion from compound (X) to compound (XI) is carried out using imidazole in the same manner as described above for the conversion of (VII) ~ (VI). When n is 3 or greater, the reaction temperature is between about 0 and , .
100C., preferably between 25 and 80C.
The.reduction of the keto imidaæole of formula (XI) to the hydroxy imidazole of formula (II) is carried out as previously described for the conversion of ~ (IIa).
Certain compounds o~ formula (IIc) may also be prepared by an altcrnate procedure dcpicted in reaction scheme E-- , . :
'' -' ' ' .. . ' . , - ~- ,. ...
`- "` . 1077493 .
Reactlon Schemc E
RlCOCH=CH2--~RlCOCH-CH2--~(X) ~ lC (C 2)3 N ~ N
(VIII) (XII) (IIc) involving the conversion of the previously described vinyl ketone of the formula (VIII) to the corresponding cyclo-. propyl ketone of the formula (XII), followed by conversion to the y-halo ketone of formula (X), n=3, and then, as described above, to the hydroxy imidazole of formula (IIc).
The cyclopropanation of the vinyl ketone of formula (VIII) may be accomplished by methods known ~ se, for example as disclosed in J. Am. Chem. Soc., 87, p. 1353 . . (1965). The resulting cyclopropyl ketone is then opened .: 15 to afford the y-halo ketone by treatment with a hydrohalic . acid such as, for-example, hydrobrOmic acid.
: . Certain compounds of formula (II) may also be prepared according to reaction scheme F below.
Reaction Scheme F
RlCBO ~ CH2sCH-(CH2)n_2Y >
. ....... .
. (IV) . ~XI~I) .
. RICO(CH2)nY ~ RlCO(CH2)n-N N
~ .
~X) (XI) . ~ R CH(CII2)n-N N
0~1 .~II) .
wherein Y is chloro or bromo.
, .
` ` ~077493 This reaction scheme is particularly useful for pre-paring compounds wherein n is 4 or greater, but may also be used to prepare compounds where n is 2 or 3. In this scheme, the previously described aldehyde of formula (IV) is reacted with an ~-halo terminal alkene of formula ~XIII), readily prepared, for example, by halogenation of the corresponding alcohol, in a free radical addition reaction to afford the previously described halo ketone of formula (X), which is then converted as previously described through the ~eto imidazole of formula (XI), to the hydroxy imidazole of formula (II). The conversion (IV) ~ (XIII)~ (X) is conveniently carried out using a free radical source such as, for example, diacetyl peroxide, di-tert-butyl peroxide, dibenzoyl peroxide, azobisisobutyronitrile; or photochemi-.: .
i5 cally, at a temperature between about 50 and 150C., most '~ preferably between about 60 and 80C., using an excess of .
~ the aldehyde as a solvent medium.
.; . . . .
Certain compounds of formula (II) may be also prepared as demonstrated below in reaction scheme G
Reaction Scheme G
R COY + C~2=cH-(cH2)n-2-x (XIV) (XIII) .~ I . . .
RlCO (C~2)n~ > XI - ~ IT
ZS ' ~X) wherein Y is chloro or bromo.
This reaction scheme is conveniently utilized where com-pounds having n equal to or greater than 4 are desired~.
In this reaction scheme an acid halide of formula (XIV), -lG-' ,~, `.
readily preparcd from the corrcsponding carboxylic acid, is reacted with the previously described w-halo terminaL
alkene of formula (XIII) to afford the haio ketqne of the formula (X), which is then converted, as shown above, to the hydroxy imidazole of formula (II). The addition reaction between compounds of formulas (XIV) and (XIII) is conven-iently carried out under conditions as described in G. Olah, "Friedel Crafts and Related Reactions", Vol. 3, Part 2, Inter-science Publishers, New York, (1964).
In yet another reaction sequence certain compounds of formula (II) wherein n is 1 or greater may be prepared.
This is illustrated below in reaction scheme H
Reaction Scheme H
R-CH=CH2 + YCO(CH2)nY ~ RlCO~CH2)nY
- ~XV) (XVI) (X) ~
(II) wherein Rl is RCH2CH2 and Y is chloro or bromo.
In this scheme the w-halo ketone of formula (X), described above, is prepared starting with a terminal olefin of formula (XV) and an w-halo acyl halide of formula (XVI), readily prepared, for example, from the corresponding hydroxyacid.
This reaction is carried out under the conditions described above for Reaction Scheme G.
-- - _ .
:
` ^ . 1077493 In reaction scheme I shown below there are illustrated Dlt~rnative methods for preparing certain compounds of ormula ~II) whereln n is 1, Reaction Scheme I
5`
o /~ , R CHO + 03P=CHCOC~ -N N
- (XVII) ~ ~XIX) ~ o ~
¦ R -CH=CH-COCH2-N N i IIa xe tXVIII) ~
R CHO + 03P=CHCOCB2Y > ROCH=C~COCH2y ~XVII) (XXI) - (XXII) Rl is R-CH=CH- or RCH7CH2- and Y is chloro'or bromo.
- 'In this scheme an aldehyde of formula (XVII) is reacted, in' a Wittig reaction, with an ylide of formula (XIX) or (XXI) to afford the corresponding olefin of formula (XX) or (XXII).
.
The ylide ~XXI) is formed, according to methods known ~ se, from the corresponding phosphonium salt (XVIII), prepared in turn from triphenylphosphine and the corresponding dihalo ace-tone. To form the ylide of formula ~XIX) the phosphonium salt is reacted with an excess of imidazole, in an inert organic . solvent such as acetonitrile,'dimethylformamide at a temperature between about 25 and 100C., preferably between about 50 and 80C., thus affording the imidazole substituted ylide of formula ~XIX) which, upon reaction with the aldehyde of formu~a ~XVII) under standard Wittig conditions, (e.g., in ~cetonitrile at 80C.) affords th unsaturated ~eto imida-ole of formula ~XX).
. ' .
. ~"
~lternatively, reaction of the aldchyde of formula ~XVII) with the ylide of formula (XXI), prepared in the normal manner from phos~honium salt ~XVIII) by treatment with a base such as an alkali metal carbonate, affords the : S halo unsaturated ketone of formula (XXII). This compound may then be converted to the corresponding imidazole compound of formula (XX) by treatment with imidazole as described above for the conversion (VII)- > (VI). Reduction of the ~ keto group of compound (XX)affords the hydroxy imidazole of formula tIIa). The double bond adjacent to the hydroxy moiety may be hydrogenated to afford a compound of formula (IIa) having a phenyl lower alkyl or substituted phenyl lower alkyl moiety as ~1. Such hydrogenation may be carried out using standard conditions, for example, using a palladium on charcoal catalyst in a solvent such as methanol. Alter-- natively, hydrogenation may be performed prior to reduction of the ketone. -The compounds of formula (II) are converted to the final products of formula (I) wherein X is O and R2 is 'O substituted or unsubstituted phenyl straight chain lower ~lkyl or phenyl straight chain lower alkenyl, by O-alkylation ~with the appropriate R2Y wherein Y is a leaving group such as halide (chloride, bromide or iodide) or sulfonate ester (e.g., p-toluenesulfonate or methanesulfonate).
'S The alkylation is carried out by converting the hydroxy group of the compound of formula (II) to its alkali metal salt ~y treatment with a strong base such as, for example, an alkali metal hydride such as sodium hydride; and alkali mctal amide such as sodium amide or potassium amide; and the like. This is preferably done in an inert organic solvent such as, for examplc, dimethylformamide, hexamcthyl-phosphoramide~ tc~rahydrofuran, and thc likc. The alkali 19~
. ~
" . 1077493 metal salt is then contacted with the ~2y~ preferably in the same solvent system, at a temperature between about 0 and, 80C., most p~eferably between about 0 and 60C.
', , Compounds of formula (I) wherein R2 is substituted or unsubstituted phenyl ~i.e., phenolic ethers or thioethers) may be prepared from the compounds of formula (II) by a two-step sequence involving conversion of the hydroxy group to a suitable.leaving group such as a halide (e.g., a - ~ chloride or bromide) or a sulfonate ester (e.g., methane-sulfonate or p-toluenesulfonate) which is then reacted with a metal salt of the corresponding phenol R2OH or thiophenol R SH.
.
, The conversion from the alcohol to the halide or sulfonate ester is carried out by means well known in the art. For example, the alcohol may ~e halogenated using a , halogenating agent such as thionyl chloride or thionyl , bromide, either neat, or in an inert organic solvent such as dichloromethane or chloroform, at a temperature between , about 0 and 80C., pref,erably between about 20 and 80C.
' 20 ~he halogenation reaction may be carried out in the presence , of a molar e~uivalent of a base ~e.g., pyridine) if desired.
,Alternate halogenation procedures include, for example, th;
use of triphenylphosphine with either carbon tetrachloride, , carbon tetrabromide, or N-chloro ~or N-bromo) succinimide.
When utilizing thionyl chloride or thionyl bromide without ' the use of added base, the hydrochloride or hydrobromide , 8alt of the corresponding halo compound is produced. This salt may be neutraliz'ed (e.g., with potassium carbonate) ' prior to its use in the alkylation step, or the salt ', 30 may be used dircctly if excess phenol or thiophcnol ., .
- . . .. . . , .:
`1077493 salt is utilized.
Sulfonate esters may be prepared by the standard proce-dure of treating the alcohol with an excess of, for example, methanesulfonyl chloride or p-toluenesulfonyl chloride, in the presence of a base, for example pyridine or triethylamine.
This reaction is carried out at a temperature from about -20 to +50C., preferably between about 0 and 20C.
- The halide or sulfonate ester prepared as described above, is then treated with a metal salt, preferably an alkali metal salt such as the sodium or potassium salt, of the correspon-ding phenol or thiophenol, in the presence of an inert organic solvent such as acetone, methanol, and the like, at a tempe-rature of about 20 to about 80C. If desired, the metal salt of the phenyl or thiophenol may be preformed prior to addition ~ 15 of the halide.
^~ Compounds of formula (I) wherein X is S and R is sub-~ stituted or unsubstituted phenyl straight chain lower alkyl or . .
phenyl straight chain lower alkenyl, may be prepared by react-ing the above~entioned halide or sulfonate ester with the metal salt, preferably an alkali metal salt such as the sodium or . .
potassium salt, of a thiol R SH. This reaction is carried out in an inert organic solvent such as, for example, tetrahydro-furan, diethylether, methanol, and the like. The salt is formed with a strong base such as for example, sodium hydride, sodium amide, sodium methoxide and the like at a temperature between about 20 and 80C.
Compounds of formula (I) wherein n is l, X is S and R is substituted or unsubstituted phenyl straight chain lower alkyl may also be prepared as depicted in reaction scheme J below : .: .. . : :., .: - -: :
- . .. .
1C~77493 Reaction_Schcme J
R1-CH-CH2 I R2Se >
or R SH
(III) Rl-CH-CH2-SR2 ~ Rl-fH-CH2-SR2 and~or Rl-C~-CH2-Y
(XXIII) (XXIV) ~ 10 ,, . .
'' ' ', \ ~
R -CH-CH -N N
S~
(I) wherein Y is a leaving group.
- In this scheme the epoxide of formula (III) described earlier, is opened with a thiol or thiophenol or a metal salt thereof, to afford the compound of formula ~XXIII).
This reaction is carried out utilizing, preferably, an alkali metal salt of the thiol or thiophenol, most preferably the sodium salt, in an inert organic solvent such as, for example, tetrahydrofuran or acetone at a temperature of .
between about 0 and 67C., or using the free thiol or thio-phenol in the presence of an acid catalyst, e.g., perchloric acid, under similar conditions.
In the next step the hydroxy group of the compound of formula (XXIII) is converted to a leaving group such as a . halide ~e.g., chloro or bromo) or sulfonate ester (e.g., l p-toluenesulfonate or methanesulfonate) by treatment with, ~~ .
~22-:
.. __.. _ . . .. ., ... , ........ ,, _.. ~.. . . .. _.. _ ., ~ _.. _ .. ....... .".. _ . _ . .... . . . .... .
` ` iQ77493 e.g., a halogenating agent such as, for example, thionyl chloride, neat, or preferably in an inert solvent such as dichloromethane, or with, for example, p-toluenesulfonyl chloride, in a solvent such as pyridine. The product of formula (XXIV) may exist in either or both forms depicted, and may be interconvertible through an episulfonium inter-mediate.
In the final step, the compound of formu1a (XXIV) is converted to the final product of formula (I) by treatment 10 - with imidazole. This reaction is carried out in an inert organic solvent such as for example acetonitrile, dimethyl-formamide, and the like, at a temperature of about 0 to about 80C.
Alternatively, certain compounds of formula (I) may be formed, in a final step, by hydrogenation of a compound of the formula .. . .
R -fH- (CH2, n~N 1~
' ' ' X R2' or an acid addition salt thereof wherein Rl and R are identical with Rl and R2, respectively, except that Rl and/or R2 contains aliphatic olefinic unsaturation, i.e., wherein Rl and/or R2 is a substituted or unsubstituted phenyl lower alkenyl group. Such hydrogenation may be carried out using conditions well known in the art. ~or D example, the hydrogenation may be carried out at about , atmospheric pressure or at higher pressure, and at tempera-tures from about 0 to about 100C., in the presence of a suitable supported, unsupported or soluble metal catalyst such as palladium, platinum or tris (triphenylphosphine) .. . .
- 3-.. ~
': ' , '' ' ' ' ' :
" . , .. , ~ . ' ' chlororhodium, in an inert solvent such as benzene, acetone, methanol, and the like, for a time su~ficient to allow the uptake of the required amount of hydrogen.
~he subject compounds of the instant invention can be isolated as free bases; however, since many of the compounds in base form are oils, it is more convenient to isolate and characterize the compounds as acid addition salts. These salts are prepared in the usual manner, i.e., by reaction of the base compound with a suitable inorganic or organic acid, described above. Salts formed with dibasic acids (e.g., oxalic acid) may contain one or two molecules of base per molecule of acid. All oxalates described herein contain - ~ one molecule of oxalic acid per molecule of imidazole base.
- If desired, the salts can be readily converted to the free .~ i base form by treatment with alkali, such as potassium car-.
¦ bonate, sodium carbonate or sodium or potassium hydroxide.
i! ¦ For following specific examples are illustrative of ¦ the present invention and should not be considered as I limit~tive thereof in any manner.
;.
:~ . .. ..
. . . --- , , . , :' .~-- , . . . - .~ : .
..
- . : ' .: . ' .: .. .: --: -. . ~ .. ' . ' ,: . . . -- . . . .: .
-- .
. . .. . .
.
- .
PREP~R~TION 1 This preparation illustrates the process in reaction scheme A.
3-Phenylpropionaldehyde (26.8 g.) is added under nitro-gen to the ylide prepared from trimethylsulfoxonium iodide (48.4 g.) and sodium hydride ~55% dispersion in oil; 9.6 g.) in dry dimethylsulfoxide (200 ml.), according to the proce-dure in Journal of the American Chemical Society, Vol. 84, page 867 (1962) and Vol. 87, page 1353 (1965). After one hour, the solution was poured into 1 liter of water and the product extracted with ether (3 x 300 ml.). The extract was washed with water ~2 x 150 ml-.) dried ~MgSO4) and evaporated to give an oil, 1,2-epoxy-4-phenylbutane, used directly in the next step .
The oil from above in 50 ml. of dimethylformamide was treated with imidazole (70 g.) and the mixture stirred at 40C. overnight. ~he resulting solution was poured into a mixture of 700 ml. water and 200 ml. hexane, stirred until crystallization was complete, and the product was filtered off as buff granules (28.2 g.). Recrystallization from ethyl acetate gave 1-(2-hydroxy-4-phenylbutyl)imidazole as colorless crystals, m.p. 106-107C.
Similarly, proceeding as above, substituting the appropriate aldehyde for 3-phenylpropionaldehyde, there may be prepared, for example, the following compounds of formula (IIa):
l-t2-hydroxy-4-(4-chlorophenyl)butyl]imidazole ' 1-12-hydroxy-4-(2,4-dichlorophenyl~butyl~imidazole .
-2~- ~
. . .
` 1077493 1-l2-hydroxy-4-(4-tert-butylphenyl)butyl]imidazole , 1-~2-hydroxy-4-(4-fluorophenyl)butyllimidazole 5 and - l-t2-hydroxy-4-(2~4-dimethylphenyl)butyl~imidazole .
.~
i - .
.~' .
~, ~, .,, ,, .
., ..1 ., ..
~, :;1 -,A
:, , ,' ` ' ' . , ,' ` ` ' ' .'~ ' ' ", , ' ' ~ . ' ' ` . ' ' ` . ' ' . ' ''.
~ ' .. ' ' . ' ', ' ., ~ ' ' ' ' ' ~ ' ' ' . ' ':' . . , . ~ , ~ ' ' . '' . ' . ,' `
.. . .
.' ' . ~ ' .
" lQ77493 P~EP~RATION 2 This preparation illustrates the process in reaction scheme B.
Bromomethyl styryl ketone (22.5 g., reference Tetra-hedron, Vol. 29, page 1625-8, 1973) in a few ml. of dimethyl-formamide was added dropwise to a well-stirred,ice cooled solution of imidazole (35 g.) in dimethylformamide (25 ml.), ' keeping the temperature below 13C. The mixture was stirred for three hours at 0C., then overnight at 25C., and poured into 1 liter of water. The solution was extracted success-, , ively with benzene (600 ml.) and ether (600 ml.) and the combined extracts were dried (MgS04) and evaporated.
Addition of benzene to the residue gave lemon-yellow granules ~12 g.). Treatment of a solution of this product in methanol " with ethereal hydrogen chloride, removal of the solvent and , trituration of the residue with ethyl acetate (100 ml.) gave ,, 5.75 g. of 1-(4-phenylbut-3-en-2-onyl)imidazole hydrochloride as a white solid, m.p. 208-210C.
The above ketone ~5.50 g.) in 50 ml. of methanol at , ' , OC. was treated with stirring with excess sodium borohydride.
' When the reaction was complete, the solvent was evaporated , and the residue treated with ice,-cold water (10 ml.).
~, Filtration and washing with a small quantity of ice water gave an off-white powder (5.40 g.), recrystallized from benzene to give 1-(2-hydroxy-4-phenylbut-3-enyl)imidazole '' (5.20 g.), m.p. 125-127.5C.
Similarly procee~ing as above, substituting the appro-priate halo ketone for bromomethyl styryl ketone, there may be prepared, for example, the following compounds of .
' -26-.~ .
~I Y~
' ' ' ' - .
.... .'' . ~ ' , . .
.
~ ` ~
` ~ ~774g3 formula (IIa):
2-hydroxy-3-phenylpropyl)imidazole ~'`
.~ . . ... .
`i l-[2-hydroxy-3-(4-chlorophenyl~propyl]imidazole " .
and ., .
l-[2-hydroxy-4-(4-chlorophenyl)but-3-enyl]imida20le ~ ~ .
,, . ., .. , ............. . . ... . _ .. . . _ . _ . . .. . . .. _ . _ ~
!.
: ~ ' ' .
~ I .
, .
,~
.', -I .
,, , . :' ~,.. , . , , .' . :
' ~ ' ` ~ : ' , ' ' . ' : ' ~ . ' ~ , .: , ' :' ' - ' ' ' . .
' ~ ' ' ' .
':, . .
PREP~R~TION 3 . This preparation illustrates the process in reaction ' scheme C.
A. 7.0 g. of 2,4-dichlorophenyl vinyl ketone ~pre-pared by Jones oxidation of 2~4-dichlorophenyl vinyl car-binol using the general method described in J; Chem Soc. (C?, 1966, p. 1972) in 350 ml. of anhydrous ether was treated with 3.5 g. of imidazole,' the solution stirred overnight 0 .2 and then washed with water 13 x 30 ml.). The solution is dried (MgSO4) and evaporated to give 2,4-dichloro~
imidazolyl)propiophenone as an amber gum ~8.65 g.). The hydrochloride salt may be precipitated from ether and recrystallized from methanol/acetone'as colorless rods, lS m.p. 105.5-110C.
B. 13.1 g. of 2,4-dichlorobenzoylethyl trimethyl-ammonium iodide ~prepared by Mannich reaction of 2,4-dichlora-- acetophenone with paraformaldehyde and dimethylamine hydro-chloride, followed by quaternization with methyl iodide in ether) and 12 g. of imidazole in dimethylformamide (50 ml.) was stirred overnight at room temperature and poured into 500 ml. of water. The product was extracted'with ether ' ~3 x 300 ml.), the extracts washed with water (3 x 75 ml.) . and dried. Addition of ethereal hydrogen chloride precipi-tated the hydrochloride of 2,4-dichloro-~-(1-imidazolyl) propiophenone, which was recrystallized from methanol/acetone, m.p. 105-109C.
C. The ketone 'prepared in part A or part B aboYe may be reduced to the corresponding alcohol, 1-13-hydroxy-3-; 30 (2,4-dichlorophenyl)propyl]imidazole, m.p. 112-114.5C.
following the procedure described in Preparation 2.
`
.. . ..
*~
107~93 .
D. Similarly procccding as above, substituting the appropriate vinyl ketone or Mannich quaternary salt for those indicated in Part A or B, there may be prepared, for example, the following compounds of formula (IIb):
1-13-hydroxy-3-(4-chlorophenyl)propyl~imidazole, m.p. 95-100C.
1-[3-hydroxy-3-(4-tert-butylphenyl)propyl]imidazole, m.p. 139.5-140.5C.
1-[3-hydroxy-3-~4-fluorophenyl)propyl]imidazole, m.p. 104.5-110C.
1-~3-hydroxy-3-(2,4-dimethylphenyl)propyl]imidazole (3-hydroxy-4-phenylbutyl)imidazole . ,. , ,' , .
1-[3-hydroxy-4-(4-chlorophenyl)butyl]imidazole ~ 1-[3-hydroxy-4-(4-methylphenyl)butyl]imidazole : . . . .
1-[3-hydroxy-5-(4-chlorophenyl)pentyl)imidazole and -- .
1-[3-hydroxy-3-(2-trifluoromethylphenyl]propyl]
imidazole 1-[2-hydroxy-3-(2,4-dibromophenyl)propyl)]imidazole l-r3-hydroxy-3-(2,4-difluorophenyl)propyl]imidazole ._. . - . . . -..
,: . . . : :
- ~ . . :
, - -~ ' , ' ' ' 11~77493 PRE~AR~TION 4 .
This preparation illustrates the process of reaction scheme D.
S A. B-Chloropropiophenone (16.8 g.) and imidazole ~35 g.) in dimethylformamide ~25 ml.) were stirred at 0C.
for three hours and poured into 700 ml. water. The product was filtered off as buff flakes (15.9 g.) and recrystallized from cyclohexane as colorless flakes of ~ imidazolyl)pro-piophenone, m.p. 96-99.5C.
The above material (5.60 g.) in 70 ml. of methanol was treated at 0C. with excess sodium borohydride. ~hen the reaction was complete, the solvent was evaporated, 100 ml. of water was added and t~e product (4.90 g.) was filtered off.
` 15 Recrystallization from ethyl acetate gave 1-(3-hydroxy-3-. .
phenylpropyl)imidazole as colorless rods, m.p. 106.5-108C.
- B. To a 0C. slurry of 8.24 g. of imidazole in 15 ml.
dry dimethylformamide was added 5.79 g. of p-t-butyl-y-chlorobutyrophenone and the mixture was stirred overnight at room temperature, then one day at 60C. The above solution was poured into 400 ml. of water and extracted three times with ethyl acetate. The combined extracts were washed with' water, dried over magnesium sulfate and the solvent evaporated to afford 5.25 g. of 1-[4-(4-t-butylphenyl)butan-4-onyl]imida-zole as a golden oil. ~: :
~o a 0C. solution of 5.0 g. of the above ketone in 150 ml. of anhydrous methanol was added excess sodium boro-hydrid~, and the mixture stirred for one hour. After removal of the solvent, a small quanti~y of water was added and the mixture was extracted with ethyl acetate. The combined ~ 7493 cxtracts were dried over magnesium sulfate and evaporated to afford lt4-hydroxy-4-14-t-butylphenyl)butyl]imidazole, which was converted to the oxalate salt and recrystallized from ethyl acetate/ethanol, m.p. 205-207C. (foaming).
Similarly, proceeding as above, substituting the appropriate haloketone for those indicated in part A or B, there may be prepared, for example, the first four compounds of formula (IIb) listed in Preparation 3, as well as the ~ following compounds of formula ~
tO l-14-hydroxy-4-(4-chlorophenyl)butyl]imidazole l-[4-hydroxy-4-(2,4-dichlorophenyl)butyl]imidazole ', ' '' ' . , ' ' .
l-[4-hydroxy-4-(4-fluorophenyl)butyl]imidazole, m.p. 91.5-94C.
1-[4-hydroxy-4-(2,4-dimethylphenyl)butyl]imidazole , l-14-hydroxy-4-(4-bromophenyl)butyl]imidazole~
m.p. 113.5-115C.
l-(4-hydroxy-5-phenylpentyl)imidazole ~- ~ l-14-hydroxy-5-(4-chlorophenyl)pentyl]imidazole .
~ l-14-hydroxy-6-~4-chlorophenyl)hexyl]imidazole " ~S, l-~6 hydroxy-6-phenylhexyl)imidazole ' l-16-hydroxy-6-(4-chlorophenyl)hexyl]imidazole , 1-16-hydroxy-7-(4-chlorophenyl)heptyl]imidazole ' ~377493 ~ 1-(6-hydroxy-8-phenyloctyl)imidazole .
. 1-(6-hydroxy-10-phenyldecyl)imidazole l-(9-hydroxy-9-phenylnonyl)imidazole 1-[9-hydroxy-9-(4-chlorophenyl?nonyl]imidazole .
r ' l-l9-hydroxy-10-(4-chlorophenyl)decyl~imidazole l-(9-hydroxy-11-phenylundecyl)imidazole .
~nd : l-(9-hydroxy-13-phenyltridecyl)imidazole .
, .
:
.
. . .
.. , . , . ~ . . .
.: , . : , : . .. : , . .
.: . : . . , :
1077gg3 - PR~P~R~TION 5 ~his preparation illustrates the process of reaction scheme I.
7.3 g. of chloroacetylmethyl triphenylphosphonium chloride and 7.3 g. of imidazole in acetonitrile (60 ml.) were stirred and heated at 80C. for two days. The resulting solution was evaporated and the residue treated with water, -extracted with benzene, and the extract washed with water, , dried (MgSO4) and evaporated. Recrystallization from ethylacetate~cyclohexane afforded l-imidazolylacetylmethylene-triphenylphosphorane, as colorless blades, m.p. 154.5-158C.
The above phosphorane (3.85 g.) and p-tolualdehyde 12.4 g.~ were stirred in 30 ml. of acetonitrile and refluxed overnight. After evaporation to dryness, the residue was chromatographed on silica gel eiuting with acetone/dichloro-methane to afford 1-[4-(4-methylphenyl)but-3-en-2-onyl]imid-azoIe as a colorless solid.
~his material was reduced with sodium borohydride, following the procedure in Preparation 2 to afford l-~2-hydroxy-414-methylphenyl)but-3-enyl]imidazole.
In a similar manner, substituting benzaldehyde for p-tolualdehyde, there was prepared l-(2-hydroxy-4-phenylbut-3-enyl) imidazole, m.p. 125-127.5C.
2.5 g. of this material in 30 ml. of methanol was hydrogenated at ambient temperature and pressure over a 10% palladium on charcoal catalyst. When the uptake of hydrogen ceased, the solution was filtered, and the residue was recrystallized from benzene/cyclohexane to give white microcrystals ~2.37 a.) of l-(2-hydroxy-4-phenylbutyl)imida-zole, m.p. 10~-109.5C.
' .
1~77493 Similarly proc~eding as above, substituting the appro-priate aldehyde for those indicated, th~re may be prepared, for example, the followlng compounds of formula ~Ia):
1-[2-hydroxy-4-(4-chlorophenyl)but-3-enyl]imidazole 1-12-hydroxy-4-(4-chlorophenyl)butyl]imidazole .- .
~ 1-[2-hydroxy-4-(2,4-dichlorophenyl)but-3-enyl]imidazole , 1-12-hydroxy-4-(2,4-dichlorophenyl)buty~]imidazole 1-[2-hydroxy-4-(4-tert-butylphenyl)but-3-enyl]imidazole , . . .
- 1-[2-hydroxy-4-(4-tert-butylphenyl)butyl)imidazole . 15 1-[2-hydroxy-4-(4-fluorophenyl)but-3-enyl]imidazole , . . .
~ 1-[2-hydroxy-4-(4-fluorophenyl)butyl]imidazole .. . .
, 20 1-[2-hydroxy-4-(2,4-dimethylphenyl)but-3-enyl]imidazole , ............................ . .
and . .
l-t2-hydroxy-4-(2,4-dimethylphenyl)butyl]imidazole ,- :
. I .
. :~ - ,: . : : . -. , .
. : - . . : :. ~ - . . - , . . . . . .
- - .. . . - . : . , .
. . . ,: . - , . . .
` . IU77493 EX~MPLE 1 A. A mixture of 430 mg. of 1-(2-hydroxy-4-phenylbutyl) .
imidazole and 96 mg. of sodium hydride tS6~ dispersion in mineral oil) in 3 ml. of dry hexamethylphosphoramide was stirred under nitrogen at room temperature for one hour and at 45C. for one hour. After the evolution of hydrogen ceased,the solution was cooled in an ice bath and a solution c of 430 mg. of 2,4-dichlorobenzyl chloride in 2 ml. hexamethyl-phosphoramide added dropwise keeping the temperature below 10C. The solution was stirred for one hour at room tempera-ture, 2 hours at 45C. and let stand overnight. The resulting mixture was then poured into water, extracted with ether, the ether extracts washed with water, dried and evaporated.
The oily product, 1-[2-(2,4-dichlorobenzyloxy)-4-phenylbutyl~
imidazole, was converted to its nitrate salt by treatment of an ethereal solution with concentrated nitric acid, which ~; salt was recrystallized from ethyl acetate as large color-less flakes, m.p. 121-124C.
B. trans-l-[2-Hydroxy-4-phenylbut-3-enyl]imidazole ', (430 mg.) in S ml. dr~ tetrahydrofuran was treated under nitrogen with stirring with 96 mg. of sodium hydride ~6 dispersion in mineral oi~ and the mixture heated under reflux for 30 minutes. After cooling in an ice bath the mixture was treated with stirring with 430 mg. of a,2,4-trichlorotoluene in 5 ml. tetrahydrofuran for 30 minutes ! at OPC., one hour at 25C. and overnight under reflux. The resulting mixture was evaporated to dryness, ether (150 ml.) added and the ether extract washed with water, dried over magnesium sulfate and evaporated to afford trans-1-[2-~2,4-~ -35-: `, ~ ~ ' - , dichlorobcnzyloxy)-4-phenylbut-3-enyl]imidazole. The nitrate salt precipitated from ethér and was crystallized from ethyl acetate, m.p. 133.5 134.5C. (foaming).
:~ .
' .
:
~, ..... . . ., . . ,: . . . . , ... .. : -. : . : ...
,. . : . . :,: . : . - -,, , . . . .. : , ., . : . : . :. : -.
, , . , . ~ , - . . .. -- . . . . .. ~
- - . :: . -1077~93 , ' A solution of -1.00 g. of 1-(2-hydroxy-4-phenylbutyl) imidazole in 40 ml. of dichloromethane was treated with 5 1 ml. of thionyl chloride with stirring and the solution heated to gentle reflux for one hour. Evaporation to dry-ness afforded 1-(2-chloro-4-phenylbutyl)imidazole hydro-ohloriae as a white solid.
The free base may be obtained for use in the subsequent alkylation steps, if desired, by shaking the hydrochloride in dichloromethane with excess aqueous potassium car-, bonate solution,, washing the organic layer with water, drying over magnesium sulfate and evaporating to dryness.
' ' ': ' ' ' ' .
1~77~93 EX~M~LE 3 .
600 Mg. of 1-(2-chloro-4-phenylbutyl)imidazole hydro-chloride was added to a fully reacted mixture of 1.1 g. of 3,4-dichlorobenzylmercaptan and 400 mg. of 56% sodium hydride dispersion in mineral oil in 30 ml. of tetrahydro-furan. After stirring under reflux for 12 hours the solvent was evaporate~ under vacuum and lS0 ml. of ether was added.
t The resulting mixture was washed twice with water and the ethereal solution dried and evaporated to afford 1-~2-(3,4-- dichlorobenzylthio)-4-phenylbutyl]imidazole, as an oil.
, . ~his material was converted to the oxalate salt by treatment j~ o~ an ethereal solution with oxalic acid ln ether until precipitation was complete, which salt was recrystallized ; lS from acetone/ethyl acetate as colorless flakes (660 mg.~, m.p. 143.5-146C.
: . ... , .. . : .. , : -.. . . . . , - ~ .. -- : . : : . - . .
,- .......... ~ ~ . .. . ..
... . - . . - . . . -. . - , : .
.,, . , . . ~
:: . ~ , ~ : . . : :
,' '` ... '. .. ' -,; ' - .~ ' . ~.:' ':,' - :,, ' 1~ ~7493 EXI~M~r,E ~1 ~ mixturc oE 600 m~. o~ 1- t2-chloro-~-pllcn:,~ll)ut:Yl)illlida-zolc hydrochlorid~, 1.2 g. of 3,~-dichlorothiophcnol and 800 mg.
o potassium carbonatc in 40 ml. of acetone was stirred and ~efluxed for 4 hours. The solvent was evaporated under vacuum and 50 ml. of water was added. The resul ting - mixture was extracted with ether and the et~er e~tract was washed with saturated sodium chloride solution, dried and evaporated to afford 1-~2-(3,4-dichlorophenylthio)-4-phenyl-butyl~imidazole as an oil; This material was converted to the oxalate salt by treatment with oxalic acid in ether, which salt was recrystallized from acetone/ethyl acetate as colorless flakes t850 mg.), m.p. 145-147C.
.. .The free base was also converted to the nitrate salt by treatment with nitric acid in ether, which salt was recrystallized from ethyl acetate, m.p. 99-105C.(dec.); LD50 (oral, acute, mice) >1000 mg./kg.
~' .~ ' '.. ~',' ' . .
.
;
; . EX~MPLE 5 - = ~ ........................ .
~, .~
-- . 1,2-Epoxy-4-phenyl~utane (1.48 g.) in dry tetrahydro-furan (10 ml.) was added to the clear solution obtained from the reaction of 50 mg. of 56% sodium hydride dispersion in mineral oil with 2.25 g. of 3,4-dichlorobenzylmercaptan in S0 ml. of dry tetrahydrofuran.
After stirring for four hours at 60C. the solvent was removed, the residue treated with water and extracted with ether. The ether extract was dried and evaporated to afford a colorless oil.
The above oil in 30 ml. dichloromethane was treated with 2 ml. of thionyl chloride at room temperature for 30 minutes, and the solution evaporated to dryness. The residue was treated with 4 g. of imidazole and 15 ml. of acetonitrile and stirred overnight at room temperature and for one day at 50C. The solvent was evaporated and after the addition of 50 ml. water the residue was extracted with ether. The ether extract was washed with water, dried - and evaporated to afford 1-[2-(3,4-dichlorobenzylthio)-4-phenylbutyl]imidazole as an oil, which was further character-ized as its oxalate salt, m.p. 143.5-146C.
. .. . .
. . . ~ . :. ~ ...
.
.. . . . . - . ..
. -.
EX~MPL~ 6 , . Following the procedures in Preparations 1, 2 or 5, and Examples 1; 2,3; 2,4; or S, using equivalent amounts of the appropriate starting materials, there may be obtained the following compounds. Where indicated, the compounds may be further characterized by conversion to the indicated acid addition salt.
2-~3,4-dichlorobenzylthio)-3-phenylpropyl]imidazole ' 10 . ' :
2-(4-chlorophenylthio)-3-phenylpropyl]imidazole , ~. 1-12-~2,4-dichlorophenoxy)3-phenylpropyl]imidazole . . .
1-12-(3,4,5-trichlorophenylthio)-3-phenylpropyl~imida-; zole 1-12-(2,4-dichlorobenzylthio)-3-~4-chlorophenyl)propyl]
imidazole 1-12-(4-fluorophenylthio)-3-(4-chlorophenyl)propyl]
imidazole - - .
. 1-12-(4-tert-butylphenoxy)-3-(4-chlorophenyl)propyl]
.imidazole 1-l2-(3~4-dichlorophenylthio)-3-~4-chlorophenyl) propyl]imidazole . 25 1-[2-(2,4-dichlorobenzylthio)-4-phenylbutyl]imidazole ; 1-[2-(3,4-dichlorobenzyloxy)-4-phenylbutyl]imidazole . 1-[2-(3,4-dichlorophenoxy)-4-phenylbutyl]imidazole -~ , - . .
~`` 1077493 1-[2-~2,3,4,5,6-pentachlorophenylthio)-4-phenylbutyl]
imidazole l-t2-(4-bromobenzylthio)-4-phenylbutyl]imidazole .
S 1-[2-(4-fluorophenoxy)-4-phenylbutyl]imidazole ,. .
1-[2-(4-methylphenylthio)-4-phenylbutyllimidazole . .
1-[2-cinnamyloxy-4-phenylbutyl]imidazole , 10 1-12-(4-chlorophenylthio)-4-t4-chlorophenyl)butyl]
imidazole-nitrate salt, m.p. 116-119C.
1-[2-(i-chlorophenoxy)-4-(4-chlorophenyl)butyl]
imidazole 1-12-(4-chlorobenzylthio)-4-(4-chlorophenyl)butyl~
- imidazole-oxalate salt, m.p. 143-144C.
; 1-[2-(4-chlorobenzyloxy)-4-(4-chlorophenyl)butyl]
imidazole 1-12-(2,4-dichlorobenzyloxy)-4-~4-chlorophenyl)butyl]
imidazole :' .
1-[2-(2,4-dichlorobenzylthio)-4-(4-chlorophenyl)butyl]
imidazole 1-12-(3,4-dichlorobenzyloxy)-4-(4-chlorophenyl)butyl]
. imidazole 1-[2-(3,4-dichlorophenylthio)-4-(4-chlorophenyl)butyl]
imidazole - nitrate salt, m.p. 84-89C. (dec.).
1-[2-(3,4-dichlorobenzylth1o)-4-~4-chlorophenyl) butyl]imidazole ; 1-12-~2,4,5-trichlorophenylthio)-4-~4-chlorophenyl) 3~ butyllimidazole 1-12-cinnamyloxy-9-~4-chlorophcnyl)~utyl]imiclazole ;`
~ ` . ' , ' . : . .
` --` 1077493 1-[2- ~2,4-dic}lloroph~nylthio) -4- I~l-chloroph~nyl) butyllimidazol~ - nitrate salt, m.p. 113.5-115C
l~t2-~4-chlorocinnamyloxy)-4-~4-chlorophenyl)butyl]
imidazole .-l-t2-(4-fluorocinnamylthio)~4-~4-chlorophenyl)but imidazole l-t2-~4-trifluoromethylphenylthio)-4-l4-chlorophenyl) butyl~imidazole . .l-t2-(4-chloro-3-trifluoromethylphenylthio)-4-(4 lo ; chlorophenyl)butyl]imidazole . l-t2-(4-trifluoromethylbenzyloxy)-4-(4-chlorophenyl) butyl]imidazole 2-(benzylthio)-4-(2,4-dichlorophenyl)butyl]imidazole : 15 - 1-[2-(4-chlorobenzyloxy)-4-(2,4-dichlorophenyl)butyl]
~midazole 1-l2-~2,4-dichlorobenzylthio)-4-(2,4-dichlorophenyl) . - .
: butyl]imidazole . . -. l-t2-(3,4-dichlorobenzylthio)-4-(2,4-dichlorophenyl) butyllimidazole : 1-[2-~4-text-butylbenzyloxy)-4-(2,4-dichlorophenyl) :. butyl]imidazole .
l-t2-cinnamyloxy-4-(2,4-dichlorophenyl)butyl]imidazole .
1-12-~4-chlorocinnamylthio)-4-(2,4-dichlorophenyl) butyl]imidazole 1-l2-(4-phenylbutylthio)-4-(2,4-dichlorophenyl)butyl]
. : imidazole ~-t2-~4-chlorophcnylthio)-4-(4-tert-butylphenyl)butyl]
~midazol~ : -2-~2,4-dichlorobcnzyloxy)-4-(4-tert-butylphcnyl) butyllimidazolc .
~ -~3-` -` 1077493 ` .
1-l2-~3~4-dichlorophenylthio)-4-(4-fluorophenvl)hutyl]
imidazole -1-[2-(2,4-dichlorobenzyloxy)-4-(4-fluorophenyl) butyl]imidazole 1-t2-~3,4-dichlorobenzylthio)-4-(4-fluoroph~nyl)butyl]
imidazole l-t2-(3,4-dichlorobenzylthio)-4-(2,4-dimethylphenyl) butyllimidazole ` l-t2-(4-chlorophenoxy)-4-t2,4-dimethylphenyl)butyl]
imidazole .. .. .
trans-112-(3,4-dichlorophenylthio)-4-phenylbut-3-enyllimidazole - oxalate salt, m.p. 171.5-175.5C. (dec.).
trans-1-[2-(3,4-dichlorobenzylthio)-4-phenylbut-3-enyl~imidazole - nitrate salt, m.p. 138-139C. (foamingj trans-l- l ?- (2,4-dichlorobenzyloxy)-4-phenylbut-3-enyllimidazole - nitrate salt, m.p. 133.5-134.5C. (foaming) - l-t2-(4-chlorobenzylthio)-4-phenylbut-3-enyl]imidazole ' - . .
l-t2-~4-chlorophenylthio)-4-phenylbut-3-enyl~imidazole ; 1-[2-~4-chlorophenoxy)-4-phenylbut-3-enyl~imidazole 1-[2-(i-bromobenzylthio)-4-phenylbut-3-enyl]imidazole 1-[2-~4-fluorophenoxy)-4-phenylbut-3-enyl]imidazole .
i l-[2-~3-phenylpropyloxy)-4-phenylbut-3-enyl]imidazole :
1-12-cinnamyloxy-4-phenylbut-3-enyllimidazole .
. . . . . - . . . . .
-,- . . .. .. - . . . . .
.. . .. .. . . . .
1-l2-~4-chlorocinnamyloxy)-4-phenylbut-3-enyl]imidazole 2-(4-phenylbutylthio)-4-phenylbut-3-enyl~imidazole 1-12-(3,4-dichlorophenylthio)-4-(4-chlorophenyl)but-3-enyl]imidazole 1-[2-(4-chlorophenoxy)-4-(4-chlorophenyl)but-3-enyl]
- imidazole .
l-t2-(2,4,5-trichlorophenylthio)-4-(4-chlorophenyl) but-3-enyl]imidazole -- . 1-[2-(2,3,4,5,6-pentachlorophenylthio)-4-(4-chlorophenyl) - - . but-3-enyl]imidazole 1-[2-~cinnamylthio)-4-(4-chlorophenyl)but-3-enyl]
. imidazole lS 1-[2-(4-chlorocinnamyloxy?-4-(4-chlorophenyl)but-3-enyl]imidazole ..
1-12-(4-chlorophenylthio)-4-(4-chlorophenyl)but-3-. enyllimidazole . 1-[2-(4-chlorobenzyloxy)-4-(4-chlorophenyl)but-3-enyl]
imidazole l-r2-(4-chlorobenzylthio)-4-(4-chlorophenyl)but-3-. enyl]imidazole 1-[2-(2,4-dichlorobenzyloxy)-4-(4-chlorophenyl)but-3-enyl]imidazole 1-[2-(2,4-dichlorophenylthio)-4-phenylbutyl]imidazole 1-[2-(4-chlorobenzylthio)-4-phenylbutyl]imidazole 1-[2-(4-chlorobenzyloxy-4-phenylbutyl]imidazole 1-[2-(4-chlorobenzylthio)-4-(4-fluorophenyl)butyl]-imidazole . . , - . .~
l-l2-(2,~-dichloro~cnzyl~hio)-~-t~-1uorophcnyl)l.u~yl~-~m~d~zolc (2~-dichlorophcnylthio)~ luorophcnyl)butyl]
; ~m~dazole . - ..
~, .
~ . . . .. .
. - , ... . ~ . .
' : ' ': ~, .' .
- . . . .
,, . . .. - . .
. ~: - . : ~ . -., . : . - : . . - . -.: . :. ..
.
..
~: . .
` - ~'` 1077493 EX~MPLE 7 Following the procedures in Preparations 3 or 4, and Examples 1; 2,3; or 2,4, using equivalent amounts of the appropriate starting materials~there may be obtained the following compounds. Where indicated, the compounds may be further characterized by conversion to the indicated acid addition salt.
~ 3-(4-chlorophenylthio)-3-(4-chlorophenyl)propyl]
imidazole - oxalate salt, m.p. 108-112C.
1-~3-(4-chlorobenzylthio)-3-(4-chlorophenyl)propyl~
imidazole - oxalate salt, m.p. 115-156C.
1-13-(4-chlorobenzyloxy)-3-(4-chlorophenyl)propyl~
imidazole - oxalate salt, m.p. 105-106C.
1-[3-(4-bromo-3-methylphenylthio)-3-(4-chlorophenyl) propyl]imidazole - nitrate salt, m.p. 107-108C.(dec.) 1-[3-(4-tert-butylphenylthio)-3-(4-chlorophenyl)propyl]
imidazole - oxalate salt, m.p. 127.5-129C.(dec.) 1-[3-(4-fluorophenylthio)-3-(4-chlorophenyl)propyl]
imidazole 1-[3-(4-bromobenzyloxy)-3-(4-chlorophenyl)propyl]
imidaæole 1-[3-(2,4-dichlorophenylthio)-3-(4-chlorophenyl)propyl]
imidazole 1-[3-(3,4-dichlorophenylthio)-3-(4-chlorophenyl) propyl]imidazole 1-[3-(4-trifluoromethylphenylthio)-3-(4-chlorophenyl) propyllimidazole 1-[3-(4-trifluoromethylbenzyloxy)-3-(4-chlorophcnyl) propyl]imid~zole 1-~3-(4-chlorocinnamylo~y)-3-(4-chlorophcnyl)propyl]
imidazole ` 1077493 1-[3-(2~4-dichlorocinnamylthio)-3-~4-chlorophenyl) propyl]imidazole 1-~3-(4-phenylbutyloxy)-3-(4-chlorophenyl)propyl]
imidazole 1-t3-(4-methylbenzylthio)-3-(2,4-dichlorophenyl)propyl~
` imidazole - nitrate salt, m.p. 69.5-75C. (dec.) 1-[3-(4-chlorobenzylthio-3-(2,4-dichlorophenyl)propyl]
imidazole - nitrate salt, m.p. 63-66.5C. (dec.) ~ 1-[3-(4-chlorophenylthio)-3-(2,4-dichlorophenyl)propyl]
imidazole- nitrate salt, m.p. 123.5-L25.5C. (dec.) l-t3-~2,4-dichlorophenylthio)-3-(2,4-dichlorophenyl) ; propyl]imidazole 1-13-(3,4-dichlorophenylthio)-3-~2,4-dichlorophenyl) propyl]imidazole -- 15 - 1-13-(4-trifluoromethylphenylthio)-3-(2,4-dichlorophenyl) propyl]imldazole 1-[3-(4-trifluoromethylbenzyloxy)-3-(2,4-dichlorophenyl) propyl]imidazole ; 1-13-(4-tert-butylphenylthio)-3-(2,4-dichlorophenyl) propyl]imidazole l-t3-(4-methylbenzyloxy)-3-(2,4-dichlorophenyl)propyl]
imidazole 1-[3-(4-chlorocinnamyloxy)-3-(2,4-dichlorophenyl) propyl~imidazole 1-13-(3,4-dichlorobenzyloxy)-3-(2,4-dichlorophenyl) propyl]imidazole 1-l3-(2~4~5-trichlorophenylthio)-3-(2~4-dichlorophcnyl) . propyl]imidazole 1-13-~4-phenylbutyltl-io)-3-(2,4-dichlorophenyl)propyl) imidazole .. . .
': . . ~. ` - ~ - .
` 1077493 1-13-(4-chlorobenzyloxy)-3-(2,4-dichlorophenyl) propyl]imidaæole l-t3-(2,4-dichlorobenzyloxy)-3-~2,4-dichlorophenyl)-propyl]imidazole S 1-13-(4-chlorophenylthio)-3-(4-tert-butylphenyl)propyl]
imidazole 1-[3-(2,4-dichlorobenzylthio)-3-(4-tert-butylphenyl) propyl]imidazole ... ...... . . , . , , . " , . , . . . . , .. , .. .. _ . .. .
- l-t3-(2,4,5-trichlorophenylthio)-3-t4-fluorophenyl) propyllimidazole - oxalate salt, coalesces 76C. final m.p. 99C.
1-[3-(4-chlorobenzylthio)-3-14-fluorophenyl)propyl]
imidazole 1-13-(4-tert-butylphenylthio)-3-(4-fiuorophenyl)propyl]
imidazole lS l-t3-(4-chlorocinnamyloxy~-3-(4-fluorophenyl)propyl]
imidazole 1-13-(4-chlorocinnamyloxy)-3-(2,4-dimethylphenyl) propyl]imidazole 1- r 3-(2,4-dichlorobenzylthio)-3-(2,4-dimethylphenyl) propyllimidazole 1-13-(4-`bromophenylthio)-3-~2,4-dimethylphenyl)propyl]
imidazole l-t3-(4-methylbenzylthio)-3-(4-tert-butylphenyl) propyllimidazole- nitrate salt, m.p. 132-134C. (dec.) 1-13-cinnamyloxy-3-(4-tert-butylphenyl)propyl]imidazole l-t3-(4-chlorophenylthio)-4-phenylbutyl]imidazole l-t3-(2,4-dichlorobenzylthio)-4-phenylbutyl]imidazole 3o .
... . ~ , .. . .
., : , - . . .
.
` .
.1-[3-(4-tert-butylphcnylthio)-4-phenylbutyl)imidazole , ' 1-[3-t4-chlorocinnamyloxy)-4-phenylbutyl]imidazole ~' ~ . . . .
- 5 1-[3-(2,4-dichlorophenylthio)-4-(4-chlorophenyl) : butyllimidazole 1-[3-(4-methylbenzylthio)-4-(4-chlorophenyl)butyl]
. imidazole . l-t3-~4-chlorobenzylthio)-4-(4-methylphenyl)butyl~
imidazole 1-13-(2,4-dichlorophenoxy)-4-(4-methylphenyl)butyl]
- . imidazole .. ..... _ ................ .... ,__ ._.. ..... .. . . ... . .
~ 3-(4-chlorocinnamyloxy)-4-(4-methylphenyl)butyl]
- ;. . imidazole .......................... ... ... ... .... ~........... .
~, ~ 15 1-13-(2,4-dichlorobenzylthio)-5-~4-chlorophenyl)pentyl]
imidazole . 1-13-(4-bromobenzyloxy)-5-(4-chlorophenyl)pentyl]
.~ , .
imidazole ~ 1-13-(g-chlorobenzylthio)-5-(4-chlorophenyl)pentyl]
"! 20 imidazole ~i 1-[3-(2,4,5-trichlorophenylthio)-5-(4-chlorophenyl) .' pentyl~imidazole 1-[3-(4-tert-butylbenzylthio)-5-(4-chlorophenyl) pentyl]imidazole ! . 1- [3-(3,4-dichlorophenylthio)-3-~2-trifluoromethyl-3 phenyl)propyl]imidazole ,~I 1-[3-(3,4-dichlorobenzylthio)-3-(2-trifluoromethyl-. . phenyl)propyl]imidazole .
' .1-[3-(4-chlorophenylthio)-3-~2,4-dibromophenyl)propyll 30 . imidazole . --.', ' ~f , .
_,S g_ , .... .. . .. . . . ....... .. ~ .
.. ,. .. . ~ . . . . .
1~77493 1-[3-(4-chlorophenylthio)-3-(2,4-difluorophenyl)-propyl]imidazole 1-[3-(4-fluorophenylthio)-3-(2,4-dichlorophenyl)-propyl]imidazole . 5 1-[3-4-(fluorobenzylthio)-3-(2,4-dichlorophenyl)-i propyl]imidazole.
, . ...... ., . , , ~ , . , . . . .. - . .
` ` -` 1C~77493 EXAMPL~ 8 .
Followlng the procedures in Preparation 4, and Examples 1; 2,3; or 2,4, using equivalent amounts of the appropriate starting materialstthere may be obtained the following compounds. Where indicated, the compounds may be further characterized by conversion to the indicated acid addition salt.
~ 1-14-(3,4-dichlorophenylthio)-4-(4-chlorophenyl)butyl]
imidazole - nitrate salt, m.p. 100-104.5C., oxalate salt m.p. 118-123C. (foaming) 1-14-~3,4-dichlorophenoxy)-4-(4-chlorophenyl3butyl]
imidazole - nitrate salt, m.p. 128-130.5C.
1-14-(4-chlorobenzylthio)-4-(4-chlorophenyl)butyl]
- lmidazole - nitrate salt, m.p. 123-125C. (foaming) l-t4-(2,4-dichlorobenzyloxy)-4-(4-chlorophenyl)butyl]
imidazole - nitrate salt, m.p. 91-114C.
.
1-[4-(3,4-dichlorobenzyloxy-4-(4-chlorophenyl) butyllimidazole ..
1-l4-(4-bromobenzylthio)-4-(4-chlorophenyl)butyl]
imidazole
': ' , '' ' ' ' ' :
" . , .. , ~ . ' ' chlororhodium, in an inert solvent such as benzene, acetone, methanol, and the like, for a time su~ficient to allow the uptake of the required amount of hydrogen.
~he subject compounds of the instant invention can be isolated as free bases; however, since many of the compounds in base form are oils, it is more convenient to isolate and characterize the compounds as acid addition salts. These salts are prepared in the usual manner, i.e., by reaction of the base compound with a suitable inorganic or organic acid, described above. Salts formed with dibasic acids (e.g., oxalic acid) may contain one or two molecules of base per molecule of acid. All oxalates described herein contain - ~ one molecule of oxalic acid per molecule of imidazole base.
- If desired, the salts can be readily converted to the free .~ i base form by treatment with alkali, such as potassium car-.
¦ bonate, sodium carbonate or sodium or potassium hydroxide.
i! ¦ For following specific examples are illustrative of ¦ the present invention and should not be considered as I limit~tive thereof in any manner.
;.
:~ . .. ..
. . . --- , , . , :' .~-- , . . . - .~ : .
..
- . : ' .: . ' .: .. .: --: -. . ~ .. ' . ' ,: . . . -- . . . .: .
-- .
. . .. . .
.
- .
PREP~R~TION 1 This preparation illustrates the process in reaction scheme A.
3-Phenylpropionaldehyde (26.8 g.) is added under nitro-gen to the ylide prepared from trimethylsulfoxonium iodide (48.4 g.) and sodium hydride ~55% dispersion in oil; 9.6 g.) in dry dimethylsulfoxide (200 ml.), according to the proce-dure in Journal of the American Chemical Society, Vol. 84, page 867 (1962) and Vol. 87, page 1353 (1965). After one hour, the solution was poured into 1 liter of water and the product extracted with ether (3 x 300 ml.). The extract was washed with water ~2 x 150 ml-.) dried ~MgSO4) and evaporated to give an oil, 1,2-epoxy-4-phenylbutane, used directly in the next step .
The oil from above in 50 ml. of dimethylformamide was treated with imidazole (70 g.) and the mixture stirred at 40C. overnight. ~he resulting solution was poured into a mixture of 700 ml. water and 200 ml. hexane, stirred until crystallization was complete, and the product was filtered off as buff granules (28.2 g.). Recrystallization from ethyl acetate gave 1-(2-hydroxy-4-phenylbutyl)imidazole as colorless crystals, m.p. 106-107C.
Similarly, proceeding as above, substituting the appropriate aldehyde for 3-phenylpropionaldehyde, there may be prepared, for example, the following compounds of formula (IIa):
l-t2-hydroxy-4-(4-chlorophenyl)butyl]imidazole ' 1-12-hydroxy-4-(2,4-dichlorophenyl~butyl~imidazole .
-2~- ~
. . .
` 1077493 1-l2-hydroxy-4-(4-tert-butylphenyl)butyl]imidazole , 1-~2-hydroxy-4-(4-fluorophenyl)butyllimidazole 5 and - l-t2-hydroxy-4-(2~4-dimethylphenyl)butyl~imidazole .
.~
i - .
.~' .
~, ~, .,, ,, .
., ..1 ., ..
~, :;1 -,A
:, , ,' ` ' ' . , ,' ` ` ' ' .'~ ' ' ", , ' ' ~ . ' ' ` . ' ' ` . ' ' . ' ''.
~ ' .. ' ' . ' ', ' ., ~ ' ' ' ' ' ~ ' ' ' . ' ':' . . , . ~ , ~ ' ' . '' . ' . ,' `
.. . .
.' ' . ~ ' .
" lQ77493 P~EP~RATION 2 This preparation illustrates the process in reaction scheme B.
Bromomethyl styryl ketone (22.5 g., reference Tetra-hedron, Vol. 29, page 1625-8, 1973) in a few ml. of dimethyl-formamide was added dropwise to a well-stirred,ice cooled solution of imidazole (35 g.) in dimethylformamide (25 ml.), ' keeping the temperature below 13C. The mixture was stirred for three hours at 0C., then overnight at 25C., and poured into 1 liter of water. The solution was extracted success-, , ively with benzene (600 ml.) and ether (600 ml.) and the combined extracts were dried (MgS04) and evaporated.
Addition of benzene to the residue gave lemon-yellow granules ~12 g.). Treatment of a solution of this product in methanol " with ethereal hydrogen chloride, removal of the solvent and , trituration of the residue with ethyl acetate (100 ml.) gave ,, 5.75 g. of 1-(4-phenylbut-3-en-2-onyl)imidazole hydrochloride as a white solid, m.p. 208-210C.
The above ketone ~5.50 g.) in 50 ml. of methanol at , ' , OC. was treated with stirring with excess sodium borohydride.
' When the reaction was complete, the solvent was evaporated , and the residue treated with ice,-cold water (10 ml.).
~, Filtration and washing with a small quantity of ice water gave an off-white powder (5.40 g.), recrystallized from benzene to give 1-(2-hydroxy-4-phenylbut-3-enyl)imidazole '' (5.20 g.), m.p. 125-127.5C.
Similarly procee~ing as above, substituting the appro-priate halo ketone for bromomethyl styryl ketone, there may be prepared, for example, the following compounds of .
' -26-.~ .
~I Y~
' ' ' ' - .
.... .'' . ~ ' , . .
.
~ ` ~
` ~ ~774g3 formula (IIa):
2-hydroxy-3-phenylpropyl)imidazole ~'`
.~ . . ... .
`i l-[2-hydroxy-3-(4-chlorophenyl~propyl]imidazole " .
and ., .
l-[2-hydroxy-4-(4-chlorophenyl)but-3-enyl]imida20le ~ ~ .
,, . ., .. , ............. . . ... . _ .. . . _ . _ . . .. . . .. _ . _ ~
!.
: ~ ' ' .
~ I .
, .
,~
.', -I .
,, , . :' ~,.. , . , , .' . :
' ~ ' ` ~ : ' , ' ' . ' : ' ~ . ' ~ , .: , ' :' ' - ' ' ' . .
' ~ ' ' ' .
':, . .
PREP~R~TION 3 . This preparation illustrates the process in reaction ' scheme C.
A. 7.0 g. of 2,4-dichlorophenyl vinyl ketone ~pre-pared by Jones oxidation of 2~4-dichlorophenyl vinyl car-binol using the general method described in J; Chem Soc. (C?, 1966, p. 1972) in 350 ml. of anhydrous ether was treated with 3.5 g. of imidazole,' the solution stirred overnight 0 .2 and then washed with water 13 x 30 ml.). The solution is dried (MgSO4) and evaporated to give 2,4-dichloro~
imidazolyl)propiophenone as an amber gum ~8.65 g.). The hydrochloride salt may be precipitated from ether and recrystallized from methanol/acetone'as colorless rods, lS m.p. 105.5-110C.
B. 13.1 g. of 2,4-dichlorobenzoylethyl trimethyl-ammonium iodide ~prepared by Mannich reaction of 2,4-dichlora-- acetophenone with paraformaldehyde and dimethylamine hydro-chloride, followed by quaternization with methyl iodide in ether) and 12 g. of imidazole in dimethylformamide (50 ml.) was stirred overnight at room temperature and poured into 500 ml. of water. The product was extracted'with ether ' ~3 x 300 ml.), the extracts washed with water (3 x 75 ml.) . and dried. Addition of ethereal hydrogen chloride precipi-tated the hydrochloride of 2,4-dichloro-~-(1-imidazolyl) propiophenone, which was recrystallized from methanol/acetone, m.p. 105-109C.
C. The ketone 'prepared in part A or part B aboYe may be reduced to the corresponding alcohol, 1-13-hydroxy-3-; 30 (2,4-dichlorophenyl)propyl]imidazole, m.p. 112-114.5C.
following the procedure described in Preparation 2.
`
.. . ..
*~
107~93 .
D. Similarly procccding as above, substituting the appropriate vinyl ketone or Mannich quaternary salt for those indicated in Part A or B, there may be prepared, for example, the following compounds of formula (IIb):
1-13-hydroxy-3-(4-chlorophenyl)propyl~imidazole, m.p. 95-100C.
1-[3-hydroxy-3-(4-tert-butylphenyl)propyl]imidazole, m.p. 139.5-140.5C.
1-[3-hydroxy-3-~4-fluorophenyl)propyl]imidazole, m.p. 104.5-110C.
1-~3-hydroxy-3-(2,4-dimethylphenyl)propyl]imidazole (3-hydroxy-4-phenylbutyl)imidazole . ,. , ,' , .
1-[3-hydroxy-4-(4-chlorophenyl)butyl]imidazole ~ 1-[3-hydroxy-4-(4-methylphenyl)butyl]imidazole : . . . .
1-[3-hydroxy-5-(4-chlorophenyl)pentyl)imidazole and -- .
1-[3-hydroxy-3-(2-trifluoromethylphenyl]propyl]
imidazole 1-[2-hydroxy-3-(2,4-dibromophenyl)propyl)]imidazole l-r3-hydroxy-3-(2,4-difluorophenyl)propyl]imidazole ._. . - . . . -..
,: . . . : :
- ~ . . :
, - -~ ' , ' ' ' 11~77493 PRE~AR~TION 4 .
This preparation illustrates the process of reaction scheme D.
S A. B-Chloropropiophenone (16.8 g.) and imidazole ~35 g.) in dimethylformamide ~25 ml.) were stirred at 0C.
for three hours and poured into 700 ml. water. The product was filtered off as buff flakes (15.9 g.) and recrystallized from cyclohexane as colorless flakes of ~ imidazolyl)pro-piophenone, m.p. 96-99.5C.
The above material (5.60 g.) in 70 ml. of methanol was treated at 0C. with excess sodium borohydride. ~hen the reaction was complete, the solvent was evaporated, 100 ml. of water was added and t~e product (4.90 g.) was filtered off.
` 15 Recrystallization from ethyl acetate gave 1-(3-hydroxy-3-. .
phenylpropyl)imidazole as colorless rods, m.p. 106.5-108C.
- B. To a 0C. slurry of 8.24 g. of imidazole in 15 ml.
dry dimethylformamide was added 5.79 g. of p-t-butyl-y-chlorobutyrophenone and the mixture was stirred overnight at room temperature, then one day at 60C. The above solution was poured into 400 ml. of water and extracted three times with ethyl acetate. The combined extracts were washed with' water, dried over magnesium sulfate and the solvent evaporated to afford 5.25 g. of 1-[4-(4-t-butylphenyl)butan-4-onyl]imida-zole as a golden oil. ~: :
~o a 0C. solution of 5.0 g. of the above ketone in 150 ml. of anhydrous methanol was added excess sodium boro-hydrid~, and the mixture stirred for one hour. After removal of the solvent, a small quanti~y of water was added and the mixture was extracted with ethyl acetate. The combined ~ 7493 cxtracts were dried over magnesium sulfate and evaporated to afford lt4-hydroxy-4-14-t-butylphenyl)butyl]imidazole, which was converted to the oxalate salt and recrystallized from ethyl acetate/ethanol, m.p. 205-207C. (foaming).
Similarly, proceeding as above, substituting the appropriate haloketone for those indicated in part A or B, there may be prepared, for example, the first four compounds of formula (IIb) listed in Preparation 3, as well as the ~ following compounds of formula ~
tO l-14-hydroxy-4-(4-chlorophenyl)butyl]imidazole l-[4-hydroxy-4-(2,4-dichlorophenyl)butyl]imidazole ', ' '' ' . , ' ' .
l-[4-hydroxy-4-(4-fluorophenyl)butyl]imidazole, m.p. 91.5-94C.
1-[4-hydroxy-4-(2,4-dimethylphenyl)butyl]imidazole , l-14-hydroxy-4-(4-bromophenyl)butyl]imidazole~
m.p. 113.5-115C.
l-(4-hydroxy-5-phenylpentyl)imidazole ~- ~ l-14-hydroxy-5-(4-chlorophenyl)pentyl]imidazole .
~ l-14-hydroxy-6-~4-chlorophenyl)hexyl]imidazole " ~S, l-~6 hydroxy-6-phenylhexyl)imidazole ' l-16-hydroxy-6-(4-chlorophenyl)hexyl]imidazole , 1-16-hydroxy-7-(4-chlorophenyl)heptyl]imidazole ' ~377493 ~ 1-(6-hydroxy-8-phenyloctyl)imidazole .
. 1-(6-hydroxy-10-phenyldecyl)imidazole l-(9-hydroxy-9-phenylnonyl)imidazole 1-[9-hydroxy-9-(4-chlorophenyl?nonyl]imidazole .
r ' l-l9-hydroxy-10-(4-chlorophenyl)decyl~imidazole l-(9-hydroxy-11-phenylundecyl)imidazole .
~nd : l-(9-hydroxy-13-phenyltridecyl)imidazole .
, .
:
.
. . .
.. , . , . ~ . . .
.: , . : , : . .. : , . .
.: . : . . , :
1077gg3 - PR~P~R~TION 5 ~his preparation illustrates the process of reaction scheme I.
7.3 g. of chloroacetylmethyl triphenylphosphonium chloride and 7.3 g. of imidazole in acetonitrile (60 ml.) were stirred and heated at 80C. for two days. The resulting solution was evaporated and the residue treated with water, -extracted with benzene, and the extract washed with water, , dried (MgSO4) and evaporated. Recrystallization from ethylacetate~cyclohexane afforded l-imidazolylacetylmethylene-triphenylphosphorane, as colorless blades, m.p. 154.5-158C.
The above phosphorane (3.85 g.) and p-tolualdehyde 12.4 g.~ were stirred in 30 ml. of acetonitrile and refluxed overnight. After evaporation to dryness, the residue was chromatographed on silica gel eiuting with acetone/dichloro-methane to afford 1-[4-(4-methylphenyl)but-3-en-2-onyl]imid-azoIe as a colorless solid.
~his material was reduced with sodium borohydride, following the procedure in Preparation 2 to afford l-~2-hydroxy-414-methylphenyl)but-3-enyl]imidazole.
In a similar manner, substituting benzaldehyde for p-tolualdehyde, there was prepared l-(2-hydroxy-4-phenylbut-3-enyl) imidazole, m.p. 125-127.5C.
2.5 g. of this material in 30 ml. of methanol was hydrogenated at ambient temperature and pressure over a 10% palladium on charcoal catalyst. When the uptake of hydrogen ceased, the solution was filtered, and the residue was recrystallized from benzene/cyclohexane to give white microcrystals ~2.37 a.) of l-(2-hydroxy-4-phenylbutyl)imida-zole, m.p. 10~-109.5C.
' .
1~77493 Similarly proc~eding as above, substituting the appro-priate aldehyde for those indicated, th~re may be prepared, for example, the followlng compounds of formula ~Ia):
1-[2-hydroxy-4-(4-chlorophenyl)but-3-enyl]imidazole 1-12-hydroxy-4-(4-chlorophenyl)butyl]imidazole .- .
~ 1-[2-hydroxy-4-(2,4-dichlorophenyl)but-3-enyl]imidazole , 1-12-hydroxy-4-(2,4-dichlorophenyl)buty~]imidazole 1-[2-hydroxy-4-(4-tert-butylphenyl)but-3-enyl]imidazole , . . .
- 1-[2-hydroxy-4-(4-tert-butylphenyl)butyl)imidazole . 15 1-[2-hydroxy-4-(4-fluorophenyl)but-3-enyl]imidazole , . . .
~ 1-[2-hydroxy-4-(4-fluorophenyl)butyl]imidazole .. . .
, 20 1-[2-hydroxy-4-(2,4-dimethylphenyl)but-3-enyl]imidazole , ............................ . .
and . .
l-t2-hydroxy-4-(2,4-dimethylphenyl)butyl]imidazole ,- :
. I .
. :~ - ,: . : : . -. , .
. : - . . : :. ~ - . . - , . . . . . .
- - .. . . - . : . , .
. . . ,: . - , . . .
` . IU77493 EX~MPLE 1 A. A mixture of 430 mg. of 1-(2-hydroxy-4-phenylbutyl) .
imidazole and 96 mg. of sodium hydride tS6~ dispersion in mineral oil) in 3 ml. of dry hexamethylphosphoramide was stirred under nitrogen at room temperature for one hour and at 45C. for one hour. After the evolution of hydrogen ceased,the solution was cooled in an ice bath and a solution c of 430 mg. of 2,4-dichlorobenzyl chloride in 2 ml. hexamethyl-phosphoramide added dropwise keeping the temperature below 10C. The solution was stirred for one hour at room tempera-ture, 2 hours at 45C. and let stand overnight. The resulting mixture was then poured into water, extracted with ether, the ether extracts washed with water, dried and evaporated.
The oily product, 1-[2-(2,4-dichlorobenzyloxy)-4-phenylbutyl~
imidazole, was converted to its nitrate salt by treatment of an ethereal solution with concentrated nitric acid, which ~; salt was recrystallized from ethyl acetate as large color-less flakes, m.p. 121-124C.
B. trans-l-[2-Hydroxy-4-phenylbut-3-enyl]imidazole ', (430 mg.) in S ml. dr~ tetrahydrofuran was treated under nitrogen with stirring with 96 mg. of sodium hydride ~6 dispersion in mineral oi~ and the mixture heated under reflux for 30 minutes. After cooling in an ice bath the mixture was treated with stirring with 430 mg. of a,2,4-trichlorotoluene in 5 ml. tetrahydrofuran for 30 minutes ! at OPC., one hour at 25C. and overnight under reflux. The resulting mixture was evaporated to dryness, ether (150 ml.) added and the ether extract washed with water, dried over magnesium sulfate and evaporated to afford trans-1-[2-~2,4-~ -35-: `, ~ ~ ' - , dichlorobcnzyloxy)-4-phenylbut-3-enyl]imidazole. The nitrate salt precipitated from ethér and was crystallized from ethyl acetate, m.p. 133.5 134.5C. (foaming).
:~ .
' .
:
~, ..... . . ., . . ,: . . . . , ... .. : -. : . : ...
,. . : . . :,: . : . - -,, , . . . .. : , ., . : . : . :. : -.
, , . , . ~ , - . . .. -- . . . . .. ~
- - . :: . -1077~93 , ' A solution of -1.00 g. of 1-(2-hydroxy-4-phenylbutyl) imidazole in 40 ml. of dichloromethane was treated with 5 1 ml. of thionyl chloride with stirring and the solution heated to gentle reflux for one hour. Evaporation to dry-ness afforded 1-(2-chloro-4-phenylbutyl)imidazole hydro-ohloriae as a white solid.
The free base may be obtained for use in the subsequent alkylation steps, if desired, by shaking the hydrochloride in dichloromethane with excess aqueous potassium car-, bonate solution,, washing the organic layer with water, drying over magnesium sulfate and evaporating to dryness.
' ' ': ' ' ' ' .
1~77~93 EX~M~LE 3 .
600 Mg. of 1-(2-chloro-4-phenylbutyl)imidazole hydro-chloride was added to a fully reacted mixture of 1.1 g. of 3,4-dichlorobenzylmercaptan and 400 mg. of 56% sodium hydride dispersion in mineral oil in 30 ml. of tetrahydro-furan. After stirring under reflux for 12 hours the solvent was evaporate~ under vacuum and lS0 ml. of ether was added.
t The resulting mixture was washed twice with water and the ethereal solution dried and evaporated to afford 1-~2-(3,4-- dichlorobenzylthio)-4-phenylbutyl]imidazole, as an oil.
, . ~his material was converted to the oxalate salt by treatment j~ o~ an ethereal solution with oxalic acid ln ether until precipitation was complete, which salt was recrystallized ; lS from acetone/ethyl acetate as colorless flakes (660 mg.~, m.p. 143.5-146C.
: . ... , .. . : .. , : -.. . . . . , - ~ .. -- : . : : . - . .
,- .......... ~ ~ . .. . ..
... . - . . - . . . -. . - , : .
.,, . , . . ~
:: . ~ , ~ : . . : :
,' '` ... '. .. ' -,; ' - .~ ' . ~.:' ':,' - :,, ' 1~ ~7493 EXI~M~r,E ~1 ~ mixturc oE 600 m~. o~ 1- t2-chloro-~-pllcn:,~ll)ut:Yl)illlida-zolc hydrochlorid~, 1.2 g. of 3,~-dichlorothiophcnol and 800 mg.
o potassium carbonatc in 40 ml. of acetone was stirred and ~efluxed for 4 hours. The solvent was evaporated under vacuum and 50 ml. of water was added. The resul ting - mixture was extracted with ether and the et~er e~tract was washed with saturated sodium chloride solution, dried and evaporated to afford 1-~2-(3,4-dichlorophenylthio)-4-phenyl-butyl~imidazole as an oil; This material was converted to the oxalate salt by treatment with oxalic acid in ether, which salt was recrystallized from acetone/ethyl acetate as colorless flakes t850 mg.), m.p. 145-147C.
.. .The free base was also converted to the nitrate salt by treatment with nitric acid in ether, which salt was recrystallized from ethyl acetate, m.p. 99-105C.(dec.); LD50 (oral, acute, mice) >1000 mg./kg.
~' .~ ' '.. ~',' ' . .
.
;
; . EX~MPLE 5 - = ~ ........................ .
~, .~
-- . 1,2-Epoxy-4-phenyl~utane (1.48 g.) in dry tetrahydro-furan (10 ml.) was added to the clear solution obtained from the reaction of 50 mg. of 56% sodium hydride dispersion in mineral oil with 2.25 g. of 3,4-dichlorobenzylmercaptan in S0 ml. of dry tetrahydrofuran.
After stirring for four hours at 60C. the solvent was removed, the residue treated with water and extracted with ether. The ether extract was dried and evaporated to afford a colorless oil.
The above oil in 30 ml. dichloromethane was treated with 2 ml. of thionyl chloride at room temperature for 30 minutes, and the solution evaporated to dryness. The residue was treated with 4 g. of imidazole and 15 ml. of acetonitrile and stirred overnight at room temperature and for one day at 50C. The solvent was evaporated and after the addition of 50 ml. water the residue was extracted with ether. The ether extract was washed with water, dried - and evaporated to afford 1-[2-(3,4-dichlorobenzylthio)-4-phenylbutyl]imidazole as an oil, which was further character-ized as its oxalate salt, m.p. 143.5-146C.
. .. . .
. . . ~ . :. ~ ...
.
.. . . . . - . ..
. -.
EX~MPL~ 6 , . Following the procedures in Preparations 1, 2 or 5, and Examples 1; 2,3; 2,4; or S, using equivalent amounts of the appropriate starting materials, there may be obtained the following compounds. Where indicated, the compounds may be further characterized by conversion to the indicated acid addition salt.
2-~3,4-dichlorobenzylthio)-3-phenylpropyl]imidazole ' 10 . ' :
2-(4-chlorophenylthio)-3-phenylpropyl]imidazole , ~. 1-12-~2,4-dichlorophenoxy)3-phenylpropyl]imidazole . . .
1-12-(3,4,5-trichlorophenylthio)-3-phenylpropyl~imida-; zole 1-12-(2,4-dichlorobenzylthio)-3-~4-chlorophenyl)propyl]
imidazole 1-12-(4-fluorophenylthio)-3-(4-chlorophenyl)propyl]
imidazole - - .
. 1-12-(4-tert-butylphenoxy)-3-(4-chlorophenyl)propyl]
.imidazole 1-l2-(3~4-dichlorophenylthio)-3-~4-chlorophenyl) propyl]imidazole . 25 1-[2-(2,4-dichlorobenzylthio)-4-phenylbutyl]imidazole ; 1-[2-(3,4-dichlorobenzyloxy)-4-phenylbutyl]imidazole . 1-[2-(3,4-dichlorophenoxy)-4-phenylbutyl]imidazole -~ , - . .
~`` 1077493 1-[2-~2,3,4,5,6-pentachlorophenylthio)-4-phenylbutyl]
imidazole l-t2-(4-bromobenzylthio)-4-phenylbutyl]imidazole .
S 1-[2-(4-fluorophenoxy)-4-phenylbutyl]imidazole ,. .
1-[2-(4-methylphenylthio)-4-phenylbutyllimidazole . .
1-[2-cinnamyloxy-4-phenylbutyl]imidazole , 10 1-12-(4-chlorophenylthio)-4-t4-chlorophenyl)butyl]
imidazole-nitrate salt, m.p. 116-119C.
1-[2-(i-chlorophenoxy)-4-(4-chlorophenyl)butyl]
imidazole 1-12-(4-chlorobenzylthio)-4-(4-chlorophenyl)butyl~
- imidazole-oxalate salt, m.p. 143-144C.
; 1-[2-(4-chlorobenzyloxy)-4-(4-chlorophenyl)butyl]
imidazole 1-12-(2,4-dichlorobenzyloxy)-4-~4-chlorophenyl)butyl]
imidazole :' .
1-[2-(2,4-dichlorobenzylthio)-4-(4-chlorophenyl)butyl]
imidazole 1-12-(3,4-dichlorobenzyloxy)-4-(4-chlorophenyl)butyl]
. imidazole 1-[2-(3,4-dichlorophenylthio)-4-(4-chlorophenyl)butyl]
imidazole - nitrate salt, m.p. 84-89C. (dec.).
1-[2-(3,4-dichlorobenzylth1o)-4-~4-chlorophenyl) butyl]imidazole ; 1-12-~2,4,5-trichlorophenylthio)-4-~4-chlorophenyl) 3~ butyllimidazole 1-12-cinnamyloxy-9-~4-chlorophcnyl)~utyl]imiclazole ;`
~ ` . ' , ' . : . .
` --` 1077493 1-[2- ~2,4-dic}lloroph~nylthio) -4- I~l-chloroph~nyl) butyllimidazol~ - nitrate salt, m.p. 113.5-115C
l~t2-~4-chlorocinnamyloxy)-4-~4-chlorophenyl)butyl]
imidazole .-l-t2-(4-fluorocinnamylthio)~4-~4-chlorophenyl)but imidazole l-t2-~4-trifluoromethylphenylthio)-4-l4-chlorophenyl) butyl~imidazole . .l-t2-(4-chloro-3-trifluoromethylphenylthio)-4-(4 lo ; chlorophenyl)butyl]imidazole . l-t2-(4-trifluoromethylbenzyloxy)-4-(4-chlorophenyl) butyl]imidazole 2-(benzylthio)-4-(2,4-dichlorophenyl)butyl]imidazole : 15 - 1-[2-(4-chlorobenzyloxy)-4-(2,4-dichlorophenyl)butyl]
~midazole 1-l2-~2,4-dichlorobenzylthio)-4-(2,4-dichlorophenyl) . - .
: butyl]imidazole . . -. l-t2-(3,4-dichlorobenzylthio)-4-(2,4-dichlorophenyl) butyllimidazole : 1-[2-~4-text-butylbenzyloxy)-4-(2,4-dichlorophenyl) :. butyl]imidazole .
l-t2-cinnamyloxy-4-(2,4-dichlorophenyl)butyl]imidazole .
1-12-~4-chlorocinnamylthio)-4-(2,4-dichlorophenyl) butyl]imidazole 1-l2-(4-phenylbutylthio)-4-(2,4-dichlorophenyl)butyl]
. : imidazole ~-t2-~4-chlorophcnylthio)-4-(4-tert-butylphenyl)butyl]
~midazol~ : -2-~2,4-dichlorobcnzyloxy)-4-(4-tert-butylphcnyl) butyllimidazolc .
~ -~3-` -` 1077493 ` .
1-l2-~3~4-dichlorophenylthio)-4-(4-fluorophenvl)hutyl]
imidazole -1-[2-(2,4-dichlorobenzyloxy)-4-(4-fluorophenyl) butyl]imidazole 1-t2-~3,4-dichlorobenzylthio)-4-(4-fluoroph~nyl)butyl]
imidazole l-t2-(3,4-dichlorobenzylthio)-4-(2,4-dimethylphenyl) butyllimidazole ` l-t2-(4-chlorophenoxy)-4-t2,4-dimethylphenyl)butyl]
imidazole .. .. .
trans-112-(3,4-dichlorophenylthio)-4-phenylbut-3-enyllimidazole - oxalate salt, m.p. 171.5-175.5C. (dec.).
trans-1-[2-(3,4-dichlorobenzylthio)-4-phenylbut-3-enyl~imidazole - nitrate salt, m.p. 138-139C. (foamingj trans-l- l ?- (2,4-dichlorobenzyloxy)-4-phenylbut-3-enyllimidazole - nitrate salt, m.p. 133.5-134.5C. (foaming) - l-t2-(4-chlorobenzylthio)-4-phenylbut-3-enyl]imidazole ' - . .
l-t2-~4-chlorophenylthio)-4-phenylbut-3-enyl~imidazole ; 1-[2-~4-chlorophenoxy)-4-phenylbut-3-enyl~imidazole 1-[2-(i-bromobenzylthio)-4-phenylbut-3-enyl]imidazole 1-[2-~4-fluorophenoxy)-4-phenylbut-3-enyl]imidazole .
i l-[2-~3-phenylpropyloxy)-4-phenylbut-3-enyl]imidazole :
1-12-cinnamyloxy-4-phenylbut-3-enyllimidazole .
. . . . . - . . . . .
-,- . . .. .. - . . . . .
.. . .. .. . . . .
1-l2-~4-chlorocinnamyloxy)-4-phenylbut-3-enyl]imidazole 2-(4-phenylbutylthio)-4-phenylbut-3-enyl~imidazole 1-12-(3,4-dichlorophenylthio)-4-(4-chlorophenyl)but-3-enyl]imidazole 1-[2-(4-chlorophenoxy)-4-(4-chlorophenyl)but-3-enyl]
- imidazole .
l-t2-(2,4,5-trichlorophenylthio)-4-(4-chlorophenyl) but-3-enyl]imidazole -- . 1-[2-(2,3,4,5,6-pentachlorophenylthio)-4-(4-chlorophenyl) - - . but-3-enyl]imidazole 1-[2-~cinnamylthio)-4-(4-chlorophenyl)but-3-enyl]
. imidazole lS 1-[2-(4-chlorocinnamyloxy?-4-(4-chlorophenyl)but-3-enyl]imidazole ..
1-12-(4-chlorophenylthio)-4-(4-chlorophenyl)but-3-. enyllimidazole . 1-[2-(4-chlorobenzyloxy)-4-(4-chlorophenyl)but-3-enyl]
imidazole l-r2-(4-chlorobenzylthio)-4-(4-chlorophenyl)but-3-. enyl]imidazole 1-[2-(2,4-dichlorobenzyloxy)-4-(4-chlorophenyl)but-3-enyl]imidazole 1-[2-(2,4-dichlorophenylthio)-4-phenylbutyl]imidazole 1-[2-(4-chlorobenzylthio)-4-phenylbutyl]imidazole 1-[2-(4-chlorobenzyloxy-4-phenylbutyl]imidazole 1-[2-(4-chlorobenzylthio)-4-(4-fluorophenyl)butyl]-imidazole . . , - . .~
l-l2-(2,~-dichloro~cnzyl~hio)-~-t~-1uorophcnyl)l.u~yl~-~m~d~zolc (2~-dichlorophcnylthio)~ luorophcnyl)butyl]
; ~m~dazole . - ..
~, .
~ . . . .. .
. - , ... . ~ . .
' : ' ': ~, .' .
- . . . .
,, . . .. - . .
. ~: - . : ~ . -., . : . - : . . - . -.: . :. ..
.
..
~: . .
` - ~'` 1077493 EX~MPLE 7 Following the procedures in Preparations 3 or 4, and Examples 1; 2,3; or 2,4, using equivalent amounts of the appropriate starting materials~there may be obtained the following compounds. Where indicated, the compounds may be further characterized by conversion to the indicated acid addition salt.
~ 3-(4-chlorophenylthio)-3-(4-chlorophenyl)propyl]
imidazole - oxalate salt, m.p. 108-112C.
1-~3-(4-chlorobenzylthio)-3-(4-chlorophenyl)propyl~
imidazole - oxalate salt, m.p. 115-156C.
1-13-(4-chlorobenzyloxy)-3-(4-chlorophenyl)propyl~
imidazole - oxalate salt, m.p. 105-106C.
1-[3-(4-bromo-3-methylphenylthio)-3-(4-chlorophenyl) propyl]imidazole - nitrate salt, m.p. 107-108C.(dec.) 1-[3-(4-tert-butylphenylthio)-3-(4-chlorophenyl)propyl]
imidazole - oxalate salt, m.p. 127.5-129C.(dec.) 1-[3-(4-fluorophenylthio)-3-(4-chlorophenyl)propyl]
imidazole 1-[3-(4-bromobenzyloxy)-3-(4-chlorophenyl)propyl]
imidaæole 1-[3-(2,4-dichlorophenylthio)-3-(4-chlorophenyl)propyl]
imidazole 1-[3-(3,4-dichlorophenylthio)-3-(4-chlorophenyl) propyl]imidazole 1-[3-(4-trifluoromethylphenylthio)-3-(4-chlorophenyl) propyllimidazole 1-[3-(4-trifluoromethylbenzyloxy)-3-(4-chlorophcnyl) propyl]imid~zole 1-~3-(4-chlorocinnamylo~y)-3-(4-chlorophcnyl)propyl]
imidazole ` 1077493 1-[3-(2~4-dichlorocinnamylthio)-3-~4-chlorophenyl) propyl]imidazole 1-~3-(4-phenylbutyloxy)-3-(4-chlorophenyl)propyl]
imidazole 1-t3-(4-methylbenzylthio)-3-(2,4-dichlorophenyl)propyl~
` imidazole - nitrate salt, m.p. 69.5-75C. (dec.) 1-[3-(4-chlorobenzylthio-3-(2,4-dichlorophenyl)propyl]
imidazole - nitrate salt, m.p. 63-66.5C. (dec.) ~ 1-[3-(4-chlorophenylthio)-3-(2,4-dichlorophenyl)propyl]
imidazole- nitrate salt, m.p. 123.5-L25.5C. (dec.) l-t3-~2,4-dichlorophenylthio)-3-(2,4-dichlorophenyl) ; propyl]imidazole 1-13-(3,4-dichlorophenylthio)-3-~2,4-dichlorophenyl) propyl]imidazole -- 15 - 1-13-(4-trifluoromethylphenylthio)-3-(2,4-dichlorophenyl) propyl]imldazole 1-[3-(4-trifluoromethylbenzyloxy)-3-(2,4-dichlorophenyl) propyl]imidazole ; 1-13-(4-tert-butylphenylthio)-3-(2,4-dichlorophenyl) propyl]imidazole l-t3-(4-methylbenzyloxy)-3-(2,4-dichlorophenyl)propyl]
imidazole 1-[3-(4-chlorocinnamyloxy)-3-(2,4-dichlorophenyl) propyl~imidazole 1-13-(3,4-dichlorobenzyloxy)-3-(2,4-dichlorophenyl) propyl]imidazole 1-l3-(2~4~5-trichlorophenylthio)-3-(2~4-dichlorophcnyl) . propyl]imidazole 1-13-~4-phenylbutyltl-io)-3-(2,4-dichlorophenyl)propyl) imidazole .. . .
': . . ~. ` - ~ - .
` 1077493 1-13-(4-chlorobenzyloxy)-3-(2,4-dichlorophenyl) propyl]imidaæole l-t3-(2,4-dichlorobenzyloxy)-3-~2,4-dichlorophenyl)-propyl]imidazole S 1-13-(4-chlorophenylthio)-3-(4-tert-butylphenyl)propyl]
imidazole 1-[3-(2,4-dichlorobenzylthio)-3-(4-tert-butylphenyl) propyl]imidazole ... ...... . . , . , , . " , . , . . . . , .. , .. .. _ . .. .
- l-t3-(2,4,5-trichlorophenylthio)-3-t4-fluorophenyl) propyllimidazole - oxalate salt, coalesces 76C. final m.p. 99C.
1-[3-(4-chlorobenzylthio)-3-14-fluorophenyl)propyl]
imidazole 1-13-(4-tert-butylphenylthio)-3-(4-fiuorophenyl)propyl]
imidazole lS l-t3-(4-chlorocinnamyloxy~-3-(4-fluorophenyl)propyl]
imidazole 1-13-(4-chlorocinnamyloxy)-3-(2,4-dimethylphenyl) propyl]imidazole 1- r 3-(2,4-dichlorobenzylthio)-3-(2,4-dimethylphenyl) propyllimidazole 1-13-(4-`bromophenylthio)-3-~2,4-dimethylphenyl)propyl]
imidazole l-t3-(4-methylbenzylthio)-3-(4-tert-butylphenyl) propyllimidazole- nitrate salt, m.p. 132-134C. (dec.) 1-13-cinnamyloxy-3-(4-tert-butylphenyl)propyl]imidazole l-t3-(4-chlorophenylthio)-4-phenylbutyl]imidazole l-t3-(2,4-dichlorobenzylthio)-4-phenylbutyl]imidazole 3o .
... . ~ , .. . .
., : , - . . .
.
` .
.1-[3-(4-tert-butylphcnylthio)-4-phenylbutyl)imidazole , ' 1-[3-t4-chlorocinnamyloxy)-4-phenylbutyl]imidazole ~' ~ . . . .
- 5 1-[3-(2,4-dichlorophenylthio)-4-(4-chlorophenyl) : butyllimidazole 1-[3-(4-methylbenzylthio)-4-(4-chlorophenyl)butyl]
. imidazole . l-t3-~4-chlorobenzylthio)-4-(4-methylphenyl)butyl~
imidazole 1-13-(2,4-dichlorophenoxy)-4-(4-methylphenyl)butyl]
- . imidazole .. ..... _ ................ .... ,__ ._.. ..... .. . . ... . .
~ 3-(4-chlorocinnamyloxy)-4-(4-methylphenyl)butyl]
- ;. . imidazole .......................... ... ... ... .... ~........... .
~, ~ 15 1-13-(2,4-dichlorobenzylthio)-5-~4-chlorophenyl)pentyl]
imidazole . 1-13-(4-bromobenzyloxy)-5-(4-chlorophenyl)pentyl]
.~ , .
imidazole ~ 1-13-(g-chlorobenzylthio)-5-(4-chlorophenyl)pentyl]
"! 20 imidazole ~i 1-[3-(2,4,5-trichlorophenylthio)-5-(4-chlorophenyl) .' pentyl~imidazole 1-[3-(4-tert-butylbenzylthio)-5-(4-chlorophenyl) pentyl]imidazole ! . 1- [3-(3,4-dichlorophenylthio)-3-~2-trifluoromethyl-3 phenyl)propyl]imidazole ,~I 1-[3-(3,4-dichlorobenzylthio)-3-(2-trifluoromethyl-. . phenyl)propyl]imidazole .
' .1-[3-(4-chlorophenylthio)-3-~2,4-dibromophenyl)propyll 30 . imidazole . --.', ' ~f , .
_,S g_ , .... .. . .. . . . ....... .. ~ .
.. ,. .. . ~ . . . . .
1~77493 1-[3-(4-chlorophenylthio)-3-(2,4-difluorophenyl)-propyl]imidazole 1-[3-(4-fluorophenylthio)-3-(2,4-dichlorophenyl)-propyl]imidazole . 5 1-[3-4-(fluorobenzylthio)-3-(2,4-dichlorophenyl)-i propyl]imidazole.
, . ...... ., . , , ~ , . , . . . .. - . .
` ` -` 1C~77493 EXAMPL~ 8 .
Followlng the procedures in Preparation 4, and Examples 1; 2,3; or 2,4, using equivalent amounts of the appropriate starting materialstthere may be obtained the following compounds. Where indicated, the compounds may be further characterized by conversion to the indicated acid addition salt.
~ 1-14-(3,4-dichlorophenylthio)-4-(4-chlorophenyl)butyl]
imidazole - nitrate salt, m.p. 100-104.5C., oxalate salt m.p. 118-123C. (foaming) 1-14-~3,4-dichlorophenoxy)-4-(4-chlorophenyl3butyl]
imidazole - nitrate salt, m.p. 128-130.5C.
1-14-(4-chlorobenzylthio)-4-(4-chlorophenyl)butyl]
- lmidazole - nitrate salt, m.p. 123-125C. (foaming) l-t4-(2,4-dichlorobenzyloxy)-4-(4-chlorophenyl)butyl]
imidazole - nitrate salt, m.p. 91-114C.
.
1-[4-(3,4-dichlorobenzyloxy-4-(4-chlorophenyl) butyllimidazole ..
1-l4-(4-bromobenzylthio)-4-(4-chlorophenyl)butyl]
imidazole
4-(4-fluor~phenylthio)-4-(4-chlorophenyl)butyl]
imidazole 1-[4-(4-methylbenzyloxy)-4-(4-chlorophenyl)butyl]
imidazole l-t4-(4-chlorophenylthio)-4-(2,4-dichlorophenyl)butyl]
imidazole - oxalate salt, m.p. 69-75C, (foaming) 1-[4-(4-mcthylphenylthio)-4-(2,4-dichlorophenyl)butyl]
imidazole 1-t4-(4-chlorobcnzylthio)-4-(2,4-dichlorophQnyl)butyl]
imidazole - oxalate salt, m.p. 62.5-65C. (foaming) l-t4-bcnzylthio-4-(2,4-dichlorophenyl)b-ltyllimidazole . ' ' .
..
.
1-[4-~2,4-dichlorobcnzyloxy)-4-~2,4-dichlorophenyl) butyl]imidazole 1-[4-(4-chlorobenzyloxy)-4-(2,4-dichlorophenyl)butyl~
imidazole - nitrate salt, coalesces 98.5C., final m.p. 108C.
1-14-(4-phenylbutylthio)-4-(2,4-dichlorophenyl)butyl]
imidazole 1-[4-(4-fluorobenzylthio)-4-(2,4-dichlorophenyl) ; butyl]imidazole - oxalate salt, m.p. 95-101.5C.
4-(4-tert-butylphenylthio)-4-(4-fluorophenyl)butyl]
imidazole 1-14-(3,4-dichlorophenylthio)-4-(4-fluorophenyl)butyl]
imidazole 1-14-(4-tert-butylbenzyloxy)-4-(4-fluorophenyl)butyl]
imidazole - oxalate salt, m.p. 49.5-51C.
1-14-phenylpropylthio-4-(4-fluorophenyl)butyllimidazole-oxalate salt, m.p. 97-99C.
1-14-phenylthio-4-(4-tert-butylphenyl)butyl]imidazole nitrate salt, m.p. 121.5-123.5C.(dec.) 1-14-(4-chlorophenylthio)-4-(4-tert-butylphenyl)butyl]
imidazole 1-14-(2,4-dichlorobenzylthio)-4-(4-tert-butylphenyl) butyl]imidazole 1-[4-(4-fluorophenylthio)-4-(2,4-dimethylphenyl)butyll imidazole 1-14-cinnamyloxy-4-(2,4-dimethylphenyl)butyl]imidazole 1-14-(4-methylbenzylthio)-4-t4-bromophenyl)butyl]
imidazole - nitrate salt, m.p. 93-95C. (dec.) ~ 1-[4-(4-bromobenzyloxy)-4-(4-bromophenyl)butyl]imidazole _ ; 30 nitrate salt, m.p. 117-123.5C.
--51-- , .
.
1~77493 1-l4-~4-chlorophcnylthio)-5-phcnylpentyl]imidazole 4-(2,4-dichlorobenzylthio)-5-phenylpentyl]imidazole ' S i-14-~4-tert-butylphenoxy)-5-phenylpentyl~imidazole ' 1-14-(4-chlorocinnamyloxy)-5-phenylpentyl]imidazole l-t4-(2,4-dichlorophenylthio)-5-(4-chlorophenyl)pentylJ
imidazole 1-[4-(4-methylbenzylthio)-5-(4-chlorophenyl)pentyl]
. imidazole .
1-[4-(2,4-dichlorobenzylthio)-6-(4-chlorophenyl)hexyl]
. imidazole ï- 14-(4-bromobenzyloxy)-6-(4-chlorophenyl)hexyl]
imidazole 1-[4-(4-chlorobenzylthio)-6-(4-chlorophenyl)hexyl]
imidazole 1-14-(2,4,5-trichlorophenylthio-6-(4-chlorophenyl) .
hexyl]imidazole .
,v .. .. .
. ~: ~ , , .
.. . .
' - ' ' : ..
.
-: ' ~ : : .
` ``` 1077493 1-[4-~4-tert-butylbcnzylthio)-6-(4-chlorophenyl)hexyl]
imidazole l-t4-(4-trifluoromethylphenylthio)-6-(4-chlorophenyl) hexyl]imidazole 1-14-~4-trifluoromethylbenzyloxy)-6-(4-chlorophenyl) hexyl]imidazole .
l-t6-(2,i-dichlorobenzyloxy)-6-phenylhexyl]imidazole .
1-[6-(4-chlorobenzylthio)-6-phenylhexyllimidazole 1-[6-(4-methylphenylthio)-6-phenylhexyl]imidazole 1-[6-(4-chlorophenylthio)-6-phenylhexyl]imidazole ` ` ` ' 1-[6-(4-chlorobenzYloXY)-6-(4-chlorophenyl)hexyl]
imidazole 1-[6-benzylthi-6-(4-chlorophenyl)hexyl]imidazole l-~6-(4-fluorobenzylthio)-6-(4-chlorophenyl)hexyl]
imidazole -[6-(3,4-dichlorobenzyloxy)-6-(4-chlorophenyl) hexyl]imidazole 1-[6-cinnamyloxY-6-(4-chlorophenyl)hexyl]imidazole l-[6-~2~4-dichlorobenzyloxy)-7- (4-chlorophenyl)hept imidazole l-t6-(2,4-dichlorobenzylthio)-8-phenyloctyl]imidazole . . . . . . . .
1~774~3 1-l6-~4-chlorobenzyloxy)-lo-phenyldecyl]i.~idazole ~, .
~ 9-benzyloxy-9-phenylnonyl)imidazole S
l-t9-(4-fluorophenylthio)-9-phenylnonyl]imidazole l-[9-phenoxy-9-(4-chlorophenyl~nonyl]imidazole .
- 1-19-(2,4,5-trichlorobenzylthio)-9-(4-chlorophenyl) nonyl]imidazole l-[9-cinnamyloxy-9-(4-chlorophenyl)nonyl]imidazole ~'~ 1-[9-~2,4-dichlorobenzyloxy)-10-(4-chlorophenyl)decyl3 15 imidazole i ~ . .
~,~ . 1-19-(2 4-dichlorobenzylthio)-11-phenylundecyl]imida-:~ . zole . ~ . .- - . . . .
1-19-~4-chlorobenzyloxy)-13-phenyltridecyl]imidazole t4-(4-fluorophenylthio)-4-(2,4-dichlorophenyl)butyl]-imidazo1e~
:~, o ~.
. . , . ., ~,....................... . .
;~' -'. ' ~ ~ ;.. - .
.
~, - . -.
:'' .
.. . .
.: - . -- - - .
1~77493 EX~MPLE 9 Nitric acid (70%; d = 1.42) was added dropwise to a stirred solution of 2.0 g. of 1-~2-(2,~-dichlorobenzyloxy)-4-phenylbutyl]imidazole in 30 ml. of anhydrous ether until precipitation was complete. The product was filtered off, washed with ether, air dried, and recrystallized from ethyl acetate to yield l-~2-(2,4-dichlorobenzyloxy)-4-phenylbutyl]
imidazole nitrate, m.p. 121-124C.
. . .
In similar manner, all compounds of Formula (I) in base form can be converted to their antimicrobial acid addition salts ; by treatment with the appropriate acid, for example, hydro-chloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid! malic acid, maleic acid, fumaric acid, .
tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid or salicylic acid.
~ .. . . . . .
~ . ~ . . . . .
: . : .. ... .
. . , .. : , .
. . . . . , .. : - . -. .. : ~ . . - .. . . .-. ~ , . . ~ - , . - . : .. - :
` 1~77493 '' , ' , 1-12-(2,4-Dichlorobenzyloxy)-4-phenylbutyl]imidazole nitrate (2.0 g.) in 100 ml. of dichloromethane was shaken S with excess dilute potassium carbonate solution until the salt was completely dissolved. The organic layer was then separated, washed twice with water, dried over masnesium sulfate and evaporated to yield l-t2-~2,4-dichlorobenzyloxy-~ 4-phenylbutyl]imidazole as an oil.
In similar manner, the antimicrobial acid addition ; salts of all compounds of Formula (I) can be conve~ted to the corresponding compounds in base form.
~ ' ' .~
:s :.
. ., , . ,. , ~ ~
,: ~
~077493 The following illustrates the preparation of represen-tative pharmaceutical formulations which may be used for controlling fungi, bacteria and protozoa, utilizing an active compound such as a salt of 1-[2-t3,4-dichlorophenylthio)-4-phenylbutyl]imidazole.
A Topical Formulation .
~rams Active compound 0.2 - 2 Span 60 2 Tween 60 2 Mineral oil 5 Petrolatum 10 Methyl paraben 0.15 Propyl paraben 0.05 BHA (butylated hydroxy anisole) 0.01 Water qs 100 All of the above ingredients, except water, are combined and heated at 60C, with stirring. A sufficient quantity of ; 20 water at 60C. is then added with vigorous stirring to pro-vide lOO g. of the cream formulation which is then cooled, , to room temperature.
.
~ B. I.V. Formulation .
, Active compound 0.5 g.
Propylene glycol 20 g.
Polyethylene glycol 400 20 g.
~ Tween 80 (trademark)1 g~
- 0.9 Saline solution qs100 ml.
The active compound is dissolved in propylene glycol, polyethylene glycol 400 and Tween 80. A sufficient quantity ~ .
; 6 ~;'' -.
~'. ~` ,.
- ', , ~ 077493 of 0.9~ saline solution is then added with stirring to pro-vide 100 ml. of the I.V. solution which is filtered through a 0.2 micron membrane filter and packaged under sterile conditions.
C. Oral Formulation parts b~ weight Active compound 200 Magnesium stearate 3 Starch 30 Lactose 116 PVP (polyvinylpyrrolidone) 3 The above ingredients are combined and granulated using methanol as the solvent. The formulation is then dried and formed into tablets (containing 200 mg. of active compound) with an appropriate tabletting machine.
: - - .
:
: -'~
:
' ~ :
EXAMpLE 12 .
.
The anti-fungal activity of certain compounds of the present invention is illustrated by the following assay pro-cedure.
Test organisms were:
1. Candida albicans (ATCC 10231) - C.a.l , 2. Candida albicans (ATCC 14053) - C.a.2 3. Epidermophxton floccosum (ATCC 15693) - E.f.
., 4. Trichophyton mentagrophytes (ATCC 11481)- T.m.
imidazole 1-[4-(4-methylbenzyloxy)-4-(4-chlorophenyl)butyl]
imidazole l-t4-(4-chlorophenylthio)-4-(2,4-dichlorophenyl)butyl]
imidazole - oxalate salt, m.p. 69-75C, (foaming) 1-[4-(4-mcthylphenylthio)-4-(2,4-dichlorophenyl)butyl]
imidazole 1-t4-(4-chlorobcnzylthio)-4-(2,4-dichlorophQnyl)butyl]
imidazole - oxalate salt, m.p. 62.5-65C. (foaming) l-t4-bcnzylthio-4-(2,4-dichlorophenyl)b-ltyllimidazole . ' ' .
..
.
1-[4-~2,4-dichlorobcnzyloxy)-4-~2,4-dichlorophenyl) butyl]imidazole 1-[4-(4-chlorobenzyloxy)-4-(2,4-dichlorophenyl)butyl~
imidazole - nitrate salt, coalesces 98.5C., final m.p. 108C.
1-14-(4-phenylbutylthio)-4-(2,4-dichlorophenyl)butyl]
imidazole 1-[4-(4-fluorobenzylthio)-4-(2,4-dichlorophenyl) ; butyl]imidazole - oxalate salt, m.p. 95-101.5C.
4-(4-tert-butylphenylthio)-4-(4-fluorophenyl)butyl]
imidazole 1-14-(3,4-dichlorophenylthio)-4-(4-fluorophenyl)butyl]
imidazole 1-14-(4-tert-butylbenzyloxy)-4-(4-fluorophenyl)butyl]
imidazole - oxalate salt, m.p. 49.5-51C.
1-14-phenylpropylthio-4-(4-fluorophenyl)butyllimidazole-oxalate salt, m.p. 97-99C.
1-14-phenylthio-4-(4-tert-butylphenyl)butyl]imidazole nitrate salt, m.p. 121.5-123.5C.(dec.) 1-14-(4-chlorophenylthio)-4-(4-tert-butylphenyl)butyl]
imidazole 1-14-(2,4-dichlorobenzylthio)-4-(4-tert-butylphenyl) butyl]imidazole 1-[4-(4-fluorophenylthio)-4-(2,4-dimethylphenyl)butyll imidazole 1-14-cinnamyloxy-4-(2,4-dimethylphenyl)butyl]imidazole 1-14-(4-methylbenzylthio)-4-t4-bromophenyl)butyl]
imidazole - nitrate salt, m.p. 93-95C. (dec.) ~ 1-[4-(4-bromobenzyloxy)-4-(4-bromophenyl)butyl]imidazole _ ; 30 nitrate salt, m.p. 117-123.5C.
--51-- , .
.
1~77493 1-l4-~4-chlorophcnylthio)-5-phcnylpentyl]imidazole 4-(2,4-dichlorobenzylthio)-5-phenylpentyl]imidazole ' S i-14-~4-tert-butylphenoxy)-5-phenylpentyl~imidazole ' 1-14-(4-chlorocinnamyloxy)-5-phenylpentyl]imidazole l-t4-(2,4-dichlorophenylthio)-5-(4-chlorophenyl)pentylJ
imidazole 1-[4-(4-methylbenzylthio)-5-(4-chlorophenyl)pentyl]
. imidazole .
1-[4-(2,4-dichlorobenzylthio)-6-(4-chlorophenyl)hexyl]
. imidazole ï- 14-(4-bromobenzyloxy)-6-(4-chlorophenyl)hexyl]
imidazole 1-[4-(4-chlorobenzylthio)-6-(4-chlorophenyl)hexyl]
imidazole 1-14-(2,4,5-trichlorophenylthio-6-(4-chlorophenyl) .
hexyl]imidazole .
,v .. .. .
. ~: ~ , , .
.. . .
' - ' ' : ..
.
-: ' ~ : : .
` ``` 1077493 1-[4-~4-tert-butylbcnzylthio)-6-(4-chlorophenyl)hexyl]
imidazole l-t4-(4-trifluoromethylphenylthio)-6-(4-chlorophenyl) hexyl]imidazole 1-14-~4-trifluoromethylbenzyloxy)-6-(4-chlorophenyl) hexyl]imidazole .
l-t6-(2,i-dichlorobenzyloxy)-6-phenylhexyl]imidazole .
1-[6-(4-chlorobenzylthio)-6-phenylhexyllimidazole 1-[6-(4-methylphenylthio)-6-phenylhexyl]imidazole 1-[6-(4-chlorophenylthio)-6-phenylhexyl]imidazole ` ` ` ' 1-[6-(4-chlorobenzYloXY)-6-(4-chlorophenyl)hexyl]
imidazole 1-[6-benzylthi-6-(4-chlorophenyl)hexyl]imidazole l-~6-(4-fluorobenzylthio)-6-(4-chlorophenyl)hexyl]
imidazole -[6-(3,4-dichlorobenzyloxy)-6-(4-chlorophenyl) hexyl]imidazole 1-[6-cinnamyloxY-6-(4-chlorophenyl)hexyl]imidazole l-[6-~2~4-dichlorobenzyloxy)-7- (4-chlorophenyl)hept imidazole l-t6-(2,4-dichlorobenzylthio)-8-phenyloctyl]imidazole . . . . . . . .
1~774~3 1-l6-~4-chlorobenzyloxy)-lo-phenyldecyl]i.~idazole ~, .
~ 9-benzyloxy-9-phenylnonyl)imidazole S
l-t9-(4-fluorophenylthio)-9-phenylnonyl]imidazole l-[9-phenoxy-9-(4-chlorophenyl~nonyl]imidazole .
- 1-19-(2,4,5-trichlorobenzylthio)-9-(4-chlorophenyl) nonyl]imidazole l-[9-cinnamyloxy-9-(4-chlorophenyl)nonyl]imidazole ~'~ 1-[9-~2,4-dichlorobenzyloxy)-10-(4-chlorophenyl)decyl3 15 imidazole i ~ . .
~,~ . 1-19-(2 4-dichlorobenzylthio)-11-phenylundecyl]imida-:~ . zole . ~ . .- - . . . .
1-19-~4-chlorobenzyloxy)-13-phenyltridecyl]imidazole t4-(4-fluorophenylthio)-4-(2,4-dichlorophenyl)butyl]-imidazo1e~
:~, o ~.
. . , . ., ~,....................... . .
;~' -'. ' ~ ~ ;.. - .
.
~, - . -.
:'' .
.. . .
.: - . -- - - .
1~77493 EX~MPLE 9 Nitric acid (70%; d = 1.42) was added dropwise to a stirred solution of 2.0 g. of 1-~2-(2,~-dichlorobenzyloxy)-4-phenylbutyl]imidazole in 30 ml. of anhydrous ether until precipitation was complete. The product was filtered off, washed with ether, air dried, and recrystallized from ethyl acetate to yield l-~2-(2,4-dichlorobenzyloxy)-4-phenylbutyl]
imidazole nitrate, m.p. 121-124C.
. . .
In similar manner, all compounds of Formula (I) in base form can be converted to their antimicrobial acid addition salts ; by treatment with the appropriate acid, for example, hydro-chloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid! malic acid, maleic acid, fumaric acid, .
tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid or salicylic acid.
~ .. . . . . .
~ . ~ . . . . .
: . : .. ... .
. . , .. : , .
. . . . . , .. : - . -. .. : ~ . . - .. . . .-. ~ , . . ~ - , . - . : .. - :
` 1~77493 '' , ' , 1-12-(2,4-Dichlorobenzyloxy)-4-phenylbutyl]imidazole nitrate (2.0 g.) in 100 ml. of dichloromethane was shaken S with excess dilute potassium carbonate solution until the salt was completely dissolved. The organic layer was then separated, washed twice with water, dried over masnesium sulfate and evaporated to yield l-t2-~2,4-dichlorobenzyloxy-~ 4-phenylbutyl]imidazole as an oil.
In similar manner, the antimicrobial acid addition ; salts of all compounds of Formula (I) can be conve~ted to the corresponding compounds in base form.
~ ' ' .~
:s :.
. ., , . ,. , ~ ~
,: ~
~077493 The following illustrates the preparation of represen-tative pharmaceutical formulations which may be used for controlling fungi, bacteria and protozoa, utilizing an active compound such as a salt of 1-[2-t3,4-dichlorophenylthio)-4-phenylbutyl]imidazole.
A Topical Formulation .
~rams Active compound 0.2 - 2 Span 60 2 Tween 60 2 Mineral oil 5 Petrolatum 10 Methyl paraben 0.15 Propyl paraben 0.05 BHA (butylated hydroxy anisole) 0.01 Water qs 100 All of the above ingredients, except water, are combined and heated at 60C, with stirring. A sufficient quantity of ; 20 water at 60C. is then added with vigorous stirring to pro-vide lOO g. of the cream formulation which is then cooled, , to room temperature.
.
~ B. I.V. Formulation .
, Active compound 0.5 g.
Propylene glycol 20 g.
Polyethylene glycol 400 20 g.
~ Tween 80 (trademark)1 g~
- 0.9 Saline solution qs100 ml.
The active compound is dissolved in propylene glycol, polyethylene glycol 400 and Tween 80. A sufficient quantity ~ .
; 6 ~;'' -.
~'. ~` ,.
- ', , ~ 077493 of 0.9~ saline solution is then added with stirring to pro-vide 100 ml. of the I.V. solution which is filtered through a 0.2 micron membrane filter and packaged under sterile conditions.
C. Oral Formulation parts b~ weight Active compound 200 Magnesium stearate 3 Starch 30 Lactose 116 PVP (polyvinylpyrrolidone) 3 The above ingredients are combined and granulated using methanol as the solvent. The formulation is then dried and formed into tablets (containing 200 mg. of active compound) with an appropriate tabletting machine.
: - - .
:
: -'~
:
' ~ :
EXAMpLE 12 .
.
The anti-fungal activity of certain compounds of the present invention is illustrated by the following assay pro-cedure.
Test organisms were:
1. Candida albicans (ATCC 10231) - C.a.l , 2. Candida albicans (ATCC 14053) - C.a.2 3. Epidermophxton floccosum (ATCC 15693) - E.f.
., 4. Trichophyton mentagrophytes (ATCC 11481)- T.m.
5. Microsporum gypseum (ATCC 14683) - M.g.
Organisms 1 and 2 are generally classified as yeast-like organisms and 3, 4 and 5 are dermatophytes. Because of their different characteristics there were some differences in how these were handled, Incubation of all organisms was in roller drum tubes containing 5 ml of medium incubated at 25C.
, Test compounds were dissolved in 0.6 ml of dimethyl sulfoxide, ethanol or sterile distilled water and to these solutions 30 ml of sterile Sabouraud Dextrose Broth was added to produce the first level of compound desired. Ali- ' quots of these stock solutions were appropriately diluted with sterile Sabouraud Dextrose Broth (Difco). Generally, dilutions were in geometric progressions, e.g., 300, 100, 30, 10, 3 and 1 ~g/ml. Approximately 5 ml of each dilution was added to each sterile test tube (16 mm) and tubes were innocu-lated with two drops of inoculum, Tubes were incubated under , aerobic conditions by roller drum agitation at 25C, For inocula, yeasts were transferred from Sabouraud Dextrose Agar (Difco) slants to Sabouraud Dextrose Broth and - 6b-.. . . ..
1C~77493 incubated ~t 25C oYerni~ht. Two drops of one-tenth dilutions ; of these 16 hour-old cultures were used as inocula for each ; tube, Stocks of dermatophytic fungi were cultured on Sabouraud Dextrose Agar or Neutral Wort Agar slants that had been incu--S
bated at 25C for at least four weeks. Approximately 10 ml of 0.7% sodium chloride solution was added to the agar slants and suspensions were made by scraping the agar surface and vortexing the suspensions, These suspensions were filtered through two layers of sterile stainless steel funnels (40 x 40 mesh and 100 x 100 mesh). This procedure separated parti-' cles of agar and fungal mycelium on agar from the spores that were réquired for the test. After microscopic examination for suitability of inocula, two drops of these suspensions ' - were added to various dilutions of the test compiunds in Sabouraud Dextrose Broth.
Fungistatic endpoints, that is, the concentrations at which growth was prevented, were determined by visualization and reported as minimal inhibitory concentrations (MIC) in ~g/ml. Yeast readings were made after three days' incubation, endpoints with fungi 4 and 5 were determined after five days' incubation and with organism 3, determinations were made after seven days' incubation.
MIC (~g/ml) 1-13-(4-chlorobenzylthio)-3-(2,4-dichlorophenyl)propyl]-imidazole nitrate ,, .
q~ E.f. - < 0.1 -~l C.a.2 .
,' ' ~
-56c-,, .
~ ~ .
1-[3-(4-methylbenz~lthio)-3-(2~4-dichloropheny1)prop~1]-imidazole nitrate _ ~ . . . . . . . . .
E~f, ~ < 0.1 C.a,2 1-[3-(4-chlorophenylthio)-3-(2 r 4-dichlorophenyl)propyl]-imidazole nitrate-E,f. - 0.3 ~ C.a,2 - 1 : 10 1-[3-(4-tert-butylphenylthio)-3-(4-chlorophenyl)propyl]-_ imidazole oxalate T.m.
C.a.l - 10 C.a.2 - 10 1-[3-(4-bromo-3-methylphenylthio)-3-(4-chlorophenyl)propyl~-~ imidazole nitrate - -- - ---; T.m, - 1 C.a.l - 10 C.a,2 - 10 1-[2-(4-chlorobenzylthio)-4-(4~chlorophenyl)butyl]-imidazole oxalate -._ M.g. - 3 E.~. - <0.1 C.a.l - 3 C.a.2 - 3 ., .
.' ' ~
~ -56d~
.
.. .
1-~2~(3,4-dichlorophenylthio~4-~4-chlorophenyl)butyl]- -imidazole nitrate ;
... . . .
- M,~. ~ 3 : E.f, ~ <0.1 C.a,l ~ 3 C.a.2 - 3 .
1-[2-(4-chlorophenylthio)-4-(4-chlorophenyl)butyl~-imidazole nitrate M~g. _ 3 E.f. - <0.1 C.a,l - 3 C.a.2 ~ 3 1-[2~(3,4-dichlorophenylthio)-4-phenyibutyl]-imidazole oxalate . . .
C.a.l - 3 C.a.2 - 3 ' ' . . .
1-[4-(3,4~dichlorophenylthio)-4-~4-chlorophenyl)butyl]-imidazole nitrate M.g~ - 3 T.m.
; 1-[4-(4-chlorobenzylthio)-4-(4~chlorophenyl)butyl]-imidazole nitrate C.a.l - 10 . 1-[4-(2,4-dichlorobenzyloxy)-4-(4-chlorophenyl)butyl]-imidazole nitrate ' -, T.m. _ 3 -56e-1-[4-~4-chlorobenz~lox~)-4-(2r4-dichloroDhen~l)but~l]-imidazole nitrate _ T~m, ~ 1 1-~4-(4-chlorobenzylthio)-4-(2,4-dichlorophenyl~butyl]-imidazole nitrate -C.a.2 - 10 1-[4-(4-chlorophenylthio)-4-(2,4-dichlorophenyl)butyl]-imidazole oxalate C.a.2 - 10 ,; .
.
.. . . .. . . .. , , . . - ,.
, . . , . : ~ . - -- , . . .- ,,: - .
.... . ' ' . ' . '.
SUPPLEMENTARY DISCLOSURE
The present invention relates to 1-[2-(halo-phenylthio)-4-(p-chloro- or -fluorophenyl)-n-butyl] imidazoles and to processes for the preparation thereof. These compounds are useful as antifungal, antibacterial and antiprotozoal agents.
The preceeding principal dislcosure discloses a class of certain substituted N-alkyl imidazole compounds represented by the following generic formula:
R - 7H- ( CH2 ) n ~ N N
. X- R \~/
.
: (A) wherein Rl and R2 are each independently phenyl, phenyl ~ straight chain lower alkyl, or phenyl straight chain lower - 15 alkenyl; or one of the above substituted in the phenyl ring with one or more substituents independently selected from the group consisting of lower alkyl of from one to four carbon ,~
atoms, halo and trifluoromethyl; X is oxygen or sulfur; n .
is an integer of from 1 to 8 with the proviso that n is not 1 when Rl is phenyl or substituted phenyl; and the anti-microbial acid addition salts thereof. The class of compounds represented by the above formula plus salts thereof are ;~ described to exhibit antifungal, antibacterial and antipro-~`~ tozoal activity.
: -~::
Now it has been discovered that a group of compounds of the above class are particularly active. This group of compounds, as a highly active class different from that disclosed earlier and represented by Formula (A) above, is characterized by the following formula:
~ 30 ': .
~ - 57 -: \
: :`` ``` 1077493 .` X~ CH2-C~I2-F~I-CH2-`. S
;~ \~Yn : 5 ~I) '.'' ~:
.-: and the antimicrobial acid addition salts thereof, :
~:. wherein X is chloro or fluoro, each Y is bromo or chloro ~
~ ;.............................................. .
or fluoro, at least one Y being in the 2'-position, n is .: 10 1 to 5 when Y is chloro, and n is 1 or 2 when Y is other `: than chloro.
~ Preferred groups of compounds hereof are those of :~ the formulas: .
' .~: ', , ':
. ~. 15 X ~ 2 C~2 FE~ CH2-N ~ :
,- . . S
.~., ~,~ . .
. (Ia) ~ Wm .,: . .
~ 20 X ~ CH2-C~2-l~-CH2-N ~
.," , ~
: ; (Ib) Z ~ : .
and the antimicrobial acid addition salts thereof, wherein X is chloro or fluoro, each W is bromo or chloro or fluoro, at least one W being in the 2'-position, m is 1 to -.
;: 4 when W is chloro, m is 1 or 2 when W is other than chloro, !, j, ' each Z is bromo or chloro or fluoro, p is 0 to 3 when Z is . chloro, and p is O when Z is other than chloro.
~ 30 Particularly preferred of the compounds of Formulas (I), :~ .
. -:: ~7 . ~ .
.. . .
``` 1~77493 ~Ia) and (Ib), and the antimicrobial acid addition salts there-of, are those wherein n is 1 to 3 or m is 1 to 3 or p is 0 or 1 (Y or W or Z being chloro when n is 1 to 3, m is 1 to 3, or p is 1 and being other than chloro when n is 1 or 2, m is 1 or 2, or p is O) and those thereof wherein X is chloro, or when X is fluoro, then Y (or W or Z) is chloro. Further preferred are those wherein X and Y (or W or Z) are chloro. Particularly pre-ferred of the latter are those wherein n is 2, m is 2 or p is 0 and those thereof wherein the two (Y or ~ or Z) chloro groups are in the 2',6'-positions of the phenyl ring. Thus, particularly preferred is the compound l-[2-(2,6-dichloro-phenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole, as well as the antimicrobial acid addition salts thereof.
The compounds of the present invention characterized by-Formulas (I), (Ia) and (Ib) above, and the defined salts thereof, are distinguished by the discovery that certain specific molecular features provide a highly active class of compounds. These features are defined by 1) a 1,4-butylene chain linking the imidazole moiety and a p-chloro- or -fluoro-phenyl moiety, 2) a halophenylthio moiety attached to the C-2 carbon of the 1,4-butylene chain counting from the imidazole moiety and, most notably, 3) at least one halo being in the 2'-position of the phenyl ring in the halophenylthio ~25 moiety. This combination of features provides a surprisingly ; highly active, different class of compounds.
In a secondaspect the present invention is concerned with a method of combatting fungi, bacteria and protozoa by administering a compound of the present invention or a compo-sition containing same.
As used in the specification and the appended claims,unless specified to the contrary, the following terms have ~0774.93 the meaning indicated. The term "halo" refers to bromo, -chloro and fluoro. "Antimicrobial acid addition salts" of the subject bases refers to those salts which retain the anti-microbial properties of the free bases and which are neither biologicallynor otherwise undesirable, formed with, for example, inorganic acids such as hydrochloric acid, hydro-bromic acid, sulfuric acid, nitric acid or phosphoric acid;
or inorganic acids such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, `10 succinic acid, malic acid, maleic acid, fumaric acid, tar-taric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
All compounds of Formula (I) possess at least one chiral center, i.e., the carbon atom to which are attached the S, H and two CH2 moieties. Accordingly, the compounds of the present invention may be prepared in either optically active form, or as a racemic mixture. Unless otherwise ~ -r! specified, the compounds described herein are all in the racemic form. However, the scope of the subject invention herein is not to be considered limited to the racemic form, - --but to encOmpass theindividual optical isomers of the subject compounds, and various mixtures thereof.
~! If desired, racemic intermediates or final products ; 25 prepared herein may be resolved into their optical antipodes by conventional resolution means known per se, for example, by the separation (e.g., fractional crystallization) of the diastereomeric salts formed by reaction of, e.g., racemic compounds of Formula (I) with an optically active acid, or by the separation of the diastereomeric salts or esters formed by reaction of racemic compounds of Formula (II), infra, ~ , , .
.. . . . .
.. , , ~
1~77493 with an optically active acid. Exemplary of such optically active acids are the optically active forms of camphor-10-sulfonic acid, ~-bromo-camphor-~-sulfonic acid, camphoric acid, menthoxy-acetic acid, tartaric acid, malic acid, diacetyltartaric acid, pyrrolidone-5-carboxylic acid, and the like. The separated pure diastereomeric salts or esters may then be cleaved by standard means to afford the respec-tive optical isomers of the compounds of Formula (I) or (II).
The subject compounds of Formula (I) exhibit anti-fungal, anti-bacterial and anti-protozoal activity. For example, compounds of the present invention exhibit anti-fungal activity against human and animal pathogens such as Microsporum audouini, Microsporum gypseum, Microsporum gypseum - canis, Epidermophyton floccosum, Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton tonsurans, Candida albicans, and Cryptococcus neoformans.
The compounds of the present invention also exhibit anti-fungal activity against the following fungi primarily of agri-; cultural significance Aspergillus flavus, Aspergillus niger, Cladosporium herbarum, Penicillium oxalicum, Fusarium graminearum, Penicillium spinulosum, Penicillium notatum, and Pithomyces chartarum.
In addition, the compounds of the present invention exhibit 30 anti-bacterial activity against human and animal pathogens, such "~
as Staphylococcus aureus, Streptococcus faecalis, Corynebacterium acnes, Erysipelothrix insidiosa, Escherichia coli, Proteus vulgaris, 'Salmonella choleraesuis, Pasteurella multocida, and Pseudomonas aeruginosa.
Moreover, the compounds of the present invention exhibit anti-protozoal activity against protozoa such as Trichomonas vaginalis and Trichomonas foetus. -In general, the subject compounds of the instant invention exhibit a low level of toxicity. Moreover, these compounds ' demonstrate good solubility in the stratum corneum. Since dermatophyte (i.e., parasitic fungal) infections are usually localized in the dead tissue of the stratum corneum, solubility of anti-fungal agents in this tissue significantly enhances their effectiveness.
In view of the aforementioned activities, the subject compounds are found to be useful antimicrobials, having not only pharmaceutical but also agricultural and industrial application.
~ccordingly, a further aspect of thepresent invention relates to compositions for pharmaceutical, agricultural, and industrial use, which compositions comprise the subject ., .. . - - . -.
', - ' : ., .. . . .. ,; - . - ..
. .
: . .
- ~ ' : ~: : .
`I ` ~` . .
compounds of formula (I) in combination with a suitable carrier. A still further aspect of the present invention ` relates to methods of inhibiting the growth of fungi, bacteria and protozoa by applying to a host object containing, or S subject to attack by, fungi, bacteria or protozoa, an effective amount of a compound of the present invention or a suitable composition containing same.
In pharmaceutical applications, compositions may be solid, semi-solid or liquid in form such as tablets, cap-sules, powders, suppositories, liquid solutions, suspensions, creams, lotions, ointments and the like. Pharmaceutically acceptable non-toxic carriers, or excipients normally employed for solid formulationsinclude tricalcium phosphate, calcium carbonate, koalin, bentonite, talcum, gelatin, lactose, starch and the like; for semi-solid formulations there may be mentioned, for example, poly-alkylene glycols, vaseline and other cream bases; for liquid formulations there may be mentioned, for example, water, oils of vege-table origin and low boiling solvents such as isopropanol, hydrogenated naphthalenes and the like. The pharmaceutical compositions containing the compounds of the present invention may be subjected to conventional pharmaceutical expedients such as sterilization and can contain conventional pharmaceutical excipients such as preservatives, stabilizing agents, emulsifying agents, salts for the adjustment of osmotic pressure and buffers. The compositions may also contain other therapeutically active materials. In pharma-ceutical applications, the subject compounds and composi-tions may be administered to humans and animals by conven-tional methods, e.g. topically, orally, parenterally and 10~7493 the like. Parenteral administration includes intramuscular as well as subcutaneous and intravenous administration.
Intravenous injection of imidazole-type anti-fungals has been demonstrated to be effective in the treatment of systemic mycoses (see for example, Drugs 9, pp. 419-420, 1975, which described the intravenous administration of miconazole, i.e. 1-[2,4-dichloro-~-(2',4'-dichlorobenzyloxy)phenethyl]-imidazole nitrate, to patients with systemic candidiasis).
Topical application is the preferred method of administration for pharmaceutical applications. For such treatment, an area having an existing fungal, bacterial or protozoal growth, or to be protected against attack by fungi, bacteria or protozoa, may be treated with the subject compounds o~
compositions by, for example, dusing, sprinkling, spraying, rinsing, brushing, dipping, smearing, coating, impregnating and the like. Topical pharmaceutical compositions containing the compounds of the present invention exhibit anti-fungal `
anti-bacterial and anti-protozoal activity over a wide range of concentration, for example, from about 0.1 to 10.0%
by weight of the composition. In any event, the composition to be administered will contain a quantity of the subject compound in an amount effective for relief or prevention of the specific condition being treated.
The pharmaceutical compositions hereof typically com-prise one or more subject compounds of Formula (I) and a pharmaceutically acceptable, non-toxic carrier, and are preferably formulated in unit dosage form to facilitate administration (unit dosage being the amount of active ingredient administered on one occasion).
In general, for systemic (e.g. oral or parenteral) 1~77'~93 administration it is expedient to administer the active ingredient in amounts between about 1 and 100 ms/kg. body weight per day, preferably between about 5 and 50 mg/kg body weight per day; preferably distributed over several applications (e.g., in 3 individual doses) in order to achieve most effective results. For localized (e.g. topical) administra-tion, however, proportionately less of the active ingredient is required.
The exact regimen for pharmaceutical administration of the compounds and compositions disclosed herein will necessarily be dependent upon the needs of the individual subject being treated, the type of treatment, e.g., whether preventative or curative, the type of organism involved and, of course, the judgment of the attending practitioner.
In agricultural applications, the subject compounds may be applied directly to plants (e.g. seeds, foliage) or to soil. For example, compounds of the present invention may be applied to seeds alone or in admixture with a powdered solid carrier. Typical powdered carriers are the various mineral silicates, e.g. mica, talc, pyrophyllite, and clays. The subject compounds may also be applied to the seeds in admixture with a conventional surface-active wetting agent with or without additional solid carrier.
Surface-active wetting agents that can be used are any of.
.. . .. . .. . . .
- .: : . :: : : : . : : ~ . -: . . : . , - : : .. .. .
., ,: . . , .. ~, ,. ., , ~ , :
::: :, - . . . , ~. : . , . , : ' . . , -~ :,, ' ' : ' :
the conventional anionic, non-anionic or cationic types.
As a soil treatment for fungi and the like, the subject compounds can be applied as a dust in admixture with sand, soil or a powdered solid carrier such as a mineral silicate with or without additional surface-active agent, or the subject compounds can be applied as an aqueous spray optionally containing a surface-active dispersing agent and - a powdered solid carrier. As a foliage treatment, the sub-ject compounds may be applied to growing plants as an aqueous spray which contains a surface-active dispersing agent with or without a powdered solid carrier and hydro-carbon solvents.
In industrial applications, the subject compounds may be u~ed to control bacteria and fungi by contacting the pathogens with the compounds in any known manner. Materials capable of supporting bacteria and fungi may be protected by contacting, mixing or impregnating these materials with the subject compounds. In order to increase their effect, the subject compounds may be combined with other pesticidal control agents such as fungicides, bactericides, insecti-cides, miticides and the like. A particularly important industrial/agricultural use for the subject compounds of the present invention is as a food preservative against bacteria and fungi which cause deterioration and spoilage of foods.
., :
:
~077493 The compounds of Formula (I) may be prepared by forming a thioether from a suitable alcohol of Formula (II) X ~CH2-CH2-CH-CH2-N~N
(II) wherein X is as defined above. Compounds of Formula (II) may be prepared by a variety of reaction sequences.
'For example, compounds of Formula (II) may be prepared by reaction Scheme A shown below.
Reaction Scheme A
10X ~ 2 2 ~ X ~ CH2-CH2-cH-cH2 (IV) ~ (III) ~15~ H2-CH2-CH CH2 X ~ 2 CH2 fH-CH2-N ~N
OH
(V) (II) wherein X is as defined above .~ . .
, In this reaction scheme the imidazole alcohol of Formula (II) is formed by opening of a terminal epoxide of Formula (III) with imidazole. This reaction is generally carried out using at least one mole and preferably an excess of imidazole -relative to epoxide optionally in the presence of a salt (preferably an alkali metal salt) of imidazole. The reaction may either be carried out in the absence of solvent or, preferably, in an inert organic solvent, for example, a solvent suchas dimethylformamide, hexamethylphosphoramide, acetonitrile, ;
and the like. The temperature normally employed for such ~;
epoxide opening is in the range of from about -20 to about 100C.
:: . .
Organisms 1 and 2 are generally classified as yeast-like organisms and 3, 4 and 5 are dermatophytes. Because of their different characteristics there were some differences in how these were handled, Incubation of all organisms was in roller drum tubes containing 5 ml of medium incubated at 25C.
, Test compounds were dissolved in 0.6 ml of dimethyl sulfoxide, ethanol or sterile distilled water and to these solutions 30 ml of sterile Sabouraud Dextrose Broth was added to produce the first level of compound desired. Ali- ' quots of these stock solutions were appropriately diluted with sterile Sabouraud Dextrose Broth (Difco). Generally, dilutions were in geometric progressions, e.g., 300, 100, 30, 10, 3 and 1 ~g/ml. Approximately 5 ml of each dilution was added to each sterile test tube (16 mm) and tubes were innocu-lated with two drops of inoculum, Tubes were incubated under , aerobic conditions by roller drum agitation at 25C, For inocula, yeasts were transferred from Sabouraud Dextrose Agar (Difco) slants to Sabouraud Dextrose Broth and - 6b-.. . . ..
1C~77493 incubated ~t 25C oYerni~ht. Two drops of one-tenth dilutions ; of these 16 hour-old cultures were used as inocula for each ; tube, Stocks of dermatophytic fungi were cultured on Sabouraud Dextrose Agar or Neutral Wort Agar slants that had been incu--S
bated at 25C for at least four weeks. Approximately 10 ml of 0.7% sodium chloride solution was added to the agar slants and suspensions were made by scraping the agar surface and vortexing the suspensions, These suspensions were filtered through two layers of sterile stainless steel funnels (40 x 40 mesh and 100 x 100 mesh). This procedure separated parti-' cles of agar and fungal mycelium on agar from the spores that were réquired for the test. After microscopic examination for suitability of inocula, two drops of these suspensions ' - were added to various dilutions of the test compiunds in Sabouraud Dextrose Broth.
Fungistatic endpoints, that is, the concentrations at which growth was prevented, were determined by visualization and reported as minimal inhibitory concentrations (MIC) in ~g/ml. Yeast readings were made after three days' incubation, endpoints with fungi 4 and 5 were determined after five days' incubation and with organism 3, determinations were made after seven days' incubation.
MIC (~g/ml) 1-13-(4-chlorobenzylthio)-3-(2,4-dichlorophenyl)propyl]-imidazole nitrate ,, .
q~ E.f. - < 0.1 -~l C.a.2 .
,' ' ~
-56c-,, .
~ ~ .
1-[3-(4-methylbenz~lthio)-3-(2~4-dichloropheny1)prop~1]-imidazole nitrate _ ~ . . . . . . . . .
E~f, ~ < 0.1 C.a,2 1-[3-(4-chlorophenylthio)-3-(2 r 4-dichlorophenyl)propyl]-imidazole nitrate-E,f. - 0.3 ~ C.a,2 - 1 : 10 1-[3-(4-tert-butylphenylthio)-3-(4-chlorophenyl)propyl]-_ imidazole oxalate T.m.
C.a.l - 10 C.a.2 - 10 1-[3-(4-bromo-3-methylphenylthio)-3-(4-chlorophenyl)propyl~-~ imidazole nitrate - -- - ---; T.m, - 1 C.a.l - 10 C.a,2 - 10 1-[2-(4-chlorobenzylthio)-4-(4~chlorophenyl)butyl]-imidazole oxalate -._ M.g. - 3 E.~. - <0.1 C.a.l - 3 C.a.2 - 3 ., .
.' ' ~
~ -56d~
.
.. .
1-~2~(3,4-dichlorophenylthio~4-~4-chlorophenyl)butyl]- -imidazole nitrate ;
... . . .
- M,~. ~ 3 : E.f, ~ <0.1 C.a,l ~ 3 C.a.2 - 3 .
1-[2-(4-chlorophenylthio)-4-(4-chlorophenyl)butyl~-imidazole nitrate M~g. _ 3 E.f. - <0.1 C.a,l - 3 C.a.2 ~ 3 1-[2~(3,4-dichlorophenylthio)-4-phenyibutyl]-imidazole oxalate . . .
C.a.l - 3 C.a.2 - 3 ' ' . . .
1-[4-(3,4~dichlorophenylthio)-4-~4-chlorophenyl)butyl]-imidazole nitrate M.g~ - 3 T.m.
; 1-[4-(4-chlorobenzylthio)-4-(4~chlorophenyl)butyl]-imidazole nitrate C.a.l - 10 . 1-[4-(2,4-dichlorobenzyloxy)-4-(4-chlorophenyl)butyl]-imidazole nitrate ' -, T.m. _ 3 -56e-1-[4-~4-chlorobenz~lox~)-4-(2r4-dichloroDhen~l)but~l]-imidazole nitrate _ T~m, ~ 1 1-~4-(4-chlorobenzylthio)-4-(2,4-dichlorophenyl~butyl]-imidazole nitrate -C.a.2 - 10 1-[4-(4-chlorophenylthio)-4-(2,4-dichlorophenyl)butyl]-imidazole oxalate C.a.2 - 10 ,; .
.
.. . . .. . . .. , , . . - ,.
, . . , . : ~ . - -- , . . .- ,,: - .
.... . ' ' . ' . '.
SUPPLEMENTARY DISCLOSURE
The present invention relates to 1-[2-(halo-phenylthio)-4-(p-chloro- or -fluorophenyl)-n-butyl] imidazoles and to processes for the preparation thereof. These compounds are useful as antifungal, antibacterial and antiprotozoal agents.
The preceeding principal dislcosure discloses a class of certain substituted N-alkyl imidazole compounds represented by the following generic formula:
R - 7H- ( CH2 ) n ~ N N
. X- R \~/
.
: (A) wherein Rl and R2 are each independently phenyl, phenyl ~ straight chain lower alkyl, or phenyl straight chain lower - 15 alkenyl; or one of the above substituted in the phenyl ring with one or more substituents independently selected from the group consisting of lower alkyl of from one to four carbon ,~
atoms, halo and trifluoromethyl; X is oxygen or sulfur; n .
is an integer of from 1 to 8 with the proviso that n is not 1 when Rl is phenyl or substituted phenyl; and the anti-microbial acid addition salts thereof. The class of compounds represented by the above formula plus salts thereof are ;~ described to exhibit antifungal, antibacterial and antipro-~`~ tozoal activity.
: -~::
Now it has been discovered that a group of compounds of the above class are particularly active. This group of compounds, as a highly active class different from that disclosed earlier and represented by Formula (A) above, is characterized by the following formula:
~ 30 ': .
~ - 57 -: \
: :`` ``` 1077493 .` X~ CH2-C~I2-F~I-CH2-`. S
;~ \~Yn : 5 ~I) '.'' ~:
.-: and the antimicrobial acid addition salts thereof, :
~:. wherein X is chloro or fluoro, each Y is bromo or chloro ~
~ ;.............................................. .
or fluoro, at least one Y being in the 2'-position, n is .: 10 1 to 5 when Y is chloro, and n is 1 or 2 when Y is other `: than chloro.
~ Preferred groups of compounds hereof are those of :~ the formulas: .
' .~: ', , ':
. ~. 15 X ~ 2 C~2 FE~ CH2-N ~ :
,- . . S
.~., ~,~ . .
. (Ia) ~ Wm .,: . .
~ 20 X ~ CH2-C~2-l~-CH2-N ~
.," , ~
: ; (Ib) Z ~ : .
and the antimicrobial acid addition salts thereof, wherein X is chloro or fluoro, each W is bromo or chloro or fluoro, at least one W being in the 2'-position, m is 1 to -.
;: 4 when W is chloro, m is 1 or 2 when W is other than chloro, !, j, ' each Z is bromo or chloro or fluoro, p is 0 to 3 when Z is . chloro, and p is O when Z is other than chloro.
~ 30 Particularly preferred of the compounds of Formulas (I), :~ .
. -:: ~7 . ~ .
.. . .
``` 1~77493 ~Ia) and (Ib), and the antimicrobial acid addition salts there-of, are those wherein n is 1 to 3 or m is 1 to 3 or p is 0 or 1 (Y or W or Z being chloro when n is 1 to 3, m is 1 to 3, or p is 1 and being other than chloro when n is 1 or 2, m is 1 or 2, or p is O) and those thereof wherein X is chloro, or when X is fluoro, then Y (or W or Z) is chloro. Further preferred are those wherein X and Y (or W or Z) are chloro. Particularly pre-ferred of the latter are those wherein n is 2, m is 2 or p is 0 and those thereof wherein the two (Y or ~ or Z) chloro groups are in the 2',6'-positions of the phenyl ring. Thus, particularly preferred is the compound l-[2-(2,6-dichloro-phenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole, as well as the antimicrobial acid addition salts thereof.
The compounds of the present invention characterized by-Formulas (I), (Ia) and (Ib) above, and the defined salts thereof, are distinguished by the discovery that certain specific molecular features provide a highly active class of compounds. These features are defined by 1) a 1,4-butylene chain linking the imidazole moiety and a p-chloro- or -fluoro-phenyl moiety, 2) a halophenylthio moiety attached to the C-2 carbon of the 1,4-butylene chain counting from the imidazole moiety and, most notably, 3) at least one halo being in the 2'-position of the phenyl ring in the halophenylthio ~25 moiety. This combination of features provides a surprisingly ; highly active, different class of compounds.
In a secondaspect the present invention is concerned with a method of combatting fungi, bacteria and protozoa by administering a compound of the present invention or a compo-sition containing same.
As used in the specification and the appended claims,unless specified to the contrary, the following terms have ~0774.93 the meaning indicated. The term "halo" refers to bromo, -chloro and fluoro. "Antimicrobial acid addition salts" of the subject bases refers to those salts which retain the anti-microbial properties of the free bases and which are neither biologicallynor otherwise undesirable, formed with, for example, inorganic acids such as hydrochloric acid, hydro-bromic acid, sulfuric acid, nitric acid or phosphoric acid;
or inorganic acids such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, `10 succinic acid, malic acid, maleic acid, fumaric acid, tar-taric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
All compounds of Formula (I) possess at least one chiral center, i.e., the carbon atom to which are attached the S, H and two CH2 moieties. Accordingly, the compounds of the present invention may be prepared in either optically active form, or as a racemic mixture. Unless otherwise ~ -r! specified, the compounds described herein are all in the racemic form. However, the scope of the subject invention herein is not to be considered limited to the racemic form, - --but to encOmpass theindividual optical isomers of the subject compounds, and various mixtures thereof.
~! If desired, racemic intermediates or final products ; 25 prepared herein may be resolved into their optical antipodes by conventional resolution means known per se, for example, by the separation (e.g., fractional crystallization) of the diastereomeric salts formed by reaction of, e.g., racemic compounds of Formula (I) with an optically active acid, or by the separation of the diastereomeric salts or esters formed by reaction of racemic compounds of Formula (II), infra, ~ , , .
.. . . . .
.. , , ~
1~77493 with an optically active acid. Exemplary of such optically active acids are the optically active forms of camphor-10-sulfonic acid, ~-bromo-camphor-~-sulfonic acid, camphoric acid, menthoxy-acetic acid, tartaric acid, malic acid, diacetyltartaric acid, pyrrolidone-5-carboxylic acid, and the like. The separated pure diastereomeric salts or esters may then be cleaved by standard means to afford the respec-tive optical isomers of the compounds of Formula (I) or (II).
The subject compounds of Formula (I) exhibit anti-fungal, anti-bacterial and anti-protozoal activity. For example, compounds of the present invention exhibit anti-fungal activity against human and animal pathogens such as Microsporum audouini, Microsporum gypseum, Microsporum gypseum - canis, Epidermophyton floccosum, Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton tonsurans, Candida albicans, and Cryptococcus neoformans.
The compounds of the present invention also exhibit anti-fungal activity against the following fungi primarily of agri-; cultural significance Aspergillus flavus, Aspergillus niger, Cladosporium herbarum, Penicillium oxalicum, Fusarium graminearum, Penicillium spinulosum, Penicillium notatum, and Pithomyces chartarum.
In addition, the compounds of the present invention exhibit 30 anti-bacterial activity against human and animal pathogens, such "~
as Staphylococcus aureus, Streptococcus faecalis, Corynebacterium acnes, Erysipelothrix insidiosa, Escherichia coli, Proteus vulgaris, 'Salmonella choleraesuis, Pasteurella multocida, and Pseudomonas aeruginosa.
Moreover, the compounds of the present invention exhibit anti-protozoal activity against protozoa such as Trichomonas vaginalis and Trichomonas foetus. -In general, the subject compounds of the instant invention exhibit a low level of toxicity. Moreover, these compounds ' demonstrate good solubility in the stratum corneum. Since dermatophyte (i.e., parasitic fungal) infections are usually localized in the dead tissue of the stratum corneum, solubility of anti-fungal agents in this tissue significantly enhances their effectiveness.
In view of the aforementioned activities, the subject compounds are found to be useful antimicrobials, having not only pharmaceutical but also agricultural and industrial application.
~ccordingly, a further aspect of thepresent invention relates to compositions for pharmaceutical, agricultural, and industrial use, which compositions comprise the subject ., .. . - - . -.
', - ' : ., .. . . .. ,; - . - ..
. .
: . .
- ~ ' : ~: : .
`I ` ~` . .
compounds of formula (I) in combination with a suitable carrier. A still further aspect of the present invention ` relates to methods of inhibiting the growth of fungi, bacteria and protozoa by applying to a host object containing, or S subject to attack by, fungi, bacteria or protozoa, an effective amount of a compound of the present invention or a suitable composition containing same.
In pharmaceutical applications, compositions may be solid, semi-solid or liquid in form such as tablets, cap-sules, powders, suppositories, liquid solutions, suspensions, creams, lotions, ointments and the like. Pharmaceutically acceptable non-toxic carriers, or excipients normally employed for solid formulationsinclude tricalcium phosphate, calcium carbonate, koalin, bentonite, talcum, gelatin, lactose, starch and the like; for semi-solid formulations there may be mentioned, for example, poly-alkylene glycols, vaseline and other cream bases; for liquid formulations there may be mentioned, for example, water, oils of vege-table origin and low boiling solvents such as isopropanol, hydrogenated naphthalenes and the like. The pharmaceutical compositions containing the compounds of the present invention may be subjected to conventional pharmaceutical expedients such as sterilization and can contain conventional pharmaceutical excipients such as preservatives, stabilizing agents, emulsifying agents, salts for the adjustment of osmotic pressure and buffers. The compositions may also contain other therapeutically active materials. In pharma-ceutical applications, the subject compounds and composi-tions may be administered to humans and animals by conven-tional methods, e.g. topically, orally, parenterally and 10~7493 the like. Parenteral administration includes intramuscular as well as subcutaneous and intravenous administration.
Intravenous injection of imidazole-type anti-fungals has been demonstrated to be effective in the treatment of systemic mycoses (see for example, Drugs 9, pp. 419-420, 1975, which described the intravenous administration of miconazole, i.e. 1-[2,4-dichloro-~-(2',4'-dichlorobenzyloxy)phenethyl]-imidazole nitrate, to patients with systemic candidiasis).
Topical application is the preferred method of administration for pharmaceutical applications. For such treatment, an area having an existing fungal, bacterial or protozoal growth, or to be protected against attack by fungi, bacteria or protozoa, may be treated with the subject compounds o~
compositions by, for example, dusing, sprinkling, spraying, rinsing, brushing, dipping, smearing, coating, impregnating and the like. Topical pharmaceutical compositions containing the compounds of the present invention exhibit anti-fungal `
anti-bacterial and anti-protozoal activity over a wide range of concentration, for example, from about 0.1 to 10.0%
by weight of the composition. In any event, the composition to be administered will contain a quantity of the subject compound in an amount effective for relief or prevention of the specific condition being treated.
The pharmaceutical compositions hereof typically com-prise one or more subject compounds of Formula (I) and a pharmaceutically acceptable, non-toxic carrier, and are preferably formulated in unit dosage form to facilitate administration (unit dosage being the amount of active ingredient administered on one occasion).
In general, for systemic (e.g. oral or parenteral) 1~77'~93 administration it is expedient to administer the active ingredient in amounts between about 1 and 100 ms/kg. body weight per day, preferably between about 5 and 50 mg/kg body weight per day; preferably distributed over several applications (e.g., in 3 individual doses) in order to achieve most effective results. For localized (e.g. topical) administra-tion, however, proportionately less of the active ingredient is required.
The exact regimen for pharmaceutical administration of the compounds and compositions disclosed herein will necessarily be dependent upon the needs of the individual subject being treated, the type of treatment, e.g., whether preventative or curative, the type of organism involved and, of course, the judgment of the attending practitioner.
In agricultural applications, the subject compounds may be applied directly to plants (e.g. seeds, foliage) or to soil. For example, compounds of the present invention may be applied to seeds alone or in admixture with a powdered solid carrier. Typical powdered carriers are the various mineral silicates, e.g. mica, talc, pyrophyllite, and clays. The subject compounds may also be applied to the seeds in admixture with a conventional surface-active wetting agent with or without additional solid carrier.
Surface-active wetting agents that can be used are any of.
.. . .. . .. . . .
- .: : . :: : : : . : : ~ . -: . . : . , - : : .. .. .
., ,: . . , .. ~, ,. ., , ~ , :
::: :, - . . . , ~. : . , . , : ' . . , -~ :,, ' ' : ' :
the conventional anionic, non-anionic or cationic types.
As a soil treatment for fungi and the like, the subject compounds can be applied as a dust in admixture with sand, soil or a powdered solid carrier such as a mineral silicate with or without additional surface-active agent, or the subject compounds can be applied as an aqueous spray optionally containing a surface-active dispersing agent and - a powdered solid carrier. As a foliage treatment, the sub-ject compounds may be applied to growing plants as an aqueous spray which contains a surface-active dispersing agent with or without a powdered solid carrier and hydro-carbon solvents.
In industrial applications, the subject compounds may be u~ed to control bacteria and fungi by contacting the pathogens with the compounds in any known manner. Materials capable of supporting bacteria and fungi may be protected by contacting, mixing or impregnating these materials with the subject compounds. In order to increase their effect, the subject compounds may be combined with other pesticidal control agents such as fungicides, bactericides, insecti-cides, miticides and the like. A particularly important industrial/agricultural use for the subject compounds of the present invention is as a food preservative against bacteria and fungi which cause deterioration and spoilage of foods.
., :
:
~077493 The compounds of Formula (I) may be prepared by forming a thioether from a suitable alcohol of Formula (II) X ~CH2-CH2-CH-CH2-N~N
(II) wherein X is as defined above. Compounds of Formula (II) may be prepared by a variety of reaction sequences.
'For example, compounds of Formula (II) may be prepared by reaction Scheme A shown below.
Reaction Scheme A
10X ~ 2 2 ~ X ~ CH2-CH2-cH-cH2 (IV) ~ (III) ~15~ H2-CH2-CH CH2 X ~ 2 CH2 fH-CH2-N ~N
OH
(V) (II) wherein X is as defined above .~ . .
, In this reaction scheme the imidazole alcohol of Formula (II) is formed by opening of a terminal epoxide of Formula (III) with imidazole. This reaction is generally carried out using at least one mole and preferably an excess of imidazole -relative to epoxide optionally in the presence of a salt (preferably an alkali metal salt) of imidazole. The reaction may either be carried out in the absence of solvent or, preferably, in an inert organic solvent, for example, a solvent suchas dimethylformamide, hexamethylphosphoramide, acetonitrile, ;
and the like. The temperature normally employed for such ~;
epoxide opening is in the range of from about -20 to about 100C.
:: . .
-6~
- ~i, most preferably from about 20 to about 60C.
Epoxides of Formula (III), insofar as they may not be known, may be prepared by a variety of well known methods, for example epoxidation of a terminal olefin (e.g., (V)) with, for example, a peracid, or by reaction of an aldehyde having ` one fewer carbon atom (e.g., (IV)) with the ylide prepared from trimethylsulfoxonium iodide or trimethylsulfonium iodide as described, for example, in J. Am. Chem. Soc., 84, p. 867 : (1962); ibid, 87, p. 1353 (1965).
Another reaction scheme for preparing compounds of Formula (II) is shown in reaction Scheme B presented below ; Reaction Scheme B
, X~{:H2-CH2-COcH2Y ' ~ X~CH2cH2-cocH2-~N
l~3i 15 (VII) (VI) "i ,-.
b: . X~ 'CH2--cH2- IcH CH2 5, OH
, 20 (II) " : :
wherein X is as defined above and Y' is chloro or bromo.
In this reaction scheme the hydroxy compound of Formula (II) is prepared by reduction of the corresponding ketone (VI), which in turn is prepared by reaction of an a-halo ketone (VII) with imidazole.~
The a-halo ~etones may be readily prepared by general methods known in the art, for example from the corresponding dihydrocinnamic acid by reaction of the acid chloride or bromide with diazomethane followed by treatment of the . , , ~8 resulting diazoketone with HY'.
The a-halo ketone is contacted with imidazole in an inert organic solvent to afford the keto imidazole of Formula (VI). The reaction is carried out utilizing at least a molar amount and, preferably, an excess of imidazole relative to halo ketone. The reaction may be carried out in the absence of solvent or, preferably, in an inert organic solvent such as for example dimethylformamide, hexa-methylphosphoramide, acetonitrile, and the like. The reaction is suitably carried out at a temperature initially between about -10 and 100C most preferably between about 25C and 80C.
In the next step the keto imidazole of Formula (VI) is reduced to the hydroxy imidazole of Formula (II) utilizing a conventional metal hydride reducing agent such as, for example, sodium borohydride. The reaction is suitably carried out in an alcoholic solvent such as, for example, methanol -or ethanol at a reduced temperatur~, for example, between about -10 and +25C., most preferably about 0C.
Compounds of Formula (I) may be prepared from the com-pounds of Formula (II) by a two-step sequence involving conversion of the hydroxy group to a suitable leaving group such as a halide (e~g., a chloride or bromide) or a sulfonate ester (e.g., methanesulfonate or p-toluenesulfonate) which is then reacted with the corresponding thiophenol HS ~ , where Y and n are as defined above, preferably in the Yn presence of base, e.g. potassium carbonate, or by using a metal salt thereof.
The converstion from the alcohol to the halide or sulfonate . ~ ,, .
i: 1077493 ester is carried out by means well known in the art. For example, the alcohol may be halogenated using a halogenating agent such as thionyl chloride or thionyl bromide, either neat, or in an inert organic solvent such as dichloromethane or chloroform, at a temperature between about 0 and 80C., preferably between about 20 and 80C. The halogènation reac-tion may be carried out in the presence of a molar equivalent of a base (e.g., pyridine) if desired. Alternate halogenation procedures include, for example, the use of triphenylphosphine wth either carbon tetrachloride, carbon tetrabromide, or N-chloro (or N-bromo) succinimide. When utilizing thionyl chloride or thionyl bromide without the use of added base, the hydrochloride or hydrobromide salt of the corresponding halo compound is produced. This salt may be neutralized (e.g., with potassium carbonate) prior to its use in the alkylation step, or the salt may be used directly if excess thiophenol salt is utilized.
SuIfonate esters may be prepared by the standard procedure of treating the alcohol with an excess of, for example, methanesulfonyl chloride or p-toluenesulfonyl chloride, in the presence of a base, for example pyridine or triethylamine. This reaction is carried out at a temperature from about -20 to +50C., preferably between about 0 and 20C.
The halide or sulfonate ester prepared as described above, is then treated with thiophenol preferably in the pres-ence of base, or with a salt, preferably an alkali metal salt such as the sodium or potassium salt, of the corresponding thiophenol, in the presence of an inert organic solvent such as acetone, methanol, and the like, at a temperature of about 20 about 80C. If desired, the metal salt of the thiophenol ~ 70-~, ~ . , .
` 1077493 may be performed prior to addition of the halide.
Compounds of Formula (I) may also be prepared as depicted in reaction Scheme C below .
Reaction Scheme C
X~3CH2-CH2-C~1 H2 y_~ S/~ >
(III) or ~SH
Yn 'O `
X ~ CH -CH -CH-CH -S ~ ---t x ~ C~2-C~l2-1~ C~2 ; and/or and/or :~
X~CH2-CH2-CH-CH20H ~CH2--CH2--ICH CH2 (V}II) ~ n(IX) ~ ~
,~''' .
X ~ CH2-CH2-1CH-CH2 N\==
S
(I) .
wherein Y' is a leaving group and each of X, Y and n is as defined above.
In this scheme the epoxide of Formula (III) described earlier, is opened with a thiophenol or a metal salt thereof, to afford the compound of Formula (VIII). This :
` reaction is carried out utilizing, preferably, an alkali metal .! salt of the thiophenol, most preferably the sodium salt, in an inert organic solvent such as, for example, tetra-, .
-71- .
;. ,~., :
5~.;~' .. . . . . .
', ' : ' ' '~ : : '' ' ~ 77493 hydrofuran or acetone at a temperature of between about 0 and 67C., or using the free thiophenol in the presence of an acid catalyst, e.g., perchloric acid, under similar conditions.
In the next step the hydroxy group of the compound of ` Formula (VIII) is converted to a leaving group such as a halide (e.g., chloro or bromo) or sulfonate ester (e.g., p-toluenesulfonate or methanesulfonate) by treatment with, e.g., a halogenating agent such as, for example, thionyl chloride, neat, or preferably in an inert solvent such as dichloromethane, or with, for example, p-toluenesulfonyl chloride, in a solvent such as pyridine. The product of Formula (IX) may exist in either or both forms depicted, and may be interconvertible through an episulfonium inter-medlate.
In the final step, the compound of Formula (IX) is y converted to the final product of Formula (I) by treatment `~ with imidazole. This reaction is carried out in an inert organic solvent such as for example acetonitrile, dimethyl-20 formamide, and the like, at a temperature of about 0 to about 100C.
The thiophenol reagents can be prepared from the corres-ponding phenols by methods known generally in the art, for example, as described by M. S. Newman ardH. A. Karnes, J. ~ -Org. Chem. 1973, Vol. 31, p. 3980.
The subject compounds of the instant invention can be isolated as free bases; however, since some of the compounds in base form are oils, it is more convenient to isolate and characterize the compounds as acid addition salts. These salts are prepared in the usual manner, i.e., by reaction of :: .
:
.,~
. , ~. .
.
the base compound with a suitable inorganic or,organic acid, described above. Salts formed with dibasic acids (e.g., oxalic acid) may contain one or two molecules of base per molecule of acid. All oxalates described herein contain one molecule of oxalic acid per molecule of imidazole base. If ' desired, the salts can be readily converted to the free base form by treatment with alkali, such as potassium carbonate, sodium carbonate or sodium or potassium,hydroxide. - -; The follow~ng specific preparations and examples are illustrative of the present invention and should not be '~ considered as limitative thereof in any manner.
' '::
~ ' ' '; "
-, ' ' .:, , ~;,' , ' , :
,, .
~,~ ' .
` `` 1077493 ~ 3-(4-Fluorophenyl)-l-propanol (34 g.) in anhydrous methylene i chloride (200 ml.) was added directly to a well stirred sus-pension of pyridinium chlorochromate (71.5 g.) in methylene - 5 chloride (400 ml.). After two hours at room temperature, ether was added to precipitate the reagent, the reaction mix-ture decanted and the residue washed with ether. The combined v organic extracts were filtered through Florisil, evaporated and the product distilled under reduced pressure to give 3-(4-fluorophenyl~propionaldehyde as a colorless oil.
In a similar manner, 3-t4-chlorophenyl)propionaldehyde~
an oil, was prepared.
,, .
This preparation illustrates the process in reaction , ................................................. . .
; Scheme A.
.
~-(4-Fluorophenyl)propionaldehyde (20.6 g.) was added under nitrogen to the ylide prepared from trimethylsulfonium iodide (31.8 g.) and sodium hydride (55% dispersion in oil;
- ~i, most preferably from about 20 to about 60C.
Epoxides of Formula (III), insofar as they may not be known, may be prepared by a variety of well known methods, for example epoxidation of a terminal olefin (e.g., (V)) with, for example, a peracid, or by reaction of an aldehyde having ` one fewer carbon atom (e.g., (IV)) with the ylide prepared from trimethylsulfoxonium iodide or trimethylsulfonium iodide as described, for example, in J. Am. Chem. Soc., 84, p. 867 : (1962); ibid, 87, p. 1353 (1965).
Another reaction scheme for preparing compounds of Formula (II) is shown in reaction Scheme B presented below ; Reaction Scheme B
, X~{:H2-CH2-COcH2Y ' ~ X~CH2cH2-cocH2-~N
l~3i 15 (VII) (VI) "i ,-.
b: . X~ 'CH2--cH2- IcH CH2 5, OH
, 20 (II) " : :
wherein X is as defined above and Y' is chloro or bromo.
In this reaction scheme the hydroxy compound of Formula (II) is prepared by reduction of the corresponding ketone (VI), which in turn is prepared by reaction of an a-halo ketone (VII) with imidazole.~
The a-halo ~etones may be readily prepared by general methods known in the art, for example from the corresponding dihydrocinnamic acid by reaction of the acid chloride or bromide with diazomethane followed by treatment of the . , , ~8 resulting diazoketone with HY'.
The a-halo ketone is contacted with imidazole in an inert organic solvent to afford the keto imidazole of Formula (VI). The reaction is carried out utilizing at least a molar amount and, preferably, an excess of imidazole relative to halo ketone. The reaction may be carried out in the absence of solvent or, preferably, in an inert organic solvent such as for example dimethylformamide, hexa-methylphosphoramide, acetonitrile, and the like. The reaction is suitably carried out at a temperature initially between about -10 and 100C most preferably between about 25C and 80C.
In the next step the keto imidazole of Formula (VI) is reduced to the hydroxy imidazole of Formula (II) utilizing a conventional metal hydride reducing agent such as, for example, sodium borohydride. The reaction is suitably carried out in an alcoholic solvent such as, for example, methanol -or ethanol at a reduced temperatur~, for example, between about -10 and +25C., most preferably about 0C.
Compounds of Formula (I) may be prepared from the com-pounds of Formula (II) by a two-step sequence involving conversion of the hydroxy group to a suitable leaving group such as a halide (e~g., a chloride or bromide) or a sulfonate ester (e.g., methanesulfonate or p-toluenesulfonate) which is then reacted with the corresponding thiophenol HS ~ , where Y and n are as defined above, preferably in the Yn presence of base, e.g. potassium carbonate, or by using a metal salt thereof.
The converstion from the alcohol to the halide or sulfonate . ~ ,, .
i: 1077493 ester is carried out by means well known in the art. For example, the alcohol may be halogenated using a halogenating agent such as thionyl chloride or thionyl bromide, either neat, or in an inert organic solvent such as dichloromethane or chloroform, at a temperature between about 0 and 80C., preferably between about 20 and 80C. The halogènation reac-tion may be carried out in the presence of a molar equivalent of a base (e.g., pyridine) if desired. Alternate halogenation procedures include, for example, the use of triphenylphosphine wth either carbon tetrachloride, carbon tetrabromide, or N-chloro (or N-bromo) succinimide. When utilizing thionyl chloride or thionyl bromide without the use of added base, the hydrochloride or hydrobromide salt of the corresponding halo compound is produced. This salt may be neutralized (e.g., with potassium carbonate) prior to its use in the alkylation step, or the salt may be used directly if excess thiophenol salt is utilized.
SuIfonate esters may be prepared by the standard procedure of treating the alcohol with an excess of, for example, methanesulfonyl chloride or p-toluenesulfonyl chloride, in the presence of a base, for example pyridine or triethylamine. This reaction is carried out at a temperature from about -20 to +50C., preferably between about 0 and 20C.
The halide or sulfonate ester prepared as described above, is then treated with thiophenol preferably in the pres-ence of base, or with a salt, preferably an alkali metal salt such as the sodium or potassium salt, of the corresponding thiophenol, in the presence of an inert organic solvent such as acetone, methanol, and the like, at a temperature of about 20 about 80C. If desired, the metal salt of the thiophenol ~ 70-~, ~ . , .
` 1077493 may be performed prior to addition of the halide.
Compounds of Formula (I) may also be prepared as depicted in reaction Scheme C below .
Reaction Scheme C
X~3CH2-CH2-C~1 H2 y_~ S/~ >
(III) or ~SH
Yn 'O `
X ~ CH -CH -CH-CH -S ~ ---t x ~ C~2-C~l2-1~ C~2 ; and/or and/or :~
X~CH2-CH2-CH-CH20H ~CH2--CH2--ICH CH2 (V}II) ~ n(IX) ~ ~
,~''' .
X ~ CH2-CH2-1CH-CH2 N\==
S
(I) .
wherein Y' is a leaving group and each of X, Y and n is as defined above.
In this scheme the epoxide of Formula (III) described earlier, is opened with a thiophenol or a metal salt thereof, to afford the compound of Formula (VIII). This :
` reaction is carried out utilizing, preferably, an alkali metal .! salt of the thiophenol, most preferably the sodium salt, in an inert organic solvent such as, for example, tetra-, .
-71- .
;. ,~., :
5~.;~' .. . . . . .
', ' : ' ' '~ : : '' ' ~ 77493 hydrofuran or acetone at a temperature of between about 0 and 67C., or using the free thiophenol in the presence of an acid catalyst, e.g., perchloric acid, under similar conditions.
In the next step the hydroxy group of the compound of ` Formula (VIII) is converted to a leaving group such as a halide (e.g., chloro or bromo) or sulfonate ester (e.g., p-toluenesulfonate or methanesulfonate) by treatment with, e.g., a halogenating agent such as, for example, thionyl chloride, neat, or preferably in an inert solvent such as dichloromethane, or with, for example, p-toluenesulfonyl chloride, in a solvent such as pyridine. The product of Formula (IX) may exist in either or both forms depicted, and may be interconvertible through an episulfonium inter-medlate.
In the final step, the compound of Formula (IX) is y converted to the final product of Formula (I) by treatment `~ with imidazole. This reaction is carried out in an inert organic solvent such as for example acetonitrile, dimethyl-20 formamide, and the like, at a temperature of about 0 to about 100C.
The thiophenol reagents can be prepared from the corres-ponding phenols by methods known generally in the art, for example, as described by M. S. Newman ardH. A. Karnes, J. ~ -Org. Chem. 1973, Vol. 31, p. 3980.
The subject compounds of the instant invention can be isolated as free bases; however, since some of the compounds in base form are oils, it is more convenient to isolate and characterize the compounds as acid addition salts. These salts are prepared in the usual manner, i.e., by reaction of :: .
:
.,~
. , ~. .
.
the base compound with a suitable inorganic or,organic acid, described above. Salts formed with dibasic acids (e.g., oxalic acid) may contain one or two molecules of base per molecule of acid. All oxalates described herein contain one molecule of oxalic acid per molecule of imidazole base. If ' desired, the salts can be readily converted to the free base form by treatment with alkali, such as potassium carbonate, sodium carbonate or sodium or potassium,hydroxide. - -; The follow~ng specific preparations and examples are illustrative of the present invention and should not be '~ considered as limitative thereof in any manner.
' '::
~ ' ' '; "
-, ' ' .:, , ~;,' , ' , :
,, .
~,~ ' .
` `` 1077493 ~ 3-(4-Fluorophenyl)-l-propanol (34 g.) in anhydrous methylene i chloride (200 ml.) was added directly to a well stirred sus-pension of pyridinium chlorochromate (71.5 g.) in methylene - 5 chloride (400 ml.). After two hours at room temperature, ether was added to precipitate the reagent, the reaction mix-ture decanted and the residue washed with ether. The combined v organic extracts were filtered through Florisil, evaporated and the product distilled under reduced pressure to give 3-(4-fluorophenyl~propionaldehyde as a colorless oil.
In a similar manner, 3-t4-chlorophenyl)propionaldehyde~
an oil, was prepared.
,, .
This preparation illustrates the process in reaction , ................................................. . .
; Scheme A.
.
~-(4-Fluorophenyl)propionaldehyde (20.6 g.) was added under nitrogen to the ylide prepared from trimethylsulfonium iodide (31.8 g.) and sodium hydride (55% dispersion in oil;
7.48 g.) in dry dimethylsulfoxide (100 ml.), according to the procedure in Journal of the American Chemical Society, Vol. 87, page 1353 (1965). ~fter one hour at -10, the solution was allowed to come to 0, poured into 500 ml. of ice water and the product extracted with ether i 25 (3 x 300 ml.). The extract was washed well with water, dried J (MgSO4) and evaporated to give an oil, 1,2-epoxy-4-(4-fluoro-phenyl)bUtane , used directly in the next step.
~ The oil from above in a few ml. of tetrahydrofuran was - added to a mixtur~ prepared by reacting imidazole (9.18 g.) r; 30 and sodium hydride (50~ dispersion in mineral oil; 3.24 g.) r~ .
'~7 4~
.
~ ~ .
''' ' ' ' - ' ' ' - .
`' ' ' ~ ' in 200 ml. tetrahydrofuran until the evolution of hydrogen ceases. The mixture was heated under reflux overnight, evap- -orated to dryness and the residue extracted with a small volume of dichloromethane. This solution was filtered and chromatographed on silica gel eluting with 10~ methanol in dichloromethane. Trituration with ethyl acetate/hexane gave 1-[2-hydroxy-4-(4-fluorophenyl)-n-butyl]imidazole as colorless crystals, m.p. 120.5-122.5C.
Similarly, proceding as above, substituting 3-(4-chloro-phenYl)propionaldehyde for 3-(4-fluorophenyl)propionalde- -~
hyde, there is prepared 1-~2-hydroxy-4-(4-chlorophenyl)-n-butyl]imidazole, m.p.
105-109C.
.
A solution of 6.0 g. of 1-[2-hydroxy-4-(4-chlorophenyl)-n-butyl]imidazole in 30 ml. of thionyl chloride was warmed at 65-70C. for one hour. Evaporation to dryness afforded 1-~2-chloro-4-(4-chlorophenyl)-n-butyl]imidazole hydro-chloride.
Similarly, 1-[2-chloro-4-(4-fluorophenyl)-n-butyl]-imidazole hydrochloride is prepared The free base may be obtained for use in the subsequent alkylation steps, if desired, by shaking the hydrochloride in dichloromethane with excess aqueous potassium carbonate solution, washing the organic layer with water, drying over magnesium sulfate and evaporating to dryness in vacuo to remove all traces of dichloromethane.
~ -.
- , . .. ~ . . . .
-~ ` 1077493 EX~MPLE 13 A mixture of 6.46 g. of 1-[2-chloro-4-(4-chlorophenyl)-n-butyl]imidazole, 8.5 g. of 2,6-dichlorothiophenol and 6.4 g.
of anhydrous potassium carbonate in 100 ml. of acetone was S stirred and refluxed for 18 hours. The solvent was evaporated under reduced pressure and 100 ml. of water was added. The resulting mixture was extracted with 300 ml. of ether and the ether extract washed twice with water and dried (MgSO4) to afford a solution containing 1-[2-(2,6-dichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole.
The nitrate salt was precipitated by the dropwise addition of 70~ nitric acid (d=1.42) to the etheral solution until precipitation was complete. The resulting salt was recrystallized from acetone-ethyl acetate as colorless blades, ~15 m.p. 162-163 (foaming).
,.; , . . . : .
In a similar manner, 1-[2-(2,6-dichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]imidazole nitrate salt, m.p. 131.5-'I 132.5~ was prepared.
~20 A mixture of 1,2-expoxy-4-(4-chlorophenyl)butane (3.65g.), , 2,6-dichlorothiophenol (4.0g.) and anhydrous potassium carbonate (200 mg.) in acetone (60 ml.) was stirred under reflux under nitrogen for about 4 hours. After removal of : .
the solvent, ether (150 ml.) was added and the extract washed with water, dried (MgSO4) and evaporated.
The above material in 100 ml. dichloromethane was treated with 6 ml. of thionyl chloride, heated under gentle reflux for - one hour, and the solution evaporated to dryness and evacuated to remove traces of thionyl chloride. The residue was treated with 7 g. of imidazole and 30 ml. of acetonitrile and stirred ' .r ~"~
-` 1077493 overnight at 55C and for one day at 85C. The solvent was evaporated and after the addition of 50 ml. water the residue was extracted with ether. ~he ether extract was washed well with water and dried (MgSO4) to afford a solution containing 1-[2-(2,6-dichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]imi-dazole, which was precipated and purified as its nitrate salt, -~ m.p. 162.5-164.5C.
Similarly, 1-[2-(2,6-dichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]imidazole-nitrate salt, m.p. 131.5-132.5C, was prepared.
Following the procedures in Preparations 1, 2 and 3, and Examples 1 or 2 using equivalent amounts of the appropriate starting materials, there may be obtained the following compounds. Where indicated, the compounds may be further characterized by conversion to the indicated ` acid addition salt.
.
1-[2-(2,5-dichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]-imidazole - nitrate salt, m.p. 155.5-157C.
1-[2-(2,3-dichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]-~20 imidazole - nitrate salt, m.p. 136-139.5C.
1-[2-(2-chlorophenylthio)-4-(4-chlorophenyl)-n-butyl]-imidazole - nitrate salt, m.p-. 136-136.5C.
1-[2-(2-bromophenylthio)-4-(4-chlorophenyl)-n-butyl]
imidazole - nitrate salt, m.p. 137-138C.
1-[2-(2,6-dibromophenylthio)-4-(4-chlorophenyl~n-butyl]-. , .
imidazole 1-[2-(2,4-dibromophenylthio)-4-(4-chlorophenyl)-n-butyl]-`~ imidazole ; 1-[2-(2,4,6-trichlorophenylthio)-4-(4-chlorophenyl)-n~butyl]-imidazole m.p. 136-137C; nitrate salt, m.p. 165-166C.
. . ~i . .
r ~ ~
` ~' 1077493 , ,.....
[2-t2,5-dichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]-`` imidazole - nitrate salt, m.p. 128.5-131C.
1-[2-(2,3-dichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]-, . .
~ imidazole `S 1-~2-t2-chlorophenylthio)-4-(4-fluorophenyl)-n-butyl]-imidazole - nitrate salt, m.p. 123-124C.
1-[2-(2-bromophenylthio)-4-(4-fluorophenyl)butyl]-.:
imidazole 1-[2-(2,6-dibromophenylthio)-4-(4-fluorophenyl)-n-butyl]-0 imidazole 1-[2-(2,4-dibromophenylthio)-4-(4-fluorophenyl)-n-butyl]-imidazole ., -~ .
1-[2-(2,4,6-trichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]imidazole - nitrate salt, m.p. 163-164C.
1-[2-(2,3,6-trichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]-imidazole - nitrate salt, m.p. 138-142C ~foaming).
1-[2-(2,3,4-trichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]-imidazole 1-[2-(2,3,5-trichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]-~0 imidazole 1-[2-(2,3,4,5-tetrachlorophenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole ' 1-[2-(2,3,4,6-tetrachlorophenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole ;5 1-[2-(2,3,5,6-tetrachlorophenylthio)-4-(4-chlorophenyl)-n- butyl]imidazole 1-[2-(2,3-dibromophenylthio)-4-(4-chlorophenyl)-n-butyl]-imidazole ; 1-[2-(2,5-dibromophenylthio)-4-(4-chlorophenyl)-n-butyl]-0 imidazole ' ~,.~
"
. . .
:. :
. 1-[2-(2,6-difluorophenylthio)-4-(4-chlorophenyl)-n-butyl]-- imidazole . 1-[2-(2,5-difluorophenyithio)-4-(4-chlorophenyl)-n-butyl]-: imidazole :5 1-[2-(2,4-difluorophenylthio)-4-(4-chlorophenyl)-n-butyl]-imidazole 1-[2-(2-fluorophenylthio)-4-(4-chloropheny~-n-butyl]-.. imidazole ~ 1-[2-(2,3-difluorophenylthio)-4-(4-chlorophenyl)-n-butyl]-: , .
.0 imidazole , .
1-[2-(2,3,4-trichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]-`:~ imidazole ,...
: 1-[2-(2,3,6-trichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]-.... .
"! imidazole l.~"
.; ., -5 1-[2-(2,3,5-trichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]imidazole 1-[2-(2,3,4,6-tetrachlorophenylthio)-4-(4-fluorophenyl n-butyl]imidazole 1-[2-(2,3,5,6-tetrachlorophenylthio)-4-(4-fluorophenyl)-.:20 n-butyl]imidazole .. :. 1-[2-(2,3,4,5-tetrachlorophenylthio)-4-(4-fluorophenyl)-n-~i ~. .butyl]imidazole '.'. i , i` . 1-[2-(2,3-dibromophenylthio)-4-(4-fluorophenyl)-n-butyl]-.~
imidazole .
1-[2-(2,5-dibromophenyl~hio)-4-(4-fluorophenyl)-n-butyl]-imidazole 1-[2-(2-fluorophenylthioj-4-(4-fluorophenyl)-n-butyl]-. . .
~-' imidazole 1-[2-(2,3-difluorophenylthio)-4-(4-fluorophenyl)-n-butyl]-, o imidazole ~ - 79-,. ~ , :,' . , . -, , . - :
,.. . .
: ~- - ', ` . - - - :
: ::: - - .
.. . .
` ~077493 [2-~2,4-di~luo~op}lenylthio)-~-(4~fluorophenyl)-n-butyl]~
imidazole 1-[2-(2,5-difluorophenylthio)-4-(4-fluorophenyl)-n-butyl]-.... .
imidazole and ~; :; -1-~2-(2,6-difluorophenylthio)-4-(4-fluorophenyl)-n-butyl]-` imidazole.
~ EXAMPLE 16 ,< Nitric acid (70%; d = 1.42) was added dropwise to a stirred solution of 2.0 g. of 1-[2-(2-chlorophenylthio)-4-` (4-chlorophenyl)-n-butyl]imidazole in 30 ml. of anhydrous ether . ............................................... .
until precipitation was complete. The product was filtered sj? off, washed with ether, air dried, and recrystallized from , . .
ethyl acetate to yield 1-[2-(~chlorophenylthio)-4-(4-chloro-~15 phenyl~n-butyl]imidazole nitrate, m.p. 136-136.5C.
~ In similar manner, all compounds of Formula (I) in base -~
; form can be converted to their antimicrobial acid addition salts by treatment with the appropriate acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric ~20 acid, phosphoric acid, acetic acid, propionic acid, glycolic '~ acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, .~ succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid or salicyclic acid.
,.
..
~ EX~MPLE 17 .:.
1-[2-(2,6-Dichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]-. . .
; imidazole nitrate (2.0 g.) in 100 ml. of ether was stirred with excess dilute potassium carbonate solution until the ~ 30 salt was completely dissolved. The organic layer was then ., ,:
.~,..;
. , . . ~.~ .
,, .
., .
., . ` .
separated, washed twice with water, dricd over magnesium sulfate and evaporated to yield 1-[2-(2,6-dichlorophenylthio-4-(4-chlorophenyl)-n-butyl]imidazole, m.p. 68-70.5C. (foaming) after crystallization from cyclohexane.
S In similar manner, the antimicrobial acid addition salts -of all compounds of Formula (I) can be converted to the ` corresponding compounds in base form.
The following illustrates the preparation of represen-~ .,.
L0 tative pharmaceutical formulations which may be used for controlling fungi, bacteria and protozoa, utilizing an active compound such as a salt of 1-[2-(2,6-dichlorophenylthio)-- .
4-(4-chlorophenyl)-n-butyl]imidazole.
A. Topical Formulation . . . .
~L5 grams Active compound 0.2 - 2 Span 60 2 Tween 60 2 . .
Mineral oil 5 Petrolatum 10 : Methyl paraben 0.15 :, ;
Propyl paraben 0.05 BHA (butylated hydroxy anisole) 0.01 Water qs 100 ;25 All of the above ingredients, except water, are combined ,,, and heated at 60C, with stirring. A sufficient quantity of water at 60C. is then added with vigorous stirring to pro-vide 100 g. of the cream formulation which is then cooled / to room temperature.
,, ,~10 , .
; ~ 81-.,, ' :
. ~ .
:
~.077493 .
,~ B. I.V. Formulation ~- Active compound 0.5 g.
, Propylene glycol 20 g.
, Polyethylene glycol 40020 g.
,;~t 5 Tween 80 1 g.
'A;'``' 0~ 9 Saline solution qs100 ml.
. .
The active compound is dissolved in propylene glycol, polyethylene glycol 400 and Tween ~0. A sufficient quantity of 0.9% sallne solution is then added with stirrins to pro-vide 100 ml. of the I.V. solution which is filtered through a 0.2 micron membrane filter and packaged under sterile `, conditions.
; ~, C. Oral ~ormulationparts by weight Active compound 200 ~" Magnesium stearate 3 , .;
- Starch 30 ; .
~ `Lactose 116 , ~, PVP (polyvinylpyrrolidone) 3 ~i"., :, . ;
` The above ingredients are combined and granulated using :; .: .
,~ methanol as the solvent. The formulation is then dried and : ,;, ' formed into tablets (containing 200 mg. of active compound) with an appropriate tabletting machine.
:.~
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, :~
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. , i .
, ; 1~77493 .
The antifungal activity of certain compounds of the i` present invention is illustrated by the following assay procedure:
~::
A. Trichophyton mentagrophytes fungus culture for infection was grown on agar slants of Sabouraud dextrose for 4 weeks at .,~,.. . .
room temperature. A 2% solution of corn starch was prepared ; by heating the starch in sterile distilled water. Approximately ~; 7 ml. of corn starch solution was added to each of 8 slants of culture. Suspension of organism was accomplished with vigorous pipetting and vortexing of the slants.
Guinea pigs (250-350 grams) were assigned to ten experi-; mental groups of ten animals (5 female, 5 male). One day pre-challenge, all guinea pigs were clipped and shaved in the interscapular region, avoiding any abrasions or lacerations.
Animals were challenged by rubbing a toothbrush, which had been dipped in fungal suspension, over a 1.5 cm x 1.5 cm shaved area. The rubbing continued until slight reddening occurred.
... .
Treatment with test compound began 3 days post-challenge and was continued once daily for 5 consecutive days. At each ~ treatment approximately 1 ml. of formula~ion was applied to the ,i infected area using a tongue depressor. Ten animals were not ~; treated and served as untreated infection controls.
~, ~
Hair was pluc~ed from 10-20 sites in the infected area , of each guinea pig. The hairs were innoculated onto plates containing Mycosel agar. One plate was used ~or each animal : .
.,, : . . .
{
.. ,, , , " ~ - ' ' .
..
.
`~;:
~ at each culture time (3, 7, and 14 days post-in~ection).
.. ..
.. Plates were incubated at room temperature (approximately . 21C) and read 7 days after innoculation.
. ;:. . .
Summary of Culture Results Days Post Challenge .. ;. 3* 4 7 14 ~ Test Compound ,,~' ~ Untreated controls 10/10** 10/10 10/10 8/10 ... . .
0.5% Miconazole~in cream: 10/10 3/10 2/10 9/10 ~10 ~1-[2,4-dichloro-~-(2,4-~
'............. dichlorobenzyloxy)phen-;¦ ethyl]-imidazole nitrate~
; 0.5% 1-[2-(2-chloro- 10/10 0/10 0/10 0/10 phenylthio)-4-(4-chlorophenyl)-n-butyl]-~
~15 imidazole nitrate~in cream , _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ., . ~ .
~ Untreated controls10/1010/1010/1010/10 .... . .
Ø3% Miconazole~in cream 10/10 3/10 0/10 3/10 . 0.1% 1-[2-(2,5-dichloro- 10/100/100/10 0/10 ;~ phenylthio)-4-(4-;: chlorophenyl)-n-butyl]-imidazole nitrate,in cream .~",:, .
:.;;: .
Untreated controls10/1010/1010/1010/10 ~:4 0.3% Miconazole~in cream 10/10 3/10 0/10 3/10 i 0.1% 1-E2-(2-bromo-10/10 2/100/10 0/10 -.25 phenyLthio)-4-.. ii chlorophenyl)n-~"', f butyl]imidazole nitrate,in cream ; -, . .
,. ~
', * Pretreatment culture . .
** Animi~ls with positive culture/Total animals in group . '' .
. , . - . . -... .
`~ B. Swiss/Webster mice 17-20 gram, female, were given .; 0.25 mg. of ~-estradiol suspension, in a 0.2 ml. volume, sub-- cutaneously on Days 1, 3 and 5 to induce estrus. Estrus was then maintained with an injection o~ ~-estradiol every 7 days. -~; A clinical isolate was obtained from human sputum.
Organism to be injected is grown for 72 hours on Sabouraud Dextrose Agar (SDA) slants at 30C. On the day of the chal-i-,f lenge 2-3 ml. of Sabouraud Dextrose Broth~(SDB) was added to - 10 each slant of the organism and mixed by pipetting to achieve a homogenous suspension. Concentration of organisms for ; injection is approximately 101 org./ml. (2-3 ml. of SDB
I is added to culture of organism growing on SDA slant). 7 ; days after 1st estradiol injection approximately 25 ~1 of culture suspension is injected into each mouse vagina using a 20 gauge, 2 mm. ball-tipped animal feeding needle.
~;' The mice were initially treated 6 hours post-challenge .:~.; . :
and then twice daily, 6 hours apart, using a ball-tipped feeding needle for cream or liquid type formulations. The fluid type formulations were injected into the vagina until it overflowed. Treatments were carried out for 5 consecutive days. Ali animals received one treatment only on the fifth day so that they could be cult~red during working hours, 6 r;~
~- hours post-treatment. ~he mice were cultured on Day 4 post-challenge (6 hours post-treatment) and Day 7 post-challenge ,,1, ', ' (72 hours post-treatment). Cultures were obtained by vaginal i," washing using approximately 0.1 ml. of sterile distilled water ~, with an 18-20 gauge, 2 mm. ball-tipped feeding needle. The ~i wash was inoculated into a tube of SDB containing 100 ~g '6'''' 30 oxytetracycline/ml. Cultures were incubated at 30C. for... .
;
~:, i; ,.,~ . . , - .
,i, , : . : , .. . .
-~,; .
: 48-72 h~ours then read microscopically. Candida albicans was confirmed by germ tube formation in 2-3 hours in sheep serum at 37C.
, . . .
~ 5 ,~
.~ Summary of Culture Results 6 Hours Post- 72 Hours Post-Treatment Treatment Test Compound % Negative % Negative .
: Untreated 0 :
.~ 2% Econazole, in 10 0 cream fl-[2,4-dichloro-p-1 (4-chlorobenzyloxy)-~
`- )phenethyl]imidazole ) ` 15 Lnitrate ;, , .:~ 2% 1-[2-(2,4,6-tri- 80 56 s chlorophenylthio)-4-(4-fluorophenyl)-n-butyl]imidazole nitrate, in cream 20 Untreated 0 0 .j .
: 2% Miconazole, in 80 20 cream . 2% 1-~2-(2,6-di- 100 100 chlorophenylthio)-` 4-(4-chlorophenyl)-n-butyl]imidazole A nitrate, in cream '~ 25 .;, ., ~ .
., .
. -: . .
~ .
...
.
.. 30 ;,'',' ' .
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:
, 1~7~493 -~i EXAMPLE 20 Mouse Acute Oral Toxicity (LD50) Protocol: The test material is suspended in a 0.5%
low viscosity sodium carboxymethylcellulose vehicle. Con-centrations are adjusted so that doses can be given in ,. .
~ volumes of 0.1 ml./10 g. body weight. Six groups (comprising - 5 male and 5 female mice in each group) of mice are used.
A single oral dose, per kilogram of body weight, of either ~'; 100 mg., 200 mg., 400 mg., 800 mg., 1600 mg. or 3200 mg.
-~ 10 of 1-[2-(2,6-dichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole nitrate is administered to the mice. After ~,`!, administration, the mice are observed for a two-t~eek period.
Using the above protocol, the acute oral LD50 of 1-[2-(2,6-dichlorophenylthio)-4-(4-chlorophenyl~n-butyl]imidazole nitrate is estimated to be >3200 mg./kg.
~; Three mice, given 3200 mg./kg., showed signs of toxicity.
No signs of toxicity were seen for any of the other mice on this study.
,,;,.. .
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~t ~'''`'` ' . . .
~`~. t
~ The oil from above in a few ml. of tetrahydrofuran was - added to a mixtur~ prepared by reacting imidazole (9.18 g.) r; 30 and sodium hydride (50~ dispersion in mineral oil; 3.24 g.) r~ .
'~7 4~
.
~ ~ .
''' ' ' ' - ' ' ' - .
`' ' ' ~ ' in 200 ml. tetrahydrofuran until the evolution of hydrogen ceases. The mixture was heated under reflux overnight, evap- -orated to dryness and the residue extracted with a small volume of dichloromethane. This solution was filtered and chromatographed on silica gel eluting with 10~ methanol in dichloromethane. Trituration with ethyl acetate/hexane gave 1-[2-hydroxy-4-(4-fluorophenyl)-n-butyl]imidazole as colorless crystals, m.p. 120.5-122.5C.
Similarly, proceding as above, substituting 3-(4-chloro-phenYl)propionaldehyde for 3-(4-fluorophenyl)propionalde- -~
hyde, there is prepared 1-~2-hydroxy-4-(4-chlorophenyl)-n-butyl]imidazole, m.p.
105-109C.
.
A solution of 6.0 g. of 1-[2-hydroxy-4-(4-chlorophenyl)-n-butyl]imidazole in 30 ml. of thionyl chloride was warmed at 65-70C. for one hour. Evaporation to dryness afforded 1-~2-chloro-4-(4-chlorophenyl)-n-butyl]imidazole hydro-chloride.
Similarly, 1-[2-chloro-4-(4-fluorophenyl)-n-butyl]-imidazole hydrochloride is prepared The free base may be obtained for use in the subsequent alkylation steps, if desired, by shaking the hydrochloride in dichloromethane with excess aqueous potassium carbonate solution, washing the organic layer with water, drying over magnesium sulfate and evaporating to dryness in vacuo to remove all traces of dichloromethane.
~ -.
- , . .. ~ . . . .
-~ ` 1077493 EX~MPLE 13 A mixture of 6.46 g. of 1-[2-chloro-4-(4-chlorophenyl)-n-butyl]imidazole, 8.5 g. of 2,6-dichlorothiophenol and 6.4 g.
of anhydrous potassium carbonate in 100 ml. of acetone was S stirred and refluxed for 18 hours. The solvent was evaporated under reduced pressure and 100 ml. of water was added. The resulting mixture was extracted with 300 ml. of ether and the ether extract washed twice with water and dried (MgSO4) to afford a solution containing 1-[2-(2,6-dichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole.
The nitrate salt was precipitated by the dropwise addition of 70~ nitric acid (d=1.42) to the etheral solution until precipitation was complete. The resulting salt was recrystallized from acetone-ethyl acetate as colorless blades, ~15 m.p. 162-163 (foaming).
,.; , . . . : .
In a similar manner, 1-[2-(2,6-dichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]imidazole nitrate salt, m.p. 131.5-'I 132.5~ was prepared.
~20 A mixture of 1,2-expoxy-4-(4-chlorophenyl)butane (3.65g.), , 2,6-dichlorothiophenol (4.0g.) and anhydrous potassium carbonate (200 mg.) in acetone (60 ml.) was stirred under reflux under nitrogen for about 4 hours. After removal of : .
the solvent, ether (150 ml.) was added and the extract washed with water, dried (MgSO4) and evaporated.
The above material in 100 ml. dichloromethane was treated with 6 ml. of thionyl chloride, heated under gentle reflux for - one hour, and the solution evaporated to dryness and evacuated to remove traces of thionyl chloride. The residue was treated with 7 g. of imidazole and 30 ml. of acetonitrile and stirred ' .r ~"~
-` 1077493 overnight at 55C and for one day at 85C. The solvent was evaporated and after the addition of 50 ml. water the residue was extracted with ether. ~he ether extract was washed well with water and dried (MgSO4) to afford a solution containing 1-[2-(2,6-dichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]imi-dazole, which was precipated and purified as its nitrate salt, -~ m.p. 162.5-164.5C.
Similarly, 1-[2-(2,6-dichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]imidazole-nitrate salt, m.p. 131.5-132.5C, was prepared.
Following the procedures in Preparations 1, 2 and 3, and Examples 1 or 2 using equivalent amounts of the appropriate starting materials, there may be obtained the following compounds. Where indicated, the compounds may be further characterized by conversion to the indicated ` acid addition salt.
.
1-[2-(2,5-dichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]-imidazole - nitrate salt, m.p. 155.5-157C.
1-[2-(2,3-dichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]-~20 imidazole - nitrate salt, m.p. 136-139.5C.
1-[2-(2-chlorophenylthio)-4-(4-chlorophenyl)-n-butyl]-imidazole - nitrate salt, m.p-. 136-136.5C.
1-[2-(2-bromophenylthio)-4-(4-chlorophenyl)-n-butyl]
imidazole - nitrate salt, m.p. 137-138C.
1-[2-(2,6-dibromophenylthio)-4-(4-chlorophenyl~n-butyl]-. , .
imidazole 1-[2-(2,4-dibromophenylthio)-4-(4-chlorophenyl)-n-butyl]-`~ imidazole ; 1-[2-(2,4,6-trichlorophenylthio)-4-(4-chlorophenyl)-n~butyl]-imidazole m.p. 136-137C; nitrate salt, m.p. 165-166C.
. . ~i . .
r ~ ~
` ~' 1077493 , ,.....
[2-t2,5-dichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]-`` imidazole - nitrate salt, m.p. 128.5-131C.
1-[2-(2,3-dichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]-, . .
~ imidazole `S 1-~2-t2-chlorophenylthio)-4-(4-fluorophenyl)-n-butyl]-imidazole - nitrate salt, m.p. 123-124C.
1-[2-(2-bromophenylthio)-4-(4-fluorophenyl)butyl]-.:
imidazole 1-[2-(2,6-dibromophenylthio)-4-(4-fluorophenyl)-n-butyl]-0 imidazole 1-[2-(2,4-dibromophenylthio)-4-(4-fluorophenyl)-n-butyl]-imidazole ., -~ .
1-[2-(2,4,6-trichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]imidazole - nitrate salt, m.p. 163-164C.
1-[2-(2,3,6-trichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]-imidazole - nitrate salt, m.p. 138-142C ~foaming).
1-[2-(2,3,4-trichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]-imidazole 1-[2-(2,3,5-trichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]-~0 imidazole 1-[2-(2,3,4,5-tetrachlorophenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole ' 1-[2-(2,3,4,6-tetrachlorophenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole ;5 1-[2-(2,3,5,6-tetrachlorophenylthio)-4-(4-chlorophenyl)-n- butyl]imidazole 1-[2-(2,3-dibromophenylthio)-4-(4-chlorophenyl)-n-butyl]-imidazole ; 1-[2-(2,5-dibromophenylthio)-4-(4-chlorophenyl)-n-butyl]-0 imidazole ' ~,.~
"
. . .
:. :
. 1-[2-(2,6-difluorophenylthio)-4-(4-chlorophenyl)-n-butyl]-- imidazole . 1-[2-(2,5-difluorophenyithio)-4-(4-chlorophenyl)-n-butyl]-: imidazole :5 1-[2-(2,4-difluorophenylthio)-4-(4-chlorophenyl)-n-butyl]-imidazole 1-[2-(2-fluorophenylthio)-4-(4-chloropheny~-n-butyl]-.. imidazole ~ 1-[2-(2,3-difluorophenylthio)-4-(4-chlorophenyl)-n-butyl]-: , .
.0 imidazole , .
1-[2-(2,3,4-trichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]-`:~ imidazole ,...
: 1-[2-(2,3,6-trichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]-.... .
"! imidazole l.~"
.; ., -5 1-[2-(2,3,5-trichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]imidazole 1-[2-(2,3,4,6-tetrachlorophenylthio)-4-(4-fluorophenyl n-butyl]imidazole 1-[2-(2,3,5,6-tetrachlorophenylthio)-4-(4-fluorophenyl)-.:20 n-butyl]imidazole .. :. 1-[2-(2,3,4,5-tetrachlorophenylthio)-4-(4-fluorophenyl)-n-~i ~. .butyl]imidazole '.'. i , i` . 1-[2-(2,3-dibromophenylthio)-4-(4-fluorophenyl)-n-butyl]-.~
imidazole .
1-[2-(2,5-dibromophenyl~hio)-4-(4-fluorophenyl)-n-butyl]-imidazole 1-[2-(2-fluorophenylthioj-4-(4-fluorophenyl)-n-butyl]-. . .
~-' imidazole 1-[2-(2,3-difluorophenylthio)-4-(4-fluorophenyl)-n-butyl]-, o imidazole ~ - 79-,. ~ , :,' . , . -, , . - :
,.. . .
: ~- - ', ` . - - - :
: ::: - - .
.. . .
` ~077493 [2-~2,4-di~luo~op}lenylthio)-~-(4~fluorophenyl)-n-butyl]~
imidazole 1-[2-(2,5-difluorophenylthio)-4-(4-fluorophenyl)-n-butyl]-.... .
imidazole and ~; :; -1-~2-(2,6-difluorophenylthio)-4-(4-fluorophenyl)-n-butyl]-` imidazole.
~ EXAMPLE 16 ,< Nitric acid (70%; d = 1.42) was added dropwise to a stirred solution of 2.0 g. of 1-[2-(2-chlorophenylthio)-4-` (4-chlorophenyl)-n-butyl]imidazole in 30 ml. of anhydrous ether . ............................................... .
until precipitation was complete. The product was filtered sj? off, washed with ether, air dried, and recrystallized from , . .
ethyl acetate to yield 1-[2-(~chlorophenylthio)-4-(4-chloro-~15 phenyl~n-butyl]imidazole nitrate, m.p. 136-136.5C.
~ In similar manner, all compounds of Formula (I) in base -~
; form can be converted to their antimicrobial acid addition salts by treatment with the appropriate acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric ~20 acid, phosphoric acid, acetic acid, propionic acid, glycolic '~ acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, .~ succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid or salicyclic acid.
,.
..
~ EX~MPLE 17 .:.
1-[2-(2,6-Dichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]-. . .
; imidazole nitrate (2.0 g.) in 100 ml. of ether was stirred with excess dilute potassium carbonate solution until the ~ 30 salt was completely dissolved. The organic layer was then ., ,:
.~,..;
. , . . ~.~ .
,, .
., .
., . ` .
separated, washed twice with water, dricd over magnesium sulfate and evaporated to yield 1-[2-(2,6-dichlorophenylthio-4-(4-chlorophenyl)-n-butyl]imidazole, m.p. 68-70.5C. (foaming) after crystallization from cyclohexane.
S In similar manner, the antimicrobial acid addition salts -of all compounds of Formula (I) can be converted to the ` corresponding compounds in base form.
The following illustrates the preparation of represen-~ .,.
L0 tative pharmaceutical formulations which may be used for controlling fungi, bacteria and protozoa, utilizing an active compound such as a salt of 1-[2-(2,6-dichlorophenylthio)-- .
4-(4-chlorophenyl)-n-butyl]imidazole.
A. Topical Formulation . . . .
~L5 grams Active compound 0.2 - 2 Span 60 2 Tween 60 2 . .
Mineral oil 5 Petrolatum 10 : Methyl paraben 0.15 :, ;
Propyl paraben 0.05 BHA (butylated hydroxy anisole) 0.01 Water qs 100 ;25 All of the above ingredients, except water, are combined ,,, and heated at 60C, with stirring. A sufficient quantity of water at 60C. is then added with vigorous stirring to pro-vide 100 g. of the cream formulation which is then cooled / to room temperature.
,, ,~10 , .
; ~ 81-.,, ' :
. ~ .
:
~.077493 .
,~ B. I.V. Formulation ~- Active compound 0.5 g.
, Propylene glycol 20 g.
, Polyethylene glycol 40020 g.
,;~t 5 Tween 80 1 g.
'A;'``' 0~ 9 Saline solution qs100 ml.
. .
The active compound is dissolved in propylene glycol, polyethylene glycol 400 and Tween ~0. A sufficient quantity of 0.9% sallne solution is then added with stirrins to pro-vide 100 ml. of the I.V. solution which is filtered through a 0.2 micron membrane filter and packaged under sterile `, conditions.
; ~, C. Oral ~ormulationparts by weight Active compound 200 ~" Magnesium stearate 3 , .;
- Starch 30 ; .
~ `Lactose 116 , ~, PVP (polyvinylpyrrolidone) 3 ~i"., :, . ;
` The above ingredients are combined and granulated using :; .: .
,~ methanol as the solvent. The formulation is then dried and : ,;, ' formed into tablets (containing 200 mg. of active compound) with an appropriate tabletting machine.
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The antifungal activity of certain compounds of the i` present invention is illustrated by the following assay procedure:
~::
A. Trichophyton mentagrophytes fungus culture for infection was grown on agar slants of Sabouraud dextrose for 4 weeks at .,~,.. . .
room temperature. A 2% solution of corn starch was prepared ; by heating the starch in sterile distilled water. Approximately ~; 7 ml. of corn starch solution was added to each of 8 slants of culture. Suspension of organism was accomplished with vigorous pipetting and vortexing of the slants.
Guinea pigs (250-350 grams) were assigned to ten experi-; mental groups of ten animals (5 female, 5 male). One day pre-challenge, all guinea pigs were clipped and shaved in the interscapular region, avoiding any abrasions or lacerations.
Animals were challenged by rubbing a toothbrush, which had been dipped in fungal suspension, over a 1.5 cm x 1.5 cm shaved area. The rubbing continued until slight reddening occurred.
... .
Treatment with test compound began 3 days post-challenge and was continued once daily for 5 consecutive days. At each ~ treatment approximately 1 ml. of formula~ion was applied to the ,i infected area using a tongue depressor. Ten animals were not ~; treated and served as untreated infection controls.
~, ~
Hair was pluc~ed from 10-20 sites in the infected area , of each guinea pig. The hairs were innoculated onto plates containing Mycosel agar. One plate was used ~or each animal : .
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~ at each culture time (3, 7, and 14 days post-in~ection).
.. ..
.. Plates were incubated at room temperature (approximately . 21C) and read 7 days after innoculation.
. ;:. . .
Summary of Culture Results Days Post Challenge .. ;. 3* 4 7 14 ~ Test Compound ,,~' ~ Untreated controls 10/10** 10/10 10/10 8/10 ... . .
0.5% Miconazole~in cream: 10/10 3/10 2/10 9/10 ~10 ~1-[2,4-dichloro-~-(2,4-~
'............. dichlorobenzyloxy)phen-;¦ ethyl]-imidazole nitrate~
; 0.5% 1-[2-(2-chloro- 10/10 0/10 0/10 0/10 phenylthio)-4-(4-chlorophenyl)-n-butyl]-~
~15 imidazole nitrate~in cream , _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ., . ~ .
~ Untreated controls10/1010/1010/1010/10 .... . .
Ø3% Miconazole~in cream 10/10 3/10 0/10 3/10 . 0.1% 1-[2-(2,5-dichloro- 10/100/100/10 0/10 ;~ phenylthio)-4-(4-;: chlorophenyl)-n-butyl]-imidazole nitrate,in cream .~",:, .
:.;;: .
Untreated controls10/1010/1010/1010/10 ~:4 0.3% Miconazole~in cream 10/10 3/10 0/10 3/10 i 0.1% 1-E2-(2-bromo-10/10 2/100/10 0/10 -.25 phenyLthio)-4-.. ii chlorophenyl)n-~"', f butyl]imidazole nitrate,in cream ; -, . .
,. ~
', * Pretreatment culture . .
** Animi~ls with positive culture/Total animals in group . '' .
. , . - . . -... .
`~ B. Swiss/Webster mice 17-20 gram, female, were given .; 0.25 mg. of ~-estradiol suspension, in a 0.2 ml. volume, sub-- cutaneously on Days 1, 3 and 5 to induce estrus. Estrus was then maintained with an injection o~ ~-estradiol every 7 days. -~; A clinical isolate was obtained from human sputum.
Organism to be injected is grown for 72 hours on Sabouraud Dextrose Agar (SDA) slants at 30C. On the day of the chal-i-,f lenge 2-3 ml. of Sabouraud Dextrose Broth~(SDB) was added to - 10 each slant of the organism and mixed by pipetting to achieve a homogenous suspension. Concentration of organisms for ; injection is approximately 101 org./ml. (2-3 ml. of SDB
I is added to culture of organism growing on SDA slant). 7 ; days after 1st estradiol injection approximately 25 ~1 of culture suspension is injected into each mouse vagina using a 20 gauge, 2 mm. ball-tipped animal feeding needle.
~;' The mice were initially treated 6 hours post-challenge .:~.; . :
and then twice daily, 6 hours apart, using a ball-tipped feeding needle for cream or liquid type formulations. The fluid type formulations were injected into the vagina until it overflowed. Treatments were carried out for 5 consecutive days. Ali animals received one treatment only on the fifth day so that they could be cult~red during working hours, 6 r;~
~- hours post-treatment. ~he mice were cultured on Day 4 post-challenge (6 hours post-treatment) and Day 7 post-challenge ,,1, ', ' (72 hours post-treatment). Cultures were obtained by vaginal i," washing using approximately 0.1 ml. of sterile distilled water ~, with an 18-20 gauge, 2 mm. ball-tipped feeding needle. The ~i wash was inoculated into a tube of SDB containing 100 ~g '6'''' 30 oxytetracycline/ml. Cultures were incubated at 30C. for... .
;
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: 48-72 h~ours then read microscopically. Candida albicans was confirmed by germ tube formation in 2-3 hours in sheep serum at 37C.
, . . .
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.~ Summary of Culture Results 6 Hours Post- 72 Hours Post-Treatment Treatment Test Compound % Negative % Negative .
: Untreated 0 :
.~ 2% Econazole, in 10 0 cream fl-[2,4-dichloro-p-1 (4-chlorobenzyloxy)-~
`- )phenethyl]imidazole ) ` 15 Lnitrate ;, , .:~ 2% 1-[2-(2,4,6-tri- 80 56 s chlorophenylthio)-4-(4-fluorophenyl)-n-butyl]imidazole nitrate, in cream 20 Untreated 0 0 .j .
: 2% Miconazole, in 80 20 cream . 2% 1-~2-(2,6-di- 100 100 chlorophenylthio)-` 4-(4-chlorophenyl)-n-butyl]imidazole A nitrate, in cream '~ 25 .;, ., ~ .
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.. 30 ;,'',' ' .
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, 1~7~493 -~i EXAMPLE 20 Mouse Acute Oral Toxicity (LD50) Protocol: The test material is suspended in a 0.5%
low viscosity sodium carboxymethylcellulose vehicle. Con-centrations are adjusted so that doses can be given in ,. .
~ volumes of 0.1 ml./10 g. body weight. Six groups (comprising - 5 male and 5 female mice in each group) of mice are used.
A single oral dose, per kilogram of body weight, of either ~'; 100 mg., 200 mg., 400 mg., 800 mg., 1600 mg. or 3200 mg.
-~ 10 of 1-[2-(2,6-dichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole nitrate is administered to the mice. After ~,`!, administration, the mice are observed for a two-t~eek period.
Using the above protocol, the acute oral LD50 of 1-[2-(2,6-dichlorophenylthio)-4-(4-chlorophenyl~n-butyl]imidazole nitrate is estimated to be >3200 mg./kg.
~; Three mice, given 3200 mg./kg., showed signs of toxicity.
No signs of toxicity were seen for any of the other mice on this study.
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Claims (108)
PROPERTY OF PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the formula:
(I) wherein R1 and R2 are each independently phenyl, phenyl straight chain lower alkyl, or phenyl straight chain lower alkenyl; or one of the above substituted in the phenyl ring with one or more substituents independently selected from the group consisting of lower alkyl of from one to four carbon atoms, halo or trifluoromethyl; X is oxygen or sulfur; n is an integer of from 1 to 8 with the proviso that N is not 1 when R1 is phenyl or substituted phenyl; or an antimicrobial acid addition salt thereof, which comprises:
a. converting a compound of the formula:
(II) wherein R1 and n are as above to an ether by reaction with base and R2Y wherein R2 is substituted or unsubstituted phenyl straight chain lower alkyl or phenyl straight chain lower alkenyl, and Y is a leaving group, or b. converting a compound of the formula:
wherein R1, n and Y are as defined above, or an acid addition salt thereof, to an ether or thioether by reaction with base and R2OH or R2SH, wherein R2 is substituted or unsubstituted phenyl straight chain lower alkyl or phenyl straight chain lower alkyl; or c. converting a compound of the formula:
wherein R1, n and Y are as defined above, or an acid addition salt thereof, to a thioether by reaction with base and R2SH, wherein R2 is substituted or unsubstituted phenyl straight chain lower alkyl or phenyl straight chain lower alkenyl; or d. reacting a compound of the formula:
and/or wherein R1 is substituted or unsubstituted phenyl straight chain lower alkyl and R2 is substituted or unsubstituted phenyl, phenyl straight chain lower alkyl or phenyl straight chain lower alkenyl, and Y is as defined above, with imidazole;
or e. hydrogenating a compound of the formula:
or an acid addition salt thereof, wherein R1' and R2' are identical with R1 and R2, respectively, as defined for formula (I), except that R1' and/or R2' contains aliphatic olefinic unsaturation; and f. optionally converting a free base to its acid addition salt, or g. optionally converting an acid addition salt to the corresponding free base.
(I) wherein R1 and R2 are each independently phenyl, phenyl straight chain lower alkyl, or phenyl straight chain lower alkenyl; or one of the above substituted in the phenyl ring with one or more substituents independently selected from the group consisting of lower alkyl of from one to four carbon atoms, halo or trifluoromethyl; X is oxygen or sulfur; n is an integer of from 1 to 8 with the proviso that N is not 1 when R1 is phenyl or substituted phenyl; or an antimicrobial acid addition salt thereof, which comprises:
a. converting a compound of the formula:
(II) wherein R1 and n are as above to an ether by reaction with base and R2Y wherein R2 is substituted or unsubstituted phenyl straight chain lower alkyl or phenyl straight chain lower alkenyl, and Y is a leaving group, or b. converting a compound of the formula:
wherein R1, n and Y are as defined above, or an acid addition salt thereof, to an ether or thioether by reaction with base and R2OH or R2SH, wherein R2 is substituted or unsubstituted phenyl straight chain lower alkyl or phenyl straight chain lower alkyl; or c. converting a compound of the formula:
wherein R1, n and Y are as defined above, or an acid addition salt thereof, to a thioether by reaction with base and R2SH, wherein R2 is substituted or unsubstituted phenyl straight chain lower alkyl or phenyl straight chain lower alkenyl; or d. reacting a compound of the formula:
and/or wherein R1 is substituted or unsubstituted phenyl straight chain lower alkyl and R2 is substituted or unsubstituted phenyl, phenyl straight chain lower alkyl or phenyl straight chain lower alkenyl, and Y is as defined above, with imidazole;
or e. hydrogenating a compound of the formula:
or an acid addition salt thereof, wherein R1' and R2' are identical with R1 and R2, respectively, as defined for formula (I), except that R1' and/or R2' contains aliphatic olefinic unsaturation; and f. optionally converting a free base to its acid addition salt, or g. optionally converting an acid addition salt to the corresponding free base.
2. A process of claim 1, wherein the thioether compound is prepared by steps b, c, d or e and optionally steps f or g.
3. A process of claim 1 for preparing the ether compound by steps a, b, or e and optionally steps f or g.
4. A process of claim 1, wherein steps a, b, c or e N is 1.
5. A process of claim 4, wherein the selected step the compound to be reacted R1 is phenethyl, styryl, or halo-substi-tuted phenethyl or styryl and R2 is phenyl, benzyl, cinnamyl or halo-substituted phenyl, benzyl or cinnamyl.
6. A process of claim 5, wherein the halo substitution in R1 is 4-chloro, 4-bromo, 4-fluoro, 2,4-dichloro or 3,4-dichloro.
7. A process of claim 5, wherein the halo substitution in R2 is 4-chloro, 4-bromo, 4-fluoro, 2,4-dichloro or 3,4-di-chloro; and when R2 is substituted phenylthio, additionally 2,4,5-trichloro or 2,3,4,5,6-pentachloro.
8. A process of claim 5 for preparing 1-[2-(3,4-dichloro-phenylthio)-4-phenylbutyl]imidazole and the acid addition salts thereof, wherein steps b, c, d or e for preparing the thioether, R1 is phenyl and R2 is 3,4-dichlorophenyl.
9. A process of claim 5 for preparing 1-[2-(3,4-dichloro-benzylthio)-4-phenylbutyl]imidazole and the acid addition salts thereof, wherein steps b, c, d or e for preparing the thioether, R1 is phenyl and R2 is 3,4-dichlorobenzyl and optionally followed by either steps f or g.
10. A process of claim 5 for preparing 1-[2-(2,4-dichloro-benzyloxy)-4-phenylbutyl]imidazole and the acid addition salts thereof, wherein steps a, b or 3 for preparing the ether R1 is phenyl and R2 is 2,4-dichlorobenzyl and optionally followed by either steps f or g.
11. A process of claim 5 for preparing 1-[2-(4-chloro-phenylthio)-4-(4-chlorophenyl)butyl]imidazole and the acid addition salts thereof, wherein steps b, c, d or e for preparing the thioether, R1 is 4-chlorophenyl and R2 is 4-chlorophenyl and optionally followed by either steps f or g.
12. A process of claim 5 for preparing 1-[2-(4-chloro-benzylthio)-4-(4-chlorophenyl)butyl]imidazole and the acid addition salts thereof, wherein steps b, c, d or e for preparing the thioether, R1 is 4-chlorophenyl and R2 is 4-chlorobenzyl and optionally followed by either steps f or g.
13. A process of claim 5 for preparing 1-[2-(3,4-dichloro-phenylthio)-4-(4-chlorophenyl)ibutyl]imidazole and the acid addition salts thereof, wherein steps b, c, d or e for preparing the thioether, R1 is 4-chlorophenyl and R2 is 3,4-dichlorophenyl and optionally followed by either steps f or g.
14. A process of claim 5 for preparing 1-[2-(2,4-dichloro-phenylthio)-4-(4-chlorophenyl)butyl]imidazole and the acid addition salts thereof, wherein steps b, c, d or e for preparing the thioether, R1 is 4-chlorophenyl and R2 is 2,4-chlorophenyl and optionally followed by either steps f or g.
15. A process of claim 1, wherein steps a, b, c, or e n is 2 or 3.
16. A process of claim 15, wherein steps a, b, c or e R1 is phenyl or halo-substituted phenyl and R2 is independently phenyl, benzyl or halo-substituted phenyl or benzyl.
17. A process of claim 16, wherein the halo substitution in R1 is 4-chloro, 4-bromo, 4-fluoro, 2,4-dichloro, 2,4-difluoro or 2,4-bromo.
18. A process of claim 17, wherein the halo substitution in R2 is 4-chloro, 4-bromo, 4-fluoro, 2,4-dichloro or 3,4-dichloro; and when R2 is substituted phenylthio, additionally 2,4,5-trichloro or 2,3,4,5,6-pentachloro.
19. A process of claim 16 for preparing 1-[3-(4-chloro-benzylthio)-3-(2,4-dichlorophenyl)propyl]imidazole and the acid addition salts thereof, wherein steps b, c or e for pre-paring the thioether, R1 is 2,4-dichlorophenyl and R2 is 4-chlorobenzyl and optionally followed by steps f or g.
20. A process of claim 16 for preparing 1-[3-(4-chloro-phenylthio)-3-(2,4-dichlorophenyl)propyl]imidazole and the acid addition salts thereof, wherein steps b, c or e for preparing the thioether, R1 is 2,4-dichlorophenyl and R2 is 4-chlorophenyl and optionally followed by steps f or g.
21. A process of claim 16 for preparing 1-[4-(3,4-dichloro-phenylthio)-4-(4-chlorophenyl)butyl]imidazole and the acid addition salts thereof, wherein steps b, c or e for preparing the thioether, R1 is 4-chlorophenyl and R2 is 3,4-dichlorophenyl and optionally followed by steps f or g.
22. A process of claim 16 for preparing 1-[4-(4-chloro-benzylthio)-4-(4-chlorophenyl)butyl]imidazole and the acid addition salts thereof, wherein steps b, c or e for preparing the thioether, R1 is 4-chlorophenyl and R2 is 4-chlorobenzyl and optionally followed by steps f or g.
23. A process of claim 16 for preparing 1-[4-(2,4-dichloro-benzyloxy)-4-(4-chlorophenyl)butyl]imidazole and the acid addition salts thereof, wherein steps b, c or e for preparing the thioether, R1 is 4-chlorophenyl and R2 is 2,4-dichloro-benzyl and optionally followed by steps f or g.
24. A process of claim 16 for preparing 1-[4-(4-chloro-phenylthio)-4-(2,4-dichlorophenyl)butyl]imidazole and the acid addition salts thereof, wherein steps b, c or e for preparing the thioether, R1 is 2,4-dichlorophenyl and R2 is 4-chlorophenyl and optionally followed by steps f or g.
25. A process of claim 16 for preparing 1-[4-(4-chloro-benzylthio)-4-(2,4-dichlorophenyl)butyl]imidazole and the acid addition salts thereof, wherein steps b, c or e for preparing the thioether, R1 is 2,4-dichlorophenyl and R2 is 4-chloro-benzyl and optionally followed by steps f or g.
26. A process of claim 16 for preparing 1-[4-(4-fluoro-benzylthio)-4-(2,4-dichlorophenyl)butyl]imidazole and the acid addition salts thereof, wherein steps b, c or 3 for preparing the thioether, R1 is 2,4-dichlorophenyl and R2 is 4-chloro-benzyl and optionally followed by steps f or g.
27. A process of claim 16 for preparing 1-[4-(4-chloro-benzyloxy)-4-(2,4-dichlorophenyl)butyl]imidazole and the acid addition salts thereof, wherein steps b, c or e for preparing the thioether, R1 is 2,4-dichlorophenyl and R2 is 4-chloro-benzyl and optionally followed by steps f or g.
28. A compound of the formula (I) wherein R1 and R2 are each independently phenyl, phenyl straight chain lower alkyl or phenyl straight chain lower alkenyl, or one of the above substituted in the phenyl ring with one or more substituents independently selected from the group con-sisting of lower alkyl of from one to four carbon atoms, halo and trifluoromethyl; X is oxygen or sulfur, n is an integer of from 1 to 8 with the proviso that n is not 1 when R1 is phenyl or substituted phenyl; and the antimicrobial acid addition salts thereof, when prepared by the process of claim 1.
29. The compound of claim 28, wherein X is sulfur when prepared by the process of claim 2.
30. The compound of claim 28, wherein X is oxygen, when prepared by the process of claim 3.
31. The compound of claim 28, wherein n is 1, when prepared by the process of claim 4.
32. A compound of the formula:
(I) wherein R1 is phenethyl, styryl, or halo-substituted phenethyl, or styryl, R2 is phenyl, benzyl, cinnamyl or halo-substituted phenyl, benzyl or cinnamyl, X is oxygen or sulfur, n is 1 and the antimicrobial addition salts thereof, when prepared by the process of claim 5.
(I) wherein R1 is phenethyl, styryl, or halo-substituted phenethyl, or styryl, R2 is phenyl, benzyl, cinnamyl or halo-substituted phenyl, benzyl or cinnamyl, X is oxygen or sulfur, n is 1 and the antimicrobial addition salts thereof, when prepared by the process of claim 5.
33. The compound of claim 32 wherein the halo substitution in R1 is 4-chloro, 4-bromo, 4-fluoro, 2,4-dichloro or 3,4-dichloro, when prepared by the process of claim 6.
34. The compound of claim 32, wherein the halo substitution in R2 is 4-chloro, 4-bromo-, 4-fluoro- 2,4-dichloro or 3,4-dichloro; and when R2 is substituted phenylthio, additionally 2,4,5-trichloro or 2,3,4,5,6-pentachloro, when prepared by the process of claim 7.
35. The compound of claim 32, which is 1-[2-(3,4-dichloro-phenylthio)-4-phenylbutyl]imidazole and the acid addition salts thereof, when prepared by the process of claim 8.
36. The compound of claim 32,which is 1-[2-(3,4-dichloro-phenylthio)-4-phenylbutyl]imidazole and the acid addition salts thereof, when prepared by the process of claim 9.
37. The compound of claim 32 which is 1-[2-(2,4-dichloro-benzyloxy)-4-phenylbutyl]imidazole and the acid addition salts thereof, when prepared by the process of claim 10.
38. The compound of claim 32 which is 1-[2-(4-chloro-phenylthio)-4-(4-chlorophenyl)butyl]imidazole and the acid addition salts thereof, when prepared by the process of claim 11.
39. The compound of claim 32 which is 1-[2-(4-chloro-benzylthio)-4-(4-chlorophenyl)butyl]imidazole and the acid addition satls thereof, when prepared by the process of claim 12.
40. The compound of claim 32 which is 1-[2-(3,4-dichloro-phenylthio)-4-(4-chlorophenyl)butyl]imidazole and the acid addition salts thereof, when prepared by the process of claim 13.
41. The compound of claim 32 which is 1-[2-(2,4-dichloro-phenylthio)-4-(4-chlorophenyl)butyl]imidazole and the acid addition salts thereof, when prepared by the process of claim 14.
42. The compound of claim 28, wherein n is 2 or 3, when prepared by the process of claim 15.
43. A compound of the formula:
(I) wherein R1 is phenyl or halo-substituted phenyl, R2 is inde-pendently phenyl, benzyl or halo-substituted phenyl or benzyl;
X is oxygen or sulfur; n is 2 or 3 and the antimicrobial addi-tion salts thereof, when prepared by the process of claim 16.
(I) wherein R1 is phenyl or halo-substituted phenyl, R2 is inde-pendently phenyl, benzyl or halo-substituted phenyl or benzyl;
X is oxygen or sulfur; n is 2 or 3 and the antimicrobial addi-tion salts thereof, when prepared by the process of claim 16.
44. The compound of claim 28, wherein the halo substitution in R1 is 4-chloro, 4-bromo, 4-fluoro, 2,4-dichloro, 2,4-difluoro, or 2,4-dibromo and n is 2 or 3, when prepared by the process of claim 17.
45. The compound of claim 28, wherein the halosubstitution in R2 is 4-chloro, 4-bromo, 4-fluoro, 2,4-dichloro or 3,4-dichloro; and when R is substituted phenylthio, additionally 2,4,5-trichloro or 2,3,4,5,6-pentachloro and n is 2 or 3, when prepared by the process of claim 18.
46. The compound of claim 43 which is 1-[3-(4-chlorobenzyl-thio)-3-(2,4-dichlorophenyl)propyl]imidazole and the acid addition salts thereof, when prepared by the process of claim 19.
47. The compound of claim 43, which is 1-[3-(4-chlorophenyl-thio)-3-(2,4-dichlorophenyl)propyl]imidazole and the acid addition salts thereof, when prepared by the process of claim 20.
48. The compound of claim 43 which is 1-[4-(3,4-dichloro-phenylthio)-4-(4-chlorophenyl)butyl]imidazole and the acid addition salts thereof, when prepared by the process of claim 21.
49. The compound of claim 43 which is 1-[4-(4-chlorobenzyl-thio)-4-(4-chlorophenyl)butyl]imidazole and the acid addition salts thereof, when prepared by the process of claim 22.
50. The compound of claim 43 which is 1-[4-(2,4-dichloro-benzyloxy)-4-(4-chlorophenyl)butyl]imidazole and the acid addition salts thereof, when prepared by the process of claim 23.
51. The compound of claim 43 which is 1-[4-(4-chlorophenyl-thio)-4-(2,4-dichlorophenyl)butyl]imidazole and the acid addition salts thereof, when prepared by the process of claim 24.
52. The compound of claim 43 which is 1-[4-(4-chlorobenzyl-thio)-4-(2,4-dichlorophenyl)butyl]imidazole and the acid addition salts thereof, when prepared by the process of claim 25.
53. The compound of claim 43 which is 1-[4-(4-fluorobenzyl-thio)-4-(2,4-dichlorophenyl)butyl]imidazole and the acid addi-tion salts thereof, when prepared by the process of claim 26.
54. The compound of claim 43 which is 1-[4-(4-chlorobenzyl-oxy)-4-(2,4-dichlorophenyl)butyl]imidazole and the acid addition salts thereof, when prepared by the process of claim 27.
CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE
CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE
55. A process for the preparation of a compound of the formula:
(I) and the antimicrobial acid addition salts thereof, wherein X is chloro or fluoro, Y is halo, at least one Y being in the 2'-position, n is 1 to 5 when Y is chloro, and n is 1 or 2 when Y is other than chloro, which comprises:
a. converting a compound of the formula:
wherein X is as defined above and Y' is a leaving group, or an acid addition salt thereof, to a thioether by reaction with wherein Y and n are as defined, or with a salt thereof; or b. reacting a compound of the formula:
and/or wherein X, Y, Y' and n are as defined above, with imidazole; or c. optionally converting a free base of formula (I) to its acid addition salt; or d. optionally converting an acid addition salt to the corresponding free base of formula (I).
(I) and the antimicrobial acid addition salts thereof, wherein X is chloro or fluoro, Y is halo, at least one Y being in the 2'-position, n is 1 to 5 when Y is chloro, and n is 1 or 2 when Y is other than chloro, which comprises:
a. converting a compound of the formula:
wherein X is as defined above and Y' is a leaving group, or an acid addition salt thereof, to a thioether by reaction with wherein Y and n are as defined, or with a salt thereof; or b. reacting a compound of the formula:
and/or wherein X, Y, Y' and n are as defined above, with imidazole; or c. optionally converting a free base of formula (I) to its acid addition salt; or d. optionally converting an acid addition salt to the corresponding free base of formula (I).
56. A process of claim 55, wherein steps a, b, c or d n is 1 to 3.
57. A process of claim 56, wherein steps a or b X is chloro.
58. A process of claim 57, wherein steps a or b Y is chloro.
59. A process of claim 57, wherein steps a or b X is fluoro and Y is chloro.
60. A process of claim 58 wherein steps a or b n is 2.
61. A process of claim 55 for preparing a compound of the formula:
and the antimicrobial acid addition salts thereof, wherein X is chloro or fluoro, each W is bromo or chloro or fluoro, at least one W being in the 2'-position, m is 1 to 4 when W is chloro, and m is 1 or 2 when W is other than chloro, wherein steps a or b Y is bromo or chloro or fluoro at least one Y being in the 2'-position, n is 1 to 4 when Y is chloro and m is 1 or 2 when Y is other than chloro, with a hydrogen in the 4'-position and X is chloro or fluoro.
and the antimicrobial acid addition salts thereof, wherein X is chloro or fluoro, each W is bromo or chloro or fluoro, at least one W being in the 2'-position, m is 1 to 4 when W is chloro, and m is 1 or 2 when W is other than chloro, wherein steps a or b Y is bromo or chloro or fluoro at least one Y being in the 2'-position, n is 1 to 4 when Y is chloro and m is 1 or 2 when Y is other than chloro, with a hydrogen in the 4'-position and X is chloro or fluoro.
62. A process of claim 61, wherein steps a or b n is 1, 2 or 3.
63. A process of claim 62 wherein steps a or b X is chloro.
64. A process of claim 63 wherein steps a or b Y is chloro.
65. A process of claim 62, wherein steps a or b X is fluoro and Y is chloro.
66. A process of claim 64, wherein steps a or b m is 2.
67. A process of claim 55 for preparing a compound of the formula:
and the antimicrobial acid addition salts thereof, wherein X is chloro or fluoro, each Z is bromo or chloro or fluoro, p is 0 to 3 when Z is chloro, and p is 0 when Z is other than chloro wherein steps a or b Y is bromo or chloro or fluoro, n is 0 to 3 when Y is chloro, p is 0 when Y is other than chloro and when n is 2 or 3 at least two Ys are in the 2'- and 6'-positions and X is chloro or fluoro.
and the antimicrobial acid addition salts thereof, wherein X is chloro or fluoro, each Z is bromo or chloro or fluoro, p is 0 to 3 when Z is chloro, and p is 0 when Z is other than chloro wherein steps a or b Y is bromo or chloro or fluoro, n is 0 to 3 when Y is chloro, p is 0 when Y is other than chloro and when n is 2 or 3 at least two Ys are in the 2'- and 6'-positions and X is chloro or fluoro.
68. A process of claim 67, wherein steps a or b Y is 0 or 1.
69. A process of claim 68 wherein steps a or b X is chloro.
70. A process of claim 69, wherein steps a or b Y is chloro.
71. A process of claim 68, wherein steps a or b X is fluoro and Y is chloro.
72. A process of claim 70, wherein steps a or b Y is 0.
73. A process of claim 55 for preparing a compound 1-[2-(2, 6-dichlorophenylthio-4-(4-chlorophenyl)-n-butyl]imidazole and the antimicrobial acid addition salts thereof, wherein steps a or b X is chloro and Y is 2,6-dichloro and optionally followed by steps c or d to prepare the acid addition salt or the free base.
74. A process of claim 55 for preparing a compound 1-[2-(2, 6-dichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole and the antimicrobial acid addition salts thereof, wherein steps a or b X is chloro and Y is 2,5-dichloro and optionally followed by steps c or d to prepare the acid addition salt or the free base.
75. A process of claim 55 for preparing a compound 1-[2-(2-chlorophenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole and the antimicrobial acid addition salts thereof, wherein steps a and b X is chloro and Y is 2-chloro and optionally followed by steps c or d to prepare the acid addition salt or the free base.
76. A process of claim 55 for preparing a compound 1-[2-(2, 3-dichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole and the antimicrobial acid addition salts thereof, wherein steps a or b X is chloro and Y is 2,3-dichloro, and optionally follow-ed by steps c or d to prepare the acid addition salt or the free base.
77. A process of claim 55 for preparing a compound 1-[2-(2-bromophenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole and the antimicrobial acid addition salts thereof, wherein steps a or b X is chloro and Y is 2-bromo and optionally followed by steps c or d to prepare the acid addition salt or the free base.
78. A process of claim 55 for preparing a compound 1-[2-(2, 6-dichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]imidazole and the antimicrobial acid addition salts thereof, wherein steps a or b X is fluoro and Y is 2,6-dichloro and optionally followed by steps c or d to prepare the acid addition salt or the free base.
79. A process of claim 55 for preparing a compound 1-[2-(2, 4,6-trichlorophenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole and the antimicrobial acid addition salts thereof, wherein steps a or b X is chloro and Y is 2,4,6-trichloro and optionally followed by steps c or d to prepare the acid addition salt or the free base.
80. A process of claim 55 for preparing a compound 1-[2-(2, 5-dichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]imidazole and the antimicrobial acid addition salts thereof, wherein steps a or b X is fluoro and Y is 2,5-dichloro and optionally followed by steps c or d to prepare the acid addition salt or the free base.
81. A process of claim 55 for preparing a compound 1-[2-(2, 4,6-trichlorophenylthio)-4-(4-fluorophenyl)-n-butyl]imidazole and the antimicrobial acid addition salts thereof, wherein steps a or b X is fluoro and Y is 2,4,6-trichloro and optionally followed by steps c or d to prepare the acid addition salt or the free base.
82. A compound of the formula:
(I) and the antimicrobial acid addition salts thereof, wherein X is chloro or fluoro, each Y is bromo or chloro or fluoro, at least one Y being in the 2'-position, n is 1 to 5 when Y
is chloro, and n is 1 or 2 when Y is other than chloro, when prepared by the process of claim 55.
(I) and the antimicrobial acid addition salts thereof, wherein X is chloro or fluoro, each Y is bromo or chloro or fluoro, at least one Y being in the 2'-position, n is 1 to 5 when Y
is chloro, and n is 1 or 2 when Y is other than chloro, when prepared by the process of claim 55.
83. The compound of claim 82, wherein n is 1 to 3, when prepared by the process of claim 56.
84. The compound of claim 82, wherein X is chloro and n is 1 to 3 when prepared by the process of claim 57.
85. The compound of claim 82, wherein X and Y are chloro and n is 1 to 3 when prepared by the process of claim 58.
86. The compound of claim 84, wherein X is fluoro, when prepared by the process of claim 59.
87. The compound of claim 85, wherein n is 2, when prepared by the process of claim 60.
88. A compound of the formula:
and the antimicrobial acid addition salts thereof, wherein X is chloro or fluoro, each W is bromo or chloro or fluoro, at least one W being in the 2'-position, m is 1 to 4 when W is is chloro, and m is 1 to 2 when W is other than chloro, when prepared by the process of claim 61.
and the antimicrobial acid addition salts thereof, wherein X is chloro or fluoro, each W is bromo or chloro or fluoro, at least one W being in the 2'-position, m is 1 to 4 when W is is chloro, and m is 1 to 2 when W is other than chloro, when prepared by the process of claim 61.
89. The compound of claim 88, wherein m is 1 to 3, when prepared by the process of claim 62.
90. The compound of claim 88, wherein X is chloro and m is 1 to 3 when prepared by the process of claim 63.
91. The compound of claim 88, wherein X and W are chloro and m is 1 to 3 when prepared by the process of claim 64.
92. The compound of claim 88, wherein X is fluoro and W
is chloro and m is 1 to 3, when prepared by the process of claim 65.
is chloro and m is 1 to 3, when prepared by the process of claim 65.
93. The compound of claim 88, wherein X is chloro and m is 2 when prepared by the process of claim 65.
94. A compound of the formula:
and the antimicrobial acid addition salts thereof, wherein X
is chloro or fluoro, each Z is bromo or chloro or fluoro, p is 0 to 3 when Z is chloro, and p is 0 when Z is other than chloro, when prepared by the process of claim 67.
and the antimicrobial acid addition salts thereof, wherein X
is chloro or fluoro, each Z is bromo or chloro or fluoro, p is 0 to 3 when Z is chloro, and p is 0 when Z is other than chloro, when prepared by the process of claim 67.
95. The compound of claim 94, wherein p is 0 or 1, when prepared by the process of claim 68.
96. The compound of claim 94, wherein X is chloro and p is 0 or 1, when prepared by the process of claim 69.
97. The compound of claim 94, wherein X and Z are chloro and p is 0 or 1, when prepared by the process of claim 70.
98. The compound of claim 95, wherein X is fluoro and Z
is chloro, when prepared by the process of claim 71.
is chloro, when prepared by the process of claim 71.
99. The compound of claim 97, wherein p is 0, when prepared the process of claim 72.
100. The compound of claim 82 which is 1-[2-(2,6-dichloro-phenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole and the anti-microbial acid addition salts thereof, when prepared by the process of claim 73.
101. The compound of claim 82 which is 1-[2-(2,5-dichloro-phenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole and the anti-microbial acid addition salts thereof, when prepared by the process of claim 74.
102. The compound of claim 82 which is 1-[2-(2-chlorophenyl-thio)-4-(4-chlorophenyl)-n-butyl]imidazole and the antimicro-bial acid addition salts thereof, when prepared by the process of claim 75.
103. The compound of claim 82 which is 1-[2-(2,3-dichloro-phenylthio)-4-(4-chlorophenyl)-n-butyl]imidazoleand the antimicrobial acid addition salts thereof, when prepared by the process of claim 76.
104. The compound of claim 82 which is 1-[2-(2-bromophenyl-thio)-4-(4-chlorophenyl)-n-butyl]imidazole and the antimicrobial acid addition salts thereof, when prepared by the process of claim 77.
105. The compound of claim 82 which is 1-[2-(2,6-dichloro-phenylthio)-4-(4-fluorophenyl)-n-butyl]imidazole and the antimibrocial acid addition salts thereof, when prepared by the process of claim 78.
106. The compound of claim 82 which is 1-[2-(2,4,6-trichloro-phenylthio)-4-(4-chlorophenyl)-n-butyl]imidazole and the antimibrocial acid addition salts thereof, when prepared by the process of claim 79.
107. The compound of claim 82 which is 1-[2-(2,5-dichloro-phenylthio)-4-(4-fluorophenyl)-n-butyl]imidazole and the antimicrobial acid addition salts thereof, when prepared by the process of claim 80.
108. The compound of claim 82 which is 1-[2-(2,4,6-trichloro-phenylthio)-4-(4-fluorophenyl)-n-butyl]imidazole and the anti-microbial acid addition salts thereof, when prepared by the process of claim 81.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US59961875A | 1975-07-28 | 1975-07-28 | |
| US66502376A | 1976-03-08 | 1976-03-08 | |
| US05/758,094 US4078071A (en) | 1976-03-08 | 1977-01-10 | Derivatives of substituted N-alkyl imidazoles |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1077493A true CA1077493A (en) | 1980-05-13 |
Family
ID=27416786
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA257,718A Expired CA1077493A (en) | 1975-07-28 | 1976-07-23 | Derivatives of substituted n-alkyl imidazoles |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1077493A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105198818A (en) * | 2015-10-09 | 2015-12-30 | 株洲千金药业股份有限公司 | Method for industrially producing butoconazole nitrate |
-
1976
- 1976-07-23 CA CA257,718A patent/CA1077493A/en not_active Expired
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105198818A (en) * | 2015-10-09 | 2015-12-30 | 株洲千金药业股份有限公司 | Method for industrially producing butoconazole nitrate |
| CN105198818B (en) * | 2015-10-09 | 2018-03-20 | 株洲千金药业股份有限公司 | A kind of method of industrialized production Butoconazole Nitrate |
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