Combination cancer therapy using quinoline carboxamide derivatives
阅读说明：本技术 使用喹啉羧酰胺衍生物的癌症联用疗法 (Combination cancer therapy using quinoline carboxamide derivatives ) 是由 浅井章良 津金桃实 小西宏明 吉永晓子 高桥宽行 饭岛崇裕 于 2019-09-17 设计创作，主要内容包括：本发明提供一种抗肿瘤效果强且副作用少的STAT3抑制剂的使用方法。一种抗肿瘤剂,是将选自ALK抑制剂、EGFR抑制剂、多激酶抑制剂、HER2/EGFR抑制剂、mTOR抑制剂、BRAF抑制剂、MEK抑制剂和BCR－ABL抑制剂中的1种以上的癌症分子靶向药物与下述式(I)：〔式中,R～1,R～2,R～3,R～4,R～5和R～6相同或不同且表示氢原子、取代或非取代的芳基、取代或非取代的芳香族杂环基、COOR～7(式中,R～7表示取代或非取代的烷基)或OR～8(式中,R～8表示取代或非取代的烷基)。〕表示的喹啉羧酰胺衍生物或它们的药理学上允许的盐组合而成的。(The invention provides a use method of a STAT3 inhibitor with strong anti-tumor effect and less side effect. An antitumor agent, which is prepared by combining 1 or more cancer molecule targeting drugs selected from an ALK inhibitor, an EGFR inhibitor, a multi-kinase inhibitor, a HER2/EGFR inhibitor, an mTOR inhibitor, a BRAF inhibitor, a MEK inhibitor and a BCR-ABL inhibitor with the following formula (I): [ in the formula, R 1 ，R 2 ，R 3 ，R 4 ，R 5 And R 6 Identical or different and represent a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, a COOR 7 (in the formula, R 7 Represents a substituted OR unsubstituted alkyl group) OR OR 8 (in the formula, R 8 Represents a substituted or unsubstituted alkyl group). Quinoline carboxamide derivatives represented by (a) or pharmacologically acceptable salts thereof.)
1. An antitumor agent which comprises a combination of a quinoline carboxamide derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof and at least one cancer molecule-targeting drug selected from the group consisting of an ALK inhibitor, an EGFR inhibitor, a multi-kinase inhibitor, a HER2/EGFR inhibitor, an mTOR inhibitor, a BRAF inhibitor, a MEK inhibitor and a BCR-ABL inhibitor,
in the formula, R1、R2、R3、R4、R5And R6Identical or different and represent a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, a COOR7OR OR8Wherein R is7Represents a substituted or unsubstituted alkyl group, R8Represents a substituted or unsubstituted alkyl group.
2. The antitumor agent according to claim 1, which is a kit comprising: a medicament comprising a quinoline carboxamide derivative represented by formula (I) or a pharmacologically acceptable salt thereof, and a medicament comprising at least one cancer molecule-targeting drug selected from the group consisting of an ALK inhibitor, an EGFR inhibitor, a multi-kinase inhibitor, a HER2/EGFR inhibitor, an mTOR inhibitor, a BRAF inhibitor, a MEK inhibitor and a BCR-ABL inhibitor.
3. The anti-tumor agent according to claim 1, which is a compounding agent.
4. The antitumor agent according to any one of claims 1 to 3, wherein R in the formula (I)1And R2The same or different, and is a substituted or unsubstituted aryl group, or a substituted or unsubstituted aromatic heterocyclic group.
5. The antitumor agent according to claim 4, wherein R in the formula (I)3、R4、R5And R6At least one group in (b) is a group other than a hydrogen atom.
6. The antitumor agent according to any one of claims 1 to 5, wherein R in the formula (I)1And R2Aryl in (A) is benzeneThe aromatic heterocyclic group is furyl.
7. The antitumor agent according to any one of claims 1 to 5, wherein R in the formula (I)1Is furyl, R2Is substituted or unsubstituted phenyl.
8. The antitumor agent according to any one of claims 1 to 7, wherein R3、R4、R5And R6At least one group of (a) is a trifluoromethoxy group.
9. The antitumor agent according to any one of claims 1 to 7, wherein R4Is trifluoromethoxy.
10. The antitumor agent as claimed in any one of claims 1 to 9, wherein the quinolinecarboxamide derivative represented by the formula (I) is N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-2-phenyl-6-trifluoromethoxy-4-quinolinecarboxamide.
11. The antitumor agent according to any one of claims 1 to 10, wherein the cancer-molecule-targeting drug is 1 or more selected from crizotinib, aratinib, ceritinib, oxitinib, sorafenib, vandetanib, lenvatinib, lapatinib, everolimus, dalafinib, trametinib, imatinib, and dasatinib.
12. The antitumor agent according to any one of claims 1 to 10, wherein the cancer-molecule-targeting drug is 1 or more selected from crizotinib, aratinib, ceritinib, oxicetib, sorafenib, vandetanib, lenvatinib, everolimus, dalafenib, trametinib, imatinib, and dasatinib.
13. The antitumor agent according to any one of claims 1 to 12, wherein the cancer is 1 or more selected from the group consisting of non-small cell lung cancer, tongue cancer, thyroid cancer, hepatocellular cancer, breast cancer, ovarian cancer, endometrial cancer, melanoma, and leukemia.
14. An antitumor agent comprising, as an active ingredient, a quinolinecarboxamide derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof,
characterized in that it is administered in combination with 1 or more cancer molecule-targeted drugs selected from an ALK inhibitor, an EGFR inhibitor, a multi-kinase inhibitor, a HER2/EGFR inhibitor, an mTOR inhibitor, a BRAF inhibitor, a MEK inhibitor and a BCR-ABL inhibitor,
in the formula, R1、R2、R3、R4、R5And R6Identical or different and represent a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, a COOR7OR OR8Wherein R is7Represents a substituted or unsubstituted alkyl group, R8Represents a substituted or unsubstituted alkyl group.
15. An antitumor effect enhancer which is an antitumor effect enhancer of at least 1 cancer molecule-targeted drug selected from an ALK inhibitor, an EGFR inhibitor, a multi-kinase inhibitor, a HER2/EGFR inhibitor, an mTOR inhibitor, a BRAF inhibitor, a MEK inhibitor and a BCR-ABL inhibitor,
quinoline carboxamide derivatives represented by the following formula (I) or pharmacologically acceptable salts thereof as an active ingredient,
in the formula, R1、R2、R3、R4、R5And R6Identical or different and represent a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, a COOR7OR OR8Wherein R is7Represents a substituted or unsubstituted alkyl group, R8Represents a substituted or unsubstituted alkyl group.
16. A pharmaceutical composition comprising:
a quinoline carboxamide derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof, and
more than 1 cancer molecule targeting drug selected from ALK inhibitor, EGFR inhibitor, multi-kinase inhibitor, HER2/EGFR inhibitor, mTOR inhibitor, BRAF inhibitor, MEK inhibitor and BCR-ABL inhibitor,
in the formula, R1、R2、R3、R4、R5And R6Identical or different and represent a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, a COOR7OR OR8Wherein R is7Represents a substituted or unsubstituted alkyl group, R8Represents a substituted or unsubstituted alkyl group.
17. A combination of quinoline carboxamide derivatives represented by the following formula (I) or pharmacologically acceptable salts thereof and 1 or more cancer molecule-targeting drugs selected from ALK inhibitors, EGFR inhibitors, multi-kinase inhibitors, HER2/EGFR inhibitors, mTOR inhibitors, BRAF inhibitors, MEK inhibitors and BCR-ABL inhibitors,
in the formula, R1、R2、R3、R4、R5And R6Identical or different and represent a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, a COOR7OR OR8Wherein R is7Represents a substituted or unsubstituted alkyl group, R8Represents a substituted or unsubstituted alkyl group.
18. A quinoline carboxamide derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof for use in combination with 1 or more cancer molecule-targeting drugs selected from an ALK inhibitor, an EGFR inhibitor, a multi-kinase inhibitor, a HER2/EGFR inhibitor, an mTOR inhibitor, a BRAF inhibitor, a MEK inhibitor and a BCR-ABL inhibitor in the treatment of tumors,
in the formula, R1、R2、R3、R4、R5And R6Identical or different and represent a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, a COOR7OR OR8Wherein R is7Represents a substituted or unsubstituted alkyl group, R8Represents a substituted or unsubstituted alkyl group.
19. A method of treating a tumor by administering to a patient a therapeutically effective amount of:
a quinoline carboxamide derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof, and
more than 1 cancer molecule targeting drug selected from ALK inhibitor, EGFR inhibitor, multi-kinase inhibitor, HER2/EGFR inhibitor, mTOR inhibitor, BRAF inhibitor, MEK inhibitor and BCR-ABL inhibitor,
in the formula, R1、R2、R3、R4、R5And R6Identical or different and represent a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, a COOR7OR OR8Wherein R is7Represents a substituted or unsubstituted alkyl group, R8Represents a substituted or unsubstituted alkyl group.
20. Use of a combination of a quinoline carboxamide derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof and 1 or more cancer molecule-targeting drugs selected from an ALK inhibitor, an EGFR inhibitor, a multi-kinase inhibitor, a HER2/EGFR inhibitor, an mTOR inhibitor, a BRAF inhibitor, a MEK inhibitor and a BCR-ABL inhibitor for the manufacture of an antitumor agent,
in the formula, R1、R2、R3、R4、R5And R6Identical or different and represent a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, a COOR7OR OR8Wherein R is7Represents a substituted or unsubstituted alkyl group, R8Represents a substituted or unsubstituted alkyl group.
21. A quinoline carboxamide derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof,
for the manufacture of an anti-tumor agent for administration in combination with 1 or more cancer molecule-targeted drugs selected from an ALK inhibitor, an EGFR inhibitor, a multi-kinase inhibitor, a HER2/EGFR inhibitor, an mTOR inhibitor, a BRAF inhibitor, a MEK inhibitor and a BCR-ABL inhibitor,
in the formula, R1、R2、R3、R4、R5And R6Identical or different and represent a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, a COOR7OR OR8Wherein R is7Represents a substituted or unsubstituted alkyl group, R8Represents a substituted or unsubstituted alkyl group.
22. A quinoline carboxamide derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof,
used for enhancing the antitumor effect of more than 1 cancer molecule targeting drug selected from ALK inhibitor, EGFR inhibitor, multi-kinase inhibitor, HER2/EGFR inhibitor, mTOR inhibitor, BRAF inhibitor, MEK inhibitor and BCR-ABL inhibitor,
in the formula, R1、R2、R3、R4、R5And R6Identical or different and represent a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, COOR7OR OR8Wherein R is7Represents a substituted or unsubstituted alkyl group, R8Represents a substituted or unsubstituted alkyl group.
23. A method for enhancing the antitumor effect of a cancer molecule-targeted drug which is 1 or more selected from the group consisting of an ALK inhibitor, an EGFR inhibitor, a multi-kinase inhibitor, a HER2/EGFR inhibitor, an mTOR inhibitor, a BRAF inhibitor, a MEK inhibitor and a BCR-ABL inhibitor,
the method comprises administering to a patient a therapeutically effective amount of a quinoline carboxamide derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof,
in the formula, R1、R2、R3、R4、R5And R6Identical or different and represent a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, a COOR7OR OR8Wherein R is7Represents a substituted or unsubstituted alkyl group, R8Represents a substituted or unsubstituted alkyl group.
24. A quinoline carboxamide derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof,
for the manufacture of an antitumor effect enhancer for enhancing the antitumor effect of 1 or more cancer molecule-targeting drugs selected from an ALK inhibitor, an EGFR inhibitor, a multi-kinase inhibitor, a HER2/EGFR inhibitor, an mTOR inhibitor, a BRAF inhibitor, a MEK inhibitor and a BCR-ABL inhibitor,
in the formula, R1、R2、R3、R4、R5And R6Identical or different and represent a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, COOR7OR OR8Wherein R is7Represents a substituted or unsubstituted alkyl group, R8Represents a substituted or unsubstituted alkyl group.
Technical Field
The present invention relates to a combination cancer therapy using quinoline carboxamide derivatives.
Background
STATs (Signal Transducers and Activators of Transcription) as Transcription regulators are DNA-binding proteins, and their activities are regulated by stimulation with various cytokines (IL-6, interferon, etc.) or growth factors (EGF, PDGF, etc.). The STAT activated by dimer formation migrates into the nucleus, specifically recognizes and binds to a specific DNA sequence located in the promoter region of a gene, and induces transcription of many genes. That is, STAT is a mediator essential for a pathway of transmitting a signal from the cell surface to the nucleus, and is closely involved in cell proliferation, differentiation, and the like.
As for STAT, 7 different members are known, and STAT3 is expressed in most cell types, and its general activation and overexpression are found in cancer cells such as lung cancer, skin cancer, pancreatic cancer, ovarian cancer, myeloma, breast cancer, prostate cancer, brain tumor, head and neck cancer, melanoma, leukemia lymphoma, and multiple myeloma, and the proliferation and infiltration of these cancer cells are considered to be dependent on STAT 3.
Therefore, STAT3 is considered to be useful as a target molecule for these types of cancers, and an inhibitor thereof is expected to be an anticancer agent. For example, it has been reported that a specific quinolinecarboxamide derivative has excellent STAT3 inhibitory activity and has antitumor activity against various cancers (patent document 1).
Documents of the prior art
Patent document
Patent document 1: japanese patent No. 5650529
Disclosure of Invention
The invention relates to a use method of a STAT3 inhibitor with strong anti-tumor effect and few side effects.
The present inventors have conducted extensive studies to further improve the antitumor effect of a quinolinecarboxamide derivative represented by the following formula (I), and as a result, have found that: excellent antitumor effects are obtained by combining specific cancer molecule-targeting drugs with the quinoline carboxamide derivative.
That is, the present invention is the following inventions 1) to 24).
1) An antitumor agent comprising a combination of a quinoline carboxamide derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof and at least one cancer molecule-targeting drug selected from the group consisting of an ALK inhibitor, an EGFR inhibitor, a multi-kinase inhibitor, a HER2/EGFR inhibitor, an mTOR inhibitor, a BRAF inhibitor, a MEK inhibitor and a BCR-ABL inhibitor.
2) The antitumor agent according to 1), which is a kit comprising: a medicament comprising a quinoline carboxamide derivative represented by formula (I) or a pharmacologically acceptable salt thereof, and a medicament comprising at least one cancer molecule-targeting drug selected from the group consisting of an ALK inhibitor, an EGFR inhibitor, a multi-kinase inhibitor, a HER2/EGFR inhibitor, an mTOR inhibitor, a BRAF inhibitor, a MEK inhibitor and a BCR-ABL inhibitor.
3) The antitumor agent according to 1), which is a compounding agent.
4) The antitumor agent according to any one of 1) to 3), wherein R in the formula (I)1And R2Same or differentAnd is a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic group.
5) The antitumor agent according to 4), wherein R in the formula (I)3、R4、R5And R6At least one group in (b) is a group other than a hydrogen atom.
6) The antitumor agent according to any one of 1) to 5), wherein R in the formula (I)1And R2The aryl in (1) is phenyl, and the aromatic heterocyclic group is furyl.
7) The antitumor agent according to any one of 1) to 5), wherein R in the formula (I)1Is furyl, R2Is substituted or unsubstituted phenyl.
8) The antitumor agent according to any one of 1) to 7), wherein R3、R4、R5And R6At least one group of (a) is a trifluoromethoxy group.
9) The antitumor agent according to any one of 1) to 7), wherein R4Is trifluoromethoxy.
10) The antitumor agent as described in any one of 1) to 9), wherein the quinolinecarboxamide derivative represented by the formula (I) is N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-2-phenyl-6-trifluoromethoxy-4-quinolinecarboxamide.
11) The antitumor agent according to any one of 1) to 10), wherein the cancer molecule-targeting drug is at least 1 selected from the group consisting of crizotinib, azintanib, ceritinib, oxitinib, sorafenib, vandetanib, lenvatinib, lapatinib, everolimus, dabrafenib, trametinib, imatinib and dasatinib.
12) The antitumor agent according to any one of 1) to 10), wherein the cancer molecule-targeting drug is at least 1 selected from the group consisting of crizotinib, aratinib, ceritinib, oxitinib, sorafenib, vandetanib, lenvatinib, everolimus, dalafenib, trametinib, imatinib and dasatinib.
13) The antitumor agent according to any one of 1) to 12), wherein the cancer is at least 1 selected from the group consisting of non-small cell lung cancer, tongue cancer, thyroid cancer, hepatocellular carcinoma, breast cancer, ovarian cancer, endometrial cancer, melanoma, and leukemia.
14) An antitumor agent comprising as an active ingredient a quinoline carboxamide derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof, characterized in that the agent is administered in combination with 1 or more cancer molecule-targeting drugs selected from an ALK inhibitor, an EGFR inhibitor, a multi-kinase inhibitor, a HER2/EGFR inhibitor, an mTOR inhibitor, a BRAF inhibitor, a MEK inhibitor and a BCR-ABL inhibitor.
15) An antitumor effect enhancer which is an antitumor effect enhancer of 1 or more cancer molecule-targeting drugs selected from an ALK inhibitor, an EGFR inhibitor, a multi-kinase inhibitor, a HER2/EGFR inhibitor, an mTOR inhibitor, a BRAF inhibitor, a MEK inhibitor and a BCR-ABL inhibitor, wherein a quinoline carboxamide derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof is an active ingredient.
16) A pharmaceutical composition comprising: quinoline carboxamide derivatives or their pharmacologically acceptable salts, and 1 or more cancer molecule-targeting drugs selected from ALK inhibitors, EGFR inhibitors, multi-kinase inhibitors, HER2/EGFR inhibitors, mTOR inhibitors, BRAF inhibitors, MEK inhibitors, and BCR-ABL inhibitors.
17) A combination of quinoline carboxamide derivatives represented by formula (I) below or their pharmacologically acceptable salts with 1 or more cancer molecule-targeting drugs selected from ALK inhibitors, EGFR inhibitors, multi-kinase inhibitors, HER2/EGFR inhibitors, mTOR inhibitors, BRAF inhibitors, MEK inhibitors and BCR-ABL inhibitors for treating tumors.
18) A quinoline carboxamide derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof for use in combination with 1 or more cancer molecule-targeting drugs selected from an ALK inhibitor, an EGFR inhibitor, a multi-kinase inhibitor, a HER2/EGFR inhibitor, an mTOR inhibitor, a BRAF inhibitor, a MEK inhibitor and a BCR-ABL inhibitor in the treatment of tumors.
19) A method of treating a tumor by administering to a patient a therapeutically effective amount of:
a quinoline carboxamide derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof, and
more than 1 cancer molecule targeting drug selected from the group consisting of ALK inhibitors, EGFR inhibitors, multi-kinase inhibitors, HER2/EGFR inhibitors, mTOR inhibitors, BRAF inhibitors, MEK inhibitors and BCR-ABL inhibitors.
20) Use of a combination of a quinoline carboxamide derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof and 1 or more cancer molecule-targeting drugs selected from an ALK inhibitor, an EGFR inhibitor, a multi-kinase inhibitor, a HER2/EGFR inhibitor, an mTOR inhibitor, a BRAF inhibitor, a MEK inhibitor and a BCR-ABL inhibitor for the manufacture of an antitumor agent.
21) Use of a quinoline carboxamide derivative represented by formula (I) below or a pharmacologically acceptable salt thereof for the manufacture of an antitumor agent to be administered in combination with 1 or more cancer molecule-targeted drugs selected from an ALK inhibitor, an EGFR inhibitor, a multi-kinase inhibitor, a HER2/EGFR inhibitor, an mTOR inhibitor, a BRAF inhibitor, a MEK inhibitor and a BCR-ABL inhibitor.
22) A quinoline carboxamide derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof for enhancing the antitumor effect of 1 or more cancer molecule-targeting drugs selected from an ALK inhibitor, an EGFR inhibitor, a multi-kinase inhibitor, a HER2/EGFR inhibitor, an mTOR inhibitor, a BRAF inhibitor, a MEK inhibitor and a BCR-ABL inhibitor.
23) A method for enhancing the antitumor effect of a cancer molecule-targeted drug which is 1 or more selected from the group consisting of an ALK inhibitor, an EGFR inhibitor, a multi-kinase inhibitor, a HER2/EGFR inhibitor, an mTOR inhibitor, a BRAF inhibitor, a MEK inhibitor and a BCR-ABL inhibitor,
the method comprises administering to a patient a therapeutically effective amount of a quinoline carboxamide derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof.
24) Use of a quinoline carboxamide derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof for producing an antitumor effect potentiator that potentiates the antitumor effect of 1 or more cancer molecule-targeting drugs selected from an ALK inhibitor, an EGFR inhibitor, a multi-kinase inhibitor, a HER2/EGFR inhibitor, an mTOR inhibitor, a BRAF inhibitor, a MEK inhibitor, and a BCR-ABL inhibitor.
[ in the formula, R1、R2、R3、R4、R5And R6Identical or different and represent a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, a COOR7(in the formula, R7Represents a substituted or unsubstituted alkyl group. ) OR OR8(in the formula, R8Represents a substituted or unsubstituted alkyl group. ) Angle (c)
According to the antitumor agent of the present invention, cancer treatment with a high antitumor effect can be performed while suppressing the onset of side effects, and the long-term survival of patients can be brought about.
Drawings
FIG. 1 shows inhibition of the STAT3 pathway and ALK pathway in combination with Alanib for STX-1159.
Detailed Description
In the quinoline carboxamide derivatives represented by the general formula (I), R1、R2、R3、R4、R5And R6Identical or different and represent a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, a COOR7(in the formula, R7Represents a substituted or unsubstituted alkyl group. ) OR OR8(in the formula, R8Represents a substituted or unsubstituted alkyl group).
Examples of the substituent in the alkyl group include a halogen atom and a hydroxyl group. In addition, as aryl, arylThe substituent of the aromatic heterocyclic group may be an alkyl group having 1 to 6 carbon atoms, an alkenyl group, an alkynyl group, a cycloalkyl group, an aralkyl group, ORa、NRbRc、S(O)qRd(wherein q represents 0, 1 or 2), CORe、COORf、OCORg、CONRhRi、NRjCORk、NRlCOORm、NRnSO2Ro、C(＝NRp)NRqRr、NRsSO2NRtRu、SO2NRvRwNitro, cyano, halogen atoms and the like. Here, Ra～RwMay represent, identically or differently, a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, etc.
The number of substitution of these substituents may be the same or different, and the maximum number of hydrogen atoms present in each group is preferably 1 to 10, more preferably 1 to 5.
The details of each group defined in the above general formula (I) are shown below. In addition, the group having positional isomers in each group represents all possible positional isomers.
Examples of the alkyl group and the alkyl moiety of the alkoxy group include straight-chain or branched alkyl groups having 1 to 12 carbon atoms, and specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like.
Examples of the cycloalkyl group include a 3 to 12-membered cycloalkyl group which may be saturated or may have a part of unsaturated bonds, and the cycloalkyl group may be a monocyclic cycloalkyl group, a polycyclic condensed cycloalkyl group in which a plurality of monocyclic cycloalkyl groups are condensed, or a polycyclic condensed cycloalkyl group in which a monocyclic cycloalkyl group is condensed with an aryl group or an aromatic heterocyclic group. Examples of the monocyclic cycloalkyl group include monocyclic cycloalkyl groups having 3 to 8 carbon atoms, specifically cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, cyclohexyl groups, cycloheptyl groups, cyclooctyl groups, cyclododecyl groups, and 1-cyclohexenyl groups, and examples of the polycyclic cycloalkyl groups include polycyclic cycloalkyl groups having 5 to 12 carbon atoms, specifically pinanyl groups, adamantyl groups, bicyclo [3.3.1] octyl groups, and bicyclo [3.1.1] heptyl groups.
Examples of the alkenyl group include a straight-chain or branched alkenyl group having 2 to 12 carbon atoms, and specific examples thereof include a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, a methacryl group, a butenyl group, a1, 3-butadienyl group, a crotyl group, a pentenyl group, a hexenyl group, a heptenyl group, a decenyl group, and a dodecenyl group.
Examples of the alkynyl group include straight-chain or branched alkynyl groups having 2 to 12 carbon atoms, and specific examples thereof include ethynyl, propargyl, 1-propynyl, isopropynyl, 2-butynyl, pentynyl, 2-penten-4-ynyl, hexynyl, heptynyl, decynyl, and dodecenyl groups.
Examples of the aryl group include aryl groups having 6 to 14 carbon atoms, and specific examples thereof include phenyl, naphthyl, anthryl, phenanthryl, and the like.
The aromatic heterocyclic group may be the same or different and is composed of a 5-or 6-membered aromatic heterocyclic group containing at least 1 or more hetero atoms such as nitrogen, oxygen, sulfur and the like, and the heterocyclic group may be a monocyclic heterocyclic group, a polycyclic condensed aromatic heterocyclic group in which a plurality of the monocyclic heterocyclic groups are condensed, or a polycyclic condensed aromatic heterocyclic group in which the monocyclic heterocyclic group is condensed with an aryl group, and may be, for example, a bicyclic or tricyclic heterocyclic group. Specific examples of the monocyclic aromatic heterocyclic group include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like,Azolyl radical, isoAzolyl group,Oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyridyl, pyrimidineExamples of the polycyclic condensed aromatic heterocyclic group include a furyl group, a benzothienyl group, an indolyl group, an isoindolyl group, an indazolyl group, a benzimidazolyl group, a benzotriazolyl group, and a triazinyl groupAzolyl, benzothiazolyl, carbazolyl, purinyl, quinolyl, isoquinolyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, pyridopyrimidinyl, pyrimidopyrimidinyl, pteridinyl, acridinyl, thianthrenyl, thiophenylThienyl, thiophenOxazinyl, phenothiazinyl, phenazinyl, and the like.
Examples of the halogen atom include fluorine, chlorine, bromine, and iodine atoms.
Among the quinoline carboxamide derivatives represented by formula (I), R is preferable1And R2A compound which is the same or different and is a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group; specific examples of the aryl group include preferably a phenyl group, a naphthyl group and the like, and specific examples of the aromatic heterocyclic group include a furyl group, a thienyl group and the like. In addition, R is more preferable1Is furyl and R2Examples of the substituent for the group of the substituted phenyl group include an alkyl group such as a methyl group, a substituted or unsubstituted alkoxy group such as a methoxy group or a difluoromethoxy group, a halogen atom such as a fluorine atom or a chlorine atom, an alkoxycarbonyl group such as a hydroxyl group or a tert-butoxycarbonyl group, an amino group, a nitro group, a cyano group, and the like, and examples of the substituent for the substituted furyl group or the substituted thienyl group include an alkyl group such as a methyl group, a halogen atom such as a chlorine atom, and the like.
Further, R is more preferably3、R5And R6Is a hydrogen atom and R4Is OR8(preferably, it isMethoxy or trifluoromethoxy) compounds.
As specific examples of these compounds (I), N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-2-phenyl-4-quinolinecarboxamide, N- [ 5- (3-furyl) -1, 3, 4-Diazol-2-yl]-2-phenyl-4-quinolinecarboxamide, 2-phenyl-N- (5-phenyl-1, 3, 4-Oxadiazol-2-yl) -4-quinolinecarboxamide, N- [ 5- (4-chlorophenyl) -1, 3, 4-Diazol-2-yl]-2-phenyl-4-quinolinecarboxamide, N- [ 5- (4-nitrophenyl) -1, 3, 4-Diazol-2-yl]-2-phenyl-4-quinolinecarboxamide, 2-phenyl-N- [ 5- (3-pyridyl) -1, 3, 4-Diazol-2-yl]-4-quinolinecarboxamide, N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-2- (3-nitrophenyl) -4-quinolinecarboxamide, 2- (4-cyanophenyl) -N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-4-quinolinecarboxamide, 2- (2-furyl) -N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-4-quinolinecarboxamide, 2- (5-chloro-2-thienyl) -N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-4-quinolinecarboxamide, N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-6-methoxy-2-phenyl-4-quinolinecarboxamide, 2- (1-butoxy) -N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-4-quinolinecarboxamide, 2- (2-chlorophenyl) -N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-4-quinolinecarboxamide, N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-2- (2-hydroxyphenyl) -4-quinolinecarboxamide, 2- (2-aminophenyl) -N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-4-quinolinecarboxamide, 2- (3-chlorophenyl) -N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-4-quinolinecarboxamide, N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-2- (3-methoxyphenyl) -4-quinolinecarboxamide, 2- (3-cyanophenyl) -N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-4-quinolinecarboxamide, 2- (3-tert-butoxycarbonylphenyl) -N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-4-quinolinecarboxamide, 2- (4-fluorophenyl) -N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-4-quinolinecarboxamide, 2- (4-chlorophenyl) -N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-4-quinolinecarboxamide, N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-2- (4-methylphenyl) -4-quinolinecarboxamide, 2- (4-difluoromethoxyphenyl) -N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-4-quinolinecarboxamide, N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-2- (4-hydroxyphenyl) -4-quinolinecarboxamide, N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-2- (4-methoxyphenyl) -4-quinolinecarboxamide, N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-2- (4-nitrophenyl) -4-quinolinecarboxamide,2- (4-tert-Butoxycarbonylphenyl) -N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-4-quinolinecarboxamide, N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-2- (2, 4-dimethylphenyl) -4-quinolinecarboxamide, N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-2- (3, 4-dimethoxyphenyl) -4-quinolinecarboxamide, N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-2- (3, 4-methylenedioxyphenyl) -4-quinolinecarboxamide, N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-2- (1-naphthyl) -4-quinolinecarboxamide, N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-2- (6-methoxy-2-naphthyl) -quinolinecarboxamide, N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-2- (5-methyl-2-furyl) -4-quinolinecarboxamide, N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-2-phenyl-6-trifluoromethoxy-4-quinolinecarboxamide, N- [ 5- (5-nitro-2-furanyl) -1, 3, 4-Diazol-2-yl]-2-phenyl-4-quinolinecarboxamide, N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-6- (4-hydroxyphenyl) -2-phenyl-4-quinolinecarboxamide, N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-6- (3-thienyl) -2-phenyl-4-quinolinecarboxamide, N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-6- (3-pyridyl) -2-phenyl-4-quinolinecarboxamide, N- (5-phenyl-1, 3, 4-Oxadiazol-2-yl) -2-phenyl-6-trifluoromethoxy-4-quinolinecarboxamide, N- [ 5- (2-chlorophenyl) -1, 3, 4-Diazol-2-yl]-2-phenyl-6-trifluoromethoxy-4-quinolinecarboxamide, N- [ 5- (4-methoxyphenyl) -1, 3, 4-Diazol-2-yl]-2-phenyl-6-trifluoromethoxy-4-quinolinecarboxamide, N- [ 5- (5-chloro-2-thienyl) -1, 3, 4-Diazol-2-yl]-2-phenyl-4-quinolinecarboxamide, N- [ 5- (4-methoxyphenyl) -1, 3, 4-Diazol-2-yl]-2-phenyl-4-quinolinecarboxamide and N- (5-phenyl)－1,3,4－Oxadiazol-2-yl) -2- (2-thienyl) -4-quinolinecarboxamide and the like, more preferably N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-2-phenyl-6-trifluoromethoxy-4-quinolinecarboxamide.
Pharmacologically acceptable salts of the quinolinecarboxamide derivative represented by formula (I) include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like. Examples of the pharmacologically acceptable acid addition salts include various inorganic acid salts such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and boric acid, carboxylic acids such as formic acid, acetic acid, propionic acid, fumaric acid, malonic acid, succinic acid, maleic acid, tartaric acid, citric acid, and benzoic acid, sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid, and amino acids such as glutamic acid and aspartic acid. Examples of the pharmacologically acceptable metal salts include alkali metal salts such as lithium, sodium and potassium, alkaline earth metal salts such as magnesium and calcium, metal salts such as aluminum and zinc, pharmacologically acceptable ammonium salts include ammonium and tetramethylammonium, pharmacologically acceptable organic amine salts include triethylamine, piperidine, morpholine and toluidine, and pharmacologically acceptable amino acid addition salts include addition salts of lysine, glycine and phenylalanine.
The quinolinecarboxamide derivative represented by formula (I) or a salt thereof of the present invention is described as a STAT3 inhibitor in japanese patent No. 5650529 (patent document 1) and can be produced by the method described in the publication. It is known that the quinolinecarboxamide derivative or a salt thereof inhibits dimer formation of STAT3 to exert an antitumor effect.
The cancer molecule-targeted drug of the present invention is a drug developed for the purpose of inhibiting not only primary tumors but also tumor metastasis by inhibiting the proliferation of tumor cells and inhibiting the progress of tumors by targeting molecules related to the proliferation, infiltration, and metastasis of tumor cells.
Examples of the cancer molecule-targeted drug of the present invention include 1 or more selected from an ALK inhibitor, an EGFR inhibitor, a multi-kinase inhibitor, a HER2/EGFR inhibitor, an mTOR inhibitor, a BRAF inhibitor, a MEK inhibitor, and a BCR-ABL inhibitor (hereinafter, referred to as "the cancer molecule-targeted drug of the present invention").
Here, the "ALK inhibitor" inhibits tyrosine kinase of Anaplastic Lymphoma Kinase (ALK)
The "EGFR inhibitor" inhibits mutation of T790M gene and activating mutation of Epidermal Growth Factor Receptor (Epidermal Growth Factor Receptor: EGFR),
"multikinase inhibitors" inhibit a plurality of tyrosine kinases such as RAF, Vascular Endothelial Growth Factor Receptor (VEGFR), Platelet-derived growth factor Receptor (PDGFR), and rearrangement during Transfection (RET) involved in tumor cell proliferation and angiogenesis,
the "HER 2/EGFR inhibitor" inhibits both EGFR and HER2(EGFR2) of the EGFR family,
an "mTOR inhibitor" inhibits the mammalian target of rapamycin (mTOR),
the 'BRAF inhibitor' inhibits the kinase activity of mutant BRAF (V600E, V600K and V600D are positive in variation),
"MEK inhibitors" inhibit the kinase activity of Mitogen-activated extracellular signal-regulated kinase (MEK) 1/MEK2,
"BCR-ABL inhibitors" inhibit tyrosine kinases of the Breakpoint cluster region-Abelson (BreakPoint cluster-Abelson, Bcr-ABL), KIT, PDGFR.
Specifically, examples of the ALK inhibitor include Crizotinib (Crizotinib), aletinib (aletinib), Ceritinib (Ceritinib), loratinib (loretinib), bugatitinib (Brigatinib), and entretinib (Entrectinib); examples of EGFR inhibitors include oxitinib (Osimertinib), Gefitinib (Gefitinib), Erlotinib (Erlotinib), Afatinib (Afatinib), Dacomitinib (Dacomitinib), Cetuximab (Cetuximab), Panitumumab (Panitumumab); examples of the multi-kinase inhibitor include Sorafenib (Sorafenib), Vandetanib (Vandetanib), Lenvatinib (Lenvatinib), Regorafenib (Regorafenib), Sunitinib (Sunitinib), Axitinib (Axitinib), Pazopanib (Pazopanib), Cabozantinib (Cabozantinib), and Nintedanib (Nintedanib); examples of the HER2/EGFR inhibitor include Lapatinib (Lapatinib); examples of mTOR inhibitors include Everolimus (Everolimus), Temsirolimus (Temsirolimus), GDC-0980 (RG7422), AZD2014, PI-103, KU-0063794, AZD8055, GSK1059615, OSI-027, PF-04691502, PF-05212384 (PKI-587), WAY-600, GSK2126458, PP242, WYE-125132, WYE-687, PP-121, Torin 2, Torin 1, INK 128; examples of BRAF inhibitors include Dabrafenib (Dabrafenib), Vemurafenib (Vemurafenib), and canofenib (Encorafenib); examples of MEK inhibitors include Trametinib (Trametinib), bimetinib (Binimetinib); examples of the BCR-ABL inhibitor include Imatinib (Imatinib), Dasatinib (Dasatinib), Bosutinib (Bosutinib), Ponatinib (Ponatinib), and Nilotinib (Nilotinib). Preferred cancer molecule-targeting drugs include azafenib, crizotinib, ceritinib, oxitinib, sorafenib, vandetanib, lenvatinib, lapatinib, everolimus, darafenib, trametinib, imatinib, and dasatinib.
Among them, from the viewpoint of the effect of the combination with the quinoline carboxamide derivative represented by formula (I) or a salt thereof, as a cancer molecule-targeting drug, an ALK inhibitor, an EGFR inhibitor, a multi-kinase inhibitor, an mTOR inhibitor, a BRAF inhibitor, a MEK inhibitor, or a BCR-ABL inhibitor is preferable, and an ALK inhibitor and a multi-kinase inhibitor are more preferable. Further, as the cancer molecule-targeting drug, preferred are adriamib, crizotinib, ceritinib, oxitinib, sorafenib, vandetanib, lenvatinib, everolimus, dalafinib, trametinib, imatinib, dasatinib, and more preferred are adriamib, crizotinib, ceritinib, sorafenib, and vandetanib.
As will be described later in examples, the quinoline carboxamide derivative represented by formula (I) or a salt thereof and the cancer molecule-targeting drug of the present invention are administered in combination, whereby a significantly stronger cell-killing activity and antitumor effect are exhibited than when a single agent is administered. The cell killing activity showed a synergistic effect with a CI of 0.9 or less in the evaluation of the combined effect (combination index: CI) calculated by the mean-effect method (Pharmacol Rev 58:621-681,2006) using the combined effect analysis software Calcusyn (HULINKS).
Therefore, a combination of the quinoline carboxamide derivative represented by formula (I) or a salt thereof and the cancer molecule-targeting drug of the present invention is useful as an antitumor agent. In addition, the quinoline carboxamide derivative represented by formula (I) or a salt thereof is useful as an antitumor agent to be administered in combination with the cancer molecule-targeting drug of the present invention. In addition, the quinoline carboxamide derivative represented by formula (I) or a salt thereof is useful as an enhancer of the antitumor effect of the cancer molecule-targeting drug of the present invention, and the cancer molecule-targeting drug of the present invention is useful as an enhancer of the antitumor effect of the quinoline carboxamide derivative represented by formula (I) or a salt thereof.
The cancer treatable by the antitumor agent of the present invention is not particularly limited, and examples thereof include non-small cell lung cancer, tongue cancer, thyroid cancer, hepatocellular cancer, breast cancer, ovarian cancer, endometrial cancer, melanoma, leukemia, and the like, and non-small cell lung cancer, tongue cancer, thyroid cancer, hepatocellular cancer, ovarian cancer, and endometrial cancer are preferable.
The antitumor agent comprising the combination of the quinoline carboxamide derivative represented by formula (I) or a salt thereof and a cancer molecule-targeting drug of the present invention may be a pharmaceutical agent in which the effective amounts of each of the quinoline carboxamide derivative represented by formula (I) or a salt thereof and the cancer molecule-targeting drug as compounding agents are formulated into one dosage form at an appropriate compounding ratio (1 dosage form), or a pharmaceutical agent in which the effective amounts of each of the pharmaceutical agents containing the above components are formulated separately so as to be used simultaneously or separately at intervals (2 dosage form).
The administration form of the above preparation is not particularly limited, and may be appropriately selected depending on the purpose of treatment, and specifically, oral preparations (tablets, coated tablets, powders, granules, capsules, liquids, and the like), injections, suppositories, patches, ointments, and the like can be exemplified. The quinoline carboxamide derivative represented by formula (I) or a salt thereof and the cancer molecule-targeting drug may be administered in different modes or in the same mode.
The formulations containing the quinoline carboxamide derivative represented by formula (I) or a salt thereof according to the present invention and/or the cancer molecule-targeting drug according to the present invention can be prepared using a pharmacologically acceptable carrier by a conventionally known method. Examples of the carrier include various carriers commonly used in general pharmaceutical preparations, such as an excipient, a binder, a disintegrant, a lubricant, a diluent, a solubilizer, a suspending agent, an isotonic agent, a pH adjuster, a buffer, a stabilizer, a coloring agent, a flavoring agent, and a corrigent.
Examples of the excipient include lactose, sucrose, sodium chloride, glucose, maltose, mannitol, erythritol, xylitol, maltitol, inositol, dextran, sorbitol, albumin, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, methyl cellulose, glycerin, sodium alginate, gum arabic, and a mixture thereof. Examples of the lubricant include purified talc, stearate, borax, polyethylene glycol, and a mixture thereof. Examples of the binder include simple syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethyl cellulose, shellac, methyl cellulose, ethyl cellulose, water, ethanol, potassium phosphate, and a mixture thereof. Examples of the disintegrating agent include dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, glyceryl monostearate, starch, lactose, and a mixture thereof. Examples of the diluent include water, ethanol, polyethylene glycol (Macrogol), propylene glycol, ethoxylated isostearyl alcohol, polyoxyisostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and mixtures thereof. Examples of the stabilizer include sodium metabisulfite, ethylenediaminetetraacetic acid, thioglycolic acid, thiolactic acid, and a mixture thereof. Examples of the isotonic adjusting agent include sodium chloride, boric acid, glucose, glycerin, and a mixture thereof. Examples of the pH adjuster and the buffer include sodium citrate, citric acid, sodium acetate, sodium phosphate, and a mixture thereof. Examples of the painless agent include procaine hydrochloride, lidocaine hydrochloride, and a mixture thereof.
The amount of the quinoline carboxamide derivative represented by formula (I) or a salt thereof and the cancer molecule-targeting drug of the present invention to be incorporated into the above preparation can be appropriately set, and generally, the amount of the quinoline carboxamide derivative represented by formula (I) or a salt thereof in the preparation is 0.001 to 5000mg, preferably 0.1 to 1000mg, and more preferably 1 to 500 mg. The cancer molecule-targeting drug can be appropriately set within the allowable range in each agent. For example, 150 to 600mg for Alanib, and 200 to 800mg for Sorafenib.
When the antitumor agent of the present invention is prepared as a kit, a pharmaceutical preparation containing the quinoline carboxamide derivative represented by formula (I) or a salt thereof prepared as described above and the cancer molecule-targeting drug of the present invention may be packaged separately, and the pharmaceutical preparation may be taken out of each package for use at the time of administration. In addition, each pharmaceutical preparation may also be packaged in a form suitable for 1-time combined administration.
The amount of the quinoline carboxamide derivative represented by formula (I) or a salt thereof in the present invention and the cancer molecule-targeting drug in the present invention to be administered is not particularly limited as long as the quinoline carboxamide derivative represented by formula (I) or a salt thereof and the cancer molecule-targeting drug of the present invention synergistically exhibit antitumor effects and can effectively treat cancer, and may be appropriately set depending on the age, cancer type, disease stage, presence or absence of metastasis, treatment history, presence or absence of other antitumor agents, and the like of a patient, and the amount of the quinoline carboxamide derivative represented by formula (I) or a salt thereof is 0.001 to 5000 mg/day, preferably 0.1 to 1000 mg/day, and more preferably 1 to 500mg in terms of the amount of the quinoline carboxamide derivative represented by formula (I). The cancer molecule-targeting drug can be appropriately set within the allowable range in each agent. For example, in case of Alanib, 150 to 600 mg/day can be exemplified, and in case of Sorafenib, 200 to 800 mg/day can be exemplified.
The order and interval of administration of the quinoline carboxamide derivative represented by formula (I) or a salt thereof and the cancer molecule-targeting drug of the present invention are not particularly limited as long as a synergistic effect can be obtained. Alternatively, when formulated as a kit, the individual formulations may be administered simultaneously or at intervals.
Examples
< materials and Experimental methods >
1. Cell culture
NCI-H2228, NCI-H1975, SK-BR-3, Hep3B, MCF-7, Caov-3, A2058, K562 and SUP-B15 were obtained from the American Type Culture Collection, SAS and HuH-7 were obtained from the national institute for research and development, human Foundation of medicine, health and Nutrition research institute, K1, FTC-133 and Ishikawa were obtained from the European Cell line/Collection of microorganisms. Cells were cultured in the medium of Table 1 containing 100U/mL penicillin (penillin), 100. mu.g/mL streptomycin (Thermo Fisher Scientific, code 15140-122) in 5% CO2Subculture was carried out at 37 ℃ for experiments. Fetal bovine serum (Fetal bovine serum) (hereinafter, abbreviated as FBS) and MCDB 105 medium were purchased from Sigma Aldrich (trade codes 172012 and 117-.
[ Table 1]
2. Medicament
N- [ 5- (2-furyl) -1, 3, 4-Diazol-2-yl]-2-phenyl-6-trifluoromethoxy-4-quinolinecarboxamide (hereinafter, referred to as "STX-1159") was synthesized according to the method described in patent document 1.
Crizotinib (Crizotinib), everolimus (everolimus) and trametinib (trametinib) were purchased from LC Laboratories (commercial codes C-7900, E-4040, V-2800 and T-8123). Alaninib (Alectonib), oxitinib (osimertinib), Lenvatinib (Lenvatinib) were purchased from Selleckchem.com (commercial codes S2762, S7297 and S1164), ceritinib (ceritinib) was purchased from Active Biochem (commercial code A-1189). Sorafenib (Sorafenib) is available from Cayman Chemical (trade code 10009644), vandetanib (vandetanib), lapatinib (lapatinib) and dabrafenib (dabrafenib) is available from Santa Cruz Biotechnology (trade codes sc-220364, sc-202205 and sc-364477). Imatinib (Imatinib) is available from Cell Signaling Technology (trade code 9084) and dasatinib (dasatinib) is available from Bio Vision (trade code 1586). All the agents were dissolved in dimethyl sulfoxide (hereinafter, abbreviated as DMSO).
EXAMPLE 1 evaluation of Effect of combination of drugs
(1) Setting of reference dose
Each cell was seeded in a 96-well plate at a density shown in Table 2 in 5% CO2And cultured at 37 ℃. Each agent was added separately the next day after inoculation. DMSO was added in the blank to reach a final concentration of 0.05%. Then at 5% CO2After culturing at 37 ℃ for the time shown in Table 2, the number of viable cells was evaluated by WST-8 analysis. That is to say that the first and second electrodes,WST-8 kit solution (Kishida Chemical, code 260-2And culturing at 37 ℃ for 1-2 hours. The absorbance at 450nm of water-soluble blue-violet Formazan (Formazan) produced by the enzymatic activity of intracellular mitochondria was measured using a microplate reader (Molecular Devices, model spectra max Plus). The number of viable cells was evaluated to calculate a 50% cell growth inhibitory concentration (hereinafter abbreviated as IC)50). The reference dose of each drug is based on IC50And the setting was made (table 3).
[ Table 2] cell density and culture time
Cell name
Cell density
Incubation time after addition of the agent
NCI-H2228
2500 cells/well
72 hours
NCI-H1975
2500 cells/well
72 hours
SAS
2500 cells/well
48 hours
K1
2500 cells/well
72 hours
FTC-133
2500 cells/well
72 hours
Hep3B
2500 cells/well
72 hours
HuH-7
2500 cells/well
72 hours
SK-BR-3
2500 cells/well
72 hours
MCF-7
2500 cells/well
72 hours
Caov-3
2500 cells/well
72 hours
Ishikawa
2500 cells/well
72 hours
A2058
2500 cells/well
72 hours
K562
2500 cells/well
48 hours
SUP-B15
7500 cells/well
72 hours
[ Table 3]
Reference dose
(2) Evaluation of combined effect based on mean-effect method
Each cell was seeded in a 96-well plate at a density shown in Table 2 in 5% CO2And cultured at 37 ℃. The next day after inoculation, STX-1159 and each agent were added in separate groups at final concentrations of 1/4, 1/2, 1,2 and 4 times the baseline dose, and in combination groups at final concentrations of STX-1159 and each agent of 1/4 times each other, 1/2 times each other, 1 times each other, 2 times each other and 4 times each other, combined with each other, in the baseline dose. DMSO was added in a blank to reach a final concentration of 0.1%. Then, at 5% CO2After culturing at 37 ℃ for the time shown in Table 2, the number of viable cells was determined by WST-8 analysis. The influence score (hereinafter abbreviated as fa) is calculated from the following equation.
fa ═ 1- (number of living cells in drug-exposed group)/(number of living cells in blank group)
The combination index (hereinafter, abbreviated as "CI") was calculated from the fa when STX-1159 and each drug were used alone or in combination for exposure, by the mean-effect method using the software Calcusyn (HULINKS) for analyzing the effect of combination. Evaluation of the effect of the combinations was according to the CI-based ranking of table 4. Note that, when calculating CI, the average value of the experimental values of 2 times or more similarly performed was used.
[ Table 4]
Ranking of combined effects based on CI
CI
Coupling effect
CI≦0.1
Very strong synergistic effect
0.1＜CI≤0.3
Strong synergistic effect
0.3＜CI≦0.7
Synergistic effect
0.7＜CI≦0.85
Moderate degree of synergistic effect
0.85＜CI≦0.9
Mild synergistic effect
0.9＜CI≦1.1
Approximately additive effect
1.1＜CI≤1.2
Mild antagonism
1.2＜CI≦1.45
Moderate antagonism
1.45＜CI≦3.3
Antagonism
3.3＜CI≦10
Strong antagonistic action
10＜CI
Very strong antagonism
(3) Results
The effect of the combination of STX-1159 and each agent was evaluated by the median-effect method, and as a result, the combination of STX-1159 and crizotinib, alitanib, ceritinib, oxitinib, sorafenib, vandetanib, lenvatinib, lapatinib, everolimus, dabrafenib, trametinib, imatinib, or dasatinib exhibited a synergistic effect (Table 5). Based on the results, it is suggested that the combination of STX-1159 with these agents is effective as a combination drug therapy.
[ Table 5]
Evaluation results of coupling Effect
Example 2 inhibition of STAT3 and ALK signaling pathway building molecules based on the combination of STX-1159 and Alanib
(1) Evaluation based on Western blotting
To confirm that STX-1159, which exhibits synergistic inhibition of proliferation of NCI-H2228 cells, in combination with ALENNI, inhibits intracellular STAT3 or ALK, the effect of two agents on the protein quality of phosphorylated STAT3, phosphorylated ALK, survivin (survivin) and c-myc in NCI-H2228 cells was studied by Western blotting.
NCI-H2228 cells to 2X 105Cell/well format seeded in 6-well plates at 5% CO2And cultured at 37 ℃. The next day after inoculation STX-1159 was brought to a final concentration of 5. mu.M or Alanib was brought to a final concentration of 0.01 or 0.1. mu.M, alone or in combination. DMSO was added in the blank to reach a final concentration of 0.1%. After addition of the drug, at 5% CO2After culturing at 37 ℃ for 24 hours, the cells were recovered. The cells were washed 1 time with ice-cold PBS, and the cells were lysed by adding RIPA Buffer (25mM Tris-HCl, pH7.6, 1% NP-40, 1% sodium deoxycholate, 0.1% SDS, 0.15M NaCl) to which a protease inhibitor mixture (Nacalai Tesque, Inc., product code 25955-11) and a phosphatase inhibitor mixture (Nacalai Tesque, product code 07574) were added. The lysate was subjected to electrophoresis, and proteins in the acrylamide gel were transcribed on an Immobilon PVDF membrane using a semidry transcription apparatus. After transcription, the membrane was blocked and the antibody (anti-phosphorylated STAT3(Y705) antibody: Cell Signaling Technology, commercially available CST9131, anti-STAT 3 antibody: Cell Signaling Technology, commercially available CST4904, phosphorylated ALK (Y1278/Y1282/Y1283) antibody: Cell Signaling Technology, commercially available CST3983, anti-ALK antibody: Cell Signaling Technology, commercially available CST3633, anti-antibiotic antibody: R at 4 ℃ 1 time&D Systems, commercially available AF886, anti-c-myc antibody: cell Signaling Technology, commercially available code for CST9402 and anti- β -actin antibodies: sigma Aldrich, code A5316) overnight. After the membrane was further immersed in the antibody solution 2 times at room temperature for 1 hour, the target protein on the membrane was detected using ECL select (GE Healthcare Japan, product code RPN 2235).
(2) Results
The results of western blotting are shown in fig. 1.
Studies were conducted as to whether STX-1159 in combination with Alanib inhibited intracellular STAT3 or ALK. It is thought that phosphorylated STAT3, survivin and c-myc were reduced by STX-1159 alone, and in addition phosphorylated ALK, phosphorylated STAT3 and c-myc were reduced by Alanib alone. Phosphorylated STAT3 and c-myc (downstream factors of the STAT3 pathway and ALK pathway) are believed to achieve a further reduction by combining the two agents compared to each single agent. From this result, it is considered that the combination of STX-1159 with adriamine synergistically exerts a cell proliferation inhibitory effect by repeatedly inhibiting the STAT3 pathway.
Example 3 evaluation of the Effect of the combination of STX-1159 and mTOR inhibitor
(1) Setting of reference dose
Respectively taking human breast cancer cell strain MDA-MB-231 cell or MDA-MB-468 (in the case of rapamycin) as 2.5 × 103Per 100. mu.L/well or 1.0X 103Seeded at 100. mu.L/well in 96-well plates at 5% CO2And cultured at 37 ℃. On the next day after inoculation, each drug described in table 7 was added alone. DMSO was added to the blank in a manner to reach a final concentration of 0.05%. Then, at 5% CO2After culturing at 37 ℃ for 48 hours, the number of viable cells was evaluated by WST-8 analysis. That is, 10. mu.L of a WST-8 kit solution (Kishida Chemical, trade code 260-96162) was added to each well in 5% CO2And culturing at 37 ℃ for 1-2 hours. The absorbance at 450nm of water-soluble blue-violet formazan produced by the enzymatic activity of mitochondria in cells was measured using a microplate reader (Molecular Devices, model spectra max Plus). The number of viable cells was evaluated to calculate a 50% cell growth inhibitory concentration (hereinafter abbreviated as IC)50). The reference dose of each drug is based on IC50And the setting was made (table 6).
[ Table 6]
Reference dose
(2) Experimental method for WST-8 analysis
Respectively taking human breast cancer cell strain MDA-MB-231 cell or MDA-MB-468 (in the case of rapamycin) as 2.5 × 103Per 100. mu.L/well or 1.0X 103The cells were seeded in 96-well plates at a rate of 100. mu.L/well. CO at 37 deg.C2After incubation in the incubator for 24hr, the supernatant was discarded, and 80. mu.L of the medium for analysis was added. To this solution, 10. mu.L of mTOR inhibitor solution (the agent described in Table 7) was added after gradient dilution, followed by 10. mu.L of STX-1159 solution after gradient dilution. In CO2Standing in incubator for 48 hr, removing supernatant, and purifying with chloroformPBS (-) 100. mu.L was washed 1 time. A WST-8 solution diluted 10 times in an assay medium was added to 100. mu.L/well, and the absorbance at a wavelength of 450nm was measured with a microplate reader. CI is calculated using the measured value.
(3) Calculation of CI values
The effect of STX-1159 in combination with an mTOR inhibitor was analyzed by using Calcusyn software (BIOSOFT, Cambridge, UK). The grading of the effect of the combination based on CI uses the same criteria as in table 4 of example 1. The results are shown in Table 7.
(4) Results
STX-1159 showed a synergistic effect in combination with the mTOR inhibitors described in table 7 (table 7). Based on the results, it is suggested that the combination of STX-1159 with these agents is effective as a combination drug therapy.
[ Table 7]
Combination drug
CI
Coupling effect
GDC-0980(RG7422)
0.86
Mild synergistic effect
AZD2014
0.51
Synergistic effect
PI-103
0.60
Synergistic effect
KU-0063794
0.36
Synergistic effect
AZD8055
0.36
Synergistic effect
GSK1059615
0.64
Synergistic effect
OSI-027
0.49
Synergistic effect
PF-04691502
0.73
Moderate degree of synergistic effect
PF-05212384(PKI-587)
0.63
Synergistic effect
WAY-600
0.64
Synergistic effect
GSK2126458
0.63
Synergistic effect
PP242
0.84
Moderate degree of synergistic effect
WYE-125132
0.40
Synergistic effect
WYE-687
0.85
Moderate degree of synergistic effect
PP-121
0.88
Mild synergistic effect
Torin 2
0.66
Synergistic effect
Torin 1
0.68
Synergistic effect
INK 128
0.56
Synergistic effect
Rapamycin
0.79
Moderate degree of synergistic effect
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