CN103864680A - Chloroxoquinoline derivatives with anti-tumor activity - Google Patents

Chloroxoquinoline derivatives with anti-tumor activity Download PDF

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CN103864680A
CN103864680A CN201310652191.5A CN201310652191A CN103864680A CN 103864680 A CN103864680 A CN 103864680A CN 201310652191 A CN201310652191 A CN 201310652191A CN 103864680 A CN103864680 A CN 103864680A
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chloro
quinoline
compound
oxo
alkyl
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CN103864680B (en
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王子厚
曹日晖
张晓东
荣祖元
陈西敬
张训缨
黄汉源
李忠野
徐�明
王忠奎
李键茹
任政华
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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
    • 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
    • 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
    • C07D215/18—Halogen atoms or nitro radicals
    • 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
    • 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
    • C07D215/38—Nitrogen atoms
    • 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
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
    • 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4

Abstract

The invention relates to a chloroxoquinoline derivatives with anti-tumor activity and specifically relates to compounds of a formula I as shown in the specification and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein R1 is selected from hydrogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl and -C1-6 alkyl-phenyl, and the alkyl, the alkenyl, the alkynyl and the phenyl can be optionally substituted by halogens, nitryl, cyan, hydroxyl, -C1-6 alkoxy and phenyl; R3 is selected from hydrogen, -CONHR31 and -COOR32, the R31 and the R32 are independently selected from -C1-6 alkyl and -C1-6 alkylamino, respectively, and the amino can be optionally substituted by 1 to 2 -C1-6 alkyls; R7 is selected from halogens, -C1-6 alkoxy, morpholinyl and piperazine; the formula I is as shown in the specification.

Description

There is the 7-chloro-4-oxo-quinoline derivative of anti-tumor activity
Technical field
The present invention relates to the 7-chloro-4-oxo-quinoline derivative that a class has anti-tumor activity, also relate to the preparation method of this type of 7-chloro-4-oxo-quinoline derivative, and they are in the application of preparing in anti-tumor drug.
Background technology
The chloro-4-oxo-quinoline of 7-, is generally called 7-chloro-4-oxo-quinoline by people, and molecular formula is: C 9h 6clNO, molecular weight: 179.6, fusing point is 282-285 DEG C, and proterties is white or off-white powder, and its chemical structural formula is as follows:
Figure BDA0000431113500000011
This compound has tautomerism, and its tautomer is 7-chloro-4-hydroxyl-quinoline, and the two variation relation is as follows:
Figure BDA0000431113500000012
Known 7-chloro-4-oxo-quinoline is the national PTS that Tonghua, Jilin Province Mao Xiang pharmaceutical Co. Ltd develops voluntarily, belongs to the pharmaceutical chemicals first kind.This medicine is put into country's " 1035 " engineering and country " 95 " program for tackling key problems in science and technology; In April, 2002, check and accept by Department of Science and Technology's Life Sci-Tech centre of development; In September, 2002, obtain " invention patent certificate " that State Intellectual Property Office issues.Obtain two New Drug Certificates (bulk drug and capsule) and two medicine registration official written replies that National Drug Administration issues on April 23rd, 2003.
As far back as nineteen forty-six, Hammer and Surrey have just reported taking m-chloro aniline and methyl-oxalacetic ester as raw material, through the method (J.Am.Chem.Soc.68 (1946) 113-116) of the synthetic 7-chloro-4-hydroxyl-quinoline of reaction such as condensation, closed loop, decarboxylation.Subsequently, Roberts and Price have reported the synthetic route that a kind of yield is higher, taking m-chloro aniline and oxyethyl group methylene radical dimethyl malonate as raw material, through the method for the synthetic 7-chloro-4-hydroxyl-quinoline of reaction such as condensation, Guan Huan, depickling, the total recovery of three-step reaction is up to 75%(J.Am.Chem.Soc.68 (1946) 1204-1208).Compared with last method, the method has advantages of two aspects: (1) ring closure reaction does not have the isomer that 5-chlorine replaces to produce; (2) overall yield of reaction is high.2009, Langer etc. have reported an easier synthetic route, taking m-chloro aniline and isopropylidene malonate as raw material, can obtain 7-chloro-4-hydroxyl-quinoline through condensation and Guan Huan two-step reaction, this route is for having the symmetrical aniline raw material that replaces halogen atom on phenyl ring, yield is higher, but the method is for the mono-substituted aniline of phenyl ring, can generate the isomer (Synthesis1 (2009) 69-78) of 5 replacements.
7-chloro-4-oxo-quinoline is used for clinical antineoplaston with the form of oral capsule at present, it has wider antitumor spectra clinical confirmation, especially more remarkable for advanced breast cancer and nonsmall-cell lung cancer, lifetime can obviously be extended, improve the quality of living, and it is slight to have toxic side effects, the bone marrow depression of anticarcinogen and immunosuppressive action as none, the feature of easy administration.
In addition, take 7-chloro-4-oxo-quinoline patient curative effect in the time accepting radiotherapy also more obvious, analysis may possess the effect of radiation sensitivity simultaneously.
The Anticancer Effect and Mechanism of 7-chloro-4-oxo-quinoline is by causing lysosome in cancer cells to increase the damage of DNA of tumor cell template, cause breaking, discharging multiple lytic enzyme, thereby causes cancer cells self-dissolving death.
But 7-chloro-4-oxo-quinoline, as the antitumor original new drug of China's chemistry one class, is deposited problem both ways: (1) 7-chloro-4-oxo-quinoline bulk drug solubleness in water is very little, at present so cannot adopt clinically the form administration of injection.Adopt clinically at present the dosage form of oral capsule, limited the performance of the interior bioavailability of its body and antitumor curative effect.Therefore, the solubility problem of this compounds urgently to be resolved hurrily.(2) 7-chloro-4-oxo-quinoline is only 30% left and right to the antitumor tumour inhibiting rate of bearing mouse model of S180 sarcoma and ehrlich carcinoma solid-type at present, and its anti-tumor activity has much room for improvement.
Therefore be necessary taking 7-chloro-4-oxo-quinoline as primer, find the derivative with new biologic activity feature, in the hope of obtaining the new anti-cancer drug that is better than former medicine for clinical application.
Summary of the invention
At present still need to find the novel 7-chloro-4-oxo-quinoline compounds with anti-tumor activity for clinical application.The present invention finds to have the compound shown in general formula I and have the anti-tumor activity of desirable.The present invention is based on this discovery and be accomplished.
First aspect present invention provides with following formula I compound:
Figure BDA0000431113500000021
And pharmacologically acceptable salts, solvate, prodrug, wherein
R 1be selected from hydrogen ,-C 1-6alkyl ,-C 2-6thiazolinyl ,-C 2-6alkynyl ,-C 1-6alkyl-phenyl, wherein said alkyl, thiazolinyl, alkynyl and phenyl can be optionally by halogen, nitro, cyano group, hydroxyl ,-C 1-6alkoxyl group, phenyl replace;
R 3be selected from hydrogen ,-CONHR 31,-COOR 32, wherein said R 31and R 32independently be selected from separately-C 1-6alkyl and-C 1-6alkylamino, wherein said amino is optionally by 1～2-C 1-6alkyl replaces;
R 7be selected from halogen ,-C 1-6alkoxyl group,
Figure BDA0000431113500000022
According to the compound of first aspect present invention, wherein R 1be selected from hydrogen ,-C 1-6alkyl ,-C 2-6thiazolinyl ,-C 1-6alkyl-phenyl, wherein said alkyl, thiazolinyl and phenyl can be optionally by halogen, nitro, cyano group, hydroxyl ,-C 1-6alkoxyl group.
According to the compound of first aspect present invention, wherein R 1be selected from hydrogen ,-C 1-6alkyl ,-C 2-6thiazolinyl ,-C 1-6alkyl-phenyl.
According to the compound of first aspect present invention, wherein R 1be selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, allyl group, propenyl, phenmethyl, hydrocinnamyl, normal-butyl.
According to the compound of first aspect present invention, wherein R 3be selected from hydrogen ,-CONHR 31,-COOR 32, wherein said R 31and R 32independently be selected from separately-C 1-4alkyl and-C 1-4alkylamino, wherein said amino is optionally by 1～2-C 1-4alkyl replaces.
According to the compound of first aspect present invention, wherein R 3be selected from hydrogen ,-COO-C 1-4alkyl ,-CONH-C 1-4alkyl ,-CONH-C 1-4alkyl-NH-C 1-4alkyl ,-CONH-C 1-4alkyl-N (C 1-4alkyl) 2.
According to the compound of first aspect present invention, wherein R 3be selected from hydrogen ,-COOCH 2cH 3,-CONH-(CH 2) 2-N (C 2h 5) 2,-CONH-(CH 2) 3-N (C 2h 5) 2,-CONH-(CH 2) 3-NH 2.
According to the compound of first aspect present invention, wherein R 7be selected from halogen ,-C 1-4alkoxyl group,
Figure BDA0000431113500000032
According to the compound of first aspect present invention, wherein R 7be selected from fluorine, chlorine, bromine, methoxyl group,
Figure BDA0000431113500000033
Figure BDA0000431113500000034
According to the compound of first aspect present invention, wherein R 1and R 3when different, be hydrogen.
According to the compound of first aspect present invention, its exclusion condition is: R 1and R 3be hydrogen simultaneously, and R 7for halogen.
According to the compound of first aspect present invention, it is to be selected from following compound:
The fluoro-1-methyl-4-of 7-oxo-quinoline,
The chloro-1-methyl-4-of 7-oxo-quinoline,
The bromo-1-methyl-4-of 7-oxo-quinoline,
7-methoxyl group-1-methyl-4-oxo-quinoline,
The chloro-1-sec.-propyl-4-of 7-oxo-quinoline,
The chloro-4-oxo-quinoline in 1-allyl group-7,
The chloro-4-oxo-quinoline of 1-benzyl-7-,
The chloro-1-of 7-(3-hydrocinnamyl)-4-oxo-quinoline,
The bromo-4-oxo-quinoline of 1-benzyl-7-,
7-morpholinyl-4 (1H) Oxoquinoline,
1-methyl-7-(4-methylpiperazine-1-yl)-4-oxo-quinoline,
1-benzyl-7-morpholinyl-4-oxo-quinoline,
N-(3-(diethylamino) propyl group) fluoro-4 (1H)-Oxoquinoline-3-of-7-methane amide,
The chloro-N-of 7-(3-(diethylamino) propyl group)-4 (1H)-Oxoquinoline-3-methane amide,
The bromo-N-of 7-(3-(diethylamino) propyl group)-4 (1H)-Oxoquinoline-3-methane amide,
N-(3-diethylamino) propyl group-7-methoxyl group-4-(1H)-Oxoquinoline-3-methane amide,
The chloro-1-methyl-4-of ethyl 7-oxo-quinoline-3-carboxylic acid ester,
The chloro-1-ethyl-4-of ethyl 7-oxo-quinoline-3-carboxylic acid ester,
The chloro-4-oxo-quinoline-3-carboxylic acid of ethyl 1-allyl group-7-ester,
The chloro-4-oxo-quinoline-3-carboxylic acid of ethyl 1-butyl-7-ester,
The chloro-4-oxo-quinoline-3-carboxylic acid of ethyl 1-benzyl-7-ester,
The chloro-1-of ethyl 7-(3-hydrocinnamyl)-4-oxo-quinoline-3-carboxylic acid ester,
The chloro-N-[2-of 7-(diethylamino) ethyl]-1-methyl-4-oxo-quinoline-3-methane amide,
The chloro-N-[3-of 7-(diethylamino) propyl group]-1-methyl-4-oxo-quinoline-3-methane amide,
The chloro-N-[2-of 7-(diethylamino) ethyl]-1-ethyl-4-oxo-quinoline-3-methane amide,
The chloro-N-[2-of 7-(diethylamino) propyl group]-1-ethyl-4-oxo-quinoline-3-methane amide,
The chloro-N-[2-of 1-allyl group-7-(diethylamino) ethyl]-4-oxo-quinoline-3-methane amide,
The chloro-N-[3-of 1-allyl group-7-(diethylamino) propyl group]-4-Oxoquinoline-3-methane amide,
The chloro-N-[2-of 1-butyl-7-(diethylamino) ethyl]-4-oxo-quinoline-3-methane amide,
The chloro-N-[3-of 1-butyl-7-(diethylamino) propyl group]-4-oxo-quinoline-3-methane amide,
The chloro-N-[2-of 1-benzyl-7-(diethylamino) ethyl]-4-oxo-quinoline-3-methane amide,
The chloro-N-[2-of 1-benzyl-7-(diethylamino) propyl group]-4-oxo-quinoline-3-methane amide,
The chloro-N-[3-of 7-(diethylamino) propyl group]-1-(3-hydrocinnamyl)-4-oxo-quinoline-3-methane amide,
The chloro-1-ethyl-4-of N-(3-aminopropyl)-7-oxo-quinoline-3-methane amide,
The chloro-4-oxo-quinoline-3-of 1-allyl group-N-(3-aminopropyl)-7-methane amide,
N-(3-aminopropyl)-chloro-4-oxo-quinoline-3-of 1-butyl-7-methane amide,
The chloro-1-benzyl-4-of N-(3-aminopropyl)-7-oxo-quinoline-3-methane amide,
The chloro-1-of N-(3-aminopropyl)-7-(3-hydrocinnamyl)-4-oxo-quinoline-3-methane amide,
And their pharmacologically acceptable salts, solvate, prodrug.
Second aspect present invention relates to formula I compound, its tautomer, raceme or optical isomer, its pharmaceutical salts or solvate described in first aspect present invention any one and can be used for the purposes in the medicine of prevention or treatment tumour in preparation.
Fourth aspect present invention provides a kind of pharmaceutical composition, wherein contain the formula I compound of at least one first aspect present invention and hereinafter described formula II, formula III compound or its pharmacologically acceptable salts, solvate, prodrug, and optional pharmaceutical carrier or vehicle.According in this respect, the invention still further relates to described pharmaceutical composition as the application for preventing or treat the medicine of the diseases such as tumour.
Fifth aspect present invention provides the method that prevents and/or treats tumour, and the method comprises the formula I compound from the first aspect of significant quantity to the experimenter who has these needs and hereinafter described formula II, formula III compound or its pharmacologically acceptable salts, solvate, the prodrug that prevent and/or treat.
Sixth aspect present invention provides the method for the formula I compound of preparation first aspect or its pharmacologically acceptable salts, solvate, prodrug, and it comprises the following steps:
A) make formula
Figure BDA0000431113500000041
compound reacts (for example, under heating condition, for example, at 80～120 DEG C) with ethoxy methylene diethyl malonate, obtain following formula: compound:
Figure BDA0000431113500000042
B) by step a) gained compound for example join, in suitable solvent (phenyl ether), under heating condition, (for example, under this solvent boiling or reflux conditions) reacts mixture, after reaction finishes, add sherwood oil, separate and obtain following formula: compound:
Figure BDA0000431113500000051
C) for example, to step b) is added to alkali aqueous solution (aqueous sodium hydroxide solution in gained compound, for example 5～20% aqueous sodium hydroxide solutions), heating (for example refluxing) reaction, reaction finishes rear for example, with acid (hydrochloric acid, for example concentrated hydrochloric acid) acidifying, obtain following formula: compound
Figure BDA0000431113500000052
D) by step c) gained compound for example join, in suitable solvent (phenyl ether), under heating condition, (for example under reflux conditions) reacts mixture, after reaction finishes, add sherwood oil, separate and obtain 7-replacement-4-(the 1H)-oxoquinoline compound shown in following formula:
Figure BDA0000431113500000053
with
E) make steps d) gained compound dissolution for example, in suitable solvent (DMF), add NaH, then add halogenated alkane R 1-Y makes to react, and obtains R 3following formula: compound of the present invention for hydrogen:
Figure BDA0000431113500000054
Wherein,
X represent halogen or-C 1-4alkoxyl group,
Y represents halogen,
R 1be selected from-C 1-6alkyl ,-C 2-6thiazolinyl ,-C 1-6alkyl-phenyl, particularly for example R 1be selected from methyl, ethyl, propyl group, sec.-propyl, allyl group, propenyl, phenmethyl, hydrocinnamyl, normal-butyl.
Sixth aspect present invention also provides the method for the formula I compound of preparation first aspect or its pharmacologically acceptable salts, solvate, prodrug, and it comprises the following steps:
A) for example, in suitable solution (Isosorbide-5-Nitrae-dioxane), at KN[Si (CH3) 3] 2under existence, make formula
Figure BDA0000431113500000055
compound reacts (for example lower reaction under heating condition, for example under reflux conditions reaction) with morpholine or N methyl piperazine, obtain following formula: compound of the present invention:
Figure BDA0000431113500000056
wherein R 1for hydrogen or-C 1-6alkyl is methyl such as, R 7for
Figure BDA0000431113500000057
or
Figure BDA0000431113500000061
or
B), for example, in suitable solution (DMSO), under cuprous iodide, L-PROLINE, Tripotassium phosphate exist, make formula
Figure BDA0000431113500000062
compound reacts (for example lower reaction under heating condition, for example under reflux conditions reaction) with morpholine, obtain following formula: compound of the present invention: wherein R 1for-C 1-6alkyl-phenyl is benzyl such as, R 7for
Sixth aspect present invention also provides the method for the formula I compound of preparation first aspect or its pharmacologically acceptable salts, solvate, prodrug, and it comprises the following steps:
A) make the 7-of ethyl shown in following formula replace-4 (1H)-Oxoquinoline-3-carboxylic acid esters
Figure BDA0000431113500000065
Mix with 3-(diethylamino) propylamine, heating (for example, at 120～180 DEG C) makes reaction, obtains following formula: compound of the present invention:
Figure BDA0000431113500000066
Wherein X be halogen or-C 1-6alkoxyl group, for example X is fluorine, chlorine, bromine or methoxyl group.
Sixth aspect present invention also provides the method for the formula I compound of preparation first aspect or its pharmacologically acceptable salts, solvate, prodrug, and it comprises the following steps:
A) make formula
Figure BDA0000431113500000067
compound for example, in suitable solvent (DMF), NaH exist under with formula R 1the halogenated alkane that-Y represents reacts, and obtains following formula: compound of the present invention:
and optionally further,
B) make a) gained compound and formula H of step 2n-(CH 2) n-NH 2, H 2n-(CH 2) n-N (C 2h 5) 2the diamines representing mixes, and heating (for example, at 120～180 DEG C) makes reaction, obtains following formula: compound of the present invention:
Figure BDA0000431113500000071
or
Wherein
Y represents halogen,
N is 2 or 3,
R 1be selected from-C 1-6alkyl ,-C 2-6thiazolinyl ,-C 1-6alkyl-phenyl, particularly for example R 1be selected from methyl, ethyl, propyl group, sec.-propyl, allyl group, propenyl, phenmethyl, hydrocinnamyl, normal-butyl.
In the inventive method aspect the above the 6th, wherein the definition of each symbol is as described in first aspect present invention any one formula I compound.
Seventh aspect present invention provides a kind of compound, and it is with compound shown in Formula Il
Figure BDA0000431113500000073
And pharmacologically acceptable salts, solvate, prodrug, wherein
R 4be selected from halogen (for example chlorine, fluorine, bromine, iodine) ,-C 1-6alkyl (for example methyl, ethyl, propyl group, sec.-propyl, normal-butyl) ,-C 1-6alkoxyl group (for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy) ,-NH-C 1-6alkyl-N (C 1-4alkyl) 2;
R 7be selected from halogen (for example chlorine, fluorine, bromine, iodine) ,-C 1-6alkyl (for example methyl, ethyl, propyl group, sec.-propyl, normal-butyl) ,-C 1-6alkoxyl group (for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy) ,-C 1-6thiazolinyl oxygen base (for example vinyloxy group, propenyloxy group, butenyloxy) ,-C 1-6alkyl-phenyl ,-C 1-6alkyl-halo (for example chlorine, fluorine, bromine, iodo) phenyl.
According to the compound of seventh aspect present invention, it is selected from:
4,7-dichloroquinoline,
The chloro-7-methoxy quinoline of 4-,
7-chloro-4-methoxy quinoline,
The chloro-4-ethoxyquinoline of 7-,
The chloro-4-isopropoxy of 7-quinoline,
4,7-dimethoxy-quinoline,
4-oxyethyl group-7-methoxy quinoline,
The chloro-7-hydroxyquinoline of 4-,
The chloro-7-ethoxyquinoline of 4-,
The chloro-7-n-butoxy of 4-quinoline,
The positive hexyloxy quinoline of the chloro-7-of 4-,
The chloro-7-allyloxy of 4-quinoline,
The chloro-7-isopropoxy of 4-quinoline,
The chloro-7-isobutoxy of 4-quinoline,
The chloro-7-benzyloxy of 4-quinoline,
The chloro-7-of 4-(4-fluorine benzyloxy) quinoline,
The chloro-7-of 4-(3-benzene oxyethyl group) quinoline,
The chloro-7-of 4-(3-benzene propoxy-) quinoline,
N 1-(7-ethoxyquinoline-4-yl)-N 2, N 2-diethyl ethane-1,2-diamines,
N 1, N 1-diethyl-N 2-(7-hexyloxy quinolyl-4) ethane-1,2-diamines,
N 1-(7-allyloxy quinolyl-4)-N 2, N 2-diethyl ethane-1,2-diamines,
N 1, N 1-diethyl-N 2-(7-isopropoxy quinolyl-4) ethane-1,2-diamines,
N 1-(7-benzyloxy quinolyl-4)-N 2, N 2-diethyl ethane-1,2-diamines,
N 1, N 1-diethyl-N 2-(7-(4-fluorine benzyloxy) quinolyl-4) ethane-1,2-diamines,
N 1-(7-ethoxyquinoline-4-yl)-N 2, N 2-diethyl propane-1,2-diamines,
N 1-(7-allyloxy quinolyl-4)-N 2, N 2-diethyl propane-1,2-diamines,
N 1, N 1-diethyl-N 2-(7-(4-fluorine benzyloxy) quinolyl-4) propane-1,2-diamines,
And pharmacologically acceptable salts, solvate, prodrug.
Eighth aspect present invention provides a kind of compound, and it is compound shown in following formula III
Figure BDA0000431113500000081
And pharmacologically acceptable salts, solvate, prodrug, wherein
Y is 1 to 4 group that is selected from halogen, and for example Y is 1-2 group that is selected from fluorine, chlorine, bromine, iodine, and for example Y is 2 chlorine.
According to the compound of eighth aspect present invention, it is selected from:
The chloro-4-of 5,8-bis-(1H)-Oxoquinoline, and
The chloro-4-of 6,8-bis-(1H)-Oxoquinoline,
And pharmacologically acceptable salts, solvate, prodrug.
The feature that any one of either side of the present invention or this either side has is equally applicable to any one of other either side or this other either side, as long as they can be not conflicting, certainly, at where applicable each other, necessary words can be done suitably to modify to individual features.In the present invention, for example, while, mentioning " first aspect present invention any one ", this " any one " refers to the arbitrary sub-aspect of first aspect present invention; In the time that other side is mentioned in a similar manner, also there is identical meanings.
Be further described with feature to various aspects of the present invention below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to be explained, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.
Below, for formula I group definition that compound is done, composition explanation, usage description of use etc., if can not produce contradiction, these descriptive explanations go for formula II compound and formula III compound equally.
The term " halogen ", " halogen ", " Hal " or " halo " that in the present invention, adopt refer to fluorine, chlorine, bromine and iodine.
The term " alkyl ", " alkenyl " and " alkynyl " that in the present invention, adopt have general sense well known in the art, they are hydrocarbyl groups of straight or branched, such as but not limited to methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, allyl group, propenyl, proyl etc., and described " alkyl ", " alkenyl " and " alkynyl " can be referred to as " alkyl " or " chain alkylene ".In preferred embodiment of the present invention, described " alkyl " refers to that alkyl comprises for example C1-C6 alkyl of alkyl group and cycloalkyl, particularly alkyl group.
As used herein, term " aryl " is such as but not limited to phenyl, naphthyl.
As used herein, phrase " replacement or unsubstituted C1-C6 alkyl " refers to have the replacement or the unsubstituted alkyl group that specify number carbon atom, and the example includes but not limited to: methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, amyl group, neo-pentyl, hexyl.
The present invention relates to a series of compounds that comprise quinazolone ring, for convenience of identification, this quinazolone ring and annular atoms numbering thereof can represent in the following order
Figure BDA0000431113500000091
wherein theheterocyclic nitrogen atom is 1, and the ring carbon of oxo Ji Chu is 4.
In the present invention, group " C 1-C 6alkyl " and " C 1-6alkyl " the two has identical meanings, all represents to have the straight or branched alkyl of 1-6 carbon atom.Other situation also can be done similar understanding.
In the present invention, group " C 1-6alkyl " for example can be selected from C 1-5alkyl, C 1-4alkyl.Similarly ,-C 1-6alkoxyl group for example can be selected from C 1-5alkoxyl group, C 1-4alkoxyl group ,-C 2-6thiazolinyl for example can be selected from C 2-5thiazolinyl, C 2-4thiazolinyl ,-C 2-6alkynyl for example can be selected from C 2-5alkynyl, C 2-4alkynyl.
In the method for synthetic compound of formula i of the present invention, the various starting material that react used are that those skilled in the art can prepare according to existing knowledge, or can make by the known method of document, or can buy by business.In above reaction scheme, intermediate used, starting material, reagent, reaction conditions etc. all can be made appropriate change according to those skilled in the art existing knowledge.Or, other formula I compound that those skilled in the art also can specifically not enumerate according to the synthetic the present invention of second aspect present invention method.
According to the present invention, the pharmaceutical salts of formula I compound can be acid salt or the salt with alkali formation.Acid salt says it can is that inorganic acid salt is such as but not limited to hydrochloride, vitriol, phosphoric acid salt, hydrobromate for example; Or organic acid salt is such as but not limited to acetate, oxalate, lemon salt, gluconate, succinate, tartrate, tosilate, mesylate, benzoate, lactic acid salt and maleate; Formula I compound and alkali form salt and say for example it can is that an alkali metal salt is such as but not limited to lithium, sodium and sylvite; Alkaline earth salt is such as but not limited to calcium and magnesium salts; Organic alkali salt is such as but not limited to diethanolamine salt and choline salt etc.; Or chirality alkali salt is such as but not limited to alkyl phenyl amine salt.
The solvate of compound of the present invention can be that hydrate or the recrystallisation solvent that comprises other are as such as ethanol of alcohols.
According to the present invention, can there is cis/trans isomer in formula I compound, the present invention relates to the mixture of cis form and trans forms and these forms.If needed, the preparation of single stereoisomers can split mixture according to conventional methods, or by for example synthetic preparation of three-dimensional selection.If there is motor-driven hydrogen atom, the present invention also relates to the tautomeric form of formula I compound.
Therefore the present invention also relates at least one the formula I compound containing as the effective dose of active ingredient, or the pharmaceutical composition of its pharmaceutical salts and/or its steric isomer and conventional medicine vehicle or assistant agent.Conventionally pharmaceutical composition of the present invention contains 0.1-90 % by weight formula I compound and/or its physiologically acceptable salt.Pharmaceutical composition can be prepared according to methods known in the art.When this object, if needed, formula I compound and/or steric isomer and one or more solids or liquid medicine vehicle and/or assistant agent can be combined, make and can be used as suitable administration form or the dosage form that people uses.
Formula I compound of the present invention or the pharmaceutical composition that contains it can unit dosage form administrations, and route of administration can be enteron aisle or non-enteron aisle, as in oral, muscle, subcutaneous, knurl, nasal cavity, oral mucosa, skin, peritonaeum or rectum etc.Form of administration is tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, liposome, transdermal agent, buccal tablet, suppository, lyophilized injectable powder, injection etc. such as.Can be ordinary preparation, sustained release preparation, controlled release preparation and various particulate delivery system.For unit form of administration is made to tablet, can be widely used various carrier well known in the art.Example about carrier is that for example thinner and absorption agent, as starch, dextrin, calcium sulfate, lactose, N.F,USP MANNITOL, sucrose, sodium-chlor, glucose, urea, calcium carbonate, white bole, Microcrystalline Cellulose, pure aluminium silicate etc.; Wetting agent and tackiness agent, as water, glycerine, polyoxyethylene glycol, ethanol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, Xylo-Mucine, lac, methylcellulose gum, potassiumphosphate, polyvinylpyrrolidone etc.; Disintegrating agent, such as dry starch, alginates, agar powder, laminaran, sodium bicarbonate and Citric Acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.; Disintegration inhibitor, for example sucrose, Tristearoylglycerol, theobroma oil, hydrogenation wet goods; Absorption enhancer, such as quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant, such as talcum powder, silicon-dioxide, W-Gum, stearate, boric acid, whiteruss, polyoxyethylene glycol etc.Tablet further can also be made to coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.For pill is made in administration unit, can be widely used various carrier well known in the art.Example about carrier is that for example thinner and absorption agent, as glucose, lactose, starch, theobroma oil, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talcum powder etc.; Tackiness agent is as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or batter etc.; Disintegrating agent, as agar powder, dry starch, alginates, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.For suppository is made in administration unit, can be widely used various carrier well known in the art.Example about carrier is, the such as ester of polyoxyethylene glycol, Yelkin TTS, theobroma oil, higher alcohols, higher alcohols, gelatin, semi-synthetic glyceryl ester etc.For capsule is made in administration unit, effective constituent formula I compound or its steric isomer are mixed with above-mentioned various carriers, and the mixture obtaining is thus placed in to hard obviously capsule or soft capsule.Also effective constituent formula I compound or its steric isomer can be made to microcapsule, be suspended in aqueous medium and form suspensoid, also can pack in hard capsule or make injection application.For injection preparation is made in administration unit, as solution, emulsion, lyophilized injectable powder and suspensoid, can use the conventional all thinners in this area, for example, the isooctadecanol of water, ethanol, polyoxyethylene glycol, 1,3-PD, ethoxylation, isooctadecanol, the Polyoxyethylene Sorbitol Fatty Acid Esters etc. of polyoxy.In addition, to ooze injection liquid in order preparing etc., can in injection preparation, to add appropriate sodium-chlor, glucose or glycerine, in addition, can also add conventional solubility promoter, buffer reagent, pH adjusting agent etc.
In addition,, as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives, sweeting agent or other material.
Formula I compound of the present invention, or the dosage of its isomer depends on many factors, for example, to prevent or treat character and the severity of disease, sex, age, body weight and the individual reaction of patient or animal, particular compound used, route of administration and administration number of times etc.Above-mentioned dosage can single dose form or be divided into several, for example two, three or four dosage form administrations.
Term used herein " composition " means to comprise the product of the each appointment composition that comprises specified amount, and any product of the combination results of direct or indirect each appointment composition from specified amount.
The active compound amount of gained can change the actual dose level of each activeconstituents in pharmaceutical composition of the present invention, so that can effectively obtain required therapeutic response for concrete patient, composition and administering mode.Dosage level must according to the activity of particular compound, route of administration, the severity of the patient's condition for the treatment of and the patient's to be treated patient's condition and medical history select.But the way of this area is, the dosage of compound is from lower than level that required result for the treatment of requires, increasing gradually dosage, until obtain required effect for obtaining.
Compound of the present invention can be used for preparing antitumor drug.Described tumour is including but not limited to malignant tumour and leukemia such as melanoma, cancer of the stomach, lung cancer, mammary cancer, kidney, liver cancer, oral cavity epidermal carcinoma, cervical cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, colorectal carcinoma, bladder cancer, tumor of head and neck, nasopharyngeal carcinoma, skin carcinomas.Described cancer of the stomach comprises adenocarcinoma of stomach; Described lung cancer comprises adenocarcinoma of lung; Described colorectal carcinoma comprises adenocarcinoma of colon; Described ovarian cancer comprises adenocarcinoma ovaries; Described kidney comprises kidney clear cell adenocarcinoma; Leukemia comprises acute lymphoblastic leukemia, chronic leukemia, specific type leukemia.
When treating and/or preventing or other treatment and/or when prevention for above-mentioned, a kind of the compounds of this invention that treats and/or prevents significant quantity can be applied with pure form, or with the acceptable ester of pharmacy or prodrug forms (in the situation that there are these forms) application.Or described compound can be accepted to contain this object compound and one or more medicines the pharmaceutical composition administration of vehicle.The compounds of this invention that word " prevents and/or treats significant quantity " refers to be applicable to the reasonable effect/risk of any medical prophylaxis and/or treatment than the compound of the q.s for the treatment of obstacle.But the total daily dosage portion that it should be understood that the compounds of this invention and composition must maked decision within the scope of medical judgment reliably by attending physician.For any concrete patient, concrete treatment effective dose level must be determined according to many factors, and described factor comprises the severity of treated obstacle He this obstacle; The activity of the particular compound adopting; The concrete composition adopting; Patient's age, body weight, general health situation, sex and diet; Administration time, route of administration and the excretion rate of the particular compound adopting; The treatment time length; The medicine that is used in combination with adopted particular compound or uses simultaneously; And the known similar factor of medical field.For example, the way of this area is, the dosage of compound is from lower than level that required result for the treatment of requires, increasing gradually dosage, until obtain required effect for obtaining.In general, particularly people's dosage can be between 0.001～1000mg/kg body weight/day, for example, between 0.01～100mg/kg body weight/day, for example, between 0.01～10mg/kg body weight/day for Mammals for formula I compound of the present invention.
Embodiment
The present invention can be further illustrated by the following example, but these examples of implementation do not mean that any limitation of the invention.
Following synthetic route 1 has described to prepare some intermediates of the compounds of this invention and the general method of compounds more of the present invention.
synthetic route 1
the general synthesis technique of compound 6a-d:
(1) Xi Fushi alkali 3a-d's is synthetic:
Aniline 1a-d (100mmol) between corresponding and ethoxy methylene diethyl malonate 2 (23.3g, 108mmol) are mixed, and stirring at room temperature to solution is clarified.Subsequently above-mentioned reaction mixture is reacted 2 hours in 100 DEG C of heated and stirred, react complete, do not need aftertreatment and purifying, reaction mixture (being Xi Fushi alkali 3a-d) is directly added in next step reaction flask.
(2) Oxoquinoline-3-carboxylic acid ester 4a-d's is synthetic
Phenyl ether (100ml) is added in the round-bottomed flask of 250ml, be heated with stirring to boiling.Then while hot previous step reaction is obtained in phenyl ether solution that Xi Fushi alkali 3a-d is added drop-wise to boiling.Finish, continue heating reflux reaction, about approximately 15 minutes, bottle wall is separated out white solid, and about approximately 45 minutes, solid is full of whole bottle solution flavescence gradually.Stopped reaction, cooling reaction solution, to room temperature, adds 60-90 DEG C of sherwood oil (100ml) in reaction flask, after stirring, filters, and petroleum ether, obtains white solid, is intermediate Oxoquinoline-3-carboxylic acid ester 4a-d.
Fluoro-4 (the 1H)-Oxoquinoline-3-carboxylic acid esters (4a) of ethyl 7-
Taking m-fluoroaniline 1a (100mmol) as raw material, obtain white solid (16.9g, 72%).
Chloro-4 (the 1H)-Oxoquinoline-3-carboxylic acid esters (4b) of ethyl 7-
Taking m-chloro aniline 1b (100mmol) as raw material, obtain white solid (19.6g, 78%).
Bromo-4 (the 1H)-Oxoquinoline-3-carboxylic acid esters (4c) of ethyl 7-
Taking m-bromoaniline 1c (100mmol) as raw material, obtain white solid (22.2g, 75%).
Ethyl 7-methoxyl group-4 (1H)-Oxoquinoline-3-carboxylic acid ester (4d)
Taking 3-anisidine 1d (100mmol) as raw material, obtain white solid (16.3g, 66%).
(3) Oxoquinoline-3-carboxylic acid 5a-d's is synthetic
Product Oxoquinoline-3-carboxylic acid ester 4a-d obtained in the previous step (20mmol) is added in round-bottomed flask, add subsequently 10%NaOH solution (150ml), reflux 1 hour under agitation condition.Cooling reaction solution, to room temperature, adds 500ml water dilute reaction solution and with concentrated hydrochloric acid adjusting pH to 6.0, separates out faint yellow solid, filters, and water fully washs, dry, obtains white solid, is intermediate Oxoquinoline-3-carboxylic acid 5a-d.
Fluoro-4 (the 1H)-Oxoquinoline-3-carboxylic acids (5a) of 7-: obtain white solid (4.1g, 98%).
Chloro-4 (the 1H)-Oxoquinoline-3-carboxylic acids (5b) of 7-: obtain white solid (4.3g, 97%).
Bromo-4 (the 1H)-Oxoquinoline-3-carboxylic acids (5c) of 7-: obtain white solid (5.2g, 98%).
7-methoxyl group-4 (1H)-Oxoquinoline-3-carboxylic acid (5d): obtain white solid (4.2g, 96%).
(4) 7-replacement-4-(1H)-Oxoquinoline 6a-d's is synthetic
Previous step is reacted to the corresponding intermediate Oxoquinoline-3-carboxylic acid 5a-d (16.0g) obtaining and mix with phenyl ether (100ml), heating reflux reaction.Carboxylic acid does not first dissolve.Along with temperature raises, insoluble solids reduces and gradually with a large amount of Bubble formations.Heating reflux reaction approximately 30 minutes, without Bubble formation, stopped reaction, cooling reaction solution, to room temperature, has pale solid to separate out.Add 60-90 DEG C of sherwood oil (100ml), after stirring, filter, obtain white solid.
fluoro-4 (the 1H)-Oxoquinolines (6a) of 7-
Obtain white solid (1.5g, 92%).ESI-MS?m/z164[M+H] +. 1H?NMR(300MHz,DMSO-d 6):δ11.75(1H,s),8.07-8.13(1H,m),7.88(1H,d,J=7.2Hz),7.23-7.27(1H,m),7.13-7.17(1H,m),6.02(1H,d,J=7.2Hz).
chloro-4 (the 1H)-Oxoquinolines (6b) of 7-
Obtain white solid (1.5g, 86%).ESI-MS?m/z180[M+H] +. 1H?NMR(300MHz,DMSO-d 6):δ11.75(1H,s),8.03(1H,d,J=8.7Hz),7.88(1H,d,J=7.2Hz),7.55(1H,d,J=2.1Hz),7.28(1H,dd,J=8.7Hz,J=2.1Hz),6.02(1H,d,J=7.2Hz).
bromo-4 (the 1H)-Oxoquinolines (6c) of 7-
Obtain white solid (2.0g, 88%).ESI-MS?m/z224[M] +. 1H?NMR(300MHz,DMSO-d 6):δ11.75(1H,s),7.95(1H,d,J=8.7Hz),7.88(1H,d,J=7.5Hz),7.71(1H,d,J=1.8Hz),7.41(1H,dd,J=8.7Hz,J=2.1Hz),6.02(1H,d,J=7.5Hz). 13C?NMR(75MHz,CDCl 3)δ177.1,141.6,140.6,128.0,126.8,125.7,125.2,121.1,110.0.
7-methoxyl group-4 (1H)-Oxoquinoline (6d)
Obtain white solid (1.6g, 86%).ESI-MS?m/z176[M+H] +. 1H?NMR(300MHz,DMSO-d 6):δ11.63(1H,s),7.93(1H,d,J=8.7Hz),7.76(1H,d,J=7.5Hz),6.91(1H,d,J=2.4Hz),6.88(1H,dd,J=8.7Hz,J=2.4Hz)5.91(1H,d,J=7.5Hz),3.83(3H,s).
the general synthesis technique of the compounds of this invention 7a to 7i:
7-replacement-4-(1H)-Oxoquinoline (10mmol) is dissolved in to DMF (60ml), stirring at room temperature is to clarification, add 60%NaH (0.8g, 20mmol), stirring at room temperature 5 minutes, add corresponding haloalkane (15-25mmol), stirring at room temperature reaction, TLC follows the tracks of detection.React complete, reaction mixture is poured into water, ethyl acetate extraction (150ml × 3), merges organic phase, washing, saturated salt washing.By organic phase acidifying (pH1～2), be evaporated near doing, dehydrated alcohol band water 2 times, residue acetone recrystallization with concentrated hydrochloric acid.Filter, obtain yellow solid.By water-soluble above-mentioned yellow solid, sodium bicarbonate alkalization, ethyl acetate extraction, anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated into dry, and residue ether or ether/sherwood oil recrystallization, obtain target product 7a-i.Wherein
embodiment 1: preparation 7-fluoro-1-methyl-4-oxo-quinoline (compound 7a)
Taking fluoro-4 (the 1H)-Oxoquinoline 6a (5.0mmol) of 7-and methyl iodide (7.5mmol) as raw material.Obtain white solid (0.86g, 86%).ESI-MS?m/z178[M+H] +. 1H?NMR(300MHz,CDCl 3):δ8.40-8.45(1H,m),7.47(1H,d,J=7.5Hz),7.00-7.11(2H,m),6.20(1H,d,J=7.5Hz),3.74(3H,s).
embodiment 2: preparation 7-chloro-1-methyl-4-oxo-quinoline (compound 7b)
Taking chloro-4 (the 1H)-Oxoquinoline 6b (5.0mmol) of 7-and methyl iodide (7.5mmol) as raw material.Obtain white solid (0.67g, 69%), mp233-234 DEG C.ESI-MS?m/z194[M+H] +. 1H?NMR(300MHz,CDCl 3):δ8.30(1H,d,J=8.7Hz),7.43(1H,d,J=7.8Hz),7.34(1H,d,J=1.8Hz),7.28(1H,dd,J=8.7Hz,J=1.8Hz),6.18(1H,d,J=7.8Hz),3.74(3H,s). 13CNMR(75MHz,CDCl 3)δ177.6(C=O),144.1,141.4,138.8,128.8,125.5,124.5,115.4,110.8,41.0.
embodiment 3: preparation 7-bromo-1-methyl-4-oxo-quinoline (compound 7c)
Taking bromo-4 (the 1H)-Oxoquinoline 6c (5.0mmol) of 7-and methyl iodide (7.5mmol) as raw material.Obtain white solid (1.0g, 88%).ESI-MS?m/z239[M+H] +. 1H?NMR(300MHz,CDCl 3):δ8.27(1H,d,J=8.7Hz),7.44-7.54(3H,m),6.23(1H,d,J=7.8Hz),3.76(3H,s). 13C?NMR(75MHz,CDCl 3)δ176.5,146.1,128.5,128.4,127.1,126.6,126.0,120.0,109.9,40.8.
embodiment 4: preparation 7-methoxyl group-1-methyl-4-oxo-quinoline (compound 7d)
Taking 7-methoxyl group-4 (1H)-Oxoquinoline 6d (5.0mmol) and methyl iodide (7.5mmol) as raw material.Obtain white solid (0.76g, 80%).Mp179-180℃。ESI-MS?m/z190[M+H] +. 1H?NMR(300MHz,DMSO-d 6):δ8.31(1H,d,J=8.7Hz),7.40(1H,d,J=7.5Hz),6.94(1H,dd,J=8.7Hz,J=1.8Hz),6.66(1H,s),6.15(1H,d,J=7.5Hz),3.91(3H,s),3.71(3H,s). 13C?NMR(75MHz,CDCl 3)δ176.4,162.8,145.4,142.9,128.0,121.2,113.4,109.1,99.2,56.4,40.9.
embodiment 5: preparation 7-chloro-1-sec.-propyl-4-oxo-quinoline (compound 7e)
Taking chloro-4 (the 1H)-Oxoquinoline 6b (5.0mmol) of 7-and 2-N-PROPYLE BROMIDE (20mmol) as raw material, obtain white solid (0.75g, 68%).ESI-MS?m/z222[M+H] +. 1H?NMR(300MHz,CDCl 3):δ9.08(1H,d,J=6.9Hz),8.28-8.32(2H,m),7.82(1H,dd,J=9.0Hz,J=2.1Hz),7.54(1H,d,J=6.9Hz),5.20-5.32(1H,m),1.49(3H,s),1.47(3H,s). 13CNMR(75MHz,CDCl 3)δ167.5(C=O),147.9,139.8,139.5,129.7,125.9,119.9,119.8,104.2,76.1,22.0.
embodiment 6: the preparation chloro-4-oxo-quinoline in 1-allyl group-7 (compound 7f)
Taking chloro-4 (the 1H)-Oxoquinoline 6b (5.0mmol) of 7-and allyl bromide 98 (7.5mmol) as raw material, obtain white solid (0.9g, 82%).ESI-MS?m/z220[M+H] +. 1H?NMR(300MHz,CDCl 3):δ8.32(1H,d,J=8.4Hz),7.46(1H,d,J=7.8Hz),7.26-7.32(2H,m),6.23(1H,d,J=7.8Hz),5.90-6.03(1H,m),5.09-5.34(2H,m),4.64-4.67(2H,m). 13CNMR(75MHz,CDCl 3)δ177.5(C=O),143.6,140.8,138.6,130.9,128.7,125.6,124.4,119.0,115.8,111.0,55.2.
embodiment 7: the preparation chloro-4-oxo-quinoline of 1-benzyl-7-(compound 7g)
Taking chloro-4 (the 1H)-Oxoquinoline 6b (5.0mmol) of 7-and cylite (7.5mmol) as raw material, obtain white solid (0.95g, 70%).Mp202-203℃。ESI-MS?m/z270[M+H] +. 1H?NMR(300MHz,CDCl 3):δ8.34(1H,d,J=9.0Hz),7.58(1H,d,J=7.8Hz),7.25-7.36(5H,m),7.12(2H,d，J=6.9Hz),6.30(1H,d,J=7.8Hz),5.27(2H,s). 13C?NMR(75MHz,CDCl 3)δ177.6(C=O),144.1,141.0,138.7,134.7,129.5,128.8,128.7,126.3,125.8,124.6,116.0,111.1,56.7.
embodiment 8: the preparation chloro-1-of 7-(3-hydrocinnamyl)-4-oxo-quinoline (compound 7h)
Taking chloro-4 (the 1H)-Oxoquinoline 6b (5.0mmol) of 7-and 1-(3-bromopropyl) benzene (25mmol) as raw material, obtain yellow oil (1.0g, 68%).ESI-MS?m/z298[M+H] +. 1H?NMR(300MHz,CDCl 3):δ8.35(1H,d,J=8.7Hz),7.40(1H,d,J=7.8Hz),7.18-7.34(7H,m),6.22(1H,d,J=7.8Hz),4.03(2H,t,J=7.5Hz),2.74(2H,t,J=7.5Hz),2.16-2.26(2H,m). 13C?NMR(75MHz,CDCl 3)δ177.5(C=O),143.6,140.5,139.8,138.7,129.0,128.5,126.9,125.8,124.4,115.3,110.8,52.6,32.8,30.1.
embodiment 9: the preparation bromo-4-oxo-quinoline of 1-benzyl-7-(compound 7i)
Taking bromo-4 (1H)-Oxoquinoline 6c (5.0mmol) a of 7-and cylite (7.5mmol) as raw material, obtain white solid (1.32g, 84%).ESI-MS?m/z315[M+H] +. 1H?NMR(300MHz,CDCl 3):δ8.29(1H,d,J=8.7Hz),7.56(1H,d,J=7.8Hz),7.32-7.48(5H,m),7.13-7.16(2H,m),6.31(1H,d,J=7.8),5.26(2H,s). 13C?NMR(75MHz,CDCl 3)δ177.1,144.0,141.1,134.7,129.5,128.9,128.7,127.3,126.4,126.2,119.1,111.2,111.1,56.6.
Following synthetic route 2 has described to prepare some intermediates of the compounds of this invention and the general method of compounds more of the present invention.
synthetic route 2:
Figure BDA0000431113500000151
synthesizing of embodiment 10:7-morpholinyl-4 (1H)-Oxoquinoline (compound 15)
In the round-bottomed flask of 50ml, add successively Isosorbide-5-Nitrae-dioxane (6ml), morpholine (0.21ml, 2.4mmol), KN[Si (CH3) 3] 2bromo-4 (the 1H)-Oxoquinolines (0.45g, 2mmol) of (2.64ml, 2.4mmol) and 7-, finish stirring at room temperature 5 minutes, subsequently back flow reaction in 100 DEG C of oil baths, TLC follows the tracks of detection, reacts complete, and cooling reaction solution is to room temperature, add 20ml water termination reaction, regulate pH value to 6.0, be evaporated to dry, dehydrated alcohol band water 3 times, residue silica gel column chromatography, methylene dichloride: methyl alcohol=10:1, obtain yellow oil (0.16g, 35%).ESI-MS?m/z230.8[M+H] +. 1H?NMR(300MHz,DMSO-d 6):δ11.38(1H,s),7.88(1H,d,J=7.2Hz),7.69-7.73(1H,m),7.02(1H,dd,J=7.2Hz,1.2Hz),6.71(1H,s),5.87(1H,d,J=7.2Hz),3.73(4H,t,J=4.5Hz),3.20(4H,t,J=4.5Hz). 13C?NMR(75MHz,CDCl 3)δ177.1,153.8,142.3,139.4,126.6,119.3,113.4,108.9,100.1,66.7,48.2.
synthesizing of embodiment 11:1-methyl-7-(4-methylpiperazine-1-yl)-4-oxo-quinoline (compound 16)
In the round-bottomed flask of 50ml, add successively Isosorbide-5-Nitrae-dioxane (12ml), N methyl piperazine (0.4ml, 3.6mmol), KN[Si (CH3) 3] 2the bromo-1-of (4ml, 3.64mmol) and 7-methyl-4 (1H)-Oxoquinoline (0.48g, 2mmol), finishes, and vacuumizes immediately, takes out completely, is filled with immediately N 2, repeatedly take out each 1 minute 4 times.Then reaction mixture is put in 100 DEG C of oil baths and refluxed approximately 15 hours, TLC follows the tracks of detection.React complete, cooling reaction solution, to room temperature, adds 5ml water termination reaction, is evaporated to dry, dissolve with methanol reaction residue, filters and removes insolubles, and filtrate is concentrated into dry, silica gel column chromatography, methylene dichloride: methyl alcohol=30:1 washing, obtains yellow oil (0.16g, 31%).ESI-MS?m/z257.9[M+H] +. 1H?NMR(300MHz,DMSO-d 6):δ8.25(1H,d,J=9.0Hz),7.36(1H,d,J=7.5Hz),6.99(1H,dd,J=9.0Hz,2.1Hz),6.49(1H,d,J=2.1Hz),6.13(1H,d,J=7.5Hz),3.70(3H,s),3.38(4H,t,J=4.8Hz),2.59(4H,t,J=4.8Hz),2.36(3H,s). 13C?NMR(75MHz,CDCl 3)δ177.1,153.8,142.3,139.4,126.6,119.3,113.4,108.9,100.1,66.7,48.2.
synthesizing of embodiment 12:1-benzyl-7-morpholinyl-4-oxo-quinoline (compound 17):
In the round-bottomed flask of 50ml, add successively the bromo-1-of 7-benzyl-4 (1H)-Oxoquinoline (0.64g, 2mmol), cuprous iodide (0.05g), L-PROLINE (0.05g, 1mmol), Tripotassium phosphate (0.42g, 2mmol), morpholine (0.2ml, 1.5mmol) and DMSO (1.5ml), finish, in 90 DEG C of oil baths, react, TLC follows the tracks of detection.React complete, add 0.5ml ammoniacal liquor termination reaction, add subsequently 10ml water and 20ml methylene dichloride, separate organic phase, water dichloromethane extraction twice, merges organic phase, washing, saturated salt washing, anhydrous sodium sulfate drying.Filter, filtrate decompression is concentrated into dry, residue silica gel column chromatography, and methylene dichloride: methyl alcohol=100:1 is eluent, obtains yellow oil (0.26g, 40%).ESI-MS?m/z320.9[M+H] +. 1H?NMR(300MHz,DMSO-d 6):δ8.28(1H,d,J=9.0Hz),7.53(1H,d,J=7.8Hz),7.29-7.34(3H,m),7.14-7.17(1H,m),6.93(1H,dd,J=9.0Hz,2.1Hz),6.42(1H,d,J=2.1Hz),6.24(1H,d,J=7.8Hz),5.23(2H,s),3.78(4H,t,J=4.8Hz),3.12(4H,t,J=4.8Hz). 13C?NMR(75MHz,CDCl 3)δ177.8,153.8,143.6,141.9,135.6,129.4,128.4,128.2,126.3,120.4,113.0,110.2,99.3,66.7,57.0,48.2.
Following synthetic route 3 has described to prepare some intermediates of the compounds of this invention and the general method of compounds more of the present invention.
synthetic route 3:
Figure BDA0000431113500000161
the general synthesis technique of compound 18a-d
Ethyl 7-is replaced to-4 (1H)-Oxoquinoline-3-carboxylic acid esters (5.0mmol) and 3-(diethylamino) propylamine (5.0ml) mixing, and 150 DEG C of microwave heatings are reacted 30 minutes.Cooling reaction solution is to room temperature, in reaction mixture, add 100ml water, dichloromethane extraction (50mL × 3), merges organic phase, washing, saturated salt washing, anhydrous sodium sulfate drying, filters, be evaporated to dry, silica gel column chromatography, methylene dichloride: methyl alcohol=50:1 is eluent, obtains target product.
embodiment 13: preparation N-(3-(diethylamino) propyl group) fluoro-4 (1H)-Oxoquinoline-3-of-7-methane amide (compound 18a)
Taking fluoro-4 (the 1H)-Oxoquinoline-3-carboxylic acid ester 4a (5.0mmol) of ethyl 7-as raw material, obtain white solid (0.72,45%) .ESI-MS m/z320[M+H] +. 1h NMR (300MHz, CDCl 3) δ 10.45 (s, 1H), 8.82 (s, 1H), 8.35-8.40 (m, 1H), 7.23-7.27 (m, 1H), 7.08-7.14 (m, 1H), 3.56 (q, J=5.1Hz, 2H), 2.53-2.60 (m, 6H), 1.78-1.88 (m, 2H), 1.02 (t, J=6.9Hz, 6H). 13cNMR (75MHz, CDCl 3) δ 176.6,166.4,163.4,144.6,141.8,129.1,123.8,114.2,111.3,104.8,50.5,47.0,38.0,27.4,11.6.
embodiment 14: the preparation chloro-N-of 7-(3-(diethylamino) propyl group)-4 (1H)-Oxoquinoline-3-methane amide (compound 18b)
Taking chloro-4 (the 1H)-Oxoquinoline-3-carboxylic acid ester 4b (5.0mmol) of ethyl 7-as raw material, obtain white solid (0.87g, 52%) .ESI-MS m/z336[M+H] +. 1h NMR (300MHz, CDCl 3) δ 10.48 (s, 1H), 8.84 (s, 1H), 8.34 (d, J=8.7Hz, 1H), 7.63 (d, J=1.5Hz, 1H), 7.36 (dd, J=8.7,1.5Hz, 1H), 3.55 (q, J=5.1Hz, 2H), 2.58-2.65 (m, 6H), 1.78-1.94 (m, 2H), 1.07 (t, J=7.2Hz, 6H). 13c NMR (75MHz, CDCl 3) δ 176.7,166.4,144.6,140.9,138.8,127.9,125.8,125.4,118.9,111.5,50.5,47.1,38.1,27.4,11.6.
embodiment 15: the preparation bromo-N-of 7-(3-(diethylamino) propyl group)-4 (1H)-Oxoquinoline-3-methane amide (compound 18c)
Taking bromo-4 (the 1H)-Oxoquinoline-3-carboxylic acid ester 4c (5.0mmol) of ethyl 7-as raw material, obtain white solid (0.93,49%) .ESI-MS m/z380[M+H] +. 1h NMR (300MHz, CDCl 3) δ 10.52 (s, 1H), 8.84 (s, 1H), 8.26 (d, J=8.7Hz, 1H), 7.81 (d, J=1.5Hz, 1H), 7.51 (dd, J=8.7,1.5Hz, 1H), 3.56 (q, J=5.1Hz, 2H), 2.58-2.65 (m, 6H), 1.82-1.91 (m, 2H), 1.06 (t, J=7.2Hz, 6H). 13c NMR (75MHz, CDCl 3) δ 176.8,166.5,144.5,141.1,128.6,127.9,127.2,125.8,122.1,111.5,50.6,47.1,38.1,27.4,11.7.
embodiment 16: preparation N-(3-diethylamino) propyl group-7-methoxyl group-4-(1H)-Oxoquinoline-3-methane amide (compound 18d)
Taking ethyl 7-methoxyl group-4 (1H)-Oxoquinoline-3-carboxylic acid ester 4d (5.0mmol) as raw material, obtain white solid (0.96g, 58%) .ESI-MSm/z332[M+H] +. 1h NMR (300MHz, CDCl 3) δ 10.50 (s, 1H), 8.78 (s, 1H), 8.30 (d, J=9.0Hz, 1H), 7.00 (dd, J=9.0,1.8Hz, 1H), 6.91 (d, J=1.8Hz, 1H), 3.89 (s, 3H), 3.54 (q, J=5.4Hz, 2H), 2.51-2.59 (m, 6H), 1.78-1.87 (m, 2H), 1.02 (t, J=7.2Hz, 6H). 13c NMR (75MHz, CDCl 3) δ 176.6,166.3,162.9,143.1,141.1,127.6,120.7,115.8,110.8,99.7,55.6,50.3,46.7,37.8,27.2,11.4.
Following synthetic route 4 has described to prepare some intermediates of the compounds of this invention and the general method of compounds more of the present invention.
synthetic route 4:
Figure BDA0000431113500000171
the general synthesis technique of compound 19a-f
In the round-bottomed flask of 100ml, add chloro-4 (the 1H)-Oxoquinoline-3-carboxylic acid ester 4b (2.51g of ethyl 7-, 10mmol) and DMF (50ml), stirring at room temperature 10 minutes, add subsequently 60%NaH (0.8g, 20mmol), stirring at room temperature 15 minutes, then adds corresponding halogenated alkane (15-30mmol), stirring at room temperature reaction, TLC follows the tracks of detection.React complete, reaction mixture is poured into water, ethyl acetate extraction, merges organic phase, washing, saturated salt washing..With concentrated hydrochloric acid, by organic phase acidifying, pressurization is concentrated into dry, dehydrated alcohol band water 3 times, and acetone recrystallization, filters to obtain yellow solid.By water-soluble above-mentioned yellow solid, sodium bicarbonate alkalization, ethyl acetate extraction, washing, saturated salt washing, anhydrous sodium sulfate drying, be evaporated to dry, silica gel column chromatography, ethyl acetate/petroleum ether=2:1 wash-out, obtains target product.
embodiment 17: prepare the chloro-1-methyl-4-of ethyl 7-oxo-quinoline-3-carboxylic acid ester (compound 19a)
Taking methyl iodide (15mmol) as raw material, obtain white solid (1.7g, 65%) .ESI-MS m/z288[M+Na] +. 1h NMR (300MHz, CDCl 3) δ 8.42-8.45 (m, 2H), 7.38-7.41 (m, 2H), 4.39 (q, J=7.2Hz, 2H), 3.86 (s, 3H), 1.42 (t, J=7.2Hz, 3H). 13c NMR (75MHz, CDCl 3) δ 172.9,164.9,151.2,141.3,138.2,128.8,127.1,125.8,117.7,110.8,60.6,41.8,15.1.
embodiment 18: prepare the chloro-1-ethyl-4-of ethyl 7-oxo-quinoline-3-carboxylic acid ester (compound 19b)
Taking iodoethane (15mmol) as raw material, obtain white solid (1.9g, 69%) .ESI-MS m/z302[M+Na] +. 1h NMR (300MHz, CDCl 3) δ 8.44-8.47 (m, 2H), 7.25-7.43 (m, 2H), 4.39 (q, J=7.2Hz, 2H), 4.21 (q, J=7.2Hz, 2H), 1.56 (t, J=7.2Hz, 3H), 1.41 (t, J=7.2Hz, 3H). 13c NMR (75MHz, CDCl 3) δ 173.5,165.2,148.9,139.4,139.1,129.5,127.5,125.5,115.8,111.5,61.1,49.2,14.7.
embodiment 19: prepare the chloro-4-oxo-quinoline-3-carboxylic acid of ethyl 1-allyl group-7-ester (compound 19c)
Taking allyl bromide 98 (15mmol) as raw material, obtain white solid (2.2g, 75%) .ESI-MS m/z314[M+Na] +. 1h NMR (300MHz, CDCl 3) δ 8.48 (s, 1H), 8.42 (d, J=8.7Hz, 1H), 7.34-7.39 (m, 2H), 5.94-5.07 (m, 1H), 5.40 (d, J=10.5Hz, 1H), 5.20 (d, J=17.1Hz, 1H), 4.79 (m, 2H), 4.38 (q, J=6.9Hz, 2H), 1.41 (t, J=6.9Hz, 3H). 13c NMR (75MHz, CDCl 3) δ 173.8,165.2,149.7,140.0,139.2,130.5,129.4,127.3,125.8,119.8,116.5,111.6,61.2,56.2,14.8.
embodiment 20: prepare the chloro-4-oxo-quinoline-3-carboxylic acid of ethyl 1-butyl-7-ester (compound 19d)
Taking iodo-n-butane (30mmol) as raw material, obtain white solid (1.9g, 62%) .ESI-MS m/z330[M+Na] +. 1hNMR (300MHz, DMSO-d 6): δ 8.62 (s, 1H), 8.17 (d, J=8.7Hz, 1H), 7.87 (d, J=1.8Hz, 1H), 7.47 (dd, J=8.7Hz, 1.8Hz, 1H), 4.33 (t, J=7.2Hz, 2H), 4.20 (q, J=7.2Hz, 2H), 1.64-1.73 (m, 2H), 1.24-1.34 (m, 5H), 0.88 (t, J=7.2Hz, 3H). 13c NMR (75MHz, CDCl 3) δ 172.8,165.0,150.5,140.3,138.4,129.2,127.5,125.8,117.4,111.1,60.7,53.3,31.3,19.9,15.1,14.3.
embodiment 21: prepare the chloro-4-oxo-quinoline-3-carboxylic acid of ethyl 1-benzyl-7-ester (compound 19e)
Taking cylite (15mmol) as raw material, obtain white solid (2.9g, 85%) .ESI-MS m/z364[M+Na] +. 1h NMR (300MHz, DMSO-d 6): δ 8.54 (s, 1H), 8.43 (d, J=8.1Hz, 1H), 7.30-7.38 (m, 5H), 7.14-7.18 (m, 2H), 5.34 (s, 2H), 4.38 (q, J=7.2Hz, 2H), 1.41 (t, J=7.2Hz, 3H). 13c NMR (75MHz, CDCl 3) δ 173.6,165.0,150.0,140.1,139.1,134.0,129.5,129.4,128.8,127.5,126.4,125.7,116.7,111.7,61.1,57.5,14.8.
embodiment 22: prepare the chloro-1-of ethyl 7-(3-hydrocinnamyl)-4-oxo-quinoline-3-carboxylic acid ester (compound 19f)
Taking 1-(3-bromopropyl) benzene (50mmol) as raw material, obtain white solid (2.4 g, 65%) and .ESI-MS m/z392[M+Na] +. 1hNMR (300MHz, CDCl 3) δ 8.44 (d, J=8.7Hz, 1H), 8.37 (s, 1H), 7.43-7.15 (m, 7H), 4.40 (q, J=7.2Hz, 2H), 4.10 (t, J=7.2Hz, 2H), 2.77 (t, J=7.2Hz, 2H), 2.32 – 2.20 (m, 2H), 1.42 (t, J=7.2Hz, 3H). 13c NMR (75MHz, CDCl 3) δ 173.2,164.9,149.1,139.2,139.1,138.8,129.4,128.6,128.1,127.9,127.3,126.5,125.3,115.3,111.2,60.8,52.9,32.3,29.6,14.4.
General synthesis technique has described to prepare the general method of the compounds of this invention compound 20a-k and 21a-e below.
Chloro-4 (the 1H)-Oxoquinoline-3-carboxylic acid esters (5.0mmol) of ethyl 7-that 1-is replaced and corresponding diamines (5.0ml) mix, and 150 DEG C of microwave heatings are reacted 30 minutes.Cooling reaction solution is to room temperature, in reaction mixture, add 100ml water, dichloromethane extraction (50mL × 3), merges organic phase, washing, saturated salt washing, anhydrous sodium sulfate drying, filters, be evaporated to dry, silica gel column chromatography, methylene dichloride: methyl alcohol=50:1 is eluent, obtains target product.
embodiment 23: the preparation chloro-N-[2-of 7-(diethylamino) ethyl]-1-methyl-4-oxo-quinoline-3-methane amide (compound 20a)
With ethyl 7-chloro-1-methyl-4-oxo-quinoline-3-carboxylic acid ester 19a (5.0mmol) and N, N-diethyl ethylenediamine (5.0ml) is raw material, obtains white solid (1.1g, 68%) .ESI-MS m/z336[M+H] +. 1h NMR (300MHz, CDCl 3) δ 9.92 (s, 1H), 8.73 (s, 1H), 8.45 (d, J=8.4Hz, 1H), 7.43-7.50 (m, 2H), 3.91 (s, 3H), 3.55 (q, J=6.3Hz, 2H), 2.61-2.67 (m, 6H), 1.79-1.91 (m, 2H), 1.08 (t, J=7.2Hz, 6H). 13c NMR (75MHz, CDCl 3) δ 176.0,164.6,148.8,140.7,139.5,129.1,126.3,125.9,116.0,112.7,52.1,47.5,41.8,37.7,12.2.
embodiment 24: the preparation chloro-N-[3-of 7-(diethylamino) propyl group]-1-methyl-4-oxo-quinoline-3-methane amide (compound 20b)
Taking ethyl 7-chloro-1-methyl-4-oxo-quinoline-3-carboxylic acid ester 19a (5.0mmol) and 3-(diethylamino) propylamine (5.0ml) as raw material, obtain white solid (0.9g, 54%) .ESI-MS m/z350[M+H] +. 1h NMR (300MHz, CDCl 3) δ 9.92 (s, 1H), 8.73 (s, 1H), 8.45 (d, J=8.7Hz, 1H), 7.43-7.50 (m, 2H), 3.91 (s, 3H), 3.55 (q, J=6.3Hz, 2H), 2.61-2.67 (m, 6H), 1.79-1.91 (m, 2H), 1.08 (t, J=7.2Hz, 6H). 13c NMR (75MHz, CDCl 3) δ 176.1,164.6,148.9,140.7,139.6,129.0,125.9,116.0,112.7,50.6,47.1,41.8,38.0,27.4,11.9.
embodiment 25: the preparation chloro-N-[2-of 7-(diethylamino) ethyl]-1-ethyl-4-oxo-quinoline-3-methane amide (compound 20c)
With ethyl 7-chloro-1-ethyl-4-oxo-quinoline-3-carboxylic acid ester 19b (5.0mmol) and N, N-diethyl ethylenediamine (5.0ml) is raw material, obtains white solid (1.0g, 58%) .ESI-MS m/z350[M+H] +. 1h NMR (300MHz, CDCl 3) δ 9.95 (s, 1H), 8.77 (s, 1H), 8.44 (d, J=8.4Hz, 1H), 7.50 (d, J=1.5Hz, 1H), 7.43 (d, J=8.4Hz, 1.5Hz, 1H), (4.29 q, J=7.2Hz, 2H), (3.55 q, J=6.6Hz, 2H), (2.82 t, J=6.9Hz, 2H), (2.64 q, J=7.2Hz, 4H), (1.57 t, J=7.2Hz, 3H), 1.10 (t, J=7.2Hz, 6H). 13cNMR (75MHz, CDCl 3) δ 175.9,164.7,147.6,139.6,139.4,129.3,126.6,125.6,115.7,112.9,52.1,49.3,47.5,37.7,14.8,12.3.
embodiment 26: the preparation chloro-N-[2-of 7-(diethylamino) propyl group]-1-ethyl-4-oxo-quinoline-3-methane amide (compound 20d)
Taking ethyl 7-chloro-1-ethyl-4-oxo-quinoline-3-carboxylic acid ester 19b (5.0mmol) and 3-(diethylamino) propylamine (5.0ml) as raw material, obtain white solid (1.06g, 57%) .ESI-MS m/z364[M+H] +. 1h NMR (300MHz, CDCl 3) δ 9.92 (s, 1H), 8.77 (s, 1HH), 8.45 (d, J=8.7Hz, 1H), 7.51 (d, J=1.8Hz, 1H), 7.43 (dd, J=8.7,1.8Hz, 1H), 4.28 (q, J=7.2Hz, 2H), 3.49 (q, J=6.9Hz, 2H), 2.54 (m, 6H), 1.86-1.74 (m, 2H), 1.57 (t, J=7.2Hz, 3H), 1.04 (t, J=7.2Hz, 6H). 13cNMR (75MHz, CDCl 3) δ 176.0,164.6,147.7,139.5,129.3,126.6,125.7,115.7,112.9,50.7,49.4,47.2,38.0,27.6,14.9,12.1.
embodiment 27: the preparation chloro-N-[2-of 1-allyl group-7-(diethylamino) ethyl]-4-oxo-quinoline-3-methane amide (compound 20e)
With ethyl 1-allyl group-7-chloro-4-oxo-quinoline-3-carboxylic acid ester 19c (5.0mmol) and N, N-diethyl ethylenediamine (5.0ml) is raw material, obtains white solid (0.96g, 53%) .ESI-MS m/z362[M+H] +. 1h NMR (300MHz, CDCl 3) δ 10.00 (s, 1H), 8.75 (s, 1H), 8.44 (d, J=8.7Hz, 1H), 7.46 (d, J=1.5Hz, 1H), 7.42 (dd, J=8.7,1.5Hz, 1H), 5.94-6.07 (m, 1H), 5.40 (d, J=10.2Hz, 1H), 5.20 (d, J=17.1Hz, 1H), 4.81-4.84 (m, 2H), 3.64 (q, J=6.6Hz, 2H), 2.82 (t, J=6.6Hz, 2H), 2.74 (q, J=6.9Hz, 4H), 1.17 (t, J=7.2Hz, 6H). 13c NMR (75MHz, CDCl 3) δ 176.0,164.6,148.3,140.1,139.4,130.3,129.1,126.4,125.8,119.9,116.4,112.9,56.2,52.1,47.5,37.8.12.2.
embodiment 28: the preparation chloro-N-[3-of 1-allyl group-7-(diethylamino) propyl group]-4-Oxoquinoline-3-methane amide (compound 20f)
Taking ethyl 1-allyl group-7-chloro-4-oxo-quinoline-3-carboxylic acid ester 19c (5.0mmol) and 3-(diethylamino) propylamine (5.0ml) as raw material, obtain white solid (1.24g, 66%) .ESI-MS m/z376[M+H] +. 1h NMR (300MHz, CDCl 3) δ 9.91 (s, 1H), 8.76 (s, 1H), 8.45 (d, J=8.7Hz, 1H), 7.46 (d, J=1.8Hz, 1H), 7.40-7.44 (m, 1H), 5.94-6.07 (m, 1H), (5.40 d, J=10.5Hz, 1H), (5.20 d, J=17.1Hz, 1H), 4.81-4.83 (m, 2H), 3.50 (q, J=6.6Hz, 2H), 2.56-2.63 (m, 6H), 1.79-1.89 (m, 2H), 1.08 (t, J=7.2Hz, 6H). 13c NMR (75MHz, CDCl 3) δ 171.4,159.8,143.4,135.4,134.7,125.5,124.4,121.7,121.1,115.3,111.7,108.3,51.5,46.0,42,5,33.3,22.8,7.4.
embodiment 29: the preparation chloro-N-[2-of 1-butyl-7-(diethylamino) ethyl]-4-oxo-quinoline-3-methane amide (compound 20g)
With ethyl 1-butyl-7-chloro-4-oxo-quinoline-3-carboxylic acid ester 19d (5.0mmol) and N, N-diethyl ethylenediamine (5.0ml) is raw material, obtains white solid (1.23g, 65%) .ESI-MS m/z378[M+H] +. 1h NMR (300MHz, CDCl 3) δ 9.96 (s, 1H), 8.72 (s, 1H), 8.46 (d, J=8.7Hz, 1H), 7.49 (d, J=1.5Hz, 1H), 7.43 (dd, J=8.7,1.5Hz, 1H), 4.20 (t, J=7.2Hz, 2H), 3.58 (q, J=6.6Hz, 2H), 2.73 (t, J=6.6Hz, 2H), 2.66 (q, J=6.9Hz, 4H), 1.84-1.94 (m, 2H), 1.40-1.52 (m, 2H), (1.10 t, J=7.2Hz, 6H), 1.01 (t, J=7.2Hz, 3H). 13c NMR (75MHz, CDCl 3) δ 175.9,164.7,148.2,139.9,139.4,129.4,126.7,125.7,115.8,112.7,54.3,52.2,47.6,37.8,31.2,20.3,13.9,12.3.
embodiment 30: the preparation chloro-N-[3-of 1-butyl-7-(diethylamino) propyl group]-4-oxo-quinoline-3-methane amide (compound 20h)
Taking ethyl 1-butyl-7-chloro-4-oxo-quinoline-3-carboxylic acid ester 19d (5.0mmol) and 3-(diethylamino) propylamine (5.0ml) as raw material, obtain white solid (1.22g, 63%) .ESI-MS m/z392[M+H] +. 1h NMR (300MHz, CDCl 3) δ 9.96 (s, 1H), 8.72 (s, 1H), 8.45 (d, J=8.7Hz, 1H), 7.49 (d, J=1.5Hz, 1H), 7.43 (dd, J=8.7,1.5Hz, 1H), (4.21 t, J=7.5Hz, 2H), (3.50 q, J=6.6Hz, 2H), 2.65-2.71 (m, 6H), 1.84-1.94 (m, 4H), 1.40-1.52 (m, 2H), (1.13 t, J=7.2Hz, 6H), 1.02 (t, J=7.2Hz, 3H). 13c NMR (75MHz, CDCl 3) δ 176.0,164.6,148.2,139.9.139.4,129.3,126.6,125.7,115.9,112.7,54.3,50.8,47.2,38.1,31.2,27.6,20.3,14.0,12.1.
embodiment 31: the preparation chloro-N-[2-of 1-benzyl-7-(diethylamino) ethyl]-4-oxo-quinoline-3-methane amide (compound 20i)
Ethyl 1-benzyl-7-chloro-4-oxo-quinoline-3-carboxylic acid ester 19e (5mmol) and N, N-diethyl ethylenediamine (5.0ml) is raw material, obtains white solid (1.4g, 68%) .ESI-MS m/z412[M+H] +. 1h NMR (300MHz, CDCl 3) δ 9.94 (s, 1H), 8.88 (s, 1H), 8.45 (d, J=9.0Hz, 1H), 7.32-7.39 (m, 5H), 7.15-7.17 (m, 2H), 5.40 (s, 2H), 3.57 (q, J=6.6Hz, 2H), 2.72 (t, J=6.6Hz, 2H), 2.63 (q, J=7.2Hz, 4H), 1.09 (t, J=7.2Hz, 6H). 13c NMR (75MHz, CDCl 3) δ 176.1,164.6,148.9,140.2,139.4,134.0,129.6,129.2,128.9,126.7,126.4,125.6,116.7,113.0,57.852.1,47.6,37.8,12.3.
embodiment 32: the preparation chloro-N-[2-of 1-benzyl-7-(diethylamino) propyl group]-4-oxo-quinoline-3-methane amide (compound 20j)
Ethyl 1-benzyl-7-chloro-4-oxo-quinoline-3-carboxylic acid ester 19e (5mmol) and 3-(diethylamino) propylamine (5.0ml) are raw material, obtain white solid (1.2g, 56%) .ESI-MS m/z426[M+H] +. 1h NMR (300MHz, DMSO-d 6): δ 10.04 (s, 1H), 8.85 (1H, s), 8.41 (d, J=9.0Hz, 1H), 7.34-7.40 (m, 5H), 7.14-7.16 (m, 2H), 5.42 (s, 2H), 3.55 (q, J=6.3Hz, 2H), 2.90-3.01 (m, 6H), 1.82-1.87 (m, 2H), 1.29 (t, J=7.2Hz, 6H). 13c NMR (75MHz, CDCl 3) δ 176.2,164.5,149.0,140.2,139.5,133.9,129.6,129.2,129.0,126.6,126.4,125.9,116.7,113.0,57.9,50.7,47.2,38.1,27.5,12.0.
embodiment 33: the preparation chloro-N-[3-of 7-(diethylamino) propyl group]-1-(3-hydrocinnamyl)-4-oxo-quinoline-3-methane amide (compound 20k)
Taking the chloro-1-of ethyl 7-(3-hydrocinnamyl)-4-oxo-quinoline-3-carboxylic acid ester 19f (5.0mmol) and 3-(diethylamino) propylamine (5.0ml) as raw material, obtain white solid (1.4g, 63%) .ESI-MS m/z454[M+H] +. 1h NMR (300MHz, CDCl 3) δ 9.91 (s, 1H), 8.71 (s, 1H), 8.43 (d, J=8.7Hz, 1H), 7.40 (d, J=8.7Hz, 1H), 7.37-7.17 (m, 6H), (4.17 t, J=7.2Hz, 2H), (3.48 q, J=6.6Hz, 2H), (2.78 t, J=7.2Hz, 2H), 2.53-2.60 (m, 6H), 2.19-2.30 (m, 2H), 1.76-1.86 (m, 2H), 1.05 (t, J=7.2Hz, 6H). 13c NMR (75MHz, CDCl 3) δ 175.6,164.2,147.8,139.4,139.1,128.9,128.7,128.1,126.5,126.2,125.4,115.4,112.3,53.1,50.3,46.8,37.6,32.4,30.0,27.0,11.6.
embodiment 34: preparation N-(3-aminopropyl)-7-chloro-1-ethyl-4-oxo-quinoline-3-methane amide (compound 21a)
For raw material, obtain white solid (0.9g, 60%) .ESI-MS m/z308[M+H with ethyl 7-chloro-1-ethyl-4-oxo-quinoline-3-carboxylic acid ester 19b (5.0mmol) and 1,3-propylene diamine (5.0ml)] +. 1h NMR (300MHz, CDCl 3) δ 9.95 (s, 1H), 8.77 (s, 1H), 8.44 (d, J=8.7Hz, 1H), 7.51 (s, 1H), 7.43 (d, J=8.7Hz, 1H), 4.29 (q, J=7.2Hz, 2H), 3.55 (q, J=6.3Hz, 2H), 2.82 (t, J=6.9Hz, 2H), 1.72-1.92 (m, 2H), 1.57 (t, J=7.2Hz, 3H). 13c NMR (75MHz, CDCl 3) δ 176.0,164.9,147.7,139.6,129.2,126.5,125.8,115.8,112.7,49.4,39.7,36.7,33.7,14.9.
embodiment 35: preparation 1-allyl group-N-(3-aminopropyl)-7-chloro-4-oxo-quinoline-3-methane amide (compound 21b)
For raw material, obtain white solid (0.9g, 58%) .ESI-MS m/z320[M+H with ethyl 1-allyl group-7-chloro-4-oxo-quinoline-3-carboxylic acid ester 19c (5.0mmol) and 1,3-propylene diamine (5.0ml)] +. 1h NMR (300MHz, CDCl 3) δ 9.91 (s, 1H), 8.75 (s, 1H), 8.43 (d, J=8.7Hz, 1H), 7.41-7.48 (m, 2H), 5.94-6.07 (m, 1H), 5.39 (d, J=10.5Hz, 1H), 5.19 (d, J=17.1Hz, 1H), 4.82-4.84 (m, 2H), 3.55 (q, J=6.6Hz, 2H), 2.82 (t, J=6.9Hz, 2H), 1.69-1.81 (m, 2H). 13c NMR (75MHz, CDCl 3) δ 176.1,165.0,164.8,148.5,140.3,140.1,139.5,130.3,129.0,126.4,125.9,120.0,116.5,112.7,56.3,39.6,36.8,33.5.
embodiment 36: preparation N-(3-the aminopropyl)-chloro-4-oxo-quinoline-3-of 1-butyl-7-methane amide (compound 21c)
For raw material, obtain white solid (1.2g, 70%) .ESI-MS m/z336[M+H with ethyl 1-butyl-7-chloro-4-oxo-quinoline-3-carboxylic acid ester 19d (5.0mmol) and 1,3-propylene diamine (5.0ml)] +. 1h NMR (300MHz, CDCl 3) δ 9.98 (s, 1H), 8.74 (s, 1H), 8.46 (d, J=8.7Hz, 1H), 7.51 (d, J=1.8Hz, 1H), 7.44 (dd, J=8.7,1.8Hz, 1H), 4.23 (t, J=7.5Hz, 2H), 3.52 (q, J=6.6Hz, 2H), 2.78 (t, J=6.3Hz, 2H), 1.80-1.91 (m, 4H), 1.40-1.52 (m, 2H), 1.03 (t, J=7.2Hz, 3H). 13c NMR (75MHz, CDCl 3) δ 176.1,165.7,148.5,139.7.139.3,128.9,126.2,125.6,115.8,111.6,54.1,38.0,36.1,30.9,27.9,19.9,13.6.
embodiment 37: preparation N-(3-aminopropyl)-7-chloro-1-benzyl-4-oxo-quinoline-3-methane amide (compound 21d)
For raw material, obtain white solid (1.1g, 62%) .ESI-MS m/z370[M+H with ethyl 7-chloro-1-benzyl-4-oxo-quinoline-3-carboxylic acid ester 19e (5.0mmol) and 1,3-propylene diamine (5.0ml)] +. 1h NMR (300MHz, DMSO-d 6): δ 9.95 (s, 1H), 8.89 (s, 1H), 8.43 (d, 1H, J=9.3Hz), 7.34-7.40 (m, 5H), 7.14-7.16 (m, 2H), 5.42 (s, 2H), 3.56 (q, J=6.6Hz, 2H), 2.84 (t, J=6.6Hz2H), 1.84-1.88 (m, 2H). 13c NMR (75MHz, CDCl 3) δ 176.2,164.7,148.9,140.1,139.4,133.7,129.5,129.0,128.9,126.5,126.2,125.8,116.5,112.7,57.6,39.5,36.5,33.4.
embodiment 38: the preparation chloro-1-of N-(3-aminopropyl)-7-(3-hydrocinnamyl)-4-oxo-quinoline-3-methane amide (compound 21e)
For raw material, obtain white solid (0.9g, 45%) .ESI-MS m/z398[M+H with the chloro-1-of ethyl 7-(3-hydrocinnamyl)-4-oxo-quinoline-3-carboxylic acid ester 19f (5.0mmol) and 1,3-propylene diamine (5.0ml)] +. 1h NMR (300MHz, CDCl 3) δ 9.97 (s, 1H), 8.71 (s, 1H), 8.43 (d, J=8.7Hz, 1H), 7.45-7.38 (m, 1H), 7.38-7.14 (m, 6H), 4.18 (t, J=7.2Hz, 2H), 3.57 (q, J=6.9Hz, 2H), 2.85 (t, J=6.6Hz, 2H), 2.79 (t, J=7.2Hz, 2H), 2.34 – 2.20 (m, 2H), 1.76 – 1.88 (m, 2H). 13c NMR (75MHz, CDCl 3) δ 175.6,164.5,147.8,139.4,139.1,128.8,128.7,128.1,126.5,126.2,125.5,115.4,112.2,53.2,39.3,36.4,33.3,32.4,30.0.
Following synthetic route 5 has described to prepare compound 8 in general manner awith compound 8b and compound 9 ato 9 ebuilding-up process.
synthetic route 5:
Figure BDA0000431113500000221
The general synthesis technique of compound 8a-b: chloro-7-4-(1H)-Oxoquinoline 6b or 7-methoxyl group-4-(1H)-Oxoquinoline 6d (10mmol) are added in round-bottomed flask, add subsequently POCl 3(20ml), mixed solution reflux 1h.Cooling reaction solution, adds POCl 3(10ml), continue back flow reaction 1h.React complete, cooling reaction solution is to room temperature.Slowly pour reaction solution in frozen water (very exothermic), sodium hydroxide solution regulates pH to 9.0, separates out white cotton-shaped solid, filter, and washing, dry (easily distillation), obtains pale solid.
embodiment 39: preparation 4,7-dichloroquinoline (compound 8a)
Taking chloro-4 (the 1H)-Oxoquinoline 6b (10mmol) of 7-as raw material, obtain white solid (1.68g, 85%).ESI-MS?m/z197[M] +. 1HNMR(300MHz,CDCl 3):δ8.74(1H,d,J=4.8Hz),8.09-8.15(2H,m),7.54-7.58(1H,m),7.45(1H,d,J=4.8Hz). 13C?NMR(75MHz,CDCl 3)δ151.0,149.4,142.8,136.7,128.8(2C),125.7,125.1,121.6.
embodiment 40: the preparation chloro-7-methoxy quinoline of 4-(compound 8b)
Taking 7-methoxyl group-4 (1H)-Oxoquinoline 6d (10mmol) as raw material, obtain white solid (1.7g, 88%).ESI-MS?m/z194[M+H] +. 1H?NMR(300MHz,CDCl 3):δ8.67(1H,d,J=4.8Hz),8.09(1H,d,J=9.0Hz),7.42(1H,d,J=2.4Hz),7.33(1H,d,J=4.8Hz),7.28(1H,dd,J=9.0Hz,J=2.4Hz),3.97(3H,s). 13C?NMR(75MHz,CDCl 3)δ161.3,151.0,150.2,142.4,125.3,121.7,120.8,119.3,107.7,55.9.
embodiment 41: preparation 7-chloro-4-methoxy quinoline (compound 9a)
Anhydrous methanol (50ml) is added in 100ml round-bottomed flask, add subsequently sodium Metal 99.5 (1.05g, 50mmol), after sodium Metal 99.5 disappears, add 4,7-, bis-chlorine-quinolines (10mmol), reflux 2h.React complete, cooling reaction solution is to room temperature, and decompression steams residue methyl alcohol, obtains white solid, in bottle, adds 50ml water, filter, and washing, dry, obtain pale solid (1.66g, 84%).ESI-MS?m/z194[M+H] +. 1H?NMR(300MHz,CDCl 3):δ8.71(1H,d,J=5.1Hz),8.09(1H,d,J=8.7Hz),7.99(1H,d,J=2.1Hz),7.40(1H,dd，J=8.7Hz,J=2.1Hz),6.70(1H,d,J=5.1Hz),4.03(3H,s). 13C?NMR(75MHz,CDCl 3)δ162.4,152.7,149.7,135.8,128.0,126.7,123.6,120.0,100.6,56.1.
embodiment 42: the preparation chloro-4-ethoxyquinoline of 7-(compound 9b)
Dehydrated alcohol (50ml) is added in 100ml round-bottomed flask, add subsequently sodium Metal 99.5 (1.05g, 50mmol), after sodium Metal 99.5 disappears, add 4,7-, bis-chlorine-quinolines (10mmol), reflux 2h.React complete, cooling reaction solution is to room temperature, and decompression steams residue ethanol, obtains white solid, in bottle, adds 50ml water, filter, and washing, dry, obtain pale solid (1.8g, 87%).ESI-MS?m/z208[M+H] +. 1H?NMR(300MHz,CDCl 3):δ8.68(1H,d,J=5.1Hz),8.11(1H,d,J=9.0Hz),7.98(1H,d,J=2.1Hz),7.39(1H,dd，J=8.7Hz,J=2.1Hz),6.67(1H,d,J=5.1Hz),4.21(2H,q，J=6.9Hz),1.54(3H,t，J=7.2Hz). 13C?NMR(75MHz,CDCl 3)δ161.7,152.6,149.8,135.7,128.0,126.5,123.7,120.0,101.1,64.6,14.8.
embodiment 43: preparation 7-chloro-4-isopropoxy quinoline (compound 9c)
Virahol (50ml) is added in 100ml round-bottomed flask, add subsequently sodium Metal 99.5 (1.05g, 50mmol), after sodium Metal 99.5 disappears, add 4,7-, bis-chlorine-quinolines (10mmol), reflux 8h.TLC follows the tracks of detection, reacts complete, and cooling reaction solution is to room temperature, decompression steams residue Virahol, obtains yellow oil, in residue, adds water (50ml), dichloromethane extraction three times, washing, saturated salt washing, anhydrous sodium sulfate drying, be evaporated to dry, silica gel column chromatography, methylene chloride/methanol=200:1 wash-out, be evaporated to dryly, obtain yellow oil (1.51g, 68%).ESI-MS?m/z222[M+H] +. 1H?NMR(300MHz,CDCl 3):δ8.68(1H,d,J=5.1Hz),8.12(1H,d,J=8.7Hz),7.98(1H,d,J=2.1Hz),7.41(1H,dd，J=8.7Hz,J=2.1Hz),6.69(1H,d,J=5.1Hz),4.78-4.86(1H,m),1.50(3H,s)，1.48(3H,s). 13C?NMR(75MHz,CDCl 3)δ160.8,152.5,150.1,135.7,127.9,126.4,123.9,120.7,101.8,71.3,22.1.
embodiment 44: preparation 4,7-dimethoxy-quinoline (compound 9d)
Methyl alcohol (50ml) is added in 100ml round-bottomed flask, add subsequently sodium Metal 99.5 (1.05g, 50mmol), after sodium Metal 99.5 disappears, add the chloro-7-methoxy quinoline of 4-(10mmol), reflux 8h.TLC follows the tracks of detection, reacts complete, and cooling reaction solution is to room temperature, decompression steams residue methyl alcohol, obtains yellow oil, in residue, adds water (50ml), dichloromethane extraction three times, washing, saturated salt washing, anhydrous sodium sulfate drying, be evaporated to dry, silica gel column chromatography, sherwood oil/acetone=4:1 wash-out, be evaporated to dryly, obtain white solid (1.66g, 88%).ESI-MS?m/z190[M+H] +. 1H?NMR(300MHz,CDCl 3):δ8.63(1H,d,J=5.1Hz),8.04(1H,d,J=9.0Hz),7.34(1H,d,J=2.4Hz),7.12(1H,dd,J=9.0Hz,J=2.4Hz),6.60(1H,d,J=5.1Hz),4.00(3H,s),3.93(3H,s). 13C?NMR(75MHz,CDCl 3)δ162.3,160.9,151.8,151.1,123.1,118.3,116.1,107.3,98.9,55.7,55.6.
embodiment 45: preparation 4-oxyethyl group-7-methoxy quinoline (compound 9e)
Dehydrated alcohol (50ml) is added in 100ml round-bottomed flask, adds subsequently sodium Metal 99.5 (1.05g, 50mmol), after sodium Metal 99.5 disappears, add the chloro-7-methoxy quinoline of 4-(10mmol),, reflux 2h.React complete, cooling reaction solution is to room temperature, and decompression steams residue ethanol, in residue, add 50ml water, ethyl acetate extraction (100ml × 3), merges organic phase, washing, saturated salt washing, anhydrous sodium sulfate drying, filter, be evaporated to dryly, obtain faint yellow oily matter, silica gel column chromatography, sherwood oil/acetone=4:1 wash-out, is evaporated to dry, obtain white solid (1.58g, 78%).ESI-MS?m/z204[M+H] +. 1H?NMR(300MHz,CDCl 3):δ8.60(1H,d,J=5.4Hz),8.06(1H,d,J=9.3Hz),7.33(1H,d,J=2.4Hz),7.11(1H,dd,J=9.3Hz,J=2.4Hz),6.56(1H,d,J=5.4Hz),4.20(2H,q,J=6.9Hz),3.92(3H,s),1.54(3H,t,J=6.9Hz). 13C?NMR(75MHz,CDCl 3)δ161.6,160.9,151.8,151.2,123.3,118.1,116.1,107.2,99.4,64.1,55.6,14.7.
Following synthetic route 6 has described to prepare the building-up process of compound 12a and compound 12b and compound 13,14 in general manner.
synthetic route 6:
Figure BDA0000431113500000241
embodiment 46: the preparation chloro-4-of 5,8-bis-(1H)-Oxoquinoline (compound 13)
The sub-isopropyl ester of propanedioic acid (4.32g, 30mmol) and trimethyl orthoformate (53g, 500mmol) are mixed, reflux 2h, cooling reaction solution, to room temperature, adds 2 subsequently, 5-dichlorphenamide bulk powder (3.24g, 20mmol), reaction mixture reflux 2h.Cooling reaction solution, to room temperature, is separated out white crystal, filters, and methanol wash, obtains white solid.
Above-mentioned white solid is mixed to reflux 1h with phenyl ether (40ml).Cooling reaction solution, to room temperature, adds 50ml sherwood oil, after stirring, filters, and obtains brown solid 3.0g.Silica gel column chromatography, methylene chloride/methanol=25:1 wash-out, obtains compound 13 for white solid (2.5g, 69%).ESI-MS?m/z215[M+H] +. 1H?NMR(300MHz,CDCl 3):δ11.23(1H,s),7.71-7.75(2H,m),7.26(1H,d,J=7.2Hz),6.08(1H,d,J=7.2Hz).
embodiment 47: the preparation chloro-4-of 6,8-bis-(1H)-Oxoquinoline (compound 14)
The sub-isopropyl ester of propanedioic acid (4.32g, 30mmol) and trimethyl orthoformate (53g, 500mmol) are mixed, reflux 2h, cooling reaction solution, to room temperature, adds 3 subsequently, 4-dichlorphenamide bulk powder (3.24g, 20mmol), reaction mixture reflux 2h.Cooling reaction solution, to room temperature, is separated out white crystal, filters, and methanol wash, obtains white solid.
Above-mentioned white solid is mixed to reflux 1h with phenyl ether (40ml).Cooling reaction solution, to room temperature, adds 50ml sherwood oil, after stirring, filters, and obtains brown solid 3.0g.Recrystallizing methanol, obtains compound 14 for white solid (2.6g, 72%).ESI-MS?m/z215[M+H] +. 1H?NMR(300MHz,CDCl 3):δ11.54(1H,s),7.96-7.99(2H,m),7.85(1H,d,J=6.9Hz),6.13(1H,d,J=6.9Hz).
synthetic route 7:
Figure BDA0000431113500000242
embodiment 48: the preparation chloro-7-hydroxyquinoline of 4-(compound 22)
By chloro-4-7-methoxy quinoline 8b (3.86g, 20mmol), 40%HBr (30mL) and acetic anhydride (20mL) mix post-heating and reflux, and TLC follows the tracks of detection, reacts complete, and cooling reaction solution is to room temperature.With adding the dilution of 100mL water in backward reaction solution, 20%NaOH solution regulates pH to 6.0, has a large amount of solids to separate out, filter, and washing, dry, obtain pale solid (3.53g, 98.6%).
embodiment 49: the preparation chloro-7-ethoxyquinoline of 4-(compound 23a)
In the round-bottomed flask of 100ml, add the chloro-7-hydroxyquinoline of 4-(0.72g, 4mmol), DMF (10ml) and 60%NaH (0.4g, 10mmol), stirring at room temperature 15min, adds 1-monobromethane (20mmol) to continue reaction, and TLC follows the tracks of detection.React complete, reaction mixture is poured into water, ethyl acetate extraction, merges organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, be evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=200/1), obtain light yellow solid (0.56g, productive rate 67.2%).Mp70-71℃.MS(ESI):m/z(M+H) +207.8. 1H?NMR(300MHz,CDCl 3)δ8.66(d,J=4.7Hz,1H,ArH),8.09(d,J=9.2Hz,1H,ArH),7.39(d,J=1.8Hz,1H,ArH),7.32(d,J=4.7Hz,1H,ArH),7.29–7.20(m,1H,ArH),4.19(q,J=6.9Hz,2H,CH 2),1.50(t,J=7.0Hz,3H,CH 3). 13C?NMR(75MHz,CDCl 3)δ160.3,150.6,149.8,142.0,124.9,121.2,120.7,118.8,107.8,63.7,14.6.
embodiment 50: preparation 4-chloro-7-n-butoxy quinoline (compound 23b)
In the round-bottomed flask of 100ml, add the chloro-7-hydroxyquinoline of 4-(0.89g, 5mmol), acetone (40ml) and anhydrous K 2cO 3(2.0g) stirring at room temperature refluxes 15 minutes, adds subsequently iodo to levy butane (20mmol), and TLC follows the tracks of detection.React complete, acetone is removed in underpressure distillation, adds 150mL water, ethyl acetate extraction, merge organic phase, add concentrated hydrochloric acid acidifying, dehydrated alcohol band water, obtain yellow oil, acetone recrystallization, separates out white crystal, alkalization after filtering, obtain white solid (0.57g, productive rate 47.6%).Mp37-38℃.MS(ESI):m/z(M+H) +236.1. 1H?NMR(300MHz,CDCl 3)δ8.65(d,J=4.8Hz,1H,ArH),8.08(d,J=9.2Hz,1H,ArH),7.39(d,J=1.9Hz,1H,ArH),7.31(d,J=4.8Hz,1H,ArH),7.29–7.23(m,1H,ArH),4.12(t,J=6.5Hz,2H,CH 2CH 2CH 2CH 3),1.92–1.79(m,2H,CH 2CH 2CH 2CH 3),1.62–1.47(m,2H,CH 2CH 2CH 2CH 3),1.00(t,J=7.3Hz,3H,CH 2CH 2CH 2CH 3). 13C?NMR(75MHz,CDCl 3)δ160.5,150.7,149.8,142.0,124.9,121.2,120.8,118.8,108.0,68.0,31.0,19.2,13.8.
embodiment 50: the preparation positive hexyloxy quinoline of the chloro-7-of 4-(compound 23c)
In the round-bottomed flask of 100ml, add the chloro-7-hydroxyquinoline of 4-(0.36g, 2mmol), DMF (10ml) and 60%NaH (0.2g, 5mmol), stirring at room temperature 10min, adds isobutane bromide (3.5mmol) to continue reaction, and TLC follows the tracks of detection.React complete, reaction mixture is poured into water, ethyl acetate extraction, merges organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, be evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=200/1), obtain yellow oil (0.22g, productive rate 68.0%).Mp?yellow?oil.MS(ESI):m/z(M+H)+263.9. 1H?NMR(300MHz,CDCl 3)δ8.65(d,J=4.8Hz,1H,ArH),8.07(d,J=9.2Hz,1H,ArH),7.38(d,J=2.4Hz,1H,ArH),7.30(d,J=4.8Hz,1H,ArH),7.26(dd,J=9.1,2.5Hz,1H,ArH),4.11(t,J=6.5Hz,2H,OCH 2(CH 2) 4CH 3),1.94–1.79(m,1H,OCH 2CH 2(CH 2) 3CH 3),1.49(dd,J=14.4,7.2Hz,2H,O(CH 2) 2CH 2(CH 2) 2CH 3),1.37(dt,J=7.1,4.7Hz,4H,O(CH 2) 3CH 2CH 2CH 3),0.91(t,J=6.9Hz,3H,CH 3). 13C?NMR(75MHz,CDCl 3)δ160.7,150.8,149.9,142.2,125.0,121.3,121.0,118.9,108.1,68.4,31.6,29.0,25.8,22.7,14.1.
embodiment 50: preparation 4-chloro-7-allyloxy quinoline (compound 23d)
In the round-bottomed flask of 100ml, add the chloro-7-hydroxyquinoline of 4-(0.36g, 2mmol), DMF (10ml) and 60%NaH (0.2g, 5mmol), stirring at room temperature 10min, adds 1-bromine allyl alkane (3.5mmol) to continue reaction, and TLC follows the tracks of detection.React complete, reaction mixture is poured into water, ethyl acetate extraction, merges organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, be evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=200/1), obtain light yellow solid (0.37g, productive rate 78.4%).Mp36-37℃.MS(ESI):m/z(M+H) +219.8. 1H?NMR(300MHz,CDCl 3)δ8.66(d,J=4.6Hz,1H,ArH),8.09(d,J=9.1Hz,1H,ArH),7.41(s,1H,ArH),7.29(dd,J=15.9,6.2Hz,2H,ArH),6.10(ddt,J=15.9,10.4,5.3Hz,1H,CH 2=CH),5.48(d,J=17.2Hz,1H,CH 2=CH),5.34(d,J=10.4Hz,1H,CH 2=CH),4.69(d,J=4.8Hz,2H,OCH 2). 13C?NMR(75MHz,CDCl 3)δ159.9,150.5,149.9,142.1,132.2,125.1,121.4,120.8,119.0,118.1,108.4,68.9.
embodiment 50: preparation 4-chloro-7-isopropoxy quinoline (compound 23e)
In the round-bottomed flask of 100ml, add the chloro-7-hydroxyquinoline of 4-(0.36g, 2mmol), DMF (10ml) and 60%NaH (0.2g, 5mmol), stirring at room temperature 10min, add 1-bromine isopropyl alkane (3.5mmol) to continue reaction, TLC follows the tracks of detection, reaction 24h.React complete, reaction mixture is poured into water, ethyl acetate extraction, merges organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, be evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=200/1), obtain light yellow solid (0.28g, productive rate 54.6%).Mp65-66℃.MS(ESI):m/z(M+H) +221.8. 1H?NMR(300MHz,CDCl 3)δ8.65(d,J=4.7Hz,1H,ArH),8.08(d,J=9.2Hz,1H,ArH),7.39(s,1H,ArH),7.30(d,J=4.7Hz,1H,ArH),7.27–7.20(m,1H,ArH),4.82–4.67(m,1H,CH),1.43(d,J=6.0Hz,6H,CH 3). 13C?NMR(75MHz,CDCl 3)δ159.3,150.5,149.7,142.1,125.0,121.5,121.0,118.7,108.8,70.2,21.7.
embodiment 50: preparation 4-chloro-7-isobutoxy quinoline (compound 23f)
In the round-bottomed flask of 100ml, add the chloro-7-hydroxyquinoline of 4-(0.36g, 2mmol), DMF (10ml) and 60%NaH (0.2g, 5mmol), stirring at room temperature 10min, add isobutane bromide (3.5mmol) to continue reaction, TLC follows the tracks of detection, reaction 8h.React complete, reaction mixture is poured into water, ethyl acetate extraction, merges organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, be evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=200/1), obtain white solid (0.26g, productive rate 88.7%).Mp57-58℃.MS(ESI):m/z(M+H) +235.8. 1H?NMR(300MHz,CDCl 3)δ8.65(d,J=4.8Hz,1H,ArH),8.09(d,J=9.2Hz,1H,ArH),7.38(d,J=2.4Hz,1H,ArH),7.31(d,J=4.8Hz,1H,ArH),7.28(dd,J=9.2,2.4Hz,1H,ArH),3.88(d,J=6.5Hz,2H,CH 2),2.18(dp,J=13.3,6.6Hz,1H,CH),1.07(d,J=6.7Hz,6H,CH 3). 13CNMR(75MHz,CDCl 3)δ160.7,150.8,149.9,142.2,125.0,121.3,121.0,118.9,108.1,74.7,28.1,19.3.
embodiment 50: preparation 4-chloro-7-benzyloxy quinoline (compound 23g)
In the round-bottomed flask of 100ml, add the chloro-7-hydroxyquinoline of 4-(0.89g, 5mmol), acetone (40ml), cylite (7.5mmol) and anhydrous K 2cO 3(2.0g), stirring at room temperature reaction, TLC follows the tracks of detection.React complete, acetone is gone out in underpressure distillation, adds 150mL water, is extracted with ethyl acetate, and merges organic phase, add concentrated hydrochloric acid acidifying, dehydrated alcohol band water, obtains dark oily matter, acetone recrystallization, crystallize out, alkalization after filtering, obtains white solid (0.63g, productive rate 46.8%).Mp87-88℃.MS(ESI):m/z(M+H) +269.8. 1HNMR(300MHz,CDCl 3)δ8.67(d,J=4.7Hz,1H,ArH),8.12(d,J=9.2Hz,1H,ArH),7.52–7.30(m,8H,ArH),5.21(s,2H,CH 2). 13C?NMR(75MHz,CDCl 3)δ160.2,150.7,150.0,142.2,135.9,128.5,128.1,127.5,125.2,121.6,120.9,119.2,108.7,70.3.
embodiment 50: preparation 4-chloro-7-(4-fluorine benzyloxy) quinoline (compound 23h)
In the round-bottomed flask of 100ml, add the chloro-7-hydroxyquinoline of 4-(0.36g, 2mmol), DMF (15ml) and 60%NaH (0.2g, 5mmol), stirring at room temperature 10min, then add 4-fluorobenzyl chloride (3.5mmol) to continue reaction, TLC follows the tracks of detection.React complete, reaction mixture is poured into water, ethyl acetate extraction, merges organic phase, add concentrated hydrochloric acid acidifying, dehydrated alcohol band water, obtains yellow oil, re-crystallizing in ethyl acetate, separate out pale yellow crystals, alkalization after filtering, obtains yellow solid (0.57g, productive rate 89.2%).Mp98-99℃.MS(ESI):m/z(M+H) +287.9. 1H?NMR(300MHz,CDCl 3)δ8.67(d,J=4.8Hz,1H,ArH),8.12(d,J=9.2Hz,1H,ArH),7.49–7.42(m,3H,ArH),7.36–7.30(m,2H,ArH),7.08(t,J=8.7Hz,2H,ArH),5.17(s,2H,CH 2). 13C?NMR(75MHz,CDCl 3)δ162.4(d,J=246.4Hz),159.9,150.6,150.0,142.2,131.7(d,J=2.2Hz),129.4(d,J=8.1Hz),125.2,121.6,120.8,119.2,115.44(d,J=21.5Hz),108.6,69.5.
embodiment 50: preparation 4-chloro-7-(3-benzene oxyethyl group) quinoline (compound 23i)
In the round-bottomed flask of 100ml, add the chloro-7-hydroxyquinoline of 4-(0.36g, 2mmol), DMF (10ml) and 60%NaH (0.2g, 5mmol), stirring at room temperature 10min, add 1-bromine 2-diphenylphosphino ethane (3.5mmol) to continue reaction, TLC follows the tracks of detection.React complete, reaction mixture is poured into water, ethyl acetate extraction, merges organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, be evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=200/1), obtain light yellow solid (0.14g, productive rate 23.3%).Mp84-85℃.MS(ESI):m/z(M+H) +283.8. 1H?NMR(300MHz,CDCl 3)δ8.64(d,J=4.0Hz,1H,ArH),8.07(d,J=9.1Hz,1H,ArH),7.40(s,1H,ArH),7.36–7.19(m,7H,ArH),4.34(t,J=6.7Hz,2H,OCH 2CH 2),3.18(t,J=6.7Hz,2H,OCH 2CH 2). 13C?NMR(75MHz,CDCl 3)δ160.1150.6,149.8,142.0,137.7,128.7,128.3,126.4,124.9,121.3,120.7,118.9,108.1,68.7,35.4.
embodiment 50: preparation 4-chloro-7-(3-benzene propoxy-) quinoline (compound 23j)
In the round-bottomed flask of 100ml, add the chloro-7-hydroxyquinoline of 4-(0.45g, 2.5mmol) and DMF (15ml), stirring at room temperature 10min, then add 60%NaH (0.2g, 5mmol), stirring at room temperature 10min, adds 1-bromine 3-phenyl-propane (5mmol) to continue reaction, and TLC follows the tracks of detection.React complete, reaction mixture is poured into water, and ethyl acetate extraction, merges organic phase, be evaporated to dry, obtain yellow oil, add concentrated hydrochloric acid acidifying, occur white solid, with 20mL acetone/sherwood oil=3:1 recrystallization, obtain using again alkalization after solid, obtain white crystal (0.03g, productive rate 53.6%).Mp51-52℃.MS(ESI):m/z(M+H) +297.9. 1H?NMR(300MHz,CDCl 3)δ8.64(d,J=4.3Hz,1H,ArH),8.08(d,J=9.1Hz,1H,ArH),7.36(s,1H,ArH),7.33–7.15(m,7H,ArH),4.10(t,J=6.0Hz,2H,OCH 2CH 2CH 2),2.84(t,J=7.4Hz,2H,OCH 2CH 2CH 2),2.26–2.10(m,2H,OCH 2CH 2CH 2). 13C?NMR(75MHz,CDCl 3)δ160.4150.6,149.8,142.0,140.9,128.2(C=2),125.8,124.9,121.3,120.7,118.9,108.0,67.2,32.1,30.5.
synthetic route 8:
Figure BDA0000431113500000271
embodiment 51: preparation N 1 -(7-ethoxyquinoline-4-yl)-N 2 , N 2 -diethyl ethane-1,2-diamines (compound 24a)
In 100mL flask, add compound 23a (0.35g, 1.7mmol) and N, N-diethyl ethylenediamine (4mL), heating reflux reaction 3.5h, TLC follows the tracks of detection.React complete, add about 100mL water, ethyl acetate extraction, merges organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=100/1), obtains light yellow solid (0.36g, productive rate 73.7%).Mp84-85℃.MS(ESI):m/z(M+H) +287.9. 1H?NMR(300MHz,CDCl 3)δ8.44(d,J=5.2Hz,1H,ArH),7.61(d,J=9.1Hz,1H,ArH),7.28(s,1H,ArH)),7.04(d,J=9.0Hz,1H,ArH),6.25(d,J=5.3Hz,1H,ArH),5.98(s,1H,NH),4.13(q,J=6.9Hz,2H,OCH 2CH 3),3.20(dd,J=10.1,5.1Hz,2H,NHCH 2CH 2),2.75(t,J=5.8Hz,2H,NHCH 2CH 2),2.56(q,J=7.0Hz,4H,N(CH 2CH 3) 2),1.46(t,J=6.9Hz,1H,OCH 2CH 3),1.04(t,J=7.1Hz,6H,N(CH 2CH 3) 2). 13C?NMR(75MHz,CDCl 3)δ159.2,151.1,150.0,149.7,120.6,116.9,113.2,108.5,97.8,63.3,50.6,46.4,39.7,14.7,12.0.
embodiment 52: preparation N 1 , N 1 -diethyl-N 2 -(7-hexyloxy quinolyl-4) ethane-1,2-diamines (compound 24b)
In 100mL flask, add 23c (0.53g, 2mmol) and N, N-diethyl ethylenediamine (4mL), heating reflux reaction 3.5h, TLC follows the tracks of detection.React complete, add about 100mL water, ethyl acetate extraction, merges organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=100/1), obtains yellow solid (0.59g, productive rate 85.4%).Mp92-93℃.MS(ESI):m/z(M+H) +344.0. 1H?NMR(300MHz,CDCl 3)δ8.43(d,J=5.3Hz,1H,ArH),7.61(d,J=9.1Hz,1H,ArH),7.28(d,J=2.0Hz,1H,ArH),7.04(dd,J=9.0,2.2Hz,1H,ArH),6.26(d,J=5.3Hz,1H,ArH),5.98(s,1H,NH),4.06(t,J=6.5Hz,2H,OCH 2(CH 2) 4CH 3),3.22(dd,J=10.3,5.4Hz,2H,NHCH 2CH 2),2.77(t,J=5.8Hz,2H,NHCH 2CH 2),2.57(q,J=7.0Hz,4H,N(CH 2CH 3) 2),1.89-1.76(m,2H,OCH 2CH 2(CH 2) 3CH 3),1.54-1.42(m,2H,O(CH 2) 2CH 2(CH 2) 2CH 3),1.34(d,J=3.5Hz,4H,O(CH 2) 3(CH 2) 2CH 3,1.05(t,J=7.1Hz,6H,N(CH 2CH 3) 2),0.90(t,J=6.5Hz,3H,O(CH 2) 5CH 3). 13C?NMR(75MHz,CDCl 3)δ159.5,151.1,145.0,149.8,120.6,117.1,113.2,108.6,97.8,68.0,50.7,46.5,39.8,31.6,29.1,25.8,22.6,14.1,12.1.
embodiment 53: preparation N 1 -(7-allyloxy quinolyl-4)-N 2 , N 2 -diethyl ethane-1,2-diamines (compound 24c)
In 100mL flask, add 23d (0.33g, 1.5mmol) and N, N-diethyl ethylenediamine (4mL), heating reflux reaction 4h, TLC follows the tracks of detection.React complete, add about 100mL water, ethyl acetate extraction, merges organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=100/1), obtains white solid (0.36g, productive rate 79.8%).Mp?yellow?oil.MS(ESI):m/z(M+H) +300.1. 1H?NMR(300MHz,CDCl 3)δ8.43(d,J=5.3Hz,1H,ArH),7.62(d,J=9.1Hz,1H,ArH),7.30(d,J=2.1Hz,1H,ArH),7.08(dd,J=9.2,1.9Hz,1H,ArH),6.28(d,J=5.3Hz,1H,ArH),6.09(ddd,J=15.8,10.5,5.2Hz,1H,CH 2=CH),5.97(s,1H,NH),5.46(d,J=17.2Hz,1H,CH 2=CH),5.31(d,J=10.5Hz,1H,CH 2=CH),4.65(d,J=5.0Hz,2H,OCH 2CH=CH 2),3.25(dd,J=10.6,5.4Hz,2H,NHCH 2CH 2),2.80(t,J=5.8Hz,2H,NHCH 2CH 2),2.59(q,J=7.1Hz,4H,(CH 2CH 3) 2),1.07(t,J=7.1Hz,6H,(CH 2CH 3) 2). 13C?NMR(75MHz,CDCl 3)δ158.4,150.4,149.5,149.3,132.2,120.8,117.1,116.3,113.1,108.2,97.2,68.1,50.3,46.0,39.5,11.4.
embodiment 54: preparation N 1 , N 1 -diethyl-N 2 -(7-isopropoxy quinolyl-4) ethane-1,2-diamines (compound 24d)
In 100mL flask, add 23e (0.20g, 0.9mmol) and N, N-diethyl ethylenediamine (4mL), heating reflux reaction 5h, TLC follows the tracks of detection.React complete, add about 100mL water, ethyl acetate extraction, merges organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=100/1), obtains yellow oil (0.12g, productive rate 10.9%).Mp?yellow?oil.MS(ESI):m/z(M+H) +302.1. 1H?NMR(300MHz,CDCl 3)δ8.42(d,J=5.3Hz,1H,ArH),7.61(d,J=9.1Hz,1H,ArH),7.29(d,J=2.0Hz,1H,ArH),7.01(dd,J=9.1,2.1Hz,1H,ArH),6.26(d,J=5.3Hz,1H,ArH),5.99(s,1H,NH),4.80–4.62(m,1H,OCH(CH 3) 2),3.24(dd,J=10.5,5.3Hz,2H,NHCH 2CH 2),2.79(t,J=5.9Hz,2H,NHCH 2CH 2),2.58(q,J=7.1Hz,4H,N(CH 2CH 3) 2),1.40(d,J=6.0Hz,6H,OCH(CH 3) 2),1.06(t,J=7.1Hz,6H,N(CH 2CH 3) 2). 13C?NMR(75MHz,CDCl 3)δ158.2,150.7,149.8,149.7,120.8,117.7,113.1,109.5,97.6,69.7,50.7,46.4439.8,21.8,12.0.
embodiment 55: preparation N 1 -(7-benzyloxy quinolyl-4)-N 2 , N 2 -diethyl ethane-1,2-diamines (compound 24e)
In 100mL flask, add 23g (0.12g, 0.4mmol) and N, N-diethyl ethylenediamine (2mL), heating reflux reaction 2.5h, TLC follows the tracks of detection.React complete, add dehydrated alcohol, amine is removed in high-temperature pressure-reduction distillation, and silica gel column chromatography (moving phase: methylene chloride/methanol=100/1), obtains light yellow solid (0.09g, productive rate 57.7%).Mp93-94℃.MS(ESI):m/z(M+H) +349.9. 1H?NMR(300MHz,CDCl 3)δ8.44(d,J=4.7Hz,1H,ArH),7.63(d,J=9.0Hz,1H,ArH),7.47(d,J=7.3Hz,2H,ArH),7.34(dd,J=13.5,7.7Hz,4H,ArH),7.13(d,J=9.0Hz,1H,ArH),6.28(d,J=5.1Hz,1H,ArH),5.99(s,1H,NH),5.17(s,2H,OCH 2),3.25(d,J=4.7Hz,2H,NHCH 2CH 2),2.80(t,J=5.4Hz,2H,NHCH 2CH 2),2.59( q,J=6.8Hz,4H,N(CH 2CH 3) 2),1.07(t,J=6.9Hz,6H,N(CH 2CH 3) 2). 13C?NMR(75MHz,CDCl 3)δ159.1,151.1,149.9,136.5,128.4,127.9,127.5,120.9,117.1,113.6,109.6,109.2,105.24,98.0,70.0,50.8,46.5,39.8,12.1.
embodiment 56: preparation N 1 , N 1 -diethyl-N 2 -(7-(4-fluorine benzyloxy) quinolyl-4) ethane-1,2-diamines (compound 24f)
In 100mL flask, add 23h (0.14g, 0.5mmol) and N, N-diethyl ethylenediamine (4mL), heating reflux reaction 3h, TLC follows the tracks of detection.React complete, add about 100mL water, ethyl acetate extraction, merges organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=100/1), obtains white solid (0.10g, productive rate 55.9%).Mp67-68℃.MS(ESI):m/z(M+H)+367.7. 1H?NMR(300MHz,CDCl 3)δ8.44(d,J=5.3Hz,1H,ArH),7.63(d,J=9.1Hz,1H,ArH),7.42(dd,J=8.3,5.5Hz,2H,ArH),7.36(d,J=2.4Hz,1H,ArH),7.10(dd,J=9.1,2.5Hz,1H,ArH),7.04(t,J=8.6Hz,2H,ArH),6.27(d,J=5.3Hz,1H,ArH),5.99(d,J=2.5Hz,1H,NH),5.11(s,2H,OCH 2),3.23(dd,J=10.4,5.4Hz,2H,NHCH 2CH 2),2.78(t,J=5.9Hz,2H,NHCH 2CH 2),2.58(q,J=7.1Hz,4H,NCH 2CH 3),1.06(t,J=7.1Hz,6H,NCH 2CH 3). 13C?NMR(75MHz,CDCl 3)δ162.32(d,J=246.0Hz),159.0,151.0,149.9,149.8,132.3,129.32(d,J=7.9Hz),121.0,117.0,115.33(d,J=21.5Hz),113.6,109.1,98.0,69.3,50.8,46.6,39.9,12.1.
synthetic route 9:
Figure BDA0000431113500000291
embodiment 57: preparation N 1 -(7-ethoxyquinoline-4-yl)-N 2 , N 2 -diethyl propane-1,2-diamines (compound 25a)
In 100mL flask, add 23a (0.31g, 1.5mmol) and 3-diethyl amino propylamine (4mL), heating reflux reaction 4.5h, TLC follows the tracks of detection.React complete, add about 100mL water, ethyl acetate extraction, merges organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=100/1), obtains yellow oil (0.34g, productive rate 75.2%).Mp?yellow?oil.MS(ESI):m/z(M+H) +302.1. 1H?NMR(400MHz,CDCl 3)δ8.41(d,J=5.3Hz,1H,ArH),7.83(s,1H,NH),7.64(d,J=9.1Hz,1H,ArH),7.30(s,1H,ArH),7.02(d,J=9.1Hz,1H,ArH),6.23(d,J=5.3Hz,1H,ArH),4.16(q,J=6.9Hz,2H,CH 2CH 3),3.38(d,J=4.5Hz,2H,NCH 2),2.65(dt,J=14.1,6.1Hz,6H,CH 2N(CH 2CH 3) 2),1.97–1.83(m,2H,NHCH 2CH 2CH 2),1.47(t,J=6.8Hz,3H,CH 2CH 3),1.09(t,J=7.0Hz,6H,N(CH 2CH 3) 2). 13C?NMR(100MHz,CDCl 3)δ159.0,150.5,150.3,149.5,121.4,116.0,113.1,107.8,96.5,62.9,52.5,46.4,43.5.
embodiment 58: preparation N 1 -(7-allyloxy quinolyl-4)-N 2 , N 2 -diethyl propane-1,2-diamines (compound 25b)
In 100mL flask, add 23d (0.33g, 2mmol) and 3-diethyl amino propylamine (4mL), heating reflux reaction 2.5h, TLC follows the tracks of detection.React complete, add about 100mL water, ethyl acetate extraction, merges organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=100/1), obtains yellow oil (0.15g, productive rate 31.9%).Mp?yellow?oil.MS(ESI):m/z(M+H) +313.9. 1H?NMR(300MHz,CDCl 3)δ8.40(d,J=5.3Hz,1H,ArH),7.83(s,1H,NH),7.64(d,J=9.1Hz,1H,ArH),7.03(dd,J=9.1,1.6Hz,1H,ArH),6.20(d,J=5.4Hz,1H,ArH),6.08(ddd,J=21.5,10.4,5.2Hz,1H,CH=CH 2),5.45(d,J=17.2Hz,1H,CH=CH 2),5.29(d,J=10.5Hz,1H,CH=CH 2),4.63(d,J=5.2Hz,2H,OCH 2),3.34(d,J=3.9Hz,2H,NCH 2(CH 2) 2),2.61(dd,J=13.9,6.7Hz,6H,CH 2N(CH 2CH 3) 2),1.94–1.81(m,2H,NCH 2CH 2CH 2),1.07(t,J=7.1Hz,6H,N(CH 2CH 3) 2). 13C?NMR(75MHz,CDCl 3)δ158.8,151.0,150.5,149.8,132.8,121.7,117.7,116.5,113.6,108.7,97.0,68.7,53.4,47.0,44.4,24.5,11.6.
embodiment 59: preparation N 1 , N 1 -diethyl-N 2 -(7-(4-fluorine benzyloxy) quinolyl-4) propane-1,2-diamines (compound 25c)
In 100mL flask, add 23h (0.29g, 1mmol) and 3-diethyl amino propylamine (4mL), heating reflux reaction 1.5h, TLC follows the tracks of detection.React complete, add about 100mL water, ethyl acetate extraction, merges organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=100/1), obtains yellow oil (0.26g, productive rate 67.5%).Mp?yellow?oil.MS(ESI):m/z(M+H) +382.4. 1H?NMR(300MHz,CDCl 3)δ8.41(d,J=5.2Hz,1H,ArH),7.83(s,1H,NH),7.66(d,J=9.1Hz,1H,ArH),7.45-7.36(m,2H,ArH),7.34(s,1H,ArH),7.13-6.95(m,3H,ArH),6.20(d,J=5.1Hz,1H,ArH),5.08(s,2H,OCH 2),3.32(s,2H,NHCH 2(CH 2) 2),2.67-2.53(m,6H,CH 2N(CH 2CH 3) 2),1.84(s,2H,NHCH 2CH 2CH 2),1.06(t,J=6.8Hz,6H,N(CH 2CH 3) 2). 13C?NMR(75MHz,CDCl 3)δ162.0(d,J=245.7Hz),158.6,151.0,150.3,149.7,132.11(d,J=2.0Hz),129.0(d,J=8.0Hz),121.7,116.1,115.0(d,J=21.4Hz),113.6,108.8,96.8,68.9,53.0,46.7,44.1,24.3,11.4.
experimental example 1: anti tumor activity in vitro test
Oxoquinoline derivatives of the present invention is as the pharmacological research of preparation treatment cancer drug purposes.The compound of all tests is all prepared into hydrochloride form before test, using conventional clinically antitumor drug-cis-platinum as positive control medicine.
Select respectively Human Laryngeal Cancer Cell (Hep-2), breast cancer cell line (MCF-7), gastric carcinoma cell lines (BGC-823), hepatoma cell line (HepG2), colon carcinoma cell line (HCT-8), cervical cancer tumer line (Hela), the clones such as prostate cancer cell line (PC-3), adopt mtt assay to test.Concrete grammar is as follows: respectively by good growth conditions, cell strain in logarithmic phase with 5 × 10 4the concentration of individual/ml is inoculated in 96 orifice plates, 160 μ l are inoculated in every hole, subsequently 96 orifice plates are placed in to 37 DEG C, cultivate 24 hours containing the incubator of 5%CO2, abandon old liquid, change fresh medium, add the oxoquinoline derivatives of sterilising treatment, continue to cultivate after 48 hours, discard nutrient solution, every hole adds the RPMI-1640 nutrient solution of 20ul containing 5mg/ml MTT, continue to cultivate 4 hours, carefully remove after supernatant, every hole adds the DMSO of 200 μ l, and about 10min dissolution precipitation vibrates, detect OD value, wavelength 490nm by microplate reader subsequently.Obtain the cell survival rate under each sample concentration with following formula: average OD value × 100% of the average OD value/control group of survival rate %=sample sets.To the mapping of drug level logarithm, obtain the IC of each sample with cell survival rate by graphing method 50value, the results are shown in following table.
Oxoquinoline derivatives extracorporeal anti-tumor result (IC of the present invention 50, μ M a)
Figure BDA0000431113500000311
Figure BDA0000431113500000321
aiC 50value representation suppresses 50% the needed drug level of growth of tumour cell.
btumor cell line comprises people's Human Laryngeal Cancer Cell (Hep-2), breast cancer cell line (MCF-7), gastric carcinoma cell lines (BGC-823), hepatoma cell line (HepG2), colon carcinoma cell line (HCT-8), cervical cancer tumer line (Hela), prostate cancer cell line (PC-3).
cin table, each numerical value represents the mean value of three parallel test results.

Claims (13)

1. formula I compound:
And pharmacologically acceptable salts, solvate, prodrug, wherein
R 1be selected from hydrogen ,-C 1-6alkyl ,-C 2-6thiazolinyl ,-C 2-6alkynyl ,-C 1-6alkyl-phenyl, wherein said alkyl, thiazolinyl, alkynyl and phenyl can be optionally by halogen, nitro, cyano group, hydroxyl ,-C 1-6alkoxyl group, phenyl replace;
R 3be selected from hydrogen ,-CONHR 31,-COOR 32, wherein said R 31and R 32independently be selected from separately-C 1-6alkyl and-C 1-6alkylamino, wherein said amino is optionally by 1～2-C 1-6alkyl replaces;
R 7be selected from halogen ,-C1-6 alkoxyl group,
2. the compound of claim 1, wherein R 1be selected from hydrogen ,-C 1-6alkyl ,-C 2-6thiazolinyl ,-C 1-6alkyl-phenyl; For example, R wherein 1be selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, allyl group, propenyl, phenmethyl, hydrocinnamyl, normal-butyl.
3. the compound of claim 1, wherein R 3be selected from hydrogen ,-COO-C 1-4alkyl ,-CONH-C 1-4alkyl ,-CONH-C 1-4alkyl-NH-C 1-4alkyl ,-CONH-C 1-4alkyl-N (C 1-4alkyl) 2; For example, wherein R3 is selected from hydrogen ,-COOCH 2cH 3,
-CONH-(CH 2) 2-N(C 2H 5) 2、-CONH-(CH 2) 3-N(C 2H 5) 2、-CONH-(CH 2) 3-NH 2。
4. the compound of claim 1, wherein R 7be selected from halogen ,-C1-4 alkoxyl group,
Figure FDA0000431113490000013
Figure FDA0000431113490000014
for example, R wherein 7be selected from fluorine, chlorine, bromine, methoxyl group,
Figure FDA0000431113490000015
5. with compound shown in Formula Il
Figure FDA0000431113490000016
And pharmacologically acceptable salts, solvate, prodrug, wherein
R 4be selected from halogen (for example chlorine, fluorine, bromine, iodine) ,-C 1-6alkyl (for example methyl, ethyl, propyl group, sec.-propyl, normal-butyl) ,-C 1-6alkoxyl group (for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy) ,-NH-C 1-6alkyl-N (C 1-4alkyl) 2;
R 7be selected from halogen (for example chlorine, fluorine, bromine, iodine) ,-C 1-6alkyl (for example methyl, ethyl, propyl group, sec.-propyl, normal-butyl) ,-C 1-6alkoxyl group (for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy) ,-C 1-6thiazolinyl oxygen base (for example vinyloxy group, propenyloxy group, butenyloxy) ,-C 1-6alkyl-phenyl ,-C 1-6alkyl-halo (for example chlorine, fluorine, bromine, iodo) phenyl.
6. compound shown in following formula III
Figure FDA0000431113490000021
And pharmacologically acceptable salts, solvate, prodrug, wherein
Y is 1 to 4 group that is selected from halogen, and for example Y is 1-2 group that is selected from fluorine, chlorine, bromine, iodine, and for example Y is 2 chlorine.
7. according to the compound of claim 1-6 any one, it is to be selected from following compound:
The fluoro-1-methyl-4-of 7-oxo-quinoline,
The chloro-1-methyl-4-of 7-oxo-quinoline,
The bromo-1-methyl-4-of 7-oxo-quinoline,
7-methoxyl group-1-methyl-4-oxo-quinoline,
The chloro-1-sec.-propyl-4-of 7-oxo-quinoline,
The chloro-4-oxo-quinoline in 1-allyl group-7,
The chloro-4-oxo-quinoline of 1-benzyl-7-,
The chloro-1-of 7-(3-hydrocinnamyl)-4-oxo-quinoline,
The bromo-4-oxo-quinoline of 1-benzyl-7-,
7-morpholinyl-4 (1H) Oxoquinoline,
1-methyl-7-(4-methylpiperazine-1-yl)-4-Oxoquinoline,
1-benzyl-7-morpholinyl-4-oxo-quinoline,
N-(3-(diethylamino) propyl group) fluoro-4 (1H)-Oxoquinoline-3-of-7-methane amide,
The chloro-N-of 7-(3-(diethylamino) propyl group)-4 (1H)-Oxoquinoline-3-methane amide,
The bromo-N-of 7-(3-(diethylamino) propyl group)-4 (1H)-Oxoquinoline-3-methane amide,
N-(3-diethylamino) propyl group-7-methoxyl group-4-(1H)-Oxoquinoline-3-methane amide,
The chloro-1-methyl-4-of ethyl 7-oxo-quinoline-3-carboxylic acid ester,
The chloro-1-ethyl-4-of ethyl 7-oxo-quinoline-3-carboxylic acid ester,
The chloro-4-oxo-quinoline-3-carboxylic acid of ethyl 1-allyl group-7-ester,
The chloro-4-oxo-quinoline-3-carboxylic acid of ethyl 1-butyl-7-ester,
The chloro-4-oxo-quinoline-3-carboxylic acid of ethyl 1-benzyl-7-ester,
The chloro-1-of ethyl 7-(3-hydrocinnamyl)-4-oxo-quinoline-3-carboxylic acid ester,
The chloro-N-[2-of 7-(diethylamino) ethyl]-1-methyl-4-oxo-quinoline-3-methane amide,
The chloro-N-[3-of 7-(diethylamino) propyl group]-1-methyl-4-oxo-quinoline-3-methane amide,
The chloro-N-[2-of 7-(diethylamino) ethyl]-1-ethyl-4-oxo-quinoline-3-methane amide,
The chloro-N-[2-of 7-(diethylamino) propyl group]-1-ethyl-4-oxo-quinoline-3-methane amide,
The chloro-N-[2-of 1-allyl group-7-(diethylamino) ethyl]-4-oxo-quinoline-3-methane amide,
The chloro-N-[3-of 1-allyl group-7-(diethylamino) propyl group]-4-Oxoquinoline-3-methane amide,
The chloro-N-[2-of 1-butyl-7-(diethylamino) ethyl]-4-oxo-quinoline-3-methane amide,
The chloro-N-[3-of 1-butyl-7-(diethylamino) propyl group]-4-oxo-quinoline-3-methane amide,
The chloro-N-[2-of 1-benzyl-7-(diethylamino) ethyl]-4-oxo-quinoline-3-methane amide,
The chloro-N-[2-of 1-benzyl-7-(diethylamino) propyl group]-4-oxo-quinoline-3-methane amide,
The chloro-N-[3-of 7-(diethylamino) propyl group]-1-(3-hydrocinnamyl)-4-oxo-quinoline-3-methane amide,
The chloro-1-ethyl-4-of N-(3-aminopropyl)-7-oxo-quinoline-3-methane amide,
The chloro-4-oxo-quinoline-3-of 1-allyl group-N-(3-aminopropyl)-7-methane amide,
N-(3-aminopropyl)-chloro-4-oxo-quinoline-3-of 1-butyl-7-methane amide,
The chloro-1-benzyl-4-of N-(3-aminopropyl)-7-oxo-quinoline-3-methane amide,
The chloro-1-of N-(3-aminopropyl)-7-(3-hydrocinnamyl)-4-oxo-quinoline-3-methane amide,
4,7-dichloroquinoline,
The chloro-7-methoxy quinoline of 4-,
7-chloro-4-methoxy quinoline,
The chloro-4-ethoxyquinoline of 7-,
The chloro-4-isopropoxy of 7-quinoline,
4,7-dimethoxy-quinoline,
4-oxyethyl group-7-methoxy quinoline,
The chloro-4-of 5,8-bis-(1H)-Oxoquinoline,
The chloro-4-of 6,8-bis-(1H)-Oxoquinoline,
The chloro-7-hydroxyquinoline of 4-
The chloro-7-ethoxyquinoline of 4-
The chloro-7-n-butoxy of 4-quinoline
The positive hexyloxy quinoline of the chloro-7-of 4-
The chloro-7-allyloxy of 4-quinoline
The chloro-7-isopropoxy of 4-quinoline
The chloro-7-isobutoxy of 4-quinoline
The chloro-7-benzyloxy of 4-quinoline
The chloro-7-of 4-(4-fluorine benzyloxy) quinoline
The chloro-7-of 4-(3-benzene oxyethyl group) quinoline
The chloro-7-of 4-(3-benzene propoxy-) quinoline
N 1-(7-ethoxyquinoline-4-yl)-N 2, N 2-diethyl ethane-1,2-diamines
N 1, N 1-diethyl-N 2-(7-hexyloxy quinolyl-4) ethane-1,2-diamines
N 1-(7-allyloxy quinolyl-4)-N 2, N 2-diethyl ethane-1,2-diamines
N 1, N 1-diethyl-N 2-(7-isopropoxy quinolyl-4) ethane-1,2-diamines
N 1-(7-benzyloxy quinolyl-4)-N 2, N 2-diethyl ethane-1,2-diamines
N 1, N 1-diethyl-N 2-(7-(4-fluorine benzyloxy) quinolyl-4) ethane-1,2-diamines
N 1-(7-ethoxyquinoline-4-yl)-N 2, N 2-diethyl propane-1,2-diamines
N 1-(7-allyloxy quinolyl-4)-N 2, N 2-diethyl propane-1,2-diamines
N 1, N 1-diethyl-N 2-(7-(4-fluorine benzyloxy) quinolyl-4) propane-1,2-diamines
And their pharmacologically acceptable salts, solvate, prodrug.
8. the pharmaceutical applications of formula I, formula II or formula III compound or its pharmacologically acceptable salts, solvate, prodrug described in claim 1-7 any one, preparation can be used for prevention or treatment tumour medicine in purposes.
9. purposes according to Claim 8, it is characterized in that, described tumour is including but not limited to malignant tumour and leukemia such as melanoma, cancer of the stomach, lung cancer, mammary cancer, kidney, liver cancer, oral cavity epidermal carcinoma, cervical cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, colorectal carcinoma, bladder cancer, tumor of head and neck, nasopharyngeal carcinoma, skin carcinomas; Described cancer of the stomach comprises adenocarcinoma of stomach; Described lung cancer comprises adenocarcinoma of lung; Described colorectal carcinoma comprises adenocarcinoma of colon; Described ovarian cancer comprises adenocarcinoma ovaries; Described kidney comprises kidney clear cell adenocarcinoma; Leukemia comprises urgency; Property Lymphocytic leukemia, chronic leukemia, specific type leukemia.
10. a pharmaceutical composition, wherein contains described at least one claim 1-7 any one formula I, formula II or formula III compound or its pharmacologically acceptable salts, solvate, prodrug, and optional pharmaceutical carrier or vehicle.
11. prepare the method for formula I compound described in claim 1-7 any one or its pharmacologically acceptable salts, solvate, prodrug, and it comprises the following steps:
A) make formula
Figure FDA0000431113490000041
compound reacts (for example, under heating condition, for example, at 80～120 DEG C) with ethoxy methylene diethyl malonate, obtain following formula: compound:
B) by step a) gained compound for example join, in suitable solvent (phenyl ether), under heating condition, (for example, under this solvent boiling or reflux conditions) reacts mixture, after reaction finishes, add sherwood oil, separate and obtain following formula: compound:
Figure FDA0000431113490000043
C) for example, to step b) is added to alkali aqueous solution (aqueous sodium hydroxide solution in gained compound, for example 5～20% aqueous sodium hydroxide solutions), heating (for example refluxing) reaction, reaction finishes rear for example, with acid (hydrochloric acid, for example concentrated hydrochloric acid) acidifying, obtain following formula: compound
Figure FDA0000431113490000044
D) by step c) gained compound for example join, in suitable solvent (phenyl ether), under heating condition, (for example under reflux conditions) reacts mixture, after reaction finishes, add sherwood oil, separate and obtain 7-replacement-4-(the 1H)-oxoquinoline compound shown in following formula:
Figure FDA0000431113490000051
with
E) make steps d) gained compound dissolution for example, in suitable solvent (DMF), add NaH, then add halogenated alkane R1-Y to make to react, obtaining R3 is the following formula: compound of the present invention of hydrogen:
Figure FDA0000431113490000052
Wherein,
X represent halogen or-C 1-4alkoxyl group,
Y represents halogen,
R 1be selected from-C 1-6alkyl ,-C 2-6thiazolinyl ,-C 1-6alkyl-phenyl, particularly for example R1 is selected from methyl, ethyl, propyl group, sec.-propyl, allyl group, propenyl, phenmethyl, hydrocinnamyl, normal-butyl.
12. prepare the method for formula I compound described in claim 1-7 any one or its pharmacologically acceptable salts, solvate, prodrug, and it comprises the following steps:
A) for example, in suitable solution (Isosorbide-5-Nitrae-dioxane), at KN[Si (CH3) 3] 2under existence, make formula
Figure FDA0000431113490000053
compound reacts (for example lower reaction under heating condition, for example under reflux conditions reaction) with morpholine or N methyl piperazine, obtain following formula: compound of the present invention:
Figure FDA0000431113490000054
wherein R 1for hydrogen or-C 1-6alkyl is methyl such as, R 7for
Figure FDA0000431113490000055
or or
B), for example, in suitable solution (DMSO), under cuprous iodide, L-PROLINE, Tripotassium phosphate exist, make formula
Figure FDA0000431113490000057
compound reacts (for example lower reaction under heating condition, for example under reflux conditions reaction) with morpholine, obtain following formula: compound of the present invention:
Figure FDA0000431113490000061
wherein R 1for-C 1-6alkyl-phenyl is benzyl such as, R 7for
Figure FDA0000431113490000062
13. prepare the method for formula I compound described in claim 1-7 any one or its pharmacologically acceptable salts, solvate, prodrug, and it comprises the following steps:
Make the 7-of ethyl shown in following formula replace-4 (1H)-Oxoquinoline-3-carboxylic acid esters
Figure FDA0000431113490000063
Mix with 3-(diethylamino) propylamine, heating (for example, at 120～180 DEG C) makes reaction, obtains following formula: compound of the present invention:
Figure FDA0000431113490000064
Wherein X be halogen or-C 1-6alkoxyl group, for example X is fluorine, chlorine, bromine or methoxyl group;
Or the method comprises the following steps:
A) make formula
Figure FDA0000431113490000065
compound for example, in suitable solvent (DMF), NaH exist under with formula R 1the halogenated alkane that-Y represents reacts, and obtains following formula: compound of the present invention:
and optionally further,
B) make a) gained compound and formula H of step 2n-(CH 2) n-NH 2, H 2n-(CH 2) n-N (C 2h 5) 2the diamines representing mixes, and heating (for example, at 120～180 DEG C) makes reaction, obtains following formula: compound of the present invention:
Figure FDA0000431113490000067
or
Figure FDA0000431113490000068
Wherein: Y represents halogen; N is 2 or 3; R 1be selected from-C 1-6alkyl ,-C 2-6thiazolinyl ,-C 1-6alkyl-phenyl, particularly for example R 1be selected from methyl, ethyl, propyl group, sec.-propyl, allyl group, propenyl, phenmethyl, hydrocinnamyl, normal-butyl.
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