ES2740779T3 - Moduladores de SHIP1 - Google Patents
Moduladores de SHIP1 Download PDFInfo
- Publication number
- ES2740779T3 ES2740779T3 ES14710727T ES14710727T ES2740779T3 ES 2740779 T3 ES2740779 T3 ES 2740779T3 ES 14710727 T ES14710727 T ES 14710727T ES 14710727 T ES14710727 T ES 14710727T ES 2740779 T3 ES2740779 T3 ES 2740779T3
- Authority
- ES
- Spain
- Prior art keywords
- optionally substituted
- alkyl
- heterocyclyl
- heteroaryl
- heteroarylalkyl
- 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.)
- Active
Links
- 101000616502 Homo sapiens Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1 Proteins 0.000 title description 29
- 102100021797 Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1 Human genes 0.000 title description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 700
- -1 polycyclic hydrocarbon radical Chemical class 0.000 claims abstract description 267
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 254
- 239000000203 mixture Substances 0.000 claims abstract description 212
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 182
- 239000001257 hydrogen Substances 0.000 claims abstract description 177
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 161
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 149
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 146
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims abstract description 144
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 134
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims abstract description 120
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 107
- 125000003118 aryl group Chemical group 0.000 claims abstract description 107
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 106
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 104
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 100
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract description 91
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 84
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 82
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 49
- 150000003839 salts Chemical class 0.000 claims abstract description 48
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 46
- 125000004450 alkenylene group Chemical group 0.000 claims abstract description 41
- 125000001424 substituent group Chemical group 0.000 claims abstract description 37
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 36
- 125000004419 alkynylene group Chemical group 0.000 claims abstract description 34
- 150000002367 halogens Chemical group 0.000 claims abstract description 34
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 34
- 239000012453 solvate Substances 0.000 claims abstract description 34
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 33
- 150000003254 radicals Chemical group 0.000 claims abstract description 30
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 29
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 28
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 28
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 24
- 125000001118 alkylidene group Chemical group 0.000 claims abstract description 21
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims abstract description 11
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 8
- 239000004215 Carbon black (E152) Substances 0.000 claims abstract description 6
- 229930195733 hydrocarbon Natural products 0.000 claims abstract description 6
- 125000004449 heterocyclylalkenyl group Chemical group 0.000 claims abstract 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 115
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 103
- 238000000034 method Methods 0.000 claims description 67
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 60
- 208000035475 disorder Diseases 0.000 claims description 53
- 201000010099 disease Diseases 0.000 claims description 50
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 47
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 32
- 241000124008 Mammalia Species 0.000 claims description 27
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 150000002430 hydrocarbons Chemical group 0.000 claims description 10
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 9
- 208000023275 Autoimmune disease Diseases 0.000 claims description 8
- 230000001613 neoplastic effect Effects 0.000 claims description 5
- ATOHKNFTLZVMMU-HOJFQYKESA-N (1S,3aS,4R,5S,7aS)-4-(aminomethyl)-5-[(1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-7a-methyl-1-phenyl-3,3a,4,5,6,7-hexahydro-2H-inden-1-ol Chemical compound NC[C@H]1[C@@H]2CC[C@@]([C@]2(CC[C@@H]1[C@@]1([C@H](C[C@H](CC1)O)CO)C)C)(O)C1=CC=CC=C1 ATOHKNFTLZVMMU-HOJFQYKESA-N 0.000 claims description 4
- PPYSKFPNXNEUPX-OYWYNUBDSA-N (1s,3s,4r)-4-[(4r,5s)-1,1-dimethyl-4-[[(1-methylpiperidin-4-yl)amino]methyl]-2,3,4,5,6,7-hexahydroinden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound C1CN(C)CCC1NC[C@H]1C(CCC2(C)C)=C2CC[C@@H]1[C@]1(C)[C@@H](CO)C[C@@H](O)CC1 PPYSKFPNXNEUPX-OYWYNUBDSA-N 0.000 claims description 4
- GBRMAPHUVGDGQH-KBINAZFZSA-N 1-[[(4r,5s)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-1,1-dimethyl-2,3,4,5,6,7-hexahydroinden-4-yl]methyl]-3-pyridin-3-ylurea Chemical compound C([C@@H]1[C@H](CCC2=C1CCC2(C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NC(=O)NC1=CC=CN=C1 GBRMAPHUVGDGQH-KBINAZFZSA-N 0.000 claims description 4
- NNPJIFNHUGTFCQ-ZRRUVYEKSA-N 1-cyano-3-[[(4R,5S)-5-[(1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-1,1-dimethyl-2,3,4,5,6,7-hexahydroinden-4-yl]methyl]-2-methylguanidine Chemical compound CNC(NC[C@@H]1[C@H](CCC2=C1CCC2(C)C)[C@@]1(C)CC[C@H](O)C[C@@H]1CO)=N/C#N NNPJIFNHUGTFCQ-ZRRUVYEKSA-N 0.000 claims description 4
- HZNGYHIAEWUDCW-ZRRUVYEKSA-N 1-ethyl-3-[[(4r,5s)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-1,1-dimethyl-2,3,4,5,6,7-hexahydroinden-4-yl]methyl]urea Chemical compound C[C@]1([C@@H]2[C@H](C3=C(C(CC3)(C)C)CC2)CNC(=O)NCC)CC[C@H](O)C[C@@H]1CO HZNGYHIAEWUDCW-ZRRUVYEKSA-N 0.000 claims description 4
- NKOOSJMGUWQDAV-QPNVGHEYSA-N [(5r,6s)-5-[(3as,4r,5s,7as)-4-(hydroxymethyl)-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2h-inden-5-yl]-5-methyl-1,4,6,7-tetrahydroindazol-6-yl]methanol Chemical compound C([C@]([C@H](C1)CO)(C)[C@H]2CC[C@]3([C@H]([C@@H]2CO)CCC3=C)C)C2=C1NN=C2 NKOOSJMGUWQDAV-QPNVGHEYSA-N 0.000 claims description 4
- 230000004663 cell proliferation Effects 0.000 claims description 4
- 125000004447 heteroarylalkenyl group Chemical group 0.000 claims description 4
- 230000004968 inflammatory condition Effects 0.000 claims description 4
- XXCUJTSIKSYMIF-OYNCYEILSA-N n-[[(4r,5s)-5-[(1r,2s,4s)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-1,1-dimethyl-2,3,4,5,6,7-hexahydroinden-4-yl]methyl]pyridine-3-carboxamide Chemical compound C([C@@H]1[C@H](CCC2=C1CCC2(C)C)[C@]1(C)[C@H](C[C@@H](O)CC1)CO)NC(=O)C1=CC=CN=C1 XXCUJTSIKSYMIF-OYNCYEILSA-N 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- AWJUKAOTVTXQJP-QPNVGHEYSA-N [(5R,6S)-5-[(3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2H-inden-5-yl]-5-methyl-6,7-dihydro-4H-2,1-benzoxazol-6-yl]methanol Chemical compound C[C@]12CC[C@@H]([C@@H](CO)[C@@H]1CCC2=C)[C@@]1(C)Cc2conc2C[C@@H]1CO AWJUKAOTVTXQJP-QPNVGHEYSA-N 0.000 claims description 3
- YCMIOWAQXYEUMK-UQHLGXRBSA-N (1S,3S,4R)-4-[(1S,2R,3aS,4aS,5R,5'R,6S,8aS,8bR)-5-(aminomethyl)-1,5',8a-trimethylspiro[3a,4,4a,5,6,7,8,8b-octahydro-1H-indeno[2,1-b]furan-2,2'-oxane]-6-yl]-3-(hydroxymethyl)-4-methylcyclohexan-1-ol Chemical compound NC[C@H]1[C@@H]2C[C@@H]3O[C@]4([C@H]([C@@H]3[C@]2(CC[C@@H]1[C@@]1([C@H](C[C@H](CC1)O)CO)C)C)C)OC[C@@H](CC4)C YCMIOWAQXYEUMK-UQHLGXRBSA-N 0.000 claims description 2
- JJUZAZGMMZOWLH-PTHYOWMMSA-N (1S,3aS,4R,5S,7aS)-4-(aminomethyl)-5-[(1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-1,7a-dimethyl-3,3a,4,5,6,7-hexahydro-2H-inden-1-ol Chemical compound NC[C@H]1[C@@H]2CC[C@@]([C@]2(CC[C@@H]1[C@@]1([C@H](C[C@H](CC1)O)CO)C)C)(O)C JJUZAZGMMZOWLH-PTHYOWMMSA-N 0.000 claims description 2
- LWTKCGSQGFMHMK-PTHYOWMMSA-N (1S,3aS,4R,5S,7aS)-5-[(1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl]-4-(hydroxymethyl)-1,7a-dimethyl-3,3a,4,5,6,7-hexahydro-2H-inden-1-ol Chemical compound O[C@@H]1C[C@@H]([C@@](CC1)(C)[C@@H]1[C@H]([C@@H]2CC[C@@]([C@]2(CC1)C)(O)C)CO)CO LWTKCGSQGFMHMK-PTHYOWMMSA-N 0.000 claims description 2
- LIKWRTDIXRUYNE-BHMKJSQQSA-N N-[(1S,3S,4R)-4-[(3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2H-inden-5-yl]-3-(hydroxymethyl)-4-methylcyclohexyl]acetamide Chemical compound CC(=O)N[C@H]1CC[C@@](C)([C@@H](CO)C1)[C@H]1CC[C@@]2(C)[C@@H](CCC2=C)[C@@H]1CO LIKWRTDIXRUYNE-BHMKJSQQSA-N 0.000 claims description 2
- YNXNMJIMLYYEGY-JXNBOPDTSA-N [(5R,6S)-5-[(4R,5S)-4-(hydroxymethyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydroinden-5-yl]-5-methyl-6,7-dihydro-4H-1,2-benzoxazol-6-yl]methanol Chemical compound CC1(C)CCC2=C1CC[C@@H]([C@H]2CO)[C@@]1(C)Cc2cnoc2C[C@@H]1CO YNXNMJIMLYYEGY-JXNBOPDTSA-N 0.000 claims description 2
- VXIRWSIEDUGWPG-RZAWSJAESA-N [(5S,6R)-6-[(3aS,4R,5S,7aS)-4-(hydroxymethyl)-7a-methyl-1-methylidene-3,3a,4,5,6,7-hexahydro-2H-inden-5-yl]-2,6-dimethyl-5,7-dihydro-4H-1,3-benzothiazol-5-yl]methanol Chemical compound Cc1nc2C[C@H](CO)[C@](C)(Cc2s1)[C@H]1CC[C@@]2(C)[C@@H](CCC2=C)[C@@H]1CO VXIRWSIEDUGWPG-RZAWSJAESA-N 0.000 claims description 2
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 claims 53
- 150000002431 hydrogen Chemical group 0.000 claims 32
- 125000001183 hydrocarbyl group Chemical group 0.000 abstract 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 273
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 257
- 239000000243 solution Substances 0.000 description 202
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 185
- 235000019439 ethyl acetate Nutrition 0.000 description 128
- 239000000460 chlorine Substances 0.000 description 96
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 86
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 86
- 238000010898 silica gel chromatography Methods 0.000 description 83
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 78
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 75
- 239000012300 argon atmosphere Substances 0.000 description 69
- 239000012044 organic layer Substances 0.000 description 59
- 239000012267 brine Substances 0.000 description 57
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 57
- 239000006260 foam Substances 0.000 description 52
- 238000006243 chemical reaction Methods 0.000 description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 43
- 238000010533 azeotropic distillation Methods 0.000 description 43
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 43
- 239000007787 solid Substances 0.000 description 41
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 35
- 238000000746 purification Methods 0.000 description 33
- 239000008346 aqueous phase Substances 0.000 description 31
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
- 230000015572 biosynthetic process Effects 0.000 description 29
- 229950010765 pivalate Drugs 0.000 description 29
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 29
- 238000005481 NMR spectroscopy Methods 0.000 description 28
- 238000003786 synthesis reaction Methods 0.000 description 28
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 26
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 25
- 239000000010 aprotic solvent Substances 0.000 description 24
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 19
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 19
- 239000002253 acid Substances 0.000 description 18
- 239000000725 suspension Substances 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 17
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 229910052760 oxygen Inorganic materials 0.000 description 15
- 239000001301 oxygen Chemical group 0.000 description 15
- 229940002612 prodrug Drugs 0.000 description 15
- 239000000651 prodrug Substances 0.000 description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 14
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 14
- 239000010410 layer Substances 0.000 description 13
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 13
- 239000011734 sodium Substances 0.000 description 13
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 12
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 11
- LUQNIQXWMBORJA-UHFFFAOYSA-N 8H-phenanthro[9,10-d][1,3]dioxol-7-one Chemical compound O1COC2=C1C1=CC=CCC1=C1C(C=CC=C12)=O LUQNIQXWMBORJA-UHFFFAOYSA-N 0.000 description 10
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 239000008194 pharmaceutical composition Substances 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 9
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
- 239000012298 atmosphere Substances 0.000 description 8
- 239000003085 diluting agent Substances 0.000 description 8
- 239000003586 protic polar solvent Substances 0.000 description 8
- 125000003226 pyrazolyl group Chemical group 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 102100027824 3'(2'),5'-bisphosphate nucleotidase 1 Human genes 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 150000005840 aryl radicals Chemical class 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- 239000012535 impurity Substances 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 6
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Classifications
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- Otolaryngology (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201361786020P | 2013-03-14 | 2013-03-14 | |
| PCT/US2014/019126 WO2014158654A1 (en) | 2013-03-14 | 2014-02-27 | Ship1 modulators and methods related thereto |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2740779T3 true ES2740779T3 (es) | 2020-02-06 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES14710727T Active ES2740779T3 (es) | 2013-03-14 | 2014-02-27 | Moduladores de SHIP1 |
Country Status (14)
| Country | Link |
|---|---|
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| EP (1) | EP2970122B1 (enExample) |
| JP (1) | JP6407951B2 (enExample) |
| KR (3) | KR20220110337A (enExample) |
| CN (2) | CN108892637A (enExample) |
| AU (1) | AU2014242041B2 (enExample) |
| BR (1) | BR112015023009A2 (enExample) |
| CA (1) | CA2902768A1 (enExample) |
| ES (1) | ES2740779T3 (enExample) |
| IL (1) | IL240968A0 (enExample) |
| MX (1) | MX2015012111A (enExample) |
| RU (1) | RU2679805C2 (enExample) |
| WO (1) | WO2014158654A1 (enExample) |
| ZA (1) | ZA201506674B (enExample) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108752236A (zh) | 2013-01-09 | 2018-11-06 | 阿奎诺克斯药物(加拿大)公司 | Ship1调节剂和与其相关的方法 |
| ES2740779T3 (es) | 2013-03-14 | 2020-02-06 | Aquinox Pharmaceuticals Canada Inc | Moduladores de SHIP1 |
| EP2970100A1 (en) | 2013-03-14 | 2016-01-20 | Aquinox Pharmaceuticals (Canada) Inc. | Ship1 modulators and methods related thereto |
| WO2016210146A1 (en) | 2015-06-26 | 2016-12-29 | Aquinox Pharmaceuticals (Canada) Inc. | Crystalline solid forms of the acetate salt of (1s,3s,4r)-4-((3as,4r,5s,7as)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1h-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol |
| AU2017209430A1 (en) | 2016-01-20 | 2018-07-12 | Aquinox Pharmaceuticals (Canada) Inc. | Synthesis of a substituted indene derivative |
| WO2017149052A1 (en) * | 2016-03-02 | 2017-09-08 | Patheon Austria Gmbh Co. & Kg | Process and intermediates for the production of 17(20)-ene b-seco steroids |
| WO2018126040A1 (en) | 2016-12-28 | 2018-07-05 | Aquinox Pharmaceuticals (Canada) Inc. | Crystalline solid forms of (1s,3s,4r)-4-((3as,4r,5s,7as)-4- (aminomethyl)-7a-methyl-1-methyleneoctahydro-1h-inden-5-yl)-3- (hydroxymethyl)-4-methylcyclohexanol |
| IL277904B2 (en) * | 2018-04-06 | 2024-05-01 | Aquinox Pharmaceuticals Canada Inc | History of indan for use in the treatment of pain and inflammation |
| EP4292655A2 (en) | 2018-04-06 | 2023-12-20 | Taro Pharmaceuticals Inc. | Hexadecahydro-1h-cyclopenta[a]phenanthrene derivatives useful in treating pain and inflammation |
| CN112533905A (zh) * | 2018-04-06 | 2021-03-19 | 塔罗制药公司 | 可用于治疗疼痛和炎症的茚衍生物 |
| CN112940062B (zh) * | 2021-02-23 | 2022-09-06 | 浙江神洲药业有限公司 | 一种16-去氢黄体酮的制备方法 |
| CN117024374A (zh) * | 2023-08-08 | 2023-11-10 | 安庆百谊生物科技有限公司 | 一种3-甲基-1,2,4-噻二唑-5-碳酰肼或其盐的合成方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE1084718B (de) | 1958-07-08 | 1960-07-07 | Bayer Ag | Verfahren zur Herstellung von Secosteroiden |
| SE345995B (enExample) | 1969-01-31 | 1972-06-19 | Bristol Myers Co | |
| US3682983A (en) | 1969-11-12 | 1972-08-08 | Klaus Prezewowsky | Preparation of {66 {11 {11 -17 ethinyl steroids |
| US3869467A (en) | 1972-06-05 | 1975-03-04 | Hoffmann La Roche | 17-{62 -Hydroxy-17-{60 -methyl-5-{60 -androstano{9 3,2-c{9 or{8 2,3-d{9 isoxazoles |
| US3962275A (en) | 1972-06-05 | 1976-06-08 | Hoffmann-La Roche Inc. | 7-oxa steroids |
| JPH01290624A (ja) | 1988-05-16 | 1989-11-22 | Shiono Chem Kk | 5,6―セコ―ステロール誘導体血清脂質低下剤 |
| WO1993013124A1 (en) | 1991-12-20 | 1993-07-08 | Glaxo Inc. | Inhibitors of 5-alpha-testosterone reductase |
| JPH05221901A (ja) | 1992-02-17 | 1993-08-31 | Shiono Chem Kk | セコステロール誘導体 |
| JPH05221924A (ja) | 1992-02-17 | 1993-08-31 | Shiono Chem Kk | セコステロール化合物 |
| US5464866A (en) | 1992-08-17 | 1995-11-07 | Alcon Laboratories, Inc. | Substituted hydrindanes for the treatment of angiogenesis-dependent diseases |
| AP459A (en) | 1992-12-18 | 1996-02-14 | Glaxo Wellcome Inc | Substituted 6-azaandrostenones. |
| DK0707566T3 (da) | 1993-07-09 | 2000-09-04 | Theramex | Hidtil ukendte strukturelle analoger til vitamin D |
| US5541322A (en) | 1994-10-14 | 1996-07-30 | Glaxo Wellcome Inc. | Synthesis of 6-azaandrostenones |
| US6046185A (en) | 1996-07-11 | 2000-04-04 | Inflazyme Pharmaceuticals Ltd. | 6,7-oxygenated steroids and uses related thereto |
| WO2000063323A1 (en) | 1999-04-16 | 2000-10-26 | Nippon Mitsubishi Oil Corporation | Fluids for traction drive |
| BR0110419A (pt) | 2000-04-28 | 2004-02-25 | Inflazyme Pharm Ltd | Esteróides de 3-nitrogênio-6,7-dioxigênio e usos relacionados aos mesmos |
| AU2002257453B2 (en) | 2001-05-22 | 2008-04-10 | Inflazyme Pharmaceuticals Limited | Process for the production of 6, 7 - dihydroxy steroid compounds by allylic oxidation of steroid - 5 - ene compounds to steroid - 5 - ene - 7 - one compounds followed by hydroboration and oxidation and intermediates of this process |
| CA2463136A1 (en) | 2001-10-17 | 2003-04-24 | Raymond Andersen | Ship 1 modulators |
| JP4753581B2 (ja) | 2002-10-17 | 2011-08-24 | ザ・ユニバーシティ・オブ・ブリティッシュ・コロンビア | Ship1モデュレーター |
| DE602004031410D1 (de) | 2003-04-15 | 2011-03-31 | Aquinox Pharmaceuticals Inc | Inden derivate als pharmazeutika |
| US20110263539A1 (en) | 2006-06-21 | 2011-10-27 | The University Of British Columbia | Ship 1 modulator compounds |
| WO2008038965A1 (en) * | 2006-09-26 | 2008-04-03 | Kyungpook National University Industry-Academic Cooperation Foundation | 7alpha-aminosteroid derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and composition for anticancer or antibiotics containing the same as an active ingredient |
| CA2781661A1 (en) | 2009-12-04 | 2011-06-09 | Aquinox Pharmaceuticals Inc. | Ship1 modulators and methods related thereto |
| US9000050B2 (en) | 2010-08-20 | 2015-04-07 | The University Of British Columbia | SHIP1 modulators and related methods |
| JP2013545809A (ja) * | 2010-12-13 | 2013-12-26 | ラトガース ユニバーシティ | 骨格筋および皮膚の成長、修復、および維持を促進するようにブラシノステロイドを産生および使用する方法 |
| EP2970100A1 (en) | 2013-03-14 | 2016-01-20 | Aquinox Pharmaceuticals (Canada) Inc. | Ship1 modulators and methods related thereto |
| ES2740779T3 (es) | 2013-03-14 | 2020-02-06 | Aquinox Pharmaceuticals Canada Inc | Moduladores de SHIP1 |
| WO2016210146A1 (en) | 2015-06-26 | 2016-12-29 | Aquinox Pharmaceuticals (Canada) Inc. | Crystalline solid forms of the acetate salt of (1s,3s,4r)-4-((3as,4r,5s,7as)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1h-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol |
| AU2017209430A1 (en) | 2016-01-20 | 2018-07-12 | Aquinox Pharmaceuticals (Canada) Inc. | Synthesis of a substituted indene derivative |
| WO2018058144A1 (en) | 2016-09-26 | 2018-03-29 | Aquinox Pharmaceuticals (Canada) Inc. | Ship1 activator for treating prostatis |
-
2014
- 2014-02-27 ES ES14710727T patent/ES2740779T3/es active Active
- 2014-02-27 RU RU2015143676A patent/RU2679805C2/ru active
- 2014-02-27 CN CN201810634778.6A patent/CN108892637A/zh active Pending
- 2014-02-27 MX MX2015012111A patent/MX2015012111A/es unknown
- 2014-02-27 EP EP14710727.0A patent/EP2970122B1/en active Active
- 2014-02-27 US US14/772,731 patent/US9765085B2/en not_active Expired - Fee Related
- 2014-02-27 AU AU2014242041A patent/AU2014242041B2/en not_active Ceased
- 2014-02-27 KR KR1020227025934A patent/KR20220110337A/ko not_active Abandoned
- 2014-02-27 WO PCT/US2014/019126 patent/WO2014158654A1/en not_active Ceased
- 2014-02-27 KR KR1020157028154A patent/KR102308319B1/ko not_active Expired - Fee Related
- 2014-02-27 BR BR112015023009A patent/BR112015023009A2/pt not_active Application Discontinuation
- 2014-02-27 CN CN201480024563.2A patent/CN105164108B/zh not_active Expired - Fee Related
- 2014-02-27 JP JP2016500472A patent/JP6407951B2/ja not_active Expired - Fee Related
- 2014-02-27 KR KR1020217030879A patent/KR102427491B1/ko active Active
- 2014-02-27 CA CA2902768A patent/CA2902768A1/en not_active Abandoned
-
2015
- 2015-08-31 IL IL240968A patent/IL240968A0/en unknown
- 2015-09-09 ZA ZA2015/06674A patent/ZA201506674B/en unknown
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2017
- 2017-08-14 US US15/676,726 patent/US10174046B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN105164108A (zh) | 2015-12-16 |
| US10174046B2 (en) | 2019-01-08 |
| WO2014158654A1 (en) | 2014-10-02 |
| US20180155359A9 (en) | 2018-06-07 |
| US20160031899A1 (en) | 2016-02-04 |
| US20170247389A2 (en) | 2017-08-31 |
| EP2970122A1 (en) | 2016-01-20 |
| KR20220110337A (ko) | 2022-08-05 |
| KR20150127205A (ko) | 2015-11-16 |
| HK1220180A1 (en) | 2017-04-28 |
| IL240968A0 (en) | 2015-11-30 |
| AU2014242041B2 (en) | 2018-07-26 |
| RU2015143676A (ru) | 2017-04-27 |
| BR112015023009A2 (pt) | 2017-08-22 |
| EP2970122B1 (en) | 2019-05-08 |
| KR102308319B1 (ko) | 2021-10-06 |
| US9765085B2 (en) | 2017-09-19 |
| AU2014242041A1 (en) | 2015-09-24 |
| JP6407951B2 (ja) | 2018-10-17 |
| CN108892637A (zh) | 2018-11-27 |
| CA2902768A1 (en) | 2014-10-02 |
| RU2679805C2 (ru) | 2019-02-13 |
| US20170362250A1 (en) | 2017-12-21 |
| HK1217704A1 (zh) | 2017-01-20 |
| ZA201506674B (en) | 2016-11-30 |
| JP2016517409A (ja) | 2016-06-16 |
| CN105164108B (zh) | 2018-07-17 |
| KR20210120137A (ko) | 2021-10-06 |
| KR102427491B1 (ko) | 2022-08-01 |
| MX2015012111A (es) | 2016-05-05 |
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