CN104974109B - Propine amide derivatives and its preparation method and pharmaceutical composition and purposes containing thiazole - Google Patents
Propine amide derivatives and its preparation method and pharmaceutical composition and purposes containing thiazole Download PDFInfo
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- CN104974109B CN104974109B CN201410133649.0A CN201410133649A CN104974109B CN 104974109 B CN104974109 B CN 104974109B CN 201410133649 A CN201410133649 A CN 201410133649A CN 104974109 B CN104974109 B CN 104974109B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—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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- 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 present invention relates to propine amide derivatives shown in Formulas I, officinal salt, and preparation method thereof, the purposes of composition and such compound containing this one or more compound in terms for the treatment of tumor disease.
Description
Invention field
The present invention relates to propine amide derivatives shown in Formulas I, officinal salt, hydrate and solvate,
Polycrystalline and eutectic, the precursor or derivative of same biological function, and preparation method thereof, contain this one or more compound
The purposes of composition and such compound in terms for the treatment of tumor disease.
Background of invention
Recent years greatly promotees due to the raising of the understanding to enzyme and some other biomolecule relevant to disease
Into the discovery or development of the new drug for the treatment of disease, protein kinase is exactly a kind of important one kind studied extensively, it is one
Large family, it is related with the intracellular control of various signal transduction processes.Due to they structure and catalysis conservative it
Be considered evolving from a common ancestral gene.Nearly all kinases all contains a similar 250-300 ammonia
Base acid catalysis domain.These protein kinases are divided into multiple families, such as protein tyrosine kinase, egg according to the difference of phosphorylated substrate
White serine/threonine kinase, lipoid etc..Generally, protein kinase is turned by influencing a phosphoryl from a ribonucleoside triphosphote
It moves on to a protein receptor relevant to signal transduction pathway and carrys out signal transduction in mediated cell.These phosphorylated events, which are used as, divides
Sub switch adjusts the biological function of target protein, is finally excited and reacts to various extracellular and other stimulations.Kinases exists
In multilayer signal transduction path, receptor tyrosine kinase be located at Tumor Angiongesis Signal transduction pathway upstream and tumour it is thin
The upstream of born of the same parents' Signal transduction pathway.Serine/threonine protein kitase is located at tumour and the signal of Tumor Angiongesis cell turns
The downstream of guiding path.Research shows that block Raf/MEK/ERK in downstream by blocking VEGFR and pdgf receptor in upstream, it can
It reduces the angiogenesis of tumour simultaneously and inhibits the duplication of tumour cell, to hinder the growth of tumour.
In addition, stem cell (stem cell, SC) is a kind of cell with self-renewing and differentiation potential, it is divided into embryo
Stem cell and adult stem cell (ASC).Cancer may originate from the vicious transformation of normal ASC.When normal ASC is due to hereditary or outer
When boundary's factor mutagenesis, the adjusting of the access of self-renewing is abnormal, and differentiation and maturation obstacle or is dedifferented, and sc sample is converted to
Cancer cell.Therefore scientist is it is proposed that a kind of it is assumed that there are the cells of a small set of stem cell properties, referred to as sc sample cancer in cancerous tissue
Cell, i.e. cancer are in cell (cancer stem cell, CSC) or tumor stem cell.Research is thought, during Sc self-renewing
Abnormal signal is adjusted, and leads to its unconfined growth, generates CSC, it is likely to tumorigenic vital earliest events.
The signal transduction pathway for adjusting SC self-renewing process mainly has Hh (Hedgehog), wnL/beta-catenin and Notch
Deng the self-renewing process of these accesses participation hematopoiesis SC, nerve SC and mammary gland Sc etc..In rodent models, these
The abnormal of signal transduction pathway adjusts the generation for causing tumour；Experiments have shown that these are logical in the generating process of certain human tumors
Abnormal adjust on road also plays an important role.
Many diseases are associated with abnormal cell effect of protein kinase mediated event initiation.These disease packets
It includes, but is not limited to, tumour, inflammation disease, immunological diseases, bone disease, metabolic disease, neurological disease, cardiovascular and cerebrovascular disease, hormone
Relevant disease etc..Consequently found that being very important with searching kinases inhibitor as therapeutic agent.In addition, control
The adjusting of the signal transduction pathway of CSC self-renewing process is for inhibiting metastases to be also very important.Although many hairs
It is bright that very big contribution has been made to this field, but to improve medication effect, this field still is continuing to study.
Summary of the invention
The purpose of the present invention is to provide propine amide derivatives, officinal salt, solvations shown in general formula I
Object, prodrug, polycrystalline or eutectic.
Another object of the present invention is to provide the preparation methods of propine amide derivatives shown in general formula I.
A further object of the present invention is to provide a kind of pharmaceutical compositions containing propine amide derivatives shown in general formula I
Object.
Another object of the present invention is to provide purposes of such compound in anticancer drug.
In order to complete the purpose of the present invention, following technical solution can be used:
The present invention is to be related to having structure propine amide derivatives shown in general formula I:
Or its officinal salt, hydrate and solvate, polycrystalline and eutectic, the precursor of same biological function or spread out
Biology.
The invention also discloses the methods for preparing the compounds of this invention, including following route steps:
The method for preparing the compound of claim 1, includes the following steps:
Route 1
This route is characterized in that, first connects R2 group, re-forms benzothiazole ring, and last alkynes is acylated.
In step (a), to be raw material to R2 m-Nitrobenzoic Acid 1, it is converted into acyl chlorides with common reagent and method, in turn
It is reacted with adjacent mercaptoaniline and generates amide, cyclization is heated under acidic environment and generates benzothiazole 2；Or by acid 1 and adjacent sulfydryl benzene
Amine directly passes through dehydrating agent or condensing agent condensation generates amide and heats cyclization and generates benzothiazole 2.
In step (b), the nitro in compound 2 is reduced to amido with common methods and generates compound 3.
In step (c), acetylenic acid and compound 3 are reacted with 3 by condensing agent dehydration or alkynes acyl chlorides and generate alkynyl amide targeted
Close object I.
Route 2
This route is characterized in that, is initially formed benzothiazole ring, reconnects R2 group.
It is raw material with carboxyl compound 4 in step (a), directly heats condensation with adjacent mercaptoaniline in the presence of a dehydrating agent
Form benzothiazole cycle compound 7.
Be raw material with aldehyde compound 5 in step (b), in the presence of catalyst such as dibrominated zinc or palladium acetate with adjacent mercapto
Base aniline direct polycondensation forms benzothiazole cycle compound 7.
It is raw material with chloride compounds 6 in step (c), is first reacted with adjacent mercaptoaniline and generate amide, under acidic environment
It heats cyclization and generates benzothiazole cycle compound 7.
In step (d), compound 7 under alkaline (such as potassium carbonate) environment with R2H reaction generates compound 2.
In process step (e), the nitro in compound 2 is reduced to amido with common methods and generates compound 3.
In step (f), acetylenic acid and compound 3 are reacted with 3 by condensing agent dehydration or alkynes acyl chlorides and generate alkynyl amide targeted
Close object I.
Route 3
This route is characterized in that, is first connected R2 group, is re-formed alkynyl amide, eventually form benzothiazole ring.
With compound 8 it is raw material in step (a), its nitro is reduced to amido with common methods and generates compound 9.Step
(b) in, acetylenic acid and compound 9 are reacted with 9 by condensing agent dehydration or alkynes acyl chlorides and generate alkynyl amide compound 10.Step (c)
In, 10 ester hydrolysis obtains carboxylic acid compound 12 under alkaline condition or under the conditions of enzymatic.
In step (d), it is converted into acyl chlorides with common reagent and method by 12, and then is reacted with adjacent mercaptoaniline and generates acyl
Amine heats cyclization under acidic environment and generates benzothiazole target compound I；Or by acid 12 with neighbour mercaptoaniline directly pass through it is de-
Aqua or condensing agent condensation, which generate amide and heat cyclization, generates benzothiazole target compound I.
In step (e), compound 10 is reduced directly to aldehyde 11 with reducing agent.
In step (f), compound 11 directly contracts with adjacent mercaptoaniline in the presence of catalyst such as dibrominated zinc or palladium acetate
Conjunction obtains benzothiazole target compound I.
In addition, the starting material and intermediate in above-mentioned reaction are easy to get, or to those skilled in the art
It can be easy to synthesize with the conventional method in organic synthesis.
Propine amide derivatives described in Formulas I can exist in the form of solvate or non-solvent compound, using different
Solvent carries out crystallization and is likely to be obtained different solvates.Pharmaceutically acceptable salt described in Formulas I includes different acid-addition salts, such as
The acid-addition salts of following inorganic acid or organic acid: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, trifluoro second
Acid, fructus lycii acid, maleic acid, tartaric acid, fumaric acid, citric acid, lactic acid.All these salt within the scope of the present invention all can be used
Conventional method preparation.In the preparation process of the propine amide derivatives and its solvate and its salt, the not syncrystallization
Condition is likely to occur polycrystalline or eutectic.
The invention further relates to the pharmaceutical compositions using the compounds of this invention as active ingredient.The pharmaceutical composition can basis
Method preparation well known in the art.It can be by by the compounds of this invention and one or more pharmaceutically acceptable solids or liquid
Excipient and/or adjuvant combine, and any dosage form used suitable for human or animal is made.The compounds of this invention is in its pharmaceutical composition
In content be usually 0.1-95 weight %.
The compounds of this invention can be administered in a unit containing its pharmaceutical composition, and administration route can be enteron aisle
Or non-bowel, such 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 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, controlled release preparation, targeting preparation and various that the compounds of this invention, which can be made ordinary preparation, also be made,
Particulate delivery system.
In order to which tablet is made in the compounds of this invention, various excipient well known in the art can be widely used, including dilute
Release agent, binder, wetting agent, disintegrating agent, lubricant, glidant.Diluent can be starch, dextrin, sucrose, glucose, cream
Sugar, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate etc.；Wetting agent can be water, second
Alcohol, isopropanol etc.；Adhesive can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, Arabic gum
Slurry, gelatine size, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, card
Wave nurse, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrating agent can be dried starch, microcrystalline cellulose, low substituted hydroxy-propyl fiber
Element, crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxy second
Alkene sorbitan fatty acid ester, dodecyl sodium sulfate etc.；Lubricant and glidant can be talcum powder, silica, tristearin
Hydrochlorate, 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.
In order to which capsule is made in administration unit, effective component the compounds of this invention and diluent, glidant can be mixed
It closes, mixture is placed directly in hard capsule or soft capsule.It can also effective component the compounds of this invention is first and diluent, bonding
Particle or pellet is made in agent, disintegrating agent, then is placed in hard capsule or soft capsule.It is used to prepare each dilute of the compounds of this invention tablet
Release agent, binder, wetting agent, disintegrating agent, glidant kind can also be used for preparing the capsule of the compounds of this invention.
For injection is made in the compounds of this invention, water, ethyl alcohol, isopropanol, propylene glycol or their mixture can be used
Make solvent and appropriate solubilizer commonly used in the art, cosolvent, pH adjustment agent, osmotic pressure regulator is added.Solubilizer or hydrotropy
Agent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin etc.；PH adjustment agent can be phosphate, acetate, hydrochloric acid, hydrogen
Sodium oxide molybdena etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate etc..Such as prepare freeze-dried powder
Mannitol, glucose etc. can be also added as proppant in injection.
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 dosage of the compounds of this invention pharmaceutical composition is according to the property and serious journey to be prevented or be treated disease
The individual instances of degree, patient or animal, administration route and dosage form etc. can have large-scale variation.In general, of the present inventionization
The daily Suitable dosage ranges for closing object are 0.001-150mg/Kg weight, preferably 0.01-100mg/Kg weight.Above-mentioned dosage
With a dosage unit or several dosage unit administrations can be divided into, this depends on the clinical experience of doctor and including with other
The dosage regimen for the treatment of means.
The compound of the present invention or composition can individually be taken, or merge use with other treatment drug or symptomatic drugs.
When the compound of the present invention and other therapeutic agents, which exist, to act synergistically, its dosage should be adjusted according to the actual situation.
The compounds of this invention is multiple target point kinases inhibitor or its precursor, these protein kinases are according to phosphorylated substrate
Difference be divided into multiple families, such as protein tyrosine kinase, Protein Serine/threonine kinase, lipoid etc..Generally, albumen
Kinases is transferred to a protein receptor relevant to signal transduction pathway from a ribonucleoside triphosphote by influencing a phosphoryl
Carry out signal transduction in mediated cell.These phosphorylated events adjust the biological function of target protein as molecular switch, are finally swashed
Hair reacts to various extracellular and other stimulations.Kinases is present in multilayer signal transduction path, receptor tyrosine kinase
Positioned at the upstream of Tumor Angiongesis Signal transduction pathway and the upstream of tumour cell Signal transduction pathway.Serine/threonine
Protein kinase is located at the downstream of the Signal transduction pathway of tumour and Tumor Angiongesis cell.Research shows that by blocking in upstream
VEGFR and pdgf receptor block Raf/MEK/ERK in downstream, can reduce the angiogenesis of tumour simultaneously and inhibit tumour thin
The duplication of born of the same parents, to hinder the growth of tumour.The compounds of this invention bioavilability with higher can be used for a variety of mankind and dislike
The treatment of property tumour, is liver cancer including the tumor disease, gastric cancer, kidney, lung cancer, cancer of pancreas, colorectal cancer, bladder cancer and
Breast cancer, oophoroma, squamous cell carcinoma, glioma, leukaemia, head-neck carcinoma.
Specific embodiment
Invention is described further below with reference to embodiment, but is not limit the scope of the invention.
Determining instrument: NMR spectrum Vaariaan Mercury300 or 400 type Nuclear Magnetic Resonance.Mass spectrum is used
ZAD-2F and VG300 mass spectrograph.
Embodiment 1.2- (3- (crotonylene-acylamino-) -4- methoxyphenyl) benzothiazole
The synthesis of 2- (the fluoro- 3- nitrobenzophenone of 4-) benzothiazole
The fluoro- 3- nitrobenzoic acid (3.7g, 20mmol) of 4- is dissolved in the dry DCM of 50mL, the DMF of catalytic amount, ice are added
Oxalyl chloride (3.4mL, 40mmol) is added dropwise under water-bath, after stirring 30min, moves to and stirs 2h at room temperature.It is spin-dried for reaction solution, is added
40mL dry toluene, is made solution of acid chloride, and sealing is stand-by.It is dry that near amino thiophenols (2.5g, 20mmol) are dissolved in 20mL
Toluene in, stirring the solution of acid chloride prepared, N are added dropwise down2Protect lower 110 DEG C of reactions 3h.It is cooled to room temperature, reaction solution second
Acetoacetic ester (100ml) and saturated sodium bicarbonate solution (50mL) dilution, extraction, separate organic phase, water phase with ethyl acetate (2 ×
50ml), organic phase washing is collected, silica gel column chromatography after anhydrous sodium sulfate is dried, filtered, is concentrated obtains 2- (the fluoro- 3- nitrobenzene of 4-
Base) benzothiazole yellow solid 5.1g.1H NMR(300MHz,DMSO-d6):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- nitrobenzophenone) benzothiazole
2- (the fluoro- 3- nitrobenzophenone of 4-) benzothiazole (822mg, 3mmol) is dissolved in the dry DMF of 10mL, and methanol is added
(9mmol) and CsCO3(9mmol) reacts overnight at 25 DEG C.It is diluted with ethyl acetate (50mL), water (25mL) extraction, water is added
Layer is extracted twice with ethyl acetate (2 × 25mL), collects ethyl acetate layer, washing, anhydrous sodium sulfate drying.Filtering, decompression rotation
Solvent is removed, target compound 2- (4- methoxyl group -3- nitrobenzophenone) benzothiazole is obtained.
The synthesis of 2- (4- methoxyl group -3- aminophenyl) benzothiazole
2- (4- methoxyl group -3- nitrobenzophenone) benzothiazole (1.5mmol) is dissolved in methanol (15ml), zinc powder is added
(975mg, 15mmol) and ammonium chloride (802mg, 15mmol), 65 DEG C of reaction 2h.It is cooled to room temperature, filters, collect filtrate, be spin-dried for
Obtain crude product 2- (4- methoxyl group -3- aminophenyl) benzothiazole.Without isolation, it is directly used in and reacts in next step.
The synthesis of 2- (3- (crotonylene-acylamino-) -4- methoxyphenyl) benzothiazole
Tetrolic acid (252mg, 3mmol) is dissolved in benzene (5mL), is added dropwise oxalyl chloride (507mL, 6mmol), is reacted at 50 DEG C
2h.It is spin-dried for reaction solution, dry THF(5ml is added), butine solution of acid chloride is made, sealing is stand-by.By 2- (4- methoxyl group -3- ammonia
Base phenyl) benzothiazole (1.5mmol) is dissolved in dry THF(5mL), pyridine (0.16mL, 2mmol) and butine obtained is added
Solution of acid chloride reacts 3h at room temperature.Solvent is removed in rotation, and silica gel column chromatography obtains target compound 2- (3- (crotonylene-acylamino-) -4-
Methoxyphenyl) benzothiazole,1HNMR(300MHz,DMSO-d6):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,OCH3),2.05(s,3H,CH3).MS
(FAB) (M++ 1=323)
Embodiment 2.2- (3- (crotonylene-acylamino-) -4- ethoxyl phenenyl) benzothiazole
2- (4- methoxyl group -3- nitrobenzophenone) benzothiazole is replaced with 2- (4- ethyoxyl -3- nitrobenzophenone) benzothiazole,
The operating process of reference implementation example 1 obtains 2- (3- (crotonylene-acylamino-) -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,CH2),2.05(s,3H,CH3),1.42-1.37(t,3H,
CH3) .MS (FAB) (M++ 1=337)
Embodiment 3.2- (3- (crotonylene-acylamino-) -4- propoxyphenyl) benzothiazole
2- (4- methoxyl group -3- nitrobenzophenone) benzothiazole is replaced with 2- (4- propoxyl group -3- nitrobenzophenone) benzothiazole,
The operating process of reference implementation example 1 obtains 2- (3- (crotonylene-acylamino-) -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,CH2),2.05(s,3H,CH3),1.83-1.76(m,2H,
CH2), 1.03-0.98 (t, 3H, CH3) .MS (FAB) (M++ 1=351)
Embodiment 4.2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy phenyl) benzothiazole
2- (4- methoxyl group -3- nitrobenzophenone) benzo is replaced with 2- (4- ethoxyethoxy -3- nitrobenzophenone) benzothiazole
Thiazole, the operating process of reference implementation example 1 obtain 2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy phenyl) benzo thiophene
Azoles.1H NMR(300MHz,CDCl3):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,OCH2),3.79(m,2H,OCH2),3.64-3.57(m,2H,OCH2),2.01(s,3H,CH3),
1.29-1.24(m,3H,CH3).MS (FAB) (M++ 1=381)
Embodiment 5.2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) benzothiazole
2- (4- methoxyl group -3- nitrobenzophenone) is replaced with 2- (4- ethoxyethoxy ethyoxyl -3- nitrobenzophenone) benzothiazole
Benzothiazole, the operating process of reference implementation example 1 obtain 2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl)
Benzothiazole.1H NMR(300MHz,CDCl3):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,OCH2),3.90(m,2H,OCH2),3.72-3.54(m,6H,3OCH2),2.03(s,3H,CH3),1.22(m,3H,CH3).MS
(FAB) (M++ 1=425)
Embodiment 6.2- (3- (crotonylene-acylamino-) -4- (3- dimethylamino propoxyl group) phenyl) benzothiazole
2- (4- methoxyl group -3- nitrobenzene is replaced with 2- (4- (3- dimethylamino propoxyl group) -3- nitrobenzophenone) benzothiazole
Base) benzothiazole, the operating process of reference implementation example 1 obtains 2- (3- (crotonylene-acylamino-) -4- (third oxygen of 3- dimethylamino
Base) phenyl) benzothiazole.1H NMR(300MHz,CDCl3): 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,OCH2),2.71-2.59(m,2H,NCH2),2.37(s,6H,2NCH3),2.05(s,
1H,CH3),1.26(m,2H,CH2) .MS (FAB) (M++ 1=394)
Embodiment 7.2- (3- (crotonylene-acylamino-) -4- (2- dimethylamino ethoxy) phenyl) benzothiazole
2- (4- methoxyl group -3- nitrobenzene is replaced with 2- (4- (2- dimethylamino ethoxy) -3- nitrobenzophenone) benzothiazole
Base) benzothiazole, the operating process of reference implementation example 1 obtains 2- (3- (crotonylene-acylamino-) -4- (2- dimethylamino ethoxy
Base) phenyl) benzothiazole.1H NMR(300MHz,CDCl3): 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,OCH2),2.69(m,2H,NCH2),2.39(s,6H,
2NCH3),2.02(s,1H,CH3) .MS (FAB) (M++ 1=380)
Embodiment 8.2- (3- (crotonylene-acylamino-) -4-(2- piperidines -1- ethyoxyl) phenyl) benzothiazole
With 2- (4-(2- piperidines -1- ethyoxyl) -3- nitrobenzophenone) benzothiazole replaces 2- (4- methoxyl group -3- nitrobenzene
Base) benzothiazole, the operating process of reference implementation example 1 obtains 2- (3- (crotonylene-acylamino-) -4-(2- piperidines -1- ethoxy
Base) phenyl) benzothiazole.1H NMR(300MHz,CDCl3): 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,OCH2),2.72-2.68(t,2H,NCH2),2.51(s,4H,
2NCH2),2.02(s,1H,CH3),1.70-1.67(m,4H,2CH2),1.49-1.48(m,2H,CH2) .MS (FAB) (M++1=
420)
Embodiment 9.2- (3- (crotonylene-acylamino-) -4-(2- thiophene -2- ethyoxyl) phenyl) benzothiazole
With 2- (4-(2- thiophene -2- ethyoxyl) -3- nitrobenzophenone) benzothiazole replaces 2- (4- methoxyl group -3- nitrobenzene
Base) benzothiazole, the operating process of reference implementation example 1 obtains 2- (3- (crotonylene-acylamino-) -4-(2- thiophene -2- ethoxy
Base) phenyl) benzothiazole.1H NMR(300MHz,DMSO-d6):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,OCH2),3.17-3.12(t,2H,CH2),2.08(s,1H,CH3) .MS (FAB) (M++ 1=419)
Embodiment 10.2- (3- (crotonylene-acylamino-) -4-(2- morpholine -1- ethyoxyl) phenyl) benzothiazole
With 2- (4-(2- morpholine -1- ethyoxyl) -3- nitrobenzophenone) benzothiazole replaces 2- (4- methoxyl group -3- nitrobenzene
Base) benzothiazole, the operating process of reference implementation example 1 obtains 2- (3- (crotonylene-acylamino-) -4-(2- morpholine -1- ethoxy
Base) phenyl) benzothiazole.1H NMR(400MHz,DMSO-d6):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,OCH2),3.65-3.60
(m,4H,2OCH2),2.79(s,2H,NCH2),2.56(s,4H,2NCH2),2.07(s,3H,CH3) .MS (FAB) (M++ 1=422)
Embodiment 11.2- (3- (crotonylene-acylamino-) -4-(3- morpholine -1- propoxyl group) phenyl) benzothiazole
With 2- (4-(3- morpholine -1- propoxyl group) -3- nitrobenzophenone) benzothiazole replaces 2- (4- methoxyl group -3- nitrobenzene
Base) benzothiazole, the operating process of reference implementation example 1 obtains 2- (3- (crotonylene-acylamino-) -4-(3- morpholine third oxygen of -1-
Base) phenyl) benzothiazole.1H NMR(400MHz,DMSO-d6):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,OCH2),3.59(s,4H,
2OCH2),2.48-2.44(t,2H,NCH2),2.38(s,4H,2NCH2),2.07(s,3H,CH3),1.97-1.94(m,2H,
CH2) .MS (FAB) (M++ 1=436)
Embodiment 12.2- (3- (crotonylene-acylamino-) -4- cyclopropyl methoxyphenyl) benzothiazole
2- (4- methoxyl group -3- nitrobenzophenone) benzo is replaced with 2- (4- cyclopropyl methoxyl group -3- nitrobenzophenone) benzothiazole
Thiazole, the operating process of reference implementation example 1 obtain 2- (3- (crotonylene-acylamino-) -4- cyclopropyl methoxyphenyl) benzo thiophene
Azoles.1H NMR(400MHz,DMSO-d6):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,OCH2),2.07(s,3H,CH3),1.32(m,1H,CH),
0.63-0.58(m,2H,CH2),0.41-0.40(m,2H,CH2) .MS (FAB) (M++ 1=363)
Embodiment 13.2- (3- (crotonylene-acylamino-) -4- methoxyethoxy phenyl) benzothiazole
2- (4- methoxyl group -3- nitrobenzophenone) benzo is replaced with 2- (4- methoxyethoxy -3- nitrobenzophenone) benzothiazole
Thiazole, the operating process of reference implementation example 1 obtain 2- (3- (crotonylene-acylamino-) -4- methoxyethoxy phenyl) benzo thiophene
Azoles.1H NMR(400MHz,DMSO-d6):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,OCH2),3.74(s,2H,OCH2),3.35(s,3H,OCH3),
2.07(s,3H,CH3) .MS (FAB) (M++ 1=337)
Embodiment 14.2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -5- methoxybenzothiazole
The synthesis of two (4- methoxyl group -2- 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 overnight.It is cooled to room temperature, is acidified to pH2-3, K with concentrated hydrochloric acid2CO3Adjust pH to neutrality, ethyl acetate (200mL) extraction, water
Layer is extracted twice again with ethyl acetate (2 × 150mL), collects ethyl acetate layer, washing, anhydrous sodium sulfate drying.Filtering, decompression
Concentration, silica gel column chromatography obtain two sulphur of intermediate two (4- methoxyl group -2- amino) phenyl.
Two (4- methoxyl group -2-(3- nitro -4- fluorobenzoyl) amino) phenyl two sulphur synthesis
Two (4- methoxyl group -2- amino) phenyl, two sulphur (22mmol) is dissolved in dry toluene (40mL), the fluoro- 3- of 4- is added
Toluene (60mL) solution of nitrobenzoyl chloride (24.2mmol), 110 DEG C of reactions are overnight.It is cooled to room temperature, reaction solution is poured into
In saturated sodium bicarbonate solution, solid is precipitated, filters, is washed with water, drains up to two (4- methoxyl group -2-(3- nitro -4- fluorine
Benzoyl) amino) two sulphur of phenyl.
The synthesis of 2- (3- nitro -4- fluorophenyl) -5- methoxybenzothiazole
By two (4- methoxyl group -2-(3- nitro -4- fluorobenzoyl) amino) phenyl two sulphur (3.21g, 5mmoL) be dissolved in toluene
PTsOH(190mg, 1mmol is added in (50mL)) and PPh3(1.32g, 5mmol), 110 DEG C of reactions are overnight.It is cooled to room temperature, revolves
Dry solvent, ethyl acetate (200mL) extraction, aqueous layer with ethyl acetate (2 × 150mL) are extracted twice again, collect ethyl acetate layer,
Washing, anhydrous sodium sulfate are dry.Filtering, silica gel column chromatography obtains intermediate 2- (3- nitro -4- fluorophenyl) -5- first after reduced pressure
The synthesis of oxygroup benzothiazole.
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, adds
Enter carbitol (6.0mmol), cesium carbonate (1.95g, 6.0mmol), reacts at room temperature 12h.After concentration with ethyl acetate/
Water extraction, organic phase water and saturation NaCl solution are successively washed, anhydrous Na2SO4It dries, filters, 2- (3- nitro-is obtained after concentration
4- ethoxyethoxy ethoxyl phenenyl) -5- methoxybenzothiazole.
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
In 10ml methanol, 1ml water, NH is added4Cl (752mg, 14.0mmol), Zn (912mg, 14.0mmol), back flow reaction 2h, filtering
Zn is removed, is successively washed after concentration with ethyl acetate/water extraction, organic phase water and saturation NaCl solution, anhydrous Na2SO4It is dry
Dry, filtering obtains 2- (3- amino -4- ethoxyethoxy ethoxyl phenenyl) -5- methoxybenzothiazole after concentration.
The synthesis of 2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -5- methoxybenzothiazole:
Tetrolic acid (252mg, 3mmol) is dissolved in benzene (5mL), is added dropwise oxalyl chloride (507mL, 6mmol), is reacted at 50 DEG C
2h.It is spin-dried for reaction solution, dry THF(5ml is added), butine solution of acid chloride is made, sealing is stand-by.By 2- (3- amino -4- ethoxy
Ethoxyethoxy phenyl) -5- methoxybenzothiazole (1.5mmol) is dissolved in dry THF(5mL), be added pyridine (0.16mL,
2mmol) with butine solution of acid chloride obtained, 3h is reacted at room temperature.Solvent is removed in rotation, and silica gel column chromatography obtains target compound 2- (3-
(crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -5- methoxybenzothiazole.1H NMR(300MHz,DMSO-d6):
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,OCH2),3.86-
3.61(m,5H,OCH2,OCH3),3.52-3.51(m,2H,OCH2),3.48-3.44(m,2H,OCH2),3.43-3.40(m,2H,
OCH2),2.06(s,3H,CH3),1.12-1.07(m,3H,CH3) .MS (FAB) (M++ 1=455)
Embodiment 15.2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -5- chloro benzothiazole
2- amino -5- methoxybenzothiazole, the operation of reference implementation example 14 are replaced with 2- amino -5- chloro benzothiazole
Journey obtains 2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -5- chloro benzothiazole.1HNMR(400MHz,
DMSO-d6):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,OCH2),3.85-3.83
(m,2H,OCH2),3.64-3.62(s,2H,OCH2),3.51-3.53(m,2H,OCH2),3.45-3.43(m,2H,OCH2),
2.07(s,3H,CH3),1.10(m,3H,CH3) .MS (FAB) (M++ 1=459)
Embodiment 16.2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -5- trifluoromethyl benzo thiophene
Azoles
2- amino -5- methoxybenzothiazole is replaced with 2- amino -5- trifluoromethylbenzothiazole, reference implementation example 14
Operating process obtains 2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -5- trifluoromethylbenzothiazole.1H
NMR(300MHz,DMSO-d6):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,
OCH2),3.85(s,2H,OCH2),3.64-3.63(m,2H,OCH2),3.54-3.52(m,2H,OCH2),3.48-3.41(m,
2H,OCH2),2.07(s,3H,CH3),1.12-1.07(m,3H,CH3) .MS (FAB) (M++ 1=493)
Embodiment 17.2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -6- fluoro benzothiazole
2- amino -5- methoxybenzothiazole, the operation of reference implementation example 14 are replaced with 2- amino -6- fluoro benzothiazole
Journey obtains 2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -6- fluoro benzothiazole.1HNMR(300MHz,
DMSO-d6):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,OCH2),3.84-
3.82(m,2H,OCH2),3.65-3.63(m,2H,OCH2),3.53-3.51(m,2H,OCH2),3.47-3.42(m,2H,
OCH2),2.07(s,3H,CH3),1.12-1.09(m,3H,CH3) .MS (FAB) (M++ 1=443)
Embodiment 18.2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -6- chloro benzothiazole
2- amino -5- methoxybenzothiazole, the operation of reference implementation example 14 are replaced with 2- amino -6- chloro benzothiazole
Journey obtains 2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -6- chloro benzothiazole.1HNMR(400MHz,
DMSO-d6):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,OCH2),3.89-3.84(m,2H,OCH2),3.63-3.65(m,2H,OCH2),3.52-3.50(m,2H,OCH2),3.47-
3.42(m,2H,OCH2),2.07(s,3H,CH3),1.12-1.08(m,3H,CH3) .MS (FAB) (M++ 1=459)
Embodiment 19.2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -6- bromo benzothiazole
2- amino -5- methoxybenzothiazole, the operation of reference implementation example 14 are replaced with 2- amino -6- bromo benzothiazole
Journey obtains 2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -6- bromo benzothiazole.1HNMR(400MHz,
DMSO-d6):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,
OCH2),3.84(s,2H,OCH2),3.63(m,2H,OCH2),3.52(s,2H,OCH2),3.47-3.42(m,2H,OCH2),2.07
(s,3H,CH3),1.12-1.08(m,3H,CH3) .MS (FAB) (M++ 1=504)
Embodiment 20.2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -6- trifluoromethoxy benzo
Thiazole
2- amino -5- methoxybenzothiazole, reference implementation example 14 are replaced with trifluoromethoxybenzathiazole
Operating process, obtain 2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -6- trifluoromethoxy benzo thiophene
Azoles.1H NMR(400MHz,DMSO-d6):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,OCH2),3.85-3.64(m,2H,OCH2),3.62-3.58(m,2H,OCH2),3.53-
3.50(m,2H,OCH2),3.48-3.40(m,2H,OCH2),2.07(s,3H,CH3),1.12-1.06(m,3H,CH3).MS
(FAB) (M++ 1=509)
Embodiment 21.2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -6- methylbenzothiazole
2- amino -5- methoxybenzothiazole, the operation of reference implementation example 14 are replaced with 2- amino -6- methylbenzothiazole
Process obtains 2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -6- methylbenzothiazole.1HNMR
(400MHz,DMSO-d6):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,OCH2),3.82-3.84(m,2H,OCH2),3.64-3.62(m,2H,OCH2),3.53-3.51
(m,2H,OCH2),3.47-3.42(m,2H,OCH2),2.45(s,3H,CH3),2.07(s,3H,CH3),1.12-1.08(m,3H,
CH3) .MS (FAB) (M++ 1=439)
Embodiment 22.2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -6- methoxybenzothiazole
2- amino -5- methoxybenzothiazole, the behaviour of reference implementation example 14 are replaced with 2- amino -6- methoxybenzothiazole
Make process, obtains 2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -6- methoxybenzothiazole.1H NMR
(400MHz,DMSO-d6):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,OCH2),3.85-3.83(m,5H,OCH2,OCH3),3.66-3.62(m,2H,OCH2),3.53-3.50(m,2H,
OCH2),3.47-3.42(m,2H,OCH2),2.06(s,3H,CH3),1.11-1.08(m,3H,CH3) .MS (FAB) (M++ 1=455)
Embodiment 23.2- (3- (crotonylene-acylamino-) -4- (3- morpholine -1- propoxyl group) phenyl) -6- methoxyl group benzo thiophene
Azoles
Carbitol is replaced with 3- morpholine -1- propyl alcohol, the operating process of reference implementation example 22 obtains 2- (3- (fourth
Alkynes -2- acylamino-) -4- (3- morpholine -1- propoxyl group) phenyl) -6- methoxybenzothiazole.1H NMR(300MHz,DMSO-d6):
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,OCH2),
3.84-3.86(m,4H,2OCH2),3.61(s,3H,OCH3),2.47-2.44(m,4H,2NCH2),2.07(s,3H,CH3),
1.97(m,2H,NCH2),1.84-1.86(m,2H,CH2) .MS (FAB) (M++ 1=466)
Pharmacological activity
External activity evaluation:
Mtt assay measures tumor cell survival
It is 0.8~2 × 10 that concentration is configured to after the cell of logarithmic growth phase is digested with pancreatin4Cell/ml cell liquid,
96 orifice plates are inoculated in by 1000/hole, every hole adds 100 μ l.Next day addition drug containing various concentration and coordinative solvent compare new
Fresh culture medium, every hole add 100 μ l(DMSO final concentration < 0.5%), every medicine sets 5~7 dosage groups, and every group at least sets three in parallel
Supernatant is abandoned, every hole adds the serum-free of the MTT containing 0.5mg/ml of 100 μ l Fresh to train after 37 DEG C are continued to cultivate 120hr in hole
Base is supported, continues to cultivate 4hr, abandons culture supernatant, every hole adds 200 μ l DMSO dissolution MTT first hairpin precipitating, vibrated with microoscillator
It mixes, OD value (OD) is measured under the conditions of reference wavelength 450nm, Detection wavelength 570nm with MK3 type microplate reader, with solvent
The tumour cell of control treatment is control group, calculates drug to the inhibiting rate of tumour cell with following formula, and press middle efficacious prescriptions journey
Calculate IC50:
MTT the selection result
Claims (12)
1. propine amide derivatives shown in Formulas I, officinal salt；
In formula:
R1Selected from chlorine, bromine, methyl, ethyl, isopropyl, tert-butyl, methylol, 1- ethoxy, 1- hydroxyl isopropyl, dimethylamino；
R2Selected from fluorine, chlorine, methyl, ethyl, isopropyl, tert-butyl, isopropoxy, isobutoxy, isoamoxy, dissident's oxygroup, uncle
Butoxy, 2- methyl butoxy, 3- methyl amoxy, perchloro- ethyoxyl, i-butylamino, isoamylamino, 2- methylbutylamino,
3- methylpentylamino, isopentylthio, 3- methyl penta sulfenyl；
R2It is also selected from having structure:
Wherein, D is selected from-O- ,-S- ,-NH-,
B and C are respectively and independently selected from singly-bound ,-O- ,-N- ,-S- ,-CH2-；
A is selected from H, piperidyl, piperazinyl, morpholinyl, pyranose, 1,4- dioxane, furyl, thienyl, pyrrole radicals, miaow
Oxazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazoles base, cyclopropyl, cyclohexyl, methoxyl group, ethoxy
Base, isopropoxy, tert-butoxy, methylamino, ethylamino, lignocaine, isopropylamino, diisopropylaminoethyl, tertiary fourth amino, hydroxyl
Base, dimethylamino, cyano, carboxyl, methanesulfonamido, mesyl, trifyl, sulfamoyl, aminoacyl,
n1,n2,n30,1,2,3,4 are respectively and independently selected from,
R3Selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, amino, methylamino, dimethylamino, carboxyl, methyl, trifluoromethyl, methoxy
Base, trifluoromethoxy, methanesulfonamido, mesyl, sulfamoyl, acetyl group, ethyl, isopropyl, tert-butyl, ethyoxyl,
Isopropoxy, tert-butoxy, ethylamino, lignocaine, isopropylamino, diisopropylaminoethyl, tertiary fourth amino.
2. the compound according to claim 1, which is characterized in that
Wherein:
R1Selected from chlorine, bromine, methyl, ethyl, isopropyl, tert-butyl, methylol, 1- ethoxy, 1- hydroxyl isopropyl, dimethylamino；
R2Selected from fluorine, chlorine, methyl, ethyl, isopropyl, isopropoxy, isobutoxy, isoamoxy, dissident's oxygroup, tert-butoxy,
2- methyl butoxy, 3- methyl amoxy, i-butylamino, isoamylamino, 2- methylbutylamino, 3- methylpentylamino, isoamyl sulphur
Base, 3- methyl penta sulfenyl；
R2It is also selected from having structure:
Wherein, D is selected from-O- ,-NH-,
B and C are respectively and independently selected from singly-bound ,-O- ,-N- ,-S- ,-CH2,
A is selected from H, piperidyl, piperazinyl, morpholinyl, pyranose, 1,4- dioxane, pyrrole radicals, imidazole radicals, pyrazolyl, evil
Oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazoles base, cyclopropyl, cyclohexyl, methoxyl group, ethyoxyl, isopropoxy, first
Amino, ethylamino, lignocaine, isopropylamino, diisopropylaminoethyl, tertiary fourth amino, hydroxyl, dimethylamino, cyano, carboxyl, first
Sulfonamido, mesyl, trifyl, sulfamoyl, aminoacyl,
n1,n2,n30,1,2,3,4 are respectively and independently selected from,
R3Selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, amino, methylamino, dimethylamino, carboxyl, methyl, trifluoromethyl, methoxy
Base, trifluoromethoxy, methanesulfonamido, mesyl, sulfamoyl, acetyl group, ethyl, isopropyl, tert-butyl, ethyoxyl,
Isopropoxy, tert-butoxy, ethylamino, lignocaine, isopropylamino, diisopropylaminoethyl, tertiary fourth amino.
3. the compound according to claim 2, which is characterized in that
R1Selected from chlorine, bromine, methyl, ethyl, isopropyl, tert-butyl, methylol, 1- ethoxy, 1- hydroxyl isopropyl；
R2Selected from fluorine, chlorine, methyl, isopropyl, isopropoxy, isobutoxy, isoamoxy, dissident's oxygroup, tert-butoxy, 2- first
Base butoxy, 3- methyl amoxy, i-butylamino, isoamylamino, 2- methylbutylamino, 3- methylpentylamino, isopentylthio；
R2It is also selected from having structure:
Wherein, D is selected from-O- ,-NH-,
B and C are respectively and independently selected from singly-bound ,-O- ,-N- ,-S- ,-CH2,
A is selected from H, piperidyl, piperazinyl, morpholinyl, pyranose, 1,4- dioxane, pyrrole radicals, imidazole radicals, pyrazolyl, evil
Oxazolyl, thiazolyl, triazolyl, oxadiazoles base, cyclopropyl, cyclohexyl, methoxyl group, ethyoxyl, isopropoxy, tert-butoxy, first
Amino, ethylamino, lignocaine, isopropylamino, diisopropylaminoethyl, tertiary fourth amino, hydroxyl, dimethylamino, cyano, methylsulfonyl ammonia
Base, mesyl, trifyl, sulfamoyl, aminoacyl；
n1,n2,n3It is respectively and independently selected from 0,1,2,3；
R3Selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, amino, methylamino, dimethylamino, carboxyl, methyl, trifluoromethyl, methoxy
Base, trifluoromethoxy, methanesulfonamido, mesyl, sulfamoyl, acetyl group, ethyl, isopropyl, tert-butyl, ethyoxyl,
Isopropoxy, ethylamino, lignocaine, isopropylamino.
4. the compound according to claim 3, which is characterized in that
R1Selected from methyl, ethyl, isopropyl, tert-butyl；
R2Selected from fluorine, chlorine, methyl, isopropoxy, isobutoxy, isoamoxy, dissident's oxygroup, tert-butoxy, 2- methyl fourth oxygen
Base, 3- methyl amoxy；
R2It is also selected from having structure:
Wherein, D is selected from-O-,
B and C are respectively and independently selected from singly-bound ,-O- ,-N- ,-S- ,-CH2,
A is selected from H, piperidyl, piperazinyl, morpholinyl, pyranose, pyrrole radicals, imidazole radicals, pyrazolyl, thiazolyl, triazolyl, evil
Di azoly, cyclopropyl, cyclohexyl, methoxyl group, ethyoxyl, isopropoxy, tert-butoxy, methylamino, ethylamino, lignocaine,
Isopropylamino, diisopropylaminoethyl, tertiary fourth amino, hydroxyl, dimethylamino, cyano, carboxyl, methanesulfonamido, mesyl, trifluoro
Mesyl, sulfamoyl, aminoacyl；
n1,n2,n3It is respectively and independently selected from 0,1,2,3；
R3Selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, amino, methylamino, dimethylamino, methyl, trifluoromethyl, methoxyl group, trifluoro
Methoxyl group, methanesulfonamido, mesyl, sulfamoyl, acetyl group, ethyl, isopropyl, tert-butyl.
5. a kind of compound is selected from:
2- (3- (crotonylene-acylamino-) -4- methoxyphenyl) benzothiazole
2- (3- (crotonylene-acylamino-) -4- ethoxyl phenenyl) benzothiazole
2- (3- (crotonylene-acylamino-) -4- propoxyphenyl) benzothiazole
2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy phenyl) benzothiazole
2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) benzothiazole
2- (3- (crotonylene-acylamino-) -4- (3- dimethylamino propoxyl group) phenyl) benzothiazole
2- (3- (crotonylene-acylamino-) -4- (2- dimethylamino ethoxy) phenyl) benzothiazole
2- (3- (crotonylene-acylamino-) -4- (2- piperidines -1- ethyoxyl) phenyl) benzothiazole
2- (3- (crotonylene-acylamino-) -4- (2- thiophene -2- ethyoxyl) phenyl) benzothiazole
2- (3- (crotonylene-acylamino-) -4- (2- morpholine -1- ethyoxyl) phenyl) benzothiazole
2- (3- (crotonylene-acylamino-) -4- (3- morpholine -1- propoxyl group) phenyl) benzothiazole
2- (3- (crotonylene-acylamino-) -4- cyclopropyl methoxyphenyl) benzothiazole
2- (3- (crotonylene-acylamino-) -4- methoxyethoxy phenyl) benzothiazole
2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -5- methoxybenzothiazole
2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -5- chloro benzothiazole
2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -5- trifluoromethylbenzothiazole
2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -6- fluoro benzothiazole
2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -6- chloro benzothiazole
2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -6- bromo benzothiazole
2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -6- trifluoromethoxy benzo thiazole
2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -6- methylbenzothiazole
2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -6- methoxybenzothiazole
2- (3- (crotonylene-acylamino-) -4- (3- morpholine -1- propoxyl group) phenyl) -6- methoxybenzothiazole
6. the compound according to claim 1, which is characterized in that the officinal salt includes: hydrochloride, hydrobromate, phosphorus
Hydrochlorate, sulfate, mesylate, tosilate, acetate, trifluoroacetate, salicylate, amino-acid salt, fructus lycii acid
Salt, maleate, tartrate, fumarate, citrate, lactate.
7. the method for preparing the compound of claim 1, includes the following steps:
Route 1
Route 2
Route 3
8. preparation method according to claim 7, which is characterized in that in route 1, first connect R2Group re-forms benzothiazole
Ring, last alkynes are acylated；To R in step (a)2M-Nitrobenzoic Acid 1 is raw material, is converted into acyl with common reagent and method
Chlorine, and then reacted with adjacent mercaptoaniline and generate amide, cyclization is heated under acidic environment generates benzothiazole 2；Or by acid 1 with it is adjacent
Mercaptoaniline directly passes through dehydrating agent or condensing agent condensation generates amide and heats cyclization and generates benzothiazole 2；In step (b),
The nitro in compound 2 is reduced to amido with common methods and generates compound 3；In step (c), acetylenic acid passes through with compound 3
Condensing agent dehydration or alkynes acyl chlorides are reacted with 3 generates alkynyl amide target compound I.
9. preparation method according to claim 7, which is characterized in that in route 2, be initially formed benzothiazole ring, reconnect R2Base
Group；It is raw material with carboxyl compound 4 in step (a), directly heats condensation with adjacent mercaptoaniline in the presence of a dehydrating agent and form benzene
And thiazole cycle compound 7；It is raw material with aldehyde compound 5 in step (b), in the presence of catalyst dibrominated zinc or palladium acetate
Benzothiazole cycle compound 7 is formed with adjacent mercaptoaniline direct polycondensation；Be raw material with chloride compounds 6 in step (c), first with
Adjacent mercaptoaniline reaction generates amide, and cyclization is heated under acidic environment and generates benzothiazole cycle compound 7；In step (d), change
Close object 7 under alkaline environment with R2H reaction generates compound 2；In step (e), with common methods by the nitro in compound 2
It is reduced to amido and generates compound 3；In step (f), acetylenic acid reacts life with 3 by condensing agent dehydration or alkynes acyl chlorides with compound 3
At alkynyl amide target compound I.
10. preparation method according to claim 7, which is characterized in that in route 3, first connect R2Group re-forms alkynyl amide,
Eventually form benzothiazole ring；With compound 8 it is raw material in step (a), its nitro is reduced to amido with common methods and is generated
Compound 9；In step (b), acetylenic acid and compound 9 are reacted with 9 by condensing agent dehydration or alkynes acyl chlorides and generate alkynyl amide compound
10；In step (c), 10 ester hydrolysis obtains carboxylic acid compound 12 under alkaline condition or under the conditions of enzymatic；In step (d), by 12
It is converted into acyl chlorides with common reagent and method, and then is reacted with adjacent mercaptoaniline and generates amide, heats and closes under acidic environment
Ring generates benzothiazole target compound I；Or acid 12 and adjacent mercaptoaniline are directly passed through into dehydrating agent or condensing agent condensation generation
Amide simultaneously heats cyclization generation benzothiazole target compound I；In step (e), compound 10 is reduced directly to reducing agent
Aldehyde 11；In step (f), compound 11 is directly condensed to yield with adjacent mercaptoaniline in the presence of catalyst dibrominated zinc or palladium acetate
Benzothiazole target compound I.
11. a kind of composition of drug, which is characterized in that the acceptable carrier of compound and galenic pharmacy containing claim 1.
12. the compound of claim 1 is in the drug that preparation prevents and treats lung cancer, cancer of pancreas, colorectal cancer, head-neck carcinoma
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| WO1999006396A1 (en) * | 1997-07-29 | 1999-02-11 | Warner-Lambert Company | Irreversible bicyclic inhibitors of tyrosine kinases |
| CN102264745A (en) * | 2008-11-10 | 2011-11-30 | 财团法人卫生研究院 | Fused bicyclic and tricyclic pyrimidine compounds as tyrosine kinase inhibitors |
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| WO1999006396A1 (en) * | 1997-07-29 | 1999-02-11 | Warner-Lambert Company | Irreversible bicyclic inhibitors of tyrosine kinases |
| CN102264745A (en) * | 2008-11-10 | 2011-11-30 | 财团法人卫生研究院 | Fused bicyclic and tricyclic pyrimidine compounds as tyrosine kinase inhibitors |
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