WO2020156150A1 - Polymorph of pomalidomide prodrug salt - Google Patents

Polymorph of pomalidomide prodrug salt Download PDF

Info

Publication number
WO2020156150A1
WO2020156150A1 PCT/CN2020/072032 CN2020072032W WO2020156150A1 WO 2020156150 A1 WO2020156150 A1 WO 2020156150A1 CN 2020072032 W CN2020072032 W CN 2020072032W WO 2020156150 A1 WO2020156150 A1 WO 2020156150A1
Authority
WO
WIPO (PCT)
Prior art keywords
polymorph
crystal form
cancer
toluenesulfonate
degrees
Prior art date
Application number
PCT/CN2020/072032
Other languages
French (fr)
Chinese (zh)
Inventor
刘飞
赵欣
吴刚
蔡璇
刘伟
祁智
杨许东
Original Assignee
南京诺瑞特医药科技有限公司
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 南京诺瑞特医药科技有限公司 filed Critical 南京诺瑞特医药科技有限公司
Publication of WO2020156150A1 publication Critical patent/WO2020156150A1/en

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

Definitions

  • the present invention relates to the field of medicine, in particular to L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1-
  • L-valine 3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1-
  • Pomalidomide was developed by Xaar Gene Corporation and was approved for listing in the United States for the first time in February 2013. Pomalidomide is the third immunomodulator of its kind to be marketed after thalidomide and lenalidomide. It can enhance the immune response mediated by T cells and natural killer cells, while inhibiting monocytes from producing pro-inflammatory cells. Factors (such as TNF- ⁇ , IL-6, etc.). In addition, pomalidomide can inhibit tumor cell proliferation and induce cell apoptosis, and multiple myeloma cell lines resistant to lenalidomide also have a strong proliferation inhibitory effect.
  • pomalidomide is a poorly soluble drug.
  • the solubility of pomalidomide in purified water, pH 6.8 phosphate buffer, pH 4.5 acetate buffer and 0.1 mol/L hydrochloric acid was determined to be 17.8, 17.0, 18.7 and 18.9 ⁇ g/mL.
  • the low solubility of pomalidomide not only increases the difficulty of the preparation process, but also limits the dissolution and absorption process of the active ingredient in the gastrointestinal tract, thereby affecting the oral bioavailability.
  • L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1 provided by PCT application PCT/CN2017/098281 -Yl) methyl ester is a pomalidomide prodrug, the structure of the compound is shown in the following structural formula (I-1):
  • the structure of formula (I-1) is a pomalidomide prodrug with good solubility and significantly improved bioavailability, which can be rapidly metabolized into pomalidomide in the body to exert its efficacy.
  • the bis-p-toluenesulfonate of formula (I-1) is L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6 -Dioxopiperidin-1-yl) methyl ester bis-p-toluenesulfonate has improved stability.
  • compositions have polymorphism, and the change of crystal form usually causes the active ingredients to have different melting points, solubility, hygroscopicity, stability, biological activity, etc., all of which affect the difficulty of drug preparation, storage stability, and difficulty in preparation. Important factors such as ease and bioavailability. Because specific polymorphs have specific thermodynamic properties and stability, it is important to understand the crystal forms of the compounds used in each dosage form during the preparation process to ensure that the same form of drugs is used in the production process. Therefore, it is necessary to ensure that the active ingredient is a single crystal form or a known mixture of some crystal forms.
  • An object of the present invention is to provide L-valine represented by formula (I) (3-(4-amino-1,3-dioxoisoindoline-2-
  • L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine- Polymorph of 1-yl)methyl bistosylate (formula I).
  • the polymorph is crystal form A, wherein the crystal form A has the following properties:
  • the crystal form A further has one or more characteristic X-ray powder diffraction peaks expressed in degrees 2 ⁇ selected from the following group: 7.1 ⁇ 0.2, 13.6 ⁇ 0.2.
  • the crystal form A further has one or more characteristic X-ray powder diffraction peaks expressed in degrees 2 ⁇ selected from the following group: 12.3 ⁇ 0.2, 19.1 ⁇ 0.2, 26.1 ⁇ 0.2, 27.7 ⁇ 0.2.
  • the polymorph is crystal form A, wherein the crystal form A has the following properties:
  • the polymorph is crystal form A, wherein the crystal form A has a powder X-ray diffraction pattern substantially as shown in FIG. 1.
  • the polymorph is crystal form A, and under the condition of a heating rate of 10°C/min, the differential heat scan of the crystal form A has a maximum endotherm at 183.57 ⁇ 2°C Peak-to-peak value.
  • the polymorph is crystal form A, and under the condition of a heating rate of 10°C/min, the crystal form A has a differential thermal analysis endothermic curve as shown in FIG. 2 Figure.
  • the present invention provides a method for preparing crystal form A, including
  • step (2) The reaction system obtained in step (1) is stirred at room temperature to obtain the crystal form A of the compound bis-p-toluenesulfonate represented by formula (I).
  • the preparation method of the crystal form A further includes:
  • the purity of the crystal form A after storage at 40°C for 5 days is less than 0.2%; preferably less than 0.1%; more preferably less than 0.05%; or
  • the purity change after storage at 40°C for 10 days is less than 0.3%; preferably less than 0.2%; more preferably less than 0.1%; or
  • the purity of the crystal form A after storage at 60°C for 5 days is less than 0.6%; preferably less than 0.3%; more preferably less than 0.05%; or
  • the purity change after storage at 60°C for 10 days is less than 1.5%; preferably less than 1.0%; more preferably less than 0.2%.
  • the polymorph is crystal form B, wherein the crystal form B has the following properties:
  • the crystal form B further has one or more characteristic X-ray powder diffraction peaks expressed in degrees 2 ⁇ selected from the group consisting of: 11.9 ⁇ 0.2, 20.8 ⁇ 0.2.
  • the crystal form B further has one or more characteristic X-ray powder diffraction peaks expressed in degrees 2 ⁇ selected from the group consisting of: 7.2 ⁇ 0.2, 12.3 ⁇ 0.2, 13.2 ⁇ 0.2, 23.3 ⁇ 0.2, 27.3 ⁇ 0.2.
  • the polymorph is crystal form B, wherein the crystal form B has the following properties:
  • the polymorph is crystal form B, wherein the crystal form B has the following properties:
  • the polymorph is crystal form B, wherein the crystal form B has a powder X-ray diffraction pattern substantially as shown in FIG. 3.
  • the polymorph is crystal form B, and under the condition of a heating rate of 10°C/min, the differential heat scan of the crystal form B has a maximum endotherm at 177.99 ⁇ 2°C Peak-to-peak value.
  • the polymorph is crystalline form B, and under the condition of a heating rate of 10°C/min, the crystalline form B has a differential thermal analysis endothermic curve substantially as shown in FIG. 4 Figure.
  • the present invention provides a method for preparing crystal form B, including
  • step (2) The reaction system obtained in step (1) is stirred at room temperature to obtain the crystalline form B of the compound bis-p-toluenesulfonate represented by formula (I).
  • the preparation method of the crystal form B further includes:
  • the polymorph is used to prepare a medicine for treating multiple myeloma and prostate cancer.
  • the pharmaceutical composition contains L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine
  • L-valine 3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine
  • the pharmaceutical composition contains L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine
  • L-valine 3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine
  • the pharmaceutical composition is used to prepare a medicine for treating multiple myeloma and prostate cancer.
  • a crystalline composition wherein L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6
  • the crystalline composition of dioxopiperidin-1-yl) methyl ester bis-p-toluenesulfonate crystal form A means that the crystal form A in the composition accounts for more than 50% of the weight of the composition, preferably more than 80%, More preferably 90% or more, most preferably 95% or more, the crystalline composition may contain a small amount of L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl) Other crystalline or amorphous forms of -2,6-dioxopiperidin-1-yl) methyl ester bis-p-toluenesulfonate, including but not limited to crystalline form B or amorphous; wherein L-valine ( 3-(4-Amino-1,3-
  • the cancer is multiple myeloma or prostate cancer.
  • a medicine for treating cancer containing the polymorph, crystalline composition, and pharmaceutical composition.
  • the cancer is multiple myeloma or prostate cancer.
  • a method for treating cancer comprising administering the polymorph, crystalline composition, or pharmaceutical composition to a subject in need of cancer treatment.
  • the cancer is multiple myeloma or prostate cancer.
  • the method of administration of the polymorph or pharmaceutical composition of the present invention is not particularly limited.
  • Representative administration methods 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.
  • the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with at least one of the following ingredients: (a) filler or extender Solvents such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; c) Humectants, for example, glycerin; (d) Disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) Soothing agents, for example Paraffin wax; (f) absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetylene glycol
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of active ingredients in such compositions may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active ingredient may also be formed into a microcapsule form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage form of the polymorph of the present invention for topical administration includes ointment, powder, patch, propellant and inhalant.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • polymorphs of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the polymorph of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage when administered is a pharmaceutically effective dosage that is considered to be an effective dosage for a 60kg body weight.
  • the daily dose is usually 1 to 200 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skill range of a skilled physician.
  • the compounds described in the present invention include two asymmetric centers, and therefore may exist in various isomeric forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds described in the present invention may be individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and enriched one A mixture of one or more stereoisomers.
  • the isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers can be separated by Prepared by asymmetric synthesis.
  • the present invention additionally includes the compounds described herein as individual isomers substantially free of other isomers, or as a mixture of multiple isomers.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur, Nitrogen or halogen, optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also known as Heavy hydrogen), tritium (T, also known as super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, and nitrogen isotopes include 14 N And 15 N, the isotopes of fluorine include 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, and the isotopes of bromine include 79 Br and 81 Br.
  • carbon isotopes include 12 C, 13 C and 14 C
  • hydrogen isotopes include protium (H), de
  • "having a powder X-ray diffraction pattern substantially as shown in Figure 1” means at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the powder X-ray diffraction spectrum , Or at least 95%, or at least 99% of the peaks appear in the powder X-ray diffraction pattern given.
  • the diffraction spectrum obtained from the crystalline compound is often characteristic for a specific crystal form, and the relative intensity of the band (especially at low angles) may be affected by the crystallization conditions, particle size and The effect of the dominant orientation produced by the difference of other measurement conditions varies. Therefore, the relative intensities of the diffraction peaks are not characteristic of the crystal form. When judging whether they are the same as the known crystal form, more attention should be paid to the relative positions of the peaks rather than their relative intensities.
  • the XRD spectra are similar in the whole, and the 2 ⁇ angle error of the peak position is generally within ⁇ 2%, for example, due to temperature changes, sample movement or instrumental changes during sample analysis.
  • the position of the peak may move; the relative intensity error may be large, but the change trend is consistent. It should also be pointed out that in the identification of the mixture, some of the diffraction lines will be missing due to factors such as the decrease in content. At this time, there is no need to rely on all the bands observed in the high-purity sample, and even a few bands may be incorrect. The given crystal is characteristic.
  • the absorption peak in the differential thermal scanning analysis is an inherent physical property of the crystal form of the present invention, but in actual measurement, in addition to measurement errors, it may sometimes be caused by the mixing of allowable amounts of impurities.
  • the melting point changes, this possibility is also undeniable. Therefore, those skilled in the art can fully understand to what extent the actual measured value of the endothermic peak temperature in the present invention can be changed.
  • the error that can be assumed is about ⁇ 5°C in some cases, preferably It is about ⁇ 3°C, more preferably about ⁇ 2°C, and most preferably about ⁇ 1°C.
  • the subjects described herein include but are not limited to humans and other mammals; humans are preferred.
  • the method of determining the X-ray powder diffraction of the crystal form is known in the art.
  • a Bruker D8advance diffractometer is used, a Cu-Ka filled tube (40kV, 40mA) is used as an X-ray source with a wide-angle goniometer, and the spectrum is acquired at a scanning color of 2.4°/min.
  • DSC measurement methods are known in the art. For example, use Mettler DSC 3+ to complete differential thermal analysis. The temperature was increased from 25°C to 250°C at a heating rate of 10°C/min to obtain the DSC scan pattern of the crystal form.
  • polymorphs of the present invention are very stable, so they are suitable for storage and transportation, and then used to prepare pharmaceutical compositions;
  • the polymorph of the present invention has the characteristic of being difficult to raise, so that it is easy to collect during the pharmaceutical manufacturing process such as dispensing, and is not easy to cause waste, and helps protect the health of operators;
  • the polymorphs of the present invention are environmentally friendly, non-toxic, easy to obtain, and have a high preparation yield.
  • Figure 1 shows the powder X-ray powder diffraction spectrum of crystal form A
  • Figure 2 shows the differential thermal analysis spectrum of crystal form A
  • Figure 3 shows the powder X-ray powder diffraction spectrum of crystal form B
  • Figure 4 shows the differential thermal analysis spectrum of crystal form B
  • Figure 5 shows the relationship between drug concentration in dog plasma and time after administration.
  • Step1 Under the protection of nitrogen, add S.M.B (20g, 73.2mmol, 1.00eq) and DMF (400ml) to a 1000mL three-necked reaction flask, and stir electromagnetically. Then slowly add sodium hydride (3.5g, 87.5mmol, 1.2eq), continue to stir for 30min, add potassium iodide (12g, 72.2mmol, 0.99eq) and TBAB (tetrabutylammonium bromide) (3.52g, 10.9 mmol, 0.15 eq), after stirring for 15 min, SM1 (23.8 g, 72.8 mmol, 0.99 eq) was added and stirred for 12 h.
  • S.M.B 20g, 73.2mmol, 1.00eq
  • DMF 400ml
  • Step2 Under the protection of nitrogen, add Int 1-01 (500mg, 1mmol, 1.00eq), DCM 5ml to a 100ml three-necked reaction flask, stir at room temperature for 10min, add HCl/EA (10ml, 10mmol, 10.0eq) at once, Continue to stir for 40 minutes. The reaction was stopped, filtered and dried to obtain 380 mg of yellow solid product with a yield of 86.9%
  • Step3 Add 4g L-valine (3-(4-(amino)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine to a 200mL three-necked flask -1-yl) methyl ester hydrochloride (Int 1-02), 40mL ethyl acetate, stir for 5min under ice-water bath, then pour 30mL ice water, continue to add 30mL saturated sodium bicarbonate, stir for 5-10min, water The phases were extracted with ethyl acetate (40 mL) once, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain L-valine (3-(4-amino-1,3-dioxoiso) 3g of indolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl ester for use.
  • L-valine 3-(4-amino
  • Packing condition 1 cillin bottle inner package + aluminum plastic outsourcing
  • the polymorph of the present invention is very stable and suitable for use in pharmaceutical compositions. Moreover, the polymorph of the present invention is not easy to lift up, easy to collect, and not easy to cause waste during the pharmaceutical manufacturing process such as dispensing, and helps to protect the health of operators. It should be particularly noted that the reagents used in the preparation of the crystal form A of the present invention are environmentally friendly, non-toxic, easy to obtain, and have a high preparation yield.
  • the one used in this example is male Beagles, weighing 8.6-10.6 kg, were purchased from Beijing Max Biotechnology Co., Ltd. The test animals were all over 1 year old, and the animals were at least two weeks apart from the last test.
  • the three dogs adopt a crossover design, and the cleaning interval is at least three days.
  • the cleaning interval is at least three days.
  • NORA0310A4 di-p-toluenesulfonate
  • NORA0312 pomalidomide 4mg Oral capsules (POMALID, manufactured by Natco Pharma Limited).
  • One capsule is given by oral administration in each cycle, with 50mL of water to assist swallowing.
  • Test method Before administration, blood samples were collected at 0.5, 1, 2, 4, 6, 8, 10, 24, and 48 hours after administration, and the whole blood was collected in an anticoagulation tube containing EDTA-2K and stored on wet ice , And centrifuged at 1800 ⁇ g for 5 minutes at 4°C within 1 hour to obtain a plasma sample. The separated plasma samples will be added with 2% formic acid at a ratio of 4:1 and shaken evenly, immediately placed in dry ice for temporary storage and then transferred to the -20°C refrigerator. LC/MS/MS was used for detection, and the non-compartmental model of WinNonlin software was used to calculate the pharmacokinetic parameters of dogs after administration. The data are shown in Table-1 and Figure-5.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a polymorph of L-valine(3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl ester bis-p-tosylate, and the use of same as an immunomodulator.

Description

泊马度胺前体药物盐的多晶型物Polymorphs of pomalidomide prodrug salt 技术领域Technical field
本发明涉及医药领域，尤其涉及L-缬氨酸(3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲酯双对甲苯磺酸盐的多晶型物和包含上述多晶型物的药物组合物，及其在制备治疗癌症的药物中的应用。The present invention relates to the field of medicine, in particular to L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1- The polymorphs of phenyl)methyl bis-p-toluenesulfonate and pharmaceutical compositions containing the above polymorphs, and their use in the preparation of drugs for the treatment of cancer.
背景技术Background technique
泊马度胺由美国赛尔基因公司研发，并于2013年2月首次在美国获准上市。泊马度胺是继沙利度胺，来那度胺后第三个上市的同类免疫调节剂，能够增强T细胞和自然杀伤细胞介导的免疫反应，同时抑制单核细胞产生促炎性细胞因子(如TNF-α、IL-6等)。此外，泊马度胺能够抑制肿瘤细胞增生并诱导细胞凋亡，对来那度胺耐药的多发性骨髓瘤细胞株亦具有较强的增殖抑制作用。泊马度胺常见的不良反应有中性粒细胞减少，疲乏虚弱，贫血，便秘，腹泻，血小板减少，上呼吸道感染，背痛发热，还可能引起血栓，且可能导致胎儿出现严重的出生缺陷。根据文献报道，泊马度胺属于难溶性药物，测定其在纯化水，pH 6.8磷酸盐缓冲液，pH 4.5醋酸盐缓冲液和0.1mol/L盐酸中的溶解度，结果分别是17.8、17.0、18.7和18.9μg/mL。泊马度胺的低溶解度不仅增加了制剂工艺的难度，也限制了活性成分在胃肠道的溶出和吸收过程，进而影响口服生物利用度。Pomalidomide was developed by Xaar Gene Corporation and was approved for listing in the United States for the first time in February 2013. Pomalidomide is the third immunomodulator of its kind to be marketed after thalidomide and lenalidomide. It can enhance the immune response mediated by T cells and natural killer cells, while inhibiting monocytes from producing pro-inflammatory cells. Factors (such as TNF-α, IL-6, etc.). In addition, pomalidomide can inhibit tumor cell proliferation and induce cell apoptosis, and multiple myeloma cell lines resistant to lenalidomide also have a strong proliferation inhibitory effect. The common adverse reactions of pomalidomide include neutropenia, fatigue, weakness, anemia, constipation, diarrhea, thrombocytopenia, upper respiratory tract infection, backache and fever, and may also cause blood clots and may cause serious birth defects in the fetus. According to literature reports, pomalidomide is a poorly soluble drug. The solubility of pomalidomide in purified water, pH 6.8 phosphate buffer, pH 4.5 acetate buffer and 0.1 mol/L hydrochloric acid was determined to be 17.8, 17.0, 18.7 and 18.9 μg/mL. The low solubility of pomalidomide not only increases the difficulty of the preparation process, but also limits the dissolution and absorption process of the active ingredient in the gastrointestinal tract, thereby affecting the oral bioavailability.
PCT申请PCT/CN2017/098281提供的L-缬氨酸(3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲酯是一种泊马度胺前体药物，该化合物的结构如下结构式(I-1)所示：L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1 provided by PCT application PCT/CN2017/098281 -Yl) methyl ester is a pomalidomide prodrug, the structure of the compound is shown in the following structural formula (I-1):
Figure PCTCN2020072032-appb-000001
Figure PCTCN2020072032-appb-000001
式(I-1)结构是一种具有良好溶解度，且显著改善生物利用度的泊马度胺前体药物，在体内能快速代谢成泊马度胺发挥药效。但研究发现该结构稳定性较差，室温放置容易降解。而式(I-1)结构的双对甲苯磺酸盐，即L-缬氨酸(3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲酯双对甲苯磺酸盐具有改善的稳定性。The structure of formula (I-1) is a pomalidomide prodrug with good solubility and significantly improved bioavailability, which can be rapidly metabolized into pomalidomide in the body to exert its efficacy. However, studies have found that the structure has poor stability and is easily degraded when placed at room temperature. The bis-p-toluenesulfonate of formula (I-1) is L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6 -Dioxopiperidin-1-yl) methyl ester bis-p-toluenesulfonate has improved stability.
药用化合物存在多晶型现象，晶型的变化通常导致活性成分具有不同的熔点、溶解度、吸湿性、稳定性、生物活性等，这些均是影响药物制备的难易、储存稳定性、制剂难易和生物利用度等的重要因素。由于特定多晶型物具有特异性的热力学性质和稳定性，因此在制备的过程中，了解在各个剂型中应用的化合物的晶型是重要的，以保证生产过程应用相同形态的药物。因此，保证活性成分是单一的晶型或是一些晶型的已知混 合物是必要的。Pharmaceutical compounds have polymorphism, and the change of crystal form usually causes the active ingredients to have different melting points, solubility, hygroscopicity, stability, biological activity, etc., all of which affect the difficulty of drug preparation, storage stability, and difficulty in preparation. Important factors such as ease and bioavailability. Because specific polymorphs have specific thermodynamic properties and stability, it is important to understand the crystal forms of the compounds used in each dosage form during the preparation process to ensure that the same form of drugs is used in the production process. Therefore, it is necessary to ensure that the active ingredient is a single crystal form or a known mixture of some crystal forms.
药用化合物的新的多晶型物的发现提供了改善药物物理特性的机会，即扩展了物质的全部性质，从而可以更好地指导活性成分及其制剂的研究，因此本发明提供的L-缬氨酸(3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲酯盐的多晶型物在药物的制造及其它应用中有商业价值。The discovery of new polymorphic forms of medicinal compounds provides an opportunity to improve the physical properties of drugs, that is, to expand all the properties of the substance, which can better guide the research of active ingredients and their formulations. Therefore, the L- Polymorphs of valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl) methyl ester salt It has commercial value in drug manufacturing and other applications.
发明内容Summary of the invention
本发明的一个目的是提供式(I)所示L-缬氨酸(3-(4-氨基-1,3-二氧代异吲哚啉-2-An object of the present invention is to provide L-valine represented by formula (I) (3-(4-amino-1,3-dioxoisoindoline-2-
基)-2,6-二氧代哌啶-1-基)甲酯双甲苯磺酸盐的多晶型物(Yl)-2,6-dioxopiperidin-1-yl)methyl bis-toluenesulfonate polymorph
Figure PCTCN2020072032-appb-000002
Figure PCTCN2020072032-appb-000002
在本发明的第一方面，提供了L-缬氨酸(3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲酯双甲苯磺酸盐(式I)的多晶型物。In the first aspect of the present invention, L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine- Polymorph of 1-yl)methyl bistosylate (formula I).
在另一优选例中，所述多晶型物为晶型A，其中，该晶型A具有如下性质：In another preferred example, the polymorph is crystal form A, wherein the crystal form A has the following properties:
其使用Cu-Ka辐射，以度2θ表示的X-射线粉末衍射光谱在3.9±0.2，13.1±0.2，14.4±0.2，20.6±0.2处有峰。It uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed in degrees 2θ has peaks at 3.9±0.2, 13.1±0.2, 14.4±0.2, and 20.6±0.2.
在一更优选例中，所述晶型A还具有一个或多个选自下组的以度2θ表示的X-射线粉末衍射特征峰：7.1±0.2，13.6±0.2。In a more preferred example, the crystal form A further has one or more characteristic X-ray powder diffraction peaks expressed in degrees 2θ selected from the following group: 7.1±0.2, 13.6±0.2.
在一更优选例中，所述晶型A还具有一个或多个选自下组的以度2θ表示的X-射线粉末衍射特征峰：12.3±0.2，19.1±0.2，26.1±0.2，27.7±0.2。In a more preferred example, the crystal form A further has one or more characteristic X-ray powder diffraction peaks expressed in degrees 2θ selected from the following group: 12.3±0.2, 19.1±0.2, 26.1±0.2, 27.7± 0.2.
在另一优选例中，所述多晶型物为晶型A，其中，该晶型A具有如下性质：In another preferred example, the polymorph is crystal form A, wherein the crystal form A has the following properties:
其使用Cu-Ka辐射，以度2θ表示的X-射线粉末衍射光谱在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处有峰。It uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed in degrees 2θ is 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 There are peaks everywhere.
在另一优选例中，所述多晶型物为晶型A，其中所述晶型A具有基本如图1所示的粉末X射线衍射图谱。In another preferred embodiment, the polymorph is crystal form A, wherein the crystal form A has a powder X-ray diffraction pattern substantially as shown in FIG. 1.
在另一优选例中，所述多晶型物为晶型A，在加热速度为10℃/分的条件下，其中所述晶型A的差示热量扫描在183.57±2℃有最大吸热峰峰值。In another preferred example, the polymorph is crystal form A, and under the condition of a heating rate of 10°C/min, the differential heat scan of the crystal form A has a maximum endotherm at 183.57±2°C Peak-to-peak value.
在另一优选例中，所述多晶型物为晶型A，在加热速度为10℃/分的条件下，其中所述晶型A具有基本如图2所示的差热分析吸热曲线图。In another preferred example, the polymorph is crystal form A, and under the condition of a heating rate of 10°C/min, the crystal form A has a differential thermal analysis endothermic curve as shown in FIG. 2 Figure.
再一方面，本发明提供了一种晶型A的制备方法，包括In another aspect, the present invention provides a method for preparing crystal form A, including
(1)将式(I)所示化合物双对甲苯磺酸盐溶解于丙酮2-丁酮；和(1) Dissolving bis-p-toluenesulfonate of the compound represented by formula (I) in acetone 2-butanone; and
(2)将步骤(1)得到的反应体系在室温下搅拌，从而得到式(I)所示化合物双对甲苯磺酸盐的晶型A。(2) The reaction system obtained in step (1) is stirred at room temperature to obtain the crystal form A of the compound bis-p-toluenesulfonate represented by formula (I).
在一优选例中，所述晶型A的制备方法还包括：In a preferred example, the preparation method of the crystal form A further includes:
(3)干燥步骤(2)得到的固体。(3) Dry the solid obtained in step (2).
在一优选例中，所述晶型A在40℃下储存5天后的纯度变化小于0.2％；优选小于0.1％；更优选小于0.05％；或者In a preferred example, the purity of the crystal form A after storage at 40°C for 5 days is less than 0.2%; preferably less than 0.1%; more preferably less than 0.05%; or
在40℃下储存10天后的纯度变化小于0.3％；优选小于0.2％；更优选小于0.1％；或者The purity change after storage at 40°C for 10 days is less than 0.3%; preferably less than 0.2%; more preferably less than 0.1%; or
所述晶型A在60℃下储存5天后的纯度变化小于0.6％；优选小于0.3％；更优选小于0.05％；或者The purity of the crystal form A after storage at 60°C for 5 days is less than 0.6%; preferably less than 0.3%; more preferably less than 0.05%; or
在60℃下储存10天后的纯度变化小于1.5％；优选小于1.0％；更优选小于0.2％。The purity change after storage at 60°C for 10 days is less than 1.5%; preferably less than 1.0%; more preferably less than 0.2%.
在另一优选例中，所述多晶型物为晶型B，其中，该晶型B具有如下性质：In another preferred embodiment, the polymorph is crystal form B, wherein the crystal form B has the following properties:
其使用Cu-Ka辐射，以度2θ表示的X-射线粉末衍射光谱在4.0±0.2，8.9±0.2，14.6±0.2，19.3±0.2处有峰。It uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed in degrees 2θ has peaks at 4.0±0.2, 8.9±0.2, 14.6±0.2, and 19.3±0.2.
在一更优选例中，所述晶型B还具有一个或多个选自下组的以度2θ表示的X-射线粉末衍射特征峰：11.9±0.2，20.8±0.2。In a more preferred example, the crystal form B further has one or more characteristic X-ray powder diffraction peaks expressed in degrees 2θ selected from the group consisting of: 11.9±0.2, 20.8±0.2.
在一更优选例中，所述晶型B还具有一个或多个选自下组的以度2θ表示的X-射线粉末衍射特征峰：7.2±0.2，12.3±0.2，13.2±0.2，23.3±0.2，27.3±0.2。In a more preferred example, the crystal form B further has one or more characteristic X-ray powder diffraction peaks expressed in degrees 2θ selected from the group consisting of: 7.2±0.2, 12.3±0.2, 13.2±0.2, 23.3± 0.2, 27.3±0.2.
在另一优选例中，所述多晶型物为晶型B，其中，该晶型B具有如下性质：In another preferred embodiment, the polymorph is crystal form B, wherein the crystal form B has the following properties:
其使用Cu-Ka辐射，以度2θ表示的X-射线粉末衍射光谱在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处有峰。It uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed in degrees 2θ is 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 There are peaks everywhere.
在另一优选例中，所述多晶型物为晶型B，其中，该晶型B具有如下性质：In another preferred embodiment, the polymorph is crystal form B, wherein the crystal form B has the following properties:
其使用Cu-Ka辐射，以度2θ表示的X-射线粉末衍射光谱在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处有峰。It uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed in degrees 2θ is 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 there is a peak.
在另一优选例中，所述多晶型物为晶型B，其中所述晶型B具有基本如图3所示的粉末X射线衍射图谱。In another preferred embodiment, the polymorph is crystal form B, wherein the crystal form B has a powder X-ray diffraction pattern substantially as shown in FIG. 3.
在另一优选例中，所述多晶型物为晶型B，在加热速度为10℃/分的条件下，其中所述晶型B的差示热量扫描在177.99±2℃有最大吸热峰峰值。In another preferred example, the polymorph is crystal form B, and under the condition of a heating rate of 10°C/min, the differential heat scan of the crystal form B has a maximum endotherm at 177.99±2°C Peak-to-peak value.
在另一优选例中，所述多晶型物为晶型B，在加热速度为10℃/分的条件下，其中所述晶型B具有基本如图4所示的差热分析吸热曲线图。In another preferred example, the polymorph is crystalline form B, and under the condition of a heating rate of 10°C/min, the crystalline form B has a differential thermal analysis endothermic curve substantially as shown in FIG. 4 Figure.
再一方面，本发明提供了一种晶型B的制备方法，包括In another aspect, the present invention provides a method for preparing crystal form B, including
(1)将式(I)所示化合物双对甲苯磺酸盐溶解于1,4-二氧六环；和(1) Dissolving the compound bis-p-toluenesulfonate of formula (I) in 1,4-dioxane; and
(2)将步骤(1)得到的反应体系在室温下搅拌，从而得到式(I)所示化合物双对甲苯磺酸盐的晶型B。(2) The reaction system obtained in step (1) is stirred at room temperature to obtain the crystalline form B of the compound bis-p-toluenesulfonate represented by formula (I).
在一优选例中，所述晶型B的制备方法还包括：In a preferred example, the preparation method of the crystal form B further includes:
(3)干燥步骤(2)得到的固体。(3) Dry the solid obtained in step (2).
在本发明的第二方面，提供了本发明多晶型物的用途，用于制备治疗癌症的药物中的应用。In the second aspect of the present invention, there is provided the use of the polymorphs of the present invention for the preparation of drugs for treating cancer.
在另一优选例中，所述的多晶型物用于制备治疗多发性骨髓瘤，***癌的药物。In another preferred embodiment, the polymorph is used to prepare a medicine for treating multiple myeloma and prostate cancer.
在本发明的第三方面，提供了一种药物组合物，其含有L-缬氨酸(3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲酯双对甲苯磺酸盐的多晶型物和药用载体。In the third aspect of the present invention, there is provided a pharmaceutical composition containing L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2, The polymorph and pharmaceutical carrier of 6-dioxopiperidin-1-yl) methyl ester bis-p-toluenesulfonate.
在另一优选例中，药物组合物含有L-缬氨酸(3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲酯双对甲苯磺酸盐的晶型A和药用载体。In another preferred embodiment, the pharmaceutical composition contains L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine The crystalline form A of -1-yl) methyl ester bis-p-toluenesulfonate and a pharmaceutical carrier.
在另一优选例中，药物组合物含有L-缬氨酸(3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲酯双对甲苯磺酸盐的晶型B和药用载体。In another preferred embodiment, the pharmaceutical composition contains L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine The crystalline form B of -1-yl) methyl ester bis-p-toluenesulfonate and a pharmaceutical carrier.
在本发明的第四方面，提供了药物组合物用于制备治疗癌症的药物中的应用。In the fourth aspect of the present invention, there is provided the application of the pharmaceutical composition for preparing a medicine for treating cancer.
在另一优选例中，所述的药物组合物用于制备治疗多发性骨髓瘤，***癌的药物。In another preferred embodiment, the pharmaceutical composition is used to prepare a medicine for treating multiple myeloma and prostate cancer.
在本发明的第五方面，提供了一种结晶组合物，其中L-缬氨酸(3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲酯双对甲苯磺酸盐晶型A的结晶组合物是指，组合物中晶型A占组合物重量的50％以上，优选在80％以上，更优选在90％以上，最优选在95％以上，该结晶组合物可以含有少量L-缬氨酸(3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲酯双对甲苯磺酸盐的其他结晶或无定形形式，包括但不限于晶型B或无定形物；其中L-缬氨酸(3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲酯双对甲苯磺酸盐晶型B的结晶组合物是指，组合物中晶型B占组合物重量的50％以上，优选在80％以上，更优选在90％以上，最优选在95％以上，该结晶组合物可以含有少量L-缬氨酸(3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲酯双对甲苯磺酸盐的其他结晶或无定形形式，包括但不限于晶型A或无定形物。In the fifth aspect of the present invention, there is provided a crystalline composition, wherein L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6 The crystalline composition of dioxopiperidin-1-yl) methyl ester bis-p-toluenesulfonate crystal form A means that the crystal form A in the composition accounts for more than 50% of the weight of the composition, preferably more than 80%, More preferably 90% or more, most preferably 95% or more, the crystalline composition may contain a small amount of L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl) Other crystalline or amorphous forms of -2,6-dioxopiperidin-1-yl) methyl ester bis-p-toluenesulfonate, including but not limited to crystalline form B or amorphous; wherein L-valine ( 3-(4-Amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl) methyl ester bis-p-toluenesulfonate crystal form B The crystalline composition means that the crystal form B in the composition accounts for more than 50% of the weight of the composition, preferably more than 80%, more preferably more than 90%, most preferably more than 95%, and the crystalline composition may contain a small amount of L- Valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl) methyl ester bis-p-toluenesulfonate Other crystalline or amorphous forms of, including but not limited to crystalline form A or amorphous.
在本发明的第六方面，提供了所述的结晶组合物用于制备治疗癌症的药物中的应用。In the sixth aspect of the present invention, there is provided the application of the crystalline composition in the preparation of drugs for treating cancer.
在另一优选例中，所述的癌症是多发性骨髓瘤或***癌。In another preferred example, the cancer is multiple myeloma or prostate cancer.
在本发明的第七方面，提供了含有所述多晶型物、结晶组合物、药物组合物的用于治疗癌症的药物。In the seventh aspect of the present invention, there is provided a medicine for treating cancer containing the polymorph, crystalline composition, and pharmaceutical composition.
在一优选例中，所述癌症为多发性骨髓瘤或***癌。In a preferred example, the cancer is multiple myeloma or prostate cancer.
在本发明的第八方面，提供了癌症的治疗方法，所述方法包括将所述的多晶型物、结晶组合物、药物组合物给予需要治疗癌症的对象。In the eighth aspect of the present invention, a method for treating cancer is provided, the method comprising administering the polymorph, crystalline composition, or pharmaceutical composition to a subject in need of cancer treatment.
在一优选例中，所述癌症为多发性骨髓瘤或***癌。In a preferred example, the cancer is multiple myeloma or prostate cancer.
本发明的多晶型物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。The method of administration of the polymorph or pharmaceutical composition of the present invention is not particularly limited. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), And topical administration.
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性成分与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分中的至少一种混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。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 mixed with at least one of the following ingredients: (a) filler or extender Solvents such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; c) Humectants, for example, glycerin; (d) Disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) Soothing agents, for example Paraffin wax; (f) absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, For example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性成分也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of active ingredients in such compositions may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active ingredient may also be formed into a microcapsule form with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredients, the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、娇味剂和香料。In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
除了活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。In addition to the active ingredients, the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。The composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
用于局部给药的本发明的多晶型物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。The dosage form of the polymorph of the present invention for topical administration includes ointment, powder, patch, propellant and inhalant. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
本发明的多晶型物可以单独给药，或者与其他药学上可接受的化合物联合给药。The polymorphs of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
使用药物组合物时，是将安全有效量的本发明的多晶型物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药 剂量通常为1～200mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。When the pharmaceutical composition is used, a safe and effective amount of the polymorph of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage when administered is a pharmaceutically effective dosage that is considered to be an effective dosage for a 60kg body weight. In general, the daily dose is usually 1 to 200 mg. Of course, the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skill range of a skilled physician.
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
本发明描述的化合物包括两个不对称中心，且因此可以存在多种异构体形式，例如，对映异构体和/或非对映异构体形式。例如，本发明描述的化合物可为单独的对映异构体、非对映异构体或几何异构体，或者可为立体异构体的混合物的形式，包括外消旋混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来制备。本发明另外包括作为基本上不含其它异构体的单独异构体、或者作为多种异构体的混合物的本文描述的化合物。The compounds described in the present invention include two asymmetric centers, and therefore may exist in various isomeric forms, for example, enantiomeric and/or diastereomeric forms. For example, the compounds described in the present invention may be individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and enriched one A mixture of one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers can be separated by Prepared by asymmetric synthesis. The present invention additionally includes the compounds described herein as individual isomers substantially free of other isomers, or as a mixture of multiple isomers.
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素，任选地进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括 12C、 13C和 14C，氢的同位素包括氕(H)、氘(D，又称为重氢)、氚(T，又称为超重氢)，氧的同位素包括 16O、 17O和 18O，硫的同位素包括 32S、 33S、 34S和 36S，氮的同位素包括 14N和 15N，氟的同位素包括 19F，氯的同位素包括 35Cl和 37Cl，溴的同位素包括 79Br和 81Br。 The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur, Nitrogen or halogen, optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also known as Heavy hydrogen), tritium (T, also known as super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, and nitrogen isotopes include 14 N And 15 N, the isotopes of fluorine include 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, and the isotopes of bromine include 79 Br and 81 Br.
本发明中“具有基本如图1所示的粉末X射线衍射图谱”是指粉末X-射线衍射光谱中至少50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少99％的峰出现在所给出的粉末X射线衍射图谱中。In the present invention, "having a powder X-ray diffraction pattern substantially as shown in Figure 1" means at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the powder X-ray diffraction spectrum , Or at least 95%, or at least 99% of the peaks appear in the powder X-ray diffraction pattern given.
需要说明的是，在XRD中，由结晶化合物得到的衍射谱图对于特定的晶型往往是特征性的，其中谱带(尤其是在低角度)的相对强度可能会因为结晶条件、粒径和其它测定条件的差异而产生的优势取向效果而变化。因此，衍射峰的相对强度对所针对的晶型并非是特征性的，判断是否与已知的晶型相同时，更应该注意的是峰的相对位置而不是它们的相对强度。对于同种化合物的同种晶型，其XRD谱图在整体上具有相似性，表征峰位置的2θ角误差一般在±2％之内，例如由于分析样品时温度的变化、样品移动或仪器的标定等，峰的位置可能移动；相对强度误差可较大，但变化趋势一致。还应指出的是，在混合物的鉴定中，由于含量下降等因素会造成部分衍射线的缺失，此时，无需依赖高纯试样中观察到的全部谱带，甚至几条谱带也可能对给定的结晶是特征性的。It should be noted that in XRD, the diffraction spectrum obtained from the crystalline compound is often characteristic for a specific crystal form, and the relative intensity of the band (especially at low angles) may be affected by the crystallization conditions, particle size and The effect of the dominant orientation produced by the difference of other measurement conditions varies. Therefore, the relative intensities of the diffraction peaks are not characteristic of the crystal form. When judging whether they are the same as the known crystal form, more attention should be paid to the relative positions of the peaks rather than their relative intensities. For the same crystal form of the same compound, the XRD spectra are similar in the whole, and the 2θ angle error of the peak position is generally within ±2%, for example, due to temperature changes, sample movement or instrumental changes during sample analysis. For calibration, the position of the peak may move; the relative intensity error may be large, but the change trend is consistent. It should also be pointed out that in the identification of the mixture, some of the diffraction lines will be missing due to factors such as the decrease in content. At this time, there is no need to rely on all the bands observed in the high-purity sample, and even a few bands may be incorrect. The given crystal is characteristic.
同样需要说明的是，差示热量扫描分析中的吸收峰是本发明晶型具有的固有物性，但在实际的测定中，除了测定误差外，有时会由于混入可容许的量的杂质等原因导致熔点发生变动，这种可能性也是不能否定的。因此，本领域技术人员能够充分理解本发明中的吸热峰温度的实测值可以以何种程度发生变动，举例来说，可以设想的误差是，某些情况下为±5℃左右，优选地为±3℃左右，更优选地为±2℃左右，最优选地为±1℃左右。It should also be noted that the absorption peak in the differential thermal scanning analysis is an inherent physical property of the crystal form of the present invention, but in actual measurement, in addition to measurement errors, it may sometimes be caused by the mixing of allowable amounts of impurities. The melting point changes, this possibility is also undeniable. Therefore, those skilled in the art can fully understand to what extent the actual measured value of the endothermic peak temperature in the present invention can be changed. For example, the error that can be assumed is about ±5°C in some cases, preferably It is about ±3°C, more preferably about ±2°C, and most preferably about ±1°C.
本文所述的对象包括但不限于人和其它哺乳动物；优选人。The subjects described herein include but are not limited to humans and other mammals; humans are preferred.
本发明使用的分析方法：Analysis method used in the present invention:
1)X射线粉末衍射1) X-ray powder diffraction
测定晶型的X射线粉末衍射的方法在本领域中是已知的。例如使用Bruker D8advance衍射仪，采用Cu-Ka填充管(40kV,40mA)作为具有广角测角仪的X射线源，以2.4°/分的扫描色的，获取图谱。The method of determining the X-ray powder diffraction of the crystal form is known in the art. For example, a Bruker D8advance diffractometer is used, a Cu-Ka filled tube (40kV, 40mA) is used as an X-ray source with a wide-angle goniometer, and the spectrum is acquired at a scanning color of 2.4°/min.
2)差示扫描量热法2) Differential scanning calorimetry
DSC测定方法在本领域中是已知的。例如使用Mettler DSC 3+完成差热分析。以10℃/分的升温速率，从25℃升温至250℃，获取晶型的DSC扫描图谱。DSC measurement methods are known in the art. For example, use Mettler DSC 3+ to complete differential thermal analysis. The temperature was increased from 25°C to 250°C at a heating rate of 10°C/min to obtain the DSC scan pattern of the crystal form.
本发明的优点：Advantages of the invention:
1.本发明的多晶型物非常稳定，从而适合储存和运输，进而用于制备药物组合物；1. The polymorphs of the present invention are very stable, so they are suitable for storage and transportation, and then used to prepare pharmaceutical compositions;
2.本发明的多晶型物具备不易扬起的特性，从而在分装等药品制造过程中，易收集，不易造成浪费，并有助于保护操作人员的身体健康；2. The polymorph of the present invention has the characteristic of being difficult to raise, so that it is easy to collect during the pharmaceutical manufacturing process such as dispensing, and is not easy to cause waste, and helps protect the health of operators;
3.本发明的多晶型物，特别是晶型A的制备过程中使用的试剂环保，无毒性，且容易获得，制备收率高。3. The polymorphs of the present invention, especially the reagents used in the preparation of crystal form A, are environmentally friendly, non-toxic, easy to obtain, and have a high preparation yield.
附图说明Description of the drawings
图1显示了晶型A的粉末X-射线粉末衍射光谱；Figure 1 shows the powder X-ray powder diffraction spectrum of crystal form A;
图2显示了晶型A的差热分析图谱；Figure 2 shows the differential thermal analysis spectrum of crystal form A;
图3显示了晶型B的粉末X-射线粉末衍射光谱；Figure 3 shows the powder X-ray powder diffraction spectrum of crystal form B;
图4显示了晶型B的差热分析图谱；Figure 4 shows the differential thermal analysis spectrum of crystal form B;
图5显示了给药后犬血浆中药物浓度和时间的关系。Figure 5 shows the relationship between drug concentration in dog plasma and time after administration.
具体实施方式detailed description
下面结合具体实施，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。本发明所用原料若非特别说明，均市售可得。The present invention will be further explained below in conjunction with specific implementation. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods that do not indicate specific conditions in the following examples usually follow the conventional conditions or the conditions recommended by the manufacturer. The raw materials used in the present invention are all commercially available unless otherwise specified.
实施例1.L-缬氨酸(3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲酯的制备(Compound 1)的制备Example 1. L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl) methyl ester Preparation of (Compound 1) Preparation
Figure PCTCN2020072032-appb-000003
Figure PCTCN2020072032-appb-000003
Step1：氮气保护下，向1000mL三颈反应瓶中加入S.M.B(20g，73.2mmol，1.00eq)和DMF(400ml)，电磁搅拌。随后缓慢加入氢化钠(3.5g，87.5mmol，1.2eq)，继续搅拌30min后，加入碘化钾(12g，72.2mmol，0.99eq)和TBAB(四丁基溴化铵)(3.52g，10.9 mmol，0.15eq)，搅拌15min后，将S.M.1(23.8g，72.8mmol，0.99eq)加入，搅拌12h。停止反应，将反应体系倒入2L水中，搅拌1h，有固体析出，过滤，得到黄色固体滤饼，滤饼以500ml DCM(二氯甲烷)洗涤，分液，取有机相减压浓缩，柱层析(PE:EA＝1.5:1)，得13.20g黄色固体产品，收率35.8％.Step1: Under the protection of nitrogen, add S.M.B (20g, 73.2mmol, 1.00eq) and DMF (400ml) to a 1000mL three-necked reaction flask, and stir electromagnetically. Then slowly add sodium hydride (3.5g, 87.5mmol, 1.2eq), continue to stir for 30min, add potassium iodide (12g, 72.2mmol, 0.99eq) and TBAB (tetrabutylammonium bromide) (3.52g, 10.9 mmol, 0.15 eq), after stirring for 15 min, SM1 (23.8 g, 72.8 mmol, 0.99 eq) was added and stirred for 12 h. Stop the reaction, pour the reaction system into 2L of water, stir for 1h, solids precipitate out, filter to obtain a yellow solid filter cake, the filter cake is washed with 500ml DCM (dichloromethane), separation, take the organic phase and concentrate under reduced pressure, column layer Analysis (PE:EA=1.5:1), 13.20g yellow solid product was obtained, the yield was 35.8%.
Step2：氮气保护下，向100ml三颈反应瓶中加入Int 1-01(500mg，1mmol，1.00eq)，DCM 5ml，室温搅拌10min后，一次性加入HCl/EA(10ml，10mmol，10.0eq)，继续搅拌40min。停止反应，过滤干燥得380mg黄色固体产物，收率86.9％Step2: Under the protection of nitrogen, add Int 1-01 (500mg, 1mmol, 1.00eq), DCM 5ml to a 100ml three-necked reaction flask, stir at room temperature for 10min, add HCl/EA (10ml, 10mmol, 10.0eq) at once, Continue to stir for 40 minutes. The reaction was stopped, filtered and dried to obtain 380 mg of yellow solid product with a yield of 86.9%
HPLC:97.05％HPLC: 97.05%
LCMS:403.2(M+H-HCl)LCMS: 403.2(M+H-HCl)
1H NMR(400MHz,DMSO)δ8.56-8.51(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). 1 H NMR(400MHz,DMSO)δ8.56-8.51(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).
Step3：200mL三口瓶中，加入4g L-缬氨酸(3-(4-(氨基)-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲酯盐酸盐(Int 1-02)，40mL乙酸乙酯，冰水浴条件下搅拌5min，然后倒入30mL冰水，继续加入30mL饱和碳酸氢钠，搅拌5-10min，水相再用乙酸乙酯(40mL)萃取一次，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，得L-缬氨酸(3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲酯3g备用。Step3: Add 4g L-valine (3-(4-(amino)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine to a 200mL three-necked flask -1-yl) methyl ester hydrochloride (Int 1-02), 40mL ethyl acetate, stir for 5min under ice-water bath, then pour 30mL ice water, continue to add 30mL saturated sodium bicarbonate, stir for 5-10min, water The phases were extracted with ethyl acetate (40 mL) once, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain L-valine (3-(4-amino-1,3-dioxoiso) 3g of indolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl ester for use.
实施例2多晶型物的制备Example 2 Preparation of polymorphs
将1.0g的L-缬氨酸(3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲酯溶解于50mL乙酸乙酯中，滴加对甲苯磺酸一水合物的乙酸乙酯溶液(1.03g/50mL)，约15分钟滴加完毕。室温搅拌过夜。过滤，滤饼真空干燥。得到双对甲苯磺酸盐1.0g。经图谱分析确认L-缬氨酸(3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲酯与对甲苯磺酸的摩尔比例为1:2。1.0 g of L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl) methyl ester Dissolve in 50mL ethyl acetate, add dropwise the ethyl acetate solution of p-toluenesulfonic acid monohydrate (1.03g/50mL), and the addition is completed in about 15 minutes. Stir at room temperature overnight. Filter and vacuum dry the filter cake. 1.0 g of bis-p-toluenesulfonate was obtained. Spectral analysis confirmed that L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl) methyl ester The molar ratio with p-toluenesulfonic acid is 1:2.
1H NMR(400MHz,DMSO)δ8.33(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). 1 H NMR(400MHz,DMSO)δ8.33(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晶型A的制备方法和固态表征：2.1 Preparation method and solid state characterization of crystal form A:
取上述制备获得的双盐49.1mg，加入到反应瓶中，再加入丙酮2-丁酮0.8mL，反应体系再于室温下搅拌72h。离心，弃去上清液，固体40度下真空干燥，得产品35mg(收率71％)。49.1 mg of the double salt obtained by the above preparation was added to the reaction flask, and 0.8 mL of acetone 2-butanone was added, and the reaction system was stirred at room temperature for 72 hours. After centrifugation, the supernatant was discarded, and the solid was dried under vacuum at 40 degrees to obtain 35 mg of product (yield 71%).
利用X-射线粉末衍射和差示扫描量热法对晶型A进行了固态表征，其固态表征参数及图谱如下表和附图所示。X-ray powder diffraction and differential scanning calorimetry were used to perform solid state characterization of crystal form A. The solid state characterization parameters and patterns are shown in the following table and drawings.
Figure PCTCN2020072032-appb-000004
Figure PCTCN2020072032-appb-000004
2.2晶型B的制备方法和固态表征：2.2 Preparation method and solid state characterization of crystal form B:
取上述制备获得的双盐49.1mg，加入到反应瓶中，再加入1,4-二氧六环1mL，反应体系于室温下搅拌72h。离心，弃去上清液，固体40度下真空干燥，得产品10mg(收率20％)。Take 49.1 mg of the double salt obtained by the above preparation and add it to the reaction flask, then add 1 mL of 1,4-dioxane, and the reaction system is stirred at room temperature for 72 hours. After centrifugation, the supernatant was discarded, and the solid was dried under vacuum at 40 degrees to obtain 10 mg of product (yield 20%).
利用X-射线粉末衍射和差示扫描量热法对晶型B进行了固态表征，其固态表征参数及图谱如下表和附图所示。X-ray powder diffraction and differential scanning calorimetry were used to perform solid-state characterization of crystal form B. The solid-state characterization parameters and patterns are shown in the following table and drawings.
Figure PCTCN2020072032-appb-000005
Figure PCTCN2020072032-appb-000005
实施例3.多晶型物的稳定性Example 3. Stability of polymorphs
在40℃和60℃的试验条件下，取适量晶型A储存1-10天。多批次实验的结果如下所示：Under the test conditions of 40°C and 60°C, take an appropriate amount of crystal form A and store it for 1-10 days. The results of the multi-batch experiment are as follows:
Figure PCTCN2020072032-appb-000006
Figure PCTCN2020072032-appb-000006
Figure PCTCN2020072032-appb-000007
Figure PCTCN2020072032-appb-000007
包装条件1：西林瓶内包+铝塑外包Packing condition 1: cillin bottle inner package + aluminum plastic outsourcing
从以上结果可以看出，晶型A十分稳定；且相比较新制备的(0天)晶型A而言，纯度基本没有变化，始终在98％以上。From the above results, it can be seen that the crystal form A is very stable; and compared with the newly prepared (0 day) crystal form A, the purity is basically unchanged, always above 98%.
因此，本发明所述的多晶型物非常稳定，适合用于药物组合物。而且本发明的多晶型物在分装等药品制造过程中，不易扬起，易收集，不易造成浪费，有助于保护操作人员的身体健康。特别需要注意的是，本发明的晶型A制备过程中使用的试剂环保，无毒性，且容易获得，制备收率高。Therefore, the polymorph of the present invention is very stable and suitable for use in pharmaceutical compositions. Moreover, the polymorph of the present invention is not easy to lift up, easy to collect, and not easy to cause waste during the pharmaceutical manufacturing process such as dispensing, and helps to protect the health of operators. It should be particularly noted that the reagents used in the preparation of the crystal form A of the present invention are environmentally friendly, non-toxic, easy to obtain, and have a high preparation yield.
实施例4犬的药动学数据Example 4 Pharmacokinetic data of dogs
本实施例中所使用的为雄性
Figure PCTCN2020072032-appb-000008
比格犬，体重8.6-10.6kg，购自北京玛斯生物技术有限公司，试验动物皆大于1岁，动物距离上次试验至少有两周以上的间隔。 The one used in this example is male
Figure PCTCN2020072032-appb-000008
Beagles, weighing 8.6-10.6 kg, were purchased from Beijing Max Biotechnology Co., Ltd. The test animals were all over 1 year old, and the animals were at least two weeks apart from the last test.
三只犬采用交叉的设计，清洗间隔至少三天以上，轮流给药NORA0310A4(双对甲苯磺酸盐)10mg口服胶囊(相当于3.7mg的泊马度胺)和NORA0312(泊马度胺)4mg口服胶囊(POMALID,由Natco Pharma limited生产)。各周期以口服投药的方式给予一颗胶囊，配合50mL的水协助吞咽。The three dogs adopt a crossover design, and the cleaning interval is at least three days. Take turns to administer NORA0310A4 (di-p-toluenesulfonate) 10mg oral capsules (equivalent to 3.7mg pomalidomide) and NORA0312 (pomalidomide) 4mg Oral capsules (POMALID, manufactured by Natco Pharma Limited). One capsule is given by oral administration in each cycle, with 50mL of water to assist swallowing.
试验方法：给药前，给药后0.5、1、2、4、6、8、10、24和48小时采集血样，采入含有EDTA-2K的抗凝管中的全血于湿冰上存放，并在1小时内于1800×g，4℃下离心5分钟来获得血浆样品。分离取得的血浆样品会以4:1的比例加入2％甲酸摇荡均匀，立即放在干冰中暂存然后转移至-20℃冰箱中。采用LC/MS/MS进行检测，利用软件WinNonlin的非室模型计算犬给药后的药代动力学参数，数据如表-1所示，图-5所示。Test method: Before administration, blood samples were collected at 0.5, 1, 2, 4, 6, 8, 10, 24, and 48 hours after administration, and the whole blood was collected in an anticoagulation tube containing EDTA-2K and stored on wet ice , And centrifuged at 1800×g for 5 minutes at 4°C within 1 hour to obtain a plasma sample. The separated plasma samples will be added with 2% formic acid at a ratio of 4:1 and shaken evenly, immediately placed in dry ice for temporary storage and then transferred to the -20℃ refrigerator. LC/MS/MS was used for detection, and the non-compartmental model of WinNonlin software was used to calculate the pharmacokinetic parameters of dogs after administration. The data are shown in Table-1 and Figure-5.
表1Table 1
Figure PCTCN2020072032-appb-000009
Figure PCTCN2020072032-appb-000009
结论：由上述试验结果可知，各组给药后，在体内均只检出泊马度胺，说明它们进入体内后均迅速代谢为泊马度胺。在相近的给药剂量下，本发明盐相比泊马度胺，C max值升高4倍以上，AUC last升高1.5倍以上，表明本发明的盐与泊马度胺相比具有更好的口服生物利用度。 Conclusion: It can be seen from the above test results that after administration of each group, only pomalidomide was detected in the body, indicating that they were rapidly metabolized to pomalidomide after entering the body. At similar dosages, compared with pomalidomide, the Cmax value of the salt of the present invention increased by more than 4 times, and the AUC last increased by more than 1.5 times, indicating that the salt of the present invention has better properties than pomalidomide. Oral bioavailability.
以上所述仅是本发明的优选实施方式，应当指出，对于本领域技术的普通技术人员 来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。The above are only the preferred embodiments of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications are also It should be regarded as the protection scope of the present invention.

Claims (20)

  1. 一种式(I)所示化合物双对甲苯磺酸盐的多晶型物，A polymorph of the compound bis-p-toluenesulfonate of formula (I),
    Figure PCTCN2020072032-appb-100001
    Figure PCTCN2020072032-appb-100001
  2. 如权利要求1所述的多晶型物，其特征在于，所述多晶型物为L-缬氨酸(3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲酯双对甲苯磺酸盐的晶型A，其中，该晶型A具有如下性质：The polymorph of claim 1, wherein the polymorph is L-valine (3-(4-amino-1,3-dioxoisoindoline-2- (2,6-dioxopiperidin-1-yl)methyl bis-p-toluenesulfonate in the crystal form A, wherein the crystal form A has the following properties:
    其使用Cu-Ka辐射，以度2θ表示的X-射线粉末衍射光谱在3.9±0.2，13.1±0.2，14.4±0.2，20.6±0.2处有峰。It uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed in degrees 2θ has peaks at 3.9±0.2, 13.1±0.2, 14.4±0.2, and 20.6±0.2.
  3. 如权利要求2所述的多晶型物，其特征在于，所述多晶型物为晶型A，其中所述晶型A还具有一个或多个选自下组的以度2θ表示的X-射线粉末衍射特征峰：7.1±0.2，13.6±0.2。The polymorph according to claim 2, wherein the polymorph is crystal form A, wherein the crystal form A further has one or more selected from the group consisting of X expressed in degrees 2θ Characteristic peaks of -ray powder diffraction: 7.1±0.2, 13.6±0.2.
  4. 如权利要求3所述的多晶型物，其特征在于，所述多晶型物为晶型A，其中所述晶型A还具有一个或多个选自下组的以度2θ表示的X-射线粉末衍射特征峰：12.3±0.2，19.1±0.2，26.1±0.2，27.7±0.2。The polymorph of claim 3, wherein the polymorph is a crystal form A, wherein the crystal form A further has one or more selected from the group consisting of X expressed in degrees 2θ -Ray powder diffraction characteristic peaks: 12.3 ± 0.2, 19.1 ± 0.2, 26.1 ± 0.2, 27.7 ± 0.2.
  5. 如权利要求2所述的多晶型物，其特征在于，所述多晶型物为晶型A，其中所述晶型A具有基本如图1所示的粉末X射线衍射图谱。3. The polymorph of claim 2, wherein the polymorph is crystal form A, wherein the crystal form A has a powder X-ray diffraction pattern substantially as shown in FIG.
  6. 如权利要求1-5中任一项所述的多晶型物，其特征在于，所述多晶型物为晶型A，在加热速度为10℃/分的条件下，其中所述晶型A的差示热量扫描在183.57±2℃有最大吸热峰峰值。The polymorph according to any one of claims 1 to 5, wherein the polymorph is crystal form A, and the heating rate is 10°C/min, wherein the crystal form The differential heat scan of A has the maximum endothermic peak at 183.57±2℃.
  7. 如权利要求6所述的多晶型物，其特征在于，所述多晶型物为晶型A，在加热速度为10℃/分的条件下，其中所述晶型A具有基本如图2所示的差热分析吸热曲线图。The polymorph according to claim 6, wherein the polymorph is crystal form A, and under the condition of a heating rate of 10°C/min, wherein the crystal form A has a shape substantially as shown in Fig. 2 The differential thermal analysis endothermic graph shown.
  8. 如权利要求1所述的多晶型物，其特征在于，所述多晶型物为L-缬氨酸(3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲酯双对甲苯磺酸盐的晶型B，其中，该晶型B具有如下性质：The polymorph of claim 1, wherein the polymorph is L-valine (3-(4-amino-1,3-dioxoisoindoline-2- (Yl)-2,6-dioxopiperidin-1-yl)methyl bis-p-toluenesulfonate crystal form B, wherein the crystal form B has the following properties:
    其使用Cu-Ka辐射，以度2θ表示的X-射线粉末衍射光谱在4.0±0.2，8.9±0.2，14.6±0.2，19.3±0.2处有峰。It uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed in degrees 2θ has peaks at 4.0±0.2, 8.9±0.2, 14.6±0.2, and 19.3±0.2.
  9. 如权利要求8所述的多晶型物，其特征在于，所述多晶型物为晶型B，其中所述晶型B还具有一个或多个选自下组的以度2θ表示的X-射线粉末衍射特征峰：11.9±0.2，20.8±0.2处有峰。The polymorph according to claim 8, wherein the polymorph is crystal form B, wherein the crystal form B further has one or more selected from the group consisting of X expressed in degrees 2θ -Ray powder diffraction characteristic peaks: 11.9±0.2, with peaks at 20.8±0.2.
  10. 如权利要求9所述的多晶型物，其特征在于，所述多晶型物为晶型B，其中所述晶型B还具有一个或多个选自下组的以度2θ表示的X-射线粉末衍射特征峰：7.2±0.2，12.3±0.2，13.2±0.2，23.3±0.2，27.3±0.2The polymorph according to claim 9, wherein the polymorph is crystal form B, wherein the crystal form B further has one or more selected from the group consisting of X expressed in degrees 2θ -Ray powder diffraction characteristic peaks: 7.2±0.2, 12.3±0.2, 13.2±0.2, 23.3±0.2, 27.3±0.2
  11. 如权利要求8所述的多晶型物，其特征在于，所述多晶型物为晶型B，其中所述晶型B具有基本如图3所示的粉末X射线衍射图谱。The polymorph according to claim 8, wherein the polymorph is crystal form B, wherein the crystal form B has a powder X-ray diffraction pattern substantially as shown in FIG. 3.
  12. 如权利要求8-11中任一项所述的多晶型物，其特征在于，所述多晶型物为晶型B，在加热速度为10℃/分的条件下，其中所述晶型B的差示热量扫描在177.99±2℃有最大吸热峰峰值。The polymorph according to any one of claims 8-11, wherein the polymorph is crystal form B, and the heating rate is 10°C/min, wherein the crystal form The differential heat scan of B has the maximum endothermic peak at 177.99±2℃.
  13. 如权利要求12所述的多晶型物，其特征在于，所述多晶型物为晶型B，在加热速度为10℃/分的条件下，其中所述晶型B具有基本如图4所示的差热分析吸热曲线图。The polymorph of claim 12, wherein the polymorph is crystal form B, and under the condition of a heating rate of 10° C./min, wherein the crystal form B has a shape substantially as shown in FIG. 4 The differential thermal analysis endothermic graph shown.
  14. 结晶组合物，其中权利要求1-13中任意一项所述的L-缬氨酸(3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲酯双对甲苯磺酸盐的多晶型物占结晶组合物重量的50％以上，优选在80％以上，更优选在90％以上，最优选在95％以上。A crystalline composition, wherein the L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6 of any one of claims 1-13 The polymorph of -dioxopiperidin-1-yl) methyl ester bis-p-toluenesulfonate accounts for more than 50% of the weight of the crystalline composition, preferably more than 80%, more preferably more than 90%, most preferably above 95.
  15. 一种药物组合物，其含有权利要求1-13中任意一项所述的L-缬氨酸(3-(4-氨基-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)甲酯双对甲苯磺酸盐的多晶型物和药用载体。A pharmaceutical composition containing the L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-as described in any one of claims 1-13 The polymorph and pharmaceutical carrier of 2,6-dioxopiperidin-1-yl) methyl ester bis-p-toluenesulfonate.
  16. 权利要求1-13中所述的多晶型物、权利要求14的结晶组合物、权利要求15的药物组合物在制备治疗癌症的药物中的用途。The use of the polymorph described in claims 1-13, the crystalline composition of claim 14, and the pharmaceutical composition of claim 15 in the preparation of drugs for the treatment of cancer.
  17. 权利要求16所述的用途，其中所述的癌症为多发性骨髓瘤或***癌。The use of claim 16, wherein the cancer is multiple myeloma or prostate cancer.
  18. 权利要求1-13中所述的多晶型物、权利要求14的结晶组合物、权利要求15的药物组合物，用作治疗癌症的药物。The polymorphs described in claims 1-13, the crystalline composition of claim 14, and the pharmaceutical composition of claim 15 are used as drugs for the treatment of cancer.
  19. 含有权利要求1-13中所述的多晶型物、权利要求14的结晶组合物、权利要求15的药物组合物的用于治疗癌症的药物。A drug for the treatment of cancer comprising the polymorph described in claims 1-13, the crystalline composition of claim 14, and the pharmaceutical composition of claim 15.
  20. 一种癌症的治疗方法，所述方法包括将权利要求1-13中所述的多晶型物、权利要求14的结晶组合物、权利要求15的药物组合物给予需要治疗癌症的对象。A method for treating cancer, the method comprising administering the polymorph described in claims 1-13, the crystalline composition of claim 14, and the pharmaceutical composition of claim 15 to a subject in need of treatment of cancer.
PCT/CN2020/072032 2019-01-31 2020-01-14 Polymorph of pomalidomide prodrug salt WO2020156150A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910095078.9A CN111499610A (en) 2019-01-31 2019-01-31 Polymorphs of pomalidomide prodrug salt
CN201910095078.9 2019-01-31

Publications (1)

Publication Number Publication Date
WO2020156150A1 true WO2020156150A1 (en) 2020-08-06

Family

ID=71840828

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/072032 WO2020156150A1 (en) 2019-01-31 2020-01-14 Polymorph of pomalidomide prodrug salt

Country Status (2)

Country Link
CN (1) CN111499610A (en)
WO (1) WO2020156150A1 (en)

Citations (6)

* Cited by examiner, † Cited by third party
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
WO2004085422A1 (en) * 2003-03-27 2004-10-07 Tian Jin Hemay Bio-Tech Co., Ltd. Water-soluble thalidomine derivatives
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
WO2006105697A1 (en) * 2005-04-07 2006-10-12 Tianjin Hemay Bio-Tech Co. Ltd Piperidyl-2, 6-dione derivatives used to inhibit cells 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

Patent Citations (6)

* Cited by examiner, † Cited by third party
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
WO2004085422A1 (en) * 2003-03-27 2004-10-07 Tian Jin Hemay Bio-Tech Co., Ltd. Water-soluble thalidomine derivatives
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
WO2006105697A1 (en) * 2005-04-07 2006-10-12 Tianjin Hemay Bio-Tech Co. Ltd Piperidyl-2, 6-dione derivatives used to inhibit cells 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
CN111499610A (en) 2020-08-07

Similar Documents

Publication Publication Date Title
CN109311832B (en) Pamoic acid salt of vortioxetine and crystal forms thereof
KR101424013B1 (en) 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid crystalline form and the producing method thereof
JP2007302658A (en) POLYMORPHIC FORM AND NEW CRYSTAL FORM AND AMORPHOUS FORM OF IMATINIB MESYLATE, AND METHOD FOR PREPARING FORMalpha
MX2008002541A (en) Delta and epsilon crystal forms of imatinib mesylate.
US7977348B2 (en) Polymorphic forms of imatinib mesylate and processes for preparation of novel crystalline forms as well as amorphous and form α
KR102142797B1 (en) Crystalline forms of mesylate salts of pyridinylaminopyrimidine derivatives, methods for their preparation, and uses thereof
KR20210018557A (en) Crystal of pyrrole derivative and method for producing the same
WO2011140816A1 (en) Thienopyridine ester derivative containing nitrile, preparation method, use and composition thereof
WO2012080195A2 (en) Polymorphic forms of asenapine maleate and processes for their preparation
JP2014051517A (en) Polymorphic form of deferasirox(icl670a)
JP6748123B2 (en) Sucbitryl calcium salt
JP2014144916A (en) Crystal of 2-acylamino thiazole compound
JP2011529859A (en) Prasugrel bisulfate and its drug composition and its application
CA2518999A1 (en) Crystalline and amorphous solids of pantoprazole and processes for their preparation
WO2020173417A1 (en) Acryloyl-containing nuclear transport regulator and uses thereof
WO2020156150A1 (en) Polymorph of pomalidomide prodrug salt
US20170128427A1 (en) Polymorphs of deuterated omega-diphenylurea or salts thereof
JP2023539639A (en) SSAO inhibitor polymorphism
US9464086B2 (en) Crystalline forms of N,N-dicyclopropyl-4-(1,5-dimethyl-1 H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-D]pyrrolo[2,3-B]pyridine-7-carboxamide for the treatment of myeloproliferative disorders
US10377725B2 (en) Phenyl amino pyrimidine compound or polymorph of salt thereof
WO2019200502A1 (en) Crystal form of abemaciclib mesylate, preparation method therefor and pharmaceutical composition thereof
WO2013166966A1 (en) Polymorphs of flourine-containing deuterium-substituted omega-diphenylurea or salts thereof
JP2019089822A (en) New crystal form of topiroxostat, and preparation method therefor
WO2022143897A1 (en) POLYMORPHIC SUBSTANCE OF A-DECARBURIZATION-5α ANDROSTANE COMPOUND
US20100204296A1 (en) Novel Polymorphs of Darifenacin Free Base and its Hydrobromide Salt

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20749623

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20749623

Country of ref document: EP

Kind code of ref document: A1