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CN111617081A - Pharmaceutical composition combining substituted butenamide and mTOR inhibitor and application of pharmaceutical composition - Google Patents

Pharmaceutical composition combining substituted butenamide and mTOR inhibitor and application of pharmaceutical composition Download PDF

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Publication number
CN111617081A
CN111617081A CN202010520670.1A CN202010520670A CN111617081A CN 111617081 A CN111617081 A CN 111617081A CN 202010520670 A CN202010520670 A CN 202010520670A CN 111617081 A CN111617081 A CN 111617081A
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cancer
substituted
mtor inhibitor
butenamide
pharmaceutically acceptable
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CN111617081B (en
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唐海涛
种法政
葛海涛
王正俊
曹苏闵
马继梅
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Jiangsu Suzhong Pharmaceutical Research Institute Co Ltd
Suzhong Pharmaceutical Group Co ltd
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Nanjing Suzhong Pharmaceuticals Research Co ltd
Jiangsu Suzhong Pharmaceutical Group Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3

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Abstract

The invention discloses a pharmaceutical composition of substituted butene amide combined with an mTOR inhibitor and application thereof, and particularly relates to a composition or a kit containing at least one substituted butene amide or pharmaceutically acceptable salt or solvate thereof and at least one mTOR inhibitor, and application of the at least one substituted butene amide or pharmaceutically acceptable salt or solvate thereof combined with at least one mTOR inhibitor in preparation of a medicament or a kit for treating cancer. Compared with the prior art, the invention has the following advantages: the substituted butenamide or the pharmaceutically acceptable salt thereof combined with the mTOR inhibitor has the effect of inhibiting proliferation of various cancers, and has a remarkable synergistic effect when combined.

Description

Pharmaceutical composition combining substituted butenamide and mTOR inhibitor and application of pharmaceutical composition
Technical Field
The invention belongs to the field of biomedicine, and particularly relates to a pharmaceutical composition of substituted butenamide combined with an mTOR inhibitor and application of the pharmaceutical composition in preparation of a medicament or a kit for treating cancer.
Background
Malignant tumor is a serious disease which endangers the life and health of people. In recent years, with the rapid development of tumor biology and related disciplines, specific anti-tumor drugs aiming at abnormal signal system targets in tumor cells are the focus of new drug development. Meanwhile, the combination of multiple antitumor drugs for treating tumor diseases is also a hot spot of scientific research.
Molecular targeted therapy targeting the human Epidermal Growth Factor Receptor (EGFR) has become the most important way to treat NSCLC. EGFR is the expression product of proto-oncogene C-erbB-1, the gene is located on chromosome 7 and belongs to transmembrane receptor tyrosine kinase. After EGFR is combined with its ligand, it can activate downstream signal path, regulate the proliferation, differentiation, angiogenesis and apoptosis inhibition of tumor cells, thereby regulating a series of tumor biological behaviors.
Currently, the clinically used targeted drug for EGFR is an EGFR tyrosine kinase inhibitor (EGFR-TKI), and the EGFR-TKI blocks an EGFR signal conduction pathway by inhibiting the autophosphorylation of EGFR, so that the proliferation and differentiation of tumor cells are inhibited, and the targeted therapy is realized. EGFR mutations can occur at any site in the EGFR sequence. Typically, EGFR mutants are derived from mutations in the kinase domain (i.e., exons 18-24 in the EGFR sequence) or the extracellular domain (i.e., exons 2-16 in the EGFR sequence). There is a clinical need for new methods of inhibiting cells having EGFR mutations. Substituted butenamides and their salt-type compounds, such as (E) -N- {4- [ (3-ethynylphenylamino) -3-cyano-7-ethoxy-6-quinolinyl ] } -4- (dimethylamino) -2-butenamide, exhibit antitumor biological activity as described in W02010151710.
The EGFR targeting drug has common skin toxicity effect clinically, and an effective means is also lacked in the aspects of improving the drug effect and reducing the toxic and side effects, so that the development of an anti-tumor drug composition with synergistic effect is necessary.
Disclosure of Invention
The purpose of the invention is as follows: the technical problem to be solved by the present invention is to overcome the defects of the prior art, and to provide a pharmaceutical composition comprising a combination of at least one substituted butenamide or a pharmaceutically acceptable salt or solvate thereof and at least one mTOR inhibitor.
Another object of the present invention is to provide the use of at least one substituted butenamide or a pharmaceutically acceptable salt or solvate thereof in combination with at least one mTOR inhibitor for the manufacture of a medicament for the treatment of cancer.
Another technical problem to be solved by the present invention is to provide the use of at least one substituted butenamide or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of cancer in combination with at least one mTOR inhibitor.
Another technical problem to be solved by the present invention is to provide a kit, which comprises the following components: (a) at least one substituted butenamide or a pharmaceutically acceptable salt or solvate thereof and (b) at least one mTOR inhibitor.
It is a further technical problem to provide a method for the treatment of cancer comprising administering to a patient a therapeutic amount of at least one substituted butenamide or a pharmaceutically acceptable salt or solvate thereof and at least one mTOR inhibitor.
To solve the first technical problem mentioned above, the present invention provides a combination comprising at least one substituted butenamide or a pharmaceutically acceptable salt or solvate thereof and at least one mTOR inhibitor; wherein, the substituted butene amide is a compound shown in a formula I:
Figure BDA0002530400120000021
wherein,
R1and R2Each independently selected from hydrogen, deuterium, halogen, trifluoromethyl, optionally substituted alkoxy, optionally substituted deuterated alkoxy or optionally substituted aminocarbonyl;
x is C-CN;
R3～R6each independently selected from hydrogen or deuterium;
R7～R11each independently selected from hydrogen, deuterium, CH3，CD3，CH2D，CHD2Halogen, cyano, trifluoromethyl, optionally substituted alkoxy, optionally substituted deuterated alkoxy, optionally substituted C2-C6Alkynyl or optionally substituted deuterated C2-C6
Alkynyl, optionally substituted aminocarbonyl or urea.
Preferably, the substituted aminocarbonyl group is a group of formula II:
Figure BDA0002530400120000022
wherein the hydrogen of the substituted aminocarbonyl group is further substituted with deuterium;
in some embodiments, the compound of formula I is (E) -N- (3-cyano-7-ethoxy-4- (3-ethynylphenylamino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide of formula III:
Figure BDA0002530400120000031
in some embodiments, the mTOR inhibitor is selected from sirolimus (rapamycin), rapamycin derivatives, diphospholimus (AP23573, MK-8669), everolimus (RAD-001), temsirolimus (CCI-779), oxazololimus (ABT-578) or bivorolimus a9 (umimilimus), preferably rapamycin or a derivative thereof.
In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of a hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanillite, mandelate, succinate, gluconate, lactobionate or laurylsulfonate salt; preferably the hydrochloride, p-toluenesulfonate, methanesulfonate or maleate salt; further preferred is a hydrochloride or maleate salt.
In some embodiments, the solvate is a hydrate, preferably a hemihydrate or monohydrate.
In some embodiments, the molar ratio of the at least one substituted butenamide or pharmaceutically acceptable salt or solvate thereof to the at least one mTOR inhibitor is 100-1: 1, further 90-5: 1, further 75-6: 1, preferably 50-8: 1, preferably 37-11: 1, preferably 31-17: 1, preferably 28-15: 1, preferably 22-16: 1, preferably 24-19: 1, preferably 20-18: 1, preferably 24: 1, 19: 1.
To solve the second technical problem, the present invention provides the use of at least one substituted butenamide or a pharmaceutically acceptable salt or solvate thereof in combination with at least one mTOR inhibitor for the manufacture of a medicament for the treatment of cancer; wherein the substituted butenamide is a compound represented by formula I:
Figure BDA0002530400120000032
wherein,
R1and R2Each independently selected from hydrogen, deuterium, halogen, trifluoromethyl, optionally substituted alkoxy, optionally substituted deuterated alkoxy or optionally substituted aminocarbonyl;
x is C-CN;
R3～R6each independently selected from hydrogen or deuterium;
R7～R11each independently selected from hydrogen, deuterium, CH3，CD3，CH2D，CHD2Halogen, cyano, trifluoromethyl, optionally substituted alkoxy, optionally substituted deuterated alkoxy, optionally substituted C2-C6Alkynyl or optionally substituted deuteration
C2-C6Alkynyl, optionally substituted aminocarbonyl or urea.
Preferably, the substituted aminocarbonyl group is a compound of formula II:
Figure BDA0002530400120000041
wherein the hydrogen of the substituted aminocarbonyl group is further substituted with deuterium.
In some embodiments, wherein the compound of formula I is (E) -N- (3-cyano-7-ethoxy-4- (3-ethynylphenylamino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide of formula III:
Figure BDA0002530400120000042
in some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of a hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate or laurylsulfonate salt; preferably the hydrochloride, p-toluenesulfonate, methanesulfonate or maleate salt; further preferred is a hydrochloride or maleate salt.
In some embodiments, the solvate is preferably a hydrate.
In some embodiments, the hydrate is a hemihydrate, monohydrate.
In some embodiments, the mTOR inhibitor is selected from sirolimus (rapamycin), rapamycin derivatives, diphospholimus (AP23573, MK-8669), everolimus (RAD-001), temsirolimus (CCI-779), oxazololimus (ABT-578) or bivorolimus a9 (umimilimus), preferably rapamycin or a derivative thereof.
In some embodiments, the cancer is selected from the group consisting of lung cancer (e.g., non-small cell lung cancer: NSCLC) including squamous carcinoma, adenocarcinoma (e.g., large cell carcinoma and bronchoalveolar carcinoma), melanoma (e.g., advanced melanoma), breast cancer, liver cancer (e.g., hepatocellular carcinoma), gastric cancer, intestinal cancer (e.g., advanced colorectal cancer), renal cancer (e.g., renal cell carcinoma), preferably from breast cancer, non-small cell lung cancer, colon cancer, large intestine cancer, ovarian cancer, or skin cancer; further selected from adenocarcinoma lung cancer; further selected from EGFR and HER2 positive and K-ras mutated lung cancer or EGFR-L858R, EGFR-T790M mutated lung cancer.
In some embodiments, the molar ratio of the substituted butenamide or the pharmaceutically acceptable salt or solvate thereof to the mTOR inhibitor is 100-1: 1, further 90-5: 1, further 75-6: 1, preferably 50-8: 1, preferably 37-11: 1, preferably 31-17: 1, preferably 28-15: 1, preferably 22-16: 1, preferably 24-19: 1, preferably 20-18: 1, preferably 24: 1, 19: 1.
In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof according to the present invention is administered once daily, twice daily, three times daily, once weekly, two weeks, three weeks, four weeks, or once monthly in combination with the mTOR inhibitor pharmaceutical composition; preferably once a week, two weeks, three weeks, four weeks or one month; the compound of formula I or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, three times a day, once a week, once in three weeks, once every four weeks, or once a month.
The compound shown in the combined formula I or the pharmaceutically acceptable salt thereof and the mTOR inhibitor have synergistic drug effect.
In some embodiments, the synergistic pharmacodynamic effect comprises one of the following effects: enhancing the therapeutic efficacy of the cancer treatment drug or kit, reducing the dosage of the cancer treatment drug or kit, and reducing the side effects of the cancer treatment drug or kit.
The administration route of the compound of formula I or a pharmaceutically acceptable salt thereof in combination with the mTOR inhibitor composition in the present invention may be oral, parenteral, transdermal, including but not limited to intravenous, subcutaneous, intramuscular.
In some embodiments, the compound of formula I is administered orally as a solid.
In some embodiments, the compound of formula I is in the form of a tablet, including fillers, disintegrants, binders, lubricants; the bulking agent is selected from carbohydrates, preferably saccharides, and more preferably sugar alcohols; the sugar alcohol is selected from one or more of mannitol, xylitol, sorbitol and lactose, and more preferably one or more of mannitol and lactose. The disintegrating agent is one or two of sodium carboxymethyl starch and croscarmellose sodium, preferably sodium carboxymethyl starch. The adhesive is one or two of hydroxypropyl cellulose or hydroxypropyl methylcellulose, and preferably hydroxypropyl cellulose. The lubricant is one or more of glyceryl behenate, sodium stearyl fumarate and pulvis Talci, preferably glyceryl behenate.
In some embodiments, the pharmaceutical combination of the invention is administered by injection.
In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof is administered in combination with the mTOR inhibitor, thereby enhancing antitumor activity and improving the therapeutic effect of tumor diseases.
To solve the third technical problem, the present invention provides a use of at least one substituted butenamide or a pharmaceutically acceptable salt or solvate thereof for the preparation of a medicament for the treatment of cancer in combination with at least one mTOR inhibitor, wherein the substituted butenamide is a compound represented by formula I:
Figure BDA0002530400120000061
wherein,
R1and R2Each independently selected from hydrogen, deuterium, halogen, trifluoromethyl, optionally substituted alkoxy, optionally substituted deuterated alkoxy or optionally substituted aminocarbonyl,
x is C-CN;
R3～R6each independently selected from hydrogen or deuterium;
R7～R11each independently selected from hydrogen, deuterium, CH3，CD3，CH2D，CHD2Halogen, cyano, trifluoromethyl, or
Optionally substituted alkoxy, optionally substituted deuterated alkoxy, optionally substituted C2-C6Alkynyl or optionally substituted deuterated C2-C6Alkynyl, optionally substituted aminocarbonyl or urea.
Preferably, the substituted aminocarbonyl group is a compound of formula II:
Figure BDA0002530400120000062
wherein the hydrogen of the substituted aminocarbonyl group is further substituted with deuterium;
in some embodiments, wherein the compound of formula I is (E) -N- (3-cyano-7-ethoxy-4- (3-ethynylphenylamino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide of formula III:
Figure BDA0002530400120000071
in some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of a hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate or laurylsulfonate salt; preferably the hydrochloride, p-toluenesulfonate, methanesulfonate or maleate salt; further preferred is a hydrochloride or maleate salt.
In some embodiments, the solvate is preferably a hydrate.
In some embodiments, the hydrate is a hemihydrate, monohydrate.
In some embodiments, the mTOR inhibitor is selected from sirolimus (rapamycin), rapamycin derivatives, diphospholimus (AP23573, MK-8669), everolimus (RAD-001), temsirolimus (CCI-779), oxazololimus (ABT-578) or bivorolimus a9 (umimilimus), preferably rapamycin or a derivative thereof.
In some embodiments, the cancer is selected from the group consisting of lung cancer (e.g., non-small cell lung cancer (NSCLC) including squamous carcinoma, adenocarcinoma (e.g., large cell carcinoma) and bronchoalveolar carcinoma), melanoma (e.g., advanced melanoma), breast cancer, liver cancer (e.g., hepatocellular carcinoma), gastric cancer, intestinal cancer (e.g., advanced colorectal cancer), renal cancer (e.g., renal cell carcinoma), preferably from breast cancer, non-small cell lung cancer, colon cancer, large intestine cancer, ovarian cancer or skin cancer; further selected from adenocarcinoma lung cancer; further selected from EGFR and HER2 positive and K-ras mutated lung cancer, or EGFR-L858R, EGFR-T790M mutated lung cancer.
In some embodiments, the molar ratio of the substituted butenamide or the pharmaceutically acceptable salt or solvate thereof to the mTOR inhibitor is 100-1: 1, further 90-5: 1, further 75-6: 1, preferably 50-8: 1, preferably 37-11: 1, preferably 31-17: 1, preferably 28-15: 1, preferably 22-16: 1, preferably 24-19: 1, preferably 20-18: 1, preferably 24: 1, 19: 1.
In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof according to the present invention is administered once daily, twice daily, three times daily, once weekly, two weeks, three weeks, four weeks, or once monthly in combination with the mTOR inhibitor pharmaceutical composition; preferably once a week, two weeks, three weeks, four weeks or one month; the compound shown in the formula I or the pharmaceutically acceptable salt thereof is administered once a day, twice a day, three times a day, once a week, once a three week, once a four week or once a month.
The compound shown in the combined formula I or the pharmaceutically acceptable salt thereof and the mTOR inhibitor have synergistic drug effect.
In some embodiments, the synergistic pharmacodynamic effect comprises one of the following effects: enhancing the therapeutic efficacy of the cancer treatment drug or kit, reducing the dosage of the cancer treatment drug or kit, and reducing the side effects of the cancer treatment drug or kit.
The route of administration of the compound of formula I or a pharmaceutically acceptable salt thereof in combination with the mTOR inhibitor composition or kit of the present invention may be oral, parenteral, transdermal, including but not limited to intravenous, subcutaneous, intramuscular.
In some embodiments, the compound of formula I is administered orally as a solid.
In some embodiments, the compound of formula I is in the form of a tablet, including fillers, disintegrants, binders, lubricants; the bulking agent is selected from carbohydrates, preferably saccharides, and more preferably sugar alcohols; the sugar alcohol is selected from one or more of mannitol, xylitol, sorbitol and lactose, and more preferably one or more of mannitol and lactose. The disintegrating agent is one or two of sodium carboxymethyl starch and croscarmellose sodium, preferably sodium carboxymethyl starch. The adhesive is one or two of hydroxypropyl cellulose or hydroxypropyl methylcellulose, and preferably hydroxypropyl cellulose. The lubricant is one or more of glyceryl behenate, sodium stearyl fumarate and pulvis Talci, preferably glyceryl behenate.
In some embodiments, the pharmaceutical combination of the invention is administered by injection.
In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof is administered in combination with the mTOR inhibitor, thereby enhancing antitumor activity and improving the therapeutic effect of tumor diseases.
In order to solve the fourth technical problem, the invention provides a kit, which comprises the following components: (a) at least one substituted butenamide or a pharmaceutically acceptable salt or solvate thereof and (b) at least one mTOR inhibitor, wherein the substituted butenamide is a compound of formula I:
Figure BDA0002530400120000081
wherein,
R1and R2Each independently selected from hydrogen, deuterium, halogen, trifluoromethyl, optionally substituted alkoxy, optionally substituted deuterated alkoxy or optionally substituted aminocarbonyl;
x is C-CN;
R3～R6each independently selected from hydrogen or deuterium;
R7～R11each independently selected from hydrogen, deuterium, CH3，CD3，CH2D，CHD2Halogen, cyano, trifluoromethyl, optionally substituted alkoxy, optionally substituted deuterated alkoxy, optionally substituted C2-C6Alkynyl or optionally substituted deuterated C2-C6
Alkynyl, optionally substituted aminocarbonyl or urea.
Preferably, the substituted aminocarbonyl group is a compound of formula II:
Figure BDA0002530400120000091
wherein the hydrogen of the substituted aminocarbonyl group is further substituted with deuterium.
In some embodiments, the compound of formula I is (E) -N- (3-cyano-7-ethoxy-4- (3-ethynylphenylamino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide of formula III:
Figure BDA0002530400120000092
in some embodiments, the mTOR inhibitor is selected from sirolimus (rapamycin), rapamycin derivatives, diphospholimus (AP23573, MK-8669), everolimus (RAD-001), temsirolimus (CCI-779), oxazololimus (ABT-578) or bivorolimus a9 (umimilimus), preferably rapamycin or a derivative thereof.
In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of a hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate or laurylsulfonate salt; preferably the hydrochloride, p-toluenesulfonate, methanesulfonate or maleate salt; further preferred is a hydrochloride or maleate salt.
In some embodiments, the solvate is preferably a hydrate.
In some embodiments, the hydrate is a hemihydrate, monohydrate.
In some embodiments, the cancer is selected from the group consisting of lung cancer (e.g., non-small cell lung cancer (NSCLC) including squamous carcinoma, adenocarcinoma (e.g., large cell carcinoma) and bronchoalveolar carcinoma), melanoma (e.g., advanced melanoma), breast cancer, liver cancer (e.g., hepatocellular carcinoma), gastric cancer, intestinal cancer (e.g., advanced colorectal cancer), renal cancer (e.g., renal cell carcinoma), preferably from breast cancer, non-small cell lung cancer, colon cancer, large intestine cancer, ovarian cancer or skin cancer; further selected from glandular lung cancer, further selected from EGFR and HER2 positive and K-ras mutated lung cancer or EGFR-L858R, EGFR-T790M mutated lung cancer.
In some embodiments, the molar ratio of the substituted butenamide or the pharmaceutically acceptable salt or solvate thereof to the mTOR inhibitor is 100-1: 1, further 90-5: 1, further 75-6: 1, preferably 50-8: 1, preferably 37-11: 1, preferably 31-17: 1, preferably 28-15: 1, preferably 22-16: 1, preferably 24-19: 1, preferably 20-18: 1, preferably 24: 1, 19: 1.
In some embodiments, wherein the at least one substituted butenamide or pharmaceutically acceptable salt or solvate thereof and the at least one mTOR inhibitor are contained in separate containers.
To solve the above fifth technical problem, the present invention provides a method for treating cancer, comprising administering to a patient a therapeutic amount of at least one substituted butenamide or a pharmaceutically acceptable salt or solvate thereof and at least one mTOR inhibitor.
Wherein the cancer is selected from the group consisting of lung cancer (e.g., non-small cell lung cancer (NSCLC) including squamous carcinoma, adenocarcinoma (e.g., large cell carcinoma) and bronchoalveolar carcinoma), melanoma (e.g., advanced melanoma), breast cancer, liver cancer (e.g., hepatocellular carcinoma), gastric cancer, intestinal cancer (e.g., advanced colorectal cancer), renal cancer (e.g., renal cell carcinoma), preferably from breast cancer, non-small cell lung cancer, colon cancer, large intestine cancer, ovarian cancer or skin cancer; further selected from glandular lung cancer, further selected from EGFR and HER2 positive and K-ras mutated lung cancer or EGFR-L858R, EGFR-T790M mutated lung cancer.
In some embodiments, the molar ratio of the substituted butenamide or the pharmaceutically acceptable salt or solvate thereof to the mTOR inhibitor is 100-1: 1, further 90-5: 1, further 75-6: 1, preferably 50-8: 1, preferably 37-11: 1, preferably 31-17: 1, preferably 28-15: 1, preferably 22-16: 1, preferably 24-19: 1, preferably 20-18: 1, preferably 24: 1, 19: 1.
Unless otherwise defined, the terms and abbreviations used in the present invention have the following meanings:
the invention relates to a method of administration which is "combination", and which means that at least one dose of a compound of formula I or a pharmaceutically acceptable salt thereof and at least one dose of an mTOR inhibitor are administered over a period of time, wherein both substances show pharmacological effects. The time period may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, within 6 days, within 5 days, within 4 days, within 3 days, within 2 days or within 24 hours, and the compound of formula I or a pharmaceutically acceptable salt thereof and the mTOR inhibitor may be administered simultaneously or sequentially. Such terms include treatments in which the compound of formula I or a pharmaceutically acceptable salt thereof and the mTOR inhibitor are administered by the same route of administration or different routes of administration. The mode of administration of the combinations of the invention is selected from simultaneous administration, separate formulation and co-administration or separate formulation and sequential administration.
SZMD4-mal is the maleate monohydrate of (E) -N- (3-cyano-7-ethoxy-4- (3-ethynylphenylamino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide.
Repamycin, also rapamycin.
Compared with the prior art, the invention has the following advantages:
the compound shown in the formula I or the medicinal salt thereof combined with the mTOR inhibitor has the effect of inhibiting proliferation of various cancers, and has a remarkable synergistic effect when combined.
Detailed Description
The invention will be better understood from the following examples. However, those skilled in the art will readily appreciate that the description of the embodiments is only for illustrating the present invention and should not be taken as limiting the invention as detailed in the claims.
(E) N- (3-cyano-7-ethoxy-4- (3-ethynylphenylamino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide maleate monohydrate, also named (E) -maleate salt of N- {4- [ (3-ethynylphenylamino) -3-cyano-7-ethoxy-6-quinolinyl ] } -4- (dimethylamino) -2-butenamide, was prepared as described in CN 104513200A.
EXAMPLE 1 pharmacodynamic Effect of SZMD4-mal alone and in combination with rapamycin on EGFR-L858R, EGFR-T790M mutated human Lung cancer cell NCL-H1975 subcutaneous tumor model nude mice
The SZMD4-mal salt referred to in this example is the maleate monohydrate of (E) -N- (3-cyano-7-ethoxy-4- (3-ethynylphenylamino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide.
1. Laboratory animal
Mice, BALB/c-nu/nu nude mice, female, 4-6 weeks, 17-22 g. A breeding environment: SPF grade.
2. Test drug
The name of the medicine is: SZMD 4-mal; rapamycin (rapamycin).
The configuration method comprises the following steps: SZMD4-mal, adding sterile deionized water under aseptic condition, grinding, mixing, adding deionized water to required volume, shaking, preparing once per week, storing in a refrigerator at 4 deg.C, taking out before use, standing to room temperature, and mixing thoroughly by vortex; rapamycin, ground in an agate mortar under sterile conditions with physiological saline containing 10% PEG400, was formulated as a uniform suspension, formulated once a week and stored in a refrigerator at 4 ℃, taken out to room temperature just before use, and vortexed well prior to dosing.
3. Cells
EGFR-L858R, EGFR-T790M mutant human lung cancer cells NCL-H1975 were cultured in RPMI 1640(GIBCO, USA) containing 10% fetal bovine serum FBS (GIBCO, USA) and 1% penicillin/streptomycin (Jinuo). The cells were cultured in a medium containing 5% CO237 ℃ incubator.
4. Experimental procedure
Establishing subcutaneous tumor transplantation model of nude mice by cell inoculation method, collecting EGFR-L858R and EGFR-T790M mutant human lung cancer NCL-H1975 tumor cells in logarithmic growth phase, counting, suspending in 1 × PBS, and adjusting cell suspension concentration to 2.5 × 107And/ml. The nude mice were inoculated subcutaneously on the right back with a 1mL syringe (No. 4 needle)Tumor cell, 5 × 1060.2 ml/mouse.
When the tumor volume reaches 50-250mm3At the same time, animal tumor volumes were randomly grouped by a random block method such that the difference in tumor volume between groups was less than 10% of the mean, 8 tumors per group, 12 controls, and dosing was started on the day of grouping. Specific doses and methods of administration are shown in table 1. Animal body weights and tumor sizes were determined twice a week during the experiment. Clinical symptoms were recorded with daily observations. At the end of the last dose, all animals were sacrificed, plasma was collected, tumors were detached, weighed and recorded by photography. If the tumor size of the control group is less than 1000mm at the end of the administration3The observation period is extended according to the situation. The calculation of the tumor related parameters refers to the CFDA technical guidance principle of non-clinical research of cytotoxic antitumor drugs in China.
The calculation formula of Tumor Volume (TV) is that TV is a × b2Wherein a and b represent the measured length and width of the tumor, respectively, the percent (%) tumor inhibition ratio (average tumor weight of negative control group-average tumor weight of administration group)/average tumor weight of negative control group × 100% was determined.
5. Data analysis
The experimental data are expressed as mean + SEM, SEM ═ SD/sqrt (n), and n ═ number of experimental animals. The group comparisons were performed using a t-test (Microsoft office Excel), with significant differences at P < 0.05 and very significant differences at P < 0.01.
6. Results of the experiment
NCL-H1975 cells in logarithmic growth phase were harvested, and the nude mice were inoculated subcutaneously in the right dorsal part with tumor cells, actually inoculated with 5.0 × 1060.2 ml/mouse.
In the test, the SZMD4-mal is continuously administrated for 20 days at 15, 30 and 45mg/kg dose, the related inhibition effect of the dose is shown, the average tumor weight after the administration is respectively 1.611 +/-0.190 g, 0.906 +/-0.219 g and 0.358 +/-0.047 g, the tumor inhibition rate is respectively 18.4%, 54.1% and 81.9%, and the tumor weight is compared with a negative control group (1.974 +/-0.252 g), and each dose group of the SZMD4-mal has obvious difference (P < 0.05 or P < 0.01). The results are shown in tables 2 and 3.
The average tumor weight of the rapamycin after the end of the administration of the 2mg/kg dose group is 0.991 +/-0.115 g (P is less than 0.01), and the tumor inhibition rate is 49.8%. The average tumor weight of rapamycin at the end of the 30mg/kg dose combination of 2mg/kg and SZMD4-mal was 0.261 + -0.033 g, and the tumor inhibition rate was 86.8%, which was significantly different (P < 0.05 or P < 0.01) from the rapamycin alone dose group and the SZMD4-mal 30mg/kg dose group. The results show that SZMD4-mal potentiates the effect of rapamycin when used in combination. The results are shown in tables 2 and 3.
TABLE 1 dosage and dosing regimen for anti-tumor effect of SZMD4-mal combination with rapamycin in a human lung carcinoma NCI-H1975 nude mouse graft tumor model
Figure BDA0002530400120000131
Note: p.o: orally taking; i.p.: performing intraperitoneal injection; qd: once a day; qd 1-5/w: the medicine is administered on the 1 st to 5 th days of each week; day: day; wk: and (4) week.
TABLE 2 antitumor Effect of SZMD4-mal single drug and combination with rapamycin on EGFR-L858R, EGFR-T790M mutated human lung cancer NCL-H1975 nude mouse transplantable tumor
Figure BDA0002530400120000132
*: p is less than 0.05; **: p is less than 0.01, compared with a negative control group;
#: p is less than 0.05; # #: p is less than 0.01, compared with SZMD4-mal-15mg/kg group;
+: p is less than 0.05; ++: p is less than 0.01, compared with SZMD4-mal-30mg/kg group;
Δ：p＜0.05；ΔΔ: p is less than 0.01, compared with SZMD4-mal-45mg/kg group;
a tangle-solidup: p is less than 0.05; a tangle-solidup root: p < 0.01, compared to rapamycin-2 mg/kg group.
TABLE 3 Effect of SZMD4-mal on tumor size in EGFR-L858R, EGFR-T790M mutated human Lung cancer NCL-H1975 nude mouse transplantable tumor model with combination of SZMD4-mal and rapamycin
Figure BDA0002530400120000141
*: p is less than 0.05; **: p is less than 0.01, compared with a negative control group;
#: p is less than 0.05; # #: p is less than 0.01, compared with SZMD4-mal-15mg/kg group;
+: p is less than 0.05; ++: p is less than 0.01, compared with SZMD4-mal-30mg/kg group;
Δ：p＜0.05；ΔΔ: p is less than 0.01, compared with SZMD4-mal-45mg/kg group;
a tangle-solidup: p is less than 0.05; a tangle-solidup root: p < 0.01, compared to rapamycin-2 mg/kg group.
EXAMPLE 2 pharmacodynamic Effect of SZMD4-mal alone and in combination with rapamycin on EGFR and HER2 positive and K-ras mutated human Lung cancer cell A549 subcutaneous tumor model nude mice
The SZMD4-mal salt referred to in this example is the maleate monohydrate of (E) N- (3-cyano-7-ethoxy-4- (3-ethynylphenylamino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide.
1. Laboratory animal
Mice, BALB/c-nu/nu nude mice, female, 4-6 weeks, 17-22 g. A breeding environment: SPF grade.
2. Test drug
The name of the medicine is: SZMD 4-mal; rapamycin (rapamycin).
The configuration method comprises the following steps: SZMD4-mal, adding sterile deionized water under aseptic condition, grinding, mixing, adding deionized water to required volume, shaking, preparing once per week, storing in a refrigerator at 4 deg.C, taking out before use, standing to room temperature, and mixing thoroughly by vortex; rapamycin, formulated as a solution in physiological saline under sterile conditions, once per week and stored in a-20 ℃ freezer, taken out to room temperature immediately prior to use, and vortexed prior to administration.
3. Cells
EGFR and HER2 positive and K-ras mutated human lung cancer cell line a549 was cultured in RPMI 1640(GIBCO, usa) containing 10% fetal bovine serum FBS (GIBCO, usa) and 1% penicillin/streptomycin (geno). The cells were cultured in a medium containing 5% CO237 ℃ incubator.
4. Experimental procedure
Establishing subcutaneous transplantation model of tumor nude mice by cell inoculation method, collecting EGFR and HER2 positive and K-ras mutated human lung cancer A549 tumor cells in logarithmic growth phase, counting, suspending in 1 × PBS, and adjusting cell suspension concentration to 2.5 × 107Nude mice were inoculated with tumor cells subcutaneously in the right dorsal part using a 1mL syringe (No. 4 needle), 5 × 1060.2 ml/mouse.
When the tumor volume reaches 50-250mm3At the same time, animal tumor volumes were randomly grouped by a random block method such that the difference in tumor volume between groups was less than 10% of the mean, 8 tumors per group, 12 controls, and dosing was started on the day of grouping. Specific doses and methods of administration are shown in table 4.
Animal body weights and tumor sizes were determined twice a week during the experiment. Clinical symptoms were recorded with daily observations. At the end of the last dose, all animals were sacrificed, plasma was collected, tumors were detached, weighed and recorded by photography. If the tumor size of the control group is less than 1000mm at the end of the administration3The observation period is extended according to the situation. The calculation of the tumor related parameters refers to the CFDA technical guidance principle of non-clinical research of cytotoxic antitumor drugs in China.
The calculation formula of Tumor Volume (TV) is that TV is a × b2Wherein a and b represent the measured length and width of the tumor, respectively, the percent (%) tumor inhibition ratio (average tumor weight of negative control group-average tumor weight of administration group)/average tumor weight of negative control group × 100% was determined.
Animal weight Change (Change of body weight,%) (measured weight-weight at group)/weight at group × 100%.
5. Data analysis
The experimental data are expressed as mean + SEM, SEM ═ SD/sqrt (n), and n ═ number of experimental animals. The group comparisons were performed using a t-test (Microsoft office Excel), with significant differences at P < 0.05 and very significant differences at P < 0.01.
6. Results of the experiment
A549 cells in logarithmic growth phase are harvested, and the tumor cells are inoculated subcutaneously on the right back of a nude mouse and are actually inoculated with 5.0 × 1060.2 ml/mouse.
In the test, the SZMD4-mal is continuously administrated for 20 days at the dose of 12mg/kg, 24mg/kg and 36mg/kg, the related inhibition effect of the dose is shown, the average tumor weight after the administration is respectively 0.763 +/-0.066 g, 0.733 +/-0.058 g and 0.367 +/-0.049 g, the tumor inhibition rate is respectively 20.4%, 23.6% and 61.2%, and the tumor weight is compared with a negative control group (0.959 +/-0.156 g), and the SZMD4-mal has obvious difference (P is less than 0.01) in a high dose group. The results are shown in tables 5 and 6.
The average tumor weight of the rapamycin after the end of the administration of the 2mg/kg dose group is 0.742 +/-0.140 g (P is less than 0.01), and the tumor inhibition rate is 22.6%. The average tumor weight of rapamycin after the end of the combined administration of 24mg/kg at 2mg/kg in SZMD4-mal and 24mg/kg was 0.339 +/-0.034 g, and the tumor inhibition rate was 64.7%, and the tumor weights were significantly different (P < 0.01) compared with the single dose group of rapamycin and the 24mg/kg dose group of SZMD 4-mal. The results show that SZMD4-mal potentiates the effect of rapamycin when used in combination. The results are shown in tables 5 and 6.
TABLE 4 anti-tumor efficacy of combination of SZMD4-mal and rapamycin (rapamycin) in EGFR and HER2 positive and K-ras mutated human lung carcinoma A549 nude mouse transplant tumor model
Figure BDA0002530400120000161
Note: p.o.: orally taking; i.p.: performing intraperitoneal injection; qd: once a day; qd 1-5/w: the medicine is administered on the 1 st to 5 th days of each week; day: day; wk: and (4) week.
TABLE 5 antitumor Effect of SZMD4-mal single drug and combination with rapamycin against EGFR and HER2 positive and K-ras mutated human Lung carcinoma A549 nude mouse transplantable tumors
Figure BDA0002530400120000162
*: p is less than 0.05; **: p is less than 0.01, compared with a negative control group;
#: p is less than 0.05; # #: p is less than 0.01, compared with SZMD4-mal-12mg/kg group;
+: p is less than 0.05; ++: p is less than 0.01, compared with SZMD4-mal-24mg/kg group;
Δ：p＜0.05；ΔΔ: p is less than 0.01, compared with SZMD4-mal-36mg/kg group;
it: p is less than 0.05; it is: p < 0.01, compared to rapamycin-2 mg/kg group.
TABLE 6 tumor size effects of SZMD4-mal single drug and combination with rapamycin on human lung carcinoma A549 nude mouse graft tumor model
Figure BDA0002530400120000171
*: p is less than 0.05; **: p is less than 0.01, compared with a negative control group;
#: p is less than 0.05; # #: p is less than 0.01, compared with SZMD4-mal-12mg/kg group;
+: p is less than 0.05; ++: p is less than 0.01, compared with SZMD4-mal-24mg/kg group;
Δ：p＜0.05；ΔΔ: p is less than 0.01, compared with SZMD4-mal-36mg/kg group;
it: p is less than 0.05; it is: p < 0.01, compared to rapamycin-2 mg/kg group.
The invention provides a method and a method for preparing a medicament composition of substituted butenamide and a medicinal salt thereof combined with an mTOR inhibitor, and application thereof in preparing a medicament or a kit for treating cancer, and particularly provides a plurality of methods and ways for realizing the technical scheme. All the components not specified in the present embodiment can be realized by the prior art.

Claims (11)

1. A pharmaceutical composition comprising a combination of at least one substituted butenamide or a pharmaceutically acceptable salt or solvate thereof and at least one mTOR inhibitor; wherein, the substituted butene amide is a compound shown in a formula I:
Figure FDA0002530400110000011
wherein,
R1and R2Each independently selected from hydrogen, deuterium, halogen, trifluoromethyl, optionally substituted alkoxy, optionally substituted deuterated alkoxy or optionally substituted aminocarbonyl;
x is C-CN;
R3～R6each independently selected from hydrogen or deuterium;
R7～R11each independently selected from hydrogen, deuterium, CH3，CD3，CH2D，CHD2Halogen, cyano, trifluoromethyl, optionally substituted alkoxy, optionally substituted deuterated alkoxy, optionally substituted C2-C6Alkynyl or optionally substituted deuterated C2-C6Alkynyl, optionally substituted aminocarbonyl or urea;
wherein said substituted aminocarbonyl group is preferably a compound of formula II:
Figure FDA0002530400110000012
wherein the hydrogen of the substituted aminocarbonyl group is further substituted with deuterium.
2. Use of at least one substituted butenamide or a pharmaceutically acceptable salt or solvate thereof, in combination with at least one mTOR inhibitor, for the manufacture of a medicament for the treatment of cancer, wherein the substituted butenamide is a compound of formula I:
Figure FDA0002530400110000021
wherein R isI～R11And X has the definition as set forth in claim 1.
3. Use of a substituted butenamide or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for use in the treatment of cancer in combination with at least one mTOR inhibitor, wherein the substituted butenamide is a compound of formula I:
Figure FDA0002530400110000022
wherein R is1～R11And X has the definition as set forth in claim 1.
4. A kit, comprising the following components: (a) at least one substituted butenamide or a pharmaceutically acceptable salt or solvate thereof and (b) at least one mTOR inhibitor; wherein the substituted butenamide is a compound represented by formula I:
Figure FDA0002530400110000023
wherein R is1～R11And X has the definition as set forth in claim 1.
5. A composition according to claim 1 or a use according to any one of claims 2 to 3, or a kit according to claim 4, wherein the compound of formula I is (E) -N- (3-cyano-7-ethoxy-4- (3-ethynylphenylamino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide.
6. A composition according to claim 1 or a use according to any one of claims 2 to 3, or a kit according to claim 4, wherein the mTOR inhibitor is selected from rapamycin, a rapamycin derivative, ridaforolimus, everolimus, temsirolimus, zolsirolimus or temsirolimus a9, preferably is rapamycin or a derivative thereof.
7. The composition of claim 1 or the use of any one of claims 2 to 3, or the kit of claim 4, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanillite, mandelate, succinate, gluconate, lactobionate or laurylsulfonate; preferably the hydrochloride, p-toluenesulfonate, methanesulfonate or maleate salt; further preferred is a hydrochloride or maleate salt.
8. The composition of claim 1 or the use of any one of claims 2 to 3, or the kit of claim 4, wherein the solvate is a hydrate, preferably a hemihydrate or monohydrate.
9. The composition of claim 1 or the use of any one of claims 2 to 3, or the kit of claim 4, wherein the molar ratio of the substituted butenamide or the pharmaceutically acceptable salt or solvate thereof to the mTOR inhibitor is 100-1: 1, further 90-5: 1, further 75-6: 1, preferably 50-8: 1, preferably 37-11: 1, preferably 31-17: 1, preferably 28-15: 1, preferably 22-16: 1, preferably 24-19: 1, preferably 20-18: 1, preferably 24: 1, 19: 1.
10. Use according to claim 2 or 3, wherein the cancer is selected from lung cancer, melanoma, breast cancer, liver cancer, stomach cancer, intestinal cancer or kidney cancer; preferably breast cancer, non-small cell lung cancer, colon cancer, colorectal cancer, ovarian cancer or skin cancer; further selected from adenocarcinoma lung cancer; further selected from EGFR and HER2 positive and K-ras mutated lung cancer or EGFR-L858R, EGFR-T790M mutated lung cancer.
11. A method for treating cancer comprising administering to a patient a therapeutic amount of at least one substituted butenamide which is a compound of formula I:
Figure FDA0002530400110000031
Figure FDA0002530400110000041
wherein R is1～R11And X has the definition as set forth in claim 1.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021104340A1 (en) * 2019-11-27 2021-06-03 江苏苏中药业集团股份有限公司 Substituted crotonamide pharmaceutical composition and preparation method therefor

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101300029A (en) * 2005-11-04 2008-11-05 惠氏公司 Antitumor combinations of mTOR inhibitors, herceptins and/or HKI-272
CN102625797A (en) * 2009-06-25 2012-08-01 迈德药物研发技术有限公司 Substituted heterocyclic compounds as kinase inhibitors and methods of use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101300029A (en) * 2005-11-04 2008-11-05 惠氏公司 Antitumor combinations of mTOR inhibitors, herceptins and/or HKI-272
CN102625797A (en) * 2009-06-25 2012-08-01 迈德药物研发技术有限公司 Substituted heterocyclic compounds as kinase inhibitors and methods of use thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021104340A1 (en) * 2019-11-27 2021-06-03 江苏苏中药业集团股份有限公司 Substituted crotonamide pharmaceutical composition and preparation method therefor

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