JP4630192B2 - Prolyl oligopeptidase inhibitor - Google Patents
Prolyl oligopeptidase inhibitor Download PDFInfo
- Publication number
- JP4630192B2 JP4630192B2 JP2005514106A JP2005514106A JP4630192B2 JP 4630192 B2 JP4630192 B2 JP 4630192B2 JP 2005514106 A JP2005514106 A JP 2005514106A JP 2005514106 A JP2005514106 A JP 2005514106A JP 4630192 B2 JP4630192 B2 JP 4630192B2
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- JP
- Japan
- Prior art keywords
- group
- substituted
- amino
- lower alkyl
- benzyloxy
- 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.)
- Expired - Fee Related
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- 239000003649 prolyl endopeptidase inhibitor Substances 0.000 title claims description 37
- -1 N-protected pyrrolidinyl group Chemical group 0.000 claims description 228
- 125000000217 alkyl group Chemical group 0.000 claims description 120
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 77
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 62
- 125000003118 aryl group Chemical group 0.000 claims description 58
- 125000003282 alkyl amino group Chemical group 0.000 claims description 44
- 125000003545 alkoxy group Chemical group 0.000 claims description 42
- 125000004104 aryloxy group Chemical group 0.000 claims description 40
- 125000001072 heteroaryl group Chemical group 0.000 claims description 40
- 125000002252 acyl group Chemical group 0.000 claims description 39
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 39
- 125000001424 substituent group Chemical group 0.000 claims description 39
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 36
- 239000003814 drug Substances 0.000 claims description 33
- 150000003951 lactams Chemical class 0.000 claims description 33
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 32
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 31
- 125000005100 aryl amino carbonyl group Chemical group 0.000 claims description 30
- 125000001041 indolyl group Chemical group 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
- 125000000542 sulfonic acid group Chemical group 0.000 claims description 30
- 125000006501 nitrophenyl group Chemical group 0.000 claims description 28
- 125000005843 halogen group Chemical group 0.000 claims description 25
- 125000003277 amino group Chemical group 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 22
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 17
- 125000004414 alkyl thio group Chemical group 0.000 claims description 17
- 229940124597 therapeutic agent Drugs 0.000 claims description 17
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 239000004480 active ingredient Substances 0.000 claims description 14
- 125000005090 alkenylcarbonyl group Chemical group 0.000 claims description 14
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 14
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 14
- 208000028698 Cognitive impairment Diseases 0.000 claims description 12
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 12
- 208000010877 cognitive disease Diseases 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 12
- 206010027175 memory impairment Diseases 0.000 claims description 12
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 125000001769 aryl amino group Chemical group 0.000 claims description 10
- 125000005241 heteroarylamino group Chemical group 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 10
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 10
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 230000003449 preventive effect Effects 0.000 claims description 7
- 230000000069 prophylactic effect Effects 0.000 claims description 7
- 206010001935 American trypanosomiasis Diseases 0.000 claims description 6
- 208000024699 Chagas disease Diseases 0.000 claims description 6
- 241000223109 Trypanosoma cruzi Species 0.000 claims description 6
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 230000000144 pharmacologic effect Effects 0.000 claims description 4
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 3
- 150000001924 cycloalkanes Chemical class 0.000 claims description 3
- 208000000044 Amnesia Diseases 0.000 claims description 2
- 208000031091 Amnestic disease Diseases 0.000 claims description 2
- 206010012289 Dementia Diseases 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 230000006986 amnesia Effects 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 208000015181 infectious disease Diseases 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 230000002554 disease preventive effect Effects 0.000 claims 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 2
- 239000002831 pharmacologic agent Substances 0.000 claims 2
- 108010032563 oligopeptidase Proteins 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 229940127557 pharmaceutical product Drugs 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 285
- 239000000243 solution Substances 0.000 description 214
- 150000001875 compounds Chemical class 0.000 description 190
- 239000011734 sodium Substances 0.000 description 108
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 106
- 239000000203 mixture Substances 0.000 description 97
- 238000005160 1H NMR spectroscopy Methods 0.000 description 85
- 238000006243 chemical reaction Methods 0.000 description 76
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 66
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 64
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- 238000010828 elution Methods 0.000 description 63
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 60
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 60
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 58
- 238000004896 high resolution mass spectrometry Methods 0.000 description 56
- 239000013078 crystal Substances 0.000 description 55
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 53
- 235000017557 sodium bicarbonate Nutrition 0.000 description 53
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 52
- 150000004682 monohydrates Chemical class 0.000 description 49
- 159000000000 sodium salts Chemical class 0.000 description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 41
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 34
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 32
- 150000002148 esters Chemical class 0.000 description 32
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 30
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 30
- 238000001914 filtration Methods 0.000 description 28
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 20
- XVFMJDKBSMALCI-UHFFFAOYSA-N NC(CCN(C1=O)N)C1(NS(O)(=O)=O)[PH2]=O Chemical compound NC(CCN(C1=O)N)C1(NS(O)(=O)=O)[PH2]=O XVFMJDKBSMALCI-UHFFFAOYSA-N 0.000 description 19
- 102000056251 Prolyl Oligopeptidases Human genes 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 17
- 101001095266 Homo sapiens Prolyl endopeptidase Proteins 0.000 description 16
- 238000004440 column chromatography Methods 0.000 description 16
- 239000010410 layer Substances 0.000 description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- 230000000694 effects Effects 0.000 description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 238000001816 cooling Methods 0.000 description 14
- 238000010438 heat treatment Methods 0.000 description 14
- BRBNGYAMFATDBX-KRWDZBQOSA-N benzyl n-[(3s)-1-[bis(propylamino)phosphoryl]-2-oxopiperidin-3-yl]carbamate Chemical compound O=C1N(P(=O)(NCCC)NCCC)CCC[C@@H]1NC(=O)OCC1=CC=CC=C1 BRBNGYAMFATDBX-KRWDZBQOSA-N 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 10
- 238000000746 purification Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- OAKVLRXDYFSWCP-UHFFFAOYSA-N S(=O)(=O)(O)NC1C(N(CCC1)[PH2]=O)=O Chemical compound S(=O)(=O)(O)NC1C(N(CCC1)[PH2]=O)=O OAKVLRXDYFSWCP-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 229940088598 enzyme Drugs 0.000 description 8
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- PPKVBFFSXJFTOK-UHFFFAOYSA-N O=C(C(C=C1)=CC=C1F)NC(CCCN1[PH2]=O)C1=O Chemical compound O=C(C(C=C1)=CC=C1F)NC(CCCN1[PH2]=O)C1=O PPKVBFFSXJFTOK-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 208000024827 Alzheimer disease Diseases 0.000 description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- MZCJHEBTJUTUOV-NSHDSACASA-N benzyl n-[(3s)-1-diaminophosphoryl-2-oxopiperidin-3-yl]carbamate Chemical compound O=C1N(P(N)(=O)N)CCC[C@@H]1NC(=O)OCC1=CC=CC=C1 MZCJHEBTJUTUOV-NSHDSACASA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- QSKWJTXWJJOJFP-UHFFFAOYSA-N chloroform;ethoxyethane Chemical compound ClC(Cl)Cl.CCOCC QSKWJTXWJJOJFP-UHFFFAOYSA-N 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- CCOOGCOZORIURJ-UHFFFAOYSA-N C(CC)(=O)C1(C(C(N(CC1)N)=O)([PH2]=O)NS(=O)(=O)O)N Chemical compound C(CC)(=O)C1(C(C(N(CC1)N)=O)([PH2]=O)NS(=O)(=O)O)N CCOOGCOZORIURJ-UHFFFAOYSA-N 0.000 description 4
- RNYCZJBZIWHOAL-UHFFFAOYSA-N C(CCCCC)(=O)NC1C(C(N(CC1)N)=O)([PH2]=O)NS(=O)(=O)O Chemical compound C(CCCCC)(=O)NC1C(C(N(CC1)N)=O)([PH2]=O)NS(=O)(=O)O RNYCZJBZIWHOAL-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- FPHIXFQQULAHJH-UHFFFAOYSA-N [Na].NN1C(CCCC1)=O Chemical compound [Na].NN1C(CCCC1)=O FPHIXFQQULAHJH-UHFFFAOYSA-N 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 4
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 4
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 4
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- 102100026450 POU domain, class 3, transcription factor 4 Human genes 0.000 description 3
- 101710133389 POU domain, class 3, transcription factor 4 Proteins 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 125000006242 amine protecting group Chemical group 0.000 description 3
- MZCJHEBTJUTUOV-LLVKDONJSA-N benzyl n-[(3r)-1-diaminophosphoryl-2-oxopiperidin-3-yl]carbamate Chemical compound O=C1N(P(N)(=O)N)CCC[C@H]1NC(=O)OCC1=CC=CC=C1 MZCJHEBTJUTUOV-LLVKDONJSA-N 0.000 description 3
- KOQQIZKHWRVHRS-HNNXBMFYSA-N benzyl n-[(3s)-1-[bis(ethylamino)phosphoryl]-2-oxopiperidin-3-yl]carbamate Chemical compound O=C1N(P(=O)(NCC)NCC)CCC[C@@H]1NC(=O)OCC1=CC=CC=C1 KOQQIZKHWRVHRS-HNNXBMFYSA-N 0.000 description 3
- SFLWVDDNCHZGLW-ZDUSSCGKSA-N benzyl n-[(3s)-1-[bis(methylamino)phosphoryl]-2-oxopiperidin-3-yl]carbamate Chemical compound O=C1N(P(=O)(NC)NC)CCC[C@@H]1NC(=O)OCC1=CC=CC=C1 SFLWVDDNCHZGLW-ZDUSSCGKSA-N 0.000 description 3
- CLXMBMDVHKPOJT-JTQLQIEISA-N benzyl n-[(3s)-1-diaminophosphoryl-2-oxopyrrolidin-3-yl]carbamate Chemical compound O=C1N(P(N)(=O)N)CC[C@@H]1NC(=O)OCC1=CC=CC=C1 CLXMBMDVHKPOJT-JTQLQIEISA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 125000004888 n-propyl amino group Chemical group [H]N(*)C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- JXGVXCZADZNAMJ-NSHDSACASA-N (2s)-1-phenylmethoxycarbonylpyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)OCC1=CC=CC=C1 JXGVXCZADZNAMJ-NSHDSACASA-N 0.000 description 2
- AHYFYYVVAXRMKB-KRWDZBQOSA-N (2s)-3-(1h-indol-3-yl)-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)OCC1=CC=CC=C1 AHYFYYVVAXRMKB-KRWDZBQOSA-N 0.000 description 2
- CANZBRDGRHNSGZ-NSHDSACASA-N (2s)-3-methyl-2-(phenylmethoxycarbonylamino)butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 CANZBRDGRHNSGZ-NSHDSACASA-N 0.000 description 2
- RRONHWAVOYADJL-HNNXBMFYSA-N (2s)-3-phenyl-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 RRONHWAVOYADJL-HNNXBMFYSA-N 0.000 description 2
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- 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
- 125000004706 n-propylthio group Chemical group C(CC)S* 0.000 description 1
- JVXXKQIRGQDWOJ-UHFFFAOYSA-N naphthalene-2-carboxamide Chemical compound C1=CC=CC2=CC(C(=O)N)=CC=C21 JVXXKQIRGQDWOJ-UHFFFAOYSA-N 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000005184 naphthylamino group Chemical group C1(=CC=CC2=CC=CC=C12)N* 0.000 description 1
- PCJGZPGTCUMMOT-ISULXFBGSA-N neurotensin Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 PCJGZPGTCUMMOT-ISULXFBGSA-N 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 1
- 229960001723 oxytocin Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229940117953 phenylisothiocyanate Drugs 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- RVLHQTNUNYWCIH-UHFFFAOYSA-N pyrrolidin-2-ylidenemethanone Chemical class O=C=C1CCCN1 RVLHQTNUNYWCIH-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Inorganic materials O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- XKXIQBVKMABYQJ-UHFFFAOYSA-N tert-butyl hydrogen carbonate Chemical compound CC(C)(C)OC(O)=O XKXIQBVKMABYQJ-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- QIQITDHWZYEEPA-UHFFFAOYSA-N thiophene-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=CS1 QIQITDHWZYEEPA-UHFFFAOYSA-N 0.000 description 1
- 229960002898 threonine Drugs 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/664—Amides of phosphorus acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/5532—Seven-(or more) membered rings
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
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- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
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Description
本発明は、新規なプロリルオリゴペプチダーゼ阻害剤、及び記憶及び認識障害改善若しくは治療剤、及びシャガス病予防若しくは治療剤を提供し、またα−アシルアミノ−N−(ジアミノホスフィニル)ラクタム誘導体、その塩、その水和物又はその溶媒和物、並びに該化合物を含有する医薬組成物を提供するものである。 The present invention provides novel prolyl oligopeptidase inhibitors, memory and cognitive impairment improving or treating agents, and Chagas disease preventing or treating agents, and α-acylamino-N- (diaminophosphinyl) lactam derivatives, The salt, the hydrate or the solvate thereof, and the pharmaceutical composition containing the compound are provided.
従来、アルツハイマー病の脳内においてコリンアセチルトランスフェラーゼ活性の減少が、またアセチルコリンエステラーゼ活性が優位に変動していることが報告され、これに従って脳内のアセチルコリン量を増加させるような薬剤としてアセチルコリンエステラーゼ阻害剤を中心に、コリン作動性の神経細胞の賦活剤等の開発がなされてきた(非特許文献1:Brain,Vol.99,p.459(1976))。
現在、アセチルコリン系の薬剤とともにアルツハイマー病の脳に蓄積するアミロイドβ蛋白及びその前駆体に焦点をあてた新たな観点から記憶の改善を目指す薬剤の開発が待たれている。Conventionally, it has been reported that choline acetyltransferase activity decreases in the brain of Alzheimer's disease, and that acetylcholinesterase activity fluctuates predominantly, and acetylcholinesterase inhibitors are drugs that increase the amount of acetylcholine in the brain accordingly. In particular, cholinergic neuron activators have been developed (Non-Patent Document 1: Brain, Vol. 99, p. 459 (1976)).
Currently, development of a drug that aims to improve memory from a new point of view focusing on amyloid β protein and its precursor accumulated in the brain of Alzheimer's disease together with acetylcholine drugs is awaited.
プロリルオリゴペチダーゼ(EC 3.4.21.26)はオキシトシンの不活性化酵素として発見され(非特許文献2:Science,Vol.173,p.827(1971))、その基質特異性に関する詳細な検討から、その機能はプロリンのC末端側の特異的な切断に帰せられることが明らかとなった(非特許文献3:J.Biol.Chem.,Vol.251,p.7593(1976)、非特許文献4:Science,Vol.221,p.1310(1983))。
その後の研究でプロリルオリゴペチダーゼは神経伝達物質であるニューロテンシンやサブスタンスP、記憶に関係していると考えられているTHR(甲状腺刺激ホルモン)やバソプレシンなどを不活性化することが判明した(非特許文献5:Nature,Vol.308,p.276(1984)、非特許文献6:Biochem.Biophys.Acta,Vol.422,p.138(1976))。これらのことから、プロリルオリゴペチダーゼが神経伝達系の制御に関与していると考えられた。そこで様々な病気の患者におけるプロリルオリゴペチダーゼ活性が調べられた結果、アルツハイマー病患者の脳内での酵素活性の上昇が確認された(非特許文献7:Experientia,Vol.46,p.94(1990))。Prolyl oligopeptidase (EC 3.4.21.26) was discovered as an inactivating enzyme for oxytocin (Non-patent Document 2: Science, Vol. 173, p. 827 (1971)) and relates to its substrate specificity. Detailed examination revealed that the function was attributed to specific cleavage at the C-terminal side of proline (Non-patent Document 3: J. Biol. Chem., Vol. 251, p. 7593 (1976)). Non-Patent Document 4: Science, Vol. 221, p. 1310 (1983)).
Subsequent studies revealed that prolyl oligopeptidase inactivates neurotransmitters such as neurotensin, substance P, and THR (thyroid stimulating hormone) and vasopressin, which are thought to be related to memory. (Non-patent document 5: Nature, Vol. 308, p. 276 (1984), Non-patent document 6: Biochem. Biophys. Acta, Vol. 422, p. 138 (1976)). From these results, it was considered that prolyl oligopeptidase is involved in the control of the neurotransmission system. Therefore, as a result of examining prolyl oligopeptidase activity in patients with various diseases, an increase in enzyme activity in the brain of Alzheimer's disease patients was confirmed (Non-patent Document 7: Expertia, Vol. 46, p. 94). (1990)).
更に、プロリルオリゴペチダーゼはアミロイド前駆体蛋白質からアミロイドβ蛋白質が切り出される際のC末端部分を切断する可能性のある酵素の候補として報告されている(非特許文献8:Biochem.Biophys.Res.Commun.,Vol.235,p.641(1997))。そのため、本酵素活性の上昇がアルツハイマー病の原因の一つと考えられ、プロリルオリゴペチダーゼ阻害剤によるアルツハイマー病などの記憶及び認識障害治療剤の研究が進められるようになった(非特許文献9:Drugs of Today,Vol.36,p.415(2000))。 Furthermore, prolyl oligopeptidase has been reported as a candidate for an enzyme that may cleave the C-terminal part when amyloid β protein is cleaved from amyloid precursor protein (Non-patent Document 8: Biochem. Biophys. Res). Commun., Vol.235, p.641 (1997)). Therefore, the increase in the enzyme activity is considered to be one of the causes of Alzheimer's disease, and research on therapeutic and therapeutic agents for memory and cognitive impairment such as Alzheimer's disease using a prolyl oligopeptidase inhibitor has been advanced (Non-patent Document 9). : Drugs of Today, Vol.36, p.415 (2000)).
本酵素の阻害剤としては、プロリルチアゾリジド誘導体のS17092(非特許文献10:CNS Drug Reviews,Vol.8,p.31(2002))、2−カルボニルピロリジン誘導体のONO1603(非特許文献11:J.Pharmacol.Exp.Ther.,Vol.288,p.6(1999))など数多く知られているが、いずれも本発明化合物とは基本骨格が全く異なるものである。また、本発明の一般式(1)で表される化合物に類似した骨格を有する化合物としてはスルフォスチン及びその類縁体が知られているが、これらの化合物の記憶及び認識障害、並びにプロリルオリゴペプチダーゼに対する作用は知られていない(特許文献1:国際公開第99/25719号、特許文献2:特開2000−327689号公報)。なお、一般式(1)においてRがベンジルオキシ基、Xがカルボニル基(−CO−)であり、かつY及びZの両方が水素原子の組み合わせと、Y及びZの一方が水素原子で他方がスルホン酸基の組み合わせである化合物は特許文献2(特開2000−327689号公報)に記載の化合物である。 As an inhibitor of this enzyme, prolyl thiazolidide derivative S17092 (Non-patent Document 10: CNS Drug Reviews, Vol. 8, p.31 (2002)), 2-carbonylpyrrolidine derivative ONO1603 (Non-patent Document 11: J. Pharmacol.Exp.Ther., Vol.288, p.6 (1999)), etc. are known, but all of them have completely different basic skeletons from the compounds of the present invention. In addition, as compounds having a skeleton similar to the compound represented by the general formula (1) of the present invention, sulfostine and its analogs are known. Memory and recognition deficiencies of these compounds, and prolyl oligopeptidase Is not known (Patent Document 1: International Publication No. 99/25719, Patent Document 2: JP 2000-327689 A). In the general formula (1), R is a benzyloxy group, X is a carbonyl group (—CO—), both Y and Z are hydrogen atoms, one of Y and Z is a hydrogen atom, and the other is The compound which is a combination of sulfonic acid groups is a compound described in Patent Document 2 (Japanese Patent Laid-Open No. 2000-327689).
また、動物以外のプロリルオリゴペプチダーゼ様作用の酵素としては、Tc80が知られている(非特許文献12:Biochem.J.,Vol.325,p.129(1997))。この酵素はシャガス病の原因虫であるTrypanozoma cruziから発見された80kDaの蛋白分解酵素で、細胞外マトリックスのコラーゲンI及びIVを特異的に切断することが知られている。また、プロリルオリゴペプチダーゼ阻害剤がT.cruziの細胞内への侵入を阻害することが報告されている(非特許文献13:J.Biol.Chem.,Vol.276,p.47078(2001))。そのため、Trypanozoma cruziがヒト細胞内への侵入する際に、このTc80が重要な役割をなしていると考えられている。これらのことから、プロリルオリゴペプチダーゼ阻害剤はTc80も阻害するためにシャガス病の予防若しくは治療剤としての可能性が示唆され、これら酵素の選択性に関する研究が進められるようになってきた(非特許文献14:Bioorg.Med.Chem.,Vol.10,p.1719(2002))。
本発明の目的は、新規なα−アシルアミノ−N−(ジアミノホスフィニル)ラクタム誘導体及びこれらを有効成分とする記憶及び認識障害に対する治療剤又は予防剤及びプロリルオリゴペプチダーゼ阻害剤を提供することにある。 An object of the present invention is to provide a novel α-acylamino-N- (diaminophosphinyl) lactam derivative, a therapeutic or preventive agent and a prolyl oligopeptidase inhibitor for memory and cognitive impairments containing these as active ingredients. It is in.
本発明者らは、スルフォスチン誘導体について鋭意研究を行ったところ、一般式(1)で表される新規なα−アシルアミノ−N−(ジアミノホスフィニル)ラクタム誘導体及びその薬理学的に許容し得る塩がプロリルオリゴペプチダーゼ阻害活性を有することを見い出し、本発明を完成するに至った。 As a result of intensive research on the sulfostin derivative, the present inventors have found that the novel α-acylamino-N- (diaminophosphinyl) lactam derivative represented by the general formula (1) and its pharmacologically acceptable condition. It was found that the salt has prolyl oligopeptidase inhibitory activity, and the present invention has been completed.
すなわち、本発明は次の(1)〜(28)に関するものである。
(1)一般式(1)That is, the present invention relates to the following (1) to (28).
(1) General formula (1)
[式中、Rは水素原子、低級アルキル基、シクロアルキル基、アリール基、ヘテロアリール基、低級アルケニル基、低級アルキルアミノ基、アリールアミノ基、ヘテロアリールアミノ基、低級アルコキシ基、アリールオキシ基、ピロリジニル基、N−保護ピロリジニル基、ベンジル基、又はベンジルオキシ基を示し、それぞれの基は置換されてもよく、置換される場合には低級アルキル基、シクロアルキル基、アリール基、ヘテロアリール基、低級アルコキシ基、ベンジルオキシ基、アリールオキシ基、水酸基、アミノ基、低級アルキルアミノ基、ジ低級アルキルアミノ基、N−保護アミノ基、カルボキシル基、低級アルコキシカルボニル基、ベンジルオキシカルボニル基、チオール基、低級アルキルチオ基、ハロゲン原子、シアノ基、ニトロ基、カルバモイル基、低級アルキルアミノカルボニル基、又はアリールアミノカルボニル基で置換される。Xはカルボニル基(−CO−)、チオカルボニル基(−CS−)、又はスルホニル基(−SO2−)を示す。Y及びZは同一又は異なっていてよく、水素原子、スルホン酸基、低級アルキル基、アリール基、ヘテロアリール基、シクロアルキル基、低級アシル基、アリールカルボニル基、ヘテロアリールカルボニル基、シクロアルカンカルボニル基、低級アルケニルカルボニル基、低級アルキルアミノカルボニル基、又はアリールアミノカルボニル基を示し、それぞれの基は置換されてもよく、置換される場合には低級アルキル基、アリール基、ヘテロアリール基、低級アルコキシ基、アリールオキシ基、ベンジルオキシ基、ニトロ基、ハロゲン原子、水酸基、アミノ基、低級アルキルアミノ基、ジ低級アルキルアミノ基、N−保護アミノ基、カルボキシル基、低級アルコキシカルボニル基、又はシアノ基で置換される。Qは−(CH2)n−(nは0〜3を示す)を示す。]で表されるα−アシルアミノ−N−(ジアミノホスフィニル)ラクタム誘導体又はその薬理学的に許容される塩を有効成分とするプロリルオリゴペプチダーゼ阻害剤、
(2)一般式(1)において、Rは水素原子、低級アルキル基、シクロアルキル基、アリール基、ヘテロアリール基、低級アルケニル基、低級アルキルアミノ基、アリールアミノ基、ヘテロアリールアミノ基、低級アルコキシ基、アリールオキシ基、ピロリジニル基、N−保護ピロリジニル基、ベンジル基、又はベンジルオキシ基を示し、それぞれの基は置換されてもよく、置換される場合には低級アルキル基、シクロアルキル基、アリール基、ヘテロアリール基、低級アルコキシ基、ベンジルオキシ基、アリールオキシ基、水酸基、アミノ基、低級アルキルアミノ基、ジ低級アルキルアミノ基、N−保護アミノ基、カルボキシル基、低級アルコキシカルボニル基、ベンジルオキシカルボニル基、チオール基、低級アルキルチオ基、ハロゲン原子、シアノ基、ニトロ基、カルバモイル基、低級アルキルアミノカルボニル基、及びアリールアミノカルボニル基からなる群から選択される1〜3個の置換基で置換され、Xはカルボニル基(−CO−)又はスルホニル基(−SO2−)を示す前記(1)記載のプロリルオリゴペプチダーゼ阻害剤、
(3)一般式(1)において、Rは低級アルキル基、ベンジル基、又はベンジルオキシ基を示し、低級アルキル基並びにベンジル基は置換されてもよく、低級アルキル基が置換される場合にはアリール基、ヘテロアリール基、シクロアルキル基、アリールオキシ基、アルキルチオ基、及びN−保護アミノ基からなる群から選択される1〜3個の置換基で置換され、ベンジル基が置換される場合には低級アルコキシ基又はニトロ基で置換され、Xはカルボニル基(−CO−)又はスルホニル基(−SO2−)を示す前記(1)記載のプロリルオリゴペプチダーゼ阻害剤、
(4)一般式(1)において、Rは低級アルキル基、ベンジル基、又はベンジルオキシ基を示し、低級アルキル基並びにベンジル基は置換されてもよく、低級アルキル基が置換される場合にはアリール基、ヘテロアリール基、シクロアルキル基、アリールオキシ基、アルキルチオ基、及びN−保護アミノ基からなる群から選択される1〜3個の置換基で置換され、ベンジル基が置換される場合には低級アルコキシ基又はニトロ基で置換され、Xカルボニル基(−CO−)を示す前記(1)記載のプロリルオリゴペプチダーゼ阻害剤、
(5)一般式(1)において、Rは低級アルキル基又はベンジルオキシ基を示し、低級アルキル基は置換されてもよく、置換される場合にはフェニル基、メトキシフェニル基、ニトロフェニル基、インドリル基、シクロヘキシル基、ベンジルオキシカルボニルアミノ基からなる群から選択される1〜2個の置換基で置換され、Xはカルボニル基(−CO−)を示す前記(1)記載のプロリルオリゴペプチダーゼ阻害剤、[Wherein, R represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a lower alkenyl group, a lower alkylamino group, an arylamino group, a heteroarylamino group, a lower alkoxy group, an aryloxy group, Pyrrolidinyl group, N-protected pyrrolidinyl group, benzyl group, or benzyloxy group, each group may be substituted, and when substituted, a lower alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, Lower alkoxy group, benzyloxy group, aryloxy group, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group, N-protected amino group, carboxyl group, lower alkoxycarbonyl group, benzyloxycarbonyl group, thiol group, Lower alkylthio group, halogen atom, cyano group, nito Group, a carbamoyl group, is substituted with a lower alkylaminocarbonyl group, or an arylaminocarbonyl group. X represents a carbonyl group (—CO—), a thiocarbonyl group (—CS—), or a sulfonyl group (—SO 2 —). Y and Z may be the same or different and are a hydrogen atom, a sulfonic acid group, a lower alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a lower acyl group, an arylcarbonyl group, a heteroarylcarbonyl group, a cycloalkanecarbonyl group. , A lower alkenylcarbonyl group, a lower alkylaminocarbonyl group, or an arylaminocarbonyl group, each group may be substituted, and when substituted, a lower alkyl group, an aryl group, a heteroaryl group, a lower alkoxy group , Aryloxy group, benzyloxy group, nitro group, halogen atom, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group, N-protected amino group, carboxyl group, lower alkoxycarbonyl group, or cyano group Is done. Q is - (CH 2) n - shows the (n denotes 0 to 3). A prolyl oligopeptidase inhibitor comprising as an active ingredient an α-acylamino-N- (diaminophosphinyl) lactam derivative represented by the formula:
(2) In the general formula (1), R is a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a lower alkenyl group, a lower alkylamino group, an arylamino group, a heteroarylamino group, or a lower alkoxy. Group, aryloxy group, pyrrolidinyl group, N-protected pyrrolidinyl group, benzyl group, or benzyloxy group, each group may be substituted, and if substituted, lower alkyl group, cycloalkyl group, aryl Group, heteroaryl group, lower alkoxy group, benzyloxy group, aryloxy group, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group, N-protected amino group, carboxyl group, lower alkoxycarbonyl group, benzyloxy Carbonyl group, thiol group, lower alkylthio group, halogen Substituted with 1 to 3 substituents selected from the group consisting of a cyano group, a cyano group, a nitro group, a carbamoyl group, a lower alkylaminocarbonyl group, and an arylaminocarbonyl group, and X is a carbonyl group (—CO—) or a sulfonyl group (-SO 2 -) wherein indicating the (1), wherein the prolyl oligopeptidase inhibitor,
(3) In the general formula (1), R represents a lower alkyl group, a benzyl group, or a benzyloxy group. The lower alkyl group and the benzyl group may be substituted, and when the lower alkyl group is substituted, aryl When substituted with 1 to 3 substituents selected from the group consisting of a group, a heteroaryl group, a cycloalkyl group, an aryloxy group, an alkylthio group, and an N-protected amino group, and the benzyl group is substituted The prolyl oligopeptidase inhibitor according to the above (1), which is substituted with a lower alkoxy group or a nitro group, and X represents a carbonyl group (—CO—) or a sulfonyl group (—SO 2 —);
(4) In the general formula (1), R represents a lower alkyl group, a benzyl group, or a benzyloxy group, and the lower alkyl group and the benzyl group may be substituted, and when the lower alkyl group is substituted, aryl When substituted with 1 to 3 substituents selected from the group consisting of a group, a heteroaryl group, a cycloalkyl group, an aryloxy group, an alkylthio group, and an N-protected amino group, and the benzyl group is substituted The prolyl oligopeptidase inhibitor according to the above (1), which is substituted with a lower alkoxy group or a nitro group and represents an X carbonyl group (-CO-),
(5) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group Inhibition of prolyl oligopeptidase according to (1) above, wherein X is substituted with 1 to 2 substituents selected from the group consisting of a group, a cyclohexyl group and a benzyloxycarbonylamino group, and X represents a carbonyl group (—CO—) Agent,
(6)一般式(1)において、Rは低級アルキル基又はベンジルオキシ基を示し、低級アルキル基は置換されてもよく、置換される場合にはフェニル基、メトキシフェニル基、ニトロフェニル基、インドリル基、シクロヘキシル基、ベンジルオキシカルボニルアミノ基からなる群から選択される1〜2個の置換基で置換され、Xはカルボニル基(−CO−)を示し、Y及びZはどちらか一方は水素原子を示し、他方はスルホン酸基、低級アルキル基、アリール基、ヘテロアリール基、シクロアルキル基、低級アシル基、アリールカルボニル基、ヘテロアリールカルボニル基、シクロアルカンカルボニル基、低級アルケニルカルボニル基、低級アルキルアミノカルボニル基、又はアリールアミノカルボニル基を示し、それぞれの基は置換されてもよく、置換される場合には低級アルキル基、アリール基、ヘテロアリール基、低級アルコキシ基、アリールオキシ基、ベンジルオキシ基、ニトロ基、ハロゲン原子、水酸基、アミノ基、低級アルキルアミノ基、ジ低級アルキルアミノ基、N−保護アミノ基、カルボキシル基、低級アルコキシカルボニル基、又はシアノ基で置換される前記(1)記載のプロリルオリゴペプチダーゼ阻害剤、
(7)一般式(1)において、Rは低級アルキル基又はベンジルオキシ基を示し、低級アルキル基は置換されてもよく、置換される場合にはフェニル基、メトキシフェニル基、ニトロフェニル基、インドリル基、シクロヘキシル基、ベンジルオキシカルボニルアミノ基からなる群から選択される1〜2個の置換基で置換され、Xはカルボニル基(−CO−)を示し、Y及びZはどちらか一方は水素原子を示し、他方はスルホン酸基、低級アシル基、アリールカルボニル基、ヘテロアリールカルボニル基、シクロアルカンカルボニル基、低級アルケニルカルボニル基、又はアリールアミノカルボニル基を示し、それぞれの基は置換されてもよく、置換される場合には低級アルキル基、アリール基、低級アルコキシ基、アリールオキシ基、ベンジルオキシ基、ニトロ基、ハロゲン原子、又は水酸基で置換される前記(1)記載のプロリルオリゴペプチダーゼ阻害剤、
(8)一般式(1)において、Rは低級アルキル基又はベンジルオキシ基を示し、低級アルキル基は置換されてもよく、置換される場合にはフェニル基、メトキシフェニル基、ニトロフェニル基、インドリル基、シクロヘキシル基、ベンジルオキシカルボニルアミノ基からなる群から選択される1〜2個の置換基で置換され、Xはカルボニル基(−CO−)を示し、Y及びZはどちらか一方は水素原子を示し、他方はスルホン酸基、低級アシル基、又はアリールアミノカルボニル基を示し、低級アシル基及びアリールアミノカルボニル基は置換されてもよく、置換される場合には低級アルコキシ基、アリールオキシ基、ベンジルオキシ基、ハロゲン原子、又は水酸基で置換される前記(1)記載のプロリルオリゴペプチダーゼ阻害剤、
(9)一般式(1)において、Rは低級アルキル基又はベンジルオキシ基を示し、低級アルキル基は置換されてもよく、置換される場合にはフェニル基、メトキシフェニル基、ニトロフェニル基、インドリル基、シクロヘキシル基、ベンジルオキシカルボニルアミノ基からなる群から選択される1〜2個の置換基で置換され、Xはカルボニル基(−CO−)を示し、Y及びZはどちらか一方は水素原子を示し、他方はスルホン酸基、低級アシル基、又はフェニルアミノカルボニル基を示し、低級アシル基は置換されてもよく、置換される場合にはフェノキシ基、又はベンジルオキシ基で置換される前記(1)記載のプロリルオリゴペプチダーゼ阻害剤、
(10)一般式(1)において、Rは低級アルキル基又はベンジルオキシ基を示し、低級アルキル基は置換されてもよく、置換される場合にはフェニル基、メトキシフェニル基、ニトロフェニル基、インドリル基、シクロヘキシル基、ベンジルオキシカルボニルアミノ基からなる群から選択される1〜2個の置換基で置換され、Xはカルボニル基(−CO−)を示し、Y及びZはどちらか一方は水素原子を示し、他方はスルホン酸基、低級アシル基、又はフェニルアミノカルボニル基を示し、低級アシル基は置換されてもよく、置換される場合にはフェノキシ基、又はベンジルオキシ基で置換され、Qは−(CH2)2−を示す前記(1)記載のプロリルオリゴペプチダーゼ阻害剤、(6) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group Substituted with 1 to 2 substituents selected from the group consisting of a group, a cyclohexyl group and a benzyloxycarbonylamino group, X represents a carbonyl group (—CO—), and one of Y and Z represents a hydrogen atom. The other is a sulfonic acid group, lower alkyl group, aryl group, heteroaryl group, cycloalkyl group, lower acyl group, arylcarbonyl group, heteroarylcarbonyl group, cycloalkanecarbonyl group, lower alkenylcarbonyl group, lower alkylamino group Carbonyl group or arylaminocarbonyl group, each group is substituted Well, when substituted, lower alkyl group, aryl group, heteroaryl group, lower alkoxy group, aryloxy group, benzyloxy group, nitro group, halogen atom, hydroxyl group, amino group, lower alkylamino group, di-lower alkyl group The prolyl oligopeptidase inhibitor according to (1), which is substituted with an amino group, an N-protected amino group, a carboxyl group, a lower alkoxycarbonyl group, or a cyano group,
(7) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group Substituted with 1 to 2 substituents selected from the group consisting of a group, a cyclohexyl group and a benzyloxycarbonylamino group, X represents a carbonyl group (—CO—), and one of Y and Z represents a hydrogen atom. The other represents a sulfonic acid group, a lower acyl group, an arylcarbonyl group, a heteroarylcarbonyl group, a cycloalkanecarbonyl group, a lower alkenylcarbonyl group, or an arylaminocarbonyl group, each group may be substituted, When substituted, lower alkyl group, aryl group, lower alkoxy group, aryloxy group, benzine Oxy group, a nitro group, a halogen atom, or a hydroxyl group in the substituted (1), wherein the prolyl oligopeptidase inhibitor,
(8) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group Substituted with 1 to 2 substituents selected from the group consisting of a group, a cyclohexyl group and a benzyloxycarbonylamino group, X represents a carbonyl group (—CO—), and one of Y and Z represents a hydrogen atom. The other represents a sulfonic acid group, a lower acyl group, or an arylaminocarbonyl group, and the lower acyl group and the arylaminocarbonyl group may be substituted, and if substituted, a lower alkoxy group, an aryloxy group, The prolyl oligopeptidase inhibitor according to (1), which is substituted with a benzyloxy group, a halogen atom, or a hydroxyl group;
(9) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group Substituted with 1 to 2 substituents selected from the group consisting of a group, a cyclohexyl group and a benzyloxycarbonylamino group, X represents a carbonyl group (—CO—), and one of Y and Z represents a hydrogen atom. And the other represents a sulfonic acid group, a lower acyl group, or a phenylaminocarbonyl group, and the lower acyl group may be substituted, and when substituted, the above-mentioned substituted with a phenoxy group or a benzyloxy group ( 1) The prolyl oligopeptidase inhibitor according to the above,
(10) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group Substituted with 1 to 2 substituents selected from the group consisting of a group, a cyclohexyl group and a benzyloxycarbonylamino group, X represents a carbonyl group (—CO—), and one of Y and Z represents a hydrogen atom. The other represents a sulfonic acid group, a lower acyl group, or a phenylaminocarbonyl group, and the lower acyl group may be substituted, and if substituted, is substituted with a phenoxy group or a benzyloxy group, and Q is The prolyl oligopeptidase inhibitor according to (1), which represents-(CH 2 ) 2- ,
(11)一般式(1)において、Rはベンジルオキシ基を示すか、又はフェニル基、メトキシフェニル基、ニトロフェニル基、インドリル基、シクロヘキシル基、及びベンジルオキシカルボニルアミノ基からなる群から選択される1〜2個の置換基で置換されているメチル基又はエチル基を示し、Xはカルボニル基(−CO−)を示し、Y及びZはどちらか一方は水素原子を示し、他方はスルホン酸基、フェノキシアセチル基、ベンジルオキシアセチル基、又はフェニルアミノカルボニル基を示し、Qは−(CH2)2−を示す前記(1)記載のプロリルオリゴペプチダーゼ阻害剤、
(12)記憶及び認識障害を改善又は治療するための前記(1)〜(11)のいずれか一項に記載のプロリルオリゴペプチダーゼ阻害剤、
(13)記憶及び認識障害が健忘症である前記(12)記載のプロリルオリゴペプチダーゼ阻害剤、
(14)記憶及び認識障害が痴呆症である前記(12)記載のプロリルオリゴペプチダーゼ阻害剤、
(15)シャガス病を予防又は治療するための前記(1)〜(11)のいずれか一項に記載のプロリルオリゴペプチダーゼ阻害剤、(11) In the general formula (1), R represents a benzyloxy group or selected from the group consisting of a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group, a cyclohexyl group, and a benzyloxycarbonylamino group. 1 represents a methyl group or an ethyl group substituted with 1 to 2 substituents, X represents a carbonyl group (—CO—), one of Y and Z represents a hydrogen atom, and the other represents a sulfonic acid group. , A phenoxyacetyl group, a benzyloxyacetyl group, or a phenylaminocarbonyl group, and Q represents — (CH 2 ) 2 —, the prolyl oligopeptidase inhibitor according to the above (1),
(12) The prolyl oligopeptidase inhibitor according to any one of (1) to (11) above for improving or treating memory and cognitive impairment,
(13) The prolyl oligopeptidase inhibitor according to (12), wherein the memory and cognitive impairment is amnesia,
(14) The prolyl oligopeptidase inhibitor according to (12), wherein the memory and cognitive impairment is dementia,
(15) The prolyl oligopeptidase inhibitor according to any one of (1) to (11) above for preventing or treating Chagas disease,
(16)トリパノゾーマの細胞内への感染を阻害するための前記(15)記載のプロリルオリゴペプチダーゼ阻害剤、
(17)一般式(1)(16) The prolyl oligopeptidase inhibitor according to the above (15), which inhibits infection of trypanosomes into cells.
(17) General formula (1)
(式中、Rは水素原子、低級アルキル基、シクロアルキル基、アリール基、ヘテロアリール基、低級アルケニル基、低級アルキルアミノ基、アリールアミノ基、ヘテロアリールアミノ基、低級アルコキシ基、アリールオキシ基、ピロリジニル基、N−保護ピロリジニル基、ベンジル基、又はベンジルオキシ基を示し、それぞれの基は置換されてもよく、置換される場合には低級アルキル基、シクロアルキル基、アリール基、ヘテロアリール基、低級アルコキシ基、ベンジルオキシ基、アリールオキシ基、水酸基、アミノ基、低級アルキルアミノ基、ジ低級アルキルアミノ基、N−保護アミノ基、カルボキシル基、低級アルコキシカルボニル基、ベンジルオキシカルボニル基、チオール基、低級アルキルチオ基、ハロゲン原子、シアノ基、ニトロ基、カルバモイル基、低級アルキルアミノカルボニル基、又はアリールアミノカルボニル基で置換される。Xはカルボニル基(−CO−)、チオカルボニル基(−CS−)、又はスルホニル基(−SO2−)を示す。Y及びZは同一又は異なっていてよく、水素原子、スルホン酸基、低級アルキル基、アリール基、ヘテロアリール基、シクロアルキル基、低級アシル基、アリールカルボニル基、ヘテロアリールカルボニル基、シクロアルカンカルボニル基、低級アルケニルカルボニル基、低級アルキルアミノカルボニル基、又はアリールアミノカルボニル基を示し、それぞれの基は置換されてもよく、置換される場合には低級アルキル基、アリール基、ヘテロアリール基、低級アルコキシ基、アリールオキシ基、ベンジルオキシ基、ニトロ基、ハロゲン原子、水酸基、アミノ基、低級アルキルアミノ基、ジ低級アルキルアミノ基、N−保護アミノ基、カルボキシル基、低級アルコキシカルボニル基、又はシアノ基で置換される。Qは−(CH2)n−(nは0〜3を示す)を示す。但し、Rがベンジルオキシ基、Xがカルボニル基(−CO−)であり、かつY及びZの両方が水素原子の組み合わせと、Y及びZの一方が水素原子で他方がスルホン酸基の組み合わせである化合物群は除く。)で表されるα−アシルアミノ−N−(ジアミノホスフィニル)ラクタム誘導体又はその薬理学的に許容される塩、
(18)一般式(1)において、Rは水素原子、低級アルキル基、シクロアルキル基、アリール基、ヘテロアリール基、低級アルケニル基、低級アルキルアミノ基、アリールアミノ基、ヘテロアリールアミノ基、低級アルコキシ基、アリールオキシ基、ピロリジニル基、N−保護ピロリジニル基、ベンジル基、又はベンジルオキシ基を示し、それぞれの基は置換されてもよく、置換される場合には低級アルキル基、シクロアルキル基、アリール基、ヘテロアリール基、低級アルコキシ基、ベンジルオキシ基、アリールオキシ基、水酸基、アミノ基、低級アルキルアミノ基、ジ低級アルキルアミノ基、N−保護アミノ基、カルボキシル基、低級アルコキシカルボニル基、ベンジルオキシカルボニル基、チオール基、低級アルキルチオ基、ハロゲン原子、シアノ基、ニトロ基、カルバモイル基、低級アルキルアミノカルボニル基、及びアリールアミノカルボニル基からなる群から選択される1〜3個の置換基で置換され、Xはカルボニル基(−CO−)又はスルホニル基(−SO2−)を示す前記(17)記載のα−アシルアミノ−N−(ジアミノホスフィニル)ラクタム誘導体又はその薬理学的に許容される塩、
(19)一般式(1)において、Rは低級アルキル基、ベンジル基、又はベンジルオキシ基を示し、低級アルキル基並びにベンジル基は置換されてもよく、低級アルキル基が置換される場合にはアリール基、ヘテロアリール基、シクロアルキル基、アリールオキシ基、アルキルチオ基、及びN−保護アミノ基からなる群から選択される1〜3個の置換基で置換され、ベンジル基が置換される場合には低級アルコキシ基又はニトロ基で置換されることを示し、Xはカルボニル基(−CO−)又はスルホニル基(−SO2−)を示す前記(17)記載のα−アシルアミノ−N−(ジアミノホスフィニル)ラクタム誘導体又はその薬理学的に許容される塩、
(20)一般式(1)において、Rは低級アルキル基、ベンジル基、又はベンジルオキシ基を示し、低級アルキル基並びにベンジル基は置換されてもよく、低級アルキル基が置換される場合にはアリール基、ヘテロアリール基、シクロアルキル基、アリールオキシ基、アルキルチオ基、及びN−保護アミノ基からなる群から選択される1〜3個の置換基で置換され、ベンジル基が置換される場合には低級アルコキシ基又はニトロ基で置換され、Xはカルボニル基(−CO−)を示す前記(17)記載のα−アシルアミノ−N−(ジアミノホスフィニル)ラクタム誘導体又はその薬理学的に許容される塩、Wherein R is a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a lower alkenyl group, a lower alkylamino group, an arylamino group, a heteroarylamino group, a lower alkoxy group, an aryloxy group, Pyrrolidinyl group, N-protected pyrrolidinyl group, benzyl group, or benzyloxy group, each group may be substituted, and when substituted, a lower alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, Lower alkoxy group, benzyloxy group, aryloxy group, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group, N-protected amino group, carboxyl group, lower alkoxycarbonyl group, benzyloxycarbonyl group, thiol group, Lower alkylthio group, halogen atom, cyano group, nito Group, carbamoyl group, lower alkylaminocarbonyl group, or .X substituted with arylaminocarbonyl group carbonyl group (-CO-), a thiocarbonyl group (-CS-), or a sulfonyl group - a (-SO 2) Y and Z may be the same or different, and may be a hydrogen atom, a sulfonic acid group, a lower alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a lower acyl group, an arylcarbonyl group, a heteroarylcarbonyl group, a cycloalkane. A carbonyl group, a lower alkenylcarbonyl group, a lower alkylaminocarbonyl group, or an arylaminocarbonyl group, each group may be substituted, and when substituted, the lower alkyl group, aryl group, heteroaryl group, lower group Alkoxy group, aryloxy group, benzyloxy group, nitro Group, halogen atom, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group, N-protected amino group, carboxyl group, lower alkoxycarbonyl group, or cyano group, Q is — (CH 2 ). n- (n represents 0 to 3), provided that R is a benzyloxy group, X is a carbonyl group (-CO-), and both Y and Z are a combination of hydrogen atoms, Y and Z An α-acylamino-N- (diaminophosphinyl) lactam derivative represented by the following formula: or a pharmacologically acceptable salt thereof:
(18) In the general formula (1), R represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a lower alkenyl group, a lower alkylamino group, an arylamino group, a heteroarylamino group, or a lower alkoxy. Group, aryloxy group, pyrrolidinyl group, N-protected pyrrolidinyl group, benzyl group, or benzyloxy group, each group may be substituted, and when substituted, lower alkyl group, cycloalkyl group, aryl Group, heteroaryl group, lower alkoxy group, benzyloxy group, aryloxy group, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group, N-protected amino group, carboxyl group, lower alkoxycarbonyl group, benzyloxy Carbonyl group, thiol group, lower alkylthio group, halogen Substituted with 1 to 3 substituents selected from the group consisting of an atom, a cyano group, a nitro group, a carbamoyl group, a lower alkylaminocarbonyl group, and an arylaminocarbonyl group, and X is a carbonyl group (—CO—) or An α-acylamino-N- (diaminophosphinyl) lactam derivative or a pharmaceutically acceptable salt thereof according to (17), which represents a sulfonyl group (—SO 2 —);
(19) In the general formula (1), R represents a lower alkyl group, a benzyl group, or a benzyloxy group. The lower alkyl group and the benzyl group may be substituted, and when the lower alkyl group is substituted, aryl When substituted with 1 to 3 substituents selected from the group consisting of a group, a heteroaryl group, a cycloalkyl group, an aryloxy group, an alkylthio group, and an N-protected amino group, and the benzyl group is substituted Α-acylamino-N- (diaminophosphini) described in the above (17), wherein X represents a carbonyl group (—CO—) or a sulfonyl group (—SO 2 —). E) lactam derivatives or pharmacologically acceptable salts thereof,
(20) In the general formula (1), R represents a lower alkyl group, a benzyl group, or a benzyloxy group. The lower alkyl group and the benzyl group may be substituted, and when the lower alkyl group is substituted, aryl When substituted with 1 to 3 substituents selected from the group consisting of a group, a heteroaryl group, a cycloalkyl group, an aryloxy group, an alkylthio group, and an N-protected amino group, and the benzyl group is substituted The α-acylamino-N- (diaminophosphinyl) lactam derivative according to the above (17), which is substituted with a lower alkoxy group or a nitro group and X represents a carbonyl group (—CO—), or a pharmacologically acceptable salt thereof salt,
(21)一般式(1)において、Rは低級アルキル基又はベンジルオキシ基を示し、低級アルキル基は置換されてもよく、置換される場合にはフェニル基、メトキシフェニル基、ニトロフェニル基、インドリル基、シクロヘキシル基、ベンジルオキシカルボニルアミノ基からなる群から選択される1〜2個の置換基で置換され、Xはカルボニル基(−CO−)を示す前記(17)記載のα−アシルアミノ−N−(ジアミノホスフィニル)ラクタム誘導体又はその薬理学的に許容される塩、
(22)一般式(1)において、Rは低級アルキル基又はベンジルオキシ基を示し、低級アルキル基は置換されてもよく、置換される場合にはフェニル基、メトキシフェニル基、ニトロフェニル基、インドリル基、シクロヘキシル基、ベンジルオキシカルボニルアミノ基からなる群から選択される1〜2個の置換基で置換され、Xはカルボニル基(−CO−)を示し、Y及びZはどちらか一方は水素原子を示し、他方はスルホン酸基、低級アルキル基、アリール基、ヘテロアリール基、シクロアルキル基、低級アシル基、アリールカルボニル基、ヘテロアリールカルボニル基、シクロアルカンカルボニル基、低級アルケニルカルボニル基、低級アルキルアミノカルボニル基、又はアリールアミノカルボニル基を示し、それぞれの基は置換されてもよく、置換される場合には低級アルキル基、アリール基、ヘテロアリール基、低級アルコキシ基、アリールオキシ基、ベンジルオキシ基、ニトロ基、ハロゲン原子、水酸基、アミノ基、低級アルキルアミノ基、ジ低級アルキルアミノ基、N−保護アミノ基、カルボキシル基、低級アルコキシカルボニル基、又はシアノ基で置換される前記(17)記載のα−アシルアミノ−N−(ジアミノホスフィニル)ラクタム誘導体又はその薬理学的に許容される塩、
(23)一般式(1)において、Rは低級アルキル基又はベンジルオキシ基を示し、低級アルキル基は置換されてもよく、置換される場合にはフェニル基、メトキシフェニル基、ニトロフェニル基、インドリル基、シクロヘキシル基、ベンジルオキシカルボニルアミノ基からなる群から選択される1〜2個の置換基で置換され、Xはカルボニル基(−CO−)を示し、Y及びZはどちらか一方は水素原子を示し、他方はスルホン酸基、低級アシル基、アリールカルボニル基、ヘテロアリールカルボニル基、シクロアルカンカルボニル基、低級アルケニルカルボニル基、又はアリールアミノカルボニル基を示し、それぞれの基は置換されてもよく、置換される場合には低級アルキル基、アリール基、低級アルコキシ基、アリールオキシ基、ベンジルオキシ基、ニトロ基、ハロゲン原子、又は水酸基で置換される前記(17)記載のα−アシルアミノ−N−(ジアミノホスフィニル)ラクタム誘導体又はその薬理学的に許容される塩、
(24)一般式(1)において、Rは低級アルキル基又はベンジルオキシ基を示し、低級アルキル基は置換されてもよく、置換される場合にはフェニル基、メトキシフェニル基、ニトロフェニル基、インドリル基、シクロヘキシル基、ベンジルオキシカルボニルアミノ基からなる群から選択される1〜2個の置換基で置換され、Xはカルボニル基(−CO−)を示し、Y及びZはどちらか一方は水素原子を示し、他方はスルホン酸基、低級アシル基、又はアリールアミノカルボニル基を示し、低級アシル基及びアリールアミノカルボニル基は置換されてもよく、置換される場合には低級アルコキシ基、アリールオキシ基、ベンジルオキシ基、ハロゲン原子、又は水酸基で置換される前記(17)記載のα−アシルアミノ−N−(ジアミノホスフィニル)ラクタム誘導体又はその薬理学的に許容される塩、
(25)一般式(1)において、Rは低級アルキル基又はベンジルオキシ基を示し、低級アルキル基は置換されてもよく、置換される場合にはフェニル基、メトキシフェニル基、ニトロフェニル基、インドリル基、シクロヘキシル基、ベンジルオキシカルボニルアミノ基からなる群から選択される1〜2個の置換基で置換され、Xはカルボニル基(−CO−)を示し、Y及びZはどちらか一方は水素原子を示し、他方はスルホン酸基、低級アシル基、又はフェニルアミノカルボニル基を示し、低級アシル基は置換されてもよく、置換される場合にはフェノキシ基、又はベンジルオキシ基で置換される前記(17)記載のα−アシルアミノ−N−(ジアミノホスフィニル)ラクタム誘導体又はその薬理学的に許容される塩、(21) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group Α-acylamino-N described in the above (17), which is substituted with 1 to 2 substituents selected from the group consisting of a group, a cyclohexyl group and a benzyloxycarbonylamino group, wherein X represents a carbonyl group (—CO—) -(Diaminophosphinyl) lactam derivative or a pharmacologically acceptable salt thereof,
(22) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group Substituted with 1 to 2 substituents selected from the group consisting of a group, a cyclohexyl group and a benzyloxycarbonylamino group, X represents a carbonyl group (—CO—), and one of Y and Z represents a hydrogen atom. The other is a sulfonic acid group, lower alkyl group, aryl group, heteroaryl group, cycloalkyl group, lower acyl group, arylcarbonyl group, heteroarylcarbonyl group, cycloalkanecarbonyl group, lower alkenylcarbonyl group, lower alkylamino group Carbonyl group or arylaminocarbonyl group, each group is substituted If substituted, a lower alkyl group, aryl group, heteroaryl group, lower alkoxy group, aryloxy group, benzyloxy group, nitro group, halogen atom, hydroxyl group, amino group, lower alkylamino group, di-lower group The α-acylamino-N- (diaminophosphinyl) lactam derivative according to the above (17), which is substituted with an alkylamino group, an N-protected amino group, a carboxyl group, a lower alkoxycarbonyl group, or a cyano group, or a pharmacological thereof Acceptable salt,
(23) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group Substituted with 1 to 2 substituents selected from the group consisting of a group, a cyclohexyl group and a benzyloxycarbonylamino group, X represents a carbonyl group (—CO—), and one of Y and Z represents a hydrogen atom. The other represents a sulfonic acid group, a lower acyl group, an arylcarbonyl group, a heteroarylcarbonyl group, a cycloalkanecarbonyl group, a lower alkenylcarbonyl group, or an arylaminocarbonyl group, each group may be substituted, When substituted, the lower alkyl group, aryl group, lower alkoxy group, aryloxy group, Aryloxy group, a nitro group, a halogen atom, or wherein is substituted with a hydroxyl group (17), wherein the α- acylamino -N- (diamino phosphinyl) lactam derivative or a pharmacologically acceptable salt thereof,
(24) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group Substituted with 1 to 2 substituents selected from the group consisting of a group, a cyclohexyl group and a benzyloxycarbonylamino group, X represents a carbonyl group (—CO—), and one of Y and Z represents a hydrogen atom. The other represents a sulfonic acid group, a lower acyl group, or an arylaminocarbonyl group, and the lower acyl group and the arylaminocarbonyl group may be substituted, and if substituted, a lower alkoxy group, an aryloxy group, Α-Acylamino-N- (diaminophos) described in the above (17) substituted with a benzyloxy group, a halogen atom or a hydroxyl group Iniru) lactam derivative or a pharmacologically acceptable salt thereof,
(25) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group Substituted with 1 to 2 substituents selected from the group consisting of a group, a cyclohexyl group and a benzyloxycarbonylamino group, X represents a carbonyl group (—CO—), and one of Y and Z represents a hydrogen atom. And the other represents a sulfonic acid group, a lower acyl group, or a phenylaminocarbonyl group, and the lower acyl group may be substituted, and when substituted, the above-mentioned substituted with a phenoxy group or a benzyloxy group ( 17) α-acylamino-N- (diaminophosphinyl) lactam derivative or a pharmaceutically acceptable salt thereof according to 17),
(26)一般式(1)において、Rは低級アルキル基又はベンジルオキシ基を示し、低級アルキル基は置換されてもよく、置換される場合にはフェニル基、メトキシフェニル基、ニトロフェニル基、インドリル基、シクロヘキシル基、ベンジルオキシカルボニルアミノ基からなる群から選択される1〜2個の置換基で置換されることを示し、Xはカルボニル基(−CO−)を示し、Y及びZはどちらか一方は水素原子を示し、他方はスルホン酸基、低級アシル基、又はフェニルアミノカルボニル基を示し、低級アシル基は置換されてもよく、置換される場合にはフェノキシ基、又はベンジルオキシ基で置換される、Qは−(CH2)2−を示す前記(17)記載のα−アシルアミノ−N−(ジアミノホスフィニル)ラクタム誘導体又はその薬理学的に許容される塩、
(27)一般式(1)において、Rはベンジルオキシ基を示すか、又はフェニル基、メトキシフェニル基、ニトロフェニル基、インドリル基、シクロヘキシル基、及びベンジルオキシカルボニルアミノ基からなる群から選択される1〜2個の置換基で置換されているメチル基又はエチル基を示し、Xはカルボニル基(−CO−)を示し、Y及びZはどちらか一方は水素原子を示し、他方はスルホン酸基、フェノキシアセチル基、ベンジルオキシアセチル基、又はフェニルアミノカルボニル基を示し、Qは−(CH2)2−を示す前記(17)記載のα−アシルアミノ−N−(ジアミノホスフィニル)ラクタム誘導体又はその薬理学的に許容される塩、
(28)前記(17)〜(27)のいずれか一項に記載の化合物又はその薬理学的に許容される塩を有効成分とする哺乳動物の医薬品又は疾病の予防若しくは治療剤。(26) In the general formula (1), R represents a lower alkyl group or a benzyloxy group, and the lower alkyl group may be substituted, and when substituted, a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group X represents a carbonyl group (—CO—), and Y and Z are either ones selected from the group consisting of a group consisting of a group, a cyclohexyl group, and a benzyloxycarbonylamino group. One represents a hydrogen atom, the other represents a sulfonic acid group, a lower acyl group, or a phenylaminocarbonyl group. The lower acyl group may be substituted, and if substituted, is substituted with a phenoxy group or a benzyloxy group. is the, Q is - (CH 2) 2 - wherein showing the (17) alpha-acylamino -N- (diamino phosphinyl) according lactam derivative or its Pharmacologically acceptable salts,
(27) In the general formula (1), R represents a benzyloxy group or selected from the group consisting of a phenyl group, a methoxyphenyl group, a nitrophenyl group, an indolyl group, a cyclohexyl group, and a benzyloxycarbonylamino group. 1 represents a methyl group or an ethyl group substituted with 1 to 2 substituents, X represents a carbonyl group (—CO—), one of Y and Z represents a hydrogen atom, and the other represents a sulfonic acid group. , A phenoxyacetyl group, a benzyloxyacetyl group, or a phenylaminocarbonyl group, and Q represents — (CH 2 ) 2 —, α-acylamino-N- (diaminophosphinyl) lactam derivative or Its pharmacologically acceptable salts,
(28) A pharmaceutical or preventive or therapeutic agent for mammals comprising the compound according to any one of (17) to (27) or a pharmacologically acceptable salt thereof as an active ingredient.
本発明によれば、スルフォスチン誘導体の新規な用途としてプロリルオリゴペプチダーゼ阻害作用が提供され、また新規な化合物としてα−アシルアミノ−N−(ジアミノホスフィニル)ラクタム誘導体が提供される。また本発明によれば、新規な記憶及び認識障害改善剤が提供され、更には新規なα−アシルアミノ−N−(ジアミノホスフィニル)ラクタム誘導体を有効成分とする哺乳動物の医薬が提供される。 According to the present invention, a prolyl oligopeptidase inhibitory action is provided as a novel use of a sulfostine derivative, and an α-acylamino-N- (diaminophosphinyl) lactam derivative is provided as a novel compound. In addition, according to the present invention, a novel memory and cognitive impairment improving agent is provided, and further, a mammalian pharmaceutical comprising a novel α-acylamino-N- (diaminophosphinyl) lactam derivative as an active ingredient is provided. .
本発明において、低級アルキル基とは炭素数1〜6の直鎖又は分岐鎖のアルキル基を示し、例えばメチル基、エチル基,n−プロピル基、イソプロピル基,n−ブチル基、sec−ブチル基、tert−ブチル基、n−ペンチル基、n−ヘキシル基等を挙げることができる。これらのうち、好ましい基としてはメチル基、エチル基、n−プロピル基、イソプロピル基、n−ブチル基、イソブチル基を挙げることができる。更に好ましくはメチル基、エチル基が挙げられる。 In the present invention, the lower alkyl group represents a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group. Tert-butyl group, n-pentyl group, n-hexyl group and the like. Among these, preferred groups include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and an isobutyl group. More preferably, a methyl group and an ethyl group are mentioned.
本発明において、アリール基とは炭素数6〜14の芳香族炭化水素基を示し、例えばフェニル基、ビフェニル基、ナフチル基、アントリル基、フェナントリル基等を挙げることができる。これらのうち、好ましい基としてはフェニル基を挙げることができる。 In the present invention, the aryl group represents an aromatic hydrocarbon group having 6 to 14 carbon atoms, and examples thereof include a phenyl group, a biphenyl group, a naphthyl group, an anthryl group, and a phenanthryl group. Among these, a preferred group is a phenyl group.
本発明において、ヘテロアリール基とはヘテロ原子として窒素原子、酸素原子又は硫黄原子を同一の又は異なるヘテロ原子として1〜3個含む複素芳香族基を示し、例えばフリル基、チエニル基、イミダゾリル基、オキサゾリル基、チアゾリル基、ピリジル基、インドリル基、ピリミジニル基、ピリダジニル基等を挙げることができる。これらのうち、好ましい基としてはピリジル基、インドリル基を挙げることができる。 In the present invention, the heteroaryl group means a heteroaromatic group containing 1 to 3 of the same or different heteroatoms as nitrogen atoms, oxygen atoms or sulfur atoms as heteroatoms, such as a furyl group, a thienyl group, an imidazolyl group, An oxazolyl group, a thiazolyl group, a pyridyl group, an indolyl group, a pyrimidinyl group, a pyridazinyl group, and the like can be given. Among these, preferred groups include a pyridyl group and an indolyl group.
本発明において、低級アルコキシ基とは低級アルキルオキシ基のことで低級アルキル基は前述の通り、炭素数1〜6の直鎖又は分岐鎖のアルキル基を示し、例えばメトキシ基、エトキシ基、n−プロポキシ基、イソプロポキシ基、n−ブトキシ基、イソブトキシ基、tert−ブトキシ基等を挙げることができる。これらのうち、好ましい基としてはメトキシ基、エトキシ基、tert−ブトキシ基を挙げることができる。 In the present invention, the lower alkoxy group means a lower alkyloxy group, and the lower alkyl group represents a linear or branched alkyl group having 1 to 6 carbon atoms as described above, for example, methoxy group, ethoxy group, n- Examples thereof include a propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, and a tert-butoxy group. Among these, preferred groups include a methoxy group, an ethoxy group, and a tert-butoxy group.
本発明において、アリールオキシ基のアリール基は前述の通り、炭素数6〜14の芳香族炭化水素基を示し、例えば、フェノキシ基、ナフトキシ基、ビフェニルオキシ基、アントリルオキシ基、フェナントリルオキシ基等を挙げることができる。これらのうち、好ましい基としてはフェノキシ基、ナフトキシ基を挙げることができる。 In the present invention, as described above, the aryl group of the aryloxy group represents an aromatic hydrocarbon group having 6 to 14 carbon atoms, such as a phenoxy group, a naphthoxy group, a biphenyloxy group, an anthryloxy group, a phenanthryloxy group. Groups and the like. Of these, preferred groups include a phenoxy group and a naphthoxy group.
本発明において、低級アルケニル基とは炭素数2〜6の直鎖又は分岐鎖のアルケニル基を示し、例えばビニル基、アリル基、イソプロペニル基、3−ブテニル基等を挙げることができる。これらのうち、好ましい基としてはビニル基を挙げることができる。 In the present invention, the lower alkenyl group means a straight or branched alkenyl group having 2 to 6 carbon atoms, and examples thereof include a vinyl group, an allyl group, an isopropenyl group, and a 3-butenyl group. Among these, a preferable group is a vinyl group.
本発明において、シクロアルキル基とは炭素数3〜8の飽和環状炭化水素基を示し、例えばシクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基、シクロオクチル基を挙げることができる。これらのうち、好ましい基としてはシクロペンチル基、シクロヘキシル基を挙げることができる。 In the present invention, the cycloalkyl group represents a saturated cyclic hydrocarbon group having 3 to 8 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. Of these, preferred groups include a cyclopentyl group and a cyclohexyl group.
本発明において、ハロゲン原子とはフッ素原子、塩素原子、臭素原子、ヨウ素原子を示す。これらのうち、好ましい原子としてはフッ素原子、塩素原子、臭素原子を挙げることができる。 In the present invention, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Among these, preferred atoms include a fluorine atom, a chlorine atom, and a bromine atom.
本発明において、低級アルキルアミノ基とは前述の低級アルキル基が結合したアミノ基を示し、例えばメチルアミノ基、エチルアミノ基、n−プロピルアミノ基、イソプロピルアミノ基、n−ブチルアミノ基、n−ヘキシルアミノ基等を挙げることができる。これらのうち、好ましい基としてはメチルアミノ基、エチルアミノ基、n−プロピルアミノ基を挙げることができる。 In the present invention, the lower alkylamino group refers to an amino group to which the above-mentioned lower alkyl group is bonded. For example, a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, an n-butylamino group, an n- A hexylamino group etc. can be mentioned. Of these, preferred groups include a methylamino group, an ethylamino group, and an n-propylamino group.
本発明において、ジ低級アルキルアミノ基とは前述の低級アルキル基が二つ結合したアミノ基を示し、例えばジメチルアミノ基、ジエチルアミノ基、ジn−プロピルアミノ基等を挙げることができる。これらのうち、好ましい基としてはジメチルアミノ基、ジエチルアミノ基を挙げることができる。 In the present invention, the di-lower alkylamino group represents an amino group in which two of the aforementioned lower alkyl groups are bonded, and examples thereof include a dimethylamino group, a diethylamino group, and a di-n-propylamino group. Of these, preferred groups include a dimethylamino group and a diethylamino group.
本発明において、低級アルコキシカルボニル基とは前述の低級アルコキシ基にカルボニルが結合した基を示し、例えばメトキシカルボニル基、エトキシカルボニル基、n−プロポキシカルボニル基、イソプロポキシカルボニル基、n−ブトキシカルボニル基、イソブトキシカルボニル基、tert−ブトキシカルボニル基等を挙げることができる。これらのうち、好ましい基としてはメトキシカルボニル基、エトキシカルボニル基を挙げることができる。 In the present invention, the lower alkoxycarbonyl group refers to a group in which a carbonyl is bonded to the above-mentioned lower alkoxy group, such as a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, An isobutoxycarbonyl group, a tert-butoxycarbonyl group, etc. can be mentioned. Of these, preferred groups include a methoxycarbonyl group and an ethoxycarbonyl group.
本発明において、アリールアミノ基とは前述のアリール基にアミノ基が結合した基を示し、例えばフェニルアミノ基、ビフェニルアミノ基、ナフチルアミノ基、アントリルアミノ基、フェナントリルアミノ基等を挙げることができる。これらのうち、好ましい基としてはフェニルアミノ基を挙げることができる。 In the present invention, the arylamino group means a group in which an amino group is bonded to the aforementioned aryl group, and examples thereof include a phenylamino group, a biphenylamino group, a naphthylamino group, an anthrylamino group, a phenanthrylamino group, and the like. Can do. Of these, a preferred group includes a phenylamino group.
本発明において、ヘテロアリールアミノ基とは前述のヘテロアリール基にアミノ基が結合した基を示し、例えばフリルアミノ基、チエニルアミノ基、イミダゾリルアミノ基、オキサゾリルアミノ基、チアゾリルアミノ基、ピリジルアミノ基、インドリルアミノ基、ピリミジニルアミノ基、ピリダジニルアミノ基等を挙げることができる。これらのうち、好ましい基としてはピリジルアミノ基、フリルアミノ基を挙げることができる。 In the present invention, the heteroarylamino group refers to a group in which an amino group is bonded to the above-described heteroaryl group, such as a furylamino group, a thienylamino group, an imidazolylamino group, an oxazolylamino group, a thiazolylamino group, a pyridylamino group, An indolylamino group, a pyrimidinylamino group, a pyridazinylamino group, and the like can be given. Among these, preferred groups include a pyridylamino group and a furylamino group.
本発明において、低級アルキルアミノカルボニル基とは前述の低級アルキルアミノ基が結合したカルボニル基を示し、例えばメチルアミノカルボニル基、エチルアミノカルボニル基、n−プロピルアミノカルボニル基、イソプロピルアミノカルボニル基、n−ブチルアミノカルボニル基等を挙げることができる。これらのうち、好ましい基としてはエチルアミノ基、n−プロピルアミノ基を挙げることができる。 In the present invention, the lower alkylaminocarbonyl group refers to a carbonyl group to which the above-mentioned lower alkylamino group is bonded. For example, a methylaminocarbonyl group, an ethylaminocarbonyl group, an n-propylaminocarbonyl group, an isopropylaminocarbonyl group, an n- A butylaminocarbonyl group etc. can be mentioned. Of these, preferred groups include an ethylamino group and an n-propylamino group.
本発明において、アリールアミノカルボニル基とは前述のアリールアミノ基にカルボニル基が結合した基を示し、例えばフェニルアミノカルボニル基、ビフェニルアミノカルボニル基、ナフチルアミノカルボニル基、アントリルアミノカルボニル基、フェナントリルアミノカルボニル基等を挙げることができる。これらのうち、好ましい基としてはフェニルアミノカルボニル基を挙げることができる。 In the present invention, the arylaminocarbonyl group means a group in which a carbonyl group is bonded to the above-mentioned arylamino group, for example, phenylaminocarbonyl group, biphenylaminocarbonyl group, naphthylaminocarbonyl group, anthrylaminocarbonyl group, phenanthryl. An aminocarbonyl group etc. can be mentioned. Of these, a preferred group is a phenylaminocarbonyl group.
本発明において、低級アシル基とは前述の低級アルキル基にカルボニル基が結合した基を示し、例えばアセチル基、プロピオニル基、ブタノイル基、ペンタノイル基等を挙げることができる。これらのうち、好ましい基としてアセチル基を挙げることができる。 In the present invention, the lower acyl group means a group in which a carbonyl group is bonded to the above-mentioned lower alkyl group, and examples thereof include an acetyl group, a propionyl group, a butanoyl group, and a pentanoyl group. Of these, preferred examples include acetyl groups.
本発明において、アリールカルボニル基とは前述のアリール基にカルボニル基が結合した基を示し、例えばベンゾイル基、ナフトイル基等を挙げることができる。これらのうち、好ましい基としてベンゾイル基を挙げることができる。 In the present invention, the arylcarbonyl group refers to a group in which a carbonyl group is bonded to the aforementioned aryl group, and examples thereof include a benzoyl group and a naphthoyl group. Among these, a benzoyl group can be mentioned as a preferred group.
本発明において、ヘテロアリールカルボニル基とは前述のヘテロアリール基にカルボニル基が結合した基を示し、例えばニコチノイル基、イソニコチノイル基、チオフェンカルボニル基、ピラジンカルボニル基、フロイル基等を挙げることができる。これらのうち好ましい基としてチオフェンカルボニル基を挙げることができる。 In the present invention, the heteroarylcarbonyl group refers to a group in which a carbonyl group is bonded to the above-described heteroaryl group, and examples thereof include a nicotinoyl group, an isonicotinoyl group, a thiophenecarbonyl group, a pyrazinecarbonyl group, and a furoyl group. Among these, a preferred group is a thiophenecarbonyl group.
本発明において、シクロアルカンカルボニル基とは前述のシクロアルキル基にカルボニル基が結合した基を示し、例えばシクロプロパンカルボニル基、シクロブタンカルボニル基、シクロペンタンカルボニル基、シクロヘキサンカルボニル基、シクロヘプタンカルボニル基、シクロオクタンカルボニル基等を挙げることができる。これらのうち、好ましい基としてシクロヘキサンカルボニル基を挙げることができる。 In the present invention, the cycloalkanecarbonyl group refers to a group in which a carbonyl group is bonded to the above-described cycloalkyl group. For example, a cyclopropanecarbonyl group, a cyclobutanecarbonyl group, a cyclopentanecarbonyl group, a cyclohexanecarbonyl group, a cycloheptanecarbonyl group, a cyclohexane group, An octanecarbonyl group etc. can be mentioned. Among these, a preferred group is a cyclohexanecarbonyl group.
本発明において、低級アルケニルカルボニル基とは前述の低級アルケニル基にカルボニル基が結合した基を示し、例えばアクリロイル基、クロトニル基、ビニルアセチル基、4−ペンテノイル基等を挙げることができる。これらのうち、好ましい基としてアクリロイル基を挙げることができる。 In the present invention, the lower alkenylcarbonyl group refers to a group in which a carbonyl group is bonded to the aforementioned lower alkenyl group, and examples thereof include an acryloyl group, a crotonyl group, a vinylacetyl group, and a 4-pentenoyl group. Among these, acryloyl group can be mentioned as a preferable group.
本発明において、低級アルキルチオ基とは前述の低級アルキル基が結合したチオール基を示し、例えばメチルチオ基、エチルチオ基、n−プロピルチオ基、イソプロピルチオ基、n−ブチルチオ基、n−ヘキシルチオ基等を挙げることができる。これらのうち、好ましい基としてはメチルチオ基を挙げることができる。 In the present invention, the lower alkylthio group means a thiol group to which the aforementioned lower alkyl group is bonded, and examples thereof include a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, and an n-hexylthio group. be able to. Among these, a preferred group is a methylthio group.
本発明において、N−保護アミノ基とは通常使われているアミンの保護基が結合したアミノ基を示し、アミンの保護基としてはアシル型、カルバメート型、イミド型などがあり、例えばアシル型ではアセチル基、プロパノイル基、ブタノイル基、ペンタノイル基、アクリロイル基、クロトニル基、シクロプロパンカルボニル基、シクロブタンカルボニル基、シクロペンタンカルボニル基、シクロヘキサンカルボニル基、シクロヘプタンカルボニル基等が挙げられる。また、カルバメート型では、置換基を有していてもよいベンジルオキシカルボニル基、tert−ブトキシカルボニル基、9−フルオレニルメトキシカルボニル基等が、イミド型ではフタロイル基等が挙げられる。これらのうち、好ましい保護基としてはアセチル基、プロパノイル基、ブタノイル基、シクロヘキサンカルボニル基、ベンジルオキシカルボニル基、tert−ブトキシカルボニル基を挙げることができる。 In the present invention, the N-protected amino group refers to an amino group to which a commonly used amine protecting group is bonded. Examples of the amine protecting group include an acyl type, a carbamate type, and an imide type. Examples include acetyl group, propanoyl group, butanoyl group, pentanoyl group, acryloyl group, crotonyl group, cyclopropanecarbonyl group, cyclobutanecarbonyl group, cyclopentanecarbonyl group, cyclohexanecarbonyl group, cycloheptanecarbonyl group and the like. In the carbamate type, an optionally substituted benzyloxycarbonyl group, tert-butoxycarbonyl group, 9-fluorenylmethoxycarbonyl group and the like are exemplified, and in the imide type, a phthaloyl group and the like are mentioned. Among these, preferred protecting groups include acetyl group, propanoyl group, butanoyl group, cyclohexanecarbonyl group, benzyloxycarbonyl group, and tert-butoxycarbonyl group.
本発明において、N−保護ピロリジニル基とはアミンに保護基が結合したピロリジニル基を示し、アミンの保護基とは前述の通りで、例えばN−アセチルピロリジニル基、N−プロパノイルピロリジニル基、N−ブタノイルピロリジニル基、N−(シクロヘキサンカルボニル)ピロリジニル基、置換基を有していてもよいN−(ベンジルオキシカルボニル)ピロリジニル基、N−(tert−ブトキシカルボニル)ピロリジニル基、N−フタロイルピロリジニル基等が挙げられる。これらのうち、好ましい保護基としてはN−アセチルピロリジニル基、N−プロパノイルピロリジニル基、N−ブタノイルピロリジニル基、N−(シクロヘキサンカルボニル)ピロリジニル基、N−(ベンジルオキシカルボニル)ピロリジニル基、N−(tert−ブトキシカルボニル)ピロリジニル基を挙げることができる。 In the present invention, the N-protected pyrrolidinyl group refers to a pyrrolidinyl group in which a protecting group is bonded to an amine, and the amine protecting group is as described above, for example, an N-acetylpyrrolidinyl group, N-propanoylpyrrolidinyl. Group, N-butanoylpyrrolidinyl group, N- (cyclohexanecarbonyl) pyrrolidinyl group, optionally substituted N- (benzyloxycarbonyl) pyrrolidinyl group, N- (tert-butoxycarbonyl) pyrrolidinyl group, N-phthaloylpyrrolidinyl group etc. are mentioned. Among these, preferred protecting groups include N-acetylpyrrolidinyl group, N-propanoylpyrrolidinyl group, N-butanoylpyrrolidinyl group, N- (cyclohexanecarbonyl) pyrrolidinyl group, N- (benzyloxycarbonyl). ) Pyrrolidinyl group and N- (tert-butoxycarbonyl) pyrrolidinyl group.
本発明において、ラクタム環中のQは−(CH2)n−で表されるアルキル鎖であり、nは0〜3を示し、ラクタム環の大きさとしては4〜7員環となる。好ましくはnが1又は2(メチレン基又はエチレン基)の場合である。In the present invention, Q in the lactam ring is an alkyl chain represented by — (CH 2 ) n —, n represents 0 to 3, and the size of the lactam ring is a 4 to 7 membered ring. Preferably, n is 1 or 2 (methylene group or ethylene group).
一般式(1)で表される化合物は不斉炭素と化合物によっては不斉リン原子を有すことにより、単一の光学活性体、ラセミ体又は光学異性体の混合物として存在する。そのような化合物は光学活性体、ラセミ体又は光学異性体の混合物として得られる。本発明の化合物は、これら光学活性体、ラセミ体又は光学異性体の混合物のいずれも包含することとして理解されるべきである。 The compound represented by the general formula (1) exists as a single optically active substance, a racemate or a mixture of optical isomers by having an asymmetric carbon and an asymmetric phosphorus atom depending on the compound. Such compounds are obtained as optically active, racemic or optical isomer mixtures. The compounds of the present invention should be understood as encompassing any of these optically active, racemic or optical isomer mixtures.
本発明化合物の薬理学的に許容し得る塩としては、塩酸、硫酸等の鉱酸との塩、酢酸、安息香酸、コハク酸、フマル酸、マレイン酸、クエン酸、乳酸、酒石酸、メタンスルホン酸、ベンゼンスルホン酸等の有機酸との塩、またナトリウム、カリウム、リチウム、カルシウム等の無機金属等の無機塩基との塩、メチルアミン、エチルアミン、ジエタノールアミン等の有機アミン塩などが挙げられる。これらの塩は常法に従って製造することができる。 The pharmacologically acceptable salts of the compounds of the present invention include salts with mineral acids such as hydrochloric acid and sulfuric acid, acetic acid, benzoic acid, succinic acid, fumaric acid, maleic acid, citric acid, lactic acid, tartaric acid, methanesulfonic acid And salts with organic acids such as benzenesulfonic acid, salts with inorganic bases such as inorganic metals such as sodium, potassium, lithium and calcium, and organic amine salts such as methylamine, ethylamine and diethanolamine. These salts can be produced according to a conventional method.
一般式(1)で表される化合物としては、例えば以下のような化合物が挙げられる。
(1)(3S,PR)−3−ベンゾイルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(2)(3S,PR)−3−(4−ブロモベンゾイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(3)(3S,PR)−3−(3−ブロモベンゾイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(4)(3S,PR)−3−(2−ブロモベンゾイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(5)(3S,PR)−3−(4−クロロベンゾイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(6)(3S,PR)−3−(4−フルオロベンゾイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(7)(3S,PR)−3−(4−メチルベンゾイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(8)(3S,PR)−3−(3−メチルベンゾイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(9)(3S,PR)−3−(2−メチルベンゾイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(10)(3S,PR)−3−(4−メトキシベンゾイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドンExamples of the compound represented by the general formula (1) include the following compounds.
(1) (3S, PR) -3-Benzoylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (2) (3S, PR) -3- (4-bromobenzoyl) amino-1-amino (sulfoamino) Phosphinyl-2-piperidone (3) (3S, PR) -3- (3-bromobenzoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (4) (3S, PR) -3- (2-bromo Benzoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (5) (3S, PR) -3- (4-chlorobenzoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (6) (3S , PR) -3- (4-fluorobenzoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (7) 3S, PR) -3- (4-Methylbenzoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (8) (3S, PR) -3- (3-methylbenzoyl) amino-1-amino (sulfoamino) ) Phosphinyl-2-piperidone (9) (3S, PR) -3- (2-methylbenzoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (10) (3S, PR) -3- (4- Methoxybenzoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone
(11)(3S,PR)−3−(4−ニトロベンゾイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(12)(3S,PR)−3−(4−シアノベンゾイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(13)(3S,PR)−3−(4−ヒドロキシベンゾイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(14)(3S,PR)−3−(4−アミノベンゾイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(15)(3S,PR)−3−(4−メチルアミノベンゾイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(16)(3S,PR)−3−(4−ジメチルアミノベンゾイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(17)(3S,PR)−3−シクロヘキサンカルボニルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(18)(3S,PR)−3−シクロペンタンカルボニルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(19)(3S,PR)−3−(2−ナフトイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(20)(3S,PR)−3−(1−ナフトイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン(11) (3S, PR) -3- (4-Nitrobenzoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (12) (3S, PR) -3- (4-cyanobenzoyl) amino-1 -Amino (sulfoamino) phosphinyl-2-piperidone (13) (3S, PR) -3- (4-hydroxybenzoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (14) (3S, PR) -3 -(4-Aminobenzoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (15) (3S, PR) -3- (4-methylaminobenzoyl) amino-1-amino (sulfoamino) phosphinyl-2- Piperidone (16) (3S, PR) -3- (4-dimethylaminobenzoyl) amino-1-amino (sulfo Mino) phosphinyl-2-piperidone (17) (3S, PR) -3-cyclohexanecarbonylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (18) (3S, PR) -3-cyclopentanecarbonylamino-1 -Amino (sulfoamino) phosphinyl-2-piperidone (19) (3S, PR) -3- (2-naphthoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (20) (3S, PR) -3- (1-Naphthoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone
(21)(3S,PR)−3−(4−フェニルベンゾイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(22)(3S,PR)−3−ニコチノイルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(23)(3S,PR)−3−アクリロイルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(24)(3S,PR)−3−trans−クロトニルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(25)(3S,PR)−3−イソニコチノイルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(26)(3S,PR)−3−シンナモイルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(27)(3S,PR)−3−カプロイルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(28)(3S,PR)−3−バレリルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(29)(3S,PR)−3−ブタノイルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(30)(3S,PR)−3−プロピオニルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン(21) (3S, PR) -3- (4-Phenylbenzoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (22) (3S, PR) -3-nicotinoylamino-1-amino (sulfoamino) ) Phosphinyl-2-piperidone (23) (3S, PR) -3-acryloylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (24) (3S, PR) -3-trans-crotonylamino-1- Amino (sulfoamino) phosphinyl-2-piperidone (25) (3S, PR) -3-isonicotinoylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (26) (3S, PR) -3-cinnamoylamino -1-amino (sulfoamino) phosphinyl-2-piperidone (27) (3S, PR) -3 Caproylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (28) (3S, PR) -3-valerylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (29) (3S, PR) -3- Butanoylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (30) (3S, PR) -3-propionylamino-1-amino (sulfoamino) phosphinyl-2-piperidone
(31)(3S,PR)−3−アセチルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(32)(3S,PR)−3−ホルミルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(33)(3S,PR)−3−tert−ブチルアセチルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(34)(3S,PR)−3−フェニルアセチルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(35)(3S,PR)−3−(4−メトキシフェニル)アセチルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(36)(3S,PR)−3−(4−ニトロフェニル)アセチルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(37)(3S,PR)−3−(3−フェニルプロピオニル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(38)(3S,PR)−3−(2−ピリジルアセチル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(39)(3S,PR)−3−(フェノキシアセチル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(40)(3S,PR)−3−(3−シクロヘキサンプロピオニル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン(31) (3S, PR) -3-Acetylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (32) (3S, PR) -3-formylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (33) (3S, PR) -3-tert-butylacetylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (34) (3S, PR) -3-phenylacetylamino-1-amino (sulfoamino) phosphinyl 2-piperidone (35) (3S, PR) -3- (4-methoxyphenyl) acetylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (36) (3S, PR) -3- (4-nitro Phenyl) acetylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (37) 3S, PR) -3- (3-Phenylpropionyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (38) (3S, PR) -3- (2-pyridylacetyl) amino-1-amino (sulfoamino) ) Phosphinyl-2-piperidone (39) (3S, PR) -3- (phenoxyacetyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (40) (3S, PR) -3- (3-cyclohexanepropionyl) Amino-1-amino (sulfoamino) phosphinyl-2-piperidone
(41)(3S,PR)−3−(1−ナフトキシアセチル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(42)(3S,PR)−3−(N’−メチルウレイド)−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(43)(3S,PR)−3−(N’−エチルウレイド)−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(44)(3S,PR)−3−(N’−n−プロピルウレイド)−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(45)(3S,PR)−3−(N’−n−ブチルウレイド)−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(46)(3S,PR)−3−(N’−フェニルウレイド)−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(47)(3S,PR)−3−(N’−(3−シアノフェニル)ウレイド)−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(48)(3S,PR)−3−(N’−(1”−ナフチル)ウレイド)−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(49)(3S,PR)−3−(N’−(2”−ナフチル)ウレイド)−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(50)(3S,PR)−3−(N’−(3”−ピリジル)ウレイド)−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン(41) (3S, PR) -3- (1-naphthoxyacetyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (42) (3S, PR) -3- (N′-methylureido)- 1-amino (sulfoamino) phosphinyl-2-piperidone (43) (3S, PR) -3- (N′-ethylureido) -1-amino (sulfoamino) phosphinyl-2-piperidone (44) (3S, PR) — 3- (N′-n-propylureido) -1-amino (sulfoamino) phosphinyl-2-piperidone (45) (3S, PR) -3- (N′-n-butylureido) -1-amino (sulfoamino) Phosphinyl-2-piperidone (46) (3S, PR) -3- (N′-phenylureido) -1-amino (sulfoamino) phosphinyl-2-piperidone (4 ) (3S, PR) -3- (N ′-(3-cyanophenyl) ureido) -1-amino (sulfoamino) phosphinyl-2-piperidone (48) (3S, PR) -3- (N ′-(1 "-Naphthyl) ureido) -1-amino (sulfoamino) phosphinyl-2-piperidone (49) (3S, PR) -3- (N '-(2" -naphthyl) ureido) -1-amino (sulfoamino) phosphinyl- 2-piperidone (50) (3S, PR) -3- (N ′-(3 ″ -pyridyl) ureido) -1-amino (sulfoamino) phosphinyl-2-piperidone
(51)(3S,PR)−3−(N’−ベンジルウレイド)−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(52)(3S,PR)−3−(tert−ブトキシカルボニル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(53)(3S,PR)−3−(エトキシカルボニル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(54)(3S,PR)−3−(メトキシカルボニル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(55)(3S,PR)−3−(フェノキシカルボニル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(56)(3S,PR)−3−(6’−(ベンジルオキシカルボニルアミノ)ヘキサノイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(57)(3S,PR)−3−(4’−(ベンジルオキシカルボニルアミノ)ブタノイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(58)(3S,PR)−3−((ベンジルオキシカルボニルアミノ)アセチル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(59)(3S,PR)−3−(2’−(ベンジルオキシカルボニルアミノ)プロピオニル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(60)(3S,PR)−3−(2’−(ベンジルオキシカルボニルアミノ)−3’−メチルブタノイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン(51) (3S, PR) -3- (N′-Benzylureido) -1-amino (sulfoamino) phosphinyl-2-piperidone (52) (3S, PR) -3- (tert-butoxycarbonyl) amino-1 -Amino (sulfoamino) phosphinyl-2-piperidone (53) (3S, PR) -3- (ethoxycarbonyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (54) (3S, PR) -3- ( Methoxycarbonyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (55) (3S, PR) -3- (phenoxycarbonyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (56) (3S, PR) -3- (6 ′-(benzyloxycarbonylamino) hexanoyl) amino-1-a No (sulfoamino) phosphinyl-2-piperidone (57) (3S, PR) -3- (4 ′-(benzyloxycarbonylamino) butanoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (58) (3S , PR) -3-((benzyloxycarbonylamino) acetyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (59) (3S, PR) -3- (2 ′-(benzyloxycarbonylamino) propionyl Amino-1-amino (sulfoamino) phosphinyl-2-piperidone (60) (3S, PR) -3- (2 ′-(benzyloxycarbonylamino) -3′-methylbutanoyl) amino-1-amino (sulfoamino) ) Phosphinyl-2-piperidone
(61)(3S,PR)−3−(2’−(ベンジルオキシカルボニルアミノ)−4’−メチルペンタノイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(62)(3S,PR)−3−(2’−(ベンジルオキシカルボニルアミノ)−3’−メチルペンタノイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(63)(3S,PR)−3−(2’−(ベンジルオキシカルボニルアミノ)−3’−フェニルプロピオニル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(64)(3S,PR)−3−(2’−(1’−(ベンジルオキシカルボニル)ピペリジン)カルボニル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(65)(3S,PR)−3−(2’−(ベンジルオキシカルボニルアミノ)−3’−カルバモイルプロピオニル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(66)(3S,PR)−3−(2’−(ベンジルオキシカルボニルアミノ)−4’−カルバモイルブタノイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(67)(3S,PR)−3−(2’−(ベンジルオキシカルボニルアミノ)−4’−(メチルチオ)ブタノイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(68)(3S,PR)−3−(2’−(ベンジルオキシカルボニルアミノ)−3’−(3”−インドリル)プロピオニル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(69)(3S,PR)−3−((tert−ブトキシカルボニルアミノ)アセチル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(70)(3S,PR)−3−(2’−(tert−ブトキシカルボニルアミノ)−3’−(ベンジルオキシ)プロピオニル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン(61) (3S, PR) -3- (2 ′-(Benzyloxycarbonylamino) -4′-methylpentanoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (62) (3S, PR) -3- (2 '-(benzyloxycarbonylamino) -3'-methylpentanoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (63) (3S, PR) -3- (2'-( Benzyloxycarbonylamino) -3′-phenylpropionyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (64) (3S, PR) -3- (2 ′-(1 ′-(benzyloxycarbonyl) piperidine) ) Carbonyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (65) (3S, PR) -3- (2 ′-( Benzyloxycarbonylamino) -3′-carbamoylpropionyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (66) (3S, PR) -3- (2 ′-(benzyloxycarbonylamino) -4 ′ -Carbamoylbutanoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (67) (3S, PR) -3- (2 '-(benzyloxycarbonylamino) -4'-(methylthio) butanoyl) amino- 1-amino (sulfoamino) phosphinyl-2-piperidone (68) (3S, PR) -3- (2 ′-(benzyloxycarbonylamino) -3 ′-(3 ″ -indolyl) propionyl) amino-1-amino ( Sulfoamino) phosphinyl-2-piperidone (69) (3S, PR) -3-((tert-bu Xoxycarbonylamino) acetyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (70) (3S, PR) -3- (2 ′-(tert-butoxycarbonylamino) -3 ′-(benzyloxy) propionyl Amino-1-amino (sulfoamino) phosphinyl-2-piperidone
(71)(3S,PR)−3−(2’−(tert−ブトキシカルボニルアミノ)−3’−(ベンジルオキシ)ブタノイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(72)(3S,PR)−3−(2’−(tert−ブトキシカルボニルアミノ)−3’−(ベンジルオキシカルボニル)プロピオニル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(73)(3S,PR)−3−(2’−(tert−ブトキシカルボニルアミノ)−3’−(ベンジルオキシカルボニル)ブタノイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(74)(3S,PR)−3−(2’−(tert−ブトキシカルボニルアミノ)−3’−(4”−ベンジルオキシフェニル)プロピオニル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(75)(3S,PR)−3−(2’−(tert−ブトキシカルボニルアミノ)−5’−ニトロアミジノペンタノイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(76)(3S,P(RS))−3−メタンスルホニルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(77)(3S,P(RS))−3−ベンゼンスルホニルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(78)(3S,P(RS))−3−(4’−ブロモベンゼンスルホニル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(79)(3S,P(RS))−3−(4’−トルエンスルホニル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(80)(3S,P(RS))−3−(N’−フェニルチオウレイド)−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン(71) (3S, PR) -3- (2 ′-(tert-butoxycarbonylamino) -3 ′-(benzyloxy) butanoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (72) (3S , PR) -3- (2 ′-(tert-butoxycarbonylamino) -3 ′-(benzyloxycarbonyl) propionyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (73) (3S, PR) — 3- (2 '-(tert-butoxycarbonylamino) -3'-(benzyloxycarbonyl) butanoyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone (74) (3S, PR) -3- (2 '-(Tert-butoxycarbonylamino) -3'-(4 "-benzyloxyphenyl) propionyl) amino -1-amino (sulfoamino) phosphinyl-2-piperidone (75) (3S, PR) -3- (2 ′-(tert-butoxycarbonylamino) -5′-nitroamidinopentanoyl) amino-1-amino (sulfoamino) ) Phosphinyl-2-piperidone (76) (3S, P (RS))-3-methanesulfonylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (77) (3S, P (RS))-3-benzene Sulfonylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (78) (3S, P (RS))-3- (4′-bromobenzenesulfonyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone ( 79) (3S, P (RS))-3- (4′-toluenesulfonyl) amino-1-amino (sulfur Amino) phosphinyl-2-piperidone (80) (3S, P (RS)) - 3- (N'- phenyl thioureido) -1-amino (sulfoamino) phosphinyl-2-piperidone
(81)(3S,P(RS))−3−(N’−エチルチオウレイド)−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(82)(3S)−3−ベンジルオキシカルボニルアミノ−1−ビス(メチルアミノ)ホスフィニル−2−ピペリドン
(83)(3S)−3−ベンジルオキシカルボニルアミノ−1−ビス(エチルアミノ)ホスフィニル−2−ピペリドン
(84)(3S)−3−ベンジルオキシカルボニルアミノ−1−ビス(n−プロピルアミノ)ホスフィニル−2−ピペリドン
(85)(3S)−3−ベンジルオキシカルボニルアミノ−1−ビス(イソプロピルアミノ)ホスフィニル−2−ピペリドン
(86)(3S)−3−ベンジルオキシカルボニルアミノ−1−ビス(n−ブチルアミノ)ホスフィニル−2−ピペリドン
(87)(3S)−3−ベンジルオキシカルボニルアミノ−1−ビス(フェニルアミノ)ホスフィニル−2−ピペリドン
(88)(3S,P(RS))−3−ベンジルオキシカルボニルアミノ−1−アミノ(n−プロピルアミノ)ホスフィニル−2−ピペリドン
(89)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(シクロヘキシルアミノ)ホスフィニル−2−ピペリドン
(90)(3S,PR))−3−ベンジルオキシカルボニルアミノ−1−アミノ(フェニルアミノ)ホスフィニル−2−ピペリドン(81) (3S, P (RS))-3- (N′-ethylthioureido) -1-amino (sulfoamino) phosphinyl-2-piperidone (82) (3S) -3-benzyloxycarbonylamino-1- Bis (methylamino) phosphinyl-2-piperidone (83) (3S) -3-benzyloxycarbonylamino-1-bis (ethylamino) phosphinyl-2-piperidone (84) (3S) -3-benzyloxycarbonylamino- 1-bis (n-propylamino) phosphinyl-2-piperidone (85) (3S) -3-benzyloxycarbonylamino-1-bis (isopropylamino) phosphinyl-2-piperidone (86) (3S) -3-benzyl Oxycarbonylamino-1-bis (n-butylamino) phosphinyl-2-piperidone (8 7) (3S) -3-Benzyloxycarbonylamino-1-bis (phenylamino) phosphinyl-2-piperidone (88) (3S, P (RS))-3-benzyloxycarbonylamino-1-amino (n- Propylamino) phosphinyl-2-piperidone (89) (3S, PR) -3-benzyloxycarbonylamino-1-amino (cyclohexylamino) phosphinyl-2-piperidone (90) (3S, PR))-3-benzyloxy Carbonylamino-1-amino (phenylamino) phosphinyl-2-piperidone
(91)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−(アセチルアミノ)アミノホスフィニル−2−ピペリドン
(92)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(n−プロピオニルアミノ)ホスフィニル−2−ピペリドン
(93)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(n−ブタノイルアミノ)ホスフィニル−2−ピペリドン
(94)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(tert−ブチルアセチルアミノ)ホスフィニル−2−ピペリドン
(95)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(ヒドロキシアセチルアミノ)ホスフィニル−2−ピペリドン
(96)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(アミノアセチルアミノ)ホスフィニル−2−ピペリドン
(97)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(メチルアミノアセチルアミノ)ホスフィニル−2−ピペリドン
(98)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(ジメチルアミノアセチルアミノ)ホスフィニル−2−ピペリドン
(99)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ((N−ベンゾイルアミノアセチル)アミノ)ホスフィニル−2−ピペリドン
(100)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ((N−ベンジルオキシカルボニルアミノアセチル)アミノ)ホスフィニル−2−ピペリドン(91) (3S, PR) -3-Benzyloxycarbonylamino-1- (acetylamino) aminophosphinyl-2-piperidone (92) (3S, PR) -3-benzyloxycarbonylamino-1-amino ( n-propionylamino) phosphinyl-2-piperidone (93) (3S, PR) -3-benzyloxycarbonylamino-1-amino (n-butanoylamino) phosphinyl-2-piperidone (94) (3S, PR)- 3-Benzyloxycarbonylamino-1-amino (tert-butylacetylamino) phosphinyl-2-piperidone (95) (3S, PR) -3-benzyloxycarbonylamino-1-amino (hydroxyacetylamino) phosphinyl-2- Piperidone (96) (3S, PR) -3-benzyloxycal Nylamino-1-amino (aminoacetylamino) phosphinyl-2-piperidone (97) (3S, PR) -3-benzyloxycarbonylamino-1-amino (methylaminoacetylamino) phosphinyl-2-piperidone (98) (3S , PR) -3-benzyloxycarbonylamino-1-amino (dimethylaminoacetylamino) phosphinyl-2-piperidone (99) (3S, PR) -3-benzyloxycarbonylamino-1-amino ((N-benzoylamino Acetyl) amino) phosphinyl-2-piperidone (100) (3S, PR) -3-benzyloxycarbonylamino-1-amino ((N-benzyloxycarbonylaminoacetyl) amino) phosphinyl-2-piperidone
(101)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(カルボキシアセチルアミノ)ホスフィニル−2−ピペリドン
(102)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(メトキシアセチルアミノ)ホスフィニル−2−ピペリドン
(103)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(フェニルアセチルアミノ)ホスフィニル−2−ピペリドン
(104)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(フェニルプロピオニルアミノ)ホスフィニル−2−ピペリドン
(105)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(フェノキシアセチルアミノ)ホスフィニル−2−ピペリドン
(106)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(ベンジルオキシアセチルアミノ)ホスフィニル−2−ピペリドン
(107)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(シンナモイルアミノ)ホスフィニル−2−ピペリドン
(108)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(シクロヘキサンカルボニルアミノ)ホスフィニル−2−ピペリドン
(109)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(2−チオフェンカルボニルアミノ)ホスフィニル−2−ピペリドン
(110)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(ニコチノイルアミノ)ホスフィニル−2−ピペリドン(101) (3S, PR) -3-Benzyloxycarbonylamino-1-amino (carboxyacetylamino) phosphinyl-2-piperidone (102) (3S, PR) -3-benzyloxycarbonylamino-1-amino (methoxy) Acetylamino) phosphinyl-2-piperidone (103) (3S, PR) -3-benzyloxycarbonylamino-1-amino (phenylacetylamino) phosphinyl-2-piperidone (104) (3S, PR) -3-benzyloxy Carbonylamino-1-amino (phenylpropionylamino) phosphinyl-2-piperidone (105) (3S, PR) -3-benzyloxycarbonylamino-1-amino (phenoxyacetylamino) phosphinyl-2-piperidone (106) (3S , PR) -3 Benzyloxycarbonylamino-1-amino (benzyloxyacetylamino) phosphinyl-2-piperidone (107) (3S, PR) -3-benzyloxycarbonylamino-1-amino (cinnamoylamino) phosphinyl-2-piperidone (108 ) (3S, PR) -3-benzyloxycarbonylamino-1-amino (cyclohexanecarbonylamino) phosphinyl-2-piperidone (109) (3S, PR) -3-benzyloxycarbonylamino-1-amino (2-thiophene) Carbonylamino) phosphinyl-2-piperidone (110) (3S, PR) -3-benzyloxycarbonylamino-1-amino (nicotinoylamino) phosphinyl-2-piperidone
(111)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(ベンゾイルアミノ)ホスフィニル−2−ピペリドン
(112)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(4−メトキシベンゾイルアミノ)ホスフィニル−2−ピペリドン
(113)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(4−ニトロベンゾイルアミノ)ホスフィニル−2−ピペリドン
(114)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(4−シアノベンゾイルアミノ)ホスフィニル−2−ピペリドン
(115)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(4−フルオロベンゾイルアミノ)ホスフィニル−2−ピペリドン
(116)(3S)−3−ベンジルオキシカルボニルアミノ−1−ビス(4−フルオロベンゾイルアミノ)ホスフィニル−2−ピペリドン
(117)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(4−クロロベンゾイルアミノ)ホスフィニル−2−ピペリドン
(118)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(4−ブロモベンゾイルアミノ)ホスフィニル−2−ピペリドン
(119)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(フェニルウレイド)ホスフィニル−2−ピペリドン
(120)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(4−ブロモフェニルウレイド)ホスフィニル−2−ピペリドン(111) (3S, PR) -3-Benzyloxycarbonylamino-1-amino (benzoylamino) phosphinyl-2-piperidone (112) (3S, PR) -3-benzyloxycarbonylamino-1-amino (4- Methoxybenzoylamino) phosphinyl-2-piperidone (113) (3S, PR) -3-benzyloxycarbonylamino-1-amino (4-nitrobenzoylamino) phosphinyl-2-piperidone (114) (3S, PR) -3 -Benzyloxycarbonylamino-1-amino (4-cyanobenzoylamino) phosphinyl-2-piperidone (115) (3S, PR) -3-benzyloxycarbonylamino-1-amino (4-fluorobenzoylamino) phosphinyl-2 -Piperidone (116) (3S) -3 Benzyloxycarbonylamino-1-bis (4-fluorobenzoylamino) phosphinyl-2-piperidone (117) (3S, PR) -3-benzyloxycarbonylamino-1-amino (4-chlorobenzoylamino) phosphinyl-2- Piperidone (118) (3S, PR) -3-benzyloxycarbonylamino-1-amino (4-bromobenzoylamino) phosphinyl-2-piperidone (119) (3S, PR) -3-benzyloxycarbonylamino-1- Amino (phenylureido) phosphinyl-2-piperidone (120) (3S, PR) -3-benzyloxycarbonylamino-1-amino (4-bromophenylureido) phosphinyl-2-piperidone
(121)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(エチルウレイド)ホスフィニル−2−ピペリドン
(122)(3S)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ピペリドン
(123)(3R)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ピペリドン
(124)(3S)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ペルヒドロアゼピノン
(125)(3R)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ペルヒドロアゼピノン
(126)(3S)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ピロリジノン
(127)(3R)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ピロリジノン
(128)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(129)(3R,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(130)(3S,PS)−3−ベンジルオキシカルボニルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン(121) (3S, PR) -3-Benzyloxycarbonylamino-1-amino (ethylureido) phosphinyl-2-piperidone (122) (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2 Piperidone (123) (3R) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone (124) (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2-per Hydroazepinone (125) (3R) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2-perhydroazepinone (126) (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl -2-pyrrolidinone (127) (3R) -3-benzyloxycarboni Amino-1-diaminophosphinyl-2-pyrrolidinone (128) (3S, PR) -3-benzyloxycarbonylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (129) (3R, PR) -3- Benzyloxycarbonylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (130) (3S, PS) -3-benzyloxycarbonylamino-1-amino (sulfoamino) phosphinyl-2-piperidone
(131)(3R,PS)−3−ベンジルオキシカルボニルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン
(132)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ペルヒドロアゼピノン
(133)(3R,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ペルヒドロアゼピノン
(134)(3S,PS)−3−ベンジルオキシカルボニルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ペルヒドロアゼピノン
(135)(3R,PS)−3−ベンジルオキシカルボニルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ペルヒドロアゼピノン
(136)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(スルホミノ)ホスフィニル−2−ピロリジノン
(137)(3R,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピロリジノン
(138)(3S,PS)−3−ベンジルオキシカルボニルアミノ−1−アミノ(スルホミノ)ホスフィニル−2−ピロリジノン
(139)(3R,PS)−3−ベンジルオキシカルボニルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピロリジノン
(140)(3S,PR)−3−シクロヘキシルプロピオニルアミノ−1−アミノ(フェニルウレイド)ホスフィニル−2−ピペリドン
(141)(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ((ベンジルオキシカルボニルアミノ)アセチルアミノ)ホスフィニル−2−ピペリドン(131) (3R, PS) -3-Benzyloxycarbonylamino-1-amino (sulfoamino) phosphinyl-2-piperidone (132) (3S, PR) -3-benzyloxycarbonylamino-1-amino (sulfoamino) phosphinyl 2-perhydroazepinone (133) (3R, PR) -3-benzyloxycarbonylamino-1-amino (sulfoamino) phosphinyl-2-perhydroazepinone (134) (3S, PS) -3-benzyloxy Carbonylamino-1-amino (sulfoamino) phosphinyl-2-perhydroazepinone (135) (3R, PS) -3-benzyloxycarbonylamino-1-amino (sulfoamino) phosphinyl-2-perhydroazepinone (136) (3S, PR) -3-Benzyloxyca Bonylamino-1-amino (sulfomino) phosphinyl-2-pyrrolidinone (137) (3R, PR) -3-benzyloxycarbonylamino-1-amino (sulfoamino) phosphinyl-2-pyrrolidinone (138) (3S, PS) -3 -Benzyloxycarbonylamino-1-amino (sulfomino) phosphinyl-2-pyrrolidinone (139) (3R, PS) -3-benzyloxycarbonylamino-1-amino (sulfoamino) phosphinyl-2-pyrrolidinone (140) (3S, PR) -3-Cyclohexylpropionylamino-1-amino (phenylureido) phosphinyl-2-piperidone (141) (3S, PR) -3-benzyloxycarbonylamino-1-amino ((benzyloxycarbonylamino) acetylamino Phosphinyl-2-piperidone
本発明の化合物はスルフォスチンの合成法(特開2000−327689号公報)に準じて、以下のようにして製造することができる。
まず、側鎖にアミノ基を有するアミノ酸のメチルエステル等のエステル体に塩基等を作用させて環化(ラクタム化)させることにより容易に製造可能な、又は試薬(例えばシグマ社から販売されているQが−(CH2)3−のα−アミノ−ε−カプロラクタムなど)として購入可能な、一般式(2)The compound of the present invention can be produced as follows in accordance with a method for synthesizing sulfostin (Japanese Patent Laid-Open No. 2000-327689).
First, it can be easily produced by cyclization (lactamization) by reacting an ester such as methyl ester of an amino acid having an amino group in the side chain with a base or the like, or a reagent (for example, sold by Sigma) Q is - (CH 2) 3 - Bruno α- amino -ε- caprolactam, etc.) which can be purchased as the general formula (2)
(式中、Qは前記に記載の通りである。)の化合物に、アシル化の場合には塩基性条件下で対応する酸クロリド、酸無水物、活性エステル体などを作用させ、スルホニル化の場合には対応するスルホン酸クロリドなどを作用させ、カルバメート化の場合には対応するオキシカルボニルクロリド、ジカーボナート、活性カーボナートエステルなどを作用させ、ウレイド化の場合には対応するイソシアナート化合物を作用させ、チオウレイド化の場合には対応するイソチオイソシアナートなどを作用させて反応を行い、一般式(3) In the case of acylation, a corresponding acid chloride, acid anhydride, active ester or the like is allowed to act on the compound of the formula (wherein Q is as described above) under basic conditions. In some cases, the corresponding sulfonic acid chloride is allowed to act, in the case of carbamate formation, the corresponding oxycarbonyl chloride, dicarbonate, active carbonate ester, etc. In the case of thioureidation, the reaction is carried out by reacting the corresponding isothioisocyanate, etc.
(式中のQ、及びR及びXは前記に記載の通りである。)で表される化合物とすることができる。次いで、Y及びZに低級アルキル基、アリール基、ヘテロアリール基、シクロアルキル基を含まない化合物群は、ラクタム環内のアミドをn−ブチルリチウム、水素化ナトリウムなどの塩基によって活性化した後に、オキシ塩化リンなどのオキシハロゲン化リン、アンモニアを順に作用させるジアミノホスフィニル基導入反応を行うことにより、一般式(4) (Wherein Q, R and X are as described above). Next, a compound group not containing a lower alkyl group, aryl group, heteroaryl group or cycloalkyl group in Y and Z is obtained by activating the amide in the lactam ring with a base such as n-butyllithium or sodium hydride, By carrying out a diaminophosphinyl group introduction reaction in which phosphorus oxyhalide such as phosphorus oxychloride and ammonia act in this order, the general formula (4)
(式中のQ及び、R及びXは前記に記載の通りである。)で表される本発明の化合物とすることができる。また、Y又はZが、スルホン酸基である化合物群は、三酸化イオウーアミン錯体などを作用させ、低級アシル基、アリールカルボニル基、ヘテロアリールカルボニル基、シクロアルカンカルボニル基、アルケニルカルボニル基の場合には対応する酸クロリド、酸無水物などを作用させ、アルキルアミノカルボニル基及びアリールアミノカルボニル基の場合には対応するイソシアナート試薬を作用させることによって、また必要に応じてこれらの反応を組み合わせることによって、下記一般式(1) (Wherein Q, R and X are as described above). In the case where Y or Z is a sulfonic acid group, a sulfur trioxide amine complex is allowed to act, and in the case of a lower acyl group, arylcarbonyl group, heteroarylcarbonyl group, cycloalkanecarbonyl group, alkenylcarbonyl group, By reacting the corresponding acid chloride, acid anhydride, etc., in the case of alkylaminocarbonyl groups and arylaminocarbonyl groups, by reacting the corresponding isocyanate reagents, and combining these reactions as required, The following general formula (1)
(式中のQ及びRは前記に記載の通りである。)で表される本発明の化合物に導くことができる。一方、Y及びZに低級アルキル基、アリール基、ヘテロアリール基、シクロアルキル基を含む化合物群は、ジアミノホスフィニル基導入反応の際、アンモニアの代わりに、対応する低級アルキルアミン、アリールアミン、ヘテロアリールアミン、シクロアルキルアミンを作用させ、また必要に応じてこれらの対応するアミンとアンモニアとを組み合わせて作用させることによって、一般式(1)で表される本発明の化合物に導くことができる。 (Q and R in the formula are as described above). On the other hand, a compound group containing a lower alkyl group, an aryl group, a heteroaryl group, and a cycloalkyl group in Y and Z is substituted with a corresponding lower alkylamine, arylamine, instead of ammonia during the diaminophosphinyl group introduction reaction. It can be led to the compound of the present invention represented by the general formula (1) by acting a heteroarylamine or cycloalkylamine and, if necessary, a combination of these corresponding amine and ammonia. .
また更には、ラクタム環1位にアミノ(スルホアミノ)ホスフィニル基を有する本発明化合物は、特開2000−327689公報の方法によって合成可能な下記一般式(5) Furthermore, the compound of the present invention having an amino (sulfoamino) phosphinyl group at the 1-position of the lactam ring can be synthesized by the method of JP-A No. 2000-327689 and has the following general formula (5)
(式中のQは前記に記載の通りである。)で表されるスルフォスチン類縁体に、塩基性条件下、酸クロリド、酸無水物、活性エステル体などによってアシル化反応を、塩基性条件下、イソシアナート化合物によってウレイド化を、チオイソシアナート化合物によってチオウレイド化を、スルホン酸クロリドなどによってスルホン化を行うことによっても合成可能である。 (In the formula, Q is as described above.) The sulfostin analog represented by the formula is subjected to an acylation reaction under basic conditions under an acid chloride, acid anhydride, active ester, etc. under basic conditions. It can also be synthesized by ureiding with an isocyanate compound, thioureating with a thioisocyanate compound, and sulfonated with sulfonic acid chloride or the like.
上記の各製法により得た反応混合物から目的物を単離及び精製するには、常法による溶媒抽出、濃縮、結晶化、蒸留、懸濁精製、各種クロマトグラフィーなどを、必要に応じ用いることができる。 In order to isolate and purify the target product from the reaction mixture obtained by each of the above-mentioned production methods, solvent extraction, concentration, crystallization, distillation, suspension purification, various chromatographies, etc. can be used as necessary. it can.
本発明化合物が記憶及び認識障害の予防剤若しくは治療剤又はプロリルオリゴペプチダーゼ阻害剤として用いられる場合は、単独又は賦形剤若しくは担体と混合して、懸濁液、乳剤、注射剤、吸入剤、錠剤、丸剤、顆粒剤、細粒剤、散剤、カプセル剤、経口用液剤、坐剤、点眼剤、眼軟膏、経皮用液剤、経皮用貼付剤、軟膏剤、経粘膜液剤、経粘膜貼付剤、スプレー剤等の製剤とし、経口的に、又は非経口的に投与される。賦形剤又は担体等の添加剤としては薬剤学的に許容されるものが選ばれ、その種類及び組成は投与経路や投与方法によって決まる。例えば注射剤の場合、一般に食塩、グルコース、マンニトール等の糖類を用いることができる。経口剤の場合、でんぷん、乳糖、結晶セルロース、ステアリン酸マグネシウム等を用いることができる。所望に応じて上記製剤中に助剤、安定剤、湿潤剤、乳化剤、緩衝液又はその他の通常使用される添加剤が含まれていてもよい。 When the compound of the present invention is used as a preventive or therapeutic agent for memory and cognitive impairment or as a prolyl oligopeptidase inhibitor, it is used alone or mixed with an excipient or carrier to form a suspension, emulsion, injection, inhalant Tablets, pills, granules, fine granules, powders, capsules, oral solutions, suppositories, eye drops, eye ointments, transdermal solutions, transdermal patches, ointments, transmucosal solutions, transmucosal It can be administered orally or parenterally as a preparation such as a mucosal patch or spray. As an additive such as an excipient or a carrier, a pharmaceutically acceptable one is selected, and its kind and composition are determined by the administration route and the administration method. For example, in the case of injections, sugars such as sodium chloride, glucose, mannitol and the like can be generally used. In the case of an oral preparation, starch, lactose, crystalline cellulose, magnesium stearate and the like can be used. If desired, auxiliary, stabilizer, wetting agent, emulsifier, buffer solution or other commonly used additives may be contained in the preparation.
製剤中における本化合物の含量は製剤により種々異なるが通常0.1〜100重量%、好ましくは1〜98重量%である。例えば注射剤の場合には、通常0.1〜30重量%、好ましくは1〜10重量%の有効成分を含むようにすることがよい。経口剤の場合には、添加剤とともに錠剤、カプセル剤、散剤、顆粒剤、液剤、ドライシロップ剤等の形態で用いられる。カプセル剤、錠剤、顆粒、散剤は一般に5〜100重量%、好ましくは25〜98重量%の有効成分を含む。
投与量は、患者の年令、性別、体重、症状、治療目的等により決定されるが、治療量は通常、非経口投与で0.001〜200mg/kg/日であり、経口投与では0.01〜500mg/kg/日,好ましくは0.1〜100mg/kg/日、これを1回又は2〜5回に分けて投与する。The content of the present compound in the preparation varies depending on the preparation, but is usually 0.1 to 100% by weight, preferably 1 to 98% by weight. For example, in the case of an injection, the active ingredient is usually 0.1 to 30% by weight, preferably 1 to 10% by weight. In the case of an oral preparation, it is used in the form of tablets, capsules, powders, granules, liquids, dry syrups and the like together with additives. Capsules, tablets, granules, powders generally contain 5-100% by weight, preferably 25-98% by weight, of the active ingredient.
The dose is determined depending on the age, sex, weight, symptoms, therapeutic purpose, etc. of the patient. The therapeutic amount is usually 0.001 to 200 mg / kg / day for parenteral administration, and 0. 01 to 500 mg / kg / day, preferably 0.1 to 100 mg / kg / day, which is administered once or divided into 2 to 5 times.
次に参考例として化合物の合成例を、実施例として本発明化合物の合成例及び薬理実験例を示して本発明を具体的に説明するが、本発明はこれらに限定されるものではない。また、以下で室温とは10〜30℃を示す。
NMRにおいて内部標準物質がない場合は、溶媒のピーク(D2Oのときは4.65ppm、DMSO−D6のときは2.49ppm、CD3ODのときは3.30ppm)を基準とした。Next, the present invention will be specifically described with reference to synthesis examples of compounds as reference examples and synthesis examples and pharmacological experimental examples of the compounds of the present invention as examples. However, the present invention is not limited thereto. Moreover, below, room temperature shows 10-30 degreeC.
When there was no internal standard substance in NMR, the solvent peak (4.65 ppm for D 2 O, 2.49 ppm for DMSO-D 6 and 3.30 ppm for CD 3 OD) was used as a reference.
参考例1
(3S)−3−ベンジルオキシカルボニルアミノ−2−ピペリドン
氷冷下、メタノール(1.2L)に塩化チオニル(69.2mL,0.9487mol)を加え、20分間攪拌した。次いで、L−オルニチン塩酸塩(80.00g,0.4744mol)を4回に分けて加え、同温で3時間、室温で19時間攪拌した。
反応液を減圧濃縮した後、エーテル−ヘキサンで結晶化、次いでエーテルで洗浄を行い、無色結晶を得た。
得られた無色結晶を水(1L)に溶解し、氷冷下、炭酸水素ナトリウム(119.56g,1.4232mol)を数回に分けて加え、室温で15時間攪拌した。
次に反応液にTHF(0.5L)及び炭酸水素ナトリウム(59.78g,0.7116mol)を加えた後、氷冷下で塩化ベンジルオキシカルボニル(81.3mL,0.5695mol)を加え、室温で18時間攪拌した。
二層になっている反応液を分離し、水層を塩酸で中和した後、クロロホルムで抽出した。先に分離した有機層と合わせ、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、溶媒を留去した。残査にエーテルを加えて結晶化した後、エーテルで洗浄を行い、粗結晶(105.60g)を得た。この結晶化母液及びエーテル洗浄液を合わせ、シリカゲルクロマトグラフィー(クロロホルム:酢酸エチル=10:1〜2:1)で精製を行い、粗結晶(2.20g)を得た。粗結晶を合わせて再結晶(クロロホルム−エーテル)を行い、目的化合物(106.34g)を得た。Reference example 1
(3S) -3-Benzyloxycarbonylamino-2-piperidone Under ice-cooling, thionyl chloride (69.2 mL, 0.9487 mol) was added to methanol (1.2 L), and the mixture was stirred for 20 minutes. Next, L-ornithine hydrochloride (80.00 g, 0.4744 mol) was added in four portions, and the mixture was stirred at the same temperature for 3 hours and at room temperature for 19 hours.
The reaction solution was concentrated under reduced pressure, crystallized with ether-hexane, and then washed with ether to obtain colorless crystals.
The obtained colorless crystals were dissolved in water (1 L), sodium hydrogen carbonate (119.56 g, 1.4232 mol) was added in several portions under ice cooling, and the mixture was stirred at room temperature for 15 hours.
Next, THF (0.5 L) and sodium hydrogen carbonate (59.78 g, 0.7116 mol) were added to the reaction solution, and then benzyloxycarbonyl chloride (81.3 mL, 0.5695 mol) was added under ice-cooling. For 18 hours.
The reaction solution in two layers was separated, and the aqueous layer was neutralized with hydrochloric acid and extracted with chloroform. The organic layer separated above was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. After ether was added to the residue for crystallization, the residue was washed with ether to obtain crude crystals (105.60 g). The crystallized mother liquor and the ether wash were combined and purified by silica gel chromatography (chloroform: ethyl acetate = 10: 1 to 2: 1) to obtain crude crystals (2.20 g). The crude crystals were combined and recrystallized (chloroform-ether) to obtain the target compound (106.34 g).
1H−NMR(CDCl3、内部標準TMS)
7.28−7.38(5H,m),6.36(1H,br s),5.79(1H,br s),5.11(2H,s),4.06−4.12(1H,m),3.27−3.33(2H,m),2.46−2.53(1H,m),1.82−1.95(2H,m),1.61(1H,tdd,J=11.7,12.7,5.4Hz).
MS(FAB,POS)
m/z:249(M+H)+,271(M+Na)+. 1 H-NMR (CDCl 3 , internal standard TMS)
7.28-7.38 (5H, m), 6.36 (1H, br s), 5.79 (1H, br s), 5.11 (2H, s), 4.06-4.12 ( 1H, m), 3.27-3.33 (2H, m), 2.46-2.53 (1H, m), 1.82-1.95 (2H, m), 1.61 (1H, tdd, J = 11.7, 12.7, 5.4 Hz).
MS (FAB, POS)
m / z: 249 (M + H) + , 271 (M + Na) + .
参考例2
(3S)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ピペリドン
窒素気流下、参考例1の化合物(40.00g,0.1611mol)を無水THF(450mL)に溶解し、外温−78℃で冷却後、n−ブチルリチウムヘキサン溶液(1.54M,99mL,0.1525mol)をゆっくりと加え、45分間攪拌した。次に同温で塩化ホスホリル(15.0mL,0.1609mol)の無水THF(20mL)溶液を加えて1.5時間、室温で1時間攪拌した。再び外温−78℃で冷却後、液体アンモニア(15mL,0.6791mol)を加えて5分間攪拌した。
反応液に飽和食塩水(約500mL)を加え、二層になった反応液を分離し、水層をクロロホルムで抽出した。分離した有機層と合わせ飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、溶媒を留去した。残査をクロロホルム−エーテルで結晶化を行い、目的化合物(19.63g)を得た。Reference example 2
(3S) -3-Benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone The compound of Reference Example 1 (40.00 g, 0.1611 mol) was dissolved in anhydrous THF (450 mL) under a nitrogen stream, and the outside After cooling at a temperature of −78 ° C., n-butyllithium hexane solution (1.54M, 99 mL, 0.1525 mol) was slowly added and stirred for 45 minutes. Next, a solution of phosphoryl chloride (15.0 mL, 0.1609 mol) in anhydrous THF (20 mL) was added at the same temperature, and the mixture was stirred for 1.5 hours and at room temperature for 1 hour. After cooling again at an external temperature of −78 ° C., liquid ammonia (15 mL, 0.6791 mol) was added and stirred for 5 minutes.
Saturated brine (about 500 mL) was added to the reaction solution, the reaction solution in two layers was separated, and the aqueous layer was extracted with chloroform. The separated organic layer was combined and washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was crystallized from chloroform-ether to obtain the target compound (19.63 g).
1H−NMR(DMSO−D6)
7.28−7.41(5H,m),5.00(2H,s),4.19(2H,br s),4.14(2H,br s),4.06−4.12(1H,m),3.55−3.61(1H,m),3.43−3.48(1H,m),1.98−2.03(1H,m),1.73−1.78(2H,m),1.58−1.66(1H,m).
MS(FAB,POS)
m/z:327(M+H)+. 1 H-NMR (DMSO-D 6 )
7.28-7.41 (5H, m), 5.00 (2H, s), 4.19 (2H, br s), 4.14 (2H, br s), 4.06-4.12 ( 1H, m), 3.55-3.61 (1H, m), 3.43-3.48 (1H, m), 1.98-2.03 (1H, m), 1.73-1. 78 (2H, m), 1.58-1.66 (1H, m).
MS (FAB, POS)
m / z: 327 (M + H) + .
参考例3
(3S)−3−ベンジルオキシカルボニルアミノ−2−カプロラクタム
3(S)−アミノ−2−カプロラクタム(5.00g,39.01mmol)をTHF(20mL)及び水(40mL)に溶解した溶液に、氷冷下で炭酸水素ナトリウム(4.92g,58.56mol)、塩化ベンジルオキシカルボニル(5.57mL,39.01mmol)を加え、室温で18時間攪拌した。
反応液を減圧濃縮後、水を加え、析出している結晶を濾取した。結晶をエーテルで洗浄後、クロロホルムに溶解し、無水硫酸ナトリウムで乾燥した。溶媒を留去した後、再結晶(クロロホルム−エーテル)を行い、目的化合物(5.23g)を得た。Reference example 3
(3S) -3-Benzyloxycarbonylamino-2-caprolactam To a solution of 3 (S) -amino-2-caprolactam (5.00 g, 39.01 mmol) in THF (20 mL) and water (40 mL) was added ice. Under cooling, sodium hydrogen carbonate (4.92 g, 58.56 mol) and benzyloxycarbonyl chloride (5.57 mL, 39.01 mmol) were added, and the mixture was stirred at room temperature for 18 hours.
The reaction mixture was concentrated under reduced pressure, water was added, and the precipitated crystals were collected by filtration. The crystals were washed with ether, dissolved in chloroform, and dried over anhydrous sodium sulfate. After the solvent was distilled off, recrystallization (chloroform-ether) was performed to obtain the target compound (5.23 g).
1H−NMR(CDCl3)
7.26−7.36(5H,m),6.14−6.24(2H,m),5.10(2H,d,J=2.8Hz),4.34(1H,ddd,J=1.6,6.8,13.6Hz),3.19−3.31(2H,m),2.09−2.15(1H,m),1.98−2.05(1H,m),1.73−1.87(2H,m),1.48−1.58(1H,m),1.33−1.44(1H,m). 1 H-NMR (CDCl 3 )
7.26-7.36 (5H, m), 6.14-6.24 (2H, m), 5.10 (2H, d, J = 2.8 Hz), 4.34 (1H, ddd, J = 1.6, 6.8, 13.6 Hz), 3.19-3.31 (2H, m), 2.09-2.15 (1H, m), 1.98-2.05 (1H, m), 1.73-1.87 (2H, m), 1.48-1.58 (1H, m), 1.33-1.44 (1H, m).
参考例4
(3S)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−カプロラクタム
窒素気流下、参考例3の化合物(4.00g,15.25mmol)を無水THF(120mL)に溶解した溶液に、外温−78℃でn−ブチルリチウムヘキサン溶液(1.55M,8.9mL,13.80mmol)をゆっくり加え、30分間攪拌した。次いで塩化ホスホリル(2.57g,16.76mmol)の無水THF(10mL)溶液を加えて同温で2時間、室温で30分間攪拌した。反応液を再び外温−78℃で冷却し、液体アンモニア(2mL,90.55mmol)を加えて5分間攪拌した。
反応液に飽和食塩水を加え、水層と有機層に分離し、水層をクロロホルムで抽出した。分離した有機層と合わせ、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、溶媒を留去した。残査をシリカゲルクロマトグラフィー(クロロホルム:メタノール=29:1〜14:1)で精製し、得られた結晶をクロロホルム−エーテルで洗浄を行い、目的化合物(1.55g)を得た。Reference example 4
(3S) -3-Benzyloxycarbonylamino-1-diaminophosphinyl-2-caprolactam To a solution of the compound of Reference Example 3 (4.00 g, 15.25 mmol) in anhydrous THF (120 mL) under a nitrogen stream. Then, an n-butyllithium hexane solution (1.55 M, 8.9 mL, 13.80 mmol) was slowly added at an external temperature of −78 ° C., and the mixture was stirred for 30 minutes. Next, a solution of phosphoryl chloride (2.57 g, 16.76 mmol) in anhydrous THF (10 mL) was added and stirred at the same temperature for 2 hours and at room temperature for 30 minutes. The reaction solution was cooled again at an external temperature of −78 ° C., liquid ammonia (2 mL, 90.55 mmol) was added, and the mixture was stirred for 5 minutes.
Saturated saline was added to the reaction solution, the aqueous layer and the organic layer were separated, and the aqueous layer was extracted with chloroform. Combined with the separated organic layer, washed with saturated brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (chloroform: methanol = 29: 1-14: 1), and the obtained crystals were washed with chloroform-ether to obtain the desired compound (1.55 g).
1H−NMR(DMSO−D6)
7.25−7.38(5H,m),5.01(2H,d,J=4.8Hz),4.39−4.45(1H,m)4.162H,br s),4.11(2H,br s),3.20−3.30(2H,m),1.48−1.80(5H,m),1.33−1.43(1H,m).
MS(FAB,POS)
m/z:341(M+H)+. 1 H-NMR (DMSO-D 6 )
7.25-7.38 (5H, m), 5.01 (2H, d, J = 4.8 Hz), 4.39-4.45 (1H, m) 4.162H, br s), 4. 11 (2H, br s), 3.20-3.30 (2H, m), 1.48-1.80 (5H, m), 1.33-1.43 (1H, m).
MS (FAB, POS)
m / z: 341 (M + H) + .
参考例5
L−(N−ベンジルオキシカルボニル)グルタミン メチルエステル
L−(N−ベンジルオキシカルボニル)グルタミン(8.00g,28.54mmol)をDMF(80mL)に溶解した溶液に炭酸水素ナトリウム(4.80g,57.14mol)及びヨウ化メチル(4.44mL,71.32mmol)を加え、室温で22時間攪拌した。
反応液に水を加え、酢酸エチルで抽出した。酢酸エチル層を10%チオ硫酸ナトリウム水溶液及び飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、溶媒を留去した。残査を酢酸エチル−エーテルで洗浄し、目的化合物(6.60g)を得た。Reference Example 5
L- (N-benzyloxycarbonyl) glutamine methyl ester L- (N-benzyloxycarbonyl) glutamine (8.00 g, 28.54 mmol) was dissolved in DMF (80 mL) in sodium bicarbonate (4.80 g, 57 .14 mol) and methyl iodide (4.44 mL, 71.32 mmol) were added, and the mixture was stirred at room temperature for 22 hours.
Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 10% aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was washed with ethyl acetate-ether to obtain the target compound (6.60 g).
1H−NMR(CD3OD)
7.26−7.37(5H,m),5.09(2H,s),4.21(1H,dd,J=5.2,9.2Hz),3.72(3H,s),2.31(2H,t,J=7.8Hz),2.10−2.19(1H,m),1.88−1.97(1H,m). 1 H-NMR (CD 3 OD)
7.26-7.37 (5H, m), 5.09 (2H, s), 4.21 (1H, dd, J = 5.2, 9.2 Hz), 3.72 (3H, s), 2.31 (2H, t, J = 7.8 Hz), 2.10-2.19 (1H, m), 1.88-1.97 (1H, m).
参考例6
(3S)−3−ベンジルオキシカルボニルアミノ−2−ピロリドン
ビス(トリフルオロアセトキシ)ヨードベンゼン(10.45g,24.30mmol)をアセトニトリル(50mL)、水(50mL)及びピリジン(3.02mL,37.34mmol)に懸濁した溶液に、参考例5の化合物(5.50g,18.69mmol)を加え、室温で4時間攪拌した。
反応液を減圧濃縮し、水を加えた後、酢酸エチルで抽出した。酢酸エチル層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、溶媒を留去した。
残査をクロロホルム(100mL)に溶解した溶液に,炭酸水素ナトリウム水溶液(5g/100mL)を加え、室温で17時間攪拌した。
反応液を水層とクロロホルム層に分離し、水層をクロロホルムで抽出した。クロロホルム層を合わせ、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、溶媒を留去する。残査をエーテルで洗浄し、目的化合物(2.41g)を得た。Reference Example 6
(3S) -3-Benzyloxycarbonylamino-2-pyrrolidone bis (trifluoroacetoxy) iodobenzene (10.45 g, 24.30 mmol) in acetonitrile (50 mL), water (50 mL) and pyridine (3.02 mL, 37. 34 mmol), the compound of Reference Example 5 (5.50 g, 18.69 mmol) was added, and the mixture was stirred at room temperature for 4 hours.
The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated.
To a solution obtained by dissolving the residue in chloroform (100 mL), an aqueous sodium hydrogen carbonate solution (5 g / 100 mL) was added, and the mixture was stirred at room temperature for 17 hours.
The reaction solution was separated into an aqueous layer and a chloroform layer, and the aqueous layer was extracted with chloroform. The chloroform layers are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue was washed with ether to obtain the target compound (2.41 g).
1H−NMR(CDCl3、内部標準TMS)
7.28−7.38(5H,m),6.49(1H,br s),5.49(1H,br d,J=4.9Hz),5.11(2H,s),4.21−4.27(1H,m),3.29−3.38(2H,m),2.65−2.73(1H,m),1.98(1H,qd,J=9.8,12.2Hz). 1 H-NMR (CDCl 3 , internal standard TMS)
7.28-7.38 (5 H, m), 6.49 (1 H, br s), 5.49 (1 H, br d, J = 4.9 Hz), 5.11 (2 H, s), 4. 21-4.27 (1H, m), 3.29-3.38 (2H, m), 2.65-2.73 (1H, m), 1.98 (1H, qd, J = 9.8) , 12.2 Hz).
参考例7
(3S)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ピロリドン
窒素気流下、参考例6の化合物(3.00g,12.81mmol)を無水THF(210mL)に溶解した溶液に、外温−78℃でn−ブチルリチウムヘキサン溶液(1.54M,7.9mL,12.17mmol)をゆっくり加え、45分間攪拌した。次いで塩化ホスホリル(1.96g,12.78mmol)の無水THF(4mL)溶液を加え、同温で50分間、室温で1時間攪拌した。反応液を再び外温−78℃で冷却し、液体アンモニア(2.5mL,113mmol)を加え、5分間攪拌した。
溶媒を減圧留去し、残査に食塩水を加え、水層をヘキサン及びクロロホルムで洗浄した後、HP−20SSで精製した。得られた結晶をクロロホルム−エーテルで洗浄を行い、目的化合物(1.83g)を得た。Reference Example 7
(3S) -3-Benzyloxycarbonylamino-1-diaminophosphinyl-2-pyrrolidone To a solution of the compound of Reference Example 6 (3.00 g, 12.81 mmol) dissolved in anhydrous THF (210 mL) under a nitrogen stream. Then, an n-butyllithium hexane solution (1.54M, 7.9 mL, 12.17 mmol) was slowly added at an external temperature of −78 ° C., and the mixture was stirred for 45 minutes. Next, a solution of phosphoryl chloride (1.96 g, 12.78 mmol) in anhydrous THF (4 mL) was added, and the mixture was stirred at the same temperature for 50 minutes and at room temperature for 1 hour. The reaction solution was cooled again at an external temperature of −78 ° C., liquid ammonia (2.5 mL, 113 mmol) was added, and the mixture was stirred for 5 minutes.
The solvent was distilled off under reduced pressure, brine was added to the residue, the aqueous layer was washed with hexane and chloroform, and then purified with HP-20SS. The obtained crystals were washed with chloroform-ether to obtain the target compound (1.83 g).
1H−NMR(CD3OD)
7.26−7.37(5H,m),5.01(2H,s),4.35(1H,dd,J=8.4,11.2Hz),3.72(1H,dd,J=8.8,10.0Hz),3.53(1H,td,J=10.0,6.4Hz),2.37−2.44(1H,m),1.95−2.06(1H,m).
MS(FAB,POS)
m/z:313(M+H)+,335(M+Na)+. 1 H-NMR (CD 3 OD)
7.26-7.37 (5H, m), 5.01 (2H, s), 4.35 (1H, dd, J = 8.4, 11.2 Hz), 3.72 (1H, dd, J = 8.8, 10.0 Hz), 3.53 (1 H, td, J = 10.0, 6.4 Hz), 2.37-2.44 (1 H, m), 1.95-2.06 ( 1H, m).
MS (FAB, POS)
m / z: 313 (M + H) + , 335 (M + Na) + .
参考例8
(3S,PR)−3−ベンジルオキシカルボニルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン ナトリウム塩
スルフォスチン1水和物(600.6mg,2.0694mmol)を水(15mL)に溶解した溶液に炭酸水素ナトリウム(434.6mg,5.1732mmol)、テトラヒドロフラン(10mL)、及びベンジルオキシカルボニルクロリド(0.38mL,2.6618mmol)を加え、室温で一晩撹拌した。
反応液のテトラヒドロフランを減圧留去した後、ダイアイオンHP−20(150mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(752.4mg,85%)を得た。Reference Example 8
(3S, PR) -3-Benzyloxycarbonylamino-1-amino (sulfoamino) phosphinyl-2-piperidone sodium salt Sulfostin monohydrate (600.6 mg, 2.0694 mmol) was dissolved in water (15 mL). Sodium hydrogen carbonate (434.6 mg, 5.1732 mmol), tetrahydrofuran (10 mL), and benzyloxycarbonyl chloride (0.38 mL, 2.6618 mmol) were added, and the mixture was stirred overnight at room temperature.
Tetrahydrofuran of the reaction solution was distilled off under reduced pressure, then purified with Diaion HP-20 (150 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (752.4 mg, 85%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.39−7.48(5H,m),5.12−5.21(2H,m),4.32(1H,dd,J=11.7,6.8),3.70−3.79(1H,m),3.55−3.67(1H,m),2.15−2.25(1H,m),1.98−2.07(1H,m),1.85−1.95(1H,m),1.76(1H,tdd,J=11.7,9.3,6.8Hz).
MS(FAB,POS)
m/z:451(M+Na)+. 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.39-7.48 (5H, m), 5.12-5.21 (2H, m), 4.32 (1H, dd, J = 11.7, 6.8), 3.70-3 .79 (1H, m), 3.55-3.67 (1H, m), 2.15-2.25 (1H, m), 1.98-2.07 (1H, m), 1.85 -1.95 (1H, m), 1.76 (1H, tdd, J = 11.7, 9.3, 6.8 Hz).
MS (FAB, POS)
m / z: 451 (M + Na) + .
参考例9
(3R)−3−ベンジルオキシカルボニルアミノ−2−ピペリドン
氷冷下、メタノール(300mL)に塩化チオニル(13.0mL,178.22mmol)を加え、30分間攪拌した。次いで、D−オルニチン塩酸塩(20.00g,118.61mmol)を20分間かけて加え、同温で30分間、室温で終夜攪拌した。
反応液を減圧濃縮した後、得られたオイルを水(200mL)に溶解し、氷冷下、炭酸水素ナトリウム(29.89g,355.79mmol)を数回に分けて加え、室温で20時間攪拌した。
次に反応液にTHF(100mL)及び炭酸水素ナトリウム(14.95g,177.90mmol)を加えた後、氷冷下で塩化ベンジルオキシカルボニル(22.0mL,154.10mmol)を加え、室温で18時間攪拌した。
反応液を濃縮し、水を加えた後、酢酸エチルで抽出した。酢酸エチル層は飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、溶媒を留去した。残査にエーテル−n−ヘキサンを加えて結晶化した後、エーテル−n−ヘキサンで洗浄を行い、目的化合物(21.46g,73%)を得た。Reference Example 9
(3R) -3-Benzyloxycarbonylamino-2-piperidone Under ice-cooling, thionyl chloride (13.0 mL, 178.22 mmol) was added to methanol (300 mL), and the mixture was stirred for 30 minutes. Next, D-ornithine hydrochloride (20.00 g, 118.61 mmol) was added over 20 minutes, and the mixture was stirred at the same temperature for 30 minutes and at room temperature overnight.
After concentrating the reaction solution under reduced pressure, the obtained oil was dissolved in water (200 mL), and sodium hydrogen carbonate (29.89 g, 355.79 mmol) was added in several portions under ice cooling, followed by stirring at room temperature for 20 hours. did.
Next, THF (100 mL) and sodium hydrogen carbonate (14.95 g, 177.90 mmol) were added to the reaction solution, and then benzyloxycarbonyl chloride (22.0 mL, 154.10 mmol) was added under ice-cooling. Stir for hours.
The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. After ether-n-hexane was added to the residue for crystallization, the residue was washed with ether-n-hexane to obtain the target compound (21.46 g, 73%).
1H−NMR(CDCl3、内部標準TMS)
7.30−7.37(5H,m),6.43(1H,br s),5.81(1H,br s),5.03(2H,s),4.09(1H,td,J=5.8,11.6Hz),3.27−3.32(2H,m),2.45−2.52(1H,m),1.83−1.95(2H,m),1.61(1H,tdd,J=11.6,12.8,5.2Hz). 1 H-NMR (CDCl 3 , internal standard TMS)
7.30-7.37 (5H, m), 6.43 (1H, br s), 5.81 (1H, br s), 5.03 (2H, s), 4.09 (1H, td, J = 5.8, 11.6 Hz), 3.27-3.32 (2H, m), 2.45-2.52 (1H, m), 1.83-1.95 (2H, m), 1.61 (1H, tdd, J = 11.6, 12.8, 5.2 Hz).
参考例10
(3R)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ピペリドン
窒素気流下、参考例9の化合物(16.00g,64.44mmol)を無水THF(200mL)に溶解し、外温−78℃で冷却後、n−ブチルリチウムヘキサン溶液(2.46M,25mL,61.50mmol)をゆっくりと加え、1.5時間攪拌した。次に同温で塩化ホスホリル(11.86g,77.35mmol)の無水THF(40mL)溶液を加えて35分間攪拌した。更に液体アンモニア(8.8mL,398.40mmol)を加えて5分間攪拌した。
反応液を濃縮後、ダイアイオンHP−20(500mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(4.91g,23%)を得た。Reference Example 10
(3R) -3-Benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone The compound of Reference Example 9 (16.00 g, 64.44 mmol) was dissolved in anhydrous THF (200 mL) under a nitrogen stream, After cooling at a temperature of −78 ° C., n-butyllithium hexane solution (2.46 M, 25 mL, 61.50 mmol) was slowly added and stirred for 1.5 hours. Next, a solution of phosphoryl chloride (11.86 g, 77.35 mmol) in anhydrous THF (40 mL) was added at the same temperature and stirred for 35 minutes. Further, liquid ammonia (8.8 mL, 398.40 mmol) was added and stirred for 5 minutes.
The reaction mixture was concentrated and purified with Diaion HP-20 (500 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the desired compound (4.91 g, 23%).
1H−NMR(DMSO−D6、内部標準TMS)
7.42(1H,d,J=8.9Hz),7.30−7.39(5H,m),5.03(2H,s),4.21(2H,br s),4.16(2H,br s),4.10(1H,td,J=7.9,11.9Hz),3.56−3.62(1H,m),3.44−3.50(1H,m),1.98−2.06(1H,m),1.74−1.80(2H,m),1.59−1.67(1H,m).
MS(FAB,POS)
m/z:327(M+H)+ 1 H-NMR (DMSO-D 6 , internal standard TMS)
7.42 (1H, d, J = 8.9 Hz), 7.30-7.39 (5H, m), 5.03 (2H, s), 4.21 (2H, br s), 4.16 (2H, br s), 4.10 (1H, td, J = 7.9, 11.9 Hz), 3.56-3.62 (1H, m), 3.44-3.50 (1H, m ), 1.98-2.06 (1H, m), 1.74-1.80 (2H, m), 1.59-1.67 (1H, m).
MS (FAB, POS)
m / z: 327 (M + H) +
実施例1
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−ベンゾイルアミノ−2−ピペリドンナトリウム塩
スルフォスチン1水和物(100.3mg,0.3456mmol)を水(2mL)に溶解した溶液に炭酸水素ナトリウム(145.2mg,1.7284mmol)、アセトニトリル(2mL)、及びベンゾイルクロリド(0.080mL,0.6892mmol)を加え、室温で1時間撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(86.0mg,63%)を得た。Example 1
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3-benzoylamino-2-piperidone sodium salt Sulfostin monohydrate (100.3 mg, 0.3456 mmol) dissolved in water (2 mL) was dissolved in carbonic acid. Sodium hydride (145.2 mg, 1.7284 mmol), acetonitrile (2 mL), and benzoyl chloride (0.080 mL, 0.6892 mmol) were added, and the mixture was stirred at room temperature for 1 hour.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (86.0 mg, 63%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.83(2H,d,J=7.8Hz),7.64(1H,t,J=7.8Hz),7.55(2H,t,J=7.8Hz),4.79(1H,dd,J=11.2,6.8Hz),3.68−3.83(2H,m),2.25−2.31(1H,m),2.06−2.17(1H,m),1.86−2.03(2H,m).
HR−MS(ESI,POS)
m/z:found,421.0342(M+Na)+
calcd.for C12H16N4Na2O6,421.0324 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.83 (2H, d, J = 7.8 Hz), 7.64 (1H, t, J = 7.8 Hz), 7.55 (2H, t, J = 7.8 Hz), 4.79 (1H , Dd, J = 11.2, 6.8 Hz), 3.68-3.83 (2H, m), 2.25-2.31 (1H, m), 2.06-2.17 (1H, m), 1.86-2.03 (2H, m).
HR-MS (ESI, POS)
m / z: found, 421.0342 (M + Na) +
calcd. for C 12 H 16 N 4 Na 2 O 6, 421.0324
実施例2
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−(4−ブロモベンゾイル)アミノ−2−ピペリドン ナトリウム塩
スルフォスチン1水和物(150.5mg,0.5186mmol)を水(3mL)に溶解した溶液に炭酸水素ナトリウム(217.8mg,2.5925mmol)、アセトニトリル(3mL)、及び4−ブロモベンゾイルクロリド(227.6mg,1.0370mmol)を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(218.8mg,88%)を得た。Example 2
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (4-bromobenzoyl) amino-2-piperidone sodium salt Sulfostin monohydrate (150.5 mg, 0.5186 mmol) dissolved in water (3 mL) To the solution was added sodium bicarbonate (217.8 mg, 2.5925 mmol), acetonitrile (3 mL), and 4-bromobenzoyl chloride (227.6 mg, 1.0370 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (218.8 mg, 88%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.68−7.74(4H,m),4.69(1H,dd,J=10.7,6.8Hz),3.81(1H,tdd、J=9.3,7.8,4.9Hz),3.63−3.71(1H,m),2.21−2.28(1H,m),2.01−2.10(1H,m),1.82−1.92(2H,m).
HR−MS(ESI,POS)
m/z:found,498.9433(M+Na)+
calcd.for C12H15BrN4Na2O6PS,498.9429 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.68-7.74 (4H, m), 4.69 (1H, dd, J = 10.7, 6.8 Hz), 3.81 (1H, tdd, J = 9.3, 7.8, 4.9 Hz), 3.63-3.71 (1H, m), 2.21-2.28 (1H, m), 2.01-2.10 (1H, m), 1.82-1. 92 (2H, m).
HR-MS (ESI, POS)
m / z: found, 498.9433 (M + Na) +
calcd. for C 12 H 15 BrN 4 Na 2 O 6 PS, 498.9429
実施例3
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−(3−ブロモベンゾイル)アミノ−2−ピペリドン ナトリウム塩
スルフォスチン1水和物(151.5mg,0.5220mmol)を水(3mL)に溶解した溶液に炭酸水素ナトリウム(219.3mg,2.6104mmol)、アセトニトリル(3mL)、及び3−ブロモベンゾイルクロリド(0.137mL,1.0439mmol)を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(151.2mg,61%)を得た。Example 3
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (3-bromobenzoyl) amino-2-piperidone sodium salt Sulfostin monohydrate (151.5 mg, 0.5220 mmol) dissolved in water (3 mL) To the resulting solution were added sodium hydrogen carbonate (219.3 mg, 2.6104 mmol), acetonitrile (3 mL), and 3-bromobenzoyl chloride (0.137 mL, 1.0439 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (151.2 mg, 61%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.98−8.00(1H,m),7.75−7.89(2H,m),7.44(1H,t,J=7.8Hz),4.72(1H,dd,J=11.2,6.8Hz),3.78−3.85(1H,m),3.65−3.72(1H,m),2.22−2.30(1H,m),2.03−2.12(1H,m),1.83−2.00(2H,m).
HR−MS(ESI,POS)
m/z:found,498.9409(M+Na)+
calcd.for C12H15BrN4Na2O6PS,498.9429 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.98-8.00 (1H, m), 7.75-7.89 (2H, m), 7.44 (1H, t, J = 7.8 Hz), 4.72 (1H, dd, J = 11.2, 6.8 Hz), 3.78-3.85 (1H, m), 3.65-3.72 (1H, m), 2.22-2.30 (1H, m), 2 .03-2.12 (1H, m), 1.83-2.00 (2H, m).
HR-MS (ESI, POS)
m / z: found, 498.9409 (M + Na) +
calcd. for C 12 H 15 BrN 4 Na 2 O 6 PS, 498.9429
実施例4
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−(2−ブロモベンゾイル)アミノ−2−ピペリドン ナトリウム塩
スルフォスチン1水和物(151.5mg,0.5220mmol)を水(3mL)に溶解した溶液に炭酸水素ナトリウム(219.3mg,2.6104mmol)、アセトニトリル(3mL)、及び2−ブロモベンゾイルクロリド(0.136mL,1.0404mmol)を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(173.5mg,70%)を得た。Example 4
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (2-bromobenzoyl) amino-2-piperidone sodium salt Sulfostin monohydrate (151.5 mg, 0.5220 mmol) dissolved in water (3 mL) To the solution was added sodium hydrogen carbonate (219.3 mg, 2.6104 mmol), acetonitrile (3 mL), and 2-bromobenzoyl chloride (0.136 mL, 1.0404 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, purification was performed with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (173.5 mg, 70%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.72(1H,d,J=7.8Hz),7.54(1H,dd,J=7.8,2.0Hz),7.49(1H,t,J=7.8Hz),7.42(1H,td,J=7.8,2.0Hz),4.68(1H,dd,J=10.7,6.8Hz),3.79−3.86(1H,m),3.62−3.69(1H,m),2.28−2.37(1H,m),2.02−2.09(1H,m),1.84−2.00(2H,m).
HR−MS(ESI,POS)
m/z:found,498.9412(M+Na)+
calcd.for C12H15BrN4Na2O6PS,498.9429 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.72 (1H, d, J = 7.8 Hz), 7.54 (1H, dd, J = 7.8, 2.0 Hz), 7.49 (1H, t, J = 7.8 Hz), 7 .42 (1H, td, J = 7.8, 2.0 Hz), 4.68 (1H, dd, J = 10.7, 6.8 Hz), 3.79-3.86 (1H, m), 3.62-3.69 (1H, m), 2.28-2.37 (1H, m), 2.02-2.09 (1H, m), 1.84-2.00 (2H, m) ).
HR-MS (ESI, POS)
m / z: found, 498.9412 (M + Na) +
calcd. for C 12 H 15 BrN 4 Na 2 O 6 PS, 498.9429
実施例5
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−(4−クロロベンゾイル)アミノ−2−ピペリドン ナトリウム塩
スルフォスチン1水和物(150.3mg,0.5179mmol)を水(3mL)に溶解した溶液に炭酸水素ナトリウム(217.5mg,2.5890mmol)、アセトニトリル(3mL)、及び4−クロロベンゾイルクロリド(0.13mL,1.0229mmol)を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(133.4mg,60%)を得た。Example 5
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (4-chlorobenzoyl) amino-2-piperidone sodium salt Sulfostin monohydrate (150.3 mg, 0.5179 mmol) dissolved in water (3 mL) To the solution was added sodium hydrogen carbonate (217.5 mg, 2.5890 mmol), acetonitrile (3 mL), and 4-chlorobenzoyl chloride (0.13 mL, 1.0229 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (133.4 mg, 60%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.79(2H,d,J=8.3Hz),7.54(2H,d,J=8.3Hz),4.71(1H,dd,J=11.2,6.8Hz),3.78−3.85(1H,m),3.65−3.71(1H,m),2.22−2.28(1H,m),2.02−2.11(1H,m),1.83−2.00(2H,m).
HR−MS(ESI,POS)
m/z:found,454.9929(M+Na)+
calcd.for C12H15ClN4Na2O6PS,454.9934 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.79 (2H, d, J = 8.3 Hz), 7.54 (2H, d, J = 8.3 Hz), 4.71 (1H, dd, J = 11.2, 6.8 Hz), 3 .78-3.85 (1H, m), 3.65-3.71 (1H, m), 2.22-2.28 (1H, m), 2.02-2.11 (1H, m) , 1.83-2.00 (2H, m).
HR-MS (ESI, POS)
m / z: found, 454.9929 (M + Na) +
calcd. for C 12 H 15 ClN 4 Na 2 O 6 PS, 454.9934
実施例6
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−(4−フルオロベンゾイル)アミノ−2−ピペリドン ナトリウム塩
スルフォスチン1水和物(150.3mg,0.5179mmol)を水(3mL)に溶解した溶液に炭酸水素ナトリウム(217.5mg,2.5890mmol)、アセトニトリル(3mL)、及び4−フルオロベンゾイルクロリド(0.12mL,1.0232mmol)を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(98.7mg,46%)を得た。Example 6
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (4-fluorobenzoyl) amino-2-piperidone sodium salt Sulfostin monohydrate (150.3 mg, 0.5179 mmol) dissolved in water (3 mL) To the solution was added sodium hydrogen carbonate (217.5 mg, 2.5890 mmol), acetonitrile (3 mL), and 4-fluorobenzoyl chloride (0.12 mL, 1.0232 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (98.7 mg, 46%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.87(1H,d,J=8.3Hz),7.86(1H,d,J=8.3Hz),7.27(1H,d,J=8.3Hz),7.25(1H,d,J=8.3Hz),4.71(1H,dd,J=10.7,6.8Hz),3.78−3.86(1H,m),3.65−3.72(1H,m),2.21−2.31(1H,m),2.02−2.12(1H,m),1.83−2.00(2H,m).
HR−MS(ESI,POS)
m/z:found,439.0229(M+Na)+
calcd.for C12H15FN4Na2O6PS,439.0229 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.87 (1H, d, J = 8.3 Hz), 7.86 (1H, d, J = 8.3 Hz), 7.27 (1H, d, J = 8.3 Hz), 7.25 (1H , D, J = 8.3 Hz), 4.71 (1H, dd, J = 10.7, 6.8 Hz), 3.78-3.86 (1H, m), 3.65-3.72 ( 1H, m), 2.21-2.31 (1H, m), 2.02-2.12 (1H, m), 1.83-2.00 (2H, m).
HR-MS (ESI, POS)
m / z: found, 439.0229 (M + Na) +
calcd. for C 12 H 15 FN 4 Na 2 O 6 PS, 439.0229
実施例7
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−(4−メチルベンゾイル)アミノ−2−ピペリドン ナトリウム塩
スルフォスチン1水和物(150.5mg,0.5186mmol)を水(3mL)に溶解した溶液に炭酸水素ナトリウム(217.8mg,2.5925mmol)、アセトニトリル(3mL)、及び4−メチルベンゾイルクロリド(0.137mL,1.0359mmol)を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(179.5mg,84%)を得た。Example 7
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (4-methylbenzoyl) amino-2-piperidone sodium salt Sulfostin monohydrate (150.5 mg, 0.5186 mmol) dissolved in water (3 mL) To the solution was added sodium hydrogen carbonate (217.8 mg, 2.5925 mmol), acetonitrile (3 mL), and 4-methylbenzoyl chloride (0.137 mL, 1.0359 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (179.5 mg, 84%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.73(2H,d,J=8.3Hz),7.37(2H,d,J=8.3Hz),4.76(1H,dd,J=11.2,6.8Hz),3.76−3.83(1H,m),3.68−3.74(1H,m),2.41(3H,s),2.23−2.30(1H,m),2.05−2.14(1H,m),1.85−2.00(2H,m).
HR−MS(ESI,POS)
m/z:found,435.0493(M+Na)+
calcd.for C13H18N4Na2O6PS,435.0480 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.73 (2H, d, J = 8.3 Hz), 7.37 (2H, d, J = 8.3 Hz), 4.76 (1H, dd, J = 11.2, 6.8 Hz), 3 .76-3.83 (1H, m), 3.68-3.74 (1H, m), 2.41 (3H, s), 2.23-2.30 (1H, m), 2.05 -2.14 (1H, m), 1.85-2.00 (2H, m).
HR-MS (ESI, POS)
m / z: found, 435.0493 (M + Na) +
calcd. for C 13 H 18 N 4 Na 2 O 6 PS, 435.0480
実施例8
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−(3−メチルベンゾイル)アミノ−2−ピペリドン ナトリウム塩
スルフォスチン1水和物(150.0mg,0.5168mmol)を水(3mL)に溶解した溶液に炭酸水素ナトリウム(217.1mg,2.5842mmol)、アセトニトリル(3mL)、及び3−メチルベンゾイルクロリド(0.14mL,1.0622mmol)を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(61.2mg,29%)を得た。Example 8
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (3-methylbenzoyl) amino-2-piperidone sodium salt Sulfostin monohydrate (150.0 mg, 0.5168 mmol) dissolved in water (3 mL) To the solution was added sodium hydrogen carbonate (217.1 mg, 2.5842 mmol), acetonitrile (3 mL), and 3-methylbenzoyl chloride (0.14 mL, 1.0622 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (61.2 mg, 29%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.65(1H,s),7.62(1H,d,J=7.8Hz),7.47(1H,d,J=7.8Hz),7.43(1H,d,J=7.8Hz),4.72(1H,dd,J=11.2,6.8Hz),3.78−3.85(1H,m),3.65−3.72(1H,m),2.41(3H,s),2.23−2.29(1H,m),2.03−2.12(1H,m),1.83−2.00(2H,m).
HR−MS(ESI,POS)
m/z:found,435.0499(M+Na)+
calcd.for C13H18N4Na2O6PS,435.0480 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.65 (1H, s), 7.62 (1H, d, J = 7.8 Hz), 7.47 (1H, d, J = 7.8 Hz), 7.43 (1H, d, J = 7) .8 Hz), 4.72 (1H, dd, J = 11.2, 6.8 Hz), 3.78-3.85 (1H, m), 3.65-3.72 (1H, m), 2 .41 (3H, s), 2.23-2.29 (1H, m), 2.03-2.12 (1H, m), 1.83-2.00 (2H, m).
HR-MS (ESI, POS)
m / z: found, 435.0499 (M + Na) +
calcd. for C 13 H 18 N 4 Na 2 O 6 PS, 435.0480
実施例9
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−(2−メチルベンゾイル)アミノ−2−ピペリドン ナトリウム塩
スルフォスチン1水和物(150.0mg,0.5168mmol)を水(3mL)に溶解した溶液に炭酸水素ナトリウム(217.1mg,2.5842mmol)、アセトニトリル(3mL)、及び2−メチルベンゾイルクロリド(0.14mL,1.0773mmol)を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(83.3mg,39%)を得た。Example 9
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (2-methylbenzoyl) amino-2-piperidone sodium salt Sulfostin monohydrate (150.0 mg, 0.5168 mmol) dissolved in water (3 mL) To the solution was added sodium hydrogen carbonate (217.1 mg, 2.5842 mmol), acetonitrile (3 mL), and 2-methylbenzoyl chloride (0.14 mL, 1.0773 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (83.3 mg, 39%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.42−7.47(2H,m),7.30−7.37(2H,m),4.68(1H,dd,J=11.2,6.8Hz),3.83(1H,tdd,J=4.9,12.2,7.3Hz),3.63−3.70(1H,m),2.40(3H,s),2.24−2.35(1H,m),2.01−2.10(1H,m),1.82−2.00(2H,m).
HR−MS(ESI,POS)
m/z:found,435.0499(M+Na)+
calcd.for C13H18N4Na2O6PS,435.0480 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.42-7.47 (2H, m), 7.30-7.37 (2H, m), 4.68 (1H, dd, J = 11.2, 6.8 Hz), 3.83 (1H , Tdd, J = 4.9, 12.2, 7.3 Hz), 3.63-3.70 (1H, m), 2.40 (3H, s), 2.24-2.35 (1H, m), 2.01-2.10 (1H, m), 1.82-2.00 (2H, m).
HR-MS (ESI, POS)
m / z: found, 435.0499 (M + Na) +
calcd. for C 13 H 18 N 4 Na 2 O 6 PS, 435.0480
実施例10
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−(4−メトキシベンゾイル)アミノ−2−ピペリドン ナトリウム塩
4−メトキシ安息香酸(118.3mg,0.7775mmol)、ジシクロヘキシルカルボジイミド(160.5mg,0.7779mmol)及びN−ヒドロキシスクシンイミド(89.5mg,0.7777mmol)にアセトニトリル(5mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(150.5mg,0.5186mmol)及び炭酸水素ナトリウム(47.9mg,0.5702mmol)を水(3mL)に溶解した溶液に、4−メトキシ安息香酸活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(93.0mg,42%)を得た。Example 10
(3S, PR) -1-amino (sulfoamino) phosphinyl-3- (4-methoxybenzoyl) amino-2-piperidone sodium salt 4-methoxybenzoic acid (118.3 mg, 0.7775 mmol), dicyclohexylcarbodiimide (160.5 mg) , 0.7779 mmol) and N-hydroxysuccinimide (89.5 mg, 0.7777 mmol) were added acetonitrile (5 mL), and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were filtered off. Then, 4-methoxybenzoic acid active ester solution was added to a solution of sulfostine monohydrate (150.5 mg, 0.5186 mmol) and sodium bicarbonate (47.9 mg, 0.5702 mmol) in water (3 mL). And stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (93.0 mg, 42%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.82(2H,td,J=2.0,8.8Hz),7.08(2H,td,J=2.0,8.8Hz),4.76(1H,dd,J=11.2,6.8Hz)3.89(3H,s),3.79(1H,tdd,J=4.9,12.7,7.3Hz),3.67−3.74(1H,m),2.23−2.30(1H,m),2.08−2.15(1H,m),1.85−2.03(2H,m).
HR−MS(ESI,POS)
m/z:found,451.0443(M+Na)+
calcd.for C13H18N4Na2O7PS,451.0429 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.82 (2H, td, J = 2.0, 8.8 Hz), 7.08 (2H, td, J = 2.0, 8.8 Hz), 4.76 (1H, dd, J = 1.11. 2,6.8 Hz) 3.89 (3H, s), 3.79 (1 H, tdd, J = 4.9, 12.7, 7.3 Hz), 3.67-3.74 (1 H, m) 2.23-2.30 (1H, m), 2.08-2.15 (1H, m), 1.85-2.03 (2H, m).
HR-MS (ESI, POS)
m / z: found, 451.0443 (M + Na) +
calcd. for C 13 H 18 N 4 Na 2 O 7 PS, 451.0429
実施例11
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−(4−ニトロベンゾイル)アミノ−2−ピペリドン ナトリウム塩
4−ニトロ安息香酸(129.8mg,0.7767mmol)、ジシクロヘキシルカルボジイミド(160.3mg,0.7769mmol)及びN−ヒドロキシスクシンイミド(89.4mg,0.7769mmol)にアセトニトリル(5mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(150.3mg,0.5179mmol)及び炭酸水素ナトリウム(47.9mg,0.5702mmol)を水(3mL)に溶解した溶液に、4−ニトロ安息香酸活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(177.0mg,77%)を得た。Example 11
(3S, PR) -1-amino (sulfoamino) phosphinyl-3- (4-nitrobenzoyl) amino-2-piperidone sodium salt 4-nitrobenzoic acid (129.8 mg, 0.7767 mmol), dicyclohexylcarbodiimide (160.3 mg) , 0.7769 mmol) and N-hydroxysuccinimide (89.4 mg, 0.7769 mmol) were added acetonitrile (5 mL), the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Then, 4-nitrobenzoic acid active ester solution was added to a solution of sulfostine monohydrate (150.3 mg, 0.5179 mmol) and sodium bicarbonate (47.9 mg, 0.5702 mmol) in water (3 mL). And stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (177.0 mg, 77%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
8.35(2H,d,J=8.8Hz),8.00(2H,d,J=8.8Hz),4.82(1H,dd,J=11.7,6.8Hz),3.68−3.84(2H,m),2.28−2.35(1H,m),2.08−2.17(1H,m),1.88−2.05(2H,m).
HR−MS(ESI,POS)
m/z:found,466.0211(M+Na)+
calcd.for C12H15N5Na2O8PS,466.0174 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
8.35 (2H, d, J = 8.8 Hz), 8.00 (2H, d, J = 8.8 Hz), 4.82 (1H, dd, J = 11.7, 6.8 Hz), 3 68-3.84 (2H, m), 2.28-2.35 (1H, m), 2.08-2.17 (1H, m), 1.88-2.05 (2H, m) .
HR-MS (ESI, POS)
m / z: found, 466.00211 (M + Na) +
calcd. for C 12 H 15 N 5 Na 2 O 8 PS, 466.0174
実施例12
(3S,PR)−3−シクロヘキサンカルボニルアミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン ナトリウム塩
スルフォスチン1水和物(150.0mg,0.5168mmol)を水(3mL)に溶解した溶液に炭酸水素ナトリウム(217.1mg,2.5842mmol)、アセトニトリル(3mL)、及びシクロヘキサンカルボニルクロリド(0.14mL,1.0773mmol)を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(142.7mg,68%)を得た。Example 12
(3S, PR) -3-cyclohexanecarbonylamino-1-amino (sulfoamino) phosphinyl-2-piperidone sodium salt Sulfostin monohydrate (150.0 mg, 0.5168 mmol) was dissolved in water (3 mL) in a solution of carbonic acid. Sodium hydride (217.1 mg, 2.5842 mmol), acetonitrile (3 mL), and cyclohexanecarbonyl chloride (0.14 mL, 1.0773 mmol) were added, and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (142.7 mg, 68%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
4.48(1H,dd,J=11.2,6.8Hz),3.77(1H,tdd,J=4.9,12.2,7.9Hz),3.58−3.65(1H,m),2.29(1H,td,J=11.7,3.4Hz),2.13(1H,td,J=12.2,5.9Hz),1.95−2.03(1H,m),1.66−1.92(7H,m),1.15−1.44(5H,m).
HR−MS(ESI,POS)
m/z:found,427.0808(M+Na)+
calcd.for C12H22N4Na2O6PS,427.0793 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
4.48 (1H, dd, J = 11.2, 6.8 Hz), 3.77 (1H, tdd, J = 4.9, 12.2, 7.9 Hz), 3.58-3.65 ( 1H, m), 2.29 (1H, td, J = 11.7, 3.4 Hz), 2.13 (1H, td, J = 12.2, 5.9 Hz), 1.95-2.03 (1H, m), 1.66-1.92 (7H, m), 1.15-1.44 (5H, m).
HR-MS (ESI, POS)
m / z: found, 427.0808 (M + Na) +
calcd. for C 12 H 22 N 4 Na 2 O 6 PS, 427.0793
実施例13
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−(2−ナフタレンカルボニル)アミノ−2−ピペリドン ナトリウム塩
2−ナフタレンカルボン酸(134.1mg,0.7788mmol)、ジシクロヘキシルカルボジイミド(160.7mg,0.7788mmol)及びN−ヒドロキシスクシンイミド(89.6mg,0.7785mmol)にアセトニトリル(5mL)及びジメチルホルムアミド(1mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(150.7mg,0.5192mmol)及び炭酸水素ナトリウム(48.0mg,0.5714mmol)を水(3mL)に溶解した溶液に、2−ナフタレンカルボン酸活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(90.2mg,39%)を得た。Example 13
(3S, PR) -1-amino (sulfoamino) phosphinyl-3- (2-naphthalenecarbonyl) amino-2-piperidone sodium salt 2-naphthalenecarboxylic acid (134.1 mg, 0.7788 mmol), dicyclohexylcarbodiimide (160.7 mg) , 0.7788 mmol) and N-hydroxysuccinimide (89.6 mg, 0.7785 mmol) were added acetonitrile (5 mL) and dimethylformamide (1 mL), and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Then, 2-naphthalenecarboxylic acid active ester solution was added to a solution of sulfostine monohydrate (150.7 mg, 0.5192 mmol) and sodium hydrogen carbonate (48.0 mg, 0.5714 mmol) in water (3 mL). And stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (90.2 mg, 39%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
8.26(1H,s),7.96(1H,d,J=8.3Hz),7.92(2H,d,J=8.3Hz),7.75(1H,dd,J=8.3,2.0Hz),7.58−7.66(2H,m),4.74(1H,dd,J=11.2,6.8Hz),3.78−3.85(1H,m),3.64−3.73(1H,m),2.22−2.28(1H,m),2.07−2.15(1H,m),1.86−2.02(2H,m).
HR−MS(ESI,POS)
m/z:found,471.0500(M+Na)+
calcd.for C16H18N4Na2O6PS,471.0480 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
8.26 (1H, s), 7.96 (1H, d, J = 8.3 Hz), 7.92 (2H, d, J = 8.3 Hz), 7.75 (1H, dd, J = 8) .3, 2.0 Hz), 7.58-7.66 (2H, m), 4.74 (1H, dd, J = 11.2, 6.8 Hz), 3.78-3.85 (1H, m), 3.64-3.73 (1H, m), 2.22-2.28 (1H, m), 2.07-2.15 (1H, m), 1.86-2.02 ( 2H, m).
HR-MS (ESI, POS)
m / z: found, 471.0500 (M + Na) +
calcd. for C 16 H 18 N 4 Na 2 O 6 PS, 471.0480
実施例14
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−ニコチノイルアミノ−2−ピペリドン ナトリウム塩
ニコチン酸(96.0mg,0.7798mmol)、ジシクロヘキシルカルボジイミド(160.8mg,0.7793mmol)及びN−ヒドロキシスクシンイミド(89.7mg,0.7794mmol)にアセトニトリル(5mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(150.8mg,0.5196mmol)及び炭酸水素ナトリウム(48.0mg,0.5714mmol)を水(3mL)に溶解した溶液に、ニコチン酸活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(110.0mg,53%)を得た。Example 14
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3-nicotinoylamino-2-piperidone sodium salt Nicotinic acid (96.0 mg, 0.7798 mmol), dicyclohexylcarbodiimide (160.8 mg, 0.7793 mmol) and N Acetonitrile (5 mL) was added to -hydroxysuccinimide (89.7 mg, 0.7794 mmol), the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Subsequently, nicotinic acid active ester solution was added to a solution of sulfostin monohydrate (150.8 mg, 0.5196 mmol) and sodium hydrogen carbonate (48.0 mg, 0.5714 mmol) in water (3 mL), and at room temperature. Stir overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (110.0 mg, 53%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
8.93(1H,dd,J=2.5,1.5Hz),8.71(1H,dd,J=4.9,1.5Hz),8.25(1H,ddd,J=7.8,2.5,1.5Hz),7.59(1H,ddd,J=7.8,4.9,1.5Hz),4.82(1H,dd,J=11.2,6.8Hz),3.77−3.84(1H,m),3.69−3.76(1H,m),2.27−2.34(1H,m),2.07−2.16(1H,m),1.88−2.05(2H,m).
HR−MS(ESI,POS)
m/z:found,422.0272(M+Na)+
calcd.for C11H15N5Na2O6PS,422.0276 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
8.93 (1H, dd, J = 2.5, 1.5 Hz), 8.71 (1H, dd, J = 4.9, 1.5 Hz), 8.25 (1H, ddd, J = 7. 8, 2.5, 1.5 Hz), 7.59 (1H, ddd, J = 7.8, 4.9, 1.5 Hz), 4.82 (1H, dd, J = 11.2, 6.). 8Hz), 3.77-3.84 (1H, m), 3.69-3.76 (1H, m), 2.27-2.34 (1H, m), 2.07-2.16 ( 1H, m), 1.88-2.05 (2H, m).
HR-MS (ESI, POS)
m / z: found, 422.0272 (M + Na) +
calcd. for C 11 H 15 N 5 Na 2 O 6 PS, 422.0276
実施例15
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−イソニコチノイルアミノ−2−ピペリドン ナトリウム塩
イソニコチン酸(96.0mg,0.7798mmol)、ジシクロヘキシルカルボジイミド(160.8mg,0.7793mmol)及びN−ヒドロキシスクシンイミド(89.7mg,0.7794mmol)にアセトニトリル(5mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(150.8mg,0.5196mmol)及び炭酸水素ナトリウム(48.0mg,0.5714mmol)を水(3mL)に溶解した溶液に、先ほど結晶を濾去した溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(138.0mg,67%)を得た。Example 15
(3S, PR) -1-amino (sulfoamino) phosphinyl-3-isonicotinoylamino-2-piperidone sodium salt isonicotinic acid (96.0 mg, 0.7798 mmol), dicyclohexylcarbodiimide (160.8 mg, 0.7793 mmol) Acetonitrile (5 mL) was added to N-hydroxysuccinimide (89.7 mg, 0.7794 mmol), and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Next, to the solution of sulfostine monohydrate (150.8 mg, 0.5196 mmol) and sodium hydrogen carbonate (48.0 mg, 0.5714 mmol) dissolved in water (3 mL), the solution obtained by filtering the crystals is added. Stir at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (138.0 mg, 67%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
8.71(2H,d,J=4.9Hz),7.77(2H,d,J=4.9Hz),4.78−4.84(1H,m),3.62−3.84(2H,m),2.27−2.33(1H,m),2.07−2.16(1H,m),1.87−2.04(2H,m).
HR−MS(ESI,POS)
m/z:found,422.0267(M+Na)+
calcd.for C11H15N5Na2O6PS,422.0276 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
8.71 (2H, d, J = 4.9 Hz), 7.77 (2H, d, J = 4.9 Hz), 4.78-4.84 (1H, m), 3.62-3.84 (2H, m), 2.27-2.33 (1H, m), 2.07-2.16 (1H, m), 1.87-2.04 (2H, m).
HR-MS (ESI, POS)
m / z: found, 422.0267 (M + Na) +
calcd. for C 11 H 15 N 5 Na 2 O 6 PS, 422.0276
実施例16
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−シンナモイルアミノ−2−ピペリドン ナトリウム塩
スルフォスチン1水和物(200.2mg,0.6898mmol)を水(4mL)に溶解した溶液に炭酸水素ナトリウム(289.8mg,3.4496mmol)、アセトニトリル(4mL)、及びシンナモイルクロリド(229.9mg,1.3799mmol)を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(121.8mg,42%)を得た。Example 16
(3S, PR) -1-amino (sulfoamino) phosphinyl-3-cinnamoylamino-2-piperidone sodium salt Sulfostin monohydrate (200.2 mg, 0.6898 mmol) was dissolved in water (4 mL) in a solution of carbonic acid. Sodium hydride (289.8 mg, 3.496 mmol), acetonitrile (4 mL), and cinnamoyl chloride (229.9 mg, 1.3799 mmol) were added, and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (121.8 mg, 42%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.63−7.68(2H,m),7.57(1H,d,J=16.1Hz),7.45−7.53(3H,m),6.68(1H,d,J=16.1Hz),4.60(1H,dd,J=11.2,6.8Hz),3.83(1H,tdd,J=4.9,12.2,7.3Hz),3.63(1H,tdd,J=4.9,11.2,7.3Hz),2.18−2.26(1H,m)、1.99−2.08(1H,m),1.75−1.96(2H,m).
HR−MS(ESI,POS)
m/z:found,447.0498(M+Na)+
calcd.for C14H18N4Na2O6PS,447.0480 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.63-7.68 (2H, m), 7.57 (1H, d, J = 16.1 Hz), 7.45-7.53 (3H, m), 6.68 (1H, d, J = 16.1 Hz), 4.60 (1 H, dd, J = 11.2, 6.8 Hz), 3.83 (1 H, tdd, J = 4.9, 12.2, 7.3 Hz), 3. 63 (1H, tdd, J = 4.9, 11.2, 7.3 Hz), 2.18-2.26 (1H, m), 1.99-2.08 (1H, m), 1.75 -1.96 (2H, m).
HR-MS (ESI, POS)
m / z: found, 447.0498 (M + Na) +
calcd. for C 14 H 18 N 4 Na 2 O 6 PS, 447.0480
実施例17
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−n−カプロイルアミノ−2−ピペリドン ナトリウム塩
スルフォスチン1水和物(120.8mg,0.4162mmol)を水(3mL)に溶解した溶液に炭酸水素ナトリウム(139.9mg,1.6653mmol)、アセトニトリル(3mL)、及び無水n−カプロン酸(0.15mL,0.6481mmol)を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(146.2mg,90%)を得た。Example 17
(3S, PR) -1-amino (sulfoamino) phosphinyl-3-n-caproylamino-2-piperidone sodium salt Sulfostin monohydrate (120.8 mg, 0.4162 mmol) dissolved in water (3 mL) Were added sodium hydrogen carbonate (139.9 mg, 1.6653 mmol), acetonitrile (3 mL), and n-caproic anhydride (0.15 mL, 0.6481 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, purification was performed with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (146.2 mg, 90%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
4.47(1H,dd,J=11.2,6.8Hz),3.75−3.82(1H,m),3.56−3.63(1H,m),2.31(2H,t,J=7.3Hz),2.09−2.19(1H,m),1.94−2.03(1H,m),1.81−1.92(1H,m),1.68−1.78(1H,m),1.58−1.66(2H,m),1.26−1.37(4H,m),0.88(3H,t,J=7.3Hz).
HR−MS(ESI,POS)
m/z:found,415.0786(M+Na)+
calcd.for C11H22N4Na2O6PS,415.0793 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
4.47 (1H, dd, J = 11.2, 6.8 Hz), 3.75-3.82 (1H, m), 3.56-3.63 (1H, m), 2.31 (2H , T, J = 7.3 Hz), 2.09-2.19 (1H, m), 1.94-2.03 (1H, m), 1.81-1.92 (1H, m), 1 .68-1.78 (1H, m), 1.58-1.66 (2H, m), 1.26-1.37 (4H, m), 0.88 (3H, t, J = 7. 3 Hz).
HR-MS (ESI, POS)
m / z: found, 415.0786 (M + Na) +
calcd. for C 11 H 22 N 4 Na 2 O 6 PS, 415.0793
実施例18
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−(フェニルアセチル)アミノ−2−ピペリドン ナトリウム塩
スルフォスチン1水和物(150.1mg,0.5172mmol)を水(3mL)に溶解した溶液に炭酸水素ナトリウム(217.2mg,2.5854mmol)、アセトニトリル(3mL)、及びフェニルアセチルクロリド(0.14mL,1.0586mmol)を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(110.9mg,52%)を得た。Example 18
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (phenylacetyl) amino-2-piperidone sodium salt Sulfostin monohydrate (150.1 mg, 0.5172 mmol) dissolved in water (3 mL) Were added sodium hydrogen carbonate (217.2 mg, 2.5854 mmol), acetonitrile (3 mL), and phenylacetyl chloride (0.14 mL, 1.0586 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (110.9 mg, 52%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.36−7.45(5H,m),4.50(1H,dd,J=11.2,6.8Hz),3.76(1H,tdd,J=4.9,12.2,7.3Hz),3.68(2H,s),3.57−3.65(1H,m),2.09−2.17(1H,m),1.94−2.04(1H,m),1.81−1.92(1H,m),1.68−1.77(1H,m).
HR−MS(ESI,POS)
m/z:found,435.0499(M+Na)+
calcd.for C13H18N4Na2O6PS,435.0480 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.36-7.45 (5H, m), 4.50 (1H, dd, J = 11.2, 6.8Hz), 3.76 (1H, tdd, J = 4.9, 12.2, 7.3 Hz), 3.68 (2H, s), 3.57-3.65 (1H, m), 2.09-2.17 (1H, m), 1.94-2.04 (1H, m), 1.81-1.92 (1H, m), 1.68-1.77 (1H, m).
HR-MS (ESI, POS)
m / z: found, 435.0499 (M + Na) +
calcd. for C 13 H 18 N 4 Na 2 O 6 PS, 435.0480
実施例19
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−((4−メトキシフェニル)アセチル)アミノ−2−ピペリドン ナトリウム塩
4−メトキシフェニル酢酸(129.3mg,0.7781mmol)、ジシクロヘキシルカルボジイミド(160.5mg,0.7779mmol)及びN−ヒドロキシスクシンイミド(89.5mg,0.7777mmol)にアセトニトリル(5mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(150.5mg,0.5186mmol)及び炭酸水素ナトリウム(47.9mg,0.5702mmol)を水(3mL)に溶解した溶液に、4−メトキシフェニル酢酸活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(160.0mg,70%)を得た。Example 19
(3S, PR) -1-amino (sulfoamino) phosphinyl-3-((4-methoxyphenyl) acetyl) amino-2-piperidone sodium salt 4-methoxyphenylacetic acid (129.3 mg, 0.7781 mmol), dicyclohexylcarbodiimide ( Acetonitrile (5 mL) was added to 160.5 mg, 0.77779 mmol) and N-hydroxysuccinimide (89.5 mg, 0.7777 mmol), and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were filtered off. Then, 4-methoxyphenylacetic acid active ester solution was added to a solution of sulfostine monohydrate (150.5 mg, 0.5186 mmol) and sodium bicarbonate (47.9 mg, 0.5702 mmol) in water (3 mL). And stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (160.0 mg, 70%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.30(2H,d,J=8.8Hz),7.00(2H,d,J=8.8Hz),4.55(1H,dd,J=11.7,6.8Hz),3.84(3H,s),3.70−3.77(1H,m),3.57−3.68(1H,m),3.62(2H,s),2.11−2.19(1H,m),1.98−2.08(1H,m),1.85−1.95(1H,m),1.69−1.80(1H,m).
HR−MS(ESI,POS)
m/z:found,465.0598(M+Na)+
calcd.for C14H20N4Na2O7PS,465.0586 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.30 (2H, d, J = 8.8 Hz), 7.00 (2H, d, J = 8.8 Hz), 4.55 (1H, dd, J = 11.7, 6.8 Hz), 3 .84 (3H, s), 3.70-3.77 (1H, m), 3.57-3.68 (1H, m), 3.62 (2H, s), 2.11-2.19 (1H, m), 1.98-2.08 (1H, m), 1.85-1.95 (1H, m), 1.69-1.80 (1H, m).
HR-MS (ESI, POS)
m / z: found, 465.0598 (M + Na) +
calcd. for C 14 H 20 N 4 Na 2 O 7 PS, 465.0586
実施例20
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−((4−ニトロフェニル)アセチル)アミノ−2−ピペリドン ナトリウム塩
4−ニトロフェニル酢酸(140.7mg,0.7767mmol)、ジシクロヘキシルカルボジイミド(160.3mg,0.7769mmol)及びN−ヒドロキシスクシンイミド(89.4mg,0.7768mmol)にアセトニトリル(5mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(150.3mg,0.5179mmol)及び炭酸水素ナトリウム(47.9mg,0.5702mmol)を水(3mL)に溶解した溶液に、4−ニトロフェニル酢酸活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(162.0mg,68%)を得た。Example 20
(3S, PR) -1-amino (sulfoamino) phosphinyl-3-((4-nitrophenyl) acetyl) amino-2-piperidone sodium salt 4-nitrophenylacetic acid (140.7 mg, 0.7767 mmol), dicyclohexylcarbodiimide ( Acetonitrile (5 mL) was added to 160.3 mg, 0.7769 mmol) and N-hydroxysuccinimide (89.4 mg, 0.7768 mmol), and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were filtered off. Then, 4-nitrophenylacetic acid active ester solution was added to a solution of sulfostine monohydrate (150.3 mg, 0.5179 mmol) and sodium bicarbonate (47.9 mg, 0.5702 mmol) in water (3 mL). And stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (162.0 mg, 68%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
8.22(2H,td,J=2.4,8.8Hz),7.54(2H,td,J=2.4,8.8Hz),4.58(1H,dd,J=11.2,6.8Hz),3.83(2H,s),3.74(1H,tdd,J=4.9,12.2,5.9Hz),3.60−3.68(1H,m),2.18(1H,td,J=12.2,5.9Hz),1.99−2.09(1H,m),1.86−1.97(1H,m),1.78(1H,tdd,J=12.2,9.3,6.4Hz).
HR−MS(ESI,POS)
m/z:found,480.0338(M+Na)+
calcd.for C13H17N5Na2O8PS,480.0331 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
8.22 (2H, td, J = 2.4, 8.8 Hz), 7.54 (2H, td, J = 2.4, 8.8 Hz), 4.58 (1H, dd, J = 1.11. 2,6.8 Hz), 3.83 (2H, s), 3.74 (1 H, tdd, J = 4.9, 12.2, 5.9 Hz), 3.60-3.68 (1 H, m ), 2.18 (1H, td, J = 12.2, 5.9 Hz), 1.99-2.09 (1H, m), 1.86-1.97 (1H, m), 1.78. (1H, tdd, J = 12.2, 9.3, 6.4 Hz).
HR-MS (ESI, POS)
m / z: found, 480.0338 (M + Na) +
calcd. for C 13 H 17 N 5 Na 2 O 8 PS, 480.0331
実施例21
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−(3−フェニルプロピオニル)アミノ−2−ピペリドン ナトリウム塩
3−フェニルプロピオン酸(117.1mg,0.7797mmol)、ジシクロヘキシルカルボジイミド(160.8mg,0.7793mmol)及びN−ヒドロキシスクシンイミド(89.7mg,0.7794mmol)にアセトニトリル(5mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(150.8mg,0.5196mmol)及び炭酸水素ナトリウム(48.0mg,0.5714mmol)を水(3mL)に溶解した溶液に、3−フェニルプロピオン酸活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(187.0mg,84%)を得た。Example 21
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (3-phenylpropionyl) amino-2-piperidone sodium salt 3-phenylpropionic acid (117.1 mg, 0.7797 mmol), dicyclohexylcarbodiimide (160.8 mg) , 0.7793 mmol) and N-hydroxysuccinimide (89.7 mg, 0.7794 mmol) were added acetonitrile (5 mL), and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Then, 3-phenylpropionic acid active ester solution was added to a solution of sulfostine monohydrate (150.8 mg, 0.5196 mmol) and sodium hydrogen carbonate (48.0 mg, 0.5714 mmol) in water (3 mL). And stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (187.0 mg, 84%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.35−7.40(2H,m),7.27−7.31(3H,m),4.37(1H,dd,J=12.2,6.4Hz),3.72(1H,tdd,J=4.9,12.2,7.9Hz),3.52−3.59(1H,m),2.89−3.02(2H,m),2.56−2.68(2H,m),1.84−1.93(2H,m),1.73−1.84(1H,m),1.44−1.54(1H,m).
HR−MS(ESI,POS)
m/z:found,449.0645(M+Na)+
calcd.for C14H20N4Na2O6PS,449.0637 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.35-7.40 (2H, m), 7.27-7.31 (3H, m), 4.37 (1H, dd, J = 12.2, 6.4 Hz), 3.72 (1H , Tdd, J = 4.9, 12.2, 7.9 Hz), 3.52-3.59 (1H, m), 2.89-3.02 (2H, m), 2.56-2. 68 (2H, m), 1.84-1.93 (2H, m), 1.73-1.84 (1H, m), 1.44-1.54 (1H, m).
HR-MS (ESI, POS)
m / z: found, 449.0645 (M + Na) +
calcd. for C 14 H 20 N 4 Na 2 O 6 PS, 449.00637
実施例22
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−(フェノキシアセチル)アミノ−2−ピペリドン ナトリウム塩
スルフォスチン1水和物(151.5mg,0.5220mmol)を水(3mL)に溶解した溶液に炭酸水素ナトリウム(2219.3mg,2.6104mmol)、アセトニトリル(3mL)、及びフェノキシアセチルクロリド(0.144mL,1.0424mmol)を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(207.7mg,93%)を得た。Example 22
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (phenoxyacetyl) amino-2-piperidone sodium salt Sulfostin monohydrate (151.5 mg, 0.5220 mmol) dissolved in water (3 mL) Were added sodium hydrogen carbonate (2219.3 mg, 2.6104 mmol), acetonitrile (3 mL), and phenoxyacetyl chloride (0.144 mL, 1.0424 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (207.7 mg, 93%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.41(2H,t,J=7.8Hz),7.10(1H,t,J=7.8Hz),7.05(2H,d,J=7.8Hz),4.70(2H,d,J=6.4Hz),4.64(1H,dd,J=11.7,6.8Hz),3.75(1H,tdd,J=4.9,12.2,7.8Hz),3.62−3.69(1H,m),2.12−2.20(1H,m),1.98−2.07(1H,m),1.85−1.95(1H,m),1.73−1.83(1H,m).
HR−MS(ESI,POS)
m/z:found,451.0442(M+Na)+
calcd.for C13H18N4Na2O7PS,451.0429 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.41 (2H, t, J = 7.8 Hz), 7.10 (1H, t, J = 7.8 Hz), 7.05 (2H, d, J = 7.8 Hz), 4.70 (2H , D, J = 6.4 Hz), 4.64 (1H, dd, J = 11.7, 6.8 Hz), 3.75 (1H, tdd, J = 4.9, 12.2, 7.8 Hz) ), 3.62-3.69 (1H, m), 2.12-2.20 (1H, m), 1.98-2.07 (1H, m), 1.85-1.95 (1H) , M), 1.73-1.83 (1H, m).
HR-MS (ESI, POS)
m / z: found, 451.0442 (M + Na) +
calcd. for C 13 H 18 N 4 Na 2 O 7 PS, 451.0429
実施例23
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−(3−シクロヘキシルプロピオニル)アミノ−2−ピペリドン ナトリウム塩
3−シクロヘキシルプロピオン酸(122.7mg,0.7854mmol)、ジシクロヘキシルカルボジイミド(162.1mg,0.7856mmol)及びN−ヒドロキシスクシンイミド(90.4mg,0.7855mmol)にアセトニトリル(5mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(152.0mg,0.5237mmol)及び炭酸水素ナトリウム(48.4mg,0.5761mmol)を水(3mL)に溶解した溶液に、3−シクロヘキシルプロピオン酸活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(130.0mg,57%)を得た。Example 23
(3S, PR) -1-amino (sulfoamino) phosphinyl-3- (3-cyclohexylpropionyl) amino-2-piperidone sodium salt 3-cyclohexylpropionic acid (122.7 mg, 0.7854 mmol), dicyclohexylcarbodiimide (162.1 mg) , 0.7856 mmol) and N-hydroxysuccinimide (90.4 mg, 0.7855 mmol) were added acetonitrile (5 mL), the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Next, a solution of 3-cyclohexylpropionic acid active ester was added to a solution of sulfostine monohydrate (152.0 mg, 0.5237 mmol) and sodium bicarbonate (48.4 mg, 0.5761 mmol) in water (3 mL). And stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (130.0 mg, 57%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
4.46(1H,dd,J=10.7,6.8Hz),3.75−3.64(1H,m),3.56−3.64(1H,m),2.31−2.35(2H,m),2.09−2.17(1H,m),1.93−2.03(1H,m),1.81−1.91(1H,m),1.58−1.78(6H,m),1.48−1.55(2H,m),1.09−1.29(4H,m),0.85−0.97(2H,m).
HR−MS(ESI,POS)
m/z:found,455.1130(M+Na)+
calcd.for C14H26N4Na2O6PS,455.1106 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
4.46 (1H, dd, J = 10.7, 6.8 Hz), 3.75-3.64 (1H, m), 3.56-3.64 (1H, m), 2.31-2 .35 (2H, m), 2.09-2.17 (1H, m), 1.93-2.03 (1H, m), 1.81-1.91 (1H, m), 1.58 -1.78 (6H, m), 1.48-1.55 (2H, m), 1.09-1.29 (4H, m), 0.85-0.97 (2H, m).
HR-MS (ESI, POS)
m / z: found, 455.1130 (M + Na) +
calcd. for C 14 H 26 N 4 Na 2 O 6 PS, 455.1106
実施例24
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−(1−ナフトキシアセチル)アミノ−2−ピペリドン ナトリウム塩
1−ナフトキシ酢酸(157.5mg,0.7789mmol)、ジシクロヘキシルカルボジイミド(160.8mg,0.7793mmol)及びN−ヒドロキシスクシンイミド(89.7mg,0.7794mmol)にアセトニトリル(5mL)及びジメチルホルムアミド(1mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(150.7mg,0.5192mmol)及び炭酸水素ナトリウム(48.0mg,0.5714mmol)を水(3mL)に溶解した溶液に、1−ナフトキシ酢酸活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(175.9mg,71%)を得た。Example 24
(3S, PR) -1-amino (sulfoamino) phosphinyl-3- (1-naphthoxyacetyl) amino-2-piperidone sodium salt 1-naphthoxyacetic acid (157.5 mg, 0.7789 mmol), dicyclohexylcarbodiimide (160.8 mg) , 0.7793 mmol) and N-hydroxysuccinimide (89.7 mg, 0.7794 mmol) were added acetonitrile (5 mL) and dimethylformamide (1 mL), and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were filtered off. Next, 1-naphthoxyacetic acid active ester solution was added to a solution of sulfostine monohydrate (150.7 mg, 0.5192 mmol) and sodium hydrogen carbonate (48.0 mg, 0.5714 mmol) in water (3 mL), Stir at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (175.9 mg, 71%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
8.23−8.28(1H,m),7.88−7.91(1H,m),7.54−7.61(3H,m),7.40(1H,t,J=7.8Hz),6.82(1H,d,J=7.8Hz),4.73(1H,t,J=15.1Hz),4.65(1H,t,J=15.1Hz),4.59(1H,dd,J=12.2,7.3Hz),3.74(1H,tdd,J=4.9,12.2,7.3Hz),3.60−3.69(1H,m),2.12−2.19(1H,m),1.97−2.07(1H,m),1.84−1.94(1H,m),1.76(1H,tdd,J=5.9,18.1,9.8Hz).
HR−MS(ESI,POS)
m/z:found,501.0600(M+Na)+
calcd.for C17H20N4Na2O7PS,501.0586 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
8.23-8.28 (1H, m), 7.88-7.91 (1H, m), 7.54-7.61 (3H, m), 7.40 (1H, t, J = 7) .8 Hz), 6.82 (1 H, d, J = 17.8 Hz), 4.73 (1 H, t, J = 15.1 Hz), 4.65 (1 H, t, J = 15.1 Hz), 4 .59 (1H, dd, J = 12.2, 7.3 Hz), 3.74 (1H, tdd, J = 4.9, 12.2, 7.3 Hz), 3.60-3.69 (1H , M), 2.12-2.19 (1H, m), 1.97-2.07 (1H, m), 1.84-1.94 (1H, m), 1.76 (1H, tdd , J = 5.9, 18.1, 9.8 Hz).
HR-MS (ESI, POS)
m / z: found, 501.0600 (M + Na) +
calcd. for C 17 H 20 N 4 Na 2 O 7 PS, 501.0586
実施例25
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−(N’−ベンジルウレイド)−2−ピペリドン ナトリウム塩
スルフォスチン1水和物(151.5mg,0.5220mmol)を水(3mL)に溶解した溶液に炭酸水素ナトリウム(219.3mg,2.6104mmol)、アセトニトリル(3mL)、及びベンジルイソシアナート(0.144mL,1.0404mmol)を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(197.7mg,89%)を得た。Example 25
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (N′-benzylureido) -2-piperidone sodium salt Sulfostin monohydrate (151.5 mg, 0.5220 mmol) dissolved in water (3 mL) To the solution was added sodium hydrogen carbonate (219.3 mg, 2.6104 mmol), acetonitrile (3 mL), and benzyl isocyanate (0.144 mL, 1.0404 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (197.7 mg, 89%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.31−7.44(5H,m),4.27−4.40(3H,m),3.75−3.83(1H,m),3.53−3.60(1H,m),2.11−2.19(1H,m),1.92−2.02(1H,m),1.80−1.91(1H,m),1.64−1.75(1H,m).
HR−MS(ESI,POS)
m/z:found,450.0581(M+Na)+
calcd.for C13H19N5Na2O6PS,450.0589 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.31-7.44 (5H, m), 4.27-4.40 (3H, m), 3.75-3.83 (1H, m), 3.53-3.60 (1H, m) ), 2.11-2.19 (1H, m), 1.92-2.02 (1H, m), 1.80-1.91 (1H, m), 1.64-1.75 (1H) , M).
HR-MS (ESI, POS)
m / z: found, 450.0581 (M + Na) +
calcd. for C 13 H 19 N 5 Na 2 O 6 PS, 450.0589
実施例26
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−(4’−(ベンジルオキシカルボニルアミノ)ブタノイル)アミノ−2−ピペリドン ナトリウム塩
4−(ベンジルオキシカルボニルアミノ)酪酸(184.3mg,0.7768mmol)、ジシクロヘキシルカルボジイミド(160.3mg,0.7769mmol)及びN−ヒドロキシスクシンイミド(89.4mg,0.7768mmol)にアセトニトリル(5mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(150.3mg,0.5179mmol)及び炭酸水素ナトリウム(47.9mg,0.5702mmol)を水(3mL)に溶解した溶液に、4−(ベンジルオキシカルボニルアミノ)酪酸活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(177.0mg,77%)を得た。Example 26
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (4 ′-(benzyloxycarbonylamino) butanoyl) amino-2-piperidone sodium salt 4- (benzyloxycarbonylamino) butyric acid (184.3 mg, 0 7768 mmol), dicyclohexylcarbodiimide (160.3 mg, 0.7769 mmol) and N-hydroxysuccinimide (89.4 mg, 0.7768 mmol) were added with acetonitrile (5 mL), and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were filtered off. did. Then, 4- (benzyloxycarbonylamino) butyric acid activity was added to a solution of sulfostine monohydrate (150.3 mg, 0.5179 mmol) and sodium hydrogen carbonate (47.9 mg, 0.5702 mmol) in water (3 mL). The ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (177.0 mg, 77%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.38−7.48(5H,m),5.01(2H,s),4.51(1H,dd,J=11.7,6.8Hz),3.69−3.77(1H,m),3.56−3.65(1H,m),3.18(2H,t,J=6.4Hz),3.18(2H,t,J=6.8Hz),2.33(2H,t,J=6.8Hz),2.07−2.16(1H,m),1.96−2.05(1H,m),1.67−1.92(4H,m).
HR−MS(ESI,POS)
m/z:found,536.0944(M+Na)+
calcd.for C17H25N5Na2O8PS,536.0957 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.38-7.48 (5H, m), 5.01 (2H, s), 4.51 (1H, dd, J = 11.7, 6.8 Hz), 3.69-3.77 (1H M), 3.56-3.65 (1H, m), 3.18 (2H, t, J = 6.4 Hz), 3.18 (2H, t, J = 6.8 Hz), 2.33 (2H, t, J = 6.8 Hz), 2.07-2.16 (1H, m), 1.96-2.05 (1H, m), 1.67-1.92 (4H, m) .
HR-MS (ESI, POS)
m / z: found, 536.0944 (M + Na) +
calcd. for C 17 H 25 N 5 Na 2 O 8 PS, 536.0957
実施例27
(3S,PR)−3−(6’−(ベンジルオキシカルボニルアミノ)カプロイル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン ナトリウム塩
6−(ベンジルオキシカルボニルアミノ)カプロン酸(137.8mg,0.5194mmol)、ジシクロヘキシルカルボジイミド(107.2mg,0.5196mmol)及びN−ヒドロキシスクシンイミド(59.8mg,0.5196mmol)にアセトニトリル(4mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(100.5mg,0.3463mmol)及び炭酸水素ナトリウム(32.0mg,0.3809mmol)を水(3mL)に溶解した溶液に、6−(ベンジルオキシカルボニルアミノ)カプロン酸活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(110.3mg,59%)を得た。Example 27
(3S, PR) -3- (6 ′-(benzyloxycarbonylamino) caproyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone sodium salt 6- (benzyloxycarbonylamino) caproic acid (137.8 mg, 0.5194 mmol), dicyclohexylcarbodiimide (107.2 mg, 0.5196 mmol) and N-hydroxysuccinimide (59.8 mg, 0.5196 mmol) were added with acetonitrile (4 mL), and the mixture was stirred at room temperature for 2 hours. Left. Subsequently, 6- (benzyloxycarbonylamino) caproic acid was added to a solution of sulfostine monohydrate (100.5 mg, 0.3463 mmol) and sodium bicarbonate (32.0 mg, 0.3809 mmol) in water (3 mL). The active ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (110.3 mg, 59%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.38−7.48(5H,m),5.11(2H,s),4.52(1H,dd,J=11.7,6.8Hz),3.69−3.77(1H,m),3.58−3.65(1H,m),3.12(2H,t,J=6.4Hz),2.30(2H,t,J=6.8Hz),2.09−2.17(1H,m),1.96−2.05(1H,m),1.81−1.92(1H,m),1.68−1.78(1H,m),1.58−1.68(2H,m),1.46−1.54(2H,m),1.28−1.36(2H,m).
HR−MS(ESI,POS)
m/z:found,564.1262(M+Na)+
calcd.for C19H29N5Na2O8PS,564.1270 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.38-7.48 (5H, m), 5.11 (2H, s), 4.52 (1H, dd, J = 11.7, 6.8 Hz), 3.69-3.77 (1H M), 3.58-3.65 (1H, m), 3.12 (2H, t, J = 6.4 Hz), 2.30 (2H, t, J = 6.8 Hz), 2.09 -2.17 (1H, m), 1.96-2.05 (1H, m), 1.81-1.92 (1H, m), 1.68-1.78 (1H, m), 1 .58-1.68 (2H, m), 1.46-1.54 (2H, m), 1.28-1.36 (2H, m).
HR-MS (ESI, POS)
m / z: found, 564.1262 (M + Na) +
calcd. for C 19 H 29 N 5 Na 2 O 8 PS, 5644.1270
実施例28
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−(tert−ブトキシカルボニル)アミノ−2−ピペリドン ナトリウム塩
スルフォスチン1水和物(306.8mg,1.0571mmol)を水(5mL)に溶解した溶液に炭酸水素ナトリウム(97.7mg,1.1630mmol)、テトラヒドロフラン(5mL)、及び無水tert−ブトキシカルボン酸(253.8mg,1.1629mmol)を加え、室温で終夜撹拌した。
反応液のテトラヒドロフランを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(312.0mg,75%)を得た。Example 28
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (tert-butoxycarbonyl) amino-2-piperidone sodium salt Sulfostin monohydrate (306.8 mg, 1.0571 mmol) dissolved in water (5 mL) To this solution were added sodium hydrogen carbonate (97.7 mg, 1.1630 mmol), tetrahydrofuran (5 mL), and anhydrous tert-butoxycarboxylic acid (253.8 mg, 1.1629 mmol), and the mixture was stirred at room temperature overnight.
Tetrahydrofuran in the reaction solution was distilled off under reduced pressure, then purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (312.0 mg, 75%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
4.26(1H,dd,J=11.7,6.8Hz),3.69−3.77(1H,m),3.60−3.67(1H,m),2.15−2.23(1H,m),1.98−2.08(1H,m),1.86−1.97(1H,m),1.68−1.79(1H,m),1.46(9H,s).
HR−MS(ESI,POS)
m/z:found,417.0606(M+Na)+
calcd.for C10H20N4Na2O7PS,417.0586 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
4.26 (1H, dd, J = 11.7, 6.8 Hz), 3.69-3.77 (1H, m), 3.60-3.67 (1H, m), 2.15-2 .23 (1H, m), 1.98-2.08 (1H, m), 1.86-1.97 (1H, m), 1.68-1.79 (1H, m), 1.46 (9H, s).
HR-MS (ESI, POS)
m / z: found, 417.0606 (M + Na) +
calcd. for C10H 20 N 4 Na 2 O 7 PS, 417.0586
実施例29
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−((ベンジルオキシカルボニルアミノ)アセチル)アミノ−2−ピペリドン ナトリウム塩
N−ベンジルオキシカルボニルグリシン(325.4mg,1.5554mmol)、ジシクロヘキシルカルボジイミド(321.0mg,1.5558mmol)及びN−ヒドロキシスクシンイミド(179.0mg,1.5553mmol)にアセトニトリル(15mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(301.0mg,1.0371mmol)及び炭酸水素ナトリウム(87.1mg,1.0367mmol)を水(5mL)及びアセトニトリル(3mL)に溶解した溶液に、N−ベンジルオキシカルボニルグリシン活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(466.1mg,93%)を得た。Example 29
(3S, PR) -1-amino (sulfoamino) phosphinyl-3-((benzyloxycarbonylamino) acetyl) amino-2-piperidone sodium salt N-benzyloxycarbonylglycine (325.4 mg, 1.5554 mmol), dicyclohexylcarbodiimide Acetonitrile (15 mL) was added to (321.0 mg, 1.5558 mmol) and N-hydroxysuccinimide (179.0 mg, 1.5553 mmol), and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were filtered off. Then, N-benzyloxycarbonyl was added to a solution of sulfostine monohydrate (301.0 mg, 1.0371 mmol) and sodium hydrogen carbonate (87.1 mg, 1.0367 mmol) in water (5 mL) and acetonitrile (3 mL). Glycine active ester solution was added and stirred overnight at room temperature.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (466.1 mg, 93%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.39−7.48(5H,m),5.16(2H,s),4.59(1H,dd,J=11.7,6.8Hz),3.90(2H,s),3.70−3.77(1H,m),3.61−3.68(1H,m),1.53−2.19(4H,m).
HR−MS(ESI,POS)
m/z:found,508.0623(M+Na)+
calcd.for C15H21N5Na2O8PS,508.0644 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.39-7.48 (5H, m), 5.16 (2H, s), 4.59 (1H, dd, J = 11.7, 6.8 Hz), 3.90 (2H, s), 3.70-3.77 (1H, m), 3.61-3.68 (1H, m), 1.53-2.19 (4H, m).
HR-MS (ESI, POS)
m / z: found, 508.0623 (M + Na) +
calcd. for C 15 H 21 N 5 Na 2 O 8 PS, 508.0644
実施例30
(3S,PR,2’S)−1−アミノ(スルホアミノ)ホスフィニル−3−(2’−(ベンジルオキシカルボニルアミノ)プロピオニル)アミノ−2−ピペリドン ナトリウム塩
N−ベンジルオキシカルボニル−L−アラニン(173.0mg,0.7750mmol)、ジシクロヘキシルカルボジイミド(160.0mg,0.7755mmol)及びN−ヒドロキシスクシンイミド(89.2mg,0.7750mmol)にアセトニトリル(6mL)及びジメチルホルムアミド(1mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(150.0mg,0.5168mmol)及び炭酸水素ナトリウム(47.8mg,0.5690mmol)を水(5mL)に溶解した溶液に、N−ベンジルオキシカルボニル−L−アラニン活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(188.6mg,73%)を得た。Example 30
(3S, PR, 2 ′S) -1-Amino (sulfoamino) phosphinyl-3- (2 ′-(benzyloxycarbonylamino) propionyl) amino-2-piperidone sodium salt N-benzyloxycarbonyl-L-alanine (173 0.06 mg, 0.7750 mmol), dicyclohexylcarbodiimide (160.0 mg, 0.7755 mmol) and N-hydroxysuccinimide (89.2 mg, 0.7750 mmol) were added acetonitrile (6 mL) and dimethylformamide (1 mL), and 2 at room temperature. The mixture was stirred for a period of time, and the precipitated crystals were removed by filtration. Next, N-benzyloxycarbonyl-L-alanine activity was dissolved in a solution of sulfostin monohydrate (150.0 mg, 0.5168 mmol) and sodium hydrogen carbonate (47.8 mg, 0.5690 mmol) in water (5 mL). The ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (188.6 mg, 73%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.37−7.48(5H,m),5.01−5.23(2H,m),4.48−4.56and4.25−4.37(1H,m),4.17(1H,q,J=7.3Hz),3.52−3.79(2H,m),1.34−2.20(4H,m),1.40(3H,d,J=7.3Hz).
HR−MS(ESI,POS)
m/z:found,522.0792(M+Na)+
calcd.for C16H23N5Na2O8PS,522.0800 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.37-7.48 (5H, m), 5.01-5.23 (2H, m), 4.48-4.56 and 4.25-4.37 (1H, m), 4.17 (1H , Q, J = 7.3 Hz), 3.52-3.79 (2H, m), 1.34-2.20 (4H, m), 1.40 (3H, d, J = 7.3 Hz) .
HR-MS (ESI, POS)
m / z: found, 522.0792 (M + Na) +
calcd. for C 16 H 23 N 5 Na 2 O 8 PS, 522.0800
実施例31
(3S,PR,2’S)−1−アミノ(スルホアミノ)ホスフィニル−3−(2’−(ベンジルオキシカルボニルアミノ)−3’−メチルブタノイル)アミノ−2−ピペリドン ナトリウム塩
N−ベンジルオキシカルボニル−L−バリン(196.6mg,0.7824mmol)、ジシクロヘキシルカルボジイミド(161.4mg,0.7822mmol)及びN−ヒドロキシスクシンイミド(90.0mg,0.7820mmol)にアセトニトリル(6mL)及びジメチルホルムアミド(1mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(151.4mg,0.5217mmol)及び炭酸水素ナトリウム(48.2mg,0.5734mmol)を水(5mL)に溶解した溶液に、N−ベンジルオキシカルボニル−L−バリン活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(201.1mg,73%)を得た。Example 31
(3S, PR, 2'S) -1-Amino (sulfoamino) phosphinyl-3- (2 '-(benzyloxycarbonylamino) -3'-methylbutanoyl) amino-2-piperidone sodium salt N-benzyloxycarbonyl -L-valine (196.6 mg, 0.7824 mmol), dicyclohexylcarbodiimide (161.4 mg, 0.7822 mmol) and N-hydroxysuccinimide (90.0 mg, 0.7820 mmol) in acetonitrile (6 mL) and dimethylformamide (1 mL) The mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Then, N-benzyloxycarbonyl-L-valine activity was added to a solution of sulfostine monohydrate (151.4 mg, 0.5217 mmol) and sodium hydrogen carbonate (48.2 mg, 0.5734 mmol) in water (5 mL). The ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (201.1 mg, 73%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4ナトリウム塩)
7.38−7.48(5H,m),5.04−5.24(2H,m),4.55and4.31−4.38(1H,dd,J=11.2,6.8Hz,and m),3.97and3.87−3.92(1H,d,J=6.8Hz,and m),3.53−3.79(2H,m),1.44−2.22(5H,m),0.98and0.94(6H,d,J=6.8Hz).
HR−MS(ESI,POS)
m/z:found,550.1082(M+Na)+
calcd.for C18H27N5Na2O8PS,550.1113 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.38-7.48 (5H, m), 5.04-5.24 (2H, m), 4.55 and 4.31-4.38 (1H, dd, J = 11.2, 6.8 Hz, and m), 3.97 and 3.87-3.92 (1H, d, J = 6.8 Hz, and m), 3.53-3.79 (2H, m), 1.44-2.22 (5H). , M), 0.98 and 0.94 (6H, d, J = 6.8 Hz).
HR-MS (ESI, POS)
m / z: found, 550.10.82 (M + Na) +
calcd. for C 18 H 27 N 5 Na 2 O 8 PS, 550.1113
実施例32
(3S,PR,2’S)−1−アミノ(スルホアミノ)ホスフィニル−3−(2’−(ベンジルオキシカルボニルアミノ)−4’−メチルペンタノイル)アミノ−2−ピペリドン ナトリウム塩
N−ベンジルオキシカルボニル−L−ロイシン(206.8mg,0.7795mmol)、ジシクロヘキシルカルボジイミド(160.8mg,0.7793mmol)及びN−ヒドロキシスクシンイミド(89.7mg,0.7794mmol)にアセトニトリル(6mL)及びジメチルホルムアミド(1mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(150.8mg,0.5196mmol)及び炭酸水素ナトリウム(48.0mg,0.5714mmol)を水(5mL)に溶解した溶液に、N−ベンジルオキシカルボニル−L−ロイシン活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(140.0mg,50%)を得た。Example 32
(3S, PR, 2 ′S) -1-Amino (sulfoamino) phosphinyl-3- (2 ′-(benzyloxycarbonylamino) -4′-methylpentanoyl) amino-2-piperidone sodium salt N-benzyloxycarbonyl -L-leucine (206.8 mg, 0.7795 mmol), dicyclohexylcarbodiimide (160.8 mg, 0.7793 mmol) and N-hydroxysuccinimide (89.7 mg, 0.7794 mmol) in acetonitrile (6 mL) and dimethylformamide (1 mL) The mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Then, N-benzyloxycarbonyl-L-leucine activity was dissolved in a solution of sulfostine monohydrate (150.8 mg, 0.5196 mmol) and sodium bicarbonate (48.0 mg, 0.5714 mmol) in water (5 mL). The ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (140.0 mg, 50%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.37−7.48(5H,m),5.04−5.25(2H,m),4.53and4.28−4.36(1H,dd,J=11.2,6.8Hz,and m),4.16(1H,d,J=7.3Hz),3.54−3.78(2H,m),2.10−2.19(2H,m),1.97−2.08(1H,m),1.87−1.97(1H,m),1.64−1.83(1H,m),1.62(2H,t,J=6.8Hz),0.94(3H,d,J=6.8Hz),0.89(3H,d,J=6.8Hz).
HR−MS(ESI,POS)
m/z:found,564.1248(M+Na)+
calcd.for C19H29N5Na2O8PS,564.1270 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.37-7.48 (5H, m), 5.04-5.25 (2H, m), 4.53 and 4.28-4.36 (1H, dd, J = 11.2, 6.8 Hz, and m), 4.16 (1H, d, J = 7.3 Hz), 3.54-3.78 (2H, m), 2.10-2.19 (2H, m), 1.97-2. .08 (1H, m), 1.87-1.97 (1H, m), 1.64-1.83 (1H, m), 1.62 (2H, t, J = 6.8 Hz), 0 .94 (3H, d, J = 6.8 Hz), 0.89 (3H, d, J = 6.8 Hz).
HR-MS (ESI, POS)
m / z: found, 5644.1248 (M + Na) +
calcd. for C 19 H 29 N 5 Na 2 O 8 PS, 5644.1270
実施例33
(3S,PR,2’S,3’S)−1−アミノ(スルホアミノ)ホスフィニル−3−(2’−(ベンジルオキシカルボニルアミノ)−3’−メチルペンタノイル)アミノ−2−ピペリドン ナトリウム塩
N−ベンジルオキシカルボニル−L−イソロイシン(206.8mg,0.7795mmol)、ジシクロヘキシルカルボジイミド(160.8mg,0.7793mmol)及びN−ヒドロキシスクシンイミド(89.7mg,0.7794mmol)にアセトニトリル(6mL)及びジメチルホルムアミド(1mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(150.8mg,0.5196mmol)及び炭酸水素ナトリウム(48.0mg,0.5714mmol)を水(5mL)に溶解した溶液に、N−ベンジルオキシカルボニル−L−イソロイシン活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(190.0mg,68%)を得た。Example 33
(3S, PR, 2 ′S, 3 ′S) -1-Amino (sulfoamino) phosphinyl-3- (2 ′-(benzyloxycarbonylamino) -3′-methylpentanoyl) amino-2-piperidone sodium salt N -Benzyloxycarbonyl-L-isoleucine (206.8 mg, 0.7795 mmol), dicyclohexylcarbodiimide (160.8 mg, 0.7793 mmol) and N-hydroxysuccinimide (89.7 mg, 0.7794 mmol) in acetonitrile (6 mL) and dimethyl Formamide (1 mL) was added, the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Next, N-benzyloxycarbonyl-L-isoleucine activity was dissolved in a solution of sulfostin monohydrate (150.8 mg, 0.5196 mmol) and sodium hydrogen carbonate (48.0 mg, 0.5714 mmol) in water (5 mL). The ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (190.0 mg, 68%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.38−7.48(5H,m),5.04−5.24(2H,m),4.55(1H,dd,J=11.2,6.8Hz),4.00(1H,d,J=6.8HZ),3.61−3.78(2H,m),2.12−2.20(1H,m),1.98−2.07(1H,m),1.71−1.96(3H,m),1.42−1.52(1H,m),1.16−1.26(1H,m),0.98(3H,d,J=6.8Hz),0.88(3H,t,J=7.3Hz).
HR−MS(ESI,POS)
m/z:found,564.1250(M+Na)+
calcd.for C19H29N5Na2O8PS,564.1270 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.38-7.48 (5H, m), 5.04-5.24 (2H, m), 4.55 (1H, dd, J = 11.2, 6.8 Hz), 4.00 (1H , D, J = 6.8HZ), 3.61-3.78 (2H, m), 2.12-2.20 (1H, m), 1.98-2.07 (1H, m), 1 .71-1.96 (3H, m), 1.42-1.52 (1H, m), 1.16-1.26 (1H, m), 0.98 (3H, d, J = 6. 8 Hz), 0.88 (3H, t, J = 7.3 Hz).
HR-MS (ESI, POS)
m / z: found, 5644.1250 (M + Na) +
calcd. for C 19 H 29 N 5 Na 2 O 8 PS, 5644.1270
実施例34
(3S,PR,2’S)−1−アミノ(スルホアミノ)ホスフィニル−3−(2’−(ベンジルオキシカルボニルアミノ)−3’−フェニルプロピオニル)アミノ−2−ピペリドン ナトリウム塩
N−ベンジルオキシカルボニル−L−フェニルアラニン(234.4mg,0.7831mmol)、ジシクロヘキシルカルボジイミド(161.6mg,0.7832mmol)及びN−ヒドロキシスクシンイミド(90.1mg,0.7829mmol)にアセトニトリル(6mL)及びジメチルホルムアミド(1mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(151.5mg,0.5220mmol)及び炭酸水素ナトリウム(48.2mg,0.5737mmol)を水(5mL)に溶解した溶液に、N−ベンジルオキシカルボニル−L−フェニルアラニン活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(204.2mg,68%)を得た。Example 34
(3S, PR, 2 ′S) -1-amino (sulfoamino) phosphinyl-3- (2 ′-(benzyloxycarbonylamino) -3′-phenylpropionyl) amino-2-piperidone sodium salt N-benzyloxycarbonyl- L-phenylalanine (234.4 mg, 0.7831 mmol), dicyclohexylcarbodiimide (161.6 mg, 0.7832 mmol) and N-hydroxysuccinimide (90.1 mg, 0.7829 mmol) were mixed with acetonitrile (6 mL) and dimethylformamide (1 mL). The mixture was further stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Subsequently, N-benzyloxycarbonyl-L-phenylalanine activity was dissolved in a solution of sulfostine monohydrate (151.5 mg, 0.5220 mmol) and sodium hydrogen carbonate (48.2 mg, 0.5737 mmol) in water (5 mL). The ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (204.2 mg, 68%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.23−7.43(10H,m),5.06and5.00(2H,d,J=12.7Hz),4.32−4.57(2H,m),3.55−3.78(2H,m),3.25and3.18(1H,dd,J=14.2,4.4Hz),2.91(1H,dd,J=14.2,9.8Hz),1.50−2.20(4H,m).
HR−MS(ESI,POS)
m/z:found,598.1086(M+Na)+
calcd.for C22H27N5Na2O8PS,598.1113 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.23-7.43 (10H, m), 5.06 and 5.00 (2H, d, J = 12.7 Hz), 4.32-4.57 (2H, m), 3.55-3.78 (2H, m), 3.25 and 3.18 (1H, dd, J = 14.2, 4.4 Hz), 2.91 (1H, dd, J = 14.2, 9.8 Hz), 1.50− 2.20 (4H, m).
HR-MS (ESI, POS)
m / z: found, 598.186 (M + Na) +
calcd. for C 22 H 27 N 5 Na 2 O 8 PS, 598.1113
実施例35
(3S,PR,2’S)−1−アミノ(スルホアミノ)ホスフィニル−3−((2’−(1’−ベンジルオキシカルボニル)ピペリジン)カルボニル)アミノ−2−ピペリドン ナトリウム塩の合成
N−ベンジルオキシカルボニル−L−プロリン(195.2mg,0.7831mmol)、ジシクロヘキシルカルボジイミド(161.6mg,0.7832mmol)及びN−ヒドロキシスクシンイミド(90.1mg,0.7829mmol)にアセトニトリル(6mL)及びジメチルホルムアミド(1mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(151.5mg,0.5220mmol)及び炭酸水素ナトリウム(48.2mg,0.5737mmol)を水(5mL)に溶解した溶液に、N−ベンジルオキシカルボニル−L−プロリン活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(176.6mg,64%)を得た。Example 35
Synthesis of (3S, PR, 2 ′S) -1-amino (sulfoamino) phosphinyl-3-((2 ′-(1′-benzyloxycarbonyl) piperidine) carbonyl) amino-2-piperidone sodium salt N-benzyloxy Carbonyl-L-proline (195.2 mg, 0.7831 mmol), dicyclohexylcarbodiimide (161.6 mg, 0.7832 mmol) and N-hydroxysuccinimide (90.1 mg, 0.7829 mmol) in acetonitrile (6 mL) and dimethylformamide (1 mL) The mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Subsequently, N-benzyloxycarbonyl-L-proline activity was added to a solution of sulfostine monohydrate (151.5 mg, 0.5220 mmol) and sodium hydrogen carbonate (48.2 mg, 0.5737 mmol) in water (5 mL). The ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (176.6 mg, 64%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.37−7.49(5H,m),5.17(1H,d,J=12.2Hz),5.04(1H,d,J=12.2Hz),4.33(1H,dd,J=7.8,4.9Hz),4.29(1H,dd,J=11.7,6.8Hz),3.51−3.80(4H,m),2.27−2.39(1H,m),1.85−2.07(4H,m),1.73−1.83(1H,m),1.63−1.71(1H,m),1.37−1.47(1H,m).
HR−MS(ESI,POS)
m/z:found,548.0949(M+Na)+
calcd.for C18H25N5Na2O8PS,548.0957 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.37-7.49 (5 H, m), 5.17 (1 H, d, J = 12.2 Hz), 5.04 (1 H, d, J = 12.2 Hz), 4.33 (1 H, dd) , J = 7.8, 4.9 Hz), 4.29 (1H, dd, J = 11.7, 6.8 Hz), 3.51-3.80 (4H, m), 2.27-2. 39 (1H, m), 1.85-2.07 (4H, m), 1.73-1.83 (1H, m), 1.63-1.71 (1H, m), 1.37- 1.47 (1H, m).
HR-MS (ESI, POS)
m / z: found, 548.0949 (M + Na) +
calcd. for C 18 H 25 N 5 Na 2 O 8 PS, 548.0957
実施例36
(3S,PR,2’S)−1−アミノ(スルホアミノ)ホスフィニル−3−(2’−(ベンジルオキシカルボニルアミノ)−3’−カルバモイルプロピオニル)アミノ−2−ピペリドン ナトリウム塩
N−ベンジルオキシカルボニル−L−アスパラギン(210.1mg,0.7891mmol)、ジシクロヘキシルカルボジイミド(162.8mg,0.7890mmol)及びN−ヒドロキシスクシンイミド(90.8mg,0.7891mmol)にアセトニトリル(6mL)及びジメチルホルムアミド(1mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(152.7mg,0.5261mmol)及び炭酸水素ナトリウム(48.6mg,0.5785mmol)を水(5mL)に溶解した溶液に、N−ベンジルオキシカルボニル−L−アスパラギン活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(220.8mg,77%)を得た。Example 36
(3S, PR, 2 ′S) -1-amino (sulfoamino) phosphinyl-3- (2 ′-(benzyloxycarbonylamino) -3′-carbamoylpropionyl) amino-2-piperidone sodium salt N-benzyloxycarbonyl- L-asparagine (210.1 mg, 0.7891 mmol), dicyclohexylcarbodiimide (162.8 mg, 0.7890 mmol) and N-hydroxysuccinimide (90.8 mg, 0.7891 mmol) were mixed with acetonitrile (6 mL) and dimethylformamide (1 mL). The mixture was further stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Subsequently, N-benzyloxycarbonyl-L-asparagine activity was added to a solution of sulfostine monohydrate (152.7 mg, 0.5261 mmol) and sodium hydrogen carbonate (48.6 mg, 0.5785 mmol) in water (5 mL). The ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (220.8 mg, 77%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.38−7.49(5H,m),5.10−5.20(2H,m),4.51−4.59(2H,m),3.55−3.77(2H,m),2.86(1H,dd,J=15.6,4.9Hz),2.72(1H,dd,J=15.6,8.8Hz),1.48−2.16(4H,m).
HR−MS(ESI,POS)
m/z:found,565.0830(M+Na)+
calcd.for C17H24N6Na2O9PS,565.0859 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.38-7.49 (5H, m), 5.10-5.20 (2H, m), 4.51-4.59 (2H, m), 3.55-3.77 (2H, m) ), 2.86 (1H, dd, J = 15.6, 4.9 Hz), 2.72 (1H, dd, J = 15.6, 8.8 Hz), 1.48-2.16 (4H, m).
HR-MS (ESI, POS)
m / z: found, 565.0830 (M + Na) +
calcd. for C 17 H 24 N 6 Na 2 O 9 PS, 565.0859
実施例37
(3S,PR,2’S)−1−アミノ(スルホアミノ)ホスフィニル−3−(2’−(ベンジルオキシカルボニルアミノ)−4’−カルバモイルブタノイル)アミノ−2−ピペリドン ナトリウム塩
N−ベンジルオキシカルボニル−L−グルタミン(220.6mg,0.7870mmol)、ジシクロヘキシルカルボジイミド(162.4mg,0.7871mmol)及びN−ヒドロキシスクシンイミド(90.6mg,0.7872mmol)にアセトニトリル(6mL)及びジメチルホルムアミド(1mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(152.3mg,0.5248mmol)及び炭酸水素ナトリウム(48.5mg,0.5773mmol)を水(5mL)に溶解した溶液に、N−ベンジルオキシカルボニル−L−グルタミン活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(247.7mg,85%)を得た。Example 37
(3S, PR, 2 ′S) -1-Amino (sulfoamino) phosphinyl-3- (2 ′-(benzyloxycarbonylamino) -4′-carbamoylbutanoyl) amino-2-piperidone sodium salt N-benzyloxycarbonyl -L-glutamine (220.6 mg, 0.7870 mmol), dicyclohexylcarbodiimide (162.4 mg, 0.7871 mmol) and N-hydroxysuccinimide (90.6 mg, 0.7872 mmol) in acetonitrile (6 mL) and dimethylformamide (1 mL) The mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Next, N-benzyloxycarbonyl-L-glutamine activity was dissolved in a solution of sulfostin monohydrate (152.3 mg, 0.5248 mmol) and sodium hydrogen carbonate (48.5 mg, 0.5773 mmol) in water (5 mL). The ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (247.7 mg, 85%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.37−7.48(5H,m),5.04−5.25(2H,m),4.52−4.59and4.31−4.38(1H,m),4.07−4.17(1H,m),3.54−3.77(2H,m),2.41(2H,t,J=7.3Hz),1.43−2.19(6H,m).
HR−MS(ESI,POS)
m/z:found,579.1001(M+Na)+
calcd.for C18H26N6Na2O9PS,579.1015 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.37-7.48 (5H, m), 5.04-5.25 (2H, m), 4.52-4.59 and 4.31-4.38 (1H, m), 4.07-4 .17 (1H, m), 3.54-3.77 (2H, m), 2.41 (2H, t, J = 7.3 Hz), 1.43-2.19 (6H, m).
HR-MS (ESI, POS)
m / z: found, 579.1001 (M + Na) +
calcd. for C 18 H 26 N 6 Na 2 O 9 PS, 579.
実施例38
(3S,PR,2’S)−1−アミノ(スルホアミノ)ホスフィニル−3−(2’−(ベンジルオキシカルボニルアミノ)−4’−(メチルチオ)ブタノイル)アミノ−2−ピペリドン ナトリウム塩
N−ベンジルオキシカルボニル−L−メチオニン(220.8mg,0.7792mmol)、ジシクロヘキシルカルボジイミド(160.8mg,0.7793mmol)及びN−ヒドロキシスクシンイミド(89.7mg,0.7793mmol)にアセトニトリル(6mL)及びジメチルホルムアミド(1mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(150.8mg,0.5196mmol)及び炭酸水素ナトリウム(48.0mg,0.5714mmol)を水(5mL)に溶解した溶液に、N−ベンジルオキシカルボニル−L−メチオニン活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(198.5mg,68%)を得た。Example 38
(3S, PR, 2 ′S) -1-Amino (sulfoamino) phosphinyl-3- (2 ′-(benzyloxycarbonylamino) -4 ′-(methylthio) butanoyl) amino-2-piperidone sodium salt N-benzyloxy Carbonyl-L-methionine (220.8 mg, 0.7792 mmol), dicyclohexylcarbodiimide (160.8 mg, 0.7793 mmol) and N-hydroxysuccinimide (89.7 mg, 0.7793 mmol) in acetonitrile (6 mL) and dimethylformamide (1 mL) The mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Next, N-benzyloxycarbonyl-L-methionine activity was added to a solution of sulfostine monohydrate (150.8 mg, 0.5196 mmol) and sodium hydrogen carbonate (48.0 mg, 0.5714 mmol) in water (5 mL). The ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, it was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (198.5 mg, 68%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.38−7.48(5H,m),5.15(2H,q,J=12.7Hz),4.55and4.26−4.38(1H,dd,J=11.2,6.8Hz and m),4.29(1H,dd,J=9.3,4.4Hz),3.54−3.78(2H,m),2.53−2.71(2H,m),1.40−2.20(6H,m),2.10(3H,s).
HR−MS(ESI,POS)
m/z:found,582.0809(M+Na)+
calcd.for C18H27N5Na2O8PS2,582.0834 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.38-7.48 (5H, m), 5.15 (2H, q, J = 12.7 Hz), 4.55 and 4.26-4.38 (1H, dd, J = 11.2, 6. 8 Hz and m), 4.29 (1H, dd, J = 9.3, 4.4 Hz), 3.54-3.78 (2H, m), 2.53-2.71 (2H, m), 1.40-2.20 (6H, m), 2.10 (3H, s).
HR-MS (ESI, POS)
m / z: found, 582.0809 (M + Na) +
calcd. for C 18 H 27 N 5 Na 2 O 8 PS 2 , 582.0834
実施例39
(3S,PR,2’S)−1−アミノ(スルホアミノ)ホスフィニル−3−(2’−(ベンジルオキシカルボニルアミノ)−3’−(3”−インドリル)プロピオニル)アミノ−2−ピペリドン ナトリウム塩
N−ベンジルオキシカルボニル−L−トリプトファン(264.6mg,0.7820mmol)、ジシクロヘキシルカルボジイミド(161.3mg,0.7818mmol)及びN−ヒドロキシスクシンイミド(90.0mg,0.7820mmol)にアセトニトリル(6mL)及びジメチルホルムアミド(1mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(151.3mg,0.5213mmol)及び炭酸水素ナトリウム(48.2mg,0.5737mmol)を水(5mL)に溶解した溶液に、N−ベンジルオキシカルボニル−L−トリプトファン活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(238.9mg,75%)を得た。Example 39
(3S, PR, 2 ′S) -1-Amino (sulfoamino) phosphinyl-3- (2 ′-(benzyloxycarbonylamino) -3 ′-(3 ″ -indolyl) propionyl) amino-2-piperidone sodium salt N -Benzyloxycarbonyl-L-tryptophan (264.6 mg, 0.7820 mmol), dicyclohexylcarbodiimide (161.3 mg, 0.7818 mmol) and N-hydroxysuccinimide (90.0 mg, 0.7820 mmol) in acetonitrile (6 mL) and dimethyl Formamide (1 mL) was added, and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were filtered off, then sulfostin monohydrate (151.3 mg, 0.5213 mmol) and sodium hydrogen carbonate (48.2 mg, 0.5737 mmol). ) Water (5m The solution in), the N- benzyloxycarbonyl -L- tryptophan active ester solution, and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (238.9 mg, 75%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.65(1H,d,J=7.8Hz),7.50(1H,d,J=7.8Hz),7.33−7.43(3H,m),7.17−7.27(4H,m),7.13(1H,t,J=7.8Hz),5.05(1H,d,J=12.7Hz),4.94(1H,d,J=12.7Hz),4.52(1H,dd,J=8.8,5.4Hz),4.46(1H,dd,J=12.2,6.8Hz),3.66−3.76(1H,m),3.52−3.66(1H,m),3.36(1H,dd,J=14.7,5.4Hz),3.17(1H,dd,J=14.7,8.8Hz),1.43−2.04(4H,m).
HR−MS(ESI,POS)
m/z:found,637.1174(M+Na)+
calcd.for C24H28N6Na2O8PS,637.1222 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.65 (1H, d, J = 7.8 Hz), 7.50 (1H, d, J = 7.8 Hz), 7.33-7.43 (3H, m), 7.17-7.27 (4H, m), 7.13 (1H, t, J = 7.8Hz), 5.05 (1H, d, J = 12.7Hz), 4.94 (1H, d, J = 12.7Hz) , 4.52 (1H, dd, J = 8.8, 5.4 Hz), 4.46 (1H, dd, J = 12.2, 6.8 Hz), 3.66-3.76 (1H, m ), 3.52-3.66 (1H, m), 3.36 (1H, dd, J = 14.7, 5.4 Hz), 3.17 (1H, dd, J = 14.7, 8.. 8Hz), 1.43-2.04 (4H, m).
HR-MS (ESI, POS)
m / z: found, 637.1174 (M + Na) +
calcd. for C 24 H 28 N 6 Na 2 O 8 PS, 637.1222
実施例40
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−((tert−ブトキシカルボニルアミノ)アセチル)アミノ−2−ピペリドン ナトリウム塩
N−tert−ブトキシカルボニルグリシン(137.3mg,0.7838mmol)、ジシクロヘキシルカルボジイミド(161.8mg,0.7842mmol)及びN−ヒドロキシスクシンイミド(90.2mg,0.7837mmol)にアセトニトリル(6mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(151.7mg,0.5227mmol)及び炭酸水素ナトリウム(48.3mg,0.5749mmol)を水(5mL)に溶解した溶液に、N−tert−ブトキシカルボニルグリシン活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(125.0mg,53%)を得た。Example 40
(3S, PR) -1-amino (sulfoamino) phosphinyl-3-((tert-butoxycarbonylamino) acetyl) amino-2-piperidone sodium salt N-tert-butoxycarbonylglycine (137.3 mg, 0.7838 mmol), Acetonitrile (6 mL) was added to dicyclohexylcarbodiimide (161.8 mg, 0.7842 mmol) and N-hydroxysuccinimide (90.2 mg, 0.7837 mmol), and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Subsequently, N-tert-butoxycarbonylglycine active ester solution was added to a solution of sulfostine monohydrate (151.7 mg, 0.5227 mmol) and sodium hydrogen carbonate (48.3 mg, 0.5749 mmol) in water (5 mL). And stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (125.0 mg, 53%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
4.61(1H,dd,J=11.7,6.8Hz),3.83(2H,brs),3.74(1H,tdd,J=4.8,12.2,7.8Hz),3.62−3.69(1H,m),2.14−2.22(1H,m),2.02−2.09(1H,m),1.87−1.98(1H,m),1.73−1.84(1H,m),1.45(9H,s).
HR−MS(ESI,POS)
m/z:found,474.0794(M+Na)+
calcd.for C12H23N5Na2O8PS,474.0800 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
4.61 (1H, dd, J = 11.7, 6.8 Hz), 3.83 (2H, brs), 3.74 (1H, tdd, J = 4.8, 12.2, 7.8 Hz) 3.62-3.69 (1H, m), 2.14-2.22 (1H, m), 2.02-2.09 (1H, m), 1.87-1.98 (1H, m), 1.73-1.84 (1H, m), 1.45 (9H, s).
HR-MS (ESI, POS)
m / z: found, 474.0794 (M + Na) +
calcd. for C 12 H 23 N 5 Na 2 O 8 PS, 474.0800
実施例41
(3S,PR,2’S)−1−アミノ(スルホアミノ)ホスフィニル−3−(2’−(tert−ブトキシカルボニルアミノ)−3’−(ベンジルオキシ)プロピオニル)アミノ−2−ピペリドン ナトリウム塩
N−tert−ブトキシカルボニル−O−ベンジル−L−セリン(383.0mg,1.2969mmol)、ジシクロヘキシルカルボジイミド(267.6mg,1.2970mmol)及びN−ヒドロキシスクシンイミド(149.2mg,1.2964mmol)にアセトニトリル(10mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(250.9mg,0.8645mmol)及び炭酸水素ナトリウム(79.9mg,0.9511mmol)を水(5mL)に溶解した溶液に、N−tert−ブトキシカルボニル−O−ベンジル−L−セリン活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(448.3mg,91%)を得た。Example 41
(3S, PR, 2 ′S) -1-Amino (sulfoamino) phosphinyl-3- (2 ′-(tert-butoxycarbonylamino) -3 ′-(benzyloxy) propionyl) amino-2-piperidone sodium salt N— tert-Butoxycarbonyl-O-benzyl-L-serine (383.0 mg, 1.2969 mmol), dicyclohexylcarbodiimide (267.6 mg, 1.2970 mmol) and N-hydroxysuccinimide (149.2 mg, 1.2964 mmol) in acetonitrile ( 10 mL) was added, and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Then, N-tert-butoxycarbonyl-O-benzyl was dissolved in a solution of sulfostine monohydrate (250.9 mg, 0.8645 mmol) and sodium bicarbonate (79.9 mg, 0.9511 mmol) in water (5 mL). -L-Serine active ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (448.3 mg, 91%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.38−7.48(5H,m),4.57−4.65(2H,m),4.54(1H,dd,J=11.7,6.8Hz),4.30−4.40(1H,m),3.80−3.90(2H,m),3.74(1H,tdd,J=4.9,12.7,7.3Hz),3.60−3.68(1H,m),2.13−2.22(1H,m),1.98−2.08(1H,m),1.86−1.97(1H,m),1.71−1.83(1H,m),1.44(9H,s).
HR−MS(ESI,POS)
m/z:found,594.1353(M+Na)+
calcd.for C20H31N5Na2O9PS,594.1376 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.38-7.48 (5H, m), 4.57-4.65 (2H, m), 4.54 (1H, dd, J = 11.7, 6.8 Hz), 4.30-4 .40 (1H, m), 3.80-3.90 (2H, m), 3.74 (1H, tdd, J = 4.9, 12.7, 7.3 Hz), 3.60-3. 68 (1H, m), 2.13-2.22 (1H, m), 1.98-2.08 (1H, m), 1.86-1.97 (1H, m), 1.71- 1.83 (1H, m), 1.44 (9H, s).
HR-MS (ESI, POS)
m / z: found, 594.1353 (M + Na) +
calcd. for C 20 H 31 N 5 Na 2 O 9 PS, 5944.1376
実施例42
(3S,PR,2’S,3’R)−1−アミノ(スルホアミノ)ホスフィニル−3−(2’−(tert−ブトキシカルボニルアミノ)−3’−(ベンジルオキシ)ブタノイル)アミノ−2−ピペリドン ナトリウム塩
N−tert−ブトキシカルボニル−O−ベンジル−L−トレオニン(401.8mg,1.2988mmol)、ジシクロヘキシルカルボジイミド(268.0mg,1.2989mmol)及びN−ヒドロキシスクシンイミド(149.5mg,1.2990mmol)にアセトニトリル(10mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(251.3mg,0.8659mmol)及び炭酸水素ナトリウム(80.0mg,0.9523mmol)を水(5mL)に溶解した溶液に、N−tert−ブトキシカルボニル−O−ベンジル−L−トレオニン活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(212.2mg,42%)を得た。Example 42
(3S, PR, 2'S, 3'R) -1-Amino (sulfoamino) phosphinyl-3- (2 '-(tert-butoxycarbonylamino) -3'-(benzyloxy) butanoyl) amino-2-piperidone Sodium salt N-tert-butoxycarbonyl-O-benzyl-L-threonine (401.8 mg, 1.29888 mmol), dicyclohexylcarbodiimide (268.0 mg, 1.2989 mmol) and N-hydroxysuccinimide (149.5 mg, 1.2990 mmol) ) Was added acetonitrile (10 mL), and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Next, N-tert-butoxycarbonyl-O-benzyl was dissolved in a solution of sulfostin monohydrate (251.3 mg, 0.8659 mmol) and sodium hydrogen carbonate (80.0 mg, 0.9523 mmol) in water (5 mL). -L-threonine active ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (212.2 mg, 42%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.36−7.46(5H,m),4.66(1H,d,J=11.2Hz),4.46−4.55(2H,m),4.18(2H,s),3.71−3.79(1H,m),3.59−3.67(1H,m),2.10−2.21(1H,m),1.97−2.08(1H,m),1.85−1.97(1H,m),1.67−1.79(1H,m),1.46(9H,s),1.29(3H,d,J=5.4Hz).
HR−MS(ESI,POS)
m/z:found,608.1489(M+Na)+
calcd.for C21H33N5Na2O9PS,608.1532 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.36-7.46 (5H, m), 4.66 (1H, d, J = 11.2 Hz), 4.46-4.55 (2H, m), 4.18 (2H, s), 3.71-3.79 (1H, m), 3.59-3.67 (1H, m), 2.10-2.21 (1H, m), 1.97-2.08 (1H, m ), 1.85-1.97 (1H, m), 1.67-1.79 (1H, m), 1.46 (9H, s), 1.29 (3H, d, J = 5.4 Hz) ).
HR-MS (ESI, POS)
m / z: found, 608.1489 (M + Na) +
calcd. for C 21 H 33 N 5 Na 2 O 9 PS, 608.1532
実施例43
(3S,PR,2’S)−1−アミノ(スルホアミノ)ホスフィニル−3−(2’−tert−(ブトキシカルボニルアミノ)−3’−(ベンジルオキシカルボニル)プロピオニル)アミノ−2−ピペリドン ナトリウム塩
N−tert−ブトキシカルボニル−L−アスパラギン酸 4−ベンジルエステル(418.3mg,1.2936mmol)、ジシクロヘキシルカルボジイミド(266.9mg,1.2936mmol)及びN−ヒドロキシスクシンイミド(148.9mg,1.2938mmol)にアセトニトリル(10mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(250.3mg,0.8624mmol)及び炭酸水素ナトリウム(79.7mg,0.9487mmol)を水(5mL)に溶解した溶液に、N−tert−ブトキシカルボニル−L−アスパラギン酸 4−ベンジルエステル−1−活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(425.6mg,82%)を得た。Example 43
(3S, PR, 2 ′S) -1-amino (sulfoamino) phosphinyl-3- (2′-tert- (butoxycarbonylamino) -3 ′-(benzyloxycarbonyl) propionyl) amino-2-piperidone sodium salt N -Tert-Butoxycarbonyl-L-aspartic acid 4-benzyl ester (418.3 mg, 1.2936 mmol), dicyclohexylcarbodiimide (266.9 mg, 1.2936 mmol) and N-hydroxysuccinimide (148.9 mg, 1.2938 mmol) Acetonitrile (10 mL) was added, the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Then, N-tert-butoxycarbonyl-L-asparagine was added to a solution of sulfostine monohydrate (250.3 mg, 0.8624 mmol) and sodium bicarbonate (79.7 mg, 0.9487 mmol) in water (5 mL). Acid 4-benzyl ester-1-active ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (425.6 mg, 82%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.40−7.49(5H,m),5.21(2H,brs),4.46−4.57(2H,m),3.68−3.78(1H,m),3.58−3.67(1H,m),3.01(1H,dd,J=16.6,4.9Hz),2.82−2.93(1H,m),1.97−2.20(2H,m),1.82−1.95(1H,m),1.67−1.79(1H,m),1.42(9H,m).
HR−MS(ESI,POS)
m/z:found,622.1363(M+Na)+
calcd.for C21H31N5Na2O10PS,622.1325 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.40-7.49 (5H, m), 5.21 (2H, brs), 4.46-4.57 (2H, m), 3.68-3.78 (1H, m), 3. 58-3.67 (1H, m), 3.01 (1H, dd, J = 16.6, 4.9 Hz), 2.82-2.93 (1H, m), 1.97-2.20. (2H, m), 1.82-1.95 (1H, m), 1.67-1.79 (1H, m), 1.42 (9H, m).
HR-MS (ESI, POS)
m / z: found, 622.1363 (M + Na) +
calcd. for C 21 H 31 N 5 Na 2 O 10 PS, 622.1325
実施例44
(3S,PR,2’S)−1−アミノ(スルホアミノ)ホスフィニル−3−(2’−(tert−ブトキシカルボニルアミノ)−3’−(ベンジルオキシカルボニル)ブタノイル)アミノ−2−ピペリドン ナトリウム塩
N−tert−ブトキシカルボニル−L−グルタミン酸 5−ベンジルエステル(436.4mg,1.2935mmol)、ジシクロヘキシルカルボジイミド(266.9mg,1.2936mmol)及びN−ヒドロキシスクシンイミド(148.9mg,1.2938mmol)にアセトニトリル(10mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(250.3mg,0.8624mmol)及び炭酸水素ナトリウム(79.7mg,0.9487mmol)を水(5mL)に溶解した溶液に、N−tert−ブトキシカルボニル−L−グルタミン酸 5−ベンジルエステル−1−活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(338.1mg,64%)を得た。Example 44
(3S, PR, 2 ′S) -1-Amino (sulfoamino) phosphinyl-3- (2 ′-(tert-butoxycarbonylamino) -3 ′-(benzyloxycarbonyl) butanoyl) amino-2-piperidone sodium salt N -Tert-Butoxycarbonyl-L-glutamic acid 5-benzyl ester (436.4 mg, 1.2935 mmol), dicyclohexylcarbodiimide (266.9 mg, 1.2936 mmol) and N-hydroxysuccinimide (148.9 mg, 1.2938 mmol) in acetonitrile (10 mL) was added, and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration. Subsequently, N-tert-butoxycarbonyl-L-glutamic acid was added to a solution of sulfostine monohydrate (250.3 mg, 0.8624 mmol) and sodium hydrogen carbonate (79.7 mg, 0.9487 mmol) in water (5 mL). 5-Benzyl ester-1-active ester solution was added and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (338.1 mg, 64%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.40−7.48(5H,m),5.19(2H,s),4.53(1H,dd,J=12.2,6.8Hz),4.03−4.14(1H,m),3.74(1H,tdd,J=4.9,12.7,7.3Hz),3.60−3.68(1H,m),2.55−2.63(2H,m),2.12−2.23(2H,m),1.86−2.07(3H,m),1.71−1.83(1H,m),1.42(9H,s).
HR−MS(ESI,POS)
m/z:found,636.1438(M+Na)+
calcd.for C22H33N5Na2O10PS,636.1481 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.40-7.48 (5H, m), 5.19 (2H, s), 4.53 (1H, dd, J = 12.2, 6.8 Hz), 4.03-4.14 (1H M), 3.74 (1H, tdd, J = 4.9, 12.7, 7.3 Hz), 3.60-3.68 (1H, m), 2.55-2.63 (2H, m), 2.12-2.23 (2H, m), 1.86-2.07 (3H, m), 1.71-1.83 (1H, m), 1.42 (9H, s) .
HR-MS (ESI, POS)
m / z: found, 636.1438 (M + Na) +
calcd. for C 22 H 33 N 5 Na 2 O 10 PS, 636.1481
実施例45
(3S,PR,2’S)−1−アミノ(スルホアミノ)ホスフィニル−3−(2’−(tert−ブトキシカルボニルアミノ)−3’−(4”−ベンジルオキシフェニル)プロピオニル)アミノ−2−ピペリドン ナトリウム塩
N−tert−ブトキシカルボニル−O−ベンジル−L−チロシン(481.4mg,1.2961mmol)、ジシクロヘキシルカルボジイミド(267.4mg,1.2960mmol)及びN−ヒドロキシスクシンイミド(149.2mg,1.2964mmol)にアセトニトリル(10mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(250.8mg,0.8641mmol)及び炭酸水素ナトリウム(79.9mg,0.9511mmol)を水(5mL)に溶解した溶液に、N−tert−ブトキシカルボニル−O−ベンジル−L−チロシン活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(503.8mg,78%)を得た。Example 45
(3S, PR, 2 ′S) -1-Amino (sulfoamino) phosphinyl-3- (2 ′-(tert-butoxycarbonylamino) -3 ′-(4 ″ -benzyloxyphenyl) propionyl) amino-2-piperidone Sodium salt N-tert-butoxycarbonyl-O-benzyl-L-tyrosine (481.4 mg, 1.2961 mmol), dicyclohexylcarbodiimide (267.4 mg, 1.2960 mmol) and N-hydroxysuccinimide (149.2 mg, 1.2964 mmol) Acetonitrile (10 mL) was added to the mixture, and the mixture was stirred at room temperature for 2 hours, and the precipitated crystals were removed by filtration, then sulfostin monohydrate (250.8 mg, 0.8641 mmol) and sodium hydrogen carbonate (79.9 mg, 0 .9511 mmol) in water (5 mL To a solution of the added N-tert-butoxycarbonyl -O- benzyl -L- tyrosine active ester solution was stirred overnight at room temperature.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (503.8 mg, 78%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.03−7.22(7H,m),6.68−6.78(2H,m),4.74and4.67(2H,brs),4.48−4.57(1H,m),4.24−4.38(1H,m),3.72−3.82(1H,m),3.60−3.72(1H,m),3.08−3.18(1H,m),2.66−2.76(1H,m),2.09−2.20(1H,m),1.97−2.08(1H,m),1.86−1.96(1H,m),1.71−1.85(1H,m),1.19(9H,s).
HR−MS(ESI,POS)
m/z:found,670.1651(M+Na)+
calcd.for C26H35N5Na2O9PS,670.1689 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.03-7.22 (7H, m), 6.68-6.78 (2H, m), 4.74 and 4.67 (2H, brs), 4.48-4.57 (1H, m), 4.24-4.38 (1H, m), 3.72-3.82 (1H, m), 3.60-3.72 (1H, m), 3.08-3.18 (1H, m ), 2.66-2.76 (1H, m), 2.09-2.20 (1H, m), 1.97-2.08 (1H, m), 1.86-1.96 (1H) , M), 1.71-1.85 (1H, m), 1.19 (9H, s).
HR-MS (ESI, POS)
m / z: found, 670.1651 (M + Na) +
calcd. for C 26 H 35 N 5 Na 2 O 9 PS, 670.1689
実施例46
(3S,PR,2’S)−1−アミノ(スルホアミノ)ホスフィニル−3−((2’−tert−ブトキシカルボニルアミノ)−5’−ニトロアミジノペンタノイル)アミノ−2−ピペリドン ナトリウム塩
Nα−tert−ブトキシカルボニル−Nω−ニトロアルギニン(413.9mg,1.2962mmol)、ジシクロヘキシルカルボジイミド(267.4mg,1.2960mmol)及びN−ヒドロキシスクシンイミド(149.2mg,1.2964mmol)にアセトニトリル(10mL)を加え、室温で2時間撹拌し、析出した結晶を濾去した。次いで、スルフォスチン1水和物(250.8mg,0.8641mmol)及び炭酸水素ナトリウム(79.9mg,0.9511mmol)を水(5mL)に溶解した溶液に、Nα−tert−ブトキシカルボニル−Nω−ニトロアルギニン活性エステル溶液を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(256.7mg,50%)を得た。Example 46
(3S, PR, 2 ′S) -1-amino (sulfoamino) phosphinyl-3-((2′-tert-butoxycarbonylamino) -5′-nitroamidinopentanoyl) amino-2-piperidone sodium salt Nα-tert Acetonitrile (10 mL) was added to -butoxycarbonyl-Nω-nitroarginine (413.9 mg, 1.2962 mmol), dicyclohexylcarbodiimide (267.4 mg, 1.2960 mmol) and N-hydroxysuccinimide (149.2 mg, 1.2964 mmol). The mixture was stirred at room temperature for 2 hours, and the precipitated crystals were filtered off. Then, a solution of sulfostine monohydrate (250.8 mg, 0.8641 mmol) and sodium bicarbonate (79.9 mg, 0.9511 mmol) in water (5 mL) was added to Nα-tert-butoxycarbonyl-Nω-nitro. Arginine active ester solution was added and stirred overnight at room temperature.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (256.7 mg, 50%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
4.56(1H,dd,J=11.2,6.4Hz),4.02−4.12(1H,m),3.74(1H,tdd,J=4.9,12.2,7.8Hz),3.62−3.70(1H,m),3.28−3.36(2H,m),2.15−2.26(1H,m),2.00−2.10(1H,m),1.68−1.98(6H,m),1.43(9H,s).
HR−MS(ESI,POS)
m/z:found,618.1423(M+Na)+
calcd.for C16H31N9Na2O10PS,618.1448 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
4.56 (1H, dd, J = 11.2, 6.4 Hz), 4.02-4.12 (1H, m), 3.74 (1H, tdd, J = 4.9, 12.2, 7.8 Hz), 3.62-3.70 (1H, m), 3.28-3.36 (2H, m), 2.15-2.26 (1H, m), 2.00-2. 10 (1H, m), 1.68-1.98 (6H, m), 1.43 (9H, s).
HR-MS (ESI, POS)
m / z: found, 618.1423 (M + Na) +
calcd. for C 16 H 31 N 9 Na 2 O 10 PS, 618.1448
実施例47
(3S,P(RorS))−1−(アセチルアミノ)アミノホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン及び(3S,P(SorR))−1−(アセチルアミノ)アミノホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン
(3S)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ピペリドン(2.00g,6.13mmol)をピリジン(80mL)に加温溶解した溶液に、室温でアセチルクロリド(0.52mL,7.31mmol)を滴下し、同温で6時間攪拌した。
反応液を減圧濃縮した後、得られた残渣に30%アセトン水溶液を加え、析出している結晶を濾取した。得られた結晶にアセトンを加え不溶物をろ過した後、ろ液を濃縮し、結晶を酢酸エチル−エーテルの混合溶媒で洗浄することにより目的の(3S,P(SorR))−3−ベンジルオキシカルボニルアミノ−1−(アセチルアミノ)アミノホスフィニル−2−ピペリドン(0.41g,18%)を得た。
また、結晶母液と洗浄液をあわせてダイアイオンHP−20(100mL,水−アセトン勾配溶出)カラムクロマトにて精製を行い、溶出部を減圧濃縮後、得られた結晶を酢酸エチルに溶解して不溶物をろ過した。このろ液を減圧濃縮し、得られた結晶をエーテルで洗浄することにより目的の(3S,P(RorS))−3−ベンジルオキシカルボニルアミノ−1−(アセチルアミノ)アミノホスフィニル−2−ピペリドン(0.72g,32%)を得た。Example 47
(3S, P (RorS))-1- (acetylamino) aminophosphinyl-3-benzyloxycarbonylamino-2-piperidone and (3S, P (SorR))-1- (acetylamino) aminophosphinyl -3-Benzyloxycarbonylamino-2-piperidone (3S) -3-Benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone (2.00 g, 6.13 mmol) was dissolved in pyridine (80 mL) by heating. To this solution, acetyl chloride (0.52 mL, 7.31 mmol) was added dropwise at room temperature, and the mixture was stirred at the same temperature for 6 hours.
After concentrating the reaction solution under reduced pressure, 30% acetone aqueous solution was added to the resulting residue, and the precipitated crystals were collected by filtration. Acetone was added to the obtained crystals, insolubles were filtered off, the filtrate was concentrated, and the crystals were washed with a mixed solvent of ethyl acetate-ether to obtain the desired (3S, P (SorR))-3-benzyloxy. Carbonylamino-1- (acetylamino) aminophosphinyl-2-piperidone (0.41 g, 18%) was obtained.
The crystal mother liquor and the washing solution were combined and purified by Diaion HP-20 (100 mL, water-acetone gradient elution) column chromatography, and the eluate was concentrated under reduced pressure. The product was filtered. The filtrate was concentrated under reduced pressure, and the resulting crystals were washed with ether to give the desired (3S, P (RorS))-3-benzyloxycarbonylamino-1- (acetylamino) aminophosphinyl-2- Piperidone (0.72 g, 32%) was obtained.
(3S,P(SorR))−1−(アセチルアミノ)アミノホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン(実施例47A)
1H−NMR(DMSO−D6,内部標準TMS)
9.41(1H,brs),7.48(1H,d,J=8.8Hz),7.29−7.39(5H,m),5.03(2H,s),4.63(2H,brs),4.00−4.07(1H,m),3.52−3.63(2H,m),1.96−2.04(1H,m),1.90(3H,s),1.74−1.81(2H,m),1.61−1.72(1H,m).
13C−NMR(DMSO−D6,内部標準TMS)
173.1,171.9,155.9,136.9,128.3(X2),127.7(X3),65.3,51.2,43.4,25.9,23.7,20.8.
HR−MS(ESI,POS)
m/z:391(M+Na)+.(3S, P (SorR))-1- (acetylamino) aminophosphinyl-3-benzyloxycarbonylamino-2-piperidone (Example 47A)
1 H-NMR (DMSO-D 6 , internal standard TMS)
9.41 (1H, brs), 7.48 (1H, d, J = 8.8 Hz), 7.29-7.39 (5H, m), 5.03 (2H, s), 4.63 ( 2H, brs), 4.00-4.07 (1H, m), 3.52-3.63 (2H, m), 1.96-2.04 (1H, m), 1.90 (3H, s), 1.74-1.81 (2H, m), 1.61-1.72 (1H, m).
13 C-NMR (DMSO-D 6 , internal standard TMS)
173.1, 171.9, 155.9, 136.9, 128.3 (X2), 127.7 (X3), 65.3, 51.2, 43.4, 25.9, 23.7, 20.8.
HR-MS (ESI, POS)
m / z: 391 (M + Na) + .
(3S,P(RorS))−1−(アセチルアミノ)アミノホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン(実施例47B)
1H−NMR(DMSO−D6,内部標準TMS)
9.40(1H,brs),7.46(1H,d,J=8.3Hz),7.29−7.39(5H,m),5.03(2H,s),4.59(2H,brs),4.14(1H,td,J=7.8,11.7Hz),3.71−3.79(1H,m),3.46−3.54(1H,m),1.97−2.05(1H,m),1.83−1.94(1H,m),1.89(3H,s),1.70−1.80(1H,m),1.52−1.62(1H,m).
13C−NMR(DMSO−D6,内部標準TMS)
173.2,171.7,156.0,136.9,128.2(X2),127.7(X2),127.6,65.3,51.2,43.0,25.6,23.7,20.4.
HR−MS(ESI,POS)
m/z:391(M+Na)+.(3S, P (RorS))-1- (acetylamino) aminophosphinyl-3-benzyloxycarbonylamino-2-piperidone (Example 47B)
1 H-NMR (DMSO-D 6 , internal standard TMS)
9.40 (1H, brs), 7.46 (1H, d, J = 8.3 Hz), 7.29-7.39 (5H, m), 5.03 (2H, s), 4.59 ( 2H, brs), 4.14 (1H, td, J = 7.8, 11.7 Hz), 3.71-3.79 (1H, m), 3.46-3.54 (1H, m), 1.97-2.05 (1H, m), 1.83-1.94 (1H, m), 1.89 (3H, s), 1.70-1.80 (1H, m), 1. 52-1.62 (1H, m).
13 C-NMR (DMSO-D 6 , internal standard TMS)
173.2, 171.7, 156.0, 136.9, 128.2 (X2), 127.7 (X2), 127.6, 65.3, 51.2, 43.0, 25.6 23.7, 20.4.
HR-MS (ESI, POS)
m / z: 391 (M + Na) + .
実施例48
(3S,P(SR))−1−アミノ(n−ブタノイルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン
(3S)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ピペリドン(520.5mg,1.5952mmol)をピリジン(20mL)に加温溶解した溶液に、室温で酪酸無水物(0.31mL,1.8950mmol)を滴下し、外温60℃で2日間攪拌した。
反応液を減圧濃縮した後、得られた残渣に30%アセトン水溶液を加え、ダイアイオンHP−20(20mL,水−アセトン勾配溶出)にて精製を行った。得られたオイルをセファデックスLH−20(200mL,メタノール)にて精製を行うことにより目的化合物(300.3mg,47%)を得た。Example 48
(3S, P (SR))-1-amino (n-butanoylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2 -Butyric anhydride (0.31 mL, 1.8950 mmol) was added dropwise at room temperature to a solution obtained by dissolving piperidone (520.5 mg, 1.5952 mmol) in pyridine (20 mL) at room temperature, followed by stirring at an external temperature of 60 ° C. for 2 days. did.
After concentrating the reaction solution under reduced pressure, 30% acetone aqueous solution was added to the resulting residue, and purification was performed with Diaion HP-20 (20 mL, water-acetone gradient elution). The obtained oil was purified with Sephadex LH-20 (200 mL, methanol) to obtain the target compound (300.3 mg, 47%).
1H−NMR(CDCl3,内部標準TMS)
立体異性体A
7.85−7.93(1H,m),7.29−7.37(5H,m),5.65−5.72(1H,m),5.11(2H,m),4.21−4.31(1H,m),3.82−4.02(3H,m),3.67−3.75(1H,m),2.32−2.46(1H,m),2.26(2H,t,J=7.3Hz),1.80−1.96(2H,m),1.52−1.66(3H,m),0.91(3H,t,J=7.3Hz).
立体異性体B
7.74−7.84(1H,m),7.29−7.37(5H,m),5.57−5.65(1H,m),5.11(2H,m),4.21−4.31(1H,m),3.82−4.02(3H,m),3.56−3.66(1H,m),2.32−2.46(1H,m),2.26(2H,t,J=7.3Hz),2.00−2.10(1H,m),1.80−1.96(1H,m),1.52−1.66(3H,m),0.91(3H,t,J=7.3Hz).
HR−MS(ESI,POS)
m/z:419(M+Na)+. 1 H-NMR (CDCl 3 , internal standard TMS)
Stereoisomer A
7.85-7.93 (1H, m), 7.29-7.37 (5H, m), 5.65-5.72 (1H, m), 5.11 (2H, m), 4. 21-4.31 (1H, m), 3.82-4.02 (3H, m), 3.67-3.75 (1H, m), 2.32-2.46 (1H, m), 2.26 (2H, t, J = 7.3 Hz), 1.80-1.96 (2H, m), 1.52-1.66 (3H, m), 0.91 (3H, t, J = 7.3 Hz).
Stereoisomer B
7.74-7.84 (1H, m), 7.29-7.37 (5H, m), 5.57-5.65 (1H, m), 5.11 (2H, m), 4. 21-4.31 (1H, m), 3.82-4.02 (3H, m), 3.56-3.66 (1H, m), 2.32-2.46 (1H, m), 2.26 (2H, t, J = 7.3 Hz), 2.00-2.10 (1H, m), 1.80-1.96 (1H, m), 1.52-1.66 (3H , M), 0.91 (3H, t, J = 7.3 Hz).
HR-MS (ESI, POS)
m / z: 419 (M + Na) + .
実施例49
(3S,P(SR))−1−アミノ(t−ブチルアセチルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン
(3S)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ピペリドン(503.0mg,1.5416mmol)をピリジン(20mL)に加温溶解した溶液に、室温でt−ブチルアセチルクロリド(0.26mL,1.8716mmol)を滴下し、同温で3日間攪拌した。
反応液を減圧濃縮した後、得られた残渣に30%アセトン水溶液を加え、ダイアイオンHP−20(20mL,水−アセトン勾配溶出)カラムクロマトにて精製を行った。溶出部のアセトンを減圧留去し、酢酸エチルで抽出した。酢酸エチル溶液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、濃縮した。得られたオイルをn−ヘキサンにて結晶化を行うことにより目的化合物(624.7mg,95%)を得た。Example 49
(3S, P (SR))-1-amino (t-butylacetylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2 -To a solution obtained by dissolving piperidone (503.0 mg, 1.5416 mmol) in pyridine (20 mL) by heating, t-butylacetyl chloride (0.26 mL, 1.8716 mmol) was added dropwise at room temperature, and the mixture was stirred at the same temperature for 3 days. did.
After concentrating the reaction solution under reduced pressure, a 30% aqueous acetone solution was added to the resulting residue, and purification was performed by Diaion HP-20 (20 mL, water-acetone gradient elution) column chromatography. The acetone in the eluate was distilled off under reduced pressure and extracted with ethyl acetate. The ethyl acetate solution was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained oil was crystallized from n-hexane to obtain the target compound (624.7 mg, 95%).
1H−NMR(DMSO−D6,内部標準TMS)
立体異性体A
9.28(1H,brd,J=9.8Hz),7.41(1H,brd,J=8.3Hz),7.29−7.38(5H,m),5.03(2H,s),4.57(1H,brs),4.56(1H,brs),4.14(1H,td,J=7.8,12.2Hz),3.77−3.84(1H,m),3.44−3.57(1H,m),1.97−2.07(3H,m),1.84−1.93(1H,m),1.72−1.81(1H,m),1.56(1H,tt,J=12.2,7.8Hz),0.94(9H,s).
立体異性体B
9.28(1H,brd,J=9.8Hz),7.47(1H,brd,J=8.8Hz),7.29−7.38(5H,m),5.03(2H,s),4.59(1H,brs),4.58(1H,brs),3.95−4.04(1H,m),3.61−3.68(1H,m),3.44−3.57(1H,m),1.97−2.07(3H,m),1.62−1.81(3H,m),0.94(9H,s).
HR−MS(ESI,POS)
m/z:447(M+Na)+. 1 H-NMR (DMSO-D 6 , internal standard TMS)
Stereoisomer A
9.28 (1H, brd, J = 9.8 Hz), 7.41 (1H, brd, J = 8.3 Hz), 7.29-7.38 (5H, m), 5.03 (2H, s ), 4.57 (1H, brs), 4.56 (1H, brs), 4.14 (1H, td, J = 7.8, 12.2 Hz), 3.77-3.84 (1H, m ), 3.44-3.57 (1H, m), 1.97-2.07 (3H, m), 1.84-1.93 (1H, m), 1.72-1.81 (1H) , M), 1.56 (1H, tt, J = 12.2, 7.8 Hz), 0.94 (9H, s).
Stereoisomer B
9.28 (1H, brd, J = 9.8 Hz), 7.47 (1H, brd, J = 8.8 Hz), 7.29-7.38 (5H, m), 5.03 (2H, s ), 4.59 (1H, brs), 4.58 (1H, brs), 3.95-4.04 (1H, m), 3.61-3.68 (1H, m), 3.44- 3.57 (1H, m), 1.97-2.07 (3H, m), 1.62-1.81 (3H, m), 0.94 (9H, s).
HR-MS (ESI, POS)
m / z: 447 (M + Na) + .
実施例50
(3S,P(SR))−1−アミノ(シクロヘキサンカルボニルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン
(3S)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ピペリドン(545.4mg,1.6715mmol)をピリジン(20mL)に加温溶解した溶液に、室温でシクロヘキサンカルボニルクロリド(0.27mL,2.0183mmol)を滴下し、氷冷下3時間、室温で4時間攪拌した。
反応液を減圧濃縮した後、得られた残渣に30%アセトン水溶液を加え、ダイアイオンHP−20(20mL,水−アセトン勾配溶出)にて精製を行った。溶出部のアセトンを減圧留去し、酢酸エチルで抽出した。酢酸エチル溶液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、濃縮した。得られたオイルをエーテル−n−ヘキサンにて結晶化を行うことにより目的化合物(555.2mg,69%)を得た。Example 50
(3S, P (SR))-1-amino (cyclohexanecarbonylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone (545.4 mg, 1.6715 mmol) was dissolved in pyridine (20 mL) by heating, and cyclohexanecarbonyl chloride (0.27 mL, 2.0183 mmol) was added dropwise at room temperature, and the mixture was cooled with ice for 3 hours and at room temperature for 4 hours. Stir.
After concentrating the reaction solution under reduced pressure, 30% acetone aqueous solution was added to the resulting residue, and purification was performed with Diaion HP-20 (20 mL, water-acetone gradient elution). The acetone in the eluate was distilled off under reduced pressure and extracted with ethyl acetate. The ethyl acetate solution was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained oil was crystallized from ether-n-hexane to obtain the target compound (555.2 mg, 69%).
1H−NMR(DMSO−D6,内部標準TMS)
立体異性体A
9.23(1H,brs),7.42(1H,d,J=8.3Hz),7.28−7.38(5H,m),5.02(2H,s),4.53−4.57(2H,m),4.11(1H,td,J=7.8,12.2Hz),3.73−3.82(1H,m),3.53−3.63(1H,m),2.14−2.23(1H,m),1.95−2.04(1H,m),1.47−1.92(7H,m),1.06−1.30(6H,m).
立体異性体B
9.23(1H,brs),7.46(1H,d,J=8.3Hz),7.28−7.38(5H,m),5.02(2H,s),4.53−4.57(2H,m),3.94−4.02(1H,m),3.43−3.52(2H,m),2.14−2.23(1H,m),1.95−2.04(1H,m),1.47−1.92(7H,m),1.06−1.30(6H,m).
HR−MS(ESI,POS)
m/z:459(M+Na)+. 1 H-NMR (DMSO-D 6 , internal standard TMS)
Stereoisomer A
9.23 (1H, brs), 7.42 (1H, d, J = 8.3 Hz), 7.28-7.38 (5H, m), 5.02 (2H, s), 4.53- 4.57 (2H, m), 4.11 (1H, td, J = 7.8, 12.2 Hz), 3.73-3.82 (1H, m), 3.53-3.63 (1H M), 2.14-2.23 (1H, m), 1.95-2.04 (1H, m), 1.47-1.92 (7H, m), 1.06-1.30. (6H, m).
Stereoisomer B
9.23 (1H, brs), 7.46 (1H, d, J = 8.3 Hz), 7.28-7.38 (5H, m), 5.02 (2H, s), 4.53- 4.57 (2H, m), 3.94-4.02 (1H, m), 3.43-3.52 (2H, m), 2.14-2.23 (1H, m), 1. 95-2.04 (1H, m), 1.47-1.92 (7H, m), 1.06-1.30 (6H, m).
HR-MS (ESI, POS)
m / z: 459 (M + Na) + .
実施例51
(3S,P(SR))−1−アミノ(フェノキシアセチルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン
(3S)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ピペリドン(504.0mg,1.5446mmol)をピリジン(20mL)に加温溶解した溶液に、室温でフェノキシアセチルクロリド(0.32mL,2.3165mmol)を滴下し、室温で16時間攪拌した。
反応液を減圧濃縮した後、得られた残渣に30%アセトン水溶液を加え、ダイアイオンHP−20(20mL,水−アセトン勾配溶出)カラムクロマトにて精製を行った。溶出部のアセトンを減圧留去した後、酢酸エチルで抽出した。酢酸エチル溶液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られたオイルをエーテル−n−ヘキサンにて結晶化を行うことにより目的化合物(421.2mg,67%)を得た。Example 51
(3S, P (SR))-1-amino (phenoxyacetylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone To a solution obtained by heating and dissolving (504.0 mg, 1.5446 mmol) in pyridine (20 mL), phenoxyacetyl chloride (0.32 mL, 2.3165 mmol) was added dropwise at room temperature, and the mixture was stirred at room temperature for 16 hours.
After concentrating the reaction solution under reduced pressure, a 30% aqueous acetone solution was added to the resulting residue, and purification was performed by Diaion HP-20 (20 mL, water-acetone gradient elution) column chromatography. Acetone in the eluate was distilled off under reduced pressure, followed by extraction with ethyl acetate. The ethyl acetate solution was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil was crystallized from ether-n-hexane to obtain the target compound (421.2 mg, 67%).
1H−NMR(DMSO−D6,内部標準TMS)
立体異性体A
9.57(1H,brs),7.52(1H,d,J=8.3Hz),7.27−7.39(7H,m),6.95(1H,t,J=7.3Hz),6.87(2H,d,J=7.3Hz),5.03(2H,s),4.82(1H,brs),4.81(1H,brs),4.55(2H,q,J=16.1Hz),4.14(1H,td,J=7.8,12.2Hz),3.72−3.80(1H,m),3.48−3.58(1H,m),1.96−2.06(1H,m),1.64−1.88(2H,m),1.56(1H,tt,J=12.2,7.8Hz).
立体異性体B
9.57(1H,brs),7.53(1H,d,J=8.3Hz),7.27−7.39(7H,m),6.95(1H,t,J=7.3Hz),6.84(2H,d,J=7.3Hz),5.04(2H,s),4.82(1H,brs),4.81(1H,brs),4.50−4.64(2H,m),3.98−4.07(1H,m),3.48−3.66(2H,m),1.96−2.06(1H,m),1.64−1.88(3H,m).
HR−MS(ESI,POS)
m/z:483(M+Na)+. 1 H-NMR (DMSO-D 6 , internal standard TMS)
Stereoisomer A
9.57 (1H, brs), 7.52 (1H, d, J = 8.3 Hz), 7.27-7.39 (7H, m), 6.95 (1H, t, J = 7.3 Hz) ), 6.87 (2H, d, J = 7.3 Hz), 5.03 (2H, s), 4.82 (1H, brs), 4.81 (1H, brs), 4.55 (2H, q, J = 16.1 Hz), 4.14 (1H, td, J = 7.8, 12.2 Hz), 3.72-3.80 (1H, m), 3.48-3.58 (1H M), 1.96-2.06 (1H, m), 1.64-1.88 (2H, m), 1.56 (1H, tt, J = 12.2, 7.8 Hz).
Stereoisomer B
9.57 (1H, brs), 7.53 (1H, d, J = 8.3 Hz), 7.27-7.39 (7H, m), 6.95 (1H, t, J = 7.3 Hz) ), 6.84 (2H, d, J = 7.3 Hz), 5.04 (2H, s), 4.82 (1H, brs), 4.81 (1H, brs), 4.50-4. 64 (2H, m), 3.98-4.07 (1H, m), 3.48-3.66 (2H, m), 1.96-2.06 (1H, m), 1.64 1.88 (3H, m).
HR-MS (ESI, POS)
m / z: 483 (M + Na) + .
実施例52
(3S,P(SR))−1−アミノ(シンナモイルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン
(3S)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ピペリドン(835.5mg,2.5606mmol)をピリジン(33mL)に加温溶解した溶液に、室温でシンナモイルクロリド(511.9mg,3.0726mmol)を加え、室温で18時間攪拌した。
反応液を減圧濃縮した後、得られた残渣に30%アセトン水溶液を加え、ダイアイオンHP−20(20mL,水−アセトン勾配溶出)カラムクロマトにて精製を行った。溶出部のアセトンを減圧留去し、酢酸エチルで抽出した。酢酸エチル溶液を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した後、減圧濃縮した。得られたオイルをエーテル−n−ヘキサンにて結晶化を行うことにより目的化合物(833.3mg,73%)を得た。Example 52
(3S, P (SR))-1-amino (cinnamoylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone Cinnamoyl chloride (511.9 mg, 3.0726 mmol) was added at room temperature to a solution obtained by heating (835.5 mg, 2.5606 mmol) in pyridine (33 mL), and the mixture was stirred at room temperature for 18 hours.
After concentrating the reaction solution under reduced pressure, a 30% aqueous acetone solution was added to the resulting residue, and purification was performed by Diaion HP-20 (20 mL, water-acetone gradient elution) column chromatography. The acetone in the eluate was distilled off under reduced pressure and extracted with ethyl acetate. The ethyl acetate solution was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil was crystallized from ether-n-hexane to obtain the target compound (833.3 mg, 73%).
1H−NMR(DMSO−D6,内部標準TMS)
立体異性体A
9.61(1H,s),7.57−7.60(2H,m),7.52(1H,d,J=16.1Hz),7.41−7.48(4H,m),7.27−7.37(5H,m),6.72(1H,d,J=16.1Hz),5.00(2H,s),4.72(1H,brs),4.72(1H,brs),4.18(1H,td,J=7.8,11.7Hz),3.82−3.90(1H,m),3.51−3.59(1H,m),1.54−2.07(4H,m).
立体異性体B
9.61(1H,s),7.57−7.60(2H,m),7.52(1H,d,J=16.1Hz),7.41−7.48(4H,m),7.27−7.37(5H,m),6.72(1H,d,J=16.1Hz),5.00(2H,s),4.75(1H,brs),4.75(1H,brs),4.03(1H,q,J=6.8Hz),3.58−3.72(2H,m),1.54−2.07(4H,m).
HR−MS(ESI,POS)
m/z:479(M+Na)+. 1 H-NMR (DMSO-D 6 , internal standard TMS)
Stereoisomer A
9.61 (1H, s), 7.57-7.60 (2H, m), 7.52 (1H, d, J = 16.1 Hz), 7.41-7.48 (4H, m), 7.27-7.37 (5H, m), 6.72 (1H, d, J = 16.1 Hz), 5.00 (2H, s), 4.72 (1H, brs), 4.72 ( 1H, brs), 4.18 (1H, td, J = 7.8, 11.7 Hz), 3.82-3.90 (1H, m), 3.51-3.59 (1H, m), 1.54-2.07 (4H, m).
Stereoisomer B
9.61 (1H, s), 7.57-7.60 (2H, m), 7.52 (1H, d, J = 16.1 Hz), 7.41-7.48 (4H, m), 7.27-7.37 (5H, m), 6.72 (1H, d, J = 16.1 Hz), 5.00 (2H, s), 4.75 (1H, brs), 4.75 ( 1H, brs), 4.03 (1H, q, J = 6.8 Hz), 3.58-3.72 (2H, m), 1.54-2.07 (4H, m).
HR-MS (ESI, POS)
m / z: 479 (M + Na) + .
実施例53
(3S,P(RS))−1−アミノ(4−メトキシベンゾイルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン
(3S)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ピペリドン(602.0mg,1.8450mmol)をピリジン(24mL)に加温溶解した溶液に、室温で4−メトキシベンゾイルクロリド(377.7mg,2.4121mmol)を加え、同温で6時間攪拌した。
反応液を減圧濃縮した後、得られた残渣に30%アセトン水溶液を加え、結晶を濾取した。得られた結晶にアセトンを加え不溶物をろ過した後、ろ液を減圧濃縮し、得られた結晶を酢酸エチル−エーテルの混合溶媒で洗浄することにより目的化合物(220.1mg,26%)を得た。Example 53
(3S, P (RS))-1-amino (4-methoxybenzoylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2 -To a solution obtained by dissolving piperidone (602.0 mg, 1.8450 mmol) in pyridine (24 mL) by heating, 4-methoxybenzoyl chloride (377.7 mg, 2.4121 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 6 hours. .
The reaction mixture was concentrated under reduced pressure, 30% acetone aqueous solution was added to the obtained residue, and the crystals were collected by filtration. Acetone was added to the obtained crystals, insolubles were filtered off, the filtrate was concentrated under reduced pressure, and the obtained crystals were washed with a mixed solvent of ethyl acetate-ether to obtain the target compound (220.1 mg, 26%). Obtained.
1H−NMR(DMSO−D6,内部標準TMS)
立体異性体A
9.49(1H,brs),7.89(2H,d,J=8.8Hz),7.47(1H,d,J=8.8Hz),7.27−7.37(5H,m),7.01(2H,dd,J=8.8,2.0Hz),4.99(2H,s),4.69−4.73(2H,m),4.12−4.20(1H,m),3.84−3.93(1H,m),3.82(3H,s),3.53−3.62(1H,m),1.50−2.07(4H,m).
立体異性体B
9.49(1H,brs),7.89(2H,d,J=8.8Hz),7.43(1H,d,J=8.8Hz),7.27−7.37(5H,m),7.01(2H,dd,J=8.8,2.0Hz),4.99(2H,s),4.69−4.73(2H,m),3.99−4.07(1H,m),3.81(3H,s),3.62−3.72(2H,m),1.50−2.07(4H,m).
HR−MS(ESI,POS)
m/z:483(M+Na)+. 1 H-NMR (DMSO-D 6 , internal standard TMS)
Stereoisomer A
9.49 (1H, brs), 7.89 (2H, d, J = 8.8 Hz), 7.47 (1H, d, J = 8.8 Hz), 7.27-7.37 (5H, m ), 7.01 (2H, dd, J = 8.8, 2.0 Hz), 4.99 (2H, s), 4.69-4.73 (2H, m), 4.12-4.20. (1H, m), 3.84-3.93 (1H, m), 3.82 (3H, s), 3.53-3.62 (1H, m), 1.50-2.07 (4H , M).
Stereoisomer B
9.49 (1H, brs), 7.89 (2H, d, J = 8.8 Hz), 7.43 (1H, d, J = 8.8 Hz), 7.27-7.37 (5H, m ), 7.01 (2H, dd, J = 8.8, 2.0 Hz), 4.99 (2H, s), 4.69-4.73 (2H, m), 3.99-4.07 (1H, m), 3.81 (3H, s), 3.62-3.72 (2H, m), 1.50-2.07 (4H, m).
HR-MS (ESI, POS)
m / z: 483 (M + Na) + .
実施例54
(3S,P(RorS))−1−アミノ(ベンジルオキシアセチルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン及び(3S,P(SorR))−1−アミノ(ベンジルオキシアセチルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン
(3S)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ピペリドン(666.0mg,2.04mmol)をピリジン(26mL)に加温溶解した溶液に、室温でベンジルオキシアセチルクロリド(0.48mL,3.04mmol)を加え、同温で5時間攪拌した。
反応液を減圧濃縮した後、得られた残渣をダイアイオンHP−20SS(25mL,水−アセトン勾配溶出)カラムクロマトで精製を行い、溶出部から析出した結晶を濾取することにより(3S,P(RorS))−3−ベンジルオキシカルボニルアミノ−1−アミノ(ベンジルオキシアセチルアミノ)ホスフィニル−2−ピペリドン(470.9mg,49%)を得た。
結晶濾液を減圧濃縮後、再度ダイアイオンHP−20SS(25mL,水−アセトン勾配溶出)で精製を行うことにより、(3S,P(SorR))−3−ベンジルオキシカルボニルアミノ−1−アミノ(ベンジルオキシアセチルアミノ)ホスフィニル−2−ピペリドン(100.5mg,10%)を得た。Example 54
(3S, P (RorS))-1-amino (benzyloxyacetylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone and (3S, P (SorR))-1-amino (benzyloxyacetylamino) phosphinyl -3-Benzyloxycarbonylamino-2-piperidone (3S) -3-Benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone (666.0 mg, 2.04 mmol) was dissolved in pyridine (26 mL) by heating. To the solution was added benzyloxyacetyl chloride (0.48 mL, 3.04 mmol) at room temperature, and the mixture was stirred at the same temperature for 5 hours.
After the reaction solution was concentrated under reduced pressure, the resulting residue was purified by Diaion HP-20SS (25 mL, water-acetone gradient elution) column chromatography, and the crystals precipitated from the eluate were collected by filtration (3S, P (RorS))-3-Benzyloxycarbonylamino-1-amino (benzyloxyacetylamino) phosphinyl-2-piperidone (470.9 mg, 49%) was obtained.
The crystal filtrate was concentrated under reduced pressure, and purified again with Diaion HP-20SS (25 mL, water-acetone gradient elution) to give (3S, P (SorR))-3-benzyloxycarbonylamino-1-amino (benzyl Oxyacetylamino) phosphinyl-2-piperidone (100.5 mg, 10%) was obtained.
(3S,P(RorS))−1−アミノ(ベンジルオキシアセチルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン(実施例54A)
1H−NMR(CDCl3,内部標準TMS)
7.90(1H,brd,J=12.2Hz),7.30−7.40(10H,m),5.44(1H,brd,J=6.8Hz),5.12(1H,s),5.11(1H,s),4.57(1H,s),4.57(1H,s),4.25−4.33(1H,m),4.05(1H,qd,J=6.3,12.7Hz),3.93(1H,s),3.92(1H,s),3.73(1H,brs),3.72(1H,brs),3.58−3.68(1H,m),2.36−2.46(1H,m),2.04−2.14(1H,m),1.82−1.92(1H,m),1.51−1.63(1H,m).
MS(APCI,POS)
m/z:475(M+H)+.(3S, P (RorS))-1-amino (benzyloxyacetylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (Example 54A)
1 H-NMR (CDCl 3 , internal standard TMS)
7.90 (1H, brd, J = 12.2 Hz), 7.30-7.40 (10H, m), 5.44 (1H, brd, J = 6.8 Hz), 5.12 (1H, s ), 5.11 (1H, s), 4.57 (1H, s), 4.57 (1H, s), 4.25-4.33 (1H, m), 4.05 (1H, qd, J = 6.3, 12.7 Hz), 3.93 (1H, s), 3.92 (1H, s), 3.73 (1H, brs), 3.72 (1H, brs), 3.58. -3.68 (1H, m), 2.36-2.46 (1H, m), 2.04-2.14 (1H, m), 1.82-1.92 (1H, m), 1 .51-1.63 (1H, m).
MS (APCI, POS)
m / z: 475 (M + H) + .
(3S,P(SorR))−1−アミノ(ベンジルオキシアセチルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン(実施例54B)
1H−NMR(DMSO−D6,内部標準TMS)
7.85−7.93(1H,m),7.30−7.40(10H,m),5.53(1H,brd,J=5.9Hz),5.11(2H,s),4.56(1H,s),4.19−4.33(1H,m),3.86−3.96(3H,m),3.70−3.82(3H,m),2.43−2.53(1H,m),1.91−1.99(2H,m),1.55−1.66(1H,m).
MS(APCI,POS)
m/z:475(M+H)+.(3S, P (SorR))-1-amino (benzyloxyacetylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (Example 54B)
1 H-NMR (DMSO-D 6 , internal standard TMS)
7.85-7.93 (1H, m), 7.30-7.40 (10H, m), 5.53 (1H, brd, J = 5.9 Hz), 5.11 (2H, s), 4.56 (1H, s), 4.19-4.33 (1H, m), 3.86-3.96 (3H, m), 3.70-3.82 (3H, m), 2. 43-2.53 (1H, m), 1.91-1.99 (2H, m), 1.55-1.66 (1H, m).
MS (APCI, POS)
m / z: 475 (M + H) + .
実施例55
(3S,P(RS))−1−アミノ(ベンゾイルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン
(3S)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ピペリドン(333.0mg,1.02mmol)をピリジン(8mL)に加温溶解した溶液に、室温でベンゾイルクロリド(0.18mL,1.55mmol)を加え、同温で3日間攪拌した。
反応液を減圧濃縮した後、得られた残渣をシリカゲル(クロロホルム:メタノール=14:1〜9:1)カラムクロマトにて精製を行うことにより目的化合物(248.6mg,57%)を得た。Example 55
(3S, P (RS))-1-amino (benzoylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone ( To a solution obtained by heating and dissolving 333.0 mg, 1.02 mmol) in pyridine (8 mL), benzoyl chloride (0.18 mL, 1.55 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 3 days.
The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (chloroform: methanol = 14: 1 to 9: 1) to give the target compound (248.6 mg, 57%).
1H−NMR(DMSO−D6,内部標準TMS)
立体異性体A
9.71(1H,brs),7.84−7.92(2H,m),7.56−7.62(1H,m),7.40−7.52(3H,m),7.27−7.37(5H,m),4.99(2H,s),4.70−4.78(2H,m),4.16(1H,td,J=7.8,11.7Hz),3.84−3.94(1H,m),3.54−3.64(1H,m),1.89−2.09(2H,m),1.75−1.87(1H,m),1.56(1H,tt,J=12.7,7.8Hz).
立体異性体B
9.71(1H,brs),7.84−7.92(2H,m),7.56−7.62(1H,m),7.40−7.52(3H,m),7.27−7.37(5H,m),4.99(2H,s),4.70−4.78(2H,m),4.03(1H,td,J=7.8,11.7Hz),3.64−3.74(2H,m),1.97−2.07(1H,m),1.75−1.87(2H,m),1.68(1H,tt,J=12.7,7.8Hz).
MS(APCI,POS)
m/z:431(M+H)+. 1 H-NMR (DMSO-D 6 , internal standard TMS)
Stereoisomer A
9.71 (1H, brs), 7.84-7.92 (2H, m), 7.56-7.62 (1H, m), 7.40-7.52 (3H, m), 7. 27-7.37 (5H, m), 4.99 (2H, s), 4.70-4.78 (2H, m), 4.16 (1 H, td, J = 7.8, 11.7 Hz) ), 3.84-3.94 (1H, m), 3.54-3.64 (1H, m), 1.89-2.09 (2H, m), 1.75-1.87 (1H) M), 1.56 (1H, tt, J = 12.7, 7.8 Hz).
Stereoisomer B
9.71 (1H, brs), 7.84-7.92 (2H, m), 7.56-7.62 (1H, m), 7.40-7.52 (3H, m), 7. 27-7.37 (5H, m), 4.99 (2H, s), 4.70-4.78 (2H, m), 4.03 (1H, td, J = 7.8, 11.7 Hz) ), 3.64-3.74 (2H, m), 1.97-2.07 (1H, m), 1.75-1.87 (2H, m), 1.68 (1H, tt, J = 12.7, 7.8 Hz).
MS (APCI, POS)
m / z: 431 (M + H) + .
実施例56
(3S,P(RS))−1−アミノ(2−チオフェンカルボニルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン
(3S)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ピペリドン(502.0mg,1.54mmol)をピリジン(24mL)に加温溶解した溶液に、室温で2−チオフェンカルボニルクロリド(0.20mL,1.87mmol)を加え、同温で6時間攪拌した。
反応液を減圧濃縮した後、得られた残渣に30%アセトン水溶液を加え、ダイアイオンHP−20(30mL,水−アセトン勾配溶出)カラムクロマトにて精製を行った。溶出部のアセトンを減圧留去し、酢酸エチルで抽出した。酢酸エチル溶液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られたオイルをエーテル−n−ヘキサンにて結晶化を行うことにより目的化合物(345.0mg,51%)を得た。Example 56
(3S, P (RS))-1-amino (2-thiophenecarbonylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2 -To a solution obtained by dissolving piperidone (502.0 mg, 1.54 mmol) in pyridine (24 mL) by heating, 2-thiophenecarbonyl chloride (0.20 mL, 1.87 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 6 hours. .
After concentrating the reaction solution under reduced pressure, a 30% aqueous acetone solution was added to the resulting residue, and purification was performed by Diaion HP-20 (30 mL, water-acetone gradient elution) column chromatography. The acetone in the eluate was distilled off under reduced pressure and extracted with ethyl acetate. The ethyl acetate solution was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil was crystallized from ether-n-hexane to obtain the target compound (345.0 mg, 51%).
1H−NMR(DMSO−D6,内部標準TMS)
立体異性体A
9.79(1H,brs),8.01(1H,td,J=3.9,1.0Hz),7.88(1H,t,J=3.9Hz),7.47(1H,t,J=3.3Hz),7.28〜7.38(5H,m),7.18(1H,ddd,J=4.9,3.9,2.4Hz),5.00(2H,s),4.81(1H,brs),4.80(1H,brs),4.18(1H,td,J=8.3,12.2Hz),3.85(1H,td,J=12.2,6.4Hz),3.62−3.71(1H,m),1.51−2.06(4H,m).
立体異性体B
9.79(1H,brs),8.01(1H,td,J=3.9,1.0Hz),7.88(1H,t,J=3.9Hz),7.47(1H,t,J=8.3Hz),7.28〜7.38(5H,m),7.18(1H,ddd,J=4.9,3.9,2.4Hz),5.00(2H,s),4.78(1H,brs),4.77(1H,brs),4.04(1H,td,J=8.3,11.7Hz),3.56(1H,qd,J=8.8,3.9Hz),3.62−3.71(1H,m),1.51−2.06(4H,m).
MS(APCI,POS)
m/z:437(M+H)+. 1 H-NMR (DMSO-D 6 , internal standard TMS)
Stereoisomer A
9.79 (1H, brs), 8.01 (1H, td, J = 3.9, 1.0 Hz), 7.88 (1H, t, J = 3.9 Hz), 7.47 (1H, t , J = 3.3 Hz), 7.28-7.38 (5H, m), 7.18 (1H, ddd, J = 4.9, 3.9, 2.4 Hz), 5.00 (2H, s), 4.81 (1H, brs), 4.80 (1H, brs), 4.18 (1H, td, J = 8.3, 12.2 Hz), 3.85 (1H, td, J = 12.2, 6.4 Hz), 3.62-3.71 (1H, m), 1.51-2.06 (4H, m).
Stereoisomer B
9.79 (1H, brs), 8.01 (1H, td, J = 3.9, 1.0 Hz), 7.88 (1H, t, J = 3.9 Hz), 7.47 (1H, t , J = 8.3 Hz), 7.28-7.38 (5H, m), 7.18 (1H, ddd, J = 4.9, 3.9, 2.4 Hz), 5.00 (2H, s), 4.78 (1H, brs), 4.77 (1H, brs), 4.04 (1H, td, J = 8.3, 11.7 Hz), 3.56 (1H, qd, J = 8.8, 3.9 Hz), 3.62-3.71 (1H, m), 1.51-2.06 (4H, m).
MS (APCI, POS)
m / z: 437 (M + H) + .
実施例57
(3S,P(RS))−1−アミノ(4−ニトロベンゾイルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン
(3S)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ピペリドン(606.0mg,1.84572mmol)をピリジン(24mL)に加温溶解した溶液に、室温で4−ニトロベンゾイルクロリド(413.6mg,2.2289mmol)を加え、同温で6時間攪拌した。
反応液を減圧濃縮した後、得られた残渣に30%アセトン水溶液を加え、結晶を濾取した。得られた結晶にアセトンを加え不溶物をろ過した後、ろ液を減圧濃縮し、得られた結晶を酢酸エチル−エーテルの混合溶媒で洗浄することにより目的化合物(448.0mg,51%)を得た。Example 57
(3S, P (RS))-1-amino (4-nitrobenzoylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2 -To a solution obtained by dissolving piperidone (606.0 mg, 1.845572 mmol) in pyridine (24 mL) by heating, 4-nitrobenzoyl chloride (413.6 mg, 2.2289 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 6 hours. .
The reaction mixture was concentrated under reduced pressure, 30% acetone aqueous solution was added to the obtained residue, and the crystals were collected by filtration. Acetone was added to the obtained crystals, insolubles were filtered off, the filtrate was concentrated under reduced pressure, and the obtained crystals were washed with a mixed solvent of ethyl acetate-ether to obtain the target compound (448.0 mg, 51%). Obtained.
1H−NMR(DMSO−D6,内部標準TMS)
立体異性体A
10.16(1H,brs),8.32(2H,dd,J=8.8,2.9Hz),8.09(2H,dd,J=8.8,2.9Hz),7.49(1H,d,J=8.8Hz),7.27−7.37(5H,m),4.99(2H,s),4.80or4.84(1H,brs),4.81or4.85(1H,brs),4.14(1H,ddd,J=11.7,8.3,7.3Hz),3.83−3.91(1H,m),3.56−3.66(1H,m),1.53−2.06(4H,m).
立体異性体B
10.16(1H,brs),8.32(2H,dd,J=8.8,2.9Hz),8.09(2H,dd,J=8.8,2.9Hz),7.46(1H,d,J=8.8Hz),7.27−7.37(5H,m),4.98(1H,s),4.97(1H,s),4.84or4.80(1H,brs),4.85or4.81(1H,brs)4.04(1H,td,J=7.8,11.7Hz),3.64−3.72(2H,m),1.53−2.06(4H,m).
MS(APCI,POS)
m/z:476(M+H)+. 1 H-NMR (DMSO-D 6 , internal standard TMS)
Stereoisomer A
10.16 (1H, brs), 8.32 (2H, dd, J = 8.8, 2.9 Hz), 8.09 (2H, dd, J = 8.8, 2.9 Hz), 7.49 (1H, d, J = 8.8 Hz), 7.27-7.37 (5H, m), 4.99 (2H, s), 4.80 or 4.84 (1H, brs), 4.81 or 4.85 (1H, brs), 4.14 (1H, ddd, J = 11.7, 8.3, 7.3 Hz), 3.83-3.91 (1H, m), 3.56-3.66 ( 1H, m), 1.53-2.06 (4H, m).
Stereoisomer B
10.16 (1H, brs), 8.32 (2H, dd, J = 8.8, 2.9 Hz), 8.09 (2H, dd, J = 8.8, 2.9 Hz), 7.46 (1H, d, J = 8.8 Hz), 7.27-7.37 (5H, m), 4.98 (1H, s), 4.97 (1H, s), 4.84 or 4.80 (1H , Brs), 4.85 or 4.81 (1H, brs) 4.04 (1H, td, J = 7.8, 11.7 Hz), 3.64-3.72 (2H, m), 1.53- 2.06 (4H, m).
MS (APCI, POS)
m / z: 476 (M + H) + .
実施例58
(3S,P(RS))−1−アミノ(4−フルオロベンゾイルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン及び(3S)−3−ベンジルオキシカルボニルアミノ−1−ビス(4−フルオロベンゾイルアミノ)ホスフィニル−2−ピペリドンの合成
(3S)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ピペリドン(335.5mg,1.0282mmol)をピリジン(24mL)に加温溶解した溶液に、室温で4−フルオロベンゾイルクロリド(377.7mg,2.4121mmol)を加え、同温で6時間攪拌した。
反応液を減圧濃縮した後、得られた残渣をシリカゲル(クロロホルム:メタノール=14:1〜9:1)カラムクロマトにて精製を行うことにより、(3S,P(RS))−3−ベンジルオキシカルボニルアミノ−1−アミノ(4−フルオロベンゾイルアミノ)ホスフィニル−2−ピペリドン(210.9mg,46%)及び(3S)−3−ベンジルオキシカルボニルアミノ−1−ビス(4−フルオロベンゾイルアミノ)ホスフィニル−2−ピペリドン(88.8mg,15%)を得た。Example 58
(3S, P (RS))-1-amino (4-fluorobenzoylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone and (3S) -3-benzyloxycarbonylamino-1-bis (4-fluoro Synthesis of benzoylamino) phosphinyl-2-piperidone (3S) -3-Benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone (335.5 mg, 1.0282 mmol) was dissolved in pyridine (24 mL) by heating. 4-Fluorobenzoyl chloride (377.7 mg, 2.4121 mmol) was added to the solution at room temperature, and the mixture was stirred at the same temperature for 6 hours.
After the reaction solution was concentrated under reduced pressure, the obtained residue was purified by silica gel (chloroform: methanol = 14: 1 to 9: 1) column chromatography to obtain (3S, P (RS))-3-benzyloxy. Carbonylamino-1-amino (4-fluorobenzoylamino) phosphinyl-2-piperidone (210.9 mg, 46%) and (3S) -3-benzyloxycarbonylamino-1-bis (4-fluorobenzoylamino) phosphinyl- 2-Piperidone (88.8 mg, 15%) was obtained.
(3S,P(RS))−1−アミノ(4−フルオロベンゾイルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン(実施例58A)
1H−NMR(DMSO−D6,内部標準TMS)
立体異性体A
9.71(1H,brs),7.95−7.99(2H,m),7.44(1H,brd,J=8.8Hz),7.28−7.37(7H,m),4.99(2H,s),4.74(1H,brs),4.73(1H,brs),4.15(1H,td,J=7.8,12.2Hz),3.83−3.91(1H,m),3.57(1H,qd,J=8.3,4.4Hz),1.89−2.05(2H,m),1.75−1.85(1H,m),1.56(1H,tt,J=12.2,7.8Hz).
立体異性体B
9.71(1H,brs),7.95−7.99(2H,m),7.48(1H,brd,J=8.8Hz),7.28−7.37(7H,m),4.99(2H,s),4.77(1H,brs),4.76(1H,brs),3.99−4.07(1H,m),3.63−3.71(2H,m),1.96−2.05(1H,m),1.75−1.85(2H,m),1.62−1.73(1H,m).
MS(APCI,POS)
m/z:449(M+H)+.(3S, P (RS))-1-amino (4-fluorobenzoylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (Example 58A)
1 H-NMR (DMSO-D 6 , internal standard TMS)
Stereoisomer A
9.71 (1H, brs), 7.95-7.99 (2H, m), 7.44 (1H, brd, J = 8.8 Hz), 7.28-7.37 (7H, m), 4.99 (2H, s), 4.74 (1H, brs), 4.73 (1H, brs), 4.15 (1H, td, J = 7.8, 12.2 Hz), 3.83- 3.91 (1H, m), 3.57 (1H, qd, J = 8.3, 4.4 Hz), 1.89-2.05 (2H, m), 1.75-1.85 (1H , M), 1.56 (1H, tt, J = 12.2, 7.8 Hz).
Stereoisomer B
9.71 (1H, brs), 7.95-7.99 (2H, m), 7.48 (1H, brd, J = 8.8 Hz), 7.28-7.37 (7H, m), 4.99 (2H, s), 4.77 (1H, brs), 4.76 (1H, brs), 3.99-4.07 (1H, m), 3.63-3.71 (2H, m), 1.96-2.05 (1H, m), 1.75-1.85 (2H, m), 1.62-1.73 (1H, m).
MS (APCI, POS)
m / z: 449 (M + H) + .
(3S)−3−ベンジルオキシカルボニルアミノ−1−ビス(4−フルオロベンゾイルアミノ)ホスフィニル−2−ピペリドン(実施例58B)
1H−NMR(DMSO−D6,内部標準TMS)
9.88−10.02(2H,m),7.92−8.00(4H,m),7.38−7.50(5H,m),7.23−7.33(5H,m),4.95(1H,s),4.94(1H,s),4.17(1H,td,J=7.8,11.7Hz),3.86−3.94(1H,m),3.64−3.74(1H,m),2.00−2.10(1H,m),1.92−2.00(1H,m),1.82−1.92(1H,m),1.63(1H,tt,J=12.2,7.8Hz).
MS(APCI,POS)
m/z:571(M+H)+.(3S) -3-Benzyloxycarbonylamino-1-bis (4-fluorobenzoylamino) phosphinyl-2-piperidone (Example 58B)
1 H-NMR (DMSO-D 6 , internal standard TMS)
9.88-10.02 (2H, m), 7.92-8.00 (4H, m), 7.38-7.50 (5H, m), 7.23-7.33 (5H, m ), 4.95 (1H, s), 4.94 (1H, s), 4.17 (1H, td, J = 7.8, 11.7 Hz), 3.86-3.94 (1H, m ), 3.64-3.74 (1H, m), 2.00-2.10 (1H, m), 1.92-2.00 (1H, m), 1.82-1.92 (1H) M), 1.63 (1H, tt, J = 12.2, 7.8 Hz).
MS (APCI, POS)
m / z: 571 (M + H) + .
実施例59
(3S,P(RS))−1−アミノ(フェニルウレイド)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン
(3S)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ピペリドン(460.6mg,1.4116mmol)をピリジン(12mL)に加温溶解した溶液に、室温でフェニルイソシアナート(0.31mL,2.8418mmol)を加え、同温で終夜攪拌した。更にフェニルイソシアナート(0.31mL,2.8418mmol)を加え、同温で5時間攪拌した。
反応液を減圧濃縮した後、得られた残渣をシリカゲル(クロロホルム:メタノール=14:1〜9:1)カラムクロマトにて精製を行うことにより目的化合物(250.2mg,40%)を得た。Example 59
(3S, P (RS))-1-amino (phenylureido) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone ( To a solution obtained by heating and dissolving 460.6 mg, 1.4116 mmol) in pyridine (12 mL), phenyl isocyanate (0.31 mL, 2.8418 mmol) was added at room temperature, and the mixture was stirred at the same temperature overnight. Further, phenyl isocyanate (0.31 mL, 2.8418 mmol) was added, and the mixture was stirred at the same temperature for 5 hours.
The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (chloroform: methanol = 14: 1 to 9: 1) to give the target compound (250.2 mg, 40%).
1H−NMR(DMSO−D6,内部標準TMS)
立体異性体A
8.79(1H,d,J=7.8Hz),7.89or7.84(1H,d,J=9.8Hz),7.48(1H,d,J=8.8Hz),7.24−7.40(9H,m),6.95−7.01(1H,m),5.01(2H,s),4.78(1H,brs),4.79(1H,brs),4.19(1H,td,J=7.8,11.7Hz),3.79−3.89(1H,m),3.50−3.64(1H,m),1.89−2.08(2H,m),1.76−1.84(1H,m),1.55−1.65(1H,m).
立体異性体B
8.79(1H,d,J=7.8Hz),7.84or7.89(1H,d,J=9.8Hz),7.48(1H,d,J=8.8Hz),7.24−7.40(9H,m),6.95−7.01(1H,m),5.01(2H,s),4.78(1H,brs),4.79(1H,brs),4.06(1H,td,J=7.8,11.7Hz),3.64−3.72(1H,m),3.50−3.64(1H,m),1.98−2.10(2H,m),1.75−1.85(1H,m),1.54−1.76(1H,m).
MS(APCI,POS)
m/z:446(M+H)+. 1 H-NMR (DMSO-D 6 , internal standard TMS)
Stereoisomer A
8.79 (1H, d, J = 7.8 Hz), 7.89 or 7.84 (1H, d, J = 9.8 Hz), 7.48 (1H, d, J = 8.8 Hz), 7.24 -7.40 (9H, m), 6.95-7.01 (1H, m), 5.01 (2H, s), 4.78 (1H, brs), 4.79 (1H, brs), 4.19 (1H, td, J = 7.8, 11.7 Hz), 3.79-3.89 (1H, m), 3.50-3.64 (1H, m), 1.89-2 .08 (2H, m), 1.76-1.84 (1H, m), 1.55-1.65 (1H, m).
Stereoisomer B
8.79 (1H, d, J = 7.8 Hz), 7.84 or 7.89 (1H, d, J = 9.8 Hz), 7.48 (1H, d, J = 8.8 Hz), 7.24 -7.40 (9H, m), 6.95-7.01 (1H, m), 5.01 (2H, s), 4.78 (1H, brs), 4.79 (1H, brs), 4.06 (1H, td, J = 7.8, 11.7 Hz), 3.64-3.72 (1H, m), 3.50-3.64 (1H, m), 1.98-2 .10 (2H, m), 1.75-1.85 (1H, m), 1.54-1.76 (1H, m).
MS (APCI, POS)
m / z: 446 (M + H) + .
実施例60
(3S,P(RorS))−1−アミノ(N’−(4”−ブロモフェニル)ウレイド)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン及び(3S,P(SorR))−1−アミノ(N’−(4”−ブロモフェニル)ウレイド)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン
(3S)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ピペリドン(500.3mg,1.5333mmol)をピリジン(20mL)に加温溶解した溶液に、室温で4−ブロモフェニルイソシアナート(364.4mg,1.8401mmol)を加え、同温で終夜攪拌した。
反応液を減圧濃縮した後、得られた残渣に50%アセトン水溶液を加え、結晶を濾取した。得られた結晶を50%アセトンで洗浄することにより(3S,P(SorR))−1−アミノ(N’−(4”−ブロモフェニル)ウレイド)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン(200.5mg,25%)を得た。また、結晶濾液と洗浄液を合わせてダイアイオンHP−20(30mL,水−アセトン勾配溶出)カラムクロマトにて精製を行った後、溶出部のアセトンを減圧留去し、酢酸エチルで抽出した。酢酸エチル溶液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られたオイルをエーテル−n−ヘキサンにて結晶化を行うことにより、3S,P(RorS))−1−アミノ(N’−(4”−ブロモフェニル)ウレイド)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン(225.1mg,28%)を得た。Example 60
(3S, P (RorS))-1-amino (N ′-(4 ″ -bromophenyl) ureido) phosphinyl-3-benzyloxycarbonylamino-2-piperidone and (3S, P (SorR))-1-amino (N ′-(4 ″ -Bromophenyl) ureido) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone (500.3 mg , 1.5333 mmol) was dissolved in pyridine (20 mL) with heating, 4-bromophenyl isocyanate (364.4 mg, 1.8401 mmol) was added at room temperature, and the mixture was stirred overnight at the same temperature.
The reaction mixture was concentrated under reduced pressure, 50% acetone aqueous solution was added to the obtained residue, and the crystals were collected by filtration. The obtained crystals were washed with 50% acetone to obtain (3S, P (SorR))-1-amino (N ′-(4 ″ -bromophenyl) ureido) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (200.5 mg, 25%) The crystal filtrate and the washing solution were combined and purified by Diaion HP-20 (30 mL, water-acetone gradient elution) column chromatography, and then acetone in the elution part was removed. After distilling off under reduced pressure, extraction with ethyl acetate, the ethyl acetate solution was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. 3S, P (RorS))-1-amino (N ′-(4 ″ -bromophenyl) ureido) phosphinyl-3-benzyloxycarbonylamino- - was obtained piperidone (225.1mg, 28%).
(3S,P(SorR))−1−アミノ(N’−(4”−ブロモフェニル)ウレイド)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン(実施例60A)
1H−NMR(DMSO−D6,内部標準TMS)
8.95(1H,brs),7.98(1H,brs),7.49(1H,d,J=8.3Hz),7.43−7.46(2H,m),7.31−7.38(7H,m),5.01(2H,s),4.80(1H,brs),4.79(1H,brs),4.04−4.08(1H,m),3.64−3.72(1H,m),3.55−3.63(1H,m),1.97−2.05(1H,m),1.76−1.84(2H,m),1.64−1.74(1H,m).
MS(APCI,POS)
m/z:526(M+H)+.(3S, P (SorR))-1-amino (N ′-(4 ″ -bromophenyl) ureido) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (Example 60A)
1 H-NMR (DMSO-D 6 , internal standard TMS)
8.95 (1H, brs), 7.98 (1H, brs), 7.49 (1H, d, J = 8.3 Hz), 7.43-7.46 (2H, m), 7.31- 7.38 (7H, m), 5.01 (2H, s), 4.80 (1H, brs), 4.79 (1H, brs), 4.04-4.08 (1H, m), 3 .64-3.72 (1H, m), 3.55-3.63 (1H, m), 1.97-2.05 (1H, m), 1.76-1.84 (2H, m) , 1.64-1.74 (1H, m).
MS (APCI, POS)
m / z: 526 (M + H) + .
(3S,P(RorS))−1−アミノ(N’−(4”−ブロモフェニル)ウレイド)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン(実施例60B)
1H−NMR(DMSO−D6,内部標準TMS)
8.92(1H,brs),7.89(1H,brd,J=8.3Hz),7.49(1H,brd,J=8.8Hz),7.44(2H,d,J=8.8Hz),7.28−7.38(7H,m),5.01(2H,s),4.81(1H,brs),4.80(1H,brs),4.18(1H,td,J=8.3,16.1Hz),3.78−3.87(1H,m),3.50−3.58(1H,m),1.88−2.06(2H,m),1.72−1.84(1H,m),1.54−1.65(1H,m).
MS(APCI,POS)
m/z:526(M+H)+.(3S, P (RorS))-1-Amino (N ′-(4 ″ -bromophenyl) ureido) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (Example 60B)
1 H-NMR (DMSO-D 6 , internal standard TMS)
8.92 (1H, brs), 7.89 (1H, brd, J = 8.3 Hz), 7.49 (1H, brd, J = 8.8 Hz), 7.44 (2H, d, J = 8) .8 Hz), 7.28-7.38 (7H, m), 5.01 (2H, s), 4.81 (1H, brs), 4.80 (1H, brs), 4.18 (1H, td, J = 8.3, 16.1 Hz), 3.78-3.87 (1H, m), 3.50-3.58 (1H, m), 1.88-2.06 (2H, m) ), 1.72-1.84 (1H, m), 1.54-1.65 (1H, m).
MS (APCI, POS)
m / z: 526 (M + H) + .
実施例61
(3S,PR)−1−アミノ(スルホアミノ)ホスフィニル−3−(N’−フェニル)チオウレイド−2−ピペリドン ナトリウム塩
スルフォスチン1水和物(136.0mg,0.4686mmol)を水(3mL)に溶解した溶液に炭酸水素ナトリウム(59.0mg,0.7023mmol)、アセトニトリル(3mL)、及びフェニルイソチオシアナート(0.112mL,0.9362mmol)を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアニオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(170.6mg,85%)を得た。Example 61
(3S, PR) -1-Amino (sulfoamino) phosphinyl-3- (N′-phenyl) thioureido-2-piperidone sodium salt Sulfostin monohydrate (136.0 mg, 0.4686 mmol) dissolved in water (3 mL) To the solution was added sodium hydrogen carbonate (59.0 mg, 0.7023 mmol), acetonitrile (3 mL), and phenyl isothiocyanate (0.112 mL, 0.9362 mmol), and the mixture was stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified by dianion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (170.6 mg, 85%). It was.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.49(2H,t,J=7.3Hz),7.38(1H,tt,J=7.3,1.5Hz),7.34(2H,td,J=1.5,7.3Hz),3.69−3.79(1H,m),3.60−3.68(1H,m),2.25−2.35(1H,m),1.86−1.96(1H,m),1.68−1.82(1H,m).
HR−MS(ESI,POS)
m/z:found,452.0217(M+Na)+.
calcd.for C12H17N5Na2O5PS2,452.0204 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.49 (2H, t, J = 7.3 Hz), 7.38 (1H, tt, J = 7.3, 1.5 Hz), 7.34 (2H, td, J = 1.5, 7. 3Hz), 3.69-3.79 (1H, m), 3.60-3.68 (1H, m), 2.25-2.35 (1H, m), 1.86-1.96 ( 1H, m), 1.68-1.82 (1H, m).
HR-MS (ESI, POS)
m / z: found, 452.0217 (M + Na) + .
calcd. for C 12 H 17 N 5 Na 2 O 5 PS 2, 452.0204
実施例62
(3S,PR)−3−(4’−ブロモベンゼンスルホニル)アミノ−1−アミノ(スルホアミノ)ホスフィニル−2−ピペリドン ナトリウム塩
スルフォスチン1水和物(100.5mg,0.3463mmol)を水(3mL)に溶解した溶液に炭酸水素ナトリウム(87.3mg,1.0392mmol)、アセトニトリル(3mL)、及び4−ブロモベンゼンスルホリルクロリド(0.1327mg,0.5193mmol)を加え、室温で終夜撹拌した。
反応液のアセトニトリルを減圧留去した後、ダイアイオンHP−20SS(30mL,水〜メタノール勾配溶出)にて精製し、溶出部を減圧留去することにより目的化合物(122.2mg,69%)を得た。Example 62
(3S, PR) -3- (4′-Bromobenzenesulfonyl) amino-1-amino (sulfoamino) phosphinyl-2-piperidone sodium salt Sulfostin monohydrate (100.5 mg, 0.3463 mmol) in water (3 mL) Sodium hydrogen carbonate (87.3 mg, 1.0392 mmol), acetonitrile (3 mL), and 4-bromobenzenesulfolyl chloride (0.1327 mg, 0.5193 mmol) were added to the solution dissolved in 1, and stirred at room temperature overnight.
After the acetonitrile in the reaction solution was distilled off under reduced pressure, the residue was purified with Diaion HP-20SS (30 mL, water-methanol gradient elution), and the eluate was distilled off under reduced pressure to obtain the target compound (122.2 mg, 69%). Obtained.
1H−NMR(D2O、内部標準3−(トリメチルシリル)プロピオン酸−2,2,3,3−D4 ナトリウム塩)
7.81(4H,brs),4.05(1H,dd,J=11.2,6.8Hz),3.68−3.76(1H,m),3.50(1H,ddd,J=12.7,7.8,4.4Hz),1.86−2.02(2H,m),1.61−1.83(2H,m).
HR−MS(ESI,POS)
m/z:found,536.9040(M+Na)+.
calcd.for C11H15BrN4Na2O7PS2,536.9078 1 H-NMR (D 2 O, internal standard 3- (trimethylsilyl) propionic acid-2,2,3,3-D 4 sodium salt)
7.81 (4H, brs), 4.05 (1H, dd, J = 11.2, 6.8 Hz), 3.68-3.76 (1H, m), 3.50 (1H, ddd, J = 12.7, 7.8, 4.4 Hz), 1.86-2.02 (2H, m), 1.61-1.83 (2H, m).
HR-MS (ESI, POS)
m / z: found, 536.9040 (M + Na) + .
calcd. for C 11 H 15 BrN 4 Na 2 O 7 PS 2 , 536.9078
実施例63
(3S)−3−ベンジルオキシカルボニルアミノ−1−ビス(メチルアミノ)ホスフィニル−2−ピペリドン
(3S)−3−ベンジルオキシカルボニルアミノ−2−ピペリドン(3.73g,15.02mmol)のテトラヒドロフラン(60mL)溶液を外温−78℃で冷却した後、n−ブチルリチウムヘキサン溶液(1.54M,9.3mL,14.32mmol)を20分間かけて滴下し、同温で20分間攪拌した。次いでオキシ塩化リン(2.30g,15.00mmol)のテトラヒドロフラン(10mL)溶液を加え、20分間攪拌した後、メチルアミン(40%水溶液,5.8mL,74.69mmol)のテトラヒドロフラン(50mL)溶液を炭酸カリウムで乾燥した後に加え、10分間攪拌した。
反応液を減圧濃縮し、水を加えた後、クロロホルムで抽出した。クロロホルム溶液を、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した後、溶媒を減圧濃縮し、淡黄色オイルを得た。このオイルをダイアイオンHP−20(200mL,水−メタノール勾配溶出)カラムクロマトで精製を行うことにより目的化合物(1.98g,37%)を得た。Example 63
(3S) -3-Benzyloxycarbonylamino-1-bis (methylamino) phosphinyl-2-piperidone (3S) -3-Benzyloxycarbonylamino-2-piperidone (3.73 g, 15.02 mmol) in tetrahydrofuran (60 mL) ) After cooling the solution at an external temperature of −78 ° C., an n-butyllithium hexane solution (1.54M, 9.3 mL, 14.32 mmol) was added dropwise over 20 minutes, and the mixture was stirred at the same temperature for 20 minutes. Next, a solution of phosphorus oxychloride (2.30 g, 15.00 mmol) in tetrahydrofuran (10 mL) was added and stirred for 20 minutes, and then a solution of methylamine (40% aqueous solution, 5.8 mL, 74.69 mmol) in tetrahydrofuran (50 mL) was added. It was added after drying with potassium carbonate and stirred for 10 minutes.
The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. The chloroform solution was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure to obtain a pale yellow oil. This oil was purified by Diaion HP-20 (200 mL, water-methanol gradient elution) column chromatography to obtain the target compound (1.98 g, 37%).
1H−NMR(CDCl3,内部標準TMS)
7.30−7.37(5H,m),5.61(1H,brd,J=5.4Hz),5.12(2H,s),4.26−4.31(1H,m),3.93(1H,qd,J=5.3Hz,13.2Hz),3.48−3.56(1H,m),3.06−3.15(1H,m),2.98−3.06(1H,m),2.61(3H,t,J=5.9Hz),2.58(3H,t,J=5.9Hz),2.47−2.55(1H,m),1.86−1.95(2H,m),1.55(1H,tt,J=13.2Hz,8.3Hz).
MS(FAB,POS)
m/z:355(M+H)+. 1 H-NMR (CDCl 3 , internal standard TMS)
7.30-7.37 (5H, m), 5.61 (1H, brd, J = 5.4 Hz), 5.12 (2H, s), 4.26-4.31 (1H, m), 3.93 (1H, qd, J = 5.3 Hz, 13.2 Hz), 3.48-3.56 (1H, m), 3.06-3.15 (1H, m), 2.98-3 .06 (1H, m), 2.61 (3H, t, J = 5.9 Hz), 2.58 (3H, t, J = 5.9 Hz), 2.47-2.55 (1H, m) , 1.86-1.95 (2H, m), 1.55 (1H, tt, J = 13.2 Hz, 8.3 Hz).
MS (FAB, POS)
m / z: 355 (M + H) + .
実施例64
(3S)−3−ベンジルオキシカルボニルアミノ−1−ビス(エチルアミノ)ホスフィニル−2−ピペリドン
(3S)−3−ベンジルオキシカルボニルアミノ−2−ピペリドン(3.73g,15.02mmol)のテトラヒドロフラン(60mL)溶液を外温−78℃で冷却した後、n−ブチルリチウムヘキサン溶液(1.54M,9.3mL,14.32mmol)を15分間かけて滴下し、同温で20分間攪拌した。次いでオキシ塩化リン(2.30g,15.00mmol)のテトラヒドロフラン(6mL)溶液を加え、30分間攪拌した後、エチルアミン(70%水溶液,5.47mL,84.92mmol)のテトラヒドロフラン(50mL)溶液を炭酸カリウムで乾燥した後に加え、5分間攪拌した。
反応液を減圧濃縮し、水を加えた後、クロロホルムで抽出した。クロロホルム溶液を、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、溶媒を減圧濃縮し、淡黄色オイルを得た。このオイルをシリカゲルクロマトグラフィー(150g,クロロホルム:メタノール=19:1)で精製を行い、オイルを得た。このオイルを6回に分けてセファデックスLH−20(180mL,メタノール)カラムクロマトで精製を行った後、再度シリカゲル(100g,クロロホルム:メタノール=29:1〜19:1〜14:1)カラムクロマトで精製を行い、オイル(1.95g)を得た。得られたオイルをエタノール−エーテルで結晶化を行うことにより目的化合物(1.78g,31%)を得た。Example 64
(3S) -3-Benzyloxycarbonylamino-1-bis (ethylamino) phosphinyl-2-piperidone (3S) -3-Benzyloxycarbonylamino-2-piperidone (3.73 g, 15.02 mmol) in tetrahydrofuran (60 mL) ) After cooling the solution at an external temperature of −78 ° C., an n-butyllithium hexane solution (1.54M, 9.3 mL, 14.32 mmol) was added dropwise over 15 minutes, followed by stirring at the same temperature for 20 minutes. Next, a solution of phosphorus oxychloride (2.30 g, 15.00 mmol) in tetrahydrofuran (6 mL) was added and stirred for 30 minutes, and then a solution of ethylamine (70% aqueous solution, 5.47 mL, 84.92 mmol) in tetrahydrofuran (50 mL) was carbonated. It was added after drying with potassium and stirred for 5 minutes.
The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. The chloroform solution was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give a pale yellow oil. This oil was purified by silica gel chromatography (150 g, chloroform: methanol = 19: 1) to obtain an oil. This oil was divided into 6 portions and purified by Sephadex LH-20 (180 mL, methanol) column chromatography, and then silica gel (100 g, chloroform: methanol = 29: 1 to 19: 1 to 14: 1) column chromatography again. To obtain an oil (1.95 g). The obtained oil was crystallized from ethanol-ether to obtain the target compound (1.78 g, 31%).
1H−NMR(CDCl3,内部標準TMS)
7.29−7.33(5H,m),5.60(1H,brd,J=4.9Hz),5.13(2H,s),4.22−4.28(1H,m),3.95(1H,qd,J=5.9Hz,13.2Hz),3.47−3.56(1H,m),3.12−3.18(1H,m),2.89−3.08(5H,m),2.48−2.54(1H,m),1.84−1.96(2H,m),1.53(1H,tt,J=13.2Hz,8.3Hz),1.12(3H,t,J=6.8Hz),1.11(3H,t,J=6.8Hz).
MS(FAB,POS)
m/z:383(M+H)+. 1 H-NMR (CDCl 3 , internal standard TMS)
7.29-7.33 (5H, m), 5.60 (1H, brd, J = 4.9 Hz), 5.13 (2H, s), 4.22-4.28 (1H, m), 3.95 (1H, qd, J = 5.9 Hz, 13.2 Hz), 3.47-3.56 (1H, m), 3.12-3.18 (1H, m), 2.89-3 .08 (5H, m), 2.48-2.54 (1H, m), 1.84-1.96 (2H, m), 1.53 (1H, tt, J = 13.2 Hz, 8. 3 Hz), 1.12 (3H, t, J = 6.8 Hz), 1.11 (3H, t, J = 6.8 Hz).
MS (FAB, POS)
m / z: 383 (M + H) + .
実施例65
(3S)−3−ベンジルオキシカルボニルアミノ−1−ビス(n−プロピルアミノ)ホスフィニル−2−ピペリドン
(3S)−3−ベンジルオキシカルボニルアミノ−2−ピペリドン(3.73g,15.02mmol)のテトラヒドロフラン(45mL)溶液を外温−78℃で冷却した後、n−ブチルリチウムヘキサン溶液(1.54M,9.3mL,14.32mmol)を15分間かけて滴下し、同温で20分間攪拌した。次いでオキシ塩化リン(2.30g,15.00mmol)のテトラヒドロフラン(5mL)溶液を加え、30分間攪拌した後、n−プロピルアミン(d=0.719,5.2mL,63.25mmol)を加え、1時間攪拌した。
反応液を減圧濃縮し、水を加えた後、クロロホルムで抽出した。クロロホルム溶液を、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、溶媒を減圧濃縮し、淡黄色オイルを得た。このオイルをシリカゲルクロマトグラフィー(100g,クロロホルム:メタノール=29:1〜19:1)で2回精製を行うことにより目的化合物(0.98g,16%)を得た。Example 65
Tetrahydrofuran of (3S) -3-benzyloxycarbonylamino-1-bis (n-propylamino) phosphinyl-2-piperidone (3S) -3-benzyloxycarbonylamino-2-piperidone (3.73 g, 15.02 mmol) (45 mL) After cooling the solution at an external temperature of −78 ° C., an n-butyllithium hexane solution (1.54 M, 9.3 mL, 14.32 mmol) was added dropwise over 15 minutes, and the mixture was stirred at the same temperature for 20 minutes. Then, a solution of phosphorus oxychloride (2.30 g, 15.00 mmol) in tetrahydrofuran (5 mL) was added and stirred for 30 minutes, then n-propylamine (d = 0.719, 5.2 mL, 63.25 mmol) was added, Stir for 1 hour.
The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. The chloroform solution was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give a pale yellow oil. This oil was purified twice by silica gel chromatography (100 g, chloroform: methanol = 29: 1 to 19: 1) to obtain the target compound (0.98 g, 16%).
1H−NMR(CDCl3,内部標準TMS)
7.30−7.37(5H,m),5.58−5.63(1H,m),5.12(2H,s),4.22−4.29(1H,m),3.96(1H,qd,J=5.9Hz,13.7Hz),3.46〜3.55(1H,m),3.17−3.24(1H,m),3.03〜3.11(1H,m),2.83−2.95(4H,m),2.49−2.57(1H,m),1.84−1.96(2H,m),1.43−1.57(5H,m),0.89(3H,t,J=7.3Hz),0.88(3H,t,J=7.3Hz).
MS(FAB,POS)
m/z:411(M+H)+. 1 H-NMR (CDCl 3 , internal standard TMS)
7.30-7.37 (5H, m), 5.58-5.63 (1H, m), 5.12 (2H, s), 4.22-4.29 (1H, m), 3. 96 (1H, qd, J = 5.9 Hz, 13.7 Hz), 3.46 to 3.55 (1 H, m), 3.17-3.24 (1 H, m), 3.03 to 3.11. (1H, m), 2.83-2.95 (4H, m), 2.49-2.57 (1H, m), 1.84-1.96 (2H, m), 1.43-1 .57 (5H, m), 0.89 (3H, t, J = 7.3 Hz), 0.88 (3H, t, J = 7.3 Hz).
MS (FAB, POS)
m / z: 411 (M + H) + .
実施例66
(3S,P(RS))−1−アミノ(n−プロピルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン
(3S)−3−ベンジルオキシカルボニルアミノ−2−ピペリドン(3.73g,15.02mmol)のテトラヒドロフラン(60mL)溶液を外温−78℃で冷却した後、n−ブチルリチウムヘキサン溶液(1.54M,9.3mL,14.32mmol)を15分間かけて滴下し、同温で30分間攪拌した。次いでオキシ塩化リン(2.30g,15.00mmol)のテトラヒドロフラン(10mL)溶液を加え、30分間攪拌した後、n−プロピルアミン(d=0.719,0.93mL,11.31mmol)及びトリエチルアミン(d=0.7225,1.58mL,11.28mmol)のテトラヒドロフラン(5mL)溶液をゆっくり加え、10分間攪拌した。次いで、アンモニアのクロロホルム溶液(1M,40mL,40.00mmol)を加え、10分間攪拌した。
反応液に食塩水を加えた後、n−ヘキサンを加えて2層を分離した。水層をクロロホルムで抽出した後、有機層を合わせて減圧濃縮し、ダイアイオンHP−20(200mL,水−メタノール勾配溶出)カラムクロマトで精製を行うことにより目的化合物(0.34g,6%)を得た。Example 66
(3S, P (RS))-1-amino (n-propylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-2-piperidone (3.73 g, 15 0.02 mmol) in tetrahydrofuran (60 mL) was cooled at an external temperature of −78 ° C., and then n-butyllithium hexane solution (1.54 M, 9.3 mL, 14.32 mmol) was added dropwise over 15 minutes. Stir for 30 minutes. Next, a solution of phosphorus oxychloride (2.30 g, 15.00 mmol) in tetrahydrofuran (10 mL) was added and stirred for 30 minutes, and then n-propylamine (d = 0.719, 0.93 mL, 11.31 mmol) and triethylamine ( d = 0.7225, 1.58 mL, 11.28 mmol) in tetrahydrofuran (5 mL) was slowly added and stirred for 10 minutes. Then, a chloroform solution of ammonia (1M, 40 mL, 40.00 mmol) was added and stirred for 10 minutes.
After adding brine to the reaction solution, n-hexane was added to separate the two layers. After the aqueous layer was extracted with chloroform, the organic layers were combined, concentrated under reduced pressure, and purified by Diaion HP-20 (200 mL, water-methanol gradient elution) column chromatography to obtain the target compound (0.34 g, 6%). Got.
1H−NMR(CDCl3,内部標準TMS)
7.30〜7.39(5H,m),5.63(1H,brd,J=4.9Hz),5.12(2H,s),4.20〜4.28(1H,m),3.90(1H,qd,J=5.9Hz,13.7Hz),3.52〜3.60(1H,m),3.30and3.25(2H,brs),3.14and3.08(1H,brq,J=7.8Hz),2.78〜2.96(2H,m),2.46〜2.54(1H,m),1.87〜1.95(2H,m),1.53〜1.63(1H,m),1.43〜1.52(2H,m)0.89and0.88(3H,t,J=7.3Hz).
MS(FAB,POS)
m/z:369(M+H)+. 1 H-NMR (CDCl 3 , internal standard TMS)
7.30-7.39 (5H, m), 5.63 (1H, brd, J = 4.9 Hz), 5.12 (2H, s), 4.20-4.28 (1H, m), 3.90 (1H, qd, J = 5.9 Hz, 13.7 Hz), 3.52 to 3.60 (1H, m), 3.30 and 3.25 (2H, brs), 3.14 and 3.08 (1H , Brq, J = 7.8 Hz), 2.78 to 2.96 (2H, m), 2.46 to 2.54 (1H, m), 1.87 to 1.95 (2H, m), 1 .53 to 1.63 (1H, m), 1.43 to 1.52 (2H, m) 0.89 and 0.88 (3H, t, J = 7.3 Hz).
MS (FAB, POS)
m / z: 369 (M + H) + .
実施例67
(3S,P(RorS))−1−アミノ(フェニルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン及び((3S,P(SorR))−1−アミノ(フェニルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン
(3S)−3−ベンジルオキシカルボニルアミノ−2−ピペリドン(2.48g,9.99mmol)のテトラヒドロフラン(30mL)溶液を外温−78℃で冷却した後、n−ブチルリチウムヘキサン溶液(1.59M,6.2mL,9.86mmol)を20分間かけて滴下し、同温で30分間攪拌した。次いでオキシ塩化リン(1.53g,9.98mmol)のテトラヒドロフラン(3mL)溶液を加え、30分間攪拌した後、アニリン(d=1.022,1.8mL,19.75mmol)を加え、1時間攪拌した。次いで、アンモニアのクロロホルム溶液(1.15M,17.4mL,20.01mmol)を加え、30分間攪拌した。
反応液を減圧濃縮し、食塩水を加えた後、クロロホルムで抽出した。クロロホルム溶液を、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、溶媒を減圧濃縮し、淡黄色オイルを得た。このオイルをシリカゲルクロマトグラフィー(100g,クロロホルム:酢酸エチル=4:1〜3:1〜2:1)で2回精製を行い、目的の(3S,P(RorS))−1−アミノ(フェニルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン(0.10g,2%),及び(3S,P(SorR))−1−アミノ(フェニルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン(0.06g,1%)を得た。Example 67
(3S, P (RorS))-1-amino (phenylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone and ((3S, P (SorR))-1-amino (phenylamino) phosphinyl-3- After cooling a solution of benzyloxycarbonylamino-2-piperidone (3S) -3-benzyloxycarbonylamino-2-piperidone (2.48 g, 9.99 mmol) in tetrahydrofuran (30 mL) at an external temperature of −78 ° C., n- A butyllithium hexane solution (1.59 M, 6.2 mL, 9.86 mmol) was added dropwise over 20 minutes, and the mixture was stirred at the same temperature for 30 minutes, followed by phosphorus oxychloride (1.53 g, 9.98 mmol) in tetrahydrofuran (3 mL). ) Solution was added and stirred for 30 minutes, then aniline (d = 1.022, 1.8). mL, 19.75 mmol) was added, and the mixture was stirred for 1 hour, and then a solution of ammonia in chloroform (1.15 M, 17.4 mL, 20.01 mmol) was added and stirred for 30 minutes.
The reaction mixture was concentrated under reduced pressure, brine was added, and the mixture was extracted with chloroform. The chloroform solution was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give a pale yellow oil. This oil was purified twice by silica gel chromatography (100 g, chloroform: ethyl acetate = 4: 1-3: 1 to 2: 1) to obtain the desired (3S, P (RorS))-1-amino (phenylamino). ) Phosphinyl-3-benzyloxycarbonylamino-2-piperidone (0.10 g, 2%), and (3S, P (SorR))-1-amino (phenylamino) phosphinyl-3-benzyloxycarbonylamino-2- Piperidone (0.06 g, 1%) was obtained.
(3S,P(RorS))−1−アミノ(フェニルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン(実施例67A)
1H−NMR(CDCl3,内部標準TMS)
7.30−7.38(5H,m),7.23(2H,t,J=7.8Hz),7.05(2H,d,J=7.8Hz),7.01(1H,t,J=7.8Hz),5.52(1H,brd,J=6.8Hz),5.43(1H,brd,J=2.0Hz),5.08−5.14(2H,m),4.16−4.22(1H,m),3.92(1H,tdd,J=6.8Hz,13.7Hz,4.8Hz),3.54(2H,brs),3.46−3.53(1H,m),2.20−2.28(1H,m),1.70−1.78(1H,m),1.42−1.52(1H,m),1.22−1.31(1H,m)
MS(FAB,POS)
m/z:403(M+H)+.
MS(FAB,NEG)
m/z:401(M−H)−.(3S, P (RorS))-1-amino (phenylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (Example 67A)
1 H-NMR (CDCl 3 , internal standard TMS)
7.30-7.38 (5H, m), 7.23 (2H, t, J = 7.8 Hz), 7.05 (2H, d, J = 7.8 Hz), 7.01 (1H, t , J = 7.8 Hz), 5.52 (1H, brd, J = 6.8 Hz), 5.43 (1H, brd, J = 2.0 Hz), 5.08-5.14 (2H, m) 4.16-4.22 (1H, m), 3.92 (1H, tdd, J = 6.8 Hz, 13.7 Hz, 4.8 Hz), 3.54 (2H, brs), 3.46- 3.53 (1H, m), 2.20-2.28 (1H, m), 1.70-1.78 (1H, m), 1.42-1.52 (1H, m), 1. 22-1.31 (1H, m)
MS (FAB, POS)
m / z: 403 (M + H) + .
MS (FAB, NEG)
m / z: 401 (M−H) − .
(3S,P(SorR))−1−アミノ(フェニルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン(実施例67B)
1H−NMR(CDCl3,内部標準TMS)
7.30−7.38(5H,m),7.23(2H,t,J=7.8Hz),7.01(2H,d,J=7.8Hz),7.00(1H,t,J=7.8Hz),5.48−5.52(1H,m),5.44(1H,brd,J=7.3Hz),5.10(2H,s),3.94−4.03(1H,m),3.88−3.94(1H,m),3.55(2H,brs),3.50−3.54(1H,m),2.40−2.47(1H,m),1.85−1.94(1H,m),1.73−1.83(1H,m),1.52−1.63(1H,m).
MS(FAB,POS)
m/z:403(M+H)+.
MS(FAB,NEG)
m/z:401(M−H)−.(3S, P (SorR))-1-amino (phenylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone (Example 67B)
1 H-NMR (CDCl 3 , internal standard TMS)
7.30-7.38 (5H, m), 7.23 (2H, t, J = 7.8 Hz), 7.01 (2H, d, J = 7.8 Hz), 7.00 (1H, t , J = 7.8 Hz), 5.48-5.52 (1H, m), 5.44 (1H, brd, J = 7.3 Hz), 5.10 (2H, s), 3.94-4 .03 (1H, m), 3.88-3.94 (1H, m), 3.55 (2H, brs), 3.50-3.54 (1H, m), 2.40-2.47 (1H, m), 1.85-1.94 (1H, m), 1.73-1.83 (1H, m), 1.52-1.63 (1H, m).
MS (FAB, POS)
m / z: 403 (M + H) + .
MS (FAB, NEG)
m / z: 401 (M−H) − .
実施例68
(3S,P(RS))−1−アミノ((ベンジルオキシカルボニルアミノ)アセチルアミノ)ホスフィニル−3−ベンジルオキシカルボニルアミノ−2−ピペリドン
ベンジルオキシカルボニルグリシン(836.8mg,4.0000mmol)をトルエン(15mL)及びテトラヒドロフラン(15mL)に溶解した溶液に塩化チオニル(0.29mL,3.9757mmol)を加え、室温で2時間攪拌した。この溶液を(3S)−3−ベンジルオキシカルボニルアミノ−1−ジアミノホスフィニル−2−ピペリドン(652.9mg,2.0010mmol)をピリジン(20mL)に加温溶解した溶液に加え、室温で2時間攪拌した。
反応液を減圧濃縮した後、飽和食塩水を加え、クロロホルムで抽出。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲル(クロロホルム:メタノール=14:1〜9:1)カラムクロマトにて精製を行うことにより目的化合物(278.2mg,27%)を得た。Example 68
(3S, P (RS))-1-amino ((benzyloxycarbonylamino) acetylamino) phosphinyl-3-benzyloxycarbonylamino-2-piperidone benzyloxycarbonylglycine (836.8 mg, 4.0000 mmol) was dissolved in toluene ( To a solution dissolved in 15 mL) and tetrahydrofuran (15 mL) was added thionyl chloride (0.29 mL, 3.9757 mmol), and the mixture was stirred at room temperature for 2 hours. This solution was added to a solution obtained by heating and dissolving (3S) -3-benzyloxycarbonylamino-1-diaminophosphinyl-2-piperidone (652.9 mg, 2.0010 mmol) in pyridine (20 mL). Stir for hours.
The reaction mixture was concentrated under reduced pressure, saturated brine was added, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel (chloroform: methanol = 14: 1 to 9: 1) column chromatography to obtain the target compound (278.2 mg, 27%).
1H−NMR(CDCl3,内部標準TMS)
8.61(1H,brs),7.24−7.37(10H,m),5.99and5.58(1H,m),5.74and5.45(1H,s),5.00−5.15(4H,m),3.52−4.27(7H,m),1.46−2.32(4H,m).
MS(APCI,POS)
m/z:518(M+H)+. 1 H-NMR (CDCl 3 , internal standard TMS)
8.61 (1H, brs), 7.24-7.37 (10H, m), 5.99 and 5.58 (1H, m), 5.74 and 5.45 (1H, s), 5.00-5. 15 (4H, m), 3.52-4.27 (7H, m), 1.46-2.32 (4H, m).
MS (APCI, POS)
m / z: 518 (M + H) + .
実施例69
(3S,P(RorS))−3−アミノ−1−アミノ(フェニルウレイド)ホスフィニル−2−ピペリドン 臭化水素酸塩
実施例60Bの化合物(200.2mg,0.3818mmol)をメタノール(10mL)に溶解した溶液にパラジウム黒(20.0mg)を加え、水素雰囲気下、室温で2時間攪拌した。反応液をろ過し、ろ液を減圧濃縮することにより目的化合物(160.0mg,97%)を得た。Example 69
(3S, P (RorS))-3-Amino-1-amino (phenylureido) phosphinyl-2-piperidone hydrobromide Compound of Example 60B (200.2 mg, 0.3818 mmol) in methanol (10 mL) Palladium black (20.0 mg) was added to the dissolved solution, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (160.0 mg, 97%).
1H−NMR(CDCl3,内部標準TMS)
7.43(2H,t,J=7.3Hz),7.35(2H,d,J=7.3Hz),7.25(1H,t,J=7.3Hz),4.16(1H,dd,J=12.2,6.8Hz),3.81−3.89(1H,m),3.68−3.76(1H,m),2.35−2.45(1H,m),2.06−2.14(1H,m),1.94−2.05(1H,m),1.79−1.90(1H,m). 1 H-NMR (CDCl 3 , internal standard TMS)
7.43 (2H, t, J = 7.3 Hz), 7.35 (2H, d, J = 7.3 Hz), 7.25 (1H, t, J = 7.3 Hz), 4.16 (1H , Dd, J = 12.2, 6.8 Hz), 3.81-3.89 (1H, m), 3.68-3.76 (1H, m), 2.35-2.45 (1H, m), 2.06-2.14 (1H, m), 1.94-2.05 (1H, m), 1.79-1.90 (1H, m).
実施例70
(3S,P(RorS))−1−アミノ(フェニルウレイド)ホスフィニル−3−シクロヘキシルプロピオニルアミノ−2−ピペリドン
3−シクロヘキシルプロピオン酸(31.2mg,0.1997mmol)、ジシクロヘキシルカルボジイミド(41.2mg,0.1997mmol)及びN−ヒドロキシスクシンイミド(27.1mg,0.2005mmol)にジメチルホルムアミド(5mL)を加え、室温で2時間撹拌した溶液に、実施例69の化合物(19.0mg,0.0440mmol)及びトリエチルアミン(0.05mL,0.3570mmol)を加え、室温で2時間撹拌した。
反応液に水を加え、酢酸エチルで抽出。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥。溶媒を減圧留去し、得られた残渣をシリカゲル(クロロホルム:メタノール=14:1〜9:1)カラムクロマトにて精製を行うことにより目的化合物(14.5mg,73%)を得た。Example 70
(3S, P (RorS))-1-amino (phenylureido) phosphinyl-3-cyclohexylpropionylamino-2-piperidone 3-cyclohexylpropionic acid (31.2 mg, 0.1997 mmol), dicyclohexylcarbodiimide (41.2 mg, 0 (1997 mmol) and N-hydroxysuccinimide (27.1 mg, 0.2005 mmol) were added dimethylformamide (5 mL) and stirred at room temperature for 2 hours. Triethylamine (0.05 mL, 0.3570 mmol) was added and stirred at room temperature for 2 hours.
Add water to the reaction mixture and extract with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel (chloroform: methanol = 14: 1 to 9: 1) column chromatography to obtain the target compound (14.5 mg, 73%).
1H−NMR(CDCl3,内部標準TMS)
8.83(1H,m),7.43−7.47(1H,m),7.39(2H,d,J=7.3Hz),7.26(2H,t,J=7.3Hz),7.05(1H,t,J=7.3Hz),6.58(1H,brd,J=7.3Hz),4.58(1H,td,J=6.8,12.2Hz),3.98(2H,brd,J=3.9Hz),3.89−3.97(1H,m),3.63−3.72(1H,m),2.19−2.27(2H,m),1.87−2.01(2H,m),1.47−1.71(8H,m),1.08−1.24(4H,m),0.80−0.92(2H,m).
MS(APCI,POS)
m/z:450(M+H)+. 1 H-NMR (CDCl 3 , internal standard TMS)
8.83 (1H, m), 7.43-7.47 (1H, m), 7.39 (2H, d, J = 7.3 Hz), 7.26 (2H, t, J = 7.3 Hz) ), 7.05 (1H, t, J = 7.3 Hz), 6.58 (1H, brd, J = 7.3 Hz), 4.58 (1H, td, J = 6.8, 12.2 Hz) 3.98 (2H, brd, J = 3.9 Hz), 3.89-3.97 (1H, m), 3.63-3.72 (1H, m), 2.19-2.27 ( 2H, m), 1.87-2.01 (2H, m), 1.47-1.71 (8H, m), 1.08-1.24 (4H, m), 0.80-0. 92 (2H, m).
MS (APCI, POS)
m / z: 450 (M + H) + .
薬理試験例1
プロリルオリゴペプチダーゼ阻害活性の測定
プロリルオリゴペプチダーゼ阻害活性はYoshimotoら(Biochim.Biophys.Acta,569,184−192(1979))の方法に準じて行った。0.5mMベンジルオキシカルボニル・グリシル・プロリル・β−ナフチルアミドの20%ジオキサン水溶液0.04mL、50mMトリス−塩酸緩衝液(pH7.8)0.1mLに薬剤及び水を加えて、最終容量を0.2mLに調整した。混合溶液は37℃で10分間加温し、Koidaら(J.Biol.Chem.,251,7593−7599(1976))の方法に従って、ブタ腎臓を用いて部分精製したプロリルオリゴペプチダーゼ溶液の1mMジチオスレイトール及び1mMエチレンジアミン四酢酸・二ナトリウム塩を含有する25mMリン酸ナトリウム緩衝液(pH6.8)0.01mLを加え、37℃で1時間反応させた。反応終了後、0.2%ファーストガーネットGBC塩の10%ポリオキシエチレン(20)ソルビターンモノウレートを含む0.5Mクエン酸ナトリウム緩衝液(pH3.78)0.1mLを加え、遊離したβ−ナフチルアミンのジアゾ化合物を525nmにおける吸光度で測定した。薬剤の阻害率は検体を含む吸光度(a)及び検体を含まない盲検の吸光度(b)、またそれぞれのプロリルオリゴペプチダーゼを加えないときの吸光度(a’、b’)を次式により計算した。
阻害率={(b−b’)−(a−a’)/(b−b’)}×100
この方法により算出した阻害率から本発明化合物のプロリルオリゴペプチダーゼの50%阻害活性値を求め、表1に示す。Pharmacological test example 1
Measurement of prolyl oligopeptidase inhibitory activity Prolyl oligopeptidase inhibitory activity was performed according to the method of Yoshimoto et al. (Biochim. Biophys. Acta, 569, 184-192 (1979)). Drug and water are added to 0.04 mL of 20% aqueous dioxane solution of 0.5 mM benzyloxycarbonyl, glycyl, prolyl, β-naphthylamide and 0.1 mL of 50 mM Tris-HCl buffer (pH 7.8) to bring the final volume to 0. Adjusted to 2 mL. The mixed solution was heated at 37 ° C. for 10 minutes, and 1 mM of a prolyl oligopeptidase solution partially purified using a porcine kidney according to the method of Koida et al. (J. Biol. Chem., 251, 7593-7599 (1976)). 0.01 mL of 25 mM sodium phosphate buffer (pH 6.8) containing dithiothreitol and 1 mM ethylenediaminetetraacetic acid / disodium salt was added and reacted at 37 ° C. for 1 hour. After completion of the reaction, 0.1 mL of 0.5 M sodium citrate buffer solution (pH 3.78) containing 10% polyoxyethylene (20) sorbitan monourate of 0.2% first garnet GBC salt was added to release β -The diazo compound of naphthylamine was measured by absorbance at 525 nm. The inhibition rate of the drug is calculated by the following formula: Absorbance including the sample (a), Absorbance of the blind not including the sample (b), and Absorbance (a ′, b ′) when each prolyl oligopeptidase is not added did.
Inhibition rate = {(bb ′) − (aa ′) / (bb ′)} × 100
The 50% inhibitory activity value of prolyl oligopeptidase of the compound of the present invention was determined from the inhibition rate calculated by this method, and is shown in Table 1.
表1
化合物のプロリルオリゴペプチダーゼ50%阻害活性値(単位:マイクログラム/ミリリットル)
化合物番号 50%阻害活性値
参考例2の化合物 0.0023
参考例4の化合物 0.10
参考例7の化合物 0.0022
参考例8の化合物 0.0020
参考例10の化合物 0.035Table 1
50% inhibitory activity value of prolyl oligopeptidase of the compound (unit: microgram / milliliter)
Compound No. 50% Inhibitory Activity Value Compound of Reference Example 0.0023
Compound of Reference Example 4 0.10
Compound of Reference Example 7 0.0022
Compound of Reference Example 8 0.0020
Compound of Reference Example 10 0.035
実施例1の化合物 0.069
実施例2の化合物 0.13
実施例3の化合物 0.031
実施例4の化合物 0.15
実施例5の化合物 0.10
実施例6の化合物 0.050
実施例7の化合物 0.48
実施例8の化合物 0.10
実施例9の化合物 0.10
実施例10の化合物 0.12Compound of Example 1 0.069
Compound of Example 2 0.13
Compound of Example 3 0.031
Compound of Example 4 0.15
Compound of Example 5 0.10
Compound of Example 6 0.050
Compound of Example 7 0.48
Compound of Example 8 0.10
Compound of Example 9 0.10
Compound of Example 10 0.12
実施例11の化合物 0.094
実施例12の化合物 0.012
実施例13の化合物 0.036
実施例14の化合物 0.036
実施例15の化合物 0.064
実施例16の化合物 0.480
実施例17の化合物 0.0053
実施例18の化合物 0.0039
実施例19の化合物 0.0022
実施例20の化合物 0.0010Compound of Example 11 0.094
Compound of Example 12 0.012
Compound of Example 13 0.036
Compound of Example 14 0.036
Compound of Example 15 0.064
Compound of Example 16 0.480
Compound of Example 17 0.0053
Compound of Example 18 0.0039
Compound of Example 19 0.0022
Compound of Example 20 0.0010
実施例21の化合物 0.0035
実施例22の化合物 0.013
実施例23の化合物 0.00080
実施例24の化合物 0.0025
実施例25の化合物 0.013
実施例26の化合物 0.0099
実施例27の化合物 0.0016
実施例28の化合物 0.049
実施例29の化合物 0.090
実施例30の化合物 0.041Compound of Example 21 0.0035
Compound of Example 22 0.013
Compound of Example 23 0.00080
Compound of Example 24 0.0025
Compound of Example 25 0.013
Compound of Example 26 0.0099
Compound of Example 27 0.0016
Compound of Example 28 0.049
Compound of Example 29 0.090
Compound of Example 30 0.041
実施例31の化合物 0.011
実施例32の化合物 0.014
実施例33の化合物 0.0041
実施例34の化合物 0.00097
実施例35の化合物 0.021
実施例36の化合物 0.087
実施例37の化合物 0.25
実施例38の化合物 0.0055
実施例39の化合物 0.00067
実施例40の化合物 0.056Compound of Example 31 0.011
Compound of Example 32 0.014
Compound of Example 33 0.0041
Compound of Example 34
Compound of Example 35 0.021
Compound of Example 36 0.087
Compound of Example 37 0.25
Compound of Example 38 0.0055
Compound of Example 39 0.00067
Compound of Example 40 0.056
実施例41の化合物 0.041
実施例42の化合物 0.19
実施例43の化合物 0.020
実施例44の化合物 0.033
実施例45の化合物 0.031
実施例46の化合物 0.45
実施例47Aの化合物 0.080
実施例47Bの化合物 0.0029
実施例48の化合物 0.0029
実施例49の化合物 0.0039Compound of Example 41 0.041
Compound of Example 42 0.19
Compound of Example 43 0.020
Compound of Example 44 0.033
Compound of Example 45 0.031
Compound of Example 46 0.45
Compound of Example 47A 0.080
Compound of Example 47B 0.0029
Compound of Example 48 0.0029
Example 49 Compound 0.0039
実施例50の化合物 0.0043
実施例51の化合物 0.0025
実施例52の化合物 0.0023
実施例53の化合物 0.0045
実施例54Aの化合物 0.00089
実施例54Bの化合物 0.014
実施例55の化合物 0.0073
実施例56の化合物 0.0046
実施例57の化合物 0.0026
実施例58Aの化合物 0.0033Compound of Example 50 0.0043
Compound of Example 51 0.0025
Compound of Example 52 0.0023
Compound of Example 53 0.0045
Compound of Example 54A 0.00089
Compound of Example 54B 0.014
Compound of Example 55 0.0073
Compound of Example 56 0.0046
Compound of Example 57 0.0026
Compound of Example 58A 0.0033
実施例58Bの化合物 0.30
実施例59の化合物 0.0025
実施例60Aの化合物 0.25
実施例60Bの化合物 0.0013
実施例61の化合物 0.18
実施例62の化合物 0.0067
実施例63の化合物 0.40
実施例64の化合物 0.11
実施例65の化合物 0.18
実施例66の化合物 0.013Compound of Example 58B 0.30
Compound of Example 59 0.0025
Compound of Example 60A 0.25
Compound of Example 60B 0.0013
Compound of Example 61 0.18
Compound of Example 62 0.0067
Compound of Example 63 0.40
Compound of Example 64 0.11
Compound of Example 65 0.18
Compound of Example 66 0.013
実施例67Aの化合物 0.0024
実施例67Bの化合物 0.13
実施例68の化合物 0.013
実施例70の化合物 0.0016
SUAM14746 0.016Compound of Example 67A 0.0024
Compound of Example 67B 0.13
Compound of Example 68 0.013
Compound of Example 70 0.0016
SUAM14746 0.016
以上、本発明のα−アシルアミノ−N−(ジアミノホスフィニル)ラクタム誘導体は強力なプロリルオリゴペプチダーゼ作用を有していた。またSUAM14746(一般名:3−[[4−(2−(E)−Styrylphenoxy)Butanoyl]−L−4−Hydroxyprolyl]−Thiazolidine、株式会社ペプチド研究所)よりも本発明の化合物は活性が強いことが明らかになった。以上のことから、本発明の化合物は記憶及び認識障害などのプロリルオリゴペプチダーゼが関与していると考えられる疾病の予防若しくは治療剤に、また、シャガス病の予防若しくは治療剤になり得ることが明らかになった。 As described above, the α-acylamino-N- (diaminophosphinyl) lactam derivative of the present invention has a strong prolyl oligopeptidase action. In addition, the compound of the present invention is more active than SUAM14746 (generic name: 3-[[4- (2- (E) -Styrylphenoxy) Butanoyl] -L-4-Hydroxypropyl] -Thiazolidene, Peptide Institute, Inc.). Became clear. Based on the above, the compound of the present invention can be used as a prophylactic or therapeutic agent for diseases considered to involve prolyl oligopeptidases such as memory and cognitive impairment, and as a prophylactic or therapeutic agent for Chagas disease. It was revealed.
Claims (27)
(式中、Rは水素原子、低級アルキル基、シクロアルキル基、アリール基、ヘテロアリール基、低級アルケニル基、低級アルキルアミノ基、アリールアミノ基、ヘテロアリールアミノ基、低級アルコキシ基、アリールオキシ基、ピロリジニル基、N−保護ピロリジニル基、ベンジル基、又はベンジルオキシ基を示し、それぞれの基は置換されてもよく、置換される場合には低級アルキル基、シクロアルキル基、アリール基、ヘテロアリール基、低級アルコキシ基、ベンジルオキシ基、アリールオキシ基、水酸基、アミノ基、低級アルキルアミノ基、ジ低級アルキルアミノ基、N−保護アミノ基、カルボキシル基、低級アルコキシカルボニル基、ベンジルオキシカルボニル基、チオール基、低級アルキルチオ基、ハロゲン原子、シアノ基、ニトロ基、カルバモイル基、低級アルキルアミノカルボニル基、又はアリールアミノカルボニル基で置換される。Xはカルボニル基(−CO−)、チオカルボニル基(−CS−)、又はスルホニル基(−SO2−)を示す。Y及びZは同一又は異なっていてよく、水素原子、スルホン酸基、低級アルキル基、アリール基、ヘテロアリール基、シクロアルキル基、低級アシル基、アリールカルボニル基、ヘテロアリールカルボニル基、シクロアルカンカルボニル基、低級アルケニルカルボニル基、低級アルキルアミノカルボニル基、又はアリールアミノカルボニル基を示し、それぞれの基は置換されてもよく、置換される場合には低級アルキル基、アリール基、ヘテロアリール基、低級アルコキシ基、アリールオキシ基、ベンジルオキシ基、ニトロ基、ハロゲン原子、水酸基、アミノ基、低級アルキルアミノ基、ジ低級アルキルアミノ基、N−保護アミノ基、カルボキシル基、低級アルコキシカルボニル基、又はシアノ基で置換される。Qは−(CH2)n−(nは0〜3を示す)を示す。)で表されるα−アシルアミノ−N−(ジアミノホスフィニル)ラクタム誘導体又はその薬理学的に許容される塩を有効成分とするプロリルオリゴペプチダーゼ阻害剤。General formula (1)
Wherein R is a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a lower alkenyl group, a lower alkylamino group, an arylamino group, a heteroarylamino group, a lower alkoxy group, an aryloxy group, Pyrrolidinyl group, N-protected pyrrolidinyl group, benzyl group, or benzyloxy group, each group may be substituted, and when substituted, a lower alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, Lower alkoxy group, benzyloxy group, aryloxy group, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group, N-protected amino group, carboxyl group, lower alkoxycarbonyl group, benzyloxycarbonyl group, thiol group, Lower alkylthio group, halogen atom, cyano group, nito Group, carbamoyl group, lower alkylaminocarbonyl group, or .X substituted with arylaminocarbonyl group carbonyl group (-CO-), a thiocarbonyl group (-CS-), or a sulfonyl group - a (-SO 2) Y and Z may be the same or different, and may be a hydrogen atom, a sulfonic acid group, a lower alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a lower acyl group, an arylcarbonyl group, a heteroarylcarbonyl group, a cycloalkane. A carbonyl group, a lower alkenylcarbonyl group, a lower alkylaminocarbonyl group, or an arylaminocarbonyl group, each group may be substituted, and when substituted, the lower alkyl group, aryl group, heteroaryl group, lower group Alkoxy group, aryloxy group, benzyloxy group, nitro Substituted with a group, halogen atom, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group, N-protected amino group, carboxyl group, lower alkoxycarbonyl group, or cyano group, Q is — (CH 2 ). n- (n represents 0 to 3).) Prolyl containing an α-acylamino-N- (diaminophosphinyl) lactam derivative represented by the following formula or a pharmacologically acceptable salt thereof: Oligopeptidase inhibitor.
(式中、Rは水素原子、低級アルキル基、シクロアルキル基、アリール基、ヘテロアリール基、低級アルケニル基、低級アルキルアミノ基、アリールアミノ基、ヘテロアリールアミノ基、低級アルコキシ基、アリールオキシ基、ピロリジニル基、N−保護ピロリジニル基、ベンジル基、又はベンジルオキシ基を示し、それぞれの基は置換されてもよく、置換される場合には低級アルキル基、シクロアルキル基、アリール基、ヘテロアリール基、低級アルコキシ基、ベンジルオキシ基、アリールオキシ基、水酸基、アミノ基、低級アルキルアミノ基、ジ低級アルキルアミノ基、N−保護アミノ基、カルボキシル基、低級アルコキシカルボニル基、ベンジルオキシカルボニル基、チオール基、低級アルキルチオ基、ハロゲン原子、シアノ基、ニトロ基、カルバモイル基、低級アルキルアミノカルボニル基、又はアリールアミノカルボニル基で置換される。Xはカルボニル基(−CO−)、チオカルボニル基(−CS−)、又はスルホニル基(−SO2−)を示す。Y及びZは同一又は異なっていてよく、水素原子、スルホン酸基、低級アルキル基、アリール基、ヘテロアリール基、シクロアルキル基、低級アシル基、アリールカルボニル基、ヘテロアリールカルボニル基、シクロアルカンカルボニル基、低級アルケニルカルボニル基、低級アルキルアミノカルボニル基、又はアリールアミノカルボニル基を示し、それぞれの基は置換されてもよく、置換される場合には低級アルキル基、アリール基、ヘテロアリール基、低級アルコキシ基、アリールオキシ基、ベンジルオキシ基、ニトロ基、ハロゲン原子、水酸基、アミノ基、低級アルキルアミノ基、ジ低級アルキルアミノ基、N−保護アミノ基、カルボキシル基、低級アルコキシカルボニル基、又はシアノ基で置換される。Qは−(CH2)n−(nは0〜3を示す)を示す。但し、Rがベンジルオキシ基、Xがカルボニル基(−CO−)であり、かつY及びZの両方が水素原子の組み合わせと、Y及びZの一方が水素原子で他方がスルホン酸基の組み合わせである化合物群は除く。)で表されるα−アシルアミノ−N−(ジアミノホスフィニル)ラクタム誘導体又はその薬理学的に許容される塩を有効成分とする哺乳動物の医薬品又は疾病の予防若しくは治療剤。General formula (1)
Wherein R is a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a lower alkenyl group, a lower alkylamino group, an arylamino group, a heteroarylamino group, a lower alkoxy group, an aryloxy group, Pyrrolidinyl group, N-protected pyrrolidinyl group, benzyl group, or benzyloxy group, each group may be substituted, and when substituted, a lower alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, Lower alkoxy group, benzyloxy group, aryloxy group, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group, N-protected amino group, carboxyl group, lower alkoxycarbonyl group, benzyloxycarbonyl group, thiol group, Lower alkylthio group, halogen atom, cyano group, nito Group, carbamoyl group, lower alkylaminocarbonyl group, or .X substituted with arylaminocarbonyl group carbonyl group (-CO-), a thiocarbonyl group (-CS-), or a sulfonyl group - a (-SO 2) Y and Z may be the same or different, and may be a hydrogen atom, a sulfonic acid group, a lower alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a lower acyl group, an arylcarbonyl group, a heteroarylcarbonyl group, a cycloalkane. A carbonyl group, a lower alkenylcarbonyl group, a lower alkylaminocarbonyl group, or an arylaminocarbonyl group, each group may be substituted, and when substituted, the lower alkyl group, aryl group, heteroaryl group, lower group Alkoxy group, aryloxy group, benzyloxy group, nitro Substituted with a group, halogen atom, hydroxyl group, amino group, lower alkylamino group, di-lower alkylamino group, N-protected amino group, carboxyl group, lower alkoxycarbonyl group, or cyano group, Q is — (CH 2 ). n- (n represents 0 to 3), provided that R is a benzyloxy group, X is a carbonyl group (-CO-), and both Y and Z are a combination of hydrogen atoms, Y and Z An α-acylamino-N- (diaminophosphinyl) lactam derivative represented by the following formula: or a pharmacologically acceptable salt thereof : A mammalian pharmaceutical or disease preventive or therapeutic agent as an active ingredient .
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JPS5412391A (en) * | 1977-06-28 | 1979-01-30 | Yamanouchi Pharmaceut Co Ltd | Novel nitrosourea derivative |
WO1999025719A1 (en) * | 1997-11-18 | 1999-05-27 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Novel physiologically active substance sulphostin, process for producing the same, and use thereof |
WO2000069868A1 (en) * | 1999-05-17 | 2000-11-23 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Sulphostin analogues and processes for the preparation of sulphostin and analogues thereof |
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JPS5412391A (en) * | 1977-06-28 | 1979-01-30 | Yamanouchi Pharmaceut Co Ltd | Novel nitrosourea derivative |
WO1999025719A1 (en) * | 1997-11-18 | 1999-05-27 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Novel physiologically active substance sulphostin, process for producing the same, and use thereof |
WO2000069868A1 (en) * | 1999-05-17 | 2000-11-23 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Sulphostin analogues and processes for the preparation of sulphostin and analogues thereof |
JP2000327689A (en) * | 1999-05-17 | 2000-11-28 | Microbial Chem Res Found | Sulfostin analogue, and production of sulfostin and its analogue |
WO2002055088A1 (en) * | 2001-01-16 | 2002-07-18 | Nippon Kayaku Kabushiki Kaisha | Remedies for bone marrow suppression and infectious diseases and white blood cell count elevating agents |
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