WO2017054484A1 - 嘧啶或吡啶并吡啶酮类化合物及其应用 - Google Patents
嘧啶或吡啶并吡啶酮类化合物及其应用 Download PDFInfo
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- WO2017054484A1 WO2017054484A1 PCT/CN2016/084056 CN2016084056W WO2017054484A1 WO 2017054484 A1 WO2017054484 A1 WO 2017054484A1 CN 2016084056 W CN2016084056 W CN 2016084056W WO 2017054484 A1 WO2017054484 A1 WO 2017054484A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention relates to the technical field of pharmaceutical preparation, in particular to a pyrimidine or pyridopyridone compound and application thereof.
- CDK Cyclin-dependent kinase
- cyclin is important factors in cell cycle regulation.
- CDK can form a heterodimer with cyclin, in which CDK is a catalytic subunit, cyclin is a regulatory subunit, and various cyclin-CDK complexes are formed, which phosphorylate different substrates and promote the phase of different cell cycle. Transformation.
- CDK kinases that bind to G1 phase cyclins mainly include CDK2, CDK4 and CDK6.
- Cyclin D mainly binds to CDK4 and CDK6 and regulates the latter activity;
- cyclin E binds to CDK2 in G1/S phase, exhibiting CDK2 kinase activity and promoting cell entry into S phase.
- the G2/M phase is mainly regulated by CDK1 kinase, Cyclin A and cyclin B bind to CDK1, and CDK1 phosphorylates the substrate protein.
- M-phase triggering factor activates the late-promoting factor APC, which binds ubiquitin to cycli A and cyclin B, and is degraded by the proteasome by multi-ubiquitination to complete a cell cycle (Malumbres M. et al. Nat Cell Biol 11:1275, 2009; Malumbres M. et al. Nat Rev Cancer 9: 153, 2009).
- Uncontrolled cell cycle is a common feature of human tumors.
- Tumor cells typically undergo unconventional proliferation, genomic instability (increased DNA mutations and chromosomal aberrations) and chromosomal instability (increased number of chromosomes).
- the cell cycle is regulated by the CDKs family kinase. Tumor cells cause abnormal CDKs activity due to changes in CDKs themselves or their modulators or mitogenic upstream pathway-related genes and tabular genes (Cicenas JJ Cancer Res Clin Oncol 147: 1409, 2011; Rizzolio F. et al. Curr Drug Targets 11:279, 2010).
- CDK inhibitors have emerged as a new anti-tumor drug in the global pharmaceutical industry, with more than 20 CDK inhibitors entering clinical development. Despite the significant pre-clinical pharmacodynamics of CDK inhibitors, most of the previous clinical trials were unsatisfactory. The main problems include the lack of efficacy and toxicity in solid tumors. (Guha M. Nat Rev Drug Dis 11:892, 2012). CDK inhibitors AG-24322, ZK-304709, SNS-032, R547, Seliciclib, and AZD5438 terminated clinical studies due to efficacy and toxicity. However, after analyzing the causes of serious toxic side effects, these drugs were found to be insensitive to inhibition of CDK subtypes, thus causing serious side effects.
- CDK1 is involved in normal cell cycle regulation. In the case where other CDKs are inhibited, the CDK1 activity is retained sufficient to maintain a normal cell cycle. The toxic side effects of CDK inhibitors are associated with inhibition of CDK1 and CDK2. In contrast, CDK4 and CDK6 subtypes are not required for the lactation cell cycle, they play an important role only in the proliferation of specific cell types, which are key targets for tumor suppression (Guha M. Nat Rev Drug Dis 11:892, 2012).
- CDK4 and CDK6 are two closely related kinases that bind to Cyclin D during the tumor cell cycle and cause the G1 phase to enter the S phase, which is required for the cell cycle progression of DNA replication and cell division.
- G1-S phase transition control mechanism changes through various genetic and biochemical adaptations.
- P16 and human retina Retinoblastoma (Rb) is an important tumor suppressor protein that regulates the cell cycle.
- the P16 gene protein inhibits the feedback loop of CDK4, CyclinD1 and Rb, and prevents the excessive proliferation of cells by regulating the protein activity of Rb to achieve tumor suppression.
- CDK4 and CDK6 have been shown to cause cell cycle changes to occur in human tumors such as breast cancer and myeloma. Inhibition of CDK4 and CDK6 prevents the inactivation of the tumor suppressor protein Rb and interferes with tumor cell cycle progression (Choi YJ and Anders L, Oncogene 33: 1890-903, 2014).
- CDK6 induces the expression of the tumor suppressor gene p16 INK4a and the pro-angiogenic factor VEGF-A as part of a transcriptional complex. CDK6 exerts its tumor promoting effect by enhancing cell proliferation and angiogenesis stimulation (Kollmann K. et al. Cancer Cell 24: 167, 2013).
- Palbociclib (PD-0332991) selectively inhibits CDK4 and CDK6 and restores cell cycle control, thereby blocking tumor cell proliferation.
- Pfizer filed an application for NDA with the US Food and Drug Administration (FDA) based on the results of its mid-term clinical trials.
- palbociclib has a lower oral absorption of blood.
- Phase I clinical results showed a single oral dose of 25-150 mg with a blood concentration of 10-91 mg/ml and an AUC of 58-641 ng h/ml. Due to the long elimination half-life (average 25.9 hours), repeated daily dosing resulted in drug accumulation (Keith T, et al. Clin Cancer Res 18: 568, 2011).
- CDK4 and CDK6 inhibitors entered a phase III clinical trial for the treatment of advanced breast cancer. Because CDK4/6 plays a key role in the regulation of cell cycle control in various solid tumors and hematological tumors.
- the clinical evaluation of these drugs also includes metastatic breast cancer, liposarcoma, non-small cell lung cancer, liver cancer, ovarian cancer, glioblastoma, melanoma, multiple myeloma and lymphoma.
- the object of the present invention is to overcome the drawbacks of the prior art lack of selectivity of CDK inhibitors, and to provide a pyrimidine or pyridopyridone compound which selectively inhibits cell cycle-dependent kinases (Cdks).
- CDK4 and CDK6 have almost no inhibitory activity against CDK2 kinase, and therefore, such compounds can be used in the treatment of various diseases caused by disorders of cell cycle control involving CDK4 and CDK6, particularly in the treatment of malignant tumors.
- Y is selected from: C or N, and when Y is selected from N, there is no R 6 substitution;
- R 1 is selected from the group consisting of: C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl substituted methyl;
- R 2 is selected from the group consisting of halogen, COR 5 , COOR 5 ;
- R 3 is selected from the group consisting of: H, C1-C6 alkyl
- R 4 is selected from the group consisting of: C 1 -C 6 alkyl, hydroxy substituted C 1 -C 6 alkyl, alkoxy substituted C 1 -C 6 alkyl, phenyl, halogen substituted phenyl;
- R 5 is selected from the group consisting of: H, C1-C6 alkyl, C1-C6 fluorine-containing alkyl; C3-C6 cycloalkyl;
- R 6 is selected from the group consisting of: H, F, CN, CH 3 ;
- n is selected from: 0, 1 or 2;
- n is selected from: 1, 2 or 3;
- p is selected from: 1, 2 or 3.
- R 4 is selected from the group consisting of: C 1 -C 6 alkyl, hydroxy substituted C 1 -C 6 alkyl, alkoxy substituted C 1 -C 6 alkyl.
- a hydroxy-substituted C1-C6 alkyl group is preferably a hydroxy-substituted ethyl group.
- R 4 is selected from the group consisting of methyl, ethyl, propyl, and isopropyl.
- R 4 is preferably a methyl group.
- m is selected from the group consisting of: 1; n is selected from: 2; and p is selected from: 1 or 2.
- Y is selected from the group consisting of: N.
- R 1 is selected from the group consisting of: C 3 -C 6 cycloalkyl;
- R 2 is selected from: COR 5 ;
- R 3 is selected from: C 1 -C 6 alkyl;
- R 5 is selected from: C 1 -C 6 alkyl;
- 6 is selected from: H.
- R 1 is selected from the group consisting of: cyclopentyl
- R 2 is selected from: COR 5
- R 3 is selected from: methyl
- R 5 is selected from the group consisting of methyl, ethyl
- R 5 is preferably methyl
- 6 is selected from: H.
- the compound is selected from the group consisting of:
- the invention also discloses the use of the above pyrimidine or pyridopyridone compound or a pharmaceutically acceptable salt or stereoisomer thereof for preparing a medicament for controlling tumors.
- the tumor is a solid tumor and a blood tumor.
- the solid tumor and hematological tumor comprise breast cancer, liposarcoma, non-small cell lung cancer, liver cancer, ovarian cancer, glioblastoma, melanoma, multiple myeloma, and mantle cell lymphoma .
- the breast cancer comprises: a locally advanced or metastatic breast cancer that is negative for estrogen receptor positive and/or negative for human epidermal growth factor receptor 2 in postmenopausal women.
- the present invention also discloses a pharmaceutical composition for controlling tumors, comprising the pyrimidine or pyridopyridone compound according to any one of claims 1 to 9 as an active ingredient, or a pharmaceutically acceptable salt or stereoisomer thereof Body, and a pharmaceutically acceptable carrier.
- the present invention has the following beneficial effects:
- the pyrimidine or pyridopyridone compound of the formula I of the present invention is a novel series of compounds which selectively inhibit CDK4 and CDK6 and can be used for CDK4 and CDK6 involved in cell cycle control disorders.
- the compound when the R 4 group is alkyl, the compound has high activity of CDK6 and CDK4; when the R 4 group is an aromatic group, the compound loses the activity of CDK6.
- the compounds showed very superior characteristics in the pharmacokinetic experiments.
- the AUC value of the compound of the present invention was higher than that of the positive control, especially the compound 2 therein. Its AUC is about 9 times that of the positive control and has a very good oral absorption effect.
- Figure 1 is a schematic diagram showing the inhibition of Rb phosphorylation by MDA-MB-231 breast cancer cells by CDK4/6 inhibitor in Example 6;
- Figure 2 is a graph showing the drug time of PD-0332991 in Example 7 after oral administration of rats;
- Figure 3 is a graph showing the drug time of Compound 1 in Example 7 as a function of time after oral administration of the rat;
- Figure 4 is a graph showing the drug time of Compound 2 in Example 7 after oral administration in rats;
- Figure 5 is a graph showing changes in tumor volume after oral administration of a mouse in Example 8.
- Fig. 6 is a graph showing changes in body weight after oral administration of a mouse in Example 8.
- the compounds of the invention can be prepared using the reactions as shown in the scheme below.
- the following illustrative exemplifications are not intended to limit the scope of the invention, and are not intended to limit the scope of the invention.
- Step 1a Preparation of 5-iodine-2-chloro-4-cyclopentyl-aminopyrimidine (Compound 102).
- Step 1b (E)-3-(2-Chloro-4-cyclopentylaminopyrimidin-5-yl)-2-butenoic acid ethyl ester ((E)-Ethyl-3-(2-chloro-4- Preparation of (cyclopentylamino)pyrimidin-5-yl)but-2-enoate) (Compound 104).
- Step 1c 2-Chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (2-chloro-8-cyclopentyl-5-methyl-8H-pyrido Preparation of [2,3-d]pyrimidin-7-one) (Compound 105).
- Ethyl (E)-3-(2-chloro-4-cyclopentylaminopyrimidin-5-yl)-2-butenoic acid ethyl ester (104) (20.00 g, 0.0647 mol, 1.0 eq.) was dissolved in dimethyl In a carboxamide (200 ml), cesium carbonate (42.16 g, 0.1294 mol, 2.0 eq.) was then added and stirred at room temperature. HPLC Monitoring The reaction was terminated when the peak area ratio of Compound 104 was less than 1%. The reaction solution was filtered, and the filtered cake was washed with m.
- Step 1d 6-bromo-2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (6-br omo-2-chloro-8- Preparation of cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one) (Compound 106).
- Step 1e tert-butyl-4-(6-aminopyridin-3-yl)piperidine-1-carboxylate (tert-butyl-4-(6-amino) Preparation of pyridin-3-yl)piperidine-1-carboxylate) (Compound 107).
- the above compound 107C (3.53 g, 11.6 mmol, 1.0 eq.) was dissolved in 100 ml of methanol, then palladium carbon (0.353 g) was added. The reaction was stirred at room temperature under hydrogen overnight. After completion of the reaction, filtration was carried out to remove palladium carbon in the reaction liquid, and the filter cake was washed with methanol several times, and the filtrate was concentrated under reduced pressure.
- Step 1f 4-(6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl) Tert-butyl 4-(6-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2] , 3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperidine-1-carboxylate) (Compound 108).
- Step 1g 4-(6-(8-Cyclopentyl-6-(1-ethoxyvinyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyridin-2-amino)pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (tert-butyl 4-(6-((8-cyclopentyl-6-(1-ethoxyvinyl)-5-methyl) Preparation of -7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-1-carboxylate) (Compound 109).
- Step 1h 6-Acetyl-8-cyclopentyl-5-methyl-2-(5-(piperidin-4-yl)pyridin-2-amino)pyrido[2,3-d]pyrimidine- 7-(8H)-one (6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin- Preparation of 7(8H)-one) (Compound 110).
- Step 1i Preparation of 2-(methylsulfonyl)ethylmethanesulfonate (Compound 111-1).
- Step 1j 6-Acetyl-8-cyclopentyl-5-methyl-2-(5-(1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)pyridin-2-amine Pyridyl[2,3-d]pyrimidin-7(8H)-one (6-acetyl-8-cyclopentyl-5-methyl-2-((5-(1-(2-(methylsulfonyl)ethyl)piperidin) Preparation of -4-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one) (Compound 1).
- Step 2a Preparation of 1-bromo-3-methylsulfonylpropane (Compound 112-2). 3-Methanesulfonylpropanol (50 mg, 0.36 mmol, 1.0 eq.) was dissolved in 10 mL of dichloromethane under N2, and then evaporated. , 1.2 equivalents). The reaction solution was then allowed to warm to room temperature and the reaction was stirred for 15 hours. The reaction solution was slowly added to ice water, extracted with dichloromethane, and the mixture was separated, and the organic phase was washed with water, dried and concentrated to give 1-bromo-3-methylsulfonyl-propane as a colorless oil (49 mg, yield :68%).
- Step 2b 6-Acetyl-8-cyclopentyl-5-methyl-2-(5-(1-(3-(methylsulfonyl)propyl)piperidin-4-yl)pyridin-2-amine Pyridyl[2,3-d]pyrimidin-7(8H)-one (6-acetyl-8-cyclopentyl-5-methyl-2-((5-(1-(3-(methylsulfonyl)propyl)))) Preparation of -4-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one) (Compound 2).
- Step 3a Preparation of 1-((2-bromoethyl)sulfonyl)-4-chlorobenzene (Compound 112-4).
- Step 3b 6-Acetyl-2-(5-(1-(2-(4-chlorophenylsulfonyl)ethyl)piperidin-4-yl)pyridin-2-yl)-8-cyclopentyl -5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (6-acetyl-2-((5-(1-(2-(2-chlorophenyl)sulfonyl)ethyl)piperidin Preparation of -4-yl)pyridin-2-yl)amino)-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one) (Compound 4).
- Step 4a 2-Chloro-8-cyclopentyl-6-iodo-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (2-chloro-8-cyclopentyl-6-iodo Preparation of 5-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one) (Compound 201).
- Step 4b 2-Chloro-8-cyclopentyl-6-(1-ethoxyvinyl)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (2-chloro Preparation of 8-cyclopentyl-6-(1-ethoxyvinyl)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one) (Compound 202).
- Step 4c 3-(6-aminopyridin-3-yl)piperidine-1-carboxylate (203) Preparation of).
- 2-Nitro-5-bromopyridine (107A) (1.0 g, 4.98 mmol, 1.0 eq.), bistriphenylphosphine palladium dichloride (174 mg, 0.25 mmol, 0.05 eq.). 2.43 g, 7.47 mmol, 1.5 eq.) mixed with 5 ml of water and 50 ml of N,N-dimethylformamide. Add compound 5-pinacol borate-3,4-dihydropyridine under nitrogen. -1 (2H)-tert-butyl carboxylate (203A) (2.13 g, 6.89 mmol, 1.4 eq.). After 1 hour. The mixture was cooled to rt.
- Step 4d 3-(6-((8-Cyclopentyl-6-(1-ethoxyvinyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3 -d]pyrimidin-2-yl)amino)pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (tert-butyl 3-(6-((8-cyclopentyl-6-(1-ethoxyvinyl)-) Preparation of 5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperidine-1-carboxylate) (Compound 204).
- Step 4e 6-Acetyl-8-cyclopentyl-5-methyl-2-(5-(1-(piperidin-3-yl)pyridin-2-yl)pyrido[2,3-d Pyrimidine-7(8H)-one (6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-3-yl)pyridin-2-yl)amino)pyrido[2,3-d Preparation of pyrrimidin-7(8H)-one) (Compound 205).
- Step 4f 6-Acetyl-8-cyclopentyl-5-methyl-2-(5-(1-(2-methanesulfonylethyl)piperidin-3-yl)pyridin-2-yl) Pyrido[2,3-d]pyrimidin-7(8H)-one (6-acetyl-8-cyclopentyl-5-methyl-2-((5-(1-(2-(methylsulfonyl)ethyl)piperidin-3) Preparation of -yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one) (Compound 5).
- Step 5a Preparation of 2-chloro-5-iodopyridin-4-amine (Compound 302).
- 2-Chloro-4-aminopyridine (301) (15 g, 0.116 mol, 1 eq.) was dissolved in acetonitrile (200 mL) under N2, and the mixture was heated to 70 ° C in an oil bath, slowly adding iodosuccinyl Imine (NIS) (33 g, 0.139 mol, 1.2 eq.) was stirred for 16 h. After cooling to room temperature, a saturated sodium thiosulfate solution was added until the reaction system was milky white, then the pH of the reaction system was adjusted to 9-10 by adding a saturated aqueous solution of sodium carbonate, and ethyl acetate (500 ml) was added to extract.
- NMS iodosuccinyl Imine
- Step 5b Preparation of 2-chloro-cyclopentylamino-5-iodopyridine (2-chloro-N-cyclopentyl-5-iodopyridin-4-amine (Compound 303).
- Step 5c (E)-3-[6-Chloro-4-cyclopentylaminopyridin-3-yl]-2-butenoic acid ethyl ester (ethyl(E)-3-(6-chloro-4-( Preparation of cyclopentylamino)pyridin-3-yl)but-2-enoate) (Compound 304).
- Step 5d 7-Chloro-1-cyclopentyl-4-methyl-1,6-naphthyridin-2(1H)-one (7-chloro-1-cyclope ntyl-4-methyl-1,6-naphthyridin Preparation of -2(1H)-one) (Compound 305).
- Step 5e 3-bromo-7-chloro-1-cyclopentyl-4-methyl-1,6-naphthyridin-2(1H)-one (3-bromo-7-chloro-1-cyclopentyl-4- Preparation of methyl-1,6-naphthyridin-2(1H)-one) (Compound 306).
- Step 5f 7-Chloro-1-cyclopentyl-3-(1-ethoxyvinyl)-4-methyl-1,6-naphthyridin-2(1H)-one (7-chloro-1- Preparation of cyclopentyl-3-(1-ethoxyvinyl)-4-methyl-1,6-naphthyridin-2(1H)-one) (Compound 307).
- Step 5g 4-(6-(1-Cyclopentyl-3-(1-ethoxyvinyl)-4-methyl-2-oxo-1,2-dihydro-1,6-naphthyridine -7-Amino)pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (tert-butyl 4-(6-((1-cyclopentyl-3-(1-ethoxyvinyl)-4-methyl-2-) Preparation of oxo-1,2-dihydro-1,6-naphthyridin-7-yl)amino)pyridin-3-yl)piperidine-1-carboxylate) (Compound 308).
- Step 5h 3-Acetyl-1-cyclopentyl-4-methyl-7-(5-(piperidin-4-yl)pyridin-2-yl)-1,6-naphthyridine-2 (1H -keto(3-acetyl-1-cyclopentyl-4-methyl-7-((5-(piperidin-4-yl)pyridin-2-yl)amino)-1,6-naphthyridin-2(1H)-one (Preparation of Compound 309).
- Step 5i 3-acetyl-1-cyclopentyl-4-methyl-7-(5-(1-(2-(methylsulfonyl)ethyl) Pyridin-4-yl)pyridin-2-amino)-1,6-naphthyridin-2(1H)-one (3-acetyl-1-cyclopentyl-4-methyl-7-((5-(1-( Preparation of 2-(methylsulfonyl)ethyl)piperidin-4-yl)pyridin-2-yl)amino)-1,6-naphthyridin-2(1H)-one) (Compound 13).
- CDK2 protein kinase activity was determined using the Caliper mobility shift assay (see J Biomol Screen 14:31, 2009).
- the compound obtained above was dissolved in DMSO and diluted with kinase buffer (20 mM HEPES-pH 7.5, 0.01% Triton X-100, 10 mM MgCl 2 , 2 mM DTT), and 5 ⁇ l of 10% DMSO dissolved 5 was added to a 384-well plate.
- the compound-free control well was 5 ⁇ l of 10% DMSO
- the enzyme-free control well was 5 ⁇ l of kinase buffer.
- CDK4 protein kinase activity was determined using the Caliper mobility shift assay (see J Biomol Screen 14:31, 2009).
- the compound obtained above was dissolved in DMSO and diluted with kinase buffer (20 mM HEPES-pH 7.5, 0.01% Triton X-100, 10 mM MgCl2, 2 mM DTT), and 5 ⁇ l of 10% DMSO was added in 5 times in a 384-well plate.
- the final concentration of the compound, the compound-free control well was 5 ⁇ l of 10% DMSO, and the enzyme-free control well was 5 ⁇ l of kinase buffer.
- CDK6 protein kinase activity was determined using the Caliper mobility shift assay (see J Biomol Screen 14:31, 2009).
- the compound obtained above was dissolved in DMSO and diluted with kinase buffer (20 mM HEPES-pH 7.5, 0.01% Triton X-100, 1OmM MgCl 2 , 2 mM DTT), and 5 ⁇ l of 10% DMSO dissolved 5 was added to a 384-well plate.
- the compound-free control well was 5 ⁇ l of 10% DMSO
- the enzyme-free control control well was 5 ⁇ l of kinase buffer.
- I indicates IC 50 >500 nM
- II indicates 500 nM ⁇ IC 50 >100 nM
- III indicates 100 nM ⁇ IC 50 >50 nM
- IV indicates 50 nM ⁇ IC 50 >10 nM
- V indicates IC 50 ⁇ 10 nM.
- the compounds provided by the present invention have an IC 50 for inhibition of CDK2 of 1, i.e., at least >500 nM, and have almost no inhibitory activity, while the IC 50 for inhibition of CDK6 is 50 nM or less (except compound 4), for CDK4.
- inhibition IC 50 of 10nM or less i.e., such compounds can selectively inhibit CDK4 and CDK6, almost no inhibitory activity on the CDK2, and a higher inhibitory activity against CDK4 and CDK6, can reach 50 nM, 10nM or even less, having a high selectivity Characteristics of sexuality and high activity.
- Cell viability was assessed by measuring the amount of adenosine triphosphate (ATP) using the CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega, Madison, WI).
- Tumor cell lines SW620, ZR-75-1, MDA-MB-231) were purchased from the Shanghai Fudan IBS Cell Resource Center and the American Type Culture Collection (ATCC). The cells were trypsinized from the cell culture plate and resuspended in DPBS medium, and the cell density was determined by counting with a Scepter automatic cell counter (Millipore #PHCC00000). The cells were diluted to a solution containing 44,000 cells per ml. The adjusted cell solution was added to the cell assay plate at 90 microliters per well.
- ATP adenosine triphosphate
- the plates were placed in a 37 ° C, 5% CO 2 incubator for 24 hours and then added with different concentrations of test compound.
- the cells were incubated with the compound for 72 hours in the presence of 10% fetal bovine serum. use The Luminescent Cell Viability Assay kit (see manufacturer's instructions) was assayed for ATP content to assess cell growth inhibition. Briefly, add 30 ⁇ l to each well. The reagents were shaken for 10 minutes, cell lysis was induced, and fluorescent signals were recorded using Fluoroskan Ascent FL (Thermo).
- the cells were treated with dimethyl sulfoxide for 72 hours to obtain the maximum signal value. The minimum signal value was obtained from a separate medium (zero cell number).
- Inhibition rate % (maximum signal value - compound signal value) / (maximum signal value - minimum signal value) X 100.
- I represent IC 50> 5 ⁇ M
- II represents 5 ⁇ M ⁇ IC 50> 1 ⁇ M
- III represents 1 ⁇ M ⁇ IC 50> 0.5 ⁇ M
- IV represents 0.5 ⁇ M ⁇ IC 50> 0.1 ⁇ M
- V represents the IC 50 ⁇ 0.1 ⁇ M.
- the cell cycle and apoptosis assay kit (Beyotime, C1052) used in this experiment is a A kit for detecting cell cycle and apoptosis by the Propidium staining (PI staining) method.
- Propidium (PI) is a fluorescent dye of double-stranded DNA.
- the combination of propidium iodide and double-stranded DNA produces fluorescence, and the fluorescence intensity is directly proportional to the amount of double-stranded DNA.
- the DNA content of the cells can be measured by flow cytometry, and then the cell cycle and apoptosis analysis can be performed according to the distribution of the DNA content.
- MDA-MB-231 cells were seeded in a 6-well culture plate at 3 ⁇ 10 5 cells per well, and cultured for 24 hours. After adding the test compound or reference substance (PD-0332991 or LY2835219) for 24 hours, the cells were collected by centrifugation at 1000 rcf for 3 min, washed twice with PBS (phosphate buffer solution); fixed by pre-cooled 70% ethanol at 4 ° C overnight, centrifuged at 1000 rcf for 10 min, Wash twice with 1 ⁇ PBS; stain with PI staining solution for 30 min; detect and analyze cell cycle G1 block by flow cytometry.
- PBS phosphate buffer solution
- CDK4 and CDK6 bind to cyclin D during the tumor cell cycle, causing the G1 phase to enter the S phase.
- CDK4/6 inhibitors selectively block the G1 phase of tumor cells into the S phase.
- Flow cytometry detection of MDA-MB-231 breast cancer cell cycle results showed that the CDK4/6 inhibitor compound provided by the present invention stopped G1 phase cell growth and S phase cell decrease in a concentration-dependent manner, as shown in the following table.
- test compound or reference compound PD-0332991 or LY2835219
- test compound or reference compound PD-0332991 or LY2835219
- washing twice with pre-cooled PBS collecting cells
- homogenizing with biological sample homogenizer 2-3 times centrifuged at 13,000 rpm for 10 min at 4 ° C, and the supernatant was taken.
- the protein concentration was determined by Branfor method, and the sample buffer (Beyotime, #P0015L) was added to cook at 100 ° C for 8 min, and the protein was separated by 8%-10% SDS-PAGE and transferred to a PVDF membrane with 5% skim milk powder.
- CDK4/6 can cause the Rb protein to lose its cell cycle arrest by phosphorylating the tumor suppressor protein Rb protein.
- the CDK4/6 inhibitor prevents the inactivation of the tumor suppressor protein Rb and restores the cell cycle arrest effect of Rb.
- the compounds 1, 2 provided by the present invention act on MDA-MB-231 breast cancer cells, and can effectively reduce the phosphorylation of Rb at the Ser780 site.
- T max refers to the peak time
- C max refers to the maximum blood concentration
- T 1/2 is the half life
- AUC last refers to the area under the 0-24 hour time-concentration curve
- AUC inf refers to the 0-Inf time. - Area under the concentration curve.
- the compounds 1 and 2 provided by the present invention have good absorption and high blood exposure after intragastric administration.
- the compound Cmax was about 4-7 times higher and the AUC was about 3-9 times larger.
- Phase I clinical results showed that palbociclib (PD-0332991) had a lower oral blood exposure, and due to a long elimination half-life (average 25.9 hours), repeated daily dosing resulted in drug accumulation (Keith T, et al. Clin Cancer Res 18: 568, 2011).
- Compounds 1 and 2 were well absorbed orally, Cmax and AUC were significantly increased, and half-life was relatively short.
- MDA-MB-435 breast cancer cells were obtained from the Shanghai Cell Bank of the Chinese Academy of Sciences.
- the frozen cells were thawed in a 37 ° C water bath and placed in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS) and 1% insulin (Shanghai Baoman Biotechnology Co., Ltd.) in tissue culture at 5% CO 2 . Incubate in an incubator incubator. When the cell culture reached the desired amount, the cells were collected and washed with serum-free Dulbecco's phosphate buffer (DPBS).
- DPBS serum-free Dulbecco's phosphate buffer
- PD-0332991 showed a significant decrease in mean body weight after oral administration at 150 mg/kg once daily, and then the dose was adjusted to 100 mg/kg once daily.
- Compound 1 was orally administered twice daily at 75 mg/kg, and administration of PD-0332991 and Compound 1 was stopped 2 weeks after administration, and tumor size and body weight change were continuously observed.
- Fig. 5 is a graph showing changes in tumor volume size
- Fig. 6 is a graph showing changes in body weight of mice.
- PD-0332991 and Compound 1 inhibited tumor growth, and after 14 days of administration, the T/C values of PD-0332991 and Compound 1 were 41% and 25%, respectively.
- Compound 1 was suggested to have higher anti-cancer activity and greater safety than PD-0332991 at the maximum tolerated dose.
- the T/C values of PD-0332991 and Compound 1 were 35% and 32%, respectively. Prompt both have a longer effect.
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Abstract
Description
化合物 | CDK6 | CDK4 | CDK2 | 化合物 | CDK6 | CDK4 | CDK2 |
1 | IV | V | I | 2 | IV | V | I |
4 | I | 5 | IV | IV | I | ||
13 | IV | V | I | ||||
PD-0332991 | V | V | I | ||||
LY2835219 | IV | V | IV | ||||
LEE011 | III |
化合物 | SW620 | ZR-75-1 | MDA-MB-231 |
1 | IV | IV | IV |
2 | IV | V | IV |
5 | IV | IV | III |
13 | II | III | III |
PD-0332991 | IV | IV | IV |
LY2835219 | IV | V | IV |
LEE011 | III | V | II |
Claims (13)
- 根据权利要求1所述的嘧啶或吡啶并吡啶酮类化合物或者其药学上可接受的盐或立体异构体,其特征在于,R4选自:C1-C6烷基,羟基取代C1-C6烷基,烷氧基取代C1-C6烷基。
- 根据权利要求2所述的嘧啶或吡啶并吡啶酮类化合物或者其药学上可接受的盐或立体异构体,其特征在于,R4选自:甲基,乙基,丙基,异丙基。
- 根据权利要求1所述的嘧啶或吡啶并吡啶酮类化合物或者其药学上可接受的盐或立体异构体,其特征在于,m选自:1;n选自:2;p选自:1或2。
- 根据权利要求1所述的嘧啶或吡啶并吡啶酮类化合物或者其药学上可接受的盐或立体异构体,其特征在于,Y选自:N。
- 根据权利要求1-5任一项所述的嘧啶或吡啶并吡啶酮类化合物或者其药学上可接受的盐或立体异构体,其特征在于,R1选自:C3-C6环烷基;R2选自:COR5;R3选自:C1-C6烷基;R5选自:C1-C6烷基;R6选自:H。
- 根据权利要求6所述的嘧啶或吡啶并吡啶酮类化合物或者其药学上可接受的盐或立体异构体,其特征在于,R1选自:环戊基;R2选自:COR5;R3选自:甲基;R5选自:甲基,乙基;R6选自:H。
- 权利要求1-8任一项所述的嘧啶或吡啶并吡啶酮类化合物或者其药学上可接受的盐或立体异构体在制备防治肿瘤药物中的应用。
- 根据权利要求9所述的应用,其特征在于:所述肿瘤为实体肿瘤和血液肿瘤。
- 根据权利要求10所述的应用,其特征在于:所述实体肿瘤和血液肿瘤包括乳腺癌,脂肪肉瘤,非小细胞肺癌,肝癌,卵巢癌,胶质母细胞瘤,黑素瘤,多发性骨髓瘤和套细胞淋巴瘤。
- 根据权利要求11所述的应用,其特征在于:所述乳腺癌包括:在绝经后女性雌激素受体阳性和/或人表皮生长因子受体2阴性的局部晚期或转移性乳腺癌。
- 一种防治肿瘤的药物组合物,其特征在于,包括作为活性成份的权利要求1-8任一项所述的嘧啶或吡啶并吡啶酮类化合物或者其药学上可接受的盐或立体异构体,以及药学上可接受的载体。
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SI201630949T SI3357922T1 (sl) | 2015-09-30 | 2016-05-31 | 2-((5-(1-(3-(metilsulfonil)propil)piperidin-4-il)piridin-2-il)amino) pirido(2,3-D)pirimidin-7(8H)-on derivati in sorodne spojine kot CDK4 inhibitorji za zdravljenje tumorjev |
AU2016333188A AU2016333188B2 (en) | 2015-09-30 | 2016-05-31 | Pyrimidine or pyridopyridone compound and application thereof |
ES16850109T ES2828984T3 (es) | 2015-09-30 | 2016-05-31 | Derivados de 2-((5-(1-(3-(metilsulfonil)propil)piperidin-4-il)piridin-2-il)amino)pirido[2,3-D]pirimidin-7(8H)-ona y compuestos relacionados como inhibidores de CDK4 para tratar tumores |
EP16850109.6A EP3357922B1 (en) | 2015-09-30 | 2016-05-31 | 2-((5-(1-(3-(methylsulfonyl)propyl)piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8h)-one derivatives and related compounds as cdk4 inhibitors for treating tumors |
CA3000548A CA3000548C (en) | 2015-09-30 | 2016-05-31 | Pyrimido- or pyridopyridone compound and use as a cyclin-dependent kinase inhibitor |
JP2018536324A JP6556369B2 (ja) | 2015-09-30 | 2016-05-31 | ピリミジン又はピリドピロドン類化合物、及びその応用 |
PL16850109T PL3357922T3 (pl) | 2015-09-30 | 2016-05-31 | Pochodne 2-((5-(1-(3-(metylosulfonylo)propylo)piperydyn-4-ylo)pirydyn-2-ylo)amino)pirydo[2,3-d]pirymidyn-7(8h)-onu i związki pokrewne jako inhibitory cdk4 do leczenia nowotworów |
DK16850109.6T DK3357922T3 (da) | 2015-09-30 | 2016-05-31 | 2-((5-(1-(3-(methylsulfonyl)propyl)piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8h)-on-derivater og relaterede forbindelser som cdk4-inhibitorer til behandling af tumorer |
US15/764,884 US10183941B2 (en) | 2015-09-30 | 2016-05-31 | Pyrimidine or pyridopyridone compound and application thereof |
HK18110804.5A HK1251547A1 (zh) | 2015-09-30 | 2018-08-22 | 嘧啶或吡啶並吡啶酮類化合物及其應用 |
HRP20201727TT HRP20201727T1 (hr) | 2015-09-30 | 2020-10-26 | 2-((5-(1-(3-(metilsulfonil)propil)piperidin-4-il)piridin-2-il)amino)pirido[2,3-d]pirimidin-7(8h)-on derivati i srodni spojevi kao cdk4 inhibitori za liječenje tumora |
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CN (1) | CN105130986B (zh) |
AU (1) | AU2016333188B2 (zh) |
CA (1) | CA3000548C (zh) |
DK (1) | DK3357922T3 (zh) |
ES (1) | ES2828984T3 (zh) |
HK (1) | HK1251547A1 (zh) |
HR (1) | HRP20201727T1 (zh) |
HU (1) | HUE052454T2 (zh) |
PL (1) | PL3357922T3 (zh) |
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WO2022113003A1 (en) | 2020-11-27 | 2022-06-02 | Rhizen Pharmaceuticals Ag | Cdk inhibitors |
WO2022149057A1 (en) | 2021-01-05 | 2022-07-14 | Rhizen Pharmaceuticals Ag | Cdk inhibitors |
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EP3357922A4 (en) | 2019-06-05 |
DK3357922T3 (da) | 2020-11-02 |
HRP20201727T1 (hr) | 2020-12-25 |
HK1251547A1 (zh) | 2019-02-01 |
AU2016333188A1 (en) | 2018-05-17 |
AU2016333188B2 (en) | 2018-10-25 |
ES2828984T3 (es) | 2021-05-28 |
US20180297995A1 (en) | 2018-10-18 |
SI3357922T1 (sl) | 2020-12-31 |
PL3357922T3 (pl) | 2021-02-08 |
JP2018534352A (ja) | 2018-11-22 |
US10183941B2 (en) | 2019-01-22 |
EP3357922A1 (en) | 2018-08-08 |
CA3000548A1 (en) | 2017-04-06 |
CN105130986A (zh) | 2015-12-09 |
JP6556369B2 (ja) | 2019-08-07 |
EP3357922B1 (en) | 2020-08-26 |
HUE052454T2 (hu) | 2021-04-28 |
CN105130986B (zh) | 2017-07-18 |
PT3357922T (pt) | 2020-10-29 |
CA3000548C (en) | 2020-09-22 |
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