CN103980264B - A kind of aminopyridines antifungal compound and preparation and application thereof - Google Patents
A kind of aminopyridines antifungal compound and preparation and application thereof Download PDFInfo
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Abstract
The present invention relates to pharmaceutical technology field.The invention provides a kind of aminopyridines antifungal compound 2 amino ((5 N substituted amine methyl thiophene 2 base) methyl) nicotinamide compound and its esters, shown in formula I, wherein R represents phenyl or substituted-phenyl to its chemical constitution.Present invention also offers the preparation method and applications of above-claimed cpd.The compound of the present invention has stronger antifungal activity, and has the advantages such as low, the has a broad antifungal spectrum of toxicity, can be used for preparing antifungal drug.
Description
Technical field
The present invention relates to pharmaceutical technology field, be specifically related to a kind of aminopyridines antifungal compound and
Preparation and application.
Background technology
Antifungal drug is that a class has killing or suppresses fungus growth, the general designation of medicine of breeding.From 1939
Year, since first antifungal drug griseofulvin finds, the mankind continue for 70 with the struggle of fungal infection
For many years, along with fungus understanding is constantly deepened and the development of medicament research and development technology, a large amount of different structure occurs
Antifungal drug with mechanism of action.The mechanism of action of the antifungal drug being widely used clinically is main
There are three kinds, the triazole type (such as fluconazol) with cytochrome P 450 Enzyme 14 α demethylase as target spot,
Many alkenes (such as amphotericin B) with the ergosterol on cell membrane as target spot and with the β on cell wall-(1,
3)-D-glucan synthase is the echinocandin class (such as Caspofungin) of target spot.
Height drug resistance phenomenon, the toxic and side effects of amphotericin B and the reality of echinocandin class in view of fungus
By factors such as property are the strongest, therefore research and develop anti-true in the hope of more safe efficient, low toxicity of up-to-date mechanism of action
Bacterium medicine is the most urgent.
Cell wall is the maximum feature that fungus is different from mammalian cell, so with fungal cell wall composition
Antifungal drug for target spot is always the focus of antifungal drug research field.Cell wall is not only for very
Bacterium cell maintains self normal physiological function to have important function, and is that its attack to host causes infection
Main tool.
The virulence factor being currently known includes that adhesin, modality associated protein, invasion etc. are all located at
On cell wall, and substantially broadly fall into and account for cell wall protein (Cell wall Protein, the CWP) overwhelming majority
(88%) GPI-anchorin (Glycosylphosphatidylinositol (GPI)-anchored
proteins).There is the GPI-anchorin of multiple family in fungal cell wall, they serve not only as cell wall
Important component part maintain fungal cell normal physiological function, and formed invasive infection process
(adhere to, attack, modality, biofilm formation etc.) multiple links play a crucial role.Although
Structurally there is the biggest difference in the GPI-anchorin of each family, but they have similar cell
Interior transporting pathway, is i.e. transported to cell membrane, then by GPI anchor (GPI, glycolsyl-phosphatidylinositol)
Be transported to cell wall again, play biological function (see document [1] Tsukahara, K., Hata, K.,
Nakamoto,K.,Sagane,K.,Watanabe,N.A.,Kuromitsu,J.,Kai,J.,Tsuchiya,M.,
Ohba,F.,Jigami,Y.,Yoshimatsu,K.,and Nagasu,T.(2003)Medicinal genetics
approach towards identifying the molecular target of a novel inhibitor of fungal
cell wall assembly.Mol.Microbiol.48,1029.)。
For the bioprocess design medicine of fungus G PI anchor synthesis, develop fungal cell wall GPI-grappling egg
White inhibitor, plays antifungic action not only by the 26S Proteasome Structure and Function destroying fungal cell wall, and
And virulence (adhere to, attack, modality, the biofilm formation etc.) resistance of fungal cell can be suppressed
The formation of disconnected invasive infection.Owing to GPI anchorin is the major part of fungal microbe cell wall,
Human body cell is probably free from side effects by the medicine as shot design.
Tsukahara etc., by SCREENED COMPOUND, find that compound BIQ can suppress the GPI of cell surface
The synthesis of anchorin and there is dose-dependence.The research of structure activity relationship is carried out with BIQ for parent nucleus
And transformation, finding that compound E1210 has more preferable antifungic action, activity is higher, and selectivity is the most more
High.A few activity preferably compound found during compound 10b simply research E1210.
And gepinacin is that the only one that Catherine A.McLellan etc. is found by high flux screening is effective
Compound, with MIC80This index is weighed, and its activity is not the most prominent in fact.But also
Explanation can suppress parent nucleus not only one of which that GPI anchorin synthesizes (see document [2] Watanabe,
N.A.,Miyazaki,M.,Horii,T.,Sagane,K.,Tsukahara,K.,and Hata,K.(2012)
E1210,a new broad-spectrum antifungal,suppresses Candida albicans hyphal
growth through inhibition of glycosylphosphatidylinositol biosynthesis.
Antimicrob.Agents Chemother.56,960.；[2]Nakamoto,K.,Tsukada,I.,Tanaka,K.,
Matsukura,M.,Haneda,T.,Inoue,S.,Murai,N.,Abe,S.,Ueda,N.,Miyazaki,M.,
Watanabe,N.,Asada,M.,Yoshimatsu,K.,and Hata,K.(2010)Synthesis and
evaluation of novel antifungal agents-quinoline and pyridine amide derivatives.
Bioorg.Med.Chem.Lett.20,4624.；[3]Catherine A.McLellan,Luke Whitesell,
Oliver D.King,Alex K.Lancaster,Ralph Mazitschek and Susan Lindquist.(2012)
Inhibiting GPI Anchor Biosynthesis in Fungi Stresses the Endoplasmic Reticulum
and Enhances Immunogenicity.ACS Chem.Biol.2012,7,1520.)。
Summary of the invention
It is an object of the invention to the bioprocess design medicine for the synthesis of fungus G PI anchor, develop fungal cell
Wall GPI-anchorin inhibitor, and then develop a kind of antifungal drug with novel mechanism of action.
The main technical schemes of the present invention is: if designed drug main is closed by suppression GPI anchorin
This step of inositol acetylation during one-tenth, makes the synthesis of GPI anchorin be affected, then reaches
The synthesis of suppression cell wall.
A first aspect of the present invention, it is provided that a class aminopyridines or its salt pharmacologically allowed,
Its chemical constitution of described aminopyridines is shown in formula I:
In Formulas I, R group represents phenyl or substituted-phenyl, and the substituent group in substituted-phenyl can be located at phenyl ring
Each position, can be monosubstituted or polysubstituted, and substituent group is selected from a, b or c:
D. halogen, such as F, Cl, Br, I；Particularly preferably fluorine atom；
The low alkyl group of the most individual carbon atom, such as methyl, ethyl, the low alkyl group of halogen substiuted, uncle
Butyl；Particularly preferably methyl；
F. three-dimensional substituent group or hydrophobic substituent, such as isopropyl, the tert-butyl group；Particularly preferably isopropyl.
The part preferred compound of the present invention, its chemical constitution is shown in Table 1.
6a:2-amino-N-((5-((2-aminotoluene) methyl) thiophene-2-base) methyl) nicotiamide,
6b:2-amino-N-((5-((3-monomethylaniline .) methyl) thiophene-2-base) methyl) nicotiamide,
6c:2-amino-N-((5-((4-monomethylaniline .) methyl) thiophene-2-base) methyl) nicotiamide,
6d:2-amino-N-((5-((2-fluoroaniline) methyl) thiophene-2-base) methyl) nicotiamide,
6e:2-amino-N-((5-((3-fluoroaniline) methyl) thiophene-2-base) methyl) nicotiamide,
6f:2-amino-N-((5-((4-fluoroaniline) methyl) thiophene-2-base) methyl) nicotiamide,
6g:2-amino-N-((5-((aniline) methyl) thiophene-2-base) methyl) nicotiamide,
6h:2-amino-N-((5-((3-chloroaniline) methyl) thiophene-2-base) methyl) nicotiamide,
6i:2-amino-N-((5-((2-MEA) methyl) thiophene-2-base) methyl) nicotiamide,
6j:2-amino-N-((5-((3-MEA) methyl) thiophene-2-base) methyl) nicotiamide,
6k:2-amino-N-((5-((2-isopropyl aniline) methyl) thiophene-2-base) methyl) nicotiamide,
6l:2-amino-N-((5-((3-isopropyl aniline) methyl) thiophene-2-base) methyl) nicotiamide, or
6m:2-amino-N-((5-((2-chloroaniline) methyl) thiophene-2-base) methyl) nicotiamide.
Described aminopyridine analog derivative, in the preferred embodiment of the invention, it is 6a, 6d and 6e.
Table 1: part preferred compound of the present invention
Further, present invention also offers the salt that above-mentioned aminopyridines pharmacologically allows,
The described salt (pharmaceutical salts) pharmacologically allowed is inorganic acid salt or acylate.
Mineral acid refers to hydrochloric acid, sulphuric acid, phosphoric acid, diphosphonic acid, hydrobromic acid or nitric acid etc.；
Organic acid refer to acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, lactic acid, Loprazolam,
P-methyl benzenesulfonic acid, salicylic acid or oxalic acid etc..
The preferred pharmaceutical salts of the compounds of this invention is hydrochlorate, hydrobromate or methane sulfonates.
A second aspect of the present invention, it is provided that above-mentioned aminopyridines or its pharmacologically allow
The preparation method of salt, described preparation method is as follows:
Reaction process one
Concretely comprise the following steps:
Step one: prepare target compound (3)
5-formylthien-2-formonitrile HCN (1) and substituted aniline (2) are dissolved in methanol, add a concentrated hydrochloric acid,
Add sodium cyanoborohydride to carry out reacting overnight under reduction amination, room temperature, generate 5-((substituted benzene
Amine) methyl) thiophene-2-formonitrile HCN (3).
Step 2: prepare target compound (4)
5-((substituted aniline) methyl) thiophene-2-formonitrile HCN (3) is dissolved in anhydrous tetrahydro furan, adds hydrogenation
Lithium aluminum carries out reduction reaction, after reacting 1h, generates N-((5-(amine methyl) thiophene-2-base) at 50 DEG C
Methyl-substituted aniline (4).
Step 3: prepare target compound (6)
By compound N-((5-(amine methyl) thiophene-2-base) methyl-substituted aniline (4) is dissolved in N, N-diformazan
Base Methanamide, adds diisopropylethylamine, hexafluorophosphoric acid benzotriazole-1-base-epoxide tripyrrole alkyl and 2-
Amino-nicotinic acid (5), at room temperature carries out condensation reaction, and ((5-((replaces to generate 2-amino-N-after reaction 5h
Aniline) methyl) thiophene-2-base) methyl) nicotiamide (6).
The pharmaceutical salts of the compounds of this invention is on the basis of above-mentioned reaction, makees further to react as follows:
Reaction process two:
Wherein HX inorganic acid salt or acylate, special representative's hydrochlorate, hydrobromate or Loprazolam
Salt.
Step 4: prepare target compound (7)
Take 2-amino-N-((5-((substituted aniline) methyl) thiophene-2-base) methyl) nicotiamide (6) and be dissolved in dichloromethane
In, add mineral acid or organic acid, stir 3 hours under room temperature, generate 2-amino-N-((5-((substituted aniline)
Methyl) thiophene-2-base) methyl) nicotiamide pharmaceutical salts.
A third aspect of the present invention, there is provided above-mentioned aminopyridines or it pharmacologically allows
Salt application in preparing antifungal drug.
The present invention has selected following 4 kinds of common human body cause illness's standard fungal bacterial strains as screening object: white
Color candidiasis (Candida albicans, type strain SC5314)；Candida parapsilosis (Candida
Parapsilosis, ATCC22019)；Cryptococcus histolyticus (Cryptococcus neoformans, type strain
32609)；Oidium tropicale (Candida tropicalis ATCC22019).Test result indicate that: above-mentioned
Test result indicate that, the compounds of this invention has preferable antifungal activity, and In Vitro Bacteriostatic is all better than
Fluconazol.And the compounds of this invention also to have toxicity low, the advantage such as antifungal spectrum width, can be used for preparing
Antifungal drug.
The compound of the present invention can be as fungal cell wall GPI-anchorin inhibitor.
Antifungal agent prepared by aminopyridines of the present invention or its salt pharmacologically allowed
Application in thing, preparing antifungal drug is by aminopyridines or its salt pharmacologically allowed
The pharmaceutical composition made as active component and conventional pharmaceutical carrier.
Described pharmaceutical composition can be tablet, dispersible tablet, buccal tablet, oral cavity disintegration tablet, slow releasing tablet, capsule,
Soft capsule, drop pill, granule, injection, injectable powder or aerosol etc..
The present invention is that antifungal treatment provides new medicine.
Detailed description of the invention
In conjunction with embodiment, the present invention is described in detail, but the enforcement of the present invention is not limited only to this.
Agents useful for same of the present invention and raw material the most maybe can be prepared by literature method.In the following example
The experimental technique of unreceipted actual conditions, generally according to normal condition, or according to proposed by manufacturer
Condition.
The preparation of embodiment 1:6a2-amino-N-((5-((2-aminotoluene) methyl) thiophene-2-base) methyl) nicotiamide
The preparation of step one: 5-((2-aminotoluene) methyl) thiophene-2-formonitrile HCN
5-formylthien-2-formonitrile HCN (1mmol) and 2-aminotoluene (1mmol) are dissolved in methanol (10mL)
In, add sodium cyanoborohydride (188mg), concentrated hydrochloric acid one, react under room temperature overnight, be spin-dried for solution thick
Product are directly used in next step.
Step 2: the N-(preparation of (5-(amine methyl) thiophene-2-base) methyl-2-aminotoluene
5-((2-aminotoluene) methyl) thiophene-2-formonitrile HCN (crude product 1mmol) is dissolved in anhydrous tetrahydro furan
(25mL), add lithium aluminium hydride (4eq), react 1h, TLC monitoring at 50 DEG C, after reaction completely, add
Entering shrend to go out, solid filters, and filtrate is spin-dried for, and obtains crude product and is directly used in next step.
Step 3: the preparation of 2-amino-N-((5-((2-aminotoluene) methyl) thiophene-2-base) methyl) nicotiamide
By compound N-((5-(amine methyl) thiophene-2-base) methyl-2-aminotoluene (crude product 1mmol)
It is dissolved in DMF (5mL), adds diisopropylethylamine (2eq), hexafluorophosphoric acid benzotriazole
-1-base-epoxide tripyrrole alkyl (1.1eq) and 2-amino-nicotinic acid (1eq), react 5h, after reaction completely, falls
Entering in water, be extracted with ethyl acetate three times, organic facies saturated sodium-chloride water solution washes 2 times, organic facies
Being dried with anhydrous sodium sulfate, filter, after filtrate reduced in volume, residue, through column chromatography purification, obtains white
Solid 6a (170mg, yield 48%).
H1NMR,300MHz CDCl3-d1
δ: 8.15-8.13 (dd, 1H, J=4.8,1.8Hz), 7.64-7.61 (dd, 1H, J=7.6,1.6Hz), 7.24 (s, 1H), 7.18-7.1
4(m,2H),6.96-6.87(m,4H),6.62-6.57(m,1H),6.51-6.41(m,3H),5.18(s,2H),4.75-4.73(
D, 2H, J=5.5Hz), 2.25 (s, 3H)
The preparation of embodiment 2:6b2-amino-N-((5-((3-monomethylaniline .) methyl) thiophene-2-base) methyl) nicotiamide
The preparation of step one: 5-((3-monomethylaniline .) methyl) thiophene-2-formonitrile HCN
5-formylthien-2-formonitrile HCN (1mmol) and 3-monomethylaniline. (1mmol) are dissolved in methanol (10mL)
In, add sodium cyanoborohydride (188mg), concentrated hydrochloric acid one, react under room temperature overnight, be spin-dried for solution thick
Product are directly used in next step.
Step 2: the N-(preparation of (5-(amine methyl) thiophene-2-base) methyl-3-monomethylaniline.
5-((3-monomethylaniline .) methyl) thiophene-2-formonitrile HCN (crude product 1mmol) is dissolved in anhydrous tetrahydro furan
(25mL), add lithium aluminium hydride (4eq), react 1h, TLC monitoring at 50 DEG C, after reaction completely, add
Entering shrend to go out, solid filters, and filtrate is spin-dried for, and obtains crude product and is directly used in next step.
Step 3: the preparation of 2-amino-N-((5-((3-monomethylaniline .) methyl) thiophene-2-base) methyl) nicotiamide
By compound N-((5-(amine methyl) thiophene-2-base) methyl-3-monomethylaniline. (crude product 1mmol)
It is dissolved in DMF (5mL), adds diisopropylethylamine (2eq), hexafluorophosphoric acid benzotriazole
-1-base-epoxide tripyrrole alkyl (1.1eq) and 2-amino-nicotinic acid (1eq), react 5h, after reaction completely, falls
Entering in water, be extracted with ethyl acetate three times, organic facies saturated sodium-chloride water solution washes 2 times, organic facies
Being dried with anhydrous sodium sulfate, filter, after filtrate reduced in volume, residue, through column chromatography purification, obtains white
Solid 6b (160mg, yield 45%).
H1NMR,300MHz CDCl3-d1
δ: 8.15-8.13 (dd, 1H, J=4.8,1.6Hz), 7.61-7.58 (dd, 1H, J=7.8,1.6Hz), 7.28-7.25 (m, 1H), 7.
10-7.05 (t, 1H, J=7.3Hz), 6.87-6.86 (m, 2H), 6.60-6.56 (m, 2H), 6.49-6.41 (m, 5H), 4.70-4.
68 (d, 2H, J=5.5Hz), 4.45 (s, 2H), 2.27 (s, 3H)
The preparation of embodiment 3:6c2-amino-N-((5-((4-monomethylaniline .) methyl) thiophene-2-base) methyl) nicotiamide
The preparation of step one: 5-((4-monomethylaniline .) methyl) thiophene-2-formonitrile HCN
5-formylthien-2-formonitrile HCN (1mmol) and 4-monomethylaniline. (1mmol) are dissolved in methanol (10mL)
In, add sodium cyanoborohydride (188mg), concentrated hydrochloric acid one, react under room temperature overnight, be spin-dried for solution thick
Product are directly used in next step.
Step 2: the N-(preparation of (5-(amine methyl) thiophene-2-base) methyl-4-monomethylaniline.
5-((4-monomethylaniline .) methyl) thiophene-2-formonitrile HCN (crude product 1mmol) is dissolved in anhydrous tetrahydro furan
(25mL), add lithium aluminium hydride (4eq), react 1h, TLC monitoring at 50 DEG C, after reaction completely, add
Entering shrend to go out, solid filters, and filtrate is spin-dried for, and obtains crude product and is directly used in next step.
Step 3: the preparation of 2-amino-N-((5-((4-monomethylaniline .) methyl) thiophene-2-base) methyl) nicotiamide
By compound N-((5-(amine methyl) thiophene-2-base) methyl-4-monomethylaniline. (crude product 1mmol)
It is dissolved in DMF (5mL), adds diisopropylethylamine (2eq), hexafluorophosphoric acid benzotriazole
-1-base-epoxide tripyrrole alkyl (1.1eq) and 2-amino-nicotinic acid (1eq), react 5h, after reaction completely, falls
Entering in water, be extracted with ethyl acetate three times, organic facies saturated sodium-chloride water solution washes 2 times, organic facies
Being dried with anhydrous sodium sulfate, filter, after filtrate reduced in volume, residue, through column chromatography purification, obtains white
Solid 6c (180mg, yield 50%).
H1NMR,300MHz CDCl3-d1
δ: 8.14-8.12 (dd, 1H, J=4.8,1.6Hz), 7.63-7.60 (dd, 1H, J=7.8,1.6Hz), 7.28-7.25 (m, 1H), 7.
01-6.98 (d, 2H, J=8.1Hz), 6.88-6.85 (dd, 2H, J=6.9,3.7Hz), 6.61-6.58 (m, 3H), 6.49-6.48 (
M, 3H), 4.70-4.68 (d, 2H, J=5.5Hz), 4.44 (s, 2H), 2.24 (s, 3H)
The preparation of embodiment 4:6d2-amino-N-((5-((2-fluoroaniline) methyl) thiophene-2-base) methyl) nicotiamide
The preparation of step one: 5-((2-fluoroaniline) methyl) thiophene-2-formonitrile HCN
5-formylthien-2-formonitrile HCN (1mmol) and 2-fluoroaniline (1mmol) are dissolved in methanol (10mL),
Add sodium cyanoborohydride (188mg), concentrated hydrochloric acid one, react under room temperature overnight, be spin-dried for solution crude product straight
Connect for next step.
Step 2: the N-(preparation of (5-(amine methyl) thiophene-2-base) methyl-2-fluoroaniline
5-((2-fluoroaniline) methyl) thiophene-2-formonitrile HCN (crude product 1mmol) is dissolved in anhydrous tetrahydro furan (25
ML), add lithium aluminium hydride (4eq), at 50 DEG C, react 1h, TLC monitoring, after reaction completely, add water
Cancellation, solid filters, and filtrate is spin-dried for, and obtains crude product and is directly used in next step.
Step 3: the preparation of 2-amino-N-((5-((2-fluoroaniline) methyl) thiophene-2-base) methyl) nicotiamide
By compound N-((5-(amine methyl) thiophene-2-base) methyl-2-fluoroaniline (crude product 1mmol) is dissolved in
DMF (5mL), addition diisopropylethylamine (2eq), hexafluorophosphoric acid benzotriazole-1-base-
Epoxide tripyrrole alkyl (1.1eq) and 2-amino-nicotinic acid (1eq), react 5h, after reaction completely, pour water into
In, it being extracted with ethyl acetate three times, organic facies saturated sodium-chloride water solution is washed 2 times, organic facies nothing
Aqueous sodium persulfate is dried, and filters, and after filtrate reduced in volume, residue, through column chromatography purification, obtains white solid
6d (150mg, yield 42%).
H1NMR,300MHz CDCl3-d1
δ: 8.16-8.13 (dd, 1H, J=4.8,1.6Hz), 7.62-7.59 (dd, 1H, J=7.8,1.6Hz), 7.25 (m, 1H), 7.02-6.
96(m,2H),6.88-6.78(m,2H),6.78-6.64(m,2H),6.61-6.57(m,1H),6.42(brs,2H),4.71-4.
69 (d, 2H, J=5.5Hz), 4.50 (s, 2H)
The preparation of embodiment 5:6e2-amino-N-((5-((3-fluoroaniline) methyl) thiophene-2-base) methyl) nicotiamide
The preparation of step one: 5-((3-fluoroaniline) methyl) thiophene-2-formonitrile HCN
5-formylthien-2-formonitrile HCN (1mmol) and 3-fluoroaniline (1mmol) are dissolved in methanol (10mL),
Add sodium cyanoborohydride (188mg), concentrated hydrochloric acid one, react under room temperature overnight, be spin-dried for solution crude product straight
Connect for next step.
Step 2: the N-(preparation of (5-(amine methyl) thiophene-2-base) methyl-3-fluoroaniline
5-((3-fluoroaniline) methyl) thiophene-2-formonitrile HCN (crude product 1mmol) is dissolved in anhydrous tetrahydro furan (25
ML), add lithium aluminium hydride (4eq), at 50 DEG C, react 1h, TLC monitoring, after reaction completely, add water
Cancellation, solid filters, and filtrate is spin-dried for, and obtains crude product and is directly used in next step.
Step 3: the preparation of 2-amino-N-((5-((3-fluoroaniline) methyl) thiophene-2-base) methyl) nicotiamide
By compound N-((5-(amine methyl) thiophene-2-base) methyl-3-fluoroaniline (crude product 1mmol) is dissolved in
DMF (5mL), addition diisopropylethylamine (2eq), hexafluorophosphoric acid benzotriazole-1-base-
Epoxide tripyrrole alkyl (1.1eq) and 2-amino-nicotinic acid (1eq), react 5h, after reaction completely, pour water into
In, it being extracted with ethyl acetate three times, organic facies saturated sodium-chloride water solution is washed 2 times, organic facies nothing
Aqueous sodium persulfate is dried, and filters, and after filtrate reduced in volume, residue, through column chromatography purification, obtains white solid
6e (145mg, yield 41%).
H1NMR,300MHz CDCl3-d1
δ: 8.02-8.00 (dd, 1H, J=4.8,1.6Hz), 7.73-7.70 (dd, 1H, J=7.8,1.6Hz), 7.26 (m, 1H), 7.14-7.
06(m,1H),6.91-6.87(m,2H),6.79(s,1H),6.69(s,1H),6.63-6.58(m,1H),6.44-6.33(m,3
H), 4.71-4.69 (d, 2H, J=5.5Hz), 4.45 (s, 2H)
The preparation of embodiment 6:6f2-amino-N-((5-((4-fluoroaniline) methyl) thiophene-2-base) methyl) nicotiamide
The preparation of step one: 5-((4-fluoroaniline) methyl) thiophene-2-formonitrile HCN
5-formylthien-2-formonitrile HCN (1mmol) and 4-fluoroaniline (1mmol) are dissolved in methanol (10mL),
Add sodium cyanoborohydride (188mg), concentrated hydrochloric acid one, react under room temperature overnight, be spin-dried for solution crude product straight
Connect for next step.
Step 2: the N-(preparation of (5-(amine methyl) thiophene-2-base) methyl-4-fluoroaniline
5-((4-fluoroaniline) methyl) thiophene-2-formonitrile HCN (crude product 1mmol) is dissolved in anhydrous tetrahydro furan (25
ML), add lithium aluminium hydride (4eq), at 50 DEG C, react 1h, TLC monitoring, after reaction completely, add water
Cancellation, solid filters, and filtrate is spin-dried for, and obtains crude product and is directly used in next step.
Step 3: the preparation of 2-amino-N-((5-((4-fluoroaniline) methyl) thiophene-2-base) methyl) nicotiamide
By compound N-((5-(amine methyl) thiophene-2-base) methyl-4-fluoroaniline (crude product 1mmol) is dissolved in
DMF (5mL), addition diisopropylethylamine (2eq), hexafluorophosphoric acid benzotriazole-1-base-
Epoxide tripyrrole alkyl (1.1eq) and 2-amino-nicotinic acid (1eq), react 5h, after reaction completely, pour water into
In, it being extracted with ethyl acetate three times, organic facies saturated sodium-chloride water solution is washed 2 times, organic facies nothing
Aqueous sodium persulfate is dried, and filters, and after filtrate reduced in volume, residue, through column chromatography purification, obtains white solid
6f (150mg, yield 42%).
H1NMR,300MHz CDCl3-d1
δ: 8.11 (s, 1H), 7.70-7.67 (d, 1H, J=7.5Hz), 6.95-6.89 (m, 4H), 6.65-6.63 (m, 4H), 4.74-4.7
2 (d, 2H, J=5.5Hz), 4.45 (s, 2H)
The preparation of embodiment 7:6g2-amino-N-((5-((aniline) methyl) thiophene-2-base) methyl) nicotiamide
The preparation of step one: 5-((aniline) methyl) thiophene-2-formonitrile HCN
5-formylthien-2-formonitrile HCN (1mmol) and aniline (1mmol) are dissolved in methanol (10mL), add
Sodium cyanoborohydride (188mg), concentrated hydrochloric acid one, reacts under room temperature overnight, is spin-dried for solution crude product and directly uses
In next step.
Step 2: the N-(preparation of (5-(amine methyl) thiophene-2-base) metlyl-phenylamine
5-((aniline) methyl) thiophene-2-formonitrile HCN (crude product 1mmol) is dissolved in anhydrous tetrahydro furan (25mL),
Add lithium aluminium hydride (4eq), at 50 DEG C, react 1h, TLC monitoring, after reaction completely, add shrend and go out,
Solid filters, and filtrate is spin-dried for, and obtains crude product and is directly used in next step.
Step 3: the preparation of 2-amino-N-((5-((aniline) methyl) thiophene-2-base) methyl) nicotiamide
By compound N-((5-(amine methyl) thiophene-2-base) monomethylaniline. (crude product 1mmol) is dissolved in N, N-
Dimethylformamide (5mL), adds diisopropylethylamine (2eq), hexafluorophosphoric acid benzotriazole-1-base-epoxide
Tripyrrole alkyl (1.1eq) and 2-amino-nicotinic acid (1eq), react 5h, after reaction completely, be poured into water,
Being extracted with ethyl acetate three times, organic facies saturated sodium-chloride water solution washes 2 times, the anhydrous sulfur of organic facies
Acid sodium be dried, filter, after filtrate reduced in volume, residue through column chromatography purification, obtain white solid 6g (220mg,
Yield 65%).
H1NMR,300MHz CDCl3-d1
δ: 8.15-8.13 (dd, 1H, J=4.8,1.6Hz), 7.61-7.58 (dd, 1H, J=7.8,1.6Hz), 7.26-7.24 (m, 1H), 7.
22-7.16 (m, 2H), 6.89-6.87 (m, 2H), 6.77-6.73 (t, 1H, J=7.2Hz), 6.68-6.66 (d, 2H, J=7.6Hz
), 6.61-6.56 (m, 1H), 6.41-6.40 (m, 3H), 4.71-4.69 (d, 2H, J=5.5Hz), 4.47 (s, 2H)
The preparation of embodiment 8:6h2-amino-N-((5-((3-chloroaniline) methyl) thiophene-2-base) methyl) nicotiamide
The preparation of step one: 5-((3-chloroaniline) methyl) thiophene-2-formonitrile HCN
5-formylthien-2-formonitrile HCN (1mmol) and 3-chloroaniline (1mmol) are dissolved in methanol (10mL),
Add sodium cyanoborohydride (188mg), concentrated hydrochloric acid one, react under room temperature overnight, be spin-dried for solution crude product straight
Connect for next step.
Step 2: the N-(preparation of (5-(amine methyl) thiophene-2-base) methyl-3-chloroaniline
5-((3-chloroaniline) methyl) thiophene-2-formonitrile HCN (crude product 1mmol) is dissolved in anhydrous tetrahydro furan (25
ML), add lithium aluminium hydride (4eq), at 50 DEG C, react 1h, TLC monitoring, after reaction completely, add water
Cancellation, solid filters, and filtrate is spin-dried for, and obtains crude product and is directly used in next step.
Step 3: the preparation of 2-amino-N-((5-((3-chloroaniline) methyl) thiophene-2-base) methyl) nicotiamide
By compound N-((5-(amine methyl) thiophene-2-base) methyl-3-chloroaniline (crude product 1mmol) is dissolved in
DMF (5mL), addition diisopropylethylamine (2eq), hexafluorophosphoric acid benzotriazole-1-base-
Epoxide tripyrrole alkyl (1.1eq) and 2-amino-nicotinic acid (1eq), react 5h, after reaction completely, pour water into
In, it being extracted with ethyl acetate three times, organic facies saturated sodium-chloride water solution is washed 2 times, organic facies nothing
Aqueous sodium persulfate is dried, and filters, and after filtrate reduced in volume, residue, through column chromatography purification, obtains white solid
6h (160mg, yield 43%).
H1NMR,300MHz CDCl3-d1
δ: 8.15-8.12 (dd, 1H, J=4.8,1.6Hz), 7.63-7.60 (dd, 1H, J=7.8,1.6Hz), 7.24 (m, 1H), 7.11-7.
06(m,1H),6.89-6.86(m,2H),6.72-6.69(m,1H),6.64-6.57(m,2H),6.54-6.51(m,1H),6.
43 (brs, 3H), 4.71-4.69 (d, 2H, J=5.5Hz), 4.45-4.44 (d, 2H, J=5.3Hz)
The preparation of embodiment 9:6i2-amino-N-((5-((2-MEA) methyl) thiophene-2-base) methyl) nicotiamide
The preparation of step one: 5-((2-MEA) methyl) thiophene-2-formonitrile HCN
5-formylthien-2-formonitrile HCN (1mmol) and 2-MEA (1mmol) are dissolved in methanol (10mL)
In, add sodium cyanoborohydride (188mg), concentrated hydrochloric acid one, react under room temperature overnight, be spin-dried for solution thick
Product are directly used in next step.
Step 2: the N-(preparation of (5-(amine methyl) thiophene-2-base) methyl-2-MEA
5-((2-MEA) methyl) thiophene-2-formonitrile HCN (crude product 1mmol) is dissolved in anhydrous tetrahydro furan
(25mL), add lithium aluminium hydride (4eq), react 1h, TLC monitoring at 50 DEG C, after reaction completely, add
Entering shrend to go out, solid filters, and filtrate is spin-dried for, and obtains crude product and is directly used in next step.
Step 3: the preparation of 2-amino-N-((5-((2-MEA) methyl) thiophene-2-base) methyl) nicotiamide
By compound N-((5-(amine methyl) thiophene-2-base) methyl-2-MEA (crude product 1mmol)
It is dissolved in DMF (5mL), adds diisopropylethylamine (2eq), hexafluorophosphoric acid benzotriazole
-1-base-epoxide tripyrrole alkyl (1.1eq) and 2-amino-nicotinic acid (1eq), react 5h, after reaction completely, falls
Entering in water, be extracted with ethyl acetate three times, organic facies saturated sodium-chloride water solution washes 2 times, organic facies
Being dried with anhydrous sodium sulfate, filter, after filtrate reduced in volume, residue, through column chromatography purification, obtains white
Solid 6i (120mg, yield 32%).
H1NMR,300MHz CDCl3-d1
δ: 8.13-8.11 (m, 1H), 7.64-7.61 (d, 1H, J=7.8Hz), 7.25 (s, 1H), 7.14-7.09 (m, 2H), 6.89 (s, 2
H), 6.78-6.67 (m, 2H), 6.61-6.57 (m, 1H), 6.52-6.41 (m, 1H), 4.71-4.69 (d, 2H, J=5.5Hz), 4
(s, 2H) .51 2.54-2.47 (q, 2H, J=7.1,14.5Hz), 1.28-1.23 (t, 3H, J=7.5Hz)
The preparation of embodiment 10:6j2-amino-N-((5-((3-MEA) methyl) thiophene-2-base) methyl) nicotiamide
The preparation of step one: 5-((3-MEA) methyl) thiophene-2-formonitrile HCN
5-formylthien-2-formonitrile HCN (1mmol) and 3-MEA (1mmol) are dissolved in methanol (10mL)
In, add sodium cyanoborohydride (188mg), concentrated hydrochloric acid one, react under room temperature overnight, be spin-dried for solution thick
Product are directly used in next step.
Step 2: the N-(preparation of (5-(amine methyl) thiophene-2-base) methyl-3-MEA
5-((3-MEA) methyl) thiophene-2-formonitrile HCN (crude product 1mmol) is dissolved in anhydrous tetrahydro furan
(25mL), add lithium aluminium hydride (4eq), react 1h, TLC monitoring at 50 DEG C, after reaction completely, add
Entering shrend to go out, solid filters, and filtrate is spin-dried for, and obtains crude product and is directly used in next step.
Step 3: the preparation of 2-amino-N-((5-((3-MEA) methyl) thiophene-2-base) methyl) nicotiamide
By compound N-((5-(amine methyl) thiophene-2-base) methyl-3-MEA (crude product 1mmol)
It is dissolved in DMF (5mL), adds diisopropylethylamine (2eq), hexafluorophosphoric acid benzotriazole
-1-base-epoxide tripyrrole alkyl (1.1eq) and 2-amino-nicotinic acid (1eq), react 5h, after reaction completely, falls
Entering in water, be extracted with ethyl acetate three times, organic facies saturated sodium-chloride water solution washes 2 times, organic facies
Being dried with anhydrous sodium sulfate, filter, after filtrate reduced in volume, residue, through column chromatography purification, obtains white
Solid 6j (120mg, yield 32%).
H1NMR,300MHz CDCl3-d1
δ: 8.19-8.17 (dd, 1H, J=1.5,4.8Hz), 7.62-7.59 (dd, 1H, J=1.6,7.7Hz), 7.15-7.10 (t, 1H, J=7.
7Hz), 6.89 (s, 2H), 6.64-6.51 (m, 4H), 6.39 (brs, 3H), 4.73-4.71 (d, 2H, J=5.5Hz) 4.48 (s, 2H
), 2.63-2.55 (q, 2H, J=7.1,14.5Hz), 1.25-1.20 (t, 3H, J=7.5Hz)
Embodiment 11:6k2-amino-N-((5-((2-isopropyl aniline) methyl) thiophene-2-base) methyl) nicotiamide
Preparation
The preparation of step one: 5-((2-isopropyl aniline) methyl) thiophene-2-formonitrile HCN
5-formylthien-2-formonitrile HCN (1mmol) and 2-isopropyl aniline (1mmol) are dissolved in methanol (10mL)
In, add sodium cyanoborohydride (188mg), concentrated hydrochloric acid one, react under room temperature overnight, be spin-dried for solution thick
Product are directly used in next step.
Step 2: the N-(preparation of (5-(amine methyl) thiophene-2-base) methyl-2-isopropyl aniline
5-((2-isopropyl aniline) methyl) thiophene-2-formonitrile HCN (crude product 1mmol) is dissolved in anhydrous tetrahydrochysene furan
Mutter (25mL), adds lithium aluminium hydride (4eq), reacts 1h, TLC monitoring at 50 DEG C, after reaction completely,
Adding shrend to go out, solid filters, and filtrate is spin-dried for, and obtains crude product and is directly used in next step.
Step 3: the preparation of 2-amino-N-((5-((2-isopropyl aniline) methyl) thiophene-2-base) methyl) nicotiamide
By compound N-((5-(amine methyl) thiophene-2-base) methyl-2-isopropyl aniline (crude product 1mmol)
It is dissolved in DMF (5mL), adds diisopropylethylamine (2eq), hexafluorophosphoric acid benzotriazole
-1-base-epoxide tripyrrole alkyl (1.1eq) and 2-amino-nicotinic acid (1eq), react 5h, after reaction completely, falls
Entering in water, be extracted with ethyl acetate three times, organic facies saturated sodium-chloride water solution washes 2 times, organic facies
Being dried with anhydrous sodium sulfate, filter, after filtrate reduced in volume, residue, through column chromatography purification, obtains white
Solid 6k (90mg, yield 23%).
H1NMR,300MHz CDCl3-d1
δ:8.10-8.09(m,1H),7.69-7.67(m,1H),7.25-7.09(m,2H),6.93-6.90(m,2H),6.82-6.77(
M, 1H), and 6.73-6.47 (m, 6H), 4.74-4.72 (d, 2H, J=5.5Hz), 4.53-4.48 (brs, 2H) 2.94-2.81 (m, 1
H),1.29-1.22(m,6H)
The system of embodiment 12:6l2-amino-N-((5-((3-isopropyl aniline) methyl) thiophene-2-base) methyl) nicotiamide
Standby
The preparation of step one: 5-((3-isopropyl aniline) methyl) thiophene-2-formonitrile HCN
5-formylthien-2-formonitrile HCN (1mmol) and 3-isopropyl aniline (1mmol) are dissolved in methanol (10mL)
In, add sodium cyanoborohydride (188mg), concentrated hydrochloric acid one, react under room temperature overnight, be spin-dried for solution thick
Product are directly used in next step.
Step 2: the N-(preparation of (5-(amine methyl) thiophene-2-base) methyl-3-isopropyl aniline
5-((3-isopropyl aniline) methyl) thiophene-2-formonitrile HCN (crude product 1mmol) is dissolved in anhydrous tetrahydrochysene furan
Mutter (25mL), adds lithium aluminium hydride (4eq), reacts 1h, TLC monitoring at 50 DEG C, after reaction completely,
Adding shrend to go out, solid filters, and filtrate is spin-dried for, and obtains crude product and is directly used in next step.
Step 3: the preparation of 2-amino-N-((5-((3-isopropyl aniline) methyl) thiophene-2-base) methyl) nicotiamide
By compound N-((5-(amine methyl) thiophene-2-base) methyl-3-isopropyl aniline (crude product 1mmol)
It is dissolved in DMF (5mL), adds diisopropylethylamine (2eq), hexafluorophosphoric acid benzotriazole
-1-base-epoxide tripyrrole alkyl (1.1eq) and 2-amino-nicotinic acid (1eq), react 5h, after reaction completely, falls
Entering in water, be extracted with ethyl acetate three times, organic facies saturated sodium-chloride water solution washes 2 times, organic facies
Being dried with anhydrous sodium sulfate, filter, after filtrate reduced in volume, residue, through column chromatography purification, obtains white
Solid 6l (100mg, yield 26%).
H1NMR,300MHz CDCl3-d1
δ: 8.15-8.13 (m, 1H), 7.64-7.62 (d, 1H, J=7.7Hz), 7.16-7.11 (t, 1H, J=7.8Hz), 6.89 (m, 2H),
6.67-6.48 (brs, 6H), 4.72-4.70 (d, 2H, J=5.5Hz), 4.48 (s, 2H) 2.88-2.79 (m, 1H), 1.25-1.22 (
D, 6H, J=6.9Hz)
The preparation of embodiment 13:6m2-amino-N-((5-((2-chloroaniline) methyl) thiophene-2-base) methyl) nicotiamide
The preparation of step one: 5-((2-fluoroaniline) methyl) thiophene-2-formonitrile HCN
5-formylthien-2-formonitrile HCN (1mmol) and 2-chloroaniline (1mmol) are dissolved in methanol (10mL),
Add sodium cyanoborohydride (188mg), concentrated hydrochloric acid one, react under room temperature overnight, be spin-dried for solution crude product straight
Connect for next step.
Step 2: the N-(preparation of (5-(amine methyl) thiophene-2-base) methyl-2-chloroaniline
5-((2-chloroaniline) methyl) thiophene-2-formonitrile HCN (crude product 1mmol) is dissolved in anhydrous tetrahydro furan (25
ML), add lithium aluminium hydride (4eq), at 50 DEG C, react 1h, TLC monitoring, after reaction completely, add water
Cancellation, solid filters, and filtrate is spin-dried for, and obtains crude product and is directly used in next step.
Step 3: the preparation of 2-amino-N-((5-((2-chloroaniline) methyl) thiophene-2-base) methyl) nicotiamide
By compound N-((5-(amine methyl) thiophene-2-base) methyl-2-chloroaniline (crude product 1mmol) is dissolved in
DMF (5mL), addition diisopropylethylamine (2eq), hexafluorophosphoric acid benzotriazole-1-base-
Epoxide tripyrrole alkyl (1.1eq) and 2-amino-nicotinic acid (1eq), react 5h, after reaction completely, pour water into
In, it being extracted with ethyl acetate three times, organic facies saturated sodium-chloride water solution is washed 2 times, organic facies nothing
Aqueous sodium persulfate is dried, and filters, and after filtrate reduced in volume, residue, through column chromatography purification, obtains white solid
6m (160mg, yield 43%).
H1NMR,300MHz CDCl3-d1
δ: 8.16-8.13 (dd, 1H, J=4.8,1.6Hz), 7.62-7.59 (dd, 1H, J=7.8,1.6Hz), 7.25 (m, 1H), 7.02-6.
96(m,2H),6.88-6.78(m,2H),6.78-6.64(m,2H),6.61-6.57(m,1H),6.42(brs,2H),4.71-4.
69 (d, 2H, J=5.5Hz), 4.50 (s, 2H)
Embodiment 14: compound 6d2-amino-N-((5-((2-fluoroaniline) methyl) thiophene-2-base) methyl) nicotinoyl amine salt
The preparation of hydrochlorate
Take compound 6d338mg (1mmol) to be dissolved in 5mL dichloromethane, add 2mL hydrochloric acid, room temperature
Lower stirring 3 hours.Reaction terminates rear concentration of reaction solution, separates out precipitation, filters to obtain 2-amino-N-((5-((2-
Fluoroaniline) methyl) thiophene-2-base) methyl) nicotinamide hydrochloride 310mg, productivity 90.3%.
Remaining target compound is with different substituted anilines as synthesis material, as listed in table 1, repeats embodiment
1 and embodiment 5 in step, just can synthesize required aminopyridines or its esters.Embodiment
Middle agents useful for same is commercially available analytical pure.
Embodiment 15: the antibacterial experiment in vitro of the compounds of this invention
(1) experimental technique: use conventional antibacterial experiment in vitro method (to refer to: Antimicrob Agents
Chemother1995,39(5):1169)
1. materials and methods
(1) experimental strain
This experiment has selected following 4 kinds of common human body cause illness's standard fungal bacterial strains as screening object, fungus
Bacterial strain is provided by Shanghai Long March Hospital's Mycology Lab (or purchased from medicine institute of the Chinese Academy of Sciences).
Candida albicans (Candida albicans, type strain SC5314)
Candida parapsilosis (Candida parapsilosis, ATCC22019)
Cryptococcus histolyticus (Cryptococcus neoformans, type strain 32609)
Oidium tropicale (Candida tropicalis ATCC22019)
(2) test method
Bacteria suspension is prepared: above-mentioned fungus is cultivated 16 hours through YEPD fluid medium 35 DEG C, twice activation,
Count with blood cell counting plate, with RPM1640 fluid medium adjustment bacteria concentration to 1*104～1*105
Individual/mL.
Drug solution preparing: take testing compound of the present invention and be dissolved in dimethyl sulfoxide, is made into the medicine storage of 0.8mg/mL
Liquid storage, tests front RPM1640 and is diluted to 8 μ g/mL.
Inoculation: 96 orifice plate 1 holes add RPM1640100 μ L and make blank；3-12 hole respectively adds bacterium and hangs
Liquid 100 μ L, No. 2 holes add bacteria suspension 200 μ L and medicinal liquid 2 μ L, and the drug level in 2-11 hole makees 10 grades
Doubling dilution, each hole drug level is followed successively by 8,4,2,1,0.5,0.25,0.125,0.0625,0.0313,
0.0156μg/mL.No. 12 holes are not added with medicinal liquid, make positive control.Drug control selects fluconazol
(2) experimental result
Antibacterial experiment in vitro the results are shown in Table 2
Table 2 target compound In Vitro Anti fungus minimal inhibitory concentration value (MIC80, μ g/mL)
Above-mentioned test result indicate that, the compounds of this invention has preferable antifungal activity, and In Vitro Bacteriostasis is lived
Property is all better than fluconazol.
And the compounds of this invention advantages such as also to have toxicity low, antifungal spectrum width, can be used for preparation anti-true
Bacterium medicine.
Below preferred embodiment to the invention is illustrated, but the invention is not
Being limited to described embodiment, those of ordinary skill in the art are on the premise of the invention spirit
Also can make modification or the replacement of all equivalents, modification or the replacement of these equivalents are all contained in the application
In claim limited range.
Claims (9)
1. a class aminopyridines or its salt pharmacologically allowed, it is characterised in that described amino
The chemical constitution of pyridine compounds and their is shown in formula I:
In Formulas I, R group represents phenyl or substituted-phenyl, and the substituent group in substituted-phenyl can be located at phenyl ring
Each position, can be monosubstituted or polysubstituted, and substituent group is selected from a, b or c:
a.F、Cl、Br、I；
B. the low alkyl group of 1-4 carbon atom of methyl, ethyl, halogen substiuted, the tert-butyl group；
C. isopropyl, the tert-butyl group.
A class aminopyridines the most according to claim 1 or its salt pharmacologically allowed, its
Being characterised by, described aminopyridines is:
2-amino-N-((5-((2-aminotoluene) methyl) thiophene-2-base) methyl) nicotiamide,
2-amino-N-((5-((3-monomethylaniline .) methyl) thiophene-2-base) methyl) nicotiamide,
2-amino-N-((5-((4-monomethylaniline .) methyl) thiophene-2-base) methyl) nicotiamide,
2-amino-N-((5-((2-fluoroaniline) methyl) thiophene-2-base) methyl) nicotiamide,
2-amino-N-((5-((3-fluoroaniline) methyl) thiophene-2-base) methyl) nicotiamide,
2-amino-N-((5-((4-fluoroaniline) methyl) thiophene-2-base) methyl) nicotiamide,
2-amino-N-((5-((aniline) methyl) thiophene-2-base) methyl) nicotiamide,
2-amino-N-((5-((3-chloroaniline) methyl) thiophene-2-base) methyl) nicotiamide,
2-amino-N-((5-((2-MEA) methyl) thiophene-2-base) methyl) nicotiamide,
2-amino-N-((5-((3-MEA) methyl) thiophene-2-base) methyl) nicotiamide,
2-amino-N-((5-((2-isopropyl aniline) methyl) thiophene-2-base) methyl) nicotiamide,
2-amino-N-((5-((3-isopropyl aniline) methyl) thiophene-2-base) methyl) nicotiamide, or
2-amino-N-((5-((2-chloroaniline) methyl) thiophene-2-base) methyl) nicotiamide.
A class aminopyridines the most according to claim 1 and 2 or its salt pharmacologically allowed,
It is characterized in that, the described salt pharmacologically allowed is inorganic acid salt or acylate.
A class aminopyridines the most according to claim 3 or its salt pharmacologically allowed, its
Being characterised by, mineral acid refers to hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid or nitric acid；Organic acid refer to acetic acid,
Maleic acid, fumaric acid, tartaric acid, succinic acid, lactic acid, Loprazolam, p-methyl benzenesulfonic acid, salicylic acid
Or oxalic acid.
5. an aminopyridines as claimed in claim 1 or the preparation of its salt pharmacologically allowed
Method, it is characterised in that the preparation method of described aminopyridines is as follows:
Reaction process:
Concretely comprise the following steps:
Step one: prepare target compound 3
5-formylthien-2-formonitrile HCN 1 and substituted aniline 2 are dissolved in methanol, add a concentrated hydrochloric acid,
Add sodium cyanoborohydride to carry out reacting overnight under reduction amination, room temperature, generate 5-((substituted benzene
Amine) methyl) thiophene-2-formonitrile HCN 3；
Step 2: prepare target compound 4
5-((substituted aniline) methyl) thiophene-2-formonitrile HCN 3 is dissolved in anhydrous tetrahydro furan, adds lithium hydride
Aluminum carries out reduction reaction, after reacting 1h, generates N-((5-(amine methyl) thiophene-2-base) first at 50 DEG C
Base-substituted aniline 4；
Step 3: prepare target compound 6
By compound N-((5-(amine methyl) thiophene-2-base) methyl-substituted aniline (4) is dissolved in N, N-diformazan
Base Methanamide, adds diisopropylethylamine, hexafluorophosphoric acid benzotriazole-1-base-epoxide tripyrrole alkyl and 2-
Amino-nicotinic acid 5, at room temperature carries out condensation reaction, generates 2-amino-N-((5-((substituted aniline) after reaction 5h
Methyl) thiophene-2-base) methyl) nicotiamide 6.
Aminopyridines the most according to claim 5 or the preparation side of its salt pharmacologically allowed
Method, it is characterised in that the preparation method of the salt pharmacologically allowed of described aminopyridines
After step one is to three, also include:
Reaction process:
Wherein HX is mineral acid or organic acid；
Concretely comprise the following steps: prepare target compound 7
Take 2-amino-N-((5-((substituted aniline) methyl) thiophene-2-base) methyl) nicotiamide 6 and be dissolved in dichloromethane
In, add mineral acid or organic acid, stir 3 hours under room temperature, generate 2-amino-N-((5-((substituted aniline)
Methyl) thiophene-2-base) methyl) nicotiamide pharmaceutical salts 7.
7. an aminopyridines as claimed in claim 1 or its salt pharmacologically allowed are in preparation
Application in antifungal drug.
Aminopyridines the most according to claim 7 or its salt pharmacologically allowed are anti-in preparation
Application in fungi-medicine, it is characterised in that described antifungal drug is by aminopyridines
Or the pharmaceutical composition that its salt pharmacologically allowed is made as active component and conventional pharmaceutical carrier.
Aminopyridines the most according to claim 8 or its salt pharmacologically allowed are anti-in preparation
Application in fungi-medicine, it is characterised in that described pharmaceutical composition be tablet, capsule, drop pill,
Granule, injection, injectable powder or aerosol.
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| Synthesis and evaluation of novel antifungal agents-quinoline and pyridine amide derivatives;Kazutaka Nakamoto et al.;《Bioorg.Med.Chem.Lett.》;20100608;第20卷;第4625页第2段以及方案1，第4626页化合物15以及表1 * |
| 新型烟酰胺类杀菌剂-啶酰菌胺;颜范勇等;《农药》;20080210;第47卷(第2期);第132-135页 * |
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