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WO2019011217A1 - Composés de pyrrolo[1,2-b]pyridazine ou leurs sels pharmacologiquement acceptables et leur utilisation - Google Patents

Composés de pyrrolo[1,2-b]pyridazine ou leurs sels pharmacologiquement acceptables et leur utilisation Download PDF

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WO2019011217A1
WO2019011217A1 PCT/CN2018/095033 CN2018095033W WO2019011217A1 WO 2019011217 A1 WO2019011217 A1 WO 2019011217A1 CN 2018095033 W CN2018095033 W CN 2018095033W WO 2019011217 A1 WO2019011217 A1 WO 2019011217A1
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Inventor
杨春皓
缪泽鸿
陈建阳
宦霞娟
丁健
陈奕
谭村
贺茜
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Shanghai Institute of Materia Medica of CAS
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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 the field of medicinal chemistry, and in particular to pyrrole [1,2-b]pyridazine compounds or pharmaceutically acceptable salts thereof and uses thereof.
  • PARP Poly(adenosine diphosphate [ADP]-ribose) polymerase
  • ADP-ribose Novel functions for an old molecule. Nat. Rev. Mol. Cell Bio, 2006, 7, 517-528).
  • the ADP-ribosyltransferases (ARTs) currently have a total of 18 subtypes found and identified, of which only 6 subtypes have the ability to form poly ADP-ribosylation, which are PARP-1, PARP, respectively.
  • PARP-1, PARP respectively.
  • PARP-3, PARP-4 vPARP
  • PARP-5a TNKS1
  • PARP-5b TNKS2
  • PARP-1 is the most abundant and widely studied member, playing more than 90% of the functions in the PARP family.
  • Human PARP-1 is a polypeptide chain with a molecular weight of 113 kDa and consists of three major functional domains: a DNA binding domain (DBD) containing two zinc finger fingers at the amino (N)-terminus. ), an Automodification domain, and a Catalytic domain at the carboxyl (C)-terminus.
  • DBD DNA binding domain
  • Human PARP-2 is a polypeptide chain with a molecular weight of 62 kDa, which is structurally most similar to PARP-1. Its catalytic domain shares 69% homology with the catalytic domain of PARP-1 and the DNA binding domain does not contain zinc finger structure.
  • PARP-1 and PARP-2 play an important role in DNA damage repair, genomic stability, and apoptosis regulation through base excision repair, making it one of the most important anti-tumor drug research targets in recent years (Yelamos, J.; Farres, Jordi.; Llacuna, Laura.; Ampurdanes, Coral; Martin-Caballero, Juan.; PARP-1 and PARP-2: New players in tumour development. Am. J. Cancer Res. 2011 1(3), 328-346; Weaver, AN; Yang, ESBeyond DNA repair: additional functions of PARP-1 in cancer. Front. Oncol. 2013, 3, 290).
  • Human DNA is caused by exogenous factors (such as ultraviolet radiation, particle radiation, alkylating agents, topoisomerase and platinum drugs) or endogenous factors (such as the spontaneous metabolism of human body and the chemical nature of DNA itself) Under the action of sexual reaction, DNA gaps are easily generated, and most of these gaps will be converted into DNA single-strand breaks, causing DNA damage. DNA damage can affect a wide range of cellular processes and is an important cause of tumorigenesis and other diseases. Studies have shown that the catalytic activity of PARP-1/2 is rapidly activated by DNA strand breaks.
  • BRCA-1/2 is a key repair factor for the Homologous recombination (HR) repair pathway.
  • HR Homologous recombination
  • inhibition of PARP will result in increased accumulation of DNA single-strand breaks, and due to the collapse of the replication fork in progress, DNA single-strand breaks will be converted into double-strand breaks, and these tumor cells will The double-strand break can be repaired because of the inability to initiate the HR pathway, which ultimately leads to cell death due to genomic instability.
  • the inhibition of PARP and the phenomenon of BRCA-1/2 deficiency in killing cells are also known as synthetic lethality.
  • PARP is involved in multiple biological processes, including gene transcription, cell cycle progression, cell death, and chromatin function.
  • PARP inhibitors have been proven to be useful in a number of therapeutic medicinal chemistries (in addition to malignant tumors), including stroke, myocardial ischemia, inflammation, antiviral and diabetes (Reference: Virág, L Szabó, C., The Therapeutic Potential of Poly (ADP-Ribose) Polymerase Inhibitors. Pharmacol Rev 2002, 54(3), 375-429).
  • the pyrrole [1,2-b]pyridazine structure is an advantageous structure in medicinal chemistry.
  • Compounds containing such structures exhibit a wide variety of biological activities in the pharmaceutical field, such as hypolipidemic/cholesterol (patent CN 1056690 discloses a class of compounds containing this predominant structure and their use in the treatment of hypercholesterolemia and high Application in lipemia), anti-tumor (patent WO 2011/014817 discloses JANUS kinase inhibitors containing such structures), anti-inflammatory, antibacterial (Butnariu, RM; Mangalagiu, II, New pyridazine derivatives: Synthesis, chemistry and Biological activity.
  • J Heterocyclic Chem 2007, 44(5), 1149-1152), antiviral (patent CN103288832 discloses a class to Pyrrole [1,2-b]pyridazine derivatives for the treatment or prevention of HIV infection or other viral infections; WO 2004/087708 A1 and WO 2007/069671 respectively disclose corticotropin releasing factor (CRF) inhibition with this predominant structure
  • CRF corticotropin releasing factor
  • the use of the agent in pharmacy and the patent WO2010022240A1 disclose a class of derivatives containing such structures, which are capable of modulating the activity and/or activity of hypoxia-inducible factor (HIF) by effectively inhibiting the activity of HIF hydroxylase.
  • R 1 is hydrogen, C 1-4 alkyl or halogen
  • R 4 is hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy
  • X 1 is S, O or NH
  • X 2 is CH or N
  • Y 1 , Y 2 , Y 5 and Y 6 are independently a substituted or unsubstituted methylene group, a substituted or unsubstituted ethylene group, a substituted or unsubstituted propylene group or a substituted or unsubstituted butylene group.
  • the substitution is substituted with at least one substituent selected from the group consisting of halogen, C 1-6 alkyl, C 3-6 cycloalkyl and C 1-4 alkoxy;
  • Y 3 and Y 4 are independently hydrogen, substituted or unsubstituted C 1-4 alkyl or substituted or unsubstituted C 3-6 cycloalkyl, the substituent being selected from halogen, C 1-6 alkyl Substituting at least one substituent of C 3-6 cycloalkyl and C 1-4 alkoxy;
  • Y 7 is NR 8 or CHR 9 ,
  • the R 9 is hydrogen, -OR 12 , an amino group substituted with at least one C 1-4 alkyl group, or a substituted or unsubstituted five- to six-membered saturated heterocyclic group, wherein the R 12 is hydrogen, substituted or An unsubstituted C 1-4 alkyl group or a substituted or unsubstituted C 3-6 cycloalkyl group, which is selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, amino, at least At least one substituent of a C 1-4 alkyl-substituted amino group, a nitrile group, a hydroxyl group, and a nitro group is substituted.
  • R 1 is hydrogen, methyl, ethyl, propyl, fluorine, chlorine or bromine;
  • R 3 is hydrogen, methyl, ethyl or propyl
  • R 4 is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy or propoxy;
  • X 1 is S, O or NH
  • X 2 is CH or N
  • Y 1 , Y 2 , Y 5 and Y 6 are independently a substituted or unsubstituted methylene group, a substituted or unsubstituted ethylene group, a substituted or unsubstituted propylene group or a substituted or unsubstituted butylene group.
  • the substitution is selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, and ring. Substituting at least one substituent of pentyl, cyclohexyl, methoxy, ethoxy or propoxy;
  • Y 3 and Y 4 are independently hydrogen, methyl, ethyl, propyl, isopropyl or butyl;
  • Y 7 is NR 8 or CHR 9 ,
  • the R 9 is hydrogen, -OR 12 , N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, pyrrolidinyl, tetrahydrofuranyl, piperidine Or a piperazinyl group, a morpholinyl group or a dioxane group, wherein the R 12 is hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or a ring Hexyl, the substitution is selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, amino, N-methylamino, N-ethylamino, N, N Substituting at least one substituent of dimethylamino, N,N-diethylamino, nitrile,
  • Formula I has the structure represented by Formula II:
  • said R 1 is a halogen, more preferably chlorine.
  • said X 1 is S or O, more preferably S.
  • the general formula II has a structure represented by the general formula II-a:
  • the Formula I has a structure represented by Formula III:
  • said R 1 is a halogen, more preferably chlorine.
  • said R 4 is a halogen, more preferably fluorine.
  • said R 5 is -CH 2 -.
  • said Y 3 and Y 4 are independently hydrogen, methyl, ethyl, propyl, isopropyl or butyl, more preferably methyl.
  • the general formula III has the structure represented by the general formula III-a:
  • the Formula I has a structure represented by Formula IV:
  • said R 1 is a halogen, more preferably chlorine.
  • said R 4 is a halogen, more preferably fluorine.
  • the general formula IV has the structure represented by the general formula IV-a:
  • the Formula I has a structure represented by Formula V:
  • said R 1 is a halogen, more preferably chlorine.
  • said R 4 is hydrogen or halogen, and said halogen is preferably fluorine.
  • the general formula V has a structure represented by the general formula V-a:
  • the pyrrole [1,2-b]pyridazine compound represented by the general formula I is one of the following compounds:
  • the invention further provides the use of a pyrrole [1,2-b]pyridazine compound of the formula I or a pharmaceutically acceptable salt thereof for the preparation of a PARP inhibitor.
  • the PARP inhibitor has a selective inhibitory effect on PARP-1 and/or PARP-2.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising one or more therapeutically effective amounts of a pyrrole [1,2-b]pyridazine compound of the formula I or a pharmaceutically acceptable salt thereof, or a Or a plurality of therapeutically effective amounts of an ester, prodrug, hydrate or crystal of the pyrrole [1,2-b]pyridazine compound.
  • the pharmaceutical composition has an inhibitory effect on PARP, particularly a selective inhibitory effect on PARP-1 and/or PARP-2.
  • the pharmaceutical composition is for use in preventing and/or treating a PARP-related disease, including a tumor (breast cancer, ovarian cancer, liver cancer, melanoma, prostate cancer, colon cancer) , solid tumors such as gastric cancer), ischemic diseases (brain, heart, etc.) and neurodegenerative diseases (Parkinson's disease, Alzheimer's disease, etc.).
  • a tumor breast cancer, ovarian cancer, liver cancer, melanoma, prostate cancer, colon cancer
  • solid tumors such as gastric cancer
  • ischemic diseases brain, heart, etc.
  • neurodegenerative diseases Parkinsoninson's disease, Alzheimer's disease, etc.
  • the invention further provides a preparation method of the pyrrole [1,2-b]pyridazine compound represented by the general formula I, comprising the following steps:
  • Aromatic aldehyde is reacted with a solution of ethynylmagnesium bromide in tetrahydrofuran (THF) to obtain an aromatic alkynyl alcohol I-b in the following reaction formula;
  • N-amino-5-iodopyrrole-2-carboxylic acid methyl ester derivative Ia and the aromatic acetylenic alcohol Ib are subjected to a coupling cyclization reaction in a solvent under microwave conditions in the presence of palladium acetate, cuprous iodide and DBU.
  • Compound I-0 is used as a solvent in a saturated methanol solution of ammonia gas, and sealed at 90 ° C for 20 hours to 24 hours, or directly with concentrated ammonia water, the solvent is methanol, and the reaction tube is reacted at 90 ° C for 20 hours to 24 hours to obtain the above.
  • the present invention further provides a method for preparing a pyrrole [1,2-b]pyridazine compound represented by the general formula II or the general formula II-a, and the synthesis route thereof is as follows:
  • the amide F is fused to a ring to obtain a compound under the action of phosphorus oxychloride, and then the compound is reduced under the condition of sodium borohydride to further reduce the imine and further protect the free amino group with Boc anhydride to obtain the compound I;
  • the present invention designs and synthesizes a series of PARP inhibitors by using pyrrole [1,2-b]pyridazine-7-carboxamide as a core structure, and the compounds of the present invention have a selection of PARP-1 and PARP-2 of the PARP family. It has a sexual inhibitory effect and exhibits good biological activity both in vitro and in vivo, and is expected to develop into a novel antitumor drug and a drug for preventing and/or treating a PARP-related disease.
  • alkyl refers to a straight or branched alkyl group.
  • alkoxy refers to a straight or branched alkoxy group.
  • substituted refers to the replacement of one or more hydrogen atoms.
  • Tumors as referred to herein include benign tumors and malignant tumors.
  • the "pyrrole [1,2-b]pyridazine compound” described herein includes optical isomers.
  • a method for preparing a pyrrole [1,2-b]pyridazine compound represented by the formula I comprising the steps of:
  • the scheme 1 comprises: the pyrrole-2-carboxylic acid methyl ester derivative A is obtained by heating under reflux of a base (such as 4-dimethylaminopyridine (DMAP)) in a solvent (such as methanol) to obtain a compound B, a compound B is stirred under the action of silver trifluoroacetate and iodine in a solvent such as chloroform to obtain Compound C in a base such as potassium t-butoxide and O-(4-nitrobenzoyl). Under the action of hydroxylamine, in a solvent (such as N-methylpyrrolidone (NMP)) stirred at room temperature overnight to obtain compound Ia;
  • a base such as 4-dimethylaminopyridine (DMAP)
  • a solvent such as methanol
  • Scheme 2 includes: Compound B can be prepared by stirring a base (such as potassium t-butoxide) and O-(4-nitrobenzoyl)hydroxylamine in a solvent (such as NMP) at room temperature overnight to obtain compound D. D can be prepared under conditions of potassium iodide and hydrogen peroxide in a solvent (such as acetic acid) for 3 hours at room temperature;
  • a base such as potassium t-butoxide
  • NMP NMP
  • D can be prepared under conditions of potassium iodide and hydrogen peroxide in a solvent (such as acetic acid) for 3 hours at room temperature;
  • the starting reagents, solvents and materials except the special instructions are supplied by Sinopharm Reagent Group; the microwave reaction uses CEMNULL type microwave reactor; 1 H NMR is performed by Brucher AM-400 or GeMINI-300 NMR spectrometer Recording, chemical shifts are expressed in ⁇ (ppm); mass spectra were recorded by an Agilent Model 1200-6110 Single Quadrupole Liquid Chromatography Mass Spectrometer. Separation silica gel is used to produce 200-300 mesh column chromatography silica gel from Qingdao Ocean Chemical Plant.
  • the chemical reagents represented by the English abbreviation are as follows:
  • NBS N-bromosuccinimide
  • reaction solution was poured into 300 mL of dichloromethane, and then quenched with ice water, the organic phase was separated, and the aqueous phase was extracted twice with dichloromethane (400 mL). The mixture was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate and evaporated.
  • the compound 15 (120 mg, 0.24 mmol) was placed in a 100 mL round bottom flask, 5 mL of anhydrous dichloromethane was added, and 5 mL of HCl methyl acetate solution was added thereto, and the mixture was stirred at 40 ° C for 2 hours to precipitate a white solid to be cooled. After room temperature, it was filtered to give the hydrochloride salt of methyl 5-chloro-2-[4-(N-piperazinyl)phenyl]-pyrrole[1,2-b]pyridazin-7-carboxylate. Mg.
  • 3-fluoro-4-formylbenzoic acid (1 g, 6 mmol, its preparation method refers to document EP2526945A1, the raw material used is 3-fluoro-4-methylbenzoic acid purchased from Shanghai Shuya Medicine), N-tert-butoxy Formylpiperazine (1.1 g, 5.66 mmol), HOBt (764 mg, 5.66 mmol), EDCI (1.3 g, 6.8 mmol) and DMAP (20 mg) were used as the starting material. The yield was 89%.
  • the compound 6 (218 mg, 0.7 mmol) and the compound 18 (420 mg, 1.2 mmol) were used as a starting material.
  • the retention time of the first enantiomer was 8.68 min and the solvent was removed in vacuo to give a yellow solid: 2-(4-[(3R)-tert-butoxyformylpiperidin-3-yl]-phenyl)-5 -Chloro-pyrrole [1,2-b]pyridazine-7-carboxamide (Compound 53-R, 99.9% ee).
  • the retention time of the second enantiomer was 9.07 min.
  • the compound 53-S (50 mg, 0.11 mmol) was used as a material.
  • the compound 53-R (50 mg, 0.11 mmol) was used as a material.
  • 4,5,6,7-tetrahydrothiophene [3,2-c]pyridine hydrochloride (10 g, 56.9 mmol) in 150 mL of dichloromethane, EtOAc (EtOAc)
  • EtOAc EtOAc
  • the methylene chloride solution was stirred at room temperature for 1 hour, 20 ml of a saturated ammonium chloride solution was added, and after stirring for 10 minutes, the organic phase was separated, the aqueous layer was extracted with dichloromethane, and the organic phase was combined and washed with saturated sodium chloride Dry over anhydrous sodium sulfate and concentrate to give 12.5 g of white solid.
  • the compound I-34 (75 mg, 0.21 mmol) was used as a starting material. m.p.
  • the compound 72 (866 mg, 2.3 mmol) was used as a starting material, and 357 mg of a colorless oil was obtained with reference to the preparation of compound 61, yield 50%.
  • 2-Thiophenethylamine (1.3 g, 10 mmol, purchased from Tosoh Chemical) and cyclopropylcarbonyl chloride (1.3 g, 12.4 mmol) were used as a starting material.
  • ELISA Enzyme-Linked Immunosorbent Assay
  • PAR polyadenosine diphosphate ribose
  • anti-PAR anti-PAR antibodies
  • inhibition rate (%) (OD control well-OD administration well) / OD control well ⁇ 100% (OD is absorbance value); and according to the inhibition rate, calculated by the Logit method to achieve 50% inhibition Drug concentration, which is the IC 50 value. (At the molecular level IC 50 ⁇ 1000 nM, +; ⁇ 500 nM, ++; ⁇ 100 nM, +++; - > 1000 nM or not determined), the results are shown in Table 1:
  • the compound I-34 was prepared as a monohydrochloride salt as a yellow powder, which was dissolved in a yellow turbid liquid by using water for injection, and precipitated after standing. The mixture was thoroughly mixed before administration, and the above compound was formulated once a week.
  • the positive control drug AZD2281 anticancer drug olaparib olaparib
  • I-34 hydrochloride was set up in two dose groups, 100 mg/kg and 20 mg/kg, respectively.
  • the positive control drug AZD2281 dose was 30 mg/kg.
  • BALB/cA nude mice female, 4-5 weeks old, weighing 19 ⁇ 2 g, provided by Shanghai Institute of Materia Medica, Chinese Academy of Sciences, production license number: SCXK (Shanghai) 2013-001. Use certificate number: SYXK (Shanghai) 2013-0049.
  • the number of animals in each group 12 in the negative control group and 6 in the drug-administered group.
  • Human breast cancer MDA-MB-436 cell line was preserved by our laboratory. The cell strain was inoculated subcutaneously into the right axilla of the nude mice, and the inoculation amount was 5 ⁇ 106/piece, and the transplanted tumor was formed and then used in nude mice for 2 generations.
  • the tumor tissue in the vigorous growth period was cut into 1.5 mm 3 and inoculated subcutaneously in the right axilla of nude mice under aseptic conditions.
  • the diameter of the transplanted tumor was measured with a vernier caliper in nude mice. After the average tumor volume grew to about 200 mm 3 , the animals were randomly divided into groups.
  • Compound I-34 hydrochloride 100 mg/kg and 20 mg/kg groups were orally administered once a day for 21 consecutive days.
  • the positive control drug AZD2281 30 mg/kg was orally administered once a day for 21 days.
  • the solvent control was given an equal amount of water for injection.
  • the diameter of the transplanted tumor was measured twice a week during the entire experiment, and the body weight of the mice was weighed.
  • V 0 is the measured tumor volume at the time of sub-cage administration (i.e., d 0 )
  • V t is the tumor volume at each measurement.
  • I-34 hydrochloride 100mg/kg and 20mg/kg groups were administered orally once a day for 21 days, which had a significant inhibitory effect on the growth of human breast cancer MDA-MB-436 nude mice.
  • the T/C percentages obtained on day 21 were 1.47% and 5.70%, respectively, and one mouse tumor in the high dose group completely resolved.
  • AZD2281 30mg/kg, once orally administered once a day for 21 days, inhibited the growth of human breast cancer MDA-MB-436 nude mice subcutaneously transplanted.
  • the percentage of T/C obtained on the 21st day was 51.41. %.
  • I-34 hydrochloride activity was significantly better than AZD2281.
  • T-test (vs solvent control group), *p ⁇ 0.05**p ⁇ 0.001"()" is the number of tumor regression mice

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Abstract

L'invention concerne des composés de pyrrolo[1,2-b]pyridazine ou des sels pharmacologiquement acceptables de ceux-ci et leur utilisation. Les composés de pyrrolo[1,2-b]pyridazine ou leurs sels pharmacologiquement acceptables ont des effets inhibiteurs sur la poly(ADP-ribose) polymérase (PARP), et en particulier, ont des effets inhibiteurs sélectifs sur PARP-1 et PARP-2 dans une famille de PARP, présentent une bonne bioactivité à la fois in vitro et in vivo, et peuvent par conséquent être utilisés en tant qu'inhibiteurs de PARP dans des compositions pharmaceutiques destinées à la prévention et/ou au traitement de maladies associées à PARP, telles que des tumeurs, des maladies ischémiques et des maladies neurodégénératives.
PCT/CN2018/095033 2017-07-10 2018-07-09 Composés de pyrrolo[1,2-b]pyridazine ou leurs sels pharmacologiquement acceptables et leur utilisation Ceased WO2019011217A1 (fr)

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US20230142739A1 (en) * 2020-04-03 2023-05-11 The Regents Of The University Of California Protein-protein interaction stabilizers
CN113461597B (zh) * 2021-08-02 2023-07-21 天津太平洋化学制药有限公司 一种尼拉帕尼中间体的制备方法
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