CN104974109A - Propynamide derivatives containing thiazole as well as preparation method, drug composition and application thereof - Google Patents
Propynamide derivatives containing thiazole as well as preparation method, drug composition and application thereof Download PDFInfo
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- CN104974109A CN104974109A CN201410133649.0A CN201410133649A CN104974109A CN 104974109 A CN104974109 A CN 104974109A CN 201410133649 A CN201410133649 A CN 201410133649A CN 104974109 A CN104974109 A CN 104974109A
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- benzothiazole
- amido
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- PVMXDQGTJNTNQI-UHFFFAOYSA-N CCOc(ccc(-c1nc2ccccc2[s]1)c1)c1NC(C#CC)=O Chemical compound CCOc(ccc(-c1nc2ccccc2[s]1)c1)c1NC(C#CC)=O PVMXDQGTJNTNQI-UHFFFAOYSA-N 0.000 description 2
- QBXXUXOGTXYATO-UHFFFAOYSA-N CC#CC(Nc(cc(cc1)-c2nc3ccccc3[s]2)c1OCCN1CCCCC1)=O Chemical compound CC#CC(Nc(cc(cc1)-c2nc3ccccc3[s]2)c1OCCN1CCCCC1)=O QBXXUXOGTXYATO-UHFFFAOYSA-N 0.000 description 1
- BBUBDLTVMQLYHC-UHFFFAOYSA-N CCCOc(ccc(-c1nc2ccccc2[s]1)c1)c1NC(C#CC)=O Chemical compound CCCOc(ccc(-c1nc2ccccc2[s]1)c1)c1NC(C#CC)=O BBUBDLTVMQLYHC-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
- C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention relates to propynamide derivatives shown in a formula I as well as pharmaceutically acceptable salt and preparation method thereof, a composition containing one or more of the compounds, and an application of the compounds to treatment of tumor diseases. The formula I is shown in the specification.
Description
Invention field
The present invention relates to the propiolyl amino derivative shown in formula I, its pharmacologically acceptable salt, its hydrate and solvate, its polycrystalline and eutectic, the precursor of its same biological function or derivative, and preparation method thereof, the composition containing this compound one or more, and the purposes of this compounds in treatment tumor disease.
Background of invention
Recent years, due to the raising of the understanding of the biomolecules to enzyme and some other and disease-related, greatly facilitate discovery or the development of the new drug of disease therapy, protein kinase is exactly an a kind of important class of extensive research, it is extended familys, relevant with the control of signal transduction process various in cell.Due to their structure and catalysis conservative property they be considered to evolve from a common ancestral gene.Nearly all kinases all contains a 250-300 similar amino acid catalytic domain.These protein kinases are divided into multiple family according to the difference of phosphorylated substrate, as protein tyrosine kinase, and Protein Serine/threonine kinase, lipoid etc.Generally, protein kinase is transferred to a protein receptor relevant to signal transduction pathway from a ribonucleoside triphosphote carry out signal transduction in mediated cell by being affected a phosphoryl.These phosphorylated events regulate the biological function of target protein as molecular switch, are finally excited to react to various extracellular and other stimulation.Kinases is present in multilayer signal transduction path, and receptor tyrosine kinase is positioned at the upstream of tumor-blood-vessel growth Signal transduction pathway and the upstream of tumour cell Signal transduction pathway.Serine/threonine protein kitase is positioned at the downstream of the Signal transduction pathway of tumour and tumor-blood-vessel growth cell.Research shows, by upstream retardance VEGFR and pdgf receptor, at downstream retardance Raf/MEK/ERK, to reduce the vasculogenesis of tumour and copying of inhibition tumor cell simultaneously, thus hinder the growth of tumour.
In addition, stem cell (stem cell, SC) is the cell that a class has self and differentiation potential, is divided into embryonic stem cell and adult stem cell (ASC).Cancer may originate from the vicious transformation of normal ASC.When normal ASC is due to heredity or extraneous factor mutagenesis, the path of its self regulates and occurs abnormal, and differentiation and maturation obstacle or dedifferente, changes into the cancer cells of sc sample.Therefore scientist once proposed a kind of hypothesis, and there is the cell of a small set of stem cell properties in cancerous tissue, be called sc sample cancer cells, namely cancer is in cell (cancer stem cell, CSC) or tumor stem cell.Research is thought, the abnormal signal in Sc self process regulates, and causes its unconfined growth, produces CSC, is likely tumorigenic vital earliest events.Regulate the signal transduction pathway of SC self process to mainly contain Hh (Hedgehog), wnL/beta-catenin and Notch etc., these paths participate in the self process of hematopoiesis SC, neural SC and mammary gland Sc etc.In rodent models, the exception of these signal transduction pathways regulates the generation causing tumour; Experiment proves that the exception of these paths in the generating process of some human tumor regulates and also plays an important role.
Numerous disease is that the abnormal cell response caused with protein kinase mediated event is associated.These diseases include, but not limited to tumour, inflammatory disease, Immunological diseases, osteopathia, metabolic trouble, sacred disease, cardiovascular and cerebrovascular diseases, the disease etc. that hormone is relevant.Therefore find and find kinases inhibitor to be very important as medicine.In addition, the adjustment of the signal transduction pathway of control CSC self process is also very important for Tumor suppression transfer.Although many inventions have made very large contribution to this area, for improving medication effect, this area is still in continuation research.
Summary of the invention
The object of the present invention is to provide the propiolyl amino derivative shown in general formula I, its pharmacologically acceptable salt, its solvate, its prodrug, its polycrystalline or eutectic.
Another object of the present invention is to the preparation method that the propiolyl amino derivative shown in general formula I is provided.
Another object of the present invention is to provide a kind of pharmaceutical composition containing the propiolyl amino derivative shown in general formula I.
Another object of the present invention is to provide the purposes of this compounds in cancer therapy drug.
In order to complete the object of the present invention, following technical scheme can be adopted:
The present invention relates to the having structure propiolyl amino derivative had shown in general formula I:
Or its pharmacologically acceptable salt, its hydrate and solvate, its polycrystalline and eutectic, the precursor of its same biological function or derivative.
The invention also discloses the method preparing the compounds of this invention, comprise following route steps:
The method of the described compound of preparation claim 1, comprises the steps:
Route 1
The feature of this route is, first connects R2 group, then forms benzothiazole ring, last alkynes acidylate.
In step (a), with to R2 M-NITROBENZOIC ACID 1 for raw material, be converted into acyl chlorides with common reagent and method, and then react with adjacent mercaptoaniline and generate acid amides, under sour environment, heat cyclization generate benzothiazole 2; Or acid 1 and adjacent mercaptoaniline directly generated acid amides by dewatering agent or condensing agent condensation and heated cyclization generate benzothiazole 2.
In step (b), be that amido generates compound 3 by the nitroreduction in compound 2 by common methods.
In step (c), acetylenic acid and compound 3 are dewatered by condensing agent, or alkynes acyl chlorides and 3 reacts and generates alkynyl amide target compound I.
Route 2
The feature of this route is, first forms benzothiazole ring, then connects R2 group.
In step (a), with carboxylic compound 4 for raw material, form benzothiazole cyclic cpds 7 with the condensation of adjacent mercaptoaniline direct heating in the presence of a dehydrating agent.
In step (b), with aldehyde compound 5 for raw material, under catalyzer is as dibrominated zinc or palladium existence, form benzothiazole cyclic cpds 7 with adjacent mercaptoaniline direct polycondensation.
In step (c), with chloride compounds 6 for raw material, first react with adjacent mercaptoaniline and generate acid amides, under sour environment, heat cyclization generate benzothiazole cyclic cpds 7.
In step (d), compound 7 alkalescence (as salt of wormwood) environment under with R
2h reacting generating compound 2.
In process step (e), be that amido generates compound 3 by the nitroreduction in compound 2 by common methods.
In step (f), acetylenic acid and compound 3 are dewatered by condensing agent, or alkynes acyl chlorides and 3 reacts and generates alkynyl amide target compound I.
Route 3
The feature of this route is, first connects R2 group, then forms alkynyl amide, finally forms benzothiazole ring.
In step (a) with compound 8 for raw material, be that amido generates compound 9 by its nitroreduction by common methods.In step (b), acetylenic acid and compound 9 are dewatered by condensing agent, or alkynes acyl chlorides and 9 reacts and generates alkynyl amide compound 10.In step (c), 10 Ester hydrolysis in the basic conditions or under enzymatic condition obtain carboxylic acid cpd 12.
In step (d), be converted into acyl chlorides by 12 with common reagent and method, and then react with adjacent mercaptoaniline and generate acid amides, under sour environment, heat cyclization generate benzothiazole target compound I; Or acid 12 and adjacent mercaptoaniline directly generated acid amides by dewatering agent or condensing agent condensation and heat cyclization generate benzothiazole target compound I.
In step (e), be aldehyde 11 with reductive agent by compound 10 direct-reduction.
In step (f), compound 11 directly obtains benzothiazole target compound I with adjacent mercaptoaniline condensation under catalyzer is as dibrominated zinc or palladium existence.
In addition, the starting raw material in above-mentioned reaction and intermediate easily obtain, or can be easy to synthesis to those skilled in the art by the ordinary method in organic synthesis.
Propiolyl amino derivative described in formula I can the form of solvate or non-solvent compound exist, and utilizes different solvents to carry out crystallization and may obtain different solvates.Pharmacy acceptable salt described in formula I comprises different acid salt, as following mineral acid or organic acid acid salt: hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid, methylsulfonic acid, tosic acid, trifluoroacetic acid, matrimony vine acid, toxilic acid, tartrate, fumaric acid, citric acid, lactic acid.All these salt within the scope of the present invention all can adopt ordinary method to prepare.In the preparation process of described propiolyl amino derivative and solvate thereof and its salt, may there is polycrystalline or eutectic in different crystallization condition.
The invention still further relates to the pharmaceutical composition using the compounds of this invention as active ingredient.This pharmaceutical composition can be prepared according to method well known in the art.By pharmaceutically acceptable to the compounds of this invention and one or more solid or liquid excipient and/or assistant agent being combined, make any formulation being suitable for human or animal and using.The content of the compounds of this invention in its pharmaceutical composition is generally 0.1-95 % by weight.
The compounds of this invention or the pharmaceutical composition containing it can administrations in a unit, route of administration can be enteron aisle or non-bowel, as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.
Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
The compounds of this invention can be made ordinary preparation, also make is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
In order to the compounds of this invention is made tablet, various vehicle well known in the art can be widely used, comprise thinner, tamanori, wetting agent, disintegrating agent, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, calcium carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate, sodium bicarbonate and Citric Acid, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate etc.; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.
Tablet can also be made coating tablet further, such as sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
In order to administration unit is made capsule, effective constituent the compounds of this invention can be mixed with thinner, glidant, mixture is directly placed in hard capsule or soft capsule.Also effective constituent the compounds of this invention first particle or micropill be can be made with thinner, tamanori, disintegrating agent, then hard capsule or soft capsule are placed in.Also the capsule preparing the compounds of this invention is can be used for for the preparation of each thinner of the compounds of this invention tablet, tamanori, wetting agent, disintegrating agent, glidant kind.
For the compounds of this invention is made injection, can with water, ethanol, Virahol, propylene glycol or their mixture as solvent and add the conventional solubilizing agent in appropriate this area, solubility promoter, pH adjust agent, osmotic pressure regulator.Solubilizing agent or solubility promoter can be poloxamer, Yelkin TTS, hydroxypropyl-beta-cyclodextrin etc.; PH adjustment agent can be phosphoric acid salt, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can be sodium-chlor, N.F,USP MANNITOL, glucose, phosphoric acid salt, acetate etc.As prepared lyophilized injectable powder, N.F,USP MANNITOL, glucose etc. also can be added as propping agent.
In addition, as needs, also tinting material, sanitas, spices, correctives or other additive can be added in pharmaceutical preparation.
For reaching medication object, strengthen result for the treatment of, medicine of the present invention or pharmaceutical composition can with any known medication administrations.
The dosage of the compounds of this invention pharmaceutical composition is according to preventing or the character of disease therapy and severity, and the individual instances of patient or animal, route of administration and formulation etc. can have large-scale change.In general, the Suitable dosage ranges of the every day of the compounds of this invention is 0.001-150mg/Kg body weight, is preferably 0.01-100mg/Kg body weight.Above-mentioned dosage can a dose unit or be divided into several dosage unit administration, and this depends on the clinical experience of doctor and comprises the dosage regimen using other treatment means.
Compound of the present invention or composition can be taken separately, or merge with other treatment medicine or symptomatic drugs and use.When compound of the present invention and other medicine exist act synergistically time, its dosage should be adjusted according to practical situation.
The compounds of this invention is Mutiple Targets kinases inhibitor or its precursor, and these protein kinases are divided into multiple family according to the difference of phosphorylated substrate, as protein tyrosine kinase, and Protein Serine/threonine kinase, lipoid etc.Generally, protein kinase is transferred to a protein receptor relevant to signal transduction pathway from a ribonucleoside triphosphote carry out signal transduction in mediated cell by being affected a phosphoryl.These phosphorylated events regulate the biological function of target protein as molecular switch, are finally excited to react to various extracellular and other stimulation.Kinases is present in multilayer signal transduction path, and receptor tyrosine kinase is positioned at the upstream of tumor-blood-vessel growth Signal transduction pathway and the upstream of tumour cell Signal transduction pathway.Serine/threonine protein kitase is positioned at the downstream of the Signal transduction pathway of tumour and tumor-blood-vessel growth cell.Research shows, by upstream retardance VEGFR and pdgf receptor, at downstream retardance Raf/MEK/ERK, to reduce the vasculogenesis of tumour and copying of inhibition tumor cell simultaneously, thus hinder the growth of tumour.The compounds of this invention has higher bioavailability, can be used for the treatment of multiple human malignancies, comprising described tumor disease is liver cancer, cancer of the stomach, kidney, lung cancer, carcinoma of the pancreas, colorectal cancer, bladder cancer and mammary cancer, ovarian cancer, squamous cell carcinoma, neurospongioma, leukemia, incidence cancer.
Embodiment
Below with reference to embodiment, invention is described further, but does not limit the scope of the invention.
Determining instrument: NMR (Nuclear Magnetic Resonance) spectrum Vaariaan Mercury300 or 400 type nuclear magnetic resonance analyser.Mass spectrum ZAD-2F and VG300 mass spectrograph.
Embodiment 1.2-(3-(crotonylene-amido)-4-p-methoxy-phenyl) benzothiazole
The synthesis of 2-(the fluoro-3-nitrophenyl of 4-) benzothiazole
Fluoro-for 4-3-nitrobenzoic acid (3.7g, 20mmol) is dissolved in the DCM of 50mL drying, adds the DMF of catalytic amount, under ice-water bath, drip oxalyl chloride (3.4mL, 40mmol), after stirring 30min, move to stirred at ambient temperature 2h.Be spin-dried for reaction solution, add the toluene of 40mL drying, make solution of acid chloride, seal stand-by.Near amino thiophenols (2.5g, 20mmol) is dissolved in the toluene of 20mL drying, stirs and drip the solution of acid chloride prepared down, N
2protect lower 110 DEG C of reaction 3h.Be cooled to room temperature, reaction solution ethyl acetate (100ml) and saturated sodium bicarbonate solution (50mL) dilution, extraction, be separated organic phase, aqueous phase, with ethyl acetate (2 × 50ml), collects organic phase washing, anhydrous sodium sulfate drying, filter, concentrate rear silica gel column chromatography, obtain 2-(the fluoro-3-nitrophenyl of 4-) benzothiazole yellow solid 5.1g.
1H NMR(300MHz,DMSO-d
6):δ(ppm):8.74-8.71(dd,1H,ArH),8.47-8.42(m,1H,ArH),8.20-8.17(d,1H,ArH),8.11-8.10(d,1H,ArH),7.80-7.74(dd,1H,ArH),7.60-7.47(m,2H,ArH).
The synthesis of 2-(4-methoxyl group-3-nitrophenyl) benzothiazole
2-(the fluoro-3-nitrophenyl of 4-) benzothiazole (822mg, 3mmol) is dissolved in the DMF of 10mL drying, adds methyl alcohol (9mmol) and CsCO
3(9mmol), react at 25 DEG C and spend the night.With ethyl acetate (50mL) dilution, add water (25mL) extraction, aqueous layer with ethyl acetate (2 × 25mL) extracting twice, collect ethyl acetate layer, washing, anhydrous sodium sulfate drying.Filter, desolventizing is revolved in decompression, obtains target compound 2-(4-methoxyl group-3-nitrophenyl) benzothiazole.
The synthesis of 2-(4-methoxyl group-3-aminophenyl) benzothiazole
2-(4-methoxyl group-3-nitrophenyl) benzothiazole (1.5mmol) is dissolved in methyl alcohol (15ml), adds zinc powder (975mg, 15mmol) and ammonium chloride (802mg, 15mmol), 65 DEG C of reaction 2h.Be cooled to room temperature, filter, collect filtrate, be spin-dried for obtain crude product 2-(4-methoxyl group-3-aminophenyl) benzothiazole.Without separation, be directly used in next step reaction.
The synthesis of 2-(3-(crotonylene-amido)-4-p-methoxy-phenyl) benzothiazole
Butynoic acid (252mg, 3mmol) is dissolved in benzene (5mL), drips oxalyl chloride (507mL, 6mmol), at 50 DEG C, react 2h.Be spin-dried for reaction solution, add dry THF(5ml), make butine solution of acid chloride, seal stand-by.2-(4-methoxyl group-3-aminophenyl) benzothiazole (1.5mmol) is dissolved in dry THF(5mL), add pyridine (0.16mL, 2mmol) and obtained butine solution of acid chloride, under room temperature, react 3h.Revolve desolventizing, silica gel column chromatography obtains target compound 2-(3-(crotonylene-amido)-4-p-methoxy-phenyl) benzothiazole,
1hNMR (300MHz, DMSO-d
6): δ (ppm): 9.81 (s, 1H, NH), 8.54 (s, 1H, ArH), 8.11-8.09 (d, 1H, ArH), 8.03-8.00 (d, 1H, ArH), 7.87-7.85 (d, 1H, ArH), 7.54-7.49 (m, 1H, ArH), 7.44-7.40 (m, 1H, ArH), 7.24-7.21 (d, 1H, ArH), 3.91 (s, 3H, OCH
3), 2.05 (s, 3H, CH
3) .MS (FAB) (M
++ 1=323)
Embodiment 2.2-(3-(crotonylene-amido)-4-ethoxyl phenenyl) benzothiazole
2-(4-methoxyl group-3-nitrophenyl) benzothiazole is replaced with 2-(4-oxyethyl group-3-nitrophenyl) benzothiazole, the operating process of reference example 1, obtains 2-(3-(crotonylene-amido)-4-ethoxyl phenenyl) benzothiazole.
1HNMR(300MHz,DMSO-d6):δ(ppm):9.72(s,1H,NH),8.55(s,1H,ArH),8.11-8.09(d,1H,ArH),8.03-8.00(d,1H,ArH),7.84-7.82(d,1H,ArH),7.54-7.50(t,1H,ArH),7.44-7.40(t,1H，ArH),7.22-7.19(d,1H,ArH),4.22-4.15(m,2H,CH
2),2.05(s,3H,CH
3),1.42-1.37(t,3H,CH
3).MS(FAB)（M
++1=337）
Embodiment 3.2-(3-(crotonylene-amido)-4-propoxyphenyl) benzothiazole
2-(4-methoxyl group-3-nitrophenyl) benzothiazole is replaced with 2-(4-propoxy--3-nitrophenyl) benzothiazole, the operating process of reference example 1, obtains 2-(3-(crotonylene-amido)-4-propoxyphenyl) benzothiazole.
1HNMR(300MHz,DMSO-d6):δ(ppm):9.71(s,1H,NH),8.49(s,1H,ArH),8.11-8.09(d,1H,ArH),8.03-8.00(d,1H,ArH),7.85-7.83(d,1H,ArH),7.54-7.49(t,1H,ArH),7.44-7.40(t,1H,ArH),7.23-7.20(d,1H,ArH),4.09-4.05(t,2H,CH
2),2.05(s,3H,CH
3),1.83-1.76(m,2H,CH
2),1.03-0.98(t,3H,CH3).MS(FAB)（M
++1=351）
Embodiment 4.2-(3-(crotonylene-amido)-4-ethoxyethoxy phenyl) benzothiazole
2-(4-methoxyl group-3-nitrophenyl) benzothiazole is replaced with 2-(4-ethoxyethoxy-3-nitrophenyl) benzothiazole, the operating process of reference example 1, obtains 2-(3-(crotonylene-amido)-4-ethoxyethoxy phenyl) benzothiazole.
1H NMR(300MHz,CDCl
3):δ(ppm):9.02(s,1H,NH),8.24(s,1H,ArH),8.04-8.02(d,1H,ArH),7.88-7.86(d,2H,ArH),7.48-7.43(t,1H,ArH),7.37-7.32(t,1H,ArH),7.02-6.99(d,1H,ArH),4.26(m,2H,OCH
2),3.79(m,2H,OCH
2),3.64-3.57(m,2H,OCH
2),2.01(s,3H,CH
3),1.29-1.24(m,3H,CH
3)。MS(FAB)（M
++1=381）
Embodiment 5.2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl) benzothiazole
2-(4-methoxyl group-3-nitrophenyl) benzothiazole is replaced with 2-(4-ethoxyethoxy oxyethyl group-3-nitrophenyl) benzothiazole, the operating process of reference example 1, obtains 2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl) benzothiazole.
1H NMR(300MHz,CDCl
3):δ(ppm):9.02(s,1H,NH),8.22(s,1H,ArH),8.04-8.02(m,1H,ArH),7.88-7.86(m,2H,ArH),7.46-7.35(m,2H,ArH),7.02-6.99(m,1H,ArH),4.29(m,2H,OCH
2),3.90(m,2H,OCH
2),3.72-3.54(m,6H,3OCH
2),2.03(s,3H,CH
3),1.22(m,3H,CH
3).MS(FAB)（M
++1=425）
Embodiment 6.2-(3-(crotonylene-amido)-4-(3-dimethylin propoxy-) phenyl) benzothiazole
2-(4-methoxyl group-3-nitrophenyl) benzothiazole is replaced with 2-(4-(3-dimethylin propoxy-)-3-nitrophenyl) benzothiazole, the operating process of reference example 1, obtains 2-(3-(crotonylene-amido)-4-(3-dimethylin propoxy-) phenyl) benzothiazole.
1H NMR(300MHz,CDCl
3):δ(ppm):9.01(s,1H,NH)，8.35（s,1H,ArH）,8.02(m,1H,ArH),7.87(m,2H,ArH),7.47-7.43(m,1H,ArH),7.38-7.36(m,1H,ArH),7.01-6.98(d,1H,ArH),4.32-4.21(m,2H,OCH
2),2.71-2.59(m,2H,NCH
2),2.37(s,6H,2NCH
3),2.05(s,1H,CH
3),1.26(m,2H,CH
2).MS(FAB)（M
++1=394）
Embodiment 7.2-(3-(crotonylene-amido)-4-(2-dimethylamino ethoxy) phenyl) benzothiazole
2-(4-methoxyl group-3-nitrophenyl) benzothiazole is replaced with 2-(4-(2-dimethylamino ethoxy)-3-nitrophenyl) benzothiazole, the operating process of reference example 1, obtains 2-(3-(crotonylene-amido)-4-(2-dimethylamino ethoxy) phenyl) benzothiazole.
1H NMR(300MHz,CDCl
3):δ(ppm):9.88(s,1H,NH)，8.98（s,1H,ArH）,8.04-8.02(d,1H,ArH),7.89-7.85(m,2H,ArH),7.48-7.43(m,1H,ArH),7.37-7.32(m,1H,ArH),7.07-7.04(d,1H,ArH),4.20-4.17(t,2H,OCH
2),2.69(m,2H,NCH
2),2.39(s,6H,2NCH
3),2.02(s,1H,CH
3).MS(FAB)（M
++1=380）
Embodiment 8.2-(3-(crotonylene-amido)-4-(2-piperidines-1-oxyethyl group) phenyl) benzothiazole
With 2-(4-(2-piperidines-1-oxyethyl group)-3-nitrophenyl) benzothiazole replacement 2-(4-methoxyl group-3-nitrophenyl) benzothiazole, the operating process of reference example 1, obtains 2-(3-(crotonylene-amido)-4-(2-piperidines-1-oxyethyl group) phenyl) benzothiazole.
1H NMR(300MHz,CDCl
3):δ(ppm):8.99(s,1H,NH)，8.93（s，1H,ArH）,8.5-8.02(d,1H,ArH),7.89-7.87(d,2H,ArH),7.49-7.44(m,1H,ArH),7.37-7.33(m,1H,ArH),7.06-7.03(d,1H,ArH),4.28-4.24(m,2H,OCH
2),2.72-2.68(t,2H,NCH
2),2.51(s,4H,2NCH
2),2.02(s,1H,CH
3),1.70-1.67(m,4H,2CH
2),1.49-1.48(m,2H,CH
2).MS(FAB)（M
++1=420）
Embodiment 9.2-(3-(crotonylene-amido)-4-(2-thiophene-2-oxyethyl group) phenyl) benzothiazole
With 2-(4-(2-thiophene-2-oxyethyl group)-3-nitrophenyl) benzothiazole replacement 2-(4-methoxyl group-3-nitrophenyl) benzothiazole, the operating process of reference example 1, obtains 2-(3-(crotonylene-amido)-4-(2-thiophene-2-oxyethyl group) phenyl) benzothiazole.
1H NMR(300MHz,DMSO-d
6):δ(ppm):9.56(s,1H,NH),8.55(s,1H,ArH),8.11-8.08(d,1H,ArH),8.03-8.00(d,1H,ArH),7.84-7.81(d,1H,ArH),7.54-7.48(m,2H,ArH),7.44-7.37(m,2H,ArH),7.27-7.25(d,1H,ArH),7.16-7.15(d,1H,ArH),4.34-4.30(t,2H,OCH
2),3.17-3.12(t,2H,CH
2),2.08(s,1H,CH
3).MS(FAB)（M
++1=419）
Embodiment 10.2-(3-(crotonylene-amido)-4-(2-morpholine-1-oxyethyl group) phenyl) benzothiazole
With 2-(4-(2-morpholine-1-oxyethyl group)-3-nitrophenyl) benzothiazole replacement 2-(4-methoxyl group-3-nitrophenyl) benzothiazole, the operating process of reference example 1, obtains 2-(3-(crotonylene-amido)-4-(2-morpholine-1-oxyethyl group) phenyl) benzothiazole.
1H NMR(400MHz,DMSO-d
6):δ(ppm):9.74(s,1H,NH),8.59(s,1H,ArH),8.13-8.11(d,1H,ArH),8.04-8.02(d,1H,ArH),7.86-7.81(m,1H,ArH),7.55-7.51(t,1H,ArH),7.46-7.42(m,1H,ArH),7.32-7.30(d,1H,ArH),4.30-4.27(m,2H,OCH
2),3.65-3.60(m,4H,2OCH
2),2.79(s,2H,NCH
2),2.56(s,4H,2NCH
2),2.07(s,3H,CH
3).MS(FAB)（M
++1=422）
Embodiment 11.2-(3-(crotonylene-amido)-4-(3-morpholine-1-propoxy-) phenyl) benzothiazole
With 2-(4-(3-morpholine-1-propoxy-)-3-nitrophenyl) benzothiazole replacement 2-(4-methoxyl group-3-nitrophenyl) benzothiazole, the operating process of reference example 1, obtains 2-(3-(crotonylene-amido)-4-(3-morpholine-1-propoxy-) phenyl) benzothiazole.
1H NMR(400MHz,DMSO-d
6):δ(ppm):9.72(s,1H,NH),8.52(s,1H,ArH),8.12-8.10(d,1H,ArH),8.04-8.02(d,1H,ArH),7.86-7.84(d,1H,ArH),7.55-7.51(m,1H,ArH),7.45-7.41(m,1H,ArH),7.24-7.22(d,1H,ArH),4.17-4.14(t,2H,OCH
2),3.59(s,4H,2OCH
2),2.48-2.44(t,2H,NCH
2),2.38(s,4H,2NCH
2),2.07(s,3H,CH
3),1.97-1.94(m,2H,CH
2).MS(FAB)（M
++1=436）
Embodiment 12.2-(3-(crotonylene-amido)-4-ring third p-methoxy-phenyl) benzothiazole
2-(4-methoxyl group-3-nitrophenyl) benzothiazole is replaced with 2-(4-ring third methoxyl group-3-nitrophenyl) benzothiazole, the operating process of reference example 1, obtains 2-(3-(crotonylene-amido)-4-ring third p-methoxy-phenyl) benzothiazole.
1H NMR(400MHz,DMSO-d
6):δ(ppm):9.68(s,1H,NH),8.52(s,1H,ArH),8.12-8.10(d,1H,ArH),8.03-8.01(d,1H,ArH),7.85-7.83(d,1H,ArH),7.54-7.51(m,1H,ArH),7.45-7.41(m,1H,ArH),7.24-7.21(d,1H,ArH),4.01-3.99(m,2H,OCH
2),2.07(s,3H,CH
3),1.32(m,1H,CH),0.63-0.58(m,2H,CH
2),0.41-0.40(m,2H,CH
2).MS(FAB)（M
++1=363）
Embodiment 13.2-(3-(crotonylene-amido)-4-methoxyethoxy phenyl) benzothiazole
2-(4-methoxyl group-3-nitrophenyl) benzothiazole is replaced with 2-(4-methoxyethoxy-3-nitrophenyl) benzothiazole, the operating process of reference example 1, obtains 2-(3-(crotonylene-amido)-4-methoxyethoxy phenyl) benzothiazole.
1H NMR(400MHz,DMSO-d
6):δ(ppm):9.67(s,1H,NH),8.60(s,1H,ArH),8.12-8.10(d,1H,ArH),8.04-8.02(d,1H,ArH),7.85-7.83(d,1H,ArH),7.54-7.51(m,1H,ArH),7.45-7.41(m,1H,ArH),7.29-7.26(d,1H,ArH),4.27(s,2H,OCH
2),3.74(s,2H,OCH
2),3.35(s,3H,OCH
3),2.07(s,3H,CH
3).MS(FAB)（M
++1=337）
Embodiment 14.2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-5-methoxybenzothiazole
The synthesis of two (4-methoxyl group-2-is amino) phenyl two sulphur
2-amino-5-methoxybenzothiazole (76mmoL) is dissolved in the aqueous solution (10M, 100mL) of NaOH, at 100 DEG C, reaction is spent the night.Be cooled to room temperature, be acidified to pH2-3 with concentrated hydrochloric acid, K
2cO
3adjust pH to neutral, ethyl acetate (200mL) extracts, aqueous layer with ethyl acetate (2 × 150mL) extracting twice again, collects ethyl acetate layer, washing, anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure, silica gel column chromatography obtains intermediate two (4-methoxyl group-2-is amino) phenyl two sulphur.
Two (4-methoxyl group-2-(3-nitro-4-fluorobenzoyl) is amino) synthesis of phenyl two sulphur
Two (4-methoxyl group-2-is amino) phenyl two sulphur (22mmol) is dissolved in dry toluene (40mL), and add toluene (60mL) solution of the fluoro-3-nitrobenzoyl chloride (24.2mmol) of 4-, 110 DEG C of reactions are spent the night.Be cooled to room temperature, poured into by reaction solution in saturated sodium bicarbonate solution, separate out solid, suction filtration, washes with water, drains and obtain two (4-methoxyl group-2-(3-nitro-4-fluorobenzoyl) amino) phenyl two sulphur.
The synthesis of 2-(3-nitro-4-fluorophenyl)-5-methoxybenzothiazole
Two (4-methoxyl group-2-(3-nitro-4-fluorobenzoyl) is amino) phenyl two sulphur (3.21g, 5mmoL) is dissolved in toluene (50mL), adds pTsOH(190mg, 1mmol) and PPh
3(1.32g, 5mmol), 110 DEG C of reactions are spent the night.Be cooled to room temperature, be spin-dried for solvent, ethyl acetate (200mL) extracts, aqueous layer with ethyl acetate (2 × 150mL) extracting twice again, collects ethyl acetate layer, washing, anhydrous sodium sulfate drying.Filter, after concentrating under reduced pressure, silica gel column chromatography obtains the synthesis of intermediate 2-(3-nitro-4-fluorophenyl)-5-methoxybenzothiazole.
The synthesis of 2-(3-nitro-4-ethoxyethoxy ethoxyl phenenyl)-5-methoxybenzothiazole:
Compound 2-(3-nitro-4-fluorophenyl)-5-methoxybenzothiazole (1.2mmol) is dissolved in 70ml DMF, add carbitol (6.0mmol), cesium carbonate (1.95g, 6.0mmol), room temperature reaction 12h.Concentrated rear ethyl acetate/water extraction, organic phase washed with water and saturated NaCl solution are washed successively, anhydrous Na
2sO
4drying, filters, and obtains 2-(3-nitro-4-ethoxyethoxy ethoxyl phenenyl)-5-methoxybenzothiazole after concentrated.
The synthesis of 2-(3-amino-4-ethoxyethoxy ethoxyl phenenyl)-5-methoxybenzothiazole:
Compound 2-(3-nitro-4-ethoxyethoxy ethoxyl phenenyl)-5-methoxybenzothiazole (1.4mmol) is dissolved in 10ml methyl alcohol, adds 1ml water, NH
4cl (752mg, 14.0mmol), Zn (912mg, 14.0mmol), back flow reaction 2h, crosses and filters Zn, and concentrated rear ethyl acetate/water extraction, organic phase washed with water and saturated NaCl solution are washed successively, anhydrous Na
2sO
4drying, filters, and obtains 2-(3-amino-4-ethoxyethoxy ethoxyl phenenyl)-5-methoxybenzothiazole after concentrated.
The synthesis of 2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-5-methoxybenzothiazole:
Butynoic acid (252mg, 3mmol) is dissolved in benzene (5mL), drips oxalyl chloride (507mL, 6mmol), at 50 DEG C, react 2h.Be spin-dried for reaction solution, add dry THF(5ml), make butine solution of acid chloride, seal stand-by.2-(3-amino-4-ethoxyethoxy ethoxyl phenenyl)-5-methoxybenzothiazole (1.5mmol) is dissolved in dry THF(5mL), add pyridine (0.16mL, 2mmol) and obtained butine solution of acid chloride, under room temperature, react 3h.Revolve desolventizing, silica gel column chromatography obtains target compound 2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-5-methoxybenzothiazole.
1H NMR(300MHz,DMSO-d
6):δ(ppm):9.56(s,1H,NH),8.58(s,1H,ArH),7.98-7.94(m,1H,ArH),7.81-7.78(d,1H,ArH),7.60(s,1H,ArH),7.28-7.25(m,1H,ArH),7.08-7.05(m,1H,ArH),4.26(s,2H,OCH
2),3.86-3.61(m,5H,OCH
2,OCH
3),3.52-3.51(m,2H,OCH
2),3.48-3.44(m,2H,OCH
2),3.43-3.40(m,2H,OCH
2),2.06(s,3H,CH
3),1.12-1.07(m,3H,CH
3).MS(FAB)（M
++1=455）
Embodiment 15.2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-5-chloro benzothiazole
Replace 2-amino-5-methoxybenzothiazole with 2-amino-5-chloro benzothiazole, the operating process of reference example 14, obtains 2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-5-chloro benzothiazole.
1HNMR(400MHz,DMSO-d
6):δ(ppm):9.64(s,1H,NH),8.60(s,1H,ArH),8.17-8.12(m,2H,ArH),7.83(s,1H,ArH),7.50-7.48(d,1H,ArH),7.30-7.28(d,1H,ArH),4.28-4.27(m,2H,OCH
2),3.85-3.83(m,2H,OCH
2),3.64-3.62(s,2H,OCH
2),3.51-3.53(m,2H,OCH
2),3.45-3.43(m,2H,OCH
2),2.07(s,3H,CH
3),1.10(m,3H,CH
3).MS(FAB)（M
++1=459）
Embodiment 16.2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-5-trifluoromethylbenzothiazole
2-amino-5-methoxybenzothiazole is replaced with 2-amino-5-trifluoromethylbenzothiazole, the operating process of reference example 14, obtains 2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-5-trifluoromethylbenzothiazole.
1H NMR(300MHz,DMSO-d
6):δ(ppm):9.67(s,1H,NH),8.64(s,1H,ArH),8.39-8.38(m,2H,ArH),7.89-7.87(d,1H，ArH),7.78-7.75(d,1H,ArH),7.33-7.30(d,1H,ArH),4.28-4.30(m,2H,OCH
2),3.85(s,2H,OCH
2),3.64-3.63(m,2H,OCH
2),3.54-3.52(m,2H,OCH
2),3.48-3.41(m,2H,OCH
2),2.07(s,3H,CH
3),1.12-1.07(m,3H,CH
3).MS(FAB)（M
++1=493）
Embodiment 17.2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-6-fluoro benzothiazole
Replace 2-amino-5-methoxybenzothiazole with 2-amino-6-fluoro benzothiazole, the operating process of reference example 14, obtains 2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-6-fluoro benzothiazole.
1HNMR(300MHz,DMSO-d
6):δ(ppm):9.62(s,1H,NH),8.59(s,1H,ArH),8.07-8.04(m,2H,ArH),7.82-7.80(d,1H,ArH),7.42-7.38(m,1H,ArH),7.29-7.27(d,1H,ArH),4.26-4.28(m,2H,OCH
2),3.84-3.82(m,2H,OCH
2),3.65-3.63(m,2H,OCH
2),3.53-3.51(m,2H,OCH
2),3.47-3.42(m,2H,OCH
2),2.07(s,3H,CH
3),1.12-1.09(m,3H,CH
3).MS(FAB)（M
++1=443）
Embodiment 18.2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-6-chloro benzothiazole
Replace 2-amino-5-methoxybenzothiazole with 2-amino-6-chloro benzothiazole, the operating process of reference example 14, obtains 2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-6-chloro benzothiazole.
1HNMR(400MHz,DMSO-d
6):δ(ppm):9.62(s,1H,NH),8.60(s,1H,ArH),8.27(s,1H,ArH),8.03-8.01(d,1H,ArH),7.83-7.81(d,1H,ArH),7.56-7.54(d,1H,ArH),7.29-7.27(d,1H,ArH),4.28-4.22(m,2H,OCH
2),3.89-3.84(m,2H,OCH
2),3.63-3.65(m,2H,OCH
2),3.52-3.50(m,2H,OCH
2),3.47-3.42(m,2H,OCH
2),2.07(s,3H,CH
3),1.12-1.08(m,3H,CH
3).MS(FAB)（M
++1=459）
Embodiment 19.2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-6-bromo benzothiazole
Replace 2-amino-5-methoxybenzothiazole with 2-amino-6-bromo benzothiazole, the operating process of reference example 14, obtains 2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-6-bromo benzothiazole.
1HNMR(400MHz,DMSO-d
6):δ(ppm):9.63(s,1H,NH),8.60(s,1H,ArH),8.41(s,1H,ArH),7.97-7.95(d,1H,ArH),7.84-7.82(d,1H,ArH),7.68-7.66(d,1H,ArH),7.29-7.27(d,1H,ArH),4.28(s,2H,OCH
2),3.84(s,2H,OCH
2),3.63(m,2H,OCH
2),3.52(s,2H,OCH
2),3.47-3.42(m,2H,OCH
2),2.07(s,3H,CH
3),1.12-1.08(m,3H,CH
3).MS(FAB)（M
++1=504）
Embodiment 20.2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-6-trifluoromethoxy benzo thiazole
2-amino-5-methoxybenzothiazole is replaced with trifluoromethoxybenzathiazole, the operating process of reference example 14, obtains 2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-6-trifluoromethoxy benzo thiazole.
1H NMR(400MHz,DMSO-d
6):δ(ppm):9.65(s,1H,-NH-),8.61(s,1H,ArH),8.27(s,1H,ArH),8.14-8.11(d,1H,ArH),7.86-7.84(d,1H,ArH),7.53-7.51(d,1H,ArH),7.31-7.29(d,1H,ArH),4.58-4.55(m,2H,OCH
2),3.85-3.64(m,2H,OCH
2),3.62-3.58(m,2H,OCH
2),3.53-3.50(m,2H,OCH
2),3.48-3.40(m,2H,OCH
2),2.07(s,3H,CH
3),1.12-1.06(m,3H,CH
3).MS(FAB)（M
++1=509）
Embodiment 21.2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-6-methylbenzothiazole
Replace 2-amino-5-methoxybenzothiazole with 2-amino-6-methylbenzothiazole, the operating process of reference example 14, obtains 2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-6-methylbenzothiazole.
1HNMR(400MHz,DMSO-d
6):δ(ppm):9.60(s,1H,NH),8.57(s,1H,ArH),7.92-7.90(m,1H,ArH),7.81-7.79(d,1H,ArH),7.35-7.33(d,1H,ArH),7.35-7.33(d,1H,ArH),7.28-7.26(d,1H,ArH),4.27-4.25(m,2H,OCH
2),3.82-3.84(m,2H,OCH
2),3.64-3.62(m,2H,OCH
2),3.53-3.51(m,2H,OCH
2),3.47-3.42(m,2H,OCH
2),2.45(s,3H,CH
3),2.07(s,3H,CH
3),1.12-1.08(m,3H,CH
3).MS(FAB)（M
++1=439）
Embodiment 22.2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-6-methoxybenzothiazole
Replace 2-amino-5-methoxybenzothiazole with 2-amino-6-methoxybenzothiazole, the operating process of reference example 14, obtains 2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-6-methoxybenzothiazole.
1H NMR(400MHz,DMSO-d
6):δ(ppm):9.56(s,1H,NH),8.54(s,1H,ArH),7.92-7.90(d,1H,ArH),7.77-7.75(d,1H,ArH),7.69(s,1H,ArH),7.27-7.24(d,1H,ArH),7.13-7.10(d,1H,ArH),4.26(s,2H,OCH
2),3.85-3.83(m,5H,OCH
2,OCH
3),3.66-3.62(m,2H,OCH
2),3.53-3.50(m,2H,OCH
2),3.47-3.42(m,2H,OCH
2),2.06(s,3H,CH
3),1.11-1.08(m,3H,CH
3).MS(FAB)（M
++1=455）
Embodiment 23.2-(3-(crotonylene-amido)-4-(3-morpholine-1-propoxy-) phenyl)-6-methoxybenzothiazole
Replace carbitol with 3-morpholine-1-propyl alcohol, the operating process of reference example 22, obtains 2-(3-(crotonylene-amido)-4-(3-morpholine-1-propoxy-) phenyl)-6-methoxybenzothiazole.
1H NMR(300MHz,DMSO-d
6):δ(ppm):9.74(s,1H,NH),8.43(s,1H,ArH),7.92-7.89(d,1H,ArH),7.80-7.77(d,1H,ArH),7.70(s,1H,ArH),7.24-7.21(d,1H,ArH),7.13-7.10(d,1H,ArH),4.14-4.16(m,2H,OCH
2),3.84-3.86(m,4H,2OCH
2),3.61(s,3H,OCH
3),2.47-2.44(m,4H,2NCH
2),2.07(s,3H,CH
3),1.97(m,2H,NCH
2),1.84-1.86(m,2H,CH
2).MS(FAB)（M
++1=466）
Pharmacologically active
External activity is evaluated:
Mtt assay measures tumor cell survival
Be 0.8 ~ 2 × 10 by being mixed with concentration after the cell trysinization of logarithmic phase
4the enchylema of cell/ml, is inoculated in 96 orifice plates by 1000/hole, and every hole adds 100 μ l.Add the fresh culture containing different concns medicine and coordinative solvent contrast next day, every hole adds 100 μ l(DMSO final concentration <0.5%), 5 ~ 7 dosage groups established by every medicine, often organize and at least establish three parallel holes, after continuing to cultivate 120hr in 37 DEG C, abandon supernatant, every hole adds the freshly prepared serum free medium containing 0.5mg/ml MTT of 100 μ l, continue to cultivate 4hr, abandon culture supernatant, every hole adds 200 μ l DMSO and dissolves MTT first hairpin precipitation, with microoscillator vibration mixing, by MK3 type microplate reader at reference wavelength 450nm, optical density value (OD) is measured under determined wavelength 570nm condition, with the tumour cell of solvent control process for control group, with the inhibiting rate of formulae discovery drug on tumor cell the following, and by middle effect Equation for Calculating IC
50:
MTT the selection result
Claims (14)
1. the propiolyl amino derivative shown in formula I, its pharmacologically acceptable salt;
In formula:
R
1be selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, sec.-propyl, the tertiary butyl, methylol, 1-hydroxyethyl, 1-hydroxyl sec.-propyl, phenyl, chlorophenyl, bromo phenyl, difluorophenyl, methylamino-, dimethylamino, diethylin, diisopropylaminoethyl;
R
2be selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, sec.-propyl, the tertiary butyl, isopropoxy, isobutoxy, isopentyloxy, different hexyloxy, tert.-butoxy, 2-methylbutoxy group, 3-methyl pentyloxy, 2-ethyl-butoxy, trifluoromethoxy, perchloro oxyethyl group, isopropylamino, i-butylamino, isoamylamino, tertiary fourth is amino, 2-methylbutylamino, 3-methylpentylamino, 2-ethyl fourth is amino, fluoroform is amino, perchloro ethylamino, isopropyisulfanyl, isobutylthio, isopentylthio, tertiary butylthio, 2-methylbutylthio, 3-methylpent sulfenyl, 2-ethyl butylthio, trifluoromethylthio, perchloro ethylmercapto group, the ring propoxy-replaced, the cyclobutoxy group replaced, the cyclohexyloxy replaced, the cyclopropylamino replaced, the ring fourth replaced is amino, the Cyclohexylamino replaced, the piperidines oxygen base replaced, the piperazine oxygen base replaced, the pyrroles's alkoxyl group replaced, the pyrroline oxygen base replaced, the pyrazoline oxygen base replaced, the pyrazoles alkoxyl group replaced, the tetrahydroglyoxaline oxygen base replaced, the imidazoles alkoxyl group replaced, the morpholine oxygen base replaced, the pyran oxygen base replaced, 1, the 3-dioxolane oxygen base replaced, Isosorbide-5-Nitrae-dioxane oxygen the base replaced, the piperidines replaced is amino, the piperazine replaced is amino, the tetramethyleneimine replaced is amino, the pyrroline replaced is amino, the pyrazoline replaced is amino, the pyrazolidine replaced is amino, the tetrahydroglyoxaline replaced is amino, the imidazolidine replaced is amino, the morpholine replaced is amino, the pyrans replaced is amino, 1, the 3-dioxolane replaced is amino, the Isosorbide-5-Nitrae replaced-dioxane is amino, the piperidyl replaced, the piperazinyl replaced, the pyrrolidyl replaced, the pyrrolinyl replaced, the pyrazolinyl replaced, the pyrazolidyl replaced, the imidazolinyl replaced, the imidazolidyl replaced, the morpholinyl replaced, wherein: substituting group is selected from fluorine, chlorine, bromine, hydroxyl, dimethylamino, cyano group, carboxyl, ester group, trifluoromethyl, sulfonamido, methanesulfonamido, methylsulfonyl, trifyl, sulfamyl, aminoacyl, alkylsulfonyl, methyl, ethyl, sec.-propyl, the tertiary butyl, methoxyl group, oxyethyl group, isopropoxy, tert.-butoxy, methylamino-, ethylamino, diethylin, isopropylamino, diisopropylaminoethyl, tertiary fourth is amino, cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, cyclopropane oxygen base, tetramethylene oxygen base, pentamethylene oxygen base, hexamethylene alkoxyl group, cyclopropane is amino, tetramethylene is amino, pentamethylene is amino, hexanaphthene is amino,
R2 also can be selected from having structure:
Wherein, D is selected from-O-,-S-,-NH-;
B and C is independently selected from singly-bound, H ,-O-,-N-,-S-,-CH
2-,-CH=CH-,-C ≡ C-, pyridyl, furyl, thienyl, pyrryl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl, bis-oxazolyl, phenyl, naphthyl,
A is selected from H, piperidyl, piperazinyl, pyrrolidyl, pyrrolinyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, morpholinyl, pyranyl, 1, 3-dioxolane base, 1, 4-dioxane base, pyridyl, furyl, thienyl, pyrryl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl, Er oxazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxyl group, oxyethyl group, isopropoxy, tert.-butoxy, methylamino-, ethylamino, diethylin, isopropylamino, diisopropylaminoethyl, tertiary fourth is amino, hydroxyl, dimethylamino, cyano group, carboxyl, ester group, sulfonamido, methanesulfonamido, methylsulfonyl, trifyl, sulfamyl, aminoacyl, alkylsulfonyl, n
1, n
2, n
3independently be selected from 0,1,2,3,4,5,
R3 is selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano group, amino, methylamino-, dimethylamino, carboxyl, ester group, methyl, trifluoromethyl, methoxyl group, trifluoromethoxy, sulfonamido, methanesulfonamido, methylsulfonyl, sulfamyl, ethanoyl, ethyl, sec.-propyl, the tertiary butyl, oxyethyl group, isopropoxy, tert.-butoxy, ethylamino, diethylin, isopropylamino, diisopropylaminoethyl, tertiary fourth is amino, cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, cyclopropane oxygen base, tetramethylene oxygen base, pentamethylene oxygen base, hexamethylene alkoxyl group, cyclopropane is amino, tetramethylene is amino, pentamethylene is amino, hexanaphthene is amino, piperidyl, piperazinyl, pyrrolidyl, pyrrolinyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, morpholinyl, piperidines oxygen base, piperazine oxygen base, pyrroles's alkoxyl group, pyrroline oxygen base, pyrazoline oxygen base, pyrazoles alkoxyl group, tetrahydroglyoxaline oxygen base, imidazoles alkoxyl group, morpholine oxygen base, pyran oxygen base, 1,3-dioxolane oxygen base, Isosorbide-5-Nitrae-dioxane oxygen base, piperidines is amino, piperazine is amino, tetramethyleneimine is amino, pyrroline is amino, pyrazoline is amino, pyrazolidine is amino, tetrahydroglyoxaline is amino, imidazolidine is amino, morpholine is amino, pyrans is amino, 1,3-dioxolane is amino, Isosorbide-5-Nitrae-dioxane is amino.
2., according to the compound of claim 1, it is characterized in that,
R
1more preferably from hydrogen, chlorine, bromine, methyl, ethyl, sec.-propyl, the tertiary butyl, methylol, 1-hydroxyethyl, 1-hydroxyl sec.-propyl, phenyl, chlorophenyl, dimethylamino;
R2 is more preferably from hydrogen, fluorine, chlorine, methyl, ethyl, sec.-propyl, the tertiary butyl, isopropoxy, isobutoxy, isopentyloxy, different hexyloxy, tert.-butoxy, 2-methylbutoxy group, 3-methyl pentyloxy, perchloro oxyethyl group, i-butylamino, isoamylamino, 2-methylbutylamino, 3-methylpentylamino, isopentylthio, 3-methylpent sulfenyl; R2 is also more preferably from having structure:
Wherein, D is selected from-O-,-S-,-NH-,
B and C is independently more preferably from singly-bound, H ,-O-,-N-,-S-,-CH
2-,-CH=CH-,-C ≡ C-, pyridyl, furyl, thienyl, pyrryl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl, bis-oxazolyl, phenyl;
A is more preferably from H, piperidyl, piperazinyl, pyrrolidyl, pyrrolinyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, morpholinyl, pyranyl, 1, 3-dioxolane base, 1, 4-dioxane base, pyridyl, furyl, thienyl, pyrryl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl, Er oxazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxyl group, oxyethyl group, isopropoxy, tert.-butoxy, methylamino-, ethylamino, diethylin, isopropylamino, diisopropylaminoethyl, tertiary fourth is amino, hydroxyl, dimethylamino, cyano group, carboxyl, ester group, sulfonamido, methanesulfonamido, methylsulfonyl, trifyl, sulfamyl, aminoacyl, alkylsulfonyl,
N
1, n
2, n
3independently be selected from 0,1,2,3,4,
R3 is more preferably from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano group, amino, methylamino-, dimethylamino, carboxyl, ester group, methyl, trifluoromethyl, methoxyl group, trifluoromethoxy, sulfonamido, methanesulfonamido, methylsulfonyl, sulfamyl, ethanoyl, ethyl, sec.-propyl, the tertiary butyl, oxyethyl group, isopropoxy, tert.-butoxy, ethylamino, diethylin, isopropylamino, diisopropylaminoethyl, tertiary fourth is amino, cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, cyclopropane oxygen base, tetramethylene oxygen base, cyclopropane is amino, tetramethylene is amino, piperidyl, piperazinyl, pyrrolidyl, pyrrolinyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, morpholinyl, piperidines oxygen base, piperazine oxygen base, pyrroles's alkoxyl group, pyrroline oxygen base, pyrazoline oxygen base, pyrazoles alkoxyl group, tetrahydroglyoxaline oxygen base, imidazoles alkoxyl group, morpholine oxygen base, pyran oxygen base, 1,3-dioxolane oxygen base, Isosorbide-5-Nitrae-dioxane oxygen base, piperidines is amino, piperazine is amino, tetramethyleneimine is amino, pyrroline is amino, pyrazoline is amino, pyrazolidine is amino, tetrahydroglyoxaline is amino, imidazolidine is amino, morpholine is amino, pyrans is amino, 1,3-dioxolane is amino, Isosorbide-5-Nitrae-dioxane is amino.
3., according to the compound of claim 2, it is characterized in that,
Wherein:
R
1more preferably from hydrogen, chlorine, bromine, methyl, ethyl, sec.-propyl, the tertiary butyl, methylol, 1-hydroxyethyl, 1-hydroxyl sec.-propyl, dimethylamino;
R2 is more preferably from hydrogen, fluorine, chlorine, methyl, ethyl, sec.-propyl, isopropoxy, isobutoxy, isopentyloxy, different hexyloxy, tert.-butoxy, 2-methylbutoxy group, 3-methyl pentyloxy, i-butylamino, isoamylamino, 2-methylbutylamino, 3-methylpentylamino, isopentylthio, 3-methylpent sulfenyl;
R2 is also more preferably from having structure:
Wherein, D is selected from-O-,-NH-,
B and C is independently more preferably from singly-bound, H ,-O-,-N-,-S-,-CH
2-,-CH=CH-,-C ≡ C-, pyridyl, furyl, thienyl, pyrryl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl, bis-oxazolyl, phenyl,
A is more preferably from H, piperidyl, piperazinyl, pyrrolidyl, pyrrolinyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, morpholinyl, pyranyl, 1, 3-dioxolane base, 1, 4-dioxane base, pyridyl, furyl, thienyl, pyrryl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl, Er oxazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxyl group, oxyethyl group, isopropoxy, tert.-butoxy, methylamino-, ethylamino, diethylin, isopropylamino, diisopropylaminoethyl, tertiary fourth is amino, hydroxyl, dimethylamino, cyano group, carboxyl, ester group, sulfonamido, methanesulfonamido, methylsulfonyl, trifyl, sulfamyl, aminoacyl, alkylsulfonyl,
N
1, n
2, n
3independently be selected from 0,1,2,3,4,
R3 is more preferably from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano group, amino, methylamino-, dimethylamino, carboxyl, ester group, methyl, trifluoromethyl, methoxyl group, trifluoromethoxy, sulfonamido, methanesulfonamido, methylsulfonyl, sulfamyl, ethanoyl, ethyl, sec.-propyl, the tertiary butyl, oxyethyl group, isopropoxy, tert.-butoxy, ethylamino, diethylin, isopropylamino, diisopropylaminoethyl, tertiary fourth amino.
4., according to the compound of claim 3, it is characterized in that,
R
1particularly preferably from hydrogen, chlorine, bromine, methyl, ethyl, sec.-propyl, the tertiary butyl, methylol, 1-hydroxyethyl, 1-hydroxyl sec.-propyl;
R2 is particularly preferably from hydrogen, fluorine, chlorine, methyl, sec.-propyl, isopropoxy, isobutoxy, isopentyloxy, different hexyloxy, tert.-butoxy, 2-methylbutoxy group, 3-methyl pentyloxy, i-butylamino, isoamylamino, 2-methylbutylamino, 3-methylpentylamino, isopentylthio;
R2 is also particularly preferably from having structure:
Wherein, D is selected from-O-,-NH-,
B and C is independently particularly preferably from singly-bound, H ,-O-,-N-,-S-,-CH
2-,-CH=CH-,-C ≡ C-pyridyl, furyl, thienyl, pyrryl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl, bis-oxazolyl, phenyl,
A is more preferably from H, piperidyl, piperazinyl, pyrrolidyl, pyrrolinyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, morpholinyl, pyranyl, 1, 3-dioxolane base, 1, 4-dioxane base, pyridyl, furyl, thienyl, pyrryl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl, Er oxazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxyl group, oxyethyl group, isopropoxy, tert.-butoxy, methylamino-, ethylamino, diethylin, isopropylamino, diisopropylaminoethyl, tertiary fourth is amino, hydroxyl, dimethylamino, cyano group, carboxyl, ester group, sulfonamido, methanesulfonamido, methylsulfonyl, trifyl, sulfamyl, aminoacyl, alkylsulfonyl,
N
1, n
2, n
3independently be selected from 0,1,2,3;
R3 is particularly preferably from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano group, amino, methylamino-, dimethylamino, carboxyl, ester group, methyl, trifluoromethyl, methoxyl group, trifluoromethoxy, sulfonamido, methanesulfonamido, methylsulfonyl, sulfamyl, ethanoyl, ethyl, sec.-propyl, the tertiary butyl, oxyethyl group, isopropoxy, tert.-butoxy, ethylamino, diethylin, isopropylamino, diisopropylaminoethyl, tertiary fourth amino.
5., according to the compound of claim 4, it is characterized in that,
R
1most preferably from hydrogen, methyl, ethyl, sec.-propyl, the tertiary butyl;
R2 is most preferably from hydrogen, fluorine, chlorine, methyl, isopropoxy, isobutoxy, isopentyloxy, different hexyloxy, tert.-butoxy, 2-methylbutoxy group, 3-methyl pentyloxy;
R2 is also most preferably from having structure:
Wherein, D is selected from-O-,
B and C is independently particularly preferably from singly-bound, H ,-O-,-N-,-S-,-CH
2-,-CH=CH-,-C ≡ C-, A is most preferably from H, piperidyl, piperazinyl, pyrrolidyl, pyrrolinyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, morpholinyl, pyranyl, 1, 3-dioxolane base, pyridyl, furyl, thienyl, pyrryl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl, Er oxazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxyl group, oxyethyl group, isopropoxy, tert.-butoxy, methylamino-, ethylamino, diethylin, isopropylamino, diisopropylaminoethyl, tertiary fourth is amino, hydroxyl, dimethylamino, cyano group, carboxyl, ester group, sulfonamido, methanesulfonamido, methylsulfonyl, trifyl, sulfamyl, aminoacyl, alkylsulfonyl,
N
1, n
2, n
3independently be selected from 0,1,2,3;
R3 is most preferably from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano group, amino, methylamino-, dimethylamino, carboxyl, ester group, methyl, trifluoromethyl, methoxyl group, trifluoromethoxy, sulfonamido, methanesulfonamido, methylsulfonyl, sulfamyl, ethanoyl, ethyl, sec.-propyl, the tertiary butyl, oxyethyl group, isopropoxy, tert.-butoxy, diethylin, diisopropylaminoethyl.
6., according to the compound of claim 1-5, described compound is selected from:
2-(3-(crotonylene-amido)-4-p-methoxy-phenyl) benzothiazole
2-(3-(crotonylene-amido)-4-ethoxyl phenenyl) benzothiazole
2-(3-(crotonylene-amido)-4-propoxyphenyl) benzothiazole
2-(3-(crotonylene-amido)-4-ethoxyethoxy phenyl) benzothiazole
2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl) benzothiazole
2-(3-(crotonylene-amido)-4-(3-dimethylin propoxy-) phenyl) benzothiazole
2-(3-(crotonylene-amido)-4-(2-dimethylamino ethoxy) phenyl) benzothiazole
2-(3-(crotonylene-amido)-4-(2-piperidines-1-oxyethyl group) phenyl) benzothiazole
2-(3-(crotonylene-amido)-4-(2-thiophene-2-oxyethyl group) phenyl) benzothiazole
2-(3-(crotonylene-amido)-4-(2-morpholine-1-oxyethyl group) phenyl) benzothiazole
2-(3-(crotonylene-amido)-4-(3-morpholine-1-propoxy-) phenyl) benzothiazole
2-(3-(crotonylene-amido)-4-ring third p-methoxy-phenyl) benzothiazole
2-(3-(crotonylene-amido)-4-methoxyethoxy phenyl) benzothiazole
2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-5-methoxybenzothiazole
2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-5-chloro benzothiazole
2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-5-trifluoromethylbenzothiazole
2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-6-fluoro benzothiazole
2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-6-chloro benzothiazole
2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-6-bromo benzothiazole
2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-6-trifluoromethoxy benzo thiazole
2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-6-methylbenzothiazole
2-(3-(crotonylene-amido)-4-ethoxyethoxy ethoxyl phenenyl)-6-methoxybenzothiazole
2-(3-(crotonylene-amido)-4-(3-morpholine-1-propoxy-) phenyl)-6-methoxybenzothiazole
。
7., according to the compound of claim 1, it is characterized in that, described pharmacologically acceptable salt comprises: hydrochloride, hydrobromate, phosphoric acid salt, vitriol, mesylate, tosilate, acetate, trifluoroacetate, salicylate, amino acid salts, matrimony vine hydrochlorate, maleate, tartrate, fumarate, Citrate trianion, lactic acid salt.
8. prepare the method for the described compound of claim 1, comprise the steps:
Route 1
Route 2
Route 3
。
9. the preparation method of route 1 according to Claim 8, is characterized in that, first connects R2 group, then forms benzothiazole ring, last alkynes acidylate; In step (a) with to R2 M-NITROBENZOIC ACID 1 for raw material, be converted into acyl chlorides with common reagent and method, and then react with adjacent mercaptoaniline and generate acid amides, under sour environment, heat cyclization generate benzothiazole 2; Or acid 1 and adjacent mercaptoaniline directly generated acid amides by dewatering agent or condensing agent condensation and heated cyclization generate benzothiazole 2; In step (b), be that amido generates compound 3 by the nitroreduction in compound 2 by common methods; In step (c), acetylenic acid and compound 3 are dewatered by condensing agent, or alkynes acyl chlorides and 3 reacts and generates alkynyl amide target compound I.
10. the preparation method of route 2 according to Claim 8, is characterized in that, first forms benzothiazole ring, then connects R2 group; In step (a), with carboxylic compound 4 for raw material, form benzothiazole cyclic cpds 7 with the condensation of adjacent mercaptoaniline direct heating in the presence of a dehydrating agent; In step (b), with aldehyde compound 5 for raw material, under catalyzer is as dibrominated zinc or palladium existence, form benzothiazole cyclic cpds 7 with adjacent mercaptoaniline direct polycondensation; In step (c), with chloride compounds 6 for raw material, first react with adjacent mercaptoaniline and generate acid amides, under sour environment, heat cyclization generate benzothiazole cyclic cpds 7; In step (d), compound 7 alkalescence (as salt of wormwood) environment under with R
2h reacting generating compound 2; In process step (e), be that amido generates compound 3 by the nitroreduction in compound 2 by common methods; In step (f), acetylenic acid and compound 3 are dewatered by condensing agent, or alkynes acyl chlorides and 3 reacts and generates alkynyl amide target compound I.
The preparation method of 11. routes 3 according to Claim 8, is characterized in that, first connects R2 group, then forms alkynyl amide, finally forms benzothiazole ring; In step (a) with compound 8 for raw material, be that amido generates compound 9 by its nitroreduction by common methods; In step (b), acetylenic acid and compound 9 are dewatered by condensing agent, or alkynes acyl chlorides and 9 reacts and generates alkynyl amide compound 10; In step (c), 10 Ester hydrolysis in the basic conditions or under enzymatic condition obtain carboxylic acid cpd 12; In step (d), be converted into acyl chlorides by 12 with common reagent and method, and then react with adjacent mercaptoaniline and generate acid amides, under sour environment, heat cyclization generate benzothiazole target compound I; Or acid 12 and adjacent mercaptoaniline directly generated acid amides by dewatering agent or condensing agent condensation and heat cyclization generate benzothiazole target compound I; In step (e), be aldehyde 11 with reductive agent by compound 10 direct-reduction; In step (f), compound 11 directly obtains benzothiazole target compound I with adjacent mercaptoaniline condensation under catalyzer is as dibrominated zinc or palladium existence.
The composition of 12. 1 kinds of medicines, is characterized in that, the compound containing claim 1 and technology of pharmaceutics acceptable carrier.
The application of compound in the medicine preparing prevention and therapy tumor disease of 13. claims 1.
14. application according to claim 13, is characterized in that, described tumor disease is liver cancer, kidney, lung cancer, carcinoma of the pancreas, cancer of the stomach, colorectal cancer, bladder cancer, mammary cancer, ovarian cancer, skin carcinoma, thyroid carcinoma, leukemia, squamous cell carcinoma, neurospongioma, incidence cancer.
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| CN110698426A (en) * | 2019-11-04 | 2020-01-17 | 陕西师范大学 | Method for preparing 1, 3-benzothiazole derivative by efficient catalysis of potassium tert-butoxide |
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| CN110698426A (en) * | 2019-11-04 | 2020-01-17 | 陕西师范大学 | Method for preparing 1, 3-benzothiazole derivative by efficient catalysis of potassium tert-butoxide |
| CN110698426B (en) * | 2019-11-04 | 2022-08-23 | 陕西师范大学 | Method for preparing 1, 3-benzothiazole derivative by efficient catalysis of potassium tert-butoxide |
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