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WO2023122945A1 - Composés polypeptidiques cycliques et leurs utilisations - Google Patents

Composés polypeptidiques cycliques et leurs utilisations Download PDF

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Publication number
WO2023122945A1
WO2023122945A1 PCT/CN2021/142028 CN2021142028W WO2023122945A1 WO 2023122945 A1 WO2023122945 A1 WO 2023122945A1 CN 2021142028 W CN2021142028 W CN 2021142028W WO 2023122945 A1 WO2023122945 A1 WO 2023122945A1
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Prior art keywords
group
alkyl
amino
substituted
cancer
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Chinese (zh)
Inventor
张哲峰
李海德
丁伟
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Zhihe Shandong Pharmaceutical Factory Co Ltd
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Zhihe Shandong Pharmaceutical Factory Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • 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
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids

Definitions

  • the present invention relates to a class of cyclic polypeptide compounds or pharmaceutically acceptable salts, esters, stereoisomers or solvates and pharmaceutical compositions thereof.
  • the present invention relates to but not limited to the technical field of medicinal chemistry, especially to the preparation of PD-1/ Use in a PD-L1 inhibitor medicament.
  • PD-1 programmed death receptor 1
  • CD279 cluster of differentiation 279
  • CD279 cluster of differentiation 279
  • PD-1 contains a membrane-proximal immune receptor tyrosine inhibitory unit and a membrane-remote tyrosine-based switch motif, which regulates the immune system by down-regulating the immune system's response to human cells and by inhibiting T-cell inflammatory activity and promote self-tolerance.
  • PD-1 is mainly expressed on immune cells such as activated CD4+T cells, CD8+T cells, B cells, NK cells, monocytes and dendritic cells, and promotes the maturation of T cells.
  • PD-L1 and PD-L2 Two ligands of PD-1 have been identified: PD-L1 and PD-L2.
  • PD-L1 is also a type I transmembrane protein, mainly expressed in antigen-presenting cells, B cells, T cells, epithelial cells, muscle cells, endothelial cells, etc.
  • PD-L1 ligand is sufficient in a variety of human cancers, and the interaction between PD-1 and PD-L1 leads to a decrease in tumor-infiltrating lymphocytes, a decrease in T cell receptor-mediated proliferation, in cancer, pregnancy, tissue transplantation and suppression of the immune system in autoimmune diseases.
  • the immune mechanism can be reversed by inhibiting the interaction of PD-1 and PD-L1.
  • Evidence has shown that interfering with or blocking the interaction of PD-1 and PD-L1 can attenuate or eliminate immune suppression.
  • the development of PD-1/PD-L1 inhibitors is mainly concentrated in the field of monoclonal antibodies.
  • Monoclonal antibodies such as Nivolumab, Lambrolizumab, Atezolizumab, Durvalumab, and Avelumab have been marketed at home and abroad, and can be used to treat non-small cell lung cancer, melanoma, etc. Diseases for which conventional treatment methods do not respond well have significant therapeutic effects.
  • the progress of peptide inhibitors in this field has been slow. Therefore, research and development of inhibitors that inhibit the interaction of PD-1/PD-L1 has important clinical significance.
  • the cyclic polypeptide molecules provided by this application have been proved to have the ability to block the interaction between PD-1 and PD-L1 in biochemical and cell-based experiments, and are a good class of PD-1/PD-L1 inhibitors.
  • the present invention relates to a class of PD-1/PD-L1 inhibitors of cyclic polypeptide compounds or pharmaceutically acceptable salts, esters, stereoisomers, solvates or prodrugs thereof for the treatment of malignant tumors.
  • the application provides a cyclic polypeptide compound represented by general formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug thereof:
  • R is hydrogen or methyl
  • R 0 is a group L 3 , or the following group substituted by a group L 3 :
  • the group L3 is one of the following groups: amino group, hydroxyl group;
  • X 1 and X 2 are each independently selected from oxygen, sulfur, nitrogen;
  • R 1 and R 2 are each independently selected from hydrogen, C1-C6 alkyl substituted by group L 4 , C2-C6 alkenyl substituted by group L 4 , C2-C6 substituted by group L 4 Alkynyl group, C3-C8 cycloalkyl group substituted by group L4 ; when X1 or X2 is oxygen or sulfur, correspondingly, R1 or R2 does not exist; said group L4 is the following One or more of the groups: C1-C6 alkoxy, C1-C8 alkoxycarbonyl, carboxyl, hydroxyl, amino, mono (C1-C6 alkyl) amino, bis (C1-C6 alkyl base) amino, -CONH 2 , phenyl, biphenyl, naphthyl;
  • R 3 and R 4 are each independently selected from: hydrogen, C1-C6 alkoxy, C1-C6 alkyl, nitro, cyano, hydroxyl, carboxyl, amino, halogen and trifluoromethyl;
  • At most one of Y 1 , Y 2 , Y 3 and Y 4 is a nitrogen atom, and the rest are carbon atoms;
  • At most one of Y 5 , Y 6 , Y 7 and Y 8 is a nitrogen atom, and the rest are carbon atoms;
  • R 5 is hydrogen, or substituted or unsubstituted C1-C6 alkyl; the substituent is selected from the group consisting of: H, C1-C6 alkoxy, C1-C8 alkoxycarbonyl, carboxyl, hydroxyl, amino, Single (C1-C6 alkyl) amino, bis (C1-C6 alkyl) amino, -CONH 2 , phenyl, biphenyl, naphthyl; in one embodiment, R is substituted or Unsubstituted C1-C3 alkyl; in some specific embodiments, the substituent is selected from carboxyl, hydroxyl, amino, amino substituted by group Z, -CONH 2 ;
  • R 8 is hydrogen, substituted or unsubstituted C1-C6 alkyl; the substituent is selected from: H, C1-C6 alkoxy, C1-C8 alkoxycarbonyl, carboxyl, hydroxyl, amino, mono (C1-C6 alkyl) amino group, bis (C1-C6 alkyl) amino group, -CONH 2 , phenyl, biphenyl, naphthyl;
  • R 9 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 aminoalkyl; the substituent is selected from the group Z, -CONH 2 or -CH 2 CONH 2 ;
  • R 10 is hydrogen, C5-C14 aromatic heterocycle, C1-C6 alkyl substituted by C5-C14 aromatic heterocycle, unsubstituted C1-C6 alkyl, or C1-C6 substituted by group L4 the alkyl group;
  • R 13 is hydrogen, substituted or unsubstituted C1-C6 alkyl; or when R 11 and R 12 and the atoms connected to it form a 4-7 membered ring together, R 13 and R 11 and R 12 and connected to it
  • the 4-7 membered rings formed by the atoms together form a condensed ring structure;
  • the substituents are selected from the group consisting of: H, C1-C6 alkoxy, C1-C8 alkoxycarbonyl, carboxyl, hydroxyl, amino, single ( C1-C6 alkyl) amino group, bis (C1-C6 alkyl) amino group, -CONH 2 , phenyl, biphenyl, naphthyl; preferably, the substituent is selected from H, carboxyl, hydroxyl , amino, -CONH 2 , phenyl, biphenyl, naphthyl;
  • R 6 and R 7 , R 11 and R 12 , and R 14 and R 15 each independently form a 4-7 membered heterocyclic ring with the atoms they are connected to, optionally, the 4-7 membered ring may be substituted by a substituent , can also form a fused ring or a spiro ring with other rings; the substituent is selected from H, carboxyl, hydroxyl, amino, cyano; optionally, the 4-7 membered heterocycle contains 1-3 members selected from N, A heterocyclic ring with O or S heteroatoms;
  • R 16 is the following groups: hydrogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, single (C1-C6 alkyl) amino, bis (C1- C6 alk) amino, phenyl, halogen;
  • Fragment L1 is independently selected from the following structural fragments:
  • Fragment L2 is independently selected from: (where Indicates that it is connected to a carbonyl group, means connecting to an amino group); wherein, R 19 , R 22 , R 26 , R 30 and R 31 are each independently: hydrogen, or a C1-C6 alkyl group;
  • R 17 , R 18 , R 20 and R 21 are each independently: hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C2-C6 alkenyl; or, R 17 and R 18 A carbon chain is connected to form an 8-16-membered ring with or without unsaturated bonds, or R 18 and R 20 are connected with a carbon chain to form an 8-16-membered ring with or without unsaturated bonds, or R 20 and R 21 Linked by a carbon chain to form an 8-16-membered ring with or without an unsaturated bond; when the end of segment L2 contains a ring and R20 is hydrogen, R18 and R21 are not butyl at the same time; the substituents are selected from H, carboxyl, hydroxyl, amino, -CONH 2 , phenyl, biphenyl, naphthyl;
  • R 23 , R 24 and R 25 are each independently: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, or R 24 and R 25 are connected by a carbon chain to form 8-16 membered rings with or without unsaturated bonds;
  • R 27 , R 28 and R 29 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, or R 27 and R 28 are linked by a carbon chain to form a Or an 8-16 membered ring without unsaturated bonds.
  • the group Z is one of the following groups, and the dotted line is the connecting bond:
  • the application provides a compound such as general formula (II):
  • the group R is hydrogen; in some embodiments, the group R is methyl;
  • group R is hydroxyl; in some embodiments, group R is amino; in some embodiments, group R is an amino acid residue substituted by group L; in some embodiments In, R 0 is an amino-substituted glycine residue; in some embodiments, R 0 is an amino-substituted alanine residue; in a specific embodiment, R 0 is In a specific embodiment, L 3 is amino;
  • both X and X are nitrogen; in some embodiments, both X and X are sulfur; in some embodiments, X is sulfur and X is nitrogen; in some embodiments In, X 1 is sulfur and X 2 is oxygen; in some embodiments, X 1 is nitrogen and X 2 is sulfur; in some embodiments, X 1 is nitrogen and X 2 is oxygen.
  • R 1 and R 2 are both H; in some embodiments, R 1 is selected from C1-C6 alkyl substituted by group L 4 ; said group L 4 is the following group One or more: C1-C6 alkoxy, C1-C6 alkoxycarbonyl, carboxyl, hydroxyl, amino, mono (C1-C6 alkyl) amino, bis (C1-C6 alkyl) amine Base, -CONH 2 , phenyl, biphenyl, naphthyl, R 2 is H; is C1-C6 alkyl substituted by carboxyl, R 2 is H;.
  • both R3 and R4 are hydrogen; in some embodiments, R3 and R4 can be one or both of the following groups: C1-C6 alkoxy, nitro, cyano radical, hydroxyl, carboxyl, amino, halogen, trifluoromethyl.
  • one of Y 1 , Y 2 , Y 3 , and Y 4 is a nitrogen atom; in some embodiments, all of Y 1 , Y 2 , Y 3 , and Y 4 are carbon atoms.
  • one of Y 5 , Y 6 , Y 7 , and Y 8 is a nitrogen atom; in some embodiments, Y 5 , Y 6 , Y 7 , and Y 8 are all carbon atoms; in some specific In the embodiment, Y 5 , Y 6 and Y 7 are all carbon atoms.
  • R 5 is hydrogen; in some embodiments, R 5 is an amino-substituted C1-C6 alkyl group; R 5 is an amino-substituted C1-C6 alkyl group F substituted; in some In more specific embodiments, R is the following group substituted with amino: methyl, ethyl, propyl; in some more specific embodiments , R is the following group substituted with amino substituted by group F: Methyl, ethyl, propyl.
  • R 6 and R 7 , R 11 and R 12 , R 14 and R 15 each independently form a 4-7 membered ring with the atoms they are attached to, and the 4-7 membered ring is selected from the following structures One or more of:
  • the substituent is selected from the group consisting of H, C1-C3 alkoxy, C1-C3 alkoxycarbonyl, carboxyl, hydroxyl, amino, mono(C1-C3 alkyl)amine, bis( C1-C3 alkyl) amino, -CONH 2 , phenyl, biphenyl, naphthyl; in some specific embodiments, R 8 is selected from methyl, ethyl, isopropyl, isobutyl, 2-methylpropyl, isopentyl, phenyl, biphenyl; In some embodiments, R is selected from the group consisting of hydroxyl, amino, amino, the following groups substituted with amino substituents: methyl, ethyl, Propyl; In some embodiments, the amine substituent of R is methylamino, dimethylamino.
  • R 9 is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 aminoalkyl; the substituent is selected from the group Z, -CONH 2 or -CH 2 CONH 2 .
  • R 9 is hydrogen; in some embodiments, R 9 is the following groups substituted with amino: methyl, ethyl, propyl, butyl; in some embodiments, R 9 is - The following groups substituted by CONH2 or -CH2 CONH2 substituted amino groups: methyl, ethyl, propyl, butyl; In some embodiments, R9 is the following groups substituted by amino groups substituted by group Z: methyl, ethyl base, propyl, butyl, preferably methyl.
  • R 10 is hydrogen; in some embodiments, R 10 is benzimidazole, indole; in some embodiments, R 10 is ethyl substituted with group L 4 .
  • R 13 is —CH 2 CONH 2 ; in some embodiments, R 1 3 forms a fused ring structure together with the 4-7 membered ring jointly formed by adjacent R 11 and R 12 and the atoms connected thereto.
  • R 16 is selected from the group consisting of hydrogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, mono(C1-C6 alkyl)amino, bis(C1- C6 alk)amino, phenyl, halogen, trifluoromethyl; in some embodiments, R16 is the following groups: hydrogen, hydroxyl, amino, C1-C3 alkyl, trifluoromethyl, C1-C3 Alkoxy, mono(C1-C3 alkyl)amino, bis(C1-C3 alkyl)amino, phenyl, halogen.
  • fragment L2 is: In some embodiments, fragment L2 is: In some embodiments, fragment L2 is: (where Indicates that it is connected to a carbonyl group, Indicates that it is connected to an amino group);
  • R 19 , R 22 , R 26 , R 30 and R 31 are each independently: hydrogen, or C1-C3 alkyl; in some embodiments, R 19 , R 22 , R 26 , R 30 and R 31 are each independently selected from: hydrogen, methyl.
  • fragment L2 is When, R 17 , R 18 , R 20 and R 21 are each independently selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, when R 20 is hydrogen, R 18 and R 21 are not n-butyl at the same time; in some embodiments, R 17 and R 18 are linked by a carbon chain to form an 8-16-membered ring with or without unsaturated bonds; in some embodiments, R 18 and R 20 is connected with a carbon chain to form an 8-16-membered ring with or without unsaturated bonds; in some embodiments, R 20 and R 21 are connected with a carbon chain to form an 8-16-membered ring with or without unsaturated bonds .
  • R 23 is selected from: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl; R 24 and R 25 are based on carbon The chains are connected to form 8-16 membered rings with or without unsaturated bonds; the substituents are selected from H, carboxyl, hydroxyl, amino, -CONH 2 , phenyl, biphenyl, naphthyl; in some embodiments , R 23 , R 24 and R 25 are each independently selected from: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; in some embodiments, R 24 and R 25 have a carbon chain Linked to form 8-16 membered rings with or without unsaturated bonds.
  • R 27 , R 28 and R 29 are each independently selected from: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; in some embodiments, R 27 and R 28 is connected by a carbon chain to form an 8-16-membered ring with or without unsaturated bonds; in some embodiments, R 29 is selected from: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, R 27 and R 28 are connected by carbon chains to form an 8-16-membered ring with or without unsaturated bonds.
  • group L is C1-C6 alkoxycarbonyl; in some embodiments , group L is carboxyl, hydroxyl, amino; in some embodiments, group L is dimethylamine or methylamino; in some embodiments, group L is phenyl, biphenyl, naphthyl.
  • group L3 is hydroxyl; in some embodiments, group L3 is amino.
  • the group Z is
  • the group Z is
  • the group Z is
  • the C1-C6 hydrocarbon group represents a saturated or unsaturated aliphatic hydrocarbon group with 1-6 carbon atoms, including a straight chain, branched chain or cyclic structure, for example including but not limited to: 1-6 Alkyl groups of 1-6 carbon atoms, hydrocarbon groups of 1-6 carbon atoms containing unsaturated bonds;
  • the C1-C6 alkoxy group represents a saturated or unsaturated aliphatic oxy group with 1-6 carbon atoms, including straight-chain, branched-chain or cyclic structures;
  • the C1-C6 alkoxycarbonyl group means that a carboxyl group forms an ester bond with a C1-C6 alkoxy group, including straight chain, branched chain or cyclic structures;
  • the C1-C6 alkyl group represents a saturated aliphatic hydrocarbon group with 1-6 carbon atoms, including straight chain, branched chain or cyclic structure, for example including but not limited to: methyl, ethyl , propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropylmethyl, 2-cyclopropyl-ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • the unsaturated aliphatic hydrocarbon group of 1-6 carbon atoms includes straight chain, branched chain or cyclic structure, for example including but not limited to: for example including but not limited to: vinyl, allyl Base, 1-butene-4-oxyl group, 3-hexyn-1-yl group, 1-enylpentyloxy group, 2-ethyl-1-ene-butyl group, (1-cyclopentene)methyl group, Cyclohexen-4-yl;
  • the saturated aliphatic oxy group with 1-6 carbon atoms includes straight chain, branched chain or cyclic structure, for example including but not limited to: methoxy, ethoxy, propoxy radical, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropylmethoxy, 2-cyclopropyl-ethoxy, cyclopropoxy, Cyclobutoxy, cyclopentyloxy, cyclohexyloxy, 2-ethylbutoxy.
  • the unsaturated aliphatic oxy group with 1-6 carbon atoms includes straight chain, branched chain or cyclic structure, for example including but not limited to: for example including but not limited to: ethyleneoxy , Allyloxy, 1-methyl-alkenyloxy, 1-butenyloxy, 4-hexyne-1-oxyl, 2-methyl-allyloxy, 1-enepentyloxy, 2 -Ethyl-1-ene-butoxy, (1-cyclopentene)methoxy, cyclohexene-4-oxyl.
  • the 8-16-membered ring with or without unsaturated bonds refers to a ring composed of 8-16 atoms, wherein the 8-16-membered ring with unsaturated bonds refers to at least There is a carbon-carbon double bond or a carbon-carbon triple bond, or both.
  • R 6 and R 7 , R 11 and R 12 , R 14 and R 15 each independently form a 4-7 membered ring with the atoms they are connected to, and the R (n) and R ( n+1) and the atoms connected to it together form a 4-7-membered ring, which means that R (n) and R (n+1) , and the nitrogen atom and carbon atom connected to it form a 4-7-membered ring together, Where n is 6, 11, 14.
  • the ring may be substituted by other substituents, or the ring and the substituent together form a fused ring or a spiro ring; except for the nitrogen atom, there may be a heteroatom (such as O, N, S) or no heteroatom on the ring; so
  • the substituents on the ring include but are not limited to the following groups: C1-C6 hydrocarbon group, C6-C12 aryl group, halogen, hydroxyl, amino, hydroxyl or amino-substituted C1-C6 hydrocarbon group.
  • the halogen refers to fluorine, chlorine, bromine, iodine; in some specific embodiments, it is preferably fluorine, chlorine, bromine.
  • the C5-C14 aromatic heterocycle represents an aromatic ring structure containing 5-14 atoms and at least one heteroatom, which may be a single ring, a double ring or a biphenyl aromatic heterocycle, Including but not limited to: thiophene, furan, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, triazole, thiadiazole, oxadiazole, tetrazole, thiatriazole, oxatriazole, pyridine, Pyrimidine, pyrazine, pyridazine, triazine, tetrazine, purine, benzoxazole, benzofuran, benzothiazole, benzothiadiazole, benzotriazole, benzimidazole, indole, (2- Pyridyl)benzene, (3-pyridyl)benzene, (4-pyr
  • the C6-C12 aryl group has an aromatic ring structure with 6-12 carbon atoms, including but not limited to: phenyl, naphthyl, biphenyl.
  • the compound in formula (I) or formula (II) or its pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug is used to develop PD-1/PD-L1 as the target point peptide inhibitors.
  • the prodrugs described in the compound of formula (I) include but are not limited to: X 1 and/or X 2 are nitrogen atoms, and when one or both of R 1 and R 2 are hydrogen, the nitrogen atom and -((CH 2 ) n3 -O) n4 -P(O)(OH) 2 Phosphoric acid prodrug formed by phase edge, wherein n3 and n4 are 1, 2, 3, 4 independently.
  • Such tumors include blood cancers, nervous system cancers, gastrointestinal cancers, esophageal cancers, urinary system cancers, lung cancers, liver cancers, and skin cancers; including but not limited to lymphoma, non-small cell lung cancer, small cell lung cancer, head and neck cell carcinoma , glioma, neuroblastoma, lung squamous cell carcinoma, lung adenocarcinoma, bladder cancer, gastric cancer, colon cancer, colorectal cancer, kidney cancer, bile duct cancer, gastric cancer, esophageal squamous cell carcinoma, ovarian cancer, pancreatic cancer, breast cancer , prostate cancer, liver cancer, brain cancer, melanoma, multiple myeloma, skin cancer, epithelial cell carcinoma, leukemia or cervical cancer, as well as metastatic lesions in other tissues or organs far from the primary site of the tumor.
  • lymphoma non-small cell lung cancer, small cell lung cancer, head and neck cell carcinoma , glio
  • the drugs for preventing or treating tumors described in the present invention are cancer immunotherapy drugs, cancer chemotherapy drugs or cancer targeted therapy drugs.
  • a pharmaceutical composition comprising a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is tablet, capsule, granule, powder, syrup, oral liquid or injection.
  • the present invention unexpectedly found that the compound obtained by structural modification of cyclic peptide in the prior art field can effectively bind PD-1/PD-L1, thereby blocking or inhibiting the combination of PD-1 and PD-L1, and blocking negative regulation Signal to restore the activity of T cells, and then enhance the immune response to treat tumors.
  • Figure 1 is a trend chart of the mouse subcutaneous tumor bearing (lung cancer) test.
  • the compound 3d obtained in the previous step was dissolved in 15mL of acetone, the reaction system was cooled to 0°C, and 573mg of the hydrochloride of compound 3e was slowly added, and 15mL of 10% sodium carbonate aqueous solution was added dropwise into the system. The system was reacted at 25°C for 24h. The system was concentrated to dryness, extracted with ethyl acetate, and washed successively with saturated sodium bicarbonate, water, and saturated brine. The organic phase was concentrated to dryness, and the crude product was separated by silica gel column chromatography to obtain 1.46 g of compound 3f, with a yield of 86%, ESI-MS (+): m/z 533.30 [M+H].
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • Embodiment 8 is a diagrammatic representation of Embodiment 8
  • Embodiment 9 is a diagrammatic representation of Embodiment 9:
  • DCM dichloromethane
  • swells Rink Amide-AM Resin resin dissolves Fmoc-Gly-OH in DMF solution, and couples to the resin under the action of condensing agent HBTU/DIEA or DIC/HOBt or PyBOP or other similar condensing agents , washing resin;
  • the resin is added to a DCM solution of 1% TFA (trifluoroacetic acid), and the resin is washed;
  • the resin was swollen in DCM, and the linear peptide was cyclized under the action of tris(2-carboxyethyl)phosphine (TCEP) and diisopropylethylamine (DIEA).
  • TCEP tris(2-carboxyethyl)phosphine
  • DIEA diisopropylethylamine
  • DCM dichloromethane
  • swells Rink Amide-AM Resin resin dissolves Fmoc-Gly-OH in DMF solution, and couples to the resin under the action of condensing agent HBTU/DIEA or DIC/HOBt or PyBOP or other similar condensing agents , washing resin;
  • the protected long aliphatic side chain (see the figure below) is coupled to the peptide chain.
  • the resin is added to a DCM solution of 1% TFA (trifluoroacetic acid), and the resin is washed;
  • the resin was swollen in DCM, and the linear peptide was cyclized under the action of tris(2-carboxyethyl)phosphine (TCEP) and diisopropylethylamine (DIEA).
  • TCEP tris(2-carboxyethyl)phosphine
  • DIEA diisopropylethylamine
  • PD-L1 Human PD-L1[28-8]SimpleStep Kit, Cat. No. ab214565
  • mice were subcutaneously inoculated with mouse LLC cells (mouse Lewis lung cancer cells). When the tumor volume reached 50-100 mm 3 , the mice were randomly divided into 6 groups, 5 mice in each group.
  • Group 1 was intravenously injected with normal saline as a blank control;
  • Group 2-5 was intravenously injected with normal saline solution (4 mg.kg -1 ) of the compound of the present invention once a day as the compound group;
  • Group 3 was injected intraperitoneally with mouse PD-L1 Monoclonal antibody (clone number 10F.9G2), dosed at 10 mg.kg -1 once every two days, served as the positive control group.
  • Embodiment 15 sepsis animal model test
  • mice were put back into the sterilized mouse cage and allowed to eat freely.
  • the surviving rats were randomly divided into 5 groups, with at least 6 animals in each group.
  • Group 1 was the blank control group (water for injection was given twice a day)
  • group 3 was the experimental drug group (groups DSC2312 and DSC2336 were given water for injection every day). 2 times, 700mg/kg each time, DSC2345 group was administered once every 2 days, 1g/kg each time)
  • group 1 was the antibiotic (cefetadine) group (administered 2 times a day, 200mg/kg each time) , observed for 6 weeks to investigate its survival rate.
  • the survival rate of blank control group was 14.2% (1/7), DSC2312 group was 62.5% (5/8), DSC2336 group was 42.9% (3/7), DSC2345 group was 57.1% (4/7), antibiotic (cephalosporin He set) group was 75% (6/8).
  • This test proves that the compound of the present invention has a therapeutic effect on sepsis in rats. At the same time, because its mechanism is significantly different from that of antibiotics and it inhibits PD-1 and PD-L1, it is understood that it exerts its unique pharmacological effect through the immune system.
  • mice were randomly divided into 4 groups, with at least 6 mice in each group.
  • Group 1 was the blank control group (administered water for injection once a day), and group 2 was the experimental drug group (group DSC2304 was administered once a day, each time 0.5mg/kg, DSC2343 group administered once every 2 days, every 0.75mg/kg), group 1 was Entecavir group (administered once a day, 0.07mg/kg each time), observed for 20 days to investigate its viral load .
  • the virus DNA content in the mouse serum was detected by PCR, and the level of the blank control group was still 10 4 to 10 5 copies/ml, the levels of the DSC2304 and DSC2343 groups were 10 3 to 10 4 respectively, and the levels of the entecavir group were 10 2 to 10 3 .
  • This test proves that the compound of the present invention has a therapeutic effect on chronic HBV, and may regulate the immune system by inhibiting the action of PD-1 and PD-L1 to exert its unique pharmacological effect.

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Abstract

L'invention concerne des composés polypeptidiques cycliques et leurs utilisations. Les composés polypeptidiques cycliques sont tels que représentés dans la formule (I), et les composés peuvent être utilisés en tant qu'inhibiteurs de PD-1/PD-L1.
PCT/CN2021/142028 2021-12-28 2021-12-28 Composés polypeptidiques cycliques et leurs utilisations Ceased WO2023122945A1 (fr)

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