CN103102382A - Crystal form B of glycyrrhetinic acid-30-amide derivative and preparation method thereof - Google Patents
Crystal form B of glycyrrhetinic acid-30-amide derivative and preparation method thereof Download PDFInfo
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- CN103102382A CN103102382A CN2011103592271A CN201110359227A CN103102382A CN 103102382 A CN103102382 A CN 103102382A CN 2011103592271 A CN2011103592271 A CN 2011103592271A CN 201110359227 A CN201110359227 A CN 201110359227A CN 103102382 A CN103102382 A CN 103102382A
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Abstract
The invention provides a crystal form compound of N-[(3-o-chlorophenyl-isoxazol-5-yl)methyl]-11-desoxy-glycyrrhetinamide, namely a crystal form B. The invention also provides a method for preparing the crystal form B. The invention also provides a pharmaceutical composition containing the crystal form used as an active ingredient. The invention simultaneously provides application of the crystal form in the preparation of adrenal cortical hormone replacement medicaments, such as anti-inflammation, anti-allergy and the like. The crystal form can be also used for the preparation of liver protection medicaments, antiviral medicaments and the like.
Description
Technical field
The present invention relates to a kind of glycyrrhetinic acid-new crystal of 30-amide derivatives, preparation method, and comprise described crystal formation as the medicinal compositions of active ingredient, and use in preparation adrenocortical hormone alternative medicine, for example for the preparation of anti-inflammatory, antianaphylactic medicine, in addition, can also for the preparation of protect the liver, antiviral drug.
Background technology
Glycyrrhetinic acid has anti-inflammatory, analgesia, antianaphylaxis, antiviral, reducing blood-fat, promotion absorption of insulin, anti-curing oncoma, protection liver, improve the multiple effects such as immunity of organisms.But use in a large number clinically this class medicine often with the hormone medicine side effect, intend the side effect of aldosterone sample, cause that sodium retention, potassium excretion increase, and cause a series of side effects such as oedema, hypertension, hypokalemia.
In order to overcome the deficiency in the glycyrrhetinic acid clinical application, CN200510015371.8 (publication number CN1948332A) discloses the 30-amide derivatives and preparation method thereof of the glycyrrhetinic acid of series of new, has anti-inflammatory, analgesia isoreactivity preferably through determination of activity.It can be applicable to during adrenocortical hormone substitutes, and as anti-inflammatory, antianaphylaxis etc., can also conduct protects the liver the application with the aspect such as antiviral.But because the molecule of glycyrrhetinic acid own is larger, after derivatize, molecule further strengthens, and dissolves and absorb relatively poor.
CN200710060528.8 (publication number CN101229172A) discloses a kind of solid dispersion that contains above-mentioned glycyrrhetinic acid 30-amide derivatives active component and preparation method thereof in order to overcome the lower deficiency of 30-amide derivatives absolute bioavailability of glycyrrhetinic acid.
The ability that exists with the different crystal forms compound structure is called as polytropism, and known its is present in many organic compound.These different crystal formations are referred to as " polymorphic form ", and different with other descriptive nature aspects with the accumulation mode of its crystalline solid state, geometry arrangement.The different polymorphic form of material has different lattice energies, and it has shown different physical propertiess when solid-state thus, shape for example, color density, hardness, deformability, stability and solvability etc.
We have studied the heteromorphism of glycyrrhetinic acid-30-amide derivatives for this reason, wish to seek with this have better solvability, the better crystal formation of bioavailability, for the solid dispersion that preparation can be taken is laid a good foundation.
Summary of the invention
Therefore, an object of the present invention is to provide a kind of glycyrrhetinic acid-30-amide derivatives---the adjacent chloro phenyl of N-[(3--isoxazole-5-bases) methyl]-crystal form B of 11-deoxidation-Radix Glycyrrhizae time acid amides, it is characterized in that using Cu-K α radiation,
Can have in the X-ray powder diffraction that represents with 2 θ angles at the highest absorption peak at 18.6 ± 0.2 places with at the inferior high absorption peak at 14.7 ± 0.2 places;
And/or described crystal form B can be at 3460cm with KBr pressed disc method survey infrared absorption spectrum
-1, 3351cm
-1, 3142cm
-1, 2974cm
-1, 2936cm
-1, 2871cm
-1There is characteristic peak at the place.
According to a kind of glycyrrhetinic acid of the present invention-30-amide derivatives---the adjacent chloro phenyl of N-[(3--isoxazole-5-bases) methyl]-crystal formation of 11-deoxidation-Radix Glycyrrhizae time acid amides, wherein, described use Cu-K α radiation,
The X-ray powder diffraction that represents with 2 θ angles can also have 8.6 ± 0.2,9.4 ± 0.2, the characteristic peak at l2.9 ± 0.2,13.8 ± 0.2,14.4 ± 0.2,17.0 ± 0.2,18.2 ± 0.2,26.3 ± 0.2,30.2 ± 0.2 and 31.9 ± 0.2 places.
According to a kind of glycyrrhetinic acid of the present invention-30-amide derivatives---the adjacent chloro phenyl of N-[(3--isoxazole-5-bases) methyl]-crystal formation of 11-deoxidation-Radix Glycyrrhizae time acid amides, wherein, the described crystal formation infrared absorption spectrum that adopts the KBr pressed disc method to record can be as shown in Figure 1.
According to a kind of glycyrrhetinic acid of the present invention-30-amide derivatives---the adjacent chloro phenyl of N-[(3--isoxazole-5-bases) methyl]-crystal formation of 11-deoxidation-Radix Glycyrrhizae time acid amides, wherein, described crystal formation adopt Cu-K α radiation,
Can be as shown in Figure 2 with the X-ray powder diffraction that 2 θ angles represent.
Another object of the present invention is to provide the adjacent chloro phenyl of N-[(3--isoxazole-5-bases) methyl]-preparation method of the crystal form B of 11-deoxidation-Radix Glycyrrhizae time acid amides, can comprise the steps:
1) with the adjacent chloro phenyl of N-[(3--isoxazole-5-bases) methyl]-11-deoxidation-Radix Glycyrrhizae time acid amides is placed in dehydrated alcohol, and reflux is dissolved to solution clear and bright
2) standing 1～7 day crystallization under 20～30 ℃ of normal temperature.
This preparation method is easy, practical, can amplify industrialization.
Further purpose of the present invention is to provide a kind of pharmaceutical composition, and it can comprise the adjacent chloro phenyl-isoxazole-5-base of N-[(3-of significant quantity) methyl]-crystal form B and one or more pharmaceutically acceptable carriers of 11-deoxidation-Radix Glycyrrhizae time acid amides.
Preparation in accordance with the present invention, wherein, the formulation of described composition can be selected from: tablet, powder, granule, capsule, injection, syrup, suppository, inhalation, aerosol, eye drops or external preparation.
Preparation in accordance with the present invention, wherein, described external preparation can be selected from ointment, gel or plaster.
A further object of the present invention is to provide the adjacent chloro phenyl of N-[(3--isoxazole-5-bases) methyl]-crystal form B of 11-deoxidation-Radix Glycyrrhizae time acid amides uses in the adrenocortical hormone alternative medicine, for example for the preparation of anti-inflammatory, antianaphylactic medicine; And for the preparation of protecting the liver or antiviral drug.
Description of drawings
Below, describe by reference to the accompanying drawings embodiment of the present invention in detail, wherein:
The adjacent chloro phenyl of the N-[(3-of Fig. 1 embodiment 1-isoxazole-5-bases) methyl]-infared spectrum (IR) of 11-deoxidation-Radix Glycyrrhizae time acid amides crystal form B.
The adjacent chloro phenyl of the N-[(3-of Fig. 2 embodiment 1-isoxazole-5-bases) methyl]-the X-ray powder diffraction (PXRD) of 11-deoxidation-Radix Glycyrrhizae time acid amides crystal form B.
Fig. 3 is to the adjacent chloro phenyl of the N-[(3-of embodiment 1-isoxazole-5-bases) methyl]-result data of the peak value retrieval of the X-ray powder diffraction (PXRD) of 11-deoxidation-Radix Glycyrrhizae time acid amides crystal form B.
Embodiment
The invention provides the crystal form B of a kind of glycyrrhetinic acid-30-amide derivatives.
" crystal formation " of the present invention, a kind of crystal of intention is a kind of existence form of compound.
According to one embodiment of the invention, described glycyrrhetinic acid-30-amide derivatives is the adjacent chloro phenyl of N-[(3--isoxazole-5-bases) methyl]-11-deoxidation-Radix Glycyrrhizae time acid amides, its crystal form B be characterised in that use Cu-K α radiation,
Have in the X-ray powder diffraction that represents with 2 θ angles at the highest absorption peak at 18.6 ± 0.2 places with at the inferior high absorption peak at 14.7 ± 0.2 places.
Described glycyrrhetinic acid-30-amide derivatives has following structure:
According to the preferred embodiment of the invention, described crystal form B use Cu-K α radiation,
The X-ray powder diffraction that represents with 2 θ angles also has the characteristic peak at 8.6 ± 0.2,9.4 ± 0.2,12.9 ± 0.2,13.8 ± 0.2,14.4 ± 0.2,17.0 ± 0.2,18.2 ± 0.2,26.3 ± 0.2,30.2 ± 0.2,31.9 ± 0.2 places.2 θ angles of X-ray powder diffraction spectrum may be due to the reasons such as sample batch and testing tool deviation to some extent, and usually, the deviation at 2 θ angles is ± 0.2.
The further preferred embodiment according to the present invention, described crystal form B have the X-ray powder diffraction as shown in Figure 1 of using Cu-K α radiation, representing with 2 θ angles.
The preferred embodiment according to the present invention, described crystal form B is surveyed infrared absorption spectrum at 3460cm with the KBr pressed disc method
-1, 3351cm
-1, 3142cm
-1, 2974cm
-1, 2936cm
-1, 2871cm
-1There is characteristic peak at the place.The infrared spectra wave number may be due to the reasons such as sample batch and testing tool deviation to some extent, and deviation is ± 5.
According to another embodiment of the invention, the invention provides a kind of method for preparing described crystal form B, preferred method comprises the steps:
(1) the adjacent chloro phenyl of N-[(3--isoxazole-5-bases) methyl]-11-deoxidation-Radix Glycyrrhizae time acid amides is placed in dehydrated alcohol, and reflux is dissolved to solution clear and bright;
(2) standing 1～7 day crystallization under normal temperature 20-30 ℃.
In addition, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition contains the adjacent chloro phenyl of described N-[(3--isoxazole-5-bases of significant quantity) methyl]-crystal form B and one or more pharmaceutically acceptable carriers of 11-deoxidation-Radix Glycyrrhizae time acid amides.
Preferably, the formulation of described pharmaceutical composition is selected from: tablet, powder, granule, capsule, injection, syrup, suppository, inhalation, aerosol, eye drops and external preparation, the preferred ointment of described exterior-applied formulation, gel, plaster.
The present invention also provides the adjacent chloro phenyl of described N-[(3--isoxazole-5-bases) methyl]-crystal formation of 11-deoxidation-Radix Glycyrrhizae time acid amides uses in the adrenocortical hormone alternative medicine, as prepare anti-inflammatory, Claritin etc., can also protect the liver and the antiviral application that waits the medicine aspect as preparation.
According to a specific embodiment of the present invention, the invention provides a kind of with the drug combination preparation of described crystal formation as activeconstituents, described preparation comprises the adjacent chloro phenyl of the N-[(3-that treats effective dose-isoxazole-5-bases) methyl]-composition of 11-deoxidation-Radix Glycyrrhizae time acid amides crystal form B and one or more pharmaceutical excipients, optionally, also can contain other therapeutic component.Its vehicle comprises tackiness agent, thinner, disintegrating agent, sanitas, dispersion agent, glidant and lubricant etc.When making oral preparations, can directly use thing of the present invention, also can with suitable additive, such as when adding the usual excipients such as lactose, N.F,USP MANNITOL, W-Gum, yam starch, Trisodium Citrate, with derivatived celluloses such as crystalline cellulose, hydroxypropylcelluloses; The wedding agents such as gum arabic, W-Gum, gelatin: the disintegrating agents such as W-Gum, yam starch, calcium carboxymethylcellulose; The lubricant such as talcum, Magnesium Stearate; Also have in addition the appropriate combination such as extender, wetting agent, buffer reagent, preservatives, spices, make the formulations such as tablet, powder, granule or capsule.In addition, according to illness kind and patient's situation, also can be made into and illness kind and patient's situation other formulation except above-mentioned formulation the most accordingly, for example, can be made into the formulations such as injection, syrup, suppository, inhalation, aerosol, eye drops, external preparation (ointment, gel, plaster).
Crystal form B of the present invention is preferably taken with the form of pharmaceutical composition, can oral or non-oral administration, perhaps with the oral or non-oral administration of composition (as tablet, sustained release preparation, the capsule) safety that forms with pharmaceutically acceptable carrier, vehicle and other additive.When oral administration, composition can be mixed with tablet or capsule.For the preparation combination of oral medication can adopt lactose or starch to do carrier, gelatin, Xylo-Mucine, methylcellulose gum, polyvinylpyrrolidone etc. are suitable wedding agents or become granular agent.Can select starch or Microcrystalline Cellulose as disintegrating agent, often with talcum powder, santocedl, stearin, calcium stearate or magnesium etc. are as suitable antiadhesives and lubricant.For example, can prepare tablet by the compacting wet granular.Activeconstituents and carrier and optionally with a disintegration additive composition mixture; the aqueous solution of this mixture and tackiness agent; alcohol or aqueous alcohol solution carry out granulating in suitable equipment; dried particles adds other disintegrating agent subsequently, and lubricant and antisticking agent are with this mixture compressing tablet.
In order to prepare above-mentioned composition, can form by the pressing mold of randomly granulating together with one or more vehicle as tablet, optionally can carry out dressing or embossing to tablet; Capsule too can with one or more mixed with excipients, be filled in capsule shell by granulating or not granulating and make.
Compound of the present invention is effective in quite wide dosage range.The dosage of for example taking every day can be in the scope of the about 0.1mg-500mg of per kilogram of body weight.In adult's treatment, dosage range is taken once or several times preferably at 1mg/kg-50mg/kg.The actual dosage of taking compound should be decided according to relevant situation by the doctor, and these situations comprise the person's of being treated physical state, the person's of choosing route of administration, age, body weight, the patient individual reaction to medicine, severity of patient's symptom etc.
The invention provides and comprise the adjacent chloro phenyl of described N-[(3--isoxazole-5-bases in pharmaceutical acceptable carrier) methyl]-medicinal compositions of 11-deoxidation-Radix Glycyrrhizae time acid amides crystal form B or any other combination.
The adjacent chloro phenyl of N-[(3-provided by the invention-isoxazole-5-bases) methyl]-11-deoxidation-Radix Glycyrrhizae time acid amides crystal form B has good circulation ratio, and preparation technology is simple and easy to do, has stronger practicality and operability.
The adjacent chloro phenyl of N-[(3-used in the present invention-isoxazole-5-bases) methyl]-11-deoxidation-Radix Glycyrrhizae time acid amides is by disclosed method preparation in patent CN200510015371.8.Wherein, in CN200510015371.8, disclosed DG4 is this compound N-[(the adjacent chloro phenyl of 3--isoxazole-5-bases) methyl]-11-deoxidation-Radix Glycyrrhizae time acid amides, the preparation method is as follows: with 11-deoxidation-glycyrrhetinic acid, 1-hydroxy benzo triazole, N, the N-dicyclohexylcarbodiimide is dissolved in methylene dichloride and N, in dinethylformamide, be added dropwise to the dichloromethane solution reaction of 3-Chloro-O-Phenyl-5-amine methyl-isoxazoles under cooling after 2 hours, naturally rise to room temperature, continue reaction, TLC Indicator Reaction terminal point.After reaction finishes, filter the precipitation of generation, mother liquor is concentrated into dried, after adding a small amount of dissolution with solvents, post separates (ethyl acetate: sherwood oil 60-90 ℃ 1: 5～1: 2, V/V) gradient elution gets the adjacent chloro phenyl of product N-[(3--isoxazole-5-bases) methyl]-11-deoxidation-Radix Glycyrrhizae time acid amides.
The present embodiment is used for the adjacent chloro phenyl of explanation N-[(3--isoxazole-5-bases) methyl]-preparation of 11-deoxidation-Radix Glycyrrhizae time acid amides crystal form B.
The adjacent chloro phenyl of N-[(3--isoxazole-5-bases) methyl]-11-deoxidation-Radix Glycyrrhizae time acid amides 10g is in the 750mL dehydrated alcohol, and reflux is dissolved clear and bright, then in 20-30 ℃ of standing 7 days crystallization, filter, collect solid, be drying to obtain white powder solid 8.9g, crystal form B.Adopt respectively BRUKERALPHA-T type Fourier transform infrared spectrometer, Rigaku D/max-2500X ray diffraction diffractometer that it is characterized, result as shown in Figure 1, 2, the result data of peak value retrieval is seen Fig. 3.
The present embodiment is used for illustrating the adjacent chloro phenyl of N-[(3-of the present invention-isoxazole-5-bases) methyl]-pharmacodynamic experiment of 11-deoxidation-Radix Glycyrrhizae time acid amides crystal form B.
Experimental subjects: ICR kind male mice
Administering mode: gavage
The medicine preparation: crystal form B is 2mg/mL with the abundant mixing of Semen Maydis oil, its concentration, and the administration volume is the 0.2ml/10g body weight
ICR kind male mice is divided into 6 groups at random, 10 every group.Each administration group administration 1 time.The positive drug group gives acetylsalicylic acid, and control group gives with the volume refined maize oil.Only cause inflammation at the right back sufficient pad subcutaneous injection 1% lrish moss mucilage 0.025ml/ of section of mouse after administration.Respectively cause scorching before and cause scorching after 0.5,1,2,3 hour, measure 0.2cm place, every mouse right hind ankle joint below diameter with projector (amplifying 8 times), with cause scorching before and the swelling difference that causes the rear different time points of inflammation as swelling.Carry out statistics T test.Result shows, can reduce very significantly the swelling of mouse toes, still has anti-inflammatory action significantly after Yu Zhiyan in 3 hours.Measurement result is as shown in table 1:
The adjacent chloro phenyl-isoxazole-5-base of table 1:N-[(3-) methyl]-time acid amides administration of 11-deoxidation-Radix Glycyrrhizae is on the swollen impact of mouse carrageen colloidality pin
The present embodiment is used for illustrating the adjacent chloro phenyl of N-[(3-of the present invention-isoxazole-5-bases) methyl]-the pharmacokinetics experiment of 11-deoxidation-Radix Glycyrrhizae time acid amides crystal form A.
Experimental subjects: 6 of SD rats, male and female half and half
Administering mode: gavage
Dosage: 10mg/kg
The medicine preparation: crystal form A is 2mg/mL with the abundant mixing of Semen Maydis oil, its concentration, and the administration volume is the 0.5mL/100g body weight
Measurement result is as shown in table 2 and table 3:
Table 2 crystal formation Plasma Concentration
In upper table, ♀ represents that female rats, ♂ represent male rat.
Claims (10)
1. the adjacent chloro phenyl-isoxazole-5-base of a N-[(3-) methyl]-crystal formation of 11-deoxidation-Radix Glycyrrhizae time acid amides, it is characterized in that:
Described crystal formation use Cu-K α radiation,
The X-ray powder diffraction that represents with 2 θ angles has at the highest absorption peak at 18.6 ± 0.2 places with at the inferior high absorption peak at 14.7 ± 0.2 places; And/or
Described crystal formation is surveyed infrared absorption spectrum at 3460cm with the KBr pressed disc method
-1, 3351cm
-1, 3142cm
-1, 2974cm
-1, 2936cm
-1, 2871cm
-1There is characteristic peak at the place.
2. crystal formation according to claim 1, is characterized in that, use Cu-K α radiation,
The X-ray powder diffraction that represents with 2 θ angles also has the characteristic peak at 8.6 ± 0.2,9.4 ± 0.2,12.9 ± 0.2,13.8 ± 0.2,14.4 ± 0.2,17.0 ± 0.2,18.2 ± 0.2,26.3 ± 0.2,30.2 ± 0.2 and 31.9 ± 0.2 places.
3. crystal formation according to claim 1, is characterized in that, the infrared absorption spectrum that described crystal formation employing KBr pressed disc method records as shown in Figure 1.
4. the described crystal formation of according to claim 1 to 3 any one, is characterized in that, described crystal formation employing Cu-K α radiation,
The X-ray powder diffraction that represents with 2 θ angles as shown in Figure 2.
5. the preparation method as the described crystal formation of claim 1 to 4 any one, comprise the steps:
(1) the adjacent chloro phenyl of N-[(3--isoxazole-5-bases) methyl]-11-deoxidation-Radix Glycyrrhizae time acid amides is placed in dehydrated alcohol, and reflux is dissolved to solution clear and bright;
(2) standing 1～7 day crystallization under normal temperature 20-30 ℃.
6. a pharmaceutical composition, is characterized in that, described pharmaceutical composition comprises according to claim 1-4 described crystal formations of any one and one or more pharmaceutically acceptable carriers of significant quantity.
7. pharmaceutical composition according to claim 6, is characterized in that, the formulation of described composition is selected from: tablet, powder, granule, capsule, injection, syrup, suppository, inhalation, aerosol, eye drops or external preparation.
8. pharmaceutical composition according to claim 7, is characterized in that, described external preparation is selected from ointment, gel or plaster.
9. the purposes of according to claim 1-4 described crystal formations of any one in preparation adrenocortical hormone alternative medicine, perhaps preparation protect the liver or antiviral drug in purposes.
10. purposes according to claim 9, is characterized in that, described medicine is anti-inflammatory or antianaphylactic medicine.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106265692A (en) * | 2015-05-22 | 2017-01-04 | 天津药物研究院有限公司 | A kind of transdermal formulation of enoxolone 30-amide derivatives and its production and use |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1948332A (en) * | 2005-10-14 | 2007-04-18 | 天津药物研究院 | Glycyrrhetinic acid-30-acylamide derivatives and its use |
| CN101229172A (en) * | 2007-12-28 | 2008-07-30 | 天津药物研究院 | Solid dispersing agent of glycyrrhetinic acid 30-acylamide derivatives, preparing method and uses thereof |
| EP2258713A1 (en) * | 2009-06-02 | 2010-12-08 | onepharm Research & Development GmbH | Antiviral Triterpene Derivatives |
-
2011
- 2011-11-14 CN CN2011103592271A patent/CN103102382A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1948332A (en) * | 2005-10-14 | 2007-04-18 | 天津药物研究院 | Glycyrrhetinic acid-30-acylamide derivatives and its use |
| CN101229172A (en) * | 2007-12-28 | 2008-07-30 | 天津药物研究院 | Solid dispersing agent of glycyrrhetinic acid 30-acylamide derivatives, preparing method and uses thereof |
| EP2258713A1 (en) * | 2009-06-02 | 2010-12-08 | onepharm Research & Development GmbH | Antiviral Triterpene Derivatives |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106265692A (en) * | 2015-05-22 | 2017-01-04 | 天津药物研究院有限公司 | A kind of transdermal formulation of enoxolone 30-amide derivatives and its production and use |
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Application publication date: 20130515 |