CN101486714B - 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 follow; 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 the purposes of oxazine compounds and platelet aggregation-against thereof.
Technical background
Clinical study shows, diseases such as common cardiovascular and cerebrovascular diseases such as hypertension, diabetes, stenocardia, myocardial infarction, cerebral infarction and hematencephalon clinically, all change relevant (Tianjin medicine, 1992,20 (11): 684) with Abnormal Blood Rheology with platelet function.Therefore, prevent that platelet aggregation is significant.
Thrombocyte is to be produced by megalokaryocyte cracking ripe in the marrow, and the volume of platelets that just generates is larger, has the ability of synthetic protein, and adhesion is strong, is easy to assemble and release reaction occurs, 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, hemodynamic change or when being subject to extraneous chemical substance and stimulating, three kinds of reactions that are associated then occur in thrombocyte, namely adhere to, discharge and gathering, and medicament for resisting platelet aggregation is divided into the medicine that (1) suppresses the metabolism of thrombocyte arachidonic acid; (2) medicine of Camp content in the increase thrombocyte; (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 affect the factor of platelet aggregation, some medicine remains in uncertain therapeutic efficacy to be cut, stability is not enough, have the 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 the multiple physiologically actives such as antitumor, anti-inflammatory and cardiovascular and cerebrovascular diseases.(Harborne?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: Chemical Industry Press .2001,39-69).The platelet aggregation that 4-chromanone Mannich alkaloid compound is induced ADP all has significant inhibition active, 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, the recklessly synthetic and anti-inflammatory activity research of spring .4-chromanone compound. 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-chromanone Mannich alkaloid compound poor stability, we carry out structural modification to flavonoid compound and 4-chromanone compound, having designed and synthesized one is the 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, the 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 aromatic group.
Wherein R can independently be selected from H, an alkyl group to four carbon atom, and benzyl perhaps replaces or unsubstituted aromatic group.
Wherein R can independently be selected from H, an alkyl group to four carbon atom, and benzyl perhaps replaces or unsubstituted aromatic group.
Wherein R can independently be selected from H, an alkyl group to four carbon atom, and benzyl perhaps replaces or unsubstituted aromatic group.
Wherein R can independently be selected from H, an alkyl group to four carbon atom, and benzyl perhaps replaces or unsubstituted aromatic group.
Wherein R can independently be selected from H, an alkyl group to four carbon atom, and benzyl perhaps replaces or unsubstituted aromatic 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 affect content of the present invention.The compound process infrared spectra (IR) of telling, 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 the ice bath cooling, drip the 5mmol benzylamine that has been dissolved in 2-3mL 95% ethanol, stirred overnight at room temperature, concentrated by silica gel column chromatography separation (sherwood oil: ethyl acetate=30: 1) get 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 be reacted 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 be reacted 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-(2,6-3,5-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-(2,6-3,5-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 be reacted 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 be reacted 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 be reacted 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
1.2mL 37% formalin is mixed with the 5mmol benzylamine that is dissolved in 2-3mL 95% ethanol, after reflux stirs several minutes, add the 5mmol 7-hydroxychroman that is dissolved in 10mL 95% ethanol, 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%.MSm/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 be reacted 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 be reacted 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-(2,6-3,5-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-(2,6-3,5-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 be reacted 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 be reacted 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 be reacted 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
1.2mL 37% formalin is mixed with the 5mmol benzylamine that is dissolved in 2-3mL 95% ethanol, after reflux stirs several minutes, add the 5mmol 6-hydroxychroman that is dissolved in 10mL 95% ethanol, 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 be reacted 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 be reacted 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-(2,6-3,5-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-(2,6-3,5-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 be reacted 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 be reacted 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 be reacted 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 2mL 95% ethanol, adds 1.2mL 37% formalin, stir several minutes, under the ice bath cooling, drip the 5mmol benzylamine that has been dissolved in 2-3mL 95% ethanol, stirred overnight at room temperature, concentrated by silica gel column chromatography separation (sherwood oil: ethyl acetate=30: 1) get 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 be reacted 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 be reacted 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-(2,6-3,5-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-(2,6-3,5-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 be reacted 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 be reacted 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 be reacted 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 the ice bath cooling, drip the 5mmol benzylamine that has been dissolved in 2-3mL 95% ethanol, stirred overnight at room temperature, concentrated by silica gel column chromatography separation (sherwood oil: ethyl acetate=30: 1) get 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, and 10-six hydrogen chromenes are [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 be reacted 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 be reacted 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-(2,6-3,5-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-(2,6-3,5-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 be reacted 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 be reacted 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 be reacted 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 the ice bath cooling, drip the 5mmol benzylamine that has been dissolved in 2-3mL 95% ethanol, stirred overnight at room temperature, concentrated by silica gel column chromatography separation (sherwood oil: ethyl acetate=30: 1) get 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 be reacted 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 be reacted 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-(2,6-3,5-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-(2,6-3,5-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 be reacted 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 be reacted 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 be reacted 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, Ce tomacrogol 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 enter
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 for suction
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 for suction
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 for suction
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 306.6mg, 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 tributylcitrate 0.4mg, tween-80 0.14mg, Eudragit NE30D 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
The preparation of A. instiling and filling a prescription
In a Glass tubing, mix synthetic DPPC (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, then decompression thus, forms lipid membrane on the Glass tubing surface. in this lipid, add the aqueous solution (0.9%NaCl), 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 the 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 the matter of gained particle (MMAD) is about 2 μ m.
Embodiment 64: to the restraining effect of adenosine diphosphate (ADP) (ADP) induced platelet gathering
Animal: rabbit, 3-5kg, male and female dual-purpose.
Instrument: SHANDA PA-196 type platelet aggregation instrument.
The Pharmaceutical setting 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, after blood vessel expands, smear Vaseline at ear edge place, cut open blood vessel, collect 36mL blood with the preparation test tube, blood is mixed, turn/the centrifugal 8-10min of min with 900, isolate supernatant blood plasma PRP (being rich in thrombocyte blood plasma), then turn/the centrifugal 8-10min of min with 3500, isolate supernatant blood plasma PPP (the poor thrombocyte blood plasma that contains).The accurate 250uLPRP of absorption adds and assembles in the pipe, add the 40% methanol aqueous solution 20uL that contains medicine in the pipe to assembling, to be marked with respectively the gathering pipe of the PPP of 250uL and PRP blood plasma at 37 ± 0.01 ℃ of preheating 5min, return to zero with PPP250uL, in cuvette, add the gathering of 10uL adenosine diphosphate (ADP) (ADP) induced platelet again, 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 L-Arginine.Assemble inhibiting rate=(blank is assembled inhibiting rate-sample collection 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 that the ADP induced platelet is assembled that suppresses.
Embodiment 65: to the restraining effect of collagen-induced platelet gathering
Animal: rabbit, 3-5kg, male and female dual-purpose.
Pharmaceutical setting 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 respectively the solution for standby that concentration is 30umol/mL, 10umol/mL, 3umol/mL, 1umol/mL, 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 respectively as above concentration with standardized solution I and standardized solution II.
Experimental technique: in the 10mL plastic test tube, add the 1mL3.8% Sodium Citrate aqueous solution, carefully clean the rabbit ear with alcohol, clean the rabbit ear with dimethylbenzene again, after blood vessel expands, smear Vaseline at ear edge place, cut open blood vessel, collect 9mL blood with the preparation test tube, blood is mixed, turn/the centrifugal 8-10min of min with 900, isolate supernatant blood plasma PRP (being rich in thrombocyte blood plasma), then turn/the centrifugal 8-10min of min with 3500, 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, add sample solution 20uL in the cuvette, 37 ± 0.01 ℃ hatch 2min after, add the 20uL collagen-induced platelet in the cuvette 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 L-Arginine.The sample segment inhibiting rate is listed as follows:
The result shows that compound of the present invention has the effect that collagen-induced platelet is assembled that suppresses.
Embodiment 66: to the restraining effect of acetic acid inducing mouse writhing
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 acetic acid commonly used, respectively to each group mouse peritoneal injection blank or medicine 0.2ml, inject respectively again 0.6% acetic acid normal saline solution 0.2ml behind the 1h, begin to count the number of times of mouse writhing in 10 minutes after 5 minutes, it is suppressed that the writhing number of times is designated as the pain sensation less than or equal to 5 times mouse, it is not suppressed then to be designated as the pain sensation greater than 5 times, calculates 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 front 60min intraperitoneal injection.Take by weighing respectively the 0.5mg medicine and place the 5ml volumetric flask, with 0.2%CMCNa normal saline solution wiring solution-forming.Every mouse is injected respectively 0.3ml blank or medicine.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, as swelling, and relatively group difference significance 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 (4)
1. oxazine compounds is selected from:
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-(2,6-3,5-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-2,3,4,6,7,8-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-(2,6-3,5-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.
2. medicinal compositions, it is characterized in that: said composition contains compound claimed in claim 1 or its pharmacy acceptable salt of significant quantity, and pharmaceutically acceptable carrier.
3. the application of compound claimed in claim 1 in the preparation medicament for resisting platelet aggregation.
4. the application of medicinal compositions claimed in claim 2 in the preparation medicament for resisting platelet aggregation.
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| CN201210398563.1A Division CN102924475B (en) | 2009-02-09 | 2009-02-09 | Novel oxazine compound and use of oxazine compound for anti-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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