CN103788044B - Nicousamide crystalline substance I type, its preparation method and its pharmaceutical composition and purposes - Google Patents
Nicousamide crystalline substance I type, its preparation method and its pharmaceutical composition and purposes Download PDFInfo
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- CN103788044B CN103788044B CN201410017423.4A CN201410017423A CN103788044B CN 103788044 B CN103788044 B CN 103788044B CN 201410017423 A CN201410017423 A CN 201410017423A CN 103788044 B CN103788044 B CN 103788044B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
Abstract
The invention discloses five kinds of crystal-form substances of nicousamide as medicine material；Relate to the preparation method containing five kinds of crystal-form substances of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crude drug；It is directed to use with five kinds of crystal formation sterlings and various medicines that different proportion mixed crystal sample manufactures and pharmaceutical composition thereof as medicine material active component；In addition, the invention still further relates to utilize 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystal form samples as medicine material application in the diseases such as treatment diabetic nephropathy, hypertensive nephropathy, hypertension, diabetic complication, and make medicine blood drug level in vivo improve and play therapeutical effect due to crystal formation impact in treating various lysises.
Description
The application is the divisional application of Chinese patent application 200810227626.0, the Shen of original application 200810227626.0
Please be on November 28th, 2008 day, its entitled " five crystal forms of nicousamide compound, its preparation method and its pharmaceutical composition and use
On the way ".
Technical field
The present invention relates to five kinds of crystal-form substances of nicousamide as medicine material；Relate to containing 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin former
The preparation method of material five kinds of crystal-form substances of medicine；It is directed to use with five kinds of crystal formation sterlings and different proportion mixed crystal sample as medicine material
Various medicines that active component manufactures and pharmaceutical composition thereof；Moreover, it relates to utilize 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystal formation sample
Product as medicine material application in the treatment disease such as diabetic nephropathy, hypertensive nephropathy, hypertension, diabetic complication,
And make medicine blood drug level in vivo improve and play treatment due to crystal formation impact in treating various lysises
Effect.
Background technology
3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin (chemical name: 3-(3 '-carboxyl-4 '-hydroxyanilines carbonyl)-6-nitro-7-hydroxyl-8-methylcoumarin
Element；English name: 3-(3 '-carboxy-4 '-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-
Methyl-coumarin), compound structure is as follows
Nicousamide structure
At Chinese patent CN1207392A(publication number) in recorded institute of Materia Medica,Chinese Academy of Medical Sciences invention " dimension
Formyl coumarin kind compound and preparation method thereof and the pharmaceutical composition containing compound "[1].Wherein, relate to 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin and
The preparation method of its derivant, and the pharmaceutical composition containing this compounds.
At Chinese patent CN1506359A(publication number) and CN1829506(publication number) in recorded China Medical Science
" new Diarbarone derivant and preparation method thereof and its pharmaceutical composition and the purposes " of institute of materia medica of institute invention[2,3].Wherein,
Relate to the preparation method of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin and derivant thereof, and the pharmaceutical composition containing this compounds is being protected as kidney
Protect, become before hypertension, cardiovascular and cerebrovascular disease, type ii diabetes, tumor, cancer and application in edema drugs.
At Chinese patent CN11955175A(publication number) in recorded institute of Materia Medica,Chinese Academy of Medical Sciences invention
" coumarin derivative and preparation method thereof and pharmaceutical composition and purposes "[4].Wherein, relate to the system of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin and derivant thereof
Preparation Method, and the pharmaceutical composition containing this compounds is in treatment chronic kidney hypofunction, diabetes, hypertension and cardiovascular and cerebrovascular vessel disease
Application in sick and liver cirrhosis and prostate hyperplasia medicine.
Summary of the invention
One of the object of the invention: the brilliant I type of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin sample, brilliant II type, brilliant type III, brilliant IV type and brilliant V-type etc. are provided
Five kinds of solid matter existence forms.
The two of the object of the invention: the brilliant I type of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin sample, brilliant II type, brilliant type III, brilliant IV type and brilliant V-type etc. are provided
The process of preparing of five kinds of solid matters.
The three of the object of the invention: the brilliant I type containing 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin, brilliant II type, brilliant type III, brilliant IV type and brilliant V-type are provided
Crystal formation sterling is as medicine material, or the medicine using above-mentioned five kinds of crystal form samples to make mixing crystal formation by different proportion proportioning is former
Material, is being used for treating in the lysises such as diabetic nephropathy, hypertensive nephropathy, hypertension, diabetic complication, due to solids
The crystal formation difference of matter and improve blood drug level change in produced organism when medicine plays therapeutical effect.
The four of the object of the invention: provide the brilliant I type containing 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin, brilliant II type, brilliant type III, brilliant IV type, brilliant V-type pure
Product or containing the mixing crystal form samples obtained by any different ratio by above-mentioned five kinds of crystal formations as medicine material, and be mixed with one
Kind or the compositions of multiple pharmaceutical excipient, the different medicines such as the tablet made, capsule, pill, injection and various slow, controlled release preparations
Thing dosage form.
The five of the object of the invention: 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I type, brilliant II type, brilliant type III, brilliant IV type, brilliant V-type sterling and mixed are provided
Crystal form samples, as the active raw materials of solid drugs, is used for treating diabetic nephropathy, hypertensive nephropathy, hypertension, glycosuria
The medicines of various diseases such as sick complication and combinations thereof thing.
In order to complete the purpose of the present invention, can adopt the following technical scheme that
The morphological characteristic of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I pattern product:
1. 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I type solid matter, it is characterised in that when using single crystal X-ray diffraction to carry out structural analysis,
Showing as having anorthic system symmetry, space group is P1, and cell parameter value is α=98.95 °, β=116.03 °, γ=99.98 °.Except containing nitre in brilliant I type solid sample
Gram willow amine C18H12N2O9Outside molecule, still contain N, N '-dimethyl Methanamide (or claiming DMF) (CH3)2The recrystallisation solvent molecule of NCHO
Exist.Containing 4 identical nicousamide molecules and 5.5 DMF molecules, nitre gram in lower 1 asymmetry unit of crystalline state
Willow amine with have N, N '-dimethyl Methanamide molecular ratios is 4.0:5.5.Fig. 1 provides 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin sample molecule structure chart, Fig. 2
Providing 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin molecule stereo structure projection, Fig. 3 provides the molecule structure cell of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I pattern product and piles up projection.
Table 1 provides non-hydrogen atom coordinate parameters and equivalent temperature factor values, and table 2 provides bond distance's value of bonding atom, and it is former that table 3 provides bonding
The bond angle value of son.
The non-hydrogen atom coordinate parameters (relative coordinate) of table 1 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I pattern product
The bonding atomic bond long value of table 2 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I pattern product
Bonding atomic bond angle value (°) of table 3 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I pattern product
2. 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I type the solid matter, it is characterised in that (CuK when using powder x-ray diffraction analysisαSpoke
Penetrate), show as diffraction maximum position: 2-Theta value (°) or d valueWith diffraction maximum relative intensity: peak height value (Height%) has
There is a crystalline solid material (table 4, Fig. 4) during following characteristic peaks:
The powder X-ray diffraction characteristic peaks of table 4 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I pattern product
3. 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I type solid matter, it is characterised in that in its DSC collection of illustrative plates, (Fig. 5) exists an endothermic peak, turns
At about 121 DEG C, there is an exothermic peak in variate, transformation value is at about 342 DEG C.
4. 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I type solid matter, it is characterised in that its infrared absorption spectroscopy (Fig. 6) 3564.6,
3341.8、3296.2、3084.9、2930.4、1917.2、1721.1、1670.8、1621.7、1557.0、1536.1、1486.8、
1444.4、1385.3、1313.6、1302.0、1286.3、1238.7、1196.5、1117.8、1071.4、1016.6、965.1、
912.5、849.9、830.5、791.1、763.7、746.9、727.1、674.7、620.8、578.9、557.7、527.6、
508.4、460.0、436.8cm-1There is absworption peak at place, wherein 3341.8,3296.2,2930.4,1917.2,1721.1,
1670.8、1557.0、1385.3、1302.2、1238.7、1196.5、912.5、849.9、791.1、620.8、436.8cm-1Peak
Principal character absworption peak for 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I type solid matter.
The morphological characteristic of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance II pattern product:
1. 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance II type solid matter, it is characterised in that when using single crystal X-ray diffraction to carry out structural analysis,
Showing as having monoclinic symmetry, space group is P21, cell parameter value is α=90 °, β=87.77 °, γ=90 °, except containing 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin in brilliant II type solid sample
C18H12N2O9Outside molecule, still contain a certain proportion of dimethylamine (CH3)2NH recrystallisation solvent and H2O crystalline water molecules exists.Crystalline state
Lower 1 asymmetry unit contains 2 identical nicousamide molecules and 0.5 dimethylamine and 0.5 crystallization moisture
Son composition, 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin is 2.0:0.5:0.5 with the molecular ratios of dimethylamine and water of crystallization.Fig. 7 provides 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance II type
The molecule structure cell of sample piles up projection.Table 5 provides 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance II pattern product non-hydrogen atom coordinate parameters and equivalent temperature
Factor values, table 6 provides bond distance's value of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance II pattern product bonding atom, and table 7 provides 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance II pattern product
The bond angle value of key atom.
The non-hydrogen atom coordinate parameters (relative coordinate) of table 5 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance II pattern product
The bonding atomic bond long value of table 6 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance II pattern product
The bonding atomic bond angle value of table 7 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance II pattern product
2. 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance II type the solid matter, it is characterised in that (CuK when using powder x-ray diffraction analysisαSpoke
Penetrate), show as diffraction maximum position: 2-Theta value (°) or d valueWith diffraction maximum relative intensity: peak height value (Height%) has
There is a crystalline solid material (table 8, Fig. 8) during following characteristic peaks:
The powder X-ray diffraction characteristic peaks of table 8 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance II pattern product
3. 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance II type solid matter, it is characterised in that in its DSC collection of illustrative plates, (Fig. 9) exists two exothermic peaks,
Transformation value is respectively about 307 DEG C solids and about 345 DEG C.
4. 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance II type solid matter, it is characterised in that its infrared absorption spectroscopy (Figure 10) 3299.0,
3138.1、3068.8、2786.8、2448.4、1911.8、1720.0、1662.8、1621.6、1547.9、1486.1、1471.4、
1442.0、1376.1、1351.7、1312.4、1286.3、1240.5、1193.4、1147.4、1117.4、1070.7、1018.8、
965.3、954.1、914.9、850.5、836.1、790.2、762.5、747.0、726.1、716.4、680.2、621.7、
580.1、564.0、527.0、508.5、458.5cm-1There is absworption peak at place, wherein 3299.0,3138.1,3068.8,2786.8,
2448.4、1911.8、1720.0、1662.8、1547.9、1376.1、1351.7、1240.5、1193.4、954.1、914.9、
836.1、716.4、680.2、564.0、458.5cm -1Peak is the principal character absworption peak of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance II type solid matter.
The morphological characteristic of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance type III sample:
The 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance type III solid matter that the present invention obtains, it is characterised in that carry out when using single crystal X-ray diffraction
During structural analysis, showing as having anorthic system symmetry, space group is P1, and cell parameter value isα=90.43 °, β=91.73 °, γ=72.74 °.In brilliant type III solid-like
Except containing 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin C in product18H12N2Outside O9 molecule, still contain dimethylamine (CH3)2NH recrystallisation solvent molecule exists, under crystalline state
An asymmetry unit in 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin molecule and dimethylamine molecular ratios be 2:2.Figure 11 provides 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance type III
Structure cell pile up projection.Table 9 provides non-hydrogen atom coordinate parameters and equivalent temperature factor values, the table of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance type III
Bond distance's value of the 10 bonding atoms providing 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance type III, table 11 provides the key of the bonding atom of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance type III
Angle value.
The atomic coordinates parameter (relative coordinate) of the brilliant type III 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance III sample of table 9
The bonding atomic bond long value of the brilliant type III 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin sample of table 10
Bonding atomic bond angle value (°) of the brilliant type III 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin sample of table 11
2. 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance type III solid matter, it is characterised in that (the CuK α spoke when using powder x-ray diffraction analysis
Penetrate), show as diffraction maximum position: 2-Theta value (°) or d valueWith diffraction maximum relative intensity: peak height value (Height%) has
There is a crystalline solid material (table 12, Figure 12) during following characteristic peaks:
The powder X-ray diffraction characteristic peaks of table 12 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance type III sample
3. 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance type III solid matter, it is characterised in that in its DSC collection of illustrative plates, (Figure 13) exists a heat absorption
Peak, at about 191 DEG C, there is an exothermic peak in transformation value, transformation value is at about 293.5 DEG C.
4. 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance type III solid matter, it is characterised in that its infrared absorption spectroscopy (Figure 14) 3238.6,
3081.4、2787.8、2469.8、1728.7、1670.1、1621.1、1557.1、1529.8、1488.3、1472.0、1443.3、
1361.5、1346.3、1314.6、1284.3、1234.4、1195.6、1117.9、1071.0、1022.7、968.2、916.6、
907.1、893.4、834.3、825.1、786.8、763.0、746.5、727.1、705.2、673.9、622.9、578.7、
558.9、529.2、508.3、461.0、425.6cm-1There is absworption peak at place, wherein 3081.4,2469.8,1728.7,1529.8,
1284.3、1234.4、1195.6、907.1、825.1、786.8、705.2、425.6cm-1Peak is 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance type III solid
The principal character absworption peak of material.
The morphological characteristic of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance IV pattern product:
1. 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance IV pattern product are when using single crystal X-ray diffraction structural analysis, containing a kind of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin
Brilliant IV type solid matter, it is characterised in that when using single crystal X-ray diffraction to carry out structural analysis, show as that there is anorthic system
Symmetry, space group is P-1, and cell parameter value is α=98.91 °, β=
102.20 °, γ=91.55 °.Except containing 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin C in brilliant IV type solid sample18H12N2O9Outside molecule, still contain N, N '-
Dimethylformamide (or referred to as DMF) (CH3)2NCHO recrystallisation solvent molecule exists.Containing nitre gram in one asymmetry unit of crystalline state
Willow amine is 1:1 with the ratio of DMF molecule.Figure 15 provides the structure cell of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance IV type molecule and piles up projection.Table 13 is given
The non-hydrogen atom coordinate parameters of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance IV type and equivalent temperature factor values, table 14 provides the bonding of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance IV type
Bond distance's value of atom, table 15 provides the bond angle value of the bonding atom of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance IV type.
The atomic coordinates parameter (relative coordinate) of table 13 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance IV pattern product
The bonding atomic bond long value of table 14 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance IV pattern product
Bonding atomic bond angle value (°) of table 15 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance IV pattern product
2. 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance IV type the solid matter, it is characterised in that (CuK when using powder x-ray diffraction analysisαSpoke
Penetrate), show as diffraction maximum position: 2-Theta value (°) or d valueWith diffraction maximum relative intensity: peak height value (Height%) has
There is a crystalline solid material (table 16, Figure 16) during following characteristic peaks:
The powder X-ray diffraction characteristic peaks of table 16 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance IV pattern product
3. 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance IV type solid matter, it is characterised in that in its DSC collection of illustrative plates, (Figure 17) exists two endothermic peaks,
At about 94 DEG C and about 172 DEG C, there is an exothermic peak in transformation value, transformation value at about 342 DEG C respectively.
4. 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance IV type solid matter, it is characterised in that its infrared absorption spectroscopy (Figure 18) 3565.3,
3488.9、3238.7、3104.2、1719.8、1669.1、1621.6、1560.6、1537.0、1488.0、1471.6、1445.9、
1379.1、1359.7、1313.6、1285.7、1258.6、1152.8、1237.1、1194.2、1118.6、1071.3、1021.5、
968.3、917.5、893.2、848.5、835.4、789.2、763.4、746.7、727.2、674.4、623.1、579.1、
559.4、528.8、506.1、427.9cm-1There is absworption peak at place, wherein 3565.3,3488.9,3238.7,1719.8,1669.1,
1560.6、1379.1、1258.6、1237.1、1194.2、835.4、427.9cm-1Peak is 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance IV type solid matter
Principal character absworption peak.
The morphological characteristic of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance V-type (amorphous state) sample:
1. 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance V-type (amorphous state) solid matter, it is characterised in that containing associated water in non-crystalline solids sample
And do not contain other solvent molecule, (the CuK when using powder x-ray diffraction analysisαRadiation), show as diffraction maximum position: 2-
Theta value (°) or d valueWith diffraction maximum relative intensity: peak height value (Height%) has solids during following characteristic peaks
Matter (table 17, Figure 19):
The powder X-ray diffraction characteristic peaks of table 17 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance V-type sample
2. 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance V-type (amorphous state) solid matter, it is characterised in that in its DSC collection of illustrative plates, (Figure 20) exists
Endothermic peak, at about 169 DEG C, there is an exothermic peak in transformation value, transformation value is at about 345 DEG C.
3. 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance V-type (amorphous state) solid matter, it is characterised in that its infrared absorption spectroscopy (Figure 21) exists
3565.3、3488.9、3238.7、3104.2、1719.8、1669.1、1621.6、1560.6、1537.0、1488.0、1471.6、
1445.9、1379.1、1359.7、1313.6、1285.7、1258.6、1152.8、1237.1、1194.2、1118.6、1071.3、
1021.5、968.3、917.5、893.2、848.5、835.4、789.2、763.4、746.7、727.2、674.4、623.1、
579.1、559.4、528.8、506.1、427.9cm-1There is absworption peak at place, wherein 3565.3,3488.9,3238.7,1719.8,
1669.1、1560.6、1379.1、1258.6、1237.1、1194.2、835.4、427.9cm-1Peak is that 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance IV type is solid
The principal character absworption peak of body material.
Further aspect of the present invention further relates to the pharmaceutical composition using the compounds of this invention crystal formation as active ingredient.
This pharmaceutical composition can be prepared according to method well known in the art.Can be by by the compounds of this invention and one or many
Plant pharmaceutically acceptable solid or liquid excipient and/or adjuvant combines, make and be suitable to any dosage form that human or animal uses.
The compounds of this invention content in its pharmaceutical composition is usually 0.1-95 weight %.
The compounds of this invention or the pharmaceutical composition containing it can be administered in a unit, and route of administration can be intestinal
Or non-bowel, as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin,
Vagina, rectum etc..
Form of administration can be liquid dosage form, solid dosage forms or semisolid dosage form.Liquid dosage form can be that solution (includes
True solution and colloid solution), Emulsion (including o/w type, w/o type and emulsion), suspensoid, injection (include aqueous injection, injectable powder
And transfusion), eye drop, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet (include ordinary tablet, enteric coatel tablets, buccal tablet,
Dispersible tablet, chewable tablet, effervescent tablet, oral cavity disintegration tablet), capsule (including hard capsule, soft capsule, enteric coated capsule), granule, dissipate
Agent, micropill, drop pill, suppository, membrane, paster, gas (powder) mist agent, spray etc.；Semisolid dosage form can be ointment, gel
Agent, paste etc..
The compounds of this invention can make ordinary preparation, also to make be slow releasing preparation, controlled release preparation, targeting preparation and various
Particulate delivery system.
In order to the compounds of this invention is made tablet, well known in the art various excipient can be widely used, including dilute
Release agent, adhesive, wetting agent, disintegrating agent, lubricant, fluidizer.Diluent can be starch, dextrin, sucrose, glucose, breast
Sugar, mannitol, sorbitol, xylitol, microcrystalline Cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate etc.；Wetting agent can be water,
Ethanol, isopropanol etc.；Binding agent can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline Cellulose, Arab
Rubber cement, gelatine size, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin,
Carbomer, polyvinylpyrrolidone, Polyethylene Glycol etc.；Disintegrating agent can be dried starch, microcrystalline Cellulose, low substituted hydroxy-propyl fibre
Dimension element, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, sodium bicarbonate and citric acid, polyoxy
Ethylene sorbitan fatty acid ester, dodecyl sodium sulfate etc.；Lubricant and fluidizer can be Pulvis Talci, silicon dioxide, hard
Fat acid salt, tartaric acid, liquid paraffin, Polyethylene Glycol etc..
Tablet can also be made coated tablet, such as sugar coated tablet, thin membrane coated tablet, ECT further, or double
Synusia and multilayer tablet.
In order to administration unit is made capsule, effective ingredient the compounds of this invention can be mixed with diluent, fluidizer
Close, mixture is placed directly within hard capsule or soft capsule.Also can be by first for effective ingredient the compounds of this invention and diluent, bonding
Granule or micropill are made in agent, disintegrating agent, then are placed in hard capsule or soft capsule.For preparing each dilute of the compounds of this invention tablet
Release agent, adhesive, wetting agent, disintegrating agent, fluidizer kind can also be used for preparing the capsule of the compounds of this invention.
For the compounds of this invention is made injection, water, ethanol, isopropanol, propylene glycol or their mixture can be used
Make solvent and add solubilizing agent the most commonly used in the art, cosolvent, pH adjust agent, osmotic pressure regulator.Solubilizing agent or hydrotropy
Agent can be poloxamer, lecithin, HP-β-CD etc.；PH adjustment agent can be phosphate, acetate, hydrochloric acid, hydrogen
Sodium oxide etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate etc..As prepared lyophilized powder
Injection, also can add mannitol, glucose etc. as proppant.
Additionally, if desired, coloring agent, preservative, spice, correctives or other interpolation can also be added in pharmaceutical preparation
Agent.
For reaching medication purpose, strengthening therapeutic effect, the medicine of the present invention or pharmaceutical composition can be given known to any
Prescription method is administered.
The dosage of the compounds of this invention pharmaceutical composition is according to prevent or to treat the character of disease and serious journey
Degree, patient or the individual instances of animal, route of administration and dosage form etc. can have change on a large scale.In general, of the present inventionization
The Suitable dosage ranges of the every day of compound is 0.001-150mg/Kg body weight, preferably 0.1-100mg/Kg body weight, more preferably
1-60mg/Kg body weight, most preferably 2-30mg/Kg body weight.Above-mentioned dosage can a dosage unit or be divided into several dosage list
Position is administered, and this depends on the clinical experience of doctor and includes using the dosage regimen of other treatment means.
The compound of the present invention or compositions can individually be taken, or merge use with other treatment medicine or symptomatic drugs.
When the compound of the present invention exists synergism with other medicine, its dosage should be adjusted according to practical situation.
This patent be found that 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin there are five kinds of different crystal forms solid matters (brilliant I type, brilliant II type, brilliant type III,
Brilliant IV type and brilliant V-type) existence；And invented the process of preparing of five kinds of different crystal forms samples；It is found that different crystal forms
3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin sample blood drug level in vivo is different；Invent five kinds of crystal formation sterlings of application or obtained by different proportion proportioning
The medicine material medicine made as active component of mixed crystal sample and the solid composite medicament of different dosage form, it was found that nitre
Gram willow amine crystal form samples can be as medicine material at treatment diabetic nephropathy, hypertensive nephropathy, hypertension, diabetic complication etc.
Application in disease；Being found that crystal form state affects 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin medicine blood drug level in vivo, crystal formation can improve medicine
Clinical efficacy and play the preventive and therapeutic effect to disease.
N, N '-dimethyl Methanamide (or claiming DMF) molecular formula (CH3)2NCHO
Accompanying drawing illustrates:
The molecular structure of Fig. 1 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin sample
Fig. 2 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance molecule stereo structure projection
The molecule structure cell of Fig. 3 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I pattern product piles up projection
The x-ray diffractogram of powder spectrum of Fig. 4 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I pattern product
The DSC collection of illustrative plates of Fig. 5 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I pattern product
The infrared absorption spectroscopy of Fig. 6 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I pattern product
The molecule structure cell of Fig. 7 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance II pattern product piles up projection
The x-ray diffractogram of powder spectrum of Fig. 8 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance II pattern product
The DSC collection of illustrative plates of Fig. 9 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance II pattern product
The infrared absorption spectroscopy of Figure 10 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance II pattern product
The molecule structure cell of Figure 11 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance type III sample piles up projection
The x-ray diffractogram of powder spectrum of Figure 12 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance type III sample
The DSC collection of illustrative plates of Figure 13 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance type III sample
The infrared absorption spectroscopy of Figure 14 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance type III sample
The molecule structure cell of Figure 15 nitre gram Liu Jing IV type amine sample piles up projection
The x-ray diffractogram of powder spectrum of Figure 16 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance IV pattern product
The DSC collection of illustrative plates of Figure 17 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance IV pattern product
The infrared absorption spectroscopy of Figure 18 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance IV pattern product
The x-ray diffractogram of powder spectrum of Figure 19 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance V-type (amorphous state) sample
The DSC collection of illustrative plates of Figure 20 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance V-type (amorphous state) sample
The infared spectrum of Figure 21 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance V-type (amorphous state) sample
Detailed description of the invention
For better illustrating technical scheme, spy provides following example, but in the present invention is not limited to this
Hold.
Embodiment 1
The preparation method of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I pattern product:
After using DMF solvent system to be dissolved by 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin sample, it is placed on temperature range degree 65% to 75 DEG C, the wettest
In the environment of degree scope is within 50%, through recrystallization growth time 3 days, the brilliant I type solid matter sample finally prepared
Product.
The preparation method of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I pattern product:
After using DMF, water mixed solvent system to be dissolved by 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin sample, it is placed on temperature range degree 65 DEG C to 75
DEG C, in the environment of RH range is within 50%, through recrystallization growth time 3 days, the brilliant I type finally prepared was solid
Body material sample.
Embodiment 2
The preparation method of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance II type samples:
After using DMF solvent system to be dissolved by 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin sample, it is placed on temperature range degree 75 DEG C to 85 DEG C, the wettest
In the environment of degree scope is within 50%, through recrystallization growth time 2 days, the brilliant II type solid matter sample finally prepared
Product.
The preparation method of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance II type samples:
After using DMF, water mixed solvent system to be dissolved by 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin sample, it is placed on temperature range degree 75 DEG C to 85
DEG C, in the environment of RH range is within 50%, through recrystallization growth time 2 days, the brilliant II type finally prepared
Solid matter sample.
Embodiment 3
The preparation method of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance type III samples:
After using DMF solvent system to be dissolved by 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin sample, it is placed on temperature range degree 65 DEG C to 75 DEG C, the wettest
In the environment of degree scope is within 50%, through recrystallization growth time 5 days, the brilliant type III solid matter sample finally prepared
Product.
The preparation method of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance type III samples:
After using DMF, water mixed solvent system to be dissolved by 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin sample, it is placed on temperature range degree 65 DEG C to 75
DEG C, in the environment of RH range is within 50%, through recrystallization growth time 5 days, the brilliant type III finally prepared
Solid matter sample.
Embodiment 4
The preparation method of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance IV type samples:
After using DMF solvent system to be dissolved by 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin sample, it is placed on temperature range degree 85 DEG C to 95 DEG C, the wettest
In the environment of degree scope is within 50%, through recrystallization growth time 3 days, the brilliant IV type solid matter sample finally prepared
Product.
The preparation method of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance IV type samples:
After using DMF, water mixed solvent system to be dissolved by 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin sample, it is placed on temperature range degree 85 DEG C to 95
DEG C, in the environment of RH range is within 50%, through recrystallization growth time 3 days, the brilliant IV type finally prepared was solid
Body material sample.
Embodiment 5
The preparation method of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance V-type samples:
After using DMF solvent system to be dissolved by 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin sample, it is placed on temperature range degree 75 DEG C to 85 DEG C, the wettest
In the environment of degree scope is within 50%, through recrystallization growth time 2 days, then carry out turning brilliant more than 1 day through dilute hydrochloric acid, finally
The brilliant V-type solid matter sample prepared.
After using DMF, water mixed solvent system to be dissolved by 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin sample, it is placed on temperature range degree 75 DEG C to 85
DEG C, in the environment of RH range is within 50%, through recrystallization growth time 2 days, then carry out turning brilliant 1 day through dilute hydrochloric acid
Above, the brilliant V-type solid matter sample finally prepared.
Embodiment 6
The preparation method (tablet) of combined pharmaceutical formulation:
A kind of preparation method of combined pharmaceutical formulation, it is characterised in that use several excipient by 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I, II,
III, IV, V-type pure crystal formation solid sample or by different crystal forms press different proportion proportioning mixing obtain mixed crystal solid sample as medicine
The active ingredient raw materials of thing, makes the tablet that every content of dispersion is 5～100mg, and table 18 provides tablet formulation:
Table 18 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin solid drug tablets formula
Using 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystal formation sterling or the mixed crystal solid sample that is mixed by a certain percentage by different crystal forms as medicine
Thing active raw materials, the method being prepared as tablet is: mixed homogeneously with crude drug by several excipient, adds 1% methylol fine
Dimension element sodium solution is appropriate, makes soft material, granulation of sieving, and wet grain is dried, and sieve granulate, and addition magnesium stearate and Pulvis Talci mixing are all
Even, tabletting and get final product.
List of references
1, Chinese patent, publication number CN1207392A
2, Chinese patent, publication number CN1506359A
3, Chinese patent, publication number CN1829506
4, Chinese patent, publication number CN11955175A.
Claims (15)
1. the brilliant I type of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin, it is characterised in that when using single crystal X-ray diffraction to carry out structural analysis, show as having
Anorthic system symmetry, space group is P1, and cell parameter value is α=
98.95 °, β=116.03 °, γ=99.98 °；Except containing 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin C in brilliant I type solid sample18H12N2O9Outside molecule, still
Containing N, N '-dimethyl Methanamide recrystallisation solvent molecule exists, and 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin is 4.0: 5.5 with the ratio of solvent molecule.
3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I type the most according to claim 1, it is characterised in that use CuK when using powder x-ray diffraction analysisα
During radiation experiments condition, show as diffraction maximum position: 2-Theta value (°) or d valueWith diffraction maximum relative intensity: peak height value
(Height%) there is following characteristic peaks:
3. according to 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I type arbitrary in claim 1-2, it is characterised in that its DSC collection of illustrative plates exists a heat absorption
Peak, at 121 DEG C, there is an exothermic peak in transformation value, transformation value is at 342 DEG C.
4. according to 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I type arbitrary in claim 1-2, it is characterised in that its infrared absorption spectroscopy 3341.8,
3296.2、2930.4、1917.2、1721.1、1670.8、1557.0、1385.3、1302.2、1238.7、1196.5、912.5、
849.9、791.1、620.8、436.8cm-1Peak is the principal character absworption peak of 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I type solid matter.
5. the mixing crystal formation of a 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin, it is characterised in that containing the brilliant I type any one of claim 1-4.
6. a crude drug for 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin, containing the brilliant I type any one of claim 1-4 or the mix-crystal of claim 5
Type.
7. on a pharmaceutical composition, brilliant I type any one of claim 1-4 containing effective dose and pharmacodynamics acceptable
Carrier.
8. a pharmaceutical composition, the 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin mixing crystal formation of the claim 5 containing effective dose and pharmacodynamics can connect
The carrier being subject to.
9. according to the compositions any one of claim 7-8, it is characterised in that described pharmaceutical composition is selected from tablet, glue
Capsule, pill, injection.
10. according to the compositions any one of claim 7-8, it is characterised in that described pharmaceutical composition is selected from slow, controlled release
Preparation.
3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I type any one of 11. claim 1-4 is at preparation treatment hypertension, diabetes complicated disease
The application of medicine.
The 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin mixing crystal formation of 12. claim 5 treats answering of the medicine of hypertension, diabetes complicated disease in preparation
With.
13. according to the application any one of claim 11 and 12, it is characterised in that described hypertension complication is selected from high blood
Pressure nephropathy, diabetic complication is selected from diabetic nephropathy.
The preparation method of the 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I type according to any one of 14. claim 1-4, it is characterised in that use DMF mono-
One solvent；First sample is completely dissolved, is placed on temperature range at 65 DEG C to 75 DEG C, RH range within 50%, warp
Overweight crystal growth time 3 days, the brilliant I type solid matter sample finally prepared.
The preparation method of the 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin crystalline substance I type according to any one of 15. claim 1-4, it is characterised in that use DMF and
Aqueous solvent, makes mixed solvent system with different ratio；First sample is completely dissolved, is placed on temperature range at 65 DEG C to 75
DEG C, RH range is within 50%, through recrystallization growth time 3 days, the brilliant I type solid matter sample finally prepared
Product.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1049662A (en) * | 1989-07-31 | 1991-03-06 | 三共株式会社 | Coumarin derivatives and preparation thereof and the application in the treatment cerebrovascular disorders |
| CN1506359A (en) * | 2002-12-05 | 2004-06-23 | �й�ҽѧ��ѧԺҩ���о��� | Coumarin amide derivative and its prepn, medicinal composition and use |
| CN101074222A (en) * | 2006-05-19 | 2007-11-21 | 中国医学科学院药物研究所 | 3-substituted cumarin compound, its production, medicinal composition and use |
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2008
- 2008-11-28 CN CN201410017423.4A patent/CN103788044B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1049662A (en) * | 1989-07-31 | 1991-03-06 | 三共株式会社 | Coumarin derivatives and preparation thereof and the application in the treatment cerebrovascular disorders |
| CN1506359A (en) * | 2002-12-05 | 2004-06-23 | �й�ҽѧ��ѧԺҩ���о��� | Coumarin amide derivative and its prepn, medicinal composition and use |
| CN101074222A (en) * | 2006-05-19 | 2007-11-21 | 中国医学科学院药物研究所 | 3-substituted cumarin compound, its production, medicinal composition and use |
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