CN103524409B - Quinolines and preparation method thereof and application - Google Patents

Quinolines and preparation method thereof and application Download PDF

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CN103524409B
CN103524409B CN201310446924.XA CN201310446924A CN103524409B CN 103524409 B CN103524409 B CN 103524409B CN 201310446924 A CN201310446924 A CN 201310446924A CN 103524409 B CN103524409 B CN 103524409B
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dimethoxy
quinoline
oxygen base
dihydroquinoline
methane amides
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CN103524409A (en
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不公告发明人
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Shanghai Yifeng Biotechnology Co.,Ltd.
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Shanghai Ren Li Pharmaceutical Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to medical art, particularly a class quinoline tyrosine kinase inhibitor, its preparation method and preparing the application in antitumor drug, this compounds has general structure (I): compound disclosed by the invention has good tyrosine-kinase enzyme inhibition activity, particularly VEGFR2 and VEGFR3 inhibit activities, part preferred compound has also carried out the research of hepatomicrosome metabolic rate, absorption characteristic research in Caco-2 model and pharmacokinetics research.

Description

Quinolines and preparation method thereof and application
Technical field
The present invention relates to medical art, particularly a class quinoline tyrosine kinase inhibitor, its preparation method and preparing the application in antitumor drug.
Background technology
Malignant tumour has a strong impact on one of human health, the principal disease threatening human life, and the World Health Organization and hygiene department of national governments are all classified as capture cancer as a top priority.At present, cancer therapy drug mainly cytotoxic drug conventional clinically, this kind of medicine has the shortcoming such as poor selectivity, strong, the easy generation resistance of toxic side effect being difficult to avoid because of its cytotoxic inherent nature.Therefore, find specificity high, toxicity is little, the new target drone of patient's better tolerance just become cancer therapy drug research in the urgent need to.In recent years, along with the develop rapidly of life science, numerous specificity target spot based on cancer cells generation, development mechanism is out identified, as: the vascular endothelial growth factor (VEGFR1 of Tumor suppression vasculogenesis, VEGFR2, VEGFR3) etc.Vasculogenesis (angiogenesis) refers to from already present blood vessel grows the vascular system made new advances.Normal vasculogenesis only exists, as reproduction, wound healing etc. in some short-term, specific physiological process.The vasculogenesis of exception is then one of pathological manifestations of the malignant diseases such as tumour, rheumatic arthritis, diabetic retinopathy.Since Folkman propose vasculogenesis and tumour develop closely-related hypothesis since, a large amount of clinical practices and experimental study confirm that vasculogenesis that Tumor suppression mediates can the growth of Tumor suppression and transfer effectively.
Vegf receptor is the important target of angiogenesis inhibitor.In recent years; the research of the micromolecular inhibitor of target vegf receptor is very active; the inhibitor of a large amount of configurations is in the news; but still there are some problems in these inhibitor at present; such as they are all the competitive inhibitors of ATP; and the ATP concentration in cell especially in cancer cells can reach more than 5mmol/L, therefore inhibitor activity at least should reach nmole level level and just can show effective restraining effect.In addition, vegf receptor belongs to Tyrosylprotein kinase superfamily, the conduction of bio signal in this family member's wide participation body.Due to the homology of sequence, the three-dimensional structure of their ATP-binding site is high conservative, therefore how to improve the selectivity of inhibitor in these family members of crucial importance.The present invention's design, synthesize novel VEGFR1, VEGFR2, VEGFR3 acceptor inhibitor series compound, find VEGFR2, VEGFR3 acceptor inhibitor that is efficient, low toxicity.
Summary of the invention
The object of the present invention is to provide the tyrosine kinase inhibitor of a class formation novelty, particularly VEGFR inhibitor; Another object of the present invention is to provide the preparation method of this compounds; Another object of the present invention is to provide the application of this compounds in preparation prevention or tumor.
Concrete technical scheme of the present invention is as follows:
In a first aspect of the present invention, in the process that contriver studies at antitumor drug, found that a class is such as formula the compound shown in I, or its each optical isomer, each crystal formation, pharmaceutically acceptable inorganic or organic salt, hydrate, solvate or prodrug, wherein structural formula I is:
Wherein R is selected from H, C 1-10alkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 1-6alkoxyl group, C 1-6alkylthio, C 1-6carbonyl, C 1-6the carbonylamino of carbalkoxy, carbonylamino, replacement, sulfuryl amino, phenyl, substituted-phenyl, cycloalkyl, substituted cycloalkyl, Heterocyclylalkyl, substituted heterocycle alkyl, heteroaryl or substituted heteroaryl.
Described " alkyl ", except as otherwise noted, refers to containing 1-10 carbon atom.Alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl.Described " alkoxyl group " refers to oxygen containing alkyl.The alkyl definition related in described alkoxyl group, alkylthio, alkyl carbonyl, alkoxy carbonyl etc. is as above-mentioned.
Described " thiazolinyl " refers to the straight or branched alkyl of 2-6 the carbon atom containing one or more carbon-carbon double bond.Include but not limited to vinyl, propenyl and butenyl.
Described " aryl ", except as otherwise noted, refers to the mononuclear aromatics containing 6 carbon atoms, the double ring arene of 10 carbon atoms, the thrcylic aromatic hydrocarbon of 14 carbon atoms, and each ring can have 1-4 substituting group.Aryl includes but not limited to phenyl, naphthyl, anthryl.
Described " cycloalkyl ", except as otherwise noted, refers to containing the saturated of 3-8 carbon atom or the undersaturated cyclic hydrocarbon of part.Cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl.
Described " heteroaryl ", refers to the double ring arene of the mononuclear aromatics of 5-8 atom, a 8-12 atom or the thrcylic aromatic hydrocarbon of 11-14 atom, and containing one or more heteroatomss (such as N, O, S).Heteroaryl includes but not limited to pyridyl, furyl, imidazolyl, benzimidazolyl-, pyrimidyl, thienyl, quinolyl, indyl.
Described " Heterocyclylalkyl ", refers to the monocycle non-aromatics alkyl containing 3-8 atom, the dicyclo of a 8-12 atom or the tricyclic hydrocarbon base of 11-14 atom, and containing one or more heteroatomss (such as N, O, S).Heterocyclylalkyl includes but not limited to piperazinyl, pyrrolidyl, alkyl dioxin, morpholinyl, tetrahydrofuran base.
The present invention also comprises all accordingly pharmaceutically acceptable salt of above-claimed cpd, hydrate or prodrug.These salt can by part positively charged in compound with there is the electronegative of opposite-sign formed; Or formed with positive charge by part electronegative in compound.
The compounds of this invention can contain a nonaromatic double bond, has one or more asymmetric center.So these compounds can exist as racemic mixture, independent enantiomer, independent diastereomer, non-enantiomer mixture, cis or trans-isomer(ide).All these isomer are all expected.
Described " prodrug of structural formula I " is often referred to a kind of material, after using by appropriate means, can carry out metabolism or chemical reaction and be transformed at least one compound or its salt of structural formula I in subject.
Preferably, the R group in formula I is selected from H, C 1-10alkyl, C 1-6alkoxyl group, or be selected from having structure unit:
Wherein, R 1, R 2independently be selected from H, halogen, C separately 1-6alkyl, C 1-6thiazolinyl, cyano group, C 1-6alkynyl, C 1-6alkoxyl group, nitro, trifluoromethyl, trifluoromethoxy or C 1-6alkyl-carbonyl.
Preferred, formula I compound of the present invention, is selected from following compound:
N-(2,4,4-trimethylpentane-2-base)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-01)
N-(2-ethylphenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-02)
N-(2,4-3,5-dimethylphenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-03)
N-(2-isopropyl phenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-04)
N-(4-n-butylphenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-05)
N-(4-p-methoxy-phenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-06)
N-(3-p-methoxy-phenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-07)
N-(2-p-methoxy-phenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-08)
N-(2-methoxyl group-5-aminomethyl phenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-10)
N-(4-acetylphenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-11)
N-(4-fluorophenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-12)
N-(3-fluorophenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-13)
N-(2-fluorophenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-14)
N-(2,4 difluorobenzene base)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-15)
N-(4-chloro-phenyl-)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-16)
N-(3-chloro-phenyl-)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-17)
N-(2-chloro-phenyl-)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-18)
N-(4-chloro-2-methyl phenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-19)
N-(4-(trifluoromethyl) phenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-20)
N-(2-(trifluoromethyl) phenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-21)
N-(4-cyano-phenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-22)
N-(2-chloro-4 nitrophenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H-methane amide (compound number KL-23)
N-(the chloro-3-nitrophenyl of 4-)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-24)
N-(2-methyl-4-nitrophenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-25)
N-cyclopentyl-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-26)
N-cyclohexyl-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-27)
N-(benzo ［ d ］ ［ 1,3 ］ dioxolane-5-base)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (compound number KL-28).
Compound listed by the present invention, as structural formula is afoul with name, is as the criterion with chemical structural formula.
Preferred structure of the present invention is listed in table 1:
Table 1
Compound of the present invention conventionally can be prepared as the form of pharmaceutical salts; Comprise its organic acid salt and inorganic acid salt: mineral acid includes, but is not limited to hydrochloric acid, sulfuric acid, phosphoric acid, bisphosphate, Hydrogen bromide, nitric acid etc., organic acid includes, but is not limited to acetic acid, toxilic acid, fumaric acid, tartrate, succsinic acid, lactic acid, tosic acid, Whitfield's ointment, oxalic acid etc.
As a second aspect of the present invention, compound of the present invention can prepare with following methods:
Synthetic route is as follows:
(1) chloro-6, the 7-dimethoxy-quinolines of 4-and 6-hydroxyl-1,2,3,4-tetrahydroquinoline react generation 6,7-dimethoxy-4 '-(1,2,3,4-tetrahydroquinoline-6 oxygen base) quinoline (II) under the existence of alkali, catalyzer;
(2) 6,7-dimethoxy-4 '-(1,2,3,4-tetrahydroquinoline-6 oxygen base) quinoline (II) and the isocyanate compound of various replacement react and generate corresponding N-and replace-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-Carbox amide (I);
(3) form of pharmacy acceptable salt is conventionally prepared as.
Present invention also offers a kind of pharmaceutical composition, it contains pharmaceutically acceptable vehicle or carrier, and above-mentioned compound or its each optical isomer, each crystal formation, pharmaceutically acceptable inorganic or organic salt, hydrate, solvate or prodrug.
Present invention also offers the purposes of compound of the present invention or its each optical isomer, each crystal formation, pharmaceutically acceptable inorganic or organic salt, hydrate, solvate or prodrug, it is used to prepare tyrosine kinase inhibitor.
Present invention also offers the purposes of compound of the present invention or its each optical isomer, each crystal formation, pharmaceutically acceptable inorganic or organic salt, hydrate, solvate or prodrug, it is used to prepare the medicine that suppresses tyrosine kinase activity or for the preparation for the treatment of, prevention and alleviate the medicine to the too high relevant disease of tyrosine kinase activity.
In a preference of the present invention, described is selected from tumour with the too high relative disease of tyrosine kinase activity, includes but not limited to liver cancer, lung cancer, brain tumor, cancer of the stomach, kidney, colorectal carcinoma, mammary cancer, ovarian cancer, prostate cancer, osteocarcinoma, leukemia, skin carcinoma.
Simultaneously, vegf receptor family is the closest with vasculogenesis (angiogenesis) relation in known at present family tyrosine kinase member, those skilled in the art should anticipate, there is good inhibiting compound to vegf receptor family member, should also have good restraining effect to tumor-blood-vessel growth.
Given this, present invention also offers the purposes of compound of the present invention or its each optical isomer, each crystal formation, pharmaceutically acceptable inorganic or organic salt, hydrate, solvate or prodrug, it is used to prepare angiogenesis inhibitor.
Present invention also offers the purposes of compound of the present invention or its each optical isomer, each crystal formation, pharmaceutically acceptable inorganic or organic salt, hydrate, solvate or prodrug, it is used to the medicine preparing prevention or treatment tumour.
For the compound of evaluation the present invention synthesis and the anti-tumor activity of pharmaceutical composition thereof, compound in the present invention is carried out to the pharmacologically active test of molecular level, result shows this compounds and generally has good vitro inhibition tyrosine kinase activity, particularly has good inhibit activities to VEGFR2 and VEGFR3.
Accompanying drawing explanation
Fig. 1 is the linear lower-most point concentration chromatogram of quantitative limit in compound K L-11 pharmacokinetic studies.
Fig. 2 is the linear vertex concentration chromatogram of quantitative limit in compound K L-11 pharmacokinetic studies.
Fig. 3 is the typical color spectrogram of compound K L-11 and interior mark KL-13 in gavage group blood plasma in pharmacokinetic studies.
Fig. 4 is gavage group rat 1N-11 blood concentration-time data scatter situation in compound K L-11 pharmacokinetic studies.
Fig. 5 is the mean blood plasma concentration-time curve of gavage group rat in compound K L-11 pharmacokinetic studies.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.Should be understood that following examples only for illustration of the present invention but not for limiting scope of the present invention.
Embodiment 1:
The preparation of 6,7-dimethoxy-4 '-(1,2,3,4-tetrahydroquinoline-6 oxygen base) quinoline (II)
Chloro-6, the 7-dimethoxy-quinoline 22.5g(100.6mmol of 4-are added in 250ml round-bottomed bottle), 6-hydroxyl-1,2,3,4-tetrahydroquinoline 15g(100.5mmol), N-Methyl pyrrolidone (NMP) 100ml, uniform stirring dissolves, lower point of ice bath adds tertiary butyl potassium alcoholate 33.9g(301.8mmol for three times), be heated to 100 DEG C, stirring reaction about 16 hours, TLC follows the tracks of reaction (developping agent is sherwood oil: ethyl acetate=2.5:2.5), reacts complete and carries out aftertreatment.Pressure reducing and steaming NMP, residue is washed, and obtains faint yellow solid, methyl alcohol-sherwood oil recrystallization, filters, dry, obtains sterling 19g.Productive rate: 56.2%.
1HNMR(600MHz,DMSO)δ8.43(d,J=5.2Hz,1H),7.49(s,1H),7.36(s,1H),6.77(d,J=2.7Hz,1H),6.76(s,1H),6.53(d,J=8.2Hz,1H),6.40(d,J=5.2Hz,1H),5.74(s,1H),3.94(s,3H),3.93(s,3H),3.22-3.19(m,2H),2.69(t,J=6.2Hz,2H),1.83-1.78(m,2H).HRMS[M+H]337.48
The synthesis of embodiment 2(KL-01)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets tertiary octyl group isocyanic ester 0.47g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is methylene dichloride: methyl alcohol=4.5:0.5), room temperature reaction 70 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product adds normal hexane to micro-muddiness after dissolving with a small amount of methylene dichloride, reheats to clarification, places, crystallization, and filter, solid obtains fine work 0.18g with Preparative TLC silica-gel plate purifying again.Productive rate: 24.3%.
1HNMR(600MHz,DMSO)δ8.48(d,J=5.2Hz,1H),7.54(d,J=8.8Hz,1H),7.49(s,1H),7.39(s,1H),7.02-6.96(m,2H),6.52(d,J=5.2Hz,1H),6.43(d,J=7.8Hz,1H),3.95(s,3H),3.93(s,3H),3.61-3.58(m,2H),3.40-3.37(m,2H),2.71(t,J=6.5Hz,2H),1.87-1.08(m,17H).HRMS[M+H]492.56。
The synthesis of embodiment 3(KL-02)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets 2-ethylphenyl isocyanic ester 0.44g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is ethyl acetate: methyl alcohol=4.7:0.3), altogether room temperature reaction 65 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product adds normal hexane to micro-muddiness after dissolving with a small amount of methylene dichloride, reheats to clarification, places, crystallization, and filter, solid obtains fine work 0.25g with Preparative TLC silica-gel plate purifying again.Productive rate: 34.5%.
1HNMR(600MHz,DMSO)δ8.48(d,J=5.2Hz,1H),8.26(s,1H),7.72(dd,J=11.4,4.4Hz,1H),7.61(d,J=8.9Hz,1H),7.50(s,1H),7.39(s,1H),7.34-7.31(m,1H),7.24(dd,J=7.5,1.5Hz,1H),7.08(d,J=2.6Hz,1H),7.04(dd,J=8.5,3.0Hz,1H),7.01(td,J=7.6,0.8Hz,1H),6.52(d,J=5.2Hz,1H),3.94(s,3H),3.93(s,3H),3.80-3.76(m,2H),2.79(t,J=6.5Hz,2H),2.63(dd,J=15.1,7.6Hz,2H),1.97–1.92(m,2H),1.15(t,J=7.5Hz,3H).HRMS[M+H]484.40。
The synthesis of embodiment 4(KL-03)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets 2,4-dimethylphenyl isocyanate 0.44g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, and TLC follows the tracks of reaction (developping agent is ethyl acetate: methyl alcohol=4.7:0.3), room temperature reaction 65 hours altogether, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product adds normal hexane to micro-muddiness after dissolving with a small amount of methylene dichloride, reheats to clarification, places, crystallization, and filter, solid obtains fine work 0.20g with Preparative TLC silica-gel plate purifying again.Productive rate: 27.6%.
1HNMR(600MHz,DMSO)δ8.48(d,J=5.2Hz,1H),8.23(s,1H),7.62(d,J=8.9Hz,1H),7.50(s,1H),7.39(s,1H),7.19(d,J=8.1Hz,1H),7.07(d,J=2.6Hz,1H),7.04–7.01(m,2H),6.96(d,J=8.4Hz,1H),6.53(d,J=5.2Hz,1H),3.95(s,3H),3.93(s,3H),3.78-3.75(m,2H),2.78(t,J=6.5Hz,2H),2.25(s,3H),2.18(s,3H),1.93(dt,J=13.8,6.7Hz,2H).HRMS[M+H]484.45。
The synthesis of embodiment 5(KL-04)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets 2-isopropyl benzene isocyanic ester 0.48g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is ethyl acetate: methyl alcohol=4.7:0.3), altogether room temperature reaction 65 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product adds normal hexane to micro-muddiness after dissolving with a small amount of methylene dichloride, reheats to clarification, places, crystallization, and filter, solid obtains fine work 0.31g with Preparative TLC silica-gel plate purifying again.Productive rate: 41.6%.
1HNMR(600MHz,DMSO)δ8.48(d,J=5.2Hz,1H),8.29(s,1H),7.61(d,J=8.9Hz,1H),7.50(s,1H),7.39(s,1H),7.32-7.30(m,1H),7.27-7.24(m,1H),7.21-7.14(m,2H),7.07(d,J=3.3Hz,1H),7.03(dd,J=8.8,2.8Hz,1H),6.52(d,J=5.3Hz,1H),3.94(s,3H),3.93(s,3H),3.80-3.77(m,2H),3.19-3.13(m,1H),2.79(t,J=6.6Hz,2H),1.97-1.91(m,2H),1.17(d,J=6.8Hz,6H).HRMS[M+H]498.41。
The synthesis of embodiment 6(KL-05)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets 4-normal-butyl phenol isocyanic ester 0.53g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is ethyl acetate: methyl alcohol=4.7:0.3), altogether room temperature reaction 65 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product adds normal hexane to micro-muddiness after dissolving with a small amount of methylene dichloride, reheats to clarification, places, crystallization, and filter, solid obtains fine work 0.38g with Preparative TLC silica-gel plate purifying again.Productive rate: 49.5%.
1HNMR(600MHz,DMSO)δ8.77(s,1H),8.50(d,J=5.2Hz,1H),7.50-7.48(m,2H),7.40-7.38(m,3H),7.10-7.07(m,3H),7.02(dd,J=9.0,2.8Hz,1H),6.56(d,J=5.2Hz,1H),3.95(s,3H),3.93(s,3H),3.76-3.73(m,2H),2.78(t,J=6.3Hz,2H),2.53-2.50(m,2H),1.94-1.90(m,2H),1.55-1.50(m,2H),1.29(dt,J=15.1,7.6Hz,2H),0.89(t,J=7.4Hz,3H).HRMS[M+H]512.44。
The synthesis of embodiment 7(KL-06)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets p-Methoxyphenyl isocyanate 0.45g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is ethyl acetate: methyl alcohol=4.7:0.3), altogether room temperature reaction 65 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product adds normal hexane to micro-muddiness after dissolving with a small amount of methylene dichloride, reheats to clarification, places, crystallization, and filter, solid obtains fine work 0.29g with Preparative TLC silica-gel plate purifying again.Productive rate: 39.8%.
1HNMR(600MHz,DMSO)δ8.70(s,1H),8.49(d,J=5.3Hz,1H),7.51(d,J=8.8Hz,2H),7.41-7.37(m,3H),7.07(s,1H),7.02(d,J=7.6Hz,1H),6.86(d,J=8.0Hz,2H),6.55(d,J=4.7Hz,1H),3.95(s,3H),3.93(s,3H),3.76-3.73(m,2H),3.72(s,3H),2.77(t,J=6.2Hz,2H),1.94-1.89(m,2H).HRMS[M+H]486.35。
The synthesis of embodiment 8(KL-07)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets m-methoxy phenyl isocyanate 0.45g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is ethyl acetate: methyl alcohol=4.7:0.3), altogether room temperature reaction 65 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product obtains fine work 0.37g with ether purifying.Productive rate: 50.8%.
1HNMR(600MHz,CDCl 3)δ8.52(d,J=5.6Hz,1H),7.67(s,1H),7.56(s,1H),7.48(d,J=9.0Hz,1H),7.21-7.17(m,2H),7.09-7.06(m,2H),6.93(s,1H),6.84(dd,J=7.9,1.6Hz,1H),6.64-6.63(m,1H),6.62(d,J=2.4Hz,1H),4.09(s,3H),4.07(s,3H),3.87(t,J=6.3Hz,2H),3.81(s,3H),2.84(t,J=6.6Hz,2H),2.07-2.03(m,2H).HRMS[M+H]486.40。
The synthesis of embodiment 9(KL-08)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets O-methoxy phenylisocyanate 0.45g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is ethyl acetate: methyl alcohol=4.7:0.3), altogether room temperature reaction 72 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product obtains fine work 0.26g with ether purifying.Productive rate: 35.7%.
1HNMR(600MHz,CDCl 3)δ8.51(d,J=5.5Hz,1H),8.29-8.27(m,1H),7.81(s,1H),7.57(d,J=9.0Hz,3H),7.08-7.05(m,2H),7.00-6.97(m,2H),6.86–6.84(m,1H),6.57(d,J=5.3Hz,1H),4.08(s,3H),4.07(s,3H),3.91-3.88(m,2H),3.80(s,3H),2.84(t,J=6.6Hz,2H),2.07-2.02(m,2H).HRMS[M+H]486.40。
The synthesis of embodiment 10(KL-10)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets 2-methoxyl group-5-methylbenzene isocyanic ester 0.49g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is ethyl acetate: methyl alcohol=4.7:0.3), altogether room temperature reaction 55 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product adds normal hexane to micro-muddiness after dissolving with a small amount of methylene dichloride, reheats to clarification, places, crystallization, filters, and solid adds normal hexane to micro-muddiness after dissolving with methylene dichloride again, reheats to clarification, and place, crystallization obtains fine work 0.40g.Productive rate: 53.3%.
1HNMR(600MHz,CDCl 3)δ8.51(d,J=5.4Hz,1H),8.13(d,J=1.7Hz,1H),7.77(s,1H),7.58-7.53(m,3H),7.08-7.04(m,2H),6.78(dd,J=8.2,1.3Hz,1H),6.73(d,J=8.2Hz,1H),6.56(d,J=5.4Hz,1H),4.08(s,3H),4.07(s,3H),3.90-3.87(m,2H),3.77(s,3H),2.83(t,J=6.6Hz,2H),2.32(s,3H),2.05(p,J=6.5Hz,2H).HRMS[M+H]500.46。
The synthesis of embodiment 11(KL-11)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets 4-phenyl methyl ketone based isocyanate 0.48g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is ethyl acetate: methyl alcohol=4.7:0.3), altogether room temperature reaction 70 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product, with methylene dichloride 15ml reflux, has insoluble solids, filters, filtrate is concentrated goes major part, add normal hexane to micro-muddiness, reheat to clarification, place, crystallization, filter, solid adds normal hexane to micro-muddiness after dissolving with methylene dichloride again, reheats to clarification, place, crystallization obtains fine work 0.37g.Productive rate: 49.6%.
1HNMR(600MHz,CDCl 3)δ8.53(d,J=5.5Hz,1H),7.93(d,J=8.7Hz,2H),7.61(d,J=8.5Hz,1H),7.55(s,1H),7.51(d,J=8.7Hz,2H),7.46(d,J=8.4Hz,1H),7.16(s,1H),7.12-7.09(m,2H),6.63(d,J=5.3Hz,1H),4.08(s,3H),4.07(s,3H),3.89(t,J=6.3Hz,2H),2.84(t,J=6.6Hz,2H),2.57(s,3H),2.06(p,J=6.5Hz,2H).HRMS[M+H]498.38。
The synthesis of embodiment 12(KL-12)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets 4-fluorophenylisocyanate 0.41g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is ethyl acetate: methyl alcohol=20:1), altogether room temperature reaction 65 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product, with q. s. methylene chloride reflux, has insoluble solids, filters, filtrate is concentrated goes part, add sherwood oil to micro-muddiness, reheat to clarification, place, crystallization, filter, solid adds sherwood oil to micro-muddiness after dissolving with methylene dichloride again, reheats to clarification, place, crystallization obtains fine work 0.18g.Productive rate: 25.4%.
1HNMR(600MHz,CDCl 3)δ8.52(d,J=5.6Hz,1H),8.29(d,J=8.7Hz,1H),7.65(s,1H),7.59-7.54(m,3H),7.50(d,J=8.6Hz,1H),7.43(s,1H),7.17(t,J=7.6Hz,1H),7.12-7.08(m,2H),6.56(d,J=5.5Hz,1H),4.10(s,3H),4.08(s,3H),3.90(t,J=6.3Hz,2H),2.85(t,J=6.7Hz,2H),2.06(p,J=6.6Hz,2H).HRMS[M+H]474.38。
The synthesis of embodiment 13(KL-13)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets 3-fluorophenylisocyanate 0.41g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is ethyl acetate: methyl alcohol=20:1), altogether room temperature reaction 65 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product, with q. s. methylene chloride reflux, has insoluble solids, filters, filtrate is concentrated goes part, add sherwood oil to micro-muddiness, reheat to clarification, place, crystallization, filter, solid adds sherwood oil to micro-muddiness after dissolving with methylene dichloride again, reheats to clarification, place, crystallization obtains fine work 0.20g.Productive rate: 28.2%.
1HNMR(600MHz,CDCl 3)δ8.52(s,1H),7.98(s,2H),7.60(s,1H),7.54(d,J=8.7Hz,1H),7.39(d,J=11.2Hz,1H),7.11(d,J=7.7Hz,2H),7.03(d,J=9.7Hz,1H),6.97(s,1H),6.78(dd,J=8.1,2.0Hz,1H),6.76(d,J=1.7Hz,1H),4.14(s,3H),4.09(s,3H),3.89(t,J=6.2Hz,2H),2.87(t,J=6.6Hz,2H),2.10-2.05(m,2H).HRMS[M+H]474.36。
The synthesis of embodiment 14(KL-14)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets 2-fluorophenylisocyanate 0.41g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is ethyl acetate: methyl alcohol=4.5:0.5), altogether room temperature reaction 70 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product, with q. s. methylene chloride reflux, has insoluble solids, filters, filtrate is concentrated goes part, add sherwood oil to micro-muddiness, reheat to clarification, place, crystallization, filter, solid adds sherwood oil to micro-muddiness after dissolving with methylene dichloride again, reheats to clarification, place, crystallization obtains fine work 0.31g.Productive rate: 43.7%.
1HNMR(600MHz,CDCl 3)δ8.53(d,J=5.5Hz,1H),8.24(td,J=8.2,1.5Hz,1H),7.57-7.50(m,3H),7.29(d,J=3.2Hz,1H),7.15(t,J=8.0Hz,1H),7.10(dd,J=8.6,2.8Hz,1H),7.08-7.03(m,2H),7.02-6.97(m,1H),6.59(d,J=5.4Hz,1H),4.08(s,3H),4.06(s,3H),3.89(t,J=6.3Hz,2H),2.84(t,J=6.6Hz,2H),2.06(p,J=6.6Hz,2H).HRMS[M+H]474.35。
The synthesis of embodiment 15(KL-15)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets 2,4-difluorophenyl isocyanate 0.47g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, and TLC follows the tracks of reaction (developping agent is methylene dichloride: methyl alcohol=6.5:0.5), room temperature reaction 70 hours altogether, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product, with q. s. methylene chloride reflux, has insoluble solids, filters, filtrate is concentrated goes part, add sherwood oil to micro-muddiness, reheat to clarification, place, crystallization, filter, solid adds sherwood oil to micro-muddiness after dissolving with methylene dichloride again, reheats to clarification, place, crystallization obtains fine work 0.25g.Productive rate: 33.8%.
1HNMR(600MHz,CDCl 3)δ8.53(d,J=5.4Hz,1H),8.15(td,J=9.1,5.9Hz,1H),7.55(s,1H),7.53(s,1H),7.51(d,J=8.6Hz,1H),7.14(d,J=2.7Hz,1H),7.11-7.06(m,2H),6.91-6.81(m,2H),6.58(d,J=5.4Hz,1H),4.07(s,3H),4.06(s,3H),3.88(t,J=6.3Hz,2H),2.83(t,J=6.6Hz,2H),2.05(p,J=6.6Hz,2H).HRMS[M+H]492.36。
The synthesis of embodiment 16(KL-16)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets 4-chlorophenyl isocyanate 0.46g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, and TLC follows the tracks of reaction (developping agent is methylene dichloride: methyl alcohol=4.5:0.5), altogether room temperature reaction 72 hours, complete reaction, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product, with q. s. methylene chloride reflux, has insoluble solids, filters, filtrate is concentrated goes part, add sherwood oil to micro-muddiness, reheat to clarification, place, crystallization, filter, solid adds sherwood oil to micro-muddiness after dissolving with methylene dichloride again, reheats to clarification, place, crystallization obtains fine work 0.39g.Productive rate: 52.7%.
1HNMR(600MHz,CDCl 3)δ8.53(d,J=5.5Hz,1H),7.64(s,1H),7.56(s,1H),7.47(d,J=8.2Hz,1H),7.36(d,J=8.8Hz,2H),7.28(s,2H),7.10-7.07(m,2H),6.94(s,1H),6.63(d,J=4.8Hz,1H),4.09(s,3H),4.06(s,3H),3.87(t,J=6.3Hz,2H),2.84(t,J=6.6Hz,2H),2.07-2.01(m,2H).HRMS[M+H]490.35。
The synthesis of embodiment 17(KL-17)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets 3-chlorophenyl isocyanate 0.46g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is methylene dichloride: methyl alcohol=4.5:0.5), altogether room temperature reaction 72 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product, with q. s. methylene chloride reflux, has insoluble solids, filters, filtrate is concentrated goes part, add sherwood oil to micro-muddiness, reheat to clarification, place, crystallization, filter, solid adds sherwood oil to micro-muddiness after dissolving with methylene dichloride again, reheats to clarification, place, crystallization obtains fine work 0.32g.Productive rate: 43.2%.
1HNMR(600MHz,CDCl3)δ8.53(d,J=5.6Hz,1H),7.61(s,1H),7.56(s,1H),7.50(t,J=1.9Hz,1H),7.46(d,J=8.4Hz,1H),7.22(t,J=8.0Hz,2H),7.11-7.07(m,2H),7.04(d,J=8.4Hz,1H),6.95(s,1H),6.63(d,J=5.5Hz,1H),4.08(s,3H),4.06(s,3H),3.87(t,J=6.3Hz,2H),2.84(t,J=6.6Hz,2H),2.07-2.03(m,2H).HRMS[M+H]490.32。
The synthesis of embodiment 18(KL-18)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets 2-chlorophenyl isocyanate 0.46g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is methylene dichloride: methyl alcohol=4.5:0.5), altogether room temperature reaction 65 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product, with q. s. methylene chloride reflux, has insoluble solids, filters, filtrate is concentrated goes part, add sherwood oil to micro-muddiness, reheat to clarification, place, crystallization, filter, solid adds sherwood oil to micro-muddiness after dissolving with methylene dichloride again, reheats to clarification, place, crystallization obtains fine work 0.37g.Productive rate: 50%.
1HNMR(600MHz,CDCl 3)δ8.52(d,J=5.4Hz,1H),8.38(dd,J=8.3,1.4Hz,1H),7.73(s,1H),7.57(d,J=9.6Hz,2H),7.54(s,1H),7.33(dd,J=8.0,1.4Hz,1H),7.30–7.27(m,1H),7.11(dd,J=8.6,2.7Hz,1H),7.08(d,J=2.7Hz,1H),6.98(td,J=7.8,1.5Hz,1H),6.54(d,J=5.4Hz,1H),4.08(s,3H),4.07(s,3H),3.91(t,J=6.3Hz,2H),2.85(t,J=6.6Hz,2H),2.06(p,J=6.6Hz,2H).HRMS[M+H]490.43。
The synthesis of embodiment 19(KL-19)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets 2-methyl-4-chlorophenyl isocyanate 0.5g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is methylene dichloride: methyl alcohol=4.5:0.5), altogether room temperature reaction 75 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product, with q. s. methylene chloride reflux, has insoluble solids, filters, filtrate is concentrated goes part, add sherwood oil to micro-muddiness, reheat to clarification, place, crystallization, filter, solid adds sherwood oil to micro-muddiness after dissolving with methylene dichloride again, reheats to clarification, place, crystallization obtains fine work 0.22g.Productive rate: 28.9%.
1HNMR(600MHz,CDCl 3)δ8.51(d,J=5.4Hz,1H),7.84(d,J=8.7Hz,1H),7.56-7.51(m,3H),7.19(dd,J=8.7,2.4Hz,1H),7.14(d,J=2.2Hz,1H),7.08(dd,J=6.1,3.0Hz,2H),6.84(s,1H),6.54(d,J=5.4Hz,1H),4.08(s,3H),4.06(s,3H),3.88(t,J=6.3Hz,2H),2.84(t,J=6.6Hz,2H),2.14(s,3H),2.08-2.03(m,2H).HRMS[M+H]504.43。
The synthesis of embodiment 20(KL-20)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets 4-trifluoromethylbenzene based isocyanate 0.56g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is methylene dichloride: methyl alcohol=4.5:0.5), altogether room temperature reaction 75 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product, with q. s. methylene chloride reflux, has insoluble solids, filters, filtrate is concentrated goes part, add sherwood oil to micro-muddiness, reheat to clarification, place, crystallization, filter, solid adds sherwood oil to micro-muddiness after dissolving with methylene dichloride again, reheats to clarification, place, crystallization obtains fine work 0.25g.Productive rate: 31.6%.
1HNMR(600MHz,CDCl 3)δ8.54(d,J=5.3Hz,1H),7.58-7.51(m,6H),7.45(t,J=7.7Hz,1H),7.12-7.08(m,3H),6.62(d,J=4.7Hz,1H),4.09(s,3H),4.06(s,3H),3.89(t,J=6.3Hz,2H),2.84(t,J=6.6Hz,2H),2.09-2.03(m,2H).HRMS[M+H]524.32。
The synthesis of embodiment 21(KL-21)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets 2-trifluoromethylbenzene based isocyanate 0.56g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is methylene dichloride: methyl alcohol=4.5:0.5), altogether room temperature reaction 70 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product, with q. s. methylene chloride reflux, has insoluble solids, filters, filtrate is concentrated goes part, add sherwood oil to micro-muddiness, reheat to clarification, place, crystallization, filter, solid adds sherwood oil to micro-muddiness after dissolving with methylene dichloride again, reheats to clarification, place, crystallization obtains fine work 0.17g.Productive rate: 21.5%.
1HNMR(600MHz,CDCl3)δ8.53(d,J=5.5Hz,1H),7.61-7.53(m,6H),7.47(t,J=8.2Hz,1H),7.15-7.07(m,3H),6.56(d,J=5.5Hz,1H),4.10(s,3H),4.08(s,3H),3.90(t,J=6.3Hz,2H),2.85(t,J=6.7Hz,2H),2.10-2.04(m,2H).HRMS[M+H]524.37。
The synthesis of embodiment 22(KL-22)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets 4-cyano-phenyl isocyanic ester 0.43g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is methylene dichloride: methyl alcohol=4.5:0.5), altogether room temperature reaction 75 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product, with q. s. methylene chloride reflux, has insoluble solids, filters, filtrate is concentrated goes part, add sherwood oil to micro-muddiness, reheat to clarification, place, crystallization, filter, solid adds sherwood oil to micro-muddiness after dissolving with methylene dichloride again, reheats to clarification, place, crystallization obtains fine work 0.30g.Productive rate: 41.7%.
1HNMR(600MHz,CDCl 3)δ8.53(d,J=5.3Hz,1H),7.60-7.58(m,2H),7.55-7.52(m,3H),7.50(s,1H),7.41(d,J=8.7Hz,1H),7.21(s,1H),7.12-7.09(m,2H),6.59(d,J=5.3Hz,1H),4.07(s,3H),4.06(s,3H),3.88(t,J=6.4Hz,2H),2.83(t,J=6.6Hz,2H),2.05(m,J=6.6Hz,2H).HRMS[M+H]481.33。
The synthesis of embodiment 23(KL-23)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets 2-chloro-4 nitrophenyl isocyanic ester 0.6g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is methylene dichloride: methyl alcohol=4.5:0.5), altogether room temperature reaction 70 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product, with q. s. methylene chloride reflux, has insoluble solids, filters, filtrate is concentrated goes part, add sherwood oil to micro-muddiness, reheat to clarification, place, crystallization, filter, solid adds sherwood oil to micro-muddiness after dissolving with methylene dichloride again, reheats to clarification, place, crystallization obtains fine work 0.27g.Productive rate: 33.8%.
1HNMR(600MHz,CDCl 3)δ8.69(d,J=9.3Hz,1H),8.53(d,J=5.6Hz,1H),8.28(dd,J=13.0,2.6Hz,1H),8.19(dd,J=9.3,2.5Hz,1H),8.09(s,1H),7.67(s,1H),7.58-7.53(m,2H),7.17-7.11(m,2H),6.57(d,J=4.6Hz,1H),4.10(s,3H),4.07(s,3H),3.93(t,J=6.4Hz,2H),2.87(t,J=6.6Hz,2H),2.10(p,J=6.5Hz,2H).HRMS[M+H]535.27。
The synthesis of embodiment 24(KL-24)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets 3-nitro-4-chlorophenyl isocyanate 0.6g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is methylene dichloride: methyl alcohol=4.5:0.5), altogether room temperature reaction 70 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product, with q. s. methylene chloride reflux, has insoluble solids, filters, filtrate is concentrated goes part, add sherwood oil to micro-muddiness, reheat to clarification, place, crystallization, filter, solid adds sherwood oil to micro-muddiness after dissolving with methylene dichloride again, reheats to clarification, place, crystallization obtains fine work 0.36g.Productive rate: 45%.
1HNMR(600MHz,CDCl 3)δ8.52(d,J=5.8Hz,1H),8.04(d,J=2.5Hz,1H),7.88(d,J=86.2Hz,1H),7.67(dd,J=8.8,2.5Hz,2H),7.57(s,1H),7.46(dt,J=15.6,7.6Hz,2H),7.13(dt,J=4.6,2.6Hz,2H),6.72(d,J=5.7Hz,1H),4.09(s,3H),4.08(s,3H),3.89(t,J=6.3Hz,2H),2.85(t,J=6.6Hz,2H),2.09-2.04(m,2H).HRMS[M+H]535.29。
The synthesis of embodiment 25(KL-25)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets 2-methyl-4-nitro isocyanic ester 0.53g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is methylene dichloride: methyl alcohol=4.5:0.5), altogether room temperature reaction 75 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product, with q. s. methylene chloride reflux, has insoluble solids, filters, filtrate is concentrated goes part, add sherwood oil to micro-muddiness, reheat to clarification, place, crystallization, filter, solid adds sherwood oil to micro-muddiness after dissolving with methylene dichloride again, reheats to clarification, place, crystallization obtains fine work 0.31g.Productive rate: 40.3%.
1HNMR(600MHz,CDCl 3)δ8.52(d,J=5.7Hz,1H),8.40(d,J=9.1Hz,1H),8.14(d,J=2.4Hz,1H),8.04(d,J=2.3Hz,1H),7.69(s,1H),7.57-7.53(m,2H),7.28(s,1H),7.15-7.12(m,2H),6.59(d,J=4.5Hz,1H),4.10(s,3H),4.08(s,3H),3.92(t,J=6.3Hz,2H),2.87(t,J=6.2Hz,2H),2.19(s,3H),2.11-2.07(m,2H).HRMS[M+H]515.36。
The synthesis of embodiment 26(KL-26)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets cyclopentyl isocyanic ester 0.33g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is methylene dichloride: methyl alcohol=4.5:0.5), altogether room temperature reaction 75 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product, with q. s. methylene chloride reflux, has insoluble solids, filters, filtrate is concentrated goes part, add sherwood oil to micro-muddiness, reheat to clarification, place, crystallization, filter, solid adds sherwood oil to micro-muddiness after dissolving with methylene dichloride again, reheats to clarification, place, crystallization obtains fine work 0.19g.Productive rate: 28.4%.
1HNMR(600MHz,CDCl 3)δ8.51(d,J=5.3Hz,1H),7.54(s,1H),7.47(s,1H),7.40(d,J=8.5Hz,1H),7.01(dd,J=9.4,3.5Hz,2H),6.55(d,J=5.3Hz,1H),4.99(d,J=6.9Hz,1H),4.22-4.16(m,1H),4.06(s,3H),4.05(s,3H),3.78-3.75(m,2H),2.77(t,J=6.6Hz,2H),2.04-1.94(m,4H),1.67-1.60(m,4H),1.42-1.35(m,2H).HRMS[M+H]448.51。
The synthesis of embodiment 27(KL-27)
6,7-dimethoxy-4 '-(1,2 are added in 100ml round-bottomed bottle, 3,4-tetrahydroquinoline-6 oxygen base) quinoline 0.5g(1.5mmol), chloroform 10ml, dissolve, stirring at room temperature, separately gets cyclohexyl isocyanate 0.38g(3.0mmol) extremely dissolve in chloroform 2ml, slowly add in round-bottomed bottle after dissolving, room temperature reaction is after 1 hour, TLC follows the tracks of reaction (developping agent is methylene dichloride: methyl alcohol=4.5:0.5), altogether room temperature reaction 75 hours, aftertreatment.
Reaction solution moves in separating funnel, and chloroform layer adds water 10ml vibration washing 2 times, and chloroform layer washs 1 time with saturated sodium bicarbonate solution 5ml again, add water 10ml vibration washing 2 times again, chloroform layer was with anhydrous magnesium sulfate 1.5g drying 1 hour, and filter, evaporate to dryness chloroform obtains crude product.Crude product, with q. s. methylene chloride reflux, has insoluble solids, filters, filtrate is concentrated goes part, add sherwood oil to micro-muddiness, reheat to clarification, place, crystallization, filter, solid adds sherwood oil to micro-muddiness after dissolving with methylene dichloride again, reheats to clarification, place, crystallization obtains fine work 0.33g.Productive rate: 47.8%.
1HNMR(600MHz,DMSO)δ8.51(d,J=5.3Hz,1H),7.55(d,J=8.8Hz,1H),7.52(s,1H),7.40(s,1H),7.02(d,J=2.7Hz,1H),6.99(dd,J=8.8,2.8Hz,1H),6.56(d,J=5.2Hz,1H),6.44(d,J=7.5Hz,1H),3.96(s,3H),3.94(s,3H),3.61-3.58(m,2H),3.38(q,J=7.0Hz,1H),2.72(t,J=6.5Hz,2H),1.86-1.70(m,6H),1.29-1.24(m,4H),1.10(dd,J=12.5,5.5Hz,2H).HRMS[M+H]462.50。
Test example 1: vitro inhibition tyrosine kinase activity is tested
(1) experimental technique
The preparation of (a) damping fluid
With 50mMHEPES, pH7.5,0.0015%Brij-35,10mMMgCl 2, 2mMDTT kinases preparation damping fluid, 100mMHEPES(pH7.5), 0.015%Brij-35,0.2%CoatingReagent#3,50mMEDTA prepare stop buffer.
The preparation of (b) sample solution
Survey the storage liquid before living, given the test agent being made into 10mM, under guarantee DMSO concentration is the prerequisite of 10%, is diluted to desired concn with damping fluid; As the inhibiting rate under a certain concentration only need be measured, then adopt a concentration; If need IC be measured 50value, then initial concentration is 10mM, and extension rate is 3, and arrange 10 concentration, each concentration establishes multiple hole.
(c) kinase reaction
Kinases is added to prepare kinase buffer liquid in basis buffer; FAM-labeled peptide and ATP is added to prepare peptide damping fluid in basis buffer.Add the sample solution of 10 μ l different concns in the test hole of 384 orifice plates, during institute is porose, add 10 μ l kinase buffer liquid, after at room temperature cultivating 10min, in institute is porose, add 10 μ l peptide damping fluids, and continue to cultivate 60min at 28 DEG C.Add 25 μ l stop buffers subsequently with stopped reaction, make curve by instrument image data, obtain IC 50value.
We test the inhibiting rate to VEGFR-2 (KDR) and VEGFR-3 (FLT4) under whole compound 30nM concentration, carry out preliminary screening:
Table 1: kinase species and experiment condition
(1) experimental result
Inhibiting rate experiment under table 2:30nM concentration
In inhibiting rate experiment under 30nM concentration, that contrast is selected is Staurosporine (Staurosporine, STS), to the IC of VEGFR-2 50for 7.2nM, to the IC of VEGFR-3 50for 1.5nM.
We select to have carried out IC to VEGFR-2 (KDR) and the higher compound of VEGFR-3 (FLT4) inhibiting rate under 30nM 50the mensuration of value:
Table 3: the kinase inhibition IC of part preferred compound 50the mensuration of value
Staurosporine (Staurosporine) is selected in contrast.VEGFR Inhibition test is presented at tested compound all has certain restraining effect to VEGFR-2 (KDR) or VEGFR-3 (FLT4), wherein part of compounds all has stronger restraining effect to two kinds of acceptors, active in contrast Staurosporine.
Above kinase activity test is all carried out in Shanghai Ruizhi Chemical Study Co., Ltd., and above data all select from the project report provided by wise and farsighted chemistry.
The hepatomicrosome metabolic rate research of test example 2 part preferred compound
1. the preparation of reference substance:
Weigh: precision takes each 3mg of KL-07, KL-11, KL-13 and KL-17 in EP pipe;
Dissolve: add 1mL methyl alcohol, 4mLDMSO dissolves, and final concentration is 0.6mg/mL.
2. Preparatory work of experiment
Acetonitrile solution about 100 μm of ol/L of 1.1 preparation KL-07, KL-11, KL-13 and KL-17 are as storing solution, A5 (chemical name: N-(5-(4-(4-((dimethylamino) methyl) phenyl) quinoline-6-base)-2-picoline-3-base)-2, the 4-phenyl-difluoride sulphonamide) solution of another preparation 100 μm of ol/L contrasts;
1.2PBS solution;
1.3β-NADPH16.7mg/mL；
1.4 rat liver microsomes;
The preparation of 1.5 inner mark solutions
KL-07, KL-11, KL-13, KL-17 and A5 are with the N-of 100ng/mL (4-acetyl phenyl)-6-(6,7-dimethoxyquinazoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (2N-27) solution is interior mark, N-(4-acetyl phenyl)-6-(6,7-dimethoxyquinazoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amide (2N-27) are interior mark with the KL-17 of 100ng/mL.
3. the analysis condition of compound
KL-07：
Chromatographic condition:
Chromatographic column: Shiseido 3.0 × 100,3 μm; Flow velocity: 0.4mL/min; Sample size: 5 μ L; Moving phase: 5mmol ammonium acetate+0.1% formic acid water: acetonitrile=55:45; Analysis time: 10min.
Mass Spectrometry Conditions:
Positive ion mode, SIM monitors [M+H] +486.0
Dry gas volume: 10L
Nebulizer pressure: 40psig; Dry gas temperature: 350 DEG C
Cracking voltage: 70eV.
KL-11：
Chromatographic condition:
Chromatographic column: Shiseido 3.0 × 100,3 μm; Flow velocity: 0.4mL/min; Sample size: 5 μ L; Moving phase: 5mmol ammonium acetate+0.1% formic acid water: acetonitrile=55:45; Analysis time: 10min.
Mass Spectrometry Conditions:
Positive ion mode, SIM monitors [M+H] +497.90
Dry gas volume: 10L
Nebulizer pressure: 40psig; Dry gas temperature: 350 DEG C
Cracking voltage: 70eV.
KL-13：
Chromatographic condition:
Chromatographic column: Shiseido 3.0 × 100,3 μm; Flow velocity: 0.4mL/min; Sample size: 5 μ L; Moving phase: 5mmol ammonium acetate+0.1% formic acid water: acetonitrile=55:45; Analysis time: 10min.
Mass Spectrometry Conditions:
Positive ion mode, SIM monitors [M+H] +474.0
Dry gas volume: 10L
Nebulizer pressure: 40psig; Dry gas temperature: 350 DEG C
Cracking voltage: 70eV.
KL-17：
Chromatographic condition:
Chromatographic column: Shiseido 3.0 × 100,3 μm; Flow velocity: 0.4mL/min; Sample size: 5 μ L; Moving phase: 5mmol ammonium acetate+0.1% formic acid water: acetonitrile=55:45; Analysis time: 10min.
Mass Spectrometry Conditions:
Positive ion mode, SIM monitors [M+H] +490.0
Dry gas volume: 10L
Nebulizer pressure: 40psig; Dry gas temperature: 350 DEG C
Cracking voltage: 70eV.
4. sample determination result:
The measurement result of table 4:KL-07
The measurement result of table 5:KL-11
The measurement result of table 6:KL-13
The measurement result of table 7:KL-17
The measurement result of table 8:A5
The absorption characteristic research of test example 3 part preferred compound in Caco-2 model
1. the preparation of need testing solution
A series of concentration of preparation KL-07, KL-11, KL-13 and KL-17: 20 μm of ol/L, 10 μm of ol/L, 5 μm of ol/L, 2 μm of ol/L, 1 μm of ol/L, 0.5 μm of ol/L, 0.2 μm of ol/L, 0.1 μm of ol/L.
2. cell cultures and toxicity test
Inoculating cell: be mixed with single Caco-2 cell (deriving from ATCC) suspension with the MEM substratum containing 10% foetal calf serum, be inoculated in 96 orifice plates with 5000, every hole cell.
Be placed in incubator to cultivate, administration after cell is all adherent (at least adherent reach 80%).
After cultivation 24-36h, each hole adds 20 μ LMTT, and (5mg/mL PBS prepares, pH=7.4) sucking-off supernatant liquor after cultivating 4h also adds 150 μ LDMSO, jolting 10min, select 492nm wavelength, enzyme linked immunological monitor measures each hole absorbance value, record result, take time as X-coordinate, light absorption value is that ordinate zou draws cell growth curve.
Get the concentration administration Caco-2 Cell uptake model of the inhibiting rate <2% of relative Caco-2 cell, measure its apparent permeability coefficients.Result, four compounds, 20 μm of ol/L, 10 μm of ol/L, 5 μm of ol/L show obvious cyto-inhibition to Caco-2 cell, final KL-11, KL-13, KL-17 choose 1 μM, and the safe administration concentration that KL-27 chooses 0.5 μM carries out the transmitance experiment of Caco-2 cell.
3. transport experiment
3.1Caco-2 cell model is set up
Caco-2 cell at MEM substratum (containing 10%FBS, 1%NEAA, 100UmL -1pen .-Strep, 10mmolL -1hEPES), the 5%CO of 37 DEG C 2cultivate in constant incubator.Cell cultures, after 21 days, is verified cell model, chooses cell transmembrane resistance and is greater than 600 Ω cm 2and uranine transmitance is lower than 0.6%h -1cm -2cell carry out drug transport experiment.
The transhipment of 3.2 compounds and picked-up experiment
Cell HBSS liquid carefully cleans three times, hatches 30min for the last time in incubator, blots HBSS liquid.Blank group all adds HBSS liquid in AP and BL both sides, and administration group adds the HBSS liquid (AP side 0.5ml, BL side 1.5ml) of 0.5 μM of 2N-27 in administration side, and receiver side adds blank HBSS liquid.Then culture plate is put into incubator to hatch, collect BL side and AP side respectively 0,30,60,90 and the solution 100 μ L of 120min, add blank HBSS liquid 100 μ L after sampling, it is frozen that sample is placed in-20 DEG C of refrigerators.By the chemical composition in HPLC quantitative analysis transhipment liquid.
The preparation of 3.3 linear solvent
Get KL-07, KL-11, KL-13 and KL-17 HBSS solution preparation and obtain the HBSS liquid that concentration is 1 μm of ol/mL, 0.5 μm of ol/mL, 0.25 μm of ol/mL, 0.125 μm of ol/mL, 0.0625 μm of ol/mL, 0.3125 μm of ol/mL; Get 100 μ LHBSS liquid+300 μ L(containing interior mark) acetonitrile.The centrifugal 5min of vortex 20S gets supernatant and namely obtains linear sample; Inner mark solution acetontrile: 100ng/mLKL-17 and 100ng/mL2N-27.
Concentration determination adopts high performance liquid chromatography.Chromatographic column: Shiseido C 183.0 × 100mm3 μm; Flow velocity: 0.4mL/min sample size: 5 μ L, moving phase: 5mmol ammonium acetate+0.1% formic acid water: acetonitrile=55:45; Analysis time: 10min.
Table 9
y=0.7707x-0.1367R 2=0.976
Table 10
y=0.5721x-0.11R 2=0.9038
Table 11
y=0.1692x-0.0399R 2=0.9698
Can find out from above data, the compound apparent permeability coefficients P of mensuration appall be greater than 10 -5, (two other compound does not reach quantitative limit and cannot measure) be it is generally acknowledged, apparent permeability coefficients P appbe greater than 10 -6show that the oral absorption of compound is good.This explanation, the absorption characteristic of KL-11 and KL-13 is very good, the compound provided due to the application all has identical parent nucleus, chemical structure difference is less to each other, therefore those skilled in the art should estimate, the compound that the application provides should all have good absorption, is expected to develop the high oral preparations of bioavailability.
The pharmacokinetic studies of test example 4 compound K L-11
1. analysis condition
Chromatographic condition
Chromatographic column: Shiseido 3.0 × 100mm, 3 μm, C 18post; Sample size: 5 μ L; Flow velocity: shunt 1:1 after 0.8mL/min post;
Moving phase: 0.1% formic acid water: acetonitrile=64:36
Mass Spectrometry Conditions: positive ion mode, SIM=498.2 (KL-11) SIM=474.0 (KL-13)
Dry gas volume: 10L
Nebulizer pressure: 40psig; Dry gas temperature: 350 DEG C
Cracking voltage: 70eV
2, sample treatment
Inside being designated as KL-13(concentration is 60.5ng/mL)
Be followed successively by the standardized solution of 13ug/ml, 6.5ug/ml, 3.25ug/ml, 1.3ug/ml, 0.65ug/ml, 0.325ug/ml, 0.013ug/ml, 0.065ug/ml by acetontrile concentration, obtain typical curve 1;
Add 190ul after each concentration 10ul adds 100ul plasma sample in label taking directrix curve 1 respectively and contain interior target acetonitrile solution, after vortex 30S, 12000rpm, centrifugal 10min, get the analysis of supernatant liquor sample introduction.
Three, experimental result
Table 12: gavage group KL-11 typical curve
y=9.4248x-0.0994
R2=0.9992
Table 13:KL-11 lower limit of quantitation experimental result
Table 14:KL-11 withinday precision experimental result
Table 15:KL-11 matrix effect and extraction recovery experimental result
Table 16: gavage group rat KL-11 Plasma Concentration (ug/ml)
The pharmacokinetic parameter of 1N-11 concentration in table 17 gavage group rat plasma
More than show and describe ultimate principle of the present invention and principal character.Those skilled in the art should understand; the present invention is not restricted to the described embodiments; what describe in above-described embodiment and specification sheets just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention.Application claims protection domain is defined by appending claims and equivalent thereof.

Claims (9)

1. the compound shown in formula I, or its pharmaceutically acceptable inorganic or organic salt:
Wherein R is selected from H, C 1-10alkyl, C 1-6thiazolinyl, C 1-6carbonyl, or be selected from having structure unit:
Wherein, R 1, R 2independently be selected from H, halogen, C separately 1-6alkyl, C 1-6thiazolinyl, C 1-6alkynyl, C 1-6alkoxyl group, nitro or C 1-6alkyl-carbonyl.
2. compound according to claim 1, is characterized in that, described compound is selected from following compound:
N-(2,4,4-trimethylpentane-2-base)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(2-ethylphenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(2,4-3,5-dimethylphenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(2-isopropyl phenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(4-n-butylphenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(4-p-methoxy-phenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(3-p-methoxy-phenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(2-p-methoxy-phenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(2-methoxyl group-5-aminomethyl phenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(4-acetylphenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(4-fluorophenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(3-fluorophenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(2-fluorophenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(2,4 difluorobenzene base)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(4-chloro-phenyl-)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(3-chloro-phenyl-)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(2-chloro-phenyl-)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(4-chloro-2-methyl phenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(4-(trifluoromethyl) phenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(3-(trifluoromethyl) phenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(4-cyano-phenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(2-chloro-4 nitrophenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(the chloro-3-nitrophenyl of 4-)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(2-methyl-4-nitrophenyl)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-cyclopentyl-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-cyclohexyl-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides;
N-(benzo [d] [1,3] dioxolane-5-base)-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-methane amides.
3. prepare a method for compound as claimed in claim 1, it is characterized in that, containing following steps:
(1) chloro-6, the 7-dimethoxy-quinolines of 4-and 6-hydroxyl-1,2,3,4-tetrahydroquinoline react generation 6,7-dimethoxy-4 '-(1,2,3,4-tetrahydroquinoline-6 oxygen base) quinoline (II) under the existence of alkali, catalyzer;
(2) 6,7-dimethoxy-4 '-(1,2,3,4-tetrahydroquinoline-6 oxygen base) quinoline (II) and the isocyanate compound of various replacement react and generate corresponding N-and replace-6-(6,7-dimethoxy-quinoline-4-oxygen base)-3,4-dihydroquinoline-1 (2H)-Carbox amide (I);
(3) form of pharmacy acceptable salt is conventionally prepared as.
4. a pharmaceutical composition, is characterized in that, it contains pharmaceutically acceptable vehicle or carrier, and compound according to claim 1 or its pharmaceutically acceptable inorganic or organic salt.
5. a purposes for compound according to claim 1 or its pharmaceutically acceptable inorganic or organic salt, is characterized in that, for the preparation of tyrosine kinase inhibitor.
6. the purposes of a compound according to claim 1 or its pharmaceutically acceptable inorganic or organic salt, it is characterized in that, for the preparation of suppressing the medicine of tyrosine kinase activity or for the preparation for the treatment of, prevention and alleviate and the medicine of the too high relative disease of tyrosine kinase activity.
7. purposes as claimed in claim 6, is characterized in that, is describedly selected from tumour with the too high relative disease of tyrosine kinase activity.
8. a purposes for compound according to claim 1 or its pharmaceutically acceptable inorganic or organic salt, is characterized in that, for the preparation of angiogenesis inhibitor.
9. a purposes for compound according to claim 1 or its pharmaceutically acceptable inorganic or organic salt, is characterized in that, for the preparation of the medicine of prevention or treatment tumour.
CN201310446924.XA 2013-09-26 2013-09-26 Quinolines and preparation method thereof and application Active CN103524409B (en)

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Citations (3)

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CN102863438A (en) * 2012-06-13 2013-01-09 华南理工大学 N-(4-(4-(pyridine-2-radical) piperazine-1-radical) pyrimidine-2-radical) amide and salt and preparation method and application thereof

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Publication number Priority date Publication date Assignee Title
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CN1933839A (en) * 2004-01-23 2007-03-21 安进公司 Compounds and methods of use
CN102863438A (en) * 2012-06-13 2013-01-09 华南理工大学 N-(4-(4-(pyridine-2-radical) piperazine-1-radical) pyrimidine-2-radical) amide and salt and preparation method and application thereof

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