WO2014154026A1 - Promédicament inhibiteur de pi3k et/ou mtor - Google Patents

Promédicament inhibiteur de pi3k et/ou mtor Download PDF

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Publication number
WO2014154026A1
WO2014154026A1 PCT/CN2014/000343 CN2014000343W WO2014154026A1 WO 2014154026 A1 WO2014154026 A1 WO 2014154026A1 CN 2014000343 W CN2014000343 W CN 2014000343W WO 2014154026 A1 WO2014154026 A1 WO 2014154026A1
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Prior art keywords
group
membered
alkyl
trifluoromethyl
hydroxyl
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PCT/CN2014/000343
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English (en)
Chinese (zh)
Inventor
吴永谦
薛建军
李琳
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山东轩竹医药科技有限公司
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Priority to CN201480010513.9A priority Critical patent/CN105121442B/zh
Publication of WO2014154026A1 publication Critical patent/WO2014154026A1/fr
Priority to HK16101002.6A priority patent/HK1213242A1/zh

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the present invention relates to prodrugs of PI3K and/or mTOR inhibitors, pharmaceutically acceptable salts thereof and stereoisomers thereof, and pharmaceutical compositions comprising these compounds.
  • the present invention also relates to a process for the preparation of the above-mentioned prodrug compound and its use in the preparation of a medicament for the treatment and/or prevention of a proliferative disease. Background technique
  • a tumor is a new organism formed by the body under the action of various tumorigenic factors, causing changes in cellular genetic material, resulting in abnormal gene expression and abnormal cell proliferation.
  • Tumor cells lose normal growth regulation and have the ability to grow autonomously or relatively independently. When the tumorigenic factors stop, they can continue to grow and consume a lot of nutrients. If found and treated in time, cancer cells can also be transferred to all parts of the body to grow and reproduce, and release a variety of toxins, leading to body weight loss, anemia, impaired organ function and even death.
  • PI3K phosphatidylinositol 3-kinase pathway
  • mTOR mammalian target of rapamycin
  • PI3K a member of the lipid kinase family, regulates cellular metabolism and growth by producing phosphoryl phosphatidylinositol triphosphate (PIP3) via phosphorylation of the phosphatidyl alcohol.
  • PIP3 phosphoryl phosphatidylinositol triphosphate
  • mTOR is a silk/threonine protein kinase present in the cytoplasm and belongs to the phosphoinositide 3 kinase-associated protein kinase family. It exists in the form of two complexes in vivo, namely mTORCl (the action of rapamycin). Target) and mTORC2 (not inhibited by rapamycin).
  • mTOR is a cell signal transduction protein that regulates the response of tumor cells to nutrients and growth factors and controls the blood supply to the tumor by acting on vascular endothelial growth factor. mTOR inhibitors can starve cancer cells and shrink tumor size by inhibiting the action of mTOR.
  • PI3K and/or mTOR inhibiting compounds are disclosed in International Application No. PCT/CN2013/001061, filed on Sep. 12, 2013, which is incorporated herein by reference.
  • the compound is prepared as a prodrug, the prodrug compound has the physical and chemical properties of the original drug, improves the selectivity of the drug to the target site, and improves the pharmacokinetic process of absorption, distribution, transport and metabolism of the drug in the body.
  • the development of crystal forms is of great significance.
  • the invention relates to:
  • a and B are each independently CR 6 , and R 6 is hydrogen, a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, -(CH 2 ) n NR 8a R 8b , -(CH 2 ) n C(0)R 9 , (CH 2 ) n C(0)NR 8a R 8b , -(CH 2 ) n OC(0)R 9 , -(CH 2 ) n C(0)(CH 2 ) n OR 9 , -(CH 2 ) n N(R 8a )C(0)R 9 , or optionally 1-3 C 1-6 alkyl, alkoxy substituted with a halogen atom, a hydroxyl group, a carboxyl group;
  • R 1 is hydrogen, or C 1-6 alkyl, C 2-8 alkenyl, C 2-8 block, C 3-8 cycloalkyl, 6-14, optionally substituted by 1-5 R 7a
  • R 2 is hydrogen, or C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 6-14, optionally substituted by 1 to 5 R 7b
  • R 3 is hydrogen, or optionally 1-3 alkyl groups selected from a halogen atom, a hydroxyl group, a carboxyl group;
  • R 4 and R 5 are each independently hydrogen, or optionally 1-3 are selected from a halogen atom, a hydroxyl group or a carboxyl group substituted d. 6 alkyl group;
  • n 1 ⁇ 3;
  • E is hydrogen, or a cation of an inorganic or organic base capable of forming a salt with phosphoric acid
  • R 7a and R 7b are each independently
  • R 8a and R 8b are each independently hydrogen, or optionally 1 to 3 hydroxyl groups, a halogen atom, a cyano group, a carboxyl group, (this group is defined by R 8a , R 8b , R 8a , R 8b ) ⁇ sulfonyl group , carbamoyl, sulfonylamino substituted alkyl,. . 38 cycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl;
  • R 9 is hydrogen, or optionally 1-3 C 1-6 alkyl group selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, -(CH 2 ) n NR 8a R 8b , a sulfonyl group, a decanoyl group , C 1-6 alkoxy; n is 0 to 4.
  • a and B are each independently CR 6 , R 6 is hydrogen, or optionally 1-3 d. 6 alkyl groups selected from a halogen atom, a hydroxyl group, a carboxyl group;
  • R 1 is a 6-10 membered aryl group optionally substituted by 1 to 3 R 7a , a 5-6 membered monoheteroaryl group, a 9-10 membered heteroaryl group, a 5-6 membered monoheterocyclic group, 9- 10-membered fused heterocyclic group;
  • R 2 is a 6-10 membered aryl group optionally substituted by 1 to 3 R 7b , a 5-6 membered monoheteroaryl group, a 9-10 membered heteroaryl group, a 5-6 membered monoheterocyclic group, 9- 10-membered fused heterocyclic group;
  • R 3 is hydrogen
  • R 4 and R 5 are each independently hydrogen or d. 6 alkyl
  • E is hydrogen, or a metal cation of an inorganic or organic base capable of forming a salt with phosphoric acid
  • R 7a and R 7b are each independently
  • R 8a and R 8b are each independently hydrogen or d_6 alkyl
  • R 9 is hydrogen or an alkyl group
  • n 0 ⁇ 2.
  • a and B are each independently CR 6 and R 6 is hydrogen or an alkyl group
  • R 4 and R 5 are each independently hydrogen
  • n 1;
  • E is hydrogen or sodium ion.
  • R 1 is phenyl optionally substituted by 1-3 R 7a , 5-6 membered monoheteroaryl;
  • R 2 is phenyl optionally substituted by 1 to 3 R 7b , 5-6 membered monoheteroaryl, 9-10 membered fused heteroaryl;
  • a halogen atom a cyano group, a hydroxyl group, a trifluoromethyl group, -NR 8a R 8b , -C(0)R 9 , -C(0)NR 8a R 8b , -OC(0)R 9 , -N (R 8a )C(0)R 9 ,
  • R 8a and R 8b are each independently hydrogen or d_6 alkyl
  • R 9 is hydrogen or an alkyl group.
  • R 1 is phenyl, pyridinium 5 ⁇ , pyrimidine 1 ⁇ optionally substituted by 3 1 7 <
  • R 2 is optionally substituted with 1-3
  • R 7b is phenyl, pyridyl, pyrimidinyl, thienyl, pyrazolyl, indazolyl 11 sit yl, indazol noise, pyrazolyl, pyrrolyl and 17 set, and each of the pyrazole-pyrazol P ⁇ J ⁇ , pyridinopyridin>3 ⁇ 4 ⁇ , phenyl group;
  • halogen atom a hydroxyl group, a trifluoromethyl group, -NH 2 , -C(0)R 9 , -SR 9 , -S(0) 2 R 9 , -NHC(0)R 9 ,
  • pyrrolyl optionally pyrrolyl, pyrazolyl, imidazole selected from 1 to 3 halogen atoms, hydroxy, cyano, trifluoromethyl, C- 4 alkyl, Ci- 4 alkoxy, -NH 2 Base, piperidinyl, piperazinyl, morpholinyl;
  • R 9 is hydrogen or d. 4 alkyl.
  • R 1 is phenyl, pyridyl 1 ⁇ optionally substituted by 1-3 1 73 ;
  • R 2 is phenyl, pyridyl, pyrimidinyl, thienyl, pyrazolyl, oxazolyl, anthranyl, pyridopyrrolyl, pyrrolopyridyl "pyridyl", optionally substituted by 1-3 1 715 Zizolopyryl 3 ⁇ 4 ⁇ , quinolinyl;
  • a halogen atom a cyano group, a hydroxyl group, a trifluoromethyl group, -NH 2 , (2) optionally consisting of 1-2 methyl, ethyl, isopropyl groups selected from hydroxy, cyano, trifluoromethyl,
  • halogen atom a cyano group, a hydroxyl group, a trifluoromethyl group, -NH 2 , -SR 9 , -S(0) 2 R 9 , -NHC(0)R 9 ,
  • R 9 is hydrogen, decyl or ethyl.
  • halogen atom as used in the present invention includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • d- 6 alkyl group as used in the present invention means a straight or branched alkyl group having 1 to 6 carbon atoms, and specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, and Butyl, 2-methylpropyl, 1-methylpropyl, 1 ,1-didecylethyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl Base, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl,
  • C 3-8 cycloalkyl group as used in the present invention means a cyclic alkyl group having 3 to 8 carbon atoms, and specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclooctyl and the like.
  • the "C 2-8 alkenyl group” may be straight-chain or branched, and includes, for example, “C 2 - 6 alkenyl", “C 2 - 4 alkenyl”, “C 2 - 3 alkenyl", “C” 3 _6 cycloalkenyl” and the like, specific examples include, but are not limited to: vinyl, 1-propanyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadiene, 1 -pentenyl,
  • the "C 2-8 alkynyl group” may be linear or branched, and includes, for example, “Cw alkynyl group”, “C 2-4 alkynyl group”, “C 2-3 alkynyl group”, C 3-8 block "", specific examples include but are not limited to: ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentyne , 2-hexynyl, 3-hexynyl, 5-methyl-2-hexynyl, 2-heptynyl, 5-methyl-2-heptynyl, 2-octynyl, 3- Octyl group and the like.
  • CM alkoxy group as used in the present invention means "CW alkyl group - 0-", wherein "Cw alkyl group” is as defined above.
  • the "6-14 membered aryl group" of the present invention includes a 6 to 8 membered monocyclic aryl group and a 8 to 14 membered fused ring aryl group.
  • the 6 to 8 membered monocyclic aryl group includes, for example, a phenyl group, a cyclooctadecenyl group, and the like.
  • the 8 ⁇ 14 membered fused ring aryl group includes naphthalene, phenanthrene, 2,3-dihydroindenyl, fluorenyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, etc. (recommendation: Aryl groups already have a well-known meaning, and it is recommended that such groups be no longer customized to reduce errors and save space and thus reduce costs).
  • the "5-14 membered heteroaryl group" of the present invention includes a 5-8 membered monoheteroaryl group, a 6-14 membered fused heteroaryl group, and the hetero atom has nitrogen, oxygen, sulfur, etc., and includes a carbon atom. The case where the nitrogen atom and the sulfur atom are replaced by oxo.
  • 5-8 membered monoheteroaryl group include, but are not limited to, a furyl group, a thiop group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, a thiadiazolyl group, a thiol group, an isoxazolyl group, and an oxox group.
  • the "6-14 membered heteroaryl group” include, but are not limited to, benzofuranyl, benzisofuranyl, benzothienyl, fluorenyl, isoindole, benzoxazolyl, benzo Imidazolyl, carbazolyl, benzotriazolyl, quinolinyl, 2-quinolinone, 4-quinolinone, isoquinolinone, isoquinolyl, acridinyl, phenanthryl, benzopyrene Azinyl, pyridazinyl, quinazolinyl, quinoxalinyl, phenolzinyl, acridinyl, fluorenyl, naphthyridinyl, phenazine, phenothiazine, etc., preferably "9-10 yuan thick heteroaryl" base".
  • the "5-10 membered heteroaryl group" of the present invention includes a monocyclic heteroaryl group and a fused ring heteroaryl group, and the hetero atom includes nitrogen, oxygen, sulfur, etc., and includes a carbon atom, a nitrogen atom and a sulfur atom. The case of being replaced by oxygen.
  • the "3-14 membered heterocyclic group" described in the present invention includes a 3-8 membered monoheterocyclic group and a 6-14 membered fused heterocyclic group.
  • the hetero atom includes nitrogen, oxygen, sulfur, and the like, and includes a case where a carbon atom, a nitrogen atom, and a sulfur atom are substituted by oxo.
  • 3-8 membered monoheterocyclic group examples include, but are not limited to: aziridine group, 2/7-azetidinyl group, diaziryl group, 3-diazepine Heterocyclic propenyl, azetidinyl, 1,2-diazetanyl, azetidinyl, 1,2-dioxetane,
  • the "6-14 membered fused heterocyclic group" of the present invention include, but are not limited to, tetrahydroimidazo[4,5-c]pyridinyl, 3,4-dihydroquinazolinyl, 1, 2-dihydroquinoxalinyl, benzo[[1,3]dioxolyl, 1, 3-dihydroisobenzofuranyl, 2-chromogenyl, 2//-chromogen Alk-2-one, 4-alkenyl, 4//-chromen-4-one, chromanyl, 4 -1 ,3-benzoxazinyl, 4,6-dihydrofuran 3,4- ⁇ ]Imidazolyl, 3 ⁇ ,4,6,6-tetrahydrofuro[3,4-imidazolyl, 4,6-dihydrothieno[3,4-t]imidazolyl, 4,6-di Hydropyrrolo[3,4-imidazolyl, 4,5,6,7-
  • the "5-10 membered heterocyclic group" as used in the present invention includes a monoheterocyclic group and a fused heterocyclic group, and the hetero atom includes nitrogen, oxygen, sulfur, and the like, and includes a carbon atom, a nitrogen atom, and a sulfur atom by oxygen. Generation.
  • the "7-12-membered bridged ring group" as used in the present invention means a structure in which any two rings share two non-adjacent atoms and contains 7 to 12 carbon atoms or/and hetero atoms, and the hetero atom has Nitrogen, oxygen and sulfur, etc., include, for example, “7-10 yuan bridge ring", “7-9 yuan bridge ring”, “7-8 yuan bridge ring”, “7-8 yuan bridge ring” and the like. Examples thereof include, but are not limited to, for example:
  • 7-12 membered spirocyclyl as used in the present invention means a structure having at least two rings sharing one atom and having 7 to 12 carbon atoms or/and hetero atoms, said hetero atom having nitrogen, oxygen and Sulfur, etc., include, for example, “7-10 yuan spiro ring", “7-9 yuan spiro ring”, “7-8 element spiro ring”, “7-8 element spiro ring", and the like. Examples include, but are not limited to, for example:
  • the compounds of the present invention can be synthesized by the methods described in the following schemes and/or other techniques known to those of ordinary skill in the art, but are not limited to the following methods.
  • the intermediate 2 is dissolved in a suitable solvent (e.g., methanol, ethanol or tetrahydrofuran) which is miscible with water, and an aqueous solution of three equivalents of lithium hydroxide is added dropwise. After the dropwise addition was completed, the reaction was carried out at room temperature for 4 hours. After completion of the reaction, the solvent is removed by rotary evaporation, an appropriate amount of water is added, and the pH is adjusted with hydrochloric acid until the product is completely precipitated, and the intermediate 3 is obtained by suction filtration or recrystallization or column chromatography.
  • a suitable solvent e.g., methanol, ethanol or tetrahydrofuran
  • the intermediate 3 was suspended in an appropriate amount of thionyl chloride for several hours, and concentrated to remove volatile substances. It is then dispersed in an appropriate amount of tetrahydrofuran to control the temperature at 0. Under C, a mixture of an appropriate amount of triethylamine and a protecting agent-containing amine shield (PG-NH 2 ) was added dropwise. The reaction solution was stirred at room temperature until the reaction was completed by TLC, solvent was evaporated, and Intermediate 4 was obtained by recrystallization or column chromatography.
  • PG-NH 2 protecting agent-containing amine shield
  • the intermediate 4 was dispersed in an appropriate amount of ethyl chloroformate, and stirred under reflux until the completion of the reaction was confirmed by TLC, and the volatile matter was removed by rotary evaporation, and the intermediate 5 was obtained by recrystallization or column chromatography.
  • the raw material 2 and an appropriate amount of an organic or inorganic base, and a palladium reagent and/or a corresponding phosphine ligand are placed in an organic solvent (such as toluene, dioxane, dimethylformamide, ethylene glycol dimethyl ether, etc.) and In a mixed solvent of water, under a nitrogen atmosphere, the reaction was heated to TLC to monitor the consumption of the starting material, and the compound of the formula ( ⁇ ) was isolated by column chromatography.
  • an organic solvent such as toluene, dioxane, dimethylformamide, ethylene glycol dimethyl ether, etc.
  • the intermediate 8 was dissolved in methanol, and a base was added thereto, and the mixture was stirred for 10 minutes, and the solvent was evaporated to dryness and dried to give the compound of the formula (I).
  • RR 2 , R 3 , R 4 , R 5 , A, B, E and m are as defined above, and Hal represents a halogen selected from a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, preferably a chlorine atom.
  • the "pharmaceutically acceptable salt" of the compound of the formula (I) of the present invention means an acidic functional group (for example, -COOH, -OH, S0 3 H, etc.) present in the compound of the formula (I) with an appropriate inorganic base or organic A salt formed by a cation of a base, such as an alkali metal salt; and a salt formed by a basic functional group (for example, -NH 2 or the like) present in the compound of the formula (I) with an appropriate inorganic acid or organic acid anion.
  • E has been defined above as a cation, not a salt).
  • the compound of the formula (I), a pharmaceutically acceptable salt thereof and stereoisomers thereof of the present invention can be administered orally, parenterally (intravenously, intramuscularly, subcutaneously or rectally, etc.), pulmonaryly, locally, etc.
  • the method is administered to a mammal, such as a human.
  • the daily dose of the compound of the present invention may be from about 5 mg to 500 mg, preferably from 50 to 300 mg.
  • the compound of the formula (I), a pharmaceutically acceptable salt thereof and stereoisomers thereof of the present invention may be formulated into a pharmaceutical composition with one or more pharmaceutically acceptable carriers, and may be formulated into any pharmaceutically acceptable dosage form. It is administered orally, parenterally, or the like to a patient in need of such treatment.
  • the compound of the formula (I) of the present invention for oral administration, the compound of the formula (I) of the present invention, a pharmaceutically acceptable salt thereof and stereoisomers thereof, and conventional fillers, binders, disintegrators, lubricants and/or Or a diluent or the like to prepare a conventional solid preparation, such as a tablet, a capsule, a pill, a granule, etc.; or an oral liquid preparation, such as a solution of a mouth I, a suspension of a sputum, a syrup, etc. ;
  • parenteral administration it can be formulated into injections, including injections, sterile powders for injection and concentrated solutions for injection.
  • the compounds of the formula (I), pharmaceutically acceptable salts thereof and stereoisomers thereof of the present invention can be used for the treatment and/or prevention of proliferative diseases, and can be combined with one or more other therapies
  • the agent is especially a combination of an antitumor agent and an immunosuppressive agent.
  • the anti-tumor agent and immunosuppressive agent are selected from the group consisting of antimetabolites, including but not limited to capecitabine, gemcitabine, pemetrexed disodium; growth factor inhibitors, including but not limited to pazopanib, imatin Nie, erlotinib, lapatinib, gefitinib, vandetanib; antibodies, including but not limited to Herceptin, bevacizumab; mitotic inhibitors, including but not limited to paclitaxel, vinorelbine , docetaxel, doxorubicin; anti-tumor hormones, including but not limited to letrozole, tamoxifen, fulvestrant, flutamide, triptorelin; alkylating agents, including but Not limited to cyclophosphamide, nitrogen mustard, melphalan, cyclamate, carmustine; metal platinum, including but not limited to carboplatin, cisplatin, oxaliplatin; topoisome
  • the invention further relates to the use of a compound of formula U), a pharmaceutically acceptable salt thereof, and a stereoisomer thereof, for the manufacture of a medicament for the treatment and/or prevention of a proliferative disease, such as a tumor.
  • the proliferative diseases include cancer and non-cancerous proliferative diseases selected from the group consisting of brain tumors, lung cancer, squamous cells, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer.
  • cervical cancer endometrial cancer
  • rectal cancer liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, solid tumor, prostate cancer, thyroid cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone Cancer, skin cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, glioma or sarcoma; the non-cancerous proliferative disease is selected from, for example, skin or Benign hyperplasia of the prostate.
  • the compounds of the present invention are PI3K and/or mTOR inhibitors, have a good therapeutic effect on proliferative diseases such as (malignant tumors) caused by abnormal expression of PDKa and/or mTOR signaling pathway; and the compounds of the present invention have good solubility,
  • the physicochemical properties are stable, which is beneficial to the development of injectable preparations.
  • the in vivo pharmacokinetic experiments of injection administration prove that the compound has good pharmacokinetic properties, fast onset, and can be administered by injection, which can effectively solve the problem that critically ill patients cannot be taken orally.
  • the problem of drug administration is to expand the clinical application.
  • HEPES hydroxyethylpiperazine ethyl sulphate
  • EGTA ethylene glycol diethyl ether diamine tetraacetic acid
  • PIP2 4,5-diphosphophosphatidylinositol
  • ATP adenosine triphosphate
  • DMSO dimethyl sulfoxide
  • Tween-20 Tween 20.
  • Experimental Example 1 In vitro enzymatic inhibitory activity of compounds A and B
  • Test compound Compounds A, B prepared from Examples 1 and 3;
  • 1.1 1X kinase buffer 50 mM HEPES, pH 7.5, 10 mM MgCl 2 , 1 mM EGTA, 3 mM MnCl 2 , 0.01% Tween-20, 2 mM DTT;
  • test solution 100 times of DMSO solution was prepared in 100% DMSO, diluted 25 times with 1 ⁇ kinase buffer to obtain 4 times different concentrations of test substance solution;
  • test solution Prepare a test solution containing 2 times the final concentration of EDTA and 4EBP1 phosphorylated antibody.
  • the final concentration of EDTA is 8 mM
  • the final concentration of 4EBP phosphorylated antibody is 2 nM.
  • Inhibition rate % (sample value - minimum value) / (maximum value - minimum value) ⁇ 100
  • the “maximum value” is the DMSO control well reading and the “minimum” is the control well reading without the kinase.
  • 1.1 1X kinase buffer 50 mM HEPES, pH 7.5, 3 mM MgCl 2 , 1 mM EGTA, 100 mM NaCl, 0.03 % CHAPS, 2 mM DTT;
  • test solution 100 times of DMSO solution was prepared in 100% DMSO, diluted 25 times with 1 ⁇ kinase buffer to obtain 4 times different concentrations of test substance solution;
  • the “maximum” is the control well reading without kinase, and the “minimum” is the DMSO control well reading.
  • Test compound Compound A prepared by the preparation of Example 1;
  • A549 human lung cancer packet
  • U87MG human brain astrocyte cell line
  • PC-3 human prostate cancer cell line
  • SKOV-3 human ovarian cancer cell line
  • XTT test working solution Weigh 100 mg of methyltetrazolium salt (XTT) powder, dissolve it in 300 mL of phenol red-free serum-free RPMI1640 medium heated to 50 °C, filter, and dispense. Use immediately or within a week, all processes need to be protected from light.
  • XTT methyltetrazolium salt
  • test compound stock solution Dissolve the compound powder in DMSO at a concentration of 10 mM.
  • the cell cryotube was taken out from the liquid nitrogen and placed in a 37 ° C ⁇ 39 ° C water bath for rapid melting. Transfer the cryopreservation solution to a 15 mL sterile centrifuge tube, add 10 times the volume of the cryopreservation solution, and centrifuge at 1000 rpm for 5 min at 4 °C. Discard the medium in the centrifuge tube, force the medium containing 10% FBS, resuspend the cells, transfer to the flask, and change the solution the next day.
  • Logarithmic growth phase cells were digested with digestive juice containing 0.25% trypsin and 0.02% EDTA to prepare a cell suspension, which was centrifuged at 1000 rpm for 5 min at 4 °C. The culture solution was discarded, and a cryopreservation solution containing 10% DMSO and 90% FBS was added, and the cells were resuspended, and 2 ⁇ 10 6 cells per tube were dispensed into a cryotube. The cryotubes were placed in a programmed cooling box and placed at -80 °C for 24 h, then transferred to liquid nitrogen for cryopreservation.
  • Drug treatment Add the diluted test compound to the cell culture plate for a total of three replicates, 100 final volume per well, 200 initial concentration of 10 ⁇ , 4 fold dilution, a total of 10 concentration gradients; put into C0 2 cells Incubate in an incubator for 72 hours;
  • XTT assay for cell viability remove the medium, add XTT assay solution, 150 per well, place in a 37 ° C, 5 % C0 2 cell incubator for 2 hours, and place in the microplate reader to read 450 nm absorbance. ;
  • Inhibition rate % (solvent control well reading - test substance well reading) / (solvent control well reading White control well reading) ⁇ 100%;
  • Test animals Male SD rats, 3 / route of administration / compound, weighing 230-250 g. testing sample
  • the compound of the present invention prepared by the preparation of Example 2, was dissolved in 30% DMF + 70% sterile water for injection.
  • the compound 1 of the present invention is converted into the active compound A by a catalytic or non-enzymatic action of an enzyme in a rat to exert a pharmacological action, and the active compound A is referred to as a original drug of the compound of the present invention, so LC-MS/MS monitors and analyzes The blood concentration of Compound A.
  • Compound A prepared as in Example 1, was prepared using 30% DMF + 50 °/. PEG400+2 0% (0.9% sodium chloride injection) (with hydrochloric acid water.
  • test sample is administered by intravenous bolus injection (iv) at a dose of 2 mg/kg, a concentration of 1 mg/kg, and a dose of 2 mL/kg; the test article is administered by gavage (po), The dose was 4 mg/kg, the concentration was 1 mg/kg, and the dose was 4 mL/kg.
  • the sample was subjected to protein precipitation: 20 plasma was added, 200 ⁇ m internal standard (BEZ-235 methanol solution 50 ng/mL) was added, vortexed at 1500 rpm for 3 min, and then centrifuged at 12,000 rpm. Centrifuge for 5 min, take supernatant 50 and add 150 water, vortex and mix.
  • 20 ⁇ m internal standard BEZ-235 methanol solution 50 ng/mL
  • the blood concentration of the prodrug compound 1 and its prodrug compound A was simultaneously measured by LC-MS/MS.
  • the prodrug compound 1 IV was administered at 2 mg/kg for 5 min.
  • the average plasma concentration of the prodrug compound 1 of the three animals was about 700 ng/mL, and the average blood concentration of 15 mm was about 50 ng/mL, 30 min and later.
  • the blood concentration was not detected at the time point, indicating that the prodrug compound 1 was converted into the original drug compound A within 30 min;
  • AUCi as t represents the area under the curve of medicine 0 ⁇ t
  • V ss represents the steady-state apparent volume of distribution
  • T 1/2 represents half life
  • T max represents the peak time of blood medicine
  • c max represents peak plasma concentration
  • the prodrug compound 1 was administered to rats IV and PO, and all of them were rapidly converted into the original drug compound A in rats. As seen from Tables 3 and 4 above, both Compound 1 and Compound A of the present invention have good pharmacokinetic properties. After administration of Compound 1 in rats, the pharmacokinetic profile of Compound A was monitored similar to the pharmacokinetic characteristics of Compound A monomer administration, such as clearance, AUC, and bioavailability, indicating that Compound 1 is transformed in rats.
  • the original drug compound A which exerts pharmacological activity by the compound A, and the compound A is prepared as the prodrug compound 1, does not affect the pharmacological activity of the compound itself, and indicates that the compound of the present invention is caused by abnormal expression of the PDKct and mTOR signaling pathways. For example, tumors have significant Inhibition.
  • Example 4 Comparison of dissolution properties of Compound 1 and Compound A of the present invention
  • Test article The drug compound A of the compound 1 of the present invention was obtained by the preparation of Example 1.
  • Compound 1 of the present invention is prepared by the preparation of Example 2;
  • Buffer 0.02 mol/L ammonium dihydrogen phosphate (add 0.2% triethylamine and adjust the pH to 6.0 with phosphoric acid)
  • Test compound of the present invention 1 solution is:
  • test sample 2 mg put it into a suitable container, add 0.5 mL of pH 6.0 buffer, sonicate for 5 min, filter, and take the filtrate as the test solution.
  • test sample 2 mg two parts, put in a suitable container, add the appropriate amount of pH 7.0, pH 9.0 buffer solution, record the volume of each added solvent, shake until completely dissolved, as the test solution.
  • test sample 2 mg three parts, add 2 mL of pH 5.0, pH 7.0, pH 9.0 buffer, ultrasonic for 5 min, filter, and take the filtrate as the test solution.
  • each reference (C) is plotted on the abscissa and the peak area (Y) is plotted on the ordinate.
  • Linear regression is performed to obtain a linear equation.
  • the peak area of each test solution was substituted into a linear equation to obtain the solution concentration of the test solution.
  • Test product The original drug compound B of the compound 14 of the present invention was obtained by the preparation of Example 3.
  • the compound of the present invention 14 was prepared by the preparation of Example 4; the crude drug compound C of the compound 31 of the present invention was obtained by the preparation of Example 5.
  • the compound 31 of the present invention is prepared by the method of Example 6; Experimental method: 2 mg of each of the compound 14, the compound B, the compound 31, and the compound C are separately added, and ultrapure water is successively added, each ultrasonication for 5 minutes, until the sample is completely dissolved.
  • Compound C has a solubility in water of less than 0.1 mg/mL.
  • the solubility of compound 31 in water is > 5 mg/mL;
  • the prodrug compound of the present invention has better physicochemical properties, facilitates the preparation of a pharmaceutically acceptable dosage form, and in particular can be formulated as an injection, and can effectively expand the development of clinical dosage forms.
  • PE petroleum ether
  • HATU 2-(7-azobenzotriazole)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluron hexafluorotate
  • DCM dichloromethane
  • Ethyl 4,6-dichloro-1,5-naphthyridine-3-carboxylate (5.4 g, 20 mmol) (for the preparation method, see WO2013/2071698, page 38), m-trifluoromethylaniline (4.5 g, 28 mmol) and potassium carbonate (5.5 g, 40 mmol) were added to 150 mL of tert-butanol and heated to 90 ° C for 18 hours. The reaction solution was cooled to room temperature and then dried. EtOAc (3 mL, EtOAc) Ethyl fluoromethyl)phenyl)amino)-1,5-naphthyridine-3-carboxylate as a yellow solid (6.0 g).
  • Ethyl 6-chloro-4-((3-(trifluoromethyl)phenyl)amino)-1,5-naphthyridine-3-carboxylate (3.95 g, 10 mmol) was dissolved in 50 mL methanol and 50 mL A solution of lithium hydroxide (1.26 g, 30 mmol) in water (50 mL) was added dropwise in tetrahydrofuran. After the completion of the dropwise addition, the reaction was carried out at room temperature for 4 hours. The reaction mixture was concentrated, water (200 mL) was added, and the mixture was adjusted to pH 3 with hydrochloric acid, and the obtained solid was filtered, and then evaporated to dryness to give a white solid (3.6 g:).
  • 6-Chloro-4-((3-(trifluoromethyl)phenyl)amino)-1,5-naphthyridin-3-carboxylic acid (3.6 g, 9.8 mmol) was suspended in 50 mL of thionyl chloride Stir and heat to 75 ° (maintaining the reaction for 4 hours. Cool to room temperature and concentrate to give a yellow solid. Dissolve in 100 mL of tetrahydrofuran, and add triethylamine (3.03 g, 30 mmol) at 0 °C and A mixture of p-methoxybenzylamine (1.6 g, 13 mmol). The reaction mixture was stirred at room temperature for 4 hr, then evaporated and evaporated.
  • Ethyl 6-chloro-4-((4-(2-cyanopropan-2-yl)phenyl)amino)-1,5-naphthyridin-3-carboxylate (6.9 g, 17.5 mmol)
  • 50 mL of an aqueous solution of lithium hydroxide (2.2 g, 52.4 mmol) was added dropwise at room temperature. After the dropwise addition was completed, the reaction was carried out for 4 hours at room temperature.
  • the reaction solution was concentrated, water (200 mL) was added, and the mixture was adjusted to pH 2-3 with hydrochloric acid.
  • Ethyl chloroantimonate (1.36 g, 12.5 mmol) was slowly added dropwise to the reaction solution under a water bath, and after the completion of the dropwise addition, the mixture was heated to 60 ° C for 16 hours. After cooling to room temperature, the mixture was poured into EtOAc EtOAc (EtOAc). 0 ⁇ 1/5), gave a pale yellow solid (1.2 g).

Abstract

Cette invention concerne un composé représenté par la formule générale (I), un sel pharmaceutiquement acceptable et un stéréoisomère de celui-ci, et une composition pharmaceutique le contenant. Les utilisations du composé selon l'invention, de son sel pharmaceutiquement acceptable et stéréoisomère dans la préparation de médicaments destinés à traiter et/ou à prévenir des maladies prolifératives sont en outre décrites.
PCT/CN2014/000343 2013-03-28 2014-03-28 Promédicament inhibiteur de pi3k et/ou mtor WO2014154026A1 (fr)

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HK16101002.6A HK1213242A1 (zh) 2013-03-28 2016-01-29 和/或 抑制劑的前藥

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Citations (5)

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TW201113286A (en) * 2009-09-03 2011-04-16 Array Biopharma Inc Substituted pyrazolo[1,5-a]pyrimidine compounds as mTOR inhibitors
CN102256966A (zh) * 2008-10-17 2011-11-23 白头生物医学研究所 可溶性mTOR复合物和其调节剂
CN102399218A (zh) * 2010-09-16 2012-04-04 和记黄埔医药（上海）有限公司 一类并合三杂环及其作为pi3k抑制剂的用途
CN102399220A (zh) * 2010-09-15 2012-04-04 黄振华 三并环类PI3K和mTOR双重抑制剂
CN102625803A (zh) * 2009-09-11 2012-08-01 赛林药物股份有限公司 药学上有用的杂环-取代的内酰胺

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JP5878628B2 (ja) * 2011-06-04 2016-03-08 シュアンジュ・ファーマ・カンパニー・リミテッド ピリドナフチリジン型ＰＩ３ＫおよびｍＴＯＲ二重阻害薬ならびにその調製および使用

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Publication number Priority date Publication date Assignee Title
CN102256966A (zh) * 2008-10-17 2011-11-23 白头生物医学研究所 可溶性mTOR复合物和其调节剂
TW201113286A (en) * 2009-09-03 2011-04-16 Array Biopharma Inc Substituted pyrazolo[1,5-a]pyrimidine compounds as mTOR inhibitors
CN102625803A (zh) * 2009-09-11 2012-08-01 赛林药物股份有限公司 药学上有用的杂环-取代的内酰胺
CN102399220A (zh) * 2010-09-15 2012-04-04 黄振华 三并环类PI3K和mTOR双重抑制剂
CN102399218A (zh) * 2010-09-16 2012-04-04 和记黄埔医药（上海）有限公司 一类并合三杂环及其作为pi3k抑制剂的用途

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