CN102875634B - 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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- CN102875634B CN102875634B CN201210408602.1A CN201210408602A CN102875634B CN 102875634 B CN102875634 B CN 102875634B CN 201210408602 A CN201210408602 A CN 201210408602A CN 102875634 B CN102875634 B CN 102875634B
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- diene
- acid methyl
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- 239000013078 crystal Substances 0.000 title claims abstract description 48
- 239000002253 acid Substances 0.000 title claims abstract description 25
- 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
- 150000004702 methyl esters Chemical class 0.000 claims description 21
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 13
- 238000001228 spectrum Methods 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 36
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 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
- 230000015572 biosynthetic process Effects 0.000 description 8
- 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
- 238000001757 thermogravimetry curve Methods 0.000 description 3
- 238000009736 wetting Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 2
- 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
- 0 C[C@@](CC(C)(C)CC1)C(C([C@@](C2)(CC3)[C@]2(CC[C@@](C)(C(C)(C)C2=O)C4(C)C=C2C#*)C4=C2)C2=O)[C@]13C(OC)=O Chemical compound C[C@@](CC(C)(C)CC1)C(C([C@@](C2)(CC3)[C@]2(CC[C@@](C)(C(C)(C)C2=O)C4(C)C=C2C#*)C4=C2)C2=O)[C@]13C(OC)=O 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
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000006731 degradation 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
- 230000000694 effects Effects 0.000 description 1
- 230000006698 induction Effects 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
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 pharmaceutical chemistry field, be specifically related to 2-cyano group-3,12-dioxo olea-1, several crystal formations of the adaptation drug development of 9 (11)-diene-28-acid methyl esters.
Background technology
The biosynthesizing of triterpene is mainly 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 effect.2-cyano group-3,12-dioxo olea-1,9 (11)-diene-28-acid methyl esters is 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-3,12-dioxo olea-1, the anhydrous crystal forms of 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, having crystal seed induction or comparatively high temps and the potential risk that changes into other crystal formations in humidity environment.In semibenzene solvate, benzene belongs to a kind solvent, very large to the toxicity of human body, and can not be at people's vivo degradation, is not suitable for carrying out drug development.Dimethanol compound crystal formation is unstable, and easily the some or all of methyl alcohol of sloughing, is transformed into other crystal formations, and empirical tests dimethanol compound is placed and within 7 days, all changed afterwards anhydrous crystal forms in closed environment.
In addition, also reported a kind of its water one methyl alcohol compound in scientific literature (Acta Cryst. (2002) .C58,0199-0200), this crystal formation is unstable equally, easily sloughs water or methyl alcohol, and crystal conversion occurs.
Therefore find solubleness good, bioavailability is high, stable, 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-3,12-dioxo olea-1, several new crystal of 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, by the research of the water one methyl alcohol compound to bibliographical information, has found 2-cyano group-3,12-dioxo olea-1, and 9 (11)-diene-28-acid methyl esters list methyl alcohol compound, is also 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 is as Fig. 1.
Form IV is 2-cyano group-3,12-dioxo olea-1, single methyl alcohol compound of 9 (11)-diene-28-acid methyl esters.
Single methanol solvate compound preparation method of the present invention is as follows: by 2-cyano group-3,12-dioxo olea-1, one water one methyl alcohol compound of 9 (11)-diene-28-acid methyl esters, under nitrogen purging, be heated to 30 ° of C, constant temperature, obtaining white solid and be single methanol solvate compound, is also 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 obtaining, it is good stability not only, 2 weeks crystal formations of the airtight placement 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 at spectrum d-spacing 12.05,8.90,8.49,8.13,7.92,7.29,6.64,4.67 and 3.65 dusts.As Fig. 2.
The preparation method of crystal form V of the present invention is as follows: form IV is heated under nitrogen purging to 50-100 ° of C, constant temperature, obtains white solid and be crystal form V.
On basis at crystal form V without hydrate, contriver studies again and has obtained 2-cyano group-3,12-dioxo olea-1, the pipeline dihydrate of 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 at spectrum d-spacing 8.81,8.48,7.91,7.32,5.09,4.24,3.58,3.36 and 3.17 dusts.As Fig. 3.
Crystal form V I weightlessness in the time being heated to 100 ° of C is 3.77%.Its thermogravimetric analysis figure is shown in Fig. 4.
The differential scanning calorimetric thermogram of crystal form V I has an endotherm(ic)peak in the time being heated to 92 ° of C, and enthalpy is 130.8J/g.See Fig. 5.
The preparation method of crystal form V I is as follows: by crystal form V, be heated to 50-100 ° of C under nitrogen purging, constant temperature, obtains white solid and be crystal form V I.
Crystal form V of the present invention and crystal form V I wetting ability are strong, and the Form A in the far super patent US8088824B2 of the wetting ability in water, is shown in 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 in patent US8088824B2, Form A concentration after 24 hours in the aqueous solution can not be detected, and sees Fig. 7.
Brief description of the 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 in crystal form V, crystal form V I and patent US8088824B2.
Fig. 7 is the dissolution rate comparison diagram of Form A in crystal form V, crystal form V I and patent US8088824B2.
Embodiment
Embodiment 1
By 2-cyano group-3,12-dioxo olea-1, one water one methyl alcohol compound 20mg of 9 (11)-diene-28-acid methyl esters, at 30 ° of C constant temperature, under nitrogen 25mL/min purges, 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 is also form IV.
Its X-ray powder diffraction figure is shown in Fig. 1.
Embodiment 2
By 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, under nitrogen 25mL/min purges, continue 1 hour, obtain white solid 18.2mg, be 2-cyano group-3,12-dioxo olea-1,9 (11)-diene-28-acid methyl esters, without hydrate, is also crystal form V.
Its X-ray powder diffraction figure is shown in Fig. 2.
Embodiment 3
By 2-cyano group-3,12-dioxo olea-1,9 (11)-diene-28-acid methyl esters, without hydrate 20mg, at 30 ° of C constant temperature, exposes and places under 50%-95% humidity, 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 is also crystal form V I.
Its X-ray powder diffraction figure is shown in Fig. 3, and thermogravimetric analysis figure is shown in Fig. 4, and differential scanning calorimetric thermogram is shown in Fig. 5.
Claims (3)
1. 2-cyano group-3,12-dioxo olea-1, the form IV of 9 (11)-diene-28-acid methyl esters, is characterized in that: its X-ray powder diffraction figure 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 have characteristic peak.
2. 2-cyano group-3,12-dioxo olea-1, the crystal form V of 9 (11)-diene-28-acid methyl esters, is characterized in that: its X-ray powder diffraction figure is in spectrum d-spacing 12.05,8.90,8.49,8.13,7.92,7.29,6.64,4.67 and 3.65 dusts have characteristic peak.
3. 2-cyano group-3,12-dioxo olea-1, the crystal form V I of 9 (11)-diene-28-acid methyl esters, is characterized in that: its X-ray powder diffraction figure is in spectrum d-spacing 8.81,8.48,7.91,7.32,5.09,4.24,3.58,3.36 and 3.17 dusts have characteristic peak.
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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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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019014412A1 (en) | 2017-07-13 | 2019-01-17 | Pliva Hrvatska D.O.O. | New crystalline polymorphs of bardoxolone methyl |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUE047994T2 (en) | 2010-04-12 | 2020-05-28 | Reata Pharmaceuticals Inc | Bardoxolone methyl for the treatment of obesity |
| TWI623548B (en) | 2012-04-27 | 2018-05-11 | 瑞塔醫藥有限責任公司 | 2,2-difluoropropionamide derivatives of bardoxolone methyl, polymorphic forms and methods of use thereof |
| KR102486434B1 (en) | 2016-11-08 | 2023-01-09 | 리아타 파마슈티컬즈 홀딩스, 엘엘씨 | Methods of treating Alport syndrome using bardoxolone methyl or analogs thereof |
| AU2021273460A1 (en) | 2020-05-09 | 2022-12-08 | Reata Pharmaceuticals Holdings, LLC | 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 |
Citations (1)
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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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
Non-Patent Citations (2)
| Title |
|---|
| "New Synthetic Triterpenoids:Potent Agents for Prevention and Treatment of Tissue Injury Caused by Inflammatory and Oxidative Stress";Michael B.Sporn et al.;《J.Nat.Prod.》;20110210;第74卷;537-545 * |
| 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.》.2011,第74卷537-545. |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019014412A1 (en) | 2017-07-13 | 2019-01-17 | Pliva Hrvatska D.O.O. | New crystalline polymorphs of bardoxolone methyl |
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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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