CN109897008A - - 4 (3H)-Quinazol derivative of 2- benzoyl -6- amino and its preparation method and use - Google Patents
- 4 (3H)-Quinazol derivative of 2- benzoyl -6- amino and its preparation method and use Download PDFInfo
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- CN109897008A CN109897008A CN201910212680.6A CN201910212680A CN109897008A CN 109897008 A CN109897008 A CN 109897008A CN 201910212680 A CN201910212680 A CN 201910212680A CN 109897008 A CN109897008 A CN 109897008A
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Abstract
Invention is related to a kind of -4 (3H)-Quinazol derivative of 2- benzoyl -6- amino and its preparation method and use, belongs to technical field of pharmaceuticals, is related to logical formula (I), R1, R2, R3, R4For different substituent groups.The invention discloses the inhibitory activity of the inhibitory activity and phosphodiesterase 5 of these compound structures and synthetic method and acetylcholinesterase, can be developed further into treat the drug of Alzheimer's disease.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, be related to a kind of -4 (3H)-Quinazol derivative of 2- benzoyl -6- amino with
And its synthetic method and application medically.
Technical background
Alzheimer's disease (Alzheimer ' s disease, AD) is a kind of nerve of the progress sexual development of onset concealment
System degenerative disease.It is mainly shown as the psychoneurals such as gradual memory obstacle, decrease of cognitive function, behavior and aphasis
Symptom seriously affects social, work and viability.The pathogenesis of AD is very complicated, currently, the whole world has nearly 30,000,000 AD to suffer from
Person, AD are huge burdens for patient, family and country.Therefore the drug for diagnosing, preventing and treating AD is researched and developed
It is one of the ultimate challenge that medical chemistry man faces now.
The therapeutic agent of AD is broadly divided into two classes at present: acetylcholinesterase inhibitor and N-methyl-D-aspartate by
Body (nmda receptor) antagonist.Acetylcholinesterase inhibitor mainly has: Tacrine, donepezil, galanthamine, benefit cut down this
Bright and huperzine.The nmda receptor antagonist listed has Memantine.Since the pathogenesis of AD is very complicated, single target spot
Drug is difficult to fight AD well, and pays no attention to there are therapeutic effect and think of the problems such as side effect is obvious, therefore the drug of the disease is opened
Hair needs to consider multiple target point treatment method.
2003,2004/054985 A1 of WO disclosed the synthetic method and conduct of 4 (3H)-Quinazol derivatives
The purposes of monoamine oxidase selective depressant.2006, Chinese patent CN1720238A disclosed a kind of neural activity chemical combination
Object and preparation method thereof and purposes as drug or veterinary drug, it is disclosed that 8- hydroxyl -4 (3H)-quinazolinone, and carry out
I clinical trial phase of AD is treated, discovery can reduce the A β in blood plasma.2009, Chinese patent CN101357905A was disclosed
The preparation method of 4- [the chloro- 4- of 3- (3- fluorine benzyloxy)-phenylamino] -6- substituted-amino quinazoline derivant.Above-mentioned three correlations
Although disclosing 4 (3H)-Quinazol derivatives or quinazoline derivant in the stronger patent of property, it is not directed to 2- benzoyl
- 4 (3H)-quinazolinone analog derivative of base -6- amino, is also not directed to the inhibitory activity of its acetylcholinesterase.
The invention discloses a kind of -4 (3H)-quinazolinone analog derivative of 2- benzoyl -6- amino and its synthesis sides
Method and purposes have three-stage aromatic structure, have good inhibitor activity to acetylcholinesterase and phosphodiesterase 5,
It can be further developed as the drug for the treatment of Alzheimer's disease.
Summary of the invention
The object of the present invention is to provide a series of with good acetylcholinesterase and phosphodiesterase 5 inhibitory activity
- 4 (3H)-Quinazol derivative of 2- benzoyl -6- amino, specifically the 2- benzoyl -6- ammonia of three-stage aromatic structure
Base -4 (3H)-Quinazol derivative.
- 4 (3H)-Quinazol derivative of 2- benzoyl -6- amino of three-stage aromatic structure of the invention has logical
The structure of formula (I).
R1Selected from unsubstituted monosubstituted or disubstituted benzenesulfonyl, pyridine sulfonyl sulfonyl base, pyrimidine sulfonyl base, triazine sulphonyl
Base, pyrroles's sulfonyl, furans sulfonyl, thiophen sulfuryl, imidazoles sulfonyl, thiazole sulfonyl, oxazole sulfonyl, piperazine acetyl
Base, piperidines acetyl group, morpholine acetyl group, hexamethylene acetyl group, substituent group therein be independently selected from H, F, Cl, Br, OH,
NO2、CN、CF3、OCF3、SCF3、SH、NH2、C1-5Alkyl, OC1-5Alkyl, SC1-5Alkyl, NHC1-5Alkyl, N (C1-5Alkyl)2、
OCOC0-5Alkyl, SCOC0-5Alkyl, NHCOC0-5Alkyl；
R2、R3And R4To be independently selected from H, F, Cl, Br, OH, NO2、CN、CF3、OCF3、SCF3、SH、NH2、C1-5Alkane
Base, OC1-5Alkyl, SC1-5Alkyl, NHC1-5Alkyl, N (C1-5Alkyl)2、OCOC0-5Alkyl, SCOC0-5Alkyl, NHCOC0-5Alkyl.
All kinds of groups in formula (I) can be replaced with bioisostere or homologous series group.
Another object of the present invention is to provide the above-mentioned 2- benzoyl -6- amino -4 with three stage structure
The preparation method of (3H)-Quinazol derivative.
The preparation method of -4 (3H)-Quinazol derivative of 2- benzoyl -6- amino of the invention, it is characterized in that using
2- amino -5- nitrobenzoic acid is raw material, generates 2- amino -5- nitrobenzamide with thionyl chloride and ammonium hydroxide, then with substitution
The female ring that cyclization reaction generates 4 (3H)-quinazolinones occurs for acetophenone, obtains phase with all kinds of acyl chloride reactions after nitro restores
The compound answered.
Specific reaction step is as follows:
Compound according to the present invention is studied by Pharmacodynamic, and the compound has good second as the result is shown
Acetylcholinesterase and phosphodiesterase 5 inhibitory activity can further develop the drug for becoming treatment Alzheimer disease.
Specific implementation method
Following embodiment is intended to illustrate invention rather than limitation of the invention further.
Embodiment 1
- 4 (3H)-quinazolinone (I of 2- (4- methyl benzoyl) -6- tolysulfonyl amino1) preparation
(1) preparation of 2- amino -5- nitrobenzamide
9.1g 2- amino -5- nitrobenzoic acid is added in dry 100mL round-bottomed flask, is slowly added dropwise
10mLSOCl2, add 3 drop DMF and make catalyst, back flow reaction 3h at 65 DEG C, revolving removes extra SOCl2.By 3mL ammonium hydroxide
It is dissolved in 16mL dichloroethanes, adds 5.8g sodium carbonate, maintain 10-15 DEG C of temperature, the acyl containing above-mentioned preparation is slowly added dropwise
The dichloroethane solution of chlorine is warming up to 25 DEG C of reaction 3h after 1h.It filters, filtrate uses dilute hydrochloric acid (2 × 50mL), 10% respectively
NaHCO3(2 × 50mL), saturation NaCl (2 × 50mL) and water (2 × 50mL) washing are depressurized dense after anhydrous magnesium sulfate drying
Contract to obtain product 2- amino -5- nitrobenzamide 5.9g, yield 65%.
(2) preparation of 2- (4- methyl benzoyl) -6- nitro -4 (3H)-quinazolinone
3mL melilotal is dissolved in 10mL DMSO, 2.8g iodine is slowly added to, 3.6g 2- is added dropwise under stirring at normal temperature
Amino -5- nitrobenzamide is dissolved in the solution of 20mL DMSO, 110 DEG C of reaction 2h.Reaction system is added in 150mL water, with (3
× 60mL) ethyl acetate extraction, then NaHSO is saturated with (2 × 40mL)3Solution washing removes iodine, uses anhydrous magnesium sulfate after washing
Dry, evaporating solvent under reduced pressure, residue obtains 2- (4- through chromatography post separation (eluant, eluent: ethyl acetate: petroleum ether=1:2)
Methyl benzoyl) -6- nitro -4 (3H)-quinazolinone 4.2g, yield 68%, 186-188 DEG C of fusing point.
(3) preparation of 2- (4- methyl benzoyl) -6- amino -4 (3H)-quinazolinone
4.0g 2- (4- methyl benzoyl) -6- nitro -4 (3H)-quinazolinone is dissolved in the mixed of 25mL water and 50mL ethyl alcohol
It closes in liquid, lower addition 6.0g iron powder is stirred at room temperature, 8.0mL concentrated hydrochloric acid is then slowly added dropwise.Continue to be stirred to react 4h at room temperature, instead
PH to 11 should be adjusted with lye after the completion, filtered, filtrate decompression concentration, ethyl acetate solution extraction, with the NaCl solution of saturation
Washing 3 times, anhydrous magnesium sulfate is dry, and evaporating solvent under reduced pressure obtains 2- (4- methyl benzoyl) -6- amino -4 (3H)-quinazoline
Ketone 2.6g, yield 71%.
(4) -4 (3H)-quinazolinone (I of 2- (4- methyl benzoyl) -6- tolysulfonyl amino1) preparation
1.0g2- (4- methyl benzoyl) -6- amino -4 (3H)-quinazolinone is dissolved in the anhydrous chloroform of 15mL, room
Temperature is lower to be added 0.8mL triethylamine, the solution that 0.68g paratoluensulfonyl chloride is dissolved in 15mL chloroform is added dropwise after 0.5h, at room temperature
Continue to be stirred to react 4h.Isometric 26% ammonium hydroxide quenching reaction is added.Split-phase, water phase are extracted with chloroform (2 × 50mL), are closed
And chloroform phase, saturated salt solution are washed to neutrality.Solvent is evaporated off through drying in organic phase, and residue chromatographed column through column and (washes
De- agent: ethyl acetate: petroleum ether=1:3) obtain product (I1) 1.05g, yield 68%, fusing point is 242-245 DEG C.
Embodiment 2
2- (4- methyl benzoyl) -6- [2- (N methyl piperazine base) acetylamino] -4 (3H)-quinazolinone (I2)
Preparation
(1) preparation of 2- (4- methyl benzoyl) -6- (2- chloro acetylamino) -4 (3H)-quinazolinone
0.63g 2- (4- methyl benzoyl) -6- amino -4 (3H)-quinazolinone is dissolved in the anhydrous chloroform of 20mL,
0.5mL triethylamine is added at room temperature, the solution that 0.2mL chloracetyl chloride is dissolved in 15mL chloroform is then added dropwise, continues at room temperature
It is stirred to react 4h.Isometric 26% ammonium hydroxide quenching reaction is added.Split-phase, water phase are extracted with chloroform (2 × 50mL), merge three
Chloromethanes phase, saturated salt solution are washed to neutrality.For organic phase after drying, filtering, solvent evaporated, residue chromatographed column through column
(eluant, eluent: ethyl acetate: petroleum ether=1:3) obtains 2- (4- methyl benzoyl) -6- (2- chloro acetylamino) -4 (3H) -
Quinazolinone 0.49g, yield 61%.
(2) 2- (4- methyl benzoyl) -6- [2- (N methyl piperazine base) acetylamino] -4 (3H)-quinazolinone (I2)
Preparation
0.2mL N methyl piperazine is dissolved in 10mL ethyl acetate, and 0.38g K is added at room temperature2CO3, it is added dropwise after 0.5h
0.49g2- (4- methyl benzoyl) -6- (2- chloro acetylamino) -4 (3H)-quinazolinone is dissolved in the molten of 15mL ethyl acetate
Liquid, 65 DEG C of back flow reaction 4h.20mL water is added into reaction system, then is extracted with (3 × 30mL) ethyl acetate, merges organic
Phase, after anhydrous magnesium sulfate is dry, evaporating solvent under reduced pressure, residue through column chromatographed column (eluant, eluent: ethyl acetate: petroleum ether=
1:4) obtain product (I2) 491mg, yield 64%, fusing point is 186-189 DEG C.
Embodiment 3
- 4 (3H)-quinazolinone (I of 2- (3- trifluoromethylbenzoyl) -6- tolysulfonyl amino3) preparation
(1) preparation of 2- (3- trifluoromethylbenzoyl) -6- nitro -4 (3H)-quinazolinone
3mL (TrifluoroMethyl)acetophenone is dissolved in 10mL DMSO, 2.5g iodine is slowly added to, is added dropwise under stirring at normal temperature
3.3g2- amino -5- nitrobenzamide is dissolved in the solution of 20mL DMSO, 110 DEG C of reaction 2h.150mL water is added in reaction system,
It is extracted with (3 × 60mL) ethyl acetate, then is saturated NaHSO with (2 × 40mL)3Solution washing removes iodine, with anhydrous sulphur after washing
Sour magnesium is dry, and evaporating solvent under reduced pressure, residue must be produced through chromatography post separation (eluant, eluent: ethyl acetate: petroleum ether=1:2)
Product 2- (3- trifluoromethylbenzoyl) -6- nitro -4 (3H)-quinazolinone 4.1g, yield 63%, 172-175 DEG C of fusing point.
(2) preparation of 2- (3- trifluoromethylbenzoyl) -6- amino -4 (3H)-quinazolinone
4.3g 2- (3- trifluoromethylbenzoyl) -6- nitro -4 (3H)-quinazolinone is dissolved in 25mL water and 50mL ethyl alcohol
Mixed liquor in, lower addition 6.0g iron powder is stirred at room temperature, 8.0mL concentrated hydrochloric acid is then slowly added dropwise.Continue to be stirred to react at room temperature
4h adjusts pH to 10 with lye after the reaction was completed, filters, filtrate decompression concentration, ethyl acetate solution extraction, with the NaCl of saturation
Solution washs 3 times, and anhydrous magnesium sulfate is dry, and evaporating solvent under reduced pressure obtains 2- (3- trifluoromethylbenzoyl) -6- amino -4
(3H)-quinazolinone 2.9g, yield 75%.
(3) -4 (3H)-quinazolinone (I of 2- (3- trifluoromethylbenzoyl) -6- tolysulfonyl amino3) preparation
266mg 2- (3- trifluoromethylbenzoyl) -6- amino -4 (3H)-quinazolinone is dissolved in anhydrous three chloromethane of 10mL
In alkane, 0.2mL triethylamine is added at room temperature, the solution that 152mg paratoluensulfonyl chloride is dissolved in 10mL chloroform is added dropwise after 0.5h,
Continue to be stirred to react 4h at room temperature.Isometric 26% ammonium hydroxide quenching reaction is added.Split-phase, water phase is with chloroform (2 × 30mL)
Extraction, merges chloroform phase, and saturated salt solution is washed to neutrality.Solvent, residue is evaporated off after drying, filtering in organic phase
Column (eluant, eluent: ethyl acetate: petroleum ether=1:3), which was chromatographed, through column obtains product (I3) 259mg, yield 67%, fusing point is
196-199℃。
Embodiment 4
2- (3- trifluoromethylbenzoyl) -6- [2- (N methyl piperazine base) acetylamino] -4 (3H)-quinazolinones
(I4) preparation
(1) preparation of 2- (3- trifluoromethylbenzoyl) -6- (2- chloro acetylamino) -4 (3H)-quinazolinone
319mg 2- (3- trifluoromethylbenzoyl) -6- amino -4 (3H)-quinazolinone is dissolved in anhydrous three chloromethane of 10mL
In alkane, 0.2mL triethylamine is added at room temperature, the solution that 80 μ L chloracetyl chlorides are dissolved in 10mL chloroform is then added dropwise, at room temperature
Continue to be stirred to react 4h.Isometric 26% ammonium hydroxide quenching reaction is added.Split-phase, water phase are extracted with chloroform (2 × 30mL), are closed
And chloroform phase, saturated salt solution are washed to neutrality.After drying, filtering, solvent evaporated, residue chromatographs organic phase through column
Column (eluant, eluent: ethyl acetate: petroleum ether=1:3) is crossed, 2- (3- trifluoromethylbenzoyl) -6- (2- chloro-acetyl chloride is obtained
Base) -4 (3H)-quinazolinone 231mg, yield 59%.
(2) 2- (3- trifluoromethylbenzoyl) -6- [2- (N methyl piperazine base) acetylamino] -4 (3H)-quinazolinones
(I4) preparation
100 μ LN- methyl piperazines are dissolved in 6mL ethyl acetate, and 0.18g K is added at room temperature2CO3, it is added dropwise after 0.5h
360mg2- (3- trifluoromethylbenzoyl) -6- (2- chloro acetylamino) -4 (3H)-quinazolinone is dissolved in 15mL ethyl acetate
Solution, 65 DEG C of back flow reaction 4h.It after 15mL water is added in reaction system, is extracted, is merged organic with (3 × 30mL) ethyl acetate
Phase, anhydrous magnesium sulfate are dry, evaporating solvent under reduced pressure, residue through column chromatographed column (eluant, eluent: ethyl acetate: petroleum ether=1:
4) product (I is obtained4) 256mg, yield 62%, fusing point is 289-291 DEG C.
Embodiment 5
- 4 (3H)-quinazolinone (I of 2- (2- hydroxy benzoyl) -6- tolysulfonyl amino5) preparation
(1) preparation of 2- (2- hydroxy benzoyl) -6- nitro -4 (3H)-quinazolinone
2.5mL o-hydroxyacetophenone is dissolved in 10mL DMSO, is slowly added to 2.8g iodine, 3.6g 2- is added dropwise under stirring at normal temperature
Amino -5- nitrobenzamide is dissolved in the solution of 20mL DMSO, 110 DEG C of reaction 2h.Reaction system is added in 150mL water, with (3
× 60mL) ethyl acetate extraction, then NaHSO is saturated with (2 × 40mL)3Solution washing removes iodine, uses anhydrous magnesium sulfate after washing
Dry, evaporating solvent under reduced pressure, residue obtains product 2- through chromatography post separation (eluant, eluent: ethyl acetate: petroleum ether=1:3)
(2- hydroxy benzoyl) -6- nitro -4 (3H)-quinazolinone 4.5g, yield 73%, 162-165 DEG C of fusing point.
(2) preparation of 2- (2- hydroxy benzoyl) -6- amino -4 (3H)-quinazolinone
4.0g 2- (2- hydroxy benzoyl) -6- nitro -4 (3H)-quinazolinone is dissolved in the mixed of 25mL water and 50mL ethyl alcohol
It closes in liquid, lower addition 6.0g iron powder is stirred at room temperature, 8.0mL concentrated hydrochloric acid is then slowly added dropwise.Continue to be stirred to react 4h at room temperature, instead
PH to 9 should be adjusted with lye after the completion, filtered, filtrate decompression concentration, ethyl acetate solution extraction is washed with the NaCl solution of saturation
It washs 3 times, anhydrous magnesium sulfate is dry, and evaporating solvent under reduced pressure obtains 2- (2- hydroxy benzoyl) -6- amino -4 (3H)-quinazoline
Ketone 2.5g, yield 69%.
(3) -4 (3H)-quinazolinone (I of 2- (2- hydroxy benzoyl) -6- tolysulfonyl amino5) preparation
0.5g 2- (2- hydroxy benzoyl) -6- amino -4 (3H)-quinazolinone is dissolved in the anhydrous chloroform of 15mL,
0.4mL triethylamine is added at room temperature, the solution that 340mg paratoluensulfonyl chloride is dissolved in 10mL chloroform, room temperature are added dropwise after 0.5h
Under continue to be stirred to react 4h.Isometric 26% ammonium hydroxide quenching reaction is added.Split-phase, water phase are extracted with chloroform (2 × 40mL),
Merge chloroform phase, saturated salt solution is washed to neutrality.Solvent, residue is evaporated off after anhydrous magnesium sulfate is dry in organic phase
Column (eluant, eluent: ethyl acetate: petroleum ether=1:4), which was chromatographed, through column obtains product (I5) 556mg, yield 72%, fusing point is
265-268℃。
Embodiment 6
2- (2- hydroxy benzoyl) -6- [2- (N methyl piperazine base) acetylamino] -4 (3H)-quinazolinone (I6)
Preparation
(1) preparation of 2- (2- hydroxy benzoyl) -6- (2- chloro acetylamino) -4 (3H)-quinazolinone
700mg 2- (2- hydroxy benzoyl) -6- amino -4 (3H)-quinazolinone is dissolved in the anhydrous chloroform of 20mL,
0.6mL triethylamine is added at room temperature, the solution that 200 μ L chloracetyl chlorides are dissolved in 10mL chloroform is then added dropwise, continues at room temperature
It is stirred to react 4h.Isometric 26% ammonium hydroxide quenching reaction is added.Split-phase, water phase are extracted with chloroform (2 × 40mL), merge three
Chloromethanes phase, saturated salt solution are washed to neutrality.After anhydrous magnesium sulfate is dry solvent is evaporated off, residue is through column layer in organic phase
Column (eluant, eluent: ethyl acetate: petroleum ether=1:2) was analysed, 2- (2- hydroxy benzoyl) -6- (2- chloro acetylamino) -4 is obtained
(3H)-quinazolinone 472mg, yield 53%.
(2) 2- (2- hydroxy benzoyl) -6- [2- (N methyl piperazine base) acetylamino] -4 (3H)-quinazolinone (I6)
Preparation
200 μ L N methyl piperazines are dissolved in 10mL ethyl acetate, and 0.36g K is added at room temperature2CO3, it is added dropwise after 0.5h
643mg2- (2- hydroxy benzoyl) -6- (2- chloro acetylamino) -4 (3H)-quinazolinone is dissolved in the molten of 20mL ethyl acetate
Liquid, 65 DEG C of back flow reaction 4h.20mL water is added into reaction system, then is extracted with (3 × 40mL) ethyl acetate, merges organic
Phase, after anhydrous magnesium sulfate is dry, evaporating solvent under reduced pressure, residue through column chromatographed column (eluant, eluent: ethyl acetate: petroleum ether=
1:3) obtain product (I6) 394mg, yield 52%, fusing point is 213-215 DEG C.
Embodiment 7
- 4 (3H)-quinazolinone (I of 2- benzoyl -6- tolysulfonyl amino7) preparation
(1) preparation of -4 (3H)-quinazolinone of 2- benzoyl -6- nitro
1.5mL acetophenone is dissolved in 10mL DMSO, 1.8g iodine is slowly added to, 2.3g 2- ammonia is added dropwise under stirring at normal temperature
Base -5- nitrobenzamide is dissolved in the solution of 20mL DMSO, 110 DEG C of reaction 2h.Reaction system is added in 150mL water, with (3 ×
50mL) ethyl acetate extracts, then is saturated NaHSO with (2 × 30mL)3Solution washing removes iodine, dry with anhydrous magnesium sulfate after washing
Dry, evaporating solvent under reduced pressure, residue obtains product 2- benzene through chromatography post separation (eluant, eluent: ethyl acetate: petroleum ether=1:3)
- 4 (3H)-quinazolinone 2.9g of formoxyl -6- nitro, yield 75%, 181-183 DEG C of fusing point.
(2) preparation of -4 (3H)-quinazolinone of 2- benzoyl -6- amino
- 4 (3H)-quinazolinone of 3.5g 2- benzoyl -6- nitro is dissolved in the mixed liquor of 25mL water and 50mL ethyl alcohol,
Lower addition 6.0g iron powder is stirred at room temperature, 8.0mL concentrated hydrochloric acid is then slowly added dropwise.Continue to be stirred to react 4h at room temperature, reaction is completed
PH to 11 is adjusted with lye afterwards, is filtered, filtrate decompression concentration, ethyl acetate solution extraction washs 3 with the NaCl solution of saturation
Secondary, anhydrous magnesium sulfate is dry, and evaporating solvent under reduced pressure obtains -4 (3H)-quinazolinone 2.2g of 2- benzoyl -6- amino, yield
71%.
(3) -4 (3H)-quinazolinone (I of 2- benzoyl -6- tolysulfonyl amino7) preparation
- 4 (3H)-quinazolinone of 0.6g 2- benzoyl -6- amino is dissolved in the anhydrous chloroform of 15mL, at room temperature plus
Enter 0.5mL triethylamine, the solution that 440mg paratoluensulfonyl chloride is dissolved in 10mL chloroform is added dropwise after 0.5h, continues to stir at room temperature
Mix reaction 4h.Isometric 26% ammonium hydroxide quenching reaction is added.Split-phase, water phase are extracted with chloroform (3 × 40mL), merge trichlorine
Methane phase, saturated salt solution are washed to neutrality.After anhydrous magnesium sulfate is dry solvent is evaporated off, residue is chromatographed through column in organic phase
It crosses column (eluant, eluent: ethyl acetate: petroleum ether=1:4) and obtains product (I7) 665mg, yield 69%, fusing point 167-170
℃。
Embodiment 8
2- benzoyl -6- [2- (N methyl piperazine base) acetylamino] -4 (3H)-quinazolinone (I8) preparation
(1) preparation of -4 (3H)-quinazolinone of 2- benzoyl -6- (2- chloro acetylamino)
- 4 (3H)-quinazolinone of 456mg 2- benzoyl -6- amino is dissolved in the anhydrous chloroform of 20mL, at room temperature plus
Enter 0.4mL triethylamine, 150 μ L chloracetyl chlorides are then added dropwise and are dissolved in 10mL chloroform soln, continue to be stirred to react 4h at room temperature.
Isometric 26% ammonium hydroxide quenching reaction is added.Split-phase, water phase are extracted with chloroform (3 × 40mL), merge chloroform phase, are satisfied
Neutrality is washed to saline solution.Organic phase is after anhydrous magnesium sulfate is dry, solvent evaporated, and residue chromatographed column (elution through column
Agent: ethyl acetate: petroleum ether=1:3), -4 (3H)-quinazolinone 354mg of 2- benzoyl -6- (2- chloro acetylamino) is obtained,
Yield is 61%.
(2) 2- benzoyl -6- [2- (N methyl piperazine base) acetylamino] -4 (3H)-quinazolinone (I8) preparation
200 μ L N methyl piperazines are dissolved in 10mL ethyl acetate, and 0.36g K is added at room temperature2CO3, it is added dropwise after 0.5h
- 4 (3H)-quinazolinone of 609mg2- benzoyl -6- (2- chloro acetylamino) is dissolved in the solution of 20mL ethyl acetate, and 65 DEG C are returned
Stream reaction 4h.20mL water is added into reaction system, then is extracted with (3 × 40mL) ethyl acetate, merges organic phase, anhydrous slufuric acid
After magnesium is dry, evaporating solvent under reduced pressure, residue chromatographed column (eluant, eluent: ethyl acetate: petroleum ether=1:4) through column and obtains product
(I8) 380mg, yield 52%, fusing point is 202-205 DEG C.
Embodiment 9
- 4 (3H)-quinazolinone (I of 2- (3,4- Dimethoxybenzoyl) -6- tolysulfonyl amino9) preparation
(1) preparation of 2- (3,4- Dimethoxybenzoyl) -6- nitro -4 (3H)-quinazolinone
By 2.3g 3,4- dimethoxy-acetophenone is dissolved in 10mL DMSO, is slowly added to 1.8g iodine, is dripped under stirring at normal temperature
2.3g2- amino -5- nitrobenzamide is added to be dissolved in the solution of 20mL DMSO, 110 DEG C of reaction 2h.150mL water is added and is reacted
System is extracted with (3 × 50mL) ethyl acetate, then is saturated NaHSO with (2 × 40mL)3Solution washing removes iodine, uses nothing after washing
Water magnesium sulfate is dry, and evaporating solvent under reduced pressure, residue is through chromatography post separation (eluant, eluent: ethyl acetate: petroleum ether=1:2)
2- (3,4- Dimethoxybenzoyl) -6- nitro -4 (3H)-quinazolinone 3.1g, yield 67%, 247-249 DEG C of fusing point.
(2) preparation of 2- (3,4- Dimethoxybenzoyl) -6- amino -4 (3H)-quinazolinone
3.6g 2- (3,4- Dimethoxybenzoyl) -6- nitro -4 (3H)-quinazolinone is dissolved in 25mL water and 50mL second
In the mixed liquor of alcohol, lower addition 6.0g iron powder is stirred at room temperature, 8.0mL concentrated hydrochloric acid is then slowly added dropwise.It is anti-to continue stirring at room temperature
4h is answered, adjusts pH to 10 with lye after the reaction was completed, is filtered, filtrate decompression concentration, ethyl acetate solution extraction, with saturation
NaCl solution is washed 3 times, and anhydrous magnesium sulfate is dry, and evaporating solvent under reduced pressure obtains 2- (3,4- Dimethoxybenzoyl) -6- ammonia
Base -4 (3H)-quinazolinone 2.5g, yield 77%.
(3) -4 (3H)-quinazolinone (I of 2- (3,4- Dimethoxybenzoyl) -6- tolysulfonyl amino9) preparation
568mg 2- (3,4- Dimethoxybenzoyl) -6- amino -4 (3H)-quinazolinone is dissolved in the anhydrous trichlorine of 15mL
In methane, 0.5mL triethylamine is added at room temperature, 330mg paratoluensulfonyl chloride is added dropwise after 0.5h and is dissolved in the molten of 10mL chloroform
Liquid continues to be stirred to react 4h at room temperature.Isometric 26% ammonium hydroxide quenching reaction is added.Split-phase, water phase with chloroform (3 ×
It 40mL) extracts, merges chloroform phase, saturated salt solution is washed to neutrality.Organic phase is evaporated off molten after anhydrous magnesium sulfate is dry
Agent, residue chromatographed column (eluant, eluent: ethyl acetate: petroleum ether=1:4) through column and obtain product (I9) 505mg, yield is
62%, fusing point is 242-245 DEG C.
Embodiment 10
2- (3,4- Dimethoxybenzoyl) -6- [2- (N methyl piperazine base) acetylamino] -4 (3H)-quinazolinones
(I10) preparation
(1) preparation of 2- (3,4- Dimethoxybenzoyl) -6- (2- chloro acetylamino) -4 (3H)-quinazolinone
426mg 2- (3,4- Dimethoxybenzoyl) -6- amino -4 (3H)-quinazolinone is dissolved in the anhydrous trichlorine of 15mL
In methane, 0.4mL triethylamine is added at room temperature, 100 μ L chloracetyl chlorides are then added dropwise and are dissolved in 10mL chloroform soln, at room temperature
Continue to be stirred to react 4h.Isometric 26% ammonium hydroxide quenching reaction is added.Split-phase, water phase are extracted with chloroform (3 × 40mL), are closed
And chloroform phase, saturated salt solution are washed to neutrality.Organic phase is after anhydrous magnesium sulfate is dry, solvent evaporated, residue warp
Column chromatographed column (eluant, eluent: ethyl acetate: petroleum ether=1:3), obtained 2- (3,4- Dimethoxybenzoyl) -6- (2- chlorine
Acetylamino) -4 (3H)-quinazolinone 308mg, yield 59%.
(2) 2- (3,4- Dimethoxybenzoyl) -6- [2- (N methyl piperazine base) acetylamino] -4 (3H)-quinazolines
Ketone (I10) preparation
200 μ L N methyl piperazines are dissolved in 10mL ethyl acetate, and 0.36g K is added at room temperature2CO3, it is added dropwise after 0.5h
610mg2- (3,4- Dimethoxybenzoyl) -6- (2- chloro acetylamino) -4 (3H)-quinazolinone is dissolved in 20mL ethyl acetate
Solution, 65 DEG C of back flow reaction 4h.20mL water is added into reaction system, then is extracted with (3 × 40mL) ethyl acetate, is associated with
Machine phase, anhydrous magnesium sulfate are dry, evaporating solvent under reduced pressure, residue through column chromatographed column (eluant, eluent: ethyl acetate: petroleum ether=
1:3) obtain product (I10) 410mg, yield 49%, fusing point is 254-256 DEG C.
Embodiment 11
- 4 (3H)-quinazolinone (I of 2- (4- cyanobenzoyl) -6- tolysulfonyl amino11) preparation
(1) preparation of 2- (4- cyanobenzoyl) -6- nitro -4 (3H)-quinazolinone
0.9g 4- cyano-acetophenone is dissolved in 10mL DMSO, 0.8g iodine is slowly added to, 1.1g is added dropwise under stirring at normal temperature
2- amino -5- nitrobenzamide is dissolved in the solution of 10mL DMSO, 110 DEG C of reaction 2h.Reaction system is added in 100mL water, is used
The extraction of (3 × 40mL) ethyl acetate, then NaHSO is saturated with (2 × 30mL)3Solution washing removes iodine, uses anhydrous slufuric acid after washing
Magnesium is dry, evaporating solvent under reduced pressure, and residue obtains product through chromatography post separation (eluant, eluent: ethyl acetate: petroleum ether=1:3)
2- (4- cyanobenzoyl) -6- nitro -4 (3H)-quinazolinone 1.4g, yield 72%, 265-268 DEG C of fusing point.
(2) preparation of 2- (4- cyanobenzoyl) -6- amino -4 (3H)-quinazolinone
1.5g 2- (4- cyanobenzoyl) -6- nitro -4 (3H)-quinazolinone is dissolved in the mixed of 25mL water and 50mL ethyl alcohol
It closes in liquid, lower addition 4.0g iron powder is stirred at room temperature, 5.0mL concentrated hydrochloric acid is then slowly added dropwise.Continue to be stirred to react 4h at room temperature, instead
PH to 10 should be adjusted with lye after the completion, filtered, filtrate decompression concentration, ethyl acetate solution extraction, with the NaCl solution of saturation
Washing 3 times, anhydrous magnesium sulfate is dry, and evaporating solvent under reduced pressure obtains 2- (4- cyanobenzoyl) -6- amino -4 (3H)-quinoline azoles
Quinoline ketone 0.9g, yield 69%.
(3) -4 (3H)-quinazolinone (I of 2- (4- cyanobenzoyl) -6- tolysulfonyl amino11) preparation
272mg 2- (4- cyanobenzoyl) -6- amino -4 (3H)-quinazolinone is dissolved in the anhydrous chloroform of 10mL,
0.2mL triethylamine is added at room temperature, the solution that 180mg paratoluensulfonyl chloride is dissolved in 8mL chloroform is added dropwise after 0.5h, at room temperature
Continue to be stirred to react 4h.Isometric 26% ammonium hydroxide quenching reaction is added.Split-phase, water phase are extracted with chloroform (3 × 40mL), are closed
And chloroform phase, saturated salt solution are washed to neutrality.Solvent, residue warp is evaporated off after anhydrous magnesium sulfate is dry in organic phase
Column chromatographed column (eluant, eluent: ethyl acetate: petroleum ether=1:4) and obtains product (I11) 300mg, yield 75%, fusing point is
185-188℃。
Embodiment 12
2- (4- cyanobenzoyl) -6- [2- (N methyl piperazine base) acetylamino] -4 (3H)-quinazolinone (I12)
Preparation
(1) preparation of 2- (4- cyanobenzoyl) -6- (2- chloro acetylamino) -4 (3H)-quinazolinone
408mg 2- (4- cyanobenzoyl) -6- amino -4 (3H)-quinazolinone is dissolved in the anhydrous chloroform of 15mL,
0.3mL triethylamine is added at room temperature, the solution that 180 μ L chloracetyl chlorides are dissolved in 8mL chloroform is then added dropwise, continues to stir at room temperature
Mix reaction 4h.Isometric 26% ammonium hydroxide quenching reaction is added.Split-phase, water phase are extracted with chloroform (3 × 40mL), merge trichlorine
Methane phase, saturated salt solution are washed to neutrality.After anhydrous magnesium sulfate is dry, solvent evaporated, residue chromatographs organic phase through column
Column (eluant, eluent: ethyl acetate: petroleum ether=1:3) is crossed, 2- (4- cyanobenzoyl) -6- (2- chloro acetylamino) -4 is obtained
(3H)-quinazolinone 344mg, yield 67%.
(2) 2- (4- cyanobenzoyl) -6- [2- (N methyl piperazine base) acetylamino] -4 (3H)-quinazolinone (I12)
Preparation
It weighs 100 μ L N methyl piperazines to be dissolved in 6mL ethyl acetate, 0.18g K is added at room temperature2CO3, it is added dropwise after 0.5h
315mg 2- (4- cyanobenzoyl) -6- (2- chloro acetylamino) -4 (3H)-quinazolinone is dissolved in the molten of 15mL ethyl acetate
Liquid, 65 DEG C of back flow reaction 4h.20mL water is added into reaction system, then is extracted with (3 × 40mL) ethyl acetate, merges organic
Phase, after anhydrous magnesium sulfate is dry, evaporating solvent under reduced pressure, residue through column chromatographed column (eluant, eluent: ethyl acetate: petroleum ether=
1:3) obtain product (I12) 197mg, yield 51%, fusing point is 272-275 DEG C.
Embodiment 13
- 4 (3H)-quinazolinone (I of 2- (3- nitro benzoyl) -6- tolysulfonyl amino13) preparation
(1) preparation of 2- (3- nitro benzoyl) -6- nitro -4 (3H)-quinazolinone
0.9g 3- nitro-acetophenone is dissolved in 10mL DMSO, 0.8g iodine is slowly added to, 1.1g is added dropwise under stirring at normal temperature
2- amino -5- nitrobenzamide is dissolved in 10mL DMSO solution, 110 DEG C of reaction 2h.Reaction system is added in 100mL water, with (3
× 40mL) ethyl acetate extraction, then NaHSO is saturated with (2 × 30mL)3Solution washing removes iodine, uses anhydrous magnesium sulfate after washing
Dry, evaporating solvent under reduced pressure, residue obtains product 2- through chromatography post separation (eluant, eluent: ethyl acetate: petroleum ether=1:3)
(3- nitro benzoyl) -6- nitro -4 (3H)-quinazolinone 1.3g, yield 62%, 283-285 DEG C of fusing point.
(2) preparation of 2- (3- nitro benzoyl) -6- amino -4 (3H)-quinazolinone
1.7g 2- (3- nitro benzoyl) -6- nitro -4 (3H)-quinazolinone is dissolved in the mixed of 25mL water and 50mL ethyl alcohol
It closes in liquid, lower addition 4.0g iron powder is stirred at room temperature, 5.0mL concentrated hydrochloric acid is then slowly added dropwise.Continue to be stirred to react 4h at room temperature, instead
PH to 10 should be adjusted with lye after the completion, filtered, filtrate decompression concentration, ethyl acetate solution extraction, with the NaCl solution of saturation
Washing 3 times, after anhydrous magnesium sulfate is dry, evaporating solvent under reduced pressure obtains 2- (3- nitro benzoyl) -6- amino -4 (3H)-quinoline
Oxazoline ketone 1.1g, yield 73%.
(3) -4 (3H)-quinazolinone (I of 2- (3- nitro benzoyl) -6- tolysulfonyl amino13) preparation
184mg 2- (3- nitro benzoyl) -6- amino -4 (3H)-quinazolinone is dissolved in the anhydrous chloroform of 10mL,
0.2mL triethylamine is added at room temperature, the solution that 120mg paratoluensulfonyl chloride is dissolved in 8mL chloroform is added dropwise after 0.5h, at room temperature
Continue to be stirred to react 4h.Isometric 26% ammonium hydroxide quenching reaction is added.Split-phase, water phase are extracted with chloroform (3 × 40mL), are closed
And chloroform phase, saturated salt solution are washed to neutrality.Solvent, residue warp is evaporated off after anhydrous magnesium sulfate is dry in organic phase
Column chromatographed column (eluant, eluent: ethyl acetate: petroleum ether=1:2) and obtains product (I13) 181mg, yield 65%, fusing point is
267-269℃。
Embodiment 14
2- (3- nitro benzoyl) -6- [2- (N methyl piperazine base) acetylamino] -4 (3H)-quinazolinone (I14)
Preparation
(1) preparation of 2- (3- nitro benzoyl) -6- (2- chloro acetylamino) -4 (3H)-quinazolinone
276mg 2- (3- nitro benzoyl) -6- amino -4 (3H)-quinazolinone is dissolved in the anhydrous chloroform of 15mL,
0.2m L triethylamine is added at room temperature, the solution that 120 μ L chloracetyl chlorides are dissolved in 8mL chloroform is then added dropwise, continues at room temperature
It is stirred to react 4h.Isometric 26% ammonium hydroxide quenching reaction is added.Split-phase, water phase are extracted with chloroform (3 × 30mL), merge three
Chloromethanes phase, saturated salt solution are washed to neutrality.After anhydrous magnesium sulfate is dry solvent is evaporated off, residue is through column layer in organic phase
Column (eluant, eluent: ethyl acetate: petroleum ether=1:3) was analysed, 2- (3- nitro benzoyl) -6- (2- chloro acetylamino) -4 is obtained
(3H)-quinazolinone 212mg, yield 61%.
(2) 2- (3- nitro benzoyl) -6- [2- (N methyl piperazine base) acetylamino] -4 (3H)-quinazolinone (I14)
Preparation
100 μ L N methyl piperazines are dissolved in 6mL ethyl acetate, and 0.18g K is added at room temperature2CO3, it is added dropwise after 0.5h
348mg2- (3- nitro benzoyl) -6- (2- chloro acetylamino) -4 (3H)-quinazolinone is dissolved in the molten of 15mL ethyl acetate
Liquid, 65 DEG C of back flow reaction 4h.20mL water is added into reaction system, then is extracted with (3 × 40mL) ethyl acetate, merges organic
Phase, after anhydrous magnesium sulfate is dry, evaporating solvent under reduced pressure, residue through column chromatographed column (eluant, eluent: ethyl acetate: petroleum ether=
1:3) obtain product (I14) 276mg, yield 68%, fusing point is 255-257 DEG C.
Compound activity test result
The test philosophy of inhibiting activity of acetylcholinesterase is as follows: AChE can promptly divide substrate acetylthiocholine
Solution is thiocholine and acetic acid, and again with color developing agent 5, bis- thiobis of 5'- (2-nitrobenzoic acid) (DTNB) is quantitative to be tied thiocholine
It closes and generates yellow substance, which has stronger absorption at 405nm.Because of index and the corresponding extinction of yellow substance concentration
The wired sexual intercourse of angle value, and then the height of corresponding AChE vigor is obtained by thiocholine yield in certain period of time.
The test philosophy of phosphodiesterase 5 inhibitory activity are as follows: using human phosphodiester in double antibody sandwich method measurement sample
Enzyme 5 is horizontal.Be coated with microwell plate with 5 antibody of human phosphodiester enzyme of purifying, solid phase antibody be made, toward in the micropore for being coated with monoclonal antibody according to
Secondary addition phosphodiesterase 5, then in conjunction with the phosphodiesterase 5 antibody of horseradish peroxidase (HRP) label, it is anti-to form antibody
Former hrp-antibody complex, after thoroughly washing plus 3,3', 5,5'- tetramethyl benzidine (TMB) of substrate develops the color.TMB is in HRP
Au bleu is converted under the catalysis of enzyme, the phosphodiesterase 5 in the depth and sample of color is positively correlated, with microplate reader in 450nm
Absorbance is measured under wavelength.
The acetylcholinesterase of compound and phosphodiesterase 5 inhibitory activity result are as shown in the table in the present invention.
Claims (5)
1. a kind of -4 (3H)-Quinazol derivative of 2- benzoyl -6- amino, it is characterized in that having the structure of logical formula (I)；
R1Selected from unsubstituted monosubstituted or disubstituted benzenesulfonyl, pyridine sulfonyl sulfonyl base, pyrimidine sulfonyl base, triazine sulfonyl, pyrrole
Cough up sulfonyl, furans sulfonyl, thiophen sulfuryl, imidazoles sulfonyl, thiazole sulfonyl, oxazole sulfonyl, piperazine acetyl, piperazine
Pyridine acetyl group, morpholine acetyl group, hexamethylene acetyl group, substituent group therein are to be independently selected from H, F, Cl, Br, OH, NO2、
CN、CF3、OCF3、SCF3、SH、NH2、C1-5Alkyl, OC1-5Alkyl, SC1-5Alkyl, NHC1-5Alkyl, N (C1-5Alkyl)2、OCOC0-5
Alkyl, SCOC0-5Alkyl, NHCOC0-5Alkyl；
R2、R3And R4To be independently selected from H, F, Cl, Br, OH, NO2、CN、CF3、OCF3、SCF3、SH、NH2、C1-5Alkyl,
OC1-5Alkyl, SC1-5Alkyl, NHC1-5Alkyl, N (C1-5Alkyl)2、OCOC0-5Alkyl, SCOC0-5Alkyl, NHCOC0-5Alkyl.
2. -4 (3H)-Quinazol derivative of 2- benzoyl -6- amino according to claim 1, it is characterized in that having
The compound I of following structures1~I14In any compound:
3. compound of any of claims 1 or 2 is used to prepare acetylcholinesterase inhibitor and PDE5 inhibitor
Using.
4. the application that compound of any of claims 1 or 2 is used to prepare Alzheimer disease drug.
5. a kind of preparation method of -4 (3H)-Quinazol derivative of 2- benzoyl -6- amino of any of claims 1 or 2,
It is characterized in that: using 2- amino -5- nitrobenzoic acid for raw material, 2- amino -5- nitrobenzoyl is generated with thionyl chloride and ammonium hydroxide
Amide, then with substituted acetophenone occur cyclization reaction generate 4 (3H)-quinazolinones female ring, after nitro restores with it is all kinds of
Acyl chloride reaction obtains corresponding compound, and steps are as follows for the synthetic reaction of use:
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| CN1720238A (en) * | 2002-10-04 | 2006-01-11 | 普拉纳生物技术有限公司 | Neurologically-active compounds |
| WO2012173952A1 (en) * | 2011-06-13 | 2012-12-20 | Emory University | Piperazine derivatives, compositions, and uses related thereto |
| CN106146410A (en) * | 2015-04-03 | 2016-11-23 | 中南大学 | 6-amino-4 (3H)-Quinazol derivative and preparation method and use thereof |
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|---|---|---|---|---|
| CN1720238A (en) * | 2002-10-04 | 2006-01-11 | 普拉纳生物技术有限公司 | Neurologically-active compounds |
| WO2012173952A1 (en) * | 2011-06-13 | 2012-12-20 | Emory University | Piperazine derivatives, compositions, and uses related thereto |
| CN106146410A (en) * | 2015-04-03 | 2016-11-23 | 中南大学 | 6-amino-4 (3H)-Quinazol derivative and preparation method and use thereof |
Non-Patent Citations (1)
| Title |
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| YAN-PING ZHU ET,AL.: "Direct One-Pot Synthesis of Luotonin F and Analogues via Rational Logical Design", 《ORGANIC LETTERS》 * |
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