CN105777664B - Carboxylate of 2 (2 benzyl hydrazono-) thiazole 5 and preparation method thereof and medical usage - Google Patents
Carboxylate of 2 (2 benzyl hydrazono-) thiazole 5 and preparation method thereof and medical usage Download PDFInfo
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- CN105777664B CN105777664B CN201610061123.5A CN201610061123A CN105777664B CN 105777664 B CN105777664 B CN 105777664B CN 201610061123 A CN201610061123 A CN 201610061123A CN 105777664 B CN105777664 B CN 105777664B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses the carboxylic ester derivative of 2 shown in structural formula I (2 benzyl hydrazono-) thiazole 5 and its pharmaceutically acceptable salt, its preparation method and pharmaceutical composition and its application in influenza virus neuraminidase inhibitor is prepared.Wherein, R is selected from：C1~C2、C3~C4Straight chain or C3~C4Branched alkyl；R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight or branched alkyl, trifluoromethyl；X1、X5It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro；X2、X4It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro；X3It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, carboxyl or alkoxy carbonyl group.
Description
Technical field
The present invention relates to a kind of noval chemical compound, its preparation method and application, specifically 2- (2- benzyls hydrazono-) thiazole -5- carboxylics
Acid ester derivant, its preparation method and its preparing the application of influenza virus neuraminidase inhibitor.
Background technology
5- carboxylate thiazole hydrazones and the like have extensive bioactivity, P.Makam etc. [Eur.J.Med.Chem.,
2013.69:564-576, Eur.J.Pharm.Sci., 2014.52:138-145] report serial 2- (2- hydrazono-s) thiazole and spread out
Biological (A) has good Killing Mycobacterium Tuberculosis effect and anti-malarial effect；A.Grozav etc. [Int.J.Mol.Sci.,
2014.15(12):22059-22072] serial benzyl hydrazono- thiazolium compounds (B) has been synthesized, find part of compounds to two kinds
Cancer cell (MDA-MB231 and HeLa) has obvious antiproliferative activity；M.H.Shin etc. [Chem.Pharm.Bull., 2007.55
(8):1126-1135] find that some cyclosubstituted thiazole hydrazones (C) of fragrance have certain inoxidizability；A.Ignat etc.
[Arch.Pharm.Chem.Life Sci.,2012.345(7):574-583] find the thiazole hydrazone (D) of the phenazinyl containing thiophene to knot
Intestinal cancer and liver cancer cells have antiproliferative activity.
Chinese invention patent [CN104774199A] describes 2- (2- benzyls hydrazono-) -5- (1,2,4- triazol-1-yl) thiophene
The synthesis of azoles and its inhibitory activity of Neuraminidase in Influenza Virus.
The content of the invention
Present invention solves the technical problem that it is to provide a kind of 2- (2- benzyls hydrazono-) thiazole-5-carboxylic acid ester derivant, its system
Preparation Method, pharmaceutical composition and purposes.
To solve the technical problem of the present invention, the present invention provides following technical scheme：
The first aspect of technical solution of the present invention there is provided one kind as shown in structural formula I 2- (2- benzyls hydrazono-) thiazole-
5- carboxylic ester derivatives：
Wherein, R is selected from：C1~C2、C3~C4Straight chain or C3~C4Branched alkyl；R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4
Straight or branched alkyl, trifluoromethyl；X in formula1、X5It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine,
Chlorine, bromine, iodine, nitro；X2、X4It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl, hydroxyl, methoxyl group, ethoxy
Base, fluorine, chlorine, bromine, iodine, nitro；X3It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitre
Base, carboxyl or alkoxy carbonyl group.
A kind of 2- (2- benzyls hydrazono-) thiazole-5-carboxylic acid ester derivant that the first aspect of technical solution of the present invention also provides
Selected from following compounds：
((3- fluorine benzyl is sub- by 2- by 2- (2- (3- methoxyl group -4- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acids ethyl ester, 2-
Diazanyl)) -4- methyl thiazole-5-carboxyl acids ethyl ester, 2- (2- (2,4- dihydroxy benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid second
((4- methoxycarbonyl groups benzyl is sub- by 2- by ester, 2- (2- (3- methoxyl group -2- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acids ethyl ester, 2-
Diazanyl)) -4- methyl thiazole-5-carboxyl acids ethyl ester or 2- (2- (4- carboxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid ethyl esters, its
Structural formula is as follows：
The second aspect of technical solution of the present invention there is provided the system of 2- (2- benzyls hydrazono-) thiazole-5-carboxylic acid ester derivant
Preparation Method, it is characterised in that its preparation reaction is as follows：
Or
Wherein, R is selected from：C1~C2、C3~C4Straight chain or C3~C4Branched alkyl；R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4
Straight or branched alkyl, trifluoromethyl；X in formula1、X5It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine,
Chlorine, bromine, iodine, nitro；X2、X4It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl, hydroxyl, methoxyl group, ethoxy
Base, fluorine, chlorine, bromine, iodine, nitro；X3It is selected from：Hydrogen, deuterium, C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitre
Base, carboxyl or alkoxy carbonyl group；HX is selected from：Hydrochloric acid, hydrobromic acid.
The third aspect of technical solution of the present invention, which is to provide, contains compound described in first aspect and its pharmaceutically acceptable
Salt pharmaceutical composition, the pharmaceutical composition contains 2- (2- benzyls hydrazono-) thiazole -5- carboxylics of the invention of therapeutically effective amount
Acid ester derivant and its pharmaceutically acceptable salt, and optional contain pharmaceutical carrier.Wherein described pharmaceutical carrier refers to medicine
The conventional pharmaceutical carrier in field；The pharmaceutical composition can be prepared according to method well known in the art.Can be by by the present inventionization
Compound and its pharmaceutically acceptable salt and one or more pharmaceutically acceptable solids or liquid excipient and/or assistant agent group
Close, any formulation used suitable for human or animal is made.The compounds of this invention and its pharmaceutically acceptable salt are in its medicine group
Content in compound is usually 0.1%~95% percentage by weight.
The compounds of this invention and its pharmaceutically acceptable salt can be in a unit containing its pharmaceutical composition
Administration, method of administration can be enteron aisle or non-bowel, and such as oral, intravenous injection, intramuscular injection, hypodermic injection, nasal cavity, oral cavity are glued
Film, eye, lung and respiratory tract, skin, vagina, rectum etc..
Form of administration can be liquid dosage form, solid dosage forms or semisolid dosage form.Liquid dosage form can be solution (including
True solution and colloidal solution), emulsion (including o/w types, w/o types and emulsion), supensoid agent, injection (including liquid drugs injection, powder-injection
And transfusion), eye drops, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet (including ordinary tablet, enteric coatel tablets, lozenge,
Dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (including hard shell capsules, soft capsule, capsulae enterosolubilis), granule, dissipate
Agent, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, spray etc.；Semisolid dosage form can be ointment, gel
Agent, paste etc..
It is sustained release preparation, control that the compounds of this invention and its pharmaceutically acceptable salt, which can be made ordinary preparation, also be made,
Release formulation, targeting preparation and various particulate delivery systems.
In order to which the compounds of this invention and its pharmaceutically acceptable salt are made into tablet, can widely use known in this field
Various excipient, including diluent, binder, wetting agent, disintegrant, lubricant, glidant.Diluent can be starch,
Dextrin, sucrose, glucose, lactose, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate
Deng；Wetting agent can be water, ethanol, isopropanol etc.；Adhesive can be starch slurry, dextrin, syrup, honey, glucose solution,
Microcrystalline cellulose, mucialga of arabic gummy, gelatine size, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl
Cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrant can be dried starch, crystallite fibre
Tie up element, low-substituted hydroxypropyl cellulose, PVPP, Ac-Di-Sol, sodium carboxymethyl starch, carbon
Sour hydrogen sodium and citric acid, polyoxyethylene sorbitol fatty acid ester, dodecyl sodium sulfate etc.；Lubricant and glidant can be
Talcum powder, silica, stearate, tartaric acid, atoleine, polyethylene glycol etc..
Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets, or it is double
Synusia and multilayer tablet.
, can be by active ingredient the compounds of this invention and its pharmaceutically acceptable in order to which administration unit is made into capsule
Salt is mixed with diluent, glidant, and mixture is placed directly within hard shell capsules or soft capsule.Also can be by the active ingredient present inventionization
First particle or micropill is made with diluent, binder, disintegrant in compound and its pharmaceutically acceptable salt, then be placed in hard shell capsules or
In soft capsule.For preparing each diluent, binder, wetting of the compounds of this invention and its pharmaceutically acceptable salt tablet
Agent, disintegrant, glidant kind can also be used for preparing the capsule of the compounds of this invention and its pharmaceutically acceptable salt.
For the compounds of this invention and its pharmaceutically acceptable salt are made into injection, can use water, ethanol, isopropanol,
Propane diols or their mixture as solvent simultaneously add appropriate solubilizer commonly used in the art, cosolvent, pH adjustments agent, osmotic pressure
Conditioning agent.Solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin etc.；PH adjustment agent can be phosphorus
Hydrochlorate, acetate, hydrochloric acid, sodium hydroxide etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, vinegar
Hydrochlorate etc..Freeze drying powder injection is such as prepared, mannitol, glucose etc. can be also added and be used as proppant.
In addition, if desired, colouring agent, preservative, spices, flavouring or other additions can also be added into pharmaceutical preparation
Agent.
To reach medication purpose, strengthen therapeutic effect, medicine of the invention or pharmaceutical composition known can be given with any
Prescription method is administered.
The fourth aspect of technical solution of the present invention is to provide 2- of the present invention (2- benzyls hydrazono-) thiazole-5-carboxylic acid ester and spread out
Biology and its pharmaceutically acceptable salt and third aspect described pharmaceutical composition are preparing influenza neuraminidase suppression
Application in terms of preparation.
2- (2- (2- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acids ethyl ester, 2- (2- (4- hydroxyl benzyls hydrazono-)) -
4- methyl thiazole-5-carboxyl acids ethyl ester or 2- (2- (3- methoxyl group -4- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid ethyl esters
And its pharmaceutically application of the acceptable salt in influenza virus neuraminidase inhibitor.
Advantageous effects：
2- (2- benzyls hydrazono-) thiazole-5-carboxylic acid ester derivant of the present invention is a kind of new construction type with influenza disease
The compound of malicious neuraminic acid enzyme inhibition activity.
Embodiment
Following examples are intended to illustrate invention rather than limitation of the invention further.
Embodiment 1
The preparation of 2- (2- (4- methoxycarbonyl group benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acids carbethoxy hydrochloride (2aHCl)
1.18g (5mmol) 2- (4- methoxycarbonyl phenyls hydrazono-) thioformamide 1a and 0.84g (5.1mmol) 2- chloroethenes
Ethyl acetoacetic acid ethyl ester is dissolved in 20mL absolute ethyl alcohols, and flow back 2h, cools down, and filters, and filter cake uses ethanol, saturated aqueous common salt and washing successively,
Dry light yellow solid 2- (2- (4- methoxycarbonyl group benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid carbethoxy hydrochlorides, yield
91%, m.p.231~233 DEG C.1H NMR (400MHz, DMSO-d6)δ：8.17 (s, 1H ,=CH), 8.01 (d, J=8.4Hz,
2H, C6H4), 7.82 (d, J=8.4Hz, 2H, C6H4), 4.22 (q, J=7.2Hz, 2H, OCH2), 3.87 (s, 3H, OCH3), 2.49
(s, 3H, thiazole ring-CH3), 1.27 (t, J=7.2Hz, 3H, CH3)。
2- (2- (4- methoxycarbonyl group benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid carbethoxy hydrochlorides neutralize through NaOH solution
Obtain 2- (2- (4- methoxycarbonyl group benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid ethyl esters.
Embodiment 2
The preparation of 2- (2- (2,4- dihydroxy benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acids carbethoxy hydrochloride (2bHCl)
1.05g (5mmol) 2- (2,4- dihydroxy benzyls hydrazono-) thioformamide 1b and 0.84g (5.1mmol) 2- chloroethenes
Ethyl acetoacetic acid ethyl ester is dissolved in 20mL absolute ethyl alcohols, and flow back 2h, pours into saturated aqueous common salt, separates out a large amount of pale solids, filters, filter
Cake uses ethanol and washing successively, and ethanol/water recrystallizes to obtain pale solid 2- (2- (2,4- dihydroxy benzyl hydrazono-)) -4- methyl
Thiazole-5-carboxylic acid ethyl ester hydrochloride, yield 69%, m.p.250~252 DEG C.1H NMR (400MHz, DMSO-d6)δ：10.39 (s,
1H, NH), 8.34 (s, 1H ,=CH), 7.44 (d, J=8.4Hz, 1H, C6H3), 6.38 (d, J=2.0Hz, 1H, C6H3), 6.36
(dd, 1H, J=8.4Hz, J=2.0Hz, C6H3), 4.20 (q, J=7.2Hz, 2H, OCH2), 2.46 (s, 3H, thiazole ring-CH3),
1.27 (t, J=7.2Hz, 3H, CH3)。
2- (2- (2,4- dihydroxy benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid carbethoxy hydrochlorides neutralize through NaOH solution
Obtain 2- (2- (2,4- dihydroxy benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid ethyl esters.
Embodiment 3
2- (2- (3- methoxyl group -4- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acids carbethoxy hydrochloride (2cHCl)
Preparation
5mmol2- (3- methoxyl group -4- hydroxyl benzyls hydrazono-) thioformamide 1c and 5.1mmol 2- chloroethene ethyl acetoacetic acid second
Ester is dissolved in 20mL absolute ethyl alcohols, and flow back 2h, cools down, and filters, filter cake uses ethanol, saturated aqueous common salt and washing successively, shallowly dry
Yellow solid 2- (2- (3- methoxyl group -4- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid carbethoxy hydrochlorides, yield 83%,
M.p.213~215 DEG C.1H NMR (400MHz, DMSO-d6)δ：8.03 (s, 1H ,=CH), 7.24 (d, J=1.8Hz, 1H,
C6H3), 7.11 (dd, J=8.2,1.8Hz, 1H, C6H3), 6.85 (d, J=8.2Hz, 1H, C6H3), 4.21 (q, J=7.2Hz,
2H, OCH2), 3.82 (s, 3H, OCH3), 2.48 (s, 3H, thiazole ring-CH3), 1.26 (t, J=7.2Hz, 3H, CH3)。
2- (2- (3- methoxyl group -4- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid carbethoxy hydrochlorides are through NaOH solution
Neutralization obtains 2- (2- (3- methoxyl group -4- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid ethyl esters.
Embodiment 4
The preparation of 2- (2- (3- fluorine benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acids carbethoxy hydrochloride (2dHCl)
0.99g (5mmol) 2- (3- fluorine benzyls hydrazono-) thioformamide 1d and 0.84g (5.1mmol) 2- chloroethene ethyl acetoacetic acids
The tert-butyl ester is dissolved in 20mL absolute ethyl alcohols, and flow back 2h, cools down, and filters, and filter cake uses ethanol, saturated aqueous common salt and washing successively, dries
Obtain light yellow solid 2- (2- (3- fluorine benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid carbethoxy hydrochlorides, yield 92%, m.p.197
~199 DEG C.1H NMR (400MHz, DMSO-d6)δ：12.61 (s, 1H, NH), 8.12 (s, 1H ,=CH), 7.54~7.46 (m,
3H, C6H4), 7.28~7.21 (m, 1H, C6H4), 4.21 (q, J=7.2Hz, 2H, OCH2), 2.48 (s, 3H, thiazole ring-CH3),
1.27 (t, J=7.2Hz, 3H, CH3)。
2- (2- (3- fluorine benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid carbethoxy hydrochlorides neutralize to obtain 2- through NaOH solution
(2- (3- fluorine benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid ethyl esters.
Embodiment 5
2- (2- (3- methoxyl group -4- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid t-butyl ester hydrochlorides (2e
HCl preparation)
1.13g (5mmol) 2- (3- methoxyl group -4- hydroxyl benzyls hydrazono-) thioformamide 1e and 0.84g (5.1mmol) 2-
Chloracetyl tert-butyl acetate is dissolved in 20mL absolute ethyl alcohols, and flow back 2h, cools down, and filters, filter cake successively with ethanol, saturated aqueous common salt and
Washing, dry white solid 2- (2- (3- methoxyl group -4- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid tert-butyl ester salt
Hydrochlorate, yield 49%, m.p.197~199 DEG C.1H NMR (400MHz, CDCl3)δ：13.36 (s, 1H, NH), 8.30 (s, 1H ,=
CH), 7.24~7.23 (m, 2H, C6H3), 6.97 (d, J=8.4Hz, 1H, C6H3), 6.07 (s, 1H, OH), 3.97 (s, 3H,
OCH3), 2.64 (s, 3H, thiazole ring-CH3), 1.59 (s, 9H, 3 × CH3)。
2- (2- (3- methoxyl group -4- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid t-butyl ester hydrochlorides are molten through NaOH
Liquid neutralizes to obtain 2- (2- (3- methoxyl group -4- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid tert-butyl esters.
Embodiment 6
2- (2- (3- methoxyl group -2- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acids carbethoxy hydrochloride (2fHCl)
Preparation
0.76g (5mmol) o-vanillin, 0.455g (5mmol) thiosemicarbazides and 0.85g (5mmol) 2- chloroethene ethyl acetoacetic acids
Ethyl ester is dissolved in 25mL absolute ethyl alcohols, and flowed back 6.8h, cools down, and filters, and filter cake is washed with ethanol, dry white solid 2- (2- (3- first
Epoxide -2- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid carbethoxy hydrochlorides, yield 54.3%, m.p.220~222 DEG C.1H NMR (400MHz, DMSO-d6)δ：9.75 (s, 1H, OH), 8.43 (s, 1H ,=CH), 7.25 (d, J=7.6Hz, 1H,
C6H3), 7.01 (d, J=7.6Hz, 1H, C6H3), 6.85 (t, J=7.6Hz, 1H, C6H3), 4.21 (q, J=7.2Hz, 2H,
OCH2), 3.83 (s, 3H, OCH3), 2.47 (s, 3H, thiazole ring-CH3), 1.27 (t, J=7.2Hz, 3H, CH3)。
2- (2- (3- methoxyl group -2- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid carbethoxy hydrochlorides are through NaOH solution
Neutralization obtains 2- (2- (3- methoxyl group -2- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid ethyl esters.
Embodiment 7
The preparation of 2- (2- (2- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acids carbethoxy hydrochloride (2gHCl)
0.61g (5mmol) salicylide, 0.455g (5mmol) thiosemicarbazides and 0.85g (5mmol) 2- chloroethene ethyl acetoacetic acid second
Ester is dissolved in 25mL absolute ethyl alcohols, and flowed back 0.8h, cools down, and filters, and filter cake is washed with ethanol, dry yellow solid 2- (2- (2- hydroxyls
Benzyl hydrazono-)) -4- methyl thiazole-5-carboxyl acid carbethoxy hydrochlorides, yield 52.6%, m.p.175~177 DEG C.1H NMR
(400MHz, DMSO-d6)δ：10.36 (s, 1H, OH), 8.44 (s, 1H ,=CH), 7.65 (d, J=7.6Hz, 1H, C6H4), 7.26
(t, J=7.6Hz, 1H, C6H4), 6.94 (d, J=7.6Hz, 1H, C6H4), 6.89 (t, J=7.6Hz, 1H, C6H4), 4.21 (q, J
=7.2Hz, 2H, OCH2), 2.47 (s, 3H, thiazole ring-CH3), 1.27 (t, J=7.2Hz, 3H, CH3)。
2- (2- (2- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid carbethoxy hydrochlorides neutralize to obtain through NaOH solution
2- (2- (2- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid ethyl esters.
Embodiment 8
The preparation of 2- (2- (4- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acids carbethoxy hydrochloride (2hHCl)
0.61g (5mmol) parahydroxyben-zaldehyde, 0.455g (5mmol) thiosemicarbazides and 0.85g (5mmol) 2- chloracetyls
Ethyl acetate is dissolved in 25mL absolute ethyl alcohols, and flowed back 7.4h, cools down, and filters, and filter cake is washed with ethanol, dry yellow solid 2- (2-
(4- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid carbethoxy hydrochlorides, yield 55.5%, m.p.170~172 DEG C.1H
NMR (400MHz, DMSO-d6)δ：8.06 (s, 1H ,=CH), 7.52 (d, J=8.8Hz, 2H, C6H4), 6.84 (d, J=8.8Hz,
2H, C6H4), 4.18 (q, J=7.2Hz, 2H, OCH2), 2.45 (s, 3H, CH3), 1.24 (t, J=7.2Hz, 3H, CH3)。
2- (2- (4- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid carbethoxy hydrochlorides neutralize to obtain through NaOH solution
2- (2- (4- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid ethyl esters.
Embodiment 9
The preparation of 2- (2- (4- carboxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acids carbethoxy hydrochloride (2iHCl)
0.75g (5mmol) p -carboxybenzaldehyde, 0.455g (5mmol) thiosemicarbazides and 0.85g (5mmol) 2- chloracetyls
Ethyl acetate is dissolved in 25mL absolute ethyl alcohols, and flowed back 7.5h, cools down, and filters, and filter cake is washed with ethanol, dry yellow solid 2- (2-
(4- carboxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid carbethoxy hydrochlorides, yield 24.9%, m.p.316~318 DEG C.1H
NMR (400MHz, DMSO-d6)δ：12.85 (s, 1H, COOH), 8.13 (s, 1H ,=CH), 7.98 (d, J=8.0Hz, 2H,
C6H4), 7.78 (d, J=8.0Hz, 2H, C6H4), 4.20 (m, 2H, OCH2), 2.48 (s, 3H, CH3), 1.26 (t, J=7.2Hz,
3H, CH3)。
2- (2- (4- carboxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid carbethoxy hydrochlorides neutralize to obtain through NaOH solution
2- (2- (4- carboxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid ethyl esters.
Embodiment 10
The resisiting influenza virus neuraminidase activity of 2- (2- benzyls hydrazono-) thiazole-5-carboxylic acid ester derivant
1. experimental principle
Compound MUNANA is the specific substrate of neuraminidase, the caused metabolite under neuraminic acid enzyme effect
In the case where 360nm irradiations excite, 450nm fluorescence can be produced, the change of fluorescence intensity can delicately react neuraminic acid enzyme activity
Property.Enzyme both is from A/PR/8/34 (H1N1) virus stain.
2. experimental method
In enzyme reaction system, finite concentration sample is suspended in reaction buffer (pH 6.5) with influenza virus god NA,
Add fluorogenic substrate MUNANA and start reaction system, after 37 DEG C are incubated 40 minutes, add reaction terminating liquid terminating reaction.In excitation wave
Under long 360nm and the Parameter Conditions that launch wavelength is 450nm, fluorescence intensity level is determined.The fluorescence intensity of reaction system can be anti-
Reflect the activity of enzyme.Inhibiting rate of the compound to NA activity can be calculated according to the decrement of fluorescence intensity.
3. detect sample：Embodiment compound
4. Activity Results
Preferred compound is in reaction system to the inhibiting rate and IC of neuraminidase during 40.0 μ g/mL of detectable concentration50Value
It is included in table 1：
Inhibitory activity of the 2- of table 1 (2- benzyls hydrazono-) the thiazole-5-carboxylic acid ester derivants to neuraminidase
2- (2- benzyls hydrazono-) thiazole-5-carboxylic acid ester derivant has resisiting influenza virus neuraminidase activity, can be used for
Prepare influenza virus neuraminidase inhibitor.
Claims (6)
1. 2- (2- benzyls hydrazono-) thiazole-5-carboxylic acid ester derivants shown in a kind of chemical structural formula I and its pharmaceutically acceptable
Salt：
Wherein, R is selected from：C3~C4Straight chain or C3~C4Branched alkyl；R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight or branched
Alkyl or trifluoromethyl；X1、X5It is selected from：Hydrogen or C1~C2Alkyl；X2、X4It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, methoxyl group or second
Epoxide；X3It is selected from：Hydroxyl, methoxy or ethoxy.
2. 2- (2- benzyls hydrazono-) thiazole-5-carboxylic acid ester derivants and its pharmaceutically acceptable salt described in claim 1, its
It is characterised by, described pharmaceutically acceptable salt is selected from：2- (2- (3- methoxyl group -4- hydroxyl benzyls hydrazono-)) -4- methyl thiazoliums
Azoles -5- carboxylic acid tert-butyl ester hydrochlorides.
3. 2- (2- benzyls hydrazono-) thiazole-5-carboxylic acid ester derivants and its pharmaceutically acceptable salt described in claim 1 or 2
Application in influenza virus neuraminidase inhibitor is prepared.
4. 2- (2- benzyls hydrazono-) thiazole-5-carboxylic acid ester derivants shown in a kind of chemical structural formula I and its pharmaceutically acceptable
Application of the salt in influenza virus neuraminidase inhibitor is prepared：
Wherein, R is selected from：C1~C2、C3~C4Straight chain or C3~C4Branched alkyl；R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain
Or branched alkyl or trifluoromethyl；X1、X5It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, methoxy or ethoxy；X2、X4It is selected from：Hydrogen,
C1~C2Alkyl, hydroxyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine or iodine；X3It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, methoxyl group, second
Epoxide, carboxyl or methoxycarbonyl group.
5. the application described in claim 4,2- (2- benzyls hydrazono-) thiazole-5-carboxylic acid ester derivant wherein shown in formula I is selected from：
2- (2- (3- methoxyl group -4- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acids ethyl ester, 2- (2- (3- fluorine benzyls hydrazono-)) -4-
Methyl thiazole-5-carboxyl acid ethyl ester, 2- (2- (2,4- dihydroxy benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acids ethyl ester, 2- (2- (3-
Methoxyl group -2- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acids ethyl ester, 2- (2- (4- methoxycarbonyl group benzyls hydrazono-)) -4- first
Base thiazole-5-carboxylic acid ethyl ester or 2- (2- (4- carboxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid ethyl esters.
6. the application described in claim 4,2- (2- benzyls hydrazono-) thiazole-5-carboxylic acid ester derivant pharmacy wherein shown in formula I
Upper acceptable salt is selected from：2- (2- (2,4- dihydroxy benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acids carbethoxy hydrochloride, 2- (2-
(3- methoxyl group -4- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acids carbethoxy hydrochloride, 2- (2- (3- methoxyl group -2- hydroxyls
Benzyl hydrazono-)) -4- methyl thiazole-5-carboxyl acids carbethoxy hydrochloride, 2- (2- (3- methoxyl group -4- hydroxyl benzyls hydrazono-)) -4- methyl
Thiazole-5-carboxylic acid t-butyl ester hydrochloride, 2- (2- (4- methoxycarbonyl group benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid ethyl esters
Salt, 2- (2- (3- fluorine benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acids carbethoxy hydrochloride, 2- (2- (2- hydroxyl benzyls hydrazono-)) -4-
Methyl thiazole-5-carboxyl acid carbethoxy hydrochloride, 2- (2- (4- hydroxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid carbethoxy hydrochlorides
Or 2- (2- (4- carboxyl benzyls hydrazono-)) -4- methyl thiazole-5-carboxyl acid carbethoxy hydrochlorides.
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| CN108503604B (en) * | 2018-04-24 | 2020-04-24 | 湖南大学 | (4-alkyl-5-acyl-2-thiazole) hydrazone derivatives and medical application thereof |
| CN111909082B (en) * | 2019-05-07 | 2022-09-13 | 湖南大学 | Pyridine hydrazone derivatives, and preparation method and application thereof |
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