JP2015536928A - 新規の抗菌性化合物およびその生物医学的用途 - Google Patents
新規の抗菌性化合物およびその生物医学的用途 Download PDFInfo
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- 239000003022 immunostimulating agent Substances 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000007422 luminescence assay Methods 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical class [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000011565 manganese chloride Substances 0.000 description 1
- 235000002867 manganese chloride Nutrition 0.000 description 1
- 229940099607 manganese chloride Drugs 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 1
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- DGEBKXQDSTZEEX-UHFFFAOYSA-N morpholine;phenylmethanamine Chemical compound C1COCCN1.NCC1=CC=CC=C1 DGEBKXQDSTZEEX-UHFFFAOYSA-N 0.000 description 1
- 210000005012 myelin Anatomy 0.000 description 1
- MUJNAWXXOJRNGK-UHFFFAOYSA-N n-[3-(6-methyl-1,2,3,4-tetrahydrocarbazol-9-yl)propyl]cyclohexanamine Chemical compound C1=2CCCCC=2C2=CC(C)=CC=C2N1CCCNC1CCCCC1 MUJNAWXXOJRNGK-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- RCSBCWXPGSPJNF-UHFFFAOYSA-N n-[4-[5-[3-chloro-4-(trifluoromethoxy)phenyl]-1,3,4-oxadiazol-2-yl]butyl]-4-(1,8-naphthyridin-2-yl)butanamide Chemical compound C1=C(Cl)C(OC(F)(F)F)=CC=C1C(O1)=NN=C1CCCCNC(=O)CCCC1=CC=C(C=CC=N2)C2=N1 RCSBCWXPGSPJNF-UHFFFAOYSA-N 0.000 description 1
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 1
- YSNXOQGDHGUKCZ-UHFFFAOYSA-N n-benzylhydroxylamine;hydron;chloride Chemical compound Cl.ONCC1=CC=CC=C1 YSNXOQGDHGUKCZ-UHFFFAOYSA-N 0.000 description 1
- ANPWLBTUUNFQIO-UHFFFAOYSA-N n-bis(phenylmethoxy)phosphanyl-n-propan-2-ylpropan-2-amine Chemical compound C=1C=CC=CC=1COP(N(C(C)C)C(C)C)OCC1=CC=CC=C1 ANPWLBTUUNFQIO-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- XYEOALKITRFCJJ-UHFFFAOYSA-N o-benzylhydroxylamine Chemical compound NOCC1=CC=CC=C1 XYEOALKITRFCJJ-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- PFGVNLZDWRZPJW-OPAMFIHVSA-N otamixaban Chemical compound C([C@@H](C(=O)OC)[C@@H](C)NC(=O)C=1C=CC(=CC=1)C=1C=C[N+]([O-])=CC=1)C1=CC=CC(C(N)=N)=C1 PFGVNLZDWRZPJW-OPAMFIHVSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000007918 pathogenicity Effects 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000006187 phenyl benzyl group Chemical group 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000008300 phosphoramidites Chemical class 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 239000002952 polymeric resin Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 108010071077 quinupristin-dalfopristin Proteins 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- TZSZZENYCISATO-WIOPSUGQSA-N rodatristat Chemical compound CCOC(=O)[C@@H]1CC2(CN1)CCN(CC2)c1cc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)nc(N)n1 TZSZZENYCISATO-WIOPSUGQSA-N 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- OGNAOIGAPPSUMG-UHFFFAOYSA-N spiro[2.2]pentane Chemical compound C1CC11CC1 OGNAOIGAPPSUMG-UHFFFAOYSA-N 0.000 description 1
- FYGUBWKMMCWIKB-UHFFFAOYSA-N spiro[2.3]hexane Chemical compound C1CC11CCC1 FYGUBWKMMCWIKB-UHFFFAOYSA-N 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 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
- 238000005991 sulfenylation reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 229940020707 synercid Drugs 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 150000003569 thioglycosides Chemical class 0.000 description 1
- SYRHIZPPCHMRIT-UHFFFAOYSA-N tin(4+) Chemical class [Sn+4] SYRHIZPPCHMRIT-UHFFFAOYSA-N 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- YXFVVABEGXRONW-JGUCLWPXSA-N toluene-d8 Chemical compound [2H]C1=C([2H])C([2H])=C(C([2H])([2H])[2H])C([2H])=C1[2H] YXFVVABEGXRONW-JGUCLWPXSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000004950 trifluoroalkyl group Chemical group 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- 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
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
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- A61K31/66—Phosphorus compounds
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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Abstract
Description
−A1およびA2は、互いに同一又は異なり、H、(C1〜C6)アルキル、(C1〜C6)フルオロアルキル、(C2〜C6)アルケニル、(C2〜C6)アルキニル、(C1〜C6)アルキル−ORa、(C1〜C6)アルキル−SRa、(C1〜C6)アルキル−NRaRb、ORa、SRa、NRaRbまたはCORaであり、
−A3は、HまたはOHであるか、あるいは、A4とカルボニルを形成しており、
−A4は、HまたはOHであるか、あるいは、A3とカルボニルを形成しており、
−A5は、H、CRaRbOH、FまたはOHであるか、あるいは、XがCHである場合にはXと二重結合を形成しており、
−A6は、HまたはFであり、
−Xは、CH2、CHF、CF2、CHOH、O、S、NRa、または単結合であるか、あるいは、A5と二重結合を形成する場合にはCHであり、
−Yは、P(O)(ORa)(ORb)またはP(O)(ORa)(NRaRb)であり、
−Vは、OまたはSであり、
−A7は、H、(C1〜C6)アルキル、(C1〜C6)フルオロアルキル、(C2〜C6)アルケニル、(C2〜C6)アルキニルまたは(C1〜C6)アルキル−ORaであり、
−A8は、OHまたはHであり、
−RaおよびRbは、互いに同一又は異なり、H、(C1〜C6)アルキル、(C1〜C6)フルオロアルキル、(C1〜C6)アルキル−OHおよび(C1〜C6)アルキル−O−(C1〜C6)アルキルからなる群から選択される。)
D−アルトロノヒドロキサム酸6−(二水素リン酸エステル);
N−ヒドロキシ−N−ホルミルアミノ−1−デオキシ−D−リビトール−5−リン酸エステル;
[6−(ホルミル−ヒドロキシ−アミノ)−(3R,4R,5S)−3,4,5−トリヒドロキシ−ヘキシル]−ホスホン酸;
[6−(ホルミル−ヒドロキシ−アミノ)−(3R,4R,5S)−1,3,4,5−テトラヒドロキシ−ヘキシル]−ホスホン酸;
[5−(ホルミル−ヒドロキシ−アミノ)−(2S,3S,4S)−2,3,4−トリヒドロキシ−ペンチル]−ホスホン酸;
[1−(N−ベンジルオキシ−N−ホルミルアミノ)−1,5−ジデオキシ−D−リビトール]−5−ホスホン酸;
[1−(N−ベンジルオキシ−N−ホルミルアミノ)−1−デオキシ−5,6−ジヒドロキシ−D−リボ−ヘキシトール]−6−ホスホン酸;
[(3R,4R,5S)−6−(ホルミル−ヒドロキシ−アミノ)−3,4,5,7−テトラヒドロキシ−ヘプチル]−ホスホン酸(ジアステレオ異性体DIA1及びDIA2);
[1−フルオロ−6−(ホルミル−ヒドロキシ−アミノ)−(3R,4R,5S)−3,4,5−トリヒドロキシ−ヘキシル]−ホスホン酸;
[(3R,4S,5R)−3,4,5−トリヒドロキシ−6−(N−ヒドロキシホルムアミド)−ヘキシル]−ホスホン酸;
[(3R,4R,5R)−3,4,5−トリヒドロキシ−6−(N−ヒドロキシホルムアミド)−ヘキシル]−ホスホン酸;
[1,1−ジフルオロ−6−(ホルミル−ヒドロキシ−アミノ)−(3R,4R,5S)−3,4,5−トリヒドロキシ−ヘキシル]−ホスホン酸;
[1−(N−ヒドロキシ−N−ホルミルアミノ)−1,6−ジデオキシ−D−allo/L−talo−ヘキシトール]−6−ホスホン酸;
[1−(N−ベンジルオキシ−N−ホルミルアミノ)−1−デオキシ−D−リボ−5−(E)−ヘキセニトール]−6−ホスホン酸;
およびこれらの酸および/または塩基付加塩(特に、ナトリウム塩)が挙げられ得る。
下記の一般式(II)で表される化合物を、上記の一般式(I)で表される化合物に変換することを含み得る。
なお、前記反応としては、例えば、以下の反応が挙げられる。
反応性官能基の保護;
保護された官能基の脱保護;
ハロゲン化;
メタセシス;
エポキシ化;
エポキシド開環;
脱ハロゲン化;
脱アルキル化;
アルキル化;
酸化;
カルボニル基に対するウィッティヒ型の反応;
光延型の反応;
炭素−炭素二重結合のジヒドロキシ化反応;
ニトロ、エステル、シアノ、カルボニル、チオエーテル、二重結合、三重結合、およびヒドロキシからなる群から選択される少なくとも一種の、還元;
脱酸素;
遷移金属触媒反応;
エーテル化;
アシル化;
スルホニル化(スルホニル基の導入);
ケン化(エステル基の加水分解);
ハロゲン交換;
アミン、チオールまたはアルコールを用いた求核置換;
還元的アミノ化;
リン酸化;
硫酸化;
亜リン酸化、アルブゾフ反応、ミカエリス−ベッカー反応;
ホスホニル化、(フルオロ)メチルホスホニル化;
アミド化;
ホスホルアミド化;
ケト基に対するヒドロキシルアミンの付加またはニトログリカールの還元によるオキシム形成;
A1、A2、A5、A7、XまたはYに対するRa,Rbの導入;
GがPGである場合の当該Gを水素原子とする脱保護;
ジアステレオ異性体の単離;および
塩化(salification)。
反応性官能基の保護及び脱保護に関する、Peter G. M. Wuts, Theodora W. Greene, Greene's Protective Groups in Organic Synthesis, 4th Edition, Wiley, 2006);
ハロゲン化反応に関する、Hanessian, Preparative Carbohydrate Chemistry, CRC Press, 1997;
脱離基がヒドロキシ基であり、これをフッ素化する場合には、DASTを使用する;
ヒドロキサメート部位形成に関する、J. Org. Chem. 1998, 63, 1910;
ハロゲノアシル化反応に関する、Journal of Carbohydrate Chemistry 2007, 26, 141;
ハロゲノヒドロキシ化に関する、Journal of Carbohydrate Chemistry 2001, 20, 359;
エポキシド形成及びエポキシド開環に関する、J. Org. Chem. 1993, 58, 3761; Tet. Lett. 1994, 35, 8433;
ハロゲノリン酸化反応に関する、Chem. Eur. J. 2008, 14, 9530;
メタセシス反応に関する、Tet. Lett. 2011, 52, 6767;
酸化反応に関する、Chem. Eur. J., 2010, 16, 8545;
ケト基に対するヒドロキシルアミンの付加によるオキシム形成に関する、Carbohydr. Res. 2009, 344, 2127;Carbohydr. Res. 1999, 320, 250;Tetrahedron 2001, 57, 7919;Tetrahedron: Asymmetry 2011, 22, 109;
ニトログリカールの還元によるオキシム形成に関する、Eur. J. Org. Chem. 2010, 3579;
カルボニル基に対するウィッティヒ型の反応及びグリニャール試薬を用いた増炭に関する、J. Org. Chem. 2000, 65, 6493;Chem. Eur. J. 2008, 14, 9530;Pol. J. Chem. 1996, 70, 45;Angew. Chem. 2008, 120, 1731;Carbohydr. Res. 2005, 340, 2808;Carbohydr. Res. 1986, 152, 329;J. Am. Chem. Soc. 2006, 128, 8078;Tet. Lett. 2011, 52, 6767;Carbohydr. Res. 2001, 332, 225;
炭素−炭素二重結合のジヒドロキシ化反応に関する、Noe, M. C., Letavic, M. A., Snow, S. L. 2005;
アルケン部位の非対称ジヒドロキシ化に関する、Organic Reactions. 109-625;
遷移金属触媒反応に関する、Matthias Beller, Carsten Bolm, Transition Metals for Organic Synthesis, Wiley, 2004;
光延反応の条件に関する、J. Org. Chem. 1998, 63, 1910;
リン酸化反応に関する、Chem. Eur. J. 2011, 17, 11305 - 11313;Carbohydrate Research 2005, 340, 2808;Carbohydrate Research 2003, 338, 2571;Tetrahedron Letters 1999, 40, 1869;Org. Lett. 2001, 3, 2009;J. Org. Chem. 2000, 65, 4498;およびEur. J. Org. Chem. 2000, 3433;
が挙げられる。
下記の一般式(III)で表される化合物またはその塩に、変換を施すことで製造され得て、その変換は、下記の一般式(III)で表される化合物
さらに、適宜、
先に列挙した反応も含めた一般式(II)で表される化合物を一般式(I)で表される化合物に変換するための反応のうち、少なくとも1種の反応を実行することにより達成され得るが、必ずしもこれに限定されない。
下記の一般式(IV)もしくは(V)で表される化合物またはその塩に、変換を施すことで製造され得る。具体的に述べると、その変換は、下記の一般式(IV)もしくは(V)で表される化合物またはその塩
さらに、適宜、
先に列挙した反応も含めた一般式(II)で表される化合物を一般式(I)で表される化合物に変換するための反応のうち、少なくとも1種の反応を実行することにより達成され得るが、必ずしもこれに限定されない。
下記の一般式(VI)もしくは(VII)で表される化合物またはその塩に、変換を施すことで製造され得るが、それに限定されない。
さらに、適宜、
先に列挙した反応も含めた一般式(II)で表される化合物を一般式(I)で表される化合物に変換するための反応のうち、少なくとも1種の反応を実行することにより達成され得るが、必ずしもこれに限定されない。
下記の一般式(VIII)で表される化合物またはその塩
さらに、適宜、
先に列挙した反応も含めた一般式(II)で表される化合物を一般式(I)で表される化合物に変換するための反応のうち、少なくとも1種の反応を実行することにより製造され得るが、必ずしもこれに限定されない。
下記の一般式(IX)もしくは(X)で表される化合物またはその塩:
さらに、適宜、
先に列挙した反応も含めた一般式(II)で表される化合物を一般式(I)で表される化合物に変換するための反応のうち、少なくとも1種の反応を実行することにより製造され得るが、必ずしもこれに限定されない。
下記の一般式(IX)で表される化合物またはその塩:
さらに、適宜、
先に列挙した反応も含めた一般式(II)で表される化合物を一般式(I)で表される化合物に変換するための反応のうち、少なくとも1種の反応を実行することにより製造され得るが、必ずしもこれに限定されない。
下記の一般式(XI)で表される化合物またはその塩:
さらに、適宜、
先に列挙した反応も含めた一般式(II)で表される化合物を一般式(I)で表される化合物に変換するための反応のうち、少なくとも1種の反応を実行することにより製造され得るが、必ずしもこれに限定されない。
下記の一般式(XII)で表される化合物またはその塩:
さらに、適宜、
先に列挙した反応も含めた一般式(II)で表される化合物を一般式(I)で表される化合物に変換するための反応のうち、少なくとも1種の反応を実行することにより製造され得るが、必ずしもこれに限定されない。
下記の一般式(XIII)で表される化合物またはその塩に、変換を施すことで製造され得る。
具体的に述べると、その変換は、下記の一般式(XIII)で表される化合物またはその塩:
さらに、適宜、
先に列挙した反応も含めた一般式(II)で表される化合物を一般式(I)で表される化合物に変換するための反応のうち、少なくとも1種の反応を実行することにより達成され得るが、必ずしもこれに限定されない。
下記の一般式(XIV)で表される化合物またはその塩に、変換を施すことで製造され得る。
具体的に述べると、その変換は、下記の一般式(XIV)で表される化合物またはその塩:
さらに、適宜、
先に列挙した反応も含めた一般式(II)で表される化合物を一般式(I)で表される化合物に変換するための反応のうち、少なくとも1種の反応を実行することにより達成され得るが、必ずしもこれに限定されない。
下記の一般式(XV)もしくは(XVI)で表される化合物:
A7−C(V)LG3を用いてアシル化を実行し、
さらに、適宜、
先に列挙した反応も含めた一般式(II)で表される化合物を一般式(I)で表される化合物に変換するための反応のうち、少なくとも1種の反応を実行することにより製造され得るが、必ずしもこれに限定されない。
実施例では、どの化学物質も、特記しない限り、市販製品を更に精製することなくそのまま使用した。プロトン核磁気共鳴(NMR)スペクトルは、300MHz、400MHzまたは600MHzについて、Bruker社製の装置を用いて記録した。テトラメチルシラン(TMS)を内部標準として、低磁場側の化学シフト(ppm)を算出している。NMRデータの略称は、次のとおりである:s=シングレット;d=ダブレット;t=トリプレット;q=カルテット;quint=クインテット;sext=セクステット;m=マルチプレット;dd=ダブレットオブダブレット;dt=ダブレットオブトリプレット;td=トリプレットオブダブレット;tt=トリプレットオブトリプレット;およびbr=ブロード。Jは、NMRカップリング係数(Hzでの測定)を指す。CDCl3は、ジュウテリオクロロホルムを指す。DMSO−d6は、ヘキサジュウテリオジメチルスルホキシドを指す。CD3ODは、テトラジュウテリオメタノールを指す。質量スペクトルは、Agilent1100シリーズLCMSおよびWaters2795AllianceLCMSを用いて、エレクトロスプレーイオン化(ESI)法で得た。薄層クロマトグラフィー法には、AnaltechシリカゲルGF薄層板およびE.Merckシリカゲル60F−254薄層板を使用した。フラッシュクロマトグラフィー法は、FlashsmartPackカートリッジの、不規則形状シリカ(40〜60μm)または球状シリカ(20〜40μm)を用いて実行した。分取薄層クロマトグラフィー法は、AnaltechシリカゲルGF(1000μm;20×20cm)を用いて実行した。
工程1:1,2,3,4,6−ペンタ−O−アセチル−D−アルトロピラノース(1a)
13CNMR(CDCl3,75MHz,α−anomer)δ:170.7,169.6,169.4,169.4(CO,Ac),135.2(Cq,Ph),131.9,129.2,127.9,(CH,Ph),86.1(C−1),71.4(C−2),66.9(C−3),65.6,65.3(C−4,C−5),62.8(C−6).
1HNMR(MeOD,300MHz)δ:7.58−7.48(m,2H,Ph),7.33−7.15(m,3H,Ph),5.27(brd,1H,H−1,J1,2=1.6Hz),4.33(ddd,1H,H−5),4.08(dd,1H,H−2,J1,2=1.6Hz,J2,3=3.6Hz),3.96−3.74(m,4H,H−3,H−4,CH2−6,J3,4=3.6Hz,J4,5=9.7Hz,J5,6a=2.9Hz,J5,6b=5.2Hz,J6a,6b=11.7Hz).
13CNMR(MeOD,75MHz)δ:139.0(Cq,Ph),132.2,129.8,127.8,(CH,Ph),89.7(C−1),74.4(C−2),71.7,71.4(C−3,C−5),66.0(C−4),63.0(C−6).
HRMS(ESI+):C12H16O5S[M+NH4]+計算値290.1057,実績値290.1056.
1HNMR(CDCl3,300MHz)δ:7.52−7.44(m,2H,Ph),7.33−7.20(m,3H,Ph),5.31(d,1H,H−1,J1,2=2.4Hz),4.37(ddd,1H,H−5),4.18(ddd,1H,H−2),4.11−3.98(m,3H,H−3,H−4,H−6a,J5,6a=4.8Hz,J6a,6b=10.0Hz),3.93(dd,partB of ABXsystem,1H,H−6b,J5,6b=7.7Hz),3.71(d,1H,OH,J=1.6Hz),2.85(d,1H,OH,J=1.6Hz),2.18(d,1H,OH−2,J=6.3Hz),1.14−1.05(m,21H,3×i−Pr,TIPS).
13CNMR(CDCl3,75MHz)δ:136.3(Cq,Ph),131.2,129.1,127.3,(CH,Ph),87.9(C−1),71.9(C−3),70.1(C−2),69.5(C−4),68.4(C−5),66.3(C−6),18.0(Me,i−Pr,TIPS),11.9(CH,i−Pr,TIPS).
HRMS(ESI+):C21H36O5SSi[M+Na]+計算値451.1945,実績値451.1958.
1HNMR(CDCl3,600MHz)δ:7.53−7.50(m,2H,Ph),7.39−7.17(m,18H,Ph),5.47(br.s,1H,H−1),4.71(d,partAofABsystem,1H,H−a,Bn,J=12.4Hz),4.62(d,partBofABsystem,1H,H−b,Bn),4.57(d,partAofABsystem,1H,H−a,Bn,J=12.4Hz),4.54−4.47(m,3H,CH2,Bn,H−5),4.39(d,partB of ABsystem,1H,H−b,Bn),4.03−3.95(m,3H,H−4,CH2−6,J5,6a=4.0Hz,J6a,6b=11.0Hz)3.96(dd,1H,H−2,J1,2=1.5Hz,J2,3=4.1Hz),3.83(t,1H,H−3,J2,3=J3,4),1.14−1.04(m,21H,3×i−Pr,TIPS).
13CNMR(CDCl3,150MHz)δ:138,7,138.4,138.3,138.1(4×Cq,Ph),130.5,128.8,128.6,128.5,128.4,128.1,128.0,127.9,127.8,127.7,127.6,126.6(CH,Ph),85.6(C−1),78.1(C−2),73.7(C−3),72.9(C−4),72.6,72.3,72.0,72.0,70.2(4×CH2Ph,C−5),63.2(C−6),18.2,18.1(Me,i−Pr,TIPS)12.2(CH,i−Pr,TIPS).
HRMS(ESI+):C42H54O5SSi[M+NH4]+計算値716.3799,実績値716.3803.
1HNMR(トルエン−d8,600MHz)δ:7.56−7.53(m,2H,Ph),7.39−7.36(m,2H,Ph),7.23−7−20(m,2H,Ph),7.17−6.97(m,14H,Ph),5.61(br.s,1H,H−1),4.79(dt,1H,H−5,J5,6a=J5,6b=3.3Hz,J4,5=9.8Hz),4.65(d,partAofABsystem,1H,H−a,Bn,J=12.4Hz),4.56(d,partBofABsystem,1H,H−b,Bn),4.34(s,2H,CH2,Bn),4.26(d,partA of AB system,1H,H−a,Bn,J=12.1Hz),4.09−4.05(m,2H,H−b,Bn,H−4,J3,4=2.9Hz),4,00(br.d,1H,H−2,J2,3=3.7Hz),3.88−3.83(m,2H,H−3,H−6),3.81(dd,partB of ABX system,1H,H−6b,J5,6a=4.0Hz,J6a,6b=11.7Hz).
13CNMR(トルエン−d8,150MHz)δ:86.5(C−1),78.8(C−2),74.0(C−3),73.6,73.1,72.1,71.8(C−4,3×CH2Ph),69.5(C−5),62.6(C−6).
HRMS(ESI+):C33H34O5S[M+NH4]+計算値560.2465,実績値560.2467;[M+Na]+計算値565.2019,実績値565.2024.
1HNMR(CDCl3,300MHz)δ:7.50−7.42(m,2H,Ph),7.40−7.15(m,28H,Ph),5.46(br.s,1H,H−1),4.74(ddd,1H,H−5),4.68(d,partA of AB system,1H,H−a,Bn,J=12.3Hz),4.61−4.49(m,4H,CH2−6,H−b,Bn,H−a,Bn),4.38(d,partB of AB system,1H,H−a,Bn,J=12.2Hz),4.30(br.s,1H,CH2Ph),3.98(dd,1H,H−2,J2,3=3.5Hz),3.90(dd,1H,H−4,J3,4=2.9Hz,J4,5=10.0Hz),3.82(t,1H,H−3).
13CNMR(CDCl3,75MHz)δ:150.7,137.9,137.6(Cq,Ph),130.7,129.8,129.7,129.7,129.0,128.6,128.5,128.5,128.1,128.0,127.9,127.8,126.9,125.3,120.4,120.3,120.3,120.3(CH,Ph),85.9(C−1),77.4(C−2),72.6,72.4,72.3,72.1(2xCH2Ph,C−3,C−4),71.5(CH2Ph),68.5(C−6,JC−6,P=5.6Hz),67.3(C−5,JC−5,P=8.2Hz).
31PNMR(CDCl3,121.5MHz)δ:−11.97
13CNMR(CDCl3,75MHz)δ:150.8,150.7,138.0,137.8,137.7,137.6,137.0(Cq,Ph),129.8,129.8,128.8,128.8,128.7,128.6,128.6,128.5,128.4,128.2,128.2,128.1,128.1,128.1,128.0,125.3,125.3,120.5,120.4,120.4,120.3(CH,Ph),93.1(C−1α),92.0(C−1β),76.9(C−2β),74.9(C−2α),74.3,74.3,73.6,73.3,72.3,72.2,72.2,72.0,71.9(CH2Ph,C−3,C−4,α,β),71.3(C−5β,JC−5,P=8.2Hz),68.5(C−6β,JC−6,P=6.2Hz),68.4(C−6α,JC−6,P=5.9Hz),66.1(C−5α,JC5,P=8.2Hz).
31PNMR(CDCl3,121.5MHz)δ:−11.87,−12.02.
HRMS(ESI+):C39H39O9P[M+NH4]+計算値700.267,実績値700.2668.
1HNMR(CDCl3,300MHz)δ:7.38−7.10(m,23H,Ph),6.95−6.87(m,2H,Ph),4.81−4.70(m,2H,H−5,H−a,Bn,J=11.8Hz),4.57−4.48(m,H−b,Bn,CH2−6,CH2Ph),4.35(2d,ABsystem,2H,CH2Ph,J=11.4Hz),4.13(dd,1H,H−4,J3,4=2.4Hz,J4,5=8.9Hz),4.06(d,1H,H−2,J2,3=4.2Hz),3.87(dd,1H,H−3).
31PNMR(CDCl3,121.5MHz)δ:−12.18.
13CNMR(CDCl3,75MHz)δ:167.2(CO),150.6,150.4,137.4,137.2(Cq,Ph),130.0,130.0,130.0,129.8,128.3,128.3,128.2,128.0,125.7,125.7,125.6,120.8,120.4,120.3,120.3,120.3(CH,Ph),76.4(C−5,JC−5,P=8.4Hz),74.9(C−2),73.3(C−3),73.2(CH2Ph),72.9,72.6(2xCH2Ph),70.6(C−2),67.0(C−6,JC−5,P=5.4Hz).
HRMS(ESI+):C39H37O9P[M+H]+計算値681.2248,実績値681.2266;[M+NH4]+計算値698.2513,実績値698.253.
13CNMR(D2O,150MHz,lactone)δ:176.7(C−1),80.7(C−4),77.8(C−2),73.6(C−3),69.9(d,C−5,JC−5,P=7.7Hz),66.2(d,C−6,JC−6,P=4.9Hz).
31PNMR(CDCl3,242.9MHz)δ:0.27.
LCMS:[M+H]+259;[M+Na]+281;[M−H]+257.
Acid:[M−H]+275
31PNMR(D2O,242.9MHz)δ:2.67.
LCMS:[M+H]+292;[M−H]−290.
工程1:トリイソプロピル−((2R,3R,4R)−2,3,4−トリス−ベンジルオキシ−5,5−ビス−エチルスルファニル−ペンチルオキシ)−シラン(2a)
1HNMR(300MHz,CDCl3):δ7.36−7.22(15H,3xPh),4.98−4.57(m,6H,3xOCH2Ph),4.26(d,1H,J1,2=3.3Hz,H−1),4.13(dd,1H,J3,2=7.5Hz,J3,4=1.9Hz,H−3),4.05(dd,1H,J2,1=3.3Hz,J2,3=7.5Hz,H−2),3.99−3.91(m,2H,H−4,H−5a),3.89−3.79(m,1H,H−5b),2.70−2.55(m,4H,2xSCH2CH3),1.24−1.13(m,6H,2xSCH2CH3),1.05−0.95[m,21H,Si(CHMe2)3].
13CNMR(150MHz,CDCl3):δ139.00,138.62,138.51(3xarom.C),128.25,128.15,128.11,127.82,127.68,127.47,127.80,127.28,127.26(aromC),82.78(C−2),81.04(C−4),78.81(C−3),74.75,73.15,72.93(3xOCH2Ph),64.10(C−5),54.14(C−1),26.21,24.95(2xSCH2CH3),18.02[Si(CHMe2)3],14.46,14.44[2xSi(CH(CH3)2]3,11.91[Si(CH(CH3)2)3].
HRMS ESI+C39H58O4S2Si[M+Na]+:計算値:705.3438実績値:705.3437.
1HNMR(300MHz,CDCl3):δ9.44(d,1H,J=0.9Hz,CHO),7.36−7.24(m,15H,3xPh),4.85−4.47(m,6H,3xOCH2Ph),4.10(dd,1H,J2,3=2.1Hz,H−2),4.03−3.91(m,2H,H−3,H−5a),3.84−3.76(m,2H,H−4,H−5b),1.13−0.96[m,21H,Si(CHMe2)3].
13CNMR(75MHz,CDCl3):δ201.41(CHOq),138.27,137.77,137.59(3xaromC),128.46,128.39,128.21,127.94,127.89,127.85,127.80,127.44(aromCH),82.60(C−2),80.87(C−3),78.63(C−4),73.17,73.11,72.74(3xOCH2Ph),63.53(C−5),18.04,18.03[Si(CH(CH3)2)3],11.958[Si(CH(CH3)2)3].
LCMS:[M+H]+577.45.
1HNMR(300MHz,CDCl3):δ7.33−7.21(20H,4xPh),5.92(bs,1H,NH),4.80−4.48(m,8H,4xOCH2Ph),4.12(dt,1H,J1b,2=8.0Hz,J1a,2=3.3Hz,H−2),4.00(dd,1H,J5a,5b=10.7Hz,J5a,4=3.7Hz,H−5a),3.88(dd,1H,J3,2=3.4Hz,J3,4=6.1Hz,H−3),3.83(dd,1H,J5b,4=6.0Hz,H−5b),3.62(dt,1H,H−4),3.27(dd,1H,J1a,1b=13.7Hz,J1a,2=3.3Hz,H−1a),3.11(dd,1H,J1b,2=8.1,H−1b),1.14−0.96[m,21H,Si(CHMe2)3].
13CNMR(75MHzCDCl3):δ138.67,138.56,138.51,138.21(4xaromC),128.34,128.28,128.26,128.23,127.92,127.89,127.84,127.61,127.53,127.51,127.41(aromCH),80.25(C−4),78.67(C−3),76.28(C−2),75.62(NOCH2Ph),73.55,73.19,72.20(3xOCH2Ph),64.16(C−5),52.30(C−1),18.06[Si(CH(CH3)2)3],11.95(Si(CH(CH3)2)3).
HRMSESI+:C42H57NO5Si[M+H]+計算値684.4079,実績値684.4078.
1HNMR(600MHz,トルエン,80℃):δ8.07(bs,1H,NCHO),7.33−7.02(20H,4xPh),4.79−4.55(m,8H,4xOCH2Ph),4.23−4.19(m,1H,H−2),4.03(dd,1H,J5a,5b=10.6Hz,J5a,4=3.7Hz,H−5a),3.93−3.88(m,2H,H−3,H−5b),3.82−3.71(m,3H,H−4,CH2N),1.08−1.03[m,21H,Si(CHMe2)3].13CNMR(150MHz,トルエン−d8,80℃,HSQCdata*):δ139.54,139.33,139.12(3 x arom C, トルエンシグナルと重複),129.56,129.27,128.74,128.70,128.60,128.55,128.36,128.32,127.84,127.80(aromCH),81.30(C−4),80.10(C−3),77.23(C−2),77.33(NOCH2Ph),73.98,73.83,72.29(3xOCH2Ph),64.87(C−5),48.94*(C−1),18.42[Si(CH(Me2)3],12.76[Si(CHMe2)3].
HRMSESI+:C43H57NO6Si[M+H]+計算値712.4028,実績値712.4037.
1HNMR(600MHz,トルエン,80℃):δ8.06(bs,1H,NCHO),7.25−7.02(20H,4xPh),4.65−4.40(m,8H,4xOCH2Ph),4.12−4.08(m,1H,H−2),3.81(dd,1H,J=6.5Hz,J=2.5Hz,H−3),3.75−3.62(m,4H,H−H−5a,H−5b,NH2),3.60−3.56(m,1H,H−4).
13CNMR(150MHz,トルエン,80℃):δ129.19,128.91,128.39,128.36,128.34,128.26,128.10,128.00,127.96(aromCH),79.92(C−4),79.84(C−3),77.11(NOCH2Ph),76.94(C−2*),73.96,72.91,72.56(3xOCH2Ph),61.52(C−5),48.66*(C−1).*HSQCにより決定.
HRMS ESI+:C34H37NO6[M+H]+計算値556.2694,実績値556.2702.
1HNMR(600MHz,トルエン,80℃):δ8.04(bs,1H,NCHO),7.33−6.99(30H,6xPh),4.95−4.87(m,2H,P(O)CH2Ph),4.66−4.41(m,9H,4xOCH2Ph,H−5a),4.25−4.20(m,1H,H−5b),4.12−4.09(m,1H,H−2),3.84−3.79(m,2H,H−3,H−4),3.75−3.58(m,2H,CH2N).
13CNMR(150MHz,トルエン,80℃):δ129.59,129.28,128.77,128.68,128.65,128.63,128.53,128.50,128.36(OCH2PhCH),79.56(C−3),78.86(JP=6.2Hz,C−4),77.45(NOCH2Ph),77.17(C−2),74.17,73.33,73.19(3xOCH2Ph),69.48(2xPOCH2Ph),67.05(JP=5.44,C−5),49.63*(C−1).*HSQCにより決定.
HRMS ESI+:C48H50NO9P[M+Na]+計算値838.3115,実績値838.3116.
13CNMR(150MHz,D2O):δ160.2(NCHO),73.64(C−3),72.41(JC,P=6.5Hz,C−4),68.66(C−2),,66.74(JC,P=4.4Hz,C−5),54.27(C−1).
31PNMR(242MHz,D2O):δ2.97,2.92.
LCMS[M−H]−:273.90.
合成法I:
工程1:2,3,4−トリ−O−ベンジル−1−(N−ベンジルオキシ−N−ホルミルアミノ)−1−デオキシ−5−オキソ−D−リビトール(3a)
1HNMR(300MHz,CDCl3):δ9.47(s,1H,CHO),8.28−7.26(m,21H,H−Ar,H−formyl),5.30(s,0.4H),5.06−4.40(br.m,8H,CH2Ar),4.31−3.20(br.m,5H,H−2,H−3,H−4,H−1a,H−1b).HR−MS:C34H35NO6[M+Na]+計算値:576.2357;実績値576.2365
1HNMR(トルエン−d8,70℃):δ8.04(s,1H,HC=O),7.28-6.91(m,31H,30xH−Ar,H−5),6.08(m,1H,H−6),4.95-4.89(m,4H,2XCH2−Ar),4.60-4.50(m,4H,2xCH2−Ar),4.44(AB,2H,CH2−Ar),4.29(AB,2H,CH2−Ar),4.13(bt,1H,H−4),3.98(bt,1H,H−2),3.67(m,3H,H−3,H−1a,H−1b),13CNMR(トルエン−d8,70℃):δ149.4(C−formyl),137.1(6xC−pAr),129.0-124.3(24xCAr),121.5(C−5),120.3(C−6),81.6(C−3),79.6(C−4),77.2(C−2),76.7(CH2−Ar),73.6,72.6,71.9(3xCH2−Ar),66.9(CH2−Ar),47.3(C−1).HR−MS:C56H47N2O4P[M+H]+計算値:812.3609,実績値:812.3623.
1HNMR(600MHz,D2O,ratio of rotamers5.5:1):δ8.42(s,H−formyl minor rotamer),7.97(s,H−formyl major rotamer),4.15(ddd,1H,J=2.5,J=5.9Hz,H−2),3.79(dd,1H,J=2.5,J=14.9Hz,H−1a),3.76(ddd,1H,J=2.6,J=6.3,J=9.1Hz,H−4),3.72(dd,1H,J=9.2,J=15.0Hz,H−1b),3.69(dd,1H,H−3),1.96(dddd,1H,J=2.8,J=4.6,J=11.9Hz,H−5a),1.83(ddd,1H,J=4.5,J=11.9Hz,H−6a),1.69(dddd,1H,J=4.6,J=9.1Hz,H−5b),1.61(ddd,1H,J=4.6,J=11.5Hz,H−6b).31PNMR:δ25.47.13CNMR(150MHz,D2O):δ160.9(CHO),76.0(C−3),72.8(d,C−4),68.2(C−2),54.0(C−1),27.2(C−5),25.3(C−6).HR−MS:C7H16NO8P[M]−計算値:272.0541,実績値:272.0552.
工程1:メチル(1R,2R,3R,4R)−2,3−O−イソプロピリデン−5−O−トリフルオロメチルスルホニル−beta−D−リボフラノシド(3−II−a)
19FNMR(235MHz,CDCl3):δ−74.5(CF 3 )
LC−MS APCI+:C8H18O7P[M+H]+計算値257.1,実績値257.1
LC−MS APCI+:C15H25NO7P[M+H]+計算値362.1実績値362.3
LC−MS APCI+:C15H27NO7P[M+H]+計算値364.15,実績値364.02.
LC−MS APCI+:C16H26NO8P[M+H]+計算値392.15,実績値391.9.
15NNMR(50MHz,D2O):δ172ppm(d,2J=25Hz)
LC−MS ESI+:C9H20NNaO8P[M+Na]+計算値324.1,実績値323.8.
31PNMR(101MHz,D2O):δ25.8ppm
LC−MS ESI−:C7H15NO8P[M−H]−計算値272.0,実績値272.1
工程1:[1−ベンジルオキシ−2−(3R,4R,5R,6R)−(6−メトキシ−2,2−ジメチル−テトラヒドロ−フロ[3,4−d][1,3]ジオキソール−4−イル)−エチル]−ホスホン酸ジエチル(4a)
LC−MS ESI+:C21H34O8P[M+H]+計算値445.2,実績値444.8;[M+NH4]+実績値461.8
LC−MS ESI+:C14H28O8P[M+H]+計算値355.1,実績値355.0
LC−MS ESI+:C10H22O8P[M+H]+計算値301.1,実績値300.9,[M+Na]+計算値323.1,実績値322.9
LC−MS APCI+:C17H29NO8P[M+H]+計算値406.2,実績値406.2
31PNMR(101MHz,D2O):δ27.3(major diastereomer),26.2(minor diastereomer)
LC−MS APCI+:C17H31NO8P[M+H]+計算値408.2,実績値408.0.
31PNMR(101MHz,D2O):δ27.2(major diastereomer),26.1(minor diastereomer)
LC−MS APCI+:C18H31NO9P[M+H]+計算値436.2,実績値435.7
31PNMR(101MHz,D2O):δ27.3(major diastereomer),26.2(minor diastereomer)
LC−MS APCI+:C11H25NO9P[M+H]+計算値346.1,実績値345.9
31PNMR(101MHz,D2O):δ17.8(major diastereomer),16.9(minor diastereomer)
LC−MS ESI−:C7H15NO9P[M−H]−計算値288.1,実績値288.1
工程1:2,3,4−トリ−O−ベンジル−1−(N−ベンジルオキシ−N−ホルミルアミノ)−1,5−ジデオキシ−5−ヨード−D−リビトール
1HNMR(DMSO,600MHz,90℃)δ8.14(bs,1H,C(=O)H),7.0−7.24(m,20H,4xOCH2Ph),4.92−4.89(m,2H,NOCH2Ph),4.74−4.56(m,6H,2xOCH2Ph),4.14−4.08(m,1H,H−4),4.03−3.95(m,6H,H−2,H−3,2xOCH2CH3),3.88−3.80(m,2H,H−1a,H−1b),2.23(ddd,1H,J5a,5b15.8,J5a,44.4,J5a,P18.4Hz,H−5a),2.15(ddd,1H,J5b,5a15.8,J5b,47.4,J5b,P17.6Hz,H−5b),1.24−1.20(m,6H,2xOCH2CH3).
31PNMR(DMSO,242MHz,90℃)δ28.78(P(O)(OCH2CH3)2).
13CNMR(DMSO,150MHz,90℃):δ137.64,137.52,137.37(Cq,3xC−Ar),134.38(Cq,NOCH2Bn),128.92,128.88,128.26,127.67,127.51,127.39,127.31,127.26,126.85,126.83,126.79,126.64,126.61,126.54(C−Ar),79.88(d,JC4,P10.3Hz,C−3),75.37(OCH2Ph),74.72(C−2),74.15(C−4),71.94,71.10,71.05(OCH2Ph),60.25(d,JP,OCH2CH36Hz,POCH2CH3),60.15(d,JP,OCH2CH36Hz,POCH2CH3),46.82*(*det by HSQC,NCH2),27.02(d,JP,C−5139Hz,C−5),15.31,15.27,15.24(2xOCH2CH3);HRESI−MS:C38H46NO8P[M+Na]+計算値698.2853,実績値698.2582.
1HNMR(600MHz,D2O):δ8.33(s,0.2H,NC(=O)H,minor rotamer),7.89(s,0.8H,NC(=O)H,major rotamer),4.07−4.02(m,1H,H−4),4.02−3.98(dt,1H,H−3),3.75(dd,1H,J1a,1b14.9,J1a,22.2Hz,H−1a),3.67−3.61(m,2H,H−2,H−1b),1.83(ddd,1H,J5a,5b14.9,J5a,43.7,J5a,P17.8Hz,H−5a),1.61(ddd,1H,J5b,5a15.0,J5b,49.4,J5b,P15.1Hz,H−5b).31PNMR(D2O,242MHz)δ20.54(P(O)(OH)2).13CNMR(D2O,150MHz):δ161.08(CHO),76.72(d,J11.9Hz,C−3),69.19(d,J3.3Hz,C−4),68.44(C−2,minor rotamer),67.76(C−2,major rotamer),54.12(C−1,major rotamer),50.07(C−1,minor rotamer),31.53(d,J128.39,C−5);HRESI−MS:C6H14NO8P[M−H]−計算値258.0384,実績値258.0383.
工程1:[2,3,4−トリ−O−ベンジル−1−(N−ベンジルオキシ−N−ホルミルアミノ)−1−デオキシ−5,6−ジヒドロキシ−D−リボ−ヘキシトール)]6−ホスホン酸ジベンジル(6a)
1HNMR(600MHz,トルエン−d880℃):δ8.09(s,1H,H−formyl),7.30-6.96(m,30H,H−Ar),5.02(d,2H,CH2−Ar),4.87(d,2H,CH2−Ar)4.70-4.62(m,6H,3xCH2−Ar),4.54(s,2H,CH2−Ar),4.44(t,1H,J=6.9Hz,H−5),4.41(d,1H,J=9.7Hz,H−6),4.19(dd,1H,J=4.2Hz,J=2.5Hz,H−3),4.08(m,2H,H−3,H−2),3.80(bs,2H,H−1a,H−1b);13CNMR(150MHz):δ138.5-124.5(30xC−Ar),80.4(C−4),79.4(C−2),76.8(C−3),76.4(CH2−Ar),74.5(CH2−Ar),73.5,72.7(2xCH2−Ar),70.6(C−5),68.8(CH2−Ar),68.5(C−6),67.5(CH2−Ar),48.9(C−1).HR−MS:C7H16NO8P[M+H]+計算値:846.3402,実績値:846.3401.
1HNMR(D2O,600MHz,pH=7):δ8.29(s,0.2H,NC(O)H,minor rotamer),7.84(s,0.8H,NC(O)H,major rotamer),4.22(m,1H,J=5Hz,H−2),4.01(dt,1H,H−5),3.88(m,2H,H−3,H−4),3.83(dd,1H,J6,5=2.5Hz,J6,P=10Hz,H−6),3.72(dd,1H,J1a,2=2Hz,J1b,1a=15Hz,H−1a),3.65(dd,1H,J1b,2=9Hz,H−1b).13CNMR(150MHz):δ159.7(CH=O),74.65(C−3),72.85(C−5),72.1(C−4),69.3(C−6),68.4(C−2)and54.4(C−1).LC−MS(HILIC)計算値C7H16NO10P(305.0512),実績値:305.9(M+H)+,303.8(M−H)−
工程1:トリイソプロピル−((2R,3S,4S)−2,3,4−トリス−ベンジルオキシ−ヘキサ−5−エニルオキシ)−シラン(7a)
7h−DIA2:1HNMR(400MHz,CDCl3):δ8.27(s,0.21H,NCHO,minor rotamer),7.73(s,0.79H,NCHO,major rotamer),7.28−6.86(m,35H,7xPh),5.15(d,1H,J=12Hz),4.52−4.01(m,10H),3.74−3.55(m,6H),3.10(t,1H,J6,OH=4Hz,OH),3.44−3.28(m,2H).
31PNMR(161MHz,CDCl3):δ18.65.
LCMS[[M+H]+−BnOH]+:734.2.
31PNMR(161MHz,D2O):δ26.72.
MS ESI−:302.
工程1:N−ベンジルオキシ−N−((2S,3S,4S)−2,3,4−トリス−ベンジルオキシ−5−オキソ−1−トリチルオキシメチル−ペンチル)−ホルムアミド(8i−DIA2)
31PNMR(161MHz,CDCl3):δ18.72.
LC MS[[M+H]+−BnOH]+:734.2.
31PNMR(161MHz,D2O):δ25.95.
MS ESI−:302.
工程1:トリフルオロ−メタンスルホン酸1−(ジエトキシ−ホスホリル)−(3R,4R,5R,6R)−2−(6−メトキシ−2−メチル−テトラヒドロ−フロ[3,4−d][1,3]ジオキソール−4−イル)−エチル(9a)
LC−MS APCI+:C15H27F3O10PS[M+H]+計算値487.1,実績値486.6
31PNMR(101MHz,CDCl3):δ17.8(d,J31P−19F=75Hz,0.4P,minor diastereomer),17.2(d,J31P−19F=75Hz,0.6P,major diastereomer)
19FNMR(235MHz,CDCl3):δ−208.45(d,J31P−19F=75Hz,0.6F,major diastereomer),−213.0(d,J31P−19F=75Hz,0.4F,minor diastereomer)
LC−MS APCI+:C14H27FO7P[M+H]+計算値357.1,実績値356.9
LC−MS APCI+:C10H21FO7P[M+H]+計算値303.1,実績値302.9
LC−MS APCI+:C17H28FNO7P[M+H]+計算値408.1,実績値407.7
LC−MS APCI+:C17H30FNO7P[M+H]+計算値410.2,実績値410.0.
19FNMR(235MHz,D2O):δ−207.6(d,J31P−19F=79Hz,0.6F,major diastereomer),−213.2(d,J31P−19F=76Hz,0.4F,minor diastereomer)
LC−MS APCI+:C18H30FNO8P[M+H]+計算値438.2,実績値437.8.
31PNMR(101MHz,D2O):δ20.5(d,J31P−19F=77Hz,0.45P,minor diastereomer),19.8(d,J31P−19F=79Hz,0.55P,major diastereomer)
19FNMR(235MHz,D2O):δ−207.5(d,J31P−19F=79Hz,0.55F,major diastereomer),−213.4(d,J31P−19F=76Hz,0.45F,minor diastereomer)
LC−MS APCI+:C11H24FNO8P[M+H]+計算値348.1,実績値347.9
31PNMR(101MHz,D2O):δ12.3(d,J31P−19F=62Hz,0.45P,minor diastereomer),12.0(d,J31P−19F=64Hz,0.55P,major diastereomer)
19FNMR(235MHz,D2O):δ−200.3(d,J31P−19F=64Hz,0.55F,major diastereomer),−204.8(d,J31P−19F=62Hz,0.45F,minor diastereomer)
LC−MS ESI−:C7H14FNO8P[M−H]−計算値290.0,実績値290.0
工程1:(2R,3S,4S)−5,5−ビス(エチルチオ)ペンタン−1,2,3,4−テトラオール(10a)の合成.
1HNMR(400MHz,DMSO−d6):δ4.99(d,1H,J=6.0Hz),4.47(t,1H,J=11.2Hz),4.25−4.17(m,3H),3.83(t,1H,J=15.2Hz),3.73−3.68(q,1H,J=18.8Hz),3.54(t,1H,J=16.8Hz),3.43−3.36(m,2H),2.66−2.61(m,4H),1.21−1.16(m,6H).
Crude1HNMR(400MHz,DMSO−d6):δ9.65(s,1H),7.36−7.25(m,15H),4.70−4.45(m,6H),4.29(d,1H,J=2.4Hz),4.07(t,1H,J=7.6Hz),3.89(d,1H,J=4.0Hz),3.80−3.75(m,2H),1.06−0.93(m,21H).
1HNMR(400MHz,CDCl3):δ7.38−7.26(m,20H),5.92−5.92(bs,1H),4.75−4.50(m,8H),4.00−3.93(m,2H),3.80−3.79(m,2H),3.66−6.63(m,1H),3.32−3.31(m,1H),3.20−3.16(m,1H),1.09−0.98(m,21H).
1HNMR(400MHz,CDCl3):δ8.18−7.91(bs,1H),7.32−7.26(m,20H),4.95−4.39(m,8H),4.11−3.67(m,5H),3.49(bs,2H),1.03−0.92(m,21H).
1HNMR(400MHz,DMSO−d6):δ8.27−7.97(bs,1H),7.36−7.25(m,20H),4.89−4.82(m,3H),4.70−4.67(m,3H),4.53−4.38(m,3H),3.94−3.90(m,2H),3.70−3.63(m,4H),不純物として酢酸エチル.
1HNMR(400MHz,CDCl3):δ9.68−9.67(bs,1H,CHO),8.17−7.88(bs,1H,CHO),7.34−7.24(m,20H),4.95−4.92(bs,1H),4.71−4.68(d,2H,J=11.6Hz),4.55−4.41(m,5H),4.02−3.94(m,4H),3.61−3.59(bs,1H).
1HNMR(400MHz,DMSO−d6):δ8.20−7.95(bs,1H,NCHO),7.35−7.23(m,20H),6.73(bs,1H),6.09(bs,1H),4.88−4.64(m,2H),4.61−4.38(m,7H),3.94(s,1H),3.82(bs,1H),3.67−3.64(m,2H),3.60−3.53(m,6H).
ES−MS(M−H)272.0.
工程1:(2R,3R,4S)−5,5−ビス(エチルチオ)ペンタン−1,2,3,4−テトラオール(11a)
1HNMR(400MHz,DMSO−d6):δ4.63(d,1H,J=7.2Hz),4.43(d,1H,J=5.6Hz),4.31(d,1H,J=8.0Hz),4.01(d,1H,J=8.8Hz),3.87(t,1H,J=7.2Hz),3.78−3.74(m,2H),3.67−3.63(m,1H),3.52−3.47(m,1H)2.65−2.59(m,4H),1.19−1.15(m,6H),1.10−0.99(m,21H).
1HNMR(400MHz,CDCl3):δ7.35−7.22(m,20H),5.85−5.82(bs,1H),4.77−4.48(m,8H),4.06−3.76(m,5H),3.36−3.17(m,1H),3.09−2.91(m,1H),1.10−1.01(m,21H).
1HNMR(400MHz,DMSO−d6):δ8.31and7.96(2xs,1H,1:1rotamers,N−CHO),7.47−7.23(m,20H),4.91−4.44(m,8H),4.12−3.54(m,7H),1.09−0.97(m,21H).
1HNMR(400MHz,DMSO−d6):δ8.30and7.96(s,1H,1:1rotamers,N−CHO),7.39−7.21(m,20H),4.91−4.42(m,8H),4.06−3.52(m,7H).
1HNMR(400MHz,CDCl3):δ9.69and9.58(s,1H,rotamers of CHO),8.18and7.88(s,1H,rotamers of N−CHO),7.44−7.21(m,20H),4.97−3.71(m,13H).
1HNMR(400MHz,CDCl3):δ8.17and7.73(2xs,1H,1:1rotamers,N−CHO),7.34−7.26(m,20H),6.91(brs,1H),6.02(brs,1H),4.88−3.51(m,19H),異性体の混合物.
1HNMR(400MHz,CDCl3)δ8.19and7.82(s,1H,1:1rotamers,N−CHO),7.33−7.26(m,20H),4.79−4.41(m,8H),3.91−3.33(m,11H),2.05−1.64(m,4H).
1HNMR(400MHz,DMSO−d6):δ8.24and7.92(2xbs,1H,rotamersofNCHO),7.30−7.23(m,20H),4.92−4.87(m,2H),4.68−4.59(m,1H),4.56−4.34(m,5H),4.01−3.27(m,5H),2.08−2.03(m,2H),1.89−1.43(m,2H).
31PNMR(D2O),δ25.6(P(O)(OH)2).C6H16NO8P.
ES−MS(m/z):272.0(M−H).
工程1:[1,1−ジフルオロ−2−(3R,4R,5R,6R)−(6−メトキシ−2,2−ジメチル−テトラヒドロ−フロ[3,4−d][1,3]ジオキソール−4−イル)−エチル]−ホスホン酸ジエチル(12a)
LC−MS ESI+:C14H26F2O7P[M+H]+計算値375.1,実績値374.9
LC−MS APCI+:C17H27F2NO7P[M+H]+計算値426.1,実績値426.2
LC−MS APCI+:C17H29F2NO7P[M+H]+計算値428.2,実績値427.8
LC−MS APCI+:C15H23F2NO7P[M−H]−計算値398.1,実績値398.0
LC−MS ESI−:C16H23F2NO8P[M−Na]−計算値426.1,実績値425.9
LC−MS ESI−:C9H17F2NO8P[M−H]−計算値336.1,実績値336.0
31PNMR(101MHz,D2O):δ5.4(tapp.,J31P−19F=86Hz)
19FNMR(235MHz,D2O):δ−108.0(dd,J31P−19F=86HzandJ19F−19F=282Hz,1F),−110.2(dd,J31P−19F=86HzandJ19F−19F=282Hz,1F)
LC−MS ESI−:C7H13F2NO8P[M−H]−計算値308.0,実績値307.9
工程1:[2,3,4−トリ−O−ベンジル−1−(N−ベンジルオキシ−N−ホルミルアミノ)−1,6−ジデオキシ−D−allo/L−talo−ヘキシトール)]6−ホスホン酸ジベンジル(13a)
1HNMR−Data for 13a’(トルエン−d890℃,major isomer):δ7.27-6.95(m,30H,H−Ar),4.92-4.80(m,4H,2xCH2−Ar),4.68-4.48(m,9H,4xCH2−Ar,H−5),4.13(ddd,1H,H−2),3.94(dd,1H,J=4.6Hz,H−3),3.82(dd,1H,J=4.9Hz,H−4),3.36(dd,1H,J=4Hz,J=14Hz,H−1a),3.21(dd,1H,J=7Hz,H−1b),2.26(ddd,1H,J=3,J=15Hz,H−6a),2.14(ddd,1H,J=7Hz,H−6b).13CNMR:δ137.4-124.4(36C−Ar),82.4(d,C−Pcoupling,J=15Hz,C−4),80.2(C−3),77.1(C−2),75.7,74.0,73.5,72.4(4xCH2−Ar),67.6(d,C−Pcoupling,J=5Hz,C−5),67.0,66.9(2xCH2−Ar),52.8(C−1),29.9(d,C−PcouplingJ=140Hz,C−6).31PNMR(242MHz):δ32.5(s).LC−MSデータでの予想値801.34,実績値802.4(M++H).
工程1:ジチオ炭酸O−[(5R,6S,6aR)−5−(2,2−ジメチル−[1,3]ジオキソラン−4−イル)−2,2−ジメチル−テトラヒドロ−フロ[2,3−d][1,3]ジオキソール−6−イル]S−メチル(15a)
31PNMR(D2O):δ25.61(P(O)(OH)2).
ES−MS(m/z):256.0(M−H).
エリスロマイシン(1〜5mg/mL)の添加または非添加条件で、生理学的食塩水(発熱性物質不含水の0.9%塩化ナトリウム水溶液)中またはグルコース溶液(発熱性物質不含水の1〜5%グルコース水溶液)中に、実施例2の化合物を1〜20mg/mLで希釈することにより、静脈内投与用の溶液を準備した。
GmhAの酵素活性の抑制(発光アッセイ):
アッセイバッファー「AB」は、50mMのHepes(pH7.5)、1mMの塩化マンガン、25mMの塩化カリウム、0.012%のTriton−X100、1mMのジチオトレイトール(DTT)および0.1μMのミエリン塩基性タンパク質(MBP)を含んでいた。以下の構成成分を、白色ポリスチレンコースタープレート中に、30μLになるまで加えた。30μL中、10μLはDMSO/水(DMSO/水=50/50)中に溶解された抑制剤であり、20μLはアッセイバッファー中の大腸菌のGmhAであった。室温で30分間予備培養した後、アッセイバッファー中の基質混合物(substrate mix)30μLを加え、プレートの各穴の最終容量を60μLとした。この反応混合物には、アッセイバッファー中、2nMのGmhA、3μMのセドヘプツロース−7−リン酸(Sigma),3μMのATP(Sigma)および50nMの大腸菌のHldEが含まれていた。室温で30分間培養した後、さらに100μLの検出用混合液(revelation mix)を最終的な容量が160μLとなるまで添加した。前記検出用混合液は、各構成成分を最終的な濃度として、10000光単位/mLのルシフェラーゼ(Sigma)、20μMのD−ルシフェリン(Sigma)、100μMのN−アセチルシステアミン(Aldrich)で含んでいた。添加後、発光強度を速やかにルミノスキャン(サーモフィッシャー)で測定し、抑制率へと変換した。IC50の判断に当たり、6〜10の異なる濃度で抑制剤の試験を行い、XLFIT(IDBS)を用いて、関連する抑制率を、典型的なラングミラー型平衡モデルによりフィッティングした。
原理:大腸菌のC7(018:K1:H7)は、新生児髄膜炎大腸菌(Newborn Meningitidis E. coli (NMEC))株であり、この株は、典型的な、リピドAと、これに続いて結合する内側および外側のコアオリゴ糖と、さらに結合するO抗原繰り返し単位とで構成されるリポ多糖(LPS)を呈する。内側コアは、複数のヘプトース残基を含む。LPSのヘプトシレーション経路の抑制剤は、それゆえ、画期的にLPSの大きさを低減させ、完全長から、いわゆる「Re−LPS」と呼ばれる、リピドAにKdo2残基が付加した構造へと低減させるであろう。LPSのサイズおよび組成をモニターする簡単な方法は、LPSのゲル電気泳動を行うことである(図1)。図1では野生型大腸菌株は、完全なLPSおよびコア部を含む複数のバンドを呈しているが、Re−LPSではバンドを呈しない。なお、LPS−ヘプトシレーション生合成について欠損しているdelta−hldE変異体は、Re−LPSバンドのみを呈している。
実施例5、6、10、11および15で得られた化合物は、大腸菌GmhAに関し、IC50値が500nM〜100μMである。
実施例1〜4、7〜9および12〜14で得られた化合物は、大腸菌GmhAに関し、IC50値が500nM未満である。
実施例2、4、7〜9、12および13に記載された化合物は、100μMのG6Pの存在下で、濃度1mM未満での大腸菌C7のLPSヘプトシレーションを少なくとも50%抑制する。
一部の実施例の化合物の抑制活性のデータを、以下の表に示す。
供試化合物を、10mMの原液から、50mMのHEPESバッファー(pH7.4)中で希釈した。次いで5μLの化合物希釈液またはバッファーを、無菌状態の透明丸底96ウェルポリスチレンマイクロプレート(コーニング)中に供給した。
参照抗生物質[エリスロマイシン(Fluka)、リファンピシン(Fluka)またはシナシッド(Synercid)(モナーク・ファーマシューティカルズ製)]をDMSO中で連続2倍希釈した希釈液5μLを加えた。LB中で指数関数的に成長している大腸菌C7(O18:K1:H7)の前培養物(preculture)を1e4 cfu/mLへ希釈し、100μMのG6Pを加え、得られた懸濁物90μLを、前記マイクロプレートへ添加した。37℃で一晩培養後、供試化合物の各濃度に対して、拡大せずに細菌ペレットを目視できない場合を最も低い抗生物質濃度として、前記抗生物質の最小発育阻止濃度(MIC)を判定した。
実施例2の化合物は、1mM未満の濃度で、100μMのG6Pの存在下、エリスロマイシンを32倍増強し(MIC:32μg/mLが1μg/mLへ)、リファンピシンを16倍増強し(MIC:4μg/mLが0.25μg/mLへ)、シナシッドを16倍増強する(MIC:128μg/mLが8μg/mLへ)。
ヘプトースを欠如する細菌に対して得られたデータによると、このような化合物は、宿主の補体または洗浄剤および疎水性抗生物質に対して、グラム陰性菌の感度を高くする可能性があることを示す。したがって、本発明の新規化合物は、単独でまたは抗生物質、抗ウィルス剤、あるいは免疫促進剤(Annu. Rev. Biochem. 2002, 635)と組み合わせて、細菌の感染の予防力または抑制力を有している。
このような抑制剤は、片利共生叢(commensal flora)に影響を与えることなく、従来の抗生物質より低い選択圧で、病原性のグラム陰性菌によって引き起こされる血流伝染病を治療または予防するための新規な方法を提供する。
Claims (23)
- 下記の一般式(I)で表され、純粋なジアステレオ異性体の形態およびジアステレオ異性体の混合物の形態、またはカルボニル基及びヒドロキシ基を有する場合には環式へミケタール体もしくは環式ヘミアセタール体の形態を有する化合物、ならびにその酸および/または塩基付加塩。
−A1およびA2は、互いに同一又は異なり、H、(C1〜C6)アルキル、(C1〜C6)フルオロアルキル、(C2〜C6)アルケニル、(C2〜C6)アルキニル、(C1〜C6)アルキル−ORa、(C1〜C6)アルキル−SRa、(C1〜C6)アルキル−NRaRb、ORa、SRa、NRaRbまたはCORaであり、
−A3は、HまたはOHであるか、あるいは、A4とカルボニルを形成しており、
−A4は、HまたはOHであるか、あるいは、A3とカルボニルを形成しており、
−A5は、H、CRaRbOH、FまたはOHであるか、あるいは、XがCHである場合にはXと二重結合を形成しており、
−A6は、HまたはFであり、
−Xは、CH2、CHF、CF2、CHOH、O、S、NRa、または単結合であるか、あるいは、A5と二重結合を形成する場合にはCHであり、
−Yは、P(O)(ORa)(ORb)またはP(O)(ORa)(NRaRb)であり、
−Vは、OまたはSであり、
−A7は、H、(C1〜C6)アルキル、(C1〜C6)フルオロアルキル、(C2〜C6)アルケニル、(C2〜C6)アルキニルまたは(C1〜C6)アルキル−ORaであり、
−A8は、OHまたはHであり、
−RaおよびRbは、互いに同一又は異なり、H、(C1〜C6)アルキル、(C1〜C6)フルオロアルキル、(C1〜C6)アルキル−OHおよび(C1〜C6)アルキル−O−(C1〜C6)アルキルからなる群から選択される。) - 前記一般式(I)において、YがP(O)(OH)2である請求項1に記載の化合物、ならびにその酸および/または塩基付加塩。
- 前記一般式(I)において、XがCH2、CHF、CF2、CHOHまたはOである、請求項1または2に記載の化合物、ならびにその酸および/または塩基付加塩。
- 前記一般式(I)において、Wが、請求項1に記載のW1である、請求項1から3のいずれか一項に記載の化合物、ならびにその酸および/または塩基付加塩。
- 前記一般式(I)において(式中、Raの定義は請求項1と同じ)、
A1およびA2がHであるか、
A1およびA2のうちの一方がHであって他方が(C1〜C6)アルキルであるか、
A1およびA2のうちの一方がHであって他方がフルオロ(C1〜C6)アルキルであるか、
A1およびA2のうちの一方がHであって他方が(C1〜C6)アルキル−ORaであるか、
A1およびA2のうちの一方がHであって他方が(C1〜C6)アルキル−SRaであるか、
A1およびA2のうちの一方がHであって他方がCORaであるか、あるいは、
A1およびA2のうちの一方がHであって他方がOHである、
請求項1から4のいずれか一項に記載の化合物、ならびにその酸および/または塩基付加塩。 - 前記一般式(I)において(式中、RaおよびRbの定義は請求項1と同じ)、
A3がA4とカルボニルを形成する場合、A5がOHまたはCRaRbOHであり、
A3がA4とカルボニルを形成しない場合、A5がHまたはFである、
請求項1から5のいずれか一項に記載の化合物、ならびにその酸および/または塩基付加塩。 - 前記一般式(I)において、A7がHまたは(C1〜C6)アルキルである、請求項1から6のいずれか一項に記載の化合物、ならびにその酸および/または塩基付加塩。
- 当該化合物が:
D−アルトロノヒドロキサム酸6−(二水素リン酸エステル);
N−ヒドロキシ−N−ホルミルアミノ−1−デオキシ−D−リビトール−5−リン酸エステル;
[6−(ホルミル−ヒドロキシ−アミノ)−(3R,4R,5S)−3,4,5−トリヒドロキシ−ヘキシル]−ホスホン酸;
[6−(ホルミル−ヒドロキシ−アミノ)−(3R,4R,5S)−1,3,4,5−テトラヒドロキシ−ヘキシル]−ホスホン酸;
[(2S,3S,4S)−5−(ホルミル−ヒドロキシ−アミノ)−2,3,4−トリヒドロキシ−ペンチル]−ホスホン酸;
[1−(N−ベンジルオキシ−N−ホルミルアミノ)−1,5−ジデオキシ−D−リビトール]−5−ホスホン酸;
[1−(N−ベンジルオキシ−N−ホルミルアミノ)−1−デオキシ−5,6−ジヒドロキシ−D−リボ−ヘキシトール]−6−ホスホン酸;
[(3R,4R,5S)−6−(ホルミル−ヒドロキシ−アミノ)−3,4,5,7−テトラヒドロキシ−ヘプチル]−ホスホン酸(ジアステレオ異性体DIA1及びDIA2);
[1−フルオロ−6−(ホルミル−ヒドロキシ−アミノ)−(3R,4R,5S)−3,4,5−トリヒドロキシ−ヘキシル]−ホスホン酸;
[(3R,4S,5R)−3,4,5−トリヒドロキシ−6−(N−ヒドロキシホルムアミド)−ヘキシル]−ホスホン酸;
[(3R,4R,5R)−3,4,5−トリヒドロキシ−6−(N−ヒドロキシホルムアミド)−ヘキシル]−ホスホン酸;
[1,1−ジフルオロ−6−(ホルミル−ヒドロキシ−アミノ)−(3R,4R,5S)−3,4,5−トリヒドロキシ−ヘキシル]−ホスホン酸;
[1−(N−ヒドロキシ−N−ホルミルアミノ)−1,6−ジデオキシ−D−アロ/L−タロ−ヘキシトール]−6−ホスホン酸;もしくは
[1−(N−ベンジルオキシ−N−ホルミルアミノ)−1−デオキシ−D−リボ−5−(E)−ヘキセニトール]−6−ホスホン酸;である、請求項1に記載の化合物ならびにその酸および/または塩基付加塩(特に、ナトリウム塩)。 - 請求項1に記載の一般式(I)で表される化合物を製造する方法であって、
下記の一般式(II)で表される化合物
に、下記の少なくとも1種の反応:
反応性官能基の保護;
保護された官能基の脱保護;
ハロゲン化;
メタセシス;
エポキシ化;
エポキシド開環;
脱ハロゲン化;
脱アルキル化;
アルキル化;
酸化;
カルボニル基に対するウィッティヒ型の反応;
光延型の反応;
炭素−炭素二重結合のジヒドロキシ化反応;
ニトロ、エステル、シアノ、カルボニル、チオエーテル、二重結合、三重結合、およびヒドロキシからなる群から選択される少なくとも一種の、還元;
脱酸素;
遷移金属触媒反応;
エーテル化;
アシル化;
スルホニル化(スルホニル基の導入);
ケン化(エステル基の加水分解);
ハロゲン交換;
アミン、チオールまたはアルコールを用いた求核置換;
還元的アミノ化;
リン酸化;
硫酸化;
亜リン酸化、アルブゾフ反応、ミカエリス−ベッカー反応;
ホスホニル化、(フルオロ)メチルホスホニル化;
アミド化;
ホスホルアミド化;
ケト基に対するヒドロキシルアミンの付加またはニトログリカールの還元によるオキシム形成;
A1、A2、A5、A7、XまたはYに対するRa,Rbの導入;
GがPGである場合の当該Gを水素原子とする脱保護;
ジアステレオ異性体の単離;および
塩化;
を適切な順番で実行することにより、Wおよび/またはXおよび/またはYおよび/またはA1および/またはA2および/またはA3および/またはA4および/またはA5および/またはA6および/またはA7および/またはGに所望の変換を施す工程、
を含む、製造方法。 - 請求項1に記載の一般式(I)で表される化合物を製造する方法であって、
下記の一般式(IV)もしくは(V)で表される化合物またはその塩に、P(ORa)3、HP(O)(ORa)(NRaRb)またはHP(O)(ORa)(ORb)を、任意で適切な塩基および/または触媒の存在下で反応させる工程を含み;
さらに、適宜、
請求項9に記載の反応も含めた一般式(II)で表される化合物を一般式(I)で表される化合物に変換するための反応のうち、少なくとも1種の反応を実行する、製造方法。 - 請求項1に記載の一般式(I)で表される化合物を製造する方法であって、
下記の一般式(VI)もしくは(VII)で表される化合物またはその塩に、Y−XH、P(ORa)3、HP(O)(ORa)(NRaRb)、HP(O)(ORa)(ORb)または[P(O)(ORa)(ORb)]2CH2を、任意で適切な塩基および/または触媒の存在下で反応させる工程を含み;
さらに、適宜、
請求項9に記載の反応も含めた一般式(II)で表される化合物を一般式(I)で表される化合物に変換するための反応のうち、少なくとも1種の反応を実行する、製造方法。 - 請求項1に記載の一般式(I)で表される化合物を製造する方法であって、
下記の一般式(VIII)で表される化合物またはその塩に、A7−C(V)LG3をカップリングさせて反応させる工程を含み、
さらに、適宜、
請求項9に記載の反応も含めた一般式(II)で表される化合物を一般式(I)で表される化合物に変換するための反応のうち、少なくとも1種の反応を実行する、製造方法。 - 請求項1に記載の一般式(I)で表される化合物を製造する方法であって、
下記の一般式(XIII)で表される化合物またはその塩に、Y−XHまたはP(ORa)3を反応させる工程を含み、
さらに、適宜、
請求項9に記載の反応も含めた一般式(II)で表される化合物を一般式(I)で表される化合物に変換するための反応のうち、少なくとも1種の反応を実行する、製造方法。 - 請求項1に記載の一般式(I)で表される化合物を製造する方法であって、
下記の一般式(XV)もしくは(XVI)で表される化合物
に、NH2−OG(式中、Gの定義は上記のとおりである。)を、適切な還元剤の存在下ならびに任意で適切な塩基および/または触媒との存在下で反応させる工程、
を含み、この工程後、
A7−C(V)LG3(式中、A7およびVの定義は請求項1に記載されたものと同じであり、LG3の定義は請求項12に記載されたものと同じである)を用いてアシル化を実行し、
さらに、適宜、
請求項9に記載の反応も含めた一般式(II)で表される化合物を一般式(I)で表される化合物に変換するための反応のうち、少なくとも1種の反応を実行する、製造方法。 - 薬剤として用いられる、請求項1に記載の一般式(I)で表される化合物、ならびにその薬学的に許容可能な酸および/または塩基付加塩。
- 薬剤として用いられる、請求項2から7のいずれか一項に記載の一般式(I)で表される化合物、ならびにその薬学的に許容可能な酸および/または塩基付加塩。
- 薬剤として用いられる、請求項8に記載の一般式(I)で表される化合物、ならびにその医薬的に許容可能な酸および/または塩基付加塩。
- グラム陰性菌によるヒトまたは動物の感染の、予防用および/または治療処置用の薬剤として用いられる、請求項1〜8および15〜17のいずれか一項に記載の一般式(I)で表される化合物、ならびにその薬学的に許容可能な酸および/または塩基付加塩。
- 抗菌剤、抗病原性物質剤、宿主の自然免疫を増強する薬剤またはこれらの組合せとの併用の薬剤として用いられる、請求項1〜8および15〜18のいずれか一項に記載の一般式(I)で表される化合物、ならびにその薬学的に許容可能な酸および/または塩基付加塩。
- マクロライド類、ストレプトグラミン類、プレウロムチリン類、FabI阻害剤、リファマイシン類、リポペプチド類、GM−CSFまたはこれらの組合せとの併用の薬剤として用いられる、請求項1〜8および15〜19のいずれか一項に記載の一般式(I)で表される化合物、ならびにその薬学的に許容可能な酸および/または塩基付加塩。
- 請求項1〜8および15〜20のいずれか一項に記載の一般式(I)で表される化合物、またはその薬学的に許容可能な酸または塩基付加塩を有効成分として含有する、医薬組成物。
- 請求項1〜8のいずれか一項に記載の一般式(I)で表される化合物、またはその薬学的に許容可能な酸または塩基付加塩と、
抗菌剤、抗病原性物質剤、宿主の自然免疫を増強する薬剤またはこれらの組合せと
を有効成分として含有する、混合物または併用医薬。 - 請求項1〜8のいずれか一項に記載の一般式(I)で表される化合物、またはその薬学的に許容可能な酸または塩基付加塩と、
マクロライド類、ストレプトグラミン類、プレウロムチリン類、FabI阻害剤、リファマイシン類、リポペプチド類、GM−CSFまたはこれらの組合せと
を有効成分として含有する、混合物または併用医薬。
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