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WO2020143779A1 - 泊马度胺前体药物的盐 - Google Patents

泊马度胺前体药物的盐 Download PDF

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WO2020143779A1
WO2020143779A1 PCT/CN2020/071472 CN2020071472W WO2020143779A1 WO 2020143779 A1 WO2020143779 A1 WO 2020143779A1 CN 2020071472 W CN2020071472 W CN 2020071472W WO 2020143779 A1 WO2020143779 A1 WO 2020143779A1
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valine
amino
dioxopiperidin
methyl ester
acid
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PCT/CN2020/071472
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English (en)
French (fr)
Inventor
刘飞
赵欣
吴刚
蔡璇
刘伟
祁智
杨许东
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南京诺瑞特医药科技有限公司
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    • 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

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-dioxopiperidin-1- Base) methyl ester salts and pharmaceutical compositions containing the above salts, and their use in the preparation of medicaments for the treatment of cancer.
  • L-valine 3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1- Base
  • methyl ester salts and pharmaceutical compositions containing the above salts, and their use in the preparation of medicaments for the treatment of cancer.
  • Pomalidomide (Formula A structure) was developed by Cell Genetics of the United States and was first approved for listing in the United States in February 2013. Pomalidomide is the third immunomodulator on the market after thalidomide and lenalidomide. It can enhance the immune response mediated by T cells and natural killer cells, while inhibiting the production of proinflammatory cells by monocytes. Factors (such as TNF- ⁇ , IL-6, etc.). In addition, pomalidomide can inhibit tumor cell proliferation and induce apoptosis, and also has a strong proliferation inhibitory effect on lenalidomide-resistant multiple myeloma cell lines.
  • pomalidomide Common adverse reactions of pomalidomide include neutropenia, fatigue and weakness, anemia, constipation, diarrhea, thrombocytopenia, upper respiratory tract infection, back pain and fever, and may also cause thrombosis and may cause serious birth defects in the fetus.
  • pomalidomide is a poorly soluble drug. Its solubility in purified water, pH 6.8 phosphate buffer, pH 4.5 acetate buffer and 0.1mol/L hydrochloric acid was measured. The results were 17.8, 17.0, 18.7 and 18.9 ⁇ g/mL.
  • the low solubility of pomalidomide not only increases the difficulty of the formulation process, but also limits the dissolution and absorption process of the active ingredient in the gastrointestinal tract, which in turn affects oral bioavailability.
  • the structure of formula (B) is a prodrug of pomalidomide with good solubility and capable of significantly improving bioavailability.
  • this structure has poor stability and is easily degraded when placed at room temperature.
  • the purpose of the present invention is to provide novel L-valine (3-(4-amino-1,3-dioxo) with high stability, good solubility, improved bioavailability, low toxicity and side effects or long-term potential Salt of isoindolin-2-yl)-2,6-dioxopiperidin-1-yl) methyl ester.
  • the first aspect of the present invention provides L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1 -Acid addition salts of methyl) methyl esters (structure B).
  • the acid addition salt is selected from the group consisting of hydrochloride, sulfate, phosphate, maleate, fumarate, citrate, malate, oxalate, salicylate Acid salt, p-toluenesulfonate, 1,5-naphthalene disulfonate, 2-naphthalene sulfonate, or sulfonate.
  • the acid addition salt is selected from hydrochloride, p-toluenesulfonic acid monosalt, dip-toluenesulfonic acid salt, p-toluenesulfonic acid 1.5 salt, naphthalene disulfonic acid half salt or male Acid monosalt.
  • the solubility of the acid addition salt in water is not less than 24 mg/ml; preferably, not less than 40 mg/ml; more preferably, not less than 45 mg/ml.
  • the purity of the acid addition salt stored at 40°C for 5 days is less than 1%; preferably less than 0.7%; more preferably less than 0.2%; or
  • the acid addition salt stored at 40°C for 10 days has a purity change of less than 0.8%; preferably less than 0.5%; more preferably less than 0.4%; or
  • the acid addition salt stored at 60°C for 5 days has a purity change of less than 1%; preferably less than 0.9%; more preferably less than 0.3%; or
  • the acid addition salt stored at 60°C for 10 days has a purity change of less than 1.5%; preferably less than 1%; more preferably less than 0.5%.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and L-valine (3-(4-amino-1,3-dioxoisoindoline Acid addition salt of -2-yl)-2,6-dioxopiperidin-1-yl) methyl ester.
  • the acid addition salt is selected from L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-di Hydrochloride of oxopiperidin-1-yl) methyl ester, L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6- Sulfate of dioxopiperidin-1-yl) methyl ester, L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6- Phosphate of dioxopiperidin-1-yl) methyl ester, L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6- Maleate of dioxopiperidin-1-yl) methyl ester, L-valine (3-(4-amino-1,3-dioxois
  • the acid addition salt is selected from L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6- Dihydropiperidin-1-yl) methyl ester hydrochloride, L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6 -P-toluenesulfonic acid monosalt of dioxopiperidin-1-yl) methyl ester, L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl) -2,6-dioxopiperidin-1-yl) methyl bis-p-toluenesulfonate, L-valine (3-(4-amino-1,3-dioxoisoindoline- 2-yl)-2,6-dioxopiperidin-1-yl) methyl ester of p
  • the third aspect of the present invention provides L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1 -The use of acid addition salts of methyl) methyl esters and pharmaceutical compositions containing said salts in the preparation of medicaments for the treatment of cancer.
  • the cancer includes but is not limited to multiple myeloma, prostate cancer, and the like.
  • the fourth aspect of the present invention provides the acid addition salt or the pharmaceutical composition for treating cancer.
  • the cancer is multiple myeloma or prostate cancer.
  • a medicament for treating cancer containing the acid addition salt or the pharmaceutical composition.
  • the cancer is multiple myeloma or prostate cancer.
  • a method for treating cancer comprising administering the acid addition salt or the pharmaceutical composition to a subject in need of treatment for cancer.
  • the cancer is multiple myeloma or prostate cancer.
  • the compounds described in the present invention include two asymmetric centers, and thus can exist in various isomeric forms, for example, enantiomers 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 rich in 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 obtained by Prepared by asymmetric synthesis.
  • the invention additionally includes the compounds described herein as individual isomers that are substantially free of other isomers, or as a mixture of multiple isomers.
  • the acid addition salt of the present invention is the compound of formula (B) described above, ie, L-valine (3-(4-amino-1,3-dioxoisoind Indoline-2-yl)-2,6-dioxopiperidin-1-yl) methyl ester and acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, maleic acid, fumaric acid, citric acid, malic acid, oxalic acid , Salicylic acid, p-toluenesulfonic acid, 1,5-naphthalene disulfonic acid, 2-naphthalene sulfonic acid or sulfamic acid salt.
  • acid such as hydrochloric acid, sulfuric acid, phosphoric acid, maleic acid, fumaric acid, citric acid, malic acid, oxalic acid , Salicylic acid, p-toluenesulfonic acid, 1,5-naphthalene disulfonic acid, 2-na
  • the "p-toluenesulfonic acid monosalt” described herein means that each molecule of the single salt is composed of an equimolar amount of the free base of formula B and p-toluenesulfonic acid; the "bis-p-toluenesulfonate” described herein It means that the double salt per molecule is composed of a single mole of free base and two moles of p-toluenesulfonic acid; "p-toluenesulfonic acid 1.5 salt” as used herein means that 1.5 salts per molecule is composed of two moles of free base and three moles of p-toluene Sulfonic acid composition; "Naphthalene disulfonic acid half salt” described herein means that each molecule of half salt is composed of two moles of free base and a single mole of naphthalene disulfonic acid.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen and sulfur involved in the groups and compounds of the present invention, Nitrogen or halogen, optionally further replaced by one or more of their corresponding isotopes, where carbon isotopes include 12 C, 13 C and 14 C, and hydrogen isotopes include protium (H) and 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, nitrogen isotopes include 14 N And 15 N, fluorine isotopes include 19 F, chlorine isotopes include 35 Cl and 37 Cl, bromine isotopes include 79 Br and 81 Br.
  • carbon isotopes include 12 C, 13 C and 14 C
  • hydrogen isotopes include protium (H
  • the pharmaceutical composition refers to a composition containing the acid addition salt according to the present invention and a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism such as a human or other mammal.
  • a pharmaceutically acceptable carrier means that it can form a pharmaceutical composition together with a specific agent, and can be solid or liquid.
  • Subjects described herein include but are not limited to humans and other mammals; preferably humans.
  • solubility of the salt of the present invention in water is significantly higher than that of pomalidomide, so that it can have excellent drug forming properties;
  • the salt of the present invention can have excellent stability, thereby facilitating storage and transportation;
  • the salt of the present invention has better oral bioavailability than pomalidomide.
  • Figure 1 shows the relationship between drug concentration and time in rat plasma after administration.
  • Figure 2 shows the relationship between drug concentration in dog plasma and time after administration.
  • FIG 3 shows the plasma metabolism of Compound A and Compound 1 of the present invention in rats after administration.
  • the inventor selected a variety of acids (including sulfuric acid, phosphoric acid, hydrochloric acid, formic acid, acetic acid, oxalic acid, oleic acid, lactic acid, nicotinic acid, tartaric acid, methanesulfonic acid, maleic acid, citric acid, fumaric acid, benzenesulfonic acid Acid, malic acid, lactobionic acid, hippuric acid, benzoic acid, cinnamic acid, adipic acid, stearic acid, orotic acid, glycolic acid, salicylic acid, citric acid, L-tartaric acid, p-toluenesulfonic acid, 4 -Chlorobenzenesulfonic acid, D-glutamic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene disulfonic acid), a variety of solvent systems (including ethyl acetate, isopropanol, acetonitrile,
  • hydrochloric acid, sulfuric acid, phosphoric acid, maleic acid, fumaric acid, citric acid, malic acid, oxalic acid, salicylic acid, p-toluenesulfonic acid, 1,5-naphthalene disulfonic acid, 2 -Naphthalene sulfonic acid and fipronil can form salts and have solid shapes.
  • 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 sodium hydride (3.5g, 87.5mmol, 1.2eq) was slowly added, and after stirring for 30min, potassium iodide (12g, 72.2mmol, 0.99eq) and TBAB (tetrabutylammonium bromide) (3.52g, 10.9mmol, 0.15) were added 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 nitrogen protection, add Int 1-01 (500mg, 1mmol, 1.00eq), 5ml of DCM to a 100ml three-necked reaction flask, after stirring at room temperature for 10min, add HCl/EA (10ml, 10mmol, 10.0eq) at one time. Continue stirring for 40 min. Stop the reaction, filter and dry to obtain 380mg of yellow solid product, yield 86.9%
  • Step3 In a 200mL three-necked bottle, add 4g of L-valine (3-(4-(amino)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine -1-yl) methyl ester hydrochloride (Int 1-02), 40mL ethyl acetate, stirred for 5min under ice-water bath conditions, then poured into 30mL of ice water, continue to add 30mL of saturated sodium bicarbonate, stirred for 5-10min, water The phase was extracted once more with ethyl acetate (40 mL), 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 Indoline-2-yl)-2,6-dioxopiperidin-1-yl) methyl ester 3g for use.
  • L-valine 3-(
  • tert-butoxycarbonyl-L-valine (3-(4-(amino)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine -1-yl) methyl ester (Int 1-01) was suspended in 139 mL of methylene chloride and stirred at 0°C. 139mL of hydrochloric acid ethyl acetate solution was added, and the temperature was naturally raised to room temperature for 1 hour. Filter and dry the filter cake in vacuo. The dried solid was slurried with 100 mL of methylene chloride at room temperature for 2 hours. Filter and dry the filter cake in vacuo. The target product 4.58g was obtained.
  • the saturated solubility of the sample is not determined, but an appropriate amount of sample is selected to test the solubility of the sample.
  • the solubility of the salt of the present invention is not less than 24mg/ml.
  • the solubility of pomalidomide in water is about 0.01 mg/ml, which is far lower than the solubility of the salt of the present invention.
  • the free base structure of formula (B) has poor structural stability and is easily degraded when left at room temperature, while the salt of the present invention has significantly improved stability.
  • the male SD rats (SPF grade) used in this example weighing 250-330g, were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and were more than 8 weeks old. In carbonate cages (up to 5 animals/sex/cage). Drink water freely and freely eat qualified feed 5CC4 (same as 5CR4, PMI Nutrition International LLC, USA).
  • the SD rats were divided into NORA0310 group (hydrochloride) and NORA0312 group (pomadimide) by using randomized group design. Each group was administered by gavage (i.g.), and the dose was set at 2 mg/kg (calculated as pomalidomide).
  • Test method Before administration, blood samples were collected at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours after administration, and the whole blood samples were collected into anticoagulation tubes containing EDTA-2K Blood was stored on wet ice and centrifuged at 3500 rpm and 4°C for 5 minutes within 30 minutes to obtain plasma samples. The separated plasma samples were immediately placed in dry ice for temporary storage and then transferred to the refrigerator at -60 to -80°C. LC/MS/MS was used for detection, and the non-compartment model of software WinNonlin was used to calculate the pharmacokinetic parameters of rats after administration. The data is shown in Table-3.
  • Beagle dogs weighing 8.6-10.6 kg, were purchased from Beijing Mas Biotechnology Co., Ltd.
  • the test animals are all over 1 year old, and the animals are at least two weeks apart from the last test.
  • the three dogs adopt a cross-over design, and the cleaning interval is at least three days.
  • NORA0310A4 di-p-toluenesulfonate
  • NORA0312 pomadolamine
  • Oral capsules POMALID, manufactured by Natco Pharma Limited.
  • Each cycle was given a capsule by oral administration with 50mL of water to assist swallowing.
  • Test method Before administration, blood samples were collected 0.5, 1, 2, 4, 6, 8, 10, 24 and 48 hours after administration, and whole blood was collected in anticoagulation tubes containing EDTA-2K and stored on wet ice , And centrifuged at 1800 ⁇ g, 4°C for 5 minutes within 1 hour to obtain plasma samples. The separated plasma sample will be added with 2% formic acid in a 4:1 ratio and shaken evenly, immediately placed on dry ice for temporary storage and then transferred to a -20°C refrigerator. LC/MS/MS was used for detection, and the non-compartment model of the software WinNonlin was used to calculate the pharmacokinetic parameters of dogs after administration. The data is shown in Table-4.
  • the salt of the present invention has a Cmax value that is more than 4 times higher than that of pomalidomide, and an AUC last that is more than 1.5 times higher, indicating that the salt of the present invention is better than pomalidomide. Oral bioavailability.
  • the present inventors prepared other pomalidomide prodrugs (compound A) according to the prior art literature, for example, as described in US20080051432/WO2006105697.
  • the structure of the prodrug and Compound 1 of the present invention are shown below:
  • compound 1 can be rapidly metabolized to pomalidomide, which can reduce the side effects caused by the prodrug itself.
  • Table 5 and Figure 3 The specific results are shown in Table 5 and Figure 3.

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Abstract

本发明涉及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)甲酯的盐，及其作为免疫调节剂的应用。

Description

泊马度胺前体药物的盐 技术领域
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)甲酯的盐和包含上述盐的药物组合物，及其在制备治疗癌症的药物中的应用。
背景技术
泊马度胺(式A结构)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。
Figure PCTCN2020071472-appb-000001
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。
本发明人在PCT申请PCT/CN2017/098281中公开了一种泊马度胺前体药物，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，该化合物的结构如下结构式(B)所示：
Figure PCTCN2020071472-appb-000002
式(B)结构是一种具有良好溶解度，且能够显著改善生物利用度的泊马度胺前体药物。但该结构稳定性较差，室温放置容易降解。
发明内容
本发明的目的在于提供新颖的具有高稳定性，良好溶解度，改善生物利用度，低毒副作用或具备长效潜力的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)甲酯的盐。
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(式B结构)的酸加成盐。
在一个实施例中，所述的酸加成盐选自盐酸盐、硫酸盐、磷酸盐、马来酸盐、富马酸盐、枸橼酸盐、苹果酸盐、草酸盐、水杨酸盐、对甲苯磺酸盐、1,5-萘二磺酸盐、2-萘磺酸盐或扑酸盐。
在一个优选实施例中，所述的酸加成盐选自盐酸盐、对甲苯磺酸单盐、双对甲苯磺酸盐、对甲苯磺酸1.5盐、萘二磺酸半盐或马来酸单盐。
在一个优选实施例中，所述的酸加成盐在水中的溶解度不小于24mg/ml；优选地，不小于40mg/ml；更优选地，不小于45mg/ml。
在一个优选实施例中，所述的酸加成盐在40℃下储存5天的纯度变化小于1％；优选小于0.7％；更优选小于0.2％；或者
所述的酸加成盐在40℃下储存10天的纯度变化小于0.8％；优选小于0.5％；更优选小于0.4％；或者
所述的酸加成盐在60℃下储存5天的纯度变化小于1％；优选小于0.9％；更优选小于0.3％；或者
所述的酸加成盐在60℃下储存10天的纯度变化小于1.5％；优选小于1％；更优选小于0.5％。
本发明的第二方面，提供了一种药物组合物，所述药物组合物包含可药用载体和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)甲酯的酸加成盐。
在一个实施例中，所述的酸加成盐选自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)甲酯的盐酸盐、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)甲酯的硫酸盐、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)甲酯的磷酸盐、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)甲酯的马来酸盐、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)甲酯的富马酸盐、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)甲酯的枸橼酸盐、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)甲酯的苹果酸盐、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)甲酯的草酸盐、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)甲酯的水杨酸盐、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)甲酯的对甲苯磺酸盐、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1,5-萘二磺酸盐、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2-萘磺酸盐或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)甲酯的扑酸盐。
在一个优选实施例中，所述的酸加成盐选自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)甲酯的盐酸盐、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)甲酯的对甲苯磺酸单盐、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)甲酯的双对甲苯磺酸盐、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)甲酯的对甲苯磺酸1.5盐、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)甲酯的萘二磺酸半盐或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)甲酯的马来酸单盐。
本发明的第三方面，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)甲酯的酸加成盐，及包含所述盐的药物组合物，在制备治疗癌症的药物中的用途。
在一个实施例中，所述癌症包括但不限于多发性骨髓瘤，前列腺癌等。
本发明的第四方面，提供了所述的酸加成盐或所述的药物组合物，用于治疗癌症。
在一优选例中，所述癌症为多发性骨髓瘤或前列腺癌。
本发明的第五方面，提供了含有所述的酸加成盐或所述的药物组合物的用于治疗癌症的药物。
在一优选例中，所述癌症为多发性骨髓瘤或前列腺癌。
本发明的第六方面，提供了癌症的治疗方法，所述方法包括将所述的酸加成盐或所述的药物组合物给予需要治疗癌症的对象。
在一优选例中，所述癌症为多发性骨髓瘤或前列腺癌。
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。
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。
本文所述的“酸加成盐”具有本领域普通技术人员常规理解的含义。在具体的实施方式中，本发明的酸加成盐是上文所述的式(B)化合物，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)甲酯与酸，例如盐酸、硫酸、磷酸、马来酸、富马酸、枸橼酸、苹果酸、草酸、水杨酸、对甲苯磺酸、1,5-萘二磺酸、2-萘磺酸或扑酸形成的盐。进一步地，本文所述的“对甲苯磺酸单盐”是指每分子单盐是由等摩尔量的式B游离碱与对甲苯磺酸组成；本文所述的“双对甲苯磺酸盐”是指每分子双盐是由单摩尔游离碱和二摩尔对甲苯磺酸组成；本文所述的“对甲苯磺酸1.5盐”是指每分子1.5盐是由二摩尔游离碱和三摩尔对甲苯磺酸组成；本文所述的“萘二磺酸半盐”是指每分子半盐是由二摩尔游离碱和单摩尔萘二磺酸组成。具体地，本文所述的“对甲苯磺酸单盐”、“双对甲苯磺酸盐”、“对甲苯磺酸1.5盐”和“萘二磺酸半盐”的结构分别如下所示：
Figure PCTCN2020071472-appb-000003
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。
药物组合物是指包含本发明所述的酸加成盐和药学上可接受载体的组合物。药物组合物的目的是促进化合物向诸如人或其他哺乳动物的生物体的给药。
药学可接受的载体是指可与特定药剂一起形成药物组合物，可以是固体或液体。
本文所述的对象包括但不限于人和其它哺乳动物；优选人。
本发明的优点：
1.本发明的盐在水中的溶解度显著高于泊马度胺，从而能够具备优异的成药性；
2.本发明的盐能够具备优异的稳定性，从而有利于储存和运输；
3.本发明的盐的与泊马度胺相比具有更好的口服生物利用度。
附图说明
图1显示了给药后大鼠血浆中药物浓度和时间的关系。
图2显示了给药后犬血浆中药物浓度和时间的关系。
图3显示了给药后，化合物A与本发明的化合物1在大鼠中的血浆代谢情况。
具体实施方式
下面将结合实施例对本发明作进一步说明，可以使本领域技术人员更全面地理解本发明，但不以任何方式限制本发明。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。
实施例1 盐的制备
本发明人选用了多种酸(包括硫酸、磷酸、盐酸、甲酸、乙酸、草酸、油酸、乳酸、烟酸、扑酸、甲磺酸、马来酸、柠檬酸、富马酸、苯磺酸、苹果酸、乳糖酸、马尿酸、苯甲酸、肉桂酸、己二酸、硬脂酸、乳清酸、乙醇酸、水杨酸、枸橼酸、L-酒石酸、对甲苯磺酸、4-氯苯磺酸、D-谷氨酸、2-萘磺酸、1,5-萘二磺酸)，多种溶剂体系(包括乙酸乙酯、异丙醇、乙腈、二氯甲烷、正丙醇、2-丁酮、四氢呋喃、乙酸异丙酯、乙醇、正丁醇和正庚烷中的一种或多种)进行初步试验。
经过大量试验后，其中仅有盐酸、硫酸、磷酸、马来酸、富马酸、枸橼酸、苹果酸、草酸、水杨酸、对甲苯磺酸、1,5-萘二磺酸、2-萘磺酸和扑酸，能够成盐且具有固体形状。
实施例1.1
Compound 1的制备
Figure PCTCN2020071472-appb-000004
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，10.9mmol，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％.
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％
HPLC:97.05％
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).
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。
实施例1.2 盐酸盐的制备
将7.0g的叔丁氧羰基-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(Int 1-01)悬浮于139mL的二氯甲烷中，在0℃下搅拌。加入139mL的盐酸乙酸乙酯溶液，自然升至室温反应1小时。过滤，滤饼真空干燥。干燥后的固体用100mL二氯甲烷室温打浆2小时。过滤，滤饼真空干燥。得目标产物4.58g。
实施例1.3 对甲苯磺酸单盐的制备
将2.0g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90mL乙酸异丙脂中，加入对甲苯磺酸的乙酸异丙脂溶液(855mg/20mL)，室温搅拌3小时。过滤，滤饼真空干燥。得目标产物2.5g。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: 1。
1H NMR(400MHz,DMSO)δ8.31(brs,2H),7.63–7.43(m,3H),7.12(d,J＝7.9Hz,2H),7.05–7.03(m,2H),6.38–5.81(m,4H),5.74–5.62(m,1H),5.23(m,1H),3.95(d,J＝3.4Hz,1H),3.16–2.94(m,1H),2.83(d,J＝17.5Hz,1H),2.69–2.51(m,1H),2.28(s,3H),2.19-2.06(m,2H),1.03–0.79(m,6H).
实施例1.4 双对甲苯磺酸盐的制备
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，加入对甲苯磺酸一水合物的乙酸乙酯溶液(1.03g/50mL)，室温搅拌过夜。过滤，滤饼真空干燥。得目标产物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。
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).
实施例1.5 萘二磺酸半盐的制备
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20mL乙酸乙脂和15mL异丙醇的混合溶剂中，加入1,5-萘二磺酸的异丙醇溶液(0.35g/20mL)，室温搅拌3小时。过滤，滤饼真空干燥。得目标产物0.9g。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)甲酯与萘二磺酸的摩尔比例为2:1。
实施例1.6 马来酸单盐的制备
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乙酸乙脂和15mL异丙醇的混合溶剂中，加入马来酸的乙酸乙酯溶液(0.29g/6mL)，室温搅拌3小时。过滤，滤饼真空干燥。得目标产物0.97g。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)甲酯与马来酸的摩尔比例为1:1。
实施例2 本发明盐的溶解度测定
将适量样品与1ml水混合，室温搅拌，判断样品的溶解能力。结果如表1所示。
表1
样品 室温下水中的溶解度(mg/ml)
盐酸盐(实施例1.1) 48>溶解度>24
对甲苯磺酸盐单盐(实施例1.2) 溶解度>45
萘二磺酸半盐(实施例1.4) 溶解度>47
本试验未测定样品的饱和溶解度，而是采用选取适量样品，测试样品的溶解能力。由试验得出，本发明盐溶解度不小于24mg/ml。而泊马度胺在水中的溶解度约为0.01mg/ml，远低于本发明盐的溶解能力。
实施例3 本发明盐的稳定性测定
取适量样品各自独立的放置于不同环境条件下，测定0天，5天，10天时样品的百分含量，评价样品的稳定性。式(B)游离碱结构稳定性较差，室温放置容易降解，而本发明盐具有显著改善的稳定性。
表2
Figure PCTCN2020071472-appb-000005
“/”表示未测定；
实施例4 SD大鼠的药动学数据
本实施例中所使用的为雄性SD大鼠(SPF级)，体重250～330g，购自北京维通利华实验动物技术有限公司，大于8周龄，动物群养在装有垫料的聚碳酸酯笼具里(最多5只动物/性别/笼)。自由饮水，每日自由采食合格饲料5CC4(同5CR4，PMI Nutrition International LLC,美国)。
采用随机区组设计的分组，对试验用SD大鼠进行分组，分为NORA0310组(盐酸盐)、NORA0312组(泊马度胺)。各组以灌胃(i.g.)的方式给药，给药剂量设为2mg/kg(以泊马度胺计)。
试验方法：给药前，给药后0.25、0.5、1、2、3、4、6、8、12、24、36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30分钟内于3500rpm，4℃下离心5分钟来获得血浆样品。分离取得的血浆样品立即放在干冰中暂存然后转移至-60至-80℃冰箱中。采用LC/MS/MS进行检测，利用软件WinNonlin的非室模型计算大鼠给药后的药代动力学参数，数据如表-3所示。
表3
Figure PCTCN2020071472-appb-000006
Figure PCTCN2020071472-appb-000007
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2mg/kg的剂量下，给药后，本发明盐相比泊马度胺，C max值升高3倍以上，AUC last升高2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。
实施例5 犬的药动学数据
本实施例中所使用的为雄性
Figure PCTCN2020071472-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。
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。
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-4所示。
表4
Figure PCTCN2020071472-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。
实施例6 化合物1与其它泊马度胺前药的比较
本发明人根据现有技术文献，例如US20080051432/WO2006105697所述制备了其它泊马度胺前药(化合物A)。该前药以及本发明的化合物1的结构如下所示：
Figure PCTCN2020071472-appb-000010
随后，本发明人比较了上述两个结构相近化合物的血浆代谢情况，具体实验如下所述：
样品母液配制：
精密称取化合物A和化合物1样品20mg于5ml容量中，乙腈溶解并定容至刻度。
吸取新鲜大鼠血液2.0ml于西林瓶中，放入搅拌子置37度水浴中预热。
供试品溶液配制：
吸取样品母液0.1ml于上述西林瓶中，压盖，置37度水浴搅拌，分别于5min、10min、15min、30min、1h、2h、4h时打开西林瓶，吸取0.2ml血液置1ml塑料离心管中，加入0.2ml乙腈，超声2min，以10000r/min的转速离心5min，吸取上清液与衬管中，放入进样小瓶注入液相色谱仪。
空白溶液配制：
吸取新鲜大鼠血液0.2ml置1ml塑料离心管中，加入0.2ml乙腈，超声2min，以10000r/min的转速离心5min，吸取上清液与衬管中，放入进样小瓶注入液相色谱仪。
有关物质测定方法：
Figure PCTCN2020071472-appb-000011
Figure PCTCN2020071472-appb-000012
试验结果：
相比化合物A，化合物1能够迅速代谢成泊马度胺，从而能够降低前药本身引起的副作用。具体结果如表5和图3所示。
表5
Figure PCTCN2020071472-appb-000013
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。

Claims (12)

  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)甲酯的酸加成盐。
  2. 如权利要求1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)甲酯的酸加成盐，其中所述酸加成盐选自对甲苯磺酸盐、盐酸盐、硫酸盐、磷酸盐、马来酸盐、富马酸盐、枸橼酸盐、苹果酸盐、草酸盐、水杨酸盐、1,5-萘二磺酸盐、2-萘磺酸盐或扑酸盐。
  3. 如权利要求1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)甲酯的酸加成盐，其中所述酸加成盐选自双对甲苯磺酸盐、对甲苯磺酸单盐、对甲苯磺酸1.5盐、萘二磺酸半盐、马来酸单盐或盐酸盐。
  4. 药物组合物，其包含可药用载体和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)甲酯的酸加成盐。
  5. 如权利要求4所述的药物组合物，其中所述酸加成盐选自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)甲酯的盐酸盐、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)甲酯的硫酸盐、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)甲酯的磷酸盐、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)甲酯的马来酸盐、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)甲酯的富马酸盐、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)甲酯的枸橼酸盐、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)甲酯的苹果酸盐、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)甲酯的草酸盐、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)甲酯的水杨酸盐、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)甲酯的对甲苯磺酸盐、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1,5-萘二磺酸盐、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2-萘磺酸盐或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)甲酯的扑酸盐。
  6. 如权利要求4所述的药物组合物，其中所述酸加成盐选自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)甲酯的双对甲苯磺酸盐、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)甲酯的盐酸盐、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)甲酯的对甲苯磺酸单盐、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)甲酯的对甲苯磺酸1.5盐、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)甲酯的萘二磺酸半盐、或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)甲酯的马来酸单盐。
  7. 权利要求1-3中任意一项所述的酸加成盐在制备治疗癌症的药物中的用途。
  8. 权利要求4-6中任意一项所述的药物组合物在制备治疗癌症的药物中的用途。
  9. 权利要求7或8中所述的用途，其中所述的癌症为多发性骨髓瘤或前列腺癌。
  10. 权利要求1-3中任意一项所述的酸加成盐或权利要求4-6中任意一项所述的药物组合物，用于治疗癌症。
  11. 含有权利要求1-3中任意一项所述的酸加成盐或权利要求4-6中任意一项所述的药物组合物的用于治疗癌症的药物。
  12. 一种癌症的治疗方法，所述方法包括将权利要求1-3中任意一项所述的酸加成盐或权利要求4-6中任意一项所述的药物组合物给予需要治疗癌症的对象。
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CN101735276A (zh) * 2009-12-17 2010-06-16 廖国超 水溶性磷酸单酯衍生物及其应用
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