GB2025395A - Therapeutically active substituted dibenzyl ethers - Google Patents
Therapeutically active substituted dibenzyl ethers Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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Abstract
Novel compounds I and their acid addition salts <IMAGE> in which R is phenyl or phenylthio show activity against some fungi, yeasts and gram positive aerobic and anaerobic bacteria. The new compounds can be prepared by condensing 1-(2',4'- dichlorophenyl)-2-(N-imidazolyl- methyl)-ethanol with 4-chloromethyl- biphenyl, 4-bromomethyl-biphenyl, 1- phenylthio-4-chloromethyl-benzene or 1-phenylthio-4-bromomethyl-benzene in a solvent, most preferably dimethylsulphoxide.
Description
SPECIFICATION
Therapeutically active substituted dibenzyl ethers
The invention relates to substituted dibenzyl ethers, to methods for their preparation and to pharmaceutical compositions containing them.
The invention provides compounds of the general formula I
wherein R represents a phenyl or phenylthio group, that is 2,4-dichloro-4'-phenyl-a-(N-imidazolyl- methyl)-dibenzyl ether and 2,4-dichloro-4'-phenylthio-a-(N-imidazolyl-methyl)-dibenzyl ether, and pharmaceutically acceptable acid addition salts thereof.
Pr'eferred pharmaceutically acceptable acid addition salts of the compounds I include those formed from both mineral and organic acids, such as hydrochloric, nitric, sulphuric, phosphoric, methane-sulphonic, succinic, maleic, fumaric, citric and tartaric acids. These salts may be prepared by conventional methods, for example by adding to the base of equimolecular amount the desired acid and then crystallizing the salt so obtained from a suitable solvent.
The compounds I and their salts are of interest for the activity they show against some fungi, yeasts and gram positive aerobic and anaerobic bacteria. The activity is coupled with a low toxicity. The compounds of the invention have been compared with two well-known antimycotic products, clotrimazole, i.e. [(imidazol-1 -yl)-2-(o-chlorophenyl)-2,2-diphenylmethane], and miconazole.
Particularly interesting was the comparison between the activity and toxicity of the compounds I and of miconazole, which is 2,2' ,4,4'-tetrachloro-a-(N-imidazolyl-methyl)-dibenzyl ether. In miconazole both benzyl groups are substituted in the 2- and 4-positions by chlorine atoms, whereas in the compounds I the benzyl group which is a-unsubstituted is substituted in the 4-position by a phenyl or phenylthio group. This difference involves a notable reduction of toxicity which, for the new products, is from 3 to 4 times lower than that of miconazole, whereas the antifungal and antibacterial activity is about the same.The compounds according to the invention can be conveniently employed in human therapy for the local treatment of dermatosis, such as trichophytosis and candidosis, and further infections caused by fungi stapilylococci and streptococci. The compounds according to the invention may be admixed with pharmaceutically acceptable diluents or carriers to form pharmaceutical compositions, which may be in any suitable form, for example powders, ointments, creams, suspensions and dispersions.
The results obtained in biological assays are reported in Tables I, II and Ill.
In Table I are reported the acute toxicity values (LDso) of the compounds I and of both the comparison substances. Toxicity, given in mg/Kg, has been evaluated per os in the mouse by conventional methods.
In Table II are reported the minimal inhibent concentrations (MIC) of the compounds I and of both the comparison substances. For MIC, the minimal concentration is intended, able to inhibit the growth of several fungi and yeasts. The MIC values have been determined according to the usual two-fold serial broth dilution technique.
The MIC values of the products under examination and of both comparison substances, referred to a certain number of gram positive bacteria and determined according to the conventional two-fold serial broth dilution technique, are reported in Table Ill.
Experimental conditions were as follows: For fungi Medium: Sabouraud liquid pH 5.7 (5 ml per tube)
Inoculum: A ten days agar culture was washed with a physiological solution containing 10%
Tween 80, then filtered through gauze and again suspended in physiological solution until the solution showed on a Coleman Jr II spectrophotometer, at a wavelength of 650 nm, a 50% transparence (T) (0.1 ml of spore suspension per ml). For Aspergillus niger, after filtration, a 1/10 dilution in physiological solution was prepared. 0.1 ml of this dilution constituted the inoculum for 5 ml.
Temperature and incubation time: 250C for 7 days.
For Yeasts
Medium: Sabouraud liquid pH 5.7 (5 ml per tube)
Inoculum: Yeasts were grown in Sabouraud liquid for 24 hours (Cryptococcus neoformans for 2 days). Cells were collected by centrifugation at 6500 rpm and again suspended in physiological solution so as to have a suspension giving on a Coleman Ji: II spectrophotometer, at a wavelength of 650 nm, a 50% transparence (T). 0.1 ml of this suspension constituted the inoculum for 5 ml.
Temperature and incubation time: 370C for 48 hours.
For Gram Positive Bacteria
Medium: Tryptic soy broth pH 7.3(5 ml per tube).
Inoculum:The day before the test, the microorganisms to be tested were transplanted in their respective media. After 18 hours incubation at 370C, 0.1 ml of a 1:100 diluted suspension of each strain in broth, were inoculated in 5 ml of medium containing the products under examination at a serial concentration of from 0.009 to 160 mcg/ml.
Temperature and incubation time: 370C for 18 hours.
TABLE I
Acute toxicity (LD 50) per OS in the mouse in mg/kg.
Formula I Formula I I: R=C6Hs I: R=C6H5S Miconazole Clotrimazole 2400 3000 870 880 TABLE II
Antimycotic activity (MIC) in mcg/ml
Phatogenous Formula I Formula Agent R= C6H5 R= 06H,8 Micanazole Clotrimazole C. Albicans R 5 40 5 10 C. Albicans Grúnenthal 5 40 5 10 C. Albicans 1040 10 80 20 40 C. Albicans 1041 20 80 20 40 C. Neoformans 0.312 0.156 0.078 0.625 T. Mentagroph. 2538 0.156 0.156 0.078 0.078 T. Mentagroph. 10148 0.625 0.625 0.625 1.25 T. Mentagroph. 5865 1.25 1.25 0.31 0.62 T Verrucosum 10 1.25 2.5 1.25 T. Rubrum 2121 0.625 0.625 0.312 1.25 M. Canis 28 20 2.5 5 2.5 A. Niger 20 10 40 10 P. Chrysogenum 20 5 20 40 E. Floccosum 10 5 5 5 TABLE Ill
Antibacterial activity (MIC) in mcg/ml
Phatogenous Formula I Formula I Agent R= 06H5 R= C6HsS Miconazole Clotrimazole S, aureus SG 511 0.039 0.039 0.312 0.312 S. aureus 10 B 0.039 0.018 0.312 1.25 Str. hemolyt 821 0.156 0.156 1.25 2.5 B. subtilis 0.156 0.078 0.625 2.5 Cl. novyi < 1.25 5.0 < 1.25 > 160 Str. hemolyt 203 0.312 0.078 0.625 5 The invention further provides a method for the preparation of compounds of the general formula I as hereinbefore defined, the method comprising condensing in a solvent 1 -(2',4'-dichlorophenyl)-2-(N- imidazolyl)-ethanol with a halobenzyl compound of the general formula V
wherein R has the meaning previousiy ascribed to it and X represents a chlorine or bromine atom.
As so vent, aromatic hydrocarbon, dimethylformamide, tetrahydrofuran, hexamethylphosphoramide and/or a mixture thereof can be employed, but it has been verified that condensation is more complete if dimethylsulphoxide is used. This leads to a higher yield and to a purer product. In this case it is not necessary to submit the base obtained from condensation to a purification through chromatographic column, whereas said purification is necessary using as solvents dimethylformamide or hexamethylphosphoramide. A simple filtration of the base solution through a silica gel column is in fact abie to retain the small amounts of impurities. For the compound I, in which R represents a phenyl group, not even the filtration is necessary, and crystallization of the nitrate leads to a product sufficiently pure for pharmaceutical purposes.With the aprotic solvents specified above, there is usually used an alkali metal hydride, or amide, which is able to salify the hydroxy group of the ethanol derivative.
Alternatively the condensation solvent may be an aliphatic alcohol having from 3 to 6 carbon atoms, such as t-butanol, and in this case the alkali metal hydride or amide should be replaced by an alkali metal alcoholate, for example potassium t-butylate.
A further very useful expedient is to add small amounts of potassium iodide as catalyst before adding the halobenzyl derivative.
The 1 -(2',4'-dichlorophenyl)-2-(N-imidazolyl)-ethanol may be prepared from 1 -chloroacetyl-2,4- dichloro-benzene (Beilstein-Handbuch der Org. Chem. IVO ed. vol. 7, page 28) by reduction of the keto group using sodium borohydride and condensation with imidazole. The reduction and condensation can be effected in either order. The reduction may be effected in methanol and the condensation may be effected in dimethylformamide and methanol in the presence of sodium. The halobenzyl compounds of the general formula V are known. The preparation of 4-chloromethyl-biphenyl is described in Chem. Ber.
66B, 1471, 1933 and the preparation of 1 -bromomethyl-4-phenylthiobenzene is described in United
States Patent Specification No. 3,242,193.
Examples 1 to 4, which follow, illustrate the invention while Examples A and B describe the preparation of the starting materials used in Examples 1 to 4.
EXAMPLE A 1 -(2',4'-dichlorophenyl)-2-chloro-ethanol 49.5 g of sodium borohydride were added slowly and in small parts to a suspension of 233 g of 1 (1 '-hydroxy-2'-chloro-ethyl)-2,4-dichloro-benzene in 1 litre of methanol stirred at room temperature.
The solution thus obtained was stirred at room temperature for a further two hours, and it was then poured into 1 litre of 5N hydrochloric acid cooled with ice. After extraction with ethyl acetate or chloroform, the extract was washed with water, with 1N sodium hydroxide, then again with water until neutrality, and finally with a saturated sodium chloride solution. The extract was dried, the solvent evaporated off and 220 g of an oil were obtained. The oil solidified on standing and the solid melted at 48-51 0C.
Analysis for C8H7Cl30 C% H% CI% Calculated 42.61 3.13 47.17
Found 42.75 3.19 4743 EXAMPLE B 1 -(2',4'-dichlorophenyl)-2-(N-imidazolyl)-ethanol
30 g of sodium were added to a solution of 88.5 g of imidazole in 600 ml of methanol; the solvent was then evaporated off. The residue was dissolved in 300 ml of dimethylformamide and heated to 1 15--1200C. To the solution so obtained was added, dropwise and under stirring, a solution of 225 g of 1 -(2',4'-dichlorophenyl)-2-chloro-ethanol in 400 ml of dimethylformamide. The mixture was heated to 1 15--1200C and maintained at that temperature for 20 minutes and, after subsequent cooling to 400 C, 2500 ml of iced water were added under vigorous stirring.The product precipitated under stirring over a period of about two hours, the upper liquid was then decanted off, a further 2500 ml of water were added and, after standing, the whole was filtered. The precipitate thus obtained was dried and crystallized from toluene. 170 g of the desired product, melting at 1 34-1 350C, was obtained.
Analysis for C"H 10Ci2N20 C% H% N% Cl% Calculated 51.38 3.92 10.89 27.58
Found 51.62 3.80 10.73 27.76
EXAMPLE 1 2,4-Dichloro-4'-phenylthio-ez-(N-imidazolyl-methyl)-dibenzyl ether (I: R=C6H5S) Method I
A solution of 2.57 g of 1-(2',4'-dichíorophenyl)-2-(N-imidazolyl)-ethanol, prepared as described in
Example B, in 10 ml of hexamethylphosphoramide was dropped at 250C into a suspension of 0.52 g of sodium hydride (50% in oil) in 5 ml of hexamethylphosphoramide. When hydrogen emission was over, the salification was completed by heating for 1 hour at SOOC. After cooling to 250 C, 2.58 g of 1chloromethyl-4-phenylthio-benzene were added.The temperature was raised to 500C and maintained at that temperature for 12 hours. At the end of the reaction, the mixture was poured into 200 ml of water, the product was extracted with diethyl ether, the solvent was evaporated off and the residue was purified twice on a silica gel column, using ethyl acetate as eluant and testing the various fractions by
TLC. The solvent was evaporated off the middle fractions to give 2.4 g of the desired base as a yellowish oil, showing a single spot on TLC.
Analysis for C24H20N2CI20S C% H% N% Cl% S% Calculated 63.30 4.44 6.13 15.57 7.04
Found 63.86 4.24 6.41 15.29 6.97 Method 11 0.66 g of sodium hydride (50% in oil) were added at 20-300C and under nitrogen atmosphere to 3.86 g of 1-(2',4'-dichlorophenyl)-2-(N-imidazolyl)-ethanol in 15 ml of dimethylsulphoxide (dried on calcium hydride).
The mixture was heated under stirring at 50-600C until gas emission was over. After coo!ing to 20-250C, 0.5 g of potassium iodide were added and slowly a solution of 3.51 g of 1-chloromethyl-4phenylthio-benzene in 4 ml of dimethylsulphoxide was dropped in. The mixture was stirred at 2S25 C until addition of the 1 -chloromethyl-4-phenylthio-benzene was over. The mixture was then poured into 1 50 ml of water and extracted with diethyl ether. To the etheric solution, after drying on anhydrous sodium sulphate, was added excess 4N nitric acid solution in diethyl ether: the desired product precipitated as nitrate, an oil which solidified on standing. After standing for 20 hours, the etheric liquid was decanted off and the residue was crystallized from ethanol.The nitrate thus obtained, not compietely pure, was dissolved in water and excess sodium carbonate was added in order to liberate the base which was then extracted with ethyl acetate. The base, obtained by filtration, was purified on a silica gel column using ethyl acetate as eluant. The combined fractions containing the desired product were evaporated to dryness. The residue was dissolved in diethyl ether, again transformed into the nitrate and crystallized from ethanol.
Yield: 3.1 g of a white crystalline power, melting at 1340 C.
Analysis for C24H20N2CI20S.HNO3 C% H% N% Calculated 55.61 4.08 8.11 13.68 6.18
Found 55.32 4.08 8.16 13.56 6.32
EXAMPLE 2 2,4-Dichloro-4'-phenyl-a-( N-imidazolyl-methyl)-dibenzyl ether (1: R=C6H5)
Method I
A mixture consisting af 2.02 g of potassium t-butylate in 30 ml of t-butanol was prepared at 20-250C and in nitrogen atmosphere. 3.86 g of 1-(2',4'-dichlorophenyi)-2-(N-imidazolyl)-ethanol, prepared according to Example B, were added. The solution was refluxed for 1 hour and then cooled to 20-250C. 3.03 g of 4-chloro-methyl-biphenyl were added, and the solution was again refluxed for 5 hours.After cooling to 20-25 C the whole was poured into water and the base extracted with ethyl acetate. The extract was washed with diethyl ether and the solvent evaporated off. The residue was dissolved in diethyl ether (80 ml) and left to stand overnight. The insoluble substances were filtered off and the filtrate was treated with nitric acid dissolved in diethyl ether. An oil, which solidified on standing, was obtained. The residue, consisting off 2,4-dichloro-4'-phenyl-a-(N-imidazolyl-methyl)- dibenzyl ether nitrate, was crystallised from ethanol or ethyl acetate. A product (4.3 g), shown to be pure on TLC and melting 140-141 0C, was obtained.
Analysis for C24H20N2CI20.HNO3 C% H% N% Cl% Calculated 59.25 4.35 8.64 14.57
Found 59.17 4.14 8.61 14.46 Method! (a) To a solution of 0.37 g of sodium metal in20 ml of n-propanol, 4.1 g of 1-(2',4'-dichlorophenyl)2-(N-imidazolyl)-ethanol were added and the mixture was refluxed for two hours under stirring. After cooling to room temperature, 0.5 g of potassium iodide and 3.25 g of 4-chloromethyl-biphenyl were added under stirring and the mixture was again refluxed. At the end of the reaction, the mixture was filtered off and washed with ethanol. The filtrate was evaporated to dryness and the residue dissolved in diethyl ether.The insoluble residue was filtered off and the clear etheric solution thus obtained was treated with a mixture of nitric acid and diethyl ether. The 2,4-dichloro-4'-phenyl-α-(N-imidazolyl)- methyl)-dibenzyl ether nitrate so formed was crystallized from ethanol. A product (2.1 g) having the same characteristics as that prepared according to the previous method and showing a single spot on
TLC was obtained.
Method II 0.66 g of sodium hydride were added, under nitrogen atmosphere and at 2S25 C, to a solution of 3.86 g of 1 -(2',4'-dichlornphenyI)-2(N-imidazolyl)-ethanpl in 15 ml of dimethylsulphoxide (dried on calcium hydride). The mixture was heated at 5060 C until gas emission was over. The mixture was then cooled to 20-250C, 0.5 g of potassium iodide were added and a solution of 3.03 g of 4-chloromethyl-biphenyl in 7 ml of dimethylsulphoxide (dried on calcium hydride) was dropped in.
The whole was stirred for about 20 hours at 20--250C and then poured into water. The product was extracted with ethyl acetate and then treated as described in Method I. Yield 4.6 g.
EXAMPLE 3
Salts of 2,4-dichloro-4'-phenylthio-cr-(N-imidazolyl-methyl)-dibenzyl ether were prepared by reacting the free base, dissolved in ethanol, with an alcohol solution of the desired acid and subsequently crystallizing the salt so obtained from a suitable solvent. The free base was prepared according to Example 1. Method I, or by liberation from its nitrate, prepared according to Method II, by treatment with sodium carbonate, extraction with diethyl ether and evaporation.
In Table IV the solvents of crystallization, the elemental analysis and the melting points of some salts are reported.
In Table V are listed the same data for some salts of 2,4-dichloro-4'-phenyl-a-(N-imidazolyi- methyl)-dibenzyl ether, obtained using the methods described above.
TABLE IV
Solvent of Calculated Found Salt crystalllzation M.P. C% H% N% Cl% S% C% H% N% Cl% S% Hydrochlforlde Isopropanol 181-183 C 58,61 4,30 5.89 21,82 6,51 58,42 4,31 5,67 21,40 6,79 Maleate Ethanol 117-118 C 58,85 4,23 4.90 12,41 5,61 58,61 4,50 4,77 12,24 5,91 Methane- Ethanol 153-156 C 54,56 4,39 5.08 12,86 11,63 64,21 4,32 4,78 12,97 11,94 sulphonate p-toluene Ethanol 127-128 C 59,33 4,50 4,48 11,30 10,22 59,43 4,49 4,43 11,63 10,44 sulphonate Phosphate Ethanol 143-145 C 52,09 4,19 5,06 12,81 5,79 51,86 4,18 5,12 12,90 5,91 TABLE V
Solvent of Calculated Found Salt crystalllzation M.P. C% H% N% Cl% S% C% H% N% Cl% S% Hydrochloride Ethyl Acetate 171-172 C 62,69 4,60 6,09 23,13 62,40 4,80 5,86 23,18 Sulphate Ethanol 72-80 C 53.28 4,25 5,37 13,60 6,15 54,99 3,90 5,25 13,48 6,23 Maleate Ethanol 128-128 C 62,36 4,48 5,19 13,14 62,05 4,18 4,91 13,51 p-toluene Ethanol 182-184 C 64,25 4,87 4,83 12,23 5,53 63,81 4,82 4,54 12,52 5,63 sulphonate Citrate Ethanol 150 C 58,55 4,58 4,55 11,52 58,97 4,47 4,61 11,80 EXAMPLE 4
Pharmaceutical antifungal and antibacterial formulations, comprising active compounds according to the invention at concentrations of from 0.5 to 5% by weight, preferably from 1 to 3% by weight, in admixture with pharmaceutically acceptable diluents or carriers, were prepared. Examples of the composition of an ointment, a powder, a glycolic solution and a gel are given below.
Ointment 2,4-dich Ioro-4'-phenylthio-a-( N-i midazolyl- methyl)-dibenzyl ether nitrate 2 g
Lanolin 20 g
Vaseline q.s. to 100 g Glycobic solution 2,4-dichloro-4'-phenylthio-a-( N-imidazolyl-methyl)
dibenzyl ether nitrate 2 9
Propylene Glycol q.s. to 100 ml Powder
2,4-dichloro-4'-phenylthio-a-(N-imidazolyl- methyl)-dibenzyl ether nitrate 2 g Lanoiin 1.5 9 Soybean lecithin 29 Talc q.s. to
Gel 2,4-dichloro-4'-phenylthio-a-( N-imidazolyl- methyl)-dibenzyl ether nitrate 2g Carbopol 2g Water 29 Polyethylene glycol q.s. to 100 g Triethanolaminesq.s. to about pH 3
Claims (14)
1. 2,4-Dichloro-4'-phenylthio--(N-imidazolyl-methyl)-dibenzyl ether or a pharmaceutically acceptable acid addition salt thereof.
2. 2,4-Dichloro-4'-phenyl-,x-(N-imidazolyl-methyl)-dibenzyl ether or a pharmaceutically acceptable acid addition salt thereof.
3. An acid addition salt according to claim 1, being a hydrochloride, nitrate, maleate, methanesulphonate, p-toluenesulphonate or phosphate.
4. An acid addition salt according to claim 2, being a hydrochloride, nitrate, sulphate, a maleate, ptoluenesulphonate or citrate.
5. A process for the preparation of a compound of the general formula I
wherein R represents a phenyl or phenylthio group, the process comprising condensing 1-(2',4'dichlorophenyl)-2-(N-imidazolyl-methyl)-ethanol with a halobenzyl derivative of the general formula V as herein defined in a solvent.
6. A process according to claim 5'in which the solvent is an aromatic hydrocarbon, dimethylformamide, tetrahydrofuran, hexamethylphosphoramide or dimethyl sulphoxide and the condensation is carried out in the presence of an alkali metal hydride or amide.
7. A process according to claim 5 in which the solvent is an aliphatic alcohol having from 3 to 6 carbon atoms and the reaction is carried out in the presence of an alkali metal alcoholate.
8. A process according to any of claims 5 to 7 carried out in the presence of potassium iodide as catalyst.
9. A process according to any of claims 5 to 8 carried out at a temperature of from 20 to 1 000C for from 6 to 36 hours.
10. A pharmaceutical composition comprising a compound according to any of claims 1 to 4 in admixture with a pharmaceutically acceptable diluent or carrier.
1 A pharmaceutical composition according to claim 10 in which the compound according to any of claims 1 to 4 is present in an amount of from 0.5 to 5% by weight.
12. A pharmaceutical composition according to claim 10 or claim 11 in which the compound according to any of claims 1 to 4 is present in an amount of from 0.5 to 5% by weight.
13. A pharmaceutical composition according to any of claims 10 to 12, being an ointment, a powder, a glycolic solution or a gel.
14. A pharmaceutical composition substantially as described herein with reference to Example 4.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT23546/78A IT1096361B (en) | 1978-05-18 | 1978-05-18 | THERAPEUTICALLY ACTIVE REPLACED BONDS |
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| Publication Number | Publication Date |
|---|---|
| GB2025395A true GB2025395A (en) | 1980-01-23 |
| GB2025395B GB2025395B (en) | 1982-07-28 |
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| Application Number | Title | Priority Date | Filing Date |
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| GB7916670A Expired GB2025395B (en) | 1978-05-18 | 1979-05-14 | Therapeutically active substituted dibenzyl ethers |
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| ES (1) | ES480552A1 (en) |
| FI (1) | FI71309C (en) |
| FR (1) | FR2426047A1 (en) |
| GB (1) | GB2025395B (en) |
| GR (1) | GR68396B (en) |
| HU (1) | HU182565B (en) |
| IE (1) | IE48372B1 (en) |
| IL (1) | IL57245A (en) |
| IT (1) | IT1096361B (en) |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0195116A2 (en) * | 1985-03-19 | 1986-09-24 | ISTITUTO FARMACO BIOLOGICO RIPARI GERO S.r.l. | Compound having antibacterial and antimycotic activities, preparation thereof and pharmaceutical compositions containing it |
| WO2006029811A1 (en) * | 2004-09-13 | 2006-03-23 | Ferrer Internacional, S.A. | Method for manufacturing enantiomeric imidazole compounds |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1155853A (en) * | 1980-06-06 | 1983-10-25 | Joseph A. Martin | Imidazole derivatives and preparation thereof |
| FR2541114B1 (en) * | 1983-02-23 | 1986-04-11 | Sanofi Sa | ANTIFUNGAL PHARMACEUTICAL COMPOSITIONS FOR ORAL USE CONTAINING OMOCONAZOLE |
| DK79184A (en) * | 1983-02-23 | 1984-08-24 | Sanofi Sa | FUNGICIDE PHARMACEUTICAL AGENTS CONTAINING AN IMIDAZOLD DERIVATIVE |
| CA1250586A (en) * | 1984-02-02 | 1989-02-28 | Manuel Raga | 1h-imidazole derivatives and process for their production |
| DE3413365A1 (en) * | 1984-04-09 | 1985-12-19 | Merz + Co GmbH & Co, 6000 Frankfurt | SUBSTITUTED PHENYLETHYL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU557755A3 (en) * | 1968-08-19 | 1977-05-05 | Янссен Фармасьютика Н.В. (Фирма) | Method for preparing imidazole derivatives |
| GB1475271A (en) * | 1975-04-30 | 1977-06-01 | Pfizer Ltd | 1-aryl-2-1-imidazolyl-alkyl ethers and thioethers and their use as antifungal agents |
-
1978
- 1978-05-18 IT IT23546/78A patent/IT1096361B/en active Protection Beyond IP Right Term
-
1979
- 1979-04-24 PT PT69537A patent/PT69537A/en unknown
- 1979-04-26 ZA ZA792015A patent/ZA792015B/en unknown
- 1979-04-27 DE DE2917244A patent/DE2917244C2/en not_active Expired
- 1979-04-29 EG EG250/79A patent/EG14345A/en active
- 1979-05-07 GR GR59034A patent/GR68396B/el unknown
- 1979-05-07 AR AR276430A patent/AR219596A1/en active
- 1979-05-07 HU HU79RE645A patent/HU182565B/en unknown
- 1979-05-09 AT AT0345079A patent/AT372950B/en not_active IP Right Cessation
- 1979-05-10 IL IL57245A patent/IL57245A/en unknown
- 1979-05-10 PH PH22475A patent/PH14782A/en unknown
- 1979-05-10 NZ NZ190412A patent/NZ190412A/en unknown
- 1979-05-11 CA CA327,426A patent/CA1115718A/en not_active Expired
- 1979-05-14 GB GB7916670A patent/GB2025395B/en not_active Expired
- 1979-05-14 DD DD79212866A patent/DD143608A5/en unknown
- 1979-05-14 NO NO791599A patent/NO152840C/en unknown
- 1979-05-14 ES ES480552A patent/ES480552A1/en not_active Expired
- 1979-05-14 DK DK196579A patent/DK153838C/en not_active IP Right Cessation
- 1979-05-14 YU YU01122/79A patent/YU112279A/en unknown
- 1979-05-15 FI FI791543A patent/FI71309C/en not_active IP Right Cessation
- 1979-05-16 CH CH456979A patent/CH639075A5/en not_active IP Right Cessation
- 1979-05-16 JP JP54060971A patent/JPS605592B2/en not_active Expired
- 1979-05-16 NL NLAANVRAGE7903872,A patent/NL189255C/en not_active IP Right Cessation
- 1979-05-17 SE SE7904319A patent/SE444812B/en not_active IP Right Cessation
- 1979-05-17 SU SU792771698A patent/SU816399A3/en active
- 1979-05-17 AU AU47149/79A patent/AU523053B2/en not_active Expired
- 1979-05-17 FR FR7912638A patent/FR2426047A1/en active Granted
- 1979-05-18 MX MX797989U patent/MX5927E/en unknown
- 1979-08-08 IE IE958/79A patent/IE48372B1/en not_active IP Right Cessation
-
1993
- 1993-02-19 NL NL930014C patent/NL930014I2/en unknown
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0195116A2 (en) * | 1985-03-19 | 1986-09-24 | ISTITUTO FARMACO BIOLOGICO RIPARI GERO S.r.l. | Compound having antibacterial and antimycotic activities, preparation thereof and pharmaceutical compositions containing it |
| EP0195116A3 (en) * | 1985-03-19 | 1987-06-03 | Ripari Gero Ist Farm Biolog | Compound having antibacterial and antimycotic activities, preparation thereof and pharmaceutical compositions containing it |
| WO2006029811A1 (en) * | 2004-09-13 | 2006-03-23 | Ferrer Internacional, S.A. | Method for manufacturing enantiomeric imidazole compounds |
| US7626038B2 (en) | 2004-09-13 | 2009-12-01 | Ferrer Internacional, S.A. | Method for manufacturing enantiomeric imidazole compounds |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 711A | Proceeding under section 117(1) patents act 1977 | ||
| CTFF | Supplementary protection certificate filed |
Free format text: SPC/GB93/107, 930628 |
|
| CTFG | Supplementary protection certificate granted |
Free format text: SPC/GB93/107, 931112, EXPIRES:20001013 |
|
| PE20 | Patent expired after termination of 20 years |
Effective date: 19990513 |
|
| CTFL | Supplementary protection certificate lapsed |
Free format text: SPC/GB93/107, 19991113 |