CN113679720A - Pharmaceutical composition combining substituted butenamide and platinum compound and application thereof - Google Patents

Pharmaceutical composition combining substituted butenamide and platinum compound and application thereof Download PDF

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Publication number
CN113679720A
CN113679720A CN202010427810.0A CN202010427810A CN113679720A CN 113679720 A CN113679720 A CN 113679720A CN 202010427810 A CN202010427810 A CN 202010427810A CN 113679720 A CN113679720 A CN 113679720A
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cancer
substituted
compound
pharmaceutically acceptable
acceptable salt
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唐海涛
种法政
王正俊
葛海涛
曹苏闵
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Jiangsu Suzhong Pharmaceutical Research Institute Co ltd
Jiangsu Suzhong Pharmaceutical Group Co ltd
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Jiangsu Suzhong Pharmaceutical Research Institute 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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The invention discloses a pharmaceutical composition of substituted butenamide combined with platinum compounds and application thereof. The pharmaceutical composition is a combination comprising at least one substituted butenamide or a pharmaceutically acceptable salt or solvate thereof and at least one platinum compound. The application is the application of a composition containing at least one substituted butene amide or pharmaceutically acceptable salt or solvate thereof and at least one platinum compound in preparing a medicament or a kit for treating cancer. Compared with the prior art, the substituted butenamide or the medicinal salt thereof combined with the platinum compound has the effect of inhibiting the proliferation of various cancers, and has a remarkable synergistic effect when combined.

Description

Pharmaceutical composition combining substituted butenamide and platinum compound and application thereof
Technical Field
The invention belongs to the field of biological medicine, and particularly relates to a pharmaceutical composition of substituted butenamide combined with platinum compounds and application thereof in preparation of a medicine 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 WO 2010151710.
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 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 platinum compound, aiming at the deficiencies of the prior art.
Another object of the present invention is to provide a method for treating cancer, comprising the step of administering at least one substituted butenamide or a pharmaceutically acceptable salt or solvate thereof in combination with at least one platinum compound.
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 for the manufacture of a medicament for the treatment of cancer in combination with at least one platinum compound.
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 platinum compound.
It is a further object of the present invention to provide 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 platinum compound.
To solve the first technical problem, the present invention provides a combination comprising at least one substituted butenamide or a pharmaceutically acceptable salt or solvate thereof and at least one platinum compound; wherein, the substituted butene amide is a compound shown in a formula I:
Figure BDA0002498026620000021
wherein the content of the first and second substances,
R1and R2Each independently selected from hydrogen, deuterium, halogen, trifluoromethyl, optionally substituted alkoxy, optionally substituted deuteroAlkoxy 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.
Preferably, the substituted aminocarbonyl group is a group of formula II:
Figure BDA0002498026620000031
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 BDA0002498026620000032
in some embodiments, the platinum compound is selected from cisplatin, carboplatin, sulforaphane, nedaplatin, oxaliplatin, lobaplatin (lobaplatin), satraplatin (satraplatin), Miboplatin (Miboplatin), Enloplatin (Enloplatin), Iproplatin (Iproplatin), or Dicycloplatin (Dicycloplatin), preferably cisplatin.
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 weight ratio of the at least one substituted butenamide or pharmaceutically acceptable salt or solvate thereof to the at least one platinum compound is 32-1: 1 or 16-2: 1, further 12-4: 1 or 11-5: 1, further 10-6: 1 or 9-7: 1, preferably 8: 1; the molar ratio is 12-1: 1, further 8-1: 1, further 6-2: 1 or 5-3: 1, preferably 4: 1.
In order to solve the second technical problem, the invention provides the use of at least one substituted butenamide or a pharmaceutically acceptable salt or solvate thereof in combination with at least one platinum compound for preparing a medicament for treating cancer; wherein the substituted butenamide is a compound represented by formula I:
Figure BDA0002498026620000041
wherein the content of the first and second substances,
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 substitutedSubstituted deuterated alkoxy, optionally substituted C2-C6Alkynyl or optionally substituted deuterated C2-C6Alkynyl, optionally substituted aminocarbonyl or urea.
Preferably, the substituted aminocarbonyl group is a group of formula II:
Figure BDA0002498026620000042
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 BDA0002498026620000051
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 platinum compound is selected from cisplatin, carboplatin, sulforaphane, nedaplatin, oxaliplatin, lobaplatin (lobaplatin), satraplatin (satraplatin), Miboplatin (Miboplatin), platinum (Enloplatin), Iproplatin (Iproplatin), or Dicycloplatin (Dicycloplatin), preferably cisplatin.
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.
In some embodiments, the weight ratio of the substituted butenamide or the pharmaceutically acceptable salt or solvate thereof to the platinum compound is 32-1: 1 or 16-2: 1, further 12-4: 1 or 11-5: 1, further 10-6: 1 or 9-7: 1, and preferably 8: 1; the molar ratio is 12-1: 1, further 8-1: 1, further 6-2: 1 or 5-3: 1, preferably 4: 1.
In some embodiments, the dosage of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from 0.1-36mg/kg, 0.3-24mg/kg, 0.4-12mg/kg, 0.5-6mg/kg, 0.5-3 mg/kg. May be 0.75mg/kg, 1mg/kg, 1.5mg/kg, 2mg/kg, 2.5mg/kg, 3mg/kg, 3.5mg/kg, 4mg/kg, 4.5mg/kg, 5mg/kg, 5.5mg/kg, 6mg/kg, 6.5mg/kg, 7mg/kg, 7.5mg/kg, 8mg/kg, 8.5mg/kg, 9mg/kg, 9.5mg/kg, 10mg/kg, 10.5mg/kg, 11mg/kg, 11.5mg/kg, 12mg/kg, 12.5mg/kg, 13mg/kg, 13.5mg/kg, 14mg/kg, 14.5mg/kg, 15mg/kg, 15.5mg/kg, 16mg/kg, 16.5mg/kg, 17mg/kg, 17.5mg/kg, 18mg/kg, 18.5mg/kg, 19mg/kg, 19.5mg/kg, 20mg/kg, 20.5mg/kg, 21mg/kg, 21.5mg/kg, 22mg/kg, 22.5mg/kg, 23mg/kg, 23.5mg/kg, 24mg/kg, 24.5mg/kg, 25mg/kg, 25.5mg/kg, 26mg/kg, 26.5mg/kg, 27mg/kg, 27.5mg/kg, 28mg/kg, 28.5mg/kg, 29mg/kg, 29.5mg/kg, 30mg/kg, 30.5mg/kg, 31mg/kg, 31.5mg/kg, 32mg/kg, 32.5me/kg, 33mg/kg, 33.5mg/kg, 34mg/kg, 34.5mg/kg, 35mg/kg, 35.5mg/kg, 36 mg/kg; preferably 36mg/kg, 24mg/kg, 12mg/kg, 6mg/kg, 3mg/kg, 1.5mg/kg and 0.75 mg/kg.
In some embodiments, the dose of the platinum-based compound is selected from 0.01 to 5 mg/kg; preferably 0.05-2 mg/kg; more preferably 0.1 to 0.5mg/kg, and may be 0.05mg/kg, 0.1me/kg, 0.2mg/kg, 0.5mg/kg, 1mg/kg, 2.0mg/kg, 2.2mg/kg, 2.4mg/kg, 2.6mg/kg, 2.7mg/kg, 2.8mg/kg, 2.9mg/kg, 3.0mg/kg, 3.1mg/kg, 3.2mg/kg, 3.3mg/kg, 3.4mg/kg, 3.5mg/kg, 3.6mg/kg, 3.7mg/kg, 3.8mg/kg, 3.9mg/kg, 4.0 mg/kg.
In some embodiments, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is 1mg/kg and the dose of the platinum compound is 0.15 mg/kg; further preferably, the compound shown in the formula I or the pharmaceutically acceptable salt thereof is (E), N, the maleate monohydrate of (3-cyano-7-ethoxy-4- (3-ethynylphenylamino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide, and the platinum compound is cisplatin.
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, once every three weeks, once every four weeks, or once a month in combination with a platinum compound 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 platinum compound 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 the pharmaceutically acceptable salt thereof in combination with the platinum compound composition in the invention can be oral administration, parenteral administration and transdermal administration, and the parenteral administration includes but is not limited to intravenous injection, subcutaneous injection and intramuscular injection.
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, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in combination with the platinum-based compound, thereby enhancing the antitumor activity and improving the therapeutic effect of the tumor diseases.
In order to solve the third technical problem, the present invention provides a use of at least one substituted butene amide or a pharmaceutically acceptable salt or solvate thereof for preparing a medicament for treating cancer in combination with at least one platinum compound, wherein the substituted butene amide is a compound represented by formula I:
Figure BDA0002498026620000071
wherein the content of the first and second substances,
R1and R2Are respectively and independentlySelected 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.
Preferably, the substituted aminocarbonyl group is a group of formula II:
Figure BDA0002498026620000081
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 BDA0002498026620000082
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 platinum compound is selected from cisplatin, carboplatin, sulforaphane, nedaplatin, oxaliplatin, lobaplatin (lobaplatin), satraplatin (satraplatin), Miboplatin (Miboplatin), platinum (Enloplatin), Iproplatin (Iproplatin), or Dicycloplatin (Dicycloplatin), preferably cisplatin.
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 the group consisting of breast cancer, non-small cell lung cancer, colon cancer, large intestine cancer, ovarian cancer, and skin cancer; further selected from adenocarcinoma lung cancer, further selected from EGFR and HER2 positive and K-ras mutated lung cancer.
In some embodiments, the substituted butenamide or pharmaceutically acceptable salt or solvate thereof and the platinum compound; the molar ratio is 12-1: 1, further 8-1: 1, further 6-2: 1 or 5-3: 1, preferably 4: 1.
In some embodiments, the dosage of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from 0.1-36mg/kg, 0.3-24mg/kg, 0.4-12mg/kg, 0.5-6mg/kg, 0.5-3 mg/kg. May be 0.75mg/kg, 1mg/kg, 1.5mg/kg, 2mg/kg, 2.5mg/kg, 3mg/kg, 3.5mg/kg, 4mg/kg, 4.5mg/kg, 5mg/kg, 5.5mg/kg, 6mg/kg, 6.5mg/kg, 7mg/kg, 7.5mg/kg, 8mg/kg, 8.5mg/kg, 9mg/kg, 9.5mg/kg, 10mg/kg, 10.5mg/kg, 11mg/kg, 11.5mg/kg, 12mg/kg, 12.5mg/kg, 13mg/kg, 13.5mg/kg, 14mg/kg, 14.5mg/kg, 15mg/kg, 15.5mg/kg, 16mg/kg, 16.5mg/kg, 17mg/kg, 17.5mg/kg, 18mg/kg, 18.5mg/kg, 19mg/kg, 19.5mg/kg, 20mg/kg, 20.5mg/kg, 21mg/kg, 21.5mg/kg, 22mg/kg, 22.5mg/kg, 23mg/kg, 23.5mg/kg, 24mg/kg, 24.5mg/kg, 25mg/kg, 25.5mg/kg, 26mg/kg, 26.5mg/kg, 27mg/kg, 27.5mg/kg, 28mg/kg, 28.5mg/kg, 29mg/kg, 29.5mg/kg, 30mg/kg, 30.5mg/kg, 31mg/kg, 31.5mg/kg, 32mg/kg, 32.5mg/kg, 33mg/kg, 33.5mg/kg, 34mg/kg, 34.5mg/kg, 35mg/kg, 35.5mg/kg, 36 mg/kg; preferably 36mg/kg, 24mg/kg, 12mg/kg, 6mg/kg, 3mg/kg, 1.5mg/kg and 0.75 mg/kg.
In some embodiments, the dose of the platinum-based compound is selected from 0.01 to 5 mg/kg; preferably 0.05-2 mg/kg; more preferably 0.1 to 0.5mg/kg, and may be 0.05mg/kg, 0.1mg/kg, 0.2mg/kg, 0.5mg/kg, 1mg/kg, 2.0mg/kg, 2.2mg/kg, 2.4mg/kg, 2.6mg/kg, 2.7mg/kg, 2.8mg/kg, 2.9mg/kg, 3.0mg/kg, 3.1mg/kg, 3.2mg/kg, 3.3mg/kg, 3.4mg/kg, 3.5mg/kg, 3.6mg/kg, 3.7mg/kg, 3.8mg/kg, 3.9mg/kg, 4.0 mg/kg.
In some embodiments, the dose of the compound represented by formula I or a pharmaceutically acceptable salt thereof is lmg/kg, and the dose of the platinum compound is 0.15 mg/kg; further preferably, the compound shown in the formula I or the pharmaceutically acceptable salt thereof is maleic acid salt monohydrate of (E) -N- (3-cyano-7-ethoxy-4- (3-ethynylphenylamino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide, and the platinum compound is cisplatin.
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, once every three weeks, once every four weeks, or once a month in combination with a platinum compound 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 platinum compound 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 the pharmaceutically acceptable salt thereof in combination with the platinum compound composition or the kit in the invention can be oral administration, parenteral administration and transdermal administration, and the parenteral administration includes but is not limited to intravenous injection, subcutaneous injection and intramuscular injection.
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, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in combination with the platinum-based compound, thereby enhancing the antitumor activity and improving the therapeutic effect of the 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 platinum compound, wherein the substituted butenamide is a compound represented by formula I:
Figure BDA0002498026620000111
wherein the content of the first and second substances,
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.
Preferably, the substituted aminocarbonyl group is a group of formula II:
Figure BDA0002498026620000112
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 BDA0002498026620000121
in some embodiments, the platinum compound is selected from cisplatin, carboplatin, sulforaphane, nedaplatin, oxaliplatin, lobaplatin (lobaplatin), satraplatin (satraplatin), Miboplatin (Miboplatin), platinum (Enloplatin), Iproplatin (Iproplatin), or Dicycloplatin (Dicycloplatin), preferably cisplatin.
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 the group consisting of breast cancer, non-small cell lung cancer, colon cancer, large intestine cancer, ovarian cancer, and skin cancer; further selected from adenocarcinoma lung cancer, further selected from EGFR and HER2 positive and K-ras mutated lung cancer.
In some embodiments, the substituted butenamide or pharmaceutically acceptable salt or solvate thereof and the platinum compound; the molar ratio is 12-1: 1, further 8-1: 1, further 6-2: 1 or 5-3: 1, preferably 4: 1.
In some embodiments, the dosage of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from 0.1-36mg/kg, 0.3-24mg/kg, 0.4-12mg/kg, 0.5-6mg/kg, 0.5-3 mg/kg. May be 0.75mg/kg, 1mg/kg, 1.5mg/kg, 2mg/kg, 2.5mg/kg, 3mg/kg, 3.5mg/kg, 4mg/kg, 4.5mg/kg, 5mg/kg, 5.5mg/kg, 6mg/kg, 6.5mg/kg, 7mg/kg, 7.5mg/kg, 8mg/kg, 8.5mg/kg, 9mg/kg, 9.5mg/kg, 10mg/kg, 10.5mg/kg, 11mg/kg, 11.5mg/kg, 12mg/kg, 12.5mg/kg, 13mg/kg, 13.5mg/kg, 14mg/kg, 14.5mg/kg, 15mg/kg, 15.5mg/kg, 16mg/kg, 16.5mg/kg, 17mg/kg, 17.5mg/kg, 18mg/kg, 18.5mg/kg, 19mg/kg, 19.5mg/kg, 20mg/kg, 20.5mg/kg, 21mg/kg, 21.5mg/kg, 22mg/kg, 22.5mg/kg, 23mg/kg, 23.5mg/kg, 24mg/kg, 24.5mg/kg, 25mg/kg, 25.5mg/kg, 26mg/kg, 26.5mg/kg, 27mg/kg, 27.5mg/kg, 28mg/kg, 28.5mg/kg, 29mg/kg, 29.5mg/kg, 30mg/kg, 30.5mg/kg, 31mg/kg, 31.5mg/kg, 32mg/kg, 32.5mg/kg, 33mg/kg, 33.5mg/kg, 34mg/kg, 34.5mg/kg, 35mg/kg, 35.5mg/kg, 36 mg/kg; preferably 36mg/kg, 24mg/kg, 12mg/kg, 6mg/kg, 3mg/kg, 1.5mg/kg and 0.75 mg/kg.
In some embodiments, the dose of the platinum-based compound is selected from 0.01 to 5 mg/kg; preferably 0.05-2 mg/kg; more preferably 0.1 to 0.5mg/kg, and may be 0.05mg/kg, 0.1mg/kg, 0.2mg/kg, 0.5mg/kg, 1mg/kg, 2.0mg/kg, 2.2mg/kg, 2.4mg/kg, 2.6mg/kg, 2.7mg/kg, 2.8mg/kg, 2.9mg/kg, 3.0mg/kg, 3.1mg/kg, 3.2mg/kg, 3.3mg/kg, 3.4mg/kg, 3.5mg/kg, 3.6mg/kg, 3.7mg/kg, 3.8mg/kg, 3.9mg/kg, 4.0 mg/kg.
In some embodiments, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is 1mg/kg and the dose of the platinum compound is 0.15 mg/kg; further preferably, the compound shown in the formula I or the pharmaceutically acceptable salt thereof is maleic acid salt monohydrate of (E) -N- (3-cyano-7-ethoxy-4- (3-ethynylphenylamino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide, and the platinum compound is cisplatin.
In some embodiments, wherein the at least one substituted butenamide or pharmaceutically acceptable salt or solvate thereof and the at least one platinum-based compound 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 platinum compound.
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 platinum compound is 12-1: 1, further 8-1: 1, further 6-2: 1 or 5-3: 1, preferably 4: 1.
in some embodiments, the at least one substituted butenamide or pharmaceutically acceptable salt or solvate thereof is administered at a dose of 0.1 to 36 mg/kg; 0.3-24mg/kg, 0.4-12mg/kg, 6mg/kg, 3mg/kg, 1.5mg/kg, 1.0mg/kg and 0.75 mg/kg; the dosage of at least one platinum compound is 0.01-5 mg/kg; preferably 0.05-2 mg/kg; further preferably 0.1 to 0.5 mg/kg.
Unless otherwise defined, the terms and abbreviations used in the present invention have the following meanings:
the present invention relates to a method of administration which is a combination of at least one dose of a compound of formula I or a pharmaceutically acceptable salt thereof and at least one dose of a platinum compound, wherein both substances show pharmacological effects, over a period of time. The time period may be within one administration period, 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, the compound of formula I or a pharmaceutically acceptable salt thereof and the platinum compound may be administered simultaneously or sequentially. Such terms include treatments wherein the compound of formula I or a pharmaceutically acceptable salt thereof and the platinum-based compound 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.
SZMD4-2HCl-T is the hydrochloride salt of (E) -N- (3-cyano-7-ethoxy-4- (3-ethynylphenylamino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide.
SZMD4-mal is the maleate monohydrate of (E) -N- (3-cyano-7-ethoxy-4- (3-ethynylphenylamino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide.
CDDP, is cissplatin, also cisplatin.
Compared with the prior art, the invention has the following advantages:
the compound shown in the formula I or the medicinal salt thereof and the platinum compound have the effect of inhibiting the proliferation of various cancers, and have a remarkable synergistic effect when being used together.
Drawings
FIG. 1 Effect of SZMD4-2HCl-T in combination with cisplatin on the viability of EGFR and HER2 positive A549 cells.
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.
The (E) -N- (3-cyano-7-ethoxy-4- (3-ethynylphenylamino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide, which is the hydrochloride prepared according to the process described in WO2010151710 and reacted with hydrochloric acid, (E) -N- (3-cyano-7-ethoxy-4- (3-ethynylphenylamino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide maleate monohydrate prepared according to the process described in CN104513200A and also named (E) -N- {4- [ (3-ethynylphenylamino) -3-cyano-7-ethoxy-6-quinolinyl ] } - Maleate salt of 4- (dimethylamino) -2-butenamide.
Example 1 growth inhibition of SZMD4-2HCl-T in combination with cisplatin on EGFR and HER2 positive A549 tumor cells cultured in vitro
This example relates to SZMD4-2HCl-T as the hydrochloride salt of (E) -N- (3-cyano-7-ethoxy-4- (3-ethynylphenylamino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide.
First, experimental material
Cell: a549; cells were cultured at 37 ℃ and 5% CO2Culturing in an incubator.
Culture medium: RPMI-1640(Cat # Cl1875, GIBCO); FBS (Cat #10099-141, GIBCO).
Culture additives and other reagents: L-Glutamine (Cat # GNM21051, GIBCO), CCK-8(Cell counting Kit-8, Cat # CK04-20), available from DOJINDO Molecular Technologies, INC, double antibody P/S (Cat # GNM15140, available from Ginko Biomedicine Technologies, Inc., Hangzhou).
Test and positive control drugs: SZMD4-2 HCl-T; cisplatin for injection (Cisplatin/CDDP), purchased from Zingible pharmaceutical Co., Ltd.
Second, Experimental methods
1. Information on cell culture is shown in Table 1
TABLE 1 cell culture information
Figure BDA0002498026620000151
2. Preparation and preservation of test substance
Preparation of test substance stock solution (operation in dark): the test substance SZMD4-2HCl-T was dissolved sufficiently in sterile water, and cisplatin was prepared in physiological saline. Are all prepared to a concentration of 10-2Stock of M (-20 ℃ C.).
Dilution of the test substance: and (3) diluting the stock solution of the test object by taking a corresponding culture medium required by cell culture without fetal calf serum as a diluent so as to obtain required experimental doses.
WST method drug combination test experiment
1) Dosing (operation in dark):
the highest concentration is 10-2M, 1: 10 or appropriate ratio serial dilution to obtain 5 required dose concentrations of SZMD4-2HCl-T was added to 96-well culture plates at 50. mu.L/well and 3 wells/well, and the volume of the diluent to make up to 100. mu.L/well as compound SZMD4-2HCl-T drug group.
The highest concentration is 10-2M, 1: 10 or proper proportion serial dilution to obtain 5 cisplatin with required dosage concentration, adding into 96-well culture plate, 50 μ L/well, 3 multiple wells/concentration, and diluting to make up volume of 100 μ L/well to obtain cisplatin drug group.
The 5 dose concentrations of the SZMD4-2HCl-T drug group and the cisplatin drug group which are respectively selected are respectively added into a 96-well culture plate in a one-to-one correspondence mode, 50 mu L of each drug is mixed in each well, and 3 wells are mixed in each concentration to serve as a combined drug group.
At the same time, 3 wells were set with 100. mu.L of diluent as cell control wells, and 3 wells with 200. mu.L of diluent as negative control wells.
2) Seeding cells (dark operation):
in addition to the negative control wells, 100. mu.L of complete medium cell suspension containing the corresponding number of cells was added to each test well to ensure that the cells of the cell control group just filled the bottom of the well at the time required for culture.
3)37℃，CO2The culture was carried out in an incubator for 72 hours. The details are shown in Table 1.
4) The remaining liquid in the test well was discarded.
5) Each test well was filled with 100. mu.L of CCK-8 assay medium (10% CCK-8, 5% FBS in medium), CO at 37 ℃ and2incubate in incubator for 3-4 hours.
6) The OD value was measured by microplate reader A450 nm.
4. Data analysis
For the WST method combination test experiments, the percentage (%) of cell inhibition was calculated using the following formula:
100- (o.d. test well o.d. negative control well)/(o.d. cell control well o.d. negative control well) x 100.
Judging the effect of the two medicaments; the Combination Index (CI) of drug combinations, CI > 1 indicates drug antagonism, CI ═ 1 indicates additive effects between drugs, and CI < 1 indicates synergistic effects between drugs. The CI values for ED50, ED75, ED90 (drug concentrations at 50%, 75% and 90% inhibition) were calculated using CalcuSyn software (Biosoft, Ferguson, MO, USA) analysis. A CI value less than 1 is synergistic.
Third, experimental results
The data of the drug combination show that the CI values of the SZMD4-2HCl-T and cisplatin in the test substances are all less than 1 in the combination of the ED50, ED75 and ED90 on the non-small cell lung cancer cell A549, and the drug combination has a synergistic effect. See table 2 and fig. 1 for details.
TABLE 2 concentrations of the combinations ED50, ED75, ED90 correspond to CI values
Concentration of CI value
ED50 0.536
ED75 0.445
ED90 0.379
EXAMPLE 2 pharmacodynamic Effect of SZMD4-mal alone and in combination with cisplatin in EGFR and HER2 positive and K-ras mutated human Lung cancer A549 nude mouse transplanted tumor model
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; cisplatin (cissplatin).
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; cisplatin, prepared as a solution in physiological saline under aseptic conditions, was dispensed once a week and stored in a freezer at-20 deg.C, removed 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 a tumor nude mouse subcutaneous transplantation model by a cell inoculation method: collecting EGFR and HER2 positive and K-ras mutated human lung cancer A549 tumor cells in logarithmic growth phase, counting, re-suspending in 1 × PBS, and adjusting cell suspension concentration to 2.5 × 107And/ml. Nude mice were inoculated with tumor cells subcutaneously on the right dorsal side of the nude mice using a 1mL syringe (No. 4 needle), 5X 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 3.
TABLE 3 anti-tumor efficacy of combination of SZMD4-mal and Cisplatin (Cisplatin) in a human Lung cancer A549 nude mouse transplant tumor model
Figure BDA0002498026620000181
Note: p.o.: orally taking; i.p.: performing intraperitoneal injection; iv: intravenous injection; qd: once a day; qw: once per week;
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.
Tumor(s)The volume (Tumor volume, TV) is calculated as: TV as a × b2/2. Where a, b represent tumor measurement length and width, respectively. The Relative Tumor Volume (RTV) is calculated as: RTV-Vt/V0. Wherein V0Tumor volume at the time of group administration and Vt is the tumor volume at the time of measurement. Tumor inhibition (%) (average tumor weight in negative control group-average tumor weight in administration group)/average tumor weight in negative control group × 100%.
Animal weight Change (Change of body weight,%) (measured weight-weight at group)/weight at group × 100%.
5. Data analysis
Tumor growth curves were plotted with time points as X-axis tumor volume as Y-axis and the experimental data expressed as mean + SEM, SEM SD/sqrt (n), n the 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
Harvesting A549 cells in logarithmic growth phase, inoculating tumor cells subcutaneously on the right back of nude mice, and actually inoculating 5.0 × 1060.2 ml/mouse. The experiment is divided into 52 animals, the tumor volume is 95.3-186.4mm3。
In this trial, SZMD4-mal was administered at doses of 12, 24 and 36mg/kg for 20 consecutive days. After the end of the administration, the mean tumor weights of the SZMD4-mal in 12, 24 and 36mg/kg dose groups are respectively 0.763 +/-0.066 g, 0.733 +/-0.058 g and 0.367 +/-0.049 g, the tumor inhibition rates are respectively 20.4%, 23.6% and 61.2%, and the tumor weights are compared with those of a negative control group (0.959 +/-0.156 g), and the SZMD4-mal has a significant difference (P < 0.01) in a high dose group. The results are shown in tables 4 and 5.
The average tumor weight of the cisplatin after the administration of the cisplatin in the 3mg/kg dose group is 0.954 +/-0.072 g (P is more than 0.05), and the tumor inhibition rate is 0.52 percent. The cisplatin 3mg/kg and SZMD4-mal 24mg/kg are jointly administered, the average tumor weight after the administration is 0.463 +/-0.052 g, the tumor inhibition rate is 51.7%, and the tumor weight is small compared with that of the cisplatin and SZMD4-mal single-dose group, and has a remarkable difference (P is less than 0.01). The combined medication result shows that the SZMD4-mal and the cisplatin have the effects of synergy and dosage reduction. The results are shown in tables 4 and 5.
In the experiment, the combined medicine has no obvious effect on inhibiting the weight gain, the animal state is good, and other reactions are not observed. The results are shown in tables 4 and 5.
TABLE 4 antitumor Effect of SZMD4-mal single drug and combination with cisplatin on EGFR and HER2 positive and K-ras mutated human lung carcinoma A549 nude mouse transplanted tumors
Figure BDA0002498026620000191
*: p is less than 0.05; **: p is less than 0.01, compared with a control group;
#: p is less than 0.05; # #: p is less than 0.01, compared with SZMD4-mal-12 mg/kg;
+: p is less than 0.05; ++: p is less than 0.01, compared with SZMD4-ma1-24 mg/kg;
and (delta): p is less than 0.05; and delta: p is less than 0.01, compared with SZMD4-mal-36 mg/kg;
a tangle-solidup: p is less than 0.05; a tangle-solidup root: p is less than 0.01, and cis-platinum is 3 mg/kg.
TABLE 5 Effect of SZMD4-mal as a single agent and in combination with cisplatin on tumor size and animal body weight in EGFR and HER2 positive and K-ras mutated human Lung cancer A549 nude mouse transplanted tumor model
Figure BDA0002498026620000201
*: p is less than 0.05; **: p is less than 0.01, compared with a control group;
#: p is less than 0.05; # #: p is less than 0.01, compared with SZMD4-mal-12 mg/kg;
+: p is less than 0.05; ++: p is less than 0.01, compared with SZMD4-mal-24 mg/kg;
and (delta): p is less than 0.05; and delta: p is less than 0.01, compared with SZMD4-mal-36 mg/kg;
a tangle-solidup: p is less than 0.05; a tangle-solidup root: p is less than 0.01, compared with cisplatin-3 mg/kg.
The present invention provides a method and a method for preparing a pharmaceutical composition of substituted butenamide and its pharmaceutically acceptable salt in combination with a platinum compound, and a use thereof in preparing a medicament or a kit for treating cancer, and the method and the way for realizing the technical scheme are many, and the above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and embellishments can be made without departing from the principle of the present invention, and these modifications and embellishments should also be regarded as the protection scope of the present invention. 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 platinum compound; wherein, the substituted butene amide is a compound shown in a formula I:
Figure FDA0002498026610000011
wherein the content of the first and second substances,
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, optionally substituted deuterated C2-C6Alkynyl, optionally substituted aminocarbonyl or urea;
wherein said substituted aminocarbonyl group is preferably a group of formula II:
Figure FDA0002498026610000012
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 platinum compound in the manufacture of a medicament for the treatment of cancer, wherein the substituted butenamide is a compound of formula I:
Figure FDA0002498026610000021
wherein R is1～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 combination with at least one platinum compound in the treatment of cancer, wherein the substituted butenamide is a compound of formula I:
Figure FDA0002498026610000022
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 platinum compound; wherein the substituted butenamide is a compound represented by formula I:
Figure FDA0002498026610000023
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. The composition according to claim 1, or the use according to any one of claims 2 to 3, or the kit according to claim 4, wherein the platinum compound is selected from cisplatin, carboplatin, sulforaphane, nedaplatin, oxaliplatin, lobaplatin, satraplatin, miboplatin, carboplatin, iproplatin, or dicycloplatin, preferably cisplatin.
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 platinum compound is 12-1: 1, further 8-1: 1, further 6-2: 1 or 5-3: 1, preferably 4: 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, large intestine cancer, ovarian cancer or skin cancer; further selected from adenocarcinoma lung cancer, further selected from EGFR and HER2 positive lung cancer, further selected from EGFR and HER2 positive and K-ras 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 FDA0002498026610000041
wherein R is1～R11And X has the meaning as set forth in claim 1, wherein the dose of the compound of formula I or a pharmaceutically acceptable salt or solvate thereof is any one of 0.1 to 36mg/kg, 0.3 to 24mg/kg, 0.4 to 12mg/kg, 6mg/kg, 3mg/kg, 1.5mg/kg, 1.0mg/kg and 0.75 mg/kg; the dose of the platinum compound is 0.01-5 mg/kg; preferably 0.05-2 mg/kg; further preferably 0.1 to 0.5 mg/kg.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002300985B2 (en) * 1997-12-11 2004-12-02 Minnesota Mining And Manufacturing Company Imidazonaphthyridines And Their Use In Inducing Cytokine Biosynthesis
CA2599115A1 (en) * 2005-02-28 2006-08-31 Eisai R & D Management Co., Ltd. Novel combinational use of sulfonamide compound
CN101848895A (en) * 2007-11-09 2010-09-29 卫材R&D管理有限公司 Combination of anti-angiogenic substance and anti-tumor platinum complex

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002300985B2 (en) * 1997-12-11 2004-12-02 Minnesota Mining And Manufacturing Company Imidazonaphthyridines And Their Use In Inducing Cytokine Biosynthesis
CA2599115A1 (en) * 2005-02-28 2006-08-31 Eisai R & D Management Co., Ltd. Novel combinational use of sulfonamide compound
CN101848895A (en) * 2007-11-09 2010-09-29 卫材R&D管理有限公司 Combination of anti-angiogenic substance and anti-tumor platinum complex

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
XIAO X, YU S, LI S, ET AL.: "Exosomes: decreased sensitivity of lung cancer A549 cells to cisplatin", PLOS ONE *
ZHANG C, LI C, WANG Y, ET AL.: "Chemotherapeutic paclitaxel and cisplatin differentially induce pyroptosis in A549 lung cancer cells via caspase-3/GSDME activation", APOPTOSIS *
叶青松;楼丽广;刘伟平;余尧;侯树谦;: "铂类抗肿瘤药物靶向给药的研究进展", 中国药学杂志, no. 20 *

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