GB2161483A - New antifungal 1,2,4-triazole derivative, production and use - Google Patents
New antifungal 1,2,4-triazole derivative, production and use Download PDFInfo
- Publication number
- GB2161483A GB2161483A GB08517526A GB8517526A GB2161483A GB 2161483 A GB2161483 A GB 2161483A GB 08517526 A GB08517526 A GB 08517526A GB 8517526 A GB8517526 A GB 8517526A GB 2161483 A GB2161483 A GB 2161483A
- Authority
- GB
- United Kingdom
- Prior art keywords
- compound
- pharmaceutically acceptable
- salt
- formula
- compound according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/08—Compounds containing oxirane rings with hydrocarbon radicals, substituted by halogen atoms, nitro radicals or nitroso radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The levorotatory enantiomer of the compound of formula I <IMAGE> is indicated for use as a pharmaceutical in particular as an anti-mycotic.
Description
SPECIFICATION
New azole, process for its production and its use
The present invention concerns a new azole, namely the levorotatory enantiomer of the compound of formula I
as well as a process for its production, pharmaceutical compositions which contain it and its use as a
pharmaceutical, in particular as an antimycotic. The term "levorotatory" may be replaced by the prefix
GB 2,136,423-A and 2,064,520-A each describe a wide range of triazole and imidazole derivatives but make no specific mention of the (-)-enantiomer according to the invention or its advantageous antimycotic properties.
The compound of the invention in free form or a salt- or metal- complex form may be obtained according to the invention by reaction of a compound of formula II.
wherein M represents hydrogen, a metal or trialkylsilyl group with the levorotatary enantiomer of a compound of formula Ill
or a reactive functional derivative thereof and recovering the compound thus obtained in free form or in salt- or metal-complex form.
The process can be carried out in conventional manner e.g. as described in GB 2,136,423-A or in the examples hereinafter.
The compound of the invention is obtained in free base form or in acid addition salt or metal complex form. The sale or metal complexes may be obtained from the corresponding free form in conventional manner and vice.versa.
The compounds of the invention may be isolated from the reaction mixture and purified according to methods known per se.
Insofar as the preparation of the starting materials is not described, they are either known or may be obtained analogously to procedures described herein or to known procedures.
The compounds of the invention possess interesting biological, particularly antimycotic properties and are therefore indicated for use as pharmaceuticals in particular as antimycotics. The antimycotic activity can be established by in vitro tests, e.g. the in vitro series dilution test on various families and species of mycetes, such as yeasts, mold fungi and dermatophytes at concentrations of about 0.4 to about 10011g/ml and also by in vivo tests, e.g. by systemic, p.o. application of dosages of ca. 0.4 to 100 mg/kg body weight to mice which have been intra-vaginally infected with Candida albicans.
An indicated suitable daily dosage is for example in the range of from 70 to 2000 mg, administered e.g.
in divided doses 1 to 4 times a day or in sustained release form; dosage forms suitable for e.g. oral administration comprise then from 17.5 to 2000 mg, preferably 17.5 to 500 mg of active ingredient.
It has been established in such tests that the levortotory enantiomer according to the invention exhibits a considerably better activity than the corresponding racemate or the dextrorotatory (+)enantiomer. In a comparative test employing the candida-vaginitis model in the rate the following percentage rates of cure were observed following two applications p.o.
Dose (mgikg) Racemate (-)-enatiomer (-)-enantiomer 1.6 93 93% 93 % 2% 0.8 73 % 84 % 3% 0.4 41 % 72 % 0 % The compound of the invention may be prepared and used in the free base form or in the form of pharmaceutically acceptable salts (acid addition salts or alcoholates). In general the salt forms exhibit the same order of activity as the free base forms. Acids that may be used in preparing acid addition salt forms include by way of illustration hydrochloric, hydrobromic, sulphuric, nitric, fumaric and naphthaline1,5-disulphonic acids.
The compounds may be admixed with conventional pharmaceutically acceptable diluents and carriers, and, optionally other excipients and administered orally, topically, i.v. or parenterally in such forms as tablets, capsules, creams, tinctures or injectable preparations.
Such compositions also form part of the invention.
The invention therefore also concerns a method of combatting infections and diseases caused by mycetes comprising administering to a subject in need of such treatment an effective amount of a compound of formula I in free base form or in the form of a pharmaceutically acceptable salt thereof and such compounds for use a pharmaceuticals, in particular as anti-mycotic agents.
The compounds of the invention in free form or in agriculturally acceptable salt or metal complex form are also suitable for combatting phytopathogenic fungi. This fungicidal activity can be demonstrated i.a.
in in vivo tests against Uromyces appendiculatus (bean rust) on runner beans as well as against other rust fungi (e.g. Hemileia, Puccinia) on coffee, wheat, flax and ornamentals (e.g. pelargonium, snapdragon); and against Erysiphe cichoracearum on cucumber as well as against other powdery mildews (e.g.
E. graminis f. sp. tritici. E. gram. f. sp. hordei, Podosphaera leucotricha, Uncinula recator) on wheat, bar iey, apply and vines.
The following example illustrate the invention.
EXAMPLE 1: (- )-(x-(4-Chlorpheny1 )-α-(1-cyclopropyl-1-methylethyl)-1 H-1 ,2,4-triazol-1 -ethanol
0.5 g of (-)-2-(4-chlorophenyi)-2-(1-cyclopropyl-1-methylethyl)- oxirane are stirred at RT for 2 days with triazole sodium (prepared from 0.29 g of 1,2,4-triazole and 0.1 g NaH) in 5ml of dry dimethylformamide. The resulting mixture is evaporated in vacuum and the residue taken up in water/dichloromethane. The organic phase is isolated, washed with water, dried (MgSO4) and concentrated by evaporation. The crude product thus obtained may be purified by recrystallisation from n-hexane or chromatography on silica gel with ethylacetate. White crystals are obtained m.p. 104-105 , [a] o20 = -87.5 .
The absolute configuration of the levorotatory-or (--)-enantiomer according to the invention is "R" and the compound may thus be designated R(-)-a-(4-chlorophenyl)-a- (1 -cyclopropyl-1 -methylethyl)-1 H-1 ,2,4- triazol-1 -ethanol.
The starting material may be prepared as follows:
a) 4-Chlor-"-(1-cycloprnpyl-1 -1 -methylethyl)-a-(4-methylbenzosulf inyl)-methylbenzylalcohol 3.1 g R( i )-Methyl-p-toly(sulfoxide in 75 ml of tetrahydrofuran are added at -5 dropwise to a solution of lithiumdiisopropylamine in tetrahydrofuran (prepared from 2.37 g of diisopropylamine and 14.4 ml of 1.6 N BuLi (hexane) in 120 ml of dry tetrahydrofuran) and the mixture stirred for 1 hour at -5". 4.6 g of 1 (4-chlorophenyl)-2-cyclopropyl-2methyl- propan-1 -one are then added whereupon the temperature rises to 0 and the mixture is allowed to rise to RT and treated with 40 ml sat. aqueous NH4CI. The organic phase is separated and the aqueous phase extracted with ethylacetate. The combined organic phases are dried (MgSO4) and concentrated by evaporation. The residue is separated by chromatography on silica gel with n- hexanelethylacetate to obtain the two diastereoisomers A-1 and A-2.
A-1 = colourless oil, [ot12 = + 115 (acetone)
A-2 = colourless oil, [a]20 = + 48 (acetone) b) (-)-4-Ch loro-(x-( 1 )A-Chloro-a-(1-cycloprnpyl-l-methylethyl)-a-(4-methylphenyl) thiomethylbenzylalcohol 0.75 g NaBh,,. are added slowly in portions to 2.8 g of compound A-1 (cf.a) and 1.77 g CoCI26H20 in 120 ml of dry ethanol at -10 . Stirring is continued for 2 hours at RT and 3N HC1 then added until the aqueous phase becomes pink. Extraction is carried out with diethylether and the ether phase is washed with sat. aqueous NaCI, dried (MgSO4) and concentrated by evaporation.The crude product thus obtained can be purified by chromatography on silica gel with toluene. Colourless oil [aj2J = - 15.7 acetone
c) (-)-2-(4-Chlorophenyl)-2-(1-Cyclopropyl-l-methylethyl)oxirane 1.37 g of Triethyloxoniumtetrafluoroborate are added at 0 to lg of (-)-4-chloro-a-(1-cyclopropyl-l- methylethyl)-a-(4-methylphenyl)- thio-methylbenzylalcohol in 10ml of dry dichloromethane and the mixture stirred for 2.5 hours at RT. Following addition of 5 ml of 10% aq. NaOH stirring is carried out for 2.5 hours at RT and the organic phase separated off. This is washed with water, dried (MgSO4) and concentrated by evaporation. The crude product thus obtained can be purified by chromatography on silica gel with toluene/n-hexane (1/1) to obtain white crystals, m.p. 57-58, [a]2D5= -44' (acetone).
Claims (8)
1. The levorotatory enantiomer of the compound of formula I
2. R( - )-a-(4-chlorophenyl)-a-( 1 -cyclopropyl-1 -methyl ethyl)- 1 H-1 ,2,4-triazol-1 -ethanol.
3. A compound according to Claim 1 or 2 in the form of a salt or a metal complex.
4. A pharmaceutical composition comprising a compound according to Claim 1 or 2 in free form or in the form of a pharmaceutically acceptable salt, together with a pharmaceutically acceptable diluent or carrier.
5. A method of combatting infections and diseases caused by mycetes comprising administering to a subject in need of such treatment an effective amount of a compound of formula I in free base form or in the form of a pharmaceutically acceptable salt thereof.
6. A compound according to Claim 1 or 2 in free form or in the form of a pharmaceutically acceptable salt for us as a pharmaceutical.
7. A compound according to Claim 1 or 2 in free form or in the form of a pharmaceutically acceptable salt for use as an anti-mycotic.
8. A process for preparing a compound according to Claim 1 in free form or a salt- or metal-complex form which comprises reacting a compound of formula II.
wherein M represents hydrogen, a metal or a trialkylsilyl group with the levorotatary enantiomer of a compound of formula Ill.
or a reactive functional derivative thereof and recovering the compound thus obtained in free form or in salt- or metal-complex form.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE3425848 | 1984-07-13 |
Publications (3)
Publication Number | Publication Date |
---|---|
GB8517526D0 GB8517526D0 (en) | 1985-08-14 |
GB2161483A true GB2161483A (en) | 1986-01-15 |
GB2161483B GB2161483B (en) | 1988-07-13 |
Family
ID=6240558
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB08517526A Expired GB2161483B (en) | 1984-07-13 | 1985-07-11 | A 1,2,4-triazole derivative, its preparation and use as an anti-fungal |
Country Status (17)
Country | Link |
---|---|
JP (1) | JPS6144878A (en) |
AU (1) | AU582761B2 (en) |
BE (1) | BE902837A (en) |
CH (1) | CH668772A5 (en) |
DE (1) | DE3524296C2 (en) |
DK (1) | DK163058C (en) |
FR (1) | FR2567515B1 (en) |
GB (1) | GB2161483B (en) |
IE (1) | IE58516B1 (en) |
IL (1) | IL75774A (en) |
IT (1) | IT1200087B (en) |
LU (1) | LU86001A1 (en) |
NL (1) | NL8501962A (en) |
NZ (1) | NZ212718A (en) |
PH (1) | PH23287A (en) |
SE (1) | SE456679B (en) |
ZA (1) | ZA855286B (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2136423A (en) * | 1983-03-04 | 1984-09-19 | Sandoz Ltd | Fungicidal 1h-azole-1-ethanol derivatives |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH647513A5 (en) * | 1979-11-13 | 1985-01-31 | Sandoz Ag | TRIAZOLE DERIVATIVES, THEIR PRODUCTION AND USE. |
JPS5697276A (en) * | 1979-11-13 | 1981-08-05 | Sandoz Ag | Alphaaaryll1hh1*2*44triazolee11ethanols |
ZA817473B (en) * | 1980-11-19 | 1982-10-27 | Ici Plc | Triazole and imidazole compounds |
-
1985
- 1985-07-04 CH CH2871/85A patent/CH668772A5/en not_active IP Right Cessation
- 1985-07-06 DE DE3524296A patent/DE3524296C2/en not_active Expired - Lifetime
- 1985-07-08 FR FR8510531A patent/FR2567515B1/en not_active Expired
- 1985-07-09 NL NL8501962A patent/NL8501962A/en active Search and Examination
- 1985-07-09 IT IT48324/85A patent/IT1200087B/en active
- 1985-07-09 BE BE1/011292A patent/BE902837A/en not_active IP Right Cessation
- 1985-07-11 IL IL75774A patent/IL75774A/en not_active IP Right Cessation
- 1985-07-11 PH PH32517A patent/PH23287A/en unknown
- 1985-07-11 AU AU44779/85A patent/AU582761B2/en not_active Expired
- 1985-07-11 SE SE8503443A patent/SE456679B/en not_active IP Right Cessation
- 1985-07-11 NZ NZ212718A patent/NZ212718A/en unknown
- 1985-07-11 IE IE174785A patent/IE58516B1/en not_active IP Right Cessation
- 1985-07-11 DK DK318185A patent/DK163058C/en not_active IP Right Cessation
- 1985-07-11 GB GB08517526A patent/GB2161483B/en not_active Expired
- 1985-07-12 JP JP60155017A patent/JPS6144878A/en not_active Expired - Lifetime
- 1985-07-12 ZA ZA855286A patent/ZA855286B/en unknown
- 1985-07-12 LU LU86001A patent/LU86001A1/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2136423A (en) * | 1983-03-04 | 1984-09-19 | Sandoz Ltd | Fungicidal 1h-azole-1-ethanol derivatives |
Non-Patent Citations (1)
Title |
---|
J B STENLAKE, }FOUNDATIONS OF MOLECULAR PHARMACOLOGY, VOL. 2 THE CHEMICAL BASIS OF DRUG ACTION}, 1979, ATHLONE PRESS (UNIV. OF LONDON) * |
Also Published As
Publication number | Publication date |
---|---|
AU582761B2 (en) | 1989-04-13 |
IL75774A0 (en) | 1985-11-29 |
FR2567515B1 (en) | 1988-09-09 |
CH668772A5 (en) | 1989-01-31 |
DK318185A (en) | 1986-01-14 |
NZ212718A (en) | 1989-01-27 |
DE3524296C2 (en) | 1994-08-25 |
IE851747L (en) | 1986-01-13 |
IL75774A (en) | 1989-12-15 |
DK318185D0 (en) | 1985-07-11 |
BE902837A (en) | 1986-01-09 |
SE8503443D0 (en) | 1985-07-11 |
DK163058C (en) | 1992-06-09 |
DE3524296A1 (en) | 1986-01-16 |
SE8503443L (en) | 1986-01-14 |
PH23287A (en) | 1989-06-30 |
LU86001A1 (en) | 1986-02-12 |
IT1200087B (en) | 1989-01-05 |
ZA855286B (en) | 1987-02-25 |
GB8517526D0 (en) | 1985-08-14 |
GB2161483B (en) | 1988-07-13 |
AU4477985A (en) | 1986-01-16 |
IT8548324A0 (en) | 1985-07-09 |
SE456679B (en) | 1988-10-24 |
NL8501962A (en) | 1986-02-03 |
FR2567515A1 (en) | 1986-01-17 |
DK163058B (en) | 1992-01-13 |
IE58516B1 (en) | 1993-10-06 |
JPS6144878A (en) | 1986-03-04 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
732E | Amendments to the register in respect of changes of name or changes affecting rights (sect. 32/1977) | ||
PE20 | Patent expired after termination of 20 years |
Effective date: 20050710 |