CN103724342B - Antifungal drug compounds, its composition and purposes - Google Patents
Antifungal drug compounds, its composition and purposes Download PDFInfo
- Publication number
- CN103724342B CN103724342B CN201410023210.2A CN201410023210A CN103724342B CN 103724342 B CN103724342 B CN 103724342B CN 201410023210 A CN201410023210 A CN 201410023210A CN 103724342 B CN103724342 B CN 103724342B
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- China
- Prior art keywords
- pharmaceutical composition
- compound
- injection
- acceptable salt
- pharmacy acceptable
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- 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
-
- 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
Abstract
The present invention relates to a kind of broad-spectrum antifungal medical compounds, a kind of broad-spectrum antifungal pharmaceutical composition, described compound or composition at the application prepared in broad-spectrum antifungal medicine and described compound or composition for the preparation of the application in microbial bad attack sexuality dye (comprising candida krusei) of beads for the treatment of Aspergillosis and/or fluconazole resistant and/or the medicine of severe infections that caused by Scedosporium and Fusarium.Of the present invention have extensive and powerful anti-mycotic activity, its pharmacokinetic property and security better.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology.Particularly, the present invention relates to a kind of broad-spectrum antifungal medical compounds, a kind of broad-spectrum antifungal pharmaceutical composition, described compound or composition at the application prepared in broad-spectrum antifungal medicine and described compound or composition for the preparation of the application in microbial bad attack sexuality dye (comprising candida krusei) of beads for the treatment of Aspergillosis and/or fluconazole resistant and/or the medicine of severe infections that caused by Scedosporium and Fusarium.
Background technology
In view of current global serious fungal infections incidence continues to rise, especially the fungi infestation mortality ratio of immunocompromised persons's (as tumour patient, AIDS patient, Organ Transplantation Patients etc.) is quite high, the epidemiology of whole world pathogenic bacteria there occurs remarkable change: Candida is still deep fungal infection most commonly encountered diseases substance at present, wherein candida albicans infection obviously declines, and non-white monilial infection increases; The intrinsic Resistant strain of fluconazole---Candida glabrata, gram Rou Shi candidiasis and mould (particularly aspergillus tubigensis) infect and obviously rise; Deep fungal significantly rises year by year to fluconazole resistant rate, domestic by 10.3% of calendar year 2001 rise to 2013 25.9%.Cause clinically in the urgent need to wide spectrum, potent, safe, economic antimycotic new drug.
Summary of the invention
One object of the present invention is, provides a kind of medical compounds of broad-spectrum antifungal.Another object of the present invention is, provides a kind of pharmaceutical composition of broad-spectrum antifungal.Another object of the present invention is, provides described compound or composition preparing the application in broad-spectrum antifungal medicine.
For foregoing invention object, the invention provides following technical scheme:
On the one hand, the invention provides a kind of following formula (formula 1) compound or its pharmacy acceptable salt:
Molecular formula is: C23N3S2O2H21
Chemical name is: 3-methyl isophthalic acid-[[6-(1H-pyrryl)-2-methylsulfonyl-1-phenyl] benzothiazole]-1H-pyrroles-2-alcohol
On the other hand, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition comprises formula 1 compound or its pharmacy acceptable salt, and preferably, said composition also comprises one or more pharmaceutically acceptable carrier and/or vehicle.
Preferably, the concrete formulation of pharmaceutical composition of the present invention is injection or oral preparations, and further preferably, described injection is powder injection or injection liquid, and described oral preparations is tablet or capsule.
Further preferably, the content of tablet Chinese style 1 compound of the present invention or its pharmacy acceptable salt is 0.1-0.5g/ sheet; Preferably, be 0.15-0.4g/ sheet; Further preferably, be 0.2-0.3g/ sheet.
On the other hand, the invention provides a kind of formula 1 compound or its pharmacy acceptable salt is preparing the application in broad-spectrum antifungal medicine.
On the other hand, the invention provides a kind of formula 1 compound or its pharmacy acceptable salt for the preparation of the application in microbial bad attack sexuality dye (comprising candida krusei) of beads for the treatment of Aspergillosis and/or fluconazole resistant and/or the medicine of severe infections that caused by Scedosporium and Fusarium.
The following specifically describes each technical scheme of the present invention and preferred implementation.
Formula 1 compound of the present invention is white or off-white powder, and be a kind of triazole species new compound with the antifungic action of wide spectrum, its indication specifically comprises: treatment Aspergillosis; Treat microbial bad attack sexuality dye (comprising candida krusei) of the beads of fluconazole resistant; Treat the severe infections caused by Scedosporium and Fusarium.
Compared with prior art, the present invention has following obvious advantage:
Formula 1 compound is a kind of new antifungal drug, compare before similar medicine, this formula 1 compound has extensive and powerful anti-mycotic activity, its pharmacokinetic property and security better.For deep fungal infection, formula 1 compound is better than similar drugs in anti-microbial activity and resistance.
The present inventor is through verification experimental verification, formula 1 compound can kill aspergillus tubigensis clinically, fabulous anti-microbial activity is had to the Candida albicans of resistance to fluconazole, lower than fluconazole 10 ~ 100 times to the minimal inhibitory concentration (MICs) of Candida albicans, to the saccharomycetic anti-microbial activity of pathogenicity bo higher than fluconazole, confirm that fluconazole is to filamentous fungus invalid (MIC90 > 512mg/L), but formula 1 compound but (comprises the rare mould Pseudomonas of sufficient branch to pathogenic filamentous fungus widely, Fusarium, Histoplasma capsulatum, Blastomyces dermatitidis and cryptococcus neoformans etc.) there is excellent external activity.Such fungi for the treatment of cryptococcal meningitis clinical discovery has produced resistance (MIC >=64ug/mg) to fluconazole, and comparatively fluconazole is strong to the activity of such fungi for formula 1 compound, and persistent, be a more promising antimycotic new compound.
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.But these embodiments are only limitted to illustrate that the present invention and being not used in limits the scope of the invention.The experimental technique of unreceipted specific experiment condition in the following example, usually conveniently condition, or according to the condition that manufacturer advises.
The preparation of embodiment 1 formula 1 compound and qualification test
1, in 500ml three-necked bottle, add 2-chloro-2,4-difluoro acetophenone (30.5g, 0.14mol), 3,5 two bromo-1H-[1,2,4] triazole (34g, 0.15mol), salt of wormwood (27.6g, 0.2mol), tributyl amine bromide (2.0g) and methane 300ml, return stirring 8h.Cooling, filters, filter residue CH
2cl
2washing, merges organic layer, and washing is dry, is concentrated into dry, with sherwood oil/ethyl acetate (1/1,200ml) recrystallization, obtains light yellow solid 38.0g, yield 78.5%, fusing point 184-5 DEG C.
2, under nitrogen by the ethane solution (80ml of 2.5M n-Butyl Lithium, 0.2mol) join in three-necked bottle, diisopropylamine (10g is dripped under ice-water bath, tetrahydrofuran (THF) 100ml solution 0.2mol), stir 30 minutes, cooling, drip the fluoro-6-ethyl-pyrimidine of the chloro-5-of 5-(32.1g, tetrahydrofuran (THF) 300ml 0.2mol), stirs 3h at this temperature.Add the tetrahydrofuran (THF) 500ml of 1-(2,4 dichloro benzene base)-2-(the bromo-1H-of 3,5-bis-[1,2,4]-triazole-1-base) ethyl ketone (76.2g, 0.2mol) ,-60 DEG C are stirred 2h; Be cooled to-50 DEG C, the aqueous solution adding glacial acetic acid 12g makes reaction all standing, is warming up to room temperature, separates organic layer, extracts water layer with ethyl acetate 100ml, merges organic layer, dry, concentrated, purification by silica gel column chromatography.Collect isomer A. fusing point 110-60 DEG C, continue wash-out, collect isomer B, fusing point 90-15 DEG C.
3, isomer A is dissolved in ethanol 250ml, add salt of wormwood (17.4g, 0.126mol) 10%Pd/c (2.3g), 40 DEG C of logical H-H reactions, to completely, are filtered, with ethanol 50ml filter wash slag, are concentrated into dry, add CH
2cl
2(150ml), water 150ml, adjust PH=11 with 40%NaOH, layering, water layer CH
2cl
2(100ml) extract, merge organic layer, washing 100ml is dry, concentrated, adds Virahol 20ml, and heating makes it dissolve, and stirs cooling, filters, obtains white solid 15.8g.
4, by upper step 3 gained solid (40g; 0.12mol) be dissolved in acetone 900ml; add R-(-)-10-camphorsulfonic acid (20.5g; methyl alcohol 300ml 0.12mol); mixture is back to whole dissolving; stirring is chilled to 20 DEG C, granulation of spending the night, and obtains white solid 30.4g. molten some 156-157 DEG C. by dissolution of solid in CH
2cl
2(300ml), water 300ml, adjusts PH10 with 40%NaOH, layering, water layer CH
2cl
2(200ml) wash, organic layer is dry, concentrated, obtains solid, adds Virahol 15ml, and heating makes it dissolve, and stirs cooling, separates out white solid.Filter, dry, obtain solid 17g.The solid finally obtained is formula 1 compound 3-methyl isophthalic acid-[[6-(1H-pyrryl)-2-methylsulfonyl-1-phenyl] benzothiazole]-1H-pyrroles-2-alcohol, fusing point 171 DEG C.
Embodiment 2
Using formula 1 compound as activeconstituents, according to the following formulation and preparation technology make injection liquid:
2.1 specifications: every bottle containing new compound 0.1g.
The composition of 2.2 injection liquids and formula:
The preparation technology of 2.3 injection liquids:
In aseptic technique, take new compound (formula 1 compound) 100g, add 4L ethanol, be stirred to dissolve, add 100g gac, stir after 40 minutes, filtering decarbonization, by the sterile film of filtrate by 0.22 μm, enter in 100 grades of clean grooves; In above-mentioned solution, slowly add water for injection (hiding through refrigerator and cooled) 20L, limit edged stirs, and adds and continues stirring 50 minutes, leave standstill crystallization after 3 hours, suction filtration, filter cake water for injection washs, gained solid under 70 DEG C of conditions, drying under reduced pressure 6 hours.Be sub-packed in 10ml cillin bottle after the assay was approved, every bottle of 0.1g, moulding plug, rolls aluminium lid, labels, finished product inspection, packs and get final product.
The untoward reaction rate simultaneous test of embodiment 3 formula 1 compound and former voriconazole compound
Under two kinds of different administering modes (A oral administration/B intravenous drip), the new compound (200 example) shown in formula 1 and existing product (former voriconazole compound is first given respectively to 391 routine acute Aspergillosis patients, 191 examples) treatment, sequential antifungal drug treatment of having permitted with other afterwards, and have rated the untoward reaction contrast of formula 1 compound (180 example) and commercially available voriconazole (196 example) treatment Esophageal candidiasis.The untoward reaction difference of formula 1 compound and former voriconazole compound is huge.Concrete contrast and experiment is as shown in table 1 below:
The untoward reaction rate simultaneous test of table 1. formula 1 compound and commercially available voriconazole
Wherein, former voriconazole is commercially available usual products, chemical name is (2R, 3S)-2-(2,4-difluorophenyl)-3-(fluorine-based-4-pyrimidine of 5-)-1-(1H-1,2,4-triazol-1-yl) compound of-2-butanols, new compound is formula 1 compound of the present invention.
Embodiment 4 formula 1 compound is at the preventive trial of chemotherapy for acute myeloid leukemia induction period
Double-blind comparison's test that the present embodiment is the new compound shown in chemotherapy for acute myeloid leukemia induction period prophylactic application formula 1.
4.1 objects:
Invasive infections with fungi is that long-term grain lacks the frequently-occurring disease of patient and dead common cause, use and can cause the arguement for the treatment of Best Times about antifungal therapy as original voriconazole " (2R; 3S)-2-(2; 4-difluorophenyl)-3-(fluorine-based-4-pyrimidine of 5-)-1-(1H-1; 2,4-triazol-1-yl)-2-butanols " broad-spectrum antifungal medicine that patient can tolerate like that.We conducted a clinical trial, be intended to the new compound shown in analysis and inspection formula 1 prevents pulmonary infiltrates validity and security at chemotherapy for acute myeloid leukemia induction period.
4.2 methods:
The three phases test that this is a prediction carried out in the patient in chemotherapy for acute myeloid leukemia inducer remission stage, random, double blinding, placebo control, the new compound shown in patient's every day twice oral 200mg formula 1 is until check out that pulmonary infiltrates or agranulocytosis terminate just now.Main level of signification is the sickness rate that chemotherapy starts latter 21 days pulmonary infiltrates.Secondary index is the incidence of infection, hospital stays, antifungal therapy time, first fever time and Drug safety.
4.3 results:
Amount to 25 patient's random packet and accept the new compound (n=10) shown in formula 1 and placebo (n=15) administration.Sickness rate test group to 21 days pulmonary infiltrates is 0 (0%), control group is 12 (80%) (P=0.06), average hospital days test group is short, new compound group (median 21.9 days) shown in formula 1, placebo (median 37.3 days, P=0.09).In the following up a case by regular visits to of surrounding thereafter, liver spleen moniliosis (P=0.01) is diagnosed out for 10 the patient of placebo.Adverse events in two groups and toxicity indifference.
4.4 conclusions:
New compound shown in preventative oral twice on the one 200mg formula 1 of chemotherapy for acute myeloid leukemia induction period can lower pulmonary infiltrates and the oidiomycotic sickness rate of liver spleen.Present embodiment shows that the new compound shown in formula 1 is safety and better tolerance.
Claims (9)
1. a following formula: compound or its pharmacy acceptable salt:
2. a pharmaceutical composition, is characterized in that, described pharmaceutical composition comprises compound according to claim 1 or its pharmacy acceptable salt.
3. pharmaceutical composition according to claim 2, is characterized in that, described pharmaceutical composition is injection or oral preparations.
4. pharmaceutical composition according to claim 3, is characterized in that, described injection is powder injection or injection liquid, and described oral preparations is tablet or capsule.
5. pharmaceutical composition according to claim 4, is characterized in that, described injection liquid is the aqueous solution, the compound according to claim 1 wherein containing 2-5mg/ml or its pharmacy acceptable salt.
6. pharmaceutical composition according to claim 4, is characterized in that, described powder injection is used by sodium chloride injection or glucose injection dilution.
7. pharmaceutical composition according to claim 4, is characterized in that, in described tablet, the content of compound according to claim 1 or its pharmacy acceptable salt is 0.1-0.5g/ sheet.
8. compound according to claim 1 or its pharmacy acceptable salt are preparing the application in broad-spectrum antifungal medicine.
9. compound according to claim 1 or its pharmacy acceptable salt application in the medicine of the sexy severe infections contaminated and/or caused by Scedosporium and Fusarium of the microbial bad attack of beads for the preparation for the treatment of Aspergillosis and/or fluconazole resistant.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410023210.2A CN103724342B (en) | 2014-01-11 | 2014-01-11 | Antifungal drug compounds, its composition and purposes |
| IE20140060A IE20140060A1 (en) | 2014-01-11 | 2014-03-06 | Antifungal compounds, compositions and uses thereof |
| GB1403995.2A GB2522081A (en) | 2014-01-11 | 2014-03-06 | Antifungal compounds, compositions and uses thereof |
| NL2012394A NL2012394C2 (en) | 2014-01-11 | 2014-03-11 | Antifungal compounds, compositions and uses. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410023210.2A CN103724342B (en) | 2014-01-11 | 2014-01-11 | Antifungal drug compounds, its composition and purposes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103724342A CN103724342A (en) | 2014-04-16 |
| CN103724342B true CN103724342B (en) | 2016-03-02 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410023210.2A Expired - Fee Related CN103724342B (en) | 2014-01-11 | 2014-01-11 | Antifungal drug compounds, its composition and purposes |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN103724342B (en) |
| GB (1) | GB2522081A (en) |
| IE (1) | IE20140060A1 (en) |
| NL (1) | NL2012394C2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103864775A (en) * | 2014-02-12 | 2014-06-18 | 珠海海滨医药生物科技有限公司 | 3-methyl-1-[[6-(1H-pyrryl)-2-methylsulfonyl-1-phenyl] benzothiazole]-1H-pyrrole-2-alcohol crystal form and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1685836A2 (en) * | 1998-09-17 | 2006-08-02 | University Of North Carolina At Chapel Hill | Antifungal activity of dicationic molecules |
| CN101575330A (en) * | 2008-05-05 | 2009-11-11 | 丽珠医药集团股份有限公司 | Novel voriconazole broad-spectrum antifungal medicine compound, broad-spectrum antifungal medicine composition and application thereof |
| WO2013143477A1 (en) * | 2012-03-28 | 2013-10-03 | Sun Weixin | 1,4-dihydroxy-6-methyl-2-pyridone compound, and preparation method and application thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001192386A (en) * | 1999-10-29 | 2001-07-17 | Meiji Seika Kaisha Ltd | New triazol derivative and antifungal agent containing the same as active ingredient |
| EP2351744B1 (en) * | 2008-10-17 | 2015-01-07 | Shionogi & Co., Ltd. | Acetic acid amide derivative having inhibitory activity on vascular endothelial lipase |
| TW201408665A (en) * | 2012-07-09 | 2014-03-01 | 必治妥美雅史谷比公司 | Sulfonyl containing benzothiazole inhibitors of endothelial lipase |
-
2014
- 2014-01-11 CN CN201410023210.2A patent/CN103724342B/en not_active Expired - Fee Related
- 2014-03-06 GB GB1403995.2A patent/GB2522081A/en not_active Withdrawn
- 2014-03-06 IE IE20140060A patent/IE20140060A1/en not_active IP Right Cessation
- 2014-03-11 NL NL2012394A patent/NL2012394C2/en not_active IP Right Cessation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1685836A2 (en) * | 1998-09-17 | 2006-08-02 | University Of North Carolina At Chapel Hill | Antifungal activity of dicationic molecules |
| CN101575330A (en) * | 2008-05-05 | 2009-11-11 | 丽珠医药集团股份有限公司 | Novel voriconazole broad-spectrum antifungal medicine compound, broad-spectrum antifungal medicine composition and application thereof |
| WO2013143477A1 (en) * | 2012-03-28 | 2013-10-03 | Sun Weixin | 1,4-dihydroxy-6-methyl-2-pyridone compound, and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| GB201403995D0 (en) | 2014-04-23 |
| CN103724342A (en) | 2014-04-16 |
| NL2012394C2 (en) | 2015-07-16 |
| GB2522081A (en) | 2015-07-15 |
| IE20140060A1 (en) | 2014-07-16 |
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Effective date of registration: 20160530 Address after: 130000 B9, North Lake Science Park Industrial Park, 3333 North Sheng street, hi tech North Zone, Jilin, Changchun Patentee after: Changchun hi tech incubation Co., Ltd. Address before: 519020 Ling Nan Road, Xiangzhou District, Guangdong 68-1065, Zhuhai Patentee before: ZHUHAI BINHAI PHARMACEUTICAL BIOTECHNOLOGY CO., LTD. |
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