KR101755742B1 - Ｃｇｒｐ 수용체 길항제 - Google Patents
Ｃｇｒｐ 수용체 길항제 Download PDFInfo
- Publication number
- KR101755742B1 KR101755742B1 KR1020127012197A KR20127012197A KR101755742B1 KR 101755742 B1 KR101755742 B1 KR 101755742B1 KR 1020127012197 A KR1020127012197 A KR 1020127012197A KR 20127012197 A KR20127012197 A KR 20127012197A KR 101755742 B1 KR101755742 B1 KR 101755742B1
- Authority
- KR
- South Korea
- Prior art keywords
- hydrogen
- pyridin
- difluorophenyl
- tetrahydro
- cyclohepta
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 108010078311 Calcitonin Gene-Related Peptide Receptors Proteins 0.000 title abstract description 17
- 102000008323 calcitonin gene-related peptide receptor activity proteins Human genes 0.000 title abstract description 12
- 229940044551 receptor antagonist Drugs 0.000 title abstract description 6
- 239000002464 receptor antagonist Substances 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 67
- 238000000034 method Methods 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 238000011282 treatment Methods 0.000 claims abstract description 18
- 208000019695 Migraine disease Diseases 0.000 claims abstract description 17
- 206010027599 migraine Diseases 0.000 claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- -1 hydroxy, azido, amino Chemical group 0.000 claims description 125
- 229910052739 hydrogen Inorganic materials 0.000 claims description 124
- 239000001257 hydrogen Substances 0.000 claims description 124
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 63
- 150000002431 hydrogen Chemical class 0.000 claims description 61
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 41
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 17
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 16
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- ZUXYCGUNLBKKQW-FHLBMDLUSA-N 1-[1-[2-[(5s,6s,9r)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5h-cyclohepta[b]pyridin-9-yl]acetyl]piperidin-4-yl]-3h-imidazo[4,5-b]pyridin-2-one Chemical compound C1([C@H]2[C@@H](C3=CC=CN=C3[C@@H](CC(=O)N3CCC(CC3)N3C(NC4=NC=CC=C43)=O)CC2)N)=CC=CC(F)=C1F ZUXYCGUNLBKKQW-FHLBMDLUSA-N 0.000 claims description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 2
- 125000004212 difluorophenyl group Chemical group 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 2
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 3
- 108090000932 Calcitonin Gene-Related Peptide Proteins 0.000 abstract description 23
- 206010019233 Headaches Diseases 0.000 abstract description 12
- 231100000869 headache Toxicity 0.000 abstract description 8
- 230000006378 damage Effects 0.000 abstract description 6
- 208000007920 Neurogenic Inflammation Diseases 0.000 abstract description 5
- 208000027418 Wounds and injury Diseases 0.000 abstract description 5
- 208000006673 asthma Diseases 0.000 abstract description 5
- 230000005796 circulatory shock Effects 0.000 abstract description 5
- 208000014674 injury Diseases 0.000 abstract description 5
- 230000024883 vasodilation Effects 0.000 abstract description 5
- 230000001272 neurogenic effect Effects 0.000 abstract description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 208000035475 disorder Diseases 0.000 abstract description 3
- 208000027866 inflammatory disease Diseases 0.000 abstract description 3
- 230000009245 menopause Effects 0.000 abstract description 3
- 238000011010 flushing procedure Methods 0.000 abstract description 2
- 102100025588 Calcitonin gene-related peptide 1 Human genes 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 296
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 140
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 132
- 239000000243 solution Substances 0.000 description 108
- 235000019439 ethyl acetate Nutrition 0.000 description 99
- 238000006243 chemical reaction Methods 0.000 description 92
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 70
- 239000000047 product Substances 0.000 description 69
- 239000000203 mixture Substances 0.000 description 63
- 239000010410 layer Substances 0.000 description 60
- 239000000543 intermediate Substances 0.000 description 59
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 51
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 49
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 45
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 38
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 36
- 238000000746 purification Methods 0.000 description 33
- 239000012044 organic layer Substances 0.000 description 31
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 31
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 239000012267 brine Substances 0.000 description 30
- 239000003921 oil Substances 0.000 description 30
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 30
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 29
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 29
- 229910052938 sodium sulfate Inorganic materials 0.000 description 29
- 235000011152 sodium sulphate Nutrition 0.000 description 29
- 239000007787 solid Substances 0.000 description 26
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 25
- 125000003545 alkoxy group Chemical group 0.000 description 24
- 229910052757 nitrogen Inorganic materials 0.000 description 23
- 102000004414 Calcitonin Gene-Related Peptide Human genes 0.000 description 22
- 238000001819 mass spectrum Methods 0.000 description 22
- 125000004438 haloalkoxy group Chemical group 0.000 description 21
- 238000003756 stirring Methods 0.000 description 20
- 125000003282 alkyl amino group Chemical group 0.000 description 19
- 125000004663 dialkyl amino group Chemical group 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 14
- 239000012230 colorless oil Substances 0.000 description 14
- 238000003818 flash chromatography Methods 0.000 description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
- 235000017557 sodium bicarbonate Nutrition 0.000 description 13
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 13
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 125000005843 halogen group Chemical group 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 125000001188 haloalkyl group Chemical group 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 125000004093 cyano group Chemical group *C#N 0.000 description 9
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 0 *[C@](CC[C@]1c(cccc2F)c2F)c(nccc2)c2C1=O Chemical compound *[C@](CC[C@]1c(cccc2F)c2F)c(nccc2)c2C1=O 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 210000000078 claw Anatomy 0.000 description 7
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
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- 125000000468 ketone group Chemical group 0.000 description 6
- 125000003386 piperidinyl group Chemical group 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 102000014468 Calcitonin Gene-Related Peptide Receptors Human genes 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- 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 5
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- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- 102100024654 Calcitonin gene-related peptide type 1 receptor Human genes 0.000 description 4
- 101710118454 Calcitonin gene-related peptide type 1 receptor Proteins 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
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- 238000010168 coupling process Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
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- 230000009885 systemic effect Effects 0.000 description 4
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 4
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
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- 125000003118 aryl group Chemical group 0.000 description 3
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- YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 3
- 108010050923 calcitonin gene-related peptide (8-37) Proteins 0.000 description 3
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- 125000000719 pyrrolidinyl group Chemical group 0.000 description 3
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- BSVHTRRLCAVQCZ-JDEXMCKMSA-N (2s)-1-[(2s)-1-[(2s)-1-[(2s)-1-[(2s)-1-[(2s)-1-[(2s)-2-[[(2s)-1-[(2s)-2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3-carboxypropanoyl]pyrrolidine-2-carbonyl]amino]propanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]pyrro Chemical compound C([C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=C(O)C=C1 BSVHTRRLCAVQCZ-JDEXMCKMSA-N 0.000 description 2
- RSGBRYRHNRENCA-OWRWGESLSA-N (5r,6s,9r)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5h-cyclohepta[b]pyridine-5,9-diol Chemical compound C1([C@@H]2CC[C@H](C3=NC=CC=C3[C@@H]2O)O)=CC=CC(F)=C1F RSGBRYRHNRENCA-OWRWGESLSA-N 0.000 description 2
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- PDKIEIZTEPXCNT-OWRWGESLSA-N (6s,8r,9s)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5h-cyclohepta[b]pyridine-8,9-diol Chemical compound C1([C@@H]2C[C@H]([C@H](C3=NC=CC=C3C2)O)O)=CC=CC(F)=C1F PDKIEIZTEPXCNT-OWRWGESLSA-N 0.000 description 2
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- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 2
- MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 0.000 description 2
- OTLNPYWUJOZPPA-UHFFFAOYSA-M 4-nitrobenzoate Chemical compound [O-]C(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-M 0.000 description 2
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- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
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- 206010061218 Inflammation Diseases 0.000 description 2
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- MGTFJAYMAWIDJN-UGSOOPFHSA-N tert-butyl n-[(5s,6s)-6-(2,3-difluorophenyl)-9-oxo-5,6,7,8-tetrahydrocyclohepta[b]pyridin-5-yl]carbamate Chemical compound C1([C@H]2[C@@H](C3=CC=CN=C3C(=O)CC2)NC(=O)OC(C)(C)C)=CC=CC(F)=C1F MGTFJAYMAWIDJN-UGSOOPFHSA-N 0.000 description 1
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- YNIAAQHUSABKJA-XCRHUMRWSA-N tert-butyl n-[(5s,6s,9r)-6-(2,3-difluorophenyl)-9-hydroxy-6,7,8,9-tetrahydro-5h-cyclohepta[b]pyridin-5-yl]carbamate Chemical compound C1([C@H]2[C@@H](C3=CC=CN=C3[C@H](O)CC2)NC(=O)OC(C)(C)C)=CC=CC(F)=C1F YNIAAQHUSABKJA-XCRHUMRWSA-N 0.000 description 1
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- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 102000027257 transmembrane receptors Human genes 0.000 description 1
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- LHJCZOXMCGQVDQ-UHFFFAOYSA-N tri(propan-2-yl)silyl trifluoromethanesulfonate Chemical compound CC(C)[Si](C(C)C)(C(C)C)OS(=O)(=O)C(F)(F)F LHJCZOXMCGQVDQ-UHFFFAOYSA-N 0.000 description 1
- VHKIEYIESYMHPT-UHFFFAOYSA-N triethyl(methoxycarbonylsulfamoyl)azanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC VHKIEYIESYMHPT-UHFFFAOYSA-N 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
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| US8314117B2 (en) * | 2009-10-14 | 2012-11-20 | Bristol-Myers Squibb Company | CGRP receptor antagonists |
| US8669368B2 (en) * | 2010-10-12 | 2014-03-11 | Bristol-Myers Squibb Company | Process for the preparation of cycloheptapyridine CGRP receptor antagonists |
| US8748429B2 (en) * | 2011-04-12 | 2014-06-10 | Bristol-Myers Squibb Company | CGRP receptor antagonists |
| HUE034936T2 (hu) * | 2012-02-27 | 2018-03-28 | Bristol Myers Squibb Co | N-(5S,6S,9R)-5-amino-6-(2,3-difluorfenil)-6,7,8,9-tetrahidro-5H-ciklohepta[B-]piridin-9-il-4- (2-oxo-2,3-dihidro-1H-imidazo[4,5-B]piridin-1-IL)piperidin-1-karboxilát, hemiszulfát só |
| WO2013169563A1 (en) * | 2012-05-09 | 2013-11-14 | Merck Sharp & Dohme Corp. | Pyridine cgrp receptor antagonists |
| EP2815749A1 (en) | 2013-06-20 | 2014-12-24 | IP Gesellschaft für Management mbH | Solid form of 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione having specified X-ray diffraction pattern |
| TW201718574A (zh) * | 2015-08-12 | 2017-06-01 | 美國禮來大藥廠 | Ｃｇｒｐ受體拮抗劑 |
| GB201519196D0 (en) | 2015-10-30 | 2015-12-16 | Heptares Therapeutics Ltd | CGRP Receptor Antagonists |
| GB201519194D0 (en) | 2015-10-30 | 2015-12-16 | Heptares Therapeutics Ltd | CGRP receptor antagonists |
| GB201519195D0 (en) | 2015-10-30 | 2015-12-16 | Heptares Therapeutics Ltd | CGRP Receptor Antagonists |
| GB201707938D0 (en) | 2017-05-17 | 2017-06-28 | Univ Sheffield | Compounds |
| KR20200135465A (ko) | 2018-03-25 | 2020-12-02 | 바이오하벤 파마슈티컬 홀딩 컴퍼니 엘티디. | Cgrp 관련 장애를 위한 리메게판트 |
| CN114805206B (zh) * | 2021-01-27 | 2025-01-14 | 奥锐特药业(天津)有限公司 | 高光学纯度瑞美吉泮中间体的工业化制备方法 |
| JP2024509165A (ja) | 2021-03-02 | 2024-02-29 | シージーアールピー ダイアグノスティクス ゲーエムベーハー | 片頭痛の治療及び／又は発生の低減 |
| US20250109188A1 (en) | 2021-08-24 | 2025-04-03 | Cgrp Diagnostics Gmbh | Preventative treatment of migraine |
| CN115850266A (zh) * | 2021-09-26 | 2023-03-28 | 奥锐特药业(天津)有限公司 | 瑞美吉泮新晶型及其制备方法 |
| CN116554164B (zh) * | 2022-01-27 | 2025-10-03 | 奥锐特药业(天津)有限公司 | 一种瑞美吉泮的制备方法 |
| WO2023175632A1 (en) * | 2022-03-17 | 2023-09-21 | Msn Laboratories Private Limited, R&D Center | Solid state forms of (5s,6s,9r)-5-amino-6-(2,3difluorophenyl)-6,7,8,9-tetrahydro-5h-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1h-imidazo[4,5-b]pyridin-1-yl)-1-piperidinecarboxylate hemisulfate and processes for preparation thereof |
| CN116478211B (zh) * | 2022-04-19 | 2023-10-24 | 石家庄迪斯凯威医药科技有限公司 | 一种新型cgrp受体拮抗剂及其用途 |
| CN115060824B (zh) * | 2022-06-14 | 2024-03-12 | 浙江宏元药业股份有限公司 | 一种瑞米吉泮中间体对映异构体杂质的液相色谱检测方法 |
| CN117466893A (zh) * | 2022-07-29 | 2024-01-30 | 熙源安健医药（上海）有限公司 | 吡啶并环庚烷类衍生物及其制备方法和用途 |
| CN115677694A (zh) * | 2022-11-30 | 2023-02-03 | 南通常佑药业科技有限公司 | 一种瑞美吉泮的合成方法 |
| WO2024180562A1 (en) * | 2023-03-02 | 2024-09-06 | Natco Pharma Limited | A process for the preparation of pure crystalline rimegepant and its salts thereof |
| CN116768938B (zh) * | 2023-05-17 | 2025-11-11 | 南京艾德凯腾生物医药有限责任公司 | 一种铁催化剂及瑞美吉泮中间体的制备方法 |
| WO2025061177A1 (zh) * | 2023-09-21 | 2025-03-27 | 成都康弘药业集团股份有限公司 | 一种治疗cgrp相关障碍的小分子药物 |
| CN117486798B (zh) * | 2023-12-21 | 2025-02-07 | 南京威凯尔生物医药科技有限公司 | 一种瑞美吉泮中间体盐酸盐的晶型及其制备方法 |
| WO2025193980A2 (en) * | 2024-03-13 | 2025-09-18 | CNS Biosciences, Inc. | Method of treating neuropathic pain using an anti-cgrp inhibitor |
| CN119707808B (zh) * | 2024-12-23 | 2025-12-05 | 上海彩迩文生化科技有限公司 | 一种制备cgrp受体拮抗剂中间体的方法 |
| CN119977885A (zh) * | 2025-04-15 | 2025-05-13 | 常州制药厂有限公司 | (5S,6S,9R)-5-氨基-6-(2,3-二氟苯基)-6,7,8,9-四氢-5H-环庚[b]吡啶-9-醇L-酒石酸盐及其制备方法 |
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| WO2006044604A1 (en) | 2004-10-14 | 2006-04-27 | Bayer Materialscience Llc | Rigid foams with good insulation properties and a process for the production of such foams |
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| JO2355B1 (en) * | 2003-04-15 | 2006-12-12 | ميرك شارب اند دوم كوربوريشن | Hereditary calcitonin polypeptide receptor antagonists |
| EP1726590A4 (en) | 2004-03-05 | 2009-07-15 | Banyu Pharma Co Ltd | CYCLOALKANOPYRIDINDERIVAT |
| KR20070062997A (ko) | 2004-10-13 | 2007-06-18 | 머크 앤드 캄파니 인코포레이티드 | Ｃｇｒｐ 수용체 길항제 |
| JP2008517916A (ja) | 2004-10-22 | 2008-05-29 | メルク エンド カムパニー インコーポレーテッド | Ｃｇｒｐ受容体拮抗薬 |
| CN101421267B (zh) | 2006-04-10 | 2011-10-19 | 默沙东公司 | 制备吡啶杂环cgrp拮抗剂中间体的方法 |
| US8143403B2 (en) | 2008-04-11 | 2012-03-27 | Bristol-Myers Squibb Company | CGRP receptor antagonists |
| US8044043B2 (en) * | 2008-04-11 | 2011-10-25 | Bristol-Myers Squibb Company | CGRP receptor antagonists |
| US8314117B2 (en) * | 2009-10-14 | 2012-11-20 | Bristol-Myers Squibb Company | CGRP receptor antagonists |
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|---|---|---|---|---|
| WO2006044604A1 (en) | 2004-10-14 | 2006-04-27 | Bayer Materialscience Llc | Rigid foams with good insulation properties and a process for the production of such foams |
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| Tetrahedron Letters, 48(15), 2661-2665, 2007. |
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