CN111499610A - Polymorphs of pomalidomide prodrug salt - Google Patents
Polymorphs of pomalidomide prodrug salt Download PDFInfo
- Publication number
- CN111499610A CN111499610A CN201910095078.9A CN201910095078A CN111499610A CN 111499610 A CN111499610 A CN 111499610A CN 201910095078 A CN201910095078 A CN 201910095078A CN 111499610 A CN111499610 A CN 111499610A
- Authority
- CN
- China
- Prior art keywords
- polymorph
- minus
- plus
- dioxopiperidin
- dioxoisoindolin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
- C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention relates to L-valine (3- (4-amino-1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl ester bis-p-toluenesulfonate polymorph and its use as an immunomodulator.
Description
Technical Field
The invention relates to the field of medicines, in particular to a polymorphic substance of L-valine (3- (4-amino-1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl ester bis-p-toluenesulfonate, a pharmaceutical composition containing the polymorphic substance and application of the polymorphic substance in preparing a medicament for treating cancer.
Background
Pomalidomide was developed by american seille gene company and first marketed in the united states 2 months in 2013, pomalidomide is a similar immunomodulator that is marketed next to thalidomide, the third behind lenalidomide, and can enhance T cell and natural killer cell mediated immune responses, while inhibiting the production of proinflammatory cytokines by monocytes (e.g., TNF- α, I L-6, etc.).
PCT application PCT/CN2017/098281 provides L-valine (3- (4-amino-1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl ester, which is a pomalidomide prodrug, having the structure shown in formula (I-1):
the structure of the formula (I-1) is a pomalidomide prodrug which has good solubility and obviously improves bioavailability, and can be rapidly metabolized into pomalidomide to exert the drug effect in vivo, but the structure is found to have poor stability and is easy to degrade after being placed at room temperature, and the bis-p-toluenesulfonate with the structure of the formula (I-1), namely L-valine (3- (4-amino-1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl ester bis-p-toluenesulfonate has improved stability.
Polymorphism of medicinal compounds exists, and the change of crystal forms generally causes different melting points, solubility, hygroscopicity, stability, biological activity and the like of active ingredients, which are important factors influencing the difficulty and easiness in preparing medicaments, storage stability, preparation difficulty, bioavailability and the like. Because of the specific thermodynamic properties and stability of a particular polymorph, it is important to know the crystal form of the compound used in each dosage form during the manufacturing process to ensure that the same form of drug is used in the manufacturing process. It is therefore necessary to ensure that the active ingredient is in a single crystalline form or is in a known mixture of crystalline forms.
The discovery of new polymorphs of a pharmaceutical compound provides the opportunity to improve the physical properties of the drug, i.e., extend the overall properties of the material and thereby better guide the study of the active ingredient and its formulation, and therefore the polymorphic form of L-valine (3- (4-amino-1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl ester salt provided by the present invention is commercially valuable in the manufacture of pharmaceuticals and other applications.
Disclosure of Invention
It is an object of the present invention to provide a polymorphic form of L-valine (3- (4-amino-1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl ester bistoluene sulfonate salt.
In a first aspect of the invention, there is provided a polymorph of L-valine (3- (4-amino-1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl ester ditoluenesulfonate (formula I).
In another preferred embodiment, the polymorph is form a, wherein the form a has the following properties:
it has peaks at 3.9 + -0.2, 7.1 + -0.2, 13.1 + -0.2, 13.6 + -0.2, 14.4 + -0.2, 20.6 + -0.2 of X-ray powder diffraction spectrum expressed in degree 2 theta by using Cu-Ka radiation.
In a more preferred embodiment, the form a further has one or more X-ray powder diffraction characteristic peaks expressed in degrees 2 θ selected from the group consisting of: 12.3 plus or minus 0.2, 19.1 plus or minus 0.2, 26.1 plus or minus 0.2 and 27.7 plus or minus 0.2.
In another preferred embodiment, the polymorph is form a, wherein the form a has the following properties:
it has peaks at 3.9 + -0.2, 7.1 + -0.2, 12.3 + -0.2, 13.1 + -0.2, 13.6 + -0.2, 14.4 + -0.2, 19.1 + -0.2, 20.6 + -0.2 in the X-ray powder diffraction spectrum expressed in degree 2 theta by using Cu-Ka radiation.
In another preferred embodiment, the polymorph is form a, wherein the form a has a powder X-ray diffraction pattern substantially as shown in figure 1.
In another preferred embodiment, the polymorph is form a, wherein the differential thermal scan of form a has a maximum endothermic peak at 183.57 ± 2 ℃ under a heating rate of 10 ℃/min.
In another preferred embodiment, the polymorph is form a having a differential thermal analysis endotherm profile substantially as shown in figure 2 at a heating rate of 10 ℃/minute.
In yet another aspect, the present invention provides a process for the preparation of form a comprising a) dissolving amorphous di-p-toluenesulfonate in acetone; b) form a was isolated from acetone.
Wherein the amount of acetone in step a) is preferably such that the di-p-toluenesulfonate is completely dissolved. If necessary, stirring crystallization or standing crystallization can be carried out.
In another preferred embodiment, the polymorph is form B, wherein the form B has the following properties:
it has peaks at 4.0 + -0.2, 8.9 + -0.2, 11.9 + -0.2, 14.6 + -0.2, 19.3 + -0.2, 20.8 + -0.2 of X-ray powder diffraction spectrum expressed in degree 2 theta by using Cu-Ka radiation.
In a more preferred embodiment, the form B further has one or more X-ray powder diffraction characteristic peaks expressed in degrees 2 θ selected from the group consisting of: 7.2 plus or minus 0.2, 12.3 plus or minus 0.2, 13.2 plus or minus 0.2, 23.3 plus or minus 0.2 and 27.3 plus or minus 0.2.
In another preferred embodiment, the polymorph is form B, wherein the form B has the following properties:
it has peaks at 4.0 + -0.2, 7.2 + -0.2, 8.9 + -0.2, 11.9 + -0.2, 13.2 + -0.2, 14.6 + -0.2, 19.3 + -0.2, 20.8 + -0.2 in X-ray powder diffraction spectrum expressed by degree 2 theta by using Cu-Ka radiation.
In another preferred embodiment, the polymorph is form B, wherein the form B has the following properties:
it has peaks at 4.0 + -0.2, 7.2 + -0.2, 8.9 + -0.2, 11.9 + -0.2, 12.3 + -0.2, 13.2 + -0.2, 14.6 + -0.2, 19.3 + -0.2, 20.8 + -0.2, 23.3 + -0.2, 27.3 + -0.2 in the X-ray powder diffraction spectrum expressed by degree 2 theta by using Cu-Ka radiation.
In another preferred embodiment, the polymorph is form B, wherein the form B has a powder X-ray diffraction pattern substantially as shown in figure 3.
In another preferred embodiment, the polymorph is form B, wherein the differential thermal scan of form B has a maximum endothermic peak at 177.99 ± 2 ℃ under a heating rate of 10 ℃/min.
In another preferred embodiment, the polymorph is form B having a differential thermal analysis endotherm substantially as shown in figure 4 at a heating rate of 10 ℃/minute.
In yet another aspect, the present invention provides a process for preparing form B comprising a) dissolving amorphous bis-p-toluenesulfonate with 1, 4-dioxane; b) isolating form B from 1, 4-dioxane.
Wherein the amount of 1, 4-dioxane in step a) is preferably such that the bis-p-toluenesulfonate is completely dissolved. If necessary, stirring crystallization or standing crystallization can be carried out.
In a second aspect of the invention there is provided the use of a polymorph according to the invention for the manufacture of a medicament for the treatment of cancer.
In another preferred embodiment, the polymorph is used for preparing a medicament for treating multiple myeloma and prostatic cancer.
In a third aspect of the invention, there is provided a pharmaceutical composition comprising a polymorph of L-valine (3- (4-amino-1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl ester ditoluenesulfonate and a pharmaceutically acceptable carrier.
In another preferred embodiment, the pharmaceutical composition comprises form A of L-valine (3- (4-amino-1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl ester bis-p-toluenesulfonate and a pharmaceutically acceptable carrier.
In another preferred embodiment, the pharmaceutical composition comprises form B of L-valine (3- (4-amino-1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl ester bis-p-toluenesulfonate and a pharmaceutically acceptable carrier.
In a fourth aspect of the invention, there is provided the use of a pharmaceutical composition for the manufacture of a medicament for the treatment of cancer.
In another preferred embodiment, the pharmaceutical composition is used for preparing a medicament for treating multiple myeloma and prostate cancer.
In a fifth aspect of the invention, a crystalline composition is provided, wherein L-valine (3- (4-amino-1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl ester bis-p-toluenesulfonate form a crystalline composition is defined as crystalline form a which comprises greater than 50%, preferably greater than 80%, more preferably greater than 90%, most preferably greater than 95% by weight of the composition, which may contain a minor amount L-valine (3- (4-amino-1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl ester bis-p-toluenesulfonate in other crystalline or amorphous forms, including but not limited to form B or amorphous forms, wherein L-valine (3- (4-amino-1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl ester bis-p-toluenesulfonate form B is defined as crystalline form B which comprises greater than 50%, preferably greater than 80%, more than 90% by weight of the composition, preferably greater than 95% crystalline form a or amorphous form B which comprises 3- (4-amino-1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) -2, most preferably 95% or amorphous forms B.
In a sixth aspect of the invention, there is provided the use of a crystalline composition for the manufacture of a medicament for the treatment of cancer.
In another preferred embodiment, the solution composition is used for preparing a medicament for treating multiple myeloma and prostatic cancer.
The mode of administration of the polymorph or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with at least one of the following: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be delayed in a certain portion of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active ingredient may also be in microencapsulated form with one or more of the above excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly employed in the art such as water or other solvents, solubilizing agents and emulsifiers, e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, and oils, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active ingredients, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these materials, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the polymorphic forms of the invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The polymorphs of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When the pharmaceutical composition is used, a safe and effective amount of the polymorphic substance of the invention is suitable for mammals (such as human beings) needing treatment, wherein the administration dosage is a dosage which is considered to be effective in pharmacy, and for a human body with the weight of 60kg, the daily administration dosage is 1-200 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
For example, the compounds described herein can be in the form of individual enantiomers, diastereomers, or geometric isomers, or can be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.
Carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the invention all include isotopes thereof, and carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include12C、13C and14c, isotopes of hydrogen including protium (H), deuterium (D, also known as deuterium), tritium (T, also known as deuterium), and isotopes of oxygen including16O、17O and18isotopes of O, sulfur including32S、33S、34S and36isotopes of S, nitrogen include14N and15isotopes of N, F include19Isotopes of F, chlorine including35Cl and37cl, isotopes of bromine including79Br and81Br。
"having a powder X-ray diffraction pattern substantially as shown in figure 1" in the present invention means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the powder X-ray diffraction spectrum appear in the given powder X-ray diffraction pattern.
It is noted that in XRD, the diffraction pattern obtained from a crystalline compound is often characteristic for a particular crystalline form, where the relative intensities of the bands (especially at low angles) may vary due to the dominant orientation effects arising from differences in crystallization conditions, particle size, and other measurement conditions. Therefore, the relative intensities of the diffraction peaks are not characteristic of the crystal form in question, and when judging whether the diffraction peaks are the same as the known crystal form, the relative positions of the peaks rather than their relative intensities should be noted. For the same crystal form of the same compound, the XRD spectrogram has similarity on the whole, and the 2 theta angle error representing the peak position is generally within +/-2 percent, for example, the peak position may move due to the change of temperature, the movement of a sample or the calibration of an instrument and the like when the sample is analyzed; the relative intensity error may be large but the trend of the variation is consistent. It should also be noted that in the identification of mixtures, the loss of part of the diffraction lines may be due to, for example, a reduction in the content, in which case it is not necessary to rely on all the bands observed in the high-purity sample, even several bands may be characteristic for a given crystal.
Similarly, although the absorption peak in the differential thermal scanning analysis is an inherent property of the crystal form of the present invention, in actual measurement, in addition to measurement errors, the melting point may vary due to incorporation of an allowable amount of impurities or the like, and this possibility cannot be denied. Therefore, the skilled person can fully understand how the measured value of the endothermic peak temperature in the present invention may vary, and for example, the error is assumed to be about ± 5 ℃ in some cases, preferably about ± 3 ℃, more preferably about ± 2 ℃, and most preferably about ± 1 ℃.
The analytical method used in the present invention:
1) powder X-ray diffraction
Methods for determining X-ray powder diffraction of crystalline forms are known in the art. The spectra were acquired, for example, using a Bruker D8advance diffractometer using a Cu-Ka filled tube (40kV,40mA) as the X-ray source with a wide angle goniometer, scanning the color at 2.4 °/min.
2) Differential scanning calorimetry
DSC measurement methods are known in the art. Differential thermal analysis is done, for example, using Mettler DSC 3 +. And (3) heating from 25 ℃ to 250 ℃ at the heating rate of 10 ℃/min to obtain the DSC scanning map of the crystal form.
Drawings
FIG. 1 powder X-ray powder diffraction Spectroscopy of form A
FIG. 2 differential thermal analysis spectrum of form A
FIG. 3 powder X-ray powder diffraction Spectroscopy of form B
FIG. 4 differential thermal analysis spectrum of form B
FIG. 5 shows the relationship between drug concentration in plasma of dogs and time after administration
Detailed Description
The invention is further illustrated with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. The starting materials used in the present invention are commercially available unless otherwise specified.
EXAMPLE 1 preparation of 1L-valine (3- (4-amino-1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl ester (Compound 1)
Step1, under the protection of nitrogen, adding S.M.B (20g, 73.2mmol, 1.00eq) and DMF (400ml) into a 1000m L three-necked reaction flask, stirring magnetically, then slowly adding sodium hydride (3.5g, 87.5mmol, 1.2eq), stirring for 30min, adding potassium iodide (12g, 72.2mmol, 0.99eq) and TBAB (tetrabutylammonium bromide) (3.52g, 10.9mmol, 0.15eq), stirring for 15min, adding S.M.1(23.8g, 72.8mmol, 0.99eq), stirring for 12h, stopping the reaction, pouring the reaction system into 2L water, stirring for 1h, precipitating solids, filtering to obtain a yellow solid filter cake, washing the filter cake with 500ml DCM (dichloromethane), separating, concentrating the organic pressure, and performing column chromatography to obtain a yellow solid product with yield of 1.5: 1 g, subtracting 13.20g from the yellow solid product, and subtracting the yellow solid product from the yellow solid yield of 1.20.8%.
Step 2: int 1-01(500mg, 1mmol, 1.00eq) and DCM5ml were added to a 100ml three-necked reaction flask under nitrogen, stirred at room temperature for 10min, added with HCl/EA (10ml, 10mmol, 10.0eq) in one portion, and stirred for 40 min. The reaction was stopped, filtered and dried to obtain 380mg of a yellow solid product with a yield of 86.9%
HPLC:97.05％
LCMS:403.2(M+H-HCl)
1H NMR(400MHz,DMSO)8.56-8.51(d,3H),7.51-7.47(dd,1H),7.06–7.04(d,1H),7.01-7.02(d,1H),6.56(bs,2H),5.91-5.85(dd,1H),5.74-5.69(t,1H),5.28-5.23(m,1H),3.92(s,1H),2.25(m,1H),2.88-2.84(d,1H),2.61-2.51(m,1H),2.16-2.10(m,2H),0.96-0.92(m,6H).
Step 3: 200m L three-necked bottle, adding 4g of L-valine (3- (4- (amino) -1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl ester hydrochloride (Int 1-02), 40m L ethyl acetate, stirring for 5min under ice-water bath, pouring 30m L ice water, adding 30m L saturated sodium bicarbonate, stirring for 5-10min, extracting the aqueous phase with ethyl acetate (40m L) once, combining organic phases, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain 3g of L-valine (3- (4-amino-1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl ester for later use.
Example 2 preparation of polymorph
L-valine (3- (4-amino-1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl ester (1.0 g) was dissolved in 50m L ethyl acetate, and an ethyl acetate solution of p-toluenesulfonic acid monohydrate (1.03g/50m L) was added dropwise thereto over about 15 minutes, followed by stirring overnight at room temperature, filtration and vacuum drying of the cake to obtain 1.0g of bis-p-toluenesulfonate, which was confirmed by pattern analysis to be L-valine (3- (4-amino-1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl ester and p-toluenesulfonic acid at a molar ratio of 1: 2.
1H NMR(400MHz,DMSO)8.33(brs,3H),7.70–7.43(m,5H),7.17(d,J＝7.8Hz,4H),7.05(m,2H),6.42–5.83(m,4H),5.76–5.66(m,1H),5.25(m,1H),3.97(d,J＝3.4Hz,1H),3.21–2.96(m,1H),2.86(d,J＝17.5Hz,1H),2.70–2.53(m,1H),2.30(s,6H),2.13(m,2H),1.06–0.74(m,6H).
2.1 preparation method and solid state characterization of crystal form A:
49.1mg of the double salt obtained by the preparation is taken and added into a reaction bottle, then 0.8m of acetone 2-butanone L is added, the reaction system is stirred for 72 hours at room temperature, the supernatant is removed by centrifugation, and vacuum drying is carried out at 40 ℃ to obtain 35mg of the product (yield is 71%).
Solid state characterization of form a was performed using X-ray powder diffraction and differential scanning calorimetry, with solid state characterization parameters and profiles as described herein.
2.2 preparation method and solid state characterization of form B:
49.1mg of the double salt obtained in the above preparation was taken and added to a reaction flask, 1, 4-dioxane 1m L was further added, the reaction system was stirred at room temperature for 72 hours, centrifuged, the supernatant was discarded, and the solid was dried under vacuum at 40 ℃ to obtain 10mg of the product (yield 20%).
Solid state characterization of form B was performed using X-ray powder diffraction and differential scanning calorimetry, with solid state characterization parameters and profiles as described herein.
Example 3 stability of polymorph
Under the test conditions of 40 ℃ and 60 ℃, a proper amount of the crystal form A is stored for 1-10 days, and the result shows that: the crystal form A is very stable; compared with the newly prepared (0 day) crystal form A, the purity of the crystal form A is basically unchanged and is always more than 98 percent.
Thus, the polymorph according to the invention is very stable and suitable for use in pharmaceutical compositions. In addition, the polymorphic substance is not easy to raise, collect and waste in the manufacturing process of split charging and other medicines, and is beneficial to protecting the health of operators. Particularly, the reagent used in the preparation process of the crystal form A is environment-friendly, nontoxic, easy to obtain and high in preparation yield.
Example 4 pharmacokinetic data for dogs
Male is used in this example
Beagle dogs, weighing 8.6-10.6kg, were purchased from Beijing Mars Biotechnology, Inc., and the animals tested were all over 1 year old, and the animals were at least two weeks apart from the previous test.
Three dogs were crossed over each other and washed at intervals of at least three days, and NORA0310a4 (bis-p-toluenesulfonate) 10mg oral capsules (equivalent to 3.7mg pomalidomide) and NORA0312 (pomalidomide) 4mg oral capsules (POMA L ID, manufactured by Natco pharmalimited) were alternately administered one capsule per cycle with 50m L of water to aid swallowing.
The test method comprises the steps of collecting blood samples 0.5, 1, 2, 4, 6, 8, 10, 24 and 48 hours after administration before administration, storing whole blood in an anticoagulation tube containing EDTA-2K on wet ice, and centrifuging at 1800 × g for 5 minutes at 4 ℃ within 1 hour to obtain plasma samples, adding 2% formic acid into the separated plasma samples at a ratio of 4:1, shaking uniformly, immediately storing the plasma samples in dry ice for temporary storage, transferring the samples to a refrigerator at-20 ℃, carrying out detection by adopting L C/MS/MS, and calculating pharmacokinetic parameters of dogs after administration by using a non-chamber model of software WinNonlin, wherein the data are shown in Table-1 and figure-5.
TABLE 1
And (4) conclusion: from the above test results, it can be seen that only pomalidomide is detected in vivo after each group is administered, which indicates that they are rapidly metabolized into pomalidomide after entering the body. At similar dosages, the salts of the invention are compared with pomalidomide, CmaxThe value is increased by more than 4 times, AUClastThe increase is more than 1.5 times, which shows that the salt of the invention has better oral bioavailability compared with pomalidomide.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and improvements can be made without departing from the principle of the present invention, and these modifications and improvements should also be construed as the protection scope of the present invention.
Claims (15)
1. A polymorphic form of the bis-p-toluenesulfonate salt of the compound of formula (I),
2. the polymorph of claim 1, wherein the polymorph is form a of L-valine (3- (4-amino-1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl ester bis-p-toluenesulfonate, wherein form a has the following properties:
it has peaks at 3.9 + -0.2, 7.1 + -0.2, 13.1 + -0.2, 13.6 + -0.2, 14.4 + -0.2, 20.6 + -0.2 of X-ray powder diffraction spectrum expressed in degree 2 theta by using Cu-Ka radiation.
3. The polymorph of claim 2, wherein the polymorph is form a, wherein the form a further comprises one or more X-ray powder diffraction characteristic peaks expressed in degrees 2 Θ selected from the group consisting of: 12.3 plus or minus 0.2, 19.1 plus or minus 0.2, 26.1 plus or minus 0.2 and 27.7 plus or minus 0.2.
4. The polymorph of claim 2, wherein the polymorph is form a, wherein the form a has a powder X-ray diffraction pattern substantially as shown in figure 1.
5. The polymorph of claim 2 or 3, wherein the polymorph is form A, wherein the differential thermal scan of form A has a peak maximum endothermic peak at 183.57 ± 2 ℃ at a heating rate of 10 ℃/min.
6. The polymorph of claim 2 or 3, wherein the polymorph is form A, wherein the polymorph has a differential thermal analysis endotherm substantially as shown in figure 2, at a heating rate of 10 ℃/min.
7. The polymorph of claim 1, wherein the polymorph is form B of L-valine (3- (4-amino-1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl ester bis-p-toluenesulfonate, wherein form B has the following properties:
it has peaks at 4.0 + -0.2, 8.9 + -0.2, 11.9 + -0.2, 14.6 + -0.2, 19.3 + -0.2, 20.8 + -0.2 of X-ray powder diffraction spectrum expressed in degree 2 theta by using Cu-Ka radiation.
8. The polymorph of claim 7, wherein the polymorph is form B, wherein the form B further comprises one or more characteristic X-ray powder diffraction peaks expressed in degrees 2 θ selected from the group consisting of: 7.2 plus or minus 0.2, 12.3 plus or minus 0.2, 13.2 plus or minus 0.2, 23.3 plus or minus 0.2, 27.3 plus or minus 0.2
9. The polymorph of claim 7, wherein said polymorph is form B, wherein said form B has a powder X-ray diffraction pattern substantially as shown in figure 3.
10. The polymorph of claim 7 or 8, wherein the polymorph is form B, wherein the polymorph has a differential thermal scan with a peak endotherm peak at 177.99 ± 2 ℃ c at a heating rate of 10 ℃/min.
11. The polymorph of claim 7 or 8, wherein the polymorph is form B, wherein the polymorph has a differential thermal analysis endotherm substantially as shown in figure 4, at a heating rate of 10 ℃/min.
12. Crystalline composition, wherein the polymorph of L-valine (3- (4-amino-1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl ester ditoluenesulfonate according to any one of claims 1 to 11 comprises more than 50%, preferably more than 80%, more preferably more than 90%, most preferably more than 95% by weight of the crystalline composition.
13. A pharmaceutical composition comprising the polymorphic form of L-valine (3- (4-amino-1, 3-dioxoisoindolin-2-yl) -2, 6-dioxopiperidin-1-yl) methyl ester ditoluene sulfonate salt of any one of claims 1-11 and a pharmaceutically acceptable carrier.
14. Use of the polymorph of claims 1 to 11, the crystalline composition of claim 12, the pharmaceutical composition of claim 13 for the manufacture of a medicament for the treatment of cancer.
15. The use of claim 14, wherein the cancer is multiple myeloma, prostate cancer.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910095078.9A CN111499610A (en) | 2019-01-31 | 2019-01-31 | Polymorphs of pomalidomide prodrug salt |
| PCT/CN2020/072032 WO2020156150A1 (en) | 2019-01-31 | 2020-01-14 | Polymorph of pomalidomide prodrug salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910095078.9A CN111499610A (en) | 2019-01-31 | 2019-01-31 | Polymorphs of pomalidomide prodrug salt |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111499610A true CN111499610A (en) | 2020-08-07 |
Family
ID=71840828
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910095078.9A Pending CN111499610A (en) | 2019-01-31 | 2019-01-31 | Polymorphs of pomalidomide prodrug salt |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN111499610A (en) |
| WO (1) | WO2020156150A1 (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1215397A (en) * | 1996-04-09 | 1999-04-28 | 格吕伦塔尔有限公司 | Acylated N-hydroxy methyl thalidomide prodrugs with immunomodulator action |
| WO2005016326A2 (en) * | 2003-07-11 | 2005-02-24 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Analogs of thalidomide as potential angiogenesis inhibitors |
| CN100383139C (en) * | 2005-04-07 | 2008-04-23 | 天津和美生物技术有限公司 | Piperidine-2,6-dione derivatives capable of inhibiting cell from releasing tumor necrosis factor |
| CN100488959C (en) * | 2003-03-27 | 2009-05-20 | 天津和美生物技术有限公司 | Water soluble thalidomide derivative |
| CN101735276A (en) * | 2009-12-17 | 2010-06-16 | 廖国超 | Water-soluble phosphate monoester derivatives and application thereof |
| WO2011160042A2 (en) * | 2010-06-18 | 2011-12-22 | Makoto Life Sciences, Inc. | Prpk-tprkb modulators and uses thereof |
-
2019
- 2019-01-31 CN CN201910095078.9A patent/CN111499610A/en active Pending
-
2020
- 2020-01-14 WO PCT/CN2020/072032 patent/WO2020156150A1/en active Application Filing
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1215397A (en) * | 1996-04-09 | 1999-04-28 | 格吕伦塔尔有限公司 | Acylated N-hydroxy methyl thalidomide prodrugs with immunomodulator action |
| CN100488959C (en) * | 2003-03-27 | 2009-05-20 | 天津和美生物技术有限公司 | Water soluble thalidomide derivative |
| WO2005016326A2 (en) * | 2003-07-11 | 2005-02-24 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Analogs of thalidomide as potential angiogenesis inhibitors |
| CN100383139C (en) * | 2005-04-07 | 2008-04-23 | 天津和美生物技术有限公司 | Piperidine-2,6-dione derivatives capable of inhibiting cell from releasing tumor necrosis factor |
| CN101735276A (en) * | 2009-12-17 | 2010-06-16 | 廖国超 | Water-soluble phosphate monoester derivatives and application thereof |
| WO2011160042A2 (en) * | 2010-06-18 | 2011-12-22 | Makoto Life Sciences, Inc. | Prpk-tprkb modulators and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2020156150A1 (en) | 2020-08-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10189837B2 (en) | Crystalline (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt | |
| KR101470715B1 (en) | Polymorphs of Dasatinib, preparation methods and pharmaceutical compositions thereof | |
| CN115175908A (en) | Aryl or heteroaryl pyridone or pyrimidone derivative and preparation method and application thereof | |
| MX2014014961A (en) | Compounds and compositions for modulating egfr activity. | |
| US10550101B2 (en) | Crystalline forms of mesylate salt of pyridinyl amino pyrimidine derivative, preparation methods therefor, and applications thereof | |
| EP2603503A1 (en) | Dabigatran etexilate bismesylate salt, solid state forms and process for preparation thereof | |
| CN115109078A (en) | Pyrimidopyridine inhibitor and preparation method and application thereof | |
| CN111777595A (en) | Novel crystal form of cyclohexane carboxamide compound and preparation method thereof | |
| EP2651952A2 (en) | Polymorphic forms of asenapine maleate and processes for their preparation | |
| CN112867717A (en) | Compounds useful as kinase inhibitors and uses thereof | |
| CN113045570A (en) | Spiro-containing quinazoline compounds | |
| CN114644642B (en) | Crystal form A of thienopyridine compound, preparation method and pharmaceutical composition thereof | |
| CN111499610A (en) | Polymorphs of pomalidomide prodrug salt | |
| CN112125910A (en) | Alvatinib crystal form and preparation method thereof | |
| CN111670191B (en) | Crystal form of pyridone derivative, preparation method and application | |
| CN111217807A (en) | Dasatinib amorphous form and preparation method thereof | |
| EP3315493B1 (en) | Phenyl amino pyrimidine compound or polymorph of salt thereof | |
| WO2014193881A1 (en) | Crystalline form of n,n-dicyclopropyl-4-(1,5-dimethyl-1 h-pyrazol-3-ylamino)-6-ethyl-1 -methyl-1,6-dihyrdroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide for the treatment of myeloproliferative disorders | |
| CN115677698B (en) | High-efficiency antiviral compound and application thereof | |
| CN112645929B (en) | Polymorphs of isopropylsulfonylphenylpyrimidines or salts thereof | |
| KR102423393B1 (en) | Crystalline form of 3,4-dihydrothieno[3,2-D]pyrimidine compound and method for preparing same | |
| CN115504976A (en) | Adagrasib crystal form and preparation method thereof | |
| CN106316963B (en) | Polymorphs of a morpholino phenylaminopyrimidine compound or salt thereof | |
| CN117624241A (en) | Polymorphic form preparation of TLR agonist or salt thereof | |
| JP2023532217A (en) | Crystal forms of SHP2 inhibitors, compositions thereof, methods of preparation and applications thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| AD01 | Patent right deemed abandoned |
Effective date of abandoning: 20220311 |
|
| AD01 | Patent right deemed abandoned |