CN104072411A - Mesylate C crystal form of amide derivatives as well as preparation method and application thereof - Google Patents
Mesylate C crystal form of amide derivatives as well as preparation method and application thereof Download PDFInfo
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- CN104072411A CN104072411A CN201410322732.2A CN201410322732A CN104072411A CN 104072411 A CN104072411 A CN 104072411A CN 201410322732 A CN201410322732 A CN 201410322732A CN 104072411 A CN104072411 A CN 104072411A
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- mesylate
- nicotinamide derivative
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- Pyridine Compounds (AREA)
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Abstract
The invention discloses a mesylate C crystal form of amide derivatives as well as a preparation method and application thereof. The XRPD (X-ray powder diffraction) of the mesylate C crystal form of amide derivatives has diffraction peaks at the places in which 2*theta is equal to 5.978, 10.961, 11.201, 11.821, 12.202, 13.602, 14.023, 14.619, 15.821, 17.72, 18.739, 19.72, 20.9, 22.261, 23.139, 24.117, 24.996, 25.478, 25.899, 26.921, 28.081, 29.098, 30.38, 31.058, 31.701, 33.284 and 33.845, wherein the error range of the value of 2*theta is 0.2. The mesylate C crystal form of amide derivatives provided by the invention can be applied to medicines for treating advanced non-small cell lung cancer, gastric cancer, liver cancer and breast cancer; moreover, the qualitative and quantitative information of the crystal form is of great significance for further researches on the curative effect of the solid medicines.
Description
Technical field
The present invention relates to molecular targeted antitumor drug, be specifically related to mesylate C crystal formation of nicotinamide derivative and its preparation method and application.
Background technology
Nicotinamide derivative (aptinib), molecular formula C
25h
27n
5o
4s, chemical name is N-[4-(1-cyan cyclopentyl) phenyl]-2-(4-picolyl) amino-Niacinamide, it is a kind of molecular targeted antitumor drug, be a kind of typical small molecules vascular endothelial growth factor tyrosine kinase inhibitor, can be used for treating advanced Non-small cell lung, cancer of the stomach, liver cancer and mammary cancer etc.Chinese invention patent CN101676267 discloses preparation method and the application of the mesylate of above-mentioned nicotinamide derivative.
As everyone knows, the different crystal forms of same medicine, may there is notable difference in the aspects such as its stability and bioavailability, thereby affect the curative effect of medicine.Therefore, the new crystal of research and development nicotinamide derivative, for the research of solid pharmaceutical crystal formation provides more qualitative, quantitative information to have very important significance.
Summary of the invention
Problem to be solved by this invention is how to research and develop the new crystal of nicotinamide derivative, for the effectiveness study of solid pharmaceutical provides the problem of more qualitative, quantitative information.
In order to solve the problems of the technologies described above, the technical solution adopted in the present invention is to provide a kind of mesylate C crystal formation of nicotinamide derivative, its XRPD collection of illustrative plates is in 2 θ=5.978, 10.961, 11.201, 11.821, 12.202, 13.602, 14.023, 14.619, 15.821, 17.72, 18.739, 19.72, 20.9, 22.261, 23.139, 24.117, 24.996, 25.478, 25.899, 26.921, 28.081, 29.098, 30.38, 31.058, 31.701, 33.284, 33.845 locate to there is diffraction peak, wherein the limit of error of 2 θ values is 0.2.
In the mesylate C of above-mentioned nicotinamide derivative crystal formation, its XRPD collection of illustrative plates as shown in Figure 1.
In the mesylate C of above-mentioned nicotinamide derivative crystal formation, water content is 2.5～4.5%.
The present invention also provides a kind of method of preparing the mesylate C crystal formation of above-mentioned nicotinamide derivative, comprise the following steps: the mesylate of 500mg nicotinamide derivative is dissolved in the dimethyl formamide solution of 20ml, slowly add pure water direct muddy to solution, under room temperature static 12 hours, then filtration, vacuum-drying, obtain the mesylate C crystal formation that white powder is nicotinamide derivative.
The application of the mesylate C crystal formation that the present invention also provides above-mentioned nicotinamide derivative in the medicine for the treatment of advanced Non-small cell lung, cancer of the stomach, liver cancer or mammary cancer.
The mesylate C crystal formation of nicotinamide derivative provided by the invention, can be applicable to treat advanced Non-small cell lung, cancer of the stomach, liver cancer and breast cancer medicines, and the qualitative, quantitative information of this crystal formation, has great importance to the curative effect of further this type of solid pharmaceutical of research.
Accompanying drawing explanation
Fig. 1 is the XRPD collection of illustrative plates of the mesylate C crystal formation of nicotinamide derivative provided by the invention;
Fig. 2 is the XRPD collection of illustrative plates of the mesylate C crystal formation high-temperature stability test of nicotinamide derivative provided by the invention;
Fig. 3 is the XRPD collection of illustrative plates of the mesylate C crystal formation high humidity stability test of nicotinamide derivative provided by the invention;
Fig. 4 is the XRPD collection of illustrative plates of the mesylate C crystal formation light durability test of nicotinamide derivative provided by the invention.
Embodiment
Below in conjunction with Figure of description, the present invention is described in detail.
The mesylate C crystal formation of nicotinamide derivative provided by the invention, as shown in Figure 1, embodiments is as follows for its XRPD (X-ray powder diffraction) collection of illustrative plates:
| 2-Theta(2θ) | d | I％ |
| 5.978 | 14.7713 | 12.9 |
| 10.961 | 8.0653 | 6.3 |
| 11.201 | 7.893 | 6.6 |
| 11.821 | 7.48 | 27.2 |
| 12.202 | 7.2475 | 4.8 |
| 13.602 | 6.5047 | 6.4 |
| 14.023 | 6.3104 | 16.2 |
| 14.619 | 6.0543 | 10.2 |
| 15.821 | 5.5968 | 5.2 |
| 17.72 | 5.0012 | 100 |
| 18.739 | 4.7313 | 43.8 |
| 19.72 | 4.4981 | 23.2 |
| 20.9 | 4.2469 | 79.3 |
| 22.261 | 3.9902 | 23.9 |
| 23.139 | 3.8407 | 7.5 |
| 24.117 | 3.6872 | 15.6 |
| 24.996 | 3.5595 | 9.8 |
| 25.478 | 3.4932 | 17 |
| 25.899 | 3.4373 | 13.3 |
| 26.921 | 3.3091 | 12.3 |
| 28.081 | 3.175 | 11.7 |
| 29.098 | 3.0663 | 16.3 |
| 30.38 | 2.9398 | 7.3 |
| 31.058 | 2.8772 | 11 |
| 31.701 | 2.8202 | 9.2 |
| 33.284 | 2.6896 | 4.3 |
| 33.845 | 2.6463 | 3.2 |
D is the interplanar distance of adjacent two crystal faces in crystal lattices, Yi Aiwei unit, and I% is intensity.
As shown in Figure 1, the XRPD collection of illustrative plates of the mesylate C crystal formation of nicotinamide derivative provided by the invention in 2 θ=5.978,10.961,11.201,11.821,12.202,13.602,14.023,14.619,15.821,17.72,18.739,19.72,20.9,22.261,23.139,24.117,24.996,25.478,25.899,26.921,28.081,29.098,30.38,31.058,31.701,33.284,33.845 places have diffraction peak, wherein the limit of error of 2 θ values is 0.2.
The preparation method of the mesylate C crystal formation of above-mentioned nicotinamide derivative provided by the invention is as follows:
Embodiment 1.
The mesylate of 500mg nicotinamide derivative is dissolved in the dimethyl formamide solution of 20ml, slowly add pure water direct muddy to solution, under room temperature static 12 hours, then filter, vacuum-drying, obtain the mesylate C crystal formation that white powder is nicotinamide derivative.
The mesylate C crystal formation of nicotinamide derivative provided by the invention, adopts auto moisture instrument to detect, and its water content is 2.5～4.5%.
The mesylate C crystal formation of nicotinamide derivative provided by the invention is general at the steady condition stability inferior of high temperature, high humidity and illumination, can be used as in treatment advanced Non-small cell lung, cancer of the stomach, liver cancer and breast cancer medicines and applies, and specific experiment result is as follows:
(1) high-temperature stability is investigated.
The mesylate C crystal form samples of nicotinamide derivative is placed in the airtight baking oven of 60 ℃, within 5 days, take out and carry out XRPD test afterwards, as shown in Figure 2, the comparative result by Fig. 1 and Fig. 2 shows its XRPD collection of illustrative plates, and the mesylate C crystal formation of nicotinamide derivative is general at this high temperatures.
(2) high humidity stability.
The mesylate C crystal form samples of nicotinamide derivative is placed in to the encloses container under 92.5% humidity condition, within 5 days, take out and carry out XRPD test afterwards, its XRPD collection of illustrative plates as shown in Figure 3, comparative result by Fig. 1 and Fig. 3 shows, the mesylate C crystal formation of nicotinamide derivative is general at this high humidity environment stability inferior.
(3) light durability.
The mesylate C crystal form samples of nicotinamide derivative is placed in to transparent encloses container, and under 4500lux intensity of illumination, within 5 days, take out and carry out XRPD test afterwards, its XRPD collection of illustrative plates as shown in Figure 4, comparative result by Fig. 1 and Fig. 4 shows, the mesylate C crystal formation of nicotinamide derivative is general at this condition stability inferior.
The above-mentioned qualitative, quantitative information of the mesylate C crystal formation of nicotinamide derivative provided by the invention, has great importance to the further research of this type of solid pharmaceutical curative effect.
The present invention is not limited to above-mentioned preferred forms, and anyone should learn the structural changes of making under enlightenment of the present invention, and every have identical or close technical scheme with the present invention, within all falling into protection scope of the present invention.
Claims (5)
1. the mesylate C crystal formation of nicotinamide derivative, it is characterized in that, its XRPD collection of illustrative plates in 2 θ=5.978,10.961,11.201,11.821,12.202,13.602,14.023,14.619,15.821,17.72,18.739,19.72,20.9,22.261,23.139,24.117,24.996,25.478,25.899,26.921,28.081,29.098,30.38,31.058,31.701,33.284,33.845 places have diffraction peak, wherein the limit of error of 2 θ values is 0.2.
2. the mesylate C crystal formation of nicotinamide derivative as claimed in claim 1, is characterized in that, its XRPD collection of illustrative plates as shown in Figure 1.
3. the mesylate C crystal formation of nicotinamide derivative as claimed in claim 1 or 2, is characterized in that, water content is 2.5～4.5%.
4. prepare the method for the mesylate C crystal formation of nicotinamide derivative as claimed in claim 3, it is characterized in that, comprise the following steps: the mesylate of 500mg nicotinamide derivative is dissolved in the dimethyl formamide solution of 20ml, slowly add pure water direct muddy to solution, under room temperature static 12 hours, then filtration, vacuum-drying, obtain the mesylate C crystal formation that white powder is nicotinamide derivative.
5. the application of the mesylate C crystal formation of nicotinamide derivative in the medicine for the treatment of advanced Non-small cell lung, cancer of the stomach, liver cancer or mammary cancer as claimed in claim 3.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105541708A (en) * | 2014-10-28 | 2016-05-04 | 华东理工常熟研究院有限公司 | New crystal form of apatinib sulfate |
| CN105622498A (en) * | 2014-10-28 | 2016-06-01 | 华东理工常熟研究院有限公司 | New crystal of apatinib sulfate |
| CN105622499A (en) * | 2014-10-28 | 2016-06-01 | 华东理工常熟研究院有限公司 | New crystal of apatinib sulfate |
| CN105801476A (en) * | 2016-04-13 | 2016-07-27 | 上海宣创生物科技有限公司 | Crystal form II of Apatinib mesylate as well as preparation method and application of crystal form II |
| CN106038566A (en) * | 2016-06-10 | 2016-10-26 | 青岛科瑞元生物科技有限公司 | Pharmaceutical composition for treating gastric carcinoma and application of pharmaceutical composition |
| WO2020051173A1 (en) | 2018-09-05 | 2020-03-12 | Assia Chemical Industries Ltd | New crystalline polymorphs of rivoceranib and rivoceranib mesylate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1502608A (en) * | 2002-11-27 | 2004-06-09 | 南京凯衡科贸有限公司 | Hexavalent amino amidate derivative with function of inhibiting blood vessel growth activity |
| CN101676267A (en) * | 2008-09-16 | 2010-03-24 | 江苏恒瑞医药股份有限公司 | N-4-(1-cyan cyclopentyl) phenyl-2-(4-picolyl) amidogen-3-pyridinecarboxamide salt |
| CN102579454A (en) * | 2009-10-28 | 2012-07-18 | 江苏恒瑞医药股份有限公司 | Drug composition for curing tumour diseases |
-
2014
- 2014-07-08 CN CN201410322732.2A patent/CN104072411A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1502608A (en) * | 2002-11-27 | 2004-06-09 | 南京凯衡科贸有限公司 | Hexavalent amino amidate derivative with function of inhibiting blood vessel growth activity |
| CN101676267A (en) * | 2008-09-16 | 2010-03-24 | 江苏恒瑞医药股份有限公司 | N-4-(1-cyan cyclopentyl) phenyl-2-(4-picolyl) amidogen-3-pyridinecarboxamide salt |
| CN102579454A (en) * | 2009-10-28 | 2012-07-18 | 江苏恒瑞医药股份有限公司 | Drug composition for curing tumour diseases |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105541708A (en) * | 2014-10-28 | 2016-05-04 | 华东理工常熟研究院有限公司 | New crystal form of apatinib sulfate |
| CN105622498A (en) * | 2014-10-28 | 2016-06-01 | 华东理工常熟研究院有限公司 | New crystal of apatinib sulfate |
| CN105622499A (en) * | 2014-10-28 | 2016-06-01 | 华东理工常熟研究院有限公司 | New crystal of apatinib sulfate |
| CN105801476A (en) * | 2016-04-13 | 2016-07-27 | 上海宣创生物科技有限公司 | Crystal form II of Apatinib mesylate as well as preparation method and application of crystal form II |
| CN106038566A (en) * | 2016-06-10 | 2016-10-26 | 青岛科瑞元生物科技有限公司 | Pharmaceutical composition for treating gastric carcinoma and application of pharmaceutical composition |
| CN106038566B (en) * | 2016-06-10 | 2018-11-27 | 江阴市人民医院 | A kind of pharmaceutical composition and its application for curing gastric cancer |
| WO2020051173A1 (en) | 2018-09-05 | 2020-03-12 | Assia Chemical Industries Ltd | New crystalline polymorphs of rivoceranib and rivoceranib mesylate |
| US11434202B2 (en) | 2018-09-05 | 2022-09-06 | Assia Chemical Industries Ltd. | Crystalline polymorphs of Rivoceranib and Rivoceranib mesylate |
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Application publication date: 20141001 |