CN115246846A - New crystal form of rubitinid and preparation thereof - Google Patents
New crystal form of rubitinid and preparation thereof Download PDFInfo
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- CN115246846A CN115246846A CN202111398172.5A CN202111398172A CN115246846A CN 115246846 A CN115246846 A CN 115246846A CN 202111398172 A CN202111398172 A CN 202111398172A CN 115246846 A CN115246846 A CN 115246846A
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- 239000013078 crystal Substances 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title description 5
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 10
- 238000000862 absorption spectrum Methods 0.000 claims 2
- 206010041067 Small cell lung cancer Diseases 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 238000011518 platinum-based chemotherapy Methods 0.000 description 4
- 208000000587 small cell lung carcinoma Diseases 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 102000008096 B7-H1 Antigen Human genes 0.000 description 2
- 108010074708 B7-H1 Antigen Proteins 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 238000002651 drug therapy Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229960004768 irinotecan Drugs 0.000 description 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- IRZTUXPRIUZXMP-UHFFFAOYSA-N rubiadin Chemical compound C1=CC=C2C(=O)C3=C(O)C(C)=C(O)C=C3C(=O)C2=C1 IRZTUXPRIUZXMP-UHFFFAOYSA-N 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- 229910016523 CuKa Inorganic materials 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000012271 PD-L1 inhibitor Substances 0.000 description 1
- 102000009572 RNA Polymerase II Human genes 0.000 description 1
- 108010009460 RNA Polymerase II Proteins 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 229960003852 atezolizumab Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 229940121656 pd-l1 inhibitor Drugs 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011519 second-line treatment Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D515/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
The invention relates to new crystal forms C and D of rubitinide; the XRPD pattern of form C has characteristic bragg angles at 4.0 °, 7.8 °, 10.1 °, 11.9 °, 18.2 °, and 25.4 °; the XRPD pattern of form D has characteristic bragg angles at 4.7 °, 7.9 °, 9.4 °, 11.9 °, 13.0 °, 16.8 °, 20.3 °, 24.6 °, and 25.5 °.
Description
Technical Field
The invention relates to a new crystal form of rubitinid and a preparation method thereof.
Background
Rubistatin (Lurbiectedin, PM01183, CAS: 497871-47-3) is developed by Spanish Mark pharmaceutical (Pharmamar SA) company, is a small cell lung cancer therapeutic drug which is firstly marketed in the United states in 2020, and has the action mechanism of RNA polymerase II inhibitor combined with the minor groove on the DNA double helix structure, so that tumor cells are distorted and apoptotic in the mitosis process, and finally the reduction of cell proliferation belongs to phosphodiesterase inhibitors. First-line therapy for small cell lung cancer generally employs platinum-based chemotherapy (platinum-based compounds + irinotecan/etoposide, etc.). These active substances are effective in most patients during the initial phase of treatment, and the condition of the patient may be stable for a period of time. However, most patients subsequently relapse and must then be transferred to second-line drug therapy. In foreign countries, some three-phase clinical studies currently use PD-L1 inhibitors in combination with platinum-based chemotherapy to improve the first-line therapeutic effect of SCLC (atezolizumab + irinotecan + platinum). Clinical data show that platinum-based chemotherapy in combination with PD-L1 is effective in a small fraction of patients, significantly reducing mortality, but has no significant effect in most cases. And recurrences in almost all cases. In other words, if a normative treatment is used, almost every small cell lung cancer patient will undergo platinum-based chemotherapy (including the combination of PD-L1), and the next second-line drug therapy, which is initiated after chemotherapy, will be used clinically primarily for the treatment of heart failure. In the past, topotecan has been the standard second-line treatment for small cell lung cancer. Until the FDA accelerated approval of rubitinin in 2020, physicians did not have new second line therapeutic drugs for SCLC. Lubitinin is a broad-spectrum anticancer drug, and currently, many clinical studies abroad adopt lubitinin to treat various solid tumors.
The chemical name of the product is as follows: (1 ' R,6aR,7R,13S,14S, 16R) -8, 14-dihydroxy-6 ', 9-dimethoxy-4, 10, 23-trimethyl-19-oxo-2 ',3',4',6,7,9',12,13,14, 16-decahydro-6 aH-spiro [7, 13-imino-6, 16- (epithiopropyloxymethylene) [1,3] dioxo [7,8] isoquinolin [3,2-b ] [3] phenylalanyl-azocine-20, 1' -pyrido [3,4-b ] indol ] -5-yl acetate.
There are two crystal forms for preparing rubitinin which are published and reported at present. The research of the patent WO2021/099635A1 finds that the rubiadin has 2 different crystal forms, namely a crystal form A and a crystal form B. Form a is amorphous; the XRPD of the crystal form B characterizes a Bragg angle (2 theta) of 6.2 +/-0.2 DEG7.6 +/-0.2 °, 9.0 +/-0.2 °, 10.9 +/-0.2 °, 14.9 +/-0.2 °, 15.3 +/-0.2 ° (the relative enantiomeric density is 79 +/-6%, 100 +/-3%, 63 +/-3%, 100 +/-3%, 76 +/-3% and 75 +/-3%); the crystal form has no melting point and is completely decomposed at about 172 ℃; has the following typical IR characteristic peaks: 2928. 1755, 1626, 1485, 1456, 1370, 1197, 1150, 1088, 1003, 959, 916 and 587cm -1 。
Disclosure of Invention
The key point of the invention is to newly discover a new crystal form C and a new crystal form D of lubitridine, and the crystal form C and the new crystal form D are used for researching the biological activity, the bioavailability and the like of a medicament.
The XRPD data of the new crystal form of the rubitinid is measured by an EMPYREAN X-ray derivative instrument of PANALYLTIC company, and relevant test parameters are as follows: 45KV,40mA, radiation wavelength CuKa
Scan range 3-40 °, step Size =0.0167[ ° 2Th [ ]],Scan Step Time＝17.85(s)。
The XRPD pattern of form C shows that this form has characteristic bragg angles at 4.0 °, 7.8 °, 10.1 °, 11.9 °, 18.2 ° and 25.4 °, with the following associated pattern signals:
the infrared absorption (IR) spectrum of the crystal form C shows that the crystal form C has obvious characteristic signals at 2928, 1755, 1726, 1589, 1433, 1373, 1252, 1291, 1147, 1086, 1040, 1004, 957, 801 and 587 cm-1.
The XRPD pattern of form D shows that this form has characteristic bragg angles at 4.7 °, 7.9 °, 9.4 °, 11.9 °, 13.0 °, 16.8 °, 20.3 °, 24.6 ° and 25.5 °, with the following associated pattern signals:
the infrared absorption (IR) spectrum of form D shows distinct characteristic signals at 2927, 1754, 1739, 1591, 1457, 1359, 1194, 1168, 1146, 1083, 999, 729, 585 cm-1.
Drawings
Figure 1 is an XRPD pattern of rubitinid form C;
figure 2 is an XRPD pattern of rubitinid form D;
Detailed Description
The present invention will be more specifically understood from the following examples, which are given by way of illustration and are not intended to limit the scope of the present invention.
Examples
1. Preparation of Crystal form Lubipetidine Crystal form C
Adding rubitinin (0.5 g) into ethyl acetate (10 mL), heating and stirring for 2h, filtering while hot, and vacuum drying the obtained solid at 25 ℃ to obtain the crystal form C of rubitinin. The crystal form has characteristic Bragg angles (as shown in figure 1) at 4.0 degrees, 7.8 degrees, 10.1 degrees, 11.9 degrees, 18.2 degrees and 25.4 degrees; the infrared absorption (IR) spectrum of the crystal form shows that the crystal form has obvious characteristic signals at 2928, 1755, 1726, 1589, 1433, 1373, 1252, 1291, 1147, 1086, 1040, 1004, 957, 801 and 587cm < -1 >.
2. Preparation of crystalline form Lubitridine form D
Adding rubistatin (1.5 g) into dichloromethane (50 mL), stirring at room temperature for dissolving, slowly dropwise adding n-pentane (40 mL) to separate out a solid, stirring for 1h after dropwise adding, filtering, and drying the obtained solid in vacuum at 25 ℃ to obtain the crystal form D of the rubistatin. The crystal form has characteristic Bragg angles (shown as figure 2) at 4.7 degrees, 7.9 degrees, 9.4 degrees, 11.9 degrees, 13.0 degrees, 16.8 degrees, 20.3 degrees, 24.6 degrees and 25.5 degrees; the infrared absorption (IR) spectrum of the crystal form shows obvious characteristic signals at 2927, 1754, 1739, 1591, 1457, 1359, 1194, 1168, 1146, 1083, 999, 729 and 585 cm-1.
Claims (4)
1. The crystal form C of lubiperidine has characteristic Bragg angles at 4.0 degrees, 7.8 degrees, 10.1 degrees, 11.9 degrees, 18.2 degrees and 25.4 degrees in XRPD pattern.
2. Form C according to claim 1 having an infrared absorption spectrum in the region of 2928, 1755, 1726, 1589, 1433, 1373, 1252, 1291, 1147, 1086, 1040, 1004, 957, 801, 587cm -1 A distinct characteristic signal is present.
3. The crystal form D of lubiperidine has characteristic Bragg angles at the XRPD pattern of 4.7 degrees, 7.9 degrees, 9.4 degrees, 11.9 degrees, 13.0 degrees, 16.8 degrees, 20.3 degrees, 24.6 degrees and 25.5 degrees.
4. Form D according to claim 3 having an infrared absorption spectrum in the region of 2927, 1754, 1739, 1591, 1457, 1359, 1194, 1168, 1146, 1083, 999, 729, 585cm -1 A distinct characteristic signal is present.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111398172.5A CN115246846A (en) | 2021-11-19 | 2021-11-19 | New crystal form of rubitinid and preparation thereof |
| PCT/CN2022/132675 WO2023088394A2 (en) | 2021-11-19 | 2022-11-17 | New crystal forms of lurbinectedin and preparation thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111398172.5A CN115246846A (en) | 2021-11-19 | 2021-11-19 | New crystal form of rubitinid and preparation thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115246846A true CN115246846A (en) | 2022-10-28 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111398172.5A Pending CN115246846A (en) | 2021-11-19 | 2021-11-19 | New crystal form of rubitinid and preparation thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN115246846A (en) |
| WO (1) | WO2023088394A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114940682A (en) * | 2022-05-18 | 2022-08-26 | 博瑞制药(苏州)有限公司 | Crystal form of ribitdine, preparation method and application thereof |
| CN115304619A (en) * | 2022-04-08 | 2022-11-08 | 上海皓元医药股份有限公司 | Crystal form of rubitinid and preparation method thereof |
| WO2023088394A3 (en) * | 2021-11-19 | 2023-09-21 | 江苏慧聚药业股份有限公司 | New crystal forms of lurbinectedin and preparation thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1564822A (en) * | 2001-08-07 | 2005-01-12 | 法马马有限公司 | Antitumoral analogs |
| WO2012062920A1 (en) * | 2010-11-12 | 2012-05-18 | Pharma Mar, S.A. | Combination therapy with an antitumor alkaloid |
| WO2021099635A1 (en) * | 2019-11-21 | 2021-05-27 | Pharma Mar, S.A. | New solid state form of lurbinectedin |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115246846A (en) * | 2021-11-19 | 2022-10-28 | 江苏慧聚药业股份有限公司 | New crystal form of rubitinid and preparation thereof |
-
2021
- 2021-11-19 CN CN202111398172.5A patent/CN115246846A/en active Pending
-
2022
- 2022-11-17 WO PCT/CN2022/132675 patent/WO2023088394A2/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1564822A (en) * | 2001-08-07 | 2005-01-12 | 法马马有限公司 | Antitumoral analogs |
| WO2012062920A1 (en) * | 2010-11-12 | 2012-05-18 | Pharma Mar, S.A. | Combination therapy with an antitumor alkaloid |
| WO2021099635A1 (en) * | 2019-11-21 | 2021-05-27 | Pharma Mar, S.A. | New solid state form of lurbinectedin |
Non-Patent Citations (1)
| Title |
|---|
| WEIMING HE, ET AL.: "A Scalable Total Synthesis of the Antitumor Agents Et-743 and Lurbinectedin", 《ANGEWANDTE CHEMIE INTERNATIONAL EDITION》, vol. 58, no. 12, 31 December 2019 (2019-12-31), pages 3972 - 3975, XP055733376, DOI: 10.1002/anie.201900035 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023088394A3 (en) * | 2021-11-19 | 2023-09-21 | 江苏慧聚药业股份有限公司 | New crystal forms of lurbinectedin and preparation thereof |
| CN115304619A (en) * | 2022-04-08 | 2022-11-08 | 上海皓元医药股份有限公司 | Crystal form of rubitinid and preparation method thereof |
| WO2023193440A1 (en) * | 2022-04-08 | 2023-10-12 | 上海皓元医药股份有限公司 | Lurbinectedin crystal form and method for preparing same |
| CN114940682A (en) * | 2022-05-18 | 2022-08-26 | 博瑞制药(苏州)有限公司 | Crystal form of ribitdine, preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2023088394A2 (en) | 2023-05-25 |
| WO2023088394A3 (en) | 2023-09-21 |
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