WO2020077944A1 - Dérivé de purine, son procédé de préparation et son utilisation - Google Patents

Dérivé de purine, son procédé de préparation et son utilisation Download PDF

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WO2020077944A1
WO2020077944A1 PCT/CN2019/078465 CN2019078465W WO2020077944A1 WO 2020077944 A1 WO2020077944 A1 WO 2020077944A1 CN 2019078465 W CN2019078465 W CN 2019078465W WO 2020077944 A1 WO2020077944 A1 WO 2020077944A1
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group
pharmaceutically acceptable
compound
solvate
acceptable salt
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PCT/CN2019/078465
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赵立峰
苟小军
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成都大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/50—Three nitrogen atoms

Definitions

  • the invention relates to arylaminopurine derivatives and belongs to the field of medicinal chemistry.
  • chemotherapeutic drugs are poorly selective and highly toxic.
  • Targeted drugs act on the key molecules that regulate cell proliferation and their signal transduction pathways in tumor cells, which are very different from normal cells. They have the characteristics of high selectivity for tumor cells and low toxicity to normal tissues.
  • EGFR epidermal growth factor receptor
  • EGFR inhibitors used in clinical treatment of tumors, including: Gefitinib (Gefitinib), Erlotinib (Erlotinib), icotinib ( Icotinib) and so on.
  • the patient's tumor cell EGFR itself is prone to secondary mutations on the basis of the original mutation, that is, the EGFR T790M mutation, secondary
  • the development of EGFR kinase inhibitors directed against the T790M mutation is the most direct and effective way to solve tumor resistance.
  • the technical scheme of the present invention is to provide a new series of purine derivatives.
  • the invention also provides the preparation method and use of the purine series derivatives.
  • the present invention provides a purine derivative represented by formula (I) or its stereochemical isomer, solvate or pharmaceutically acceptable salt:
  • R 2 is cycloalkyl C 3 ⁇ C 7 alkyl group, a cycloalkyl group with -C m H (2m + 1) substituted C 3 ⁇ C 7, and an aryl group containing 6 to 10 carbon atoms or Aromatic heterocyclic groups containing 6 to 10 carbon atoms;
  • R 3 is C 3 to C 7 cycloalkyl, -H, -NH 2 , -OH, -F, -Cl, -Br, -CF 3 , -C m H (2m + 1) , -OC m H (2m + 1) , -NHC m H (2m + 1) , an aryloxy group containing 6 to 10 carbon atoms or an arylamine group containing 6 to 10 carbon atoms;
  • A is a substituted phenyl or substituted six-membered nitrogen-containing aromatic heterocyclic group, and its structure is shown in formula (II);
  • B is a substituted phenyl group or a substituted six-membered nitrogen-containing aromatic heterocyclic group, and its structure is shown in formula (III);
  • X 1 -X 7 is C or N;
  • R 1 is -NH (R 9 ), -N (R 9 ) (R 10 ), -N (R 9 ) CO (R 10 ), -N (R 9 ) SO 2 (R 10 ), -N (R 9 ) SO (R 10 ), -COOH, -C (O) OR 9 , -C (O) O (R 9 ), -C (O) NH 2 , -C (O) NH (R 9 ),- C (O) NH (R 9 ) (R 10 ), -SO 2 R 9 , -SOR 9 , -SR 9 , -SO 2 NR 9 R 10 , -SONR 9 R 10 , -OR 9 , -CN 3 , -NO 2 , -F, -Cl, -Br, -I, C 1 -C 7 alkyl, alkenyl, alkynyl, halogenated alkane, aryl, aralkane, alkoxy
  • aromatic heterocyclic group contains 1-10 nitrogen, oxygen and sulfur heteroatoms.
  • the aromatic heterocyclic group contains an aromatic heterocyclic ring of C, H, N, O or S or an aromatic heterocyclic ring with a substituted base, and the substituent is -NH 2 , -OH, -F, -Cl, Br and / or CF 3 .
  • R 3 is -H, -NH 2 , -OH, -F, -Cl, -Br, -CF 3 , -C m H (2m + 1) , -OC m H (2m + 1) , -NHC m H (2m + 1)
  • R 1 is -NH (R 9 ), -N (R 9 ) (R 10 ), -N (R 9 ) CO (R 10 ), -C (O) OR 9 , -C (O) O (R 9 ), -C (O) NH 2 , -C (O) NH (R 9 ), -C (O) NH (R 9 ) (R 10 ), -NO 2 , -F, -Cl, -Br,- I, C 1 ⁇ C 7 alkyl, alkenyl, alkynyl, haloalkane, alkoxy; R 9 , R 10 are H, alkyl, alkenyl, vinyl, C 3 ⁇ C 8 ring Alkyl, C 3 ⁇ C 8 heterocyclic;
  • R 4 to R 8 are -H, -F, -Cl, -Br, -CF 3 , -OCF 3 , -OC m H (2m + 1) ,
  • R 3 is -H, -C m H (2m + 1) , -OC m H (2m + 1) , -NHC m H (2m + 1) ;
  • R 1 is -NH (R 9 ), -N (R 9 ) (R 10 ), -N (R 9 ) CO (R 10 ), -C (O) NH (R 9 ), -C (O) NH (R 9 ) (R 10 ), -NO 2 , -F, -Cl, -Br, -I, C 1 -C 7 alkyl group, C 1 -C 7 alkoxy group; wherein, R 9 , R 10 is H, C 1 ⁇ C 3 alkyl, C 3 ⁇ C 8 alkenyl, vinyl;
  • R 4 to R 8 are -H, -F, -Cl, -Br, -CF 3, or -OC m H (2m + 1), respectively .
  • the compound is:
  • the invention also provides a preparation method of the compound formula (I), which includes the following steps:
  • the invention also provides the use of the quinoline derivative or its stereochemical isomers, solvates or pharmaceutically acceptable salts in the preparation of antitumor drugs.
  • the tumor is non-small cell lung cancer.
  • the tumor is non-small cell lung cancer with epidermal growth factor receptor (EGFR) exon 19 deletion mutation or 21 exon L858R point mutation.
  • EGFR epidermal growth factor receptor
  • the invention also provides a pharmaceutical composition, which is a preparation prepared from the compound or its stereoisomer, solvate or pharmaceutically acceptable salt thereof, plus pharmaceutically acceptable auxiliary materials .
  • the purine derivative of the present invention has an inhibitory effect on non-small cell lung cancer of epidermal growth factor receptor (EGFR) 19 exon deletion mutation or 21 exon L858R point mutation, and the drug is safe and provides a new drug for clinic select.
  • EGFR epidermal growth factor receptor
  • Example 1-1 Preparation of 2-chloro-4-((3-carbamic acid tert-butyl ester) anilino) -5-nitropyrimidine
  • Example 1-2 4-((3-tert-butyl carbamate) anilino) -2- (2-methoxy-4- (4-methylpiperazin-1-yl) anilinyl) ⁇ 5 ⁇ Nitropyrimidine Preparation
  • Example 1-3 4-((3-tert-butyl carbamate) anilino) -2- (2-methoxy-4- (4-methylpiperazin-1-yl) anilinyl) ⁇ 5 ⁇ aminopyrimidine preparation
  • Example 1-4 4-((3-carbamic acid tert-butyl ester group) anilino group)-2- (2-methoxy group (4-methylpiperazine-1-yl) anilino group)- 5 ⁇ amino ⁇ 8 ⁇ anilino ⁇ 9H ⁇ purine preparation
  • Example 1-5 4-((3-tert-butyl carbamate) anilino) -2- (2-methoxy-2- (4-methylpiperazin-1-yl) anilinyl) ⁇ 5 ⁇ amino ⁇ 8 ⁇ anilino ⁇ 9H ⁇ purine preparation
  • Example 2-1 Preparation of 4-((3-carbamic acid tert-butyl ester group) anilino) -2- (4- (4-methylpiperazine-1-yl) anilinyl) -5-nitropyrimidine
  • Example 2-2 Preparation of 4-((3-carbamic acid tert-butyl ester group) anilino) -2- (4- (4-methylpiperazine-1-yl) anilino) -5-aminopyrimidine
  • Example 2-4 Preparation of 9- (3-aminophenyl) -2- (4- (4-methylpiperazin-1-yl) anilino) -8-anilino-9H-purine
  • Example 2-5 9-((3-acrylamido) phenyl) -2- (4- (4-methylpiperazin-1-yl) anilino) -8-anilino-9H-purine preparation
  • Example 3-2 2- (2-methoxy-4- (4-methylpiperazine-1-yl) anilinyl) -4-((3-carbamic acid tert-butyl ester) anilinyl) ⁇ 5 ⁇ Nitropyrimidine Preparation
  • Example 3-3 2- (2-methoxy-4- (4-methylpiperazine-1-yl) anilino) -4-((3-carbamic acid tert-butyl ester) anilino)- 5 ⁇ aminopyrimidine preparation
  • Example 4-1 Preparation of 4-((3-carbamic acid tert-butyl ester group) anilino) -2- (2,4-dimethoxyanilino) -5-nitropyrimidine
  • Example 4-2 Preparation of 4-((3-carbamic acid tert-butyl ester group) anilino) -2- (2,4-dimethoxyanilino) -5-aminopyrimidine
  • a 4ml (4.8g, 1.0eq) compound was dissolved in 50ml of ethanol in a 250ml round bottom flask, and 13ml of water and ammonium chloride (1.7g, 2.0eq) were added. After stirring at room temperature for 5 minutes, the temperature was raised to 90 At °C, iron powder (2.4g, 4eq) was added. After TLC detected the reaction was complete, it was filtered while hot and spin-dried. After recrystallization, a purple-black solid 2.4g was obtained with a yield of 53%.
  • Example 4-3 Preparation of 9-((3-tert-butyl carbamate) phenyl) -2- (2,4-dimethoxyanilino) -8-anilino-9H-purine
  • Example 4-4 Preparation of 9- (3-aminophenyl) -2- (2,4-dimethoxyanilino) -8-anilino-9H-purine
  • Example 4-5 Preparation of 9-((3-acrylamido) phenyl) -2-2- (2,4-dimethoxyanilino) -8-anilino-9H-purine
  • Example 5 ⁇ 1 9 ⁇ ((3 ⁇ propionamido) phenyl) ⁇ 2 ⁇ (4 ⁇ (4-methylpiperazin ⁇ 1 ⁇ yl) anilinyl) ⁇ 8 ⁇ anilinyl ⁇ 9H-purine preparation
  • Example 6 ⁇ 1 9 ⁇ ((3 ⁇ tert-butyl carbamate) phenyl) ⁇ 2 ⁇ (4 ⁇ (4-methylpiperazin-1-yl) anilinyl) ⁇ 8 ⁇ (pyridine ⁇ 3 -Yl) -anilino-9H-purine preparation
  • Example 7 ⁇ 1 9 ⁇ ((3 ⁇ acrylamido) phenyl) ⁇ 2 ⁇ (4 ⁇ (4 ⁇ methylpiperazin ⁇ 1 ⁇ yl) anilinyl) ⁇ 8 ⁇ (pyridin-3-yl) ⁇ 9H ⁇ Purine Preparation
  • Example 8-1 4-((3-tert-butyl carbamate) anilino) -2- (2-methoxy-2- (4-methylpiperazin-1-yl) anilinyl)- 5 ⁇ Amino ⁇ 8 ⁇ (pyridin-3-yl) ⁇ 9H ⁇ purine preparation
  • Example 8-2 4-((3-tert-butyl carbamate) anilino) -2- (2-methoxy-4- (4-methylpiperazin-1-yl) anilinyl) ⁇ 5 ⁇ Amino ⁇ 8 ⁇ (pyridin-3-yl) ⁇ 9H ⁇ purine preparation
  • Example 8 ⁇ 3 9 ⁇ ((3 ⁇ acrylamido) phenyl) ⁇ 2 ⁇ (2 ⁇ methoxy-4 - ⁇ (4-methylpiperazin-1-yl) anilinyl) ⁇ 8 ⁇ ( Pyridin-3-yl) -9H-purine preparation
  • Example 9 ⁇ 1 Preparation of 4 - ⁇ ((3- ⁇ carbamic acid tert-butyl ester) anilino) ⁇ 2 ⁇ anilino ⁇ 5 ⁇ nitropyrimidine
  • Example 9-2 Preparation of 4-((3-tert-butyl carbamate) anilinyl) -2-anilinyl-5-aminopyrimidine
  • a 9ml (4.2g, 1.0eq) compound was dissolved in 50ml of ethanol in a 250ml round bottom flask, and 13ml of water and ammonium chloride (1.7g, 2.0eq) were added. After stirring at room temperature for 5 minutes, the temperature was raised to 90 At °C, iron powder (2.4g, 4eq) was added. After TLC detected the reaction was complete, it was filtered while hot and spin-dried. After recrystallization, a purple-black solid 2.1g was obtained with a yield of 54%.
  • Example 9-3 Preparation of 9-((3-carbamic acid tert-butyl ester) phenyl) -2-anilino-8-anilino-9H-purine
  • Example 9-5 Preparation of 9-((3-acrylamido) phenyl) -2-anilino-8-anilino-9H-purine
  • Example 10-1 Preparation of 4-((3-tert-butyl carbamate) anilinyl) -2-cyclopentylamino-5-nitropyrimidine
  • Example 10-2 Preparation of 4-((3-carbamic acid tert-butyl ester group) anilino) -2-cyclopentylamino-5-aminopyrimidine
  • Example 10-3 Preparation of 9-((3-tert-butyl carbamate) phenyl) -2-cyclopentylamino-8-anilino-9H-purine
  • Example 10-4 Preparation of 9- (3-aminophenyl) -2-cyclopentylamino-8-anilino-9H-purine
  • Example 10-5 Preparation of 9-((3-acrylamido) phenyl) -2-cyclopentylamino-8-anilino-9H-purine
  • Example 11-1 Preparation of 4-((3-carbamic acid tert-butyl ester group) anilino) -2- (4-isopropylanilinyl) -5-nitropyrimidine
  • Example 11-2 Preparation of 4-((3-tert-butyl carbamate) anilinyl) -2- (4-isopropylanilinyl) -5-aminopyrimidine
  • Example 11-3 Preparation of 9-((3-tert-butyl carbamate) phenyl) -2- (4-isopropylanilino) -8-anilino-9H-purine
  • Example 11-4 Preparation of 9- (3-aminophenyl) -2- (4-isopropylanilinyl) -8-anilinyl-9H-purine
  • Example 11-5 Preparation of 9-((3-acrylamido) phenyl) -2- (4-isopropylanilinyl) -8-anilinyl-9H-purine
  • Test Example 1 EGFR wild-type, L858R and L858R / T790M kinase inhibitory activity test
  • the purpose of this experiment is to detect the inhibitory activity of the invented compound on in vitro kinase, using the method of isotope labeling.
  • the EGFR including wild-type, L858R mutant and L858R / T790M double-mutated EGFR
  • Staurosporine is a positive control.
  • Kinase inhibitory activity of test compound IC 50 half maximal inhibitory concentration. The IC 50 value can be obtained by calculating the inhibition rate of the test compound on the kinase activity at a series of different concentrations.
  • a reaction tube In a reaction tube, were added buffer (8mM MOPS, pH 7.0,0.2mM EDTA, 10mM MnC1 2), the test kinase (5-10mU) (EGFR), a substrate for the kinase to be tested (Reference Test material), As well as 10 mM magnesium acetate and ⁇ 33 P-ATP solutions, different concentrations of test compounds.
  • the reaction starts with the addition of MgATP ((The final concentration of ATP is the Km value of the corresponding kinase, ie: EGFR wild type is 10 ⁇ M, EGFR L858R is 200 ⁇ M, EGFR L858R / T790M is 45 ⁇ M), and incubated at room temperature for 40 minutes.
  • the compounds of the present invention were tested for their inhibitory activity against EGFR (including wild type, L858R mutant and L858R / T790M double mutant) kinases.
  • Table 1 shows the test compound against EGFR (including wild-type, L858R mutant and L858R / T790M double mutant) and VEGFR2 kinase inhibitory activity of IC 50 values.
  • the purpose of this experiment was to detect the inhibitory activity of the compound of the invention on tumor cell proliferation in vitro.
  • the method used was the MTT (tetramethyl azozole salt) colorimetric method.
  • RPMI-1640, fetal bovine serum, pancreatin, etc. were purchased from Gibco BRL (Invitrogen Corporation, USA), and IMDM medium was purchased from ATCC (American Type Culture Collection). Tetramethyl azozole salt (MTT) and dimethyl sulfoxide (DMSO) are products of Sigma (USA). The test compound was synthesized by the inventors. In vitro experiments were prepared with 100% DMSO into a 10 mM stock solution, placed in a -20 ° C refrigerator protected from light for future use, and diluted with culture medium to the desired concentration during testing.
  • the human non-small cell lung cancer cell lines HCC827 and H1975 (EGFR L858R / T790M mutation) used in this experiment were purchased from American ATCC company and kept by our laboratory. All the above non-small cell lung cancer cell lines were cultured in RPMI-1640 complete medium with 10% fetal bovine serum, 100 U / ml penicillin, and 100 ⁇ g / ml streptomycin under 5% CO 2 at 370 ° C.
  • the purpose of this experiment is to test the anti-tumor effect of the invented compound in vivo.
  • the experimental subcutaneous tumor model of BALB / c mice was used to test the anti-tumor activity of compound C-ZLF002 in vivo.
  • the cell lines used were human non-small cell lung cancer lines HCC827 and H1975.
  • Fetal bovine serum, culture medium, pancreatin, etc. were purchased from Gibco BRL (Invitrogen Corporation, USA), culture medium was purchased from ATCC (American Type Culture Collection), human non-small cell lung cancer strains HCC827 and H1975 were purchased from American ATCC company, NOD -Bablc mice were purchased from Beijing Huafukang Animal Experiment Center.
  • mice Using 6-8 weeks of NOD-Bablc mice, inoculate the mice under the subcutaneous ribs at a concentration of about 1 ⁇ 10 7 cells / 0.1ml / HCC827 or H1975. After the tumor grows to a certain volume, the mice are randomly divided into groups And began oral administration.
  • HCC827 experimental grouping drug solvent control group (12.5% EL + 12.5% EtOH + 75% water)
  • Observation indicators Measure the tumor long diameter and short neck of the mouse scale every 3 days and calculate the tumor volume (long diameter ⁇ short diameter 2 ⁇ 0.52). Observe for diarrhea, cramps, rash, and significant weight loss.
  • the tumor growth curves of various groups measured in the experiment are shown in Figure 1,2.
  • the experimental results show that the test compound C-ZLF002 has a significant in vivo growth inhibitory effect on HCC827 and H1975.
  • no adverse reactions such as weight loss, rash, and diarrhea were found in the mice, indicating that the tested compound C-ZLF002 was very toxic within the administered dose range at the test dose.

Abstract

L'invention concerne un dérivé de purine tel que représenté dans la formule (Ⅰ) ou un isomère stéréochimique, un solvate ou un sel pharmaceutiquement acceptable de celui-ci. L'invention concerne également un procédé de préparation et une utilisation du composé selon l'invention. Le dérivé de purine selon la présente invention a un effet inhibiteur sur le cancer du poumon non à petites cellules ayant une mutation 19 de délétion de l'exon 19 ou une mutation ponctuelle de l'exon 21 L858R d'un récepteur du facteur de croissance épidermique (EGFR), le dérivé de purine étant sûr sur le plan médical et fournissant un nouveau choix de médicament pour une thérapie.
PCT/CN2019/078465 2018-10-16 2019-03-18 Dérivé de purine, son procédé de préparation et son utilisation WO2020077944A1 (fr)

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CN113582995B (zh) * 2021-08-17 2022-08-16 西安交通大学 9-位含有丙烯酰氨基片段的-9h-嘌呤类化合物及其盐和应用
CN114805369B (zh) * 2022-05-30 2023-05-16 自贡市第四人民医院(自贡市急救中心) 一种2，6-二取代嘌呤类化合物及制备方法及应用

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