WO2022021785A1 - 一种含有tsl-1502m的药物组合物及其应用 - Google Patents

一种含有tsl-1502m的药物组合物及其应用 Download PDF

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WO2022021785A1
WO2022021785A1 PCT/CN2020/140555 CN2020140555W WO2022021785A1 WO 2022021785 A1 WO2022021785 A1 WO 2022021785A1 CN 2020140555 W CN2020140555 W CN 2020140555W WO 2022021785 A1 WO2022021785 A1 WO 2022021785A1
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tsl
pharmaceutical composition
pharmaceutical
drug
injection
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French (fr)
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杨海龙
李德馨
马晓慧
唐海
蔡金勇
周水平
郭建飞
范立君
沈伟生
王萍
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江苏天士力帝益药业有限公司
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    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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 invention belongs to the technical field of pharmaceutical preparation, and in particular relates to a pharmaceutical composition containing the intermediate TSL-1502M of the PARP inhibitor TSL-1502 and its application.
  • PARP inhibitor TSL-1502 chemical name is (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(3-methyl-1-((S)-1-propyl) Pyrrolidin-3-yl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinoline-5-oxy)tetrahydro-2H-pyran-2-
  • the compound of formic acid set its number as TSL-1502
  • the compound first appeared in 201180002886.8 publication number CN102510863A, authorized announcement number CN102510863B, hereinafter referred to as the 2011 patent
  • the compound of paragraph 0177 its structural formula is shown in formula I.
  • the above patent discloses specific tumor types in claim 16, such as head cancer, thyroid cancer, neck cancer, eye cancer, skin cancer, oral cancer, throat cancer, esophagus cancer, breast cancer, bone cancer, blood cancer, bone marrow cancer, lung cancer , colon cancer, sigmoid colon cancer, rectal cancer, stomach cancer, prostate cancer, breast cancer, ovarian cancer, kidney cancer, liver cancer, pancreatic cancer, brain cancer, colon cancer, heart cancer, adrenal cancer, subcutaneous tissue cancer, lymph node cancer, pigment cancer , malignant glioma, etc.
  • the therapeutic effect of melanoma and human breast cancer cell lines was confirmed only in Example 19, and other tumors were not involved.
  • TSL-1502M is an intermediate for the preparation of TSL-1502, its application number is 201910465780.X, and the name of the invention is an intermediate TSL-1502M of a PARP inhibitor and its preparation method, (application date: May 31, 2019 , the publication number is CN112010850A), the structural formula is shown in formula II,
  • TSL-1502M The compound of formula II is designated as TSL-1502M.
  • TSL-1502M As an intermediate, it can be used for the preparation of TSL-1502 and the detection of TSL-1502. It is useful as a reference substance. However, the document does not disclose the information on the drug use of TSL-1502M and the related information on combination with other anticancer drugs.
  • TSL-1502M TSL-1502M and other drugs.
  • the present invention studies the combined application of TSL-1502M and other drugs. It is unexpectedly found that it is combined with temozolomide, 7-ethyl-10-hydroxycamptothecin, iris The combined use of Kang and topotecan has a synergistic effect.
  • the present invention provides a compound pharmaceutical composition containing TSL-1502M and another antitumor drug, wherein the structure of the TSL-1502M is as follows
  • the other antitumor drug is selected from temozolomide, 7-ethyl-10-hydroxycamptothecin, irinotecan and topotecan.
  • the present invention includes a pharmaceutical preparation composition containing two active ingredients of TSL-1502M and another antitumor drug, or a separate pharmaceutical preparation containing TSL-1502M and another antitumor drug, and the combination of the two preparations packaged together .
  • the preparation of the pharmaceutical composition of the present invention includes the step of mixing TSL-1502M and another antitumor drug.
  • the TSL-1502M and another antitumor drug are prepared into drug preparations respectively, and the two preparations are combined and packaged together, so that the two drugs can be conveniently used in combination.
  • TSL-1502M can be prepared into injections, and another anti-tumor drug can be prepared into injections.
  • the two unit doses of injections are packaged together in the same packaging box, and can be injected separately or together when used.
  • the pharmaceutical composition of TSL-1502M and another anti-tumor drug according to the present invention wherein the dose of each drug is a pharmaceutically effective amount, and the "effective amount" refers to that each drug can be used alone or in combination.
  • composition of the present invention comprises TSL-1502M and another antitumor drug, and the weight ratio of the two can be formulated according to their respective effective amounts, such as 1:1000 to 1000:1.
  • the weight ratio of TSL-1502M and temozolomide is 3-10 nm: 10-30 ⁇ m, preferably 3 nm: 10-30 ⁇ m.
  • the weight of TSL-1502M and 7-ethyl-10-hydroxycamptothecin or irinotecan is 3-10 ⁇ M: 0.1-1 nM, preferably 3-10 ⁇ M: 0.1 nM.
  • the preparation method of the pharmaceutical composition of the present invention comprises the steps of preparing a pharmaceutical preparation that can be taken according to the conventional techniques of preparation by taking the required amount of TSL-1502M and another anti-tumor drug together or separately as the active pharmaceutical ingredients.
  • the composition, its dosage form includes injection, preferably dry powder injection, particularly preferably freeze-dried injection.
  • the injection of the present invention can be prepared without adding auxiliary materials or adding one or more pharmaceutical auxiliary materials, such as glucose, lactose, mannitol, sodium chloride, hydroxypropyl-B-cyclodextrin, etc., and then using an appropriate method injection.
  • auxiliary materials such as glucose, lactose, mannitol, sodium chloride, hydroxypropyl-B-cyclodextrin, etc.
  • the use method of the present invention includes preparing an injection containing a required amount of TSL-1502M and another antitumor drug together as two active pharmaceutical ingredients for injection together.
  • the required amount of TSL-1502M and another antitumor drug can also be made into injections and used separately.
  • the pharmaceutical preparation composition of the present invention can be in any ingestible pharmaceutical form: such as: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral Liquids, buccal preparations, granules, granules, pills, powders, ointments, pills, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, patches .
  • the pharmaceutical preparation composition of the present invention is preferably in the form of a unit dose pharmaceutical preparation.
  • the unit dose of the pharmaceutical preparation may contain the TSL-1502M of the present invention, and another antitumor drug 0.1-1000 mg, and the rest It is a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable adjuvants can be 0.01-99.99% by weight of the total weight of the formulation.
  • the dosage of the pharmaceutical preparation composition of the present invention is determined according to the patient's condition, such as 1-3 times a day, 1-20 tablets at a time, etc.
  • the pharmaceutical preparation composition of the present invention is an oral preparation or an injection.
  • the oral preparation is selected from capsules, tablets, dropping pills, granules, concentrated pills, and oral liquids.
  • the injection is selected from liquid, semi-solid, solid, powder form, preferably injection, powder injection.
  • the pharmaceutical preparation composition of the present invention may contain adjuvants such as binders, fillers, diluents, tableting agents, lubricants, disintegrating agents, coloring agents, flavoring agents and wetting agents, as necessary Tablets may be coated.
  • adjuvants such as binders, fillers, diluents, tableting agents, lubricants, disintegrating agents, coloring agents, flavoring agents and wetting agents, as necessary Tablets may be coated.
  • Suitable fillers include cellulose, mannitol, lactose and other similar fillers.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable humectants include sodium lauryl sulfate.
  • the pharmaceutical preparation of the present invention can be prepared as a solid oral composition by mixing, filling, tableting and other common methods. Repeated mixing allows the active to be distributed throughout those compositions where large amounts of fillers are used.
  • Oral liquid preparations can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or can be a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats, Emulsifiers such as lecithin, sorbitan monooleate or acacia; non-aqueous carriers (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters such as glycerol esters, propylene glycol or ethanol; preservatives agents such as methylparaben or propylparaben or sorbic acid and, if desired, conventional flavoring or coloring agents.
  • suspending agents for example sorbitol, syrup, methylcellulose, gelatin, hydroxy
  • liquid unit dosage forms are prepared containing the active substance of the present invention and a sterile carrier. Depending on the carrier and concentration, the compound can be suspended or dissolved. Solutions are usually prepared by dissolving the active substance in a carrier, filter sterilizing before filling into a suitable vial or ampoule, and sealing. Adjuvants such as a local anesthetic, preservatives and buffering agents can also be dissolved in the carrier. To improve its stability, the composition can be frozen after filling into a vial and the water removed under vacuum.
  • the present invention further provides the application of the composition of the present invention in the preparation of anti-tumor drugs.
  • the dosage of TSL-1502M and another anti-tumor drug can be 0.01 mg-2000 mg per day.
  • TSL-1502M significantly enhanced the inhibitory effect of temozolomide on the proliferation of MDA-MB-436 cells (breast cancer cell line); combined with temozolomide, it induced the phosphorylation level of ⁇ -H2AX in MDA-MB-436 cells Significantly increased, promoting the process of apoptosis in tumor cells.
  • TSL-1502M After the combination of TSL-1502M and temozolomide, the inhibitory effect on tumor cells is better than that of TSL-1502M or temozolomide alone.
  • TSL-1502M alone can inhibit MDA-MB-436 at a concentration of 30nM.
  • the inhibition rate of cells (breast cancer) was 67.5 ⁇ 1.5%, and the inhibition rate of TMZ alone at 30 ⁇ M was 8.5 ⁇ 3.5%.
  • the combination of the two can further increase the inhibition rate of MDA-MB-436 cell proliferation to 80.2 ⁇ 3.5% , this synergistic effect is more pronounced at lower drug concentrations.
  • TSL-1502M significantly enhanced the inhibitory effect of SN38, the active metabolite of irinotecan, on the proliferation of SW620 cells (colon cancer cell line).
  • TSL-1502M and SN38 the active metabolite of irinotecan
  • Table 3-2 the inhibitory rate of SW620 cells (colorectal cancer, specifically colon cancer) was 37.2 ⁇ 17.9% when TSL-1502M was administered alone at a concentration of 10 ⁇ M, and SN38 (the active metabolite of irinotecan) was administered alone.
  • the inhibition rate was 62.3 ⁇ 18.1%
  • the combination of the two could further increase the inhibition rate of MDA-MB-436 cell proliferation to 98.3 ⁇ 1.3%, and this synergistic effect was more pronounced at lower drug concentrations. obvious.
  • FIG. 1 Effects of TSL-1502 and TSL-1502M on cell proliferation in vitro
  • FIG. 1 Inhibitory effect of TSL-1502, TSL-1502M and cytotoxic drugs on the proliferation of MDA-MB-436 and SW620 cells;
  • the present invention provides a compound drug freeze-dried injection composed of TSL-1502M and another antitumor drug, temozolomide, 7-ethyl-10-hydroxycamptothecin, irinotecan and topotecan.
  • TSL-1502M Take 20g of TSL-1502M, and optionally any one of the following drugs, temozolomide, 10g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan, and dissolve them in a 1000ml aqueous solution containing 100g of mannitol, respectively, Canned into 2g vials, each with a total of 500 vials, placed in a freeze-drying box before capping, vacuum-dried for 24 hours, capped, and taken 1 vial for combined packaging.
  • drugs temozolomide
  • 10g of 7-ethyl-10-hydroxycamptothecin irinotecan
  • topotecan topotecan
  • TSL-1502M Take 5g of TSL-1502M, and optionally any one of the following drugs, temozolomide, 10g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan, and dissolve together in a 1000ml aqueous solution containing 100g of mannitol, Mix evenly, canned into 2g vials, a total of 500 vials, before capping, put in a freeze-drying box, vacuum dry for 24 hours, capped, and packaged.
  • drugs temozolomide, 10g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan
  • TSL-1502M Take 5g of TSL-1502M, and optionally any one of the following drugs, temozolomide, 20g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan, and dissolve together in a 1000ml aqueous solution containing 100g of mannitol, Mix evenly, canned into 2g vials, a total of 500 vials, before capping, put in a freeze-drying box, vacuum dry for 24 hours, capped, and packaged.
  • drugs temozolomide, 20g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan
  • TSL-1502M Take 5g of TSL-1502M, and optionally any one of the following drugs, temozolomide, 50g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan, and dissolve together in a 1000ml aqueous solution containing 100g of mannitol, Mix evenly, canned into 2g vials, a total of 500 vials, before capping, put in a freeze-drying box, vacuum dry for 24 hours, capped, and packaged.
  • drugs temozolomide, 50g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan
  • TSL-1502M Take 5g of TSL-1502M, and optionally any one of the following drugs, temozolomide, 100g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan, and dissolve together in a 1000ml aqueous solution containing 100g of mannitol, Mix evenly, canned into 2g vials, a total of 500 vials, before capping, put in a freeze-drying box, vacuum dry for 24 hours, capped, and packaged.
  • drugs temozolomide, 100g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan
  • TSL-1502M Take 10g of TSL-1502M, and optionally any one of the following drugs, temozolomide, 5g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan, and dissolve together in a 1000ml aqueous solution containing 100g of mannitol, Mix evenly, canned into 2g vials, a total of 500 vials, before capping, put in a freeze-drying box, vacuum dry for 24 hours, capped, and packaged. or
  • TSL-1502M Take 20g of TSL-1502M, and optionally any one of the following drugs, temozolomide, 5g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan, and dissolve together in a 1000ml aqueous solution containing 100g of mannitol, Mix evenly, canned into 2g vials, a total of 500 vials, before capping, put in a freeze-drying box, vacuum dry for 24 hours, capped, and packaged. or
  • TSL-1502M Take 50g of TSL-1502M, and optionally any one of the following drugs, temozolomide, 5g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan, and dissolve together in a 1000ml aqueous solution containing 100g of mannitol, Mix evenly, canned into 2g vials, a total of 500 vials, before capping, put in a freeze-drying box, vacuum dry for 24 hours, capped, and packaged. or
  • TSL-1502M Take 100g of TSL-1502M, and optionally any one of the following drugs, temozolomide, 5g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan, and dissolve together in a 1000ml aqueous solution containing 100g of mannitol, Mix evenly, canned into 2g vials, a total of 500 vials, before capping, put in a freeze-drying box, vacuum dry for 24 hours, capped, and packaged.
  • drugs temozolomide, 5g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan
  • TSL-1502M Take 2g of TSL-1502M, and optionally any one of the following drugs, temozolomide, 1g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan, and dissolve in 1000ml of aqueous solution containing 100g of mannitol, respectively, Canned into 2g vials, each with a total of 500 vials, placed in a freeze-drying box before capping, vacuum-dried for 24 hours, capped, and taken 1 vial for combined packaging.
  • drugs temozolomide, 1g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan
  • TSL-1502M Take 10g of TSL-1502M, and optionally any one of the following drugs, temozolomide, 5g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan, and dissolve in 1000ml of aqueous solution containing 100g of mannitol, respectively, Canned into 2g vials, each with a total of 500 vials, placed in a freeze-drying box before capping, vacuum-dried for 24 hours, capped, and taken 1 vial for combined packaging.
  • drugs temozolomide, 5g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan
  • TSL-1502M Take 5g of TSL-1502M, and optionally any one of the following drugs, temozolomide, 2.5g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan, and dissolve them in a 1000ml aqueous solution containing 100g of mannitol respectively. , canned into 2g vials, each with a total of 500 vials, placed in a freeze-drying box before capping, vacuum-dried for 24 hours, capped, and 1 vial was combined and packaged, that is.
  • Get TSL-1502M 5g and optionally any one of the following drugs temozolomide, 7-ethyl-10-hydroxycamptothecin, irinotecan, topotecan 5g, respectively dissolve in 1000ml aqueous solution containing 100g mannitol, Canned into 2g vials, each with a total of 500 vials, placed in a freeze-drying box before capping, vacuum-dried for 24 hours, capped, and taken 1 vial for combined packaging.
  • temozolomide 7-ethyl-10-hydroxycamptothecin
  • irinotecan irinotecan
  • topotecan 5g respectively dissolve in 1000ml aqueous solution containing 100g mannitol, Canned into 2g vials, each with a total of 500 vials, placed in a freeze-drying box before capping, vacuum-dried for 24 hours, capped, and taken 1 vial for combined packaging.
  • TSL-1502M Take 50g of TSL-1502M, and optionally any one of the following drugs, temozolomide, 5g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan, and dissolve in 1000ml of aqueous solution containing 100g of mannitol, respectively, Canned into 2g vials, each with a total of 500 vials, placed in a freeze-drying box before capping, vacuum-dried for 24 hours, capped, and taken 1 vial for combined packaging.
  • drugs temozolomide, 5g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan
  • Get TSL-1502M 5g and optionally any one of the following drugs temozolomide, 7-ethyl-10-hydroxycamptothecin, irinotecan, topotecan 50g, respectively dissolve in 1000ml aqueous solution containing 100g mannitol, Canned into 2g vials, each with a total of 500 vials, placed in a freeze-drying box before capping, vacuum-dried for 24 hours, capped, and taken 1 vial for combined packaging.
  • TSL-1502M Take 5g of TSL-1502M, and optionally any one of the following drugs, temozolomide, 10g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan, and dissolve in 1000ml of aqueous solution containing 100g of mannitol, respectively, Canned into 2g vials, each with a total of 500 vials, placed in a freeze-drying box before capping, vacuum-dried for 24 hours, capped, and taken 1 vial for combined packaging.
  • drugs temozolomide, 10g of 7-ethyl-10-hydroxycamptothecin, irinotecan, and topotecan
  • the reference application number is 201910465780.X, the invention name is a kind of PARP inhibitor intermediate TSL-1502M and Example 1 of its preparation method:
  • Quenching after the reaction is completed, slowly add hydrochloric acid (73 g, 2 mol) with a mass percentage concentration of 36 to 38% to the reaction mixture, adjust the pH to between 4 and 5, control the rate of addition, and add 20% sodium hydroxide to the reaction mixture. Absorb a large amount of gas, and control the temperature to 20 °C ⁇ 30 °C in order to prevent the material from being punched.
  • hydrochloric acid 73 g, 2 mol
  • Post-processing S1, the quenched reaction solution is concentrated under reduced pressure to remove ethanol, and the temperature does not exceed 70 °C;
  • the combined organic phase obtained in S7 and S6 is washed twice with 3% aqueous sodium bicarbonate solution and then dried with anhydrous sodium sulfate, filtered to remove the sodium sulfate solid, and the filtrate is concentrated under reduced pressure and then vacuum-dried to obtain the intermediate TSL of the PARP inhibitor. -1502M 226g.
  • TSL-1502 white powder, batch number 120301, purity 99.56%, water content 16.65%, sealed, stored at 2-8°C, provided by the applicant;
  • TSL-1502M white powder, batch number 20150801, purity 98.6%, sealed, stored at 2-8°C, provided by the applicant;
  • ABT-888 (Veliparib, Veliparib): white powder, batch number HM-069-8-20101112, purity 98.12%, sealed, stored at 2-8°C, purchased from Shanghai Haoyuan Company, ABT-888 is a new type of potent PARP-1 and PARP-2 inhibitors, mainly for breast cancer;
  • AZD2281 (Olaparib, Olaparib): white powder, batch number 20131105, purity 99.15%, sealed, stored at 2-8°C, purchased from Shanghai Demo Company, AZD2281 is a PARP inhibitor, approved indications include ovarian cancer , breast cancer, pancreatic cancer, prostate cancer;
  • Temozolomide (abbreviation: TMZ): white powder, batch number 20150418, sealed, stored at 2-8°C, temozolomide is an imidazole tetrazine derivative, mainly used for glioblastoma multiforme;
  • SN-38 (7-ethyl-10-hydroxycamptothecin, the active metabolite of irinotecan.
  • the cas number is 86639-52-3): pale yellow powder, purity 99.1%, batch number E060206, sealed, 2-8°C Preserved, purchased from Shanghai Junjie Biotechnology Company, irinotecan is a semi-synthetic derivative of camptothecin, mainly used for colon (rectal) cancer.
  • TSL-1502, TSL-1502M, AZD2281 and ABT-888 were made into 10 mM stock solution with DMSO, and stored in aliquots at -70°C; TMZ was made into 200 mM stock solution with DMSO, and aliquoted and stored at -70°C.
  • RPMI1640, L-15, F-10, DMEM and IMDM were purchased from Gibco BRL; FBS was purchased from Gibco BRL; SRB was purchased from Sigma; anti-Rad51 primary antibody was purchased from Santa Cruz; anti-P- ⁇ -H2AX and PARP Primary antibody was purchased from Cell Signaling Technology; primary anti- ⁇ -Tubulin antibody was purchased from Sigma; horseradish peroxidase-labeled goat anti-rabbit and goat anti-mouse secondary antibodies were purchased from Calbiochem; Alexa 488 goat anti-rabbit fluorescent secondary antibody was purchased from Molecular Probes Company; Immobilon Western HRP Substrate luminal reagent was purchased from Millipore Company; other common chemical reagents were domestic analytical pure (AR) reagents;
  • Multifunctional microplate reader Synergy H4 was purchased from BioTek Company; carbon dioxide incubator (Model 3111) was purchased from Thermo Company; inverted microscope XDS-1B was purchased from Chongqing Optoelectronics Instrument Co., Ltd.; flow cytometer (FACS Calibur flow cytometer) was purchased from Beckman Dickson company; laser confocal microscope from Olympus; Western blot imager from GlinxScience instruments.
  • SRB method Sulfonylrhodamine B protein staining method
  • a certain number of cells in logarithmic growth phase were seeded in 96-well culture plates. After 24 hours of adherent growth, different concentrations (1, 3, 10, 30, 100, 300, 1000, 3000, 10000 nM) of drugs were added. After 10 days of drug action, cells were fixed with trichloroacetic acid. Then the SRB solution was stained; finally, Tris solution was added to dissolve the SRB, and the OD value was measured at a wavelength of 510 nm by a microplate reader, and the cell growth inhibition rate was calculated by the following formula:
  • Inhibition rate (OD value control well - OD value administration well )/OD value control well ⁇ 100%
  • the median inhibitory concentration IC 50 was calculated.
  • MDA-MB-436 was inoculated in a six-well plate (2 ⁇ 10 5 /ml), added with different concentrations of TSL-1502M or AZD2281 (100, 1000, 10000nM) for 1.5 hours, then 1mM TMZ was added for 0.5 hours, and 1 Cells were lysed with ⁇ SDS gel loading buffer (50 mM Tris-HCl (pH 6.8), 100 mM DTT, 2% SDS, 10% glycerol, 0.1% bromophenol blue). The cell lysate was denatured by heating in a boiling water bath, and subjected to SDS-PAGE electrophoresis.
  • ⁇ SDS gel loading buffer 50 mM Tris-HCl (pH 6.8), 100 mM DTT, 2% SDS, 10% glycerol, 0.1% bromophenol blue.
  • the protein was transferred to a PVDF membrane using a wet transfer system, and the PVDF membrane was placed in blocking solution (5% nonfat dry milk diluted in TBS/T). Block at room temperature, and then react with I and II antibodies; after washing the membrane, use Immobilon Western HRP Substrate luminal reagent to develop color, and take pictures with a Western blot imager.
  • blocking solution 5% nonfat dry milk diluted in TBS/T.
  • TSL-1502 and TSL-1502M inhibit the proliferation of various in vitro cultured tumor cells
  • TSL-1502M has a very significant inhibitory effect on the proliferation of BRCA gene-deficient or mutant cells (V-C8, MDA-MB-436, Capan-1 and UWB1.289), with IC 50 of 0.2 ⁇ 0.0nM and 0.9 ⁇ 0.2nM, respectively , 100.6 ⁇ 73.8nM, 1.9 ⁇ 0.4nM), the inhibitory effect was significantly stronger than its prodrug TSL-1502 (IC 50 were 132.1 ⁇ 4.7nM, 79.6 ⁇ 12.5nM, ⁇ 10000nM, 935.7 ⁇ 526.6nM, respectively), and the reference Than drugs AZD2281 (IC 50 were 18.6 ⁇ 1.3nM, 4.0 ⁇ 0.7nM, 586.1 ⁇ 89.4nM, ⁇ 1nM (inhibition rate was slightly weaker than TSL-1502M)) and ABT-888 (IC 50 were 314.2 ⁇ 24.4nM, 114.7 ⁇ 60.8nM, NA, 2102.5 ⁇ 1470.1nM);
  • TSL-1502M TSL-1502
  • AZD2281 and ABT-888 all had weaker proliferation inhibition.
  • TSL-1502M is more sensitive to BRCA1/2-deficient cells, and has a selective inhibitory effect on cell proliferation. , AZD2281 and ABT-888 strong.
  • TSL-1502 and TSL-1502M synergistic cytotoxic drugs
  • TSL-1502 and TSL-1502M were tested. The results are shown in Tables 3-1, 3-2, 3-3, 3-4 and FIG. 2 .
  • Table 3-1 Inhibitory effect on the proliferation of MDA-MB-436 cells. Inhibition rate (%, Mean ⁇ SD)
  • TSL-1502, TSL-1502M and the reference compounds AZD2281 and ABT-888 could significantly enhance the inhibitory effect of TMZ on the proliferation of MDA-MB-436 cells.
  • TMZ alone ( ⁇ 30 ⁇ M) had almost no inhibitory effect on the proliferation of MDA-MB-436 cells, while 10 ⁇ M TMZ combined with 3nM TSL-1502M had a synergistic effect with a Q value of 1.62; 30 ⁇ M TMZ combined with 3nM or 10nM When used in combination with TSL-1502M, the Q values were 1.84 and 1.16 for synergy.
  • the drug concentrations of TSL-1502M and TMZ in tumor cells or tumor tissues are in the range of 3-10nM and 10-30 ⁇ M, respectively, which have a synergistic effect on tumor inhibition.
  • the better effect is TSL-1502M 3nM and TMZ 10-30 ⁇ M, The better effect is the combination of TSL-1502M 3nM and TMZ 30 ⁇ M.
  • both TSL-1502M and the reference compound AZD2281 can significantly enhance the inhibitory effect of TMZ on the proliferation of SW620 cells.
  • SN38 ⁇ 1nM
  • TSL-1502M ⁇ 10 ⁇ M
  • the highest inhibition rate on SW620 cells was 62.3 ⁇ 18.1, 37.2 ⁇ 17.9; when the two were used in combination, the inhibition rate could be increased to 98.3 ⁇ 1.3%;
  • the combined application of TSL-1502M (3 ⁇ M ⁇ 10 ⁇ M) and SN38 (0.1nM ⁇ 1nM) showed a synergistic effect with Q values greater than 1.15.
  • TSL-1502M has a synergistic effect on cytotoxic drugs in BRCA gene mutation or normal tumor cells.
  • Phosphorylated histone H2AX ( ⁇ -H2AX) is a marker of DNA damage, and we examined the effect of TSL-1502M combined with TMZ on DNA damage repair in BRCA1-mutated MDA-MB-436 cells. After TSL-1502M and the reference compound AZD2281 are combined with TMZ, the results of the effect on ⁇ -H2AX are shown in Figure 3, and the combined part is shown in the circled part in the figure. The results show:
  • TSL-1502M significantly potentiates the proliferation-inhibitory effect of temozolomide on MDA-MB-436 cells (BRCA1 mutant) and the active metabolite of irinotecan SN38 on SW620 cells (normal BRCA1/2); combined with temozolomide induces MDA-MB-436
  • the phosphorylation level of ⁇ -H2AX in the cells was significantly increased, suggesting that the synergistic effect was achieved by promoting the apoptosis of tumor cells; the effect of TSL-1502M was similar to that of the reference compound AZD2281, and the activity of TSL-1502M was stronger than that of AZD2281.

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Abstract

一种含有TSL-1502M的药物组合物及其应用，所述药物组合物是由化合物TSL-1502M和替莫唑胺或伊立替康组成的复方药物组合物，所述药物组合物的制备方法，包括将含有效量的TSL-1502M和有效量的另外一种抗肿瘤药物一起或分别作为药物活性成分，根据制剂学常规技术制备成可供服用的药物组合物，其剂型包括注射剂，对TSL-1502M和其他药物的联合应用进行了研究，TSL-1502M和替莫唑胺、7-乙基-10-羟基喜树碱、伊立替康、拓扑替康联合使用具有协同增效作用。

Description

一种含有TSL-1502M的药物组合物及其应用 技术领域
本发明属于药物制备技术领域，具体涉及一种含有PARP抑制剂TSL-1502的中间体TSL-1502M的药物组合物及其应用。
背景技术
PARP抑制剂TSL-1502，化学名为(2S,3S,4S,5R,6S)-3,4,5-三羟基-6-(3-甲基-1-((S)-1-丙基吡咯烷-3-基)-6,7,8,9-四氢-3H-吡唑并[3,4-c]异喹啉-5-氧基)四氢-2H-吡喃-2-甲酸的化合物(设定其编号为TSL-1502)，该化合物最早出现在201180002886.8(公开号为CN102510863A，授权公告号为CN102510863B，以下简称为2011年专利)的0177段化合物，其结构式见式Ⅰ。
Figure PCTCN2020140555-appb-000001
上述专利在权利要求16公开了具体肿瘤类型，如头部癌、甲状腺癌、颈癌、眼癌、皮肤癌、口腔癌、咽喉癌、食道癌、胸癌、骨癌、血癌、骨髓癌、肺癌、结肠癌、乙状结肠癌、直肠癌、胃癌、前列腺癌、乳腺癌、卵巢癌、肾癌、肝癌、胰腺癌、脑癌、肠癌、心脏癌、肾上腺癌、皮下组织癌、淋巴结癌、色素癌、恶性神经胶质瘤等。然而实际上，也仅在实施例19证实了黑色素瘤、人乳腺癌细胞株的治疗效果，对其他肿瘤没有涉及。
TSL-1502M，是制备TSL-1502的中间体，其申请号为201910465780.X，发明名称为一种PARP抑制剂的中间体TSL-1502M及其制备方法，(申请日为2019年05月31日，公开号为CN112010850A)，结构式见式Ⅱ，
Figure PCTCN2020140555-appb-000002
式Ⅱ化合物设定其编号为：TSL-1502M，其作为中间体即可以用于制备TSL-1502，又可以用于TSL-1502的检测，作为对照品是有用的。但是该文献中并没有公开TSL-1502M的药物用途信息及与其他抗癌药物组合的相关信息。
发明人在研究TSL-1502M时，意外发现其对PARP酶的抑制活性高于TSL-1502，提示了其作为PARP抑制剂的药物用途。
TSL-1502M和其他药物联合应用未见报道，本发明对TSL-1502M和其他药物的联合应用进行了研究，意外的发现，其和替莫唑胺，7-乙基-10-羟基喜树碱、伊立替康、拓扑替康联合使用具有协同增效作用。
发明内容
本发明提供一种含有TSL-1502M和另外一种抗肿瘤药物的复方药物组合物，其中，所述TSL-1502M结构如下
Figure PCTCN2020140555-appb-000003
其中所述另外一种抗肿瘤药物选自替莫唑胺，7-乙基-10-羟基喜树碱、伊立替康、拓扑替康。
本发明包括含有TSL-1502M和另外一种抗肿瘤药物两种活性成分的药物制剂组合物，或分立的含有TSL-1502M和另外一种抗肿瘤药物的药物制剂，两种制剂包装在一起的组合。
本发明所述的药物组合物的制备包括将含有TSL-1502M和另外一种抗肿瘤药物混合的步骤。
或将含有TSL-1502M和另外一种抗肿瘤药物分别制备成药物制剂，将两种制剂组合包装在一起，使用时可以方便的联合应用两种药物。如所述组合包装可以将TSL-1502M制备成注射剂，另外一种抗肿瘤药物制备成注射剂，两种单位剂量的注射剂一起包装在同一个包装盒中，使用时可以分别注射，也可以一起注射。
本发明所述的TSL-1502M和另外一种抗肿瘤药物的药物组合物，其中每一种药物的剂量采用药物有效量，所述“有效量”是指每一种药物单独或联合应用时能够实现临床上预防或治疗疾病而起效的量。如制备成注射剂，是单位剂量形式，如分装成不同颜色，不同规格大 小的无菌小瓶，每瓶含有药物活性成分0.1-2000mg，小瓶封装后，再置入包装盒子中；还可进一步置入可装有2-100瓶的包装盒子中，方便储存和运输。
本发明所述组药物合物包含TSL-1502M和另外一种抗肿瘤药物，两者重量比可以根据各自的有效量进行配比，如为1∶1000至1000∶1。
对于乳腺癌，TSL-1502M和替莫唑胺的重量比为3-10nm：10-30μm，优选为3nm：10-30μm。
对于大肠癌或结肠癌，TSL-1502M和7-乙基-10-羟基喜树碱或伊立替康的重量为3-10μM：0.1-1nM，优选为3-10μM：0.1nM。
本发明所述的药物组合物的制备方法，包括将含所需量的TSL-1502M和另外一种抗肿瘤药物一起或分别作为药物活性成分，根据制剂学常规技术制备成可供服用的药物制剂组合物，其剂型包括，注射剂，优选干粉注射剂，特别优选冷冻干燥注射剂。
本发明的注射剂可以不加入辅料或加入一种或多种药用辅料，如：葡萄糖，乳糖，甘露醇，氯化钠，羟丙基-B-环糊精等，然后使用适当的方法制成注射剂。
本发明的使用方法包括，将含所需量的TSL-1502M和另外一种抗肿瘤药物一起作为两种药物活性成分制备成注射剂一起注射使用。也可将含所需量的TSL-1502M和另外一种抗肿瘤药物分别作成注射剂，分别注射使用。
本发明所述药物制剂组合物，可以是任何可服用的药物形式：如：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、滴剂、贴剂。
本发明的药物制剂组合物，优选的是单位剂量的药物制剂形式，如在制成药剂时，单位剂量的药剂可含有本发明的TSL-1502M，以及另外一种抗肿瘤药物0.1-1000mg，其余为药学上可接受的辅料。药学上可接受的辅料以重量计可以是制剂总重量的0.01-99.99％。
本发明的药物制剂组合物在使用时根据病人的情况确定用法用量，如一日1-3次，一次1-20片等。
优选的，本发明的药物制剂组合物为口服制剂或注射剂。其中，所述口服制剂选自胶囊剂、片剂、滴丸、颗粒剂、浓缩丸、口服液中的一种。其中，所述注射剂选自液体、半固体，固体，粉剂形式，优选注射液，粉针中的一种。
本发明的药物制剂组合物，其口服给药的制剂可含有辅料，诸如粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色剂、调味剂和湿润剂，必要时可对片剂进行包衣。
适用的填充剂包括纤维素、甘露糖醇、乳糖和其它类似的填充剂。适宜的崩解剂包括淀 粉、聚乙烯吡咯烷酮和淀粉衍生物，例如羟基乙酸淀粉钠。适宜的润滑剂包括，例如硬脂酸镁。适宜的药物可接受的湿润剂包括十二烷基硫酸钠。
本发明的药物制剂可通过混合，填充，压片等常用的方法制备固体口服组合物。进行反复混合可使活性物质分布在整个使用大量填充剂的那些组合物中。
口服液体制剂的形式例如可以是水性或油性悬浮液、溶液、乳剂、糖浆剂或酏剂，或者可以是一种在使用前可用水或其它适宜的载体复配的干燥产品。这种液体制剂可含有常规的添加剂，诸如悬浮剂，例如山梨醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化食用脂肪，乳化剂，例如卵磷脂、脱水山梨醇一油酸酯或阿拉伯胶；非水性载体(它们可以包括食用油)，例如杏仁油、分馏椰子油、诸如甘油的酯的油性酯、丙二醇或乙醇；防腐剂，例如对羟基苯甲酯或对羟基苯甲酸丙酯或山梨酸，并且如果需要，可含有常规的香味剂或着色剂。
对于注射剂，制备的液体单位剂型含有本发明的活性物质和无菌载体。根据载体和浓度，可以将此化合物悬浮或者溶解。溶液的制备通常是通过将活性物质溶解在一种载体中，在将其装入一种适宜的小瓶或安瓿前过滤消毒，然后密封。辅料例如一种局部麻醉剂、防腐剂和缓冲剂也可以溶解在这种载体中。为了提高其稳定性，可在装入小瓶以后将这种组合物冰冻，并在真空下将水除去。
本发明进一步提供本发明的组合物在制备抗肿瘤药物中的应用，所述应用时，TSL-1502M和另外一种抗肿瘤药物的使用剂量可以是一天0.01mg-2000mg。
本发明的应用取得了意想不到的技术效果，有关应用的实例见本发明实验例。
本发明提供的抗肿瘤的药物组合，具有以下特点：
1、发明人试验发现，TSL-1502M明显增效替莫唑胺对MDA-MB-436细胞(乳腺癌细胞株)的增殖抑制作用；与替莫唑胺合用后诱导MDA-MB-436细胞的γ-H2AX磷酸化水平显著增加，促进肿瘤细胞的细胞凋亡过程。
2、TSL-1502M与替莫唑胺合用后，对肿瘤细胞的抑制作用优于单独使用TSL-1502M或替莫唑胺，如表3-1所示，单独给予TSL-1502M在浓度为30nM时对MDA-MB-436细胞(乳腺癌)的抑制率为67.5±1.5％，单独使用TMZ在30μM时的抑制率为8.5±3.5％，二者联合可进一步将MDA-MB-436细胞增殖抑制率提高到80.2±3.5％，这种协同增效作用在较低的药物浓度时更为明显。
3、TSL-1502M明显增效伊立替康活性代谢产物SN38对SW620细胞(结肠癌细胞株)的增殖抑制作用。
4、TSL-1502M与伊立替康活性代谢产物SN38合用，对肿瘤细胞的抑制作用优于单独使 用TSL-1502M或替莫唑胺。如表3-2所示，单独给予TSL-1502M在浓度为10μM时对SW620细胞(大肠癌，具体为结肠癌)的抑制率为37.2±17.9％，单独使用SN38(伊立替康的活性代谢物)在1nM时的抑制率为62.3±18.1％，二者联合可进一步将MDA-MB-436细胞增殖抑制率提高到98.3±1.3％，这种协同增效作用在较低的药物浓度时更为明显。
附图说明
图1：TSL-1502及TSL-1502M对体外培养细胞增殖的影响；
图2：TSL-1502、TSL-1502M与细胞毒药物合用对MDA-MB-436、SW620细胞增殖的抑制作用；
图3：TSL-1502M对MDA-MB-436细胞γ-H2AX磷酸化的影响。
具体实施方式
实施例1
本发明提供TSL-1502M和另外一种抗肿瘤药物替莫唑胺，7-乙基-10-羟基喜树碱、伊立替康、拓扑替康组成的复方药物冷冻干燥注射剂，
制备实例：
取TSL-1502M 20g，以及任选的以下任意一种药物替莫唑胺，7-乙基-10-羟基喜树碱、伊立替康、拓扑替康10g，分别溶于含有100g甘露醇的1000ml水溶液中，分别罐装到2g的小瓶中，各共计500瓶，封盖前，置入冷冻干燥箱中，真空干燥24小时，封盖，各取1瓶组合包装，即得。
实施例2
取TSL-1502M 5g，以及任选的以下任意一种药物替莫唑胺，7-乙基-10-羟基喜树碱、伊立替康、拓扑替康10g，共同溶于含有100g甘露醇的1000ml水溶液中，混合均匀，罐装到2g的小瓶中，共计500瓶，封盖前，置入冷冻干燥箱中，真空干燥24小时，封盖，包装，即得。
或
取TSL-1502M 5g，以及任选的以下任意一种药物替莫唑胺，7-乙基-10-羟基喜树碱、伊立替康、拓扑替康20g，共同溶于含有100g甘露醇的1000ml水溶液中，混合均匀，罐装到2g的小瓶中，共计500瓶，封盖前，置入冷冻干燥箱中，真空干燥24小时，封盖，包装，即得。
或
取TSL-1502M 5g，以及任选的以下任意一种药物替莫唑胺，7-乙基-10-羟基喜树碱、伊立替康、拓扑替康50g，共同溶于含有100g甘露醇的1000ml水溶液中，混合均匀，罐装到 2g的小瓶中，共计500瓶，封盖前，置入冷冻干燥箱中，真空干燥24小时，封盖，包装，即得。
或
取TSL-1502M 5g，以及任选的以下任意一种药物替莫唑胺，7-乙基-10-羟基喜树碱、伊立替康、拓扑替康100g，共同溶于含有100g甘露醇的1000ml水溶液中，混合均匀，罐装到2g的小瓶中，共计500瓶，封盖前，置入冷冻干燥箱中，真空干燥24小时，封盖，包装，即得。
或
取TSL-1502M 10g，以及任选的以下任意一种药物替莫唑胺，7-乙基-10-羟基喜树碱、伊立替康、拓扑替康5g，共同溶于含有100g甘露醇的1000ml水溶液中，混合均匀，罐装到2g的小瓶中，共计500瓶，封盖前，置入冷冻干燥箱中，真空干燥24小时，封盖，包装，即得。或
取TSL-1502M 20g，以及任选的以下任意一种药物替莫唑胺，7-乙基-10-羟基喜树碱、伊立替康、拓扑替康5g，共同溶于含有100g甘露醇的1000ml水溶液中，混合均匀，罐装到2g的小瓶中，共计500瓶，封盖前，置入冷冻干燥箱中，真空干燥24小时，封盖，包装，即得。或
取TSL-1502M 50g，以及任选的以下任意一种药物替莫唑胺，7-乙基-10-羟基喜树碱、伊立替康、拓扑替康5g，共同溶于含有100g甘露醇的1000ml水溶液中，混合均匀，罐装到2g的小瓶中，共计500瓶，封盖前，置入冷冻干燥箱中，真空干燥24小时，封盖，包装，即得。或
取TSL-1502M 100g，以及任选的以下任意一种药物替莫唑胺，7-乙基-10-羟基喜树碱、伊立替康、拓扑替康5g，共同溶于含有100g甘露醇的1000ml水溶液中，混合均匀，罐装到2g的小瓶中，共计500瓶，封盖前，置入冷冻干燥箱中，真空干燥24小时，封盖，包装，即得。
实施例3
取TSL-1502M 2g，以及任选的以下任意一种药物替莫唑胺，7-乙基-10-羟基喜树碱、伊立替康、拓扑替康1g，分别溶于含有100g甘露醇的1000ml水溶液中，分别罐装到2g的小瓶中，各共计500瓶，封盖前，置入冷冻干燥箱中，真空干燥24小时，封盖，各取1瓶组合包装，即得。
或
取TSL-1502M 10g，以及任选的以下任意一种药物替莫唑胺，7-乙基-10-羟基喜树碱、伊 立替康、拓扑替康5g，分别溶于含有100g甘露醇的1000ml水溶液中，分别罐装到2g的小瓶中，各共计500瓶，封盖前，置入冷冻干燥箱中，真空干燥24小时，封盖，各取1瓶组合包装，即得。
实施例4
取TSL-1502M 5g，以及任选的以下任意一种药物替莫唑胺，7-乙基-10-羟基喜树碱、伊立替康、拓扑替康2.5g，分别溶于含有100g甘露醇的1000ml水溶液中，罐装到2g的小瓶中，各共计500瓶，封盖前，置入冷冻干燥箱中，真空干燥24小时，封盖，各取1瓶组合包装，即得。
实施例5
取TSL-1502M 5g，以及任选的以下任意一种药物替莫唑胺，7-乙基-10-羟基喜树碱、伊立替康、拓扑替康5g，分别溶于含有100g甘露醇的1000ml水溶液中，分别罐装到2g的小瓶中，各共计500瓶，封盖前，置入冷冻干燥箱中，真空干燥24小时，封盖，各取1瓶组合包装，即得。
实施例6
取TSL-1502M 50g，以及任选的以下任意一种药物替莫唑胺，7-乙基-10-羟基喜树碱、伊立替康、拓扑替康5g，分别溶于含有100g甘露醇的1000ml水溶液中，分别罐装到2g的小瓶中，各共计500瓶，封盖前，置入冷冻干燥箱中，真空干燥24小时，封盖，各取1瓶组合包装，即得。
实施例7
取TSL-1502M 5g，以及任选的以下任意一种药物替莫唑胺，7-乙基-10-羟基喜树碱、伊立替康、拓扑替康50g，分别溶于含有100g甘露醇的1000ml水溶液中，分别罐装到2g的小瓶中，各共计500瓶，封盖前，置入冷冻干燥箱中，真空干燥24小时，封盖，各取1瓶组合包装，即得。
实施例8
取TSL-1502M 5g，以及任选的以下任意一种药物替莫唑胺，7-乙基-10-羟基喜树碱、伊立替康、拓扑替康10g，分别溶于含有100g甘露醇的1000ml水溶液中，分别罐装到2g的小瓶中，各共计500瓶，封盖前，置入冷冻干燥箱中，真空干燥24小时，封盖，各取1瓶组合包装，即得。
实施例9：TSL-1502M的制备
参考申请号为201910465780.X，发明名称为一种PARP抑制剂的中间体TSL-1502M及其制备方法的实施例1：
反应：反应釜中，加入主原料(S)-3-甲基-1-(吡咯烷-3-基)-3,4,6,7,8,9-六氢-5H-吡唑并[3,4-c]异喹啉-5-酮(2S,3S)-2,3-二(苯甲酰氧基)丁二酸盐(630.0g，1mol)和乙醇(3800mL)，搅拌，降温至10℃，加入氰基硼氢化钠(125.7g，2mol)，再滴加丙醛(116.2g，2mol)，滴加过程中温度不超过20℃，滴加完毕后，继续在10℃～25℃搅拌反应1h～2h。
淬灭：反应结束后，向反应混合物中缓慢滴加质量百分浓度为36～38％的盐酸(73g，2mol)，调节pH至4-5之间，控制滴加速度，以20％氢氧化钠吸收大量冒出的气体，为防止冲料，同时控制温度为20℃～30℃。
后处理：S1、淬灭后的反应液减压浓缩蒸除乙醇，温度不超过70℃；
S2、向S1的残留物中加入水与二氯甲烷(水与二氯甲烷的重量比为1：4)，使用量为式Ⅰ化合物重量的7倍，在5℃～15℃温度下用40％的氢氧化钠水溶液调节混合液的pH至9～10，搅拌，静置，分层，有机相保留；
S3、S2所得水相用二氯甲烷继续萃取1次，所得有机相与S2所得有机相合并，水相保留；
S4、S3所得合并后的有机相用40％的氢氧化钠水溶液萃取，所得水相与S3所得水相合并，有机相保留；
S5、S4所得合并后的水相用36～38％的盐酸调节pH至4～5，再加入二氯甲烷，二氯甲烷使用量为式Ⅰ化合物重量的5倍，搅拌后静置分层，有机相保留；
S6、S5所得水相用二氯甲烷继续萃取2次，所得有机相与S4、S5所得有机相合并；
S7、S6所得合并后的有机相用3％碳酸氢钠水溶液洗涤2次后再用无水硫酸钠干燥，过滤除去硫酸钠固体，滤液减压浓缩后真空干燥，得到PARP抑制剂的中间体TSL-1502M 226g。
实验例1
一、实验材料
1、受试药物
TSL-1502：白色粉末，批号120301，纯度99.56％，含水量16.65％，密封，2-8℃保存，申请人自备；
TSL-1502M:白色粉末，批号20150801，纯度98.6％，密封，2-8℃保存，申请人自备；
ABT-888(维利帕尼，Veliparib)：白色粉末，批号HM-069-8-20101112，纯度98.12％，密封，2-8℃保存，购自上海皓元公司，ABT-888是一种新型的强效PARP-1和PARP-2抑制剂，主要用于乳腺癌；
AZD2281(奥拉帕利，Olaparib)：白色粉末，批号20131105，纯度99.15％，密封，2-8℃保存，购自上海德默公司，AZD2281是一种PARP抑制剂，已批准适应症包括卵巢癌、乳腺 癌、胰腺癌、前列腺癌；
替莫唑胺(简称：TMZ)：白色粉末，批号20150418，密封，2-8℃保存，替莫唑胺是咪唑四嗪衍生物，主要用于多形性胶质母细胞瘤；
SN-38(伊立替康的活性代谢物7-乙基-10-羟基喜树碱。cas号为86639-52-3)：淡黄色粉末，纯度99.1％，批号E060206，密封，2-8℃保存，购自上海骏杰生物技术公司，伊立替康是喜树碱的半合成衍生物，主要用于结肠(直肠)癌。
2、药品配制方法：
TSL-1502、TSL-1502M、AZD2281和ABT-888用DMSO配成10mM的原液，分装保存于-70℃；TMZ用DMSO配成200mM的原液，分装保存于-70℃。
3、细胞株选择依据及细胞株来源
参考FDA批准上市的PARP抑制剂Olaparib(LYNPARZA)、Rucaparib(RUBRACA)和Niraparib(ZEJULA)的药效学研究情况，选择BRCA1/2突变型及野生型细胞来评价TSL-1502及其代谢产物的体外抗肿瘤活性。细胞来源及培养条件见表1
表1：细胞来源及类型
Figure PCTCN2020140555-appb-000004
4、试剂及仪器
RPMI1640，L-15，F-10，DMEM及IMDM购自Gibco BRL公司；FBS购自Gibco BRL公司；SRB购自Sigma公司；抗Rad51一抗购自Santa Cruz公司；抗P-γ-H2AX和PARP一抗购自Cell Signaling Technology公司；抗β-Tubulin一抗购自Sigma公司；辣根过氧化酶标记的羊抗兔和羊抗鼠二抗购自Calbiochem公司；Alexa
Figure PCTCN2020140555-appb-000005
488 goat anti-rabbit荧光二抗购自Molecular Probes公司；Immobilon Western HRP Substrate luminal reagent购自Millipore公司；其它普通的化学试剂系国产分析纯(AR)试剂；
多功能酶标仪Synergy H4购自BioTek公司；二氧化碳培养箱(Model 3111)购自Thermo公司；倒置显微镜XDS-1B购自重庆光电仪器有限公司；流式细胞仪(FACS Calibur flow  cytometer)购自Beckman Dickson公司；激光共聚焦显微镜购自奥林巴斯公司；Western blot成像仪购自GlinxScience instruments。
二、实验方法
1、磺酰罗丹明B蛋白染色法(SRB法)
接种一定数量的对数生长期细胞于96孔培养板。贴壁生长24小时后，加入不同浓度(1、3、10、30、100、300、1000、3000、10000nM)的药物。药物作用10天后，用三氯乙酸固定细胞。然后SRB溶液染色；最后加入Tris溶液溶解SRB，酶标仪510nm波长下测定OD值，以下列公式计算细胞生长抑制率：
抑制率＝(OD值 对照孔－OD值 给药孔)/OD值 对照孔×100％
根据各浓度抑制率，计算半数抑制浓度IC 50。
2、Western blot法
γ-H2AX的磷酸化的检测：
MDA-MB-436接种于六孔板(2×10 5/ml)，加入不同浓度的TSL-1502M或AZD2281(100、1000、10000nM)作用1.5小时后，再加入1mM TMZ作用0.5小时，加入1×SDS凝胶上样缓冲液(50mM Tris-HCl(pH 6.8)，100mM DTT，2％SDS，10％甘油，0.1％溴酚蓝)裂解细胞。细胞裂解物在沸水浴中加热变性，进行SDS-PAGE电泳，电泳结束后，用湿转系统将蛋白转移至PVDF膜，将PVDF膜置于封闭液(5％脱脂奶粉稀释于TBS/T)中室温封闭，然后I，II抗反应；洗膜后，用Immobilon Western HRP Substrate luminal reagent试剂发色，Western blot成像仪拍照。
三、实验结果
1、TSL-1502、TSL-1502M抑制多种体外培养肿瘤细胞的增殖
TSL-1502、AZD2281、ABT-888作用于细胞240小时(120小时更换新配药物一次)后，检测其对细胞的增殖抑制作用。结果如表2和图1所示：
对BRCA基因缺陷或突变细胞(V-C8、MDA-MB-436、Capan-1和UWB1.289)，TSL-1502M的增殖抑制作用十分显著，IC 50分别为0.2±0.0nM、0.9±0.2nM、100.6±73.8nM、1.9±0.4nM)，该抑制作用显著强于其前药TSL-1502(IC 50分别为132.1±4.7nM、79.6±12.5nM、≈10000nM、935.7±526.6nM)，以及参比药物AZD2281(IC 50分别为18.6±1.3nM、4.0±0.7nM、586.1±89.4nM、≈1nM(抑制率稍弱于TSL-1502M))和ABT-888(IC 50分别为314.2±24.4nM、114.7±60.8nM、NA、2102.5±1470.1nM)；
但对BRCA1突变的HCC1937细胞，TSL-1502M、TSL-1502、AZD2281和ABT-888的增殖抑制均较弱。
对BRCA基因正常细胞(V-C8#13-5和UWB1.289BRCA1)，TSL-1502M、TSL-1502、AZD2281和ABT-888的增殖抑制作用均较弱；但对BRCA功能正常的MDA-MB-468细胞，TSL-1502M和AZD2281有一定增殖抑制作用(IC 50分别为73.6±19.5nM和541.1±93.8nM)。
总体而言，TSL-1502M对BRCA1/2功能缺陷的细胞更为敏感，对细胞的增殖抑制作用具有选择性，其选择性的作用特点与AZD2281和ABT-888相似，其抑制作用比TSL-1502、AZD2281和ABT-888强。
表2：对体外培养细胞增殖的影响(n＝2)
Figure PCTCN2020140555-appb-000006
2、TSL-1502、TSL-1502M增效细胞毒药物抗肿瘤活性
检测了TSL-1502和TSL-1502M与细胞毒药物的联合抗肿瘤作用。结果如表3-1、3-2、3-3、3-4和图2所示。
2.1 TSL-1502和TSL-1502M对MDA-MB-436细胞的增殖抑制作用：见表3-1
表3-1：对MDA-MB-436细胞增殖的抑制作用。抑制率(％，Mean±SD)
Figure PCTCN2020140555-appb-000007
Figure PCTCN2020140555-appb-000008
表3-2金氏公式计算TSL-1502M和TMZ两种药物的联合作用Q值
C 1502M(nM) C TMZ(μM) Q 协同作用
3 10 1.62 是
10 10 1.13 否
30 10 1.10 否
3 30 1.84 是
10 30 1.16 是
30 30 1.14 否
在BRCA1突变的MDA-MB-436细胞中，TSL-1502、TSL-1502M和参比化合物AZD2281、ABT-888均能够明显增效TMZ对MDA-MB-436细胞的增殖抑制作用。单独使用TMZ(≤30μM)对MDA-MB-436细胞的增殖几乎没有抑制作用，而10μM的TMZ与3nM的TSL-1502M联合使用时，Q值为1.62具有协同作用；30μM的TMZ与3nM或10nM的TSL-1502M联合使用时，Q值分别为1.84和1.16具有协同作用。即肿瘤细胞或肿瘤组织中TSL-1502M与TMZ的药物浓度分别在3-10nM和10-30μM范围内，对肿瘤的抑制具有协同作用，效果较佳的是TSL-1502M 3nM和TMZ 10-30μM，效果更佳的是TSL-1502M 3nM和TMZ 30μM的组合。
2.2：TSL-1502和TSL-1502M对SW620细胞的增殖抑制作用。见表3-3
表3-3：对SW620细胞的增殖抑制作用。抑制率(％，Mean±SD)
Figure PCTCN2020140555-appb-000009
表3-4金氏公式计算TSL-1502M和SN38两种药物的联合作用Q值
C 1502M(μM) C  SN38(nM) Q 协同作用
3 1 1.41 是
10 1 1.29 是
3 0.1 2.01 是
10 0.1 1.51 是
在BRCA基因正常的SW620细胞中，TSL-1502M和参比化合物AZD2281均能够明显增效TMZ对SW620细胞的增殖抑制作用。单独给予SN38(≤1nM)或TSL-1502M(≤10μM)，对SW620细胞的抑制率最高分别为62.3±18.1、37.2±17.9；当两者联合使用时，抑制率可提高到98.3±1.3％；TSL-1502M(3μM～10μM)和SN38(0.1nM～1nM)联合应用，Q值均大于1.15具有协同作用。
上述结果表明，在BRCA基因突变或正常的肿瘤细胞中，TSL-1502M对细胞毒药物均有增效作用。
3、TSL-1502M与TMZ合用明显增强MDA-MB-436细胞γ-H2AX的磷酸化
磷酸化的组蛋白H2AX(γ-H2AX)是DNA损伤的标志物，我们在BRCA1突变的MDA-MB-436细胞中检测了TSL-1502M与TMZ合用后对DNA损伤修复的影响。TSL-1502M以及参比对照化合物AZD2281合用TMZ后，对γ-H2AX的影响结果见图3，合用部分见图中圆圈的部分，结果显示：
TSL-1502M或参比化合物AZD2281与TMZ合用后γ-H2AX的磷酸化明显增强。
上述结果表明，TSL-1502M及AZD2281能抑制DNA损伤修复，TSL-1502M活性强于AZD2281。
试验结论：
TSL-1502M明显增效替莫唑胺对MDA-MB-436细胞(BRCA1突变)和伊立替康活性代谢产物SN38对SW620细胞(BRCA1/2正常)的增殖抑制作用；与替莫唑胺合用后诱导MDA-MB-436细胞的γ-H2AX磷酸化水平显著增加，提示协同增效作用通过促进肿瘤细胞的细胞凋亡而实现；TSL-1502M的作用特点与参比化合物AZD2281相似，TSL-1502M的活性比AZD2281强。

Claims (10)

  1. 一种含有TSL-1502M的药物组合物，由TSL-1502M和另外一种抗肿瘤药物组成，其中，所述TSL-1502M结构如下：
    Figure PCTCN2020140555-appb-100001
  2. 根据权利要求1所述的药物组合物，其特征在于，包括含有TSL-1502M和另外一种抗肿瘤药物两种活性成分的药物制剂组合物，或分立的含有TSL-1502M和另外一种抗肿瘤药物的药物制剂，两种制剂包装在一起的组合。
  3. 根据权利要求1所述的药物组合物，其特征在于，该药物组合物是注射剂，单位剂量形式，每单位剂量含有药物活性成分0.1-2000mg。
  4. 根据权利要求1所述的药物组合物，其特征在于，包含TSL-1502M和另外一种抗肿瘤药物，两者重量比为1∶1000至1000∶1。
  5. 根据权利要求1所述的药物组合物，其特征在于，每一种药物的剂量采用药物有效量。
  6. 根据权利要求1所述的药物组合物，其特征在于，该药物组合物是任何可服用的药物形式。
  7. 根据权利要求1所述的药物组合物，其特征在于，所述另外一种抗肿瘤药物选自替莫唑胺，7-乙基-10-羟基喜树碱、伊立替康、拓扑替康。
  8. 根据权利要求1所述的药物组合物，其特征在于，其使用方法包括，将含所需量的TSL-1502M和另外一种抗肿瘤药物一起作为两种药物活性成分制备成注射剂一起注射使用，也可将含所需量的TSL-1502M和另外一种抗肿瘤药物分别作成注射剂，分别注射使用。
  9. 根据权利要求1-8任一项所述的药物组合物的制备方法，包括将含所需量的TSL-1502M和另外一种抗肿瘤药物一起或分别作为药物活性成分，根据制剂学常规技术制备成可供服用的药物组合物。
  10. 根据权利要求9所述的制备方法，其特征在于，该药物组合物的剂型为注射剂其中可以不加入辅料或加入一种或多种药用辅料，所述辅料选自：葡萄糖，乳糖，甘露醇，氯化钠，羟丙基-B-环糊精，然后制成注射剂。
PCT/CN2020/140555 2020-07-30 2020-12-29 一种含有tsl-1502m的药物组合物及其应用 WO2022021785A1 (zh)

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