JP2021066690A - Opioid peptide derivatives and pharmaceutical compositions containing same - Google Patents
Opioid peptide derivatives and pharmaceutical compositions containing same Download PDFInfo
- Publication number
- JP2021066690A JP2021066690A JP2019193339A JP2019193339A JP2021066690A JP 2021066690 A JP2021066690 A JP 2021066690A JP 2019193339 A JP2019193339 A JP 2019193339A JP 2019193339 A JP2019193339 A JP 2019193339A JP 2021066690 A JP2021066690 A JP 2021066690A
- Authority
- JP
- Japan
- Prior art keywords
- lower alkyl
- alkyl
- amino
- hydrogen
- compound
- 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.)
- Pending
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 13
- 239000003399 opiate peptide Substances 0.000 title abstract description 21
- 108010093625 Opioid Peptides Proteins 0.000 title abstract description 8
- 102000001490 Opioid Peptides Human genes 0.000 title abstract description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 136
- 150000001875 compounds Chemical class 0.000 claims description 58
- -1 guanidino, imino Chemical group 0.000 claims description 46
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 40
- 239000001257 hydrogen Substances 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 29
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 11
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 8
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 claims description 7
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 6
- 125000004442 acylamino group Chemical group 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 150000002431 hydrogen Chemical group 0.000 claims 9
- 208000002193 Pain Diseases 0.000 abstract description 10
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract description 10
- 230000036407 pain Effects 0.000 abstract description 10
- FHZPGIUBXYVUOY-VWGYHWLBSA-N Dermorphin Chemical class C([C@H](N)C(=O)N[C@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)C1=CC=C(O)C=C1 FHZPGIUBXYVUOY-VWGYHWLBSA-N 0.000 abstract description 7
- 239000003908 antipruritic agent Substances 0.000 abstract description 4
- 210000004899 c-terminal region Anatomy 0.000 abstract description 4
- QWCKQJZIFLGMSD-VKHMYHEASA-N L-alpha-aminobutyric acid Chemical group CC[C@H](N)C(O)=O QWCKQJZIFLGMSD-VKHMYHEASA-N 0.000 abstract description 3
- 230000003502 anti-nociceptive effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 37
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 31
- 239000000203 mixture Substances 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 108090000765 processed proteins & peptides Proteins 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 235000001014 amino acid Nutrition 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 150000001413 amino acids Chemical class 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 230000000202 analgesic effect Effects 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 125000000539 amino acid group Chemical group 0.000 description 6
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 6
- 229940005483 opioid analgesics Drugs 0.000 description 6
- 101800002242 Dermorphin Proteins 0.000 description 5
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- 238000010647 peptide synthesis reaction Methods 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 102000003840 Opioid Receptors Human genes 0.000 description 4
- 108090000137 Opioid Receptors Proteins 0.000 description 4
- 208000003251 Pruritus Diseases 0.000 description 4
- 150000001350 alkyl halides Chemical class 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 235000009697 arginine Nutrition 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 229930182817 methionine Natural products 0.000 description 3
- 229960005181 morphine Drugs 0.000 description 3
- 239000007790 solid phase Substances 0.000 description 3
- 238000010532 solid phase synthesis reaction Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- SQNJWNSQFKPEND-UHFFFAOYSA-N benzyl 2h-pyridine-1-carboxylate Chemical compound C1C=CC=CN1C(=O)OCC1=CC=CC=C1 SQNJWNSQFKPEND-UHFFFAOYSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- AEULIVPVIDOLIN-UHFFFAOYSA-N cep-11981 Chemical compound C1=C2C3=C4CNC(=O)C4=C4C5=CN(C)N=C5CCC4=C3N(CC(C)C)C2=CC=C1NC1=NC=CC=N1 AEULIVPVIDOLIN-UHFFFAOYSA-N 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 238000003795 desorption Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- 150000002917 oxazolidines Chemical class 0.000 description 2
- 150000002993 phenylalanine derivatives Chemical class 0.000 description 2
- 229920005990 polystyrene resin Polymers 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 229920003002 synthetic resin Polymers 0.000 description 2
- 239000000057 synthetic resin Substances 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- DPRJPRMZJGWLHY-HNGSOEQISA-N (e,3r,5s)-7-[5-(4-fluorophenyl)-3-propan-2-yl-1-pyrazin-2-ylpyrazol-4-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)/C=C/C=1C(C(C)C)=NN(C=2N=CC=NC=2)C=1C1=CC=C(F)C=C1 DPRJPRMZJGWLHY-HNGSOEQISA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- LNOLJFCCYQZFBQ-BUHFOSPRSA-N (ne)-n-[(4-nitrophenyl)-phenylmethylidene]hydroxylamine Chemical compound C=1C=C([N+]([O-])=O)C=CC=1C(=N/O)/C1=CC=CC=C1 LNOLJFCCYQZFBQ-BUHFOSPRSA-N 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- YSEQNZOXHCKLOG-UHFFFAOYSA-N 2-methyl-octanoic acid Chemical compound CCCCCCC(C)C(O)=O YSEQNZOXHCKLOG-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 0 CC(C)(C)OC(NC(Cc(cc1)ccc1O)C(NC(CCS(C)C**)C(NC(Cc1ccccc1)C(N1C2(CC3)C3C(CC(OC)=O)CC12)=O)=O)=O)=O Chemical compound CC(C)(C)OC(NC(Cc(cc1)ccc1O)C(NC(CCS(C)C**)C(NC(Cc1ccccc1)C(N1C2(CC3)C3C(CC(OC)=O)CC12)=O)=O)=O)=O 0.000 description 1
- HJCFESMRUBXKIY-UHFFFAOYSA-N CC(C)(C)OC(NC(Cc(cc1)ccc1OC(C)=O)C(NC(CCS(C)C1OC1)C(NC(Cc1ccccc1)C(N1C(CCC2)C3C2C(CC(OC)=O)CC13)=O)=O)=O)=O Chemical compound CC(C)(C)OC(NC(Cc(cc1)ccc1OC(C)=O)C(NC(CCS(C)C1OC1)C(NC(Cc1ccccc1)C(N1C(CCC2)C3C2C(CC(OC)=O)CC13)=O)=O)=O)=O HJCFESMRUBXKIY-UHFFFAOYSA-N 0.000 description 1
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 1
- JQTQHQGLMFPGBT-LRANUGSDSA-N CCN[C@@H](Cc(cc1)ccc1OC(C)=O)C(N[C@H](CCS(C)=O)C(N[C@@H](Cc1ccccc1)C(N(C1C2C(C3)CCC1)C2C3C(OC)=O)=O)O)=O Chemical compound CCN[C@@H](Cc(cc1)ccc1OC(C)=O)C(N[C@H](CCS(C)=O)C(N[C@@H](Cc1ccccc1)C(N(C1C2C(C3)CCC1)C2C3C(OC)=O)=O)O)=O JQTQHQGLMFPGBT-LRANUGSDSA-N 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- 125000000030 D-alanine group Chemical group [H]N([H])[C@](C([H])([H])[H])(C(=O)[*])[H] 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- 150000008574 D-amino acids Chemical class 0.000 description 1
- ODKSFYDXXFIFQN-SCSAIBSYSA-N D-arginine Chemical compound OC(=O)[C@H](N)CCCNC(N)=N ODKSFYDXXFIFQN-SCSAIBSYSA-N 0.000 description 1
- FFEARJCKVFRZRR-SCSAIBSYSA-N D-methionine Chemical compound CSCC[C@@H](N)C(O)=O FFEARJCKVFRZRR-SCSAIBSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 108010065372 Dynorphins Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108010049140 Endorphins Proteins 0.000 description 1
- 102000009025 Endorphins Human genes 0.000 description 1
- 108010092674 Enkephalins Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000781993 Erythrina humeana Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 241000581650 Ivesia Species 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- URLZCHNOLZSCCA-VABKMULXSA-N Leu-enkephalin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 URLZCHNOLZSCCA-VABKMULXSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- HPKJGHVHQWJOOT-ZJOUEHCJSA-N N-[(2S)-3-cyclohexyl-1-oxo-1-({(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)propan-2-yl]-1H-indole-2-carboxamide Chemical compound C1C(CCCC1)C[C@H](NC(=O)C=1NC2=CC=CC=C2C=1)C(=O)N[C@@H](C[C@H]1C(=O)NCC1)C=O HPKJGHVHQWJOOT-ZJOUEHCJSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000269431 Phyllomedusa sauvagii Species 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 241000283080 Proboscidea <mammal> Species 0.000 description 1
- 102100024622 Proenkephalin-B Human genes 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 241001493546 Suina Species 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 229940124532 absorption promoter Drugs 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 230000003496 anti-amnesic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000003493 decenyl group Chemical group [H]C([*])=C([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005070 decynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000012351 deprotecting agent Substances 0.000 description 1
- CGWFOWZGURYLHA-UHFFFAOYSA-L dichlorotitanium;propan-2-ol Chemical compound Cl[Ti]Cl.CC(C)O.CC(C)O CGWFOWZGURYLHA-UHFFFAOYSA-L 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical class CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 125000005066 dodecenyl group Chemical group C(=CCCCCCCCCCC)* 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000007661 gastrointestinal function Effects 0.000 description 1
- 239000003629 gastrointestinal hormone Substances 0.000 description 1
- 238000001641 gel filtration chromatography Methods 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 102000051367 mu Opioid Receptors Human genes 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- VQSRKMNBWMHJKY-YTEVENLXSA-N n-[3-[(4ar,7as)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide Chemical compound C1=NC(OC)=CN=C1C(=O)NC1=CC=C(F)C([C@@]23[C@@H](CN(C2)C=2N=CC(F)=CN=2)CSC(N)=N3)=C1 VQSRKMNBWMHJKY-YTEVENLXSA-N 0.000 description 1
- YRCHYHRCBXNYNU-UHFFFAOYSA-N n-[[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]carbamothioyl]-2-(4-fluorophenyl)acetamide Chemical compound N1=CC(CNCCOC)=CC=C1C1=CC2=NC=CC(OC=3C(=CC(NC(=S)NC(=O)CC=4C=CC(F)=CC=4)=CC=3)F)=C2S1 YRCHYHRCBXNYNU-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000005187 nonenyl group Chemical group C(=CCCCCCCC)* 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005071 nonynyl group Chemical group C(#CCCCCCCC)* 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005069 octynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000024351 regulation of hormone secretion Effects 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000005063 tetradecenyl group Chemical group C(=CCCCCCCCCCCCC)* 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000005040 tridecenyl group Chemical group C(=CCCCCCCCCCCC)* 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-O triethanolammonium Chemical class OCC[NH+](CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-O 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000003667 tyrosine derivatives Chemical class 0.000 description 1
- 125000005065 undecenyl group Chemical group C(=CCCCCCCCCC)* 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 108020001612 μ-opioid receptors Proteins 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
本発明は、含窒素複素環式基を有するオピオイドペプチド誘導体及びこれを含む医薬組成物に関する。 The present invention relates to an opioid peptide derivative having a nitrogen-containing heterocyclic group and a pharmaceutical composition containing the opioid peptide derivative.
がん性疼痛に代表される重度の疼痛の鎮痛には、オピオイドの一種であるモルヒネが汎用されている。モルヒネは、μ、δ及びκの３種に大別されるオピオイド受容体のうち、主にμ受容体にアゴニストとして作用して強力な抗侵害活性を示すが、薬物依存性（麻薬性）という深刻な副作用を伴う。 Morphine, which is a type of opioid, is widely used for analgesia of severe pain represented by cancerous pain. Of the opioid receptors classified into three types, μ, δ, and κ, morphine mainly acts as an agonist on the μ receptor and exhibits strong anti-noxious activity, but is called drug-dependent (narcotic). With serious side effects.
オピオイドは、オピオイド受容体に結合してモルヒネ様活性を有する物質の総称であり、植物由来の天然オピオイド（アルカロイド）、合成オピオイド及び内因性オピオイドに大きく分けられる。内因性オピオイドは、元々生体内に発現して機能しているオピオイドであり、生体に対して安全性の高い鎮痛性物質であると考えられている。内因性オピオイドであるオピオイドペプチド（opioid peptide）としては、エンドルフィン、エンケファリン、ダイノルフィン、デルモルフィン等が知られている。 Opioids are a general term for substances that bind to opioid receptors and have morphine-like activity, and are broadly divided into plant-derived natural opioids (alkaloids), synthetic opioids, and endogenous opioids. Endogenous opioids are opioids that are originally expressed and function in the living body, and are considered to be highly safe analgesic substances for the living body. As the opioid peptide which is an endogenous opioid, endorphin, enkephalin, dynorphin, dermorphin and the like are known.
デルモルフィン（dermorphin）は、南米に生息するソバージュネコメガエル（Phyllomedusa sauvagii）の皮膚から単離された、D-アラニンを有するヘプタペプチドである。デルモルフィンは、モルヒネを大きく上回る抗侵害活性を示すことから、構造活性相関について数多くの研究が行われ、様々な誘導体が合成されている（例えば特許文献１〜３）。これまでに、デルモルフィンの機能的単位はN末端側4残基（Tyr-D-Ala-Phe-Ala）であること、N末端のTyr及び2番目のD型アミノ酸が鎮痛活性に重要であること、D-AlaをD-Arg又はD-Metに置換することで鎮痛活性が増強されること等が明らかにされている。 Dermorphin is a D-alanine-bearing heptapeptide isolated from the skin of the Waxy monkey tree frog (Phyllomedusa sauvagii) that inhabits South America. Since dermorphin exhibits an anti-noxious activity that greatly exceeds that of morphine, many studies have been conducted on the structure-activity relationship, and various derivatives have been synthesized (for example, Patent Documents 1 to 3). To date, the functional unit of dermorphin is the N-terminal 4 residues (Tyr-D-Ala-Phe-Ala), and the N-terminal Tyr and the second D-amino acid are important for analgesic activity. It has been clarified that the analgesic activity is enhanced by replacing D-Ala with D-Arg or D-Met.
一方、デルモルフィン及び幾つかのその誘導体は、経口摂取された際の低い腸管吸収性（低経口バイオアベイラビリティ）という問題を有している。本発明者らは、デルモルフィン誘導体の１つであるNα-1-iminoethyl-Tyr-D-MetO-Phe-MeβAla-OHについて、その高い水溶性が低経口バイオアベイラビリティの一因であるとの想定から、C末端のエステル化又はN末端のチロシン残基のアシル化によって脂溶性を高めた種々の誘導体を合成した（非特許文献１）。そのうち、幾つかの誘導体について、抗侵害活性の上昇及び経口バイオアベイラビリティの改善が認められた。 On the other hand, dermorphin and some derivatives thereof have a problem of low intestinal absorption (low oral bioavailability) when ingested orally. The present inventors have stated that the high water solubility of N α -1-iminoethyl-Tyr-D-MetO-Phe-MeβAla-OH, which is one of the delmorphine derivatives, contributes to the low oral bioavailability. From the assumption, various derivatives whose lipophilicity was enhanced by esterification of the C-terminal or acylation of the tyrosine residue at the N-terminal were synthesized (Non-Patent Document 1). Among them, for some derivatives, an increase in anti-noxious activity and an improvement in oral bioavailability were observed.
本発明は、経口バイオアベイラビリティが改善された、新たなオピオイドペプチド誘導体を提供することを目的とするものである。 An object of the present invention is to provide a novel opioid peptide derivative having improved oral bioavailability.
本発明者らは、デルモルフィン誘導体の１つであるNα-1-iminoethyl-Tyr-D-MetO-Phe-MeβAla-OHのC末端であるβ-メチルアラニン残基を含窒素複素環式基に置き換えることで、経口バイオアベイラビリティが改善されることを見いだし、以下の発明を完成させた。 The present inventors have a nitrogen-containing heterocyclic group containing a β-methylalanine residue at the C-terminal of N α -1-iminoethyl-Tyr-D-MetO-Phe-Me βAla-OH, which is one of the dermorphin derivatives. We found that oral bioavailability was improved by replacing with, and completed the following invention.
（１） 一般式（Ｉ）
で表される化合物であって、式中、
Yは、水素、低級アルキル又はR8N=C(R9)-であり、ここでR8は、水素、ヒドロキシ、低級アルキル又は低級アルコキシであり、R9は、低級アルキル又はアミノであり、
R1及びR2は、それぞれ独立して、水素、ハロゲン、低級アルキル又はハロゲン化低級アルキルであり、
Xは、水素、ハロゲン、ヒドロキシ、-O-CO-R10又は-O-CO-O-R11であり、ここでR10及びR11は、それぞれ独立して、C1-16アルキル、ヒドロキシC1-16アルキル、アミノC1-16アルキル、（モノ低級アルキル）アミノC1-16アルキル、（ジ低級アルキル）アミノC1-16アルキル、C3-10シクロアルキル、C3-10シクロアルキル置換低級アルキル、C2-16アルケニル、C2-16アルキニル、複素環、アリール又はアリール置換低級アルキルであり、
R3は、アミノ、（モノ低級アルキル）アミノ、低級アシルアミノ、グアニジノ、低級アルキル置換グアニジノ、イミノ低級アルキル、ウレイド、低級アルキル置換ウレイド、低級アルキルチオ、低級アルキルスルフィニル、低級アルキルスルホニル、低級アシル又はヒドロキシ低級アルキルであり、
lは、1〜4の整数であり、
R4及びR5は、それぞれ独立して、水素、ハロゲン、低級アルキル又はハロゲン化低級アルキルであり、
R6は、水素、ハロゲン、ヒドロキシ、-O-R12又は-CO-O-R13であり、ここでR12及びR13は、それぞれ独立して、水素、ハロゲン、低級アルキル又はハロゲン化低級アルキルであり、
R7は、水素、ハロゲン、低級アルキル又はハロゲン化低級アルキルであり、
m及びnは、それぞれ独立して、1〜4の整数である、前記化合物又は薬学的に許容されるその塩。
（２） Yが、水素、メチル又はR8N=C(R9)-であり、ここでR8は水素であり、R9はメチル、エチル又はアミノである、（１）に記載の化合物又は薬学的に許容されるその塩。
（３） Xが、-O-CO-R10であり、ここでR10はC1-16アルキルである、（１）又は（２）に記載の化合物又は薬学的に許容されるその塩。
（４） R3がメチルスルフィニル又はグアニジノである、（１）から（３）のいずれか一項に記載の化合物又は薬学的に許容されるその塩。
（５） R6がカルボキシルである、（１）から（４）のいずれか一項に記載の化合物又は薬学的に許容されるその塩。
（６） YがHN=C(CH3)-であり、Xが-O-CO-CH3であり、R3がメチルスルフィニル又はグアニジノであり、R6がカルボキシルである、（１）に記載の化合物又は薬学的に許容されるその塩。
（７） 以下の一般式（ＩＩ）又は（ＩＩＩ）で表される、（１）に記載の化合物又は薬学的に許容されるその塩。
（１）から（７）のいずれか一項に記載の化合物又は薬学的に許容されるその塩を含有する、医薬組成物。
(1) General formula (I)
It is a compound represented by, and in the formula,
Y is hydrogen, lower alkyl or R 8 N = C (R 9 )-where R 8 is hydrogen, hydroxy, lower alkyl or lower alkoxy and R 9 is lower alkyl or amino.
R 1 and R 2 are independently hydrogen, halogen, lower alkyl or halogenated lower alkyl, respectively.
X is hydrogen, halogen, hydroxy, -O-CO-R 10 or -O-CO-OR 11 , where R 10 and R 11 are independently C 1-16 alkyl, hydroxy C 1 respectively. -16 alkyl, amino C 1-16 alkyl, (mono lower alkyl) amino C 1-16 alkyl, (di lower alkyl) amino C 1-16 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl substituted lower Alkyl, C 2-16 alkenyl, C 2-16 alkynyl, heterocycle, aryl or aryl substituted lower alkyl,
R 3 is amino, (monolower alkyl) amino, lower acylamino, guanidino, lower alkyl substituted guanidino, imino lower alkyl, ureido, lower alkyl substituted ureido, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower acyl or hydroxy lower Alkyl and
l is an integer from 1 to 4
R 4 and R 5 are independently hydrogen, halogen, lower alkyl or halogenated lower alkyl, respectively.
R 6 is hydrogen, halogen, hydroxy, -OR 12 or -CO-OR 13 , where R 12 and R 13 are independently hydrogen, halogen, lower alkyl or halogenated lower alkyl, respectively.
R 7 is a hydrogen, halogen, lower alkyl or halogenated lower alkyl,
m and n are each independently an integer of 1 to 4, said compound or a pharmaceutically acceptable salt thereof.
(2) The compound according to (1), wherein Y is hydrogen, methyl or R 8 N = C (R 9 )-where R 8 is hydrogen and R 9 is methyl, ethyl or amino. Or its pharmaceutically acceptable salt.
(3) The compound according to (1) or (2) or a pharmaceutically acceptable salt thereof, wherein X is -O-CO-R 10 , where R 10 is C 1-16 alkyl.
(4) The compound according to any one of (1) to (3) or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl sulfinyl or guanidine.
(5) The compound according to any one of (1) to (4) or a pharmaceutically acceptable salt thereof, wherein R 6 is carboxyl.
(6) Described in (1), where Y is HN = C (CH 3 )-, X is -O-CO-CH 3 , R 3 is methylsulfinyl or guanidino, and R 6 is carboxyl. Compound or pharmaceutically acceptable salt thereof.
(7) The compound according to (1) or a pharmaceutically acceptable salt thereof, which is represented by the following general formula (II) or (III).
A pharmaceutical composition containing the compound according to any one of (1) to (7) or a pharmaceutically acceptable salt thereof.
本発明の化合物は、優れた抗侵害活性及び高められた経口バイオアベイラビリティを有していることから、従来のオピオイドペプチドに代わり得る新たなオピオイドペプチド誘導体として、がん性疼痛に代表される重度の疼痛の鎮痛剤としての利用、さらには鎮痒剤としての利用が期待される。 Since the compound of the present invention has excellent anti-noxious activity and enhanced oral bioavailability, it is a novel opioid peptide derivative that can replace the conventional opioid peptide, and is represented by severe cancer pain. It is expected to be used as an analgesic for pain and also as an antipruritic agent.
本発明は、一般式（Ｉ）
Yは、水素、低級アルキル又はR8N=C(R9)-であり、ここでR8は、水素、ヒドロキシ、低級アルキル又は低級アルコキシであり、R9は、低級アルキル又はアミノであり、
R1及びR2は、それぞれ独立して、水素、ハロゲン、低級アルキル又はハロゲン化低級アルキルであり、
Xは、水素、ハロゲン、ヒドロキシ、-O-CO-R10又は-O-CO-O-R11であり、ここでR10及びR11は、それぞれ独立して、C1-16アルキル、ヒドロキシC1-16アルキル、アミノC1-16アルキル、（モノ低級アルキル）アミノC1-16アルキル、（ジ低級アルキル）アミノC1-16アルキル、C3-10シクロアルキル、C3-10シクロアルキル置換低級アルキル、C2-16アルケニル、C2-16アルキニル、複素環、アリール又はアリール置換低級アルキルであり、
R3は、アミノ、（モノ低級アルキル）アミノ、低級アシルアミノ、グアニジノ、低級アルキル置換グアニジノ、イミノ低級アルキル、ウレイド、低級アルキル置換ウレイド、低級アルキルチオ、低級アルキルスルフィニル、低級アルキルスルホニル、低級アシル又はヒドロキシ低級アルキルであり、
lは、1〜4の整数であり、
R4及びR5は、それぞれ独立して、水素、ハロゲン、低級アルキル又はハロゲン化低級アルキルであり、
R6は、水素、ハロゲン、ヒドロキシ、-O-R12又は-CO-O-R13であり、ここでR12及びR13は、それぞれ独立して、水素、ハロゲン、低級アルキル又はハロゲン化低級アルキルであり、
R7は、水素、ハロゲン、低級アルキル又はハロゲン化低級アルキルであり、
m及びnは、それぞれ独立して、1〜4の整数である、前記化合物又は薬学的に許容されるその塩に関する。
The present invention has the general formula (I).
Y is hydrogen, lower alkyl or R 8 N = C (R 9 )-where R 8 is hydrogen, hydroxy, lower alkyl or lower alkoxy and R 9 is lower alkyl or amino.
R 1 and R 2 are independently hydrogen, halogen, lower alkyl or halogenated lower alkyl, respectively.
X is hydrogen, halogen, hydroxy, -O-CO-R 10 or -O-CO-OR 11 , where R 10 and R 11 are independently C 1-16 alkyl, hydroxy C 1 respectively. -16 alkyl, amino C 1-16 alkyl, (mono lower alkyl) amino C 1-16 alkyl, (di lower alkyl) amino C 1-16 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl substituted lower Alkyl, C 2-16 alkenyl, C 2-16 alkynyl, heterocycle, aryl or aryl substituted lower alkyl,
R 3 is amino, (monolower alkyl) amino, lower acylamino, guanidino, lower alkyl substituted guanidino, imino lower alkyl, ureido, lower alkyl substituted ureido, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower acyl or hydroxy lower Alkyl and
l is an integer from 1 to 4
R 4 and R 5 are independently hydrogen, halogen, lower alkyl or halogenated lower alkyl, respectively.
R 6 is hydrogen, halogen, hydroxy, -OR 12 or -CO-OR 13 , where R 12 and R 13 are independently hydrogen, halogen, lower alkyl or halogenated lower alkyl, respectively.
R 7 is a hydrogen, halogen, lower alkyl or halogenated lower alkyl,
m and n each independently relate to the compound or a pharmaceutically acceptable salt thereof, which is an integer of 1 to 4.
本明細書において、低級アルキルは、1〜6個の炭素原子を持つ直鎖又は分岐鎖のアルキルを表し、その例としては、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、tert-ブチル、n-ペンチル、2-ペンチル、3-ペンチル、ネオペンチル、n-ヘキシル、2-ヘキシル及び3-ヘキシルを挙げることができる。また、本明細書において、C1-16アルキルは、1〜16個の炭素原子を持つ直鎖又は分岐鎖のアルキルを表し、その例としては、上記低級アルキルで例示したものに加えて、直鎖又は分岐鎖のヘプチル、オクチル、ノニル、デシル、ウンデシル、ドデシル、トリデシル、テトラデシル、ペンタデシル及びヘキサデシルを挙げることができる。 In the present specification, the lower alkyl represents a linear or branched alkyl having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. -Butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl and 3-hexyl can be mentioned. Further, in the present specification, C 1-16 alkyl represents a linear or branched-chain alkyl having 1 to 16 carbon atoms, and examples thereof include direct alkyl in addition to those exemplified by the above lower alkyl. Chain or branched chain heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecylic, tetradecyl, pentadecyl and hexadecyl can be mentioned.
本明細書において、C2-16アルケニルは、2〜16個の炭素原子を持つ直鎖又は分岐鎖のアルケニルを表し、その例としては、ビニル、プロパ-1-エン-1-イル、プロパ-2-エン-1-イル（アリル）、プロパ-1-エン-2-イル（イソプロペニル）、2-メチルプロパ-2-エン-1-イル、ブタ-1-エン-1-イル、ブタ-1-エン-2-イル、ブタ-2-エン-1-イル、ブタ-2-エン-2-イル及びブタ-3-エン-1-イル、さらには直鎖又は分岐鎖のペンテニル、ヘキセニル、ヘプテニル、オクテニル、ノネニル、デセニル、ウンデセニル、ドデセニル、トリデセニル、テトラデセニル、ペンタデセニル及びヘキサデセニルを挙げることができる。 As used herein, C 2-16 alkenyl represents a linear or branched chain alkenyl having 2 to 16 carbon atoms, such as vinyl, propa-1-en-1-yl, propa-. 2-en-1-yl (allyl), propa-1-en-2-yl (isopropenyl), 2-methylprop-2-en-1-yl, porcine-1-en-1-yl, porcine-1 -En-2-yl, porcine-2-en-1-yl, porcine-2-en-2-yl and porcine-3-en-1-yl, as well as straight or branched chain pentenyl, hexenyl, heptenyl , Octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl and hexadecenyl.
本明細書において、C2-16アルキニルは、2〜16個の炭素原子を持つ直鎖又は分岐鎖のアルキニルを表し、その例としては、エチニル、1-プロピニル、2-プロピニル、1-ブチニル、2-ブチニル、3-ブチニル及び1-メチル-2-プロピニル、さらには直鎖又は分岐鎖のペンチニル、ヘキシニル、ヘプチニル、オクチニル、ノニニル、デシニル、ウンデシニル、ドデシニル、トリデシニル、テトラデシニル、ペンタデシニル及びヘキサデシニルを挙げることができる。 As used herein, C 2-16 alkynyl represents a linear or branched chain alkynyl having 2 to 16 carbon atoms, and examples thereof include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and so on. Examples include 2-butynyl, 3-butynyl and 1-methyl-2-propynyl, as well as linear or branched pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, tridecynyl, tetradecynyl, pentadecynyl and hexadecynyl. Can be done.
本明細書において、C3-10シクロアルキルは、3〜10個の炭素原子を持つシクロアルキルを表し、その例としては、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル及びアダマンチル等を挙げることができる。 In the present specification, C 3-10 cycloalkyl represents cycloalkyl having 3 to 10 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl. it can.
本明細書において、アリールは、1又は複数個の環からなる芳香族置換基を指し、その例としては、フェニル、ナフチル、アントラセニリル及びフェナントリル等を挙げることができる。 As used herein, aryl refers to an aromatic substituent consisting of one or more rings, and examples thereof include phenyl, naphthyl, anthraceniryl, and phenanthryl.
本明細書において、複素環は、窒素原子、酸素原子及び硫黄原子からなる群から選択される少なくとも１種類の原子を環原子として含む、飽和、不飽和又は部分不鉋和の炭素環式環を指し、その例としては、ピリジル、フラニル及びチオフェニル等を挙げることができる。 In the present specification, the heterocycle is a saturated, unsaturated or partially unsaturated carbocyclic ring containing at least one atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom as a ring atom. As an example thereof, pyridyl, furanyl, thiophenyl and the like can be mentioned.
本明細書において、ハロゲンは、フッ素、塩素、臭素又はヨウ素を指す。また、本明細書において、ハロゲン化低級アルキルは、水素原子がハロゲン原子で置換された低級アルキルである。ハロゲン化低級アルキルにおけるハロゲン原子の置換位置、個数及び種類に特に制限はなく、複数のハロゲン原子が存在する場合、それらは同一であっても異なっていてもよい。ハロゲン化低級アルキルの例としては、クロロメチル、ブロモメチル、フルオロメチル、2-クロロエチル、トリフルオロメチル及び2,2,2-トリフルオロエチル等を挙げることができる。 As used herein, halogen refers to fluorine, chlorine, bromine or iodine. Further, in the present specification, the lower alkyl halide is a lower alkyl in which a hydrogen atom is substituted with a halogen atom. The substitution position, number and type of halogen atoms in the lower alkyl halide are not particularly limited, and when a plurality of halogen atoms are present, they may be the same or different. Examples of lower alkyl halides include chloromethyl, bromomethyl, fluoromethyl, 2-chloroethyl, trifluoromethyl and 2,2,2-trifluoroethyl.
本明細書において、低級アルコキシは、1〜6個の炭素原子を持つ直鎖又は分岐鎖のアルコキシを表し、その例としては、メトキシ、エトキシ、n-プロポキシ、イソプロポキシ、n-ブトキシ、イソブトキシ、sec-ブトキシ及びtert-ブトキシ等を挙げることができる。 In the present specification, the lower alkoxy represents a linear or branched-chain alkoxy having 1 to 6 carbon atoms, and examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and isobutoxy. Examples thereof include sec-butoxy and tert-butoxy.
本明細書において、低級アシルは、1〜6個の炭素原子を持つ直鎖又は分岐鎖のアシルを表し、その例としては、ホルミル、アセチル、n-プロピオニル、イソプロピオニル、n-ブチロイル、イソブチロイル、sec-ブチロイル及びtert-ブチロイル等を挙げることができる。また、本明細書において、低級アシルアミノは、アミノ基の水素原子の一方又は両方が低級アシルで置換された置換基であって、２つの低級アシルで置換されている場合、それらは同一であっても異なっていてもよい。低級アシルアミノの例としては、モノアセチルアミノ、ジアセチルアミノ等を挙げることができる。 In the present specification, the lower acyl represents a linear or branched acyl having 1 to 6 carbon atoms, and examples thereof include formyl, acetyl, n-propionyl, isopropionyl, n-butyroyl, and isobutyroyl. Examples thereof include sec-butyroyl and tert-butyroyl. Further, in the present specification, the lower acylamino is a substituent in which one or both of the hydrogen atoms of the amino group are substituted with a lower acyl, and when they are substituted with two lower acyls, they are the same. May also be different. Examples of lower acylamino include monoacetylamino, diacetylamino and the like.
本明細書において、C3-10シクロアルキル置換低級アルキル及びアリール置換低級アルキルは、水素原子がそれぞれC3-10シクロアルキル及びアリールで置換された低級アルキルであって、置換基の位置、個数及び種類に特に制限はなく、複数の置換基が存在する場合、それらは同一であっても異なっていてもよい。同様に、ヒドロキシ低級アルキルは、水素原子がヒドロキシで置換された低級アルキルであって、ヒドロキシの位置及び個数に特に制限はない。 In the present specification, the C 3-10 cycloalkyl-substituted lower alkyl and the aryl-substituted lower alkyl are lower alkyls in which a hydrogen atom is substituted with C 3-10 cycloalkyl and aryl, respectively, and the position, number and number of substituents and the substituents are used. The type is not particularly limited, and when a plurality of substituents are present, they may be the same or different. Similarly, the hydroxy lower alkyl is a lower alkyl in which a hydrogen atom is substituted with hydroxy, and the position and number of hydroxys are not particularly limited.
本明細書において、ヒドロキシC1-16アルキル及びアミノC1-16アルキルは、水素原子がそれぞれヒドロキシ及びアミノで置換されたC1-16アルキルであって、置換基の位置及び個数に特に制限はない。ヒドロキシC1-16アルキルの例としてはヒドロキシメチル及び2-ヒドロキシエチル等を、アミノC1-16アルキルの例としてはアミノメチル及び2-アミノエチル等を挙げることができる。 In the present specification, hydroxy C 1-16 alkyl and amino C 1-16 alkyl, a hydrogen atom a C 1-16 alkyl substituted with each hydroxy and amino, particularly limited in the position and number of substituents Absent. Examples of hydroxy C 1-16 alkyl include hydroxymethyl and 2-hydroxyethyl, and examples of amino C 1-16 alkyl include aminomethyl and 2-aminoethyl.
本明細書において、（モノ低級アルキル）アミノ及び（ジ低級アルキル）アミノは、アミノ基の水素原子のそれぞれ一方及び両方が低級アルキルで置換された置換基であって、（ジ低級アルキル）アミノにおける２つの低級アルキルは同一であっても異なっていてもよい。（モノ低級アルキル）アミノの例としてはメチルアミノ及びエチルアミノ等を、（ジ低級アルキル）アミノの例としてはジメチルアミノ、ジエチルアミノ及びメチルエチルアミノ等を挙げることができる。 As used herein, (mono-lower alkyl) amino and (di-lower alkyl) amino are substituents in which one or both of the hydrogen atoms of the amino group are substituted with lower alkyl, and are used in (di-lower alkyl) amino. The two lower alkyls may be the same or different. Examples of the (monolower alkyl) amino include methylamino and ethylamino, and examples of the (dilower alkyl) amino include dimethylamino, diethylamino and methylethylamino.
本明細書において、（モノ低級アルキル）アミノC1-16アルキル及び（ジ低級アルキル）アミノC1-16アルキルは、水素原子がそれぞれ（モノ低級アルキル）アミノ及び（ジ低級アルキル）アミノで置換されたC1-16アルキルであって、置換基の位置及び個数に特に制限はない。（モノ低級アルキル）アミノC1-16アルキルの例としては3-(メチルアミノ)-n-プロニル及び2-(エチルアミノ)-n-ペンチル等を、（ジ低級アルキル）アミノC1-16アルキルの例としては2-(ジメチルアミノ)エチル及び2-(ジエチルアミノ)エチル等を挙げることができる。 As used herein, the (monolower alkyl) amino C 1-16 alkyl and the (dilower alkyl) amino C 1-16 alkyl are hydrogen atoms substituted with (monolower alkyl) amino and (dilower alkyl) amino, respectively. It is a C 1-16 alkyl, and the position and number of substituents are not particularly limited. Examples of (monolower alkyl) amino C 1-16 alkyl include 3- (methylamino) -n-pronyl and 2- (ethylamino) -n-pentyl, and (dilower alkyl) amino C 1-16 alkyl. Examples of the above include 2- (dimethylamino) ethyl and 2- (diethylamino) ethyl.
一般式（Ｉ）において、Yは、水素、低級アルキル又はR8N=C(R9)-であり、ここでR8は、水素、ヒドロキシ、低級アルキル又は低級アルコキシであり、R9は、低級アルキル又はアミノである。Yは、好ましくは水素、メチル、HN=C(CH3)-、HN=C(C2H5)-又はHN=C(NH2)-であり、より好ましくはHN=C(CH3)-である。 In general formula (I), Y is hydrogen, lower alkyl or R 8 N = C (R 9 )-where R 8 is hydrogen, hydroxy, lower alkyl or lower alkoxy and R 9 is. Lower alkyl or amino. Y is preferably hydrogen, methyl, HN = C (CH 3 )-, HN = C (C 2 H 5 )-or HN = C (NH 2 )-, and more preferably HN = C (CH 3 ). -.
一般式（Ｉ）において、Xは、水素、ハロゲン、ヒドロキシ、-O-CO-R10又は-O-CO-O-R11であり、ここでR10及びR11は、それぞれ独立して、C1-16アルキル、ヒドロキシC1-16アルキル、アミノC1-16アルキル、（モノ低級アルキル）アミノC1-16アルキル、（ジ低級アルキル）アミノC1-16アルキル、C3-10シクロアルキル、C3-10シクロアルキル置換低級アルキル、C2-16アルケニル、C2-16アルキニル、複素環、アリール又はアリール置換低級アルキルである。Xは、ヒドロキシ、又は生体内で代謝されてヒドロキシに変換される基、例えば-O-CO- C1-16アルキルであることが好ましく、より好ましくは-O-CO-CH3である。 In the general formula (I), X is hydrogen, halogen, hydroxy, -O-CO-R 10 or -O-CO-OR 11 , where R 10 and R 11 are independently C 1 -16 alkyl, hydroxy C 1-16 alkyl, amino C 1-16 alkyl, (mono lower alkyl) amino C 1-16 alkyl, (di lower alkyl) amino C 1-16 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl substituted lower alkyl, C 2-16 alkenyl, C 2-16 alkynyl, heterocycle, aryl or aryl substituted lower alkyl. X is preferably hydroxy, or a group that is metabolized in vivo and converted to hydroxy, such as -O-CO-C 1-16 alkyl, more preferably -O-CO-CH 3 .
一般式（Ｉ）において、R3は、アミノ、（モノ低級アルキル）アミノ、低級アシルアミノ、グアニジノ、低級アルキル置換グアニジノ、イミノ低級アルキル、ウレイド、低級アルキル置換ウレイド、低級アルキルチオ、低級アルキルスルフィニル、低級アルキルスルホニル、低級アシル又はヒドロキシ低級アルキルであり、lは、1〜4の整数である。R3は、好ましくはメチルスルフィニル又はグアニジノであり、より好ましくはメチルスルフィニルである。lは、好ましくは1又は2である。R3がメチルスルフィニルであり、lが2であるとき、-(CH2)l -R3を側鎖とするアミノ酸残基はメチオニンである。また、R3がグアニジノであり、lが2であるとき、-(CH2)l -R3を側鎖とするアミノ酸残基はアルギニンである。-(CH2)l -R3を側鎖とするアミノ酸残基はD体であることが好ましい。 In general formula (I), R 3 is amino, (monolower alkyl) amino, lower acylamino, guanidino, lower alkyl substituted guanidino, imino lower alkyl, ureido, lower alkyl substituted ureido, lower alkylthio, lower alkylsulfinyl, lower alkyl. It is a sulfonyl, lower acyl or hydroxy lower alkyl, where l is an integer from 1 to 4. R 3 is preferably methyl sulfinyl or guanidino, more preferably methyl sulfinyl. l is preferably 1 or 2. When R 3 is methylsulfinyl and l is 2, the amino acid residue with- (CH 2 ) l -R 3 as the side chain is methionine. Also, when R 3 is guanidine and l is 2, the amino acid residue with- (CH 2 ) l -R 3 as the side chain is arginine. The amino acid residue having-(CH 2 ) l -R 3 as a side chain is preferably D-form.
一般式（Ｉ）において、R6は、水素、ハロゲン、ヒドロキシ、-O-R12又は-CO-O-R13であり、ここでR12及びR13は、それぞれ独立して、水素、ハロゲン、低級アルキル又はハロゲン化低級アルキルであり、m及びnは、それぞれ独立して、1〜4の整数である。ここで、R6の相対的配置はexo又はendoのいずれでもよい。R6は、好ましくはカルボキシである。m及びnは、好ましくは、それぞれ独立して1又は2である。 In general formula (I), R 6 is hydrogen, halogen, hydroxy, -OR 12 or -CO-OR 13 , where R 12 and R 13 are independently hydrogen, halogen, lower alkyl or It is a lower alkyl halide, where m and n are independently integers from 1 to 4. Here, the relative arrangement of R 6 may be either exo or endo. R 6 is preferably carboxy. m and n are preferably 1 or 2 independently of each other.
一般式（Ｉ）において、R1、R2、R4、R5及びR7は、それぞれ独立して、水素、ハロゲン、低級アルキル又はハロゲン化低級アルキルである。R1、R2、R4、R5及びR7は、好ましくは、それぞれ独立して水素又はメチルである。 In general formula (I), R 1 , R 2 , R 4 , R 5 and R 7 are independently hydrogen, halogen, lower alkyl or halogenated lower alkyl, respectively. R 1 , R 2 , R 4 , R 5 and R 7 are preferably hydrogen or methyl, respectively.
特に好ましい本発明の化合物は、以下の一般式（ＩＩ）又は（ＩＩＩ）で示される化合物である。
本発明の化合物は、一般式（Ｉ）で表される化合物の任意のエナンチオマー若しくはその混合物、ジアステレオマー若しくはその混合物、又はこれらの任意の混合物を包含する。 The compounds of the present invention include any enantiomer or mixture thereof, diastereomers or mixtures thereof, or any mixture thereof of the compounds represented by the general formula (I).
また、本発明の化合物の薬学的に許容される塩は、酸付加塩又は塩基付加塩であることができる。酸付加塩としては、例えば塩酸塩、臭化水素酸塩、硫酸塩、ヨウ化水素酸塩、硝酸塩、リン酸塩等の無機酸塩、クエン酸塩、シュウ酸塩、酢酸塩、ギ酸塩、プロピオン酸塩、安息香酸塩、トリフルオロ酢酸塩、マレイン酸塩、酒石酸塩、メタンスルホン酸塩、ベンゼンスルホン酸塩、パラトルエンスルホン酸塩等の有機酸塩が挙げられる。塩基付加塩としては、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、アンモニウム塩等の無機塩基塩、トリエチルアンモニウム塩、トリエタノールアンモニウム塩、ピリジニウム塩、ジイソプロピルアンモニウム塩等の有機塩基塩等が挙げられる。さらに、アルギニン、アスパラギン酸、グルタミン酸等の塩基性あるいは酸性アミノ酸といったアミノ酸塩が挙げられる。一般式（Ｉ）で表される化合物の薬学的に許容される好ましい塩としては、例えば塩酸塩等が挙げられる。 Further, the pharmaceutically acceptable salt of the compound of the present invention can be an acid addition salt or a base addition salt. Examples of acid addition salts include hydrochlorides, hydrobromates, sulfates, hydroiodates, nitrates, phosphates and other inorganic acid salts, citrates, oxalates, acetates, formates, etc. Examples thereof include organic acid salts such as propionate, benzoate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, and paratoluenesulfonate. Examples of the base addition salt include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt and ammonium salt, and organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt and diisopropylammonium salt. .. Further, amino acid salts such as basic or acidic amino acids such as arginine, aspartic acid and glutamic acid can be mentioned. Preferred pharmaceutically acceptable salts of the compound represented by the general formula (I) include, for example, hydrochlorides and the like.
さらに、本発明は、一般式（Ｉ）で表される化合物又はその薬理学的に許容される塩の溶媒和物、例えば水和物又はエタノール和物等をも提供する。 Furthermore, the present invention also provides a solvate of a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof, for example, a hydrate or an ethanol solvate.
本発明の化合物は、一般的なペプチド合成法に従って、例えばペプチド液相合成法又はペプチド固相合成法を用いてペプチドカルボキシル末端より順次アミノ酸の縮合反応を行うことにより、製造することができる。 The compound of the present invention can be produced by sequentially carrying out a condensation reaction of amino acids from the peptide carboxyl terminal using, for example, a peptide liquid phase synthesis method or a peptide solid phase synthesis method according to a general peptide synthesis method.
ペプチド結合を形成するための縮合剤としては、例えば、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド（EDC）、N,N-ジシクロヘキシルカルボジイミド（DCC）、1-エチル-3-(3’-ジメチルアミノプロピル)カルボジイミド（WSC）、1H-ベンゾトリアゾール-1-イル-オキシ-トリス-(ジメチルアミノ)-ホスホニウムヘキサフルオロホスフェート（BOP）、1H-ベンゾトリアゾール-1-イル-オキシ-トリス-ピロリジノ-ホスホニウムヘキサフルオロホスフェート（pyBOP）、2-(1H-ベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウムヘキサフルオロホスフェート（HBTU）、2-(1H-ベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウムテトラフルオロボレート等が挙げられる。また、N-ヒドロキシベンゾトリアゾール（HOBt）と上記縮合剤を好ましい割合で混合して用いてもよい。 Examples of the condensing agent for forming a peptide bond include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), N, N-dicyclohexylcarbodiimide (DCC), and 1-ethyl-3- (3). '-Dimethylaminopropyl) carbodiimide (WSC), 1H-benzotriazole-1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate (BOP), 1H-benzotriazole-1-yl-oxy-tris- Pyrrolidino-phosphonium hexafluorophosphate (pyBOP), 2- (1H-benzotriazole-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2- (1H-benzotriazole- 1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate and the like can be mentioned. Further, N-hydroxybenzotriazole (HOBt) and the above condensing agent may be mixed and used in a preferable ratio.
また、ペプチド結合の形成にはカルボキシル末端を活性化してもよく、その活性化剤としては、例えば、N-ヒドロキシスクシンイミド、p-ニトロフェニルエステルやペンタフルオロフェニルエステル等が挙げられる。ペプチド結合を形成する際に用いる塩基としては、例えば、トリエチルアミン（Et3N）、ジイソプロピルエチルアミン（DIEA）等を挙げることができる。 Further, the carboxyl terminal may be activated for the formation of the peptide bond, and examples of the activator include N-hydroxysuccinimide, p-nitrophenyl ester, pentafluorophenyl ester and the like. Examples of the base used for forming a peptide bond include triethylamine (Et 3 N) and diisopropylethylamine (DIEA).
ペプチド結合形成反応に用いる溶媒としては、例えば、クロロホルム、塩化メチレン、アセトニトリル、N,N-ジメチルホルムアミド（DMF）やジメチルスルホキシド等を挙げることができる。 Examples of the solvent used for the peptide bond formation reaction include chloroform, methylene chloride, acetonitrile, N, N-dimethylformamide (DMF), dimethyl sulfoxide and the like.
前記合成法に用いるアミノ酸又はアミノ酸誘導体において、それらの官能基は必要に応じてt-ブチルオキシカルボニル基（Boc）や9-フルオレニルメチルオキシカルボニル基（Fmoc）、t-ブチル基（tBu）、トリチル基（Trt）、ベンジル基（Bzl）、2,2,5,7,8-ペンタメチルクロマンスルフォニル基（Pmc）等の保護基で保護される。また、これらの保護基はそれぞれに適した脱保護剤、例えば、トリフルオロ酢酸（TFA）又はピペリジンにより除去することができる。ペプチドのアミノ酸残基の側鎖官能基の保護基は、例えば、TFA、フッ化水素（HF）、トリフルオロメタンスルホン酸等により除去することができる。 In the amino acids or amino acid derivatives used in the synthesis method, their functional groups are t-butyloxycarbonyl group (Boc), 9-fluorenylmethyloxycarbonyl group (Fmoc) and t-butyl group (tBu), if necessary. , Trityl group (Trt), benzyl group (Bzl), 2,2,5,7,8-pentamethylchromansulfonyl group (Pmc) and other protective groups. Also, these protecting groups can be removed with a suitable deprotecting agent, such as trifluoroacetic acid (TFA) or piperidine. The protecting group of the side chain functional group of the amino acid residue of the peptide can be removed by, for example, TFA, hydrogen fluoride (HF), trifluoromethanesulfonic acid or the like.
また、ペプチド固相合成法において、ペプチド又はアミノ酸残基の側鎖官能基に保護基が付いているペプチドをペプチド固相合成樹脂より脱離させる方法としては、例えば、TFAが用いられる。ペプチド固相樹脂からのペプチドの脱離と、アミノ酸残基の側鎖官能基の保護基の脱離は、それぞれ同一反応系内で同時に行うこともできる。あるいは、それぞれ独立に行うこともできる。ペプチド固相合成用のペプチド固相合成樹脂としては、例えば、4-ヒドロキシメチル-3-メトキシフェノキシ酪酸−ベンズヒドリルアミン−ポリスチレン樹脂、p-ベンジルオキシベンジルアルコール−ポリスチレン樹脂やオキシム樹脂等の通常市販されているものを用いることができる。 Further, in the peptide solid phase synthesis method, for example, TFA is used as a method for removing a peptide having a protecting group on the side chain functional group of the peptide or amino acid residue from the peptide solid phase synthetic resin. Desorption of the peptide from the peptide solid phase resin and desorption of the protecting group of the side chain functional group of the amino acid residue can also be performed simultaneously in the same reaction system. Alternatively, each can be performed independently. Examples of the peptide solid phase synthetic resin for peptide solid phase synthesis include 4-hydroxymethyl-3-methoxyphenoxybutyric acid-benzhydrylamine-polystyrene resin, p-benzyloxybenzyl alcohol-polystyrene resin, and oxime resin, which are usually commercially available. Can be used.
一般式（Ｉ）で表される化合物へのYの導入は、低級アルキル又はR8N=C(R9)-でN-置換された若しくは置換されていないフェニルアラニン誘導体を上記のペプチド合成用のアミノ酸として利用することによって行うことができ、又はフェニルアラニンを利用して一般式（Ｉ）で表される化合物を合成後に必要に応じてフェニルアラニンのアミノ基を低級アルキル又はR8N=C(R9)-で置換することによって行うこともできる。 The introduction of Y into the compound represented by the general formula (I) is carried out by using a lower alkyl or a phenylalanine derivative N-substituted or not substituted with R 8 N = C (R 9)-for peptide synthesis described above. It can be carried out by using it as an amino acid, or after synthesizing a compound represented by the general formula (I) using phenylalanine, the amino group of phenylalanine is optionally changed to a lower alkyl or R 8 N = C (R 9). It can also be done by replacing with)-.
一般式（Ｉ）で表される化合物へのX、R1及びR2の導入は、X、R1及びR2で置換された若しくは置換されていないフェニルアラニン誘導体を上記のペプチド合成用のアミノ酸として利用することによって行うことができ、又はR1及びR2を有するチロシン誘導体を利用して一般式（Ｉ）で表される化合物を合成後に必要に応じてチロシンの水酸基を-O-CO-R10又は-O-CO-O-R11に変換することによって行うこともできる。 The introduction of X, R 1 and R 2 into the compound represented by the general formula (I) uses a phenylalanine derivative substituted or not substituted with X, R 1 and R 2 as an amino acid for the above peptide synthesis. It can be carried out by using, or after synthesizing the compound represented by the general formula (I) using a tyrosine derivative having R 1 and R 2, the hydroxyl group of tyrosine is changed to -O-CO-R as needed. It can also be done by converting to 10 or -O-CO-OR 11.
一般式（Ｉ）で表される化合物への-(CH2)l -R3の導入は、-(CH2)l -R3を側鎖として有するアミノ酸、好ましくはD型メチオニン又はアルギニン、より好ましくはD型メチオニンを上記のペプチド合成用のアミノ酸として利用することによって行うことができる。 The introduction of- (CH 2 ) l -R 3 into the compound represented by the general formula (I) is carried out by using an amino acid having- (CH 2 ) l -R 3 as a side chain, preferably D-type methionine or arginine. Preferably, D-type methionine can be used as an amino acid for the above-mentioned peptide synthesis.
一般式（Ｉ）で表される化合物へのR4及びR5の導入は、R4及びR5を置換基として有するフェニルアラニン、例えば特開2007-261958に記載された方法に準じて合成したジアルキルフェニルアラニン又はモノアルキルフェニルアラニン等を上記のペプチド合成用のアミノ酸として利用することによって行うことができる。 The introduction of R 4 and R 5 into the compound represented by the general formula (I) is carried out by phenylalanine having R 4 and R 5 as a substituent, for example, a dialkyl synthesized according to the method described in JP-A-2007-261958. This can be done by using phenylalanine, monoalkylphenylalanine, or the like as the amino acids for peptide synthesis described above.
一般式（Ｉ）で表される化合物への含窒素複素環式基の導入は、必要に応じてR7で置換された、mに応じた環員数を有する含窒素複素単環式化合物に対して、R6で置換された、nの数に応じた炭素数を有するアルケンを反応させることによってR6で置換された含窒素複素二環式化合物を合成し（Sibasish et al., Tetrahedron Letters, 2011, 52 (46), p.6166-6169等を参照されたい）、次いでこれをフェニルアラニン残基のカルボキシル基と反応させることによって行うことができる。R6がカルボキシであり、m及びnが1である場合の含窒素複素二環式化合物の合成スキームを以下に示す。
一般式（Ｉ）で表される化合物の特定のエナンチオマー又はジアステレオマーは、その構造及び合成プロセスを考慮して、エナンチオ選択的合成法、ジアステレオ選択的合成法又はラセミ体光学分割法を適宜選択して合成することができる。例えば、一般式（ＩＩ）又は（ＩＩＩ）に示される化合物のエナンチオマーは、後の実施例に示されるように、N-Cbz-1,2-ジヒドロピリジンにオキサゾリジン誘導体の光学活性体を反応させて得られる含窒素複素二環式化合物（光学活性イソキヌクリジン誘導体）を用いることで、合成することができる。 The specific enantiomer or diastereomer of the compound represented by the general formula (I) is appropriately subjected to an enantioselective synthesis method, a diastereoselective synthesis method or a racemic chiral resolution method in consideration of its structure and synthetic process. It can be selected and synthesized. For example, the enantiomer of the compound represented by the general formula (II) or (III) can be obtained by reacting N-Cbz-1,2-dihydropyridine with an optically active substance of an oxazolidine derivative, as shown in a later example. It can be synthesized by using a nitrogen-containing heterobicyclic compound (optically active isoquinucrine derivative).
本発明の化合物又はその合成中間体は、例えばイオンクロマトグラフィー、ゲル濾過クロマトグラフィー、逆相クロマトグラフィー、順相クロマトグラフィー、再結晶、抽出、分別結晶化等の種々の公知の方法により単離、精製を行うことができる。また、本発明の化合物は、常法によって適当な薬学的に許容される塩の形態に変換することができる。 The compound of the present invention or a synthetic intermediate thereof is isolated by various known methods such as ion chromatography, gel filtration chromatography, reverse phase chromatography, normal phase chromatography, recrystallization, extraction, and fractional crystallization. Purification can be performed. In addition, the compounds of the present invention can be converted into suitable pharmaceutically acceptable salt forms by conventional methods.
一般式（Ｉ）中の含窒素複素環式基がβメチルアラニンである幾つかの化合物は、当業者に公知のオピオイドペプチド誘導体である（例えばOgawa et al, Chem. Pharm. Bull., 2003, 51(7), p.759-771；特開2018-027911号公報等）。本発明の化合物は、そのC末端に含窒素複素環式基を有するオピオイドペプチド誘導体であることを特徴としている。理論に拘束されるものではないが、含窒素複素環式基は立体的に嵩高く、剛直なかご型構造であるので立体配置の制御を可能とすること、及びかご型構造は脂溶性を増大させること等の理由により、本発明の化合物は優れた抗侵害活性及び高められた経口バイオアベイラビリティを有するものと推測される。さらに、N末端チロシンの水酸基をアシル化すること及び／又は含窒素複素環式基のβ位にカルボキシル基を導入することは、本発明の化合物の抗侵害活性及び経口バイオアベイラビリティをより高めるものと期待される。 Some compounds in which the nitrogen-containing heterocyclic group in general formula (I) is β-methylalanine are opioid peptide derivatives known to those skilled in the art (eg, Ogawa et al, Chem. Pharm. Bull., 2003, 51 (7), p.759-771; Japanese Patent Application Laid-Open No. 2018-027911 etc.). The compound of the present invention is characterized by being an opioid peptide derivative having a nitrogen-containing heterocyclic group at its C-terminal. Although not bound by theory, the nitrogen-containing heterocyclic group is sterically bulky and has a rigid cage structure, which enables control of the configuration, and the cage structure increases lipophilicity. It is presumed that the compound of the present invention has excellent anti-noxious activity and enhanced oral bioavailability for reasons such as making it. Furthermore, acylating the hydroxyl group of the N-terminal tyrosine and / or introducing a carboxyl group at the β-position of the nitrogen-containing heterocyclic group further enhances the anti-noxious activity and oral bioavailability of the compound of the present invention. Be expected.
本発明の化合物及び薬学的に許容されるその塩は、オピオイド受容体に対する特異的親和性を有し、優れた鎮痛作用及び種々のモルヒネ様生理活性を発現し得る。モルヒネ様生理活性の例としては、オピオイド受容体を経由して発現する種々の中枢性及び末梢性応答、例えば麻酔、鎮静、呼吸・脈動・消化管機能の調節、ホルモン分泌調節、心筋収縮調節等を挙げることができるが、本発明の適用対象はこれらには限定されない。 The compounds of the present invention and their pharmaceutically acceptable salts have specific affinity for opioid receptors and may exhibit excellent analgesic activity and various morphine-like bioactivities. Examples of morphine-like bioactivity include various central and peripheral responses expressed via opioid receptors, such as anesthesia, sedation, regulation of respiratory / pulsating / gastrointestinal function, regulation of hormone secretion, regulation of myocardial contraction, etc. However, the scope of application of the present invention is not limited to these.
本発明は、一般式（Ｉ）で表される化合物又は薬学的に許容されるその塩を有効成分とする医薬組成物をさらなる態様として提供する。本発明の医薬組成物は、上述の有効成分以外の薬物又は緩衝剤、抗酸化剤、保存剤、タンパク質、親水性ポリマー、アミノ酸、キレート化剤、非イオン性界面活性剤、賦形剤、安定化剤、担体等の薬学的に許容される成分を含んでもよい。薬学的に許容される成分は当業者において周知であり、当業者が通常の実施能力の範囲内で、例えば第十七改正日本薬局方その他の規格書に記載された成分から製剤の形態に応じて適宜選択して使用することができる。 The present invention provides, as a further embodiment, a pharmaceutical composition containing the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical compositions of the present invention are drugs or buffers other than the above-mentioned active ingredients, antioxidants, preservatives, proteins, hydrophilic polymers, amino acids, chelating agents, nonionic surfactants, excipients, stables. It may contain pharmaceutically acceptable components such as an agent and a carrier. Pharmaceutically acceptable ingredients are well known to those skilled in the art, and those skilled in the art can use the ingredients described in the 17th revised Japanese Pharmacopoeia and other standards within the range of normal practicability, depending on the form of the formulation. Can be appropriately selected and used.
本発明の医薬組成物の形態は任意であるが、経口剤（錠剤、カプセル剤、散剤、顆粒剤、細粒剤、丸剤、懸濁剤、乳剤、液剤、シロップ剤等）及び非経口製剤（注射剤、点滴剤、外用剤等）の形態を好ましい例として挙げることができる。 The form of the pharmaceutical composition of the present invention is arbitrary, but is an oral preparation (tablets, capsules, powders, granules, fine granules, pills, suspensions, emulsions, liquids, syrups, etc.) and parenteral preparations. The form of (injection agent, drip agent, external preparation, etc.) can be mentioned as a preferable example.
本発明の化合物及び薬学的に許容されるその塩並びにそれらを含む医薬組成物は、例えば、鎮痛剤、鎮痛麻酔剤、催眠剤、鎮痒剤、抗健忘剤、抗不安剤、消化管ホルモン促進剤、電解質吸収促進剤、腸管ぜん動抑制による下痢改善剤等として利用することができ、特に鎮痛剤又は鎮痒剤として有用である。 The compounds of the present invention, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them are, for example, analgesics, analgesic anesthetics, hypnotics, antipruritic agents, anti-amnestic agents, anti-anxiety agents, gastrointestinal hormone promoters. , Electrolyte absorption promoter, diarrhea improving agent by suppressing intestinal peristalsis, etc., and is particularly useful as an analgesic or antipruritic agent.
本発明の医薬組成物の投与方法は、特に制限されないが、非経口製剤である場合は、例えば血管内投与（好ましくは静脈内投与）、腹腔内投与、腸管内投与、皮下投与等を挙げることができる。好ましい実施形態の一つにおいて、本発明の医薬組成物は、経口投与、静脈内投与又は経皮投与により生体に投与される。 The method for administering the pharmaceutical composition of the present invention is not particularly limited, but in the case of a parenteral preparation, for example, intravascular administration (preferably intravenous administration), intraperitoneal administration, intestinal administration, subcutaneous administration and the like can be mentioned. Can be done. In one of the preferred embodiments, the pharmaceutical composition of the present invention is administered to a living body by oral administration, intravenous administration or transdermal administration.
本発明における医薬組成物の投与量は、用法、対象の年齢、疾患の種類及び部位その他の条件に応じて適宜選択されるが、通常成人に対して体重1kgあたり10μg〜2000μg、好ましくは50μg〜1000μg、より好ましくは100μg〜500μgであり、これを1日に1回若しくは複数回に分けて、又は間歇的に投与することができる。 The dose of the pharmaceutical composition in the present invention is appropriately selected according to the usage, the age of the subject, the type and site of the disease, and other conditions, but is usually 10 μg to 2000 μg, preferably 50 μg to 1 kg of body weight for an adult. It is 1000 μg, more preferably 100 μg to 500 μg, and this can be administered once a day, in multiple divided doses, or intermittently.
本発明における対象とは任意の動物を意味し、好ましくは哺乳動物の個体、例えば、ヒト、チンパンジー等の霊長類、マウス、ラット、モルモット、ハムスター等の齧歯類、ウシ、ヤギ、ヒツジ等の偶蹄目、ウマ等の奇蹄目、ウサギ、イヌ、ネコ等の個体であり、さらに好ましくはヒトの個体である。 The object in the present invention means any animal, preferably an individual mammal, for example, primates such as humans and chimpanzees, rodents such as mice, rats, guinea pigs and hamsters, cows, goats, sheep and the like. Individuals such as Artiodactyla, Odd-toed elephants such as horses, rabbits, dogs, and cats, and more preferably humans.
本発明は、疼痛若しくは掻痒を訴える対象又は鎮痛若しくは鎮痒を必要とする対象に有効量の本発明の化合物若しくは薬学的に許容されるその塩又はそれらを含む医薬組成物を投与することを含む、疼痛若しくは掻痒の抑制方法又は鎮痛若しくは鎮痒方法をも提供する。 The present invention comprises administering to a subject who complains of pain or pruritus or a subject in need of pain relief or pruritus an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing them. A method for controlling pain or pruritus or a method for suppressing pain or pruritus is also provided.
以下の実施例によって本発明をさらに詳細に説明するが、本発明はこれらに限定されるものではない。 The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.
実施例１．オピオイドペプチド誘導体の合成
（１）N-Boc-Tyr-D-MetO-Phe-OHの合成
(1) Synthesis of N-Boc-Tyr-D-MetO-Phe-OH
得られた化合物 3 (309mg) を0°Cにて4N塩酸/酢酸エチル溶液 (9.3mL)に溶解し、室温にて1時間撹拌した。反応液にジエチルエーテルを滴下し、得られた沈殿物をろ別し、減圧乾燥した。得られた粗生成物である H-D-MetO-Phe-OMe 塩酸塩 4 を0°CでDMF (30mL) に溶解し、N-Boc-Tyr-OH 5 (224mg)及びHOBt (196mg) を加えた後、-10°Cに冷却した反応液にトリエチルアミン (0.12mL)、EDC・HCl (167mg) を加えて1時間撹拌し、さらに室温で16時間撹拌した。反応液に酢酸エチルを加え、1N塩酸、飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧濃縮して得られた残留物をシリカゲルカラムクロマトグラフィー (EtOAc：MeOH = 20：1にて溶出) で精製して、N-Boc-Tyr-D-MetO-Phe-OMe 6 (265mg、収率62%) を得た。 The obtained compound 3 (309 mg) was dissolved in a 4N hydrochloric acid / ethyl acetate solution (9.3 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Diethyl ether was added dropwise to the reaction mixture, and the obtained precipitate was filtered off and dried under reduced pressure. The obtained crude product HD-MetO-Phe-OMe hydrochloride 4 was dissolved in DMF (30 mL) at 0 ° C, and N-Boc-Tyr-OH 5 (224 mg) and HOBt (196 mg) were added. After that, triethylamine (0.12 mL) and EDC / HCl (167 mg) were added to the reaction solution cooled to -10 ° C, and the mixture was stirred for 1 hour, and further stirred at room temperature for 16 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluted at EtOAc: MeOH = 20: 1) to purify N-Boc-Tyr-D. -MetO-Phe-OMe 6 (265 mg, 62% yield) was obtained.
得られた化合物 6 (265mg) をメタノール (3.0mL) に溶解し、0°Cにて2N NaOH (0.40mL) を加え、室温で2時間撹拌した。反応液を水で希釈し、減圧濃縮をしてメタノールを除去し、ジエチルエーテルで洗浄した。水層に1N塩酸を加えた後、酢酸エチルにて抽出し、飽和塩化ナトリウム水溶液で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧濃縮して得られた残留物をシリカゲルカラムクロマトグラフィー (CHCl3：MeOH =10：1にて溶出) で精製して、N-Boc-Tyr-D-MetO-Phe-OH 7 (238mg、収率92%) を得た。 The obtained compound 6 (265 mg) was dissolved in methanol (3.0 mL), 2N NaOH (0.40 mL) was added at 0 ° C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, concentrated under reduced pressure to remove methanol, and washed with diethyl ether. After adding 1N hydrochloric acid to the aqueous layer, the mixture was extracted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography ( eluted with CHCl 3 : MeOH = 10: 1) to purify N-Boc-Tyr-. D-MetO-Phe-OH 7 (238 mg, yield 92%) was obtained.
（２）イソキヌクリジン誘導体の合成
得られた化合物 10 を分取用薄層クロマトグラフィープレート (Hexane：EtOAc =10：1にて展開) による多重展開によって分離精製し、endo体である化合物 10a (収率61%) とexo体である化合物 10b (収率39%) とに分別した。それぞれの化合物をメタノール (100mL) に溶解し、10%パラジウム存在下、水素ガスを用いて水素化反応を行い、endo体のイソキヌクリジン誘導体である化合物 11a (419mg、収率91%) 及びexo体のイソキヌクリジン誘導体である化合物 11b (265mg、収率 90%) を得た。 The obtained compound 10 was separated and purified by multiple expansion using a thin layer chromatography plate for preparative use (developed at Hexane: EtOAc = 10: 1), and compound 10a (yield 61%) and exo compound, which are endo compounds, were used. It was separated into a certain compound 10b (yield 39%). Each compound was dissolved in methanol (100 mL), and a hydrogenation reaction was carried out using hydrogen gas in the presence of 10% palladium. Compound 11b (265 mg, 90% yield), which is an isoquinucrine derivative, was obtained.
（３）endo typeオピオイドペプチド誘導体の合成
得られた化合物 12 (141mg) を0°CでDMF (10mL) に溶解し、酢酸 (0.02mL)、DMAP (2.4mg) 及びEDC・HCl (45mg) を加え1時間撹拌し、さらに室温で16時間撹拌した。反応液に酢酸エチルを加え、1N塩酸、飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧濃縮して得られた残留物をシリカゲルカラムクロマトグラフィー (CHCl3：MeOH = 20：1にて溶出) で精製して、化合物 13 (133mg、収率89%) を得た。 The obtained compound 12 (141 mg) was dissolved in DMF (10 mL) at 0 ° C., acetic acid (0.02 mL), DMAP (2.4 mg) and EDC / HCl (45 mg) were added, and the mixture was stirred for 1 hour, and further at room temperature 16 Stirred for hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography ( eluted at CHCl 3 : MeOH = 20: 1) to obtain Compound 13 (133 mg, yield). Rate 89%) was obtained.
得られた化合物 13 (133mg) のN末端のBoc基をトリフルオロ酢酸を用いて除去し、DMF (10mL) 、アセトイミド酸エチル塩酸塩 (86mg) 及びトリエチルアミン (0.15mL) を加え、室温で24時間撹拌した。反応液に酢酸エチルを加え、水、飽和塩化ナトリウム水溶液で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧濃縮して得られた残留物を分取用薄層クロマトグラフィープレート (CHCl3：MeOH = 10：1にて展開) による多重展開によって精製し、化合物 14 (11mg、収率9%) を得た。 The N-terminal Boc group of the obtained compound 13 (133 mg) was removed using trifluoroacetic acid, DMF (10 mL), ethyl acetate hydrochloride (86 mg) and triethylamine (0.15 mL) were added, and the mixture was added at room temperature for 24 hours. Stirred. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the obtained residue was purified by multiple expansion using a preparative thin layer chromatography plate (CHCl 3 : MeOH = 10: 1). Compound 14 (11 mg, 9% yield) was obtained.
得られた化合物 14 をメタノール (2.0mL) に溶解し、0°Cにて2N NaOH (0.02mL)を加え、室温で3時間撹拌した。反応液を水で希釈し、減圧濃縮をしてメタノールを除去し、ジエチルエーテルで洗浄した。水層に1N塩酸を加えた後、酢酸エチルにて抽出し、飽和塩化ナトリウム水溶液で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧濃縮して得られた残留物をシリカゲルカラムクロマトグラフィー (CHCl3：MeOH =10：1 にて溶出) で精製して、endo体オピオイドペプチド誘導体である化合物 15 (9.9mg、収率92%) のラセミ混合物を得た。 The obtained compound 14 was dissolved in methanol (2.0 mL), 2N NaOH (0.02 mL) was added at 0 ° C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, concentrated under reduced pressure to remove methanol, and washed with diethyl ether. After adding 1N hydrochloric acid to the aqueous layer, the mixture was extracted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer is dried over anhydrous sodium sulfate, the solvent is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography ( eluted with CHCl 3 : MeOH = 10: 1) with an endo opioid peptide derivative. A racemic mixture of 15 (9.9 mg, 92% yield) of a compound was obtained.
（４）exo typeオピオイドペプチド誘導体の合成
（５）光学活性イソキヌクリジン誘導体の合成
リチウムメトキシド (2.02mL)、n-ブチルリチウム (0.95mL) を-78°CでTHF (12mL) に溶解し、あらかじめTHF (27mL) に溶解させた化合物21 (450mg) を加え、0°Cで24時間撹拌した。反応後、飽和塩化アンモニウム水溶液を加え、クロロホルムにて抽出し、飽和塩化ナトリウム水溶液で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧濃縮して残留物をシリカゲルカラムクロマトグラフィー (Hexane：EtOAc = 4：1にて溶出)で精製して、光学活性イソキヌクリジン誘導体 22 (124mg、収率42%) を得た。 Lithium methoxyde (2.02 mL), n-butyllithium (0.95 mL) was dissolved in THF (12 mL) at -78 ° C, compound 21 (450 mg) previously dissolved in THF (27 mL) was added, and 0 ° C. Was stirred for 24 hours. After the reaction, a saturated aqueous solution of ammonium chloride was added, the mixture was extracted with chloroform, and washed with a saturated aqueous solution of sodium chloride. The organic layer is dried over anhydrous sodium sulfate, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluted at Hexane: EtOAc = 4: 1) to obtain an optically active isoquinucrine derivative 22 (124 mg, yield). 42%) was obtained.
得られた化合物 22 (121mg) をメタノール (30mL) に溶解し、10%パラジウム炭素(42.8mg) 存在下、水素ガスを用いて水素化反応を室温で2時間行い、光学活性イソキヌクリジン誘導体である化合物 23 ((1R,4S,7R)-2-azabicyclo-[2.2.2]octane-7-metylcarboxylate、61mg、収率90%) を得た。 The obtained compound 22 (121 mg) was dissolved in methanol (30 mL), and a hydrogenation reaction was carried out at room temperature for 2 hours using hydrogen gas in the presence of 10% palladium carbon (42.8 mg). 23 ((1R, 4S, 7R) -2-azabicyclo-[2.2.2] octane-7-metylcarboxylate, 61 mg, yield 90%) was obtained.
（６）光学活性かご型オピオイドペプチド誘導体の合成
実施例２．オピオイドペプチド誘導体の抗侵害活性評価
本発明のオピオイドペプチド誘導体の抗侵害活性は、試験物質を経口又は皮下投与したマウスを用いて、Tail-flick法によって測定することができる。
測定には、Tail-Flick Unit (Ugo Basile, Italy)を使用する。マウスの尾部先端より2 cmの部位へ熱光線を照射してから逃避反応として尾を動かすまでの時間（反応潜時）を測定する。熱光線の強度は、あらかじめ薬物無処置のマウスが2〜3秒で逃避反応を示すように設定する。マウス尾部の損傷を最低限に抑えるために、最大熱刺激時間 (cut-off time)を10秒とする。抗侵害作用は、次式に従い、最大有効反応率 (maximum possible effect; %MPE)として評価する。
%MPE ＝ [(T1 − T0) / (Tc − T0)] × 100
T0: 薬物投与前の反応潜時（秒）
T1: 薬物投与後の反応潜時（秒）
Tc: cut-off time（10秒）
最大有効反応率の用量応答曲線からED50値を得る。さらに、ED50（p.o.）/ ED50（s.c.）を算出し、経口バイオアベイラビリティーの指標とする。
Example 2. Evaluation of Anti-Noxious Activity of Opioid Peptide Derivative The anti-noxious activity of the opioid peptide derivative of the present invention can be measured by the Tail-flick method using mice to which the test substance was orally or subcutaneously administered.
A Tail-Flick Unit (Ugo Basile, Italy) is used for the measurement. The time (reaction latency) from irradiating a region 2 cm from the tip of the tail of a mouse to moving the tail as an escape reaction is measured. The intensity of the heat ray is set in advance so that the drug-untreated mouse shows an escape reaction in 2 to 3 seconds. The maximum cut-off time is 10 seconds to minimize damage to the mouse tail. The anti-noxious effect is evaluated as the maximum possible effect (% MPE) according to the following equation.
% MPE = [(T 1 − T 0 ) / (Tc − T 0 )] × 100
T 0 : Reaction latency (seconds) before drug administration
T 1 : Reaction latency (seconds) after drug administration
Tc: cut-off time (10 seconds)
Obtain the ED 50 value from the dose response curve for maximum effective response rate. Furthermore, ED 50 (po) / ED 50 (sc) is calculated and used as an index of oral bioavailability.
Claims (8)
で表される化合物であって、式中、
Yは、水素、低級アルキル又はR8N=C(R9)-であり、ここでR8は、水素、ヒドロキシ、低級アルキル又は低級アルコキシであり、R9は、低級アルキル又はアミノであり、
R1及びR2は、それぞれ独立して、水素、ハロゲン、低級アルキル又はハロゲン化低級アルキルであり、
Xは、水素、ハロゲン、ヒドロキシ、-O-CO-R10又は-O-CO-O-R11であり、ここでR10及びR11は、それぞれ独立して、C1-16アルキル、ヒドロキシC1-16アルキル、アミノC1-16アルキル、（モノ低級アルキル）アミノC1-16アルキル、（ジ低級アルキル）アミノC1-16アルキル、C3-10シクロアルキル、C3-10シクロアルキル置換低級アルキル、C2-16アルケニル、C2-16アルキニル、複素環、アリール又はアリール置換低級アルキルであり、
R3は、アミノ、（モノ低級アルキル）アミノ、低級アシルアミノ、グアニジノ、低級アルキル置換グアニジノ、イミノ低級アルキル、ウレイド、低級アルキル置換ウレイド、低級アルキルチオ、低級アルキルスルフィニル、低級アルキルスルホニル、低級アシル又はヒドロキシ低級アルキルであり、
lは、1〜4の整数であり、
R4及びR5は、それぞれ独立して、水素、ハロゲン、低級アルキル又はハロゲン化低級アルキルであり、
R6は、水素、ハロゲン、ヒドロキシ、-O-R12又は-CO-O-R13であり、ここでR12及びR13は、それぞれ独立して、水素、ハロゲン、低級アルキル又はハロゲン化低級アルキルであり、
R7は、水素、ハロゲン、低級アルキル又はハロゲン化低級アルキルであり、
m及びnは、それぞれ独立して、1〜4の整数である、前記化合物又は薬学的に許容されるその塩。 General formula (I)
It is a compound represented by, and in the formula,
Y is hydrogen, lower alkyl or R 8 N = C (R 9 )-where R 8 is hydrogen, hydroxy, lower alkyl or lower alkoxy and R 9 is lower alkyl or amino.
R 1 and R 2 are independently hydrogen, halogen, lower alkyl or halogenated lower alkyl, respectively.
X is hydrogen, halogen, hydroxy, -O-CO-R 10 or -O-CO-OR 11 , where R 10 and R 11 are independently C 1-16 alkyl, hydroxy C 1 respectively. -16 alkyl, amino C 1-16 alkyl, (mono lower alkyl) amino C 1-16 alkyl, (di lower alkyl) amino C 1-16 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl substituted lower Alkyl, C 2-16 alkenyl, C 2-16 alkynyl, heterocycle, aryl or aryl substituted lower alkyl,
R 3 is amino, (monolower alkyl) amino, lower acylamino, guanidino, lower alkyl substituted guanidino, imino lower alkyl, ureido, lower alkyl substituted ureido, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower acyl or hydroxy lower Alkyl and
l is an integer from 1 to 4
R 4 and R 5 are independently hydrogen, halogen, lower alkyl or halogenated lower alkyl, respectively.
R 6 is hydrogen, halogen, hydroxy, -OR 12 or -CO-OR 13 , where R 12 and R 13 are independently hydrogen, halogen, lower alkyl or halogenated lower alkyl, respectively.
R 7 is a hydrogen, halogen, lower alkyl or halogenated lower alkyl,
m and n are each independently an integer of 1 to 4, said compound or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition containing the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2019193339A JP2021066690A (en) | 2019-10-24 | 2019-10-24 | Opioid peptide derivatives and pharmaceutical compositions containing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2019193339A JP2021066690A (en) | 2019-10-24 | 2019-10-24 | Opioid peptide derivatives and pharmaceutical compositions containing same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2021066690A true JP2021066690A (en) | 2021-04-30 |
Family
ID=75637229
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2019193339A Pending JP2021066690A (en) | 2019-10-24 | 2019-10-24 | Opioid peptide derivatives and pharmaceutical compositions containing same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2021066690A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH11180960A (en) * | 1997-09-23 | 1999-07-06 | Hoechst Marion Roussel Deutsche Gmbh | New five-membered heterocyclic compound, production and use thereof, and pharmaceutical preparation containing the same |
| WO1999033864A1 (en) * | 1997-12-26 | 1999-07-08 | Daiichi Pharmaceutical Co., Ltd. | Peptide derivatives |
| JP2011068587A (en) * | 2009-09-25 | 2011-04-07 | Tohoku Univ | New aminoalcohol derivative salt, asymmetric organic molecule catalyst having aminoalcohol derivative salt structure and method for producing optically active compound with the asymmetric organic molecule catalyst |
-
2019
- 2019-10-24 JP JP2019193339A patent/JP2021066690A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH11180960A (en) * | 1997-09-23 | 1999-07-06 | Hoechst Marion Roussel Deutsche Gmbh | New five-membered heterocyclic compound, production and use thereof, and pharmaceutical preparation containing the same |
| WO1999033864A1 (en) * | 1997-12-26 | 1999-07-08 | Daiichi Pharmaceutical Co., Ltd. | Peptide derivatives |
| JP2011068587A (en) * | 2009-09-25 | 2011-04-07 | Tohoku Univ | New aminoalcohol derivative salt, asymmetric organic molecule catalyst having aminoalcohol derivative salt structure and method for producing optically active compound with the asymmetric organic molecule catalyst |
Non-Patent Citations (2)
| Title |
|---|
| OGAWA, T., ET AL.: ""Synthesis and antinociceptive activity of orally active opioid peptides: Improvement of oral bioava", CHEM. PHARM. BULL., vol. 51, no. 7, JPN6023031364, July 2003 (2003-07-01), pages 759 - 771, XP002613027, ISSN: 0005118442, DOI: 10.1248/cpb.51.759 * |
| 岸里涼太、外７名: "「鎮痛作用を有する新規かご型オピオイドペプチド化合物の合成研究」", メディシナルケミストリーシンポジウム講演要旨集, vol. 第３６回, JPN6023031365, 2018, pages 57, ISSN: 0005118443 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2013523599A (en) | Novel opioid dicarboxylic acid linked amino acid and peptide prodrugs and uses thereof | |
| EP3250238B1 (en) | Antibody drug conjugates | |
| JP5357022B2 (en) | Multifunctional bioactive compounds | |
| EP0350221B1 (en) | Dermorphin analogs, their methods of preparation, pharmaceutical compositions, and methods of therapeutic treatment using the same | |
| KR20120060203A (en) | Novel carbamate amino acid and peptide prodrugs of opioids and uses thereof | |
| FR2677361A1 (en) | NOVEL PEPTIDES AND PSEUDOPEPTIDES, TACHYKININ DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. | |
| WO2009092071A2 (en) | Amino acid and peptide pro-drugs of phenolic analgesics and uses thereof | |
| WO2011083304A1 (en) | Prodrugs of opioids and uses thereof | |
| JPH07503485A (en) | opioid peptide | |
| US20090264345A1 (en) | Macrocyclic peptides and methods for making and using them | |
| WO2007109620A2 (en) | Macrocyclic peptides and methods for making and using them | |
| SK2094A3 (en) | Somatostatine polypeptides, method of their preparing and using | |
| JP2002528388A (en) | Ring-modified cyclic peptide analogs | |
| Petrov et al. | Synthesis and evaluation of 3-aminopropionyl substituted fentanyl analogues for opioid activity | |
| WO2020169012A1 (en) | Method for synthesizing dopa oligopeptide intermediate and use, composition and preparation thereof | |
| JPH0359920B2 (en) | ||
| JP2021066690A (en) | Opioid peptide derivatives and pharmaceutical compositions containing same | |
| HU186375B (en) | Process for the preparation of biologically active encephalina derivatives | |
| JP2009516733A (en) | Compounds for inhibition of apoptosis | |
| EP0348564A1 (en) | Orally active antiandrogens | |
| JPH10330398A (en) | New cyclic peptide | |
| EA001001B1 (en) | Peptide derivatives | |
| KR19990044553A (en) | Peptide derivative | |
| JPWO2003082819A1 (en) | N-phenyl-N- (4-piperidinyl) amide derivatives | |
| JP7437578B2 (en) | Novel opioid peptides, glycosylated derivatives thereof, and pharmaceutical compositions containing them |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A80 | Written request to apply exceptions to lack of novelty of invention |
Free format text: JAPANESE INTERMEDIATE CODE: A80 Effective date: 20191119 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20220920 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20230726 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230801 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20240206 |