CN107235927B - N- (5- acyl group thiazol-2-yl) piperazinyl amide and its medical usage - Google Patents
N- (5- acyl group thiazol-2-yl) piperazinyl amide and its medical usage Download PDFInfo
- Publication number
- CN107235927B CN107235927B CN201710482836.3A CN201710482836A CN107235927B CN 107235927 B CN107235927 B CN 107235927B CN 201710482836 A CN201710482836 A CN 201710482836A CN 107235927 B CN107235927 B CN 107235927B
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- Prior art keywords
- alkyl
- base
- straight chained
- alkoxy
- branched
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- IYPZRUYMFDWKSS-UHFFFAOYSA-N piperazin-1-amine Chemical compound NN1CCNCC1 IYPZRUYMFDWKSS-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 56
- 150000001875 compounds Chemical class 0.000 claims description 26
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 21
- -1 C1 ~C2Alkoxy Chemical group 0.000 claims description 17
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 14
- 229940080818 propionamide Drugs 0.000 claims description 14
- 102000005348 Neuraminidase Human genes 0.000 claims description 13
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- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 206010022000 influenza Diseases 0.000 claims description 8
- GPEOAEVZTOQXLG-UHFFFAOYSA-N 4-piperazin-1-ium-1-ylphenolate Chemical compound C1=CC(O)=CC=C1N1CCNCC1 GPEOAEVZTOQXLG-UHFFFAOYSA-N 0.000 claims description 7
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 claims description 7
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
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- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
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- VNZLQLYBRIOLFZ-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazine Chemical compound COC1=CC=CC=C1N1CCNCC1 VNZLQLYBRIOLFZ-UHFFFAOYSA-N 0.000 claims description 3
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- XWINCPYLXQTPQV-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1.C1CNCCN1 XWINCPYLXQTPQV-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses (5- acyl group thiazol-2-yl) the piperazinyl amide of N- shown in structural formula I and II and its pharmaceutically acceptable salt, preparation method and pharmaceutical composition and its preparing the application in influenza virus neuraminidase inhibitor.
Description
Technical field
The present invention relates to a kind of noval chemical compound, preparation method and application, specifically N- (5- acyl group thiazol-2-yl) piperazines
Base amide, preparation method and its in the application for preparing resisiting influenza virus neuraminidase inhibitor.
Background technique
Gurdal etc. [J Enzyme Inhibition and Med Chem, 2015,30 (4): 649-654] describes 4-
Pyridylpiperazine acetamide derivative 1 is to human colon cancer cell HCT-116, human breast cancer cell line Bcap-37 and human liver cancer cell
The inhibitory activity of HUH-7 is preferable；Wherein, 5 FU 5 fluorouracil is better than to the inhibitory activity of HCT-116 and HUH-7.Abou-Seri etc.
It is raw to blood vessel endothelium that [Eur J Med Chem, 2016,107:165-179] describes 4- pyridazinyl piperazineacetamide derivative 2
The inhibitory activity of growth factor receptor body -2 (VEGFR-2) kinases, IC50It is 0.40 ± 0.04 μM, with vatarani (IC500.18±
0.02 μM) it is close.
El-Messery and Hassan etc. [Eur J Med Chem, 2012,54:615-625；Bioorg&Med Chem
Lett, 2012,22 (20): 6318-6323] to describe N- [thiazol-2-yl] piperazine second/propanamide derivative 3 thin to a variety of cancers
The external inhibitory activity of born of the same parents is higher.
Hoi etc. [Bioorg&Med Chem Lett, 2012,22 (16): 5297-5302] describes 4- Acetylpiperazine third
Amide derivatives 4 to the inhibitory activity of wild type (wild-type) oncogenic kinase (oncogenic kinase) Bcr-Abl,
EC50It is 5.21 μM.
It Zhangs younger sister equal [Chinese journal of Medicinal Chemistry, 2016 (1): 1-9] and passes through bioisosterism and principle of hybridization, with
Nucleozin is lead compound, has designed and synthesized isoxazole piperazine ring amides influenza nucleoprotein inhibitor, activity
Test discovery part of compounds anti-influenza virus activity is better than positive control Ribavirin；Wherein, isoxazole formyl piperazine chemical combination
5 activity of object is preferable, EC50Value is 2.7 μM.
Yanmei ZHANGs etc. [CN104447625B, 2016.08.12] describe the benzamide compound containing piperazine ring,
Host cell can be entered by apparent blocking virus nucleoprotein in vitro, show the activity for significantly inhibiting influenza virus.Activity
The IC of preferable compound 6~850Value is respectively 1.2 μM, 1.1 μM and 0.8 μM.
Hung etc. [Antiviral Research, 2009,81 (2): 123-131] is determined a variety of by high flux screening
The marketed drug of purposes is to the inhibitory activity of neuraminidase influenza, wherein NA suppression of the ketoconazole (9) under 50 μM of test concentrations
System activity is 72.2%.
Ye etc. [Eur J Med Chem, 2012,54 (12): 764-770] tests the zanamivir modified with piperazine ring
Analog is to the inhibitory activity of influenza NA, wherein the IC of the compound 10 and 11 pair H3N2 containing piperazine ring50Value respectively 836.3 ±
267.2 μM and 271.3 ± 153.3 μM, to the IC of H5N150Value is respectively 760.8 ± 30.5 μM and 122.3 ± 60.5 μM.
Wen etc. [Bioorg&Med Chem, 2010,18 (11): 4074-84] describes the zanamivir class of C-4 modifications
Like the inhibitory activity of object Neuraminidase in Influenza Virus；The wherein IC of the compound 12 and 13 pair H1N1NA containing piperazine ring50Value
Respectively 2.15 μM and 6.50 μM；EC50Value is respectively 0.77 μM and 10.7 μM.
Summary of the invention
The technical problem to be solved by the present invention is to provide a kind of N- (5- acyl group thiazol-2-yl) piperazinyl amides, its preparation side
Method, pharmaceutical composition and purposes.
To solve technical problem of the invention, the invention provides the following technical scheme:
The first aspect of technical solution of the present invention provides one kind N- as shown in structural formula I (5- acyl group thiazol-2-yl)
Piperazinyl amide and its pharmaceutically acceptable salt:
R in formula1It is selected from: H, C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；R2It is selected from: C1~C2Alkane
Base, C3~C4Straight chained alkyl or C3~C4Branched alkyl, C1~C2Alkoxy, C3~C4Unbranched alkoxy or C3~C4Branch alcoxyl
Base；R3It is selected from: H, C1~C2Alkyl, C3~C6Straight chained alkyl；R4It is selected from: H, C1~C2Alkyl, C3~C4Straight chained alkyl；R5It is selected from:
C1~C2Alkyl, C3~C6Straight chained alkyl or C3~C6Branched alkyl, methylol or ethoxy；N is selected from: 1,2,3,4,5 or 6.
The first aspect of technical solution of the present invention additionally provides one kind N- as shown in structural formula II (5- acyl group thiazole -2-
Base) piperazinyl amide and its pharmaceutically acceptable salt:
R in formula1It is selected from: H, C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；R2It is selected from: C1~C2Alkane
Base, C3~C4Straight chained alkyl or C3~C4Branched alkyl, C1~C2Alkoxy, C3~C4Unbranched alkoxy or C3~C4Branch alcoxyl
Base；R3—R4It is selected from: H, C1~C2Alkyl, C3~C6Straight chained alkyl or C3~C6Branched alkyl；N is selected from: 1,2,3,4,5 or 6；Y1
It is selected from: hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy or SH；Y2It is selected from: hydrogen, C1~C2Alkyl；Y3It is selected from: hydrogen, C1~C2Alkane
Base, hydroxyl, C1~C2Alkoxy, methylol, ethoxy or SH.
Further, preferred compound is selected from:
N- (5- acetyl group -4- methylthiazol -2- base) -2- (4- methylpiperazine-1-yl) acetamide, N- (5- acetyl group -4-
Methylthiazol -2- base) -2- (4- ethyl piperazidine -1- base) acetamide, N- (5- acetyl group -4- methylthiazol -2- base) -2- (4- benzene
Base piperazine -1- base) acetamide, N- (5- acetyl group -4- methylthiazol -2- base) -2- [4- (4- hydroxy phenyl) piperazine -1- base)]
Acetamide, N- (5- acetyl group -4- methylthiazol -2- base) -3- (4- phenylpiperazine -1- base) propionamide, N- (5- acetyl group -4-
Methylthiazol -2- base) and -3- [4- (2- methoxyphenyl) piperazine -1- base)] propionamide, N- (5- acetyl group -4- methylthiazol -2-
Base) -3- [4- methylpiperazine-1-yl)] propionamide or N- (5- acetyl group -4- methylthiazol -2- base) -3- [4- (4- hydroxy benzenes
Base) piperazine -1- base)] propionamide.
There is provided (the 5- acyl group thiophenes of N- shown in general formula II described in first aspect for the second aspect of technical solution of the present invention
Azoles -2- base) piperazinyl amide preparation method, it is characterised in that it preparation reaction it is as follows:
R in formula1It is selected from: H, C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；R2It is selected from: C1~C2Alkane
Base, C3~C4Straight chained alkyl or C3~C4Branched alkyl, C1~C2Alkoxy, C3~C4Unbranched alkoxy or C3~C4Branch alcoxyl
Base；R3It is selected from: H, C1~C2Alkyl, C3~C6Straight chained alkyl；R4It is selected from: H, C1~C2Alkyl, C3~C4Straight chained alkyl；R5It is selected from:
C1~C2Alkyl, C3~C6Straight chained alkyl or C3~C6Branched alkyl, methylol or ethoxy；N is selected from: 1,2,3,4,5 or 6；X choosing
From: chlorine, bromine or iodine.
There is provided (the 5- acyl group thiophenes of N- shown in general formula II described in first aspect for the second aspect of technical solution of the present invention
Azoles -2- base) piperazinyl amide preparation method, it is characterised in that it preparation reaction it is as follows:
R in formula1It is selected from: H, C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；R2It is selected from: C1~C2Alkane
Base, C3~C4Straight chained alkyl or C3~C4Branched alkyl, C1~C2Alkoxy, C3~C4Unbranched alkoxy or C3~C4Branch alcoxyl
Base；R3—R4It is selected from: H, C1~C2Alkyl, C3~C6Straight chained alkyl or C3~C6Branched alkyl；N is selected from: 1,2,3,4,5 or 6；Y1
It is selected from: hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy or SH；Y2It is selected from: hydrogen, C1~C2Alkyl；Y3It is selected from: hydrogen, C1~C2Alkane
Base, hydroxyl, C1~C2Alkoxy, methylol, ethoxy or SH；X is selected from: chlorine, bromine or iodine.
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, which contains N- (5- acyl group thiazol-2-yl) piperazine of the invention of therapeutically effective amount
Base amide and its pharmaceutically acceptable salt, and optional contain pharmaceutical carrier.Wherein the pharmaceutical carrier refers to that pharmacy is led
The common pharmaceutical carrier in domain；The pharmaceutical composition can be prepared according to method well known in the art.It can be by by the compounds of this invention
And its pharmaceutically acceptable salt is combined with one or more pharmaceutically acceptable solids or liquid excipient and/or adjuvant,
It is made and is suitable for any dosage form that human or animal uses.The compounds of this invention and its pharmaceutically acceptable salt are in its pharmaceutical composition
In content be usually 0.1%~95% weight percent.
The compounds of this invention and its pharmaceutically acceptable salt can be in a unit containing its pharmaceutical composition
Administration, administration route can be enteron aisle or non-bowel, and such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral cavity are viscous
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 type, w/o type and emulsion), suspension, injection (including liquid drugs injection, powder-injection
And infusion), 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 capsule, soft capsule, capsulae enterosolubilis), granule, dissipate
Agent, pellet, dripping pill, suppository, film, patch, 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 tablet is made in the compounds of this invention and its pharmaceutically acceptable salt, can be widely used known in this field
Various excipient, including diluent, binder, wetting agent, disintegrating agent, 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, ethyl alcohol, 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.；It is fine that disintegrating agent can be dried starch, crystallite
Tie up element, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, carbon
Sour hydrogen sodium and citric acid, polyoxyethylene sorbitol aliphatic 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 double
Synusia and multilayer tablet.
It, can be by effective component the compounds of this invention and its pharmaceutically acceptable in order to which capsule is made in administration unit
Salt is mixed with diluent, glidant, and mixture is placed directly in hard capsule or soft capsule.It can also be by the effective component present inventionization
Close object and its pharmaceutically acceptable salt and particle or pellet first be made with diluent, binder, disintegrating agent, then be placed in hard capsule or
In soft capsule.It is used to prepare the compounds of this invention and its each diluent of pharmaceutically acceptable salt tablet, binder, wetting
Agent, disintegrating agent, glidant kind can also be used for preparing the capsule of the compounds of this invention and its pharmaceutically acceptable salt.
For injection is made in the compounds of this invention and its pharmaceutically acceptable salt, can with water, ethyl alcohol, isopropanol,
Simultaneously appropriate solubilizer commonly used in the art, cosolvent, pH adjustment agent, osmotic pressure is added in propylene glycol or their mixture as solvent
Regulator.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 also be added as proppant.
In addition, if desired, colorant, preservative, fragrance, corrigent or other additions can also be added into pharmaceutical preparation
Agent.
To reach medication purpose, enhance therapeutic effect, drug of the invention or pharmaceutical composition well known can be given with any
The administration of prescription method.
The fourth aspect of technical solution of the present invention is to provide N- described in first aspect present invention (5- acyl group thiazol-2-yl) piperazine
Piperazine base amide and its pharmaceutically acceptable salt and third aspect described pharmaceutical composition are preparing influenza virus neuraminidase
Application in terms of enzyme inhibitor.
Advantageous effects:
N- (5- acyl group thiazol-2-yl) piperazinyl amide of the invention is a kind of new construction type with influenza virus mind
Compound through propylhomoserin enzyme inhibition activity.
Specific embodiment
Following embodiment is intended to illustrate invention rather than limitation of the invention further.
Embodiment 1
The preparation of N- (5- acetyl group -4- methylthiazol -2- base) -3- chlorine propionamide
75mmol 3- chloropropionic acid and 75mmol DCC are dissolved in 60mL methylene chloride, put into catalyst DMAP 2g, and system becomes
Yellowly stirs the hydrobromate 4.8g that 2- amino -4- methylthiazol -5- ethyl ketone is added after ten minutes at room temperature, and yellow disappears,
About 48h is stirred at room temperature, filters, methylene chloride washs filter cake, and filtrate successively uses saturated salt solution and saturation NaHCO3It washs for several times,
Water layer is extracted with dichloromethane, and merges organic layer, and anhydrous sodium sulfate is dry, and column chromatographs (VPetroleum ether: VEthyl acetate=2:1), revolving recycling
Solvent seasoning obtains white powder N- (4- methyl -5- acetylthiazole -2- base) -3- chlorine propionamide 5.84g, yield 70.3%,
M.p.163~166 DEG C,1HNMR (400MHz, CDCl3) δ: 2.52 (s, 3H, CH3), 2.64 (s, 3H, CH3), 2.96 (t, J=
6.3Hz, 2H, COCH2), 3.90 (t, J=6.2Hz, 2H, CH2)。
Embodiment 2
The preparation of N- (5- acetyl group -4- methylthiazol -2- base) -2- (4- methylpiperazine-1-yl) acetamide
0.86mmol N- (5- acetyl group -4- methylthiazol -2- base) -2- chloracetyl, 5mL THF, 1.72mmol N- first
Base piperazine and 0.86mmol triethylamine, stirring at normal temperature 8h；After having reacted, recycling design, methylene chloride dissolution, saturated common salt are rotated
Washing collects, merges organic layer, and anhydrous sodium sulfate is dry, adds petroleum ether that solid is precipitated, and filters, filter cake petroleum ether and a small amount of
Dehydrated alcohol is washed, dry, obtains pale yellow powder N- (5- acetyl group -4- methylthiazol -2- base) -2- (4- methylpiperazine-1-yl)
Acetamide 0.19g, yield 74.5%, m.p.135~137 DEG C,1HNMR (400MHz, CDCl3) δ: 2.34 (s, 3H, NCH3),
2.52 (s, 7H, piperazine+CH3), 2.67 (s, 7H, piperazine+CH3CO), 3.28 (s, 2H, COCH2), 10.34 (s, 1H, NH).
Embodiment 3
The preparation of N- (5- acetyl group -4- methylthiazol -2- base) -2- (4- ethyl piperazidine -1- base) acetamide
0.64mmol N- (5- acetyl group -4- methylthiazol -2- base) -2- chloracetyl, 5mL THF, 1.28mmol N- second
Base piperazine and 0.64mmol triethylamine, stirring at normal temperature 6h；After having reacted, recycling design, methylene chloride dissolution, saturated common salt are rotated
Washing collects, merges organic layer, and anhydrous sodium sulfate is dry, adds petroleum ether that solid is precipitated, and filters, filter cake petroleum ether and a small amount of
Dehydrated alcohol is washed, dry pale yellow powder N- (5- acetyl group -4- methylthiazol -2- base) -2- (4- ethyl piperazidine -1- base) second
Amide 0.15g, yield 75.2%, m.p.138~141 DEG C,1HNMR (400MHz, CDCl3) δ: 1.11 (t, J=7.2Hz, 3H,
CH3), 2.47 (q, J=7.2Hz, 2H, CH2), 2.52 (s, 4H, piperazines), 2.57 (s, 3H, CH3), 2.66 (s, 4H, piperazines),
2.68 (s, 3H, CH3CO), 3.28 (s, 2H, COCH2), 10.35 (s, 1H, NH).
Embodiment 4
The preparation of N- (5- acetyl group -4- methylthiazol -2- base) -2- (4- phenylpiperazine -1- base) acetamide
0.60mmol N- (5- acetyl group -4- methylthiazol -2- base) -2- chloracetyl, 5mL THF, 1.28mmol N- benzene
Base piperazine and 0.60mmol triethylamine, stirring at normal temperature 5h；Recycling design, methylene chloride dissolution are rotated, saturated common salt water washing is received
Collection merges organic layer, and anhydrous sodium sulfate is dry, adds petroleum ether that solid is precipitated, and ethyl alcohol recrystallization filters, filter cake petroleum ether and
Ice ethanol washing, dry white powder N- (5- acetyl group -4- methylthiazol -2- base) -2- (4- phenylpiperazine -1- base) acetyl
Amine 0.13g, yield 60.5%, m.p.175~178 DEG C,1HNMR (400MHz, CDCl3) δ: 2.52 (s, 3H, CH3), 2.66 (s,
3H, CH3CO), 2.80 (t, J=4.4Hz, 4H, piperazine), 3.28 (t, J=4.4Hz, 4H, piperazines), 3.35 (s, 2H, COCH2),
6.90~7.30 (m, 5H, C6H5), 10.37 (s, 1H, NH).
Embodiment 5
The preparation of N- (5- acetyl group -4- methylthiazol -2- base) -2- [4- (4- hydroxy phenyl) piperazine -1- base)] acetamide
1.50mmol N- (5- acetyl group -4- methylthiazol -2- base) -2- chloroacetamide, 5mLTHF, 0.90mmol 1-
(4- hydroxy phenyl) piperazine and 0.60mmol triethylamine, stirring at normal temperature 23h；Rotate recycling design, methylene chloride dissolution, saturation food
Salt water washing collects, merges organic layer, and anhydrous sodium sulfate is dry, adds petroleum ether that solid is precipitated, and ethyl alcohol recrystallization filters, filter cake
With petroleum ether and ice ethanol washing, dry white powder N- (5- acetyl group -4- methylthiazol -2- base) -2- [4- (4- hydroxyl
Phenyl) piperazine -1- base] acetamide 0.16g, yield 28.5%, m.p.200~202 DEG C,1HNMR (400MHz, CDCl3) δ: 2.53
(s, 3H, CH3), 2.68 (s, 3H, CH3CO), 2.73 (t, J=4.0Hz, 4H, piperazine), 2.89 (t, J=4.0Hz, 4H, piperazines),
3.32 (s, 2H, COCH2), 6.76 (d, J=8.8Hz, 2H, C6H42,6-H), 6.81 (d, J=8.8Hz, 2H, C6H43,5-H).
Embodiment 6
The preparation of N- (5- acetyl group -4- methylthiazol -2- base) -3- (4- phenylpiperazine -1- base) propionamide
0.813mmol N- (5- acetyl group -4- methylthiazol -2- base) -3- chlorine propionyl, 5mL THF, 1.6mmol N- benzene
Base piperazine and 0.86mmol triethylamine, stirring at normal temperature 8h；Recycling design, methylene chloride dissolution are rotated, saturated common salt water washing is received
Collection merges organic layer, and anhydrous sodium sulfate is dry, adds petroleum ether that solid is precipitated, and ethyl alcohol recrystallization filters, filter cake petroleum ether and
Ice ethanol washing, dry pale powder N- (5- acetyl group -4- methylthiazol -2- base) -2- (4- phenylpiperazine -1- base) third
Amide 0.22g, yield 73%, m.p.184~186 DEG C,1HNMR (400MHz, CDCl3) δ: 2.49 (s, 3H, CH3), 2.60 (s,
3H, CH3CO), 2.66~2.70 (m, 2H, COCH2), 2.79~2.81 (m, 2H, CH2), 2.81~2.85 (m, 4H, piperazines),
3.35~3.40 (m, 4H, piperazines), 6.91~7.30 (m, 5H, C6H5), 12.71 (s, 1H, NH).
Embodiment 7
The system of N- (5- acetyl group -4- methylthiazol -2- base) -3- [4- (2- methoxyphenyl) piperazine -1- base)] propionamide
It is standby
0.813mmol N- (5- acetyl group -4- methylthiazol -2- base) -3- chlorine propionyl, 5mL THF, 1.6mmol 1- (2-
Anisyl) piperazine and 0.86mmol triethylamine, stirring at normal temperature 7h；Rotate recycling design, methylene chloride dissolution, saturated salt solution
Washing collects, merges organic layer, and anhydrous sodium sulfate is dry, adds petroleum ether that solid is precipitated, and ethyl alcohol recrystallization filters, filter cake stone
Oily ether and ice ethanol washing obtain white powder N- (5- acetyl group -4- methylthiazol -2- base) -2- [4- (2- methoxy benzene after dry
Base) piperazine -1- base] propionamide 0.26g, yield 80%, m.p.164~166 DEG C,1HNMR (400MHz, CDCl3) δ: 2.50 (s,
3H, CH3), 2.62 (s, 3H, CH3CO), 2.69 (s, 2H, COCH2) 2.86 (m, 6H, piperazine, CH2), 3.27 (s, 4H, piperazines),
3.89 (s, 3H, OCH3), 6.90~7.06 (m, 4H, C6H4), 12.89 (s, 1H, NH).
Embodiment 8
The preparation of N- (5- acetyl group -4- methylthiazol -2- base) -3- [4- methylpiperazine-1-yl)] propionamide
0.813mmol N- (5- acetyl group -4- methylthiazol -2- base) -3- chlorine propionamide, 5mL THF, 0.813mmol first
18h is reacted in base piperazine and 0.86mmol triethylamine, stirring at normal temperature, TLC monitoring；Recycling design is rotated, methylene chloride dissolution is satisfied
And brine It, it collects, merge organic layer, anhydrous sodium sulfate is dry, and add petroleum ether to be precipitated solid, re-crystallizing in ethyl acetate,
It filters, filter cake petroleum ether and ice ethanol washing, obtains pale yellow powder shape solid N- (5- acetyl group -4- methylthiazol-after dry
2- yl) -3- [4- methylpiperazine-1-yl)] propionamide 0.18g, yield 72.0%, m.p.169~171 DEG C,1HNMR (400MHz,
CDCl3) δ: 2.33 (s, 3H, CH3), 2.46 (s, 3H, CH3), 2.57~2.63 (m, 13H, CH2NCH2×2+COCH2+NCH3),
2.74 (t, J=5.6Hz, 2H, NCH2), 4.81 (s, 1H, NH).
Embodiment 9
The preparation of N- (5- acetyl group -4- methylthiazol -2- base) -3- [4- (4- hydroxy phenyl) piperazine -1- base)] propionamide
0.813mmol N- (5- acetyl group -4- methylthiazol -2- base) -3- chlorine propionamide, 5mL THF, 1.60mmol 4-
18h is reacted in hydroxy phenyl piperazine and 0.86mmol triethylamine, stirring at normal temperature, TLC monitoring；Recycling design is rotated, methylene chloride is molten
Solution, saturated common salt water washing collect, merge organic layer, and anhydrous sodium sulfate is dry, and petroleum ether is added to be precipitated solid, ethyl alcohol recrystallization,
It filters, filter cake petroleum ether and ice ethanol washing, obtains lavender pulverulent solids N- (5- acetyl group -4- methylthiazol-after dry
2- yl) -3- [4- (4- hydroxy phenyl) piperazine -1- base)] propionamide 0.22g, yield 69.8%, m.p.171~173 DEG C,1HNMR
(400MHz, DMSO) δ: 2.47 (s, 3H, CH3), 2.55 (d, J=6.0Hz, 7H, CH3+(CH2)2), 2.68 (m, 4H, piperazines),
2.94 (s, 4H, piperazines), 6.77 (d, J=8.5Hz, 2H, C6H4), 8.80 (s, 1H, NH), 12.49 (s, 1H, OH).
Embodiment 10
The resisiting influenza virus neuraminidase activity of N- (5- acyl group thiazol-2-yl) piperazinyl amide and its salt
1. experimental principle
Compound MUNANA is the specific substrate of neuraminidase, the metabolite generated under neuraminic acid enzyme effect
Under 360nm irradiation excitation, 450nm fluorescence can produce, the variation of fluorescence intensity can delicately reflect neuraminidase activity.
Enzyme is all from A/PR/8/34 (H1N1) virus stain.
2. experimental method
In enzyme reaction system, a certain concentration sample and influenza neuraminidase NA are suspended in reaction buffer
(pH6.5), fluorogenic substrate MUNANA is added and starts reaction system, 37 DEG C are incubated for after forty minutes, and reaction terminating liquid is added to terminate reaction.
Under the Parameter Conditions that excitation wavelength 360nm and launch wavelength are 450nm, fluorescence intensity level is measured.According to subtracting for fluorescence intensity
Compound can be calculated on a small quantity to the active inhibiting rate of NA.
3. test sample: embodiment compound
4. Activity Results
Preferred compound is in reaction system to the inhibiting rate and its IC of neuraminidase when 40.0 μ g/mL of detectable concentration50
It is worth tabulated below 1:
Inhibitory activity of 1 N- of table (5- acyl group thiazol-2-yl) the piperazinyl amide to neuraminidase
N- (5- acyl group thiazol-2-yl) piperazinyl amide has good resisiting influenza virus neuraminidase activity, can use
In preparing influenza virus neuraminidase inhibitor.
Claims (10)
1. N- (5- acyl group thiazol-2-yl) piperazinyl amide and its pharmaceutically acceptable salt shown in a kind of chemical structural formula I:
R in formula1It is selected from: H, C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；R2It is selected from: C1~C2Alkyl, C3~
C4Straight chained alkyl or C3~C4Branched alkyl, C1~C2Alkoxy, C3~C4Unbranched alkoxy or C3~C4Branched alkoxy；R3Choosing
From: H, C1~C2Alkyl, C3~C6Straight chained alkyl；R4It is selected from: H, C1~C2Alkyl, C3~C4Straight chained alkyl；R5It is selected from: C1~C2Alkane
Base, C3~C6Straight chained alkyl or C3~C6Branched alkyl, methylol or ethoxy；N is selected from: 1,2,3,4,5 or 6；
Wherein: the compound that the compound of formula I does not comprise the following structure:
2. N- (5- acyl group thiazol-2-yl) piperazinyl amide shown in a kind of chemical structural formula II and its pharmaceutically acceptable
Salt:
R in formula1It is selected from: H, C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；R2It is selected from: C1~C2Alkyl, C3~
C4Straight chained alkyl or C3~C4Branched alkyl, C1~C2Alkoxy, C3~C4Unbranched alkoxy or C3~C4Branched alkoxy；R3—R4
It is selected from: H, C1~C2Alkyl, C3~C6Straight chained alkyl or C3~C6Branched alkyl；N is selected from: 1,2,3,4,5 or 6；Y1It is selected from: hydrogen, C1
~C2Alkyl, hydroxyl, C1~C2Alkoxy or SH；Y2It is selected from: hydrogen, C1~C2Alkyl；Y3It is selected from: hydrogen, C1~C2Alkyl, hydroxyl, C1
~C2Alkoxy, methylol, ethoxy or SH；
Wherein: the compound that the Formula II compound does not comprise the following structure:
3. N- (5- acyl group thiazol-2-yl) piperazinyl amide described in claim 1 and its pharmaceutically acceptable salt, feature
It is, the compound is selected from:
N- (5- acetyl group -4- methylthiazol -2- base) -2- (4- methylpiperazine-1-yl) acetamide, N- (5- acetyl group -4- methyl
Thiazol-2-yl) -2- (4- ethyl piperazidine -1- base) acetamide or N- (5- acetyl group -4- methylthiazol -2- base) -3- [4- methyl
Piperazine -1- base)] propionamide.
4. N- (5- acyl group thiazol-2-yl) piperazinyl amide as claimed in claim 2 and its pharmaceutically acceptable salt, feature
It is, the compound is selected from:
N- (5- acetyl group -4- methylthiazol -2- base) -2- (4- phenylpiperazine -1- base) acetamide, N- (5- acetyl group -4- methyl
Thiazol-2-yl) and -2- [4- (4- hydroxy phenyl) piperazine -1- base)] acetamide, N- (5- acetyl group -4- methylthiazol -2- base) -3-
(4- phenylpiperazine -1- base) propionamide, N- (5- acetyl group -4- methylthiazol -2- base) -3- [4- (2- methoxyphenyl) piperazine -
1- yl)] and propionamide or N- (5- acetyl group -4- methylthiazol -2- base) -3- [4- (4- hydroxy phenyl) piperazine -1- base)] propionyl
Amine.
5. the preparation method of 2- (5- acyl group thiazole -2- imino group) -4- thiazolinone described in claim 1, it is characterised in that
Its preparation reaction is as follows:
In formula, n, R1~R5As described in claim 1；X is selected from: chlorine, bromine or iodine.
6. the preparation method of N- (5- acyl group thiazol-2-yl) piperazinyl amide as claimed in claim 2, which is characterized in that it
Preparation reaction is as follows:
In formula, n, R1~R4,Y1~Y3As claimed in claim 2；X is selected from: chlorine, bromine or iodine.
7. one kind N- as shown in formula I (5- acyl group thiazol-2-yl) piperazinyl amide is preparing influenza neuraminidase suppression
Application in preparation:
R in formula1It is selected from: H, C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；R2It is selected from: C1~C2Alkyl, C3~
C4Straight chained alkyl or C3~C4Branched alkyl, C1~C2Alkoxy, C3~C4Unbranched alkoxy or C3~C4Branched alkoxy；R3Choosing
From: H, C1~C2Alkyl, C3~C6Straight chained alkyl；R4It is selected from: H, C1~C2Alkyl, C3~C4Straight chained alkyl；R5It is selected from: C1~C2Alkane
Base, C3~C6Straight chained alkyl or C3~C6Branched alkyl, methylol or ethoxy；N is selected from: 1,2,3,4,5 or 6.
8. one kind N- as shown in formula II (5- acyl group thiazol-2-yl) piperazinyl amide is preparing influenza neuraminidase suppression
Application in preparation:
R in formula1It is selected from: H, C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；R2It is selected from: C1~C2Alkyl, C3~
C4Straight chained alkyl or C3~C4Branched alkyl, C1~C2Alkoxy, C3~C4Unbranched alkoxy or C3~C4Branched alkoxy；R3—R4
It is selected from: H, C1~C2Alkyl, C3~C6Straight chained alkyl or C3~C6Branched alkyl；N is selected from: 1,2,3,4,5 or 6；Y1It is selected from: hydrogen, C1
~C2Alkyl, hydroxyl, C1~C2Alkoxy or SH；Y2It is selected from: hydrogen, C1~C2Alkyl；Y3It is selected from: hydrogen, C1~C2Alkyl, hydroxyl, C1
~C2Alkoxy, methylol, ethoxy or SH.
9. N- described in claim 3 or 4 (5- acyl group thiazol-2-yl) piperazinyl amide is preparing influenza neuraminidase
Application in inhibitor.
10. can in a kind of pharmaceutical composition, including the described in any item at least one compounds of Claims 1 to 4 and pharmaceutics
Carrier.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150250768A1 (en) * | 2009-06-26 | 2015-09-10 | Romark Laboratories L.C. | Compounds and methods for treating influenza |
| CN106083839A (en) * | 2016-08-22 | 2016-11-09 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of Dasatinib compound |
-
2017
- 2017-06-22 CN CN201710482836.3A patent/CN107235927B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150250768A1 (en) * | 2009-06-26 | 2015-09-10 | Romark Laboratories L.C. | Compounds and methods for treating influenza |
| CN106083839A (en) * | 2016-08-22 | 2016-11-09 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of Dasatinib compound |
Non-Patent Citations (7)
| Title |
|---|
| RN号为1071295-44-7;REGISTRY;《STN》;20081107 |
| RN号为885438-10-8、885427-00-9、885422-44-6、885420-49-5;REGISTRY;《STN》;20060524 |
| RN号为890296-85-2;REGISTRY;《STN》;20060702 |
| RN号为896215-75-1、896261-38-4;REGISTRY;《STN》;20060727 |
| RN号为902695-58-3;REGISTRY;《STN》;20060818 |
| RN号为946793-30-2;REGISTRY;《STN》;20070912 |
| Substituted thiazoles VI. Synthesis and antitumor activity of new 2-acetamido- and 2 or 3-propanamido-thiazole analogs;Shahenda M. El-Messery et al;《European Journal of Medicinal Chemistry》;20120618;第54卷;第615-625页 |
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