CN103108882A - Polycrystalline type object of CDDO BIEA and use thereof - Google Patents
Polycrystalline type object of CDDO BIEA and use thereof Download PDFInfo
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Abstract
The invention relates to the compositions represented by the polycrystalline type state of the formula I(namely, ethy 2- cyanogens-3, 12- olean-1,9(11) diene-28- ester(CDDO BIEA)), and the method using the same to cure various illnesses such as cancers and other conditions provided with the inflammation. The formula I.
Description
The related application of cross reference
It is the right of priority of the PCT international application of PCT/CN2012/082278 that the application requires the international application no that on September 28th, 2012 submitted to, should incorporate by reference this paper at this at the full content of first to file.
Technical field
The application relates to triterpenoid, ethyl 2-cyano group-3,12-dioxo volatile oil-1, the polymorphs form of 9 (11) dienes-28-ester (CDDO ethyl ester), and utilize their at least a polymorphs form treatment various disease states, be generally the method with the morbid state of inflammation-related.
Background technology
Triterpenoid is that the cyclization by squalene in plant carries out biosynthesizing.Although triterpenoid is candidate's medical compounds, the molecule of these natural generations shows relatively weak biological activity.Therefore, chemists have attempted the similar compound that synthetic effect improves people such as (, 1997 and 1998) Honda.
It is reported, again the forming of the derivable nitricoxide synthase of cytokine (iNOS) and cyclooxygenase-2 (COX-2) in the scavenger cell that some synthetic similar compounds have suppressed to be stimulated by IFN-γ or LPS (people such as Suh, 1998; The people such as Honda, 2002).Wherein, 2-cyano group-3,12-dioxo volatile oil-1,9(11) diene-28-ester (CDDO) demonstrates anti-inflammatory and antiproliferative activity (people such as Honda, 1998 and 2000).As described, triterpenoid is as the inhibition of iNOS activity, particularly to the inhibiting research of the generation of NO, shown the efficient (IC of CDDO and CDDO methyl ester
50＜lnM level).Referring to the people such as Honda (2000).In any case, believe that their treatment potential also is not utilized fully, the CDDO ethyl ester still less up to now.
In order to be familiar with the treatment potential suc as formula the CDDO ethyl ester shown in I, the inventor has studied the polymorphs form of this compound.Therefore, the contriver has disclosed three kinds of crystal formation forms of CDDO ethyl ester, and these three kinds of crystal formation forms have some favourable character (for example, pharmacokinetic performance and higher system expose preferably), and this makes them become desirable candidate's new drug.
Summary of the invention
On the one hand, the invention provides the polymorphic form of the compound shown in the formula I, and/or its hydrate or solvate.
Formula I
Wherein, these polymorphic forms comprise at least two kinds of compound shown in the formula I pure crystal habit and a kind of pure glassy solids forms basically basically.For convenient, these two kinds of crystal habits are in this called after form I and form II.
In some embodiments, polymorphic form is the glassy solids form of compound shown in the formula I, and its feature is that Tg is about 52 ° of C ± 10 ° C.
In other embodiments, polymorphic form is the glassy solids form of compound shown in the formula I, and its feature is that its X-ray powder diffraction pattern is about 14.3 ° at diffraction angle 2 θ and locates to have characteristic peak.
In other embodiments, the characteristics of the glassy solids form of compound shown in the formula I are, its purity 〉=85%(namely: be 85% at least).In the other embodiment, its purity is 95% or 99% at least.
In other embodiments, this polymorphic form is the crystal habit I of compound shown in the formula I, and its feature is that its X-ray powder diffraction pattern is about 10.3 ° at diffraction angle 2 θ, locates to have characteristic peak for 14.1 ° and 14.6 °.
In other embodiments, this polymorphic form is the crystal habit I of compound shown in the formula I, and its feature is, its X-ray powder diffraction pattern is about 10.3 ° at diffraction angle 2 θ, 14.1 °, and 14.6 °, 15.8 °, locate to have characteristic peak for 16.6 ° and 19.6 °.
In other embodiments, this polymorphic form is the crystal habit I of compound shown in the formula I, and its feature is that its X-ray powder diffraction pattern has characteristic peak, represents that spacing is
With
In other embodiments, this polymorphic form is the crystal habit I of compound shown in the formula I, and its feature is that its X-ray powder diffraction pattern has characteristic peak, represents that spacing is
With
Another part of the embodiment of polymorphic form of the present invention is the crystal habit I.
In some such embodiments, the characteristics of the crystal habit I of compound shown in the formula I are, its X-ray powder diffraction pattern is about 10.3 ° at diffraction angle 2 θ, 14.1 °, and 14.6 °, 15.7 °, and 16.6 ° located to have characteristic peak.
In other embodiments, the crystal habit I of compound shown in the formula I is about 9.3 ° and 19.6 ° at diffraction angle 2 θ and locates to have extra characteristic peak in its X-ray powder diffraction pattern.
In the other embodiment, the characteristics of the crystal habit I of compound shown in the formula I are that fusing point is 174-177 ℃.
In other embodiments, the characteristics of the crystal habit I of compound shown in the formula I are, its purity 〉=85%(namely: be 85% at least).In the other embodiment, its purity is 95% or 99% at least.
Another part of the embodiment of polymorphic form of the present invention is crystal habit II.
In some such embodiments, the characteristics of the crystal habit II of compound shown in the formula I are that its X-ray powder diffraction pattern is about 10.4 ° at diffraction angle 2 θ, locates to have characteristic peak for 12.1 ° and 13.4 °.
In other embodiments, the crystal habit II of compound shown in the formula I in its X-ray powder diffraction pattern, is about 15.4 ° at diffraction angle 2 θ, locates to have extra characteristic peak for 17.8 ° and 18.8 °.
In other embodiments, the characteristics of the crystal habit II of compound shown in the formula I are that its X-ray powder diffraction pattern has characteristic peak, represents that spacing is
With
In other embodiments, the crystal habit II of compound shown in the formula I has extra characteristic peak, and the expression spacing is
With
In the other embodiment, the characteristics of the crystal habit II of compound shown in the formula I are that fusing point is 209-212 ℃.
In other embodiments, the purity of the crystal habit II of compound shown in the formula I for example is not less than 85%(, and its purity is 95% at least or is 99% at least).
On the other hand, the invention still further relates to the preparation method of the crystal polymorphic form of compound shown in the formula I.
An embodiment of described method comprises the steps: excessive compound is added to pulp in solvent, and described solvent is CH
2Cl
2, ethyl acetate, acetonitrile, ethanol, methyl alcohol, heptane or its mixture at least through 24 hours, reclaim the crystal polymorphic form or the glassy solids form that generate.
In some embodiments, the crystal habit of generation can be form I or form II.
In other embodiments, compound shown in the formula I under the condition of room temperature or 50 ° of C, pulp in mixed solvent.
In other embodiments, the pulp at least 48 hours in solvent of compound shown in the formula I.
Described solvent can be the mixture of ethyl acetate/heptane, the mixture of ethanol/heptane.For example, in the mixture of described ethyl acetate/heptane, the ratio of ethyl acetate and heptane is 1:10(weight ratio or volume ratio).
The invention provides a kind of polymorphic form, compound shown in crystallization formula I in suitable solvent system, described solvent system comprises at least a solvent, polymorphic form can obtain by following method: natural sedimentation (evaporation), cooling, or add anti-solvent (solubleness of compound of the present invention in anti-solvent is relatively low), to obtain the supersaturation of solvent system.Crystallization can also by with or do not realize with crystal seed, described crystal seed is suitable for crystallization compound of the present invention.
In other embodiments, shown in formula I of the present invention, compound is dissolved in the solvent heptane at ambient temperature, obtains desired crystal habit I by natural sedimentation afterwards, and the fusing point of this crystal habit I is 174-177 ℃.
In other embodiments, add mixed solvent to stir under room temperature or 50 ℃ of conditions compound shown in excessive formula I of the present invention, described mixed solvent is ethyl acetate/heptane (weight ratio or volume ratio are 1:10), at least 48 hours, obtain crystal habit II, the fusing point of this crystal habit II is 209-212 ℃.
In other embodiments, compound shown in excessive formula I of the present invention is dissolved in dichloromethane solvent under room temperature or 50 ℃ of conditions, obtain afterwards the glassy solids form of compound shown in the formula I by evaporating solvent, the Tg scope of this glassy solids form is 52 ° of C ± 10 ° C.
The present invention further provides the purposes of the polymorphic form (comprising crystal kenel I and II and glassy solids form) of compound shown in the formula I, be used for the treatment of uncomfortable or the state of an illness, especially with those state of an illness of inflammation, or for the preparation of the medicament that is used for treating uncomfortable or the state of an illness, for example, these states relate to serious or chronic oxidative stress and inflammation, and especially those Partial Feature are that crossing of derivable nitricoxide synthase (iNOS) or derivable epoxidase (COX-2) expressed.
Therefore, the invention still further relates to pharmaceutical composition or medicament, described pharmaceutical composition or medicament comprise crystalline form I of the present invention or Form II or the glassy solids form for the treatment of at least significant quantity, and medicine acceptable vehicle, auxiliary material or carrier.Selectable, described composition or medicament may further include at least a additional active ingredient.
Pharmaceutical composition of the present invention or medicament can be to be suitable for needing the state of an illness for the treatment of or formulation or the form (for example, tablet or capsule) of disease, and with mode administration well known in the prior art, for example, oral.
Pharmaceutical composition of the present invention or medicament can comprise the polymorphic form (for example, crystal habit I, crystal habit II, or glassy solids form) of compound shown in the formula I of 1-99 % by weight (for example, 1-70 % by weight, 10-30 % by weight).
All polymorphic forms of the present invention (comprising crystal habit or glassy solids form) basically or approximate be pure.As used herein, term " being pure basically " or " approximate is pure " (for example refer at least 85 % by weight, at least 95 % by weight, or at least 99 % by weight) the formula I shown in compound be present in polymorphic form of the present invention, especially in crystal habit I or crystal habit II.
The main peak of above-mentioned crystal and glassy solids form polymorphic form is reproducible, and in limit of error (prescribed value ± 0.2).
In the present invention, " X-ray powder diffraction pattern shown in Figure 1 " refers to as shown in Figure 1, main peak shown in the X-ray powder diffraction pattern, wherein, main peak refer in Fig. 1 those with the climax as with reference to (relative intensity at climax is appointed as 100%), relative intensity greater than 10%, be preferably greater than 30% peak.Same, in the present invention, X-ray powder diffraction pattern shown in Figure 2 refers to as shown in Figure 2, main peak shown in the X-ray powder diffraction pattern, wherein, main peak refer in Fig. 2 those with the climax as with reference to (relative intensity at climax is appointed as 100%), relative intensity is preferably greater than 30% peak greater than 10%.
The present invention also comprises the method for compound shown in the preparation formula I, and described method comprises step as shown below:
the present invention also provides compound shown in the formula I, or its polymorphic form or be selected from crystal habit I, crystal habit II, the purposes for the preparation of medicine of the form of glassy solids form, described medicine is for the generation of the NO that suppresses to be induced by IFN-γ in scavenger cell, perhaps be used for the treatment of cancer, perhaps be used for the treatment of the disease with inflammation, uncomfortable, or the state of an illness, lupus for example, or rheumatic arthritis, Crohn disease or ulcerative colitis, cardiovascular disorder, diabetes, one or more complication of diabetes, wherein, described complication is selected from following symptom: obesity, hypertension, atherosclerosis, coronary heart disease, apoplexy, peripheral vascular disease, ephrosis, neuropathy, myonecrosis, retinopathy, metabolic syndrome (X chromosome fragility syndromes), or the combination of above-mentioned two or more symptoms.
At this term used, " treatment significant quantity " refers to the amount of compound, when being a kind of disease for the treatment of, or a kind of disease or uncomfortable at least a clinical symptom and during to body administration one by one, enough be used for affecting the result for the treatment of of these diseases, discomfort or symptom.Described " treatment significant quantity " can be according to compound, disease, discomfort and/or disease or uncomfortable symptom, the seriousness of disease, discomfort and/or disease or uncomfortable symptom, the age of individuality treat by institute, and/or treat the weight of individuality and change.Appropriate vol in any specific example is obvious to those skilled in the art, maybe can determine by normal experiment.(that is, except polymorphic form of the present invention, another kind of at least active ingredient is arranged) in the situation of composite treatment, term " treatment significant quantity " refers to effectively treat disease, the total amount of the composition of discomfort or situation.
The pharmaceutical composition that comprises compound of the present invention can suck by oral, rectum, and injection or topical are to the individual administration of needs treatment.For Oral administration, described pharmaceutical composition can be conventional solid dosage, and tablet for example, powder, small-particle, capsule etc., liquid dosage form be water or oil suspension or other liquid dosage form syrup for example for example, solution, suspension etc.; For the drug administration by injection mode, described pharmaceutical composition can be solution, the aqueous solution, oil-based suspension concentrates, lyophilized powder etc.Preferably, the formulation of described pharmaceutical composition is selected from tablet, coated tablet, capsule, suppository, nasal spray or injection, more preferably tablet or capsule.Described pharmaceutical composition can be the single cell administration with exact dosage desired.In addition, described pharmaceutical composition may further include additional active ingredient.
Whole formulations of pharmaceutical composition of the present invention can prepare by the ordinary method of pharmaceutical field.For example, described active ingredient can with one or more mixed with excipients, then make the formulation that needs.Described " medicine acceptable carrier " refers to be suitable for the pharmaceutical carrier of routine of the pharmaceutical dosage form of requirement, for example: thinner, communication media is water for example, various organic solvents, etc.; Filler is starch for example, sucrose, etc.; Tamanori is derivatived cellulose for example, alginate, gelatin and polyvinylpyrrolidone (PVP); Wetting agent is glycerine for example; Disintegrating agent is agar for example, calcium carbonate, sodium bicarbonate; Absorption enhancer is as quarternary ammonium salt compound; Tensio-active agent is hexadecanol for example; Sorbent material is kaolin and bentonite for example; Lubricant is mica for example, calcium stearate, and Magnesium Stearate, polyoxyethylene glycol, etc.In addition, described pharmaceutical composition further comprises for example dispersion agent of the acceptable vehicle of other medicines, stablizer, thickening material, complexing agent, buffer reagent, penetration enhancer, polymer, perfume compound, sweeting agent, and staining agent.Preferably, described vehicle is suitable for formulation and the administering mode of requirement.
Used at this, term " solvate " refers to the chemical substance that formed by solvent and Compound Phase mutual effect.Suitable solvate is the acceptable solvate of medicine, and for example hydrate, comprise monohydrate and semihydrate.
Used at this, term " active ingredient " is used to refer to has bioactive chemical substance.In some embodiments, " promoting agent " is the compound with medicinal effectiveness.For example, promoting agent can be anticancer therapeutic agent.
Term " disease " or " discomfort " or " state of an illness " refer to any disease, discomfort, disease, symptom or sign.
Description of drawings
Fig. 1 is the X-ray powder diffraction pattern of the crystal habit I of compound shown in the formula I;
Fig. 2 is the X-ray powder diffraction pattern of the crystal habit II of compound shown in the formula I;
Fig. 3 is the X-ray powder diffraction pattern of the glassy solids form of compound shown in the formula I;
Fig. 4 is heat flux (w/g) figure of glassy solids form;
Fig. 5 is that the crystal habit II of compound shown in the formula I (CDDO ethyl ester) suppresses to stimulate the nitrogen protoxide produce an effect by IFN-g in mouse macrophage 17.
Embodiment
X-ray powder diffraction pattern (XRPD) shown in Fig. 1, Fig. 2 and Fig. 3 is generated by the PANalytical X-ray diffraction system with sharp shadow supervisory control desk.The diffraction peak position is the silicon single crystal calibration of 28.443 degree by 2 θ values.Use the k-α radiation of sharp shadow Cu LEF X-ray tube as the light source of X ray.
The present invention further illustrates by the following examples, but is not to limit.In an embodiment of the present invention, described technology or method unless specify in addition, are technology or the method for routine well known in the prior art.
Compound shown in embodiment 1, synthesis type I
Be dissolved in DMF(12L to Oleanolic Acid (1000g, 2.2mol) and salt of wormwood (604g, 4.4mol)) solution in add iodoethane (376g, 2.4mol).The gained mixture stirs under the condition of 45 ° of C and spends the night.After can't detect Oleanolic Acid with HPLC, described mixture is cooled to room temperature and pours in water (120L).The suspension agitation that obtains 30 minutes.Collect solid by whizzer, water (1L) washs and 50 ° of C vacuum-dryings, obtains 976g APSN13B-1 and be used for subsequent step.Productive rate is 92%.
At 45 ° of C to APSN13B-1(975g, 2mol), pyridine (474g), DMAP(24.4g, 0.2mol) be dissolved in THF(6L) mixture in add diacetyl oxide (612g, 6mol).Described solution stirring is spent the night.Reaction is poured described solution in water (60L) into after finishing.Solid is collected by whizzer and 45 ° of C vacuum-dryings, is obtained 847g APSN13B-2 and be used for subsequent step.Productive rate is 80%.
At ambient temperature, to APSN13B-2(846g, 1.6mol), formic acid (1L) is dissolved in DCM(5L) in solution in slowly to add mass concentration be 30% aqueous hydrogen peroxide solution (the 453g aqueous solution, 4mol hydrogen peroxide) and stir and spend the night.Add entry (2L) and extract with DCM in gained solution.The full NaHCO that closes of organic phase
3Solution washing is neutral to water, then, washes and use anhydrous Na SO with strong brine
4Dry.Filter organic phase, filtrate is evaporated under vacuum condition, obtains 871gAPSN13B-3, productive rate 100%.This material is used for next step reaction, does not carry out further purifying.
Step 4, synthetic APSN13B-4
At 45 ° of C, to APSN13B-3((871g, 1.6mol) be dissolved in the solution of acetic acid (5L) and add Hydrogen bromide (30ml) to be dissolved in the solution of acetic acid (40%), then slowly add bromine simple substance (256g) to be dissolved in the solution of acetic acid (700ml).The gained mixture stirred 30 minutes at 45 ° of C.At ambient temperature, slowly add another part bromine simple substance (512g) to be dissolved in the solution of acetic acid (1.3L), and continue to stir and spend the night.When reaction finishes, the gained mixture is poured in cold water (35L).Collect the gained solid, wash also drying in a vacuum with the full sodium sulfite solution that closes, obtain yellow solid 841g APSN13B-4, productive rate is 97%.
MS-ESI(m/z):541[M+H]
+
With APSN13B-4(840g, 1.56mol) and KOH(263g, 4.7mol) be dissolved in EtOH(4.5L) vlil 30 minutes.After removing EtOH in a vacuum, the mixture concentration that obtains is the HCl acidified aqueous solution of 6N.Solution layer extracts with ethyl acetate (3L).The full NaHCO that closes of the organic phase that obtains
3Solution washing, the strong brine washing, and use anhydrous Na SO
4Dry.Filter organic phase, filtrate is evaporated under vacuum condition, obtains 928g APSN13B-5, productive rate 100%.
MS-ESI(m/z):499[M+H]
+.
Step 6, synthetic APSN13B-6
APSN13B-5((927g, 1.8mol in the ice bath) be dissolved in the solution of acetone (5L) and drip Jones reagent (400ml).The gained mixture at room temperature stirs, until can't detect APSN13B-5 with TLC.After removing acetone, add entry in the gained mixture.The gained water mixture extracts with DCM.The organic phase that obtains is closed NaHCO with satisfying
3Solution washing, anhydrous Na SO is used in the strong brine washing
4Drying, and filter.Filtrate is evaporated under vacuum condition, obtains thick APSN13B-6.Obtain the pure APSN13B-6 of 498g, productive rate 54% by recrystallization in oil and ethyl acetate.
MS-ESI(m/z):497[M+H]
+
Step 7, synthetic APSN13B-7
To APSN13B-6(496g, 1mol) be dissolved in the solution of dry toluene (2L) and add ethyl formate (185g, 2.5mol) and CH
3ONa(216g, 4mol).The gained mixture at room temperature stirred 2 hours.Then, the gained mixture is with ethyl acetate (1L) dilution, and with 5% HCl solution washing (3 times).Water extracts with ethyl acetate again, and the organic phase that merges washs with strong brine, uses anhydrous Na SO
4Drying, and filter.Filtrate is evaporated under vacuum condition, obtains 497gAPSN13B-7, productive rate 95%.
MS-ESI(m/z):525[M+H]
+
Step 8, synthetic APSN13B-8
To APSN13B-7(496g, 0.94mol) be dissolved in EtOH(2.5L) and the solution of water (200ml) in add oxammonium hydrochloride (98g, 1.4mol).With the gained mixture heating up and refluxed 2 hours.The gained mixture is concentrated under vacuum condition, and adds entry (2L).The gained mixture extracts (3 times) with EA.Anhydrous Na SO is used in the organic phase water that gained merges and strong brine washing
4Drying, and filter.Filtrate is evaporated under vacuum condition, obtains 453gAPSN13B-8, productive rate 92%.
MS-ESI(m/z):522[M+H]
+
Step 9, synthetic APSN13B-9
To the APSN13B-8(452g, the 0.86mol that are under condition of ice bath) be dissolved in EtOH(1.5L) solution in add CH
3ONa(56g, 1.04mol).The gained mixture at room temperature stirred 1 hour.Then, the gained mixture is concentrated under vacuum condition, and adds ethyl acetate (2L).The gained mixture is with 5% HCl solution washing (3 times).Water extracts with EA again, and the organic layer that merges washs with strong brine, uses anhydrous Na SO
4Drying, and filter.Filtrate is evaporated under vacuum condition, obtains 429g APSN13B-9, productive rate 95%.
MS-ESI(m/z):522[M+H]
+
Heating and backflow APSN13B-9(428g, 0.82mol spend the night) and DDQ(205g, 0.90mol) be dissolved in the mixture of toluene.After removing by filter insolubles, filtrate is evaporated under vacuum condition and is obtained thick solid.The gained solid obtains 341g APSN13B-10 by rapid column chromatography, productive rate 80%.Products therefrom is further purified by recrystallization in ethyl acetate and sherwood oil, obtains the product of chemical purity.The maximum contaminant content of finished product is lower than 0.1%.
MS-ESI(m/z):520[M+H]
+
1H-NMR(CDCl
3):δ8.04(1H,S),5.96(1H,S),4.17(2H,t,J=6.9Hz),3.05(1H,d,J=13.5Hz),2.95(1H,d,J=4.5Hz),2.04～0.07(21H,m).
The crystal habit I of compound shown in embodiment 2, preparation formula I
Compound as shown in the formula I of method preparation as described in above-mentioned embodiment 1 is dissolved in heptane solvent in room temperature, obtains desired crystal habit I by natural sedimentation afterwards, and its fusing point is 174-177 ° of C.
Its X-ray powder diffraction pattern shown in Fig. 1 is summarized in table 1.
Table 1
The crystal habit II of compound shown in embodiment 3, preparation formula I
Compound as shown in the formula I of method preparation as described in above-mentioned embodiment 1, excessive described compound is added the mixed solvent of ethyl acetate and heptane, and (ratio of ethyl acetate and heptane is 1:10, weight ratio or volume ratio) in, stirring makes its pulp, stirred at least 48 hours under room temperature or 50 ° of C conditions, obtain crystal habit II, its fusing point is 209-212 ° of C.
Its X-ray powder diffraction pattern shown in Fig. 2 is summarized in table 2.
Table 2
The glassy solids form of compound shown in embodiment 4, preparation formula I
Compound as shown in the formula I of method preparation as described in above-mentioned embodiment 1, under room temperature or 50 ° of C conditions, the slurry suspension that will contain excessive described compound is dissolved in methylene chloride, obtain afterwards the glassy solids form of compound shown in the formula I by evaporating solvent, its Tg is about 52 ° of C ± 10 ° C.
Fig. 3 has shown the X-ray powder diffraction pattern of the glassy solids form of compound shown in the formula I; Fig. 4 has shown heat flux (w/g) figure of glassy solids form.
The preliminary pharmacokinetics of the polymorphic form of compound shown in embodiment 5, formula I
Female CD-1 mouse, three kinds of polymorphics of compound (CDDO ethyl ester) shown in abdominal injection 10mg/kg formula I and methyl 2-cyano group-3,12-dioxo volatile oil-1,9 (11) dienes-28-ester (CDDO methyl ester) is dissolved in DMSO-polyoxyethylenated castor oil-PBS(1:1:8, weight ratio or volume ratio) solution.After administration, respectively at 0.083,0.25,0.5,1,2,4,8, and 24 hours blood sample collections.Utilize the level in HPLC/MS detection blood sample, compound is added in blank blood sample as standard.
The pharmacokinetics result is as shown in table 3.The system of three kinds of polymorphic forms of the ethyl ester of Compound C DDO shown in the formula I exposes higher than the CDDO methyl ester.The below is their order: the glassy solids form of CDDO ethyl ester〉the crystal habit II of CDDO ethyl ester〉the crystal habit I of CDDO ethyl ester〉the CDDO methyl ester
Table 3
The mensuration of the stability of embodiment 6, crystal habit
The crystal habit II of compound shown in the formula I of method preparation, detect under 25 ℃/60% relative humidity and 40 ℃/75% relative humidity condition respectively as described in Example 3.The XRD figure of all samples does not significantly change.Similarly use other polymorphic form of the present invention in this research.In this research, compare with other polymorphic form of the present invention, the crystal habit II of compound shown in the formula I shows to have optimum thermodynamic stability.
The mensuration of the stability of embodiment 7, glassy solids form
The glassy solids form of compound shown in the formula I of method preparation, place a week under the condition of 25 ℃/60% relative humidity and 40 ℃/75% relative humidity respectively as described in Example 4, detects afterwards.The XRD figure of all samples does not significantly change.
The nitric oxide production detection that produces in the mouse monokaryon scavenger cell (RAW264.7) that shown in embodiment 8, use formula I, the crystal habit II of compound processes
The testing process general introduction
The RAW264.7 cell cultures
1, the RAW264.7 cell is cultivated in containing the DMEM of 10%FBS, and condition is 37 ° of C, 5%CO
2Environment.
2, use the microscopic examination culture, estimate the degree that merges and determine not exist bacterium and fungal contamination.
3, remove the substratum of using.
4, use the D-PBS washed cell individual layer of preheating.
5, use suction pipe, pipette 3ml Regular Insulin/EDTA and be added on washed cell monolayer, rotary flask makes Regular Insulin cover individual layer.
6, with the microscopy cell and confirm that whole cells are all from wall and adrift.
7, cell is suspended again so that the Regular Insulin inactivation with the substratum that contains on a small quantity fresh serum.
8, use the centrifugal method collecting cell, 1000rpm is centrifugal 5 minutes at ambient temperature.
9, in 37 ° of C at 5%CO
2The environment incubated cell.
Produce nitrogen protoxide in the RAW264.7 cell
1, seed cells on 96 porocyte culture plates, number of cells is 1 * 10
5/ hole.
2, at 37 ° of C, 5%CO
2Under environment after incubated cell 2 hours, absorb not attached cell and add the perfect medium that contains 10ng/ml IFN-γ of firm preparation and the compound of dilution.
3, in 37 ° of C at 5%CO
2Incubated cell 48 hours again under environment.
Measure the intracellular nitrogen protoxide of RAW
1, with whizzer with the rotating speed of 1000rpm centrifugal 5 minutes, collect the supernatant liquor substratum.
2, with the 0.1M nitrite standardized solution that provides according to 1:1,000 ratio is with matrix or damping fluid dilution, preparation 1ml concentration is the nitrite solution of 100 μ M, as laboratory sample.
3, preparation nitrite standardized solution, concentration is respectively 100,50,25,12.5,6.25,3.13,1.56 and 0 μ M, 50 μ l/ holes
4, make sulfanilamide (SN) solution and NED solution equilibria to room temperature (15-30 minute).
5, Xiang Kongzhong adds 50 μ l laboratory samples, and is duplicate.
6, with multichannel pipettor, 50 μ l sulfanilamide (SN) solution be assigned to all laboratory samples and contain in the hole of nitrite standardized solution of a series of dilutions.
7, lucifuge was at room temperature hatched 5-10 minute.
8, with multichannel pipettor with 50 μ lNED solution be assigned to the institute porose in.
9, lucifuge was at room temperature hatched 5-10 minute.Formed immediately purple/carmetta.
10, in 30 minutes, use with absorbing wavelength and measure absorbancy at the plate reader of the optical filtering between 520nm to 550nm.
Fig. 5 has shown that the crystal habit II of compound shown in the formula I (CDDO ethyl ester) is to inducing the nitric oxide production inhibition activity of generation (to pass through IC by IFN-g in mouse macrophage 17
50(nM) value metering).The IC of the crystal habit II of compound shown in the formula I (CDDO ethyl ester)
5034nM.The IC of the glassy solids form of compound shown in the formula I (CDDO ethyl ester)
5032nM.
Claims (45)
1. the polymorphic form of the compound shown in a formula I
Formula I.
2. polymorphic form according to claim 1, is characterized in that, described polymorphic form is the glassy solids form, and its Tg is about 52 ° of C ± 1 θ ° C.
3. polymorphic form according to claim 1, is characterized in that, described polymorphic form is crystal habit I, and its X-ray powder diffraction pattern is about 10.3 ° at diffraction angle 2 θ, locates to have characteristic peak for 14.1 ° and 14.6 °.
4. polymorphic form according to claim 3, is characterized in that, described polymorphic form is crystal habit I, and its X-ray powder diffraction pattern has characteristic peak, and the expression spacing is
With
5. polymorphic form according to claim 1, is characterized in that, described polymorphic form is crystal habit I, and its X-ray powder diffraction pattern is about 10.3 ° at diffraction angle 2 θ, 14.1 °, 14.6 °, 15.8 °, locates to have characteristic peak for 16.6 ° and 19.6 °.
6. polymorphic form according to claim 5, is characterized in that, described polymorphic form is crystal habit I, and its X-ray powder diffraction pattern has characteristic peak, and the expression spacing is
With
7. polymorphic form according to claim 1, is characterized in that, described polymorphic form is crystal habit I, and its X-ray powder diffraction pattern is about 10.3 ° at diffraction angle 2 θ, 14.1 °, and 14.6 °, 15.7 °, and 16.6 ° located to have characteristic peak.
8. polymorphic form according to claim 7, is characterized in that, in the X-ray powder diffraction pattern of described polymorphic form, is about 9.3 ° and 19.6 ° at diffraction angle 2 θ and locates to have extra characteristic peak.
9. one of according to claim 3-8 described polymorphic forms, is characterized in that, the fusing point of described polymorphic form is 174-177 ° of C.
10. one of according to claim 2-8 described polymorphic forms, is characterized in that the purity of described polymorphic form 〉=85%.
11. polymorphic form according to claim 10 is characterized in that, the purity of described polymorphic form 〉=95%.
12. polymorphic form according to claim 11 is characterized in that, the purity of described polymorphic form 〉=99%.
13. polymorphic form according to claim 1 is characterized in that, described polymorphic form is crystal habit II, and its X-ray powder diffraction pattern is about 10.4 ° at diffraction angle 2 θ, locates to have characteristic peak for 12.1 ° and 13.4 °.
14. polymorphic form according to claim 13 is characterized in that, the X-ray powder diffraction pattern of described crystal habit II is about 15.4 ° at diffraction angle 2 θ, locates to have extra characteristic peak for 17.8 ° and 18.8 °.
15. polymorphic form according to claim 13 is characterized in that, the X-ray powder diffraction pattern of described crystal habit II has characteristic peak, and the expression spacing is
With
16. polymorphic form according to claim 15 is characterized in that, the X-ray powder diffraction pattern of described crystal habit II has extra characteristic peak, and the expression spacing is
With
17. one of according to claim 13-16 described polymorphic forms is characterized in that the fusing point of described crystal habit II is 209-212 ° of C.
18. one of according to claim 13-17 described polymorphic forms is characterized in that the purity of described crystal habit II 〉=85%.
19. polymorphic form according to claim 18 is characterized in that, the purity of described crystal habit II 〉=95%.
20. polymorphic form according to claim 19 is characterized in that, the purity of described crystal habit II 〉=99%.
21. the method for the polymorphic form of compound shown in a preparation formula I, the method comprises the steps: excessive compound is added to pulp in solvent, and described solvent is CH
2Cl
2, ethyl acetate, acetonitrile, ethanol, methyl alcohol, heptane or its mixture at least through 24 hours, reclaim the crystal polymorphic or the glassy solids form that generate.
22. method according to claim 21 is characterized in that, the polymorphic form of compound shown in described formula I is crystal habit I or form II.
23. method according to claim 21 is characterized in that, compound shown in described formula I under the condition of room temperature or 50 ° of C, pulp in mixed solvent.
24. method according to claim 21 is characterized in that, the pulp at least 48 hours in solvent of compound shown in described formula I.
25. method according to claim 21 is characterized in that, described solvent is CH
2Cl
2, ethyl acetate, acetonitrile, ethanol, methyl alcohol, heptane, ethanol/heptane mixture, ethyl acetate/heptane mixture, or its mixture.
26. method according to claim 22 is characterized in that, described ethanol/heptane mixture contains ethanol and heptane, and the ratio of ethanol and heptane is 1:10(weight ratio or volume ratio).
27. the method for the polymorphic form of compound shown in a preparation formula I, the method comprises the steps: described compound is dissolved at ambient temperature the mixed solvent of ethanol and heptane, the compound natural sedimentation forms the crystal polymorphic, reclaims the crystal polymorphic that generates.
28. the method for the glassy solids form of compound shown in a preparation formula I, the method comprises the steps: described compound is dissolved in methylene chloride under room temperature or 50 ° of C conditions, obtains the glassy solids form by evaporating solvent afterwards.
29. a pharmaceutical composition is characterized in that, said composition contains one of the claim 1-20 that treats significant quantity described polymorphic form, and medicine acceptable vehicle, auxiliary material or carrier.
30. pharmaceutical composition according to claim 29 is characterized in that, described composition further comprises additional active ingredient.
31. pharmaceutical composition according to claim 29 is characterized in that, described polymorphic form is crystal habit I or the form II of compound shown in the formula I.
32. one of according to claim 29-31 described pharmaceutical compositions is characterized in that, described composition is by the oral way administration.
33. pharmaceutical composition according to claim 32 is characterized in that, described composition uses with tablet or capsule form.
34. one of according to claim 29-33 described pharmaceutical compositions is characterized in that described composition comprises the polymorphic form of 1-99 % by weight.
35. pharmaceutical composition according to claim 34 is characterized in that, described composition comprises the polymorphic form of 1-70 % by weight.
36. pharmaceutical composition according to claim 35 is characterized in that, described composition comprises the polymorphic form of 10-30 % by weight.
37. the purposes of one of according to claim 1-20 described polymorphic forms is for the preparation of the medicine of the generation of the NO that is used for suppressing being induced by IFN-γ in scavenger cell.
38. the purposes of one of according to claim 1-20 described polymorphic forms is for the preparation of being used for treating cancer, perhaps with the medicine of the state of an illness of inflammation.
39. the purposes of described polymorphic form, is characterized in that according to claim 38, the described state of an illness with inflammation is lupus, or rheumatic arthritis, Crohn disease or ulcerative colitis, cardiovascular disorder, diabetes, or the complication of diabetes.
40. the purposes of described polymorphic form, is characterized in that according to claim 39, the complication of described diabetes is fat, hypertension, atherosclerosis, coronary heart disease, apoplexy, peripheral vascular disease, ephrosis, neuropathy, myonecrosis, retinopathy, metabolic syndrome (X chromosome fragility syndromes), or the combination of above-mentioned symptom.
41. a method of regulating the generation of individual interior scavenger cell intracellular nitric oxide comprises to the individuality of needs and uses the described polymorphic form of one of claim 1-20.
42. treat individual cancer for one kind, perhaps with the method for the state of an illness of inflammation, comprise to the individuality of needs and use the described polymorphic form of one of claim 1-20.
43. described method, is characterized in that according to claim 42, the described state of an illness with inflammation is lupus, or rheumatic arthritis, Crohn disease or ulcerative colitis, cardiovascular disorder, diabetes, or the complication of diabetes.
44. described method, is characterized in that according to claim 43, the complication of described diabetes is fat, hypertension, atherosclerosis, coronary heart disease, apoplexy, peripheral vascular disease, ephrosis, neuropathy, myonecrosis, retinopathy, metabolic syndrome (X chromosome fragility syndromes), or the combination of above-mentioned symptom.
45. the method for compound shown in a preparation formula I comprises step as shown below:
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| CN201280001986.3A CN103108882B (en) | 2012-09-28 | 2012-12-06 | Polycrystalline type object of CDDO BIEA and use thereof |
| CN201410002086.1A CN103755767B (en) | 2012-09-28 | 2012-12-06 | Polymorph of CDDO ethyl ester and application thereof |
| CN201410002175.6A CN103755768B (en) | 2012-09-28 | 2012-12-06 | Polymorph of CDDO ethyl ester and application thereof |
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| CN201280001986.3A CN103108882B (en) | 2012-09-28 | 2012-12-06 | Polycrystalline type object of CDDO BIEA and use thereof |
| PCT/CN2012/086045 WO2014048033A1 (en) | 2012-09-28 | 2012-12-06 | Polymorphs of cddo ethyl ester and uses thereof |
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| CN201410002086.1A Division CN103755767B (en) | 2012-09-28 | 2012-12-06 | Polymorph of CDDO ethyl ester and application thereof |
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| CN108440636A (en) * | 2018-04-26 | 2018-08-24 | 泰州学院 | A kind of CDDO-Me derivatives, preparation method and medical usage |
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| Title |
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| HONDA, TADASHI ET AL.: "A novel dicyanotriterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile, active at picomolar concentrations for inhibition of nitric oxide production", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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| CN108440636A (en) * | 2018-04-26 | 2018-08-24 | 泰州学院 | A kind of CDDO-Me derivatives, preparation method and medical usage |
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