WO2012136080A1 - Dérivés de benzomorpholine, leur procédé de préparation et leur utilisation - Google Patents

Dérivés de benzomorpholine, leur procédé de préparation et leur utilisation Download PDF

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WO2012136080A1
WO2012136080A1 PCT/CN2012/000462 CN2012000462W WO2012136080A1 WO 2012136080 A1 WO2012136080 A1 WO 2012136080A1 CN 2012000462 W CN2012000462 W CN 2012000462W WO 2012136080 A1 WO2012136080 A1 WO 2012136080A1
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WO2012136080A8 (fr
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匡荣仁
郭建辉
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Shanghai Allist Pharmaceuticals Inc
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Shanghai Allist Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a benzomorpholine derivative and a process for the preparation thereof, a pharmaceutical composition containing the same, and their use as a phosphatidylinositol 3-kinase (PI3K) inhibitor for the preparation of a medicament and for the prevention and/or treatment of diseases application.
  • PI3K phosphatidylinositol 3-kinase
  • Phosphotidylinositol is one of a variety of phospholipids found in cell membranes and plays an important role in intracellular signal transduction. Phosphatidylinositol 3-kinase
  • PI3Ks Phosphoinositide 3-kinases
  • PI(3,4)P2 and PI(3,4,5)P3 play an important role as a second messenger in a range of cellular processes (such as cell growth, differentiation, migration, proliferation, survival) ( Carlos Garcia-Echeverria et ⁇ , Purinergic Signalling, 2009, 5 : 1 17-125 ).
  • Type I is a heterodimer consisting of a pi 10 catalytic subunit and a p85 regulatory subunit.
  • the family is further divided into types la (pi 10 ⁇ , ⁇ ⁇ ⁇ , ⁇ ⁇ ) and type lb ( ⁇ ⁇ ⁇ ) enzymes based on regulatory partners and regulatory mechanisms.
  • Type la is activated by a tyrosine kinase system and type lb is activated by a G protein coupled receptor.
  • Type II includes the PI3KC20U C2p and C2y subtypes, which are characterized by a C2 domain at the C-terminus, and PI and PI(4)P are known to be substrates for class II PI3K.
  • Class III PI3K substrates are only PI.
  • the most widely studied of the PDK subtypes is type Ia.
  • Type la is composed of the catalytic subunit of HOkDa and the regulatory subunit of 85/55 kDa. The regulatory subunit contains the SH2 domain and can be expressed by a growth factor receptor or oncogene with tyrosine kinase activity.
  • PI3K activity of the pi 10 catalytic subunit phosphorylation of its lipid substrate.
  • the la-like PI3K enzyme has a metaplastic effect directly or indirectly in various human cancers (Vivanco and Sawyers et al., Nature Reviews Cancer, 2002, 2: 489-501).
  • Other subtypes of PI3K are associated with the development of cardiovascular and immunosuppressive diseases ( Emilio Hirsch et al, Cardiovascular Research, 2009, 82: 262-271; Anne FOUGERAT et al, Clinical Science, 2009, 1 16: 791-804).
  • PI3K inhibitors have attracted much attention as anticancer agents and have become a research hotspot in the field of cancer.
  • Wortmannin Alexandre et al., Biochem. J, 1993, 296: 297-301
  • LY294002 CJ Vlahos et al., J Biol Chem, 1994, 269: 5241-5248
  • the first generation of broad-spectrum PI3K inhibitors They are less selective for PI3K subtypes and are more toxic.
  • PI3K-targeted compounds have entered clinical research, some of which are PI3K selective inhibitors, such as GDC-0941 (Class I PI3K inhibitor, Institute of Cancer Research UK), XL-147 (Class) I PI3K inhibitor, Exelixis Inc ) , and PX-866 (PI3K ⁇ , ⁇ and ⁇ isoforms inhibitor, Oncothyreon); and some are PI3K/mTOR dual inhibitors, such as ⁇ 235 and BGT226 (Novartis AG) entering clinical phase II, Entering Phase I of SF-1 126 (Semafore Pharmaceuticals Inc) and XL-765 (Exelixis Inc) (Jeffrey A. Engelman et al., NATURE REVIEWS CANCER, 2009, 9: 550-562; Zhao et al., NATURE REVIEWS Drug Discovery, 2009, 6: 627-644 ).
  • PI3K selective inhibitors such as GDC-0941 (Class I PI3K
  • the international patent application WO 2008/144463 Al discloses quinoline derivatives having the structure shown in the following formula (a), which are indicated to have inhibitory activity against PI3K, for the treatment of autoimmune diseases, inflammatory diseases, cardiovascular diseases, Neurodegenerative diseases, allergies, asthma, pancreas Inflammation, multiple organ failure, kidney disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, and lung injury.
  • WO 2008/157191 A2 discloses a class of quinazoline compounds having a structure inhibiting PI3K activity, such as the following formula (b), for autoimmune diseases, platelet aggregation, cancer, sperm motility, transplantation. Rejection, graft rejection, and lung injury.
  • the international patent application WO 2009/055418 A1 discloses a structure which inhibits the activity of PI3K enzyme, such as a sulfapyridine derivative represented by the following formula (c), for the treatment of autoimmune diseases, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases. Disease, allergy, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, and lung injury.
  • PI3K enzyme such as a sulfapyridine derivative represented by the following formula (c)
  • the international patent application WO 2009/039140 A1 describes a pyridopyrimidine derivative having the structure as a PI3K inhibitor as shown in the following formula (d), which can be used for the treatment of autoimmune diseases, inflammatory diseases, cardiovascular diseases, and neurodegenerative diseases.
  • the present invention provides a benzomorpholine compound of the following formula (I), or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from the group consisting of hydrogen, halogen, acyl, amino, hydroxy, decyl, cyano, nitro, carboxy, Cr alkoxy, and substituted or unsubstituted Cr alkyl;
  • R 2 is selected from the group consisting of amino, substituted or unsubstituted ( ⁇ ( 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 ⁇ a C 7 cycloalkyl group and a substituted or unsubstituted 3-7 membered heterocycloalkyl group;
  • R 3 is selected from aryl, heteroaryl or fused heteroaryl having 0 to 5, for example, 0, 1, 2, 3, 4 or 5 substituents selected from Group A groups or R 3 is - CO-R 4 , wherein R 4 is an aryl, heteroaryl or fused heteroaryl group having 0 to 5, for example, 0, 1, 2, 3, 4 or 5 substituents selected from Group A groups ; as well as
  • Group A groups are selected from the group consisting of: aryl, hydroxy, decyl, cyano, nitro, carboxy, Ci alkoxy, ( ⁇ ( 6 alkylalkyl, substituted or unsubstituted d Cs alkyl, substituted or not) Substituted C 3 -C 7 cycloalkyl, substituted or unsubstituted 3-7-membered heterocycloalkyl, -NRR', -S0 2 R, -CONRR', -NHS0 2 R and -NHCOR, wherein R and R' are each independently hydrogen, substituted or unsubstituted ( ⁇ ( 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted Heteroaryl, substituted or unsubstituted C 3 ⁇ (: 7 cycloalkyl, or substituted or unsubstituted 3 to 7 membered heterocycloalkyl.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, as an excipient or a diluent.
  • the present invention also provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for inhibiting PI3K enzyme activity.
  • the present invention also provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a tumor.
  • the present invention also provides a method of treating a disease which can be alleviated or treated by inhibiting PI3K activity, comprising administering to a subject in need of such treatment a compound of the formula (I) of the present invention or a pharmaceutically acceptable compound thereof The steps of the salt.
  • the present invention also provides a process for the preparation of a compound of the formula (I), which comprises the steps of: when R 3 is an aryl group, a heteroaryl group or a fused aryl group,
  • R 1 R 2 , R 3 and R 4 are as defined above; la is halogenated R 3 , preferably chloro R 3 ; and X represents [ 3 ⁇ 4] , preferably bromine.
  • the "transition metal catalyst” is a conventional transition metal catalyst commonly used in the coupling reaction in the art, including, but not limited to, for example, bis(triphenylphosphine).
  • halogen means fluorine, chlorine, bromine or iodine.
  • alkyl means an alkyl group having 1 to 6 carbon atoms, and includes, for example, a C ⁇ alkyl group; and the like includes, but is not limited to, for example, methyl, ethyl, propyl, isopropyl, butyl Base, isobutyl, sec-butyl or tert-butyl, pentyl, hexyl, etc.; preferably decyl, ethyl, propyl, isopropyl and butyl.
  • CH ⁇ alkoxy refers to a "C -0- alkyl” group, wherein “C ⁇ Cs alkyl” is as defined above, including, for example, d ⁇ C 4 alkoxy; include, but are Not limited to, for example, methoxy, ethoxy, propoxy! ⁇ , isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, etc.; preferably methoxy, ethoxy, propoxy, isopropyl Oxyl and butoxy.
  • C 3 -C 7 cycloalkyl means a cycloalkyl group having 3 to 7 carbon atoms, and includes, for example, a C 4 -C 7 cycloalkyl group, a C 5 -C 6 cycloalkyl group, and the like. And include, but are not limited to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; preferably cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the term "3 to 7-membered heterocycloalkyl” means 1 to 4 selected from N, S and
  • the 3- to 7-membered cycloalkyl group of the hetero atom of O includes, for example, a 4-6-membered heterocycloalkyl group, a 5- to 6-membered heterocycloalkyl group, and the like, and preferably, for example, an oxiranyl group, a tetrahydrofuranyl group, a tetrahydrothiophenyl group, Tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl and the like.
  • aryl refers to a carbon number of 6 ⁇ 14 aromatic hydrocarbon ring group or a fused aromatic hydrocarbon ring group, including, for example, C 6 ⁇ 1G aryl group and the like; preferably phenyl, naphthyl A phenyl group, a fluorenyl group and a phenanthryl group are more preferred.
  • heteroaryl means a 5- to 6-membered monocyclic heteroaryl group having 1 to 4 hetero atoms selected from N, S and 0, which may be partially saturated.
  • preferred heteroaryl is pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl , thiadiazolyl, pyridyl, pyridazinyl, pyrazinyl; as partially saturated heteroaryl, including but not limited to, for example, 1,4-dihydropyridine; and more preferred are pyrimidinyl and pyridyl.
  • fused heteroaryl means 1 to 4 of a tricyclic fused heteroaryl selected from N, S and 0, which may be partially saturated.
  • the bicyclic fused heteroaryl group a benzopyrimidinyl group, a thienopyrimidinyl group, a furopyrimidinyl group, a benzothienyl group, a benzothiadiazolyl group, a benzothiazolyl group, a benzimidazolyl group, a fluorene group are preferable.
  • a benzothienopyrimidinyl group As the tricyclic fused heteroaryl group, a benzothienopyrimidinyl group, a pyrazinothienophenyl group, a pyrazinothienopyrimidinyl group, a pyrazinofuranopyrimidinyl group, a benzofuranpyrimidinyl group, and a pyridyl group are preferable.
  • RR 2 and A and R and R of the formula (I) are as defined in the definition of "substituted or unsubstituted ( ⁇ 6 alkyl", “substituted or unsubstituted aryl”," a substituted or unsubstituted heteroaryl ",” substituted or unsubstituted C 3 ⁇ (: 7 cycloalkyl "and” substituted or unsubstituted 3- to 7-membered heterocyclic group "in the term” substituted "are Refers to halogen, cyano, ammonia Substituted with a hydroxy, nitro or carboxy substituent; for example, the "substituted or unsubstituted ( ⁇ ( 6 alkyl” refers to a cyclin, cyano, amino, hydroxy, nitro or carboxy substituent a substituted or unsubstituted d ⁇ C 6 alkyl group "in one preferred compounds of the formula (I) according to the present embodiment
  • R 1 is selected from the group consisting of hydrogen, C ⁇ alkyl and C ⁇ alkoxy, more preferably decyloxy and ethoxy.
  • R 2 is selected from C! C ⁇ alkyl or halogen substituted C 6 ⁇ 1Q aryl, 5 to 6 membered heteroaryl or 5 to 6 A heterocyclic group, particularly a halogen such as a fluorine or chlorine substituted phenyl group, more preferably a 2,4-difluorophenyl group and a 2,4-dichlorophenyl group.
  • a halogen such as a fluorine or chlorine substituted phenyl group, more preferably a 2,4-difluorophenyl group and a 2,4-dichlorophenyl group.
  • R 3 is a C 6 -14 aryl group having from 0 to 4 substituents selected from the group A group, preferably phenyl, naphthyl, Mercapto or phenanthryl, more preferably phenyl; Group A substituent selected from:
  • R 3 is a heterocyclic group having 0 to 4 groups selected from the group A, and contains 1 to 4 kinds of impurities selected from N, S and 0. a 5- to 6-membered monocyclic heteroaryl group of an atom, wherein a pyrimidinyl group, a pyridyl group, a pyridazinyl group, and a pyrazinyl group are preferred, and a pyrimidinyl group and a pyridyl group are more preferred;
  • the group A group is selected from the group consisting of: a fluorene group, a hydroxyl group, Anthracenyl, cyano, nitro, carboxy, ( 6 : alkoxy, C ⁇ alkylindenyl, substituted or unsubstituted ( ⁇ ( 6 alkyl, -NRR', -NHCOR and -S0 2 R, wherein R and R' are each independently
  • R 3 is a heterocyclic group having 0 to 4 groups selected from the group A, and contains 1 to 4 kinds of impurities selected from N, S and 0.
  • Atomic 5 ⁇ 6 Preferred among them are a benzopyrimidinyl group, a thienopyrimidinyl group, a furanopyrimidinyl group, a benzothienyl group, a benzothiadiazolyl group, a benzothiazolyl group, a benzimidazolyl group, a fluorenyl group, an isoindole group.
  • the base is selected from the group consisting of: a phenol, a hydroxy group, a decyl group, a cyano group, a nitro group, a carboxy group, a aryl group, a (meth) group, a substituted or unsubstituted d-C 6 alkyl group, -NRR', NHCOR and -S0 2 R, wherein R and R' are each independently hydrogen, or a substituted or unsubstituted d-C 6 alkyl group or a C 3 -C 6 cycloalkyl group.
  • R 3 is -CO-R 4 , wherein R 4 is an aryl or a heterocyclic group having 0 to 4 substituents selected from the group A group.
  • Aryl is an aryl or a heterocyclic group having 0 to 4 substituents selected from the group A group.
  • R 4 is phenyl, naphthyl, anthracenyl, phenanthryl, pyrimidinyl, pyridyl, pyridazinyl or pyrazinyl, more preferably R 4 is phenyl and pyridyl;
  • Group A substituents are selected from:
  • R 1 is selected group the group consisting of: hydrogen, hydroxy, (: Canton ⁇ alkyl and alkoxy; and / or
  • R 2 is selected from the group consisting of d-C 6 alkyl or halogen-substituted C 6 -14 aryl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclic;
  • R 3 is C substituted with 0-4 substituents selected from Group A group having 6 to 14 aryl group, containing ⁇ 4 heteroatoms selected from N, 5 ⁇ 6 membered S heteroatom and monocyclic heteroaryl 0 a bicyclic or tricyclic fused heteroaryl group having 5 to 6 membered monocyclic heteroaryl groups containing 1 to 4 hetero atoms selected from N, S and 0 fused to each other or fused to a benzene ring.
  • R 3 is -CO-R 4, wherein R 4 is with C 0 ⁇ 4 substituents selected from the group consisting of a 6 to 14 or an aryl group containing 1 to 4 heteroatoms selected from N, S and a 5- to 6-membered heteroaryl group of a hetero atom of 0; the substituent of the group A is selected from the group consisting of a halogen, an amino group, and a hydroxyl group.
  • R and R' are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl or substituted or unsubstituted C 3 -C 6 heterocycloalkyl.
  • R 3 is a C 6 ⁇ 14 aryl group having 0-3 substituents selected from group A, preferably phenyl, naphthyl, anthracenyl And a phenanthryl group; or a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 hetero atoms selected from N, S, O, having 0 to 3 substituents selected from the group A, particularly containing 1 ⁇ 3 to 6-membered monocyclic heteroaryl groups of N atoms, preferably 6-membered monocyclic heteroaryl groups having 1 to 2 N atoms, preferably pyrimidinyl, pyridyl, pyridazinyl, pyrazinyl; or a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 hetero atoms selected from N, S and 0, which are fused to a benzene ring, having 0 to 3 substituents selected from Group A
  • R 3 is a phenyl group having 0 to 2 substituents selected from the group consisting of halogen, d- 4 alkyl or d ⁇ 4 alkoxy.
  • R 3 is taken with 0 to 2 One selected from the group consisting of a steroid, an amino group, a hydroxy group, a decyl group, a cyano group, a nitro group, a carboxy group, ( ⁇ (: 4 alkoxy, alkanoyl, d ⁇ C 4 alkyl, -NRR', -NHCOR and -S0 2 R Substituted pyrimidinyl, pyridyl, pyridazinyl or pyrazinyl.
  • R 3 is taken from 0 to 3 selected from the group consisting of 13 ⁇ 4, amino, hydroxy, decyl, cyano, nitro, carboxy, d-C 4 alkane.
  • a benzopyrimidinyl group a thienopyrimidinyl group, a furanopyrimidinyl group, a quinolinyl group, an isoquinoline of a substituent of an oxy group, a C 4 alkyl group, a C alkyl group, a -NRR', -NHCOR and -S0 2 R a quinazolinyl group, a benzothienopyrimidinyl group, a pyrazinothienophenyl group, a pyrazinothienopyrimidinyl group or a pyrazinofuranopyrimidinyl group, wherein R and R' are each independently hydrogen, Ci ⁇ C 4 alkyl or C 3 ⁇ C 6 naphthenic.
  • R 3 is -CO-R 4 , wherein R 4 is 0 to 2 selected from halogen, d-C 4 alkoxy or ⁇ ⁇ (phenyl, pyridyl or pyrimidinyl of a 4- alkyl substituent.
  • R 4 is 0 to 2 selected from halogen, d-C 4 alkoxy or ⁇ ⁇ (phenyl, pyridyl or pyrimidinyl of a 4- alkyl substituent.
  • the compound of the present invention sometimes has geometric isomers and tautomers depending on the kind of the substituent, and the present invention includes the isolated isomers or a mixture thereof; the compound of the present invention sometimes has a chiral carbon atom, and thus is based on Optical isomers of chiral carbon atoms, and the present invention includes all possible optical isomers and mixtures thereof.
  • the invention also includes pharmaceutically acceptable salts of the compounds of formula (I).
  • pharmaceutically acceptable salt refers to an acid addition or base addition salt of a compound of formula (I) of the present invention which is relatively non-toxic.
  • the acid addition salt is a salt of a compound of formula (I) with a suitable inorganic or organic acid which may be prepared during the final isolation and purification of the compound or by the purification of the compound in its free base form. A suitable organic or inorganic acid is reacted and the formed salt is isolated to prepare.
  • Representative acid addition salts include, but are not limited to, for example, hydrobromide, hydrochloride, sulfate, sulfite, acetate, oxalate, valerate, oleate, palmitate, hard Fatty acid, laurate, borate, benzoate, lactate, phosphate, phthalate, citrate, maleate, fumarate, succinate, tartrate , Benzoate, sulfonate, p-toluenesulfonate, gluconate, lactobionate, lauryl sulfonate, and the like.
  • the base addition salt is a salt of a compound of formula (I) with a suitable inorganic or organic base, including, for example, a salt formed with an alkali metal, an alkaline earth metal, a quaternary ammonium cation, such as a sodium salt, a lithium salt, a potassium salt, a calcium salt, a magnesium salt, a tetradecyl quaternary ammonium salt, a tetraethyl quaternary ammonium salt, etc.; an amine salt, including a salt formed with ammonia (NH 3 ), a primary amine, a secondary amine or a tertiary amine, such as: a guanamine salt, Diammonium salt, trimethylamine salt, triethylamine salt, ethylamine salt, and the like.
  • a salt formed with an alkali metal, an alkaline earth metal a quaternary ammonium cation, such as a sodium salt,
  • the compound of the formula (I) of the present invention and a pharmaceutically acceptable salt thereof can be administered to a mammal such as a human, and can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically (for example, In the form of powder, ointment or drops, etc.).
  • the compound of the formula (I) of the present invention and a pharmaceutically acceptable salt thereof can be formulated into a solid dosage form for oral administration, including, but not limited to, for example, a capsule, a tablet, a pill, a powder, a powder, and the like. .
  • the compound of the invention is mixed with at least one conventional inert excipient (or carrier), such as with sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone , sucrose and gum arabic, etc.; (c) humectants, for example, glycerol, etc.; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates and sodium carbonate (e) a slow solvent such as paraffin or the like; (f) an absorption accelerator such as a quaternary ammonium compound; (g) a wetting agent such as cetyl alcohol and
  • the solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound in such compositions may be released in a portion of the digestive tract in a delayed manner.
  • Embedding materials that can be employed include, for example, polymeric materials and waxy materials.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may also be combined with the above excipients as necessary One or more of them form a microcapsule form.
  • the compound of the formula (I) of the present invention and a pharmaceutically acceptable salt thereof can be formulated into a liquid dosage form for oral administration, including, but not limited to, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. Wait.
  • the liquid dosage form may further comprise an inert diluent conventionally employed in the art, such as water or other solvents, solubilizers and/or emulsifiers.
  • ethanol for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide or oil, especially cottonseed oil, peanut oil, corn germ oil, olive oil, alfalfa Sesame oil or sesame oil or a mixture of these substances.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and/or perfumes may be included in these dosage forms.
  • the suspension may contain a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, micro Crystal cellulose, aluminum methoxide, agar or a mixture of these substances.
  • a suspending agent for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, micro Crystal cellulose, aluminum methoxide, agar or a mixture of these substances.
  • the compound of the formula (I) of the present invention and a pharmaceutically acceptable salt thereof may be formulated into a dosage form for parenteral injection, including, but not limited to, for example, a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension.
  • a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension A liquid or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof and the like.
  • the compound of the formula (I) of the present invention and a pharmaceutically acceptable salt thereof can be formulated into a dosage form for topical administration, including an ointment, a powder, a propellant, an inhalant and the like.
  • the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising 0.05 to 1000 mg, for example, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg > 300 mg, 500 mg, 800 mg or 1000 mg, of the above compound of the formula (I) or A pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.
  • the pharmaceutical composition of the present invention can be obtained by combining the general formula (I) of the present invention by a conventional method.
  • the preparation or a pharmaceutically acceptable salt thereof is prepared by mixing with a pharmaceutically acceptable carrier, excipient or diluent.
  • the present invention also provides a method for treating a disease which can be alleviated or treated by inhibiting PI3K activity, such as a tumor, including a formula (I) of 0.05-50 mg/kg body weight/day for a patient in need of treatment.
  • the disease is a tumor.
  • the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be administered alone or in combination with other pharmaceutically acceptable therapeutic agents, particularly in combination with other antitumor drugs.
  • the therapeutic agent includes, but is not limited to, for example, an antitumor drug acting on the chemical structure of DNA such as cisplatin, an antitumor drug affecting nucleic acid synthesis such as methotrexate (MTX), 5-fluorouracil (5FU), etc., affecting nucleic acid transcription
  • Antitumor drugs such as doxorubicin, epirubicin, aclarithromycin, phosfomycin, etc., antitumor drugs acting on tubulin synthesis such as paclitaxel, vinorelbine, etc., aromatase inhibitors such as ammonia Mitt, lantron, letrozole, ruined, etc., cell signaling pathway inhibitors such as epidermal growth factor receptor inhibitor imatinib (Imatinib), gefitin
  • the ingredients used in combination may be administered simultaneously or sequentially, in the form of a single preparation or in the form of separate preparations.
  • the combination includes not only combinations of the compounds of the invention and one other active agent, but also combinations of the compounds of the invention and two or more other active agents.
  • the compound of the present invention has a cancer cell proliferation inhibiting action and can be used for the preparation of a medicament for treating cancer.
  • the pharmacological effect of the compound of the present invention for inhibiting the proliferation of cancer cells can be determined by a conventional method.
  • a preferred evaluation method is Sulforhodamine B (SRB) protein staining: SRB is a protein-binding dye and can be used with biological macromolecules. The combination of basic amino acids and its optical density (OD) reading at 510 nm has a good linear relationship with the amount of protein, so it can be used as a quantification of the number of cells by measuring the light absorption value of the drug after it acts on cancer cells. Changes in the rate of inhibition of cancer cell proliferation by drugs.
  • Inhibition rate (%) (OD control - OD inhibitor - OD blank control) / (OD
  • OD control refers to the OD value of the wells of cells that have no drug to function normally.
  • OD inhibitor refers to the OD value of a well of a cell to which a positive or a compound to be screened is added.
  • OD blank control refers to the OD value of parallel control wells that were not seeded.
  • the half inhibitor concentration (IC 5 D) value was calculated by the software GraphPad Prism 5.
  • the invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention.
  • the experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Parts and percentages are parts by weight and percentage by weight unless otherwise stated. detailed description
  • the compound Ie-3 (0.71 mmol) prepared in Example 3 was refluxed with 4-chloro-pyrimidine hydrochloride (Ia-5, 0.71 mmol) and triethylamine (0.71 mmol) in an appropriate amount of isopropanol.
  • the compound If-5 (0.15 mmol) was obtained in an hour.
  • the compound If-5 (0.15 mmol), 1,2-dibromoethane (0.18 mmol) and potassium hydrogencarbonate (0.18 mmol) were sequentially added to DMF (5 mL), and then reacted at 60 ° C overnight. 10 mL of water was added to the reaction mixture, and the mixture was extracted three times with dichloromethane. The organic phase was combined, washed three times with saturated brine and dried over anhydrous sodium sulfate.
  • the title compound (1)-5 (0.06 mmol, yield 40%).
  • Microcrystalline cellulose 68 g According to a conventional method, the above materials are mixed and hooked, and then filled into ordinary gelatin capsules to obtain 1000 capsules.
  • Test Example 1 Inhibition of proliferation of human prostate cancer cells (PC-3) by the compound of the present invention
  • PC-3 Human prostate cancer cells in logarithmic growth phase were seeded at a density of about 5500 cells/well in a 96-well culture plate, 180 ⁇ / hole. Three holes are provided for each concentration. The corresponding concentration of the vehicle control and the cell-free zeroing hole were set.
  • TCA cold trichloroacetic acid
  • the test results showed that the compound of the present invention has a good proliferation inhibitory effect on human prostate cancer cells (PC-3).
  • Test Example 2 Inhibition of proliferation of human breast cancer cells (MDA-MB-231) by the compounds of the present invention
  • Test Example 3 Compound of the present invention inhibits proliferation of human non-small cell lung cancer cells ( ⁇ 549)
  • the IC 5 () value of the example compound for ⁇ 549 cells was obtained by calculation with reference to Test Example 1 Experimental Method: The test results show that the compound of the present invention has a good proliferation inhibition effect on human non-small cell lung cancer cells (A549).
  • Test Example 4 Inhibition of proliferation of human ovarian cancer cells (SK-OV-3) by the compound of the present invention The measurement was carried out by referring to Test Method Example 1, and the IC 5 o of the Example compound for SK-OV-3 cells was obtained by calculation. value:
  • test results show that the compound of the present invention has a good proliferation inhibition effect on human ovarian cancer cells (SK-OV-3).
  • Test Example 5 Compound of the present invention against mutant non-small cell lung cancer cells H1975
  • test results show that the compound of the present invention has a good proliferation inhibition effect on non-small cell lung cancer cells H1975 (L858R/T790M-EGFR).
  • the applicant has made a complete and detailed description of the invention. It will be apparent to those skilled in the art that the present invention may be modified, modified or modified without departing from the spirit and scope of the invention. The scope defined by the book.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des dérivés de benzomorpholine, tels que représentés par la formule suivante (I), et des compositions pharmaceutiques comportant les dérivés, ainsi que les procédés de préparation de ceux-ci, R1, R2 et R3 étant tels que définis dans la description. Les dérivés de benzomorpholine de la formule (I) sont un inhibiteur de phosphatidylinositol 3-kinases (PI3k) et ont un bon effet inhibiteur sur PI3K et sur la prolifération des cellules cancéreuses, servant ainsi d'agent thérapeutique pour le traitement de tumeurs.
PCT/CN2012/000462 2011-04-08 2012-04-09 Dérivés de benzomorpholine, leur procédé de préparation et leur utilisation Ceased WO2012136080A1 (fr)

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CN106146534B (zh) * 2016-06-29 2017-12-08 福州大学 一种三环苯并吗啉衍生物及其制备方法
CN108239075B (zh) * 2016-12-26 2021-07-02 中国医学科学院药物研究所 喹唑啉类化合物及其制备方法、用途和药物组合物

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WO2009055418A1 (fr) * 2007-10-22 2009-04-30 Smithkline Beecham Corporation Dérivés de pyridosulfonamide en tant qu'inhibiteurs de pi3 kinase
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US6087350A (en) * 1997-08-29 2000-07-11 University Of Pittsburgh Of The Commonwealth System Of Higher Education Use of pretreatment chemicals to enhance efficacy of cytotoxic agents
GEP20084317B (en) * 2000-04-25 2008-02-25 Icos Corp Inhibitors of human phosphatidyl-inositol 3-kinase delta
KR100774855B1 (ko) * 2000-04-27 2007-11-08 아스텔라스세이야쿠 가부시키가이샤 축합 헤테로아릴 유도체
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WO2004056820A1 (fr) * 2002-12-20 2004-07-08 Warner-Lambert Company Llc Benzoxazines et leurs derives en tant qu'inhibiteurs de pi3ks
WO2009055418A1 (fr) * 2007-10-22 2009-04-30 Smithkline Beecham Corporation Dérivés de pyridosulfonamide en tant qu'inhibiteurs de pi3 kinase
WO2009155121A2 (fr) * 2008-05-30 2009-12-23 Amgen Inc. Inhibiteurs de la pi3 kinase

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015506344A (ja) * 2011-12-22 2015-03-02 ノバルティス アーゲー ジヒドロ−ベンゾ−オキサジンおよびジヒドロ−ピリド−オキサジン誘導体
US9539260B2 (en) 2011-12-22 2017-01-10 Novartis Ag Dihydro-benzo-oxazine and dihydro-pyrido-oxazine derivatives
US9763952B2 (en) 2011-12-22 2017-09-19 Novartis Ag Dihydro-benzo-oxazine and dihydro-pyrido-oxazine derivatives

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WO2012136080A8 (fr) 2013-10-24
CN103534252A (zh) 2014-01-22
CN103534252B (zh) 2016-08-24

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