阅读说明：本技术 一种取代丁烯酰胺联合mTOR抑制剂的药物组合物及其用途 (Pharmaceutical composition combining substituted butenamide and mTOR inhibitor and application of pharmaceutical composition ) 是由 唐海涛 种法政 葛海涛 王正俊 曹苏闵 马继梅 于 2020-06-09 设计创作，主要内容包括：本发明公开了一种取代丁烯酰胺联合mTOR抑制剂的药物组合物及其用途,具体涉及一种包含至少一种取代丁烯酰胺或其药学上可接受的盐或溶剂合物以及至少一种mTOR抑制剂的组合物或试剂盒,以及至少一种取代丁烯酰胺或其药学上可接受的盐或溶剂合物联合至少一种mTOR抑制剂在制备治疗癌症药物或试剂盒中的用途。与现有技术相比,本发明具有如下优势：本发明的取代丁烯酰胺或其可药用盐联合mTOR抑制剂对多种癌具有抑制增殖的效果,且联合使用具有显著的协同作用效果。(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.)

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:

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;

wherein said substituted aminocarbonyl group is preferably a compound of formula II:

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:

wherein R is_I～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:

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:

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:

wherein R is₁～R₁₁And X has the definition as set forth in claim 1.

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:

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-C₆

Alkynyl, optionally substituted aminocarbonyl or urea.

Preferably, the substituted aminocarbonyl group is a group of formula II:

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:

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:

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 deuteration

C₂-C₆Alkynyl, optionally substituted aminocarbonyl or urea.

Preferably, the substituted aminocarbonyl group is a compound of formula II:

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:

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:

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, 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:

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:

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:

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-C₆

Alkynyl, optionally substituted aminocarbonyl or urea.

Preferably, the substituted aminocarbonyl group is a compound of formula II:

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:

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.