CN105017145A - Chloroxoquinoline derivative with anti-tumor activity - Google Patents
Chloroxoquinoline derivative with anti-tumor activity Download PDFInfo
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- CN105017145A CN105017145A CN201510393896.9A CN201510393896A CN105017145A CN 105017145 A CN105017145 A CN 105017145A CN 201510393896 A CN201510393896 A CN 201510393896A CN 105017145 A CN105017145 A CN 105017145A
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- 0 CC(C)(*C(C1)=*)OC1=O Chemical compound CC(C)(*C(C1)=*)OC1=O 0.000 description 2
- MBXAARWNAHOANL-UHFFFAOYSA-N C=C(C=CC1N)c2c1c(N)cc(N)c2 Chemical compound C=C(C=CC1N)c2c1c(N)cc(N)c2 MBXAARWNAHOANL-UHFFFAOYSA-N 0.000 description 1
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- 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
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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
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- 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
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- 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
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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
- C07D215/38—Nitrogen atoms
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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
- C07D215/38—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
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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
- C07D215/48—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
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Abstract
The invention relates to a chloroxoquinoline derivative with anti-tumor activity, particularly a compound shown in a formula I, and pharmaceutically acceptable salt, a solvate and a prodrug, wherein R1 is selected from hydrogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl and -C1-6 alkyl-phenyl; the alkyl, alkenyl, alkynyl and phenyl can be optionally replaced with halogen, nitryl, cyano, hydroxyl, -C1-6 alkoxyl and phenyl; R3 is selected from hydrogen, -CONHR31 and -COOR32, R31 and R32 are independently selected from -C1-6 alkyl and -C1-6 alkyl amino, respectively, and the amino is optionally substituted by 1-2 -C1-6 alkyl; R7 is selected from halogen, -C1-6 alkoxyl, morpholinyl or piperazinyl. The formula I is shown in the description.
Description
The application is the divisional application of the Chinese Patent Application No. 2013106521915 that on December 5th, 2013 submits to, and its full content is incorporated to herein by reference.
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 preparing the application in anti-tumor drug.
Background technology
The chloro-4-oxo-quinoline of 7-, be generally called 7-chloro-4-oxo-quinoline by people, 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:
This compound has tautomerism, and its tautomer is 7-chloro-4-hydroxyl-quinoline, and the two variation relation is as follows:
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 " 1035 " engineering and country's " 95 " program for tackling key problems in science and technology; In April, 2002, checked and accepted 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.Two New Drug Certificates (bulk drug and capsule) that acquisition on April 23rd, 2003 National Drug Administration issues and two drug registration official written replies.
As far back as nineteen forty-six, Hammer and Surrey just reports with m-chloro aniline and methyl-oxalacetic ester for raw material, through the method (J.Am.Chem.Soc.68 (1946) 113-116) of the Reactive Synthesis 7-chloro-4-hydroxyl-quinoline such as condensation, closed loop, decarboxylation.Subsequently, Roberts and Price reports the higher synthetic route of a kind of yield, namely with m-chloro aniline and ethoxymeyhylene dimethyl malonate for raw material, through the method for the Reactive Synthesis 7-chloro-4-hydroxyl-quinoline 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 the advantage of two aspects: the isomer that (1) ring closure reaction does not have 5-chlorine to replace produces; (2) overall yield of reaction is high.2009, Langer etc. report an easier synthetic route, namely with m-chloro aniline and isopropylidene malonate for raw material, 7-chloro-4-hydroxyl-quinoline can be obtained through condensation and Guan Huan two-step reaction, this route is for phenyl ring having the symmetrical aniline raw material replacing halogen atom, yield is higher, but the method is for the mono-substituted aniline of phenyl ring, then can generate the isomer (Synthesis 1 (2009) 69-78) of 5 replacements.
7-chloro-4-oxo-quinoline is used for clinical antineoplastic treatment with the form of oral capsule at present, clinical confirmation its have wider antitumor spectra, especially for advanced breast cancer and nonsmall-cell lung cancer more remarkable, obviously can extend lifetime, improve the quality of living, and it is slight to have toxic side effects, the bone marrow depression of anticarcinogen as none and immunosuppressive action, the feature of easy administration.
In addition, taking 7-chloro-4-oxo-quinoline patient curative effect when accepting radiotherapy also more obvious, analyzing the effect that simultaneously may possess radiation sensitivity.
The Anticancer Effect and Mechanism of 7-chloro-4-oxo-quinoline is by causing the damage of DNA of tumor cell template lysosome in cancer cells to increase, causing breaking, discharge multiple lytic enzyme, thus causes cancer cells self-dissolving dead.
But 7-chloro-4-oxo-quinoline, as the antitumor original new drug of China's chemistry one class, deposits problem both ways: (1) 7-chloro-4-oxo-quinoline bulk drug solubleness in water is very little, at present so cannot adopt the form administration of injection clinically.Adopt the dosage form of oral capsule at present clinically, limit the performance of bioavailability and antitumor curative effect in its body.Therefore, the solubility problem of this compounds urgently to be resolved hurrily.(2) the bearing mouse model antitumor tumour inhibiting rate of 7-chloro-4-oxo-quinoline to S180 sarcoma and ehrlich carcinoma solid-type is only about 30% at present, and its anti-tumor activity has much room for improvement.
Therefore be necessary to take 7-chloro-4-oxo-quinoline as primer, finding the derivative with new biologic activity feature, supplying clinical application in the hope of obtaining the new anti-cancer drug being better than former medicine.
Summary of the invention
Still need at present to find the novel 7-chloro-4-oxo-quinoline compounds with anti-tumor activity for clinical application.The present invention finds to have the anti-tumor activity that the compound shown in general formula I has desirable.The present invention is based on this find and be accomplished.
First aspect present invention provides with compounds of Formula I:
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 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-C separately
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,
Compound according to a first aspect of the 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 optionally by halogen, nitro, cyano group, hydroxyl ,-C
1-6alkoxyl group.
Compound according to a first aspect of the present invention, wherein R
1be selected from hydrogen ,-C
1-6alkyl ,-C
2-6thiazolinyl ,-C
1-6alkyl-phenyl.
Compound according to a first aspect of the present invention, wherein R
1be selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, allyl group, propenyl, phenmethyl, hydrocinnamyl, normal-butyl.
Compound according to a first aspect of the present invention, wherein R
3be selected from hydrogen ,-CONHR
31,-COOR
32, wherein said R
31and R
32independently be selected from-C separately
1-4alkyl and-C
1-4alkylamino, wherein said amino is optionally by 1 ~ 2-C
1-4alkyl replaces.
Compound according to a first aspect of the 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.
Compound according to a first aspect of the 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.
Compound according to a first aspect of the present invention, wherein R
7be selected from halogen ,-C
1-4alkoxyl group,
Compound according to a first aspect of the present invention, wherein R
7be selected from fluorine, chlorine, bromine, methoxyl group,
Compound according to a first aspect of the present invention, wherein R
1and R
3be asynchronously hydrogen.
Compound according to a first aspect of the present invention, its exclusion condition is: R
1and R
3be hydrogen simultaneously, and R
7for halogen.
Compound according to a first aspect of the present invention, it is be selected from following compound:
The fluoro-1-methyl of 7--4-oxo-quinoline,
The chloro-1-methyl of 7--4-oxo-quinoline,
The bromo-1-methyl of 7--4-oxo-quinoline,
7-methoxyl group-1-methyl-4-oxo-quinoline,
The chloro-1-sec.-propyl of 7--4-oxo-quinoline,
The chloro-4-oxo-quinoline of 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,
Fluoro-4 (1H)-Oxoquinoline-3-methane amides of N-(3-(diethylamino) propyl group)-7-,
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 of ethyl 7--4-oxo-quinoline-3-carboxylicesters,
The chloro-1-ethyl of ethyl 7--4-oxo-quinoline-3-carboxylicesters,
The chloro-4-oxo-quinoline of ethyl 1-allyl group-7--3-carboxylicesters,
The chloro-4-oxo-quinoline of ethyl 1-butyl-7--3-carboxylicesters,
The chloro-4-oxo-quinoline of ethyl 1-benzyl-7--3-carboxylicesters,
The chloro-1-of ethyl 7-(3-hydrocinnamyl)-4-oxo-quinoline-3-carboxylicesters,
The chloro-N-of 7-[2-(diethylamino) ethyl]-1-methyl-4-oxo-quinoline-3-methane amide,
The chloro-N-of 7-[3-(diethylamino) propyl group]-1-methyl-4-oxo-quinoline-3-methane amide,
The chloro-N-of 7-[2-(diethylamino) ethyl]-1-ethyl-4-oxo-quinoline-3-methane amide,
The chloro-N-of 7-[2-(diethylamino) propyl group]-1-ethyl-4-oxo-quinoline-3-methane amide,
The chloro-N-of 1-allyl group-7-[2-(diethylamino) ethyl]-4-oxo-quinoline-3-methane amide,
The chloro-N-of 1-allyl group-7-[3-(diethylamino) propyl group]-4-Oxoquinoline-3-methane amide,
The chloro-N-of 1-butyl-7-[2-(diethylamino) ethyl]-4-oxo-quinoline-3-methane amide,
The chloro-N-of 1-butyl-7-[3-(diethylamino) propyl group]-4-oxo-quinoline-3-methane amide,
The chloro-N-of 1-benzyl-7-[2-(diethylamino) ethyl]-4-oxo-quinoline-3-methane amide,
The chloro-N-of 1-benzyl-7-[2-(diethylamino) propyl group]-4-oxo-quinoline-3-methane amide,
The chloro-N-of 7-[3-(diethylamino) propyl group]-1-(3-hydrocinnamyl)-4-oxo-quinoline-3-methane amide,
The chloro-1-ethyl of N-(3-aminopropyl)-7--4-oxo-quinoline-3-methane amide,
The chloro-4-oxo-quinoline of 1-allyl group-N-(3-aminopropyl)-7--3-methane amide,
The chloro-4-oxo-quinoline of N-(3-aminopropyl)-1-butyl-7--3-methane amide,
The chloro-1-benzyl of N-(3-aminopropyl)-7--4-oxo-quinoline-3-methane amide,
N-(3-aminopropyl)-7-chloro-1-(3-hydrocinnamyl)-4-oxo-quinoline-3-methane amide,
And their pharmacologically acceptable salts, solvate, prodrug.
Second aspect present invention relate to formula I, its tautomer, raceme or optical isomer described in any one of first aspect present invention, its pharmaceutical salts or solvate preparation can be used for preventing or treatment tumour medicine in purposes.
Fourth aspect present invention provides a kind of pharmaceutical composition, formula I wherein containing 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 preventing or treating the application in the medicine of the diseases such as tumour.
Fifth aspect present invention provides the method preventing and/or treating tumour, and the method comprises formula I and hereinafter described formula II, formula III compound or its pharmacologically acceptable salts, solvate, prodrug to there being the experimenter of these needs to prevent and/or treat the first aspect of significant quantity.
Sixth aspect present invention provides the method for the preparation formula I of first aspect or its pharmacologically acceptable salts, solvate, prodrug, and it comprises the following steps:
A) formula is made
compound and ethoxy methylene diethyl malonate react (such as in a heated condition, such as, at 80 ~ 120 DEG C), obtain following formula: compound:
B) by step a) gained compound join in suitable solvent (such as phenyl ether), (such as under the boiling of this solvent or reflux conditions) makes mixture react in a heated condition, add sherwood oil after reaction terminates, be separated and obtain following formula: compound:
C) to by step b) add alkali aqueous solution (such as aqueous sodium hydroxide solution in gained compound, such as 5 ~ 20% aqueous sodium hydroxide solutions), heating (such as refluxing) reaction, reaction terminates rear acid (such as hydrochloric acid, such as concentrated hydrochloric acid) acidifying, obtain following formula: compound
D) by step c) gained compound joins in suitable solvent (such as phenyl ether), (such as under reflux conditions) makes mixture react in a heated condition, add sherwood oil after reaction terminates, be separated 7-replacement-4-(the 1H)-oxoquinoline compound obtained shown in following formula:
E) make steps d) gained compound dissolution in suitable solvent (such as 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:
Wherein,
X represents halogen or-C
1-4alkoxyl group,
Y represents halogen,
R
1be selected from-C
1-6alkyl ,-C
2-6thiazolinyl ,-C
1-6alkyl-phenyl, particularly such as R
1be selected from methyl, ethyl, propyl group, sec.-propyl, allyl group, propenyl, phenmethyl, hydrocinnamyl, normal-butyl.
Sixth aspect present invention additionally provides the method for the preparation formula I of first aspect or its pharmacologically acceptable salts, solvate, prodrug, and it comprises the following steps:
A) in suitable solution (such as Isosorbide-5-Nitrae-dioxane), at KN [Si (CH3)
3]
2under existence, make formula
compound and morpholine or N methyl piperazine react (such as lower in a heated condition react, such as under reflux conditions reaction), obtain following formula: compound of the present invention:
wherein R
1for hydrogen or-C
1-6alkyl is methyl such as, R
7for
or
or
B) in suitable solution (such as DMSO), under cuprous iodide, L-PROLINE, Tripotassium phosphate exist, formula is made
compound and morpholine react (such as react down in a heated condition, such as, under reflux conditions react), 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 additionally provides the method for the preparation formula I of first aspect or its pharmacologically acceptable salts, solvate, prodrug, and it comprises the following steps:
A) 7-of ethyl shown in following formula is made to replace-4 (1H)-Oxoquinoline-3-carboxylic acid esters
Mix with 3-(diethylamino) propylamine, heating (such as at 120 ~ 180 DEG C) makes reaction, obtains following formula: compound of the present invention:
Wherein X is halogen or-C
1-6alkoxyl group, such as X is fluorine, chlorine, bromine or methoxyl group.
Sixth aspect present invention additionally provides the method for the preparation formula I of first aspect or its pharmacologically acceptable salts, solvate, prodrug, and it comprises the following steps:
A) formula is made
compound in suitable solvent (such as DMF), with formula R under NaH exists
1the halogenated alkane that-Y represents reacts, and obtains following formula: compound of the present invention:
and optionally further,
B) step a) gained compound and formula H is made
2n-(CH
2)
n-NH
2, H
2n-(CH
2)
n-N (C
2h
5)
2the diamines mixing represented, heating (such as at 120 ~ 180 DEG C) makes reaction, obtains following formula: compound of the present invention:
Wherein
Y represents halogen,
N is 2 or 3,
R
1be selected from-C
1-6alkyl ,-C
2-6thiazolinyl ,-C
1-6alkyl-phenyl, particularly such as R
1be selected from methyl, ethyl, propyl group, sec.-propyl, allyl group, propenyl, phenmethyl, hydrocinnamyl, normal-butyl.
In the inventive method in the above 6th, wherein the definition of each symbol is as described in any one of first aspect present invention formula I.
Seventh aspect present invention provides a kind of compound, and it is for compound shown in Formula Il
And pharmacologically acceptable salts, solvate, prodrug, wherein
R
4be selected from halogen (such as chlorine, fluorine, bromine, iodine) ,-C
1-6alkyl (such as methyl, ethyl, propyl group, sec.-propyl, normal-butyl) ,-C
1-6alkoxyl group (such as methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy) ,-NH-C
1-6alkyl-N (C
1-4alkyl)
2;
R
7be selected from halogen (such as chlorine, fluorine, bromine, iodine) ,-C
1-6alkyl (such as methyl, ethyl, propyl group, sec.-propyl, normal-butyl) ,-C
1-6alkoxyl group (such as methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy) ,-C
1-6thiazolinyl oxygen base (such as vinyloxy group, propenyloxy group, butenyloxy) ,-C
1-6alkyl-phenyl ,-C
1-6alkyl-halo (such as chlorine, fluorine, bromine, iodo) phenyl.
Compound according to a seventh aspect of the 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-,
7-chloro-4-isopropoxy quinoline,
4,7-dimethoxy-quinoline,
4-oxyethyl group-7-methoxy quinoline,
The chloro-7-hydroxyquinoline of 4-,
The chloro-7-ethoxyquinoline of 4-,
4-chloro-7-n-butoxy quinoline,
The positive hexyloxy quinoline of the chloro-7-of 4-,
4-chloro-7-allyloxy quinoline,
4-chloro-7-isopropoxy quinoline,
4-chloro-7-isobutoxy quinoline,
The chloro-7-benyloxyquinoline of 4-,
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-base)-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-benyloxyquinoline-4-base)-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-base)-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
And pharmacologically acceptable salts, solvate, prodrug, wherein
Y is 1 to 4 group being selected from halogen, and such as Y is 1-2 the group being selected from fluorine, chlorine, bromine, iodine, and such as Y is 2 chlorine.
Compound according to a eighth aspect of the 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 not be conflicting, certainly at where applicable each other, necessary words can be done suitably to modify to individual features.In the present invention, such as, when mentioning " any one of first aspect present invention ", the arbitrary sub-aspect that " any one " refers to first aspect present invention is somebody's turn to do; When 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 the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.
Hereafter illustrate for group definition that formula I is done, composition, usage description of use etc., if can not produce contradiction, then these descriptive explanations go for formula II compound and formula III compound equally.
The term " halogen " adopted in the present invention, " halogen ", " Hal " or " halo " refer to fluorine, chlorine, bromine and iodine.
The term " alkyl " adopted in the present invention, " alkenyl " and " alkynyl " 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 the present invention's preferred embodiment, described " alkyl " refers to that alkyl comprises alkyl group and cycloalkyl, particularly alkyl group such as C1-C6 alkyl.
As used herein, term " aryl " is such as but not limited to phenyl, naphthyl.
As used herein, phrase " substituted or unsubstituted C1-C6 alkyl " refers to the substituted or unsubstituted alkyl group having and 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 compound comprising quinazolone ring, for convenience of identifying, this quinazolone ring and annular atoms numbering thereof can represent in the following order
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 the straight or branched alkyl with 1-6 carbon atom.Other situation also can do similar understanding.
In the present invention, group " C
1-6alkyl " such as can be selected from C
1-5alkyl, C
1-4alkyl.Similarly ,-C
1-6alkoxy is as being selected from C
1-5alkoxyl group, C
1-4alkoxyl group ,-C
2-6thiazolinyl such as can be selected from C
2-5thiazolinyl, C
2-4thiazolinyl ,-C
2-6alkynyl such as 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 reacting used are that those skilled in the art can prepare according to existing knowledge, or can be obtained by the known method of document, or can be buied by business.Intermediate used in above reaction scheme, starting material, reagent, reaction conditions etc. all can have knowledge according to those skilled in the art can make appropriate change.Or those skilled in the art also method can synthesize other not specifically enumerated formula I of the present invention according to a second aspect of the present invention.
According to the present invention, the salt that the pharmaceutical salts of formula I can be acid salt or be formed with alkali.Acid salt citing says it can is that inorganic acid salt is such as but not limited to hydrochloride, vitriol, phosphoric acid salt, hydrobromate; 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 and alkali formed salt illustrate say can be an alkali metal salt such as but be not limited to lithium, sodium and sylvite; Alkaline earth salt such as but be 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 comprising other are as alcohols such as ethanol.
According to the present invention, can there is cis/trans isomer in formula I, 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 such as Stereo-selective synthesis preparation.If there is motor-driven hydrogen atom, the present invention also relates to the tautomeric form of formula I.
Therefore the present invention also relates to containing at least one formula I as the effective dose of active ingredient, or the pharmaceutical composition of its pharmaceutical salts and/or its steric isomer and customary pharmaceutical excipients or assistant agent.Usual pharmaceutical composition of the present invention contains formula I and/or its physiologically acceptable salt of 0.1-90 % by weight.Pharmaceutical composition can be prepared according to methods known in the art.During for this object, if needed, formula I and/or steric isomer and one or more solids or liquid pharmaceutical excipients and/or assistant agent can be combined, make the suitable administration form or dosage form that can be used as people.
Formula I of the present invention or the pharmaceutical composition containing it can administrations in a unit, and route of administration can be enteron aisle or non-bowel, 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.In order to unit dosage forms for administration is made tablet, various carrier well known in the art can be widely used.Example about carrier is, such as 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, such as 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 can also be made coating tablet further, such as sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.In order to administration unit is made pill, various carrier well known in the art can be widely used.Example about carrier is, such as 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.In order to administration unit is made suppository, various carrier well known in the art can be widely used.Example about carrier is, the ester, gelatin, semi-synthetic glyceryl ester etc. of such as polyoxyethylene glycol, Yelkin TTS, theobroma oil, higher alcohols, higher alcohols.In order to administration unit is made capsule, effective constituent formula I or its steric isomer are mixed with above-mentioned various carriers, and the mixture obtained thus is placed in hard obviously capsule or soft capsule.Also effective constituent formula I or its steric isomer can be made microcapsule, be suspended in aqueous medium and form suspensoid, also can load in hard capsule or make injection application.In order to administration unit is made injection preparation, as solution, emulsion, lyophilized injectable powder and suspensoid, all thinners that this area is conventional can be used, such as, the isooctadecanol of water, ethanol, polyoxyethylene glycol, 1,3-PD, ethoxylation, polyoxygenated isooctadecanol, Polyoxyethylene Sorbitol Fatty Acid Esters etc.In addition, in order to prepare isotonic injection liquid, appropriate sodium-chlor, glucose or glycerine can be added in injection preparation, in addition, conventional solubility promoter, buffer reagent, pH adjusting agent etc. can also be added.
In addition, as needs, also tinting material, sanitas, spices, correctives, sweeting agent or other material can be added in pharmaceutical preparation.
Formula I, or the dosage of its isomer depends on many factors, such as, to prevent or the character of disease therapy and severity, the sex of patient or animal, age, body weight and individual reaction, particular compound used, route of administration and administration number of times etc.Above-mentioned dosage can single dose form or be divided into several, such as two, three or four dosage forms for administration.
Term used herein " composition " means to comprise the product of each appointment composition comprising specified amount, and any product directly or indirectly produced from the combination of each appointment composition of specified amount.
The active compound amount of gained the actual dose level of each activeconstituents in pharmaceutical composition of the present invention can be changed, so that effectively can obtain required therapeutic response for concrete patient, composition and administering mode.Dosage level must according to the activity of particular compound, route of administration, treat the severity of the patient's condition and the patient's condition of patient to be treated and medical history and select.But the way of this area is, the dosage of compound, from lower than for obtaining level that required result for the treatment of requires, increases dosage, gradually until obtain required effect.
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 for above-mentioned treat and/or prevent or other treatment and/or prevention time, a kind of the compounds of this invention treating and/or preventing significant quantity can be applied in a pure form, or with the acceptable ester of pharmacy or prodrug forms (when there are these forms) application.Or described compound can accept the pharmaceutical composition administration of vehicle containing this object compound and one or more medicines.The compounds of this invention that word " prevents and/or treats significant quantity " refers to the compound of the q.s of the reasonable effect/Hazard ratio treatment obstacle being applicable to any medical prophylaxis and/or treatment.But it should be understood that total daily dosage portion of the compounds of this invention and composition must be maked decision within the scope of reliable medical judgment by attending physician.For any concrete patient, concrete treatment effective dose level must be determined according to many factors, and described factor comprises treated obstacle and the severity of this obstacle; The activity of the particular compound adopted; The concrete composition adopted; Age of patient, body weight, general health situation, sex and diet; The administration time of the particular compound adopted, route of administration and excretion rate; The treatment time length; The medicine combinationally using with adopted particular compound or use simultaneously; And the known similar factor of medical field.Such as, the way of this area is, the dosage of compound, from lower than for obtaining level that required result for the treatment of requires, increases dosage, gradually until obtain required effect.In general, formula I is used for the dosage of Mammals particularly people can between 0.001 ~ 1000mg/kg body weight/day, such as, between 0.01 ~ 100mg/kg body weight/day, such as, between 0.01 ~ 10mg/kg body weight/day.
Embodiment
The present invention is further illustrated by the following example, but these examples of implementation do not mean that any limitation of the invention.
Following synthetic route 1 depicts the general method of some intermediates and the compounds more of the present invention preparing the compounds of this invention.
synthetic route 1
the General Synthetic Procedures of compound 6a-d:
(1) synthesis of Xi Fushi alkali 3a-d:
Aniline 1a-d (100mmol) and ethoxy methylene diethyl malonate 2 (23.3g, 108mmol) mixing between inciting somebody to action accordingly, stirring at room temperature is clarified to solution.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 (i.e. Xi Fushi alkali 3a-d) is directly added in next step reaction flask.
(2) synthesis of Oxoquinoline-3-carboxylic acid ester 4a-d
Phenyl ether (100ml) is added in the round-bottomed flask of 250ml, is heated with stirring to boiling.Then while hot previous step is obtained by reacting Xi Fushi alkali 3a-d to be added drop-wise in the phenyl ether solution of boiling.Finish, continue heating reflux reaction, within about about 15 minutes, white solid separated out by bottle wall, about about 45 minutes, and solid is full of whole bottle solution and turns yellow gradually.Stopped reaction, cooling reaction solution, to room temperature, adds 60-90 DEG C of sherwood oil (100ml) in reaction flask, and after stirring, filter, 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-
With m-fluoroaniline 1a (100mmol) for raw material, obtain white solid (16.9g, 72%).
Chloro-4 (the 1H)-Oxoquinoline-3-carboxylic acid esters (4b) of ethyl 7-
With m-chloro aniline 1b (100mmol) for raw material, obtain white solid (19.6g, 78%).
Bromo-4 (the 1H)-Oxoquinoline-3-carboxylic acid esters (4c) of ethyl 7-
With m-bromoaniline 1c (100mmol) for raw material, obtain white solid (22.2g, 75%).
Ethyl 7-methoxyl group-4 (1H)-Oxoquinoline-3-carboxylic acid ester (4d)
With 3-anisidine 1d (100mmol) for raw material, obtain white solid (16.3g, 66%).
(3) synthesis of Oxoquinoline-3-carboxylic acid 5a-d
Product Oxoquinoline-3-carboxylic acid ester 4a-d (20mmol) obtained in the previous step is added in round-bottomed flask, adds 10%NaOH solution (150ml) subsequently, reflux 1 hour under agitation condition.Cooling reaction solution is to room temperature, and add 500ml water dilute reaction solution and regulate pH to 6.0 with concentrated hydrochloric acid, separating out faint yellow solid, filter, 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-replaces the synthesis of-4-(1H)-Oxoquinoline 6a-d
The corresponding intermediate Oxoquinoline-3-carboxylic acid 5a-d (16.0g) previous step be obtained by reacting mixes with phenyl ether (100ml), heating reflux reaction.Carboxylic acid does not first dissolve.Along with temperature raises, insoluble solids reduces gradually and produces with a large amount of bubble.Heating reflux reaction about 30 minutes, bubble-free produces, stopped reaction, and cooling reaction solution, to room temperature, has pale solid to separate out.Add 60-90 DEG C of sherwood oil (100ml), filter after stirring, obtain white solid.
fluoro-4 (the 1H)-Oxoquinolines (6a) of 7-
Obtain white solid (1.5g, 92%).ESI-MS m/z 164[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/z 180[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/z 224[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/z 176[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 Synthetic Procedures of the compounds of this invention 7a to 7i:
7-is replaced-4-(1H)-Oxoquinoline (10mmol) and is dissolved in 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 is reacted, TLC tracing detection.React complete, be poured into water by reaction mixture, extraction into ethyl acetate (150ml × 3), merge organic phase, washing, saturated salt is washed.With concentrated hydrochloric acid by organic phase acidifying (pH 1 ~ 2), be evaporated near dry, dehydrated alcohol band water 2 times, residue acetone recrystallization.Filter, obtain yellow solid.By water-soluble for above-mentioned yellow solid, sodium bicarbonate alkalizes, extraction into ethyl acetate, anhydrous sodium sulfate drying, filters, and filtrate reduced in volume is to 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)
With fluoro-4 (the 1H)-Oxoquinoline 6a (5.0mmol) of 7-and methyl iodide (7.5mmol) for raw material.Obtain white solid (0.86g, 86%).ESI-MSm/z 178[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)
With chloro-4 (the 1H)-Oxoquinoline 6b (5.0mmol) of 7-and methyl iodide (7.5mmol) for raw material.Obtain white solid (0.67g, 69%), mp233-234 DEG C.ESI-MS m/z 194[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)
With bromo-4 (the 1H)-Oxoquinoline 6c (5.0mmol) of 7-and methyl iodide (7.5mmol) for raw material.Obtain white solid (1.0g, 88%).ESI-MSm/z 239[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)
With 7-methoxyl group-4 (1H)-Oxoquinoline 6d (5.0mmol) and methyl iodide (7.5mmol) for raw material.Obtain white solid (0.76g, 80%).Mp 179-180℃。ESI-MS m/z 190[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).
13CNMR(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)
With chloro-4 (the 1H)-Oxoquinoline 6b (5.0mmol) of 7-and 2-N-PROPYLE BROMIDE (20mmol) for raw material, obtain white solid (0.75g, 68%).ESI-MSm/z 222[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).
13C NMR(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 1-chloro-4-oxo-quinoline of allyl group-7 (compound 7f)
With chloro-4 (the 1H)-Oxoquinoline 6b (5.0mmol) of 7-and allyl bromide 98 (7.5mmol) for raw material, obtain white solid (0.9g, 82%).ESI-MSm/z 220[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).
13C NMR(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 1-chloro-4-oxo-quinoline of benzyl-7-(compound 7g)
With chloro-4 (the 1H)-Oxoquinoline 6b (5.0mmol) of 7-and cylite (7.5mmol) for raw material, obtain white solid (0.95g, 70%).Mp202-203℃。ESI-MS m/z 270[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: preparation 7-chloro-1-(3-hydrocinnamyl)-4-oxo-quinoline (compound 7h)
With chloro-4 (the 1H)-Oxoquinoline 6b (5.0mmol) and 1-(3-bromopropyl) benzene (25mmol) of 7-for raw material, obtain yellow oil (1.0g, 68%).ESI-MS m/z 298[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).
13CNMR(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 1-bromo-4-oxo-quinoline of benzyl-7-(compound 7i)
With bromo-4 (1H)-Oxoquinoline 6c (5.0mmol) a of 7-and cylite (7.5mmol) for raw material, obtain white solid (1.32g, 84%).ESI-MS m/z 315[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 depicts the general method of some intermediates and the compounds more of the present invention preparing the compounds of this invention.
synthetic route 2:
the synthesis of embodiment 10:7-morpholinyl-4 (1H)-Oxoquinoline (compound 15)
Isosorbide-5-Nitrae-dioxane (6ml), morpholine (0.21ml, 2.4mmol), KN [Si (CH3) is added successively in the round-bottomed flask of 50ml
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 tracing detection, reacts complete, and cooling reaction solution is to room temperature, add 20ml water termination reaction, adjust ph 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).
13CNMR(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.
the synthesis of embodiment 11:1-methyl-7-(4-methylpiperazine-1-yl)-4-oxo-quinoline (compound 16)
Isosorbide-5-Nitrae-dioxane (12ml), N methyl piperazine (0.4ml, 3.6mmol), KN [Si (CH3) is added successively in the round-bottomed flask of 50ml
3]
2the bromo-1-methyl-4 of (4ml, 3.64mmol) and 7-(1H)-Oxoquinoline (0.48g, 2mmol), finishes, vacuumizes immediately, take out complete, be filled with N immediately
2, repeatedly take out 4 times, each 1 minute.Then reaction mixture is put in 100 DEG C of oil baths and reflux about 15 hours, TLC tracing detection.React complete, cooling reaction solution, to room temperature, adds 5ml water termination reaction, is evaporated to dry, dissolve with methanol reaction residue, filter and remove insolubles, 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/z 257.9[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.
the synthesis of embodiment 12:1-benzyl-7-morpholinyl-4-oxo-quinoline (compound 17):
The bromo-1-benzyl-4 of 7-(1H)-Oxoquinoline (0.64g is added successively in the round-bottomed flask of 50ml, 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, react in 90 DEG C of oil baths, TLC tracing detection.React complete, add 0.5ml ammoniacal liquor termination reaction, add 10ml water and 20ml methylene dichloride subsequently, separate organic phase, aqueous phase dichloromethane extraction twice, merge organic phase, washing, saturated salt is washed, anhydrous sodium sulfate drying.Filter, filtrate reduced in volume is to dry, and residue silica gel column chromatography, methylene dichloride: methyl alcohol=100:1 is eluent, obtains yellow oil (0.26g, 40%).ESI-MSm/z 320.9[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 depicts the general method of some intermediates and the compounds more of the present invention preparing the compounds of this invention.
synthetic route 3:
the General Synthetic Procedures of compound 18a-d
Ethyl 7-is replaced-4 (1H)-Oxoquinoline-3-carboxylic acid esters (5.0mmol) and 3-(diethylamino) propylamine (5.0ml) mixing, 150 DEG C of microwave heatings react 30 minutes.Cooling reaction solution is to room temperature, in reaction mixture, add 100ml water, dichloromethane extraction (50mL × 3), merge organic phase, washing, saturated salt is washed, 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: fluoro-4 (1H)-Oxoquinoline-3-methane amides (compound 18a) of preparation N-(3-(diethylamino) propyl group)-7-
With fluoro-4 (1H)-Oxoquinoline-3-carboxylic acid esters 4a (5.0mmol) of ethyl 7-for raw material, obtain white solid (0.72,45%) .ESI-MS m/z 320 [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)
With chloro-4 (1H)-Oxoquinoline-3-carboxylic acid esters 4b (5.0mmol) of ethyl 7-for raw material, obtain white solid (0.87g, 52%) .ESI-MS m/z 336 [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)
With bromo-4 (1H)-Oxoquinoline-3-carboxylic acid esters 4c (5.0mmol) of ethyl 7-for raw material, obtain white solid (0.93,49%) .ESI-MS m/z 380 [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)
With ethyl 7-methoxyl group-4 (1H)-Oxoquinoline-3-carboxylic acid ester 4d (5.0mmol) for raw material, obtain white solid (0.96g, 58%) .ESI-MS m/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 depicts the general method of some intermediates and the compounds more of the present invention preparing the compounds of this invention.
synthetic route 4:
the General Synthetic Procedures of compound 19a-f
Chloro-4 (the 1H)-Oxoquinoline-3-carboxylic acid ester 4b (2.51g of ethyl 7-are added in the round-bottomed flask of 100ml, 10mmol) with DMF (50ml), stirring at room temperature 10 minutes, add 60%NaH (0.8g subsequently, 20mmol), stirring at room temperature 15 minutes, then adds corresponding halogenated alkane (15-30mmol), stirring at room temperature is reacted, TLC tracing detection.React complete, be poured into water by reaction mixture, extraction into ethyl acetate, merge organic phase, washing, saturated salt is washed..With concentrated hydrochloric acid by organic phase acidifying, pressurization is concentrated into dry, and dehydrated alcohol band water 3 times, acetone recrystallization, filters to obtain yellow solid.By water-soluble for above-mentioned yellow solid, sodium bicarbonate alkalizes, extraction into ethyl acetate, washing, and saturated salt is washed, and anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography, and ethyl acetate/petroleum ether=2:1 wash-out, obtains target product.
embodiment 17: prepare the chloro-1-methyl of ethyl 7--4-oxo-quinoline-3-carboxylicesters (compound 19a)
With methyl iodide (15mmol) for raw material, obtain white solid (1.7g, 65%) .ESI-MS m/z 288 [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).
13cNMR (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 of ethyl 7--4-oxo-quinoline-3-carboxylicesters (compound 19b)
With iodoethane (15mmol) for raw material, obtain white solid (1.9g, 69%) .ESI-MS m/z 302 [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 of ethyl 1-allyl group-7--3-carboxylicesters (compound 19c)
With allyl bromide 98 (15mmol) for raw material, obtain white solid (2.2g, 75%) .ESI-MS m/z 314 [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 of ethyl 1-butyl-7--3-carboxylicesters (compound 19d)
With iodo-n-butane (30mmol) for raw material, obtain white solid (1.9g, 62%) .ESI-MS m/z 330 [M+Na]
+.
1h NMR (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).
13cNMR (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 of ethyl 1-benzyl-7--3-carboxylicesters (compound 19e)
With cylite (15mmol) for raw material, obtain white solid (2.9g, 85%) .ESI-MS m/z 364 [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-carboxylicesters (compound 19f)
With 1-(3-bromopropyl) benzene (50mmol) for raw material, obtain white solid (2.4g, 65%) .ESI-MS m/z 392 [M+Na]
+.
1h NMR (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.
Following General Synthetic Procedures depicts the general method preparing the compounds of this invention compound 20a-k and 21a-e.
Chloro-4 (the 1H)-Oxoquinoline-3-carboxylic acid esters (5.0mmol) of ethyl 7-replace 1-and corresponding diamines (5.0ml) mixing, 150 DEG C of microwave heatings react 30 minutes.Cooling reaction solution is to room temperature, in reaction mixture, add 100ml water, dichloromethane extraction (50mL × 3), merge organic phase, washing, saturated salt is washed, 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: preparation 7-chloro-N-[2-(diethylamino) ethyl]-1-methyl-4-oxo-quinoline-3-methane amide (compound 20a)
With the chloro-1-methyl of ethyl 7--4-oxo-quinoline-3-carboxylicesters 19a (5.0mmol) and N, N-diethyl ethylenediamine (5.0ml) for raw material, obtain white solid (1.1g, 68%) .ESI-MS m/z 336 [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: preparation 7-chloro-N-[3-(diethylamino) propyl group]-1-methyl-4-oxo-quinoline-3-methane amide (compound 20b)
With the chloro-1-methyl of ethyl 7--4-oxo-quinoline-3-carboxylicesters 19a (5.0mmol) and 3-(diethylamino) propylamine (5.0ml) for raw material, obtain white solid (0.9g, 54%) .ESI-MS m/z 350 [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: preparation 7-chloro-N-[2-(diethylamino) ethyl]-1-ethyl-4-oxo-quinoline-3-methane amide (compound 20c)
With the chloro-1-ethyl of ethyl 7--4-oxo-quinoline-3-carboxylicesters 19b (5.0mmol) and N, N-diethyl ethylenediamine (5.0ml) for raw material, obtain white solid (1.0g, 58%) .ESI-MS m/z 350 [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).
13c NMR (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: preparation 7-chloro-N-[2-(diethylamino) propyl group]-1-ethyl-4-oxo-quinoline-3-methane amide (compound 20d)
With the chloro-1-ethyl of ethyl 7--4-oxo-quinoline-3-carboxylicesters 19b (5.0mmol) and 3-(diethylamino) propylamine (5.0ml) for raw material, obtain white solid (1.06g, 57%) .ESI-MS m/z 364 [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).
13c NMR (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: preparation 1-allyl group-7-chloro-N-[2-(diethylamino) ethyl]-4-oxo-quinoline-3-methane amide (compound 20e)
With ethyl 1-allyl group-7-chloro-4-oxo-quinoline-3-carboxylicesters 19c (5.0mmol) and N, N-diethyl ethylenediamine (5.0ml) for raw material, obtain white solid (0.96g, 53%) .ESI-MS m/z 362 [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: preparation 1-allyl group-7-chloro-N-[3-(diethylamino) propyl group]-4-Oxoquinoline-3-methane amide (compound 20f)
With ethyl 1-allyl group-7-chloro-4-oxo-quinoline-3-carboxylicesters 19c (5.0mmol) and 3-(diethylamino) propylamine (5.0ml) for raw material, obtain white solid (1.24g, 66%) .ESI-MS m/z 376 [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: preparation 1-butyl-7-chloro-N-[2-(diethylamino) ethyl]-4-oxo-quinoline-3-methane amide (compound 20g)
With ethyl 1-butyl-7-chloro-4-oxo-quinoline-3-carboxylicesters 19d (5.0mmol) and N, N-diethyl ethylenediamine (5.0ml) for raw material, obtain white solid (1.23g, 65%) .ESI-MS m/z 378 [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: preparation 1-butyl-7-chloro-N-[3-(diethylamino) propyl group]-4-oxo-quinoline-3-methane amide (compound 20h)
With ethyl 1-butyl-7-chloro-4-oxo-quinoline-3-carboxylicesters 19d (5.0mmol) and 3-(diethylamino) propylamine (5.0ml) for raw material, obtain white solid (1.22g, 63%) .ESI-MS m/z 392 [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).
13cNMR (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: preparation 1-benzyl-7-chloro-N-[2-(diethylamino) ethyl]-4-oxo-quinoline-3-methane amide (compound 20i)
Ethyl 1-benzyl-7-chloro-4-oxo-quinoline-3-carboxylicesters 19e (5mmol) and N, N-diethyl ethylenediamine (5.0ml) are raw material, obtain white solid (1.4g, 68%) .ESI-MS m/z 412 [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: preparation 1-benzyl-7-chloro-N-[2-(diethylamino) propyl group]-4-oxo-quinoline-3-methane amide (compound 20j)
Ethyl 1-benzyl-7-chloro-4-oxo-quinoline-3-carboxylicesters 19e (5mmol) and 3-(diethylamino) propylamine (5.0ml) are raw material, obtain white solid (1.2g, 56%) .ESI-MS m/z 426 [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: preparation 7-chloro-N-[3-(diethylamino) propyl group]-1-(3-hydrocinnamyl)-4-oxo-quinoline-3-methane amide (compound 20k)
With the chloro-1-of ethyl 7-(3-hydrocinnamyl)-4-oxo-quinoline-3-carboxylicesters 19f (5.0mmol) and 3-(diethylamino) propylamine (5.0ml) for raw material, obtain white solid (1.4g, 63%) .ESI-MS m/z 454 [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)
With the chloro-1-ethyl of ethyl 7--4-oxo-quinoline-3-carboxylicesters 19b (5.0mmol) and 1,3-propylene diamine (5.0ml) for raw material, obtain white solid (0.9g, 60%) .ESI-MS m/z 308 [M+H]
+.
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)
With ethyl 1-allyl group-7-chloro-4-oxo-quinoline-3-carboxylicesters 19c (5.0mmol) and 1,3-propylene diamine (5.0ml) for raw material, obtain white solid (0.9g, 58%) .ESI-MS m/z 320 [M+H]
+.
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-aminopropyl)-1-butyl-7-chloro-4-oxo-quinoline-3-methane amide (compound 21c)
With ethyl 1-butyl-7-chloro-4-oxo-quinoline-3-carboxylicesters 19d (5.0mmol) and 1,3-propylene diamine (5.0ml) for raw material, obtain white solid (1.2g, 70%) .ESI-MS m/z 336 [M+H]
+.
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)
With the chloro-1-benzyl of ethyl 7--4-oxo-quinoline-3-carboxylicesters 19e (5.0mmol) and 1,3-propylene diamine (5.0ml) for raw material, obtain white solid (1.1g, 62%) .ESI-MS m/z 370 [M+H]
+.
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=6.6Hz 2H), 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: preparation N-(3-aminopropyl)-7-chloro-1-(3-hydrocinnamyl)-4-oxo-quinoline-3-methane amide (compound 21e)
With the chloro-1-of ethyl 7-(3-hydrocinnamyl)-4-oxo-quinoline-3-carboxylicesters 19f (5.0mmol) and 1,3-propylene diamine (5.0ml) is raw material, obtain white solid (0.9g, 45%) .ESI-MS m/z 398 [M+H]
+.
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 depicts the building-up process preparing compound 8a and compound 8b and compound 9a to 9e in general manner.
synthetic route 5:
The General Synthetic Procedures of compound 8a-b: by chloro-for 7-4-(1H)-Oxoquinoline 6b or 7-methoxyl group-4-(1H)-Oxoquinoline 6d (10mmol) adds in round-bottomed flask, adds POCl subsequently
3(20ml), mixed solution reflux 1h.Cooling reaction solution, adds POCl
3(10ml), back flow reaction 1h is continued.React complete, cooling reaction solution is to room temperature.Reaction solution is slowly poured into (very exothermic) in frozen water, sodium hydroxide solution regulates pH to 9.0, separates out white fluffy solid, filters, washing, and dry (easily distilling), obtains pale solid.
embodiment 39: preparation 4,7-dichloroquinoline (compound 8a)
With chloro-4 (the 1H)-Oxoquinoline 6b (10mmol) of 7-for raw material, obtain white solid (1.68g, 85%).ESI-MS m/z 197[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).
13CNMR(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)
With 7-methoxyl group-4 (1H)-Oxoquinoline 6d (10mmol) for raw material, obtain white solid (1.7g, 88%).ESI-MS m/z 194[M+H]
+.
1HNMR(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, adds sodium Metal 99.5 (1.05g, 50mmol) subsequently, after sodium Metal 99.5 disappears, add 4,7-dichloro-quinoline (10mmol), reflux 2h.React complete, cooling reaction solution is to room temperature, and decompression steams residue methyl alcohol, obtains white solid, adds 50ml water in bottle, filters, and washing is dry, obtains pale solid (1.66g, 84%).ESI-MS m/z 194[M+H]
+.
1HNMR(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, adds sodium Metal 99.5 (1.05g, 50mmol) subsequently, after sodium Metal 99.5 disappears, add 4,7-dichloro-quinoline (10mmol), reflux 2h.React complete, cooling reaction solution is to room temperature, and decompression steams residue ethanol, obtains white solid, adds 50ml water in bottle, filters, and washing is dry, obtains pale solid (1.8g, 87%).ESI-MS m/z 208[M+H]
+.
1HNMR(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, adds sodium Metal 99.5 (1.05g, 50mmol) subsequently, after sodium Metal 99.5 disappears, add 4,7-dichloro-quinoline (10mmol), reflux 8h.TLC tracing detection, reacts complete, and cooling reaction solution is to room temperature, decompression steams residue Virahol, obtains yellow oil, adds water (50ml) in residue, dichloromethane extraction three times, washing, saturated salt is washed, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography, methylene chloride/methanol=200:1 wash-out, be evaporated to dry, obtain yellow oil (1.51g, 68%).ESI-MS m/z 222[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, adds sodium Metal 99.5 (1.05g, 50mmol) subsequently, after sodium Metal 99.5 disappears, add the chloro-7-methoxy quinoline (10mmol) of 4-, reflux 8h.TLC tracing detection, reacts complete, and cooling reaction solution is to room temperature, decompression steams residue methyl alcohol, obtains yellow oil, adds water (50ml) in residue, dichloromethane extraction three times, washing, saturated salt is washed, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography, sherwood oil/acetone=4:1 wash-out, be evaporated to dry, obtain white solid (1.66g, 88%).ESI-MSm/z 190[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 sodium Metal 99.5 (1.05g, 50mmol) subsequently, after sodium Metal 99.5 disappears, add the chloro-7-methoxy quinoline (10mmol) of 4-, reflux 2h.React complete, cooling reaction solution is to room temperature, and decompression steams residue ethanol, in residue, add 50ml water, extraction into ethyl acetate (100ml × 3), merge organic phase, washing, saturated salt is washed, anhydrous sodium sulfate drying, filter, be evaporated to dry, obtain pale yellow oil, silica gel column chromatography, sherwood oil/acetone=4:1 wash-out, is evaporated to dry, obtain white solid (1.58g, 78%).ESI-MS m/z 204[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 depicts the building-up process preparing compound 12a and compound 12b and compound 13,14 in general manner.
synthetic route 6:
embodiment 46: the preparation chloro-4-of 5,8-bis-(1H)-Oxoquinoline (compound 13)
Sub-for propanedioic acid isopropyl ester (4.32g, 30mmol) and trimethyl orthoformate (53g, 500mmol) are mixed, reflux 2h, cools reaction solution subsequently to room temperature, adds 2,5-dichlorphenamide bulk powder (3.24g, 20mmol), reaction mixture reflux 2h.Cooling reaction solution, to room temperature, separates out white crystal, and filter, methanol wash, obtains white solid.
Above-mentioned white solid is mixed with phenyl ether (40ml), reflux 1h.Cooling reaction solution, to room temperature, adds 50ml sherwood oil, filters, obtain brown solid 3.0g after stirring.Silica gel column chromatography, methylene chloride/methanol=25:1 wash-out, obtains compound 13 for white solid (2.5g, 69%).ESI-MS m/z 215[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)
Sub-for propanedioic acid isopropyl ester (4.32g, 30mmol) and trimethyl orthoformate (53g, 500mmol) are mixed, reflux 2h, cools reaction solution subsequently to room temperature, adds 3,4-dichlorphenamide bulk powder (3.24g, 20mmol), reaction mixture reflux 2h.Cooling reaction solution, to room temperature, separates out white crystal, and filter, methanol wash, obtains white solid.
Above-mentioned white solid is mixed with phenyl ether (40ml), reflux 1h.Cooling reaction solution, to room temperature, adds 50ml sherwood oil, filters, obtain brown solid 3.0g after stirring.Recrystallizing methanol, obtains compound 14 for white solid (2.6g, 72%).ESI-MS m/z 215[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:
embodiment 48: the preparation chloro-7-hydroxyquinoline of 4-(compound 22)
By chloro-for 4-7-methoxy quinoline 8b (3.86g, 20mmol), 40%HBr (30mL) and acetic anhydride (20mL) mix post-heating backflow, and TLC tracing detection, reacts complete, and cooling reaction solution is to room temperature.Subsequently to adding the dilution of 100mL water in reaction solution, 20%NaOH solution regulates pH to 6.0, has a large amount of solid to separate out, and filters, and washing is dry, obtains pale solid (3.53g, 98.6%).
embodiment 49: the preparation chloro-7-ethoxyquinoline of 4-(compound 23a)
The chloro-7-hydroxyquinoline (0.72g, 4mmol) of 4-is added, DMF (10ml) and 60%NaH (0.4g in the round-bottomed flask of 100ml, 10mmol), stirring at room temperature 15min, adds 1-monobromethane (20mmol) and continues reaction, TLC tracing detection.React complete, reaction mixture is poured into water, extraction into ethyl acetate, merges organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=200/1), obtain light yellow solid (0.56g, productive rate 67.2%).Mp 70-71℃.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)
The chloro-7-hydroxyquinoline (0.89g, 5mmol) of 4-is added, acetone (40ml) and anhydrous K in the round-bottomed flask of 100ml
2cO
3(2.0g) stirring at room temperature refluxes 15 minutes, adds iodo subsequently and levies butane (20mmol), TLC tracing detection.React complete, underpressure distillation removing acetone, adds 150mL water, extraction into ethyl acetate, 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%).Mp 37-38℃.MS(ESI):m/z(M+H)
+236.1.
1HNMR(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)
The chloro-7-hydroxyquinoline (0.36g, 2mmol) of 4-is added, DMF (10ml) and 60%NaH (0.2g in the round-bottomed flask of 100ml, 5mmol), stirring at room temperature 10min, adds isobutane bromide (3.5mmol) and continues reaction, TLC tracing detection.React complete, reaction mixture is poured into water, extraction into ethyl acetate, merges organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, is 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).
13CNMR(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)
The chloro-7-hydroxyquinoline (0.36g, 2mmol) of 4-is added, DMF (10ml) and 60%NaH (0.2g in the round-bottomed flask of 100ml, 5mmol), stirring at room temperature 10min, adds 1-bromine allyl alkane (3.5mmol) and continues reaction, TLC tracing detection.React complete, reaction mixture is poured into water, extraction into ethyl acetate, merges organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=200/1), obtain light yellow solid (0.37g, productive rate 78.4%).Mp 36-37℃.MS(ESI):m/z(M+H)
+219.8.
1HNMR(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)
The chloro-7-hydroxyquinoline of 4-(0.36g is added in the round-bottomed flask of 100ml, 2mmol), DMF (10ml) and 60%NaH (0.2g, 5mmol), stirring at room temperature 10min, add 1-bromine isopropyl alkane (3.5mmol) and continue reaction, TLC tracing detection, reaction 24h.React complete, reaction mixture is poured into water, extraction into ethyl acetate, merges organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=200/1), obtain light yellow solid (0.28g, productive rate 54.6%).Mp 65-66℃.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)
The chloro-7-hydroxyquinoline of 4-(0.36g is added in the round-bottomed flask of 100ml, 2mmol), DMF (10ml) and 60%NaH (0.2g, 5mmol), stirring at room temperature 10min, add isobutane bromide (3.5mmol) and continue reaction, TLC tracing detection, reaction 8h.React complete, reaction mixture is poured into water, extraction into ethyl acetate, merges organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=200/1), obtain white solid (0.26g, productive rate 88.7%).Mp 57-58℃.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).
13C NMR(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: the preparation chloro-7-benyloxyquinoline of 4-(compound 23g)
The chloro-7-hydroxyquinoline (0.89g, 5mmol) of 4-is added, acetone (40ml), cylite (7.5mmol) and anhydrous K in the round-bottomed flask of 100ml
2cO
3(2.0g), stirring at room temperature is reacted, TLC tracing 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 oil thing, acetone recrystallization, crystallize out, after filtering, alkalization, obtains white solid (0.63g, productive rate 46.8%).Mp 87-88℃.MS(ESI):m/z(M+H)
+269.8.
1H NMR(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)
The chloro-7-hydroxyquinoline of 4-(0.36g is added in the round-bottomed flask of 100ml, 2mmol), DMF (15ml) and 60%NaH (0.2g, 5mmol), stirring at room temperature 10min, then add 4-fluorobenzyl chloride (3.5mmol) and continue reaction, TLC tracing detection.React complete, reaction mixture is poured into water, extraction into ethyl acetate, merge organic phase, add concentrated hydrochloric acid acidifying, dehydrated alcohol band water, obtains yellow oil, re-crystallizing in ethyl acetate, separate out pale yellow crystals, after filtering, alkalization, obtains yellow solid (0.57g, productive rate 89.2%).Mp 98-99℃.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)
The chloro-7-hydroxyquinoline of 4-(0.36g is added in the round-bottomed flask of 100ml, 2mmol), DMF (10ml) and 60%NaH (0.2g, 5mmol), stirring at room temperature 10min, add 1-bromine 2-diphenylphosphino ethane (3.5mmol) and continue reaction, TLC tracing detection.React complete, reaction mixture is poured into water, extraction into ethyl acetate, merges organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=200/1), obtain light yellow solid (0.14g, productive rate 23.3%).Mp 84-85℃.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).
13CNMR(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)
The chloro-7-hydroxyquinoline of 4-(0.45g is added in the round-bottomed flask of 100ml, 2.5mmol) with DMF (15ml), stirring at room temperature 10min, then 60%NaH (0.2g is added, 5mmol), stirring at room temperature 10min, adds 1-bromine 3-phenyl-propane (5mmol) and continues reaction, TLC tracing detection.React complete, reaction mixture is poured into water, extraction into ethyl acetate, 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, use alkalization again after obtaining solid, obtain white crystal (0.03g, productive rate 53.6%).Mp 51-52℃.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:
embodiment 51: preparation N
1
-(7-ethoxyquinoline-4-base)-N
2
, N
2
-diethyl ethane-1,2-diamines (compound 24a)
Compound 23a (0.35g, 1.7mmol) and N, N-diethyl ethylenediamine (4mL) is added, heating reflux reaction 3.5h, TLC tracing detection in 100mL flask.React complete, add about 100mL water, extraction into ethyl acetate, merges organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=100/1), obtain light yellow solid (0.36g, productive rate 73.7%).Mp 84-85℃.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)
23c (0.53g, 2mmol) and N, N-diethyl ethylenediamine (4mL) is added, heating reflux reaction 3.5h, TLC tracing detection in 100mL flask.React complete, add about 100mL water, extraction into ethyl acetate, merges organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=100/1), obtain yellow solid (0.59g, productive rate 85.4%).Mp 92-93℃.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)
23d (0.33g, 1.5mmol) and N, N-diethyl ethylenediamine (4mL) is added, heating reflux reaction 4h, TLC tracing detection in 100mL flask.React complete, add about 100mL water, extraction into ethyl acetate, merges organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=100/1), obtain white solid (0.36g, productive rate 79.8%).Mp yellowoil.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)
23e (0.20g, 0.9mmol) and N, N-diethyl ethylenediamine (4mL) is added, heating reflux reaction 5h, TLC tracing detection in 100mL flask.React complete, add about 100mL water, extraction into ethyl acetate, merges organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=100/1), obtain yellow oil (0.12g, productive rate 10.9%).Mp yellowoil.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-benyloxyquinoline-4-base)-N
2
, N
2
-diethyl ethane-1,2-diamines (compound 24e)
23g (0.12g, 0.4mmol) and N, N-diethyl ethylenediamine (2mL) is added, heating reflux reaction 2.5h, TLC tracing detection in 100mL flask.React complete, add dehydrated alcohol, high-temperature pressure-reduction distillation removing amine, silica gel column chromatography (moving phase: methylene chloride/methanol=100/1), obtains light yellow solid (0.09g, productive rate 57.7%).Mp 93-94℃.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)
23h (0.14g, 0.5mmol) and N, N-diethyl ethylenediamine (4mL) is added, heating reflux reaction 3h, TLC tracing detection in 100mL flask.React complete, add about 100mL water, extraction into ethyl acetate, merges organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=100/1), obtain white solid (0.10g, productive rate 55.9%).Mp 67-68℃.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:
embodiment 57: preparation N
1
-(7-ethoxyquinoline-4-base)-N
2
, N
2
-diethyl propane-1,2-diamines (compound 25a)
23a (0.31g, 1.5mmol) and 3-diethyl amino propylamine (4mL) is added, heating reflux reaction 4.5h, TLC tracing detection in 100mL flask.React complete, add about 100mL water, extraction into ethyl acetate, merges organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=100/1), obtain yellow oil (0.34g, productive rate 75.2%).Mp yellowoil.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)
23d (0.33g, 2mmol) and 3-diethyl amino propylamine (4mL) is added, heating reflux reaction 2.5h, TLC tracing detection in 100mL flask.React complete, add about 100mL water, extraction into ethyl acetate, merges organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=100/1), obtain 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)
23h (0.29g, 1mmol) and 3-diethyl amino propylamine (4mL) is added, heating reflux reaction 1.5h, TLC tracing detection in 100mL flask.React complete, add about 100mL water, extraction into ethyl acetate, merges organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, is evaporated to dry, silica gel column chromatography (moving phase: methylene chloride/methanol=100/1), obtain 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 is tested
Oxoquinoline derivatives of the present invention is as the pharmacological research preparing Therapeutic cancer pharmaceutical use.The compound of all tests is all prepared into hydrochloride form before the test, using antitumor drug-cis-platinum conventional clinically as positive control medicine.
Select Human Laryngeal Cancer Cell (Hep-2) respectively, 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 for growth conditions, be in the cell strain of 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 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 cultivation after 48 hours, discard nutrient solution, every hole adds the RPMI-1640 nutrient solution of 20ul containing 5mg/ml MTT, continue cultivation 4 hours, after careful removing supernatant, every hole adds the DMSO of 200 μ l, and vibrate about 10min dissolution precipitation, OD value is detected, wavelength 490nm subsequently by microplate reader.The cell survival rate under each sample concentration is obtained: survival rate %=sample sets mean OD value/control group mean OD value × 100% with following formula.With cell survival rate to the mapping of drug level logarithm, obtain the IC of each sample by graphing method
50value, the results are shown in following table.
Oxoquinoline derivatives extracorporeal anti-tumor result (IC of the present invention
50, μM
a)
aiC
50value represents the drug level required for growth of tumour cell of suppression 50%.
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 (6)
1. with compound shown in Formula Il
And pharmacologically acceptable salts, wherein
R
4be selected from halogen (such as chlorine, fluorine, bromine, iodine) ,-C
1-6alkyl (such as methyl, ethyl, propyl group, sec.-propyl, normal-butyl) ,-C
1-6alkoxyl group (such as methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy) ,-NH-C
1-6alkyl-N (C
1-4alkyl)
2;
R
7be selected from halogen (such as chlorine, fluorine, bromine, iodine) ,-C
1-6alkyl (such as methyl, ethyl, propyl group, sec.-propyl, normal-butyl) ,-C
1-6alkoxyl group (such as methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy) ,-C
1-6thiazolinyl oxygen base (such as vinyloxy group, propenyloxy group, butenyloxy) ,-C
1-6alkyl-phenyl ,-C
1-6alkyl-halo (such as chlorine, fluorine, bromine, iodo) phenyl.
2. compound shown in following formula III
And pharmacologically acceptable salts, wherein
Y is 1 to 4 group being selected from halogen, and such as Y is 1-2 the group being selected from fluorine, chlorine, bromine, iodine, and such as Y is 2 chlorine.
3., according to the compound of any one of claim 1-2, it is be selected from following compound:
The fluoro-1-methyl of 7--4-oxo-quinoline,
The chloro-1-methyl of 7--4-oxo-quinoline,
The bromo-1-methyl of 7--4-oxo-quinoline,
7-methoxyl group-1-methyl-4-oxo-quinoline,
7-morpholinyl-4 (1H) Oxoquinoline,
1-methyl-7-(4-methylpiperazine-1-yl)-4-Oxoquinoline,
4,7-dichloroquinoline,
The chloro-7-methoxy quinoline of 4-,
7-chloro-4-methoxy quinoline,
The chloro-4-ethoxyquinoline of 7-,
7-chloro-4-isopropoxy 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-
4-chloro-7-n-butoxy quinoline
The positive hexyloxy quinoline of the chloro-7-of 4-
4-chloro-7-allyloxy quinoline
4-chloro-7-isopropoxy quinoline
4-chloro-7-isobutoxy quinoline
The chloro-7-benyloxyquinoline of 4-
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-base)-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-benyloxyquinoline-4-base)-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-base)-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.
4. the pharmaceutical applications of compound or its pharmacologically acceptable salts described in any one of claim 1-2, namely can be used for the purposes of preventing or treating in the medicine of tumour in preparation.
5. purposes according to claim 4, 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.
6. a pharmaceutical composition, wherein containing compound or its pharmacologically acceptable salts described in any one of at least one claim 1-2, and optional pharmaceutical carrier or vehicle.
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