CN101486714A - Novel oxazine compound and use for preventing platelet aggregation - Google Patents
Novel oxazine compound and use for preventing platelet aggregation Download PDFInfo
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Abstract
The invention pertains to the filed of medical technology, relating to an oxazine compound and a medical application thereof; the oxazine compound and an oxazine salt obtained from an addition reaction of pharmaceutically-applicable oxazine acid can be used as a platelet aggregation inhibitor with a structural formula shown as on the right; in structural formulas I-VI, R3 can be independently chosen from H, alkyl group with one to four carbon atoms, benzyl or substituted or un-substituted aromatic base. The oxazine compound has simple synthetic method, adapts to industrialized production and is more stable when compared with natural analogues. Shown by biological activity assay, the oxazine compound has the functions of analgesia, anti-inflammatory and antithrombin activity and is a platelet aggregation inhibiting medicament.
Description
Technical field
The invention belongs to medical technical field, She is Ji oxazine compounds and application of platelet aggregation resistance thereof.
Technical background
Clinical study shows, diseases such as common clinically cardiovascular and cerebrovascular diseases such as hypertension, diabetes, stenocardia, myocardial infarction, cerebral infarction and hematencephalon, all change relevant unusually (Tianjin medicine, 1992,20 (11): 684) with hemorheology with platelet function.Therefore, prevent that platelet aggregation is significant.
Thrombocyte is produced by sophisticated megalokaryocyte cracking in the marrow, and just the volume of platelets that generates is bigger, has the ability of synthetic protein, and adhesion is strong, is easy to assemble and release reaction takes place, and has hemostatic function.Think that at present hematoblastic physiological activity mainly contains adhesion, assemble and three aspects of release reaction.Under normal physiological condition, thrombocyte can't stick on the blood vessel endothelium, but work as vascular injury, blood flow changes or when being subjected to extraneous chemical substance and stimulating, three kinds of reactions that are associated then take place in thrombocyte, promptly adhere to, discharge and gathering, and medicament for resisting platelet aggregation is divided into the metabolic medicine of (1) inhibition thrombocyte arachidonic acid; (2) medicine of Camp content in the platelet increasing; (3) TXA
2Receptor blocking agent and synthetase inhibitors; (4) nitric oxide donors; (5) hinder the medicine that ADP mediates platelet activation; (6) thrombin inhibitors; (7) has the other drug of anticoagulant effect.Because it is a lot of to influence the factor of platelet aggregation, some medicine remains in uncertain therapeutic efficacy to be cut, stability is not enough, have shortcomings such as toxic side effect, but along with the further research of people to the mechanism of action of the physiological process of platelet aggregation and medicament for resisting platelet aggregation, the searching curative effect is strong, all has inhibiting wide spectrum anticoagulant to be still current research direction to multiple inductor.
Flavonoid compound extensively is present in the natural plants, can be divided into flavones, flavonol, isoflavones, flavane, flavanone etc. and glucoside thereof, has multiple physiologically actives such as antitumor, anti-inflammatory and cardiovascular and cerebrovascular diseases.(Harbome?JB?Flavonoids(Chinese?Edition)，Beijing：SciencePress,1983：322；Hogale?MB,Pawar?BN,Nikai?BP.J?Indian?ChemSoc,1987,64：486)。Also have document (CHINA JOURNAL OF CHINESE MATERIA MEDICA, 2003,28 (5), 420-422) report, the natural flavone compounds in the Gualou Xiebai Baijiu Tang has platelet aggregation inhibitory activity.
4-chromone and 4-chromanone compound be have anti-inflammatory action, antiplatelet aggregative activity, antitumous effect, immunosuppressive action (yellow pillow is inferior. platelet aggregation suppresses and progress [M]. // Peng Sixun. pharmaceutical chemistry progress .Vol 1. Beijing: the .2001 of Chemical Industry Press, 39-69).4-chroman ketone Mannich bases compound all has significant inhibition active to ADP inductive platelet aggregation, its platelet aggregation inhibitory activity than the strong 50-60 of acetylsalicylic acid doubly (the synthetic and bioactivity research [D] of Hu Chun .4-chromanone derivative. the doctorate paper, Shenyang: Shenyang Pharmaceutical University, 1998).Anti-inflammatory activity and platelet aggregation inhibitory activity are relevant, the platelet aggregation inhibitory activity of 4-chromanone compound is likely by the pathways metabolism that suppresses arachidonic acid (the AA) (Sun Guang that plays a role, Li Huiyuan, Yan Peng, Sun Yang, synthetic and the anti-inflammatory activity research of spring .4-chromanone compound recklessly. to see: He Fuchu, Du Shengming, Sun Jianzhong chief editor. the new drug of genome times afterwards comprehensively is found. Beijing: the .2004:216-217 of military medicine Science Press).
But the natural flavone kind compound content is low, 4-chroman ketone Mannich bases compound stability is poor, we carry out structural modification to flavonoid compound and 4-chromanone compound, having designed and synthesized one is row oxazine compounds, to overcome the above-mentioned shortcoming of natural flavone compounds and 4-chromanone compound.
Summary of the invention
An object of the present invention is to provide new medicament for resisting platelet aggregation.
Another object of the present invention provides a kind of medicinal compositions, and said composition comprises described new anti-platelet aggregation compounds or its pharmacy acceptable salt and the pharmaceutically acceptable carrier thereof of significant quantity.
Another object of the present invention provides a kind of method that produces the platelet aggregation-against effect in curee's body, this method gives the curee is enough to produce described effect quantity, described new anti-platelet aggregation compounds or its atoxic pharmacy acceptable salt.
The present invention relates to the compound of following general formula:
Wherein R can independently be selected from H, an alkyl group to four carbon atom, and benzyl perhaps replaces or unsubstituted aryl group.
Wherein R can independently be selected from H, an alkyl group to four carbon atom, and benzyl perhaps replaces or unsubstituted aryl group.
Wherein R can independently be selected from H, an alkyl group to four carbon atom, and benzyl perhaps replaces or unsubstituted aryl group.
Wherein R can independently be selected from H, an alkyl group to four carbon atom, and benzyl perhaps replaces or unsubstituted aryl group.
Wherein R can independently be selected from H, an alkyl group to four carbon atom, and benzyl perhaps replaces or unsubstituted aryl group.
Wherein R can independently be selected from H, an alkyl group to four carbon atom, and benzyl perhaps replaces or unsubstituted aryl group.
The synthetic method of this compounds of the present invention is simple, adapts to suitability for industrialized production, and more stable with respect to natural analogue, biological activity test shows that this compounds has analgesia, anti-inflammatory, and anticoagulant active is a kind of medicament for resisting platelet aggregation.
Embodiment:
To help to understand the present invention by following embodiment, but not influence content of the present invention.The compound process infrared spectra of being told (IR), nuclear magnetic resonance spectrum (
1HNMR), mass spectrum (MS) is confirmed its structure.
Embodiment 1:3-benzyl-2,3,4,6,7,8-six hydrogen chromenes are [6,7-e] [1,3] oxazine also
5mmol 7-hydroxychroman is dissolved in 2mL 95% ethanol, adds 1.2mL 37% formalin, stir several minutes, under ice bath cooling, drip the 5mmol benzylamine that has been dissolved in 2-3mL 95% ethanol, stirred overnight at room temperature, concentrate after silica gel column chromatography separate (sherwood oil: ethyl acetate=30:1) 3-benzyl-2,3,4,6,7,8-six hydrogen chromenes also [6,7-e] [1,3] oxazine white solid, yield: 31%.MSm/z(M)281.35。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，3.62(4H，s)，3.94(2H，m)，5.01(2H，s)，6.11(1H，s)，6.70(1H，s)，7.10(5H，m)。
Embodiment 2:3-phenyl-2,3,4,6,7,8-six hydrogen chromenes are [6,7-e] [1,3] oxazine also
According to embodiment 1 method, by 7-hydroxychroman and formalin, aniline reaction, column chromatography for separation obtains white solid 3-phenyl-2,3,4,6,7, and 8-six hydrogen chromenes are [6,7-e] [1,3] oxazine, yield: 42% also.MS?m/z(M)267.32。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.11(1H，s)，6.60(3H，m)，6.70(1H，s)，7.08(2H，m)。
Embodiment 3:3-(2-aminomethyl phenyl)-2,3,4,6,7,8-six hydrogen chromenes are [6,7-e] [1,3] oxazine also
According to embodiment 1 method, to react by 7-hydroxychroman and formalin, 2-aminotoluene, column chromatography for separation obtains white solid 3-(2-aminomethyl phenyl)-2,3,4,6,7, and 8-six hydrogen chromenes are [6,7-e] [1,3] oxazine, yield: 37% also.MS?m/z(M)281.35。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.35(3H，s)，2.55(2H，m)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.11(1H，s)，6.47(2H，m)，6.70(1H，s)，6.88(2H，m)。
Embodiment 4:3-(4-aminomethyl phenyl)-2,3,4,6,7,8-six hydrogen chromenes are [6,7-e] [1,3] oxazine also
According to embodiment 1 method, to react by 7-hydroxychroman and formalin, 4-monomethylaniline, column chromatography for separation obtains white solid 3-(4-aminomethyl phenyl)-2,3,4,6,7, and 8-six hydrogen chromenes are [6,7-e] [1,3] oxazine, yield: 42% also.MS?m/z(M)281.35。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.35(3H，s)，2.55(2H，m)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.11(1H，s)，6.47(2H，m)，6.70(1H，s)，6.88(2H，m)。
Embodiment 5:3-(2, the 6-3,5-dimethylphenyl)-2,3,4,6,7,8-six hydrogen chromenes are [6,7-e] [1,3] oxazine also
According to embodiment 1 method, by 7-hydroxychroman and formalin, 2, the reaction of 6-xylidine, column chromatography for separation obtains white solid 3-(2, the 6-3,5-dimethylphenyl) 2,3,4,6,7, and 8-six hydrogen chromenes are [6,7-e] [1,3] oxazine, yield: 39% also.MS?m/z(M)295.38。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.35(6H，s)，2.55(2H，m)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.11(1H，s)，6.36(1H，m)，6.69(3H，m)。
Embodiment 6:3-(2-chloro-phenyl-)-2,3,4,6,7,8-six hydrogen chromenes are [6,7-e] [1,3] oxazine also
According to embodiment 1 method, to react by 7-hydroxychroman and formalin, 2-chloroaniline, column chromatography for separation obtains white solid 3-(2-chloro-phenyl-)-2,3,4,6,7, and 8-six hydrogen chromenes are [6,7-e] [1,3] oxazine, yield: 45% also.MS?m/z(M)301.77。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.11(1H，s)，6.53(2H，m)，6.70(1H，s)，6.96(1H，m)，7.09(1H，m)。
Embodiment 7:3-(4-chloro-phenyl-)-2,3,4,6,7,8-six hydrogen chromenes are [6,7-e] [1,3] oxazine also
According to embodiment 1 method, to react by 7-hydroxychroman and formalin, 4-chloroaniline, column chromatography for separation obtains white solid 3-(4-chloro-phenyl-)-2,3,4,6,7, and 8-six hydrogen chromenes are [6,7-e] [1,3] oxazine, yield: 27% also.MS?m/z(M)301.77。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.11(1H，s)，6.53(2H，m)，6.70(1H，s)，7.09(2H，m)。
Embodiment 8:3-(4-p-methoxy-phenyl)-2,3,4,6,7,8-six hydrogen chromenes are [6,7-e] [1,3] oxazine also
According to embodiment 1 method, to react by 7-hydroxychroman and formalin, 4-anisidine, column chromatography for separation obtains white solid 3-(4-chloro-phenyl-)-2,3,4,6,7, and 8-six hydrogen chromenes are [6,7-e] [1,3] oxazine, yield: 35% also.MS?m/z(M)297.35。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，3.73(3H，s)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.11(1H，s)，6.48(2H，m)，6.59(2H，m)，6.70(1H，s)。
Embodiment 9:9-benzyl-2,3,4,8,9,10-six hydrogen chromenes are [8,7-e] [1,3] oxazine also
With 1.2mL 37% formalin be dissolved in 2-3mL 95% alcoholic acid 5mmol benzylamine and mix, after reflux stirs several minutes, add and be dissolved in 10mL 95% alcoholic acid 5mmol 7-hydroxychroman, reflux also stirs and spends the night.(sherwood oil: ethyl acetate=30:1) get 9-benzyl-2,3,4,8,9,10-six hydrogen chromenes are [8,7-e] [1,3] oxazine white solid, yield: 44% also through the silica gel column chromatography separation.MS?m/z(M)281.35。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，3.62(4H，s)，3.94(2H，m)，5.01(2H，s)，6.16(1H，m)，6.71(1H，m)，7.09(5H，m)。
Embodiment 10:9-phenyl-2,3,4,8,9,10-six hydrogen chromenes are [8,7-e] [1,3] oxazine also
According to the method for embodiment 9, by 7-hydroxychroman and formalin, aniline reaction, column chromatography for separation obtains 9-phenyl-2,3,4,8,9, and 10-six hydrogen chromenes are [8,7-e] [1,3] oxazine white solid also.Yield: 58%.MS?m/z(M)267.32。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，3.94(2H，m)4.61(2H，s)，6.00(2H，s)，6.16(1H，m)，6.60(3H，m)，6.71(1H，m)，7.08(2H，m)。
Embodiment 11:9-(2-aminomethyl phenyl)-2,3,4,8,9,10-six hydrogen chromenes are [8,7-e] [1,3] oxazine also
According to the method for embodiment 9, to react by 7-hydroxychroman and formalin, 2-aminotoluene, column chromatography for separation obtains 9-(2-aminomethyl phenyl)-2,3,4,8,9, and 10-six hydrogen chromenes are [8,7-e] [1,3] oxazine white solid also.Yield: 43%.MS?m/z(M)281.35。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.35(3H，s)，2.55(2H，m)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.16(1H，m)，6.47(2H，m)，6.71(1H，m)，6.89(2H，m)。
Embodiment 12:9-(4-aminomethyl phenyl)-2,3,4,8,9,10-six hydrogen chromenes are [8,7-e] [1,3] oxazine also
According to the method for embodiment 9, to react by 7-hydroxychroman and formalin, 4-monomethylaniline, column chromatography for separation obtains 9-(4-aminomethyl phenyl)-2,3,4,8,9, and 10-six hydrogen chromenes are [8,7-e] [1,3] oxazine white solid also.Yield: 45%.MS?m/z(M)281.35。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.35(3H，s)，2.55(2H，m)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.16(1H，m)，6.47(2H，m)，6.71(1H，m)，6.88(2H，m)。
Embodiment 13:9-(2, the 6-3,5-dimethylphenyl)-2,3,4,8,9,10-six hydrogen chromenes are [8,7-e] [1,3] oxazine also
According to the method for embodiment 9, by 7-hydroxychroman and formalin, 2, the reaction of 6-xylidine, column chromatography for separation obtains 9-(2, the 6-3,5-dimethylphenyl)-2,3,4,8,9, and 10-six hydrogen chromenes are [8,7-e] [1,3] oxazine white solid also.Yield: 38%.MS?m/z(M)295.38。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.35(6H，s)，2.55(2H，m)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.16(1H，m)，6.36(1H，m)，6.71(3H，m)。
Embodiment 14:9-(2-chloro-phenyl-)-2,3,4,8,9,10-six hydrogen chromenes are [8,7-e] [1,3] oxazine also
According to the method for embodiment 9, to react by 7-hydroxychroman and formalin, 2-chloroaniline, column chromatography for separation obtains 9-(2-chloro-phenyl-)-2,3,4,8,9, and 10-six hydrogen chromenes are [8,7-e] [1,3] oxazine white solid also.Yield: 33%.MS?m/z(M)301.77。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.16(1H，m)，6.54(2H，m)，6.71(1H，m)，6.96(1H，m)，7.09(1H，m)。
Embodiment 15:9-(4-chloro-phenyl-)-2,3,4,8,9,10-six hydrogen chromenes are [8,7-e] [1,3] oxazine also
According to the method for embodiment 9, to react by 7-hydroxychroman and formalin, 4-chloroaniline, column chromatography for separation obtains 9-(4-chloro-phenyl-)-2,3,4,8,9, and 10-six hydrogen chromenes are [8,7-e] [1,3] oxazine white solid also.Yield: 44%.MS?m/z(M)301.77。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.16(1H，m)，6.54(2H，m)，6.71(1H，m)，7.09(2H，m)。
Embodiment 16:9-(4-p-methoxy-phenyl)-2,3,4,8,9,10-six hydrogen chromenes are [8,7-e] [1,3] oxazine also
According to the method for embodiment 9, to react by 7-hydroxychroman and formalin, 4-anisidine, column chromatography for separation obtains 9-(4-p-methoxy-phenyl)-2,3,4,8,9, and 10-six hydrogen chromenes are [8,7-e] [1,3] oxazine white solid also.Yield: 37%.MS?m/z(M)297.35。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，3.73(3H，m)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.16(1H，m)，6.48(2H，m)，6.59(2H，m)，6.71(1H，m)。
Embodiment 17:3-benzyl-2,3,4,7,8,9-six hydrogen chromenes are [7,6-e] [1,3] oxazine also
With 1.2mL 37% formalin be dissolved in 2-3mL 95% alcoholic acid 5mmol benzylamine and mix, after reflux stirs several minutes, add and be dissolved in 10mL 95% alcoholic acid 5mmol 6-hydroxychroman, reflux also stirs and spends the night.(sherwood oil: ethyl acetate=30:1) get 3-benzyl-2,3,4,7,8,9-six hydrogen chromenes are [7,6-e] [1,3] oxazine white solid, yield: 51% also through the silica gel column chromatography separation.MSm/z(M)281.35。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，3.94(2H，m)，4.61(4H，s)，6.00(2H，s)，6.20(1H，s)，6.41(1H，s)，6.59(3H，m)，7.08(2H，m)。
Embodiment 18:3-phenyl-2,3,4,7,8,9-six hydrogen chromenes are [7,6-e] [1,3] oxazine also
According to the method for embodiment 17, by 6-hydroxychroman and formalin, aniline reaction, column chromatography for separation obtains 3-phenyl-2,3,4,7,8, and 9-six hydrogen chromenes are [7,6-e] [1,3] oxazine white solid also.Yield: 60%.MS?m/z(M)267.32。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.20(1H，s)，6.41(1H，s)，6.59(3H，m)，7.08(2H，m)。
Embodiment 19:3-(2-aminomethyl phenyl)-2,3,4,7,8,9-six hydrogen chromenes are [7,6-e] [1,3] oxazine also
According to the method for embodiment 17, to react by 6-hydroxychroman and formalin, 2-aminotoluene, column chromatography for separation obtains 3-(2-aminomethyl phenyl)-2,3,4,7,8, and 9-six hydrogen chromenes are [7,6-e] [1,3] oxazine white solid also.Yield: 32%.MS?m/z(M)281.35。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.35(3H，s)，2.55(2H，m)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.20(1H，s)，6.41(1H，s)，6.47(2H，m)，6.88(2H，m)。
Embodiment 20:3-(4-aminomethyl phenyl)-2,3,4,7,8,9-six hydrogen chromenes are [7,6-e] [1,3] oxazine also
According to the method for embodiment 17, to react by 6-hydroxychroman and formalin, 4-monomethylaniline, column chromatography for separation obtains 3-(4-aminomethyl phenyl)-2,3,4,7,8, and 9-six hydrogen chromenes are [7,6-e] [1,3] oxazine white solid also.Yield: 59%.MS?m/z(M)281.35。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.35(3H，s)，2.55(2H，m)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.20(1H，s)，6.41(1H，s)，6.47(2H，m)，6.88(2H，m)。
Embodiment 21:3-(2, the 6-3,5-dimethylphenyl)-2,3,4,7,8,9-six hydrogen chromenes are [7,6-e] [1,3] oxazine also
According to the method for embodiment 17, by 6-hydroxychroman and formalin, 2, the reaction of 6-xylidine, column chromatography for separation obtains 3-(2, the 6-3,5-dimethylphenyl)-2,3,4,7,8, and 9-six hydrogen chromenes are [7,6-e] [1,3] oxazine white solid also.Yield: 53%.MS?m/z(M)295.38。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.35(6H，s)，2.55(2H，m)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.20(1H，s)，6.36(1H，m)，6.41(1H，s)，6.69(2H，m)。
Embodiment 22:3-(2-chloro-phenyl-)-2,3,4,7,8,9-six hydrogen chromenes are [7,6-e] [1,3] oxazine also
According to the method for embodiment 17, to react by 6-hydroxychroman and formalin, 2-chloroaniline, column chromatography for separation obtains 3-(2-chloro-phenyl-)-2,3,4,7,8, and 9-six hydrogen chromenes are [7,6-e] [1,3] oxazine white solid also.Yield: 48%.MS?m/z(M)301.77。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.20(1H，s)，6.41(1H，s)，6.53(2H，m)，6.96(1H，m)，7.09(1H，m)。
Embodiment 23:3-(4-chloro-phenyl-)-2,3,4,7,8,9-six hydrogen chromenes are [7,6-e] [1,3] oxazine also
According to the method for embodiment 17, to react by 6-hydroxychroman and formalin, 4-chloroaniline, column chromatography for separation obtains 3-(4-chloro-phenyl-)-2,3,4,7,8, and 9-six hydrogen chromenes are [7,6-e] [1,3] oxazine white solid also.Yield: 61%.MS?m/z(M)301.77。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.20(1H，s)，6.41(1H，s)，6.53(2H，m)，7.09(2H，s)。
Embodiment 24:3-(4-p-methoxy-phenyl)-2,3,4,7,8,9-six hydrogen chromenes are [7,6-e] [1,3] oxazine also
According to the method for embodiment 17, to react by 6-hydroxychroman and formalin, 4-anisidine, column chromatography for separation obtains 3-(4-p-methoxy-phenyl)-2,3,4,7,8, and 9-six hydrogen chromenes are [7,6-e] [1,3] oxazine white solid also.Yield: 65%.MS?m/z(M)297.35。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，3.73(3H，s)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.20(1H，s)，6.41(1H，s)，6.48(2H，d)，6.59(2H，d)。
Embodiment 25:2-benzyl-1,2,3,8,9,10-six hydrogen chromenes are [5,6-e] [1,3] oxazine also
5mmol 6-hydroxychroman is dissolved in the 2mL95% ethanol, adds 1.2mL 37% formalin, stir several minutes, under ice bath cooling, drip the 5mmol benzylamine that has been dissolved in 2-3mL 95% ethanol, stirred overnight at room temperature, concentrate after silica gel column chromatography separate (sherwood oil: ethyl acetate=30:1) 3-benzyl-2,3,4,5,6,7-six hydrogen chromenes also [5,6-e] [1,3] oxazine white solid, yield: 66%.MSm/z(M)281.35。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，3.94(2H，m)，3.62(4H，s)，5.01(2H，s)，6.36(1H，d)，6.42(1H，d)，7.10(5H，m)。
Embodiment 26:2-phenyl-1,2,3,8,9,10-six hydrogen chromenes are [5,6-e] [1,3] oxazine also
According to the method for embodiment 25, by 6-hydroxychroman and formalin, aniline reaction, column chromatography for separation obtains 3-phenyl-2,3,4,5,6, and 7-six hydrogen chromenes are [5,6-e] [1,3] oxazine white solid also.Yield: 70%.MS?m/z(M)267.32。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.36(1H，d)，6.42(1H，d)，6.60(3H，m)，7.08(2H，m)。
Embodiment 27:2-(2-aminomethyl phenyl)-1,2,3,8,9,10-six hydrogen chromenes are [5,6-e] [1,3] oxazine also
According to the method for embodiment 25, to react by 6-hydroxychroman and formalin, 2-aminotoluene, column chromatography for separation obtains 3-(2-aminomethyl phenyl)-1,2,3,8,9, and 10-six hydrogen chromenes are [5,6-e] [1,3] oxazine white solid also.Yield: 35%.MS?m/z(M)281.35。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.35(3H，s)，2.55(2H，m)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.36(1H，d)，6.42(1H，d)，6.48(2H，m)，6.88(2H，m)。
Embodiment 28:2-(4-aminomethyl phenyl)-1,2,3,8,9,10-six hydrogen chromenes are [5,6-e] [1,3] oxazine also
According to the method for embodiment 25, to react by 6-hydroxychroman and formalin, 4-monomethylaniline, column chromatography for separation obtains 3-(4-aminomethyl phenyl)-2,3,4,5,6, and 7-six hydrogen chromenes are [5,6-e] [1,3] oxazine white solid also.Yield: 68%.MS?m/z(M)281.35。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.35(3H，s)，2.55(2H，m)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.36(1H，d)，6.42(1H，d)，6.47(2H，d)，6.88(2H，d)。
Embodiment 29:2-(2, the 6-3,5-dimethylphenyl)-1,2,3,8,9,10-six hydrogen chromenes are [5,6-e] [1,3] oxazine also
According to the method for embodiment 25, by 6-hydroxychroman and formalin, 2, the reaction of 6-xylidine, column chromatography for separation obtains 3-(2, the 6-3,5-dimethylphenyl)-2,3,4,5,6, and 7-six hydrogen chromenes are [5,6-e] [1,3] oxazine white solid also.Yield: 53%.MS?m/z(M)295.38。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.35(6H，s)，2.55(2H，m)，3.94(2H，m)，4.61(2H，s)，6.00(2H，s)，6.36(1H，d)，6.42(1H，d)，6.52(1H，m)，6.69(2H，m)。
Embodiment 30:2-(2-chloro-phenyl-)-1,2,3,8,9,10-six hydrogen chromenes are [5,6-e] [1,3] oxazine also
According to the method for embodiment 25, to react by 6-hydroxychroman and formalin, 2-chloroaniline, column chromatography for separation obtains 3-(2-chloro-phenyl-)-1,2,3,8,9, and 10-six hydrogen chromenes are [5,6-e] [1,3] oxazine white solid also.Yield: 39%.MS?m/z(M)301.77。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H,m)，3.94(2H,m)，4.61(2H，s)，6.00(2H，s)，6.36(1H,d)，6.42(1H,d)，6.53(2H，m)，6.96(1H,m)，7.09(1H,m)。
Embodiment 31:2-(4-chloro-phenyl-)-1,2,3,8,9,10-six hydrogen chromenes are [5,6-e] [1,3] oxazine also
According to the method for embodiment 25, to react by 6-hydroxychroman and formalin, 4-chloroaniline, column chromatography for separation obtains 3-(4-chloro-phenyl-)-1,2,3,8,9, and 10-six hydrogen chromenes are [5,6-e] [1,3] oxazine white solid also.Yield: 67%.MS?m/z(M)301.77。
1HNMR(CDCl
3)：δ2.04(2H,m)，2.55(2H,m)，3.94(2H,m)，4.61(2H，s)，6.00(2H，s)，6.36(1H,d)，6.42(1H,d)，6.53(2H,m)，7.09(2H,m)。
Embodiment 32:2-(4-p-methoxy-phenyl)-1,2,3,8,9,10-six hydrogen chromenes are [5,6-e] [1,3] oxazine also
According to the method for embodiment 25, to react by 6-hydroxychroman and formalin, 4-anisidine, column chromatography for separation obtains 3-(4-p-methoxy-phenyl)-2,3,4,5,6, and 7-six hydrogen chromenes are [5,6-e] [1,3] oxazine white solid also.Yield: 77%.MS?m/z(M)297.35。
1HNMR(CDCl
3)：δ2.04(2H,m)，2.55(2H,m)，3.73(3H，s)，3.94(2H,m)，4.61(2H，s)，6.00(2H，s)，6.36(1H,d)，6.42(1H,d)，6.48(2H,m)，6.59(2H,m)。
Embodiment 33:3-benzyl-2,3,4,8,9,10-six hydrogen chromenes are [6,5-e] [1,3] oxazine also
5mmol 5-hydroxychroman is dissolved in 2mL 95% ethanol, adds 1.2mL 37% formalin, stir several minutes, under ice bath cooling, drip the 5mmol benzylamine that has been dissolved in 2-3mL 95% ethanol, stirred overnight at room temperature, concentrate after silica gel column chromatography separate (sherwood oil: ethyl acetate=30:1) 3-benzyl-2,3,4,8,9,10-six hydrogen chromenes also [6,5-e] [1,3] oxazine white solid, yield: 55%.MS?m/z(M)281.35。
1HNMR(CDCl
3)：δ2.04(2H,m)，2.55(2H,m)，3.62(4H，s)，3.94(2H,m)，5.01(2H，s)，6.16(1H,d)，6.66(1H,d)，7.10(5H,m)。
Embodiment 34:3-phenyl-2,3,4,8,9,10-six hydrogen chromenes are [6,5-e] [1,3] oxazine also
According to the method for embodiment 33, by 5-hydroxychroman and formalin, aniline reaction, column chromatography for separation obtains 3-phenyl-2,3,4,8,9,10. six hydrogen chromenes [6,5-e] [1,3] oxazine white solid also.Yield: 43%.MS?m/z(M)267.32。
1HNMR(CDCl
3)：δ2.04(2H,m)，2.55(2H,m)，4.61(2H,s)，3.94(2H,m)，6.00(2H，s)，6.16(1H,d)，6.66(1H,d)，6.59(3H,m)，7.08(2H,m)。
Embodiment 35:3-(2-aminomethyl phenyl)-2,3,4,8,9,10-six hydrogen chromenes are [6,5-e] [1,3] oxazine also
According to the method for embodiment 33, to react by 5-hydroxychroman and formalin, 2-aminotoluene, column chromatography for separation obtains 3-(2-aminomethyl phenyl)-2,3,4,8,9, and 10-six hydrogen chromenes are [6,5-e] [1,3] oxazine white solid also.Yield: 48%.MS?m/z(M)281.35。
1HNMR(CDCl
3)：δ2.04(2H,m)，2.35(3H，s)，2.55(2H,m)，4.61(2H,s)，3.94(2H,m)，6.00(2H，s)，6.16(1H,d)，6.66(1H,d)，6.48(2H,m)，6.88(2H,m)。
Embodiment 36:3-(4-aminomethyl phenyl)-2,3,4,8,9,10-six hydrogen chromenes are [6,5-e] [1,3] oxazine also
According to the method for embodiment 33, to react by 5-hydroxychroman and formalin, 4-monomethylaniline, column chromatography for separation obtains 3-(4-aminomethyl phenyl)-2,3,4,8,9, and 10-six hydrogen chromenes are [6,5-e] [1,3] oxazine white solid also.Yield: 57%.MS?m/z(M)281.35。
1HNMR(CDCl
3)：δ2.04(2H,m)，2.35(3H，s)，2.55(2H,m)，4.61(2H,s)，3.94(2H,m)，6.00(2H，s)，6.16(1H,d)，6.66(1H,d)，6.47(2H,m)，6.89(2H,m)。
Embodiment 37:3-(2, the 6-3,5-dimethylphenyl)-2,3,4,8,9,10-six hydrogen chromenes are [6,5-e] [1,3] oxazine also
According to the method for embodiment 33, by 5-hydroxychroman and formalin, 2, the reaction of 6-xylidine, column chromatography for separation obtains 3-(2, the 6-3,5-dimethylphenyl)-2,3,4,8,9, and 10-six hydrogen chromenes are [6,5-e] [1,3] oxazine white solid also.Yield: 50%.MS?m/z(M)295.38。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.35(6H，s)，2.55(2H，m)，4.61(2H，s)，3.94(2H，m)，6.00(2H，s)，6.16(1H，d)，6.66(1H，d)，6.36(1H，m)，6.69(2H，m)。
Embodiment 38:3-(2-chloro-phenyl-)-2,3,4,8,9,10-six hydrogen chromenes are [6,5-e] [1,3] oxazine also
According to the method for embodiment 33, to react by 5-hydroxychroman and formalin, 2-chloroaniline, column chromatography for separation obtains 3-(2-chloro-phenyl-)-2,3,4,8,9, and 10-six hydrogen chromenes are [6,5-e] [1,3] oxazine white solid also.Yield: 55%.MS?m/z(M)301.77。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，4.61(2H，s)，3.94(2H，m)，6.00(2H，s)，6.16(1H，d)，6.66(1H，d)，6.54(2H，m)，6.98(2H，m)。
Embodiment 39:3-(4-chloro-phenyl-)-2,3,4,8,9,10-six hydrogen chromenes are [6,5-e] [1,3] oxazine also
According to the method for embodiment 33, to react by 5-hydroxychroman and formalin, 4-chloroaniline, column chromatography for separation obtains 3-(4-chloro-phenyl-)-2,3,4,8,9, and 10-six hydrogen chromenes are [6,5-e] [1,3] oxazine white solid also.Yield: 49%.MS?m/z(M)301.77。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，4.61(2H，s)，3.94(2H，m)，6.00(2H，s)，6.16(1H，d)，6.66(1H，d)，6.54(2H，d)，7.09(2H，d)。
Embodiment 40:3-(4-p-methoxy-phenyl)-2,3,4,8,9,10-six hydrogen chromenes are [6,5-e] [1,3] oxazine also
According to the method for embodiment 33, to react by 5-hydroxychroman and formalin, 4-anisidine, column chromatography for separation obtains 3-(4-p-methoxy-phenyl)-2,3,4,8,9, and 10-six hydrogen chromenes are [6,5-e] [1,3] oxazine white solid also.Yield: 52%.MS?m/z(M)297.35。
1HNMR(CDCl
3)：δ2.04(2H，m)，3.73(3H，s)，2.55(2H，m)，4.61(2H，s)，3.94(2H，m)，6.00(2H，s)，6.16(1H，d)，6.66(1H，d)，6.48(2H，d)，6.59(2H，d)。
Embodiment 41:3-benzyl-2,3,4,7,8,9-six hydrogen chromenes are [7,8-e] [1,3] oxazine also
5mmol 8-hydroxychroman is dissolved in 2mL 95% ethanol, adds 1.2mL 37% formalin, stir several minutes, under ice bath cooling, drip the 5mmol benzylamine that has been dissolved in 2-3mL 95% ethanol, stirred overnight at room temperature, concentrate after silica gel column chromatography separate (sherwood oil: ethyl acetate=30:1) 3-benzyl-2,3,4,7,8,9-six hydrogen chromenes also [7,8-e] [1,3] oxazine white solid, yield: 48%.MSm/z(M)281.35。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，3.62(4H，s)，3.94(2H，m)，.01(2H，s)，6.46(2H，d)，7.10(5H，m)。
Embodiment 42:3-phenyl-2,3,4,7,8,9-six hydrogen chromenes are [7,8-e] [1,3] oxazine also
According to embodiment 41 methods, by 8-hydroxychroman and formalin, aniline reaction, column chromatography for separation obtains 3-phenyl-2,3,4,7,8, and 9-six hydrogen chromenes are [7,8-e] [1,3] oxazine white solid, yield: 45% also.MS?m/z(M)267.32。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，4.61(2H，s)，3.94(2H，m)，6.00(2H，s)，6.46(2H，d)，6.60(3H，m)，7.10(2H，m)。
Embodiment 43:3-(2-aminomethyl phenyl)-2,3,4,7,8,9-six hydrogen chromenes are [7,8-e] [1,3] oxazine also
According to embodiment 41 methods, to react by 8-hydroxychroman and formalin, 2-aminotoluene, column chromatography for separation obtains 3-(2-aminomethyl phenyl)-2,3,4,7,8, and 9-six hydrogen chromenes are [7,8-e] [1,3] oxazine white solid, yield: 39% also.MS?m/z(M)281.35。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.35(3H，s)，2.55(2H，m)，4.61(2H，s)，3.94(2H，m)，6.00(2H，s)，6.46(2H，d)，6.60(2H，m)，6.89(2H，m)。
Embodiment 44:3-(4-aminomethyl phenyl)-2,3,4,7,8,9-six hydrogen chromenes are [7,8-e] [1,3] oxazine also
According to embodiment 41 methods, to react by 8-hydroxychroman and formalin, 4-monomethylaniline, column chromatography for separation obtains 3-(4-aminomethyl phenyl)-2,3,4,7,8, and 9-six hydrogen chromenes are [7,8-e] [1,3] oxazine white solid, yield: 41% also.MS?m/z(M)281.35。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.35(3H，s)，2.55(2H，m)，4.61(2H，s)，3.94(2H，m)，6.00(2H，s)，6.46(2H，d)，6.47(2H，d)，6.89(2H，d)。
Embodiment 45:3-(2, the 6-3,5-dimethylphenyl)-2,3,4,7,8,9-six hydrogen chromenes are [7,8-e] [1,3] oxazine also
According to embodiment 41 methods, by 8-hydroxychroman and formalin, 2, the reaction of 6-xylidine, column chromatography for separation obtains 3-(2, the 6-3,5-dimethylphenyl)-2,3,4,7,8, and 9-six hydrogen chromenes are [7,8-e] [1,3] oxazine white solid, yield: 40% also.MS?m/z(M)295.38。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.35(6H，s)，2.55(2H，m)，4.61(2H，s)，3.94(2H，m)，6.00(2H，s)，6.46(2H，d)，6.36(2H，m)，6.69(2H，m)。
Embodiment 46:3-(2-chloro-phenyl-)-2,3,4,7,8,9-six hydrogen chromenes are [7,8-e] [1,3] oxazine also
According to embodiment 41 methods, to react by 8-hydroxychroman and formalin, 2-chloroaniline, column chromatography for separation obtains 3-(2-chloro-phenyl-)-2,3,4,7,8, and 9-six hydrogen chromenes are [7,8-e] [1,3] oxazine white solid, yield: 47% also.MS?m/z(M)301.77。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，4.61(2H，s)，3.94(2H，m)，6.00(2H，s)，6.46(2H，d)，6.54(2H，m)，6.99(2H，m)。
Embodiment 47:3-(4-chloro-phenyl-)-2,3,4,7,8,9-six hydrogen chromenes are [7,8-e] [1,3] oxazine also
According to embodiment 41 methods, to react by 8-hydroxychroman and formalin, 4-chloroaniline, column chromatography for separation obtains 3-(4-chloro-phenyl-)-2,3,4,7,8, and 9-six hydrogen chromenes are [7,8-e] [1,3] oxazine white solid, yield: 35% also.MS?m/z(M)301.77。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，4.61(2H，s)，3.94(2H，m)，6.00(2H，s)，6.46(2H，d)，6.53(2H，d)，7.09(2H，d)。
Embodiment 48:3-(4-p-methoxy-phenyl)-2,3,4,7,8,9-six hydrogen chromenes are [7,8-e] [1,3] oxazine also
According to embodiment 41 methods, to react by 8-hydroxychroman and formalin, 4-anisidine, column chromatography for separation obtains 3-(4-p-methoxy-phenyl)-2,3,4,7,8, and 9-six hydrogen chromenes are [7,8-e] [1,3] oxazine white solid, yield: 37% also.MS?m/z(M)297.35。
1HNMR(CDCl
3)：δ2.04(2H，m)，2.55(2H，m)，3.73(3H，s)，4.61(2H，s)，3.94(2H，m)，6.00(2H，s)，6.46(2H，d)，6.48(2H，d)，6.59(2H，d)。
Following indefiniteness embodiment explanation is used for the prescription of different topical modes.In the prescription of percutaneous dosing, the consumption of compound is generally 0.001-0.2%w/w), preferred 0.01-0.1%w/w).
Embodiment 49: the ointment prescription
Micronization active compound 0.025g, whiteruss 10g adds soft Chinese wax to 100g.
Embodiment 50: the ointment prescription
Active compound 0.025g, propylene glycol 5g, Arlacel-83 5g, whiteruss 10g adds soft Chinese wax to 100g.
Embodiment 51: oil-in-water creme prescription
Active compound 0.025g, hexadecanol 5g, glyceryl monostearate 5g, whiteruss 10g, Cetomacrogol 1000 2g, citric acid 0.1g, Trisodium Citrate 0.2g, propylene glycol 35g adds water to 100g.
Embodiment 52: oil-in-water creme prescription
Micronization active compound 0.025g, soft Chinese wax 15g, whiteruss 5g, hexadecanol 5g, Sorbimacrogol stearate 2g, Arlacel-60 0.5g, Sorbic Acid 0.2g, citric acid 0.1g, Trisodium Citrate 0.2g adds water to 100g.
Embodiment 53: water-in-oil creme prescription
Active compound 0.025g, soft Chinese wax 35g, whiteruss 5g, the liquor-saturated sesquioleate 5g of dehydration sorb, Sorbic Acid 0.2g, citric acid 0.1g, Trisodium Citrate 0.2g adds water to 100g.
Embodiment 54: lotion formulation
Active compound 0.25g, Virahol 0.5mL, carboxyvinyl polymer 3mg, NaOH is an amount of, adds water to 1g.
Embodiment 55: the injection suspension formulation
Active compound 0.05-10mg, Xylo-Mucine 7mg, NaCl 7mg, polyoxyethylene (20) polyoxyethylene-sorbitan mono-oleate 0.5mg, phenylcarbinol 8mg adds sterilized water to 1ml.
Embodiment 56: be used for the aerosol formulations that oral cavity and snuffing are gone into
Active compound 0.1%w/w, sorbitan trioleate 0.7%w/w, trichlorofluoromethane 24.8%w/w, dichloro tetrafluoro ethane 24.8%w/w, Refrigerant 12 49.6%w/w.
Embodiment 57: the atomized soln prescription
Active compound 7mg, propylene glycol 5mg adds water to 10g.
Embodiment 58: the wp formula that is used to suck
Mixture with following composition is filled the phaneroplasm capsule, micronization active compound 0.1mg, and lactose 20mg sucks this powder by means of suction apparatus.
Embodiment 59: the wp formula that is used to suck
The pulvis of the nodularization multi-agent powder inhalator of packing into, every dose contains micronization active compound 0.1mg.
Embodiment 60: the wp formula that is used to suck
With the pulvis of the nodularization multi-agent powder inhalator of packing into, every dose contains micronization active compound 0.1mg, micronization lactose 1mg.
Embodiment 61: the capsule prescription
Active compound 1.0mg, little sugared ball 321mg, Aquacoat ECD 30 6.6mg, tributyl acetylcitrate 0.5mg, tween-80 0.1mg, Eudragit L 100-55 17.5mg, triethyl citrate 1.8mg, talcum powder 8.8mg, defoamer MMS 0.1mg.
Embodiment 62: capsule seedling body prescription
Active compound 2.0mg, little sugared ball 305mg, Aquocoat ECD 30 5.0mg, acetyl lemon tri-n-butyl 0.4mg, tween-80 0.14mg, Eudragit NE30 D 12.6mg, Eudragit S 10012.6mg, talcum powder 0.16mg.
Embodiment 63: the enema prescription
Active compound 00.2mg, Xylo-Mucine 25mg, disodium ethylene diamine tetraacetate 0.5mg, methyl p-hydroxybenzoate 0.8mg, propylparaben 0.2mg, sodium-chlor 7mg, citric acid 1.8mg, tween-80 0.01mg adds pure water to 1mL.
Embodiment 64: the prescription that contains liposome
A. the preparation of instiling and filling a prescription
In a Glass tubing, mix synthetic two palmitoyl Yelkin TTS (45mg), two myristoyl Yelkin TTS (7mg), DPPG (1mg) and (active compound (5mg) is dissolved in all components in the chloroform, uses N
2Evaporate most of solvent, decompression then thus, forms lipid membrane on the Glass tubing surface.Add the aqueous solution (0.9% NaCl) in this lipid, form liposome being higher than under the phase inversion temperature of lipid, the gained suspension contains the liposome that magnitude range is minimum vesica to 2 μ m.
B. suck preparation with prescription
Prepare liposome by embodiment A, the aqueous solution wherein contains 10% lactose, and lactose is 7:3 with the ratio of lipid.This liposome suspension is freezing with dry ice, and carry out lyophilize, with the desciccate micronization, the equal aerodynamic diameter of gained particulate matter (MMAD) is about 2 μ m.
Embodiment 64: to adenosine diphosphate (ADP) (ADP) induced platelet accumulative restraining effect
Animal: rabbit, 3-5kg, male and female dual-purpose.
Instrument: SHANDA PA-196 type platelet aggregation instrument.
The medicine collocation method: get 40mL methyl alcohol, 60M10.9% physiological saline mixes and to be made into standardized solution, accurately weighs 1mg sample (being accurate to 0.01mg), and being diluted to concentration with standardized solution is solution for standby about 1mg/mL.ADP is dissolved in physiological saline (250uM).
Positive control: acetylsalicylic acid also is made into as above concentration with standardized solution.
Experimental technique: in the 50mL plastic test tube, add the 4mL3.8% Sodium Citrate aqueous solution, carefully clean the rabbit ear with alcohol, clean the rabbit ear with dimethylbenzene again, treat to smear Vaseline at ear edge place after blood vessel expands, sever blood vessel, collect 36mL blood with the preparation test tube, blood is mixed,, isolate supernatant blood plasma PRP (being rich in thrombocyte blood plasma) with the centrifugal 8-10min of 900 commentaries on classics/min, then with the centrifugal 8-10min of 3500 commentaries on classics/min, isolate supernatant blood plasma PPP (the poor thrombocyte blood plasma that contains).The accurate 250uLPRP of absorption adds and assembles in the pipe, in assembling pipe, add the 40% methanol aqueous solution 20uL that contains medicine, to be marked with the gathering pipe of the PPP of 250uL and PRP blood plasma respectively at 37 ± 0.01 ℃ of preheating 5min, return to zero with PPP250uL, adding 10uL adenosine diphosphate (ADP) (ADP) induced platelet again in cuvette assembles, under 37 ℃ of agitation conditions, curve plotting, measure the thrombocyte MA, and do contrast with blank solvent, with the positive contrast of acetylsalicylic acid, calculate the anticoagulant rate.Assemble inhibiting rate=(blank is assembled inhibiting rate one sample and assembled inhibiting rate)/blank and assemble inhibiting rate * 100%.The sample segment inhibiting rate is listed as follows:
The result shows that compound of the present invention has the effect of the ADP of inhibition induced platelet accumulative.
Embodiment 65: to collagen-induced platelet accumulative restraining effect
Animal: rabbit, 3-5kg, male and female dual-purpose.
Medicine collocation method: get 90mL methyl alcohol, 10mLDMSO and mix and be made into standardized solution I.Getting 80mL methyl alcohol, 20mLDMSO mixes and is made into standardized solution.Accurately weigh sample (being accurate to 0.001g), dissolve with standardized solution I, be made into the solution for standby that concentration is 30umol/mL, 10umol/mL, 3umol/mL, 1umol/mL respectively, sample for indissoluble in standardized solution I dissolves with standardized solution II, is made into the solution for standby that concentration is 10umol/mL, 3umol/mL, 1umol/mL.
Positive control: acetylsalicylic acid also is made into as above concentration respectively with standardized solution I and standardized solution II.
Experimental technique: in the 10mL plastic test tube, add 1mL3.8% structure rafter acid sodium aqueous solution, carefully clean the rabbit ear with alcohol, clean the rabbit ear with dimethylbenzene again, treat to smear Vaseline at ear edge place after blood vessel expands, sever blood vessel, collect 9mL blood with the preparation test tube, blood is mixed,, isolate supernatant blood plasma PRP (being rich in thrombocyte blood plasma) with the centrifugal 8-10min of 900 commentaries on classics/min, then with the centrifugal 8-10min of 3500 commentaries on classics/min, isolate supernatant blood plasma PPP (the poor thrombocyte blood plasma that contains).Return to zero with PPP, the accurate 200uLPRP of absorption adds in the cuvette, in cuvette, add sample solution 20uL, 37 ± 0.01 ℃ hatch 2min after, in cuvette, add the 20uL collagen-induced platelet again and assemble, under 37 ℃ of agitation conditions, curve plotting is measured the thrombocyte MA, and does contrast with blank solvent, with the positive contrast of acetylsalicylic acid, calculate the sample of blood platelet and assemble inhibiting rate.The sample segment inhibiting rate is listed as follows:
The result shows that compound of the present invention has the effect of the collagen-induced platelet of inhibition accumulative.
Embodiment 66: the restraining effect of the acetate inducing mouse being turned round body
Kunming mouse, male and female half and half, body weight 18-22 gram, random packet, every group of 8 animals.If blank group, positive controls and new compound group.The blank group is 0.2% Xylo-Mucine normal saline solution, and all medicines disperse with 0.2% Xylo-Mucine normal saline solution, and concentration is 0.1mg/ml.
Employing causes the analgesic activities of mouse writhing model comment compound to narcotic analgesic acetate commonly used, respectively to each group mouse peritoneal injection blank or medicine 0.2ml, inject 0.6% acetate normal saline solution 0.2ml behind the 1h more respectively, begin to count the number of times of mouse writhing in 10 minutes after 5 minutes, turning round the body number of times is designated as the pain sensation smaller or equal to 5 times mouse and is suppressed, then be designated as the pain sensation greater than 5 times and be not suppressed, calculate pain sensation inhibiting rate with this.The sample segment inhibiting rate is listed as follows:
Test-results shows that The compounds of this invention all has analgesic activities.
Embodiment 67: the restraining effect of p-Xylol inducing mouse ear swelling
Male Kunming strain mice body weight 18-22 gram, random packet, every group of 8 animals.If blank group (0.2%CMCNa normal saline solution), positive controls and medicine-feeding test group.Cause scorching preceding 60min intraperitoneal injection.Take by weighing the 0.5mg medicine respectively and place the 5ml volumetric flask, with 0.2% CMCNa normal saline solution wiring solution-forming.Every mouse is injected 0.3ml blank or medicine respectively.Dimethylbenzene 50 microlitres are dripped in mouse right ear, and left ear is contrast.Put to death mouse behind the 30min, cut two ears along the auricle baseline, lay round auricle with diameter 6mm punch tool respectively at the same position of two ears, weigh, two auricle weight is poor about asking, and as the swelling degree, and the significance of comparative group differences whether.The sample segment inhibiting rate is listed as follows:
Test-results shows that The compounds of this invention all has anti-inflammatory activity.
Claims (5)
1. one kind as shown in the formula the oxazine compounds shown in the I-VI
Wherein R can independently be selected from H, an alkyl group to four carbon atom, and benzyl perhaps replaces or unsubstituted aryl group.
2. the compound of a claim 1, it is selected from:
3-benzyl-2,3,4,8,9,10-six hydrogen chromenes also [6,5-e] [1,3] oxazine,
3-phenyl-2,3,4,8,9,10-six hydrogen chromenes also [6,5-e] [1,3] oxazine,
3-(2-aminomethyl phenyl)-2,3,4,8,9,10-six hydrogen chromenes also [6,5-e] [1,3] oxazine,
3-(4-aminomethyl phenyl)-2,3,4,8,9,10-six hydrogen chromenes also [6,5-e] [1,3] oxazine,
3-(2, the 6-3,5-dimethylphenyl)-2,3,4,8,9,10-six hydrogen chromenes also [6,5-e] [1,3] oxazine,
3-(2-chloro-phenyl-)-2,3,4,8,9,10-six hydrogen chromenes also [6,5-e] [1,3] oxazine,
3-(4-chloro-phenyl-)-2,3,4,8,9,10-six hydrogen chromenes also [6,5-e] [1,3] oxazine,
3-(4-p-methoxy-phenyl)-2,3,4,8,9,10-six hydrogen chromenes are [6,5-e] [1,3] oxazine also;
3-benzyl-2,3,4,7,8,9-six hydrogen chromenes also [7,6-e] [1,3] oxazine,
3-phenyl-2,3,4,7,8,9-six hydrogen chromenes also [7,6-e] [1,3] oxazine,
3-(2-aminomethyl phenyl)-2,3,4,7,8,9-six hydrogen chromenes also [7,6-e] [1,3] oxazine,
3-(4-aminomethyl phenyl)-2,3,4,7,8,9-six hydrogen chromenes also [7,6-e] [1,3] oxazine,
3-(2, the 6-3,5-dimethylphenyl)-2,3,4,7,8,9-six hydrogen chromenes also [7,6-e] [1,3] oxazine,
3-(2-chloro-phenyl-)-2,3,4,7,8,9-six hydrogen chromenes also [7,6-e] [1,3] oxazine,
3-(4-chloro-phenyl-)-2,3,4,7,8,9-six hydrogen chromenes also [7,6-e] [1,3] oxazine,
3-(4-p-methoxy-phenyl)-2,3,4,7,8,9-six hydrogen chromenes are [7,6-e] [1,3] oxazine also;
3-benzyl-2,3,4,5,6,7-six hydrogen chromenes also [5,6-e] [1,3] oxazine,
3-phenyl-2,3,4,5,6,7-six hydrogen chromenes also [5,6-e] [1,3] oxazine,
3-(2-aminomethyl phenyl)-2,3,4,5,6,7-six hydrogen chromenes also [5,6-e] [1,3] oxazine,
3-(4-aminomethyl phenyl)-2,3,4,5,6,7-six hydrogen chromenes also [5,6-e] [1,3] oxazine,
3-(2, the 6-3,5-dimethylphenyl)-2,3,4,5,6,7-six hydrogen chromenes also [5,6-e] [1,3] oxazine,
3-(2-chloro-phenyl-)-2,3,4,5,6,7-six hydrogen chromenes also [5,6-e] [1,3] oxazine,
3-(4-chloro-phenyl-)-2,3,4,5,6,7-six hydrogen chromenes also [5,6-e] [1,3] oxazine,
3-(4-p-methoxy-phenyl)-2,3,4,5,6,7-six hydrogen chromenes are [5,6-e] [1,3] oxazine also;
3-benzyl-2,3,4,6,7,8-six hydrogen chromenes also [6,7-e] [1,3] oxazine,
3-phenyl-2,3,4,6,7,8-six hydrogen chromenes also [6,7-e] [1,3] oxazine,
3-(2-aminomethyl phenyl)-2,3,4,6,7,8-six hydrogen chromenes also [6,7-e] [1,3] oxazine,
3-(4-aminomethyl phenyl)-2,3,4,6,7,8-six hydrogen chromenes also [6,7-e] [1,3] oxazine,
3-(2, the 6-3,5-dimethylphenyl) 2,3,4,6,7,8-six hydrogen chromenes also [6,7-e] [1,3] oxazine,
3-(2-chloro-phenyl-)-2,3,4,6,7,8-six hydrogen chromenes also [6,7-e] [1,3] oxazine,
3-(4-chloro-phenyl-)-2,3,4,6,7,8-six hydrogen chromenes also [6,7-e] [1,3] oxazine,
3-(4-p-methoxy-phenyl)-2,3,4,6,7,8-six hydrogen chromenes are [6,7-e] [1,3] oxazine also.
9-benzyl-2,3,4,8,9,10-six hydrogen chromenes also [8,7-e] [1,3] oxazine,
9-phenyl-2,3,4,8,9,10-six hydrogen chromenes also [8,7-e] [1,3] oxazine,
9-(2-aminomethyl phenyl)-2,3,4,8,9,10-six hydrogen chromenes also [8,7-e] [1,3] oxazine,
9-(4-aminomethyl phenyl)-2,3,4,8,9,10-six hydrogen chromenes also [8,7-e] [1,3] oxazine,
9-(2, the 6-3,5-dimethylphenyl)-2,3,4,8,9,10-six hydrogen chromenes also [8,7-e] [1,3] oxazine,
9-(2-chloro-phenyl-)-2,3,4,8,9,10-six hydrogen chromenes also [8,7-e] [1,3] oxazine,
9-(4-chloro-phenyl-)-2,3,4,8,9,10-six hydrogen chromenes also [8,7-e] [1,3] oxazine,
9-(4-p-methoxy-phenyl)-2,3,4,8,9,10-six hydrogen chromenes are [8,7-e] [1,3] oxazine also.
3-benzyl-2,3,4,7,8,9-six hydrogen chromenes also [7,8-e] [1,3] oxazine,
3-phenyl-2,3,4,7,8,9-six hydrogen chromenes also [7,8-e] [1,3] oxazine,
3-(2-aminomethyl phenyl)-2,3,4,7,8,9-six hydrogen chromenes also [7,8-e] [1,3] oxazine,
3-(4-aminomethyl phenyl)-2,3,4,7,8,9-six hydrogen chromenes also [7,8-e] [1,3] oxazine,
3-(2, the 6-3,5-dimethylphenyl)-2,3,4,7,8,9-six hydrogen chromenes also [7,8-e] [1,3] oxazine,
3-(2-chloro-phenyl-)-2,3,4,7,8,9-six hydrogen chromenes also [7,8-e] [1,3] oxazine,
3-(4-chloro-phenyl-)-2,3,4,7,8,9-six hydrogen chromenes also [7,8-e] [1,3] oxazine,
3-(4-p-methoxy-phenyl)-2,3,4,7,8,9-six hydrogen chromenes are [7,8-e] [1,3] oxazine also.
3. medicinal compositions is characterized in that: said composition contain significant quantity claim 1 compound or its pharmacy acceptable salt, and pharmaceutically acceptable carrier.
4. the application of the described compound of claim 1 in the preparation medicament for resisting platelet aggregation.
5. the application of the described medicinal compositions of claim 3 in the preparation medicament for resisting platelet aggregation.
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| CN1056844C (en) * | 1995-02-27 | 2000-09-27 | 弗·哈夫曼-拉罗切有限公司 | Dioxide pyrrolo-pyrrolo derivatives |
| CN101072769A (en) * | 2004-08-06 | 2007-11-14 | 第一制药株式会社 | Antiplatelet agent and process for producing the same |
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| CN1056844C (en) * | 1995-02-27 | 2000-09-27 | 弗·哈夫曼-拉罗切有限公司 | Dioxide pyrrolo-pyrrolo derivatives |
| CN101072769A (en) * | 2004-08-06 | 2007-11-14 | 第一制药株式会社 | Antiplatelet agent and process for producing the same |
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| CN101948475A (en) * | 2010-08-10 | 2011-01-19 | 沈阳药科大学 | Isoflavone derivate-chromene (chroman) oxazines compound, preparation method and application thereof |
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