WO2024255830A1 - Utilisation d'un inhibiteur d'akt dans la préparation d'un médicament pour la prévention ou le traitement du cancer de l'ovaire - Google Patents

Utilisation d'un inhibiteur d'akt dans la préparation d'un médicament pour la prévention ou le traitement du cancer de l'ovaire Download PDF

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WO2024255830A1
WO2024255830A1 PCT/CN2024/099152 CN2024099152W WO2024255830A1 WO 2024255830 A1 WO2024255830 A1 WO 2024255830A1 CN 2024099152 W CN2024099152 W CN 2024099152W WO 2024255830 A1 WO2024255830 A1 WO 2024255830A1
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compound
once
formula
administration
ovarian cancer
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Chinese (zh)
Inventor
苗雷
田婷
左锐
赵廷丽
司亚璇
季晓君
周秋华
代清宇
马昌友
吴舰
徐丹
朱春霞
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Nanjing Chia Tai Tianqing Pharmaceutical Co Ltd
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Nanjing Chia Tai Tianqing Pharmaceutical Co Ltd
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Priority to CN202480031871.1A priority Critical patent/CN121419774A/zh
Publication of WO2024255830A1 publication Critical patent/WO2024255830A1/fr
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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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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 belongs to the field of biomedicine. Specifically, the present application relates to the use of an AKT inhibitor in the preparation of a drug for preventing or treating ovarian cancer.
  • Cancer is a disease with a high mortality rate second only to cardiovascular disease.
  • Ovarian cancer is a common malignant tumor in women, and its mortality rate ranks first among all tumor-related deaths in women. Since ovarian cancer lacks obvious external symptoms in the early stages and the disease is hidden, it is very easy to be misdiagnosed. Most ovarian cancer patients have metastases when diagnosed, and simple surgical treatment is difficult to completely eliminate the tumor, so postoperative recurrence is very likely to occur. More than 70% of patients are already in the advanced stage when diagnosed, and about 70% of patients relapse within two years after surgery.
  • Drug therapy is an adjunct to surgical treatment of ovarian cancer, and commonly used therapeutic drugs are platinum compounds.
  • Platinum compounds such as cisplatin and carboplatin
  • tumor cells are initially sensitive to platinum treatment, ovarian cancer patients are prone to drug resistance, and resistance to platinum may be attributed to upregulation of the ABCB1 gene, reversal of BRCA1 and BRCA2 germline alleles, or impaired apoptosis pathways. Therefore, there is an urgent need to develop a reliable drug to treat drug-resistant ovarian cancer.
  • Targeted therapy specifically targets the altered genes or proteins in tumor cells, and has the advantages of strong specificity, significant efficacy, and low toxicity and side effects. It has become a new treatment method besides the three traditional treatment methods of surgery, radiotherapy, and chemotherapy.
  • PARP-1 inhibitors are new molecular targeted anti-tumor drugs developed and marketed in recent years. They are clinically applicable to patients with advanced ovarian cancer with or without mutations in the tumor suppressor gene BRCA. PARP-1 inhibitors work through a "synergistic lethal effect", that is, in the case of DNA homologous recombination defects caused by BRCA mutations, the simultaneous action of PARP-1 inhibitors and BRCA gene mutations can further aggravate DNA damage, causing ovarian cancer cells with BRCA mutations to die because their DNA cannot be repaired by recombination.
  • PARP-1 inhibitors including olaparib, rucaparib, niraparib, talazoparib and fluzoparib, have been approved for marketing or are in clinical research.
  • AKT is a type of serine/threonine kinase that affects cell survival, growth, metabolism, proliferation, migration and differentiation through numerous downstream effectors. More than 50% of human tumors have overactivated AKT. Overactivation of AKT can lead to tumorigenesis, metastasis and drug resistance.
  • AKT has three subtypes: AKT1, AKT2 and AKT3. As a typical protein kinase, each subtype consists of an amino-terminal PH domain (Pleckstrin homology domain), a middle ATP-binding kinase domain and a carboxyl-terminal regulatory domain. About 80% of the amino acid sequences of the three subtypes are homologous, with only large changes in the PH domain and kinase domain connection region. Therefore, molecular targeted therapy targeting AKT is also an important direction for the current development of tumor targeted drugs.
  • WO2020156437A1 discloses a compound represented by formula (A), the chemical name of which is (R)-4-((1S, 6R)-5-((S)-2-(4-chlorophenyl)-3-(isopropylamino)propanoyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one, and the chemical molecular formula is shown in the following formula (A):
  • the compound represented by formula (A) is an AKT protein kinase inhibitor, which can effectively inhibit the activity of AKT kinase and is used for the treatment of locally advanced or metastatic solid tumors.
  • AKT protein kinase inhibitor which can effectively inhibit the activity of AKT kinase and is used for the treatment of locally advanced or metastatic solid tumors.
  • the purpose of the present invention is to overcome the above-mentioned defects and shortcomings in the prior art, and to provide a use of an AKT inhibitor in the preparation of a drug for preventing or treating ovarian cancer, and in particular to provide a use of an AKT inhibitor in combination with other ovarian cancer therapeutic drugs in the preparation of a drug for preventing or treating ovarian cancer.
  • the present invention provides the following technical solutions:
  • a use of an AKT inhibitor in the preparation of a drug for preventing or treating ovarian cancer wherein the AKT inhibitor is a compound represented by formula (I) (hereinafter collectively referred to as the compound of formula (I)) or a pharmaceutically acceptable salt or hydrate thereof,
  • the compound of formula (I) is a compound of formula (A) or a compound of formula (B):
  • the present invention also provides a use of an AKT inhibitor in the preparation of a drug for preventing or treating ovarian cancer, wherein the AKT inhibitor is of formula (A):
  • the compound shown hereinafter collectively referred to as the compound of formula (A)) or a pharmaceutically acceptable salt or hydrate thereof.
  • the ovarian cancer is platinum-resistant ovarian cancer.
  • the ovarian cancer is platinum-resistant high-grade serous carcinoma, platinum-resistant ovarian adenocarcinoma, platinum-resistant epithelial serous carcinoma, platinum-resistant clear cell carcinoma, platinum-resistant endometrioid ovarian cancer, platinum-resistant fallopian tube cancer or platinum-resistant primary peritoneal cancer.
  • the ovarian cancer is platinum-resistant high-grade serous carcinoma or platinum-resistant ovarian adenocarcinoma.
  • the ovarian cancer is locally advanced or metastatic ovarian cancer.
  • the ovarian cancer is locally advanced or metastatic ovarian cancer that has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.
  • the ovarian cancer is platinum-resistant locally advanced or metastatic ovarian cancer.
  • the ovarian cancer is locally advanced or metastatic ovarian cancer that is platinum-resistant and has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.
  • the compound of formula (A) is used in combination with other drugs for treating ovarian cancer.
  • the administration of the combined use is selected from simultaneous, concurrent, independent or sequential application.
  • the combined administration route is selected from oral, parenteral, rectal, pulmonary or local administration, and the parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, and intramuscular injection.
  • the other ovarian cancer therapeutic drugs include one or more of PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs, platinum drugs or alkylating agents; preferably one or more of PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs or platinum drugs.
  • the compound of formula (A) is used in combination with a PARP inhibitor.
  • the PARP inhibitor includes one or more of Niraparib, Olaparib, Rucaparib, Talazoparib or Fluzoparib; preferably Niraparib or Olaparib.
  • the PARP inhibitor is niraparib.
  • the PARP inhibitor is olaparib.
  • the dosage of the compound of formula (A) is 0.1 to 1000 mg, specifically 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg , 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 700mg, 750m
  • the administration frequency of the compound of formula (A) can be once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, once a month, 21+7 (28 days as a cycle, once a day or twice a day for the first 21 days, rest for 7 days), 4+3 (7 days as a cycle, once a day or twice a day for the first 4 days, rest for 3 days) or 5+2 (7 days as a cycle, once a day or twice a day for the first 5 days, rest for 2 days); preferably once a day, twice a day, 21+7 (28 days as a cycle, once a day or twice a day for the first 21 days, rest for 7 days), 4+3 (7 days as a cycle, once a day or twice a day for the first 4 days, rest for 3 days) or 5+2 (7 days as a cycle, once a day or twice a day for the first 5 days, rest for 2 days). Days constitute
  • the administration frequency of the compound of formula (A) is once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks or once a month; preferably once a day or twice a day.
  • the compound of formula (A) is administered once a day, twice a day or three times a day for 21 consecutive days, followed by an interval of 1 to 2 weeks without administration of the compound; or is administered for 5 or 4 consecutive days, followed by an interval of 1 to 3 days without administration of the compound.
  • the administration frequency of the compound of formula (A) is once a day or twice a day, for 21 consecutive days, followed by a 1-week interval without administration of the compound; or for 5 consecutive days, followed by a 2-day interval without administration of the compound; or for 4 consecutive days, followed by a 3-day interval without administration of the compound.
  • the dosage of the PARP inhibitor is 100-1000 mg, specifically 100 mg, 105 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710
  • the administration frequency of the PARP inhibitor may be once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, or once a month; preferably once a day, twice a day, or three times a day.
  • one cycle is 28 days; the administration frequency of the compound of formula (A) is 21+7, and the dosage is 200-400 mg/time; the administration frequency of the PARP inhibitor is once a day, and the dosage is 300 mg/time.
  • one cycle is 28 days; the administration frequency of the compound of formula (A) is 21 consecutive days, followed by a 1-week interval without administration of the compound, and the dosage is 200-400 mg/time; the administration frequency of the PARP inhibitor is once a day, and the dosage is 300 mg/time.
  • 28 days is one cycle; the administration frequency of the compound of formula (A) is 21 consecutive days, followed by a 1-week interval without administration of the compound, and the dosage is 200-400 mg/time; the administration frequency of niraparib is once a day, and the dosage is 300 mg/time.
  • 28 days is one cycle; the administration frequency of the compound of formula (A) is 21 consecutive days, followed by a 1-week interval without administration of the compound, and the dosage is 200-400 mg/time; the administration frequency of Olaparib is once a day, and the dosage is 300 mg/time.
  • the dosage ratio of the compound of formula (A) to the PARP inhibitor is selected from 1:0.1-300, preferably 1:0.1, 1:0.2, 1:0.5, 1:1, 1:2.5, 1:1.5, 1:2, 1:3, 1:5, 1:6.5, 1:8, 1:10, 1:15, 1:20, 1:30, 1:45, 1:50, 1:60, 1:75, 1:85, 1:90, 1:100, 1:120, 1:150, 1:200, 1:250 or 1:300, and values between any two of the above values (although not listed one by one, but deemed to be clearly indicated).
  • the dosage ratio of the compound of formula (A) to niraparib is selected from 1:0.01-300, preferably 1:0.01, 1:0.1, 1:0.2, 1:0.5, 1:0.75, 1:1, 1:2.5, 1:1.5, 1:2, 1:3, 1:5, 1:6.5, 1:8, 1:10, 1:15, 1:20, 1:30, 1:45, 1:50, 1:60, 1:75, 1:85, 1:90, 1:100, 1:120, 1:150, 1:200, 1:25 0 or 1:300 and values between any two of the above values (although not listed one by one, but deemed to be clearly stated); preferably 1:0.75, 1:1, 1:1.3, 1:1.5, 1:2.7, 1:3.1, 1:4.6, 1:6.3, 1:6.6, 1:7, 1:8, 1:10, 1:13, 1:20, 1:21, 1:25, 1:30, 1:33, 1:40, 1:50 or 1:60 and values between any two of the above values (although not listed one by one, but deemed to be clearly stated);
  • the dosage ratio of the compound of formula (A) to olaparib is selected from 1:0.01-300, preferably 1:0.01, 1:0.1, 1:0.2, 1:0.5, 1:0.75, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:4, 1:5, 1:6, 1:7:1:8, 1:10, 1:15, 1:20, 1:30, 1:40, 1:50, 1:60, 1:75, 1:85, 1:90, 1:100, 1:120, 1:130, 1:140, 1:150, 1:160, 1:175, 1:185, 1:190, 1:100, 1:1 ...5, 1:120, 1:130, 1:140, 1:150, 1:160, 1:175, 1:185, 1:190, 1:100, 1:1 ...5, 1:120, 1:130, 1:140, 1:150, 1:160, 1:175, 1:185, 1:190, 1:100, 1:110, 1:120, 1:130, 1:140, 1:150, 1:1 :150, 1:200, 1:250 or 1:300 and values between any two of the above values (although not listed one by one, it
  • the dosage ratio of the compound of formula (A) to olaparib is selected from 1:5 or 1:6.3 by mass ratio.
  • the dosage ratio of the compound of formula (A) to olaparib is selected from 1:1.25 by mass ratio.
  • the compound of formula (A) is used in combination with a platinum drug.
  • the platinum drug includes one or more of cisplatin, carboplatin, lobaplatin or nedaplatin; preferably carboplatin.
  • the oral dosage form of at least 200 mg to 300 mg of an oral dosage form is preferably 400 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg or 1000 mg, and values between any two of the above values (although not listed one by one, but deemed to be clearly indicated); preferably 400-800 mg; more preferably 400 mg, 500 mg, 600 mg, 700 mg or 800 mg.
  • the administration frequency of carboplatin can be once a day, once a week, once every two weeks, once every three weeks, once a month, once every two months, once every three weeks, once every four weeks, once every three weeks (administered once over 5 days), once every four weeks (administered once over 5 days).
  • one cycle is 28 days; the administration frequency of the compound of formula (A) is 21 consecutive days, followed by a 1-week interval without administration of the compound; the administration frequency of carboplatin may be once a week for 3 consecutive weeks.
  • the dosage ratio of the compound of formula (A) to carboplatin, measured by mass ratio is selected from 1:0.1-300; preferably 1:0.1, 1:0.2, 1:0.5, 1:1, 1:2.5, 1:1.5, 1:2, 1:3, 1:5, 1:6.5, 1:8, 1:10, 1:15, 1:20, 1:30, 1:45, 1:50, 1:60, 1:75, 1:85, 1:90, 1:100, 1:120, 1:150, 1:200, 1:250 or 1:300 and values between any two of the above values (although not listed one by one, but deemed to be clearly indicated); preferably 1:0.2, 1:0.5, 1:1, 1:2.5, 1:1.5, 1:2 or 1:3; more preferably 1:1, 1:1.5 or 1:2.
  • the dosage ratio of the compound of formula (A) to carboplatin is selected from 1:1 by mass ratio.
  • the compound of formula (A) is used in combination with a phytochemical chemotherapeutic agent.
  • the plant-based chemotherapy drug includes one or more of vincristine, vinblastine, etoposide or paclitaxel; preferably paclitaxel; more preferably paclitaxel injection.
  • the dosage of paclitaxel is 1-300 mg/m 2 , which can be selected from 10 mg/m 2 , 30 mg/m 2 , 50 mg/m 2 , 55 mg/m 2 , 60 mg/m 2 , 65 mg/m 2 , 70 mg/m 2 , 75 mg/m 2 , 80 mg/m 2 , 85 mg/m 2 , 90 mg/m 2 , 95 mg/m 2 , 100 mg/m 2 , 105 mg/m 2 , 110 mg/m 2 , 115 mg/m 2 , 120 mg/m 2 , 125 mg/m 2 , 130 mg/m 2 , 135 mg/m 2 , 140 mg/m 2 , 145 mg/m 2 , 150 mg/m 2 , 155mg/m 2 , 160mg/m 2 , 165mg/m 2 , 170mg/m 2 , 175mg/m 2 , 180mg/m 2 , 185mg/m 2 ,
  • the administration frequency of paclitaxel can be once a day, once a week, once every two weeks, once every three weeks, once a month, once every two months, once a week (use for 2 weeks and stop for 1 week), once a week (use for 3 weeks and stop for 1 week), once a week (use for 6 weeks and stop for 2 weeks), once every 3 weeks or once every 4 weeks; preferably once a week (use for 3 weeks and stop for 1 week).
  • one cycle is 28 days; the administration frequency of the compound of formula (A) is 21+7, and the dosage is 200-400 mg/time; the administration frequency of paclitaxel is once a week (3 weeks on and 1 week off, administered on the 1st, 8th and 15th days of each cycle), and the dosage is 80 mg/m2 / time.
  • one cycle is 28 days; the administration frequency of the compound of formula (A) is 21 consecutive days, followed by a 1-week interval without administration of the compound, and the dosage is 200-400 mg/time; the administration frequency of paclitaxel is 1, 8, and 15 days of each cycle, and the dosage is 80 mg/m2 / time.
  • the dosage ratio of the compound of formula (A) to paclitaxel is selected from 0.01-300:1, preferably 0.01:1, 0.1:1, 0.2:1, 0.5:1, 1:1, 1.5:1, 2:1, 3:1, 4:1, 5:1, 8:1, 10:1, 12:1, 15:1, 18:1, 20:1, 30:1, 40:1, 50:1, 100:1, 130:1, 150:1, 180:1.
  • the dosage ratio of the compound of formula (A) to paclitaxel is selected from 4:1 in terms of mass ratio.
  • the compound of formula (A) is used in combination with an antibiotic chemotherapeutic drug.
  • the dosage of doxorubicin is 0.1-300 mg/m 2 , specifically 1 mg/m 2 , 2.5 mg/m 2 , 5 mg/m 2 , 7.5 mg/m 2 , 10 mg/m 2 , 12.5 mg/m 2 , 15 mg/m 2 , 17.5 mg/m 2 , 20 mg/m 2 , 22.5 mg/m 2 , 25 mg/m 2 , 30 mg/m 2 , 32.5 mg/m 2 , 35 mg/m 2 , 37.5 mg/m 2 , 40 mg/m 2 , 50 mg/m 2 , 52.5 mg/m 2 , 55 mg/m 2 , 60 mg/m 2 , 65 mg/m 2 , 70 mg / m 2 , 75 mg/m 2 , 80mg/m 2 , 85mg/m 2 , 90mg/m 2 , 95mg/m 2 , 100mg/m 2 , 105mg/m 2 , 110mg/m 2 .
  • the administration frequency of doxorubicin can be once a day, once a week, once every two weeks, once every three weeks, once every four weeks, once every month, or once every two months; preferably once every two weeks, once every three weeks, or once every four weeks; more preferably once every four weeks; and further preferably once every four weeks (administered on the first day of each cycle).
  • one cycle is 28 days; the administration frequency of the compound of formula (A) is 21+7, and the dosage is 200-400 mg/time; the administration frequency of doxorubicin is once every four weeks (administered on the first day of each cycle), and the dosage is 40 mg/m2 / time.
  • 28 days is one cycle; the administration frequency of the compound of formula (A) is 21 consecutive days, followed by a 1-week interval without administration of the compound, and the dosage is 200-400 mg/time; the administration frequency of doxorubicin is on the first day of each cycle, The dosage is 80 mg/m2 / time.
  • the dosage ratio of the compound of formula (A) to doxorubicin is selected from 0.01-300:1, preferably 0.01:1, 0.1:1, 0.2:1, 0.5:1, 1:1, 1.5:1, 2:1, 3:1, 5:1, 8:1, 10:1, 12:1, 15:1, 18:1, 20:1, 30:1, 40:1, 50:1, 10 0:1, 130:1, 150:1, 180:1, 200:1, 220:1, 250:1 or 300:1 and values between any two of the above values (although not listed one by one, it is deemed to be clearly stated); preferably 3:1, 5:1, 8:1, 10:1, 12:1, 15:1, 18:1 or 20:1 and values between any two of the above values (although not listed one by one, it is deemed to be clearly stated).
  • the compound of formula (A) is used in combination with one or more of a PARP inhibitor, a plant-based chemotherapeutic drug or an antibiotic-based chemotherapeutic drug.
  • the compound of formula (A) is used in combination with niraparib, paclitaxel or doxorubicin.
  • the above-mentioned combined use method can be further used in combination with other treatment methods besides PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs or platinum drugs, for example, further combined with other chemotherapy, hormones, antibody agents, targeted drugs, and surgery and/or radiotherapy.
  • the compound of formula (A) can be administered to the patient in the form of a free base, or in the form of a pharmaceutically acceptable salt, hydrate or prodrug (which will be converted into a free base form in vivo), such as a fumarate salt, preferably a monofumarate salt.
  • the pharmaceutically acceptable salt of the compound of formula (A) is a fumarate dihydrate, the chemical name of which is (R)-4-((1S, 6R)-5-((S)-2-(4-chlorophenyl)-3-(isopropylamino)propanoyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one fumarate dihydrate, and the chemical formula is shown in the following formula (I-1):
  • other ovarian cancer therapeutic drugs can be administered to patients in the form of free bases, or in the form of pharmaceutically acceptable salts, hydrates or prodrugs (which will be converted to free base forms in vivo), such as salts of PARP inhibitors.
  • the present invention also provides a drug combination or pharmaceutical composition, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and other ovarian cancer therapeutic drugs, and one or more pharmaceutically acceptable carriers;
  • the other ovarian cancer therapeutic drugs include one or more of PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs, platinum drugs or alkylating agents; preferably one or more of PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs or platinum drugs;
  • the compound of formula (I) is a compound of formula (A) or a compound of formula (B):
  • the present invention also provides a drug combination or pharmaceutical composition, comprising a compound of formula (A) and other ovarian cancer therapeutic drugs, and one or more pharmaceutically acceptable carriers; the other ovarian cancer therapeutic drugs include one or more of PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs, platinum drugs or alkylating agents; preferably one or more of PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs or platinum drugs.
  • the PARP inhibitor includes one or more of niraparib, olaparib, rucaparib, talazoparib or fluzoparib, preferably niraparib or olaparib;
  • the plant-based chemotherapy drugs include one or more of vincristine, vinblastine, etoposide or paclitaxel; preferably paclitaxel;
  • the platinum drugs include one or more of cisplatin, carboplatin, lobaplatin or nedaplatin; preferably carboplatin;
  • the antibiotic chemotherapy drugs include one or more of actinomycin D, mitomycin, doxorubicin, doxorubicin, epirubicin or daunorubicin; preferably doxorubicin.
  • the mass ratio of the compound of formula (A) to other ovarian cancer therapeutic drugs is as described above.
  • the administration method, dosage and frequency of the compound of formula (A) and other ovarian cancer therapeutic drugs are as described above.
  • the pharmaceutical composition of the present invention can be prepared into any pharmaceutically acceptable dosage form, for example, tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injection and concentrated solutions for injection), liposomes, suppositories, inhalants or sprays.
  • pharmaceutically acceptable dosage form for example, tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injection and concentrated solutions for injection), liposomes, suppositories, inhalants or sprays.
  • the pharmaceutical composition of the present invention can also be administered to patients or subjects in need of such treatment in any suitable manner, such as oral, parenteral, rectal, pulmonary or topical administration.
  • the pharmaceutical composition can be prepared into oral preparations, such as oral solid preparations, such as tablets, capsules, pills, granules, etc.; or, oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc.
  • oral preparations may also contain suitable fillers, binders, disintegrants, lubricants, etc.
  • the pharmaceutical composition of the present invention can be administered alone, or can be further administered in combination with PARP inhibitors, plant-based chemotherapeutic drugs, antibiotics,
  • the drug is used in combination with other treatments other than chemotherapy drugs or platinum drugs, such as other chemotherapy, hormones, antibodies, targeted drugs and other therapeutic agents, as well as surgery and/or radiation therapy.
  • the present invention also provides a method for preventing and/or treating ovarian cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula (A) and other ovarian cancer therapeutic drugs, wherein the other ovarian cancer therapeutic drugs include one or more of PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs, platinum drugs or alkylating agents; preferably one or more of PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs or platinum drugs.
  • the present invention also provides a method for preventing and/or treating ovarian cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula (A) and other ovarian cancer therapeutic drugs, wherein the other ovarian cancer therapeutic drugs include one or more of niraparib, olaparib, paclitaxel, doxorubicin or carboplatin.
  • the present invention also provides a method for preventing and/or treating ovarian cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula (A) and other ovarian cancer therapeutic drugs, wherein the other ovarian cancer therapeutic drugs include niraparib, olaparib, paclitaxel, doxorubicin or carboplatin.
  • the present invention also provides a method for preventing and/or treating ovarian cancer, comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition of a compound of formula (A) and other ovarian cancer therapeutic drugs, wherein the other ovarian cancer therapeutic drugs include one or more of PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs, platinum drugs or alkylating agents; preferably one or more of PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs or platinum drugs.
  • the present invention also provides a method for preventing and/or treating ovarian cancer, comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition of a compound of formula (A) and other ovarian cancer therapeutic drugs, wherein the other ovarian cancer therapeutic drugs include one or more of niraparib, olaparib, paclitaxel, doxorubicin or carboplatin.
  • the present invention also provides a method for preventing and/or treating ovarian cancer, comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition of a compound of formula (A) and other ovarian cancer therapeutic drugs, wherein the other ovarian cancer therapeutic drugs include niraparib, olaparib, paclitaxel, doxorubicin or carboplatin.
  • the present invention provides a use of an AKT inhibitor alone or in combination with other ovarian cancer therapeutic drugs in the preparation of a drug for preventing or treating ovarian cancer, which can effectively inhibit the growth of ovarian tumor cells and cell clone formation, and the combined effect is significantly better than that of a single drug, with an additive or synergistic effect, while having low toxic and side effects on normal cells and high safety, providing a more effective method for treating ovarian cancer and having important clinical value.
  • the "combination" described herein is a mode of administration, which includes various situations in which two drugs are administered sequentially or simultaneously, and refers to administering at least one dose of the compound of formula (A) and at least one dose of other ovarian cancer therapeutic drugs (such as PARP inhibitors) in any manner within a certain time period.
  • the time period can be within a dosing cycle, and the compound of formula (A) inhibitor and other ovarian cancer therapeutic drugs can be administered simultaneously or sequentially, and any of the methods described includes administering the compound of formula (A) and other ovarian cancer therapeutic drugs through the same administration route or different administration routes.
  • one or more doses of the compound of formula (A) are administered simultaneously or separately with one or more doses of other ovarian cancer therapeutic drugs; in one embodiment, multiple doses of the compound of formula (A) are administered simultaneously or separately with multiple doses of other ovarian cancer therapeutic drugs; in one embodiment, multiple doses of the compound of formula (A) are administered simultaneously or separately with one dose of other ovarian cancer therapeutic drugs; in one embodiment, one dose of the compound of formula (A) is administered simultaneously or separately with multiple doses of other ovarian cancer therapeutic drugs; in one embodiment, one dose of the compound of formula (A) is administered simultaneously or separately with one dose of other ovarian cancer therapeutic drugs; in all embodiments, the compound of formula (A) may be administered first or the other ovarian cancer therapeutic drugs may be administered first.
  • the term “simultaneous administration” refers to The term “concurrent administration” refers to the administration of two or more drugs to a patient at the same time or very close in time.
  • the term “concurrent administration” refers to the administration of two or more drugs in the same period of time, such as on the same day, but not necessarily at the same time;
  • the term “independent administration” refers to the independent administration of a drug over a period of time, such as the independent administration of a drug over the course of several days or a week, and then the independent administration of other drugs over a subsequent period of time;
  • the term “sequential administration” refers to the administration of drugs to a patient in a specific order, with each drug administered after the previous drug, forming an ordered sequence.
  • oral administration refers to taking the drug into the body by oral administration, the drug is absorbed into the blood circulation through the gastrointestinal tract, and then distributed throughout the body or acts on specific organs.
  • parenteral administration refers to an administration method that does not pass through the gastrointestinal tract, including subcutaneous injection, intramuscular injection, intravenous injection, etc.
  • rectal administration refers to a method in which the drug is delivered into the rectum through the anus, and the drug is absorbed into the blood circulation through the rectal mucosa.
  • pulmonary administration refers to delivering the drug directly into the lungs by inhalation, and the drug is absorbed into the blood circulation through the alveoli.
  • topical administration refers to administration by coating or applying the drug directly to epidermal tissue, including the skin or mucous membranes of the mouth or vagina.
  • the therapeutic agents in these combinations can be administered simultaneously with, before, or after one or more other additional therapies or therapeutic agents.
  • the therapeutic agents can be administered in any order. In general, each therapeutic agent will be administered at a dose and/or time schedule determined for that therapeutic agent.
  • the additional therapeutic agents used in the combination can be administered together in a single composition or separately in different compositions. In general, it is expected that the additional therapeutic agents used in the combination are used at levels not exceeding those when they are used alone. In one embodiment, the levels used in the combination will be lower than the levels used in the single agent therapy.
  • the “combined use” and “combination use” described herein can be used together with a compound of formula (A) or a pharmaceutically acceptable salt thereof and other ovarian cancer therapeutic drugs.
  • the two compounds can be administered together or separately.
  • the dosage and frequency of administration can vary depending on the compound used and the specific condition to be treated. Generally, it is preferred to use the minimum dose sufficient to provide effective treatment, and it can be determined by the following criteria, such as the patient's age, weight and gender; the extent and severity of the cancer to be treated; and the judgment of the treating physician.
  • an assay suitable for the condition being treated can be used to monitor the therapeutic effect of the patient, or conventional tests and procedures well known in the art can be used to determine the optimal dose.
  • the therapeutic agent of the combination of the present invention can be administered by any suitable route, and the route of administration can vary according to, for example, the health status of the recipient of the combination and the cancer to be treated.
  • composition refers to a mixture containing at least one therapeutic agent and at least one pharmaceutically acceptable carrier
  • pharmaceutically acceptable carrier includes but is not limited to diluents, binders, disintegrants, and lubricants.
  • the “dosage” described herein refers to the amount of the therapeutic agent.
  • the tablet will contain a fumarate of the compound of formula (A) equivalent to 2 mg of the compound of formula (A).
  • the “salt” described herein may exist alone or in a mixture with the free compound of the present invention, and is preferably a pharmaceutically acceptable salt.
  • the “pharmaceutically acceptable salt” refers to an organic acid salt or an inorganic acid salt commonly used in pharmacy, wherein the organic acid salt includes but is not limited to fumarate, methanesulfonate, isethionate, ⁇ -naphthalenesulfonate, p-toluenesulfonate, 1,2-ethanedisulfonate, oxalate, maleate, citrate, succinate, L-(+)-tartrate, hippurate, L-ascorbate, L-malate, benzoate or gentisate, and the inorganic acid salt includes but is not limited to hydrochloride, sulfate or phosphate.
  • the "pharmaceutically acceptable salt” is a fumarate; preferably a fumarate; more preferably a fumarate hydrate; and
  • the "standard treatment” mentioned in this article refers to the evaluation of the patient's condition before treatment, and the selection of an appropriate treatment plan based on the patient's condition. During the treatment process, the doctor will adjust the treatment plan based on changes in the patient's condition.
  • the treatment model for ovarian cancer is surgery/neoadjuvant chemotherapy + surgery-postoperative adjuvant chemotherapy-maintenance therapy and multiple lines of treatment for recurrence after initial treatment.
  • failure of standard treatment refers to tumor progression or the appearance of new tumors after standard treatment.
  • the term "locally advanced” means that the tumor is confined to the primary organ or adjacent tissues and organs, but the onset time may be longer and the tumor is larger, but metastasis to distant organs has not yet occurred.
  • a therapeutically effective amount includes an amount sufficient to improve or prevent the symptoms or symptoms of a disorder.
  • a therapeutically effective dose of a drug can reduce the number of cancer cells; reduce the size of a tumor; inhibit (i.e., slow down to a certain extent and preferably prevent) cancer cell infiltration into surrounding organs; inhibit (i.e., slow down to a certain extent and preferably prevent) tumor metastasis; inhibit tumor growth to a certain extent; and/or alleviate one or more symptoms associated with the disorder to a certain extent.
  • a drug can prevent the growth of existing cancer cells and/or kill existing cancer cells, it can be cytostatic and/or cytotoxic.
  • in vivo efficacy can be measured by assessing duration of survival, duration of progression-free survival (PFS), response rate (RR), duration of response, and/or quality of life.
  • the “DLT” mentioned in this article is defined as the following toxic reactions related to the study drug (including definitely related, probably related, or possibly related) that occur in subjects in each dose group from the start of drug administration to the end of the first course of treatment (a total of 28 days): (1) Hematological toxicity: Grade 4 neutropenia lasting for more than 3 days; Grade 3 febrile neutropenia; Grade 4 thrombocytopenia; Grade 3 thrombocytopenia with bleeding; Grade 4 anemia; (2) Non-hematological toxicity: Grade 4 non-hematological toxicity; Grade 3 non-hematological toxicity that persists for 3 days after treatment Grade 4 hyperglycemia: blood glucose >27.8mmol/L or 500mg/dL; Grade 3 hyperglycemia: blood glucose >13.9mmol/L or 250mg/dL, which persists for ⁇ 7 days after treatment; (3) Other toxic reactions that require permanent discontinuation of the study drug or result in the total dose of the study drug received during the DLT observation period being less than 75% of the planned
  • ORR object response rate
  • DCR disease control rate
  • the duration of response (DOR) mentioned in this article is defined as the time from the start of objective response to the first occurrence of tumor progression or death due to any cause.
  • progression-free survival (PFS) is defined as the time from the start of treatment to tumor progression or death due to any cause.
  • CA-125" refers to tumor antigen 125, which is currently recognized as the most valuable observation indicator for preoperative diagnosis of ovarian cancer, observation of postoperative recurrence and prognosis evaluation.
  • GCIG Gynecologic Cancer Institute
  • the “RP2D” mentioned herein means the recommended dose for Phase II clinical trials.
  • the “synergistic effect” described herein refers to the phenomenon that the effects of two drugs used in combination are more effective than their individual effects, relative to antagonism.
  • the compound of formula (I) or formula (A) disclosed herein is an effective AKT inhibitor, and its preparation method is published in the international application WO2020156437A1.
  • the "compound” described herein includes all stereoisomers and tautomers.
  • the compounds of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers.
  • the compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure form or racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral raw materials or chiral reagents. Racemates, diastereomers, and enantiomers are all included within the scope of the present invention.
  • the dosage of the compound of formula (A) or fulvestrant refers to the dosage of the active compound. It is understood that when the application form is a pharmaceutically acceptable salt or hydrate, the dosage or the ratio of the two can still be calculated based on the active compound.
  • Solutol HS-15 Polyethylene glycol-15-hydroxystearic acid.
  • HPMC Hydroxypropyl methylcellulose
  • DMSO dimethyl sulfoxide
  • HP- ⁇ -CD Hydroxypropyl- ⁇ -cyclodextrin.
  • PBS Phosphate buffered saline
  • FBS fetal bovine serum
  • MW molecular weight
  • COLO-704 a high-grade serous carcinoma cell line.
  • SK-OV-3 epithelial serous carcinoma cell line.
  • OVCAR-3 a high-grade serous carcinoma cell line, platinum-resistant.
  • TOV-21G clear cell carcinoma cell line.
  • A2780 Ovarian adenocarcinoma cell line, platinum-resistant.
  • ES-2 clear cell carcinoma cell line.
  • Example 1 Experiment on the effect of the compound of formula (A) alone or in combination on the proliferation of ovarian cancer cells (COLO-704 and SK-OV-3) 1.
  • Experimental purpose To investigate the effect of the compound of formula (A), combined with niraparib/olaparib, on the proliferation of COLO-704 and SK-OV-3 cell lines.
  • COLO-704 cells were cultured in RPMI-1640 medium, supplemented with 1% double antibody and 10% FBS, and cultured at 37°C and 5% CO2;
  • SK-OV-3 cells were cultured in McCoy's 5A medium, supplemented with 1% double antibody and 10% FBS, and cultured at 37°C and 5% CO 2 .
  • the cells were routinely cultured until the cell confluence reached 80%-90%. When the number reached the required level, the cells were collected; b) The cells were resuspended in the corresponding culture medium, counted, and prepared into a cell suspension of appropriate density; c) The COLO-704 and SK-OV-3 cell suspensions were added to a 384-well plate and cultured in an incubator overnight.
  • the compound of formula (A) (using the monofumarate dihydrate of the compound of formula (A), the concentration is calculated based on the compound of formula (A); refer to the preparation method disclosed in WO2022017448A1 to prepare the compound of formula (A) or its salt) was diluted 3-fold for 10 concentrations starting from the stock solution of 100mM.
  • the compound of formula (A) was diluted with DMSO from 100mM to 12mM, and then 3-fold diluted for 10 concentrations.
  • Niraparib was diluted with DMSO from 100mM to 32mM, and then 2-fold diluted for 10 concentrations.
  • Olaparib was diluted with DMSO from 100mM to 80mM, 75mM, and then 2-fold diluted for 10 concentrations starting from 80mM.
  • Niraparib was diluted with DMSO from 32mM to 24mM.
  • the final concentration of DMSO was 0.5%.
  • Cells plus DMSO were used as high reading control wells.
  • Cell-free culture medium was used as low reading control wells.
  • the compound of formula (A) was combined with niraparib: 75 nL of the compound prepared in step 2.3b) + 75 nL of the compound prepared in step 2.3c) and e).
  • the compound of formula (A) was combined with olaparib: 75 nL of the compound prepared in step 2.3b) + 75 nL of the compound prepared in step 2.3d).
  • Niraparib 80000, 40000, 20000, 10000, 5000, 2500, 1250, 625, 312.5, 156.25 nM;
  • Niraparib 20000, 40000, 60000 nM, respectively, in combination with gradient concentrations of the compound of formula (A);
  • Olaparib 200000, 150000, 100000, 50000, 25000, 12500, 6250, 3125, 1562.5, 781.25 nM;
  • Olaparib 25000, 50000, 100000 nM, respectively, used in combination with gradient concentrations of the compound of formula (A).
  • the cell culture plate was centrifuged at 1000 rpm for 1 min and placed in a 37°C, 5% CO 2 incubator for 72 hours.
  • IC50 half-maximal inhibitory concentration
  • Inhibition rate 100-(compound well reading-low reading control reading)/(high reading control reading-low reading control reading)*100
  • the calculated cell viability inhibition rate was imported into the SynergyFinder website for analysis of the synergy index. Website: https://tangsoftwarelab.shinyapps.io/synergyfinder/#!/dashboard.
  • Evaluation index Synergy.score ⁇ -10, the interaction between the two compounds is antagonistic; -10 ⁇ Synergy.score ⁇ 10, the interaction between the two compounds is additive; Synergy.score>10, the interaction between the two compounds is synergistic.
  • the experiment was carried out according to the above steps, and the inhibition rate was calculated based on the readings.
  • the compound of formula (A) alone or in combination with niraparib/olaparib showed good in vitro anti-cell proliferation effect on the above tumor cells.
  • OVCAR-3 cells were cultured in RPMI 1640 medium containing 20% FBS at 37°C and 5% CO 2.
  • TOV-21G cells were cultured in RPMI 1640 medium containing 15% FBS at 37°C and 5% CO 2.
  • A2780 cells were cultured in RPMI 1640 medium containing 10% FBS at 37°C and 5% CO 2 .
  • the cells were routinely cultured until the cell confluence reached 80%-90%. When the number reached the required level, the cells were collected; b) The cells were resuspended in the corresponding culture medium, counted, and prepared into a cell suspension of appropriate density; c) The OVCAR-3, TOV-21G, and A2780 cell suspensions were inoculated into a 96-well plate at 150 ⁇ L/well and cultured in an incubator overnight.
  • Olaparib 200, 100, 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39 ⁇ M;
  • Olaparib 100, 50, 25 ⁇ M, respectively, combined with gradient concentrations of the compound of formula (A);
  • Niraparib 80, 70, 60, 50, 40, 30, 20, 10, 5, 2.5 ⁇ M;
  • Niraparib 40, 30, 20 ⁇ M, respectively, used in combination with gradient concentrations of the compound of formula (A).
  • Olaparib 200, 100, 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39 ⁇ M;
  • Olaparib 6.25, 3.13, 1.56 ⁇ M, respectively, combined with gradient concentrations of the compound of formula (A);
  • Niraparib 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39, 0.20, 0.10 ⁇ M;
  • Niraparib 3.13, 1.56, 0.78 ⁇ M, respectively, used in combination with gradient concentrations of the compound of formula (A).
  • Olaparib 200, 100, 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39 ⁇ M.
  • the cell culture plate was placed in a 37°C, 5% CO 2 incubator for 72 h.
  • IC50 half maximal inhibitory concentration
  • Inhibition rate 100-(compound well reading-low reading control reading)/(high reading control reading-low reading control reading)*100
  • the compound of formula (A) was used in combination with the PARP inhibitors olaparib and niraparib on the above ovarian cancer cells, and both had synergistic efficacy; the above experiments were carried out twice in parallel, and the results were consistent.
  • the purpose of this study is to evaluate the efficacy of compound (A) combined with olaparib in the SK-OV-3 human ovarian cancer xenograft model in female NOD SCID mice.
  • mice NoD SCID female mice, 6-8 weeks old, weighing 18-20 g, purchased from Beijing Ankai Yibo Biotechnology Co., Ltd., in an SPF environment with a temperature of (23 ⁇ 3)°C and a humidity of 40-70%.
  • Olaparib solvent 10% DMSO + 90% (10% HP- ⁇ -CD in PBS pH 7.4)
  • SK-OV-3 tumor cells were cultured in McCoy's 5a medium containing inactivated 10% fetal bovine serum, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin at 37°C in a 5% CO 2 incubator. Tumor cells in the logarithmic growth phase were used for inoculation of tumors in vivo.
  • SK-OV-3 tumor cells resuspended in serum-free McCoy's 5a culture medium were inoculated at 1 ⁇ 10 7 (0.1 mL + Matrigel) on the right rib of the experimental animals, and a total of 48 animals were inoculated.
  • the tumor grew to 239 mm 3 , 32 animals with relatively uniform tumor volumes were selected and divided into 4 groups, with 8 animals in each group.
  • the specific dosing regimen is shown in the table below:
  • po means oral administration
  • QD x 28 days means administration once a day for 28 consecutive days
  • the group of compound of formula (A) and olaparib combined administration was first given compound of formula (A), and then olaparib was administered after an interval of 1 hour
  • the dose of olaparib from the 1st day to the 17th day after grouping was 100 mg/kg
  • the dose of olaparib was adjusted to 125 mg/kg.
  • mice While measuring the tumor volume, weigh the mice. Record the relationship between the change in the weight of the mice and the administration time. At the same time, observe the survival and health status of the mice, such as the general status of animal activity and eating during the administration period.
  • T/C (%) mean relative tumor volume of the treatment group/mean relative tumor volume of the control group ⁇ 100
  • TGI Tumor growth inhibition rate
  • Tumor growth inhibition rate (TGI,%) (1-T/C) ⁇ 100
  • the animals in the experimental group were in good general condition in terms of activity and feeding, and there were no abnormalities in the animals.
  • the animals were divided into groups and given medication on the 19th day after the inoculation of SK-OV-3 tumor cells, and the average tumor volume of each group was 239 mm 3 .
  • mice NoD SCID female mice, 6-8 weeks old, weighing 18-20 g, were purchased from Beijing Ankai Yibo Biotechnology Co., Ltd.
  • the breeding environment was SPF grade, with a temperature of (23 ⁇ 3)°C and a humidity of 40-70%.
  • Paclitaxel solvent normal saline
  • TOV-21G tumor cells were cultured in a mixed medium (1:1) of MCDB 105 culture medium (1.5 g/L sodium bicarbonate) and 199 culture medium (2.2 g/L sodium bicarbonate) containing inactivated 15% fetal bovine serum, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin at 37°C in a 5% CO 2 incubator. Tumor cells in the logarithmic growth phase were used for inoculation of tumors in vivo.
  • TOV-21G tumor cells resuspended in a mixed culture medium (1:1) of serum-free MCDB 105 culture medium (1.5g/L sodium bicarbonate) and 199 culture medium (2.2g/L sodium bicarbonate) were inoculated subcutaneously on the right rib of the experimental animals at 1 ⁇ 10 7 /0.1mL+Matrigel (1:1), and a total of 60 animals were inoculated.
  • MCDB 105 culture medium 1.5g/L sodium bicarbonate
  • 199 culture medium 2.2g/L sodium bicarbonate
  • p.o. means oral administration
  • i.v. means intravenous injection
  • QD x 21 days means administration once a day for 21 consecutive days
  • QWx3 weeks means administration once a week for 3 consecutive weeks.
  • mice While measuring the tumor volume, weigh the mice. Record the relationship between the change in the weight of the mice and the administration time. At the same time, observe the survival and health status of the mice, such as the general status of animal activity and eating during the administration period.
  • T/C (%) mean relative tumor volume of the treatment group/mean relative tumor volume of the control group ⁇ 100
  • TGI Tumor growth inhibition rate
  • Tumor growth inhibition rate (TGI,%) (1-T/C) ⁇ 100
  • the results of the accompanying PK study showed that after the compound of formula (A) was combined with paclitaxel in the TOV-21G human ovarian cancer subcutaneous xenograft model, the main PK parameters of paclitaxel were not affected by each other. During the experiment, the general state of animals in all experimental groups, such as activity and eating, was good, and the animals had no abnormalities.
  • Example 5 Combination experiment of compound alone or in combination with paclitaxel or doxorubicin in ovarian cancer cells
  • TOV-21G cells were cultured in RPMI1640 medium containing 15% FBS at 37°C and 5% CO 2 ;
  • SK-OV-3 cells were cultured in McCoy's 5a medium containing 10% FBS at 37°C and 5% CO 2 ;
  • OVCAR-3 cells were cultured in RPMI1640 medium containing 20% FBS at 37°C and 5% CO 2 .
  • the cells were treated with the compound of formula (A) and paclitaxel or doxorubicin at the same time, and the samples were added using a compound titrator.
  • Paclitaxel 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05 nM.
  • Doxorubicin 30000, 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52 nM.
  • Paclitaxel 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05 nM.
  • Doxorubicin 30000, 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52 nM.
  • OVCAR-3 cells OVCAR-3 cells
  • Paclitaxel 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37 nM.
  • Doxorubicin 30000, 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15 nM.
  • the cells were treated with the compound of formula (A) and paclitaxel or doxorubicin at the same time.
  • the concentration of paclitaxel or doxorubicin was fixed and the samples were added using a compound titrator.
  • Paclitaxel 3nM, 4nM, 5nM, respectively, used in combination with gradient concentrations of the compound of formula (A).
  • Doxorubicin 20 nM, 40 nM, 80 nM, respectively, used in combination with gradient concentrations of the compound of formula (A).
  • Paclitaxel 4 nM, 8 nM, 12 nM, respectively, used in combination with gradient concentrations of the compound of formula (A).
  • Doxorubicin 40 nM, 80 nM, 120 nM, respectively, used in combination with gradient concentrations of the compound of formula (A).
  • OVCAR-3 cells OVCAR-3 cells
  • the final concentrations of the compound of formula (A) are: 100000, 33333.33, 11111.11, 3703.70, 1234.57, 411.52, 137.17, 45.72, and 15.24 nM.
  • Paclitaxel 1 nM, 2 nM, 3 nM, respectively, used in combination with gradient concentrations of the compound of formula (A).
  • Doxorubicin 50 nM, 100 nM, 200 nM, respectively, used in combination with gradient concentrations of the compound of formula (A).
  • Test Reagent Luminescent Cell Viability Test Reagent
  • IC50 half maximal inhibitory concentration
  • X log value of compound concentration
  • Y inhibition rate (%inhibition).
  • Inhibition rate 100-(compound well reading-low reading control reading)/(high reading control reading-low reading control reading)*100.
  • the calculated cell viability inhibition rate was imported into the SynergyFinder website for analysis of the combination index. Website: https://tangsoftwarelab.shinyapps.io/synergyfinder/#! / dashboard . If Synergy.score ⁇ -10, the interaction between the two compounds is antagonistic; if -10 ⁇ Synergy.score ⁇ 10, the interaction between the two compounds is additive; if Synergy.score>10, the interaction between the two compounds is synergistic.
  • Combination therapy (paclitaxel or doxorubicin fixed concentration)
  • ES-2 cells purchased from the Cell Bank of the Chinese Academy of Sciences
  • human ovarian clear cell carcinoma cell line cultured in McCoy's 5A medium with 10% FBS.
  • Carboplatin 25.0, 20.0, 17.5, 15.0, 10.0, 7.5, 5.0, 2.5, 1.3 ⁇ M.
  • Carboplatin 10, 15, 20 ⁇ M, respectively, used in combination with graded concentrations of the compound of formula (A).
  • GraphPadPrism 5 software was used to fit the dose-effect curve, and the IC 50 (half-maximal inhibitory concentration) of the compound on cell proliferation inhibition was obtained using the following nonlinear fitting formula:
  • Inhibition rate 100-(compound well reading-low reading control reading)/(high reading control reading-low reading control reading)*100
  • the Q value is the combination index, and the Q value is calculated using the following formula:
  • Q value EA+B/(EA+EB-EA ⁇ EB), where EA+B is the inhibition rate of combined medication, and EA and EB are the inhibition rates of drug A and drug B, respectively.
  • Example 7 Pharmacodynamic study of the compound of formula (A) in combination with olaparib and carboplatin in the treatment of OVCAR-3 human ovarian cancer xenograft model
  • mice NoD SCID female mice, 6-8 weeks old, weighing 18-20 g, purchased from Beijing Ankai Yibo Biotechnology Co., Ltd., in an SPF environment with a temperature of (23 ⁇ 3)°C and a humidity of 40-70%.
  • Olaparib solvent 10% DMSO + 90% (10% HP- ⁇ -CD in PBS pH 7.4)
  • Carboplatin solvent normal saline
  • OVCAR-3 tumor cells were cultured in RPMI1640 medium containing inactivated 20% fetal bovine serum, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin at 37°C in a 5% CO 2 incubator. Tumor cells in the logarithmic growth phase were used for inoculation of tumors in vivo.
  • OVCAR-3 tumor cells resuspended in serum-free RPMI1640 culture medium were inoculated subcutaneously at the right flank of experimental animals at 2 ⁇ 10 7 (0.2 mL + Matrigel), and a total of 60 animals were inoculated.
  • the tumor grew to about 222 mm 3 , 36 animals with relatively uniform tumor volume were selected and divided into groups for drug administration, for a total of 6 groups.
  • p.o. means oral administration; i.p. means intraperitoneal injection; QD x21 days means administration once a day for 21 consecutive days; QW x3 weeks means administration once a week for 3 consecutive weeks.
  • the compound of formula (A) was administered first, and then olaparib and carboplatin were administered 1 hour later.
  • mice While measuring the tumor volume, weigh the mice. Record the changes in the weight of the mice and the time of administration. At the same time, the survival and health status of the mice, such as animal activity and eating during the administration period, were observed.
  • T/C (%) mean relative tumor volume of the treatment group/mean relative tumor volume of the control group ⁇ 100
  • TGI Tumor growth inhibition rate
  • Tumor growth inhibition rate (TGI,%) (1-T/C) ⁇ 100
  • OVCAR-3 tumor cells were inoculated and divided into groups for drug administration 21 days after inoculation.
  • the mean tumor volume of each group was 222 mm 3 .
  • the mean tumor volume of the solvent control group was 2,370 mm 3 ;
  • the 40 mg/kg carboplatin monotherapy group and the 40 mg/kg carboplatin combined therapy group with the compound of formula (A) showed significant tumor growth inhibition effects.
  • the combined group had a stronger tumor inhibition effect than each monotherapy group.
  • Example 8 Safety, tolerability, pharmacokinetic properties and preliminary efficacy evaluation of the compound of formula (A) tablets combined with niraparib tosylate capsules/paclitaxel injection/doxorubicin hydrochloride liposome injection in patients with locally advanced or metastatic ovarian cancer who have failed standard treatment Study population:
  • Cohort A Patients with locally advanced/metastatic ovarian cancer confirmed by cytology or histology who have failed standard treatment, or have no standard treatment options, or are not currently suitable for standard treatment.
  • Cohort B and C patients with locally advanced/metastatic ovarian cancer confirmed by cytology or histology and platinum-resistant, who have failed standard treatment, have no standard treatment options, or are not currently suitable for standard treatment.
  • ORR DCR, DOR, PFS, CA-125 response rate (GCIG standard), and pharmacokinetic parameters.
  • Example 9 An open, randomized, positive-controlled, phase II clinical study on the efficacy and safety of the compound of formula (A) tablets combined with niraparib tosylate capsules/paclitaxel injection/doxorubicin hydrochloride liposome injection in the treatment of platinum-resistant ovarian cancer
  • Study purpose To evaluate the clinical efficacy of the compound of formula (A) combined with niraparib tosylate capsules/paclitaxel injection/doxorubicin liposome injection in the treatment of platinum-resistant ovarian cancer subjects; to further evaluate the clinical efficacy of the compound of formula (A) combined with niraparib tosylate capsules/paclitaxel injection/doxorubicin liposome injection in the treatment of platinum-resistant ovarian cancer subjects; to investigate the pharmacokinetic (PK) characteristics of the compound of formula (A) combined with niraparib tosylate capsules/paclitaxel injection/doxorubicin liposome injection in the treatment of platinum-resistant ovarian cancer subjects at steady state; to explore the pharmacokinetic (PK) characteristics of the compound of formula (A) combined with niraparib tosylate capsules/paclitaxel injection/doxorubicin liposome injection in the treatment of platinum-resistant ovarian cancer subjects; To investigate the potential effect of combined use
  • Cohort 1 Tablets of the compound of formula (A) combined with niraparib tosylate capsules;
  • Cohort 2 Tablets of the compound of formula (A) combined with paclitaxel injection
  • Cohort 3 Tablets of the compound of formula (A) combined with doxorubicin hydrochloride liposome injection;
  • Cohort 4 niraparib tosylate capsules monotherapy
  • Cohort 5 paclitaxel injection monotherapy
  • Cohort 6 monotherapy with doxorubicin hydrochloride liposome injection.
  • Tablets of the compound of formula (A) Specification: 100 mg, oral, once a day, dosage: 200 mg/time to 400 mg/time; continuous administration for 21 days, rest for 7 days, 28 days as a dosing cycle, treatment until intolerance or disease progression or subject withdrawal.
  • Niraparib Tosylate Capsules Specification: 100 mg, Dosage: 300 mg/time, oral, once a day, with a dosing cycle of 28 days, treatment until intolerance or disease progression or subject withdrawal.
  • Paclitaxel injection Specification: 30 mg (5 mL)/bottle, dosage: 80 mg/m 2 /time, intravenous infusion, administered on the 1st, 8th and 15th days of each cycle, 28 days as a dosing cycle, treatment until intolerance or disease progression or subject withdrawal.
  • Doxorubicin hydrochloride liposome injection Specifications: 10mL: 20mg, 40mg/ m2 /time, intravenous infusion, administered on the first day of each cycle, 28 days as a dosing cycle, treatment until intolerance or disease progression or subject withdrawal.
  • ORR DCR, DOR, PFS, CA-125 response rate (GCIG criteria), pharmacokinetic parameters, adverse events, vital signs, electrocardiogram (ECG), physical examination, and laboratory tests.
  • GCIG criteria CA-125 response rate
  • adverse events adverse events
  • vital signs vital signs
  • ECG electrocardiogram

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Abstract

L'invention concerne l'utilisation d'un inhibiteur d'AKT dans la préparation d'un médicament pour la prévention ou le traitement du cancer de l'ovaire, et l'utilisation d'un inhibiteur d'AKT en combinaison avec d'autres médicaments pour le traitement du cancer de l'ovaire, comprenant un ou plusieurs éléments parmi un inhibiteur de PARP, un médicament de chimiothérapie à base de plante, un médicament de chimiothérapie antibiotique, un médicament à base de platine et un agent d'alkylation, dans la préparation d'un médicament pour la prévention ou le traitement du cancer de l'ovaire. L'administration combinée peut inhiber efficacement la croissance de cellules tumorales ovariennes et la formation de colonies cellulaires, et est nettement supérieure à l'administration d'un seul médicament. De plus, l'administration combinée produit un effet additif ou synergique, entraîne peu d'effets secondaires toxiques sur des cellules normales, présente une sécurité élevée, fournit une méthode plus efficace pour traiter le cancer de l'ovaire, et revêt une valeur clinique importante.
PCT/CN2024/099152 2023-06-14 2024-06-14 Utilisation d'un inhibiteur d'akt dans la préparation d'un médicament pour la prévention ou le traitement du cancer de l'ovaire Ceased WO2024255830A1 (fr)

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WO2022017446A1 (fr) * 2020-07-22 2022-01-27 南京正大天晴制药有限公司 Composition de dosage unitaire d'inhibiteur d'akt
US20230064189A1 (en) * 2019-12-19 2023-03-02 Imperial College Innovations Limited 1h-pyrazolo[3,4-d]pyrimidine compounds useful for the treatment of platinum-resistant cancer
US20230148417A1 (en) * 2020-03-17 2023-05-11 Jiangsu Hengrui Pharmaceuticals Co., Ltd. Fused bicyclic derivative, preparation method therefor, and pharmaceutical use thereof
CN116478156A (zh) * 2022-01-17 2023-07-25 南京正大天晴制药有限公司 一种akt抑制剂化合物的富马酸盐晶型及其制备方法

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US20150174149A1 (en) * 2004-03-29 2015-06-25 University Of South Florida Compositions including triciribine and methods of use thereof
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US20230064189A1 (en) * 2019-12-19 2023-03-02 Imperial College Innovations Limited 1h-pyrazolo[3,4-d]pyrimidine compounds useful for the treatment of platinum-resistant cancer
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