CN104974104B - Propine amide derivatives and its preparation method and pharmaceutical composition and purposes containing oxazole - Google Patents
Propine amide derivatives and its preparation method and pharmaceutical composition and purposes containing oxazole Download PDFInfo
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- CN104974104B CN104974104B CN201410132933.6A CN201410132933A CN104974104B CN 104974104 B CN104974104 B CN 104974104B CN 201410132933 A CN201410132933 A CN 201410132933A CN 104974104 B CN104974104 B CN 104974104B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D263/57—Aryl or substituted aryl radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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 benzoxazoles 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 ortho-aminophenol and generates amide, cyclization is heated under acidic environment and generates benzoxazoles 2；Or by acid 1 and o-hydroxy
Amine directly passes through dehydrating agent or condensing agent condensation generates amide and heats cyclization and generates benzoxazoles 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 benzoxazoles ring, reconnects R2 group.
It is raw material with carboxyl compound 4 in step (a), directly heats condensation with ortho-aminophenol in the presence of a dehydrating agent
Form benzoxazoles 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 hydroxyl
Base aniline direct polycondensation forms benzoxazoles cycle compound 7.
It is raw material with chloride compounds 6 in step (c), is first reacted with ortho-aminophenol and generate amide, under acidic environment
It heats cyclization and generates benzoxazoles 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 benzoxazoles 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 ortho-aminophenol and generates acyl
Amine heats cyclization under acidic environment and generates benzoxazoles target compound I；Or acid 12 is directly passed through with ortho-aminophenol de-
Aqua or condensing agent condensation, which generate amide and heat cyclization, generates benzoxazoles 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 ortho-aminophenol in the presence of catalyst such as dibrominated zinc or palladium acetate
Conjunction obtains benzoxazoles 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) -5- bromine benzoxazoles
The synthesis of 2- (the fluoro- 3- nitrobenzophenone of 4-) -5- bromine benzoxazoles:
Under stirring, 2- amino-4-bromophenol (935mg, 5.0mmol) is added to the fluoro- 3- nitrobenzoyl chloride of 4-
It in the Isosorbide-5-Nitrae-dioxane solution of (5.0mmol), is added dropwise methanesulfonic acid (1ml, 15.0mmol), is heated to 100 DEG C of reaction 3h, depressurize
Steam 1,4- dioxane.Residual solution ethyl acetate/saturation NaHCO3Extraction, organic phase saturation NaHCO3And NaCl solution
It successively washs, anhydrous Na2SO4It dries, filters, concentration rear pillar chromatography obtains pale solid 1.03g.
The synthesis of 2- (3- nitro -4- methoxyphenyl) -5- bromine benzoxazoles:
Compound 2- (the fluoro- 3- nitrobenzophenone of 4-) -5- bromine benzoxazoles (403mg, 1.2mmol) is dissolved in 70mlDMF, adds
Enter methanol (192mg, 6.0mmol), cesium carbonate (1.95g, 6.0mmol), reacts at room temperature 12h.With ethyl acetate/water extraction after concentration
It takes, organic phase water and saturation NaCl solution are successively washed, anhydrous Na2SO4It dries, filters, yellow powder is obtained after concentration
489mg。。
The synthesis of 2- (3- amino-4-methoxyl phenyl) -5- bromine benzoxazoles:
Compound 2- (3- nitro -4- methoxyphenyl) -5- bromine benzoxazoles (489mg, 1.4mmol) is dissolved in 10ml methanol
In, 1ml water, NH is added4Cl (752mg, 14.0mmol), Zn (912mg, 14.0mmol), back flow reaction 2h are filtered to remove Zn,
It is successively washed after concentration with ethyl acetate/water extraction, organic phase water and saturation NaCl solution, anhydrous Na2SO4It dries, filters,
Yellow solid 280mg is obtained after concentration.
The synthesis of 2- (3- (crotonylene-acylamino-) -4- methoxyphenyl) -5- bromine benzoxazoles:
Tetrolic acid (102mg, 1.2mmol) is dissolved in 10ml benzene, is added oxalyl chloride (228mg, 1.8mmol), 50 DEG C anti-
3h is answered, benzene and oxalyl chloride is evaporated off.Butine acyl chlorides adds anhydrous THF to dissolve, and 2- (3- amino-4-methoxyl phenyl)-is added drop-wise at 0 DEG C
In the THF and pyridine solution of 5- bromine benzoxazoles (84mg, 0.24mmol), reaction 4h, reaction solution are warmed to room temperature after being added dropwise
With ethyl acetate/saturation NaHCO3Extraction, organic phase saturation NaHCO3It is successively washed with NaCl solution, anhydrous Na2SO4It is dry,
Filtering, concentration rear pillar chromatography, re-crystallizing in ethyl acetate obtain faint yellow solid 70mg.1H NMR(DMSO-d6,400MHz)δ:9.83
(s, 1H ,-CONH-), 8.62 (s, 1H, ArH), 7.99~7.96 (m, 2H, ArH), 7.75~7.73 (d, 1H, ArH), 7.54~
7.52 (dd, 1H, ArH), 7.28~7.26 (d, 1H, ArH), 3.92 (s, 3H ,-OCH3),2.04(s,3H,-CH3).MS(FAB)
(M++ 1=386)
Embodiment 2.2- (3- (crotonylene-acylamino-) -4- ethoxyl phenenyl) -5- bromine benzoxazoles
2- (3- amino-4-methoxyl phenyl) -5- is replaced with 2- (3- amino -4- ethoxyl phenenyl) -5- bromine benzoxazoles
Bromine benzoxazoles, the operating process of reference implementation example 1 obtain 2- (3- (crotonylene-acylamino-) -4- ethoxyl phenenyl) -5- bromine
Benzoxazoles faint yellow solid.1H NMR(400MHz,DMSO-d6)δ:9.73(s,1H,-CONH-),8.63(s,1H,ArH),
7.98~7.93 (m, 2H, ArH), 7.75~7.73 (d, 1H, ArH), 7.54~7.52 (d, 1H, ArH), 7.26~7.24 (d,
1H, ArH), 4.22~4.17 (q, 2H ,-OCH2-),2.05(s,3H,-CH3), 1.41~1.38 (t, 3H ,-CH2CH3).MS
(FAB) (M++ 1=400)
Embodiment 3.2- (3- (crotonylene-acylamino-) -4- propoxyphenyl) -5- bromine benzoxazoles
2- (3- amino-4-methoxyl phenyl) -5- is replaced with 2- (3- amino -4- propoxyphenyl) -5- bromine benzoxazoles
Bromine benzoxazoles, the operating process of reference implementation example 1 obtain 2- (3- (crotonylene-acylamino-) -4- propoxyphenyl) -5- bromine
Benzoxazoles faint yellow solid.1H NMR(300MHz,DMSO-d6)δ:9.75(s,1H,-CONH-),8.60(s,1H,ArH),
8.00~7.95 (m, 2H, ArH), 7.78~7.72 (m, 1H, ArH), 7.56~7.54 (m, 1H, ArH), 7.29~7.24 (m,
1H, ArH), 4.11~4.05 (m, 2H ,-OCH2-),2.06(s,3H,-CH3), 1.83~1.78 (m, 2H ,-CH2), 1.05~
0.97(t,3H,-CH3) .MS (FAB) (M++ 1=414)
Embodiment 4.2- (3- (crotonylene-acylamino-) -4- methoxyethoxy phenyl) -5- bromine benzoxazoles
2- (3- amino-4-methoxyl benzene is replaced with 2- (3- amino -4- methoxyethoxy phenyl) -5- bromine benzoxazoles
Base) -5- bromine benzoxazoles, the operating process of reference implementation example 1 obtains 2- (3- (crotonylene-acylamino-) -4- methoxyethoxy
Phenyl) -5- bromine benzoxazoles white solid.1H NMR(400MHz,DMSO-d6)δ:9.68(s,1H,-CONH-),8.66(s,
1H, ArH), 8.00~7.93 (m, 2H, ArH), 7.76~7.74 (d, 1H, ArH), 7.55~7.52 (dd, 1H, ArH), 7.32
~7.30 (d, 1H, ArH), 4.28~4.26 (t, 2H ,-OCH2), 3.75~3.72 (t, 2H ,-OCH2-),3.33(s,3H,-
OCH3),2.05(s,3H,-CH3) .MS (FAB) (M++ 1=430)
Embodiment 5.2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy phenyl) -5- bromine benzoxazoles
2- (3- amino-4-methoxyl benzene is replaced with 2- (3- amino -4- ethoxyethoxy phenyl) -5- bromine benzoxazoles
Base) -5- bromine benzoxazoles, the operating process of reference implementation example 1 obtains 2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy
Phenyl) -5- bromine benzoxazoles white solid.1H NMR(400MHz,DMSO-d6)δ:9.63(s,1H,-CONH-),8.66(s,
1H, ArH), 7.99~7.93 (m, 2H, ArH), 7.76~7.74 (d, 1H, ArH), 7.55~7.53 (d, 1H, ArH), 7.33~
7.31 (d, 1H, ArH), 4.28~4.26 (t, 2H ,-OCH2), 3.76~3.75 (t, 2H ,-OCH2), 3.53~3.51 (t,
2H,-OCH2-),2.05(s,3H,-CH3), 1.15~1.11 (t, 3H ,-CH3) .MS (FAB) (M++ 1=444)
Embodiment 6.2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -5- bromine benzoxazoles
2- (3- amino-4-methoxyl is replaced with 2- (3- amino -4- ethoxyethoxy ethoxyl phenenyl) -5- bromine benzoxazoles
Phenyl) -5- bromine benzoxazoles, the operating process of reference implementation example 1 obtains 2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy
Ethoxyl phenenyl) -5- bromine benzoxazoles white solid.1H NMR(400MHz,DMSO-d6)δ:9.63(s,1H,-CONH-),
8.63 (s, 1H, ArH), 7.99~7.92 (m, 2H, ArH), 7.75~7.73 (d, 1H, ArH), 7.54~7.52 (d, 1H,
), ArH 7.32~7.30 (d, 1H, ArH), 4.28~4.26 (t, 2H ,-OCH2), 3.83~3.81 (t, 2H ,-OCH2-),3.62
~3.60 (t, 2H ,-OCH2), 3.50~3.48 (t, 2H ,-OCH2), 3.43~3.41 (t, 2H ,-OCH2-),2.05(s,
3H ,-CH3), 1.09~1.06 (t, 3H ,-CH3) .MS (FAB) (M++ 1=488)
Embodiment 7.2- (3- (crotonylene-acylamino-) -4- cyclopropyl methoxyphenyl) -5- bromine benzoxazoles
2- (3- amino-4-methoxyl benzene is replaced with 2- (3- amino -4- cyclopropyl methoxyphenyl) -5- bromine benzoxazoles
Base) -5- bromine benzoxazoles, the operating process of reference implementation example 1 obtains 2- (3- (crotonylene-acylamino-) -4- cyclopropyl methoxyl group
Phenyl) -5- bromine benzoxazoles white solid.1H NMR(300MHz,DMSO-d6)δ:9.68(s,1H,-CONH-),8.60(s,
1H, ArH), 7.98~7.91 (m, 2H, ArH), 7.75~7.72 (d, 1H, ArH), 7.54~7.51 (d, 1H, ArH), 7.26~
7.23 (d, 1H, ArH), 4.01~3.98 (d, 2H ,-OCH2-),2.05(s,3H,-CH3), 1.41~1.29 (m, 1H ,-CH-),
0.61~0.56 (m, 2H ,-CH2), 0.40~0.36 (m, 2H ,-CH2) .MS (FAB) (M++ 1=426)
Embodiment 8.2- (3- (crotonylene-acylamino-) -4- decil phenyl) -5- bromine benzoxazoles
2- (3- amino-4-methoxyl benzene is replaced with 2- (3- amino -4- decil phenyl) -5- bromine benzoxazoles
Base) -5- bromine benzoxazoles, the operating process of reference implementation example 1 obtains 2- (3- (crotonylene-acylamino-) -4- dimethylamine ethoxy
Base phenyl) -5- bromine benzoxazoles white solid.1H NMR(300MHz,DMSO-d6)δ:10.42(s,1H,-CONH-),8.75
(s, 1H, ArH), 8.02~7.92 (m, 2H, ArH), 7.79~7.73 (m, 1H, ArH), 7.57~7.54 (dd, 1H, ArH),
7.39~7.33 (m, 1H, ArH), 4.25~4.22(t, 2H ,-OCH2-), 2.63~2.61 (t, 2H ,-NCH2-),2.26(s,
6H,-NCH3),2.05(s,3H,-CH3) .MS (FAB) (M++ 1=443)
Embodiment 9.2- (3- (crotonylene-acylamino-) -4-(thiophene -2- methoxyl group) phenyl) -5- bromine benzoxazoles
With 2- (3- amino -4-(thiophene -2- methoxyl group) phenyl) -5- bromine benzoxazoles replaces 2- (3- amino-4-methoxyl
Phenyl) -5- bromine benzoxazoles, the operating process of reference implementation example 1 obtains 2- (3- (crotonylene-acylamino-) -4-(thiophene -2-
Methoxyl group) phenyl) -5- bromine benzoxazoles white solid.1H NMR(300MHz,DMSO-d6)δ:9.80(s,1H,-CONH-),
8.59 (s, 1H, ArH), 8.02~7.96 (m, 2H, ArH), 7.78~7.76 (d, 1H, ArH), 7.60~7.55 (m, 2H,
), ArH 7.46~7.43 (d, 1H, ArH), 7.32 (s, 1H, ArH), 7.08~7.06 (d, 1H, ArH), 5.51 (s, 2H ,-
OCH2-),2.06(s,3H,-CH3) .MS (FAB) (M++ 1=467)
Embodiment 10.2- (3- (crotonylene-acylamino-) -4-(pyridine -2- methoxyl group) phenyl) -5- bromine benzoxazoles
With 2- (3- amino -4-(pyridine -2- methoxyl group) phenyl) -5- bromine benzoxazoles replaces 2- (3- amino-4-methoxyl
Phenyl) -5- bromine benzoxazoles, the operating process of reference implementation example 1 obtains 2- (3- (crotonylene-acylamino-) -4-(pyridine -2-
Methoxyl group) phenyl) -5- bromine benzoxazoles faint yellow solid1H NMR(400MHz,DMSO-d6)δ:10.15(s,1H,-
), CONH- 8.60~8.58 (d, 2H, ArH), 7.99 (s, 1H, ArH), 7.93~7.91 (d, 1H, ArH), 7.85~7.82 (m,
1H, ArH), 7.75~7.73 (d, 1H, ArH), 7.61~7.59 (d, 1H, ArH), 7.54 (s, 1H, ArH), 7.37-7.34 (m,
1H, ArH), 7.30~7.28 (d, 1H, ArH), 5.37 (s, 2H ,-OCH2-),2.06(s,3H,-CH3) .MS (FAB) (M++1=
463)
Embodiment 11.2- (3- (crotonylene-acylamino-) -4-(pyridine -3- methoxyl group) phenyl) -5- bromine benzoxazoles
With 2- (3- amino -4-(pyridine -3- methoxyl group) phenyl) -5- bromine benzoxazoles replaces 2- (3- amino-4-methoxyl
Phenyl) -5- bromine benzoxazoles, the operating process of reference implementation example 1 obtains 2- (3- (crotonylene-acylamino-) -4-(pyridine -3-
Methoxyl group) phenyl) -5- bromine benzoxazoles faint yellow solid1H NMR(400MHz,DMSO-d6)δ:9.99(s,1H,-CONH-),
8.77~8.54 (m, 1H, ArH), 8.00~7.95 (m, 2H, ArH), 7.76-7.73 (m, 1H, ArH), 7.55~7.53 (d,
1H, ArH), 7.45~7.42 (m, 1H, ArH), 7.37~7.35 (d, 2H, ArH), 7.31~7.11 (m, 2H, ArH), 5.35
(s,2H,-OCH2-),2.04(s,3H,-CH3) .MS (FAB) (M++ 1=463)
Embodiment 12.2- (3- (crotonylene-acylamino-) -4-(4- methyl piperazine base) phenyl) -5- bromine benzoxazoles
With 2- (3- amino -4-(4- methyl piperazine base) phenyl) -5- bromine benzoxazoles replaces 2- (3- amino-4-methoxyl
Phenyl) -5- bromine benzoxazoles, the operating process of reference implementation example 1 obtains 2- (3- (crotonylene-acylamino-) -4-(4- methyl piperazine
Piperazine base) phenyl) -5- bromine benzoxazoles faint yellow solid1H NMR(300MHz,DMSO-d6)δ:9.48(s,1H,-CONH-),
8.48 (s, 1H, ArH), 8.02~8.00 (d, 2H, ArH), 7.78~7.76 (d, 1H, ArH), 7.58~7.56 (d, 1H,
), ArH 7.32~7.30 (d, 1H, ArH), 2.97 (s, 4H, -2NCH2-),2.54(s,4H,-2NCH2-),2.27(s,3H,-
NCH3),2.08(s,3H,-CH3) .MS (FAB) (M++ 1=454)
Embodiment 13.2- (3- (crotonylene-acylamino-) -4-(2- morpholine ethyoxyl) phenyl) -5- bromine benzoxazoles
With 2- (3- amino -4-(2- morpholine ethyoxyl) phenyl) -5- bromine benzoxazoles replaces 2- (3- amino-4-methoxyl
Phenyl) -5- bromine benzoxazoles, the operating process of reference implementation example 1 obtains 2- (3- (crotonylene-acylamino-) -4-(2- morpholine second
Oxygroup) phenyl) -5- bromine benzoxazoles faint yellow solid1H NMR(300MHz,DMSO-d6)δ:9.78(s,1H,-CONH-),
8.65 (s, 1H, ArH), 8.00~7.94 (m, 2H, ArH), 7.77~7.74 (d, 1H, ArH), 7.56~7.53 (d, 1H,
), ArH 7.36~7.33 (d, 1H, ArH), 4.31~4.28 (t, 2H ,-OCH2), 3.68~3.58 (t, 4H, 2-OCH2-),
2.82~2.75 (m, 6H, 3-NCH2-),2.05(s,3H,-CH3) .MS (FAB) (M++ 1=485)
Embodiment 14.2- (3- (crotonylene-acylamino-) -4-(2- morpholine ethyoxyl) phenyl) -6- bromine benzoxazoles
With 2- (3- amino -4-(2- morpholine ethyoxyl) phenyl) -6- bromine benzoxazoles replaces 2- (3- amino-4-methoxyl
Phenyl) -5- bromine benzoxazoles, the operating process of reference implementation example 1 obtains 2- (3- (crotonylene-acylamino-) -4-(2- morpholine second
Oxygroup) phenyl) -6- bromine benzoxazoles faint yellow solid.1HNMR(300MHz,DMSO-d6):δ(ppm):9.73(s,1H,-
), NHCO- 8.63 (s, 1H, ArH), 8.10 (s, 1H, ArH), 7.97~7.94 (d, 1H, ArH), 7.74~7.71 (d, 1H,
), ArH 7.56~7.54 (d, 1H, ArH), 7.37~7.33 (d, 1H, ArH), 4.29~4.26 (t, 2H ,-OCH2-), 3.64~
3.59(t,4H,-OCH2), 2.75~2.71 (t, 2H ,-NCH2), 2.50~2.48 (t, 4H ,-NCH2-),2.06(s,3H,-
CH3) .MS (FAB) (M++ 1=485)
Embodiment 15.2- (3- (crotonylene-acylamino-) -4-(2- morpholine ethyoxyl) phenyl) -7- bromine benzoxazoles
With 2- (3- amino -4-(2- morpholine ethyoxyl) phenyl) -7- bromine benzoxazoles replaces 2- (3- amino-4-methoxyl
Phenyl) -5- bromine benzoxazoles, the operating process of reference implementation example 1 obtains 2- (3- (crotonylene-acylamino-) -4-(2- morpholine second
Oxygroup) phenyl) -7- bromine benzoxazoles faint yellow solid.1H-NMR(300MHz,DMSO-d6):δ(ppm):9.75(s,1H,-
), NHCO- 8.63 (s, 1H, ArH), 7.98~7.95 (m, 1H, ArH), 7.78~7.76 (d, 1H, ArH), 7.62~7.60 (d,
1H, ArH), 7.37~7.31 (m, 2H, ArH), 4.30~4.26 (t, 2H ,-OCH2), 3.62~3.60 (t, 4H ,-OCH2-),
2.76~2.72 (t, 2H ,-NCH2), 2.50~2.48 (t, 4H ,-NCH2-),2.06(s,3H,-CH3) .MS (FAB) (M++1=
485)
Embodiment 16.2- (the third amino of 3- (crotonylene-acylamino-) -4-(3- morpholine) phenyl) -5- bromine benzoxazoles
With 2- (the third amino of 3- amino -4-(3- morpholine) phenyl) -5- bromine benzoxazoles replaces 2- (3- amino-4-methoxyl
Phenyl) -5- bromine benzoxazoles, the operating process of reference implementation example 1 obtains 2- (3- (crotonylene-acylamino-) -4-(3- morpholine third
Amino) phenyl) -5- bromine benzoxazoles faint yellow solid1H NMR(300MHz,DMSO-d6)δ:8.17(s,1H,-CONH-),
8.05~7.99 (m, 1H, ArH), 7.80 (s, 1H, ArH), 7.38 (s, 3H, ArH), 6.77~6.74 (d, 1H, ArH), 3.89
~3.86 (m, 4H, -2OCH2), 3.79 (s, 1H ,-NH-), 3.37~3.33 (t, 2H ,-NCH2), 2.69~2.55 (m, 6H ,-
3NCH2-),2.02(s,3H,-CH3), 1.98~1.94 (m, 2H ,-CH2) .MS (FAB) (M++ 1=498)
Embodiment 17.2- (3- (crotonylene-acylamino-) -4-(3- morpholine propoxyl group) phenyl)-benzoxazoles
The synthesis of N- (2- hydroxyl -5- bromophenyl) -3- nitro -4- (3- morpholine propoxyl group) benzamide
Compound 3- nitro -4- (3- morpholine propoxyl group) benzoic acid (1.0g, 2.88mmol) is dissolved in 20mlTHF, is stirred
Lower addition HATU (1.7g, 4.32mmol), TEA (1.2g, 11.52mmol) and o-aminophenol (629mg, 5.76mmol) are mixed,
React at room temperature 12h, reaction solution ethyl acetate/saturation NaHCO3Extraction, organic phase saturation NaHCO3It is successively washed with NaCl solution
It washs, anhydrous Na2SO4It dries, filters, concentration rear pillar chromatographs to obtain gray solid 0.780g.
The synthesis of 2- (3- nitro -4- (3- morpholine propoxyl group) phenyl) benzoxazoles
By compound N-(2- hydroxyl -5- bromophenyl) -3- nitro -4- (3- morpholine propoxyl group) benzamide (200mg,
It 0.50mmol) is dissolved in 10ml dimethylbenzene, is added p-methyl benzenesulfonic acid (210mg, 1.10mmol), back flow reaction 4h, reaction solution is used
Ethyl acetate/water extraction, organic phase water and saturation NaCl solution are successively washed, anhydrous Na2SO4It dries, filters, after concentration
Solid 0.190g.
The synthesis of 2- (3- amino -4- (3- morpholine propoxyl group) phenyl) benzoxazoles
Compound 2- (3- nitro -4- (3- morpholine propoxyl group) phenyl) benzoxazoles (190mg, 0.50mmol) is dissolved in
In 10ml methanol, 1ml water, NH is added4Cl (267mg, 5.00mmol) and Zn (325mg, 5.00mmol), back flow reaction 2h, mistake
Zn is filtered out, is successively washed after concentration with ethyl acetate/water extraction, organic phase water and saturation NaCl solution, anhydrous Na2SO4It is dry
Dry, filtering obtains light gray solid 0.170g after concentration.
The synthesis of 2- (3- (2- butine acylamino-) -4- (3- morpholine propoxyl group) phenyl) benzoxazoles
Tetrolic acid (81mg, 0.96mmol) is dissolved in 10ml benzene, is added oxalyl chloride (183mg, 1.44mmol), 50 DEG C anti-
3h is answered, benzene and oxalyl chloride is evaporated off.Butine acyl chlorides adds anhydrous THF to dissolve, and 2- (3- amino -4- (the third oxygen of 3- morpholine is added drop-wise at 0 DEG C
Base) phenyl) benzoxazoles (170mg, 0.48mmol) THF and pyridine solution in, be added dropwise move back to room temperature reaction 4h, instead
Answer liquid ethyl acetate/saturation NaHCO3Extraction, organic phase saturation NaHCO3It is successively washed with NaCl solution, anhydrous Na2SO4
It dries, filters, concentration rear pillar chromatography, re-crystallizing in ethyl acetate obtains white solid 0.070g.1H NMR(DMSO-d6,300MHz)δ:
9.75 (s, 1H ,-CONH-), 8.59 (s, 1H, ArH), 8.00~7.97 (d, 1H, ArH), 7.79~7.76 (m, 2H, ArH),
7.41~7.38 (m, 2H, ArH), 7.31~7.28 (d, 1H, ArH), 4.21~4.17 (t, 2H ,-OCH2), 3.60~3.57
(t,4H,2-OCH2), 2.50~2.44 (t, 2H ,-NCH2), 2.40~2.38 (t, 4H, 2-NCH2-),2.07(s,3H,-
CH3), 1.99~1.94 (m, 2H ,-CH2) .MS (FAB) (M++ 1=420)
Embodiment 18.2- (3- (crotonylene-acylamino-) -4-(3- morpholine propoxyl group) phenyl) -5- bromine benzoxazoles
Ortho-Aminophenol is replaced with 2- amino-4-bromophenol, the operating process of reference implementation example 17 obtains 2- (3- (fourth
Alkynes -2- acylamino-) -4-(3- morpholine propoxyl group) phenyl) -5- bromine benzoxazoles faint yellow solid.1H NMR(300MHz,DMSO-
d6) δ: 9.77 (s, 1H ,-CONH-), 8.60 (s, 1H, ArH), 8.01~7.96 (m, 2H, ArH), 7.78~7.75 (d, 1H,
), ArH 7.57~7.54 (dd, 1H, ArH), 7.31~7.28 (d, 1H, ArH), 4.21~4.17 (t, 2H ,-OCH2), 3.61
~3.59 (t, 4H, 2-OCH2), 2.50~2.48 (t, 2H ,-NCH2), 2.45~2.43 (t, 4H, 2-NCH2-),2.07(s,
3H,-CH3), 1.98~1.92 (m, 2H ,-CH2) .MS (FAB) (M++ 1=499)
Embodiment 19.2- (3- (crotonylene-acylamino-) -4-(3- morpholine propoxyl group) phenyl) -6- bromine benzoxazoles
Ortho-Aminophenol is replaced with 2- amino -5- bromophenol, the operating process of reference implementation example 17 obtains 2- (3- (fourth
Alkynes -2- acylamino-) -4-(3- morpholine propoxyl group) phenyl) -6- bromine benzoxazoles white solid.1H NMR(300MHz,DMSO-d6)
δ: 9.74 (s, 1H ,-CONH-), 8.56 (s, 1H, ArH), 8.08 (s, 1H, ArH), 7.96~7.93 (d, 1H, ArH), 7.72~
7.69 (d, 1H, ArH), 7.55~7.53 (d, 1H, ArH), 7.28~7.25 (d, 1H, ArH), 4.18~4.14 (t, 2H ,-
OCH2), 3.60~3.57 (t, 4H, 2-OCH2), 2.50~2.44 (t, 2H ,-NCH2), 2.38~2.36 (t, 4H, 2-
NCH2-),2.04(s,3H,-CH3), 1.96~1.92 (m, 2H ,-CH2) .MS (FAB) (M++ 1=499)
Embodiment 20.2- (3- (crotonylene-acylamino-) -4-(3- morpholine propoxyl group) phenyl) -7- bromine benzoxazoles
Ortho-Aminophenol is replaced with 2- amino -6- bromophenol, the operating process of reference implementation example 17 obtains 2- (3- (fourth
Alkynes -2- acylamino-) -4-(3- morpholine propoxyl group) phenyl) -7- bromine benzoxazoles white solid.1H NMR(300MHz,DMSO-d6)
δ: 9.78 (s, 1H ,-CONH-), 8.57 (s, 1H, ArH), 7.99~7.96 (m, 1H, ArH), 7.76~7.73 (d, 1H, ArH),
7.61~7.59 (d, 1H, ArH), 7.36~7.31 (m, 2H, ArH), 4.19~4.14 (t, 2H ,-OCH2-), 3.57~3.55
(t,4H,2-OCH2), 2.50~2.44 (t, 2H ,-NCH2), 2.38~2.36 (t, 4H, 2-NCH2-),2.06(s,3H,-
CH3), 1.96~1.92 (m, 2H ,-CH2) .MS (FAB) (M++ 1=499)
Embodiment 21.2- (3- (crotonylene-acylamino-) -4-(3- morpholine propoxyl group) phenyl) -6- fluorine benzoxazoles
Ortho-Aminophenol is replaced with 2- amino-5-fluorine phenol, the operating process of reference implementation example 17 obtains 2- (3- (fourth
Alkynes -2- acylamino-) -4-(3- morpholine propoxyl group) phenyl) -6- fluorine benzoxazoles LightPink solid.1H NMR(300MHz,DMSO-
d6) δ: 9.73 (s, 1H ,-CONH-), 8.56 (s, 1H, ArH), 7.94~7.91 (d, 1H, ArH), 7.79~7.75 (dd, 2H,
), ArH 7.28~7.21 (m, 2H, ArH), 4.18~4.14 (t, 2H ,-OCH2), 3.58~3.55 (t, 4H, 2-OCH2-),
2.48~2.42 (t, 2H ,-NCH2), 2.38~2.36 (t, 4H, 2-NCH2-), 2.04 (s, 3H ,-CH3), 1.96~1.92 (m,
2H,-CH2) .MS (FAB) (M++ 1=438)
Embodiment 22.2- (3- (crotonylene-acylamino-) -4-(3- morpholine propoxyl group) phenyl) -6- chlorobenzene diozaiole
Ortho-Aminophenol is replaced with 2- amino -5- chlorophenol, the operating process of reference implementation example 17 obtains 2- (3- (fourth
Alkynes -2- acylamino-) -4-(3- morpholine propoxyl group) phenyl) -6- chlorobenzene diozaiole white solid.1H NMR(300MHz,DMSO-d6)
δ: 9.74 (s, 1H ,-CONH-), 8.56 (s, 1H, ArH), 7.96~7.93 (d, 2H, ArH), 7.77~7.75 (d, 1H, ArH),
7.41~7.40 (d, 1H, ArH), 7.29~7.26 (d, 1H, ArH), 4.19~4.14 (t, 2H ,-OCH2), 3.57~3.55
(t,4H,2-OCH2), 2.50~2.44 (t, 2H ,-NCH2), 2.38~2.36 (t, 4H, 2-NCH2-),2.04(s,3H,-
CH3), 1.96~1.92 (m, 2H ,-CH2) .MS (FAB) (M++ 1=455)
Embodiment 23.2- (3- (crotonylene-acylamino-) -4-(3- morpholine propoxyl group) phenyl) -7- chlorobenzene diozaiole
Ortho-Aminophenol is replaced with 2- amino -6- chlorophenol, the operating process of reference implementation example 17 obtains 2- (3- (fourth
Alkynes -2- acylamino-) -4-(3- morpholine propoxyl group) phenyl) -7- chlorobenzene diozaiole white solid.1H NMR(300MHz,DMSO-
D6): δ (ppm): 9.78 (s, 1H ,-NHCO-), 8.58 (s, 1H, ArH), 7.99~7.97 (d, 1H, ArH), 7.76~7.73
(d, 1H, ArH), 7.50~7.48 (d, 1H, ArH), 7.42~7.37 (m, 1H, ArH) 7.30~7.27 (d, 1H, ArH) 4.19
~4.14 (t, 2H ,-OCH2), 3.57~3.55 (t, 4H ,-OCH2), 2.50~2.44 (t, 2H ,-NCH2), 2.38~2.36
(t,4H,-NCH2-),2.06(s,3H,-CH3), 1.96~1.92 (m, 2H ,-CH2) .MS (FAB) (M++ 1=455).
Embodiment 24.2- (3- (4- dimethylamino crotonylene-acylamino-) -4-(2- morpholine ethyoxyl) phenyl) -5- bromobenzene
And oxazole
By 2- (3- amino -4-(2- morpholine ethyoxyl) phenyl) -5- bromine benzoxazoles (136mg, 0.33mmol) is dissolved in
In 10ml methylene chloride, the dichloromethane solution of triphosgene (148mg, 0.5mmol), N is added2Lower normal-temperature reaction 12h is protected, it is dense
Add diethyl ether filtering after contracting reaction solution, obtains white solid.Dimethylaminopropyne (60mg, 0.66mmol) plus anhydrous THF dissolution ,-
In the cyclohexane solution (0.4ml, 0.66mmol) of 40 DEG C of dropwise addition n-BuLis, 1h is reacted.Obtained white solid is molten with THF
Reaction solution is added dropwise to after solution, after move to room temperature reaction 12h, reaction solution is extracted with ethyl acetate/water, organic phase 2N HCl
It is successively washed with NaCl solution, anhydrous Na2SO4It dries, filters, concentration rear pillar chromatography obtains 2- (3- (4- dimethylamino crotonylene-
Acylamino-) -4-(2- morpholine ethyoxyl) phenyl) -5- bromine benzoxazoles white solid.1H NMR(400MHz,DMSO-d6)δ:
8.84 (s, 1H ,-CONH-), 8.00 (s, 1H, ArH), 7.84~7.81 (dd, 1H, ArH), 7.78~7.75 (d, 1H, ArH),
7.56-7.54 (d, 2H, ArH), 7.27~7.25 (d, 1H, ArH), 4.29~4.26 (t, 2H ,-OCH2), 3.58~3.56
(t,4H,2-OCH2-),3.29(s,2H,-NCH2-),2.99(s,6H,-2NCH3), 2.79~2.77 (t, 2H ,-NCH2),
2.50~2.48 (t, 4H, 2-NCH2-).MS (FAB) (M++ 1=528)
Embodiment 25.2- (3- (phenyl propyne acylamino-) -4-(2- morpholine ethyoxyl) phenyl) -5- bromine benzoxazoles
Dimethylamine propine is replaced with phenylacetylene, the operating process of reference implementation example 21 obtains 2- (3- (phenyl propyne acyl ammonia
Base) -4-(2- morpholine ethyoxyl) phenyl) -5- bromine benzoxazoles white solid.1H NMR(400MHz,DMSO-d6)δ:10.08
(s, 1H ,-CONH-), 8.66 (s, 1H, ArH), 8.01~7.98 (d, 2H, ArH), 7.77~7.75 (d, 1H, ArH), 7.67-
7.65 (d, 2H, ArH), 7.56~7.49 (dd, 4H, ArH), 7.39~7.37 (d, 1H, ArH), 4.31~4.29 (t, 2H ,-
OCH2), 3.58~3.56 (t, 4H, 2-OCH2), 2.76~2.74 (t, 2H ,-NCH2), 2.50~2.48 (t, 4H, 2-
NCH2) .MS (FAB) (M++ 1=547)
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 (9)
1. propine amide derivatives or its officinal salt shown in Formulas I；
R1Selected from methyl, ethyl, isopropyl, tert-butyl, phenyl, chlorophenyl, difluorophenyl, dimethylamino methyl；
R2 is selected from isobutoxy, isoamoxy, dissident's oxygroup, 2- methyl butoxy, 3- methyl amoxy；
R2 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- ,-CH2,
A is selected from H, piperidyl, piperazinyl, pyrrolidinyl, morpholinyl, thienyl, pyridyl group, cyclopropyl, lignocaine, diformazan ammonia
Base,
n1,n2,n3It is respectively and independently selected from 0,1,2,3；
R3 is selected from fluorine, chlorine, bromine, cyano.
2. a kind of propine amide derivatives or its officinal salt, the derivative are selected from:
2- (3- (crotonylene-acylamino-) -4- hydroxy phenyl) benzoxazoles
2- (3- (crotonylene-acylamino-) -4- ethoxyl phenenyl) -5- bromine benzoxazoles
2- (3- (crotonylene-acylamino-) -4- propoxyphenyl) -5- bromine benzoxazoles
2- (3- (crotonylene-acylamino-) -4- methoxyethoxy phenyl) -5- bromine benzoxazoles
2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy phenyl) -5- bromine benzoxazoles
2- (3- (crotonylene-acylamino-) -4- ethoxyethoxy ethoxyl phenenyl) -5- bromine benzoxazoles
2- (3- (crotonylene-acylamino-) -4- cyclopropyl methoxyphenyl) -5- bromine benzoxazoles
2- (3- (crotonylene-acylamino-) -4- decil phenyl) -5- bromine benzoxazoles
2- (3- (crotonylene-acylamino-) -4- (thiophene -2- methoxyl group) phenyl) -5- bromine benzoxazoles
2- (3- (crotonylene-acylamino-) -4- (pyridine -2- methoxyl group) phenyl) -5- bromine benzoxazoles
2- (3- (crotonylene-acylamino-) -4- (pyridine -3- methoxyl group) phenyl) -5- bromine benzoxazoles
2- (3- (crotonylene-acylamino-) -4- (2- morpholine ethyoxyl) phenyl) -5- bromine benzoxazoles
2- (3- (crotonylene-acylamino-) -4- (2- morpholine ethyoxyl) phenyl) -6- bromine benzoxazoles
2- (3- (crotonylene-acylamino-) -4- (2- morpholine ethyoxyl) phenyl) -7- bromine benzoxazoles
2- (3- (crotonylene-acylamino-) -4- (the third amino of 3- morpholine) phenyl) -5- bromine benzoxazoles
2- (3- (crotonylene-acylamino-) -4- (3- morpholine propoxyl group) phenyl)-benzoxazoles
2- (3- (crotonylene-acylamino-) -4- (3- morpholine propoxyl group) phenyl) -5- bromine benzoxazoles
2- (3- (crotonylene-acylamino-) -4- (3- morpholine propoxyl group) phenyl) -6- bromine benzoxazoles
2- (3- (crotonylene-acylamino-) -4- (3- morpholine propoxyl group) phenyl) -7- bromine benzoxazoles
2- (3- (crotonylene-acylamino-) -4- (3- morpholine propoxyl group) phenyl) -6- fluorine benzoxazoles
2- (3- (crotonylene-acylamino-) -4- (3- morpholine propoxyl group) phenyl) -6- chlorobenzene diozaiole
2- (3- (crotonylene-acylamino-) -4- (3- morpholine propoxyl group) phenyl) -7- chlorobenzene diozaiole
2- (3- (diformazan ammonia propine acylamino-) -4- (2- morpholine ethyoxyl) phenyl) -5- bromine benzoxazoles
2- (3- (phenyl propyne acylamino-) -4- (2- morpholine ethyoxyl) phenyl) -5- bromine benzoxazoles
3. the compound according to claims 1 or 2, which is characterized in that the officinal salt includes: hydrochloride, hydrobromate,
Phosphate, sulfate, mesylate, tosilate, acetate, trifluoroacetate, salicylate, amino-acid salt, fructus lycii
Hydrochlorate, maleate, tartrate, fumarate, citrate, lactate.
4. the method for preparing the compound of claim 1, includes the following steps:
Route 1
Route 2
Route 3
5. according to the preparation method of claim 4 route 1, which is characterized in that R2 group is first connected, benzoxazoles ring is re-formed,
Last alkynes is acylated；To be raw material to R2 m-Nitrobenzoic Acid 1 in step (a), it is converted into acyl chlorides with common reagent and method, into
And reacted with ortho-aminophenol or adjacent mercaptoaniline and generate amide, cyclization is heated under acidic environment generates benzoxazoles 2；Or it will
Acid 1 directly passes through dehydrating agent with ortho-aminophenol or condensing agent condensation generates amide and heats cyclization and generates benzoxazoles 2；Step
(b) in, the nitro in compound 2 is reduced to amido with common methods and generates compound 3；In step (c), acetylenic acid and compound
3 react generation alkynyl amide target compound I with 3 by condensing agent dehydration or alkynes acyl chlorides.
6. according to the preparation method of claim 4 route 2, which is characterized in that be initially formed benzoxazoles ring, reconnect R2 group；
It is raw material with carboxyl compound 4 in step (a), directly heats condensation with ortho-aminophenol in the presence of a dehydrating agent and form benzo
Oxazole cycle compound 7；Be raw material with aldehyde compound 5 in step (b), in the presence of catalyst dibrominated zinc or palladium acetate with
Ortho-aminophenol direct polycondensation forms benzoxazoles cycle compound 7；It is raw material with chloride compounds 6 in step (c), it is first and adjacent
Hydroxyanilines reaction generates amide, and cyclization is heated under acidic environment and generates benzoxazoles cycle compound 7；In step (d), chemical combination
Object 7 under alkaline environment with R2H reaction generates compound 2；In step (e), with common methods by the nitro in compound 2 also
It originally was that amido generates compound 3；In step (f), acetylenic acid reacts generation with 3 by condensing agent dehydration or alkynes acyl chlorides with compound 3
Alkynyl amide target compound I.
7. according to the preparation method of claim 4 route 3, which is characterized in that first connect R2 group, re-form alkynyl amide, finally
Form benzoxazoles ring；With compound 8 it is raw material in step (a), its nitro is reduced to amido with common methods and generates chemical combination
Object 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 with often
The reagent and method seen are converted into acyl chlorides, and then react with ortho-aminophenol and generate amide, and it is raw that cyclization is heated under acidic environment
At benzoxazoles target compound I；Or acid 12 and ortho-aminophenol are directly passed through into dehydrating agent or condensing agent condensation generation amide
And it heats cyclization and generates benzoxazoles target compound I；In step (e), compound 10 is reduced directly to aldehyde 11 with reducing agent；
In step (f), compound 11 is directly condensed to yield benzo with ortho-aminophenol in the presence of catalyst dibrominated zinc or palladium acetate
Oxazole target compound I.
8. a kind of composition of drug, which is characterized in that the acceptable carrier of compound and galenic pharmacy containing claim 1.
9. application of the compound of claims 1 or 2 in the drug that preparation prevents and treats tumor disease, which is characterized in that
The tumor disease is lung cancer, cancer of pancreas, colorectal cancer, glioma.
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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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