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WO2009109071A1 - Composés imidazopyridines - Google Patents

Composés imidazopyridines Download PDF

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Publication number
WO2009109071A1
WO2009109071A1 PCT/CN2008/000517 CN2008000517W WO2009109071A1 WO 2009109071 A1 WO2009109071 A1 WO 2009109071A1 CN 2008000517 W CN2008000517 W CN 2008000517W WO 2009109071 A1 WO2009109071 A1 WO 2009109071A1
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Prior art keywords
substituted
group
fluorenyl
alkyl
phenyl
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Ceased
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PCT/CN2008/000517
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English (en)
Chinese (zh)
Inventor
张嘉杰
王广发
伍小云
吴少瑜
刘中秋
万山河
庞建新
徐伟
游文玮
吴曙光
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Southern Medical University
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Southern Medical University
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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
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Protein kinases are a class of phosphotransferases that act to transfer the Y phosphate group of ATP to a specific amino acid residue of a substrate to phosphorylate the protein. Protein kinase plays a major role in signal transduction in two ways: First, phosphorylation regulates protein activity, phosphorylation and dephosphorylation are common mechanisms for reversible activation of most signaling pathway components, and some proteins are phosphorylated. After the activity, some are active after dephosphorylation; the second is through the phosphorylation of the protein, the signal is amplified step by step, causing cell reaction.
  • protein kinase activity is not only directly related to tumors, but also lead to a range of other human diseases associated with inflammation or proliferative responses, such as rheumatoid arthritis, cardiovascular and neurological diseases, asthma, psoriasis. The main reason for waiting. More than 400 human diseases are known to be directly or indirectly related to protein kinases. This makes protein kinases another important class of drug targets following G-protein coupled receptors.
  • the protein kinase family consists of more than 500 members and is usually classified into protein tyrosine kinases (PTKs) and serine-threonine kinases.
  • Receptor kinases are generally tyrosine kinases, also known as receptor tyrosine kinases (RTKs), which are composed of a receptor moiety, a transmembrane region, and an intracellular portion of the cell membrane surface. The kinase moiety is located within the cell. Serine - threonine kinase majority located intracellularly, or is a non-receptor kinases called cytoplasmic kinase (cytosolic kinases) 0
  • a typical representative of the RTKs family is growth factor receptors, which have at least 19 subfamilies. Here are a few major subfamilies:
  • HER family tyrosine receptor kinases including EGFR (epithelial growth factor receptor) ⁇ HER2, HER3 and HER4.
  • EGFR epidermal growth factor receptor
  • HER2 epidermal growth factor receptor
  • HER3 epidermal growth factor receptor
  • EGFR epidermal growth factor receptor
  • IGF-1R insulin-like growth factor I receptor
  • IRR insulin receptor-associated receptors
  • the PDGFRs family including PDGFRc PDGFRp, CSF1R, c_kit, and c-fms.
  • One of the members is the molecular target of the leukemia treatment Gleevec®.
  • VEGFRs vascular endothelial growth factor receptors
  • FLT1 Fms-like tyrosine kinase 1 or VEGFR1
  • KDR or VEGFR-2
  • FLT4 or VEGFR3
  • Avastin® is the molecular target of the colorectal cancer treatment drug Avastin®.
  • FGFRs Family of fibroblast growth factor receptors (FGFRs), including FGFR1, FGFR2, FGFR3 and FGFR4 and seven ligands FGF1, FGF2, FGF3, FGF4, FGF5, FGF6 and FGF7.
  • FGFRs fibroblast growth factor receptors
  • FGF1, FGF2, FGF3, FGF4, FGF5, FGF6 and FGF7 members of the drug as molecular targets are still in clinical trials.
  • MET family including c-Met or human hepatocyte growth factor receptor or hHGFR and RON.
  • c-Met plays an important role in the growth and metastasis of initial tumors. Its drug as a molecular target is still in clinical trials.
  • the activity of protein kinases is associated with many diseases in humans and is a drug target for the treatment of these diseases.
  • receptor kinases there are many kinds of receptor kinases, and it is necessary to constantly seek new drugs.
  • imidazopyridines are a wide variety of compounds that are widely used in medicine, and there are many kinds of imidazoles which inhibit the activity of protein kinases (such as VEGFR2, FLT3, c-KIT, CSF1R, etc.).
  • a pyridine compound such as an imidazole as a PAF/Hi antagonist, described in an invention patent entitled "Imidazopyridine PAF/H, Antagonist” (CN1064275), which was issued by the National Science and Technology Bureau on September 9, 1992.
  • a pyridine compound for treating allergic inflammation the molecular structure of which is shown in the following formula;
  • Imidazopyridine as a cell cycle-dependent kinase inhibitor described in the patent application of the "New imidazopyridine as a cell cycle-dependent kinase inhibitor" disclosed by the National Patent Office on November 30, 2005 a compound for controlling diseases associated with cell cycle-dependent kinases, such as various cancers, tumors, and leukemias, the molecular structure of which is shown below;
  • the molecular structure of the novel imidazopyridine compound provided by the present invention is as shown in Formula I,
  • R1 and R2 are independent, respectively:
  • R3 means:
  • fluorenyl substituted fluorenyl group a 3-12 membered saturated or partially saturated heterocyclic substituted fluorenyl group, a 3-12 membered saturated or partially saturated heterocyclic substituted Cm fluorenyl substituted fluorenyl group, Cw 2 a mercapto-substituted fluorenyl-substituted fluorenyl group, d.
  • (9) a 3-12 membered saturated or partially saturated heterocyclic group, a 12 fluorenyl substituted 3-12 membered saturated or partially saturated heterocyclic group, an amino group, a hydroxy group, a cyano group, a halogen, a nitro group, a carboxy group or a fluorenyl group substituted d.
  • 12 alkoxy substituted 3-12 membered saturated or partially saturated heterocyclic group d 12 alkyl substituted amino substituted d.
  • Q 2 is alkyl with a substituted amino group substituted alkylsulfinyl _ 12 alkyl with a substituted 3-12-membered saturated or Partially saturated heterocyclyl, Q). 12 alkyl substituted aminosulfonyl group substituted with a d. 12 alkyl substituted 3-12 membered saturated or partially saturated heterocyclic group, Q). 12 embankment substituted ureas substituted .
  • X represents oxygen, sulfur, N-CN, or N-N0 2 ;
  • Ar and Ar' are each independently and represent an aryl or heteroaryl group, and 1 to 4 hydrogens on the aromatic ring or heteroaryl ring may be substituted by R3, aryl or heteroaryl.
  • the compounds of the present invention also include racemates and enantiomers of the structure of formula I.
  • R1 in the compound represents hydrogen
  • R2 represents an amino group.
  • R1 in the compound represents an amino group
  • R2 represents hydrogen.
  • X in the compound represents oxygen.
  • Ar and Ar' in the compound are a benzene ring, a pyridine, a pyridone, a tetrahydropyridone, an acetidine, a pyrazine, a pyridazine, an imidazole, a thiazole, a thiophene, a furan, Any one of hydrazine, azaindene, benzimidazole, porphyrin or fluorenone, and 1 to 4 hydrogens on the benzene ring or heterocyclic ring may be substituted by R3, aryl or heteroaryl.
  • R1 in the compound represents hydrogen or an amino group
  • R2 represents hydrogen or an amino group
  • X represents oxygen
  • Ar represents a benzene ring
  • Ar' represents a benzene ring or is 1 or 2 identical or different groups.
  • a group-substituted benzene ring the group being a halogen, a methyl group, a methoxy group, a halogen-substituted methyl group or a halogen-substituted methoxy group; the compound described in the present scheme may be further selected from any one of Table 1. .
  • the compound of the present invention is a 1-aminoimidazo[1, 5-a] pyridine compound, the compound The chemical synthesis method is as shown in the following formula II.
  • compound 11 is equivalent to a compound when R1 in formula I is an amino group.
  • Compound 1 is reduced to a primary amine containing 2 with a reducing agent in an organic solvent;
  • the organic solvent is methanol, ethanol, isopropanol, n-butanol, tert-butanol, ethyl acetate, Ether, propyl ether, toluene, benzene, xylene, tetrahydrofuran, acetonitrile, 1,2-dimethoxyacetamidine, etc.
  • the reducing agent is hydrogen, lithium tetrahydrogenate, sodium borohydride, diisobutylaluminum hydride, Red aluminum, etc.;
  • the agent is hydrogen, lithium aluminum hydride, sodium borohydride, diisobutylaluminum hydride, red aluminum or the like.
  • the starting material in the above reaction that is, the compound 1 is R3 substituted 3-bromo-2-cyanopyridine, is commercially available.
  • the compound of the present invention is a 3-aminoimidazo[1,5-a] pyridine compound, and the chemical synthesis method of the compound is as shown in Formula III. .
  • the starting material a in the above reaction is R3 substituted 2-bromo-6-formylpyridine, which is commercially available; the starting materials a and b are subjected to metal-catalyzed coupling reaction to obtain compound c; c is reductively aminated to obtain compound b.
  • VEGFR2 vascular endothelial growth factor receptor 2
  • FLT3 tyrosine kinase 3
  • c-Kit human stem cell factor receptor
  • ⁇ for the preparation of drugs for the treatment of diseases caused by abnormal increase in VEGFR2, FLT3 and c-Kit activity, such as cancer, psoriasis, cirrhosis, diabetes Eye diseases such as AMD, rheumatoid arthritis and other inflammations, immune system diseases (such as autoimmune diseases), cardiovascular diseases (such as atherosclerosis) and kidney diseases.
  • the compounds of the present invention are useful for treating diseases caused by abnormalities in the activity of VEGFR2, FLT3 and c-kit,
  • the effective dose is 0.1 to 100 mg per kilogram of body weight per day, and the optimized dose is 1 to 70 mg per kilogram of body weight per day; the frequency of administration depends on different diseases, usually 1 to 4 times per day, preferably 2 to 3 times.
  • the medicament for treating diseases caused by abnormal activity of VEGFR2, FLT3 and c-kit of the present invention mainly consists of the compound of the present invention and a pharmaceutically acceptable adjuvant, and may also contain other auxiliary drugs, such as antibacterial agents, One or more of an antifungal agent, an antimicrobial agent, a vitamin, an antitumor drug, and the like, the compound of the present invention may be present in the drug by the following means:
  • a pharmaceutically acceptable salt that is, a salt formed by reacting a compound of the present invention with a medically acceptable acid or base, and the acid may be an inorganic acid or an organic acid such as hydrochloric acid or hydrobromic acid.
  • a solvate that is, a stable substance formed by covalent bond, ionic bond, hydrogen bond, van der Waals force, complexation, inclusion, and the like of the compound of the present invention and a pharmaceutically-usual solvent
  • the solvent may be Is methanol, ethanol, propanol, butanol, ethylene glycol, propylene glycol, polyethylene glycol, acetone, etc.;
  • a prodrug that is, a compound of the present invention is converted into another compound by chemical synthesis or physical means, and when the compound is administered to a mammal, it is converted into a compound of the invention in its body.
  • the "prodrug” method is usually used to overcome the poor or poor physicochemical properties or drug-forming properties of the drug compound itself.
  • the compounds of the present invention may also exist in their tautomeric form (Tautomers), rotamers (rotamers), cis and trans isomers and the like, these concepts can be in J. March in "Advanced Organic Chemistry," 4 th edition Found and understood.
  • these isomers have the same effect of inhibiting protein kinase activity as the compounds of the present invention, these isomers are also encompassed by the present invention.
  • the compound of the present invention is administered to a mammal such as a human, it is highly known in the art that it is metabolized into various metabolites by different enzymes in the animal as long as these metabolites have the same properties as the compounds of the present invention.
  • the effect of inhibiting protein kinase activity, these metabolites are also encompassed by the present invention.
  • the medicament of the present invention can be administered orally, for example, into tablets, capsules, syrups, gels, pills, oral liquids, etc.; and can also be administered by injection, such as preparation into sterile solutions, suspensions, emulsions. Etc.; can also be administered by anal plug, such as preparation of a suppository, gel, etc.; can also be administered by inhalation through the nostrils, such as preparation into a spray, an aerosol, and the like.
  • the packaging and preservation of the medicament of the invention are similar to those of a general western medicine.
  • the solid dosage form of the medicine can be directly loaded into a glass, a plastic, a paper or a metal bottle, and a desiccant or the like is preferably placed in the bottle to maintain the quality of the drug;
  • the dosage form of the drug is generally contained in a glass, plastic or metal bottle or hose;
  • the aerosol type drug is generally contained in a metal or plastic container with a pressure-resistant device such as a pressure reducing valve.
  • Mercapto refers to a straight chain, branched chain, and cyclic hydrocarbon group having the specified number of carbon atoms.
  • c 1-12 fluorenyl refers to a straight chain, branched chain having a minimum of 1 and a maximum of 12 carbon atoms.
  • C. Represents a covalent chemical bond.
  • the fluorenyl group in the present invention includes, but is not limited to, methyl, ethyl, propyl, butyl, cyclopentyl, cyclohexyl, isopropyl, neopentyl, 2-methyl-1-hexyl and the like.
  • One or all of the hydrogen atoms in the fluorenyl group may be substituted by halogen, amino, hydroxy, cyano, nitro, carboxy, decyl, oxy (OXO) and the like.
  • oxiranyloxy group in the present invention includes, but is not limited to, a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a cyclopentyloxy group, a cyclohexyloxy group, an isopropoxy group, a neopentyloxy group, a 2-methyl group. Ke-1-hexyloxy and the like.
  • One or all of the hydrogen atoms in the alkoxy group may be substituted by the following groups: halogen, amino, hydroxy, cyano, nitro, carboxy, decyl, oxy (0X0) and the like.
  • Halogen means fluoro, chloro, bromo, iodo.
  • the "3-12 membered saturated or partially saturated heterocyclic group” means a monocyclic or polycyclic fluorenyl group composed of 3 to 12 atoms, wherein at least one of the atoms is 0, N, S, S0, S0 2 , P or Si.
  • these monocyclic or polycyclic fluorenyl groups may contain double or triple bonds, but do not constitute all conjugated aromatic structures.
  • These monocyclic or polycyclic fluorenyl groups may exist in the form of fused rings, bridged rings or spiro rings.
  • the 3-12 membered saturated or partially saturated heterocyclic group in the present invention includes, but is not limited to, piperidine, morpholine, piperazine, pyrrolidine, porphyrin, tetrahydropyridine, tetrahydrofuran, tropinol, etc., as shown in Table 2.
  • One or all of the hydrogen atoms in the heterocyclic group may be substituted by halogen, amino, hydroxy, cyano, nitro, carboxy, decyl, oxy (0X0) and the like.
  • Aryl means a monocyclic or polycyclic structure consisting of 5 to 12 carbon atoms, at least one of which has a conjugated aromatic structure (i.e., conforms to the N+2 rule), but the entire structure does not have to be fully conjugated.
  • the aryl group may also be present in the form of a subunit, i.e., two points of attachment to other groups in the conjugated aromatic structure.
  • the aryl group in the present invention includes, but is not limited to, a phenyl group, a naphthyl group, an anthracenyl group, an indanyl group, a tetrahydronaphthalene or the like.
  • One or all of the hydrogen atoms in the aryl group may be substituted with a halogen, an amino group, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, a decyl group, an oxy group (OXO) or the like.
  • Heteroaryl means a monocyclic or polycyclic structure consisting of 5-12 atoms, wherein at least one atom is 0, N, S, S0, S0 2 , P or Si, and at least one ring has a conjugation
  • the aromatic structure ie conforms to the N+2 rule, but the entire structure does not have to be fully conjugated.
  • Heteroaryl groups can also occur in the form of subunits, that is, two points of attachment to other groups in the conjugated aromatic structure.
  • Heteroaryl groups in the present invention include, but are not limited to, pyridine, pyridone, tetrahydropyridone, imidazine, pyrazine, pyridazine, imidazole, thiazole, thiophene, furan, anthraquinone, azaindole, benzimidazole, Porphyrin, anthrone, quinone, etc., as shown in Table 3; one or all of the hydrogen atoms in the aryl group may be substituted by the following groups: halogen, amino, hydroxy, cyano, nitro, carboxy, fluorenyl, Oxyl (OXO) and the like.
  • High performance liquid chromatography was performed using a Waters 2695 Z0RBAX high performance liquid chromatograph (Bx_C 8 5 ⁇ 150 x 4. 6 mm column).
  • the melting point was determined using an Electrothermal digital melting point apparatus IA9100 and was uncorrected.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • the results of the magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i 6 ) ⁇ 8.39 (d, IH), 7.74 (s, IH), 7.54 (d, 2H), 7.43 (d, 2H), 7.27 - 7.40 (m, 3H), 6.60-6.72 (m, 2H), 2.32 (s, 3H).
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • (6) Preparation of the final product l-[4-(l-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-bromophenyl)urea: 4 -(1 -Nitroimidazole [1, 5-a]pyridin-8-yl)aniline (508 mg, 2 mmol dissolved in DCM 25 mL), then 2-bromophenylisocyanate (386 mg, 2 mmol). After 5 hours, the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Acetic acid (480 mg, 8 mmol) and EDC.HC1 (1.917 g, 10 mmol) were suspended in DCM (20 mL) and diisopropylethylamine (2.585 g, 20 mmol) was added dropwise with stirring After the addition was completed, the mixture was stirred at room temperature for half an hour, (3 - bromopyridin-2-yl)methylamine hydrochloride (0. 894 g, 4 mmol) was added and stirring was continued for 2 hr. The solvent was removed by rotary evaporation and the residue was applied to silica gel column .
  • Phosphorus oxychloride (1 mL) was added to a solution of (3-bromopyridin-2-yl)methylacetamide (0. 687 g, 3 mmol) in toluene (4 mL). The mixture was refluxed for 7 hours. Excess phosphorus oxychloride and solvent were removed by rotary evaporation, and the resulting viscous liquid was hydrolyzed with ice water at 0 ° C and basified with concentrated aqueous ammonia. The aqueous phase was extracted with EtOAc (EtOAc)EtOAc.
  • Steps (1) to (5) are the same as in Example 24.
  • Steps (1) to (5) are the same as in Example 24.
  • Steps (1) to (5) are the same as in Example 24.
  • Steps (1) to (5) are the same as in Example 24.
  • Steps (1) to (5) are the same as in Example 24.
  • Steps (1) to (4) are the same as in Example 30;
  • Steps (1) to (4) are the same as in Example 30;
  • Steps (1) to (4) are the same as in Example 30;
  • Steps (1) to (4) are the same as in Example 30;
  • Step (1:) ⁇ (4) is the same as in Example 30;
  • Steps (1) to (4) are the same as in Example 30;
  • the concentration of the peptide substrate (Biotin-Ahx-AEEEYFFLFA-amide) is 4 ⁇ , and the concentration of adenosine triphosphate (ATP) is 1 mM, the corresponding kinase and urea compound inhibitor was reacted in the following solution for 1 hour at room temperature: 50 mM Hepes/NaOH H 7. 5, 10 mM MgCl 2 , 2 mM MnCl 2 , 2. 5 mM DTT, 0.1 mM orthovanadate, and 0.
  • the inhibitor of the present invention was added to the wells of a 96-well plate at a final concentration of 3.2 nM to 50 ⁇ M with 5% DMS0 as a co-solvent.
  • the reaction was stopped by the following method: 10 ⁇ M per well of 0.5 M EDTA, followed by containing streptavidin-allophycocyanin (prozyme; 1. 1 g/mL and PT66 antibody europium cryptate (Ci s-Bio; 0.1 g/mL) Plate reading method: After adding the detection reagent for 1-4 hours, the fluorescence was measured with a Packard Discovery instrument (the ratio of 665 to 615). The detected signal-to-noise ratio is between 10 and 15.
  • the semi-inhibitory concentration is at least two tests.
  • the average value of the biochemical semi-inhibitory concentrations (IC 5 ) of VEGFR, FLT3, and c-KIT of the compounds obtained in Examples 1 to 38 are shown in Table 4.
  • Example 11 Compound 8 23 15
  • Example 12 Compound 370 43 79
  • the compounds of the present invention have a good inhibitory effect on VEGFR, FLT3, c-KIT, and the biochemical half-inhibitory concentration (IC 5 ) is mostly less than 100 ⁇ , wherein 1- [4- (1-amino) Imidazole [l,5-a]pyridin-8-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea, 1-[4-(1-aminoimidazole[1, 5- a]pyridin-8-yl)phenyl]-3-(4-fluoro-3-methylphenyl)urea, 1-[4-(1-aminoimidazo[1,5-a]pyridin-8 -yl)phenyl]-3-(3-fluorophenyl)urea, 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(3 -Methylphenyl)urea, 1-[4-(1-aminoimidazo[1,5
  • the target compound 1_[4-(1-aminoimidazo[1, 5-a]pyridin-8-yl)phenyl]-3-(2-fluoride) of Example 32 was compared with the model group. After the administration of 5-methylphenyl)urea, the medium- and high-dose oral administration had a significant inhibitory effect on the subcutaneous transplantation of human colon cancer Colo205 cells in BALB/c nude mice, and the tumor inhibition rate was 11.8% and 16.
  • tumor volume they were randomly divided into model group, high (20 mg/kg), medium (10 mg/kg), and low dose group (5 mg/kg), with 8 rats in each group, half male and half female. It was administered by intragastric administration for 12 consecutive days. The long and short diameters of the tumor were measured on the 4th, 7th, and 12th day after administration, and the tumor volume and tumor inhibition rate were calculated.
  • Tumor volume /6 (long diameter short diameter 2).
  • Tumor inhibition rate (average volume of the model group - average volume of the administration group) / average volume of the model group X 100%.
  • the target compound of Example 2 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-), was compared with the model group. 4 days after the administration of fluoro-5-methylphenyl) urea, medium and high doses of oral administration of human gastric cancer HS-746T cells BALB/c nude mice subcutaneously transplanted tumors have a significant inhibitory effect, the tumor inhibition rate was 11.
  • Example 1 Dropping pills (dosage: 25 mg/granule) [Formulation prescription]
  • Example 2 target compound 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl] 3-(2-Fluoro-5-methylphenyl)urea 2. 5g
  • a total of 100 capsules were prepared, each containing 25 rag of the compound.
  • [Preparation method] Weigh the compound 2. 5 g, 5 ml of absolute ethanol (37 ° C), and set aside. Another PGE6000 was dissolved in a water bath at 80 ° C, mixed with PEG400, and stirred. Insulation, slowly add the prepared compound ethanol solution, stir while stirring, make it fully mixed and have no alcohol flavor, add glycerin, filter with gauze while hot, place in a storage bottle, keep warm at 80 °C, use the inside of the tube , the outer diameter of 9. 0mm, 9.
  • Example 2 Dropping pills (dosage: 50 mg/granule) [Formulation prescription]
  • Example 2 target compound 1 - [4-(1-aminoimidazo[1, 5-a]pyridin-8-yl)phenyl] -3 - (2-Fluoro-5-methylphenyl)urea 5g
  • a total of 100 capsules were prepared, each containing 50 mg of the compound.
  • the dropping speed is 40 drops / min, dripping into the liquid paraffin (the outer layer is ice water bath) in the cooling liquid, condensing into pellets, sucking off the paper with burrs Attached liquid paraffin, that is, (every 0. 2g), quality inspection, packaging, that is.
  • Example 3 Tablet (dosage: 25 mg/tablet)
  • Example 2 target compound 1- [4-(1-aminoimidazo[1, 5-a]pyridin-8-yl)phenyl] -3 - (2-Fluoro-5-methylphenyl)urea 2. 5 g
  • a total of 100 tablets were prepared, each containing 25 mg of the compound.
  • [Preparation method] Weigh the compound 2. 5g, ball milled into a very fine powder, and set aside. Take PVP water bath heating (80 ⁇ ) to dissolve, add the prepared compound fine powder, stir the hook, then add microcrystalline cellulose, wheat starch, add appropriate amount of anhydrous ethanol to soft material, use 14 mesh sieve to make granules, set 70- After drying at 80 ° C, the granules were sieved on a 12-mesh sieve, and talc powder was added thereto, and the tablets were granulated (0.25 g/tablet), and quality inspection was obtained.
  • Example 4 Tablet (dosage: 50 mg/tablet) [Formulation Formulation]
  • Example 2 target compound 1- [4-(1-aminoimidazo[1, 5-a]pyridin-8-yl)phenyl] -3 - (2-Fluoro-5-methylphenyl)urea 5g
  • a total of 100 tablets were prepared, each containing 50 n) g of the compound.
  • [Preparation method] 5 g of the compound was weighed and ball-milled into a very fine powder for use. Take PVP water bath heating (80 ° C) to dissolve, add the prepared compound fine powder, stir well, then add microcrystalline cellulose, wheat starch, add appropriate amount of anhydrous ethanol to soft material, use 14 mesh sieve to make the grain, set After drying at 70-80 ° C, the granules were sieved on a 12-mesh sieve, and talc powder was added, and the tablets were compressed (0.3 g/tablet). Check, that is.
  • Example 2 target compound 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-fluoro-5-methylphenyl) Urea 2.5 g
  • a total of 100 capsules of hard capsules were prepared, each containing 25 mg of the compound.
  • [Preparation method] Take the compound into a fine powder, pass through a 80 mesh sieve, and set aside; take a 10% starch slurry and add a small amount of edible orange (maximum dosage is one ten thousandth) to make a yellow paste; After mixing the wheat starch, add yellow paste, make soft material, granulate through 14 mesh nylon sieve, dry at 70 °C to below 3% of water, fill it into empty capsule after whole grain, get (5 capsules, each capsule 0.1 g), quality inspection, packaging, that is.
  • Example 6 Capsule [prescription]
  • Example 2 target compound 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea 5 g wheat Starch 19g

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Abstract

Cette invention concerne des imidazopyridines de formule I. Ces composés présentent une activité inhibitrice des protéines kinases, en particulier des récepteurs de VEGFR2, FLT3 et C-KIT, entre autres, et peuvent être utilisés dans la préparation du médicament pour traiter les maladies associées avec un taux anormalement élevé de l'activité kinase, comme le cancer.
PCT/CN2008/000517 2008-03-05 2008-03-17 Composés imidazopyridines Ceased WO2009109071A1 (fr)

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WO2013045653A1 (fr) 2011-09-30 2013-04-04 Oncodesign S.A. Inhibiteurs de kinase flt3 macrocycliques
US8759344B2 (en) 2010-07-06 2014-06-24 Sanofi Imidazopyridine derivatives, process for preparation thereof and therapeutic use thereof
US20150072986A1 (en) * 2013-06-11 2015-03-12 Kala Pharmaceuticals, Inc. Urea derivatives and uses thereof
US10174022B2 (en) 2014-12-10 2019-01-08 Kala Pharmaceuticals, Inc. 1-amino-triazolo(1,5-A)pyridine-substituted urea derivative and uses thereof
WO2019040102A1 (fr) * 2017-08-22 2019-02-28 Gilead Sciences, Inc. Composés hétérocycliques thérapeutiques
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US9452164B2 (en) 2010-07-06 2016-09-27 Sanofi Imidazopyridine derivatives, process for preparation thereof and therapeutic use thereof
WO2013014170A1 (fr) 2011-07-27 2013-01-31 Ab Science Dérivés d'oxazole et de thiazole comme inhibiteurs sélectifs de protéines kinases (c-kit)
US9168245B2 (en) 2011-07-27 2015-10-27 Ab Science Selective protein kinase inhibitors
US9370519B2 (en) 2011-09-30 2016-06-21 Oncodesign S.A. Macrocyclic FLT3 kinase inhibitors
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US9090630B2 (en) 2011-09-30 2015-07-28 Oncodesign S.A. Macrocyclic FLT3 kinase inhibitors
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