JPH11302243A - Diethylenetriamine pentaacetic acid derivative - Google Patents
Diethylenetriamine pentaacetic acid derivativeInfo
- Publication number
- JPH11302243A JPH11302243A JP10114562A JP11456298A JPH11302243A JP H11302243 A JPH11302243 A JP H11302243A JP 10114562 A JP10114562 A JP 10114562A JP 11456298 A JP11456298 A JP 11456298A JP H11302243 A JPH11302243 A JP H11302243A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- nhc
- nhr
- group
- metal ion
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- QTONSPKDOKVNBJ-UHFFFAOYSA-N acetic acid;n'-(2-aminoethyl)ethane-1,2-diamine Chemical class CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.NCCNCCN QTONSPKDOKVNBJ-UHFFFAOYSA-N 0.000 title 1
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 17
- 238000003745 diagnosis Methods 0.000 claims abstract description 11
- 230000005298 paramagnetic effect Effects 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims abstract description 4
- 230000002285 radioactive effect Effects 0.000 claims abstract description 4
- -1 t-butyloxycarbonyl group Chemical group 0.000 claims description 33
- 239000002872 contrast media Substances 0.000 claims description 18
- 125000002252 acyl group Chemical group 0.000 claims description 15
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical class OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 4
- 238000001727 in vivo Methods 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 abstract description 116
- 238000006243 chemical reaction Methods 0.000 abstract description 13
- 239000002904 solvent Substances 0.000 abstract description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 abstract description 5
- RAZLJUXJEOEYAM-UHFFFAOYSA-N 2-[bis[2-(2,6-dioxomorpholin-4-yl)ethyl]azaniumyl]acetate Chemical compound C1C(=O)OC(=O)CN1CCN(CC(=O)O)CCN1CC(=O)OC(=O)C1 RAZLJUXJEOEYAM-UHFFFAOYSA-N 0.000 abstract description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 238000003756 stirring Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 210000000056 organ Anatomy 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
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- 239000000203 mixture Substances 0.000 description 7
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- 238000002360 preparation method Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
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- 125000003277 amino group Chemical group 0.000 description 4
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 239000002616 MRI contrast agent Substances 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
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- 239000006188 syrup Substances 0.000 description 3
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- 230000008685 targeting Effects 0.000 description 3
- OLQJQHSAWMFDJE-UHFFFAOYSA-N 2-(hydroxymethyl)-2-nitropropane-1,3-diol Chemical compound OCC(CO)(CO)[N+]([O-])=O OLQJQHSAWMFDJE-UHFFFAOYSA-N 0.000 description 2
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 description 2
- 229910052692 Dysprosium Inorganic materials 0.000 description 2
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- 229910052688 Gadolinium Inorganic materials 0.000 description 2
- 229910052689 Holmium Inorganic materials 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 229910052779 Neodymium Inorganic materials 0.000 description 2
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910004298 SiO 2 Inorganic materials 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910052771 Terbium Inorganic materials 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- DIKBFYAXUHHXCS-UHFFFAOYSA-N bromoform Chemical compound BrC(Br)Br DIKBFYAXUHHXCS-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
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- 229960003681 gluconolactone Drugs 0.000 description 2
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- 229910052739 hydrogen Inorganic materials 0.000 description 2
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
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- OFMQLVRLOGHAJI-FGHAYEPSSA-N (4r,7s,10s,13r,16s,19r)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-10-[3-(diaminomethylideneamino)propyl]-7-[(1r)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-3,3-dimethyl-6,9,12,15,18 Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(=O)N[C@@H](C(SSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=CC=CC=1)(C)C)C(=O)N[C@@H]([C@H](O)C)C(N)=O)[C@@H](C)O)C1=CC=C(O)C=C1 OFMQLVRLOGHAJI-FGHAYEPSSA-N 0.000 description 1
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- LUEWUZLMQUOBSB-OUBHKODOSA-N maltotetraose Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@H](CO)O[C@@H](O[C@@H]2[C@@H](O[C@@H](O[C@@H]3[C@@H](O[C@@H](O)[C@H](O)[C@H]3O)CO)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O LUEWUZLMQUOBSB-OUBHKODOSA-N 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
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- 150000002739 metals Chemical class 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- XWCCTMBMQUCLSI-UHFFFAOYSA-N n-ethyl-n-propylpropan-1-amine Chemical compound CCCN(CC)CCC XWCCTMBMQUCLSI-UHFFFAOYSA-N 0.000 description 1
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- 229910052759 nickel Inorganic materials 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
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- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、４個以上の糖鎖を
糖酸アミドとして含有する新規なジエチレントリアミン
五酢酸（以下、ＤＴＰＡと略記する。）誘導体および金
属イオンと錯化した該誘導体に関し、さらにはその製造
中間体、前記誘導体を必須成分とする造影剤、並びに体
内診断用医薬組成物に存する。本発明は、特に、Ｘ線造
影および磁気共鳴造影（以下、ＭＲＩと略記する。）に
おけるコントラスト剤となる金属キレートの用途に関す
る。TECHNICAL FIELD The present invention relates to a novel diethylenetriaminepentaacetic acid (hereinafter abbreviated as DTPA) derivative containing four or more sugar chains as a sugar amide and to a derivative complexed with a metal ion. Further, the present invention relates to a production intermediate thereof, a contrast agent containing the above derivative as an essential component, and a pharmaceutical composition for in vivo diagnosis. The present invention particularly relates to the use of a metal chelate as a contrast agent in X-ray imaging and magnetic resonance imaging (hereinafter abbreviated as MRI).
【０００２】[0002]
【従来の技術および発明が解決しようとする課題】Ｘ
線、核磁気共鳴およびシンチフォトグラフィー診断にお
ける金属のキャリアーとしてキレート剤が用いられてい
る。とりわけ、ＭＲＩ診断においてＤＴＰＡを含むポリ
アミノポリカルボン酸のガドリニウム（Ｇｄ）錯体がコ
ントラスト剤としてすでに臨床の現場で利用されてい
る。しかし、これら臨床応用されているＧｄ錯体はその
有用性は広く認められているものの、その細胞外液性、
すなわち静注投与後急速に血管からもれ出し、細胞内に
取り込まれることなく細胞間質に拡散分布するという性
質に由来する限界があった。これを打破し、臓器、組織
特異的にＭＲＩコントラストを増強し、あるいは緩和を
増幅できれば、投与量の削減が可能となるのみならず、
従来の診断法では得難い情報が得られることが期待され
ている。たとえば、造影剤に血液プール性を付与するこ
とで細胞外液性や、造影剤では不可能、あるいは限界の
あったＭＲアンギオグラフィー、毛細血管透過性の評価
（腫瘍の悪性度等の情報が得られる）、心筋虚血の評価
などが行なえる。また、肝細胞に選択的に取り込まれる
造影剤を例に取れば、肝腫瘤検出、肝癌の分化度の鑑別
などをより容易に行なうことが可能となり、ＭＲＩがダ
イナミックＣＴやＣＴＡＰを省略できる検査法となり得
ると期待されている（Ｉｎｎｅｒｖｉｓｉｏｎ，１２，
６２（１９９７）参照）。2. Description of the Related Art X
Chelating agents have been used as carriers for metals in X-ray, nuclear magnetic resonance and scintigraphy diagnostics. In particular, gadolinium (Gd) complexes of polyaminopolycarboxylic acids containing DTPA in MRI diagnosis have already been used in clinical practice as contrast agents. However, although the usefulness of these clinically applied Gd complexes is widely recognized, their extracellular fluidity,
That is, there is a limit derived from the property that the compound rapidly leaks from blood vessels after intravenous administration and is diffused and distributed in the interstitium of the cells without being taken up into cells. If this can be overcome and the MRI contrast can be enhanced or the relaxation can be enhanced in an organ or tissue-specific manner, not only can the dose be reduced,
It is expected that information that is difficult to obtain with conventional diagnostic methods will be obtained. For example, by adding blood pooling properties to a contrast agent, extracellular fluid properties, MR angiography that was impossible or limited by a contrast agent, and evaluation of capillary permeability (information on tumor malignancy, etc., can be obtained. And evaluation of myocardial ischemia. In addition, taking a contrast agent that is selectively taken into hepatocytes as an example, it becomes possible to more easily detect a liver tumor, distinguish the degree of differentiation of liver cancer, and the like, and a test method in which MRI can omit dynamic CT or CTAP. (Innervision, 12 ,
62 (1997)).
【０００３】造影剤に臓器、組織特異性を持たせる試み
は数多く行なわれている。とりわけ、血液プール性、肝
選択性造影剤の研究は活発である。しかし、従来の血液
プール性造影剤の多くは蛋白質、ポリサッカライドなど
の生体分子にキレーター部をカップリングしたものであ
り、製造、取り扱い上の、また単一化合物でない（キレ
ーター部の結合位置が不定な、ある分布を持った分子量
の異った化合物の集合体）ことによる代謝、毒性上の問
題点を有していた。また、臓器選択性に関しては臓器を
ターゲットとしたものが最も良く研究されているが、肝
臓への取り込みの機序として構造式に脂溶性の基を付加
することで脂溶性を高め膜通過性を亢進するようデザイ
ンした常磁性造影剤が多く、一部は臨床治験が実施され
ているものもあるが、肝臓に取り込まれ胆汁排泄される
効率もそれほど高くない。一方、肝細胞への取り込みの
機序として肝細胞に存在するアシアロ糖蛋白レセプター
（以下、ＧＳＧＰ−Ｒと略記する）を標的とした造影剤
の研究が行なわれている。ＧＳＧＰ−Ｒの本来のリガン
ドであるアシアロ糖蛋白質（以下、ＧＳＧＰと略記す
る）に似せ多数の末端ガラクトース残基を結合した酸化
鉄コロイド、Ｔｃ−キレートアルブミンが開発されてい
る（たとえば、ＡＪＲ，１５５，１１６１（１９９
０）；Ｒａｄｉｏｌｏｇｙ，１７８，７６９（１９９
１）参照）。最近、２個のガラクトース末端を持つＤＴ
ＰＡ誘導体が報告されたが（ＣｈｅｍｉｃａｌＪｏｕｒ
ｎａｌ ｏｆ Ｃｈｉｎｅｓｅ Ｕｎｉｖｅｒｓｉｔｉ
ｅｓ，１８，１０７２（１９９７）参照）、レセプター
による識別、取り込み効率をより高めるためには多くの
末端ガラクトース残基を結合した分子であることが求め
られる。ちなみに、レクチンと高い親和性を有するヒト
血清中の代表的糖タンパク由来のアシアロオロソムコイ
ドには１４個の末端ガラクトース残基があることが知ら
れており、上記の２個のガラクトース末端を持つＤＴＰ
Ａ誘導体ではレセプターによる識別、取り込み効率が不
十分であることは、このことからも予想できる。従っ
て、レセプターによる識別、取り込み効率が向上した新
たなＤＴＰＡ誘導体が望まれていた。[0003] Many attempts have been made to make organs and tissues specific to contrast agents. In particular, research on blood pooling and hepatic selective contrast agents is active. However, many of the conventional blood pool contrast agents are obtained by coupling a chelator moiety to a biomolecule such as protein or polysaccharide, and are not a single compound in production, handling, or the compound (the binding position of the chelator moiety is undefined). An aggregate of compounds having a certain distribution and different molecular weights) caused problems in metabolism and toxicity. Regarding organ selectivity, studies targeting organs are best studied.However, as a mechanism of uptake into the liver, a lipid-soluble group is added to the structural formula to increase lipid solubility and increase membrane permeability. There are many paramagnetic contrast agents designed to enhance the activity, and some of them have undergone clinical trials, but their efficiency in taking up into the liver and excreting bile is not so high. On the other hand, as a mechanism of incorporation into hepatocytes, studies of a contrast agent targeting asialoglycoprotein receptor (hereinafter abbreviated as GSGP-R) present in hepatocytes have been conducted. Tc-chelate albumin, an iron oxide colloid that resembles asialoglycoprotein (hereinafter abbreviated as GSGP), which is the original ligand of GSGP-R, and has a large number of terminal galactose residues, has been developed (for example, AJR , 155). , 1161 (199
0); Radiology , 178, 769 (199).
1)). Recently, DT with two galactose ends
PA derivatives were reported (ChemicalJour)
nal of China University
es, 18 , 1072 (1997)). In order to further enhance the efficiency of discrimination and uptake by the receptor, the molecule must have many terminal galactose residues bonded thereto. Incidentally, it is known that asialoorosomucoids derived from typical glycoproteins in human serum having a high affinity for lectin have 14 terminal galactose residues, and the DTP having two galactose ends described above is known.
It can also be expected from this that the A derivative has insufficient recognition and uptake efficiency by the receptor. Therefore, a new DTPA derivative with improved recognition and uptake efficiency by a receptor has been desired.
【０００４】[0004]
【課題を解決するための手段】本発明者らは、前述の目
的を達成すべく鋭意検討を重ねた結果、分子中に、生体
内在の受容体に認識、結合される、またはされない４個
以上の糖鎖を糖酸アミドとして含有したＤＴＰＡ誘導体
で上記課題が達成できることを初めて見出し、本発明を
完成するに至った。生体内在のレセプターに識別され得
る糖鎖としては、たとえば前述の肝実質細胞に対するガ
ラクトース残基をはじめ、肝クッパー細胞、線維芽細胞
に対するマンノース残基、ルイス肺癌細胞に対するαー
グルコース残基などを末端に含むものが挙げられ、これ
らを結合した本発明の化合物により対象とする臓器、
（病変）組織を選択的に造影することが可能となり、こ
れにより病変部位の存在診断のみならず悪性度等の鑑別
診断、場合によれば臓器の機能診断も行なえる。一方、
レセプターに取り込まれることのない任意の糖鎖を選
び、血液プール性を示すに充分な高分子量になる数だけ
結合することで血液プール性を付与された造影剤を製造
できる。もちろん、レセプターに識別される糖鎖を血液
プール性が現れるほど結合することも構わないし、むし
ろ対象臓器外への拡散が抑えられ、投与量の低減化等好
ましい効果が得られる場合もある。いずれにしても、本
発明の含糖鎖化合物は、ポリサッカライドを結合した従
来の造影剤と異なり単一化合物であるという大きな特徴
がある。Means for Solving the Problems The inventors of the present invention have conducted intensive studies to achieve the above-mentioned object, and as a result, in a molecule, four or more molecules that are recognized or bound to or not bound to a receptor existing in a living body. It has been found for the first time that the above-mentioned object can be achieved with a DTPA derivative containing a sugar chain as a sugar amide, and the present invention has been completed. Examples of sugar chains that can be identified as receptors in the body include, for example, the aforementioned galactose residues for hepatocytes, hepatic Kupffer cells, mannose residues for fibroblasts, and α-glucose residues for Lewis lung cancer cells. Including, the target organ by the compound of the present invention bound to them,
(Lesion) The tissue can be selectively contrasted, whereby not only the existence diagnosis of the lesion site but also the differential diagnosis of malignancy or the like, and in some cases, the function diagnosis of the organ can be performed. on the other hand,
An arbitrary sugar chain which is not taken up by the receptor is selected and bound by a number that has a high molecular weight sufficient to exhibit blood pooling properties, whereby a contrast agent having blood pooling properties can be produced. Needless to say, the sugar chain identified as a receptor may be bound to the extent that blood pool properties appear, or rather, diffusion outside the target organ may be suppressed, and a favorable effect such as a reduced dose may be obtained in some cases. In any case, the sugar chain compound of the present invention has a great feature that it is a single compound, unlike a conventional contrast agent to which a polysaccharide is bonded.
【０００５】即ち本発明の要旨は、下記一般式（１）That is, the gist of the present invention is that the following general formula (1)
【０００６】[0006]
【化３】 Embedded image
【０００７】（式中、Ｒは一般式−Ｎ（（ＣＨ2 ）k Ｎ
ＨＲ1 ）2 （式中、ｋは２から５の整数を表わし、Ｒ1
はベンジルオキシカルボニル基（以下「Ｚ基」と表すこ
ともある）、ｔ−ブチルオキシカルボニル基（以下「Ｂ
ｏｃ基」と表すこともある）、水素原子、または糖鎖ア
シル残基を表わす）、−ＮＨ（ＣＨ2 ）l Ｎ（（Ｃ
Ｈ2）k ＮＨＲ1 ）2 （式中、ｋ、Ｒ1 は上記と同義を
表わし、ｌはｋと同義を表わすが、ｋと同一でも異なっ
ていてもよい。）、−ＮＨＣＨm （ＣＨ2 ＡＲ2 ）3- m
（式中、ｍは０または１を表わし、Ａは単結合、−（Ｃ
Ｈ2 ）2 、−ＣＨ2 ＣＯ、−Ｏ（ＣＨ2 ）3 、−Ｏ（Ｃ
Ｈ2 ）2 ＣＯ、または−ＣＯを表わし、Ｒ2 は−ＮＨＲ
1 、−ＮＨ（ＣＨ2 ）k ＮＨＲ1 、−Ｎ（（ＣＨ2 ）k
ＮＨＲ1 ）2 、または−ＮＨ（ＣＨ2 ）l Ｎ（（Ｃ
Ｈ2 ）k ＮＨＲ1 ）2 （式中、ｋ、ｌおよびＲ1 は前記
と同義を表わす）。ただし、ｍが１を表わす時、Ａは−
ＣＯのみを表わす。）を表わす）で表わされるジエチレ
ントリアミン五酢酸誘導体；下記一般式（２）(Where R is a general formula -N ((CH 2 ) k N)
HR 1) 2 (wherein, k represents an integer of 2 to 5, R 1
Represents a benzyloxycarbonyl group (hereinafter sometimes referred to as “Z group”), a t-butyloxycarbonyl group (hereinafter “B”).
oc sometimes expressed as group "), represents a hydrogen atom or a sugar chain-acyl residues,), - NH (CH 2 ) l N ((C
H 2 ) k NHR 1 ) 2 (where k and R 1 have the same meanings as described above, and 1 has the same meaning as k, but may be the same or different from k.), —NHCH m (CH 2 AR 2) 3- m
(Wherein m represents 0 or 1, A is a single bond,-(C
H 2) 2, -CH 2 CO , -O (CH 2) 3, -O (C
H 2 ) 2 CO or —CO, and R 2 is —NHR
1, -NH (CH 2) k NHR 1, -N ((CH 2) k
NHR 1 ) 2 or —NH (CH 2 ) 1 N ((C
H 2 ) k NHR 1 ) 2 (where k, l and R 1 are as defined above). However, when m represents 1, A is-
Represents CO only. A) a diethylenetriaminepentaacetic acid derivative represented by the following general formula (2):
【０００８】[0008]
【化４】ＨＲ （２）HR (2)
【０００９】（式中、Ｒは上記と同義を表わす。但し、
Ｒ中Ｒ1 は水素原子を除いた意味を表わし、またＲが−
Ｎ（（ＣＨ2 ）k ＮＨＲ1 ）2 の時、Ｒ1 は糖鎖アシル
基を表わさない。Ｒ′は水素原子、Ｚ基、Ｂｏｃ基を表
わすが、Ｒ中にＺ基またはＢｏｃ基を有する場合には、
おのおのそれらの意味を表わさない。）で表わされるア
ミノ化合物；金属イオンと錯化した前記ＤＴＰＡ誘導
体；前記ＤＴＰＡ誘導体を必須成分とする造影剤；並び
に、前記ＤＴＰＡ誘導体及び薬学的に許容される担体を
含んでなる体内診断用医薬組成物に存する。(Wherein, R is as defined above, provided that
R, R 1 represents a meaning other than a hydrogen atom, and R is -
When N ((CH 2 ) k NHR 1 ) 2 , R 1 does not represent a sugar chain acyl group. R ′ represents a hydrogen atom, a Z group or a Boc group. When R has a Z group or a Boc group,
Each does not express their meaning. A) a DTPA derivative complexed with a metal ion; a contrast agent containing the DTPA derivative as an essential component; and a pharmaceutical composition for in vivo diagnosis comprising the DTPA derivative and a pharmaceutically acceptable carrier. Exist in things.
【００１０】本発明の好ましい態様として、前記誘導体
と錯化する金属イオンが、常磁性金属イオン及び放射性
金属イオンのいずれかからなる群より選択されること、
が挙げられる。In a preferred embodiment of the present invention, the metal ion complexing with the derivative is selected from the group consisting of a paramagnetic metal ion and a radioactive metal ion.
Is mentioned.
【００１１】[0011]
【発明の実施の形態】以下本発明につき詳細に説明す
る。DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.
【００１２】上記の定義において、Ｒ1 で定義される
「糖鎖アシル残基」としては、単一の糖カルボン酸のア
シル残基であれば特に制限はされないが、入手の容易さ
の点から、たとえば下記一般式（３）In the above definition, the “sugar chain acyl residue” defined by R 1 is not particularly limited as long as it is an acyl residue of a single sugar carboxylic acid, but from the viewpoint of availability. For example, the following general formula (3)
【００１３】[0013]
【化５】 Embedded image
【００１４】（式中、ｐは０〜１０の整数を表わす）で
表わされる単糖オリゴ糖（多糖）が好ましい。また、臓
器、組織選択性を付与したい場合には末端が（単糖の場
合にはそのものが）レセプターに対し親和性を示す糖単
位となった糖が選ばれる。具体例としては、Ｄ−グルコ
ン酸、Ｄ−ガラクトン酸、Ｄ−マンノン酸、Ｄ−フコン
酸等の単糖酸のアシル残基、Ｄ−マルトビオン酸、Ｄ−
ラクトビオン酸、などの二糖酸のアシル残基、（Ｇｌｃ
α１→４）q Ｇｌｃ（Ｇｌｃ：グルコース）で表わされ
るマルトトリオース（ｑ＝２）、マルトテトラオース
（ｑ＝３）、マルトペンタオース（ｑ＝４）、マルトヘ
キサオース（ｑ＝５）、マルトヘプタオース（ｑ＝
６）、等のオリゴ（多）糖の還元末端がカルボン酸に酸
化された糖酸のアシル残基などが挙げられる。A monosaccharide oligosaccharide (polysaccharide) represented by the formula (where p represents an integer of 0 to 10) is preferred. In addition, when it is desired to impart organ or tissue selectivity, a saccharide whose terminal is a saccharide unit exhibiting affinity for the receptor (in the case of a monosaccharide, itself) is selected. Specific examples include acyl residues of monosaccharide acids such as D-gluconic acid, D-galactonic acid, D-mannonic acid, D-fuconic acid, D-maltobionic acid, and D-maltobionic acid.
Acyl residues of disaccharide acids such as lactobionic acid, (Glc
α1 → 4) q Maltotriose (q = 2), maltotetraose (q = 3), maltopentaose (q = 4), maltohexaose (q = 5) represented by Glc (Glc: glucose), Maltoheptaose (q =
6), and the like, and an acyl residue of a sugar acid in which the reducing end of an oligo (poly) saccharide is oxidized to a carboxylic acid.
【００１５】以下、上記一般式（１）で表わされる化合
物の具体例を示す。ただし、糖鎖構成単位糖を略記号
（Ｇｌｃ：グルコース、Ｇａｌ：ガラクトース、Ｍａ
ｎ：マンノース）で表わすが、還元末端糖はＣＯを付し
アシル残基となっていることを示す。Hereinafter, specific examples of the compound represented by the general formula (1) will be shown. However, a sugar chain constituent unit sugar is represented by an abbreviation (Glc: glucose, Gal: galactose, Ma).
n: mannose), and shows that the reducing terminal sugar is CO and is an acyl residue.
【００１６】（１）Ｒ＝−Ｎ（（ＣＨ2 ）k ＮＨＲ1 ）
2 の場合 Ｒ＝−Ｎ（（ＣＨ2 ）2 ＮＨＺ）2 、−Ｎ（（ＣＨ2 ）
2 ＮＨＢｏｃ）2 、−Ｎ（（ＣＨ2 ）2 ＮＨ2 ）2 、−
Ｎ（（ＣＨ2 ）2 ＮＨＧｌｃＣＯ）2 、−Ｎ（（Ｃ
Ｈ2 ）2 ＮＨＧａｌＣＯ）2 、−Ｎ（（ＣＨ2 ）2 ＮＨ
（ＭａｎＣＯ））2、−Ｎ（（ＣＨ2 ）2 ＮＨ（Ｇａｌ
α１→４ＧｌｃＣＯ））2 、−Ｎ（（ＣＨ2）2 ＮＨ
（（Ｇｌｃα１→４）2 ＧｌｃＣＯ）2 、−Ｎ（（ＣＨ
2 ）2 ＮＨ（（Ｇｌｃα１→４）3 ＧｌｃＣＯ））2 、
−Ｎ（（ＣＨ2 ）2 ＮＨ（（Ｇｌｃα１→４）4 Ｇｌｃ
ＣＯ））2 、−Ｎ（（ＣＨ2 ）2 ＮＨ（（Ｇｌｃα１→
４）5 ＧｌｃＣＯ））2 、−Ｎ（（ＣＨ2 ）2 ＮＨ
（（Ｇｌｃα１→４）6 ＧｌｃＣＯ））2 、−Ｎ（（Ｃ
Ｈ2 ）3 ＮＨＺ）2 、−Ｎ（（ＣＨ2 ）3 ＮＨＢｏｃ）
2 、−Ｎ（（ＣＨ2 ）3 ＮＨ2 ）2 、−Ｎ（（ＣＨ2 ）
3 ＮＨＧａｌＣＯ）2 、−Ｎ（（ＣＨ2 ）3 ＮＨ（Ｍａ
ｎＣＯ））2 、−Ｎ（（ＣＨ2 ）3 ＮＨ（Ｇａｌα１→
４ＧｌｃＣＯ））2 、(1) R = -N ((CH 2 ) k NHR 1 )
2 where R = -N ((CH 2) 2 NHZ) 2, -N ((CH 2)
2 NHBoc) 2 , —N ((CH 2 ) 2 NH 2 ) 2 ,
N ((CH 2) 2 NHGlcCO ) 2, -N ((C
H 2) 2 NHGalCO) 2, -N ((CH 2) 2 NH
(ManCO)) 2 , —N ((CH 2 ) 2 NH (Gal
α1 → 4GlcCO)) 2 , —N ((CH 2 ) 2 NH
((Glcα1 → 4) 2 GlcCO) 2 , -N ((CH
2 ) 2 NH ((Glcα1 → 4) 3 GlcCO) 2 ,
-N ((CH 2 ) 2 NH ((Glcα1 → 4) 4 Glc
CO)) 2 , -N ((CH 2 ) 2 NH ((Glcα1 →
4) 5 GlcCO)) 2, -N ((CH 2) 2 NH
((Glcα1 → 4) 6 GlcCO)) 2 , −N ((C
H 2) 3 NHZ) 2, -N ((CH 2) 3 NHBoc)
2, -N ((CH 2) 3 NH 2) 2, -N ((CH 2)
3 NHGalCO) 2 , —N ((CH 2 ) 3 NH (Ma
nCO)) 2 , —N ((CH 2 ) 3 NH (Galα1 →
4GlcCO)) 2 ,
【００１７】（２）Ｒ＝−ＮＨ（ＣＨ2 ）l Ｎ（（ＣＨ
2 ）k ＮＨＲ1 ）2 の場合 −ＮＨ（ＣＨ2 ）2 Ｎ（（ＣＨ2 ）2 ＮＨＺ）2 、−Ｎ
Ｈ（ＣＨ2 ）2 Ｎ（（ＣＨ2 ）2 ＮＨＢｏｃ）2 、−Ｎ
Ｈ（ＣＨ2 ）2 Ｎ（（ＣＨ2 ）2 ＮＨ2 ）2 、−ＮＨ
（ＣＨ2 ）2 Ｎ（（ＣＨ2 ）2 ＮＨＧａｌＣＯ）2 、−
ＮＨ（ＣＨ2 ）2Ｎ（（ＣＨ2 ）2 ＮＨＭａｎＣ
Ｏ）2 、−ＮＨ（ＣＨ2 ）2 Ｎ（（ＣＨ2 ）2 ＮＨＧｌ
ｃＣＯ）2 、−ＮＨ（ＣＨ2 ）2 Ｎ（（ＣＨ2 ）2 ＮＨ
（Ｇａｌα１→４ＧｌｃＣＯ））2 、−ＮＨ（ＣＨ2 ）
2 Ｎ（（ＣＨ2 ）2 ＮＨ（（Ｇｌｃα１→４）2 Ｇｌｃ
ＣＯ））2 、−ＮＨ（ＣＨ2 ）2 Ｎ（（ＣＨ2 ）2 ＮＨ
（（Ｇｌｃα１→４）3 ＧｌｃＣＯ））2 、−ＮＨ（Ｃ
Ｈ2 ）2 Ｎ（（ＣＨ2 ）2 Ｎ（（Ｇｌｃα１→４）4 Ｇ
ｌｃＣＯ））2 、−ＮＨ（ＣＨ2 ）2 Ｎ（（ＣＨ2 ）2
ＮＨ（（Ｇｌｃα１→４）5 ＧｌｃＣＯ））2 、−ＮＨ
（ＣＨ2 ）2 Ｎ（（ＣＨ2 ） 2 Ｎ（（Ｇｌｃα１→４）
6 ＧｌｃＣＯ））2 、−ＮＨ（ＣＨ2 ）2 Ｎ（（Ｃ
Ｈ 2 ）3 ＮＨＺ）2 、−ＮＨ（ＣＨ2 ）2 Ｎ（（Ｃ
Ｈ2 ）3 ＮＨ2 ）2 、−ＮＨ（ＣＨ2 ）2 Ｎ（（Ｃ
Ｈ2 ）3 ＮＨＧａｌＣＯ）2 、−ＮＨ（ＣＨ2 ）2 Ｎ
（（ＣＨ2 ）3 ＮＨＭａｎＣＯ）2 、−ＮＨ（ＣＨ2 ）
2 Ｎ（（ＣＨ2 ）3 ＮＨ（Ｇａｌα１→４ＧｌｃＣ
Ｏ））2 、−ＮＨ（ＣＨ2 ）2 Ｎ（（ＣＨ2 ）3 ＮＨ
（（Ｇｌｃα１→４）2 ＧｌｃＣＯ））2 、−ＮＨ（Ｃ
Ｈ2 ）2 Ｎ（（ＣＨ2 ）3 ＮＨ（（Ｇｌｃα１→４）3
ＧｌｃＣＯ））2 、−ＮＨ（ＣＨ2 ）2 Ｎ（（ＣＨ2 ）
3 ＮＨ（（Ｇｌｃα１→４）4 ＧｌｃＣＯ））2 、−Ｎ
Ｈ（ＣＨ2 ）2 Ｎ（（ＣＨ2 ）3 ＮＨ（（Ｇｌｃα１→
４）5 ＧｌｃＣＯ））2 、−ＮＨ（ＣＨ2 ）2 Ｎ（（Ｃ
Ｈ2 ）3 ＮＨ（（Ｇｌｃα１→４）6 ＧｌｃＣ
Ｏ））2 、−ＮＨ（ＣＨ2）3 Ｎ（（ＣＨ2 ）2 ＮＨ
Ｚ）2 、−ＮＨ（ＣＨ2 ）3 Ｎ（（ＣＨ2 ）2 ＮＨ2）
2 、−ＮＨ（ＣＨ2 ）3 Ｎ（（ＣＨ2 ）2 ＮＨＧａｌＣ
Ｏ）2 、−ＮＨ（ＣＨ 2 ）3 Ｎ（（ＣＨ2 ）2 ＮＨＭａ
ｎＣＯ）2 、(2) R = -NH (CHTwo)lN ((CH
Two)kNHR1)TwoIn the case of -NH (CHTwo)TwoN ((CHTwo)TwoNHZ)Two, -N
H (CHTwo)TwoN ((CHTwo)TwoNHBoc)Two, -N
H (CHTwo)TwoN ((CHTwo)TwoNHTwo)Two, -NH
(CHTwo)TwoN ((CHTwo)TwoNHGalCO)Two, −
NH (CHTwo)TwoN ((CHTwo)TwoNHManC
O)Two, -NH (CHTwo)TwoN ((CHTwo)TwoNHGl
cCO)Two, -NH (CHTwo)TwoN ((CHTwo)TwoNH
(Galα1 → 4GlcCO))Two, -NH (CHTwo)
TwoN ((CHTwo)TwoNH ((Glcα1 → 4)TwoGlc
CO))Two, -NH (CHTwo)TwoN ((CHTwo)TwoNH
((Glcα1 → 4)ThreeGlcCO))Two, -NH (C
HTwo)TwoN ((CHTwo)TwoN ((Glcα1 → 4)FourG
lcCO))Two, -NH (CHTwo)TwoN ((CHTwo)Two
NH ((Glcα1 → 4)FiveGlcCO))Two, -NH
(CHTwo)TwoN ((CHTwo) TwoN ((Glcα1 → 4)
6GlcCO))Two, -NH (CHTwo)TwoN ((C
H Two)ThreeNHZ)Two, -NH (CHTwo)TwoN ((C
HTwo)ThreeNHTwo)Two, -NH (CHTwo)TwoN ((C
HTwo)ThreeNHGalCO)Two, -NH (CHTwo)TwoN
((CHTwo)ThreeNHManCO)Two, -NH (CHTwo)
TwoN ((CHTwo)ThreeNH (Galα1 → 4GlcC
O))Two, -NH (CHTwo)TwoN ((CHTwo)ThreeNH
((Glcα1 → 4)TwoGlcCO))Two, -NH (C
HTwo)TwoN ((CHTwo)ThreeNH ((Glcα1 → 4)Three
GlcCO))Two, -NH (CHTwo)TwoN ((CHTwo)
ThreeNH ((Glcα1 → 4)FourGlcCO))Two, -N
H (CHTwo)TwoN ((CHTwo)ThreeNH ((Glcα1 →
4)FiveGlcCO))Two, -NH (CHTwo)TwoN ((C
HTwo)ThreeNH ((Glcα1 → 4)6GlcC
O))Two, -NH (CHTwo)ThreeN ((CHTwo)TwoNH
Z)Two, -NH (CHTwo)ThreeN ((CHTwo)TwoNHTwo)
Two, -NH (CHTwo)ThreeN ((CHTwo)TwoNHGalC
O)Two, -NH (CH Two)ThreeN ((CHTwo)TwoNHMa
nCO)Two,
【００１８】 （３）Ｒ＝−ＮＨＣＨm （ＣＨ2 ＡＲ2 ）3-m の場合 １）ｍ＝０の時 （ａ）Ａ＝単結合の場合 −ＮＨＣ（ＣＨ2 Ｎ（（ＣＨ2 ）2 ＮＨＺ）2 ）3 、−
ＮＨＣ（ＣＨ2 Ｎ（（ＣＨ2 ）2 ＮＨ2 ）2 ）3 、−Ｎ
ＨＣ（ＣＨ2 Ｎ（（ＣＨ2 ）2 ＮＨＧａｌＣ
Ｏ）2 ）3 、−ＮＨＣ（ＣＨ2 Ｎ（（ＣＨ2 ）2 ＮＨＧ
ｌｃＣＯ）2 ）3 、−ＮＨＣ（ＣＨ2 Ｎ（（ＣＨ2 ）2
ＮＨＭａｎＣＯ）2 ）3 、−ＮＨＣ（ＣＨ2 Ｎ（（ＣＨ
2 ）2 ＮＨＧａｌα１→４ＧｌｃＣＯ）2 ）3 、−ＮＨ
Ｃ（ＣＨ2 Ｎ（（ＣＨ2 ）2 ＮＨＧｌｃα１→４Ｇｌｃ
ＣＯ）2 ）3 、−ＮＨＣ（ＣＨ2 Ｎ（（ＣＨ 2 ）2 ＮＨ
（Ｇｌｃα１→４）2 ＧｌｃＣＯ）2 ）3 、−ＮＨＣ
（ＣＨ2 Ｎ（（ＣＨ2 ）2 ＮＨ（Ｇｌｃα１→４）3 Ｇ
ｌｃＣＯ）2 ）3 、−ＮＨＣ（ＣＨ2 Ｎ（（ＣＨ2 ）2
ＮＨ（Ｇｌｃα１→４）4 ＧｌｃＣＯ）2 ）3 、−ＮＨ
Ｃ（ＣＨ 2 Ｎ（（ＣＨ2 ）2 ＮＨ（Ｇｌｃα１→４）5
ＧｌｃＣＯ）2 ）3 、−ＮＨＣ（ＣＨ2 Ｎ（（ＣＨ2 ）
3 ＮＨＺ）2 ）3 、−ＮＨＣ（ＣＨ2 Ｎ（（ＣＨ2 ）3
ＮＨ2 ）2 ）3 、−ＮＨＣ（ＣＨ2 Ｎ（（ＣＨ2 ）3 Ｎ
ＨＧａｌＣＯ）2 ）3 、ＮＨＣ（ＣＨ2 Ｎ（（ＣＨ2 ）
3 ＮＨＧｌｃＣＯ）2 ）3 、−ＮＨＣ（ＣＨ2 Ｎ（（Ｃ
Ｈ2 ）3 ＮＨＭａｎＣＯ）2 ）3 、−ＮＨＣ（ＣＨ2 Ｎ
（（ＣＨ2 ）3 ＮＨＧａｌα１→４ＧｌｃＣ
Ｏ）2 ）3 、−ＮＨＣ（ＣＨ2 Ｎ（（ＣＨ2 ）3 ＮＨＧ
ｌｃα１→４ＧｌｃＣＯ）2 ）3 、−ＮＨＣ（ＣＨ2 Ｎ
（（ＣＨ2 ）3 ＮＨ（Ｇｌｃα１→４）2 ＧｌｃＣＯ）
2 ）3 、−ＮＨＣ（ＣＨ2 Ｎ（（ＣＨ2 ）3 ＮＨ（Ｇｌ
ｃα１→４）3 ＧｌｃＣＯ）2 ）3 、−ＮＨＣ（ＣＨ2
Ｎ（（ＣＨ2 ）3ＮＨ（Ｇｌｃα１→４）4 ＧｌｃＣ
Ｏ）2 ）3 、(3) R = —NHCHm(CHTwoARTwo)3-m1) When m = 0 (a) When A = single bond —NHC (CHTwoN ((CHTwo)TwoNHZ)Two)Three, −
NHC (CHTwoN ((CHTwo)TwoNHTwo)Two)Three, -N
HC (CHTwoN ((CHTwo)TwoNHGalC
O)Two)Three, -NHC (CHTwoN ((CHTwo)TwoNHG
lcCO)Two)Three, -NHC (CHTwoN ((CHTwo)Two
NHManCO)Two)Three, -NHC (CHTwoN ((CH
Two)TwoNHGalα1 → 4GlcCO)Two)Three, -NH
C (CHTwoN ((CHTwo)TwoNHGlcα1 → 4Glc
CO)Two)Three, -NHC (CHTwoN ((CH Two)TwoNH
(Glcα1 → 4)TwoGlcCO)Two)Three, -NHC
(CHTwoN ((CHTwo)TwoNH (Glcα1 → 4)ThreeG
lcCO)Two)Three, -NHC (CHTwoN ((CHTwo)Two
NH (Glcα1 → 4)FourGlcCO)Two)Three, -NH
C (CH TwoN ((CHTwo)TwoNH (Glcα1 → 4)Five
GlcCO)Two)Three, -NHC (CHTwoN ((CHTwo)
ThreeNHZ)Two)Three, -NHC (CHTwoN ((CHTwo)Three
NHTwo)Two)Three, -NHC (CHTwoN ((CHTwo)ThreeN
HGalCO)Two)Three, NHC (CHTwoN ((CHTwo)
ThreeNHGlcCO)Two)Three, -NHC (CHTwoN ((C
HTwo)ThreeNHManCO)Two)Three, -NHC (CHTwoN
((CHTwo)ThreeNHGalα1 → 4GlcC
O)Two)Three, -NHC (CHTwoN ((CHTwo)ThreeNHG
lcα1 → 4GlcCO)Two)Three, -NHC (CHTwoN
((CHTwo)ThreeNH (Glcα1 → 4)TwoGlcCO)
Two)Three, -NHC (CHTwoN ((CHTwo)ThreeNH (Gl
cα1 → 4)ThreeGlcCO)Two)Three, -NHC (CHTwo
N ((CHTwo)ThreeNH (Glcα1 → 4)FourGlcC
O)Two)Three,
【００１９】（ｂ）Ａ＝−（ＣＨ2 ）2 の場合 −ＮＨＣ（（ＣＨ2 ）3 Ｎ（（ＣＨ2 ）2 ＮＨＺ）2 ）
3 、−ＮＨＣ（（ＣＨ 2 ）3 Ｎ（（ＣＨ2 ）2 ＮＨ2 ）
2 ）3 、−ＮＨＣ（（ＣＨ2 ）3 Ｎ（（ＣＨ2）3 ＮＨ
Ｚ）2 ）3 、−ＮＨＣ（（ＣＨ2 ）3 Ｎ（（ＣＨ2 ）3
ＮＨ2 ）2 ）3、−ＮＨＣ（（ＣＨ2 ）3 Ｎ（（Ｃ
Ｈ2 ）2 ＮＨＧｌｃＣＯ）2 ）3 、−ＮＨＣ（（Ｃ
Ｈ2 ）3 Ｎ（（ＣＨ2 ）2 ＮＨＧａｌＣＯ）2 ）3 、−
ＮＨＣ（（ＣＨ2）3 Ｎ（（ＣＨ2 ）2 ＮＨＧｌｃα１
→４ＧｌｃＣＯ）2 ）3 、−ＮＨＣ（（ＣＨ2 ）3 Ｎ
（（ＣＨ2 ）2 ＮＨ（Ｇｌｃα１→４）2 ＧｌｃＣＯ）
2 ）3 、−ＮＨＣ（（ＣＨ2 ）3 Ｎ（（ＣＨ2 ）2 ＮＨ
（Ｇｌｃα１→４）3 ＧｌｃＣＯ）2）3 、−ＮＨＣ
（（ＣＨ2 ）3 Ｎ（（ＣＨ2 ）2 ＮＨ（Ｇｌｃα１→
４）4 ＧｌｃＣＯ）2 ）3 (B) A =-(CHTwo)TwoIn the case of -NHC ((CHTwo)ThreeN ((CHTwo)TwoNHZ)Two)
Three, -NHC ((CH Two)ThreeN ((CHTwo)TwoNHTwo)
Two)Three, -NHC ((CHTwo)ThreeN ((CHTwo)ThreeNH
Z)Two)Three, -NHC ((CHTwo)ThreeN ((CHTwo)Three
NHTwo)Two)Three, -NHC ((CHTwo)ThreeN ((C
HTwo)TwoNHGlcCO)Two)Three, -NHC ((C
HTwo)ThreeN ((CHTwo)TwoNHGalCO)Two)Three, −
NHC ((CHTwo)ThreeN ((CHTwo)TwoNHGlcα1
(→ 4GlcCO)Two)Three, -NHC ((CHTwo)ThreeN
((CHTwo)TwoNH (Glcα1 → 4)TwoGlcCO)
Two)Three, -NHC ((CHTwo)ThreeN ((CHTwo)TwoNH
(Glcα1 → 4)ThreeGlcCO)Two)Three, -NHC
((CHTwo)ThreeN ((CHTwo)TwoNH (Glcα1 →
4)FourGlcCO)Two)Three
【００２０】（ｃ）Ａ＝−ＣＨ2 ＣＯの場合 −ＮＨＣ（（ＣＨ2 ）2 ＣＯＮＨ（ＣＨ2 ）2 ＮＨＺ）
3 、−ＮＨＣ（（ＣＨ 2 ）2 ＣＯＮＨ（ＣＨ2 ）Ｎ
Ｈ2 ）3 、−ＮＨＣ（（ＣＨ2 ）2 ＣＯＮ（（ＣＨ 2 ）
2 ＮＨＺ）2 ）3 、−ＮＨＣ（（ＣＨ2 ）2 ＣＯＮ
（（ＣＨ2 ）2 ＮＨ2 ） 2 ）3 、−ＮＨＣ（（ＣＨ2 ）
2 ＣＯＮ（（ＣＨ2 ）2 ＮＨＧｌｃＣＯ）2 ）3、−Ｎ
ＨＣ（（ＣＨ2 ）2 ＣＯＮ（（ＣＨ2 ）2 ＮＨＧａｌＣ
Ｏ）2 ）3 、−ＮＨＣ（（ＣＨ2 ）2 ＣＯＮ（（Ｃ
Ｈ2 ）2 ＮＨＭａｎＣＯ）2 ）3 、−ＮＨＣ（（Ｃ
Ｈ2 ）2 ＣＯＮ（（ＣＨ2 ）2 ＮＨＧｌｃα１→４Ｇｌ
ｃＣＯ）2 ）3 、−ＮＨＣ（（ＣＨ2 ）2 ＣＯＮ（（Ｃ
Ｈ2 ）2 ＮＨＧａｌα１→４ＧｌｃＣＯ）2）3 、−Ｎ
ＨＣ（（ＣＨ2 ）2 ＣＯＮ（（ＣＨ2 ）2 ＮＨ（Ｇａｌ
α１→４）ＧｌｃＣＯ）2 ）3 、−ＮＨＣ（（ＣＨ2 ）
2 ＣＯＮ（（ＣＨ2 ）2 ＮＨ（Ｇｌｃα１→４）Ｇｌｃ
ＣＯ）2 ）3 、−ＮＨＣ（（ＣＨ2 ）2 ＣＯＮ（（ＣＨ
2 ）2ＮＨ（Ｇｌｃα１→４）4 ＧｌｃＣＯ）2 ）3 、
−ＮＨＣ（（ＣＨ2 ）2 ＣＯＮ（（ＣＨ2 ）2 ＮＨ（Ｇ
ｌｃα１→４）5 ＧｌｃＣＯ）2 ）3 、−ＮＨＣ（（Ｃ
Ｈ2 ）2 ＣＯＮ（（ＣＨ2 ）3 ＮＨＺ）2 ）3 、−ＮＨ
Ｃ（（ＣＨ2 ）2 ＣＯＮ（ＣＨ2 ）3 ＮＨ2 ）2 ）3 、(C) A = -CHTwoIn the case of CO -NHC ((CHTwo)TwoCONH (CHTwo)TwoNHZ)
Three, -NHC ((CH Two)TwoCONH (CHTwo) N
HTwo)Three, -NHC ((CHTwo)TwoCON ((CH Two)
TwoNHZ)Two)Three, -NHC ((CHTwo)TwoCON
((CHTwo)TwoNHTwo) Two)Three, -NHC ((CHTwo)
TwoCON ((CHTwo)TwoNHGlcCO)Two)Three, -N
HC ((CHTwo)TwoCON ((CHTwo)TwoNHGalC
O)Two)Three, -NHC ((CHTwo)TwoCON ((C
HTwo)TwoNHManCO)Two)Three, -NHC ((C
HTwo)TwoCON ((CHTwo)TwoNHGlcα1 → 4Gl
cCO)Two)Three, -NHC ((CHTwo)TwoCON ((C
HTwo)TwoNHGalα1 → 4GlcCO)Two)Three, -N
HC ((CHTwo)TwoCON ((CHTwo)TwoNH (Gal
α1 → 4) GlcCO)Two)Three, -NHC ((CHTwo)
TwoCON ((CHTwo)TwoNH (Glcα1 → 4) Glc
CO)Two)Three, -NHC ((CHTwo)TwoCON ((CH
Two)TwoNH (Glcα1 → 4)FourGlcCO)Two)Three,
-NHC ((CHTwo)TwoCON ((CHTwo)TwoNH (G
lcα1 → 4)FiveGlcCO)Two)Three, -NHC ((C
HTwo)TwoCON ((CHTwo)ThreeNHZ)Two)Three, -NH
C ((CHTwo)TwoCON (CHTwo)ThreeNHTwo)Two)Three,
【００２１】（ｄ）Ａ＝−Ｏ（ＣＨ2 ）3 の場合 −ＮＨＣ（ＣＨ2 Ｏ（ＣＨ2 ）3 ＮＨＺ）3 、−ＮＨＣ
（ＣＨ2 Ｏ（ＣＨ2 ） 3 ＮＨ2 ）3 、−ＮＨＣ（ＣＨ2
Ｏ（ＣＨ2 ）3 ＮＨＢｏｃ）3 、−ＮＨＣ（ＣＨ2 Ｏ
（ＣＨ2 ）3 ＮＨＧｌｃＣＯ）3 、−ＮＨＣ（ＣＨ2 Ｏ
（ＣＨ2 ）3 ＮＨＧａｌＣＯ）3 、−ＮＨＣ（ＣＨ2 Ｏ
（ＣＨ2 ）3 ＮＨＭａｎＣＯ）3 、−ＮＨＣ（ＣＨ2 Ｏ
（ＣＨ2 ）3 ＮＨＧｌｃα１→４ＧｌｃＣＯ）3 、−Ｎ
ＨＣ（ＣＨ 2 Ｏ（ＣＨ2 ）3 ＮＨＧａｌα１→４Ｇｌｃ
ＣＯ）3 、−ＮＨＣ（ＣＨ2 Ｏ（ＣＨ2 ）3 ＮＨ（Ｇｌ
ｃα１→４）2 ＧｌｃＣＯ）3 、−ＮＨＣ（ＣＨ2 Ｏ
（ＣＨ 2 ）3 ＮＨ（Ｇｌｃα１→４）3 ＧｌｃＣ
Ｏ）3 、−ＮＨＣ（ＣＨ2 Ｏ（ＣＨ2）4 ＮＨ（Ｇｌｃ
α１→４）4 ＧｌｃＣＯ）3 (D) A = -O (CHTwo)ThreeIn the case of -NHC (CHTwoO (CHTwo)ThreeNHZ)Three, -NHC
(CHTwoO (CHTwo) ThreeNHTwo)Three, -NHC (CHTwo
O (CHTwo)ThreeNHBoc)Three, -NHC (CHTwoO
(CHTwo)ThreeNHGlcCO)Three, -NHC (CHTwoO
(CHTwo)ThreeNHGalCO)Three, -NHC (CHTwoO
(CHTwo)ThreeNHManCO)Three, -NHC (CHTwoO
(CHTwo)ThreeNHGlcα1 → 4GlcCO)Three, -N
HC (CH TwoO (CHTwo)ThreeNHGalα1 → 4Glc
CO)Three, -NHC (CHTwoO (CHTwo)ThreeNH (Gl
cα1 → 4)TwoGlcCO)Three, -NHC (CHTwoO
(CH Two)ThreeNH (Glcα1 → 4)ThreeGlcC
O)Three, -NHC (CHTwoO (CHTwo)FourNH (Glc
α1 → 4)FourGlcCO)Three
【００２２】（ｅ）Ａ＝−Ｏ（ＣＨ2 ）2 ＣＯの場合 −ＮＨＣ（ＣＨ2 Ｏ（ＣＨ2 ）2 ＣＯＮ（（ＣＨ2 ）2
ＮＨＺ）2 ）3 、−ＮＨＣ（ＣＨ2 Ｏ（ＣＨ2 ）2 ＣＯ
Ｎ（（ＣＨ2 ）2 ＮＨ2 ）2 ）3 、−ＮＨＣ（ＣＨ2 Ｏ
（ＣＨ2 ）2 ＣＯＮ（（ＣＨ2 ）2 ＮＨＢｏ
ｃ）2 ）3 、−ＮＨＣ（ＣＨ2 Ｏ（ＣＨ2 ）2 ＣＯＮ
（（ＣＨ2 ）2 ＮＨＧｌｃＣＯ）2 ）3 、−ＮＨＣ（Ｃ
Ｈ2 Ｏ（ＣＨ2 ）2 ＣＯＮ（（ＣＨ2 ）2 ＮＨＧａｌＣ
Ｏ）2 ）3 、−ＮＨＣ（ＣＨ2 Ｏ（ＣＨ2 ）2 ＣＯＮ
（（ＣＨ2 ）2 ＮＨＭａｎＣＯ）2 ）3 、−ＮＨＣ（Ｃ
Ｈ2 Ｏ（ＣＨ2 ）2 ＣＯＮ（（ＣＨ2 ）2 ＮＨＧｌｃα
１→４ＧｌｃＣＯ）2 ）3 、−ＮＨＣ（ＣＨ2 Ｏ（ＣＨ
2 ）2 ＣＯＮ（（ＣＨ2 ）2 ＮＨＧａｌα１→４Ｇｌｃ
ＣＯ）2 ）3 、−ＮＨＣ（ＣＨ2 Ｏ（ＣＨ2 ）2 ＣＯＮ
（（ＣＨ2）2 ＮＨ（Ｇｌｃα１→４）2 ＧｌｃＣＯ）
2 ）3 、−ＮＨＣ（ＣＨ2 Ｏ（ＣＨ 2 ）2 ＣＯＮ（（Ｃ
Ｈ2 ）2 ＮＨ（Ｇｌｃα１→４）3 ＧｌｃＣ
Ｏ）2 ）3 、−ＮＨＣ（ＣＨ2 Ｏ（ＣＨ2 ）2 ＣＯＮ
（（ＣＨ2 ）2 ＮＨ（Ｇｌｃα１→４）4ＧｌｃＣＯ）
2 ）3 、−ＮＨＣ（ＣＨ2 Ｏ（ＣＨ2 ）2 ＣＯＮ（（Ｃ
Ｈ2 ）3 ＮＨＺ）2 ）3 、−ＮＨＣ（ＣＨ2 Ｏ（Ｃ
Ｈ2 ）2 ＣＯＮ（（ＣＨ2 ）3 ＮＨ2 ） 2 ）3 、−ＮＨ
Ｃ（ＣＨ2 Ｏ（ＣＨ2 ）2 ＣＯＮ（（ＣＨ2 ）3 ＮＨＢ
ｏｃ）2）3 、−ＮＨＣ（ＣＨ2 Ｏ（ＣＨ2 ）2 ＣＯＮ
（（ＣＨ2 ）4 ＮＨＺ）2 ）3 、−ＮＨＣ（ＣＨ2 Ｏ
（ＣＨ2 ）2 ＣＯＮ（（ＣＨ2 ）4 ＮＨ2 ）2 ）3 (E) A = -O (CHTwo)TwoIn the case of CO -NHC (CHTwoO (CHTwo)TwoCON ((CHTwo)Two
NHZ)Two)Three, -NHC (CHTwoO (CHTwo)TwoCO
N ((CHTwo)TwoNHTwo)Two)Three, -NHC (CHTwoO
(CHTwo)TwoCON ((CHTwo)TwoNHBo
c)Two)Three, -NHC (CHTwoO (CHTwo)TwoCON
((CHTwo)TwoNHGlcCO)Two)Three, -NHC (C
HTwoO (CHTwo)TwoCON ((CHTwo)TwoNHGalC
O)Two)Three, -NHC (CHTwoO (CHTwo)TwoCON
((CHTwo)TwoNHManCO)Two)Three, -NHC (C
HTwoO (CHTwo)TwoCON ((CHTwo)TwoNHGlcα
1 → 4GlcCO)Two)Three, -NHC (CHTwoO (CH
Two)TwoCON ((CHTwo)TwoNHGalα1 → 4Glc
CO)Two)Three, -NHC (CHTwoO (CHTwo)TwoCON
((CHTwo)TwoNH (Glcα1 → 4)TwoGlcCO)
Two)Three, -NHC (CHTwoO (CH Two)TwoCON ((C
HTwo)TwoNH (Glcα1 → 4)ThreeGlcC
O)Two)Three, -NHC (CHTwoO (CHTwo)TwoCON
((CHTwo)TwoNH (Glcα1 → 4)FourGlcCO)
Two)Three, -NHC (CHTwoO (CHTwo)TwoCON ((C
HTwo)ThreeNHZ)Two)Three, -NHC (CHTwoO (C
HTwo)TwoCON ((CHTwo)ThreeNHTwo) Two)Three, -NH
C (CHTwoO (CHTwo)TwoCON ((CHTwo)ThreeNHB
oc)Two)Three, -NHC (CHTwoO (CHTwo)TwoCON
((CHTwo)FourNHZ)Two)Three, -NHC (CHTwoO
(CHTwo)TwoCON ((CHTwo)FourNHTwo)Two)Three
【００２３】２）ｍ＝１の時 −ＮＨＣＨ（ＣＨ2 ＣＯＮ（（ＣＨ2 ）2 ＮＨＺ）2 ）
2 、−ＮＨＣＨ（ＣＨ 2 ＣＯＮ（（ＣＨ2 ）2 ＮＨ2 ）
2 ）2 、−ＮＨＣＨ（ＣＨ2 ＣＯＮ（（ＣＨ2）2 ＮＨ
ＧａｌＣＯ）2 ）2 、−ＮＨＣＨ（ＣＨ2 ＣＯＮ（（Ｃ
Ｈ2 ）2 ＮＨＭａｎＣＯ）2 ）2 、−ＮＨＣＨ（ＣＨ2
ＣＯＮ（（ＣＨ2 ）2 ＮＨ（Ｇａｌα１→４ＧｌｃＣ
Ｏ）2 ）2 ）2 、−ＮＨＣＨ（ＣＨ2 ＣＯＮ（（Ｃ
Ｈ2 ）2 ＮＨ（Ｇｌｃα１→４ＧｌｃＣ
Ｏ）2 ）2 ）2 、−ＮＨＣＨ（ＣＨ2 ＣＯＮ（ＣＨ2 ）
2 ＮＨ（Ｇｌｃα１→４）2 ＧｌｃＣＯ）2 ）2 、−Ｎ
ＨＣＨ（ＣＨ2 ＣＯＮ（（ＣＨ2 ）2 Ｎ（（Ｇｌｃα１
→４）4 ＧｌｃＣＯ）2 ）2 、−ＮＨＣＨ（ＣＨ 2 ＣＯ
ＮＨ（ＣＨ2 ）2 ＮＨＺ）2 、−ＮＨＣＨ（ＣＨ2 ＣＯ
ＮＨ（ＣＨ2 ）2ＮＨ2 ）2 、−ＮＨＣＨ（ＣＨ2 ＣＯ
ＮＨ（ＣＨ2 ）2 ＮＨＧａｌα１→４ＧｌｃＣＯ）2 、
−ＮＨＣＨ（ＣＨ2 ＣＯＮＨ（ＣＨ2 ）2 ＮＨ（Ｇａｌ
α１→４） 4 ＧｌｃＣＯ）2 、−ＮＨＣＨ（ＣＨ2 ＣＯ
ＮＨ（ＣＨ2 ）2 Ｎ（（ＣＨ2 ）2ＮＨＺ）2 ）2 、−
ＮＨＣＨ（ＣＨ2 ＣＯＮＨ（ＣＨ2 ）2 Ｎ（（ＣＨ2 ）
2 ＮＨ2 ）2 ）2 、−ＮＨＣＨ（ＣＨ2 ＣＯＮＨ（ＣＨ
2 ）2 Ｎ（（ＣＨ2 ）2 ＮＨＧａｌα１→４ＧｌｃＣ
Ｏ）2 ）2 、−ＮＨＣＨ（ＣＨ2 ＣＯＮＨ（ＣＨ2 ）2
Ｎ（（ＣＨ2 ）2 ＮＨ（Ｇｌｃα１→４）4 ＧｌｃＣ
Ｏ）2 ）2 、2) When m = 1: -NHCH (CHTwoCON ((CHTwo)TwoNHZ)Two)
Two, -NHCH (CH TwoCON ((CHTwo)TwoNHTwo)
Two)Two, -NHCH (CHTwoCON ((CHTwo)TwoNH
GalCO)Two)Two, -NHCH (CHTwoCON ((C
HTwo)TwoNHManCO)Two)Two, -NHCH (CHTwo
CON ((CHTwo)TwoNH (Galα1 → 4GlcC
O)Two)Two)Two, -NHCH (CHTwoCON ((C
HTwo)TwoNH (Glcα1 → 4GlcC
O)Two)Two)Two, -NHCH (CHTwoCON (CHTwo)
TwoNH (Glcα1 → 4)TwoGlcCO)Two)Two, -N
HCH (CHTwoCON ((CHTwo)TwoN ((Glcα1
→ 4)FourGlcCO)Two)Two, -NHCH (CH TwoCO
NH (CHTwo)TwoNHZ)Two, -NHCH (CHTwoCO
NH (CHTwo)TwoNHTwo)Two, -NHCH (CHTwoCO
NH (CHTwo)TwoNHGalα1 → 4GlcCO)Two,
-NHCH (CHTwoCONH (CHTwo)TwoNH (Gal
α1 → 4) FourGlcCO)Two, -NHCH (CHTwoCO
NH (CHTwo)TwoN ((CHTwo)TwoNHZ)Two)Two, −
NHCH (CHTwoCONH (CHTwo)TwoN ((CHTwo)
TwoNHTwo)Two)Two, -NHCH (CHTwoCONH (CH
Two)TwoN ((CHTwo)TwoNHGalα1 → 4GlcC
O)Two)Two, -NHCH (CHTwoCONH (CHTwo)Two
N ((CHTwo)TwoNH (Glcα1 → 4)FourGlcC
O)Two)Two,
【００２４】次に本発明の化合物の製法について説明す
る。一般式（１）で表わされる化合物（以下、化合物
（１）と略記する）は、たとえば一般式（２）で表わさ
れる化合物（以下、化合物（２）と略記する）の内Ｒ′
＝水素原子である化合物とＤＴＰＡジ無水物と水、ｉ−
プロピルアルコール、ジメチルホルムアミド（ＤＭ
Ｆ）、ジメチルスルホキシド（ＤＭＳＯ）など適当な溶
媒中、−５０℃から２００℃、好ましくは−３０℃から
５０℃で、３０分から５日間、好ましくは１時間から２
４時間反応させる方法により製造でき、また、Ｒ′が
Ｚ、Ｂｏｃ基である化合物（２）を経てＲ′が水素原子
である化合物（２）が製造できるので、まず、Ｒ′が水
素原子である化合物（２）の製法を説明する。なお、一
般式ＨＮ（（ＣＨ 2 ）k ＮＨＲ1 で表わされるアミノ化
合物の内、Ｒ1 がＧｌｃＣＯ、ｋが３である化合物など
は文献既知（Ａｎａｌｙｔｉｃａｌ Ｂｉｏｃｈｅｍｉ
ｓｔｒｙ，１３０，４８５（１９８３）参照）であり、
文献に現れない他の糖鎖化合物も同様の方法にて製造で
きる。Next, the method for producing the compound of the present invention will be described.
You. A compound represented by the general formula (1) (hereinafter, compound
(Abbreviated as (1)) is represented, for example, by the general formula (2).
Of the compounds (hereinafter abbreviated as compound (2))
= Hydrogen atom compound, DTPA dianhydride and water, i-
Propyl alcohol, dimethylformamide (DM
F), dimethyl sulfoxide (DMSO)
In a medium, from -50 ° C to 200 ° C, preferably from -30 ° C
At 50 ° C., for 30 minutes to 5 days, preferably 1 hour to 2 days
The reaction can be carried out for 4 hours.
R 'is a hydrogen atom via compound (2) which is a Z or Boc group
First, R ′ can be prepared from water
The method for producing compound (2), which is an elemental atom, will be described. In addition, one
The general formula HN ((CH Two)kNHR1Amination represented by
R in the compound1Is GlcCO, a compound in which k is 3, etc.
Is known in the literature (Analytical Biochemi)
try,130, 485 (1983)).
Other sugar chain compounds that do not appear in the literature can be manufactured in a similar manner.
Wear.
【００２５】 （１）Ｒ＝−Ｎ（（ＣＨ2 ）k ＮＨＲ1 ）2 の場合 たとえば、スキーム１の方法により製造できる。スキー
ム１(1) When R = —N ((CH 2 ) k NHR 1 ) 2 For example, it can be produced by the method of Scheme 1. Scheme 1
【００２６】[0026]
【化６】 Embedded image
【００２７】（式中、Ｒ1 はＺまたはＢｏｃを、ＸはＣ
ｌまたはＢｒを表わす）すなわち、ジアミンＨ2 Ｎ（Ｃ
Ｈ2 ）k ＮＨ2 から容易に製造できる一般式（Ａ）で表
わされる化合物（以下、化合物（Ａ）と略記）とハロゲ
ン化アルキルアミンのハロゲン化水素酸塩より調製でき
る一般式（Ｂ）で表わされる化合物（以下、化合物
（Ｂ）と略記）とをトリエチルアミン、ジイソプロピル
エチルアミン等の有機塩基、炭酸水素ナトリウム等の無
機塩基の存在下、テトラヒドロフラン、エタノール等適
当な溶媒中、反応させることにより化合物（２ａ）が製
造できる。３級アミンの副生を抑えるためには化合物
（Ａ）を過剰に用いるのが好ましい。この場合、過剰の
化合物（Ａ）が塩基の役割をはたすため、塩基を用いな
くてもよい。 （２）Ｒ＝−ＮＨ（ＣＨ2 ）l Ｎ（（ＣＨ2 ）k ＮＨＲ
1 ）2 の場合 たとえば、スキーム２の経路により製造できる。スキー
ム２(Wherein R 1 is Z or Boc, X is C
l or Br), that is, diamine H 2 N (C
H 2 ) k A compound represented by the general formula (A) which can be easily produced from NH 2 (hereinafter abbreviated as compound (A)) and a general formula (B) which can be prepared from a hydrohalide of a halogenated alkylamine. A compound represented by the formula (hereinafter abbreviated as compound (B)) is reacted with an appropriate base such as tetrahydrofuran or ethanol in the presence of an organic base such as triethylamine or diisopropylethylamine or an inorganic base such as sodium hydrogen carbonate. 2a) can be manufactured. In order to suppress the tertiary amine by-product, it is preferable to use the compound (A) in excess. In this case, since the excess compound (A) plays the role of a base, it is not necessary to use a base. (2) R = —NH (CH 2 ) 1 N ((CH 2 ) k NHR
1 ) In the case of 2 , for example, it can be produced by the route of Scheme 2. Scheme 2
【００２８】[0028]
【化７】 Embedded image
【００２９】（式中、Ｒ3 、Ｒ4 はＺまたはＢｏｃを、
ＸはＣｌまたはＢｒを表わす） すなわち、化合物（Ａ）あるいは（Ｂ）の製造に用いた
のと同様の反応で調製できる、あるいは同一の化合物で
ある一般式（Ｃ）、（Ｄ）で表わされる化合物（それぞ
れ、化合物（Ｃ）、（Ｄ）と略記する）を（１）と同様
な反応に付し、一般式（Ｅ）で表わされる化合物（以
下、化合物（Ｅ）と略記）を製造できる。この際、化合
物（Ｃ）および（Ｄ）中のＲ3 とＲ4 が表わすＺ基とＢ
ｏｃ基は互いに異なる組み合わせとなる化合物を用い
る。化合物（Ｅ）から、Ｒ3 がＢｏｃ基である場合は、
Ｚ基存在下Ｂｏｃ基脱保護の行なえる方法（Ｐｒｏｔｅ
ｃｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ
Ｓｙｎｔｈｅｓｉｓ，Ｔ．Ｗ．Ｇｒｅｅｎｅ，Ｐ．Ｇ．
Ｍ．Ｗｕｔｓ，Ｊｏｈｎ Ｗｉｌｅｙ ＆ Ｓｏｎｓ，
Ｉｎｃ．１９９１，参照）、たとえば塩化メチレン等適
当な溶媒中、あるいは無溶媒でトリフルオロ酢酸を作用
させる、酢酸、酢酸エチル等適当な溶媒中、塩化水素あ
るいは臭化水素酸を作用させるなどにより、またＲ3 が
Ｚ基である場合には、Ｐｄ触媒の存在下、加水素分解を
行なう方法などによりＲ3 を除去し、Ｒ1がＺ基または
Ｂｏｃ基である化合物（２ｂ）を製造できる。また、化
合物（Ｅ）から、前記の方法を用い、Ｒ4 の除去を行な
い一般式（Ｆ）で表わされる化合物（以下、化合物
（Ｆ）と略記する）を製造できる。化合物（Ｆ）から
は、たとえば、下記一般式（４）で表わされる糖ラクト
ン化合物（以下、「化合物（４）」と略記する）、ｐは
前記と同義を表わす。(Wherein R 3 and R 4 represent Z or Boc,
X represents Cl or Br) That is, it can be prepared by the same reaction as used in the production of compound (A) or (B), or is the same compound represented by formulas (C) and (D) Compounds (abbreviated as compounds (C) and (D), respectively) are subjected to the same reaction as in (1) to produce a compound represented by the general formula (E) (hereinafter abbreviated as compound (E)). . At this time, Z group represented by R 3 and R 4 in compounds (C) and (D) and B
As the oc group, compounds having different combinations are used. From the compound (E), when R 3 is a Boc group,
Method that can perform Boc group deprotection in the presence of Z group (Prote
cctive Groups in Organic
Synthesis, T .; W. Greene, P .; G. FIG.
M. Wuts, John Wiley & Sons,
Inc. 1991, trifluoroacetic acid in a suitable solvent such as methylene chloride or without a solvent, hydrogen chloride or hydrobromic acid in a suitable solvent such as acetic acid and ethyl acetate, and the like. When 3 is a Z group, the compound (2b) in which R 1 is a Z group or a Boc group can be produced by removing R 3 by a method of performing hydrogenolysis in the presence of a Pd catalyst. Further, from the compound (E), the compound represented by the general formula (F) (hereinafter abbreviated as compound (F)) can be produced by removing R 4 using the above-mentioned method. From the compound (F), for example, a sugar lactone compound represented by the following general formula (4) (hereinafter abbreviated as “compound (4)”), and p has the same meaning as described above.
【００３０】[0030]
【化８】 Embedded image
【００３１】との縮合反応により一般式（Ｇ）で表わさ
れる化合物（以下、化合物（Ｇ）と略記）を製造でき
る。The compound represented by formula (G) (hereinafter abbreviated as compound (G)) can be produced by a condensation reaction with
【００３２】化合物（４）は市販品を入手できるものも
あるが、対応する市販の糖類から、たとえばアルカリ性
条件下、臭素、ヨウ素などで酸化して得られる糖酸を脱
水する通常の方法で製造できる。この脱水反応はたとえ
ば糖酸にメタノール、エタノールなどのアルコールを加
え減圧蒸留を繰り返しトルエンで共沸脱水するなど簡単
な操作によって行なえる。化合物（４）と化合物（Ｆ）
との縮合反応は、たとえば両者をメタノール、エタノー
ル、エチレングリコールなどのアルコール系溶媒、ジメ
チルホルムアミド、ジメチルスルホキシドなどの非プロ
トン性極性溶媒など適当な溶媒中、−５０℃から２００
℃、好ましくは室温から１５０℃で、場合によってはＮ
ａＣＮなど適当な触媒の存在下、１０分から１２０時
間、好ましくは１時間から１０時間反応させ製造でき
る。また、反応性の低いアミンの場合は、高圧下の反応
（Ｂｕｌｌ．Ｓｏｃ．Ｃｈｅｍ．Ｊｐｎ．，６２，３１
３８（１９８９）参照）も利用できる。また、化合物
（４）の代りに糖酸のγ−ラクトン、グルクロン酸ラク
トンなどの糖酸ラクトンの使用も可能である。Compound (4) may be a commercially available product, but is produced from a corresponding commercially available saccharide by a conventional method of dehydrating a sugar acid obtained by oxidation with, for example, bromine or iodine under alkaline conditions. it can. This dehydration reaction can be performed by a simple operation, for example, adding alcohol such as methanol or ethanol to a sugar acid, repeating distillation under reduced pressure, and performing azeotropic dehydration with toluene. Compound (4) and compound (F)
The condensation reaction is carried out in a suitable solvent such as an alcoholic solvent such as methanol, ethanol and ethylene glycol, and an aprotic polar solvent such as dimethylformamide and dimethylsulfoxide.
° C, preferably from room temperature to 150 ° C, optionally with N
The reaction can be carried out in the presence of a suitable catalyst such as aCN for 10 minutes to 120 hours, preferably 1 hour to 10 hours. In the case of an amine having low reactivity, the reaction under high pressure (Bull. Soc. Chem. Jpn., 62 , 31)
38 (1989)). In addition, sugar acid lactones such as sugar acid γ-lactone and glucuronic acid lactone can be used in place of compound (4).
【００３３】化合物（Ｇ）から、前述した方法によりＺ
基あるいはＢｏｃ基を除去しＲ1 が糖鎖アシル残基であ
る化合物（２ｂ）を製造できる。From the compound (G), Z was prepared by the method described above.
The compound (2b) wherein R 1 is a sugar chain acyl residue can be produced by removing the group or Boc group.
【００３４】 （３）Ｒ＝−ＮＨＣＨm （ＣＨ2 ＡＲ2 ）3-m の場合 １）ｍ＝０の時 （ａ）Ａ＝単結合の場合 たとえば、スキーム３の経路により製造できる。スキー
ム３(3) R = —NHCH m (CH 2 AR 2 ) 3-m 1) When m = 0 (a) A = single bond For example, it can be produced by the route of Scheme 3. Scheme 3
【００３５】[0035]
【化９】 Embedded image
【００３６】（式中、Ｒ1 はＺ、Ｂｏｃまたは糖鎖アシ
ル残基を表わす。Ｒ3 はＺまたはＢｏｃを表わすが、Ｒ
1 とＲ3 は互いに異なる意味を表わす。ｋは前記と同義
を、Ｍｓはメタンスルホニル基を表わす） すなわち、市販のトリス（ヒドロキシメチル）アミノメ
タン化合物（Ｈ）より容易に調製できる、あるいは文献
既知（Ｃｈｅｍ．Ｅｕｒ．Ｊ．，２，１１１６（１９９
６）参照）の一般式（Ｉ）で表わされる化合物（以下、
化合物（Ｉ）と略記する）にピリジン中あるいは塩化メ
チレン、テトラヒドロフラン等適当な溶媒中、塩化メタ
ンスルホニルを作用し、一般式（Ｊ）で表わされる化合
物（以下、化合物（Ｊ）と略記する）を製造できる。化
合物（Ｊ）に、上記スキーム１で製造した化合物（２
ａ）を、スキーム２に示した化合物（Ｅ）の製造に用い
たのと同様の方法で反応させ一般式（Ｋ）で表わされる
化合物（以下、化合物（Ｋ）と略記する）を製造でき
る。この際、反応させる化合物（２ａ）中のＲ1 は、化
合物（Ｊ）中のＲ3 と異なるものを用いる。化合物
（Ｋ）からは、Ｒ3 を先と同様な方法で除去し、目的と
するＲ1 がＺまたはＢｏｃである化合物（２ｃ）を製造
できる。また、スキーム２の化合物（Ｅ）から、化合物
（Ｆ）、（Ｇ）を経て化合物（２ｂ）を得たのと同様な
経路で、化合物（Ｋ）から１）Ｒ1 の除去、２）糖酸ラ
クトンの反応、３）Ｒ3 の除去によりＲ1 が糖酸アシル
残基である化合物（２）を製造できる。(Wherein R 1 represents Z, Boc or a sugar acyl residue; R 3 represents Z or Boc;
1 and R 3 have different meanings. k has the same meaning as described above, and Ms represents a methanesulfonyl group. That is, it can be easily prepared from a commercially available tris (hydroxymethyl) aminomethane compound (H), or is known in the literature (Chem. Eur. J., 2, 1116). (199
6)), a compound represented by the general formula (I)
Compound (I) is reacted with methanesulfonyl chloride in pyridine or an appropriate solvent such as methylene chloride or tetrahydrofuran to give a compound represented by formula (J) (hereinafter abbreviated as compound (J)). Can be manufactured. Compound (J) is added to the compound (2
a) is reacted in the same manner as in the production of the compound (E) shown in Scheme 2 to produce a compound represented by the general formula (K) (hereinafter abbreviated as compound (K)). At this time, R 1 in the compound (2a) to be reacted is different from R 3 in the compound (J). From compound (K), R 3 can be removed in the same manner as above to produce compound (2c) in which R 1 is Z or Boc. In addition, 1) removal of R 1 from compound (K) and 2) sugar from compound (K) by a route similar to that of obtaining compound (2b) from compound (E) of Scheme 2 via compounds (F) and (G). Reaction of acid lactone, 3) removal of R 3 can produce compound (2) wherein R 1 is a sugar acid acyl residue.
【００３７】さらに、化合物（Ｊ）の代りに文献既知の
トリス（ヒドロキシメチル）ニトロメタンのトリスメタ
ンスルホナート（Ｓｙｎｔｈｅｓｉｓ，７４２（１９８
７）参照）を用いＲ1 がＢｏｃである化合物（２ａ）を
作用させ、化合物（Ｋ）に相当するニトロ体を製造でき
る。この化合物から、ニトロ基のアミノ基への還元で化
合物（２ｃ）（Ｒ1 ＝Ｂｏｃ基）、またはＢｏｃを除去
し、糖酸ラクトンを反応させた後、ニトロ基のアミノ基
への変換で、Ｒ1 が糖酸アシル残基である化合物（２
ｃ）を製造できる。Further, instead of compound (J), trismethanesulfonate of tris (hydroxymethyl) nitromethane (Synthesis, 742 (198)
The compound (2a) wherein R 1 is Boc is reacted with the compound (2) to produce a nitro compound corresponding to the compound (K). From this compound, the compound (2c) (R 1 = Boc group) or Boc is removed by reduction of a nitro group to an amino group, and a sugar acid lactone is reacted. Then, conversion of the nitro group to an amino group is performed. Compound (2) wherein R 1 is a sugar acid acyl residue
c) can be manufactured.
【００３８】（ｂ）Ａ＝−（ＣＨ2 ）2 の場合 たとえば、前述スキーム３において、化合物（Ｈ）の代
りに市販品のビスホモトリスを用いることで製造でき
る。また、トリス（ヒドロキシメチル）ニトロメタンの
代りに市販のニトロメタントリスプロピオン酸よりカル
ボキシル基の還元（たとえば、テトラヒドロフラン中、
メタノール存在下、水素化ホウ素ナトリウムを作用す
る）により得られるトリス（３−ヒドロキシプロピル）
ニトロメタンを用い、同様な反応により化合物（２）を
製造できる。 （ｃ）Ａ＝−ＣＨ2 ＣＯの場合 たとえば、スキーム４の経路により製造できる。(B) In the case of A =-(CH 2 ) 2 For example, in the above-mentioned scheme 3, the compound (H) can be produced by using a commercially available bis homotris instead of the compound (H). Also, instead of tris (hydroxymethyl) nitromethane, the reduction of carboxyl groups from commercially available nitromethane trispropionic acid (for example, in tetrahydrofuran,
(Acting with sodium borohydride in the presence of methanol))
Compound (2) can be produced by a similar reaction using nitromethane. (C) When A = —CH 2 CO For example, it can be produced by the route of Scheme 4.
【００３９】[0039]
【化１０】 Embedded image
【００４０】（式中、Ｒ1 、Ｒ3 およびｋはスキーム３
でのＲ1 、Ｒ3 、ｋと同義を表わす。） すなわち、文献既知の化合物（Ｌ）（Ｊ．Ｏｒｇ．Ｃｈ
ｅｍ．，５６，７１６２（１９９１）参照）から、ｔ−
ブチルエステルを加水分解する方法、たとえばトリフル
オロ酢酸を室温で作用させる、あるいは酢酸中、ｐ−ト
ルエンスルホン酸を加え加熱する、などの方法により化
合物（Ｍ）を製造できる。化合物（Ｍ）から、アミノ酸
のアミノ基のＺ化、Ｂｏｃ化に用いられる方法により、
一般式（Ｎ）で表わされる化合物（以下、化合物（Ｎ）
と略記する）を製造でき、これにアミン、化合物（２
ａ）をカルボニルジイミダゾール、ジシクロヘキシルカ
ルボニルジイミド等の縮合剤を用いる方法、あるいは化
合物（Ｎ）を対応する酸塩化物、ｉ−ブチル炭酸無水
物、メタンスルホニル無水物等に活性化後作用させるな
ど通常のアミド結合形成反応により、一般式（Ｏ）で表
わされる化合物（以下、化合物（Ｏ）と略記する）を製
造できる。この際、アミン反応剤としてＨＮ（（Ｃ
Ｈ2 ）k ＮＨＲ1 ）2 の代りに、Ｈ2 Ｎ（ＣＨ2 ）k Ｎ
ＨＲ1 、Ｈ2 Ｎ（ＣＨ 2 ）l Ｎ（ＣＨ2 ）k ＮＨＲ1 ）
2 （いずれも前述）を使用すれば化合物（Ｏ）に相当す
る対応するアミド化合物が製造できる。これら化合物
（Ｏ）および対応する化合物からＲ1 あるいはＲ3 の除
去を経て、目的とする化合物（２）を製造できる。 （ｄ）Ａ＝−Ｏ（ＣＨ2 ）3 の場合 たとえば、スキーム５の経路により製造できる。スキー
ム５(Where R1, RThreeAnd k are scheme 3
R at1, RThree, K. That is, the compound (L) (J. Org. Ch) known in the literature
em. ,56, 7162 (1991)).
Hydrolysis of butyl ester, for example, trifle
Oroacetic acid is allowed to act at room temperature, or
Addition of ruenesulfonic acid and heating, etc.
Compound (M) can be produced. From compound (M), amino acid
According to the method used for Z-formation and Boc-formation of the amino group of
A compound represented by the general formula (N) (hereinafter, compound (N)
Abbreviated as), to which amine, compound (2)
a) is carbonyldiimidazole, dicyclohexylca
A method using a condensing agent such as rubonyl diimide, or
Compound (N) is converted to the corresponding acid chloride, i-butyl carbonate anhydrous
Chemicals, methanesulfonyl anhydride, etc. after activation
The compound represented by the general formula (O)
(Hereinafter abbreviated as compound (O))
Can be built. At this time, HN ((C
HTwo)kNHR1)TwoInstead of HTwoN (CHTwo)kN
HR1, HTwoN (CH Two)lN (CHTwo)kNHR1)
Two(Each of the above) corresponds to compound (O).
Corresponding amide compounds can be prepared. These compounds
From (O) and the corresponding compound1Or RThreeRemoval of
Through the reaction, the desired compound (2) can be produced. (D) A = -O (CHTwo)ThreeIn the case of, for example, it can be produced by the route of Scheme 5. Ski
5
【００４１】[0041]
【化１１】 Embedded image
【００４２】（式中、Ｒ1 はＺ基または糖鎖アシル残基
を表わす） すなわち、既知の化合物（Ｐ）をＢｏｃ化し化合物
（Ｑ）とした後、アンモニア存在下のラネーニッケル触
媒による接触水素添加反応などの還元反応により化合物
（Ｒ）を製造できる。化合物（Ｒ）からは、前述の方法
によりＲ1 がＺあるいは糖鎖アシル残基である化合物
（２）が製造できる。(In the formula, R 1 represents a Z group or a sugar chain acyl residue.) That is, a known compound (P) is Boc-converted into a compound (Q), and then catalytic hydrogenation with a Raney nickel catalyst in the presence of ammonia. Compound (R) can be produced by a reduction reaction such as a reaction. From compound (R), compound (2) wherein R 1 is Z or a sugar chain acyl residue can be produced by the method described above.
【００４３】（ｅ）Ａ＝−Ｏ（ＣＨ2 ）2 ＣＯの場合 たとえば、前述のスキーム４における化合物（Ｌ）の代
りに既知のアミン、Ｈ 2 ＮＣ（ＣＨ2 Ｏ（ＣＨ2 ）2 Ｃ
Ｏ2 Ｅｔ）3 を用い、同様の反応を繰り返すことにより
製造できる。(E) A = -O (CHTwo)TwoIn the case of CO For example, instead of the compound (L) in the aforementioned scheme 4,
Known amine, H TwoNC (CHTwoO (CHTwo)TwoC
OTwoEt)ThreeAnd by repeating the same reaction
Can be manufactured.
【００４４】本発明の化合物（２）はアミノ基を有する
単一の糖誘導体、あるいはこれを製造するために有用な
化合物であり、これらを含有する、あるいは利用するこ
とにより得られる化合物に付与されるターゲッティン
グ、血液プール性の機能は、キレート化剤のみならず他
の診断薬あるいは治療薬に適応しても発揮可能である。
たとえば、Ｘ線診断に用いられる５−アミノ−２，４，
６−トリヨードイソフタル酸誘導体に本発明の化合物
（２）を含有させれば臓器選択性あるいは血液プール性
を持った新しいＸ線診断用の造影剤となる。The compound (2) of the present invention is a single saccharide derivative having an amino group or a compound useful for producing the same, and is imparted to a compound obtained by containing or utilizing these. The functions of targeting and blood pooling can be exhibited not only by chelating agents but also by adapting to other diagnostic or therapeutic agents.
For example, 5-amino-2,4, used for X-ray diagnosis
When the 6-triiodoisophthalic acid derivative contains the compound (2) of the present invention, it becomes a new X-ray diagnostic contrast agent having organ selectivity or blood pooling property.
【００４５】本発明においては、上記のようにして得ら
れた一般式（１）で表わされる化合物に、金属イオンを
錯化させた化合物も、その要旨として含まれる。ここで
金属イオンとは、常磁性金属イオン、放射性金属イオン
のいずれかであれば、いずれも使用可能である。特に、
Ｐｒ、Ｎｄ、Ｓｍ、Ｅｕ、Ｔｂ、Ｄｙ、Ｈｏ、Ｅｒ、Ｔ
ｍ、Ｙｂ等のランタノイド陽イオンは、可視〜近赤外領
域、長い寿命、狭い波長幅等の特徴を持つ蛍光を発する
点で好適であり、ＭＲＩ造影剤等陽イオンの常磁性を利
用する場合においてはＰｒ、Ｎｄ、Ｅｕ、Ｇｄ、Ｔｂ、
Ｄｙ、Ｈｏ、Ｅｒ、Ｔｍ、Ｙｂ等のランタノイド陽イオ
ンが好適である。その他、Ｍｇ、Ｃａ、Ｓｃ、Ｔｉ、
Ｖ、Ｃｒ、Ｍｎ、Ｆｅ、Ｃｏ、Ｎｉ、Ｃｕ、Ｚｎ、Ｇ
ａ、Ｓｒ、Ｚｒ、Ｔｃ、Ｒｕ、Ｉｎ、Ｈｆ、Ｗ、Ｒｅ、
Ｏｓ、Ｐｄ、Ｌａ、及びＢｉ等のイオンも好ましい例と
して挙げることができる。In the present invention, a compound obtained by complexing a metal ion with the compound represented by the general formula (1) obtained as described above is also included as a gist thereof. Here, as the metal ion, any one of a paramagnetic metal ion and a radioactive metal ion can be used. Especially,
Pr, Nd, Sm, Eu, Tb, Dy, Ho, Er, T
Lanthanoid cations such as m and Yb are suitable in that they emit fluorescence having characteristics such as a visible to near-infrared region, a long life span, and a narrow wavelength width. In the case of utilizing the paramagnetism of a cation such as an MRI contrast agent , Pr, Nd, Eu, Gd, Tb,
Lanthanoid cations such as Dy, Ho, Er, Tm, and Yb are preferred. In addition, Mg, Ca, Sc, Ti,
V, Cr, Mn, Fe, Co, Ni, Cu, Zn, G
a, Sr, Zr, Tc, Ru, In, Hf, W, Re,
Ions such as Os, Pd, La, and Bi can also be mentioned as preferable examples.
【００４６】上記のようにして得られた一般式（１）で
表わされる化合物を金属イオンと錯化した化合物は、造
影剤として使用可能である。また、薬学的に許容される
担体を含んでなる体内診断用医薬組成物としても利用可
能である。The compound obtained by complexing the compound represented by the general formula (1) thus obtained with a metal ion can be used as a contrast agent. In addition, it can also be used as a pharmaceutical composition for in vivo diagnosis comprising a pharmaceutically acceptable carrier.
【００４７】本発明の化合物をＭＲＩ造影剤として用い
る場合、通常静脈内投与などの非経口投与の方法が用い
られるが、経口投与することもできる。非経口剤投与の
製剤、即ち注射剤等の製造に用いられる溶剤、または懸
濁化剤としては、たとえば水、プロピレングリコール、
ポリエチレングリコール、ベンジルアルコール、オレイ
ン酸エチル、レシチン等が挙げられる。製剤の調製は常
法によればよい。また経口投与する場合、単独または薬
学的に許容される担体と複合して、例えば顆粒剤、細粒
剤、散剤、錠剤、硬シロップ剤、軟カプセル剤、シロッ
プ剤、乳剤、懸濁剤、リポソーム、液剤等の剤形にして
経口投与する。固体製剤を製造する際に用いられる賦形
剤としては、例えば乳糖、ショ糖、デンプン、タルク、
セルロース、デキストリン、カオリン、炭酸カルシウム
等が挙げられる。経口投与のための液体製剤、即ち乳
剤、シロップ剤、懸濁剤、液剤等は、一般的に用いられ
る不活性な希釈剤、例えば植物油等を含む。この製剤は
不活性な希釈剤以外に補助剤、例えば湿潤剤、懸濁補助
剤、甘味剤、芳香剤、着色剤または保存剤等を含むこと
もできる。液体製剤にして、ゼラチンのような吸収され
うる物質のカプセル中に含ませてもよい。When the compound of the present invention is used as an MRI contrast agent, a method for parenteral administration such as intravenous administration is usually used, but it can also be administered orally. Preparations for parenteral administration, that is, solvents or suspending agents used in the production of injections and the like include, for example, water, propylene glycol,
Examples include polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like. Preparation of the preparation may be performed by a conventional method. For oral administration, alone or in combination with a pharmaceutically acceptable carrier, for example, granules, fine granules, powders, tablets, hard syrups, soft capsules, syrups, emulsions, suspensions, liposomes Orally in the form of a liquid or the like. Examples of excipients used in producing a solid preparation include lactose, sucrose, starch, talc,
Examples include cellulose, dextrin, kaolin, calcium carbonate and the like. Liquid preparations for oral administration, ie emulsions, syrups, suspensions, solutions and the like, contain commonly used inert diluents, such as vegetable oils. The preparation may also contain, in addition to the inert diluent, auxiliary substances such as wetting agents, suspending aids, sweetening agents, flavoring agents, coloring agents or preservatives. Liquid preparations may be included in capsules of absorbable substances such as gelatin.
【００４８】本発明によるＭＲＩ造影剤は、一般に所望
の造影効果が副作用を伴うことなく得られる投与量で投
与される。その具体的な値は、医師の判断で決定される
べきであるが、一般に一回の診断につき成分当たり０．
１ｍｇ〜１０ｇ、好ましくは１ｍｇ〜５ｇである。本発
明の化合物は有効成分として一回の診断につき、成人当
たり１ｍｇ〜５ｇ、更に好ましくは３ｍｇ〜３ｇ含有さ
れ投与されても良い。The MRI contrast agent according to the present invention is generally administered at a dose that provides the desired contrast effect without side effects. The specific value should be determined at the discretion of the physician, but is generally 0,1 per component per diagnosis.
It is 1 mg to 10 g, preferably 1 mg to 5 g. The compound of the present invention may be administered as an active ingredient in an amount of 1 mg to 5 g, more preferably 3 mg to 3 g per adult per one diagnosis.
【００４９】[0049]
【実施例】以下、実施例によって本発明を具体的に説明
するが、本発明はその要旨を超えない限り以下に限定さ
れるものではない。 実施例１EXAMPLES The present invention will be described below in detail with reference to examples, but the present invention is not limited to the following unless it exceeds the gist. Example 1
【００５０】[0050]
【化１２】 Embedded image
【００５１】アミン２．２５ｇ、ブロム体１．０ｇ、テ
トラヒドロフラン８ｍｌの混合物を２昼夜かきまぜなが
ら加熱還流した。反応混合物は一旦溶液となり、次いで
結晶が析出してくる。室温にまで冷却後、結晶を濾別、
洗浄（冷テトラヒドロフラン）し、濾液を濃縮して得た
残渣をＳｉＯ2 カラムクロマトグラフィー（展開液ＣＨ
Ｃｌ3 ：ＭｅＯＨ ２０：１→５：２）に付し、目的と
する２級アミノ化合物１．２６ｇ（８７％、ブロム体を
基にして）を得た。A mixture of 2.25 g of an amine, 1.0 g of a bromo compound, and 8 ml of tetrahydrofuran was heated to reflux while stirring for 2 days and nights. The reaction mixture once becomes a solution, and then crystals precipitate. After cooling to room temperature, the crystals were filtered off,
The residue obtained by washing (cold tetrahydrofuran) and concentrating the filtrate is subjected to SiO 2 column chromatography (developing solution CH).
Cl 3 : MeOH 20: 1 → 5: 2) to give 1.26 g (87%, based on the bromo form) of the desired secondary amino compound.
【００５２】1Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣ
ｌ3 ）δ １．３２（ｂｓ，１Ｈ），２．６９（ｂｔ，
Ｊ＝５．３Ｈｚ，４Ｈ），３．２４（ｂｍ，４Ｈ），
５．０７（ｓ，４Ｈ），５．３２（ｂｔ，Ｊ＝５．５Ｈ
ｚ，２Ｈ），７．３０（ｍ，１０Ｈ）． 実施例２ 1 H-NMR (300 MHz, CDC
l 3 ) δ 1.32 (bs, 1H), 2.69 (bt,
J = 5.3 Hz, 4H), 3.24 (bm, 4H),
5.07 (s, 4H), 5.32 (bt, J = 5.5H)
z, 2H), 7.30 (m, 10H). Example 2
【００５３】[0053]
【化１３】 Embedded image
【００５４】アミン体１．２４ｇのＤＭＦ４ｍｌ溶液に
かきまぜながらＤＴＰＡジ無水物を加えた。約３０℃に
まで昇温し、１時間程で均一溶液となった。一晩室温に
放置後、真空ポンプを用い溶媒を留去した。残渣に水、
ＣＨ2 Ｃｌ2 を加え、ＣＨ2Ｃｌ2 層を分液、水洗、濃
縮し目的とするジアシド体１．７５ｇ（９５％）を得
た。DTPA dianhydride was added to a solution of 1.24 g of the amine compound in 4 ml of DMF while stirring. The temperature was raised to about 30 ° C., and a uniform solution was obtained in about one hour. After standing at room temperature overnight, the solvent was distilled off using a vacuum pump. Water in the residue,
CH 2 Cl 2 was added, and the CH 2 Cl 2 layer was separated, washed with water and concentrated to obtain 1.75 g (95%) of the desired diacid.
【００５５】1Ｈ−ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−
ｄ6 ）δ ２．８８（ｂｍ，４Ｈ），２．９４（ｂｍ，
４Ｈ），３．１５（ｂｍ，８Ｈ），３．２９（ｂｍ，８
Ｈ），３．４２（ｂｓ，４Ｈ），３．４６（ｂｓ，２
Ｈ），３．６０（ｂｓ，４Ｈ），５．０１ ａｎｄ
５．０２（おのおのｓ，各２Ｈ），７．３３（ｍ，２
Ｈ），７．５０（ｂｔ，Ｊ＝５．６Ｈｚ，２Ｈ）． 実施例３ 1 H-NMR (300 MHz, DMSO-
d 6 ) δ 2.88 (bm, 4H), 2.94 (bm,
4H), 3.15 (bm, 8H), 3.29 (bm, 8
H), 3.42 (bs, 4H), 3.46 (bs, 2
H), 3.60 (bs, 4H), 5.01 and
5.02 (each s, 2H each), 7.33 (m, 2
H), 7.50 (bt, J = 5.6 Hz, 2H). Example 3
【００５６】[0056]
【化１４】 Embedded image
【００５７】ジエチレントリアミン２６０ｍｇのＤＭＳ
Ｏ４ｍｌ溶液にラクトビオン酸ラクトン１．７２ｇを加
え室温でかきまぜた。ラクトンが溶解後、５０℃油浴上
さらに３時間かきまぜを続けた。極一部を取り分析を行
うと、ほぼ純粋な糖酸アミド体であった。260 mg of diethylenetriamine in DMS
1.72 g of lactobionic lactone was added to a 4 ml solution of O and stirred at room temperature. After the lactone had dissolved, stirring was continued for a further 3 hours on a 50 ° C. oil bath. When a very small part was taken and analyzed, it was a substantially pure sugar amide.
【００５８】13Ｃ−ＮＭＲ（１２５ＭＨｚ，ＤＭＳＯ−
ｄ6 ）δ ３８．３，４８．１，６０．７，６２．４，
６８．３，７０．５，７１．１，７１．４，７２．１，
７３．２，７５．７，８２．９，１０４．６，１７２．
３ 13 C-NMR (125 MHz, DMSO-
d 6 ) δ 38.3, 48.1, 60.7, 62.4,
68.3, 70.5, 71.1, 71.4, 72.1,
73.2, 75.7, 82.9, 104.6, 172.
3
【００５９】反応混合物にＤＭＦ１２ｍｌを加え、ＤＴ
ＰＡジ無水物４５０ｍｇのＤＭＳＯ１０ｍｌ溶液を氷水
浴上かきまぜながら滴下した。浴を取り去り室温で一昼
夜かきまぜた。溶媒を減圧留去（７０℃）し得た残渣
を、少量の水に溶解、イオン交換樹脂（ダイアイオンＷ
Ｋ−４０）にて精製し、目的とするラクトビオン酸基を
４つ持つＤＴＰＡ誘導体１．５５ｇ（６５％）を得た。12 ml of DMF was added to the reaction mixture, and DT was added.
A solution of 450 mg of PA dianhydride in 10 ml of DMSO was added dropwise with stirring on an ice water bath. The bath was removed and stirred overnight at room temperature. The residue obtained by distilling off the solvent under reduced pressure (70 ° C.) was dissolved in a small amount of water and ion-exchange resin (Diaion W
K-40) to obtain 1.55 g (65%) of the desired DTPA derivative having four lactobionic acid groups.
【００６０】13Ｃ−ＮＭＲ（１２５ＭＨｚ，ＤＭＳＯ−
ｄ6 ）δ ３６．６，３７．０，４５．１，４６．５，
５０．２，５１．４，５４．９，５６．１，６０．７，
６２．４，６８．３，７０．６，７１．２，７１．４，
７３．３，７５．７，８３．０，１０４．５，１６９．
５，１７０．２，１７２．７，１７２．８，１７３．０ 13 C-NMR (125 MHz, DMSO-
d 6 ) δ 36.6, 37.0, 45.1, 46.5
50.2, 51.4, 54.9, 56.1, 60.7,
62.4, 68.3, 70.6, 71.2, 71.4,
73.3, 75.7, 83.0, 104.5, 169.
5, 170.2, 172.7, 172.8, 173.0
【００６１】上記で得たＤＴＰＡ誘導体１．４ｇを水５
ｍｌに溶解し、酸化ガドリニウム１３２ｍｇを加えた
後、１００℃の油浴上６時間かきまぜた。反応混合物を
濃縮しほぼ純粋な目的とするＧｄ媒体を得た。1.4 g of the DTPA derivative obtained above was added to water 5
The mixture was dissolved in 100 ml of water, and 132 mg of gadolinium oxide was added, followed by stirring on an oil bath at 100 ° C. for 6 hours. The reaction mixture was concentrated to obtain an almost pure target Gd medium.
【００６２】分析条件：Ｌ−ｃｏｌｕｍｎ（ＯＤＳ）、
溶離液２０ｍＭリン酸バッファー（ｐＨ７．０）−１％
ＭｅＯＨ、２１５ｎｍ検出、Ｒｔ＝４．５ｍｉｎ 実施例４Analysis conditions: L-column (ODS),
Eluent 20 mM phosphate buffer (pH 7.0) -1%
MeOH, 215 nm detection, Rt = 4.5 min Example 4
【００６３】[0063]
【化１５】 Embedded image
【００６４】ブロム体９．６６ｇ、アミン３．００ｇ、
ジｉ−プロピルエチルアミン６．５ｍｌ、テトラヒドロ
フラン２５ｍｌの混合物をかきまぜながら２昼夜加熱還
流した。氷水浴で冷却後、析出結晶を濾別、冷テトラヒ
ドロフランにて洗浄した。濾液を濃縮して得た残渣をＳ
ｉＯ2 カラムクロマト（展開液ｎ−ヘキサン：酢酸エチ
ル２：１→３：２→４：３）に付し、目的とする３級ア
ミン体３．９３ｇ（４０％）を得た。9.66 g of a bromo compound, 3.00 g of an amine,
The mixture was heated and refluxed for 2 days and night while stirring a mixture of 6.5 ml of di-propylethylamine and 25 ml of tetrahydrofuran. After cooling in an ice water bath, the precipitated crystals were separated by filtration and washed with cold tetrahydrofuran. The residue obtained by concentrating the filtrate was treated with S
The residue was subjected to iO 2 column chromatography (developing solution n-hexane: ethyl acetate 2: 1 → 3: 2 → 4: 3) to obtain 3.93 g (40%) of the target tertiary amine compound.
【００６５】1Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣ
ｌ3 ）δ １．３７（ｓ，９Ｈ），２．５２（ｍ，６
Ｈ），３．１２（ｂｍ，２Ｈ），３．２０（ｂｍ，４
Ｈ），５．０６（ｂｓ，５Ｈ），５．５１（ｂｓ，２
Ｈ），７．２８（ｍ，１０Ｈ） 実施例５ 1 H-NMR (300 MHz, CDC
l 3 ) δ 1.37 (s, 9H), 2.52 (m, 6
H), 3.12 (bm, 2H), 3.20 (bm, 4
H), 5.06 (bs, 5H), 5.51 (bs, 2
H), 7.28 (m, 10H) Example 5
【００６６】[0066]
【化１６】 Embedded image
【００６７】Ｂｏｃ体１．７５ｇに氷水浴上かきまぜな
がらトリフルオロ酢酸６ｍｌを滴下した。浴を取り去
り、室温で一晩かきまぜた後、エバポレーターにて濃縮
し、残渣に１Ｎ水酸化ナトリウム水溶液を加えた。塩化
メチレン抽出し、有機層を水洗、濃縮すると目的とする
一級アミン１．３２ｇ（９３％）が得られた。6 ml of trifluoroacetic acid was added dropwise to 1.75 g of the Boc compound while stirring on an ice water bath. After removing the bath and stirring overnight at room temperature, the mixture was concentrated with an evaporator, and a 1N aqueous sodium hydroxide solution was added to the residue. Extraction with methylene chloride, washing of the organic layer with water and concentration gave 1.32 g (93%) of the desired primary amine.
【００６８】13Ｃ−ＮＭＲ（７５ＭＨｚ，ＣＤＣｌ3 ）
δ ３９．１，３９．６，５３．９，５６．６，６６．
４，１２７．８５，１２７．８９，１２８．３１，１３
６．７，１５６．７ 実施例６ 13 C-NMR (75 MHz, CDCl 3 )
δ 39.1, 39.6, 53.9, 56.6, 66.
4,127.85,127.89,128.31,13
6.7, 156.7 Example 6
【００６９】[0069]
【化１７】 Embedded image
【００７０】ジＺ体９２０ｍｇをメタノール１０ｍｌ溶
液中、Ｐｄ／Ｃ（１０％）８０ｍｇにて室温で一昼夜反
応させ加水素分解した。触媒の濾去、洗浄後、濾液を濃
縮して目的とするフリーアミン体４４６ｍｇ（定量的）
を得た。920 mg of the di-Z form was reacted with 80 mg of Pd / C (10%) in 10 ml of methanol at room temperature for 24 hours to undergo hydrogenolysis. After the catalyst was removed by filtration and washed, the filtrate was concentrated to obtain 446 mg of the desired free amine compound (quantitative).
I got
【００７１】1Ｈ−ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ−
ｄ6 ）δ １．３５（ｓ，９Ｈ），２．４０（ｔ，Ｊ＝
６．０Ｈｚ，６Ｈ），２．６０（ｂｍ，４Ｈ），２．９
４（ｂｍ，２Ｈ），３．６３（ｂｍ，４Ｈ），６．８０
（ｂｓ，１Ｈ）． 1 H-NMR (300 MHz, DMSO-
d 6 ) δ 1.35 (s, 9H), 2.40 (t, J =
6.0 Hz, 6H), 2.60 (bm, 4H), 2.9
4 (bm, 2H), 3.63 (bm, 4H), 6.80
(Bs, 1H).
【００７２】上記で得た粗フリーアミン体２０６ｍｇを
ＤＭＳＯ１０ｍｌに溶解し、これにＤ−グルコノラクト
ン３００ｍｇを加え室温で一昼夜かきまぜた。濃縮後、
残渣をイオン交換樹脂（ダイアイオンＷＫ−４０）に保
存、水洗後、０．５Ｎアンモニア水で展開し、目的物の
フラクションより目的とする糖酸アミド２４７ｍｇ（４
９％）を得た。206 mg of the crude free amine obtained above was dissolved in 10 ml of DMSO, and 300 mg of D-gluconolactone was added thereto, followed by stirring at room temperature for 24 hours. After concentration,
The residue was stored in an ion-exchange resin (Diaion WK-40), washed with water, developed with 0.5 N aqueous ammonia, and 247 mg (4 mg) of the target sugar amide was obtained from the target fraction.
9%).
【００７３】13Ｃ−ＮＭＲ（１２５ＭＨｚ，ＤＭＳＯ−
ｄ6 ）δ ２８．３，３６．６，３８．３，５３．１，
５３．４，６３．４，７０．１，７１．５，７２．４，
７３．７，７７．６，１５５．７，１７２．５ 実施例７ 13 C-NMR (125 MHz, DMSO-
d 6 ) δ 28.3, 36.6, 38.3, 53.1,
53.4, 63.4, 70.1, 71.5, 72.4
73.7, 77.6, 155.7, 172.5 Example 7
【００７４】[0074]
【化１８】ＢｏｃＨＮＣ（ＣＨ2 Ｏ（ＣＨ2 ）2 ＣＮ）
3→ ＢｏｃＨＮＣ（ＣＨ2 Ｏ（ＣＨ2 ）3 ＮＨＺ）3 Embedded image BocHNC (CH 2 O (CH 2 ) 2 CN)
3 → BocHNC (CH 2 O (CH 2 ) 3 NHZ) 3
【００７５】トリスニトリル体８．１５ｇ、ラネーＮｉ
（５０％水スラリー、アルドリッチ社製）１２ｍｌを
水、メタノールで洗浄、デカントしたもの、７Ｎアンモ
ニア／メタノール１５０ｍｌをオートクレーブ中、水素
雰囲気下（７ａｔｍ）ではげしくかきまぜた。反応終了
後、触媒を濾過、洗浄し、濾液を濃縮して得た残渣を水
２０ｍｌに溶解した。氷水浴上、はげしくかきまぜなが
ら、ＺＣｌ １０．１ｍｌと１Ｎ ＮａＯＨ７０ｍｌを
交互に加えた。氷水浴でさらに５時間かきまぜた後、塩
化メチレン層を加え、セライト濾過した。濾液から塩化
メチレン層を分液し、乾燥（ＭｇＳＯ4 ）、濃縮により
得た残渣をＳｉＯ2 カラムクロマト精製（ｎ−ヘキサ
ン：酢酸エチル＝５：１→１：１）に付し、目的とする
トリスＺ体９．１ｇ（５３％）を得た。8.15 g of trisnitrile, Raney Ni
12 ml (50% water slurry, manufactured by Aldrich) was washed with water and methanol, decanted, and 150 ml of 7N ammonia / methanol was vigorously stirred in a hydrogen atmosphere (7 atm) in an autoclave. After completion of the reaction, the catalyst was filtered and washed, and the residue obtained by concentrating the filtrate was dissolved in 20 ml of water. On an ice-water bath, 10.1 ml of ZCl and 70 ml of 1N NaOH were alternately added with vigorous stirring. After further stirring for 5 hours in an ice water bath, a methylene chloride layer was added, and the mixture was filtered through celite. The methylene chloride layer was separated from the filtrate, dried (MgSO 4 ), and the residue obtained by concentration was purified by SiO 2 column chromatography (n-hexane: ethyl acetate = 5: 1 → 1: 1) to obtain the desired compound. 9.1 g (53%) of Tris Z form was obtained.
【００７６】1Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣ
ｌ3 ）δ １．４０（ｓ，９Ｈ），１．６８（ｂｍ，６
Ｈ），３．２３（ｂｍ，６Ｈ），３．４２（ｂｓ，６
Ｈ），３．５９（ｓ，６Ｈ），４．９０（ｓ，１Ｈ），
５．０７（ｓ，６Ｈ），５．２５（ｂｓ，３Ｈ），７．
３２（ｍ，１５Ｈ）． 実施例８ 1 H-NMR (300 MHz, CDC
l 3 ) δ 1.40 (s, 9H), 1.68 (bm, 6
H), 3.23 (bm, 6H), 3.42 (bs, 6
H), 3.59 (s, 6H), 4.90 (s, 1H),
5.07 (s, 6H), 5.25 (bs, 3H), 7.
32 (m, 15H). Example 8
【００７７】[0077]
【化１９】ＢｏｃＨＮＣ（ＣＨ2 Ｏ（ＣＨ2 ）3 ＮＨ
Ｚ）3→ ＢｏｃＨＮＣ（ＣＨ2 Ｏ（ＣＨ2 ）3 Ｎ
Ｈ2 ）3 Embedded image BocHNC (CH 2 O (CH 2 ) 3 NH
Z) 3 → BocHNC (CH 2 O (CH 2 ) 3 N
H 2 ) 3
【００７８】Ｚ体１．９４ｇ（２．４４ｍｍｏｌ）のメ
タノール（１５ｍｌ）溶液に１０％Ｐｄ／Ｃ１８０ｍｇ
を加え、水素雰囲気下２４時間、室温にてはげしくかき
まぜた。触媒を濾過、メタノールにて洗浄し、濾液を濃
縮した。目的とするトリアミン体１．０ｇ（定量的）を
得た。To a solution of 1.94 g (2.44 mmol) of the Z-form in methanol (15 ml), 180 mg of 10% Pd / C was added.
And vigorously stirred at room temperature for 24 hours under a hydrogen atmosphere. The catalyst was filtered, washed with methanol, and the filtrate was concentrated. 1.0 g (quantitative) of the desired triamine was obtained.
【００７９】1Ｈ−ＮＭＲ（５００ＭＨｚ，ＤＭＳＯ−
ｄ6 ，７０℃）δ １．３７（ｓ，９Ｈ），１．５８
（ｍ，６Ｈ），２．６８（ｂｓ，６Ｈ），２．９４（ｂ
ｍ，６Ｈ），３．４２（ｔ，Ｊ＝６．０Ｈｚ，６Ｈ），
３．５０（ｓ，６Ｈ），６．０１（ｂｓ，１Ｈ）． 実施例９ 1 H-NMR (500 MHz, DMSO-
d 6 , 70 ° C.) δ 1.37 (s, 9H), 1.58
(M, 6H), 2.68 (bs, 6H), 2.94 (b
m, 6H), 3.42 (t, J = 6.0 Hz, 6H),
3.50 (s, 6H), 6.01 (bs, 1H). Example 9
【００８０】[0080]
【化２０】 Embedded image
【００８１】トリアミン体４２０ｍｇ、Ｄ−グルコノラ
クトン５７２ｍｇをジメチルスルホキシド８ｍｌに溶解
し、室温にて一昼夜かきまぜた。濃縮で得た残渣を、イ
オン交換樹脂（ダイアイオンＷＫ−４０）に保持し、水
洗後、０．５Ｎアンモニア水で展開し、目的物のフラク
ションを集め濃縮した。収量４４６ｍｇ（４５％）。A triamine compound (420 mg) and D-gluconolactone (572 mg) were dissolved in dimethyl sulfoxide (8 ml) and stirred at room temperature for 24 hours. The residue obtained by concentration was retained on an ion exchange resin (Diaion WK-40), washed with water, developed with 0.5N aqueous ammonia, and the desired fraction was collected and concentrated. Yield 446 mg (45%).
【００８２】13Ｃ−ＮＭＲ（１２５ＭＨｚ，ＤＭＳＯ−
ｄ6 ）δ ２８．２，２９．２，３５．８，５８．５，
６３．３，６８．５，６８．８，７０．０，７１．５，
７２．４，７３．６，１５４．３，１７２．３ 実施例１０ 13 C-NMR (125 MHz, DMSO-
d 6 ) δ 28.2,29.2,35.8,58.5
63.3, 68.5, 68.8, 70.0, 71.5,
72.4, 73.6, 154.3, 172.3 Example 10
【００８３】[0083]
【化２１】ＢｏｃＨＮＣ（ＣＨ2 Ｏ（ＣＨ2 ）3 ＮＨ
Ｚ）3→ Ｈ2 ＮＣ（ＣＨ2 Ｏ（ＣＨ2 ）3 ＮＨＺ）3 Embedded image BocHNC (CH 2 O (CH 2 ) 3 NH
Z) 3 → H 2 NC (CH 2 O (CH 2 ) 3 NHZ) 3
【００８４】Ｂｏｃ体５７０ｍｇの塩化メチレン０．７
ｍｌ溶液に、氷冷下、かきまぜながらトリフルオロ酢酸
０．６ｍｌを滴下した。浴をはずし、一晩かきまぜた
後、エバポレーターにて濃縮、残渣に１Ｎ水酸化ナトリ
ウム水溶液を加え塩化メチレン抽出した。塩化メチレン
層を水洗、乾燥、濃縮し、目的とするアミン体４８０ｍ
ｇ（定量的）を得た。次工程には、精製せず用いた。570 mg of Boc compound in 0.7 of methylene chloride
0.6 ml of trifluoroacetic acid was added dropwise to the ml solution while stirring under ice cooling. After removing the bath and stirring overnight, the mixture was concentrated with an evaporator, and a 1N aqueous sodium hydroxide solution was added to the residue, followed by extraction with methylene chloride. The methylene chloride layer was washed with water, dried and concentrated to obtain the desired amine compound (480 m).
g (quantitative) was obtained. In the next step, it was used without purification.
【００８５】1Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣ
ｌ3 ）δ １．６９（ｂｔ，Ｊ＝５．２Ｈｚ，６Ｈ），
３．２５（ｔ，Ｊ＝６．３Ｈｚ，６Ｈ），３．２７
（ｓ，６Ｈ），３．４１（ｂｍ，６Ｈ），５．０６
（ｓ，６Ｈ），５．３６（ｂｓ，３Ｈ），７．３１
（ｍ，１５Ｈ） 実施例１１ 1 H-NMR (300 MHz, CDC
l 3 ) δ 1.69 (bt, J = 5.2 Hz, 6H),
3.25 (t, J = 6.3 Hz, 6H), 3.27
(S, 6H), 3.41 (bm, 6H), 5.06
(S, 6H), 5.36 (bs, 3H), 7.31
(M, 15H) Example 11
【００８６】[0086]
【化２２】 Embedded image
【００８７】実施例１０で合成したアミン体４３８ｍｇ
のジメチルホルムアミド（ＤＭＦ）１．５ｍｌ溶液に氷
冷下、かきまぜながらＤＴＰＡジ無水物１１３ｍｇを少
量ずつ加えた。２時間後、浴を取り去り、さらに一晩か
きまぜを続けた。ＤＭＦを留去しほぼ純粋な目的物５５
６ｍｇ（定量的）を得た。438 mg of the amine compound synthesized in Example 10
To a solution of dimethylformamide (DMF) in 1.5 ml, 113 mg of DTPA dianhydride was added little by little while stirring under ice-cooling. After 2 hours, the bath was removed and stirring continued overnight. DMF is distilled off and the almost pure target product 55
6 mg (quantitative) were obtained.
【００８８】13Ｃ−ＮＭＲ（１２５ＭＨｚ，ＤＭＳＯ−
ｄ6 ）δ ２９．１，３７．５，５２．１，５２．２，
５４．８，５５．２，５８．４，５９．０，６４．７，
６８．３，６８．９，１２６．７８，１２６．８４，１
２７．５，１３６．８，１５５．４，１６９．４，１７
１．１，１７１．３ 13 C-NMR (125 MHz, DMSO-
d 6 ) δ 29.1, 37.5, 52.1, 52.2
54.8, 55.2, 58.4, 59.0, 64.7,
68.3, 68.9, 126.78, 126.84, 1
27.5, 136.8, 155.4, 169.4, 17
1.1, 171.3
【００８９】[0089]
【発明の効果】本発明によれば、臓器、組織選択性を有
し、かつ、血液プール性を有する新規な造影剤として利
用可能な化合物が得られる。According to the present invention, a compound which has selectivity for organs and tissues and which can be used as a novel contrast agent having a blood pooling property is obtained.
Claims (6)
ｋは２から５の整数を表わし、Ｒ1 はベンジルオキシカ
ルボニル基、ｔ−ブチルオキシカルボニル基、水素原
子、または糖鎖アシル残基を表わす）；−ＮＨ（Ｃ
Ｈ2 ）l Ｎ（（ＣＨ2 ） k ＮＨＲ1 ）2 （式中、ｋ、Ｒ
1 は上記と同義を表わし、ｌはｋと同義を表わすが、ｋ
と同一でも異なっていてもよい。）；−ＮＨＣＨm （Ｃ
Ｈ2 ＡＲ2 ）3-m（式中、ｍは０または１を表わし、Ａ
は単結合、−（ＣＨ2 ）2 、−ＣＨ2 ＣＯ、−Ｏ（ＣＨ
2 ）3 、−Ｏ（ＣＨ2 ）2 ＣＯ、または−ＣＯを表わ
し、Ｒ2 は−ＮＨＲ1 、−ＮＨ（ＣＨ2 ）k ＮＨＲ1 、
−Ｎ（（ＣＨ2 ）k ＮＨＲ1 ）2 、または−ＮＨ（ＣＨ
2 ）l Ｎ（（ＣＨ2 ）k ＮＨＲ1 ）2 （式中、ｋ、ｌお
よびＲ 1 は前記と同義を表わす）。ただし、ｍが１を表
わす時、Ａは−ＣＯのみを表わす。）を表わす）で表わ
されるジエチレントリアミン５酢酸誘導体。1. The following general formula (1):(Wherein R is -N ((CHTwo)kNHR1)Two(Where
k represents an integer of 2 to 5;1Is benzyloxyca
Rubonyl group, t-butyloxycarbonyl group, hydrogen atom
-NH (C represents a sugar chain acyl residue);
HTwo)lN ((CHTwo) kNHR1)Two(Where k, R
1Has the same meaning as above, l has the same meaning as k,
And may be the same or different. ); -NHCHm(C
HTwoARTwo)3-m(Wherein m represents 0 or 1;
Is a single bond,-(CHTwo)Two, -CHTwoCO, -O (CH
Two)Three, -O (CHTwo)TwoRepresents CO or -CO
Then RTwoIs -NHR1, -NH (CHTwo)kNHR1,
-N ((CHTwo)kNHR1)TwoOr -NH (CH
Two)lN ((CHTwo)kNHR1)Two(Where k, l and
And R 1Is as defined above). However, m represents 1.
When saying, A represents -CO only. Represents))
A diethylenetriaminepentaacetic acid derivative.
1 は水素原子を除いた意味を表わし、またＲが−Ｎ
（（ＣＨ2 ）k ＮＨＲ1 ）2 の時、Ｒ1 は糖鎖アシル基
を表わさない。Ｒ′は水素原子、ベンジルオキシカルボ
ニル基、ｔ−ブチルオキシカルボニル基を表わすが、Ｒ
中にベンジルオキシカルボニル基またはｔ−ブチルオキ
シカルボニル基を有する場合には、おのおのそれらの意
味を表わさない。）で表わされるアミノ化合物。2. The following general formula (2): R′-R (2) (wherein R has the same meaning as in claim 1;
1 represents a meaning excluding a hydrogen atom, and R represents -N
In the case of ((CH 2 ) k NHR 1 ) 2 , R 1 does not represent a sugar chain acyl group. R 'represents a hydrogen atom, a benzyloxycarbonyl group or a t-butyloxycarbonyl group;
When they have a benzyloxycarbonyl group or a t-butyloxycarbonyl group, they have no meaning. An amino compound represented by).
導体。3. The derivative according to claim 1, which is complexed with a metal ion.
射性金属イオンのいずれかからなる群より選択される請
求項３記載の誘導体。4. The derivative according to claim 3, wherein the metal ion is selected from the group consisting of a paramagnetic metal ion and a radioactive metal ion.
造影剤。5. A contrast agent comprising the derivative according to claim 3 as an essential component.
される担体を含んでなる体内診断用医薬組成物。6. A pharmaceutical composition for in vivo diagnosis comprising the derivative according to claim 3 and a pharmaceutically acceptable carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10114562A JPH11302243A (en) | 1998-04-24 | 1998-04-24 | Diethylenetriamine pentaacetic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10114562A JPH11302243A (en) | 1998-04-24 | 1998-04-24 | Diethylenetriamine pentaacetic acid derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH11302243A true JPH11302243A (en) | 1999-11-02 |
Family
ID=14640929
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10114562A Pending JPH11302243A (en) | 1998-04-24 | 1998-04-24 | Diethylenetriamine pentaacetic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH11302243A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001028982A1 (en) * | 1999-10-22 | 2001-04-26 | Mitsubishi Pharma Corporation | Diethylenetriaminepenta acetic acid derivatives |
| JP2007516189A (en) * | 2003-07-08 | 2007-06-21 | ジェンフィ | Production of 1,3-diphenylprop-2-en-1-one derivatives |
| EP2423201A1 (en) | 2006-08-15 | 2012-02-29 | The Regents of The University of California | Luminescent macrocyclic lanthanide complexes |
-
1998
- 1998-04-24 JP JP10114562A patent/JPH11302243A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001028982A1 (en) * | 1999-10-22 | 2001-04-26 | Mitsubishi Pharma Corporation | Diethylenetriaminepenta acetic acid derivatives |
| JP2007516189A (en) * | 2003-07-08 | 2007-06-21 | ジェンフィ | Production of 1,3-diphenylprop-2-en-1-one derivatives |
| EP2423201A1 (en) | 2006-08-15 | 2012-02-29 | The Regents of The University of California | Luminescent macrocyclic lanthanide complexes |
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