ES2871142T3 - Compuestos de aminopurina sustituidos, composiciones de los mismos y métodos de tratamiento con los mismos - Google Patents
Compuestos de aminopurina sustituidos, composiciones de los mismos y métodos de tratamiento con los mismos Download PDFInfo
- Publication number
- ES2871142T3 ES2871142T3 ES15848476T ES15848476T ES2871142T3 ES 2871142 T3 ES2871142 T3 ES 2871142T3 ES 15848476 T ES15848476 T ES 15848476T ES 15848476 T ES15848476 T ES 15848476T ES 2871142 T3 ES2871142 T3 ES 2871142T3
- Authority
- ES
- Spain
- Prior art keywords
- purin
- cyclohexanecarboxamide
- ylamino
- chloro
- dichloro
- 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.)
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- -1 aminopurine compounds Chemical class 0.000 title claims description 535
- 238000000034 method Methods 0.000 title claims description 121
- 238000011282 treatment Methods 0.000 title claims description 19
- 239000000203 mixture Chemical class 0.000 title description 248
- 150000001875 compounds Chemical class 0.000 claims abstract description 159
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 47
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 32
- 125000003118 aryl group Chemical group 0.000 claims abstract description 30
- 150000002367 halogens Chemical class 0.000 claims abstract description 27
- 125000001424 substituent group Chemical group 0.000 claims abstract description 27
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 22
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 16
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 13
- 125000005936 piperidyl group Chemical group 0.000 claims abstract description 10
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims abstract description 10
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims abstract description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 8
- 125000003566 oxetanyl group Chemical group 0.000 claims abstract description 8
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 5
- 125000002877 alkyl aryl group Chemical group 0.000 claims abstract description 4
- 125000005843 halogen group Chemical group 0.000 claims abstract 5
- PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 claims description 229
- 125000000217 alkyl group Chemical group 0.000 claims description 86
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 201000001441 melanoma Diseases 0.000 claims description 28
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 239000003981 vehicle Substances 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000003551 oxepanyl group Chemical group 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 230000004663 cell proliferation Effects 0.000 claims description 3
- 238000000338 in vitro Methods 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 108091000080 Phosphotransferase Proteins 0.000 claims description 2
- 102000001253 Protein Kinase Human genes 0.000 claims description 2
- 102000020233 phosphotransferase Human genes 0.000 claims description 2
- 108060006633 protein kinase Proteins 0.000 claims description 2
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 claims 28
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract description 12
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 204
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 202
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 192
- 239000000243 solution Substances 0.000 description 162
- 238000006243 chemical reaction Methods 0.000 description 141
- 238000005160 1H NMR spectroscopy Methods 0.000 description 107
- 239000007787 solid Substances 0.000 description 85
- 239000002904 solvent Substances 0.000 description 75
- 238000000746 purification Methods 0.000 description 73
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 72
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 66
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 58
- 238000010626 work up procedure Methods 0.000 description 54
- 239000012074 organic phase Substances 0.000 description 50
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 48
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 48
- 239000000706 filtrate Substances 0.000 description 42
- 150000003254 radicals Chemical group 0.000 description 41
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 39
- 239000011734 sodium Chemical class 0.000 description 39
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- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 33
- 238000010898 silica gel chromatography Methods 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
- 239000000725 suspension Substances 0.000 description 29
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 28
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- 239000002253 acid Substances 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 26
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 26
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 26
- 239000000460 chlorine Substances 0.000 description 24
- 239000012043 crude product Substances 0.000 description 24
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- 238000003756 stirring Methods 0.000 description 24
- 238000005481 NMR spectroscopy Methods 0.000 description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 206010028980 Neoplasm Diseases 0.000 description 21
- 239000001257 hydrogen Substances 0.000 description 21
- 229910052763 palladium Inorganic materials 0.000 description 21
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 20
- 229920005989 resin Polymers 0.000 description 19
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
- 125000000623 heterocyclic group Chemical group 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 17
- 125000000753 cycloalkyl group Chemical group 0.000 description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 239000007821 HATU Substances 0.000 description 14
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 239000008346 aqueous phase Substances 0.000 description 14
- 230000037396 body weight Effects 0.000 description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
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- 241001465754 Metazoa Species 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 201000011510 cancer Diseases 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
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- 102100034741 Cyclin-dependent kinase 20 Human genes 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
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- UAIXEOIQIOOYES-DGCLKSJQSA-N (3S,4R)-N-benzyl-3-methyloxan-4-amine Chemical compound C(C1=CC=CC=C1)N[C@H]1[C@@H](COCC1)C UAIXEOIQIOOYES-DGCLKSJQSA-N 0.000 description 6
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07D239/50—Three nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
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| US201462060339P | 2014-10-06 | 2014-10-06 | |
| PCT/US2015/053941 WO2016057370A1 (en) | 2014-10-06 | 2015-10-05 | Substituted aminopurine compounds, compositions thereof, and methods of treatment therewith |
Publications (1)
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|---|---|
| ES2871142T3 true ES2871142T3 (es) | 2021-10-28 |
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| ES20214685T Active ES2980464T3 (es) | 2014-10-06 | 2015-10-05 | Productos intermedios sintéticos útiles para preparar compuestos de aminopurina sustituidos |
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| ES20214685T Active ES2980464T3 (es) | 2014-10-06 | 2015-10-05 | Productos intermedios sintéticos útiles para preparar compuestos de aminopurina sustituidos |
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| LT3204386T (lt) * | 2014-10-06 | 2021-07-12 | Signal Pharmaceuticals, Llc | Pakeistieji aminopurino junginiai, jų kompozicijos ir gydymo būdai jais |
| EP3233808B1 (en) | 2014-12-16 | 2021-07-14 | Signal Pharmaceuticals, LLC | Medical uses comprising methods for measurement of inhibition of c-jun n-terminal kinase in skin |
| CA2975260C (en) | 2015-01-29 | 2024-05-21 | Signal Pharmaceuticals Llc | Isotopologues of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide |
| CN107635992B (zh) | 2015-03-18 | 2020-05-22 | 百时美施贵宝公司 | 用作tnf抑制剂的三环杂环化合物 |
| EA201792054A1 (ru) | 2015-03-18 | 2018-01-31 | Бристол-Майерс Сквибб Компани | Гетероциклические соединения, применимые в качестве ингибиторов tnf |
| CA2980159A1 (en) | 2015-03-18 | 2016-09-22 | Bristol-Myers Squibb Company | Substituted tricyclic heterocyclic compounds |
| MX385379B (es) | 2015-07-24 | 2025-03-18 | Celgene Corp | Metodos de sintesis de clorhidrato de (1r,2r,5r)-5-amino-2-metilciclohexanol e intermedios utiles en este. |
| MX2018001173A (es) | 2015-08-03 | 2018-04-24 | Squibb Bristol Myers Co | Compuestos ciclicos utiles como moduladores del factor de necrosis tumoral (tnf) alfa. |
| CN109069512B (zh) * | 2016-04-01 | 2022-06-14 | 西格诺药品有限公司 | 取代的氨基嘌呤化合物、其组合物以及相关治疗方法 |
| PT3436019T (pt) * | 2016-04-01 | 2021-11-04 | Signal Pharm Llc | (1s,4s)-4-(2-(((3s,4r)-3-fluorotetra-hidro-2h-piran-4- il)amino)-8-((2,4,6-triclorofenil)amino)-9h-purin-9-il)-1- metilciclo-hexano-1-carboxamida e métodos de utilização dos mesmos |
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| ES2926149T3 (es) * | 2016-06-02 | 2022-10-24 | Celgene Corp | Agentes antipalúdicos animales y humanos |
| BR112020006599B1 (pt) * | 2017-10-04 | 2024-02-20 | Celgene Corporation | Cápsulas compreendendo cis-4-[2-{[(3s,4r)-3-fluoro-oxan-4-il]amino}-8-(2,4,6-tricl oroanilino)-9h-purin-9-il]-1-metilciclohexano-1-carb oxamida |
| US10590136B2 (en) * | 2017-10-04 | 2020-03-17 | Celgene Corporation | Processes for the preparation of cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide |
| WO2022002118A1 (zh) * | 2020-07-01 | 2022-01-06 | 四川海思科制药有限公司 | 一种并环杂环衍生物及其在医药上的应用 |
| US12084453B2 (en) | 2021-12-10 | 2024-09-10 | Incyte Corporation | Bicyclic amines as CDK12 inhibitors |
| CN114478326B (zh) * | 2022-01-21 | 2023-10-03 | 安徽宁亿泰科技有限公司 | 一种苯嘧磺草胺关键中间体的合成方法 |
Family Cites Families (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL99699A (en) | 1990-10-10 | 2002-04-21 | Autoimmune Inc | Drug with the option of oral, intra-intestinal, or inhaled dosing for suppression of autoimmune response associated with type I diabetes |
| FI109088B (fi) | 1997-09-19 | 2002-05-31 | Leiras Oy | Tabletti ja menetelmä sen valmistamiseksi |
| CZ27399A3 (cs) | 1999-01-26 | 2000-08-16 | Ústav Experimentální Botaniky Av Čr | Substituované dusíkaté heterocyklické deriváty, způsob jejich přípravy, tyto deriváty pro použití jako léčiva, farmaceutická kompozice a kombinovaný farmaceutický přípravek tyto deriváty obsahující a použití těchto derivátů pro výrobu léčiv |
| US7672705B2 (en) * | 2004-07-19 | 2010-03-02 | Resonant Medical, Inc. | Weighted surface-to-surface mapping |
| US7521446B2 (en) | 2005-01-13 | 2009-04-21 | Signal Pharmaceuticals, Llc | Haloaryl substituted aminopurines, compositions thereof, and methods of treatment therewith |
| US7723340B2 (en) * | 2005-01-13 | 2010-05-25 | Signal Pharmaceuticals, Llc | Haloaryl substituted aminopurines, compositions thereof, and methods of treatment therewith |
| US7759342B2 (en) | 2005-01-13 | 2010-07-20 | Signal Pharmaceuticals, Llc | Methods of treatment and prevention using haloaryl substituted aminopurines |
| CN101360725B (zh) | 2005-11-18 | 2011-09-21 | 阿斯利康公司 | 固体制剂 |
| TWI398252B (zh) | 2006-05-26 | 2013-06-11 | Novartis Ag | 吡咯并嘧啶化合物及其用途 |
| KR20150028857A (ko) | 2006-10-27 | 2015-03-16 | 시그날 파마소티칼 엘엘씨 | 4-[9-(테트라하이드로-퓨란-3-일)-8-(2,4,6-트리플루오로-페닐아미노)-9ｈ-퓨린-2-일아미노]-사이클로헥산-1-올을포함하는 고체 형태들, 이들의 조성물들 및 이들의 용도 |
| US8491930B2 (en) | 2008-04-23 | 2013-07-23 | Farmasierra Manufacturing, S.L. | Pharmaceutical formulation containing ibuprofen and codeine |
| WO2011071491A1 (en) | 2009-12-09 | 2011-06-16 | Signal Pharmaceuticals, Llc | Isotopologues of 4-[9-(tetrahydro-furan-3-yl)-8-(2, 4, 6- trifluoro-phenylamino)-9h-purin-2-ylamino]-cyclohexan-1-ol |
| US8680076B2 (en) * | 2010-10-25 | 2014-03-25 | Signal Pharmaceuticals, Llc | Methods of treatment, improvement and prevention using haloaryl substituted aminopurines |
| US8603527B2 (en) | 2010-10-25 | 2013-12-10 | Signal Pharmaceuticals, Llc | Pharmaceutical formulations of a substituted diaminopurine |
| WO2014172616A2 (en) | 2013-04-18 | 2014-10-23 | President And Fellows Of Harvard College | Methods, compositions and kits for promoting motor neuron survival and treating and diagnosing neurodegenerative disorders |
| GB201321737D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic Agents |
| LT3204386T (lt) | 2014-10-06 | 2021-07-12 | Signal Pharmaceuticals, Llc | Pakeistieji aminopurino junginiai, jų kompozicijos ir gydymo būdai jais |
| PT3436019T (pt) | 2016-04-01 | 2021-11-04 | Signal Pharm Llc | (1s,4s)-4-(2-(((3s,4r)-3-fluorotetra-hidro-2h-piran-4- il)amino)-8-((2,4,6-triclorofenil)amino)-9h-purin-9-il)-1- metilciclo-hexano-1-carboxamida e métodos de utilização dos mesmos |
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