JPH0311095A - Novel cyclophosphamide compound and synthesis thereof - Google Patents
Novel cyclophosphamide compound and synthesis thereofInfo
- Publication number
- JPH0311095A JPH0311095A JP1143999A JP14399989A JPH0311095A JP H0311095 A JPH0311095 A JP H0311095A JP 1143999 A JP1143999 A JP 1143999A JP 14399989 A JP14399989 A JP 14399989A JP H0311095 A JPH0311095 A JP H0311095A
- Authority
- JP
- Japan
- Prior art keywords
- group
- amino
- ring
- hydroxyl
- oxyazaphosphorinane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229960004397 cyclophosphamide Drugs 0.000 title claims description 14
- -1 cyclophosphamide compound Chemical class 0.000 title claims description 13
- 230000015572 biosynthetic process Effects 0.000 title description 3
- 238000003786 synthesis reaction Methods 0.000 title 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 21
- 235000000346 sugar Nutrition 0.000 claims abstract description 14
- 125000003277 amino group Chemical group 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 11
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 125000005639 glycero group Chemical group 0.000 claims abstract description 7
- 150000001414 amino alcohols Chemical class 0.000 claims abstract description 6
- 150000002772 monosaccharides Chemical class 0.000 claims abstract description 5
- 125000006239 protecting group Chemical group 0.000 claims abstract description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 3
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims description 5
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- IQPMYTNILJQKBS-UHFFFAOYSA-N 2-chloro-n-(2-chloroethyl)-n-dichlorophosphorylethanamine Chemical compound ClCCN(P(Cl)(Cl)=O)CCCl IQPMYTNILJQKBS-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000002417 D-glucofuranosyl group Chemical group [H]OC([H])([H])[C@@]([H])(O[H])[C@@]1([H])OC([H])(*)[C@]([H])(O[H])[C@@]1([H])O[H] 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- IFMNWWRDKCBFTO-UHFFFAOYSA-N 2-chloro-n-dichlorophosphorylethanamine Chemical compound ClCCNP(Cl)(Cl)=O IFMNWWRDKCBFTO-UHFFFAOYSA-N 0.000 claims 1
- 125000000222 D-xylofuranosyl group Chemical group [H]OC([H])([H])[C@@]1([H])OC([H])(*)[C@]([H])(O[H])[C@@]1([H])O[H] 0.000 claims 1
- 239000002243 precursor Substances 0.000 abstract description 3
- 230000003327 cancerostatic effect Effects 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 230000001093 anti-cancer Effects 0.000 description 8
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- HMFHBZSHGGEWLO-IOVATXLUSA-N D-xylofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@H]1O HMFHBZSHGGEWLO-IOVATXLUSA-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
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 description 2
- AFINAILKDBCXMX-PBHICJAKSA-N (2s,3r)-2-amino-3-hydroxy-n-(4-octylphenyl)butanamide Chemical compound CCCCCCCCC1=CC=C(NC(=O)[C@@H](N)[C@@H](C)O)C=C1 AFINAILKDBCXMX-PBHICJAKSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- AVVWPBAENSWJCB-IVMDWMLBSA-N D-glucofuranose Chemical class OC[C@@H](O)[C@H]1OC(O)[C@H](O)[C@H]1O AVVWPBAENSWJCB-IVMDWMLBSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- 150000002243 furanoses Chemical class 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000003214 pyranose derivatives Chemical class 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241000555825 Clupeidae Species 0.000 description 1
- WQZGKKKJIJFFOK-CBPJZXOFSA-N D-Gulose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O WQZGKKKJIJFFOK-CBPJZXOFSA-N 0.000 description 1
- WQZGKKKJIJFFOK-IVMDWMLBSA-N D-allopyranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@H](O)[C@@H]1O WQZGKKKJIJFFOK-IVMDWMLBSA-N 0.000 description 1
- HMFHBZSHGGEWLO-ZRMNMSDTSA-N D-arabinofuranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H]1O HMFHBZSHGGEWLO-ZRMNMSDTSA-N 0.000 description 1
- HMFHBZSHGGEWLO-AGQMPKSLSA-N D-lyxofuranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@H]1O HMFHBZSHGGEWLO-AGQMPKSLSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 1
- SDKQRNRRDYRQKY-UHFFFAOYSA-N Dioxacarb Chemical class CNC(=O)OC1=CC=CC=C1C1OCCO1 SDKQRNRRDYRQKY-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- GZCGUPFRVQAUEE-ZXXMMSQZSA-N aldehydo-D-idose Chemical compound OC[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)C=O GZCGUPFRVQAUEE-ZXXMMSQZSA-N 0.000 description 1
- PYMYPHUHKUWMLA-VPENINKCSA-N aldehydo-D-xylose Chemical compound OC[C@@H](O)[C@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-VPENINKCSA-N 0.000 description 1
- 150000001312 aldohexoses Chemical class 0.000 description 1
- 150000001315 aldopentofuranoses Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- WDPNDMPWBDGXDB-UHFFFAOYSA-N dichloro-hydroxy-imino-$l^{5}-phosphane Chemical compound NP(Cl)(Cl)=O WDPNDMPWBDGXDB-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000002303 glucose derivatives Chemical class 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical class ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 150000003018 phosphorus compounds Chemical class 0.000 description 1
- 235000019512 sardine Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- UDEJEOLNSNYQSX-UHFFFAOYSA-J tetrasodium;2,4,6,8-tetraoxido-1,3,5,7,2$l^{5},4$l^{5},6$l^{5},8$l^{5}-tetraoxatetraphosphocane 2,4,6,8-tetraoxide Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P1(=O)OP([O-])(=O)OP([O-])(=O)OP([O-])(=O)O1 UDEJEOLNSNYQSX-UHFFFAOYSA-J 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は諸費格を有するシクロホスファミド化合物およ
びその合成法に関する。DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a cyclophosphamide compound having various costs and a method for synthesizing the same.
本発明シクロホスファミド化合物は新規物質であり、そ
れ自体またはそれを前駆物質とする各種誘導体に抗腫瘍
性、抗癌性が期待されるものである。The cyclophosphamide compound of the present invention is a new substance, and antitumor and anticancer properties are expected for itself or various derivatives using it as a precursor.
（従来の技術）
公知の五員環シクロホスファミド類は下式のように、エ
ポキシドを出発原料とした２−アミノアルコールと適当
なリン酸誘導体のジクロリドとの縮合反応により０−Ｐ
−Ｎ結合を環内に含むヘテロ環を形成させて得られてい
た。(Prior art) Known five-membered ring cyclophosphamides are produced by a condensation reaction between a 2-amino alcohol using epoxide as a starting material and dichloride of an appropriate phosphoric acid derivative, as shown in the following formula.
It was obtained by forming a heterocycle containing a -N bond within the ring.
同様な方法によりそれぞれ下記１および２式に示すよう
なシクロホスファミドおよびイソホスファミド誘導体が
従来合成されていた。Cyclophosphamide and isophosphamide derivatives shown in Formulas 1 and 2 below, respectively, have been synthesized by similar methods.
但し、Ｒ冨００Ｈ，ＯＨ
Ｘ ＝ＣＨ２ＣＨ２Ｃ１
このような環内に０−Ｐ−Ｎ結合を有するシクロホスフ
ァミドおよびイソホスファミド誘導体は様々なタイプの
抗癌剤のうちでも著効を示すものとして広く知られてい
る。However, R 00H, OH There is.
（発明が解決しようとする課題）
しかし乍ら、上記シクロホスファミド系抗癌剤は抗癌作
用の作用部位に・選択性を持たせることが困難であり、
正常細胞に対する副作用などの弊害を軽減せんがために
、充分な薬理作用を発揮することができなかった。(Problems to be Solved by the Invention) However, it is difficult for the above-mentioned cyclophosphamide-based anticancer drugs to have selectivity in the site of action of the anticancer effect;
In order to reduce harmful effects such as side effects on normal cells, it has not been possible to exert sufficient pharmacological effects.
本発明者は最近報道された糖類と癌細胞との親和性に着
目し、この親和性を利用した抗癌剤の作用部位の選択性
改善を指向し、本発明に到達したものである。The present inventor has focused on the recently reported affinity between saccharides and cancer cells, and has aimed to improve the selectivity of the action site of an anticancer drug by utilizing this affinity, thereby arriving at the present invention.
すなわち、本発明の目的は、癌細胞親和性を有する諸費
格と抗癌作用を発揮するオキシアザホスホリナン環とを
同一分子内に有する新規なシクロホスファミド化合物を
提供するにある。That is, an object of the present invention is to provide a novel cyclophosphamide compound having, in the same molecule, a compound having an affinity for cancer cells and an oxyazaphosphorinane ring exhibiting an anticancer effect.
別の目的は、かかる新規なシクロホスファミド化合物を
簡単且つ容易な工程を以って効率よく取得するための合
成法を提供するにある。Another object is to provide a synthetic method for efficiently obtaining such novel cyclophosphamide compounds through simple and easy steps.
（課題を解決するための手段）
上述の目的を達成する本発明の新規シクロホスファミド
化合物は、単糖類の基準炭素原子に結合した窒素原子と
、基準炭素原子に近いグリセロ基の酸素原子とを含むオ
キシアザホスホリナン環を有する。(Means for Solving the Problems) The novel cyclophosphamide compound of the present invention that achieves the above-mentioned object has a nitrogen atom bonded to a reference carbon atom of a monosaccharide, and an oxygen atom of a glycero group close to the reference carbon atom. It has an oxyazaphosphorinane ring containing
かかるシクロホスファミド化合物の好ましい態様は、下
記−服代、
〔但し、Ｒは低級アルキル基、フェニル基またはベンジ
ル基を示す〕
で表わされる。A preferred embodiment of such a cyclophosphamide compound is represented by the following formula: [wherein R represents a lower alkyl group, a phenyl group, or a benzyl group].
また別の態様は、下記−服代、
〔但し、Ｒは低級アルキル基、フェニル基またはベンジ
ル基を示す〕
で表わされる。Another embodiment is represented by the following formula: [wherein R represents a lower alkyl group, a phenyl group, or a benzyl group].
上記の新規シクロホスファミド化合物の合成法は、単糖
の基準炭素原子上に１級アミノ基を有し、それに近い１
個のグリセロ基を除く他のグリセロ基の水酸基を適宜な
保護基を以て保護してなるアミノアルコールに、Ｎ、Ｎ
−ジ−（２−クロロエチル）−ホスホロアミデイックジ
クロリドを縮合させて、オキシアザホスホリナン環を糖
骨格上に構築することよりなる。The above method for synthesizing the novel cyclophosphamide compound has a primary amino group on the standard carbon atom of the monosaccharide, and
N,N
-Di-(2-chloroethyl)-phosphoramidic dichloride is condensed to construct an oxyazaphosphorinane ring on the sugar skeleton.
かかる合成法は更に具体的には、Ｄ−グルコフラノース
のＣ１，２およびＣ５，６位の水酸基をそれぞれジ−Ｏ
−イソプロピリデン化する工程、０３位のアノマー水酸
基を低級アルキル基、フェニル基またはベンジル基で保
護する工程、酸による部分的加水分解によりＣ５，６位
のイソプロピリデン基を外す工程、０６位の水酸基をト
シル化した後にアジド化する工程、アジド基をアミノ基
に還元する工程、および０６位のアミノ基と０５位の水
酸基にＮ、Ｎ−ジ−（２−クロロエチル）−ホスホロア
ミデインクジクロリドを縮合させてオキシアザホスホリ
ナン環を糖骨格上に構築する工程をこの順序で含んでな
る。More specifically, this synthesis method involves converting the hydroxyl groups at the C1,2 and C5,6 positions of D-glucofuranose to di-O
-Process of isopropylidene formation, process of protecting the anomeric hydroxyl group at position 03 with a lower alkyl group, phenyl group or benzyl group, process of removing isopropylidene group at positions C5 and 6 by partial hydrolysis with acid, hydroxyl group at position 06 a step of tosylating and then azidating, a step of reducing the azide group to an amino group, and adding N,N-di-(2-chloroethyl)-phosphoroamide ink dichloride to the amino group at position 06 and the hydroxyl group at position 05. This sequence comprises the steps of condensing the oxyazaphosphorinane ring onto the sugar skeleton.
また合成法の別の態様は、Ｄ−キシロフラノースのＣ１
，２位の水酸基をジ−Ｏ−イソプロピリデン化する工程
、０５位の水酸基をトシル化した後にアジド化する工程
、アジド基をアミノ基に還元する工程、および０５位の
アミノ基と０３位の水酸基にＮ、Ｎジー（２−クロロエ
チル）−ホスホロアミデイックジクロリドを縮合させて
オキシアザホスホリナン環を糖骨格上に構築する工程を
この順序で含んでなる。Another aspect of the synthesis method is the C1 of D-xylofuranose.
, a step of converting the hydroxyl group at position 2 to di-O-isopropylidene, a step of tosylating the hydroxyl group at position 05 and then converting it to azidation, a step of reducing the azide group to an amino group, and a step of converting the hydroxyl group at position 05 to the amino group at position 03. The method includes, in this order, the steps of condensing N,N-di(2-chloroethyl)-phosphoramidic dichloride to the hydroxyl group to construct an oxyazaphosphorinane ring on the sugar skeleton.
以下本発明の構成をその作用と共に更に詳述する。Hereinafter, the structure of the present invention will be explained in more detail along with its operation.
本発明方法に適用するＩ［はフラノース型、ピラノース
型の何れでもよく、好ましくは例えば、Ｄ−リボフラノ
ース、Ｄ−アラビノフラノース、Ｄ−キシロフラノース
、Ｄ−リキソフラノース等のアルドペントフラノース類
、およびＤ−グルコース、Ｄ−マンノース、Ｄ−アロー
ス、Ｄ−アルドロース、Ｄ−グロース、Ｄ−イドース、
Ｄ−ガラクトース、Ｄ−クロース等アルドヘキソース類
のフラノース型およびピラノース型の環状へミアセクー
ルである。I applied to the method of the present invention may be either a furanose type or a pyranose type, preferably an aldopentofuranose such as D-ribofuranose, D-arabinofuranose, D-xylofuranose, or D-lyxofuranose. , and D-glucose, D-mannose, D-allose, D-aldrose, D-gulose, D-idose,
It is a furanose type and pyranose type cyclic hemiasecure of aldohexoses such as D-galactose and D-claose.
以下の説明においては便宜上、出発物質として諸費格に
Ｄ−グルコースを用いる。In the following description, for convenience, D-glucose is used as the starting material.
（イ）Ｄ−クルコースを原料としたｐ４ルエンスルホニ
ルクロリド（トシルクロリド）によるｐ−トルエンスル
ホニル化（トシル化）。(a) p-toluenesulfonylation (tosylation) using p4 luenesulfonyl chloride (tosyl chloride) using D-glucose as a raw material.
Ｄ−グルコースを常法によりアセトン中、無水硫酸銅、
硫酸を用いてジ−Ω−イソプロピリデン化する。D-glucose was added to anhydrous copper sulfate in acetone by a conventional method.
Di-Ω-isopropylidene using sulfuric acid.
次いで残された０３位の水酸基を適宜な保護基、例えば
メチル基、エチル基などの低級アルキル基、フェニル基
、ベンジル基などで保護した後、希酸によりイソプロピ
リデン基を選択的に部分加水分解して、Ｃ５，Ｃ６位の
イソプロピリデン基を外し、ジオール（５）を得る。Next, the remaining hydroxyl group at position 03 is protected with an appropriate protecting group, such as a lower alkyl group such as methyl group or ethyl group, phenyl group, benzyl group, etc., and then the isopropylidene group is selectively partially hydrolyzed with dilute acid. The isopropylidene groups at the C5 and C6 positions are removed to obtain diol (5).
得られたジオール（５，）のＣ６位の水酸基をトシルク
ロリドによりトシル化して３４−メチル−１，２−０−
イソプロピリデン−６４−トシル−α−９−グルコフラ
ノース（６）を得る。The hydroxyl group at the C6 position of the obtained diol (5,) was tosylated with tosyl chloride to give 34-methyl-1,2-0-
Isopropylidene-64-tosyl-α-9-glucofuranose (6) is obtained.
（ロ）上記６−Ｑ−）シルートグルコフラノース誘導体
（６）のアジ化ナトリウムによるアジド化および水素化
トリブチルスズによるアミノアルコールへの還元。(b) Azidation of the above 6-Q-) silute glucofuranose derivative (6) with sodium azide and reduction to amino alcohol with tributyltin hydride.
前記工程（イ）で得たトシル化物（６，）の卦トシル基
をジメチルホルムアミド（ＤＭＦ）中、アジ化ナトリウ
ムによりアジド基に変換した後、トルエン中、水素化ト
リブチルスズにより、−級アミン基に還元し、アミノア
ルコール誘導体である６−アミノ−３〜ｑ−メチル−６
−ジオキシ−１、２４−イソプロピリデン−α −Ω−
グルコフラノース（８）を得る。The tosyl group of the tosylated compound (6,) obtained in the above step (a) was converted into an azide group with sodium azide in dimethylformamide (DMF), and then converted into a -grade amine group with tributyltin hydride in toluene. reduced to 6-amino-3~q-methyl-6, which is an aminoalcohol derivative
-dioxy-1,24-isopropylidene-α -Ω-
Glucofuranose (8) is obtained.
（ハ）前記アミノアルコール（旦）とＮ、Ｎ−ジ−（２
−クロロエチル）−ホスホロアミデイックジクロリドの
反応。(c) The amino alcohol (tan) and N,N-di-(2
-Chloroethyl)-phosphoramidic dichloride reaction.
アミノアルコール８のアミノ基、ヒドロキシル基と上記
のリン酸誘導体の二塩化物の縮合反応によりアザオキシ
ホスホリナン環を有するシクロホスファミドのグルコー
ス誘導体である５−Ｑ−６４−Ｑ−グルコへシクロアザ
オキシホスホリナン環ｍＲ体（９）を合成する。5-Q-64-Q-gluco, which is a glucose derivative of cyclophosphamide having an azaoxyphosphorinane ring, is produced by a condensation reaction between the amino group and hydroxyl group of amino alcohol 8 and the dichloride of the above-mentioned phosphoric acid derivative. Azaoxyphosphorinane ring mR form (9) is synthesized.
以上のような反応経路により各種糖のシクロホスファミ
ド化合物が得られる。Cyclophosphamide compounds of various sugars can be obtained through the reaction routes described above.
例えば出発物質として諸費格にＤ−キシロースを用いた
場合は、０３位の水酸基を保護基で保護する工程を施す
ことなく、他は上記と実質的に同様な工程を経て、Ｎ−
Ｐ−０結合を含むヘテロ６員環を導入したキシロフラノ
ース、即ち３−Ｑ−５４−（ジアルキルアミノ）シクロ
アザオキシアザホスホリナン−１，２−Ｑ−イソプロピ
リデン−α−Ｄ−キシロフラノース（１０）が生成する
。For example, when D-xylose is used as a starting material, the step of protecting the hydroxyl group at the 03-position with a protecting group is not carried out, and the other steps are substantially the same as those described above.
Xylofuranose into which a 6-membered hetero ring containing a P-0 bond is introduced, namely 3-Q-54-(dialkylamino)cycloazaoxyazaphosphorinane-1,2-Q-isopropylidene-α-D-xylofuranose ( 10) is generated.
ｎ ＲｚＮＰＣｆｆｉ□ を用いた場合であり、１０式のＲも同義である。n RzNPCffi□ is used, and R in formula 10 also has the same meaning.
か（して得られた生成物は、
（ａ） ５−Ｑ−６−！！−旦−グルコノーシクロアザ
オキシホスホリナン環誘導体、
（ｂ） ３−！１２−５−！！−二−キシロノホリナン
環誘導体、
シクロアザオキシホス
（Ｃ）上記（ａ） 、 （ｂ）の位置異性シクロホスフ
ァミド類、
（ｄ）上記（ａ） 、 （ｂ） 、 （ｃ）以外の各種
糖のシクロホスファミド誘導体、および
（ｅ） ｔＪ！骨格を含むシクロホスファミド、リン酸
エステルおよびその誘導体
を含む。かかる本発明シクロホスファミド化合物は、単
糖類のカルボニル基より最遠端の炭素原子すなわち基準
炭素原子に結合した窒素原子と、基準炭素原子に最も近
いグリセロ基の酸素原子と、それらを結ぶリン原子とよ
りなるＮ−Ｐ−０結合を含むヘテロ５員環または６員環
を糖骨格上に形成してなる。シクロホスファミド誘導体
（前記１および２）の抗癌作用は既に証明されており、
また糖の癌細胞に対する親和性もまた確認されていると
ころから、抗癌物質を結合担持した形の諸費格が癌細胞
に集中する結果、抗癌作用部位に選択性を与えることが
予想され、抗癌作用の増大が期待される。(a) 5-Q-6-!!-dan-gluconocycloazaoxyphosphorinane ring derivative, (b) 3-!12-5-!!-2- xylonophorinan ring derivatives, cycloazaoxyphos (C) regioisomeric cyclophosphamides of (a) and (b) above, (d) cyclophos of various sugars other than (a), (b), and (c) above. famid derivatives, and (e) cyclophosphamides, phosphate esters, and derivatives thereof containing a tJ! A sugar skeleton is a hetero 5- or 6-membered ring containing an N-P-0 bond consisting of a nitrogen atom bonded to a reference carbon atom, an oxygen atom of the glycero group closest to the reference carbon atom, and a phosphorus atom connecting them. The anticancer effect of the cyclophosphamide derivatives (1 and 2 above) has already been proven.
Furthermore, since the affinity of sugar for cancer cells has also been confirmed, it is expected that the various substances carrying anticancer substances will be concentrated in cancer cells, thereby imparting selectivity to the site of anticancer action. It is expected that the anticancer effect will be increased.
（実施例） 以下に本発明を実施例により更に詳述する。(Example) The present invention will be explained in more detail below using examples.
災施皿上二主
６−アミノ−３−Ｑ−ベンジル−６−ジオキシ−１，２
−Ω−イソプロピリデン−α−Ｄ−グルコフラノース０
．３１ ｇの乾燥ジオキ′サン１０ｄ溶液中にトリエチ
ルアミン１．５−とＮ、Ｎ−ジ−（２−クロロエチル）
−ホスホロアミデイックジクロリド０．４７ ｇを加え
室温にて２時間撹拌した。塩化アンモニウム塩を濾過後
、水で洗いクロロホルム（１０ｉｆｘ３）で抽出した。6-amino-3-Q-benzyl-6-dioxy-1,2
-Ω-isopropylidene-α-D-glucofuranose 0
．． Triethylamine 1.5- and N,N-di-(2-chloroethyl) in a solution of 31 g of dry dioxane 10d
-0.47 g of phosphoramidic dichloride was added and stirred at room temperature for 2 hours. After filtering the ammonium chloride salt, it was washed with water and extracted with chloroform (10ifx3).
無水硫酸ナトリウムで乾燥後溶媒を減圧上留去し、３−
ｑ−ベンジルー５４−６−ｊｑ−（ジー（２′−クロロ
エチル）アミノ〕シクロアザオキシホスホリナン−１，
２−Ｑ−イソプロピリデン−α−トグルコフラノース０
．２８ ｇのシラツブを得た。収率５６％
０３位の保護基をメチル基に変えたもの、および糖をＤ
−キシロースとしたものについて同様な操作を行い、得
られた生成物の収率、ＩＲによる構造確認、質量分析の
結果を第１表に示す。After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 3-
q-Benzyl-54-6-jq-(di(2'-chloroethyl)amino)cycloazaoxyphosphorinane-1,
2-Q-isopropylidene-α-toglucofuranose 0
．． 28 g of sardines were obtained. Yield 56% The protecting group at position 03 was changed to a methyl group, and the sugar was changed to D
-xylose was subjected to the same operation, and Table 1 shows the yield of the obtained product, structure confirmation by IR, and mass spectrometry results.
（発明の効果）
上述の説明から明らかな通り、本発明は次のような数多
くの優れた効果を奏する。(Effects of the Invention) As is clear from the above description, the present invention has many excellent effects as described below.
（ａ） Ｆ骨格を有しているので従来のシクロホスファ
ミド化合物に比べ作用部位の選択性が飛躍的に増加し抗
ガン作用などの生理活性作用が一層期待できる。(a) Since it has an F skeleton, the selectivity of the action site is dramatically increased compared to conventional cyclophosphamide compounds, and more bioactive effects such as anticancer effects can be expected.
（ｂ）反応の各段階は単純であり装置も筒便で、ある。(b) Each step of the reaction is simple and the equipment is convenient.
また原料は豊富且つ安価であり目的物も高収率で得られ
るため工業化に適している。In addition, the raw materials are abundant and inexpensive, and the target product can be obtained in high yield, making it suitable for industrialization.
（ｃ）原料の糖やリン化合物は種々あるので、多数の誘
導体が多量に合成可能である。(c) Since there are various raw material sugars and phosphorus compounds, many derivatives can be synthesized in large quantities.
（ｄ） シクロアザオキシホスホリナン環の形成の際
に糖の立体化学は保持されるので生成物の立体異性体を
生成することなく純粋な生成物を得ることができ、その
立体化学は容易に決定できる。(d) Since the stereochemistry of the sugar is preserved during the formation of the cycloazaoxyphosphorinane ring, a pure product can be obtained without forming stereoisomers of the product, and its stereochemistry can be easily changed. You can decide.
（ｅ）本発明シクロホスファミド化合物はそれ自体、作
用部位の選択性を有する抗癌剤として著効が期待される
のみならず、それから誘導される各種抗癌剤などの新規
化合物の前駆体または中間体ともなり得るものと思われ
る。(e) The cyclophosphamide compound of the present invention is not only expected to be highly effective as an anticancer agent with selectivity in its action site, but also as a precursor or intermediate of new compounds such as various anticancer agents derived from it. It seems possible.
Claims (1)
炭素原子に近いグリセロ基の酸素原子とを含むオキシア
ザホスホリナン環を有する新規シクロホスファミド化合
物。 ２、下記一般式、 ▲数式、化学式、表等があります▼ 〔但し、Ｒは低級アルキル基、フェニル基またはベンジ
ル基を示す〕 で表わされる請求項１記載の化合物。 ３、下記一般式、 ▲数式、化学式、表等があります▼ 〔但し、Ｒは低級アルキル基、フェニル基またはベンジ
ル基を示す〕 で表わされる請求項１記載の化合物。 ４、単糖の基準炭素原子上に１級アミノ基を有し、それ
に近い１個のグリセロ基を除く他のグリセロ基の水酸基
を適宜な保護基を以て保護してなるアミノアルコールに
、Ｎ，Ｎ−ジ−（２−クロロエチル）−ホスホロアミデ
イックジクロリドを縮合させて、オキシアザホスホリナ
ン環を糖骨格上に構築することよりなる新規シクロホス
ファミド化合物の合成法。 ５、Ｄ−グルコフラノースのＣ１、２およびＣ５、６位
の水酸基をそれぞれジ−￥Ｏ￥−イソプロピリデン化す
る工程、Ｃ３位のアノマー水酸基を低級アルキル基、フ
ェニル基またはベンジル基で保護する工程、酸による部
分的加水分解によりＣ５、６位のイソプロピリデン基を
外す工程、Ｃ６位の水酸基をトシル化した後にアジド化
する工程、アジド基をアミノ基に還元する工程、および
Ｃ６位のアミノ基とＣ５位の水酸基にＮ，Ｎ−ジ−（２
−クロロエチル）−ホスホロアミディックジクロリドを
縮合させてオキシアザホスホリナン環を糖骨格上に構築
する工程をこの順序で含んでなる新規シクロホスファミ
ド化合物の合成法。 ６、Ｄ−キシロフラノースのＣ１、２位の水酸基をジ−
Ｏ−イソプロピリデン化する工程、Ｃ５位の水酸基をト
シル化した後にアジド化する工程、アジド基をアミノ基
に還元する工程、およびＣ５位のアミノ基とＣ３位の水
酸基にＮ，Ｎ−ジ−（２−クロロエチル）−ホスホロア
ミディックジクロリドを縮合させてオキシアザホスホリ
ナン環を糖骨格上に構築する工程をこの順序で含んでな
る新規シクロホスファミド化合物の合成法。[Scope of Claims] 1. A novel cyclophosphamide compound having an oxyazaphosphorinane ring containing a nitrogen atom bonded to a reference carbon atom of a monosaccharide and an oxygen atom of a glycero group close to the reference carbon atom. 2. The compound according to claim 1, which is represented by the following general formula: ▲A mathematical formula, a chemical formula, a table, etc.▼ [However, R represents a lower alkyl group, a phenyl group, or a benzyl group]. 3. The compound according to claim 1, which is represented by the following general formula: ▲A mathematical formula, a chemical formula, a table, etc.▼ [However, R represents a lower alkyl group, a phenyl group, or a benzyl group]. 4. An amino alcohol having a primary amino group on the standard carbon atom of a monosaccharide and protecting the hydroxyl groups of the glycero groups other than the one glycero group with an appropriate protecting group, N,N A method for synthesizing a novel cyclophosphamide compound, which comprises constructing an oxyazaphosphorinane ring on a sugar skeleton by condensing -di-(2-chloroethyl)-phosphoramidic dichloride. 5. Step of converting the hydroxyl groups at the C1, 2 and C5, 6 positions of D-glucofuranose into di-\O\-isopropylidene, respectively; Protecting the anomeric hydroxyl group at the C3 position with a lower alkyl group, phenyl group or benzyl group , a step of removing isopropylidene groups at the C5 and 6 positions by partial hydrolysis with an acid, a step of tosylating the hydroxyl group at the C6 position and then azidation, a step of reducing the azide group to an amino group, and an amino group at the C6 position. and N,N-di-(2
-Chloroethyl)-phosphoroamidic dichloride is condensed to construct an oxyazaphosphorinane ring on a sugar skeleton in this order. 6. The hydroxyl groups at the C1 and 2 positions of D-xylofuranose are di-
A step of converting the hydroxyl group at the C5-position to an O-isopropylidene, a step of tosylating the hydroxyl group at the C5-position and then converting it to an azidation, a step of reducing the azide group to an amino group, and a step of converting the amino group at the C5-position and the hydroxyl group at the C3-position into N,N-di- A method for synthesizing a novel cyclophosphamide compound, comprising the steps of condensing (2-chloroethyl)-phosphoroamidic dichloride to construct an oxyazaphosphorinane ring on a sugar skeleton in this order.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1143999A JPH06104677B2 (en) | 1989-06-08 | 1989-06-08 | Novel cyclophosphamide compound and synthetic method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1143999A JPH06104677B2 (en) | 1989-06-08 | 1989-06-08 | Novel cyclophosphamide compound and synthetic method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0311095A true JPH0311095A (en) | 1991-01-18 |
| JPH06104677B2 JPH06104677B2 (en) | 1994-12-21 |
Family
ID=15351961
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1143999A Expired - Fee Related JPH06104677B2 (en) | 1989-06-08 | 1989-06-08 | Novel cyclophosphamide compound and synthetic method thereof |
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| Country | Link |
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| US8598629B2 (en) | 2005-07-20 | 2013-12-03 | Sony Corporation | High-frequency device including high-frequency switching circuit |
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1989
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| Title |
|---|
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|---|---|---|---|---|
| US8598629B2 (en) | 2005-07-20 | 2013-12-03 | Sony Corporation | High-frequency device including high-frequency switching circuit |
| US9105564B2 (en) | 2005-07-20 | 2015-08-11 | Sony Corporation | High-frequency device including high-frequency switching circuit |
| US9406696B2 (en) | 2005-07-20 | 2016-08-02 | Sony Corporation | High-frequency device including high-frequency switching circuit |
| US9824986B2 (en) | 2005-07-20 | 2017-11-21 | Sony Corporation | High-frequency device including high-frequency switching circuit |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH06104677B2 (en) | 1994-12-21 |
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