CN101255138A - Quinazoline ketone anticoccidial medicament - Google Patents
Quinazoline ketone anticoccidial medicament Download PDFInfo
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- CN101255138A CN101255138A CNA2008100442285A CN200810044228A CN101255138A CN 101255138 A CN101255138 A CN 101255138A CN A2008100442285 A CNA2008100442285 A CN A2008100442285A CN 200810044228 A CN200810044228 A CN 200810044228A CN 101255138 A CN101255138 A CN 101255138A
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- ketone
- bromo
- quinazoline
- phenyl
- methoxy
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Abstract
A series quinazoline ketones compounds with halogeno- quinazolone ring, propa-2-ketone group or buta-2ketone group or guaiacyl are synthesized by condensing halogeno- quinazoline-4-ketone and bromium-3-(2-methoxylbenz)propa-2-ketone or 1-bromium-4-(2-methoxyl benz )buta-2-ketone at 70-80 degree C for 1-7h under existing condition of sodium hydride, potassium carbonate, potassium tert butoxide, sodium methoxide or sodium ethylate using DMSO or DMF as a dissolvent. Proved by bioactivity experiment, the compounds have anticoccidial activity.
Description
Invention field
The invention belongs to technical field of medicine synthesis, be specifically related to quinazoline ketone anticoccidial medicament.
Background technology
Changshan is a kind of Chinese medicine that malaria is used for the treatment of, bibliographical information also have anti-chicken coccidia effect (Chinese animal doctor's science and technology, 2000, NO 05,37; Support fowl and poultry disease prevention and control, 2006, NO 09,10), but have side effects (J.Med.Chem.1970, Vol 13,867) such as diarrhoea and vomiting simultaneously.Chinese chemist Zhao Cheng felicitys in 1949 etc. have confirmed that its effective constituent is febrifugin(e) (febrifugine) (1) and NSC 290495 (isofebrifugine) (2) (J.Am.Chem.Soc.1948,70 (5): 1765), they all are quinazolinone type alkaloids from chemical structure, molecular formula: C
16H
19N
3O
3
Halofuginone hydrobromide (halofuginone) (3) chemical name that uses as anticoccidial drug in aquaculture is at present: 7-bromo-6-chloro-3-[3-(3-hydroxyl-2-sends the pyridine base)-2-oxygen propyl group (acetonyl)]-4-(3H)-quinazolinone, has unique effect aspect the anti-coccidiosis of domestic fowls, similar anticoccidial drug with other compares that to have little, the anti-medicine persistence of consumption good and toxicity is little and security characteristics (feed research feed research preferably, 2005, NO6,35).American cyanamide (Cynaamid) company (USP3320124,2775597) and Shanghai Yinnuo Biochemical Science and Technology Co., Ltd. (CN1651428A) are respectively to its synthetic relevant report of having carried out.
Halofuginone hydrobromide is by 7-bromo-6-chloro-quinazoline ketone and two important intermediates of piperidyl bromo ketone, through making (reaction formula one) behind condensation and the demethoxylation.
The wherein synthetic route of 7-bromo-6 chloro-quinazoline ketone such as reaction formula two, and the synthetic route of piperidyl bromo ketone such as reaction formula three (Yangzhou University's journal (agricultural and life science version), 1988, NO 04,17; 1984, NO 02,1).
From above-mentioned reaction formula as can be seen, the synthetic of this compound needed for 18 steps altogether, and long synthetic route causes the on the high side of this compound, influences the use of product.In order to seek the lower anticoccidial drug of cost, we utilize 1-bromo-3-(2-p-methoxy-phenyl) third-2-ketone to be connected with the halo quinazolinone with 1-bromo-4-(2-p-methoxy-phenyl) fourth-2-ketone, the synthetic new quinazolinones anticoccidial drug of a class.
Goal of the invention
The present invention designs and synthesizes quinazoline ketone anticoccidial medicament, and this compounds can be used for prevention and treatment coccidiosis of chicken.
Summary of the invention
The present invention keeps the quinazolinone part in the febrifugin(e) compounds, utilize 1-bromo-3-(2-p-methoxy-phenyl) third-2-ketone and 1-bromo-4-(2-p-methoxy-phenyl) fourth-2-ketone, be connected with the halo quinazolinone, synthetic substituted quinazoline analog derivative with coccidiostat activity, its general structure is as follows:
n＝1，2
a.R
1＝H，R
2＝H，R
3＝H； b.R
1＝Cl，R
2＝H，R
3＝H；?c.R
1＝Br，R
2＝H，R
3＝H；
d.R
1＝I，R
2＝H，R
3＝H； e.R
1＝Cl，R
2＝H，R
3＝Br；f.R
1＝Cl，R
2＝H，R
3＝Cl；
g.R
1＝Br，R
2＝H，R
3＝Br；h.R
1＝I，R
2＝H，R
3＝Br；?i.R
1＝Br，R
2＝H，R
3＝Cl；
j.R
1＝F，R
2＝H，R
3＝Br；?k.R
1＝F，R
2＝H，R
3＝H；l.R
1＝H，R
2＝H，R
3＝Cl.
The constitutional features of this compounds is a class novel quinazoline quinoline ketone derivatives that contains halo quinazolinone ring, third-2-ketone group or fourth-2-ketone group and guaiacyl.They structurally with halofuginone hydrobromide compare mainly contain 2 different: (1) utilizes phenyl ring to replace the piperidine ring in the halofuginone hydrobromide; (2) utilize methoxyl group to replace the hydroxyl in the halofuginone hydrobromide.Compare synthetic this compounds with halofuginone hydrobromide and have the step weak point, the characteristics that cost is low utilize methoxyl group to replace hydroxyl to guarantee the stability of this type of change thing again simultaneously, help storing and using.
The present invention is with halo quinazoline-4-one and 1-bromo-3-(2-p-methoxy-phenyl) third-2-ketone or 1-bromo-4-(2-p-methoxy-phenyl) fourth-2-ketone is raw material, with sodium hydride, salt of wormwood, potassium tert.-butoxide, sodium methylate or sodium ethylate is alkaline reagents, methyl-sulphoxide (DMSO) or N, dinethylformamide (DMF) is a solvent, synthetic route such as reaction formula four:
The synthetic method of novel quinazoline quinoline ketone anticoccidial drug is: with halo quinazoline-4-one and 1-bromo-3-(2-p-methoxy-phenyl) third-2-ketone or 1-bromo-4-(2-p-methoxy-phenyl) fourth-2-ketone in the presence of alkali, with DMSO or DMF is that solvent carries out condensation 1～7h at 70～80 ℃, add the water suction filtration afterwards and (use ethyl acetate extraction, organic phase is through anhydrous sodium sulfate drying, remove and desolvate), promptly obtain target compound through the dehydrated alcohol recrystallization.
The invention effect
A plurality of new quianzolinones add in feed in the ratio of 9mg/kg through Agricultural University Of South China veterinary college parasite research department, carry out anti-chicken coccidia activity experiment, the result shows that this compounds has anti-chicken coccidia effect, can be used as anticoccidial drug and uses.Wherein the anti-worm index of asking of target product is respectively 147.1 and 134.5 among the embodiment 1 and 2.
Embodiment 1:6-bromo-3-[4-(2-p-methoxy-phenyl)-2-butanone base]-4-(3H)-quinazolinone synthetic
In the 50ml there-necked flask, add 2.00g (0.0089mol) 6-bromo-quinazoline-4-one, 1.0gKI, 0.43g (0.0178mol) NaH, 30ml DMSO, be warming up to 75 ℃, stir the mixed solution that drips 4.57g (0.0178mol) 1-bromo-4-(2-p-methoxy-phenyl) fourth-2-ketone and 5ml DMSO down, stirring reaction 1 hour, cooling adds 100ml water, uses ethyl acetate extraction, and organic phase is through anhydrous sodium sulfate drying, remove and desolvate, the gained solid gets white cotton-shaped solid through the dehydrated alcohol recrystallization, dry 1.86g, the productive rate 52.1% of getting.
1HNMR (CDCl
3, 400MHz) d:8.41 (d, J=2.4Hz, 1H), 7.85 (m, 1H), 7.74 (s, 1H), 7.60 (q, J
1=8.0Hz, J
2=8.4Hz, 1H), 7.21 (dd, J
1=8.0Hz, J
2=8.0Hz 1H), 7.15 (dd, J
1=7.2Hz, J
2=7.6Hz, 1H), 6.90 (q, J
1=7.6Hz, J
2=8.4Hz, 2H), 4.73 (s, 2H), 3.84 (s, 3H), 2.98 (d, J=6.4Hz, 2H), 2.92 (t, J
1=6.4Hz, J
2=7.2Hz, 2H); IR (KBr) v
Max: 3409,3072,2931,2825,1725,1691,1610,1493,750cm
-1MS m/z (%): positive ion detects: 402.1 (M+1), 403.1 (M+2), 404.1 (M+3).
Embodiment 2:8-bromo-6-chloro-3-[4-(2-p-methoxy-phenyl)-2-butanone base]-4-(3H)-quinazolinone synthetic
In the 50ml there-necked flask, add 2.31g (0.0089mol) 8-bromo-6-chloro-quinazoline-4-one, 1.0gKI, 0.86g (0.0178mol) NaH, 30ml DMSO, be warming up to 75 ℃, stir the mixed solution that drips 4.57g (0.0178mol) 1-bromo-4-(2-p-methoxy-phenyl) fourth-2-ketone and 5ml DMSO down, stirring reaction 1 hour, cooling adds 100ml water, uses ethyl acetate extraction, and organic phase is through anhydrous sodium sulfate drying, remove and desolvate, the gained solid gets white cotton-shaped solid through the dehydrated alcohol recrystallization, dry 2.21g, the productive rate 57.1% of getting.
1HNMR (CDCl
3, 400MHz) δ: 8.15 (d, J
1=2.0Hz, 1H), 7.95 (d, J
1=2.4Hz, 1H), 7.78 (s, 1H), 7.15 (dd, J
1=8.0Hz, J
2=7.6Hz, 1H), 7.06 (d, J
1=7.2Hz), 6.82 (q, J
1=7.6Hz, J
2=8.0Hz, 2H), 4.60 (s, 2H), 3.78 (s, 3H), 2.91 (t, J
1=7.2Hz, J
2=6.8Hz, 2H), 2.83 (q, J
1=6.8Hz, J
2=7.2Hz, 2H); IR (KBr) v
Max: 3437,3073,2961,2927,1725,1695,1613,1493,748cm
-1Positive ion detects: 436.1 (M+1), 437.0 (M+2), 438.1 (M+3).
Claims (2)
1. a class novel quinazoline quinoline ketone anticoccidial drug, constitutional features is a class novel quinazoline quinoline ketone derivatives that contains halo quinazolinone ring, third-2-ketone group or fourth-2-ketone group and guaiacyl, its structure can be used following general formula:
n＝1，2
a.R
1＝H，R
2＝H，R
3＝H； b.R
1＝Cl，R
2＝H，R
3＝H；?c.R
1＝Br，R
2＝H，R
3＝H；
d.R
1＝I，R
2＝H，R
3＝H； e.R
1＝Cl，R
2＝H，R
3＝Br；f.R
1＝Cl，R
2＝H，R
3＝Cl；
g.R
1＝Br，R
2＝H，R
3＝Br；h.R
1＝I，R
2＝H，R
3＝Br；?i.R
1＝Br，R
2＝H，R
3＝Cl；
j.R
1＝F，R
2＝H，R
3＝Br；?k.R
1＝F，R
2＝H，R
3＝H； l.R
1＝H，R
2＝H，R
3＝Cl.
2. the synthetic method of a class novel quinazoline quinoline ketone anticoccidial drug according to claim 1 is: with halo quinazoline-4-one and 1-bromo-3-(2-p-methoxy-phenyl) third-2-ketone or 1-bromo-4-(2-p-methoxy-phenyl) fourth-2-ketone in the presence of sodium hydride, salt of wormwood, potassium tert.-butoxide, sodium methylate or sodium ethylate, with DMSO or DMF is that solvent carries out condensation 1～7h at 70～80 ℃, add the water suction filtration afterwards and (use ethyl acetate extraction, organic phase is through anhydrous sodium sulfate drying, remove and desolvate), promptly obtain target compound through the dehydrated alcohol recrystallization.
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|---|---|---|---|
| CNA2008100442285A CN101255138A (en) | 2008-04-17 | 2008-04-17 | Quinazoline ketone anticoccidial medicament |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103275063A (en) * | 2013-06-19 | 2013-09-04 | 重庆威鹏药业有限公司 | Method for preparing halofuginone hydrobromide |
| CN105152974A (en) * | 2015-09-18 | 2015-12-16 | 深圳朗启药业有限公司 | Drug intermediate of halofuginone and synthesis method of halofuginone parent nucleus |
| CN111303055A (en) * | 2020-03-05 | 2020-06-19 | 中国农业科学院兰州畜牧与兽药研究所 | Quinazoline derivative and preparation method and application thereof |
-
2008
- 2008-04-17 CN CNA2008100442285A patent/CN101255138A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103275063A (en) * | 2013-06-19 | 2013-09-04 | 重庆威鹏药业有限公司 | Method for preparing halofuginone hydrobromide |
| CN105152974A (en) * | 2015-09-18 | 2015-12-16 | 深圳朗启药业有限公司 | Drug intermediate of halofuginone and synthesis method of halofuginone parent nucleus |
| CN111303055A (en) * | 2020-03-05 | 2020-06-19 | 中国农业科学院兰州畜牧与兽药研究所 | Quinazoline derivative and preparation method and application thereof |
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Open date: 20080903 |