CN104844652A - Isavuconazole phosphate ester, preparation method therefor and application thereof - Google Patents
Isavuconazole phosphate ester, preparation method therefor and application thereof Download PDFInfo
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- CN104844652A CN104844652A CN201510069636.6A CN201510069636A CN104844652A CN 104844652 A CN104844652 A CN 104844652A CN 201510069636 A CN201510069636 A CN 201510069636A CN 104844652 A CN104844652 A CN 104844652A
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- chinese mugwort
- saperconazole
- acid ester
- phosphoric acid
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Abstract
The present invention relates to isavuconazole phosphate ester, a synthesis method therefor and application thereof. The isavuconazole phosphate ester is obtained through chemical reactions with isavuconazole served as raw material. The isavuconazole phosphate ester can remarkably improve water solubility of isavuconazole, has good stabiltiy, and can be prepared into injections, which are thus applied to production of medicines capable of preventing, relieving and/or treating diseases caused by mucor or aspergillus infection.
Description
Technical field
The present invention relates to Chinese mugwort Saperconazole phosphoric acid ester and preparation method thereof and its purposes at field of medicaments.
Background technology
Chinese mugwort Saperconazole (chemical name: 4-[2-[(1R, 2R)-2-(2,5-difluorophenyl)-2-hydroxyl-1-methyl-3-(1H-1,2,4-triazol-1-yl) propyl group]-4-thiazolyl] cyanobenzene, English name: Isavuconazole, No. CAS: 241479-67-4), be a kind of thiazole derivative.
ai Shakang azoles
In February, 2014, FDA Food and Drug Administration (FDA) ratifies QIDP (the qualified transmissible disease product) qualification that this product is used for the treatment of mucormycosis (namely engaging germ sick).This product also obtains the QIDP qualification for the treatment of aspergillosis for 2013.Along with Chinese mugwort Saperconazole the U.S. get permission use, except the QIDP exclusivity of 5 years, this medicine also will obtain 7 years exclusive rights giving of FDA in 2013.In the U.S., Chinese mugwort Saperconazole enjoys FDA rapid passage privilege, may play an important role in life-threatening aggressive fungal infection, will become doctor and tackle the new means of this kind of thorny disease.
Ergosterol, as forming the important component of fungal cell membrane, plays an important role for maintaining the mobility of cytolemma, biological regulation and three-dimensional arrangement etc.And the sterol forming cytolemma should be C-14 position demethyl.The target enzyme mainly 14-α demethyl enzyme of Chinese mugwort Saperconazole effect.The nitrogen-atoms in triazole ring is utilized to be embedded on the iron atom of cytochrome P-450 albumen of this enzyme, suppress the catalytic activity of 14-α-demethyl enzyme, make lanosterol can not change into 14-α-demethyl sterol, and then stop the synthesis of ergosterol, make the cytolemma biosynthesis block of fungi, fungal cell is broken death.
World patent WO1999045008A1 discloses Chinese mugwort Saperconazole, synthetic method and anti-microbial activity.
Chinese mugwort Saperconazole itself is generally water-soluble, and pharmaceutical excipient need be adopted water-soluble to improve it.But, reducing formula is reduce the important means that patient may produce side reaction, the simultaneously introducing of pharmaceutical excipient has and produces potential chemical action with drug main composition, thus causes the reduction of the generation of impurity and main component content, thus brings risk for clinical application.
Summary of the invention
Phosphation is a kind of Prodrug formed designs method, can improve parent drug water-soluble, improve pharmacokinetic property, improve targeting, reduce poisonous side effect of medicine, increase medicine stability etc., obtain in modern medicines research and development and pay attention to widely and application.
Object of the present invention provides a kind of water-soluble fabulous Chinese mugwort Saperconazole phosphoric acid ester for the problems referred to above and with its preparation that suitable auxiliary material is made for main ingredient adds.
The object of the present invention is to provide a kind of Chinese mugwort Saperconazole phosphoric acid ester, its structural formula is as follows:
Another object of the present invention is the medical composition and its use providing Chinese mugwort Saperconazole phosphoric acid ester.
More detailed, the present invention includes Chinese mugwort Saperconazole hydrate, solvate and pharmaceutical salts, the hydrate of pharmaceutical salts, the solvate of pharmaceutical salts.
Chinese mugwort Saperconazole phosphoric acid ester pharmaceutical salts of the present invention, its pharmaceutical salts comprises sodium salt, sylvite, calcium salt, magnesium salts etc.
Chinese mugwort Saperconazole phosphoric acid ester provided by the invention, Chinese mugwort Saperconazole pharmaceutical salts are compared with Chinese mugwort Saperconazole, and have following advantage: this product solubleness in water is fabulous, being more suitable for exploitation becomes intravenous formulations; This product enters and under the effect of phosphoesterase, is hydrolyzed to rapidly Chinese mugwort Saperconazole in organism and plays drug effect.
The end preparation method of Saperconazole phosphoric acid ester of the present invention comprises the following two kinds: 1) with the Saperconazole that ends for raw material, dissolve with solvent, react with phosphorus oxychloride, prepare chlorine phosphate intermediate, then through hydrolysis, Chinese mugwort Saperconazole phosphoric acid ester can be obtained; 2) with the Saperconazole that ends for raw material, react in the basic conditions with phosphorus trichloride, benzylalcohol, hydrogen peroxide, then Chinese mugwort Saperconazole phosphoric acid ester can be obtained through over hydrogenation debenzylation.
The solvent of method 1 comprises acetonitrile, ethyl acetate, methylene dichloride etc.;
The hydrolysis reaction of method 1 comprises employing water and is hydrolyzed; The preparation method of its pharmaceutical salts be adopt water and methyl alcohol thereof, ethanol is reaction solvent, regulates pH can prepare Chinese mugwort Saperconazole Di-Sodium Phosphate, Chinese mugwort Saperconazole Rhodiaphos DKP to weakly alkaline with mineral alkalis such as sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide.
The solvent of method 2 comprises acetonitrile, ethyl acetate, methylene dichloride etc.; Alkaline condition can be supplied to by organic bases pyridine, triethylamine or mineral alkali salt of wormwood, sodium carbonate etc.;
The solvent of method 2 comprises alkaline aqueous solution, and alkaline condition comprises sodium hydroxide, potassium hydroxide, can obtain Chinese mugwort Saperconazole phosphoric acid ester with palladium carbon for catalyzer carries out shortening.
The synthesis of Chinese mugwort Saperconazole can prepare with reference to method synthesis disclosed in WO1999045008A1.
Medicinal compositions of the present invention ends the pharmaceutical salts of Saperconazole phosphoric acid ester or Chinese mugwort Saperconazole phosphoric acid ester as activeconstituents and pharmaceutically acceptable carrier.
Form of administration can make the pharmaceutically acceptable injection types such as little pin, lyophilized powder.
Medicinal compositions of the present invention can be used for preventing, improve and/or treatment mucormycosis or the disease that causes of aspergillin infection.
Chinese mugwort Saperconazole of the present invention or its pharmaceutical salts are by total amount administration, and its amount is every Kg body weight administration 1-100mg, the every Kg body weight 1-20mg of best first day administration, also can adopt the mode of successive administration.In order to meet people or ideal occlusion regimen for animals, this dose can adjust according to the state of an illness.
Below in conjunction with embodiment, the present invention is elaborated further, but should not be construed as limitation of the scope of the invention.
Embodiment
Embodiment 1 ends the preparation of Saperconazole phosphoric acid ester
Chinese mugwort Saperconazole 100g, add ethyl acetate 800ml, slowly drip phosphorus oxychloride 150ml, 25 DEG C of stirring reactions, react complete, in reaction solution, add water 50ml, stir 30min, concentrating under reduced pressure obtains oily matter, acetone 200ml is added in oily matter, water 40ml, stirs crystallization, must to end Saperconazole phosphoric acid ester in 30 DEG C of vacuum-dryings.
Embodiment 2 ends the preparation of Saperconazole disodium phosphate
Chinese mugwort Saperconazole 100g, add ethyl acetate 800ml, slowly drip phosphorus oxychloride 150ml, 25 DEG C of stirring reactions, react complete, in reaction solution, add water 50ml, stir 30min, concentrating under reduced pressure obtains oily matter, ethanol 200ml is added in oily matter, regulate pH to 8.0 with sodium hydroxide, stir crystallization, must to end Saperconazole disodium phosphate in 30 DEG C of vacuum-dryings.
Embodiment 3 ends the preparation of Saperconazole phosphoric acid ester
Chinese mugwort Saperconazole 52g, adds methylene dichloride 500ml, adds pyridine 50ml, stirring at room temperature 20min, be cooled to-10 DEG C under stirring at normal temperature, drip phosphorus trichloride 20ml, drip complete insulation reaction 20min, be slowly warming up to 10 DEG C, stirring reaction 2h.Drip phenylcarbinol 50ml, drip and finish 10 DEG C of insulation reaction 2h; Be cooled to 0 DEG C, slowly drip hydrogen peroxide 80ml, insulation reaction 15min, 15 DEG C of reaction 1h.React complete use 5% Sodium Pyrosulfite and extract 3 times, water, saturated aqueous common salt extract once respectively, are spin-dried for organic phase, prepare intermediate through column chromatography.Gained intermediate 50g, add aqueous sodium hydroxide solution 100ml (5g sodium hydroxide is dissolved in 100ml water), stirring at room temperature, adds 2.5g Pd/C or Pd (OH) 2/C, and normal pressure leads to hydrogen reaction to complete, be cooled to 0 DEG C, drip sulfuric acid 0.85g, stirring and crystallizing, suction filtration, washing, 40-50 DEG C of vacuum-drying.
Embodiment 4: the preparation of injection Chinese mugwort Saperconazole phosphoric acid ester
Prescription:
Chinese mugwort Saperconazole phosphoric acid ester 517g
N.F,USP MANNITOL 500g
Water for injection 10L
Method for making: take the Chinese mugwort Saperconazole phosphoric acid ester of recipe quantity, N.F,USP MANNITOL, with water for injection stirring and dissolving, through 0.22 micrometer Millipore membrane filtration, namely prepare injection Chinese mugwort Saperconazole through freeze-drying.
Embodiment 5: the preparation of injection Chinese mugwort Saperconazole phosphoric acid ester
Prescription:
Chinese mugwort Saperconazole phosphoric acid ester 517g
Physiological saline 10L
Method for making: the Chinese mugwort Saperconazole phosphoric acid ester, the 10L physiological saline that take recipe quantity, stirring and dissolving, through 0.22 micrometer Millipore membrane filtration, namely packing obtains Chinese mugwort Saperconazole phosphate injection.
Claims (4)
1. end Saperconazole phosphoric acid ester or its pharmaceutical salts, and the chemical structural formula of described Chinese mugwort Saperconazole phosphoric acid ester is as follows:
2. Chinese mugwort Saperconazole phosphoric acid ester according to claim 1 or its pharmaceutical salts, wherein said pharmaceutical salts obtains sodium salt that bound phosphate groups position formed, sylvite, calcium salt and magnesium salts in its chemical structure.
3. a medicinal compositions, is characterized in that, the compound as claimed in claim 1 or 2 containing therapeutic dose is as activeconstituents and pharmaceutically acceptable carrier.
4. the purposes of pharmaceutical composition according to claim 3, can be used for the medicine of the anti-mucormycosis of production for treating or aspergillin infection.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105111234A (en) * | 2015-09-23 | 2015-12-02 | 河北远征禾木药业有限公司 | Synthesis method of florfenicol phosphate |
| CN106749221A (en) * | 2016-12-15 | 2017-05-31 | 扬子江药业集团有限公司 | Chinese mugwort Saperconazole monohydrate crystal form and preparation method thereof |
| CN106883226A (en) * | 2017-03-30 | 2017-06-23 | 成都绿林科技有限公司 | The preparation method of Ai Shakang azoles sulfuric esters |
| CN108452848A (en) * | 2016-02-24 | 2018-08-28 | 苏州金点生物科技有限公司 | A kind of catalyst |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103857675A (en) * | 2011-06-23 | 2014-06-11 | 威尔金制药有限公司 | Metalloenzyme inhibitor compounds |
-
2015
- 2015-02-10 CN CN201510069636.6A patent/CN104844652A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103857675A (en) * | 2011-06-23 | 2014-06-11 | 威尔金制药有限公司 | Metalloenzyme inhibitor compounds |
| CN103930418A (en) * | 2011-06-23 | 2014-07-16 | 威尔金制药有限公司 | Metalloenzyme inhibitor compounds |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105111234A (en) * | 2015-09-23 | 2015-12-02 | 河北远征禾木药业有限公司 | Synthesis method of florfenicol phosphate |
| CN105111234B (en) * | 2015-09-23 | 2017-05-17 | 河北远征禾木药业有限公司 | Synthesis method of florfenicol phosphate |
| CN108452848A (en) * | 2016-02-24 | 2018-08-28 | 苏州金点生物科技有限公司 | A kind of catalyst |
| CN108452848B (en) * | 2016-02-24 | 2020-12-11 | 上海兰立生物科技有限公司 | Catalyst |
| CN106749221A (en) * | 2016-12-15 | 2017-05-31 | 扬子江药业集团有限公司 | Chinese mugwort Saperconazole monohydrate crystal form and preparation method thereof |
| CN106883226A (en) * | 2017-03-30 | 2017-06-23 | 成都绿林科技有限公司 | The preparation method of Ai Shakang azoles sulfuric esters |
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Application publication date: 20150819 |
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