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WO2024213057A1 - Utilisation d'une combinaison d'un inhibiteur de lsd1 et d'un médicament pour traiter le cancer - Google Patents

Utilisation d'une combinaison d'un inhibiteur de lsd1 et d'un médicament pour traiter le cancer Download PDF

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Publication number
WO2024213057A1
WO2024213057A1 PCT/CN2024/087283 CN2024087283W WO2024213057A1 WO 2024213057 A1 WO2024213057 A1 WO 2024213057A1 CN 2024087283 W CN2024087283 W CN 2024087283W WO 2024213057 A1 WO2024213057 A1 WO 2024213057A1
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active ingredient
cancer
substituted
unsubstituted
composition
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PCT/CN2024/087283
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English (en)
Chinese (zh)
Inventor
柳红
李佳
黄河
王江
周宇波
任雪莲
李淳朴
阚伟娟
许子超
胡小蓓
吴恒搏
汪翰林
叶云飞
邱小慧
苏明波
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中国科学院上海药物研究所
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Publication of WO2024213057A1 publication Critical patent/WO2024213057A1/fr

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    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • 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
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    • 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
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
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    • 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
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
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    • 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
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    • 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
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • the present invention relates to the fields of pharmaceutical chemistry and pharmacotherapy, and in particular to the use of a tranylcypromine-type LSD1 inhibitor in combination with a drug in the preparation of a drug for preventing and/or treating cancer.
  • Cancer is one of the diseases that seriously endangers human life and health. It refers to a malignant disease in which cells grow and metastasize uncontrolled due to abnormal proliferation and differentiation, and often leads to the death of patients. According to the latest statistics from the World Health Organization (WHO), the number of patients diagnosed with malignant tumors in the world reached 19.29 million in 2020, and 9.96 million patients died of malignant tumors. At present, malignant tumors have become the second leading cause of death after cardiovascular and cerebrovascular diseases. Therefore, the development of anti-tumor treatment strategies with good therapeutic effects is of great significance for improving the quality of life of cancer patients. With the development of molecular biology, the research on tumor molecular targeted therapy based on tumor molecular mechanisms has made significant progress.
  • WHO World Health Organization
  • the epigenetic field is one of the current focuses of tumor targeted therapy drug research. Through the dynamic regulation of histone modification, it affects the survival, proliferation and disease progression of tumor cells. However, the efficacy of epigenetic drugs alone is limited and there are certain toxic and side effects. Clinical treatment of cancer urgently needs a drug combination with significant therapeutic effects and low toxic and side effects.
  • LSD1 Lysine-specific demethylase 1
  • KDM1A ysine-specific demethylase 1
  • LSD1 consists of 852 amino acids, and its structure is highly conserved from yeast to humans. Crystal structure analysis found that LSD1 contains three main regions: an amine oxidase (Amine oxidase-like) domain at the carboxylic acid (C) terminal, a SWIRM (Swi3p/Rsc8p/Moira) domain at the amino (N) terminal, and a central protruding Tower domain.
  • the C-terminal domain of LSD1 has a high homology with monoamine oxidase MAO; it consists of two parts, the FAD binding subdomain and the substrate binding subdomain, which together construct a large cavity pocket and form a catalytic active center at the junction.
  • the Tower region is inserted into the amine oxidase region, dividing the amine oxidase domain into two parts.
  • the formed long helical structure can bind to different partner proteins, thereby regulating the demethylation activity of LSD1.
  • LSD1 is closely related to the occurrence and development of leukemia. High expression of LSD1 was found in the bone marrow of 90% of acute myeloid leukemia (AML) and 78% of acute lymphoblastic leukemia (ALL) cases. In the MLL-AF9 leukemia nude mouse experiment, LSD1 was found to be a key factor in inhibiting differentiation in MLL leukemia. Blocking LSD1 activity by small molecules or gene knockout can affect the cloning of murine and human AML cells and induce their differentiation, but has no effect on the cloning of normal hematopoietic stem cells.
  • LSD1 overexpression was found in a variety of solid tumor cells and tissues such as glioblastoma, colon cancer, small cell lung cancer, breast cancer, and prostate cancer.
  • LSD1 is closely related to the epithelial cell to mesenchymal cell transformation (EMT) process that causes malignant tumor metastasis.
  • EMT epithelial cell to mesenchymal cell transformation
  • LSD1 inhibitors can not only serve as an important tool to clarify the biological function of the enzyme, but also become potential anticancer drug molecules.
  • LSD1 small molecule inhibitors have entered the clinical research stage as anti-tumor drug candidates, among which tranylcypromine-type LSD1 inhibitors have been a hot topic of research in recent years.
  • LSD1 has an important influence on the expression of downstream genes by binding to related chaperone proteins.
  • the methylation of histones may both activate and inhibit gene transcription, depending on the site and degree of methylation.
  • LSD1 acts in conjunction with the transcriptional repression complex (CoREST), it demethylates the H3K4 site and inhibits the expression of related genes; LSD1 binds to androgen receptors or estrogen receptors and can specifically demethylate the H3K9 site, thereby activating the expression of related genes.
  • LSD1 has a variety of gene expression regulation, it is of great significance to find new drug combinations to achieve better clinical treatment effects.
  • the combination of LSD1 inhibitors and all-trans retinoic acid (ATRT) has attracted great attention. Studies have shown that LSD1 inhibitors can significantly affect the differentiation of acute promyelocytic leukemia (APL) cells and play a synergistic role in combination with ATRA.
  • APL acute promyelocytic leukemia
  • the object of the present invention is to provide a composition, a medicine kit and a combination of active ingredients for cancer treatment, and the use thereof in preparing cancer treatment drugs.
  • the present invention utilizes the synergistic effect of two active ingredients to enhance the effect of cancer treatment.
  • composition comprising:
  • a therapeutically effective amount of a second active ingredient wherein the second active ingredient is selected from the following group: kinase inhibitors, anticancer drugs that act on or affect DNA, antiviral compounds, antihypertensive compounds, antidiabetic compounds, JAK-STAT signaling pathway inhibitors, NF- ⁇ B signaling pathway inhibitors, protein synthesis inhibitors, 5-hydroxytryptamine receptor agonists, dystroglycan modulators, GABA receptor modulators, or a combination thereof.
  • the second active ingredient is selected from the following group: kinase inhibitors, anticancer drugs that act on or affect DNA, antiviral compounds, antihypertensive compounds, antidiabetic compounds, JAK-STAT signaling pathway inhibitors, NF- ⁇ B signaling pathway inhibitors, protein synthesis inhibitors, 5-hydroxytryptamine receptor agonists, dystroglycan modulators, GABA receptor modulators, or a combination thereof.
  • the tranylcypromine compound is a compound represented by Formula I or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or a mixture thereof.
  • A is selected from: substituted or unsubstituted C6-C12 aromatic ring, substituted or unsubstituted 5-12 membered aromatic heterocycle, or substituted or unsubstituted C6-C12 aromatic ring -L1-substituted or unsubstituted 5-12 membered aromatic heterocycle-, wherein the aromatic heterocycle is selected from the following group: furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, pyrimidinyl, pyrazinyl, thiazolyl, imidazolyl, tetrazolyl, and the aromatic heterocycle contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; the substitution refers to substitution by 1 to 3 (e.g., 1, 2, 3) substituents selected from the following group: hydrogen isotopes (such as deuterium), halogen, C1-C6 straight or branched alkyl, C1-C6 straight or branched hal
  • -L1- is selected from the group consisting of none, -(C1-C3 alkylene)-, -(C2-C3 alkenylene)-, -(C2-C3 alkynylene)-, -O-;
  • X is NR 1 or C(R 1 ) 2 ;
  • Each R 1 is independently selected from: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C12 aryl, -L2-L3-Ra, -NRcRd;
  • -L2- is selected from the group consisting of none, -SO 2 -, -NH-, -C(O)NH-, -C(S)NH-, -NHC(O)O-, -NHC(O)-, -C(O)O-, -C(O)-, -CH 2 O-; and -L3- is selected from the group consisting of none, -(C1-C4 alkylene)-, -(C2-C4 alkenylene)-;
  • Each Ra is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, -COO-(C1-C6 alkyl), substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 3-7 membered heterocyclyl, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted 5-10 membered heteroaryl; wherein the substitution refers to substitution by 1-3 (e.g., 1, 2, 3) substituents selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, phenyl-substituted C1-C4 alkyl-, phenyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C2-C4 ester, C1-C4 alkyl-sulfony
  • Rc is hydrogen or a substituted or unsubstituted C1-C3 straight or branched chain alkyl group
  • Rd is H
  • the derivative of the tranylcypromine compound is a derivative shown in Formula II or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or a mixture thereof.
  • R2 is selected from hydrogen
  • the composition consists of (A) a therapeutically effective amount of a first active ingredient, and (B) a therapeutically effective amount of a second active ingredient.
  • the content of the first active ingredient ranges from 0.01wt% to 99.99wt%, based on the total weight of the active ingredients of the composition; preferably 0.1wt% to 99.9wt%; more preferably 1wt% to 99wt%; more preferably 10wt% to 99wt%; more preferably 20wt% to 99wt%; more preferably 30-99wt%, more preferably 40-99wt%.
  • the content of the second active ingredient ranges from 0.01wt% to 99.99wt%, based on the total weight of the active ingredients of the composition; preferably 0.1wt% to 99.9wt%; more preferably 1wt% to 99wt%; more preferably 1wt% to 90wt%; more preferably 1wt% to 80wt%; more preferably 1-70wt%, more preferably 1-60wt%.
  • the sum of the first active ingredient and the second active ingredient accounts for 20-100 wt %, preferably 30-99 wt %, and more preferably 40-95 wt % of the total weight of the composition.
  • the first active ingredient is a compound represented by formula (1R, 2S)-Ia, (1S, 2R)-Ib, or a derivative represented by formula (1R, 2S)-IIa, (1S, 2R)-IIb, or a racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof:
  • A is a substituted or unsubstituted C6-C10 aryl group, preferably a phenyl group.
  • each R 1 is independently -L2-L3-Ra.
  • -L2- is -C(O)O-
  • -L3- is none, -(C1-C4 alkylene)- or -(C2-C4 alkenylene)-
  • Ra is substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 3-7 membered heterocyclyl, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted 5-10 membered heteroaryl.
  • -L2- is -C(O)O-
  • -L3- is none or -(C1-C4 alkylene)-
  • Ra is substituted or unsubstituted C5-C6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocyclyl, or substituted or unsubstituted C6 aryl.
  • -L2- is -C(O)O-
  • -L3- is none or -(C1-C4 alkylene)-
  • Ra is a substituted or unsubstituted 4-6 membered nitrogen-containing heterocyclic group.
  • -L2- is none
  • -L3- is -(C1-C4 alkylene)-
  • Ra is substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 3-7 membered heterocyclyl, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted 5-10 membered heteroaryl.
  • -L2- is nothing
  • -L3- is -(C1-C4 alkylene)-
  • Ra is substituted or unsubstituted C5-C6 cycloalkyl, substituted or unsubstituted 5-6 membered heterocyclyl, or substituted or unsubstituted C6 aryl.
  • -L2- is nothing
  • -L3- is -(C1-C4 alkylene)-
  • Ra is a substituted C6 aryl group, wherein the substitution refers to substitution with a carboxyl group or a C2-C4 ester group.
  • the nitrogen-containing heterocyclic group is N-containing heterocyclic group
  • the first active ingredient is a compound selected from the following group, or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or a mixture thereof:
  • the first active ingredient is compound A3, A5, A21, A67, A71-A72, or its enantiomers, GSK2879552, (1R, 2S)-A43.
  • the first active ingredient is ((1R,2S)-A43) and/or (GSK2879552).
  • the kinase inhibitor is selected from one or more of the following groups: extracellular signal-regulated kinase, tyrosine receptor kinase inhibitors, tyrosine non-receptor kinase inhibitors, multi-target kinase inhibitors, serine/threonine protein kinase inhibitors, phosphatidylinositol-3-kinase inhibitors, rapamycin (PI3K-AKT-mTOR) signaling pathway inhibitors, and cell cycle-dependent protein kinase inhibitors.
  • extracellular signal-regulated kinase tyrosine receptor kinase inhibitors
  • tyrosine non-receptor kinase inhibitors multi-target kinase inhibitors
  • serine/threonine protein kinase inhibitors phosphatidylinositol-3-kinase inhibitors
  • the kinase inhibitor is selected from one or more of the following groups: Tyrphostin AG126, Pimasertib (AS-703026), Ruxolitinib, OM-137, AS-604850,
  • the DNA anticancer drug that acts or affects is selected from one or more of the following groups: cytarabine, cisplatin, carboplatin, topotecan, carmustine, and busulfan.
  • the antidiabetic compound is selected from one or more of the following groups: Mitoglitazone, Pioglitazone, Rosiglitazone, Troglitazone.
  • the antiviral compound is selected from one or more of the following groups: Emetine, Cephaeline, and Entecavir.
  • the antihypertensive compound is selected from one or more of the following groups: valsartan, losartan, azilsartan, and olmesartan medoxomil.
  • the JAK-STAT signaling pathway inhibitor is selected from one or more of the following groups: homoharringtonine, artesunate, cryptotanshinone, and niclosamide.
  • the NF- ⁇ B signaling pathway inhibitor is selected from one or more of the following groups: Geranylgeraniol, Farnesol, and SC75741.
  • the protein synthesis inhibitor is selected from one or more of the following groups: Verrucarin A, daunorubicin, and doxorubicin.
  • the 5-hydroxytryptamine receptor agonist is selected from one or more of the following groups: PNU-22394 and 1-phenylbiguanide.
  • the dystroglycan regulator is selected from one or more of the following group: Atalureno, Viltolarsen, and Eteplirsen.
  • the GABA receptor modulator is selected from one or more of the following groups: PK-11195, CL-218872, and CGP37157.
  • the second active ingredient is selected from the following group: cytarabine, homoharringtonine, daunorubicin, cisplatin, or a combination thereof.
  • the mass ratio of the first active ingredient to the second active ingredient is 1:10000 to 10000:1; preferably 1:1000 to 1000:1; more preferably 1:500 to 500:1; more preferably 1:100 to 100:1; more preferably 10:90 to 100:1, for example 80:1, 50:1, 40:1, 30:1, 20:1, 10:1, 5:1, 2:1, 1:1, 1:2, 1:5, 1:10, 1:20, 1:30, 1:40, 1:50, 1:80.
  • the molar ratio of the first active ingredient to the second active ingredient is 1:10000 to 10000:1; preferably 1:1000 to 1000:1; more preferably 1:500 to 500:1; more preferably 1:100 to 100:1; more preferably 10:90 to 100:1, for example 80:1, 50:1, 40:1, 30:1, 20:1, 10:1, 5:1, 2:1, 1:1, 1:2, 1:5, 1:10, 1:20, 1:30, 1:40, 1:50, 1:80.
  • the first active ingredient is GSK2879552, and the second active ingredient is cytarabine.
  • the composition comprises a therapeutically effective amount of GSK2879552 and a therapeutically effective amount of cytarabine, and the composition is used to prevent and/or treat hematological tumors.
  • the molar ratio of GSK2879552 to cytarabine is 10:1 to 1:50, preferably 1:1 to 1:30, for example 1:25, 1:10, 1:5.
  • the first active ingredient is (1R, 2S)-A43
  • the second active ingredient is cytarabine
  • the composition comprises a therapeutically effective amount of (1R, 2S)-A43 and a therapeutically effective amount of cytarabine, and the composition is used to prevent and/or treat hematological tumors.
  • the molar ratio of (1R, 2S)-A43 to cytarabine is 10:1 to 1:50, preferably 1:1 to 1:30, for example 1:25, 1:10, 1:5.
  • the first active ingredient is (1R, 2S)-A43
  • the second active ingredient is homoharringtonine
  • the composition comprises a therapeutically effective amount of (1R, 2S)-A43 and a therapeutically effective amount of homoharringtonine, and the composition is used to prevent and/or treat leukemia.
  • the molar ratio of (1R, 2S)-A43 to homoharringtonine is 10:1 to 1:100, preferably 1:1 to 1:50, for example 1:30, 1:25, 1:10, 1:5.
  • the first active ingredient is (1R, 2S)-A43
  • the second active ingredient is cytarabine
  • the composition comprises a therapeutically effective amount of (1R, 2S)-A43 and a therapeutically effective amount of cytarabine, and the composition is used to prevent and/or treat leukemia, preferably monocytic leukemia.
  • the molar ratio of (1R, 2S)-A43 to cytarabine is 10:1 to 1:20, preferably 1:1 to 1:10, for example 1:2, 1:4, 1:8.
  • the first active ingredient is (1R, 2S)-A43
  • the second active ingredient is cytarabine
  • daunorubicin the composition comprises a therapeutically effective amount of (1R, 2S)-A43, a therapeutically effective amount of cytarabine, and a therapeutically effective amount of daunorubicin, and the composition is used to prevent and/or treat leukemia, preferably acute myeloid leukemia.
  • the molar ratio of (1R, 2S)-A43 to cytarabine is 10:1 to 1:50, preferably 1:1 to 1:30, for example 1:25, 1:10, 1:5; the molar ratio of (1R, 2S)-A43 to daunorubicin is 1:0.5 to 1:5, preferably 1:1 to 1:3, for example 1:1.5, 1:2, 1:2.5.
  • the first active ingredient is (1R, 2S)-A43
  • the second active ingredient is cisplatin
  • the composition comprises a therapeutically effective amount of (1R, 2S)-A43 and a therapeutically effective amount of cisplatin, and the composition is used to prevent and/or treat lung cancer.
  • the molar ratio of (1R, 2S)-A43 to cytarabine is 50:1 to 1:10, preferably 30:1 to 1:1, for example 25:1, 15:1, 10:1, 5:1.
  • the first active ingredient is (1R, 2S)-A43
  • the second active ingredient is homoharringtonine
  • the composition comprises a therapeutically effective amount of (1R, 2S)-A43 and a therapeutically effective amount of homoharringtonine, and the composition is used to prevent and/or treat leukemia, preferably acute myeloid leukemia.
  • the molar ratio of (1R, 2S)-A43 and homoharringtonine is 10:1 to 1:10, preferably 8:1 to 1:5, for example 5:1, 3:1, 2:1, 1:1.
  • the composition includes a pharmaceutical composition, a health product composition or a dietary supplement.
  • the composition further comprises a pharmaceutically acceptable carrier, a nutraceutical acceptable carrier or a food acceptable carrier.
  • the dosage form of the composition is a solid preparation, a semisolid preparation or a liquid preparation.
  • the dosage form of the composition is tablets, capsules, granules, powders, suspensions, sols, emulsions, solutions, injections, pellets, micropellets, microspheres, microcapsules or polymer micelles.
  • the dosage form of the composition is a rapid release preparation, a sustained release preparation, a controlled release preparation, or a positioned release preparation.
  • the composition is in the form of an oral preparation or an injection preparation.
  • the injection preparation includes a subcutaneous injection preparation, an intravenous injection preparation or an intraperitoneal injection preparation.
  • the pharmaceutically acceptable carrier includes one or more ingredients selected from the following group: fillers, adsorbents, disintegrants, binders, lubricants, suspending agents, solubilizers, emulsifiers, antioxidants, preservatives, colorants, sweeteners, and flavoring agents.
  • a medicine kit comprising:
  • a second preparation containing a second active ingredient wherein the second active ingredient is selected from the following group: kinase inhibitors, anticancer drugs that act or affect DNA, antiviral compounds, antihypertensive compounds, antidiabetic compounds, JAK-STAT signaling pathway inhibitors, NF- ⁇ B signaling pathway inhibitors, protein synthesis inhibitors, 5-hydroxytryptamine receptor agonists, dystroglycan modulators, GABA receptor modulators, or a combination thereof.
  • the second active ingredient is selected from the following group: kinase inhibitors, anticancer drugs that act or affect DNA, antiviral compounds, antihypertensive compounds, antidiabetic compounds, JAK-STAT signaling pathway inhibitors, NF- ⁇ B signaling pathway inhibitors, protein synthesis inhibitors, 5-hydroxytryptamine receptor agonists, dystroglycan modulators, GABA receptor modulators, or a combination thereof.
  • the medicine kit optionally further includes instructions for use.
  • the medicine kit comprises:
  • a second kit comprising a second preparation containing a second active ingredient.
  • the first active ingredient is as described in the first aspect of the present invention.
  • the second active ingredient is as described in the first aspect of the present invention.
  • the mass ratio of the first active ingredient to the second active ingredient is 1:10000 to 10000:1.
  • the molar ratio of the first active ingredient to the second active ingredient is 1:10000 to 10000:1.
  • the administration method of the medicine kit includes taking the first preparation first and then administering the second preparation after a period of time; administering the first preparation and the second preparation at the same time; or administering the second preparation first and then administering the first preparation after a period of time.
  • the administration methods of the first preparation and the second preparation are the same or different.
  • the administration methods of the first preparation and the second preparation are independently selected from oral administration, subcutaneous injection, intravenous injection or intraperitoneal injection.
  • the administration dosage of the first active ingredient is 0.01-100 mg/kg/day, preferably 0.1-10 mg/kg/day.
  • the administration dosage of the second active ingredient is 0.1-100 mg/kg/day, preferably 0.5-50 mg/kg/day.
  • the third aspect of the present invention provides an active ingredient combination, which includes the following components or is composed of the following components:
  • a second active ingredient wherein the second active ingredient is selected from the following group: kinase inhibitors, anticancer drugs that act on or affect DNA, antiviral compounds, antihypertensive compounds, antidiabetic compounds, JAK-STAT signaling pathway inhibitors, NF- ⁇ B signaling pathway inhibitors, protein synthesis inhibitors, 5-hydroxytryptamine receptor agonists, dystroglycan modulators, GABA receptor modulators, or a combination thereof.
  • the second active ingredient is selected from the following group: kinase inhibitors, anticancer drugs that act on or affect DNA, antiviral compounds, antihypertensive compounds, antidiabetic compounds, JAK-STAT signaling pathway inhibitors, NF- ⁇ B signaling pathway inhibitors, protein synthesis inhibitors, 5-hydroxytryptamine receptor agonists, dystroglycan modulators, GABA receptor modulators, or a combination thereof.
  • the first active ingredient is as described in the first aspect of the present invention.
  • the second active ingredient is as described in the first aspect of the present invention.
  • the mass ratio of the first active ingredient to the second active ingredient ranges from 1:10000 to 10000:1.
  • the molar ratio of the first active ingredient to the second active ingredient is 1:10000 to 10000:1.
  • the fourth aspect of the present invention provides the use of the composition described in the first aspect of the present invention or the combination of active ingredients described in the third aspect of the present invention for preparing a pharmaceutical composition, a health product composition or a dietary supplement for (a) inhibiting cancer cells and/or (b) preventing and/or treating cancer.
  • the cancer is selected from the group consisting of bone cancer, stomach cancer, cervical cancer, brain cancer, liver cancer, prostate cancer, lung cancer, breast cancer, colorectal cancer, colon cancer, kidney cancer, bladder cancer, pancreatic cancer, endometrial cancer, ovarian cancer, Skin cancer, blood cancer, leukemia, non-Hodgkin's lymphoma, lymphoma or malignant melanoma, or a combination thereof.
  • the leukemia is selected from the following group: acute myeloid leukemia and monocytic leukemia.
  • the cancer cell inhibition comprises one or more characteristics selected from the following group:
  • the prevention and/or treatment of cancer includes one or more features selected from the following group:
  • a fifth aspect of the present invention provides a pharmaceutical composition for treating cancer, the pharmaceutical composition comprising:
  • a therapeutically effective amount of a second active ingredient wherein the second active ingredient is selected from the group consisting of a kinase inhibitor, an anticancer drug that acts on or affects DNA, an antiviral compound, an antihypertensive compound, an antidiabetic compound, a JAK-STAT signaling pathway inhibitor, an NF- ⁇ B signaling pathway inhibitor, a protein synthesis inhibitor, a 5-hydroxytryptamine receptor agonist, a dystroglycan modulator, a GABA receptor modulator, or a combination thereof;
  • the second active ingredient is selected from the group consisting of a kinase inhibitor, an anticancer drug that acts on or affects DNA, an antiviral compound, an antihypertensive compound, an antidiabetic compound, a JAK-STAT signaling pathway inhibitor, an NF- ⁇ B signaling pathway inhibitor, a protein synthesis inhibitor, a 5-hydroxytryptamine receptor agonist, a dystroglycan modulator, a GABA receptor modul
  • the first active ingredient is as described in the first aspect of the present invention.
  • the second active ingredient is as described in the first aspect of the present invention.
  • the sixth aspect of the present invention provides a method for preventing and/or treating cancer, the method comprising the steps of administering the composition described in the first aspect of the present invention or the active ingredient combination described in the third aspect of the present invention or the pharmaceutical composition described in the fifth aspect of the present invention to a subject in need thereof.
  • the cancer is selected from: bone cancer, gastric cancer, cervical cancer, brain cancer, liver cancer, prostate cancer, lung cancer, breast cancer, colorectal cancer, colon cancer, kidney cancer, bladder cancer, pancreatic cancer, endometrial cancer, ovarian cancer, skin cancer, blood tumor, leukemia, non-Hodgkin's lymphoma, lymphoma or malignant melanoma, or a combination thereof.
  • the subject is a mammal (such as a human) or a rodent (such as a mouse).
  • the daily dosage of the composition is 0.1 mg-2000 mg.
  • the daily dosage of the first active ingredient is 0.1 mg-1000 mg
  • the daily dosage of the second active ingredient is 0.1 mg-1000 mg.
  • the administration amount is preferably calculated per kg body weight.
  • the administering comprises administering the first active ingredient and the second active ingredient sequentially, or administering the first active ingredient and the second active ingredient simultaneously.
  • FIG. 1 shows that (1R, 2S)-A43, GSK2879552 and cytarabine combined promote apoptosis of leukemia cells MV-4-11.
  • FIG. 2 shows that (1R,2S)-A43 combined with homoharringtonine inhibits leukemia cell proliferation.
  • FIG3 shows that (1R,2S)-A43 combined with homoharringtonine promotes apoptosis of leukemia cells MV-4-11.
  • FIG. 4 shows that (1R,2S)-A43 combined with homoharringtonine prolongs the survival of B-NDG mice bearing MV-4-11.
  • tranylcypromine LSD1 inhibitors or their derivatives with kinase inhibitors, anticancer drugs that act on or affect DNA, antiviral compounds, antihypertensive compounds, antidiabetic compounds, JAK-STAT signaling pathway inhibitors, NF- ⁇ B signaling pathway inhibitors, protein synthesis inhibitors, 5-hydroxytryptamine receptor agonists, dystroglycan regulators, and GABA receptor regulators can synergistically act on cancer. And the synergistic therapeutic effect is significantly better than the use of the two alone.
  • the present invention was completed on this basis.
  • the terms “comprise”, “include”, and “contain” are used interchangeably and include not only closed definitions, but also semi-closed and open definitions. In other words, the terms include “consisting of”, “consisting essentially of”.
  • the term “about” means that the value may vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
  • C1-C6 alkyl refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.”
  • C1-C6 alkyl includes C1, C2, C3, C4, C5, and C6 alkyl groups.
  • C1-C6 alkoxy refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, or the like.
  • C1-C6 alkoxy includes C1, C2, C3, C4, C5, and C6 alkoxy groups.
  • C3-C7 cycloalkyl refers to a cycloalkyl group having 3-7 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, cycloheptyl, or the like.”
  • C3-C7 cycloalkyl includes cycloalkyl groups of C3, C4, C5, C6, and C7.
  • 3-7 membered heterocyclyl refers to monocyclic and polycyclic heterocyclic rings (preferably monocyclic heterocyclic rings) having 3-7 ring atoms and 1-3 heteroatoms, such as piperidinyl, tetrahydropyrrolyl, morpholinyl, or similar groups.
  • 3-7 membered heterocyclyl includes 3, 4, 5, 6, 7 membered heterocyclyl.
  • C2-C4 ester group refers to a group having a C1-C3 alkyl-COO-structure or a A group of the structure -(COO)-C1-C3 alkyl, wherein the alkyl group may be linear or branched, for example CH3COO- , C2H5COO- , C3H8COO- , ( CH3 ) 2CHCOO- , -COOCH3 , -COOC2H5 , -COOC3H8 , or the like.
  • C2-C4 acyl refers to a group having a C1-C3 alkyl-CO- structure, wherein the alkyl group may be linear or branched, such as CH3 - CO-, C2H5 - CO-, C3H8 - CO-, or the like.
  • C6-C12 aryl refers to a group having 6 to 12 ring carbon atoms and having aromatic properties, such as phenyl, naphthyl, or the like.
  • C6-C12 aromatic ring refers to a ring having 6 to 12 ring carbon atoms and having aromaticity, such as a benzene ring, a naphthalene ring, or the like.
  • 5-12 membered heteroaryl refers to an aromatic group having 5-12 ring atoms and containing 1-4 heteroatoms independently selected from nitrogen atoms, sulfur atoms or oxygen atoms, such as pyrrolyl, thienyl, furanyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, thiazolyl, oxazolyl, triazolyl or the like.
  • “5-12 membered heteroaryl” includes 5-6 membered, 5-8 membered, 5-10 membered heteroaryl.
  • 5-12 membered aromatic heterocycle refers to an aromatic ring having 5-12 ring atoms and containing 1-4 heteroatoms independently selected from nitrogen atoms, sulfur atoms or oxygen atoms, such as a pyrrole ring, a thiophene ring, a furan ring, a pyridine ring, a pyrazole ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, an imidazole ring, a thiazole ring, an oxazole ring, a triazole ring or the like.
  • “5-12 membered aromatic heterocycle” includes 5-6 membered, 5-8 membered, 5-10 membered aromatic heterocycles.
  • halogen refers to F, Cl, Br and I.
  • substituted means that a hydrogen atom on a group is replaced by a non-hydrogen atom group, but the valence requirements need to be met and a chemically stable compound is generated by the substitution. In this specification, it should be interpreted that all substituents are unsubstituted unless explicitly described as “substituted” in this specification.
  • substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the following group: C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclic group, halogen, hydroxyl, carboxyl (-COOH), C 1-8 aldehyde, C 2-10 acyl, C 2-10 ester, amino, C 1-6 alkoxy, C 1-10 sulfonyl.
  • a substituent selected from the following group: C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclic group, halogen, hydroxyl, carboxyl (-COOH), C 1-8 aldehyde, C 2-10 acyl, C 2-10 ester, amino, C 1-6 alkoxy, C 1-10 sulfonyl.
  • the compounds of the present invention or their pharmaceutically acceptable salts may contain one or more chiral carbon atoms, and thus may produce enantiomers, diastereomers and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof.
  • the preparation of the compounds of the present invention may select racemates, diastereomers or enantiomers as raw materials or intermediates.
  • the (1R, 2S) configuration is preferably selected.
  • a substituent may be attached to a parent group or substrate at any atom unless its attachment violates valence requirements; the hydrogen atoms of the parent group or substrate may be on the same atom or on different atoms.
  • the first active ingredient of the present invention is a tranylcypromine compound or a derivative thereof.
  • the tranylcypromine compound is a compound represented by Formula I or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof:
  • A is selected from: substituted or unsubstituted C6-C12 aromatic ring, substituted or unsubstituted 5-12 membered aromatic heterocycle, or substituted or unsubstituted C6-C12 aromatic ring -L1-substituted or unsubstituted 5-12 membered aromatic heterocycle-, wherein the aromatic heterocycle is selected from the following group: furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, pyrimidinyl, pyrazinyl, thiazolyl, imidazolyl, tetrazolyl, and the aromatic heterocycle contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; the substitution refers to substitution by 1 to 3 (e.g., 1, 2, 3) substituents selected from the following group: hydrogen isotopes (such as deuterium), halogen, C1-C6 straight or branched alkyl, C1-C6 straight or branched hal
  • -L1- is selected from the group consisting of none, -(C1-C3 alkylene)-, -(C2-C3 alkenylene)-, -(C2-C3 alkynylene)-, -O-;
  • X is NR 1 or C(R 1 ) 2 ;
  • Each R 1 is independently selected from: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C12 aryl, -L2-L3-Ra, -NRcRd;
  • -L2- is selected from the group consisting of none, -SO 2 -, -NH-, -C(O)NH-, -C(S)NH-, -NHC(O)O-, -NHC(O)-, -C(O)O-, -C(O)-, -CH 2 O-; and -L3- is selected from the group consisting of none, -(C1-C4 alkylene)-, -(C2-C4 alkenylene)-;
  • Each Ra is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, -COO-(C1-C6 alkyl), substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 3-7 membered heterocyclyl, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted 5-10 membered heteroaryl; wherein the substitution refers to substitution by 1-3 (e.g., 1, 2, 3) substituents selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, phenyl-substituted C1-C4 alkyl, phenyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C2-C4 ester, C1-C4 alkyl-sulfonyl
  • Rc is hydrogen or a substituted or unsubstituted C1-C3 straight or branched chain alkyl group
  • Rd is H.
  • the derivative of the tranylcypromine compound is a derivative represented by Formula II or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof:
  • the derivative of the tranylcypromine compound is a derivative shown in Formula II or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or a mixture thereof.
  • R2 is selected from hydrogen
  • the first active ingredient is a compound represented by formula (1R, 2S)-Ia, (1S, 2R)-Ib, or a derivative represented by formula (1R, 2S)-IIa, (1S, 2R)-IIb, or a racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or a mixture thereof:
  • the first active ingredient is a compound selected from the following group, or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or a mixture thereof:
  • tranylcypromine compounds or their derivatives can be used alone or in combination of two or more.
  • mass ratio of each compound is not particularly limited as long as the therapeutic purpose is achieved.
  • tranylcypromine compounds there is no particular limitation on the method for obtaining tranylcypromine compounds, for example, they can be prepared by chemical synthesis or semi-chemical synthesis.
  • the second active ingredient of the present invention can be a kinase inhibitor, an anticancer drug that acts on or affects DNA, an antiviral compound, an antihypertensive compound, an antidiabetic compound, a JAK-STAT signaling pathway inhibitor, an NF- ⁇ B signaling pathway inhibitor, a protein synthesis inhibitor, a 5-hydroxytryptamine receptor agonist, a dystroglycan modulator, or a GABA receptor modulator.
  • the kinase inhibitor is selected from one or more of the following groups: extracellular signal-regulated kinase, tyrosine receptor kinase inhibitors, tyrosine non-receptor kinase inhibitors, multi-target kinase inhibitors, serine/threonine protein kinase inhibitors, phosphatidylinositol-3-kinase inhibitors, rapamycin (PI3K-AKT-mTOR) signaling pathway inhibitors, and cell cycle-dependent protein kinase inhibitors.
  • extracellular signal-regulated kinase tyrosine receptor kinase inhibitors
  • tyrosine non-receptor kinase inhibitors multi-target kinase inhibitors
  • serine/threonine protein kinase inhibitors phosphatidylinositol-3-kinase inhibitors
  • the kinase inhibitors include: Tyrphostin AG126, Pimasertib (AS-703026), Ruxolitinib, OM-137, AS-604850, wherein the structural formula of Tyrphostin AG126 is
  • the effect or influence on the DNA anticancer drug is selected from one or more of the following groups: cytarabine, cisplatin, carboplatin, topotecan, carmustine, busulfan,
  • the structural formula of cytarabine is preferably
  • the antidiabetic compound is selected from one or more of the following groups: miglitazone (Mitoglitazone), pioglitazone (Pioglitazone), rosiglitazone (Rosiglitazone), troglitazone (Troglitazone).
  • the antiviral compound is selected from one or more of the following groups: Emetine, Cephaeline, and Entecavir.
  • the antihypertensive compound is selected from one or more of the following groups: valsartan, losartan, azilsartan, and olmesartan medoxomil.
  • the JAK-STAT signaling pathway inhibitor is selected from one or more of the following groups:
  • the structural formula of homoharringtonine is preferably
  • the NF- ⁇ B signaling pathway inhibitor is selected from one or more of the following groups: Geranylgeraniol, Farnesol, and SC75741.
  • the protein synthesis inhibitor is selected from one or more of the following groups: Verrucarin A, daunorubicin, doxorubicin;
  • daunorubicin is preferably
  • the 5-hydroxytryptamine receptor agonist is selected from one or more of the following groups: PNU-22394 and 1-phenylbiguanide.
  • the dystroglycan regulator is selected from one or more of the following group: Atalureno, Viltolarsen, and Eteplirsen.
  • the GABA receptor modulator is selected from one or more of the following groups: PK-11195, CL-218872, and CGP37157.
  • composition Composition, kit, active ingredient combination and pharmaceutical composition
  • composition of the present invention may be a pharmaceutical composition (drug), a dietary supplement or a health product composition, and the composition comprises:
  • the mass ratio of the first active ingredient to the second active ingredient is 1:10000 to 10000:1; preferably, it is 1:1000 to 1000:1.
  • the content of the first active ingredient ranges from 0.01wt% to 99.99wt%, based on the total weight of the composition. Preferably, it is from 0.1wt% to 99.9wt%, and more preferably, it is from 20wt% to 99wt%.
  • the content of the second active ingredient ranges from 0.01wt% to 99.99wt%, based on the total weight of the composition. Preferably, it is from 1wt% to 99wt%, and more preferably, it is from 1wt% to 90wt%.
  • the pharmaceutical composition, dietary supplement, and health product composition containing the first active ingredient, the second active ingredient, or their derivatives described in the present invention can be various dosage forms suitable for oral administration, as well as various external administration preparations or other parenteral administration preparations.
  • the dosage form of the pharmaceutical composition includes (but is not limited to) oral preparations, injections, and external preparations.
  • Representative forms include (but are not limited to): tablets, injections, infusions, ointments, gels, solutions, microspheres, and films.
  • the composition may also include a pharmaceutically, food science, or health product acceptable carrier.
  • a pharmaceutically, food science, or health product acceptable carrier refers to a substance that is suitable for use in humans and/or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reactions), that is, a substance with a reasonable benefit/risk ratio.
  • the term “effective amount” refers to an amount that can produce a function or activity on humans and/or animals and can be accepted by humans and/or animals.
  • the term "pharmaceutically acceptable carrier” refers to a carrier for administering a therapeutic agent, including various excipients and diluents.
  • the term refers to such pharmaceutical carriers: they are not essential active ingredients themselves and are not excessively toxic after administration. Suitable carriers are well known to those of ordinary skill in the art.
  • the carrier is not particularly limited, and can be selected from materials commonly used in the art, or prepared by conventional methods, or purchased from the market.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.), gelatin, talcum powder, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting agents (such as sodium lauryl sulfate), buffers, chelating agents, thickeners, pH regulators, transdermal enhancers, colorants, flavoring agents, stabilizers, antioxidants, preservatives, antibacterial agents, pyrogen-
  • the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oil, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • the composition may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents.
  • the topical drug-administered preparation of the present invention can be further prepared into (including but not limited to): liniments, tinctures, oils, ointments, plasters, pastes, ironing agents, plasters, patches, coatings, films, gels, cataplasms, acupoint plasters, sprays, aerosols, implants, emulsions, etc. by adding surfactants, transdermal absorption enhancers, preservatives, solvents, antioxidants, moisturizers, pH adjusters, colorants, fragrances and other auxiliary materials.
  • preferred dosage forms include: various dosage forms for oral administration, implants, and injections.
  • excipients added to the composition of the present invention are commonly used excipients in the field of pharmaceutical preparations, and their types, usage methods, and sources are well known to those skilled in the art.
  • the present invention also provides a medicine box, which comprises:
  • a second preparation containing a second active ingredient wherein the second active ingredient is selected from the following group: kinase inhibitors, anticancer drugs that act or affect DNA, antiviral compounds, antihypertensive compounds, antidiabetic compounds, JAK-STAT signaling pathway inhibitors, NF- ⁇ B signaling pathway inhibitors, protein synthesis inhibitors, 5-hydroxytryptamine receptor agonists, dystroglycan modulators, GABA receptor modulators, or a combination thereof.
  • the second active ingredient is selected from the following group: kinase inhibitors, anticancer drugs that act or affect DNA, antiviral compounds, antihypertensive compounds, antidiabetic compounds, JAK-STAT signaling pathway inhibitors, NF- ⁇ B signaling pathway inhibitors, protein synthesis inhibitors, 5-hydroxytryptamine receptor agonists, dystroglycan modulators, GABA receptor modulators, or a combination thereof.
  • the medicine kit optionally further includes instructions for use.
  • the present invention also provides an active ingredient combination, which includes the following components or is composed of the following components:
  • a second active ingredient wherein the second active ingredient is selected from the following group: kinase inhibitors, anticancer drugs that act or affect DNA, antiviral compounds, antihypertensive compounds, antidiabetic compounds, JAK-STAT signaling pathway inhibitors, NF- ⁇ B signaling pathway inhibitors, protein synthesis inhibitors, 5-hydroxytryptamine receptor agonists, dystroglycan modulators, GABA receptor modulators, or a combination thereof.
  • the second active ingredient is selected from the following group: kinase inhibitors, anticancer drugs that act or affect DNA, antiviral compounds, antihypertensive compounds, antidiabetic compounds, JAK-STAT signaling pathway inhibitors, NF- ⁇ B signaling pathway inhibitors, protein synthesis inhibitors, 5-hydroxytryptamine receptor agonists, dystroglycan modulators, GABA receptor modulators, or a combination thereof.
  • the mass ratio of the first active ingredient to the second active ingredient is 1:10000 to 10000:1.
  • compositions, pharmaceutical compositions, dietary supplements and health product compositions, medicine kits, and active ingredient combinations of the present invention can all be prepared using conventional methods and equipment.
  • the active ingredient combination described in the third aspect of the present invention, and the pharmaceutical composition described in the fifth aspect of the present invention can all be as described for the composition described in the first aspect of the present invention.
  • composition Composition, kit, active ingredient combination and use and administration of pharmaceutical composition
  • the present invention provides the use of the above-mentioned composition, medicine kit, active ingredient combination and pharmaceutical composition in preparing a pharmaceutical composition, health product composition or dietary supplement for (a) inhibiting cancer cells and/or (b) preventing and/or treating cancer.
  • composition, kit, active ingredient combination and pharmaceutical composition provided by the present invention can produce a synergistic effect on the inhibition of cancer cells such as bone cancer, gastric cancer, cervical cancer, brain cancer, liver cancer, prostate cancer, lung cancer, breast cancer, colorectal cancer, colon cancer, kidney cancer, bladder cancer, pancreatic cancer, endometrial cancer, ovarian cancer, skin cancer, leukemia, non-Hodgkin's lymphoma, lymphoma or malignant melanoma.
  • cancer cells such as bone cancer, gastric cancer, cervical cancer, brain cancer, liver cancer, prostate cancer, lung cancer, breast cancer, colorectal cancer, colon cancer, kidney cancer, bladder cancer, pancreatic cancer, endometrial cancer, ovarian cancer, skin cancer, leukemia, non-Hodgkin's lymphoma, lymphoma or malignant melanoma.
  • the mechanism of the composition, kit, active ingredient combination and pharmaceutical composition of the present invention in inhibiting the growth and metastasis of cancer cells is likely to be multi
  • the first preparation and the second preparation in the medicine kit of the present invention can be administered simultaneously, separately or sequentially.
  • the safe and effective daily dosage of the active ingredient of the first preparation is generally 0.1mg-1000mg, preferably 0.1mg-500mg
  • the safe and effective daily dosage of the active ingredient of the second preparation is generally 0.1mg-1000mg, preferably 0.1mg-500mg.
  • the administration method includes: when the drug is used in combination, the first preparation can be administered orally, or it can be administered externally or other parenterally, and the second preparation can be administered orally, or it can be administered externally or other parenterally.
  • the interaction of drugs is divided into additive effect, synergistic effect and antagonistic effect according to the effect of drugs when used together.
  • Synergistic effect means that the effect of drugs used together is many times greater than that of using them alone
  • additive effect means that the effect of drugs used together is equivalent to that of using them alone
  • antagonistic effect means that the effect of drugs used together is smaller than that of using them alone.
  • the present invention also provides a method for preventing or treating cancer, the method comprising the steps of administering the composition, active ingredient combination, pharmaceutical composition and drug kit of the present invention to a subject in need thereof, wherein the daily amount of the active ingredient administered is 0.1 mg to 10 g.
  • the subject is a mammal or a rodent, preferably a human.
  • the administration method of the present invention includes sequentially administering the first active ingredient and the second active ingredient, or administering the first active ingredient and the second active ingredient simultaneously.
  • a safe and effective amount of the composition, active ingredient combination, or pharmaceutical composition of the present invention is administered to a mammal or rodent, wherein the safe and effective daily dose of the first active ingredient is usually at least about 0.1 mg, and in most cases does not exceed about 1000 mg.
  • the dose is 0.1 mg-500 mg; the safe and effective amount of the second active ingredient is usually at least about 0.1 mg, and in most cases does not exceed 1000 mg.
  • the dose range is 0.1 mg to 1000 mg. (Wherein, the safe and effective amount of the first active ingredient is usually not more than about 1000 mg/kg body weight.
  • the dose is about 0.1 mg/kg body weight to about 1000 mg/kg body weight; the safe and effective amount of the second active ingredient is usually not more than about 1000 mg/kg body weight. Preferably, the dose is about 0.1 mg/kg body weight to about 1000 mg/kg body weight.)
  • the specific dose should also take into account factors such as the route of administration and the patient's health status, which are all within the skill range of skilled physicians. When the first active ingredient and the second active ingredient are administered sequentially, there is no special requirement for the interval between administrations.
  • the first active ingredient and the second active ingredient in the composition, active ingredient combination, pharmaceutical composition and medicine kit of the present invention are administered simultaneously or sequentially by the same or different routes, including but not limited to: oral administration, injection, intratumoral administration, implantation, intracavity administration, anal administration, transdermal administration, internal and external application;
  • Preferred administration by injection includes: intravenous injection, intramuscular injection, subcutaneous injection, and intracavitary injection.
  • tranylcypromine-type LSD1 inhibitors or their derivatives with kinase inhibitors, anticancer drugs that act on or affect DNA, antiviral compounds, antihypertensive compounds, antidiabetic compounds, JAK-STAT signaling pathway inhibitors, NF- ⁇ B signaling pathway inhibitors, protein synthesis inhibitors, 5-hydroxytryptamine receptor agonists, dystroglycan modulators, and GABA receptor modulators can synergistically act on cancer cells, thereby enhancing the therapeutic effect of cancer, which is better than the sum of the effects of the two alone.
  • composition of the present invention can effectively reduce the dosage of the second active ingredient to achieve the same therapeutic effect, reduce the toxic side effects of the treatment, improve the quality of life of patients, and provide a new type of drug for the prevention and treatment of cancer.
  • the present invention can effectively slow down and delay the occurrence of cancer, prolong the life of patients and reduce mortality.
  • Example 1 Combination of tranylcypromine compounds and anticancer drugs that act or affect DNA has a synergistic effect on cancer cell inhibition
  • This example tests the inhibitory effect of tranylcypromine compounds ((1R, 2S)-A43, GSK2879552) combined with an anticancer drug that acts on or affects DNA (cytarabine) on MV-4-11 hematologic tumor cells.
  • tumor cells in the logarithmic growth phase were inoculated into 96-well culture plates at 80 ⁇ L/well, and then 20 ⁇ L/well of the drug with a concentration gradient was added. Three replicate wells were set for each concentration, and a DMSO solvent control of the corresponding concentration was set. After drug addition, the tumor cells were cultured for 3 days at 37°C and 5% CO2 . The number of MV-4-11 cells inoculated was 10,000/well. The method for determining cell survival rate was the MTS method. After the drug effect ended, 20 ⁇ L/well of MTS solution was added to each well, incubated at 37°C for 3 hours, and the OD values at 490nm and 690nm were measured by an enzyme marker.
  • the inhibition rate (%Inhibiton) and activity percentage (%Activity) of the test substance on tumor cell proliferation were calculated according to the following formula.
  • OD sample represents the absorbance value measured in the dosing well (OD 490 -OD 690 )
  • OD DMSO represents the absorbance value of the DMSO control well (OD 490 -OD 690 ).
  • the activity percentage (%Activity) was plotted against the logarithmic value of the concentration, and the fitting curve was calculated using nonlinear regression.
  • the IC 50 value was calculated using the GraphPad Prism5 software log (inhibitor) vs normolized response-Variable slope parameter setting. Each group of experiments was repeated three times independently, and 3 replicate wells were set for each concentration each time.
  • MV-4-11 cells were treated with (1R,2S)-A43, GSK2879552 and 80nM cytarabine (Arac), and cell apoptosis was detected by flow cytometry after 72h of treatment. The results are shown in Figure 1.
  • the apoptosis rates of MV-4-11 cells were 10.47% and 10.70% under the action of 0.5 ⁇ M and 2 ⁇ M test substance (1R,2S)-A43, respectively, and the apoptosis rates of 0.5 ⁇ M and 2 ⁇ M (1R,2S)-A43 combined with 80nM Arac were 62.18% and 65.41%, respectively;
  • the apoptosis rates of MV-4-11 cells were 9.64% and 10.66%, respectively, while the apoptosis rates of the same concentration of GSK2879552 combined with 80nM Arac were 58.61% and 59.71%, respectively, indicating that the combination of compound (1R,2S)-A43, GSK2879552 and cytarabine enhanced the effect of cytarabine on promoting apoptosis of MV-4-11 cells
  • Example 2 Combination of tranylcypromine compounds and JAK-STAT signaling pathway inhibitors has a synergistic effect on cancer cell growth
  • This example tests the inhibitory effect of a tranylcypromine compound ((1R, 2S)-A43) combined with a JAK-STAT signaling pathway inhibitor (homoharringtonine) on leukemia cells.
  • Example 1 According to the cell growth rate, tumor cells in the logarithmic growth phase are inoculated in a 96-well culture plate at 80 ⁇ L/well, and then 20 ⁇ L/well of a concentration gradient of drugs or drug combinations are added. Three replicate wells are set for each concentration, and a DMSO solvent control of the corresponding concentration is set. After drug addition, the tumor cells are cultured for 3 days at 37°C and 5% CO2 . The number of MV-4-11 cells inoculated is 10,000/well, and the number of Kasumi-1 cells inoculated is 30,000/well. The method for determining cell survival rate is the MTS method. After the drug effect ends, 20 ⁇ L/well of MTS solution is added to each well, incubated at 37°C for 3 hours, and the OD values at 490nm and 690nm are measured by an enzyme marker.
  • (1R,2S)-A43 combined with homoharringtonine can synergistically inhibit Kasumi-1 and MV-4-11 hematological tumor cells, and the ZIP synergistic scores reached 15.517 and 7.97, respectively.
  • Example 3 Evaluation of the anti-tumor model of tranylcypromine compounds combined with drugs at the animal level
  • This example tests the tumor-suppressing effect of a tranylcypromine compound ((1R, 2S)-A43) combined with a drug on tumor model mice.
  • the experimental design was as follows: oral administration of 5 and 10 mg/kg of (1R,2S)-A43 alone, and 0.5, 2, and 5 mg/kg of (1R,2S)-A43 combined with 20 mg/kg of cytarabine clinical drug, and a corresponding control group (weekly 20 mg/kg of AraC) was injected subcutaneously for 5 consecutive days and the administration was continued for 22 days.
  • the tumor inhibition rates of (1R,2S)-A43 at 5 and 10 mg/kg doses were 41.08% and 61.23% respectively.
  • the experimental design is as follows: oral administration of 0.25, 0.5, and 1 mg/kg of (1R,2S)-A43 alone, and 0.25, 0.5, and 1 mg/kg of (1R,2S)-A43 combined with 4 mg/kg of cytarabine clinical drug, and a corresponding control group (4 mg/kg of AraC subcutaneously injected for 5 consecutive days per week) were designed, and the drug was administered continuously for 17 days.
  • the results are shown in Table 3:
  • the tumor inhibition rates of (1R,2S)-A43 at doses of 0.25, 0.5, and 1 mg/kg were 21.34%, 20.19%, and 54.42%, respectively.
  • the experimental design is as follows: oral administration of 0.5, 1, and 2 mg/kg of (1R,2S)-A43 alone and simultaneous administration of 0.5 mg/kg of (1R,2S)-A43 in combination with clinical therapeutic drugs (7.5 mg/kg of cytarabine (AraC) subcutaneously for 5 consecutive days per week and 0.75 mg/kg of daunorubicin (DAC) intravenously for 3 days per week), and corresponding control group treatments are carried out at the same time. After 21 days of continuous administration, the administration is stopped, and the animals are kept and observed, the time of death of the animals is accurately recorded, and the death of the last animal is used as the experimental endpoint.
  • clinical therapeutic drugs 7.5 mg/kg of cytarabine (AraC) subcutaneously for 5 consecutive days per week and 0.75 mg/kg of daunorubicin (DAC) intravenously for 3 days per week
  • the median survival of the model control group was 40 days, and the median survival of the 0.5, 1, and 2 mg/kg (1R, 2S)-A43 monotherapy groups were 44.5, 46.5, and 46.5 days, respectively, which prolonged the survival of B-NDG mice bearing MV-4-11 by 4.5-6.5 days compared with the model control group.
  • the median survival of the clinical treatment drug monotherapy group (AraC 7.5 mg/kg + DAC 0.75 mg/kg) was 46 days, which was 6 days longer than the model control group.
  • the median survival of the group treated with 0.5 mg/kg (1R,2S)-A43 combined with clinical therapeutic drugs (AraC+DAC) was 55 days, which was 15 days longer than that of the model control group.
  • mice was longer than the sum of the median survival of the group treated with 0.5 mg/kg (1R,2S)-A43 alone and the group treated with clinical therapeutic drugs alone, indicating that the combination of (1R,2S)-A43 and clinical therapeutic drugs for acute myeloid leukemia has a synergistic effect.
  • the experimental design is as follows: oral administration of 2.5, 5, and 10 mg/kg of (1R,2S)-A43 alone, and a combination of 2.5 and 5 mg/kg of (1R,2S)-A43 and 0.5 mg/kg of cisplatin (Cisplatin) clinical drugs.
  • a corresponding control group was designed (0.5 mg/kg of cisplatin was injected intraperitoneally for 5 consecutive days per week), and the drug was administered continuously for 14 days.
  • the results are shown in Table 5:
  • the tumor inhibition rates of (1R,2S)-A43 at doses of 2.5, 5, and 10 mg/kg were 13.49%, 16.94%, and 51.19%, respectively.
  • the tumor inhibition rate of 0.5 mg/kg cisplatin alone was 13.11%.
  • mice in the 1 mg/kg (1R,2S)-A43 alone group and the 0.5 mg/kg homoharringtonine alone group was not much different from that in the control group, except that the survival of the last two mice was extended by 6 days and 7 days, respectively.

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Abstract

L'invention concerne l'utilisation d'une combinaison d'un inhibiteur de LSD1 et d'un médicament pour traiter le cancer. Spécifiquement, l'invention concerne une composition comprenant : un composé de tranylcypromine et/ou un dérivé de celui-ci ; et un médicament choisi parmi un inhibiteur de kinase, un médicament anticancéreux agissant sur ou affectant l'ADN, un composé antiviral, un composé antihypertension, un composé antidiabétique, un inhibiteur de la voie de signalisation JAK-STAT, un inhibiteur de la voie de signalisation NF-κB, un inhibiteur de synthèse protéique, un agoniste du récepteur 5-hydroxytryptamine, un modulateur de dystroglycane, un modulateur du récepteur GABA, ou une combinaison de ceux-ci. Les deux principes actifs ont un effet synergique, et l'effet de traitement synergique est significativement meilleur que celui des deux, ce qui permet d'améliorer remarquablement l'effet de traitement du cancer.
PCT/CN2024/087283 2023-04-12 2024-04-11 Utilisation d'une combinaison d'un inhibiteur de lsd1 et d'un médicament pour traiter le cancer WO2024213057A1 (fr)

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015123465A1 (fr) * 2014-02-13 2015-08-20 Incyte Corporation Cyclopropylamines en tant qu'inhibiteurs de lsd1
CN105233292A (zh) * 2015-10-19 2016-01-13 中国科学院北京基因组研究所 Ory-1001联合放疗和化疗用于治疗人三阴性乳腺癌的用途
WO2017157322A1 (fr) * 2016-03-16 2017-09-21 中国科学院上海药物研究所 Composé de cyclopropylamine fluorée, procédé de préparation de ce dernier, composition pharmaceutique basée sur ce dernier, et utilisations de ce dernier
CN107427699A (zh) * 2015-02-12 2017-12-01 伊美格生物科学公司 用于治疗疾病的kdm1a抑制剂
CN109195593A (zh) * 2016-03-15 2019-01-11 奥莱松基因组股份有限公司 用于治疗实体瘤的lsd1抑制剂的组合
WO2019039525A1 (fr) * 2017-08-23 2019-02-28 小野薬品工業株式会社 Produit pharmaceutique destiné au traitement du cancer comprenant un inhibiteur d'axl en tant que principe actif
CN109462980A (zh) * 2016-03-15 2019-03-12 奥莱松基因组股份有限公司 用于治疗血液恶性肿瘤的lsd1抑制剂的组合
WO2023067058A1 (fr) * 2021-10-20 2023-04-27 Queen Mary University Of London Traitements séquentiels et biomarqueurs pour inverser la résistance à des inhibiteurs de kinase
WO2023078906A1 (fr) * 2021-11-03 2023-05-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédé de traitement de la leucémie myéloïde aiguë

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015123465A1 (fr) * 2014-02-13 2015-08-20 Incyte Corporation Cyclopropylamines en tant qu'inhibiteurs de lsd1
CN107427699A (zh) * 2015-02-12 2017-12-01 伊美格生物科学公司 用于治疗疾病的kdm1a抑制剂
CN105233292A (zh) * 2015-10-19 2016-01-13 中国科学院北京基因组研究所 Ory-1001联合放疗和化疗用于治疗人三阴性乳腺癌的用途
CN109195593A (zh) * 2016-03-15 2019-01-11 奥莱松基因组股份有限公司 用于治疗实体瘤的lsd1抑制剂的组合
CN109462980A (zh) * 2016-03-15 2019-03-12 奥莱松基因组股份有限公司 用于治疗血液恶性肿瘤的lsd1抑制剂的组合
WO2017157322A1 (fr) * 2016-03-16 2017-09-21 中国科学院上海药物研究所 Composé de cyclopropylamine fluorée, procédé de préparation de ce dernier, composition pharmaceutique basée sur ce dernier, et utilisations de ce dernier
WO2019039525A1 (fr) * 2017-08-23 2019-02-28 小野薬品工業株式会社 Produit pharmaceutique destiné au traitement du cancer comprenant un inhibiteur d'axl en tant que principe actif
WO2023067058A1 (fr) * 2021-10-20 2023-04-27 Queen Mary University Of London Traitements séquentiels et biomarqueurs pour inverser la résistance à des inhibiteurs de kinase
WO2023078906A1 (fr) * 2021-11-03 2023-05-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédé de traitement de la leucémie myéloïde aiguë

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
WIRAWAN ADITYA, TAJIMA KEN, TAKAHASHI FUMIYUKI, MITSUISHI YOICHIRO, WINARDI WIRA, HIDAYAT MOULID, HAYAKAWA DAISUKE, MATSUMOTO NAOH: "A Novel Therapeutic Strategy Targeting the Mesenchymal Phenotype of Malignant Pleural Mesothelioma by Suppressing LSD1", MOLECULAR CANCER RESEARCH, vol. 20, no. 1, 1 January 2022 (2022-01-01), US , pages 127 - 138, XP093221408, ISSN: 1541-7786, DOI: 10.1158/1541-7786.MCR-21-0230 *
XIA FEI, ZHANG HAIPING: "SP2509 Induces Apoptosis and Autophagy in Osteosarcoma Cells by Regulating LSD1 Expression in Combination with Cisplatin", HEBEI MEDICINE, vol. 28, no. 7, 31 July 2022 (2022-07-31), CN , pages 1061 - 1066, XP093221410, ISSN: 1006-6233, DOI: 10.3969/j.issn.1006-6233.2022.07.02 *

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