CN113015736B - 用于诱导软骨发生以治疗关节损害的6-羟基-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺衍生物 - Google Patents
用于诱导软骨发生以治疗关节损害的6-羟基-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺衍生物 Download PDFInfo
- Publication number
- CN113015736B CN113015736B CN201980074389.5A CN201980074389A CN113015736B CN 113015736 B CN113015736 B CN 113015736B CN 201980074389 A CN201980074389 A CN 201980074389A CN 113015736 B CN113015736 B CN 113015736B
- Authority
- CN
- China
- Prior art keywords
- compound
- pharmaceutically acceptable
- enantiomer
- acceptable salt
- trifluoromethyl
- 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
- 230000001939 inductive effect Effects 0.000 title claims abstract description 15
- 230000006378 damage Effects 0.000 title abstract description 31
- 210000001503 joint Anatomy 0.000 title abstract description 26
- 230000022159 cartilage development Effects 0.000 title abstract description 4
- UBEFCVDZBYKCJC-UHFFFAOYSA-N 6-hydroxy-8-oxatricyclo[3.2.1.02,4]octane-2-carboxamide Chemical class OC1C2C3CC3(C(C1)O2)C(=O)N UBEFCVDZBYKCJC-UHFFFAOYSA-N 0.000 title abstract description 3
- 238000011282 treatment Methods 0.000 title description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 168
- 238000000034 method Methods 0.000 claims abstract description 122
- 206010003246 arthritis Diseases 0.000 claims abstract description 30
- 206010060820 Joint injury Diseases 0.000 claims abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 19
- 238000004519 manufacturing process Methods 0.000 claims abstract description 15
- 210000003035 hyaline cartilage Anatomy 0.000 claims abstract description 13
- 239000000203 mixture Substances 0.000 claims description 83
- 150000003839 salts Chemical class 0.000 claims description 61
- 210000001612 chondrocyte Anatomy 0.000 claims description 38
- 239000003814 drug Substances 0.000 claims description 28
- -1 chloro, methyl Chemical group 0.000 claims description 27
- 229940124597 therapeutic agent Drugs 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 210000000845 cartilage Anatomy 0.000 claims description 18
- 230000004069 differentiation Effects 0.000 claims description 18
- 210000000130 stem cell Anatomy 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 230000002648 chondrogenic effect Effects 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 14
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 230000008439 repair process Effects 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 238000000338 in vitro Methods 0.000 claims description 8
- 238000001727 in vivo Methods 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 claims description 6
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 210000002744 extracellular matrix Anatomy 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 239000013543 active substance Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 89
- 238000005481 NMR spectroscopy Methods 0.000 description 84
- WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 35
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 31
- 239000000543 intermediate Substances 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 18
- 229910052805 deuterium Inorganic materials 0.000 description 18
- 201000010099 disease Diseases 0.000 description 17
- 201000008482 osteoarthritis Diseases 0.000 description 17
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 208000035475 disorder Diseases 0.000 description 14
- 239000003795 chemical substances by application Substances 0.000 description 12
- 238000010348 incorporation Methods 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 102000008186 Collagen Human genes 0.000 description 8
- 108010035532 Collagen Proteins 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
- 229920001436 collagen Polymers 0.000 description 8
- 239000012847 fine chemical Substances 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 238000001356 surgical procedure Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 210000001188 articular cartilage Anatomy 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 239000003643 water by type Substances 0.000 description 6
- 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 description 5
- 206010007710 Cartilage injury Diseases 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 239000004698 Polyethylene Substances 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 239000006184 cosolvent Substances 0.000 description 5
- 239000011159 matrix material Substances 0.000 description 5
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 238000004808 supercritical fluid chromatography Methods 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 4
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 206010048873 Traumatic arthritis Diseases 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 210000002950 fibroblast Anatomy 0.000 description 4
- 239000003102 growth factor Substances 0.000 description 4
- 208000006454 hepatitis Diseases 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 230000000670 limiting effect Effects 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- FIYSWKITUMBNQB-UHFFFAOYSA-N methyl 3-bromo-7-oxabicyclo[2.2.1]hepta-2,5-diene-2-carboxylate Chemical compound BrC1=C(C2C=CC1O2)C(=O)OC FIYSWKITUMBNQB-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 210000000988 bone and bone Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000000105 evaporative light scattering detection Methods 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 230000002068 genetic effect Effects 0.000 description 3
- 231100000283 hepatitis Toxicity 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 229920002674 hyaluronan Polymers 0.000 description 3
- 229960003160 hyaluronic acid Drugs 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- IMAKHNTVDGLIRY-UHFFFAOYSA-N methyl prop-2-ynoate Chemical compound COC(=O)C#C IMAKHNTVDGLIRY-UHFFFAOYSA-N 0.000 description 3
- 239000001301 oxygen Chemical group 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 210000005065 subchondral bone plate Anatomy 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- SLUINPGXGFUMLL-UHFFFAOYSA-N 2-[(4-phenylphenyl)carbamoyl]benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)NC1=CC=C(C=2C=CC=CC=2)C=C1 SLUINPGXGFUMLL-UHFFFAOYSA-N 0.000 description 2
- FYZUENZXIZCLAZ-UHFFFAOYSA-N 2-methylhept-2-enoic acid Chemical compound CCCCC=C(C)C(O)=O FYZUENZXIZCLAZ-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 101710134784 Agnoprotein Proteins 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 102100025668 Angiopoietin-related protein 3 Human genes 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 206010071155 Autoimmune arthritis Diseases 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 102000010907 Cyclooxygenase 2 Human genes 0.000 description 2
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 244000068988 Glycine max Species 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000693085 Homo sapiens Angiopoietin-related protein 3 Proteins 0.000 description 2
- 101150088952 IGF1 gene Proteins 0.000 description 2
- 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 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 206010061246 Intervertebral disc degeneration Diseases 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 229940122245 Janus kinase inhibitor Drugs 0.000 description 2
- 206010065433 Ligament rupture Diseases 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 101100165560 Mus musculus Bmp7 gene Proteins 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 244000025272 Persea americana Species 0.000 description 2
- 235000008673 Persea americana Nutrition 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- 108010009736 Protein Hydrolysates Proteins 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 description 2
- 239000004012 Tofacitinib Substances 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 239000003463 adsorbent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000005441 aurora Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 2
- 229960003773 calcitonin (salmon synthetic) Drugs 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 208000015100 cartilage disease Diseases 0.000 description 2
- 230000003848 cartilage regeneration Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 230000011227 chondrocyte hypertrophy Effects 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 208000018180 degenerative disc disease Diseases 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 150000001975 deuterium Chemical group 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 150000002081 enamines Chemical class 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 150000002431 hydrogen Chemical group 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 208000021600 intervertebral disc degenerative disease Diseases 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 230000000155 isotopic effect Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 210000002901 mesenchymal stem cell Anatomy 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- KQEVIFKPZOGBMZ-UHFFFAOYSA-N methyl 3-bromopropanoate Chemical compound COC(=O)CCBr KQEVIFKPZOGBMZ-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000000921 morphogenic effect Effects 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 238000002600 positron emission tomography Methods 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000001172 regenerating effect Effects 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 108010068072 salmon calcitonin Proteins 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 238000002603 single-photon emission computed tomography Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 239000011593 sulfur Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 229960001350 tofacitinib Drugs 0.000 description 2
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 230000000472 traumatic effect Effects 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 2
- JBBWIOOUTUWSMJ-FSDCSDTHSA-N (1R,2R,3S,4S)-3-(2-aminopyridin-4-yl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide Chemical compound NC1=NC=CC(=C1)[C@@H]1[C@H]([C@H]2CC[C@@H]1O2)C(=O)NC2=CC(=C(C=C2)Cl)Cl JBBWIOOUTUWSMJ-FSDCSDTHSA-N 0.000 description 1
- HNLJEOAFXYIQQM-YVSFHVDLSA-N (1R,2R,3S,4S)-N-(3,4-dichlorophenyl)-3-pyridin-4-yl-7-oxabicyclo[2.2.1]heptane-2-carboxamide Chemical compound ClC=1C=C(C=CC1Cl)NC(=O)[C@H]1[C@H]2CC[C@@H]([C@@H]1C1=CC=NC=C1)O2 HNLJEOAFXYIQQM-YVSFHVDLSA-N 0.000 description 1
- ATFFWCIMTHMCPI-QFHJOOASSA-N (1R,2R,4S,5S)-N-(3,4-dichlorophenyl)-4-pyridin-4-yl-8-oxatricyclo[3.2.1.02,4]octane-2-carboxamide Chemical compound ClC=1C=C(C=CC1Cl)NC(=O)[C@]12[C@H]3CC[C@@H]([C@@]2(C1)C1=CC=NC=C1)O3 ATFFWCIMTHMCPI-QFHJOOASSA-N 0.000 description 1
- PAIQAKBTYYBSKX-SJXGUFTOSA-N (1R,2S,3R,4S)-N-(3,4-dichlorophenyl)-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]-7-oxabicyclo[2.2.1]heptane-2-carboxamide Chemical compound ClC=1C=C(C=CC1Cl)NC(=O)[C@@H]1[C@H]2CC[C@@H]([C@H]1C1=CC(=NN1C)C(F)(F)F)O2 PAIQAKBTYYBSKX-SJXGUFTOSA-N 0.000 description 1
- HNLJEOAFXYIQQM-VVLHAWIVSA-N (1R,2S,3S,4S)-N-(3,4-dichlorophenyl)-3-pyridin-4-yl-7-oxabicyclo[2.2.1]heptane-2-carboxamide Chemical compound ClC=1C=C(C=CC1Cl)NC(=O)[C@@H]1[C@H]2CC[C@@H]([C@@H]1C1=CC=NC=C1)O2 HNLJEOAFXYIQQM-VVLHAWIVSA-N 0.000 description 1
- JBBWIOOUTUWSMJ-YALNPMBYSA-N (1S,2S,3R,4R)-3-(2-aminopyridin-4-yl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide Chemical compound NC1=NC=CC(=C1)[C@H]1[C@@H]([C@@H]2CC[C@H]1O2)C(=O)NC2=CC(=C(C=C2)Cl)Cl JBBWIOOUTUWSMJ-YALNPMBYSA-N 0.000 description 1
- HNLJEOAFXYIQQM-YYIAUSFCSA-N (1S,2S,3R,4R)-N-(3,4-dichlorophenyl)-3-pyridin-4-yl-7-oxabicyclo[2.2.1]heptane-2-carboxamide Chemical compound ClC=1C=C(C=CC1Cl)NC(=O)[C@@H]1[C@@H]2CC[C@H]([C@H]1C1=CC=NC=C1)O2 HNLJEOAFXYIQQM-YYIAUSFCSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- KJTLQQUUPVSXIM-ZCFIWIBFSA-M (R)-mevalonate Chemical compound OCC[C@](O)(C)CC([O-])=O KJTLQQUUPVSXIM-ZCFIWIBFSA-M 0.000 description 1
- MICMHFIQSAMEJG-UHFFFAOYSA-N 1-bromopyrrolidine-2,5-dione Chemical compound BrN1C(=O)CCC1=O.BrN1C(=O)CCC1=O MICMHFIQSAMEJG-UHFFFAOYSA-N 0.000 description 1
- GPAAEZIXSQCCES-UHFFFAOYSA-N 1-methoxy-2-(2-methoxyethoxymethoxymethoxy)ethane Chemical compound COCCOCOCOCCOC GPAAEZIXSQCCES-UHFFFAOYSA-N 0.000 description 1
- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 description 1
- PRDFBSVERLRRMY-UHFFFAOYSA-N 2'-(4-ethoxyphenyl)-5-(4-methylpiperazin-1-yl)-2,5'-bibenzimidazole Chemical compound C1=CC(OCC)=CC=C1C1=NC2=CC=C(C=3NC4=CC(=CC=C4N=3)N3CCN(C)CC3)C=C2N1 PRDFBSVERLRRMY-UHFFFAOYSA-N 0.000 description 1
- DCYGAPKNVCQNOE-UHFFFAOYSA-N 2,2,2-triphenylacetic acid Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)O)C1=CC=CC=C1 DCYGAPKNVCQNOE-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- WXHLLJAMBQLULT-UHFFFAOYSA-N 2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-n-(2-methyl-6-sulfanylphenyl)-1,3-thiazole-5-carboxamide;hydrate Chemical compound O.C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1S WXHLLJAMBQLULT-UHFFFAOYSA-N 0.000 description 1
- CWGFSQJQIHRAAE-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol tetrahydrochloride Chemical compound Cl.Cl.Cl.Cl.OCC(N)(CO)CO CWGFSQJQIHRAAE-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000036487 Arthropathies Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 206010050245 Autoimmune thrombocytopenia Diseases 0.000 description 1
- 208000023328 Basedow disease Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- SEMITIMARMVYFE-ULQATBQFSA-N COC1=NC=CC([C@@](C2)([C@@H]3O[C@H]4C[C@H]3O)[C@@]24C(NC(C=C(C(F)(F)F)C=C2)=C2C#N)=O)=C1 Chemical compound COC1=NC=CC([C@@](C2)([C@@H]3O[C@H]4C[C@H]3O)[C@@]24C(NC(C=C(C(F)(F)F)C=C2)=C2C#N)=O)=C1 SEMITIMARMVYFE-ULQATBQFSA-N 0.000 description 1
- SEMITIMARMVYFE-CVVMMBEDSA-N COC1=NC=CC([C@](C2)([C@H]3O[C@@H]4C[C@@H]3O)[C@]24C(NC(C=C(C(F)(F)F)C=C2)=C2C#N)=O)=C1 Chemical compound COC1=NC=CC([C@](C2)([C@H]3O[C@@H]4C[C@@H]3O)[C@]24C(NC(C=C(C(F)(F)F)C=C2)=C2C#N)=O)=C1 SEMITIMARMVYFE-CVVMMBEDSA-N 0.000 description 1
- RIDYGLBJNOVULE-ZWNNTNCYSA-N C[C@]1(C[C@@H]2O)O[C@@H]2C(Br)=C1C(O)=O Chemical compound C[C@]1(C[C@@H]2O)O[C@@H]2C(Br)=C1C(O)=O RIDYGLBJNOVULE-ZWNNTNCYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 239000004381 Choline salt Substances 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
- 208000006154 Chronic hepatitis C Diseases 0.000 description 1
- 208000030939 Chronic inflammatory demyelinating polyneuropathy Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- KJTLQQUUPVSXIM-UHFFFAOYSA-N DL-mevalonic acid Natural products OCCC(O)(C)CC(O)=O KJTLQQUUPVSXIM-UHFFFAOYSA-N 0.000 description 1
- 208000016192 Demyelinating disease Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- 206010013883 Dwarfism Diseases 0.000 description 1
- 206010015218 Erythema multiforme Diseases 0.000 description 1
- 208000004332 Evans syndrome Diseases 0.000 description 1
- LKOYFWPMKRXQTI-UHFFFAOYSA-N FC1=CC=CC=C1C1=CC=C(NC(=O)C2=C(C3CCC2O3)C2=CN=CC=N2)C=C1F Chemical compound FC1=CC=CC=C1C1=CC=C(NC(=O)C2=C(C3CCC2O3)C2=CN=CC=N2)C=C1F LKOYFWPMKRXQTI-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 208000004262 Food Hypersensitivity Diseases 0.000 description 1
- 206010016946 Food allergy Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010068370 Glutens Proteins 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 1
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 208000037319 Hepatitis infectious Diseases 0.000 description 1
- 101001033249 Homo sapiens Interleukin-1 beta Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000002658 Intra-Articular Fractures Diseases 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 239000002144 L01XE18 - Ruxolitinib Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102000055008 Matrilin Proteins Human genes 0.000 description 1
- 108010072582 Matrilin Proteins Proteins 0.000 description 1
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 1
- 208000023178 Musculoskeletal disease Diseases 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- QVZCRCLUXZPFBD-UHFFFAOYSA-N N-[3-chloro-4-(2-fluorophenyl)phenyl]-3-(1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide Chemical compound FC1=CC=CC=C1C1=CC=C(NC(=O)C2=C(C3CCC2O3)C2=CC=NN2)C=C1Cl QVZCRCLUXZPFBD-UHFFFAOYSA-N 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Substances BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102100029438 Nitric oxide synthase, inducible Human genes 0.000 description 1
- 101710089543 Nitric oxide synthase, inducible Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000002804 Osteochondritis Diseases 0.000 description 1
- 201000009859 Osteochondrosis Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102000016611 Proteoglycans Human genes 0.000 description 1
- 108010067787 Proteoglycans Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 206010040954 Skin wrinkling Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000013201 Stress fracture Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 208000004732 Systemic Vasculitis Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000000491 Tendinopathy Diseases 0.000 description 1
- 208000023835 Tendon disease Diseases 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 102000013814 Wnt Human genes 0.000 description 1
- 108050003627 Wnt Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- IOMLBTHPCVDRHM-UHFFFAOYSA-N [3-[(2,4-dimethylphenyl)carbamoyl]naphthalen-2-yl] dihydrogen phosphate Chemical compound CC1=CC(C)=CC=C1NC(=O)C1=CC2=CC=CC=C2C=C1OP(O)(O)=O IOMLBTHPCVDRHM-UHFFFAOYSA-N 0.000 description 1
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- YBCVMFKXIKNREZ-UHFFFAOYSA-N acoh acetic acid Chemical compound CC(O)=O.CC(O)=O YBCVMFKXIKNREZ-UHFFFAOYSA-N 0.000 description 1
- 208000033017 acquired idiopathic inflammatory myopathy Diseases 0.000 description 1
- 150000008063 acylals Chemical class 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 210000000544 articulatio talocruralis Anatomy 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010927 atrophic thyroiditis Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 1
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 1
- 229950000971 baricitinib Drugs 0.000 description 1
- XUZMWHLSFXCVMG-UHFFFAOYSA-N baricitinib Chemical compound C1N(S(=O)(=O)CC)CC1(CC#N)N1N=CC(C=2C=3C=CNC=3N=CN=2)=C1 XUZMWHLSFXCVMG-UHFFFAOYSA-N 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 125000005620 boronic acid group Chemical class 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 208000019748 bullous skin disease Diseases 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 210000003321 cartilage cell Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 235000019417 choline salt Nutrition 0.000 description 1
- 201000005795 chronic inflammatory demyelinating polyneuritis Diseases 0.000 description 1
- AHMIRVCNZZUANP-LPBAWZRYSA-N chrysalin Chemical compound CC(O)=O.CC(O)=O.C([C@@H](C(=O)N[C@@H](C(C)C)C(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](C)N)C1=CC=CC=C1.C([C@@H](C(=O)N[C@@H](C(C)C)C(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](C)N)C1=CC=CC=C1.C([C@@H](C(=O)N[C@@H](C(C)C)C(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](C)N)C1=CC=CC=C1 AHMIRVCNZZUANP-LPBAWZRYSA-N 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000037319 collagen production Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000013066 combination product Substances 0.000 description 1
- 229940127555 combination product Drugs 0.000 description 1
- 238000011970 concomitant therapy Methods 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 206010061811 demyelinating polyneuropathy Diseases 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 239000011903 deuterated solvents Substances 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 150000004887 dithianes Chemical class 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 238000005553 drilling Methods 0.000 description 1
- 210000001513 elbow Anatomy 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 201000009580 eosinophilic pneumonia Diseases 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-L ethane-1,2-disulfonate Chemical compound [O-]S(=O)(=O)CCS([O-])(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-L 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 201000001155 extrinsic allergic alveolitis Diseases 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 210000001145 finger joint Anatomy 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 235000020932 food allergy Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 210000003108 foot joint Anatomy 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 235000021312 gluten Nutrition 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 201000001505 hemoglobinuria Diseases 0.000 description 1
- 208000005252 hepatitis A Diseases 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 210000004394 hip joint Anatomy 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 210000004276 hyalin Anatomy 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 208000022098 hypersensitivity pneumonitis Diseases 0.000 description 1
- 210000003559 hypertrophic chondrocyte Anatomy 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 201000006334 interstitial nephritis Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 210000000629 knee joint Anatomy 0.000 description 1
- BSABBBMNWQWLLU-UHFFFAOYSA-N lactaldehyde Chemical compound CC(O)C=O BSABBBMNWQWLLU-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000036244 malformation Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- CPZBTYRIGVOOMI-UHFFFAOYSA-N methylsulfanyl(methylsulfanylmethoxy)methane Chemical compound CSCOCSC CPZBTYRIGVOOMI-UHFFFAOYSA-N 0.000 description 1
- 238000004452 microanalysis Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 description 1
- 201000003631 narcolepsy Diseases 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Chemical group 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960005141 piperazine Drugs 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 201000009732 pulmonary eosinophilia Diseases 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000002278 reconstructive surgery Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 108010018091 rusalatide acetate Proteins 0.000 description 1
- 229960000215 ruxolitinib Drugs 0.000 description 1
- HFNKQEVNSGCOJV-OAHLLOKOSA-N ruxolitinib Chemical compound C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 HFNKQEVNSGCOJV-OAHLLOKOSA-N 0.000 description 1
- MOODSJOROWROTO-UHFFFAOYSA-N salicylsulfuric acid Chemical compound OC(=O)C1=CC=CC=C1OS(O)(=O)=O MOODSJOROWROTO-UHFFFAOYSA-N 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 210000002832 shoulder Anatomy 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 230000009759 skin aging Effects 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 210000001626 skin fibroblast Anatomy 0.000 description 1
- 230000036559 skin health Effects 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229940071103 sulfosalicylate Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000008736 traumatic injury Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 235000005282 vitamin D3 Nutrition 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- 229940021056 vitamin d3 Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
- 210000000707 wrist Anatomy 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
-
- 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
- A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-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
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- General Chemical & Material Sciences (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明提供了具有式(1)的6‑羟基‑8‑氧杂三环[3.2.1.02,4]辛烷‑2‑甲酰胺衍生物,其中变量如本文中所定义。本发明进一步提供了包含此类化合物的药物组合物。所述化合物在治疗或预防由关节损伤或关节炎引起的关节损害的方法中用于诱导软骨发生,并且用于引导透明软骨产生。本说明书公开了示例性化合物的制备及其药理学数据(实例1‑82;表1和表2)。示例性化合物是例如外消旋‑(1R,2R,4S,5R,6S)‑4‑(2‑氟吡啶‑4‑基)‑6‑羟基‑N‑(4‑(三氟甲基)吡啶‑2‑基)‑8‑氧杂三环[3.2.1.02,4]辛烷‑2‑甲酰胺(实例1)。
Description
相关申请的交叉引用
本申请要求于2018年12月6日提交的美国临时申请序列号62/776,271的权益,将其通过引用以其全文并入本文。
技术领域
本发明涉及用于治疗或预防由关节损伤和关节炎引起的关节损害或用于软骨修复的组合物和方法。
背景技术
骨关节炎(OA)代表最常见的肌肉骨骼障碍。目前大约有4000万美国人受到影响,且由于人口老龄化和预期寿命延长,预计在未来二十年内,这一数字将增加到6000万,使骨关节炎成为导致残疾的第四大原因。OA的特征在于关节的缓慢退行性破坏,所述关节包括关节软骨(含有细胞和基质,其为关节产生润滑和缓冲)和关节软骨下面的软骨下骨。OA可被认为是多种病因的结果。例如,骨关节炎可能由关节软骨或骨的异常生物力学应力或者遗传或后天异常引起。目前OA治疗包括使用口服NSAID或选择性环氧合酶2(COX-2)抑制剂、关节内(IA)注射药剂例如皮质类固醇和透明质酸、以及手术方法来缓解疼痛。
关节损害例如急性关节损伤(如半月板或韧带撕裂)或关节内骨折也可导致关节炎,例如创伤后关节炎。由于关节软骨的修复能力有限,所以即使很小的不可检测的损害通常也会随着时间的推移而恶化并导致OA。目前关节损伤的治疗可以包括手术和聚焦于使受伤关节再生的其他侵入性方法,以及用药剂治疗以减少疼痛和炎症。
间充质干细胞(MSC)存在于成人关节软骨中,并且在分离后可以在体外程序化以分化为软骨细胞和其他间充质细胞谱系,并且可以用于软骨再生。部分地,所述过程受生长因子(TGFβ、BMP)、血清条件和细胞间接触的调节。
WO 2011/008773描述了肽组合物及这些组合物用于治疗或预防关节炎和关节损伤的用途以及用于诱导间充质细胞分化为软骨细胞的用途。此外,WO 2012/129562描述了小分子化合物、组合物及这些组合物用于改善关节炎和关节损伤的用途以及用于诱导间充质细胞分化为软骨细胞的用途。
尽管手术技术和再生技术已经在软骨恢复、延缓退化和改善关节损害的修复上取得了一些进展,但是仍持续需要改进用于有效软骨再生、治疗关节损害、和改善或预防OA的组合物和方法。
发明内容
本发明涉及用于治疗或预防由关节损伤和关节炎引起的关节损害或用于软骨修复的组合物和方法。
在一个方面,本发明提供了具有式(1)的化合物:
或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中
W是苯基或吡啶基;
R1是氢或C1-6烷基;
R2是苯基或具有1-2个选自N、O和S的杂原子的5-6元杂芳基;其中R2是未取代的或被1-2个独立地选自卤基、C1-6烷基、C1-6卤基烷基或C1-6烷氧基的取代基取代;
R3独立地选自卤基、氰基、C1-6烷基、C1-6卤基烷基、C1-6烷氧基、C3-6环烷基和5-6元杂环基;或者当n是0时,R3是氢;并且
n是0-2。
在另一方面,本发明提供了一种药物组合物,所述药物组合物包含治疗有效量的具有式(1)或其子式的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;以及一种或多种药学上可接受的载体。
在又另一方面,本发明提供了一种组合,特别是药物组合,所述组合包含治疗有效量的具有式(1)或其子式的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;以及一种或多种治疗活性剂。
本发明的化合物,单独或与一种或多种治疗活性剂组合,可用于治疗、改善或预防急性关节损害或损伤,例如关节炎(骨关节炎、创伤性关节炎、***性类风湿性关节炎)或退行性椎间盘疾病。此外,本发明的化合物,单独或与一种或多种治疗活性剂组合,可用于诱导透明软骨产生。
具体实施方式
本发明提供了刺激受损关节中透明软骨产生的新型化合物。
在一个方面,本发明提供了用于修复软骨的新型化合物和组合物。还提供了通过向关节、软骨组织、或软骨邻近组织中、或全身性地施用本发明化合物或组合物来治疗、预防或改善关节炎或关节损伤的组合物和方法。进一步地,本发明提供用于诱导透明软骨产生的组合物和方法。
定义
出于解释本说明书的目的,将应用下面的定义,并且在适宜的情况下,以单数形式使用的术语还包括复数形式,并且反之亦然。
如本文所用,术语“C1-6烷氧基”是指具有式-ORa的基团,其中Ra是如以上通常所定义的C1-6烷基基团。C1-6烷氧基的实例包括但不限于:甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、戊氧基和己氧基。所述烷氧基的烷基部分可以任选被取代,所述取代基包括下文对烷基基团所述的那些基团。
如本文所用,术语“C1-6烷基”是指仅由碳和氢原子组成的直链或支链烃链基团,所述基团中不存在不饱和,具有通过单键连接到分子的其余部分的从一至六个碳原子。C1-6烷基的实例包括但不限于:甲基、乙基、正丙基、1-甲基乙基(异丙基)、正丁基、正戊基和1,1-二甲基乙基(叔丁基)。
如本文所用的“氨基”指基团-NH2。除非另有说明,否则包含氨基部分的本发明的化合物可以包括其被保护的衍生物。适于氨基部分的保护基包括乙酰基、叔丁氧羰基、苄氧羰基等。
如本文所用的“杂环基”或“杂环的”是指包含独立地选自氮、氧和硫的1、2或3个杂原子的稳定的5元或6元非芳族单环环基团。杂环基基团可以经由碳原子或杂原子键合。杂环基的实例包括但不限于吡咯啉基、吡咯烷基、四氢呋喃基、四氢噻吩基、哌啶基、哌嗪基、四氢吡喃基、或吗啉基。
如本文所用,术语“杂芳基”是指包含1、2、3或4个独立地选自氮、氧和硫的杂原子的5元或6元芳族单环环基团。杂芳基基团可以经由碳原子或杂原子键合。杂芳基的实例包括但不限于呋喃基、吡咯基、噻吩基、吡唑基、咪唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、***基、四唑基、吡嗪基、哒嗪基、嘧啶基或吡啶基。
如本文所用的“IC50”是指产生50%抑制作用的抑制剂或调节剂的摩尔浓度。
如本文所用的“卤基(halo)”或“卤素”是指氟、氯、溴和碘。
如本文所用的“卤基取代的C1-6烷基”是指被如以上所定义的一种或多种卤基基团取代的如以上所定义的C1-6烷基基团。卤基取代的C1-6烷基的实例包括但不限于三氟甲基、二氟甲基、氟甲基、三氯甲基、2,2,2-三氟乙基、1,3-二溴丙烷-2-基、3-溴-2-氟丙基和1,4,4-三氟丁烷-2-基。
如本文所用的“被保护的衍生物”是指抑制剂的衍生物,其中一个或多个反应部位被保护基阻断。被保护的衍生物可用于制备抑制剂,或者它们自身可以具有抑制剂的活性。被保护的基团的实例包括但不限于乙酰基、四氢吡喃、甲氧基甲基醚、β-甲氧基乙氧基甲基醚、对甲氧基苄基、甲基硫代甲基醚、新戊酰、甲硅烷基醚、苄氧羰基、苄基、叔丁氧羰基、对甲氧基苯基、9-芴基甲基氧基羰基、缩醛、缩酮、缩羰酯(acylal)、二噻烷、甲基酯、苄基酯、叔丁基酯和甲硅烷基酯。合适的保护基的详细清单可以在T.W.Greene,Protecting Groupsin Organic Synthesis[有机合成中的保护基],第3版,John Wiley&Sons,Inc.[约翰·威利父子公司]1999中找到。
如本文所用,术语“软骨细胞(chondrocyte)”是指分化的软骨细胞(cartilagecell)。软骨细胞产生并维持由胶原蛋白和蛋白聚糖组成的软骨基质。软骨细胞源自软骨发生性祖细胞(CPC)的分化。分化是从不太专化的细胞类型形成专化细胞类型的过程,例如,从软骨发生性祖细胞(CPC)形成软骨细胞。
如本文所用,术语“软骨细胞分化剂”是指诱导软骨发生性祖细胞分化为成熟软骨细胞的试剂,成熟软骨细胞合成软骨细胞外基质(ECM)。
如本文所用,术语“受试者”是指哺乳动物、灵长类动物(例如,人(男性或女性))、狗、兔、豚鼠、猪、大鼠和小鼠。在某些实施例中,受试者为灵长类动物。在又其他的实施例中,受试者是人。
如本文所用,术语“抑制(inhibit、inhibition或inhibiting)”是指减少或抑制给定的病症、症状或障碍、或疾病,或在生物活性或过程的基线活性方面的显著降低。
如本文使用的,术语任何疾病或障碍的“治疗(treat、treating或treatment)”是指缓解或改善疾病或障碍(即,减慢或阻止疾病或其至少一种临床症状的发展);或缓解或改善与所述疾病或障碍相关的至少一种物理参数或生物标记,包括患者可能无法辨别的那些物理参数或生物标记。
如本文所用,术语任何疾病或障碍的“预防(prevent、preventing或prevention)”是指疾病或障碍的预防性治疗;或延迟疾病或障碍的发作或进展。
如本文所用,如果受试者将在生物学上、在医学上或在生活质量上从治疗中获益,则这样的受试者是“需要”这种治疗的。
如本文所用,术语本发明的化合物的“治疗有效量”是指将引起受试者的生物或医学响应(例如,酶或蛋白活性的减小或抑制,或改善症状、缓解病症、减慢或延迟疾病进展或预防疾病等)的本发明的化合物的量。在一个非限制性实施例中,术语“治疗有效量”是指本发明的化合物的如下量,当施用至有需要的受试者时,所述量有效地至少部分缓解、抑制、预防和/或改善关节损伤和关节炎引起的关节损害。在另一个非限制性实施例中,术语“治疗有效量”是指本发明化合物的如下量,当施用至细胞、或组织、或非细胞生物学材料或介质时,所述量有效地促进软骨发生。
如本文所用,“施用”指对特定关节的施用。
如本文所用,术语“药物组合物”是指呈适于口服或肠胃外施用的形式的本发明化合物、或其药学上可接受的盐,以及至少一种药学上可接受的载体。
如本文使用的,术语“药学上可接受的载体”是指可用于制备或使用药物组合物的物质,并且包括例如适合的稀释剂、溶剂、分散介质、表面活性剂、抗氧化剂、防腐剂、等渗剂、缓冲剂、乳化剂、吸收延迟剂、盐、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、润湿剂、甜味剂、调味剂、染料及其组合,如本领域技术人员已知的(参见,例如,Remington TheScience and Practice of Pharmacy[雷明顿:药物科学与实践],第22版,PharmaceuticalPress[药物出版社],2013,第1049-1070页)。
如本文所用,术语“一个/种(a/an)”、“所述(the)”以及在本发明的上下文中使用的类似术语(特别是在权利要求的上下文中)应被解释为涵盖单数和复数两者,本文中除非另有说明或明确与上下文相矛盾。
优选实施例的描述
本发明涉及用于治疗或预防由关节损伤和关节炎引起的关节损害或用于软骨修复的组合物和方法。
本文描述了本发明的各种列举的实施例。每个实施例中指定的特征可以与其他指定特征组合以提供本发明的另外实施例。
实施例1.一种具有式(1)的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐,如上所述。
实施例2.根据实施例1所述的具有式(1)的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中R2是苯基、吡唑基、吡啶基或嘧啶基;所述苯基、吡唑基、吡啶基或嘧啶基各自被1-2个独立地选自卤基、C1-6烷基、C1-6卤基烷基或C1-6烷氧基的取代基取代。
实施例3.根据实施例1所述的具有式(1)的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中R2选自苯基、吡唑基或嘧啶基;所述苯基、吡唑基或嘧啶基各自被1-2个独立地选自卤基、C1-6烷基、C1-6卤基烷基或C1-6烷氧基的取代基取代;或R2是被卤基、C1-6卤基烷基或C1-6烷氧基取代的吡啶基。
实施例4.根据实施例1-3中任一项所述的具有式(1)的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中
其中是/>
实施例5.根据实施例1-3中任一项所述的具有式(1)的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中是
实施例6.根据实施例1-3中任一项所述的具有式(1)的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中是/>
实施例7.根据实施例1-6中任一项所述的化合物,其中所述化合物具有式(2):
或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中
X是N、CH或CR4;并且
R4是卤基、氰基、C1-6烷基、C1-6卤基烷基或C1-6烷氧基。
实施例8A.根据实施例7所述的化合物,其中所述化合物具有式(2A):
或是其对映异构体、对映异构体混合物或其药学上可接受的盐;其中
X是N、CH或CR4;并且
R4是卤基、氰基、C1-6烷基、C1-6卤基烷基或C1-6烷氧基。
实施例8B.根据实施例7所述的化合物,其中所述化合物具有式(2B):
或是其对映异构体、对映异构体混合物或其药学上可接受的盐;其中
X是N、CH或CR4;并且
R4是卤基、氰基、C1-6烷基、C1-6卤基烷基或C1-6烷氧基。
实施例9.根据实施例1-7和8A-8B中任一项所述的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中R3,如果存在,是氟、氯、甲基、甲氧基、乙氧基、三氟甲基、氰基、环丙基或吗啉基。
实施例10.根据实施例1-7和8A-8B中任一项所述的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中R3是氢并且n是0。
实施例11A.根据实施例1-7、8A-8B和9-10中任一项所述的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中R2选自:
实施例11B.根据实施例1-7、8A-8B和9-10中任一项所述的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中R2是
实施例11C.根据实施例1-7、8A-8B和9-10中任一项所述的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中R2选自:
实施例11D.根据实施例1-7、8A-8B和9-10中任一项所述的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中R2选自
实施例11E.根据实施例1-7、8A-8B和9-10中任一项所述的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中R2是
实施例12.根据实施例1-7、8A-8B、9-10和11A-11E中任一项所述的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中R1是氢。
实施例13.根据实施例1所述的化合物,其中所述化合物选自表2或表3中的化合物;或其对映异构体、对映异构体混合物或其药学上可接受的盐。
实施例14.根据实施例1-7、8A-8B、9-10、11A-11E和12-13中任一项所述的化合物或其药学上可接受的盐,其中所述化合物具有(1R,2R,3S,4R,5S)对映异构体的至少50%、至少75%、至少85%、或至少95%的对映异构体过量。
实施例15.一种药物组合物,所述药物组合物包含根据实施例1-7、8A-8B、9-10、11A-11E和12-14中任一项所述的化合物、以及一种或多种药学上可接受的载体。
实施例16.一种组合,所述组合包含根据实施例1-7、8A-8B、9-10、11A-11E和12-14中任一项所述的化合物、以及一种或多种治疗活性剂。
实施例17.根据实施例1-7、8A-8B、9-10、11A-11E和12-14中任一项所述的化合物,并且任选地与第二治疗剂组合,用于在有需要的受试者中治疗、改善或预防关节炎或关节损伤、或用于软骨修复。
实施例18.根据实施例1-7、8A-8B、9-10、11A-11E和12-14中任一项所述的化合物,并且任选地与第二治疗剂组合,在制造用于关节炎或关节损伤或用于软骨修复的药物中的用途。
实施例19.一种用于在有需要的受试者中治疗、改善或预防关节炎或关节损伤或用于软骨修复的方法,所述方法包括施用治疗有效量的根据实施例1-7、8A-8B、9-10、11A-11E和12-14中任一项所述的、以及任选地与第二治疗剂组合的化合物;从而治疗、改善或预防所述受试者的关节炎或关节损伤,或修复软骨。
实施例20.根据实施例19所述的方法,其中所述化合物口服施用。
实施例21.根据实施例17所述的化合物、根据实施例18所述的用途或根据实施例19或20所述的方法,其中所述关节炎是骨关节炎、创伤性关节炎或自身免疫性关节炎;并且任选地,其中所述关节炎是骨关节炎或类风湿性关节炎。
实施例22.一种诱导透明软骨产生的方法,所述方法包括使软骨发生性祖细胞与治疗有效量的根据实施例1-7、8A-8B、9-10、11A-11E和12-14中任一项所述的、以及任选地与第二治疗剂组合的化合物接触;从而诱导透明软骨细胞外基质。
实施例23.一种诱导软骨发生性祖细胞分化为成熟软骨细胞的方法,所述方法包括使软骨发生性祖细胞与治疗有效量的根据实施例1-7、8A-8B、9-10、11A-11E和12-14中任一项所述的、以及任选地与第二治疗剂组合的化合物接触;从而诱导软骨祖细胞分化为成熟软骨细胞。
实施例24.根据实施例22或实施例23所述的方法,其中所述接触步骤是在哺乳动物体外或体内进行的;并且当在体内进行时,所述软骨发生性祖细胞存在于哺乳动物中。
实施例25.根据实施例24所述的方法,其中所述接触步骤发生在细胞外基质或生物相容性支架中。
实施例26.根据实施例17所述的化合物、根据实施例18所述的用途或根据实施例19-25中任一项所述的实施例,其中所述第二治疗剂是软骨细胞分化剂。
实施例27.根据实施例17所述的化合物、根据实施例18所述的用途或根据实施例19-25中任一项所述的实施例,其中所述第二治疗剂选自血管生成素样3蛋白(ANGPTL3)、胰岛素生长因子(IGF1)、SM04690、Janus激酶抑制剂、口服鲑鱼降钙素、SD-6010、维生素D3、胶原蛋白水解物、骨形态发生蛋白7(BMP7)、醋酸卢沙拉肽(rusalatide acetate)、鳄梨大豆非皂化物(ASU)、类固醇、非甾体抗炎药(NSAID)、透明质酸、kartogenin、TPX-100、以及具有如WO 2015/175487中所述的式(I)或其子式的软骨细胞分化剂。
实施例28.根据实施例27所述的化合物、根据实施例27所述的用途或根据实施例27所述的实施例,其中所述第二治疗剂是选自以下的软骨细胞分化剂:
(1R,2S,3R,4S)-N-(3,4-二氯苯基)-3-(1-甲基-3-(三氟甲基)-1H-吡唑-5-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺;
(1S,2R,3R,4R)-N-(3,4-二氯苯基)-3-(吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺;
(1S,2S,3R,4R)-3-(2-氨基吡啶-4-基)-N-(3,4-二氯苯基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺;
(1R,2S,3S,4S)-N-(3,4-二氯苯基)-3-(吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺;
N-(2-氯-2'-氟-[1,1'-联苯基]-4-基)-3-(1H-吡唑-5-基)-7-氧杂双环[2.2.1]庚-2-烯-2-甲酰胺;
(1R,2R,3S,4S)-N-(3,4-二氯苯基)-3-(吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺;
(1S,2S,3R,4R)-N-(3,4-二氯苯基)-3-(吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺;
(1R,2R,3S,4S)-3-(2-氨基吡啶-4-基)-N-(3,4-二氯苯基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺;
(1R,2R,4S,5S)-N-(3,4-二氯苯基)-4-(吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺;以及
N-(2,2'-二氟-[1,1'-联苯基]-4-基)-3-(吡嗪-2-基)-7-氧杂双环[2.2.1]庚-2-烯-2-甲酰胺;
或其药学上可接受的盐的对映异构体、对映异构体混合物。
除非另有指明,否则术语“本发明的化合物”是指具有式(1)及其子式(例如,式(2))的化合物及其对映异构体和盐,以及旋转异构体、互变异构体、同位素标记的化合物(包括氘取代)和固有形成的部分。
除非另有说明,否则本文中表示为单一对映异构体的化合物包括所示化合物的对映异构体和对映异构体的混合物,包括外消旋混合物。本发明的一种或多种化合物的任何非对称原子(例如,碳等)可以是外消旋或对映异构体富集的形式,例如(R)-、(S)-或(R,S)-构型。可以通过已知方法,例如通过手性色谱法,例如使用手性吸附剂的高压液相色谱法(HPLC),将最终产物或中间体的任何所得外消旋物拆分成旋光对映体。
在某些实施例中,每个非对称原子具有至少50%对映异构体过量、至少60%对映异构体过量、至少70%对映异构体过量、至少80%对映异构体过量、至少90%对映异构体过量、至少95%对映异构体过量、或至少99%对映异构体过量的(R)-或(S)-构型。
本文给出的任何式也旨在表示化合物的未标记形式以及同位素标记形式。同位素标记的化合物具有由本文给出的式描绘的结构,除了一个或多个原子被具有所选择的原子质量或质量数的原子替代。可以掺入本发明化合物中的同位素包括例如氢的同位素。
此外,掺入某些同位素,特别是氘(即2H或D)可以提供更高代谢稳定性导致的某些治疗优势,例如增加的体内半衰期或减少的剂量要求或治疗指数或耐受性的改善。应理解,在此上下文中的氘被认为是具有式(1)或其子式的化合物的取代基。氘的浓度可以由同位素富集因子定义。如本文所用的术语“同位素富集因子”是指同位素丰度与指定同位素的天然丰度之间的比率。如果本发明化合物中的取代基指示为氘,则这种化合物具有的针对每个指定的氘原子的同位素富集因子为至少3500(在每个指定的氘原子上52.5%氘掺入)、至少4000(60%氘掺入)、至少4500(67.5%氘掺入)、至少5000(75%氘掺入)、至少5500(82.5%氘掺入)、至少6000(90%氘掺入)、至少6333.3(95%氘掺入)、至少6466.7(97%氘掺入)、至少6600(99%氘掺入)、或至少6633.3(99.5%氘掺入)。应理解,术语“同位素富集因子”可以以与对氘描述的相同方式应用于任何同位素。
可以掺入本发明的化合物的同位素的其他实例包括氢、碳、氮、氧、磷、氟和氯的同位素,如分别是3H、11C、13C、14C、15N、18F、31P、32P、35S、36Cl、123I、124I、125I。因此,应当理解,本发明包括掺入任何上述同位素中一种或多种的化合物,包括例如放射性同位素,例如3H和14C,或其中掺入非放射性同位素例如2H和13C的那些。此类同位素标记的化合物可用于代谢研究(用14C)、反应动力学研究(例如用2H或3H)、检测或成像技术(如正电子发射断层扫描(PET)或单光子发射计算机断层扫描(SPECT),包括药物或底物组织分布测定),或用于患者的放射性治疗。特别地,18F或标记的化合物对于PET或SPECT研究可能是特别期望的。同位素标记的具有式(1)或其子式的化合物通常可以通过本领域技术人员已知的常规技术或通过与所附实例中所述的那些类似的方法,使用适当的同位素标记的试剂代替未标记的先前使用的试剂来制备。
本发明的化合物是以游离形式、作为其盐形式获得的。如本文所用,术语“盐(salt或salts)”是指本发明化合物的酸加成盐或碱加成盐。“盐”特别包括“药学上可接受的盐”。术语“药学上可接受的盐”是指保留本发明化合物的生物有效性和特性,并且典型地不是生物学上或其他方面不希望的盐。在许多情况下,由于氨基和/或羧基基团或与其类似的基团的存在,本发明的化合物能够形成酸盐和/或碱盐。
可以用无机酸和有机酸形成药学上可接受的酸加成盐。可以衍生出盐的无机酸包括,例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。可以衍生出盐的有机酸包括,例如乙酸、丙酸、乙醇酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、甲苯磺酸、磺基水杨酸等。
可以用无机碱和有机碱形成药学上可接受的碱加成盐。可以衍生出盐的无机碱包括例如铵盐和来自元素周期表第I至XII列的金属。在某些实施例中,盐衍生自钠、钾、铵、钙、镁、铁、银、锌和铜;特别合适的盐包括铵盐、钾盐、钠盐、钙盐和镁盐。可以衍生出盐的有机碱包括例如伯胺、仲胺和叔胺;取代的胺(包括天然存在的取代的胺);环胺;碱性离子交换树脂等。某些有机胺包括异丙胺、苄星、胆碱盐、二乙醇胺、二乙胺、赖氨酸、葡甲胺、哌嗪和氨丁三醇。
在另一个方面,本发明提供了呈以下形式的本发明的化合物:乙酸盐、抗坏血酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、癸酸盐、氯化物/盐酸盐、氯茶碱盐、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、谷氨酸盐、戊二酸盐、乙醇酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、乳糖醛酸盐、十二烷基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、粘酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八烷酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖醛酸盐、丙酸盐、癸二酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、硫酸盐、酒石酸盐、甲苯磺酸盐、三苯乙酸盐(trifenatate)、三氟乙酸盐或昔萘酸盐形式。
用于制备本发明的化合物的方法
在本文描述的所有方法能够以任何合适顺序进行,除非另外指明或另外与上下文明显相矛盾。
具有式(1)的化合物可以如方案1中总体说明的那样制备,其中R1、R2、R3、W和n是如上所定义的。在以下的方案中,如式(1)所描绘的式涵盖所描绘的式、和所描绘的式及其相应的对映异构体的混合物,包括外消旋混合物。
方案1
中间体1b可以经由溴化和与呋喃的狄尔斯-阿德尔(Diels-Alder)反应,由商购获得的丙炔酸甲酯(1a)制备。可以经由中间体1b的硼氢化/氧化制备中间体1c。可以经由中间体1c的TBS保护来制备中间体1d。可以通过对中间体1d进行铃木偶联来制备中间体1e。将中间体1e环丙烷化,得到中间体1f。使用中间体1f、苯胺、和LiHMDS形成酰胺键,并且随后使用TBAF进行脱保护,得到具有式(1)的化合物。
本发明进一步包括本发明方法的任何变体;例如,其中将在其任何阶段可获得的中间体产物用作起始材料,并进行其余步骤;其中起始材料在反应条件下原位形成;或其中将反应组分以其盐或光学纯物质的形式使用。本发明的化合物及中间物还可根据本领域普通技术人员通常已知的方法彼此转化。
药理学及效用
本发明提供了一种在有需要的受试者中治疗、改善或预防关节炎或关节损伤的方法,所述方法包括向所述受试者施用治疗有效量的本发明的化合物,其中所述受试者患有关节损害或关节炎或处于其风险中。本发明还提供了在人类患者中治疗、改善或预防关节炎或关节损伤的方法,所述方法包括:患者口服施用包含有效量的本发明化合物的组合物,从而在患者中治疗、改善或预防关节炎或关节损伤。在一些实施例中,患者患有关节炎或关节损伤。在一些实施例中,个体不患有关节炎或关节损伤,但有此风险。一些实施例中,关节炎是骨关节炎、创伤性关节炎、或自身免疫性关节炎。
本发明的化合物还可用于诱导透明软骨产生,包括使软骨发生性祖细胞(CPC)与治疗有效量的任选地与第二治疗剂组合的具有式(1)或其子式的化合物接触;从而诱导透明软骨产生。在一个非限制性实施例中,通过预防软骨祖细胞的软骨细胞肥大来诱导透明软骨产生。在另一个非限制性实施例中,通过诱导软骨发生性祖细胞分化为成熟软骨细胞,尤其是产生透明软骨细胞外基质的成熟软骨细胞,来诱导透明软骨产生。
CPC可以分化为不同类型的细胞,包括但不限于成骨细胞、透明软骨细胞和肥大软骨细胞。分化是从不太专化的细胞类型形成专化细胞类型的过程,例如,从软骨发生性祖细胞形成软骨细胞。在一些实施例中,所述方法是在体外进行的。在一些实施例中,所述方法在哺乳动物体内进行,并且祖细胞存在于哺乳动物中。
诱导软骨发生性祖细胞进行软骨细胞分化可以使用任何合适量的本发明化合物来完成。在一些实施例中,根据活性组分的特定应用和效力,本发明的化合物能以约0.1mg至约10000mg(例如1.0mg至1000mg,例如10mg至500mg)的量存在。在一些实施例中,本发明的化合物可以每天一次口服施用,剂量为1mg/kg至约300mg/kg。对于严重的骨关节炎,治疗持续时间从一周或更短至长期治疗不等。
预期本发明的化合物、组合物和方法可以用于治疗、改善或预防任何类型的关节软骨损害(例如,关节损害或损伤),包括例如由创伤事件、或腱或韧带撕裂引起的损害。一些实施例中,例如在存在关节炎或关节损害或关节损伤的遗传史或家族史的情况下,或在关节手术之前或期间,施用本发明的化合物或组合物以预防或改善关节炎或关节损害。一些实施例中,使用化合物、组合物和方法治疗关节损害。在特定实施例中,所述关节损害是创伤性关节损伤。在其他实施例中,所述关节损害是由年龄或不活动引起的损害。在又其他实施例中,所述关节损害是由自身免疫障碍引起的损害。在其他实施例中,所述关节损害是由代谢障碍(例如糖尿病)引起的损害。在本发明的一些实施例中,本发明的化合物、组合物和方法可用于治疗、改善或预防骨关节炎。一些实施例中,在有罹患或获得关节炎的风险的受试者中使用所述化合物、组合物和方法以改善或预防关节炎。一些实施例中,在有罹患或获得关节损害的风险的受试者中使用所述化合物、组合物和方法以改善或预防关节损害。
在一些实施例中,本发明的化合物、组合物和方法可用于刺激例如已经由于创伤性损伤或软骨病受损的软骨组织中的透明软骨产生。在特定实施例中,本发明的化合物、组合物和方法可用于治疗关节中例如在关节连接面(例如脊柱、肩膀、肘、腕、手指关节、臀、膝盖、踝和脚关节)处的软骨损害。可受益于治疗的疾病或障碍的实例包括骨关节炎、类风湿性关节炎、其他自身免疫疾病或分离性骨软骨炎。此外,软骨损坏或破坏可以因一些遗传或代谢性病症引起,软骨畸形常常以侏儒症的形式见于人类中,和/或软骨损坏或破坏常常可以因重建手术引起;因此,化合物、组合物和方法在这些患者中可以是有用的疗法,其可以单独或组合其他方法使用。
进一步预期本发明的化合物、组合物和方法可用于治疗、改善或预防各种软骨障碍和/或此类病症的相关症状或影响。用本发明的化合物、组合物和方法治疗、改善和/或预防的示例性病症或障碍包括但不限于***性红斑狼疮、类风湿性关节炎、青少年慢性关节炎、骨关节炎、退行性椎间盘疾病、脊柱关节病、埃勒斯-当洛斯(Ehlers Danlos)综合征、***性硬化病(硬皮病)或腱疾病。可能会受益于化合物的治疗以改善相关影响的其他病症或障碍包括特发性炎症性肌病(皮肌炎、多肌炎),舍格伦综合征(Sjogren's syndrome),***性血管炎,结节病,自身免疫性溶血性贫血(免疫性全血细胞减少症、阵发性睡眠性血红蛋白尿症),自身免疫性血小板减少症(特发性血小板减少性紫癜、免疫介导的血小板减少),甲状腺炎(格雷夫斯病、桥本氏甲状腺炎、幼年淋巴细胞性甲状腺炎、萎缩性甲状腺炎),糖尿病,免疫介导的肾脏疾病(肾小球性肾炎、肾小管间质性肾炎),中枢和周围神经***脱髓鞘疾病如多发性硬化、特发性脱髓鞘性多神经病或吉兰-巴雷综合征(Guillain-Barrsyndrome)和慢性炎性脱髓鞘性多神经病,肝胆疾病如传染性肝炎(甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、戊型肝炎和其他非嗜肝病毒型肝炎)、自身免疫性慢性活动性肝炎、原发性胆汁性肝硬化、肉芽肿性肝炎、和硬化性胆管炎,炎症性肠病(溃疡性结肠炎:克罗恩病),谷蛋白敏感性肠病和惠普耳氏病,自身免疫性或免疫介导的皮肤病包括大疱性皮肤病、多形性红斑和接触性皮炎、牛皮癣,过敏性疾病例如哮喘、过敏性鼻炎、特应性皮炎、食物过敏和荨麻疹,肺部免疫性疾病例如嗜酸性肺炎、特发性肺纤维化和过敏性肺炎,移植相关的疾病包括移植排斥和移植物抗宿主疾病。
预期本发明的化合物和/或组合物可以促进人皮肤成纤维细胞中胶原蛋白的表达。胶原蛋白是真皮的主要结构组分。胶原蛋白对皮肤健康至关重要,并且已被广泛用于皮肤皱纹处理和皮肤老化,并作为烧伤患者的治愈辅助剂。胶原蛋白是在成纤维细胞中产生的,且人和牛胶原蛋白都被广泛使用。因此,本发明提供了一种在成纤维细胞中增加胶原蛋白的产生的方法,所述方法通过使成纤维细胞与本发明的化合物或组合物接触,从而增加成纤维细胞中胶原蛋白的产生。可以通过在待治疗区域中直接注射所述化合物来在体内进行所述接触。可以在体外在成纤维细胞群中进行所述接触。
药物组合物、剂型和施用
在另一方面,本发明提供了一种药物组合物,所述药物组合物包含本发明化合物或其药学上可接受的盐以及药学上可接受的载体。在另一个实施例中,组合物包含至少两种药学上可接受的载体,例如本文所述的那些。药物组合物可以配制用于特定的施用途径,诸如口服施用、肠胃外施用(例如通过注射、输注、透皮或局部施用),和直肠施用。局部施用也可以涉及吸入或鼻内应用。本发明的药物组合物可以以固体形式(包括但不限于胶囊、片剂、丸剂、颗粒、粉末或栓剂)、或以液体形式(包括但不限于溶液、混悬液或乳液)制成。片剂可根据本领域已知的方法添加薄膜包衣或肠溶包衣。典型地,药物组合物是包含活性成分及以下中的一种或多种的片剂或明胶胶囊:
a)稀释剂,例如乳糖、右旋糖、蔗糖、甘露糖醇、山梨糖醇、纤维素和/或甘氨酸;
b)润滑剂,例如二氧化硅、滑石、硬酯酸、其镁盐或钙盐和/或聚乙二醇;就片剂而言还包含
c)粘合剂,例如硅酸镁铝、淀粉糊、明胶、黄芪胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯基吡咯烷酮;如果希望的话
d)崩解剂,例如淀粉、琼脂、海藻酸或其钠盐,或泡腾混合物;以及
e)吸附剂、着色剂、调味剂及甜味剂。
一般而言,本发明的化合物将以治疗有效量经由本领域中已知的任何常用且可接受的模式单独或与一或多种治疗剂组合施用。在一些实施例中,通过直接注射到关节滑液中、***性施用(口服或静脉内施用)或直接施用在软骨缺损中而应用本发明的化合物和组合物,单独或与合适的载体复合以延长化合物的释放。一些实施例中,化合物或组合物在生物相容性基质或支架中施用。
本发明的化合物、组合物和方法也可以与在受累及的关节处的外科手术一起使用。本发明的化合物或组合物的施用可以是在外科手术之前进行、期间或一起进行和/或之后进行。例如,本发明的化合物、组合物和方法可以用于扩增培养的软骨细胞群以用于自体或同种异体软骨细胞植入(ACI)。可以移植软骨细胞,任选地伴随与由施用本发明化合物和组合物组成的并行治疗。在这些程序中,例如可以从受损关节的未损伤的小负荷区域通过关节镜收获软骨细胞,并且可以在体外培养,任选地在本发明的化合物和组合物和/或其他生长因子的存在下培养以在移植前增加细胞数。然后任选地将扩增的培养物与本发明的化合物和组合物混合和/或置于关节空间中或直接置于缺损中。在某些实施例中,将扩增的培养物(任选地具有本发明的化合物)置于悬浮在基质或膜中的关节空间中。
在其他实施例中,本发明的化合物和组合物可以与一个或多个骨膜移植物或软骨膜移植物组合使用,所述骨膜移植物或软骨膜移植物含有软骨形成细胞和/或有助于将移植的软骨细胞或软骨细胞前体细胞保持在适当位置。在一些实施例中,本发明的化合物和组合物与其他程序联用以修复软骨损害,所述其他程序包括但不限于关节的灌洗、骨髓的刺激、磨削成形术、软骨下骨钻孔术或近端软骨下骨的微骨折。任选地,在本发明的化合物和组合物的施用以及软骨的生长之后,另外的手术治疗可以有利于适当地勾画新形成的一个或多个软骨表面。
本发明化合物可以与一种或多种其他的治疗剂同时施用、或在其之前或之后施用。本发明化合物可以通过与其他药剂相同或不同的施用途径分开施用,或在相同的药物组合物中一起施用。治疗剂是例如化学化合物、肽、抗体、抗体片段或核酸,当将所述治疗剂与本发明的化合物组合施用患者时,所述治疗剂具有治疗活性或增强治疗活性。
在一个实施例中,本发明提供了一种药物组合物,所述药物组合物包含具有式(1)或其子式的化合物和一种或多种第二治疗剂。所述第二药剂可以是一种或多种另外的软骨细胞分化剂。软骨细胞分化剂的实例包括但不限于血管生成素样3蛋白(ANGPTL3)、胰岛素生长因子(IGF1)、SM04690(Wnt抑制剂)、Janus激酶抑制剂(如鲁索替尼(ruxolitinib)、托法替尼(tofacitinib)、巴瑞替尼(baricitinib))、口服鲑鱼降钙素、SD-6010(iNOS抑制剂)、维生素D3(胆钙化醇)、胶原蛋白水解物、骨形态发生蛋白7(BMP7)、醋酸卢沙拉肽、鳄梨大豆非皂化物(ASU)、类固醇、非甾体抗炎药(NSAID)、或透明质酸、kartogenin、TPX-100、以及具有如WO 2015/175487中所述的式(I)或其子式的软骨细胞分化剂。化合物式(1)或其子式和另一种治疗剂可以在同一药物组合物中一起提供,或以分开的形式例如以试剂盒的形式提供,用于同时、分开或顺序地在治疗中使用。在一个实施例中,所述疗法是治疗由关节损伤或关节炎引起的关节损害。
任选地,所述药物组合物可以包含如上所述的药学上可接受的载体。对于约50-70kg的受试者,本发明的药物组合物或组合可以处于单位剂量为约1-1000mg一种或多种活性成分,或约1-500mg或约1-250mg或约1-150mg或约0.5-100mg,或约1-50mg的活性成分。化合物、药物组合物、或其组合的治疗有效剂量取决于受试者的物种、体重、年龄和所治疗的个体病症、障碍或疾病或其严重程度。具有普通技能的医师、临床医生或兽医可以容易地确定预防、治疗或抑制障碍或疾病进展所必需的每种活性成分的有效量。
使用有利的哺乳动物(例如,小鼠、大鼠、狗、猴)或其分离的器官、组织和制品在体外和体内测试中证明上述剂量特性。本发明化合物可以以溶液(例如水溶液)的形式体外应用,和例如以混悬剂或以水溶液的形式肠内、肠胃外(有利地,静脉内)体内应用。
在一个实施例中,本发明提供了一种试剂盒,所述试剂盒包含两种或更多种分开的药物组合物,其中至少一种药物组合物含有具有式(1)或其子式的化合物。在一个实施例中,所述试剂盒包含用于分别保留所述组合物的装置(例如容器、分开的瓶子、或分开的箔包)。这种试剂盒的实例是泡罩包装,如典型地用于片剂、胶囊及类似物的包装。
本发明的试剂盒可以用于施用不同剂型(例如,口服和肠胃外),用于以不同剂量间隔施用单独组合物或用于相对在彼此滴定单独组合物。为了有助于依从性,本发明的试剂盒典型地包含用于施用的用法说明书。
在本发明的组合疗法中,本发明的化合物和其他治疗剂可以由相同或不同的制造商制造和/或配制。此外,可以以下述方式将本发明化合物和其他治疗剂一起形成组合疗法:(i)在将组合产品发放给医师之前(例如在包含本发明化合物和其他治疗剂的试剂盒的情况下)进行;(ii)在施用前不久,由医师自己(或在医师的指导下)进行;(iii)由患者自己、例如在依次施用本发明的化合物和其他治疗剂期间进行。
实例
温度以摄氏度给出。终产物、中间体和起始物质的结构通过标准分析方法(例如,微量分析和光谱特征(例如,MS、IR、NMR))确认。使用的缩写是本领域常规的缩写。
用于合成本发明的化合物的所有起始材料、结构单元、试剂、酸、碱、脱水剂、溶剂和催化剂是可商购获得的或可通过本领域普通技术人员已知的有机合成方法生产(Houben-Weyl第4版1952,Methods of Organic Synthesis[有机合成方法],Thieme[蒂梅出版社],第21卷)。除非另有说明,起始材料通常可从商业来源获得,例如但不限于TCI精细化学品公司(TCI Fine Chemicals)(日本)、奥罗拉精细化学品公司(Aurora FineChemicals LLC)(圣地亚哥,加利福尼亚州)、FCH集团(FCH Group)(乌克兰)、奥德里奇化学公司(Aldrich Chemicals Co.)(密尔沃基,威斯康星州)、阿克洛斯有机公司(AcrosOrganics)(费尔劳恩,新泽西州)、美桥化工有限公司(Maybridge Chemical Company,Ltd.)(康沃尔,英格兰)、美奇丝科学公司(Matrix Scientific)(美国)、安娜敏公司(Enamine Ltd)(乌克兰)、Combi-Blocks公司(Combi-Blocks,Inc.)(圣地亚哥,美国)、奥克伍德公司(Oakwood Products,Inc.)(美国)、阿波罗科学公司(Apollo Scientific Ltd.)(英国)。
以下实例仅是说明本发明并且不限制另外要求保护的本发明的范围。此外,本发明的化合物可以通过本领域普通技术人员已知的有机合成方法生产,如以下实例所示。在需要时,可以根据标准实践,使用常规保护基来保护反应性官能团,例如,参见T.W.Greene和P.G.M.Wuts,“Protective Groups in Organic Chemistry[有机化学中的保护基]”,John Wiley and Sons[约翰·威利父子公司],1991。
缩写
如本文所用的缩写定义如下:“1x”表示一次,“2x”表示两次,“3x”表示三次,“℃”表示摄氏度,“aq”表示水性,“FCC”表示快速柱色谱法,“eq”表示当量(equivalent或equivalents),“g”表示克(gram或grams),“mg”表示毫克(milligram或milligrams),“L”表示升(liter或liters),“mL”表示毫升(milliliter或milliliters),“μL”表示微升(microliter或microliters),“N”表示正常,“M”表示摩尔,“nM”表示纳摩尔,“mol”表示摩尔(mole或moles),“mmol”表示毫摩尔(millimole或millimoles),“min”表示分钟(minute或minutes),“h”或“hrs”表示小时(hour或hours),“RT”表示室温,“ON”表示过夜,“atm”表示大气压,“psi”表示每平方英寸磅数,“conc.”表示浓度,“sat”或“sat'd”表示饱和的,“MW”表示分子量,“mw”或“μwave”表示微波,“mp”表示熔点,“Wt”表示重量,“MS”或“MassSpec”表示质谱分析法,“ESI”表示电喷雾电离质谱,“HR”表示高分辨率,“HRMS”表示高分辨质谱法,“LCMS”或“LC-MS”表示液相色谱质谱,“HPLC”表示高压液相色谱,“RP HPLC”表示反相HPLC,“TLC”或“tlc”表示薄层色谱,“NMR”表示核磁共振光谱,“nOe”表示核欧沃豪斯效应谱,“1H”表示质子,“δ”表示δ(delta),“s”表示单峰,“d”表示双重峰,“t”表示三重峰,“q”表示四重峰,“m”表示多重峰,“br”表示宽峰,“Hz”表示赫兹,“ee”表示“对映异构体过量”,并且“α”、“β”、“R”、“r”、“S”、“s”、“E”、和“Z”是本领域技术人员熟悉的立体化学指定。
本文使用的以下缩写具有对应的含义:
Δ 加热
AcOH 乙酸
AgNO3 硝酸银
app 明显的
ATP 5'-三磷酸腺苷
BINAP 外消旋2,2'-双(二苯基膦基)-1,1'-联萘
BOC 叔丁基羧基
BSA 牛血清白蛋白
CDCl3 氯仿-d
CO2 二氧化碳
dd 双二重峰
DCM 二氯甲烷
DMEM 杜尔贝科改良伊格尔培养基
DMSO 二甲亚砜
EDTA 乙二胺四乙酸
ESI 电喷雾电离
EtOAc 乙酸乙酯
EtOH 乙醇
FBS 胎牛血清
K2CO3 碳酸钾
LiHMDS 双(三甲基甲硅烷基)酰胺锂
Me3Al 三甲基铝
MeOH 甲醇
MgSO4 硫酸镁
MHz 兆赫
m/z 质荷比
NaHCO3 碳酸氢钠
Na2SO4 硫酸钠
NBS N-溴代琥珀酰亚胺
NH4Cl 氯化铵
PBS 磷酸盐缓冲盐水
PE 石油醚
ppm 百万分率
rac 外消旋的
Rt 保留时间
SFC 超临界流体色谱法
TBAF 四丁基氟化铵
TFA 三氟乙酸
THF 四氢呋喃
Tris·HCl 氨基三(羟基甲基)甲烷盐酸盐
UV 紫外线
已经使用本文披露的方法制备、分离和表征了以下实例。下列实例说明了本披露的部分范围,并不意味着限制本披露的范围。
除非另有说明,起始材料通常可从非排他性商业来源获得,例如但不限于TCI精细化学品公司(TCI Fine Chemicals)(日本)、奥罗拉精细化学品公司(Aurora FineChemicals LLC)(圣地亚哥,加利福尼亚州)、FCH集团(FCH Group)(乌克兰)、奥德里奇化学公司(Aldrich Chemicals Co.)(密尔沃基,威斯康星州)、阿克洛斯有机公司(AcrosOrganics)(费尔劳恩,新泽西州)、美桥化工有限公司(Maybridge Chemical Company,Ltd.)(康沃尔,英格兰)、美奇丝科学公司(Matrix Scientific)(美国)、安娜敏公司(Enamine Ltd)(乌克兰)、Combi-Blocks公司(Combi-Blocks,Inc.)(圣地亚哥,美国)、奥克伍德公司(Oakwood Products,Inc.)(美国)、阿波罗科学公司(Apollo Scientific Ltd.)(英国)。
实例的表征中使用的LCMS方法
在使用ChemStation软件的Agilent***上和Waters Acquity UPLC仪器上进行分析型LC/MS。Agilent***由以下组成:
·Agilent G1312二元泵
·Agilent G1367孔板自动进样器
·Agilent G1316恒温柱温箱
·Agilent G1315二极管阵列检测器
·Agilent 6140/6150质谱仪
·SOFTA蒸发光散射检测器
典型的方法条件如下:
·流速:0.9mL/min
·柱:1.8μm 2.1x50 mm Waters Acquity HSS T3 C18柱
·流动相A:水+0.05%TFA
·流动相B:乙腈+0.035%TFA
·运行时间:2.25分钟
·方法A:***在1.35分钟内运行从10%B到90%B的梯度。所述梯度后,在100%B下进行0.6分钟的洗涤。所述方法的剩余持续时间将***恢复到初始条件。除非另有说明,否则提供的实例使用方法A进行表征。
所述***Waters***由以下组成:
·带有脱气器的Acquity二元梯度管理器
·Acquity FTN样品管理器
·设定为50℃的Acquity柱管理器
·Acquity光二极管阵列检测器(PDA)
·Acquity蒸发光散射检测器(ELSD)
·Acquity QDa质谱仪
典型的方法条件如下:
·流速:1.0mL/min
·柱:1.8μm 2.1x30 mm Waters Acquity HSS T3 C18
·流动相A:水+0.1%甲酸
·流动相B:乙腈+0.1%甲酸
·运行时间:2.5分钟
·方法B:***在1.9分钟内运行从5%B到100%B的梯度。所述梯度后,在100%B下进行0.4分钟的洗涤。所述方法的剩余持续时间将***恢复到初始条件。
·方法C:***在0.7分钟内运行从5%B到100%B的梯度。所述梯度后,在100%B下进行0.3分钟的洗涤。所述方法的剩余持续时间将***恢复到初始条件。
实例的表征中使用的NMR方法
除非另有说明,否则质子光谱是在带有5mm QNP低温探头的Bruker AVANCE II400MHz或带有5mm QNP探头的Bruker AVANCE III 500MHz上记录的。化学位移以相对于二甲亚砜(δ2.50)、氯仿(δ7.26)、甲醇(δ3.34)、二氯甲烷(δ5.32)、丙酮(δ2.05)或乙腈(δ1.94)的ppm报告。将少量干燥样品(2-5mg)溶于适当的氘代溶剂(0.6mL)中。
实例的纯化中使用的ISCO方法
ISCO快速色谱是在装有预填的二氧化硅柱的Teledyne***上进行的。
实例的纯化中使用的手性制备型HPLC方法
SFC手性筛选在与Waters ZQ质谱仪连接的Thar仪器制备型观察仪(TharInstruments Prep Investigator)***上进行。Thar制备型观察仪***由以下组成:
·Leap HTC PAL自动进样器
·Thar流体递送模块(0至10mL/min)
·Thar SFC 10位柱箱
·Waters 2996PDA
·Jasco CD-2095手性检测器
·Thar自动背压调节器
所有的Thar组件都是SuperPure Discovery系列产品线的一部分。所述***以2mL/min(对于WhelkO-1柱,为4mL/min)流动,并保持在30摄氏度。***背压设置为125巴。通过具有十一个3μm柱的组对每个样品进行筛选:
·3μm 4.6x50 mm ChiralPak AD
·3μm 4.6x50 mm ChiralPak OD
·3μm 4.6x50 mm Chiralcel OJ
·3μm 4.6x50 mm ChiralPak IA
·3μm 4.6x50 mm ChiralPak IB
·3μm 4.6x50 mm ChiralPak IC
·3μm 4.6x50 mm ChiralPak IF
·3μm 4.6x50 mm ChiralPak IG
·3μm 4.6x250 mm Whelk O-1
·3μm 4.6x50 mm ChiralPak AS
·3μm 4.6x50 mm Lux-Cellulose-2
所述***在5分钟内运行从5%助溶剂到50%助溶剂的梯度,然后在50%助溶剂下保持0.5分钟,切换回5%助溶剂并在初始条件下保持0.25分钟。在每个梯度之间有4分钟的平衡方法,使5%助溶剂流过下一个有待筛选的柱。筛选的典型溶剂为MeOH、MeOH+20mMNH3、MeOH+0.5%DEA、IPA和IPA+20mM NH3。
一旦使用这些梯度方法之一检测到分离,就可以开发出等度方法,并在必要时扩大规模,以在Thar Prep80***上进行纯化。
中间体
中间体1b:甲基3-溴-7-氧杂双环[2.2.1]庚-2,5-二烯-2-甲酸酯
步骤A:向丙炔酸甲酯(1a,200g,2.38mol,198mL)在丙酮(2.50L)中的搅拌溶液中添加AgNO3(36.4g,214mmol,36.0mL)。5min后,分批添加NBS(445g,2.50mol),并将反应混合物在25℃搅拌12h。将反应混合物过滤,将滤液浓缩,并将残余物用10%EtOAc/PE(1500mL)研磨,并将滤液再次浓缩。通过柱色谱法(0-5%EtOAc/PE)纯化残余物,以给出呈黄色油状物的3-溴丙炔酸甲酯,将其直接用于下一步。
在0℃下,通过使氮气穿过反应容器2min来使3-溴丙炔酸甲酯(200g,1.23mol)和呋喃(419g,6.15mol,445mL)在甲苯(2.50L)中的溶液脱气,然后将反应混合物温热至90℃保持72小时以给出黑色溶液。将反应混合物浓缩,并将残余物通过快速柱色谱法(2%-5%EtOAc/PE)纯化,以给出甲基3-溴-7-氧杂双环[2.2.1]庚-2,5-二烯-2-甲酸酯。分别纯化四批料并合并以得到呈黄色油状物的甲基3-溴-7-氧杂双环[2.2.1]庚-2,5-二烯-2-甲酸酯(1b)。1H NMR(400MHz,CDCl3)δ7.25-7.17(m,2H),5.70(t,J=1.6Hz,1H),5.33(t,J=1.7Hz,1H),3.82-3.75(m,3H)。
中间体1c:甲基(1R,4S,5S)-3-溴-5-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯
步骤B:将甲基3-溴-7-氧杂双环[2.2.1]庚-2,5-二烯-2-甲酸酯(1b,130g,563mmol,1.00eq)在THF(800mL)中的溶液用BH3-THF(1M,563mL,563mmol)处理并在0℃下搅拌2hr。逐滴添加磷酸盐缓冲液pH=7(1000mL)的溶液,然后缓慢添加H2O2(270mL,2.81mol,30%v/v)和NaOH(2M,338mL,676mmol)的混合物并且将混合物在0℃下搅拌2hr。将反应混合物用乙酸乙酯(500mL 3x)萃取,并将合并的有机层用饱和水性NaHSO3溶液(500mL 2x)、盐水(500mL)洗涤,干燥(Na2SO4)并浓缩。将残余物通过柱色谱法(2-50%EtOAc/PE)纯化以给出所希望的产物。合并两批料并小心地通过FCC再纯化,以得到呈醇位置异构体的3:1混合物的1c,顺利得到呈黄色固体的5-羟基产物。将产物从EtOAc/庚烷中重结晶以得到作为醇位置异构体的12:1混合物的呈白色固体的中间体1c。1H NMR(400MHz,CDCl3)δ5.25-5.02(m,1H),4.94-4.74(m,1H),4.23-4.14(m,1H),3.80-3.78(m,3H),2.14-2.01(m,1H),1.91-1.81(m,1H),1.69-1.60(m,1H)。
中间体1d:甲基(1R,4S,5S)-3-溴-5-((叔丁基二甲基甲硅烷基)氧基)-7-氧杂双
环[2.2.1]庚-2-烯-2-甲酸酯
步骤C:在-78℃,将中间体1c(29.8g,120mmol)和三乙胺(50.1ml,359mmol)在无水THF(265ml)中的溶液用叔丁基二甲基甲硅烷基三氟甲磺酸(33.0ml,144mmol)逐滴处理。将反应混合物在该温度搅拌20min,然后允许反应混合物缓慢温热至室温并且搅拌1h。将反应混合物用Et2O稀释,用1.0M HCl和盐水洗涤,干燥(Na2SO4),过滤,并浓缩以得到无色油状物。将残余物从EtOH和水中重结晶并且在真空下干燥以得到中间体1d。1H NMR(400MHz,CDCl3)δ5.08(dd,J=4.4,1.3Hz,1H),4.54(d,J=1.3Hz,1H),4.04(dd,J=6.6,2.3Hz,1H),3.66(s,3H),1.88(dd,J=12.0,6.6Hz,1H),1.54(ddd,J=12.0,4.4,2.3Hz,1H),0.79(s,9H),-0.01(d,J=4.2Hz,6H)。
实例
实例1:外消旋-(1R,2R,4S,5R,6S)-4-(2-氟吡啶-4-基)-6-羟基-N-(4-(三氟甲
基)吡啶-2-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
使用方案1中的步骤D-F,从甲基(1R,4S,5S)-3-溴-5-((叔丁基二甲基甲硅烷基)氧基)-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯(中间体1d)制备标题化合物。
步骤D:将甲基(1R,4S,5S)-3-溴-5-((叔丁基二甲基甲硅烷基)氧基)-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯(1d,4g,11.0mmol)、(2-氟吡啶-4-基)硼酸(1.71g,12.1mmol)、Na2CO3(8.26ml,16.5mmol)、和四(三苯基膦)钯(0.636g,0.550mmol)在1,4-二噁烷(55ml)中的溶液用氮气吹扫并且在回流下温热2h。将反应混合物冷却至RT,用EtOAc稀释,用水和盐水洗涤,干燥(Na2SO4),过滤,并浓缩。将所得残余物通过FCC(0-60%EtOAc/庚烷)纯化,以得到甲基(1R,4R,5S)-5-((叔丁基二甲基甲硅烷基)氧基)-3-(2-氟吡啶-4-基)-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯。LC-MS:Rt=1.84min;MS m/z[M+H]+380.3。
步骤E:将三甲基碘化亚砜(1390mg,6.31mmol)在DMSO(21mL)中的溶液用NaH(252mg,6.31mmol)处理并且在室温搅拌30min。逐滴添加在DMSO(21mL)中的甲基(1R,4R,5S)-5-((叔丁基二甲基甲硅烷基)氧基)-3-(2-氟吡啶-4-基)-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯(798mg,2.10mmol)并且将所得混合物在50℃温热5min。将反应混合物用EtOAc稀释,用水(3x)和盐水洗涤,干燥(Na2SO4),过滤,并浓缩。将所得残余物通过FCC(0-100%EtOAc/庚烷)纯化,以得到甲基(1R,2R,4S,5R,6S)-6-((叔丁基二甲基甲硅烷基)氧基)-4-(2-氟吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酸酯。方法B:LC-MS:Rt=0.78min;MS m/z[M+H]+394.2。
步骤F:在RT,将甲基(1R,2R,4S,5R,6S)-6-((叔丁基二甲基甲硅烷基)氧基)-4-(2-氟吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酸酯(15mg,0.038mmol)和4-(三氟甲基)吡啶-2-胺(6.8mg,0.042mmol)在THF(0.4mL)中的溶液用在THF中的1M LiHMDS(76μl,0.076mmol)处理并且在RT搅拌14h。添加在THF中的1M TBAF(95μl,0.095mmol)并且将反应在60℃温热2h。将反应混合物冷却至RT并且加载到柱上并且直接通过FCC(0-100%EtOAc/庚烷)纯化,以得到外消旋-(1R,2R,4S,5R,6S)-4-(2-氟吡啶-4-基)-6-羟基-N-(4-(三氟甲基)吡啶-2-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺。LC-MS:Rt=1.29min;MS m/z[M+H]+410.2。1H NMR(400MHz,乙腈-d3)δ8.81(s,1H),8.54-8.48(m,1H),8.37-8.33(m,1H),8.12-8.06(m,1H),7.40-7.35(m,1H),7.13-7.07(m,1H),6.95-6.91(m,1H),4.74(d,J=4.9Hz,1H),4.39(s,1H),4.31-4.25(m,1H),3.11-3.00(m,1H),2.84-2.76(m,1H),1.95-1.92(m,1H),1.62-1.56(m,1H),1.39-1.35(m,1H)。
根据实例1所述的方案,使用甲基(1R,4S,5S)-3-溴-5-((叔丁基二甲基甲硅烷基)氧基)-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯(中间体1d)和步骤D中的各种硼酸/酯以及步骤F中的各种苯胺,合成下文描述的实例2-82。
实例2:外消旋-(1R,2R,4S,5R,6S)-N-(3-氟-4-(三氟甲基)苯基)-4-(2-氟吡啶-
4-基)-6-羟基-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.42min;MS m/z[M+H]+427.2。1H NMR(400MHz,乙腈-d3)δ8.63(s,1H),8.10-8.07(m,1H),7.75-7.69(m,1H),7.64-7.58(m,1H),7.43-7.39(m,1H),7.09-7.06(m,1H),6.91-6.89(m,1H),4.70(d,J=4.8Hz,1H),4.39(s,1H),4.28-4.22(m,1H),3.07-3.03(m,1H),2.85-2.79(m,1H),1.93-1.91(m,3H),1.61-1.54(m,1H),1.36-1.32(m,1H)。
实例3:外消旋-(1R,2R,4S,5R,6S)-N-(3-氯-4-(三氟甲基)苯基)-4-(2-氟吡啶-
4-基)-6-羟基-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.48min;MS m/z[M+H]+443.1。1H NMR(400MHz,乙腈-d3)δ8.58(s,1H),8.11-8.08(m,1H),7.93-7.89(m,1H),7.73-7.68(m,1H),7.63-7.58(m,1H),7.10-7.07(m,1H),6.93-6.89(m,1H),4.70(d,J=4.8Hz,1H),4.38(s,1H),4.28-4.22(m,1H),3.07-3.03(m,1H),2.85-2.79(m,1H),1.93-1.91(m,1H),1.61-1.55(m,1H),1.36-1.32(m,1H)。
实例4:外消旋-(1R,2R,4S,5R,6S)-N-(6-氯-4-(三氟甲基)吡啶-2-基)-4-(2-氟
吡啶-4-基)-6-羟基-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.46min;MS m/z[M+H]+444.2。1H NMR(400MHz,乙腈-d3)δ8.93(s,1H),8.31-8.28(m,1H),8.11-8.08(m,1H),7.46-7.44(m,1H),7.10-7.07(m,1H),6.93-6.90(m,1H),4.74(d,J=4.8Hz,1H),4.38(s,1H),4.29-4.24(m,1H),3.08-3.05(m,1H),2.80-2.73(m,1H),1.97-1.95(m,1H),1.62-1.56(m,1H),1.39-1.36(m,1H)。
实例5:外消旋-(1R,2R,4S,5R,6S)-N-(5-氯-4-(三氟甲基)吡啶-2-基)-4-(2-氟
吡啶-4-基)-6-羟基-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.42min;MS m/z[M+H]+444.2。1H NMR(400MHz,乙腈-d3)δ8.90(s,1H),8.52-8.45(m,2H),8.11-8.07(m,1H),7.10-7.07(m,1H),6.94-6.90(m,1H),4.74(d,J=4.9Hz,1H),4.39(s,1H),4.29-4.24(m,1H),3.10-3.02(m,1H),2.81-2.74(m,1H),1.97-1.92(m,1H),1.62-1.55(m,1H),1.39-1.36(m,1H)。
实例6:外消旋-(1R,2R,4S,5R,6S)-N-(6-环丙基-4-(三氟甲基)吡啶-2-基)-4-
(2-氟吡啶-4-基)-6-羟基-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.51min;MS m/z[M+H]+450.2。1H NMR(400MHz,乙腈-d3)δ8.61(s,1H),8.11-8.07(m,1H),8.05-8.02(m,1H),7.29-7.25(m,1H),7.12-7.08(m,1H),6.94-6.89(m,1H),4.71(d,J=4.9Hz,1H),4.37(s,1H),4.29-4.23(m,1H),3.07-3.02(m,1H),2.82-2.75(m,1H),2.12-2.07(m,1H),1.97-1.92(m,1H),1.61-1.55(m,1H),1.35-1.32(m,1H),1.02-0.96(m,4H)。
实例7:外消旋-(1R,2R,4S,5R,6S)-4-(2-氟吡啶-4-基)-6-羟基-N-(6-甲基-4-
(三氟甲基)吡啶-2-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.38min;MS m/z[M+H]+424.2。1H NMR(400MHz,乙腈-d3)δ8.71(s,1H),8.16-8.12(m,1H),8.11-8.06(m,1H),7.27-7.24(m,1H),7.12-7.08(m,1H),6.94-6.90(m,1H),4.73(d,J=4.8Hz,1H),4.38(s,1H),4.30-4.24(m,1H),3.09-3.05(m,1H),2.83-2.76(m,1H),2.50(s,3H),1.96-1.92(m,8H),1.63-1.55(m,1H),1.38-1.33(m,1H)。
实例8:外消旋-(1R,2R,4S,5R,6S)-N-(6-乙氧基-4-(三氟甲基)吡啶-2-基)-4-
(2-氟吡啶-4-基)-6-羟基-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.52min;MS m/z[M+H]+454.2。1H NMR(400MHz,乙腈-d3)δ8.68(s,1H),8.11-8.07(m,1H),7.88-7.84(m,1H),7.12-7.08(m,1H),6.94-6.91(m,1H),6.76-6.73(m,1H),4.73(d,J=4.8Hz,1H),4.38(s,1H),4.34(q,J=7.1Hz,2H),4.29-4.23(m,1H),3.08-3.03(m,1H),2.82-2.75(m,1H),1.95-1.92(m,1H),1.62-1.55(m,1H),1.37-1.33(m,4H)。
实例9:外消旋-(1R,2R,4S,5R,6S)-4-(2-氟吡啶-4-基)-6-羟基-N-(3-(三氟甲
基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法C:LC-MS:Rt=0.56min;MS m/z[M+H]+409.1。1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.16-8.09(m,1H),8.04-7.99(m,1H),7.90-7.83(m,1H),7.60-7.51(m,1H),7.46-7.40(m,1H),7.14-7.09(m,1H),7.04-6.99(m,1H),5.03-4.97(m,1H),4.75-4.70(m,1H),4.42(s,1H),4.16-4.08(m,1H),2.76-2.68(m,1H),1.85-1.79(m,1H),1.50-1.43(m,2H)。
实例10:外消旋-(1R,2R,4S,5R,6S)-4-(2-氟吡啶-4-基)-6-羟基-N-(2-甲基-3-
(三氟甲基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.35min;MS m/z[M+H]+423.2。1H NMR(400MHz,乙腈-d3)δ8.14-8.11(m,1H),7.95(s,1H),7.60-7.52(m,2H),7.39-7.33(m,1H),7.19-7.15(m,1H),6.99-6.96(m,1H),4.72(d,J=4.9Hz,1H),4.36(s,1H),4.32-4.26(m,1H),3.04-3.00(m,1H),2.93-2.84(m,1H),2.28(s,3H),1.96-1.91(m,1H),1.65-1.59(m,1H),1.34-1.30(m,1H)。
实例11:外消旋-(1R,2R,4S,5R,6S)-4-(2-氟吡啶-4-基)-6-羟基-N-(4-甲基-3-
(三氟甲基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.43min;MS m/z[M+H]+423.2。1H NMR(400MHz,乙腈-d3)δ8.37(s,1H),8.10-8.07(m,1H),7.88-7.85(m,1H),7.66-7.61(m,1H),7.34-7.29(m,1H),7.12-7.07(m,1H),6.92-6.89(m,1H),4.68(d,J=4.8Hz,1H),4.38(s,1H),4.27-4.21(m,1H),3.06-3.01(m,1H),2.91-2.83(m,1H),2.42(s,3H),1.91-1.88(m,1H),1.60-1.54(m,1H),1.33-1.30(m,1H)。
实例12:外消旋-(1R,2R,4S,5R,6S)-4-(2-氟吡啶-4-基)-6-羟基-N-(3-甲基-5-
(三氟甲基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.44min;MS m/z[M+H]+423.2。1H NMR(400MHz,乙腈-d3)δ8.40(s,1H),8.11-8.06(m,1H),7.76-7.71(m,1H),7.59-7.54(m,1H),7.28-7.23(m,1H),7.12-7.08(m,1H),6.93-6.89(m,1H),4.68(d,J=4.9Hz,1H),4.38(s,1H),4.28-4.22(m,1H),3.06-3.02(m,1H),2.91-2.82(m,1H),2.38(s,3H),1.92-1.89(m,1H),1.60-1.53(m,1H),1.34-1.31(m,1H)。
实例13:外消旋-(1R,2R,4S,5R,6S)-4-(2-氟吡啶-4-基)-6-羟基-N-(2-甲基-5-
(三氟甲基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.37min;MS m/z[M+H]+423.2。1H NMR(400MHz,乙腈-d3)δ8.14-8.09(m,1H),7.88(s,1H),7.80-7.76(m,1H),7.46-7.39(m,2H),7.19-7.15(m,1H),6.98-6.95(m,1H),4.72(d,J=4.9Hz,1H),4.36(s,1H),4.32-4.24(m,1H),3.05-3.00(m,1H),2.93-2.85(m,1H),2.25(s,3H),1.93-1.92(m,1H),1.65-1.58(m,1H),1.34-1.31(m,1H)。
实例14:外消旋-(1R,2R,4S,5R,6S)-N-(2-氟-3-(三氟甲基)苯基)-4-(2-氟吡啶-
4-基)-6-羟基-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.34min;MS m/z[M+H]+427.2。1H NMR(400MHz,乙腈-d3)δ8.15-8.07(m,2H),8.04-7.99(m,1H),7.52-7.46(m,1H),7.35-7.28(m,1H),7.16-7.13(m,1H),6.95-6.93(m,1H),4.71(d,J=4.8Hz,1H),4.38(s,1H),4.29-4.24(m,1H),3.06-3.01(m,1H),2.89-2.80(m,1H),1.95-1.92(m,1H),1.63-1.57(m,1H),1.35-1.33(m,1H)。
实例15:外消旋-(1R,2R,4S,5R,6S)-N-(4-氟-3-(三氟甲基)苯基)-4-(2-氟吡啶-
4-基)-6-羟基-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.41min;MS m/z[M+H]+427.2。1H NMR(400MHz,乙腈-d3)δ8.45(s,1H),8.11-8.07(m,1H),7.95-7.91(m,1H),7.78-7.73(m,1H),7.31-7.24(m,1H),7.12-7.08(m,1H),6.93-6.90(m,1H),4.68(d,J=4.9Hz,1H),4.37(s,1H),4.27-4.21(m,1H),3.06-3.01(m,1H),2.90-2.82(m,1H),1.92-1.89(m,1H),1.61-1.54(m,1H),1.33-1.31(m,1H)。
实例16:外消旋-(1R,2R,4S,5R,6S)-N-(3-氟-5-(三氟甲基)苯基)-4-(2-氟吡啶-
4-基)-6-羟基-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.44min;MS m/z[M+H]+427.2。1H NMR(400MHz,乙腈-d3)δ8.58(s,1H),8.12-8.07(m,1H),7.75-7.64(m,2H),7.22-7.17(m,1H),7.11-7.07(m,1H),6.94-6.90(m,1H),4.70(d,J=4.9Hz,1H),4.38(s,1H),4.28-4.22(m,1H),3.07-3.02(m,1H),2.87-2.80(m,1H),1.93-1.91(m,1H),1.61-1.55(m,1H),1.35-1.32(m,1H)。
实例17:外消旋-(1R,2R,4S,5R,6S)-N-(2-氟-5-(三氟甲基)苯基)-4-(2-氟吡啶-
4-基)-6-羟基-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.34min;MS m/z[M+H]+427.2。1H NMR(400MHz,乙腈-d3)δ8.21-8.16(m,1H),8.15-8.08(m,2H),7.54-7.49(m,1H),7.38-7.31(m,1H),7.17-7.12(m,1H),6.96-6.92(m,1H),4.71(d,J=4.8Hz,1H),4.38(s,1H),4.30-4.24(m,1H),3.06-3.02(m,1H),2.88-2.79(m,1H),1.96-1.92(m,1H),1.63-1.56(m,1H),1.36-1.32(m,1H)。
实例18:外消旋-(1R,2R,4S,5R,6S)-N-(4-氯-3-(三氟甲基)苯基)-4-(2-氟吡啶-
4-基)-6-羟基-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.45min;MS m/z[M+H]+443.1。1H NMR(400MHz,乙腈-d3)δ8.51(s,1H),8.11-8.07(m,1H),8.06-8.03(m,1H),7.78-7.73(m,1H),7.55-7.50(m,1H),7.11-7.06(m,1H),6.93-6.89(m,1H),4.69(d,J=4.9Hz,1H),4.38(s,1H),4.28-4.21(m,1H),3.06-3.02(m,1H),2.88-2.81(m,1H),1.92-1.90(m,1H),1.61-1.55(m,1H),1.34-1.31(m,1H)。
实例19:外消旋-(1R,2R,4S,5R,6S)-N-(3-氯-5-(三氟甲基)苯基)-4-(2-氟吡啶-
4-基)-6-羟基-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.49min;MS m/z[M+H]+443.1。1H NMR(400MHz,乙腈-d3)δ8.54(s,1H),8.11-8.08(m,1H),7.89-7.86(m,1H),7.84-7.81(m,1H),7.47-7.44(m,1H),7.11-7.08(m,1H),6.93-6.90(m,1H),4.69(d,J=4.8Hz,1H),4.38(s,1H),4.27-4.22(m,1H),3.07-3.03(m,1H),2.87-2.80(m,1H),1.93-1.91(m,1H),1.61-1.55(m,1H),1.35-1.32(m,1H)。
实例20:外消旋-(1R,2R,4S,5R,6S)-6-羟基-4-(2-甲氧基吡啶-4-基)-N-(4-(三
氟甲基)吡啶-2-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=0.90min;MS m/z[M+H]+422.3。1H NMR(400MHz,乙腈-d3)δ8.61(s,1H),8.52-8.46(m,1H),8.37-8.32(m,1H),8.06-8.00(m,1H),7.39-7.33(m,1H),6.80-6.73(m,1H),6.69-6.65(m,1H),4.73-4.68(m,1H),4.33(s,1H),4.32-4.24(m,1H),3.88-3.83(m,3H),3.31-2.99(m,1H),2.87-2.78(m,1H),1.91-1.87(m,1H),1.63-1.53(m,1H),1.36-1.31(m,1H)。
实例21:外消旋-(1R,2R,4S,5R,6S)-N-(6-氯-4-(三氟甲基)吡啶-2-基)-6-羟基-
4-(2-甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.14min;MS m/z[M+H]+456.1。1H NMR(400MHz,乙腈-d3)δ8.72(s,1H),8.32-8.27(m,1H),8.05-8.00(m,1H),7.46-7.41(m,1H),6.77-6.71(m,1H),6.68-6.63(m,1H),4.73-4.67(m,1H),4.33(s,1H),4.31-4.23(m,1H),3.88-3.84(m,3H),3.34-2.99(m,1H),2.82-2.75(m,1H),1.91-1.86(m,1H),1.62-1.53(m,1H),1.37-1.32(m,1H)。
实例22:外消旋-(1R,2R,4S,5R,6S)-N-(5-氯-4-(三氟甲基)吡啶-2-基)-6-羟基-
4-(2-甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.05min;MS m/z[M+H]+456.1。1H NMR(400MHz,乙腈-d3)δ8.70(s,1H),8.50-8.45(m,2H),8.05-7.99(m,1H),6.77-6.71(m,1H),6.68-6.63(m,1H),4.70(d,J=4.9Hz,1H),4.33(s,1H),4.30-4.24(m,1H),3.86(s,3H),3.07-2.96(m,1H),2.85-2.76(m,1H),1.90-1.87(m,1H),1.62-1.54(m,1H),1.38-1.31(m,1H)。
实例23:外消旋-(1R,2R,4S,5R,6S)-N-(6-环丙基-4-(三氟甲基)吡啶-2-基)-6-
羟基-4-(2-甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.15min;MS m/z[M+H]+462.4。1H NMR(400MHz,乙腈-d3)δ8.39(s,1H),8.06-8.00(m,2H),7.26(s,1H),6.79-6.73(m,1H),6.65(d,J=1.5Hz,1H),4.67(d,J=4.8Hz,1H),4.32(s,1H),4.30-4.23(m,1H),3.86(s,3H),3.31-2.97(m,1H),2.80(dd,J=12.9,7.1Hz,1H),2.12-2.02(m,1H),1.87(d,J=5.0Hz,1H),1.62-1.52(m,1H),1.30(d,J=5.1Hz,1H),1.04-0.90(m,4H)。
实例24:外消旋-(1R,2R,4S,5R,6S)-6-羟基-4-(2-甲氧基吡啶-4-基)-N-(6-甲
基-4-(三氟甲基)吡啶-2-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.00min;MS m/z[M+H]+436.3。1H NMR(400MHz,乙腈-d3)δ8.51(s,1H),8.14(s,1H),8.03(d,J=5.4Hz,1H),7.24(s,1H),6.76(dd,J=5.4,1.6Hz,1H),6.68-6.64(m,1H),4.69(d,J=4.8Hz,1H),4.33(s,1H),4.31-4.23(m,1H),3.85(s,3H),3.31-2.96(m,1H),2.82(dd,J=12.8,7.1Hz,1H),2.48(s,3H),1.88(d,J=5.0Hz,1H),1.62-1.52(m,1H),1.36-1.29(m,1H)。
实例25:外消旋-(1R,2R,4S,5R,6S)-N-(6-乙氧基-4-(三氟甲基)吡啶-2-基)-6-
羟基-4-(2-甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.16min;MS m/z[M+H]+466.3。1H NMR(400MHz,乙腈-d3)δ8.46(s,1H),8.06-8.01(m,1H),7.87-7.83(m,1H),6.79-6.72(m,2H),6.68-6.61(m,1H),4.71-4.66(m,1H),4.36-4.23(m,4H),3.85(s,3H),3.31-2.98(m,1H),2.84-2.76(m,1H),1.92-1.85(m,1H),1.62-1.52(m,1H),1.37-1.29(m,4H)。
实例26:外消旋-(1R,2R,4S,5R,6S)-6-羟基-4-(2-甲氧基吡啶-4-基)-N-(3-(三
氟甲基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.04min;MS m/z[M+H]+421.2。1H NMR(400MHz,乙腈-d3)δ8.33(s,1H),8.06-8.00(m,1H),7.94-7.89(m,1H),7.75-7.67(m,1H),7.55-7.46(m,1H),7.46-7.37(m,1H),6.79-6.73(m,1H),6.67-6.62(m,1H),4.68-4.64(m,1H),4.34(s,1H),4.29-4.21(m,1H),3.85(s,3H),3.31-2.97(m,1H),2.95-2.85(m,1H),1.88-1.82(m,1H),1.60-1.51(m,1H),1.33-1.27(m,1H)。
实例27:外消旋-(1R,2R,4S,5R,6S)-6-羟基-4-(2-甲氧基吡啶-4-基)-N-(2-甲
基-3-(三氟甲基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=0.97min;MS m/z[M+H]+435.3。1H NMR(400MHz,乙腈-d3)δ8.10-8.04(m,1H),7.79(s,1H),7.59-7.51(m,2H),7.39-7.30(m,1H),6.86-6.80(m,1H),6.73-6.68(m,1H),4.71-4.64(m,1H),4.33-4.24(m,2H),3.87(s,3H),3.31-2.95(m,1H),2.94-2.86(m,1H),2.13(s,3H),1.89-1.83(m,1H),1.64-1.55(m,1H),1.30-1.25(m,1H)。
实例28:外消旋-(1R,2R,4S,5R,6S)-6-羟基-4-(2-甲氧基吡啶-4-基)-N-(4-甲
基-3-(三氟甲基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.06min;MS m/z[M+H]+435.3。1H NMR(400MHz,乙腈-d3)δ8.24(s,1H),8.03(d,J=5.4Hz,1H),7.87-7.82(m,1H),7.64-7.57(m,1H),7.31(d,J=8.4Hz,1H),6.79-6.72(m,1H),6.66-6.61(m,1H),4.64(d,J=4.8Hz,1H),4.33(s,1H),4.28-4.20(m,1H),3.85(s,3H),3.31-2.95(m,1H),2.90(dd,J=12.8,7.1Hz,1H),2.46-2.39(m,3H),1.84(d,J=4.9Hz,1H),1.59-1.50(m,1H),1.28(d,J=4.9Hz,1H)。
实例29:外消旋-(1R,2R,4S,5R,6S)-6-羟基-4-(2-甲氧基吡啶-4-基)-N-(3-甲
基-5-(三氟甲基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.13min;MS m/z[M+H]+435.2。1H NMR(400MHz,乙腈-d3)δ8.26(s,1H),8.03(d,J=5.4Hz,1H),7.70(s,1H),7.54(s,1H),7.25(s,1H),6.76(dd,J=5.4,1.5Hz,1H),6.66-6.61(m,1H),4.64(d,J=4.8Hz,1H),4.34(s,1H),4.29-4.20(m,1H),3.85(s,3H),2.99(d,J=5.7Hz,1H),2.93-2.85(m,1H),2.38(s,3H),1.84(d,J=4.9Hz,1H),1.60-1.50(m,1H),1.29(d,J=5.0Hz,1H)。
实例30:外消旋-(1R,2R,4S,5R,6S)-6-羟基-4-(2-甲氧基吡啶-4-基)-N-(2-甲
基-5-(三氟甲基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=0.98min;MS m/z[M+H]+435.3。1H NMR(400MHz,乙腈-d3)δ8.06(d,J=5.3Hz,1H),7.78(s,1H),7.69(s,1H),7.45-7.36(m,2H),6.87-6.81(m,1H),6.72-6.65(m,1H),4.68(d,J=4.8Hz,1H),4.34-4.25(m,2H),3.86(s,3H),3.32-2.95(m,1H),2.91(dd,J=12.8,7.1Hz,1H),2.19(s,3H),1.87(d,J=4.9Hz,1H),1.64-1.54(m,1H),1.28(d,J=5.0Hz,1H)。
实例31:外消旋-(1R,2R,4S,5R,6S)-N-(2-氟-3-(三氟甲基)苯基)-6-羟基-4-(2-
甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=0.97min;MS m/z[M+H]+439.3。1H NMR(400MHz,乙腈-d3)δ8.08-7.83(m,3H),7.52-7.43(m,1H),7.37-7.27(m,1H),6.80(dd,J=5.4,1.5Hz,1H),6.70-6.66(m,1H),4.67(d,J=4.9Hz,1H),4.32(s,1H),4.30-4.24(m,1H),3.86(s,3H),3.33-2.96(m,1H),2.88-2.81(m,1H),1.88(d,J=5.0Hz,1H),1.63-1.53(m,1H),1.29(d,J=5.0Hz,1H)。
实例32:外消旋-(1R,2R,4S,5R,6S)-N-(4-氟-3-(三氟甲基)苯基)-6-羟基-4-(2-
甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.00min;MS m/z[M+H]+439.3。1H NMR(400MHz,乙腈-d3)δ8.31(s,1H),8.06-8.01(m,1H),7.90(dd,J=6.5,2.7Hz,1H),7.76-7.69(m,1H),7.31-7.22(m,1H),6.75(dd,J=5.4,1.6Hz,1H),6.67-6.62(m,1H),4.64(d,J=4.8Hz,1H),4.33(s,1H),4.29-4.20(m,1H),3.85(s,3H),3.31-2.96(m,1H),2.92-2.84(m,1H),1.84(d,J=4.9Hz,1H),1.60-1.51(m,1H),1.28(d,J=4.9Hz,1H)。
实例33:外消旋-(1R,2R,4S,5R,6S)-N-(2-氟-5-(三氟甲基)苯基)-6-羟基-4-(2-
甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.01min;MS m/z[M+H]+439.1。1H NMR(400MHz,乙腈-d3)δ8.22-8.14(m,1H),8.08-8.02(m,1H),7.95(s,1H),7.54-7.46(m,1H),7.38-7.28(m,1H),6.80(dd,J=5.4,1.5Hz,1H),6.70-6.66(m,1H),4.67(d,J=4.8Hz,1H),4.33(s,1H),4.31-4.24(m,1H),3.86(s,3H),3.00(s,1H),2.85(dd,J=12.9,7.1Hz,1H),1.89(d,J=5.0Hz,1H),1.63-1.53(m,1H),1.29(d,J=5.0Hz,1H)。
实例34:外消旋-(1R,2R,4S,5R,6S)-6-羟基-N-(4-甲氧基-3-(三氟甲基)苯基)-
4-(2-甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.00min;MS m/z[M+H]+451.1。1H NMR(400MHz,乙腈-d3)δ8.17-8.12(m,1H),8.05-8.01(m,1H),7.78-7.73(m,1H),7.70-7.63(m,1H),7.15-7.08(m,1H),6.79-6.73(m,1H),6.66-6.61(m,1H),4.65-4.60(m,1H),4.33(s,1H),4.28-4.19(m,1H),3.90-3.83(m,6H),3.30-2.96(m,1H),2.96-2.87(m,1H),1.85-1.79(m,1H),1.59-1.50(m,1H),1.29-1.23(m,1H)。
实例35:外消旋-(1R,2R,4S,5R,6S)-6-羟基-N-(3-甲氧基-5-(三氟甲基)苯基)-
4-(2-甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.09min;MS m/z[M+H]+451.1。1H NMR(400MHz,乙腈-d3)δ8.28(s,1H),8.05-8.01(m,1H),7.49-7.45(m,1H),7.37-7.31(m,1H),7.00-6.93(m,1H),6.75(dd,J=5.4,1.6Hz,1H),6.66-6.61(m,1H),4.67-4.62(m,1H),4.34(s,1H),4.29-4.20(m,1H),3.87-3.79(m,6H),2.89(dd,J=12.8,7.1Hz,1H),2.10(d,J=2.6Hz,1H),1.85(d,J=5.0Hz,1H),1.60-1.50(m,1H),1.29(d,J=5.0Hz,1H)。
实例36:外消旋-(1R,2R,4S,5R,6S)-6-羟基-N-(2-甲氧基-5-(三氟甲基)苯基)-
4-(2-甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.09min;MS m/z[M+H]+451.2。1H NMR(400MHz,乙腈-d3)δ8.47-8.41(m,1H),8.10-8.04(m,1H),7.70-7.66(m,1H),7.43-7.35(m,1H),7.10-7.02(m,1H),6.87-6.79(m,1H),6.72-6.66(m,1H),4.70-4.64(m,1H),4.35-4.27(m,2H),3.87(s,3H),3.77(s,3H),3.31-2.94(m,1H),2.86-2.77(m,1H),1.90(d,J=5.1Hz,1H),1.65-1.56(m,1H),1.27-1.21(m,1H)。
实例37:外消旋-(1R,2R,4S,5R,6S)-N-(3,5-双(三氟甲基)苯基)-6-羟基-4-(2-
甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.24min;MS m/z[M+H]+489.1。1H NMR(400MHz,乙腈-d3)δ8.51(s,1H),8.12(s,2H),8.03(d,J=5.4Hz,1H),7.71(s,1H),6.76(dd,J=5.4,1.5Hz,1H),6.68-6.63(m,1H),4.67(d,J=4.8Hz,1H),4.34(s,1H),4.26(d,J=7.0Hz,1H),3.85(s,3H),2.88(dd,J=12.9,7.1Hz,1H),2.10(d,J=2.2Hz,1H),1.88(d,J=5.0Hz,1H),1.62-1.53(m,1H),1.31(d,J=4.9Hz,1H)。
实例38:外消旋-(1R,2R,4S,5R,6S)-N-(4-氰基-3-(三氟甲基)苯基)-6-羟基-4-
(2-甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.02min;MS m/z[M+H]+446.1。1H NMR(400MHz,乙腈-d3)δ8.61(s,1H),8.15-8.10(m,1H),8.03(d,J=5.4Hz,1H),7.95-7.84(m,2H),6.77-6.70(m,1H),6.66-6.61(m,1H),4.70-4.64(m,1H),4.34(s,1H),4.29-4.21(m,1H),3.85(s,3H),3.31-2.93(m,1H),2.89-2.79(m,1H),1.91-1.85(m,1H),1.62-1.52(m,1H),1.32(d,J=5.0Hz,1H)。
实例39:外消旋-(1R,2R,4S,5R,6S)-N-(2-氰基-5-(三氟甲基)苯基)-6-羟基-4-
(2-甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=0.95min;MS m/z[M+H]+446.1。1H NMR(400MHz,乙腈-d3)δ8.17(s,1H),8.07-8.03(m,2H),7.92-7.87(m,1H),7.64-7.59(m,1H),6.85-6.81(m,1H),6.73-6.69(m,1H),4.73-4.68(m,1H),4.34-4.26(m,2H),3.86(s,3H),3.01-2.97(m,1H),2.93-2.84(m,1H),2.11-2.07(m,1H),1.67-1.59(m,1H),1.33-1.28(m,1H)。
实例39a和39b(对应于峰1和峰2)
(1R,2R,4S,5R,6S)-N-(2-氰基-5-(三氟甲基)苯基)-6-羟基-4-(2-甲氧基吡啶-
4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺或(1S,2S,4R,5S,6R)-N-(2-氰基-5-(三氟
甲基)苯基)-6-羟基-4-(2-甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
使用以下条件通过SFC手性分离外消旋-(1R,2R,4S,5R,6S)-N-(2-氰基-5-(三氟甲基)苯基)-6-羟基-4-(2-甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺得到下文所列出的化合物。
柱:21x250mm Chiralpak IG@35℃
流动相:85%CO2/15%MeOH
检测:UV@214nm
流速:80mL/min
峰1:SFC保留时间=1.20min。方法B:LC-MS:Rt=1.11min;MS m/z[M+H]+464.1。1HNMR(400MHz,乙腈-d3)δ8.17(s,1H),8.07-8.02(m,2H),7.92-7.86(m,1H),7.65-7.59(m,1H),6.86-6.81(m,1H),6.74-6.69(m,1H),4.74-4.68(m,1H),4.33-4.26(m,2H),3.86(s,3H),3.01-2.96(m,1H),2.93-2.85(m,1H),2.11-2.07(m,1H),1.67-1.59(m,1H),1.32-1.29(m,1H)。
Peak 2:SFC保留时间=1.89min。方法B:LC-MS:Rt=1.11min;MS m/z[M+H]+464.1。1H NMR(400MHz,乙腈-d3)δ8.17(s,1H),8.07-8.02(m,2H),7.92-7.87(m,1H),7.65-7.58(m,1H),6.86-6.81(m,1H),6.74-6.70(m,1H),4.73-4.69(m,1H),4.33-4.26(m,2H),3.86(s,3H),3.01-2.96(m,1H),2.92-2.84(m,1H),2.11-2.07(m,1H),1.67-1.60(m,1H),1.33-1.29(m,1H)。
实例40:外消旋-(1R,2R,4S,5R,6S)-N-(3-氯-4-(三氟甲基)苯基)-6-羟基-4-(1-
甲基-3-(三氟甲基)-1H-吡唑-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.59min;MS m/z[M+H]+496.2。1H NMR(400MHz,乙腈-d3)δ8.14(s,1H),7.94-7.90(m,1H),7.71-7.66(m,1H),7.56-7.51(m,1H),7.48(s,1H),4.65(d,J=4.8Hz,1H),4.22-4.16(m,1H),4.09(s,1H),3.83(s,3H),2.89-2.79(m,2H),1.80(d,J=5.0Hz,1H),1.61-1.53(m,1H),1.17(d,J=5.0Hz,1H)。
实例41:外消旋-(1R,2R,4S,5R,6S)-N-(3-氟-4-(三氟甲基)苯基)-6-羟基-4-(1-
甲基-3-(三氟甲基)-1H-吡唑-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.55min;MS m/z[M+H]+480.2。1H NMR(400MHz,乙腈-d3)δ8.20(s,1H),7.77-7.66(m,1H),7.63-7.55(m,1H),7.48-7.45(m,1H),7.38-7.32(m,1H),4.66(d,J=4.8Hz,1H),4.22-4.16(m,1H),4.10(s,1H),3.82(s,3H),2.90-2.76(m,2H),1.80(d,J=5.0Hz,1H),1.61-1.53(m,1H),1.17(d,J=5.0Hz,1H)。
实例42:外消旋-(1R,2R,4S,5R,6S)-6-羟基-4-(1-甲基-3-(三氟甲基)-1H-吡唑-
4-基)-N-(4-(三氟甲基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.51min;MS m/z[M+H]+462.2。1H NMR(400MHz,乙腈-d3)δ8.07(s,1H),7.69(d,J=8.7Hz,2H),7.61(d,J=8.6Hz,2H),7.51-7.46(m,1H),4.65(d,J=4.9Hz,1H),4.22-4.16(m,1H),4.09(s,1H),3.82(s,3H),2.96-2.71(m,2H),1.79(d,J=4.9Hz,1H),1.60-1.54(m,1H),1.16(d,J=5.0Hz,1H)。
实例43:外消旋-(1R,2R,4S,5R,6S)-6-羟基-4-(1-甲基-3-(三氟甲基)-1H-吡唑-
4-基)-N-(4-(三氟甲基)吡啶-2-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.47min;MS m/z[M+H]+463.2。1H NMR(400MHz,乙腈-d3)δ8.50-8.46(m,1H),8.38-8.35(m,1H),8.31(s,1H),7.52-7.50(m,1H),7.37-7.33(m,1H),4.69(d,J=4.8Hz,1H),4.23-4.19(m,1H),4.10(s,1H),3.82(s,3H),2.98-2.74(m,2H),1.84(d,J=5.1Hz,1H),1.62-1.55(m,1H),1.22(d,J=5.1Hz,1H)。
实例44:外消旋-(1R,2R,4S,5R,6S)-N-(6-氯-4-(三氟甲基)吡啶-2-基)-6-羟基-
4-(1-甲基-3-(三氟甲基)-1H-吡唑-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.58min;MS m/z[M+H]+497.1。1H NMR(400MHz,乙腈-d3)δ8.38(s,1H),8.34-8.29(m,1H),7.50-7.46(m,1H),7.46-7.42(m,1H),4.68(d,J=4.8Hz,1H),4.22-4.17(m,1H),4.10(s,1H),3.83(s,3H),2.78-2.71(m,1H),2.61-2.42(m,1H),1.84(d,J=5.1Hz,1H),1.62-1.55(m,1H),1.23(d,J=5.1Hz,1H)。
实例45:外消旋-(1R,2R,4S,5R,6S)-N-(5-氯-4-(三氟甲基)吡啶-2-基)-6-羟基-
4-(1-甲基-3-(三氟甲基)-1H-吡唑-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
/>
LC-MS:Rt=1.56min;MS m/z[M+H]+497.1。1H NMR(400MHz,乙腈-d3)δ8.49(s,1H),8.46(s,1H),8.39(s,1H),7.49-7.46(m,1H),4.69(d,J=4.8Hz,1H),4.23-4.18(m,1H),4.10(s,1H),3.82(s,3H),3.05-2.81(m,1H),2.81-2.73(m,1H),1.84(d,J=5.1Hz,1H),1.62-1.56(m,1H),1.22(d,J=5.1Hz,1H)。
实例46:外消旋-(1R,2R,4S,5R,6S)-N-(6-环丙基-4-(三氟甲基)吡啶-2-基)-6-
羟基-4-(1-甲基-3-(三氟甲基)-1H-吡唑-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.64min;MS m/z[M+H]+503.2。1H NMR(400MHz,乙腈-d3)δ8.16(s,1H),8.08-8.05(m,1H),7.50-7.48(m,1H),7.26-7.24(m,1H),4.66(d,J=4.8Hz,1H),4.22-4.17(m,1H),4.09(s,1H),3.82(s,3H),3.08-2.79(m,1H),2.79-2.72(m,1H),2.12-2.03(m,1H),1.82(d,J=5.0Hz,1H),1.61-1.54(m,1H),1.18(d,J=5.1Hz,1H),1.02-0.89(m,4H)。
实例47:外消旋-(1R,2R,4S,5R,6S)-6-羟基-4-(1-甲基-3-(三氟甲基)-1H-吡唑-
4-基)-N-(6-甲基-4-(三氟甲基)吡啶-2-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.53min;MS m/z[M+H]+477.2。1H NMR(400MHz,乙腈-d3)δ8.17(s,1H),8.16-8.14(m,1H),7.52-7.50(m,1H),7.24-7.22(m,1H),4.68(d,J=4.8Hz,1H),4.23-4.18(m,1H),4.10(s,1H),3.82(s,3H),3.10-2.83(m,1H),2.80-2.73(m,1H),2.47(s,3H),1.83(d,J=5.0Hz,1H),1.61-1.55(m,1H),1.19(d,J=5.1Hz,1H)。
实例48:外消旋-(1R,2R,4S,5R,6S)-N-(6-乙氧基-4-(三氟甲基)吡啶-2-基)-6-
羟基-4-(1-甲基-3-(三氟甲基)-1H-吡唑-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.65min;MS m/z[M+H]+507.2。1H NMR(400MHz,乙腈-d3)δ8.23(s,1H),7.91-7.87(m,1H),7.53-7.49(m,1H),6.75-6.71(m,1H),4.68(d,J=4.8Hz,1H),4.30(q,J=7.0Hz,2H),4.23-4.18(m,1H),4.10(s,1H),3.82(s,3H),3.09-2.66(m,2H),1.82(d,J=5.1Hz,1H),1.61-1.55(m,1H),1.33(t,J=7.1Hz,3H),1.19(d,J=5.4Hz,1H)。
实例49:外消旋-(1R,2R,4S,5R,6S)-6-羟基-4-(1-甲基-3-(三氟甲基)-1H-吡唑-
4-基)-N-(3-(三氟甲基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.50min;MS m/z[M+H]+462.2。1H NMR(400MHz,乙腈-d3)δ8.05(s,1H),7.93-7.90(m,1H),7.70-7.65(m,1H),7.52-7.46(m,2H),7.43-7.38(m,1H),4.64(d,J=4.8Hz,1H),4.22-4.16(m,1H),4.09(s,1H),3.82(s,3H),3.22-2.90(m,1H),2.89-2.81(m,1H),1.78(d,J=5.0Hz,1H),1.60-1.54(m,1H),1.16(d,J=4.9Hz,1H)。
实例50:外消旋-(1R,2R,4S,5R,6S)-6-羟基-4-(1-甲基-3-(三氟甲基)-1H-吡唑-
4-基)-N-(2-甲基-3-(三氟甲基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.49min;MS m/z[M+H]+476.2。1H NMR(400MHz,乙腈-d3)δ7.63(s,1H),7.59-7.54(m,1H),7.54-7.49(m,2H),7.37-7.31(m,1H),4.65(d,J=4.8Hz,1H),4.25-4.20(m,1H),4.10(s,1H),3.84(s,3H),3.24-2.93(m,1H),2.92-2.84(m,1H),2.19(s,3H),1.81(d,J=4.9Hz,1H),1.62-1.56(m,1H),1.15(d,J=4.9Hz,1H)。
实例51:外消旋-(1R,2R,4S,5R,6S)-6-羟基-4-(1-甲基-3-(三氟甲基)-1H-吡唑-
4-基)-N-(4-甲基-3-(三氟甲基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.56min;MS m/z[M+H]+476.2。1H NMR(400MHz,乙腈-d3)δ7.94(s,1H),7.84-7.81(m,1H),7.59-7.55(m,1H),7.49-7.47(m,1H),7.32-7.27(m,1H),4.63(d,J=4.8Hz,1H),4.20-4.16(m,1H),4.09(s,1H),3.82(s,3H),3.17-2.88(m,1H),2.88-2.81(m,1H),2.42(s,3H),1.77(d,J=4.9Hz,1H),1.59-1.53(m,1H),1.14(d,J=4.9Hz,1H)。
实例52:外消旋-(1R,2R,4S,5R,6S)-6-羟基-4-(1-甲基-3-(三氟甲基)-1H-吡唑-
4-基)-N-(3-甲基-5-(三氟甲基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.57min;MS m/z[M+H]+476.2。1H NMR(400MHz,乙腈-d3)δ7.97(s,1H),7.72-7.68(m,1H),7.52-7.47(m,2H),7.26-7.22(m,1H),4.64(d,J=4.8Hz,1H),4.21-4.17(m,1H),4.09(s,1H),3.83(s,3H),3.26-2.91(m,1H),2.89-2.81(m,1H),2.37(s,3H),1.78(d,J=4.9Hz,1H),1.59-1.54(m,1H),1.14(d,J=4.9Hz,1H)。
实例53:外消旋-(1R,2R,4S,5R,6S)-6-羟基-4-(1-甲基-3-(三氟甲基)-1H-吡唑-
4-基)-N-(2-甲基-5-(三氟甲基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.52min;MS m/z[M+H]+476.2。1H NMR(400MHz,乙腈-d3)δ7.79-7.77(m,1H),7.55-7.53(m,1H),7.49(s,1H),7.43-7.36(m,2H),4.66(d,J=4.8Hz,1H),4.26-4.20(m,1H),4.10(s,1H),3.83(s,3H),3.59-3.11(m,1H),2.90-2.83(m,1H),2.13(s,3H),1.83(d,J=5.0Hz,1H),1.62-1.56(m,1H),1.16(d,J=5.0Hz,1H)。
实例54:外消旋-(1R,2R,4S,5R,6S)-N-(2-氟-3-(三氟甲基)苯基)-6-羟基-4-(1-
甲基-3-(三氟甲基)-1H-吡唑-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.49min;MS m/z[M+H]+480.2。1H NMR(400MHz,乙腈-d3)δ8.02-7.95(m,1H),7.54(s,1H),7.52-7.50(m,1H),7.50-7.44(m1H),7.33-7.28(m,1H),4.64(d,J=4.9Hz,1H),4.23-4.18(m,1H),4.11(s,1H),3.84(s,3H),3.06-2.65(m,2H),1.85(d,J=5.1Hz,1H),1.62-1.55(m,1H),1.19(d,J=5.1Hz,1H)。
实例55:外消旋-(1R,2R,4S,5R,6S)-N-(4-氟-3-(三氟甲基)苯基)-6-羟基-4-(1-
甲基-3-(三氟甲基)-1H-吡唑-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
/>
LC-MS:Rt=1.52min;MS m/z[M+H]+480.2。1H NMR(400MHz,乙腈-d3)δ8.02(s,1H),7.92-7.88(m,1H),7.73-7.67(m,1H),7.49-7.45(m,1H),7.29-7.22(m,1H),4.63(d,J=4.8Hz,1H),4.21-4.16(m,1H),4.09(s,1H),3.82(s,3H),3.02-2.69(m,2H),1.78(d,J=4.9Hz,1H),1.60-1.54(m,1H),1.15(d,J=4.9Hz,1H)。
实例56:外消旋-(1R,2R,4S,5R,6S)-N-(3-氟-5-(三氟甲基)苯基)-6-羟基-4-(1-
甲基-3-(三氟甲基)-1H-吡唑-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.57min;MS m/z[M+H]+480.2。1H NMR(400MHz,乙腈-d3)δ8.17(s,1H),7.71-7.66(m,1H),7.66-7.63(m,1H),7.49-7.46(m,1H),7.20-7.15(m,1H),4.65(d,J=4.8Hz,1H),4.21-4.16(m,1H),4.10(s,1H),3.82(s,3H),3.05-2.69(m,2H),1.80(d,J=5.0Hz,1H),1.60-1.54(m,1H),1.16(d,J=4.9Hz,1H)。
实例57:外消旋-(1R,2R,4S,5R,6S)-N-(2-氟-5-(三氟甲基)苯基)-6-羟基-4-(1-
甲基-3-(三氟甲基)-1H-吡唑-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.51min;MS m/z[M+H]+480.2。1H NMR(400MHz,乙腈-d3)δ8.18-8.15(m,1H),7.57(s,1H),7.54-7.52(m,1H),7.52-7.47(m,1H),7.35-7.28(m,1H),4.65(d,J=4.9Hz,1H),4.24-4.18(m,1H),4.11(s,1H),3.86-3.80(m,3H),3.15-2.81(m,1H),2.81-2.73(m,1H),1.85(d,J=5.2Hz,1H),1.61-1.55(m,1H),1.18(d,J=5.1Hz,1H)。
实例58:外消旋-(1R,2R,4S,5R,6S)-N-(4-氯-3-(三氟甲基)苯基)-6-羟基-4-(1-
甲基-3-(三氟甲基)-1H-吡唑-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.59min;MS m/z[M+H]+496.2。1H NMR(400MHz,乙腈-d3)δ8.09(s,1H),8.02-8.00(m,1H),7.73-7.69(m,1H),7.53-7.49(m,1H),7.47-7.45(m,1H),4.64(d,J=4.8Hz,1H),4.21-4.16(m,1H),4.09(s,1H),3.82(s,3H),2.92-2.65(m,2H),1.79(d,J=5.0Hz,1H),1.60-1.54(m,1H),1.16(d,J=5.0Hz,1H)。
实例59:外消旋-(1R,2R,4S,5R,6S)-N-(3-氯-5-(三氟甲基)苯基)-6-羟基-4-(1-
甲基-3-(三氟甲基)-1H-吡唑-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.62min;MS m/z[M+H]+496.2。1H NMR(400MHz,乙腈-d3)δ8.12(s,1H),7.88-7.85(m,1H),7.79-7.77(m,1H),7.49-7.47(m,1H),7.45-7.41(m,1H),4.64(d,J=4.8Hz,1H),4.21-4.16(m,1H),4.10(s,1H),3.82(s,3H),2.86-2.79(m,1H),2.65-2.24(m,1H),1.80(d,J=5.0Hz,1H),1.61-1.54(m,1H),1.16(d,J=4.9Hz,1H)。
实例60:外消旋-(1R,2R,4S,5R,6S)-6-羟基-N-(4-甲氧基-3-(三氟甲基)苯基)-
4-(1-甲基-3-(三氟甲基)-1H-吡唑-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.48min;MS m/z[M+H]+492.2。1H NMR(400MHz,乙腈-d3)δ7.86(s,1H),7.75-7.73(m,1H),7.64-7.60(m,1H),7.49-7.47(m,1H),7.12-7.07(m,1H),4.62(d,J=4.8Hz,1H),4.20-4.15(m,1H),4.09(s,1H),3.87(s,3H),3.82(s,3H),2.91-2.61(m,2H),1.76(d,J=4.9Hz,1H),1.59-1.53(m,1H),1.12(d,J=4.9Hz,1H)。
实例61:外消旋-(1R,2R,4S,5R,6S)-6-羟基-N-(3-甲氧基-5-(三氟甲基)苯基)-
4-(1-甲基-3-(三氟甲基)-1H-吡唑-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.54min;MS m/z[M+H]+492.2。1H NMR(400MHz,乙腈-d3)δ8.00(s,1H),7.50-7.46(m,2H),7.35-7.32(m,1H),6.96-6.92(m,1H),4.64(d,J=4.8Hz,1H),4.21-4.15(m,1H),4.09(s,1H),3.82(s,3H),3.81(s,3H),2.92-2.45(m,2H),1.78(d,J=4.9Hz,1H),1.60-1.54(m,1H),1.14(d,J=4.9Hz,1H)。
实例62:外消旋-(1R,2R,4S,5R,6S)-6-羟基-N-(2-甲氧基-5-(三氟甲基)苯基)-
4-(1-甲基-3-(三氟甲基)-1H-吡唑-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.57min;MS m/z[M+H]+492.2。1H NMR(400MHz,乙腈-d3)δ8.50-8.46(m,1H),7.53-7.48(m,1H),7.43(s,1H),7.40-7.35(m,1H),7.08-7.03(m,1H),4.65(d,J=4.9Hz,1H),4.26-4.22(m,1H),4.10(s,1H),3.82(s,3H),3.77(s,3H),3.36-2.88(m,1H),2.75-2.65(m,1H),1.89(d,J=5.3Hz,1H),1.64-1.57(m,1H),1.13(d,J=5.4Hz,1H)。
实例63:外消旋-(1R,2R,4S,5R,6S)-N-(3,5-双(三氟甲基)苯基)-6-羟基-4-(1-
甲基-3-(三氟甲基)-1H-吡唑-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.66min;MS m/z[M+H]+530.2。1H NMR(400MHz,乙腈-d3)δ8.24(s,1H),8.14-8.10(m,2H),7.72-7.68(m,1H),7.49-7.47(m,1H),4.66(d,J=4.8Hz,1H),4.22-4.17(m,1H),4.11(s,1H),3.82(s,3H),3.05-2.57(m,2H),1.82(d,J=5.0Hz,1H),1.62-1.55(m,1H),1.19(d,J=5.0Hz,1H)。
实例64:外消旋-(1R,2R,4S,5R,6S)-6-羟基-4-(1-甲基-3-(三氟甲基)-1H-吡唑-
4-基)-N-(4-吗啉基-3-(三氟甲基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.52min;MS m/z[M+H]+547.2。1H NMR(400MHz,乙腈-d3)δ7.96(s,1H),7.83-7.80(m,1H),7.70-7.66(m,1H),7.50-7.47(m,1H),7.46-7.41(m,1H),4.63(d,J=4.8Hz,1H),4.21-4.15(m,1H),4.09(s,1H),3.82(s,3H),3.75-3.70(m,4H),2.88-2.81(m,5H),2.79-2.39(m,1H),1.77(d,J=4.8Hz,1H),1.59-1.53(m,1H),1.14(d,J=4.8Hz,1H)。
实例65:外消旋-(1R,2R,4S,5R,6S)-N-(4-乙氧基-3-(三氟甲基)苯基)-6-羟基-
4-(1-甲基-3-(三氟甲基)-1H-吡唑-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
LC-MS:Rt=1.56min;MS m/z[M+H]+506.2。1H NMR(400MHz,乙腈-d3)δ7.86(s,1H),7.74-7.72(m,1H),7.62-7.58(m,1H),7.49-7.46(m,1H),7.10-7.05(m,1H),4.62(d,J=4.8Hz,1H),4.19-4.16(m,1H),4.12(q,J=7.0Hz,2H),4.09(s,1H),3.82(s,3H),3.01-2.49(m,2H),1.76(d,J=4.9Hz,1H),1.59-1.53(m,1H),1.36(t,J=7.0Hz,3H),1.12(d,J=4.9Hz,1H)。
实例66:外消旋-(1R,2R,4S,5R,6S)-6-羟基-N-(3-(三氟甲基)苯基)-4-(2-(三氟
甲基)吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法C:LC-MS:Rt=0.61min;MS m/z[M+H]+459.1。1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.69-8.64(m,1H),8.01-7.96(m,1H),7.83-7.76(m,1H),7.66-7.61(m,1H),7.59-7.50(m,2H),7.44-7.37(m,1H),5.01(s,1H),4.76-4.72(m,1H),4.48(s,1H),4.12-4.04(m,1H),2.79-2.71(m,1H),1.87-1.83(m,1H),1.53-1.45(m,2H)。
实例67:外消旋-(1R,2R,4S,5R,6S)-6-羟基-N,4-双(3-(三氟甲基)苯基)-8-氧杂
三环[3.2.1.02,4]辛烷-2-甲酰胺
方法C:LC-MS:Rt=0.66min;MS m/z[M+H]+458.1。1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),7.93-7.90(m,1H),7.78-7.74(m,1H),7.64-7.59(m,1H),7.57-7.54(m,2H),7.54-7.50(m,2H),7.43-7.39(m,1H),4.89(d,J=4.8Hz,1H),4.73(d,J=4.7Hz,1H),4.32(s,1H),4.14-4.08(m,1H),2.88-2.81(m,1H),1.79(d,J=4.7Hz,1H),1.56-1.50(m,1H),1.39(d,J=4.7Hz,1H)。
实例68:外消旋-(1R,2R,4S,5R,6S)-N-(4-氰基-3-(三氟甲基)苯基)-6-羟基-4-
(1-甲基-3-(三氟甲基)-1H-吡唑-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.13min;MS m/z[M+H]+487.0。1H NMR(400MHz,氯仿-d)δ7.99-7.94(m,1H),7.81-7.68(m,2H),7.48-7.37(m,2H),4.70-4.64(m,1H),4.33-4.26(m,2H),3.90(s,3H),3.14-3.05(m,1H),2.05-1.99(m,1H),1.73-1.63(m,2H),1.06-0.99(m,1H)。
实例69:外消旋-(1R,2R,4S,5R,6S)-N-(2-氰基-5-(三氟甲基)苯基)-6-羟基-4-
(1-甲基-3-(三氟甲基)-1H-吡唑-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.01min;MS m/z[M+H]+487.1。1H NMR(400MHz,甲醇-d4)δ7.98-7.92(m,1H),7.90-7.85(m,1H),7.72-7.65(m,2H),4.80-4.75(m,1H),4.32-4.25(m,1H),4.18(s,1H),3.87(s,3H),2.98-2.89(m,1H),2.01(s,1H),1.95-1.89(m,1H),1.76-1.67(m,1H)。
实例70:外消旋-(1R,2R,4S,5R,6S)-N-(4-氯-3-(三氟甲基)苯基)-6-羟基-4-(2-
甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.16min;MS m/z[M+H]+455.1。1H NMR(400MHz,甲醇-d4)δ7.95-7.87(m,2H),7.73-7.64(m,1H),7.47-7.40(m,1H),6.70-6.64(m,1H),6.59-6.55(m,1H),4.62-4.56(m,1H),4.30(s,1H),4.25-4.18(m,1H),3.77(s,3H),2.90-2.81(m,1H),1.88-1.82(m,1H),1.59-1.49(m,1H),1.30-1.20(m,1H)。
实例71:外消旋-(1R,2R,4S,5R,6S)-N-(3-氯-5-(三氟甲基)苯基)-6-羟基-4-(2-
甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.19min;MS m/z[M+H]+455.1。1H NMR(400MHz,甲醇-d4)δ7.96-7.90(m,1H),7.86-7.80(m,1H),7.76-7.71(m,1H),7.34-7.29(m,1H),6.71-6.64(m,1H),6.60-6.55(m,1H),4.63-4.57(m,1H),4.30(s,1H),4.25-4.19(m,1H),3.80-3.74(m,3H),2.90-2.81(m,1H),1.88-1.82(m,1H),1.59-1.50(m,1H),1.33-1.22(m,1H)。
实例72:外消旋-(1R,2R,4S,5R,6S)-N-(3-氰基-5-(三氟甲基)苯基)-6-羟基-4-
(2-甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.04min;MS m/z[M+H]+446.1。1H NMR(400MHz,甲醇-d4)δ8.15-8.05(m,2H),7.96-7.90(m,1H),7.70(s,1H),6.72-6.66(m,1H),6.61-6.56(m,1H),4.64-4.58(m,1H),4.30(s,1H),4.26-4.19(m,1H),3.80-3.75(m,3H),2.90-2.82(m,1H),1.89-1.84(m,1H),1.60-1.51(m,1H),1.34-1.26(m,1H)。
实例73:外消旋-(1R,2R,4S,5R,6S)-N-(3-氟-5-(三氟甲基)苯基)-6-羟基-4-(2-
甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.12min;MS m/z[M+H]+439.1。1H NMR(400MHz,甲醇-d4)δ8.05-7.99(m,1H),7.78-7.65(m,2H),7.21-7.13(m,1H),6.80-6.74(m,1H),6.69-6.61(m,1H),4.74-4.67(m,1H),4.41(s,1H),4.35-4.28(m,1H),3.87(s,3H),3.00-2.91(m,1H),1.98-1.91(m,1H),1.69-1.60(m,1H),1.40-1.34(m,1H)。
实例74:外消旋-(1R,2R,4S,5R,6S)-N-(3-氯-4-(三氟甲基)苯基)-6-羟基-4-(2-
甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.18min;MS m/z[M+H]+455.1。1H NMR(400MHz,氯仿-d)δ8.18-8.13(m,1H),7.61-7.54(m,2H),7.23-7.16(m,1H),6.79(s,1H),6.75-6.66(m,2H),4.77-4.72(m,1H),4.45-4.36(m,2H),3.96-3.91(m,3H),2.99-2.90(m,1H),2.10-2.04(m,1H),1.82-1.71(m,2H),1.14-1.09(m,1H)。
实例75:外消旋-(1R,2R,4S,5R,6S)-N-(3-氟-4-(三氟甲基)苯基)-6-羟基-4-(2-
甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.12min;MS m/z[M+H]+439.1。1H NMR(400MHz,甲醇-d4)δ8.05-7.99(m,1H),7.76-7.68(m,1H),7.64-7.56(m,1H),7.49-7.42(m,1H),6.79-6.73(m,1H),6.69-6.64(m,1H),4.72-4.68(m,1H),4.41(s,1H),4.35-4.28(m,1H),3.87(s,3H),2.99-2.90(m,1H),1.99-1.93(m,1H),1.68-1.59(m,1H),1.39-1.33(m,1H)。
实例76:外消旋-(1R,2R,4S,5R,6S)-6-羟基-4-(2-甲氧基吡啶-4-基)-N-(4-(三
氟甲基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=0.98min;MS m/z[M+H]+421.2。1H NMR(400MHz,甲醇-d4)δ8.04-7.98(m,1H),7.77-7.70(m,2H),7.64-7.57(m,2H),6.80-6.73(m,1H),6.70-6.66(m,1H),4.73-4.68(m,1H),4.42(s,1H),4.36-4.29(m,1H),3.87(s,3H),3.01-2.92(m,1H),1.99-1.92(m,1H),1.69-1.60(m,1H),1.41-1.34(m,1H)。
实例77:外消旋-(1R,2R,4S,5R,6S)-N-(3-氰基-5-(三氟甲基)苯基)-4-(2-氟吡
啶-4-基)-6-羟基-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.05min;MS m/z[M+H]+434.1。1H NMR(400MHz,氯仿-d)δ8.23-8.17(m,1H),8.08-8.03(m,1H),7.93-7.88(m,1H),7.69-7.64(m,1H),7.37(s,1H),7.09-7.02(m,1H),6.90-6.84(m,1H),4.77-4.72(m,1H),4.45(s,1H),4.44-4.36(m,1H),3.12-3.02(m,1H),2.14-2.09(m,1H),1.83-1.73(m,2H),1.21-1.17(m,1H)。
实例78:外消旋-(1R,2R,4S,5R,6S)-N-(2-氰基-5-(三氟甲基)苯基)-4-(2-氟吡
啶-4-基)-6-羟基-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=0.94min;MS m/z[M+H]+434.1。1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.14-8.09(m,2H),7.86-7.83(m,1H),7.81-7.76(m,1H),7.28-7.23(m,1H),7.13-7.09(m,1H),5.01-4.96(m,1H),4.81-4.75(m,1H),4.37(s,1H),4.19-4.12(m,1H),2.79-2.71(m,1H),1.89-1.84(m,1H),1.62-1.50(m,1H),1.42-1.37(m,1H)。
实例79:外消旋-(1R,2R,4S,5R,6S)-N-(4-氰基-3-(三氟甲基)苯基)-6-羟基-4-
(3-(三氟甲基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.26min;MS m/z[M+H]+483.0。1H NMR(400MHz,氯仿-d)δ7.75-7.40(m,6H),6.72(s,1H),4.83-4.77(m,1H),4.45-4.36(m,2H),3.01-2.91(m,1H),2.21-2.15(m,1H),1.87-1.73(m,2H),1.26(s,1H),1.20-1.14(m,1H)。
实例80:外消旋-(1R,2R,4S,5R,6S)-N-(2-氰基-5-(三氟甲基)苯基)-6-羟基-4-
(3-(三氟甲基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.15min;MS m/z[M+H]+483.1。1H NMR(400MHz,甲醇-d4)δ7.97-7.91(m,1H),7.83-7.78(m,1H),7.71-7.56(m,4H),7.56-7.48(m,1H),4.82-4.79(m,1H),4.39-4.30(m,2H),3.09-3.00(m,1H),2.06-2.03(m,1H),1.83-1.73(m,1H),1.45-1.37(m,1H)。
实例81:外消旋-(1R,2R,4S,5R,6S)-N-(2-氟-5-(三氟甲基)苯基)-6-羟基-4-(3-
(三氟甲基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.27min;MS m/z[M+H]+476.0。1H NMR(400MHz,氯仿-d)δ8.56-8.48(m,1H),7.65-7.60(m,1H),7.60-7.57(m,1H),7.54-7.44(m,2H),7.33-7.27(m,1H),7.11-7.04(m,1H),6.74-6.65(m,1H),4.83-4.79(m,1H),4.46-4.40(m,1H),4.37(s,1H),3.00-2.92(m,1H),2.19-2.13(m,1H),1.86-1.75(m,2H),1.21-1.16(m,1H)。
实例82:外消旋-(1R,2R,4S,5R,6S)-6-羟基-4-(3-(三氟甲基)苯基)-N-(4-(三氟
甲基)吡啶-2-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
方法B:LC-MS:Rt=1.24min;MS m/z[M+H]+459.1。1H NMR(400MHz,氯仿-d)δ8.45-8.38(m,1H),8.35-8.29(m,1H),7.63-7.52(m,3H),7.52-7.40(m,2H),7.25-7.20(m,1H),4.82-4.76(m,1H),4.43-4.34(m,2H),3.07-2.97(m,1H),2.17-2.09(m,1H),1.90-1.78(m,2H),1.30-1.21(m,1H)。
生物学测定
在碱性磷酸酶(ALP)活性测定中评估了本发明的化合物,以确定所述化合物预防正常人关节软骨细胞(NHAC)中软骨细胞肥大的能力。表1中列出了所使用的试剂。
表1
细胞培养
正常人关节软骨细胞(NHAC)购自PromoCell公司(海德堡,德国),并使其在软骨细胞生长培养基(CGM;龙沙公司(Lonza),沃克斯维尔,马里兰州)中生长。
NHAC中碱性磷酸酶的染色和定量
在来自龙沙公司(Lonza)的软骨细胞生长培养基(CGM)中扩增NHAC,直至其达到60%-80%汇合。为了引发分化,将7,500个细胞以每孔指定的测试化合物剂量铺板在具有DMEM(SH30022-HyClone公司)的384孔Cell Carrier Ultra板(珀金埃尔默公司(PerkinElmer))中,所述DMEM含有10%FBS(35-015-CV-康宁公司(Corning))、1%Pen/Strep抗生素(SV30010-HyClone公司)和1%Normocin(50mg/mL-InvivoGen公司)。将细胞与测试化合物在37℃、5%CO2下一起孵育5小时,然后以最终浓度10ng/mL添加人IL-1β(AF-200-1B-派普泰克公司(Peprotech))至每个孔中,并且在37℃、5%CO2下孵育12天。
为了检测肥大细胞的存在,将NHAC用4%多聚甲醛和Hoechst 33342(英杰公司(Invitrogen))染料固定30分钟,在PBS中漂洗,然后用具有萘酚AS-MX磷酸盐碱性溶液(0.25%,855-西格玛-奥德里奇公司(Sigma-Aldrich))的固蓝RR盐(F0500-西格玛公司)染色。在37℃大约3小时后,一旦观察到细胞变蓝,将其用PBS洗涤三次。
将染色通过荧光显微术、使用561nm波长进行成像,和/或通过使用ImageXpressConfocal(美谷分子仪器公司(Molecular Devices),森尼维耳市,加利福尼亚州)的高含量成像进行定量。使用定制的多波长细胞评分应用程序进行数据分析。表2总结了本发明的化合物在ALP测定中的活性。
表2
/>
/>
/>
/>
/>
/>
应理解,本文描述的实例和实施例仅用于举例说明目的,其各种修饰或改变对于本领域技术人员将是明了的,并包括在本申请的精神和范围内和所附权利要求书的范围内。出于所有目的,本文引用的所有出版物、专利、和专利申请都通过引用特此并入。
Claims (24)
1.一种具有式(1)的化合物:
或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中
W是苯基或吡啶基;
R1是氢或C1-6烷基;
R2是苯基或具有1-2个选自N、O和S的杂原子的5-6元杂芳基;其中R2是未取代的或被1-2个独立地选自卤基、C1-6烷基、C1-6卤基烷基或C1-6烷氧基的取代基取代;
R3独立地选自卤基、氰基、C1-6烷基、C1-6卤基烷基、C1-6烷氧基、C3-6环烷基和5-6元杂环基;或者当n是0时,R3是氢;并且
n是0-2。
2.根据权利要求1所述的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中是/>
3.根据权利要求1所述的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中是/>
4.根据权利要求1所述的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中是/>
5.根据权利要求1所述的化合物,其中所述化合物具有式(2):
或是其对映异构体、对映异构体混合物或其药学上可接受的盐;其中X是N、CH或CR4;其中R4是卤基、氰基、C1-6烷基、C1-6卤基烷基或C1-6烷氧基。
6.根据权利要求1所述的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中R3,如果存在,是氟、氯、甲基、甲氧基、乙氧基、三氟甲基、氰基、环丙基或吗啉基。
7.根据权利要求1所述的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中R3是氢并且n是0。
8.根据权利要求1所述的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中R2是苯基、吡唑基、吡啶基或嘧啶基;所述苯基、吡唑基、吡啶基或嘧啶基各自被1-2个独立地选自卤基、C1-6烷基、C1-6卤基烷基或C1-6烷氧基的取代基取代。
9.根据权利要求8所述的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中R2选自:
10.根据权利要求1所述的化合物或其对映异构体、对映异构体混合物或其药学上可接受的盐;其中R1是氢。
11.根据权利要求1所述的化合物,其中所述化合物选自以下化合物;或其对映异构体、对映异构体混合物或其药学上可接受的盐,
12.根据权利要求1-11中任一项所述的化合物或其药学上可接受的盐,其中所述化合物具有(1R,2R,4S,5R,6S)对映异构体的至少50%的对映异构体过量。
13.根据权利要求1-11中任一项所述的化合物或其药学上可接受的盐,其中所述化合物具有(1R,2R,4S,5R,6S)对映异构体的至少75%的对映异构体过量。
14.根据权利要求1-11中任一项所述的化合物或其药学上可接受的盐,其中所述化合物具有(1R,2R,4S,5R,6S)对映异构体的至少85%的对映异构体过量。
15.根据权利要求1-11中任一项所述的化合物或其药学上可接受的盐,其中所述化合物具有(1R,2R,4S,5R,6S)对映异构体的至少95%的对映异构体过量。
16.一种药物组合物,所述药物组合物包含根据权利要求1-15中任一项所述的化合物、以及一种或多种药学上可接受的载体。
17.一种组合产品,所述组合产品包含根据权利要求1-15中任一项所述的化合物、以及一种或多种治疗活性剂。
18.根据权利要求1-15中任一项所述的、任选地与第二治疗剂组合的化合物在制造用于关节炎或关节损伤或用于软骨修复的药物中的用途。
19.治疗有效量的根据权利要求1-15中任一项所述、任选地与第二治疗剂组合的化合物在制造用于在有需要的受试者中治疗、改善或预防所述受试者的关节炎或关节损伤、或用于修复软骨的药物中的用途。
20.根据权利要求18或19所述的用途,其中所述化合物口服施用。
21.治疗有效量的根据权利要求1-15中任一项所述的、任选地与第二治疗剂组合的化合物在制造用于用途诱导透明软骨产生的药物中的用途。
22.根据权利要求21所述的用途,其中包括使软骨发生性祖细胞与所述药物在哺乳动物体外或体内接触;并且当在体内进行时,所述软骨发生性祖细胞存在于哺乳动物中。
23.根据权利要求22所述的用途,其中所述接触步骤发生在细胞外基质或生物相容性支架中。
24.根据权利要求21-23中任一项所述的用途,所述用途进一步包括诱导软骨祖细胞分化为成熟软骨细胞。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862776271P | 2018-12-06 | 2018-12-06 | |
US62/776,271 | 2018-12-06 | ||
PCT/IB2019/060456 WO2020115684A1 (en) | 2018-12-06 | 2019-12-04 | 6-hydroxy-8-oxatricyclo[3.2.1.02,4]octane-2-carboxamide derivatives for inducing chondrogenesis for treating joint damage |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113015736A CN113015736A (zh) | 2021-06-22 |
CN113015736B true CN113015736B (zh) | 2024-06-21 |
Family
ID=68916502
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980074389.5A Active CN113015736B (zh) | 2018-12-06 | 2019-12-04 | 用于诱导软骨发生以治疗关节损害的6-羟基-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺衍生物 |
Country Status (6)
Country | Link |
---|---|
US (1) | US20220033412A1 (zh) |
EP (1) | EP3891155B1 (zh) |
JP (1) | JP7427665B2 (zh) |
CN (1) | CN113015736B (zh) |
ES (1) | ES2965684T3 (zh) |
WO (1) | WO2020115684A1 (zh) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102625830A (zh) * | 2009-07-14 | 2012-08-01 | 斯克里普斯研究所 | 间充质干细胞分化 |
CN106459076A (zh) * | 2014-05-13 | 2017-02-22 | 诺华股份有限公司 | 用于诱导软骨发生的化合物和组合物 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9464065B2 (en) * | 2011-03-24 | 2016-10-11 | The Scripps Research Institute | Compounds and methods for inducing chondrogenesis |
JOP20190282A1 (ar) * | 2017-06-09 | 2019-12-05 | Novartis Ag | مركبات وتركيبات لحث تكوّن الغضاريف |
ES2963508T3 (es) * | 2018-12-06 | 2024-03-27 | Novartis Ag | Derivados de 5-hidroxi-7-oxabiciclo[2.2.1]heptano-2-carboxamida para inducir condrogénesis para el tratamiento del daño articular |
-
2019
- 2019-12-04 ES ES19821289T patent/ES2965684T3/es active Active
- 2019-12-04 WO PCT/IB2019/060456 patent/WO2020115684A1/en unknown
- 2019-12-04 CN CN201980074389.5A patent/CN113015736B/zh active Active
- 2019-12-04 JP JP2021525228A patent/JP7427665B2/ja active Active
- 2019-12-04 EP EP19821289.6A patent/EP3891155B1/en active Active
- 2019-12-04 US US17/299,236 patent/US20220033412A1/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102625830A (zh) * | 2009-07-14 | 2012-08-01 | 斯克里普斯研究所 | 间充质干细胞分化 |
CN106459076A (zh) * | 2014-05-13 | 2017-02-22 | 诺华股份有限公司 | 用于诱导软骨发生的化合物和组合物 |
Also Published As
Publication number | Publication date |
---|---|
JP2022509764A (ja) | 2022-01-24 |
CN113015736A (zh) | 2021-06-22 |
EP3891155A1 (en) | 2021-10-13 |
WO2020115684A1 (en) | 2020-06-11 |
ES2965684T3 (es) | 2024-04-16 |
EP3891155B1 (en) | 2023-08-30 |
JP7427665B2 (ja) | 2024-02-05 |
US20220033412A1 (en) | 2022-02-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110177788B (zh) | 作为bcl-2选择性凋亡诱导剂的化合物 | |
US10590113B2 (en) | 6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carboxamides as APJ agonists | |
JP6962941B2 (ja) | Apj受容体アゴニストとしての4−ヒドロキシ−3−スルホニルピリジン−2(1h)−オン | |
JP4732354B2 (ja) | グリシン輸送阻害薬としての二環式[3.1.0]誘導体 | |
KR20140040774A (ko) | 이미다조피리딘 화합물 | |
CN106068265B (zh) | 用于治疗代谢病症的二氢吡啶酮mgat2抑制剂 | |
KR102291444B1 (ko) | 디히드로피리디논 mgat2 억제제 | |
TW202003466A (zh) | 人類整合素α4β7拮抗劑 | |
EP2479165A1 (en) | Glycine compound | |
JP7301758B2 (ja) | 縮合二環式化合物、その組成物及び応用 | |
JP7432778B2 (ja) | 軟骨形成を誘導するための化合物及び組成物 | |
JP2014518281A (ja) | 電位依存性ナトリウムチャネル遮断薬 | |
CN113015735B (zh) | 用于诱导软骨发生以治疗关节损害的5-羟基-7-氧杂双环[2.2.1]庚烷-2-甲酰胺衍生物 | |
CN113015736B (zh) | 用于诱导软骨发生以治疗关节损害的6-羟基-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺衍生物 | |
AU2021240044A1 (en) | PHD inhibitor compounds, compositions, and use | |
WO2023114823A1 (en) | Benzothiophene derivatives as rxfp1 agonists | |
KR20230129394A (ko) | 리아노딘 수용체를 수반하는 장애를 치료하기 위한 작용제 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |