CN102887936A - Crystal forms of 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-oic acid methyl ester - Google Patents
Crystal forms of 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-oic acid methyl ester Download PDFInfo
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- CN102887936A CN102887936A CN2012104086159A CN201210408615A CN102887936A CN 102887936 A CN102887936 A CN 102887936A CN 2012104086159 A CN2012104086159 A CN 2012104086159A CN 201210408615 A CN201210408615 A CN 201210408615A CN 102887936 A CN102887936 A CN 102887936A
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- 239000013078 crystal Substances 0.000 title claims abstract description 70
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000012453 solvate Substances 0.000 claims abstract description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 29
- 239000002253 acid Substances 0.000 claims description 28
- 150000004702 methyl esters Chemical class 0.000 claims description 28
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 17
- 238000001757 thermogravimetry curve Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- -1 tetrahydrofuran solvent compound Chemical class 0.000 claims description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- 239000012296 anti-solvent Substances 0.000 claims description 6
- 238000001228 spectrum Methods 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- 230000000996 additive effect Effects 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 5
- 230000002349 favourable effect Effects 0.000 abstract 1
- 231100000956 nontoxicity Toxicity 0.000 abstract 1
- 238000005755 formation reaction Methods 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 8
- 238000002411 thermogravimetry Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000009509 drug development Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity 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
- 238000005516 engineering process Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000005057 refrigeration Methods 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
- 238000013112 stability test Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000003648 triterpenes Chemical class 0.000 description 1
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- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention relates to the field of pharmaceutical chemistry, and particularly relates to several crystal forms of 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-oic acid methyl ester suitable for medicament development. The invention is characterized in that the crystal forms are methylbenzene solvate, semi-dioxane solvate and semi-tetrahydrofuran solvate of 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-oic acid methyl ester. The several crystal forms have favorable solubility and stability, contain no toxicity and are suitable for being prepared into medicaments.
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.Its 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 easily the some or all of methyl alcohol of sloughing is transformed into other crystal formations, 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, easily sloughs water or methyl alcohol, and crystal conversion occurs.
Therefore seek solubleness good, bioavailability is high, and is 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 a class 2-cyano group-3, the solvate of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters is crystal formation I, II, III.Not only solubleness is good for they, good stability and nontoxic, is more suitable in being prepared into medicine.
The invention discloses 2-cyano group-3, the crystal formation I of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters, its X-ray powder diffraction figure is (same in spectrum d-spacing 9.65,7.58,7.18,6.29,6.06,5.47,5.21,4.77 and 3.07 dusts
) have a characteristic peak.Its X-ray powder diffraction figure such as Fig. 1.
Crystal formation I is 2-cyano group-3, the toluene solvate of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters, and weightlessness is 7.2% when being heated to 180 ° of C.Its thermogravimetric analysis figure such as Fig. 2.
The differential scanning calorimetric thermogram of crystal formation I is being located endotherm(ic)peak near 117 ℃, and enthalpy is 25.87J/g, and it is 34.88J/g that a melting hump, enthalpy are arranged when being heated to 215 ° of C.Such as Fig. 3.
Crystal formation I of the present invention can prepare with the following method: with 2-cyano group-3,12-dioxo olea-1,9 (11)-diene-28-acid methyl esters is dissolved in the toluene solution, through volatilization, obtains white solid and be toluene solvate.
The invention also discloses 2-cyano group-3, the another kind of crystal formation of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters, i.e. crystal form II.Its X-ray powder diffraction figure is in spectrum d-spacing 10.01,7.09,6.84,6.23,5.29,5.20,5.10,4.84, and 4.61 dusts have characteristic peak.Such as Fig. 4.
Crystal form II is 2-cyano group-3, half dioxane solvate of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters, and weightlessness is 8.05% when being heated to 195 ° of C.Its thermogravimetric analysis figure such as Fig. 5.
The differential scanning calorimetric thermogram of crystal form II is having endotherm(ic)peak near 150 ° of C places, and enthalpy is 58.10J/g, and a melting hump is arranged when being heated to 221 ℃, and enthalpy is 51.74J/g, such as Fig. 6.
Crystal form II can prepare with the following method: with 2-cyano group-3,12-dioxo olea-1,9 (11)-diene-28-acid methyl esters is dissolved in the mixing solutions of Isosorbide-5-Nitrae-dioxane and water, and the room temperature suspendible stirs, the white solid that obtains and get final product.
The invention also discloses 2-cyano group-3, the third crystal formation of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters, i.e. crystal form II I.Its X-ray powder diffraction figure is in spectrum d-spacing 10.00,7.14,6.80,6.65,6.10,5.62,5.29,4.88, and 4.50 dusts have characteristic peak.Such as Fig. 8.
Crystal form II I is 2-cyano group-3, half tetrahydrofuran solvent compound of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters, and weightlessness is 6.86% when being heated to 149 ° of C.Theoretical weightlessness behind the half tetrahydrofuran solvent compound desolventizing is 6.70%.Such as Fig. 9.
The differential scanning calorimetric thermogram of crystal form II I locates that near 136 ° of C the time endotherm(ic)peak is arranged, and enthalpy is 57.30J/g, and it is 57.71J/g that a melting hump, enthalpy are arranged when being heated to 221 ° of C.Such as Figure 10.
Crystal form II I can prepare with the following method: with 2-cyano group-3,12-dioxo olea-1,9 (11)-diene-28-acid methyl esters is dissolved in the tetrahydrofuran solution, it is refrigerated with anti-solvent normal heptane, with 2-cyano group-3, the tetrahydrofuran solution of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters is added drop-wise in the normal heptane through reverse anti-solvent additive process, then suspendible stirs, and get final product.
The present invention is by using toluene, dioxane and tetrahydrofuran (THF) as solvent recrystallization, it is less that the solvate that obtains has toxicity, the advantage of good stability, do not change at 1 month crystal formation of the airtight placement of room temperature, as seen X-ray powder diffraction figure before and after the result of its stability test stores by crystal formation contrasts, and sees Figure 12,13,14.As seen from the figure crystal formation I of the present invention, II and the airtight placement of III after 1 month crystal formation do not change, illustrate that three kinds of crystal formations of the present invention are more stable.Figure below among Figure 12 is freshly prepd crystal formation I, and top figure is 1 month crystal formation I afterwards of airtight placement.Figure above among Figure 13 is freshly prepd crystal form II, and following figure is 1 month crystal form II afterwards of airtight placement.Figure above among Figure 14 is freshly prepd crystal form II I, and following figure is 1 month crystal form II I afterwards of airtight placement.
Simple to operate in crystal formation I of the present invention, II, the III preparation, solvent load is few and nontoxic, and production cost is low, has clear superiority aspect industrialization.
Description of drawings
Fig. 1 is the X-ray powder diffraction figure of crystal formation I.
Fig. 2 is the thermogravimetric analysis figure of crystal formation I.
Fig. 3 is the differential scanning calorimetric thermogram of crystal formation I.
Fig. 4 is the X-ray powder diffraction figure of crystal form II.
Fig. 5 is the thermogravimetric analysis figure of crystal form II.
Fig. 6 is the differential scanning calorimetric thermogram of crystal form II.
Fig. 7 is the liquid core magnetic chart of crystal form II.
Fig. 8 is the X-ray powder diffraction figure of crystal form II I.
Fig. 9 is the thermogravimetric analysis figure of crystal form II I.
Figure 10 is the differential scanning calorimetric thermogram of crystal form II I.
Figure 11 is the liquid core magnetic chart of crystal form II I.
Figure 12 is the study on the stability X-ray powder diffraction figure of crystal formation I.
Figure 13 is the study on the stability X-ray powder diffraction figure of crystal form II.
Figure 14 is the study on the stability X-ray powder diffraction figure of crystal form II I.
Embodiment
Get 50mg 2-cyano group-3,12-dioxo olea-1,9 (11)-diene-28-acid methyl esters is dissolved in the 500 μ L toluene, is positioned over fast volatilization in the stink cupboard, and namely obtaining toluene solvate after 1 day is crystal formation I 53.8mg.
X-ray powder diffraction figure sees Fig. 1.Thermogravimetric analysis figure sees Fig. 2.Differential scanning calorimetric thermogram is seen Fig. 3.
With the 2-cyano group-3 of 200mg, 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters is dissolved in the mixing solutions of Isosorbide-5-Nitrae-dioxane of 4: 1 of 1ml volume ratio and water, stirs 24 hours the white solid 146mg that obtains through the room temperature suspendible.Purity is 99.48%.White solid is crystal form II, also is half Isosorbide-5-Nitrae-dioxane solvate.
X-ray powder diffraction figure sees Fig. 4.The thermogravimetric analysis spectrogram is seen Fig. 5.Differential scanning calorimetric thermogram is seen Fig. 6.The liquid core magnetic chart is seen Fig. 7.
2-cyano group-3 with 16.9mg, 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters is dissolved in the tetrahydrofuran solution of 0.2ml, its anti-solvent normal heptane with 4.0ml is positioned among-22 ° of C refrigeration 1 hour, the reverse anti-solvent additive process of process is with 2-cyano group-3,12-dioxo olea-1, the tetrahydrofuran solution of 9 (11)-diene-28-acid methyl esters slowly is added drop-wise in the normal heptane, then suspendible stirred 24 hours, the white solid 11.4mg. purity 99.25% that obtains.White solid is crystal form II I, also is half tetrahydrofuran solvent compound.
X-ray powder diffraction figure sees Fig. 8.Thermogravimetric analysis figure sees Fig. 9.Differential scanning calorimetric thermogram is seen Figure 10.The liquid core magnetic chart is seen Figure 11.
Claims (10)
1. 2-cyano group-3, the crystal formation I of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters, it is characterized in that: its X-ray powder diffraction figure is in spectrum d-spacing 9.65,7.58,7.18,6.29,6.06,5.47 5.21,4.77 and 3.07 dusts have characteristic peak.
2. the crystal formation I of claim 1, it is 2-cyano group-3, the toluene solvate of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters, weightlessness is 7.2% when being heated to 180 ° of C.
3. the crystal formation I of claim 1, its differential scanning calorimetric thermogram is having endotherm(ic)peak near 117 ° of C places.
4. 2-cyano group-3, the crystal form II of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters, it is characterized in that: its X-ray powder diffraction figure is in spectrum d-spacing 10.01,7.09,6.84,6.23,5.29,5.20,5.10,4.84, and 4.61 dusts have characteristic peak.
5. the crystal form II of claim 4, it is 2-cyano group-3, half dioxane solvate of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters, being heated to 195 ° of C weightlessness is 8.05%.
6. the crystal form II of claim 4, its differential scanning calorimetric thermogram is having endotherm(ic)peak near 150 ° of C places.
7. 2-cyano group-3, the crystal form II I of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters, it is characterized in that: its X-ray powder diffraction figure is in spectrum d-spacing 10.00,7.14,6.80,6.65,6.10,5.62,5.29,4.88, and 4.50 dusts have characteristic peak.
8. the crystal form II I of claim 7, it is 2-cyano group-3, half tetrahydrofuran solvent compound of 12-dioxo olea-1,9 (11)-diene-28-acid methyl esters, weightlessness is 6.86% when being heated to 149 ° of C.
9. the crystal form II I of claim 7, its differential scanning calorimetric thermogram locates to have endotherm(ic)peak near 136 ° of C the time.
10. the preparation method of the crystal form II I of claim 7, comprise: with 2-cyano group-3,12-dioxo olea-1,9 (11)-diene-28-acid methyl esters is dissolved in the tetrahydrofuran solution, and it is refrigerated with anti-solvent normal heptane, and the reverse anti-solvent additive process of process is with 2-cyano group-3,12-dioxo olea-1, the tetrahydrofuran solution of 9 (11)-diene-28-acid methyl esters is added drop-wise in the normal heptane, and then suspendible stirs, and get final product.
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9278912B2 (en) | 2012-09-10 | 2016-03-08 | Reata Pharmaceuticals, Inc. | C13-hydroxy derivatives of oleanolic acid and methods of use thereof |
| US9556222B2 (en) | 2012-06-15 | 2017-01-31 | Reata Pharmaceuticals, Inc. | A-ring epoxidized triterpenoid-based anti-inflammation modulators and methods of use thereof |
| US9593074B2 (en) | 2012-09-10 | 2017-03-14 | Reata Pharmaceuticals, Inc. | C17-alkanediyl and alkenediyl derivatives of oleanolic acid and methods of use thereof |
| 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 |
| US10093614B2 (en) | 2008-04-18 | 2018-10-09 | Reata Pharmaceuticals, Inc. | Antioxidant Inflamation modulators: oleanolic acid derivatives with amino and other modifications at C-17 |
| WO2019014412A1 (en) | 2017-07-13 | 2019-01-17 | Pliva Hrvatska D.O.O. | New crystalline polymorphs of bardoxolone methyl |
| US10398711B2 (en) | 2012-09-10 | 2019-09-03 | Reata Pharmaceuticals, Inc. | C17-heteroaryl derivatives of oleanolic acid 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 |
| 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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| US6326507B1 (en) * | 1998-06-19 | 2001-12-04 | Trustees Of Dartmouth College | Therapeutic compounds and methods of use |
| 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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| US11919838B2 (en) | 2008-04-18 | 2024-03-05 | Reata Pharmaceuticals Holdings, LLC | Antioxidant inflammation modulators: oleanolic acid derivatives with amino and other modifications at C-17 |
| US10093614B2 (en) | 2008-04-18 | 2018-10-09 | Reata Pharmaceuticals, Inc. | Antioxidant Inflamation modulators: oleanolic acid derivatives with amino and other modifications at C-17 |
| US12358866B2 (en) | 2008-04-18 | 2025-07-15 | Reata Pharmaceuticals Holdings, LLC | Antioxidant inflammation modulators: oleanolic acid derivatives with amino and other modifications at C-17 |
| US11091430B2 (en) | 2008-04-18 | 2021-08-17 | Reata Pharmaceuticals, Inc. | Antioxidant inflammation modulators: oleanolic acid derivatives with amino and other modifications at c-17 |
| US11911395B2 (en) | 2010-04-12 | 2024-02-27 | Reata Pharmaceuticals Holdings, LLC | Methods of treating obesity using antioxidant inflammation modulators |
| 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 |
| 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 |
| US12065464B2 (en) | 2012-04-27 | 2024-08-20 | Reata Pharmaceuticals Holdings, LLC | 2,2-difluoropropionamide derivatives of bardoxolone methyl, polymorphic forms and methods of use thereof |
| US9556222B2 (en) | 2012-06-15 | 2017-01-31 | Reata Pharmaceuticals, Inc. | A-ring epoxidized triterpenoid-based anti-inflammation modulators and methods of use thereof |
| US10898499B2 (en) | 2012-09-10 | 2021-01-26 | Reata Pharmaceuticals, Inc. | C17-heteroaryl derivatives of oleanolic acid and methods of use thereof |
| US9278912B2 (en) | 2012-09-10 | 2016-03-08 | Reata Pharmaceuticals, Inc. | C13-hydroxy derivatives of oleanolic acid and methods of use thereof |
| US10501489B2 (en) | 2012-09-10 | 2019-12-10 | Reata Pharmaceuticals, Inc. | C17-alkanediyl and alkenediyl derivatives of oleanolic acid and methods of use thereof |
| US10398711B2 (en) | 2012-09-10 | 2019-09-03 | Reata Pharmaceuticals, Inc. | C17-heteroaryl derivatives of oleanolic acid and methods of use thereof |
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