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WO2014154173A1 - Composé anti-angiogénique - Google Patents

Composé anti-angiogénique Download PDF

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Publication number
WO2014154173A1
WO2014154173A1 PCT/CN2014/074306 CN2014074306W WO2014154173A1 WO 2014154173 A1 WO2014154173 A1 WO 2014154173A1 CN 2014074306 W CN2014074306 W CN 2014074306W WO 2014154173 A1 WO2014154173 A1 WO 2014154173A1
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compound
fluorenyl
group
mmol
etoac
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Chinese (zh)
Inventor
侯睿
罗红蓉
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GUANGZHOU KANG RUI BIOLOGICAL PHARMACEUTICAL TECHNOLOGY CO Ltd
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GUANGZHOU KANG RUI BIOLOGICAL PHARMACEUTICAL TECHNOLOGY CO Ltd
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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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • 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

Definitions

  • the present invention relates to a novel compound and use.
  • Angiogenesis is the process of sprouting new blood vessels from existing blood vessels. This process is associated with vascular endothelial cell migration and proliferation. Angiogenesis is associated with a variety of major human diseases, such as malignant tumors. It has been found that ocular neovascular diseases, including age-related macular degeneration (AMD), diabetic retinopathy, neovascular glaucoma, etc., are common features of these diseases in the abnormal proliferation of ocular neovascularization (Jin Xiao, et al. , Research progress in the application and mechanism of anti-VEGF drugs in ophthalmic diseases, Chinese and Foreign Medical, 2012).
  • AMD age-related macular degeneration
  • neovascular glaucoma etc.
  • macular degeneration is mainly dry and wet.
  • AMD wet macular degeneration
  • Wetness quickly loses sight and is more severe than dryness.
  • photodynamic therapy has improved the therapeutic effect, it is still not ideal.
  • Lucentis vascular endothelial factor antagonist
  • Lucentis is a recombinant of a human VEGF subtype monoclonal antibody fragment that reduces neovascularization.
  • the drug was approved by the US FDA for the treatment of wet macular degeneration, and its efficacy was good.
  • this type of anti-VEGF drug has therapeutic effects on diabetic retinopathy and neovascular glaucoma.
  • Lucentis is an antibody drug, the price is extremely high, and it cannot be popularized all over the world. Therefore, the study of small-molecule angiogenesis inhibitors with good efficacy and low cost is the focus of fierce competition in the international pharmaceutical industry today.
  • the present invention provides a compound of formula A and a pharmaceutically acceptable salt or prodrug thereof:
  • r 7 is selected from hydrogen or dC 6 fluorenyl; ⁇ is selected from hydrogen or dC 6 fluorenyl; ⁇ . Selected from H, amino, hydroxy, decyl, dC 6 fluorenyl or
  • r 9 is selected from the group consisting of H, amino, hydroxy, decyl, (Cr u r 12 ) nNr 13 r 14 , (C_r u r 12 ) n0r 15 , (Cr u r 12 ) precedeC (0) Er 13
  • heterocyclic or substituted heterocyclic ring contains 1 or 2 heteroatoms selected from N, 0 or S, the substituents of which are 0, 1, or 2, each independently selected from an oxo group, C1-C6 ⁇ , C1-C6 halogenated fluorenyl, C1-C6 decyloxy, C1-C6 halodecyloxy, C 1-C 6 decanoyl, C1-C6 decylamino, C3-C7 cyclodecyl, halogen, Hydroxy, amino, carbonyl, aminocarbonyl, C1-C6 amidinocarbonyl, C1-C4 acyl, C1-C6 methoxycarbonyl, C1-C6 sulfonyl, aminos
  • Ar 2 is selected from phenyl, naphthyl, monocyclic or bicyclic heteroaryl, bicyclic or tricyclic heterocyclic groups wherein each heteroaryl or heterocyclic group has 1, 2, 3 or 4 selected from N a hetero atom of 0 or S; the phenyl, naphthyl, heteroaryl or heterocyclic group is an unsubstituted or substituted phenyl, naphthyl, heteroaryl or heterocyclic group having a substituent 1, 2, or 3, independently selected from C1-C8 fluorenyl, C1-C8 halogenated fluorenyl, hydroxy C1-C 6 fluorenyl, C1-C8 decyloxy, C1-C8 halogenated decyloxy , halogen, hydroxy, amino, amino C-C6 fluorenyl, C1-C6 decylamino, phenyl, C3-C 7 cyclodecyl, spiro C3-
  • ⁇ , r 12 and P r ls are the same or different and are each independently selected from hydrogen or C1-C4 fluorenyl; r 13 , r 14 , r 15 , r 16 and r 17 are independently selected from hydrogen, C1-C6 fluorenyl , a C1-C6 acyl group, a phenyl group and a heterocyclic ring, or a substituted C1-C6 fluorenyl group, a C1-C6 acyl group, a phenyl group and a heterocyclic ring having a substituent of 0, 1 or 2, each independently selected from C1- C4 decyloxy, C1-C4 fluorenyl, halogen, hydroxy, amino, C1-C6 amidoxime
  • Ri is selected from H, amino, hydroxy or decyl
  • R 3 is selected from H or C 1-6 fluorenyl
  • R 4 , R 5 , R 6 are each independently selected from H, halogen, C1-6 fluorenyl or halogen-substituted fluorenyl
  • R 7 is selected from H, C1-6 Sulfhydryl or halogen
  • R 2 and R 3 together with the carbon atom to which they are bonded form a substituted or unsubstituted five- or six-membered ring having from 1 to 2 heteroatoms, said hetero atom being N, 0 or S, the substituent of which is C1 -6 ⁇ base.
  • X and Y are different; selected from H or amino;
  • R 3 is selected from H or C 1-2 fluorenyl;
  • R 5 , Re are each independently selected from halogen, C 1-2 fluorenyl or halogen substituted fluorenyl;
  • R 7 is selected from H or halogen;
  • R 2 and R 3 together with the carbon atom to which they are bonded constitute a substituted or unsubstituted five- or six-membered ring containing one N, and the substituent is a fluorenyl group of C1-3.
  • R 2 is selected from an amino group or -(CH 2 ) n HR 8 ; or R 2 , a carbon atom to which it is bonded, constitutes a substituted or unsubstituted five- or six-membered ring containing one N, a substituent It is a thiol group of C1-3.
  • W3 is selected from C or a hetero atom, the hetero atom is preferably N; and R10 is a halogen.
  • halogen is F or Cl.
  • the compound is:
  • the present invention also provides the use of the above compound and a pharmaceutically acceptable salt or prodrug thereof for the preparation of an angiogenesis inhibitor.
  • angiogenesis inhibitor is a vascular endothelial growth factor receptor 2 inhibitor.
  • the inhibitor is a drug that is resistant to ocular angiogenesis.
  • the drug is a choroidal neovascularization inhibitor.
  • the medicament is a medicament for treating or preventing wet macular degeneration, diabetic retinopathy or neovascular glaucoma.
  • the invention also provides the use of the above compounds, and pharmaceutically acceptable salts or prodrugs thereof, in the manufacture of a VEGFR2, PDGFR-P or/and KIT inhibitor.
  • the present invention also provides a pharmaceutical composition which is an ophthalmic preparation containing the above compound and a pharmaceutically acceptable salt thereof.
  • other agents known to have similar therapeutic uses may be included in the formulation.
  • the ophthalmic preparation is an eye drop, an eye ointment or an ophthalmic injection.
  • Salts of the compounds of the invention can be prepared by methods known in the art. Treatment with an acid, or with a suitable anion exchanger, can form a salt with the above compounds.
  • the pharmaceutically acceptable salt of the compound of the present invention may be an organic or inorganic acid addition salt having a basic nitrogen atom from the above compound.
  • suitable inorganic acids include, but are not limited to, hydrohalic acids such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • suitable organic acids include, but are not limited to, carboxylic acids, phosphoric acids, sulfonic acids or aminocarboxylic acids such as acetic acid, propionic acid, caprylic acid, capric acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, Succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acid, such as glutamic acid or aspartic acid, maleic acid, hydroxy acid, methyl mala Acid, cyclohexyl carboxylic acid, adamant carboxylic acid, benzoic acid, salicylic acid, 4 aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, formazan or acetophenone sulfonic acid , 2 - hydroxyethanesulfonic acid, acetam-1,2-disulfonic
  • a pharmaceutically unacceptable salt such as picrate or perchlorate.
  • it can only be a pharmaceutically acceptable salt or free compound, in the form of a suitable pharmaceutical preparation.
  • the pharmaceutically acceptable prodrug of the present invention refers to a compound obtained by chemically modifying the compound to release an active ingredient by enzymatic or non-enzymatic conversion in vivo to exert a pharmacological effect.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is also isotopically labeled, and the isotopically labeled compound means the same as the compound listed herein, but one or more of the atoms are Another atomic substitution, the atomic mass or mass of the atom is different from the atomic mass or mass number that is common in nature.
  • Isotopes which may be introduced into the compound include hydrogen, carbon, nitrogen, oxygen, sulfur, i.e., 2 H, 3 H, 13 C, 14 C, 15 N, 17 0, 18 0, 35 S.
  • Compounds containing the above isotopes and I or other atomic isotopes and stereoisomers thereof, as well as pharmaceutically acceptable salts of the compounds, stereoisomers, are intended to be encompassed within the scope of the invention.
  • the key intermediates and compounds in the present invention are isolated and purified by the separation and purification methods commonly used in organic chemistry and examples of the methods include filtration, extraction, drying, spin drying, and various types of chromatography. Alternatively, the intermediate can be subjected to the next reaction without purification.
  • one or more compounds of the invention may be used in combination with one another.
  • the compounds of the invention may be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition for modulating cellular function or treating a disease. If a group of compounds is used, these compounds can be administered to the subject simultaneously, separately or sequentially.
  • the compounds of the present invention have a good anti-angiogenic effect, and it is preliminarily believed that such compounds are active by inhibiting VEGFR2 (i.e., KDR).
  • VEGFR2 i.e., KDR
  • Such compounds can be used for the treatment of diseases caused by abnormalities of protein kinases such as neovascularization and VEGFR2, such as wet macular degeneration, malignant tumors and the like.
  • Figure 3 is a graph of the results of the drug group, in which the zebrafish vascular development site is partially inhibited by the compound of the present invention.
  • Figure 4 is a graph of the results of the drug group, in which the zebrafish vascular development site is completely inhibited by the compound of the present invention.
  • Figure 5 Inhibition of VEGFR2 by the compound of the present invention in vitro
  • Fig. 6 Inhibition of choroidal neovascularization of the compound of the present invention KDR4, wherein: A: negative control, B: KDR4 Fig. 7 Inhibition of choroidal neovascularization of the compound V01 of the present invention, wherein: A: negative control, B: V01
  • FIG. 23 Effect of compound V01 on ocular neovascularization and hemorrhage in mice, A: right eye V01 treatment, B: left eye PBS control
  • Step 1 Mix Mic acid (75. 3 g, 0.522 mol) and triethyl orthoformate (92 mL, 0.55 mol), heat to 55 ° C for 90 minutes, then cool to 45 ° C.
  • PE thin layer chromatography
  • Step 2 Compound 2 (155. 9 g, 0.441 mol) was heated to 100 ° C in a Dowtherm A heat pipe (1 L) and then slowly added to the flask to which the Dowtherm A heat pipe was attached ( 500mL, preheated to 210 °C) while keeping the temperature above 207 ° C. The reaction was stirred at 210 ° C for one hour and then cooled to room temperature. The collected precipitate was filtered, washed with diethyl ether and acetone, and dried to give brown solid compound 3 (67 g, yield: 61%).
  • Step 9 Mixing the compound 9 (0.4 g, 2. llmmol), 3-trifluoromethyl aniline
  • step 1
  • step 1
  • step 1
  • step 1
  • NaOEt (2.38 g, 0.035 mol) was added to the mixture of the compound 37 (3.0 g, 0.01 mol) and formazan acetate (3.24 g, 0.03 mol) in ethanol (50 mL).
  • the reaction mixture was stirred at 90 ° C overnight and then evaporated to remove most of the solvent.
  • the residue was diluted with H20, acidified to pH 6 with 2N EtOAc, and then extracted with DCM. The organic phase was washed with EtOAc (EtOAc m.
  • Phosphorus oxychloride (P°C13, 174 mg, 1.26 mmol) was added to a DCM stirred with compound 30 (100 mg, 0.42 mmol) and N,N-dimethylaniline (0.28 mL) under nitrogen at 0 °C. (4 mL), after the addition was completed, the reaction mixture was poured into ice water, basified by the addition of solid sodium carbonate, and then extracted with DCM. The organic phase was washed with brine, dried N3 ⁇ 4S0 4 and concentrated to give the crude product, which was purified by preparative TLC to give the pure compound 31 (60 mg, 55.6%) , as a white solid.
  • Step 4 Compound 4 (1.1 g, 3.15 mmol), 4-methyl-5-(trifluoromethyl)benzene 1,2 -diamine (0.6 g, 3.15 mmol) and carbodiimide (1.2) Grams, 6.30 mmol) of THF (50 mL).
  • the reaction mixture was diluted with EA and the precipitate was filtered. The filtrate was evaporated to give a crude material, which was purified eluted from EtOAc (EtOAc: EtOAc (EtOAc)
  • Step 6 In a stirred solution of Compound 6 (60 mg, 0.1445 mmol per day) in DCM (5 mL), TEA (30) Mg, 0.289 mmol) Wo P MSCL (25 mg, 0.2168 mmol) under nitrogen at 0 °C. After the completion of the dropwise addition, the reaction was completed. The mixture was diluted with EtOAc EtOAc EtOAc m.
  • the fourth step 7-methoxyquinoline-4-carboxylic acid (2.0 g, 9.84 mmol) and DIPEA (3.82 g, 29.52 mmol) were dissolved in DMF. The reaction mixture was then cooled to 0 ° C and HATU (4.49 g, 11.81 mmol) and 3-(trifluoromethyl)aniline (1.74 g, 10.82 mmol). The mixture was covered with argon and then stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc EtOAc. The organic layer was washed with EtOAc EtOAc (EtOAc m. Rate: 79.6%) is a pale yellow solid.
  • Step 7 tert-Butylmethyl((6-(4-(3-(trifluoromethyl)phenylcarbamoyl)quinolin-7-yloxy)pyrimidin-4-yl)methyl)carbamic acid
  • a mixture of butyl ester (25 mg, 0.045 mmol) and TFA (0.25 mL) was stirred at 0 ° C for half an hour.
  • Step 4 7-methoxyquinolin-4-carboxylic acid (406 mg, 2 mmol) and DIPEA (775 mg, 6 mmol) dissolved in In DMF (5mL).
  • Step 6 N-(4-Fluoro-3-(trifluoromethyl)phenyl)-7-hydroxyquinoline-4-carboxamide (30 mg, 0.086 mmol), tert-butyl (6-chloropyrimidine) -4-yl) tert-butyl methyl(methyl)carbamate (26.5 mg, 0.103 mmol) and PK 2 CO 3
  • Step 1 Heat a mixture of diethyl oxalate (70 ml) to 120 ° C, add compound 1 (50 g, 0.4 mol), and The mixture was heated to 180 ° C for 5 minutes. The mixture was refrigerated overnight, and a white solid was collected by filtration and dried to yield Compound 2 (75.0 g, yield: 59.11%).
  • Step 5 Add BBr 3 (10 mL, 4N in DCM) to a solution of compound 5 (0.4 g, 1.12 mmol) in EtOAc (10 mL). 1/1) The reaction was completed. Then, ice was added to the reaction, and the undissolved material was removed by filtration. The filtrate was separated and extracted with DCM. The organic phase was washed with brine, dried over Na 2SO 4 and concentrated to give a crude product. Purification, a pure compound of Compound 6 (100 mg, yield: 26.02%) was obtained from TLC.
  • EtOAc EtOAc
  • Step 1 Diethyl oxalate (70 ml) was heated to 120 ° C, compound 1 (50 g, 0.4 mol) was added, and the mixture was heated to 180 ° C for 5 minutes. After cooling, the mixture was placed in a refrigerator overnight, 50 ml of water was added, and a white precipitate formed. The solid was collected and dried to give 2 (75.0 g, yield: 59.11%) as a white powder.
  • Step 2 Compound 2 (25 g, 0.11 mol) was dissolved in boiling xylene (1 L). P2S5 (9.5 g, 0.0385 mol) was slowly added and refluxed until the reaction was completed (about 5 hours) and reflux was continued.
  • Step 6 To a solution of compound 6 (64 mg, 0.189 mmol) in DMF (10 ml), K2CO3 (78 mg, 0.567 mmol) and tert-butyl(6-chloropyrimidin-4-yl)methyl (methyl) tert-butyl (6-chloropyrimidin-4-yl)methyl (methyl) carbamate, 53 mg, 0.208 mmol.
  • the reaction mixture was washed with water and extracted with EtOAc.
  • the organic phase was washed with EtOAc (3 mL).
  • Step 1 A mixture of diethyl oxalate (70 ml) was heated to 120 ° C, compound 1 (50 g, 0.4 mol) was added, and the mixture was heated to 180 ° C for 5 minutes. The mixture was refrigerated overnight to form a white precipitate. The solid was collected by filtration and dried to give 2 (75.0 g, yield: 59.11%) of compound as a white powder.
  • the zebrafish (Daniorerio) is a teleost fish of the genus Danio (Cyprinidae).
  • the similarity between the gene and the human gene is as high as 85%, and the female can lay 200 to 300 eggs at a time.
  • the fertilization and embryo development process are carried out in vitro, and the formation can be formed within 24 hours, and the embryo is transparent and easy to observe. Changes in organ tissue. Many characteristics make it one of the five fish experimental animals recognized by the International Organization for Standardization. At present, zebrafish have been widely used in human disease research, and there are many studies on cardiovascular systems.
  • This experiment uses an zebrafish that is commonly used as a screening compound for the effects of angiogenesis as an animal model. After the birth, the zebrafish embryos are selected, placed in a culture dish and placed in an incubator for 3-5 days. The compound of the present invention is directly added to the zebrafish at different concentrations (1 ⁇ , 10 ⁇ , 30 ⁇ , ⁇ ) after birth. In the culture solution. The development of spinal vascular tubes was examined 24 hours later and photographed with a fluorescence microscope. 130B was Pazopanib, and as a positive control, DMS0 was used as a negative control.
  • test results are shown in Figures 1-4, Table la, lb.
  • AI vascular inhibition rate
  • the activity of the compound DKR4 is significantly better than that of KDR3, KDR6, KDR8 and KDR8A, and the activities of the compounds V01 and V03 are significantly better than those of KDR4.
  • the compounds KDR4, V01 and V3 of the present invention can inhibit VEGFR2, and the compounds V01 and V3 are better than KDR4.
  • Test Example 3 Inhibition of choroidal neovascularization by the compound of the present invention
  • the mouse was c57/BL and was experimentally performed using a laser-induced choroidal neovascularization (CNV) animal model.
  • CNV laser-induced choroidal neovascularization
  • This model is currently the most widely used animal model used to study the effects of drugs on CNV.
  • CNV formation induced by laser retinal photocoagulation in C57/W6 mice (4 laser spots per retina) using a 532 laser.
  • KDR4 a concentration of 150 uM in the right eye
  • V01 concentration of luM in the right eye.
  • Both mice were injected with the same volume of PBS as the control.
  • the animals were sacrificed and eyeballs were taken 5 days after the injection.
  • the compounds KDR4 (150 uM) and V01 (luM) can significantly inhibit choroidal neovascularization and effectively treat or alleviate wet macular degeneration.
  • Test Example 4 Effect of the compound of the present invention on kinase
  • Protein kinases also known as protein phosphakinase 0 , are enzymes that catalyze the phosphorylation of proteins. It can transfer the ⁇ -phosphate on adenosine triphosphate (ATP) to the hydroxyl group of certain serine, threonine or tyrosine residues on the amino acid residue of the protein molecule, thereby changing the conformation and activity of the protein and enzyme. . Phosphorylation of proteins is an important part of many signaling pathways. Most important life processes in cells are inseparable from protein phosphorylation.
  • ATP adenosine triphosphate
  • Protein kinases are classified into five classes: protein serine/threonine kinase, protein tyrosine kinase, protein histidine kinase, protein tryptophan kinase, and protein aspartyl/glutamyl kinase. Protein kinases play an important role in the regulation and maintenance of cellular processes, and abnormalities in kinase activity have been observed in many disease states, including: malignant tumors, immune diseases, cardiovascular diseases, diabetes, infectious diseases, joints. Inflammation and other immune disorders, nervous systems such as Alzheimer's disease, Alzheimer's disease AD, etc., have been found to be associated with more than 400 human diseases and protein kinases.
  • VEGFR vascular endothelial growth factor receptor
  • VEGFR VEGFR2 receptor tyrosine kinases
  • VEGFR VEGFR2 receptor tyrosine kinases
  • PDGFR platelet-derived growth factor receptor
  • PDGFR a and PDGFR ⁇ receptor tyrosine kinases
  • colony-stimulating factor 1 receptor the stem cell growth factor receptor KIT, etc.
  • KIT stem cell growth factor receptor
  • Compound V01 was dissolved in 100% DMS0 and diluted to 3 series concentrations, and DMS0 was maintained at 1% in the final test. The highest concentration tested was 50 uM. Staurosporine, an activity inhibitor of non-selective protein kinase, was used as a reference with a maximum concentration of 1 uM. The results are shown in Table 3 and Figure 22.
  • Table 3 shows the inhibitory activity against KDR
  • V01 22 kinase activity inhibition assays were tested at a test concentration of 5 mM, repeated twice, at the ATP Km test. V01 was first dissolved in 100% DMS0 at a concentration of 100 times the final test concentration, and all final tests had a DMS0 of 1%. Staurosporine, an inhibitor of non-selective protein kinase activity, was used as a control with a maximum concentration of 10 mM.
  • V01 5000 30 SYK 1.74 -2.88 -0.57 4.62 0.000225 From the test results, V01 inhibits protein kinase KDR by up to 100%, and also inhibits other two tumor-associated protein kinases, among them, PDGFR- ⁇ The inhibition rate was 52.7%, and the KIT inhibition rate was 68%, but most of the other protein kinase inhibitory activities of V01 were less than 5%. It can be seen that the compounds of the present invention have high specificity and high inhibition of KDR compared with the previously developed small molecule kinase inhibitors, and two proteins closely related to tumors, PDGFR- ⁇ and KIT. Kinase also has a certain inhibitory effect, which indicates that compound V01 has potential therapeutic activity against various tumors associated with abnormal activation of KDR, PDGFR- ⁇ and KIT, and age-related wet macular degeneration.
  • VEGFR2 i.e., KDR
  • Such compounds can be used for the treatment of diseases caused by abnormalities of protein kinases such as neovascularization, VEGFR2, PDGFR- ⁇ , and KIT, such as wet macular degeneration and malignant tumors.

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Abstract

La présente invention concerne un nouveau composé anti-angiogénique et son procédé de préparation et d'utilisation. Le composé de la présente invention a un bon effet anti-angiogénique, et ce composé est initialement considéré comme agissant par l'inhibition de VEGFR2 (à savoir KDR), générant ainsi une activité. De tels composés peuvent être utilisés pour le traitement de maladies provoquées par une protéine kinase anormale, telle que la néovascularisation, VEGFR2, PDGFR-β et KIT, par exemple, une dégénérescence maculaire humide, des tumeurs malignes, etc.
PCT/CN2014/074306 2013-03-28 2014-03-28 Composé anti-angiogénique Ceased WO2014154173A1 (fr)

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JP2016515636A (ja) * 2013-04-09 2016-05-30 グアングジョウ フエイ ボー ルイ バイオロジカル ファーマシューティカル テクノロジー カンパニー，リミテッドＧｕａｎｇｚｈｏｕ Ｈｕｉ Ｂｏ Ｒｕｉ Ｂｉｏｌｏｇｉｃａｌ Ｐｈａｒａｍａｃｅｕｔｉｃａｌ Ｔｅｃｈｎｏｌｏｇｙ Ｃｏ．，Ｌｔｄ． 抗血管新生化合物、中間体ならびにその使用
CN105906553A (zh) * 2016-04-21 2016-08-31 重庆威尔德·浩瑞医药化工有限公司 N-苄基-4-甲基哌啶-3-酮盐酸盐的合成方法

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CN112194598B (zh) * 2020-10-15 2021-12-21 郑州猫眼农业科技有限公司 3-(叔丁氧基羰基-r氧基羰基甲基-氨基)-丙酸酯的制备方法
CN115572238B (zh) * 2022-09-27 2023-10-17 常州永和精细化学有限公司 N-(2-乙氧基苯基)-n'-(2-乙基苯基)-草酰胺的制备方法
CN115710222A (zh) * 2022-11-01 2023-02-24 广州康瑞泰药业有限公司 一种用于制备7-苄氧基-4-氯喹啉的方法

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DE10349587A1 (de) * 2003-10-24 2005-05-25 Merck Patent Gmbh Benzimidazolylderivate
JO3265B1 (ar) * 2008-12-09 2018-09-16 Novartis Ag مثبطات بيريديلوكسى اندولات vegf-r2 واستخدامها لعلاج المرض

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JP2016515636A (ja) * 2013-04-09 2016-05-30 グアングジョウ フエイ ボー ルイ バイオロジカル ファーマシューティカル テクノロジー カンパニー，リミテッドＧｕａｎｇｚｈｏｕ Ｈｕｉ Ｂｏ Ｒｕｉ Ｂｉｏｌｏｇｉｃａｌ Ｐｈａｒａｍａｃｅｕｔｉｃａｌ Ｔｅｃｈｎｏｌｏｇｙ Ｃｏ．，Ｌｔｄ． 抗血管新生化合物、中間体ならびにその使用
US10064864B2 (en) 2013-04-09 2018-09-04 Guangzhou Kangrui Biological Pharmaceutical Technology Co., Ltd. Anti-angiogenesis compound, intermediate and use thereof
CN105906553A (zh) * 2016-04-21 2016-08-31 重庆威尔德·浩瑞医药化工有限公司 N-苄基-4-甲基哌啶-3-酮盐酸盐的合成方法
CN105906553B (zh) * 2016-04-21 2019-01-29 重庆威尔德·浩瑞医药化工有限公司 一种n-苄基-4-甲基哌啶-3-酮盐酸盐的合成方法

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