CN102875634A - Crystal forms of 2-cyano-3, 12-dioxooleana-1, 9(11)-diene-28-oic acid methyl ester - Google Patents
Crystal forms of 2-cyano-3, 12-dioxooleana-1, 9(11)-diene-28-oic acid methyl ester Download PDFInfo
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- CN102875634A CN102875634A CN2012104086021A CN201210408602A CN102875634A CN 102875634 A CN102875634 A CN 102875634A CN 2012104086021 A CN2012104086021 A CN 2012104086021A CN 201210408602 A CN201210408602 A CN 201210408602A CN 102875634 A CN102875634 A CN 102875634A
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- Prior art keywords
- diene
- acid methyl
- olea
- dioxo
- crystal form
- Prior art date
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Links
- 239000013078 crystal Substances 0.000 title claims abstract description 54
- 239000002253 acid Substances 0.000 title claims abstract description 28
- FICQFRCPSFCFBY-UHFFFAOYSA-N 2-[bis(methylsulfanyl)methylidene]propanedinitrile Chemical compound CSC(SC)=C(C#N)C#N FICQFRCPSFCFBY-UHFFFAOYSA-N 0.000 title abstract 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 39
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- 150000004702 methyl esters Chemical class 0.000 claims description 24
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 13
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- 238000001228 spectrum Methods 0.000 claims description 6
- 238000010586 diagram Methods 0.000 claims description 4
- 238000001757 thermogravimetry curve Methods 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims 3
- 230000036571 hydration Effects 0.000 claims 1
- 238000006703 hydration reaction Methods 0.000 claims 1
- 150000004683 dihydrates Chemical class 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 231100000419 toxicity Toxicity 0.000 abstract description 2
- 230000001988 toxicity Effects 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- -1 Dimethanol compound Chemical class 0.000 description 10
- 238000005755 formation reaction Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000012453 solvate Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000010926 purge Methods 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000009509 drug development Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000002411 thermogravimetry Methods 0.000 description 3
- 238000009736 wetting Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- BXGYYDRIMBPOMN-UHFFFAOYSA-N 2-(hydroxymethoxy)ethoxymethanol Chemical compound OCOCCOCO BXGYYDRIMBPOMN-UHFFFAOYSA-N 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000003540 anti-differentiation Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000003570 biosynthesizing effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 150000003648 triterpenes Chemical class 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
-
- 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
Abstract
The invention relates to the field of pharmaceutical chemistry, in particular to crystal forms of 2-cyano-3, 12-dioxooleana-1, 9(11)-diene-28-oic acid methyl ester developable to drugs. The crystal forms are characterized by including single-methanol compound, anhydrous compound and pipeline dihydrate of the 2-cyano-3, 12-dioxooleana-1, 9(11)-diene-28-oic acid methyl ester. The crystal forms of the 2-cyano-3, 12-dioxooleana-1, 9(11)-diene-28-oic acid methyl ester are better than the existing crystal forms in solubility and are high in bioavailability and stable and low in toxicity.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to 2-cyano group-3, several crystal formations of the adaptation drug development of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters.
Background technology
The biosynthesizing of triterpene mainly is to be generated by the cyclisation of squalene in plant, it during as bulk drug biological activity relatively a little less than.Therefore scientists is sought synthetic analogues and is strengthened effectiveness.2-cyano group-3,12-dioxo olea-1,9 (11)-diene-28-acid methyl esters are exactly wherein a kind ofly to have a good anti-inflammatory, and differentiation and anti-proliferative effect possess the drug molecule of drug development potentiality.Structural formula is as follows:
At present, patent US8088824B2 has reported 2-cyano group-3, the anhydrous crystal forms of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters, amorphous, semibenzene solvate and dimethanol solvate.But there is poor solubility in anhydrous crystal forms, the problem that bioavailability is low.And amorphous thermodynamic instability, have crystal seed induce or comparatively high temps and humidity environment in change into the potential risk of other crystal formations.Benzene belongs to a kind solvent in the semibenzene solvate, and is very large to the toxicity of human body, and can not degrade in human body, is not suitable for carrying out drug development.Dimethanol compound crystal formation is unstable, and the some or all of methyl alcohol of sloughing is transformed into other crystal formations easily, and empirical tests dimethanol compound is placed in closed environment and all changed afterwards anhydrous crystal forms in 7 days into.
In addition, also reported a kind of its water one methyl alcohol compound in the scientific literature (Acta Cryst. (2002) .C58,0199-0200), this crystal formation is unstable equally, sloughs easily water or methyl alcohol, and crystal conversion occurs.
Therefore it is good to seek solubleness, and bioavailability is high, stable, the 2-cyano group-3 of nontoxic or low toxicity, and 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters new crystal is very necessary.
Summary of the invention
The invention discloses 2-cyano group-3, several new crystal of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters are its single methyl alcohol compounds, without hydrate and pipeline dihydrate.They are better than existing crystal formation solubleness, and bioavailability is high, stable and nontoxic or low toxicity.
The present invention passes through the research to a water one methyl alcohol compound of bibliographical information, has found 2-cyano group-3, and 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters list methyl alcohol compound also is form IV.The X-ray powder diffraction collection of illustrative plates of form IV is in spectrum d-spacing 8.86,8.45,8.17,7.90,7.26,4.67,6.63,6.46, and 3.64(
) dust has characteristic peak.Its X-ray powder diffraction figure such as Fig. 1.
Form IV is 2-cyano group-3, single methyl alcohol compound of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters.
Single methanol solvate compound preparation method of the present invention is as follows: with 2-cyano group-3, and a water one methyl alcohol compound of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters, under nitrogen purging, be heated to 30 ° of C, constant temperature obtains white solid and is single methanol solvate compound, also is form IV.
The present invention is by using 2-cyano group-3,12-dioxo olea-1, the research of 9 (11)-diene-28-acid methyl esters one water one methyl alcohol compound, the single methanol solvate compound that obtains, it is good stability not only, the airtight placement 2 all crystal formations of room temperature do not change, and can further prepare anhydrous crystal forms as initiator.
The invention also discloses a kind of 2-cyano group-3,12-dioxo olea-1,9 (11)-diene-28-acid methyl esters without hydrate, i.e. crystal form V.Its X-ray powder diffraction figure has characteristic peak in spectrum d-spacing 12.05,8.90,8.49,8.13,7.92,7.29,6.64,4.67 and 3.65 dusts.Such as Fig. 2.
The preparation method of crystal form V of the present invention is as follows: form IV is heated to 50-100 ° of C under nitrogen purging, constant temperature obtains white solid and is crystal form V.
On the basis of crystal form V without hydrate, the contriver studies again and has obtained 2-cyano group-3, the pipeline dihydrate of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters.Be called crystal form V I.
The X-ray powder diffraction figure of crystal form V I has characteristic peak in spectrum d-spacing 8.81,8.48,7.91,7.32,5.09,4.24,3.58,3.36 and 3.17 dusts.Such as Fig. 3.
Crystal form V I weightlessness when being heated to 100 ° of C is 3.77%.Its thermogravimetric analysis figure sees Fig. 4.
The differential scanning calorimetric thermogram of crystal form V I has an endotherm(ic)peak when being heated to 92 ° of C, enthalpy is 130.8J/g.See Fig. 5.
The preparation method of crystal form V I is as follows: with crystal form V, be heated to 50-100 ° of C under nitrogen purging, constant temperature obtains white solid and is crystal form V I.
Crystal form V of the present invention and crystal form V I wetting ability are strong, and the Form A among the far super patent US8088824B2 of the wetting ability in water sees Fig. 6; Dissolution rate is fast, crystal form V concentration after 24 hours in the aqueous solution is 0.0050mg/mL, crystal form V I concentration after 24 hours in the aqueous solution is 0.0053mg/mL, and Form A concentration after 24 hours in the aqueous solution can not be detected among the patent US8088824B2, sees Fig. 7.
Description of drawings
Fig. 1 is the X-ray powder diffraction figure of form IV.
Fig. 2 is the X-ray powder diffraction figure of crystal form V.
Fig. 3 is the X-ray powder diffraction figure of crystal form V I.
Fig. 4 is the thermogravimetric analysis figure of crystal form V I.
Fig. 5 is the differential scanning calorimetric thermogram of crystal form V I.
Fig. 6 is the wetting ability comparison diagram of Form A among crystal form V, crystal form V I and the patent US8088824B2.
Fig. 7 is the dissolution rate comparison diagram of Form A among crystal form V, crystal form V I and the patent US8088824B2.
Embodiment
Embodiment 1
With 2-cyano group-3,12-dioxo olea-1, one water, the one methyl alcohol compound 20mg of 9 (11)-diene-28-acid methyl esters, at 30 ° of C constant temperature, nitrogen 25mL/min purges lower, continue 1 hour, obtain white solid 19.4mg, be 2-cyano group-3,12-dioxo olea-1,9 (11)-diene-28-acid methyl esters list methanol solvate compound also are form IV.
Its X-ray powder diffraction figure sees Fig. 1.
Embodiment 2
With 2-cyano group-3,12-dioxo olea-1,9 (11)-diene-28-acid methyl esters one water one methyl alcohol compound 20mg, at 100 ° of C constant temperature, nitrogen 25mL/min purges lower, continue 1 hour, obtain white solid 18.2mg, be 2-cyano group-3,12-dioxo olea-1,9 (11)-diene-28-acid methyl esters also is crystal form V without hydrate.
Its X-ray powder diffraction figure sees Fig. 2.
Embodiment 3
With 2-cyano group-3,12-dioxo olea-1,9 (11)-diene-28-acid methyl esters, exposes under the 50%-95% humidity and places at 30 ° of C constant temperature without hydrate 20mg, continue 1 hour, obtain white solid 21.4mg, be 2-cyano group-3,12-dioxo olea-1,9 (11)-diene-28-acid methyl esters pipeline dihydrate also are crystal form V I.
Its X-ray powder diffraction figure sees Fig. 3, and thermogravimetric analysis figure sees Fig. 4, and differential scanning calorimetric thermogram is seen Fig. 5.
Claims (10)
1. 2-cyano group-3, the form IV of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters is characterized in that: its X ray
Powder diagram is in spectrum d-spacing 8.86,8.45,8.17,7.90,7.26,4.67,6.63,6.46, and 3.64 dusts
Has characteristic peak.
2. the form IV of claim 1, its X-ray powder diffraction figure such as Fig. 1.
3. the crystal formation I of claim 1, it is 2-cyano group-3, single methyl alcohol of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters
Compound.
4. 2-cyano group-3, the crystal form V of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters is characterized in that: its X ray powder
The end diffractogram has in spectrum d-spacing 12.05,8.90,8.49,8.13,7.92,7.29,6.64,4.67 and 3.65 dusts
Characteristic peak.
5. the crystal form V of claim 4, its X-ray powder diffraction figure such as Fig. 2.
6. the crystal form V of claim 4, it is 2-cyano group-3,12-dioxo olea-1,9 (11)-diene-28-acid methyl esters without hydration
Thing.
7. 2-cyano group-3, the crystal form V I of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters is characterized in that: its X ray
Powder diagram has in spectrum d-spacing 8.81,8.48,7.91,7.32,5.09,4.24,3.58,3.36 and 3.17 dusts
Characteristic peak.
8. the crystal form V I of claim 7, its X-ray powder diffraction figure such as Fig. 3.
9. the crystal form V I of claim 7, it is 2-cyano group-3, the pipeline two of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters
Hydrate, weightlessness is 3.77% when being heated to 100 ° of C.
10. the crystal form V I of claim 7, its differential scanning calorimetric thermogram is having endotherm(ic)peak near 92 ° of C places.
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| CN201210408602.1A CN102875634B (en) | 2012-10-24 | 2012-10-24 | Crystal forms of 2-cyano-3, 12-dioxooleana-1, 9(11)-diene-28-oic acid methyl ester |
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| CN201210408602.1A CN102875634B (en) | 2012-10-24 | 2012-10-24 | Crystal forms of 2-cyano-3, 12-dioxooleana-1, 9(11)-diene-28-oic acid methyl ester |
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| CN102875634B CN102875634B (en) | 2014-08-20 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9701709B2 (en) | 2012-04-27 | 2017-07-11 | Reata Pharmaceuticals, Inc. | 2,2-difluoropropionamide derivatives of bardoxolone methyl, polymorphic forms and methods of use thereof |
| WO2019014412A1 (en) * | 2017-07-13 | 2019-01-17 | Pliva Hrvatska D.O.O. | New crystalline polymorphs of bardoxolone methyl |
| US10953020B2 (en) | 2016-11-08 | 2021-03-23 | Reata Pharmaceuticals, Inc. | Methods of treating Alport syndrome using bardoxolone methyl or analogs thereof |
| WO2021231208A1 (en) | 2020-05-09 | 2021-11-18 | Reata Pharmaceuticals, Inc. | Methods of treating covid-19 using bardoxolone methyl or analogs thereof |
| WO2022126129A1 (en) | 2020-12-11 | 2022-06-16 | Reata Pharmaceuticals, Inc. | Synthetic triterpenoids for use in therapy |
| US11911395B2 (en) | 2010-04-12 | 2024-02-27 | Reata Pharmaceuticals Holdings, LLC | Methods of treating obesity using antioxidant inflammation modulators |
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| CN101820758A (en) * | 2007-08-15 | 2010-09-01 | 瑞阿特制药公司 | Novel forms of cddo methyl ester |
-
2012
- 2012-10-24 CN CN201210408602.1A patent/CN102875634B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101820758A (en) * | 2007-08-15 | 2010-09-01 | 瑞阿特制药公司 | Novel forms of cddo methyl ester |
Non-Patent Citations (1)
| Title |
|---|
| MICHAEL B.SPORN ET AL.: ""New Synthetic Triterpenoids:Potent Agents for Prevention and Treatment of Tissue Injury Caused by Inflammatory and Oxidative Stress"", 《J.NAT.PROD.》 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11911395B2 (en) | 2010-04-12 | 2024-02-27 | Reata Pharmaceuticals Holdings, LLC | Methods of treating obesity using antioxidant inflammation modulators |
| US9701709B2 (en) | 2012-04-27 | 2017-07-11 | Reata Pharmaceuticals, Inc. | 2,2-difluoropropionamide derivatives of bardoxolone methyl, polymorphic forms and methods of use thereof |
| US11078230B2 (en) | 2012-04-27 | 2021-08-03 | Reata Pharmaceuticals, Inc. | 2,2-difluoropropionamide derivatives of bardoxolone methyl, polymorphic forms and methods of use thereof |
| US10953020B2 (en) | 2016-11-08 | 2021-03-23 | Reata Pharmaceuticals, Inc. | Methods of treating Alport syndrome using bardoxolone methyl or analogs thereof |
| US11446313B2 (en) | 2016-11-08 | 2022-09-20 | Reata Pharmaceuticals Holdings, LLC | Methods of treating Alport syndrome using bardoxolone methyl or analogs thereof |
| WO2019014412A1 (en) * | 2017-07-13 | 2019-01-17 | Pliva Hrvatska D.O.O. | New crystalline polymorphs of bardoxolone methyl |
| US11427533B2 (en) | 2017-07-13 | 2022-08-30 | Pliva Hrvatska D.O.O. | Crystalline polymorphs of bardoxolone methyl |
| WO2021231208A1 (en) | 2020-05-09 | 2021-11-18 | Reata Pharmaceuticals, Inc. | Methods of treating covid-19 using bardoxolone methyl or analogs thereof |
| WO2022126129A1 (en) | 2020-12-11 | 2022-06-16 | Reata Pharmaceuticals, Inc. | Synthetic triterpenoids for use in therapy |
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Address after: 215123 Biological Park B4-101, No. 218 Xing Hu Street, Suzhou Industrial Park, Jiangsu Co-patentee after: SUZHOU PENGXU PHARMATECH Co.,Ltd. Patentee after: CRYSTAL PHARMATECH Co.,Ltd. Address before: 215123 Bio-nano Park A2-427, 218 Xinghu Street, Suzhou Industrial Park, Jiangsu Province Co-patentee before: SUZHOU PENGXU PHARMATECH Co.,Ltd. Patentee before: Crystal Pharmatech Co.,Ltd. |
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