CN105777664A - 2-(2-benzal hydrazine)thiazole-5-carboxylate and preparation method and medical application thereof - Google Patents
2-(2-benzal hydrazine)thiazole-5-carboxylate and preparation method and medical application thereof Download PDFInfo
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- 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
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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Abstract
The invention discloses 2-(2-benzal hydrazine)thiazole-5-carboxylate derivatives represented by the structural formula I and pharmaceutically acceptable salts thereof, and a preparation method, a pharmaceutical composition and an application thereof in an influenza virus neuraminidase inhibitor, wherein R is selected from C1-C2 alkyl, and C3-C4 straight-chain or C3-C4 branched-chain alkyl; R<1> is selected from hydrogen, C1-C2 alkyl, C3-C4 straight-chain or branched-chain alkyl, and trifluoromethyl; X<1> and X<5> are selected from hydrogen, deuterium, C1-C2 alkyl, hydroxyl, methoxyl, ethoxyl, fluorine, chlorine, bromine, iodine, and nitro; X<2> and X<4> are selected from hydrogen, deuterium, C1-C2 alkyl, C3-C4 straight-chain or branched-chain alkyl, hydroxyl, methoxyl, ethoxyl, fluorine, chlorine, bromine, iodine and nitro; and X<3> is selected from hydrogen, deuterium, C1-C2 alkyl, hydroxyl, methoxyl, ethoxyl, fluorine, chlorine, bromine, iodine, nitro, carboxyl or alkoxycarbonyl.
Description
Technical field
The present invention relates to a class noval chemical compound, its preparation method and application, specifically 2-(2-benzyl hydrazono-) thiazole-5-carboxylic acid ester
Derivative, its preparation method and preparing the application of influenza virus neuraminidase inhibitor.
Background technology
5-carboxylate thiazole hydrazone and the like has extensive biologically active, P.Makam etc. [Eur.J.Med.Chem., 2013.
69:564-576, Eur.J.Pharm.Sci., 2014.52:138-145] report series 2-(2-hydrazono-) thiazole
(A) there is good Killing Mycobacterium Tuberculosis effect and anti-malarial effect；A.Grozav etc. [Int.J.Mol.Sci., 2014.
15 (12): 22059-22072] synthesized serial benzyl hydrazono-thiazolium compounds (B), found that part of compounds is thin to two kinds of cancers
Born of the same parents (MDA-MB231 and HeLa) have obvious antiproliferative activity；M.H.Shin etc. [Chem.Pharm.Bull., 2007.
55 (8): 1126-1135] find that some aromatic rings substituted thiazole hydrazone (C) has certain non-oxidizability；[the Arch. such as A.Ignat
Pharm.Chem.Life Sci., 2012.345 (7): 574-583] find thiazole hydrazone (D) containing thiophene phenazinyl to colon cancer and
HCC has antiproliferative activity.
Chinese invention patent [CN104774199A] describes 2-(2-benzyl hydrazono-)-5-(1,2,4-triazol-1-yl) thiazole
Synthesis and the inhibitory activity of Neuraminidase in Influenza Virus thereof.
Summary of the invention
Present invention solves the technical problem that be to provide class 2-(2-benzyl hydrazono-) thiazole-5-carboxylic acid ester derivant, its preparation method,
Pharmaceutical composition and purposes.
For solving 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 class 2-(2-benzyl hydrazono-) thiazole-5-carboxylic acid as shown in structural formula I
Ester derivant:
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, ethoxy
Base, fluorine, chlorine, bromine, iodine, nitro；X2、X4It is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C4Straight or branched alkyl, hydroxyl
Base, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro；X3It is selected from: hydrogen, deuterium, C1～C2Alkyl, hydroxyl, methoxy
Base, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, carboxyl or alkoxy carbonyl group.
Class 2-(2-benzyl hydrazono-) the thiazole-5-carboxylic acid ester derivant that the first aspect of technical solution of the present invention also provides for is selected from down
Row compound:
2-(2-(3-methoxyl group-4-hydroxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid ethyl ester, 2-(2-(3-fluorine benzyl hydrazono-))-4-first
Base thiazole-5-carboxylic acid ethyl ester, 2-(2-(2,4-dihydroxy benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid ethyl ester, 2-(2-(3-methoxyl group
-2-hydroxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid ethyl ester, 2-(2-(4-methoxycarbonyl group benzyl hydrazono-))-4-methylthiazol-5-carboxylic
Acetoacetic ester or 2-(2-(4-carboxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid ethyl ester, its structural formula is as follows:
The second aspect of technical solution of the present invention there is provided the preparation method of 2-(2-benzyl hydrazono-) thiazole-5-carboxylic acid ester derivant,
It is characterized 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, ethoxy
Base, fluorine, chlorine, bromine, iodine, nitro；X2、X4It is selected from: hydrogen, deuterium, C1～C2Alkyl, C3～C4Straight or branched alkyl, hydroxyl
Base, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro；X3It is selected from: hydrogen, deuterium, C1～C2Alkyl, hydroxyl, methoxy
Base, ethyoxyl, fluorine, chlorine, bromine, iodine, nitro, carboxyl or alkoxy carbonyl group；HX is selected from: hydrochloric acid, hydrobromic acid.
The third aspect of technical solution of the present invention is to provide the medicine containing compound described in first aspect and pharmaceutically acceptable salt thereof
Compositions, this pharmaceutical composition contains 2-(2-benzyl hydrazono-) the thiazole-5-carboxylic acid ester derivant of the present invention of therapeutically effective amount
And pharmaceutically acceptable salt, and optional containing pharmaceutical carrier.Wherein said pharmaceutical carrier refers to what pharmaceutical field was commonly used
Pharmaceutical carrier；This pharmaceutical composition can be prepared according to method well known in the art.Can be by by the compounds of this invention and pharmaceutically
Acceptable salt and one or more pharmaceutically acceptable solids or liquid excipient and/or assistant agent combination, make and be suitable to people or dynamic
Any formulation that thing uses.The compounds of this invention and pharmaceutically acceptable salt content in its pharmaceutical composition thereof are usually
0.1%～95% percentage by weight.
The compounds of this invention and pharmaceutically acceptable salt or the pharmaceutical composition containing it thereof can be administered in a unit, give
Medicine approach can be enteron aisle or non-bowel, as oral, intravenous injection, intramuscular injection, hypodermic injection, nasal cavity, oral mucosa, 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 that solution (includes the most molten
Liquid and colloidal solution), emulsion (including o/w type, w/o type and emulsion), supensoid agent, injection (include liquid drugs injection, powder
Injection and transfusion), eye drops, nasal drop, lotion and liniment etc.；Solid dosage forms can be that tablet (includes ordinary tablet, enteric
Sheet, lozenge, dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (include hard shell capsules, soft capsule, enteric
Capsule), granule, powder, micropill, dripping pill, suppository, film, paster, gas (powder) mist agent, spray etc.；Half is solid
Body formulation can be ointment, gel, paste etc..
The compounds of this invention and pharmaceutically acceptable salt thereof can make ordinary preparation, also make be sustained release preparation, controlled release preparation,
Targeting preparation and various particulate delivery system.
In order to the compounds of this invention and pharmaceutically acceptable salt thereof are made tablet, can be widely used well known in the art various
Excipient, including diluent, binder, wetting agent, disintegrant, lubricant, glidant.Diluent can be starch, paste
Essence, sucrose, glucose, lactose, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, carbon
Acid calcium etc.；Wetting agent can be water, ethanol, isopropanol etc.；Adhesive can be starch slurry, dextrin, syrup, honey, Portugal
Grape sugar juice, 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, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, PVPP, Ac-Di-Sol,
Sodium carboxymethyl starch, sodium acid carbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, dodecyl sodium sulfate etc.；Lubrication
Agent and glidant can be talcum powder, silica, stearate, tartaric acid, atoleine, polyethylene glycol etc..
Tablet can also be made coating tablet, such as sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets further
And multilayer tablet.
In order to administration unit is made capsule, can be by active ingredient the compounds of this invention and pharmaceutically acceptable salt thereof with dilute
Release agent, glidant mixing, mixture is placed directly within hard shell capsules or soft capsule.Also can by active ingredient the compounds of this invention and
Its pharmaceutically acceptable salt first makes particle or micropill with diluent, binder, disintegrant, then is placed in hard shell capsules or soft capsule
In.For preparing each diluent of the compounds of this invention and pharmaceutically acceptable salt tablet thereof, binder, wetting agent, disintegration
Agent, glidant kind can also be used for preparing the capsule of the compounds of this invention and pharmaceutically acceptable salt thereof.
For the compounds of this invention and pharmaceutically acceptable salt thereof are made injection, can use water, ethanol, isopropanol, the third two
Alcohol or their mixture as solvent and add solubilizer the most commonly used in the art, cosolvent, pH adjust agent, osmotic pressure regulation
Agent.Solubilizer or cosolvent can be poloxamer, lecithin, HP-β-CD etc.；PH adjust agent can be phosphate,
Acetate, hydrochloric acid, NaOH etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetic acid
Salt etc..As prepared freeze drying powder injection, mannitol, glucose etc. also can be added as proppant.
Additionally, if desired, colouring agent, preservative, spices, flavouring or other additive can also be added in pharmaceutical preparation.
For reaching medication purpose, strengthening result for the treatment of, the medicine of the present invention or pharmaceutical composition can be by any known medication
It is administered.
The fourth aspect of technical solution of the present invention be to provide 2-of the present invention (2-benzyl hydrazono-) thiazole-5-carboxylic acid ester derivant and
Described in its pharmaceutically acceptable salt and the third aspect, pharmaceutical composition is in terms of preparing influenza virus neuraminidase inhibitor
Application.
2-(2-(2-hydroxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid ethyl ester, 2-(2-(4-hydroxyl benzyl hydrazono-))-4-methylthiazol
-5-carboxylic acid, ethyl ester or 2-(2-(3-methoxyl group-4-hydroxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid ethyl ester and pharmaceutically can connect
The salt being subject to application in influenza virus neuraminidase inhibitor.
Advantageous Effects:
2-(2-benzyl hydrazono-) the thiazole-5-carboxylic acid ester derivant of the present invention be a class new construction type to have influenza virus neural
The compound of propylhomoserin enzyme inhibition activity.
Detailed description of the invention
Following example are intended to illustrate rather than limitation of the invention further.
Embodiment 1
The preparation of 2-(2-(4-methoxycarbonyl group benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride (2a HCl)
1.18g (5mmol) 2-(4-methoxycarbonyl phenyl hydrazono-) thioformamide 1a and 0.84g (5.1mmol) 2-chloroethene
Ethyl acetoacetic acid ethyl ester is dissolved in 20mL absolute ethyl alcohol, and reflux 2h, cooling, suction filtration, and filter cake is successively with ethanol, saturated aqueous common salt
And washing, it is dried to obtain light yellow solid 2-(2-(4-methoxycarbonyl group benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride,
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 benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride neutralizes through NaOH solution and obtains
2-(2-(4-methoxycarbonyl group benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid ethyl ester.
Embodiment 2
The preparation of 2-(2-(2,4-dihydroxy benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride (2b HCl)
1.05g (5mmol) 2-(2,4-dihydroxy benzyl hydrazono-) thioformamide 1b and 0.84g (5.1mmol) 2-chloroethene
Ethyl acetoacetic acid ethyl ester is dissolved in 20mL absolute ethyl alcohol, and reflux 2h, pours in saturated aqueous common salt, separates out a large amount of pale solid,
Suction filtration, filter cake is successively with ethanol and washing, and ethanol/water recrystallizes to obtain pale solid 2-(2-(2,4-dihydroxy benzyl hydrazono-))-4-
Methyl thiazole-5-carboxyl acid carbethoxy 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 benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride neutralizes through NaOH solution and obtains
2-(2-(2,4-dihydroxy benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid ethyl ester.
Embodiment 3
The preparation of 2-(2-(3-methoxyl group-4-hydroxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride (2c HCl)
5mmol2-(3-methoxyl group-4-hydroxyl benzyl hydrazono-) thioformamide 1c and 5.1mmol 2-chloroacetyl acetacetic ester are molten
In 20mL absolute ethyl alcohol, reflux 2h, cooling, suction filtration, and filter cake with ethanol, saturated aqueous common salt and washing, is dried successively
Light yellow solid 2-(2-(3-methoxyl group-4-hydroxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride, 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 benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride neutralizes through NaOH solution
To 2-(2-(3-methoxyl group-4-hydroxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid ethyl ester.
Embodiment 4
The preparation of 2-(2-(3-fluorine benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride (2d HCl)
0.99g (5mmol) 2-(3-fluorine benzyl hydrazono-) thioformamide 1d and 0.84g (5.1mmol) 2-chloracetyl acetic acid
The tert-butyl ester is dissolved in 20mL absolute ethyl alcohol, and reflux 2h, cooling, suction filtration, and filter cake is successively with ethanol, saturated aqueous common salt and water
Wash, dry light yellow solid 2-(2-(3-fluorine benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride that to obtain, 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=7.2
Hz, 2H, OCH2), 2.48 (s, 3H, thiazole ring-CH3), 1.27 (t, J=7.2Hz, 3H, CH3)。
2-(2-(3-fluorine benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride neutralizes through NaOH solution and obtains 2-(2-(3-
Fluorine benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid ethyl ester.
Embodiment 5
The preparation of 2-(2-(3-methoxyl group-4-hydroxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid t-butyl ester hydrochloride (2e HCl)
1.13g (5mmol) 2-(3-methoxyl group-4-hydroxyl benzyl hydrazono-) thioformamide 1e and 0.84g (5.1mmol) 2-
Chloracetyl tert-butyl acetate is dissolved in 20mL absolute ethyl alcohol, and reflux 2h, cooling, suction filtration, and filter cake is successively with ethanol, saturated
Saline solution and washing, be dried to obtain white solid 2-(2-(3-methoxyl group-4-hydroxyl benzyl hydrazono-)) the tertiary fourth of-4-methyl thiazole-5-carboxyl acid
Ester hydrochloride, 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 benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid t-butyl ester hydrochloride neutralizes through NaOH solution
Obtain 2-(2-(3-methoxyl group-4-hydroxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid tert-butyl ester.
Embodiment 6
The preparation of 2-(2-(3-methoxyl group-2-hydroxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride (2f HCl)
0.76g (5mmol) o-vanillin, 0.455g (5mmol) thiosemicarbazides and 0.85g (5mmol) 2-chloroethene
Ethyl acetoacetic acid ethyl ester is dissolved in 25mL absolute ethyl alcohol, and reflux 6.8h, cooling, suction filtration, and filter cake ethanol is washed, and is dried white
Solid 2-(2-(3-methoxyl group-2-hydroxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride, 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 benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride neutralizes through NaOH solution
To 2-(2-(3-methoxyl group-2-hydroxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid ethyl ester.
Embodiment 7
The preparation of 2-(2-(2-hydroxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride (2g HCl)
0.61g (5mmol) salicylide, 0.455g (5mmol) thiosemicarbazides and 0.85g (5mmol) 2-chloracetyl
Ethyl acetate is dissolved in 25mL absolute ethyl alcohol, and reflux 0.8h, cooling, suction filtration, and filter cake ethanol is washed, dry that yellow is solid
Body 2-(2-(2-hydroxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride, 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 benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride neutralizes through NaOH solution and obtains 2-(2-(2-
Hydroxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid ethyl ester.
Embodiment 8
The preparation of 2-(2-(4-hydroxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride (2h HCl)
0.61g (5mmol) parahydroxyben-zaldehyde, 0.455g (5mmol) thiosemicarbazides and 0.85g (5mmol) 2-
Chloroacetyl acetacetic ester is dissolved in 25mL absolute ethyl alcohol, and reflux 7.4h, cooling, suction filtration, and filter cake ethanol is washed, and is dried
Yellow solid 2-(2-(4-hydroxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride, yield 55.5%, m.p.
170～172 DEG C.1H NMR (400MHz, DMSO-d6) δ: 8.06 (s, 1H ,=CH), 7.52 (d, J=8.8
Hz, 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 benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride neutralizes through NaOH solution and obtains 2-(2-(4-
Hydroxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid ethyl ester.
Embodiment 9
The preparation of 2-(2-(4-carboxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride (2i HCl)
0.75g (5mmol) p-carboxybenzaldehyde, 0.455g (5mmol) thiosemicarbazides and 0.85g (5mmol) 2-
Chloroacetyl acetacetic ester is dissolved in 25mL absolute ethyl alcohol, and reflux 7.5h, cooling, suction filtration, and filter cake ethanol is washed, and is dried
Yellow solid 2-(2-(4-carboxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride, 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 benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid carbethoxy hydrochloride neutralizes through NaOH solution and obtains 2-(2-(4-
Carboxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid ethyl ester.
Embodiment 10
The resisiting influenza virus neuraminidase activity of 2-(2-benzyl hydrazono-) thiazole-5-carboxylic acid ester derivant
1. experimental principle
Compound MUNANA is the specific substrate of neuraminidase, and the metabolite produced under neuraminidase effect exists
360nm irradiates and excites down, can produce 450nm fluorescence, and the change of fluorescence intensity can be reacted neuraminidase delicately and be lived
Property.Enzyme both is from A/PR/8/34 (H1N1) virus stain.
2. experimental technique
In enzyme reaction system, finite concentration sample and influenza virus god NA are suspended in reaction buffer (pH 6.5), add
Enter fluorogenic substrate MUNANA and start reaction system, after 37 DEG C hatch 40 minutes, add reaction terminating liquid and terminate reaction.Swashing
Send out under the Parameter Conditions of wavelength 360nm and a length of 450nm of transmitted wave, measure fluorescence intensity level.The fluorescence intensity of reaction system
The activity of enzyme can be reflected.Decrement according to fluorescence intensity can calculate the compound inhibiting rate to NA activity.
3. detection sample: embodiment compound
4. Activity Results
Preferred compound inhibiting rate and IC to neuraminidase during detectable concentration 40.0 μ g/mL in reaction system50Value lists table in
1:
Table 1 2-(2-benzyl hydrazono-) the thiazole-5-carboxylic acid ester derivant inhibitory activity to neuraminidase
2-(2-benzyl hydrazono-) thiazole-5-carboxylic acid ester derivant has resisiting influenza virus neuraminidase activity, can be used for preparation stream
Influenza Virus neuraminidase inhibitor.
Claims (4)
1. 2-(2-benzyl hydrazono-) the thiazole-5-carboxylic acid ester derivant shown in a class chemical structural formula I and pharmaceutically can connecing
The salt being subject to:
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, nitre
Base；
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.
2. 2-(2-benzyl hydrazono-) the thiazole-5-carboxylic acid ester derivant described in claim 1 and pharmaceutically acceptable salt thereof,
It is characterized in that, described compound is selected from:
2-(2-(3-methoxyl group-4-hydroxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid ethyl ester,
2-(2-(3-fluorine benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid ethyl ester,
2-(2-(2,4-dihydroxy benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid ethyl ester,
2-(2-(3-methoxyl group-2-hydroxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid ethyl ester,
2-(2-(4-methoxycarbonyl group benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid ethyl ester,
2-(2-(4-carboxyl benzyl hydrazono-))-4-methyl thiazole-5-carboxyl acid ethyl ester.
3. the preparation method of 2-(2-benzyl hydrazono-) the thiazole-5-carboxylic acid ester derivant described in claim 1, its feature exists
Preparation in it reacts as follows:
In formula, R, R1、X1～X5As claimed in claim 1, HX is selected from: hydrochloric acid, hydrobromic acid.
4. 2-(2-benzyl hydrazono-) the thiazole-5-carboxylic acid ester derivant described in any one of claim 1～2 is sick in preparation influenza
Application in poison neuraminidase inhibitor.
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| CN111100074A (en) * | 2019-07-02 | 2020-05-05 | 南华大学 | Pyridazine hydrazone derivative and preparation method and application thereof |
| CN111909082A (en) * | 2019-05-07 | 2020-11-10 | 湖南大学 | Pyridine hydrazone derivatives, and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107987033A (en) * | 2018-01-05 | 2018-05-04 | 湖南大学 | The application of vanillic aldehyde and its isomers in NA inhibitor is prepared |
| CN108503604A (en) * | 2018-04-24 | 2018-09-07 | 湖南大学 | (4- alkyl -5- acyl group -2- thiazoles) hydazone derivative and its medical usage |
| CN111909082A (en) * | 2019-05-07 | 2020-11-10 | 湖南大学 | Pyridine hydrazone derivatives, and preparation method and application thereof |
| CN111909082B (en) * | 2019-05-07 | 2022-09-13 | 湖南大学 | Pyridine hydrazone derivatives, and preparation method and application thereof |
| CN111100074A (en) * | 2019-07-02 | 2020-05-05 | 南华大学 | Pyridazine hydrazone derivative and preparation method and application thereof |
| CN111100074B (en) * | 2019-07-02 | 2022-10-28 | 南华大学 | Pyridazine hydrazone derivative and preparation method and application thereof |
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