JPH11503417A - 可逆的プロテアーゼインヒビター - Google Patents

Info

Publication number

JPH11503417A

JPH11503417A JP8529509A JP52950996A JPH11503417A JP H11503417 A JPH11503417 A JP H11503417A JP 8529509 A JP8529509 A JP 8529509A JP 52950996 A JP52950996 A JP 52950996A JP H11503417 A JPH11503417 A JP H11503417A

Authority

JP

Japan

Prior art keywords

alkyl

substituted

hydroxy

hydrogen

aryl

Prior art date

1995-03-24

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Pending

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• 239000000137 peptide hydrolase inhibitor Substances 0.000 title claims abstract description 18
• 229940124158 Protease/peptidase inhibitor Drugs 0.000 title claims abstract description 17
• 230000002441 reversible effect Effects 0.000 title abstract description 14
• 150000001875 compounds Chemical class 0.000 claims abstract description 207
• 239000003112 inhibitor Substances 0.000 claims abstract description 78
• 108010005843 Cysteine Proteases Proteins 0.000 claims abstract description 72
• 102000005927 Cysteine Proteases Human genes 0.000 claims abstract description 71
• -1 arylalkanoyl Chemical group 0.000 claims description 466
• 125000000217 alkyl group Chemical group 0.000 claims description 137
• 125000003118 aryl group Chemical group 0.000 claims description 135
• 229910052739 hydrogen Inorganic materials 0.000 claims description 131
• 239000001257 hydrogen Substances 0.000 claims description 130
• 239000000203 mixture Substances 0.000 claims description 119
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 78
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 75
• 150000002431 hydrogen Chemical class 0.000 claims description 66
• 150000003839 salts Chemical class 0.000 claims description 65
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 60
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 53
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 50
• 101000749287 Clitocybe nebularis Clitocypin Proteins 0.000 claims description 49
• 101000767029 Clitocybe nebularis Clitocypin-1 Proteins 0.000 claims description 49
• 229940094664 Cysteine protease inhibitor Drugs 0.000 claims description 49
• 125000003545 alkoxy group Chemical group 0.000 claims description 49
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 48
• 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 47
• 238000000034 method Methods 0.000 claims description 45
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 44
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 43
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 41
• 125000005843 halogen group Chemical group 0.000 claims description 41
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 39
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 38
• 102000035195 Peptidases Human genes 0.000 claims description 38
• 108091005804 Peptidases Proteins 0.000 claims description 38
• 239000004365 Protease Substances 0.000 claims description 38
• 125000001188 haloalkyl group Chemical group 0.000 claims description 36
• 125000001072 heteroaryl group Chemical group 0.000 claims description 34
• 125000001153 fluoro group Chemical group F* 0.000 claims description 30
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 28
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 28
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 27
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
• 125000001246 bromo group Chemical group Br* 0.000 claims description 26
• 230000005764 inhibitory process Effects 0.000 claims description 26
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 26
• 125000005117 dialkylcarbamoyl group Chemical group 0.000 claims description 25
• 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 24
• 125000004432 carbon atom Chemical group C* 0.000 claims description 23
• 125000005842 heteroatom Chemical group 0.000 claims description 23
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 22
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 22
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 22
• 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 22
• 235000018417 cysteine Nutrition 0.000 claims description 20
• 238000009739 binding Methods 0.000 claims description 19
• XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 19
• 125000005647 linker group Chemical group 0.000 claims description 19
• 230000027455 binding Effects 0.000 claims description 18
• 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 17
• 239000002253 acid Substances 0.000 claims description 17
• 238000010494 dissociation reaction Methods 0.000 claims description 17
• 230000005593 dissociations Effects 0.000 claims description 17
• 125000003396 thiol group Chemical class [H]S* 0.000 claims description 16
• 125000003435 aroyl group Chemical group 0.000 claims description 15
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 15
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
• 125000001624 naphthyl group Chemical group 0.000 claims description 15
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 15
• 125000005116 aryl carbamoyl group Chemical group 0.000 claims description 14
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 14
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 13
• 238000011282 treatment Methods 0.000 claims description 13
• 241001465754 Metazoa Species 0.000 claims description 12
• 125000003282 alkyl amino group Chemical group 0.000 claims description 12
• 125000004414 alkyl thio group Chemical group 0.000 claims description 12
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 12
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 12
• 230000002401 inhibitory effect Effects 0.000 claims description 12
• 238000004519 manufacturing process Methods 0.000 claims description 12
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 11
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
• 125000005153 alkyl sulfamoyl group Chemical group 0.000 claims description 10
• 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 10
• 125000004981 cycloalkylmethyl group Chemical group 0.000 claims description 10
• 125000004472 dialkylaminosulfonyl group Chemical group 0.000 claims description 10
• 125000004076 pyridyl group Chemical group 0.000 claims description 10
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 9
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 9
• 125000002541 furyl group Chemical group 0.000 claims description 9
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
• 235000018102 proteins Nutrition 0.000 claims description 9
• 102000004169 proteins and genes Human genes 0.000 claims description 9
• 108090000623 proteins and genes Proteins 0.000 claims description 9
• 238000011084 recovery Methods 0.000 claims description 9
• 125000001544 thienyl group Chemical group 0.000 claims description 9
• 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 8
• 125000004429 atom Chemical group 0.000 claims description 8
• 125000001041 indolyl group Chemical group 0.000 claims description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims description 8
• 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 8
• 150000001412 amines Chemical class 0.000 claims description 7
• 125000002883 imidazolyl group Chemical group 0.000 claims description 7
• 125000006239 protecting group Chemical group 0.000 claims description 7
• 239000011734 sodium Substances 0.000 claims description 7
• CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical group C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims description 6
• 229910052708 sodium Inorganic materials 0.000 claims description 6
• 230000001225 therapeutic effect Effects 0.000 claims description 6
• 229960004441 tyrosine Drugs 0.000 claims description 6
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
• 125000005236 alkanoylamino group Chemical group 0.000 claims description 5
• DOUHZFSGSXMPIE-UHFFFAOYSA-N hydroxidooxidosulfur(.) Chemical compound [O]SO DOUHZFSGSXMPIE-UHFFFAOYSA-N 0.000 claims description 5
• 229910052744 lithium Inorganic materials 0.000 claims description 5
• 125000001174 sulfone group Chemical group 0.000 claims description 5
• YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical group N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 4
• 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
• 241001024304 Mino Species 0.000 claims description 4
• 239000004020 conductor Substances 0.000 claims description 4
• 125000006263 dimethyl aminosulfonyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])S(*)(=O)=O 0.000 claims description 4
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 4
• 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 4
• HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical group CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 claims description 4
• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
• 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 3
• 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 claims description 3
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
• WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
• 125000004423 acyloxy group Chemical group 0.000 claims description 3
• 230000001668 ameliorated effect Effects 0.000 claims description 3
• 150000001408 amides Chemical class 0.000 claims description 3
• UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 3
• ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims description 3
• 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 claims description 3
• APVPOHHVBBYQAV-UHFFFAOYSA-N n-(4-aminophenyl)sulfonyloctadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 APVPOHHVBBYQAV-UHFFFAOYSA-N 0.000 claims description 3
• 229960002685 biotin Drugs 0.000 claims description 2
• 235000020958 biotin Nutrition 0.000 claims description 2
• 239000011616 biotin Substances 0.000 claims description 2
• 230000001590 oxidative effect Effects 0.000 claims description 2
• 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 claims description 2
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 66
• 125000001589 carboacyl group Chemical group 0.000 claims 32
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 27
• 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims 3
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims 3
• ZYUZLEUJKZZXNN-UHFFFAOYSA-N C1=CC(CC(N)C(O)=O)=CC=C1OS(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 Chemical group C1=CC(CC(N)C(O)=O)=CC=C1OS(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 ZYUZLEUJKZZXNN-UHFFFAOYSA-N 0.000 claims 2
• 125000004965 chloroalkyl group Chemical group 0.000 claims 2
• 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 claims 1
• 125000006513 pyridinyl methyl group Chemical group 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 113
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 93
• 239000000243 solution Substances 0.000 description 85
• 238000003786 synthesis reaction Methods 0.000 description 70
• 230000015572 biosynthetic process Effects 0.000 description 68
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 51
• 238000006243 chemical reaction Methods 0.000 description 49
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 48
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 48
• 239000002852 cysteine proteinase inhibitor Substances 0.000 description 45
• 230000002829 reductive effect Effects 0.000 description 44
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 43
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 43
• 235000019439 ethyl acetate Nutrition 0.000 description 38
• HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 35
• RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 35
• 239000002904 solvent Substances 0.000 description 35
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
• 239000000047 product Substances 0.000 description 29
• 102000004190 Enzymes Human genes 0.000 description 28
• 108090000790 Enzymes Proteins 0.000 description 28
• 229940088598 enzyme Drugs 0.000 description 28
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 27
• 108090000765 processed proteins & peptides Proteins 0.000 description 27
• 201000010099 disease Diseases 0.000 description 26
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 25
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 23
• 235000001014 amino acid Nutrition 0.000 description 22
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
• 229940024606 amino acid Drugs 0.000 description 20
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 20
• 235000019419 proteases Nutrition 0.000 description 20
• 229920006395 saturated elastomer Polymers 0.000 description 20
• 239000000758 substrate Substances 0.000 description 20
• 238000004809 thin layer chromatography Methods 0.000 description 20
• 229910052799 carbon Inorganic materials 0.000 description 19
• 125000001424 substituent group Chemical group 0.000 description 19
• 150000001299 aldehydes Chemical class 0.000 description 18
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 18
• 239000000126 substance Substances 0.000 description 17
• YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 16
• 239000007787 solid Substances 0.000 description 16
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 14
• 239000012267 brine Substances 0.000 description 14
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
• 125000002252 acyl group Chemical group 0.000 description 13
• 125000003275 alpha amino acid group Chemical group 0.000 description 13
• 239000000463 material Substances 0.000 description 13
• UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 13
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
• XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 12
• 150000001413 amino acids Chemical class 0.000 description 12
• 239000007864 aqueous solution Substances 0.000 description 12
• 150000001721 carbon Chemical group 0.000 description 12
• 230000000694 effects Effects 0.000 description 12
• 229910000104 sodium hydride Inorganic materials 0.000 description 12
• 150000003457 sulfones Chemical class 0.000 description 10
• CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 9
• COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 9
• 239000003814 drug Substances 0.000 description 9
• 239000002480 mineral oil Substances 0.000 description 9
• 235000010446 mineral oil Nutrition 0.000 description 9
• 229960005190 phenylalanine Drugs 0.000 description 9
• 238000006722 reduction reaction Methods 0.000 description 9
• 238000003756 stirring Methods 0.000 description 9
• 206010061218 Inflammation Diseases 0.000 description 8
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
• 206010003246 arthritis Diseases 0.000 description 8
• 238000003556 assay Methods 0.000 description 8
• 239000003153 chemical reaction reagent Substances 0.000 description 8
• 230000004054 inflammatory process Effects 0.000 description 8
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
• 229910052763 palladium Inorganic materials 0.000 description 8
• 230000009467 reduction Effects 0.000 description 8
• 235000017557 sodium bicarbonate Nutrition 0.000 description 8
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
• QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 7
• LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 7
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
• 239000006185 dispersion Substances 0.000 description 7
• 150000002148 esters Chemical class 0.000 description 7
• 238000005984 hydrogenation reaction Methods 0.000 description 7
• COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 7
• 239000004475 Arginine Substances 0.000 description 6
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
• ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 6
• OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 6
• 150000001450 anions Chemical class 0.000 description 6
• ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 6
• 239000003054 catalyst Substances 0.000 description 6
• 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
• UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
• XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
• 239000003921 oil Substances 0.000 description 6
• 235000019198 oils Nutrition 0.000 description 6
• 125000004043 oxo group Chemical group O=* 0.000 description 6
• 238000010992 reflux Methods 0.000 description 6
• 239000012312 sodium hydride Substances 0.000 description 6
• 229910052717 sulfur Inorganic materials 0.000 description 6
• 210000001519 tissue Anatomy 0.000 description 6
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