ES2772689T3 - Derivado de oxa espiro, método de preparación del mismo y aplicaciones del mismo en medicamentos - Google Patents
Derivado de oxa espiro, método de preparación del mismo y aplicaciones del mismo en medicamentos Download PDFInfo
- Publication number
- ES2772689T3 ES2772689T3 ES16854888T ES16854888T ES2772689T3 ES 2772689 T3 ES2772689 T3 ES 2772689T3 ES 16854888 T ES16854888 T ES 16854888T ES 16854888 T ES16854888 T ES 16854888T ES 2772689 T3 ES2772689 T3 ES 2772689T3
- Authority
- ES
- Spain
- Prior art keywords
- cycloalkyl
- heterocyclyl
- alkyl
- group
- heteroaryl
- 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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Links
- 238000002360 preparation method Methods 0.000 title claims description 9
- 239000003814 drug Substances 0.000 title description 16
- 229940079593 drug Drugs 0.000 title description 11
- 125000003003 spiro group Chemical group 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 145
- -1 nitro, hydroxy Chemical group 0.000 claims abstract description 117
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 113
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 108
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 93
- 239000000203 mixture Substances 0.000 claims abstract description 92
- 125000003118 aryl group Chemical group 0.000 claims abstract description 75
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 73
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 55
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 46
- 150000002367 halogens Chemical group 0.000 claims abstract description 46
- 150000003839 salts Chemical class 0.000 claims abstract description 38
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 34
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 32
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 31
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 29
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 28
- 239000001257 hydrogen Substances 0.000 claims abstract description 28
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 20
- 125000004438 haloalkoxy group Chemical group 0.000 claims abstract description 16
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 15
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 15
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 8
- 229910052805 deuterium Inorganic materials 0.000 claims abstract description 6
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 208000002193 Pain Diseases 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 238000006268 reductive amination reaction Methods 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 3
- 208000012902 Nervous system disease Diseases 0.000 claims description 3
- 208000025966 Neurological disease Diseases 0.000 claims description 3
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 208000026278 immune system disease Diseases 0.000 claims description 3
- 230000004054 inflammatory process Effects 0.000 claims description 3
- 230000000926 neurological effect Effects 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 208000020016 psychiatric disease Diseases 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 208000023504 respiratory system disease Diseases 0.000 claims description 3
- 230000002485 urinary effect Effects 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 206010014733 Endometrial cancer Diseases 0.000 claims description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 2
- 208000013452 Fallopian tube neoplasm Diseases 0.000 claims description 2
- 208000031220 Hemophilia Diseases 0.000 claims description 2
- 208000009292 Hemophilia A Diseases 0.000 claims description 2
- 206010065390 Inflammatory pain Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 208000004550 Postoperative Pain Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- 208000004296 neuralgia Diseases 0.000 claims description 2
- 208000021722 neuropathic pain Diseases 0.000 claims description 2
- 208000017443 reproductive system disease Diseases 0.000 claims description 2
- 201000000849 skin cancer Diseases 0.000 claims description 2
- 230000000472 traumatic effect Effects 0.000 claims description 2
- 208000014001 urinary system disease Diseases 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 135
- 238000006243 chemical reaction Methods 0.000 description 103
- 239000000243 solution Substances 0.000 description 96
- 230000002829 reductive effect Effects 0.000 description 67
- 238000004949 mass spectrometry Methods 0.000 description 61
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 48
- 238000010828 elution Methods 0.000 description 43
- 238000004809 thin layer chromatography Methods 0.000 description 42
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 40
- 238000005160 1H NMR spectroscopy Methods 0.000 description 34
- 239000007787 solid Substances 0.000 description 34
- 230000000694 effects Effects 0.000 description 27
- 238000003756 stirring Methods 0.000 description 26
- 108020001612 μ-opioid receptors Proteins 0.000 description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 21
- 239000003921 oil Substances 0.000 description 21
- 235000019198 oils Nutrition 0.000 description 21
- 239000000706 filtrate Substances 0.000 description 19
- 125000004432 carbon atom Chemical group C* 0.000 description 16
- 238000000746 purification Methods 0.000 description 16
- 125000001424 substituent group Chemical group 0.000 description 16
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 15
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000002474 experimental method Methods 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- NVGSPCSQFOQQPW-OAHLLOKOSA-N 2-[(9r)-9-pyridin-2-yl-6-oxaspiro[4.5]decan-9-yl]acetaldehyde Chemical compound C([C@@](C1)(CC=O)C=2N=CC=CC=2)COC21CCCC2 NVGSPCSQFOQQPW-OAHLLOKOSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 125000002619 bicyclic group Chemical group 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- 125000003367 polycyclic group Chemical group 0.000 description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
- 108091006027 G proteins Proteins 0.000 description 10
- 102000030782 GTP binding Human genes 0.000 description 10
- 108091000058 GTP-Binding Proteins 0.000 description 10
- 102100031819 Kappa-type opioid receptor Human genes 0.000 description 10
- 125000005842 heteroatom Chemical group 0.000 description 10
- 102000005962 receptors Human genes 0.000 description 10
- 108020003175 receptors Proteins 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000000556 agonist Substances 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- 229960005181 morphine Drugs 0.000 description 9
- 125000006413 ring segment Chemical group 0.000 description 9
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 8
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 8
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 0 B[C@](*)(CC[C@]1*(CC*2CC3(CCCC3)OCC2)=C)CCc2c1cc*(*)c2 Chemical compound B[C@](*)(CC[C@]1*(CC*2CC3(CCCC3)OCC2)=C)CCc2c1cc*(*)c2 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 125000003282 alkyl amino group Chemical group 0.000 description 7
- 125000004414 alkyl thio group Chemical group 0.000 description 7
- 125000000304 alkynyl group Chemical group 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 125000000000 cycloalkoxy group Chemical group 0.000 description 7
- 125000005366 cycloalkylthio group Chemical group 0.000 description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- 230000037361 pathway Effects 0.000 description 7
- 230000019491 signal transduction Effects 0.000 description 7
- 230000011664 signaling Effects 0.000 description 7
- 150000003573 thiols Chemical group 0.000 description 7
- 239000011345 viscous material Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 102000003840 Opioid Receptors Human genes 0.000 description 6
- 108090000137 Opioid Receptors Proteins 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 229940124636 opioid drug Drugs 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 229940044601 receptor agonist Drugs 0.000 description 6
- 239000000018 receptor agonist Substances 0.000 description 6
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
- 108010093625 Opioid Peptides Proteins 0.000 description 5
- 102000001490 Opioid Peptides Human genes 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 230000000202 analgesic effect Effects 0.000 description 5
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- 238000004113 cell culture Methods 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
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- 238000010898 silica gel chromatography Methods 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- VMKAFJQFKBASMU-QGZVFWFLSA-N (r)-2-methyl-cbs-oxazaborolidine Chemical compound C([C@@H]12)CCN1B(C)OC2(C=1C=CC=CC=1)C1=CC=CC=C1 VMKAFJQFKBASMU-QGZVFWFLSA-N 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 4
- PCBZRNYXXCIELG-WYFCWLEVSA-N COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 Chemical compound COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 PCBZRNYXXCIELG-WYFCWLEVSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
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- OBMZMSLWNNWEJA-XNCRXQDQSA-N C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 Chemical compound C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 OBMZMSLWNNWEJA-XNCRXQDQSA-N 0.000 description 3
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
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- 239000011591 potassium Substances 0.000 description 3
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- 125000003226 pyrazolyl group Chemical group 0.000 description 3
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- HPESSUIKVPPELT-QLBJFCOMSA-N (1R,2R)-2-methoxy-N-[2-[(9R)-9-pyridin-2-yl-6-oxaspiro[4.5]decan-9-yl]ethyl]-2,3-dihydro-1H-inden-1-amine Chemical compound CO[C@H]1[C@@H](C2=CC=CC=C2C1)NCC[C@]1(CCOC2(CCCC2)C1)C1=NC=CC=C1 HPESSUIKVPPELT-QLBJFCOMSA-N 0.000 description 2
- COOZSDXMEGONAJ-AHKZPQOWSA-N (1S)-4-ethyl-N-[2-[(9R)-9-pyridin-2-yl-6-oxaspiro[4.5]decan-9-yl]ethyl]-1,2-dihydronaphthalen-1-amine Chemical compound C(C)C1=CC[C@@H](C2=CC=CC=C12)NCC[C@]1(CCOC2(CCCC2)C1)C1=NC=CC=C1 COOZSDXMEGONAJ-AHKZPQOWSA-N 0.000 description 2
- PGNURDTWXSVADN-BFLUCZKCSA-N (1S,4R)-4-methoxy-N-[2-[(9R)-9-pyridin-2-yl-6-oxaspiro[4.5]decan-9-yl]ethyl]-1,2,3,4-tetrahydronaphthalen-1-amine Chemical compound CO[C@@H]1CC[C@@H](C2=CC=CC=C12)NCC[C@]1(CCOC2(CCCC2)C1)C1=NC=CC=C1 PGNURDTWXSVADN-BFLUCZKCSA-N 0.000 description 2
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- JRZGPXSSNPTNMA-JTQLQIEISA-N (1s)-1,2,3,4-tetrahydronaphthalen-1-amine Chemical compound C1=CC=C2[C@@H](N)CCCC2=C1 JRZGPXSSNPTNMA-JTQLQIEISA-N 0.000 description 2
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- 208000011117 substance-related disease Diseases 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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
-
- 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
- C07D405/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D405/14—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 three or more hetero rings
-
- 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
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510665328 | 2015-10-15 | ||
| CN201511032876 | 2015-12-31 | ||
| PCT/CN2016/101064 WO2017063509A1 (zh) | 2015-10-15 | 2016-09-30 | 氧杂螺环类衍生物、其制备方法及其在医药上的应用 |
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| ES2772689T3 true ES2772689T3 (es) | 2020-07-08 |
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| WO (1) | WO2017063509A1 (enExample) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| MX388643B (es) * | 2017-04-14 | 2025-03-20 | Jiangsu Hengrui Medicine Co | Composicion farmaceutica que contiene agonista de mor y agonista de kor, y sus usos |
| EP3610875B1 (en) * | 2017-04-14 | 2020-10-07 | Jiangsu Hengrui Medicine Co., Ltd. | Opioid receptor (mor) agonist salt, fumarate salt i crystal form thereof and preparation method thereof |
| CN108727347B (zh) * | 2017-04-14 | 2020-06-16 | 江苏恒瑞医药股份有限公司 | 一种阿片样物质受体(mor)激动剂的晶型及其制备方法 |
| CN109206417B (zh) * | 2017-07-04 | 2023-01-03 | 四川海思科制药有限公司 | 阿片受体激动剂及其应用 |
| US11072601B2 (en) | 2017-09-18 | 2021-07-27 | Shanghai Synergy Pharmaceutical Sciences Co., Ltd. | μ-opioid receptor agonist and preparation method therefor and use thereof in field of medicine |
| WO2019062804A1 (zh) | 2017-09-28 | 2019-04-04 | 江苏恒瑞医药股份有限公司 | 一种氧杂螺环类衍生物的制备方法及其中间体 |
| AU2018349930A1 (en) * | 2017-10-13 | 2020-04-16 | Shandong Luye Pharmaceutical Co., Ltd. | 2,6-dioxaspiro (4,5) decane derivatives and preparation method therefor and pharmaceutical applications thereof |
| JP2021505547A (ja) * | 2017-12-06 | 2021-02-18 | 江蘇恒瑞医薬股▲ふん▼有限公司 | 疼痛を治療するための薬物の製造におけるｍｏｒアゴニストと組み合わせたｋｏｒアゴニストの使用 |
| CN111836807A (zh) * | 2018-04-28 | 2020-10-27 | 四川科伦博泰生物医药股份有限公司 | 氧杂螺环类化合物及其制备方法和用途 |
| CN108424372B (zh) * | 2018-05-11 | 2021-08-10 | 浙江华贝药业有限责任公司 | 2，2，2-三氟-n-[(s)-4-羰基四氢萘-1-基]-乙酰胺的纯化工艺 |
| CN111163778B (zh) * | 2018-05-14 | 2023-01-24 | 江苏恒瑞医药股份有限公司 | 一种mor受体激动剂药物组合物 |
| CN108707086B (zh) * | 2018-05-15 | 2021-08-10 | 浙江华贝药业有限责任公司 | 一种(1s，4s)-n-（4-羟基四氢萘-1-基）叔丁氧基碳酰胺的纯化工艺 |
| WO2020073985A1 (zh) * | 2018-10-12 | 2020-04-16 | 江苏恒瑞医药股份有限公司 | 一种阿片样物质受体(mor)激动剂的结晶形式及制备方法 |
| WO2020073984A1 (zh) * | 2018-10-12 | 2020-04-16 | 江苏恒瑞医药股份有限公司 | 一种阿片样物质受体(mor)激动剂的结晶形式及制备方法 |
| CN112334465B (zh) * | 2019-01-17 | 2024-06-11 | 上海海雁医药科技有限公司 | 三环取代的氧杂螺环衍生物、其制法与医药上的用途 |
| CN111662284B (zh) * | 2019-03-06 | 2021-08-10 | 上海海雁医药科技有限公司 | 双杂环取代的氧杂螺环衍生物、其制法与医药上的用途 |
| WO2021027304A1 (zh) * | 2019-08-14 | 2021-02-18 | 上海海雁医药科技有限公司 | 镇痛化合物、其制法与医药上的用途 |
| EP4092031A4 (en) * | 2020-01-17 | 2024-02-21 | Shanghai Haiyan Pharmaceutical Technology Co., Ltd. | AZABICYCLIC SUBSTITUTED OXASPIRO DERIVATIVE, METHOD FOR THE PRODUCTION THEREOF AND ITS MEDICAL USE |
| CN118221680A (zh) | 2020-01-17 | 2024-06-21 | 上海海雁医药科技有限公司 | 光学纯的氧杂螺环取代的吡咯并吡唑衍生物、其制法与医药上的用途 |
| CN113214264B (zh) * | 2020-01-21 | 2022-08-09 | 上海海雁医药科技有限公司 | 二氢吡咯并五元杂芳基取代的氧杂螺环衍生物、其制法与医药上的用途 |
| JP7781064B2 (ja) | 2020-01-22 | 2025-12-05 | 江蘇恒瑞医薬股▲ふん▼有限公司 | 抗ｔｒｏｐ－２抗体－エキサテカン類似体複合体及びその医薬用途 |
| CN114075141B (zh) * | 2020-08-20 | 2025-02-25 | 上海致根医药科技有限公司 | 阿片受体“偏向性”配体、其制备方法及其在医药上的应用 |
| CN114539257B (zh) * | 2020-11-24 | 2023-08-11 | 江苏恒瑞医药股份有限公司 | 嘧啶二酮类螺环衍生物、其制备方法及其在医药上的应用 |
| JP7751645B2 (ja) | 2020-12-29 | 2025-10-08 | 上海海雁医薬科技有限公司 | オキシスピロ環置換ピロロピラゾール誘導体及びその中間体並びにその調製方法 |
| WO2023284788A1 (zh) | 2021-07-13 | 2023-01-19 | 上海海雁医药科技有限公司 | Mor受体激动剂的药学上可接受的盐、其多晶型物及其用途 |
| WO2023011422A1 (zh) * | 2021-08-02 | 2023-02-09 | 上海枢境生物科技有限公司 | 氧杂螺环类衍生物、制备方法及其用途 |
| CN117263956A (zh) * | 2022-01-19 | 2023-12-22 | 天地恒一制药股份有限公司 | 阿片受体激动剂及其制备方法和用途 |
| CN116589451B (zh) * | 2022-02-11 | 2024-07-09 | 成都硕德药业有限公司 | 一种6-氧杂螺[4,5]癸烷类化合物的新晶型、用途及其制备方法 |
| CN117624138A (zh) * | 2022-08-29 | 2024-03-01 | 江苏恒瑞医药股份有限公司 | 一种氧杂螺环类衍生物的可药用盐、晶型及制备方法 |
| CN119894904B (zh) * | 2022-09-27 | 2025-12-30 | 上海枢境生物科技有限公司 | 一种含螺环类衍生物的盐、晶型及其制备方法和应用 |
| KR20250137614A (ko) | 2023-01-18 | 2025-09-18 | 상하이 센후이 메디슨 컴퍼니 리미티드 | 테트라히드로-1-나프틸아민 및 이의 유도체의 제조 방법 |
| WO2026026772A1 (zh) * | 2024-07-30 | 2026-02-05 | 上海枢境生物科技有限公司 | 氧杂螺环类衍生物的富马酸盐晶型及其制备方法和应用 |
Family Cites Families (11)
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| ES2160534B1 (es) | 1999-12-30 | 2002-04-16 | Vita Invest Sa | Nuevos esteres derivados de (rr,ss)-2-hidroxibenzoato de 3-(2-dimetilaminometil-1-hidroxiciclohexil) fenilo. |
| DE10044649A1 (de) | 2000-09-08 | 2002-07-04 | Gruenenthal Gmbh | Substituierte 4-Phenyl-1-(1-phenyl-cyclohexyl)-1,2,3,6-tetrahydropyridine |
| DE102006033109A1 (de) * | 2006-07-18 | 2008-01-31 | Grünenthal GmbH | Substituierte Heteroaryl-Derivate |
| US7999107B2 (en) * | 2007-01-31 | 2011-08-16 | Merck Sharp & Dohme Corp. | Substituted pyrano[2,3-B]pyridine derivatives as cannabinoid-1 receptor modulators |
| US20090028873A1 (en) | 2007-07-27 | 2009-01-29 | Auspex Pharmaceuticals, Inc. | Substituted cyclohexanols |
| AU2009308769B2 (en) | 2008-10-31 | 2015-03-12 | Pain Therapeutics, Inc. | Filamin A-binding anti-inflammatory analgesic |
| CN102741258B (zh) | 2009-06-17 | 2015-09-30 | 德州大学体系董事会 | 作为分离剂的环果聚糖的组成物及方法 |
| SI2688403T1 (sl) * | 2011-03-23 | 2017-08-31 | Trevena, Inc. | Ligandi opioidnih receptorjev in metode uporabe in izdelave istega |
| CN104159902B (zh) | 2011-12-12 | 2016-05-04 | 格吕伦塔尔有限公司 | 制备(1r,4r)-6’-氟-(N,N-二甲基-和N-甲基)-4-苯基-4’,9’-二氢-3’H-螺[环己烷-1,1’-吡喃并[3,4,b]吲哚]-4-胺的方法 |
| PL2880037T3 (pl) | 2012-08-03 | 2019-07-31 | Johnson Matthey Public Limited Company | Sposób wytwarzania oksykodonu |
| RS55593B1 (sr) | 2012-11-13 | 2017-06-30 | Array Biopharma Inc | Jedinjenja biciklične uree, tiouree, guanidina i cijanoguanidina korisna za lečenje bola |
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Also Published As
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|---|---|
| TWI727981B (zh) | 2021-05-21 |
| CN107001347B (zh) | 2019-09-24 |
| RU2018115569A (ru) | 2019-11-18 |
| HUE048032T2 (hu) | 2020-05-28 |
| AU2016339404A1 (en) | 2018-05-24 |
| US10442793B2 (en) | 2019-10-15 |
| TW201718558A (zh) | 2017-06-01 |
| CA3000761C (en) | 2024-02-13 |
| JP6824502B2 (ja) | 2021-02-03 |
| AU2016339404B2 (en) | 2020-08-27 |
| DK3354649T3 (da) | 2020-02-24 |
| US20180297988A1 (en) | 2018-10-18 |
| RU2018115569A3 (enExample) | 2020-01-20 |
| WO2017063509A1 (zh) | 2017-04-20 |
| KR102703513B1 (ko) | 2024-09-06 |
| CA3000761A1 (en) | 2017-04-20 |
| MX382815B (es) | 2025-03-12 |
| EP3354649B1 (en) | 2019-12-04 |
| RU2733373C2 (ru) | 2020-10-01 |
| EP3354649A1 (en) | 2018-08-01 |
| BR112018006448A2 (pt) | 2018-10-16 |
| JP2018534257A (ja) | 2018-11-22 |
| PT3354649T (pt) | 2020-02-03 |
| EP3354649A4 (en) | 2018-08-08 |
| PL3354649T3 (pl) | 2020-07-27 |
| CN107001347A (zh) | 2017-08-01 |
| MX2018004175A (es) | 2018-06-06 |
| KR20180063251A (ko) | 2018-06-11 |
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