JP2013515037A - シクロフィリンの新しいインヒビター及びその使用 - Google Patents
シクロフィリンの新しいインヒビター及びその使用 Download PDFInfo
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- JP2013515037A JP2013515037A JP2012545292A JP2012545292A JP2013515037A JP 2013515037 A JP2013515037 A JP 2013515037A JP 2012545292 A JP2012545292 A JP 2012545292A JP 2012545292 A JP2012545292 A JP 2012545292A JP 2013515037 A JP2013515037 A JP 2013515037A
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- 102000001493 Cyclophilins Human genes 0.000 title description 22
- 239000003112 inhibitor Substances 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 168
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 59
- 125000003118 aryl group Chemical group 0.000 claims abstract description 54
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- 230000003902 lesion Effects 0.000 claims abstract description 4
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 46
- 125000001072 heteroaryl group Chemical group 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 29
- 125000004429 atom Chemical group 0.000 claims description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
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- 238000005481 NMR spectroscopy Methods 0.000 description 189
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 80
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 66
- 239000004202 carbamide Substances 0.000 description 64
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 51
- -1 9-fluorenyl groups Chemical group 0.000 description 46
- 238000001556 precipitation Methods 0.000 description 46
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- 238000006243 chemical reaction Methods 0.000 description 40
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- 239000000203 mixture Substances 0.000 description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 34
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 32
- 239000000243 solution Substances 0.000 description 31
- 230000015572 biosynthetic process Effects 0.000 description 28
- 239000012267 brine Substances 0.000 description 28
- 239000012071 phase Substances 0.000 description 28
- 230000002441 reversible effect Effects 0.000 description 28
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 28
- 238000003786 synthesis reaction Methods 0.000 description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 125000001424 substituent group Chemical group 0.000 description 25
- 239000000460 chlorine Substances 0.000 description 24
- 235000015165 citric acid Nutrition 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 20
- 229920006395 saturated elastomer Polymers 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 17
- 201000010099 disease Diseases 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 125000005842 heteroatom Chemical group 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 0 CC*N*(C)N*(*)C(*)=O Chemical compound CC*N*(C)N*(*)C(*)=O 0.000 description 13
- 230000008569 process Effects 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- 108010072220 Cyclophilin A Proteins 0.000 description 12
- 108010048028 Cyclophilin D Proteins 0.000 description 12
- 102100034539 Peptidyl-prolyl cis-trans isomerase A Human genes 0.000 description 12
- 102100040283 Peptidyl-prolyl cis-trans isomerase B Human genes 0.000 description 12
- 102100034943 Peptidyl-prolyl cis-trans isomerase F, mitochondrial Human genes 0.000 description 12
- 108010048032 cyclophilin B Proteins 0.000 description 12
- 230000004770 neurodegeneration Effects 0.000 description 12
- 208000015122 neurodegenerative disease Diseases 0.000 description 12
- 108010044156 peptidyl-prolyl cis-trans isomerase b Proteins 0.000 description 12
- 125000006413 ring segment Chemical group 0.000 description 12
- 238000004809 thin layer chromatography Methods 0.000 description 12
- 206010028980 Neoplasm Diseases 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 10
- 239000012230 colorless oil Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
- 201000011510 cancer Diseases 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 235000018102 proteins Nutrition 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 8
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 8
- 125000002619 bicyclic group Chemical group 0.000 description 8
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 8
- 229910052736 halogen Inorganic materials 0.000 description 8
- 150000002367 halogens Chemical class 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 238000005259 measurement Methods 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- URXUHALBOWYXJZ-UHFFFAOYSA-N tert-butyl n-[4-(aminomethyl)phenyl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(CN)C=C1 URXUHALBOWYXJZ-UHFFFAOYSA-N 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- YCWRFIYBUQBHJI-UHFFFAOYSA-N 2-(4-aminophenyl)acetonitrile Chemical group NC1=CC=C(CC#N)C=C1 YCWRFIYBUQBHJI-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
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- 125000004122 cyclic group Chemical group 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- DUVOZUPPHBRJJO-UHFFFAOYSA-N ethyl 2-isocyanatoacetate Chemical compound CCOC(=O)CN=C=O DUVOZUPPHBRJJO-UHFFFAOYSA-N 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
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- 241000699670 Mus sp. Species 0.000 description 6
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 6
- 150000003672 ureas Chemical class 0.000 description 6
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 5
- 101100459319 Arabidopsis thaliana VIII-2 gene Proteins 0.000 description 5
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- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 description 4
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- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 4
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- 125000004475 heteroaralkyl group Chemical group 0.000 description 4
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
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- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 3
- HXALGYTVKCKONE-UHFFFAOYSA-N 3-(3-hydroxyphenyl)-2-[[4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]methylcarbamoylamino]propanoic acid Chemical compound C1=CC(NC(=O)OC(C)(C)C)=CC=C1CNC(=O)NC(C(O)=O)CC1=CC=CC(O)=C1 HXALGYTVKCKONE-UHFFFAOYSA-N 0.000 description 3
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- OLROWHGDTNFZBH-XEMWPYQTSA-N Alisporivir Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N(CC)C(=O)[C@@H](C)N(C)C1=O OLROWHGDTNFZBH-XEMWPYQTSA-N 0.000 description 3
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- XMBPOSPCOWRBOY-UHFFFAOYSA-N benzyl 2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(3-phenylmethoxyphenyl)propanoate Chemical compound C=1C=CC=CC=1COC(=O)C(NC(=O)OC(C)(C)C)CC(C=1)=CC=CC=1OCC1=CC=CC=C1 XMBPOSPCOWRBOY-UHFFFAOYSA-N 0.000 description 3
- GRVIMKBWSJFTLF-UHFFFAOYSA-N benzyl 2-[[4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]methylcarbamoylamino]-3-(3-phenylmethoxyphenyl)propanoate Chemical compound C1=CC(NC(=O)OC(C)(C)C)=CC=C1CNC(=O)NC(C(=O)OCC=1C=CC=CC=1)CC1=CC=CC(OCC=2C=CC=CC=2)=C1 GRVIMKBWSJFTLF-UHFFFAOYSA-N 0.000 description 3
- KIZOACZZUANHDT-UHFFFAOYSA-N benzyl 2-amino-3-(3-hydroxyphenyl)propanoate Chemical compound C=1C=CC=CC=1COC(=O)C(N)CC1=CC=CC(O)=C1 KIZOACZZUANHDT-UHFFFAOYSA-N 0.000 description 3
- QYVGIMYQIPDNEI-UHFFFAOYSA-N benzyl 2-amino-3-(3-phenylmethoxyphenyl)propanoate Chemical compound C=1C=CC=CC=1COC(=O)C(N)CC(C=1)=CC=CC=1OCC1=CC=CC=C1 QYVGIMYQIPDNEI-UHFFFAOYSA-N 0.000 description 3
- AOGIWGWZZYCBOR-UHFFFAOYSA-N benzyl 3-(3-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound C=1C=CC=CC=1COC(=O)C(NC(=O)OC(C)(C)C)CC1=CC=CC(O)=C1 AOGIWGWZZYCBOR-UHFFFAOYSA-N 0.000 description 3
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
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Classifications
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- 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
- C07D401/14—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 three or more hetero rings
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
- C07C291/02—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C307/04—Diamides of sulfuric acids
- C07C307/06—Diamides of sulfuric acids having nitrogen atoms of the sulfamide groups bound to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
- C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
- C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/06—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms
- C07C335/10—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C335/12—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/42—Oxygen atoms attached in position 3 or 5
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
Description
[式中、
− nは、0、1、2又は3であり;
− Aは、CH又はNであるか、あるいはAは、Cであって、R1、R2及びCOと一緒に、場合により置換されている、5〜20個の原子を含むヘテロシクリル基を形成し;
− Xは、CO、SO2、又はCSであり、
− R1は、H、アルキル基、及びアラルキル基(該アルキル又はアラルキル基は、場合により置換されている)よりなる群から選択され;
− R2は、式:NR3R4又はOR5の基であり(ここで、
R3及びR4は、それぞれ独立に、H、ORa、アルキル基、アラルキル基、及びアリール基から選択的され(Raは、H、アルキル基、アリール基、及びアラルキル基よりなる群から選択される)(ここで、R3及びR4は、これらを結合している窒素原子と一緒に、場合により置換されている、5〜20個の原子を含むヘテロシクリル基を形成してもよい);
R5は、アルキル基、アリール基、及びアラルキル基から選択される(ここで、R5は、これを結合している酸素原子と一緒に、場合により置換されている、5〜20個の原子のヘテロシクリル基を形成してもよい));
− R6は、H又はアルキル基であるか、あるいはR2と一緒に、20〜30個の原子、好ましくは25〜30個の原子のヘテロシクリル基を形成してもよいか、又はR1と一緒に、10〜30個の原子のヘテロシクリル基を形成してもよく;
− R7は、アリール基、ヘテロアリール基、ヘテロシクリル基、NHPh、及びアルキル基よりなる群から選択される(ここで、
AがNであるとき、R1及びR2は、A及びCOと一緒に、場合により置換されている、5〜20個の原子を含むヘテロシクリル基を形成してもよい)]を有する化合物、又はその薬学的に許容しうる塩、水和物若しくは水和塩、又はその多形結晶構造、ラセミ体、ジアステレオマー若しくはエナンチオマーに関する。
− Rfは、H又はアルキル基であり、
− Ra、Rb、Rc、Rd、Re、Rg、Rh及びRiは、相互に独立に、以下の置換基:
H、
ハロゲン(I、Br、Cl又はFなど)、
アルキル基(該アルキル基は、場合により、詳しくは以下の置換基:グアニジニル、ハロゲン、アルケニル又はアルキニル基、アリール基、CORα、COORα、SRα、ORα又はNRαRβ基(Rα及びRβは、相互に独立に、H、アルキル基又はアリール基を表す)よりなる群において選択される1個以上の置換基により置換されている)、
−CHO、
−CN、
−NO2、
フェニル、
(ヘテロ)アリール又はヘテロシクリル(場合により置換されている)、
−SRα、ORα、−NRαRβ、−CONRαRβ、及び−NHCORα(Rα及びRβは、上記と同義である)
よりなる群において選択される。
[式中、Rは、H、又は詳しくはアルキル(場合により置換されている)、アリール(場合により置換されている)、アミノ、ヒドロキシ、及びアルコキシよりなる群から選択される置換基である]を有する基を形成する。
[式中、R’は、アルキル基(場合により、詳しくはヒドロキシ、アリール、アルコキシ又はヘテロシクリル基から選択される置換基で置換されている)である]を有する基である。
[式中、nは、0、1又は2であり、そしてRは、H、又は場合により置換されているアリール、そして好ましくは場合により置換されているフェニルである]を有する基を形成する。
[式中、
− X、A、R1、R3及びR4は、式(I)中の上記と同義であり、そして
− R8は、H、ハロゲン、アルキル、アルコキシ、チオアルコキシ(−S−アルキル)、アシル基(詳しくはアルキルカルボニル基)、及びヘテロアリール基(詳しくはフラニル、オキサゾリル、及びイソオキサゾリル基、そして更に詳しくは2−フラニル、5−オキサゾリル、及び3−イソオキサゾリル基)よりなる群から選択される]を有する化合物に関する。
[式中、R3及びR4は、式(I)中の上記と同義であるが、R3は、好ましくはエチルのようなアルキル基であり、そしてR4は、好ましくは(ヘテロ)アリール基である]を有する化合物に関する。
[式中、R”は、OH、N−フェニル−ピペラジニルのような場合により置換されているヘテロシクリル、アルコキシ、フェニルのようなアリール、ベンジルオキシのようなO−アルキルアリール、フェノキシのようなアリールオキシから選択される]を有する化合物に関する。
[式中、Rは、Clのようなハロゲン、メトキシのようなアルコキシ、及びCOMeのようなアルキルカルボニルから選択される]を有する化合物に関する。
[式中、Rは、ヒドロキシ、F又はClのようなハロゲン、メトキシのようなアルコキシ、COMeのようなアルキルカルボニル、ニトロ、及びCOOEtのようなアルキルエステルから選択される]を有する化合物に関する。
[式中、R3及びR4は、式(I)中の上記と同義であり、そして
R8は、ヘテロアリール基(詳しくは、フラニル、オキサゾリル、及びイソオキサゾリル基から、更に詳しくは2−フラニル、5−オキサゾリル、及び3−イソオキサゾリル基から選択される)である]を有する化合物に関する。
[式中、R11及びR12は、相互に独立に、H、アルキル、アルコキシ、アリール、及びアラルキルよりなる群から選択され、そして
A’は、CH2又はNHである]を有する化合物に関する。
[式中、
− A’は、式(VIII)中の上記と同義であり、
− A’1は、(CH2)mCO、(CH2)m、及びO(CH2)m(mは、1〜5まで変化する整数である)よりなる群から選択され、そして
− A’2は、アリール及びヘテロアリール基から選択され、そして特にフェニルである]を有する化合物により構成される。
[式中、R11及びR12は、相互に独立に、H、アルキル、アルコキシ、アリール、及びアラルキルよりなる群から選択される]を有する化合物により構成される。
[式中、
− X、A、R1、及びR5は、式(I)中の上記と同義であり、そして
− R8は、H、アシル基(詳しくはアルキルカルボニル基)、及びヘテロアリール基(詳しくはフラニル、オキサゾリル、及びイソオキサゾリル基、そして更に詳しくは2−フラニル、5−オキサゾリル、及び3−イソオキサゾリル基)よりなる群から選択される]を有する化合物に関する。
[式中、n、R6、及びR7は、式(I)中の上記と同義であるが、R7は、好ましくはアリール基、ヘテロアリール基、及びヘテロシクリル基よりなる群から選択され、そしてnは、好ましくは0である]を有する化合物に関する。
[式中、n及びR5は、式(I)中の上記と同義であり、そしてR7は、少なくとも1個の窒素原子及び1個の硫黄原子を環内に含み、かつ1個のNH2基を置換基として含むヘテロアリール基である]を有する化合物に関する。
[式中、
− R1、R2、A、X及びR6は、式(I)中の上記と同義であり、そして
− R7は、少なくとも1個のNH2基により置換されている、アリール基及び5又は6個の環原子を含むヘテロアリール基よりなる群から選択される]を有する化合物、又はその薬学的に許容しうる塩、水和物若しくは水和塩、又はその多形結晶構造、ラセミ体、ジアステレオマー若しくはエナンチオマーに関する;ただし、以下の化合物を除く:
[式中、R1、R2、A、X及びR6は、式(I)中の上記と同義である]を有する化合物に関する;ただし、上記1174633-24-9及び343823-60-9化合物を除く。
[式中、R1、R2、A、及びR6は、式(I)中の上記と同義である]を有する化合物に関する;ただし、上記1174633-24-9及び343823-60-9化合物を除く。
[式中、
− R1、R2、A、X及びR6は、式(I)中の上記と同義であり、そして
− R7は、好ましくは少なくとも1個のNH2基により置換されている、アリール基及び5個の環原子を含むヘテロアリール基よりなる群から選択される]を有する化合物、又はその薬学的に許容しうる塩、水和物若しくは水和塩、又はその多形結晶構造、ラセミ体、ジアステレオマー若しくはエナンチオマーに関する。
[式中、
− R1、R2、A、及びR6は、式(I)中の上記と同義であり、そして
− R7は、好ましくは少なくとも1個のNH2基により置換されている、アリール基及び5個の環原子を含むヘテロアリール基よりなる群から選択される]を有する化合物、又はその薬学的に許容しうる塩、水和物若しくは水和塩、又はその多形結晶構造、ラセミ体、ジアステレオマー若しくはエナンチオマーに関する。
[式中、
− R1、R2、A、及びR6は、式(I)中の上記と同義であり、そして
− R7は、好ましくは少なくとも1個のNH2基により置換されている、アリール基及び5個の環原子を含むヘテロアリール基よりなる群から選択される]を有する化合物、又はその薬学的に許容しうる塩、水和物若しくは水和塩、又はその多形結晶構造、ラセミ体、ジアステレオマー若しくはエナンチオマーに関する。
[式中、
− R1、R2、A、及びR6は、式(I)中の上記と同義であり、そして
− R7は、好ましくは少なくとも1個のNH2基により置換されている、アリール基及び5個の環原子を含むヘテロアリール基よりなる群から選択される]を有する化合物、又はその薬学的に許容しうる塩、水和物若しくは水和塩、又はその多形結晶構造、ラセミ体、ジアステレオマー若しくはエナンチオマーに関する。
[式中、
− R1、R2、X、及びAは、式(I)中の上記と同義であり、そして
− R7は、好ましくは少なくとも1個のNH2基により置換されている、アリール基及び5個の環原子を含むヘテロアリール基よりなる群から選択される]を有する化合物、又はその薬学的に許容しうる塩、水和物若しくは水和塩、又はその多形結晶構造、ラセミ体、ジアステレオマー若しくはエナンチオマーに関する。
[式中、R7は、少なくとも1個のNH2基により置換されている、アリール基及び5又は6個の環原子を含むヘテロアリール基よりなる群から選択される]を有する化合物に関する。
[式中、n及びR5は、式(I)中の上記と同義であり、そしてR7は、少なくとも1個の窒素原子及び1個の硫黄原子を環内に含み、かつ1個のNH2基を置換基として含むヘテロアリール基である]を有する化合物に関する。
[式中、A’、R11及びR12は、式(VIII)中の上記と同義である]を有する化合物との反応を含む方法に関する。
[式中、R11及びR12は、式(VIII)中の上記と同義である]を有する化合物との反応を含む方法に関する。
を有する化合物との、アミン:NH(R11)(R12)の存在下での反応を含む方法に関する。
A 化合物の合成
一般法。 全ての市販の試薬(Aldrich、Acros、Chembridge、Chemivate)及び溶媒(SDS)は、更に精製することなく使用した。質量スペクトルは、Micromass Q-Tofを用いてESI条件下で得た。全ての化合物の1H NMRスペクトルは、テトラメチルシラン(TMS)を内部標準として用いてBruker 200、300、400、500及び600MHz分光光度計で記録し、そしてプロトン共鳴に関する化学シフト(δ)データは、内部標準TMSに対して100万分の1(ppm)単位で報告した。薄層クロマトグラフィー(TLC)は、Macherey-Nagel製のシリカゲル60 F254プレートを用いて実施して、UV光により視覚化した。フラッシュクロマトグラフィーは、SDSシリカゲル60(35〜70メッシュ)を用いて、ヘキサン、酢酸エチル(EtOAc)、ジクロロメタン(DCM)、石油エーテル(EDP)及びメタノール(MeOH)を溶離液として行った(クロマトグラフィー溶媒の比率は容量:容量に基づいて表される)。報告される化学収量は、最適化しなかった。HPLCクロマトグラフィーは、Waters Alliance 2790(検出器UV);方法A:カラム、Thermo Hypersil C18(50×2.1mm)、溶離液の勾配、水/アセトニトリル/トリフルオロ酢酸(15分で99.9%/0%/0.1%から19.9%/80%/0.1%);方法B:カラム、Waters Atlantis C18(250×5mm)、溶離液の勾配、水/アセトニトリル/トリフルオロ酢酸(30分で99.9%/0%/0.1%から9.9%/90%/0.1%)を用いて実施した。質量スペクトルは、Bruker製のMicromass Q-TofをElectroSpray(ESI)法で用いて測定した。
イソシアナト酢酸エチル(1当量、100mg、87μl、0.77mmol)をTHF(0.4M)中又はDMF(0.4M)中に溶解した。トリエチルアミン1当量を加えたが、このアミンがHClの塩の形であるならば、アミン(1当量)は、一度に加え、そして反応混合物を室温で2時間放置した。反応が終了(TLC管理)後、この反応混合物を濃縮して、様々な手順で精製した。
1を、AcOEt/EDP中での沈殿により精製して、白色の固体200mg(87%)を得た。Rf=0.52(AcOEt)。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 2.82 (t, 4H, J = 4.3 Hz), 3.74 (t, 4H, J = 4.3 Hz), 3.79 (d, 2H, J = 6.0 Hz), 4.08 (q, 2H, J = 7.1 Hz), 4.28 (d, 2H, J = 5.8 Hz), 6.32 (t, 1H, J = 6.0 Hz), 6.56 (t, 1H, J = 5.8 Hz), 7.05 (d, 1H, J = 7.4 Hz), 7.11 (d, 1H, J = 7.3 Hz), 7.22 (d, 1H, J = 7.4 Hz), 7.27 (d, 1H, J = 7.3 Hz)。HPLC 方法A tr=8.34mn(100%)。ESI−MS m/z:322.2[M+H]+。
2を、EDP中での沈殿により精製して、白色の固体194mg(98%)を得た。Rf=0.55(AcOEt)。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 3.78 (d, 2H, J = 6.0 Hz), 4.08 (q, 2H, J = 7.1 Hz), 4.23 (d, 2H, J = 6.0 Hz), 6.36 (t, 1H, J = 6.0 Hz), 6.75 (t, 1H, J = 6.0 Hz), 7.05 (m, 3H), 7.35 (m, 1H)。HPLC 方法A tr=8.98mn(97.5%)。ESI−MS m/z:255.2[M+H]+。
3を、EDP中での沈殿により精製して、白色の固体199mg(97%)を得た。Rf=0.71(AcOEt)。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 3.73 (s, 3H), 3.78 (d, 2H, J = 6.0 Hz), 4.08 (q, 2H, J = 7.1 Hz), 4.18 (d, 2H, J = 6.0 Hz), 6.29 (t, 1H, J = 6.0 Hz), 6.66 (t, 1H, J = 6.0 Hz), 6.81 (m, 3H), 7.22 (t, 1H, J= 8.0 Hz)。HPLC 方法A tr=8.92mn(100%)。ESI−MS m/z:267.2[M+H]+。
4を、AcOEt/EDP中での沈殿により精製して、白色の固体177mg(90%)を得た。Rf=0.55(AcOEt)。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 3.78 (d, 2H, J = 6.0 Hz), 4.08 (q, 2H, J = 7.1 Hz), 4.19 (d, 2H, J = 6.0 Hz), 6.30 (t, 1H, J = 6.0 Hz), 6.69 (t, 1H, J = 6.0 Hz), 7.14 (m, 2H), 7.29 (m, 2H)。HPLC 方法A tr=8.97mn(98.1%)。ESI−MS m/z:255.2[M+H]+。
5を、EDP中での沈殿により精製して、白色の固体213mg(90%)を得た。Rf=0.53(AcOEt)。1H NMR (DMSO): δ 0.95 (t, 3H, J= 7.1 Hz), 3.54 (d, 2H, J = 6.1 Hz), 3.85 (q, 2H, J = 7.1 Hz), 4.06 (d, 2H, J = 6.1 Hz), 6.14 (t, 1H, J = 6.1 Hz), 6.58 (t, 1H, J = 6.1 Hz), 7.64 (m, 4H)。HPLC 方法A tr=11.45mn(91.2%)。ESI−MS m/z:305.2[M+H]+。
6を、EDP中での沈殿により精製して、白色の固体199mg(97%)を得た。Rf=0.43(AcOEt)。1H NMR (CDCl3): δ 1.19 (t, 3H, J= 7.1 Hz), 1.66 (sl, 1H), 3.15 (t, 2H, J= 4.5 Hz), 3.36 (q, 2H, J= 5.5 Hz), 3.91 (d, 2H, J = 5.5 Hz), 4.07 (q, 2H, J = 7.1 Hz), 5.15 (t, 1H, J = 5.5 Hz), 5.25 (t, 1H, J = 5.5 Hz), 6.53 (d, 2H, J= 7.5 Hz), 6.62 (t, 1H, J= 7.5 Hz), 7.09 (t, 2H, J= 7.5 Hz)。HPLC 方法A tr=7.30mn(96.1%)。ESI−MS m/z:266.2[M+H]+。
7を、EDP中での沈殿により精製して、白色の固体282mg(99%)を得た。Rf=0.14(AcOEt)。1H NMR (CDCl3): δ 1.19 (t, 3H, J= 7.1 Hz), 2.51 (t, 4H, J = 4.7 Hz), 2.74 (t, 2H, J = 5.3 Hz), 3.66 (t, 4H, J = 4.7 Hz), 3.89 (d, 2H, J = 5.3 Hz), 4.08 (m, 4H), 4.28 (d, 2H, J = 6.0 Hz), 5.12 (sl, 1H), 5.53 (sl, 1H), 6.77 (d, 1H, J = 8.2 Hz), 6.83 (t, 1H, J = 7.4 Hz), 7.16 (m, 2H)。HPLC 方法A tr=8.70mn(96.9%)。ESI−MS m/z:366.2[M+H]+。
8を、EDP中での沈殿により精製して、白色の固体201mg(98%)を得た。Rf=0.32(AcOEt)。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 2.55 (t, 2H, J= 7.3 Hz), 3.15 (q, 2H, J= 6.8 Hz), 3.75 (d, 2H, J = 6.0 Hz), 4.08 (q, 2H, J = 7.1 Hz), 6.11 (t, 1H, J = 6.0 Hz), 6.21 (t, 1H, J = 6.0 Hz), 6.68 (d, 2H, J= 8.3 Hz), 6.99 (d, 1H, J= 8.3 Hz), 9.16 (s, 1H)。HPLC 方法A tr=7.64mn(99.4%)。ESI−MS m/z:267.2[M+H]+。
9を、EDP中での沈殿により精製して、白色の固体209mg(99%)を得た。Rf=0.48(AcOEt)。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 3.78 (d, 2H, J = 6.0 Hz), 4.09 (q, 2H, J = 7.1 Hz), 4.22 (d, 2H, J = 6.0 Hz), 6.36 (t, 1H, J = 6.0 Hz), 6.75 (t, 1H, J = 6.0 Hz), 7.05 (d, 1H, J= 7.3 Hz), 7.27 (m, 3H)。HPLC 方法A tr=10.37mn(99.0%)。ESI−MS m/z:271.3/273.1[M+H]+。
10を、EDP中での沈殿により精製して、白色の固体66mg(35%)を得た。Rf=0.83(AcOEt)。1H NMR (DMSO): δ 1.05 (m, 2H), 1.19 (t, 3H, J= 7.1 Hz), 1.51 (m, 3H), 2.89 (t, 2H, J = 6.0 Hz), 3.24 (t, 2H, J = 11.3 Hz), 3.75 (d, 2H, J = 6.0 Hz), 3.83 (dd, 2H, J = 10.3; 3.4 Hz), 4.08 (q, 2H, J = 7.1 Hz), 6.11 (t, 1H, J = 6.0 Hz), 6.22 (t, 1H, J = 6.0 Hz)。HPLC 方法A tr=6.54mn(92.2%)。ESI−MS m/z:245.2[M+H]+。
11を、EDP中での沈殿により精製して、白色の固体217mg(92%)を得た。Rf=0.75(AcOEt)。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 3.32 (d, 2H, J = 6.0 Hz), 4.09 (q, 2H, J = 7.1 Hz), 4.22 (d, 2H, J = 6.1 Hz), 6.44 (t, 1H, J = 6.1 Hz), 6.81 (t, 1H, J = 6.0 Hz), 7.29 (d, 2H, J= 1.9 Hz), 7.46 (t, 1H, J= 1.9 Hz)。HPLC 方法A tr=12.08mn(96.1%)。ESI−MS m/z:305.1/307.1[M+H]+。
12を、AcOEt/EDP中での沈殿により精製して、白色の固体63mg(31%)を得た。Rf=0.36(AcOEt)。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 2.48 (m, 2H), 3.12 (m, 2H), 3.91 (d, 2H, J = 6.0 Hz), 4.07 (q, 2H, J = 7.1 Hz), 4.84 (s, 2H), 6.08 (t, 1H, J = 5.5 Hz), 6.21 (d, 2H, J= 5.9 Hz), 6.48 (d, 2H, J= 8.2 Hz), 6.84 (d, 2H, J= 8.2 Hz)。HPLC 方法A tr=6.12mn(97.1%)。ESI−MS m/z:266.2[M+H]+。
13を、EDP中での沈殿により精製して、白色の固体142mg(65%)を得た。Rf=0.32(AcOEt)。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 3.77 (d, 2H, J= 6.0 Hz), 4.09 (m, 4H), 5.97 (s, 1H), 6.25 (t, 1H, J = 6.0 Hz), 6.62 (t, 1H, J= 6.0 Hz), 6.75 (d, 1H, J= 8.3; 1.9 Hz), 7.80 (m, 2H)。HPLC 方法A tr=8.76mn(99.6%)。ESI−MS m/z:281.2[M+H]+。
14を、EDP中での沈殿により精製して、白色の固体100mg(41%)を得た。Rf=0.70(AcOEt)。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 3.78 (d, 2H, J = 6.0 Hz), 4.08 (q, 2H, J = 7.1 Hz), 4.18 (d, 2H, J = 6.0 Hz), 6.30 (t, 1H, J = 6.0 Hz), 6.72 (t, 1H, J = 6.0 Hz), 7.20 (d, 2H, J= 8.1 Hz), 7.50 (d, 2H, J= 8.1 Hz)。HPLC 方法A tr=10.95mn(98.4%)。ESI−MS m/z:315.1/317.1[M+H]+。
15を、EDP中での沈殿により精製して、白色の固体158mg(65%)を得た。Rf=0.22(AcOEt)。1H NMR (DMSO): δ 1.25 (t, 3H, J= 7.1 Hz), 3.85 (d, 2H, J = 6.0 Hz), 4.15 (q, 2H, J = 7.1 Hz), 4.37 (d, 2H, J = 6.0 Hz), 6.40 (t, 1H, J = 5.8 Hz), 6.85 (t, 1H, J = 5.8 Hz), 7.50 (m, 3H), 8.32 (dd, 1H, J= 7.4, 1.2 Hz), 8.38 (s, 1H), 8.95 (dd, 2H, J = 4.8, 1.2 Hz)。HPLC 方法A tr=9.07mn(93.1%)。ESI−MS m/z:315.2[M+H]+。
残留物をAcOEtを用いて取り、有機相を10%クエン酸の溶液及びブラインで洗浄し、Na2SO4で乾燥させ、濾過し、濃縮して、16を白色の固体(148mg;66%)として得た。Rf=0.47(AcOEt)。1H NMR (DMSO): δ 1.24 (t, 3H, J= 7.1 Hz), 3.84 (d, 2H, J= 6.0 Hz), 4.16 (q, 2H, J= 7.1 Hz), 4.21 (d, 2H, J= 6.0 Hz), 4.33 (m, 4H), 6.37 (t, 1H, J = 6.0 Hz), 6.55 (t, 1H, J= 6.0 Hz), 6.81 (m, 3H)。HPLC 方法A tr=9.35mn(99.6%)。ESI−MS m/z:295.2[M+H]+。
17を、EDP中での沈殿により精製して、白色の固体(95%)196mgを得た。Rf=0.47(AcOEt)。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 2.36 (s, 3H), 3.77 (d, 2H, J= 6.0 Hz), 4.10 (q, 2H, J= 7.1 Hz), 4.19 (d, 2H, J= 6.0 Hz), 6.07 (s, 1H), 6.38 (t, 1H, J = 6.0 Hz), 6.70 (t, 1H, J= 6.0 Hz)。HPLC 方法A tr=6.72mn(99.3%)。ESI−MS m/z:242.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EtOAc/MeOH 98/2)により精製して、ウレア18(210mg;81%)を白色の固体として得た。Rf=0.31(AcOEt)。1H NMR (CDCl3): δ 1.17 (t, 3H, J= 7.1 Hz), 2.34 (d, 4H, J = 4.2 Hz), 3.37 (s, 2H), 3.61 (m, 4Hz), 3.87 (m, 2H), 4.06 (q, 2H, J = 7.1 Hz), 4.24 (d, 2H, J = 5.7 Hz), 5.40 (sl, 2H), 7.13 (m, 4H)。HPLC 方法A tr=7.02mn(93.5%)。ESI−MS m/z:336.2[M+H]+。
19を、EDP中での沈殿により精製して、白色の固体230mg(98%)を得た。Rf=0.71(AcOEt)。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 3.79 (d, 2H, J = 6.0 Hz), 4.08 (q, 2H, J = 7.1 Hz), 4.38 (d, 2H, J = 5.8 Hz), 6.39 (t, 1H, J = 5.8 Hz), 6.63 (m, 1H), 6.68 (t, 1H, J = 5.8 Hz), 6.75 (d, 1H, J= 3.3 Hz), 7.33 (m, 3H), 7.65 (m, 1H), 7.81 (s, 1H)。HPLC 方法A tr=11.72mn(91.7%)。ESI−MS m/z:303.2[M+H]+。
20を、EDP中での沈殿により精製して、白色の固体133mg(53%)を得た。Rf=0.19(AcOEt)。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 3.42 (t, 4H, J= 4.9 Hz), 3.69 (t, 4H, J= 4.9 Hz,), 3.78 (d, 2H, J= 6.1 Hz), 4.08 (q, 2H, J= 7.1 Hz), 4.15 (d, 2H, J= 6.0 Hz), 6.33 (t, 1H, J = 6.1 Hz), 6.57 (d, 1H, J= 5.0 Hz), 6.68 (s, 1H), 6.72 (t, 1H, J= 6.1 Hz), 8.03 (d, 1H, J= 5.0 Hz)。HPLC 方法A tr=6.72mn(100%)。ESI−MS m/z:323.2[M+H]+。
21を、EDP中での沈殿により精製して、白色の固体208mg(89%)を得た。Rf=0.11(AcOEt)。1H NMR (DMSO): δ 1.18 (t, 3H, J= 7.1 Hz), 3.79 (d, 2H, J= 6.0 Hz), 4.08 (q, 2H, J= 7.1 Hz), 4.31 (d, 2H, J= 6.0 Hz), 6.38 (t, 1H, J = 6.0 Hz), 6.81 (t, 1H, J= 6.0 Hz), 7.30 (d, 1H, J= 7.6 Hz), 7.50 (t, 1H, J= 7.7 Hz), 7.73 (m, 2H), 8.24 (s, 1H), 9.27 (s, 1H)。HPLC 方法A tr=8.16mn(98.7%)。ESI−MS m/z:304.2[M+H]+。
22を、EDP中での沈殿により精製して、白色の固体224mg(95%)を得た。Rf=0.38(AcOEt)。1H NMR (DMSO): δ 1.21 (t, 3H, J= 7.1 Hz), 3.77 (d, 2H, J= 6.0 Hz), 4.08 (q, 2H, J= 7.1 Hz), 4.14 (d, 2H, J= 6.0 Hz), 6.47 (t, 1H, J = 6.0 Hz), 6.52 (s, 1H), 6.61 (t, 1H, J= 6.0 Hz), 7.39 (m, 4H), 7.75 (s, 1H), 8.09 (s, 1H)。HPLC 方法A tr=9.16mn(96.6%)。ESI−MS m/z:303.2[M+H]+。
粗生成物を、分取HPLCにより精製して、ウレア23(182mg;43%)を白色の固体として得た。Rf=0.76(AcOEt)。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 3.78 (d, 2H, J = 6.0 Hz), 4.11 (m, 4H), 5.58 (s, 2H), 6.19 (t, 1H, J = 6.0 Hz), 6.29 (t, 1H, J = 8.1 Hz), 6.43 (d, 1H, J = 8.1 Hz), 6.69 (t, 1H, J = 6.0 Hz), 6.95 (m, 1H)。HPLC 方法A tr=7.26mn(99.5%)。ESI−MS m/z:270.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EtOAc)により精製し、そして最終的にEDP中に沈殿させて、ウレア24(29mg;14%)を白色の固体として得た。Rf=0.55(AcOEt)。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 3.79 (d, 2H, J= 5.7 Hz), 4.08 (q, 2H, J = 7.1 Hz), 4.29 (d, 2H, J = 5.9 Hz), 6.28 (t, 1H, J= 5.7 Hz), 6.70 (t, 2H, J= 5.9 Hz), 6.93 (s, 1H), 7.21 (d, 1H, J= 8.7 Hz), 7.53 (m, 2H), 8.00 (s, 1H)。HPLC 方法A tr=9.95mn(98.5%)。ESI−MS m/z:277.2[M+H]+。
残留物をAcOEtを用いて取り、有機相を10%クエン酸の溶液及びブラインで洗浄し、Na2SO4で乾燥させ、濾過し、そして濃縮した。25を、EDP中での沈殿により精製して、黄色の固体95mg(44%)を得た。Rf=0.89(AcOEt)。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 3.82 (d, 2H, J= 5.9 Hz), 4.08 (q, 2H, J= 7.1 Hz), 4.43 (d, 2H, J= 5.7 Hz), 6.52 (t, 1H, J = 5.9 Hz), 6.83 (t, 1H, J= 5.7 Hz), 7.13 (m, 2H), 7.45 (d, 1H, J= 5.7 Hz), 7.54 (d, 1H, J= 5.7 Hz), 12.16 (s, 1H)。HPLC 方法A tr=6.48mn(98.9%)。ESI−MS m/z:277.2[M+H]+。
粗生成物を、分取HPLCにより精製して、ウレア26(81mg;36%)を白色の固体として得た。1H NMR (CDCl3): δ 1.17 (t, 3H, J= 7.1 Hz), 2.34 (d, 4H, J = 4.2 Hz), 3.37 (s, 2H), 3.61 (m, 4Hz), 3.87 (m, 2H), 4.06 (q, 2H, J = 7.1 Hz), 4.24 (d, 2H, J = 5.7 Hz), 5.40 (sl, 2H), 7.13 (m, 4H)。HPLC 方法A tr=5.64mn(100%)。ESI−MS m/z:269.2[M+H]+。
粗生成物を、分取HPLCにより精製して、ウレア27(160 61mg;31%)を白色の固体として得た。1H NMR (CDCl3): δ 1.21 (t, 3H, J= 7.1 Hz), 3.80 (d, 2H, J= 6.0 Hz), 4.10 (m, 4H), 5.03 (s, 2H), 6.25 (t, 1H, J = 6.0 Hz), 6.45 (m, 3H), 6.53 (t, 1H, J= 6.0 Hz), 6.95 (t, 1H, J= 7.5 Hz)。HPLC 方法A tr=5.02mn(99.9%)。ESI−MS m/z:252.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EtOAc/EDP 8/2)により精製して、ウレア28(30mg;17%)を白色の固体として得た。Rf=0.14(AcOEt/EDP 8/2)。1H NMR (DMSO): δ 1.21 (t, 3H, J= 7.1 Hz), 3.76 (s, 3H), 3.80 (d, 2H, J = 6.0 Hz), 4.10 (m, 4H), 6.24 (t, 1H, J = 6.0 Hz), 6.56 (t, 1H, J = 6.0 Hz), 6.70 (m, 2H), 6.84 (s, 1H), 8.83 (sl, 1H)。HPLC 方法A tr=6.98mn(98.0%)。ESI−MS m/z:283.2[M+H]+。
反応混合物を、DMF中で70℃で2時間加熱した。粗生成物を、フラッシュクロマトグラフィー(EtOAc/MeOH 7/3)により精製して、ウレア29(52mg;33%)を白色の固体として得た。Rf=0.24(AcOEt/MeOH 7/3)。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 2.54 (m, 2H), 3.08 (m, 2H), 3.75 (d, 2H, J = 6.0 Hz), 4.07 (q, 2H, J = 7.1 Hz), 4.86 (s, 1H), 6.33 (m, 2H), 6.36 (s, 2H), 11.35 (s, 1H)。HPLC 方法A tr=5.78mn(99.4)。ESI−MS m/z:284.3[M+H]+。
残留物をAcOEtを用いて取り、有機相を10%クエン酸の溶液及びブラインで洗浄し、Na2SO4で乾燥させ、濾過し、そして濃縮した。粗生成物を、フラッシュクロマトグラフィー(EtOAc)により精製して、ウレア30(28mg;19%)を白色の固体として得た。Rf=0.44(AcOEt)。1H NMR (DMSO): δ 1.20 (t, 3H, J= 7.1 Hz), 3.78 (d, 2H, J= 6.0 Hz), 4.01 (d, 2H, J= 6.0 Hz), 4.11 (q, 2H, J= 7.1 Hz), 6.16 (dd, 1H, J = 8.1; 2.3 Hz), 6.25 (d, 1H, J= 2.3 Hz), 6.40 (t, 1H, J= 6.0 Hz), 6.53 (t, 1H, J= 6.0 Hz), 6.89 (d, 1H, J= 8.1 Hz), 9.14 (s, 1H), 9.62 (s, 1H)。HPLC 方法A tr=6.88mn(98.7%)。ESI−MS m/z:269.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EtOAc)により精製して、ウレア31(41mg;29%)を白色の固体として得た。Rf=0.55(AcOEt)。1H NMR (DMSO): δ 1.20 (t, 3H, J= 7.1 Hz), 3.80 (d, 2H, J = 6.1 Hz), 3.87 (s, 3H), 4.10 (q, 2H, J = 7.1 Hz), 4.29 (d, 2H, J = 6.1 Hz), 6.38 (t, 1H, J = 6.1 Hz), 6.81 (t, 1H, J = 6.1 Hz), 7.52 (m, 2H), 7.86 (m, 2H)。HPLC 方法A tr=9.09mn(100%)。ESI−MS m/z:295.2[M+H]+。
32を、EDP中での沈殿により精製して、白色の固体221mg(92%)を得た。1H NMR (DMSO): δ 1.21 (t, 3H, J= 7.1 Hz), 3.77 (d, 2H, J= 6.0 Hz), 4.08 (q, 2H, J= 7.1 Hz), 4.14 (d, 2H, J= 6.0 Hz), 6.47 (t, 1H, J = 6.0 Hz), 6.52 (s, 1H), 6.61 (t, 1H, J= 6.0 Hz), 7.39 (m, 4H), 7.75 (s, 1H), 8.09 (s, 1H)。ESI−MS m/z:252.2[M+H]+。
T
33を、EDP中での沈殿により精製して、白色の固体182mg(83%)を得た。1H NMR (DMSO): δ 1.21 (t, 3H, J= 7.1 Hz), 3.77 (d, 2H, J= 6.0 Hz), 4.08 (q, 2H, J= 7.1 Hz), 4.14 (d, 2H, J= 6.0 Hz), 6.47 (t, 1H, J = 6.0 Hz), 6.52 (s, 1H), 6.61 (t, 1H, J= 6.0 Hz), 7.39 (m, 4H), 7.75 (s, 1H), 8.09 (s, 1H)。ESI−MS m/z:267.2[M+H]+。
34を、EDP中での沈殿により精製して、白色の固体205mg(98%)を得た。Rf=0.48(AcOEt)。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 3.78 (d, 2H, J = 6.0 Hz), 4.09 (q, 2H, J = 7.1 Hz), 4.22 (d, 2H, J = 6.0 Hz), 6.36 (t, 1H, J = 6.0 Hz), 6.75 (t, 1H, J = 6.0 Hz), 7.05 (d, 1H, J= 7.3 Hz), 7.27 (m, 3H)。ESI−MS m/z:271.3/273.1[M+H]+。
35を、EDP中での沈殿により精製して、白色の固体201mg(93%)を得た。1H NMR (DMSO): δ 1.21 (t, 3H, J= 7.1 Hz), 3.77 (d, 2H, J= 6.0 Hz), 4.08 (q, 2H, J= 7.1 Hz), 4.14 (d, 2H, J= 6.0 Hz), 6.47 (t, 1H, J = 6.0 Hz), 6.52 (s, 1H), 6.61 (t, 1H, J= 6.0 Hz), 7.39 (m, 4H), 7.75 (s, 1H), 8.09 (s, 1H)。ESI−MS m/z:260.2[M+H]+。
36を、EDP中での沈殿により精製して、白色の固体208mg(96%)を得た。1H NMR (DMSO): δ 1.21 (t, 3H, J= 7.1 Hz), 3.77 (d, 2H, J= 6.0 Hz), 4.08 (q, 2H, J= 7.1 Hz), 4.14 (d, 2H, J= 6.0 Hz), 6.47 (t, 1H, J = 6.0 Hz), 6.52 (s, 1H), 6.61 (t, 1H, J= 6.0 Hz), 7.39 (m, 4H), 7.75 (s, 1H), 8.09 (s, 1H)。ESI−MS m/z:271.2[M+H]+。
37を、EDP中での沈殿により精製して、白色の固体198mg(89%)を得た。1H NMR (DMSO): δ 1.21 (t, 3H, J= 7.1 Hz), 3.77 (d, 2H, J= 6.0 Hz), 4.08 (q, 2H, J= 7.1 Hz), 4.14 (d, 2H, J= 6.0 Hz), 6.47 (t, 1H, J = 6.0 Hz), 6.52 (s, 1H), 6.61 (t, 1H, J= 6.0 Hz), 7.39 (m, 4H), 7.75 (s, 1H), 8.09 (s, 1H)。ESI−MS m/z:259.2[M+H]+。
38を、EDP中での沈殿により精製して、白色の固体205mg(94%)を得た。1H NMR (DMSO): δ 1.21 (t, 3H, J= 7.1 Hz), 3.77 (d, 2H, J= 6.0 Hz), 4.08 (q, 2H, J= 7.1 Hz), 4.14 (d, 2H, J= 6.0 Hz), 6.47 (t, 1H, J = 6.0 Hz), 6.52 (s, 1H), 6.61 (t, 1H, J= 6.0 Hz), 7.39 (m, 4H), 7.75 (s, 1H), 8.09 (s, 1H)。ESI−MS m/z:282.2[M+H]+。
39を、EDP中での沈殿により精製して、白色の固体222mg(99%)を得た。1H NMR (DMSO): δ 1.21 (t, 3H, J= 7.1 Hz), 3.77 (d, 2H, J= 6.0 Hz), 4.08 (q, 2H, J= 7.1 Hz), 4.14 (d, 2H, J= 6.0 Hz), 6.47 (t, 1H, J = 6.0 Hz), 6.52 (s, 1H), 6.61 (t, 1H, J= 6.0 Hz), 7.39 (m, 4H), 7.75 (s, 1H), 8.09 (s, 1H)。ESI−MS m/z:237.2[M+H]+。
粗生成物を分取HPLCにより精製して、ウレア39(92mg;39%)を白色の固体として得た。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 3.78 (d, 2H, J = 6.0 Hz), 4.11 (m, 4H), 5.58 (s, 2H), 6.19 (t, 1H, J = 6.0 Hz), 6.29 (t, 1H, J = 8.1 Hz), 6.43 (d, 1H, J = 8.1 Hz), 6.69 (t, 1H, J = 6.0 Hz), 6.95 (m, 1H)。HPLC 方法A tr=7.26mn(99.5%)。ESI−MS m/z:244.2[M+H]+。
41を、EDP中での沈殿により精製して、白色の固体197mg(92%)を得た。1H NMR (DMSO): δ 1.21 (t, 3H, J= 7.1 Hz), 3.77 (d, 2H, J= 6.0 Hz), 4.08 (q, 2H, J= 7.1 Hz), 4.14 (d, 2H, J= 6.0 Hz), 6.47 (t, 1H, J = 6.0 Hz), 6.52 (s, 1H), 6.61 (t, 1H, J= 6.0 Hz), 7.39 (m, 4H), 7.75 (s, 1H), 8.09 (s, 1H)。ESI−MS m/z:287.2[M+H]+。
42を、EDP中での沈殿により精製して、白色の固体202mg(93%)を得た。1H NMR (DMSO): δ 1.21 (t, 3H, J= 7.1 Hz), 3.77 (d, 2H, J= 6.0 Hz), 4.08 (q, 2H, J= 7.1 Hz), 4.14 (d, 2H, J= 6.0 Hz), 6.47 (t, 1H, J = 6.0 Hz), 6.52 (s, 1H), 6.61 (t, 1H, J= 6.0 Hz), 7.39 (m, 4H), 7.75 (s, 1H), 8.09 (s, 1H)。ESI−MS m/z:238.2[M+H]+。
43を、EDP中での沈殿により精製して、白色の固体208mg(94%)を得た。1H NMR (DMSO): δ 1.21 (t, 3H, J= 7.1 Hz), 3.77 (d, 2H, J= 6.0 Hz), 4.08 (q, 2H, J= 7.1 Hz), 4.14 (d, 2H, J= 6.0 Hz), 6.47 (t, 1H, J = 6.0 Hz), 6.52 (s, 1H), 6.61 (t, 1H, J= 6.0 Hz), 7.39 (m, 4H), 7.75 (s, 1H), 8.09 (s, 1H)。ESI−MS m/z:238.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EtOAc/MeOH 7/3)により精製して、ウレア44(90mg;71%)を白色の固体として得た。Rf=0.28(AcOEt/MeOH 7/3)。1H NMR (DMSO): δ 0.97 (t, 3H, J= 7.1 Hz), 3.54 (d, 2H, J = 6.0 Hz), 3.77 (d, 2H, J= 5.7 Hz), 3.84 (q, 2H, J = 7.1 Hz), 5.55 (s, 2H), 5.97 (t, 1H, J = 6.0 Hz), 6.16 (d, 1H, J = 8.4 Hz), 6.25 (t, 1H, J = 5.7 Hz), 7.03 (d, 1H, J= 8.4 Hz), 7.56 (s, 1H)。HPLC 方法A tr=5.65mn(100%)。ESI−MS m/z:253.2[M+H]+。
45を、EDP中での沈殿により精製して、白色の固体201mg(92%)を得た。1H NMR (DMSO): δ 1.21 (t, 3H, J= 7.1 Hz), 3.77 (d, 2H, J= 6.0 Hz), 4.08 (q, 2H, J= 7.1 Hz), 4.14 (d, 2H, J= 6.0 Hz), 6.47 (t, 1H, J = 6.0 Hz), 6.52 (s, 1H), 6.61 (t, 1H, J= 6.0 Hz), 7.39 (m, 4H), 7.75 (s, 1H), 8.09 (s, 1H)。ESI−MS m/z:238.2[M+H]+。
(R)−2,3−ジヒドロ−1H−インデン−1,6−ジアミン(1当量、100mg、0.46mmol)及びトリエチルアミン(2.5当量、158μL、1.15mmol)を、DMF 2mLに溶解した。反応混合物を0℃で冷却し、イソシアナト酢酸エチル(1当量、59mg、51μL、0.46mmol)を滴下し、そして0℃で2時間撹拌した。反応混合物を濃縮し、逆相(H2O/MeCN)により精製して、化合物46(26mg、21%)を白色の固体として得た。Rf=0.26。1H NMR (300 MHz, DMSO): δ 6.91 (d, J = 7.8, 1H), 6.47-6.39 (m, 2H), 6.36 (d, J = 8.3 Hz, 1H), 6.11 (t, J = 5.9 Hz, 1H), 5.02-4.88 (m, 3H), 4.13 (q, J = 7.1 Hz, 2H), 3.83 (d, J = 6.0 Hz, 2H), 2.87-2.57 (m, 2H), 2.40-2.25 (m, 1H), 1.72.1.56 (m, 1H), 1.31-1.17 (t, J = 7.2 Hz, 3H)。HPLC 方法A tr=5.60mn(93.4%)。ESI−MS m/z:278.2[M+H]+。
シアノ誘導体(N≡C−R7)(0.3g、1当量)をMeOH 100mlに溶解し、次に水素圧40barを、ラネーニッケルの存在下で20時間適用した。反応混合物を、セライトを通して濾過し、濃縮した。粗生成物を、フラッシュクロマトグラフィーにより精製して、アミンを得た。アミン(1当量)をDMF(0.4M)に溶解し、次にイソシアナト酢酸エチル(1当量)を一度に加え、そして反応混合物を室温で2時間放置した。反応が完了した後(TLC管理)、反応混合物を濃縮し、そしてフラッシュクロマトグラフィーにより精製してウレアを得た。
5−シアノ−インドール(0.3g、2.11mmol)を還元して、5−アミノメチルインドール(0.18g、59%)を得た(フラッシュクロマトグラフィー(AcOEt/MeOH 7/3、次にMeOH)による精製後)。Rf=0.09(MeOH)。1H NMR (DMSO): δ 2.40 (s, 2H), 3.78 (s, 2H), 6.38 (m, 1H), 7.10 (d, 1H, J = 8.3 Hz), 7.29 (m, 1H), 7.33 (d, 1H, J = 8.3 Hz), 7.49 (s, 1H), 11.00 (s, 1H)。5−アミノメチルインドール(57mg、0.39mmol)を使用して、ウレア47(63mg、66%)を得た(EDPによる粗生成物の処理後)。Rf=0.57(AcOEt)。1H NMR (DMSO): δ 1.21 (t, 3H, J= 7.1 Hz), 3.81 (d, 2H, J = 6.0 Hz), 4.11 (q, 2H, J = 7.1 Hz), 4.28 (d, 2H, J = 5.7 Hz), 6.24 (t, 1H, J = 6.0 Hz), 6.39 (s, 1H), 6.58 (t, 1H, J = 5.7 Hz), 7.01 (d, 1H, J= 8.3 Hz), 7.38 (m, 3H), 11.03 (s, 1H)。HPLC 方法A tr=8.37mn(97.3%)。ESI−MS m/z:276.2[M+H]+。
4−シアノ−フェノール(0.3g、2.52mmol)を還元して、4−アミノメチルフェノール(0.13g、43%)を得た(フラッシュクロマトグラフィー(AcOEt/MeOH 7/3)による精製後)。Rf=0.09(AcOEt/MeOH 7/3)。1H NMR (DMSO): δ 2.40 (s, 2H), 3.53 (s, 2H), 6.69 (d, 2H, J = 8.4 Hz), 7.11 (d, 2H, J = 8.4 Hz), 9.20 (s, 1H)。4−アミノメチルフェノール(48mg、0.39mmol)を使用して、ウレア48(23mg、26%、黄色の固体)を得た(フラッシュクロマトグラフィー(DCM/MeOH 95/5 Rf=0.34)による粗生成物の精製後)。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 3.77 (d, 2H, J = 6.0 Hz), 4.08 (m, 4H), 6.20 (t, 1H, J = 6.0 Hz), 6.51 (t, 1H, J = 5.6 Hz), 6.69 (d, 2H, J= 8.4 Hz), 7.05 (d, 2H, J= 8.4 Hz), 9.25 (s, 1H)。HPLC 方法A tr=6.39mn(92.6%)。ESI−MS m/z:253.2[M+H]+。
4−アミノ−1−ナフタレンカルボニトリル(0.5g、2.98mmol)を還元して、4−アミノメチル−1−アミノ−ナフタレン(0.22g、43%)を得た(フラッシュクロマトグラフィー(AcOEt/MeOH 7/3)による精製後)。Rf=0.09(AcOEt/MeOH 7/3)。1H NMR (DMSO): δ 1.99 (s, 2H), 4.05 (s, 2H), 5.62 (s, 2H), 6.60 (d, 1H, J = 9.6 Hz), 7.20 (d, 1H, J = 7.6 Hz), 7.35 (m, 2H), 8.08 (m, 2H)。4−アミノメチル−1−アミノナフタレン(154mg、0.89mmol)を使用して、ウレア49(12mg、5%、黄色の固体)を得た(フラッシュクロマトグラフィー(AcOEt Rf=0.52)による粗生成物の精製後)。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 3.79 (d, 2H, J = 6.0 Hz), 4.08 (q, 2H, J= 7.1 Hz), 4.49 (d, 2H, J = 5.2 Hz), 5.66 (s, 2H), 6.12 (t, 1H, J = 6.0 Hz), 6.42 (t, 1H, J = 5.2 Hz), 6.61 (d, 1H, J= 7.6 Hz), 7.15 (d, 1H, J= 7.6 Hz), 7.45 (m, 2H), 7.91 (d, 1H, J = 8.1 Hz), 8.09 (d, 1H, J = 8.1 Hz)。HPLC 方法A tr=7.06mn(89,7%)。ESI−MS m/z:302.3[M+H]+。
4−アミノ−3−メトキシベンゾニトリル(0.2g、1.12mmol)を還元して、4−(アミノメチル)−2−メトキシアニリン(mtheo=202mg)を得た。粗物(202mg、1.1mmol)を使用して、ウレア(34mg、2工程の全体的収率=10%、白色の固体)を得た(フラッシュクロマトグラフィー(EDP/EtOAc)による粗生成物の精製後)。Rf=0.14(EDP/EtOAc 30/70)。1H NMR (300 MHz, DMSO): δ 6.74 (s, 1H), 6.62-6.58 (m, 2H), 6.47 (t, J = 5.7 Hz, 1H), 6.21 (t, J = 6.1 Hz, 1H), 4.62 (broad s, 2H), 4.12 (q, J= 7.2 Hz , 2H), 4.09 (d, J = 5.7 Hz, 2H), 3.81 (d, J = 6.1 Hz, 2H), 3.77 (s, 3H), 1.22 (t, J= 7.1 Hz, 3H)。HPLC 方法A tr=5.11mn(94.1%)。ESI−MS m/z:282.2[M+H]+。
4−アミノ−3−メチルベンゾニトリル(0.2g、1.5mmol)を還元して、4−(アミノメチル)−2−メチルアニリン(mtheo=206mg)を黄色の油状物として得た。粗物(206mg、1.5mmol)を使用して、ウレア(108mg、2工程の全体的収率=27%、白色の固体)を得た(フラッシュクロマトグラフィー(EDP/EtOAc)による粗生成物の精製後)。Rf=0.18(EDP/EtOAc 30/70)。1H NMR (200 MHz, DMSO): δ 6.88-6.96 (m, 2H), 6.56 (d, J = 7.9 Hz, 1H), 6.47-6.37 (m, 1H), 6.18 (t, J = 5.9 Hz, 1H), 4.75 (broad s, 2H), 4.12 (q, J = 7.0 Hz, 2H), 4.03 (d, J = 6.2 Hz, 2H), 3.80 (d, J = 6.0 Hz, 2H), 2.06 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H)。HPLC 方法A tr=5.07mn(90.5%)。ESI−MS m/z:266.2[M+H]+。
4−アミノ−3−エチルベンゾニトリル(0.2g、1.37mmol)を還元して、4−(アミノメチル)−2−エチルアニリン(mtheo=205mg)を黄色の油状物として得た。粗物(205mg、1.37mmol)を使用して、ウレア(92mg、2工程の全体的収率=24%、白色の固体)を得た(フラッシュクロマトグラフィー(EDP/EtOAc)による粗生成物の精製後)。Rf=0.3(EDP/EtOAc 30/70)。1H NMR (200 MHz, CDCl3): δ 7.02-6.88 (m, 2H), 6.61 (d, J = 7.8 Hz, 1H), 5.02 (t, J = 5.2 Hz, 1H), 4.89 (t, J = 5.4 Hz, 1H), 4.23 (d, J = 5.5 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.97 (d, J = 5.3 Hz, 2H), 3.62 (broad s, 2H), 2.48 (q, J = 7.5 Hz, 2H), 1.25 (t, J = 7,1 Hz, 3H), 1.22 (t, J = 7.4 Hz, 3H)。HPLC 方法A tr=5.86mn(86.4%)。ESI−MS m/z:280.2[M+H]+。
イソチオシアナト酢酸エチル(1当量)をTHF(0.4M)に溶解し、次にアミン(1当量、181mg)を一度に加え、そして反応混合物を室温で2時間放置した。反応が完了した後(TLC管理)、反応混合物を濃縮し、ジエチルエーテル/ヘキサン中での沈殿により精製して、チオウレア50を白色の固体(264mg、89%)として得た。HPLC 方法B tr=14.43mn(92.4%)。ESI−MS m/z:269.2[M+H]+。
IV−1 − カルボン酸類の合成
エステル54及び55の合成:
一般手順。イソシアナト酢酸エチル(1当量、100mg、87μl、0.77mmol)をTHF(0.4M)に溶解し、次にアミン(1当量)を一度に加え、反応混合物を室温で2時間放置した。反応が完了した後(TLC管理)、反応混合物を濃縮し、そしてジエチルエーテル中での沈殿により精製した。
1H NMR (DMSO): δ 1.47 (s, 9H), 3.72 (d, 2H, J= 5.7 Hz), 4.13 (d, 2H, J= 5.6 Hz), 6.14 (t, 1H, J = 5.6 Hz), 6.54 (t, 1H, J= 5.7 Hz), 7.13 (d, 2H, J= 8.5 Hz), 7.37 (d, 2H, J= 8.5 Hz), 9.26 (s, 1H), 12.21 (s, 1H)。
1H NMR (DMSO): δ 1.47 (s, 9H), 3.97 (s, 2H), 4.16 (d, 2H, J= 5.6 Hz), 6.09 (t, 1H, J = 5.0 Hz), 6.71 (t, 1H, J= 5.6 Hz), 7.60 (d, 1H, J= 8.7 Hz), 7.72 (d, 1H, J= 8.7 Hz), 8.12 (s, 1H), 9.66 (s, 1H)。
一般手順。
酸誘導体56又は57(1当量)を2mlのDCM又はDMFに溶解した。アミン(1.1当量)、ヒドロキシベンゾトリアゾール(HOBt)(1.2当量)、ジイソプロピルエチルアミン(DIEA)(2.2当量)及び1−[3−(ジメチルアミノ)プロピル]−3−エチルカルボジイミド(EDAP)(1.2当量)を連続して加え、反応混合物を室温で20時間撹拌した。反応混合物を濃縮し、AcOEt 100mlを加えた。有機相を飽和NaHCO3、10%クエン酸及びブラインで洗浄し、次にNa2SO4で乾燥させ、濾過し、そして濃縮した。粗生成物をフラッシュクロマトグラフィーにより精製して、アミドを得た。最終的に、アミドをDCM 2mlに溶解し、TFA 2mlを加え、次に反応混合物を室温で1時間放置した。反応混合物を濃縮し、AcOEt/ヘキサンを使用して沈殿により精製し、脱保護アミド58〜94bisを得た。
粗生成物を、フラッシュクロマトグラフィー(AcOEt)により精製して、保護アミド(100mg;44%)を白色の固体として得た。Rf=0.09(AcOEt)。1H NMR (DMSO): δ 1.47 (s, 9H), 1.78 (m, 2H), 1.90 (m, 4H), 3.30 (m, 4H), 3.81 (d, 2H, J = 4.9 Hz), 4.12 (d, 2H, J = 5.8 Hz), 6.06 (t, 1H, J = 4.9 Hz), 6.66 (t, 1H, J = 5.8 Hz), 7.12 (d, 2H, J = 8.5 Hz), 7.37 (d, 2H, J = 8.5 Hz), 9.27 (s, 1H)。アミドを脱保護して、化合物58を黄色の固体(73mg、70%)として得た。HPLC 方法A tr=5.60mn(95.8%)。ESI−MS m/z:277.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(100mg;40%)を白色の固体として得た。Rf=0.47(DCM/MeOH 9/1)。1H NMR (DMSO): δ 1.47 (s, 9H), 3.71 (d, 2H, J = 5.5 Hz), 4.13 (d, 2H, J = 5.7 Hz), 4.29 (d, 2H, J = 5.9 Hz), 6.18 (t, 1H, J = 5.7 Hz), 6.55 (t, 1H, J = 5.9 Hz), 7.13 (d, 2H, J = 6.0 Hz), 7.13 (m, 7H), 8.32 (t, 1H, J = 5.5 Hz), 9.27 (s, 1H)。アミドを脱保護して、化合物59を黄色の固体(64mg、61%)として得た。HPLC 方法A tr=6.33mn(99.5%)。ESI−MS m/z:313.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(84mg;34%)を白色の固体として得た。Rf=0.32(DCM/MeOH 9/1)。1H NMR (DMSO): δ 1.47 (s, 9H), 1.80 (m, 4H), 3.40 (m, 4H), 3.89 (d, 2H, J = 5.1 Hz), 4.12 (d, 2H, J = 5.8 Hz), 4.89 (s, 1H), 6.05 (t, 1H, J = 5.8 Hz), 6.68 (t, 1H, J = 5.1 Hz), 7.12 (d, 2H, J = 8.4 Hz), 7.37 (d, 2H, J = 8.4 Hz), 9.27 (s, 1H)。アミドを脱保護して、化合物60を黄色の固体(53mg、59%)として得た。HPLC 方法A tr=4.92mn(94.0%)。ESI−MS m/z:307.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(107mg;41%)を白色の油状物として得た。Rf=0.28(DCM/MeOH 9/1)。1H NMR (DMSO): δ 1.47 (s, 9H), 2.90 (s, 3H), 3.98 (d, 2H, J = 4.9 Hz), 4.14 (d, 2H, J = 6.0 Hz), 4.54 (d, 2H, J = 5.0 Hz), 6.11 (t, 1H, J = 4.9 Hz), 6.68 (t, 1H, J = 5.0 Hz), 7.30 (m, 10H), 9.27 (s, 1H)。アミドを脱保護して、化合物61を黄色の固体(78mg、68%)として得た。HPLC 方法A tr=8.52mn(97.2%)。ESI−MS m/z:327.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(120mg;48%)を白色の固体として得た。Rf=0.39(DCM/MeOH 9/1)。1H NMR (DMSO): δ 1.47 (s, 9H), 1.85 (m, 8H), 3.35 (m, 8H), 3.90 (m, 1H), 4.10 (m, 4H), 6.04 (m, 1H), 6.67 (m, 1H), 7.12 (d, 2H, J = 8.4 Hz), 7.37 (d, 2H, J = 8.4 Hz), 9.27 (s, 1H)。アミドを脱保護して、化合物62を黄色の固体(95mg、73%)として得た。HPLC 方法A tr=6.62mn(99.0%)。ESI−MS m/z:388.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(105mg;44%)を白色の固体として得た。Rf=0.55(DCM/MeOH 9/1)。1H NMR (DMSO): δ 1.47 (s, 9H), 1.52 (m, 6H), 3.40 (m, 4H), 3.88 (d, 2H, J = 4.8 Hz), 4.10 (d, 2H, J = 6.3 Hz), 6.05 (t, 1H, J = 4.8 Hz), 6.66 (t, 1H, J = 6.3 Hz), 7.12 (d, 2H, J = 8.5 Hz), 7.37 (d, 2H, J = 8.5 Hz), 9.27 (s, 1H)。アミドを脱保護して、化合物63を黄色の固体(64mg、61%)として得た。HPLC 方法A tr=5.86mn(99.1%)。ESI−MS m/z:291.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(110mg;46%)を白色の固体として得た。Rf=0.33(DCM/MeOH 9/1)。1H NMR (DMSO): δ 1.47 (s, 9H), 3.30 (m, 4H), 3.56 (m, 4H), 3.91 (d, 2H, J = 4.9 Hz), 4.12 (d, 2H, J = 5.7 Hz), 6.08 (t, 1H, J = 4.9 Hz), 6.67 (t, 1H, J = 5.7 Hz), 7.12 (d, 2H, J = 8.5 Hz), 7.37 (d, 2H, J = 8.5 Hz), 9.27 (s, 1H)。アミドを脱保護して、化合物64を黄色の固体(58mg、48%)として得た。HPLC 方法A tr=5.05mn(99.1%)。ESI−MS m/z:293.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(158mg;56%)を白色の固体として得た。Rf=0.54(DCM/MeOH 9/1)。1H NMR (DMSO): δ 1.16 (t, 3H, J = 6.8 Hz), 1.43 (s, 9H), 1.80 (m, 4H), 3.65 (m, 4H), 4.10 (m, 7H), 6.01 (t, 1H, J = 4.0 Hz), 6.64 (t, 1H, J = 5.4 Hz), 7.08 (d, 2H, J = 8.3 Hz), 7.33 (d, 2H, J = 8.3 Hz), 9.23 (s, 1H)。アミドを脱保護して、化合物65を黄色の固体(73mg、43%)として得た。HPLC 方法A tr=6.97mn(98.6%)。ESI−MS m/z:363.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(110mg;41%)を白色の固体として得た。Rf=0.37(DCM/MeOH 9/1)。アミドを脱保護して、化合物66を白色の固体(93mg、81%)として得た。1H NMR (DMSO): δ 2.00 (m, 4H), 3.52 (m, 2H), 3.64 (s, 3H), 3.90 (d, 2H, J = 5.0 Hz), 4.05 (sl, 2H), 4.21 (d, 2H, J = 5.1 Hz), 4.35 (m, 1H), 6.17 (m, 1H), 6.76 (t, 1H, J = 5.1 Hz), 7.17 (d, 2H, J = 8.1 Hz), 7.30 (d, 2H, J = 8.1 Hz)。HPLC 方法A tr=5.49mn(97.7%)。ESI−MS m/z:335.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(115mg;44%)を白色の固体として得た。Rf=0.47(DCM/MeOH 9/1)。1H NMR (DMSO): δ 1.47 (s, 9H), 2.70 (t, 2H, J = 7.0 Hz), 3.61 (d, 2H, J = 5.7 Hz), 4.10 (m, 4H), 6.12 (t, 1H, J = 5.3 Hz), 6.55 (t, 1H, J = 5.7 Hz), 7.12 (d, 2H, J = 8.5 Hz), 7.21 (m, 3H), 7.30 (t, 2H, J = 8.2 Hz), 7.38 (d, 2H, J = 8.5 Hz), 9.28 (s, 1H)。アミドを脱保護して、化合物67を黄色の固体(93mg、78%)として得た。HPLC 方法A tr=6.95mn(99.3%)。ESI−MS m/z:327.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(52mg;40%)を橙色の固体として得た。Rf=0.31(DCM/MeOH 9/1)。1H NMR (DMSO): δ 1.47 (s, 9H), 1.52 (m, 1H), 1.95 (m, 2H), 2.94 (s, 3H), 3.28 (m, 2H), 3.70 (m, 4H), 3.88 (d, 2H, J = 4.8 Hz), 4.12 (d, 2H, J = 5.9 Hz), 6.05 (t, 1H, J = 4.8 Hz), 6.67 (t, 1H, J = 5.9 Hz), 7.12 (d, 2H, J = 8.5 Hz), 7.37 (d, 2H, J = 8.5 Hz), 9.27 (s, 1H)。アミドを脱保護し、エーテル中で沈殿させて、化合物63を黄色の固体(17mg、31%)として得た。HPLC 方法A tr=6.34mn(88.2%)。ESI−MS m/z:321.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(108mg;43%)を白色の固体として得た。Rf=0.49(DCM/MeOH 9/1)。1H NMR (DMSO) (主要な配座異性体): δ1.47 (s, 9H), 2.73 (m, 2H), 2.88 (s, 3H), 3.45 (m, 2H), 3.85 (d, 1H, J = 4.8 Hz), 4.13 (d, 1H, J = 6.2 Hz), 6.04 (t, 1H, J = 4.8 Hz), 6.68 (t, 1H, J = 6.2 Hz), 7.10 (m, 2H), 7.30 (m, 7H), 9.27 (s, 1H)。アミドを脱保護して、化合物69を黄色の固体(90mg、78%)として得た。HPLC 方法A tr=8.99mn(97.5%)。ESI−MS m/z:288.4[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(110mg;46%)を橙色の固体として得た。Rf=0.14(DCM/MeOH 9/1)。1H NMR (DMSO): δ 1.47 (s, 9H), 2.30 (m, 6H), 3.18 (m, 2H), 3.35 (m, 6H), 3.66 (d, 2H, J = 5.5 Hz), 4.12 (d, 2H, J= 5.8 Hz), 6.14 (t, 1H, J = 5.5 Hz), 6.56 (t, 1H, J = 5.8 Hz), 7.12 (d, 2H, J = 8.3 Hz), 7.38 (d, 2H, J = 8.5 Hz), 7.70 (m, 1H), 9.27 (s, 1H)。アミドを脱保護し、エーテル中で沈殿させて、化合物70を黄色の固体(67mg、58%)として得た。HPLC 方法A tr=5.67mn(87.4%)。ESI−MS m/z:334.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(82mg;51%)を白色の固体として得た。Rf=0.42(DCM/MeOH 9/1)。1H NMR (DMSO): δ 1.47 (s, 9H), 3.70 (d, 2H, J = 4.5 Hz), 4.13 (d, 2H, J = 5.5 Hz), 4.29 (d, 2H, J = 5.8 Hz), 5.08 (s, 2H), 6.08 (t, 1H, J = 5.5 Hz), 6.55 (t, 1H, J = 5.8 Hz), 6.93 (t, 1H, J = 7.3 Hz), 6.99 (d, 2H, J = 8.1 Hz), 7.13 (d, 2H, J = 8.4 Hz), 7.28 (m, 4H), 7.38 (m, 4H), 8.31 (t, 1H, J = 4.5 Hz), 9.27 (s, 1H)。アミドを脱保護して、化合物71を黄色の固体(63mg、74%)として得た。HPLC 方法A tr=11.54mn(89.2%)。ESI−MS m/z:419.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(135mg;77%)を白色の固体として得た。Rf=0.39(DCM/MeOH 9/1)。1H NMR (DMSO): δ 1.47 (s, 9H), 3.80 (m, 8H), 4.05 (m, 5H), 6.05 (t, 1H, J = 4.7 Hz), 6.65 (t, 1H, J = 5.9 Hz), 7.10 (d, 2H, J = 8.3 Hz), 7.35 (d, 2H, J = 8.3 Hz), 7.89 (m, 4H), 9.27 (s, 1H)。アミドを脱保護して、化合物72を黄色の固体(104mg、74%)として得た。HPLC 方法A tr=8.91mn(95.5%)。ESI−MS m/z:452.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(82mg;58%)を白色の油状物として得た。Rf=0.45(DCM/MeOH 9/1)。1H NMR (DMSO): δ 1.47 (s, 9H), 3.13 (s, 3H), 3.50 (d, 2H, J = 4.7 Hz), 3.79 (s, 3H), 4.14 (d, 2H, J = 6.0 Hz), 6.05 (t, 1H, J = 4.7 Hz), 6.64 (t, 1H, J = 6.0 Hz), 7.02 (d, 2H, J = 9.1 Hz), 7.08 (d, 2H, J = 8.3 Hz), 7.29 (d, 2H, J = 9.1 Hz), 7.36 (d, 2H, J = 8.3 Hz), 9.27 (s, 1H)。アミドを脱保護して、化合物73を黄色の固体(59mg、69%)として得た。HPLC 方法A tr=8.33mn(96.5%)。ESI−MS m/z:343.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(54mg;37%)を白色の固体として得た。Rf=0.26(DCM/MeOH 9/1)。1H NMR (DMSO): δ 1.47 (s, 9H), 1.85 (m, 4H), 3.13 (m, 2H), 3.64 (d, 2H, J = 5.5 Hz), 3.80 (m, 3H), 4.12 (d, 2H, J = 5.7 Hz), 6.14 (t, 1H, J = 5.5 Hz), 6.55 (t, 1H, J = 5.7 Hz), 7.12 (d, 2H, J = 8.3 Hz), 7.37 (d, 2H, J = 8.3 Hz), 7.80 (t, 1H, J= 4.5 Hz), 9.27 (s, 1H)。アミドを脱保護して、化合物74を黄色の固体(30mg、53%)として得た。HPLC 方法A tr=5.52mn(93.8%)。ESI−MS m/z:307.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(62mg;48%)を白色の固体として得た。Rf=0.55(DCM/MeOH 9/1)。1H NMR (DMSO): δ 1.47 (s, 9H), 3.18 (s, 3H), 3.54 (d, 2H, J = 4.6 Hz), 4.07 (d, 2H, J = 5.4 Hz), 6.07 (t, 1H, J = 4.6 Hz), 6.65 (t, 1H, J = 5.4 Hz), 7.08 (d, 2H, J = 8.2 Hz), 7.37 (m, 5H), 7.47 (d, 2H, J = 8.3 Hz), 9.27 (s, 1H)。アミドを脱保護して、化合物75を黄色の固体(24mg、34%)として得た。HPLC 方法A tr=7.82mn(92.2%)。ESI−MS m/z:313.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(57mg;53%)を白色の固体として得た。Rf=0.29(DCM/MeOH 9/1)。1H NMR (DMSO)(主要な配座異性体): δ1.47 (s, 9H), 1.90 (m, 4H), 3.52 (m, 2H), 3.62 (s, 3H), 3.91 (d, 2H, J = 5.2 Hz), 4.12 (d, 2H, J = 5.6 Hz), 4.32 (m, 1H), 6.08 (t, 1H, J = 5.2 Hz), 6.61 (t, 1H, J = 5.6 Hz), 7.12 (d, 2H, J = 8.4 Hz), 7.37 (d, 2H, J = 8.4 Hz), 9.27 (s, 1H)。アミドを脱保護して、化合物76を黄色の固体(35mg、59%)として得た。HPLC 方法A tr=6.30mn(96.6%)。ESI−MS m/z:335.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(42mg;34%)を白色の固体として得た。Rf=0.24(DCM/MeOH 9/1)。1H NMR (DMSO): δ 1.47 (s, 9H), 2.37 (m, 4H), 3.44 (s, 2H), 3.58 (m, 4H), 3.72 (d, 2H, J = 5.7 Hz), 4.14 (d, 2H, J = 5.8 Hz), 4.30 (d, 2H, J = 5.7 Hz), 6.19 (t, 1H, J = 5.8 Hz), 6.55 (t, 1H, J = 5.7 Hz), 7.20 (m, 6H), 7.40 (d, 2H, J = 8.4 Hz), 8.35 (t, 1H, J = 5.7 Hz), 9.27 (s, 1H)。アミドを脱保護して、化合物77を黄色の固体(18mg、40%)として得た。HPLC 方法A tr=6.16mn(96.7%)。ESI−MS m/z:412.4[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(82mg;73%)を白色の固体として得た。Rf=0.46(DCM/MeOH 9/1)。1H NMR (DMSO): δ 1.48 (s, 9H), 3.75 (d, 2H, J = 5.5 Hz), 4.15 (d, 2H, J = 6.0 Hz), 4.41 (d, 2H, J= 5.8 Hz), 6.21 (t, 1H, J = 5.5 Hz), 6.58 (t, 1H, J = 5.8 Hz), 7.14 (d, 2H, J = 8.5 Hz), 7.38 (d, 2H, J = 8.5 Hz), 7.50 (m, 3H), 8.34 (m, 2H), 8.98 (d, 2H, J = 5.0 Hz), 9.30 (s, 1H)。アミドを脱保護して、化合物78を黄色の固体(64mg、76%)として得た。HPLC 方法A tr=8.11mn(97.0%)。ESI−MS m/z:391.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(46mg;51%)を白色の固体として得た。Rf=0.18(DCM/MeOH 9/1)。1H NMR (DMSO): δ 1.47 (s, 9H), 1.75 (m, 4H), 3.10 (m, 4H), 3.68 (m, 1H), 3.89 (d, 2H, J = 4.9 Hz), 4.12 (d, 2H, J = 5.6 Hz), 4.75 (d, 1H, J= 4.0 Hz), 6.03 (t, 1H, J = 4.9 Hz), 6.67 (t, 1H, J = 5.6 Hz), 7.12 (d, 2H, J = 8.5 Hz), 7.37 (d, 2H, J = 8.5 Hz), 9.27 (s, 1H)。アミドを脱保護して、化合物79を黄色の固体(23mg、48%)として得た。HPLC 方法A tr=4.92mn(91.0%)。ESI−MS m/z:307.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(52mg;47%)を白色の固体として得た。Rf=0.29(DCM/MeOH 9/1)。1H NMR (DMSO): δ 1.47 (s, 9H), 3.72 (d, 2H, J = 5.6 Hz), 4.14 (d, 2H, J = 5.8 Hz), 4.39 (d, 2H, J= 6.0 Hz), 6.25 (t, 1H, J = 5.6 Hz), 6.58 (t, 1H, J = 5.8 Hz), 7.13 (d, 2H, J = 8.5 Hz), 7.31 (d, 1H, J = 7.8 Hz), 7.36 (d, 2H, J = 8.5 Hz), 7.50 (t, 1H, J = 7.8 Hz), 7.73 (d, 1H, J = 7.8 Hz), 7.77 (s, 1H), 8.24 (s, 1H), 8.44 (t, 1H, J = 6.0 Hz), 9.26 (s, 1H), 9.36 (s, 1H)。アミドを脱保護して、化合物80を黄色の固体(23mg、42%)として得た。HPLC 方法A tr=7.20mn(98.5%)。ESI−MS m/z:380.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(61mg;61%)を白色の固体として得た。Rf=0.37(DCM/MeOH 9/1)。1H NMR (DMSO): δ 1.47 (s, 9H), 3.70 (d, 2H, J = 5.6 Hz), 3.73 (s, 3H), 4.13 (d, 2H, J = 5.8 Hz), 4.26 (d, 2H, J = 6.0 Hz), 6.19 (t, 1H, J = 5.6 Hz), 6.55 (t, 1H, J = 6.0 Hz), 6.83 (m, 3H), 7.13 (d, 2H, J = 8.5 Hz), 7.22 (t, 1H, J = 8.0 Hz), 7.36 (d, 2H, J = 8.5 Hz), 8.32 (d, 1H, J = 5.8 Hz), 9.27 (s, 1H)。アミドを脱保護して、化合物81を橙色の固体(33mg、51%)として得た。HPLC 方法A tr=7.69mn(91.3%)。ESI−MS m/z:343.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(DCM/MeOH 9/1)により精製して、保護アミド(51mg;57%)を白色の固体として得た。Rf=0.27(DCM/MeOH 9/1)。1H NMR (DMSO): δ 1.16 (t, 3H, J = 7.1 Hz), 1.47 (s, 9H), 2.72 (d, 2H, J = 5.7 Hz), 3.55 (m, 4H), 3.90 (m, 4H), 4.12 (d, 2H, J = 5.7 Hz), 4.83 (t, 1H, J = 6.0 Hz), 6.09 (m, 1H), 6.65 (t, 1H, J = 5.7 Hz), 7.12 (d, 2H, J = 8.5 Hz), 7.35 (d, 2H, J = 8.5 Hz), 8.13 (s, 1H), 9.27 (s, 1H)。アミドを脱保護して、化合物82を橙色の固体(24mg、44%)として得た。HPLC 方法A tr=6.34mn(97.3%)。ESI−MS m/z:392.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(AcOEt/MeOH 95/5)により精製して、保護アミド(72mg;88%)を白色の固体として得た。1H NMR (DMSO): δ 1.47 (s, 9H), 3.70 (d, 2H, J = 5.6 Hz), 3.73 (s, 3H), 4.13 (d, 2H, J = 5.8 Hz), 4.26 (d, 2H, J = 6.0 Hz), 6.19 (t, 1H, J = 5.6 Hz), 6.55 (t, 1H, J = 6.0 Hz), 6.83 (m, 3H), 7.13 (d, 2H, J = 8.5 Hz), 7.22 (t, 1H, J = 8.0 Hz), 7.36 (d, 2H, J = 8.5 Hz), 8.32 (d, 1H, J = 5.8 Hz), 9.27 (s, 1H)。アミドを脱保護して、化合物83を黄色の固体(68mg、96%)として得た。HPLC 方法B tr=12.41mn(98.4%)。ESI−MS m/z:267.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(AcOEt/MeOH 95/5)により精製して、保護アミド(72mg;74%)を白色の固体として得た。アミドを脱保護して、化合物84を黄色の固体(71mg、94%)として得た。HPLC 方法B tr=8.47mn(99.0%)。ESI−MS m/z:364.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(AcOEt/MeOH 95/5)により精製して、保護アミド(74mg;78%)を白色の固体として得た。1H NMR (DMSO): δ 1.47 (s, 9H), 3.70 (d, 2H, J = 5.6 Hz), 3.73 (s, 3H), 4.13 (d, 2H, J = 5.8 Hz), 4.26 (d, 2H, J = 6.0 Hz), 6.19 (t, 1H, J = 5.6 Hz), 6.55 (t, 1H, J = 6.0 Hz), 6.83 (m, 3H), 7.13 (d, 2H, J = 8.5 Hz), 7.22 (t, 1H, J = 8.0 Hz), 7.36 (d, 2H, J = 8.5 Hz), 8.32 (d, 1H, J = 5.8 Hz), 9.27 (s, 1H)。アミドを脱保護して、化合物85を黄色の固体(68mg、94%)として得た。HPLC 方法B tr=14.01mn(100%)。ESI−MS m/z:330.2[M+H]+。
粗生成物を、アセトン/ヘキサン中での沈殿により精製して、保護アミド(31mg;54%)を白色の固体として得た。アミドを脱保護して、化合物86を黄色の固体(18mg、51%)として得た。HPLC 方法B tr=13.07mn(93.0%)。ESI−MS m/z:280.0[M+H]+。
粗生成物を、アセトン/ヘキサン中での沈殿により精製して、保護アミド(55mg;82%)を白色の固体として得た。アミドを脱保護して、化合物87を黄色の固体(47mg、78%)として得た。HPLC 方法B tr=13.62mn(97.1%)。ESI−MS m/z:294.3[M+H]+。
粗生成物を、アセトン/ヘキサン中での沈殿により精製して、保護アミド(83mg;95%)を白色の固体として得た。アミドを脱保護して、化合物88を黄色の固体(79mg、88%)として得た。HPLC 方法B tr=13.92mn(99.4%)。ESI−MS m/z:355.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(AcOEt/MeOH 98/2)により精製して、保護アミド(81mg;85%)を白色の固体として得た。アミドを脱保護して、化合物89を黄色の固体(64mg、75%)として得た。HPLC 方法B tr=12.19mn(97.6%)。ESI−MS m/z:369.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(AcOEt/MeOH 95/5)により精製して、保護アミド(66mg;87%)を白色の固体として得た。アミドを脱保護して、化合物90を黄色の固体(53mg、76%)として得た。HPLC 方法B tr=23.57mn(99.8%)。ESI−MS m/z:384.4[M+H]+。
粗生成物を、AcOEt/ヘキサン中での沈殿により精製して、保護アミド(80mg;75%)を白色の固体として得た。アミドを脱保護して、化合物91を黄色の固体(62mg、73%)として得た。HPLC 方法B tr=17.19mn(99.1%)。ESI−MS m/z:360.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(AcOEt/MeOH 9/1)により精製して、保護アミド(210mg;88%)を白色の固体として得た。アミドを脱保護して、化合物92を黄色の固体(198mg、88%)として得た。HPLC 方法B tr=23.47mn(99.5%)。ESI−MS m/z:383.4[M+H]+。
粗生成物を、アセトン/ヘキサン中での沈殿により精製して、保護アミド(80mg;82%)を白色の固体として得た。アミドを脱保護して、化合物94を黄色の固体(69mg、81%)として得た。HPLC 方法B tr=19.53mn(91.5%)。ESI−MS m/z:400.1[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(AcOEt/MeOH 95/5)により精製して、保護アミド(84mg;84%)を白色の固体として得た。アミドを脱保護して、化合物94を黄色の固体(78mg、87%)として得た。HPLC 方法B tr=22.31mn(96.9%)。ESI−MS m/z:402.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(AcOEt/MeOH 8/2)により精製して、保護アミド(26mg;32%)を白色の固体として得た。アミドを脱保護して、化合物95を黄色の固体(16mg、53%)として得た。HPLC 方法B tr=15.07mn(94.5%)。ESI−MS m/z:363.1[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(AcOEt/MeOH 95/5)により精製して、保護アミド(67mg;90%)を白色の固体として得た。アミドを脱保護して、化合物96を黄色の固体(21mg、28%)として得た。HPLC 方法B tr=18.86mn(97.9%)。ESI−MS m/z:320.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(AcOEt)により精製して、保護アミド(36mg;60%)を白色の固体として得た。アミドを脱保護して、化合物97を黄色の固体(12mg、30%)として得た。HPLC 方法B tr=17.17mn(94.3%)。ESI−MS m/z:332.1[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(AcOEt/MeOH 95/5)により精製して、保護アミド(105mg;89%)を白色の固体として得た。1H NMR (DMSO): δ 1.10 (t, 3H, J= 6.7 Hz), 1.47 (s, 9H), 3.64 (q, 2H, J= 6.7 Hz), 3.99 (d, 2H, J= 4.4 Hz), 4.16 (d, 2H, J= 5.8 Hz), 4.92 (s, 2H), 6.10 (t, 1H, J= 4.4 Hz), 6.71 (t, 1H, J= 5.8 Hz), 7.45 (m, 5H), 7.60 (d, 1H, J= 8.6 Hz), 7.73 (d, 1H, J= 8.6 Hz), 8.13 (s, 1H), 9.67 (s, 1H)。アミドを脱保護して、化合物98を黄色の固体(107mg、97%)として得た。HPLC 方法B tr=17.49mn(94.5%)。ESI−MS m/z:358.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(AcOEt)により精製して、保護アミド(312mg;77%)を白色の固体として得た。アミドを脱保護して、化合物99を黄色の固体(307mg、91%)として得た。1H NMR (DMSO): δ 1.10 (m, 3H), 3.45 (s, 2H), 3.65 (m, 2H), 4.00 (s, 2H), 4.14 (s, 2H), 4.93 (s, 2H), 6.08 (s, 1H), 6.63 (s, 1H), 6.92 (m, 2H), 7.15 (m, 2H), 7.45 (m, 5H)。HPLC 方法B tr=18.32mn(96.5%)。ESI−MS m/z:357.2[M+H]+。
粗物(アミド;Rf=0.43(EtOAc))を脱保護し、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、アミン(20mg;2工程の全体的収率=8%)を得た。Rf=0.09(EDP/EtOAC 30/70)。1H NMR (300 MHz, DMSO): δ 8.12-8.05 (m, 2H), 7.22 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.3 Hz, 2H), 6.53 (d, J = 8.3 Hz, 2H), 6.50 (t, J = 5.3 Hz, 1H), 5.99 (t, J = 5.2 Hz, 1H), 5.00-4.93 (m, 4H), 4.06 (s, 2H), 4.04 (s, 2H), 4.00 (s, 3H), 3.69 (q, J = 6.8 Hz, 2H), 2.58 (s, 3H), 1.13 (t, J = 7.0 Hz, 3H)。HPLC 方法A tr=9.52mn(93.6%)。ESI−MS m/z:429.2[M+H]+。
粗物(アミド;Rf=0.43(EDP/EtOAc 30/70))を脱保護し、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、アミン(10mg;2工程の全体的収率=10%)Rf=0.14(EDP/EtOAC 30/70)を得た。1H NMR (300 MHz, DMSO) δ 7.03-6.95 (m, 3H), 6.90 (d, J = 8.4 Hz, 2H), 6.50 (d, J = 8.3 Hz, 2H), 6.45 (t, J = 5.7 Hz, 1H), 5.95 (t, J = 5.4 Hz, 1H), 4.97 (broad s, 2H), 4.84 (s, 2H), 4.03-3.97 (m, 4H), 3.80 (s, 3H), 3.72 (s, 3H), 3.63 (q, J = 7.2 Hz, 2H), 1.09 (t, J = 7.0 Hz, 3H)。HPLC 方法A tr=10.15mn(90.4%)。ESI−MS m/z:417.2[M+H]+。
粗物(アミド;Rf=0.31(EDP/EtOAc 30/70))を脱保護し、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、アミン(56mg;2工程の全体的収率=25%)を白色の固体として得た。Rf=0.4(EtOAC)。1H NMR (300 MHz, DMSO): δ 7.61-7.46 (m, 4H), 6.94 (d, J = 8.3 Hz, 2H), 6.53 (d, J = 8.3 Hz, 2H), 6.48 (t, J = 5.9 Hz, 1H), 6.03 (t, J = 5.4 Hz, 1H), 4.99-4.93 (m, 4H), 4.08-3.98 (m, 4H), 3.67 (q, J = 7.1 Hz, 2H), 1.12 (t, J = 6.9 Hz, 3H)。HPLC 方法A tr=10.97mn(97.3%)。ESI−MS m/z:391.2/393.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EtOAc/MeOH)により精製して、保護アミド(56mg;47%)を無色の油状物として得た。Rf=0.38(EtOAc/MeOH 95/5)。1H NMR (300 MHz, CDCl3): δ 8.46-8.56 (m, 1H), 7.77-7.55 (m, 1H), 7.25-7.11 (m, 5H), 6.61 (s, 1H), 5.97 (s, 1H), 5.55 (s, 1H), 4.65-4.52 (m, 2H), 4.31-4.23 (m, 2H), 4.21-4.10 (m, 2H), 3.35 (q, J = 6.9 Hz, 2H), 1.50 (s, 9H), 1.15 (t, J = 6.3 Hz, 3H)。アミドを脱保護して、アミン(30mg;70%)を黄色の油状物として得た。Rf=0.2(EtOAc/MeOH 90/10)。1H NMR (300 MHz, DMSO): δ 8.56 (dd, J = 4.1 Hz, 16.3 Hz, 1H), 7.89-7.72 (m, 1H), 7.42-7.22 (m, 2H), 6.99-6.90 (m, 2H), 6.58-6.50 (m, 3H), 6.12-6.02 (m, 1H), 5.08 (broad s, 2H), 4.63 (d, J= 6.9 Hz, 2H), 4.06 (d, J = 5.3 Hz, 2H), 4.04-3.96 (m, 2H), 3.48-3.28 (m,2H) 1.19-0.96 (m, 3H)。HPLC 方法A tr=4.42mn(88.4%)。ESI−MS m/z:342.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミド(35mg;43%)を白色の固体として得た。Rf=0.6(EtOAc)。1H NMR (200 MHz, CDCl3): δ 7.31-7.09 (m, 6H), 6.86-6.62 (m, 3H), 6.58-6.46 (m, 1H), 4.48-4.40 (m, 2H), 4.30-4.22 (m, 2H), 4.18-4.05 (m, 4H), 3.78 (d, J = 5.1 Hz, 3H), 3.39-3.13 (m, 2H), 1.50 (s, 9H), 1.20-0.94 (m, 3H)。アミドを脱保護して、アミン(15mg;53%)を白色の固体として得た。Rf=0.29(EtOAc)。1H NMR (300 MHz, DMSO) δ 7.30 (dt, J = 8.0 Hz, 19.2 Hz, 1H), 6.98-6.89 (m, 2H), 6.89-6.79 (m, 3H), 6.58-6.49 (m, 3H), 6.14-6.03 (m, 1H), 4.97 (broad s, 2H), 4.57-4.50 (m, 2H), 4.10-3.89 (m, 4H), 3.81-3.74 (m, 3H), 3.47-3.22 (m, 2H), 1.13 (t, J = 7.0 Hz, 3H)。HPLC 方法A tr=9.46mn(96.3%)。ESI−MS m/z:371.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミド(48mg;34%)を白色の固体として得た。Rf=0.66(EtOAc)。1H NMR (200 MHz, CDCl3): δ 7.35-6.73 (m, 9H), 6.49 (s, 1H), 4.47-4.35 (m, 2H), 4.32-4.23 (m, 2H), 4.16-4.11 (m, 2H), 3.80-3.77 (m, 3H), 3.24 (dq, J= 7 Hz, 20.6 Hz, 2H), 1.51 (s, 9H), 1.06 (dt, J = 7.1 Hz, 21.6 Hz, 3H)。アミドを脱保護して、アミン(31mg;81%)を黄色の固体として得た。Rf=0.27(EtOAc)。1H NMR (300 MHz, DMSO): δ 7.26-7.17 (m, 2H), 7.05-6.86 (m, 4H), 6.69-6.54 (m, 3H), 6.11 (s, 1H), 4.48 ( broad s, 2H), 4.12-4.04 (m, 2H), 4.04-3.90 (m, 2H), 3.79-3.74 (m, 3H), 3.54-318 (m, 4H), 1.13 (t, J = 6.9 Hz, 3H)。HPLC 方法A tr=8.42mn(96.3%)。ESI−MS m/z:371.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミド(50mg;52%)を無色の油状物として得た。Rf=0.17(EDP/EtOAc 50/50)。1H NMR (300 MHz, CDCl3): δ 7.30-7.07 (m, 8H), 7.05-6.96 (m, 1H), 6.57 (broad s, 1H), 4.45-4.36 (m, 2H), 4.29-4.21 (m, 2H), 4.19-4.04 (m, 2H), 3.25 (dq, J= 7.1 Hz, 14.3 Hz, 2H), 1.50 (s, 9H), 1.17-0.95 (m, 3H)。アミドを脱保護して、アミン(10mg;24%)を黄色の固体として得た。Rf=0.41(EtOAc)。HPLC 方法A tr=10.06mn(98.5%)。ESI−MS m/z:375.2/377.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミドを得た。Rf=0.37(EtOAc)。アミドを脱保護し、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、アミン(36mg;2工程の全体的収率=30%)を黄色の固体として得た。Rf=0.3(EtOAc)。HPLC 方法A tr=9.05mn(97.5%)。ESI−MS m/z:359.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミド(10mg;25%)を得た。Rf=0.11(EDP/EtOAc 30/70)。1H NMR (300 MHz, CDCl3) δ 7.96-785 (m, 1H), 7.75-7.65 (m, 1H), 7.33-7.14 (m, 6H), 6.95-6.85 (m, 1H), 6.53-6.43 (m, 1H), 4.59-4.53 (m, 1H), 4.44 (broad s, 1H), 4.34-4.26 (m, 2H), 4.19-4.11 (m, 2H), 3.94-3.85 (m, 3H), 3.43-3.23 (m, 2H), 2.59-2.49 (m, 3H), 1.50 (s, 9H), 1.21-0.98 (m, 3H)。アミドを脱保護して、アミン(5mg;63%)を黄色の油状物として得た。Rf=0.22(EtOAc)。HPLC 方法A tr=9.11mn(92.2%)。ESI−MS m/z:413.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護されたアミン(88mg;42%)を白色の固体として得た。Rf=0.34(EDP/EtOAc 30/70)。アミドを脱保護し、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、アミン(15mg;21%)を得た。Rf=0.33(EtOAc)。1H NMR (300 MHz, DMSO) δ 7.65-7.47 (m, 2H), 7.37-7.26 (m, 2H), 6.94 (d, J = 8.3 Hz, 2H), 6.53 (d, J = 8.3 Hz, 2H), 6.47 (t, J = 5.7 Hz, 1H), 6.01 (t, J = 5.5 Hz, 1H), 5.01 (s, 2H), 4.97 (s, 2H), 4.04 (d, J = 5.7 Hz, 2H), 4.00 (d, J = 5.5 Hz, 2H), 3.66 (q, J = 7.0 Hz, 2H), 1.11 (t, J = 7.0 Hz, 3H)。HPLC 方法A tr=9.76mn(98.3%)。ESI−MS m/z:375.2[M+H]+。
粗物(アミド;Rf=0.34(EDP/EtOAc 30/70))を脱保護し、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、アミン(20mg;2工程の全体的収率=12%)を得た。Rf=0.06(EDP/EtOAC 30/70)。1H NMR (300 MHz, DMSO) δ 7.45-7.34 (m, 1H), 7.11-7.05 (m, 2H), 7.06-6.99 (m, 1H), 6.96 (d, J = 8.3 Hz, 2H), 6.56 (d, J = 8.3 Hz, 2H), 6.51 (t, J = 5.7 Hz, 1H), 6.04 (t, J = 5.4 Hz, 1H), 4.99 (broad s, 2H), 4.94 (s, 2H), 4.09-4.01 (m, 4H), 3.83 (s, 3H), 3.69 (q, J = 7.0 Hz, 2H), 1.15 (t, J = 7.2 Hz 3H)。HPLC 方法A tr=9.75mn(97.8%)。ESI−MS m/z:387.2[M+H]+。
粗物(アミド;Rf=0.28(EDP/EtOAc 30/70))を脱保護し、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、アミン(25mg;2工程の全体的収率=13%)を得た;Rf=0.09(EDP/EtOAC30/70)。1H NMR (300 MHz, DMSO) δ 8.09 (s, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.53 (d, J = 8.4 Hz, 2H), 6.49 (t, J = 5.9 Hz, 1H), 6.03 (t, J = 5.5 Hz, 1H), 5.05 (s, 2H), 4.98 (broad s, 2H), 4.38 (q, J = 6.9 Hz, 2H), 4.10-3.98 (m, 4H), 3.68 (q, J= 7.0, 2H), 1.37 (t, J = 7.1, 3H), 1.13 (t, J = 7.0, 3H)。HPLC 方法A tr=10.76mn(96.8%)。ESI−MS m/z:429.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護されたアミン(32mg;12%)を白色の固体として得た。Rf=0.13(EDP/EtOAc 30/70)。アミドを脱保護し、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、アミン(10mg;38%)を得た。Rf=0.24(EtOAc)。1H NMR (300 MHz, DMSO): δ 8.39 (s, 1H), 8.31 (d, J = 7.3 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.78 (t, J = 7.9 Hz, 1H), 6.94 (d, J = 8.3 Hz, 2H), 6.53 (d, J = 8.4 Hz, 2H), 6.48 (t, J = 5.7 Hz, 1H), 6.03 (t, J = 5.3 Hz, 1H), 5.12 (s, 2H), 4.97 (s, 2H), 4.08-4.01 (m, 4H), 3.70 (q, J= 6.8 Hz, 2H), 1.14 (t, J = 7.0 Hz, 3H)。HPLC 方法A tr=9.67mn(97.6%)。ESI−MS m/z:402.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護されたアミン(71mg;42%)を白色の固体として得た。Rf=0.13(EDP/EtOAc 30/70)。アミドを脱保護し、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、アミン(26mg;46%)を得た。Rf=0.3(EtOAc)。1H NMR (300 MHz, DMSO): δ 8.33 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.3 Hz, 2H), 6.53 (d, J = 8.4 Hz, 2H), 6.48 (t, J = 6.1 Hz, 1H), 6.04 (t, J = 5.5 Hz, 1H), 5.13 (s, 2H), 4.97 (s, 2H), 4.07-4.00 (m, 4H), 3.69 (q, J= 7.1 Hz, 2H), 1.14 (t, J = 7.0 Hz, 3H)。HPLC 方法A tr=9.78mn(95.4%)。ESI−MS m/z:402.2[M+H]+。
粗物(アミド)を脱保護し、フラッシュクロマトグラフィー(EtOAc/MeOH)により精製して、アミン(50mg;2工程の全体的収率=30%)を得た。1H NMR (300 MHz, DMSO): δ 8.69-8.61 (m, 1H), 7.90 (t, J = 7.3 Hz , 1H), 7.59 (d, J = 7.4 Hz, 1H), 7.50-7.40 (m, 1H), 6.93 (d, J = 7.8 Hz, 2H), 6.53 (d, J = 8.1, 2H), 6.48 (s, 1H), 6.01 (s, 1H), 5.04 (s, 2H), 4.96 (s, 2H), 4.09-3.98 (m, 4H), 3.67 (q, J = 6.9 Hz, 2H), 1.13 (t, J = 7.0 Hz, 3H)。HPLC 方法A tr=6.22mn(99.1%)。ESI−MS m/z:358.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミドを得た。アミドを脱保護し、フラッシュクロマトグラフィー(EtOAc/MeOH)により精製して、アミン(14mg;2工程の全体的収率=7%)を得た。Rf=0.3(EtOAc/MeOH 98/2)。1H NMR (300 MHz, DMSO): δ 8.22 (s, 1H), 6.94 (d, J = 8.3 Hz, 2H), 6.91-6.85 (m, 1H), 6.79-6.73 (m, 2H), 6.53 (d, J= 8.4 Hz, 2H), 6.42 (t, J = 5.8 Hz, 1H), 6.14 (t, J = 5.3 Hz, 1H), 4.96 (broad s, 2H), 4.26 (d, J= 5.8 Hz, 2H), 4.05 (d, J = 5.3 Hz, 2H), 3.81 (s, 3H), 3.73 (d, J= 5.7 Hz, 2H)。HPLC 方法A tr=6.38mn(79.6%)。ESI−MS m/z:359.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミドを得た。Rf=0.16(EtOAc)。アミドを脱保護し、エーテル中で沈殿させて、アミン(TFA塩;22.7mg;2工程の全体的収率=14%)を白色の固体として得た。Rf=0.14(EtOAc)。HPLC 方法A tr=9.89mn(92.3%)。ESI−MS m/z:403.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミドを得た。Rf=0.22(EtOAc)。アミドを脱保護し、エーテル中で沈殿させて、アミン(TFA塩;54mg;2工程の全体的収率=33%)を白色の固体として得た。Rf=0.47(CH2Cl2/MeOH 95/5)。1H NMR (300 MHz, CDCl3): δ 7.29-7.21 (m, 2H), 7.20-7.11 (m, 2H), 6.80-6.61 (m, 3H), 6.43-6.33 (m, 1H), 5.33-5.09 (m, 1H), 4.26-4.18 (m, 2H), 4.17-4.05 (m, 2H), 3.79-3.64 (m, 6H), 3.56-3.04 (m, 2H), 2.25-2.06 (m, 1H), 1.98-1.54 (m, 4H), 1.47 (d, J = 2.1, 9H)。HPLC 方法A tr=8.73mn(99.7%)。ESI−MS m/z:413.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc、次にEtOAc/MeOH)により精製して、保護アミドを得た。Rf=0.26(EtOAc)。1H NMR (300 MHz, CDCl3): δ 7.43-6.80 (m, 8H), 6.67 (s, 1H), 5.42-5.13 (m, 1H), 4.23-4.16 (m, 2H), 4.16-4.02 (m, 1H), 3.79-3.20 (m, 3H), 2.40-2.07 (m, 1H), 2.00-1.53 (m, 4H), 1.50-1.46 (m, 9H)。アミドを脱保護し、エーテル中で沈殿させて、アミン(TFA塩;90mg;2工程の全体的収率=58%)を黄色の固体として得た。Rf=0.37(CH2Cl2/MeOH 95/5)。HPLC 方法A tr=10.16mn(83.5%)。ESI−MS m/z:387.2[M+H]+。
粗生成物(アミド;Rf=0.22(EtOAc/MeOH 90/10))を脱保護し、フラッシュクロマトグラフィー(EtOAc/MeOH)により精製して、アミン(18mg;2工程の全体的収率=12%)を得た。Rf=0.16(EtOAc/MeOH 90/10)。1H NMR (300 MHz, DMSO): δ 8.73-8.68 (m, 1H), 8.67-8.60 (m, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.54-7.46 (m, 1H), 6.94 (d, J = 8.3 Hz, 2H), 6.53 (d, J = 8.3 Hz, 2H), 6.48 (t, J = 5.5 Hz, 1H), 6.03 (t, J = 5.4 Hz, 1H), 5.07-4.93 (m, 4H), 4.09-3.97 (m, 4H), 3.68 (q, J= 6.9 Hz, 2H), 1.13 (t, J = 7.0 Hz, 3H)。HPLC 方法A tr=4.47mn(86.5%)。ESI−MS m/z:358.2[M+H]+。
粗生成物(アミド;Rf=0.32(EtOAc))を脱保護し、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、アミン(17mg;2工程の全体的収率=17%)を得た。Rf=0.15(EtOAc)。1H NMR (200 MHz, CDCl3): δ 7.08 (d, J = 8.3 Hz, 2H), 6.69 (d, J = 8.3 Hz, 2H), 5.45 (s, 1H), 5.16 (s, 1H), 4.30-4.05 (m, 8H), 3.62 (q, J= 7.1 Hz, 2H), 2.63 (t, J = 5.9 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H)。HPLC 方法A tr=6.97mn(92.6%)。ESI−MS m/z:367.2[M+H]+。
粗生成物(アミド;Rf=0.08(EtOAc))を脱保護し、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、アミン(13mg;2工程の全体的収率=11%)を得た。Rf=0.12(EtOAc)。1H NMR (200 MHz, CDCl3) δ 7.08 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 8.4 Hz, 2H), 5.50 (s, 1H), 5.24 (s, 1H), 4.30-4.06 (m, 6H), 3.90 (t, J= 6.2 Hz, 2H), 3.59 (q, J = 7.1 Hz, 2H), 2.44 (t, J = 7.3 Hz, 2H), 2.08-1.88 (m, 2H), 1.25 (t, J= 7.2 Hz, 4H), 1.14 (t, J = 7.1 Hz, 3H)。HPLC 方法A tr=7.61mn(93.6%)。ESI−MS m/z:381.3[M+H]+。
粗生成物(アミド;Rf=0.46(EtOAc))を脱保護し、フラッシュクロマトグラフィー(EtOAc/MeOH)により精製して、アミン(31mg;2工程の全体的収率=21%)を得た。Rf=0.06(EtOAc/MeOH 98/2)。1H NMR (300 MHz, CDCl3): δ 8.66-8.55 (m, 2H), 7.80-7.65 (m, 3H), 7.49-7.36 (m, 3H), 7.32-7.27 (m, 1H), 7.24-7.16 (m, 1H), 4.97 (s, 4H), 4.87 (s, 2H), 3.03 (q, J= 7.1 Hz, 2H), 1.11 (t, J = 7.1 Hz, 3H)。HPLC 方法A tr=4.46mn(95.3%)。ESI−MS m/z:358.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミドを得た。Rf=0.26(EtOAc)。アミドを脱保護し、エーテル中で沈殿させて、アミンを黄色の固体(TFA塩;16mg;2工程の全体的収率=20%)として得た。Rf=0.08(EtOAc)。HPLC 方法A tr=9.46mn(99.6%)。ESI−MS m/z:397.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc、次にEtOAc/MeOH)により精製して、保護アミドを得た。Rf=0.28(EtOAc)。1H NMR (300 MHz, CDCl3): δ 7.58-7.45 (m, 1H), 7.35-6.98 (m, 6H), 6.92-6.86 (m, 1H), 6.54 (broad s, 1H), 5.98 (t, J = 4.3 Hz, 1H), 5.86 (t, J = 4.4 Hz, 1H), 5.67-5.53 (m, 1H), 5.41-5.09 (m, 1H), 4.27-4.18 (m, 2H), 4.17-3.23 (m, 4H), 2.44-2.18 (m, 1H), 2.01-1.54 (m, 3H), 1.49 (m, 9H)。アミドを脱保護し、エーテル中で沈殿させて、アミン(TFA塩;16mg;2工程の全体的収率=19%)を褐色の固体として得た。Rf=0.08(EtOAc)。HPLC 方法A tr=9.29mn(96.1%)。ESI−MS m/z:431.2/433.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミドを得た。Rf=0.43(EtOAc)。アミドを脱保護し、エーテル中で沈殿させて、アミン(TFA塩;30.2mg;2工程の全体的収率=18%)を白色の固体として得た。Rf=0.32(EtOAc)。HPLC 方法A tr=10.15mn(96.8%)。ESI−MS m/z:441.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミドを得た。Rf=0.41(EtOAc)。1H NMR (300 MHz, CDCl3): δ 7.39-7.01 (m, 7H), 6.82-6.56 (m, 1H), 6.04-5.80 (m, 1H), 5.68-5.44 (m, 1H), 4.46-4.13 (m, 4H), 3.80-2.85 (m, 2H), 2.03-1.53 (m, 6H), 1.50 (s, 9H)。アミドを脱保護し、エーテル中で沈殿させて、アミン(TFA塩;34.7mg;2工程の全体的収率=21%)を黄色の固体として得た。Rf=0.33(EtOAc)。HPLC 方法A tr=10.66mn(90.6%)。ESI−MS m/z:435.2/437.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミドを得た。Rf=0.33(EtOAc)。1H NMR (300 MHz, CDCl3) δ 7.34-6.52 (m, 9H), 5.35-5.06 (m, 1H), 4.23 (m, 2H), 4.14-4.08 (m, 1H), 3.80 and 3.68 (2s, 3H), 3.77-3.10 (m, 3H), 2.27-2.05 (m, 1H), 1.98-1.53 (m, 3H), 1.48 (s, 9H)。アミドを脱保護し、エーテル中で沈殿させて、アミン(TFA塩;62mg;2工程の全体的収率=38%)を黄色の固体として得た。Rf=0.4(EtOAc)。HPLC 方法A tr=10.64mn(98.6%)。ESI−MS m/z:417.2/419.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc、次にEtOAc/MeOH)により精製して、保護アミドを得た。Rf=0.38(EtOAc)。1H NMR (300 MHz, CDCl3): δ 7.33-6.97 (m, 8H), 6.88-6.76 (m, 1H), 6.68-6.54 (m, 1H), 5.58-5.06 (m, 1H), 4.29-4.16 (m, 2H), 3.84-3.14 (m, 4H), 2.52-2.35 (m, 3H), 2.34-2.09 (m, 1H), 2-1.63 (m, 3H), 1.48 (m, 9H)。アミドを脱保護し、エーテル中で沈殿させて、アミン(TFA塩;77.3mg;2工程の全体的収率=49%)を黄色の固体として得た。Rf=0.32(CH2Cl2/MeOH 95/5)。HPLC 方法A tr=10.25mn(97.8%)。ESI−MS m/z:399.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミドを得た。Rf=0.54(EtOAc)。1H NMR (200 MHz, CDCl3) δ 7.51-7.02 (m, 13H), 6.52 (s, 1H), 5.70 (broad s, 1H), 5.20 (broad s, 1H), 4.26 (d, J = 5.6 Hz, 2H), 4.00-2.91 (m, 4H), 1.96-1.37 (m, 7H), 1.50 (s, 9H)。アミドを脱保護し、エーテル中で沈殿させて、アミン(TFA塩;32mg;2工程の全体的収率=19%)を黄色の固体として得た。Rf=0.32(EtOAc)。HPLC 方法A tr=11.48mn(83.1%)。ESI−MS m/z:443.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミドを得た。Rf=0.51(EtOAc)。アミドを脱保護し、エーテル中で沈殿させて、アミン(TFA塩;10.6mg;2工程の全体的収率=6%)を黄色の固体として得た。Rf=0.4(EtOAc)。1H NMR (300 MHz, CDCl3): δ 7.45-7.04 (m, 14H), 6.69 (broad s, 1H), 5.75-5.65 (m, 1H), 5.56-5.46 (m, 1H), 5.32 (t, J = 5.7 Hz, 1H), 4.29 (d, J = 5.7 Hz, 2H), 4.07-3.95 (m, 1H), 3.58-3.46 (m, 1H), 3.44-2.98 (m, 2H), 2.00-1.30 (m, 6H), 1.51 (s, 9H)。HPLC 方法A tr=11.25mn(91.9%)。ESI−MS m/z:457.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミドを得た。Rf=0.68(EtOAc)。1H NMR (300 MHz, CDCl3): δ 7.25 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 7.11-6.82 (m, 3H), 6.53 (broad s, 1H), 5.90 (broad s, 1H), 5.55-5.00 (m, 1H), 4.50-3.95 (m, 4H), 3.90-2.70 (m, 5H), 2.27 (s, 3H), 2.15-1.35 (m, 6H), 1.50 (s, 9H)。アミドを脱保護し、逆相(H2O/MeCN)により精製して、アミン(8mg;2工程の全体的収率=6%)を得た。Rf=0.4(EtOAc)。HPLC 方法A tr=9.89mn(70.3%)。ESI−MS m/z:411.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミドを得た。Rf=0.59(EtOAc)。1H NMR (300 MHz, CDCl3): δ 7.24 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.05-6.97 (m, 1H), 6.92-6.78 (m, 2H), 6.51 (s, 1H), 6.10-5.80 (m, 1H), 5.75-5.35 (m, 1H), 5.55-5.10 (m, 1H), 4.40-4.20 (m, 4H), 3.81 (s, 3H), 3.78-3.55 (m, 2H), 2.25-1.35 (m, 6H), 1.50 (s, 9H)。アミドを脱保護し、逆相(H2O/MeCN)により精製して、アミン(8mg;2工程の全体的収率=7%)を得た。Rf=0.36(EtOAc)。HPLC 方法A tr=9.56mn(89.1%)。ESI−MS m/z:397.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミド(18mg、15%)を無色の油状物として得た。Rf=0.5(EtOAc)。1H NMR (300 MHz, CDCl3): δ 7.29 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 6.53 (s, 1H), 5.50 (s, 1H), 5.18 (s, 1H), 4.36-4.20 (m, 4H), 4.19-3.71 (m, 2H), 3.05-2.55 (m, 2H), 1.73-1.53 (m, 4H), 1.52-1.44 (m, 18H)。アミドを脱保護し、逆相(H2O/MeCN)により精製して、アミン(6mg;2工程の全体的収率=61%)を得た;Rf=0.49(MeOH)。HPLC 方法A tr=4.46mn(100%)。ESI−MS m/z:292.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミドを得た。Rf=0.3(EDP/EtOAc 30/70)。1H NMR (200 MHz, CDCl3): δ 8.08 (d, J = 7.3 Hz, 1H), 7.35-6.93 (m, 7H), 6.55 (s, 1H), 5.94 (t, J = 4.5 Hz, 1H), 5.49 (t, J = 5.8 Hz, 1H), 4.28 (d, J = 5.7 Hz, 2H), 4.12 (d, J = 4.6 Hz, 2H), 3.97 (t, J = 8.4 Hz, 2H), 3.17 (t, J = 8.3 Hz, 2H), 1.50 (s, 9H)。アミドを脱保護し、エーテル中で沈殿させて、アミン(TFA塩;10.6mg;2工程の全体的収率=8%)を黄色の固体として得た。Rf=0.33(EtOAc)。1H NMR (300 MHz, DMSO): δ 8.10 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 8.3 Hz , 2H), 7.21 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 8.3 Hz, 2H), 7.04 (t, J = 7.5 Hz, 1H), 6.80 (s, 1H), 6.30 (s, 1H), 4.23 (d, J = 5.2 Hz, 2H), 4.11 (t, J = 8.5 Hz, 2H), 4.04 (broad s, 2H), 3.20 (t, J= 8.3 Hz, 2H)。HPLC 方法A tr=7.63mn(95.5%)。ESI−MS m/z:325.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミド(18mg、15%)を無色の油状物として得た。Rf=0.53(EtOAc)。アミドを脱保護し、逆相(H2O/MeCN)により精製して、アミン(6mg;61%)を得た。Rf=0.48(EtOAc)。HPLC 方法A tr=10.28mn(86.2%)。ESI−MS m/z:433.2.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミド(80mg、54%)を無色の油状物として得た。Rf=0.26(EtOAc)。アミドを脱保護し、逆相(H2O/MeCN)により精製して、アミン(12mg;2工程の全体的収率=26%)を得た。Rf=0.38(MeOH)。1H NMR (300 MHz, DMSO): δ 6.93 (d, J = 8.3 Hz, 2H), 6.53 (d, J = 8.4 Hz, 2H), 6.50 (t, J = 5.7 Hz, 1H), 5.95 (t, J = 5.1 Hz, 1H), 5.12 (t, J = 8.6 Hz, 1H), 5.00 (broad s, 2H), 4.03 (d, J = 5.7 Hz, 2H), 3.98 (d, J = 5.1 Hz, 2H), 3.45-3.29 (m, 2H), 2.86 (q, J = 6.6 Hz,, 2H), 2.05-1.84 (qn, J = 6.6 Hz, 2H)。ESI−MS m/z:278.1[M+H]+。
(R)−2−(アジドメチル)−1−Boc−ピロリジン(70mg、0.3mmol)をDCM 2mlに溶解し、TFA 2mlを加え、次に反応混合物を室温で1時間放置して、アミンをTFA塩(mtheo=73mg)として得た。溶媒を蒸発させ、次の工程は説明のように実施した。粗生成物を、フラッシュクロマトグラフィー(CH2Cl2/MeOH)により精製して、保護アミド(100mg、75%)を得た。Rf=0.54(CH2Cl2/MeOH 90/10)。1H NMR (200 MHz, CDCl3): δ 7.30 (d, J = 8.6 Hz, 2H), 7.20 (d, J= 8.6 Hz, 2H), 6.57 (broad s, 1H), 5.82 (t, J = 4.1 Hz, 1H), 5.45 (t, J= 5.4 Hz, 1H), 4.31 (d, J = 5.6 Hz, 2H), 4.17-3.17 (m, 7H), 2.15-1.76 (m, 4H), 1.50 (s, 9H)。アミドを脱保護し、逆相(H2O/MeCN)により精製して、アミン(62mg;80%)を得た。Rf=0.48(CH2Cl2/MeOH 90/10)。HPLC 方法A tr=6.60mn(99.6%)。ESI−MS m/z:332.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミド(107mg、69%)を白色の固体として得た。Rf=0.24(EtOAc)。1H NMR (300 MHz, CDCl3): δ 7.40-7.08 (m, 8H), 6.55 (s, 1H), 6.15-5.90 (m, 1H), 5.80-5.45 (m, 1H), 4.42-3.90 (m, 5H), 3.85-2.65 (m, 4H), 1.99-1.56 (m, 4H), 1.50 (s, 9H)。アミドを脱保護し、逆相(H2O/MeCN)により精製して、アミン(73mg;85%)を橙色の固体として得た。Rf=0.8(MeOH)。HPLC 方法A tr=9.78mn(96.0%)。ESI−MS m/z:401.2/403.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミド(120mg、75%)を白色の固体として得た。Rf=0.18(EtOAc)。1H NMR (300 MHz, CDCl3): δ 7.62-7.02 (m, 8H), 6.57 (broad s, 1H), 5.98-5.82 (m, 1H), 5.66-5.46 (m, 1H), 5.12-4.92 (m, 1H), 4.33-3.99 (m, 4H), 3.83-3.14 (m, 2H), 2.43-1.64 (m, 4H), 1.49 (s, 9H)。アミドを脱保護し、逆相(H2O/MeCN)により精製して、アミン(64mg;66%)を橙色の固体として得た。Rf=0.77(MeOH)。HPLC 方法A tr=9.77mn(96.5%)。ESI−MS m/z:421.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミド(120mg、82%)を白色の固体として得た。Rf=0.24(EtOAc)。1H NMR (300 MHz, CDCl3): δ 7.35-7.08 (m, 5H), 7.00-6.63 (m, 3H), 6.59 (broad s, 1H), 6.02 (broad s, 1H), 5.69 (broad s, 1H), 5.05-4.85 (m, 1H), 4.34-3.99 (m, 4H), 3.78-3.16 (m, 2H), 2.40-1.60 (m, 4H), 1.49 (s, 9H)。アミドを脱保護し、逆相(H2O/MeCN)により精製して、アミン(51mg;54%)を白色の固体として得た。Rf=0.70(MeOH)。HPLC 方法A tr=8.39mn(95.4%)。ESI−MS m/z:371.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EtOAc/MeOH)により精製して、保護アミド(120mg、76%)を白色の固体として得た。Rf=0.22(EtOAc/MeOH 60/40)。アミドを脱保護し、逆相(H2O/MeCN)により精製して、アミン(64mg;67%)を橙色の固体として得た。Rf=0.23(MeOH)。HPLC 方法A tr=6.17mn(94.8%)。ESI−MS m/z:410.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EtOAc/MeOH)により精製して、保護アミド(60mg、40%)を白色の固体として得た。Rf=0.35(EtOAc/MeOH 90/10)。1H NMR (300 MHz, CDCl3) δ 7.36-7.06 (m, 9H), 6.50 (broad s, 1H), 5.00 (broad s, 1H), 4.90 (broad s, 1H), 4.30-4.19 (m, 2H), 4.15-3.89 (m, 4H), 3.46-3.33 (m, 1H), 2.96-2.71 (m, 2H), 2.31-2.14 (m, 1H), 1.98-1.54 (m, 3H), 1.48 (s, 9H)。アミドを脱保護し、逆相(H2O/MeCN)により精製して、アミン(18mg;38%)を橙色の油状物として得た。Rf=0.61(MeOH)。HPLC 方法A tr=5.94mn(85.1%)。ESI−MS m/z:397.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミド(94mg、63%)を無色の油状物として得た。Rf=0.46(EtOAc)。1H NMR (300 MHz, CDCl3): δ 7.40-6.90 (m, 8H), 6.55 (broad s, 1H), 6.19-5.92 (m, 1H), 5.82-5.49 (m, 1H), 4.38-4.27 (m, 2H), 4.26-4.05 (m, 3H), 3.47-3.10 (m, 2H), 3.05-2.60 (m, 2H), 1.92-1.62 (m, 4H), 1.50 (s, 9H)。アミドを脱保護し、逆相(H2O/MeCN)により精製して、アミン(58mg、76%)を橙色の固体として得た。Rf=0.23(EtOAc)。HPLC 方法A tr=9.17mn(97.1%)。ESI−MS m/z:385.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミドを得た。Rf=0.5(EtOAc)。アミドを脱保護し、逆相(H2O/MeCN)により精製して、アミン(36mg;2工程の全体的収率=29%)を白色の固体として得た。Rf=0.28(EtOAc)。1H NMR (300 MHz, CDCl3): δ 7.32-6.96 (m, 8H), 6.59 (s, 2H), 6.12-5.72 (m, 1H), 5.60-5.16 (m, 1H), 4.26 (s, 2H), 4.15 (s, 1H), 4.01 (s, 2H), 3.53-3.28 (m, 2H), 3.14-2.95 (m, 1H), 2.66-2.38 (m, 1H), 1.99-1.57 (m, 4H)。HPLC 方法A tr=10.04mn(96.7%)。ESI−MS m/z:401.2/403.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、保護アミド(98mg、60%)を白色の固体として得た。Rf=0.51(EtOAc)。アミドを脱保護し、逆相(H2O/MeCN)により精製して、アミン(24mg、31%)を得た。Rf=0.05(EtOAc)。HPLC 方法A tr=9.31mn(96.9%)。ESI−MS m/z:431.2/433.2[M+H]+。
一般手順。
アミン誘導体21又は25(1当量)を、DCM 2mlに溶解した。アセチルクロリド(1当量)を加え、反応混合物を室温で20時間撹拌した。反応混合物を濃縮し、AcOEt 50mlを加えた。有機相を飽和NaHCO3、10%クエン酸及びブラインで洗浄し、次にNa2SO4で乾燥させ、濾過し、そして濃縮した。粗生成物をフラッシュクロマトグラフィーにより精製して、アミドを得た。
粗生成物を、フラッシュクロマトグラフィー(AcOEt/EDP 5/5)により精製して、アミド146(37mg;67%)を白色の固体として得た。Rf=0.59(AcOEt/EDP 5/5)。1H NMR (DMSO): δ 1.18 (t, 3H, J = 7.1 Hz), 2.03 (s, 3H), 3.82 (d, 2H, J = 6.0 Hz), 4.08 (q, 2H, J = 7.1 Hz), 4.22 (d, 2H, J = 6.4 Hz), 6.42 (t, 1H, J = 6.0 Hz), 6.95 (t, 1H, J = 9.0 Hz), 7.13 (t, 2H, J = 6.4 Hz), 7.30 (q, 1H, J = 8.2 Hz), 7.78 (d, 1H, J = 8.2 Hz), 10.52 (s, 1H)。HPLC 方法A tr=8.90mn(94.7%)。ESI−MS m/z:312.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(AcOEt/MeOH 95/5)により精製して、アミド147(17mg;17%)を白色の固体として得た。Rf=0.16(AcOEt/MeOH 95/5)。1H NMR (DMSO): δ 1.18 (t, 3H, J = 7.1 Hz), 2.03 (s, 3H), 3.82 (d, 2H, J = 6.0 Hz), 4.08 (q, 2H, J = 7.1 Hz), 4.22 (d, 2H, J = 6.4 Hz), 6.42 (t, 1H, J = 6.0 Hz), 6.95 (t, 1H, J = 9.0 Hz), 7.13 (t, 2H, J = 6.4 Hz), 7.30 (q, 1H, J = 8.2 Hz), 7.78 (d, 1H, J = 8.2 Hz), 10.52 (s, 1H)。HPLC 方法A tr=7.38mn(97.7%)。ESI−MS m/z:294.3[M+H]+。
ウレア149を、以下の反応スキームに従って調製した:
(S)−メチル 2−(3−((6−tert−ブチルオキシカルボニルアミノピリジン−3−イル)メチル)ウレイド)−3−フェニルプロパノアート(148)。
メチル (S)−2−イソシアナト−3−フェニルプロピオナート(1当量、463μl)をTHF(0.4M)に溶解し、次にアミン(1当量、474mg)を一度に加え、そして反応混合物を室温で2時間放置した。反応が完了した後(TLC管理)、反応混合物を濃縮し、ヘキサン中での沈殿により精製して、ウレア148(860mg、96%)を得た。1H NMR (DMSO): δ 1.47 (s, 9H), 2.90 (dd, 1H, J = 13.5, 5.5 Hz), 2.99 (dd, 1H, J = 13.5, 5.5 Hz), 3.61 (s, 3H), 4.12 (s, 2H), 4.43 (dd, 1H, J = 13.5, 5.5 Hz), 6.35 (d, 1H, J = 7.8 Hz), 6.57 (t, 1H, J = 5.9 Hz), 7.16 (d, 2H, J = 7.0 Hz), 7.23 (m, 1H), 7.29 (m, 2H), 7.53 (d, 1H, J = 8.1 Hz), 7.71 (d, 1H, J = 8.9 Hz), 8.09 (s, 1H), 9.66 (s, 1H)。
ウレア148(210mg)をDCM 2mlに溶解し、TFA 2mlを加え、次に反応混合物を室温で1時間放置した。反応混合物を濃縮し、AcOEt/ヘキサンを使用して沈殿により精製し、脱保護ウレア149を黄色の固体(204mg、89%)として得た。HPLC 方法B tr=17.99mn(95.8%)。ESI−MS m/z:329.3[M+H]+。
VI.1. アミン152の合成
アミン152を、以下の反応スキームに従って調製した:
tert−ブチル ベンジルオキシカルバマート(150): N−ヒドロキシベンジル−アミン(1当量、1.62g)を、THF 30mlに溶解した。Boc2O(1当量、2.87g)を加え、反応混合物を室温で20時間撹拌した。反応混合物を濃縮し、AcOEt 50mlを加えた。有機相を10%クエン酸及びブラインで洗浄し、次にNa2SO4で乾燥させ、濾過し、濃縮して、150を油状物(2.92g、99%)として得た。1H NMR (CDCl3): δ 1.42 (s, 9H), 4.73 (s, 2H), 7.37 (m, 5H), 10.03 (s, 1H)。
このスルホニルウレアを、以下の反応スキームに従って調製した:
ベンジル−N−((4−tert−ブトキシカルボニルアミノ)ベンジル)スルファモイルカルバマート(153): ベンジルアルコール(259μl、1当量)を、DCM(20ml)中の撹拌したクロロスルホニルイソシアナート(218μl、1当量)溶液に0℃でゆっくり加え、撹拌を0℃で30分間続けた。DCM(10ml)中のトリエチルアミン(2ml)を溶液に加えた。次に、得られた混合物を、DCM(40ml)中の4−(tert−ブトキシカルボニルアミノ)ベンジルアミン(0.56g、1当量)の氷冷懸濁液に滴下した。このように得られた溶液を2時間撹拌し、減圧下で蒸発させた。残留物をAcOEt(100ml)に溶解した。有機相を10%クエン酸及びブラインで洗浄し、次にNa2SO4で乾燥させ、濾過し、そして濃縮した。粗生成物を、DCM中で再結晶化して、153を白色の固体(720mg、66%)として得た。1H NMR (DMSO): δ 1.48 (s, 9H), 4.03 (d, 2H, J= 5.2 Hz), 5.03 (s, 2H), 7.17 (d, 2H, J= 8.3 Hz), 7.37 (m, 7H), 8.25 (s, 1H), 9.33 (s, 1H), 11.21 (s, 1H)。
ウレア162及び163を、以下の反応スキームに従って調製した:
エチル 2−アミノ−3−(3−ヒドロキシフェニル)プロパノアート(157): −5℃のEtOH 20mLに、撹拌しながら、SOCl20.2mLをゆっくり加えた。清澄な無色の溶液を−5℃に冷却し、メタ−チロシン510mgを加えた。5分後、得られた溶液を一晩還流した。溶液を濃縮して、157をHCl塩(690mg、99%)として得た。
161(469mg)をDCM 4mlに溶解し、TFA 4mlを加え、次に反応混合物を室温で1時間放置した。反応混合物を濃縮し、AcOEt 50mlを加えた。有機相を飽和NaHCO3及びブラインで洗浄し、次にNa2SO4で乾燥させ、濾過し、濃縮して、162を白色の固体(350mg、91%)として得た。1H NMR (DMSO): δ 1.28 (t, 3H, J= 6.5 Hz), 3.04 (m, 2H), 4.13 (d, 2H, J= 4.1 Hz), 4.19 (q, 2H, J= 6.5 Hz), 4.56 (m, 1H), 5.02 (s, 2H), 5.21 (s, 2H), 6.29 (d, 1H, J= 8.3 Hz), 6.45 (m, 1H), 6.62 (d, 2H, J= 7.3 Hz), 6.89 (d, 1H, J= 7.3 Hz), 7.00 (m, 3H), 7.33 (t, 1H, J= 7.3 Hz), 7.53 (t, 1H, J= 7.3 Hz), 7.57 (d, 1H, J= 6.7 Hz)。HPLC 方法B tr=21.65mn(97.4%)。ESI−MS m/z:448.3[M+H]+。
MeOH(20ml)中の162(205mg)の溶液を、10% Pd/Cの存在下、水素雰囲気下で1時間撹拌した。得られた混合物をセライトを通して濾過し、濾液を減圧下で蒸発させて、163を白色の固体(160mg、98%)として得た。1H NMR (DMSO): δ 1.28 (t, 3H, J= 6.4 Hz), 2.97 (m, 2H), 4.12 (m, 2H), 4.19 (q, 2H, J= 6.4 Hz), 4.51 (m, 1H), 5.02 (s, 2H), 6.24 (d, 1H, J= 8.3 Hz), 6.46 (m, 1H), 6.63 (d, 2H, J= 7.5 Hz), 6.71 (s, 2H), 6.75 (d, 1H, J= 7.5 Hz), 7.00 (d, 2H, J= 7.5 Hz), 7.19 (t, 1H, J= 7.5 Hz), 9.42 (s, 1H)。HPLC 方法B tr=17.75mn(96.3%)。ESI−MS m/z:358.2[M+H]+。
ウレア169を、以下の反応スキームに従って調製した:
エチル 2−アミノ−3−(3,4−ジヒドロキシフェニル)プロパノアート(164): −5℃でEtOH 30mLに、撹拌しながら、SOCl20.37mLをゆっくり加えた。清澄な無色の溶液を−5℃に冷却し、L−ドーパ 1gを加えた。5分後、得られた溶液を一晩還流した。溶液を濃縮して、164をHCl塩(1.30g、99%)として得た。1H NMR (DMSO): δ 1.29 (t, 3H, J= 7.4 Hz), 3.03 (m, 1H), 3.15 (m, 1H), 4.21 (m, 1H), 4.27 (m, 2H), 4.35 (sl, 3H), 6.60 (d, 1H, J= 7.9 Hz), 6.74 (s, 1H), 6.82 (d, 1H, J= 7.9 Hz), 8.63 (s, 2H)。
168(600mg)をDCM 4mlに溶解し、TFA 4mlを加え、次に反応混合物を室温で1時間放置した。反応混合物を濃縮し、AcOEt 50mlを加えた。有機相を飽和NaHCO3及びブラインで洗浄し、次にNa2SO4で乾燥させ、濾過し、濃縮して、169を白色の固体(480mg、94%)として得た。1H NMR (DMSO): δ 1.27 (t, 3H, J= 7.4 Hz), 2.95 (m, 2H), 4.15 (m, 4H), 4.51 (m, 1H), 5.09 (s, 2H), 5.22 (s, 4H), 6.22 (d, 1H, J= 7.1 Hz), 6.27 (d, 1H, J= 7.6 Hz), 6.37 (m, 1H), 6.47 (m, 1H), 6.63 (m, 2H), 6.81 (d, 1H, J= 7.4 Hz), 7.00 (m, 2H), 7.05 (s, 1H), 7.09 (d, 1H, J= 8.1 Hz), 7.24 (t, 1H, J= 8.1 Hz), 7.35 (m, 2H), 7.52 (m, 4H), 7.64 (t, 1H, J= 8.0 Hz)。
本化合物を、以下の反応スキームに従って調製した:
ベンジル 2−アミノ−3−(3−ヒドロキシフェニル)プロパノアート(170): −5℃でベンジルアルコール10mLに、撹拌しながら、SOCl20.2mLをゆっくり加えた。清澄な無色の溶液を−5℃に冷却し、メタ−チロシン490mgを加えた。5分後、得られた溶液を120℃に一晩加熱した。AcOEt 100mlを加えた。有機相を飽和NaHCO3及びブラインで洗浄し、次にNa2SO4で乾燥させ、濾過し、濃縮して、170を白色の固体(430mg、59%)として得た。1H NMR (DMSO): δ 1.90 (s, 3H), 2.87 (dd, 1H, J= 13.1, 6.5 Hz), 2.94 (dd, 1H, J= 13.1, 6.5 Hz), 3.73 (t, 1H, J= 6.5 Hz), 5.19 (s, 2H), 6.70 (d, 1H, J= 7.7 Hz), 6.75 (s, 1H), 7.17 (t, 1H, J= 7.7 Hz), 7.41 (d, 1H, J= 7.0 Hz), 7.48 (m, 5H), 9.37 (s, 1H)。
酸誘導体175(1当量)を、DMF 2mlに溶解した。アミン(1.1当量)、ヒドロキシベンゾトリアゾール(HOBt)(1.2当量)、ジイソプロピルエチルアミン(DIEA)(2.2当量)及び1−[3−(ジメチルアミノ)プロピル]−3−エチルカルボジイミド(EDAP)(1.2当量)を連続して加え、反応混合物を室温で20時間撹拌した。反応混合物を濃縮し、AcOEt 100mlを加えた。有機相を飽和NaHCO3、10%クエン酸及びブラインで洗浄し、次にNa2SO4で乾燥させ、濾過し、そして濃縮した。粗生成物を、フラッシュクロマトグラフィー(AcOEt)により精製して、アミドを白色の固体(80mg、73%)として得た。1H NMR (DMSO): δ 1.48 (s, 9H), 1.60 (m, 2H), 1.72 (m, 2H), 2.62 (m, 1H), 2.80 (dd, 1H, J= 13.4, 5.2 Hz), 3.77 (m, 2H), 3.98 (m, 2H), 4.08 (d, 2H, J= 5.3 Hz), 4.90 (m, 1H), 6.14 (d, 1H, J= 8.8 Hz), 6.43 (t, 1H, J= 5.3 Hz), 6.60 (m, 3H), 7.05 (d, 1H, J= 8.5 Hz), 7.08 (d, 2H, J= 8.2 Hz), 7.36 (d, 2H, J= 8.2 Hz), 9.25 (s, 1H), 9.27 (s, 1H)。保護ウレア(78mg)をDCM 2mlに溶解し、TFA 2mlを加え、次に反応混合物を室温で1時間放置した。反応混合物を濃縮し、AcOEt/ヘキサンを使用して沈殿により精製し、脱保護ウレア176を黄色の固体(75mg、92%)として得た。HPLC 方法B tr=15.77mn(92.3%)。ESI−MS m/z:399.4[M+H]+。
一般プロトコル: 二環式アミン(1当量)をAcOEt(30mL)に溶解し、トリホスゲン(0.33当量)を撹拌しながら−10℃で加えた。混合物を室温に温め、次に1時間還流した。4−(tert−ブトキシカルボニルアミノ)ベンジルアミン又は2−(tert−ブトキシカルボニルアミノ)−5−(2−アミノメチル)ピリジン(1当量)及びトリエチルアミン(2当量)を連続して加え、得られた溶液を室温で一晩撹拌した。AcOEt 100mlを加えた。有機相を10%クエン酸、飽和NaHCO3及びブラインで洗浄し、次にNa2SO4で乾燥させ、濾過し、そして濃縮した。粗生成物を、フラッシュクロマトグラフィーにより精製して、保護ウレアを得た。最終的に、ウレアをDCM 2mlに溶解し、TFA 2mlを加え、次に反応混合物を室温で1時間放置した。反応混合物を濃縮し、AcOEt/ヘキサンを使用して沈殿により精製し、脱保護ウレア177−180を得た。
粗生成物を、フラッシュクロマトグラフィー(AcOEt)により精製して、保護ウレア(123mg;62%)を白色の固体として得た。1H NMR (DMSO): δ 1.61 (s, 9H), 4.36 (d, 2H, J= 5.1 Hz), 7.31 (d, 2H, J= 7.5 Hz), 7.40 (t, 1H, J= 5.1 Hz), 7.54 (d, 2H, J= 7.5 Hz), 7.68 (d, 1H, J= 5.0 Hz), 8.15 (d, 1H, J= 5.0 Hz), 8.32 (s, 1H), 8.96 (s, 1H), 9.39 (s, 1H)。ウレアを脱保護して、化合物177を黄色の固体(112mg、86%)として得た。HPLC 方法B tr=13.67mn(97.3%)。ESI−MS m/z:316.1[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(AcOEt/MeOH 95/5)により精製して、保護ウレア(103mg;57%)を白色の固体として得た。1H NMR (DMSO): δ 1.59 (s, 9H), 4.37 (d, 2H, J= 4.8 Hz), 7.55 (t, 1H, J= 4.8 Hz), 7.68 (t, 1H, J= 4.5 Hz), 7.78 (d, 1H, J= 8.2 Hz), 7.89 (d, 1H, J= 8.2 Hz), 8.16 (d, 1H, J= 4.5 Hz), 8.30 (s, 1H), 8.37 (s, 1H), 8.94 (s, 1H), 9.88 (s, 1H)。ウレアを脱保護して、化合物178を黄色の固体(98mg、89%)として得た。HPLC 方法B tr=13.65mn(97.3%)。ESI−MS m/z:317.0[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(AcOEt/MeOH 95/5)により精製して、保護ウレア(133mg;67%)を白色の固体として得た。ウレアを脱保護して、化合物179を黄色の固体(108mg、86%)として得た。1H NMR (DMSO): δ 4.09 (d, 2H, J= 5.8 Hz), 5.80 (s, 2H), 6.42 (d, 1H, J= 8.6 Hz), 7.31 (d, 1H, J= 8.5 Hz), 7.39 (t, 1H, J= 5.5 Hz), 7.60 (t, 1H, J= 7.3 Hz), 7.74 (d, 1H, J= 8.0 Hz), 7.83 (s, 1H), 7.88 (t, 1H, J= 7.4 Hz), 8.18 (d, 1H, J= 8.0 Hz), 8.26 (s, 1H), 8.26 (s, 1H), 9.12 (s, 1H)。HPLC 方法B tr=15.78mn(93.8%)。ESI−MS m/z:311.0[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(AcOEt/MeOH 95/5)により精製して、保護ウレア(123mg;62%)を白色の固体として得た。ウレアを脱保護して、化合物180を黄色の固体(102mg、82%)として得た。HPLC 方法B tr=16.49mn(94.9%)。ESI−MS m/z:310.0[M+H]+。
MeOH(10ml)中の98(38mg)の溶液を、10% Pd/Cの存在下、水素雰囲気下で1時間撹拌した。得られた混合物をセライトを通して濾過し、濾液を減圧下で蒸発させて、181を白色の固体(16mg、57%)として得た。ESI−MS m/z:268.1[M+H]+。
一般手順。イソシアナト酢酸エチル(1当量、64mg、56μl、0.49mmol)を、DMF(0.4M)に溶解した。次に、アミン(1当量)を一度に加え、反応混合物を室温で24時間放置した。反応が完了した後(TLC管理)、反応混合物を濃縮し、粗生成物をフラッシュクロマトグラフィー(AcOEt/MeOH 90/10)により精製してウレアを得た:
182を精製して、黄色の固体86mg(68%)を得た。1H NMR (DMSO): δ 1.20 (t, 3H, J= 7.1 Hz), 3.78 (d, 2H, J = 6.0 Hz), 4.10 (q, 2H, J = 7.1 Hz), 4.31 (d, 2H, J = 6.0 Hz), 6.43 (t, 1H, J = 6.0 Hz), 6.92 (t, 1H, J = 6.0 Hz), 7.06 (s, 2H)。HPLC 方法A tr=4.66mn(92.70%)。ESI−MS m/z:260.1[M+H]+。
183を精製して、黄色の固体87mg(64%)を得た。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 2.88 (t, 2H, J = 6.7 Hz), 3.29 (m, 2H), 3.74 (d, 2H, J = 6.0 Hz), 4.09 (q, 2H, J = 7.1 Hz), 6.32 (m, 2H), 7.03 (s, 2H)。HPLC 方法A tr=4.83mn(98.08%)。ESI−MS m/z:274.1[M+H]+。
184を精製して、黄色の固体60mg(47%)を得た。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 3.77 (d, 2H, J = 6.0 Hz), 3.98 (d, 2H, J = 5.6 Hz), 4.09 (q, 2H, J = 7.1 Hz), 6.19 (s, 1H), 6.30 (t, 1H, J = 6.0 Hz), 6.43 (t, 1H, J = 5.6 Hz), 6.87 (s, 2H)。HPLC 方法A tr=4.77mn(98.97%)。ESI−MS m/z:259.1[M+H]+。
185を精製して、黄色の固体64mg(48%)を得た。1H NMR (DMSO): δ 1.19 (t, 3H, J= 7.1 Hz), 3.22 (m, 2H), 3.34 (m, 2H), 3.74 (d, 2H, J = 6.0 Hz), 4.09 (q, 2H, J = 7.1 Hz), 6.13 (m, 2H), 6.23 (t, 1H, J = 6.0 Hz), 6.82 (s, 2H)。HPLC 方法A tr=5.22mn(96.30%)。ESI−MS m/z:273.1[M+H]+。
(R)−エチル 6−アセトアミド−2−アミノヘキサノアート(186): Boc−Lys(Ac)−OH(1当量、0.2g、0.69mmol)を、EtOH(2mL)に溶解した。反応混合物を−10℃で冷却し、SOCl2(1.5当量、76μl、1.035mmol)を滴下した。混合物を室温に温め、次に40℃で20時間加熱した(TLC管理)。反応混合物を濃縮し、粗生成物をフラッシュクロマトグラフィー(CH2Cl2/MeOH)により精製して、化合物(120mg、80%)を白色の固体として得た。Rf=0.62(CH2Cl2/MeOH 70/30)。
(R)−エチル 6−アセトアミド−2−アミノヘキサノアート186(1当量、120mg、0.55mmol)を無水THF(4mL)に溶解し、トリホスゲン(0.33当量、55mg、0.18mmol)を撹拌しながら−10℃で加えた。混合物を室温に温め、次に2時間還流した。tert−ブチル−N−[4−(アミノメチル)フェニル]カルバマート(1当量、123mg、0.55mmol)及びトリエチルアミン(2当量、154μl、1.1mmol)を連続して加え、得られた溶液を室温で一晩撹拌した。反応混合物を濃縮し、NaHCO330mlにより洗浄し、そしてEtOAc 3×30mlにより抽出した。有機相をNa2SO4で乾燥させ、濾過し、そして濃縮した。粗生成物を、フラッシュクロマトグラフィー(CH2Cl2/MeOH)により精製して、保護ウレア(21mg、8%)を得た。Rf=0.18(CH2Cl2/MeOH 95/5)。1H NMR (200 MHz, CDCl3) δ 7.30 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 6.68 (s, 1H), 6.10-5.90 (m, 1H), 5.43 (d, J = 7.7 Hz, 1H), 5.30 (t, J = 5.7 Hz, 1H), 4.51-4.35 (m, 1H), 4.35-4.25 (m, 2H), 4.15 (q, J = 7.1 Hz, 2H), 3.26-3.08 (m, 2H), 1.91 (s, 3H), 1.85-1.15 (m, 6H), 1.50 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H)。最終的に、ウレアをDCM 2mlに溶解し、TFA 2mlを加え、次に反応混合物を室温で1時間放置した。反応混合物を濃縮し、逆相(H2O/MeCN)により精製して、脱保護ウレア(7mg、44%)を無色の油状物として得た。Rf=0.42(CH2Cl2/MeOH 90/10)。1H NMR (200 MHz, CDCl3): δ 7.06 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 8.4 Hz, 2H), 6.15-5.92 (m, 1H), 5.36 (d, J = 8.1 Hz, 1H), 5.16 (t, J = 5.8, 1H), 4.55-4.35 (m, 1H), 4.22 (d, J = 5.6 Hz, 2H), 4.14 (q, J = 7.2 Hz, 2H), 3.28-3.10 (m, 2H), 1.92 (s, 3H), 1.90-1.27 (m, 6H), 1.25 (t, J = 7.1 Hz, 3H)。HPLC 方法A tr=6.75mn(91.30%)。ESI−MS m/z:365.2[M+H]+。
(R)−エチル 2−アミノ−5−(ベンジルオキシカルボニルアミノ)ペンタノアート(188): Boc−Orn(Z)−OH(1当量、0.4g、1.1mmol)を、EtOH(4mL)に溶解した。反応混合物を−10℃で冷却し、SOCl2(1.5当量、119μl、1.65mmol)を滴下した。混合物を室温に温め、次に40℃で20時間加熱した(TLC管理)。反応混合物を濃縮し、粗生成物をフラッシュクロマトグラフィー(CH2Cl2/MeOH)により精製して、化合物188(178mg、55%)を白色の固体として得た。Rf=0.23(CH2Cl2/MeOH 90/10)。1H NMR (300 MHz, CDCl3): δ 7.37-7.27 (m, 5H), 5.54 (broad s, 1H), 5.05 (s, 2H), 4.17 (q, J = 6.9 Hz, 2H), 3.95 (broad s, 1H), 3.30-3.13 (m, 2H), 2.10-1.85 (m, 2H), 1.85-1.55 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H)。
ウレアをDCM 2mlに溶解し、TFA 2mlを加え、次に反応混合物を室温で1時間放置した。反応混合物を濃縮し、逆相(H2O/MeCN)により精製して、脱保護ウレア(43mg、61%)を白色の固体として得た。Rf=0.4(CH2Cl2/MeOH 90/10)。HPLC 方法A tr=5.52mn(98.2%)。ESI−MS m/z:351.3[M+H]+。
Tert−ブチル 4−(アミノメチル)フェニルカルバマート(1当量)、イソシアナート(1.2当量)及びDIPEA(1.2当量)を、DMFに溶解した。反応混合物を室温で20時間撹拌した。混合物をNaHCO330mlにより洗浄し、EtOAc 3×20mlにより抽出した。有機相をNa2SO4で乾燥させ、濾過し、そして濃縮した。粗生成物を、フラッシュクロマトグラフィーにより精製して、アミドを得た。最終的に、アミドをDCM 4mlに溶解し、TFA 2mlを加え、次に反応混合物を室温で1時間放置した。反応混合物を濃縮し、逆相(H2O/MeCN)により精製して、脱保護アミドを得た。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、アミド(612mg、83%)を白色の固体として得た、Rf=0.48(EDP/EtOAc 50/50)、1H NMR (200 MHz, CDCl3): δ 7.28 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 8.6 Hz, 2H), 6.60 (broad s, 1H), 5.17-5.01 (m, 2H), 4.55-4.38 (m, 1H), 4.26 (d, J = 5.6 Hz, 2H), 4.11 (q, J= 7.2 Hz, 2H), 1.79-1.33 (m, 3H), 1.50 (s, 9H), 1.23 (t, J = 7.1 Hz, 3H), 0.97-0.86 (m, 6H)。アミド(200mg、0.49mmol)を脱保護して、アミン192(130mg、100%)を白色の固体として得た、Rf=0.64(CH2Cl2/MeOH 90/10)。HPLC 方法A tr=8.91mn(100%)。ESI−MS m/z:308.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、アミド(569mg、74%)を白色の固体として得た、Rf=0.32(EDP/EtOAc 50/50)。1H NMR (200 MHz, CDCl3): δ 7.27 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 6.67 (broad s, 1H), 5.43 (d, J = 8.1 Hz, 1H), 5.26 (t, J = 5.6 Hz, 1H), 4.62-4.36 (m, 1H), 4.25 (d, J = 5.6 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 2.54-2.42 (m, 2H), 2.20-1.75 (m, 3H), 2.04 (s, 3H), 1.49 (s, 9H), 1.24 (t, J = 7.1 Hz, 3H)。アミド(200mg、0.47mmol)を脱保護して、アミン193(101mg、94%)を白色の固体として得た、Rf=0.68(CH2Cl2/MeOH 90/10)。HPLC 方法A tr=7.72mn(94.6%)。ESI−MS m/z:326.2[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、アミド(562mg、86%)を白色の固体として得た、Rf=0.25(EDP/EtOAc 50/50)。1H NMR (200 MHz, CDCl3): δ 7.28 (d, J = 8.6 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 6.57 (broad s, 1H), 5.15 (d, J = 7.6 Hz, 1H), 4.98 (t, J = 5.6 Hz, 1H), 4.46 (p, J = 7.2 Hz, 1H), 4.27 (d, J = 5.6 Hz, 2H), 4.14 (q, J = 7.1 Hz, 3H), 1.50 (s, 9H), 1.35 (d, J = 7.2 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H)。アミド(200mg、0.55mmol)を脱保護して、アミン(72mg、100%)を白色の固体として得た、Rf=0.75(MeOH)。1H NMR (300 MHz, DMSO): δ 6.95 (d, J = 8.3 Hz, 2H), 6.55 (d, J= 8.3 Hz, 2H), 6.32-6.21 (m, 2H), 4.99 (broad s, 2H), 4.21 (q, J = 7.2 Hz, 1H), 4.13 (q, J = 7.3 Hz, 2H), 4.05 (d, J = 5.7 Hz, 2H), 1.28 (d, J = 7.3 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H)。HPLC 方法A tr=5.38mn(100%)。ESI−MS m/z:266.2[M+H]+。
エステル(1当量)及びKOH(2.5当量)を、H2O/MeOH 1/1に溶解した。反応混合物を50℃で1時間30分加熱した。次に、反応物を室温で冷却し、MeOHを蒸発させた。混合物をブライン30mlにより洗浄し、EtOAc 30mlにより抽出した(不純物を有機相中で取り除いた)。水相をクエン酸によりpH=3で酸性化し、EtOAc 3×30mlにより抽出した。有機相をNa2SO4で乾燥させ、濾過し、濃縮して、カルボン酸を得た。
エステル(1当量、332mg、0.81mmol)、LiOH(2.5当量、50mg、2.08mmol)をH2O/MeOH 4ml/4mlに溶解し、反応混合物を室温で45分間撹拌した(中間体生成物を得た)。NaOH(2.5当量、82mg、2.08mmol)を加え、反応混合物を2時間還流した。カルボン酸を、2番目の有機相中で白色の固体(207mg、67%)として単離した。1H NMR (300 MHz, DMSO): δ 9.31 (broad s, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 6.60 (t, J = 4.9 Hz, 1H), 6.06 (d, J = 7.2 Hz, 1H), 4.18-4.11 (m, 2H), 3.99-3.85 (m, 1H), 1.80-1.27 (m, 3H), 1.51 (s, 9H), 0.95-0.87 (m, 6H)。カルボン酸を反応させて、アミドを得た。アミドを、フラッシュクロマトグラフィー(EDP/EtOAc)により、2つのジアステレオ異性体として単離した。108mg、黄色の固体、Rf=0.17(EDP/EtOAc 30/70)。アミドを脱保護して、アミン195(50mg、56%)を橙色の固体として得た、Rf=0.64(MeOH)。HPLC 方法A tr=11.18mn(98.8%)。ESI−MS m/z:455.2[M+H]+。
カルボン酸を、2番目の有機相中で白色の固体(283mg、93%)として単離した。1H NMR (200 MHz, DMSO): δ 12.48 (broad s, 1H), 9.31 (s, 1H), 7.41 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 6.42 (t, J = 5.9 Hz, 1H), 6.24 (d, J = 7.8 Hz, 1H), 4.23-4.05 (m, 3H), 1.50 (s, 9H), 1.24 (d, J = 7.2 Hz, 3H)。カルボン酸を反応させて、アミドを得た。アミドをフラッシュクロマトグラフィー(EDP/EtOAc)により、2つのジアステレオ異性体として単離した。118mg、Rf=0.13(EDP/EtOAc 30/70)。アミドを脱保護して、アミン196(57mg、95%)を白色の固体として得た、Rf=0.72(MeOH)。HPLC 方法A tr=9.63mn(93.5%)。ESI−MS m/z:413.2[M+H]+。
カルボン酸を、2番目の有機相中で白色の固体(159mg、53%)として単離した。1H NMR (200 MHz, DMSO)/ δ 12.63 (broad s, 1H), 9.30 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 6.42 (t, J = 5.9 Hz, 1H), 6.30 (d, J = 8.5 Hz, 1H), 4.33-4.20 (m, 1H), 4.16 (d, J = 5.8 Hz, 2H), 2.54-2.44 (m, 2H), 2.08 (s, 3H), 2.05-1.70 (m, 2H), 1.50 (s, 9H)。カルボン酸を反応させて、アミドを得た。アミドを、フラッシュクロマトグラフィー(EDP/EtOAc)により、2つのジアステレオ異性体として単離した、51mg、Rf=0.15(EDP/EtOAc 30/70)。アミドを脱保護して、アミン197(30mg、71%)を固体として得た、Rf=0.71(MeOH)。HPLC 方法A tr=10.55mn(95.0%)。ESI−MS m/z:473.2[M+H]+。
3−(3−(2−エトキシ−2−オキソエチル)ウレイド)−3−(4−ニトロフェニル)プロパン酸(198): 3−アミノ−3−(4−ニトロフェニル)プロパン酸(1当量、500mg、2.38mmol)、イソシアナト酢酸エチル(1当量、267μl、2.38mmol)及びDIPEA(2当量、830μl、4.76mmol)を、DMF 2mlに溶解した。反応混合物を室温で一晩撹拌した。混合物を濃縮し、H2O 100mlにより洗浄し、EtOAc 100mlにより抽出した(不純物を取り除いた)。水相をHCl 5%によりpH3で酸性化し、EtOAc 2×100mlにより抽出した。有機相をNa2SO4で乾燥させ、濾過し、そして濃縮した。粗生成物を、フラッシュクロマトグラフィー(EtOAc/MeOH)により精製して、化合物198(420mg、52%)を白色の固体として得た、Rf=0.25(EtOAC/MeOH 95/5)。1H NMR (200 MHz, DMSO): δ 12.45 (s, 1H), 8.23 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.1 Hz, 1H), 6.47 (t, J = 6.0 Hz, 1H), 5.14 (q, J = 7.3 Hz, 1H), 4.09 (q, J = 7.1 Hz, 4H), 3.84-3.72 (m, 2H), 2.77 (d, J = 6.9 Hz, 2H), 1.19 (t, J = 7.1 Hz, 5H)。
エチル 2−(3−(1−(4−(tert−ブトキシカルボニルアミノ)フェニル)−3−オキソ−3−(プロパ−2−イニルアミノ)プロピル)ウレイド)アセタート(108mg)をDCM 4mlに溶解し、TFA 2mlを加え、次に反応混合物を室温で2時間放置した。混合物を濃縮し、粗生成物を逆相(H2O/MeCN)により精製して、アミン201(50mg、60%)を白色の固体として得た。Rf=0.45(EtOAc/MeOH 90/10)。1H NMR (200 MHz, DMSO) δ 8.25 (t, J = 5.5 Hz, 1H), 6.94 (d, J= 8.3 Hz, 2H), 6.56 (d, J = 8.5 Hz, 1H), 6.50 (d, J = 8.3 Hz, 2H), 6.27 (t, J = 6.0 Hz, 1H), 5.05-4.79 (m, 3H), 4.10 (q, J = 7.1 Hz, 2H), 3.86-3.71 (m, 4H), 3.14-3.08 (m, 1H), 2.58-2.45 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H)。HPLC 方法A tr=5.12mn(98.1%)。ESI−MS m/z:347.1[M+H]+。
ウレア類の合成:一般手順
F703(1当量)、アルキン(1当量)、CuSO4(0.2当量;H2O中20mMの溶液)、Na−L−Asc(0.5当量、H2O中50mMの溶液)を、EtOH 8mlに溶解した(反応溶液 EtOH/H2O 8/2)。反応混合物を45℃で1時間、そして室温で一晩加熱した。混合物を濃縮した。粗生成物をフラッシュクロマトグラフィーにより精製して、アミドを得た。最終的に、アミドをDCM 2mlに溶解し、TFA 2mlを加え、次に反応混合物を室温で1時間放置した。反応混合物を濃縮し、逆相(H2O/MeCN)により精製して、脱保護アミドを得た。
粗生成物を、フラッシュクロマトグラフィー(EtOAc/MeOH)により精製して、保護アミド(19mg、36%)を得た。Rf=0.26(EtOAc/MeOH 95/5)。1H NMR (300 MHz, CDCl3) δ 7.51 (s, 1H), 7.27-7.09 (m, 6H), 6.96 -6.83 (m, 3H), 6.44 (s, 1H), 5.57-5.46 (m, 1H), 5.20-5.12 (m, 3H), 4.60-4.45 (m, 1H), 4.44-4.33 (m, 1H), 4.26 (d, J = 5.6 Hz, 2H), 4.22- 4.09 (m, 1H), 3.89-3.80 (m, 2H), 3.25-3.09 (m, 1H), 3.05-2.89 (m, 1H), 1.91-1.61 (m, 4H), 1.44 (s, 9H)。アミドを脱保護し、逆相(H2O/MeCN)により精製して、アミン(7.2mg、45%)を得た。Rf=0.11(EtOAc/MeOH 95/5)。HPLC 方法A tr=9.02mn(98.2%)。ESI−MS m/z:464.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EtOAc/MeOH)により精製して、保護アミド(21mg、36%)を得た。Rf=0.37(EtOAc/MeOH 95/5)。1H NMR (300 MHz, CDCl3) δ 7.66-7.56 (m, 1H), 7.32-7.10 (m, 5H), 6.98-6.86 (m, 2H), 6.81 (m, 1H), 6.65 (s, 1H), 5.88-5.74 (m, 1H), 5.67-5.54 (m, 1H), 5.34-5.16 (m, 1H), 4.72-3.91 (m, 8H), 3.78-3.63 (m, 1H), 3.35-3.19 (m, 1H), 3.18-3.01 (m, 1H), 2.03-1.54 (m, 4H), 1.49 (s, 9H)。アミドを脱保護し、逆相(H2O/MeCN)により精製して、アミン(9.3mg、52%)を得た。Rf=0.08(EtOAc/MeOH 95/5)。HPLC 方法A tr=9.72mn(98.7%)。ESI−MS m/z:528.3/530.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EtOAc/MeOH)により精製して、保護アミド(23mg、43%)を得た。Rf=0.26(EtOAc/MeOH 95/5)。1H NMR (300 MHz, CDCl3): δ 7.43 (s, 1H), 7.25-7.13 (m, 7H), 7.09 (d, J = 8.5 Hz, 2H), 6.68 (broad s, 1H), 5.95-5.85 (m, 1H), 5.67 (t, J = 5.4 Hz, 1H), 4.57 (s, 2H), 4.51 (s, 2H), 4.47-4.14 (m, 4H), 4.11-4.00 (m, 1H), 3.91-3.83 (m, 2H), 3.30-3.07 (m, 2H), 2.05-1.57 (m, 4H), 1.40 (s, 9H)。アミドを脱保護し、逆相(H2O/MeCN)により精製して、アミン(8.2mg、43%)を得た。HPLC 方法A tr=8.50mn(95.8%)。ESI−MS m/z:478.3[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EtOAc/MeOH)により精製して、保護アミド(8.5mg、17%)を得た。Rf=0.17(EtOAc/MeOH 95/5)。アミドを脱保護し、逆相(H2O/MeCN)により精製して、アミン(1.4mg、52%)を得た。Rf=0.11(EtOAc/MeOH 95/5)。HPLC 方法A tr=8.31mn(96.8%)。ESI−MS m/z:448.3[M+H]+。
1−(3(クロロフェニル)ピペラジン塩酸塩(1当量、200mg、0.86mmol)、プロパルギルブロミド(1当量、102mg、0.86mmol)、K2CO3(3当量、356mg、3mmol)を、DMF 4mlに溶解した。反応混合物を90℃で一晩撹拌した(TLC管理)。混合物をNaHCO360mlにより洗浄し、EtOAc 3×30mlにより抽出した。有機相をNa2SO4で乾燥させ、濾過し、そして濃縮した。粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、化合物(150mg、63%)を無色の油状物として得た。Rf=0.37(EDP/EtOAc 70/30)。1H NMR (300 MHz, CDCl3): δ 7.16 (t, J = 8.1 Hz, 1H), 6.92-6.85 (m, 1H), 6.85-6.75 (m, 2H), 3.35 (d, J = 2.4 Hz 2H), 3.29-3.18 (m, 4H), 2.72 (m, 4H), 2.28 (t, J = 2.4 Hz, 1H)。生成物を、一般的な説明のように反応させた。粗生成物を、フラッシュクロマトグラフィー(EtOAc/MeOH)により精製して、保護アミド(54mg、87%)を得た。Rf=0.11(EtOAc/MeOH 95/5)。1H NMR (300 MHz, CDCl3) δ 7.52 (s, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H), 7.14 (t, J = 8.1 Hz, 1H), 6.87-6.82 (m, 1H), 6.82-6.72 (m, 2H), 6.54 (s, 1H), 5.58-5.50 (m, 1H), 5.22-5.11 (m, 1H), 4.66-4.55 (m, 1H), 4.52-4.41 (m, 1H), 4.37-4.24 (m, 3H), 4.03- 3.93 (m, 2H), 3.74 (s, 2H), 3.40-3.22 (m, 2H), 3.22-3.15 (m, 4H), 2.71 - 2.60 (m, 4H), 2.02-1.54 (m, 4H), 1.50 (s, 9H)。アミドを脱保護し、逆相(H2O/MeCN)により精製して、アミン(25mg、54%)を得た。Rf=0.44(MeOH)。HPLC 方法A tr=8.27mn(92.3%)。ESI−MS m/z:566.4/568.4[M+H]+。
1−フェニルピペラジン(1当量、200mg、1.26mmol)、プロパルギルブロミド(1当量、147mg、1.23mmol)、K2CO3(3当量、510mg、3.69mmol)を、DMF 4mlに溶解した。反応混合物を90℃で一晩撹拌した(TLC管理)。混合物をNaHCO360mlにより洗浄し、EtOAc 3×30mlにより抽出した。有機相をNa2SO4で乾燥させ、濾過し、そして濃縮した。粗生成物を、フラッシュクロマトグラフィー(EDP/EtOAc)により精製して、化合物(205mg、82%)を白色の固体として得た、Rf=0.32(EDP/EtOAc 70/30)。1H NMR (300 MHz, CDCl3): δ 7.33-7.24 (m, 2H), 6.96 (d, J = 7.8 Hz, 2H), 6.88 (t, J = 7.3 Hz, 1H), 3.38 (d, J = 2.4 Hz, 2H), 3.29-3.22 (m, 4H), 2.80-2.71 (m, 4H), 2.30 (t, J = 2.4 Hz, 1H)。生成物を、一般的な説明のように反応させた。粗生成物を、フラッシュクロマトグラフィー(EtOAc/MeOH)により精製して、保護アミド(50mg、85%)を得た。Rf=0.1(EtOAc/MeOH 95/5)。1H NMR (300 MHz, CDCl3) δ 7.52 (s, 1H), 7.29 (d, J = 8.7 Hz, 2H), 7.25-7.23 (m, 1H), 7.23-7.18 (m, 3H), 6.90 (d, J= 7.9 Hz, 2H), 6.84 (t, J = 7.3 Hz, 1H), 6.54 (s, 1H), 5.60-5.51 (m, 1H), 5.22-5.10 (m, 1H), 4.66-4.54 (m, 1H), 4.51-4.41 (m, 1H), 4.35-4.26 (m, 3H), 3.97 (t, J = 4.6 Hz, 2H), 3.78-3.73 (m, 2H), 3.40-3.23 (m, 2H), 3.22-3.15 (m, 4H), 2.74-2.60 (m, 4H), 2.01- 1.57 (m, 4H), 1.50 (s, 9H)。アミドを脱保護し、逆相(H2O/MeCN)により精製して、アミン(12.4mg、30%)を得た。Rf=0.58(MeOH)。HPLC 方法A tr=7.13mn(100%)。ESI−MS m/z:532.4[M+H]+。
粗生成物を、フラッシュクロマトグラフィー(EtOAc/MeOH)により精製して、保護アミド(22mg、49%)を得た。Rf=0.16(EtOAc/MeOH 95/5)。1H NMR (300 MHz, CDCl3) δ 7.39 (s, 1H), 7.21 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 6.82-6.64 (m, 1H), 5.92-5.79 (m, 1H), 5.79-5.66 (m, 1H), 4.67 (s, 2H), 4.56-4.42 (m, 1H), 4.33- 4.10 (m, 4H), 4.01-3.89 (m, 1H), 3.75-3.62 (m, 1H), 3.30-3.16 (m, 1H), 3.15-3.01 (m, 1H), 1.94-1.59 (m, 4H), 1.43 (s, 9H)。アミドを脱保護し、逆相(H2O/MeCN)により精製して、アミン(11.3mg、42%)を得た。Rf=0.36(MeOH)。HPLC 方法A tr=6.51mn(100%)。ESI−MS m/z:388.3[M+H]+。
B.1. シクロフィリンの発現及び精製
タンパク質、シクロフィリンA及びBの発現及び精製:
C末端にヘキサヒスチジンタグ(His−Tag)を持つシクロフィリンA、Bタンパク質を大腸菌(Escherichia coli)で発現させて精製した。簡単に述べると、C41(DE3)細胞の培養物を、培養物が600nmで0.6の光学密度に達するまで37℃で≒1時間増殖させて、1mMイソプロピルβ−D−チオガラクトシドにより、シクロフィリンA及びシクロフィリンBについてそれぞれ37℃で4時間又は22℃で一晩誘導した。細胞ペレット(1L)を溶解緩衝液(20mM NaH2PO4(pH7.8)、300mM NaCl、7mM β−メルカプトエタノール、1mg/mlリゾチーム、0.1U/μlデスオキシリボヌクレアーゼ及びコンプリート・プロテアーゼ・インヒビター・タブレット(Roche)中に再懸濁した。超音波処理細胞溶解物は、10,000gで4℃で45分間遠心分離することにより清澄にして、Ni−NTAカラムのクロマトグラフィーに付し、緩衝液(20mM NaH2PO4(pH7.8)、300mM NaCl、50mMイミダゾール、7mM β−メルカプトエタノール、10%グリセロール)で洗浄した。結合タンパク質は、緩衝液(20mM NaH2PO4(pH7.8)、300mM NaCl、250mMイミダゾール、7mM β−メルカプトエタノール、10%グリセロール)により1ml画分で溶出して、Bradford比色分析法によりモニターした。各シクロフィリンの純度は、Coomassie染色SDS−PAGE分析により求めた。シクロフィリンが豊富な画分(純度>95%)をプールして、緩衝液(20mM NaH2PO4(pH7.8)、300mM NaCl、1mM DTT、1mM EDTA、10%グリセロール)に対して透析した。
本タンパク質は、大腸菌(Escherichia coli)BL21(DE3)株で発現させた。細菌を、LB培地中で37℃で増殖させ、イソプロピル−β−D−チオガラクトピラノシド(IPTG)によりOD 0.8前後で2時間誘導した。細胞を、超音波処理により、50mMトリス(pH7.5)、2mM EDTA及び2mM β−メルカプトエタノールよりなる緩衝液(緩衝液A)中で溶解した。細胞溶解物を40000gで30分間遠心分離した。上清を、緩衝液Aで平衡化したQ−セファロース及びS−セファロースカラムに順番に添加した。S−セファロースカラムを平衡化緩衝液で洗浄して、結合タンパク質を、0〜1M NaClの線形勾配で溶出した。合わせたピーク画分を、20mMトリス(pH7.5)、200mM NaCl、2mM EDTA及び1mMジチオトレイトールで平衡化したS75カラムに添加した。この2段階精製プロトコールにより、充分に純粋なタンパク質を入手できた。
シクロフィリンPPIアーゼ活性は、標準的キモトリプシン結合測定法を用いることにより20℃で測定した(Kofron JL, Kuzmic P, Kishore V, Colon-Bonilla E, Rich DH. Determination of kinetic constants for peptidyl prolyl cis-trans isomerases by an improved spectrophotometric assay. Biochemistry. 1991 Jun 25;30(25):6127-34)。測定緩衝液(25mMヘペス、100mM NaCl、pH7.8)及びCypA、B又はD(1900nM原液)は4℃に予冷し、次にここに1mM HCl中の50mg/mlキモトリプシン5μLを加えた。反応は、急速に反転させながらLiCl/TFE溶液中の3.2mMペプチド基質(Suc-Ala-Ala-cis-Pro-Phe-pNA)20μLを添加することにより開始させた。混合の開始から遅れて、反応が終了するまで(1分)p−ニトロアニリンの吸光度を390nMで追跡した。測定中のLiClの最終濃度は20mMであった;TFEは4%(v/v)の濃度で存在した。吸光度の読みは1秒毎に分光光度計により収集した。化合物の阻害測定は、上記と同じやり方で実施した。DMSO中の化合物のアリコート5μLを測定緩衝液中のシクロフィリン溶液に加えた。測定は、基質の添加により開始した。シクロスポリンAを対照として全ての測定に使用した。シクロフィリンPPIアーゼ活性の阻害百分率は、傾きから算出したが、得られた値は、少なくとも2回の独立した測定の平均を表す。+/-SDの平均は、<10%であった。
遺伝子型1bの2シストロン性レプリコンをHuh7細胞(Krieger, N.,V. Lohman, and R Bartenschlager. 2001. J. Virol. 75:4614-4624)にトランスフェクトして、10%ウシ胎仔血清、50IU/mLペニシリン、100μg/mLストレプトマイシン、0.1μg/mLファンギゾン(Fungizone)及び600μg/mLジェネティシン(Geneticin)(G418、Invitrogen)を補足したダルベッコー修飾イーグル培地Glutamax II(Invitrogen, Carlsbad, California)中で増殖させた。
JFH1 HCV遺伝子型2a分離株の完全長cDNA及びRenillaルシフェラーゼ遺伝子を含有する、プラスミドpJFH1を使用して、以前に報告(Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, Zhao Z, Murthy K, Habermann A, Krausslich HG, Mizokami M, Bartenschlager R, Liang TJ. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 2005; 11:791-6)されたとおりHuh7細胞培養物中の感染性HCV粒子(HCVcc)を作成した。Huh7細胞を24ウェルプレートに30,000〜50,000細胞/ウェルの密度で播種して、24時間後にHCVcc 200μlで37℃で2時間感染させた。インキュベーション後、上清を除去して、JFH1感染細胞を新鮮培地で洗浄した。上昇濃度の試験化合物を、2% DMSOを含有する培地に添加して、細胞を37℃でインキュベートした。感染の44時間後、細胞をダルベッコーPBS(Invitrogen)で1回洗浄して、Renilla溶解緩衝液(Promega, Madison, Wisconsin)100μlを各ウェルに加えた。細胞溶解物を−80℃で凍結した。凍結試料を読み取りのため1バッチで解凍して、製造業者(Promega)が指定したとおり20μlをルシフェラーゼ測定の基質と混合した。ルシフェラーゼ活性は、照度計で10秒間測定した。
Huh7及びHEK293細胞は、DMEM Glutamax-II−10% FBS中で96ウェルマイクロタイタープレートに1ウェルあたりそれぞれ2000及び1000細胞の密度で播種した。24時間後、試験化合物の連続希釈液を加えた。細胞を37℃で3日間増殖させた。次いで、以前に報告(Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983;65:55-63)されたように臭化3−(4,5−ジメチルチアゾール−2−イル)−2,5−ジフェニルテトラゾリウム比色分析法で細胞の生存を評価した。
F684の急性毒性をマウスで評価した。本試験において、メスのマウス(n=3/群)に陰性対照(PBS)又はF684(PBSに溶解した1mg/kg、10mg/kg、50mg/kg及び150mg/kg体重)を腹腔内注射により1回投与した。注射時に、マウスは約5月齢であり、体重は27〜33gの範囲であった。全てのマウスは、予定の殺処分まで生き延びた。体重、飼料消費量、臨床観察又は肉眼的臓器剖検における差は、F684投与マウスとビヒクル対照群の間に観察されなかった。このような結果は、F684が急性毒性を持たないことを示す。
Claims (15)
- ウイルス性病変又は感染症の予防及び/又は処置におけるその使用のための、式(I):
[式中、
− nは、0、1又は2であり;
− Aは、CH又はNであるか、あるいはAは、Cであって、R1、R2及びCOと一緒に、場合により置換されている、5〜20個の原子を含むヘテロシクリル基を形成し;
− Xは、CO、SO2又はCSであり、
− R1は、H、アルキル基、及びアラルキル基(該アルキル又はアラルキル基は、場合により置換されている)よりなる群から選択され;
− R2は、式:NR3R4又はOR5の基であり(ここで、
R3及びR4は、それぞれ独立に、H、ORa、アルキル基、アラルキル基、及びアリール基から選択的され(Raは、H、アルキル基、アリール基、及びアラルキル基よりなる群から選択される)(ここで、R3及びR4は、これらを結合している窒素原子と一緒に、場合により置換されている、5〜20個の原子を含むヘテロシクリル基を形成してもよい);
R5は、アルキル基、アリール基、及びアラルキル基から選択される(ここで、R5は、これを結合している酸素原子と一緒に、場合により置換されている、5〜20個の原子のヘテロシクリル基を形成してもよい));
− R6は、H又はアルキル基であるか、あるいはR2と一緒に、20〜30個の原子のヘテロシクリル基を形成してもよいか、又はR1と一緒に、10〜30個の原子のヘテロシクリル基を形成してもよく;
− R7は、アリール基、ヘテロアリール基、−NHPh、ヘテロシクリル基、及びアルキル基(ここで、R7が、アリール、ヘテロアリール又はヘテロシクリルであるとき、これは、少なくとも1個のNH2基により置換されている)よりなる群から選択される(ここで、
AがNであるとき、R1及びR2は、A及びCOと一緒に、場合により置換されている、5〜20個の原子のヘテロシクリル基を形成してもよい)]で示される化合物、又はその薬学的に許容しうる塩、水和物若しくは水和塩、又はその多形結晶構造、ラセミ体、ジアステレオマー若しくはエナンチオマー。 - 請求項13又は14に記載の化合物を薬学的に許容しうるビヒクルと合わせて含む、医薬組成物。
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US10501741B2 (en) | 2014-06-25 | 2019-12-10 | Cold Spring Harbor Laboratory | Methods and compositions for inhibiting growth and epithelial to mesenchymal transition (EMT) in cancer cells |
AU2017244139A1 (en) * | 2016-03-31 | 2018-09-13 | Merck Patent Gmbh | Compounds for the inhibition of cyclophilins and uses thereof |
US20170283425A1 (en) * | 2016-03-31 | 2017-10-05 | Merck Patent Gmbh | Compounds for the inhibition of cyclophilins and uses thereof |
US9975902B2 (en) | 2016-03-31 | 2018-05-22 | Merck Patent Gmbh | Compounds for the inhibition of cyclophilins and uses thereof |
GB2561540A (en) * | 2017-03-13 | 2018-10-24 | Nodthera Ltd | Chemical compounds |
GB201814067D0 (en) | 2018-08-29 | 2018-10-10 | Univ Edinburgh | Compounds for the inhibition of cyclophilins |
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JP2016128488A (ja) | 2016-07-14 |
JP5947724B2 (ja) | 2016-07-06 |
WO2011076784A2 (en) | 2011-06-30 |
US8901295B2 (en) | 2014-12-02 |
EP2516387A2 (en) | 2012-10-31 |
EP2516387B1 (en) | 2018-02-21 |
US20140179687A1 (en) | 2014-06-26 |
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US8802666B2 (en) | 2014-08-12 |
US20130018044A1 (en) | 2013-01-17 |
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