[go: up one dir, main page]

WO2000076980A1 - Nouveaux derives heterocycliques azotes ou leurs sels - Google Patents

Nouveaux derives heterocycliques azotes ou leurs sels Download PDF

Info

Publication number
WO2000076980A1
WO2000076980A1 PCT/JP2000/003768 JP0003768W WO0076980A1 WO 2000076980 A1 WO2000076980 A1 WO 2000076980A1 JP 0003768 W JP0003768 W JP 0003768W WO 0076980 A1 WO0076980 A1 WO 0076980A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituent
amino
carboxamide
lower alkyl
dimethylaminoethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2000/003768
Other languages
English (en)
Japanese (ja)
Inventor
Takayuki Suzuki
Kenichi Onda
Takeshi Murakami
Kenji Negoro
Kiyoshi Yahiro
Tatsuya Maruyama
Akiyoshi Shimaya
Mitsuaki Ohta
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yamanouchi Pharmaceutical Co Ltd
Original Assignee
Yamanouchi Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yamanouchi Pharmaceutical Co Ltd filed Critical Yamanouchi Pharmaceutical Co Ltd
Priority to AU51080/00A priority Critical patent/AU5108000A/en
Publication of WO2000076980A1 publication Critical patent/WO2000076980A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • 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
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a gfm nitrogen-containing heterocyclic derivative useful as a drug, particularly a protein kinase c (PKOp and a harmful agent), and a material thereof.
  • PKOp protein kinase c
  • PLC Protein kinase c
  • PKC is a Z threonine kinase.
  • PKC plays an important role in regulating cell expression and cell differentiation and proliferation in cells.
  • PKC is classified into 10 isozymes based on its molecular structure and transformation (Biochem J 291: 329-343 (1993)).
  • PKC is a single polypeptide composed of 592-737 amino acids in length, consisting of a regulatory domain and a catalytic domain. These domains can be further divided into well-preserved areas and areas that separate them.
  • the catalytic domain of PKC is very similar to the catalytic domain found in other protein kinases, the regulatory domain is unique to PKC.
  • PKC isozymes are known to have 40-80% homology at the amino acid level.
  • PKCI * Enzyme regulated by a number of factors, including membrane phospholipids, calcium, and certain umami substances (diasylglycerol generated by phospholipase activation). (Science 258: 607- 61 4 (1 992)).
  • PKC isozymes, such as 1, 2, and r, refer to membrane phospholipids, calcium and diaglycerol Z phorbol ester for complete remodeling.
  • the ⁇ and ⁇ forms of PKC are also independent of both calcium and diacylglycerol, and it is believed that only membrane phospholipids are involved in the formation.
  • PKC isozymes are involved in the onset of disease and its disease. For example, elevated blood glucose levels seen in diabetes can 11 ⁇ 1 and 2 isozymes in the retina (Am J Physiol 265: E783-793 (1993)). In diabetic renal fibers, one isozyme is also deteriorated (JClin Invest 100: 115-126 (1997)). Also vascular fibers heart However, activation of the S2 isozyme has been reported (Proc Natl Accad Sc USA 89: 11059-1 1063 (1992)). The yS2 isozyme has also been shown to be involved in leukocyte differentiation / proliferation (JBiol Chem 269: 23 230-23235 (1994)).
  • PKC plays an important role in the development and development of specific diseases, and PKC-specific inhibitors may be effective therapeutic agents.
  • the formation of lysozyme may lead to increased production of extracellular matrix and cytokines, phosphorylase A2 formation and inhibition of Na / K-ATPase, leading to various complications.
  • Dia betes 47: 859-866 (1 998) Drugs showing a strong inhibitory effect on lysozyme have been shown to improve diabetic nephropathy and retinopathy as well as improve the above abnormalities (Science 272: 728-731). (1 996). JC lin Invest 100: 1 15—126 (1 997)).
  • staurosporine an alkaloid produced by a substance
  • BB och em Biophys Res Commun 135: 397-402 (1 986) a potent inhibitor
  • staurosporine an alkaloid produced by a substance
  • BB och em Biophys Res Commun 135: 397-402 (1 986) a potent inhibitor
  • the usefulness of this agent and related compounds as therapeutic agents for diseases is limited by the lack of specificity of inhibition against other protein kinases (J Med Chem 39: 2664-2671 (1996)).
  • staurosporine is concerned about its lack of selectivity.
  • a compound having a structure similar to staurosporine, bisindolylmaleimide is known to be a compound that it it is not selective for other protein kinases and is not selective for PKC (J Med Chem 35: 994-1001 (1992) )).
  • WO 97/19065 also states that compounds represented by the following general formula are useful as proteinase inhibitors, but they are effective for diabetic complications That is not suggested or disclosed.
  • the present inventors have considered that a nitrogen-containing heterocyclic ring having carbamoyl US may be bonded to aryl, cycloalkyl, or heteroaryl via an N atom and further have a substituent via another N atom.
  • the present invention has been completed. That is, the present invention relates to a nitrogen-containing complex ring derivative represented by the following general formula (I) or a salt thereof, and an additive containing them as an active ingredient, particularly diabetic healing agent j.
  • aryl which may have a substituent
  • cycloalkyl which may have a substituent
  • heteroaryl which may have a substituent
  • R 1 -N (R 5) R 6, - good even have a substituent, a lower alkylene - N (R 5) R 6 , OH, addition to which may have a substituent ⁇ Roariru,
  • AA 2 same or different, may have a substituent, lower alkylene, bond,
  • Ring E cycloalkylene optionally having a substituent, arylene optionally having a substituent, tt heteroarylene optionally having a substituent,
  • a 3 NR 7 , CO, 0, S, which may have a substituent, lower alkylene, or a bond,
  • M may have lower alkyl
  • -c ( o) -heteroaryl optionally having a substituent
  • Aryl may have a substituent
  • Heteroaryl may have a substituent, may be a lower alkino uo-substituent, may have a lower alkyl,
  • R 1 and R 3 may be taken together with adjacent A 2 and N to represent a heteroaryl which may have a substituent, and when R 5 is a hydrogen atom, R 6 (and Hereinafter, the compound (I) of the present invention will be described in detail.
  • lower means a linear or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified.
  • lower alkyl includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, Examples include 2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, and 3-methylpentyl. Of these, those having 1 to 3 carbon atoms are preferred, and methyl and ethyl are particularly preferred.
  • the “lower alkylene” may be a branched lower alkylene such as fit methyl methylene such as methylene, ethylene, propylene and butylene.
  • Cycloalkyl means cycloalkynole having 3 to 8 carbon atoms. Particularly preferred are 5- and 6-membered alkyls.
  • Parisole J includes phenyl, naphchilile, antrizole, fenantrisole, indanile, and fluoreniz.
  • Heteroaryl j includes furyl, chenisole, pyrrolizole, imidazolyl, thiazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazyl, thiadiazolyl, triazolyl, triazolyl, triazolyl, indoleyl, triazolyl, and tetrazolino H Pyrimidinyl, 2,3-methylenedioxyphenyl, 2,3-dihydroindolyl, 1,3-dihydroisoindolinylyl, 1,3-dihydroisobenzofuranyl, 3-oxoisoindolyl, 2-oxo Examples thereof include 1,2-dihydroquinolinyl, 1,1-dioxobenzothiophenyl, and 9-oxofluoreniso bicyclic or tricyclic heteroary
  • Cycloalkylene”, “arylene”, and “heteroarylene” mean that the above-mentioned cycloalkyl J, “aryl”, and “heteroaryl” each have two bonds.
  • the bond between Y and X may be a double bond or a single bond,
  • aryl J optionally substituted cycloalkyl
  • heteroaryl optionally substituted M ⁇ ⁇ -class alkylene
  • Cycloalkylene optionally having substituent (s) "
  • arylene optionally having substituent (s) "
  • heteroarylene optionally having substituent (s) "
  • substituent (s) " optionally having substituent (s) ".
  • the compounds of the present invention include, in addition to the above-mentioned tautomers, mixtures of various isomers such as geometric isomers and optical isomers, and isolated ones.
  • the compound (I) of the present invention may form an acid addition salt.
  • a salt with a base may be formed.
  • Specific examples of such salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, m-acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, and fumaric acid.
  • Acid maleic acid, fumaric acid, linco, tartaric acid, citrate, methanesulfonate, ethanesulfonic acid, etc., aspartic acid, glutamic acid, etc., acid addition salts with hidden amino acids, sodium, potassium, magnesium, calcium
  • inorganic bases such as aluminum
  • organic bases such as methylamine, ethylamine and ethanolamine
  • salts with basic amino acids such as lysine and ornithine, and ammonium salts.
  • the present invention also includes hydrates of compound (I), various pharmaceutically acceptable solvates, and polymorphs. It should be noted that the present invention is not limited to the compounds described in the Examples below, but the nitrogen-containing heterocyclic derivative represented by the general formula (I) or a pharmaceutically acceptable derivative thereof. It includes all salts.
  • the compounds of the present invention include all compounds that are metabolized in vivo and converted into the compound having the general formula (I) or a salt thereof, and all prodrugs. It is a thing.
  • the group that forms the prodrug of the compound of the present invention includes Prog.Med.5: 2 15 7 -2 16 1
  • the compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods, utilizing characteristics based on the type of the skeleton or the substituent. At that time, depending on the type of the functional group, it may be technically effective to replace the functional group with an appropriate protecting group, that is, a group which can be easily converted to the functional group at the stage of a raw material or an intermediate. is there. Thereafter, the desired compound can be obtained by removing the protecting group according to the formula.
  • an appropriate protecting group that is, a group which can be easily converted to the functional group at the stage of a raw material or an intermediate. is there. Thereafter, the desired compound can be obtained by removing the protecting group according to the formula.
  • Such functional as a group such as amino group, hydroxyl group can be exemplified Karubokishino US etc., as their protecting groups such green (Greene) and Wuts (Wuts) Author, rp ro tective Grotps in Organic Synthesis ( third 2nd edition) ”). It may be used as appropriate.
  • L 1 in the formula denotes a leaving group, D ring,,,,, 13 ⁇ 4 2, 13 ⁇ 4 3, wherein the symbols ⁇ similar) compounds from the preparation of the compound (II) or compound (IV) (I ).
  • the elimination 3 ⁇ 4L for example Ii, androgenic atom, methylsulfanyl, methanesulfonyl O carboxymethyl, toluene sulfonyl Ruokishi, triflumizole Ruo b methanesulfonyl O carboxymethyl, 1 [Eta] "benzotriazole source ⁇ -.
  • Compound (I) can be obtained by using an equimolar amount of nucleophile (III) in excess of Si.
  • compound (IV) triarylbismucin, aryl
  • the compound (I) can be obtained by reacting an alkylating agent such as halide, aryltriflate, arylpropoic acid, etc.
  • the obtained compound (I) is treated with "chlorosuccinic acid imid b
  • Halogenation of the nitrogen-containing heterocycle can be effected by the action of a halogenating agent such as bromosuccinimide or xenon difluoride.
  • the reaction can also be performed without solvent or with benzene, toluene, or xylene.
  • Aromatic hydrocarbons such as acetyl ether, tetrahydrofuran, dioxane, etc., halogenated hydrocarbons such as dichloromethane, 1,2 "dichloroethane, and chloroform, etc., h dimethylformamide (DMF)
  • DMSO dimethylsulfoxide
  • MeCN acetonitrile
  • ethizoacetate ethizoacetate
  • the compound obtained by this production method is used for protecting a hydroxyl group or an amino group ⁇ carboxyzo U ⁇ -protected functional group (specifically, the above-mentioned rprotective Grotps in Organic Synthesis (second example), such as the benzyl in the benzylamine moiety and the alkoxy in the alkoxy ester moiety.
  • the compound having an amino group ⁇ hydroxyl group or carboxiso U ⁇ can be produced by removing the M protecting group moiety according to a conventional method.
  • This production method is a method for obtaining (I) by hydrolyzing a nitrile compound (V) under various conditions.
  • the reaction is conducted without solvent or in solvents inert to the reaction of ethers, halogenated hydrocarbons, methanol, alcohols of ethanolo H, DMF, DMSO, pyridine, water, etc., sulfuric acid, hydrochloric acid, hydrogen bromide Acid, mineral acid such as polyphosphoric acid, organic acid such as m-acetic acid or I]] under a base such as sodium oxide, hydroxide hydroxide, potassium carbonate, charcoal, thorium or ammonia.
  • This method is a method for obtaining a compound (lb) from a compound (la, lc) having an amino group or an I * ⁇ acid group.
  • the compound (la) When the compound (la) is used, it may be reacted with an organic halide such as an acid halide or a symmetrical acid anhydride or a mixed acid anhydride, or may be used as an aldehyde, sodium borohydride, or triacetoxy hydrogen.
  • the compound (lb) can be obtained by reductive amination using a metal hydride complex compound such as sodium borohydride, sodium cyanoborohydride, or hydrogenation using a metal catalyst such as radium-activated carbon.
  • compound (Id) is obtained by using compound (VI) and nucleophile (VI I) in the same manner as in knitting production method 1.
  • the reaction is preferably performed in an organic base in a solvent, and in the case of A 3 force of 0 or S, the reaction is preferably performed in a metal salt base: j.
  • the compound obtained by this production method has a hetero atom (Z) protected by penzino US
  • the compound (le) can be obtained by removing benzyl according to a conventional method like knitting. Further, the compound (le) is reacted with the compound (VI II) to obtain (If).
  • reaction S is carried out without solvent or in a solvent inert to the reaction of aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, MeCN, etc., in a solvent inert to sodium, potassium " ⁇ -butoxide, butyllithium
  • the reaction can be carried out under the flow of ⁇ 73 ⁇ 4 under a base such as sodium amide, etc.
  • Reaction S can be appropriately set depending on the compound.
  • R 9 and R 1 ° in the formula may each have a substituent, and mean lower alkyl or arylsole, and other symbols are the same as those in the compilation)
  • a compound (Ig, lh, li, U) is obtained by converting a functional group of a compound by a conventional method.
  • the compounds (l & lh, li) can be converted into each other by subjecting them to an oxidation or reduction reaction.
  • a 1, M-dimension (I j) to carbonino can be obtained by performing a reaction using phosphorus ylide ⁇ organometallic fiber.
  • the reaction can be carried out without solvent or in a solvent that is insensitive to reactions such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, MeCN, etc.
  • the reaction can be appropriately set depending on the compound. it can.
  • L 1 , L 2 , and L 3 each represent a leaving group, R "represents cyano or carbamoyl, and the other symbols are the same as 3 ⁇ 4 ⁇ ⁇ )
  • the starting compound 00 can be obtained via an intermediate (VI II, IX) by repeatedly performing the same reaction as in Method 1 of Sukki's method 1 on the compound (VI I).
  • Starting compound (XI) can be obtained by subjecting an intermediate having R "to cyano to a hydrolysis reaction in the same manner as in jf self-production method 2. Manufacturing method 7
  • R 12 i * 7K element means carboxy or carbamoyl
  • R 13 means formyl, cyano, carpamoyl, and R 4 , and other symbols are the same as those of the editor.
  • the starting compound (XVI I) can be subjected to the same substitution reaction as for compound (XIV) and the hydrolysis reaction of compound (XVI) to compound (XIV, XV) as in method (I5) Can be.
  • Intermediate (XV) can be obtained by subjecting compound (XIV) having a pyrazine ring to trifluoromethylation using the same method as in Knitting Method 8 or using xenon difluoride and trifluoroacetic acid. it can.
  • Compound (XI) can be subjected to a conventional radiocassole reaction using formamide, sulfuric acid and hydrogen peroxide, or lithium 2.2,6,6-tetramethylpi ⁇ ⁇
  • a conventional radiocassole reaction using formamide, sulfuric acid and hydrogen peroxide, or lithium 2.2,6,6-tetramethylpi ⁇ ⁇
  • the compound is treated with carbon dioxide or the like to generate a carboxylate on the nitrogen-containing heterocycle, and then amidated by a conventional method. It can be manufactured at When (XI II) of formino US is used as R 13 , it can be oxidized by a conventional method to form a carboxy group, and then amidated in the same manner as described above to obtain an intermediate compound (XIV).
  • Intermediate (XI II) is prepared by reacting compound (XI I) with an organic alkali metal salt base in the same manner as described above. Power demand : can be obtained by using ⁇ . Further, (XI II) having an ester or cyano at R 13 can be obtained by subjecting a compound (XI I) having a carboxy group or a valmoizole group at R 12 to a condensation reaction or dehydration reaction by a conventional method. it can. Intermediate (XVI) can be produced by subjecting compound ( XIII ) in which R 13 is cyano to the same substitution reaction as in Production method 1 described above. Usually, the self-organization reaction is carried out in a solvent inert to the reaction of aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, pyridine, and the like, with cooling under a reduced amount.
  • the starting compound (IV) can be obtained by subjecting the cyano of the compound (XIX) to a hydrolysis reaction in the same manner as in Production Method 2.
  • Intermediate (XIX) can be obtained by subjecting compound (XVI I I) to a substitution reaction similar to that of self-produced method 1.
  • the compound of the present invention obtained by each of the above production methods can be purified by known methods, for example, extraction, 1, fractional chromatography, fractional crystallization, recrystallization and the like.
  • the salt of the compound of the present invention can be converted into a desired salt by a usual salt formation reaction.
  • an optically active substance can be separated by a general optical resolution method, for example, fractional crystallization or chromatography.
  • the optical body can be produced from an appropriate optically active compound.
  • the compound of the present invention is useful as an activity of a rice preparation.
  • it since it has PKC activity inhibitory activity, it is useful for the prevention and control of diabetic complications, ischemia, inflammation and cancer-related pathologies involving PKC.
  • diabetic complications include diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, cardiovascular disease, and skin disease.
  • PKCP and harmful ISIt was determined by a method according to (J. Bio. Chem, 260: 10039-10043, 1985).
  • Scintillation occurs when a molecule having radioactive activity approaches (binds) to the surface of a plastic bead containing a scintillator, developed by SPA (Sc intillation Proximity As say) and Amersham. This is a system that uses.
  • the beads are pre-coated with streptavidin, to which the biotin moiety of the substrate peptide binds.
  • Anti-J heart fluid Composition: 2.5mUnit PKC isozymes (Calbioc), 50mM-HEPES (pH 7.5), 0.25mM EDTA, 0.125mM DTT, 12.5mM MgC I 2> 0.5 mM EGT A, 0.75 mM Ca CI 2 , 0.25% Triton X—100, 0.2 ⁇ biotin- ⁇ -peptide ( ⁇ ⁇ ⁇ ti ⁇ — ⁇ RMRPRKRQGSVRRRV, peptide synthesizer synthetically), 0. 2 ⁇ ATP, 0.
  • ⁇ is determined by the method according to (J. Biol. Chem, 268: 9122-9129, 1993 and Eur. J. Biochem, 194: 89-94, 1990)! I did.
  • human spleen cDNA was transformed into type III, recloned by PCR, and inserted into a pcDNA3.1 expression vector.
  • a modified PKCyS2 expression vector in which amino acids 22 to 28 (7 amino acids) had been deleted was constructed.
  • Amino acids 22-28 are a pseudosubstrate region and function to reverse PKC3 ⁇ 41 ⁇ 2. Deletion of this portion enables expression of 3 ⁇ 41 ⁇ -modified PKC / S.
  • COS 7 cells were cultured in a 24-well plate, and the activated ⁇ expression vector and pA ⁇ 1 — I uc I ferase ⁇ T ⁇ , ⁇ ⁇ ⁇ S (Stratameme ⁇ 3 ⁇ 4 ⁇ fugene (Roche D As a control, the pcDNA3.1 vector and the plasmid were transfected as a control.3 hours after transfection! ⁇ I was added (final concentration of DMSO was 0.1%) and cultured for 24 hours.Cell lysate (25 mM TrisC I (pH 7.8), 2 mM DTT, 2 mM CDTA, 10% glycerol) was added to each well.
  • Cell lysate 25 mM TrisC I (pH 7.8), 2 mM DTT, 2 mM CDTA, 10% glycerol
  • An 8-week-old male Wistar rat is intravenously administered with streptozotocin (Sigma) at 60 mgZkg under pentobarbital anesthesia to develop diabetes.
  • the test compound is orally administered once a day for 8 consecutive weeks from the day after the administration of streptozotocin. Collect urine at 2, 4, 6, and 8 weeks after administration, and measure total protein and albumin in urine.
  • the inhibitory effect of the compound on total protein and albumin leakage due to diabetes was defined as diabetic nephropathy ameliorating effect.
  • Example 17-1 showed a tendency to increase urinary albumin excretion »j after 8 weeks of oral administration of 1Q ⁇ ⁇ ⁇ ⁇ kg in the above difficulties.
  • a 13-week-old male Wistar rat is intravenously administered with streptozotocin (Sigma) at a dose of 50 mgZkg under penton-rubbital anesthesia to develop diabetes. From the day after the administration of streptozotocin, the compound (2) is orally administered once a day for 8 consecutive weeks. After continuous injection, the motor sigmoid i3 ⁇ 4 in the sciatic nerve is measured using an experiment ruler (Synax 1200, NEC Corporation). The compound's ⁇ ⁇ ⁇ ⁇ effect on the delay of boats with diabetes due to diabetes is considered to be a diabetic neuropathy ameliorating effect. I do.
  • Table C shows the results of Example 17-1 of the compound of the present invention.
  • Table C Sciatic god tree after 6 weeks of drug administration il ⁇ ⁇ sec
  • Significant difference test normal group vs diabetic group: p ⁇ 0.001, diabetic group vs 20H administration group: p ⁇ 0.05
  • the compound of the present invention successfully inhibits PKC yS 23 ⁇ 411 and is effective in improving diabetic complications. It was clarified to show a certain diabetic nephropathy improvement effect and a diabetic neuropathy improvement effect.
  • compositions containing, as an active ingredient, one or two of the compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof can be used as a carrier or excipient for commonly used pharmaceutical preparations Tablets, powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, ointments, patches, etc., using other additives, orally or parenterally Is administered.
  • the clinical dose of the compound of the present invention for humans is appropriately determined in consideration of the symptoms, body weight, age, etc. of the patient to which the compound is applied.
  • the parenteral dose is 0-01 to 100 mg, which is administered once or in several divided doses. The dose varies under various conditions. It may be enough.
  • one or more of the 14 substances may comprise at least one inactive diluent, such as ⁇ 3 ⁇ 4, mannitol, glucose, hydroxypropylcellulose, sprinkled crystalline cellulose, starch, polyvinylpyrrolidone, Mixed with magnesium aluminate metasilicate.
  • inactive diluent such as ⁇ 3 ⁇ 4, mannitol, glucose, hydroxypropylcellulose, sprinkled crystalline cellulose, starch, polyvinylpyrrolidone, Mixed with magnesium aluminate metasilicate.
  • the textile is made of additives other than diluents, such as lubricants such as magnesium stearate, disintegrators such as calcium diglycolate, stabilizers such as lactose, A solubilizing or solubilizing agent such as glutamic acid or aspartic acid may be contained.
  • Tablets or pills are coated with sugar such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc. 3 ⁇ 4JiI may be used with a film of a soluble substance.
  • Liquid compositions for oral administration include pharmaceutically acceptable solutions, solutions, syrups, syrups, elixirs, etc., and commonly used inert diluents such as iim Includes water and ethyl alcohol.
  • This product may contain solubilizing or solubilizing agents, humectants, auxiliaries such as MM agents, sweeteners, I ⁇ agents, fragrances, and preservatives in addition to the diluent.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, syrups, and syrups.
  • aqueous solutions and diluents for diluents include distilled water for sizing agents and hydraulics for sanitary facilities.
  • water-insoluble solution agents and diluents for foaming agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethyl alcohol, and sorbitol 80 (trade name). is there.
  • Such foods may further include additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents.
  • additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents.
  • additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents.
  • 2,2,6,6 "tetramethizolebiperidine 2.65 ml of butyllithium was added dropwise to a solution of 2.7 ml of tetrahydrofuran in 80 ml of ice under ice cooling, and the mixture was stirred for 10 minutes. After stirring at ⁇ 78 ° C. for 30 minutes, A solution of 2.0 g of 2,6-dichlorovirazine in 10 ml of tetrahydrofuran was added dropwise, and the mixture was stirred at the same temperature for 30 minutes, 2 g of dry ice was added to the reaction solution, and the mixture was stirred for 30 minutes.
  • the solvent was distilled off under reduced pressure, and the residue was mixed with chloroform, washed with 1 ⁇ HCl, saturated: ⁇ water, the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure, and acetone was added to the residue.
  • the insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure.
  • Example 2 to Example 14 and Example 11 to Example 18-3 were obtained in the same manner as in Example 1.
  • Example 23-1 and Example 23-2 were obtained in the same manner as in Mie.
  • Example 17-2 to Example 17 to 9, Example 2 (H to Example 20 to 3, Example 35 to 1 and Example 35-2) was.
  • Example 21-1 a compound having the composition described in Example 21-2 (5
  • Example 27-2 The compound of Example 27-2 was obtained in the same manner as in Example 27-1.
  • the obtained crystals were dissolved in 5 ml of methanol and 5 ml of tetrahydrofuran, 15 rrg of 10% radium charcoal was added, and the mixture was stirred under a hydrogen atmosphere for 20 hours.
  • the catalyst was removed by filtration, and the solvent was distilled off under reduced pressure.
  • Example 33 In the same manner as in Example 32-1, the compounds of Examples 32 and 2 were obtained.
  • Example 33 In the same manner as in Example 32-1, the compounds of Examples 32 and 2 were obtained.
  • Tables 1 to 12 show the structural formulas and physicochemical properties of the self-reference example compounds and the example compounds. Further, the compounds in Tables 13 and 14 can be easily produced in the same manner as described in Examples or Production Methods, or by applying modifications obvious to those skilled in the art. The symbols in the table have the following meanings.
  • H6 '9 ⁇ ' b * H2) 898 'C "W98 -9Z.2' (z 9W

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés utiles pour prévenir ou traiter des complications du diabète sur la base d'une inhibition de la protéine kinase C. L'invention concerne des dérivés hétérocycliques azotés, caractérisés par une structure chimique dans laquelle un hétérocycle azoté comportant un carbamoyle est lié à un aryle, à un cycloalkyle ou à un hétéroaryle par l'intermédiaire d'un atome d'azote, et à un alkylène éventuellement substitué, etc., par l'intermédiaire d'un autre atome d'azote, par exemple du 4-benzyloxy-2-[2-diméthylaminoéthyl)amino]-6-(3-méthylanilino)pyrimidine-5-carboxamide. Ces composés inhibent bien l'activité de PKC et permettent d'améliorer les complications du diabète.
PCT/JP2000/003768 1999-06-10 2000-06-09 Nouveaux derives heterocycliques azotes ou leurs sels Ceased WO2000076980A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU51080/00A AU5108000A (en) 1999-06-10 2000-06-09 Novel nitrogen-contaiing heterocyclic derivatives or salts thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP16334499 1999-06-10
JP11/163344 1999-06-10
JP16521799 1999-06-11
JP11/165217 1999-06-11

Publications (1)

Publication Number Publication Date
WO2000076980A1 true WO2000076980A1 (fr) 2000-12-21

Family

ID=26488808

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2000/003768 Ceased WO2000076980A1 (fr) 1999-06-10 2000-06-09 Nouveaux derives heterocycliques azotes ou leurs sels

Country Status (2)

Country Link
AU (1) AU5108000A (fr)
WO (1) WO2000076980A1 (fr)

Cited By (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001083460A1 (fr) * 2000-04-28 2001-11-08 Tanabe Seiyaku Co., Ltd. Composes cycliques
WO2004018435A1 (fr) * 2002-08-24 2004-03-04 Astrazeneca Ab Derives de la pyrimidine utilises comme modulateurs d'activite du recepteur de chimiokine
EP1397142A4 (fr) * 2001-06-19 2004-11-03 Bristol Myers Squibb Co Inhibiteurs pyrimidine de la phosphodiesterase (pde) 7
JP2005525381A (ja) * 2002-03-13 2005-08-25 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ ヒストンデアセチラーゼの新規な阻害剤としてのアミノ誘導体
WO2005056547A3 (fr) * 2003-12-04 2005-09-22 Vertex Pharma Quinoxalines utiles comme inhibiteurs des proteines kinases
JP2005530760A (ja) * 2002-05-03 2005-10-13 エクセリクシス， インク． プロテインキナーゼモジュレーターおよびその使用方法
US7078522B2 (en) 2001-02-26 2006-07-18 Tanabe Seiyaku Co., Ltd. Pyridopyrimidine or naphthyridine derivative
US7273868B2 (en) 2000-04-28 2007-09-25 Tanabe Seiyaku Co., Ltd. Pyrazine derivatives
US7329672B2 (en) 2002-02-01 2008-02-12 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
JP2008505955A (ja) * 2004-07-15 2008-02-28 エフ．ホフマン−ラ　ロシュ　アーゲー 新規な２，６−ジアミノピリジン−３−オン誘導体
JP2008505910A (ja) * 2004-07-08 2008-02-28 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド Ｐｋｃ−シータのインヒビターとして有用なピリミジン誘導体
US7452879B2 (en) 2003-07-30 2008-11-18 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US7459455B2 (en) 2002-02-08 2008-12-02 Smithkline Beecham Corporation Pyrimidine compounds
US7517886B2 (en) 2002-07-29 2009-04-14 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US7557207B2 (en) 2004-11-24 2009-07-07 Rigel Pharmaceuticals, Inc. Spiro 2,4-pyrimidinediamine compounds and their uses
JP2009525353A (ja) * 2005-12-06 2009-07-09 ライジェル ファーマシューティカルズ， インコーポレイテッド ピリミジン−２，４−ジアミンおよびその使用
US7582644B2 (en) 2002-07-27 2009-09-01 Astrazeneca Ab Pyrimidyl sulphone amide derivatives as chemokine receptor modulators
EP2140864A3 (fr) * 2001-01-31 2010-01-27 H.Lundbeck A/S Utilisation des antagonistes de récepteur GAL3 pour le traitement de la dépression et/ou de l'anxiété et composés utiles dans ces procédés
US7704995B2 (en) * 2002-05-03 2010-04-27 Exelixis, Inc. Protein kinase modulators and methods of use
WO2010128659A1 (fr) 2009-05-08 2010-11-11 アステラス製薬株式会社 Composé de carboxamide hétérocyclique diamino
US7838675B2 (en) 2004-08-28 2010-11-23 Astrazeneca Ab Pyrimidine sulphonamide derivatives as chemokine receptor modulators
WO2012061415A1 (fr) * 2010-11-01 2012-05-10 Portola Pharmaceuticals, Inc. Oxypyrimidines en tant que modulateurs de syk
US20120142671A1 (en) * 2010-11-01 2012-06-07 Portola Pharmaceuticals, Inc. Benzamides and nicotinamides as syk modulators
WO2013047813A1 (fr) 2011-09-30 2013-04-04 大鵬薬品工業株式会社 Dérivé de 1,2,4-triazine-6-carboxamide
JP2013136535A (ja) * 2011-12-28 2013-07-11 Fujifilm Corp 新規なニコチンアミド誘導体またはその塩
US8501944B2 (en) 2008-04-16 2013-08-06 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US8580804B2 (en) 2009-04-10 2013-11-12 Kyoto University Compound having hetero ring skeleton, and process for producing optically active compound using the aforementioned compound as asymmetric catalyst
CN103467392A (zh) * 2013-10-09 2013-12-25 重庆工商大学 一种多卤代吡嗪甲酰胺衍生物及其盐类、制备方法和用途
WO2013192049A2 (fr) 2012-06-22 2013-12-27 Portola Pharmaceuticals, Inc. Inhibiteurs de 1,2,4-triazine-6-carboxamide kinase
WO2014074661A1 (fr) * 2012-11-08 2014-05-15 Bristol-Myers Squibb Company Composés hétérocycliques substitués par amide, utiles comme modulateurs d'il-12, il-23 et/ou de réponses à l'ifnα
WO2014111031A1 (fr) * 2013-01-17 2014-07-24 四川恒康发展有限责任公司 Composé triazine, sel pharmaceutique, isomère, ou hydrate de celui-ci, et composition pharmaceutique de celui-ci
JP2014533731A (ja) * 2011-11-23 2014-12-15 ポートラ ファーマシューティカルズ， インコーポレイテッド ピラジンキナーゼ阻害剤
US8952027B2 (en) 2008-04-16 2015-02-10 Portola Pharmaceuticals, Inc. Inhibitors of syk and JAK protein kinases
EP2909174A1 (fr) * 2012-10-19 2015-08-26 F. Hoffmann-La Roche AG Inhibiteurs de syk
US9139534B2 (en) 2011-04-22 2015-09-22 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US9156798B2 (en) 2013-12-20 2015-10-13 Signal Pharmaceuticals, Llc Substituted diaminopyrimidyl compounds, compositions thereof, and methods of treatment therewith
US9365524B2 (en) 2014-01-30 2016-06-14 Signal Pharmaceuticals, Llc Solid forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
US9382246B2 (en) 2013-12-05 2016-07-05 Pharmacyclics Llc Inhibitors of Bruton's tyrosine kinase
US9513297B2 (en) 2014-12-16 2016-12-06 Signal Pharmaceuticals, Llc Methods for measurement of inhibition of c-Jun N-terminal kinase in skin
US9796685B2 (en) 2014-12-16 2017-10-24 Signal Pharmaceuticals, Llc Formulations of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-Methylcyclohexylamino)-pyrimidine-5-carboxamide
US10252981B2 (en) 2015-07-24 2019-04-09 Celgene Corporation Methods of synthesis of (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride and intermediates useful therein
US10689351B2 (en) 2015-01-29 2020-06-23 Signal Pharmaceuticals, Llc Isotopologues of 2-(tert butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide
WO2022012593A1 (fr) * 2020-07-17 2022-01-20 微境生物医药科技(上海)有限公司 Composé 5,6-dihydropyrazino[2,3-c]isoquinoléine
RU2526253C9 (ru) * 2009-05-08 2022-08-02 Астеллас Фарма Инк. Диаминогетероциклическое карбоксамидное соединение
CN115698000A (zh) * 2020-06-01 2023-02-03 微境生物医药科技(上海)有限公司 新型吡嗪化合物

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1377505A (en) * 1970-12-19 1974-12-18 Basf Ag Azo dyes from 2,6-diaminopyridine derivatives
JPH0776562A (ja) * 1992-11-27 1995-03-20 Ciba Geigy Ag ジアミノ安息香酸誘導体
WO1995017888A1 (fr) * 1993-12-30 1995-07-06 Smithkline Beecham Corporation Hexanamides de phenylmethyle et leur utilisation
WO1999031073A1 (fr) * 1997-12-15 1999-06-24 Yamanouchi Pharmaceutical Co., Ltd. Nouveaux derives de pyrimidine-5-carboxamide

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1377505A (en) * 1970-12-19 1974-12-18 Basf Ag Azo dyes from 2,6-diaminopyridine derivatives
JPH0776562A (ja) * 1992-11-27 1995-03-20 Ciba Geigy Ag ジアミノ安息香酸誘導体
WO1995017888A1 (fr) * 1993-12-30 1995-07-06 Smithkline Beecham Corporation Hexanamides de phenylmethyle et leur utilisation
WO1999031073A1 (fr) * 1997-12-15 1999-06-24 Yamanouchi Pharmaceutical Co., Ltd. Nouveaux derives de pyrimidine-5-carboxamide

Cited By (151)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001083460A1 (fr) * 2000-04-28 2001-11-08 Tanabe Seiyaku Co., Ltd. Composes cycliques
US7273868B2 (en) 2000-04-28 2007-09-25 Tanabe Seiyaku Co., Ltd. Pyrazine derivatives
US7220736B2 (en) 2000-04-28 2007-05-22 Tanabe Seiyaku Co., Ltd. Pyrimidine compounds
EP2140862A3 (fr) * 2001-01-31 2010-02-17 H.Lundbeck A/S Utilisation d'antagonistes du recepteur GAL3 dans le traitement de la dépression et/ou de l'anxiété et composés utiles dans de telles méthodes
EP2140864A3 (fr) * 2001-01-31 2010-01-27 H.Lundbeck A/S Utilisation des antagonistes de récepteur GAL3 pour le traitement de la dépression et/ou de l'anxiété et composés utiles dans ces procédés
US7078522B2 (en) 2001-02-26 2006-07-18 Tanabe Seiyaku Co., Ltd. Pyridopyrimidine or naphthyridine derivative
US7087614B2 (en) 2001-06-19 2006-08-08 Bristol-Myers Squibb Co. Pyrimidine inhibitors of phosphodiesterase (PDE) 7
EP1397142A4 (fr) * 2001-06-19 2004-11-03 Bristol Myers Squibb Co Inhibiteurs pyrimidine de la phosphodiesterase (pde) 7
US7485724B2 (en) 2002-02-01 2009-02-03 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US9416112B2 (en) 2002-02-01 2016-08-16 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US10709703B2 (en) 2002-02-01 2020-07-14 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7329672B2 (en) 2002-02-01 2008-02-12 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7329671B2 (en) 2002-02-01 2008-02-12 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7332484B2 (en) 2002-02-01 2008-02-19 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US9018204B1 (en) 2002-02-01 2015-04-28 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US9346765B2 (en) 2002-02-01 2016-05-24 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7435814B2 (en) 2002-02-01 2008-10-14 Rigel Pharmaceuticals, Inc. 2,4-Pyrimidinediamine compounds and their uses
US8835430B2 (en) 2002-02-01 2014-09-16 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7820819B2 (en) 2002-02-01 2010-10-26 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7803939B2 (en) 2002-02-01 2010-09-28 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7655797B2 (en) 2002-02-01 2010-02-02 Rigel Pharmaceuticals, Inc. Intermediates for making 2,4-pyrimidinediamine compounds
US7498435B2 (en) 2002-02-01 2009-03-03 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7642351B2 (en) 2002-02-01 2010-01-05 Rogel Pharmaceuticals, Inc. 2,4-Pyrimidinediamine compounds and their uses
US7550460B2 (en) 2002-02-01 2009-06-23 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7557210B2 (en) 2002-02-01 2009-07-07 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US10682350B2 (en) 2002-02-01 2020-06-16 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7589200B2 (en) 2002-02-01 2009-09-15 Rigel Pharmaceuticals, Inc. 5-Fluoro-4N-phenyl-4-pyrimidineamine compounds
US8334296B2 (en) 2002-02-01 2012-12-18 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US9913842B2 (en) 2002-02-01 2018-03-13 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and their uses
US7459455B2 (en) 2002-02-08 2008-12-02 Smithkline Beecham Corporation Pyrimidine compounds
JP2005525381A (ja) * 2002-03-13 2005-08-25 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ ヒストンデアセチラーゼの新規な阻害剤としてのアミノ誘導体
US7704995B2 (en) * 2002-05-03 2010-04-27 Exelixis, Inc. Protein kinase modulators and methods of use
JP2005530760A (ja) * 2002-05-03 2005-10-13 エクセリクシス， インク． プロテインキナーゼモジュレーターおよびその使用方法
US7582644B2 (en) 2002-07-27 2009-09-01 Astrazeneca Ab Pyrimidyl sulphone amide derivatives as chemokine receptor modulators
US8106063B2 (en) 2002-07-27 2012-01-31 Astrazeneca Ab Pyrimidyl sulphone amide derivatives as chemokine receptor modulators
US7812029B1 (en) 2002-07-29 2010-10-12 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US7517886B2 (en) 2002-07-29 2009-04-14 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US7825116B2 (en) 2002-07-29 2010-11-02 Rigel Pharmaceuticals, Inc. N2, N4-bis-aryl-5-fluoro-2,4-pyrimidinediamines
US8557806B2 (en) 2002-07-29 2013-10-15 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
WO2004018435A1 (fr) * 2002-08-24 2004-03-04 Astrazeneca Ab Derives de la pyrimidine utilises comme modulateurs d'activite du recepteur de chimiokine
US7482355B2 (en) 2002-08-24 2009-01-27 Astrazeneca Ab Pyrimidine derivatives as modulators of chemokine receptor activity
JP2006503906A (ja) * 2002-08-24 2006-02-02 アストラゼネカ・アクチエボラーグ ケモカインレセプター活性のモジュレーターとしてのピリミジン誘導体
US7452879B2 (en) 2003-07-30 2008-11-18 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US8178671B2 (en) 2003-07-30 2012-05-15 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2, 4-pyrimidinediamine compounds
US7582648B2 (en) 2003-07-30 2009-09-01 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US7560466B2 (en) 2003-07-30 2009-07-14 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US9751893B2 (en) 2003-07-30 2017-09-05 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US7592340B2 (en) 2003-12-04 2009-09-22 Vertex Pharmaceuticals Incorporated Quinoxalines useful as inhibitors of protein kinases
WO2005056547A3 (fr) * 2003-12-04 2005-09-22 Vertex Pharma Quinoxalines utiles comme inhibiteurs des proteines kinases
JP2008505910A (ja) * 2004-07-08 2008-02-28 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド Ｐｋｃ−シータのインヒビターとして有用なピリミジン誘導体
JP2008505955A (ja) * 2004-07-15 2008-02-28 エフ．ホフマン−ラ　ロシュ　アーゲー 新規な２，６−ジアミノピリジン−３−オン誘導体
US7838675B2 (en) 2004-08-28 2010-11-23 Astrazeneca Ab Pyrimidine sulphonamide derivatives as chemokine receptor modulators
US8722883B2 (en) 2004-08-28 2014-05-13 Astrazeneca Ab Pyrimidine sulphonamide derivatives as chemokine receptor modulators
US8269002B2 (en) 2004-08-28 2012-09-18 Astrazeneca Ab Pyrimidine sulphonamide derivatives as chemokine receptor modulators
US8410123B2 (en) 2004-08-28 2013-04-02 Astrazeneca Ab Pyrimidine sulphonamide derivatives as chemokine receptor modulators
US7557207B2 (en) 2004-11-24 2009-07-07 Rigel Pharmaceuticals, Inc. Spiro 2,4-pyrimidinediamine compounds and their uses
US7851480B2 (en) 2004-11-24 2010-12-14 Rigel Pharmaceuticals, Inc. Spiro 2,4-pyrimidinediamine compounds and their uses
JP2009525353A (ja) * 2005-12-06 2009-07-09 ライジェル ファーマシューティカルズ， インコーポレイテッド ピリミジン−２，４−ジアミンおよびその使用
US8501944B2 (en) 2008-04-16 2013-08-06 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US9579320B2 (en) 2008-04-16 2017-02-28 Portola Pharmaceuticals, Inc. Inhibitors of syk and JAK protein kinases
US9868729B2 (en) 2008-04-16 2018-01-16 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US10533001B2 (en) 2008-04-16 2020-01-14 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US11414410B2 (en) 2008-04-16 2022-08-16 Alexion Pharmaceuticals, Inc. Inhibitors of protein kinases
US8952027B2 (en) 2008-04-16 2015-02-10 Portola Pharmaceuticals, Inc. Inhibitors of syk and JAK protein kinases
US8937070B2 (en) 2008-04-16 2015-01-20 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US9073823B2 (en) 2009-04-10 2015-07-07 Kyoto University Compound having hetero ring skeleton, and process for producing optically active compound using the aforementioned compound as asymmetric catalyst
US8580804B2 (en) 2009-04-10 2013-11-12 Kyoto University Compound having hetero ring skeleton, and process for producing optically active compound using the aforementioned compound as asymmetric catalyst
RU2526253C9 (ru) * 2009-05-08 2022-08-02 Астеллас Фарма Инк. Диаминогетероциклическое карбоксамидное соединение
EP2428508A4 (fr) * 2009-05-08 2012-11-28 Astellas Pharma Inc Composé de carboxamide hétérocyclique diamino
US9487491B2 (en) 2009-05-08 2016-11-08 Astellas Pharma Inc. Diamino heterocyclic carboxamide compound
JP5364159B2 (ja) * 2009-05-08 2013-12-11 アステラス製薬株式会社 ジアミノへテロ環カルボキサミド化合物
WO2010128659A1 (fr) 2009-05-08 2010-11-11 アステラス製薬株式会社 Composé de carboxamide hétérocyclique diamino
US8969336B2 (en) 2009-05-08 2015-03-03 Astellas Pharma Inc. Diamino heterocyclic carboxamide compound
KR101614572B1 (ko) * 2009-05-08 2016-04-21 아스테라스 세이야쿠 가부시키가이샤 디아미노 헤테로환 카르복사미드 화합물
RU2526253C2 (ru) * 2009-05-08 2014-08-20 Астеллас Фарма Инк. Диаминогетероциклическое карбоксамидное соединение
EP3009428A1 (fr) 2009-05-08 2016-04-20 Astellas Pharma Inc. Composés de carboxamide hétérocycliques diamino
CN102421761A (zh) * 2009-05-08 2012-04-18 安斯泰来制药株式会社 二氨基杂环甲酰胺化合物
AU2010245545B2 (en) * 2009-05-08 2014-09-11 Astellas Pharma Inc. Diamino heterocyclic carboxamide compound
US8846928B2 (en) 2010-11-01 2014-09-30 Portola Pharmaceuticals, Inc. Benzamides and nicotinamides as Syk modulators
WO2012061418A3 (fr) * 2010-11-01 2012-08-02 Portola Pharmaceuticals, Inc. Benzamides et nicotinamides en tant que modulateurs de syk
US9359375B2 (en) 2010-11-01 2016-06-07 Portola Pharmaceuticals, Inc. Benzamides and nicotinamides as Syk modulators
WO2012061415A1 (fr) * 2010-11-01 2012-05-10 Portola Pharmaceuticals, Inc. Oxypyrimidines en tant que modulateurs de syk
US20120142671A1 (en) * 2010-11-01 2012-06-07 Portola Pharmaceuticals, Inc. Benzamides and nicotinamides as syk modulators
US10919865B2 (en) 2011-04-22 2021-02-16 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US11325890B2 (en) 2011-04-22 2022-05-10 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US9139534B2 (en) 2011-04-22 2015-09-22 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US9701643B2 (en) 2011-04-22 2017-07-11 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US10040770B2 (en) 2011-04-22 2018-08-07 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US12129237B2 (en) 2011-04-22 2024-10-29 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US10266500B2 (en) 2011-04-22 2019-04-23 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US9145414B2 (en) 2011-09-30 2015-09-29 Taiho Pharmaceutical Co., Ltd. 1,2,4-triazine-6-carboxamide derivative
WO2013047813A1 (fr) 2011-09-30 2013-04-04 大鵬薬品工業株式会社 Dérivé de 1,2,4-triazine-6-carboxamide
JPWO2013047813A1 (ja) * 2011-09-30 2015-03-30 大鵬薬品工業株式会社 １，２，４−トリアジン−６−カルボキサミド誘導体
US9359308B2 (en) 2011-11-23 2016-06-07 Portola Pharmaceuticals, Inc. Pyrazine kinase inhibitors
JP2014533731A (ja) * 2011-11-23 2014-12-15 ポートラ ファーマシューティカルズ， インコーポレイテッド ピラジンキナーゼ阻害剤
JP2013136535A (ja) * 2011-12-28 2013-07-11 Fujifilm Corp 新規なニコチンアミド誘導体またはその塩
EP2863748A4 (fr) * 2012-06-22 2015-12-09 Portola Pharm Inc Inhibiteurs de 1,2,4-triazine-6-carboxamide kinase
AU2013277476B2 (en) * 2012-06-22 2016-12-15 Alexion Pharmaceuticals, Inc. 1,2,4-triazine-6-carboxamide kinase inhibitors
JP2015520232A (ja) * 2012-06-22 2015-07-16 ポートラ ファーマシューティカルズ， インコーポレイテッド １，２，４−トリアジン−６−カルボキサミドキナーゼ阻害剤
WO2013192049A2 (fr) 2012-06-22 2013-12-27 Portola Pharmaceuticals, Inc. Inhibiteurs de 1,2,4-triazine-6-carboxamide kinase
US10112928B2 (en) 2012-10-19 2018-10-30 Hoffmann-La Roche Inc. Inhibitors of SYK
EP2909174A1 (fr) * 2012-10-19 2015-08-26 F. Hoffmann-La Roche AG Inhibiteurs de syk
EA028814B1 (ru) * 2012-11-08 2018-01-31 Бристол-Майерс Сквибб Компани АМИДЗАМЕЩЕННЫЕ ГЕТЕРОЦИКЛИЧЕСКИЕ СОЕДИНЕНИЯ, ПРИМЕНИМЫЕ В КАЧЕСТВЕ МОДУЛЯТОРОВ ОТВЕТОВ, ОПОСРЕДУЕМЫХ IL-12, IL-23 И/ИЛИ IFNα
US10000480B2 (en) 2012-11-08 2018-06-19 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFN alpha responses
AU2013341186B2 (en) * 2012-11-08 2017-03-30 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFN alpha responses
JP2020002157A (ja) * 2012-11-08 2020-01-09 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ ＩＬ−１２、ＩＬ−２３および／またはＩＦＮα応答のモジュレーターとして有用なアミド置換ヘテロ環式化合物
EP4071144A1 (fr) * 2012-11-08 2022-10-12 Bristol-Myers Squibb Company Composés hétérocycliques substitués par des groupements amides utiles en tant que modulateurs d'il-12, il-23 et/ou de réponses ifn alpha
WO2014074661A1 (fr) * 2012-11-08 2014-05-15 Bristol-Myers Squibb Company Composés hétérocycliques substitués par amide, utiles comme modulateurs d'il-12, il-23 et/ou de réponses à l'ifnα
AU2018267545B2 (en) * 2012-11-08 2020-04-02 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of il-12, il-23 and/or ifn alpha responses
KR20150081339A (ko) * 2012-11-08 2015-07-13 브리스톨-마이어스 스큅 컴퍼니 ＩＬ-12, ＩＬ-23 및/또는 ＩＦＮα 반응의 조절제로서 유용한 아미드-치환된 헤테로시클릭 화합물
US9505748B2 (en) 2012-11-08 2016-11-29 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFNα responses
US10526321B2 (en) 2012-11-08 2020-01-07 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFN alpha responses
USRE47929E1 (en) 2012-11-08 2020-04-07 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFNα responses
JP2016506369A (ja) * 2012-11-08 2016-03-03 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ ＩＬ−１２、ＩＬ−２３および／またはＩＦＮα応答のモジュレーターとして有用なアミド置換ヘテロ環式化合物
US11021475B2 (en) 2012-11-08 2021-06-01 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFN alpha responses
EP3495358A1 (fr) * 2012-11-08 2019-06-12 Bristol-Myers Squibb Company Composés hétérocycliques substitués par des groupements amides utiles en tant que modulateurs d'il-12, il-23 et/ou de réponses ifn alpha
KR102195194B1 (ko) 2012-11-08 2020-12-24 브리스톨-마이어스 스큅 컴퍼니 ＩＬ-12, ＩＬ-23 및/또는 ＩＦＮα 반응의 조절제로서 유용한 아미드-치환된 헤테로시클릭 화합물
AU2020203967B2 (en) * 2012-11-08 2020-10-22 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of il-12, il-23 and/or ifn alpha responses
CN104884454A (zh) * 2012-11-08 2015-09-02 百时美施贵宝公司 用作IL-12、IL-23和/或IFNα应答调节剂的酰胺取代的杂环化合物
CN104870437A (zh) * 2013-01-17 2015-08-26 四川恒康发展有限责任公司 三嗪化合物、其药用盐、异构体或水合物及其药物组合物
WO2014111031A1 (fr) * 2013-01-17 2014-07-24 四川恒康发展有限责任公司 Composé triazine, sel pharmaceutique, isomère, ou hydrate de celui-ci, et composition pharmaceutique de celui-ci
CN103467392A (zh) * 2013-10-09 2013-12-25 重庆工商大学 一种多卤代吡嗪甲酰胺衍生物及其盐类、制备方法和用途
CN103467392B (zh) * 2013-10-09 2016-08-17 重庆工商大学 一种多卤代吡嗪甲酰胺衍生物及其盐类、制备方法和用途
US9656988B2 (en) 2013-12-05 2017-05-23 Pharmacyclics Llc Inhibitors of Bruton's tyrosine kinase
US9382246B2 (en) 2013-12-05 2016-07-05 Pharmacyclics Llc Inhibitors of Bruton's tyrosine kinase
US9156798B2 (en) 2013-12-20 2015-10-13 Signal Pharmaceuticals, Llc Substituted diaminopyrimidyl compounds, compositions thereof, and methods of treatment therewith
US9556126B2 (en) 2013-12-20 2017-01-31 Signal Pharmaceuticals, Llc Substituted diaminopyrimidyl compounds, compositions thereof, and methods of treatment therewith
US9783505B2 (en) 2013-12-20 2017-10-10 Signal Pharmaceuticals, Llc Substituted diaminopyrimidyl compounds, compositions thereof, and methods of treatment therewith
US11241430B2 (en) 2014-01-30 2022-02-08 Signal Pharmaceuticals, Llc Solid forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
US9814713B2 (en) 2014-01-30 2017-11-14 Signal Pharmaceuticals, Llc Solid forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
US10517873B2 (en) 2014-01-30 2019-12-31 Signal Pharmaceuticals, Llc Solid forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
US10226461B2 (en) 2014-01-30 2019-03-12 Signal Pharmaceuticals, Llc Solid forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
US9365524B2 (en) 2014-01-30 2016-06-14 Signal Pharmaceuticals, Llc Solid forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
US10197579B2 (en) 2014-12-16 2019-02-05 Signal Pharmaceuticals, Llc Methods for measurement of inhibition of c-Jun N-terminal kinase in skin
US9513297B2 (en) 2014-12-16 2016-12-06 Signal Pharmaceuticals, Llc Methods for measurement of inhibition of c-Jun N-terminal kinase in skin
US9796685B2 (en) 2014-12-16 2017-10-24 Signal Pharmaceuticals, Llc Formulations of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-Methylcyclohexylamino)-pyrimidine-5-carboxamide
US10590089B2 (en) 2014-12-16 2020-03-17 Signal Pharmaceuticals, Llc Formulations of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide
US10131639B2 (en) 2014-12-16 2018-11-20 Signal Pharmaceuticals, Llc Formulations of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4methylcyclohexylamino)-pyrimidine-5-carboxamide
US11492332B2 (en) 2015-01-29 2022-11-08 Signal Pharmaceuticals, Llc Isotopologues of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide
US10975039B2 (en) 2015-01-29 2021-04-13 Signal Pharmaceuticals, Llc Isotopologues of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide
US10689351B2 (en) 2015-01-29 2020-06-23 Signal Pharmaceuticals, Llc Isotopologues of 2-(tert butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide
US11192847B2 (en) 2015-07-24 2021-12-07 Celgene Corporation Methods of synthesis of (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride and intermediates useful therein
US10252981B2 (en) 2015-07-24 2019-04-09 Celgene Corporation Methods of synthesis of (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride and intermediates useful therein
US11780801B2 (en) 2015-07-24 2023-10-10 Celgene Corporation Methods of synthesis of (1R,2R,5R)-5-amino-2-methyl-cyclohexanol hydrochloride and intermediates useful therein
US10774033B2 (en) 2015-07-24 2020-09-15 Celgene Corporation Methods of synthesis of (1R, 2R, 5R)-5-amino-2-methylcyclohexanol hydrochloride and intermediates useful therein
CN115698000A (zh) * 2020-06-01 2023-02-03 微境生物医药科技(上海)有限公司 新型吡嗪化合物
JP2023528859A (ja) * 2020-06-01 2023-07-06 ウィゲン・バイオメディシン・テクノロジー・（シャンハイ）・カンパニー・リミテッド 新規ピラジン化合物
EP4159731A4 (fr) * 2020-06-01 2024-06-26 Wigen Biomedicine Technology (Shanghai) Co., Ltd. Nouveau composé de pyrazine
JP7777544B2 (ja) 2020-06-01 2025-11-28 ウィゲン・バイオメディシン・テクノロジー・（シャンハイ）・カンパニー・リミテッド 新規ピラジン化合物
WO2022012593A1 (fr) * 2020-07-17 2022-01-20 微境生物医药科技(上海)有限公司 Composé 5,6-dihydropyrazino[2,3-c]isoquinoléine
CN116323617A (zh) * 2020-07-17 2023-06-23 微境生物医药科技(上海)有限公司 5,6-二氢吡嗪并[2,3-c]异喹啉化合物

Also Published As

Publication number Publication date
AU5108000A (en) 2001-01-02

Similar Documents

Publication Publication Date Title
WO2000076980A1 (fr) Nouveaux derives heterocycliques azotes ou leurs sels
CN113286794B (zh) Kras突变蛋白抑制剂
EP3023101B1 (fr) Agent thérapeutique pour un cancer résistant à un inhibiteur de fgfr
JP6082397B2 (ja) マクロ環状ｌｒｒｋ２キナーゼ阻害剤
WO1995008542A1 (fr) Inhibiteur de la farnesyl-transferase
JP6746613B2 (ja) ウレア誘導体、またはその薬理学的に許容される塩
IL237048A (en) Compressed history of sulphamoyl bicyclic and its use as a medicament for the treatment of jaundice b
HUP0301514A2 (hu) Benzimidazol származékok, elżállításuk és ezeket tartalmazó gyógyszerkészítmények
WO2003074525A1 (fr) Compose heterocyclique azote
EP4536662A1 (fr) Macrocycles d'indazole pour le traitement d'une maladie auto-immune
CN114195804A (zh) 一类哌啶稠环类化合物、制备方法和用途
WO2022028506A1 (fr) Inhibiteur de sos1, composition pharmaceutique le contenant et son utilisation
CN113788825A (zh) 作为vanin抑制剂的杂芳族化合物
WO2001079184A1 (fr) Composes de piperazine substitues
CN115677702A (zh) 三并环化合物及其药物组合物和应用
CN116600808A (zh) 一类作为kras突变体g12c抑制剂的四氢萘啶类衍生物、其制备方法及其应用
JP2023527204A (ja) ３，４－ジヒドロイソキノリン系化合物及びその使用
CN112867708B (zh) 一种mdm2抑制剂，及其制备方法、药物组合物和应用
CN113004282B (zh) 取代的炔基杂环化合物
CN115677730B (zh) 8-氧-3-氮杂二环[3.2.1]辛烷类化合物或其盐及其制备方法和用途
WO2022166970A1 (fr) Agent de dégradation de protéine mdm2 bifonctionnel, son procédé de préparation et composition pharmaceutique et utilisation associées
WO2022200576A1 (fr) Dérivés d'indoline utilisés en tant qu'inhibiteurs de ddr1 et ddr2
WO2002044179A1 (fr) Dérivés de 1,4,5,6-tétrahydroimidazo[4,5-d]diazépine ou sels de ces derniers
WO2014020531A1 (fr) Dérivés d'imidazo[1,2-b]pyridazin-6-amine utilisables en tant qu'inhibiteurs de la kinase jak2
RU2783521C1 (ru) Ингибиторы цитохрома 11В2 человека

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref country code: JP

Ref document number: 2001 503838

Kind code of ref document: A

Format of ref document f/p: F

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase