JPH10501221A - エラスターゼインヒビターのプロドラッグとしてのアシル化エノール誘導体 - Google Patents
エラスターゼインヒビターのプロドラッグとしてのアシル化エノール誘導体Info
- Publication number
- JPH10501221A JPH10501221A JP8500893A JP50089396A JPH10501221A JP H10501221 A JPH10501221 A JP H10501221A JP 8500893 A JP8500893 A JP 8500893A JP 50089396 A JP50089396 A JP 50089396A JP H10501221 A JPH10501221 A JP H10501221A
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- compound
- aryl
- group
- methylethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000003602 elastase inhibitor Substances 0.000 title abstract description 10
- 150000002085 enols Chemical class 0.000 title abstract description 6
- 239000000651 prodrug Substances 0.000 title abstract description 6
- 229940002612 prodrug Drugs 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 111
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 7
- 206010014561 Emphysema Diseases 0.000 claims abstract description 6
- 201000003883 Cystic fibrosis Diseases 0.000 claims abstract description 5
- -1 Val Chemical compound 0.000 claims description 171
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 77
- 238000000034 method Methods 0.000 claims description 69
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 55
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 55
- 125000003118 aryl group Chemical group 0.000 claims description 53
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- 239000000203 mixture Substances 0.000 claims description 32
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 28
- 125000006239 protecting group Chemical group 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 210000000440 neutrophil Anatomy 0.000 claims description 22
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 19
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 230000004927 fusion Effects 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 244000191761 Sida cordifolia Species 0.000 claims description 10
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 claims description 10
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 7
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 7
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 6
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 206010006458 Bronchitis chronic Diseases 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- 206010006451 bronchitis Diseases 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 208000007451 chronic bronchitis Diseases 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 150000002431 hydrogen Chemical group 0.000 claims description 4
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 claims description 4
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 3
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- 125000001295 dansyl group Chemical group [H]C1=C([H])C(N(C([H])([H])[H])C([H])([H])[H])=C2C([H])=C([H])C([H])=C(C2=C1[H])S(*)(=O)=O 0.000 claims description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[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 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 2
- 125000003412 L-alanyl group Chemical group [H]N([H])[C@@](C([H])([H])[H])(C(=O)[*])[H] 0.000 claims 6
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical group O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 150000004677 hydrates Chemical class 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 13
- 201000010099 disease Diseases 0.000 abstract description 12
- 238000006243 chemical reaction Methods 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 38
- 102000016387 Pancreatic elastase Human genes 0.000 description 35
- 108010067372 Pancreatic elastase Proteins 0.000 description 35
- 235000001014 amino acid Nutrition 0.000 description 33
- 229940024606 amino acid Drugs 0.000 description 33
- 150000001413 amino acids Chemical group 0.000 description 29
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 27
- 239000002253 acid Substances 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- 108090000765 processed proteins & peptides Proteins 0.000 description 23
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- 238000005859 coupling reaction Methods 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000010168 coupling process Methods 0.000 description 15
- 229940079593 drug Drugs 0.000 description 15
- 239000003814 drug Substances 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- 238000004293 19F NMR spectroscopy Methods 0.000 description 13
- 230000008878 coupling Effects 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- 238000004519 manufacturing process Methods 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- 239000000758 substrate Substances 0.000 description 13
- 108090000371 Esterases Proteins 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 101000851058 Homo sapiens Neutrophil elastase Proteins 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- 102000052502 human ELANE Human genes 0.000 description 10
- 210000004185 liver Anatomy 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 150000001408 amides Chemical class 0.000 description 7
- NBEMQPLNBYYUAZ-UHFFFAOYSA-N ethyl acetate;propan-2-one Chemical compound CC(C)=O.CCOC(C)=O NBEMQPLNBYYUAZ-UHFFFAOYSA-N 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 150000002576 ketones Chemical class 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 230000004224 protection Effects 0.000 description 7
- 239000011347 resin Substances 0.000 description 7
- 229920005989 resin Polymers 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 6
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 6
- 239000000443 aerosol Substances 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 238000000099 in vitro assay Methods 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 239000011159 matrix material Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- QRSXLMSDECGEOU-UHFFFAOYSA-N 6-methoxycarbonylpyridine-3-carboxylic acid Chemical compound COC(=O)C1=CC=C(C(O)=O)C=N1 QRSXLMSDECGEOU-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 5
- 229930194542 Keto Natural products 0.000 description 5
- 235000008206 alpha-amino acids Nutrition 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 235000008504 concentrate Nutrition 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- XQAMVCHQGHAELT-NHNZYLEHSA-N (2s)-1-[(2s)-3-methyl-2-[[4-(morpholine-4-carbonyl)benzoyl]amino]butanoyl]-n-(5,5,6,6,6-pentafluoro-2-methyl-4-oxohexan-3-yl)pyrrolidine-2-carboxamide Chemical compound N([C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)NC(C(C)C)C(=O)C(F)(F)C(F)(F)F)C(=O)C(C=C1)=CC=C1C(=O)N1CCOCC1 XQAMVCHQGHAELT-NHNZYLEHSA-N 0.000 description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 4
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 102000035195 Peptidases Human genes 0.000 description 4
- 108091005804 Peptidases Proteins 0.000 description 4
- 239000004365 Protease Substances 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000009435 amidation Effects 0.000 description 4
- 238000007112 amidation reaction Methods 0.000 description 4
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 4
- 238000010276 construction Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
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- 239000012071 phase Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 3
- PBKONEOXTCPAFI-UHFFFAOYSA-N 1,2,4-trichlorobenzene Chemical compound ClC1=CC=C(Cl)C(Cl)=C1 PBKONEOXTCPAFI-UHFFFAOYSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
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- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- 229940122858 Elastase inhibitor Drugs 0.000 description 3
- 201000005569 Gout Diseases 0.000 description 3
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- 206010040047 Sepsis Diseases 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000006859 Swern oxidation reaction Methods 0.000 description 3
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- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
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- 239000000047 product Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- ZMRHBJQLCDZMAH-UHFFFAOYSA-M sodium chloride hydrate hydrochloride Chemical compound [OH-].[Na+].Cl.Cl ZMRHBJQLCDZMAH-UHFFFAOYSA-M 0.000 description 3
- 239000007790 solid phase Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
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- A—HUMAN NECESSITIES
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Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.式1 K−P4−P3−P2−EAC (配列番号1) {式中、 EACは、式 [式中、 R1は、−CH3、−CH(CH3)2、−CH2CH2CH3、−CH2CH(CH3)2または−CH(CH3)CH2 CH3であり; R2は、−H、または(C1-8)アルキル、(C3-12)シクロアルキル、(C6-10)アリ ールまたは(C6-10)アリール(C1-6)アルキルであり; R3は、−H、または−Fであり; R4は、−H、−F、−CF3、−CF2CF3、−CF2CF2CF3、−C(O)OR5、もしくは −C(O)NR5R6であるか、または(C1-8)アルキル、(C3-12)シクロアルキル、(C6-10 )アリール、(C6-10)アリール(C1-6)アルキルであり; R5およびR6はそれぞれ独立に、−H、または(C1-8)アルキル、(C3-12)シク ロアルキル、(C6-10)アリールもしくは(C6-10)アリール(C1-6)アルキルである] の基であり; P2は、α−アミノ基の窒素がR基[Rは(C1-8)アルキル、(C3-12)シクロア ルキル、(C3-12)シクロアルキル(C1-6)アルキル、(C4-11)ビシクロアルキル、(C4-11 )ビシクロアルキル(C1-6)アル キル、(C6-10)アリール、(C6-10)アリール(C1-6)アルキル、(C3-7)ヘテロシクロ アルキル、(C3-7)ヘテロシクロアルキル(C1-6)アルキル、(C5-9)ヘテロアリール 、(C5-9)ヘテロアリール(C1-6)アルキル、融合(C6-10)アリール−(C3-12)シクロ アルキル、融合(C6-10)アリール−(C3-12)シクロアルキル(C1-6)アルキル、融合 (C5-9)ヘテロアリール(C3-8)シクロアルキルまたは融合(C5-9)ヘテロアリール(C3-12 )シクロアルキル(C1-6)アルキルである]によって置換されていてもよい、A la、bAla、Leu、Ile、Val、Nva、bVal、Met、Nle、Gly、Phe、Tyr、Trpもしくは Nal(1)であるか、または P2は、Pro、Ind、Tic、Pip、Tca、Pro(4-OBzl)、Aze、Pro(4-OAc)、Pro(4-O H)であり; P3は、Ala、bAla、Leu、Ile、Val、Nva、bVal、MetもしくはNleまたはN− メチル誘導体、Pro、Ind、TicもしくはTca、またはそのεアミノ基がモルホリノ −B−基で置換されたLysもしくはそのδアミノ基がモルホリノ−B−基で置換 されたOrnであり; P4は、Ala、bAla、Leu、Ile、Val、Nva、bVal、MetもしくはNle、または結 合であり; Kは、水素、ホルミル、アセチル、スクシニル、ベンゾイル、t−ブチルオ キシカルボニル、カルボベンジルオキシ、トシル、ダンシル、イソバレリル、メ トキシスクシニル、1−アダマンタンスルホニル、1−アダマンタンアセチル、 2−カルボキシベンゾイル、フェニルアセチル、t−ブチルアセチル、ビス((1 −ナフチル)メチル)アセチル、−C(O)N-(CH3)2、 Rzは6、10または12個の炭素原子を含有し、フルオロ、クロロ、ブロモ、ヨ ード、トリフルオロメチル、ヒドロキシ、炭素原子1〜6個を含有するアルキル 、炭素原子1〜6個を含有するアルコキシ、カルボキシ、アルキル基は炭素原子 1〜6個を含有するアルキルカルボニルアミノ、5−テトラゾリル、および炭素 原子1〜15個を含有するアシルスルホンアミドからなる群より独立に選択される メンバー1〜3個によって適当に置換されているアリール基(ただしアシルスル ホンアミドがアリールを含む場合には、そのアリールはさらにフルオロ、クロロ 、ブロモ、ヨードおよびニトロから選択されるメンバーによって置換されていて もよい);ならびにそれらと機能的に均等な他の末端アミノ保護基、または (式中、ZはNまたはCHであり、Bは式 で表される基であり、R′は水素またはC1-6アルキル基である)である]であ る}化合物またはそれらの水和物、アイソスターまたは医薬的に許容される塩。 2.式1において、 R1は、−CH(CH3)2または−CH2CH2CH3であり; R2は−H、(C1-8)アルキル、(C3-12)シクロアルキルまたは(C6-10)アリール であり; R3は、−Fであり; R4は、−H、−F、−CF3、−C(O)OR5、−C(O)NR5R6、(C1-8)アルキル、シ クロペンチル、シクロヘキシル、フェニルまたはベンジルであり; R5およびR6はそれぞれ独立に、−H、(C1-8)アルキル、シクロペンチル、シ クロヘキシル、フェニルまたはベンジルであり、 P2は、Pro、Pip、AzeまたはPro(4-OBzl)であり; P3は、Ile、またはAlaであり; P4は、Alaまたは結合であり; Kは、ベンゾイル、t−ブチルオキシカルボニル、カルボベンジルオキシ、 イソバレリル、−C(O)N-(CH3)2、 [式中、ZはNであり、Bは式 (式中、R′は水素またはC1-6アルキル基である)の基である]である請求項 1記載の化合物。 3.R2は−H、メチル、エチル、n−プロピル、イソプロピル、n−ブチル、シ クロペンチル、シクロヘキシル、シクロヘキシルメチル、フェニルまたはベンジ ルであり; R4は−H、−F、−CF3、−C(O)OR5、-C(O)NR5R6、メチル、エチル、n−プ ロピル、イソプロピル、n−ブチル、tert−ブチル、シクロペンチル、シクロヘ キシル、フェニル、ベンジルであり; R5およびR6はそれぞれ独立に、−H、メチル、エチル、n−プロピル、イソ プロピル、n−ブチル、tert−ブチル、シクロペンチル、シクロヘキシル、フェ ニルまたはベンジルである請求項2 記載の化合物。 4.Kは、 [式中、ZはNであり、Bは式 (式中R′はイソプロピルである)の基である]である請求項2記載の化合物 。 5.R2は−H、メチル、エチル、n−プロピル、イソプロピル、n−ブチル、シ クロペンチル、シクロヘキシル、シクロヘキシルメチル、フェニルまたはベンジ ルであり; R4は−H、−F、−CF3、−C(O)OR5、−C(O)NR5R6、メチル、エチル、n− プロピル、イソプロピル、n−ブチル、tert−ブチル、シクロペンチル、シクロ ヘキシル、フェニル、ベンジルであり; R5およびR6はそれぞれ独立に、−H、メチル、エチル、n−プ ロピル、イソプロピル、n−ブチル、tert−ブチル、シクロペンチル、シクロヘ キシル、フェニルまたはベンジルである請求項4記載の化合物。 6.R1は−CH(CH3)2であり; R2は−H、メチル、エチル、n−プロピル、イソプロピル、n−ブチル、シク ロペンチル、シクロヘキシル、シクロヘキシルメチル、フェニルまたはベンジル であり; R3は−Fであり; R4は−Fまたは−CF3であり; P2はProであり; P3はIle、ValまたはAlaであり; P4は、Alaまたは結合であり; Kは、 [式中、ZはNであり、Bは式 であり、R′はイソプロピルである請求項1記載の化合物。 7.化合物は(E)−N−[4−(4−モルホリニルカルボニル)ベン ゾイル]−L−バリル−N−[2−(アセチルオキシ)−3,3,4,4,4−ペンタフルオ ロ−1−(1−メチルエチル)−1−ブテニル]−L−プロリンアミドである請求項1 記載の化合物。 8.化合物は(E)−N−[4−(4−モルホリニルカルボニル)ベンゾイル]−L− バリル−N−[3,3,4,4,4−ペンタフルオロ−1−(1−メチルエチル)−2−(1 −オキソプロポキシ)−1−ブテニル]−L−プロリンアミドである請求項1記載 の化合物。 9.化合物は(E)−N−[4−(4−モルホリニルカルボニル)ベンゾイル]−L− バリル−N−[3,3,4,4,4−ペンタフルオロ−1−(1−メチルエチル)−2−(2 −メチル−1−オキソプロポキシ)−1−ブテニル]−L−プロリンアミドである 請求項1記載の化合物。 10.化合物は(Z)−N−[4−(4−モルホリニルカルボニル)ベンゾイル]−L− バリル−N−[2−(アセチルオキシ)−3,3,4,4,4−ペンタフルオロ−1−(1− メチルエチル)−1−ブテニル]−L−プロリンアミドである請求項1記載の化合 物。 11.化合物は(E)−N−[(1,1−ジメチルエトキシ)カルボニル]−L−アラニル −L−アラニル−N−[2−(アセチルオキシ)−3,3,3−トリフルオロ−1−(1 −メチルエチル)−1−プロペニル]−L−プロリンアミド(配列番号2)である請 求項1記載の化合物。 12.化合物は(E)−N−[4−(4−モルホリニルカルボニル)ベンゾイル]−L− バリル−N−[2−(アセチルオキシ)−3,3,3−トリフルオロ−1−(1−メチル エチル)−1−プロペニル]−L−プロリンアミドである請求項1記載の化合物。 13.化合物は(E)−N−(4−モルホリニルカルボニル)−L−バリ ル−N−[2−(アセチルオキシ)−3,3,3−トリフルオロ−1−(1−メチルエチ ル)−1−プロペニル]−L−プロリンアミドである請求項1記載の化合物。 14.化合物は(E)−N−[4−[(4−クロロフェニル)スルホニルアミノカルボニ ル]ベンゾイル]−L−バリル−N−[2−(アセチルオキシ)−3,3,3−トリフルオ ロ−1−(1−メチルエチル)−1−プロペニル]−L−プロリンアミドである請 求項1記載の化合物。 15.請求項1記載の化合物と医薬的に許容される担体からなる医薬組成物。 16.請求項1記載の化合物と担体からなる組成物。 17.好中球関連炎症性疾患の処置方法において、それを必要とする患者に式1の 化合物の抗炎症有効量を投与することからなる方法。 18.気腫の処置方法において、それを必要とする患者に式1の化合物の抗炎症有 効量を投与することからなる方法。 19.嚢胞性線維症の処置方法において、それを必要とする患者に式1の化合物の 抗炎症有効量を投与することからなる方法。 20.慢性気管支炎の処置方法において、それを必要とする患者に式1の化合物の 抗炎症有効量を投与することからなる方法。 21.炎症性腸疾患のの処置方法において、それを必要とする患者に式1の化合物 の抗炎症有効量を投与することからなる方法。
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US25279894A | 1994-06-02 | 1994-06-02 | |
US08/252,798 | 1994-06-02 | ||
US42085995A | 1995-04-19 | 1995-04-19 | |
US08/420,859 | 1995-04-19 | ||
PCT/US1995/005879 WO1995033478A1 (en) | 1994-06-02 | 1995-05-08 | Acylated enol derivatives as prodrugs of elastase inhibitors |
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JPH10501221A true JPH10501221A (ja) | 1998-02-03 |
JP4221059B2 JP4221059B2 (ja) | 2009-02-12 |
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JP50089396A Expired - Lifetime JP4221059B2 (ja) | 1994-06-02 | 1995-05-08 | エラスターゼインヒビターのプロドラッグとしてのアシル化エノール誘導体 |
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US (2) | US5698523A (ja) |
EP (1) | EP0762887B1 (ja) |
JP (1) | JP4221059B2 (ja) |
KR (1) | KR100367389B1 (ja) |
CN (1) | CN1149833A (ja) |
AT (1) | ATE206055T1 (ja) |
AU (1) | AU696292B2 (ja) |
CA (1) | CA2191844C (ja) |
DE (1) | DE69522940T2 (ja) |
DK (1) | DK0762887T3 (ja) |
ES (1) | ES2161293T3 (ja) |
FI (1) | FI964749A (ja) |
HU (1) | HU221310B1 (ja) |
IL (1) | IL113869A (ja) |
MX (1) | MX9606034A (ja) |
NO (1) | NO317185B1 (ja) |
NZ (1) | NZ287604A (ja) |
PT (1) | PT762887E (ja) |
TW (1) | TW406087B (ja) |
WO (1) | WO1995033478A1 (ja) |
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EP0763055B1 (en) * | 1994-06-02 | 1999-11-03 | Merrell Pharmaceuticals Inc. | Perfluoroalkyl ketone inhibitors of elastase and processes for making the same |
DE69522940T2 (de) * | 1994-06-02 | 2002-04-04 | Merrell Pharma Inc | Acylierte enolderivate als vorläufdrogen von elastaseinhibitoren |
US5948886A (en) * | 1996-11-20 | 1999-09-07 | Hoechst Marion Roussel, Inc. | Acylated enol derivatives of α-ketoesters and α-ketoamides |
US6172044B1 (en) | 1995-12-01 | 2001-01-09 | Aventis Pharmaceuticals Inc. | Acylated enol derivative of α-ketoesters and α-ketoamides |
CN101534824A (zh) * | 2006-11-17 | 2009-09-16 | 艾博特公司 | 作为化学活素受体拮抗剂的氨基吡咯烷 |
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DE69522940T2 (de) * | 1994-06-02 | 2002-04-04 | Merrell Pharma Inc | Acylierte enolderivate als vorläufdrogen von elastaseinhibitoren |
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- 1995-05-08 DE DE69522940T patent/DE69522940T2/de not_active Expired - Lifetime
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- 1995-05-08 AU AU26366/95A patent/AU696292B2/en not_active Ceased
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1996
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HUT76131A (en) | 1997-06-30 |
FI964749A0 (fi) | 1996-11-28 |
EP0762887A1 (en) | 1997-03-19 |
CN1149833A (zh) | 1997-05-14 |
ATE206055T1 (de) | 2001-10-15 |
IL113869A0 (en) | 1995-08-31 |
HU221310B1 (en) | 2002-09-28 |
CA2191844A1 (en) | 1995-12-14 |
ES2161293T3 (es) | 2001-12-01 |
HU9603309D0 (en) | 1997-01-28 |
NO965099L (no) | 1997-01-31 |
IL113869A (en) | 2000-01-31 |
DE69522940D1 (de) | 2001-10-31 |
NO317185B1 (no) | 2004-09-13 |
AU696292B2 (en) | 1998-09-03 |
AU2636695A (en) | 1996-01-04 |
FI964749A (fi) | 1996-11-28 |
NZ287604A (en) | 1998-12-23 |
CA2191844C (en) | 2001-07-24 |
EP0762887A4 (en) | 1999-03-31 |
US5698523A (en) | 1997-12-16 |
NO965099D0 (no) | 1996-11-29 |
MX9606034A (es) | 1998-05-31 |
WO1995033478A1 (en) | 1995-12-14 |
KR100367389B1 (ko) | 2003-07-18 |
TW406087B (en) | 2000-09-21 |
DE69522940T2 (de) | 2002-04-04 |
DK0762887T3 (da) | 2002-01-14 |
US5972897A (en) | 1999-10-26 |
EP0762887B1 (en) | 2001-09-26 |
PT762887E (pt) | 2002-01-30 |
JP4221059B2 (ja) | 2009-02-12 |
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