CN101323601A - Triazole derivatives useful in therapy - Google Patents
Triazole derivatives useful in therapy Download PDFInfo
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- CN101323601A CN101323601A CNA2008101504560A CN200810150456A CN101323601A CN 101323601 A CN101323601 A CN 101323601A CN A2008101504560 A CNA2008101504560 A CN A2008101504560A CN 200810150456 A CN200810150456 A CN 200810150456A CN 101323601 A CN101323601 A CN 101323601A
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- China
- Prior art keywords
- voriconazole
- expression
- compound
- ester hydrochloride
- phenyl
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Abstract
The invention provides a compound of Formula (I) or a medical salt thereof: R1-O-L; wherein, R1 represents a non-hydroxyl part of a triazole antifungal compound containing tert-hydroxyl, L represents an acyl part in amino acid. The compound of the invention is used for curing mycotic infection and has good water-solubility.
Description
Technical field:
This invention relates to the triazole derivative (especially for the treatment of people and other fungal infections in mannals) that is used for the treatment of, and its application method contains their preparation and their production method.
Technical background:
Many antifungal triazole compounds are known.For example: fluconazole, voriconazole, itraconazole etc. all have the excellent antibiotic activity.Yet this compound water soluble is low, must use recombiner to reach satisfied water soluble preparation.Chinese patent CN97192005.2 has related to the phosphoric acid ester of this compounds.
Summary of the invention:
The object of the present invention is to provide a kind of derivative of this compounds newly.
Its structure is: R
1-O-L
R
1The group of formula Ia preferably
R wherein
2The phenyl that expression is replaced by one or more halogens,
R
3Expression H or methyl,
R
4Expression H or and R
3Expression=CH together
2,
R
5Represent one 5 or 6 member heterocyclic ring containing nitrogens, this heterocycle can be selected to replace by one or more following groups: halogen, and=0, phenyl [can be by CN and (C
6H
4)-OCH
2CF
2CHCF
2Select to replace] or CH=CH-(C
6H
4)-CH
2CF
2CHF
2Or by the phenyl of one or more halogen and the replacement of methylpyrrole base.
Work as R
1When band is shown as mentioned above formula Ia, R
22,4 difluorobenzene base preferably, R
3Preferably H or methyl.
R
4Represent nitrogen heterocyclic ring to comprise triazolyl, pyrimidyl and thiazolyl
R
1The preferred concrete group of representative comprises:
Acyl moiety in the L represented amino acid, wherein preferred amino acids comprises: glycine, L-Ala, Methionin, leucine, Isoleucine, Xie Ansuan, phenylalanine.
The invention provides the production method of above-mentioned formula I compound and pharmaceutical salts thereof: with the esterification of formula II compound,
R
1OH II，
R wherein
1As above-mentioned definition;
Esterification process is: with formula (II) with through the amino acid (as: Boc amino acid, Fmoc amino acid) of overprotection amino, carry out the O-acylation, the preparation intermediate gets formula I compound with intermediate deprotection base again.
Compound of the present invention is useful, because they have pharmacologically active in comprising human animal.Particularly this compound is useful aspect treatment or prevention fungi infestation.For example: they can be used for the treatment that human local fungal infects, and the microorganism of infection comprises Candida, trichophyton, and microsporum, or Epidermophyton perhaps are used for the mucosal infections that Candida albicans causes.They also can be used for Candida.Cryptococcus neoformans, flavus, Aspergillus fumigatus, ring spore Pseudomonas, blastomyces brasiliensis, the whole body treatment of fungal infections that histoplasma capsulatum or blastomycete etc. causes.
The compounds of this invention can the unit dosage form administration, and route of administration can be enteron aisle or non-enteron aisle, as oral, muscle, subcutaneous, nasal cavity etc.
The The compounds of this invention route of administration can be intravenously administrable.Injection comprises intravenous injection, intramuscular injection, subcutaneous injection and acupoint injection therapy etc.
Form of administration can be pharmaceutically acceptable preparations such as tablet, capsule, dispersible tablet, oral liquid, infusion solutions, little pin, freeze-dried powder.
The compounds of this invention is by the gross weight administration, and its amount is every kg body weight 0.01-40mg, and preferably the consumption of 24h is every kg body weight 0.1-20mg, also can adopt medication several times.
Preferred plan is that the amount that gives one or more active compounds of the present invention once a day is the 0.2-20mg/kg body weight, and preferred dose is the 0.5-16mg/kg body weight.In order to meet people or ideal occlusion regimen for animals, the difference of the visual state of an illness weight of this dosage, treatment difficulty or ease and compound used therefor fluctuates up and down, or follows the doctor's advice.
Below in conjunction with embodiment the present invention is described in further detail, but should understands the non-scope that only limits to these embodiment of scope of the present invention.
Embodiment 1: the preparation of fluconazole glycinate
With fluconazole 306.3 grams (1mol), be dissolved in the 2000ml ethyl acetate, add triphenyl phosphorus 262.3g (1mol), BOC-glycine 175.2g (1mol), stir and drip diethyl azodiformate (DEAD) 174.2g (1mol) room temperature reaction 5h down, filter, feed exsiccant HCl gas in the filtrate to saturated, stirring at room 5h separates out a large amount of white solids, filters, filter cake washs with amount of ethyl acetate, dry fluconazole glycine ester hydrochloride 213.8g.
Fluconazole glycine ester hydrochloride 100g is restrained with after 500 milliliters of dissolved in purified water, slowly dripping saturated sodium carbonate solution is 9 to 9.5 to pH, three each 500ml of usefulness ethyl acetate extraction, united extraction liquid, add anhydrous sodium sulfate drying, evaporated under reduced pressure gets fluconazole glycinate 51 grams.
Embodiment 2: the preparation of voriconazole glycinate.
With voriconazole 349.3 grams (1mol), be dissolved in the 2500ml ethyl acetate, add triphenyl phosphorus 262.3g (1mol), BOC-glycine 175.2g (1mol), stir and drip diethyl azodiformate (DEAD) 174.2g (1mol) room temperature reaction 5h down, filter, feed exsiccant HCl gas in the filtrate to saturated, stirring at room 5h separates out a large amount of white solids, filters, filter cake washs with amount of ethyl acetate, dry voriconazole glycine ester hydrochloride 196.3g.
Voriconazole glycine ester hydrochloride 100g is restrained with after 500 milliliters of dissolved in purified water, slowly dripping saturated sodium carbonate solution is 8 to 9.5 to pH, three each 500ml of usefulness ethyl acetate extraction, united extraction liquid, add anhydrous sodium sulfate drying, evaporated under reduced pressure gets voriconazole glycinate 62 grams.
Embodiment 3: the preparation of voriconazole alanine ester.
With voriconazole 349.3 grams, be dissolved in the 2500ml ethyl acetate, add triphenyl phosphorus 262.3g, BOC-L-Ala 189.2g, stir and drip diethyl azodiformate (DEAD) 174.2g room temperature reaction 5h down, filter, feed exsiccant HCl gas in the filtrate to saturated, stirring at room 5h separates out a large amount of white solids, filters, filter cake washs with amount of ethyl acetate, dry voriconazole alanine ester hydrochloride 175.2g.
The sweet alanine ester hydrochloride of voriconazole 100g is restrained with after 500 milliliters of dissolved in purified water, slowly drip saturated sodium carbonate solution to pH be three each 500ml of 8 to 9 usefulness ethyl acetate extraction, united extraction liquid adds anhydrous sodium sulfate drying, and evaporated under reduced pressure gets voriconazole alanine ester 73 grams.
Embodiment 4: the preparation method of voriconazole glycine ester hydrochloride sheet
Prescription:
Voriconazole glycine ester hydrochloride 288g
Starch 80g
Microcrystalline Cellulose 120g
Magnesium stearate 2.0g
Vltra tears (E-30) (4% solution) is an amount of
Make 1000
Method for making: prepare 4% Vltra tears (E-30) solution, standby.Taking by weighing 20g starch, to put 105 ℃ of dryings 5 hours standby.Take by weighing voriconazole glycine ester hydrochloride, the Microcrystalline Cellulose of 60g starch and recipe quantity, mixing was pulverized 80 mesh sieves., granulate with 20 mesh sieves, material system softwood with 4% Vltra tears (E-30) solution in 50-60 ℃ of moisture content about 3% that is dried in the particle.Cross the whole grain of 20 mesh sieves, add dry starch (105 ℃ drying 5 hours), the magnesium stearate of recipe quantity, mix eventually, survey intermediate content, stator is heavy; Compressing tablet.
Embodiment 5: the preparation of voriconazole glycine ester hydrochloride sodium-chlor transfusion
Prescription:
Voriconazole glycine ester hydrochloride 288g
Sodium-chlor 89g
Water for injection 10L
Make 10000ml
Method for making: take by weighing the voriconazole glycine ester hydrochloride and the sodium-chlor of recipe quantity, add injection water 10L, stir; Add 0.1% gac in above-mentioned solution, stir, placed 15 minutes, 5 microns titanium rods take off charcoal, filter through the millipore filtration essence of 0.45 micron of filter cartridge and 0.22 micron again; Embedding is in the 100ml glass infusion bottle, and 115 ℃ of flowing steams were sterilized 30 minutes, promptly gets the transfusion of voriconazole glycine ester hydrochloride sodium-chlor.
Embodiment 6: the preparation of voriconazole glycine ester hydrochloride injection liquid
Prescription:
Voriconazole glycine ester hydrochloride 288g
Water for injection 1000ml
Make 1000ml
Method for making: take by weighing the voriconazole glycine ester hydrochloride of recipe quantity, add injection water 1000ml, stir dissolving; Add 0.1% gac in above-mentioned solution, stir, placed 15 minutes, 5 microns titanium rods take off charcoal, filter through the millipore filtration essence of 0.45 micron of filter cartridge and 0.22 micron again; Embedding is in the 10ml ampoule, and 100 ℃ of flowing steams were sterilized 45 minutes, promptly got voriconazole glycine ester hydrochloride injection liquid.
Embodiment 7: the preparation of injection voriconazole glycine ester hydrochloride
Prescription: voriconazole glycine ester hydrochloride 288g
Water for injection 1000ml
Make 100 bottles
After the voriconazole glycine ester hydrochloride dissolves with water for injection, accent pH is 4-6, add needle-use activated carbon absorption 30 minutes after carbon removal, Sterile Filtration (0.22 μ m), after testing, be sub-packed in after filtrate is up to specification in the control microbiotic cillin bottle, place in the vacuum freezing drying oven and carried out lyophilize 48 hours, add a cover butyl rubber plug, and roll the envelope aluminium lid and promptly get injection voriconazole glycine ester hydrochloride.
Claims (3)
1. the compound of general formula (I) or its hydrate:
R
1-O-L (I)
R
1The group of formula Ia preferably
R wherein
2The phenyl that expression is replaced by one or more halogens;
R
3Expression H or methyl;
R
4Expression H or and R
3Expression=CH together
2
R
5Represent one 5 or 6 member heterocyclic ring containing nitrogens, this heterocycle can be selected to replace by one or more following groups: halogen, and=O, phenyl [can be by CN and (C
6H
4)-OCH
2CF
2CHCF
2Select to replace] or CH=CH-(C
6H
4)-CH
2CF
2CHF
2Or by the phenyl of one or more halogen and the replacement of methylpyrrole base;
Acyl moiety in the L represented amino acid.
2. a medicinal compositions is characterized in that, contain the treatment effective dose according to claim 1 compound as activeconstituents and pharmaceutically acceptable carrier.
3. according to the purposes of the described pharmaceutical composition of claim 3, be used for the medicine of production for treating anti-fungal infection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101504560A CN101323601A (en) | 2008-07-25 | 2008-07-25 | Triazole derivatives useful in therapy |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101504560A CN101323601A (en) | 2008-07-25 | 2008-07-25 | Triazole derivatives useful in therapy |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101323601A true CN101323601A (en) | 2008-12-17 |
Family
ID=40187325
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008101504560A Pending CN101323601A (en) | 2008-07-25 | 2008-07-25 | Triazole derivatives useful in therapy |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101323601A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101744778A (en) * | 2010-02-01 | 2010-06-23 | 陕西合成药业有限公司 | Voriconazole phosphate ester for injection and preparation method thereof |
| WO2010100186A1 (en) * | 2009-03-05 | 2010-09-10 | Seps Pharma N.V. | Fluconazole carboxylic ester derivatives, synthesis, and use in long acting formulations |
-
2008
- 2008-07-25 CN CNA2008101504560A patent/CN101323601A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010100186A1 (en) * | 2009-03-05 | 2010-09-10 | Seps Pharma N.V. | Fluconazole carboxylic ester derivatives, synthesis, and use in long acting formulations |
| CN101744778A (en) * | 2010-02-01 | 2010-06-23 | 陕西合成药业有限公司 | Voriconazole phosphate ester for injection and preparation method thereof |
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| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20081217 |