WO2019034178A1 - Composé dimère de toxicité d'adn - Google Patents

Composé dimère de toxicité d'adn Download PDF

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WO2019034178A1
WO2019034178A1 PCT/CN2018/101216 CN2018101216W WO2019034178A1 WO 2019034178 A1 WO2019034178 A1 WO 2019034178A1 CN 2018101216 W CN2018101216 W CN 2018101216W WO 2019034178 A1 WO2019034178 A1 WO 2019034178A1
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group
alkyl
added
pharmaceutically acceptable
solvate
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PCT/CN2018/101216
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English (en)
Chinese (zh)
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朱义
李�杰
刘威加
万维李
卓识
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四川百利药业有限责任公司
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Publication of WO2019034178A1 publication Critical patent/WO2019034178A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to novel cytotoxic compounds and medicaments comprising these cytotoxic compounds and cell binding agents. More particularly, the present invention relates to novel benzodiazepine dimer compounds, derivatives thereof, and intermediates thereof which are pharmaceutically acceptable salts, which are useful as medicaments, especially as antiproliferative agents.
  • Benzodiazepine derivatives which have the ability to recognize and bind to specific DNA sequences, are highly potent interchain crosslinkers that react with guanine in the DNA minor groove to form DNA adducts that interfere with The processing of DNA is therefore used as an anti-tumor drug.
  • Benzodiazepine derivatives which have the ability to recognize and bind to specific DNA sequences, are highly potent interchain crosslinkers that react with guanine in the DNA minor groove to form DNA adducts that interfere with The processing of DNA is therefore used as an anti-tumor drug.
  • the DNA small groove alkylating agent of the 1-(chloromethyl)-2,3-dihydro-1H-benzo[e]indole (CBI) class is a potent cytotoxin (Atwell et al. (1999) J. Med. Chem., 42: 3400), and has been used as an effector unit for a variety of prodrugs designed for cancer therapy.
  • CBI and benzodiazepine derivatives have been linked together via an alkyl chain (Tercel et al. (2003) J. Med. Chem., 46: 2132-2151).
  • Imidazo[1,2-a]pyridine derivatives are powerful DNA binding units that have been used in the synthesis of anti-tumor antibiotics such as duocarmycins and exhibit very potent cytotoxicity. (Ronald C. Elgersma et al. (2015) Mol. Pharmaceutics. 12: 1813-1835).
  • benzodiazepine derivatives disclosed in the prior art are extremely toxic and toxic at very low doses, thus improving the lower toxicity and therapeutically active, high therapeutic window benzodiazepines. Subclass derivatives are very necessary.
  • the present invention aims to provide a cytotoxic benzodiazepine dimer derivative having a good therapeutic window.
  • the newly designed cytotoxic benzodiazepine dimer derivative has two functional groups, chloromethyl (CBI) and imine (PBD) or DNA-binding (DB) and imine (PBD).
  • CBI chloromethyl
  • PBD imine
  • DB DNA-binding
  • PBD DNA-binding
  • Chloromethyl is a prodrug structure that forms a three-membered ring structure into the body and can further undergo DNA alkylation. DNA-binding fragments have strong DNA binding.
  • the presence of these two functional groups enhances the crosslinking of the DNA.
  • the design of the present invention surprisingly found that the cytotoxic compound exhibited a much higher in vivo therapeutic index (ratio of the maximum tolerated dose to the lowest effective dose) compared to the benzodiazepine conjugates disclosed in the prior art.
  • the present invention provides a cytotoxic drug having the formula (I) or formula (II) or
  • Y is selected from one or more of H, halogen, C 1-4 alkyl, OR 4 , SR 4 , NR 4 R 5 , SO 2 R 4 , CONHR 4 , CN or COOR 4 , wherein R 4 and R 5 a hydrocarbon group selected from H, C 1-4 , a phenyl group or a substituted phenyl group;
  • X 2 is selected from halogen or OSO 2 R 5 , wherein R 5 may be independently selected from H, C 1-4 hydrocarbyl, phenyl or substituted phenyl;
  • X 1 is selected from O and NR 6 , wherein R 6 is selected from H, C 1-6 alkyl, one or more F substituted C 1-6 alkyl;
  • R 1 is selected from H,P(O) 3 H 2 , C(O)NR 7 R 8 , wherein R 7 and R 8 are selected from H, C 1-6 alkyl, one or more F substituted C 1 -6 alkyl, or R 7 and R 8 form a five- or six-membered heterocyclyl group;
  • R 3 is an optional substituent group.
  • R 2 is selected from H,P(O) 3 H 2 , C(O)NR 7 R 8 , wherein R 7 and R 8 are selected from H, C 1-6 alkyl, one or more F substituted C 1 -6 alkyl, or R 7 and R 8 form a five- or six-membered heterocyclyl group;
  • D 1 is selected from the following drug modules:
  • Double line between N and C Represents a single bond or a double bond, provided that when it is a double bond, R 9 is absent and R 10 is H, and when it is a single bond, R 9 is H or is selected from acetyl, trifluoroacetyl, uncle An amino-protecting moiety of butoxycarbonyl, benzyloxycarbonyl and 9-fluorenylmethoxycarbonyl;
  • R 10 is selected from OH, an ether represented by O R 11 , sulfite SO 3 - or OSO 3- , wherein R 11 is selected from the group consisting of 1 a linear, branched or cyclic alkyl, alkenyl or alkynyl group of -10 carbon atoms;
  • R 12 is selected from C 5-10 aryl optionally substituted by one or more substituents, wherein the substituent is selected from the group consisting of halogen, nitro, cyano, amino, ether, carboxyl, ester, C a 1-7 hydrocarbyl group, a C 3-7 heterocyclic group; when a single bond exists between C2 and C3,
  • R 12 is Wherein R 14 and R 15 are independently selected from the group consisting of H, F, C 1-4 saturated alkyl, C 2-3 alkenyl, the alkyl and alkenyl optionally substituted by a group selected from the group consisting of a C 1-4 alkyl amide group and a C 1-4 alkyl ester, or, when one of R 14 and R 15 is H, the other is selected from the group consisting of a nitrile and a C 1-4 alkyl ester;
  • Module D1" may be substituted by one or more R 13 wherein R 13 is selected from the group consisting of H, halogen, nitro, cyano, amino, ether, carboxyl, ester, C 1-7 hydrocarbyl, C 3-7 heterocyclyl ;
  • the drug, R3 is selected from the group consisting of H, OH, SH, NH 2 , N 3 , NO 2 , NO, CF 3 , CN, C(O)NH 2 , C(O)H, C(O )OH, halogen, R h , SR h , S(O)R h , S(O) 2 R h , S(O)OR h , S(O) 2 OR h , OS(O)R h , OS( O) 2 R h , OS(O)OR h , OS(O) 2 OR h , OR h , NHR h , N(R h )R i , + N(R h )(R i )R j , P( O)(OR h )(OR i ), OP(O)(OR h )(OR i ), SiR h R i R j , C(O)R h ,
  • R h , R i and R j are independently selected from H and optionally substituted C 1-15 alkyl, C 1-15 heteroalkyl, C 3-15 cycloalkyl, C 1-15 heterocycloalkane a group, a C 5-15 aryl group or a C 1-15 heteroaryl group.
  • T is selected from a C 2 -C 12 hydrocarbyl group, Z, (C 1 -C 6 alkylene)-Z-(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-Z- (C 1 -C 6 alkylene)-Z-(C 1 -C 6 alkylene), (C 1 -C 6 alkenylene)-Z-(C 1 -C 6 alkenylene), (C 1- C 6 alkynylene)-Z-(C 1 -C 6 alkynylene);
  • Z is independently selected from the group consisting of O, S, NR 1 , aryl and heteroaryl;
  • alkylene, alkenylene, aryl and heteroaryl groups are independent and optionally F, OH, O(C 1 -C 6 alkyl), NH 2 , NHCH 3 , N(CH 3 ) 2 and C 1 -C 6 alkyl substituted wherein the alkyl group is optionally substituted with one or more F;
  • the drug wherein X 1 is O, and R 1 is H;
  • the medicament wherein D1 is D1 ', the presence of a double bond between the N and C, the presence of a double bond between C2 and C3, and R 12 is methoxy substituted phenyl;
  • the medicament wherein D1 is D2 ", a double bond exists between the N and C, and R 13 is methoxy;
  • the drug wherein T is selected from the group consisting of C2-12 alkylene groups
  • the present invention provides a method of treating a patient in need thereof, comprising administering to the patient a medicament according to any one of the preceding claims, wherein the patient has a tumor, an autoimmune disease or an infectious disease .
  • compositions of the invention are useful for inhibiting abnormal cell growth or treating a value-added disease in a mammal, such as a human.
  • compositions of the invention are useful for treating diseases, such as cancer, in a mammal, such as a human.
  • the cancer is selected from the group consisting of breast cancer, gastrointestinal cancer, for example, a group consisting of colorectal cancer, pancreatic cancer, cholangiocarcinoma, hepatocellular carcinoma, osteosarcoma, lung cancer, prostate cancer, squamous cell carcinoma, ovarian cancer, testis Cancer, bladder cancer, stomach cancer, head and neck cancer, cervical cancer, kidney cancer, glioma, skin cancer, such as: malignant melanoma, thyroid cancer, leukemia, malignant lymphoma.
  • gastrointestinal cancer for example, a group consisting of colorectal cancer, pancreatic cancer, cholangiocarcinoma, hepatocellular carcinoma, osteosarcoma, lung cancer, prostate cancer, squamous cell carcinoma, ovarian cancer, testis Cancer, bladder cancer, stomach cancer, head and neck cancer, cervical cancer, kidney cancer, glioma, skin cancer, such as: malignant melanoma, thyroid cancer, leukemia, malignant lymphoma.
  • the trade name includes the product formulation, generic drug, and active pharmaceutical ingredient of the trade name product.
  • aryl refers to a polyunsaturated, generally aromatic, hydroxyl group which may be monocyclic or fused or covalently attached polycyclic (up to three rings).
  • arylhetero refers to an aryl (or ring) containing from 1 to 5 heteroatoms selected from N, O or S, wherein the nitrogen and sulfur atoms are optionally oxidized, the nitrogen atom optionally being seasoned Ammonium.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl groups include phenyl, naphthyl and diphenyl
  • non-limiting examples of heteroaryl groups include: pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, Triazinyl, quinolyl, quinoxalinyl, quinazolinyl, porphyrinyl, phthalaziniyl, benzotriazinyl, fluorenyl, benzimidazolyl, benzopyrazole, benzene And triazolyl, benzisoxazolyl, isobenzofuranyl, isodecyl, pyridazinyl, benzotriazinyl, thienopyridyl, thienopyrimidinyl, pyridopyrimidinyl, imidazopyridine , benzothiaxolyl, benzofuranyl, benzothienyl, fluorenyl
  • R', R" and R"' are independent Hydrogen-substituted, unsubstituted C1-8 alkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C1-8 alkyl, C1-8 alkoxy or C1-8 thio An alkoxy group, or an unsubstituted aryl-C1-4 alkyl group.
  • R' and R" When R' and R" are bonded to the same nitrogen atom, they may form a 3-, 4-, 5-, 6- or together with the nitrogen atom. 7-member ring.
  • -NR'R" includes 1-pyrrolidinyl and 4-morpholinyl.
  • a “derivative" of a compound as used herein refers to a substance having a chemical structure similar to that of a compound but further containing at least one chemical group not present in the compound and/or lacking a chemical group present in at least one compound.
  • the compounds to which the derivatives are compared are referred to as "parent” compounds.
  • a “derivative” can be produced from a parent compound in one or more chemical reaction steps.
  • inhibiting means reducing the detectable amount or completely preventing it.
  • cancer refers to a physiological condition or disease characterized by dysregulated cell growth.
  • Tumors include cancer cells.
  • autoimmune disease is a disease or disorder that results from tissue or protein directed against the individual's own body.
  • phrases "pharmaceutically acceptable salt” as used herein refers to a pharmaceutically acceptable organic or inorganic salt of the compound.
  • the compound may contain at least one amino or carboxyl group and thus may form an addition salt with the corresponding acid or base.
  • Exemplary salts include, but are not limited to, sulfates, trifluoroacetates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, hydrogen sulfates, phosphates, acids Phosphate, isonicotinic acid, lactate, salicylate, acidic citrate, tartrate, oleate, tannic acid, pantothenate, hydrogen tartrate, ascorbate, salicylate, Formate, orthoformate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, potassium salt, sodium salt
  • pharmaceutically acceptable salts have more than one dotted atom in the structure.
  • An example in which a plurality of charged atoms are part of a pharmaceutically acceptable salt can have multiple counterexamples.
  • a pharmaceutically acceptable salt has one or more charged atoms and/or one or more counter atoms.
  • Figure 1 is a graph showing the results of the hct116 experiment.
  • Figure 2 is a graph showing the results of the SKOV3 experiment.
  • Example 16 Compound 014: 5-((7-(Methoxy)-2-(4-methoxyphenyl)-5,11-dioxo-10-((2-(trimethylsilyl)) Oxy)methyl)-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-8-yl)oxy) Valeric acid
  • the obtained solid was dissolved in a mixed solvent of methanol/dichloromethane (4 ml + 1.5 ml), and 0.5 ml of water was added thereto with stirring, followed by the addition of 3 g of silica gel (300-400 mesh), and the reaction was stirred at room temperature. After the completion of the reaction, the reaction mixture was filtered, and then filtered and evaporated. The obtained solid was separated and purified by preparative liquid phase to give Compound 009 12.5 mg.
  • the obtained solid was dissolved in a mixed solvent of methanol/dichloromethane (4 ml + 1.5 ml), and 0.5 ml of water was added thereto with stirring, followed by the addition of 3 g of silica gel (300-400 mesh), and the reaction was stirred at room temperature. After the completion of the reaction, the reaction mixture was filtered, and then filtered and evaporated. The obtained solid was separated and purified by preparative liquid phase to give compound 026 8 mg.
  • the obtained solid was dissolved in a mixed solvent of methanol/dichloromethane (4 ml + 1.5 ml), and 0.5 ml of water was added thereto with stirring, followed by the addition of 3 g of silica gel (300-400 mesh), and the reaction was stirred at room temperature. After the completion of the reaction, the reaction mixture was filtered, and then filtered and evaporated. The obtained solid was separated and purified by preparative liquid phase to give Compound 031 8 mg.
  • BDN-001 (430 mg, 1.11 mmol) and 40 ml of DMF were added to a 150 ml single-mouth bottle, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (640 mg, 3.33 mmol) and DMAP (410 mg, 3.35 mmol) were stirred at room temperature for 2 h, then intermediate 5 (660 mg, 2.24 mmol). 100 ml of water was added to the reaction solution, and the mixture was extracted twice with 100 ml of DCM.
  • the glass bottle is dried, N2 is replaced, 5 g of the raw material 042 is dispersed in 150 ml of anhydrous dichloromethane (new system), 4 ml of DMF is added to promote dissolution, and PBr 3 4.3 g is slowly added dropwise in an ice bath (0 ⁇ 5 ° C). Gradually dissolve. Maintain the temperature for 2 h, if the raw material is left, add PBr 3 until the reaction is complete (TLC monitoring: the reaction of the raw material is complete DCM / MeOH 20:1 2 times). Adjust the pH with a saturated NaHCO3 solution in an ice bath (0 ⁇ 5 ° C). 7. A large amount of solid was produced, filtered, and purified by column chromatography (DCM / MeOH 100:1) to yield 3 g of product, yield 54% (LC-MS confirmed as the target product).

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  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

La présente invention concerne un composé dimère de toxicité d'ADN; comparé aux conjugués de benzodiazépine décrits dans la technologie précédente, le composé cytotoxique selon la présente invention affiche un indice thérapeutique in vivo beaucoup plus élevé (rapport entre la dose tolérée maximale et la dose efficace minimale).
PCT/CN2018/101216 2017-08-18 2018-08-18 Composé dimère de toxicité d'adn WO2019034178A1 (fr)

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US11753381B2 (en) * 2019-09-27 2023-09-12 Board Of Regents, The University Of Texas System Inhibitors of receptor interacting protein kinase I for the treatment of disease
CN115192732A (zh) * 2021-04-01 2022-10-18 成都百利多特生物药业有限责任公司 一种dna毒性二聚体化合物及其偶联物
AU2022353890A1 (en) 2021-09-30 2024-04-04 Jiangsu Hengrui Pharmaceuticals Co., Ltd. Pyrrolo benzodiazepine derivative, and conjugate, preparation method and use thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023178641A1 (fr) * 2022-03-25 2023-09-28 成都百利多特生物药业有限责任公司 Composé dimère toxique d'adn et conjugué de celui-ci

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