TWI662039B - 用於誘發軟骨生成之化合物及組合物 - Google Patents
用於誘發軟骨生成之化合物及組合物 Download PDFInfo
- Publication number
- TWI662039B TWI662039B TW104115093A TW104115093A TWI662039B TW I662039 B TWI662039 B TW I662039B TW 104115093 A TW104115093 A TW 104115093A TW 104115093 A TW104115093 A TW 104115093A TW I662039 B TWI662039 B TW I662039B
- Authority
- TW
- Taiwan
- Prior art keywords
- oxabicyclo
- heptane
- carboxamide
- pyridin
- biphenyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 340
- 239000000203 mixture Substances 0.000 title claims description 110
- 230000001939 inductive effect Effects 0.000 title description 14
- 230000022159 cartilage development Effects 0.000 title description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 98
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- 210000001612 chondrocyte Anatomy 0.000 claims abstract description 46
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 33
- 241000124008 Mammalia Species 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 222
- -1 1H-pyrazol-4-yl Chemical group 0.000 claims description 175
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 122
- 229910052739 hydrogen Inorganic materials 0.000 claims description 89
- 239000001257 hydrogen Substances 0.000 claims description 89
- 125000001424 substituent group Chemical group 0.000 claims description 83
- 125000005843 halogen group Chemical group 0.000 claims description 76
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 75
- 125000001072 heteroaryl group Chemical group 0.000 claims description 68
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 61
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 59
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 54
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 claims description 44
- 125000003545 alkoxy group Chemical group 0.000 claims description 38
- 150000001412 amines Chemical class 0.000 claims description 35
- 125000000623 heterocyclic group Chemical group 0.000 claims description 34
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 32
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 24
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 22
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 22
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 21
- 125000002619 bicyclic group Chemical group 0.000 claims description 21
- 229920002674 hyaluronan Polymers 0.000 claims description 20
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- 239000003795 chemical substances by application Substances 0.000 claims description 19
- 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 claims description 18
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 18
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- 229920001436 collagen Polymers 0.000 claims description 18
- 125000004429 atom Chemical group 0.000 claims description 17
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- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims description 17
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- DEOUZFWSQWEPGE-UHFFFAOYSA-N 2-methylheptanamide Chemical compound CCCCCC(C)C(N)=O DEOUZFWSQWEPGE-UHFFFAOYSA-N 0.000 claims description 16
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 16
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 15
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 14
- 125000004076 pyridyl group Chemical group 0.000 claims description 14
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 13
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 13
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 13
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 12
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 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 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 235000010469 Glycine max Nutrition 0.000 claims description 9
- 244000025272 Persea americana Species 0.000 claims description 9
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- 108010009736 Protein Hydrolysates Proteins 0.000 claims description 9
- 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 claims description 9
- 229960003773 calcitonin (salmon synthetic) Drugs 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 108010068072 salmon calcitonin Proteins 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 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 claims description 9
- 244000068988 Glycine max Species 0.000 claims description 8
- 102000004169 proteins and genes Human genes 0.000 claims description 8
- 108090000623 proteins and genes Proteins 0.000 claims description 8
- 150000003431 steroids Chemical class 0.000 claims description 8
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 7
- SDCTXBJSIRBULY-UHFFFAOYSA-N 2-methylhept-2-enamide Chemical compound CCCCC=C(C)C(N)=O SDCTXBJSIRBULY-UHFFFAOYSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 7
- 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 claims description 7
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 7
- 235000005282 vitamin D3 Nutrition 0.000 claims description 7
- 239000011647 vitamin D3 Substances 0.000 claims description 7
- 229940021056 vitamin d3 Drugs 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 6
- FUGGGSUUMHGZBG-ABFRBSLYSA-N (1R,2R,3R,4S)-N-(3,4-dichlorophenyl)-3-[6-(trifluoromethyl)pyridin-2-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=NC(=CC=C1)C(F)(F)F)O2 FUGGGSUUMHGZBG-ABFRBSLYSA-N 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
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- 210000000130 stem cell Anatomy 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 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 claims description 4
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 claims description 4
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- RSVHECROVCKUGC-YVSFHVDLSA-N (1R,2R,3S,4S)-N-(3,4-dichlorophenyl)-3-[2-(dimethylamino)pyrimidin-5-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]1C=1C=NC(=NC1)N(C)C)O2 RSVHECROVCKUGC-YVSFHVDLSA-N 0.000 claims description 3
- RUJMSTTXGZTEFM-YLFCFFPRSA-N (1R,2S,3R,4S)-N-(4-chloro-3-fluorophenyl)-3-pyridin-4-yl-7-oxabicyclo[2.2.1]heptane-2-carboxamide Chemical compound ClC1=C(C=C(C=C1)NC(=O)[C@@H]1[C@H]2CC[C@@H]([C@H]1C1=CC=NC=C1)O2)F RUJMSTTXGZTEFM-YLFCFFPRSA-N 0.000 claims description 3
- 210000000988 bone and bone Anatomy 0.000 claims description 3
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- SAMYBFPISJORKJ-KEZOAJOQSA-N (1R,2R,3R,4S)-3-(2-cyanopyridin-4-yl)-N-[3-fluoro-4-(2-fluorophenyl)phenyl]-7-oxabicyclo[2.2.1]heptane-2-carboxamide Chemical compound C(#N)C1=NC=CC(=C1)[C@H]1[C@H]([C@H]2CC[C@@H]1O2)C(=O)NC2=CC(=C(C=C2)C2=C(C=CC=C2)F)F SAMYBFPISJORKJ-KEZOAJOQSA-N 0.000 claims description 2
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- VOBYFPMODSAXHI-KPHFQPKLSA-N (1R,2R,3R,4S)-N-[2-fluoro-3-(trifluoromethyl)phenyl]-3-[(2R)-6-(trifluoromethyl)piperidin-2-yl]-7-oxabicyclo[2.2.1]heptane-2-carboxamide Chemical compound FC1=C(C=CC=C1C(F)(F)F)NC(=O)[C@H]1[C@H]2CC[C@@H]([C@H]1[C@@H]1NC(CCC1)C(F)(F)F)O2 VOBYFPMODSAXHI-KPHFQPKLSA-N 0.000 claims description 2
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| WO2014151953A1 (en) | 2013-03-15 | 2014-09-25 | The California Institute For Biomedical Research | Compounds and methods for inducing chondrogenesis |
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| IL266361B2 (en) * | 2016-11-14 | 2024-02-01 | Novartis Ag | Methods and preparations for the treatment of cartilage damage and arthritis |
| CN110809468A (zh) * | 2017-04-24 | 2020-02-18 | 斯克利普斯研究所 | 诱导软骨发生的方法 |
| JOP20190282A1 (ar) * | 2017-06-09 | 2019-12-05 | Novartis Ag | مركبات وتركيبات لحث تكوّن الغضاريف |
| ES2981903T3 (es) * | 2017-11-10 | 2024-10-14 | Novartis Ag | Formulaciones de liberación prolongada para aplicaciones intraarticulares |
| CN112424207B (zh) | 2018-07-25 | 2024-03-19 | 诺华股份有限公司 | Nlrp3炎性小体抑制剂 |
| US12365692B2 (en) * | 2018-12-06 | 2025-07-22 | Novartis Ag | 6-hydroxy-8-oxatricyclo[3.2.1.02,4]octane-2-carboxamide derivatives for inducing chondrogenesis for treating joint damage |
| WO2020115683A1 (en) | 2018-12-06 | 2020-06-11 | Novartis Ag | 5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide derivatives for inducing chondrogenesis for treating joint damage |
| CN111601789A (zh) * | 2018-12-20 | 2020-08-28 | 江苏凯迪恩医药科技有限公司 | 一种含氮杂环化合物、其制备方法及应用 |
| UY38687A (es) | 2019-05-17 | 2023-05-15 | Novartis Ag | Inhibidores del inflamasoma nlrp3, composiciones, combinaciones de los mismos y métodos para su uso |
| RU2733472C1 (ru) * | 2020-02-26 | 2020-10-01 | Федеральное государственное бюджетное учреждение науки Новосибирский институт органической химии им. Н.Н. Ворожцова Сибирского отделения Российской академии наук (НИОХ СО РАН) | N-Ацилгидразон фенхона с фрагментом эпоксиизоиндола, используемый в качестве ингибитора репродукции вируса Хантаан |
| CN114763347B (zh) * | 2021-01-15 | 2024-06-21 | 华东师范大学 | 一类用于诱导间充质干细胞向软骨分化的化合物及其应用 |
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