CN1314351A - Process for synthesizing quinazolone and quinazolone compound with anti-cancer function - Google Patents
Process for synthesizing quinazolone and quinazolone compound with anti-cancer function Download PDFInfo
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- CN1314351A CN1314351A CN01106796A CN01106796A CN1314351A CN 1314351 A CN1314351 A CN 1314351A CN 01106796 A CN01106796 A CN 01106796A CN 01106796 A CN01106796 A CN 01106796A CN 1314351 A CN1314351 A CN 1314351A
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- Prior art keywords
- quinazolinone
- quinazolone
- general formula
- reaction
- furfuryl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
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Abstract
In the present invention, quinazolone is synthesized by using anthranilic acid derivative as material and through adding excessive formamide, dropping phosphorus oxychloride as dewatering agent and reaction at 0-150 deg.c. The quinazolone compound with anticancer function is 6,7-disubsdtituent-1-furfuryl-4(1H) quinazolone. The present invention adds dewatering agent on the basis of V.Niementowski reaction to make reaction condition more moderate.
Description
The present invention relates to a kind of quinazolinone synthetic method and have a class quinazolinones of antitumous effect.
Just reported the method [v.Niementowski, J.prakt.chem., [2] 51,564 (1895)] of synthetic quinazolinone as far back as v.Niementowski in 1895, reaction formula is:
The shortcoming of this reaction is the temperature of reaction height, and when on the phenyl ring or on the amino substituting group being arranged, it is higher to react desired temperature, and reaction can not be carried out in some cases, for example:
The objective of the invention is the class quinazolinones that proposes a kind of quinazolinone synthetic method and have antitumous effect.
Quinazolinone synthetic method of the present invention,, join in the excessive methane amide as raw material with the anthranilic acid derivative shown in compound general formula (1) or (2), make material dissolution, stir down and drip excessive phosphorus oxychloride as dewatering agent, temperature of reaction is 0 ℃～150 ℃, and reaction solution is poured in the frozen water, treats that precipitation folds fully, filter, recrystallization gets quinazolinone
Compound general formula (1) is:
Compound general formula (2) is:
Reaction formula is
R
1, R
2, R
3Can be hydrogen, electrophilic and electron-donating group, as nitro, sulfoamido, halogen, itrile group, methyl, methoxyl group, R
4Can be alkyl, aromatic base, the furfuryl of C1～C4.
Class quinazolinones with antitumous effect is 6,7-is disubstituted-and 1-furfuryl-4 (1H) quinazolinone, the general formula of this compounds (3) is as follows:
R
5Can be-F-Cl ,-Br ,-I ,-CF
3,-CN ,-N (CN)
2,-C (CN)
3, R
6Can be-SO
2NH
2,-COOH ,-SO
3H ,-PO (OH) NH
2,-PO (OH) OEt ,-CONHCN.
The present invention can add dewatering agent with having substituent anthranilic acid on the phenyl ring or on the amino as the synthetic quinazolinone of raw material on the basis of v.Niementowski reaction, can make reaction conditions comparatively gentle.The present invention proposes and has synthesized the quinazolinones that a class has antitumous effect.
Embodiment 1:
The synthetic method of 1-furfuryl-6-sulfoamido-7-chloro-4-(1H) quinazolinone: 2-furylamine base-4-chloro-5 sulfamoylbenzoic acids 10 grams are dissolved in 60 milliliters of methane amides, are cooled to 0 ℃, drip POCl down in stirring
3(phosphorus oxychloride) 15 milliliters drip to finish, and continues to stir 40 minutes, and reaction solution is poured in the frozen water, waits precipitation to fold fully, filter, crude product 8 grams, promptly get pure product with 15% methane amide aqueous solution recrystallization, fusing point mp.208 ℃～210 ℃.
Embodiment 2:
The synthetic method of 6-nitro-4 (3H) quinazolinone: get 2-amino-5-nitrobenzoic acid 20 grams and join in 150 milliliters of methane amides, 85 ℃ of heating in water bath dissolve fully to raw material, drip 40 milliliters of phosphorus oxychloride under high degree of agitation, temperature is controlled at 85 ℃～90 ℃, drips and finishes, continue to stir 30 minutes, cool to room temperature is poured reaction solution in the frozen water into, fold fully Deng precipitation, filter, frozen water washs to such an extent that crude product 18.6 restrains productive rate 60.4%, the water recrystallization, fusing point mp.275 ℃～276 ℃.
Embodiment 3:
The antitumous effect and the acute toxicity test of 1-furfuryl-6-sulfoamido-7-chloro-4-(1H) quinazolinone:
(1) antitumous effect test is inoculated in 96 well culture plates with the SMMC-7721 liver cancer cell, every hole 10
3～10
4Individual cell, every pore volume 200 microlitres, nutrient solution is the RPMI1640 nutrient solution that contains 10% foetal calf serum, after treating cell attachment, discard nutrient solution, add nutrient solution 200 microlitres that contain medicine 1-furfuryl-6-sulfoamido-7-chloro-4-(1H) quinazolinone, per 6 holes are a drug dose group, and the drug dose scope is 0.001 μ mol/l～50 μ mol/l.And establish blank, and culture plate is moved in the carbonic acid gas tank, at 37 ℃, 5%CO
2And under the saturated humidity condition, cultivate after 3 days, every hole adds MTT solution (5mg/ml) 20 microlitres, and 37 ℃ were continued to hatch 4 hours, stops cultivating, the careful suction abandoned culture supernatant in the hole, every hole adds 150 microlitre DMSO (dimethyl sulfoxide (DMSO)), vibrates 10 minutes, selects 490nm, on enzyme-linked immunosorbent assay instrument, measure each hole absorbance value, the record result.1-furfuryl-6-sulfoamido-7-chloro-4-(1H) quinazolinone is to the IC of SMMC-7721 as calculated
50Be 15 μ mol/l.Cell is all dead during 40 μ mol/l.
(2) acute toxicity test, 50 of 18～22 gram Kunming mouses are divided into 5 groups at random, every group 10, give 50 mouse with the disposable respectively filling stomach of the capacity of 0.2ml/10g, dosage is respectively 0.8mg/Kg, 8mg/Kg, 80mg/Kg, 320mg/Kg, 800mg/Kg, as a result, when giving dosage and reach 800mg/Kg, mouse does not also see death, all mouse visual inspections after necrotomy, main organs such as the heart, liver, spleen, lung, kidney are not seen obvious pathological change.
Referring to 51 pages of the chief editor of Nanjing pharmaceutical college first versions " pharmaceutical chemistry " in August, 1978, according to the bioisostere principle, some atom or group in biologically active or metabolite, when being arranged same or analogous atom or group and replace (exchange), still can keep original activity (relative) by its electronic number and electronics.As Li Zhenghua chief editor " pharmaceutical chemistry " third edition, People's Health Publisher, 1993,97～98 pages, exemplified some and had the bioisostere phenomenon, the group that can change mutually has among the present invention in 1-furfuryl-6-sulfoamido-7-chloro-4-(1H) quinazolinone of antitumous effect-SO
2NH
2Substituting group can exchange with following groups :-COOH ,-SO
3H ,-PO (OH) NH
2,-PO (OH) OEt ,-CONHCN, wherein-the Cl substituting group can exchange with following groups :-F ,-Br ,-I ,-CF
3,-CN ,-N (CN)
2,-C (CN)
3, therefore 6,7-is disubstituted-and 1-furfuryl-4 (1H) quinazolinone should have antitumous effect, and the general formula of this compounds (3) is as follows:
R
5Can be-F-Cl ,-Br ,-I ,-CF
3,-CN ,-N (CN)
2,-C (CN)
3, R
6Can be-SO
2NH
2,-COOH ,-SO
3H ,-PO (OH) NH
2,-PO (OH) OEt ,-CONHCN.
Claims (2)
1, quinazolinone synthetic method,, join in the excessive methane amide as raw material with the anthranilic acid derivative shown in compound general formula (1) or (2), make material dissolution, it is characterized in that: stir down and drip excessive phosphorus oxychloride as dewatering agent, temperature of reaction is 0 ℃～150 ℃, and reaction solution is poured in the frozen water, treats that precipitation folds fully, filter, recrystallization gets quinazolinone
Compound general formula (1) is:
Compound general formula (2) is:
Reaction formula is
R wherein
1, R
2, R
3Can be hydrogen, electrophilic and electron-donating group, as nitro, sulfoamido, halogen, itrile group, methyl, methoxyl group, R
4Can be alkyl, aromatic base, the furfuryl of C1～C4.
2, have a class quinazolinones of antitumous effect, it is characterized in that: this compounds is 6,7-is disubstituted-and 1-furfuryl-4 (1H) quinazolinone, the general formula of this compounds (3) is as follows:
R
5Can be-F-Cl ,-Br ,-I ,-CF
3,-CN ,-N (CN)
2,-C (CN)
3, R
6Can be-SO
2NH
2,-COOH ,-SO
3H ,-PO (OH) NH
2,-PO (OH) OEt ,-CONHCN.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN01106796A CN1314351A (en) | 2001-03-22 | 2001-03-22 | Process for synthesizing quinazolone and quinazolone compound with anti-cancer function |
| PCT/CN2002/000185 WO2002096889A1 (en) | 2001-03-22 | 2002-03-22 | Quinazolinone compound and method of preparation and use thereof in preparing anticancerous medicament |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN01106796A CN1314351A (en) | 2001-03-22 | 2001-03-22 | Process for synthesizing quinazolone and quinazolone compound with anti-cancer function |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1314351A true CN1314351A (en) | 2001-09-26 |
Family
ID=4655767
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN01106796A Pending CN1314351A (en) | 2001-03-22 | 2001-03-22 | Process for synthesizing quinazolone and quinazolone compound with anti-cancer function |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1314351A (en) |
| WO (1) | WO2002096889A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102757661A (en) * | 2012-08-03 | 2012-10-31 | 康爱特维迅（蓬莱）化学有限公司 | Preparation method and application of 4-chloro-2-substituted quinazolone |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008052190A2 (en) | 2006-10-26 | 2008-05-02 | Flynn Gary A | Aquaporin modulators and methods of using them for the treatment of edema and fluid imbalance |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3816631A (en) * | 1972-10-12 | 1974-06-11 | Merck & Co Inc | 6-sulfamoyl-7-substituted-4(3h)-quinazolinones for decreasing uric acid concentration |
| US3825542A (en) * | 1972-10-12 | 1974-07-23 | Merck & Co Inc | 2-hetro substituted 4(3h)-quinazolinones |
| RU2214405C2 (en) * | 1998-02-18 | 2003-10-20 | НьюроСёрч А/С | Novel compounds and their application as positive modulators of ampa-receptors |
-
2001
- 2001-03-22 CN CN01106796A patent/CN1314351A/en active Pending
-
2002
- 2002-03-22 WO PCT/CN2002/000185 patent/WO2002096889A1/en not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102757661A (en) * | 2012-08-03 | 2012-10-31 | 康爱特维迅（蓬莱）化学有限公司 | Preparation method and application of 4-chloro-2-substituted quinazolone |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2002096889A1 (en) | 2002-12-05 |
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Owner name: QIU LIEQUN Free format text: FORMER OWNER: LIU ZHIHONG Effective date: 20020906 |
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| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20020906 Applicant after: Qiu Liequn Address before: 710038 Shaanxi city in Xi'an Province, northwest five cotton factory middle school Zhang Xiaoqing Applicant before: Liu Zhihong |
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| C20 | Patent right or utility model deemed to be abandoned or is abandoned |