CN-116963773-B - Compositions and methods for treating tumors

Abstract

To compositions and methods for treating tumors comprising administering an effective amount of one or more immune checkpoint inhibitors, and an effective amount of a PDE4 selective inhibitor. The composition and the method have remarkable tumor inhibiting effect.

Inventors

• XU NUO
• LIN JIAN

Assignees

• 浙江养生堂天然药物研究所有限公司

Dates

Publication Date

20260508

Application Date

20220120

Priority Date

20210121

Claims (10)

1. 1. Use of a PDE4 selective inhibitor in the manufacture of a medicament for inhibiting tumor metastasis, wherein the PDE4 selective inhibitor is roflumilast, for inhibiting metastasis of colon cancer or breast cancer.
2. 2. Use of a PDE4 selective inhibitor in the manufacture of a medicament for inhibiting tumor metastasis, wherein the PDE4 selective inhibitor is BPN14770, and the medicament is for inhibiting colon cancer metastasis.
3. 3. Use of a PDE4 selective inhibitor in the manufacture of a medicament for inhibiting tumour metastasis, wherein the PDE4 selective inhibitor is GSK256066, the medicament being for inhibiting colon cancer metastasis.
4. 4. Use of a PDE4 selective inhibitor in the manufacture of a medicament for inhibiting tumor metastasis, wherein the PDE4 selective inhibitor is dipyridamole, and the medicament is for inhibiting colon cancer metastasis.
5. 5. The use of any one of claims 1-4, wherein the medicament further comprises an immune checkpoint inhibitor.
6. 6. The use of claim 5, wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody or antigen-binding fragment thereof, or an anti-PD-1 antibody or antigen-binding fragment thereof.
7. 7. The use according to claim 5, wherein the immune checkpoint inhibitor is selected from the group consisting of nivolumab, pembrolizumab, BMS-936559, MPDL3280A, MEDI4736, AMP-224 and MSB0010718C.
8. 8. The use according to claim 6, wherein the antibody is selected from the group consisting of chimeric antibodies, humanized antibodies and fully human antibodies.
9. 9. The use according to claim 6, wherein the antigen binding fragment is selected from Fab, fv, scFv, fab 'and (Fab') 2 .
10. 10. The use of claim 5, wherein the mass ratio of the effective amount of PDE4 selective inhibitor to the effective amount of immune checkpoint inhibitor is from 9:1 to 1:4.

Description

Compositions and methods for treating tumors Technical Field The application relates to the field of biological medicine, in particular to a composition and a method for treating tumors. Background Malignant tumor is a disease which seriously jeopardizes human health, and global cancer statistics result in 2018 shows that 1819 ten thousand new cancer cases and 960 ten thousand cancer death cases exist in the world. Taking colorectal cancer as an example, colorectal cancer accounts for 10.2% of the total incidence of cancer and 9.2% of death, namely 185 ten thousand new cases and 88 die ten thousand deaths new cases of colorectal cancer are generated each year, and the new incidence of colon cancer in China is about 37 ten thousand. Clinical treatment of colorectal cancer is dominated by oxaliplatin, and clinical chemotherapy regimens have oxaliplatin in combination with Hildeda, and oxaliplatin in combination with fluorouracil, however these chemotherapy regimens have serious side effects such as damage to the digestive and blood systems, and often develop drug resistance phenomena. In addition, more than 30% of colon cancer patients in the clinic are insensitive to platinum chemotherapeutics. These all show that the chemotherapeutic drugs have different degrees of toxic and side effects or drug resistance defects while resisting tumors, and especially some tumor patients are insensitive to the chemotherapeutic drugs. Therefore, finding more effective antitumor drugs and methods is a major challenge to be solved. Disclosure of Invention The application provides a pharmaceutical combination and method for treating tumors, which essentially comprises administering an effective amount of a PDE4 (type 4 phosphodiesterase) selective inhibitor. In certain instances, the pharmaceutical combinations or methods of the application further comprise administering an effective amount of an immune checkpoint inhibitor. The pharmaceutical combination or method of the application has one or more of the following effects of 1) avoiding side effects of chemotherapy, 2) effectively inhibiting tumor (cell) growth, such as solid tumor (e.g. colorectal cancer), lymphoma and/or hematological tumor, 3) inhibiting tumor cell metastasis (e.g. inhibiting liver metastasis of tumor), 4) having no significant effect on other physiological indications (e.g. body weight) of the subject, and safety. The present application provides a pharmaceutical combination comprising: a) An effective amount of an immune checkpoint inhibitor, and B) An effective amount of a PDE4 selective inhibitor. In certain embodiments, wherein the PDE4 selective inhibitor comprises Apremilast、Crisaborole、Drotaverine、CC-1088、BPN14770、GSK356278、HT-0712、TAK-648、Zembrin、ASP9831、Etazolate、Piclamilast、Rolipram、Dipyridamole、Cilomilast、GSK256066、AWD12–281、Quinolyl oxazole、DC-TA-46、Filaminast and/or Glaucine. In certain embodiments, wherein the PDE4 selective inhibitor comprises a compound of formula I, a pharmaceutically acceptable salt thereof, or an N-oxide of pyridine or a salt thereof: Wherein one of R1 and R2 is hydrogen, C 1-C6 alkoxy, C 3-C7 cycloalkoxy, C 3-C7 cycloalkylmethoxy, benzyloxy, or C 1-C4 alkoxy substituted in whole or in part by fluorine, and the other of R1 and R2 is C 1-C4 alkoxy substituted in whole or in part by fluorine, and R3 is phenyl, pyridinyl, phenyl substituted by R31, R32 and R33, or pyridinyl substituted by R34, R35, R36 and R37, wherein R31 is hydroxy, halogen, cyano, carboxy, trifluoromethyl, C 1-C4 alkyl, C 1-C4 alkoxy, C 1-C4 alkoxycarbonyl, C 1-C4 alkylcarbonyl, C 1-C4 alkylcarbonyloxy, amino, mono-or di-C 1-C4 alkylamino or C 1-C4 alkylcarbonylamino, R32 is hydrogen, hydroxy, halogen, amino, trifluoromethyl, C 1-C4 alkyl or C 1-C4 alkoxy, R33 is hydrogen, halogen, C 1-C4 alkyl or C 1-C4 alkoxy, R34 is hydroxy, halogen, cyano, carboxy, C 1-C4 alkyl, C 1-C4 alkoxy, C 1-C4 alkoxycarbonyl or amino, R35 is hydrogen, halogen, amino or C 1-C4 alkyl, R36 is hydrogen or halogen, and R37 is hydrogen or halogen. In certain embodiments, wherein: R1 is hydrogen, C 1-C6 -alkoxy, C 3-C7 -cycloalkoxy, C 3-C7 -cycloalkylmethoxy, benzyloxy or C 1-C4 -alkoxy substituted in whole or in part by fluorine, R2 is C 1-C4 -alkoxy substituted in whole or in part by fluorine, and R3 is phenyl, pyridinyl, phenyl substituted by R31, R32 and R33 or pyridinyl substituted by R34, R35, R36 and R37, wherein R31 is hydroxy, halogen, cyano, carboxy, trifluoromethyl, C 1-C4 -alkyl, C 1-C4 -alkoxy, C 1-C4 -alkoxycarbonyl, C 1-C4 -alkylcarbonyl, C 1-C4 -alkylcarbonyloxy, amino, mono-or di-C 1-C4 -alkylamino or C 1-C4 -alkylcarbonylamino, R32 is hydrogen, hydroxy, halogen, amino, trifluoromethyl, C 1-C4 -alkyl or C 1-C4 -alkoxy, R33 is hydrogen, halogen, C 1-C4 -alkyl or C 1-C4 -alkoxy, R34 is hydroxy, halogen, cyano, carboxy, C 1-C4 -alkyl, C 1-C4 -alkoxy, C 1-C4 -alkoxycarbonyl or amino, R35 is hydrogen, halogen, amino or C 1-C4 -alkyl, R36 is hydrogen or halogen, and R37