WO2021027567A1 - Combinaison d'un antagoniste du récepteur ep4 et d'un inhibiteur de pd-1 pour le traitement du cancer - Google Patents

Combinaison d'un antagoniste du récepteur ep4 et d'un inhibiteur de pd-1 pour le traitement du cancer Download PDF

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WO2021027567A1
WO2021027567A1 PCT/CN2020/105282 CN2020105282W WO2021027567A1 WO 2021027567 A1 WO2021027567 A1 WO 2021027567A1 CN 2020105282 W CN2020105282 W CN 2020105282W WO 2021027567 A1 WO2021027567 A1 WO 2021027567A1
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ethyl
dihydro
pyran
thieno
benzoic acid
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PCT/CN2020/105282
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Chinese (zh)
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章涵堃
卢伟强
易正芳
刘明耀
杨俊杰
于薇薇
彭世鸿
周文波
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上海宇耀生物科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/78—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/78—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
    • C07D333/80—Seven-membered rings

Definitions

  • the present invention relates to the field of biomedicine, in particular to the combined use of EP4 receptor antagonists and PD-1 inhibitors for the treatment of cancer.
  • Cancer has become one of the most military killers threatening human life and health.
  • IARC International Agency for Research on Cancer
  • 18.1 million new cancer cases were added globally in 2018, and about 9.6 million people will die from Cancer, and the morbidity and mortality are still rising year by year.
  • my country's cancer incidence and death rate are the highest in the world, of which the number of new cases in my country accounts for 3.804 million and the number of deaths accounts for 2.296 million.
  • the current immune checkpoint inhibitors have many shortcomings in the treatment of cancer, especially malignant tumors, such as low objective response rate to advanced solid tumors (generally, objective remission rate ⁇ 30%); induce a variety of lethal side effects , Including colitis, neurotoxicity, pneumonia, hepatitis, pituitary inflammation, nephritis, adrenitis and heart disease. These factors cause the most deaths and are the most fatal side effects.
  • the purpose of the present invention is to develop drugs that can effectively treat cancer, especially malignant tumors.
  • the first aspect of the present invention provides a product portfolio including:
  • a first pharmaceutical composition said first pharmaceutical composition containing (a) a first active ingredient, said first active ingredient being an EP4 receptor antagonist, and a pharmaceutically acceptable carrier;
  • a second pharmaceutical composition the second pharmaceutical composition containing (b) a second active ingredient, the second active ingredient is a PD-1 inhibitor, and a pharmaceutically acceptable carrier;
  • first pharmaceutical composition and the second pharmaceutical composition are different pharmaceutical compositions, or the same pharmaceutical composition.
  • the EP4 receptor antagonist is a compound represented by formula I or a pharmaceutically acceptable salt or hydrate thereof:
  • Each is independently selected from the following group: C3-C6 carbocyclic ring, C6-C12 aryl group, five-membered or six-membered heteroaromatic ring containing one or more O, N, S atoms, wherein with May be optionally substituted by 1-3 R 5 groups;
  • X is a group selected from the following group: -O-, -S-, -N(R 7 )-;
  • Y is none, or a group selected from the following group: -CH 2 -, -O-, -S-, -SO-, -SO 2 -, -N(R 8 )-;
  • R 2 and R 3 are each independently selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or R 2 , R 3 and the carbon atom to which they are connected together form 3
  • the ring is a carbocyclic ring or a 3- to 6-membered heterocyclic ring having 1-3 heteroatoms selected from the group consisting of O, S or N (R 11 );
  • R 4 is selected from any one of the following groups: -COOR 12 (preferably -COOH, -COOCH 3 , -COOCH 2 CH 3 , -COOCH 2 CH 2 CH 3 , -COOCH(CH 3 ) 2 ), C( O)-N(Ra)(Rb), cyano group, tetrazolium group, phosphoric acid group, sulfonic acid group; wherein, Ra is selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted Substituted C1-C6 haloalkyl, substituted or unsubstituted C3-C6 cycloalkyl, and substituted or unsubstituted C1-C6 alkoxy; Rb is selected from the group consisting of H, -OH, -NH 2 , substituted or Unsubstituted C1-C6 alkyl, substituted or unsubstituted
  • Each R 5 and R 12 are each independently selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy (preferably methoxy, ethyl Oxy);
  • R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halo ring Alkyl, C6-C10 aryl, five-membered or six-membered heterocyclic aromatic group,
  • R 13 and R 14 are each independently selected from: H, C1-C6 alkyl (preferably methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, pentyl, hexyl), C1- C6 alkoxy, C6-C10 aryl, C1-C6 alkylene, -C6-C10 aryl.
  • C1-C6 alkyl preferably methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, pentyl, hexyl
  • C1- C6 alkoxy preferably methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, pentyl, hexyl
  • C1- C6 alkoxy preferably methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, pent
  • J, K, and L are each independently selected from the following group: -CH 2 -, -CH(CH 3 )-, -CH(CH 2 CH 3 )-, -C(CH 3 ) 2 -, -O-, -NR 16 -;
  • R 15 and R 16 are each independently selected from the following group: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl,
  • M, N, P, and Q are each independently selected from -CH 2 -, -CH(CH 3 )-, -CH(CH 2 CH 3 )-, -C(CH 3 ) 2 -, -O-, -NR 16 -;
  • R, S, T, U, and V are each independently selected from the following group: -CH 2 -, -CH(CH 3 )-, -CH(CH 2 CH 3 )-, -C(CH 3 ) 2- , -O-, -NR 16 -.
  • M, N, P and Q form a cyclic structure, or between M and Q, between M and P, or between N and Q, form a bridged ring structure composed of 0-4 carbon atoms.
  • R, S, T, U and V form a ring structure, or any two of R, S, T, U and V form a bridged ring structure composed of 0-4 carbon atoms .
  • X is -S-.
  • R 4 is selected from any one of the following groups: -COOR 12 (preferably -COOH, -COOCH 3 , -COOCH 2 CH 3 , -COOCH 2 CH 2 CH 3 , -COOCH (CH 3 ) 2 ), C(O)-N(Ra)(Rb), cyano group, tetrazolium group, phosphoric acid group, sulfonic acid group; wherein, Ra is selected from the following group: H, substituted or unsubstituted C1- C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, substituted or unsubstituted C3-C5 cycloalkyl, and substituted or unsubstituted C1-C4 alkoxy; Rb is selected from the following group: H, -OH , -NH 2 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C
  • Each is independently selected from the following group: C3-C6 carbocyclic ring, C6-C10 aromatic ring, five-membered or six-membered heteroaromatic ring containing one or more O, N, S atoms, wherein with May be optionally substituted with 1-3 R 5 groups.
  • the halogen includes F, Cl, Br or I.
  • Each is independently selected from the following group: benzene ring, ten-membered aromatic ring, five-membered or six-membered heteroaromatic ring containing one or more O, N, S atoms, wherein with May be optionally substituted with 1-3 R 5 groups.
  • It is a substituted or unsubstituted C5-C7 carbocyclic ring, or a substituted or unsubstituted 6-membered oxygen heterocyclic ring.
  • the EP4 receptor antagonist is selected from the following group:
  • the EP4 receptor antagonist is selected from the following group:
  • the EP4 receptor antagonist is selected from the following group:
  • the inhibitor is selected from the group consisting of antibodies, small molecule compounds, microRNA, siRNA, shRNA, or a combination thereof.
  • the weight ratio of the component (i) to the component (ii) is 1-200:1-100, preferably, 1-100:1-50, more preferably 10- 50: 1-10.
  • the content of the EP4 receptor antagonist in the product combination is 1%-99%, preferably, 10%-90%, more preferably, 50%-90%.
  • the content of the PD-1 inhibitor in the product combination is 1% to 99%, preferably, 1% to 60%, more preferably, 1% to 30%.
  • the component (i) and the component (ii) account for 0.01-99.99 wt% of the total weight of the product combination, preferably 0.1-90 wt%, more preferably Ground 1-80wt%.
  • the dosage form of the pharmaceutical composition includes an injection dosage form and an oral dosage form.
  • the oral dosage form includes tablets, capsules, films, and granules.
  • the dosage form of the pharmaceutical composition includes a sustained-release dosage form and a non-sustained-release dosage form.
  • composition which comprises:
  • the component (i) and component (ii) account for 0.01-99.99 wt% of the total weight of the kit, preferably 0.1-90 wt%, more preferably Ground 1-80wt%.
  • the composition also includes other drugs for treating malignant tumors.
  • the malignant tumor is selected from the group consisting of liver cancer, lung cancer, prostate cancer, skin cancer, colon cancer, pancreatic cancer, breast cancer, leukemia, lymphoma, ovarian cancer, stomach cancer, bladder cancer, and kidney cancer , Oral cancer, melanoma, esophageal cancer, lymphoma, cervical cancer, or a combination thereof.
  • the malignant tumor highly expresses PD-1.
  • the malignant tumor has a low expression of PD-1.
  • the malignant tumor highly expresses PD-L1.
  • the malignant tumor has low PD-L1 expression.
  • the other drugs for the treatment of malignant tumors are selected from the group consisting of CTLA4 antibody, PD-L1 antibody, nimustine, carmustine, cyclic ammonium phosphate, mustard, and deoxyfluuria Glycosides, 5-fluorouracil, 6-mercaptopurine, thioguanine, cytarabine, gemcitabine, carmofur, hydroxyurea, methotrexate, ufodine, amcitabine, actinomycin D, doxorubicin Bicin, daunorubicin, epirubicin, mitomycin, irinotecan, harringtonine, hydroxycamptothecin, vinorelbine, taxotere, topotecan, vincristine, Niposide, Etoposide, Atamestane, Anastrozole, Amluminide, Letrozole, Formestane, Metasterone, Carboplatin, Cisplatin, dacarba
  • the third aspect of the present invention provides a medicine kit including:
  • first container and the second container are the same or different containers.
  • the medicine in the first container is a single preparation containing an EP4 receptor antagonist.
  • the medicine in the second container is a unilateral preparation containing a PD-1 inhibitor.
  • the dosage form of the drug is an oral dosage form or an injection dosage form.
  • the kit also contains instructions.
  • the description records one or more descriptions selected from the following group:
  • EP4 receptor antagonists have the function of relieving chronic inflammation and pain mediated by the PGE2-EP4 signaling pathway.
  • the fourth aspect of the present invention provides the use of a combination comprising an EP4 receptor antagonist and a PD-1 inhibitor for preparing a pharmaceutical composition or a kit, and the pharmaceutical composition or a kit is used for Treat malignant tumors.
  • the malignant tumor is selected from the group consisting of liver cancer, lung cancer, prostate cancer, skin cancer, colon cancer, pancreatic cancer, breast cancer, leukemia, lymphoma, ovarian cancer, stomach cancer, bladder cancer, and kidney cancer , Oral cancer, melanoma, esophageal cancer, lymphoma, cervical cancer, or a combination thereof.
  • the malignant tumor highly expresses PD-1.
  • the malignant tumor has a low expression of PD-1.
  • the malignant tumor highly expresses PD-L1.
  • the malignant tumor has low PD-L1 expression.
  • the action concentration of the EP4 receptor antagonist is 1%-99%, preferably, 10%-90%, more preferably, 30%-70%.
  • the concentration of the PD-1 inhibitor is 1%-99%, preferably, 10%-90%, more preferably, 30%-70%.
  • the pharmaceutical composition or kit includes (a) an EP4 receptor antagonist and a PD-1 inhibitor; and (b) a pharmaceutically acceptable carrier.
  • the EP4 receptor antagonist and PD-1 inhibitor account for 0.01-99.99 wt% of the total weight of the pharmaceutical composition or kit, Preferably 0.1-90wt%, more preferably 1-80wt%.
  • the pharmaceutical composition or kit further includes other drugs for treating malignant tumors.
  • the other drugs for the treatment of malignant tumors are selected from the group consisting of nimustine, carmustine, cyclic ammonium phosphate, mustard, deoxyfluridine, 5-fluorouracil, 6- Mercaptopurine, thioguanine, cytarabine, gemcitabine, carmofur, hydroxyurea, methotrexate, ufodine, amcitabine, actinomycin D, doxorubicin, daunorubicin, Epirubicin, Mitomycin, Irinotecan, Harringtonine, Hydrocamptothecin, Vinorelbine, Taxotere, Topotecan, Vincristine, Teniposide, Etoposide, Atamestane, Anastrozole, Aluminide, Letrozole, Formestane, Metasterone, Carboplatin, Cisplatin, dacarbazine, Oxaliplatin, Loxadine, Coplatin, Mitoxantron
  • the fifth aspect of the present invention provides a method for treating malignant tumors, including:
  • EP4 receptor antagonists and PD-1 inhibitors or the product combination according to the first aspect of the present invention or the composition according to the second aspect of the present invention or the kit according to the third aspect of the present invention to a subject in need .
  • the subject includes a human or non-human mammal suffering from a malignant tumor.
  • the non-human mammals include rodents and primates, preferably mice, rats, rabbits, and monkeys.
  • the administration dose of the EP4 receptor antagonist is 1-250 mg/kg body weight, preferably 1-200 mg/kg body weight, and most preferably 1-100 mg/kg body weight.
  • the administration dose of the PD-1 inhibitor is 0.1-100 mg/kg body weight, preferably 1-50 mg/kg body weight, and most preferably 1-10 mg/kg body weight.
  • the application frequency of the EP4 receptor antagonist is 1 to 5 times/day, preferably 1 to 2 times/day.
  • the administration time of the EP4 receptor antagonist is 1 to 2000 days, preferably 1 to 700 days, and most preferably 1 to 365 days.
  • the frequency of administration of the PD-1 inhibitor is 0.1-4 per week per time, preferably once every two weeks.
  • the administration time of the PD-1 inhibitor is 1-2000 days, preferably 1-700 days, and most preferably 1-365 days.
  • the EP4 receptor antagonist and PD-1 inhibitor are administered simultaneously or sequentially.
  • Figure 1 shows the inhibitory results of compound YJ114 and PD-1 in combination with a mouse CT26 colon cancer tumor model:
  • Figure 2 shows the inhibitory results of compound YJ114 and PD-1 in combination with mouse MC38 colon cancer tumor model:
  • A represents the volume change of subcutaneous tumor bearing mice
  • B represents the weight change of mice
  • C represents the tumor weight distribution on the 20th day.
  • Figure 3 shows the inhibitory results of compound YJ114 and PD-1 in combination with AOM/DSS model induced mouse orthotopic colon cancer tumor model:
  • A represents the construction of mouse orthotopic tumor model and dosing plan
  • B represents the distribution and size of tumors in the colon
  • C represents the distribution of the number of tumors in each mouse
  • D represents the length of the colorectal.
  • Figure 4 shows the inhibitory results of compound YJ114 and PD-1 in combination with mouse RM-1 prostate cancer model:
  • Figure 5 shows the inhibitory effect of compound YJ114 in combination with PD-1 on mouse MFC gastric cancer model:
  • A represents the change of subcutaneous tumor-bearing mouse volume
  • B represents the tumor elimination rate
  • C represents the mouse survival curve obtained by using the tumor volume exceeding 2000 mm 3 as the mouse death criterion
  • D represents the weight change of the mouse.
  • the present inventors unexpectedly discovered for the first time that the combination of the EP4 receptor antagonist and PD-1 inhibitor of the present invention can effectively treat malignant tumors and has a synergistic effect. On this basis, the inventor completed the present invention.
  • C3-C6 carbocyclic ring or the term “C4-C7 carbocyclic ring” refers to a saturated or unsaturated ring composed of 3 to 6 carbon atoms or 4 to 7 carbon atoms, including monocyclic rings , Bicyclic, spiro or bridged ring, such as 6-membered alicyclic ring.
  • C6-C12 aromatic ring refers to a monovalent aromatic carbocyclic group of 6 to 12 carbon atoms, which has a single ring (such as phenyl) or a condensed ring (such as naphthyl or anthracenyl) if The connection point is on the aromatic carbon atom, and the fused ring may be non-aromatic (such as 2-benzoxazolone, 2H-1,4-benzoxazine-3(4H)-keto-7-yl, etc.).
  • the substituted or unsubstituted C6-C12 aromatic ring is selected from the following group: ortho-substituted phenyl, meta-substituted phenyl, and para-substituted phenyl.
  • Preferred aryl groups include phenyl and naphthyl.
  • the term includes substituted or unsubstituted forms, where the substituents are as defined above.
  • the substituent of the substituted phenyl group is selected from the following group: halogen, hydroxy, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, tert-butoxy, trifluoromethyl, or Its combination.
  • C6-C10 aromatic ring refers to a monovalent aromatic carbocyclic group of 6 to 10 carbon atoms, which has a single ring (such as phenyl) or a condensed ring (such as naphthyl or anthracenyl) if The connection point is on the aromatic carbon atom, and the fused ring may be non-aromatic (such as 2-benzoxazolone, 2H-1,4-benzoxazine-3(4H)-keto-7-yl, etc.).
  • the substituted or unsubstituted C6-C10 aromatic ring is selected from the following group: ortho-substituted phenyl, meta-substituted phenyl, and para-substituted phenyl.
  • Preferred aryl groups include phenyl and naphthyl.
  • the term includes substituted or unsubstituted forms, where the substituents are as defined above.
  • the substituent of the substituted phenyl group is selected from the following group: halogen, hydroxy, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, tert-butoxy, trifluoromethyl, or Its combination.
  • five- or six-membered heteroaromatic ring refers to a 5- to 6-membered aromatic ring having one or more heteroatoms selected from nitrogen, oxygen or sulfur, for example, pyridine, pyrimidine, thiazole, isothiazole, furan , Thiophene, pyrrole.
  • C1-C6 alkyl refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, including, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl , Sec-butyl, tert-butyl, pentyl and hexyl groups; preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
  • C1-C4 alkyl refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms, including, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl , Sec-butyl, tert-butyl, etc.
  • C1-C6 alkylene refers to a linear or branched alkylene group having 1 to 6 carbon atoms, including but not limited to methylene, ethylene, propylene, isopropylene, Butylene, isobutylene, sec-butylene, tert-butylene, pentylene and hexylene, etc.; preferably ethylene, propylene, isopropylene, butylene, isobutylene, ethylene Sec-butyl and tert-butylene.
  • C2-C6 alkenylene refers to a straight or branched chain alkenylene group having 2 to 6 carbon atoms containing a double bond, including but not limited to vinylene, propenylene, butenylene , Isobutenylene, pentenylene and hexenylene, etc.
  • C2-C6 alkynylene refers to a straight-chain or branched alkynylene group with 2 to 6 carbon atoms containing a triple bond, and includes, without limitation, ethynylene, propynylene, butynylene Group, isobutynylene, pentynylene and hexynylene, etc.
  • C 3 -C 6 cycloalkyl refers to a cyclic alkyl group having 3 to 6 carbon atoms in the ring, and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • C 3 -C 5 cycloalkyl refers to a cyclic alkyl group having 3 to 5 carbon atoms in the ring, and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • C6-C10 aryl group refers to an aromatic ring group having 6 to 10 carbon atoms that does not contain a hetero atom in the ring, such as a phenyl group and the like.
  • C1-C6 haloalkyl and “C1-6 halocycloalkyl” refer to a group in which the hydrogen on an alkyl group or a cycloalkyl group is replaced by one or more halogen atoms, and includes, without limitation, -CHF 2 , Chlorocyclopropyl, etc.
  • C1-C4 haloalkyl and “C1-4 halocycloalkyl” refer to a group in which the hydrogen on an alkyl group or a cycloalkyl group is replaced by one or more halogen atoms, including without limitation -CHF 2 , Chlorocyclopropyl, etc.
  • C1-C6 alkoxy group refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, and includes, without limitation, methoxy, ethoxy, propoxy, and isopropoxy And butoxy and so on.
  • C1-C4 alkoxy group refers to a straight or branched chain alkoxy group having 1 to 4 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, and isopropoxy And butoxy and so on.
  • halogenated C1-C6 alkoxy group refers to a group in which the hydrogen on the alkoxy group is replaced by one or more halogen atoms.
  • halogenated C1-C4 alkoxy group refers to a group in which the hydrogen on the alkoxy group is replaced by one or more halogen atoms.
  • halogen refers to fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.
  • the compounds of the present invention may contain one or more asymmetric centers, and therefore appear as racemates, racemic mixtures, single enantiomers, diastereomeric compounds, and single diastereomers.
  • the asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible mixtures of optical isomers and diastereomers and pure or partially pure compounds are included within the scope of the present invention.
  • the present invention includes all isomeric forms of the compounds.
  • the PD-1/PD-L1 signaling pathway is a key signaling pathway that negatively regulates T cell activation.
  • TNF- ⁇ interferon- ⁇
  • cytokines induce PD-L1 expression on macrophages, T, B cells and tumor cells through a series of signal transduction processes, and then interact with PD-1 receptors on T cells to cause T cell Inactivation and apoptosis promote the occurrence and development of tumor cells.
  • PD-1/PD-L1 pathway inhibitors can block the binding of PD-1 and PD-L1 and block negative regulatory signals, thereby restoring the killing ability of tumor-killing T cells, thereby enhancing the immune response to tumor cells.
  • Prostaglandin E2 Prostaglandin E 2 , PGE 2 .
  • Prostaglandin E2 (Prostaglandin E 2 , PGE 2 ) is the most abundant and widely distributed prostaglandin subtype in the human body. It participates in the regulation of many physiological and pathological processes including inflammation, pain, kidney function, cardiovascular system, lung function, and cancer.
  • PGE 2 binds to four different subtypes of G protein-coupled receptors EP1, EP2, EP3, EP4 (also known as PTGER1, PTGER2, PTGER2 and PTGER4) on the cell surface in an autocrine or paracrine manner, and these G Protein coupled receptor subtypes exert their biological effects by coupling different G proteins to activate different downstream signaling pathways.
  • EP2 and EP4 receptor subtypes mediate downstream signals by coupling with G s protein, their amino acid sequences have only 31% homology and there are certain structural differences, so their main physiological functions are similar. Place, but there are also many differences.
  • EP4 receptor antagonist As used herein, the "EP4 receptor antagonist", “active ingredient of the present invention”, and “compound of formula I” are used interchangeably, and all refer to those that can be used in combination with PD-1 inhibitors to synergistically treat malignant tumors. Effective compound
  • Each is independently selected from the following group: C3-C6 carbocyclic ring, C6-C12 aryl group, five-membered or six-membered heteroaromatic ring containing one or more O, N, S atoms, wherein with May be optionally substituted by 1-3 R 5 groups;
  • X is a group selected from the following group: -O-, -S-, -N(R 7 )-;
  • Y is none, or a group selected from the following group: -CH 2 -, -O-, -S-, -SO-, -SO 2 -, -N(R 8 )-;
  • R 2 and R 3 are each independently selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or R 2 , R 3 and the carbon atom to which they are connected together form 3
  • the ring is a carbocyclic ring or a 3- to 6-membered heterocyclic ring having 1-3 heteroatoms selected from the group consisting of O, S or N (R 11 );
  • R 4 is selected from any one of the following groups: -COOR 12 (preferably -COOH, -COOCH 3 , -COOCH 2 CH 3 , -COOCH 2 CH 2 CH 3 , -COOCH(CH 3 ) 2 ), C( O)-N(Ra)(Rb), cyano group, tetrazolium group, phosphoric acid group, sulfonic acid group; wherein, Ra is selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted Substituted C1-C6 haloalkyl, substituted or unsubstituted C3-C6 cycloalkyl, and substituted or unsubstituted C1-C6 alkoxy; Rb is selected from the group consisting of H, -OH, -NH 2 , substituted or Unsubstituted C1-C6 alkyl, substituted or unsubstituted
  • Each R 5 and R 12 are each independently selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy (preferably methoxy, ethyl Oxy);
  • R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halo ring Alkyl, C6-C10 aryl, five-membered or six-membered heterocyclic aromatic group,
  • R 13 and R 14 are each independently selected from: H, C1-C6 alkyl (preferably methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, pentyl, hexyl), C1- C6 alkoxy, C6-C10 aryl, C1-C6 alkylene, -C6-C10 aryl.
  • C1-C6 alkyl preferably methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, pentyl, hexyl
  • C1- C6 alkoxy preferably methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, pentyl, hexyl
  • C1- C6 alkoxy preferably methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, pent
  • the compound of the present invention is selected from the following group:
  • a particularly preferred class of compounds of formula I is selected from the following group:
  • a pharmaceutically acceptable salt of the compound of formula I is also included.
  • pharmaceutically acceptable salt refers to a salt formed by the compound of the present invention and an acid or a base suitable for use as a medicine.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts are the salts of the compounds of this invention with acids.
  • Acids suitable for salt formation include but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, toluenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • composition includes (a1) a first active ingredient, the first active ingredient being an EP4 receptor antagonist; and (a2) a second active ingredient, the second active ingredient being PD-1 Inhibitor; and (b) a pharmaceutically acceptable carrier.
  • the composition includes a pharmaceutical composition, a food composition or a health care product composition.
  • the active ingredient of the present invention can be formulated in a non-toxic, inert and pharmaceutically acceptable carrier medium.
  • the formulated pharmaceutical composition can be administered by conventional routes, including (but not limited to): oral, intramuscular, intraperitoneal, intravenous, subcutaneous, intradermal, or topical administration.
  • the present invention also provides a pharmaceutical composition, which contains a safe and effective amount of the active ingredient of the present invention and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutically acceptable carrier or excipient include (but are not limited to): saline, buffer, glucose, water, glycerol, ethanol, and combinations thereof.
  • the pharmaceutical preparation should match the mode of administration.
  • the pharmaceutical composition of the present invention can be prepared in the form of injection, for example, prepared by conventional methods with physiological saline or an aqueous solution containing glucose and other adjuvants.
  • Pharmaceutical compositions such as tablets and capsules can be prepared by conventional methods.
  • Pharmaceutical compositions such as injections, solutions, tablets and capsules should be manufactured under sterile conditions.
  • the dosage of the active ingredient is a therapeutically effective dosage, for example, about 1 microgram-10 mg/kg body weight per day.
  • the dosage of the EP4 receptor antagonist can be: 0.1-2000 mg per day for adults, preferably 1-300 mg/day .
  • the dosage of PD-1 inhibitor may be 0.1-2000 mg every two weeks for adults, preferably 1-300 mg/two weeks.
  • As a co-treatment drug for malignant tumors it can be made into oral and non-oral preparations.
  • Oral administration can be made into common dosage forms such as tablets, powders, granules, capsules, etc.
  • the excipients used can be one or more of starch, lactose, sucrose, mannose, and hydroxymethyl cellulose.
  • the disintegrant can be one or more of potato starch and hydroxymethyl cellulose.
  • the binder can be one or more of gum arabic, corn starch, gelatin, dextrin and the like.
  • oral preparations can also be made into emulsions, syrups and the like.
  • Non-oral preparations can be made into injections, which can be made into injections with water for injection, physiological saline, and glucose water, or a certain proportion of ethanol, propanol, ethylene glycol, etc. can be added to it.
  • it can also be made into common dosage forms such as nasal drops, sprays, rectal suppositories, and rectal retention enema.
  • the active ingredient of the present invention is also particularly suitable for other malignant tumor treatment drugs (such as nimustine, carmustine, cyclic ammonium phosphate, mustard, deoxyfluridine, 5-fluorouracil, 6-mercapto Purine, thioguanine, cytarabine, gemcitabine, carmofur, hydroxyurea, methotrexate, ufodine, amcitabine, actinomycin D, doxorubicin, daunorubicin, table Rubicin, mitomycin, irinotecan, harringtonine, hydroxycamptothecin, vinorelbine, taxotere, topotecan, vincristine, teniposide, etoposide, a Tametan, anastrozole, aminoglutamin, letrozole, formestane, metgestrol, carboplatin, cisplatin, dacarbazine, oxaliplatin, leroxadine, coplatin
  • the present invention also provides a medicine box, which contains:
  • first container and the second container are the same or different containers.
  • the preparation containing an EP4 receptor antagonist may be a unit dosage form containing an EP4 receptor antagonist, and the preparation containing a PD-1 inhibitor may be a unit dosage form containing a PD-1 inhibitor.
  • unit dosage form refers to the preparation of a composition into a dosage form required for single administration for the convenience of taking, including but not limited to various solid dosage forms (such as tablets), liquid dosage forms, capsules, and sustained release Agent.
  • the instructions describe the following method of use:
  • the preparation of the present invention can be taken three times a day to once every twenty days, or once every ten days in a sustained-release manner.
  • the preferred way is to take it once a day, because it facilitates the patient's adherence, thereby significantly improving the patient's compliance with medication.
  • the total daily dose in most cases should be lower (or equal to or slightly greater than) the daily daily dose of each single drug in most cases.
  • the effective dose of the active ingredient used can vary depending on the mode of administration and the expected dose. The severity of the disease to be treated will vary.
  • the present invention finds for the first time that the combined use of the EP4 receptor antagonist of the present invention and PD-1 antibody has a significantly better inhibitory effect on malignant tumor models than that of PD-1 in the single-agent group. It was detected in multiple mouse tumor models The PD-1 single-agent group can inhibit tumor growth to a certain extent, but with the extension of the treatment time, the tumor volume continues to increase, while the tumor volume in the combined drug group gradually shrinks or even subsides, achieving complete remission and greatly prolonging the tumor. The survival period of the mouse has no effect on the weight of the mouse, indicating that the combination of the EP4 receptor antagonist and PD-1 inhibitor of the present invention has achieved a significant synergistic anti-tumor effect, and has no obvious toxic and side effects on the mouse.
  • EP4 receptor antagonist YJ101-YJ131 of the present invention see Chinese Patent Application CN201711206672.8.
  • the preparation process of EP4 receptor antagonist YJ132-YJ155 is further illustrated in conjunction with the examples.
  • Tetrahydro-4H-pyran-4-one (2.00g, 20.0mmol), ethyl cyanoacetate (2.50g, 22.0mmol) and sulfur (704mg, 22.0mmol) were dissolved in 30.0mL ethanol, and then added to the solution Morpholine (1.74g, 20.0mmol) was added to it, and the mixture was stirred overnight at 50°C. The reaction was detected by TLC.
  • reaction solution was adjusted to acidic with 2M HCl, and then used Extract with ethyl acetate and water, evaporate the organic phase, and purify by column chromatography to obtain a white solid, namely 2-(3,5-difluorobenzyl)-4,7-dihydro-5H-thieno[2,3- c] Pyran-3-carboxylic acid (72 mg, yield 96%).
  • reaction solution was adjusted to acidic with 2M HCl, extracted with water and ethyl acetate, the organic phase was evaporated to dryness, and column chromatography was purified to obtain a white solid, which is the final product YJ132 (38mg, yield Rate 61%).
  • reaction solution was adjusted to acidity with 2M HCl, extracted with water and ethyl acetate, and the organic phase was evaporated to dryness. Purification by column chromatography A white solid was obtained, the final product YJ137 (39 mg, yield 66%).
  • the 3,5-difluorobenzaldehyde was replaced with 4-fluorobenzaldehyde, and the compound YJ132 was prepared according to the method for preparing compound YJ132 without the last step of hydrolysis, to obtain compound YJ146 (the yield of the last step was 76%).
  • YJ146 was added to the methanol filtrate of fresh hydroxylamine, and then KOH was added. The reaction was stirred at room temperature for 30 minutes, extracted with saturated ammonium chloride and ethyl acetate, and column chromatography was used to obtain compound YJ151 (the yield of the final reaction was 55%).
  • Example 2 The inhibitory effect of the compound YJ114 of the present invention in combination with PD-1 antibody on the mouse CT26 colon cancer tumor model
  • the dosage of YJ114 is 75mg/kg/d, and the way of administration is oral; the dosage of PD-1 antibody is 50 ⁇ g/head, twice a week, and the way of administration is abdominal cavity.
  • the administration cycle is 20 days. The tumor size and body weight changes of the mice were measured and recorded every two days.
  • mice The tumor volume of 8 out of 12 mice was reduced and disappeared, and complete remission was obtained (control group: 0/ 12; YJ114 single-drug group: 2/12; PD-1 antibody single-drug group: 4/12; YJ114+PD-1 antibody combination group: 8/12), and there is no adverse effect on the weight of mice, indicating The combined use of YJ114 and PD-1 antibody has no obvious side effects on mice.
  • Example 3 The inhibitory effect of the compound YJ114 of the present invention in combination with PD-1 antibody on mouse MC38 colon cancer tumor model
  • the dosage of YJ114 is 75mg/kg/d, and the way of administration is oral; the dosage of PD-1 antibody is 50 ⁇ g/head, twice a week, and the way of administration is abdominal cavity.
  • the administration period is 18 days. The tumor size and body weight changes of the mice were measured and recorded every two days.
  • both YJ114 and PD-1 antibody single-drug group can inhibit tumor growth to a certain extent, and the therapeutic effect of PD-1 antibody single-drug group is similar to that of YJ114 administration.
  • the efficacy of the group is similar.
  • the anti-tumor growth effect of the combination of YJ114 and PD-1 antibody is better than that of the two groups of single drugs.
  • the tumor volume of 3 out of 8 mice was reduced and disappeared, and the tumor was completely relieved.
  • the weight of the mice did not have any adverse effects, and the tumors in the other groups did not disappear completely.
  • the tumor tissue weight of each group of mice was weighed, and the statistical results were similar to the tumor volume.
  • the tumor growth inhibitory effect of the combined drug group was the most obvious, and there were no obvious toxic and side effects on mice.
  • Example 4 The inhibitory effect of the compound YJ114 of the present invention in combination with PD-1 antibody on the mouse orthotopic colon cancer tumor model induced by AOM/DSS model
  • Chronic inflammation has always been considered as one of the major causes of colorectal cancer and is accompanied by the occurrence and development of colorectal cancer.
  • These inflammatory cytokines such as IL-6, TNF, IL-1 ⁇ , IL-17 and various immune cells act as fertile soil in the environment of chronic inflammation, accumulating and promoting the development of colorectal cancer.
  • the AOM/DSS model is a model of local ulcerative colitis that is caused by chemical stimulation to damage the intestinal cells of mice, which further develops into a colon cancer model under the action of long-term inducers.
  • mice of C57BL/6 at 8-10 weeks were selected for a one-time intraperitoneal injection of 10 mg/kg AOM.
  • 2.5% of DSS was given water for 5 days and then replaced with normal drinking water for two weeks.
  • the round contains 2.5% DSS water supply cycle to construct a spontaneous mouse colon cancer model.
  • the dosage of YJ114 is 75mg/kg/d, and the way of administration is oral; the dosage of PD-1 antibody is 50 ⁇ g/head, twice a week, and the way of administration is intraperitoneal.
  • the administration period is 35 days. After the end of the dosing cycle, we took the colon of each group of mice and started to observe the formation and growth of tumors in the colon of the mice.
  • Example 5 The inhibitory effect of the compound YJ114 of the present invention in combination with PD-antibody on the mouse RM-1 prostate cancer model
  • the dose of YJ114 is 150 mg/kg/d, once a day.
  • the administration mode is oral; the administration dose of PD-1 antibody is 100 ⁇ g/bottle, twice a week, the administration mode is abdominal cavity, and the administration period is 17 days. Measure and record the changes in tumor length and width twice a week, and record the weight of the mice. After the experiment was over, the mice were killed by anesthesia, the subcutaneous tumor was stripped, weighed and photographed to record the tumor size.
  • Example 6 The inhibitory effect of the compound YJ114 of the present invention in combination with PD-1 antibody on the mouse MFC gastric cancer model
  • the dose of YJ114 is 150 mg/kg/d, once a day.
  • the method is oral; the dosage of PD1 antibody is 10 ⁇ g/bottle, twice a week, the method of administration is intraperitoneal, and the administration period is 27 days. Measure and record the changes in tumor length and width twice a week, and record the weight of the mice. After the experiment was over, the mice were killed by anesthesia, the subcutaneous tumor was stripped, weighed and photographed to record the tumor size.

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Abstract

L'invention concerne une combinaison d'un antagoniste du récepteur EP4 et d'un inhibiteur de PD-1 pour le traitement du cancer. L'invention concerne spécifiquement une combinaison de produits comprenant : (i) une première composition pharmaceutique comprenant (a) un premier ingrédient actif, le premier ingrédient actif comprenant un antagoniste du récepteur EP4 et un support pharmaceutiquement acceptable ; et (ii) une seconde composition pharmaceutique comprenant (b) un second ingrédient actif, le second ingrédient actif comprenant un inhibiteur de PD-1 et un support pharmaceutiquement acceptable. La première composition pharmaceutique et la seconde composition pharmaceutique sont des compositions pharmaceutiques différentes ou la même composition pharmaceutique. La combinaison de produits de la présente invention peut traiter de manière synergique des tumeurs malignes.
PCT/CN2020/105282 2019-08-15 2020-07-28 Combinaison d'un antagoniste du récepteur ep4 et d'un inhibiteur de pd-1 pour le traitement du cancer WO2021027567A1 (fr)

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CN110922415B (zh) * 2019-11-29 2021-12-07 四川大学 一种新型抗肿瘤活性化合物的合成与应用
CN113087719B (zh) * 2020-02-05 2024-01-26 上海宇耀生物科技有限公司 一种ep4受体拮抗剂的多晶型物及其制备方法与用途
CN113318103A (zh) * 2020-02-28 2021-08-31 华东师范大学 小分子化合物yj-5-41在制备抗胃癌药物中的应用
TW202227089A (zh) * 2020-11-30 2022-07-16 大陸商杭州阿諾生物醫藥科技有限公司 用於治療ｐｉｋ３ｃａ突變癌症的組合療法
CN112870194B (zh) * 2021-01-06 2022-06-21 广州医科大学附属肿瘤医院 治疗肝癌的组合物及其应用
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