CN105669573B - A kind of isopropylamine is for azole antifungal compound and its preparation method and application - Google Patents
A kind of isopropylamine is for azole antifungal compound and its preparation method and application Download PDFInfo
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- CN105669573B CN105669573B CN201610007802.4A CN201610007802A CN105669573B CN 105669573 B CN105669573 B CN 105669573B CN 201610007802 A CN201610007802 A CN 201610007802A CN 105669573 B CN105669573 B CN 105669573B
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- isopropylamine
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- IPLOMNLYANDDLS-UHFFFAOYSA-N CC(C)N(CC(C[n]1ncnc1)(c(ccc(F)c1)c1F)O)CC(S)=S Chemical compound CC(C)N(CC(C[n]1ncnc1)(c(ccc(F)c1)c1F)O)CC(S)=S IPLOMNLYANDDLS-UHFFFAOYSA-N 0.000 description 1
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- 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
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Abstract
The present invention relates to pharmaceutical technology field, and in particular to one kind has new nitrogen azoles alcoholic antifungal compound and preparation method and the application of following chemical structure of general formula.
Description
Technical field
The present invention relates to pharmaceutical technology field, specifically, be a kind of isopropylamine for azole antifungal compound and
Its preparation method and the application in antimycotic field.
Background technology
In recent years, the incidence of disease of deep fungal infection rises year by year, serious threat human health.Triazole type medicine is clinical
A kind of novel antifungal drugs being most widely used, it represents medicine Fluconazole, ketoconazole and voriconazole turns into treatment
The fiest-tire medication of deep fungal infection.But also long-term a large amount of uses by this class antifungal drug clinically so that fungi
Drug resistance problems become increasingly conspicuous, and clinically there is an urgent need to wide spectrum, novel antifungal drugs efficiently, less toxic.Therefore, design synthesis
Novel antifungal drugs turn into the focus in research, the synthesis especially using Fluconazole as the derivative of lead compound.
Chinese patent 2014102173842 discloses a kind of sulfur-bearing azole antifungal compound, and such compound is also same
Sample has triazole structure.Those skilled in the art know that linking group is to whole point on the right side of 3 C atoms of triazole class compounds
The physicochemical property of son, the pharmacokinetic property of molecule have considerable influence, and the linking group of different structure may have difference
Even opposite pharmacological activity.And on 1- (1H-1,2,4- triazol-1-yls) -2- (2,4 difluorophenyl) -3- [N- of the present invention
Isopropyl amido (two thio carbomethoxy of substituted benzyl)] -2- alcohol compounds and its antifungal activity, it yet there are no report.
The content of the invention
The purpose of the present invention is to be directed to deficiency of the prior art, there is provided a kind of isopropylamine is for azole antifungal chemical combination
Thing.
Another purpose of the present invention is to provide preparation side of the isopropylamine as described above for azole antifungal compound
Method.
Another purpose of the present invention is to provide purposes of the isopropylamine as described above for azole antifungal compound.
To achieve the above object, the present invention adopts the technical scheme that：
A kind of isopropylamine is for azole antifungal compound, and the isopropylamine is for azole antifungal compound structure
Formula is：
Wherein R is selected from：
I. halogen, the halogen are selected from F, Cl or Br, can be located at the o-, m- or p- position of aromatic ring；Wherein substituent F and Br are
Monosubstituted, substituent Cl can be monosubstituted or polysubstituted；
Ii. alkyl, the alkyl are the alkyl of 1-4 carbon atom, and substituent can be located at the o-, m- or p- position of aromatic ring, be
It is monosubstituted；
Iii. nitro, the nitro are located at the o-, m- or p- position of aromatic ring, are monosubstituted；Or
Iv. cyano group, the cyano group are located at the o-, m- or p- position of aromatic ring, are monosubstituted.
Preferably, the substituent R is selected from：
Halogen, the halogen are selected from F, Cl or Br, can be located at the o-, m- or p- position of aromatic ring；Wherein substituent F and Br is single
Substitution, substituent Cl can be monosubstituted or polysubstituted.
Preferably, the substituent R is selected from：
Alkyl, the alkyl are the alkyl of 1-4 carbon atom, and substituent can be located at the o-, m- or p- position of aromatic ring, singly to take
Generation.
Preferably, the substituent R is selected from：
Nitro, the nitro are located at the o-, m- or p- position of aromatic ring, are monosubstituted.
Preferably, the substituent R is selected from：
Cyano group, the cyano group are located at the o-, m- or p- position of aromatic ring, are monosubstituted.
More preferably, the substituent R is selected from as follows：
。
To realize above-mentioned second purpose, the present invention adopts the technical scheme that：
Isopropylamine as described above comprises the following steps for the preparation method of azole antifungal compound：
A) compound 1 and chloracetyl chloride reaction generation compound 2；
B) compound 2 and triazole reaction generation compound 3；
C) compound 3 and iodate trimethyl oxygen reaction of Salmon-Saxl generation compound 4；
D) compound 4 and isopropylamine reaction generation compound 5；
E) bromobenzyl and CS are substituted2Ice bath reacts, and adds compound 5 and reacts, obtains target compound 6；
The compound 1-6 structures and reaction scheme are as follows：
Preferably, the preparation method comprises the following steps that：
A) with chloracetyl chloride friedel-crafts reaction generation compound 2 occurs under the conditions of existing for aluminum trichloride (anhydrous) for compound 1；
B) compound 2 and triazole, 3-ethyl benzyl ammonium chloride (TEBA) and potassium carbonate are in CH2Cl2Middle 0-5 DEG C of reaction 5 is small
When, then in room temperature reaction 12 hours, raw compounds 3；
C) compound 3 and iodate trimethyl oxygen sulphur, trimethyl cetyl ammonium bromide, react in toluene and sodium hydroxide
Generate compound 4；
D) heating response generates compound 5 to compound 4 in ethanol with isopropylamine；
E) bromobenzyl and CS are substituted2Ice bath reacts 10 minutes, adds compound 5 and reacts at room temperature, obtains target compound 6.
More preferably, the preparation method of the step e) is as follows：
E) substitution bromobenzyl 0.6mmol and carbon disulfide 91.37mg (1.2mmol), ice bath stirring are added in 20ml eggplant types bottle
10 minutes, then add 1- (1H-1,2,4- triazol-1-yls) -2- (2,4 difluorophenyl) -3- isopropyl -2- alcohol 88.8mg
(0.3mmol), stirring, continues to react after recovering to room temperature, reacts and terminates after 9 hours, column chromatography purifies to obtain target compound.
To realize above-mentioned 3rd purpose, the present invention adopts the technical scheme that：
As above application of any isopropylamine for azole antifungal compound in antifungal drug is prepared.
Preferably, the fungi be candida albicans bacterium, it is Candida parapsilosis bacterium, Candida glabrata, newborn hidden
Coccus, microsporum canis, Trichophyton rubrum or aspergillus fumigatus.
The present invention also provides a kind of antifungal medicine composition, the as above any institute of one or more comprising therapeutically effective amount
Compound is stated, and contains customary pharmaceutical excipients, carrier or diluent.
The present invention also provides isopropylamine as described above for azole antifungal compound pharmaceutically acceptable salt.Institute
It is acylate or inorganic acid salt to state pharmaceutically acceptable salt；Wherein inorganic acid includes：Hydrochloric acid, sulfuric acid, phosphoric acid, diphosphonic acid,
Hydrobromic acid or nitric acid；Organic acid includes：Acetic acid, maleic acid, fumaric acid, tartaric acid, butanedioic acid, lactic acid, p-methyl benzenesulfonic acid, bigcatkin willow
Acid or oxalic acid.The preparation method of salt can use this area conventional meanses to prepare, such as with compound and equimolar containing phenolic hydroxyl group
Such as NaOH reactions of the alkali of amount prepare sodium salt；Phosphate etc. is prepared with the compound containing phenolic hydroxyl group and phosphatase reaction.
The present invention also provides isopropylamine as described above for the raceme of azole antifungal compound, R types or S type isomeries
Body.
The invention has the advantages that：
The compound of the present invention proves there is good anti-mycotic efficiency to deep fungal by pharmacological evaluation, faces with existing
The antifungal drug of bed application is compared, and has the advantages that efficient, hypotoxicity, antimycotic spectrum width, and new available for preparation is antimycotic
Medicine.
Embodiment
The invention will be further elucidated with reference to specific embodiments.It should be understood that these embodiments are merely to illustrate this hair
Bright rather than limitation the scope of the present invention.In addition, it is to be understood that after present disclosure has been read, art technology
Personnel can make various changes or modifications to the present invention, and these equivalent form of values equally fall within the application appended claims and limited
Fixed scope.
The preparation of the compounds of this invention of embodiment 1
The compounds of this invention to prepare reaction scheme as follows：
The first step, synthetic intermediate 4：
Second step, synthetic intermediate 5：
3rd step, synthesising target compound 6：
Specifically, preparing for the particular compound being related in above-mentioned preparation method is as follows：
(1) chloro- 2 ', the 4 '-difluoro acetophenones of 2- (intermediate 2) are prepared
With chloracetyl chloride friedel-crafts reaction generation 2- chloro- 2 ' occurs under the conditions of existing for aluminum trichloride (anhydrous) for m-difluorobenzene,
4 ' difluoro acetophenones (2).
(2) 2- (1H-1,2,4- triazol-1-yls) -2 ', 4 '-difluoro acetophenone (intermediate 3) are prepared
Chloro- 2 ', the 4 '-difluoro acetophenones of 2- and triazole, 3-ethyl benzyl ammonium chloride (TEBA) and potassium carbonate are in CH2Cl2In
0-5 DEG C is reacted 5 hours, then in room temperature reaction 12 hours, generation 2- (1H-1,2,4- triazol-1-yls) -2 ', 4 '-difluorobenzene second
Ketone (3).
(3) 1- [2- (2,4 difluorobenzene base) -2,3- glycidyl] -1H-1,2,4- triazolium methanesulfonat (intermediates are prepared
4)
2- (1H-1,2,4- triazol-1-yls) -2 ', 4 '-difluoro acetophenone and iodate trimethyl oxygen sulphur, trimethyl hexadecane
Base ammonium bromide, reaction generation 1- [2- (2,4- difluorophenyl) -2,3- glycidyl] -1H-1 in toluene and sodium hydroxide, 2,
4- triazolium methanesulfonats (4).
(4) 1- (1H-1,2,4- triazol-1-yls) -2- (2,4 difluorophenyl) -3- (N- isopropyls) amido -2- alcohol is prepared
(intermediate 5)
Intermediate 4 and isopropylamine heating response in ethanol, generate 1- (1H-1,2,4- triazol-1-yls) -2- (2,4 difluoros
Phenyl) -3- (N- isopropyls) amido -2- alcohol (5).
(5) target compound is prepared
Substitute bromobenzyl and CS2Ice bath reacts 10 minutes, adds intermediate 5 and reacts at room temperature, and generates target compound.
Specifically, target compound 1-15 preparation methods are as follows：
1st, target compound 1 is prepared：1- (1H-1,2,4- triazol-1-yls) -2- (2,4 difluorophenyl) -3- [N- isopropyls
Amido (two thio carbomethoxy of benzyl)] -2- alcohol；Using bromobenzyl as raw material, preparation of the specific preparation method with compound 2.
2nd, target compound 2 is prepared：1- (1H-1,2,4- triazol-1-yls) -2- (2,4 difluorophenyl) -3- [N- isopropyls
Amido (two thio carbomethoxy of 3- luorobenzyls)] -2- alcohol；
A) intermediate 2-5 is prepared with reference to the above method；
B) 3- fluorine bromobenzyl 113.41mg (0.6mmol) and carbon disulfide 91.37mg is added in 20ml eggplant types bottle
(1.2mmol), ice bath stir 10 minutes, and it is different then to add 1- (1H-1,2,4- triazol-1-yls) -2- (2,4 difluorophenyl) -3-
Propyl group -2- alcohol 88.8mg (0.3mmol), stirring, continues to react after recovering to room temperature, reacts and terminates after 9 hours, column chromatography purifying
1- (1H-1,2,4- triazol-1-yls) -2- (2,4 difluorophenyl) -3- [N- (two thio carbomethoxy of 3- luorobenzyls)-isopropyl] -
2- alcohol 54mg, yield 50.6%；
3rd, target compound 3 is prepared：1- (1H-1,2,4- triazol-1-yls) -2- (2,4 difluorophenyl) -3- [N- isopropyls
Amido (two thio carbomethoxy of 4- luorobenzyls)] -2- alcohol；Using 4- fluorine bromobenzyl as raw material, system of the specific preparation method with compound 2
It is standby.
4th, target compound 4 is prepared：1- (1H-1,2,4- triazol-1-yls) -2- (2,4 difluorophenyl) -3- [N- isopropyls
Amido (two thio carbomethoxy of 2- chlorobenzyls)] -2- alcohol；Using 2- chlorine bromobenzyl as raw material, system of the specific preparation method with compound 2
It is standby.
5th, target compound 5 is prepared：1- (1H-1,2,4- triazol-1-yls) -2- (2,4 difluorophenyl) -3- [N- isopropyls
Amido (two thio carbomethoxy of 3- chlorobenzyls)] -2- alcohol；Using 3- chlorine bromobenzyl as raw material, system of the specific preparation method with compound 2
It is standby.
6th, target compound 6 is prepared：1- (1H-1,2,4- triazol-1-yls) -2- (2,4 difluorophenyl) -3- [N- isopropyls
Amido (two thio carbomethoxy of 4- chlorobenzyls)] -2- alcohol；Using 4- chlorine bromobenzyl as raw material, system of the specific preparation method with compound 2
It is standby.
7th, target compound 7 is prepared：1- (1H-1,2,4- triazol-1-yls) -2- (2,4 difluorophenyl) -3- [N- isopropyls
Amido (two thio carbomethoxy of 2- bromobenzyls)] -2- alcohol；Using 2- bromines bromobenzyl as raw material, system of the specific preparation method with compound 2
It is standby.
8th, target compound 8 is prepared：1- (1H-1,2,4- triazol-1-yls) -2- (2,4 difluorophenyl) -3- [N- isopropyls
Amido (two thio carbomethoxy of 3- bromobenzyls)] -2- alcohol；Using 3- bromines bromobenzyl as raw material, system of the specific preparation method with compound 2
It is standby.
9th, target compound 9 is prepared：1- (1H-1,2,4- triazol-1-yls) -2- (2,4 difluorophenyl) -3- [N- isopropyls
Amido (two thio carbomethoxy of 4- bromobenzyls)] -2- alcohol；Using 4- bromines bromobenzyl as raw material, system of the specific preparation method with compound 2
It is standby.
10th, target compound 10 is prepared：1- (1H-1,2,4- triazol-1-yls) -2- (2,4 difluorophenyl) -3- [N- isopropyls
Base amido (two thio carbomethoxy of 3- methyl-benzyls)] -2- alcohol；Using 3- methyl bromobenzyl as raw material, specific preparation method is the same as compound 2
Preparation.
11st, target compound 11 is prepared：1- (1H-1,2,4- triazol-1-yls) -2- (2,4 difluorophenyl) -3- [N- isopropyls
Base amido (two thio carbomethoxy of 3- nitrobenzyls)] -2- alcohol；Using 3- nitros bromobenzyl as raw material, specific preparation method is the same as compound 2
Preparation.
12nd, target compound 12 is prepared：1- (1H-1,2,4- triazol-1-yls) -2- (2,4 difluorophenyl) -3- [N- isopropyls
Base amido (two thio carbomethoxy of 3- cyanobenzyls)] -2- alcohol；Using 3- cyano-benzyl bromides as raw material, specific preparation method is the same as compound 2
Preparation.
13rd, target compound 13 is prepared：1- (1H-1,2,4- triazol-1-yls) -2- (2,4 difluorophenyl) -3- [N- isopropyls
Base amido (two thio carbomethoxy of 4- cyanobenzyls)] -2- alcohol；Using 4- cyano-benzyl bromides as raw material, specific preparation method is the same as compound 2
Preparation.
14th, target compound 14 is prepared：1- (1H-1,2,4- triazol-1-yls) -2- (2,4 difluorophenyl) -3- [N- isopropyls
Base amido (two thio carbomethoxy of 2,6- dichloro benzyls)] -2- alcohol；With 2,6- dichloros bromobenzyl for raw material, specific preparation method assimilation
The preparation of compound 2.
15th, target compound 15 is prepared：1- (1H-1,2,4- triazol-1-yls) -2- (2,4 difluorophenyl) -3- [N- isopropyls
Base amido (two thio carbomethoxy of 4- t-butylbenzyls)] -2- alcohol；Using 4- tert-butyl groups bromobenzyl as raw material, specific preparation method assimilation
The preparation of compound 2.
It should be noted that when preparing remaining target compound, using the substitution bromobenzyl of corresponding R group as raw material, side
Method is same as above.Agents useful for same is that commercially available analysis is pure in the embodiment of the present invention.The chemical constitution of compound prepared above, yield,
Nucleus magnetic hydrogen spectrum data are as follows：
Chemical constitution, yield and the molecular formula of the part of compounds of table 1
The implementation of the present invention is not limited to above example, and remaining target compound can be synthesized by above method.
The pharmacological evaluation of the compounds of this invention of embodiment 2
Present invention synthesis 1- (1H-1,2,4- triazol-1-yls) -2- (2,4 difluorophenyl) -3- [N- isopropyls amido (substitutions
Two thio carbomethoxy of benzyl)] -2- alcohol compounds have antifungic action, and its pharmacological evaluation is as follows：
(1) experimental method：(referred to using the antibacterial experiment in vitro method of routine：Antimicrob Agents
Chemother 1995,39(5):1169)
1. materials and methods
(1) experimental strain
This experiment has selected following 8 kinds of common human body cause illness's standard fungal bacterial strains as screening object：
The antifungal activity in-vitro screening strain subject of table 2
(2) test method
Bacteria suspension is prepared：Above-mentioned fungi is cultivated 16 hours for 35 DEG C through YEPD fluid nutrient mediums, activates twice, uses hemocytometer
Number plate is counted, and bacteria concentration is adjusted to 1 × 10 with RPM1640 fluid nutrient mediums4~1 × 105Individual/mL.
Drug solution preparing：Take testing compound of the present invention to be dissolved in dimethyl sulfoxide, be made into 8.0mg/mL medicine storing liquid, test
It is preceding to be diluted to 640 μ g/mL with RPM1640.
Inoculation：Drug sensitive plate is taken, adds the μ l of RPMI 1640 culture mediums 200 in every No. 1 hole of row, makees blank control；No. 12 holes, which add, treats
The μ l of bacterium solution 200 are surveyed, make negative control；Drug sensitive plate often arranges 2-11 holes and adds the μ l of bacterium solution 180 respectively, fully mixes, makes each hole most
Whole drug concentration is respectively 64,32,16,8,4,2,1,0.5,0.25 and 0.125 μ g/ml, and DMSO contents are below in each hole
1%；No. 12 holes not drug containing, makees positive control.Control drug is Fluconazole (FCZ), Itraconazole (ICZ), voriconazole
(VCZ), ketoconazole (KCZ), Terbinafine (TBR), amphotericin B (AMB).
Culture and detection：If Positive control wells OD value (OD values) is 100%, lower than Positive control wells with OD value
In 80% lowest concentration of drug be minimal inhibitory concentration value (MIC80)。
(2) experimental result
Antibacterial experiment in vitro the results are shown in Table 3.
The part preferred compound of table 3 is to common causative fungi external activity (MIC80,μg/ml)
Note：KCZ. ketoconazole, FCZ. Fluconazoles, VCZ. Wo Likang azoles, ICZ. Itraconazoles, TRB. terbinafines, AMB two
Property mycin
It is above-mentioned test result indicates that compound of the present invention has good antifungal activity, multiple compounds are to selected
The external inhibitory activity of fungi much stronger than Fluconazole, illustrates that the compounds of this invention can be used for the medicine for preparing anti-fungal infection.
Described above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
Member, on the premise of the inventive method is not departed from, can also make some improvement and supplement, and these are improved and supplement also should be regarded as
Protection scope of the present invention.
Claims (6)
1. a kind of isopropylamine is for azole antifungal compound, it is characterised in that the isopropylamine is for azole antifungal
Compound structure formula is：
Wherein R is selected from：
。
2. isopropylamine described in claim 1 is for the preparation method of azole antifungal compound, it is characterised in that including as follows
Step：
A) compound 1 and chloracetyl chloride reaction generation compound 2；
B) compound 2 and triazole reaction generation compound 3；
C) compound 3 and iodate trimethyl oxygen reaction of Salmon-Saxl generation compound 4；
D) compound 4 and isopropylamine reaction generation compound 5；
E) bromobenzyl and CS are substituted2Ice bath reacts, and adds compound 5 and reacts, obtains target compound 6；Substitute in the substitution bromobenzyl
Base R substitution situation is identical with claim 1；
The compound 1-6 structures are as follows：
3. preparation method according to claim 2, it is characterised in that the preparation method comprises the following steps that：
A) with chloracetyl chloride friedel-crafts reaction generation compound 2 occurs under the conditions of existing for aluminum trichloride (anhydrous) for compound 1；
B) compound 2 and triazole, 3-ethyl benzyl ammonium chloride (TEBA) and potassium carbonate are in CH2Cl2Middle 0-5 DEG C is reacted 5 hours,
Then in room temperature reaction 12 hours, compound 3 is generated；
C) compound 3 and iodate trimethyl oxygen sulphur, trimethyl cetyl ammonium bromide, react generation in toluene and sodium hydroxide
Compound 4；
D) heating response generates compound 5 to compound 4 in ethanol with isopropylamine；
E) bromobenzyl and CS are substituted2Ice bath reacts 10 minutes, adds compound 5 and reacts at room temperature, obtains target compound 6.
4. application of the isopropylamine described in claim 1 for azole antifungal compound in antifungal drug is prepared.
5. application according to claim 4, it is characterised in that the fungi is candida albicans bacterium, nearly smooth false silk ferment
Female bacterium, Candida glabrata, neogenesis cryptococcus, microsporum canis, Trichophyton rubrum or aspergillus fumigatus.
6. a kind of antifungal medicine composition, it is characterised in that described in one or more claims 1 comprising therapeutically effective amount
Compound, and contain customary pharmaceutical excipients, carrier or diluent.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20010014742A1 (en) * | 1999-02-19 | 2001-08-16 | Jerzy Golik | Water-soluble prodrugs of azole compounds |
| CN101357906A (en) * | 2008-09-09 | 2009-02-04 | 中国人民解放军第二军医大学 | Novel triazolols antifungal compound, preparation method and application thereof |
| CN101602738A (en) * | 2009-07-20 | 2009-12-16 | 中国人民解放军第二军医大学 | Novel azole antifungal compound and preparation method thereof |
| CN104003947A (en) * | 2014-05-22 | 2014-08-27 | 中国人民解放军第二军医大学 | Sulfur/nitrogen-containing azole antifungal compound as well as preparation method and application of sulfur-containing azoles antifungal compound |
-
2016
- 2016-01-05 CN CN201610007802.4A patent/CN105669573B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20010014742A1 (en) * | 1999-02-19 | 2001-08-16 | Jerzy Golik | Water-soluble prodrugs of azole compounds |
| CN101357906A (en) * | 2008-09-09 | 2009-02-04 | 中国人民解放军第二军医大学 | Novel triazolols antifungal compound, preparation method and application thereof |
| CN101602738A (en) * | 2009-07-20 | 2009-12-16 | 中国人民解放军第二军医大学 | Novel azole antifungal compound and preparation method thereof |
| CN104003947A (en) * | 2014-05-22 | 2014-08-27 | 中国人民解放军第二军医大学 | Sulfur/nitrogen-containing azole antifungal compound as well as preparation method and application of sulfur-containing azoles antifungal compound |
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