JP2002037780A - Sialic acid derivative - Google Patents
Sialic acid derivativeInfo
- Publication number
- JP2002037780A JP2002037780A JP2001147151A JP2001147151A JP2002037780A JP 2002037780 A JP2002037780 A JP 2002037780A JP 2001147151 A JP2001147151 A JP 2001147151A JP 2001147151 A JP2001147151 A JP 2001147151A JP 2002037780 A JP2002037780 A JP 2002037780A
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Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は優れたシアリダーゼ
阻害活性を有するノイラミン酸化合物若しくはその薬理
上許容されるエステル誘導体又はそれらの薬理上許容さ
れる塩、及びそれらを有効成分として含有する医薬（特
にインフルエンザの治療剤又は予防剤）に関する。The present invention relates to a neuraminic acid compound having excellent sialidase inhibitory activity, a pharmacologically acceptable ester derivative thereof or a pharmacologically acceptable salt thereof, and a medicament containing them as an active ingredient (particularly, A therapeutic or prophylactic agent for influenza).
【０００２】[0002]
【従来の技術】特表平５−５０７０６８号公報、特開平
１０−３３０３７３号公報、特開平１０−１０９９８１
号公報等には６位に修飾されていてもよいグリセロール
単位を有する２−デオキシ−２，３−ジデヒドロ−Ｎ−
アセチルノイラミン酸誘導体がシアリダーゼ阻害活性を
有し、インフルエンザ治療剤として有効であることが開
示されている。しかし、これらの誘導体は消化管から吸
収され難く経口剤としては無効であるため、経口投与で
も有効なインフルエンザ治療剤が望まれている。2. Description of the Related Art Japanese Unexamined Patent Publication No. Hei 5-507068, Japanese Unexamined Patent Publication No. Hei 10-330373, and Japanese Unexamined Patent Publication No. Hei 10-1099981.
And the like, have 2-deoxy-2,3-didehydro-N- having a glycerol unit which may be modified at the 6-position.
It is disclosed that acetylneuraminic acid derivatives have sialidase inhibitory activity and are effective as therapeutic agents for influenza. However, since these derivatives are hardly absorbed from the digestive tract and are ineffective as oral preparations, therapeutic agents for influenza which are effective even in oral administration are desired.
【０００３】[0003]
【発明が解決しようとする課題】発明者らはノイラミン
酸骨格を有する化合物について長年にわたり鋭意検討を
行なった結果、一般式（１）で表される化合物は優れた
シアリダーゼ阻害活性を示し、更に一般式（１）で表さ
れる化合物またはその薬理上許容されるエステル誘導体
は経口投与でも抗インフルエンザ作用を有し、医薬（特
にインフルエンザ治療剤又は予防剤）として有用である
ことを見出し本発明を完成した。SUMMARY OF THE INVENTION The present inventors have conducted intensive studies on a compound having a neuraminic acid skeleton for many years, and as a result, the compound represented by the general formula (1) shows excellent sialidase inhibitory activity. The compound represented by the formula (1) or a pharmacologically acceptable ester derivative thereof has an anti-influenza activity even when administered orally, and is found to be useful as a medicament (especially a therapeutic or prophylactic agent for influenza) to complete the present invention. did.
【０００４】[0004]
【課題を解決するための手段】本発明は、次の通りであ
る。 （１） 一般式Means for Solving the Problems The present invention is as follows. (1) General formula
【０００５】[0005]
【化２】 Embedded image
【０００６】［式中、Ｒ1及びＲ2は同一又は異なって水
素原子又は水酸基を示し、Ｒ3及びＲ4は同一又は異なっ
て水素原子又は炭素数１乃至４個のアルキル基を示し、
Ｒ5及びＲ6は同一又は異なって水素原子、フッ素原子又
は炭素数１乃至４個のアルキル基を示し、Ｒ7及びＲ8は
同一又は異なって水素原子又は炭素数１乃至４個のアル
キル基を示し、Ｒ9はフッ素原子で置換されていてもよ
い炭素数１乃至４個のアルキル基であり、Ｒ10は炭素数
１乃至４個のアルキルで置換されていてもよいアミノ基
又は式−ＮＲ11Ｃ（＝ＮＲ12）Ｒ13（式中、Ｒ11及びＲ
12は同一又は異なって水素原子又は炭素数１乃至４個の
アルキル基を示し、Ｒ13は水素原子、炭素数１乃至４個
のアルキル基又は炭素数１乃至４個のアルキル基で置換
されていてもよいアミノ基を示す）で表される基を示
し、ｎは１、２又は３を示し、ｍは０、１又は２を示
す。］で表される化合物、その薬理上許容されるエステ
ル誘導体又はそれらの薬理上許容される塩。 （２） （１）において、Ｒ1及びＲ2が、同一であって
水素原子又は水酸基である化合物、その薬理上許容され
るエステル誘導体又はそれらの薬理上許容される塩。 （３） （１）において、Ｒ1及びＲ2が、同一であって
水酸基である化合物、その薬理上許容されるエステル誘
導体又はそれらの薬理上許容される塩。 （４） （１）乃至（３）において、Ｒ3及びＲ4が、同
一又は異なって水素原子又はメチル基である化合物、そ
の薬理上許容されるエステル誘導体又はそれらの薬理上
許容される塩。 （５） （１）乃至（３）において、Ｒ3及びＲ4が、同
一であって水素原子である化合物、その薬理上許容され
るエステル誘導体又はそれらの薬理上許容される塩。 （６） （１）乃至（５）において、Ｒ5及びＲ6が、ｎ
の繰り返し単位において独立して、同一又は異なって水
素原子又はフッ素原子である化合物、その薬理上許容さ
れるエステル誘導体又はそれらの薬理上許容される塩。 （７） （１）乃至（５）において、Ｒ5及びＲ6が、同
一であって水素原子である化合物、その薬理上許容され
るエステル誘導体又はそれらの薬理上許容される塩。 （８） （１）乃至（７）において、ｎが、１または２
である化合物、その薬理上許容されるエステル誘導体又
はそれらの薬理上許容される塩。 （９） （１）乃至（７）において、ｎが、２である化
合物、その薬理上許容されるエステル誘導体又はそれら
の薬理上許容される塩。 （１０） （１）乃至（９）において、ｍが、０または
１である化合物、その薬理上許容されるエステル誘導体
又はそれらの薬理上許容される塩。 （１１） （１）乃至（９）において、ｍが、０である
化合物、その薬理上許容されるエステル誘導体又はそれ
らの薬理上許容される塩。 （１２） （１）乃至（１１）において、Ｒ7及びＲ
8が、ｍの繰り返し単位において独立して、同一又は異
なって水素原子又はメチル基である化合物、その薬理上
許容されるエステル誘導体又はそれらの薬理上許容され
る塩。 （１３） （１）乃至（１１）において、Ｒ7及びＲ
8が、同一であって水素原子である化合物、その薬理上
許容されるエステル誘導体又はそれらの薬理上許容され
る塩。 （１４） （１）乃至（１３）において、Ｒ9が、フッ
素原子で置換されていてもよいメチル基である化合物、
その薬理上許容されるエステル誘導体又はそれらの薬理
上許容される塩。 （１５） （１）乃至（１３）において、Ｒ9が、メチ
ル、ジフルオロメチルまたはトリフルオロメチル基であ
る化合物、その薬理上許容されるエステル誘導体又はそ
れらの薬理上許容される塩。 （１６） （１）乃至（１３）において、Ｒ9が、メチ
ル基である化合物、その薬理上許容されるエステル誘導
体又はそれらの薬理上許容される塩。 （１７） （１）乃至（１６）において、Ｒ10が、アミ
ノ、メチルアミノ、ジメチルアミノ又は式−ＮＲ11aＣ
（＝ＮＲ12a）Ｒ13a（式中、Ｒ11a及びＲ12aは同一又は
異なって水素原子又はメチル基を示し、Ｒ13aは水素原
子、メチル、アミノ又はメチルアミノ基を示す）で表さ
れる基である化合物、その薬理上許容されるエステル誘
導体又はそれらの薬理上許容される塩。 （１８） （１）乃至（１６）において、Ｒ10が、アミ
ノ、メチルアミノ、ジメチルアミノ、ホルムイミドイル
アミノ、アセトイミドイルアミノ又はグアニジノ基であ
る化合物、その薬理上許容されるエステル誘導体又はそ
れらの薬理上許容される塩。 （１９） （１）乃至（１６）において、Ｒ10が、グア
ニジノ基である化合物、その薬理上許容されるエステル
誘導体又はそれらの薬理上許容される塩。[Wherein, R 1 and R 2 are the same or different and represent a hydrogen atom or a hydroxyl group, R 3 and R 4 are the same or different and represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,
R 5 and R 6 are the same or different and represent a hydrogen atom, a fluorine atom or an alkyl group having 1 to 4 carbon atoms, and R 7 and R 8 are the same or different and are a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. R 9 is an alkyl group having 1 to 4 carbon atoms which may be substituted by a fluorine atom, and R 10 is an amino group which may be substituted by an alkyl having 1 to 4 carbon atoms or a formula- NR 11 C (= NR 12 ) R 13 (wherein R 11 and R
12 is the same or different and represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R 13 is substituted by a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an alkyl group having 1 to 4 carbon atoms. And n represents 1, 2 or 3, and m represents 0, 1 or 2. Or a pharmacologically acceptable ester derivative thereof or a pharmacologically acceptable salt thereof. (2) The compound according to (1), wherein R 1 and R 2 are the same and are a hydrogen atom or a hydroxyl group, a pharmaceutically acceptable ester derivative thereof, or a pharmaceutically acceptable salt thereof. (3) The compound according to (1), wherein R 1 and R 2 are the same and are hydroxyl groups, a pharmaceutically acceptable ester derivative thereof, or a pharmaceutically acceptable salt thereof. (4) The compounds according to (1) to (3), wherein R 3 and R 4 are the same or different and each is a hydrogen atom or a methyl group, a pharmaceutically acceptable ester derivative thereof, or a pharmaceutically acceptable salt thereof. (5) In any of (1) to (3), compounds wherein R 3 and R 4 are the same and are hydrogen atoms, a pharmaceutically acceptable ester derivative thereof, or a pharmaceutically acceptable salt thereof. (6) In (1) to (5), R 5 and R 6 are n
A compound, a pharmaceutically acceptable ester derivative or a pharmaceutically acceptable salt thereof, which is the same or different and is a hydrogen atom or a fluorine atom independently in the repeating unit of (7) The compound according to (1) to (5), wherein R 5 and R 6 are the same and are hydrogen atoms, a pharmaceutically acceptable ester derivative thereof, or a pharmaceutically acceptable salt thereof. (8) In (1) to (7), n is 1 or 2
Or a pharmacologically acceptable ester derivative thereof or a pharmacologically acceptable salt thereof. (9) The compound according to (1) to (7), wherein n is 2, a pharmacologically acceptable ester derivative thereof, or a pharmacologically acceptable salt thereof. (10) The compound according to (1) to (9), wherein m is 0 or 1, a pharmacologically acceptable ester derivative thereof, or a pharmacologically acceptable salt thereof. (11) The compound according to (1) to (9), wherein m is 0, a pharmaceutically acceptable ester derivative thereof, or a pharmaceutically acceptable salt thereof. (12) In (1) to (11), R 7 and R
A compound, a pharmacologically acceptable ester derivative or a pharmacologically acceptable salt thereof, wherein 8 is independently the same or different hydrogen atom or methyl group in the repeating unit of m. (13) In (1) to (11), R 7 and R
A compound wherein 8 is the same and is a hydrogen atom, a pharmaceutically acceptable ester derivative thereof or a pharmaceutically acceptable salt thereof. (14) The compound according to (1) to (13), wherein R 9 is a methyl group optionally substituted by a fluorine atom,
A pharmacologically acceptable ester derivative thereof or a pharmacologically acceptable salt thereof. (15) The compound according to (1) to (13), wherein R 9 is a methyl, difluoromethyl or trifluoromethyl group, a pharmaceutically acceptable ester derivative thereof, or a pharmaceutically acceptable salt thereof. (16) The compound according to any one of (1) to (13), wherein R 9 is a methyl group, a pharmaceutically acceptable ester derivative thereof, or a pharmaceutically acceptable salt thereof. (17) In the above (1) to (16), R 10 is amino, methylamino, dimethylamino or a compound of the formula —NR 11a C
(= NR 12a ) R 13a (wherein R 11a and R 12a are the same or different and each represent a hydrogen atom or a methyl group, and R 13a represents a hydrogen atom, methyl, amino or methylamino group) Or a pharmacologically acceptable ester derivative thereof or a pharmacologically acceptable salt thereof. (18) In the compounds (1) to (16), compounds wherein R 10 is an amino, methylamino, dimethylamino, formimidoylamino, acetimidoylamino or guanidino group, a pharmaceutically acceptable ester derivative thereof, or a compound thereof. Pharmacologically acceptable salts of (19) The compound according to (1) to (16), wherein R 10 is a guanidino group, a pharmacologically acceptable ester derivative thereof, or a pharmacologically acceptable salt thereof.
【０００７】上記において、Ｒ3、Ｒ4、Ｒ5、Ｒ6、
Ｒ7、Ｒ8、Ｒ9、Ｒ11、Ｒ12及びＲ13の定義における
「炭素数１乃至４個のアルキル基」としては、例えばメ
チル、エチル、プロピル、イソプロピル、ブチル、イソ
ブチル、ｓ−ブチル、t−ブチル基を挙げることがで
き、好適にはメチルまたはエチル基であり、特に好適に
はメチル基である。In the above, R 3 , R 4 , R 5 , R 6 ,
Examples of the “alkyl group having 1 to 4 carbon atoms” in the definition of R 7 , R 8 , R 9 , R 11 , R 12 and R 13 include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl , T-butyl group, preferably a methyl or ethyl group, particularly preferably a methyl group.
【０００８】Ｒ9の定義における「フッ素原子で置換さ
れていてもよい炭素数１乃至４個のアルキル基」として
は、例えばメチル、フルオロメチル、ジフルオロメチ
ル、トリフルオロメチル、エチル、２−フルオロエチ
ル、２，２，２−トリフルオロエチル、プロピル、イソ
プロピル、ブチル、イソブチル、ｓ−ブチル、t−ブチ
ル基等を挙げることができ、好適にはフッ素原子で置換
されていてもよいメチル基であり、更に好適にはメチ
ル、ジフルオロメチルまたはトリフルオロメチル基であ
り、最も好適にはメチル基である。The "alkyl group having 1 to 4 carbon atoms which may be substituted by a fluorine atom" in the definition of R 9 includes, for example, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, 2-fluoroethyl , 2,2,2-trifluoroethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl and the like, and preferably a methyl group optionally substituted by a fluorine atom. , More preferably a methyl, difluoromethyl or trifluoromethyl group, most preferably a methyl group.
【０００９】Ｒ10及びＲ13の定義における「炭素数１乃
至４個のアルキル基で置換されていてもよいアミノ基」
としては、例えばアミノ、メチルアミノ、ジメチルアミ
ノ、エチルアミノ、ジエチルアミノ、プロピルアミノ、
ジプロピルアミノ、ブチルアミノ基を挙げることができ
る。"Amino group optionally substituted by an alkyl group having 1 to 4 carbon atoms" in the definition of R 10 and R 13
As, for example, amino, methylamino, dimethylamino, ethylamino, diethylamino, propylamino,
Examples thereof include dipropylamino and butylamino groups.
【００１０】Ｒ10における「炭素数１乃至４個のアルキ
ル基で置換されていてもよいアミノ基」は、好適にはア
ミノ、メチルアミノ又はジメチルアミノ基であり、更に
好適にはアミノ基である。[0010] "amino group which may be substituted by C 1 to 4 alkyl group having a carbon" in R 10 is preferably amino, methylamino or dimethylamino group, and more preferably is an amino group .
【００１１】Ｒ13における「炭素数１乃至４個のアルキ
ル基で置換されていてもよいアミノ基」は、好適にはア
ミノ又はメチルアミノ基であり、更に好適にはアミノ基
である。The “amino group optionally substituted by an alkyl group having 1 to 4 carbon atoms” for R 13 is preferably an amino or methylamino group, and more preferably an amino group.
【００１２】Ｒ10の定義における「式−ＮＲ11Ｃ（＝Ｎ
Ｒ12）Ｒ13（式中、Ｒ11及びＲ12は同一又は異なって水
素原子又は炭素数１乃至４個のアルキル基を示し、Ｒ13
は水素原子、炭素数１乃至４個のアルキル基又は炭素数
１乃至４個のアルキル基で置換されていてもよいアミノ
基を示す）で表される基」としては、例えばホルムイミ
ドイルアミノ、アセトイミドイルアミノ、プロピオイミ
ドイルアミノ、グアニジノ基等を挙げることができ、好
適には式−ＮＲ11aＣ（＝ＮＲ12a）Ｒ13a（式中、Ｒ11a
及びＲ12aは同一又は異なって水素原子又はメチル基を
示し、Ｒ13aは水素原子、メチル、アミノ又はメチルア
ミノ基を示す）で表される基であり、更に好適にはホル
ムイミドイルアミノ、アセトイミドイルアミノ又はグア
ニジノ基であり、最も好適にはグアニジノ基である。In the definition of R 10 , “formula —NR 11 C (= N
R 12) R 13 (wherein, R 11 and R 12 are the same or different and each represents a hydrogen atom or a C 1 to 4 alkyl group having a carbon, R 13
Represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an amino group which may be substituted with an alkyl group having 1 to 4 carbon atoms)), for example, formimidoylamino, Examples thereof include acetimidoylamino, propioimidoylamino, and a guanidino group, and are preferably represented by the formula —NR 11a C (＝ NR 12a ) R 13a (wherein, R 11a
And R 12a are the same or different and each represent a hydrogen atom or a methyl group, and R 13a represents a hydrogen atom, a methyl, amino or methylamino group), more preferably formimidoylamino, An imidoylamino or guanidino group, most preferably a guanidino group.
【００１３】Ｒ11は、好適には水素原子またはメチル基
であり、特に好適には水素原子である。R 11 is preferably a hydrogen atom or a methyl group, particularly preferably a hydrogen atom.
【００１４】Ｒ12は、好適には水素原子またはメチル基
であり、特に好適には水素原子である。R 12 is preferably a hydrogen atom or a methyl group, particularly preferably a hydrogen atom.
【００１５】Ｒ13は、好適には水素原子、メチル、エチ
ル、アミノまたはメチルアミノ基であり、更に好適には
水素原子、メチルまたはアミノ基であり、特に好適には
アミノ基である。R 13 is preferably a hydrogen atom, methyl, ethyl, amino or methylamino group, more preferably a hydrogen atom, methyl or amino group, and particularly preferably an amino group.
【００１６】Ｒ1及びＲ2は、好適には同一であって水素
原子又は水酸基であり、更に好適には同一であって水酸
基である。R 1 and R 2 are preferably the same and are a hydrogen atom or a hydroxyl group, and more preferably the same and are a hydroxyl group.
【００１７】Ｒ3及びＲ4は、好適には同一又は異なって
水素原子又はメチル基であり、更に好適には同一であっ
て水素原子である。R 3 and R 4 are preferably the same or different and are a hydrogen atom or a methyl group, and more preferably the same and a hydrogen atom.
【００１８】Ｒ5及びＲ6は、ｎの繰り返し単位において
独立して、同一又は異なっていてもよく、好適には同一
又は異なって水素原子又はフッ素原子であり、更に好適
には同一であって水素原子である。R 5 and R 6 may be independently the same or different in n repeating units, preferably are the same or different and are a hydrogen atom or a fluorine atom, more preferably the same. It is a hydrogen atom.
【００１９】ｎは、好適には１または２であり、最も好
適には２である。N is preferably 1 or 2, and most preferably 2.
【００２０】ｍは、好適には０または１であり、最も好
適には０である。M is preferably 0 or 1, and most preferably 0.
【００２１】Ｒ7及びＲ8は、ｍの繰り返し単位において
独立して、同一又は異なっていてもよく、好適には同一
又は異なって水素原子又はメチル基であり、更に好適に
は同一であって水素原子である。R 7 and R 8 may be independently the same or different in the repeating unit m, preferably the same or different and are a hydrogen atom or a methyl group, more preferably the same or different. It is a hydrogen atom.
【００２２】Ｒ9は、好適にはフッ素原子で置換されて
いてもよいメチル基であり、更に好適にはメチル、ジフ
ルオロメチルまたはトリフルオロメチル基であり、最も
好適にはメチル基である。R 9 is preferably a methyl group optionally substituted with a fluorine atom, more preferably a methyl, difluoromethyl or trifluoromethyl group, most preferably a methyl group.
【００２３】Ｒ10は、好適にはアミノ、メチルアミノ、
ジメチルアミノ又は式−ＮＲ11aＣ（＝ＮＲ12a）Ｒ13a
（式中、Ｒ11a及びＲ12aは同一又は異なって水素原子又
はメチル基を示し、Ｒ13aは水素原子、メチル、アミノ
又はメチルアミノ基を示す）で表される基であり、更に
好適にはアミノ、メチルアミノ、ジメチルアミノ、ホル
ムイミドイルアミノ、アセトイミドイルアミノ又はグア
ニジノ基であり、最も好適にはグアニジノ基である。R 10 is preferably amino, methylamino,
Dimethylamino or formula -NR 11a C (= NR 12a ) R 13a
(Wherein, R 11a and R 12a are the same or different and each represent a hydrogen atom or a methyl group, and R 13a represents a hydrogen atom, methyl, amino or methylamino group). An amino, methylamino, dimethylamino, formimidoylamino, acetimidoylamino or guanidino group, most preferably a guanidino group.
【００２４】化合物（１）は好適には下記の式で表され
る立体異性体である。The compound (1) is preferably a stereoisomer represented by the following formula.
【００２５】[0025]
【化３】 Embedded image
【００２６】化合物（１）の「薬理上許容されるエステ
ル誘導体」とは、ヒトまたは動物体内で加水分解等の化
学的若しくは生物学的方法により開裂し化合物（１）を
生成するように化合物（１）の水酸基またはカルボキシ
ル基が保護されたエステル誘導体（いわゆる「エステル
型プロドラッグ」）をいい、そのようなエステル誘導体
か否かは、ラットやマウスのような実験動物に経口、点
鼻、経鼻、経肺、静脈注射等により投与し、その後の動
物の体液を調べ、化合物（１）を検出できることにより
決定できる。The "pharmacologically acceptable ester derivative" of the compound (1) is a compound (1) which is cleaved in a human or animal body by a chemical or biological method such as hydrolysis to produce the compound (1). 1) An ester derivative in which a hydroxyl group or a carboxyl group is protected (a so-called “ester-type prodrug”). Whether such an ester derivative is orally, nasally or transdermally administered to experimental animals such as rats and mice. The compound is administered by nasal, pulmonary, intravenous injection, or the like, and then the body fluid of the animal is examined to determine the compound (1).
【００２７】そのような薬理上許容されるエステル誘導
体としては、水酸基が脂肪族又は芳香族アシル基のよう
なアシル基で修飾されたエステル誘導体及びカルボキシ
ル基が保護されたエステル誘導体を挙げることができ
る。Examples of such pharmacologically acceptable ester derivatives include ester derivatives in which a hydroxyl group is modified with an acyl group such as an aliphatic or aromatic acyl group and ester derivatives in which a carboxyl group is protected. .
【００２８】脂肪族アシル基としては、例えば、ホルミ
ル、アセチル、プロピオニル、ブタノイル、２-メチル
プロピオニル、２，２−ジメチルプロピオニル（ピバロ
イル）、ペンタノイル、イソペンタノイル、２−メチル
ブタノイル、ネオペンタノイル、ヘキサノイル、イソヘ
キサノイル、４−メチルペンタノイル、３−メチルペン
タノイル、２−メチルペンタノイル、３，３−ジメチル
ブタノイル、２，２−ジメチルブタノイル、２，３−ジ
メチルブタノイル、２−エチルブタノイル、ヘプタノイ
ル、２−メチルヘキサノイル、３−メチルヘキサノイ
ル、４−メチルヘキサノイル、５−メチルヘキサノイ
ル、４，４−ジメチルペンタノイル、オクタノイル、２
−メチルヘプタノイル、３−メチルヘプタノイル、４−
メチルヘプタノイル、５−メチルヘプタノイル、６−メ
チルヘプタノイル、２−エチルヘキサノイル、５，５−
ジメチルヘキサノイル、ノナノイル、３−メチルオクタ
ノイル、４−メチルオクタノイル、５−メチルオクタノ
イル、６−メチルオクタノイル、２−エチルヘプタノイ
ル、６，６−ジメチルヘプタノイル、デカノイル、３−
メチルノナノイル、８−メチルノナノイル、３−エチル
オクタノイル、３，７−ジメチルオクタノイル、７，７
−ジメチルオクタノイル、ウンデカノイル、４，８−ジ
メチルノナノイル、ドデカノイル、トリデカノイル、テ
トラデカノイル、ペンタデカノイル、３，７，１１−ト
リメチルドデカノイル、ヘキサデカノイル、４，８，１
２−トリメチルトリデカノイル、１−メチルペンタデカ
ノイル、１４−メチルペンタデカノイル、１３，１３−
ジメチルテトラデカノイル、ヘプタデカノイル、１５−
メチルヘキサデカノイル、オクタデカノイル、１−メチ
ルヘプタデカノイル、ノナデカノイル、アイコサノイル
またはドコサノイル基のような炭素数１乃至２２個のア
ルカノイル基；メトキシカルボニル、エトキシカルボニ
ル、プロポキシカルボニル、イソプロポキシカルボニ
ル、ブチルオキシカルボニル、イソブチルオキシカルボ
ニル、ｓ−ブチルオキシカルボニル、ｔ−ブチルオキシ
カルボニル、ペンチルオキシカルボニル、ヘキシルオキ
シカルボニル、ヘプチルオキシカルボニル、オクチルオ
キシカルボニル、ノニルオキシカルボニル、デシルオキ
シカルボニル、ウンデシルオキシカルボニル、ドデシル
オキシカルボニル、トリデシルオキシカルボニル、テト
ラデシルオキシカルボニル、ペンタデシルオキシカルボ
ニル、ヘキサデシルオキシカルボニル、ヘプタデシルオ
キシカルボニル、オクタデシルオキシカルボニル、ノナ
デシルオキシカルボニルまたはアイコサニルオキシカル
ボニル基のような炭素数２乃至２２個のアルコキシカル
ボニル基を挙げることができる。これら脂肪族アシル基
のアルキル部分は、３乃至７員環状構造及び２又は３重
結合を有していてもよい。Examples of the aliphatic acyl group include formyl, acetyl, propionyl, butanoyl, 2-methylpropionyl, 2,2-dimethylpropionyl (pivaloyl), pentanoyl, isopentanoyl, 2-methylbutanoyl and neopentanoyl , Hexanoyl, isohexanoyl, 4-methylpentanoyl, 3-methylpentanoyl, 2-methylpentanoyl, 3,3-dimethylbutanoyl, 2,2-dimethylbutanoyl, 2,3-dimethylbutanoyl, -Ethylbutanoyl, heptanoyl, 2-methylhexanoyl, 3-methylhexanoyl, 4-methylhexanoyl, 5-methylhexanoyl, 4,4-dimethylpentanoyl, octanoyl,
-Methylheptanoyl, 3-methylheptanoyl, 4-
Methylheptanoyl, 5-methylheptanoyl, 6-methylheptanoyl, 2-ethylhexanoyl, 5,5-
Dimethylhexanoyl, nonanoyl, 3-methyloctanoyl, 4-methyloctanoyl, 5-methyloctanoyl, 6-methyloctanoyl, 2-ethylheptanoyl, 6,6-dimethylheptanoyl, decanoyl, 3-
Methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, 7,7
-Dimethyloctanoyl, undecanoyl, 4,8-dimethylnonanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, 3,7,11-trimethyldodecanoyl, hexadecanoyl, 4,8,1
2-trimethyltridecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-
Dimethyltetradecanoyl, heptadecanoyl, 15-
Alkanoyl group having 1 to 22 carbon atoms such as methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, eicosanoyl or docosanoyl; methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butyloxy Carbonyl, isobutyloxycarbonyl, s-butyloxycarbonyl, t-butyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl , Tridecyloxycarbonyl, tetradecyloxycarbonyl, pentadecyloxycarbonyl, hexadecyl Alkoxycarbonyl, heptadecyl oxycarbonyl, octadecyloxycarbonyl, may be mentioned alkoxycarbonyl group having 2 to 22 carbons such as nonadecyl oxycarbonyl or icon Sa aryloxycarbonyl group. The alkyl portion of these aliphatic acyl groups may have a 3- to 7-membered cyclic structure and a double or triple bond.
【００２９】芳香族アシル基としては、例えば、ベンゾ
イル、α−ナフトイル、β−ナフトイルのような炭素数
７乃至１１個のアリールカルボニル基；２−フェニルア
セチル、３−フェニルプロピオニル、４−フェニルブチ
リル、５−フェニルペンタノイル、６−フェニルヘキサ
ノイル、７−フェニルヘプタノイル、８−フェニルオク
タノイル、９−フェニルノナノイル、１０−フェニルデ
カノイル、１０−ナフチルデカノイル基のような炭素数
８乃至３０個のアラルキルカルボニル基を挙げることが
できる。これら芳香族アシル基のアリ−ル部分は、炭素
数１乃至４個のアルキル基、ハロゲン原子または炭素数
１乃至４個のアルコキシ基で置換されていてもよい。Examples of the aromatic acyl group include arylcarbonyl groups having 7 to 11 carbon atoms such as benzoyl, α-naphthoyl and β-naphthoyl; 2-phenylacetyl, 3-phenylpropionyl, 4-phenylbutyryl C8-C such as 5-, 5-phenylpentanoyl, 6-phenylhexanoyl, 7-phenylheptanoyl, 8-phenyloctanoyl, 9-phenylnonanoyl, 10-phenyldecanoyl and 10-naphthyldecanoyl groups There may be mentioned 30 aralkylcarbonyl groups. The aryl portion of these aromatic acyl groups may be substituted with an alkyl group having 1 to 4 carbon atoms, a halogen atom or an alkoxy group having 1 to 4 carbon atoms.
【００３０】水酸基がアシル化されたエステル誘導体の
アシル基は、好適には炭素数１乃至１２個のアルカノイ
ル基であり、更に好適には炭素数１乃至６個のアルカノ
イル基である。The acyl group of the ester derivative in which the hydroxyl group is acylated is preferably an alkanoyl group having 1 to 12 carbon atoms, more preferably an alkanoyl group having 1 to 6 carbon atoms.
【００３１】カルボキシル基が保護されたエステル誘導
体のエステル残基としては、例えばメチル、エチル、プ
ロピル、イソプロピル、ブチル、イソブチル、ｓ−ブチ
ル、t−ブチル、ペンチル、イソペンチル、２−メチル
ブチル、ネオペンチル、１−エチルプロピル、ヘキシ
ル、イソヘキシル、４−メチルペンチル、３−メチルペ
ンチル、２−メチルペンチル、１−メチルペンチル、
３，３−ジメチルブチル、２，２−ジメチルブチル、
１，１−ジメチルブチル、１，２−ジメチルブチル、
１，３−ジメチルブチル、２，３−ジメチルブチル、２
−エチルブチル、ヘプチル、１−メチルヘキシル、２−
メチルヘキシル、３−メチルヘキシル、４−メチルヘキ
シル、５−メチルヘキシル、１−プロピルブチル、４，
４−ジメチルペンチル、オクチル、１−メチルヘプチ
ル、２−メチルヘプチル、３−メチルヘプチル、４−メ
チルヘプチル、５−メチルヘプチル、６−メチルヘプチ
ル、１−プロピルペンチル、２−エチルヘキシル、５，
５−ジメチルヘキシル、ノニル、３−メチルオクチル、
４−メチルオクチル、５−メチルオクチル、６−メチル
オクチル、１−プロピルヘキシル、２−エチルヘプチ
ル、６，６−ジメチルヘプチル、デシル、１−メチルノ
ニル、３−メチルノニル、８−メチルノニル、３−エチ
ルオクチル、３，７−ジメチルオクチル、７，７−ジメ
チルオクチル、ウンデシル、４，８−ジメチルノニル、
ドデシル、トリデシル、テトラデシル、ペンタデシル、
３，７，１１−トリメチルドデシル、ヘキサデシル、
４，８，１２−トリメチルトリデシル、１−メチルペン
タデシル、１４−メチルペンタデシル、１３，１３−ジ
メチルテトラデシル、ヘプタデシル、１５−メチルヘキ
サデシル、オクタデシル、１−メチルヘプタデシル、ノ
ナデシル、アイコサニルまたはドコサニル基のような炭
素数１乃至２２個のアルキル基；前記のアルキル基にお
いて１又は２個の２重結合を有する炭素数２乃至２２個
のアルケニル基；前記のアルキル基において１又は２個
の３重結合を有する炭素数２乃至２２個のアルキニル
基；ベンジル、フェネチル、３−フェニルプロピル、４
−フェニルブチル、５−フェニルペンチル、６−フェニ
ルヘキシル、８−フェニルオクチル、１０−フェニルデ
シルまたは１０−ナフチルデシル基のような炭素数７乃
至３０個のアラルキル基；アセチルオキシメチル、プロ
ピオニルオキシメチル、ブチリルオキシメチル、ペンタ
ノイルオキシメチル、ヘキサノイルオキシメチル、オク
タノイルオキシメチル、デカノイルオキシメチル、ドデ
カノイルオキシメチル、テトラデカノイルオキシメチ
ル、ヘキサデカノイルオキシメチル、オクタデカノイル
オキシメチル、１−（アセチルオキシ）エチル、１−
（プロピオニルオキシ）エチル、１−（ブチリルオキ
シ）エチル、１−（ペンタノイルオキシ）エチル、１−
（ヘキサノイルオキシ）エチル、１−（オクタノイルオ
キシ）エチル、１−（デカノイルオキシ）エチル、１−
（ドデカノイルオキシ）エチル、１−（テトラデカノイ
ルオキシ）エチル、１−（ヘキサデカノイルオキシ）エ
チル、１−（オクタデカノイルオキシ）エチル基のよう
な１−（炭素数２乃至２２個のアルカノイルオキシ）炭
素数１乃至３個のアルキル基；メトキシカルボニルオキ
シメチル、エトキシカルボニルオキシメチル、プロピル
オキシカルボニルオキシメチル、イソプロピルオキシカ
ルボニルオキシメチル、ブチルオキシカルボニルオキシ
メチル、イソブチルオキシカルボニルオキシメチル、ｓ
−ブチルオキシカルボニルオキシメチル、ｔ−ブチルオ
キシカルボニルオキシメチル、ペンチルオキシカルボニ
ルオキシメチル、２−ペンチルオキシカルボニルオキシ
メチル、３−ペンチルオキシカルボニルオキシメチル、
イソペンチルオキシカルボニルオキシメチル、ネオペン
チルオキシカルボニルオキシメチル、シクロペンチルオ
キシカルボニルオキシメチル、ヘキシルオキシカルボニ
ルオキシメチル、２−ヘキシルオキシカルボニルオキシ
メチル、３−ヘキシルオキシカルボニルオキシメチル、
イソヘキシルオキシカルボニルオキシメチル、シクロヘ
キシルオキシカルボニルオキシメチル、ヘプチルオキシ
カルボニルオキシメチル、オクチルオキシカルボニルオ
キシメチル、デシルオキシカルボニルオキシメチル、ド
デシルオキシカルボニルオキシメチル、テトラデシルオ
キシカルボニルオキシメチル、ヘキサデシルオキシカル
ボニルオキシメチル、オクタデシルオキシカルボニルオ
キシメチル、１−（メトキシカルボニルオキシ）エチ
ル、１−（エトキシカルボニルオキシ）エチル、１−
（プロピルオキシカルボニルオキシ）エチル、１−（イ
ソプロピルオキシカルボニルオキシ）エチル、１−（ブ
チルオキシカルボニルオキシ）エチル、１−（イソブチ
ルオキシカルボニルオキシ）エチル、１−（ｓ−ブチル
オキシカルボニルオキシ）エチル、１−（ｔ−ブチルオ
キシカルボニルオキシ）エチル、１−（ペンチルオキシ
カルボニルオキシ）エチル、１−（２−ペンチルオキシ
カルボニルオキシ）エチル、１−（３−ペンチルオキシ
カルボニルオキシ）エチル、１−（イソペンチルオキシ
カルボニルオキシ）エチル、１−（ネオペンチルオキシ
カルボニルオキシ）エチル、１−（シクロペンチルオキ
シカルボニルオキシ）エチル、１−（ヘキシルオキシカ
ルボニルオキシ）エチル、１−（２−ヘキシルオキシカ
ルボニルオキシ）エチル、１−（３−ヘキシルオキシカ
ルボニルオキシ）エチル、１−（イソヘキシルオキシカ
ルボニルオキシ）エチル、１−（シクロヘキシルオキシ
カルボニルオキシ）エチル、１−（ヘプチルオキシカル
ボニルオキシ）エチル、１−（オクチルオキシカルボニ
ルオキシ）エチル、１−（デシルオキシカルボニルオキ
シ）エチル、１−（ドデシルオキシカルボニルオキシ）
エチル、１−（テトラデシルオキシカルボニルオキシ）
エチル、１−（ヘキサデシルオキシカルボニルオキシ）
エチル、１−（オクタデシルオキシカルボニルオキシ）
エチル基のような１−（炭素数１乃至２２個のアルコキ
シカルボニルオキシ）炭素数１乃至３個のアルキル基を
挙げることができる。Examples of the ester residue of the ester derivative having a protected carboxyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, -Ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl,
3,3-dimethylbutyl, 2,2-dimethylbutyl,
1,1-dimethylbutyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl, 2,3-dimethylbutyl, 2
-Ethylbutyl, heptyl, 1-methylhexyl, 2-
Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,
4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,
5-dimethylhexyl, nonyl, 3-methyloctyl,
4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl 3,7-dimethyloctyl, 7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl,
Dodecyl, tridecyl, tetradecyl, pentadecyl,
3,7,11-trimethyldodecyl, hexadecyl,
4,8,12-trimethyltridecyl, 1-methylpentadecyl, 14-methylpentadecyl, 13,13-dimethyltetradecyl, heptadecyl, 15-methylhexadecyl, octadecyl, 1-methylheptadecyl, nonadecyl, eicosanyl or An alkyl group having 1 to 22 carbon atoms such as a docosanyl group; an alkenyl group having 2 to 22 carbon atoms having 1 or 2 double bonds in the above alkyl group; Alkynyl group having 2 to 22 carbon atoms having a triple bond; benzyl, phenethyl, 3-phenylpropyl, 4
Aralkyl groups having 7 to 30 carbon atoms such as -phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 8-phenyloctyl, 10-phenyldecyl or 10-naphthyldecyl; acetyloxymethyl, propionyloxymethyl, Butyryloxymethyl, pentanoyloxymethyl, hexanoyloxymethyl, octanoyloxymethyl, decanoyloxymethyl, dodecanoyloxymethyl, tetradecanoyloxymethyl, hexadecanoyloxymethyl, octadecanoyloxymethyl, 1- (Acetyloxy) ethyl, 1-
(Propionyloxy) ethyl, 1- (butyryloxy) ethyl, 1- (pentanoyloxy) ethyl, 1-
(Hexanoyloxy) ethyl, 1- (octanoyloxy) ethyl, 1- (decanoyloxy) ethyl, 1-
1- (C2-C22) groups such as (dodecanoyloxy) ethyl, 1- (tetradecanoyloxy) ethyl, 1- (hexadecanoyloxy) ethyl and 1- (octadecanoyloxy) ethyl groups Alkanoyloxy) an alkyl group having 1 to 3 carbon atoms; methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propyloxycarbonyloxymethyl, isopropyloxycarbonyloxymethyl, butyloxycarbonyloxymethyl, isobutyloxycarbonyloxymethyl, s
-Butyloxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, 2-pentyloxycarbonyloxymethyl, 3-pentyloxycarbonyloxymethyl,
Isopentyloxycarbonyloxymethyl, neopentyloxycarbonyloxymethyl, cyclopentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, 2-hexyloxycarbonyloxymethyl, 3-hexyloxycarbonyloxymethyl,
Isohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, heptyloxycarbonyloxymethyl, octyloxycarbonyloxymethyl, decyloxycarbonyloxymethyl, dodecyloxycarbonyloxymethyl, tetradecyloxycarbonyloxymethyl, hexadecyloxycarbonyloxymethyl Octadecyloxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1-
(Propyloxycarbonyloxy) ethyl, 1- (isopropyloxycarbonyloxy) ethyl, 1- (butyloxycarbonyloxy) ethyl, 1- (isobutyloxycarbonyloxy) ethyl, 1- (s-butyloxycarbonyloxy) ethyl, 1- (t-butyloxycarbonyloxy) ethyl, 1- (pentyloxycarbonyloxy) ethyl, 1- (2-pentyloxycarbonyloxy) ethyl, 1- (3-pentyloxycarbonyloxy) ethyl, 1- (iso Pentyloxycarbonyloxy) ethyl, 1- (neopentyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy) ethyl, 1- (hexyloxycarbonyloxy) ethyl, 1- (2-hexyloxycarbonyloxy) Tyl, 1- (3-hexyloxycarbonyloxy) ethyl, 1- (isohexyloxycarbonyloxy) ethyl, 1- (cyclohexyloxycarbonyloxy) ethyl, 1- (heptyloxycarbonyloxy) ethyl, 1- (octyloxy Carbonyloxy) ethyl, 1- (decyloxycarbonyloxy) ethyl, 1- (dodecyloxycarbonyloxy)
Ethyl, 1- (tetradecyloxycarbonyloxy)
Ethyl, 1- (hexadecyloxycarbonyloxy)
Ethyl, 1- (octadecyloxycarbonyloxy)
Examples thereof include an alkyl group having 1 to 3 carbon atoms such as 1- (alkoxycarbonyloxy having 1 to 22 carbon atoms) such as an ethyl group.
【００３２】カルボキシル基が保護されたエステル誘導
体のエステル残基は、好適には炭素数１乃至２２個のア
ルキル基である。抗インフルエンザ薬として経口投与で
使用される場合、好適には炭素数１乃至１２個のアルキ
ル基である。抗インフルエンザ薬として経鼻投与（又は
経肺投与）で使用される場合、好適には炭素数１２乃至
２２個のアルキル基である。The ester residue of the ester derivative having a protected carboxyl group is preferably an alkyl group having 1 to 22 carbon atoms. When used orally as an anti-influenza drug, it is preferably an alkyl group having 1 to 12 carbon atoms. When used for nasal administration (or pulmonary administration) as an anti-influenza drug, it is preferably an alkyl group having 12 to 22 carbon atoms.
【００３３】一般式（１）で表されるノイラミン酸化合
物またはその薬理上許容されるエステルは4位に塩基性
残基を有し、1位にカルボキシル基を有するので、薬理
的に毒性を示さない酸又は塩基と結合して「薬理上許容
される塩」を形成することができる。The neuraminic acid compound represented by the general formula (1) or a pharmaceutically acceptable ester thereof has a basic residue at the 4-position and a carboxyl group at the 1-position, and thus exhibits pharmacological toxicity. It can combine with non-existent acids or bases to form “pharmacologically acceptable salts”.
【００３４】「薬理上許容される塩」としては、例えば
フッ化水素酸塩、塩化水素酸塩、臭化水素酸塩、ヨウ化
水素酸塩のようなハロゲン化水素酸塩；硝酸塩、過塩素
酸塩、硫酸塩、りん酸塩のような無機酸塩；メタンスル
ホン酸塩、エタンスルホン酸塩、トリフルオロメタンス
ルホン酸塩のようなアルカンスルホン酸塩；ベンゼンス
ルホン酸塩、ｐ−トルエンスルホン酸塩のようなアリー
ルスルホン酸塩；酢酸塩、トリフルオロ酢酸塩、クエン
酸塩、酒石酸塩、しゅう酸塩、マレイン酸塩のような有
機酸塩；グリシン塩、リジン塩、アルギニン塩、オルニ
チン塩、グルタミン酸塩、アスパラギン酸塩のようなア
ミノ酸塩；リチウム塩、ナトリウム塩、カリウム塩のよ
うなアルカリ金属塩；カルシウム塩、マグネシウム塩の
ようなアルカリ土類金属塩；アルミニウム塩、鉄塩、亜
鉛塩、銅塩、ニッケル塩、コバルト塩のような金属塩；
アンモニウム塩、ｔ−オクチルアミン塩、ジベンジルア
ミン塩、モルホリン塩、グルコサミン塩、エチレンジア
ミン塩、グアニジン塩、ジエチルアミン塩、トリエチル
アミン塩、ジシクロヘキシルアミン塩、プロカイン塩、
エタノールアミン塩、ジエタノールアミン塩、ピペラジ
ン塩、テトラメチルアンモニウム塩のような有機アミン
若しくは有機アンモニウム塩等を挙げることができ、好
適にはリチウム塩、ナトリウム塩、カリウム塩のような
アルカリ金属塩；酢酸塩、トリフルオロ酢酸塩のような
有機酸塩；または塩酸塩、硫酸塩のような無機酸塩であ
る。"Pharmacologically acceptable salts" include, for example, hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide; nitrates, perchlorines Inorganic salts such as acid salts, sulfates and phosphates; alkane sulfonates such as methanesulfonate, ethanesulfonate and trifluoromethanesulfonate; benzenesulfonate and p-toluenesulfonate Aryl sulfonates such as acetate; acetic acid, trifluoroacetate, citrate, tartrate, oxalate, maleate; organic acid salts such as glycine, lysine, arginine, ornithine, glutamic acid Salts, amino acid salts such as aspartate; alkali metal salts such as lithium, sodium and potassium salts; alkaline earths such as calcium and magnesium salts Metal salts; aluminum salts, iron salts, zinc salts, copper salts, nickel salts, metal salts such as cobalt salts;
Ammonium salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, ethylenediamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, procaine salt,
Organic amines or organic ammonium salts such as ethanolamine salt, diethanolamine salt, piperazine salt and tetramethylammonium salt can be mentioned, and alkali metal salts such as lithium salt, sodium salt and potassium salt are preferable; acetate salt And organic acid salts such as trifluoroacetate; or inorganic acid salts such as hydrochloride and sulfate.
【００３５】一般式（１）で表される化合物、その薬理
上許容されるエステル誘導体及びそれらの薬理上許容さ
れる塩は、大気中に放置したり、水又は有機溶媒と混和
することによって水又は溶媒と結合し、水和物又は溶媒
和物を形成する場合があるが、これらの水和物及び溶媒
和物も本発明に含まれる。The compound represented by the general formula (1), its pharmacologically acceptable ester derivatives and their pharmacologically acceptable salts are prepared by leaving them in the air or mixing them with water or an organic solvent. Alternatively, it may combine with a solvent to form a hydrate or a solvate, and these hydrates and solvates are also included in the present invention.
【００３６】本発明の化合物及びその薬理上許容される
誘導体は表１乃至３に例示されるが、本発明はこれらに
限定されるものではない。 ［表１］The compounds of the present invention and their pharmacologically acceptable derivatives are exemplified in Tables 1 to 3, but the present invention is not limited thereto. [Table 1]
【００３７】[0037]
【化４】 Embedded image
【００３８】 --------------------------------------------------------------------- Cpd.No. R1 R2 R3 R4 (CR5R6)n (CR7R8)m R9 R10 --------------------------------------------------------------------- 1-1 OH OH H H CH2 bond CH3 NH2 1-2 OH OH H H CH2 bond CH3 NHCH3 1-3 OH OH H H CH2 bond CH3 N(CH3)2 1-4 OH OH H H CH2 bond CH3 NHC(=NH)H 1-5 OH OH H H CH2 bond CH3 NHC(=NH)CH3 1-6 OH OH H H CH2 bond CH3 NHC(=NH)CH2CH3 1-7 OH OH H H CH2 bond CH3 NHC(=NH)NH2 1-8 OH OH H H (CH2)2 bond CH3 NH2 1-9 OH OH H H (CH2)2 bond CH3 NHCH3 1-10 OH OH H H (CH2)2 bond CH3 N(CH3)2 1-11 OH OH H H (CH2)2 bond CH3 NHC(=NH)H 1-12 OH OH H H (CH2)2 bond CH3 NHC(=NH)CH3 1-13 OH OH H H (CH2)2 bond CH3 NHC(=NH)CH2CH3 1-14 OH OH H H (CH2)2 bond CH3 NHC(=NH)NH2 1-15 OH OH H H CF2CH2 bond CH3 NH2 1-16 OH OH H H CF2CH2 bond CH3 NHCH3 1-17 OH OH H H CF2CH2 bond CH3 N(CH3)2 1-18 OH OH H H CF2CH2 bond CH3 NHC(=NH)H 1-19 OH OH H H CF2CH2 bond CH3 NHC(=NH)CH3 1-20 OH OH H H CF2CH2 bond CH3 NHC(=NH)CH2CH3 1-21 OH OH H H CF2CH2 bond CH3 NHC(=NH)NH2 1-22 OH OH H H (CH2)3 bond CH3 NH2 1-23 OH OH H H (CH2)3 bond CH3 NHCH3 1-24 OH OH H H (CH2)3 bond CH3 N(CH3)2 1-25 OH OH H H (CH2)3 bond CH3 NHC(=NH)H 1-26 OH OH H H (CH2)3 bond CH3 NHC(=NH)CH3 1-27 OH OH H H (CH2)3 bond CH3 NHC(=NH)CH2CH3 1-28 OH OH H H (CH2)3 bond CH3 NHC(=NH)NH2 1-29 OH OH H H CH2 CH2 CH3 NH2 1-30 OH OH H H CH2 CH2 CH3 NHCH3 1-31 OH OH H H CH2 CH2 CH3 N(CH3)2 1-32 OH OH H H CH2 CH2 CH3 NHC(=NH)H 1-33 OH OH H H CH2 CH2 CH3 NHC(=NH)CH3 1-34 OH OH H H CH2 CH2 CH3 NHC(=NH)CH2CH3 1-35 OH OH H H CH2 CH2 CH3 NHC(=NH)NH2 1-36 OH OH H H (CH2)2 CH2 CH3 NH2 1-37 OH OH H H (CH2)2 CH2 CH3 NHCH3 1-38 OH OH H H (CH2)2 CH2 CH3 N(CH3)2 1-39 OH OH H H (CH2)2 CH2 CH3 NHC(=NH)H 1-40 OH OH H H (CH2)2 CH2 CH3 NHC(=NH)CH3 1-41 OH OH H H (CH2)2 CH2 CH3 NHC(=NH)CH2CH3 1-42 OH OH H H (CH2)2 CH2 CH3 NHC(=NH)NH2 1-43 OH OH H H CF2CH2 CH2 CH3 NH2 1-44 OH OH H H CF2CH2 CH2 CH3 NHCH3 1-45 OH OH H H CF2CH2 CH2 CH3 N(CH3)2 1-46 OH OH H H CF2CH2 CH2 CH3 NHC(=NH)H 1-47 OH OH H H CF2CH2 CH2 CH3 NHC(=NH)CH3 1-48 OH OH H H CF2CH2 CH2 CH3 NHC(=NH)CH2CH3 1-49 OH OH H H CF2CH2 CH2 CH3 NHC(=NH)NH2 1-50 OH OH H H CH2 (CH2)2 CH3 NH2 1-51 OH OH H H CH2 (CH2)2 CH3 NHCH3 1-52 OH OH H H CH2 (CH2)2 CH3 N(CH3)2 1-53 OH OH H H CH2 (CH2)2 CH3 NHC(=NH)H 1-54 OH OH H H CH2 (CH2)2 CH3 NHC(=NH)CH3 1-55 OH OH H H CH2 (CH2)2 CH3 NHC(=NH)CH2CH3 1-56 OH OH H H CH2 (CH2)2 CH3 NHC(=NH)NH2 1-57 OH OH CH3 H CH2 bond CH3 NH2 1-58 OH OH CH3 H CH2 bond CH3 NHCH3 1-59 OH OH CH3 H CH2 bond CH3 N(CH3)2 1-60 OH OH CH3 H CH2 bond CH3 NHC(=NH)H 1-61 OH OH CH3 H CH2 bond CH3 NHC(=NH)CH3 1-62 OH OH CH3 H CH2 bond CH3 NHC(=NH)CH2CH3 1-63 OH OH CH3 H CH2 bond CH3 NHC(=NH)NH2 1-64 OH OH CH3 H (CH2)2 bond CH3 NH2 1-65 OH OH CH3 H (CH2)2 bond CH3 NHCH3 1-66 OH OH CH3 H (CH2)2 bond CH3 N(CH3)2 1-67 OH OH CH3 H (CH2)2 bond CH3 NHC(=NH)H 1-68 OH OH CH3 H (CH2)2 bond CH3 NHC(=NH)CH3 1-69 OH OH CH3 H (CH2)2 bond CH3 NHC(=NH)CH2CH3 1-70 OH OH CH3 H (CH2)2 bond CH3 NHC(=NH)NH2 1-71 OH OH CH3 H CF2CH2 bond CH3 NH2 1-72 OH OH CH3 H CF2CH2 bond CH3 NHCH3 1-73 OH OH CH3 H CF2CH2 bond CH3 N(CH3)2 1-74 OH OH CH3 H CF2CH2 bond CH3 NHC(=NH)H 1-75 OH OH CH3 H CF2CH2 bond CH3 NHC(=NH)CH3 1-76 OH OH CH3 H CF2CH2 bond CH3 NHC(=NH)CH2CH3 1-77 OH OH CH3 H CF2CH2 bond CH3 NHC(=NH)NH2 1-78 OH OH CH3 H (CH2)3 bond CH3 NH2 1-79 OH OH CH3 H (CH2)3 bond CH3 NHCH3 1-80 OH OH CH3 H (CH2)3 bond CH3 N(CH3)2 1-81 OH OH CH3 H (CH2)3 bond CH3 NHC(=NH)H 1-82 OH OH CH3 H (CH2)3 bond CH3 NHC(=NH)CH3 1-83 OH OH CH3 H (CH2)3 bond CH3 NHC(=NH)CH2CH3 1-84 OH OH CH3 H (CH2)3 bond CH3 NHC(=NH)NH2 1-85 OH OH CH3 H CH2 CH2 CH3 NH2 1-86 OH OH CH3 H CH2 CH2 CH3 NHCH3 1-87 OH OH CH3 H CH2 CH2 CH3 N(CH3)2 1-88 OH OH CH3 H CH2 CH2 CH3 NHC(=NH)H 1-89 OH OH CH3 H CH2 CH2 CH3 NHC(=NH)CH3 1-90 OH OH CH3 H CH2 CH2 CH3 NHC(=NH)CH2CH3 1-91 OH OH CH3 H CH2 CH2 CH3 NHC(=NH)NH2 1-92 OH OH CH3 H (CH2)2 CH2 CH3 NH2 1-93 OH OH CH3 H (CH2)2 CH2 CH3 NHCH3 1-94 OH OH CH3 H (CH2)2 CH2 CH3 N(CH3)2 1-95 OH OH CH3 H (CH2)2 CH2 CH3 NHC(=NH)H 1-96 OH OH CH3 H (CH2)2 CH2 CH3 NHC(=NH)CH3 1-97 OH OH CH3 H (CH2)2 CH2 CH3 NHC(=NH)CH2CH3 1-98 OH OH CH3 H (CH2)2 CH2 CH3 NHC(=NH)NH2 1-99 OH OH CH3 H CF2CH2 CH2 CH3 NH2 1-100 OH OH CH3 H CF2CH2 CH2 CH3 NHCH3 1-101 OH OH CH3 H CF2CH2 CH2 CH3 N(CH3)2 1-102 OH OH CH3 H CF2CH2 CH2 CH3 NHC(=NH)H 1-103 OH OH CH3 H CF2CH2 CH2 CH3 NHC(=NH)CH3 1-104 OH OH CH3 H CF2CH2 CH2 CH3 NHC(=NH)CH2CH3 1-105 OH OH CH3 H CF2CH2 CH2 CH3 NHC(=NH)NH2 1-106 OH OH CH3 H CH2 (CH2)2 CH3 NH2 1-107 OH OH CH3 H CH2 (CH2)2 CH3 NHCH3 1-108 OH OH CH3 H CH2 (CH2)2 CH3 N(CH3)2 1-109 OH OH CH3 H CH2 (CH2)2 CH3 NHC(=NH)H 1-110 OH OH CH3 H CH2 (CH2)2 CH3 NHC(=NH)CH3 1-111 OH OH CH3 H CH2 (CH2)2 CH3 NHC(=NH)CH2CH3 1-112 OH OH CH3 H CH2 (CH2)2 CH3 NHC(=NH)NH2 1-113 OH OH H CH3 CH2 bond CH3 NH2 1-114 OH OH H CH3 CH2 bond CH3 NHCH3 1-115 OH OH H CH3 CH2 bond CH3 N(CH3)2 1-116 OH OH H CH3 CH2 bond CH3 NHC(=NH)H 1-117 OH OH H CH3 CH2 bond CH3 NHC(=NH)CH3 1-118 OH OH H CH3 CH2 bond CH3 NHC(=NH)CH2CH3 1-119 OH OH H CH3 CH2 bond CH3 NHC(=NH)NH2 1-120 OH OH H CH3 (CH2)2 bond CH3 NH2 1-121 OH OH H CH3 (CH2)2 bond CH3 NHCH3 1-122 OH OH H CH3 (CH2)2 bond CH3 N(CH3)2 1-123 OH OH H CH3 (CH2)2 bond CH3 NHC(=NH)H 1-124 OH OH H CH3 (CH2)2 bond CH3 NHC(=NH)CH3 1-125 OH OH H CH3 (CH2)2 bond CH3 NHC(=NH)CH2CH3 1-126 OH OH H CH3 (CH2)2 bond CH3 NHC(=NH)NH2 1-127 OH OH H CH3 CF2CH2 bond CH3 NH2 1-128 OH OH H CH3 CF2CH2 bond CH3 NHCH3 1-129 OH OH H CH3 CF2CH2 bond CH3 N(CH3)2 1-130 OH OH H CH3 CF2CH2 bond CH3 NHC(=NH)H 1-131 OH OH H CH3 CF2CH2 bond CH3 NHC(=NH)CH3 1-132 OH OH H CH3 CF2CH2 bond CH3 NHC(=NH)CH2CH3 1-133 OH OH H CH3 CF2CH2 bond CH3 NHC(=NH)NH2 1-134 OH OH H CH3 (CH2)3 bond CH3 NH2 1-135 OH OH H CH3 (CH2)3 bond CH3 NHCH3 1-136 OH OH H CH3 (CH2)3 bond CH3 N(CH3)2 1-137 OH OH H CH3 (CH2)3 bond CH3 NHC(=NH)H 1-138 OH OH H CH3 (CH2)3 bond CH3 NHC(=NH)CH3 1-139 OH OH H CH3 (CH2)3 bond CH3 NHC(=NH)CH2CH3 1-140 OH OH H CH3 (CH2)3 bond CH3 NHC(=NH)NH2 1-141 OH OH H CH3 CH2 CH2 CH3 NH2 1-142 OH OH H CH3 CH2 CH2 CH3 NHCH3 1-143 OH OH H CH3 CH2 CH2 CH3 N(CH3)2 1-144 OH OH H CH3 CH2 CH2 CH3 NHC(=NH)H 1-145 OH OH H CH3 CH2 CH2 CH3 NHC(=NH)CH3 1-146 OH OH H CH3 CH2 CH2 CH3 NHC(=NH)CH2CH3 1-147 OH OH H CH3 CH2 CH2 CH3 NHC(=NH)NH2 1-148 OH OH H CH3 (CH2)2 CH2 CH3 NH2 1-149 OH OH H CH3 (CH2)2 CH2 CH3 NHCH3 1-150 OH OH H CH3 (CH2)2 CH2 CH3 N(CH3)2 1-151 OH OH H CH3 (CH2)2 CH2 CH3 NHC(=NH)H 1-152 OH OH H CH3 (CH2)2 CH2 CH3 NHC(=NH)CH3 1-153 OH OH H CH3 (CH2)2 CH2 CH3 NHC(=NH)CH2CH3 1-154 OH OH H CH3 (CH2)2 CH2 CH3 NHC(=NH)NH2 1-155 OH OH H CH3 CF2CH2 CH2 CH3 NH2 1-156 OH OH H CH3 CF2CH2 CH2 CH3 NHCH3 1-157 OH OH H CH3 CF2CH2 CH2 CH3 N(CH3)2 1-158 OH OH H CH3 CF2CH2 CH2 CH3 NHC(=NH)H 1-159 OH OH H CH3 CF2CH2 CH2 CH3 NHC(=NH)CH3 1-160 OH OH H CH3 CF2CH2 CH2 CH3 NHC(=NH)CH2CH3 1-161 OH OH H CH3 CF2CH2 CH2 CH3 NHC(=NH)NH2 1-162 OH OH H CH3 CH2 (CH2)2 CH3 NH2 1-163 OH OH H CH3 CH2 (CH2)2 CH3 NHCH3 1-164 OH OH H CH3 CH2 (CH2)2 CH3 N(CH3)2 1-165 OH OH H CH3 CH2 (CH2)2 CH3 NHC(=NH)H 1-166 OH OH H CH3 CH2 (CH2)2 CH3 NHC(=NH)CH3 1-167 OH OH H CH3 CH2 (CH2)2 CH3 NHC(=NH)CH2CH3 1-168 OH OH H CH3 CH2 (CH2)2 CH3 NHC(=NH)NH2 1-169 OH OH CH3 CH3 CH2 bond CH3 NH2 1-170 OH OH CH3 CH3 CH2 bond CH3 NHCH3 1-171 OH OH CH3 CH3 CH2 bond CH3 N(CH3)2 1-172 OH OH CH3 CH3 CH2 bond CH3 NHC(=NH)H 1-173 OH OH CH3 CH3 CH2 bond CH3 NHC(=NH)CH3 1-174 OH OH CH3 CH3 CH2 bond CH3 NHC(=NH)CH2CH3 1-175 OH OH CH3 CH3 CH2 bond CH3 NHC(=NH)NH2 1-176 OH OH CH3 CH3 (CH2)2 bond CH3 NH2 1-177 OH OH CH3 CH3 (CH2)2 bond CH3 NHCH3 1-178 OH OH CH3 CH3 (CH2)2 bond CH3 N(CH3)2 1-179 OH OH CH3 CH3 (CH2)2 bond CH3 NHC(=NH)H 1-180 OH OH CH3 CH3 (CH2)2 bond CH3 NHC(=NH)CH3 1-181 OH OH CH3 CH3 (CH2)2 bond CH3 NHC(=NH)CH2CH3 1-182 OH OH CH3 CH3 (CH2)2 bond CH3 NHC(=NH)NH2 1-183 OH OH CH3 CH3 CF2CH2 bond CH3 NH2 1-184 OH OH CH3 CH3 CF2CH2 bond CH3 NHCH3 1-185 OH OH CH3 CH3 CF2CH2 bond CH3 N(CH3)2 1-186 OH OH CH3 CH3 CF2CH2 bond CH3 NHC(=NH)H 1-187 OH OH CH3 CH3 CF2CH2 bond CH3 NHC(=NH)CH3 1-188 OH OH CH3 CH3 CF2CH2 bond CH3 NHC(=NH)CH2CH3 1-189 OH OH CH3 CH3 CF2CH2 bond CH3 NHC(=NH)NH2 1-190 OH OH CH3 CH3 (CH2)3 bond CH3 NH2 1-191 OH OH CH3 CH3 (CH2)3 bond CH3 NHCH3 1-192 OH OH CH3 CH3 (CH2)3 bond CH3 N(CH3)2 1-193 OH OH CH3 CH3 (CH2)3 bond CH3 NHC(=NH)H 1-194 OH OH CH3 CH3 (CH2)3 bond CH3 NHC(=NH)CH3 1-195 OH OH CH3 CH3 (CH2)3 bond CH3 NHC(=NH)CH2CH3 1-196 OH OH CH3 CH3 (CH2)3 bond CH3 NHC(=NH)NH2 1-197 OH OH CH3 CH3 CH2 CH2 CH3 NH2 1-198 OH OH CH3 CH3 CH2 CH2 CH3 NHCH3 1-199 OH OH CH3 CH3 CH2 CH2 CH3 N(CH3)2 1-200 OH OH CH3 CH3 CH2 CH2 CH3 NHC(=NH)H 1-201 OH OH CH3 CH3 CH2 CH2 CH3 NHC(=NH)CH3 1-202 OH OH CH3 CH3 CH2 CH2 CH3 NHC(=NH)CH2CH3 1-203 OH OH CH3 CH3 CH2 CH2 CH3 NHC(=NH)NH2 1-204 OH OH CH3 CH3 (CH2)2 CH2 CH3 NH2 1-205 OH OH CH3 CH3 (CH2)2 CH2 CH3 NHCH3 1-206 OH OH CH3 CH3 (CH2)2 CH2 CH3 N(CH3)2 1-207 OH OH CH3 CH3 (CH2)2 CH2 CH3 NHC(=NH)H 1-208 OH OH CH3 CH3 (CH2)2 CH2 CH3 NHC(=NH)CH3 1-209 OH OH CH3 CH3 (CH2)2 CH2 CH3 NHC(=NH)CH2CH3 1-210 OH OH CH3 CH3 (CH2)2 CH2 CH3 NHC(=NH)NH2 1-211 OH OH CH3 CH3 CF2CH2 CH2 CH3 NH2 1-212 OH OH CH3 CH3 CF2CH2 CH2 CH3 NHCH3 1-213 OH OH CH3 CH3 CF2CH2 CH2 CH3 N(CH3)2 1-214 OH OH CH3 CH3 CF2CH2 CH2 CH3 NHC(=NH)H 1-215 OH OH CH3 CH3 CF2CH2 CH2 CH3 NHC(=NH)CH3 1-216 OH OH CH3 CH3 CF2CH2 CH2 CH3 NHC(=NH)CH2CH3 1-217 OH OH CH3 CH3 CF2CH2 CH2 CH3 NHC(=NH)NH2 1-218 OH OH CH3 CH3 CH2 (CH2)2 CH3 NH2 1-219 OH OH CH3 CH3 CH2 (CH2)2 CH3 NHCH3 1-220 OH OH CH3 CH3 CH2 (CH2)2 CH3 N(CH3)2 1-221 OH OH CH3 CH3 CH2 (CH2)2 CH3 NHC(=NH)H 1-222 OH OH CH3 CH3 CH2 (CH2)2 CH3 NHC(=NH)CH3 1-223 OH OH CH3 CH3 CH2 (CH2)2 CH3 NHC(=NH)CH2CH3 1-224 OH OH CH3 CH3 CH2 (CH2)2 CH3 NHC(=NH)NH2 1-225 H H H H CH2 bond CH3 NH2 1-226 H H H H CH2 bond CH3 NHCH3 1-227 H H H H CH2 bond CH3 N(CH3)2 1-228 H H H H CH2 bond CH3 NHC(=NH)H 1-229 H H H H CH2 bond CH3 NHC(=NH)CH3 1-230 H H H H CH2 bond CH3 NHC(=NH)CH2CH3 1-231 H H H H CH2 bond CH3 NHC(=NH)NH2 1-232 H H H H (CH2)2 bond CH3 NH2 1-233 H H H H (CH2)2 bond CH3 NHCH3 1-234 H H H H (CH2)2 bond CH3 N(CH3)2 1-235 H H H H (CH2)2 bond CH3 NHC(=NH)H 1-236 H H H H (CH2)2 bond CH3 NHC(=NH)CH3 1-237 H H H H (CH2)2 bond CH3 NHC(=NH)CH2CH3 1-238 H H H H (CH2)2 bond CH3 NHC(=NH)NH2 1-239 H H H H CF2CH2 bond CH3 NH2 1-240 H H H H CF2CH2 bond CH3 NHCH3 1-241 H H H H CF2CH2 bond CH3 N(CH3)2 1-242 H H H H CF2CH2 bond CH3 NHC(=NH)H 1-243 H H H H CF2CH2 bond CH3 NHC(=NH)CH3 1-244 H H H H CF2CH2 bond CH3 NHC(=NH)CH2CH3 1-245 H H H H CF2CH2 bond CH3 NHC(=NH)NH2 1-246 H H H H (CH2)3 bond CH3 NH2 1-247 H H H H (CH2)3 bond CH3 NHCH3 1-248 H H H H (CH2)3 bond CH3 N(CH3)2 1-249 H H H H (CH2)3 bond CH3 NHC(=NH)H 1-250 H H H H (CH2)3 bond CH3 NHC(=NH)CH3 1-251 H H H H (CH2)3 bond CH3 NHC(=NH)CH2CH3 1-252 H H H H (CH2)3 bond CH3 NHC(=NH)NH2 1-253 H H H H CH2 CH2 CH3 NH2 1-254 H H H H CH2 CH2 CH3 NHCH3 1-255 H H H H CH2 CH2 CH3 N(CH3)2 1-256 H H H H CH2 CH2 CH3 NHC(=NH)H 1-257 H H H H CH2 CH2 CH3 NHC(=NH)CH3 1-258 H H H H CH2 CH2 CH3 NHC(=NH)CH2CH3 1-259 H H H H CH2 CH2 CH3 NHC(=NH)NH2 1-260 H H H H (CH2)2 CH2 CH3 NH2 1-261 H H H H (CH2)2 CH2 CH3 NHCH3 1-262 H H H H (CH2)2 CH2 CH3 N(CH3)2 1-263 H H H H (CH2)2 CH2 CH3 NHC(=NH)H 1-264 H H H H (CH2)2 CH2 CH3 NHC(=NH)CH3 1-265 H H H H (CH2)2 CH2 CH3 NHC(=NH)CH2CH3 1-266 H H H H (CH2)2 CH2 CH3 NHC(=NH)NH2 1-267 H H H H CF2CH2 CH2 CH3 NH2 1-268 H H H H CF2CH2 CH2 CH3 NHCH3 1-269 H H H H CF2CH2 CH2 CH3 N(CH3)2 1-270 H H H H CF2CH2 CH2 CH3 NHC(=NH)H 1-271 H H H H CF2CH2 CH2 CH3 NHC(=NH)CH3 1-272 H H H H CF2CH2 CH2 CH3 NHC(=NH)CH2CH3 1-273 H H H H CF2CH2 CH2 CH3 NHC(=NH)NH2 1-274 H H H H CH2 (CH2)2 CH3 NH2 1-275 H H H H CH2 (CH2)2 CH3 NHCH3 1-276 H H H H CH2 (CH2)2 CH3 N(CH3)2 1-277 H H H H CH2 (CH2)2 CH3 NHC(=NH)H 1-278 H H H H CH2 (CH2)2 CH3 NHC(=NH)CH3 1-279 H H H H CH2 (CH2)2 CH3 NHC(=NH)CH2CH3 1-280 H H H H CH2 (CH2)2 CH3 NHC(=NH)NH2 1-281 H H CH3 H CH2 bond CH3 NH2 1-282 H H CH3 H CH2 bond CH3 NHCH3 1-283 H H CH3 H CH2 bond CH3 N(CH3)2 1-284 H H CH3 H CH2 bond CH3 NHC(=NH)H 1-285 H H CH3 H CH2 bond CH3 NHC(=NH)CH3 1-286 H H CH3 H CH2 bond CH3 NHC(=NH)CH2CH3 1-287 H H CH3 H CH2 bond CH3 NHC(=NH)NH2 1-288 H H CH3 H (CH2)2 bond CH3 NH2 1-289 H H CH3 H (CH2)2 bond CH3 NHCH3 1-290 H H CH3 H (CH2)2 bond CH3 N(CH3)2 1-291 H H CH3 H (CH2)2 bond CH3 NHC(=NH)H 1-292 H H CH3 H (CH2)2 bond CH3 NHC(=NH)CH3 1-293 H H CH3 H (CH2)2 bond CH3 NHC(=NH)CH2CH3 1-294 H H CH3 H (CH2)2 bond CH3 NHC(=NH)NH2 1-295 H H CH3 H CF2CH2 bond CH3 NH2 1-296 H H CH3 H CF2CH2 bond CH3 NHCH3 1-297 H H CH3 H CF2CH2 bond CH3 N(CH3)2 1-298 H H CH3 H CF2CH2 bond CH3 NHC(=NH)H 1-299 H H CH3 H CF2CH2 bond CH3 NHC(=NH)CH3 1-300 H H CH3 H CF2CH2 bond CH3 NHC(=NH)CH2CH3 1-301 H H CH3 H CF2CH2 bond CH3 NHC(=NH)NH2 1-302 H H CH3 H (CH2)3 bond CH3 NH2 1-303 H H CH3 H (CH2)3 bond CH3 NHCH3 1-304 H H CH3 H (CH2)3 bond CH3 N(CH3)2 1-305 H H CH3 H (CH2)3 bond CH3 NHC(=NH)H 1-306 H H CH3 H (CH2)3 bond CH3 NHC(=NH)CH3 1-307 H H CH3 H (CH2)3 bond CH3 NHC(=NH)CH2CH3 1-308 H H CH3 H (CH2)3 bond CH3 NHC(=NH)NH2 1-309 H H CH3 H CH2 CH2 CH3 NH2 1-310 H H CH3 H CH2 CH2 CH3 NHCH3 1-311 H H CH3 H CH2 CH2 CH3 N(CH3)2 1-312 H H CH3 H CH2 CH2 CH3 NHC(=NH)H 1-313 H H CH3 H CH2 CH2 CH3 NHC(=NH)CH3 1-314 H H CH3 H CH2 CH2 CH3 NHC(=NH)CH2CH3 1-315 H H CH3 H CH2 CH2 CH3 NHC(=NH)NH2 1-316 H H CH3 H (CH2)2 CH2 CH3 NH2 1-317 H H CH3 H (CH2)2 CH2 CH3 NHCH3 1-318 H H CH3 H (CH2)2 CH2 CH3 N(CH3)2 1-319 H H CH3 H (CH2)2 CH2 CH3 NHC(=NH)H 1-320 H H CH3 H (CH2)2 CH2 CH3 NHC(=NH)CH3 1-321 H H CH3 H (CH2)2 CH2 CH3 NHC(=NH)CH2CH3 1-322 H H CH3 H (CH2)2 CH2 CH3 NHC(=NH)NH2 1-323 H H CH3 H CF2CH2 CH2 CH3 NH2 1-324 H H CH3 H CF2CH2 CH2 CH3 NHCH3 1-325 H H CH3 H CF2CH2 CH2 CH3 N(CH3)2 1-326 H H CH3 H CF2CH2 CH2 CH3 NHC(=NH)H 1-327 H H CH3 H CF2CH2 CH2 CH3 NHC(=NH)CH3 1-328 H H CH3 H CF2CH2 CH2 CH3 NHC(=NH)CH2CH3 1-329 H H CH3 H CF2CH2 CH2 CH3 NHC(=NH)NH2 1-330 H H CH3 H CH2 (CH2)2 CH3 NH2 1-331 H H CH3 H CH2 (CH2)2 CH3 NHCH3 1-332 H H CH3 H CH2 (CH2)2 CH3 N(CH3)2 1-333 H H CH3 H CH2 (CH2)2 CH3 NHC(=NH)H 1-334 H H CH3 H CH2 (CH2)2 CH3 NHC(=NH)CH3 1-335 H H CH3 H CH2 (CH2)2 CH3 NHC(=NH)CH2CH3 1-336 H H CH3 H CH2 (CH2)2 CH3 NHC(=NH)NH2 1-337 H H H CH3 CH2 bond CH3 NH2 1-338 H H H CH3 CH2 bond CH3 NHCH3 1-339 H H H CH3 CH2 bond CH3 N(CH3)2 1-340 H H H CH3 CH2 bond CH3 NHC(=NH)H 1-341 H H H CH3 CH2 bond CH3 NHC(=NH)CH3 1-342 H H H CH3 CH2 bond CH3 NHC(=NH)CH2CH3 1-343 H H H CH3 CH2 bond CH3 NHC(=NH)NH2 1-344 H H H CH3 (CH2)2 bond CH3 NH2 1-345 H H H CH3 (CH2)2 bond CH3 NHCH3 1-346 H H H CH3 (CH2)2 bond CH3 N(CH3)2 1-347 H H H CH3 (CH2)2 bond CH3 NHC(=NH)H 1-348 H H H CH3 (CH2)2 bond CH3 NHC(=NH)CH3 1-349 H H H CH3 (CH2)2 bond CH3 NHC(=NH)CH2CH3 1-350 H H H CH3 (CH2)2 bond CH3 NHC(=NH)NH2 1-351 H H H CH3 CF2CH2 bond CH3 NH2 1-352 H H H CH3 CF2CH2 bond CH3 NHCH3 1-353 H H H CH3 CF2CH2 bond CH3 N(CH3)2 1-354 H H H CH3 CF2CH2 bond CH3 NHC(=NH)H 1-355 H H H CH3 CF2CH2 bond CH3 NHC(=NH)CH3 1-356 H H H CH3 CF2CH2 bond CH3 NHC(=NH)CH2CH3 1-357 H H H CH3 CF2CH2 bond CH3 NHC(=NH)NH2 1-358 H H H CH3 (CH2)3 bond CH3 NH2 1-359 H H H CH3 (CH2)3 bond CH3 NHCH3 1-360 H H H CH3 (CH2)3 bond CH3 N(CH3)2 1-361 H H H CH3 (CH2)3 bond CH3 NHC(=NH)H 1-362 H H H CH3 (CH2)3 bond CH3 NHC(=NH)CH3 1-363 H H H CH3 (CH2)3 bond CH3 NHC(=NH)CH2CH3 1-364 H H H CH3 (CH2)3 bond CH3 NHC(=NH)NH2 1-365 H H H CH3 CH2 CH2 CH3 NH2 1-366 H H H CH3 CH2 CH2 CH3 NHCH3 1-367 H H H CH3 CH2 CH2 CH3 N(CH3)2 1-368 H H H CH3 CH2 CH2 CH3 NHC(=NH)H 1-369 H H H CH3 CH2 CH2 CH3 NHC(=NH)CH3 1-370 H H H CH3 CH2 CH2 CH3 NHC(=NH)CH2CH3 1-371 H H H CH3 CH2 CH2 CH3 NHC(=NH)NH2 1-372 H H H CH3 (CH2)2 CH2 CH3 NH2 1-373 H H H CH3 (CH2)2 CH2 CH3 NHCH3 1-374 H H H CH3 (CH2)2 CH2 CH3 N(CH3)2 1-375 H H H CH3 (CH2)2 CH2 CH3 NHC(=NH)H 1-376 H H H CH3 (CH2)2 CH2 CH3 NHC(=NH)CH3 1-377 H H H CH3 (CH2)2 CH2 CH3 NHC(=NH)CH2CH3 1-378 H H H CH3 (CH2)2 CH2 CH3 NHC(=NH)NH2 1-379 H H H CH3 CF2CH2 CH2 CH3 NH2 1-380 H H H CH3 CF2CH2 CH2 CH3 NHCH3 1-381 H H H CH3 CF2CH2 CH2 CH3 N(CH3)2 1-382 H H H CH3 CF2CH2 CH2 CH3 NHC(=NH)H 1-383 H H H CH3 CF2CH2 CH2 CH3 NHC(=NH)CH3 1-384 H H H CH3 CF2CH2 CH2 CH3 NHC(=NH)CH2CH3 1-385 H H H CH3 CF2CH2 CH2 CH3 NHC(=NH)NH2 1-386 H H H CH3 CH2 (CH2)2 CH3 NH2 1-387 H H H CH3 CH2 (CH2)2 CH3 NHCH3 1-388 H H H CH3 CH2 (CH2)2 CH3 N(CH3)2 1-389 H H H CH3 CH2 (CH2)2 CH3 NHC(=NH)H 1-390 H H H CH3 CH2 (CH2)2 CH3 NHC(=NH)CH3 1-391 H H H CH3 CH2 (CH2)2 CH3 NHC(=NH)CH2CH3 1-392 H H H CH3 CH2 (CH2)2 CH3 NHC(=NH)NH2 1-393 H H CH3 CH3 CH2 bond CH3 NH2 1-394 H H CH3 CH3 CH2 bond CH3 NHCH3 1-395 H H CH3 CH3 CH2 bond CH3 N(CH3)2 1-396 H H CH3 CH3 CH2 bond CH3 NHC(=NH)H 1-397 H H CH3 CH3 CH2 bond CH3 NHC(=NH)CH3 1-398 H H CH3 CH3 CH2 bond CH3 NHC(=NH)CH2CH3 1-399 H H CH3 CH3 CH2 bond CH3 NHC(=NH)NH2 1-400 H H CH3 CH3 (CH2)2 bond CH3 NH2 1-401 H H CH3 CH3 (CH2)2 bond CH3 NHCH3 1-402 H H CH3 CH3 (CH2)2 bond CH3 N(CH3)2 1-403 H H CH3 CH3 (CH2)2 bond CH3 NHC(=NH)H 1-404 H H CH3 CH3 (CH2)2 bond CH3 NHC(=NH)CH3 1-405 H H CH3 CH3 (CH2)2 bond CH3 NHC(=NH)CH2CH3 1-406 H H CH3 CH3 (CH2)2 bond CH3 NHC(=NH)NH2 1-407 H H CH3 CH3 CF2CH2 bond CH3 NH2 1-408 H H CH3 CH3 CF2CH2 bond CH3 NHCH3 1-409 H H CH3 CH3 CF2CH2 bond CH3 N(CH3)2 1-410 H H CH3 CH3 CF2CH2 bond CH3 NHC(=NH)H 1-411 H H CH3 CH3 CF2CH2 bond CH3 NHC(=NH)CH3 1-412 H H CH3 CH3 CF2CH2 bond CH3 NHC(=NH)CH2CH3 1-413 H H CH3 CH3 CF2CH2 bond CH3 NHC(=NH)NH2 1-414 H H CH3 CH3 (CH2)3 bond CH3 NH2 1-415 H H CH3 CH3 (CH2)3 bond CH3 NHCH3 1-416 H H CH3 CH3 (CH2)3 bond CH3 N(CH3)2 1-417 H H CH3 CH3 (CH2)3 bond CH3 NHC(=NH)H 1-418 H H CH3 CH3 (CH2)3 bond CH3 NHC(=NH)CH3 1-419 H H CH3 CH3 (CH2)3 bond CH3 NHC(=NH)CH2CH3 1-420 H H CH3 CH3 (CH2)3 bond CH3 NHC(=NH)NH2 1-421 H H CH3 CH3 CH2 CH2 CH3 NH2 1-422 H H CH3 CH3 CH2 CH2 CH3 NHCH3 1-423 H H CH3 CH3 CH2 CH2 CH3 N(CH3)2 1-424 H H CH3 CH3 CH2 CH2 CH3 NHC(=NH)H 1-425 H H CH3 CH3 CH2 CH2 CH3 NHC(=NH)CH3 1-426 H H CH3 CH3 CH2 CH2 CH3 NHC(=NH)CH2CH3 1-427 H H CH3 CH3 CH2 CH2 CH3 NHC(=NH)NH2 1-428 H H CH3 CH3 (CH2)2 CH2 CH3 NH2 1-429 H H CH3 CH3 (CH2)2 CH2 CH3 NHCH3 1-430 H H CH3 CH3 (CH2)2 CH2 CH3 N(CH3)2 1-431 H H CH3 CH3 (CH2)2 CH2 CH3 NHC(=NH)H 1-432 H H CH3 CH3 (CH2)2 CH2 CH3 NHC(=NH)CH3 1-433 H H CH3 CH3 (CH2)2 CH2 CH3 NHC(=NH)CH2CH3 1-434 H H CH3 CH3 (CH2)2 CH2 CH3 NHC(=NH)NH2 1-435 H H CH3 CH3 CF2CH2 CH2 CH3 NH2 1-436 H H CH3 CH3 CF2CH2 CH2 CH3 NHCH3 1-437 H H CH3 CH3 CF2CH2 CH2 CH3 N(CH3)2 1-438 H H CH3 CH3 CF2CH2 CH2 CH3 NHC(=NH)H 1-439 H H CH3 CH3 CF2CH2 CH2 CH3 NHC(=NH)CH3 1-440 H H CH3 CH3 CF2CH2 CH2 CH3 NHC(=NH)CH2CH3 1-441 H H CH3 CH3 CF2CH2 CH2 CH3 NHC(=NH)NH2 1-442 H H CH3 CH3 CH2 (CH2)2 CH3 NH2 1-443 H H CH3 CH3 CH2 (CH2)2 CH3 NHCH3 1-444 H H CH3 CH3 CH2 (CH2)2 CH3 N(CH3)2 1-445 H H CH3 CH3 CH2 (CH2)2 CH3 NHC(=NH)H 1-446 H H CH3 CH3 CH2 (CH2)2 CH3 NHC(=NH)CH3 1-447 H H CH3 CH3 CH2 (CH2)2 CH3 NHC(=NH)CH2CH3 1-448 H H CH3 CH3 CH2 (CH2)2 CH3 NHC(=NH)NH2 --------------------------------------------------------------------- ［表２］----------------------------------------------- ---------------------- Cpd.No.R 1 R 2 R 3 R 4 (CR 5 R 6 ) n (CR 7 R 8 ) m R 9 R 10 ------------------------------------------------ --------------------- 1-1 OH OH HH CH 2 bond CH 3 NH 2 1-2 OH OH HH CH 2 bond CH 3 NHCH 3 1-3 OH OH HH CH 2 bond CH 3 N (CH 3 ) 2 1-4 OH OH HH CH 2 bond CH 3 NHC (= NH) H 1-5 OH OH HH CH 2 bond CH 3 NHC (= NH) CH 3 1 -6 OH OH HH CH 2 bond CH 3 NHC (= NH) CH 2 CH 3 1-7 OH OH HH CH 2 bond CH 3 NHC (= NH) NH 2 1-8 OH OH HH (CH 2 ) 2 bond CH 3 NH 2 1-9 OH OH HH (CH 2 ) 2 bond CH 3 NHCH 3 1-10 OH OH HH (CH 2 ) 2 bond CH 3 N (CH 3 ) 2 1-11 OH OH HH (CH 2 ) 2 bond CH 3 NHC (= NH) H 1-12 OH OH HH (CH 2 ) 2 bond CH 3 NHC (= NH) CH 3 1-13 OH OH HH (CH 2 ) 2 bond CH 3 NHC (= NH) CH 2 CH 3 1-14 OH OH HH (CH 2 ) 2 bond CH 3 NHC (= NH) NH 2 1-15 OH OH HH CF 2 CH 2 bond CH 3 NH 2 1-16 OH OH HH CF 2 CH 2 bond CH 3 NHCH 3 1-17 OH OH HH CF 2 CH 2 bond CH 3 N (CH 3 ) 2 1-18 OH OH HH CF 2 CH 2 bond CH 3 NHC (= NH) H 1-19 OH OH HH CF 2 CH 2 bon d CH 3 NHC (= NH) CH 3 1-20 OH OH HH CF 2 CH 2 bond CH 3 NHC (= NH) CH 2 CH 3 1-21 OH OH HH CF 2 CH 2 bond CH 3 NHC (= NH) NH 2 1-22 OH OH HH (CH 2 ) 3 bond CH 3 NH 2 1-23 OH OH HH (CH 2 ) 3 bond CH 3 NHCH 3 1-24 OH OH HH (CH 2 ) 3 bond CH 3 N ( CH 3 ) 2 1-25 OH OH HH (CH 2 ) 3 bond CH 3 NHC (= NH) H 1-26 OH OH HH (CH 2 ) 3 bond CH 3 NHC (= NH) CH 3 1-27 OH OH HH (CH 2 ) 3 bond CH 3 NHC (= NH) CH 2 CH 3 1-28 OH OH HH (CH 2 ) 3 bond CH 3 NHC (= NH) NH 2 1-29 OH OH HH CH 2 CH 2 CH 3 NH 2 1-30 OH OH HH CH 2 CH 2 CH 3 NHCH 3 1-31 OH OH HH CH 2 CH 2 CH 3 N (CH 3 ) 2 1-32 OH OH OH HH CH 2 CH 2 CH 3 NHC (= NH) H 1-33 OH OH HH CH 2 CH 2 CH 3 NHC (= NH) CH 3 1-34 OH OH HH CH 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1-35 OH OH HH CH 2 CH 2 CH 3 NHC (= NH) NH 2 1-36 OH OH HH (CH 2 ) 2 CH 2 CH 3 NH 2 1-37 OH OH HH (CH 2 ) 2 CH 2 CH 3 NHCH 3 1-38 OH OH HH (CH 2 ) 2 CH 2 CH 3 N (CH 3 ) 2 1-39 OH OH HH (CH 2 ) 2 CH 2 CH 3 NHC (= NH) H 1-40 OH OH HH (CH 2 ) 2 CH 2 CH 3 NHC (= NH) CH 3 1-41 OH OH HH (CH 2 ) 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1-42 OH OH HH (CH 2 ) 2 CH 2 CH 3 NHC (= NH) NH 2 1-43 OH OH HH CF 2 CH 2 CH 2 CH 3 NH 2 1-44 OH OH HH CF 2 CH 2 CH 2 CH 3 NHCH 3 1-45 OH OH HH CF 2 CH 2 CH 2 CH 3 N (CH 3 ) 2 1-46 OH OH HH CF 2 CH 2 CH 2 CH 3 NHC (= NH) H 1-47 OH OH HH CF 2 CH 2 CH 2 CH 3 NHC (= NH) CH 3 1-48 OH OH HH CF 2 CH 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1-49 OH OH HH CF 2 CH 2 CH 2 CH 3 NHC (= NH) NH 2 1-50 OH OH HH CH 2 (CH 2 ) 2 CH 3 NH 2 1-51 OH OH HH CH 2 (CH 2 ) 2 CH 3 NHCH 3 1-52 OH OH HH CH 2 (CH 2 ) 2 CH 3 N (CH 3 ) 2 1-53 OH OH HH CH 2 (CH 2 ) 2 CH 3 NHC (= NH) H 1-54 OH OH HH CH 2 (CH 2 ) 2 CH 3 NHC (= NH) CH 3 1 -55 OH OH HH CH 2 (CH 2 ) 2 CH 3 NHC (= NH) CH 2 CH 3 1-56 OH OH HH CH 2 (CH 2 ) 2 CH 3 NHC (= NH) NH 2 1-57 OH OH CH 3 H CH 2 bond CH 3 NH 2 1-58 OH OH CH 3 H CH 2 bond CH 3 NHCH 3 1-59 OH OH CH 3 H CH 2 bond CH 3 N (CH 3 ) 2 1-60 OH OH CH 3 H CH 2 bond CH 3 NHC (= NH) H 1-61 OH OH CH 3 H CH 2 bond CH 3 NHC (= NH) CH 3 1-62 OH OH CH 3 H CH 2 bond CH 3 NHC (= NH ) CH 2 CH 3 1-63 OH OH CH 3 H CH 2 bond CH 3 NHC (= NH) NH 2 1-64 OH OH CH 3 H (CH 2 ) 2 bond CH 3 NH 2 1-65 OH OH CH 3 H (CH 2 ) 2 bond CH 3 NHCH 3 1-66 OH OH CH 3 H (CH 2 ) 2 bond CH 3 N (CH 3 ) 2 1-67 OH OH CH 3 H (CH 2 ) 2 bond CH 3 NHC (= NH) H 1-68 OH OH CH 3 H (CH 2 ) 2 bond CH 3 NHC (= NH) CH 3 1-69 OH OH CH 3 H (CH 2 ) 2 bond CH 3 NHC (= NH) CH 2 CH 3 1-70 OH OH CH 3 H (CH 2 ) 2 bond CH 3 NHC (= NH) NH 2 1-71 OH OH CH 3 H CF 2 CH 2 bond CH 3 NH 2 1-72 OH OH CH 3 H CF 2 CH 2 bond CH 3 NHCH 3 1-73 OH OH CH 3 H CF 2 CH 2 bond CH 3 N (CH 3 ) 2 1-74 OH OH CH 3 H CF 2 CH 2 bond CH 3 NHC (= NH) H 1-75 OH OH CH 3 H CF 2 CH 2 bond CH 3 NHC (= NH) CH 3 1-76 OH OH CH 3 H CF 2 CH 2 bond CH 3 NHC (= NH) CH 2 CH 3 1-77 OH OH CH 3 H CF 2 CH 2 bond CH 3 NHC (= NH) NH 2 1-78 OH OH CH 3 H (CH 2 ) 3 bond CH 3 NH 2 1 -79 OH OH CH 3 H (CH 2 ) 3 bond CH 3 NHCH 3 1-80 OH OH CH 3 H (CH 2 ) 3 bond CH 3 N (CH 3 ) 2 1-81 OH OH CH 3 H (CH 2 ) 3 bond CH 3 NHC (= NH) H 1-82 OH OH CH 3 H (CH 2 ) 3 bond CH 3 NHC (= NH) CH 3 1-83 OH OH CH 3 H (CH 2 ) 3 bond CH 3 NHC (= NH) CH 2 CH 3 1-84 OH OH CH 3 H (CH 2 ) 3 bond CH 3 NHC (= NH) NH 2 1-85 OH OH CH 3 H CH 2 CH 2 CH 3 NH 2 1-86 OH OH CH 3 H CH 2 CH 2 CH 3 NHCH 3 1-87 OH OH CH 3 H CH 2 CH 2 CH 3 N (CH 3 ) 2 1 -88 OH OH CH 3 H CH 2 CH 2 CH 3 NHC (= NH) H 1-89 OH OH CH 3 H CH 2 CH 2 CH 3 NHC (= NH) CH 3 1-90 OH OH CH 3 H CH 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1-91 OH OH CH 3 H CH 2 CH 2 CH 3 NHC (= NH) NH 2 1-92 OH OH CH 3 H (CH 2 ) 2 CH 2 CH 3 NH 2 1-93 OH OH CH 3 H (CH 2 ) 2 CH 2 CH 3 NHCH 3 1-94 OH OH CH 3 H (CH 2 ) 2 CH 2 CH 3 N (CH 3 ) 2 1-95 OH OH CH 3 H (CH 2 ) 2 CH 2 CH 3 NHC (= NH) H 1-96 OH OH CH 3 H (CH 2 ) 2 CH 2 CH 3 NHC (= NH) CH 3 1-97 OH OH CH 3 H (CH 2 ) 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1-98 OH OH CH 3 H (CH 2 ) 2 CH 2 CH 3 NHC (= NH) NH 2 1-99 OH OH CH 3 H CF 2 CH 2 CH 2 CH 3 NH 2 1-100 OH OH CH 3 H CF 2 CH 2 CH 2 CH 3 NHCH 3 1-101 OH OH CH 3 H CF 2 CH 2 CH 2 CH 3 N (CH 3 ) 2 1-102 OH OH CH 3 H CF 2 CH 2 CH 2 CH 3 NHC (= NH) H 1-103 OH OH CH 3 H CF 2 CH 2 CH 2 CH 3 NHC (= NH) CH 3 1-104 OH OH CH 3 H CF 2 CH 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1-105 OH OH CH 3 H CF 2 CH 2 CH 2 CH 3 NHC (= NH) NH 2 1-10 6 OH OH CH 3 H CH 2 (CH 2 ) 2 CH 3 NH 2 1-107 OH OH CH 3 H CH 2 (CH 2 ) 2 CH 3 NHCH 3 1-108 OH OH CH 3 H CH 2 (CH 2 ) 2 CH 3 N (CH 3 ) 2 1-109 OH OH CH 3 H CH 2 (CH 2 ) 2 CH 3 NHC (= NH) H 1-110 OH OH CH 3 H CH 2 (CH 2 ) 2 CH 3 NHC (= NH) CH 3 1-111 OH OH CH 3 H CH 2 (CH 2 ) 2 CH 3 NHC (= NH) CH 2 CH 3 1-112 OH OH CH 3 H CH 2 (CH 2 ) 2 CH 3 NHC (= NH) NH 2 1-113 OH OH H CH 3 CH 2 bond CH 3 NH 2 1-114 OH OH H CH 3 CH 2 bond CH 3 NHCH 3 1-115 OH OH H CH 3 CH 2 bond CH 3 N (CH 3 ) 2 1-116 OH OH H CH 3 CH 2 bond CH 3 NHC (= NH) H 1-117 OH OH H CH 3 CH 2 bond CH 3 NHC (= NH) CH 3 1-118 OH OH H CH 3 CH 2 bond CH 3 NHC (= NH) CH 2 CH 3 1-119 OH OH H CH 3 CH 2 bond CH 3 NHC (= NH) NH 2 1-120 OH OH H CH 3 (CH 2 ) 2 bond CH 3 NH 2 1-121 OH OH H CH 3 (CH 2 ) 2 bond CH 3 NHCH 3 1-122 OH OH H CH 3 (CH 2 ) 2 bond CH 3 N (CH 3 ) 2 1-123 OH OH H CH 3 (CH 2 ) 2 bond CH 3 NHC (= NH) H 1-124 OH OH H CH 3 (CH 2 ) 2 bond CH 3 NHC (= NH) CH 3 1-125 OH OH H CH 3 (CH 2 ) 2 bond CH 3 NHC (= NH) CH 2 CH 3 1-126 OH OH H CH 3 (CH 2 ) 2 bond CH 3 NH C (= NH) NH 2 1-127 OH OH H CH 3 CF 2 CH 2 bond CH 3 NH 2 1-128 OH OH H CH 3 CF 2 CH 2 bond CH 3 NHCH 3 1-129 OH OH H CH 3 CF 2 CH 2 bond CH 3 N (CH 3 ) 2 1-130 OH OH H CH 3 CF 2 CH 2 bond CH 3 NHC (= NH) H 1-131 OH OH H CH 3 CF 2 CH 2 bond CH 3 NHC ( = NH) CH 3 1-132 OH OH H CH 3 CF 2 CH 2 bond CH 3 NHC (= NH) CH 2 CH 3 1-133 OH OH H CH 3 CF 2 CH 2 bond CH 3 NHC (= NH) NH 2 1-134 OH OH H CH 3 (CH 2 ) 3 bond CH 3 NH 2 1-135 OH OH H CH 3 (CH 2 ) 3 bond CH 3 NHCH 3 1-136 OH OH H CH 3 (CH 2 ) 3 bond CH 3 N (CH 3 ) 2 1-137 OH OH H CH 3 (CH 2 ) 3 bond CH 3 NHC (= NH) H 1-138 OH OH H CH 3 (CH 2 ) 3 bond CH 3 NHC (= NH) CH 3 1-139 OH OH H CH 3 (CH 2 ) 3 bond CH 3 NHC (= NH) CH 2 CH 3 1-140 OH OH H CH 3 (CH 2 ) 3 bond CH 3 NHC (= NH) NH 2 1-141 OH OH H CH 3 CH 2 CH 2 CH 3 NH 2 1-142 OH OH H CH 3 CH 2 CH 2 CH 3 NHCH 3 1-143 OH OH H CH 3 CH 2 CH 2 CH 3 N ( CH 3 ) 2 1-144 OH OH H CH 3 CH 2 CH 2 CH 3 NHC (= NH) H 1-145 OH OH H CH 3 CH 2 CH 2 CH 3 NHC (= NH) CH 3 1-146 OH OH H CH 3 CH 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1-147 OH OH H CH 3 CH 2 CH 2 CH 3 NHC (= NH) NH 2 1-148 OH OH H CH 3 (CH 2 ) 2 CH 2 CH 3 NH 2 1-149 OH OH H CH 3 (CH 2 ) 2 CH 2 CH 3 NHCH 3 1-150 OH OH H CH 3 (CH 2 ) 2 CH 2 CH 3 N (CH 3 ) 2 1-151 OH OH H CH 3 (CH 2 ) 2 CH 2 CH 3 NHC (= NH) H 1-152 OH OH H CH 3 (CH 2 ) 2 CH 2 CH 3 NHC (= NH) CH 3 1-153 OH OH H CH 3 (CH 2 ) 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1-154 OH OH H CH 3 (CH 2 ) 2 CH 2 CH 3 NHC (= NH) NH 2 1-155 OH OH H CH 3 CF 2 CH 2 CH 2 CH 3 NH 2 1-156 OH OH H CH 3 CF 2 CH 2 CH 2 CH 3 NHCH 3 1-157 OH OH H CH 3 CF 2 CH 2 CH 2 CH 3 N (CH 3 ) 2 1-158 OH OH H CH 3 CF 2 CH 2 CH 2 CH 3 NHC (= NH) H 1-159 OH OH H CH 3 CF 2 CH 2 CH 2 CH 3 NHC (= NH) CH 3 1-160 OH OH H CH 3 CF 2 CH 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1- 161 OH OH H CH 3 CF 2 CH 2 CH 2 CH 3 NHC (= NH) NH 2 1-162 OH OH H CH 3 CH 2 (CH 2 ) 2 CH 3 NH 2 1-163 OH OH H CH 3 CH 2 (CH 2 ) 2 CH 3 NHCH 3 1-164 OH OH H CH 3 CH 2 (CH 2 ) 2 CH 3 N (CH 3 ) 2 1-165 OH OH H CH 3 CH 2 (CH 2 ) 2 CH 3 NHC (= NH) H 1-166 OH OH H CH 3 CH 2 (CH 2 ) 2 CH 3 NHC (= NH) CH 3 1-167 OH OH H CH 3 CH 2 (CH 2 ) 2 CH 3 NHC (= NH) CH 2 CH 3 1-168 OH OH H CH 3 CH 2 (CH 2 ) 2 CH 3 NHC (= NH) NH 2 1-169 OH OH CH 3 CH 3 CH 2 bond CH 3 NH 2 1-170 OH OH CH 3 CH 3 CH 2 bond CH 3 NHCH 3 1-171 OH OH CH 3 CH 3 CH 2 bond CH 3 N (CH 3 ) 2 1-172 OH OH CH 3 CH 3 CH 2 bond CH 3 NHC (= NH) H 1-173 OH OH CH 3 CH 3 CH 2 bond CH 3 NHC (= NH) CH 3 1-174 OH OH CH 3 CH 3 CH 2 bond CH 3 NHC (= NH) CH 2 CH 3 1-175 OH OH CH 3 CH 3 CH 2 bond CH 3 NHC (= NH) NH 2 1-176 OH OH CH 3 CH 3 (CH 2 ) 2 bond CH 3 NH 2 1-177 OH OH CH 3 CH 3 (CH 2 ) 2 bond CH 3 NHCH 3 1-178 OH OH CH 3 CH 3 (CH 2 ) 2 bond CH 3 N (CH 3 ) 2 1-179 OH OH CH 3 CH 3 (CH 2 ) 2 bond CH 3 NHC (= NH) H 1-180 OH OH CH 3 CH 3 (CH 2 ) 2 bond CH 3 NHC (= NH) CH 3 1-181 OH OH CH 3 CH 3 (CH 2 ) 2 bond CH 3 NHC (= NH) CH 2 CH 3 1-182 OH OH CH 3 CH 3 (CH 2 ) 2 bond CH 3 NHC (= NH) NH 2 1-183 OH OH CH 3 CH 3 CF 2 CH 2 bond CH 3 NH 2 1- 184 OH OH CH 3 CH 3 CF 2 CH 2 bond CH 3 NHCH 3 1-185 OH OH CH 3 CH 3 CF 2 CH 2 bond CH 3 N (CH 3 ) 2 1-186 OH OH CH 3 CH 3 CF 2 CH 2 bond CH 3 NHC (= NH) H 1-187 OH OH CH 3 CH 3 CF 2 CH 2 bond CH 3 NHC (= NH) CH 3 1-188 OH OH CH 3 CH 3 CF 2 CH 2 bond CH 3 NHC (= NH) CH 2 CH 3 1-189 OH OH CH 3 CH 3 CF 2 CH 2 bond CH 3 NHC (= NH) NH 2 1-190 OH OH CH 3 CH 3 (CH 2 ) 3 bond CH 3 NH 2 1-191 OH OH CH 3 CH 3 (CH 2 ) 3 bond CH 3 NHCH 3 1-192 OH OH CH 3 CH 3 (CH 2 ) 3 bond CH 3 N (CH 3 ) 2 1-193 OH OH CH 3 CH 3 (CH 2 ) 3 bond CH 3 NHC (= NH) H 1- 194 OH OH CH 3 CH 3 (CH 2 ) 3 bond CH 3 NHC (= NH) CH 3 1-195 OH OH CH 3 CH 3 (CH 2 ) 3 bond CH 3 NHC (= NH) CH 2 CH 3 1- 196 OH OH CH 3 CH 3 (CH 2 ) 3 bond CH 3 NHC (= NH) NH 2 1-197 OH OH CH 3 CH 3 CH 2 CH 2 CH 3 NH 2 1-198 OH OH CH 3 CH 3 CH 2 CH 2 CH 3 NHCH 3 1-199 OH OH CH 3 CH 3 CH 2 CH 2 CH 3 N (CH 3 ) 2 1-200 OH OH CH 3 CH 3 CH 2 CH 2 CH 3 NHC (= NH) H 1- 201 OH OH CH 3 CH 3 CH 2 CH 2 CH 3 NHC (= NH) CH 3 1-202 OH OH CH 3 CH 3 CH 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1-203 OH OH CH 3 CH 3 CH 2 CH 2 CH 3 NHC (= NH) NH 2 1-204 OH OH CH 3 CH 3 (CH 2 ) 2 CH 2 CH 3 NH 2 1-205 OH OH CH 3 CH 3 (CH 2 ) 2 CH 2 CH 3 NHCH 3 1-206 OH OH CH 3 CH 3 (CH 2 ) 2 CH 2 CH 3 N (CH 3 ) 2 1-207 OH OH CH 3 CH 3 (CH 2 ) 2 CH 2 CH 3 NHC (= NH) H 1-208 OH OH CH 3 CH 3 (CH 2 ) 2 CH 2 CH 3 NHC (= NH) CH 3 1-209 OH OH CH 3 CH 3 (CH 2 ) 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1-210 OH OH CH 3 CH 3 (CH 2 ) 2 CH 2 CH 3 NHC (= NH) NH 2 1-211 OH OH CH 3 CH 3 CF 2 CH 2 CH 2 CH 3 NH 2 1-212 OH OH CH 3 CH 3 CF 2 CH 2 CH 2 CH 3 NHCH 3 1-213 OH OH CH 3 CH 3 CF 2 CH 2 CH 2 CH 3 N (CH 3 ) 2 1-214 OH OH CH 3 CH 3 CF 2 CH 2 CH 2 CH 3 NHC (= NH) H 1-215 OH OH CH 3 CH 3 CF 2 CH 2 CH 2 CH 3 NHC (= NH) CH 3 1-216 OH OH CH 3 CH 3 CF 2 CH 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1-217 OH OH CH 3 CH 3 CF 2 CH 2 CH 2 CH 3 NHC (= NH) NH 2 1-218 OH OH CH 3 CH 3 CH 2 (CH 2 ) 2 CH 3 NH 2 1-219 OH OH CH 3 CH 3 CH 2 (CH 2 ) 2 CH 3 NHCH 3 1-220 OH OH CH 3 CH 3 CH 2 (CH 2 ) 2 CH 3 N (CH 3 ) 2 1-221 OH OH CH 3 CH 3 CH 2 (CH 2 ) 2 CH 3 NHC (= NH ) H 1-222 OH OH CH 3 CH 3 CH 2 (CH 2 ) 2 CH 3 NHC (= NH) CH 3 1-223 OH OH CH 3 CH 3 CH 2 (CH 2 ) 2 CH 3 NHC (= NH) CH 2 CH 3 1-224 OH OH CH 3 CH 3 CH 2 (CH 2 ) 2 CH 3 NHC (= NH) NH 2 1-225 HHHH CH 2 bond CH 3 NH 2 1-226 HHHH CH 2 bond CH 3 NHCH 3 1-227 HHHH CH 2 bond CH 3 N (CH 3 ) 2 1-228 HHHH CH 2 bond CH 3 NHC (= NH) H 1-229 HHHH CH 2 bond CH 3 NHC (= NH) CH 3 1-230 HHHH CH 2 bond CH 3 NHC (= NH) CH 2 CH 3 1-231 HHHH CH 2 bond CH 3 NHC (= NH) NH 2 1-232 HHHH (CH 2 ) 2 bond CH 3 NH 2 1-233 HHHH (CH 2 ) 2 bond CH 3 NHCH 3 1-234 HHHH (CH 2 ) 2 bond CH 3 N (CH 3 ) 2 1-235 HHHH (CH 2 ) 2 bond CH 3 NHC (= NH) H 1-236 HHHH (CH 2 ) 2 bond CH 3 NHC (= NH) CH 3 1-237 HHHH (CH 2 ) 2 bond CH 3 NHC (= NH) CH 2 CH 3 1-238 HHHH (CH 2 ) 2 bond CH 3 NHC (= NH) NH 2 1-239 HHHH CF 2 CH 2 bond CH 3 NH 2 1-240 HHHH CF 2 CH 2 bond CH 3 NHCH 3 1-241 HHHH CF 2 CH 2 bond CH 3 N (CH 3 ) 2 1-242 HHHH CF 2 CH 2 bond CH 3 NHC (= NH) H 1-243 HHHH CF 2 CH 2 bond CH 3 NHC (= NH) CH 3 1-244 HHHH CF 2 CH 2 bond CH 3 NHC (= NH) CH 2 CH 3 1-245 HHHH CF 2 CH 2 bond CH 3 NHC (= NH) NH 2 1-246 HHHH (CH 2 ) 3 bond CH 3 NH 2 1-247 HHHH (CH 2 ) 3 bond CH 3 NHCH 3 1-248 HHHH (CH 2 ) 3 bond CH 3 N (CH 3 ) 2 1-249 HHHH (CH 2 ) 3 bond CH 3 NHC (= NH) H 1-250 HHHH (CH 2 ) 3 b ond CH 3 NHC (= NH) CH 3 1-251 HHHH (CH 2 ) 3 bond CH 3 NHC (= NH) CH 2 CH 3 1-252 HHHH (CH 2 ) 3 bond CH 3 NHC (= NH) NH 2 1-253 HHHH CH 2 CH 2 CH 3 NH 2 1-254 HHHH CH 2 CH 2 CH 3 NHCH 3 1-255 HHHH CH 2 CH 2 CH 3 N (CH 3 ) 2 1-256 HHHH CH 2 CH 2 CH 3 NHC (= NH) H 1-257 HHHH CH 2 CH 2 CH 3 NHC (= NH) CH 3 1-258 HHHH CH 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1-259 HHHH CH 2 CH 2 CH 3 NHC (= NH) NH 2 1-260 HHHH (CH 2 ) 2 CH 2 CH 3 NH 2 1-261 HHHH (CH 2 ) 2 CH 2 CH 3 NHCH 3 1-262 HHHH (CH 2 ) 2 CH 2 CH 3 N (CH 3 ) 2 1-263 HHHH (CH 2 ) 2 CH 2 CH 3 NHC (= NH) H 1-264 HHHH (CH 2 ) 2 CH 2 CH 3 NHC (= NH) CH 3 1-265 HHHH (CH 2 ) 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1-266 HHHH (CH 2 ) 2 CH 2 CH 3 NHC (= NH) NH 2 1-267 HHHH CF 2 CH 2 CH 2 CH 3 NH 2 1-268 HHHH CF 2 CH 2 CH 2 CH 3 NHCH 3 1-269 HHHH CF 2 CH 2 CH 2 CH 3 N (CH 3 ) 2 1-270 HHHH CF 2 CH 2 CH 2 CH 3 NHC (= NH) H 1-271 HHHH CF 2 CH 2 CH 2 CH 3 NHC (= NH) CH 3 1-272 HHHH CF 2 CH 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1-273 HHHH CF 2 CH 2 CH 2 CH 3 NHC (= NH) NH 2 1-274 HHHH CH 2 (CH 2 ) 2 CH 3 NH 2 1- 275 HHHH CH 2 (CH 2 ) 2 CH 3 NHCH 3 1-276 HHHH CH 2 (CH 2 ) 2 CH 3 N (CH 3 ) 2 1-277 HHHH CH 2 (CH 2 ) 2 CH 3 NHC (= NH) H 1-278 HHHH CH 2 (CH 2 ) 2 CH 3 NHC (= NH) CH 3 1-279 HHHH CH 2 (CH 2 ) 2 CH 3 NHC (= NH) CH 2 CH 3 1-280 HHHH CH 2 ( CH 2 ) 2 CH 3 NHC (= NH) NH 2 1-281 HH CH 3 H CH 2 bond CH 3 NH 2 1-282 HH CH 3 H CH 2 bond CH 3 NHCH 3 1-283 HH CH 3 H CH 2 bond CH 3 N (CH 3 ) 2 1-284 HH CH 3 H CH 2 bond CH 3 NHC (= NH) H 1-285 HH CH 3 H CH 2 bond CH 3 NHC (= NH) CH 3 1-286 HH CH 3 H CH 2 bond CH 3 NHC (= NH) CH 2 CH 3 1-287 HH CH 3 H CH 2 bond CH 3 NHC (= NH) NH 2 1-288 HH CH 3 H (CH 2 ) 2 bond CH 3 NH 2 1-289 HH CH 3 H (CH 2 ) 2 bond CH 3 NHCH 3 1-290 HH CH 3 H (CH 2 ) 2 bond CH 3 N (CH 3 ) 2 1-291 HH CH 3 H (CH 2 ) 2 bond CH 3 NHC (= NH) H 1-292 HH CH 3 H (CH 2 ) 2 bond CH 3 NHC (= NH) CH 3 1-293 HH CH 3 H (CH 2 ) 2 bond CH 3 NHC (= NH) CH 2 CH 3 1-294 HH CH 3 H (CH 2 ) 2 bond CH 3 NHC (= NH) NH 2 1-295 HH CH 3 H CF 2 CH 2 bond CH 3 NH 2 1-296 HH CH 3 H CF 2 CH 2 bond CH 3 NHCH 3 1-297 HH CH 3 H CF 2 CH 2 bond CH 3 N (CH 3 ) 2 1-298 HH CH 3 H CF 2 CH 2 bond CH 3 NHC (= NH) H 1-299 HH CH 3 H CF 2 CH 2 bond CH 3 NHC (= NH) CH 3 1-300 HH CH 3 H CF 2 CH 2 bond CH 3 NHC (= NH) CH 2 CH 3 1-301 HH CH 3 H CF 2 CH 2 bond CH 3 NHC (= NH) NH 2 1-302 HH CH 3 H (CH 2 ) 3 bond CH 3 NH 2 1-303 HH CH 3 H (CH 2 ) 3 bond CH 3 NHCH 3 1-304 HH CH 3 H (CH 2 ) 3 bond CH 3 N (CH 3 ) 2 1-305 HH CH 3 H (CH 2 ) 3 bond CH 3 NHC (= NH) H 1-306 HH CH 3 H (CH 2 ) 3 bond CH 3 NHC (= NH) CH 3 1-307 HH CH 3 H (CH 2 ) 3 bond CH 3 NHC (= NH) CH 2 CH 3 1-308 HH CH 3 H (CH 2 ) 3 bond CH 3 NHC (= NH) NH 2 1-309 HH CH 3 H CH 2 CH 2 CH 3 NH 2 1 -310 HH CH 3 H CH 2 CH 2 CH 3 NHCH 3 1-311 HH CH 3 H CH 2 CH 2 CH 3 N (CH 3 ) 2 1-312 HH CH 3 H CH 2 CH 2 CH 3 NHC (= NH ) H 1-313 HH CH 3 H CH 2 CH 2 CH 3 NHC (= NH) CH 3 1-314 HH CH 3 H CH 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1-315 HH CH 3 H CH 2 CH 2 CH 3 NHC (= NH) NH 2 1-316 HH CH 3 H (CH 2 ) 2 CH 2 CH 3 NH 2 1-317 HH CH 3 H (CH 2 ) 2 CH 2 CH 3 NHCH 3 1-318 HH CH 3 H (CH 2 ) 2 CH 2 CH 3 N (CH 3 ) 2 1-319 HH CH 3 H (CH 2 ) 2 CH 2 CH 3 NH C (= NH) H 1-320 HH CH 3 H (CH 2 ) 2 CH 2 CH 3 NHC (= NH) CH 3 1-321 HH CH 3 H (CH 2 ) 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1-322 HH CH 3 H (CH 2 ) 2 CH 2 CH 3 NHC (= NH) NH 2 1-323 HH CH 3 H CF 2 CH 2 CH 2 CH 3 NH 2 1-324 HH CH 3 H CF 2 CH 2 CH 2 CH 3 NHCH 3 1-325 HH CH 3 H CF 2 CH 2 CH 2 CH 3 N (CH 3 ) 2 1-326 HH CH 3 H CF 2 CH 2 CH 2 CH 3 NHC (= NH) H 1-327 HH CH 3 H CF 2 CH 2 CH 2 CH 3 NHC (= NH) CH 3 1-328 HH CH 3 H CF 2 CH 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1 -329 HH CH 3 H CF 2 CH 2 CH 2 CH 3 NHC (= NH) NH 2 1-330 HH CH 3 H CH 2 (CH 2 ) 2 CH 3 NH 2 1-331 HH CH 3 H CH 2 (CH 2 ) 2 CH 3 NHCH 3 1-332 HH CH 3 H CH 2 (CH 2 ) 2 CH 3 N (CH 3 ) 2 1-333 HH CH 3 H CH 2 (CH 2 ) 2 CH 3 NHC (= NH) H 1-334 HH CH 3 H CH 2 (CH 2 ) 2 CH 3 NHC (= NH) CH 3 1-335 HH CH 3 H CH 2 (CH 2 ) 2 CH 3 NHC (= NH) CH 2 CH 3 1 -336 HH CH 3 H CH 2 (CH 2 ) 2 CH 3 NHC (= NH) NH 2 1-337 HHH CH 3 CH 2 bond CH 3 NH 2 1-338 HHH CH 3 CH 2 bond CH 3 NHCH 3 1- 339 HHH CH 3 CH 2 bond CH 3 N (CH 3 ) 2 1-340 HHH CH 3 CH 2 bond CH 3 NHC (= NH) H 1-341 HHH CH 3 CH 2 bond CH 3 NHC (= NH) CH 3 1-342 HHH CH 3 CH 2 bond CH 3 NHC (= NH) CH 2 CH 3 1-343 HHH CH 3 CH 2 bond CH 3 NHC (= NH) NH 2 1-344 HHH CH 3 (CH 2 ) 2 bond CH 3 NH 2 1-345 HHH CH 3 (CH 2 ) 2 bond CH 3 NHCH 3 1-346 HHH CH 3 (CH 2 ) 2 bond CH 3 N (CH 3 ) 2 1-347 HHH CH 3 (CH 2 ) 2 bond CH 3 NHC (= NH) H 1-348 HHH CH 3 (CH 2 ) 2 bond CH 3 NHC (= NH) CH 3 1-349 HHH CH 3 (CH 2 ) 2 bond CH 3 NHC (= NH) CH 2 CH 3 1-350 HHH CH 3 (CH 2 ) 2 bond CH 3 NHC (= NH) NH 2 1-351 HHH CH 3 CF 2 CH 2 bond CH 3 NH 2 1-352 HHH CH 3 CF 2 CH 2 bond CH 3 NHCH 3 1-353 HHH CH 3 CF 2 CH 2 bond CH 3 N (CH 3 ) 2 1-354 HHH CH 3 CF 2 CH 2 bond CH 3 NHC (= NH) H 1-355 HHH CH 3 CF 2 CH 2 bond CH 3 NHC (= NH) CH 3 1-356 HHH CH 3 CF 2 CH 2 bond CH 3 NHC (= NH) CH 2 CH 3 1-357 HHH CH 3 CF 2 CH 2 bond CH 3 NHC (= NH) NH 2 1-358 HHH CH 3 (CH 2 ) 3 bond CH 3 NH 2 1-359 HHH CH 3 (CH 2 ) 3 bond CH 3 NHCH 3 1-360 HHH CH 3 (CH 2 ) 3 bond CH 3 N (CH 3 ) 2 1-361 HHH CH 3 (CH 2 ) 3 bond CH 3 NHC (= NH) H 1-362 HHH CH 3 (CH 2 ) 3 bond CH 3 NHC ( = NH) CH 3 1-363 HHH CH 3 (CH 2 ) 3 bond CH 3 NHC (= NH) CH 2 CH 3 1-364 HHH CH 3 (CH 2 ) 3 bond CH 3 NHC (= NH) NH 2 1-365 HHH CH 3 CH 2 CH 2 CH 3 NH 2 1-366 HHH CH 3 CH 2 CH 2 CH 3 NHCH 3 1-367 HHH CH 3 CH 2 CH 2 CH 3 N (CH 3 ) 2 1-368 HHH CH 3 CH 2 CH 2 CH 3 NHC (= NH) H 1-369 HHH CH 3 CH 2 CH 2 CH 3 NHC (= NH) CH 3 1-370 HHH CH 3 CH 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1-371 HHH CH 3 CH 2 CH 2 CH 3 NHC ( = NH) NH 2 1-372 HHH CH 3 (CH 2 ) 2 CH 2 CH 3 NH 2 1-373 HHH CH 3 (CH 2 ) 2 CH 2 CH 3 NHCH 3 1-374 HHH CH 3 (CH 2 ) 2 CH 2 CH 3 N (CH 3 ) 2 1-375 HHH CH 3 (CH 2 ) 2 CH 2 CH 3 NHC (= NH) H 1-376 HHH CH 3 (CH 2 ) 2 CH 2 CH 3 NHC (= NH ) CH 3 1-377 HHH CH 3 (CH 2 ) 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1-378 HHH CH 3 (CH 2 ) 2 CH 2 CH 3 NHC (= NH) NH 2 1 -379 HHH CH 3 CF 2 CH 2 CH 2 CH 3 NH 2 1-380 HHH CH 3 CF 2 CH 2 CH 2 CH 3 NHCH 3 1-381 HHH CH 3 CF 2 CH 2 CH 2 CH 3 N (CH 3 ) 2 1-382 HHH CH 3 CF 2 CH 2 CH 2 CH 3 NHC (= NH) H 1-383 HHH CH 3 CF 2 CH 2 CH 2 CH 3 NHC (= NH) CH 3 1-384 HHH CH 3 CF 2 CH 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1-385 HHH CH 3 CF 2 CH 2 CH 2 CH 3 NHC (= NH) NH 2 1-386 HHH CH 3 CH 2 (CH 2 ) 2 CH 3 NH 2 1-387 HHH CH 3 CH 2 (CH 2 ) 2 CH 3 NHCH 3 1-388 HHH CH 3 CH 2 (CH 2 ) 2 CH 3 N (CH 3 ) 2 1-389 HHH CH 3 CH 2 (CH 2 ) 2 CH 3 NHC (= NH) H 1-390 HHH CH 3 CH 2 (CH 2 ) 2 CH 3 NHC (= NH) CH 3 1 -391 HHH CH 3 CH 2 (CH 2 ) 2 CH 3 NHC (= NH) CH 2 CH 3 1-392 HHH CH 3 CH 2 (CH 2 ) 2 CH 3 NHC (= NH) NH 2 1-393 HH CH 3 CH 3 CH 2 bond CH 3 NH 2 1-394 HH CH 3 CH 3 CH 2 bond CH 3 NHCH 3 1-395 HH CH 3 CH 3 CH 2 bond CH 3 N (CH 3 ) 2 1-396 HH CH 3 CH 3 CH 2 bond CH 3 NHC (= NH) H 1-397 HH CH 3 CH 3 CH 2 bond CH 3 NHC (= NH) CH 3 1-398 HH CH 3 CH 3 CH 2 bond CH 3 NHC (= NH ) CH 2 CH 3 1-399 HH CH 3 CH 3 CH 2 bond CH 3 NHC (= NH) NH 2 1-400 HH CH 3 CH 3 (CH 2 ) 2 bond CH 3 NH 2 1-401 HH CH 3 CH 3 (CH 2 ) 2 bond CH 3 NHCH 3 1-402 HH CH 3 CH 3 (CH 2 ) 2 bond CH 3 N (CH 3 ) 2 1-403 HH CH 3 CH 3 (CH 2 ) 2 bond CH 3 NHC (= NH) H 1-404 HH CH 3 CH 3 (CH 2 ) 2 bond CH 3 NHC (= NH) CH 3 1-405 HH CH 3 CH 3 (CH 2 ) 2 bond CH 3 NHC (= NH) CH 2 CH 3 1-406 HH CH 3 CH 3 (CH 2 ) 2 bond CH 3 NHC (= NH) NH 2 1-407 HH CH 3 CH 3 CF 2 CH 2 bond CH 3 NH 2 1-408 HH CH 3 CH 3 CF 2 CH 2 bond CH 3 NHCH 3 1-409 HH CH 3 CH 3 CF 2 CH 2 bond CH 3 N (CH 3 ) 2 1-410 HH CH 3 CH 3 CF 2 CH 2 bond CH 3 NHC (= NH) H 1-411 HH CH 3 CH 3 CF 2 CH 2 bond CH 3 NHC (= NH) CH 3 1-412 HH CH 3 CH 3 CF 2 CH 2 bond CH 3 NHC (= NH) CH 2 CH 3 1-413 HH CH 3 CH 3 CF 2 CH 2 bond CH 3 NHC (= NH) NH 2 1-414 HH CH 3 CH 3 (CH 2 ) 3 bond CH 3 NH 2 1-415 HH CH 3 CH 3 (CH 2 ) 3 bond CH 3 NHCH 3 1-416 HH CH 3 CH 3 (CH 2 ) 3 bond CH 3 N (CH 3 ) 2 1-417 HH CH 3 CH 3 (CH 2 ) 3 bond CH 3 NHC (= NH) H 1-418 HH CH 3 CH 3 (CH 2 ) 3 bond CH 3 NHC (= NH) CH 3 1-419 HH CH 3 CH 3 (CH 2 ) 3 bond CH 3 NHC (= NH) CH 2 CH 3 1-420 HH CH 3 CH 3 (CH 2 ) 3 bond CH 3 NHC (= NH) NH 2 1-421 HH CH 3 CH 3 CH 2 CH 2 CH 3 NH 2 1-422 HH CH 3 CH 3 CH 2 CH 2 CH 3 NHCH 3 1-423 HH CH 3 CH 3 CH 2 CH 2 CH 3 N (CH 3 ) 2 1-424 HH CH 3 CH 3 CH 2 CH 2 CH 3 NHC (= NH) H 1-425 HH CH 3 CH 3 CH 2 CH 2 CH 3 NHC (= NH) CH 3 1-426 HH CH 3 CH 3 CH 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1-427 HH CH 3 CH 3 CH 2 CH 2 CH 3 NHC (= NH) N H 2 1-428 HH CH 3 CH 3 (CH 2 ) 2 CH 2 CH 3 NH 2 1-429 HH CH 3 CH 3 (CH 2 ) 2 CH 2 CH 3 NHCH 3 1-430 HH CH 3 CH 3 (CH 2 ) 2 CH 2 CH 3 N (CH 3 ) 2 1-431 HH CH 3 CH 3 (CH 2 ) 2 CH 2 CH 3 NHC (= NH) H 1-432 HH CH 3 CH 3 (CH 2 ) 2 CH 2 CH 3 NHC (= NH) CH 3 1-433 HH CH 3 CH 3 (CH 2 ) 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1-434 HH CH 3 CH 3 (CH 2 ) 2 CH 2 CH 3 NHC (= NH) NH 2 1-435 HH CH 3 CH 3 CF 2 CH 2 CH 2 CH 3 NH 2 1-436 HH CH 3 CH 3 CF 2 CH 2 CH 2 CH 3 NHCH 3 1-437 HH CH 3 CH 3 CF 2 CH 2 CH 2 CH 3 N (CH 3 ) 2 1-438 HH CH 3 CH 3 CF 2 CH 2 CH 2 CH 3 NHC (= NH) H 1-439 HH CH 3 CH 3 CF 2 CH 2 CH 2 CH 3 NHC (= NH) CH 3 1-440 HH CH 3 CH 3 CF 2 CH 2 CH 2 CH 3 NHC (= NH) CH 2 CH 3 1-441 HH CH 3 CH 3 CF 2 CH 2 CH 2 CH 3 NHC (= NH) NH 2 1-442 HH CH 3 CH 3 CH 2 (CH 2 ) 2 CH 3 NH 2 1-443 HH CH 3 CH 3 CH 2 (CH 2 ) 2 CH 3 NHCH 3 1 -444 HH CH 3 CH 3 CH 2 (CH 2 ) 2 CH 3 N (CH 3 ) 2 1-445 HH CH 3 CH 3 CH 2 (CH 2 ) 2 CH 3 NHC (= NH) H 1-446 HH CH 3 CH 3 CH 2 (CH 2 ) 2 CH 3 NHC (= NH) CH 3 1-447 HH CH 3 CH 3 CH 2 (CH 2 ) 2 CH 3 NHC (= NH) CH 2 CH 3 1-448 HH CH 3 CH 3 CH 2 (CH 2 ) 2 CH 3 NHC (= NH) NH 2 ------------------------- -------------------------------------------- [Table 2]
【００３９】[0039]
【化５】 Embedded image
【００４０】 --------------------------------------------------------------------- Cpd.No. m n R1 R2 Ra R10 --------------------------------------------------------------------- 2-1 0 1 OH OH CH3 NH2 2-2 0 1 OH OH CH3 NHCH3 2-3 0 1 OH OH CH3 N(CH3)2 2-4 0 1 OH OH CH3 NHC(=NH)H 2-5 0 1 OH OH CH3 NHC(=NH)CH3 2-6 0 1 OH OH CH3 NHC(=NH)CH2CH3 2-7 0 1 OH OH CH3 NHC(=NH)NH2 2-8 0 1 OH OH CH2CH3 NH2 2-9 0 1 OH OH CH2CH3 NHCH3 2-10 0 1 OH OH CH2CH3 N(CH3)2 2-11 0 1 OH OH CH2CH3 NHC(=NH)H 2-12 0 1 OH OH CH2CH3 NHC(=NH)CH3 2-13 0 1 OH OH CH2CH3 NHC(=NH)CH2CH3 2-14 0 1 OH OH CH2CH3 NHC(=NH)NH2 2-15 0 1 OH OH (CH2)2CH3 NH2 2-16 0 1 OH OH (CH2)2CH3 NHCH3 2-17 0 1 OH OH (CH2)2CH3 N(CH3)2 2-18 0 1 OH OH (CH2)2CH3 NHC(=NH)H 2-19 0 1 OH OH (CH2)2CH3 NHC(=NH)CH3 2-20 0 1 OH OH (CH2)2CH3 NHC(=NH)CH2CH3 2-21 0 1 OH OH (CH2)2CH3 NHC(=NH)NH2 2-22 0 1 OH OH (CH2)3CH3 NH2 2-23 0 1 OH OH (CH2)3CH3 NHCH3 2-24 0 1 OH OH (CH2)3CH3 N(CH3)2 2-25 0 1 OH OH (CH2)3CH3 NHC(=NH)H 2-26 0 1 OH OH (CH2)3CH3 NHC(=NH)CH3 2-27 0 1 OH OH (CH2)3CH3 NHC(=NH)CH2CH3 2-28 0 1 OH OH (CH2)3CH3 NHC(=NH)NH2 2-29 0 1 OH OH (CH2)4CH3 NH2 2-30 0 1 OH OH (CH2)4CH3 NHCH3 2-31 0 1 OH OH (CH2)4CH3 N(CH3)2 2-32 0 1 OH OH (CH2)4CH3 NHC(=NH)H 2-33 0 1 OH OH (CH2)4CH3 NHC(=NH)CH3 2-34 0 1 OH OH (CH2)4CH3 NHC(=NH)CH2CH3 2-35 0 1 OH OH (CH2)4CH3 NHC(=NH)NH2 2-36 0 1 OH OH (CH2)5CH3 NH2 2-37 0 1 OH OH (CH2)5CH3 NHCH3 2-38 0 1 OH OH (CH2)5CH3 N(CH3)2 2-39 0 1 OH OH (CH2)5CH3 NHC(=NH)H 2-40 0 1 OH OH (CH2)5CH3 NHC(=NH)CH3 2-41 0 1 OH OH (CH2)5CH3 NHC(=NH)CH2CH3 2-42 0 1 OH OH (CH2)5CH3 NHC(=NH)NH2 2-43 0 1 OH OH (CH2)7CH3 NH2 2-44 0 1 OH OH (CH2)7CH3 NHCH3 2-45 0 1 OH OH (CH2)7CH3 N(CH3)2 2-46 0 1 OH OH (CH2)7CH3 NHC(=NH)H 2-47 0 1 OH OH (CH2)7CH3 NHC(=NH)CH3 2-48 0 1 OH OH (CH2)7CH3 NHC(=NH)CH2CH3 2-49 0 1 OH OH (CH2)7CH3 NHC(=NH)NH2 2-50 0 1 OH OH (CH2)9CH3 NH2 2-51 0 1 OH OH (CH2)9CH3 NHCH3 2-52 0 1 OH OH (CH2)9CH3 N(CH3)2 2-53 0 1 OH OH (CH2)9CH3 NHC(=NH)H 2-54 0 1 OH OH (CH2)9CH3 NHC(=NH)CH3 2-55 0 1 OH OH (CH2)9CH3 NHC(=NH)CH2CH3 2-56 0 1 OH OH (CH2)9CH3 NHC(=NH)NH2 2-57 0 1 OH OH (CH2)11CH3 NH2 2-58 0 1 OH OH (CH2)11CH3 NHCH3 2-59 0 1 OH OH (CH2)11CH3 N(CH3)2 2-60 0 1 OH OH (CH2)11CH3 NHC(=NH)H 2-61 0 1 OH OH (CH2)11CH3 NHC(=NH)CH3 2-62 0 1 OH OH (CH2)11CH3 NHC(=NH)CH2CH3 2-63 0 1 OH OH (CH2)11CH3 NHC(=NH)NH2 2-64 0 1 OH OH (CH2)13CH3 NH2 2-65 0 1 OH OH (CH2)13CH3 NHCH3 2-66 0 1 OH OH (CH2)13CH3 N(CH3)2 2-67 0 1 OH OH (CH2)13CH3 NHC(=NH)H 2-68 0 1 OH OH (CH2)13CH3 NHC(=NH)CH3 2-69 0 1 OH OH (CH2)13CH3 NHC(=NH)CH2CH3 2-70 0 1 OH OH (CH2)13CH3 NHC(=NH)NH2 2-71 0 1 OH OH (CH2)15CH3 NH2 2-72 0 1 OH OH (CH2)15CH3 NHCH3 2-73 0 1 OH OH (CH2)15CH3 N(CH3)2 2-74 0 1 OH OH (CH2)15CH3 NHC(=NH)H 2-75 0 1 OH OH (CH2)15CH3 NHC(=NH)CH3 2-76 0 1 OH OH (CH2)15CH3 NHC(=NH)CH2CH3 2-77 0 1 OH OH (CH2)15CH3 NHC(=NH)NH2 2-78 0 1 OH OH (CH2)17CH3 NH2 2-79 0 1 OH OH (CH2)17CH3 NHCH3 2-80 0 1 OH OH (CH2)17CH3 N(CH3)2 2-81 0 1 OH OH (CH2)17CH3 NHC(=NH)H 2-82 0 1 OH OH (CH2)17CH3 NHC(=NH)CH3 2-83 0 1 OH OH (CH2)17CH3 NHC(=NH)CH2CH3 2-84 0 1 OH OH (CH2)17CH3 NHC(=NH)NH2 2-85 0 1 OH OH (CH2)19CH3 NH2 2-86 0 1 OH OH (CH2)19CH3 NHCH3 2-87 0 1 OH OH (CH2)19CH3 N(CH3)2 2-88 0 1 OH OH (CH2)19CH3 NHC(=NH)H 2-89 0 1 OH OH (CH2)19CH3 NHC(=NH)CH3 2-90 0 1 OH OH (CH2)19CH3 NHC(=NH)CH2CH3 2-91 0 1 OH OH (CH2)19CH3 NHC(=NH)NH2 2-92 0 1 H H CH3 NH2 2-93 0 1 H H CH3 NHCH3 2-94 0 1 H H CH3 N(CH3)2 2-95 0 1 H H CH3 NHC(=NH)H 2-96 0 1 H H CH3 NHC(=NH)CH3 2-97 0 1 H H CH3 NHC(=NH)CH2CH3 2-98 0 1 H H CH3 NHC(=NH)NH2 2-99 0 1 H H CH2CH3 NH2 2-100 0 1 H H CH2CH3 NHCH3 2-101 0 1 H H CH2CH3 N(CH3)2 2-102 0 1 H H CH2CH3 NHC(=NH)H 2-103 0 1 H H CH2CH3 NHC(=NH)CH3 2-104 0 1 H H CH2CH3 NHC(=NH)CH2CH3 2-105 0 1 H H CH2CH3 NHC(=NH)NH2 2-106 0 1 H H (CH2)2CH3 NH2 2-107 0 1 H H (CH2)2CH3 NHCH3 2-108 0 1 H H (CH2)2CH3 N(CH3)2 2-109 0 1 H H (CH2)2CH3 NHC(=NH)H 2-110 0 1 H H (CH2)2CH3 NHC(=NH)CH3 2-111 0 1 H H (CH2)2CH3 NHC(=NH)CH2CH3 2-112 0 1 H H (CH2)2CH3 NHC(=NH)NH2 2-113 0 1 H H (CH2)3CH3 NH2 2-114 0 1 H H (CH2)3CH3 NHCH3 2-115 0 1 H H (CH2)3CH3 N(CH3)2 2-116 0 1 H H (CH2)3CH3 NHC(=NH)H 2-117 0 1 H H (CH2)3CH3 NHC(=NH)CH3 2-118 0 1 H H (CH2)3CH3 NHC(=NH)CH2CH3 2-119 0 1 H H (CH2)3CH3 NHC(=NH)NH2 2-120 0 1 H H (CH2)4CH3 NH2 2-121 0 1 H H (CH2)4CH3 NHCH3 2-122 0 1 H H (CH2)4CH3 N(CH3)2 2-123 0 1 H H (CH2)4CH3 NHC(=NH)H 2-124 0 1 H H (CH2)4CH3 NHC(=NH)CH3 2-125 0 1 H H (CH2)4CH3 NHC(=NH)CH2CH3 2-126 0 1 H H (CH2)4CH3 NHC(=NH)NH2 2-127 0 1 H H (CH2)5CH3 NH2 2-128 0 1 H H (CH2)5CH3 NHCH3 2-129 0 1 H H (CH2)5CH3 N(CH3)2 2-130 0 1 H H (CH2)5CH3 NHC(=NH)H 2-131 0 1 H H (CH2)5CH3 NHC(=NH)CH3 2-132 0 1 H H (CH2)5CH3 NHC(=NH)CH2CH3 2-133 0 1 H H (CH2)5CH3 NHC(=NH)NH2 2-134 0 1 H H (CH2)7CH3 NH2 2-135 0 1 H H (CH2)7CH3 NHCH3 2-136 0 1 H H (CH2)7CH3 N(CH3)2 2-137 0 1 H H (CH2)7CH3 NHC(=NH)H 2-138 0 1 H H (CH2)7CH3 NHC(=NH)CH3 2-139 0 1 H H (CH2)7CH3 NHC(=NH)CH2CH3 2-140 0 1 H H (CH2)7CH3 NHC(=NH)NH2 2-141 0 1 H H (CH2)9CH3 NH2 2-142 0 1 H H (CH2)9CH3 NHCH3 2-143 0 1 H H (CH2)9CH3 N(CH3)2 2-144 0 1 H H (CH2)9CH3 NHC(=NH)H 2-145 0 1 H H (CH2)9CH3 NHC(=NH)CH3 2-146 0 1 H H (CH2)9CH3 NHC(=NH)CH2CH3 2-147 0 1 H H (CH2)9CH3 NHC(=NH)NH2 2-148 0 1 H H (CH2)11CH3 NH2 2-149 0 1 H H (CH2)11CH3 NHCH3 2-150 0 1 H H (CH2)11CH3 N(CH3)2 2-151 0 1 H H (CH2)11CH3 NHC(=NH)H 2-152 0 1 H H (CH2)11CH3 NHC(=NH)CH3 2-153 0 1 H H (CH2)11CH3 NHC(=NH)CH2CH3 2-154 0 1 H H (CH2)11CH3 NHC(=NH)NH2 2-155 0 1 H H (CH2)13CH3 NH2 2-156 0 1 H H (CH2)13CH3 NHCH3 2-157 0 1 H H (CH2)13CH3 N(CH3)2 2-158 0 1 H H (CH2)13CH3 NHC(=NH)H 2-159 0 1 H H (CH2)13CH3 NHC(=NH)CH3 2-160 0 1 H H (CH2)13CH3 NHC(=NH)CH2CH3 2-161 0 1 H H (CH2)13CH3 NHC(=NH)NH2 2-162 0 1 H H (CH2)15CH3 NH2 2-163 0 1 H H (CH2)15CH3 NHCH3 2-164 0 1 H H (CH2)15CH3 N(CH3)2 2-165 0 1 H H (CH2)15CH3 NHC(=NH)H 2-166 0 1 H H (CH2)15CH3 NHC(=NH)CH3 2-167 0 1 H H (CH2)15CH3 NHC(=NH)CH2CH3 2-168 0 1 H H (CH2)15CH3 NHC(=NH)NH2 2-169 0 1 H H (CH2)17CH3 NH2 2-170 0 1 H H (CH2)17CH3 NHCH3 2-171 0 1 H H (CH2)17CH3 N(CH3)2 2-172 0 1 H H (CH2)17CH3 NHC(=NH)H 2-173 0 1 H H (CH2)17CH3 NHC(=NH)CH3 2-174 0 1 H H (CH2)17CH3 NHC(=NH)CH2CH3 2-175 0 1 H H (CH2)17CH3 NHC(=NH)NH2 2-176 0 1 H H (CH2)19CH3 NH2 2-177 0 1 H H (CH2)19CH3 NHCH3 2-178 0 1 H H (CH2)19CH3 N(CH3)2 2-179 0 1 H H (CH2)19CH3 NHC(=NH)H 2-180 0 1 H H (CH2)19CH3 NHC(=NH)CH3 2-181 0 1 H H (CH2)19CH3 NHC(=NH)CH2CH3 2-182 0 1 H H (CH2)19CH3 NHC(=NH)NH2 2-183 0 2 OH OH CH3 NH2 2-184 0 2 OH OH CH3 NHCH3 2-185 0 2 OH OH CH3 N(CH3)2 2-186 0 2 OH OH CH3 NHC(=NH)H 2-187 0 2 OH OH CH3 NHC(=NH)CH3 2-188 0 2 OH OH CH3 NHC(=NH)CH2CH3 2-189 0 2 OH OH CH3 NHC(=NH)NH2 2-190 0 2 OH OH CH2CH3 NH2 2-191 0 2 OH OH CH2CH3 NHCH3 2-192 0 2 OH OH CH2CH3 N(CH3)2 2-193 0 2 OH OH CH2CH3 NHC(=NH)H 2-194 0 2 OH OH CH2CH3 NHC(=NH)CH3 2-195 0 2 OH OH CH2CH3 NHC(=NH)CH2CH3 2-196 0 2 OH OH CH2CH3 NHC(=NH)NH2 2-197 0 2 OH OH (CH2)2CH3 NH2 2-198 0 2 OH OH (CH2)2CH3 NHCH3 2-199 0 2 OH OH (CH2)2CH3 N(CH3)2 2-200 0 2 OH OH (CH2)2CH3 NHC(=NH)H 2-201 0 2 OH OH (CH2)2CH3 NHC(=NH)CH3 2-202 0 2 OH OH (CH2)2CH3 NHC(=NH)CH2CH3 2-203 0 2 OH OH (CH2)2CH3 NHC(=NH)NH2 2-204 0 2 OH OH (CH2)3CH3 NH2 2-205 0 2 OH OH (CH2)3CH3 NHCH3 2-206 0 2 OH OH (CH2)3CH3 N(CH3)2 2-207 0 2 OH OH (CH2)3CH3 NHC(=NH)H 2-208 0 2 OH OH (CH2)3CH3 NHC(=NH)CH3 2-209 0 2 OH OH (CH2)3CH3 NHC(=NH)CH2CH3 2-210 0 2 OH OH (CH2)3CH3 NHC(=NH)NH2 2-211 0 2 OH OH (CH2)4CH3 NH2 2-212 0 2 OH OH (CH2)4CH3 NHCH3 2-213 0 2 OH OH (CH2)4CH3 N(CH3)2 2-214 0 2 OH OH (CH2)4CH3 NHC(=NH)H 2-215 0 2 OH OH (CH2)4CH3 NHC(=NH)CH3 2-216 0 2 OH OH (CH2)4CH3 NHC(=NH)CH2CH3 2-217 0 2 OH OH (CH2)4CH3 NHC(=NH)NH2 2-218 0 2 OH OH (CH2)5CH3 NH2 2-219 0 2 OH OH (CH2)5CH3 NHCH3 2-220 0 2 OH OH (CH2)5CH3 N(CH3)2 2-221 0 2 OH OH (CH2)5CH3 NHC(=NH)H 2-222 0 2 OH OH (CH2)5CH3 NHC(=NH)CH3 2-223 0 2 OH OH (CH2)5CH3 NHC(=NH)CH2CH3 2-224 0 2 OH OH (CH2)5CH3 NHC(=NH)NH2 2-225 0 2 OH OH (CH2)7CH3 NH2 2-226 0 2 OH OH (CH2)7CH3 NHCH3 2-227 0 2 OH OH (CH2)7CH3 N(CH3)2 2-228 0 2 OH OH (CH2)7CH3 NHC(=NH)H 2-229 0 2 OH OH (CH2)7CH3 NHC(=NH)CH3 2-230 0 2 OH OH (CH2)7CH3 NHC(=NH)CH2CH3 2-231 0 2 OH OH (CH2)7CH3 NHC(=NH)NH2 2-232 0 2 OH OH (CH2)9CH3 NH2 2-233 0 2 OH OH (CH2)9CH3 NHCH3 2-234 0 2 OH OH (CH2)9CH3 N(CH3)2 2-235 0 2 OH OH (CH2)9CH3 NHC(=NH)H 2-236 0 2 OH OH (CH2)9CH3 NHC(=NH)CH3 2-237 0 2 OH OH (CH2)9CH3 NHC(=NH)CH2CH3 2-238 0 2 OH OH (CH2)9CH3 NHC(=NH)NH2 2-239 0 2 OH OH (CH2)11CH3 NH2 2-240 0 2 OH OH (CH2)11CH3 NHCH3 2-241 0 2 OH OH (CH2)11CH3 N(CH3)2 2-242 0 2 OH OH (CH2)11CH3 NHC(=NH)H 2-243 0 2 OH OH (CH2)11CH3 NHC(=NH)CH3 2-244 0 2 OH OH (CH2)11CH3 NHC(=NH)CH2CH3 2-245 0 2 OH OH (CH2)11CH3 NHC(=NH)NH2 2-246 0 2 OH OH (CH2)13CH3 NH2 2-247 0 2 OH OH (CH2)13CH3 NHCH3 2-248 0 2 OH OH (CH2)13CH3 N(CH3)2 2-249 0 2 OH OH (CH2)13CH3 NHC(=NH)H 2-250 0 2 OH OH (CH2)13CH3 NHC(=NH)CH3 2-251 0 2 OH OH (CH2)13CH3 NHC(=NH)CH2CH3 2-252 0 2 OH OH (CH2)13CH3 NHC(=NH)NH2 2-253 0 2 OH OH (CH2)15CH3 NH2 2-254 0 2 OH OH (CH2)15CH3 NHCH3 2-255 0 2 OH OH (CH2)15CH3 N(CH3)2 2-256 0 2 OH OH (CH2)15CH3 NHC(=NH)H 2-257 0 2 OH OH (CH2)15CH3 NHC(=NH)CH3 2-258 0 2 OH OH (CH2)15CH3 NHC(=NH)CH2CH3 2-259 0 2 OH OH (CH2)15CH3 NHC(=NH)NH2 2-260 0 2 OH OH (CH2)17CH3 NH2 2-261 0 2 OH OH (CH2)17CH3 NHCH3 2-262 0 2 OH OH (CH2)17CH3 N(CH3)2 2-263 0 2 OH OH (CH2)17CH3 NHC(=NH)H 2-264 0 2 OH OH (CH2)17CH3 NHC(=NH)CH3 2-265 0 2 OH OH (CH2)17CH3 NHC(=NH)CH2CH3 2-266 0 2 OH OH (CH2)17CH3 NHC(=NH)NH2 2-267 0 2 OH OH (CH2)19CH3 NH2 2-268 0 2 OH OH (CH2)19CH3 NHCH3 2-269 0 2 OH OH (CH2)19CH3 N(CH3)2 2-270 0 2 OH OH (CH2)19CH3 NHC(=NH)H 2-271 0 2 OH OH (CH2)19CH3 NHC(=NH)CH3 2-272 0 2 OH OH (CH2)19CH3 NHC(=NH)CH2CH3 2-273 0 2 OH OH (CH2)19CH3 NHC(=NH)NH2 2-274 0 2 H H CH3 NH2 2-275 0 2 H H CH3 NHCH3 2-276 0 2 H H CH3 N(CH3)2 2-277 0 2 H H CH3 NHC(=NH)H 2-278 0 2 H H CH3 NHC(=NH)CH3 2-279 0 2 H H CH3 NHC(=NH)CH2CH3 2-280 0 2 H H CH3 NHC(=NH)NH2 2-281 0 2 H H CH2CH3 NH2 2-282 0 2 H H CH2CH3 NHCH3 2-283 0 2 H H CH2CH3 N(CH3)2 2-284 0 2 H H CH2CH3 NHC(=NH)H 2-285 0 2 H H CH2CH3 NHC(=NH)CH3 2-286 0 2 H H CH2CH3 NHC(=NH)CH2CH3 2-287 0 2 H H CH2CH3 NHC(=NH)NH2 2-288 0 2 H H (CH2)2CH3 NH2 2-289 0 2 H H (CH2)2CH3 NHCH3 2-290 0 2 H H (CH2)2CH3 N(CH3)2 2-291 0 2 H H (CH2)2CH3 NHC(=NH)H 2-292 0 2 H H (CH2)2CH3 NHC(=NH)CH3 2-293 0 2 H H (CH2)2CH3 NHC(=NH)CH2CH3 2-294 0 2 H H (CH2)2CH3 NHC(=NH)NH2 2-295 0 2 H H (CH2)3CH3 NH2 2-296 0 2 H H (CH2)3CH3 NHCH3 2-297 0 2 H H (CH2)3CH3 N(CH3)2 2-298 0 2 H H (CH2)3CH3 NHC(=NH)H 2-299 0 2 H H (CH2)3CH3 NHC(=NH)CH3 2-300 0 2 H H (CH2)3CH3 NHC(=NH)CH2CH3 2-301 0 2 H H (CH2)3CH3 NHC(=NH)NH2 2-302 0 2 H H (CH2)4CH3 NH2 2-303 0 2 H H (CH2)4CH3 NHCH3 2-304 0 2 H H (CH2)4CH3 N(CH3)2 2-305 0 2 H H (CH2)4CH3 NHC(=NH)H 2-306 0 2 H H (CH2)4CH3 NHC(=NH)CH3 2-307 0 2 H H (CH2)4CH3 NHC(=NH)CH2CH3 2-308 0 2 H H (CH2)4CH3 NHC(=NH)NH2 2-309 0 2 H H (CH2)5CH3 NH2 2-310 0 2 H H (CH2)5CH3 NHCH3 2-311 0 2 H H (CH2)5CH3 N(CH3)2 2-312 0 2 H H (CH2)5CH3 NHC(=NH)H 2-313 0 2 H H (CH2)5CH3 NHC(=NH)CH3 2-314 0 2 H H (CH2)5CH3 NHC(=NH)CH2CH3 2-315 0 2 H H (CH2)5CH3 NHC(=NH)NH2 2-316 0 2 H H (CH2)7CH3 NH2 2-317 0 2 H H (CH2)7CH3 NHCH3 2-318 0 2 H H (CH2)7CH3 N(CH3)2 2-319 0 2 H H (CH2)7CH3 NHC(=NH)H 2-320 0 2 H H (CH2)7CH3 NHC(=NH)CH3 2-321 0 2 H H (CH2)7CH3 NHC(=NH)CH2CH3 2-322 0 2 H H (CH2)7CH3 NHC(=NH)NH2 2-323 0 2 H H (CH2)9CH3 NH2 2-324 0 2 H H (CH2)9CH3 NHCH3 2-325 0 2 H H (CH2)9CH3 N(CH3)2 2-326 0 2 H H (CH2)9CH3 NHC(=NH)H 2-327 0 2 H H (CH2)9CH3 NHC(=NH)CH3 2-328 0 2 H H (CH2)9CH3 NHC(=NH)CH2CH3 2-329 0 2 H H (CH2)9CH3 NHC(=NH)NH2 2-330 0 2 H H (CH2)11CH3 NH2 2-331 0 2 H H (CH2)11CH3 NHCH3 2-332 0 2 H H (CH2)11CH3 N(CH3)2 2-333 0 2 H H (CH2)11CH3 NHC(=NH)H 2-334 0 2 H H (CH2)11CH3 NHC(=NH)CH3 2-335 0 2 H H (CH2)11CH3 NHC(=NH)CH2CH3 2-336 0 2 H H (CH2)11CH3 NHC(=NH)NH2 2-337 0 2 H H (CH2)13CH3 NH2 2-338 0 2 H H (CH2)13CH3 NHCH3 2-339 0 2 H H (CH2)13CH3 N(CH3)2 2-340 0 2 H H (CH2)13CH3 NHC(=NH)H 2-341 0 2 H H (CH2)13CH3 NHC(=NH)CH3 2-342 0 2 H H (CH2)13CH3 NHC(=NH)CH2CH3 2-343 0 2 H H (CH2)13CH3 NHC(=NH)NH2 2-344 0 2 H H (CH2)15CH3 NH2 2-345 0 2 H H (CH2)15CH3 NHCH3 2-346 0 2 H H (CH2)15CH3 N(CH3)2 2-347 0 2 H H (CH2)15CH3 NHC(=NH)H 2-348 0 2 H H (CH2)15CH3 NHC(=NH)CH3 2-349 0 2 H H (CH2)15CH3 NHC(=NH)CH2CH3 2-350 0 2 H H (CH2)15CH3 NHC(=NH)NH2 2-351 0 2 H H (CH2)17CH3 NH2 2-352 0 2 H H (CH2)17CH3 NHCH3 2-353 0 2 H H (CH2)17CH3 N(CH3)2 2-354 0 2 H H (CH2)17CH3 NHC(=NH)H 2-355 0 2 H H (CH2)17CH3 NHC(=NH)CH3 2-356 0 2 H H (CH2)17CH3 NHC(=NH)CH2CH3 2-357 0 2 H H (CH2)17CH3 NHC(=NH)NH2 2-358 0 2 H H (CH2)19CH3 NH2 2-359 0 2 H H (CH2)19CH3 NHCH3 2-360 0 2 H H (CH2)19CH3 N(CH3)2 2-361 0 2 H H (CH2)19CH3 NHC(=NH)H 2-362 0 2 H H (CH2)19CH3 NHC(=NH)CH3 2-363 0 2 H H (CH2)19CH3 NHC(=NH)CH2CH3 2-364 0 2 H H (CH2)19CH3 NHC(=NH)NH2 2-365 0 3 OH OH CH3 NH2 2-366 0 3 OH OH CH3 NHCH3 2-367 0 3 OH OH CH3 N(CH3)2 2-368 0 3 OH OH CH3 NHC(=NH)H 2-369 0 3 OH OH CH3 NHC(=NH)CH3 2-370 0 3 OH OH CH3 NHC(=NH)CH2CH3 2-371 0 3 OH OH CH3 NHC(=NH)NH2 2-372 0 3 OH OH CH2CH3 NH2 2-373 0 3 OH OH CH2CH3 NHCH3 2-374 0 3 OH OH CH2CH3 N(CH3)2 2-375 0 3 OH OH CH2CH3 NHC(=NH)H 2-376 0 3 OH OH CH2CH3 NHC(=NH)CH3 2-377 0 3 OH OH CH2CH3 NHC(=NH)CH2CH3 2-378 0 3 OH OH CH2CH3 NHC(=NH)NH2 2-379 0 3 OH OH (CH2)2CH3 NH2 2-380 0 3 OH OH (CH2)2CH3 NHCH3 2-381 0 3 OH OH (CH2)2CH3 N(CH3)2 2-382 0 3 OH OH (CH2)2CH3 NHC(=NH)H 2-383 0 3 OH OH (CH2)2CH3 NHC(=NH)CH3 2-384 0 3 OH OH (CH2)2CH3 NHC(=NH)CH2CH3 2-385 0 3 OH OH (CH2)2CH3 NHC(=NH)NH2 2-386 0 3 OH OH (CH2)3CH3 NH2 2-387 0 3 OH OH (CH2)3CH3 NHCH3 2-388 0 3 OH OH (CH2)3CH3 N(CH3)2 2-389 0 3 OH OH (CH2)3CH3 NHC(=NH)H 2-390 0 3 OH OH (CH2)3CH3 NHC(=NH)CH3 2-391 0 3 OH OH (CH2)3CH3 NHC(=NH)CH2CH3 2-392 0 3 OH OH (CH2)3CH3 NHC(=NH)NH2 2-393 0 3 OH OH (CH2)4CH3 NH2 2-394 0 3 OH OH (CH2)4CH3 NHCH3 2-395 0 3 OH OH (CH2)4CH3 N(CH3)2 2-396 0 3 OH OH (CH2)4CH3 NHC(=NH)H 2-397 0 3 OH OH (CH2)4CH3 NHC(=NH)CH3 2-398 0 3 OH OH (CH2)4CH3 NHC(=NH)CH2CH3 2-399 0 3 OH OH (CH2)4CH3 NHC(=NH)NH2 2-400 0 3 OH OH (CH2)5CH3 NH2 2-401 0 3 OH OH (CH2)5CH3 NHCH3 2-402 0 3 OH OH (CH2)5CH3 N(CH3)2 2-403 0 3 OH OH (CH2)5CH3 NHC(=NH)H 2-404 0 3 OH OH (CH2)5CH3 NHC(=NH)CH3 2-405 0 3 OH OH (CH2)5CH3 NHC(=NH)CH2CH3 2-406 0 3 OH OH (CH2)5CH3 NHC(=NH)NH2 2-407 0 3 OH OH (CH2)7CH3 NH2 2-408 0 3 OH OH (CH2)7CH3 NHCH3 2-409 0 3 OH OH (CH2)7CH3 N(CH3)2 2-410 0 3 OH OH (CH2)7CH3 NHC(=NH)H 2-411 0 3 OH OH (CH2)7CH3 NHC(=NH)CH3 2-412 0 3 OH OH (CH2)7CH3 NHC(=NH)CH2CH3 2-413 0 3 OH OH (CH2)7CH3 NHC(=NH)NH2 2-414 0 3 OH OH (CH2)9CH3 NH2 2-415 0 3 OH OH (CH2)9CH3 NHCH3 2-416 0 3 OH OH (CH2)9CH3 N(CH3)2 2-417 0 3 OH OH (CH2)9CH3 NHC(=NH)H 2-418 0 3 OH OH (CH2)9CH3 NHC(=NH)CH3 2-419 0 3 OH OH (CH2)9CH3 NHC(=NH)CH2CH3 2-420 0 3 OH OH (CH2)9CH3 NHC(=NH)NH2 2-421 0 3 OH OH (CH2)11CH3 NH2 2-422 0 3 OH OH (CH2)11CH3 NHCH3 2-423 0 3 OH OH (CH2)11CH3 N(CH3)2 2-424 0 3 OH OH (CH2)11CH3 NHC(=NH)H 2-425 0 3 OH OH (CH2)11CH3 NHC(=NH)CH3 2-426 0 3 OH OH (CH2)11CH3 NHC(=NH)CH2CH3 2-427 0 3 OH OH (CH2)11CH3 NHC(=NH)NH2 2-428 0 3 OH OH (CH2)13CH3 NH2 2-429 0 3 OH OH (CH2)13CH3 NHCH3 2-430 0 3 OH OH (CH2)13CH3 N(CH3)2 2-431 0 3 OH OH (CH2)13CH3 NHC(=NH)H 2-432 0 3 OH OH (CH2)13CH3 NHC(=NH)CH3 2-433 0 3 OH OH (CH2)13CH3 NHC(=NH)CH2CH3 2-434 0 3 OH OH (CH2)13CH3 NHC(=NH)NH2 2-435 0 3 OH OH (CH2)15CH3 NH2 2-436 0 3 OH OH (CH2)15CH3 NHCH3 2-437 0 3 OH OH (CH2)15CH3 N(CH3)2 2-438 0 3 OH OH (CH2)15CH3 NHC(=NH)H 2-439 0 3 OH OH (CH2)15CH3 NHC(=NH)CH3 2-440 0 3 OH OH (CH2)15CH3 NHC(=NH)CH2CH3 2-441 0 3 OH OH (CH2)15CH3 NHC(=NH)NH2 2-442 0 3 OH OH (CH2)17CH3 NH2 2-443 0 3 OH OH (CH2)17CH3 NHCH3 2-444 0 3 OH OH (CH2)17CH3 N(CH3)2 2-445 0 3 OH OH (CH2)17CH3 NHC(=NH)H 2-446 0 3 OH OH (CH2)17CH3 NHC(=NH)CH3 2-447 0 3 OH OH (CH2)17CH3 NHC(=NH)CH2CH3 2-448 0 3 OH OH (CH2)17CH3 NHC(=NH)NH2 2-449 0 3 OH OH (CH2)19CH3 NH2 2-450 0 3 OH OH (CH2)19CH3 NHCH3 2-451 0 3 OH OH (CH2)19CH3 N(CH3)2 2-452 0 3 OH OH (CH2)19CH3 NHC(=NH)H 2-453 0 3 OH OH (CH2)19CH3 NHC(=NH)CH3 2-454 0 3 OH OH (CH2)19CH3 NHC(=NH)CH2CH3 2-455 0 3 OH OH (CH2)19CH3 NHC(=NH)NH2 2-456 0 3 H H CH3 NH2 2-457 0 3 H H CH3 NHCH3 2-458 0 3 H H CH3 N(CH3)2 2-459 0 3 H H CH3 NHC(=NH)H 2-460 0 3 H H CH3 NHC(=NH)CH3 2-461 0 3 H H CH3 NHC(=NH)CH2CH3 2-462 0 3 H H CH3 NHC(=NH)NH2 2-463 0 3 H H CH2CH3 NH2 2-464 0 3 H H CH2CH3 NHCH3 2-465 0 3 H H CH2CH3 N(CH3)2 2-466 0 3 H H CH2CH3 NHC(=NH)H 2-467 0 3 H H CH2CH3 NHC(=NH)CH3 2-468 0 3 H H CH2CH3 NHC(=NH)CH2CH3 2-469 0 3 H H CH2CH3 NHC(=NH)NH2 2-470 0 3 H H (CH2)2CH3 NH2 2-471 0 3 H H (CH2)2CH3 NHCH3 2-472 0 3 H H (CH2)2CH3 N(CH3)2 2-473 0 3 H H (CH2)2CH3 NHC(=NH)H 2-474 0 3 H H (CH2)2CH3 NHC(=NH)CH3 2-475 0 3 H H (CH2)2CH3 NHC(=NH)CH2CH3 2-476 0 3 H H (CH2)2CH3 NHC(=NH)NH2 2-477 0 3 H H (CH2)3CH3 NH2 2-478 0 3 H H (CH2)3CH3 NHCH3 2-479 0 3 H H (CH2)3CH3 N(CH3)2 2-480 0 3 H H (CH2)3CH3 NHC(=NH)H 2-481 0 3 H H (CH2)3CH3 NHC(=NH)CH3 2-482 0 3 H H (CH2)3CH3 NHC(=NH)CH2CH3 2-483 0 3 H H (CH2)3CH3 NHC(=NH)NH2 2-484 0 3 H H (CH2)4CH3 NH2 2-485 0 3 H H (CH2)4CH3 NHCH3 2-486 0 3 H H (CH2)4CH3 N(CH3)2 2-487 0 3 H H (CH2)4CH3 NHC(=NH)H 2-488 0 3 H H (CH2)4CH3 NHC(=NH)CH3 2-489 0 3 H H (CH2)4CH3 NHC(=NH)CH2CH3 2-490 0 3 H H (CH2)4CH3 NHC(=NH)NH2 2-491 0 3 H H (CH2)5CH3 NH2 2-492 0 3 H H (CH2)5CH3 NHCH3 2-493 0 3 H H (CH2)5CH3 N(CH3)2 2-494 0 3 H H (CH2)5CH3 NHC(=NH)H 2-495 0 3 H H (CH2)5CH3 NHC(=NH)CH3 2-496 0 3 H H (CH2)5CH3 NHC(=NH)CH2CH3 2-497 0 3 H H (CH2)5CH3 NHC(=NH)NH2 2-498 0 3 H H (CH2)7CH3 NH2 2-499 0 3 H H (CH2)7CH3 NHCH3 2-500 0 3 H H (CH2)7CH3 N(CH3)2 2-501 0 3 H H (CH2)7CH3 NHC(=NH)H 2-502 0 3 H H (CH2)7CH3 NHC(=NH)CH3 2-503 0 3 H H (CH2)7CH3 NHC(=NH)CH2CH3 2-504 0 3 H H (CH2)7CH3 NHC(=NH)NH2 2-505 0 3 H H (CH2)9CH3 NH2 2-506 0 3 H H (CH2)9CH3 NHCH3 2-507 0 3 H H (CH2)9CH3 N(CH3)2 2-508 0 3 H H (CH2)9CH3 NHC(=NH)H 2-509 0 3 H H (CH2)9CH3 NHC(=NH)CH3 2-510 0 3 H H (CH2)9CH3 NHC(=NH)CH2CH3 2-511 0 3 H H (CH2)9CH3 NHC(=NH)NH2 2-512 0 3 H H (CH2)11CH3 NH2 2-513 0 3 H H (CH2)11CH3 NHCH3 2-514 0 3 H H (CH2)11CH3 N(CH3)2 2-515 0 3 H H (CH2)11CH3 NHC(=NH)H 2-516 0 3 H H (CH2)11CH3 NHC(=NH)CH3 2-517 0 3 H H (CH2)11CH3 NHC(=NH)CH2CH3 2-518 0 3 H H (CH2)11CH3 NHC(=NH)NH2 2-519 0 3 H H (CH2)13CH3 NH2 2-520 0 3 H H (CH2)13CH3 NHCH3 2-521 0 3 H H (CH2)13CH3 N(CH3)2 2-522 0 3 H H (CH2)13CH3 NHC(=NH)H 2-523 0 3 H H (CH2)13CH3 NHC(=NH)CH3 2-524 0 3 H H (CH2)13CH3 NHC(=NH)CH2CH3 2-525 0 3 H H (CH2)13CH3 NHC(=NH)NH2 2-526 0 3 H H (CH2)15CH3 NH2 2-527 0 3 H H (CH2)15CH3 NHCH3 2-528 0 3 H H (CH2)15CH3 N(CH3)2 2-529 0 3 H H (CH2)15CH3 NHC(=NH)H 2-530 0 3 H H (CH2)15CH3 NHC(=NH)CH3 2-531 0 3 H H (CH2)15CH3 NHC(=NH)CH2CH3 2-532 0 3 H H (CH2)15CH3 NHC(=NH)NH2 2-533 0 3 H H (CH2)17CH3 NH2 2-534 0 3 H H (CH2)17CH3 NHCH3 2-535 0 3 H H (CH2)17CH3 N(CH3)2 2-536 0 3 H H (CH2)17CH3 NHC(=NH)H 2-537 0 3 H H (CH2)17CH3 NHC(=NH)CH3 2-538 0 3 H H (CH2)17CH3 NHC(=NH)CH2CH3 2-539 0 3 H H (CH2)17CH3 NHC(=NH)NH2 2-540 0 3 H H (CH2)19CH3 NH2 2-541 0 3 H H (CH2)19CH3 NHCH3 2-542 0 3 H H (CH2)19CH3 N(CH3)2 2-543 0 3 H H (CH2)19CH3 NHC(=NH)H 2-544 0 3 H H (CH2)19CH3 NHC(=NH)CH3 2-545 0 3 H H (CH2)19CH3 NHC(=NH)CH2CH3 2-546 0 3 H H (CH2)19CH3 NHC(=NH)NH2 2-547 1 1 OH OH CH3 NH2 2-548 1 1 OH OH CH3 NHCH3 2-549 1 1 OH OH CH3 N(CH3)2 2-550 1 1 OH OH CH3 NHC(=NH)H 2-551 1 1 OH OH CH3 NHC(=NH)CH3 2-552 1 1 OH OH CH3 NHC(=NH)CH2CH3 2-553 1 1 OH OH CH3 NHC(=NH)NH2 2-554 1 1 OH OH CH2CH3 NH2 2-555 1 1 OH OH CH2CH3 NHCH3 2-556 1 1 OH OH CH2CH3 N(CH3)2 2-557 1 1 OH OH CH2CH3 NHC(=NH)H 2-558 1 1 OH OH CH2CH3 NHC(=NH)CH3 2-559 1 1 OH OH CH2CH3 NHC(=NH)CH2CH3 2-560 1 1 OH OH CH2CH3 NHC(=NH)NH2 2-561 1 1 OH OH (CH2)2CH3 NH2 2-562 1 1 OH OH (CH2)2CH3 NHCH3 2-563 1 1 OH OH (CH2)2CH3 N(CH3)2 2-564 1 1 OH OH (CH2)2CH3 NHC(=NH)H 2-565 1 1 OH OH (CH2)2CH3 NHC(=NH)CH3 2-566 1 1 OH OH (CH2)2CH3 NHC(=NH)CH2CH3 2-567 1 1 OH OH (CH2)2CH3 NHC(=NH)NH2 2-568 1 1 OH OH (CH2)3CH3 NH2 2-569 1 1 OH OH (CH2)3CH3 NHCH3 2-570 1 1 OH OH (CH2)3CH3 N(CH3)2 2-571 1 1 OH OH (CH2)3CH3 NHC(=NH)H 2-572 1 1 OH OH (CH2)3CH3 NHC(=NH)CH3 2-573 1 1 OH OH (CH2)3CH3 NHC(=NH)CH2CH3 2-574 1 1 OH OH (CH2)3CH3 NHC(=NH)NH2 2-575 1 1 OH OH (CH2)4CH3 NH2 2-576 1 1 OH OH (CH2)4CH3 NHCH3 2-577 1 1 OH OH (CH2)4CH3 N(CH3)2 2-578 1 1 OH OH (CH2)4CH3 NHC(=NH)H 2-579 1 1 OH OH (CH2)4CH3 NHC(=NH)CH3 2-580 1 1 OH OH (CH2)4CH3 NHC(=NH)CH2CH3 2-581 1 1 OH OH (CH2)4CH3 NHC(=NH)NH2 2-582 1 1 OH OH (CH2)5CH3 NH2 2-583 1 1 OH OH (CH2)5CH3 NHCH3 2-584 1 1 OH OH (CH2)5CH3 N(CH3)2 2-585 1 1 OH OH (CH2)5CH3 NHC(=NH)H 2-586 1 1 OH OH (CH2)5CH3 NHC(=NH)CH3 2-587 1 1 OH OH (CH2)5CH3 NHC(=NH)CH2CH3 2-588 1 1 OH OH (CH2)5CH3 NHC(=NH)NH2 2-589 1 1 OH OH (CH2)7CH3 NH2 2-590 1 1 OH OH (CH2)7CH3 NHCH3 2-591 1 1 OH OH (CH2)7CH3 N(CH3)2 2-592 1 1 OH OH (CH2)7CH3 NHC(=NH)H 2-593 1 1 OH OH (CH2)7CH3 NHC(=NH)CH3 2-594 1 1 OH OH (CH2)7CH3 NHC(=NH)CH2CH3 2-595 1 1 OH OH (CH2)7CH3 NHC(=NH)NH2 2-596 1 1 OH OH (CH2)9CH3 NH2 2-597 1 1 OH OH (CH2)9CH3 NHCH3 2-598 1 1 OH OH (CH2)9CH3 N(CH3)2 2-599 1 1 OH OH (CH2)9CH3 NHC(=NH)H 2-600 1 1 OH OH (CH2)9CH3 NHC(=NH)CH3 2-601 1 1 OH OH (CH2)9CH3 NHC(=NH)CH2CH3 2-602 1 1 OH OH (CH2)9CH3 NHC(=NH)NH2 2-603 1 1 OH OH (CH2)11CH3 NH2 2-604 1 1 OH OH (CH2)11CH3 NHCH3 2-605 1 1 OH OH (CH2)11CH3 N(CH3)2 2-606 1 1 OH OH (CH2)11CH3 NHC(=NH)H 2-607 1 1 OH OH (CH2)11CH3 NHC(=NH)CH3 2-608 1 1 OH OH (CH2)11CH3 NHC(=NH)CH2CH3 2-609 1 1 OH OH (CH2)11CH3 NHC(=NH)NH2 2-610 1 1 OH OH (CH2)13CH3 NH2 2-611 1 1 OH OH (CH2)13CH3 NHCH3 2-612 1 1 OH OH (CH2)13CH3 N(CH3)2 2-613 1 1 OH OH (CH2)13CH3 NHC(=NH)H 2-614 1 1 OH OH (CH2)13CH3 NHC(=NH)CH3 2-615 1 1 OH OH (CH2)13CH3 NHC(=NH)CH2CH3 2-616 1 1 OH OH (CH2)13CH3 NHC(=NH)NH2 2-617 1 1 OH OH (CH2)15CH3 NH2 2-618 1 1 OH OH (CH2)15CH3 NHCH3 2-619 1 1 OH OH (CH2)15CH3 N(CH3)2 2-620 1 1 OH OH (CH2)15CH3 NHC(=NH)H 2-621 1 1 OH OH (CH2)15CH3 NHC(=NH)CH3 2-622 1 1 OH OH (CH2)15CH3 NHC(=NH)CH2CH3 2-623 1 1 OH OH (CH2)15CH3 NHC(=NH)NH2 2-624 1 1 OH OH (CH2)17CH3 NH2 2-625 1 1 OH OH (CH2)17CH3 NHCH3 2-626 1 1 OH OH (CH2)17CH3 N(CH3)2 2-627 1 1 OH OH (CH2)17CH3 NHC(=NH)H 2-628 1 1 OH OH (CH2)17CH3 NHC(=NH)CH3 2-629 1 1 OH OH (CH2)17CH3 NHC(=NH)CH2CH3 2-630 1 1 OH OH (CH2)17CH3 NHC(=NH)NH2 2-631 1 1 OH OH (CH2)19CH3 NH2 2-632 1 1 OH OH (CH2)19CH3 NHCH3 2-633 1 1 OH OH (CH2)19CH3 N(CH3)2 2-634 1 1 OH OH (CH2)19CH3 NHC(=NH)H 2-635 1 1 OH OH (CH2)19CH3 NHC(=NH)CH3 2-636 1 1 OH OH (CH2)19CH3 NHC(=NH)CH2CH3 2-637 1 1 OH OH (CH2)19CH3 NHC(=NH)NH2 2-638 1 1 H H CH3 NH2 2-639 1 1 H H CH3 NHCH3 2-640 1 1 H H CH3 N(CH3)2 2-641 1 1 H H CH3 NHC(=NH)H 2-642 1 1 H H CH3 NHC(=NH)CH3 2-643 1 1 H H CH3 NHC(=NH)CH2CH3 2-644 1 1 H H CH3 NHC(=NH)NH2 2-645 1 1 H H CH2CH3 NH2 2-646 1 1 H H CH2CH3 NHCH3 2-647 1 1 H H CH2CH3 N(CH3)2 2-648 1 1 H H CH2CH3 NHC(=NH)H 2-649 1 1 H H CH2CH3 NHC(=NH)CH3 2-650 1 1 H H CH2CH3 NHC(=NH)CH2CH3 2-651 1 1 H H CH2CH3 NHC(=NH)NH2 2-652 1 1 H H (CH2)2CH3 NH2 2-653 1 1 H H (CH2)2CH3 NHCH3 2-654 1 1 H H (CH2)2CH3 N(CH3)2 2-655 1 1 H H (CH2)2CH3 NHC(=NH)H 2-656 1 1 H H (CH2)2CH3 NHC(=NH)CH3 2-657 1 1 H H (CH2)2CH3 NHC(=NH)CH2CH3 2-658 1 1 H H (CH2)2CH3 NHC(=NH)NH2 2-659 1 1 H H (CH2)3CH3 NH2 2-660 1 1 H H (CH2)3CH3 NHCH3 2-661 1 1 H H (CH2)3CH3 N(CH3)2 2-662 1 1 H H (CH2)3CH3 NHC(=NH)H 2-663 1 1 H H (CH2)3CH3 NHC(=NH)CH3 2-664 1 1 H H (CH2)3CH3 NHC(=NH)CH2CH3 2-665 1 1 H H (CH2)3CH3 NHC(=NH)NH2 2-666 1 1 H H (CH2)4CH3 NH2 2-667 1 1 H H (CH2)4CH3 NHCH3 2-668 1 1 H H (CH2)4CH3 N(CH3)2 2-669 1 1 H H (CH2)4CH3 NHC(=NH)H 2-670 1 1 H H (CH2)4CH3 NHC(=NH)CH3 2-671 1 1 H H (CH2)4CH3 NHC(=NH)CH2CH3 2-672 1 1 H H (CH2)4CH3 NHC(=NH)NH2 2-673 1 1 H H (CH2)5CH3 NH2 2-674 1 1 H H (CH2)5CH3 NHCH3 2-675 1 1 H H (CH2)5CH3 N(CH3)2 2-676 1 1 H H (CH2)5CH3 NHC(=NH)H 2-677 1 1 H H (CH2)5CH3 NHC(=NH)CH3 2-678 1 1 H H (CH2)5CH3 NHC(=NH)CH2CH3 2-679 1 1 H H (CH2)5CH3 NHC(=NH)NH2 2-680 1 1 H H (CH2)7CH3 NH2 2-681 1 1 H H (CH2)7CH3 NHCH3 2-682 1 1 H H (CH2)7CH3 N(CH3)2 2-683 1 1 H H (CH2)7CH3 NHC(=NH)H 2-684 1 1 H H (CH2)7CH3 NHC(=NH)CH3 2-685 1 1 H H (CH2)7CH3 NHC(=NH)CH2CH3 2-686 1 1 H H (CH2)7CH3 NHC(=NH)NH2 2-687 1 1 H H (CH2)9CH3 NH2 2-688 1 1 H H (CH2)9CH3 NHCH3 2-689 1 1 H H (CH2)9CH3 N(CH3)2 2-690 1 1 H H (CH2)9CH3 NHC(=NH)H 2-691 1 1 H H (CH2)9CH3 NHC(=NH)CH3 2-692 1 1 H H (CH2)9CH3 NHC(=NH)CH2CH3 2-693 1 1 H H (CH2)9CH3 NHC(=NH)NH2 2-694 1 1 H H (CH2)11CH3 NH2 2-695 1 1 H H (CH2)11CH3 NHCH3 2-696 1 1 H H (CH2)11CH3 N(CH3)2 2-697 1 1 H H (CH2)11CH3 NHC(=NH)H 2-698 1 1 H H (CH2)11CH3 NHC(=NH)CH3 2-699 1 1 H H (CH2)11CH3 NHC(=NH)CH2CH3 2-700 1 1 H H (CH2)11CH3 NHC(=NH)NH2 2-701 1 1 H H (CH2)13CH3 NH2 2-702 1 1 H H (CH2)13CH3 NHCH3 2-703 1 1 H H (CH2)13CH3 N(CH3)2 2-704 1 1 H H (CH2)13CH3 NHC(=NH)H 2-705 1 1 H H (CH2)13CH3 NHC(=NH)CH3 2-706 1 1 H H (CH2)13CH3 NHC(=NH)CH2CH3 2-707 1 1 H H (CH2)13CH3 NHC(=NH)NH2 2-708 1 1 H H (CH2)15CH3 NH2 2-709 1 1 H H (CH2)15CH3 NHCH3 2-710 1 1 H H (CH2)15CH3 N(CH3)2 2-711 1 1 H H (CH2)15CH3 NHC(=NH)H 2-712 1 1 H H (CH2)15CH3 NHC(=NH)CH3 2-713 1 1 H H (CH2)15CH3 NHC(=NH)CH2CH3 2-714 1 1 H H (CH2)15CH3 NHC(=NH)NH2 2-715 1 1 H H (CH2)17CH3 NH2 2-716 1 1 H H (CH2)17CH3 NHCH3 2-717 1 1 H H (CH2)17CH3 N(CH3)2 2-718 1 1 H H (CH2)17CH3 NHC(=NH)H 2-719 1 1 H H (CH2)17CH3 NHC(=NH)CH3 2-720 1 1 H H (CH2)17CH3 NHC(=NH)CH2CH3 2-721 1 1 H H (CH2)17CH3 NHC(=NH)NH2 2-722 1 1 H H (CH2)19CH3 NH2 2-723 1 1 H H (CH2)19CH3 NHCH3 2-724 1 1 H H (CH2)19CH3 N(CH3)2 2-725 1 1 H H (CH2)19CH3 NHC(=NH)H 2-726 1 1 H H (CH2)19CH3 NHC(=NH)CH3 2-727 1 1 H H (CH2)19CH3 NHC(=NH)CH2CH3 2-728 1 1 H H (CH2)19CH3 NHC(=NH)NH2 2-729 1 2 OH OH CH3 NH2 2-730 1 2 OH OH CH3 NHCH3 2-731 1 2 OH OH CH3 N(CH3)2 2-732 1 2 OH OH CH3 NHC(=NH)H 2-733 1 2 OH OH CH3 NHC(=NH)CH3 2-734 1 2 OH OH CH3 NHC(=NH)CH2CH3 2-735 1 2 OH OH CH3 NHC(=NH)NH2 2-736 1 2 OH OH CH2CH3 NH2 2-737 1 2 OH OH CH2CH3 NHCH3 2-738 1 2 OH OH CH2CH3 N(CH3)2 2-739 1 2 OH OH CH2CH3 NHC(=NH)H 2-740 1 2 OH OH CH2CH3 NHC(=NH)CH3 2-741 1 2 OH OH CH2CH3 NHC(=NH)CH2CH3 2-742 1 2 OH OH CH2CH3 NHC(=NH)NH2 2-743 1 2 OH OH (CH2)2CH3 NH2 2-744 1 2 OH OH (CH2)2CH3 NHCH3 2-745 1 2 OH OH (CH2)2CH3 N(CH3)2 2-746 1 2 OH OH (CH2)2CH3 NHC(=NH)H 2-747 1 2 OH OH (CH2)2CH3 NHC(=NH)CH3 2-748 1 2 OH OH (CH2)2CH3 NHC(=NH)CH2CH3 2-749 1 2 OH OH (CH2)2CH3 NHC(=NH)NH2 2-750 1 2 OH OH (CH2)3CH3 NH2 2-751 1 2 OH OH (CH2)3CH3 NHCH3 2-752 1 2 OH OH (CH2)3CH3 N(CH3)2 2-753 1 2 OH OH (CH2)3CH3 NHC(=NH)H 2-754 1 2 OH OH (CH2)3CH3 NHC(=NH)CH3 2-755 1 2 OH OH (CH2)3CH3 NHC(=NH)CH2CH3 2-756 1 2 OH OH (CH2)3CH3 NHC(=NH)NH2 2-757 1 2 OH OH (CH2)4CH3 NH2 2-758 1 2 OH OH (CH2)4CH3 NHCH3 2-759 1 2 OH OH (CH2)4CH3 N(CH3)2 2-760 1 2 OH OH (CH2)4CH3 NHC(=NH)H 2-761 1 2 OH OH (CH2)4CH3 NHC(=NH)CH3 2-762 1 2 OH OH (CH2)4CH3 NHC(=NH)CH2CH3 2-763 1 2 OH OH (CH2)4CH3 NHC(=NH)NH2 2-764 1 2 OH OH (CH2)5CH3 NH2 2-765 1 2 OH OH (CH2)5CH3 NHCH3 2-766 1 2 OH OH (CH2)5CH3 N(CH3)2 2-767 1 2 OH OH (CH2)5CH3 NHC(=NH)H 2-768 1 2 OH OH (CH2)5CH3 NHC(=NH)CH3 2-769 1 2 OH OH (CH2)5CH3 NHC(=NH)CH2CH3 2-770 1 2 OH OH (CH2)5CH3 NHC(=NH)NH2 2-771 1 2 OH OH (CH2)7CH3 NH2 2-772 1 2 OH OH (CH2)7CH3 NHCH3 2-773 1 2 OH OH (CH2)7CH3 N(CH3)2 2-774 1 2 OH OH (CH2)7CH3 NHC(=NH)H 2-775 1 2 OH OH (CH2)7CH3 NHC(=NH)CH3 2-776 1 2 OH OH (CH2)7CH3 NHC(=NH)CH2CH3 2-777 1 2 OH OH (CH2)7CH3 NHC(=NH)NH2 2-778 1 2 OH OH (CH2)9CH3 NH2 2-779 1 2 OH OH (CH2)9CH3 NHCH3 2-780 1 2 OH OH (CH2)9CH3 N(CH3)2 2-781 1 2 OH OH (CH2)9CH3 NHC(=NH)H 2-782 1 2 OH OH (CH2)9CH3 NHC(=NH)CH3 2-783 1 2 OH OH (CH2)9CH3 NHC(=NH)CH2CH3 2-784 1 2 OH OH (CH2)9CH3 NHC(=NH)NH2 2-785 1 2 OH OH (CH2)11CH3 NH2 2-786 1 2 OH OH (CH2)11CH3 NHCH3 2-787 1 2 OH OH (CH2)11CH3 N(CH3)2 2-788 1 2 OH OH (CH2)11CH3 NHC(=NH)H 2-789 1 2 OH OH (CH2)11CH3 NHC(=NH)CH3 2-790 1 2 OH OH (CH2)11CH3 NHC(=NH)CH2CH3 2-791 1 2 OH OH (CH2)11CH3 NHC(=NH)NH2 2-792 1 2 OH OH (CH2)13CH3 NH2 2-793 1 2 OH OH (CH2)13CH3 NHCH3 2-794 1 2 OH OH (CH2)13CH3 N(CH3)2 2-795 1 2 OH OH (CH2)13CH3 NHC(=NH)H 2-796 1 2 OH OH (CH2)13CH3 NHC(=NH)CH3 2-797 1 2 OH OH (CH2)13CH3 NHC(=NH)CH2CH3 2-798 1 2 OH OH (CH2)13CH3 NHC(=NH)NH2 2-799 1 2 OH OH (CH2)15CH3 NH2 2-800 1 2 OH OH (CH2)15CH3 NHCH3 2-801 1 2 OH OH (CH2)15CH3 N(CH3)2 2-802 1 2 OH OH (CH2)15CH3 NHC(=NH)H 2-803 1 2 OH OH (CH2)15CH3 NHC(=NH)CH3 2-804 1 2 OH OH (CH2)15CH3 NHC(=NH)CH2CH3 2-805 1 2 OH OH (CH2)15CH3 NHC(=NH)NH2 2-806 1 2 OH OH (CH2)17CH3 NH2 2-807 1 2 OH OH (CH2)17CH3 NHCH3 2-808 1 2 OH OH (CH2)17CH3 N(CH3)2 2-809 1 2 OH OH (CH2)17CH3 NHC(=NH)H 2-810 1 2 OH OH (CH2)17CH3 NHC(=NH)CH3 2-811 1 2 OH OH (CH2)17CH3 NHC(=NH)CH2CH3 2-812 1 2 OH OH (CH2)17CH3 NHC(=NH)NH2 2-813 1 2 OH OH (CH2)19CH3 NH2 2-814 1 2 OH OH (CH2)19CH3 NHCH3 2-815 1 2 OH OH (CH2)19CH3 N(CH3)2 2-816 1 2 OH OH (CH2)19CH3 NHC(=NH)H 2-817 1 2 OH OH (CH2)19CH3 NHC(=NH)CH3 2-818 1 2 OH OH (CH2)19CH3 NHC(=NH)CH2CH3 2-819 1 2 OH OH (CH2)19CH3 NHC(=NH)NH2 2-820 1 2 H H CH3 NH2 2-821 1 2 H H CH3 NHCH3 2-822 1 2 H H CH3 N(CH3)2 2-823 1 2 H H CH3 NHC(=NH)H 2-824 1 2 H H CH3 NHC(=NH)CH3 2-825 1 2 H H CH3 NHC(=NH)CH2CH3 2-826 1 2 H H CH3 NHC(=NH)NH2 2-827 1 2 H H CH2CH3 NH2 2-828 1 2 H H CH2CH3 NHCH3 2-829 1 2 H H CH2CH3 N(CH3)2 2-830 1 2 H H CH2CH3 NHC(=NH)H 2-831 1 2 H H CH2CH3 NHC(=NH)CH3 2-832 1 2 H H CH2CH3 NHC(=NH)CH2CH3 2-833 1 2 H H CH2CH3 NHC(=NH)NH2 2-834 1 2 H H (CH2)2CH3 NH2 2-835 1 2 H H (CH2)2CH3 NHCH3 2-836 1 2 H H (CH2)2CH3 N(CH3)2 2-837 1 2 H H (CH2)2CH3 NHC(=NH)H 2-838 1 2 H H (CH2)2CH3 NHC(=NH)CH3 2-839 1 2 H H (CH2)2CH3 NHC(=NH)CH2CH3 2-840 1 2 H H (CH2)2CH3 NHC(=NH)NH2 2-841 1 2 H H (CH2)3CH3 NH2 2-842 1 2 H H (CH2)3CH3 NHCH3 2-843 1 2 H H (CH2)3CH3 N(CH3)2 2-844 1 2 H H (CH2)3CH3 NHC(=NH)H 2-845 1 2 H H (CH2)3CH3 NHC(=NH)CH3 2-846 1 2 H H (CH2)3CH3 NHC(=NH)CH2CH3 2-847 1 2 H H (CH2)3CH3 NHC(=NH)NH2 2-848 1 2 H H (CH2)4CH3 NH2 2-849 1 2 H H (CH2)4CH3 NHCH3 2-850 1 2 H H (CH2)4CH3 N(CH3)2 2-851 1 2 H H (CH2)4CH3 NHC(=NH)H 2-852 1 2 H H (CH2)4CH3 NHC(=NH)CH3 2-853 1 2 H H (CH2)4CH3 NHC(=NH)CH2CH3 2-854 1 2 H H (CH2)4CH3 NHC(=NH)NH2 2-855 1 2 H H (CH2)5CH3 NH2 2-856 1 2 H H (CH2)5CH3 NHCH3 2-857 1 2 H H (CH2)5CH3 N(CH3)2 2-858 1 2 H H (CH2)5CH3 NHC(=NH)H 2-859 1 2 H H (CH2)5CH3 NHC(=NH)CH3 2-860 1 2 H H (CH2)5CH3 NHC(=NH)CH2CH3 2-861 1 2 H H (CH2)5CH3 NHC(=NH)NH2 2-862 1 2 H H (CH2)7CH3 NH2 2-863 1 2 H H (CH2)7CH3 NHCH3 2-864 1 2 H H (CH2)7CH3 N(CH3)2 2-865 1 2 H H (CH2)7CH3 NHC(=NH)H 2-866 1 2 H H (CH2)7CH3 NHC(=NH)CH3 2-867 1 2 H H (CH2)7CH3 NHC(=NH)CH2CH3 2-868 1 2 H H (CH2)7CH3 NHC(=NH)NH2 2-869 1 2 H H (CH2)9CH3 NH2 2-870 1 2 H H (CH2)9CH3 NHCH3 2-871 1 2 H H (CH2)9CH3 N(CH3)2 2-872 1 2 H H (CH2)9CH3 NHC(=NH)H 2-873 1 2 H H (CH2)9CH3 NHC(=NH)CH3 2-874 1 2 H H (CH2)9CH3 NHC(=NH)CH2CH3 2-875 1 2 H H (CH2)9CH3 NHC(=NH)NH2 2-876 1 2 H H (CH2)11CH3 NH2 2-877 1 2 H H (CH2)11CH3 NHCH3 2-878 1 2 H H (CH2)11CH3 N(CH3)2 2-879 1 2 H H (CH2)11CH3 NHC(=NH)H 2-880 1 2 H H (CH2)11CH3 NHC(=NH)CH3 2-881 1 2 H H (CH2)11CH3 NHC(=NH)CH2CH3 2-882 1 2 H H (CH2)11CH3 NHC(=NH)NH2 2-883 1 2 H H (CH2)13CH3 NH2 2-884 1 2 H H (CH2)13CH3 NHCH3 2-885 1 2 H H (CH2)13CH3 N(CH3)2 2-886 1 2 H H (CH2)13CH3 NHC(=NH)H 2-887 1 2 H H (CH2)13CH3 NHC(=NH)CH3 2-888 1 2 H H (CH2)13CH3 NHC(=NH)CH2CH3 2-889 1 2 H H (CH2)13CH3 NHC(=NH)NH2 2-890 1 2 H H (CH2)15CH3 NH2 2-891 1 2 H H (CH2)15CH3 NHCH3 2-892 1 2 H H (CH2)15CH3 N(CH3)2 2-893 1 2 H H (CH2)15CH3 NHC(=NH)H 2-894 1 2 H H (CH2)15CH3 NHC(=NH)CH3 2-895 1 2 H H (CH2)15CH3 NHC(=NH)CH2CH3 2-896 1 2 H H (CH2)15CH3 NHC(=NH)NH2 2-897 1 2 H H (CH2)17CH3 NH2 2-898 1 2 H H (CH2)17CH3 NHCH3 2-899 1 2 H H (CH2)17CH3 N(CH3)2 2-900 1 2 H H (CH2)17CH3 NHC(=NH)H 2-901 1 2 H H (CH2)17CH3 NHC(=NH)CH3 2-902 1 2 H H (CH2)17CH3 NHC(=NH)CH2CH3 2-903 1 2 H H (CH2)17CH3 NHC(=NH)NH2 2-904 1 2 H H (CH2)19CH3 NH2 2-905 1 2 H H (CH2)19CH3 NHCH3 2-906 1 2 H H (CH2)19CH3 N(CH3)2 2-907 1 2 H H (CH2)19CH3 NHC(=NH)H 2-908 1 2 H H (CH2)19CH3 NHC(=NH)CH3 2-909 1 2 H H (CH2)19CH3 NHC(=NH)CH2CH3 2-910 1 2 H H (CH2)19CH3 NHC(=NH)NH2 2-911 2 1 OH OH CH3 NH2 2-912 2 1 OH OH CH3 NHCH3 2-913 2 1 OH OH CH3 N(CH3)2 2-914 2 1 OH OH CH3 NHC(=NH)H 2-915 2 1 OH OH CH3 NHC(=NH)CH3 2-916 2 1 OH OH CH3 NHC(=NH)CH2CH3 2-917 2 1 OH OH CH3 NHC(=NH)NH2 2-918 2 1 OH OH CH2CH3 NH2 2-919 2 1 OH OH CH2CH3 NHCH3 2-920 2 1 OH OH CH2CH3 N(CH3)2 2-921 2 1 OH OH CH2CH3 NHC(=NH)H 2-922 2 1 OH OH CH2CH3 NHC(=NH)CH3 2-923 2 1 OH OH CH2CH3 NHC(=NH)CH2CH3 2-924 2 1 OH OH CH2CH3 NHC(=NH)NH2 2-925 2 1 OH OH (CH2)2CH3 NH2 2-926 2 1 OH OH (CH2)2CH3 NHCH3 2-927 2 1 OH OH (CH2)2CH3 N(CH3)2 2-928 2 1 OH OH (CH2)2CH3 NHC(=NH)H 2-929 2 1 OH OH (CH2)2CH3 NHC(=NH)CH3 2-930 2 1 OH OH (CH2)2CH3 NHC(=NH)CH2CH3 2-931 2 1 OH OH (CH2)2CH3 NHC(=NH)NH2 2-932 2 1 OH OH (CH2)3CH3 NH2 2-933 2 1 OH OH (CH2)3CH3 NHCH3 2-934 2 1 OH OH (CH2)3CH3 N(CH3)2 2-935 2 1 OH OH (CH2)3CH3 NHC(=NH)H 2-936 2 1 OH OH (CH2)3CH3 NHC(=NH)CH3 2-937 2 1 OH OH (CH2)3CH3 NHC(=NH)CH2CH3 2-938 2 1 OH OH (CH2)3CH3 NHC(=NH)NH2 2-939 2 1 OH OH (CH2)4CH3 NH2 2-940 2 1 OH OH (CH2)4CH3 NHCH3 2-941 2 1 OH OH (CH2)4CH3 N(CH3)2 2-942 2 1 OH OH (CH2)4CH3 NHC(=NH)H 2-943 2 1 OH OH (CH2)4CH3 NHC(=NH)CH3 2-944 2 1 OH OH (CH2)4CH3 NHC(=NH)CH2CH3 2-945 2 1 OH OH (CH2)4CH3 NHC(=NH)NH2 2-946 2 1 OH OH (CH2)5CH3 NH2 2-947 2 1 OH OH (CH2)5CH3 NHCH3 2-948 2 1 OH OH (CH2)5CH3 N(CH3)2 2-949 2 1 OH OH (CH2)5CH3 NHC(=NH)H 2-950 2 1 OH OH (CH2)5CH3 NHC(=NH)CH3 2-951 2 1 OH OH (CH2)5CH3 NHC(=NH)CH2CH3 2-952 2 1 OH OH (CH2)5CH3 NHC(=NH)NH2 2-953 2 1 OH OH (CH2)7CH3 NH2 2-954 2 1 OH OH (CH2)7CH3 NHCH3 2-955 2 1 OH OH (CH2)7CH3 N(CH3)2 2-956 2 1 OH OH (CH2)7CH3 NHC(=NH)H 2-957 2 1 OH OH (CH2)7CH3 NHC(=NH)CH3 2-958 2 1 OH OH (CH2)7CH3 NHC(=NH)CH2CH3 2-959 2 1 OH OH (CH2)7CH3 NHC(=NH)NH2 2-960 2 1 OH OH (CH2)9CH3 NH2 2-961 2 1 OH OH (CH2)9CH3 NHCH3 2-962 2 1 OH OH (CH2)9CH3 N(CH3)2 2-963 2 1 OH OH (CH2)9CH3 NHC(=NH)H 2-964 2 1 OH OH (CH2)9CH3 NHC(=NH)CH3 2-965 2 1 OH OH (CH2)9CH3 NHC(=NH)CH2CH3 2-966 2 1 OH OH (CH2)9CH3 NHC(=NH)NH2 2-967 2 1 OH OH (CH2)11CH3 NH2 2-968 2 1 OH OH (CH2)11CH3 NHCH3 2-969 2 1 OH OH (CH2)11CH3 N(CH3)2 2-970 2 1 OH OH (CH2)11CH3 NHC(=NH)H 2-971 2 1 OH OH (CH2)11CH3 NHC(=NH)CH3 2-972 2 1 OH OH (CH2)11CH3 NHC(=NH)CH2CH3 2-973 2 1 OH OH (CH2)11CH3 NHC(=NH)NH2 2-974 2 1 OH OH (CH2)13CH3 NH2 2-975 2 1 OH OH (CH2)13CH3 NHCH3 2-976 2 1 OH OH (CH2)13CH3 N(CH3)2 2-977 2 1 OH OH (CH2)13CH3 NHC(=NH)H 2-978 2 1 OH OH (CH2)13CH3 NHC(=NH)CH3 2-979 2 1 OH OH (CH2)13CH3 NHC(=NH)CH2CH3 2-980 2 1 OH OH (CH2)13CH3 NHC(=NH)NH2 2-981 2 1 OH OH (CH2)15CH3 NH2 2-982 2 1 OH OH (CH2)15CH3 NHCH3 2-983 2 1 OH OH (CH2)15CH3 N(CH3)2 2-984 2 1 OH OH (CH2)15CH3 NHC(=NH)H 2-985 2 1 OH OH (CH2)15CH3 NHC(=NH)CH3 2-986 2 1 OH OH (CH2)15CH3 NHC(=NH)CH2CH3 2-987 2 1 OH OH (CH2)15CH3 NHC(=NH)NH2 2-988 2 1 OH OH (CH2)17CH3 NH2 2-989 2 1 OH OH (CH2)17CH3 NHCH3 2-990 2 1 OH OH (CH2)17CH3 N(CH3)2 2-991 2 1 OH OH (CH2)17CH3 NHC(=NH)H 2-992 2 1 OH OH (CH2)17CH3 NHC(=NH)CH3 2-993 2 1 OH OH (CH2)17CH3 NHC(=NH)CH2CH3 2-994 2 1 OH OH (CH2)17CH3 NHC(=NH)NH2 2-995 2 1 OH OH (CH2)19CH3 NH2 2-996 2 1 OH OH (CH2)19CH3 NHCH3 2-997 2 1 OH OH (CH2)19CH3 N(CH3)2 2-998 2 1 OH OH (CH2)19CH3 NHC(=NH)H 2-999 2 1 OH OH (CH2)19CH3 NHC(=NH)CH3 2-1000 2 1 OH OH (CH2)19CH3 NHC(=NH)CH2CH3 2-1001 2 1 OH OH (CH2)19CH3 NHC(=NH)NH2 2-1002 2 1 H H CH3 NH2 2-1003 2 1 H H CH3 NHCH3 2-1004 2 1 H H CH3 N(CH3)2 2-1005 2 1 H H CH3 NHC(=NH)H 2-1006 2 1 H H CH3 NHC(=NH)CH3 2-1007 2 1 H H CH3 NHC(=NH)CH2CH3 2-1008 2 1 H H CH3 NHC(=NH)NH2 2-1009 2 1 H H CH2CH3 NH2 2-1010 2 1 H H CH2CH3 NHCH3 2-1011 2 1 H H CH2CH3 N(CH3)2 2-1012 2 1 H H CH2CH3 NHC(=NH)H 2-1013 2 1 H H CH2CH3 NHC(=NH)CH3 2-1014 2 1 H H CH2CH3 NHC(=NH)CH2CH3 2-1015 2 1 H H CH2CH3 NHC(=NH)NH2 2-1016 2 1 H H (CH2)2CH3 NH2 2-1017 2 1 H H (CH2)2CH3 NHCH3 2-1018 2 1 H H (CH2)2CH3 N(CH3)2 2-1019 2 1 H H (CH2)2CH3 NHC(=NH)H 2-1020 2 1 H H (CH2)2CH3 NHC(=NH)CH3 2-1021 2 1 H H (CH2)2CH3 NHC(=NH)CH2CH3 2-1022 2 1 H H (CH2)2CH3 NHC(=NH)NH2 2-1023 2 1 H H (CH2)3CH3 NH2 2-1024 2 1 H H (CH2)3CH3 NHCH3 2-1025 2 1 H H (CH2)3CH3 N(CH3)2 2-1026 2 1 H H (CH2)3CH3 NHC(=NH)H 2-1027 2 1 H H (CH2)3CH3 NHC(=NH)CH3 2-1028 2 1 H H (CH2)3CH3 NHC(=NH)CH2CH3 2-1029 2 1 H H (CH2)3CH3 NHC(=NH)NH2 2-1030 2 1 H H (CH2)4CH3 NH2 2-1031 2 1 H H (CH2)4CH3 NHCH3 2-1032 2 1 H H (CH2)4CH3 N(CH3)2 2-1033 2 1 H H (CH2)4CH3 NHC(=NH)H 2-1034 2 1 H H (CH2)4CH3 NHC(=NH)CH3 2-1035 2 1 H H (CH2)4CH3 NHC(=NH)CH2CH3 2-1036 2 1 H H (CH2)4CH3 NHC(=NH)NH2 2-1037 2 1 H H (CH2)5CH3 NH2 2-1038 2 1 H H (CH2)5CH3 NHCH3 2-1039 2 1 H H (CH2)5CH3 N(CH3)2 2-1040 2 1 H H (CH2)5CH3 NHC(=NH)H 2-1041 2 1 H H (CH2)5CH3 NHC(=NH)CH3 2-1042 2 1 H H (CH2)5CH3 NHC(=NH)CH2CH3 2-1043 2 1 H H (CH2)5CH3 NHC(=NH)NH2 2-1044 2 1 H H (CH2)7CH3 NH2 2-1045 2 1 H H (CH2)7CH3 NHCH3 2-1046 2 1 H H (CH2)7CH3 N(CH3)2 2-1047 2 1 H H (CH2)7CH3 NHC(=NH)H 2-1048 2 1 H H (CH2)7CH3 NHC(=NH)CH3 2-1049 2 1 H H (CH2)7CH3 NHC(=NH)CH2CH3 2-1050 2 1 H H (CH2)7CH3 NHC(=NH)NH2 2-1051 2 1 H H (CH2)9CH3 NH2 2-1052 2 1 H H (CH2)9CH3 NHCH3 2-1053 2 1 H H (CH2)9CH3 N(CH3)2 2-1054 2 1 H H (CH2)9CH3 NHC(=NH)H 2-1055 2 1 H H (CH2)9CH3 NHC(=NH)CH3 2-1056 2 1 H H (CH2)9CH3 NHC(=NH)CH2CH3 2-1057 2 1 H H (CH2)9CH3 NHC(=NH)NH2 2-1058 2 1 H H (CH2)11CH3 NH2 2-1059 2 1 H H (CH2)11CH3 NHCH3 2-1060 2 1 H H (CH2)11CH3 N(CH3)2 2-1061 2 1 H H (CH2)11CH3 NHC(=NH)H 2-1062 2 1 H H (CH2)11CH3 NHC(=NH)CH3 2-1063 2 1 H H (CH2)11CH3 NHC(=NH)CH2CH3 2-1064 2 1 H H (CH2)11CH3 NHC(=NH)NH2 2-1065 2 1 H H (CH2)13CH3 NH2 2-1066 2 1 H H (CH2)13CH3 NHCH3 2-1067 2 1 H H (CH2)13CH3 N(CH3)2 2-1068 2 1 H H (CH2)13CH3 NHC(=NH)H 2-1069 2 1 H H (CH2)13CH3 NHC(=NH)CH3 2-1070 2 1 H H (CH2)13CH3 NHC(=NH)CH2CH3 2-1071 2 1 H H (CH2)13CH3 NHC(=NH)NH2 2-1072 2 1 H H (CH2)15CH3 NH2 2-1073 2 1 H H (CH2)15CH3 NHCH3 2-1074 2 1 H H (CH2)15CH3 N(CH3)2 2-1075 2 1 H H (CH2)15CH3 NHC(=NH)H 2-1076 2 1 H H (CH2)15CH3 NHC(=NH)CH3 2-1077 2 1 H H (CH2)15CH3 NHC(=NH)CH2CH3 2-1078 2 1 H H (CH2)15CH3 NHC(=NH)NH2 2-1079 2 1 H H (CH2)17CH3 NH2 2-1080 2 1 H H (CH2)17CH3 NHCH3 2-1081 2 1 H H (CH2)17CH3 N(CH3)2 2-1082 2 1 H H (CH2)17CH3 NHC(=NH)H 2-1083 2 1 H H (CH2)17CH3 NHC(=NH)CH3 2-1084 2 1 H H (CH2)17CH3 NHC(=NH)CH2CH3 2-1085 2 1 H H (CH2)17CH3 NHC(=NH)NH2 2-1086 2 1 H H (CH2)19CH3 NH2 2-1087 2 1 H H (CH2)19CH3 NHCH3 2-1088 2 1 H H (CH2)19CH3 N(CH3)2 2-1089 2 1 H H (CH2)19CH3 NHC(=NH)H 2-1090 2 1 H H (CH2)19CH3 NHC(=NH)CH3 2-1091 2 1 H H (CH2)19CH3 NHC(=NH)CH2CH3 2-1092 2 1 H H (CH2)19CH3 NHC(=NH)NH2 --------------------------------------------------------------------- ［表３］----------------------------------------------- ---------------------- Cpd.No.mn R 1 R Two Ra R Ten -------------------------------------------------- ------------------- 2-1 0 1 OH OH CH Three NH Two 2-2 0 1 OH OH CH Three NHCH Three 2-3 0 1 OH OH CH Three N (CH Three ) Two 2-4 0 1 OH OH CH Three NHC (= NH) H 2-5 0 1 OH OH CH Three NHC (= NH) CH Three 2-6 0 1 OH OH CH Three NHC (= NH) CH Two CH Three 2-7 0 1 OH OH CH Three NHC (= NH) NH Two 2-8 0 1 OH OH CH Two CH Three NH Two 2-9 0 1 OH OH CH Two CH Three NHCH Three 2-10 0 1 OH OH CH Two CH Three N (CH Three ) Two 2-11 0 1 OH OH CH Two CH Three NHC (= NH) H 2-12 0 1 OH OH CH Two CH Three NHC (= NH) CH Three 2-13 0 1 OH OH CH Two CH Three NHC (= NH) CH Two CH Three 2-14 0 1 OH OH CH Two CH Three NHC (= NH) NH Two 2-15 0 1 OH OH (CH Two ) Two CH Three NH Two 2-16 0 1 OH OH (CH Two ) Two CH Three NHCH Three 2-17 0 1 OH OH (CH Two ) Two CH Three N (CH Three ) Two 2-18 0 1 OH OH (CH Two ) Two CH Three NHC (= NH) H 2-19 0 1 OH OH (CH Two ) Two CH Three NHC (= NH) CH Three 2-20 0 1 OH OH (CH Two ) Two CH Three NHC (= NH) CH Two CH Three 2-21 0 1 OH OH (CH Two ) Two CH Three NHC (= NH) NH Two 2-22 0 1 OH OH (CH Two ) Three CH Three NH Two 2-23 0 1 OH OH (CH Two ) Three CH Three NHCH Three 2-24 0 1 OH OH (CH Two ) Three CH Three N (CH Three ) Two 2-25 0 1 OH OH (CH Two ) Three CH Three NHC (= NH) H 2-26 0 1 OH OH (CH Two ) Three CH Three NHC (= NH) CH Three 2-27 0 1 OH OH (CH Two ) Three CH Three NHC (= NH) CH Two CH Three 2-28 0 1 OH OH (CH Two ) Three CH Three NHC (= NH) NH Two 2-29 0 1 OH OH (CH Two ) Four CH Three NH Two 2-30 0 1 OH OH (CH Two ) Four CH Three NHCH Three 2-31 0 1 OH OH (CH Two ) Four CH Three N (CH Three ) Two 2-32 0 1 OH OH (CH Two ) Four CH Three NHC (= NH) H 2-33 0 1 OH OH (CH Two ) Four CH Three NHC (= NH) CH Three 2-34 0 1 OH OH (CH Two ) Four CH Three NHC (= NH) CH Two CH Three 2-35 0 1 OH OH (CH Two ) Four CH Three NHC (= NH) NH Two 2-36 0 1 OH OH (CH Two ) Five CH Three NH Two 2-37 0 1 OH OH (CH Two ) Five CH Three NHCH Three 2-38 0 1 OH OH (CH Two ) Five CH Three N (CH Three ) Two 2-39 0 1 OH OH (CH Two ) Five CH Three NHC (= NH) H 2-40 0 1 OH OH (CH Two ) Five CH Three NHC (= NH) CH Three 2-41 0 1 OH OH (CH Two ) Five CH Three NHC (= NH) CH Two CH Three 2-42 0 1 OH OH (CH Two ) Five CH Three NHC (= NH) NH Two 2-43 0 1 OH OH (CH Two ) 7 CH Three NH Two 2-44 0 1 OH OH (CH Two ) 7 CH Three NHCH Three 2-45 0 1 OH OH (CH Two ) 7 CH Three N (CH Three ) Two 2-46 0 1 OH OH (CH Two ) 7 CH Three NHC (= NH) H 2-47 0 1 OH OH (CH Two ) 7 CH Three NHC (= NH) CH Three 2-48 0 1 OH OH (CH Two ) 7 CH Three NHC (= NH) CH Two CH Three 2-49 0 1 OH OH (CH Two ) 7 CH Three NHC (= NH) NH Two 2-50 0 1 OH OH (CH Two ) 9 CH Three NH Two 2-51 0 1 OH OH (CH Two ) 9 CH Three NHCH Three 2-52 0 1 OH OH (CH Two ) 9 CH Three N (CH Three ) Two 2-53 0 1 OH OH (CH Two ) 9 CH Three NHC (= NH) H 2-54 0 1 OH OH (CH Two ) 9 CH Three NHC (= NH) CH Three 2-55 0 1 OH OH (CH Two ) 9 CH Three NHC (= NH) CH Two CH Three 2-56 0 1 OH OH (CH Two ) 9 CH Three NHC (= NH) NH Two 2-57 0 1 OH OH (CH Two ) 11 CH Three NH Two 2-58 0 1 OH OH (CH Two ) 11 CH Three NHCH Three 2-59 0 1 OH OH (CH Two ) 11 CH Three N (CH Three ) Two 2-60 0 1 OH OH (CH Two ) 11 CH Three NHC (= NH) H 2-61 0 1 OH OH (CH Two ) 11 CH Three NHC (= NH) CH Three 2-62 0 1 OH OH (CH Two ) 11 CH Three NHC (= NH) CH Two CH Three 2-63 0 1 OH OH (CH Two ) 11 CH Three NHC (= NH) NH Two 2-64 0 1 OH OH (CH Two ) 13 CH Three NH Two 2-65 0 1 OH OH (CH Two ) 13 CH Three NHCH Three 2-66 0 1 OH OH (CH Two ) 13 CH Three N (CH Three ) Two 2-67 0 1 OH OH (CH Two ) 13 CH Three NHC (= NH) H 2-68 0 1 OH OH (CH Two ) 13 CH Three NHC (= NH) CH Three 2-69 0 1 OH OH (CH Two ) 13 CH Three NHC (= NH) CH Two CH Three 2-70 0 1 OH OH (CH Two ) 13 CH Three NHC (= NH) NH Two 2-71 0 1 OH OH (CH Two ) Fifteen CH Three NH Two 2-72 0 1 OH OH (CH Two ) Fifteen CH Three NHCH Three 2-73 0 1 OH OH (CH Two ) Fifteen CH Three N (CH Three ) Two 2-74 0 1 OH OH (CH Two ) Fifteen CH Three NHC (= NH) H 2-75 0 1 OH OH (CH Two ) Fifteen CH Three NHC (= NH) CH Three 2-76 0 1 OH OH (CH Two ) Fifteen CH Three NHC (= NH) CH Two CH Three 2-77 0 1 OH OH (CH Two ) Fifteen CH Three NHC (= NH) NH Two 2-78 0 1 OH OH (CH Two ) 17 CH Three NH Two 2-79 0 1 OH OH (CH Two ) 17 CH Three NHCH Three 2-80 0 1 OH OH (CH Two ) 17 CH Three N (CH Three ) Two 2-81 0 1 OH OH (CH Two ) 17 CH Three NHC (= NH) H 2-82 0 1 OH OH (CH Two ) 17 CH Three NHC (= NH) CH Three 2-83 0 1 OH OH (CH Two ) 17 CH Three NHC (= NH) CH Two CH Three 2-84 0 1 OH OH (CH Two ) 17 CH Three NHC (= NH) NH Two 2-85 0 1 OH OH (CH Two ) 19 CH Three NH Two 2-86 0 1 OH OH (CH Two ) 19 CH Three NHCH Three 2-87 0 1 OH OH (CH Two ) 19 CH Three N (CH Three ) Two 2-88 0 1 OH OH (CH Two ) 19 CH Three NHC (= NH) H 2-89 0 1 OH OH (CH Two ) 19 CH Three NHC (= NH) CH Three 2-90 0 1 OH OH (CH Two ) 19 CH Three NHC (= NH) CH Two CH Three 2-91 0 1 OH OH (CH Two ) 19 CH Three NHC (= NH) NH Two 2-92 0 1 HH CH Three NH Two 2-93 0 1 HH CH Three NHCH Three 2-94 0 1 HH CH Three N (CH Three ) Two 2-95 0 1 HH CH Three NHC (= NH) H 2-96 0 1 HH CH Three NHC (= NH) CH Three 2-97 0 1 HH CH Three NHC (= NH) CH Two CH Three 2-98 0 1 HH CH Three NHC (= NH) NH Two 2-99 0 1 HH CH Two CH Three NH Two 2-100 0 1 HH CH Two CH Three NHCH Three 2-101 0 1 HH CH Two CH Three N (CH Three ) Two 2-102 0 1 HH CH Two CH Three NHC (= NH) H 2-103 0 1 HH CH Two CH Three NHC (= NH) CH Three 2-104 0 1 HH CH Two CH Three NHC (= NH) CH Two CH Three 2-105 0 1 HH CH Two CH Three NHC (= NH) NH Two 2-106 0 1 HH (CH Two ) Two CH Three NH Two 2-107 0 1 HH (CH Two ) Two CH Three NHCH Three 2-108 0 1 HH (CH Two ) Two CH Three N (CH Three ) Two 2-109 0 1 HH (CH Two ) Two CH Three NHC (= NH) H 2-110 0 1 HH (CH Two ) Two CH Three NHC (= NH) CH Three 2-111 0 1 HH (CH Two ) Two CH Three NHC (= NH) CH Two CH Three 2-112 0 1 HH (CH Two ) Two CH Three NHC (= NH) NH Two 2-113 0 1 HH (CH Two ) Three CH Three NH Two 2-114 0 1 HH (CH Two ) Three CH Three NHCH Three 2-115 0 1 HH (CH Two ) Three CH Three N (CH Three ) Two 2-116 0 1 HH (CH Two ) Three CH Three NHC (= NH) H 2-117 0 1 HH (CH Two ) Three CH Three NHC (= NH) CH Three 2-118 0 1 HH (CH Two ) Three CH Three NHC (= NH) CH Two CH Three 2-119 0 1 HH (CH Two ) Three CH Three NHC (= NH) NH Two 2-120 0 1 HH (CH Two ) Four CH Three NH Two 2-121 0 1 HH (CH Two ) Four CH Three NHCH Three 2-122 0 1 HH (CH Two ) Four CH Three N (CH Three ) Two 2-123 0 1 HH (CH Two ) Four CH Three NHC (= NH) H 2-124 0 1 HH (CH Two ) Four CH Three NHC (= NH) CH Three 2-125 0 1 HH (CH Two ) Four CH Three NHC (= NH) CH Two CH Three 2-126 0 1 HH (CH Two ) Four CH Three NHC (= NH) NH Two 2-127 0 1 HH (CH Two ) Five CH Three NH Two 2-128 0 1 HH (CH Two ) Five CH Three NHCH Three 2-129 0 1 HH (CH Two ) Five CH Three N (CH Three ) Two 2-130 0 1 HH (CH Two ) Five CH Three NHC (= NH) H 2-131 0 1 HH (CH Two ) Five CH Three NHC (= NH) CH Three 2-132 0 1 HH (CH Two ) Five CH Three NHC (= NH) CH Two CH Three 2-133 0 1 HH (CH Two ) Five CH Three NHC (= NH) NH Two 2-134 0 1 HH (CH Two ) 7 CH Three NH Two 2-135 0 1 HH (CH Two ) 7 CH Three NHCH Three 2-136 0 1 HH (CH Two ) 7 CH Three N (CH Three ) Two 2-137 0 1 HH (CH Two ) 7 CH Three NHC (= NH) H 2-138 0 1 HH (CH Two ) 7 CH Three NHC (= NH) CH Three 2-139 0 1 HH (CH Two ) 7 CH Three NHC (= NH) CH Two CH Three 2-140 0 1 HH (CH Two ) 7 CH Three NHC (= NH) NH Two 2-141 0 1 HH (CH Two ) 9 CH Three NH Two 2-142 0 1 HH (CH Two ) 9 CH Three NHCH Three 2-143 0 1 HH (CH Two ) 9 CH Three N (CH Three ) Two 2-144 0 1 HH (CH Two ) 9 CH Three NHC (= NH) H 2-145 0 1 HH (CH Two ) 9 CH Three NHC (= NH) CH Three 2-146 0 1 HH (CH Two ) 9 CH Three NHC (= NH) CH Two CH Three 2-147 0 1 HH (CH Two ) 9 CH Three NHC (= NH) NH Two 2-148 0 1 HH (CH Two ) 11 CH Three NH Two 2-149 0 1 HH (CH Two ) 11 CH Three NHCH Three 2-150 0 1 HH (CH Two ) 11 CH Three N (CH Three ) Two 2-151 0 1 HH (CH Two ) 11 CH Three NHC (= NH) H 2-152 0 1 HH (CH Two ) 11 CH Three NHC (= NH) CH Three 2-153 0 1 HH (CH Two ) 11 CH Three NHC (= NH) CH Two CH Three 2-154 0 1 HH (CH Two ) 11 CH Three NHC (= NH) NH Two 2-155 0 1 HH (CH Two ) 13 CH Three NH Two 2-156 0 1 HH (CH Two ) 13 CH Three NHCH Three 2-157 0 1 HH (CH Two ) 13 CH Three N (CH Three ) Two 2-158 0 1 HH (CH Two ) 13 CH Three NHC (= NH) H 2-159 0 1 HH (CH Two ) 13 CH Three NHC (= NH) CH Three 2-160 0 1 HH (CH Two ) 13 CH Three NHC (= NH) CH Two CH Three 2-161 0 1 HH (CH Two ) 13 CH Three NHC (= NH) NH Two 2-162 0 1 HH (CH Two ) Fifteen CH Three NH Two 2-163 0 1 HH (CH Two ) Fifteen CH Three NHCH Three 2-164 0 1 HH (CH Two ) Fifteen CH Three N (CH Three ) Two 2-165 0 1 HH (CH Two ) Fifteen CH Three NHC (= NH) H 2-166 0 1 HH (CH Two ) Fifteen CH Three NHC (= NH) CH Three 2-167 0 1 HH (CH Two ) Fifteen CH Three NHC (= NH) CH Two CH Three 2-168 0 1 HH (CH Two ) Fifteen CH Three NHC (= NH) NH Two 2-169 0 1 HH (CH Two ) 17 CH Three NH Two 2-170 0 1 HH (CH Two ) 17 CH Three NHCH Three 2-171 0 1 HH (CH Two ) 17 CH Three N (CH Three ) Two 2-172 0 1 HH (CH Two ) 17 CH Three NHC (= NH) H 2-173 0 1 HH (CH Two ) 17 CH Three NHC (= NH) CH Three 2-174 0 1 HH (CH Two ) 17 CH Three NHC (= NH) CH Two CH Three 2-175 0 1 HH (CH Two ) 17 CH Three NHC (= NH) NH Two 2-176 0 1 HH (CH Two ) 19 CH Three NH Two 2-177 0 1 HH (CH Two ) 19 CH Three NHCH Three 2-178 0 1 HH (CH Two ) 19 CH Three N (CH Three ) Two 2-179 0 1 HH (CH Two ) 19 CH Three NHC (= NH) H 2-180 0 1 HH (CH Two ) 19 CH Three NHC (= NH) CH Three 2-181 0 1 HH (CH Two ) 19 CH Three NHC (= NH) CH Two CH Three 2-182 0 1 HH (CH Two ) 19 CH Three NHC (= NH) NH Two 2-183 0 2 OH OH CH Three NH Two 2-184 0 2 OH OH CH Three NHCH Three 2-185 0 2 OH OH CH Three N (CH Three ) Two 2-186 0 2 OH OH CH Three NHC (= NH) H 2-187 0 2 OH OH CH Three NHC (= NH) CH Three 2-188 0 2 OH OH CH Three NHC (= NH) CH Two CH Three 2-189 0 2 OH OH CH Three NHC (= NH) NH Two 2-190 0 2 OH OH CH Two CH Three NH Two 2-191 0 2 OH OH CH Two CH Three NHCH Three 2-192 0 2 OH OH CH Two CH Three N (CH Three ) Two 2-193 0 2 OH OH CH Two CH Three NHC (= NH) H 2-194 0 2 OH OH CH Two CH Three NHC (= NH) CH Three 2-195 0 2 OH OH CH Two CH Three NHC (= NH) CH Two CH Three 2-196 0 2 OH OH CH Two CH Three NHC (= NH) NH Two 2-197 0 2 OH OH (CH Two ) Two CH Three NH Two 2-198 0 2 OH OH (CH Two ) Two CH Three NHCH Three 2-199 0 2 OH OH (CH Two ) Two CH Three N (CH Three ) Two 2-200 0 2 OH OH (CH Two ) Two CH Three NHC (= NH) H 2-201 0 2 OH OH (CH Two ) Two CH Three NHC (= NH) CH Three 2-202 0 2 OH OH (CH Two ) Two CH Three NHC (= NH) CH Two CH Three 2-203 0 2 OH OH (CH Two ) Two CH Three NHC (= NH) NH Two 2-204 0 2 OH OH (CH Two ) Three CH Three NH Two 2-205 0 2 OH OH (CH Two ) Three CH Three NHCH Three 2-206 0 2 OH OH (CH Two ) Three CH Three N (CH Three ) Two 2-207 0 2 OH OH (CH Two ) Three CH Three NHC (= NH) H 2-208 0 2 OH OH (CH Two ) Three CH Three NHC (= NH) CH Three 2-209 0 2 OH OH (CH Two ) Three CH Three NHC (= NH) CH Two CH Three 2-210 0 2 OH OH (CH Two ) Three CH Three NHC (= NH) NH Two 2-211 0 2 OH OH (CH Two ) Four CH Three NH Two 2-212 0 2 OH OH (CH Two ) Four CH Three NHCH Three 2-213 0 2 OH OH (CH Two ) Four CH Three N (CH Three ) Two 2-214 0 2 OH OH (CH Two ) Four CH Three NHC (= NH) H 2-215 0 2 OH OH (CH Two ) Four CH Three NHC (= NH) CH Three 2-216 0 2 OH OH (CH Two ) Four CH Three NHC (= NH) CH Two CH Three 2-217 0 2 OH OH (CH Two ) Four CH Three NHC (= NH) NH Two 2-218 0 2 OH OH (CH Two ) Five CH Three NH Two 2-219 0 2 OH OH (CH Two ) Five CH Three NHCH Three 2-220 0 2 OH OH (CH Two ) Five CH Three N (CH Three ) Two 2-221 0 2 OH OH (CH Two ) Five CH Three NHC (= NH) H 2-222 0 2 OH OH (CH Two ) Five CH Three NHC (= NH) CH Three 2-223 0 2 OH OH (CH Two ) Five CH Three NHC (= NH) CH Two CH Three 2-224 0 2 OH OH (CH Two ) Five CH Three NHC (= NH) NH Two 2-225 0 2 OH OH (CH Two ) 7 CH Three NH Two 2-226 0 2 OH OH (CH Two ) 7 CH Three NHCH Three 2-227 0 2 OH OH (CH Two ) 7 CH Three N (CH Three ) Two 2-228 0 2 OH OH (CH Two ) 7 CH Three NHC (= NH) H 2-229 0 2 OH OH (CH Two ) 7 CH Three NHC (= NH) CH Three 2-230 0 2 OH OH (CH Two ) 7 CH Three NHC (= NH) CH Two CH Three 2-231 0 2 OH OH (CH Two ) 7 CH Three NHC (= NH) NH Two 2-232 0 2 OH OH (CH Two ) 9 CH Three NH Two 2-233 0 2 OH OH (CH Two ) 9 CH Three NHCH Three 2-234 0 2 OH OH (CH Two ) 9 CH Three N (CH Three ) Two 2-235 0 2 OH OH (CH Two ) 9 CH Three NHC (= NH) H 2-236 0 2 OH OH (CH Two ) 9 CH Three NHC (= NH) CH Three 2-237 0 2 OH OH (CH Two ) 9 CH Three NHC (= NH) CH Two CH Three 2-238 0 2 OH OH (CH Two ) 9 CH Three NHC (= NH) NH Two 2-239 0 2 OH OH (CH Two ) 11 CH Three NH Two 2-240 0 2 OH OH (CH Two ) 11 CH Three NHCH Three 2-241 0 2 OH OH (CH Two ) 11 CH Three N (CH Three ) Two 2-242 0 2 OH OH (CH Two ) 11 CH Three NHC (= NH) H 2-243 0 2 OH OH (CH Two ) 11 CH Three NHC (= NH) CH Three 2-244 0 2 OH OH (CH Two ) 11 CH Three NHC (= NH) CH Two CH Three 2-245 0 2 OH OH (CH Two ) 11 CH Three NHC (= NH) NH Two 2-246 0 2 OH OH (CH Two ) 13 CH Three NH Two 2-247 0 2 OH OH (CH Two ) 13 CH Three NHCH Three 2-248 0 2 OH OH (CH Two ) 13 CH Three N (CH Three ) Two 2-249 0 2 OH OH (CH Two ) 13 CH Three NHC (= NH) H 2-250 0 2 OH OH (CH Two ) 13 CH Three NHC (= NH) CH Three 2-251 0 2 OH OH (CH Two ) 13 CH Three NHC (= NH) CH Two CH Three 2-252 0 2 OH OH (CH Two ) 13 CH Three NHC (= NH) NH Two 2-253 0 2 OH OH (CH Two ) Fifteen CH Three NH Two 2-254 0 2 OH OH (CH Two ) Fifteen CH Three NHCH Three 2-255 0 2 OH OH (CH Two ) Fifteen CH Three N (CH Three ) Two 2-256 0 2 OH OH (CH Two ) Fifteen CH Three NHC (= NH) H 2-257 0 2 OH OH (CH Two ) Fifteen CH Three NHC (= NH) CH Three 2-258 0 2 OH OH (CH Two ) Fifteen CH Three NHC (= NH) CH Two CH Three 2-259 0 2 OH OH (CH Two ) Fifteen CH Three NHC (= NH) NH Two 2-260 0 2 OH OH (CH Two ) 17 CH Three NH Two 2-261 0 2 OH OH (CH Two ) 17 CH Three NHCH Three 2-262 0 2 OH OH (CH Two ) 17 CH Three N (CH Three ) Two 2-263 0 2 OH OH (CH Two ) 17 CH Three NHC (= NH) H 2-264 0 2 OH OH (CH Two ) 17 CH Three NHC (= NH) CH Three 2-265 0 2 OH OH (CH Two ) 17 CH Three NHC (= NH) CH Two CH Three 2-266 0 2 OH OH (CH Two ) 17 CH Three NHC (= NH) NH Two 2-267 0 2 OH OH (CH Two ) 19 CH Three NH Two 2-268 0 2 OH OH (CH Two ) 19 CH Three NHCH Three 2-269 0 2 OH OH (CH Two ) 19 CH Three N (CH Three ) Two 2-270 0 2 OH OH (CH Two ) 19 CH Three NHC (= NH) H 2-271 0 2 OH OH (CH Two ) 19 CH Three NHC (= NH) CH Three 2-272 0 2 OH OH (CH Two ) 19 CH Three NHC (= NH) CH Two CH Three 2-273 0 2 OH OH (CH Two ) 19 CH Three NHC (= NH) NH Two 2-274 0 2 HH CH Three NH Two 2-275 0 2 HH CH Three NHCH Three 2-276 0 2 HH CH Three N (CH Three ) Two 2-277 0 2 HH CH Three NHC (= NH) H 2-278 0 2 HH CH Three NHC (= NH) CH Three 2-279 0 2 HH CH Three NHC (= NH) CH Two CH Three 2-280 0 2 HH CH Three NHC (= NH) NH Two 2-281 0 2 HH CH Two CH Three NH Two 2-282 0 2 HH CH Two CH Three NHCH Three 2-283 0 2 HH CH Two CH Three N (CH Three ) Two 2-284 0 2 HH CH Two CH Three NHC (= NH) H 2-285 0 2 HH CH Two CH Three NHC (= NH) CH Three 2-286 0 2 HH CH Two CH Three NHC (= NH) CH Two CH Three 2-287 0 2 HH CH Two CH Three NHC (= NH) NH Two 2-288 0 2 HH (CH Two ) Two CH Three NH Two 2-289 0 2 HH (CH Two ) Two CH Three NHCH Three 2-290 0 2 HH (CH Two ) Two CH Three N (CH Three ) Two 2-291 0 2 HH (CH Two ) Two CH Three NHC (= NH) H 2-292 0 2 HH (CH Two ) Two CH Three NHC (= NH) CH Three 2-293 0 2 HH (CH Two ) Two CH Three NHC (= NH) CH Two CH Three 2-294 0 2 HH (CH Two ) Two CH Three NHC (= NH) NH Two 2-295 0 2 HH (CH Two ) Three CH Three NH Two 2-296 0 2 HH (CH Two ) Three CH Three NHCH Three 2-297 0 2 HH (CH Two ) Three CH Three N (CH Three ) Two 2-298 0 2 HH (CH Two ) Three CH Three NHC (= NH) H 2-299 0 2 HH (CH Two ) Three CH Three NHC (= NH) CH Three 2-300 0 2 HH (CH Two ) Three CH Three NHC (= NH) CH Two CH Three 2-301 0 2 HH (CH Two ) Three CH Three NHC (= NH) NH Two 2-302 0 2 HH (CH Two ) Four CH Three NH Two 2-303 0 2 HH (CH Two ) Four CH Three NHCH Three 2-304 0 2 HH (CH Two ) Four CH Three N (CH Three ) Two 2-305 0 2 HH (CH Two ) Four CH Three NHC (= NH) H 2-306 0 2 HH (CH Two ) Four CH Three NHC (= NH) CH Three 2-307 0 2 HH (CH Two ) Four CH Three NHC (= NH) CH Two CH Three 2-308 0 2 HH (CH Two ) Four CH Three NHC (= NH) NH Two 2-309 0 2 HH (CH Two ) Five CH Three NH Two 2-310 0 2 HH (CH Two ) Five CH Three NHCH Three 2-311 0 2 HH (CH Two ) Five CH Three N (CH Three ) Two 2-312 0 2 HH (CH Two ) Five CH Three NHC (= NH) H 2-313 0 2 HH (CH Two ) Five CH Three NHC (= NH) CH Three 2-314 0 2 HH (CH Two ) Five CH Three NHC (= NH) CH Two CH Three 2-315 0 2 HH (CH Two ) Five CH Three NHC (= NH) NH Two 2-316 0 2 HH (CH Two ) 7 CH Three NH Two 2-317 0 2 HH (CH Two ) 7 CH Three NHCH Three 2-318 0 2 HH (CH Two ) 7 CH Three N (CH Three ) Two 2-319 0 2 HH (CH Two ) 7 CH Three NHC (= NH) H 2-320 0 2 HH (CH Two ) 7 CH Three NHC (= NH) CH Three 2-321 0 2 HH (CH Two ) 7 CH Three NHC (= NH) CH Two CH Three 2-322 0 2 HH (CH Two ) 7 CH Three NHC (= NH) NH Two 2-323 0 2 HH (CH Two ) 9 CH Three NH Two 2-324 0 2 HH (CH Two ) 9 CH Three NHCH Three 2-325 0 2 HH (CH Two ) 9 CH Three N (CH Three ) Two 2-326 0 2 HH (CH Two ) 9 CH Three NHC (= NH) H 2-327 0 2 HH (CH Two ) 9 CH Three NHC (= NH) CH Three 2-328 0 2 HH (CH Two ) 9 CH Three NHC (= NH) CH Two CH Three 2-329 0 2 HH (CH Two ) 9 CH Three NHC (= NH) NH Two 2-330 0 2 HH (CH Two ) 11 CH Three NH Two 2-331 0 2 HH (CH Two ) 11 CH Three NHCH Three 2-332 0 2 HH (CH Two ) 11 CH Three N (CH Three ) Two 2-333 0 2 HH (CH Two ) 11 CH Three NHC (= NH) H 2-334 0 2 HH (CH Two ) 11 CH Three NHC (= NH) CH Three 2-335 0 2 HH (CH Two ) 11 CH Three NHC (= NH) CH Two CH Three 2-336 0 2 HH (CH Two ) 11 CH Three NHC (= NH) NH Two 2-337 0 2 HH (CH Two ) 13 CH Three NH Two 2-338 0 2 HH (CH Two ) 13 CH Three NHCH Three 2-339 0 2 HH (CH Two ) 13 CH Three N (CH Three ) Two 2-340 0 2 HH (CH Two ) 13 CH Three NHC (= NH) H 2-341 0 2 HH (CH Two ) 13 CH Three NHC (= NH) CH Three 2-342 0 2 HH (CH Two ) 13 CH Three NHC (= NH) CH Two CH Three 2-343 0 2 HH (CH Two ) 13 CH Three NHC (= NH) NH Two 2-344 0 2 HH (CH Two ) Fifteen CH Three NH Two 2-345 0 2 HH (CH Two ) Fifteen CH Three NHCH Three 2-346 0 2 HH (CH Two ) Fifteen CH Three N (CH Three ) Two 2-347 0 2 HH (CH Two ) Fifteen CH Three NHC (= NH) H 2-348 0 2 HH (CH Two ) Fifteen CH Three NHC (= NH) CH Three 2-349 0 2 HH (CH Two ) Fifteen CH Three NHC (= NH) CH Two CH Three 2-350 0 2 HH (CH Two ) Fifteen CH Three NHC (= NH) NH Two 2-351 0 2 HH (CH Two ) 17 CH Three NH Two 2-352 0 2 HH (CH Two ) 17 CH Three NHCH Three 2-353 0 2 HH (CH Two ) 17 CH Three N (CH Three ) Two 2-354 0 2 HH (CH Two ) 17 CH Three NHC (= NH) H 2-355 0 2 HH (CH Two ) 17 CH Three NHC (= NH) CH Three 2-356 0 2 HH (CH Two ) 17 CH Three NHC (= NH) CH Two CH Three 2-357 0 2 HH (CH Two ) 17 CH Three NHC (= NH) NH Two 2-358 0 2 HH (CH Two ) 19 CH Three NH Two 2-359 0 2 HH (CH Two ) 19 CH Three NHCH Three 2-360 0 2 HH (CH Two ) 19 CH Three N (CH Three ) Two 2-361 0 2 HH (CH Two ) 19 CH Three NHC (= NH) H 2-362 0 2 HH (CH Two ) 19 CH Three NHC (= NH) CH Three 2-363 0 2 HH (CH Two ) 19 CH Three NHC (= NH) CH Two CH Three 2-364 0 2 HH (CH Two ) 19 CH Three NHC (= NH) NH Two 2-365 0 3 OH OH CH Three NH Two 2-366 0 3 OH OH CH Three NHCH Three 2-367 0 3 OH OH CH Three N (CH Three ) Two 2-368 0 3 OH OH CH Three NHC (= NH) H 2-369 0 3 OH OH CH Three NHC (= NH) CH Three 2-370 0 3 OH OH CH Three NHC (= NH) CH Two CH Three 2-371 0 3 OH OH CH Three NHC (= NH) NH Two 2-372 0 3 OH OH CH Two CH Three NH Two 2-373 0 3 OH OH CH Two CH Three NHCH Three 2-374 0 3 OH OH CH Two CH Three N (CH Three ) Two 2-375 0 3 OH OH CH Two CH Three NHC (= NH) H 2-376 0 3 OH OH CH Two CH Three NHC (= NH) CH Three 2-377 0 3 OH OH CH Two CH Three NHC (= NH) CH Two CH Three 2-378 0 3 OH OH CH Two CH Three NHC (= NH) NH Two 2-379 0 3 OH OH (CH Two ) Two CH Three NH Two 2-380 0 3 OH OH (CH Two ) Two CH Three NHCH Three 2-381 0 3 OH OH (CH Two ) Two CH Three N (CH Three ) Two 2-382 0 3 OH OH (CH Two ) Two CH Three NHC (= NH) H 2-383 0 3 OH OH (CH Two ) Two CH Three NHC (= NH) CH Three 2-384 0 3 OH OH (CH Two ) Two CH Three NHC (= NH) CH Two CH Three 2-385 0 3 OH OH (CH Two ) Two CH Three NHC (= NH) NH Two 2-386 0 3 OH OH (CH Two ) Three CH Three NH Two 2-387 0 3 OH OH (CH Two ) Three CH Three NHCH Three 2-388 0 3 OH OH (CH Two ) Three CH Three N (CH Three ) Two 2-389 0 3 OH OH (CH Two ) Three CH Three NHC (= NH) H 2-390 0 3 OH OH (CH Two ) Three CH Three NHC (= NH) CH Three 2-391 0 3 OH OH (CH Two ) Three CH Three NHC (= NH) CH Two CH Three 2-392 0 3 OH OH (CH Two ) Three CH Three NHC (= NH) NH Two 2-393 0 3 OH OH (CH Two ) Four CH Three NH Two 2-394 0 3 OH OH (CH Two ) Four CH Three NHCH Three 2-395 0 3 OH OH (CH Two ) Four CH Three N (CH Three ) Two 2-396 0 3 OH OH (CH Two ) Four CH Three NHC (= NH) H 2-397 0 3 OH OH (CH Two ) Four CH Three NHC (= NH) CH Three 2-398 0 3 OH OH (CH Two ) Four CH Three NHC (= NH) CH Two CH Three 2-399 0 3 OH OH (CH Two ) Four CH Three NHC (= NH) NH Two 2-400 0 3 OH OH (CH Two ) Five CH Three NH Two 2-401 0 3 OH OH (CH Two ) Five CH Three NHCH Three 2-402 0 3 OH OH (CH Two ) Five CH Three N (CH Three ) Two 2-403 0 3 OH OH (CH Two ) Five CH Three NHC (= NH) H 2-404 0 3 OH OH (CH Two ) Five CH Three NHC (= NH) CH Three 2-405 0 3 OH OH (CH Two ) Five CH Three NHC (= NH) CH Two CH Three 2-406 0 3 OH OH (CH Two ) Five CH Three NHC (= NH) NH Two 2-407 0 3 OH OH (CH Two ) 7 CH Three NH Two 2-408 0 3 OH OH (CH Two ) 7 CH Three NHCH Three 2-409 0 3 OH OH (CH Two ) 7 CH Three N (CH Three ) Two 2-410 0 3 OH OH (CH Two ) 7 CH Three NHC (= NH) H 2-411 03 OH OH (CH Two ) 7 CH Three NHC (= NH) CH Three 2-412 0 3 OH OH (CH Two ) 7 CH Three NHC (= NH) CH Two CH Three 2-413 0 3 OH OH (CH Two ) 7 CH Three NHC (= NH) NH Two 2-414 0 3 OH OH (CH Two ) 9 CH Three NH Two 2-415 0 3 OH OH (CH Two ) 9 CH Three NHCH Three 2-416 0 3 OH OH (CH Two ) 9 CH Three N (CH Three ) Two 2-417 0 3 OH OH (CH Two ) 9 CH Three NHC (= NH) H 2-418 0 3 OH OH (CH Two ) 9 CH Three NHC (= NH) CH Three 2-419 0 3 OH OH (CH Two ) 9 CH Three NHC (= NH) CH Two CH Three 2-420 0 3 OH OH (CH Two ) 9 CH Three NHC (= NH) NH Two 2-421 0 3 OH OH (CH Two ) 11 CH Three NH Two 2-422 0 3 OH OH (CH Two ) 11 CH Three NHCH Three 2-423 0 3 OH OH (CH Two ) 11 CH Three N (CH Three ) Two 2-424 0 3 OH OH (CH Two ) 11 CH Three NHC (= NH) H 2-425 0 3 OH OH (CH Two ) 11 CH Three NHC (= NH) CH Three 2-426 0 3 OH OH (CH Two ) 11 CH Three NHC (= NH) CH Two CH Three 2-427 0 3 OH OH (CH Two ) 11 CH Three NHC (= NH) NH Two 2-428 0 3 OH OH (CH Two ) 13 CH Three NH Two 2-429 0 3 OH OH (CH Two ) 13 CH Three NHCH Three 2-430 0 3 OH OH (CH Two ) 13 CH Three N (CH Three ) Two 2-431 0 3 OH OH (CH Two ) 13 CH Three NHC (= NH) H 2-432 0 3 OH OH (CH Two ) 13 CH Three NHC (= NH) CH Three 2-433 0 3 OH OH (CH Two ) 13 CH Three NHC (= NH) CH Two CH Three 2-434 0 3 OH OH (CH Two ) 13 CH Three NHC (= NH) NH Two 2-435 0 3 OH OH (CH Two ) Fifteen CH Three NH Two 2-436 0 3 OH OH (CH Two ) Fifteen CH Three NHCH Three 2-437 0 3 OH OH (CH Two ) Fifteen CH Three N (CH Three ) Two 2-438 0 3 OH OH (CH Two ) Fifteen CH Three NHC (= NH) H 2-439 0 3 OH OH (CH Two ) Fifteen CH Three NHC (= NH) CH Three 2-440 0 3 OH OH (CH Two ) Fifteen CH Three NHC (= NH) CH Two CH Three 2-441 0 3 OH OH (CH Two ) Fifteen CH Three NHC (= NH) NH Two 2-442 0 3 OH OH (CH Two ) 17 CH Three NH Two 2-443 0 3 OH OH (CH Two ) 17 CH Three NHCH Three 2-444 0 3 OH OH (CH Two ) 17 CH Three N (CH Three ) Two 2-445 0 3 OH OH (CH Two ) 17 CH Three NHC (= NH) H 2-446 0 3 OH OH (CH Two ) 17 CH Three NHC (= NH) CH Three 2-447 0 3 OH OH (CH Two ) 17 CH Three NHC (= NH) CH Two CH Three 2-448 0 3 OH OH (CH Two ) 17 CH Three NHC (= NH) NH Two 2-449 0 3 OH OH (CH Two ) 19 CH Three NH Two 2-450 0 3 OH OH (CH Two ) 19 CH Three NHCH Three 2-451 0 3 OH OH (CH Two ) 19 CH Three N (CH Three ) Two 2-452 0 3 OH OH (CH Two ) 19 CH Three NHC (= NH) H 2-453 0 3 OH OH (CH Two ) 19 CH Three NHC (= NH) CH Three 2-454 0 3 OH OH (CH Two ) 19 CH Three NHC (= NH) CH Two CH Three 2-455 0 3 OH OH (CH Two ) 19 CH Three NHC (= NH) NH Two 2-456 0 3 HH CH Three NH Two 2-457 0 3 HH CH Three NHCH Three 2-458 0 3 HH CH Three N (CH Three ) Two 2-459 0 3 HH CH Three NHC (= NH) H 2-460 0 3 HH CH Three NHC (= NH) CH Three 2-461 0 3 HH CH Three NHC (= NH) CH Two CH Three 2-462 0 3 HH CH Three NHC (= NH) NH Two 2-463 0 3 HH CH Two CH Three NH Two 2-464 0 3 HH CH Two CH Three NHCH Three 2-465 0 3 HH CH Two CH Three N (CH Three ) Two 2-466 0 3 HH CH Two CH Three NHC (= NH) H 2-467 0 3 HH CH Two CH Three NHC (= NH) CH Three 2-468 0 3 HH CH Two CH Three NHC (= NH) CH Two CH Three 2-469 0 3 HH CH Two CH Three NHC (= NH) NH Two 2-470 0 3 HH (CH Two ) Two CH Three NH Two 2-471 0 3 HH (CH Two ) Two CH Three NHCH Three 2-472 0 3 HH (CH Two ) Two CH Three N (CH Three ) Two 2-473 0 3 HH (CH Two ) Two CH Three NHC (= NH) H 2-474 0 3 HH (CH Two ) Two CH Three NHC (= NH) CH Three 2-475 0 3 HH (CH Two ) Two CH Three NHC (= NH) CH Two CH Three 2-476 0 3 HH (CH Two ) Two CH Three NHC (= NH) NH Two 2-477 0 3 HH (CH Two ) Three CH Three NH Two 2-478 0 3 HH (CH Two ) Three CH Three NHCH Three 2-479 0 3 HH (CH Two ) Three CH Three N (CH Three ) Two 2-480 0 3 HH (CH Two ) Three CH Three NHC (= NH) H 2-481 0 3 HH (CH Two ) Three CH Three NHC (= NH) CH Three 2-482 0 3 HH (CH Two ) Three CH Three NHC (= NH) CH Two CH Three 2-483 0 3 HH (CH Two ) Three CH Three NHC (= NH) NH Two 2-484 0 3 HH (CH Two ) Four CH Three NH Two 2-485 0 3 HH (CH Two ) Four CH Three NHCH Three 2-486 0 3 HH (CH Two ) Four CH Three N (CH Three ) Two 2-487 0 3 HH (CH Two ) Four CH Three NHC (= NH) H 2-488 0 3 HH (CH Two ) Four CH Three NHC (= NH) CH Three 2-489 0 3 HH (CH Two ) Four CH Three NHC (= NH) CH Two CH Three 2-490 0 3 HH (CH Two ) Four CH Three NHC (= NH) NH Two 2-491 0 3 HH (CH Two ) Five CH Three NH Two 2-492 0 3 HH (CH Two ) Five CH Three NHCH Three 2-493 0 3 HH (CH Two ) Five CH Three N (CH Three ) Two 2-494 0 3 HH (CH Two ) Five CH Three NHC (= NH) H 2-495 0 3 HH (CH Two ) Five CH Three NHC (= NH) CH Three 2-496 0 3 HH (CH Two ) Five CH Three NHC (= NH) CH Two CH Three 2-497 0 3 HH (CH Two ) Five CH Three NHC (= NH) NH Two 2-498 0 3 HH (CH Two ) 7 CH Three NH Two 2-499 0 3 HH (CH Two ) 7 CH Three NHCH Three 2-500 0 3 HH (CH Two ) 7 CH Three N (CH Three ) Two 2-501 0 3 HH (CH Two ) 7 CH Three NHC (= NH) H 2-502 0 3 HH (CH Two ) 7 CH Three NHC (= NH) CH Three 2-503 0 3 HH (CH Two ) 7 CH Three NHC (= NH) CH Two CH Three 2-504 0 3 HH (CH Two ) 7 CH Three NHC (= NH) NH Two 2-505 0 3 HH (CH Two ) 9 CH Three NH Two 2-506 0 3 HH (CH Two ) 9 CH Three NHCH Three 2-507 0 3 HH (CH Two ) 9 CH Three N (CH Three ) Two 2-508 0 3 HH (CH Two ) 9 CH Three NHC (= NH) H 2-509 0 3 HH (CH Two ) 9 CH Three NHC (= NH) CH Three 2-510 0 3 HH (CH Two ) 9 CH Three NHC (= NH) CH Two CH Three 2-511 0 3 HH (CH Two ) 9 CH Three NHC (= NH) NH Two 2-512 0 3 HH (CH Two ) 11 CH Three NH Two 2-513 0 3 HH (CH Two ) 11 CH Three NHCH Three 2-514 0 3 HH (CH Two ) 11 CH Three N (CH Three ) Two 2-515 0 3 HH (CH Two ) 11 CH Three NHC (= NH) H 2-516 0 3 HH (CH Two ) 11 CH Three NHC (= NH) CH Three 2-517 0 3 HH (CH Two ) 11 CH Three NHC (= NH) CH Two CH Three 2-518 0 3 HH (CH Two ) 11 CH Three NHC (= NH) NH Two 2-519 0 3 HH (CH Two ) 13 CH Three NH Two 2-520 0 3 HH (CH Two ) 13 CH Three NHCH Three 2-521 0 3 HH (CH Two ) 13 CH Three N (CH Three ) Two 2-522 0 3 HH (CH Two ) 13 CH Three NHC (= NH) H 2-523 0 3 HH (CH Two ) 13 CH Three NHC (= NH) CH Three 2-524 0 3 HH (CH Two ) 13 CH Three NHC (= NH) CH Two CH Three 2-525 0 3 HH (CH Two ) 13 CH Three NHC (= NH) NH Two 2-526 0 3 HH (CH Two ) Fifteen CH Three NH Two 2-527 0 3 HH (CH Two ) Fifteen CH Three NHCH Three 2-528 0 3 HH (CH Two ) Fifteen CH Three N (CH Three ) Two 2-529 0 3 HH (CH Two ) Fifteen CH Three NHC (= NH) H 2-530 0 3 HH (CH Two ) Fifteen CH Three NHC (= NH) CH Three 2-531 0 3 HH (CH Two ) Fifteen CH Three NHC (= NH) CH Two CH Three 2-532 0 3 HH (CH Two ) Fifteen CH Three NHC (= NH) NH Two 2-533 0 3 HH (CH Two ) 17 CH Three NH Two 2-534 0 3 HH (CH Two ) 17 CH Three NHCH Three 2-535 0 3 HH (CH Two ) 17 CH Three N (CH Three ) Two 2-536 0 3 HH (CH Two ) 17 CH Three NHC (= NH) H 2-537 0 3 HH (CH Two ) 17 CH Three NHC (= NH) CH Three 2-538 0 3 HH (CH Two ) 17 CH Three NHC (= NH) CH Two CH Three 2-539 0 3 HH (CH Two ) 17 CH Three NHC (= NH) NH Two 2-540 0 3 HH (CH Two ) 19 CH Three NH Two 2-541 0 3 HH (CH Two ) 19 CH Three NHCH Three 2-542 0 3 HH (CH Two ) 19 CH Three N (CH Three ) Two 2-543 0 3 HH (CH Two ) 19 CH Three NHC (= NH) H 2-544 0 3 HH (CH Two ) 19 CH Three NHC (= NH) CH Three 2-545 0 3 HH (CH Two ) 19 CH Three NHC (= NH) CH Two CH Three 2-546 0 3 HH (CH Two ) 19 CH Three NHC (= NH) NH Two 2-547 1 1 OH OH CH Three NH Two 2-548 1 1 OH OH CH Three NHCH Three 2-549 1 1 OH OH CH Three N (CH Three ) Two 2-550 1 1 OH OH CH Three NHC (= NH) H 2-551 1 1 OH OH CH Three NHC (= NH) CH Three 2-552 1 1 OH OH CH Three NHC (= NH) CH Two CH Three 2-553 1 1 OH OH CH Three NHC (= NH) NH Two 2-554 1 1 OH OH CH Two CH Three NH Two 2-555 1 1 OH OH CH Two CH Three NHCH Three 2-556 1 1 OH OH CH Two CH Three N (CH Three ) Two 2-557 1 1 OH OH CH Two CH Three NHC (= NH) H 2-558 1 1 OH OH CH Two CH Three NHC (= NH) CH Three 2-559 1 1 OH OH CH Two CH Three NHC (= NH) CH Two CH Three 2-560 1 1 OH OH CH Two CH Three NHC (= NH) NH Two 2-561 1 1 OH OH (CH Two ) Two CH Three NH Two 2-562 1 1 OH OH (CH Two ) Two CH Three NHCH Three 2-563 1 1 OH OH (CH Two ) Two CH Three N (CH Three ) Two 2-564 1 1 OH OH (CH Two ) Two CH Three NHC (= NH) H 2-565 1 1 OH OH (CH Two ) Two CH Three NHC (= NH) CH Three 2-566 1 1 OH OH (CH Two ) Two CH Three NHC (= NH) CH Two CH Three 2-567 1 1 OH OH (CH Two ) Two CH Three NHC (= NH) NH Two 2-568 1 1 OH OH (CH Two ) Three CH Three NH Two 2-569 1 1 OH OH (CH Two ) Three CH Three NHCH Three 2-570 1 1 OH OH (CH Two ) Three CH Three N (CH Three ) Two 2-571 1 1 OH OH (CH Two ) Three CH Three NHC (= NH) H 2-572 1 1 OH OH (CH Two ) Three CH Three NHC (= NH) CH Three 2-573 1 1 OH OH (CH Two ) Three CH Three NHC (= NH) CH Two CH Three 2-574 1 1 OH OH (CH Two ) Three CH Three NHC (= NH) NH Two 2-575 1 1 OH OH (CH Two ) Four CH Three NH Two 2-576 1 1 OH OH (CH Two ) Four CH Three NHCH Three 2-577 1 1 OH OH (CH Two ) Four CH Three N (CH Three ) Two 2-578 1 1 OH OH (CH Two ) Four CH Three NHC (= NH) H 2-579 1 1 OH OH (CH Two ) Four CH Three NHC (= NH) CH Three 2-580 1 1 OH OH (CH Two ) Four CH Three NHC (= NH) CH Two CH Three 2-581 1 1 OH OH (CH Two ) Four CH Three NHC (= NH) NH Two 2-582 1 1 OH OH (CH Two ) Five CH Three NH Two 2-583 1 1 OH OH (CH Two ) Five CH Three NHCH Three 2-584 1 1 OH OH (CH Two ) Five CH Three N (CH Three ) Two 2-585 1 1 OH OH (CH Two ) Five CH Three NHC (= NH) H 2-586 1 1 OH OH (CH Two ) Five CH Three NHC (= NH) CH Three 2-587 1 1 OH OH (CH Two ) Five CH Three NHC (= NH) CH Two CH Three 2-588 1 1 OH OH (CH Two ) Five CH Three NHC (= NH) NH Two 2-589 1 1 OH OH (CH Two ) 7 CH Three NH Two 2-590 1 1 OH OH (CH Two ) 7 CH Three NHCH Three 2-591 1 1 OH OH (CH Two ) 7 CH Three N (CH Three ) Two 2-592 1 1 OH OH (CH Two ) 7 CH Three NHC (= NH) H 2-593 1 1 OH OH (CH Two ) 7 CH Three NHC (= NH) CH Three 2-594 1 1 OH OH (CH Two ) 7 CH Three NHC (= NH) CH Two CH Three 2-595 1 1 OH OH (CH Two ) 7 CH Three NHC (= NH) NH Two 2-596 1 1 OH OH (CH Two ) 9 CH Three NH Two 2-597 1 1 OH OH (CH Two ) 9 CH Three NHCH Three 2-598 1 1 OH OH (CH Two ) 9 CH Three N (CH Three ) Two 2-599 1 1 OH OH (CH Two ) 9 CH Three NHC (= NH) H 2-600 1 1 OH OH (CH Two ) 9 CH Three NHC (= NH) CH Three 2-601 1 1 OH OH (CH Two ) 9 CH Three NHC (= NH) CH Two CH Three 2-602 1 1 OH OH (CH Two ) 9 CH Three NHC (= NH) NH Two 2-603 1 1 OH OH (CH Two ) 11 CH Three NH Two 2-604 1 1 OH OH (CH Two ) 11 CH Three NHCH Three 2-605 1 1 OH OH (CH Two ) 11 CH Three N (CH Three ) Two 2-606 1 1 OH OH (CH Two ) 11 CH Three NHC (= NH) H 2-607 1 1 OH OH (CH Two ) 11 CH Three NHC (= NH) CH Three 2-608 1 1 OH OH (CH Two ) 11 CH Three NHC (= NH) CH Two CH Three 2-609 1 1 OH OH (CH Two ) 11 CH Three NHC (= NH) NH Two 2-610 1 1 OH OH (CH Two ) 13 CH Three NH Two 2-611 1 1 OH OH (CH Two ) 13 CH Three NHCH Three 2-612 1 1 OH OH (CH Two ) 13 CH Three N (CH Three ) Two 2-613 1 1 OH OH (CH Two ) 13 CH Three NHC (= NH) H 2-614 1 1 OH OH (CH Two ) 13 CH Three NHC (= NH) CH Three 2-615 1 1 OH OH (CH Two ) 13 CH Three NHC (= NH) CH Two CH Three 2-616 1 1 OH OH (CH Two ) 13 CH Three NHC (= NH) NH Two 2-617 1 1 OH OH (CH Two ) Fifteen CH Three NH Two 2-618 1 1 OH OH (CH Two ) Fifteen CH Three NHCH Three 2-619 1 1 OH OH (CH Two ) Fifteen CH Three N (CH Three ) Two 2-620 1 1 OH OH (CH Two ) Fifteen CH Three NHC (= NH) H 2-621 1 1 OH OH (CH Two ) Fifteen CH Three NHC (= NH) CH Three 2-622 1 1 OH OH (CH Two ) Fifteen CH Three NHC (= NH) CH Two CH Three 2-623 1 1 OH OH (CH Two ) Fifteen CH Three NHC (= NH) NH Two 2-624 1 1 OH OH (CH Two ) 17 CH Three NH Two 2-625 1 1 OH OH (CH Two ) 17 CH Three NHCH Three 2-626 1 1 OH OH (CH Two ) 17 CH Three N (CH Three ) Two 2-627 1 1 OH OH (CH Two ) 17 CH Three NHC (= NH) H 2-628 1 1 OH OH (CH Two ) 17 CH Three NHC (= NH) CH Three 2-629 1 1 OH OH (CH Two ) 17 CH Three NHC (= NH) CH Two CH Three 2-630 1 1 OH OH (CH Two ) 17 CH Three NHC (= NH) NH Two 2-631 1 1 OH OH (CH Two ) 19 CH Three NH Two 2-632 1 1 OH OH (CH Two ) 19 CH Three NHCH Three 2-633 1 1 OH OH (CH Two ) 19 CH Three N (CH Three ) Two 2-634 1 1 OH OH (CH Two ) 19 CH Three NHC (= NH) H 2-635 1 1 OH OH (CH Two ) 19 CH Three NHC (= NH) CH Three 2-636 1 1 OH OH (CH Two ) 19 CH Three NHC (= NH) CH Two CH Three 2-637 1 1 OH OH (CH Two ) 19 CH Three NHC (= NH) NH Two 2-638 1 1 HH CH Three NH Two 2-639 1 1 HH CH Three NHCH Three 2-640 1 1 HH CH Three N (CH Three ) Two 2-641 1 1 HH CH Three NHC (= NH) H 2-642 1 1 HH CH Three NHC (= NH) CH Three 2-643 1 1 HH CH Three NHC (= NH) CH Two CH Three 2-644 1 1 HH CH Three NHC (= NH) NH Two 2-645 1 1 HH CH Two CH Three NH Two 2-646 1 1 HH CH Two CH Three NHCH Three 2-647 1 1 HH CH Two CH Three N (CH Three ) Two 2-648 1 1 HH CH Two CH Three NHC (= NH) H 2-649 1 1 HH CH Two CH Three NHC (= NH) CH Three 2-650 1 1 HH CH Two CH Three NHC (= NH) CH Two CH Three 2-651 1 1 HH CH Two CH Three NHC (= NH) NH Two 2-652 1 1 HH (CH Two ) Two CH Three NH Two 2-653 1 1 HH (CH Two ) Two CH Three NHCH Three 2-654 1 1 HH (CH Two ) Two CH Three N (CH Three ) Two 2-655 1 1 HH (CH Two ) Two CH Three NHC (= NH) H 2-656 1 1 HH (CH Two ) Two CH Three NHC (= NH) CH Three 2-657 1 1 HH (CH Two ) Two CH Three NHC (= NH) CH Two CH Three 2-658 1 1 HH (CH Two ) Two CH Three NHC (= NH) NH Two 2-659 1 1 HH (CH Two ) Three CH Three NH Two 2-660 1 1 HH (CH Two ) Three CH Three NHCH Three 2-661 1 1 HH (CH Two ) Three CH Three N (CH Three ) Two 2-662 1 1 HH (CH Two ) Three CH Three NHC (= NH) H 2-663 1 1 HH (CH Two ) Three CH Three NHC (= NH) CH Three 2-664 1 1 HH (CH Two ) Three CH Three NHC (= NH) CH Two CH Three 2-665 1 1 HH (CH Two ) Three CH Three NHC (= NH) NH Two 2-666 1 1 HH (CH Two ) Four CH Three NH Two 2-667 1 1 HH (CH Two ) Four CH Three NHCH Three 2-668 1 1 HH (CH Two ) Four CH Three N (CH Three ) Two 2-669 1 1 HH (CH Two ) Four CH Three NHC (= NH) H 2-670 1 1 HH (CH Two ) Four CH Three NHC (= NH) CH Three 2-671 1 1 HH (CH Two ) Four CH Three NHC (= NH) CH Two CH Three 2-672 1 1 HH (CH Two ) Four CH Three NHC (= NH) NH Two 2-673 1 1 HH (CH Two ) Five CH Three NH Two 2-674 1 1 HH (CH Two ) Five CH Three NHCH Three 2-675 1 1 HH (CH Two ) Five CH Three N (CH Three ) Two 2-676 1 1 HH (CH Two ) Five CH Three NHC (= NH) H 2-677 1 1 HH (CH Two ) Five CH Three NHC (= NH) CH Three 2-678 1 1 HH (CH Two ) Five CH Three NHC (= NH) CH Two CH Three 2-679 1 1 HH (CH Two ) Five CH Three NHC (= NH) NH Two 2-680 1 1 HH (CH Two ) 7 CH Three NH Two 2-681 1 1 HH (CH Two ) 7 CH Three NHCH Three 2-682 1 1 HH (CH Two ) 7 CH Three N (CH Three ) Two 2-683 1 1 HH (CH Two ) 7 CH Three NHC (= NH) H 2-684 1 1 HH (CH Two ) 7 CH Three NHC (= NH) CH Three 2-685 1 1 HH (CH Two ) 7 CH Three NHC (= NH) CH Two CH Three 2-686 1 1 HH (CH Two ) 7 CH Three NHC (= NH) NH Two 2-687 1 1 HH (CH Two ) 9 CH Three NH Two 2-688 1 1 HH (CH Two ) 9 CH Three NHCH Three 2-689 1 1 HH (CH Two ) 9 CH Three N (CH Three ) Two 2-690 1 1 HH (CH Two ) 9 CH Three NHC (= NH) H 2-691 1 1 HH (CH Two ) 9 CH Three NHC (= NH) CH Three 2-692 1 1 HH (CH Two ) 9 CH Three NHC (= NH) CH Two CH Three 2-693 1 1 HH (CH Two ) 9 CH Three NHC (= NH) NH Two 2-694 1 1 HH (CH Two ) 11 CH Three NH Two 2-695 1 1 HH (CH Two ) 11 CH Three NHCH Three 2-696 1 1 HH (CH Two ) 11 CH Three N (CH Three ) Two 2-697 1 1 HH (CH Two ) 11 CH Three NHC (= NH) H 2-698 1 1 HH (CH Two ) 11 CH Three NHC (= NH) CH Three 2-699 1 1 HH (CH Two ) 11 CH Three NHC (= NH) CH Two CH Three 2-700 1 1 HH (CH Two ) 11 CH Three NHC (= NH) NH Two 2-701 1 1 HH (CH Two ) 13 CH Three NH Two 2-702 1 1 HH (CH Two ) 13 CH Three NHCH Three 2-703 1 1 HH (CH Two ) 13 CH Three N (CH Three ) Two 2-704 1 1 HH (CH Two ) 13 CH Three NHC (= NH) H 2-705 1 1 HH (CH Two ) 13 CH Three NHC (= NH) CH Three 2-706 1 1 HH (CH Two ) 13 CH Three NHC (= NH) CH Two CH Three 2-707 1 1 HH (CH Two ) 13 CH Three NHC (= NH) NH Two 2-708 1 1 HH (CH Two ) Fifteen CH Three NH Two 2-709 1 1 HH (CH Two ) Fifteen CH Three NHCH Three 2-710 1 1 HH (CH Two ) Fifteen CH Three N (CH Three ) Two 2-711 1 1 HH (CH Two ) Fifteen CH Three NHC (= NH) H 2-712 1 1 HH (CH Two ) Fifteen CH Three NHC (= NH) CH Three 2-713 1 1 HH (CH Two ) Fifteen CH Three NHC (= NH) CH Two CH Three 2-714 1 1 HH (CH Two ) Fifteen CH Three NHC (= NH) NH Two 2-715 1 1 HH (CH Two ) 17 CH Three NH Two 2-716 1 1 HH (CH Two ) 17 CH Three NHCH Three 2-717 1 1 HH (CH Two ) 17 CH Three N (CH Three ) Two 2-718 1 1 HH (CH Two ) 17 CH Three NHC (= NH) H 2-719 1 1 HH (CH Two ) 17 CH Three NHC (= NH) CH Three 2-720 1 1 HH (CH Two ) 17 CH Three NHC (= NH) CH Two CH Three 2-721 1 1 HH (CH Two ) 17 CH Three NHC (= NH) NH Two 2-722 1 1 HH (CH Two ) 19 CH Three NH Two 2-723 1 1 HH (CH Two ) 19 CH Three NHCH Three 2-724 1 1 HH (CH Two ) 19 CH Three N (CH Three ) Two 2-725 1 1 HH (CH Two ) 19 CH Three NHC (= NH) H 2-726 1 1 HH (CH Two ) 19 CH Three NHC (= NH) CH Three 2-727 1 1 HH (CH Two ) 19 CH Three NHC (= NH) CH Two CH Three 2-728 1 1 HH (CH Two ) 19 CH Three NHC (= NH) NH Two 2-729 1 2 OH OH CH Three NH Two 2-730 1 2 OH OH CH Three NHCH Three 2-731 1 2 OH OH CH Three N (CH Three ) Two 2-732 1 2 OH OH CH Three NHC (= NH) H 2-733 1 2 OH OH CH Three NHC (= NH) CH Three 2-734 1 2 OH OH CH Three NHC (= NH) CH Two CH Three 2-735 1 2 OH OH CH Three NHC (= NH) NH Two 2-736 1 2 OH OH CH Two CH Three NH Two 2-737 1 2 OH OH CH Two CH Three NHCH Three 2-738 1 2 OH OH CH Two CH Three N (CH Three ) Two 2-739 1 2 OH OH CH Two CH Three NHC (= NH) H 2-740 1 2 OH OH CH Two CH Three NHC (= NH) CH Three 2-741 1 2 OH OH CH Two CH Three NHC (= NH) CH Two CH Three 2-742 1 2 OH OH CH Two CH Three NHC (= NH) NH Two 2-743 1 2 OH OH (CH Two ) Two CH Three NH Two 2-744 1 2 OH OH (CH Two ) Two CH Three NHCH Three 2-745 1 2 OH OH (CH Two ) Two CH Three N (CH Three ) Two 2-746 1 2 OH OH (CH Two ) Two CH Three NHC (= NH) H 2-747 1 2 OH OH (CH Two ) Two CH Three NHC (= NH) CH Three 2-748 1 2 OH OH (CH Two ) Two CH Three NHC (= NH) CH Two CH Three 2-749 1 2 OH OH (CH Two ) Two CH Three NHC (= NH) NH Two 2-750 1 2 OH OH (CH Two ) Three CH Three NH Two 2-751 1 2 OH OH (CH Two ) Three CH Three NHCH Three 2-752 1 2 OH OH (CH Two ) Three CH Three N (CH Three ) Two 2-753 1 2 OH OH (CH Two ) Three CH Three NHC (= NH) H 2-754 1 2 OH OH (CH Two ) Three CH Three NHC (= NH) CH Three 2-755 1 2 OH OH (CH Two ) Three CH Three NHC (= NH) CH Two CH Three 2-756 1 2 OH OH (CH Two ) Three CH Three NHC (= NH) NH Two 2-757 1 2 OH OH (CH Two ) Four CH Three NH Two 2-758 1 2 OH OH (CH Two ) Four CH Three NHCH Three 2-759 1 2 OH OH (CH Two ) Four CH Three N (CH Three ) Two 2-760 1 2 OH OH (CH Two ) Four CH Three NHC (= NH) H 2-761 1 2 OH OH (CH Two ) Four CH Three NHC (= NH) CH Three 2-762 1 2 OH OH (CH Two ) Four CH Three NHC (= NH) CH Two CH Three 2-763 1 2 OH OH (CH Two ) Four CH Three NHC (= NH) NH Two 2-764 1 2 OH OH (CH Two ) Five CH Three NH Two 2-765 1 2 OH OH (CH Two ) Five CH Three NHCH Three 2-766 1 2 OH OH (CH Two ) Five CH Three N (CH Three ) Two 2-767 1 2 OH OH (CH Two ) Five CH Three NHC (= NH) H 2-768 12 OH OH (CH Two ) Five CH Three NHC (= NH) CH Three 2-769 1 2 OH OH (CH Two ) Five CH Three NHC (= NH) CH Two CH Three 2-770 1 2 OH OH (CH Two ) Five CH Three NHC (= NH) NH Two 2-771 1 2 OH OH (CH Two ) 7 CH Three NH Two 2-772 1 2 OH OH (CH Two ) 7 CH Three NHCH Three 2-773 1 2 OH OH (CH Two ) 7 CH Three N (CH Three ) Two 2-774 1 2 OH OH (CH Two ) 7 CH Three NHC (= NH) H 2-775 1 2 OH OH (CH Two ) 7 CH Three NHC (= NH) CH Three 2-776 1 2 OH OH (CH Two ) 7 CH Three NHC (= NH) CH Two CH Three 2-777 1 2 OH OH (CH Two ) 7 CH Three NHC (= NH) NH Two 2-778 1 2 OH OH (CH Two ) 9 CH Three NH Two 2-779 1 2 OH OH (CH Two ) 9 CH Three NHCH Three 2-780 1 2 OH OH (CH Two ) 9 CH Three N (CH Three ) Two 2-781 1 2 OH OH (CH Two ) 9 CH Three NHC (= NH) H 2-782 12 OH OH (CH Two ) 9 CH Three NHC (= NH) CH Three 2-783 1 2 OH OH (CH Two ) 9 CH Three NHC (= NH) CH Two CH Three 2-784 1 2 OH OH (CH Two ) 9 CH Three NHC (= NH) NH Two 2-785 1 2 OH OH (CH Two ) 11 CH Three NH Two 2-786 1 2 OH OH (CH Two ) 11 CH Three NHCH Three 2-787 1 2 OH OH (CH Two ) 11 CH Three N (CH Three ) Two 2-788 1 2 OH OH (CH Two ) 11 CH Three NHC (= NH) H 2-789 12 OH OH (CH Two ) 11 CH Three NHC (= NH) CH Three 2-790 1 2 OH OH (CH Two ) 11 CH Three NHC (= NH) CH Two CH Three 2-791 1 2 OH OH (CH Two ) 11 CH Three NHC (= NH) NH Two 2-792 1 2 OH OH (CH Two ) 13 CH Three NH Two 2-793 1 2 OH OH (CH Two ) 13 CH Three NHCH Three 2-794 1 2 OH OH (CH Two ) 13 CH Three N (CH Three ) Two 2-795 1 2 OH OH (CH Two ) 13 CH Three NHC (= NH) H 2-796 12 OH OH (CH Two ) 13 CH Three NHC (= NH) CH Three 2-797 1 2 OH OH (CH Two ) 13 CH Three NHC (= NH) CH Two CH Three 2-798 1 2 OH OH (CH Two ) 13 CH Three NHC (= NH) NH Two 2-799 1 2 OH OH (CH Two ) Fifteen CH Three NH Two 2-800 1 2 OH OH (CH Two ) Fifteen CH Three NHCH Three 2-801 1 2 OH OH (CH Two ) Fifteen CH Three N (CH Three ) Two 2-802 12 OH OH (CH Two ) Fifteen CH Three NHC (= NH) H 2-803 12 2 OH OH (CH Two ) Fifteen CH Three NHC (= NH) CH Three 2-804 1 2 OH OH (CH Two ) Fifteen CH Three NHC (= NH) CH Two CH Three 2-805 1 2 OH OH (CH Two ) Fifteen CH Three NHC (= NH) NH Two 2-806 1 2 OH OH (CH Two ) 17 CH Three NH Two 2-807 1 2 OH OH (CH Two ) 17 CH Three NHCH Three 2-808 1 2 OH OH (CH Two ) 17 CH Three N (CH Three ) Two 2-809 1 2 OH OH (CH Two ) 17 CH Three NHC (= NH) H 2-810 1 2 OH OH (CH Two ) 17 CH Three NHC (= NH) CH Three 2-811 1 2 OH OH (CH Two ) 17 CH Three NHC (= NH) CH Two CH Three 2-812 1 2 OH OH (CH Two ) 17 CH Three NHC (= NH) NH Two 2-813 1 2 OH OH (CH Two ) 19 CH Three NH Two 2-814 1 2 OH OH (CH Two ) 19 CH Three NHCH Three 2-815 1 2 OH OH (CH Two ) 19 CH Three N (CH Three ) Two 2-816 1 2 OH OH (CH Two ) 19 CH Three NHC (= NH) H 2-817 1 2 OH OH (CH Two ) 19 CH Three NHC (= NH) CH Three 2-818 1 2 OH OH (CH Two ) 19 CH Three NHC (= NH) CH Two CH Three 2-819 1 2 OH OH (CH Two ) 19 CH Three NHC (= NH) NH Two 2-820 1 2 HH CH Three NH Two 2-821 1 2 HH CH Three NHCH Three 2-822 1 2 HH CH Three N (CH Three ) Two 2-823 1 2 HH CH Three NHC (= NH) H 2-824 1 2 HH CH Three NHC (= NH) CH Three 2-825 1 2 HH CH Three NHC (= NH) CH Two CH Three 2-826 1 2 HH CH Three NHC (= NH) NH Two 2-827 1 2 HH CH Two CH Three NH Two 2-828 1 2 HH CH Two CH Three NHCH Three 2-829 1 2 HH CH Two CH Three N (CH Three ) Two 2-830 1 2 HH CH Two CH Three NHC (= NH) H 2-831 1 2 HH CH Two CH Three NHC (= NH) CH Three 2-832 1 2 HH CH Two CH Three NHC (= NH) CH Two CH Three 2-833 1 2 HH CH Two CH Three NHC (= NH) NH Two 2-834 1 2 HH (CH Two ) Two CH Three NH Two 2-835 1 2 HH (CH Two ) Two CH Three NHCH Three 2-836 1 2 HH (CH Two ) Two CH Three N (CH Three ) Two 2-837 1 2 HH (CH Two ) Two CH Three NHC (= NH) H 2-838 1 2 HH (CH Two ) Two CH Three NHC (= NH) CH Three 2-839 1 2 HH (CH Two ) Two CH Three NHC (= NH) CH Two CH Three 2-840 1 2 HH (CH Two ) Two CH Three NHC (= NH) NH Two 2-841 1 2 HH (CH Two ) Three CH Three NH Two 2-842 1 2 HH (CH Two ) Three CH Three NHCH Three 2-843 1 2 HH (CH Two ) Three CH Three N (CH Three ) Two 2-844 1 2 HH (CH Two ) Three CH Three NHC (= NH) H 2-845 1 2 HH (CH Two ) Three CH Three NHC (= NH) CH Three 2-846 1 2 HH (CH Two ) Three CH Three NHC (= NH) CH Two CH Three 2-847 1 2 HH (CH Two ) Three CH Three NHC (= NH) NH Two 2-848 1 2 HH (CH Two ) Four CH Three NH Two 2-849 1 2 HH (CH Two ) Four CH Three NHCH Three 2-850 1 2 HH (CH Two ) Four CH Three N (CH Three ) Two 2-851 1 2 HH (CH Two ) Four CH Three NHC (= NH) H 2-852 1 2 HH (CH Two ) Four CH Three NHC (= NH) CH Three 2-853 1 2 HH (CH Two ) Four CH Three NHC (= NH) CH Two CH Three 2-854 1 2 HH (CH Two ) Four CH Three NHC (= NH) NH Two 2-855 1 2 HH (CH Two ) Five CH Three NH Two 2-856 1 2 HH (CH Two ) Five CH Three NHCH Three 2-857 1 2 HH (CH Two ) Five CH Three N (CH Three ) Two 2-858 1 2 HH (CH Two ) Five CH Three NHC (= NH) H 2-859 1 2 HH (CH Two ) Five CH Three NHC (= NH) CH Three 2-860 1 2 HH (CH Two ) Five CH Three NHC (= NH) CH Two CH Three 2-861 1 2 HH (CH Two ) Five CH Three NHC (= NH) NH Two 2-862 1 2 HH (CH Two ) 7 CH Three NH Two 2-863 1 2 HH (CH Two ) 7 CH Three NHCH Three 2-864 1 2 HH (CH Two ) 7 CH Three N (CH Three ) Two 2-865 1 2 HH (CH Two ) 7 CH Three NHC (= NH) H 2-866 12 HH (CH Two ) 7 CH Three NHC (= NH) CH Three 2-867 1 2 HH (CH Two ) 7 CH Three NHC (= NH) CH Two CH Three 2-868 1 2 HH (CH Two ) 7 CH Three NHC (= NH) NH Two 2-869 1 2 HH (CH Two ) 9 CH Three NH Two 2-870 1 2 HH (CH Two ) 9 CH Three NHCH Three 2-871 1 2 HH (CH Two ) 9 CH Three N (CH Three ) Two 2-872 1 2 HH (CH Two ) 9 CH Three NHC (= NH) H 2-873 1 2 HH (CH Two ) 9 CH Three NHC (= NH) CH Three 2-874 1 2 HH (CH Two ) 9 CH Three NHC (= NH) CH Two CH Three 2-875 1 2 HH (CH Two ) 9 CH Three NHC (= NH) NH Two 2-876 1 2 HH (CH Two ) 11 CH Three NH Two 2-877 1 2 HH (CH Two ) 11 CH Three NHCH Three 2-878 1 2 HH (CH Two ) 11 CH Three N (CH Three ) Two 2-879 1 2 HH (CH Two ) 11 CH Three NHC (= NH) H 2-880 1 2 HH (CH Two ) 11 CH Three NHC (= NH) CH Three 2-881 1 2 HH (CH Two ) 11 CH Three NHC (= NH) CH Two CH Three 2-882 1 2 HH (CH Two ) 11 CH Three NHC (= NH) NH Two 2-883 1 2 HH (CH Two ) 13 CH Three NH Two 2-884 1 2 HH (CH Two ) 13 CH Three NHCH Three 2-885 1 2 HH (CH Two ) 13 CH Three N (CH Three ) Two 2-886 1 2 HH (CH Two ) 13 CH Three NHC (= NH) H 2-887 1 2 HH (CH Two ) 13 CH Three NHC (= NH) CH Three 2-888 1 2 HH (CH Two ) 13 CH Three NHC (= NH) CH Two CH Three 2-889 1 2 HH (CH Two ) 13 CH Three NHC (= NH) NH Two 2-890 1 2 HH (CH Two ) Fifteen CH Three NH Two 2-891 1 2 HH (CH Two ) Fifteen CH Three NHCH Three 2-892 1 2 HH (CH Two ) Fifteen CH Three N (CH Three ) Two 2-893 1 2 HH (CH Two ) Fifteen CH Three NHC (= NH) H 2-894 1 2 HH (CH Two ) Fifteen CH Three NHC (= NH) CH Three 2-895 1 2 HH (CH Two ) Fifteen CH Three NHC (= NH) CH Two CH Three 2-896 1 2 HH (CH Two ) Fifteen CH Three NHC (= NH) NH Two 2-897 1 2 HH (CH Two ) 17 CH Three NH Two 2-898 1 2 HH (CH Two ) 17 CH Three NHCH Three 2-899 1 2 HH (CH Two ) 17 CH Three N (CH Three ) Two 2-900 1 2 HH (CH Two ) 17 CH Three NHC (= NH) H 2-901 1 2 HH (CH Two ) 17 CH Three NHC (= NH) CH Three 2-902 1 2 HH (CH Two ) 17 CH Three NHC (= NH) CH Two CH Three 2-903 1 2 HH (CH Two ) 17 CH Three NHC (= NH) NH Two 2-904 1 2 HH (CH Two ) 19 CH Three NH Two 2-905 1 2 HH (CH Two ) 19 CH Three NHCH Three 2-906 1 2 HH (CH Two ) 19 CH Three N (CH Three ) Two 2-907 1 2 HH (CH Two ) 19 CH Three NHC (= NH) H 2-908 1 2 HH (CH Two ) 19 CH Three NHC (= NH) CH Three 2-909 1 2 HH (CH Two ) 19 CH Three NHC (= NH) CH Two CH Three 2-910 1 2 HH (CH Two ) 19 CH Three NHC (= NH) NH Two 2-911 2 1 OH OH CH Three NH Two 2-912 2 1 OH OH CH Three NHCH Three 2-913 2 1 OH OH CH Three N (CH Three ) Two 2-914 2 1 OH OH CH Three NHC (= NH) H 2-915 2 1 OH OH CH Three NHC (= NH) CH Three 2-916 2 1 OH OH CH Three NHC (= NH) CH Two CH Three 2-917 2 1 OH OH CH Three NHC (= NH) NH Two 2-918 2 1 OH OH CH Two CH Three NH Two 2-919 2 1 OH OH CH Two CH Three NHCH Three 2-920 2 1 OH OH CH Two CH Three N (CH Three ) Two 2-921 2 1 OH OH CH Two CH Three NHC (= NH) H 2-922 2 1 OH OH CH Two CH Three NHC (= NH) CH Three 2-923 2 1 OH OH CH Two CH Three NHC (= NH) CH Two CH Three 2-924 2 1 OH OH CH Two CH Three NHC (= NH) NH Two 2-925 2 1 OH OH (CH Two ) Two CH Three NH Two 2-926 2 1 OH OH (CH Two ) Two CH Three NHCH Three 2-927 2 1 OH OH (CH Two ) Two CH Three N (CH Three ) Two 2-928 2 1 OH OH (CH Two ) Two CH Three NHC (= NH) H 2-929 2 1 OH OH (CH Two ) Two CH Three NHC (= NH) CH Three 2-930 2 1 OH OH (CH Two ) Two CH Three NHC (= NH) CH Two CH Three 2-931 2 1 OH OH (CH Two ) Two CH Three NHC (= NH) NH Two 2-932 2 1 OH OH (CH Two ) Three CH Three NH Two 2-933 2 1 OH OH (CH Two ) Three CH Three NHCH Three 2-934 2 1 OH OH (CH Two ) Three CH Three N (CH Three ) Two 2-935 2 1 OH OH (CH Two ) Three CH Three NHC (= NH) H 2-936 2 1 OH OH (CH Two ) Three CH Three NHC (= NH) CH Three 2-937 2 1 OH OH (CH Two ) Three CH Three NHC (= NH) CH Two CH Three 2-938 2 1 OH OH (CH Two ) Three CH Three NHC (= NH) NH Two 2-939 2 1 OH OH (CH Two ) Four CH Three NH Two 2-940 2 1 OH OH (CH Two ) Four CH Three NHCH Three 2-941 2 1 OH OH (CH Two ) Four CH Three N (CH Three ) Two 2-942 2 1 OH OH (CH Two ) Four CH Three NHC (= NH) H 2-943 2 1 OH OH (CH Two ) Four CH Three NHC (= NH) CH Three 2-944 2 1 OH OH (CH Two ) Four CH Three NHC (= NH) CH Two CH Three 2-945 2 1 OH OH (CH Two ) Four CH Three NHC (= NH) NH Two 2-946 2 1 OH OH (CH Two ) Five CH Three NH Two 2-947 2 1 OH OH (CH Two ) Five CH Three NHCH Three 2-948 2 1 OH OH (CH Two ) Five CH Three N (CH Three ) Two 2-949 2 1 OH OH (CH Two ) Five CH Three NHC (= NH) H 2-950 2 1 OH OH (CH Two ) Five CH Three NHC (= NH) CH Three 2-951 2 1 OH OH (CH Two ) Five CH Three NHC (= NH) CH Two CH Three 2-952 2 1 OH OH (CH Two ) Five CH Three NHC (= NH) NH Two 2-953 2 1 OH OH (CH Two ) 7 CH Three NH Two 2-954 2 1 OH OH (CH Two ) 7 CH Three NHCH Three 2-955 2 1 OH OH (CH Two ) 7 CH Three N (CH Three ) Two 2-956 2 1 OH OH (CH Two ) 7 CH Three NHC (= NH) H 2-957 2 1 OH OH (CH Two ) 7 CH Three NHC (= NH) CH Three 2-958 2 1 OH OH (CH Two ) 7 CH Three NHC (= NH) CH Two CH Three 2-959 2 1 OH OH (CH Two ) 7 CH Three NHC (= NH) NH Two 2-960 2 1 OH OH (CH Two ) 9 CH Three NH Two 2-961 2 1 OH OH (CH Two ) 9 CH Three NHCH Three 2-962 2 1 OH OH (CH Two ) 9 CH Three N (CH Three ) Two 2-963 2 1 OH OH (CH Two ) 9 CH Three NHC (= NH) H 2-964 2 1 OH OH (CH Two ) 9 CH Three NHC (= NH) CH Three 2-965 2 1 OH OH (CH Two ) 9 CH Three NHC (= NH) CH Two CH Three 2-966 2 1 OH OH (CH Two ) 9 CH Three NHC (= NH) NH Two 2-967 2 1 OH OH (CH Two ) 11 CH Three NH Two 2-968 2 1 OH OH (CH Two ) 11 CH Three NHCH Three 2-969 2 1 OH OH (CH Two ) 11 CH Three N (CH Three ) Two 2-970 2 1 OH OH (CH Two ) 11 CH Three NHC (= NH) H 2-971 21 OH OH (CH Two ) 11 CH Three NHC (= NH) CH Three 2-972 2 1 OH OH (CH Two ) 11 CH Three NHC (= NH) CH Two CH Three 2-973 2 1 OH OH (CH Two ) 11 CH Three NHC (= NH) NH Two 2-974 2 1 OH OH (CH Two ) 13 CH Three NH Two 2-975 2 1 OH OH (CH Two ) 13 CH Three NHCH Three 2-976 2 1 OH OH (CH Two ) 13 CH Three N (CH Three ) Two 2-977 2 1 OH OH (CH Two ) 13 CH Three NHC (= NH) H 2-978 2 1 OH OH (CH Two ) 13 CH Three NHC (= NH) CH Three 2-979 2 1 OH OH (CH Two ) 13 CH Three NHC (= NH) CH Two CH Three 2-980 2 1 OH OH (CH Two ) 13 CH Three NHC (= NH) NH Two 2-981 2 1 OH OH (CH Two ) Fifteen CH Three NH Two 2-982 2 1 OH OH (CH Two ) Fifteen CH Three NHCH Three 2-983 2 1 OH OH (CH Two ) Fifteen CH Three N (CH Three ) Two 2-984 2 1 OH OH (CH Two ) Fifteen CH Three NHC (= NH) H 2-985 2 1 OH OH (CH Two ) Fifteen CH Three NHC (= NH) CH Three 2-986 2 1 OH OH (CH Two ) Fifteen CH Three NHC (= NH) CH Two CH Three 2-987 2 1 OH OH (CH Two ) Fifteen CH Three NHC (= NH) NH Two 2-988 2 1 OH OH (CH Two ) 17 CH Three NH Two 2-989 2 1 OH OH (CH Two ) 17 CH Three NHCH Three 2-990 2 1 OH OH (CH Two ) 17 CH Three N (CH Three ) Two 2-991 2 1 OH OH (CH Two ) 17 CH Three NHC (= NH) H 2-992 21 OH OH (CH Two ) 17 CH Three NHC (= NH) CH Three 2-993 2 1 OH OH (CH Two ) 17 CH Three NHC (= NH) CH Two CH Three 2-994 2 1 OH OH (CH Two ) 17 CH Three NHC (= NH) NH Two 2-995 2 1 OH OH (CH Two ) 19 CH Three NH Two 2-996 2 1 OH OH (CH Two ) 19 CH Three NHCH Three 2-997 2 1 OH OH (CH Two ) 19 CH Three N (CH Three ) Two 2-998 2 1 OH OH (CH Two ) 19 CH Three NHC (= NH) H 2-999 2 1 OH OH (CH Two ) 19 CH Three NHC (= NH) CH Three 2-1000 2 1 OH OH (CH Two ) 19 CH Three NHC (= NH) CH Two CH Three 2-1001 2 1 OH OH (CH Two ) 19 CH Three NHC (= NH) NH Two 2-1002 2 1 HH CH Three NH Two 2-1003 2 1 HH CH Three NHCH Three 2-1004 2 1 HH CH Three N (CH Three ) Two 2-1005 2 1 HH CH Three NHC (= NH) H 2-1006 2 1 HH CH Three NHC (= NH) CH Three 2-1007 2 1 HH CH Three NHC (= NH) CH Two CH Three 2-1008 2 1 HH CH Three NHC (= NH) NH Two 2-1009 2 1 HH CH Two CH Three NH Two 2-1010 2 1 HH CH Two CH Three NHCH Three 2-1011 2 1 HH CH Two CH Three N (CH Three ) Two 2-1012 2 1 HH CH Two CH Three NHC (= NH) H 2-1013 2 1 HH CH Two CH Three NHC (= NH) CH Three 2-1014 2 1 HH CH Two CH Three NHC (= NH) CH Two CH Three 2-1015 2 1 HH CH Two CH Three NHC (= NH) NH Two 2-1016 2 1 HH (CH Two ) Two CH Three NH Two 2-1017 2 1 HH (CH Two ) Two CH Three NHCH Three 2-1018 2 1 HH (CH Two ) Two CH Three N (CH Three ) Two 2-1019 2 1 HH (CH Two ) Two CH Three NHC (= NH) H 2-1020 2 1 HH (CH Two ) Two CH Three NHC (= NH) CH Three 2-1021 2 1 HH (CH Two ) Two CH Three NHC (= NH) CH Two CH Three 2-1022 2 1 HH (CH Two ) Two CH Three NHC (= NH) NH Two 2-1023 2 1 HH (CH Two ) Three CH Three NH Two 2-1024 2 1 HH (CH Two ) Three CH Three NHCH Three 2-1025 2 1 HH (CH Two ) Three CH Three N (CH Three ) Two 2-1026 2 1 HH (CH Two ) Three CH Three NHC (= NH) H 2-1027 2 1 HH (CH Two ) Three CH Three NHC (= NH) CH Three 2-1028 2 1 HH (CH Two ) Three CH Three NHC (= NH) CH Two CH Three 2-1029 2 1 HH (CH Two ) Three CH Three NHC (= NH) NH Two 2-1030 2 1 HH (CH Two ) Four CH Three NH Two 2-1031 2 1 HH (CH Two ) Four CH Three NHCH Three 2-1032 2 1 HH (CH Two ) Four CH Three N (CH Three ) Two 2-1033 2 1 HH (CH Two ) Four CH Three NHC (= NH) H 2-1034 2 1 HH (CH Two ) Four CH Three NHC (= NH) CH Three 2-1035 2 1 HH (CH Two ) Four CH Three NHC (= NH) CH Two CH Three 2-1036 2 1 HH (CH Two ) Four CH Three NHC (= NH) NH Two 2-1037 2 1 HH (CH Two ) Five CH Three NH Two 2-1038 2 1 HH (CH Two ) Five CH Three NHCH Three 2-1039 2 1 HH (CH Two ) Five CH Three N (CH Three ) Two 2-1040 2 1 HH (CH Two ) Five CH Three NHC (= NH) H 2-1041 2 1 HH (CH Two ) Five CH Three NHC (= NH) CH Three 2-1042 2 1 HH (CH Two ) Five CH Three NHC (= NH) CH Two CH Three 2-1043 2 1 HH (CH Two ) Five CH Three NHC (= NH) NH Two 2-1044 2 1 HH (CH Two ) 7 CH Three NH Two 2-1045 2 1 HH (CH Two ) 7 CH Three NHCH Three 2-1046 2 1 HH (CH Two ) 7 CH Three N (CH Three ) Two 2-1047 2 1 HH (CH Two ) 7 CH Three NHC (= NH) H 2-1048 2 1 HH (CH Two ) 7 CH Three NHC (= NH) CH Three 2-1049 2 1 HH (CH Two ) 7 CH Three NHC (= NH) CH Two CH Three 2-1050 2 1 HH (CH Two ) 7 CH Three NHC (= NH) NH Two 2-1051 2 1 HH (CH Two ) 9 CH Three NH Two 2-1052 2 1 HH (CH Two ) 9 CH Three NHCH Three 2-1053 2 1 HH (CH Two ) 9 CH Three N (CH Three ) Two 2-1054 2 1 HH (CH Two ) 9 CH Three NHC (= NH) H 2-1055 2 1 HH (CH Two ) 9 CH Three NHC (= NH) CH Three 2-1056 2 1 HH (CH Two ) 9 CH Three NHC (= NH) CH Two CH Three 2-1057 2 1 HH (CH Two ) 9 CH Three NHC (= NH) NH Two 2-1058 2 1 HH (CH Two ) 11 CH Three NH Two 2-1059 2 1 HH (CH Two ) 11 CH Three NHCH Three 2-1060 2 1 HH (CH Two ) 11 CH Three N (CH Three ) Two 2-1061 2 1 HH (CH Two ) 11 CH Three NHC (= NH) H 2-1062 2 1 HH (CH Two ) 11 CH Three NHC (= NH) CH Three 2-1063 2 1 HH (CH Two ) 11 CH Three NHC (= NH) CH Two CH Three 2-1064 2 1 HH (CH Two ) 11 CH Three NHC (= NH) NH Two 2-1065 2 1 HH (CH Two ) 13 CH Three NH Two 2-1066 2 1 HH (CH Two ) 13 CH Three NHCH Three 2-1067 2 1 HH (CH Two ) 13 CH Three N (CH Three ) Two 2-1068 2 1 HH (CH Two ) 13 CH Three NHC (= NH) H 2-1069 2 1 HH (CH Two ) 13 CH Three NHC (= NH) CH Three 2-1070 2 1 HH (CH Two ) 13 CH Three NHC (= NH) CH Two CH Three 2-1071 2 1 HH (CH Two ) 13 CH Three NHC (= NH) NH Two 2-1072 2 1 HH (CH Two ) Fifteen CH Three NH Two 2-1073 2 1 HH (CH Two ) Fifteen CH Three NHCH Three 2-1074 2 1 HH (CH Two ) Fifteen CH Three N (CH Three ) Two 2-1075 2 1 HH (CH Two ) Fifteen CH Three NHC (= NH) H 2-1076 2 1 HH (CH Two ) Fifteen CH Three NHC (= NH) CH Three 2-1077 2 1 HH (CH Two ) Fifteen CH Three NHC (= NH) CH Two CH Three 2-1078 2 1 HH (CH Two ) Fifteen CH Three NHC (= NH) NH Two 2-1079 2 1 HH (CH Two ) 17 CH Three NH Two 2-1080 2 1 HH (CH Two ) 17 CH Three NHCH Three 2-1081 2 1 HH (CH Two ) 17 CH Three N (CH Three ) Two 2-1082 2 1 HH (CH Two ) 17 CH Three NHC (= NH) H 2-1083 2 1 HH (CH Two ) 17 CH Three NHC (= NH) CH Three 2-1084 2 1 HH (CH Two ) 17 CH Three NHC (= NH) CH Two CH Three 2-1085 2 1 HH (CH Two ) 17 CH Three NHC (= NH) NH Two 2-1086 2 1 HH (CH Two ) 19 CH Three NH Two 2-1087 2 1 HH (CH Two ) 19 CH Three NHCH Three 2-1088 2 1 HH (CH Two ) 19 CH Three N (CH Three ) Two 2-1089 2 1 HH (CH Two ) 19 CH Three NHC (= NH) H 2-1090 2 1 HH (CH Two ) 19 CH Three NHC (= NH) CH Three 2-1091 2 1 HH (CH Two ) 19 CH Three NHC (= NH) CH Two CH Three 2-1092 2 1 HH (CH Two ) 19 CH Three NHC (= NH) NH Two -------------------------------------------------- ------------------- [Table 3]
【００４１】[0041]
【化６】 Embedded image
【００４２】 --------------------------------------------------------------------- Cpd.No. m n R1b R2b R10 --------------------------------------------------------------------- 3-1 0 1 CH3COO OH NH2 3-2 0 1 CH3COO OH NHCH3 3-3 0 1 CH3COO OH N(CH3)2 3-4 0 1 CH3COO OH NHC(=NH)H 3-5 0 1 CH3COO OH NHC(=NH)CH3 3-6 0 1 CH3COO OH NHC(=NH)CH2CH3 3-7 0 1 CH3COO OH NHC(=NH)NH2 3-8 0 1 CH3COO CH3COO NH2 3-9 0 1 CH3COO CH3COO NHCH3 3-10 0 1 CH3COO CH3COO N(CH3)2 3-11 0 1 CH3COO CH3COO NHC(=NH)H 3-12 0 1 CH3COO CH3COO NHC(=NH)CH3 3-13 0 1 CH3COO CH3COO NHC(=NH)CH2CH3 3-14 0 1 CH3COO CH3COO NHC(=NH)NH2 3-15 0 1 CH3CH2COO OH NH2 3-16 0 1 CH3CH2COO OH NHCH3 3-17 0 1 CH3CH2COO OH N(CH3)2 3-18 0 1 CH3CH2COO OH NHC(=NH)H 3-19 0 1 CH3CH2COO OH NHC(=NH)CH3 3-20 0 1 CH3CH2COO OH NHC(=NH)CH2CH3 3-21 0 1 CH3CH2COO OH NHC(=NH)NH2 3-22 0 1 CH3CH2COO CH3CH2COO NH2 3-23 0 1 CH3CH2COO CH3CH2COO NHCH3 3-24 0 1 CH3CH2COO CH3CH2COO N(CH3)2 3-25 0 1 CH3CH2COO CH3CH2COO NHC(=NH)H 3-26 0 1 CH3CH2COO CH3CH2COO NHC(=NH)CH3 3-27 0 1 CH3CH2COO CH3CH2COO NHC(=NH)CH2CH3 3-28 0 1 CH3CH2COO CH3CH2COO NHC(=NH)NH2 3-29 0 1 CH3(CH2)2COO OH NH2 3-30 0 1 CH3(CH2)2COO OH NHCH3 3-31 0 1 CH3(CH2)2COO OH N(CH3)2 3-32 0 1 CH3(CH2)2COO OH NHC(=NH)H 3-33 0 1 CH3(CH2)2COO OH NHC(=NH)CH3 3-34 0 1 CH3(CH2)2COO OH NHC(=NH)CH2CH3 3-35 0 1 CH3(CH2)2COO OH NHC(=NH)NH2 3-36 0 1 CH3(CH2)2COO CH3(CH2)2COO NH2 3-37 0 1 CH3(CH2)2COO CH3(CH2)2COO NHCH3 3-38 0 1 CH3(CH2)2COO CH3(CH2)2COO N(CH3)2 3-39 0 1 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)H 3-40 0 1 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)CH3 3-41 0 1 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)CH2CH3 3-42 0 1 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)NH2 3-43 0 1 CH3(CH2)3COO OH NH2 3-44 0 1 CH3(CH2)3COO OH NHCH3 3-45 0 1 CH3(CH2)3COO OH N(CH3)2 3-46 0 1 CH3(CH2)3COO OH NHC(=NH)H 3-47 0 1 CH3(CH2)3COO OH NHC(=NH)CH3 3-48 0 1 CH3(CH2)3COO OH NHC(=NH)CH2CH3 3-49 0 1 CH3(CH2)3COO OH NHC(=NH)NH2 3-50 0 1 CH3(CH2)3COO CH3(CH2)3COO NH2 3-51 0 1 CH3(CH2)3COO CH3(CH2)3COO NHCH3 3-52 0 1 CH3(CH2)3COO CH3(CH2)3COO N(CH3)2 3-53 0 1 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)H 3-54 0 1 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)CH3 3-55 0 1 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)CH2CH3 3-56 0 1 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)NH2 3-57 0 1 CH3(CH2)4COO OH NH2 3-58 0 1 CH3(CH2)4COO OH NHCH3 3-59 0 1 CH3(CH2)4COO OH N(CH3)2 3-60 0 1 CH3(CH2)4COO OH NHC(=NH)H 3-61 0 1 CH3(CH2)4COO OH NHC(=NH)CH3 3-62 0 1 CH3(CH2)4COO OH NHC(=NH)CH2CH3 3-63 0 1 CH3(CH2)4COO OH NHC(=NH)NH2 3-64 0 1 CH3(CH2)4COO CH3(CH2)4COO NH2 3-65 0 1 CH3(CH2)4COO CH3(CH2)4COO NHCH3 3-66 0 1 CH3(CH2)4COO CH3(CH2)4COO N(CH3)2 3-67 0 1 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)H 3-68 0 1 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)CH3 3-69 0 1 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)CH2CH3 3-70 0 1 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)NH2 3-71 0 1 CH3(CH2)6COO OH NH2 3-72 0 1 CH3(CH2)6COO OH NHCH3 3-73 0 1 CH3(CH2)6COO OH N(CH3)2 3-74 0 1 CH3(CH2)6COO OH NHC(=NH)H 3-75 0 1 CH3(CH2)6COO OH NHC(=NH)CH3 3-76 0 1 CH3(CH2)6COO OH NHC(=NH)CH2CH3 3-77 0 1 CH3(CH2)6COO OH NHC(=NH)NH2 3-78 0 1 CH3(CH2)6COO CH3(CH2)6COO NH2 3-79 0 1 CH3(CH2)6COO CH3(CH2)6COO NHCH3 3-80 0 1 CH3(CH2)6COO CH3(CH2)6COO N(CH3)2 3-81 0 1 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)H 3-82 0 1 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)CH3 3-83 0 1 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)CH2CH3 3-84 0 1 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)NH2 3-85 0 1 CH3(CH2)8COO OH NH2 3-86 0 1 CH3(CH2)8COO OH NHCH3 3-87 0 1 CH3(CH2)8COO OH N(CH3)2 3-88 0 1 CH3(CH2)8COO OH NHC(=NH)H 3-89 0 1 CH3(CH2)8COO OH NHC(=NH)CH3 3-90 0 1 CH3(CH2)8COO OH NHC(=NH)CH2CH3 3-91 0 1 CH3(CH2)8COO OH NHC(=NH)NH2 3-92 0 1 CH3(CH2)8COO CH3(CH2)8COO NH2 3-93 0 1 CH3(CH2)8COO CH3(CH2)8COO NHCH3 3-94 0 1 CH3(CH2)8COO CH3(CH2)8COO N(CH3)2 3-95 0 1 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)H 3-96 0 1 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)CH3 3-97 0 1 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)CH2CH3 3-98 0 1 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)NH2 3-99 0 1 CH3(CH2)10COO OH NH2 3-100 0 1 CH3(CH2)10COO OH NHCH3 3-101 0 1 CH3(CH2)10COO OH N(CH3)2 3-102 0 1 CH3(CH2)10COO OH NHC(=NH)H 3-103 0 1 CH3(CH2)10COO OH NHC(=NH)CH3 3-104 0 1 CH3(CH2)10COO OH NHC(=NH)CH2CH3 3-105 0 1 CH3(CH2)10COO OH NHC(=NH)NH2 3-106 0 1 CH3(CH2)10COO CH3(CH2)10COO NH2 3-107 0 1 CH3(CH2)10COO CH3(CH2)10COO NHCH3 3-108 0 1 CH3(CH2)10COO CH3(CH2)10COO N(CH3)2 3-109 0 1 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)H 3-110 0 1 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)CH3 3-111 0 1 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)CH2CH3 3-112 0 1 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)NH2 3-113 0 1 CH3(CH2)12COO OH NH2 3-114 0 1 CH3(CH2)12COO OH NHCH3 3-115 0 1 CH3(CH2)12COO OH N(CH3)2 3-116 0 1 CH3(CH2)12COO OH NHC(=NH)H 3-117 0 1 CH3(CH2)12COO OH NHC(=NH)CH3 3-118 0 1 CH3(CH2)12COO OH NHC(=NH)CH2CH3 3-119 0 1 CH3(CH2)12COO OH NHC(=NH)NH2 3-120 0 1 CH3(CH2)12COO CH3(CH2)12COO NH2 3-121 0 1 CH3(CH2)12COO CH3(CH2)12COO NHCH3 3-122 0 1 CH3(CH2)12COO CH3(CH2)12COO N(CH3)2 3-123 0 1 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)H 3-124 0 1 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)CH3 3-125 0 1 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)CH2CH3 3-126 0 1 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)NH2 3-127 0 1 CH3(CH2)14COO OH NH2 3-128 0 1 CH3(CH2)14COO OH NHCH3 3-129 0 1 CH3(CH2)14COO OH N(CH3)2 3-130 0 1 CH3(CH2)14COO OH NHC(=NH)H 3-131 0 1 CH3(CH2)14COO OH NHC(=NH)CH3 3-132 0 1 CH3(CH2)14COO OH NHC(=NH)CH2CH3 3-133 0 1 CH3(CH2)14COO OH NHC(=NH)NH2 3-134 0 1 CH3(CH2)14COO CH3(CH2)14COO NH2 3-135 0 1 CH3(CH2)14COO CH3(CH2)14COO NHCH3 3-136 0 1 CH3(CH2)14COO CH3(CH2)14COO N(CH3)2 3-137 0 1 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)H 3-138 0 1 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)CH3 3-139 0 1 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)CH2CH3 3-140 0 1 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)NH2 3-141 0 1 CH3(CH2)16COO OH NH2 3-142 0 1 CH3(CH2)16COO OH NHCH3 3-143 0 1 CH3(CH2)16COO OH N(CH3)2 3-144 0 1 CH3(CH2)16COO OH NHC(=NH)H 3-145 0 1 CH3(CH2)16COO OH NHC(=NH)CH3 3-146 0 1 CH3(CH2)16COO OH NHC(=NH)CH2CH3 3-147 0 1 CH3(CH2)16COO OH NHC(=NH)NH2 3-148 0 1 CH3(CH2)16COO CH3(CH2)16COO NH2 3-149 0 1 CH3(CH2)16COO CH3(CH2)16COO NHCH3 3-150 0 1 CH3(CH2)16COO CH3(CH2)16COO N(CH3)2 3-151 0 1 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)H 3-152 0 1 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)CH3 3-153 0 1 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)CH2CH3 3-154 0 1 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)NH2 3-155 0 1 CH3(CH2)18COO OH NH2 3-156 0 1 CH3(CH2)18COO OH NHCH3 3-157 0 1 CH3(CH2)18COO OH N(CH3)2 3-158 0 1 CH3(CH2)18COO OH NHC(=NH)H 3-159 0 1 CH3(CH2)18COO OH NHC(=NH)CH3 3-160 0 1 CH3(CH2)18COO OH NHC(=NH)CH2CH3 3-161 0 1 CH3(CH2)18COO OH NHC(=NH)NH2 3-162 0 1 CH3(CH2)18COO CH3(CH2)18COO NH2 3-163 0 1 CH3(CH2)18COO CH3(CH2)18COO NHCH3 3-164 0 1 CH3(CH2)18COO CH3(CH2)18COO N(CH3)2 3-165 0 1 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)H 3-166 0 1 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)CH3 3-167 0 1 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)CH2CH3 3-168 0 1 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)NH2 3-169 0 2 CH3COO OH NH2 3-170 0 2 CH3COO OH NHCH3 3-171 0 2 CH3COO OH N(CH3)2 3-172 0 2 CH3COO OH NHC(=NH)H 3-173 0 2 CH3COO OH NHC(=NH)CH3 3-174 0 2 CH3COO OH NHC(=NH)CH2CH3 3-175 0 2 CH3COO OH NHC(=NH)NH2 3-176 0 2 CH3COO CH3COO NH2 3-177 0 2 CH3COO CH3COO NHCH3 3-178 0 2 CH3COO CH3COO N(CH3)2 3-179 0 2 CH3COO CH3COO NHC(=NH)H 3-180 0 2 CH3COO CH3COO NHC(=NH)CH3 3-181 0 2 CH3COO CH3COO NHC(=NH)CH2CH3 3-182 0 2 CH3COO CH3COO NHC(=NH)NH2 3-183 0 2 CH3CH2COO OH NH2 3-184 0 2 CH3CH2COO OH NHCH3 3-185 0 2 CH3CH2COO OH N(CH3)2 3-186 0 2 CH3CH2COO OH NHC(=NH)H 3-187 0 2 CH3CH2COO OH NHC(=NH)CH3 3-188 0 2 CH3CH2COO OH NHC(=NH)CH2CH3 3-189 0 2 CH3CH2COO OH NHC(=NH)NH2 3-190 0 2 CH3CH2COO CH3CH2COO NH2 3-191 0 2 CH3CH2COO CH3CH2COO NHCH3 3-192 0 2 CH3CH2COO CH3CH2COO N(CH3)2 3-193 0 2 CH3CH2COO CH3CH2COO NHC(=NH)H 3-194 0 2 CH3CH2COO CH3CH2COO NHC(=NH)CH3 3-195 0 2 CH3CH2COO CH3CH2COO NHC(=NH)CH2CH3 3-196 0 2 CH3CH2COO CH3CH2COO NHC(=NH)NH2 3-197 0 2 CH3(CH2)2COO OH NH2 3-198 0 2 CH3(CH2)2COO OH NHCH3 3-199 0 2 CH3(CH2)2COO OH N(CH3)2 3-200 0 2 CH3(CH2)2COO OH NHC(=NH)H 3-201 0 2 CH3(CH2)2COO OH NHC(=NH)CH3 3-202 0 2 CH3(CH2)2COO OH NHC(=NH)CH2CH3 3-203 0 2 CH3(CH2)2COO OH NHC(=NH)NH2 3-204 0 2 CH3(CH2)2COO CH3(CH2)2COO NH2 3-205 0 2 CH3(CH2)2COO CH3(CH2)2COO NHCH3 3-206 0 2 CH3(CH2)2COO CH3(CH2)2COO N(CH3)2 3-207 0 2 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)H 3-208 0 2 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)CH3 3-209 0 2 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)CH2CH3 3-210 0 2 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)NH2 3-211 0 2 CH3(CH2)3COO OH NH2 3-212 0 2 CH3(CH2)3COO OH NHCH3 3-213 0 2 CH3(CH2)3COO OH N(CH3)2 3-214 0 2 CH3(CH2)3COO OH NHC(=NH)H 3-215 0 2 CH3(CH2)3COO OH NHC(=NH)CH3 3-216 0 2 CH3(CH2)3COO OH NHC(=NH)CH2CH3 3-217 0 2 CH3(CH2)3COO OH NHC(=NH)NH2 3-218 0 2 CH3(CH2)3COO CH3(CH2)3COO NH2 3-219 0 2 CH3(CH2)3COO CH3(CH2)3COO NHCH3 3-220 0 2 CH3(CH2)3COO CH3(CH2)3COO N(CH3)2 3-221 0 2 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)H 3-222 0 2 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)CH3 3-223 0 2 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)CH2CH3 3-224 0 2 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)NH2 3-225 0 2 CH3(CH2)4COO OH NH2 3-226 0 2 CH3(CH2)4COO OH NHCH3 3-227 0 2 CH3(CH2)4COO OH N(CH3)2 3-228 0 2 CH3(CH2)4COO OH NHC(=NH)H 3-229 0 2 CH3(CH2)4COO OH NHC(=NH)CH3 3-230 0 2 CH3(CH2)4COO OH NHC(=NH)CH2CH3 3-231 0 2 CH3(CH2)4COO OH NHC(=NH)NH2 3-232 0 2 CH3(CH2)4COO CH3(CH2)4COO NH2 3-233 0 2 CH3(CH2)4COO CH3(CH2)4COO NHCH3 3-234 0 2 CH3(CH2)4COO CH3(CH2)4COO N(CH3)2 3-235 0 2 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)H 3-236 0 2 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)CH3 3-237 0 2 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)CH2CH3 3-238 0 2 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)NH2 3-239 0 2 CH3(CH2)6COO OH NH2 3-240 0 2 CH3(CH2)6COO OH NHCH3 3-241 0 2 CH3(CH2)6COO OH N(CH3)2 3-242 0 2 CH3(CH2)6COO OH NHC(=NH)H 3-243 0 2 CH3(CH2)6COO OH NHC(=NH)CH3 3-244 0 2 CH3(CH2)6COO OH NHC(=NH)CH2CH3 3-245 0 2 CH3(CH2)6COO OH NHC(=NH)NH2 3-246 0 2 CH3(CH2)6COO CH3(CH2)6COO NH2 3-247 0 2 CH3(CH2)6COO CH3(CH2)6COO NHCH3 3-248 0 2 CH3(CH2)6COO CH3(CH2)6COO N(CH3)2 3-249 0 2 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)H 3-250 0 2 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)CH3 3-251 0 2 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)CH2CH3 3-252 0 2 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)NH2 3-253 0 2 CH3(CH2)8COO OH NH2 3-254 0 2 CH3(CH2)8COO OH NHCH3 3-255 0 2 CH3(CH2)8COO OH N(CH3)2 3-256 0 2 CH3(CH2)8COO OH NHC(=NH)H 3-257 0 2 CH3(CH2)8COO OH NHC(=NH)CH3 3-258 0 2 CH3(CH2)8COO OH NHC(=NH)CH2CH3 3-259 0 2 CH3(CH2)8COO OH NHC(=NH)NH2 3-260 0 2 CH3(CH2)8COO CH3(CH2)8COO NH2 3-261 0 2 CH3(CH2)8COO CH3(CH2)8COO NHCH3 3-262 0 2 CH3(CH2)8COO CH3(CH2)8COO N(CH3)2 3-263 0 2 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)H 3-264 0 2 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)CH3 3-265 0 2 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)CH2CH3 3-266 0 2 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)NH2 3-267 0 2 CH3(CH2)10COO OH NH2 3-268 0 2 CH3(CH2)10COO OH NHCH3 3-269 0 2 CH3(CH2)10COO OH N(CH3)2 3-270 0 2 CH3(CH2)10COO OH NHC(=NH)H 3-271 0 2 CH3(CH2)10COO OH NHC(=NH)CH3 3-272 0 2 CH3(CH2)10COO OH NHC(=NH)CH2CH3 3-273 0 2 CH3(CH2)10COO OH NHC(=NH)NH2 3-274 0 2 CH3(CH2)10COO CH3(CH2)10COO NH2 3-275 0 2 CH3(CH2)10COO CH3(CH2)10COO NHCH3 3-276 0 2 CH3(CH2)10COO CH3(CH2)10COO N(CH3)2 3-277 0 2 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)H 3-278 0 2 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)CH3 3-279 0 2 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)CH2CH3 3-280 0 2 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)NH2 3-281 0 2 CH3(CH2)12COO OH NH2 3-282 0 2 CH3(CH2)12COO OH NHCH3 3-283 0 2 CH3(CH2)12COO OH N(CH3)2 3-284 0 2 CH3(CH2)12COO OH NHC(=NH)H 3-285 0 2 CH3(CH2)12COO OH NHC(=NH)CH3 3-286 0 2 CH3(CH2)12COO OH NHC(=NH)CH2CH3 3-287 0 2 CH3(CH2)12COO OH NHC(=NH)NH2 3-288 0 2 CH3(CH2)12COO CH3(CH2)12COO NH2 3-289 0 2 CH3(CH2)12COO CH3(CH2)12COO NHCH3 3-290 0 2 CH3(CH2)12COO CH3(CH2)12COO N(CH3)2 3-291 0 2 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)H 3-292 0 2 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)CH3 3-293 0 2 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)CH2CH3 3-294 0 2 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)NH2 3-295 0 2 CH3(CH2)14COO OH NH2 3-296 0 2 CH3(CH2)14COO OH NHCH3 3-297 0 2 CH3(CH2)14COO OH N(CH3)2 3-298 0 2 CH3(CH2)14COO OH NHC(=NH)H 3-299 0 2 CH3(CH2)14COO OH NHC(=NH)CH3 3-300 0 2 CH3(CH2)14COO OH NHC(=NH)CH2CH3 3-301 0 2 CH3(CH2)14COO OH NHC(=NH)NH2 3-302 0 2 CH3(CH2)14COO CH3(CH2)14COO NH2 3-303 0 2 CH3(CH2)14COO CH3(CH2)14COO NHCH3 3-304 0 2 CH3(CH2)14COO CH3(CH2)14COO N(CH3)2 3-305 0 2 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)H 3-306 0 2 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)CH3 3-307 0 2 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)CH2CH3 3-308 0 2 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)NH2 3-309 0 2 CH3(CH2)16COO OH NH2 3-310 0 2 CH3(CH2)16COO OH NHCH3 3-311 0 2 CH3(CH2)16COO OH N(CH3)2 3-312 0 2 CH3(CH2)16COO OH NHC(=NH)H 3-313 0 2 CH3(CH2)16COO OH NHC(=NH)CH3 3-314 0 2 CH3(CH2)16COO OH NHC(=NH)CH2CH3 3-315 0 2 CH3(CH2)16COO OH NHC(=NH)NH2 3-316 0 2 CH3(CH2)16COO CH3(CH2)16COO NH2 3-317 0 2 CH3(CH2)16COO CH3(CH2)16COO NHCH3 3-318 0 2 CH3(CH2)16COO CH3(CH2)16COO N(CH3)2 3-319 0 2 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)H 3-320 0 2 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)CH3 3-321 0 2 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)CH2CH3 3-322 0 2 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)NH2 3-323 0 2 CH3(CH2)18COO OH NH2 3-324 0 2 CH3(CH2)18COO OH NHCH3 3-325 0 2 CH3(CH2)18COO OH N(CH3)2 3-326 0 2 CH3(CH2)18COO OH NHC(=NH)H 3-327 0 2 CH3(CH2)18COO OH NHC(=NH)CH3 3-328 0 2 CH3(CH2)18COO OH NHC(=NH)CH2CH3 3-329 0 2 CH3(CH2)18COO OH NHC(=NH)NH2 3-330 0 2 CH3(CH2)18COO CH3(CH2)18COO NH2 3-331 0 2 CH3(CH2)18COO CH3(CH2)18COO NHCH3 3-332 0 2 CH3(CH2)18COO CH3(CH2)18COO N(CH3)2 3-333 0 2 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)H 3-334 0 2 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)CH3 3-335 0 2 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)CH2CH3 3-336 0 2 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)NH2 3-337 0 3 CH3COO OH NH2 3-338 0 3 CH3COO OH NHCH3 3-339 0 3 CH3COO OH N(CH3)2 3-340 0 3 CH3COO OH NHC(=NH)H 3-341 0 3 CH3COO OH NHC(=NH)CH3 3-342 0 3 CH3COO OH NHC(=NH)CH2CH3 3-343 0 3 CH3COO OH NHC(=NH)NH2 3-344 0 3 CH3COO CH3COO NH2 3-345 0 3 CH3COO CH3COO NHCH3 3-346 0 3 CH3COO CH3COO N(CH3)2 3-347 0 3 CH3COO CH3COO NHC(=NH)H 3-348 0 3 CH3COO CH3COO NHC(=NH)CH3 3-349 0 3 CH3COO CH3COO NHC(=NH)CH2CH3 3-350 0 3 CH3COO CH3COO NHC(=NH)NH2 3-351 0 3 CH3CH2COO OH NH2 3-352 0 3 CH3CH2COO OH NHCH3 3-353 0 3 CH3CH2COO OH N(CH3)2 3-354 0 3 CH3CH2COO OH NHC(=NH)H 3-355 0 3 CH3CH2COO OH NHC(=NH)CH3 3-356 0 3 CH3CH2COO OH NHC(=NH)CH2CH3 3-357 0 3 CH3CH2COO OH NHC(=NH)NH2 3-358 0 3 CH3CH2COO CH3CH2COO NH2 3-359 0 3 CH3CH2COO CH3CH2COO NHCH3 3-360 0 3 CH3CH2COO CH3CH2COO N(CH3)2 3-361 0 3 CH3CH2COO CH3CH2COO NHC(=NH)H 3-362 0 3 CH3CH2COO CH3CH2COO NHC(=NH)CH3 3-363 0 3 CH3CH2COO CH3CH2COO NHC(=NH)CH2CH3 3-364 0 3 CH3CH2COO CH3CH2COO NHC(=NH)NH2 3-365 0 3 CH3(CH2)2COO OH NH2 3-366 0 3 CH3(CH2)2COO OH NHCH3 3-367 0 3 CH3(CH2)2COO OH N(CH3)2 3-368 0 3 CH3(CH2)2COO OH NHC(=NH)H 3-369 0 3 CH3(CH2)2COO OH NHC(=NH)CH3 3-370 0 3 CH3(CH2)2COO OH NHC(=NH)CH2CH3 3-371 0 3 CH3(CH2)2COO OH NHC(=NH)NH2 3-372 0 3 CH3(CH2)2COO CH3(CH2)2COO NH2 3-373 0 3 CH3(CH2)2COO CH3(CH2)2COO NHCH3 3-374 0 3 CH3(CH2)2COO CH3(CH2)2COO N(CH3)2 3-375 0 3 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)H 3-376 0 3 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)CH3 3-377 0 3 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)CH2CH3 3-378 0 3 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)NH2 3-379 0 3 CH3(CH2)3COO OH NH2 3-380 0 3 CH3(CH2)3COO OH NHCH3 3-381 0 3 CH3(CH2)3COO OH N(CH3)2 3-382 0 3 CH3(CH2)3COO OH NHC(=NH)H 3-383 0 3 CH3(CH2)3COO OH NHC(=NH)CH3 3-384 0 3 CH3(CH2)3COO OH NHC(=NH)CH2CH3 3-385 0 3 CH3(CH2)3COO OH NHC(=NH)NH2 3-386 0 3 CH3(CH2)3COO CH3(CH2)3COO NH2 3-387 0 3 CH3(CH2)3COO CH3(CH2)3COO NHCH3 3-388 0 3 CH3(CH2)3COO CH3(CH2)3COO N(CH3)2 3-389 0 3 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)H 3-390 0 3 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)CH3 3-391 0 3 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)CH2CH3 3-392 0 3 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)NH2 3-393 0 3 CH3(CH2)4COO OH NH2 3-394 0 3 CH3(CH2)4COO OH NHCH3 3-395 0 3 CH3(CH2)4COO OH N(CH3)2 3-396 0 3 CH3(CH2)4COO OH NHC(=NH)H 3-397 0 3 CH3(CH2)4COO OH NHC(=NH)CH3 3-398 0 3 CH3(CH2)4COO OH NHC(=NH)CH2CH3 3-399 0 3 CH3(CH2)4COO OH NHC(=NH)NH2 3-400 0 3 CH3(CH2)4COO CH3(CH2)4COO NH2 3-401 0 3 CH3(CH2)4COO CH3(CH2)4COO NHCH3 3-402 0 3 CH3(CH2)4COO CH3(CH2)4COO N(CH3)2 3-403 0 3 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)H 3-404 0 3 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)CH3 3-405 0 3 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)CH2CH3 3-406 0 3 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)NH2 3-407 0 3 CH3(CH2)6COO OH NH2 3-408 0 3 CH3(CH2)6COO OH NHCH3 3-409 0 3 CH3(CH2)6COO OH N(CH3)2 3-410 0 3 CH3(CH2)6COO OH NHC(=NH)H 3-411 0 3 CH3(CH2)6COO OH NHC(=NH)CH3 3-412 0 3 CH3(CH2)6COO OH NHC(=NH)CH2CH3 3-413 0 3 CH3(CH2)6COO OH NHC(=NH)NH2 3-414 0 3 CH3(CH2)6COO CH3(CH2)6COO NH2 3-415 0 3 CH3(CH2)6COO CH3(CH2)6COO NHCH3 3-416 0 3 CH3(CH2)6COO CH3(CH2)6COO N(CH3)2 3-417 0 3 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)H 3-418 0 3 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)CH3 3-419 0 3 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)CH2CH3 3-420 0 3 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)NH2 3-421 0 3 CH3(CH2)8COO OH NH2 3-422 0 3 CH3(CH2)8COO OH NHCH3 3-423 0 3 CH3(CH2)8COO OH N(CH3)2 3-424 0 3 CH3(CH2)8COO OH NHC(=NH)H 3-425 0 3 CH3(CH2)8COO OH NHC(=NH)CH3 3-426 0 3 CH3(CH2)8COO OH NHC(=NH)CH2CH3 3-427 0 3 CH3(CH2)8COO OH NHC(=NH)NH2 3-428 0 3 CH3(CH2)8COO CH3(CH2)8COO NH2 3-429 0 3 CH3(CH2)8COO CH3(CH2)8COO NHCH3 3-430 0 3 CH3(CH2)8COO CH3(CH2)8COO N(CH3)2 3-431 0 3 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)H 3-432 0 3 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)CH3 3-433 0 3 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)CH2CH3 3-434 0 3 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)NH2 3-435 0 3 CH3(CH2)10COO OH NH2 3-436 0 3 CH3(CH2)10COO OH NHCH3 3-437 0 3 CH3(CH2)10COO OH N(CH3)2 3-438 0 3 CH3(CH2)10COO OH NHC(=NH)H 3-439 0 3 CH3(CH2)10COO OH NHC(=NH)CH3 3-440 0 3 CH3(CH2)10COO OH NHC(=NH)CH2CH3 3-441 0 3 CH3(CH2)10COO OH NHC(=NH)NH2 3-442 0 3 CH3(CH2)10COO CH3(CH2)10COO NH2 3-443 0 3 CH3(CH2)10COO CH3(CH2)10COO NHCH3 3-444 0 3 CH3(CH2)10COO CH3(CH2)10COO N(CH3)2 3-445 0 3 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)H 3-446 0 3 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)CH3 3-447 0 3 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)CH2CH3 3-448 0 3 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)NH2 3-449 0 3 CH3(CH2)12COO OH NH2 3-450 0 3 CH3(CH2)12COO OH NHCH3 3-451 0 3 CH3(CH2)12COO OH N(CH3)2 3-452 0 3 CH3(CH2)12COO OH NHC(=NH)H 3-453 0 3 CH3(CH2)12COO OH NHC(=NH)CH3 3-454 0 3 CH3(CH2)12COO OH NHC(=NH)CH2CH3 3-455 0 3 CH3(CH2)12COO OH NHC(=NH)NH2 3-456 0 3 CH3(CH2)12COO CH3(CH2)12COO NH2 3-457 0 3 CH3(CH2)12COO CH3(CH2)12COO NHCH3 3-458 0 3 CH3(CH2)12COO CH3(CH2)12COO N(CH3)2 3-459 0 3 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)H 3-460 0 3 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)CH3 3-461 0 3 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)CH2CH3 3-462 0 3 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)NH2 3-463 0 3 CH3(CH2)14COO OH NH2 3-464 0 3 CH3(CH2)14COO OH NHCH3 3-465 0 3 CH3(CH2)14COO OH N(CH3)2 3-466 0 3 CH3(CH2)14COO OH NHC(=NH)H 3-467 0 3 CH3(CH2)14COO OH NHC(=NH)CH3 3-468 0 3 CH3(CH2)14COO OH NHC(=NH)CH2CH3 3-469 0 3 CH3(CH2)14COO OH NHC(=NH)NH2 3-470 0 3 CH3(CH2)14COO CH3(CH2)14COO NH2 3-471 0 3 CH3(CH2)14COO CH3(CH2)14COO NHCH3 3-472 0 3 CH3(CH2)14COO CH3(CH2)14COO N(CH3)2 3-473 0 3 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)H 3-474 0 3 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)CH3 3-475 0 3 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)CH2CH3 3-476 0 3 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)NH2 3-477 0 3 CH3(CH2)16COO OH NH2 3-478 0 3 CH3(CH2)16COO OH NHCH3 3-479 0 3 CH3(CH2)16COO OH N(CH3)2 3-480 0 3 CH3(CH2)16COO OH NHC(=NH)H 3-481 0 3 CH3(CH2)16COO OH NHC(=NH)CH3 3-482 0 3 CH3(CH2)16COO OH NHC(=NH)CH2CH3 3-483 0 3 CH3(CH2)16COO OH NHC(=NH)NH2 3-484 0 3 CH3(CH2)16COO CH3(CH2)16COO NH2 3-485 0 3 CH3(CH2)16COO CH3(CH2)16COO NHCH3 3-486 0 3 CH3(CH2)16COO CH3(CH2)16COO N(CH3)2 3-487 0 3 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)H 3-488 0 3 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)CH3 3-489 0 3 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)CH2CH3 3-490 0 3 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)NH2 3-491 0 3 CH3(CH2)18COO OH NH2 3-492 0 3 CH3(CH2)18COO OH NHCH3 3-493 0 3 CH3(CH2)18COO OH N(CH3)2 3-494 0 3 CH3(CH2)18COO OH NHC(=NH)H 3-495 0 3 CH3(CH2)18COO OH NHC(=NH)CH3 3-496 0 3 CH3(CH2)18COO OH NHC(=NH)CH2CH3 3-497 0 3 CH3(CH2)18COO OH NHC(=NH)NH2 3-498 0 3 CH3(CH2)18COO CH3(CH2)18COO NH2 3-499 0 3 CH3(CH2)18COO CH3(CH2)18COO NHCH3 3-500 0 3 CH3(CH2)18COO CH3(CH2)18COO N(CH3)2 3-501 0 3 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)H 3-502 0 3 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)CH3 3-503 0 3 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)CH2CH3 3-504 0 3 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)NH2 3-505 1 1 CH3COO OH NH2 3-506 1 1 CH3COO OH NHCH3 3-507 1 1 CH3COO OH N(CH3)2 3-508 1 1 CH3COO OH NHC(=NH)H 3-509 1 1 CH3COO OH NHC(=NH)CH3 3-510 1 1 CH3COO OH NHC(=NH)CH2CH3 3-511 1 1 CH3COO OH NHC(=NH)NH2 3-512 1 1 CH3COO CH3COO NH2 3-513 1 1 CH3COO CH3COO NHCH3 3-514 1 1 CH3COO CH3COO N(CH3)2 3-515 1 1 CH3COO CH3COO NHC(=NH)H 3-516 1 1 CH3COO CH3COO NHC(=NH)CH3 3-517 1 1 CH3COO CH3COO NHC(=NH)CH2CH3 3-518 1 1 CH3COO CH3COO NHC(=NH)NH2 3-519 1 1 CH3CH2COO OH NH2 3-520 1 1 CH3CH2COO OH NHCH3 3-521 1 1 CH3CH2COO OH N(CH3)2 3-522 1 1 CH3CH2COO OH NHC(=NH)H 3-523 1 1 CH3CH2COO OH NHC(=NH)CH3 3-524 1 1 CH3CH2COO OH NHC(=NH)CH2CH3 3-525 1 1 CH3CH2COO OH NHC(=NH)NH2 3-526 1 1 CH3CH2COO CH3CH2COO NH2 3-527 1 1 CH3CH2COO CH3CH2COO NHCH3 3-528 1 1 CH3CH2COO CH3CH2COO N(CH3)2 3-529 1 1 CH3CH2COO CH3CH2COO NHC(=NH)H 3-530 1 1 CH3CH2COO CH3CH2COO NHC(=NH)CH3 3-531 1 1 CH3CH2COO CH3CH2COO NHC(=NH)CH2CH3 3-532 1 1 CH3CH2COO CH3CH2COO NHC(=NH)NH2 3-533 1 1 CH3(CH2)2COO OH NH2 3-534 1 1 CH3(CH2)2COO OH NHCH3 3-535 1 1 CH3(CH2)2COO OH N(CH3)2 3-536 1 1 CH3(CH2)2COO OH NHC(=NH)H 3-537 1 1 CH3(CH2)2COO OH NHC(=NH)CH3 3-538 1 1 CH3(CH2)2COO OH NHC(=NH)CH2CH3 3-539 1 1 CH3(CH2)2COO OH NHC(=NH)NH2 3-540 1 1 CH3(CH2)2COO CH3(CH2)2COO NH2 3-541 1 1 CH3(CH2)2COO CH3(CH2)2COO NHCH3 3-542 1 1 CH3(CH2)2COO CH3(CH2)2COO N(CH3)2 3-543 1 1 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)H 3-544 1 1 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)CH3 3-545 1 1 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)CH2CH3 3-546 1 1 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)NH2 3-547 1 1 CH3(CH2)3COO OH NH2 3-548 1 1 CH3(CH2)3COO OH NHCH3 3-549 1 1 CH3(CH2)3COO OH N(CH3)2 3-550 1 1 CH3(CH2)3COO OH NHC(=NH)H 3-551 1 1 CH3(CH2)3COO OH NHC(=NH)CH3 3-552 1 1 CH3(CH2)3COO OH NHC(=NH)CH2CH3 3-553 1 1 CH3(CH2)3COO OH NHC(=NH)NH2 3-554 1 1 CH3(CH2)3COO CH3(CH2)3COO NH2 3-555 1 1 CH3(CH2)3COO CH3(CH2)3COO NHCH3 3-556 1 1 CH3(CH2)3COO CH3(CH2)3COO N(CH3)2 3-557 1 1 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)H 3-558 1 1 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)CH3 3-559 1 1 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)CH2CH3 3-560 1 1 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)NH2 3-561 1 1 CH3(CH2)4COO OH NH2 3-562 1 1 CH3(CH2)4COO OH NHCH3 3-563 1 1 CH3(CH2)4COO OH N(CH3)2 3-564 1 1 CH3(CH2)4COO OH NHC(=NH)H 3-565 1 1 CH3(CH2)4COO OH NHC(=NH)CH3 3-566 1 1 CH3(CH2)4COO OH NHC(=NH)CH2CH3 3-567 1 1 CH3(CH2)4COO OH NHC(=NH)NH2 3-568 1 1 CH3(CH2)4COO CH3(CH2)4COO NH2 3-569 1 1 CH3(CH2)4COO CH3(CH2)4COO NHCH3 3-570 1 1 CH3(CH2)4COO CH3(CH2)4COO N(CH3)2 3-571 1 1 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)H 3-572 1 1 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)CH3 3-573 1 1 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)CH2CH3 3-574 1 1 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)NH2 3-575 1 1 CH3(CH2)6COO OH NH2 3-576 1 1 CH3(CH2)6COO OH NHCH3 3-577 1 1 CH3(CH2)6COO OH N(CH3)2 3-578 1 1 CH3(CH2)6COO OH NHC(=NH)H 3-579 1 1 CH3(CH2)6COO OH NHC(=NH)CH3 3-580 1 1 CH3(CH2)6COO OH NHC(=NH)CH2CH3 3-581 1 1 CH3(CH2)6COO OH NHC(=NH)NH2 3-582 1 1 CH3(CH2)6COO CH3(CH2)6COO NH2 3-583 1 1 CH3(CH2)6COO CH3(CH2)6COO NHCH3 3-584 1 1 CH3(CH2)6COO CH3(CH2)6COO N(CH3)2 3-585 1 1 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)H 3-586 1 1 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)CH3 3-587 1 1 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)CH2CH3 3-588 1 1 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)NH2 3-589 1 1 CH3(CH2)8COO OH NH2 3-590 1 1 CH3(CH2)8COO OH NHCH3 3-591 1 1 CH3(CH2)8COO OH N(CH3)2 3-592 1 1 CH3(CH2)8COO OH NHC(=NH)H 3-593 1 1 CH3(CH2)8COO OH NHC(=NH)CH3 3-594 1 1 CH3(CH2)8COO OH NHC(=NH)CH2CH3 3-595 1 1 CH3(CH2)8COO OH NHC(=NH)NH2 3-596 1 1 CH3(CH2)8COO CH3(CH2)8COO NH2 3-597 1 1 CH3(CH2)8COO CH3(CH2)8COO NHCH3 3-598 1 1 CH3(CH2)8COO CH3(CH2)8COO N(CH3)2 3-599 1 1 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)H 3-600 1 1 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)CH3 3-601 1 1 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)CH2CH3 3-602 1 1 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)NH2 3-603 1 1 CH3(CH2)10COO OH NH2 3-604 1 1 CH3(CH2)10COO OH NHCH3 3-605 1 1 CH3(CH2)10COO OH N(CH3)2 3-606 1 1 CH3(CH2)10COO OH NHC(=NH)H 3-607 1 1 CH3(CH2)10COO OH NHC(=NH)CH3 3-608 1 1 CH3(CH2)10COO OH NHC(=NH)CH2CH3 3-609 1 1 CH3(CH2)10COO OH NHC(=NH)NH2 3-610 1 1 CH3(CH2)10COO CH3(CH2)10COO NH2 3-611 1 1 CH3(CH2)10COO CH3(CH2)10COO NHCH3 3-612 1 1 CH3(CH2)10COO CH3(CH2)10COO N(CH3)2 3-613 1 1 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)H 3-614 1 1 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)CH3 3-615 1 1 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)CH2CH3 3-616 1 1 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)NH2 3-617 1 1 CH3(CH2)12COO OH NH2 3-618 1 1 CH3(CH2)12COO OH NHCH3 3-619 1 1 CH3(CH2)12COO OH N(CH3)2 3-620 1 1 CH3(CH2)12COO OH NHC(=NH)H 3-621 1 1 CH3(CH2)12COO OH NHC(=NH)CH3 3-622 1 1 CH3(CH2)12COO OH NHC(=NH)CH2CH3 3-623 1 1 CH3(CH2)12COO OH NHC(=NH)NH2 3-624 1 1 CH3(CH2)12COO CH3(CH2)12COO NH2 3-625 1 1 CH3(CH2)12COO CH3(CH2)12COO NHCH3 3-626 1 1 CH3(CH2)12COO CH3(CH2)12COO N(CH3)2 3-627 1 1 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)H 3-628 1 1 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)CH3 3-629 1 1 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)CH2CH3 3-630 1 1 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)NH2 3-631 1 1 CH3(CH2)14COO OH NH2 3-632 1 1 CH3(CH2)14COO OH NHCH3 3-633 1 1 CH3(CH2)14COO OH N(CH3)2 3-634 1 1 CH3(CH2)14COO OH NHC(=NH)H 3-635 1 1 CH3(CH2)14COO OH NHC(=NH)CH3 3-636 1 1 CH3(CH2)14COO OH NHC(=NH)CH2CH3 3-637 1 1 CH3(CH2)14COO OH NHC(=NH)NH2 3-638 1 1 CH3(CH2)14COO CH3(CH2)14COO NH2 3-639 1 1 CH3(CH2)14COO CH3(CH2)14COO NHCH3 3-640 1 1 CH3(CH2)14COO CH3(CH2)14COO N(CH3)2 3-641 1 1 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)H 3-642 1 1 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)CH3 3-643 1 1 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)CH2CH3 3-644 1 1 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)NH2 3-645 1 1 CH3(CH2)16COO OH NH2 3-646 1 1 CH3(CH2)16COO OH NHCH3 3-647 1 1 CH3(CH2)16COO OH N(CH3)2 3-648 1 1 CH3(CH2)16COO OH NHC(=NH)H 3-649 1 1 CH3(CH2)16COO OH NHC(=NH)CH3 3-650 1 1 CH3(CH2)16COO OH NHC(=NH)CH2CH3 3-651 1 1 CH3(CH2)16COO OH NHC(=NH)NH2 3-652 1 1 CH3(CH2)16COO CH3(CH2)16COO NH2 3-653 1 1 CH3(CH2)16COO CH3(CH2)16COO NHCH3 3-654 1 1 CH3(CH2)16COO CH3(CH2)16COO N(CH3)2 3-655 1 1 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)H 3-656 1 1 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)CH3 3-657 1 1 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)CH2CH3 3-658 1 1 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)NH2 3-659 1 1 CH3(CH2)18COO OH NH2 3-660 1 1 CH3(CH2)18COO OH NHCH3 3-661 1 1 CH3(CH2)18COO OH N(CH3)2 3-662 1 1 CH3(CH2)18COO OH NHC(=NH)H 3-663 1 1 CH3(CH2)18COO OH NHC(=NH)CH3 3-664 1 1 CH3(CH2)18COO OH NHC(=NH)CH2CH3 3-665 1 1 CH3(CH2)18COO OH NHC(=NH)NH2 3-666 1 1 CH3(CH2)18COO CH3(CH2)18COO NH2 3-667 1 1 CH3(CH2)18COO CH3(CH2)18COO NHCH3 3-668 1 1 CH3(CH2)18COO CH3(CH2)18COO N(CH3)2 3-669 1 1 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)H 3-670 1 1 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)CH3 3-671 1 1 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)CH2CH3 3-672 1 1 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)NH2 3-673 1 2 CH3COO OH NH2 3-674 1 2 CH3COO OH NHCH3 3-675 1 2 CH3COO OH N(CH3)2 3-676 1 2 CH3COO OH NHC(=NH)H 3-677 1 2 CH3COO OH NHC(=NH)CH3 3-678 1 2 CH3COO OH NHC(=NH)CH2CH3 3-679 1 2 CH3COO OH NHC(=NH)NH2 3-680 1 2 CH3COO CH3COO NH2 3-681 1 2 CH3COO CH3COO NHCH3 3-682 1 2 CH3COO CH3COO N(CH3)2 3-683 1 2 CH3COO CH3COO NHC(=NH)H 3-684 1 2 CH3COO CH3COO NHC(=NH)CH3 3-685 1 2 CH3COO CH3COO NHC(=NH)CH2CH3 3-686 1 2 CH3COO CH3COO NHC(=NH)NH2 3-687 1 2 CH3CH2COO OH NH2 3-688 1 2 CH3CH2COO OH NHCH3 3-689 1 2 CH3CH2COO OH N(CH3)2 3-690 1 2 CH3CH2COO OH NHC(=NH)H 3-691 1 2 CH3CH2COO OH NHC(=NH)CH3 3-692 1 2 CH3CH2COO OH NHC(=NH)CH2CH3 3-693 1 2 CH3CH2COO OH NHC(=NH)NH2 3-694 1 2 CH3CH2COO CH3CH2COO NH2 3-695 1 2 CH3CH2COO CH3CH2COO NHCH3 3-696 1 2 CH3CH2COO CH3CH2COO N(CH3)2 3-697 1 2 CH3CH2COO CH3CH2COO NHC(=NH)H 3-698 1 2 CH3CH2COO CH3CH2COO NHC(=NH)CH3 3-699 1 2 CH3CH2COO CH3CH2COO NHC(=NH)CH2CH3 3-700 1 2 CH3CH2COO CH3CH2COO NHC(=NH)NH2 3-701 1 2 CH3(CH2)2COO OH NH2 3-702 1 2 CH3(CH2)2COO OH NHCH3 3-703 1 2 CH3(CH2)2COO OH N(CH3)2 3-704 1 2 CH3(CH2)2COO OH NHC(=NH)H 3-705 1 2 CH3(CH2)2COO OH NHC(=NH)CH3 3-706 1 2 CH3(CH2)2COO OH NHC(=NH)CH2CH3 3-707 1 2 CH3(CH2)2COO OH NHC(=NH)NH2 3-708 1 2 CH3(CH2)2COO CH3(CH2)2COO NH2 3-709 1 2 CH3(CH2)2COO CH3(CH2)2COO NHCH3 3-710 1 2 CH3(CH2)2COO CH3(CH2)2COO N(CH3)2 3-711 1 2 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)H 3-712 1 2 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)CH3 3-713 1 2 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)CH2CH3 3-714 1 2 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)NH2 3-715 1 2 CH3(CH2)3COO OH NH2 3-716 1 2 CH3(CH2)3COO OH NHCH3 3-717 1 2 CH3(CH2)3COO OH N(CH3)2 3-718 1 2 CH3(CH2)3COO OH NHC(=NH)H 3-719 1 2 CH3(CH2)3COO OH NHC(=NH)CH3 3-720 1 2 CH3(CH2)3COO OH NHC(=NH)CH2CH3 3-721 1 2 CH3(CH2)3COO OH NHC(=NH)NH2 3-722 1 2 CH3(CH2)3COO CH3(CH2)3COO NH2 3-723 1 2 CH3(CH2)3COO CH3(CH2)3COO NHCH3 3-724 1 2 CH3(CH2)3COO CH3(CH2)3COO N(CH3)2 3-725 1 2 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)H 3-726 1 2 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)CH3 3-727 1 2 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)CH2CH3 3-728 1 2 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)NH2 3-729 1 2 CH3(CH2)4COO OH NH2 3-730 1 2 CH3(CH2)4COO OH NHCH3 3-731 1 2 CH3(CH2)4COO OH N(CH3)2 3-732 1 2 CH3(CH2)4COO OH NHC(=NH)H 3-733 1 2 CH3(CH2)4COO OH NHC(=NH)CH3 3-734 1 2 CH3(CH2)4COO OH NHC(=NH)CH2CH3 3-735 1 2 CH3(CH2)4COO OH NHC(=NH)NH2 3-736 1 2 CH3(CH2)4COO CH3(CH2)4COO NH2 3-737 1 2 CH3(CH2)4COO CH3(CH2)4COO NHCH3 3-738 1 2 CH3(CH2)4COO CH3(CH2)4COO N(CH3)2 3-739 1 2 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)H 3-740 1 2 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)CH3 3-741 1 2 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)CH2CH3 3-742 1 2 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)NH2 3-743 1 2 CH3(CH2)6COO OH NH2 3-744 1 2 CH3(CH2)6COO OH NHCH3 3-745 1 2 CH3(CH2)6COO OH N(CH3)2 3-746 1 2 CH3(CH2)6COO OH NHC(=NH)H 3-747 1 2 CH3(CH2)6COO OH NHC(=NH)CH3 3-748 1 2 CH3(CH2)6COO OH NHC(=NH)CH2CH3 3-749 1 2 CH3(CH2)6COO OH NHC(=NH)NH2 3-750 1 2 CH3(CH2)6COO CH3(CH2)6COO NH2 3-751 1 2 CH3(CH2)6COO CH3(CH2)6COO NHCH3 3-752 1 2 CH3(CH2)6COO CH3(CH2)6COO N(CH3)2 3-753 1 2 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)H 3-754 1 2 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)CH3 3-755 1 2 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)CH2CH3 3-756 1 2 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)NH2 3-757 1 2 CH3(CH2)8COO OH NH2 3-758 1 2 CH3(CH2)8COO OH NHCH3 3-759 1 2 CH3(CH2)8COO OH N(CH3)2 3-760 1 2 CH3(CH2)8COO OH NHC(=NH)H 3-761 1 2 CH3(CH2)8COO OH NHC(=NH)CH3 3-762 1 2 CH3(CH2)8COO OH NHC(=NH)CH2CH3 3-763 1 2 CH3(CH2)8COO OH NHC(=NH)NH2 3-764 1 2 CH3(CH2)8COO CH3(CH2)8COO NH2 3-765 1 2 CH3(CH2)8COO CH3(CH2)8COO NHCH3 3-766 1 2 CH3(CH2)8COO CH3(CH2)8COO N(CH3)2 3-767 1 2 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)H 3-768 1 2 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)CH3 3-769 1 2 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)CH2CH3 3-770 1 2 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)NH2 3-771 1 2 CH3(CH2)10COO OH NH2 3-772 1 2 CH3(CH2)10COO OH NHCH3 3-773 1 2 CH3(CH2)10COO OH N(CH3)2 3-774 1 2 CH3(CH2)10COO OH NHC(=NH)H 3-775 1 2 CH3(CH2)10COO OH NHC(=NH)CH3 3-776 1 2 CH3(CH2)10COO OH NHC(=NH)CH2CH3 3-777 1 2 CH3(CH2)10COO OH NHC(=NH)NH2 3-778 1 2 CH3(CH2)10COO CH3(CH2)10COO NH2 3-779 1 2 CH3(CH2)10COO CH3(CH2)10COO NHCH3 3-780 1 2 CH3(CH2)10COO CH3(CH2)10COO N(CH3)2 3-781 1 2 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)H 3-782 1 2 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)CH3 3-783 1 2 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)CH2CH3 3-784 1 2 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)NH2 3-785 1 2 CH3(CH2)12COO OH NH2 3-786 1 2 CH3(CH2)12COO OH NHCH3 3-787 1 2 CH3(CH2)12COO OH N(CH3)2 3-788 1 2 CH3(CH2)12COO OH NHC(=NH)H 3-789 1 2 CH3(CH2)12COO OH NHC(=NH)CH3 3-790 1 2 CH3(CH2)12COO OH NHC(=NH)CH2CH3 3-791 1 2 CH3(CH2)12COO OH NHC(=NH)NH2 3-792 1 2 CH3(CH2)12COO CH3(CH2)12COO NH2 3-793 1 2 CH3(CH2)12COO CH3(CH2)12COO NHCH3 3-794 1 2 CH3(CH2)12COO CH3(CH2)12COO N(CH3)2 3-795 1 2 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)H 3-796 1 2 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)CH3 3-797 1 2 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)CH2CH3 3-798 1 2 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)NH2 3-799 1 2 CH3(CH2)14COO OH NH2 3-800 1 2 CH3(CH2)14COO OH NHCH3 3-801 1 2 CH3(CH2)14COO OH N(CH3)2 3-802 1 2 CH3(CH2)14COO OH NHC(=NH)H 3-803 1 2 CH3(CH2)14COO OH NHC(=NH)CH3 3-804 1 2 CH3(CH2)14COO OH NHC(=NH)CH2CH3 3-805 1 2 CH3(CH2)14COO OH NHC(=NH)NH2 3-806 1 2 CH3(CH2)14COO CH3(CH2)14COO NH2 3-807 1 2 CH3(CH2)14COO CH3(CH2)14COO NHCH3 3-808 1 2 CH3(CH2)14COO CH3(CH2)14COO N(CH3)2 3-809 1 2 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)H 3-810 1 2 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)CH3 3-811 1 2 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)CH2CH3 3-812 1 2 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)NH2 3-813 1 2 CH3(CH2)16COO OH NH2 3-814 1 2 CH3(CH2)16COO OH NHCH3 3-815 1 2 CH3(CH2)16COO OH N(CH3)2 3-816 1 2 CH3(CH2)16COO OH NHC(=NH)H 3-817 1 2 CH3(CH2)16COO OH NHC(=NH)CH3 3-818 1 2 CH3(CH2)16COO OH NHC(=NH)CH2CH3 3-819 1 2 CH3(CH2)16COO OH NHC(=NH)NH2 3-820 1 2 CH3(CH2)16COO CH3(CH2)16COO NH2 3-821 1 2 CH3(CH2)16COO CH3(CH2)16COO NHCH3 3-822 1 2 CH3(CH2)16COO CH3(CH2)16COO N(CH3)2 3-823 1 2 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)H 3-824 1 2 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)CH3 3-825 1 2 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)CH2CH3 3-826 1 2 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)NH2 3-827 1 2 CH3(CH2)18COO OH NH2 3-828 1 2 CH3(CH2)18COO OH NHCH3 3-829 1 2 CH3(CH2)18COO OH N(CH3)2 3-830 1 2 CH3(CH2)18COO OH NHC(=NH)H 3-831 1 2 CH3(CH2)18COO OH NHC(=NH)CH3 3-832 1 2 CH3(CH2)18COO OH NHC(=NH)CH2CH3 3-833 1 2 CH3(CH2)18COO OH NHC(=NH)NH2 3-834 1 2 CH3(CH2)18COO CH3(CH2)18COO NH2 3-835 1 2 CH3(CH2)18COO CH3(CH2)18COO NHCH3 3-836 1 2 CH3(CH2)18COO CH3(CH2)18COO N(CH3)2 3-837 1 2 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)H 3-838 1 2 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)CH3 3-839 1 2 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)CH2CH3 3-840 1 2 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)NH2 3-841 2 1 CH3COO OH NH2 3-842 2 1 CH3COO OH NHCH3 3-843 2 1 CH3COO OH N(CH3)2 3-844 2 1 CH3COO OH NHC(=NH)H 3-845 2 1 CH3COO OH NHC(=NH)CH3 3-846 2 1 CH3COO OH NHC(=NH)CH2CH3 3-847 2 1 CH3COO OH NHC(=NH)NH2 3-848 2 1 CH3COO CH3COO NH2 3-849 2 1 CH3COO CH3COO NHCH3 3-850 2 1 CH3COO CH3COO N(CH3)2 3-851 2 1 CH3COO CH3COO NHC(=NH)H 3-852 2 1 CH3COO CH3COO NHC(=NH)CH3 3-853 2 1 CH3COO CH3COO NHC(=NH)CH2CH3 3-854 2 1 CH3COO CH3COO NHC(=NH)NH2 3-855 2 1 CH3CH2COO OH NH2 3-856 2 1 CH3CH2COO OH NHCH3 3-857 2 1 CH3CH2COO OH N(CH3)2 3-858 2 1 CH3CH2COO OH NHC(=NH)H 3-859 2 1 CH3CH2COO OH NHC(=NH)CH3 3-860 2 1 CH3CH2COO OH NHC(=NH)CH2CH3 3-861 2 1 CH3CH2COO OH NHC(=NH)NH2 3-862 2 1 CH3CH2COO CH3CH2COO NH2 3-863 2 1 CH3CH2COO CH3CH2COO NHCH3 3-864 2 1 CH3CH2COO CH3CH2COO N(CH3)2 3-865 2 1 CH3CH2COO CH3CH2COO NHC(=NH)H 3-866 2 1 CH3CH2COO CH3CH2COO NHC(=NH)CH3 3-867 2 1 CH3CH2COO CH3CH2COO NHC(=NH)CH2CH3 3-868 2 1 CH3CH2COO CH3CH2COO NHC(=NH)NH2 3-869 2 1 CH3(CH2)2COO OH NH2 3-870 2 1 CH3(CH2)2COO OH NHCH3 3-871 2 1 CH3(CH2)2COO OH N(CH3)2 3-872 2 1 CH3(CH2)2COO OH NHC(=NH)H 3-873 2 1 CH3(CH2)2COO OH NHC(=NH)CH3 3-874 2 1 CH3(CH2)2COO OH NHC(=NH)CH2CH3 3-875 2 1 CH3(CH2)2COO OH NHC(=NH)NH2 3-876 2 1 CH3(CH2)2COO CH3(CH2)2COO NH2 3-877 2 1 CH3(CH2)2COO CH3(CH2)2COO NHCH3 3-878 2 1 CH3(CH2)2COO CH3(CH2)2COO N(CH3)2 3-879 2 1 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)H 3-880 2 1 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)CH3 3-881 2 1 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)CH2CH3 3-882 2 1 CH3(CH2)2COO CH3(CH2)2COO NHC(=NH)NH2 3-883 2 1 CH3(CH2)3COO OH NH2 3-884 2 1 CH3(CH2)3COO OH NHCH3 3-885 2 1 CH3(CH2)3COO OH N(CH3)2 3-886 2 1 CH3(CH2)3COO OH NHC(=NH)H 3-887 2 1 CH3(CH2)3COO OH NHC(=NH)CH3 3-888 2 1 CH3(CH2)3COO OH NHC(=NH)CH2CH3 3-889 2 1 CH3(CH2)3COO OH NHC(=NH)NH2 3-890 2 1 CH3(CH2)3COO CH3(CH2)3COO NH2 3-891 2 1 CH3(CH2)3COO CH3(CH2)3COO NHCH3 3-892 2 1 CH3(CH2)3COO CH3(CH2)3COO N(CH3)2 3-893 2 1 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)H 3-894 2 1 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)CH3 3-895 2 1 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)CH2CH3 3-896 2 1 CH3(CH2)3COO CH3(CH2)3COO NHC(=NH)NH2 3-897 2 1 CH3(CH2)4COO OH NH2 3-898 2 1 CH3(CH2)4COO OH NHCH3 3-899 2 1 CH3(CH2)4COO OH N(CH3)2 3-900 2 1 CH3(CH2)4COO OH NHC(=NH)H 3-901 2 1 CH3(CH2)4COO OH NHC(=NH)CH3 3-902 2 1 CH3(CH2)4COO OH NHC(=NH)CH2CH3 3-903 2 1 CH3(CH2)4COO OH NHC(=NH)NH2 3-904 2 1 CH3(CH2)4COO CH3(CH2)4COO NH2 3-905 2 1 CH3(CH2)4COO CH3(CH2)4COO NHCH3 3-906 2 1 CH3(CH2)4COO CH3(CH2)4COO N(CH3)2 3-907 2 1 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)H 3-908 2 1 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)CH3 3-909 2 1 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)CH2CH3 3-910 2 1 CH3(CH2)4COO CH3(CH2)4COO NHC(=NH)NH2 3-911 2 1 CH3(CH2)6COO OH NH2 3-912 2 1 CH3(CH2)6COO OH NHCH3 3-913 2 1 CH3(CH2)6COO OH N(CH3)2 3-914 2 1 CH3(CH2)6COO OH NHC(=NH)H 3-915 2 1 CH3(CH2)6COO OH NHC(=NH)CH3 3-916 2 1 CH3(CH2)6COO OH NHC(=NH)CH2CH3 3-917 2 1 CH3(CH2)6COO OH NHC(=NH)NH2 3-918 2 1 CH3(CH2)6COO CH3(CH2)6COO NH2 3-919 2 1 CH3(CH2)6COO CH3(CH2)6COO NHCH3 3-920 2 1 CH3(CH2)6COO CH3(CH2)6COO N(CH3)2 3-921 2 1 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)H 3-922 2 1 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)CH3 3-923 2 1 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)CH2CH3 3-924 2 1 CH3(CH2)6COO CH3(CH2)6COO NHC(=NH)NH2 3-925 2 1 CH3(CH2)8COO OH NH2 3-926 2 1 CH3(CH2)8COO OH NHCH3 3-927 2 1 CH3(CH2)8COO OH N(CH3)2 3-928 2 1 CH3(CH2)8COO OH NHC(=NH)H 3-929 2 1 CH3(CH2)8COO OH NHC(=NH)CH3 3-930 2 1 CH3(CH2)8COO OH NHC(=NH)CH2CH3 3-931 2 1 CH3(CH2)8COO OH NHC(=NH)NH2 3-932 2 1 CH3(CH2)8COO CH3(CH2)8COO NH2 3-933 2 1 CH3(CH2)8COO CH3(CH2)8COO NHCH3 3-934 2 1 CH3(CH2)8COO CH3(CH2)8COO N(CH3)2 3-935 2 1 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)H 3-936 2 1 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)CH3 3-937 2 1 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)CH2CH3 3-938 2 1 CH3(CH2)8COO CH3(CH2)8COO NHC(=NH)NH2 3-939 2 1 CH3(CH2)10COO OH NH2 3-940 2 1 CH3(CH2)10COO OH NHCH3 3-941 2 1 CH3(CH2)10COO OH N(CH3)2 3-942 2 1 CH3(CH2)10COO OH NHC(=NH)H 3-943 2 1 CH3(CH2)10COO OH NHC(=NH)CH3 3-944 2 1 CH3(CH2)10COO OH NHC(=NH)CH2CH3 3-945 2 1 CH3(CH2)10COO OH NHC(=NH)NH2 3-946 2 1 CH3(CH2)10COO CH3(CH2)10COO NH2 3-947 2 1 CH3(CH2)10COO CH3(CH2)10COO NHCH3 3-948 2 1 CH3(CH2)10COO CH3(CH2)10COO N(CH3)2 3-949 2 1 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)H 3-950 2 1 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)CH3 3-951 2 1 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)CH2CH3 3-952 2 1 CH3(CH2)10COO CH3(CH2)10COO NHC(=NH)NH2 3-953 2 1 CH3(CH2)12COO OH NH2 3-954 2 1 CH3(CH2)12COO OH NHCH3 3-955 2 1 CH3(CH2)12COO OH N(CH3)2 3-956 2 1 CH3(CH2)12COO OH NHC(=NH)H 3-957 2 1 CH3(CH2)12COO OH NHC(=NH)CH3 3-958 2 1 CH3(CH2)12COO OH NHC(=NH)CH2CH3 3-959 2 1 CH3(CH2)12COO OH NHC(=NH)NH2 3-960 2 1 CH3(CH2)12COO CH3(CH2)12COO NH2 3-961 2 1 CH3(CH2)12COO CH3(CH2)12COO NHCH3 3-962 2 1 CH3(CH2)12COO CH3(CH2)12COO N(CH3)2 3-963 2 1 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)H 3-964 2 1 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)CH3 3-965 2 1 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)CH2CH3 3-966 2 1 CH3(CH2)12COO CH3(CH2)12COO NHC(=NH)NH2 3-967 2 1 CH3(CH2)14COO OH NH2 3-968 2 1 CH3(CH2)14COO OH NHCH3 3-969 2 1 CH3(CH2)14COO OH N(CH3)2 3-970 2 1 CH3(CH2)14COO OH NHC(=NH)H 3-971 2 1 CH3(CH2)14COO OH NHC(=NH)CH3 3-972 2 1 CH3(CH2)14COO OH NHC(=NH)CH2CH3 3-973 2 1 CH3(CH2)14COO OH NHC(=NH)NH2 3-974 2 1 CH3(CH2)14COO CH3(CH2)14COO NH2 3-975 2 1 CH3(CH2)14COO CH3(CH2)14COO NHCH3 3-976 2 1 CH3(CH2)14COO CH3(CH2)14COO N(CH3)2 3-977 2 1 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)H 3-978 2 1 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)CH3 3-979 2 1 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)CH2CH3 3-980 2 1 CH3(CH2)14COO CH3(CH2)14COO NHC(=NH)NH2 3-981 2 1 CH3(CH2)16COO OH NH2 3-982 2 1 CH3(CH2)16COO OH NHCH3 3-983 2 1 CH3(CH2)16COO OH N(CH3)2 3-984 2 1 CH3(CH2)16COO OH NHC(=NH)H 3-985 2 1 CH3(CH2)16COO OH NHC(=NH)CH3 3-986 2 1 CH3(CH2)16COO OH NHC(=NH)CH2CH3 3-987 2 1 CH3(CH2)16COO OH NHC(=NH)NH2 3-988 2 1 CH3(CH2)16COO CH3(CH2)16COO NH2 3-989 2 1 CH3(CH2)16COO CH3(CH2)16COO NHCH3 3-990 2 1 CH3(CH2)16COO CH3(CH2)16COO N(CH3)2 3-991 2 1 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)H 3-992 2 1 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)CH3 3-993 2 1 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)CH2CH3 3-994 2 1 CH3(CH2)16COO CH3(CH2)16COO NHC(=NH)NH2 3-995 2 1 CH3(CH2)18COO OH NH2 3-996 2 1 CH3(CH2)18COO OH NHCH3 3-997 2 1 CH3(CH2)18COO OH N(CH3)2 3-998 2 1 CH3(CH2)18COO OH NHC(=NH)H 3-999 2 1 CH3(CH2)18COO OH NHC(=NH)CH3 3-1000 2 1 CH3(CH2)18COO OH NHC(=NH)CH2CH3 3-1001 2 1 CH3(CH2)18COO OH NHC(=NH)NH2 3-1002 2 1 CH3(CH2)18COO CH3(CH2)18COO NH2 3-1003 2 1 CH3(CH2)18COO CH3(CH2)18COO NHCH3 3-1004 2 1 CH3(CH2)18COO CH3(CH2)18COO N(CH3)2 3-1005 2 1 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)H 3-1006 2 1 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)CH3 3-1007 2 1 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)CH2CH3 3-1008 2 1 CH3(CH2)18COO CH3(CH2)18COO NHC(=NH)NH2 --------------------------------------------------------------------- 表１乃至３に例示した本発明の化合物およびその薬理上
許容される誘導体のうち、好適には化合物番号１−７、
１−１２、１−１４、１−２８、２−２８、２−３５、
２−４２、２−４９、２−５６、２−６３、２−７０、
２−７７、２−８４、２−９１、２−２１０、２−２１
７、２−２２４、２−２３１、２−２３８、２−２４
５、２−２５２、２−２５９、２−２６６、２−２７
３、２−３９２、２−３９９、２−４０６、２−４１
３、２−４２０、２−４２７、２−４３４、２−４４
１、２−４４８、２−４５５、３−７、３−２１、３−
１８９、３−１７５、３−１８２、３−３４３、３−３
５７の化合物であり、更に好適には下記の化合物であ
る。----------------------------------------------- ---------------------- Cpd.No.mn R 1b R 2b R Ten -------------------------------------------------- ------------------- 3-1 0 1 CH Three COO OH NH Two 3-2 0 1 CH Three COO OH NHCH Three 3-3 0 1 CH Three COO OH N (CH Three ) Two 3-4 0 1 CH Three COO OH NHC (= NH) H 3-5 0 1 CH Three COO OH NHC (= NH) CH Three 3-6 0 1 CH Three COO OH NHC (= NH) CH Two CH Three 3-7 0 1 CH Three COO OH NHC (= NH) NH Two 3-8 0 1 CH Three COO CH Three COO NH Two 3-9 0 1 CH Three COO CH Three COO NHCH Three 3-10 0 1 CH Three COO CH Three COON (CH Three ) Two 3-11 0 1 CH Three COO CH Three COO NHC (= NH) H 3-12 0 1 CH Three COO CH Three COO NHC (= NH) CH Three 3-13 0 1 CH Three COO CH Three COO NHC (= NH) CH Two CH Three 3-14 0 1 CH Three COO CH Three COO NHC (= NH) NH Two 3-15 0 1 CH Three CH Two COO OH NH Two 3-16 0 1 CH Three CH Two COO OH NHCH Three 3-17 0 1 CH Three CH Two COO OH N (CH Three ) Two 3-18 0 1 CH Three CH Two COO OH NHC (= NH) H 3-19 0 1 CH Three CH Two COO OH NHC (= NH) CH Three 3-20 0 1 CH Three CH Two COO OH NHC (= NH) CH Two CH Three 3-21 0 1 CH Three CH Two COO OH NHC (= NH) NH Two 3-22 0 1 CH Three CH Two COO CH Three CH Two COO NH Two 3-23 0 1 CH Three CH Two COO CH Three CH Two COO NHCH Three 3-24 0 1 CH Three CH Two COO CH Three CH Two COON (CH Three ) Two 3-25 0 1 CH Three CH Two COO CH Three CH Two COO NHC (= NH) H 3-26 0 1 CH Three CH Two COO CH Three CH Two COO NHC (= NH) CH Three 3-27 0 1 CH Three CH Two COO CH Three CH Two COO NHC (= NH) CH Two CH Three 3-28 0 1 CH Three CH Two COO CH Three CH Two COO NHC (= NH) NH Two 3-29 0 1 CH Three (CH Two ) Two COO OH NH Two 3-30 0 1 CH Three (CH Two ) Two COO OH NHCH Three 3-31 0 1 CH Three (CH Two ) Two COO OH N (CH Three ) Two 3-32 0 1 CH Three (CH Two ) Two COO OH NHC (= NH) H 3-33 0 1 CH Three (CH Two ) Two COO OH NHC (= NH) CH Three 3-34 0 1 CH Three (CH Two ) Two COO OH NHC (= NH) CH Two CH Three 3-35 0 1 CH Three (CH Two ) Two COO OH NHC (= NH) NH Two 3-36 0 1 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NH Two 3-37 0 1 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHCH Three 3-38 0 1 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COON (CH Three ) Two 3-39 0 1 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) H 3-40 0 1 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) CH Three 3-41 0 1 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) CH Two CH Three 3-42 0 1 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) NH Two 3-43 0 1 CH Three (CH Two ) Three COO OH NH Two 3-44 0 1 CH Three (CH Two ) Three COO OH NHCH Three 3-45 0 1 CH Three (CH Two ) Three COO OH N (CH Three ) Two 3-46 0 1 CH Three (CH Two ) Three COO OH NHC (= NH) H 3-47 0 1 CH Three (CH Two ) Three COO OH NHC (= NH) CH Three 3-48 0 1 CH Three (CH Two ) Three COO OH NHC (= NH) CH Two CH Three 3-49 0 1 CH Three (CH Two ) Three COO OH NHC (= NH) NH Two 3-50 0 1 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NH Two 3-51 0 1 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHCH Three 3-52 0 1 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COON (CH Three ) Two 3-53 0 1 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) H 3-54 0 1 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) CH Three 3-55 0 1 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) CH Two CH Three 3-56 0 1 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) NH Two 3-57 0 1 CH Three (CH Two ) Four COO OH NH Two 3-58 0 1 CH Three (CH Two ) Four COO OH NHCH Three 3-59 0 1 CH Three (CH Two ) Four COO OH N (CH Three ) Two 3-60 0 1 CH Three (CH Two ) Four COO OH NHC (= NH) H 3-61 0 1 CH Three (CH Two ) Four COO OH NHC (= NH) CH Three 3-62 0 1 CH Three (CH Two ) Four COO OH NHC (= NH) CH Two CH Three 3-63 0 1 CH Three (CH Two ) Four COO OH NHC (= NH) NH Two 3-64 0 1 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NH Two 3-65 0 1 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHCH Three 3-66 0 1 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COON (CH Three ) Two 3-67 0 1 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) H 3-68 0 1 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) CH Three 3-69 0 1 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) CH Two CH Three 3-70 0 1 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) NH Two 3-71 0 1 CH Three (CH Two ) 6 COO OH NH Two 3-72 0 1 CH Three (CH Two ) 6 COO OH NHCH Three 3-73 0 1 CH Three (CH Two ) 6 COO OH N (CH Three ) Two 3-74 0 1 CH Three (CH Two ) 6 COO OH NHC (= NH) H 3-75 0 1 CH Three (CH Two ) 6 COO OH NHC (= NH) CH Three 3-76 0 1 CH Three (CH Two ) 6 COO OH NHC (= NH) CH Two CH Three 3-77 0 1 CH Three (CH Two ) 6 COO OH NHC (= NH) NH Two 3-78 0 1 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NH Two 3-79 0 1 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHCH Three 3-80 0 1 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COON (CH Three ) Two 3-81 0 1 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) H 3-82 0 1 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) CH Three 3-83 0 1 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) CH Two CH Three 3-84 0 1 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) NH Two 3-85 0 1 CH Three (CH Two ) 8 COO OH NH Two 3-86 0 1 CH Three (CH Two ) 8 COO OH NHCH Three 3-87 0 1 CH Three (CH Two ) 8 COO OH N (CH Three ) Two 3-88 0 1 CH Three (CH Two ) 8 COO OH NHC (= NH) H 3-89 0 1 CH Three (CH Two ) 8 COO OH NHC (= NH) CH Three 3-90 0 1 CH Three (CH Two ) 8 COO OH NHC (= NH) CH Two CH Three 3-91 0 1 CH Three (CH Two ) 8 COO OH NHC (= NH) NH Two 3-92 0 1 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NH Two 3-93 0 1 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHCH Three 3-94 0 1 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COON (CH Three ) Two 3-95 0 1 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) H 3-96 0 1 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) CH Three 3-97 0 1 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) CH Two CH Three 3-98 0 1 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) NH Two 3-99 0 1 CH Three (CH Two ) Ten COO OH NH Two 3-100 0 1 CH Three (CH Two ) Ten COO OH NHCH Three 3-101 0 1 CH Three (CH Two ) Ten COO OH N (CH Three ) Two 3-102 0 1 CH Three (CH Two ) Ten COO OH NHC (= NH) H 3-103 0 1 CH Three (CH Two ) Ten COO OH NHC (= NH) CH Three 3-104 0 1 CH Three (CH Two ) Ten COO OH NHC (= NH) CH Two CH Three 3-105 0 1 CH Three (CH Two ) Ten COO OH NHC (= NH) NH Two 3-106 0 1 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NH Two 3-107 0 1 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHCH Three 3-108 0 1 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COON (CH Three ) Two 3-109 0 1 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) H 3-110 0 1 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) CH Three 3-111 0 1 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) CH Two CH Three 3-112 0 1 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) NH Two 3-113 0 1 CH Three (CH Two ) 12 COO OH NH Two 3-114 0 1 CH Three (CH Two ) 12 COO OH NHCH Three 3-115 0 1 CH Three (CH Two ) 12 COO OH N (CH Three ) Two 3-116 0 1 CH Three (CH Two ) 12 COO OH NHC (= NH) H 3-117 0 1 CH Three (CH Two ) 12 COO OH NHC (= NH) CH Three 3-118 0 1 CH Three (CH Two ) 12 COO OH NHC (= NH) CH Two CH Three 3-119 0 1 CH Three (CH Two ) 12 COO OH NHC (= NH) NH Two 3-120 0 1 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NH Two 3-121 0 1 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHCH Three 3-122 0 1 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COON (CH Three ) Two 3-123 0 1 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) H 3-124 0 1 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) CH Three 3-125 0 1 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) CH Two CH Three 3-126 0 1 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) NH Two 3-127 0 1 CH Three (CH Two ) 14 COO OH NH Two 3-128 0 1 CH Three (CH Two ) 14 COO OH NHCH Three 3-129 0 1 CH Three (CH Two ) 14 COO OH N (CH Three ) Two 3-130 0 1 CH Three (CH Two ) 14 COO OH NHC (= NH) H 3-131 0 1 CH Three (CH Two ) 14 COO OH NHC (= NH) CH Three 3-132 0 1 CH Three (CH Two ) 14 COO OH NHC (= NH) CH Two CH Three 3-133 0 1 CH Three (CH Two ) 14 COO OH NHC (= NH) NH Two 3-134 0 1 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NH Two 3-135 0 1 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHCH Three 3-136 0 1 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COON (CH Three ) Two 3-137 0 1 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) H 3-138 0 1 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) CH Three 3-139 0 1 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) CH Two CH Three 3-140 0 1 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) NH Two 3-141 0 1 CH Three (CH Two ) 16 COO OH NH Two 3-142 0 1 CH Three (CH Two ) 16 COO OH NHCH Three 3-143 0 1 CH Three (CH Two ) 16 COO OH N (CH Three ) Two 3-144 0 1 CH Three (CH Two ) 16 COO OH NHC (= NH) H 3-145 0 1 CH Three (CH Two ) 16 COO OH NHC (= NH) CH Three 3-146 0 1 CH Three (CH Two ) 16 COO OH NHC (= NH) CH Two CH Three 3-147 0 1 CH Three (CH Two ) 16 COO OH NHC (= NH) NH Two 3-148 0 1 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NH Two 3-149 0 1 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHCH Three 3-150 0 1 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COON (CH Three ) Two 3-151 0 1 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) H 3-152 0 1 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) CH Three 3-153 0 1 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) CH Two CH Three 3-154 0 1 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) NH Two 3-155 0 1 CH Three (CH Two ) 18 COO OH NH Two 3-156 0 1 CH Three (CH Two ) 18 COO OH NHCH Three 3-157 0 1 CH Three (CH Two ) 18 COO OH N (CH Three ) Two 3-158 0 1 CH Three (CH Two ) 18 COO OH NHC (= NH) H 3-159 0 1 CH Three (CH Two ) 18 COO OH NHC (= NH) CH Three 3-160 0 1 CH Three (CH Two ) 18 COO OH NHC (= NH) CH Two CH Three 3-161 0 1 CH Three (CH Two ) 18 COO OH NHC (= NH) NH Two 3-162 0 1 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NH Two 3-163 0 1 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHCH Three 3-164 0 1 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COON (CH Three ) Two 3-165 0 1 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) H 3-166 0 1 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) CH Three 3-167 0 1 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) CH Two CH Three 3-168 0 1 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) NH Two 3-169 0 2 CH Three COO OH NH Two 3-170 0 2 CH Three COO OH NHCH Three 3-171 0 2 CH Three COO OH N (CH Three ) Two 3-172 0 2 CH Three COO OH NHC (= NH) H 3-173 0 2 CH Three COO OH NHC (= NH) CH Three 3-174 0 2 CH Three COO OH NHC (= NH) CH Two CH Three 3-175 0 2 CH Three COO OH NHC (= NH) NH Two 3-176 0 2 CH Three COO CH Three COO NH Two 3-177 0 2 CH Three COO CH Three COO NHCH Three 3-178 0 2 CH Three COO CH Three COON (CH Three ) Two 3-179 0 2 CH Three COO CH Three COO NHC (= NH) H 3-180 0 2 CH Three COO CH Three COO NHC (= NH) CH Three 3-181 0 2 CH Three COO CH Three COO NHC (= NH) CH Two CH Three 3-182 0 2 CH Three COO CH Three COO NHC (= NH) NH Two 3-183 0 2 CH Three CH Two COO OH NH Two 3-184 0 2 CH Three CH Two COO OH NHCH Three 3-185 0 2 CH Three CH Two COO OH N (CH Three ) Two 3-186 0 2 CH Three CH Two COO OH NHC (= NH) H 3-187 0 2 CH Three CH Two COO OH NHC (= NH) CH Three 3-188 0 2 CH Three CH Two COO OH NHC (= NH) CH Two CH Three 3-189 0 2 CH Three CH Two COO OH NHC (= NH) NH Two 3-190 0 2 CH Three CH Two COO CH Three CH Two COO NH Two 3-191 0 2 CH Three CH Two COO CH Three CH Two COO NHCH Three 3-192 0 2 CH Three CH Two COO CH Three CH Two COON (CH Three ) Two 3-193 0 2 CH Three CH Two COO CH Three CH Two COO NHC (= NH) H 3-194 0 2 CH Three CH Two COO CH Three CH Two COO NHC (= NH) CH Three 3-195 0 2 CH Three CH Two COO CH Three CH Two COO NHC (= NH) CH Two CH Three 3-196 0 2 CH Three CH Two COO CH Three CH Two COO NHC (= NH) NH Two 3-197 0 2 CH Three (CH Two ) Two COO OH NH Two 3-198 0 2 CH Three (CH Two ) Two COO OH NHCH Three 3-199 0 2 CH Three (CH Two ) Two COO OH N (CH Three ) Two 3-200 0 2 CH Three (CH Two ) Two COO OH NHC (= NH) H 3-201 0 2 CH Three (CH Two ) Two COO OH NHC (= NH) CH Three 3-202 0 2 CH Three (CH Two ) Two COO OH NHC (= NH) CH Two CH Three 3-203 0 2 CH Three (CH Two ) Two COO OH NHC (= NH) NH Two 3-204 0 2 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NH Two 3-205 0 2 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHCH Three 3-206 0 2 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COON (CH Three ) Two 3-207 0 2 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) H 3-208 0 2 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) CH Three 3-209 0 2 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) CH Two CH Three 3-210 0 2 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) NH Two 3-211 0 2 CH Three (CH Two ) Three COO OH NH Two 3-212 0 2 CH Three (CH Two ) Three COO OH NHCH Three 3-213 0 2 CH Three (CH Two ) Three COO OH N (CH Three ) Two 3-214 0 2 CH Three (CH Two ) Three COO OH NHC (= NH) H 3-215 0 2 CH Three (CH Two ) Three COO OH NHC (= NH) CH Three 3-216 0 2 CH Three (CH Two ) Three COO OH NHC (= NH) CH Two CH Three 3-217 0 2 CH Three (CH Two ) Three COO OH NHC (= NH) NH Two 3-218 0 2 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NH Two 3-219 0 2 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHCH Three 3-220 0 2 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COON (CH Three ) Two 3-221 0 2 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) H 3-222 0 2 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) CH Three 3-223 0 2 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) CH Two CH Three 3-224 0 2 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) NH Two 3-225 0 2 CH Three (CH Two ) Four COO OH NH Two 3-226 0 2 CH Three (CH Two ) Four COO OH NHCH Three 3-227 0 2 CH Three (CH Two ) Four COO OH N (CH Three ) Two 3-228 0 2 CH Three (CH Two ) Four COO OH NHC (= NH) H 3-229 0 2 CH Three (CH Two ) Four COO OH NHC (= NH) CH Three 3-230 0 2 CH Three (CH Two ) Four COO OH NHC (= NH) CH Two CH Three 3-231 0 2 CH Three (CH Two ) Four COO OH NHC (= NH) NH Two 3-232 0 2 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NH Two 3-233 0 2 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHCH Three 3-234 0 2 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COON (CH Three ) Two 3-235 0 2 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) H 3-236 0 2 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) CH Three 3-237 0 2 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) CH Two CH Three 3-238 0 2 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) NH Two 3-239 0 2 CH Three (CH Two ) 6 COO OH NH Two 3-240 0 2 CH Three (CH Two ) 6 COO OH NHCH Three 3-241 0 2 CH Three (CH Two ) 6 COO OH N (CH Three ) Two 3-242 0 2 CH Three (CH Two ) 6 COO OH NHC (= NH) H 3-243 0 2 CH Three (CH Two ) 6 COO OH NHC (= NH) CH Three 3-244 0 2 CH Three (CH Two ) 6 COO OH NHC (= NH) CH Two CH Three 3-245 0 2 CH Three (CH Two ) 6 COO OH NHC (= NH) NH Two 3-246 0 2 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NH Two 3-247 0 2 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHCH Three 3-248 0 2 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COON (CH Three ) Two 3-249 0 2 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) H 3-250 0 2 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) CH Three 3-251 0 2 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) CH Two CH Three 3-252 0 2 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) NH Two 3-253 0 2 CH Three (CH Two ) 8 COO OH NH Two 3-254 0 2 CH Three (CH Two ) 8 COO OH NHCH Three 3-255 0 2 CH Three (CH Two ) 8 COO OH N (CH Three ) Two 3-256 0 2 CH Three (CH Two ) 8 COO OH NHC (= NH) H 3-257 0 2 CH Three (CH Two ) 8 COO OH NHC (= NH) CH Three 3-258 0 2 CH Three (CH Two ) 8 COO OH NHC (= NH) CH Two CH Three 3-259 0 2 CH Three (CH Two ) 8 COO OH NHC (= NH) NH Two 3-260 0 2 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NH Two 3-261 0 2 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHCH Three 3-262 0 2 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COON (CH Three ) Two 3-263 0 2 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) H 3-264 0 2 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) CH Three 3-265 0 2 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) CH Two CH Three 3-266 0 2 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) NH Two 3-267 0 2 CH Three (CH Two ) Ten COO OH NH Two 3-268 0 2 CH Three (CH Two ) Ten COO OH NHCH Three 3-269 0 2 CH Three (CH Two ) Ten COO OH N (CH Three ) Two 3-270 0 2 CH Three (CH Two ) Ten COO OH NHC (= NH) H 3-271 0 2 CH Three (CH Two ) Ten COO OH NHC (= NH) CH Three 3-272 0 2 CH Three (CH Two ) Ten COO OH NHC (= NH) CH Two CH Three 3-273 0 2 CH Three (CH Two ) Ten COO OH NHC (= NH) NH Two 3-274 0 2 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NH Two 3-275 0 2 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHCH Three 3-276 0 2 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COON (CH Three ) Two 3-277 0 2 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) H 3-278 0 2 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) CH Three 3-279 0 2 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) CH Two CH Three 3-280 0 2 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) NH Two 3-281 0 2 CH Three (CH Two ) 12 COO OH NH Two 3-282 0 2 CH Three (CH Two ) 12 COO OH NHCH Three 3-283 0 2 CH Three (CH Two ) 12 COO OH N (CH Three ) Two 3-284 0 2 CH Three (CH Two ) 12 COO OH NHC (= NH) H 3-285 0 2 CH Three (CH Two ) 12 COO OH NHC (= NH) CH Three 3-286 0 2 CH Three (CH Two ) 12 COO OH NHC (= NH) CH Two CH Three 3-287 0 2 CH Three (CH Two ) 12 COO OH NHC (= NH) NH Two 3-288 0 2 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NH Two 3-289 0 2 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHCH Three 3-290 0 2 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COON (CH Three ) Two 3-291 0 2 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) H 3-292 0 2 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) CH Three 3-293 0 2 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) CH Two CH Three 3-294 0 2 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) NH Two 3-295 0 2 CH Three (CH Two ) 14 COO OH NH Two 3-296 0 2 CH Three (CH Two ) 14 COO OH NHCH Three 3-297 0 2 CH Three (CH Two ) 14 COO OH N (CH Three ) Two 3-298 0 2 CH Three (CH Two ) 14 COO OH NHC (= NH) H 3-299 0 2 CH Three (CH Two ) 14 COO OH NHC (= NH) CH Three 3-300 0 2 CH Three (CH Two ) 14 COO OH NHC (= NH) CH Two CH Three 3-301 0 2 CH Three (CH Two ) 14 COO OH NHC (= NH) NH Two 3-302 0 2 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NH Two 3-303 0 2 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHCH Three 3-304 0 2 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COON (CH Three ) Two 3-305 0 2 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) H 3-306 0 2 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) CH Three 3-307 0 2 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) CH Two CH Three 3-308 0 2 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) NH Two 3-309 0 2 CH Three (CH Two ) 16 COO OH NH Two 3-310 0 2 CH Three (CH Two ) 16 COO OH NHCH Three 3-311 0 2 CH Three (CH Two ) 16 COO OH N (CH Three ) Two 3-312 0 2 CH Three (CH Two ) 16 COO OH NHC (= NH) H 3-313 0 2 CH Three (CH Two ) 16 COO OH NHC (= NH) CH Three 3-314 0 2 CH Three (CH Two ) 16 COO OH NHC (= NH) CH Two CH Three 3-315 0 2 CH Three (CH Two ) 16 COO OH NHC (= NH) NH Two 3-316 0 2 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NH Two 3-317 0 2 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHCH Three 3-318 0 2 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COON (CH Three ) Two 3-319 0 2 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) H 3-320 0 2 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) CH Three 3-321 0 2 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) CH Two CH Three 3-322 0 2 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) NH Two 3-323 0 2 CH Three (CH Two ) 18 COO OH NH Two 3-324 0 2 CH Three (CH Two ) 18 COO OH NHCH Three 3-325 0 2 CH Three (CH Two ) 18 COO OH N (CH Three ) Two 3-326 0 2 CH Three (CH Two ) 18 COO OH NHC (= NH) H 3-327 0 2 CH Three (CH Two ) 18 COO OH NHC (= NH) CH Three 3-328 0 2 CH Three (CH Two ) 18 COO OH NHC (= NH) CH Two CH Three 3-329 0 2 CH Three (CH Two ) 18 COO OH NHC (= NH) NH Two 3-330 0 2 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NH Two 3-331 0 2 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHCH Three 3-332 0 2 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COON (CH Three ) Two 3-333 0 2 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) H 3-334 0 2 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) CH Three 3-335 0 2 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) CH Two CH Three 3-336 0 2 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) NH Two 3-337 0 3 CH Three COO OH NH Two 3-338 0 3 CH Three COO OH NHCH Three 3-339 0 3 CH Three COO OH N (CH Three ) Two 3-340 0 3 CH Three COO OH NHC (= NH) H 3-341 0 3 CH Three COO OH NHC (= NH) CH Three 3-342 0 3 CH Three COO OH NHC (= NH) CH Two CH Three 3-343 0 3 CH Three COO OH NHC (= NH) NH Two 3-344 0 3 CH Three COO CH Three COO NH Two 3-345 0 3 CH Three COO CH Three COO NHCH Three 3-346 0 3 CH Three COO CH Three COON (CH Three ) Two 3-347 0 3 CH Three COO CH Three COO NHC (= NH) H 3-348 0 3 CH Three COO CH Three COO NHC (= NH) CH Three 3-349 0 3 CH Three COO CH Three COO NHC (= NH) CH Two CH Three 3-350 0 3 CH Three COO CH Three COO NHC (= NH) NH Two 3-351 0 3 CH Three CH Two COO OH NH Two 3-352 0 3 CH Three CH Two COO OH NHCH Three 3-353 0 3 CH Three CH Two COO OH N (CH Three ) Two 3-354 0 3 CH Three CH Two COO OH NHC (= NH) H 3-355 0 3 CH Three CH Two COO OH NHC (= NH) CH Three 3-356 0 3 CH Three CH Two COO OH NHC (= NH) CH Two CH Three 3-357 0 3 CH Three CH Two COO OH NHC (= NH) NH Two 3-358 0 3 CH Three CH Two COO CH Three CH Two COO NH Two 3-359 0 3 CH Three CH Two COO CH Three CH Two COO NHCH Three 3-360 0 3 CH Three CH Two COO CH Three CH Two COON (CH Three ) Two 3-361 0 3 CH Three CH Two COO CH Three CH Two COO NHC (= NH) H 3-362 0 3 CH Three CH Two COO CH Three CH Two COO NHC (= NH) CH Three 3-363 0 3 CH Three CH Two COO CH Three CH Two COO NHC (= NH) CH Two CH Three 3-364 0 3 CH Three CH Two COO CH Three CH Two COO NHC (= NH) NH Two 3-365 0 3 CH Three (CH Two ) Two COO OH NH Two 3-366 0 3 CH Three (CH Two ) Two COO OH NHCH Three 3-367 0 3 CH Three (CH Two ) Two COO OH N (CH Three ) Two 3-368 0 3 CH Three (CH Two ) Two COO OH NHC (= NH) H 3-369 0 3 CH Three (CH Two ) Two COO OH NHC (= NH) CH Three 3-370 0 3 CH Three (CH Two ) Two COO OH NHC (= NH) CH Two CH Three 3-371 0 3 CH Three (CH Two ) Two COO OH NHC (= NH) NH Two 3-372 0 3 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NH Two 3-373 0 3 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHCH Three 3-374 0 3 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COON (CH Three ) Two 3-375 0 3 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) H 3-376 0 3 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) CH Three 3-377 0 3 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) CH Two CH Three 3-378 0 3 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) NH Two 3-379 0 3 CH Three (CH Two ) Three COO OH NH Two 3-380 0 3 CH Three (CH Two ) Three COO OH NHCH Three 3-381 0 3 CH Three (CH Two ) Three COO OH N (CH Three ) Two 3-382 0 3 CH Three (CH Two ) Three COO OH NHC (= NH) H 3-383 0 3 CH Three (CH Two ) Three COO OH NHC (= NH) CH Three 3-384 0 3 CH Three (CH Two ) Three COO OH NHC (= NH) CH Two CH Three 3-385 0 3 CH Three (CH Two ) Three COO OH NHC (= NH) NH Two 3-386 0 3 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NH Two 3-387 0 3 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHCH Three 3-388 0 3 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COON (CH Three ) Two 3-389 0 3 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) H 3-390 0 3 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) CH Three 3-391 0 3 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) CH Two CH Three 3-392 0 3 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) NH Two 3-393 0 3 CH Three (CH Two ) Four COO OH NH Two 3-394 0 3 CH Three (CH Two ) Four COO OH NHCH Three 3-395 0 3 CH Three (CH Two ) Four COO OH N (CH Three ) Two 3-396 0 3 CH Three (CH Two ) Four COO OH NHC (= NH) H 3-397 0 3 CH Three (CH Two ) Four COO OH NHC (= NH) CH Three 3-398 0 3 CH Three (CH Two ) Four COO OH NHC (= NH) CH Two CH Three 3-399 0 3 CH Three (CH Two ) Four COO OH NHC (= NH) NH Two 3-400 0 3 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NH Two 3-401 0 3 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHCH Three 3-402 0 3 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COON (CH Three ) Two 3-403 0 3 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) H 3-404 0 3 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) CH Three 3-405 0 3 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) CH Two CH Three 3-406 0 3 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) NH Two 3-407 0 3 CH Three (CH Two ) 6 COO OH NH Two 3-408 0 3 CH Three (CH Two ) 6 COO OH NHCH Three 3-409 0 3 CH Three (CH Two ) 6 COO OH N (CH Three ) Two 3-410 0 3 CH Three (CH Two ) 6 COO OH NHC (= NH) H 3-411 0 3 CH Three (CH Two ) 6 COO OH NHC (= NH) CH Three 3-412 0 3 CH Three (CH Two ) 6 COO OH NHC (= NH) CH Two CH Three 3-413 0 3 CH Three (CH Two ) 6 COO OH NHC (= NH) NH Two 3-414 0 3 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NH Two 3-415 0 3 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHCH Three 3-416 0 3 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COON (CH Three ) Two 3-417 0 3 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) H 3-418 0 3 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) CH Three 3-419 0 3 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) CH Two CH Three 3-420 0 3 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) NH Two 3-421 0 3 CH Three (CH Two ) 8 COO OH NH Two 3-422 0 3 CH Three (CH Two ) 8 COO OH NHCH Three 3-423 0 3 CH Three (CH Two ) 8 COO OH N (CH Three ) Two 3-424 0 3 CH Three (CH Two ) 8 COO OH NHC (= NH) H 3-425 0 3 CH Three (CH Two ) 8 COO OH NHC (= NH) CH Three 3-426 0 3 CH Three (CH Two ) 8 COO OH NHC (= NH) CH Two CH Three 3-427 0 3 CH Three (CH Two ) 8 COO OH NHC (= NH) NH Two 3-428 0 3 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NH Two 3-429 0 3 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHCH Three 3-430 0 3 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COON (CH Three ) Two 3-431 0 3 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) H 3-432 0 3 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) CH Three 3-433 0 3 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) CH Two CH Three 3-434 0 3 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) NH Two 3-435 0 3 CH Three (CH Two ) Ten COO OH NH Two 3-436 0 3 CH Three (CH Two ) Ten COO OH NHCH Three 3-437 0 3 CH Three (CH Two ) Ten COO OH N (CH Three ) Two 3-438 0 3 CH Three (CH Two ) Ten COO OH NHC (= NH) H 3-439 0 3 CH Three (CH Two ) Ten COO OH NHC (= NH) CH Three 3-440 0 3 CH Three (CH Two ) Ten COO OH NHC (= NH) CH Two CH Three 3-441 0 3 CH Three (CH Two ) Ten COO OH NHC (= NH) NH Two 3-442 0 3 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NH Two 3-443 0 3 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHCH Three 3-444 0 3 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COON (CH Three ) Two 3-445 0 3 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) H 3-446 0 3 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) CH Three 3-447 0 3 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) CH Two CH Three 3-448 0 3 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) NH Two 3-449 0 3 CH Three (CH Two ) 12 COO OH NH Two 3-450 0 3 CH Three (CH Two ) 12 COO OH NHCH Three 3-451 0 3 CH Three (CH Two ) 12 COO OH N (CH Three ) Two 3-452 0 3 CH Three (CH Two ) 12 COO OH NHC (= NH) H 3-453 0 3 CH Three (CH Two ) 12 COO OH NHC (= NH) CH Three 3-454 0 3 CH Three (CH Two ) 12 COO OH NHC (= NH) CH Two CH Three 3-455 0 3 CH Three (CH Two ) 12 COO OH NHC (= NH) NH Two 3-456 0 3 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NH Two 3-457 0 3 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHCH Three 3-458 0 3 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COON (CH Three ) Two 3-459 0 3 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) H 3-460 03 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) CH Three 3-461 0 3 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) CH Two CH Three 3-462 0 3 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) NH Two 3-463 0 3 CH Three (CH Two ) 14 COO OH NH Two 3-464 0 3 CH Three (CH Two ) 14 COO OH NHCH Three 3-465 0 3 CH Three (CH Two ) 14 COO OH N (CH Three ) Two 3-466 0 3 CH Three (CH Two ) 14 COO OH NHC (= NH) H 3-467 0 3 CH Three (CH Two ) 14 COO OH NHC (= NH) CH Three 3-468 0 3 CH Three (CH Two ) 14 COO OH NHC (= NH) CH Two CH Three 3-469 0 3 CH Three (CH Two ) 14 COO OH NHC (= NH) NH Two 3-470 0 3 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NH Two 3-471 0 3 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHCH Three 3-472 0 3 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COON (CH Three ) Two 3-473 0 3 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) H 3-474 0 3 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) CH Three 3-475 0 3 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) CH Two CH Three 3-476 0 3 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) NH Two 3-477 0 3 CH Three (CH Two ) 16 COO OH NH Two 3-478 0 3 CH Three (CH Two ) 16 COO OH NHCH Three 3-479 0 3 CH Three (CH Two ) 16 COO OH N (CH Three ) Two 3-480 0 3 CH Three (CH Two ) 16 COO OH NHC (= NH) H 3-481 0 3 CH Three (CH Two ) 16 COO OH NHC (= NH) CH Three 3-482 0 3 CH Three (CH Two ) 16 COO OH NHC (= NH) CH Two CH Three 3-483 0 3 CH Three (CH Two ) 16 COO OH NHC (= NH) NH Two 3-484 0 3 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NH Two 3-485 0 3 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHCH Three 3-486 0 3 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COON (CH Three ) Two 3-487 0 3 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) H 3-488 0 3 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) CH Three 3-489 0 3 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) CH Two CH Three 3-490 0 3 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) NH Two 3-491 0 3 CH Three (CH Two ) 18 COO OH NH Two 3-492 0 3 CH Three (CH Two ) 18 COO OH NHCH Three 3-493 0 3 CH Three (CH Two ) 18 COO OH N (CH Three ) Two 3-494 0 3 CH Three (CH Two ) 18 COO OH NHC (= NH) H 3-495 0 3 CH Three (CH Two ) 18 COO OH NHC (= NH) CH Three 3-496 0 3 CH Three (CH Two ) 18 COO OH NHC (= NH) CH Two CH Three 3-497 0 3 CH Three (CH Two ) 18 COO OH NHC (= NH) NH Two 3-498 0 3 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NH Two 3-499 0 3 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHCH Three 3-500 0 3 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COON (CH Three ) Two 3-501 0 3 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) H 3-502 0 3 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) CH Three 3-503 0 3 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) CH Two CH Three 3-504 0 3 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) NH Two 3-505 1 1 CH Three COO OH NH Two 3-506 1 1 CH Three COO OH NHCH Three 3-507 1 1 CH Three COO OH N (CH Three ) Two 3-508 1 1 CH Three COO OH NHC (= NH) H 3-509 1 1 CH Three COO OH NHC (= NH) CH Three 3-510 1 1 CH Three COO OH NHC (= NH) CH Two CH Three 3-511 1 1 CH Three COO OH NHC (= NH) NH Two 3-512 1 1 CH Three COO CH Three COO NH Two 3-513 1 1 CH Three COO CH Three COO NHCH Three 3-514 1 1 CH Three COO CH Three COON (CH Three ) Two 3-515 1 1 CH Three COO CH Three COO NHC (= NH) H 3-516 1 1 CH Three COO CH Three COO NHC (= NH) CH Three 3-517 1 1 CH Three COO CH Three COO NHC (= NH) CH Two CH Three 3-518 1 1 CH Three COO CH Three COO NHC (= NH) NH Two 3-519 1 1 CH Three CH Two COO OH NH Two 3-520 1 1 CH Three CH Two COO OH NHCH Three 3-521 1 1 CH Three CH Two COO OH N (CH Three ) Two 3-522 1 1 CH Three CH Two COO OH NHC (= NH) H 3-523 1 1 CH Three CH Two COO OH NHC (= NH) CH Three 3-524 1 1 CH Three CH Two COO OH NHC (= NH) CH Two CH Three 3-525 1 1 CH Three CH Two COO OH NHC (= NH) NH Two 3-526 1 1 CH Three CH Two COO CH Three CH Two COO NH Two 3-527 1 1 CH Three CH Two COO CH Three CH Two COO NHCH Three 3-528 1 1 CH Three CH Two COO CH Three CH Two COON (CH Three ) Two 3-529 1 1 CH Three CH Two COO CH Three CH Two COO NHC (= NH) H 3-530 1 1 CH Three CH Two COO CH Three CH Two COO NHC (= NH) CH Three 3-531 1 1 CH Three CH Two COO CH Three CH Two COO NHC (= NH) CH Two CH Three 3-532 1 1 CH Three CH Two COO CH Three CH Two COO NHC (= NH) NH Two 3-533 1 1 CH Three (CH Two ) Two COO OH NH Two 3-534 1 1 CH Three (CH Two ) Two COO OH NHCH Three 3-535 1 1 CH Three (CH Two ) Two COO OH N (CH Three ) Two 3-536 1 1 CH Three (CH Two ) Two COO OH NHC (= NH) H 3-537 1 1 CH Three (CH Two ) Two COO OH NHC (= NH) CH Three 3-538 1 1 CH Three (CH Two ) Two COO OH NHC (= NH) CH Two CH Three 3-539 1 1 CH Three (CH Two ) Two COO OH NHC (= NH) NH Two 3-540 1 1 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NH Two 3-541 1 1 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHCH Three 3-542 1 1 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COON (CH Three ) Two 3-543 1 1 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) H 3-544 1 1 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) CH Three 3-545 1 1 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) CH Two CH Three 3-546 1 1 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) NH Two 3-547 1 1 CH Three (CH Two ) Three COO OH NH Two 3-548 1 1 CH Three (CH Two ) Three COO OH NHCH Three 3-549 1 1 CH Three (CH Two ) Three COO OH N (CH Three ) Two 3-550 1 1 CH Three (CH Two ) Three COO OH NHC (= NH) H 3-551 1 1 CH Three (CH Two ) Three COO OH NHC (= NH) CH Three 3-552 1 1 CH Three (CH Two ) Three COO OH NHC (= NH) CH Two CH Three 3-553 1 1 CH Three (CH Two ) Three COO OH NHC (= NH) NH Two 3-554 1 1 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NH Two 3-555 1 1 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHCH Three 3-556 1 1 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COON (CH Three ) Two 3-557 1 1 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) H 3-558 1 1 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) CH Three 3-559 1 1 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) CH Two CH Three 3-560 1 1 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) NH Two 3-561 1 1 CH Three (CH Two ) Four COO OH NH Two 3-562 1 1 CH Three (CH Two ) Four COO OH NHCH Three 3-563 1 1 CH Three (CH Two ) Four COO OH N (CH Three ) Two 3-564 1 1 CH Three (CH Two ) Four COO OH NHC (= NH) H 3-565 1 1 CH Three (CH Two ) Four COO OH NHC (= NH) CH Three 3-566 1 1 CH Three (CH Two ) Four COO OH NHC (= NH) CH Two CH Three 3-567 1 1 CH Three (CH Two ) Four COO OH NHC (= NH) NH Two 3-568 1 1 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NH Two 3-569 1 1 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHCH Three 3-570 1 1 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COON (CH Three ) Two 3-571 1 1 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) H 3-572 1 1 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) CH Three 3-573 1 1 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) CH Two CH Three 3-574 1 1 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) NH Two 3-575 1 1 CH Three (CH Two ) 6 COO OH NH Two 3-576 1 1 CH Three (CH Two ) 6 COO OH NHCH Three 3-577 1 1 CH Three (CH Two ) 6 COO OH N (CH Three ) Two 3-578 1 1 CH Three (CH Two ) 6 COO OH NHC (= NH) H 3-579 1 1 CH Three (CH Two ) 6 COO OH NHC (= NH) CH Three 3-580 1 1 CH Three (CH Two ) 6 COO OH NHC (= NH) CH Two CH Three 3-581 1 1 CH Three (CH Two ) 6 COO OH NHC (= NH) NH Two 3-582 1 1 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NH Two 3-583 1 1 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHCH Three 3-584 1 1 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COON (CH Three ) Two 3-585 1 1 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) H 3-586 1 1 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) CH Three 3-587 1 1 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) CH Two CH Three 3-588 1 1 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) NH Two 3-589 1 1 CH Three (CH Two ) 8 COO OH NH Two 3-590 1 1 CH Three (CH Two ) 8 COO OH NHCH Three 3-591 1 1 CH Three (CH Two ) 8 COO OH N (CH Three ) Two 3-592 1 1 CH Three (CH Two ) 8 COO OH NHC (= NH) H 3-593 1 1 CH Three (CH Two ) 8 COO OH NHC (= NH) CH Three 3-594 1 1 CH Three (CH Two ) 8 COO OH NHC (= NH) CH Two CH Three 3-595 1 1 CH Three (CH Two ) 8 COO OH NHC (= NH) NH Two 3-596 1 1 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NH Two 3-597 1 1 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHCH Three 3-598 1 1 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COON (CH Three ) Two 3-599 1 1 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) H 3-600 1 1 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) CH Three 3-601 1 1 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) CH Two CH Three 3-602 1 1 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) NH Two 3-603 1 1 CH Three (CH Two ) Ten COO OH NH Two 3-604 1 1 CH Three (CH Two ) Ten COO OH NHCH Three 3-605 1 1 CH Three (CH Two ) Ten COO OH N (CH Three ) Two 3-606 1 1 CH Three (CH Two ) Ten COO OH NHC (= NH) H 3-607 1 1 CH Three (CH Two ) Ten COO OH NHC (= NH) CH Three 3-608 1 1 CH Three (CH Two ) Ten COO OH NHC (= NH) CH Two CH Three 3-609 1 1 CH Three (CH Two ) Ten COO OH NHC (= NH) NH Two 3-610 1 1 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NH Two 3-611 1 1 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHCH Three 3-612 1 1 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COON (CH Three ) Two 3-613 1 1 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) H 3-614 1 1 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) CH Three 3-615 1 1 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) CH Two CH Three 3-616 1 1 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) NH Two 3-617 1 1 CH Three (CH Two ) 12 COO OH NH Two 3-618 1 1 CH Three (CH Two ) 12 COO OH NHCH Three 3-619 1 1 CH Three (CH Two ) 12 COO OH N (CH Three ) Two 3-620 1 1 CH Three (CH Two ) 12 COO OH NHC (= NH) H 3-621 1 1 CH Three (CH Two ) 12 COO OH NHC (= NH) CH Three 3-622 1 1 CH Three (CH Two ) 12 COO OH NHC (= NH) CH Two CH Three 3-623 1 1 CH Three (CH Two ) 12 COO OH NHC (= NH) NH Two 3-624 1 1 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NH Two 3-625 1 1 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHCH Three 3-626 1 1 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COON (CH Three ) Two 3-627 1 1 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) H 3-628 1 1 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) CH Three 3-629 1 1 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) CH Two CH Three 3-630 1 1 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) NH Two 3-631 1 1 CH Three (CH Two ) 14 COO OH NH Two 3-632 1 1 CH Three (CH Two ) 14 COO OH NHCH Three 3-633 1 1 CH Three (CH Two ) 14 COO OH N (CH Three ) Two 3-634 1 1 CH Three (CH Two ) 14 COO OH NHC (= NH) H 3-635 1 1 CH Three (CH Two ) 14 COO OH NHC (= NH) CH Three 3-636 1 1 CH Three (CH Two ) 14 COO OH NHC (= NH) CH Two CH Three 3-637 1 1 CH Three (CH Two ) 14 COO OH NHC (= NH) NH Two 3-638 1 1 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NH Two 3-639 1 1 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHCH Three 3-640 1 1 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COON (CH Three ) Two 3-641 1 1 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) H 3-642 1 1 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) CH Three 3-643 1 1 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) CH Two CH Three 3-644 1 1 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) NH Two 3-645 1 1 CH Three (CH Two ) 16 COO OH NH Two 3-646 1 1 CH Three (CH Two ) 16 COO OH NHCH Three 3-647 1 1 CH Three (CH Two ) 16 COO OH N (CH Three ) Two 3-648 1 1 CH Three (CH Two ) 16 COO OH NHC (= NH) H 3-649 1 1 CH Three (CH Two ) 16 COO OH NHC (= NH) CH Three 3-650 1 1 CH Three (CH Two ) 16 COO OH NHC (= NH) CH Two CH Three 3-651 1 1 CH Three (CH Two ) 16 COO OH NHC (= NH) NH Two 3-652 1 1 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NH Two 3-653 1 1 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHCH Three 3-654 1 1 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COON (CH Three ) Two 3-655 1 1 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) H 3-656 1 1 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) CH Three 3-657 1 1 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) CH Two CH Three 3-658 1 1 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) NH Two 3-659 1 1 CH Three (CH Two ) 18 COO OH NH Two 3-660 1 1 CH Three (CH Two ) 18 COO OH NHCH Three 3-661 1 1 CH Three (CH Two ) 18 COO OH N (CH Three ) Two 3-662 1 1 CH Three (CH Two ) 18 COO OH NHC (= NH) H 3-663 1 1 CH Three (CH Two ) 18 COO OH NHC (= NH) CH Three 3-664 1 1 CH Three (CH Two ) 18 COO OH NHC (= NH) CH Two CH Three 3-665 1 1 CH Three (CH Two ) 18 COO OH NHC (= NH) NH Two 3-666 1 1 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NH Two 3-667 1 1 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHCH Three 3-668 1 1 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COON (CH Three ) Two 3-669 1 1 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) H 3-670 1 1 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) CH Three 3-671 1 1 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) CH Two CH Three 3-672 1 1 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) NH Two 3-673 1 2 CH Three COO OH NH Two 3-674 1 2 CH Three COO OH NHCH Three 3-675 1 2 CH Three COO OH N (CH Three ) Two 3-676 1 2 CH Three COO OH NHC (= NH) H 3-677 1 2 CH Three COO OH NHC (= NH) CH Three 3-678 1 2 CH Three COO OH NHC (= NH) CH Two CH Three 3-679 1 2 CH Three COO OH NHC (= NH) NH Two 3-680 1 2 CH Three COO CH Three COO NH Two 3-681 1 2 CH Three COO CH Three COO NHCH Three 3-682 1 2 CH Three COO CH Three COON (CH Three ) Two 3-683 1 2 CH Three COO CH Three COO NHC (= NH) H 3-684 1 2 CH Three COO CH Three COO NHC (= NH) CH Three 3-685 1 2 CH Three COO CH Three COO NHC (= NH) CH Two CH Three 3-686 1 2 CH Three COO CH Three COO NHC (= NH) NH Two 3-687 1 2 CH Three CH Two COO OH NH Two 3-688 1 2 CH Three CH Two COO OH NHCH Three 3-689 1 2 CH Three CH Two COO OH N (CH Three ) Two 3-690 1 2 CH Three CH Two COO OH NHC (= NH) H 3-691 1 2 CH Three CH Two COO OH NHC (= NH) CH Three 3-692 1 2 CH Three CH Two COO OH NHC (= NH) CH Two CH Three 3-693 1 2 CH Three CH Two COO OH NHC (= NH) NH Two 3-694 1 2 CH Three CH Two COO CH Three CH Two COO NH Two 3-695 1 2 CH Three CH Two COO CH Three CH Two COO NHCH Three 3-696 1 2 CH Three CH Two COO CH Three CH Two COON (CH Three ) Two 3-697 1 2 CH Three CH Two COO CH Three CH Two COO NHC (= NH) H 3-698 1 2 CH Three CH Two COO CH Three CH Two COO NHC (= NH) CH Three 3-699 1 2 CH Three CH Two COO CH Three CH Two COO NHC (= NH) CH Two CH Three 3-700 1 2 CH Three CH Two COO CH Three CH Two COO NHC (= NH) NH Two 3-701 1 2 CH Three (CH Two ) Two COO OH NH Two 3-702 1 2 CH Three (CH Two ) Two COO OH NHCH Three 3-703 1 2 CH Three (CH Two ) Two COO OH N (CH Three ) Two 3-704 1 2 CH Three (CH Two ) Two COO OH NHC (= NH) H 3-705 1 2 CH Three (CH Two ) Two COO OH NHC (= NH) CH Three 3-706 1 2 CH Three (CH Two ) Two COO OH NHC (= NH) CH Two CH Three 3-707 1 2 CH Three (CH Two ) Two COO OH NHC (= NH) NH Two 3-708 1 2 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NH Two 3-709 1 2 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHCH Three 3-710 1 2 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COON (CH Three ) Two 3-711 1 2 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) H 3-712 1 2 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) CH Three 3-713 1 2 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) CH Two CH Three 3-714 1 2 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) NH Two 3-715 1 2 CH Three (CH Two ) Three COO OH NH Two 3-716 1 2 CH Three (CH Two ) Three COO OH NHCH Three 3-717 1 2 CH Three (CH Two ) Three COO OH N (CH Three ) Two 3-718 1 2 CH Three (CH Two ) Three COO OH NHC (= NH) H 3-719 12 CH Three (CH Two ) Three COO OH NHC (= NH) CH Three 3-720 1 2 CH Three (CH Two ) Three COO OH NHC (= NH) CH Two CH Three 3-721 1 2 CH Three (CH Two ) Three COO OH NHC (= NH) NH Two 3-722 1 2 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NH Two 3-723 1 2 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHCH Three 3-724 1 2 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COON (CH Three ) Two 3-725 1 2 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) H 3-726 1 2 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) CH Three 3-727 1 2 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) CH Two CH Three 3-728 1 2 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) NH Two 3-729 1 2 CH Three (CH Two ) Four COO OH NH Two 3-730 1 2 CH Three (CH Two ) Four COO OH NHCH Three 3-731 1 2 CH Three (CH Two ) Four COO OH N (CH Three ) Two 3-732 1 2 CH Three (CH Two ) Four COO OH NHC (= NH) H 3-733 1 2 CH Three (CH Two ) Four COO OH NHC (= NH) CH Three 3-734 1 2 CH Three (CH Two ) Four COO OH NHC (= NH) CH Two CH Three 3-735 1 2 CH Three (CH Two ) Four COO OH NHC (= NH) NH Two 3-736 1 2 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NH Two 3-737 1 2 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHCH Three 3-738 1 2 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COON (CH Three ) Two 3-739 1 2 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) H 3-740 1 2 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) CH Three 3-741 1 2 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) CH Two CH Three 3-742 1 2 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) NH Two 3-743 1 2 CH Three (CH Two ) 6 COO OH NH Two 3-744 1 2 CH Three (CH Two ) 6 COO OH NHCH Three 3-745 1 2 CH Three (CH Two ) 6 COO OH N (CH Three ) Two 3-746 1 2 CH Three (CH Two ) 6 COO OH NHC (= NH) H 3-747 1 2 CH Three (CH Two ) 6 COO OH NHC (= NH) CH Three 3-748 1 2 CH Three (CH Two ) 6 COO OH NHC (= NH) CH Two CH Three 3-749 1 2 CH Three (CH Two ) 6 COO OH NHC (= NH) NH Two 3-750 1 2 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NH Two 3-751 1 2 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHCH Three 3-752 1 2 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COON (CH Three ) Two 3-753 1 2 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) H 3-754 1 2 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) CH Three 3-755 1 2 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) CH Two CH Three 3-756 1 2 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) NH Two 3-757 1 2 CH Three (CH Two ) 8 COO OH NH Two 3-758 1 2 CH Three (CH Two ) 8 COO OH NHCH Three 3-759 1 2 CH Three (CH Two ) 8 COO OH N (CH Three ) Two 3-760 1 2 CH Three (CH Two ) 8 COO OH NHC (= NH) H 3-761 1 2 CH Three (CH Two ) 8 COO OH NHC (= NH) CH Three 3-762 1 2 CH Three (CH Two ) 8 COO OH NHC (= NH) CH Two CH Three 3-763 1 2 CH Three (CH Two ) 8 COO OH NHC (= NH) NH Two 3-764 1 2 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NH Two 3-765 1 2 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHCH Three 3-766 1 2 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COON (CH Three ) Two 3-767 1 2 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) H 3-768 1 2 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) CH Three 3-769 1 2 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) CH Two CH Three 3-770 1 2 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) NH Two 3-771 1 2 CH Three (CH Two ) Ten COO OH NH Two 3-772 1 2 CH Three (CH Two ) Ten COO OH NHCH Three 3-773 1 2 CH Three (CH Two ) Ten COO OH N (CH Three ) Two 3-774 1 2 CH Three (CH Two ) Ten COO OH NHC (= NH) H 3-775 1 2 CH Three (CH Two ) Ten COO OH NHC (= NH) CH Three 3-776 1 2 CH Three (CH Two ) Ten COO OH NHC (= NH) CH Two CH Three 3-777 1 2 CH Three (CH Two ) Ten COO OH NHC (= NH) NH Two 3-778 1 2 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NH Two 3-779 1 2 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHCH Three 3-780 1 2 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COON (CH Three ) Two 3-781 1 2 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) H 3-782 1 2 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) CH Three 3-783 1 2 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) CH Two CH Three 3-784 1 2 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) NH Two 3-785 1 2 CH Three (CH Two ) 12 COO OH NH Two 3-786 1 2 CH Three (CH Two ) 12 COO OH NHCH Three 3-787 1 2 CH Three (CH Two ) 12 COO OH N (CH Three ) Two 3-788 1 2 CH Three (CH Two ) 12 COO OH NHC (= NH) H 3-789 12 CH Three (CH Two ) 12 COO OH NHC (= NH) CH Three 3-790 1 2 CH Three (CH Two ) 12 COO OH NHC (= NH) CH Two CH Three 3-791 1 2 CH Three (CH Two ) 12 COO OH NHC (= NH) NH Two 3-792 1 2 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NH Two 3-793 1 2 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHCH Three 3-794 1 2 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COON (CH Three ) Two 3-795 1 2 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) H 3-796 1 2 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) CH Three 3-797 1 2 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) CH Two CH Three 3-798 1 2 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) NH Two 3-799 1 2 CH Three (CH Two ) 14 COO OH NH Two 3-800 1 2 CH Three (CH Two ) 14 COO OH NHCH Three 3-801 1 2 CH Three (CH Two ) 14 COO OH N (CH Three ) Two 3-802 12 CH Three (CH Two ) 14 COO OH NHC (= NH) H 3-803 12 CH Three (CH Two ) 14 COO OH NHC (= NH) CH Three 3-804 1 2 CH Three (CH Two ) 14 COO OH NHC (= NH) CH Two CH Three 3-805 1 2 CH Three (CH Two ) 14 COO OH NHC (= NH) NH Two 3-806 1 2 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NH Two 3-807 1 2 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHCH Three 3-808 1 2 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COON (CH Three ) Two 3-809 1 2 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) H 3-810 1 2 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) CH Three 3-811 1 2 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) CH Two CH Three 3-812 1 2 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) NH Two 3-813 1 2 CH Three (CH Two ) 16 COO OH NH Two 3-814 1 2 CH Three (CH Two ) 16 COO OH NHCH Three 3-815 1 2 CH Three (CH Two ) 16 COO OH N (CH Three ) Two 3-816 1 2 CH Three (CH Two ) 16 COO OH NHC (= NH) H 3-817 1 2 CH Three (CH Two ) 16 COO OH NHC (= NH) CH Three 3-818 1 2 CH Three (CH Two ) 16 COO OH NHC (= NH) CH Two CH Three 3-819 1 2 CH Three (CH Two ) 16 COO OH NHC (= NH) NH Two 3-820 1 2 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NH Two 3-821 1 2 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHCH Three 3-822 1 2 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COON (CH Three ) Two 3-823 1 2 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) H 3-824 1 2 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) CH Three 3-825 1 2 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) CH Two CH Three 3-826 1 2 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) NH Two 3-827 1 2 CH Three (CH Two ) 18 COO OH NH Two 3-828 1 2 CH Three (CH Two ) 18 COO OH NHCH Three 3-829 1 2 CH Three (CH Two ) 18 COO OH N (CH Three ) Two 3-830 1 2 CH Three (CH Two ) 18 COO OH NHC (= NH) H 3-831 1 2 CH Three (CH Two ) 18 COO OH NHC (= NH) CH Three 3-832 1 2 CH Three (CH Two ) 18 COO OH NHC (= NH) CH Two CH Three 3-833 1 2 CH Three (CH Two ) 18 COO OH NHC (= NH) NH Two 3-834 1 2 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NH Two 3-835 1 2 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHCH Three 3-836 1 2 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COON (CH Three ) Two 3-837 1 2 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) H 3-838 1 2 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) CH Three 3-839 1 2 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) CH Two CH Three 3-840 1 2 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) NH Two 3-841 2 1 CH Three COO OH NH Two 3-842 2 1 CH Three COO OH NHCH Three 3-843 2 1 CH Three COO OH N (CH Three ) Two 3-844 2 1 CH Three COO OH NHC (= NH) H 3-845 2 1 CH Three COO OH NHC (= NH) CH Three 3-846 2 1 CH Three COO OH NHC (= NH) CH Two CH Three 3-847 2 1 CH Three COO OH NHC (= NH) NH Two 3-848 2 1 CH Three COO CH Three COO NH Two 3-849 2 1 CH Three COO CH Three COO NHCH Three 3-850 2 1 CH Three COO CH Three COON (CH Three ) Two 3-851 2 1 CH Three COO CH Three COO NHC (= NH) H 3-852 2 1 CH Three COO CH Three COO NHC (= NH) CH Three 3-853 2 1 CH Three COO CH Three COO NHC (= NH) CH Two CH Three 3-854 2 1 CH Three COO CH Three COO NHC (= NH) NH Two 3-855 2 1 CH Three CH Two COO OH NH Two 3-856 2 1 CH Three CH Two COO OH NHCH Three 3-857 2 1 CH Three CH Two COO OH N (CH Three ) Two 3-858 2 1 CH Three CH Two COO OH NHC (= NH) H 3-859 2 1 CH Three CH Two COO OH NHC (= NH) CH Three 3-860 2 1 CH Three CH Two COO OH NHC (= NH) CH Two CH Three 3-861 2 1 CH Three CH Two COO OH NHC (= NH) NH Two 3-862 2 1 CH Three CH Two COO CH Three CH Two COO NH Two 3-863 2 1 CH Three CH Two COO CH Three CH Two COO NHCH Three 3-864 2 1 CH Three CH Two COO CH Three CH Two COON (CH Three ) Two 3-865 2 1 CH Three CH Two COO CH Three CH Two COO NHC (= NH) H 3-866 2 1 CH Three CH Two COO CH Three CH Two COO NHC (= NH) CH Three 3-867 2 1 CH Three CH Two COO CH Three CH Two COO NHC (= NH) CH Two CH Three 3-868 2 1 CH Three CH Two COO CH Three CH Two COO NHC (= NH) NH Two 3-869 2 1 CH Three (CH Two ) Two COO OH NH Two 3-870 2 1 CH Three (CH Two ) Two COO OH NHCH Three 3-871 2 1 CH Three (CH Two ) Two COO OH N (CH Three ) Two 3-872 2 1 CH Three (CH Two ) Two COO OH NHC (= NH) H 3-873 2 1 CH Three (CH Two ) Two COO OH NHC (= NH) CH Three 3-874 2 1 CH Three (CH Two ) Two COO OH NHC (= NH) CH Two CH Three 3-875 2 1 CH Three (CH Two ) Two COO OH NHC (= NH) NH Two 3-876 2 1 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NH Two 3-877 2 1 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHCH Three 3-878 2 1 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COON (CH Three ) Two 3-879 2 1 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) H 3-880 2 1 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) CH Three 3-881 2 1 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) CH Two CH Three 3-882 2 1 CH Three (CH Two ) Two COO CH Three (CH Two ) Two COO NHC (= NH) NH Two 3-883 2 1 CH Three (CH Two ) Three COO OH NH Two 3-884 2 1 CH Three (CH Two ) Three COO OH NHCH Three 3-885 2 1 CH Three (CH Two ) Three COO OH N (CH Three ) Two 3-886 2 1 CH Three (CH Two ) Three COO OH NHC (= NH) H 3-887 2 1 CH Three (CH Two ) Three COO OH NHC (= NH) CH Three 3-888 2 1 CH Three (CH Two ) Three COO OH NHC (= NH) CH Two CH Three 3-889 2 1 CH Three (CH Two ) Three COO OH NHC (= NH) NH Two 3-890 2 1 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NH Two 3-891 2 1 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHCH Three 3-892 2 1 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COON (CH Three ) Two 3-893 2 1 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) H 3-894 2 1 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) CH Three 3-895 2 1 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) CH Two CH Three 3-896 2 1 CH Three (CH Two ) Three COO CH Three (CH Two ) Three COO NHC (= NH) NH Two 3-897 2 1 CH Three (CH Two ) Four COO OH NH Two 3-898 2 1 CH Three (CH Two ) Four COO OH NHCH Three 3-899 2 1 CH Three (CH Two ) Four COO OH N (CH Three ) Two 3-900 2 1 CH Three (CH Two ) Four COO OH NHC (= NH) H 3-901 2 1 CH Three (CH Two ) Four COO OH NHC (= NH) CH Three 3-902 2 1 CH Three (CH Two ) Four COO OH NHC (= NH) CH Two CH Three 3-903 2 1 CH Three (CH Two ) Four COO OH NHC (= NH) NH Two 3-904 2 1 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NH Two 3-905 2 1 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHCH Three 3-906 2 1 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COON (CH Three ) Two 3-907 2 1 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) H 3-908 2 1 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) CH Three 3-909 2 1 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) CH Two CH Three 3-910 2 1 CH Three (CH Two ) Four COO CH Three (CH Two ) Four COO NHC (= NH) NH Two 3-911 2 1 CH Three (CH Two ) 6 COO OH NH Two 3-912 2 1 CH Three (CH Two ) 6 COO OH NHCH Three 3-913 2 1 CH Three (CH Two ) 6 COO OH N (CH Three ) Two 3-914 2 1 CH Three (CH Two ) 6 COO OH NHC (= NH) H 3-915 2 1 CH Three (CH Two ) 6 COO OH NHC (= NH) CH Three 3-916 2 1 CH Three (CH Two ) 6 COO OH NHC (= NH) CH Two CH Three 3-917 2 1 CH Three (CH Two ) 6 COO OH NHC (= NH) NH Two 3-918 2 1 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NH Two 3-919 2 1 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHCH Three 3-920 2 1 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COON (CH Three ) Two 3-921 2 1 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) H 3-922 2 1 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) CH Three 3-923 2 1 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) CH Two CH Three 3-924 2 1 CH Three (CH Two ) 6 COO CH Three (CH Two ) 6 COO NHC (= NH) NH Two 3-925 2 1 CH Three (CH Two ) 8 COO OH NH Two 3-926 2 1 CH Three (CH Two ) 8 COO OH NHCH Three 3-927 2 1 CH Three (CH Two ) 8 COO OH N (CH Three ) Two 3-928 2 1 CH Three (CH Two ) 8 COO OH NHC (= NH) H 3-929 2 1 CH Three (CH Two ) 8 COO OH NHC (= NH) CH Three 3-930 2 1 CH Three (CH Two ) 8 COO OH NHC (= NH) CH Two CH Three 3-931 2 1 CH Three (CH Two ) 8 COO OH NHC (= NH) NH Two 3-932 2 1 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NH Two 3-933 2 1 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHCH Three 3-934 2 1 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COON (CH Three ) Two 3-935 2 1 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) H 3-936 2 1 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) CH Three 3-937 2 1 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) CH Two CH Three 3-938 2 1 CH Three (CH Two ) 8 COO CH Three (CH Two ) 8 COO NHC (= NH) NH Two 3-939 2 1 CH Three (CH Two ) Ten COO OH NH Two 3-940 2 1 CH Three (CH Two ) Ten COO OH NHCH Three 3-941 2 1 CH Three (CH Two ) Ten COO OH N (CH Three ) Two 3-942 2 1 CH Three (CH Two ) Ten COO OH NHC (= NH) H 3-943 2 1 CH Three (CH Two ) Ten COO OH NHC (= NH) CH Three 3-944 2 1 CH Three (CH Two ) Ten COO OH NHC (= NH) CH Two CH Three 3-945 2 1 CH Three (CH Two ) Ten COO OH NHC (= NH) NH Two 3-946 2 1 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NH Two 3-947 2 1 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHCH Three 3-948 2 1 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COON (CH Three ) Two 3-949 2 1 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) H 3-950 2 1 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) CH Three 3-951 2 1 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) CH Two CH Three 3-952 2 1 CH Three (CH Two ) Ten COO CH Three (CH Two ) Ten COO NHC (= NH) NH Two 3-953 2 1 CH Three (CH Two ) 12 COO OH NH Two 3-954 2 1 CH Three (CH Two ) 12 COO OH NHCH Three 3-955 2 1 CH Three (CH Two ) 12 COO OH N (CH Three ) Two 3-956 2 1 CH Three (CH Two ) 12 COO OH NHC (= NH) H 3-957 2 1 CH Three (CH Two ) 12 COO OH NHC (= NH) CH Three 3-958 2 1 CH Three (CH Two ) 12 COO OH NHC (= NH) CH Two CH Three 3-959 2 1 CH Three (CH Two ) 12 COO OH NHC (= NH) NH Two 3-960 2 1 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NH Two 3-961 2 1 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHCH Three 3-962 2 1 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COON (CH Three ) Two 3-963 2 1 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) H 3-964 2 1 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) CH Three 3-965 2 1 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) CH Two CH Three 3-966 2 1 CH Three (CH Two ) 12 COO CH Three (CH Two ) 12 COO NHC (= NH) NH Two 3-967 2 1 CH Three (CH Two ) 14 COO OH NH Two 3-968 2 1 CH Three (CH Two ) 14 COO OH NHCH Three 3-969 2 1 CH Three (CH Two ) 14 COO OH N (CH Three ) Two 3-970 2 1 CH Three (CH Two ) 14 COO OH NHC (= NH) H 3-971 2 1 CH Three (CH Two ) 14 COO OH NHC (= NH) CH Three 3-972 2 1 CH Three (CH Two ) 14 COO OH NHC (= NH) CH Two CH Three 3-973 2 1 CH Three (CH Two ) 14 COO OH NHC (= NH) NH Two 3-974 2 1 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NH Two 3-975 2 1 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHCH Three 3-976 2 1 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COON (CH Three ) Two 3-977 2 1 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) H 3-978 2 1 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) CH Three 3-979 2 1 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) CH Two CH Three 3-980 2 1 CH Three (CH Two ) 14 COO CH Three (CH Two ) 14 COO NHC (= NH) NH Two 3-981 2 1 CH Three (CH Two ) 16 COO OH NH Two 3-982 2 1 CH Three (CH Two ) 16 COO OH NHCH Three 3-983 2 1 CH Three (CH Two ) 16 COO OH N (CH Three ) Two 3-984 2 1 CH Three (CH Two ) 16 COO OH NHC (= NH) H 3-985 2 1 CH Three (CH Two ) 16 COO OH NHC (= NH) CH Three 3-986 2 1 CH Three (CH Two ) 16 COO OH NHC (= NH) CH Two CH Three 3-987 2 1 CH Three (CH Two ) 16 COO OH NHC (= NH) NH Two 3-988 2 1 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NH Two 3-989 2 1 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHCH Three 3-990 2 1 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COON (CH Three ) Two 3-991 2 1 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) H 3-992 2 1 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) CH Three 3-993 2 1 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) CH Two CH Three 3-994 2 1 CH Three (CH Two ) 16 COO CH Three (CH Two ) 16 COO NHC (= NH) NH Two 3-995 2 1 CH Three (CH Two ) 18 COO OH NH Two 3-996 2 1 CH Three (CH Two ) 18 COO OH NHCH Three 3-997 2 1 CH Three (CH Two ) 18 COO OH N (CH Three ) Two 3-998 2 1 CH Three (CH Two ) 18 COO OH NHC (= NH) H 3-999 2 1 CH Three (CH Two ) 18 COO OH NHC (= NH) CH Three 3-1000 2 1 CH Three (CH Two ) 18 COO OH NHC (= NH) CH Two CH Three 3-1001 2 1 CH Three (CH Two ) 18 COO OH NHC (= NH) NH Two 3-1002 2 1 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NH Two 3-1003 2 1 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHCH Three 3-1004 2 1 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COON (CH Three ) Two 3-1005 2 1 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) H 3-1006 2 1 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) CH Three 3-1007 2 1 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) CH Two CH Three 3-1008 2 1 CH Three (CH Two ) 18 COO CH Three (CH Two ) 18 COO NHC (= NH) NH Two -------------------------------------------------- ------------------- Compounds of the present invention exemplified in Tables 1 to 3 and their pharmacological properties
Among the acceptable derivatives, preferably Compound Nos. 1-7,
1-12, 1-14, 1-28, 2-28, 2-35,
2-42, 2-49, 2-56, 2-63, 2-70,
2-77, 2-84, 2-91, 2-210, 2-21
7, 2-224, 2-231, 2-238, 2-24
5, 2-252, 2-259, 2-266, 2-27
3, 2-392, 2-399, 2-406, 2-41
3, 2-420, 2-427, 2-434, 2-44
1, 2-448, 2-455, 3-7, 3-21, 3-
189, 3-175, 3-182, 3-343, 3-3
57, more preferably the following compounds:
You.
【００４３】化合物番号１−７：（4S, 5R, 6R, 2'R,
3'R, 4'R）−5―アセチルアミノ―5，6―ジヒドロ―6―
（3', 4'−ジヒドロキシ−テトラヒドロ−フラン−2'−
イル）―4―グアニジノ―4H―ピラン−2―カルボン酸 化合物番号１−１４：（4S, 5R, 6R, 2'R, 3'R, 4'R）
−5―アセチルアミノ―5，6―ジヒドロ―6―（3', 4'−
ジヒドロキシ−テトラヒドロ−ピラン−2'−イル）―4
―グアニジノ―4H―ピラン−2―カルボン酸 化合物番号１−２８：（4S, 5R, 6R, 2'R, 3'R, 4'R）
−5―アセチルアミノ―5，6―ジヒドロ―6―（3', 4'−
ジヒドロキシ−テトラヒドロ−オキセパン−2'−イル）
―4―グアニジノ―4H―ピラン−2―カルボン酸 化合物番号２−２１０：（4S, 5R, 6R, 2'R, 3'R, 4'
R）−5―アセチルアミノ―5，6―ジヒドロ―6―（3',
4'−ジヒドロキシ−テトラヒドロ−ピラン−2'−イル）
―4―グアニジノ―4H―ピラン−2―カルボン酸ブチル 化合物番号２−２１７：（4S, 5R, 6R, 2'R, 3'R, 4'
R）−5―アセチルアミノ―5，6―ジヒドロ―6―（3',
4'−ジヒドロキシ−テトラヒドロ−ピラン−2'−イル）
―4―グアニジノ―4H―ピラン−2―カルボン酸ペンチル 化合物番号２−２２４：（4S, 5R, 6R, 2'R, 3'R, 4'
R）−5―アセチルアミノ―5，6―ジヒドロ―6―（3',
4'−ジヒドロキシ−テトラヒドロ−ピラン−2'−イル）
―4―グアニジノ―4H―ピラン−2―カルボン酸ヘキシル 化合物番号２−２３１：（4S, 5R, 6R, 2'R, 3'R, 4'
R）−5―アセチルアミノ―5，6―ジヒドロ―6―（3',
4'−ジヒドロキシ−テトラヒドロ−ピラン−2'−イル）
―4―グアニジノ―4H―ピラン−2―カルボン酸オクチル 化合物番号２−２３８：（4S, 5R, 6R, 2'R, 3'R, 4'
R）−5―アセチルアミノ―5，6―ジヒドロ―6―（3',
4'−ジヒドロキシ−テトラヒドロ−ピラン−2'−イル）
―4―グアニジノ―4H―ピラン−2―カルボン酸デシル 化合物番号２−２４５：（4S, 5R, 6R, 2'R, 3'R, 4'
R）−5―アセチルアミノ―5，6―ジヒドロ―6―（3',
4'−ジヒドロキシ−テトラヒドロ−ピラン−2'−イル）
―4―グアニジノ―4H―ピラン−2―カルボン酸ドデシル 化合物番号２−２５２：（4S, 5R, 6R, 2'R, 3'R, 4'
R）−5―アセチルアミノ―5，6―ジヒドロ―6―（3',
4'−ジヒドロキシ−テトラヒドロ−ピラン−2'−イル）
―4―グアニジノ―4H―ピラン−2―カルボン酸テトラデ
シル 化合物番号２−２５９：（4S, 5R, 6R, 2'R, 3'R, 4'
R）−5―アセチルアミノ―5，6―ジヒドロ―6―（3',
4'−ジヒドロキシ−テトラヒドロ−ピラン−2'−イル）
―4―グアニジノ―4H―ピラン−2―カルボン酸ヘキサデ
シル 化合物番号２−２６６：（4S, 5R, 6R, 2'R, 3'R, 4'
R）−5―アセチルアミノ―5，6―ジヒドロ―6―（3',
4'−ジヒドロキシ−テトラヒドロ−ピラン−2'−イル）
―4―グアニジノ―4H―ピラン−2―カルボン酸オクタデ
シル 化合物番号２−２７３：（4S, 5R, 6R, 2'R, 3'R, 4'
R）−5―アセチルアミノ―5，6―ジヒドロ―6―（3',
4'−ジヒドロキシ−テトラヒドロ−ピラン−2'−イル）
―4―グアニジノ―4H―ピラン−2―カルボン酸アイコサ
ニルCompound No. 1-7: (4S, 5R, 6R, 2'R,
3'R, 4'R) -5-acetylamino-5,6-dihydro-6-
(3 ', 4'-dihydroxy-tetrahydro-furan-2'-
Yl) -4-guanidino-4H-pyran-2-carboxylic acid Compound No. 1-14: (4S, 5R, 6R, 2'R, 3'R, 4'R)
-5-acetylamino-5,6-dihydro-6- (3 ', 4'-
Dihydroxy-tetrahydro-pyran-2'-yl) -4
-Guanidino-4H-pyran-2-carboxylic acid Compound No. 1-28: (4S, 5R, 6R, 2'R, 3'R, 4'R)
-5-acetylamino-5,6-dihydro-6- (3 ', 4'-
Dihydroxy-tetrahydro-oxepan-2'-yl)
-4-guanidino-4H-pyran-2-carboxylic acid Compound No. 2-210: (4S, 5R, 6R, 2'R, 3'R, 4 '
R) -5-Acetylamino-5,6-dihydro-6- (3 ',
4'-dihydroxy-tetrahydro-pyran-2'-yl)
-Butyl 4-guanidino-4H-pyran-2-carboxylate Compound No. 2-217: (4S, 5R, 6R, 2'R, 3'R, 4 '
R) -5-Acetylamino-5,6-dihydro-6- (3 ',
4'-dihydroxy-tetrahydro-pyran-2'-yl)
―Pentyl 4-guanidino-4H-pyran-2-carboxylate Compound No. 2-224: (4S, 5R, 6R, 2'R, 3'R, 4 '
R) -5-Acetylamino-5,6-dihydro-6- (3 ',
4'-dihydroxy-tetrahydro-pyran-2'-yl)
-Hexyl-4-guanidino-4H-pyran-2-carboxylate Compound No. 2-231: (4S, 5R, 6R, 2'R, 3'R, 4 '
R) -5-Acetylamino-5,6-dihydro-6- (3 ',
4'-dihydroxy-tetrahydro-pyran-2'-yl)
-Octyl 4--4-guanidino-4H-pyran-2-carboxylate Compound No. 2-238: (4S, 5R, 6R, 2'R, 3'R, 4 '
R) -5-Acetylamino-5,6-dihydro-6- (3 ',
4'-dihydroxy-tetrahydro-pyran-2'-yl)
―4-Guanidino-4H-pyran-2-carboxylate decyl Compound No. 2-245: (4S, 5R, 6R, 2′R, 3′R, 4 ′
R) -5-Acetylamino-5,6-dihydro-6- (3 ',
4'-dihydroxy-tetrahydro-pyran-2'-yl)
―4-guanidino-4H-pyran-2-carboxylate dodecyl Compound No. 2-252: (4S, 5R, 6R, 2'R, 3'R, 4 '
R) -5-Acetylamino-5,6-dihydro-6- (3 ',
4'-dihydroxy-tetrahydro-pyran-2'-yl)
―4-guanidino-4H-pyran-2-carboxylate tetradecyl Compound No. 2-259: (4S, 5R, 6R, 2'R, 3'R, 4 '
R) -5-Acetylamino-5,6-dihydro-6- (3 ',
4'-dihydroxy-tetrahydro-pyran-2'-yl)
-Hexadecyl-4-guanidino-4H-pyran-2-carboxylate Compound No. 2-266: (4S, 5R, 6R, 2'R, 3'R, 4 '
R) -5-Acetylamino-5,6-dihydro-6- (3 ',
4'-dihydroxy-tetrahydro-pyran-2'-yl)
―4-Guanidino-4H-pyran-2-carboxylate octadecyl Compound No. 2-273: (4S, 5R, 6R, 2'R, 3'R, 4 '
R) -5-Acetylamino-5,6-dihydro-6- (3 ',
4'-dihydroxy-tetrahydro-pyran-2'-yl)
―4-Guanidino-4H-pyran-2-carboxylate eicosanil
【００４４】[0044]
【発明の実施の形態】一般式（１）で表される化合物、
その薬理上許容されるエステル誘導体及びそれらの薬理
上許容される塩は下記の方法によって製造することがで
きる。BEST MODE FOR CARRYING OUT THE INVENTION A compound represented by the general formula (1):
The pharmacologically acceptable ester derivatives and their pharmacologically acceptable salts can be produced by the following methods.
【００４５】Ａ法は、一般式（１）で表される化合物を
製造する方法であり、下記の工程式によって示される。Method A is a method for producing the compound represented by the general formula (1), and is represented by the following process formula.
【００４６】[0046]
【化７】 Embedded image
【００４７】式中、Ｒ1乃至Ｒ10、ｎ及びｍは前述と同
意義である。ＲOH 1は水酸基の保護基を示す。Ｒ1p及び
Ｒ2pはＲ1及びＲ2において水酸基が保護されていてもよ
いことを示す。Ｒ10pはＲ10に含まれるアミノ、イミノ
又はグアニジノ基が保護されていてもよいことを示す。In the formula, R 1 to R 10 , n and m are as defined above. R OH 1 represents a protecting group for a hydroxyl group. R 1p and R 2p indicate that the hydroxyl group in R 1 and R 2 may be protected. R 10p indicates that the amino, imino or guanidino group contained in R 10 may be protected.
【００４８】ＲOH 1の水酸基の保護基としては、例えば
アセチル、プロピオニル、ブチリル、ペンタノイル、ピ
バロイル、ヘキサノイル基のような炭素数１乃至６個の
アルカノイル基；ベンゾイルのような芳香族アシル基を
挙げることができる。これらのうち好適には炭素数１乃
至６個のアルカノイル基であり、更に好適にはアセチル
又はピバロイル基である。Examples of the hydroxyl-protecting group for R OH 1 include alkanoyl groups having 1 to 6 carbon atoms such as acetyl, propionyl, butyryl, pentanoyl, pivaloyl and hexanoyl; and aromatic acyl groups such as benzoyl. be able to. Of these, an alkanoyl group having 1 to 6 carbon atoms is preferable, and an acetyl or pivaloyl group is more preferable.
【００４９】Ｒ1p及びＲ2pにおける水酸基の保護基とし
ては、前述のＲOH 1の水酸基の保護基のほかに、例えば
トリメチルシリル、トリエチルシリル、ｔ−ブチルジメ
チルシリルのようなトリ（炭素数１乃至４個のアルキ
ル）シリル基；イソプロピリデン基のようなＲ1及びＲ2
の２個の水酸基を同時に保護するエーテル系保護基を挙
げることができる。これらのうち好適にはアセチル基ま
たはイソプロピリデン基である。Examples of the hydroxyl-protecting group for R 1p and R 2p include, in addition to the above-mentioned hydroxyl-protecting group for R OH 1 , tri- (trimethylsilyl, triethylsilyl and t-butyldimethylsilyl) tri- R 1 and R 2 such as four alkyl) silyl groups;
And ether-based protecting groups which simultaneously protect the two hydroxyl groups. Of these, an acetyl group or an isopropylidene group is preferred.
【００５０】Ｒ10pにおけるアミノ、イミノ又はグアニ
ジノ基の保護基としては、例えばメトキシカルボニル、
エトキシカルボニル、ｔ−ブチルオキシカルボニル基の
ような炭素数１乃至４個のアルコキシカルボニル基；ア
リルオキシカルボニル基;ベンジル、４−メトキシベン
ジルのような置換されていてもよいベンジル基；ベンジ
ルオキシカルボニル、４−ニトロベンジルオキシカルボ
ニルのような置換されていてもよいベンジルオキシカル
ボニル基を挙げることができる。これらのうち好適には
ｔ−ブチルオキシカルボニル、アリルオキシカルボニル
又は４−ニトロベンジルオキシカルボニル基であり、特
に好適にはｔ−ブチルオキシカルボニル基である。The protecting group for the amino, imino or guanidino group in R 10p includes, for example, methoxycarbonyl,
C1-C4 alkoxycarbonyl groups such as ethoxycarbonyl and t-butyloxycarbonyl; allyloxycarbonyl; optionally substituted benzyl such as benzyl and 4-methoxybenzyl; benzyloxycarbonyl; An optionally substituted benzyloxycarbonyl group such as 4-nitrobenzyloxycarbonyl can be mentioned. Of these, a t-butyloxycarbonyl, allyloxycarbonyl or 4-nitrobenzyloxycarbonyl group is preferred, and a t-butyloxycarbonyl group is particularly preferred.
【００５１】以下、各工程について詳述する。 （第Ａ−１工程）第Ａ−１工程はジエン化合物（１１）
を閉環反応に付して化合物（１２）を製造する工程であ
る。Hereinafter, each step will be described in detail. (Step A-1) Step A-1 is a diene compound (11)
Is subjected to a ring closure reaction to produce a compound (12).
【００５２】本工程は、化合物（１１）に溶媒中、閉環
剤を作用させることにより達成される。This step is achieved by reacting compound (11) with a ring-closing agent in a solvent.
【００５３】出発原料となる化合物（１１）は、後述す
るＢ法、Ｃ法またはＤ法によって製造することができ
る。Compound (11) as a starting material can be produced by Method B, Method C or Method D described later.
【００５４】使用される溶媒としては、反応を阻害せず
原料化合物や反応剤をある程度溶解するものであれば特
に制限はなく、例えばヘキサン、シクロヘキサンのよう
な飽和炭化水素類；ベンゼン、トルエン、キシレンのよ
うな芳香族炭化水素類；ジクロロメタン、ジクロロエタ
ン、クロロホルムのようなハロゲン化炭化水素類；エー
テル、テトラヒドロフラン、ジオキサンのようなエーテ
ル類；酢酸エチルのような酢酸エステル類；アセトニト
リルのようなニトリル類；ジメチルホルムアミド、ジメ
チルアセトアミドのようなアミド類を挙げることができ
る。これらのうち、好適にはハロゲン化炭化水素類（特
にジクロロメタン）である。The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent. For example, saturated hydrocarbons such as hexane and cyclohexane; benzene, toluene and xylene Aromatic hydrocarbons such as dichloromethane, dichloroethane, chloroform; ethers such as ether, tetrahydrofuran and dioxane; acetates such as ethyl acetate; nitriles such as acetonitrile; Amides such as dimethylformamide and dimethylacetamide can be mentioned. Of these, halogenated hydrocarbons (particularly dichloromethane) are preferred.
【００５５】閉環剤としては、ベンジリデン−ビス（ト
リシクロヘキシルホスフィン）ジクロロルテニウム又は
それと同様に作用する金属錯体を使用することができ
る。As the ring closing agent, benzylidene-bis (tricyclohexylphosphine) dichlororuthenium or a metal complex acting in the same manner can be used.
【００５６】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常０℃乃至溶媒の沸点
の範囲であり、好適には１０乃至５０℃である。The reaction temperature varies depending on the types of the starting compounds and the reactants used, but is usually in the range of 0 ° C. to the boiling point of the solvent, preferably 10 to 50 ° C.
【００５７】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常０．５乃至２４
時間であり、好適には１乃至６時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is usually 0.5 to 24.
Time, preferably 1 to 6 hours.
【００５８】反応終了後、化合物（１２）は通常の方法
により反応混合物から採取できる。例えば反応混合液又
は反応混合液の溶剤を留去して得られる残査に水と混合
しない有機溶剤を加え、水洗し、溶剤を留去して得られ
る。After completion of the reaction, compound (12) can be collected from the reaction mixture by a usual method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【００５９】得られた化合物（１２）は、必要ならば常
法、例えば再結晶、再沈殿又はクロマトグラフィー等に
よって更に精製することができる。 （第Ａ−２工程）第Ａ−２工程は化合物（１２）の二重
結合にＲ1及びＲ2で表される基を付加させて化合物（１
３）を製造する工程である。 （ｉ）Ｒ1及びＲ2が同一であって水素原子を示す場合 本工程は、化合物（１２）に溶媒中、水素付加剤を反応
させることによって達成される。The obtained compound (12) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step A-2) In step A- 2 , a group represented by R 1 and R 2 is added to the double bond of compound (12) to give compound (1).
This is the step of manufacturing 3). (I) When R 1 and R 2 are the Same and Represent a Hydrogen Atom This step is achieved by reacting compound (12) with a hydrogenating agent in a solvent.
【００６０】使用される溶媒としては、反応を阻害せず
原料化合物や反応剤をある程度溶解するものであれば特
に制限はなく、例えば酢酸、プロピオン酸のような有機
酸；ヘキサン、シクロヘキサンのような飽和炭化水素
類；ベンゼン、トルエン、キシレンのような芳香族炭化
水素類；ジクロロメタン、ジクロロエタン、クロロホル
ムのようなハロゲン化炭化水素類；メタノール、エタノ
ールのようなアルコール類;エーテル、テトラヒドロフ
ラン、ジオキサンのようなエーテル類；酢酸エチルのよ
うな酢酸エステル類；アセトニトリルのようなニトリル
類；ジメチルホルムアミド、ジメチルアセトアミドのよ
うなアミド類を挙げることができる。これらのうち、好
適にはアルコール類（特にエタノール）である。The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent. For example, organic acids such as acetic acid and propionic acid; hexane and cyclohexane. Saturated hydrocarbons; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane Ethers; acetates such as ethyl acetate; nitriles such as acetonitrile; amides such as dimethylformamide and dimethylacetamide. Of these, alcohols (particularly ethanol) are preferred.
【００６１】使用される水素付加剤としては、二重結合
を水素化することができるものであれば特に制限はな
い。このような水素付加剤としては、接触還元法に使用
される水素ガス−金属触媒（例えば、白金、パラジウ
ム、ロジウム、パラジウム炭素、ロジウム炭素、リンド
ラー触媒等）の組み合わせが好適であり、特に好適には
水素ガス−パラジウム炭素触媒の組み合わせである。The hydrogenating agent used is not particularly limited as long as it can hydrogenate a double bond. As such a hydrogenation agent, a combination of a hydrogen gas-metal catalyst (for example, platinum, palladium, rhodium, palladium carbon, rhodium carbon, Lindlar catalyst, etc.) used in the catalytic reduction method is preferable, and particularly preferably. Is a combination of hydrogen gas-palladium carbon catalyst.
【００６２】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常０℃乃至溶媒の沸点
の範囲であり、好適には１０乃至５０℃である。The reaction temperature varies depending on the types of the starting compounds and the reactants used, but is usually in the range of 0 ° C. to the boiling point of the solvent, preferably 10 to 50 ° C.
【００６３】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常０．５乃至２４
時間であり、好適には０．５乃至５時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is usually 0.5 to 24.
Time, preferably 0.5 to 5 hours.
【００６４】反応終了後、化合物（１３）は通常の方法
により反応混合物から採取できる。例えば反応混合液又
は反応混合液の溶剤を留去して得られる残査に水と混合
しない有機溶剤を加え、水洗し、溶剤を留去して得られ
る。After completion of the reaction, compound (13) can be collected from the reaction mixture by a usual method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【００６５】得られた化合物（１３）は、必要ならば常
法、例えば再結晶、再沈殿又はクロマトグラフィー等に
よって更に精製することができる。 （ｉｉ）Ｒ1及びＲ2が同一であって水酸基を示す場合 本工程は、化合物（１２）に溶媒中、水酸基の付加剤を
反応させることによって達成される。The obtained compound (13) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Ii) When R 1 and R 2 are the Same and Denote a Hydroxyl Group This step is achieved by reacting compound (12) with a hydroxyl group addition agent in a solvent.
【００６６】使用される溶媒としては、反応を阻害せず
原料化合物や反応剤をある程度溶解するものであれば特
に制限はなく、例えば酢酸、プロピオン酸のような有機
酸；ヘキサン、シクロヘキサンのような飽和炭化水素
類；ベンゼン、トルエン、キシレンのような芳香族炭化
水素類；ジクロロメタン、ジクロロエタン、クロロホル
ムのようなハロゲン化炭化水素類；メタノール、エタノ
ール、プロパノール、ｔ−ブタノールのようなアルコー
ル類;エーテル、テトラヒドロフラン、ジオキサンのよ
うなエーテル類；酢酸エチルのような酢酸エステル類；
アセトニトリルのようなニトリル類；ジメチルホルムア
ミド、ジメチルアセトアミドのようなアミド類を挙げる
ことができる。これらのうち、好適にはアルコール類
（特にエタノールまたはｔ−ブタノール）である。The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent. For example, organic acids such as acetic acid and propionic acid; hexane and cyclohexane. Saturated hydrocarbons; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; alcohols such as methanol, ethanol, propanol and t-butanol; ethers; Ethers such as tetrahydrofuran and dioxane; acetates such as ethyl acetate;
Examples thereof include nitriles such as acetonitrile; amides such as dimethylformamide and dimethylacetamide. Of these, alcohols (particularly ethanol or t-butanol) are preferred.
【００６７】使用される水酸基の付加剤としては、二重
結合に水酸基を付加することができるものであれば特に
制限はない。このような水酸基付加剤としては、四酸化
オスミウム、四酸化ルテニウムのような酸化金属類を挙
げることができ、好適には四酸化オスミウムである。な
お、四酸化オスミウムを触媒量とし、Ｎ−メチルモルホ
リン−Ｎ−オキシドのようなＮ−オキシド類を共用する
ことができる。The hydroxyl group-adding agent used is not particularly limited as long as it can add a hydroxyl group to a double bond. Examples of such a hydroxyl group-adding agent include metal oxides such as osmium tetroxide and ruthenium tetroxide, and osmium tetroxide is preferred. In addition, N-oxides such as N-methylmorpholine-N-oxide can be used in common with osmium tetroxide as a catalytic amount.
【００６８】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常０℃乃至溶媒の沸点
の範囲であり、好適には０乃至５０℃である。The reaction temperature varies depending on the types of the starting compounds and the reactants used, but is usually in the range of 0 ° C. to the boiling point of the solvent, preferably 0 to 50 ° C.
【００６９】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常０．５乃至４８
時間であり、好適には０．５乃至１２時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature.
Time, preferably 0.5 to 12 hours.
【００７０】反応終了後、化合物（１３）は通常の方法
により反応混合物から採取できる。例えば反応混合液又
は反応混合液の溶剤を留去して得られる残査に水と混合
しない有機溶剤を加え、水洗し、溶剤を留去して得られ
る。After completion of the reaction, compound (13) can be collected from the reaction mixture by a usual method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【００７１】得られた化合物（１３）は、必要ならば常
法、例えば再結晶、再沈殿又はクロマトグラフィー等に
よって更に精製することができる。 （ｉｉｉ）Ｒ1及びＲ2が異なって水素原子または水酸基
を示す場合 本工程は、化合物（１２）に溶媒中、エポキシ化剤を反
応させエポキシド体に導き、次いで水素化剤を作用させ
ることによって達成される。The obtained compound (13) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Iii) When R 1 and R 2 are different from each other and represent a hydrogen atom or a hydroxyl group, this step comprises reacting the compound (12) with an epoxidizing agent in a solvent to lead to an epoxide form, and then reacting the compound with the hydrogenating agent. Achieved.
【００７２】エポキシ化に使用される溶媒としては、反
応を阻害せず原料化合物や反応剤をある程度溶解するも
のであれば特に制限はなく、例えばヘキサン、シクロヘ
キサンのような飽和炭化水素類；ベンゼン、トルエン、
キシレンのような芳香族炭化水素類；ジクロロメタン、
ジクロロエタン、クロロホルムのようなハロゲン化炭化
水素類；メタノール、エタノールのようなアルコール
類;エーテル、テトラヒドロフラン、ジオキサンのよう
なエーテル類；酢酸エチルのような酢酸エステル類；ア
セトニトリルのようなニトリル類；ジメチルホルムアミ
ド、ジメチルアセトアミドのようなアミド類を挙げるこ
とができる。これらのうち、好適にはジクロロメタンで
ある。The solvent used in the epoxidation is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent. For example, saturated hydrocarbons such as hexane and cyclohexane; toluene,
Aromatic hydrocarbons such as xylene; dichloromethane,
Halogenated hydrocarbons such as dichloroethane and chloroform; alcohols such as methanol and ethanol; ethers such as ether, tetrahydrofuran and dioxane; acetates such as ethyl acetate; nitriles such as acetonitrile; dimethylformamide And amides such as dimethylacetamide. Of these, dichloromethane is preferred.
【００７３】使用されるエポキシ化剤としては、二重結
合をエポキシ化することができるものであれば特に制限
はない。このような反応剤としては、メタクロロ過安息
香酸のような有機過酸類；過酸化水素；ｔ−ブチルヒド
ロペルオキシドのような有機ヒドロペルオキシド類を使
用することができる。The epoxidizing agent used is not particularly limited as long as it can epoxidize the double bond. Examples of such a reactant include organic peracids such as metachloroperbenzoic acid; hydrogen peroxide; and organic hydroperoxides such as t-butyl hydroperoxide.
【００７４】エポキシ化の反応温度は、使用される原料
化合物及び反応剤の種類によって異なるが、通常０℃乃
至溶媒の沸点の範囲であり、好適には０乃至５０℃であ
る。The reaction temperature of the epoxidation varies depending on the type of the starting compound and the reactant used, but is usually in the range of 0 ° C. to the boiling point of the solvent, preferably 0 to 50 ° C.
【００７５】エポキシ化の反応時間は、使用される原料
化合物、反応剤及び反応温度によって異なるが、通常
０．５乃至４８時間であり、好適には０．５乃至１２時
間である。The reaction time for the epoxidation varies depending on the starting compounds used, the reactants and the reaction temperature, but is usually 0.5 to 48 hours, preferably 0.5 to 12 hours.
【００７６】反応終了後、エポキシド化合物は通常の方
法により反応混合物から採取できる。例えば反応混合液
又は反応混合液の溶剤を留去して得られる残査に水と混
合しない有機溶剤を加え、水洗し、溶剤を留去して得ら
れる。After completion of the reaction, the epoxide compound can be collected from the reaction mixture by a conventional method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【００７７】得られたエポキシド化合物は、必要ならば
常法、例えば再結晶、再沈殿又はクロマトグラフィー等
によって更に精製することができる。The obtained epoxide compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
【００７８】得られたエポキシド化合物は、次の水素化
反応に付される。The obtained epoxide compound is subjected to the following hydrogenation reaction.
【００７９】水素化に使用される溶媒としては、反応を
阻害せず原料化合物や反応剤をある程度溶解するもので
あれば特に制限はなく、例えばヘキサン、シクロヘキサ
ンのような飽和炭化水素類；ベンゼン、トルエン、キシ
レンのような芳香族炭化水素類；ジクロロメタン、ジク
ロロエタン、クロロホルムのようなハロゲン化炭化水素
類；メタノール、エタノールのようなアルコール類;エ
ーテル、テトラヒドロフラン、ジオキサンのようなエー
テル類；酢酸エチルのような酢酸エステル類；アセトニ
トリルのようなニトリル類；ジメチルホルムアミド、ジ
メチルアセトアミドのようなアミド類を挙げることがで
きる。これらのうち、好適にはアルコール類（特にメタ
ノールまたはエタノール）である。The solvent used for the hydrogenation is not particularly limited as long as it does not inhibit the reaction and dissolves the starting compounds and the reactants to some extent. For example, saturated hydrocarbons such as hexane and cyclohexane; Aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; alcohols such as methanol and ethanol; ethers such as ether, tetrahydrofuran and dioxane; Acetic acid esters; nitriles such as acetonitrile; amides such as dimethylformamide and dimethylacetamide. Of these, alcohols (particularly methanol or ethanol) are preferred.
【００８０】水素化剤としては、エポキシドを還元的に
開いてアルコールを生成することができるものであれば
特に制限はない。このような水素化剤としてはリンドラ
ー触媒、パラジウム炭素触媒のような金属触媒と水素ガ
スを組み合わせて使用することができる。The hydrogenating agent is not particularly limited as long as the epoxide can be reductively opened to produce an alcohol. As such a hydrogenating agent, a metal catalyst such as a Lindlar catalyst or a palladium carbon catalyst and hydrogen gas can be used in combination.
【００８１】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常０℃乃至溶媒の沸点
の範囲であり、好適には０乃至５０℃である。The reaction temperature varies depending on the types of the starting compounds and the reactants used, but is usually in the range of 0 ° C. to the boiling point of the solvent, preferably 0 to 50 ° C.
【００８２】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常０．５乃至２４
時間であり、好適には２．５乃至６時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is usually 0.5 to 24.
Hours, preferably 2.5 to 6 hours.
【００８３】反応終了後、化合物（１３）は通常の方法
により反応混合物から採取できる。例えば反応混合液又
は反応混合液の溶剤を留去して得られる残査に水と混合
しない有機溶剤を加え、水洗し、溶剤を留去して得られ
る。After completion of the reaction, compound (13) can be collected from the reaction mixture by a usual method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【００８４】得られた化合物（１３）は、必要ならば常
法、例えば再結晶、再沈殿又はクロマトグラフィー等に
よって更に精製することができる。 （第Ａ−３工程）第Ａ−３工程は化合物（１３）を閉環
反応に付してオキサゾリン化合物（１４）を製造する工
程である。The obtained compound (13) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step A-3) Step A-3 is a step of subjecting compound (13) to a ring closure reaction to produce an oxazoline compound (14).
【００８５】本工程は、化合物（１３）に溶媒中、酸を
作用させることにより達成され、水酸基の保護化剤を共
存させることによって、Ｒ1またはＲ2の水酸基を保護す
ることができる。This step is achieved by reacting compound (13) with an acid in a solvent, and the hydroxyl group of R 1 or R 2 can be protected by the coexistence of a hydroxyl group protecting agent.
【００８６】使用される溶媒としては、反応を阻害せず
原料化合物や反応剤をある程度溶解するものであれば特
に制限はなく、例えば酢酸、プロピオン酸のような有機
酸；ヘキサン、シクロヘキサンのような飽和炭化水素
類；ベンゼン、トルエン、キシレンのような芳香族炭化
水素類；ジクロロメタン、ジクロロエタン、クロロホル
ムのようなハロゲン化炭化水素類；メタノール、エタノ
ールのようなアルコール類;エーテル、テトラヒドロフ
ラン、ジオキサンのようなエーテル類；酢酸エチルのよ
うな酢酸エステル類；アセトニトリルのようなニトリル
類；ジメチルホルムアミド、ジメチルアセトアミドのよ
うなアミド類を挙げることができる。これらのうち、好
適には有機酸類（特に酢酸）である。The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting compounds and the reactants to some extent. For example, organic acids such as acetic acid and propionic acid; hexane and cyclohexane. Saturated hydrocarbons; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane Ethers; acetates such as ethyl acetate; nitriles such as acetonitrile; amides such as dimethylformamide and dimethylacetamide. Of these, organic acids (particularly acetic acid) are preferred.
【００８７】使用される酸としては、例えば塩酸、硫
酸、硝酸のような無機酸類；酢酸、トリフルオロ酢酸の
ような有機酸類；メタンスルホン酸、トリフルオロメタ
ンスルホン酸、ベンゼンスルホン酸のような有機スルホ
ン酸類を挙げることができるが、好適には無機酸類（特
に硫酸）である。Examples of the acid used include inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid; organic acids such as acetic acid and trifluoroacetic acid; and organic sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and benzenesulfonic acid. Acids can be mentioned, but inorganic acids (particularly sulfuric acid) are preferred.
【００８８】共存させることができる水酸基の保護化剤
としては、例えば無水酢酸、無水プロピオン酸、無水安
息香酸のような有機酸無水物を挙げることができ、好適
には無水酢酸である。Examples of the hydroxyl group-protecting agent which can coexist include organic acid anhydrides such as acetic anhydride, propionic anhydride and benzoic anhydride, and acetic anhydride is preferred.
【００８９】使用される溶媒、酸及び水酸基の保護化剤
の組み合わせとしては、好適には酢酸、硫酸及び無水酢
酸の組み合わせである。The combination of a solvent, an acid and a protecting agent for a hydroxyl group to be used is preferably a combination of acetic acid, sulfuric acid and acetic anhydride.
【００９０】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常３０℃乃至溶媒の沸
点の範囲であり、好適には３０乃至８０℃である。The reaction temperature varies depending on the type of the starting compounds and the reactants used, but is usually in the range of 30 ° C. to the boiling point of the solvent, preferably 30 to 80 ° C.
【００９１】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常１乃至２４時間
であり、好適には２乃至６時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is usually from 1 to 24 hours, preferably from 2 to 6 hours.
【００９２】反応終了後、化合物（１４）は通常の方法
により反応混合物から採取できる。例えば反応混合液又
は反応混合液の溶剤を留去して得られる残査に水と混合
しない有機溶剤を加え、水洗し、溶剤を留去して得られ
る。After completion of the reaction, compound (14) can be collected from the reaction mixture by a usual method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【００９３】得られた化合物（１４）は、必要ならば常
法、例えば再結晶、再沈殿又はクロマトグラフィー等に
よって更に精製することができる。 （第Ａ−４工程）第Ａ−４工程はオキサゾリン化合物
（１４）にアジド基を導入してオキサゾリン環を開き化
合物（１５）を製造する工程である。The obtained compound (14) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step A-4) Step A-4 is a step of introducing an azide group into the oxazoline compound (14) to open the oxazoline ring and produce the compound (15).
【００９４】本工程は、化合物（１４）に溶媒中、アジ
ド化剤を作用させることにより達成される。This step is achieved by reacting compound (14) with an azidating agent in a solvent.
【００９５】使用される溶媒としては、反応を阻害せず
原料化合物や反応剤をある程度溶解するものであれば特
に制限はなく、例えばヘキサン、シクロヘキサンのよう
な飽和炭化水素類；ベンゼン、トルエン、キシレンのよ
うな芳香族炭化水素類；ジクロロメタン、ジクロロエタ
ン、クロロホルムのようなハロゲン化炭化水素類；メタ
ノール、エタノール、ｔ−ブタノールのようなアルコー
ル類；エーテル、テトラヒドロフラン、ジオキサンのよ
うなエーテル類；酢酸エチルのような酢酸エステル類；
アセトニトリルのようなニトリル類；ジメチルホルムア
ミド、ジメチルアセトアミドのようなアミド類；ジメチ
ルスルホキシドのようなスルホキシド類を挙げることが
できる。これらのうち、好適にはアミド類（特にジメチ
ルホルムアミド）またはアルコール類（特にｔ−ブタノ
ール）である。The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent. For example, saturated hydrocarbons such as hexane and cyclohexane; benzene, toluene and xylene Aromatic hydrocarbons such as dichloromethane, dichloroethane and chloroform; alcohols such as methanol, ethanol and t-butanol; ethers such as ether, tetrahydrofuran and dioxane; Such acetates;
Examples thereof include nitriles such as acetonitrile; amides such as dimethylformamide and dimethylacetamide; and sulfoxides such as dimethylsulfoxide. Of these, amides (particularly dimethylformamide) or alcohols (particularly t-butanol) are preferred.
【００９６】アジド化剤としては、例えばナトリウムア
ジド、カリウムアジドのようなアルカリ金属アジド類ま
たはトリメチルシリルアジドのようなトリアルキルシリ
ルアジド類を挙げることができ、好適にはナトリウムア
ジドまたはトリメチルシリルアジドである。Examples of the azide agent include alkali metal azides such as sodium azide and potassium azide and trialkylsilyl azides such as trimethylsilyl azide, and preferably sodium azide or trimethylsilyl azide.
【００９７】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常３０℃乃至溶媒の沸
点の範囲であり、好適には５０乃至８５℃である。The reaction temperature varies depending on the types of the starting compounds and the reactants used, but is usually in the range of 30 ° C. to the boiling point of the solvent, preferably 50 to 85 ° C.
【００９８】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常２乃至１６時間
であり、好適には２乃至８時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is usually 2 to 16 hours, preferably 2 to 8 hours.
【００９９】反応終了後、化合物（１５）は通常の方法
により反応混合物から採取できる。例えば反応混合液又
は反応混合液の溶剤を留去して得られる残査に水と混合
しない有機溶剤を加え、水洗し、溶剤を留去して得られ
る。After completion of the reaction, compound (15) can be collected from the reaction mixture by a usual method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【０１００】得られた化合物（１５）は、必要ならば常
法、例えば再結晶、再沈殿又はクロマトグラフィー等に
よって更に精製することができる。 （第Ａ−５工程）第Ａ−５工程は、必要に応じて行われ
る工程であって、化合物（１５）の５位アセトアミド基
を所望のＲ9を有するアルカノイルアミド基へ変換して
化合物（１６）を製造する工程である。The obtained compound (15) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step A-5) Step A-5 is an optional step, wherein the 5-position acetamido group of compound (15) is converted to a desired alkanoylamide group having R 9 to give compound ( 16) is the step of manufacturing.
【０１０１】本工程は、化合物（１５）にｔ−ブトキシ
カルボニル基を導入し、次いでアセチル基及びｔ−ブト
キシカルボニル基を順次除去し、最後に所望のＲ9を有
するアルカノイル基を導入することによって達成され
る。 （１）ｔ−ブトキシカルボニル基の導入 ｔ−ブトキシカルボニル基の導入は、化合物（１５）に
溶媒中、塩基の存在下にｔ−ブトキシカルボニル化剤を
反応させることによって達成される。In this step, a t-butoxycarbonyl group is introduced into the compound (15), the acetyl group and the t-butoxycarbonyl group are sequentially removed, and finally, an alkanoyl group having a desired R 9 is introduced. Achieved. (1) Introduction of t-butoxycarbonyl group Introduction of the t-butoxycarbonyl group is achieved by reacting compound (15) with a t-butoxycarbonylating agent in a solvent in the presence of a base.
【０１０２】使用される溶媒としては、反応を阻害せず
原料化合物や反応剤をある程度溶解するものであれば特
に制限はなく、ハロゲン化炭化水素類（特にジクロロメ
タン）が好適である。The solvent to be used is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent, and halogenated hydrocarbons (particularly dichloromethane) are suitable.
【０１０３】塩基としては有機塩基類（特にジメチルア
ミノピリジン）が好適であり、ｔ−ブトキシカルボニル
化剤としては、ジ−ｔ−ブチルジカーボネイトが好適で
ある。As the base, organic bases (particularly, dimethylaminopyridine) are preferable, and as the t-butoxycarbonylating agent, di-t-butyl dicarbonate is preferable.
【０１０４】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、好適には２０乃至４０℃
である。The reaction temperature varies depending on the type of the starting compounds and the reactants used, but is preferably from 20 to 40 ° C.
It is.
【０１０５】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、好適には１乃至６時
間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is preferably 1 to 6 hours.
【０１０６】反応終了後、目的化合物は通常の方法によ
り反応混合物から採取できる。例えば反応混合液又は反
応混合液の溶剤を留去して得られる残査に水と混合しな
い有機溶剤を加え、水洗し、溶剤を留去して得られる。After completion of the reaction, the target compound can be collected from the reaction mixture by a conventional method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【０１０７】得られた化合物は、必要ならば常法、例え
ば再結晶、再沈殿又はクロマトグラフィー等によって更
に精製することができる。 （２）アセチル基の除去 アセチル基の除去は、溶媒中、脱アセチル化剤を作用さ
せることによって達成される。The obtained compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (2) Removal of acetyl group Removal of the acetyl group is achieved by allowing a deacetylating agent to act in a solvent.
【０１０８】使用される溶媒としては、反応を阻害せず
原料化合物や反応剤をある程度溶解するものであれば特
に制限はなく、好適にはアルコール類（特にメタノー
ル）である。The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent, and is preferably an alcohol (particularly methanol).
【０１０９】脱アセチル化剤としては、ナトリウムメト
キシドが好適である。As a deacetylating agent, sodium methoxide is preferred.
【０１１０】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、好適には０乃至３０℃で
ある。The reaction temperature varies depending on the type of the starting compounds and the reactants used, but is preferably from 0 to 30 ° C.
【０１１１】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、好適には０．５乃至
４時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is preferably 0.5 to 4 hours.
【０１１２】反応終了後、目的化合物は通常の方法によ
り反応混合物から採取できる。例えば反応混合液又は反
応混合液の溶剤を留去して得られる残査に水と混合しな
い有機溶剤を加え、水洗し、溶剤を留去して得られる。After completion of the reaction, the target compound can be collected from the reaction mixture by a usual method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【０１１３】得られた化合物は、必要ならば常法、例え
ば再結晶、再沈殿又はクロマトグラフィー等によって更
に精製することができる。 （３）ｔ−ブトキシカルボニル基の除去 ｔ−ブトキシカルボニル基の除去は、溶媒中、酸を作用
させることによって達成される。The obtained compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (3) Removal of t-butoxycarbonyl group Removal of the t-butoxycarbonyl group is achieved by allowing an acid to act in a solvent.
【０１１４】使用される溶媒としては、反応を阻害せず
原料化合物や反応剤をある程度溶解するものであれば特
に制限はなく、好適にはハロゲン化炭化水素類（特にジ
クロロメタン）である。The solvent to be used is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent, and is preferably a halogenated hydrocarbon (particularly dichloromethane).
【０１１５】使用される酸としては、トリフルオロ酢酸
が好適である。The acid used is preferably trifluoroacetic acid.
【０１１６】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、好適には０乃至３０℃で
ある。The reaction temperature varies depending on the type of the starting compounds and the reactants used, but is preferably from 0 to 30 ° C.
【０１１７】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、好適には０．５乃至
４時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is preferably 0.5 to 4 hours.
【０１１８】反応終了後、得られた５−アミノ化合物は
通常の方法により反応混合物から採取できる。例えば反
応混合液又は反応混合液の溶剤を留去して得られる残査
に水と混合しない有機溶剤を加え、水洗し、溶剤を留去
して得られる。After completion of the reaction, the obtained 5-amino compound can be collected from the reaction mixture by a conventional method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【０１１９】得られた化合物は、必要ならば常法、例え
ば再結晶、再沈殿又はクロマトグラフィー等によって更
に精製することができる。 （４）アルカノイル化反応 アルカノイル基の導入は、５−アミノ化合物に溶媒中、
塩基の存在下にアルカノイル化剤を作用させることによ
って達成される。The obtained compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (4) Alkanoylation reaction Introduction of an alkanoyl group is carried out by adding a 5-amino compound to a
It is achieved by acting an alkanoylating agent in the presence of a base.
【０１２０】使用される溶媒としては、反応を阻害せず
原料化合物や反応剤をある程度溶解するものであれば特
に制限はなく、例えばヘキサン、シクロヘキサンのよう
な飽和炭化水素類；ベンゼン、トルエン、キシレンのよ
うな芳香族炭化水素類；ジクロロメタン、ジクロロエタ
ン、クロロホルムのようなハロゲン化炭化水素類；メタ
ノール、エタノールのようなアルコール類；エーテル、
テトラヒドロフラン、ジオキサンのようなエーテル類；
酢酸エチルのような酢酸エステル類；アセトニトリルの
ようなニトリル類；ジメチルホルムアミド、ジメチルア
セトアミドのようなアミド類；ジメチルスルホキシドの
ようなスルホキシド類を挙げることができるが、好適に
はエーテル類又はハロゲン化炭化水素類である。The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent. For example, saturated hydrocarbons such as hexane and cyclohexane; benzene, toluene and xylene Aromatic hydrocarbons such as dichloromethane, dichloroethane and chloroform; alcohols such as methanol and ethanol; ethers;
Ethers such as tetrahydrofuran and dioxane;
Acetates such as ethyl acetate; nitriles such as acetonitrile; amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethylsulfoxide, preferably ethers or halogenated carbons. Hydrogens.
【０１２１】使用される塩基としては、例えばトリエチ
ルアミン、ピリジンのような有機塩基類；水酸化ナトリ
ウム、炭酸水素ナトリウム、炭酸カリウムのような無機
塩基類を挙げることができ、好適には有機塩基類（特に
ピリジン）である。有機塩基類を溶媒として使用するこ
ともできる。Examples of the base to be used include organic bases such as triethylamine and pyridine; and inorganic bases such as sodium hydroxide, sodium hydrogen carbonate and potassium carbonate. Especially pyridine). Organic bases can also be used as solvents.
【０１２２】使用されるアルカノイル化剤としては、例
えばトリフルオロ酢酸無水物、プロピオン酸無水物、ト
リフルオロアセチルクロリド、ブチリルクロリドのよう
な酸無水物又は酸ハロゲン化物を使用することができ
る。As the alkanoylating agent used, for example, acid anhydrides or acid halides such as trifluoroacetic anhydride, propionic anhydride, trifluoroacetyl chloride and butyryl chloride can be used.
【０１２３】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常０℃乃至溶媒の沸点
の範囲であり、好適には０乃至３０℃である。The reaction temperature varies depending on the type of the starting compounds and the reactants used, but is usually in the range of 0 ° C. to the boiling point of the solvent, preferably 0 to 30 ° C.
【０１２４】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常１乃至２４時間
であり、好適には１乃至８時間である。The reaction time varies depending on the used starting compounds, the reactants and the reaction temperature, but is usually 1 to 24 hours, preferably 1 to 8 hours.
【０１２５】反応終了後、化合物（１６）は通常の方法
により反応混合物から採取できる。例えば反応混合液又
は反応混合液の溶剤を留去して得られる残査に水と混合
しない有機溶剤を加え、水洗し、溶剤を留去して得られ
る。After completion of the reaction, compound (16) can be collected from the reaction mixture by a usual method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【０１２６】得られた化合物（１６）は、必要ならば常
法、例えば再結晶、再沈殿又はクロマトグラフィー等に
よって更に精製することができる。 （第Ａ−６工程）第Ａ−６工程はアジド化合物（１６）
のアジド基を還元してアミノ化合物（１７）を製造する
工程である。The obtained compound (16) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step A-6) Step A-6 is an azide compound (16)
Is a step of producing an amino compound (17) by reducing the azide group of
【０１２７】本工程は、アジド化合物（１６）に溶媒
中、還元剤を作用させることにより達成される。This step is achieved by reacting the azide compound (16) with a reducing agent in a solvent.
【０１２８】使用される溶媒としては、反応を阻害せず
原料化合物や反応剤をある程度溶解するものであれば特
に制限はなく、例えばヘキサン、シクロヘキサンのよう
な飽和炭化水素類；ベンゼン、トルエン、キシレンのよ
うな芳香族炭化水素類；ジクロロメタン、ジクロロエタ
ン、クロロホルムのようなハロゲン化炭化水素類；メタ
ノール、エタノールのようなアルコール類；エーテル、
テトラヒドロフラン、ジオキサンのようなエーテル類；
酢酸エチルのような酢酸エステル類；アセトニトリルの
ようなニトリル類；ジメチルホルムアミド、ジメチルア
セトアミドのようなアミド類；ジメチルスルホキシドの
ようなスルホキシド類を挙げることができる。これらの
うち、好適にはアルコール類（特にメタノールまたはエ
タノール）である。The solvent to be used is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent. For example, saturated hydrocarbons such as hexane and cyclohexane; benzene, toluene and xylene Aromatic hydrocarbons such as dichloromethane, dichloroethane and chloroform; alcohols such as methanol and ethanol; ethers;
Ethers such as tetrahydrofuran and dioxane;
Acetates such as ethyl acetate; nitriles such as acetonitrile; amides such as dimethylformamide and dimethylacetamide; and sulfoxides such as dimethylsulfoxide. Of these, alcohols (particularly methanol or ethanol) are preferred.
【０１２９】還元剤としては、アジド基を水素化してア
ミノ基を生成することができる還元剤であれば特に制限
はない。そのような還元剤としては、接触還元法に用い
られる水素ガス−金属触媒（例えば、白金、パラジウ
ム、ロジウム、パラジウム炭素、ロジウム炭素、リンド
ラー触媒等）の組み合わせが好適であり、特に好適には
水素ガス−リンドラー触媒の組み合わせをである。The reducing agent is not particularly limited as long as it can hydrogenate an azide group to generate an amino group. As such a reducing agent, a combination of a hydrogen gas and a metal catalyst (for example, platinum, palladium, rhodium, palladium carbon, rhodium carbon, Lindlar catalyst, etc.) used in the catalytic reduction method is preferable, and particularly preferably, hydrogen is used. Gas-Lindler catalyst combination.
【０１３０】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常２０℃乃至溶媒の沸
点の範囲であり、好適には２０乃至６０℃である。The reaction temperature varies depending on the types of the starting compounds and the reactants used, but is usually in the range of 20 ° C. to the boiling point of the solvent, preferably 20 to 60 ° C.
【０１３１】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常１乃至８時間で
あり、好適には２乃至６時間である。The reaction time varies depending on the used starting compounds, the reactants and the reaction temperature, but is usually 1 to 8 hours, preferably 2 to 6 hours.
【０１３２】反応終了後、化合物（１７）は通常の方法
により反応混合物から採取できる。例えば反応混合液又
は反応混合液の溶剤を留去して得られる残査に水と混合
しない有機溶剤を加え、水洗し、溶剤を留去して得られ
る。After completion of the reaction, compound (17) can be collected from the reaction mixture by a usual method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【０１３３】得られた化合物（１７）は、必要ならば常
法、例えば再結晶、再沈殿又はクロマトグラフィー等に
よって更に精製することができる。 （第Ａ−７工程）第Ａ−７工程は、化合物（１７）の４
位アミノ基を所望のＲ10または保護されたＲ10へ変換し
て化合物（１８）を製造する工程である。 （ｉ）Ｒ10が炭素数１乃至４個のアルキルで置換された
アミノ基である場合 本工程は、化合物（１７）に溶媒中、塩基の存在下にア
ルキル化剤を反応させることによって達成される。The obtained compound (17) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step A-7) Step A-7 is a step in Step 4 of Compound (17).
In this step, the amino group is converted to a desired R 10 or a protected R 10 to produce a compound (18). (I) In the case where R 10 is an amino group substituted with an alkyl having 1 to 4 carbon atoms, this step is achieved by reacting compound (17) with an alkylating agent in a solvent in the presence of a base. You.
【０１３４】使用される溶媒としては、反応を阻害せず
原料化合物や反応剤をある程度溶解するものであれば特
に制限はなく、例えばヘキサン、シクロヘキサンのよう
な飽和炭化水素類；ベンゼン、トルエン、キシレンのよ
うな芳香族炭化水素類；ジクロロメタン、ジクロロエタ
ン、クロロホルムのようなハロゲン化炭化水素類；メタ
ノール、エタノールのようなアルコール類；エーテル、
テトラヒドロフラン、ジオキサンのようなエーテル類；
酢酸エチルのような酢酸エステル類；アセトニトリルの
ようなニトリル類；ジメチルホルムアミド、ジメチルア
セトアミドのようなアミド類；ジメチルスルホキシドの
ようなスルホキシド類を挙げることができる。これらの
うち、好適にはアミド類（特にジメチルホルムアミド）
である。The solvent to be used is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent. For example, saturated hydrocarbons such as hexane and cyclohexane; benzene, toluene and xylene Aromatic hydrocarbons such as dichloromethane, dichloroethane and chloroform; alcohols such as methanol and ethanol; ethers;
Ethers such as tetrahydrofuran and dioxane;
Acetates such as ethyl acetate; nitriles such as acetonitrile; amides such as dimethylformamide and dimethylacetamide; and sulfoxides such as dimethylsulfoxide. Of these, amides (particularly dimethylformamide) are preferred
It is.
【０１３５】アルキル化剤としては、例えばヨウ化メチ
ルのようなアルキルハライド類；ジメチル硫酸のような
アルキル硫酸類を挙げることができる。Examples of the alkylating agent include alkyl halides such as methyl iodide; and alkyl sulfates such as dimethyl sulfate.
【０１３６】使用される塩基としては、例えばトリエチ
ルアミン、ピリジンのような有機塩基類；水酸化ナトリ
ウム、炭酸水素ナトリウム、炭酸カリウムのような無機
塩基類を挙げることができる。Examples of the base used include organic bases such as triethylamine and pyridine; and inorganic bases such as sodium hydroxide, sodium hydrogen carbonate and potassium carbonate.
【０１３７】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常２０℃乃至溶媒の沸
点の範囲であり、好適には２０乃至５０℃である。The reaction temperature varies depending on the types of the starting compounds and the reactants used, but is usually in the range of 20 ° C. to the boiling point of the solvent, preferably 20 to 50 ° C.
【０１３８】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常０．５乃至６時
間であり、好適には０．５乃至３時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is usually 0.5 to 6 hours, preferably 0.5 to 3 hours.
【０１３９】反応終了後、化合物（１８）は通常の方法
により反応混合物から採取できる。例えば反応混合液又
は反応混合液の溶剤を留去して得られる残査に水と混合
しない有機溶剤を加え、水洗し、溶剤を留去して得られ
る。After completion of the reaction, compound (18) can be collected from the reaction mixture by a usual method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【０１４０】得られた化合物（１８）は、必要ならば常
法、例えば再結晶、再沈殿又はクロマトグラフィー等に
よって更に精製することができる。 （ｉｉ）Ｒ10が式−ＮＲ11Ｃ（＝ＮＲ12）Ｒ13で表され
る基である場合 本工程は、化合物（１７）又は上記（ｉ）で得られた化
合物（１８）に式Ｌ−Ｃ（＝ＮＲ12p）Ｒ13p（式中、Ｌ
は脱離基を示し、Ｒ12p及びＲ13pは保護されていてもよ
い前述のＲ12及びＲ13をしめす。）で表される化合物を
反応させることによって達成される。The obtained compound (18) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Ii) When R 10 is a group represented by the formula —NR 11 C (＝ NR 12 ) R 13 In this step, the compound (17) or the compound (18) obtained in the above (i) is treated with a compound represented by the formula L -C (= NR12p ) R13p (where L
Represents a leaving group, and R 12p and R 13p represent the aforementioned R 12 and R 13 which may be protected. This is achieved by reacting the compound represented by the formula (1).
【０１４１】使用される溶媒としては、反応を阻害せず
原料化合物や反応剤をある程度溶解するものであれば特
に制限はなく、例えばヘキサン、シクロヘキサンのよう
な飽和炭化水素類；ベンゼン、トルエン、キシレンのよ
うな芳香族炭化水素類；ジクロロメタン、ジクロロエタ
ン、クロロホルムのようなハロゲン化炭化水素類；メタ
ノール、エタノールのようなアルコール類；エーテル、
テトラヒドロフラン、ジオキサンのようなエーテル類；
酢酸エチルのような酢酸エステル類；アセトニトリルの
ようなニトリル類；ジメチルホルムアミド、ジメチルア
セトアミドのようなアミド類；ジメチルスルホキシドの
ようなスルホキシド類を挙げることができる。これらの
うち、好適にはエーテル類（テトラヒドロフラン）であ
る。The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent. For example, saturated hydrocarbons such as hexane and cyclohexane; benzene, toluene and xylene Aromatic hydrocarbons such as dichloromethane, dichloroethane and chloroform; alcohols such as methanol and ethanol; ethers;
Ethers such as tetrahydrofuran and dioxane;
Acetates such as ethyl acetate; nitriles such as acetonitrile; amides such as dimethylformamide and dimethylacetamide; and sulfoxides such as dimethylsulfoxide. Of these, ethers (tetrahydrofuran) are preferred.
【０１４２】式Ｌ−Ｃ（＝ＮＲ12p）Ｒ13pで表される化
合物において、脱離基Ｌとしては、メトキシ、エトキシ
のようなアルコキシ基；メチルチオ、エチルチオのよう
なアルキルチオ基；アミノまたは保護ざれたアミノ基；
ピロール、イミダゾール、ピラゾールのような複素環
基；塩素のようなハロゲン基を挙げることができる。In the compound represented by the formula LC (= NR 12p ) R 13p , the leaving group L is an alkoxy group such as methoxy or ethoxy; an alkylthio group such as methylthio or ethylthio; an amino group or a protected group. Amino group;
Heterocyclic groups such as pyrrole, imidazole and pyrazole; and halogen groups such as chlorine.
【０１４３】式Ｌ−Ｃ（＝ＮＲ12p）Ｒ13pで表される化
合物としては、例えばメチルホルムイミデート、メチル
アセトイミデート、Ｏ−メチル尿素、Ｓ−メチルチオ尿
素、１−アミジノ−１，２−ピロール、Ｎ，Ｎ’−ビス
（ｔ−ブトキシカルボニル）アミジノ−１，２−ピラゾ
ール等を挙げることができる。Examples of the compound represented by the formula LC (= NR 12p ) R 13p include, for example, methylformimidate, methylacetoimidate, O-methylurea, S-methylthiourea, 1-amidino-1,2 -Pyrrole, N, N'-bis (t-butoxycarbonyl) amidino-1,2-pyrazole and the like.
【０１４４】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常２０℃乃至溶媒の沸
点の範囲であり、好適には２０乃至５０℃である。The reaction temperature varies depending on the type of the starting compounds and the reactants used, but is usually in the range of 20 ° C. to the boiling point of the solvent, preferably 20 to 50 ° C.
【０１４５】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常０．５乃至４８
時間であり、好適には０．５乃至１２時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is usually from 0.5 to 48.
Time, preferably 0.5 to 12 hours.
【０１４６】反応終了後、化合物（１８）は通常の方法
により反応混合物から採取できる。例えば反応混合液又
は反応混合液の溶剤を留去して得られる残査に水と混合
しない有機溶剤を加え、水洗し、溶剤を留去して得られ
る。After completion of the reaction, compound (18) can be collected from the reaction mixture by a usual method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【０１４７】得られた化合物（１８）は、必要ならば常
法、例えば再結晶、再沈殿又はクロマトグラフィー等に
よって更に精製することができる。 （第Ａ−８工程）第Ａ−８工程は、化合物（１８）のＲ
1p、Ｒ2p、Ｒ10pに含まれる保護基及び１位カルボキシ
ル基の保護基を除去して、本発明の化合物（１）を製造
する工程である。The obtained compound (18) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step A-8) Step A-8 is a reaction of the compound (18) with R
This is a step of producing the compound (1) of the present invention by removing the protecting groups contained in 1p , R 2p and R 10p and the protecting group at the 1-carboxyl group.
【０１４８】保護基の除去は、有機合成化学の分野で通
常使用される脱保護の方法を適宜組み合わせて使用する
ことにより達成することができる。The removal of the protecting group can be achieved by appropriately combining deprotection methods usually used in the field of synthetic organic chemistry.
【０１４９】なお、化合物（１）の薬理上許容される塩
及び薬理上許容されるエステル誘導体は、有機合成化学
または医薬品化学の分野で通常使用されている方法によ
って製造することができる。 ［Ｂ法］Ｂ法は、Ａ法の出発原料である化合物（１１）
のうち、ｍが０である化合物（１１ａ）を製造する方法
であり、下記の工程式によって示される。The pharmacologically acceptable salts and pharmacologically acceptable ester derivatives of the compound (1) can be produced by a method usually used in the field of synthetic organic chemistry or medicinal chemistry. [Method B] In the method B, the compound (11) which is a starting material of the method A is used.
Is a method for producing a compound (11a) wherein m is 0, and is represented by the following process formula.
【０１５０】[0150]
【化８】 Embedded image
【０１５１】式中、Ｒ3乃至Ｒ8、ＲOH 1、ｎ及びｍは前
述と同意義であり、ＴＢＳはｔ−ブチルジメチルシリル
基を示す。以下、各工程について詳述する。 （第Ｂ−１工程）第Ｂ−１工程は公知化合物（１９）に
ビニルアルキル基を導入して化合物（２０）を製造する
工程である。In the formula, R 3 to R 8 , R OH 1 , n and m have the same meanings as described above, and TBS represents a t-butyldimethylsilyl group. Hereinafter, each step will be described in detail. (Step B-1) Step B-1 is a step of producing a compound (20) by introducing a vinylalkyl group into the known compound (19).
【０１５２】本工程は、化合物（１９）に溶媒中、酸ま
たは塩基の存在下に式Ｈ2Ｃ＝ＣＲ3−（ＣＲ5Ｒ6）ｎ−
Ｘで表される化合物を作用させることにより達成され
る。In this step, compound (19) is reacted with a compound of the formula H 2 C = CR 3- (CR 5 R 6 ) n- in the presence of an acid or a base in a solvent.
This is achieved by acting a compound represented by X.
【０１５３】使用される溶媒としては、反応を阻害せず
原料化合物や反応剤をある程度溶解するものであれば特
に制限はなく、例えばヘキサン、シクロヘキサンのよう
な飽和炭化水素類；ベンゼン、トルエン、キシレンのよ
うな芳香族炭化水素類；ジクロロメタン、ジクロロエタ
ン、クロロホルムのようなハロゲン化炭化水素類；メタ
ノール、エタノールのようなアルコール類；エーテル、
テトラヒドロフラン、ジオキサンのようなエーテル類；
酢酸エチルのような酢酸エステル類；アセトニトリルの
ようなニトリル類；ジメチルホルムアミド、ジメチルア
セトアミドのようなアミド類；ジメチルスルホキシドの
ようなスルホキシド類を挙げることができる。これらの
うち、好適にはアミド類（特にジメチルホルムアミド）
である。The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent. For example, saturated hydrocarbons such as hexane and cyclohexane; benzene, toluene and xylene Aromatic hydrocarbons such as dichloromethane, dichloroethane and chloroform; alcohols such as methanol and ethanol; ethers;
Ethers such as tetrahydrofuran and dioxane;
Acetates such as ethyl acetate; nitriles such as acetonitrile; amides such as dimethylformamide and dimethylacetamide; and sulfoxides such as dimethylsulfoxide. Of these, amides (particularly dimethylformamide) are preferred
It is.
【０１５４】使用される酸としては、例えば酢酸、トリ
フルオロ酢酸のような有機酸類;メタンスルホン酸、ト
リフルオロメタンスルホン酸のような有機スルホン酸類
を挙げることができ、好適にはトリフルオロメタンスル
ホン酸である。Examples of the acid used include organic acids such as acetic acid and trifluoroacetic acid; and organic sulfonic acids such as methanesulfonic acid and trifluoromethanesulfonic acid. is there.
【０１５５】使用される塩基としては、例えばトリエチ
ルアミン、ピリジンのような有機塩基類；水酸化ナトリ
ウム、水酸化カリウムのような水酸化アルカリ金属類；
水素化ナトリウム、水素化カリウムのような水素化アル
カリ金属類；ナトリウムメトキシド、ナトリウムエトキ
シド、カリウムｔ−ブトキシドのようなアルカリ金属ア
ルコキシド類を挙げることができ、好適には水素化アル
カリ金属類（特に水素化ナトリウム）である。Examples of the base used include organic bases such as triethylamine and pyridine; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide;
Alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide, and preferably alkali metal hydrides ( Especially sodium hydride).
【０１５６】式Ｈ2Ｃ＝ＣＲ3−（ＣＲ5Ｒ6）ｎ−Ｘで表
される化合物としては、所望のＲ3、Ｒ5、Ｒ6及びｎを
有し、Ｘがハロゲン原子、スルホン酸エステル、１−イ
ミノ−2,2,2−トリクロロエトキシ基のような脱離基で
ある化合物である。ハロゲン原子としては臭素またはヨ
ウ素原子が好適であり、スルホン酸エステルとしてはト
リフルオロメタンスルホニルオキシまたはメタンスルホ
ニルオキシ基が好適である。The compound represented by the formula H 2 C ＝ CR 3- (CR 5 R 6 ) nX has desired R 3 , R 5 , R 6 and n, and X is a halogen atom, a sulfone. Acid ester, a compound which is a leaving group such as 1-imino-2,2,2-trichloroethoxy group. A bromine or iodine atom is preferable as the halogen atom, and a trifluoromethanesulfonyloxy or methanesulfonyloxy group is preferable as the sulfonic acid ester.
【０１５７】脱離基Ｘがハロゲン原子、スルホン酸エス
テルである場合には塩基と組み合わせて反応を行い、脱
離基Ｘが１−イミノ−2,2,2−トリクロロエトキシ基で
ある場合には酸と組み合わせて反応を行うことが好まし
い。When the leaving group X is a halogen atom or a sulfonic acid ester, the reaction is carried out in combination with a base. When the leaving group X is a 1-imino-2,2,2-trichloroethoxy group, It is preferred to carry out the reaction in combination with an acid.
【０１５８】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常２０℃乃至溶媒の沸
点の範囲であり、好適には３０乃至５０℃である。The reaction temperature varies depending on the types of the starting compounds and the reactants used, but is usually in the range of 20 ° C. to the boiling point of the solvent, preferably 30 to 50 ° C.
【０１５９】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常０．５乃至６時
間であり、好適には０．５乃至３時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is usually 0.5 to 6 hours, preferably 0.5 to 3 hours.
【０１６０】反応終了後、化合物（２０）は通常の方法
により反応混合物から採取できる。例えば反応混合液又
は反応混合液の溶剤を留去して得られる残査に水と混合
しない有機溶剤を加え、水洗し、溶剤を留去して得られ
る。After completion of the reaction, compound (20) can be collected from the reaction mixture by a usual method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【０１６１】得られた化合物（２０）は、必要ならば常
法、例えば再結晶、再沈殿又はクロマトグラフィー等に
よって更に精製することができる。 （第Ｂ−２工程）第Ｂ−２工程は化合物（２０）のＴＢ
Ｓ（ｔ−ブチルジメチルシリル）基に代えて水酸基の保
護基ＲOH 1を導入して化合物（２１）を製造する工程で
ある。The obtained compound (20) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step B-2) Step B-2 is a step of TB of compound (20).
It is a step for preparing the S (t-butyldimethylsilyl) compound by introducing a protecting group R OH 1 hydroxyl group in place of the group (21).
【０１６２】本工程は、化合物（２０）に溶媒中、酸を
作用させてＴＢＳ基を除去し、次いで溶媒中、塩基の存
在下に水酸基の保護化剤を作用させることにより達成さ
れる。This step is accomplished by removing the TBS group by reacting compound (20) with an acid in a solvent, and then reacting the compound with a protecting agent for a hydroxyl group in the presence of a base in the solvent.
【０１６３】ＴＢＳ基の除去において使用される溶媒と
しては、反応を阻害せず原料化合物や反応剤をある程度
溶解するものであれば特に制限はなく、例えばヘキサ
ン、シクロヘキサンのような飽和炭化水素類；ベンゼ
ン、トルエン、キシレンのような芳香族炭化水素類；ジ
クロロメタン、ジクロロエタン、クロロホルムのような
ハロゲン化炭化水素類；メタノール、エタノールのよう
なアルコール類；エーテル、テトラヒドロフラン、ジオ
キサンのようなエーテル類；酢酸エチルのような酢酸エ
ステル類；アセトニトリルのようなニトリル類；ジメチ
ルホルムアミド、ジメチルアセトアミドのようなアミド
類；ジメチルスルホキシドのようなスルホキシド類を挙
げることができる。これらのうち、好適にはエーテル類
（特にテトラヒドロフラン）である。The solvent used in the removal of the TBS group is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent; for example, saturated hydrocarbons such as hexane and cyclohexane; Aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; alcohols such as methanol and ethanol; ethers such as ether, tetrahydrofuran and dioxane; ethyl acetate Acetic acid esters such as acetonitrile; amides such as dimethylformamide and dimethylacetamide; and sulfoxides such as dimethylsulfoxide. Of these, ethers (particularly tetrahydrofuran) are preferred.
【０１６４】ＴＢＳ基の除去において使用される酸とし
ては、例えば弗化水素酸、塩酸、硫酸のような鉱酸類；
酢酸、トリフルオロ酢酸、メタンスルホン酸、トリフル
オロメタンスルホン酸、ベンゼンスルホン酸のような有
機酸類；テトラブチルアンモニウムフロオライドのよう
な強酸と弱塩基の塩類をあげることができるが、好適に
はテトラブチルアンモニウムフルオライドである。Examples of the acid used in removing the TBS group include mineral acids such as hydrofluoric acid, hydrochloric acid and sulfuric acid;
Organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid and benzenesulfonic acid; salts of strong acids and weak bases such as tetrabutylammonium fluoride; Butyl ammonium fluoride.
【０１６５】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常２０℃乃至溶媒の沸
点の範囲であり、好適には２０乃至４０℃である。The reaction temperature varies depending on the type of the starting compounds and the reactants used, but is usually in the range of 20 ° C. to the boiling point of the solvent, preferably 20 to 40 ° C.
【０１６６】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常０．５乃至６時
間であり、好適には０．５乃至２時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is usually 0.5 to 6 hours, preferably 0.5 to 2 hours.
【０１６７】反応終了後、ＴＢＳ基が除去された化合物
は通常の方法により反応混合物から採取できる。例えば
反応混合液又は反応混合液の溶剤を留去して得られる残
査に水と混合しない有機溶剤を加え、水洗し、溶剤を留
去して得られる。本化合物は次いで保護基ＲOH 1の導入
反応に付される。After completion of the reaction, the compound from which the TBS group has been removed can be collected from the reaction mixture by a conventional method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off. This compound is then subjected to a reaction for introducing a protecting group R OH 1 .
【０１６８】水酸基の保護基ＲOH 1の導入に使用される
溶媒としては、反応を阻害せず原料化合物や反応剤をあ
る程度溶解するものであれば特に制限はなく、例えばヘ
キサン、シクロヘキサンのような飽和炭化水素類；ベン
ゼン、トルエン、キシレンのような芳香族炭化水素類；
ジクロロメタン、ジクロロエタン、クロロホルムのよう
なハロゲン化炭化水素類；メタノール、エタノールのよ
うなアルコール類；エーテル、テトラヒドロフラン、ジ
オキサンのようなエーテル類；酢酸エチルのような酢酸
エステル類；アセトニトリルのようなニトリル類；ジメ
チルホルムアミド、ジメチルアセトアミドのようなアミ
ド類；ジメチルスルホキシドのようなスルホキシド類を
挙げることができる。これらのうち、好適にはハロゲン
化炭化水素類（特にジクロロメタン）である。The solvent used to introduce the hydroxyl-protecting group R OH 1 is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent. Examples thereof include hexane and cyclohexane. Saturated hydrocarbons; aromatic hydrocarbons such as benzene, toluene and xylene;
Halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; alcohols such as methanol and ethanol; ethers such as ether, tetrahydrofuran and dioxane; acetates such as ethyl acetate; nitriles such as acetonitrile; Examples include amides such as dimethylformamide and dimethylacetamide; and sulfoxides such as dimethylsulfoxide. Of these, halogenated hydrocarbons (particularly dichloromethane) are preferred.
【０１６９】水酸基の保護基ＲOH 1の導入に使用される
塩基としては、例えばトリエチルアミン、ピリジンのよ
うな有機塩基類；水酸化ナトリウム、水酸化カリウムの
ような水酸化アルカリ金属類；水素化ナトリウム、水素
化カリウムのような水素化アルカリ金属類；ナトリウム
メトキシド、ナトリウムエトキシド、カリウムｔ−ブト
キシドのようなアルカリ金属アルコキシド類を挙げるこ
とができ、好適には有機塩基類（特にピリジンまたはト
リエチルアミン）である。Examples of the base used to introduce the hydroxyl-protecting group R OH 1 include organic bases such as triethylamine and pyridine; alkali metals such as sodium hydroxide and potassium hydroxide; sodium hydride And alkali metal hydrides such as potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide, and preferably organic bases (particularly pyridine or triethylamine). It is.
【０１７０】水酸基の保護化剤としては、例えばアセチ
ルクロリド、ピバロイルクロリドのような酸ハロゲン化
物；無水酢酸のような酸無水物を挙げることができる
が、好適には無水酢酸またはピバロイルクロリドであ
る。Examples of the hydroxyl-protecting agent include acid halides such as acetyl chloride and pivaloyl chloride; and acid anhydrides such as acetic anhydride. Preferably, acetic anhydride or pivaloyl is used. It is chloride.
【０１７１】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常２０℃乃至溶媒の沸
点の範囲であり、好適には２０乃至４０℃である。The reaction temperature varies depending on the type of the starting compounds and the reactants used, but is usually in the range of 20 ° C. to the boiling point of the solvent, preferably 20 to 40 ° C.
【０１７２】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常０．５乃至１２
時間であり、好適には０．５乃至３時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is usually 0.5 to 12
Time, preferably 0.5 to 3 hours.
【０１７３】反応終了後、化合物（２１）は通常の方法
により反応混合物から採取できる。例えば反応混合液又
は反応混合液の溶剤を留去して得られる残査に水と混合
しない有機溶剤を加え、水洗し、溶剤を留去して得られ
る。After completion of the reaction, compound (21) can be collected from the reaction mixture by a usual method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【０１７４】得られた化合物（２１）は、必要ならば常
法、例えば再結晶、再沈殿又はクロマトグラフィー等に
よって更に精製することができる。 （第Ｂ−３工程）第Ｂ−３工程は化合物（２１）のイソ
プロピリデン基を除去して化合物（２２）を製造する工
程である。The obtained compound (21) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step B-3) Step B-3 is a step of producing a compound (22) by removing the isopropylidene group of the compound (21).
【０１７５】本工程は、化合物（２１）に溶媒中、酸を
作用させることにより達成される。This step is achieved by reacting compound (21) with an acid in a solvent.
【０１７６】使用される溶媒としては、反応を阻害せず
原料化合物や反応剤をある程度溶解するものであれば特
に制限はなく、例えばヘキサン、シクロヘキサンのよう
な飽和炭化水素類；ベンゼン、トルエン、キシレンのよ
うな芳香族炭化水素類；ジクロロメタン、ジクロロエタ
ン、クロロホルムのようなハロゲン化炭化水素類；メタ
ノール、エタノールのようなアルコール類；エーテル、
テトラヒドロフラン、ジオキサンのようなエーテル類；
酢酸エチルのような酢酸エステル類；アセトンのような
ケトン類；アセトニトリルのようなニトリル類；ジメチ
ルホルムアミド、ジメチルアセトアミドのようなアミド
類；ジメチルスルホキシドのようなスルホキシド類；水
またはそれらの混合溶媒を挙げることができる。これら
のうち、好適にアセトンまたはテトラヒドロフランと水
の混合溶媒である。The solvent to be used is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent. For example, saturated hydrocarbons such as hexane and cyclohexane; benzene, toluene and xylene Aromatic hydrocarbons such as dichloromethane, dichloroethane, and chloroform; alcohols such as methanol and ethanol; ethers;
Ethers such as tetrahydrofuran and dioxane;
Acetates such as ethyl acetate; ketones such as acetone; nitriles such as acetonitrile; amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethylsulfoxide; water or a mixed solvent thereof. be able to. Among them, a mixed solvent of acetone or tetrahydrofuran and water is preferable.
【０１７７】使用される酸としては、例えば弗化水素
酸、塩酸、硫酸のような鉱酸類；酢酸、トリフルオロ酢
酸、メタンスルホン酸、トリフルオロメタンスルホン
酸、ベンゼンスルホン酸のような有機酸類；テトラブチ
ルアンモニウムフロオライドのような強酸と弱塩基の塩
類をあげることができるが、好適には有機酸類（特に酢
酸）である。Examples of the acid used include mineral acids such as hydrofluoric acid, hydrochloric acid and sulfuric acid; organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid and benzenesulfonic acid; Salts of strong acids and weak bases such as butylammonium fluoride can be mentioned, but organic acids (especially acetic acid) are preferred.
【０１７８】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常２０℃乃至溶媒の沸
点の範囲であり、好適には３０乃至６０℃である。The reaction temperature varies depending on the type of the starting compounds and the reactants used, but is usually in the range of 20 ° C. to the boiling point of the solvent, preferably 30 to 60 ° C.
【０１７９】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常２乃至８時間で
あり、好適には２乃至４時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is usually 2 to 8 hours, preferably 2 to 4 hours.
【０１８０】反応終了後、化合物（２２）は通常の方法
により反応混合物から採取できる。例えば反応混合液又
は反応混合液の溶剤を留去して得られる残査に水と混合
しない有機溶剤を加え、水洗し、溶剤を留去して得られ
る。After completion of the reaction, compound (22) can be collected from the reaction mixture by a conventional method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【０１８１】得られた化合物（２２）は、必要ならば常
法、例えば再結晶、再沈殿又はクロマトグラフィー等に
よって更に精製することができる。 （第Ｂ−４工程）第Ｂ−４工程は化合物（２２）にチオ
カルボニル基を導入して化合物（２３）を製造する工程
である。The obtained compound (22) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step B-4) Step B-4 is a step of producing a compound (23) by introducing a thiocarbonyl group into the compound (22).
【０１８２】本工程は、化合物（２２）に溶媒中、塩基
の存在化、チオホスゲンを作用させることにより達成さ
れる。This step is achieved by allowing compound (22) to react with thiophosgene in a solvent in the presence of a base.
【０１８３】使用される溶媒としては、反応を阻害せず
原料化合物や反応剤をある程度溶解するものであれば特
に制限はなく、例えばヘキサン、シクロヘキサンのよう
な飽和炭化水素類；ベンゼン、トルエン、キシレンのよ
うな芳香族炭化水素類；ジクロロメタン、ジクロロエタ
ン、クロロホルムのようなハロゲン化炭化水素類；メタ
ノール、エタノールのようなアルコール類；エーテル、
テトラヒドロフラン、ジオキサンのようなエーテル類；
酢酸エチルのような酢酸エステル類；アセトニトリルの
ようなニトリル類；ジメチルホルムアミド、ジメチルア
セトアミドのようなアミド類；ジメチルスルホキシドの
ようなスルホキシド類；水またはそれらの混合溶媒を挙
げることができる。これらのうち、好適にはハロゲン化
炭化水素類（特にジクロロメタン）である。The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent. For example, saturated hydrocarbons such as hexane and cyclohexane; benzene, toluene and xylene Aromatic hydrocarbons such as dichloromethane, dichloroethane, and chloroform; alcohols such as methanol and ethanol; ethers;
Ethers such as tetrahydrofuran and dioxane;
Acetates such as ethyl acetate; nitriles such as acetonitrile; amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethylsulfoxide; water or a mixed solvent thereof. Of these, halogenated hydrocarbons (particularly dichloromethane) are preferred.
【０１８４】使用される塩基としては、例えばトリエチ
ルアミン、ピリジンのような有機塩基類；水酸化ナトリ
ウム、水酸化カリウムのような水酸化アルカリ金属類；
水素化ナトリウム、水素化カリウムのような水素化アル
カリ金属類；ナトリウムメトキシド、ナトリウムエトキ
シド、カリウムｔ−ブトキシドのようなアルカリ金属ア
ルコキシド類を挙げることができ、好適には有機塩基類
（特にジメチルアミノピリジン）である。Examples of the base used include organic bases such as triethylamine and pyridine; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide;
Alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide, and preferably organic bases (particularly dimethyl Aminopyridine).
【０１８５】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常０℃乃至溶媒の沸点
の範囲であり、好適には０乃至３０℃である。The reaction temperature varies depending on the type of the starting compounds and the reactants used, but is usually in the range of 0 ° C. to the boiling point of the solvent, preferably 0 to 30 ° C.
【０１８６】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常０．５乃至４時
間であり、好適には０．５乃至２時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is usually 0.5 to 4 hours, preferably 0.5 to 2 hours.
【０１８７】反応終了後、化合物（２３）は通常の方法
により反応混合物から採取できる。例えば反応混合液又
は反応混合液の溶剤を留去して得られる残査に水と混合
しない有機溶剤を加え、水洗し、溶剤を留去して得られ
る。After completion of the reaction, compound (23) can be collected from the reaction mixture by a usual method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【０１８８】得られた化合物（２３）は、必要ならば常
法、例えば再結晶、再沈殿又はクロマトグラフィー等に
よって更に精製することができる。 （第Ｂ−５工程）第Ｂ−５工程は化合物（２３）からチ
オカーボネイト基を除去してオレフィン化合物（１１
ａ）を製造する工程である。The obtained compound (23) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step B-5) Step B-5 is a step of removing an thiocarbonate group from compound (23) to obtain an olefin compound (11).
This is the step of manufacturing a).
【０１８９】本工程は、化合物（２３）に溶媒中、ホス
ファイト類を作用させることにより達成される。This step is achieved by reacting compound (23) with a phosphite in a solvent.
【０１９０】使用される溶媒としては、反応を阻害せず
原料化合物や反応剤をある程度溶解するものであれば特
に制限はなく、例えばヘキサン、シクロヘキサンのよう
な飽和炭化水素類；ベンゼン、トルエン、キシレンのよ
うな芳香族炭化水素類；ジクロロメタン、ジクロロエタ
ン、クロロホルムのようなハロゲン化炭化水素類；メタ
ノール、エタノールのようなアルコール類；エーテル、
テトラヒドロフラン、ジオキサンのようなエーテル類；
酢酸エチルのような酢酸エステル類；アセトニトリルの
ようなニトリル類；ジメチルホルムアミド、ジメチルア
セトアミドのようなアミド類；ジメチルスルホキシドの
ようなスルホキシド類またはそれらの混合溶媒を挙げる
ことができる。これらのうち、好適には芳香族炭化水素
類（特にトルエン）である。The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent. For example, saturated hydrocarbons such as hexane and cyclohexane; benzene, toluene and xylene Aromatic hydrocarbons such as dichloromethane, dichloroethane, and chloroform; halogenated hydrocarbons such as methanol; alcohols such as methanol and ethanol; ethers;
Ethers such as tetrahydrofuran and dioxane;
Examples thereof include acetates such as ethyl acetate; nitriles such as acetonitrile; amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethylsulfoxide; and a mixed solvent thereof. Of these, aromatic hydrocarbons (particularly toluene) are preferred.
【０１９１】使用されるホスファイト類としては、例え
ばトリメチルホスファイト、トリエチルホスファイトの
ようなトリ（炭素数１乃至４個のアルキル）ホスファイ
トを挙げることができ、好適にはトリメチルホスファイ
トである。The phosphites to be used include, for example, tri (1-4 carbon alkyl) phosphites such as trimethyl phosphite and triethyl phosphite, preferably trimethyl phosphite. .
【０１９２】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常８０℃乃至溶媒の沸
点の範囲であり、好適には１００乃至１３０℃である。The reaction temperature varies depending on the types of the starting compounds and the reactants used, but is usually in the range of 80 ° C. to the boiling point of the solvent, preferably 100 to 130 ° C.
【０１９３】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常２０乃至４８時
間であり、好適には２０乃至３０時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is usually 20 to 48 hours, preferably 20 to 30 hours.
【０１９４】反応終了後、化合物（１１ａ）は通常の方
法により反応混合物から採取できる。例えば反応混合液
又は反応混合液の溶剤を留去して得られる残査に水と混
合しない有機溶剤を加え、水洗し、溶剤を留去して得ら
れる。After completion of the reaction, compound (11a) can be collected from the reaction mixture by a usual method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【０１９５】得られた化合物（１１ａ）は、必要ならば
常法、例えば再結晶、再沈殿又はクロマトグラフィー等
によって更に精製することができる。 ［Ｃ法］Ｃ法は、Ｂ法の中間体（２１）を別途製造する
方法であり、下記の工程式によって示される。The obtained compound (11a) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. [Method C] The method C is a method for separately producing the intermediate (21) of the method B, and is represented by the following step formula.
【０１９６】[0196]
【化９】 Embedded image
【０１９７】式中、Ｒ3乃至Ｒ6、ＲOH 1、ＴＢＳ及びｎ
は前述と同意義であり、Ｂｎはベンジル基を示す。以
下、各工程について詳述する。 （第Ｃ−１工程）第Ｃ−１工程は公知化合物（１９）に
置換アルキル基を導入して化合物（２４）を製造する工
程である。Wherein R 3 to R 6 , R OH 1 , TBS and n
Has the same meaning as described above, and Bn represents a benzyl group. Hereinafter, each step will be described in detail. (Step C-1) Step C-1 is a step of producing a compound (24) by introducing a substituted alkyl group into the known compound (19).
【０１９８】本工程は、化合物（１９）に溶媒中、酸ま
たは塩基の存在下に式ＢｎＯＣＨ2−ＣＲ3−（ＣＲ
5Ｒ6）ｎ−Ｘ（式中、Ｘは前述と同意義である）で表さ
れる化合物を作用させることにより達成される。In this step, compound (19) is reacted with a compound of the formula BnOCH 2 —CR 3 — (CR
5 R 6) n-X (wherein, X is achieved by applying a compound represented by the above and are as defined).
【０１９９】なお、本工程は前述のＢ法第Ｂ−１工程と
同様にして行うことができる。 （第Ｃ−２工程）第Ｃ−２工程は化合物（２４）のＴＢ
Ｓに代えて水酸基の保護基ＲOH 1を導入して化合物（２
５）を製造する工程である。This step can be carried out in the same manner as in the above-mentioned Method B, Step B-1. (Step C-2) Step C-2 is a step of TB of compound (24).
Introducing a hydroxyl-protecting group R OH 1 in place of S to give compound (2
This is the step of manufacturing 5).
【０２００】本工程は、化合物（２４）に溶媒中、酸を
作用させてＴＢＳ基を除去し、次いで溶媒中、塩基の存
在下に水酸基の保護化剤を作用させることにより達成さ
れる。This step is achieved by removing the TBS group by reacting compound (24) with an acid in a solvent and then reacting the compound with a protecting agent for a hydroxyl group in the presence of a base in the solvent.
【０２０１】なお、本工程は前述のＢ法第Ｂ−２工程と
同様にして行うことができる。 （第Ｃ−３工程）第Ｃ−３工程は化合物（２５）のベン
ジル（Ｂｎ）基を除去して化合物（２６）を製造する工
程である。This step can be carried out in the same manner as in the above-mentioned Method B, Step B-2. (Step C-3) Step C-3 is a step of preparing compound (26) by removing the benzyl (Bn) group of compound (25).
【０２０２】本工程は、化合物（２５）に溶媒中、水素
化剤を作用させることにより達成される。This step is achieved by reacting compound (25) with a hydrogenating agent in a solvent.
【０２０３】なお、本工程は前述の第Ａ−２工程（ｉ）
と同様にして行うことができる。 （第Ｃ−４工程）第Ｃ−４工程は化合物（２６）の水酸
基を２−ニトロフェニルセレニル基で置換して化合物
（２７）を製造する工程である。This step is the same as the above-mentioned step A-2 (i).
Can be performed in the same manner as described above. (Step C-4) Step C-4 is a step of preparing compound (27) by substituting the hydroxyl group of compound (26) with a 2-nitrophenylselenyl group.
【０２０４】本工程は、化合物（２６）に溶媒中、２−
ニトロフェニルセレニル化剤を作用させることにより達
成される。In this step, compound (26) was added in a solvent to give 2-
This is achieved by acting a nitrophenylselenylating agent.
【０２０５】使用される溶媒としては、反応を阻害せず
原料化合物や反応剤をある程度溶解するものであれば特
に制限はなく、例えばヘキサン、シクロヘキサンのよう
な飽和炭化水素類；ベンゼン、トルエン、キシレンのよ
うな芳香族炭化水素類；ジクロロメタン、ジクロロエタ
ン、クロロホルムのようなハロゲン化炭化水素類；メタ
ノール、エタノールのようなアルコール類；エーテル、
テトラヒドロフラン、ジオキサンのようなエーテル類；
酢酸エチルのような酢酸エステル類；アセトニトリルの
ようなニトリル類；ジメチルホルムアミド、ジメチルア
セトアミドのようなアミド類；ジメチルスルホキシドの
ようなスルホキシド類またはそれらの混合溶媒を挙げる
ことができる。これらのうち、好適にはエーテル類（特
にテトラヒドロフラン）である。The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent. For example, saturated hydrocarbons such as hexane and cyclohexane; benzene, toluene and xylene Aromatic hydrocarbons such as dichloromethane, dichloroethane, and chloroform; alcohols such as methanol and ethanol; ethers;
Ethers such as tetrahydrofuran and dioxane;
Examples thereof include acetates such as ethyl acetate; nitriles such as acetonitrile; amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethylsulfoxide; and a mixed solvent thereof. Of these, ethers (particularly tetrahydrofuran) are preferred.
【０２０６】使用される２−ニトロフェニルセレニル化
剤としては、２−ニトロフェニルセレノシアネイトとト
リアルキルホスフィンの組み合わせを挙げることができ
るが、好適には２−ニトロフェニルセレノシアネイトと
トリブチルホスフィンの組み合わせである。Examples of the 2-nitrophenyl selenocyanating agent used include a combination of 2-nitrophenyl selenocyanate and a trialkylphosphine, and preferably 2-nitrophenyl selenocyanate and tributylphosphine. It is a combination of
【０２０７】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常２０℃乃至溶媒の沸
点の範囲であり、好適には２０乃至４０℃である。The reaction temperature varies depending on the types of the starting compounds and the reactants used, but is usually in the range of 20 ° C. to the boiling point of the solvent, preferably 20 to 40 ° C.
【０２０８】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常０．５乃至４時
間であり、好適には０．５乃至２時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is usually 0.5 to 4 hours, preferably 0.5 to 2 hours.
【０２０９】反応終了後、化合物（２７）は通常の方法
により反応混合物から採取できる。例えば反応混合液又
は反応混合液の溶剤を留去して得られる残査に水と混合
しない有機溶剤を加え、水洗し、溶剤を留去して得られ
る。After completion of the reaction, compound (27) can be collected from the reaction mixture by a usual method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【０２１０】得られた化合物（２７）は、必要ならば常
法、例えば再結晶、再沈殿又はクロマトグラフィー等に
よって更に精製することができる。 （第Ｃ−５工程）第Ｃ−５工程は化合物（２７）から２
−ニトロフェニルセレニル基を除去しながら二重結合を
導入して化合物（２１）を製造する工程である。The obtained compound (27) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step C-5) Step C-5 is a step of converting compound (27) to 2
In this step, a compound (21) is produced by introducing a double bond while removing the nitrophenylselenyl group.
【０２１１】本工程は、化合物（２７）に溶媒中、酸化
剤を作用させることにより達成される。This step is achieved by reacting compound (27) with an oxidizing agent in a solvent.
【０２１２】使用される溶媒としては、反応を阻害せず
原料化合物や反応剤をある程度溶解するものであれば特
に制限はなく、例えばヘキサン、シクロヘキサンのよう
な飽和炭化水素類；ベンゼン、トルエン、キシレンのよ
うな芳香族炭化水素類；ジクロロメタン、ジクロロエタ
ン、クロロホルムのようなハロゲン化炭化水素類；メタ
ノール、エタノールのようなアルコール類；エーテル、
テトラヒドロフラン、ジオキサンのようなエーテル類；
酢酸エチルのような酢酸エステル類；アセトニトリルの
ようなニトリル類；ジメチルホルムアミド、ジメチルア
セトアミドのようなアミド類；ジメチルスルホキシドの
ようなスルホキシド類またはそれらの混合溶媒を挙げる
ことができる。これらのうち、好適にはエーテル類（特
にテトラヒドロフラン）である。The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent. For example, saturated hydrocarbons such as hexane and cyclohexane; benzene, toluene and xylene Aromatic hydrocarbons such as dichloromethane, dichloroethane, and chloroform; halogenated hydrocarbons such as methanol; alcohols such as methanol and ethanol; ethers;
Ethers such as tetrahydrofuran and dioxane;
Examples thereof include acetates such as ethyl acetate; nitriles such as acetonitrile; amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethylsulfoxide; and a mixed solvent thereof. Of these, ethers (particularly tetrahydrofuran) are preferred.
【０２１３】使用される酸化剤としては、例えば過酸化
水素水；過酢酸、過安息香酸のような過酸類を挙げるこ
とができるが、好適には過酸化水素水である。Examples of the oxidizing agent to be used include aqueous hydrogen peroxide; and peracids such as peracetic acid and perbenzoic acid. Hydrogen peroxide is preferred.
【０２１４】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常０℃乃至溶媒の沸点
の範囲であり、好適には２０乃至４０℃である。The reaction temperature varies depending on the types of the starting compounds and the reactants used, but is usually in the range of 0 ° C. to the boiling point of the solvent, preferably 20 to 40 ° C.
【０２１５】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常０．５乃至１２
時間であり、好適には０．５乃至２時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature.
Time, preferably 0.5 to 2 hours.
【０２１６】反応終了後、化合物（２１）は通常の方法
により反応混合物から採取できる。例えば反応混合液又
は反応混合液の溶剤を留去して得られる残査に水と混合
しない有機溶剤を加え、水洗し、溶剤を留去して得られ
る。After completion of the reaction, compound (21) can be collected from the reaction mixture by a usual method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【０２１７】得られた化合物（２１）は、必要ならば常
法、例えば再結晶、再沈殿又はクロマトグラフィー等に
よって更に精製することができる。 ［Ｄ法］Ｄ法は、Ａ法の出発原料である化合物（１１）
を別途製造する方法であり、下記の工程式によって示さ
れる。The obtained compound (21) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. [Method D] In the method D, the compound (11) which is a starting material of the method A is used.
Is separately produced, and is represented by the following process formula.
【０２１８】[0218]
【化１０】 Embedded image
【０２１９】式中、Ｒ3乃至Ｒ8、ＲOH 1、ｍ及びｎは前
述と同意義である。以下、各工程について詳述する。 （第Ｄ−１工程）第Ｄ−１工程は化合物（２８）からア
ルデヒド化合物（２９）を製造する工程である。In the formula, R 3 to R 8 , R OH 1 , m and n have the same meanings as described above. Hereinafter, each step will be described in detail. (Step D-1) Step D-1 is a step of producing an aldehyde compound (29) from the compound (28).
【０２２０】本工程は、化合物（２８）に溶媒中、酸化
剤を作用させることにより達成される。This step is achieved by reacting compound (28) with an oxidizing agent in a solvent.
【０２２１】使用される溶媒としては、反応を阻害せず
原料化合物や反応剤をある程度溶解するものであれば特
に制限はなく、例えばヘキサン、シクロヘキサンのよう
な飽和炭化水素類；ベンゼン、トルエン、キシレンのよ
うな芳香族炭化水素類；ジクロロメタン、ジクロロエタ
ン、クロロホルムのようなハロゲン化炭化水素類；メタ
ノール、エタノールのようなアルコール類；エーテル、
テトラヒドロフラン、ジオキサンのようなエーテル類；
酢酸エチルのような酢酸エステル類；アセトンのような
ケトン類；アセトニトリルのようなニトリル類；ジメチ
ルホルムアミド、ジメチルアセトアミドのようなアミド
類；ジメチルスルホキシドのようなスルホキシド類；水
またはそれらの混合溶媒を挙げることができる。これら
のうち、好適にはケトン類と水の混合溶媒（特にアセト
ン−水）である。The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent. For example, saturated hydrocarbons such as hexane and cyclohexane; benzene, toluene and xylene Aromatic hydrocarbons such as dichloromethane, dichloroethane, and chloroform; alcohols such as methanol and ethanol; ethers;
Ethers such as tetrahydrofuran and dioxane;
Acetates such as ethyl acetate; ketones such as acetone; nitriles such as acetonitrile; amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethylsulfoxide; water or a mixed solvent thereof. be able to. Among these, a mixed solvent of ketones and water (particularly acetone-water) is preferred.
【０２２２】使用される酸化剤としては、例えば過ヨウ
素酸ナトリウム、過ヨウ素酸カリウムのような過ヨウ素
酸塩類を挙げることができるが、好適には過ヨウ素酸ナ
トリウムである。Examples of the oxidizing agent to be used include periodates such as sodium periodate and potassium periodate, and preferred is sodium periodate.
【０２２３】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常０℃乃至溶媒の沸点
の範囲であり、好適には０乃至５０℃である。The reaction temperature varies depending on the type of the starting compound and the reactant used, but is usually in the range of 0 ° C. to the boiling point of the solvent, preferably 0 to 50 ° C.
【０２２４】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常０．５乃至６時
間であり、好適には１乃至３時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is usually 0.5 to 6 hours, preferably 1 to 3 hours.
【０２２５】反応終了後、化合物（２９）は通常の方法
により反応混合物から採取できる。例えば反応混合液又
は反応混合液の溶剤を留去して得られる残査に水と混合
しない有機溶剤を加え、水洗し、溶剤を留去して得られ
る。After completion of the reaction, compound (29) can be collected from the reaction mixture by a usual method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【０２２６】得られた化合物（２９）は、必要ならば常
法、例えば再結晶、再沈殿又はクロマトグラフィー等に
よって更に精製することができる。 （第Ｄ−２工程）第Ｄ−２工程はアルデヒド化合物（２
９）にビニルアルキル基を導入して化合物（３０）を製
造する工程である。The obtained compound (29) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step D-2) Step D-2 is an aldehyde compound (2
This is a step of producing a compound (30) by introducing a vinylalkyl group into 9).
【０２２７】本工程は、アルデヒド化合物（２９）に溶
媒中、酸触媒の存在下、式Ｈ2Ｃ＝ＣＲ4−（ＣＲ7Ｒ8）
ｍ−Ｓｉ（Ｒ14）3で表される化合物（式中、Ｒ4、
Ｒ7、Ｒ 8及びｍは前述と同意義であり、Ｒ14は炭素数１
乃至４個のアルキル基を示す。）を作用させることによ
り達成される。In this step, the aldehyde compound (29) was dissolved.
Formula H in a medium in the presence of an acid catalystTwoC = CRFour− (CR7R8)
m-Si (R14)ThreeA compound represented by the formula:Four,
R7, R 8And m are as defined above, and R14Is 1 carbon
And represents 4 to 4 alkyl groups. By acting
Is achieved.
【０２２８】使用される溶媒としては、反応を阻害せず
原料化合物や反応剤をある程度溶解するものであれば特
に制限はなく、例えばヘキサン、シクロヘキサンのよう
な飽和炭化水素類；ベンゼン、トルエン、キシレンのよ
うな芳香族炭化水素類；ジクロロメタン、ジクロロエタ
ン、クロロホルムのようなハロゲン化炭化水素類；メタ
ノール、エタノールのようなアルコール類；エーテル、
テトラヒドロフラン、ジオキサンのようなエーテル類；
酢酸エチルのような酢酸エステル類；アセトニトリルの
ようなニトリル類；ジメチルホルムアミド、ジメチルア
セトアミドのようなアミド類；ジメチルスルホキシドの
ようなスルホキシド類を挙げることができる。これらの
うち、好適にはハロゲン化炭化水素類（特にジクロロメ
タン）である。The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent. For example, saturated hydrocarbons such as hexane and cyclohexane; benzene, toluene and xylene Aromatic hydrocarbons such as dichloromethane, dichloroethane, and chloroform; alcohols such as methanol and ethanol; ethers;
Ethers such as tetrahydrofuran and dioxane;
Acetates such as ethyl acetate; nitriles such as acetonitrile; amides such as dimethylformamide and dimethylacetamide; and sulfoxides such as dimethylsulfoxide. Of these, halogenated hydrocarbons (particularly dichloromethane) are preferred.
【０２２９】式Ｈ2Ｃ＝ＣＲ4−（ＣＲ7Ｒ8）ｍ−Ｓｉ
（Ｒ14）3で表される化合物で表される化合物として
は、所望のＲ4、Ｒ7、Ｒ8及びｍを有し、好適にはＲ14
がメチル基である。[0229] formula H 2 C = CR 4 - ( CR 7 R 8) m-Si
The compound represented by the compound represented by (R 14 ) 3 has desired R 4 , R 7 , R 8 and m, preferably R 14
Is a methyl group.
【０２３０】使用される酸触媒としては、四塩化チタン
のような金属塩化物を挙げることができ、好適には四塩
化チタンである。Examples of the acid catalyst used include metal chlorides such as titanium tetrachloride, and titanium tetrachloride is preferred.
【０２３１】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常−１００℃乃至溶媒
の沸点の範囲であり、好適には−２０乃至４０℃であ
る。The reaction temperature varies depending on the type of the starting compound and the reactants used, but is usually in the range of -100 ° C to the boiling point of the solvent, preferably -20 to 40 ° C.
【０２３２】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常１乃至８時間で
あり、好適には１乃至５時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is usually 1 to 8 hours, preferably 1 to 5 hours.
【０２３３】反応終了後、化合物（３０）は通常の方法
により反応混合物から採取できる。例えば反応混合液又
は反応混合液の溶剤を留去して得られる残査に水と混合
しない有機溶剤を加え、水洗し、溶剤を留去して得られ
る。After completion of the reaction, compound (30) can be collected from the reaction mixture by a usual method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washed with water, and the solvent is distilled off.
【０２３４】得られた化合物（３０）は、必要ならば常
法、例えば再結晶、再沈殿又はクロマトグラフィー等に
よって更に精製することができる。 （第Ｄ−３工程）第Ｄ−３工程は化合物（３０）にビニ
ルアルキル基を導入して化合物（１１）を製造する工程
である。The obtained compound (30) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step D-3) Step D-3 is a step of producing a compound (11) by introducing a vinylalkyl group into the compound (30).
【０２３５】本工程は、化合物（３０）に溶媒中、酸ま
たは塩基の存在下に式ＣＨ2＝ＣＲ3−（ＣＲ5Ｒ6）ｎ−
Ｘ（式中、Ｘは前述と同意義である）で表される化合物
を作用させることにより達成される。In this step, compound (30) is reacted with a compound of the formula CH 2 ＣＲCR 3- (CR 5 R 6 ) n- in the presence of an acid or a base in a solvent.
It is achieved by reacting a compound represented by X (wherein X is as defined above).
【０２３６】なお、本工程は前述のＢ法第Ｂ−１工程ま
たはＣ法と同様にして行うことができる。 ［Ｅ法］Ｅ法は、化合物（１）のカルボキシル基におけ
る薬理上許容されるエステル誘導体（１ａ）を製造する
方法であり、下記の工程式によって示される。This step can be performed in the same manner as in the above-mentioned Method B, Step B-1 or Method C. [Method E] Method E is a method for producing a pharmacologically acceptable ester derivative (1a) at the carboxyl group of compound (1), and is represented by the following step formula.
【０２３７】[0237]
【化１１】 Embedded image
【０２３８】式中、Ｒ1乃至Ｒ10、Ｒ1p、Ｒ2p、Ｒ10p、
ｍ及びｎは前述と同意義であり、Ｒａはカルボキシル基
における薬理上許容されるエステルのエステル残基であ
る。なお、本法のＲ1p及びＲ2pの保護基はアルカリ加水
分解で除去されず酸処理によって除去される基（例えば
イソプロピリデン基）であることが好ましい。以下、各
工程について詳述する。 （第Ｅ−１工程）第Ｅ−１工程は化合物（１８）を加水
分解反応に付してカルボン酸化合物（３１）を製造する
工程である。In the formula, R 1 to R 10 , R 1p , R 2p , R 10p ,
m and n are as defined above, and Ra is an ester residue of a pharmacologically acceptable ester at the carboxyl group. In the present method, the protecting groups for R 1p and R 2p are preferably groups which are not removed by alkali hydrolysis but are removed by acid treatment (for example, isopropylidene group). Hereinafter, each step will be described in detail. (Step E-1) Step E-1 is a step of subjecting compound (18) to a hydrolysis reaction to produce carboxylic acid compound (31).
【０２３９】本工程は、化合物（１８）に溶媒中、塩基
を作用させることにより達成される。This step is achieved by reacting compound (18) with a base in a solvent.
【０２４０】使用される溶媒としては、反応を阻害せず
原料化合物や反応剤をある程度溶解するものであれば特
に制限はなく、例えばメタノール、エタノールのような
アルコール類；エーテル、テトラヒドロフラン、ジオキ
サンのようなエーテル類；水またはそれらの混合溶媒を
挙げることができる。これらのうち、好適にはアルコー
ル類（特にメタノール）である。The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent. For example, alcohols such as methanol and ethanol; ethers, tetrahydrofuran and dioxane Ethers; water or a mixed solvent thereof. Of these, alcohols (particularly methanol) are preferred.
【０２４１】使用される塩基としては、例えば水酸化ナ
トリウム、水酸化カリウムのような水酸化アルカリ金属
類を挙げることができるが、好適には水酸化カリウムで
ある。Examples of the base used include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and potassium hydroxide is preferred.
【０２４２】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常０℃乃至溶媒の沸点
の範囲であり、好適には２０乃至５０℃である。The reaction temperature varies depending on the types of the starting compounds and the reactants used, but is usually in the range of 0 ° C. to the boiling point of the solvent, preferably 20 to 50 ° C.
【０２４３】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常０．５乃至６時
間であり、好適には０．５乃至２時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is usually 0.5 to 6 hours, preferably 0.5 to 2 hours.
【０２４４】反応終了後、化合物（３１）は通常の方法
により反応混合物から採取できる。例えば反応混合液を
中和し、反応混合液又は反応混合液の溶剤を留去して得
られる残査に水と混合しない有機溶剤を加え、水洗し、
溶剤を留去して得られる。After completion of the reaction, compound (31) can be collected from the reaction mixture by a usual method. For example, neutralize the reaction mixture, add an organic solvent that does not mix with water to the reaction mixture or the residue obtained by distilling off the solvent of the reaction mixture, wash with water,
It is obtained by distilling off the solvent.
【０２４５】なお、反応混合液を濃縮してえられる残査
から化合物（３１）のアルカリ金属塩を単離し、次の工
程に使用することもできる。The alkali metal salt of compound (31) can be isolated from the residue obtained by concentrating the reaction mixture and used in the next step.
【０２４６】得られた化合物（３１）又はそのアルカリ
金属塩は、必要ならば常法、例えば再結晶、再沈殿又は
クロマトグラフィー等によって更に精製することができ
る。 （第Ｅ−２工程）第Ｅ−２工程は化合物（３１）又はそ
のアルカリ金属塩をエステル化反応に付して化合物（３
２）を製造する工程である。The obtained compound (31) or an alkali metal salt thereof can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step E-2) Step E-2 is a step of subjecting compound (31) or an alkali metal salt thereof to an esterification reaction to give compound (3).
This is the step of manufacturing 2).
【０２４７】本工程は、化合物（３１）又はそのアルカ
リ金属塩に溶媒中、塩基の存在下に式ＲａＸ（式中、Ｘ
は脱離基を示す）で表される化合物を作用させることに
より達成される。In this step, compound (31) or an alkali metal salt thereof is reacted with a compound of the formula RaX (where X is
Represents a leaving group).
【０２４８】使用される溶媒としては、例えばヘキサ
ン、シクロヘキサンのような飽和炭化水素類；ベンゼ
ン、トルエン、キシレンのような芳香族炭化水素類；エ
ーテル、テトラヒドロフラン、ジオキサンのようなエー
テル類；アセトニトリルのようなニトリル類；ジメチル
ホルムアミド、ジメチルアセトアミドのようなアミド
類；ジメチルスルホキシドのようなスルホキシド類を挙
げることができる。これらのうち、好適にはアミド類
（特にジメチルホルムアミド）である。Examples of the solvent to be used include saturated hydrocarbons such as hexane and cyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ether, tetrahydrofuran and dioxane; acetonitrile and the like. Amides such as dimethylformamide and dimethylacetamide; and sulfoxides such as dimethylsulfoxide. Of these, amides (particularly dimethylformamide) are preferred.
【０２４９】使用される塩基としては、例えばトリエチ
ルアミン、ジイソプロピルエチルアミン、ピリジンのよ
うな有機塩基類；水素化ナトリウム、水素化カリウムの
ような水素化アルカリ金属類を挙げることができるが、
好適には水素化カリウムである。Examples of the base used include organic bases such as triethylamine, diisopropylethylamine and pyridine; and alkali metal hydrides such as sodium hydride and potassium hydride.
Preferably it is potassium hydride.
【０２５０】出発原料は、好適には化合物（３１）のア
ルカリ金属塩であり、この場合、塩基を使用しなくても
良い。The starting material is preferably an alkali metal salt of the compound (31). In this case, it is not necessary to use a base.
【０２５１】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常２０℃乃至溶媒の沸
点の範囲であり、好適には４０乃至６０℃である。The reaction temperature varies depending on the types of the starting compounds and the reactants used, but is usually in the range of 20 ° C. to the boiling point of the solvent, preferably 40 to 60 ° C.
【０２５２】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常２乃至８時間で
あり、好適には２乃至４時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is usually 2 to 8 hours, preferably 2 to 4 hours.
【０２５３】反応終了後、化合物（３２）は通常の方法
により反応混合物から採取できる。例えば、反応混合液
又は反応混合液の溶剤を留去して得られる残査に水と混
合しない有機溶剤を加え、水洗し、溶剤を留去して得ら
れる。After the completion of the reaction, the compound (32) can be collected from the reaction mixture by a usual method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, and the mixture is washed with water and the solvent is distilled off.
【０２５４】得られた化合物（３２）は、必要ならば常
法、例えば再結晶、再沈殿又はクロマトグラフィー等に
よって更に精製することができる。 （第Ｅ−３工程）第Ｅ−３工程は化合物（３２）を脱保
護反応に付して化合物（１）のカルボキシル基における
薬理上許容されるエステル誘導体（１ａ）を製造する工
程である。The obtained compound (32) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step E-3) Step E-3 is a step of subjecting compound (32) to a deprotection reaction to produce a pharmacologically acceptable ester derivative (1a) at the carboxyl group of compound (1).
【０２５５】なお、本工程は前述のＡ法第Ａ−８工程と
同様にして行うことができる。 ［Ｆ法］Ｆ法は、化合物（１）の水酸基における薬理上
許容されるエステル誘導体（１ｂ）を製造する方法であ
り、下記の工程式によって示される。This step can be carried out in the same manner as in the above-mentioned Method A, Step A-8. [Method F] Method F is a method for producing a pharmacologically acceptable ester derivative (1b) at the hydroxyl group of compound (1), and is represented by the following process formula.
【０２５６】[0256]
【化１２】 Embedded image
【０２５７】式中、Ｒ1乃至Ｒ10、Ｒ1p、Ｒ2p、Ｒ10p、
ｍ及びｎは前述と同意義であり、Ｒ 1b及びＲ2bは少なく
とも一方の水酸基がアシル化されたＲ1及びＲ2を示す。
なお、本法のＲ1p及びＲ2pの水酸基の保護基はアセチル
基のようなアルカリ加水分解で除去できる基であること
が好ましい。以下、各工程について詳述する。 （第Ｆ−１工程）第Ｆ−１工程は化合物（１８）を加水
分解反応に付して化合物（３３）を製造する工程であ
る。In the formula, R1Or RTen, R1p, R2p, R10p,
m and n are as defined above, and R 1bAnd R2bIs less
R in which one of the hydroxyl groups is acylated1And RTwoIs shown.
In addition, R of this method1pAnd R2pAcetyl protecting group is acetyl
A group that can be removed by alkaline hydrolysis, such as a group
Is preferred. Hereinafter, each step will be described in detail. (Step F-1) Step F-1 involves hydrolyzing compound (18).
A step of producing a compound (33) by subjecting it to a decomposition reaction.
You.
【０２５８】なお、本工程は前述のＥ法第Ｅ−１工程と
同様にして行うことができる。 （第Ｆ−２工程）第Ｆ−２工程は化合物（３３）のカル
ボキシル基に保護基を導入して化合物（３４）を製造す
る工程である。This step can be carried out in the same manner as in the aforementioned method E, step E-1. (Step F-2) Step F-2 is a step of producing a compound (34) by introducing a protecting group into the carboxyl group of the compound (33).
【０２５９】本工程は、化合物（３３）に溶媒中、ジフ
ェニルジアゾメタンを作用させることにより達成され
る。This step is achieved by reacting compound (33) with diphenyldiazomethane in a solvent.
【０２６０】使用される溶媒としては、反応を阻害せず
原料化合物や反応剤をある程度溶解するものであれば特
に制限はなく、例えばヘキサン、シクロヘキサンのよう
な飽和炭化水素類；ベンゼン、トルエン、キシレンのよ
うな芳香族炭化水素類；ジクロロメタン、ジクロロエタ
ン、クロロホルムのようなハロゲン化炭化水素類；メタ
ノール、エタノールのようなアルコール類；エーテル、
テトラヒドロフラン、ジオキサンのようなエーテル類；
酢酸エチルのような酢酸エステル類；アセトニトリルの
ようなニトリル類；ジメチルホルムアミド、ジメチルア
セトアミドのようなアミド類；ジメチルスルホキシドの
ようなスルホキシド類；またはそれらの混合溶媒を挙げ
ることができる。これらのうち、好適にはアルコール類
（特にメタノール）である。The solvent to be used is not particularly limited as long as it does not hinder the reaction and dissolves the starting compounds and the reactants to some extent. For example, saturated hydrocarbons such as hexane and cyclohexane; benzene, toluene and xylene Aromatic hydrocarbons such as dichloromethane, dichloroethane, and chloroform; alcohols such as methanol and ethanol; ethers;
Ethers such as tetrahydrofuran and dioxane;
Acetates such as ethyl acetate; nitriles such as acetonitrile; amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethylsulfoxide; or a mixed solvent thereof. Of these, alcohols (particularly methanol) are preferred.
【０２６１】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常０℃乃至溶媒の沸点
の範囲であり、好適には２０乃至４０℃である。The reaction temperature varies depending on the types of the starting compounds and the reactants used, but is usually in the range of 0 ° C. to the boiling point of the solvent, preferably 20 to 40 ° C.
【０２６２】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常０．５乃至２時
間であり、好適には０．５乃至１時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is usually 0.5 to 2 hours, preferably 0.5 to 1 hour.
【０２６３】反応終了後、化合物（３４）は通常の方法
により反応混合物から採取できる。例えば、反応混合液
又は反応混合液の溶剤を留去して得られる残査に水と混
合しない有機溶剤を加え、水洗し、溶剤を留去して得ら
れる。After completion of the reaction, compound (34) can be collected from the reaction mixture by a usual method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, and the mixture is washed with water and the solvent is distilled off.
【０２６４】得られた化合物（３４）は、必要ならば常
法、例えば再結晶、再沈殿又はクロマトグラフィー等に
よって更に精製することができる。 （第Ｆ−３工程）第Ｆ−３工程は化合物（３４）のＲ1
及び（又は）Ｒ2の水酸基に所望のアシル基を導入して
化合物（３５）を製造する工程である。The obtained compound (34) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step F-3) Step F-3 is a step of reacting R 1 of compound (34).
And / or) introducing a desired acyl group into the hydroxyl group of R 2 to produce compound (35).
【０２６５】本工程は、化合物（３４）に、必要に応じ
て、溶媒中ジブチル錫オキシドを作用させ、濃縮乾固さ
せた後、溶媒中、塩基の存在下にアシル化剤を作用させ
ることにより達成される。In this step, compound (34) is treated with dibutyltin oxide in a solvent, if necessary, and concentrated to dryness. Then, the compound is reacted with an acylating agent in the presence of a base in a solvent. Achieved.
【０２６６】ジブチル錫オキシドを作用させるときに使
用される溶媒としては、反応を阻害せず原料化合物や反
応剤をある程度溶解するものであれば特に制限はなく、
例えばヘキサン、シクロヘキサンのような飽和炭化水素
類；ベンゼン、トルエン、キシレンのような芳香族炭化
水素類；ジクロロメタン、ジクロロエタン、クロロホル
ムのようなハロゲン化炭化水素類；エーテル、テトラヒ
ドロフラン、ジオキサンのようなエーテル類；酢酸エチ
ルのような酢酸エステル類；メタノール、エタノールの
ようなアルコール類；アセトニトリルのようなニトリル
類；ジメチルホルムアミド、ジメチルアセトアミドのよ
うなアミド類；ジメチルスルホキシドのようなスルホキ
シド類を挙げることができる。これらのうち、好適には
アルコール類（特にメタノール）である。The solvent used for the reaction of dibutyltin oxide is not particularly limited as long as it does not inhibit the reaction and dissolves the starting compounds and the reactants to some extent.
For example, saturated hydrocarbons such as hexane and cyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; ethers such as ether, tetrahydrofuran and dioxane Acetates such as ethyl acetate; alcohols such as methanol and ethanol; nitriles such as acetonitrile; amides such as dimethylformamide and dimethylacetamide; and sulfoxides such as dimethylsulfoxide. Of these, alcohols (particularly methanol) are preferred.
【０２６７】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常５０℃乃至溶媒の沸
点の範囲であり、好適には５０乃至７０℃である。The reaction temperature varies depending on the types of the starting compounds and the reactants used, but is usually in the range of 50 ° C. to the boiling point of the solvent, preferably 50 to 70 ° C.
【０２６８】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常０．２５乃至１
時間であり、好適には０．２５乃至０．５時間である。The reaction time varies depending on the starting compound used, the reactant and the reaction temperature, but is usually from 0.25 to 1
Hours, preferably from 0.25 to 0.5 hours.
【０２６９】反応終了後、反応混合液から溶剤を留去し
て得られる残査をそのままアシル化剤との反応に付すこ
とができる。After the completion of the reaction, the residue obtained by distilling off the solvent from the reaction mixture can be directly subjected to the reaction with the acylating agent.
【０２７０】アシル化剤を作用させるときに使用される
溶媒としては、反応を阻害せず原料化合物や反応剤をあ
る程度溶解するものであれば特に制限はなく、例えばヘ
キサン、シクロヘキサンのような飽和炭化水素類；ベン
ゼン、トルエン、キシレンのような芳香族炭化水素類；
ジクロロメタン、ジクロロエタン、クロロホルムのよう
なハロゲン化炭化水素類；エーテル、テトラヒドロフラ
ン、ジオキサンのようなエーテル類；酢酸エチルのよう
な酢酸エステル類；アセトニトリルのようなニトリル
類；ジメチルホルムアミド、ジメチルアセトアミドのよ
うなアミド類；ジメチルスルホキシドのようなスルホキ
シド類を挙げることができる。これらのうち、好適には
芳香族炭化水素類（特にトルエン）である。The solvent used when the acylating agent is allowed to act is not particularly limited as long as it does not inhibit the reaction and dissolves the starting compounds and the reactants to some extent. Hydrogens; aromatic hydrocarbons such as benzene, toluene and xylene;
Halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; ethers such as ether, tetrahydrofuran and dioxane; acetates such as ethyl acetate; nitriles such as acetonitrile; amides such as dimethylformamide and dimethylacetamide And sulfoxides such as dimethyl sulfoxide. Of these, aromatic hydrocarbons (particularly toluene) are preferred.
【０２７１】使用される塩基としては、例えば水酸化ナ
トリウム、水酸化カリウムのような水酸化アルカリ金属
類;炭酸水素ナトリウム、炭酸ナトリウムのようなアル
カリ金属炭酸塩類；トリエチルアミン、ピリジンのよう
な有機塩基類を挙げることができるが、好適には有機塩
基類（特にトリエチルアミン）である。As the base to be used, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium hydrogen carbonate and sodium carbonate; organic bases such as triethylamine and pyridine Among them, organic bases (particularly, triethylamine) are preferred.
【０２７２】使用されるアシル化剤としては、例えばア
セチルクロリド、プロピオニルブロミド、デカノイルク
ロリド、ベンゾイルクロリドのようなアシルハライド類
が好適である。As the acylating agent to be used, for example, acyl halides such as acetyl chloride, propionyl bromide, decanoyl chloride and benzoyl chloride are preferred.
【０２７３】反応温度は、使用される原料化合物及び反
応剤の種類によって異なるが、通常−２０℃乃至溶媒の
沸点の範囲であり、好適には−１０乃至１０℃である。The reaction temperature varies depending on the types of the starting compounds and the reactants used, but is usually in the range of -20 ° C to the boiling point of the solvent, preferably -10 to 10 ° C.
【０２７４】反応時間は、使用される原料化合物、反応
剤及び反応温度によって異なるが、通常０．５乃至３時
間であり、好適には０．５乃至１．５時間である。The reaction time varies depending on the starting compounds used, the reactants and the reaction temperature, but is usually 0.5 to 3 hours, preferably 0.5 to 1.5 hours.
【０２７５】反応終了後、化合物（３５）は通常の方法
により反応混合物から採取できる。例えば、反応混合液
又は反応混合液の溶剤を留去して得られる残査に水と混
合しない有機溶剤を加え、水洗し、溶剤を留去して得ら
れる。After completion of the reaction, compound (35) can be collected from the reaction mixture by a usual method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, and the mixture is washed with water and the solvent is distilled off.
【０２７６】得られた化合物（３５）は、必要ならば常
法、例えば再結晶、再沈殿又はクロマトグラフィー等に
よって更に精製することができる。 （第Ｆ−４工程）第Ｆ−４工程は化合物（３５）を脱保
護反応に付して化合物（１）の水酸基における薬理上許
容されるエステル誘導体（１ｂ）を製造する工程であ
る。The obtained compound (35) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step F-4) Step F-4 is a step of subjecting compound (35) to a deprotection reaction to produce a pharmacologically acceptable ester derivative (1b) at the hydroxyl group of compound (1).
【０２７７】なお、本工程は前述のＡ法第Ａ−８工程と
同様にして行うことができる。本発明の化合物（１）、
その薬理上許容されるエステル誘導体またはそれらの薬
理上許容される塩を医薬（特にインフルエンザの治療剤
又は予防剤）として使用する場合には、それ自体あるい
は適宜の薬理学的に許容される、賦形剤、希釈剤等と混
合し、錠剤、カプセル剤、顆粒剤、散剤、シロップ剤、
注射剤、軟膏剤、液剤、懸濁剤、エアゾール剤、トロー
チ剤等の製剤として傾向的又は非経口的に投与すること
ができる。This step can be carried out in the same manner as in the above-mentioned Method A, Step A-8. Compound (1) of the present invention,
When the pharmacologically acceptable ester derivative or a pharmacologically acceptable salt thereof is used as a medicament (particularly a therapeutic or prophylactic agent for influenza), it may be used by itself or an appropriate pharmacologically acceptable agent. Mix with excipients, diluents, etc., tablets, capsules, granules, powders, syrups,
It can be administered in the form of injections, ointments, liquids, suspensions, aerosols, troches and the like, or tenderly or parenterally.
【０２７８】これらの製剤は、賦形剤（例えば、乳糖、
白糖、ブドウ糖、マンニット、ソルビットのような糖
類；トウモロコシデンプン、馬鈴薯デンプン、α−デン
プン、デキストリン、カルボキシメチルデンプンのよう
なデンプン誘導体；結晶セルロース、低置換度ヒドロキ
シプロピルセルロース、ヒドロキシプロピルメチルセル
ロース、カルボキシメチルセルロース、カルボキシメチ
ルセルロースカルシウム、内部架橋カルボキシメチルセ
ルロースナトリウムのようなセルロース誘導体；アラビ
アゴム；デキストラン；プルラン；軽質無水珪酸、合成
珪酸アルミニウム、メタ珪酸アルミン酸マグネシウムの
ような珪酸塩類；リン酸カルシウムのようなリン酸塩
類；炭酸カルシウムのような炭酸塩類；硫酸カルシウム
のような硫酸塩類等）、結合剤（例えば、前記の賦形
剤；ゼラチン；ポリビニルピロリドン；マグロゴール
等）、崩壊剤（例えば、前記の賦形剤；クロスカルメロ
ースナトリウム、カルボキシメチルスターチナトリウ
ム、架橋ポリビニルピロリドンのような化学修飾され
た、デンプンまたはセルロース誘導体等）、滑沢剤（例
えば、タルク；ステアリン酸；ステアリン酸カルシウ
ム、ステアリン酸マグネシウムのようなステアリン酸金
属塩；コロイドシリカ；ビーガム；ビーズワックス、ゲ
イロウのようなワックス類；硼酸；グリコール；フマル
酸、アジピン酸のようなカルボン酸類；安息香酸ナトリ
ウムのようなカルボン酸ナトリウム塩；硫酸ナトリウム
のような硫酸類塩；ロイシン；ラウリル硫酸ナトリウ
ム、ラウリル硫酸マグネシウムのようなラウリル硫酸
塩；無水珪酸、珪酸水和物のような珪酸類；前記の賦形
剤におけるデンプン誘導体等）、安定剤（例えば、メチ
ルパラベン、プロピルパラベンのようなパラヒドロキシ
安息香酸エステル類；クロロブタノール、ベンジルアル
コール、フェニルエチルアルコールのようなアルコール
類；塩化ベンザルコニウム；フェノール、クレゾールの
ようなフェノール類；チメロサール；無水酢酸；ソルビ
ン酸等）、矯味矯臭剤（例えば、通常使用される、甘味
料、酸味料、香料等）、懸濁化剤（例えば、ポリソルベ
ート８０、カルボキシメチルセルロースナトリウム
等）、希釈剤、製剤用溶剤（例えば、水、エタノール、
グリセリン等）等の添加物を用いて周知の方法で製造さ
れる。These preparations contain excipients (eg, lactose,
Saccharides such as sucrose, glucose, mannitol, sorbit; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose Cellulose derivatives such as sodium carboxymethylcellulose, internally crosslinked carboxymethylcellulose; gum arabic; dextran; pullulan; silicates such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium metasilicate aluminate; phosphates such as calcium phosphate; Carbonates such as calcium carbonate; sulfates such as calcium sulfate, etc., binders (eg, the above-mentioned excipients; gelatin; polyvinyl alcohol) Pyrrolidone; magrogol, etc.), disintegrants (eg, the excipients mentioned above; croscarmellose sodium, sodium carboxymethyl starch, chemically modified starch or cellulose derivatives such as cross-linked polyvinyl pyrrolidone, etc.), lubricants ( For example, talc; stearic acid; stearic acid metal salts such as calcium stearate and magnesium stearate; colloidal silica; veegum; waxes such as beeswax and gay wax; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid. Sodium carboxylate such as sodium benzoate; sulfates such as sodium sulfate; leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid and silicic acid hydrate; Excipient And starch stabilizers such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenol and cresol. Phenols; thimerosal; acetic anhydride; sorbic acid, etc.), flavoring agents (eg, commonly used sweeteners, sour agents, flavors, etc.), suspending agents (eg, polysorbate 80, sodium carboxymethylcellulose, etc.) , Diluents, formulation solvents (eg, water, ethanol,
Glycerin) using an additive such as glycerin.
【０２７９】その使用量は投与される者の症状・体重・
年齢等により異なるが、１日当たり下限０．１ｍｇ（好
適には１ｍｇ）、上限１０００ｍｇ（好適には、５００
ｍｇ）を、１日当り１乃至数回、症状に応じて投与する
ことが望ましい。[0279] The amount of use depends on the condition, body weight,
Although it depends on the age, etc., the lower limit is 0.1 mg (preferably 1 mg) and the upper limit is 1000 mg (preferably 500 mg) per day.
mg) is preferably administered once or several times daily depending on the condition.
【０２８０】[0280]
【実施例】本発明について、実施例、試験例及び製剤例
を挙げて更に詳細に説明する。 （実施例１） （4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルアミノ−
5，6−ジヒドロ−6−（3', 4'−ジヒドロキシ−テトラ
ヒドロ−フラン−2'−イル）−4−グアニジノ−4H−ピ
ラン−2−カルボン酸 トリフルオロ酢酸塩The present invention will be described in more detail with reference to Examples, Test Examples and Formulation Examples. (Example 1) (4S, 5R, 6R, 2'R, 3'R, 4'R) -5-acetylamino-
5,6-dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-furan-2'-yl) -4-guanidino-4H-pyran-2-carboxylic acid trifluoroacetate
【０２８１】[0281]
【化１３】 Embedded image
【０２８２】(i)5−アセチルアミノ−4−O−t−ブチル
ジメチルシリル−3，5−ジデオキシ−8，9−O−イソプ
ロピリデン−2−O−メチル−7−O−（2'−プロペニル）
−D−グリセロ−D−ガラクト−ノン−2−エノピラノソ
ン酸メチル 窒素雰囲気下5−アセチルアミノ−3，5−ジデオキシ−
8，9−O−イソプロピリデン−2−O−メチル−4−O−t−
ブチルジメチルシリル−D−グリセロ−D−ガラクト−ノ
ン−2−エノピラノソン酸メチル(10 g, 20.3 mmol）（Z
biral, Erich;Phadtare, S.; Schmid, Walther; Liebig
s Ann. Chem., 1987年, (1), p39-43.に記載された化合
物）をジメチルホルムアミド（60 ml）に溶解し、氷冷
下水素化ナトリウム (1.7 g, 40.6 mmol）を加え、室温
で15分攪拌した。つづいて室温でヨウ化アリル（2.18 m
l, 24.3 mmol）を滴下し、室温で1時間撹拌した。反応
液を酢酸エチル（200 ml）と飽和塩化アンモニウム水溶
液（100 ml）に分配し、有機層を分離し、飽和食塩水
（50 ml X 3）で洗浄し、硫酸ナトリウムで乾燥し、減
圧留去した。得られた残査をクロマトグラフィー（シリ
カゲル、酢酸エチル/ヘキサン＝1/2）に付して標記化合
物を黄色のオイルとして得た。（5.70 g、49％） IR (CDCl3)νmax： 2955, 1752, 1658, 1553 cm-1. MS (FAB) m/e 532 ([M+H]+). HRMS (FAB) Calcd for C25H46O9NSi: 532.2942; found
532.2933 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm： 5.98 (1H, dddd, J
= 17.2, 10.3, 5.8, 5.8 Hz), 5.29 (1H, dd, J = 17.
2, 1.6 Hz), 5.14-5.20 (2H, m), 4.13-4.30 (6H, m),
4.05 (1H, dd, J = 8.7, 7.3 Hz), 3.96(1H, dd, J = 1
0.6, 1.6 Hz), 3.78 (3H, s), 3.72 (1H, dd, J = 5.0,
1.6 Hz), 3.22 (3H, s), 2.27 (1H, d,J = 13.1, 5.0
Hz), 2.04 (3H, s), 1.95 (3H, s), 1.72 (1H, d, J =
13.1, 10.8 Hz), 1.41 (3H, s), 1.32 (3H, s), 0.86
(9H, s), 0.09 (3H, s), 0.08 (3H, s). (ii)4−O−アセチル−5−アセチルアミノ−3，5−ジデ
オキシ−2−O−メチル−7−O−（2'−プロペニル）−D
−グリセロ−D−ガラクト−ノン−2−エノピラノソン酸
メチル 実施例１(i)で得られた化合物（5.90 g, 11.0 mmol）を
テトラヒドロフラン（30ml）に溶解し、室温でテトラブ
チルアンモニウムフルオライド含有テトラヒドロフラン
（1 M）（13.3 ml, 13.3 mmol）を加え、50℃で3時間撹
拌した。反応液を減圧留去して得られた残査に無水酢酸
（15 ml）、ピリジン（15 ml）を加え、3時間攪拌し
た。反応液を減圧留去後、トルエンで共沸した。得られ
た残査に室温で酢酸（30ml）、蒸留水（3ml）を加え、5
0℃で4時間撹拌した。反応液を減圧留去後、得られた残
査をクロマトグラフィー（シリカゲル、塩化メチレン/
メタノール＝20/1）に付して標記化合物を無色アモルフ
ァスとして得た。（3.18 g、68％） IR (CDCl3)νmax： 2928, 2855, 1744, 1684, 1518 cm
-1. MS (FAB) m/e 420 ([M+H]+). HRMS (FAB) Calcd for C18H29O10NNa : 442.1690; foun
d 442.1693 ([M+Na]+).1 H NMR (400 MHz, CDCl3) δppm： 5.99 (1H, dddd, J
= 15.9, 10.5, 6.0, 5.6 Hz), 5.40 (1H, d, J = 9.8 H
z), 5.32 (1H, d, J = 15.9, 1.3 Hz), 5.30 (1H, ddd,
J = 11.7, 10.2, 5.0 Hz), 5.18(1H, d, J = 10.5, 1.
3 Hz), 4.34 (1H, ddd, J = 10.6, 10.2, 9.8 Hz), 4.2
0 (1H, dd, J = 12.3, 5.6 Hz), 4.09 (1H, dd, J = 1
2.3, 6.0 Hz), 4.00-4.05 (1H, m), 3.91 (1H, dd, J =
10.6, 1.6 Hz), 3.84-3.90 (1H, m), 3.80 (3H, s),
3.76-3.82 (1H, m), 3.57 (1H, dd,J = 8.8, 1.6 Hz),
3.29 (3H, s), 2.40 (1H, dd, J = 12.8, 5.0 Hz), 2.0
4 (3H, s), 1.95 (3H, s), 1.92 (1H, dd, J = 12.8, 1
1.7 Hz). (iii)4−O−アセチル−5−アセチルアミノ−3，5−ジデ
オキシ−8，9−O−チオカルボニル−2−O−メチル−7−
O−（2'−プロペニル）−D−グリセロ−D−ガラクト−
ノン−2−エノピラノソン酸メチル 窒素雰囲気下実施例１(ii)で得られた化合物（3.15 g,
7.50 mmol）を塩化メチレン（30ml）に溶解し、氷冷下4
-ジメチルアミノピリジン（2.20 g, 18.0 mmol）、チオ
ホスゲン（0.63 ml, 8.22 mmol）を加え、氷冷下1時間
撹拌した。反応液にメタノールを加え、減圧留去して得
られた残査をクロマトグラフィー（シリカゲル、塩化メ
チレン/メタノール＝50/1）に付して標記化合物を無色
アモルファスとして得た。（2.03 g、69 ％） IR (KBr)νmax： 3367, 2925, 2853, 1740, 1685, 164
7, 1533 cm-1. MS (FAB) m/e 462 ([M+H]+). HRMS (FAB) Calcd for C19H28O10NS : 462.1434; found
462.1425 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm： 5.96 (1H, dddd, J
= 15.9, 10.5, 6.1, 5.7 Hz), 5.44 (1H, d, J = 9.7 H
z), 5.26-5.33 (2H, m), 5.21 (1H, d, J = 10.4 Hz),
4.97-5.06 (2H, m), 4.76 (1H, dd, J = 7.5, 7.3 Hz),
4.20-4.25 (1H, m), 4.07-4.17 (3H, m), 3.80 (3H,
s), 3.74 (1H, dd, J = 10.1, 1.5 Hz),3.17 (3H, s),
2.43 (1H, dd, J = 13.0, 4.9 Hz), 2.05 (3H, s), 1.9
7 (3H, s), 1.84 (1H, dd, J = 13.0, 11.7 Hz). (iv)5−アセチルアミノ−2−O−メチル−7−O−（2'−
プロペニル）−3，5，8，9−テトラデオキシ−D−グリ
セロ−D−ガラクト−ノン−2−エノピラノソン酸メチル 窒素雰囲気下実施例１(iii)で得られた化合物（4.10 g,
9.0 mmol）を亜リン酸トリメチル（30ml）に溶解し、1
10℃で24時間撹拌した。反応液を減圧留去後、トルエン
で共沸した。得られた残査をメタノールに溶解し、室温
で4.9Mナトリウムメトキシド含有メタノール（0.18 m
l、0.9 mmol）を滴下し30分撹拌した。、次いで4M塩酸
含有1、4−ジオキサンで中和し、反応液を減圧留去後、
得られた残査をクロマトグラフィー（シリカゲル、酢酸
エチル）に付して標記化合物を無色アモルファスとして
得た。（1.80 g、63 ％） IR (CDCl3)νmax： 3367, 3086, 2955, 1751, 1661, 1
532 cm-1. MS (FAB) m/e 344 ([M+H]+). HRMS (FAB) Calcd for C16H26O7N : 344.1709; found 3
44.1714 ([M+H]+).1 H NMR (400 MHz, CDCl3)δppm： 6.59 (1H, d, br, J
= 3.5 Hz), 5.84-5.95(2H, m), 5.39-5.41 (1H, m), 5.
36-5.38 (1H, m), 5.25-5.31 (1H, m), 5.22-5.26 (1H,
m), 4.12-4.20 (2H, m), 3.98 (1H, ddd, J = 10.3,
9.3, 5.4 Hz), 3.91-3.98 (1H, m), 3.79 (3H, s), 3.6
9 (1H, dd, J = 10.3, 2.6 Hz), 3.63 (1H, ddd, J = 1
1.0, 9.3, 5.1 Hz), 3.23 (3H, s), 2.41 (1H, dd, J =
13.4, 5.1 Hz), 2.02 (3H, s), 1.66 (1H, dd, J = 1
3.4, 11.0 Hz). (v)（2S, 4S, 5R, 6R, 2'R）−5−アセチルアミノ−6−
（2'，5'−ジヒドロ−フラン−2'−イル）−4−ヒドロ
キシ−2−メトキシ−テトラヒドロ−ピラン−2−カルボ
ン酸メチル 窒素雰囲気下実施例１(iv)で得られた化合物（1.80 g,
5.24 mmol）を塩化メチレン(400 ml)に溶解し、ビス
（トリシクロヘキシルホスフィン）ベンジリデンルテニ
ウム（IV）ジクロライド（30 mg）を加え、室温で6時間
撹拌した。反応液を減圧留去後、得られた残査をクロマ
トグラフィー（シリカゲル、酢酸エチル）に付して標記
化合物を無色アモルファスとして得た。（1.60 g、97
％） IR (CDCl3)νmax： 3355, 2955, 2939, 2902, 2861, 1
752, 1659, 1524 cm-1. MS (FAB) m/e 316 ([M+H]+). HRMS (FAB) Calcd for C14H22O7N : 316.1396; found 3
16.1398 ([M+H]+).1 H NMR (400 MHz, CDCl3)δppm： 6.29 (1H, d,br, J =
4.3 Hz), 6.05-6.08(1H, m), 5.93-5.97 (1H, m), 5.1
0-5.15 (1H, m), 4.89 (1H, d,br, J = 1.5 Hz), 4.67
(1H, dddd, J = 12.9, 4.2, 2.5, 1.8 Hz), 4.58 (1H,
dddd, J = 12.9, 6.2, 2.2, 1.8 Hz), 3.99 (1H, ddd,
J = 10.2, 9.9, 4.8 Hz), 3.79 (3H, s), 3.75 (1H, d
d, J = 10.2, 2.9 Hz), 3.57 (1H, ddd, J = 9.9, 9.7,
5.1 Hz), 3.23 (3H, s), 2.41 (1H, dd, J = 13.4, 5.
1 Hz), 2.02 (3H, s), 1.67 (1H,dd, J = 13.4, 9.7 H
z). (vi)（2S, 4S, 5R, 6R, 2'R）−5−アセチルアミノ−6
−（3', 4'−ジヒドロキシ−テトラヒドロ−フラン−2'
−イル）−4−ヒドロキシ−2−メトキシ−テトラヒドロ
−ピラン−2−カルボン酸メチル 実施例１(v)で得られた化合物（0.30 g, 0.95 mmol）を
アセトン(10 ml)に溶解し、t-ブタノール(2 ml)、N-メ
チルモルホリンN−オキシド50％水溶液（284 mg, 1.21
mmol）、四酸化オスミウム（1mg, 0.004 mmol）を加
え、室温で2時間撹拌した。反応液を減圧留去し、得ら
れた残査をクロマトグラフィー（シリカゲル、塩化メチ
レン/メタノール＝10/1）に付して標記化合物を無色ア
モルファスとして得た。（0.29 g、87 %） IR (CDCl3)νmax： 3322, 3085, 2954, 1748, 1659, 1
553 cm-1. MS (FAB) m/e 350 ([M+H]+). HRMS (FAB) Calcd for C14H23O9NNa : 372.1271; found
372.1273 ([M+Na]+).1 H NMR (400 MHz, CD3OD)δppm： 4.22-4.28 (2H, m),
4.02 (1H, dd, J = 9.3, 4.5 Hz), 3.96 (1H, ddd, J =
11.2, 10.5, 4.8 Hz), 3.88 (1H, dd, J = 5.3, 1.3 H
z), 3.86 (1H, dd, J = 10.5, 10.3 Hz), 3.77 (3H,
s), 3.71 (1H, dd, J = 9.3, 3.0 Hz), 3.66 (1H, dd,
J = 10.3, 1.3 Hz), 3.22 (3H, s), 2.31(1H, dd, J =
12.9, 4.8 Hz), 1.97 (3H, s), 1.63 (1H, dd, J = 12.
9, 11.2 Hz). (vii)（4S, 5R, 6R, 2'S, 3'S, 4'R）−5−アセチルア
ミノ−4−アジド−6−（3', 4'−ジアセトキシ−テトラ
ヒドロ−フラン−2'−イル）−5，6−ジヒドロ−4H−ピ
ラン−2−カルボン酸メチル 窒素雰囲気下実施例１(vi)で得られた化合物（0.29 g,
0.830 mmol）を無水酢酸（3 ml）に溶解し、酢酸（1 m
l）、硫酸（0.3 ml）を室温で加え、80℃で3時間撹拌し
た。反応液を氷冷下酢酸エチル（30ml）と飽和炭酸水素
ナトリウム水溶液（30ml）に分配した。有機層を分離
し、食塩水（20ml）で洗浄し、硫酸ナトリウムで乾燥
し、減圧留去後、トルエンで共沸した。得られた残査を
ジメチルホルムアミド（0.4 ml）に溶解し、アジ化ナト
リウム（300 mg）、ダウエックス50W（H+）樹脂（300 m
g）を加え、60℃で5時間撹拌した。反応液を減圧濾過
し、濾物をメタノールで洗浄した。濾液、洗液を減圧留
去後、得られた残査をクロマトグラフィー（シリカゲ
ル、塩化メチレン/メタノール＝20/1）に付して標記化
合物を無色アモルファスとして得た。（150 mg、42％） IR (CDCl3)νmax： 2928, 2855, 2102, 1743, 1682, 1
511 cm-1. MS (FAB) m/e 427 ([M+H]+). HRMS (FAB) Calcd for C17H23O9N4 : 427.1465; found
427.1492 ([M+H]+).1 H NMR (400 MHz, CDCl3)δppm： 5.95 (1H, d, J = 2.
6 Hz), 5.86 (1H, d,J = 7.5 Hz), 5.52-5.56 (2H, m),
4.82 (1H, dd, J = 9.5, 2.6 Hz), 4.74 (1H, dd, J =
10.1, 1.7 Hz), 4.18-4.21 (2H, m), 3.85 (1H, dd, J
= 9.6, 4.3 Hz), 3.81 (3H, s), 3.57 (1H, ddd, J =
10.1, 9.5, 7.5 Hz), 2.10 (3H, s), 2.09 (3H, s), 2.
05 (3H, s). （viii）（4S, 5R, 6R, 2'S, 3'S, 4'R）−5−アセチル
アミノ−4−（N，N'−ビス−t−ブチルオキシカルボニ
ル）グアニジノ−6−（3', 4'−ジアセトキシ−テトラ
ヒドロ−フラン−2'−イル）−5，6−ジヒドロ−4H−ピ
ラン−2−カルボン酸メチル 実施例１(vii)で得られた化合物（140 mg, 0.328 mmo
l）をエタノール（30 ml）に溶解し、窒素雰囲気下リン
ドラー触媒（50mg）を加え、次いで水素雰囲気に置換
し、室温で3時間攪拌した。反応液をセライト濾過し濾
物をメタノールで洗浄し、濾液、洗液を減圧留去した。
得られた残査をジメチルホルムアミド(1 ml)に溶解し、
N,N'-ビス-tert-ブトキシカルボニルチオ尿素(120 mg,
0.434 mmol)、トリエチルアミン（151 μl, 1.09 mmo
l）、塩化第二水銀（118 mg, 0.434 mmol）を室温で加
え、同温にて2時間攪拌した。反応液をセライト濾過し
濾物を酢酸エチルで洗浄した。濾液、洗液を減圧留去
後、得られた残査をクロマトグラフィー（シリカゲル、
ヘキサン/酢酸エチル＝1/2）に付して標記化合物を無色
アモルファスとして得た。（106mg、50 ％） IR (CDCl3)νmax： 2960, 2928, 2855, 1602 cm-1. MS (FAB) m/e 643 ([M+H]+). HRMS (FAB) Calcd for C28H43O13N4 : 643.2826; found
643.2842 ([M+H]+).1 H NMR (400 MHz, CDCl3)δppm： 8.59 (1H, d, J = 8.
8 Hz), 6.37 (1H, d,J = 8.1 Hz), 5.84 (1H, d, J =
2.6 Hz), 5.56 (1H, ddd, J = 10.7, 5.5, 5.1Hz), 5.4
7 (1H, dd, J = 5.5, 4.3 Hz), 5.13 (1H, ddd, J = 8.
9, 8.8, 2.6 Hz), 4.24 (1H, ddd, J = 8.9, 8.9, 8.1
Hz), 4.24 (1H, dd, J = 10.7, 9.5 Hz), 4.18 (1H, d
d, J = 4.3, 1.0 Hz), 4.15 (1H, dd, J = 8.9, 1.0 H
z), 3.92(1H, dd, J = 9.5, 5.1 Hz), 3.80 (3H, s),
2.09 (3H, s), 2.08 (3H, s), 1.97 (3H, s), 1.49 (9
H, s), 1.48 (9H, s). （ix）（4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルア
ミノ−4−（N，N'−ビス−t−ブチルオキシカルボニ
ル）グアニジノ−5，6−ジヒドロ−6−（3', 4'−ジヒ
ドロキシ−テトラヒドロ−フラン−2'−イル）−4H−ピ
ラン−2−カルボン酸メチル 実施例１(viii)で得られた化合物（100 mg, 0.155 mmo
l）をメタノール（3 ml）に溶解し、窒素雰囲気下4.9
Ｍ ナトリウムメトキシド含有メタノール（3 μl, 15
μmol）を加え、室温で1時間攪拌した。塩酸含有1, 4−
ジオキサンで中和し、反応液を減圧留去後、得られた残
査をクロマトグラフィー（シリカゲル、塩化メチレン/
メタノール＝20/1）に付して標記化合物を無色アモルフ
ァスとして得た。（65 mg、75％） IR (CDCl3)νmax： 2956, 2928, 2855, 1728, 1640, 1
605, 1570 cm-1. MS (FAB) m/e 559 ([M+H]+). HRMS (FAB) Calcd for C24H39O11N4 : 559.2615; found
559.2621 ([M+H]+).1 H NMR (400 MHz, CDCl3)δppm： 8.61 (1H, d, J = 8.
8 Hz), 6.49 (1H, d,J = 8.1 Hz), 5.86 (1H, d, J =
2.8 Hz), 5.13-5.18 (1H, m), 4.42-4.46 (1H,m), 4.35
-4.38 (1H, m), 4.20-4.24 (2H, m), 4.10 (1H, dd, J
= 9.9, 4.5 Hz), 3.99 (1H, dd, J = 5.8, 1.0 Hz), 3.
86 (1H, dd, J = 9.9, 3.3 Hz), 3.79(3H, s), 3.11-3.
15 (1H, br), 2.86-2.90 (1H, br), 1.96 (3H, s), 1.5
0 (9H,s), 1.49 (9H, s). （x）（4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルア
ミノ−5，6−ジヒドロ−6−（3', 4'−ジヒドロキシ−
テトラヒドロ−フラン−2'−イル）−4−グアニジノ−4
H−ピラン−2−カルボン酸メチル トリフルオロ酢酸塩 実施例１(ix)で得られた化合物（60 mg, 0.107 mmol）
を塩化メチレン（3 ml）に溶解し、窒素雰囲気下トリフ
ルオロ酢酸（1ml）を加え、室温で3時間攪拌した。反応
液を減圧留去後、得られた残査を逆層クロマトグラフィ
ー（コスモシル、水）に付して標記化合物を無色アモル
ファスとして得た。（56 mg、quant.） IR (KBr)νmax： 3342, 2959, 1732, 1673, 1549 cm-1.1 H NMR (400 MHz, CD3OD) δppm： 8.61 (1H, d, J =
7.0 Hz), 7.27 (1H, d,J = 5.5 Hz), 5.89 (1H, d, J =
2.6 Hz), 4.31-4.37 (2H, m), 4.31 (1H, dd,J = 7.2,
4.8 Hz), 4.20 (1H, dd, J = 4.8, 4.1, 2.4 Hz), 4.1
0 (1H, ddd, J= 5.6, 5.5, 5.5 Hz), 3.96 (1H, dd, J
= 7.2, 1.8 Hz), 3.94 (1H, dd, J =9.7, 4.1 Hz), 3.8
0 (3H, s), 3.77 (1H, dd, J = 9.7, 2.4 Hz), 1.99 (3
H, s). （xi）（4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルア
ミノ−5，6−ジヒドロ−6−（3', 4'−ジヒドロキシ−
テトラヒドロ−フラン−2'−イル）−4−グアニジノ−4
H−ピラン−2−カルボン酸 トリフルオロ酢酸塩 実施例１(x)で得られた化合物（54 mg, 0.114 mmol）を
メタノール（3 ml）に溶解し、室温で1M水酸化ナトリウ
ム水溶液（0.35 ml, 0.35 mmol）を加え、同温で30分攪
拌した。次いでダウエックス50W X8（H+）樹脂を加え、
反応液のpHを2に調整した。ただちに減圧濾過し、水で
濾物を洗浄した。濾液、洗液を減圧留去後、得られた残
査を逆層クロマトグラフィー（コスモシル、水）に付し
て標記化合物を無色アモルファスとして得た。（33 m
g、63 ％） IR (KBr)νmax： 3340, 2963, 1679, 1551 cm-1. MS (FAB) m/e 345 ([M+H]+). HRMS (FAB) Calcd for C13H21O7N4 : 345.1410; found
345.1419 ([M+H]+).1 H NMR (400 MHz, D2O)δppm： 5.87 (1H, d, J = 3.1
Hz), 4.41 (1H, dd, J= 7.5, 4.8 Hz), 4.34 (1H, dd,
J = 7.0, 3.1 Hz), 4.29 (1H, dd, J = 7.7,2.6 Hz),
4.28 (1H, ddd, J = 4.8, 4.0, 2.2 Hz), 4.16 (1H, d
d, J = 7.7, 7.0 Hz), 4.01 (1H, dd, J = 10.1, 4.0 H
z), 3.97 (1H, dd, J = 7.5, 2.6 Hz),3.75 (1H, dd, J
= 10.1, 2.2 Hz), 1.98 (3H, s). [α]D 20 -21.4°(c 0.25, H2O). （実施例２） （4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチルアミノ−
5，6−ジヒドロ−6−（3', 4'−ジヒドロキシ−4'−メ
チル−テトラヒドロ−フラン−2'−イル）−4−グアニ
ジノ−4H−ピラン−2−カルボン酸 トリフルオロ酢酸塩(I) 5-acetylamino-4-O-t-butyldimethylsilyl-3,5-dideoxy-8,9-O-isopropylidene-2-O-methyl-7-O- (2'- Propenyl)
-Methyl D-glycero-D-galacto-non-2-enopyranosonate 5-acetylamino-3,5-dideoxy- under nitrogen atmosphere
8,9-O-isopropylidene-2-O-methyl-4-O-t-
Methyl butyldimethylsilyl-D-glycero-D-galacto-non-2-enopyranosonate (10 g, 20.3 mmol) (Z
biral, Erich; Phadare, S .; Schmid, Walther; Liebig
s Ann. Chem., 1987, (1), p39-43.) was dissolved in dimethylformamide (60 ml), and sodium hydride (1.7 g, 40.6 mmol) was added under ice cooling. Stirred at room temperature for 15 minutes. Allyl iodide (2.18 m
l, 24.3 mmol) was added dropwise and stirred at room temperature for 1 hour. The reaction solution was partitioned between ethyl acetate (200 ml) and a saturated aqueous ammonium chloride solution (100 ml). The organic layer was separated, washed with saturated saline (50 ml × 3), dried over sodium sulfate, and evaporated under reduced pressure. did. The obtained residue was subjected to chromatography (silica gel, ethyl acetate / hexane = 1/2) to give the title compound as a yellow oil. (5.70 g, 49%) IR (CDCl 3 ) νmax: 2955, 1752, 1658, 1553 cm -1 . MS (FAB) m / e 532 ([M + H] + ). HRMS (FAB) Calcd for C 25 H 46 O 9 NSi: 532.2942; found
532.2933 ([M + H] + ). 1 H NMR (400 MHz, CDCl 3 ) δppm: 5.98 (1H, dddd, J
= 17.2, 10.3, 5.8, 5.8 Hz), 5.29 (1H, dd, J = 17.
2, 1.6 Hz), 5.14-5.20 (2H, m), 4.13-4.30 (6H, m),
4.05 (1H, dd, J = 8.7, 7.3 Hz), 3.96 (1H, dd, J = 1
0.6, 1.6 Hz), 3.78 (3H, s), 3.72 (1H, dd, J = 5.0,
1.6 Hz), 3.22 (3H, s), 2.27 (1H, d, J = 13.1, 5.0
Hz), 2.04 (3H, s), 1.95 (3H, s), 1.72 (1H, d, J =
13.1, 10.8 Hz), 1.41 (3H, s), 1.32 (3H, s), 0.86
(9H, s), 0.09 (3H, s), 0.08 (3H, s). (Ii) 4-O-acetyl-5-acetylamino-3,5-dideoxy-2-O-methyl-7-O- (2'-propenyl) -D
-Methyl glycero-D-galacto-non-2-enopyranosonate The compound (5.90 g, 11.0 mmol) obtained in Example 1 (i) was dissolved in tetrahydrofuran (30 ml), and tetrabutylfuran containing tetrabutylammonium fluoride was added at room temperature. (1 M) (13.3 ml, 13.3 mmol) was added, and the mixture was stirred at 50 ° C for 3 hours. Acetic anhydride (15 ml) and pyridine (15 ml) were added to the residue obtained by evaporating the reaction solution under reduced pressure, and the mixture was stirred for 3 hours. After the reaction solution was distilled off under reduced pressure, the residue was azeotropically distilled with toluene. Acetic acid (30 ml) and distilled water (3 ml) were added to the obtained residue at room temperature, and 5
Stirred at 0 ° C. for 4 hours. After evaporating the reaction solution under reduced pressure, the resulting residue was chromatographed (silica gel, methylene chloride /
Methanol = 20/1) to give the title compound as a colorless amorphous. (3.18 g, 68%) IR (CDCl 3 ) νmax: 2928, 2855, 1744, 1684, 1518 cm
-1 . MS (FAB) m / e 420 ([M + H] + ). HRMS (FAB) Calcd for C 18 H 29 O 10 NNa: 442.1690; foun
d 442.1693 ([M + Na] + ). 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 5.99 (1H, dddd, J
= 15.9, 10.5, 6.0, 5.6 Hz), 5.40 (1H, d, J = 9.8 H
z), 5.32 (1H, d, J = 15.9, 1.3 Hz), 5.30 (1H, ddd,
J = 11.7, 10.2, 5.0 Hz), 5.18 (1H, d, J = 10.5, 1.
3 Hz), 4.34 (1H, ddd, J = 10.6, 10.2, 9.8 Hz), 4.2
0 (1H, dd, J = 12.3, 5.6 Hz), 4.09 (1H, dd, J = 1
2.3, 6.0 Hz), 4.00-4.05 (1H, m), 3.91 (1H, dd, J =
10.6, 1.6 Hz), 3.84-3.90 (1H, m), 3.80 (3H, s),
3.76-3.82 (1H, m), 3.57 (1H, dd, J = 8.8, 1.6 Hz),
3.29 (3H, s), 2.40 (1H, dd, J = 12.8, 5.0 Hz), 2.0
4 (3H, s), 1.95 (3H, s), 1.92 (1H, dd, J = 12.8, 1
(Iii) 4-O-acetyl-5-acetylamino-3,5-dideoxy-8,9-O-thiocarbonyl-2-O-methyl-7-
O- (2'-propenyl) -D-glycero-D-galacto-
Methyl non-2-enopyranosonate The compound obtained in Example 1 (ii) (3.15 g,
7.50 mmol) in methylene chloride (30 ml), and
-Dimethylaminopyridine (2.20 g, 18.0 mmol) and thiophosgene (0.63 ml, 8.22 mmol) were added, and the mixture was stirred under ice cooling for 1 hour. Methanol was added to the reaction solution, and the residue obtained by evaporation under reduced pressure was subjected to chromatography (silica gel, methylene chloride / methanol = 50/1) to obtain the title compound as a colorless amorphous. (2.03 g, 69%) IR (KBr) νmax: 3367, 2925, 2853, 1740, 1685, 164
7, 1533 cm -1 . MS (FAB) m / e 462 ([M + H] + ) .HRMS (FAB) Calcd for C 19 H 28 O 10 NS: 462.1434; found
462.1425 ([M + H] + ). 1 H NMR (400 MHz, CDCl 3 ) δppm: 5.96 (1H, dddd, J
= 15.9, 10.5, 6.1, 5.7 Hz), 5.44 (1H, d, J = 9.7 H
z), 5.26-5.33 (2H, m), 5.21 (1H, d, J = 10.4 Hz),
4.97-5.06 (2H, m), 4.76 (1H, dd, J = 7.5, 7.3 Hz),
4.20-4.25 (1H, m), 4.07-4.17 (3H, m), 3.80 (3H,
s), 3.74 (1H, dd, J = 10.1, 1.5 Hz), 3.17 (3H, s),
2.43 (1H, dd, J = 13.0, 4.9 Hz), 2.05 (3H, s), 1.9
7 (3H, s), 1.84 (1H, dd, J = 13.0, 11.7 Hz). (Iv) 5-Acetylamino-2-O-methyl-7-O- (2'-
Methyl propene) -3,5,8,9-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosonate The compound obtained in Example 1 (iii) (4.10 g,
9.0 mmol) in trimethyl phosphite (30 ml).
Stirred at 10 ° C. for 24 hours. After the reaction solution was distilled off under reduced pressure, the residue was azeotropically distilled with toluene. The obtained residue was dissolved in methanol, and 4.9 M sodium methoxide-containing methanol (0.18 m
l, 0.9 mmol) was added dropwise and stirred for 30 minutes. Then, neutralized with 1,4-dioxane containing 4M hydrochloric acid, and the reaction solution was distilled off under reduced pressure.
The obtained residue was subjected to chromatography (silica gel, ethyl acetate) to give the title compound as a colorless amorphous. (1.80 g, 63%) IR (CDCl 3 ) νmax: 3367, 3086, 2955, 1751, 1661, 1
532 cm -1 .MS (FAB) m / e 344 ([M + H] + ) .HRMS (FAB) Calcd for C 16 H 26 O 7 N: 344.1709; found 3
44.1714 ([M + H] + ). 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 6.59 (1H, d, br, J
= 3.5 Hz), 5.84-5.95 (2H, m), 5.39-5.41 (1H, m), 5.
36-5.38 (1H, m), 5.25-5.31 (1H, m), 5.22-5.26 (1H,
m), 4.12-4.20 (2H, m), 3.98 (1H, ddd, J = 10.3,
9.3, 5.4 Hz), 3.91-3.98 (1H, m), 3.79 (3H, s), 3.6
9 (1H, dd, J = 10.3, 2.6 Hz), 3.63 (1H, ddd, J = 1
1.0, 9.3, 5.1 Hz), 3.23 (3H, s), 2.41 (1H, dd, J =
13.4, 5.1 Hz), 2.02 (3H, s), 1.66 (1H, dd, J = 1
(V, (2S, 4S, 5R, 6R, 2'R) -5-acetylamino-6-
Methyl (2 ', 5'-dihydro-furan-2'-yl) -4-hydroxy-2-methoxy-tetrahydro-pyran-2-carboxylate The compound (1.80) obtained in Example 1 (iv) under a nitrogen atmosphere. g,
5.24 mmol) was dissolved in methylene chloride (400 ml), bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride (30 mg) was added, and the mixture was stirred at room temperature for 6 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to chromatography (silica gel, ethyl acetate) to obtain the title compound as a colorless amorphous. (1.60 g, 97
%) IR (CDCl 3 ) νmax: 3355, 2955, 2939, 2902, 2861, 1
752, 1659, 1524 cm -1 . MS (FAB) m / e 316 ([M + H] + ) .HRMS (FAB) Calcd for C 14 H 22 O 7 N: 316.1396; found 3
16.1398 ([M + H] + ). 1 H NMR (400 MHz, CDCl 3 ) δppm: 6.29 (1H, d, br, J =
4.3 Hz), 6.05-6.08 (1H, m), 5.93-5.97 (1H, m), 5.1
0-5.15 (1H, m), 4.89 (1H, d, br, J = 1.5 Hz), 4.67
(1H, dddd, J = 12.9, 4.2, 2.5, 1.8 Hz), 4.58 (1H,
dddd, J = 12.9, 6.2, 2.2, 1.8 Hz), 3.99 (1H, ddd,
J = 10.2, 9.9, 4.8 Hz), 3.79 (3H, s), 3.75 (1H, d
d, J = 10.2, 2.9 Hz), 3.57 (1H, ddd, J = 9.9, 9.7,
5.1 Hz), 3.23 (3H, s), 2.41 (1H, dd, J = 13.4, 5.
1 Hz), 2.02 (3H, s), 1.67 (1H, dd, J = 13.4, 9.7 H
z). (vi) (2S, 4S, 5R, 6R, 2'R) -5-acetylamino-6
-(3 ', 4'-dihydroxy-tetrahydro-furan-2'
-Yl) -4-Hydroxy-2-methoxy-tetrahydro-pyran-2-carboxylic acid methyl compound The compound obtained in Example 1 (v) (0.30 g, 0.95 mmol) was dissolved in acetone (10 ml), and t -Butanol (2 ml), N-methylmorpholine N-oxide 50% aqueous solution (284 mg, 1.21
mmol) and osmium tetroxide (1 mg, 0.004 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was distilled off under reduced pressure, and the obtained residue was subjected to chromatography (silica gel, methylene chloride / methanol = 10/1) to obtain the title compound as a colorless amorphous. (0.29 g, 87%) IR (CDCl 3 ) νmax: 3322, 3085, 2954, 1748, 1659, 1
553 cm -1 .MS (FAB) m / e 350 ([M + H] + ) .HRMS (FAB) Calcd for C 14 H 23 O 9 NNa: 372.1271; found
372.1273 ([M + Na] + ). 1 H NMR (400 MHz, CD 3 OD) δppm: 4.22-4.28 (2H, m),
4.02 (1H, dd, J = 9.3, 4.5 Hz), 3.96 (1H, ddd, J =
11.2, 10.5, 4.8 Hz), 3.88 (1H, dd, J = 5.3, 1.3 H
z), 3.86 (1H, dd, J = 10.5, 10.3 Hz), 3.77 (3H,
s), 3.71 (1H, dd, J = 9.3, 3.0 Hz), 3.66 (1H, dd,
J = 10.3, 1.3 Hz), 3.22 (3H, s), 2.31 (1H, dd, J =
12.9, 4.8 Hz), 1.97 (3H, s), 1.63 (1H, dd, J = 12.
(Vii) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5-acetylamino-4-azido-6- (3 ', 4'-diacetoxy-tetrahydro-furan-2). '-Yl) -5,6-Dihydro-4H-pyran-2-carboxylate methyl compound The compound obtained in Example 1 (vi) under nitrogen atmosphere (0.29 g,
0.830 mmol) was dissolved in acetic anhydride (3 ml) and acetic acid (1 m
l), sulfuric acid (0.3 ml) was added at room temperature, and the mixture was stirred at 80 ° C for 3 hours. The reaction solution was partitioned between ethyl acetate (30 ml) and a saturated aqueous sodium hydrogen carbonate solution (30 ml) under ice cooling. The organic layer was separated, washed with brine (20 ml), dried over sodium sulfate, evaporated in vacuo and azeotroped with toluene. The obtained residue was dissolved in dimethylformamide (0.4 ml), sodium azide (300 mg), Dowex 50W (H + ) resin (300 m
g) was added and stirred at 60 ° C. for 5 hours. The reaction solution was filtered under reduced pressure, and the residue was washed with methanol. After the filtrate and washings were distilled off under reduced pressure, the resulting residue was subjected to chromatography (silica gel, methylene chloride / methanol = 20/1) to obtain the title compound as a colorless amorphous. (150 mg, 42%) IR (CDCl 3 ) νmax: 2928, 2855, 2102, 1743, 1682, 1
511 cm -1 . MS (FAB) m / e 427 ([M + H] + ) .HRMS (FAB) Calcd for C 17 H 23 O 9 N 4 : 427.1465; found
427.1492 ([M + H] + ). 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 5.95 (1H, d, J = 2.
6 Hz), 5.86 (1H, d, J = 7.5 Hz), 5.52-5.56 (2H, m),
4.82 (1H, dd, J = 9.5, 2.6 Hz), 4.74 (1H, dd, J =
10.1, 1.7 Hz), 4.18-4.21 (2H, m), 3.85 (1H, dd, J
= 9.6, 4.3 Hz), 3.81 (3H, s), 3.57 (1H, ddd, J =
10.1, 9.5, 7.5 Hz), 2.10 (3H, s), 2.09 (3H, s), 2.
05 (3H, s). (Viii) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5-acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) guanidino-6 -Methyl-(3 ', 4'-diacetoxy-tetrahydro-furan-2'-yl) -5,6-dihydro-4H-pyran-2-carboxylate The compound obtained in Example 1 (vii) (140 mg, 0.328 mmo
l) was dissolved in ethanol (30 ml), Lindlar catalyst (50 mg) was added under a nitrogen atmosphere, and then the atmosphere was replaced with a hydrogen atmosphere, followed by stirring at room temperature for 3 hours. The reaction solution was filtered through celite, and the residue was washed with methanol. The filtrate and the washing were distilled off under reduced pressure.
The obtained residue was dissolved in dimethylformamide (1 ml),
N, N'-bis-tert-butoxycarbonylthiourea (120 mg,
0.434 mmol), triethylamine (151 μl, 1.09 mmo
l), mercuric chloride (118 mg, 0.434 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was filtered through celite, and the residue was washed with ethyl acetate. After the filtrate and washings were distilled off under reduced pressure, the resulting residue was chromatographed (silica gel,
Hexane / ethyl acetate = 1/2) to give the title compound as a colorless amorphous. (106 mg, 50%) IR (CDCl 3 ) νmax: 2960, 2928, 2855, 1602 cm -1 . MS (FAB) m / e 643 ([M + H] + ). HRMS (FAB) Calcd for C 28 H 43 O 13 N 4 : 643.2826; found
643.2842 ([M + H] + ). 1 H NMR (400 MHz, CDCl 3 ) δppm: 8.59 (1H, d, J = 8.
8 Hz), 6.37 (1H, d, J = 8.1 Hz), 5.84 (1H, d, J =
2.6 Hz), 5.56 (1H, ddd, J = 10.7, 5.5, 5.1Hz), 5.4
7 (1H, dd, J = 5.5, 4.3 Hz), 5.13 (1H, ddd, J = 8.
9, 8.8, 2.6 Hz), 4.24 (1H, ddd, J = 8.9, 8.9, 8.1
Hz), 4.24 (1H, dd, J = 10.7, 9.5 Hz), 4.18 (1H, d
d, J = 4.3, 1.0 Hz), 4.15 (1H, dd, J = 8.9, 1.0 H
z), 3.92 (1H, dd, J = 9.5, 5.1 Hz), 3.80 (3H, s),
2.09 (3H, s), 2.08 (3H, s), 1.97 (3H, s), 1.49 (9
H, s), 1.48 (9H, s). (Ix) (4S, 5R, 6R, 2'R, 3'R, 4'R) -5-acetylamino-4- (N, N'-bis- Methyl t-butyloxycarbonyl) guanidino-5,6-dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-furan-2'-yl) -4H-pyran-2-carboxylate Example 1 (viii) (100 mg, 0.155 mmo
l) was dissolved in methanol (3 ml) and 4.9 was added under a nitrogen atmosphere.
M methanol containing sodium methoxide (3 μl, 15
μmol) and stirred at room temperature for 1 hour. 1,4-
After neutralizing with dioxane and evaporating the reaction solution under reduced pressure, the resulting residue is subjected to chromatography (silica gel, methylene chloride /
Methanol = 20/1) to give the title compound as a colorless amorphous. (65 mg, 75%) IR (CDCl 3 ) νmax: 2956, 2928, 2855, 1728, 1640, 1
605, 1570 cm -1 . MS (FAB) m / e 559 ([M + H] + ). HRMS (FAB) Calcd for C 24 H 39 O 11 N 4 : 559.2615; found
559.2621 ([M + H] + ). 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 8.61 (1H, d, J = 8.
8 Hz), 6.49 (1H, d, J = 8.1 Hz), 5.86 (1H, d, J =
(2.8 Hz), 5.13-5.18 (1H, m), 4.42-4.46 (1H, m), 4.35
-4.38 (1H, m), 4.20-4.24 (2H, m), 4.10 (1H, dd, J
= 9.9, 4.5 Hz), 3.99 (1H, dd, J = 5.8, 1.0 Hz), 3.
86 (1H, dd, J = 9.9, 3.3 Hz), 3.79 (3H, s), 3.11-3.
15 (1H, br), 2.86-2.90 (1H, br), 1.96 (3H, s), 1.5
0 (9H, s), 1.49 (9H, s). (X) (4S, 5R, 6R, 2'R, 3'R, 4'R) -5-acetylamino-5,6-dihydro-6- (3 ', 4'-dihydroxy-
Tetrahydro-furan-2'-yl) -4-guanidino-4
H-pyran-2-carboxylate methyl trifluoroacetate Compound obtained in Example 1 (ix) (60 mg, 0.107 mmol)
Was dissolved in methylene chloride (3 ml), and trifluoroacetic acid (1 ml) was added under a nitrogen atmosphere, followed by stirring at room temperature for 3 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to reverse layer chromatography (Cosmosil, water) to obtain the title compound as a colorless amorphous. (. 56 mg, quant) IR (KBr) νmax:. 3342, 2959, 1732, 1673, 1549 cm -1 1 H NMR (400 MHz, CD 3 OD) δppm: 8.61 (1H, d, J =
7.0 Hz), 7.27 (1H, d, J = 5.5 Hz), 5.89 (1H, d, J =
2.6 Hz), 4.31-4.37 (2H, m), 4.31 (1H, dd, J = 7.2,
4.8 Hz), 4.20 (1H, dd, J = 4.8, 4.1, 2.4 Hz), 4.1
0 (1H, ddd, J = 5.6, 5.5, 5.5 Hz), 3.96 (1H, dd, J
= 7.2, 1.8 Hz), 3.94 (1H, dd, J = 9.7, 4.1 Hz), 3.8
0 (3H, s), 3.77 (1H, dd, J = 9.7, 2.4 Hz), 1.99 (3
H, s). (Xi) (4S, 5R, 6R, 2'R, 3'R, 4'R) -5-acetylamino-5,6-dihydro-6- (3 ', 4'-dihydroxy-
Tetrahydro-furan-2'-yl) -4-guanidino-4
H-pyran-2-carboxylic acid trifluoroacetate The compound (54 mg, 0.114 mmol) obtained in Example 1 (x) was dissolved in methanol (3 ml), and 1M aqueous sodium hydroxide solution (0.35 ml) was added at room temperature. , 0.35 mmol) and stirred at the same temperature for 30 minutes. Then add Dowex 50W X8 (H + ) resin,
The pH of the reaction solution was adjusted to 2. The mixture was immediately filtered under reduced pressure, and the residue was washed with water. After the filtrate and washings were distilled off under reduced pressure, the resulting residue was subjected to reverse layer chromatography (Cosmosil, water) to obtain the title compound as a colorless amorphous. (33 m
g, 63%) IR (KBr) νmax: 3340, 2963, 1679, 1551 cm -1 . MS (FAB) m / e 345 ([M + H] + ). HRMS (FAB) Calcd for C 13 H 21 O 7 N 4 : 345.1410; found
345.1419 ([M + H] + ). 1 H NMR (400 MHz, D 2 O) δ ppm: 5.87 (1H, d, J = 3.1
Hz), 4.41 (1H, dd, J = 7.5, 4.8 Hz), 4.34 (1H, dd,
J = 7.0, 3.1 Hz), 4.29 (1H, dd, J = 7.7,2.6 Hz),
4.28 (1H, ddd, J = 4.8, 4.0, 2.2 Hz), 4.16 (1H, d
d, J = 7.7, 7.0 Hz), 4.01 (1H, dd, J = 10.1, 4.0 H
z), 3.97 (1H, dd, J = 7.5, 2.6 Hz), 3.75 (1H, dd, J
= 10.1, 2.2 Hz), 1.98 (3H, s). [Α] D 20 -21.4 ° (c 0.25, H 2 O). (Example 2) (4S, 5R, 6R, 2'R, 3'S, 4 'R) -5-acetylamino-
5,6-dihydro-6- (3 ', 4'-dihydroxy-4'-methyl-tetrahydro-furan-2'-yl) -4-guanidino-4H-pyran-2-carboxylic acid trifluoroacetate
【０２８３】[0283]
【化１４】 Embedded image
【０２８４】（i）5−アセチルアミノ−4−O−t−ブチ
ルジメチルシリル−3，5−ジデオキシ−8，9−O−イソ
プロピリデン−2−O−メチル−7−O−（2'−メチル−2'
−プロペニル）−D−グリセロ−D−ガラクト−ノン−2
−エノピラノソン酸メチル 窒素雰囲気下5−アセチルアミノ−3，5−ジデオキシ−
8，9−O−イソプロピリデン−2−O−メチル−4−O−t−
ブチルジメチルシリル−D−グリセロ−D−ガラクト−ノ
ン−2−エノピラノソン酸メチル(10 g, 20.3 mmol）（Z
biral, Erich;Phadtare, S.; Schmid, Walther; Liebig
s Ann. Chem., 1987年, (1), p39-43.に記載された化合
物）を無水ジメチルホルムアミド（60 ml）に溶解し、
氷冷下水素化ナトリウム (1.7 g, 40.6 mmol）を加え、
室温で15分攪拌した。つづいて室温で3−ブロモ−2−メ
チルプロペン（2.44 ml, 24.3 mmol）を滴下し、室温で
1時間撹拌した。反応液を酢酸エチル（200 ml）と飽和
塩化アンモニウム水溶液（100 ml）に分配し、有機層を
分離し、飽和食塩水（50 ml X 3）で洗浄し、硫酸ナト
リウムで乾燥し、減圧留去した。得られた残査をクロマ
トグラフィー（シリカゲル、酢酸エチル/ヘキサン＝1/
2）に付して標記化合物を黄色のオイルとして得た。
（5.70 g、49％） IR (CDCl3)νmax： 2930, 2858, 1745, 1685, 1514 cm
-1. MS (FAB) m/e 546 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 5.23 (1H, d, J = 8.
9 Hz), 5.09 (1H, d,J = 1.0 Hz), 4.92 (1H, d, J =
1.0 Hz), 4.01-4.32 (6H, m), 3.83 (3H, s),3.72-3.82
(3H, m), 3.28 (3H, s), 2.31 (1H, dd, J = 12.8, 5.
1 Hz), 2.02 (3H, s), 1.82 (3H, s), 1.78 (1H, dd, J
= 12.8, 11.8 Hz), 1.46 (3H, s), 1.36 (3H, s), 0.9
0 (9H, s), 0.11(3H, s), 0.10(3H, s). (ii)4−O−アセチル−5−アセチルアミノ−3，5−ジデ
オキシ−8，9−O−イソプロピリデニル−2−O−メチル
−7−O−（2'−メチル−2'−プロペニル）−D−グリセ
ロ−D−ガラクト−ノン−2−エノピラノソン酸メチル 実施例２(i)で得られた化合物（6.00 g, 11.0 mmol）を
テトラヒドロフラン（30ml）に溶解し、室温で1Mテトラ
ブチルアンモニウムフルオライド含有テトラヒドロフラ
ン（13.3 ml, 13.3 mmol）を加え、50℃で3時間撹拌
し、反応液を減圧留去した。得られた残査に無水酢酸
（15 ml）、ピリジン（15 ml）を加え、3時間攪拌し
た。反応液を減圧留去後、トルエンで共沸し、標記化合
物を無色アモルファスとして得た。（5.0 g、96％） IR (CDCl3)νmax： 2929, 1743, 1687, 1516 cm-1. MS (FAB) m/e 474 ([M+H]+). HRMS (FAB) Calcd for C22H35O10NNa : 496.2159; foun
d 496.2141 ([M+Na]+).1 H NMR (400 MHz, CDCl3)δppm: 5.28 (1H, ddd, J = 1
1.8, 10.2, 5.0 Hz),5.04 (1H, d, J = 0.5 Hz), 4.87
(1H, d, J = 0.5 Hz), 4.28 (1H, ddd, J = 6.7, 6.2,
6.1 Hz), 4.24 (1H, ddd, J = 10.2, 10.2, 7.0 Hz),
4.14 (1H, d, J= 12.2 Hz), 4.14 (1H, dd, J = 8.7,
6.1 Hz), 4.04 (1H, d, J = 12.2 Hz),4.01 (1H, dd, J
= 8.7, 6.7 Hz), 3.79 (3H, s), 3.73 (1H, dd, J = 1
0.2, 1.2 Hz), 3.61 (1H, dd, J =6.2, 1.2 Hz), 3.27
(3H, s), 2.36 (1H, dd, J = 12.8, 5.0 Hz), 2.04(3H,
s), 1.95 (3H, s), 1.89 (1H, dd, J = 12.8, 11.8 H
z), 1.78 (3H, s), 1.40 (3H, s), 1.32 (3H, s). （iii）4−O−アセチル−5−アセチルアミノ−3，5−ジ
デオキシ−2−O−メチル−7−O−（2'−メチル−2'−プ
ロペニル）−D−グリセロ−D−ガラクト−ノン−2−エ
ノピラノソン酸メチル 実施例２(ii)で得られた化合物（5.00 g, 10.5 mmol）
を酢酸（30ml）、蒸留水（3ml）に溶解し、50℃で4時間
撹拌した。反応液を減圧留去後、残査をクロマトグラフ
ィー（シリカゲル、塩化メチレン/メタノール＝20/1）
に付して標記化合物を無色アモルファスとして得た。
（4.10 g、89％） IR (CDCl3)νmax： 3507, 3373, 2928, 2855, 1745, 16
83, 1518 cm-1. MS (FAB) m/e 434 ([M+H]+). HRMS (FAB) Calcd for C19H32O10N : 434.2026; found
434.2010 ([M+H]+).1 H NMR (400 MHz, CDCl3)δppm: 5.51 (1H, d, J = 9.8
Hz), 5.29 (1H, ddd,J = 11.5, 10.2, 5.0 Hz), 5.04
(1H, d, J = 0.5 Hz), 4.89 (1H, d, J = 0.5Hz), 4.35
(1H, ddd, J = 10.7, 10.2, 9.8 Hz), 4.13 (1H, d, J
= 11.9 Hz),4.04 (1H, ddd, J = 7.3, 4.6, 3.7 Hz),
3.99 (1H, d, J = 11.9 Hz), 3.95 (1H, dd, J = 10.7,
1.6 Hz), 3.87 (1H, dd, J = 11.4, 3.7 Hz), 3.82 (3
H, s), 3.79 (1H, d, J = 11.4, 4.6 Hz), 3.60 (1H, d
d, J = 7.3, 1.6 Hz), 3.31 (3H, s), 2.40 (1H, dd, J
= 12.8, 5.0 Hz), 2.06 (3H, s), 1.96 (3H, s), 1.92
(1H, dd, J = 12.8, 11.5 Hz), 1.80 (3H, s). （iv）5−アセチルアミノ−2−O−メチル−7−O−（2'
−メチル−2'−プロペニル）−3，5，8，9−テトラデオ
キシ−D−グリセロ−D−ガラクト−ノン−2−エノピラ
ノソン酸メチル 窒素雰囲気下、実施例２(iii)で得られた化合物（4.10
g, 9.45 mmol）を塩化メチレン（30ml）に溶解し、氷冷
下4-ジメチルアミノピリジン（2.77 g, 22.7 mmol）、
チオホスゲン（0.87 ml, 11.3 mmol）を加え、氷冷下1
時間撹拌した。反応液にメタノールを加え、減圧留去し
た。得られた残査を窒素雰囲気下亜リン酸トリメチル
（50ml）に溶解し、110℃で24時間撹拌した。反応液を
減圧留去後、トルエンで共沸した。得られた残査をメタ
ノールに溶解し、室温で4.9Mナトリウムメトキシド含有
メタノール（0.18 ml、0.9 mmol）を滴下し30分撹拌し
た。、次いで4M塩酸含有ジオキサン溶液で中和し、反応
液を減圧留去後、得られた残査をクロマトグラフィー
（シリカゲル、酢酸エチル）に付して標記化合物を無色
アモルファスとして得た。（2.30 g、68 ％） IR (CDCl3)νmax： 3368, 2955, 2856, 1752, 1660, 15
31 cm-1. MS (FAB) m/e 358 ([M+H]+). HRMS (FAB) Calcd for C17H27O7NNa : 380.1685; found
380.1675 ([M+Na]+).1 H NMR (400 MHz, CDCl3)δppm: 6.65 (1H, s, br), 5.
87 (1H, ddd, J = 17.3, 10.6, 6.0 Hz), 5.33-5.43 (3
H, m), 4.97 (1H, d, J = 0.5 Hz), 4.95 (1H,d, J =
0.5 Hz), 4.05 (1H, d, J = 12.6 Hz), 3.98 (1H, ddd,
J = 10.2, 9.0, 5.3 Hz), 3.88 (1H, d, J = 12.6 H
z), 3.79 (3H, s), 3.70 (1H, dd, J = 10.2, 2.7 Hz),
3.58 (1H, ddd, J = 11.0, 9.0, 5.2 Hz), 3.24 (3H,
s), 2.42 (1H, dd, J = 13.5, 5.2 Hz), 2.02 (3H, s),
1.77 (3H, s), 1.66 (1H, dd, J =13.5, 11.0 Hz). （v）（2S, 4S, 5R, 6R, 2'R）−5−アセチルアミノ−4
−ヒドロキシ−2−メトキシ−6−（4'−メチル−2', 5'
−ジヒドロ−フラン−2'−イル）−テトラヒドロ−ピラ
ン−2−カルボン酸メチル 窒素雰囲気下、実施例２(iv)で得られた化合物（2.60
g, 7.27 mmol）を塩化メチレン(400 ml)に溶解し、ビス
（トリシクロヘキシルホスフィン）ベンジリデンルテニ
ウム（IV）ジクロライド（50 mg）を加え、室温で4日間
撹拌した。次いで反応液を減圧留去後、得られた残査を
クロマトグラフィー（シリカゲル、酢酸エチル）に付し
て標記化合物を無色アモルファスとして得た。（1.60
g, 67％、回収原料0.84g, 32%） IR (CDCl3)νmax： 3355, 2940, 2854, 1752, 1658, 15
23 cm-1. MS (FAB) m/e 330 ([M+H]+). HRMS (FAB) Calcd for C15H23O7NNa : 352.1372; found
352.1379 ([M+Na]+).1 H NMR (400 MHz, CDCl3)δppm: 6.38 (1H, d, br, J =
4.0 Hz), 5.55-5.59(1H, m), 5.07-5.13 (1H, m), 5.0
6 (1H, d, J = 2.7 Hz), 4.49-4.55 (1H, m),4.37-4.43
(1H, m), 3.95-4.03 (1H, m), 3.80 (3H, s), 3.74 (1
H, d, J = 11.0 Hz), 3.70 (1H, dd, J = 10.2, 3.0 H
z), 3.56 (1H, ddd, J = 11.1, 9.0, 5.2 Hz), 3.23 (3
H, s), 2.40 (1H, dd, J = 13.3, 5.2 Hz), 2.03 (3H,
s), 1.79 (3H, s), 1.67 (1H, dd, J = 13.3, 11.1 H
z). （vi）（2S, 4S, 5R, 6R, 2'R）−5−アセチルアミノ−
6−（3', 4'−ジヒドロキシ−4'−メチル−テトラヒド
ロ−フラン−2'−イル）−4−ヒドロキシ−2−メトキシ
−テトラヒドロ−ピラン−2−カルボン酸メチル 実施例２(v)で得られた化合物（1.62 g, 4.92 mmol）を
アセトン(30 ml)に溶解し、t-ブタノール(5 ml)、N-メ
チルモルホリンN−オキシド50％水溶液（1.26g, 5.41 m
mol）、四酸化オスミウム（1mg, 0.004 mmol）を加え、
室温で12時間撹拌した。反応液を減圧留去し、得られた
残査をクロマトグラフィー（シリカゲル、塩化メチレン
/メタノール＝10/1）に付して標記化合物を無色アモル
ファスとして得た。（1.40 g、78 %） IR (CDCl3)νmax： 3320, 2957, 1749, 1658, 1552 cm
-1. MS (FAB) m/e 364 ([M+H]+). HRMS (FAB) Calcd for C15H25O9NNa : 386.1427; found
386.1417 ([M+Na]+).1 H NMR (400 MHz, CD3OD)δppm: 4.04 (1H, d, J = 9.3
Hz), 3.96 (1H, ddd,J = 11.1, 10.2, 4.7 Hz), 3.88
(1H, dd, J = 10.3, 10.2 Hz), 3.86 (1H, dd, J = 7.
5, 1.2 Hz), 3.77-3.80 (1H, m), 3.77 (3H, s), 3.71
(1H, d, J = 9.3 Hz), 3.66 (1H, dd, J = 10.3, 1.2 H
z), 3.22 (3H, s), 2.32 (1H, dd, J =12.9, 4.8 Hz),
1.96 (3H, s), 1.65 (1H, dd, J = 12.9, 11.1 Hz), 1.
27 (3H,s). （vii）（4S, 5R, 6R, 2'S, 3'S, 4'R）−5−アセチル
アミノ−4−アジド−6−（3', 4'−ジアセトキシ−4'−
メチル−テトラヒドロ−フラン−2'−イル）−5，6−ジ
ヒドロ−4H−ピラン−2−カルボン酸メチル 窒素雰囲気下、実施例２(vi)で得られた化合物（580 m
g, 1.59 mmol）を無水酢酸（5 ml）に溶解し、酢酸（2
ml）、硫酸（1 ml）を室温で加え、80℃で3時間撹拌し
た。反応液を氷冷下酢酸エチル（30ml）と飽和炭酸水素
ナトリウム水溶液（30ml）に分配した。有機層を分離
し、食塩水（20ml）で洗浄し、硫酸ナトリウムで乾燥
し、減圧留去後、得られた残査をトルエンで共沸した。
この残査をジメチルホルムアミド（0.8 ml）に溶解し、
アジ化ナトリウム（500 mg）、ダウエックス50W（H+）
樹脂（500 mg）を加えた後に60℃で5時間撹拌した。反
応液を減圧濾過し、濾物をメタノールで洗浄した。濾
液、洗液を減圧留去後、得られた残査をクロマトグラフ
ィー（シリカゲル、塩化メチレン/メタノール＝20/1）
に付して標記化合物を無色アモルファスとして得た。
（210 mg、30％） IR (CDCl3)νmax： 3450, 2928, 2101, 1740, 1682, 15
12 cm-1. MS (FAB) m/e 441 ([M+H]+). HRMS (FAB) Calcd for C18H25O9N4 : 441.1621; found
441.1631 ([M+H]+).1 H NMR (400 MHz, CDCl3)δppm: 5.95 (1H, d, J = 2.5
Hz), 5.87 (1H, d, J= 7.6 Hz), 5.31(1H, d, J = 4.9
Hz), 4.79-4.83 (2H, m), 4.11 (1H, d, J =9.6 Hz),
4.01 (1H, dd, J = 4.9, 2.0 Hz), 3.94 (1H, d, J =
9.6 Hz), 3.79(3H, s), 3.62 (1H, ddd, J = 10.3, 9.
5, 7.6 Hz), 2.10 (3H, s), 2.05 (3H,s), 2.05 (3H,
s), 1.69 (3H, s). （viii）（4S, 5R, 6R, 2'S, 3'S, 4'R）−5−アセチル
アミノ−4−（N，N'−ビス−t−ブチルオキシカルボニ
ル）グアニジノ−6−（3', 4'−ジアセトキシ−4'−メ
チル−テトラヒドロ−フラン−2'−イル）−5，6−ジヒ
ドロ−4H−ピラン−2−カルボン酸メチル 実施例２(vii)で得られた化合物（210 mg, 0.477 mmo
l）をエタノール（30 ml）に溶解し、窒素雰囲気下リン
ドラー触媒（75 mg）を加え、次いで水素雰囲気に置換
し、室温で3時間攪拌した。反応液をセライト濾過し濾
物をメタノールで洗浄し、濾液、洗液を減圧留去した。
得られた残査をジメチルホルムアミド(1 ml)に溶解し、
N,N'-ビス-t-ブトキシカルボニルチオ尿素(150 mg, 0.5
4 mmol)、トリエチルアミン（151 μl, 1.09 mmol）、
塩化第二水銀（147 mg, 0.54 mmol）を室温で加え、同
温にて2時間攪拌した。反応液をセライト濾過し濾物を
酢酸エチルで洗浄した。濾液、洗液を減圧留去して得ら
れた残査をクロマトグラフィー（シリカゲル、ヘキサン
/酢酸エチル＝1/2）に付して標記化合物を無色アモルフ
ァスとして得た。（156 mg、50 ％） MS (FAB) m/e 657 ([M+H]+). HRMS (FAB) Calcd for C29H45O13N4 : 657.2983; found
657.3006 ([M+H]+).1 H NMR (400 MHz, CDCl3)δppm: 8.59 (1H, d, J = 8.8
Hz), 6.24 (1H, d, J= 8.2 Hz), 5.86 (1H, d, J = 2.
7 Hz), 5.26 (1H, d, J = 4.9 Hz), 5.14 (1H, ddd, J
= 8.9, 8.8, 2.7 Hz), 4.33 (1H, dd, J = 9.8, 1.7 H
z), 4.24 (1H,ddd, J = 9.8, 8.9, 8.2 Hz), 4.06 (1H,
d, J = 9.5 Hz), 3.98 (1H, dd, J =4.9, 1.7 Hz), 3.
96 (1H, d, J = 9.5 Hz), 3.78 (3H, s), 2.09 (3H,
s), 2.04(3H, s), 1.95 (3H, s), 1.70 (3H, s) , 1.48
(9H, s), 1.48 (9H, s). （ix）（4S, 5R, 6R, 2'S, 3'S, 4'R）−5−アセチルア
ミノ−6−（3', 4'−ジアセトキシ−4'−メチル−テト
ラヒドロ−フラン−2'−イル）−5，6−ジヒドロ−4−
グアニジノ−4H−ピラン−2−カルボン酸メチル トリフ
ルオロ酢酸塩 実施例２(viii)で得られた化合物（70 mg, 0.106 mmo
l）を塩化メチレン（3 ml）に溶解し、窒素雰囲気下ト
リフルオロ酢酸（1ml）を加え、室温で3時間攪拌した。
反応液を減圧留去後、得られた残査を逆層クロマトグラ
フィー（コスモシル、水/メタノール＝2/1）に付して標
記化合物を無色アモルファスとして得た。（54 mg、89
％） IR (KBr)νmax： 3315, 2931, 1741, 1642, 1616, 1562
cm-1. MS (FAB) m/e 457 ([M+H]+). HRMS (FAB) Calcd for C19H29O9N4 : 457.1934; found
457.1942 ([M+H]+).1 H NMR (400 MHz, CD3OD)δppm: 5.89 (1H, d, J = 3.3
Hz), 5.31 (1H, d, J= 5.0 Hz), 4.52 (1H, dd, J =
7.7, 1.6 Hz), 4.42 (1H, dd, J = 7.2, 3.3Hz), 4.12
(1H, dd, J = 7.7, 7.2 Hz), 4.07 (1H, dd, J = 5.0,
1.6 Hz), 3.98 (1H, d, J = 9.4 Hz), 3.92 (1H, d, J
= 9.4 Hz), 3.80 (3H, s), 2.08 (3H,s), 2.04 (3H,
s), 1.98 (3H, s), 1.63 (3H, s). （x）（4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチルア
ミノ−5，6−ジヒドロ−6−（3', 4'−ジヒドロキシ−
4'−メチル−テトラヒドロ−フラン−2'−イル）−4−
グアニジノ−4H−ピラン−2−カルボン酸 トリフルオロ
酢酸塩 実施例２(ix)で得られた化合物（50 mg, 0.088 mmol）
をメタノール（3 ml）に溶解し、1M水酸化ナトリウム水
溶液（0.22 ml, 0.22 mmol）を加え、室温で30分攪拌し
た。次いでダウエックス50W X8（H+）樹脂を加え、反応
液のpHを2に調整した。ただちに減圧濾過し、水で濾物
を洗浄した。濾液、洗液を減圧留去後、得られた残査を
逆層クロマトグラフィー（コスモシル、水）に付して標
記化合物を無色アモルファスとして得た。（30 mg、72
％） IR (KBr)νmax： 3342, 2975, 1671, 1551 cm-1. HS (FAB) m/e 359 ([M+H]+). HRMS (FAB) Calcd for C14H23O7N4 : 359.1567; found
359.1561 ([M+H]+).1 H NMR (400 MHz, D2O)δppm: 5.85 (1H, d, J = 3.3 H
z), 4.29-4.33 (1H, m), 4.25-4.29 (1H, m), 4.13-4.1
7 (1H, m), 4.11-4.14 (1H, m), 3.95-3.99 (1H, m),
3.74-3.76 (2H, m), 1.96 (3H, s), 1.26 (3H, s). [α]D 20 -33.2°(c 0.55, H2O). （実施例３） （4S, 5R, 6R, 2'R, 4'R）−5−アセチルアミノ−5，6
−ジヒドロ−4−グアニジノ−6−（4'−メチル−テトラ
ヒドロ−フラン−2'−イル）−4H−ピラン−2−カルボ
ン酸 トリフルオロ酢酸塩(I) 5-acetylamino-4-O-t-butyldimethylsilyl-3,5-dideoxy-8,9-O-isopropylidene-2-O-methyl-7-O- (2'- Methyl-2 '
-Propenyl) -D-glycero-D-galacto-non-2
-Methyl enopyranosone 5-acetylamino-3,5-dideoxy- in a nitrogen atmosphere
8,9-O-isopropylidene-2-O-methyl-4-O-t-
Methyl butyldimethylsilyl-D-glycero-D-galacto-non-2-enopyranosonate (10 g, 20.3 mmol) (Z
biral, Erich; Phadare, S .; Schmid, Walther; Liebig
s Ann. Chem., 1987, (1), p39-43.) was dissolved in anhydrous dimethylformamide (60 ml),
Sodium hydride (1.7 g, 40.6 mmol) was added under ice cooling,
Stirred at room temperature for 15 minutes. Subsequently, 3-bromo-2-methylpropene (2.44 ml, 24.3 mmol) was added dropwise at room temperature, and at room temperature.
Stir for 1 hour. The reaction solution was partitioned between ethyl acetate (200 ml) and a saturated aqueous ammonium chloride solution (100 ml). The organic layer was separated, washed with saturated saline (50 ml × 3), dried over sodium sulfate, and evaporated under reduced pressure. did. The obtained residue is subjected to chromatography (silica gel, ethyl acetate / hexane = 1 /
2) gave the title compound as a yellow oil.
(5.70 g, 49%) IR (CDCl 3 ) νmax: 2930, 2858, 1745, 1685, 1514 cm
-1 . MS (FAB) m / e 546 ([M + H] + ). 1 H NMR (400 MHz, CDCl 3 ) δppm: 5.23 (1H, d, J = 8.
9 Hz), 5.09 (1H, d, J = 1.0 Hz), 4.92 (1H, d, J =
1.0 Hz), 4.01-4.32 (6H, m), 3.83 (3H, s), 3.72-3.82
(3H, m), 3.28 (3H, s), 2.31 (1H, dd, J = 12.8, 5.
1 Hz), 2.02 (3H, s), 1.82 (3H, s), 1.78 (1H, dd, J
= 12.8, 11.8 Hz), 1.46 (3H, s), 1.36 (3H, s), 0.9
0 (9H, s), 0.11 (3H, s), 0.10 (3H, s). (Ii) 4-O-acetyl-5-acetylamino-3,5-dideoxy-8,9-O-isopropylidenyl Methyl-2-O-methyl-7-O- (2'-methyl-2'-propenyl) -D-glycero-D-galacto-non-2-enopyranosonate The compound obtained in Example 2 (i) ( 6.00 g, 11.0 mmol) was dissolved in tetrahydrofuran (30 ml), 1M tetrabutylammonium fluoride-containing tetrahydrofuran (13.3 ml, 13.3 mmol) was added at room temperature, the mixture was stirred at 50 ° C. for 3 hours, and the reaction solution was distilled off under reduced pressure. . Acetic anhydride (15 ml) and pyridine (15 ml) were added to the obtained residue, and the mixture was stirred for 3 hours. After evaporating the reaction solution under reduced pressure, the residue was azeotropically distilled with toluene to obtain the title compound as a colorless amorphous. (5.0 g, 96%) IR (CDCl 3 ) νmax: 2929, 1743, 1687, 1516 cm -1 . MS (FAB) m / e 474 ([M + H] + ). HRMS (FAB) Calcd for C 22 H 35 O 10 NNa: 496.2159; foun
d 496.2141 ([M + Na] +) 1 H NMR (400 MHz, CDCl 3) δppm:. 5.28 (1H, ddd, J = 1
1.8, 10.2, 5.0 Hz), 5.04 (1H, d, J = 0.5 Hz), 4.87
(1H, d, J = 0.5 Hz), 4.28 (1H, ddd, J = 6.7, 6.2,
6.1 Hz), 4.24 (1H, ddd, J = 10.2, 10.2, 7.0 Hz),
4.14 (1H, d, J = 12.2 Hz), 4.14 (1H, dd, J = 8.7,
6.1 Hz), 4.04 (1H, d, J = 12.2 Hz), 4.01 (1H, dd, J
= 8.7, 6.7 Hz), 3.79 (3H, s), 3.73 (1H, dd, J = 1
0.2, 1.2 Hz), 3.61 (1H, dd, J = 6.2, 1.2 Hz), 3.27
(3H, s), 2.36 (1H, dd, J = 12.8, 5.0 Hz), 2.04 (3H,
s), 1.95 (3H, s), 1.89 (1H, dd, J = 12.8, 11.8 H
z), 1.78 (3H, s), 1.40 (3H, s), 1.32 (3H, s). (iii) 4-O-acetyl-5-acetylamino-3,5-dideoxy-2-O-methyl- 7-O- (2'-Methyl-2'-propenyl) -D-glycero-D-galacto-non-2-enopyranosonic acid methyl compound The compound obtained in Example 2 (ii) (5.00 g, 10.5 mmol).
Was dissolved in acetic acid (30 ml) and distilled water (3 ml) and stirred at 50 ° C. for 4 hours. After evaporating the reaction solution under reduced pressure, the residue was chromatographed (silica gel, methylene chloride / methanol = 20/1).
To give the title compound as a colorless amorphous.
(4.10 g, 89%) IR (CDCl 3 ) νmax: 3507, 3373, 2928, 2855, 1745, 16
83, 1518 cm -1 . MS (FAB) m / e 434 ([M + H] + ). HRMS (FAB) Calcd for C 19 H 32 O 10 N: 434.2026; found
. 434.2010 ([M + H] +) 1 H NMR (400 MHz, CDCl 3) δppm: 5.51 (1H, d, J = 9.8
Hz), 5.29 (1H, ddd, J = 11.5, 10.2, 5.0 Hz), 5.04
(1H, d, J = 0.5 Hz), 4.89 (1H, d, J = 0.5 Hz), 4.35
(1H, ddd, J = 10.7, 10.2, 9.8 Hz), 4.13 (1H, d, J
= 11.9 Hz), 4.04 (1H, ddd, J = 7.3, 4.6, 3.7 Hz),
3.99 (1H, d, J = 11.9 Hz), 3.95 (1H, dd, J = 10.7,
1.6 Hz), 3.87 (1H, dd, J = 11.4, 3.7 Hz), 3.82 (3
H, s), 3.79 (1H, d, J = 11.4, 4.6 Hz), 3.60 (1H, d
d, J = 7.3, 1.6 Hz), 3.31 (3H, s), 2.40 (1H, dd, J
= 12.8, 5.0 Hz), 2.06 (3H, s), 1.96 (3H, s), 1.92
(1H, dd, J = 12.8, 11.5 Hz), 1.80 (3H, s). (Iv) 5-acetylamino-2-O-methyl-7-O- (2 '
-Methyl-2'-propenyl) -3,5,8,9-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosonic acid methyl compound obtained in Example 2 (iii) under nitrogen atmosphere (4.10
g, 9.45 mmol) in methylene chloride (30 ml), and cooled under ice-cooling to 4-dimethylaminopyridine (2.77 g, 22.7 mmol),
Thiophosgene (0.87 ml, 11.3 mmol) was added, and the mixture was cooled
Stirred for hours. Methanol was added to the reaction solution, and the mixture was distilled off under reduced pressure. The obtained residue was dissolved in trimethyl phosphite (50 ml) under a nitrogen atmosphere and stirred at 110 ° C. for 24 hours. After the reaction solution was distilled off under reduced pressure, the residue was azeotropically distilled with toluene. The obtained residue was dissolved in methanol, and 4.9 M sodium methoxide-containing methanol (0.18 ml, 0.9 mmol) was added dropwise at room temperature, and the mixture was stirred for 30 minutes. Then, the mixture was neutralized with a 4M hydrochloric acid-containing dioxane solution, the reaction solution was distilled off under reduced pressure, and the obtained residue was subjected to chromatography (silica gel, ethyl acetate) to obtain the title compound as a colorless amorphous. (2.30 g, 68%) IR (CDCl 3 ) νmax: 3368, 2955, 2856, 1752, 1660, 15
31 cm -1 .MS (FAB) m / e 358 ([M + H] + ) .HRMS (FAB) Calcd for C 17 H 27 O 7 NNa: 380.1685; found
. 380.1675 ([M + Na] +) 1 H NMR (400 MHz, CDCl 3) δppm: 6.65 (1H, s, br), 5.
87 (1H, ddd, J = 17.3, 10.6, 6.0 Hz), 5.33-5.43 (3
H, m), 4.97 (1H, d, J = 0.5 Hz), 4.95 (1H, d, J =
0.5 Hz), 4.05 (1H, d, J = 12.6 Hz), 3.98 (1H, ddd,
J = 10.2, 9.0, 5.3 Hz), 3.88 (1H, d, J = 12.6 H
z), 3.79 (3H, s), 3.70 (1H, dd, J = 10.2, 2.7 Hz),
3.58 (1H, ddd, J = 11.0, 9.0, 5.2 Hz), 3.24 (3H,
s), 2.42 (1H, dd, J = 13.5, 5.2 Hz), 2.02 (3H, s),
1.77 (3H, s), 1.66 (1H, dd, J = 13.5, 11.0 Hz). (V) (2S, 4S, 5R, 6R, 2'R) -5-acetylamino-4
-Hydroxy-2-methoxy-6- (4'-methyl-2 ', 5'
-Dihydro-furan-2'-yl) -methyl tetrahydro-pyran-2-carboxylate Compound (2.60) obtained in Example 2 (iv) under a nitrogen atmosphere.
g, 7.27 mmol) was dissolved in methylene chloride (400 ml), bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride (50 mg) was added, and the mixture was stirred at room temperature for 4 days. Then, the reaction solution was evaporated under reduced pressure, and the obtained residue was subjected to chromatography (silica gel, ethyl acetate) to obtain the title compound as a colorless amorphous. (1.60
g, 67%, recovered raw material 0.84 g, 32%) IR (CDCl 3 ) νmax: 3355, 2940, 2854, 1752, 1658, 15
23 cm -1 .MS (FAB) m / e 330 ([M + H] + ) .HRMS (FAB) Calcd for C 15 H 23 O 7 NNa: 352.1372; found
352.1379 ([M + Na] + ). 1 H NMR (400 MHz, CDCl 3 ) δppm: 6.38 (1H, d, br, J =
4.0 Hz), 5.55-5.59 (1H, m), 5.07-5.13 (1H, m), 5.0
6 (1H, d, J = 2.7 Hz), 4.49-4.55 (1H, m), 4.37-4.43
(1H, m), 3.95-4.03 (1H, m), 3.80 (3H, s), 3.74 (1
H, d, J = 11.0 Hz), 3.70 (1H, dd, J = 10.2, 3.0 H
z), 3.56 (1H, ddd, J = 11.1, 9.0, 5.2 Hz), 3.23 (3
H, s), 2.40 (1H, dd, J = 13.3, 5.2 Hz), 2.03 (3H,
s), 1.79 (3H, s), 1.67 (1H, dd, J = 13.3, 11.1 H
z). (vi) (2S, 4S, 5R, 6R, 2'R) -5-acetylamino-
Methyl 6- (3 ', 4'-dihydroxy-4'-methyl-tetrahydro-furan-2'-yl) -4-hydroxy-2-methoxy-tetrahydro-pyran-2-carboxylate In Example 2 (v) The obtained compound (1.62 g, 4.92 mmol) was dissolved in acetone (30 ml), and t-butanol (5 ml) and a 50% aqueous solution of N-methylmorpholine N-oxide (1.26 g, 5.41 m) were used.
mol) and osmium tetroxide (1 mg, 0.004 mmol)
Stirred at room temperature for 12 hours. The reaction solution was evaporated under reduced pressure, and the resulting residue was subjected to chromatography (silica gel, methylene chloride).
/ Methanol = 10/1) to give the title compound as a colorless amorphous. (1.40 g, 78%) IR (CDCl 3 ) νmax: 3320, 2957, 1749, 1658, 1552 cm
-1 . MS (FAB) m / e 364 ([M + H] + ). HRMS (FAB) Calcd for C 15 H 25 O 9 NNa: 386.1427; found
. 386.1417 ([M + Na] +) 1 H NMR (400 MHz, CD 3 OD) δppm: 4.04 (1H, d, J = 9.3
Hz), 3.96 (1H, ddd, J = 11.1, 10.2, 4.7 Hz), 3.88
(1H, dd, J = 10.3, 10.2 Hz), 3.86 (1H, dd, J = 7.
5, 1.2 Hz), 3.77-3.80 (1H, m), 3.77 (3H, s), 3.71
(1H, d, J = 9.3 Hz), 3.66 (1H, dd, J = 10.3, 1.2 H
z), 3.22 (3H, s), 2.32 (1H, dd, J = 12.9, 4.8 Hz),
1.96 (3H, s), 1.65 (1H, dd, J = 12.9, 11.1 Hz), 1.
27 (3H, s). (Vii) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5-acetylamino-4-azido-6- (3 ', 4'-diacetoxy-4'-
Methyl methyl-tetrahydro-furan-2'-yl) -5,6-dihydro-4H-pyran-2-carboxylate The compound obtained in Example 2 (vi) under a nitrogen atmosphere (580 m
g, 1.59 mmol) in acetic anhydride (5 ml) and acetic acid (2
ml) and sulfuric acid (1 ml) were added at room temperature, and the mixture was stirred at 80 ° C for 3 hours. The reaction solution was partitioned between ethyl acetate (30 ml) and a saturated aqueous sodium hydrogen carbonate solution (30 ml) under ice cooling. The organic layer was separated, washed with brine (20 ml), dried over sodium sulfate, evaporated under reduced pressure, and the resulting residue was azeotroped with toluene.
This residue was dissolved in dimethylformamide (0.8 ml),
Sodium azide (500 mg), Dowex 50W (H + )
After adding the resin (500 mg), the mixture was stirred at 60 ° C. for 5 hours. The reaction solution was filtered under reduced pressure, and the residue was washed with methanol. After the filtrate and washings were distilled off under reduced pressure, the resulting residue was chromatographed (silica gel, methylene chloride / methanol = 20/1).
To give the title compound as a colorless amorphous.
(210 mg, 30%) IR (CDCl 3 ) νmax: 3450, 2928, 2101, 1740, 1682, 15
12 cm -1 .MS (FAB) m / e 441 ([M + H] + ) .HRMS (FAB) Calcd for C 18 H 25 O 9 N 4 : 441.1621; found
. 441.1631 ([M + H] +) 1 H NMR (400 MHz, CDCl 3) δppm: 5.95 (1H, d, J = 2.5
Hz), 5.87 (1H, d, J = 7.6 Hz), 5.31 (1H, d, J = 4.9
Hz), 4.79-4.83 (2H, m), 4.11 (1H, d, J = 9.6 Hz),
4.01 (1H, dd, J = 4.9, 2.0 Hz), 3.94 (1H, d, J =
9.6 Hz), 3.79 (3H, s), 3.62 (1H, ddd, J = 10.3, 9.
5, 7.6 Hz), 2.10 (3H, s), 2.05 (3H, s), 2.05 (3H,
s), 1.69 (3H, s). (viii) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5-acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) Methyl guanidino-6- (3 ', 4'-diacetoxy-4'-methyl-tetrahydro-furan-2'-yl) -5,6-dihydro-4H-pyran-2-carboxylate In Example 2 (vii) The obtained compound (210 mg, 0.477 mmo
l) was dissolved in ethanol (30 ml), Lindlar catalyst (75 mg) was added under a nitrogen atmosphere, and then the atmosphere was replaced with a hydrogen atmosphere, followed by stirring at room temperature for 3 hours. The reaction solution was filtered through celite, and the residue was washed with methanol. The filtrate and the washing were distilled off under reduced pressure.
The obtained residue was dissolved in dimethylformamide (1 ml),
N, N'-bis-t-butoxycarbonylthiourea (150 mg, 0.5
4 mmol), triethylamine (151 μl, 1.09 mmol),
Mercuric chloride (147 mg, 0.54 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was filtered through celite, and the residue was washed with ethyl acetate. The residue obtained by evaporating the filtrate and washings under reduced pressure is subjected to chromatography (silica gel, hexane).
/ Ethyl acetate = 1/2) to give the title compound as a colorless amorphous. (156 mg, 50%) MS (FAB) m / e 657 ([M + H] + ). HRMS (FAB) Calcd for C 29 H 45 O 13 N 4 : 657.2983; found
. 657.3006 ([M + H] +) 1 H NMR (400 MHz, CDCl 3) δppm: 8.59 (1H, d, J = 8.8
Hz), 6.24 (1H, d, J = 8.2 Hz), 5.86 (1H, d, J = 2.
7 Hz), 5.26 (1H, d, J = 4.9 Hz), 5.14 (1H, ddd, J
= 8.9, 8.8, 2.7 Hz), 4.33 (1H, dd, J = 9.8, 1.7 H
z), 4.24 (1H, ddd, J = 9.8, 8.9, 8.2 Hz), 4.06 (1H,
d, J = 9.5 Hz), 3.98 (1H, dd, J = 4.9, 1.7 Hz), 3.
96 (1H, d, J = 9.5 Hz), 3.78 (3H, s), 2.09 (3H,
s), 2.04 (3H, s), 1.95 (3H, s), 1.70 (3H, s), 1.48
(9H, s), 1.48 (9H, s). (Ix) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5-acetylamino-6- (3 ', 4'-diacetoxy-4'-Methyl-tetrahydro-furan-2'-yl) -5,6-dihydro-4-
Guanidino-4H-pyran-2-carboxylate methyl trifluoroacetate Compound obtained in Example 2 (viii) (70 mg, 0.106 mmo
l) was dissolved in methylene chloride (3 ml), trifluoroacetic acid (1 ml) was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 hours.
After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to reverse layer chromatography (Cosmosil, water / methanol = 2/1) to obtain the title compound as a colorless amorphous. (54 mg, 89
%) IR (KBr) νmax: 3315, 2931, 1741, 1642, 1616, 1562
cm -1 . MS (FAB) m / e 457 ([M + H] + ). HRMS (FAB) Calcd for C 19 H 29 O 9 N 4 : 457.1934; found
. 457.1942 ([M + H] +) 1 H NMR (400 MHz, CD 3 OD) δppm: 5.89 (1H, d, J = 3.3
Hz), 5.31 (1H, d, J = 5.0 Hz), 4.52 (1H, dd, J =
7.7, 1.6 Hz), 4.42 (1H, dd, J = 7.2, 3.3Hz), 4.12
(1H, dd, J = 7.7, 7.2 Hz), 4.07 (1H, dd, J = 5.0,
1.6 Hz), 3.98 (1H, d, J = 9.4 Hz), 3.92 (1H, d, J
= 9.4 Hz), 3.80 (3H, s), 2.08 (3H, s), 2.04 (3H,
(s), 1.98 (3H, s), 1.63 (3H, s). (x) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5-acetylamino-5,6-dihydro-6 -(3 ', 4'-dihydroxy-
4'-methyl-tetrahydro-furan-2'-yl) -4-
Guanidino-4H-pyran-2-carboxylic acid trifluoroacetate Compound obtained in Example 2 (ix) (50 mg, 0.088 mmol)
Was dissolved in methanol (3 ml), 1M aqueous sodium hydroxide solution (0.22 ml, 0.22 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Next, Dowex 50W X8 (H + ) resin was added to adjust the pH of the reaction solution to 2. The mixture was immediately filtered under reduced pressure, and the residue was washed with water. After the filtrate and washings were distilled off under reduced pressure, the resulting residue was subjected to reverse layer chromatography (Cosmosil, water) to obtain the title compound as a colorless amorphous. (30 mg, 72
%) IR (KBr) νmax: .. 3342, 2975, 1671, 1551 cm -1 HS (FAB) m / e 359 ([M + H] +) HRMS (FAB) Calcd for C 14 H 23 O 7 N 4 : 359.1567; found
. 359.1561 ([M + H] +) 1 H NMR (400 MHz, D 2 O) δppm: 5.85 (1H, d, J = 3.3 H
z), 4.29-4.33 (1H, m), 4.25-4.29 (1H, m), 4.13-4.1
7 (1H, m), 4.11-4.14 (1H, m), 3.95-3.99 (1H, m),
3.74-3.76 (2H, m), 1.96 (3H, s), 1.26 (3H, s). [Α] D 20 -33.2 ° (c 0.55, H 2 O). (Example 3) (4S, 5R, 6R, 2'R, 4'R) -5-acetylamino-5,6
-Dihydro-4-guanidino-6- (4'-methyl-tetrahydro-furan-2'-yl) -4H-pyran-2-carboxylic acid trifluoroacetate
【０２８５】[0285]
【化１５】 Embedded image
【０２８６】（i）（2S, 4S, 5R, 6R, 2'R, 4'R）−5−
アセチルアミノ−4−ヒドロキシ−2−メトキシ−6−
（4'−メチル−テトラヒドロ−フラン−2'−イル）−テ
トラヒドロ−ピラン−2−カルボン酸メチル 実施例２(v)で得られた化合物（0.27 g, 0.82 mmol）を
メタノール（30 ml）に溶解し、窒素雰囲気下パラジウ
ムカーボン（0.1 g）を加え、次いで水素雰囲気に置換
し、室温で2時間攪拌した。反応液をセライト濾過し濾
物をメタノールで洗浄した。濾液、洗液を減圧留去後、
得られた残査をクロマトグラフィー（シリカゲル、塩化
メチレン/メタノール＝20/1）に付して標記化合物を無
色アモルファスとして得た。（0.27 g、99％） IR (CDCl3)νmax： 3331, 2959, 2929, 2875, 1751, 16
61, 1520 cm-1. MS (FAB) m/e 332 ([M+H]+). HRMS (FAB) Calcd for C15H25O7NNa : 354.1529; found
354.1534 ([M+Na]+).1 H NMR (400 MHz, CDCl3)δppm: 6.26 (1H, s, br), 4.
39 (1H, d, br, J = 1.9 Hz), 4.21-4.29 (1H, ddd, J
= 9.7, 6.3, 1.4 Hz), 4.04-4.11 (1H, m), 3.94 (1H,
dd, J = 7.7, 7.7 Hz), 3.79 (3H, s), 3.83-3.86 (1H,
m), 3.31 (1H,dd, J = 8.8, 8.2 Hz), 3.22 (3H, s),
2.44 (1H, dd, J = 13.3, 5.1 Hz), 2.34-2.41 (1H,
m), 2.13-2.19 (1H, m), 2.04 (3H, s), 1.70 (1H, dd,
J = 13.3, 11.2 Hz), 1.47-1.55 (1H, m), 1.07 (3H,
d, J = 6.5 Hz). （ii）（4S, 5R, 6R, 2'R, 4'R）−5−アセチルアミノ
−4−アジド−5，6−ジヒドロ−6−（4'−メチル−テト
ラヒドロ−フラン−2'−イル）−4H−ピラン−2−カル
ボン酸メチル 窒素雰囲気下、実施例３(i)で得られた化合物（270 mg,
0.82 mmol）を無水酢酸（3 ml）に溶解し、酢酸（2 m
l）、硫酸（0.3 ml）を加え、80℃で3時間撹拌した。反
応液を氷冷下酢酸エチル（30ml）と飽和炭酸水素ナトリ
ウム水溶液（30ml）に分配した。有機層を分離し、食塩
水（20ml）で洗浄し、硫酸ナトリウムで乾燥し、減圧留
去後、得られた残査をトルエンで共沸した。この残査を
ジメチルホルムアミド（0.4 ml）に溶解し、室温でアジ
化ナトリウム（240 mg）、ダウエックス50W（H+）樹脂
（240 mg）を加え、60℃で5時間撹拌した。反応液を減
圧濾過し濾物をメタノールで洗浄した。濾液、洗液を減
圧留去後、得られた残査をクロマトグラフィー（シリカ
ゲル、塩化メチレン/メタノール＝20/1）に付して標記
化合物を無色アモルファスとして得た。（210 mg、79
％） IR (CDCl3)νmax： 3432, 2959, 2928, 2855, 2101, 17
36, 1680, 1509 cm-1. MS (FAB) m/e 325 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm： 6.03 (1H, d, J =
3.7 Hz), 5.92 (1H, d,J = 7.5 Hz), 4.53 (1H, dd, J
= 5.8, 3.7 Hz), 4.39 (1H, dd, J = 5.8, 5.6Hz), 4.2
3 (1H, ddd, J = 8.9, 7.5, 5.8 Hz), 3.92 (1H, dd, J
= 7.7, 7.5 Hz), 3.83 (3H, s), 3.79-3.83 (1H, m),
3.35 (1H, dd, J = 8.6, 8.5 Hz), 2.31-2.40 (1H, m),
2.18 (1H, ddd, J = 12.3, 6.8, 6.2 Hz), 2.01 (3H,
s), 1.50-1.57 (1H, m), 1.08 (3H, d, J = 6.5 Hz). （iii）（4S, 5R, 6R, 2'R, 4'R）−5−アセチルアミノ
−4−（N，N'−ビス−t−ブチルオキシカルボニル）グ
アニジノ−5，6−ジヒドロ−6−（4'−メチル−テトラ
ヒドロ−フラン−2'−イル）−4H−ピラン−2−カルボ
ン酸メチル 実施例３(ii)で得られた化合物（210 mg, 0.477 mmol）
をエタノール（30 ml）に溶解し、窒素雰囲気下リンド
ラー触媒（75 mg）を加え、次いで水素雰囲気に置換
し、室温で3時間攪拌した。反応液をセライト濾過し濾
物をメタノールで洗浄し、濾液、洗液を減圧留去した。
得られた残査をジメチルホルムアミド(1 ml)に溶解し、
N,N'-ビス-tert-ブトキシカルボニルチオ尿素(163 mg,
0.60 mmol)、トリエチルアミン（167 μl, 1.20 mmo
l）、塩化第二水銀（163 mg, 0.60 mmol）を室温で加え
たのち、同温にて2時間攪拌した。反応液をセライト濾
過し濾物を酢酸エチルで洗浄し、濾液、洗液を減圧留去
後、得られた残査をクロマトグラフィー（シリカゲル、
ヘキサン/酢酸エチル＝1/2）に付して標記化合物を無色
アモルファスとして得た。（120 mg、46 ％） IR (CDCl3)νmax： 2958, 2928, 2855, 1728, 1681, 16
38, 1605, 1567 cm-1. MS (FAB) m/e 541 ([M+H]+). HRMS (FAB) Calcd for C25H41O9N4 : 541.2873; found
541.2856 ([M+H]+).1 H NMR (400 MHz, CDCl3)δppm: 8.64 (1H, d, J = 8.6
Hz), 6.20 (1H, d, J= 8.2 Hz), 5.88 (1H, d, J = 3.
0 Hz), 5.11 (1H, ddd, J = 8.6, 8.3, 3.0 Hz), 4.22
(1H, ddd, J = 9.8, 6.8, 2.9 Hz), 4.19 (1H, ddd, J
= 8.6, 8.3, 8.2 Hz), 4.05 (1H, dd, J = 8.6, 2.9 H
z), 3.93 (1H, dd, J = 8.1, 7.1 Hz),3.80(3H, s), 3.
34 (1H, dd, J = 9.0, 8.1 Hz), 2.28-2.37 (1H, m),
2.07-2.13 (1H, m), 1.95 (3H, s), 1.63-1.71 (1H,
m), 1.49 (18H, s), 1.06 (1H, d,J = 6.5 Hz). （iv）（4S, 5R, 6R, 2'R, 4'R）−5−アセチルアミノ
−5，6−ジヒドロ−4−グアニジノ−6−（4'−メチル−
テトラヒドロ−フラン−2'−イル）−4H−ピラン−2−
カルボン酸メチル 実施例３(iii)で得られた化合物（120 mg, 0.222 mmo
l）を塩化メチレン（3 ml）に溶解し、窒素雰囲気下ト
リフルオロ酢酸（1ml）を加え、室温で3時間攪拌した。
反応液を減圧留去後得られた残査を逆層クロマトグラフ
ィー（コスモシル、水/メタノール＝1/1）に付して標記
化合物を無色アモルファスとして得た。（70 mg、69
％） IR (KBr)νmax： 3268, 3178, 2962, 2877, 1734, 166
5, 1546 cm-1. MS (FAB) m/e 341 ([M+H]+). HRMS (FAB) Calcd for C15H25O5N4 : 341.1825; found
341.1834 ([M+H]+).1 H NMR (400 MHz, CD3OD)δppm: 5.92 (1H, d, J = 4.5
Hz), 4.18-4.27 (3H,m), 4.03-4.06 (1H, m), 3.90 (1
H, dd, J =7.6, 7.4 Hz), 3.81 (3H, s), 3.22-3.27 (1
H, m), 2.27-2.37 (1H, m), 2.12 (1H, ddd, J = 12.0,
6.8, 6.0 Hz), 1.98 (3H, s), 1.70 (1H, ddd, J = 1
2.0, 10.0, 9.7 Hz), 1.06 (3H, d, J =6.5 Hz). （v）（4S, 5R, 6R, 2'R, 4'R）−5−アセチルアミノ−
5，6−ジヒドロ−4−グアニジノ−6−（4'−メチル−テ
トラヒドロ−フラン−2'−イル）−4H−ピラン−2−カ
ルボン酸 トリフルオロ酢酸塩 実施例３(iv)で得られた化合物（70 mg, 0.154 mmol）
をメタノール（3 ml）に溶解し、室温で1M水酸化ナトリ
ウム水溶液（0.22 ml, 0.22 mmol）を加え、室温で30分
攪拌した。次いでダウエックス50W X8（H+）樹脂を加
え、反応液のpHを2に調整した。ただちに減圧濾過し、
水で濾物を洗浄した。濾液、洗液を減圧留去後、得られ
た残査を逆層クロマトグラフィー（コスモシル、水）に
付して標記化合物を無色アモルファスとして得た。（45
mg、90％） IR (KBr)νmax： 3256, 2963, 2874, 1665, 1605 cm-1. MS (FAB) m/e 327 ([M+H]+). HRMS (FAB) Calcd for C14H23O5N4 : 327.1668; found
327.1659 ([M+H]+).1 H NMR (400 MHz, CD3OD) δppm: 5.60 (1H, d, J = 3.
5 Hz), 4.23 (1H, ddd, J = 9.9, 6.6, 3.7 Hz), 4.09-
4.12 (1H, m), 4.04-4.07 (1H, m), 3.95-3.98(1H, m),
3.87(1H, dd, J = 7.5, 7.5 Hz), 3.25-3.28 (1H, m),
2.23-2.32(1H, m), 2.07 (1H, ddd, J = 12.0, 6.8,
6.0 Hz), 1.99 (3H,s), 1.73 (1H, ddd,J = 12.0, 11.
0, 10.4 Hz), 1.05 (3H, d, J = 6.5 Hz). [α]D 20 -9.0°(c 0.50, H2O). （実施例４） （4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルアミノ−
5，6−ジヒドロ−6−（3', 4'−ジヒドロキシ−テトラ
ヒドロ−ピラン−2'−イル）−4−グアニジノ−4H−ピ
ラン−2−カルボン酸 水和物(I) (2S, 4S, 5R, 6R, 2'R, 4'R) -5-
Acetylamino-4-hydroxy-2-methoxy-6-
Methyl (4'-methyl-tetrahydro-furan-2'-yl) -tetrahydro-pyran-2-carboxylate The compound (0.27 g, 0.82 mmol) obtained in Example 2 (v) was added to methanol (30 ml). After dissolution, palladium carbon (0.1 g) was added under a nitrogen atmosphere, and then the atmosphere was replaced with a hydrogen atmosphere, followed by stirring at room temperature for 2 hours. The reaction solution was filtered through celite, and the residue was washed with methanol. After evaporating the filtrate and washings under reduced pressure,
The obtained residue was subjected to chromatography (silica gel, methylene chloride / methanol = 20/1) to give the title compound as a colorless amorphous. (0.27 g, 99%) IR (CDCl 3 ) νmax: 3331, 2959, 2929, 2875, 1751, 16
61, 1520 cm -1 . MS (FAB) m / e 332 ([M + H] + ). HRMS (FAB) Calcd for C 15 H 25 O 7 NNa: 354.1529; found
. 354.1534 ([M + Na] +) 1 H NMR (400 MHz, CDCl 3) δppm: 6.26 (1H, s, br), 4.
39 (1H, d, br, J = 1.9 Hz), 4.21-4.29 (1H, ddd, J
= 9.7, 6.3, 1.4 Hz), 4.04-4.11 (1H, m), 3.94 (1H,
dd, J = 7.7, 7.7 Hz), 3.79 (3H, s), 3.83-3.86 (1H,
m), 3.31 (1H, dd, J = 8.8, 8.2 Hz), 3.22 (3H, s),
2.44 (1H, dd, J = 13.3, 5.1 Hz), 2.34-2.41 (1H,
m), 2.13-2.19 (1H, m), 2.04 (3H, s), 1.70 (1H, dd,
J = 13.3, 11.2 Hz), 1.47-1.55 (1H, m), 1.07 (3H,
d, J = 6.5 Hz). (ii) (4S, 5R, 6R, 2'R, 4'R) -5-acetylamino-4-azido-5,6-dihydro-6- (4'-methyl- Methyl tetrahydro-furan-2'-yl) -4H-pyran-2-carboxylate The compound obtained in Example 3 (i) (270 mg,
0.82 mmol) was dissolved in acetic anhydride (3 ml) and acetic acid (2 m
l) and sulfuric acid (0.3 ml) were added, and the mixture was stirred at 80 ° C for 3 hours. The reaction solution was partitioned between ethyl acetate (30 ml) and a saturated aqueous sodium hydrogen carbonate solution (30 ml) under ice cooling. The organic layer was separated, washed with brine (20 ml), dried over sodium sulfate, evaporated under reduced pressure, and the resulting residue was azeotroped with toluene. This residue was dissolved in dimethylformamide (0.4 ml), sodium azide (240 mg) and Dowex 50W (H + ) resin (240 mg) were added at room temperature, and the mixture was stirred at 60 ° C. for 5 hours. The reaction solution was filtered under reduced pressure, and the residue was washed with methanol. After the filtrate and washings were distilled off under reduced pressure, the resulting residue was subjected to chromatography (silica gel, methylene chloride / methanol = 20/1) to obtain the title compound as a colorless amorphous. (210 mg, 79
%) IR (CDCl 3 ) νmax: 3432, 2959, 2928, 2855, 2101, 17
36, 1680, 1509 cm -1 . MS (FAB) m / e 325 ([M + H] + ). 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 6.03 (1H, d, J =
3.7 Hz), 5.92 (1H, d, J = 7.5 Hz), 4.53 (1H, dd, J
= 5.8, 3.7 Hz), 4.39 (1H, dd, J = 5.8, 5.6Hz), 4.2
3 (1H, ddd, J = 8.9, 7.5, 5.8 Hz), 3.92 (1H, dd, J
= 7.7, 7.5 Hz), 3.83 (3H, s), 3.79-3.83 (1H, m),
3.35 (1H, dd, J = 8.6, 8.5 Hz), 2.31-2.40 (1H, m),
2.18 (1H, ddd, J = 12.3, 6.8, 6.2 Hz), 2.01 (3H,
s), 1.50-1.57 (1H, m), 1.08 (3H, d, J = 6.5 Hz). (iii) (4S, 5R, 6R, 2'R, 4'R) -5-acetylamino-4- Methyl (N, N′-bis-t-butyloxycarbonyl) guanidino-5,6-dihydro-6- (4′-methyl-tetrahydro-furan-2′-yl) -4H-pyran-2-carboxylate Compound obtained in Example 3 (ii) (210 mg, 0.477 mmol)
Was dissolved in ethanol (30 ml), a Lindlar catalyst (75 mg) was added under a nitrogen atmosphere, the atmosphere was replaced with a hydrogen atmosphere, and the mixture was stirred at room temperature for 3 hours. The reaction solution was filtered through celite, and the residue was washed with methanol. The filtrate and the washing were distilled off under reduced pressure.
The obtained residue was dissolved in dimethylformamide (1 ml),
N, N'-bis-tert-butoxycarbonylthiourea (163 mg,
0.60 mmol), triethylamine (167 μl, 1.20 mmo
l), mercuric chloride (163 mg, 0.60 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was filtered through celite, and the residue was washed with ethyl acetate. The filtrate and washings were evaporated under reduced pressure, and the resulting residue was subjected to chromatography (silica gel,
Hexane / ethyl acetate = 1/2) to give the title compound as a colorless amorphous. (120 mg, 46%) IR (CDCl 3 ) νmax: 2958, 2928, 2855, 1728, 1681, 16
38, 1605, 1567 cm -1 . MS (FAB) m / e 541 ([M + H] + ) .HRMS (FAB) Calcd for C 25 H 41 O 9 N 4 : 541.2873; found
. 541.2856 ([M + H] +) 1 H NMR (400 MHz, CDCl 3) δppm: 8.64 (1H, d, J = 8.6
Hz), 6.20 (1H, d, J = 8.2 Hz), 5.88 (1H, d, J = 3.
0 Hz), 5.11 (1H, ddd, J = 8.6, 8.3, 3.0 Hz), 4.22
(1H, ddd, J = 9.8, 6.8, 2.9 Hz), 4.19 (1H, ddd, J
= 8.6, 8.3, 8.2 Hz), 4.05 (1H, dd, J = 8.6, 2.9 H
z), 3.93 (1H, dd, J = 8.1, 7.1 Hz), 3.80 (3H, s), 3.
34 (1H, dd, J = 9.0, 8.1 Hz), 2.28-2.37 (1H, m),
2.07-2.13 (1H, m), 1.95 (3H, s), 1.63-1.71 (1H,
m), 1.49 (18H, s), 1.06 (1H, d, J = 6.5 Hz). (iv) (4S, 5R, 6R, 2'R, 4'R) -5-acetylamino-5,6- Dihydro-4-guanidino-6- (4'-methyl-
Tetrahydro-furan-2'-yl) -4H-pyran-2-
Methyl carboxylate Compound obtained in Example 3 (iii) (120 mg, 0.222 mmo
l) was dissolved in methylene chloride (3 ml), trifluoroacetic acid (1 ml) was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 hours.
The residue obtained after evaporating the reaction solution under reduced pressure was subjected to reverse layer chromatography (Cosmosil, water / methanol = 1/1) to obtain the title compound as a colorless amorphous. (70 mg, 69
%) IR (KBr) νmax: 3268, 3178, 2962, 2877, 1734, 166
5, 1546 cm -1 .MS (FAB) m / e 341 ([M + H] + ) .HRMS (FAB) Calcd for C 15 H 25 O 5 N 4 : 341.1825; found
. 341.1834 ([M + H] +) 1 H NMR (400 MHz, CD 3 OD) δppm: 5.92 (1H, d, J = 4.5
Hz), 4.18-4.27 (3H, m), 4.03-4.06 (1H, m), 3.90 (1
H, dd, J = 7.6, 7.4 Hz), 3.81 (3H, s), 3.22-3.27 (1
H, m), 2.27-2.37 (1H, m), 2.12 (1H, ddd, J = 12.0,
6.8, 6.0 Hz), 1.98 (3H, s), 1.70 (1H, ddd, J = 1
(2.0, 10.0, 9.7 Hz), 1.06 (3H, d, J = 6.5 Hz). (V) (4S, 5R, 6R, 2'R, 4'R) -5-acetylamino-
5,6-dihydro-4-guanidino-6- (4'-methyl-tetrahydro-furan-2'-yl) -4H-pyran-2-carboxylic acid trifluoroacetate obtained in Example 3 (iv) Compound (70 mg, 0.154 mmol)
Was dissolved in methanol (3 ml), a 1M aqueous sodium hydroxide solution (0.22 ml, 0.22 mmol) was added at room temperature, and the mixture was stirred at room temperature for 30 minutes. Next, Dowex 50W X8 (H + ) resin was added to adjust the pH of the reaction solution to 2. Immediately vacuum filtration,
The cake was washed with water. After the filtrate and washings were distilled off under reduced pressure, the resulting residue was subjected to reverse layer chromatography (Cosmosil, water) to obtain the title compound as a colorless amorphous. (45
mg, 90%) IR (KBr) νmax: 3256, 2963, 2874, 1665, 1605 cm -1 . MS (FAB) m / e 327 ([M + H] + ). HRMS (FAB) Calcd for C 14 H 23 O 5 N 4 : 327.1668; found
. 327.1659 ([M + H] +) 1 H NMR (400 MHz, CD 3 OD) δppm: 5.60 (1H, d, J = 3.
5 Hz), 4.23 (1H, ddd, J = 9.9, 6.6, 3.7 Hz), 4.09-
4.12 (1H, m), 4.04-4.07 (1H, m), 3.95-3.98 (1H, m),
3.87 (1H, dd, J = 7.5, 7.5 Hz), 3.25-3.28 (1H, m),
2.23-2.32 (1H, m), 2.07 (1H, ddd, J = 12.0, 6.8,
6.0 Hz), 1.99 (3H, s), 1.73 (1H, ddd, J = 12.0, 11.
[Α] D 20 -9.0 ° (c 0.50, H 2 O). (Example 4) (4S, 5R, 6R, 2'R) , 3'R, 4'R) -5-acetylamino-
5,6-dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4-guanidino-4H-pyran-2-carboxylic acid hydrate
【０２８７】[0287]
【化１６】 Embedded image
【０２８８】（i）5−アセチルアミノ−7−O−（4'−ベ
ンジルオキシ−n−ブチル）−4−O−t−ブチルジメチル
シリル−3，5−ジデオキシ−8，9−O−イソプロピリデ
ン−2−O−メチル−D−グリセロ−D−ガラクト−ノン−
2−エノピラノソン酸メチル 窒素雰囲気下5−アセチルアミノ−3，5−ジデオキシ−
8，9−O−イソプロピリデン−2−O−メチル−4−O−t−
ブチルジメチルシリル−D−グリセロ−D−ガラクト−ノ
ン−2−エノピラノソン酸メチル(20 g, 41.1 mmol）（Z
biral, Erich; Phadtare, S.; Schmid, Walther; Liebi
gs Ann. Chem., 1987年, (1), p39-43.に記載された化
合物）を無水ジメチルホルムアミド（100 ml）に溶解
し、室温で4-ベンジルオキシ-n-ブチルメシラート（18.
6ｇ、72 mmol）、水素化ナトリウム (1.7 g, 40.6 mmo
l）を加え、室温で1時間攪拌した。反応液を酢酸エチル
（300 ml）と飽和塩化アンモニウム水溶液（150 ml）に
分配し、有機層を分離し、飽和食塩水（100 ml X 3）で
洗浄し、硫酸ナトリウムで乾燥し、減圧留去後、得られ
た残査をクロマトグラフィー（シリカゲル、酢酸エチル
/ヘキサン＝1/2）に付して標記化合物を黄色オイルとし
て得た。（10.5 g、39％） IR (CDCl3)νmax： 2929, 1746, 1686, 1513, 1462 cm
-1. MS (FAB) m/e 654 ([M+H]+). HRMS (FAB) Calcd for C33H55O10NSiNa : 676.3493; fo
und 676.3486 ([M+Na] +).1 H NMR (400 MHz, CDCl3) δppm: 7.31-7.35 (3H, m),
7.26-7.29 (2H, m), 5.38 (1H, d, J = 8.8 Hz), 4.51
(2H, s), 4.16-4.27 (2H, m), 4.09-4.15 (2H,m), 4.00
-4.05 (2H, m), 3.78 (3H, s), 3.65-3.75 (3H, m), 3.
48-3.53 (2H,m), 3.22 (3H, s), 2.27 (1H, dd, J = 1
2.9, 5.1 Hz), 1.95 (3H, s), 1.65-1.76 (3H, m), 1.4
1 (3H, s), 1.31 (3H, s), 0.86 (9H, s), 0.06 (3H,
s), 0.04(3H, s). [α]D 20 -14.0°(c 0.70, CHCl3). （ii）4−O−アセチル−5−アセチルアミノ−7−O−
（4'−ベンジルオキシ−n−ブチル）−3，5−ジデオキ
シ−8，9−O−イソプロピリデン−2−O−メチル−D−グ
リセロ−D−ガラクト−ノン−2−エノピラノソン酸メチ
ル 実施例４(i)で得られた化合物（4.0 g, 6.12 mmol）を
テトラヒドロフラン（100ml）に溶解し、室温で1Mテト
ラブチルアンモニウムフルオライド含有テトラヒドロフ
ラン（6.12 ml, 6.12 mmol）を加え、50℃で3時間撹拌
した。反応液を減圧留去して得られた残査に無水酢酸
（50 ml）、ピリジン（50 ml）を加え、3時間攪拌し
た。反応液を減圧留去後、トルエンで共沸した。得られ
た残査をクロマトグラフィー（シリカゲル、塩化メチレ
ン/メタノール＝20/1）に付して標記化合物を無色アモ
ルファスとして得た。（1.73g、49％） IR (CDCl3)νmax： 2930, 2859, 1742, 1687, 1515 cm
-1. MS (FAB) m/e 582 ([M+H]+). HRMS (FAB) Calcd for C29H44O11N : 582.2914; found
582.2899 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 7.24-7.35 (5H, m),
5.25-5.32 (2H, m), 4.50 (2H,s), 4.21-4.26 (2H, m),
4.13 (1H, dd, J = 8.5, 6.1 Hz), 4.00 (1H,dd, J =
7.1, 1.3 Hz), 3.78 (3H, s), 3.72 (1H, dd, J = 10.
5, 1.3 Hz), 3.60-3.67 (2H, m), 3.57 (1H, dd, J =
5.5, 1.3 Hz), 3.48-3.52 (2H, m), 3.25(3H, s), 2.36
(1H, dd, J = 12.8, 4.9 Hz), 2.03 (3H, s), 1.92 (3
H, s), 1.88 (1H, dd, J = 12.8, 12.1 Hz), 1.67-1.73
(4H, m), 1.40 (3H, s), 1.32 (3H, s). （iii）4−O−アセチル−5−アセチルアミノ−3，5−ジ
デオキシ−7−O−（4'−ヒドロキシ−n−ブチル）−8，
9−O−イソプロピリデン−2−O−メチル−D−グリセロ
−D−ガラクト−ノン−2−エノピラノソン酸メチル 実施例４(ii)で得られた化合物（1.72 g, 2.96 mmol）
をメタノール（100 ml）に溶解し、窒素雰囲気下パラジ
ウムカーボン（0.4 g）を加え、次いで水素雰囲気に置
換し、室温で2時間攪拌した。セライト濾過し濾物をメ
タノールで洗浄した。濾液、洗液を減圧留去後、得られ
た残査をクロマトグラフィー（シリカゲル、塩化メチレ
ン/メタノール＝20/1）に付して標記化合物を無色アモ
ルファスとして得た。（1.41g、97％） IR (CDCl3)νmax： 2929, 1743, 1686, 1518, 1438 cm
-1. MS (FAB) m/e 492 ([M+H]+). HRMS (FAB) Calcd for C22H38O11N : 492.2445; found
492.2467 ([M+H]+).1 H NMR (400 MHz, CDCl3)δppm: 5.36 (1H, d, J = 9.5
Hz), 5.27 (1H, ddd,J = 11.7, 10.2, 5.1 Hz), 4.30
(1H, ddd, J = 11.7, 9.5, 9.5 Hz), 4.21-4.29 (1H,
m), 4.15 (1H, dd, J = 8.8, 6.6 Hz), 4.01 (1H, dd,
J = 8.8, 6.6 Hz), 3.80 (3H, s), 3.55-3.75 (6H, m),
3.25 (3H, s), 2.36 (1H, dd, J = 13.2, 5.1 Hz), 2.
05 (3H, s), 1.96 (3H, s), 1.91 (1H, dd, J = 13.2,
11.7 Hz), 1.58-1.81 (4H, m), 1.41 (3H, s), 1.32 (3
H, s).[α]D 20 -88.6°(c 0.35, CHCl3). （iv）4−O−アセチル−5−アセチルアミノ−3，5−ジ
デオキシ−8，9−O−イソプロピリデン−2−O−メチル
−7−O−〔4'−（2''−ニトロフェニルセレニル）−n−
ブチル〕−D−グリセロ−D−ガラクト−ノン−2−エノ
ピラノソン酸メチル 実施例４(iii)で得られた化合物（1.41 g, 2.86 mmol）
を無水テトラヒドロフラン（30 ml）に溶解し、窒素雰
囲気下室温で2-ニトロフェニルセレノシアネート（1.30
g, 5.72 mmol）、トリブチルホスフィン（1.42 ml, 5.
72 mmol）を加え、室温で1時間攪拌した。メタノールを
加えた後に反応液を減圧留去後、得られた残査をクロマ
トグラフィー（シリカゲル、酢酸エチル/ヘキサン＝1/
2）に付して標記化合物（5）を無色アモルファスとして
得た。（1.90g、98％） IR (CDCl3)νmax： 2930, 1743, 1686, 1516 cm-1. MS (FAB) m/e 677 ([M+H]+). HRMS (FAB) Calcd for C28H41O12N2 78Se : 675.1833; f
ound 675.1841 ([M+H] +).1 H NMR (400 MHz, CDCl3)δppm: 8.28 (1H, dd, J = 8.
1, 1.5 Hz), 7.58 (1H, d, J = 7.0, 1.5 Hz), 7.52 (1
H, ddd, J = 8.1, 7.0, 1.5 Hz), 7.29 (1H, d, J = 7.
0, 7.0, 1.5 Hz), 5.23-5.29 (2H, m), 4.22-4.32 (2H,
m), 4.13 (1H,dd, J = 8.6, 6.1 Hz), 4.00 (1H, dd,
J = 8.6, 6.9 Hz), 3.78 (3H, s), 3.64-3.73 (3H, m),
3.56 (1H, dd, J = 5.8, 1.3 Hz), 3.25 (3H, s), 2.9
5-3.06(2H, m), 2.35 (1H, dd, J = 12.8, 5.0 Hz), 2.
03 (3H, s), 1.94 (3H, s), 1.79-1.95 (5H, m), 1.40
(3H, s), 1.32 (3H, s). （v）4−O−アセチル−5−アセチルアミノ−7−O−（4'
−n−ブテニル）−3，5−ジデオキシ−8，9−O−イソプ
ロピリデン−2−O−メチル−D−グリセロ−D−ガラクト
−ノン−2−エノピラノソン酸メチル 実施例４(iv)で得られた化合物（1.89 g, 2.80 mmol）
をテトラヒドロフラン（30 ml）に溶解し、室温で過酸
化水素水（30%）（0.64 ml, 5.60 mmol）を滴下し、同
温で3時間攪拌した。反応液を減圧留去後、得られた残
査をクロマトグラフィー（シリカゲル、酢酸エチル/ヘ
キサン＝1/1）に付して標記化合物を無色アモルファス
として得た。（1.33g、99％） IR (CDCl3)νmax： 2928, 1743, 1688, 1516, 1438 cm
-1. MS (FAB) m/e 474 ([M+H]+). HRMS (FAB) Calcd for C22H36O10N : 474.2339; found
474.2337 ([M+H]+).1 H NMR (400 MHz, CDCl3)δppm: 5.85 (1H, dddd, J =
17.2, 10.2, 6.8, 6.8Hz), 5.24-5.32 (1H, m), 5.23
(1H, d, J = 10.3 Hz), 5.06-5.13 (1H, m), 5.00-5.05
(1H, m), 4.22-4.32 (1H, m), 4.09-4.16 (2H, m), 4.
00 (1H, dd, J= 8.6, 6.8 Hz), 3.79 (3H, s), 3.70 (1
H, dd, J = 9.2, 1.5 Hz), 3.67 (2H,t, J = 7.0 Hz),
3.57 (1H, dd, J = 5.8, 1.5 Hz), 3.25 (3H, s), 2.35
-2.43(3H, m), 2.04 (3H, s), 1.94 (3H, s), 1.90 (1
H, dd, J = 12.8, 11.7 Hz), 1.41(3H, s), 1.32(3H,
s). [α]D 20 -64.9°(c 0.70, CHCl3). （vi）4−O−アセチル−5−アセチルアミノ−7−O−
（4'−n−ブテニル）−3，5−ジデオキシ−2−O−メチ
ル−D−グリセロ−D−ガラクト−ノン−2−エノピラノ
ソン酸メチル 実施例４(v)で得られた化合物（1.30 g, 2.74 mmol）を
酢酸（30 ml）、水（5ml）に溶解し、50℃で3時間攪拌
した。反応液を減圧留去後、得られた残査をクロマトグ
ラフィー（シリカゲル、塩化メチレン/メタノール＝10/
1）に付して標記化合物を無色アモルファスとして得
た。（0.80 g、67％） IR (CDCl3)νmax： 1744, 1682, 1518, 1438 cm-1. MS (FAB) m/e 434 ([M+H]+). HRMS (FAB) Calcd for C19H31O10NNa : 456.1845; foun
d 456.1860 ([M+Na]+).1 H NMR (400 MHz, CD3OD) δppm: 5.86 (1H, dddd, J =
17.2, 10.2, 6.8, 6.8 Hz), 5.22 (1H, ddd, J = 11.
5, 10.0, 5.1 Hz), 5.06-5.12 (1H, m), 4.98-5.03 (1
H, m), 4.17 (1H, dd, J = 10.7, 10.0 Hz), 4.03 (1H,
dd, J = 10.7, 1.2 Hz), 3.88 (1H, ddd, J = 8.5, 4.
6, 2.9 Hz), 3.81 (1H, dd, J = 11.4, 2.9 Hz), 3.78
(3H, s), 3.64 (1H, dd, J = 11.4, 4.6 Hz), 3.58 (2
H, t, J = 7.2 Hz), 3.45 (1H, dd, J = 8.5, 1.2 Hz),
2.30-2.40 (3H, m), 1.99 (3H, s),1.91 (3H, s), 1.7
9 (1H, dd, J = 12.7, 11.5 Hz). （vii）4−O−アセチル−5−アセチルアミノ−7−O−
（4'−n−ブテニル）−3，5−ジデオキシ−2−O−メチ
ル−8，9−O−チオカルボニル−D−グリセロ−D−ガラ
クト−ノン−2−エノピラノソン酸メチル 窒素雰囲気下、実施例４(vi)で得られた化合物（800 m
g, 1.85 mmol）を塩化メチレン（30 ml）に溶解し、氷
冷下4-ジメチルアミノピリジン（518 mg, 4.24mmol）、
チオホスゲン（0.155 ml, 2.04 mmol）を加え、氷冷下1
時間撹拌した。反応液にメタノールを加え、減圧留去し
た。得られた残査をクロマトグラフィー（シリカゲル、
塩化メチレン/メタノール＝50/1）に付して標記化合物
を無色アモルファスとして得た。（700 mg、80％） IR (CDCl3)νmax： 1747, 1692, 1514 cm-1. MS (FAB) m/e 476 ([M+H]+). HRMS (FAB) Calcd for C20H30O10NS : 476.1612; found
476.1590 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 5.82 (1H, dddd, J =
17.2, 10.2, 6.8, 6.8 Hz), 5.42 (1H, d, J = 9.7 H
z), 5.29 (1H, ddd, J = 11.5, 10.0, 5.1 Hz),5.08-5.
15 (1H, m), 5.04-5.08 (1H, m), 4.95-5.03 (2H, m),
4.72-4.81 (1H,m), 4.26 (1H, dd, J = 10.7, 10.0 H
z), 4.02-4.04 (1H, m), 3.81 (3H, s),3.62-3.76 (3H,
m), 3.17 (3H, s), 2.43 (1H, dd, J = 12.9. 5.1 H
z), 2.35-2.42 (2H, m), 2.05 (3H, s), 1.96 (3H, s),
1.83 (1H, dd, J = 12.9. 11.7 Hz). （viii）4−O−アセチル−5−アセチルアミノ−7−O−
（4'−n−ブテニル）−2−O−メチル−3，5，8，9−テ
トラデオキシ−D−グリセロ−D−ガラクト−ノン−2−
エノピラノソン酸メチル 窒素雰囲気下、実施例４(vii)で得られた化合物（700 m
g, 1.47 mmol）を亜リン酸トリメチル（30ml）に溶解
し、110℃で24時間撹拌した。反応液を減圧留去後、ト
ルエンで共沸し、得られた残査をクロマトグラフィー
（シリカゲル、酢酸エチル）に付して標記化合物を無色
アモルファスとして得た。（0.47 g、80％） IR (CDCl3)νmax： 1744, 1685, 1518, 1438 cm-1. MS (FAB) m/e 400 ([M+H]+). HRMS (FAB) Calcd for C19H29O8NNa : 422.1791 ; foun
d 422.1810 ([M+Na]+).1 H NMR (400 MHz, CDCl3) δppm: 5.96 (1H, ddd, J =
17.7, 9.9, 7.8 Hz),5.83 (1H, dddd, J = 17.2, 10.2,
6.8, 6.8 Hz), 5.36 (1H, d, J = 9.3 Hz),5.22-5.32
(2H, m), 5.06-5.11 (1H, m), 5.00-5.06 (1H, m), 4.1
6-4.26 (1H,m), 3.82-3.86 (1H, m), 3.79 (3H, s), 3.
74-3.81 (1H, m), 3.59 (1H, dd, J= 10.3, 2.6 Hz),
3.56 (1H, ddd, J = 9.0, 7.0, 7.0 Hz), 3.33 (1H, dd
d, J= 9.0, 7.0, 7.0 Hz), 3.23 (3H, s), 2.30-2.40
(3H, m), 2.03 (3H, s), 1.93(3H, s), 1.90 (1H, dd,
J = 12.8, 11.5 Hz). [α]D 20 -55.1°(c 0.90, CHCl3). （ix）（2S, 4S, 5R, 6R, 2'R）−4−アセトキシ−5−
アセチルアミノ−6−（5'，6'−ジヒドロ−2'H−ピラン
−2'−イル）−2−メトキシ−テトラヒドロ−ピラン−2
−カルボン酸メチル 窒素雰囲気下、実施例４(viii)で得られた化合物（0.27
g, 0.73 mmol）を塩化メチレン（50 ml）に溶解し、ビ
ス（トリシクロヘキシルホスフィン）ベンジリデンルテ
ニウム（IV）ジクロライド（8 mg）を加え、室温で24時
間撹拌した。反応液を減圧留去後、得られた残査をクロ
マトグラフィー（シリカゲル、酢酸エチル）に付して標
記化合物を無色アモルファスとして得た。（0.25g、99
％） IR (CDCl3)νmax： 2955, 2929, 2855, 1744, 1684, 15
18, 1438 cm-1. MS (FAB) m/e 372 ([M+H]+). HRMS (FAB) Calcd for C17H25O8NNa : 394.1478; found
394.1467 ([M+Na]+).1 H NMR (400 MHz, CDCl3) δppm: 6.00-6.06 (1H, m),
5.69 (1H, dd, J = 10.8, 2.0 Hz), 5.40 (1H, d, J =
8.8 Hz), 5.28 (1H, ddd, J = 11.7, 11.7, 4.8 Hz),
4.32-4.35 (1H, m), 4.18 (1H, ddd, J = 11.7, 10.7,
8.8 Hz), 4.05-4.10 (1H, m), 3.78 (3H, s), 3.68-3.7
4 (1H, m), 3.69 (1H, dd, J = 10.7, 2.0 Hz), 3.25
(3H, s), 2.37 (1H, d, J = 12.7, 4.8 Hz), 2.13-2.22
(1H, m),2.02 (3H, s), 1.96-2.06 (1H, m), 1.93 (3
H, s), 1.90 (1H, dd, J = 12.7, 11.7 Hz). [α]D 20 -63.7°(c 0.25, CHCl3). （x）（2S, 4S, 5R, 6R, 2'R）−4−アセトキシ−5−ア
セチルアミノ−6−（3'，4'−ジヒドロキシ−テトラヒ
ドロ−ピラン−2'−イル）−2−メトキシ−テトラヒド
ロ−ピラン−2−カルボン酸メチル 実施例４(ix)で得られた化合物（0.38 g, 1.02 mmol）
をアセトン(10 ml)に溶解し、t-ブタノール(2 ml)、N-
メチルモルホリンN−オキシド50％水溶液（263 mg, 1.1
3 mmol）、四酸化オスミウム（1mg, 0.004 mmol）を加
え、氷冷下5時間撹拌した。反応液を減圧留去し、得ら
れた残査をクロマトグラフィー（シリカゲル、塩化メチ
レン/メタノール＝10/1）に付して標記化合物を無色ア
モルファスとして得た。（0.37 g、87 %） IR (CDCl3)νmax： 2928, 2855, 1743, 1684, 1661, 15
19 cm-1. MS (FAB) m/e 406 ([M+H]+). HRMS (FAB) Calcd for C17H27O10NNa : 428.1533; foun
d 428.1549 ([M+Na]+).1 H NMR (400 MHz, CDCl3) δppm: 5.36 (1H, d, J = 9.
4 Hz), 5.31 (1H, ddd, J = 11.3, 10.3, 5.1 Hz), 4.3
1 (1H, ddd, J = 10.7, 10.3, 9.4 Hz), 4.17-4.22 (1
H, m), 3.96 (1H, dd, J = 9.8, 2.7 Hz), 3.90 (1H, d
dd, J = 10.5, 1.9 Hz), 3.79 (3H, s), 3.77-3.81 (1
H, m), 3.69 (1H, ddd, J = 12.8, 12.6,2.0 Hz), 3.61
(1H, ddd, J = 11.3, 11.3, 5.1 Hz), 3.61 (1H, dd,
J = 9.8,1.9 Hz), 3.30 (3H, s), 2.58-2.67 (1H, s, b
r), 2.42 (1H, dd, J = 12.8, 5.1 Hz), 2.25-2.34 (1
H, s, br), 1.90-1.97 (1H, m), 2.04 (3H, s), 1.95
(3H,s), 1.90 (1H, d, J = 12.8, 11.3 Hz), 1.78-1.83
(1H, m). （xi）（4S, 5R, 6R, 2'S, 3'S, 4'R）−5−アセチルア
ミノ−4−アジド−6−（3'，4'−ジアセトキシ−テトラ
ヒドロ−ピラン−2'−イル）−5，6−ジヒドロ−4H−ピ
ラン−2−カルボン酸メチル 窒素雰囲気下、実施例４(x)で得られた化合物（0.36 g,
0.888mmol）を無水酢酸（3 ml）に溶解し、酢酸（1 m
l）、硫酸（0.3 ml）を室温で加え、同温で12時間撹拌
した。反応液を氷冷下酢酸エチル（100ml）と飽和炭酸
水素ナトリウム水溶液（60ml）に分配した。有機層を分
離し、食塩水（50ml）で洗浄し、硫酸ナトリウムで乾燥
し、減圧留去後、トルエンで共沸した。得られた残査を
ジメチルホルムアミド（0.4 ml）に溶解し、アジ化ナト
リウム（240 mg）、ダウエックス50W（H+）樹脂（240 m
g）を加え、60℃で2時間撹拌した。反応液を減圧濾過
し、濾物をメタノールで洗浄した。濾液、洗液を減圧留
去後、得られた残査をクロマトグラフィー（シリカゲ
ル、塩化メチレン/メタノール＝20/1）に付して標記化
合物を無色アモルファスとして得た。（220mg、49％） IR (CDCl3)νmax： 2928, 2855, 2102, 1743, 1680, 15
11 cm-1. MS (FAB) m/e 441 ([M+H]+). HRMS (FAB) Calcd for C18H24O9N4K : 479.1181; found
479.1169 ([M+K]+).1 H NMR (400 MHz, CDCl3) δppm: 5.94 (1H, d, J = 2.
6 Hz), 5.85 (1H, d,J = 7.4 Hz), 5.57-5.61 (1H, m)
5.16 (1H, dd, J = 10.0, 3.0 Hz), 4.90 (1H, dd, J =
9.4, 2.6 Hz), 4.70 (1H, dd, J = 10.1, 1.8 Hz), 3.
90 (1H, dd, J= 10.0, 1.8 Hz), 3.87-3.91 (1H, m),
3.78 (3H, s), 3.67-3.73 (1H, m), 3.61 (1H, ddd, J
= 10.1, 9.4, 7.4 Hz), 2.12 (3H, s), 2.08 (3H, s),
2.03-2.11 (1H, m), 2.00 (3H, s), 1.80-1.85 (1H,
m). [α]D 20 +68.6°(c 0.30, CHCl3). （xii）（4S, 5R, 6R, 2'S, 3'S, 4'R）−5−アセチル
アミノ−4−（N，N'−ビス−t−ブチルオキシカルボニ
ル）グアニジノ−6−（3'，4'−ジアセトキシ−テトラ
ヒドロ−ピラン−2'−イル）−5，6−ジヒドロ−4H−ピ
ラン−2−カルボン酸メチル 実施例４(xi)で得られた化合物（73 mg, 0.165 mmol）
をエタノール（30 ml）に溶解し、窒素雰囲気下リンド
ラー触媒（20 mg）を加え、次いで水素雰囲気に置換
し、室温で3時間攪拌した。反応液をセライト濾過し濾
物をメタノールで洗浄し、濾液、洗液を減圧留去した。
得られた残査をジメチルホルムアミド(1 ml)に溶解し、
N,N'-ビス-t-ブトキシカルボニルチオ尿素(57 mg, 0.20
8 mmol)、トリエチルアミン（58 μl, 0.415 mmol）、
塩化第二水銀（56 mg, 0.208 mmol）を室温で加え、同
温にて2時間攪拌した。反応液をセライト濾過し濾物を
酢酸エチルで洗浄した。濾液、洗液を減圧留去後、得ら
れた残査をクロマトグラフィー（シリカゲル、ヘキサン
/酢酸エチル＝1/1）に付して標記化合物を無色アモルフ
ァスとして得た。（100mg、88 ％） IR (CDCl3)νmax： 2928, 2855, 1730, 1672, 1641, 16
06 cm-1. MS (FAB) m/e 657 ([M+H]+). HRMS (FAB) Calcd for C29H44O13N4Na : 679.2803; fou
nd 679.2826 ([M+Na]+).1 H NMR (400 MHz, CD3OD) δppm: 8.61 (1H, d, J = 8.
8 Hz), 6.68 (1H, d,J = 8.1 Hz), 5.83 (1H, d, J =
2.9 Hz), 5.56-5.60 (1H, m), 5.12-5.17 (2H,m), 4.27
(1H, ddd, J = 9.5, 8.8, 8.1 Hz), 4.02 (1H, d, J =
9.5 Hz), 3.92 (1H, dd, J = 11.7, 4.4 Hz), 3.85 (1
H, d, J = 10.3 Hz), 3.78 (3H, s), 3.69-3.73 (1H,
m), 2.10 (3H, s), 2.02-2.09 (1H, m), 2.02 (3H, s),
2.00 (3H, s), 1.76-1.82 (1H, m), 1.50 (18H, s). [α]D 20 +0.1°(c 0.45, CHCl3).（xiii）（4S, 5R, 6
R, 2'S, 3'S, 4'R）−5−アセチルアミノ−6−（3'，4'
−ジアセトキシ−テトラヒドロ−ピラン−2'−イル）−
5，6−ジヒドロ−4−グアニジノ−4H−ピラン−2−カル
ボン酸メチル トリフルオロ酢酸塩 実施例４(xii)で得られた化合物（330 mg, 0.502 mmo
l）を塩化メチレン（3 ml）に溶解し、窒素雰囲気下ト
リフルオロ酢酸（1ml）を加え、室温で3時間攪拌した。
反応液を減圧留去後、得られた残査を逆層クロマトグラ
フィー（コスモシル、水/メタノール＝2/1）に付して標
記化合物を無色アモルファスとして得た。（240 mg、83
％） IR (KBr)νmax： 3340, 3270, 3189, 1746, 1669, 155
0, 1439 cm-1. MS (FAB) m/e 457 ([M+H]+). HRMS (FAB) Calcd for C19H29O9N4 : 457.1934; found
457.1957 ([M+H]+).1 H NMR (400 MHz, CD3OD) δppm: 5.84 (1H, d, J = 2.
9 Hz), 5.52-5.57 (1H, m), 5.12 (1H, dd, J = 10.3,
2.9 Hz), 4.50 (1H, d, J = 8.8, 2.9 Hz), 4.31 (1H,
dd, J = 9.5, 2.2 Hz), 4.16 (1H, dd, J = 9.5, 8.8 H
z), 3.96 (1H,dd, J = 10.3, 2.2 Hz), 3.85 (1H, ddd,
J = 11.7, 11.0, 4.4 Hz), 3.78 (3H,s), 3.64-3.72
(1H, m), 2.09 (3H,s), 1.99-2.08 (1H, m), 2.01 (3H,
s), 1.96 (3H, s), 1.78-1.85 (1H, m). （xiv）（4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチル
アミノ−5，6−ジヒドロ−6−（3', 4'−ジヒドロキシ
−テトラヒドロ−ピラン−2'−イル）−4−グアニジノ
−4H−ピラン−2−カルボン酸 水和物 実施例４(xiii)で得られた化合物（235 mg, 0.412 mmo
l）をメタノール（3 ml）に溶解し、室温で1M水酸化ナ
トリウム水溶液（1.65 ml, 1.65 mmol）を加え、同温で
30分攪拌した。次いでダウエックス50W X8（H+）樹脂を
加え、反応液のpHを2に調整した。ただちに減圧濾過
し、水で濾物を洗浄した。濾液、洗液を減圧留去後、得
られた残査を逆層クロマトグラフィー（コスモシル、
水）に付した。減圧留去後、得られた残査をイオン交換
クロマトグラフィー（ダウエックス50Ｗ（H+）樹脂、
水、アンモニア水）に付して、標記化合物を無色アモル
ファスとして得た。（48mg、83％） IR (KBr)νmax： 3351, 2962, 2927, 1666, 1619, 1403
cm-1. MS (FAB) m/e 359 ([M+H]+). HRMS (FAB) Calcd for C14H23O7N4 : 359.1566; found
359.1584 ([M+H]+).1 H NMR (400 MHz, D2O) δppm: 5.43 (1H, d, J = 2.2
Hz), 4.26 (1H, d, J= 9.5, 2.2 Hz), 4.14 (1H, dd, J
= 11.0, 1.5 Hz), 4.02-4.07 (1H, m), 4.00(1H, dd,
J = 11.0, 9.5 Hz), 3.78 (1H, dd, J = 10.3, 2.9 H
z), 3.57 (1H,dd, J = 10.3, 1.5 Hz), 3.52-3.57 (1H,
m), 3.38-3.46 (1H, m), 1.69-1.79 (1H, m), 1.85 (3
H, s), 1.57-1.64 (1H, m). [α]D 20 +6.0°(c 0.40, H2O). （実施例５） （4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルアミノ−
4−グアニジノ−5，6−ジヒドロ−6−（3'，4'−ジヒド
ロキシ−オキセパン−2'−イル）−4H−ピラン−2−カ
ルボン酸 三水和物(I) 5-acetylamino-7-O- (4′-
Ndyloxy-n-butyl) -4-O-t-butyldimethyl
Silyl-3,5-dideoxy-8,9-O-isopropylide
2-O-methyl-D-glycero-D-galacto-non-
Methyl 2-enopyranosanoate 5-acetylamino-3,5-dideoxy- under nitrogen atmosphere
8,9-O-isopropylidene-2-O-methyl-4-O-t-
Butyldimethylsilyl-D-glycero-D-galacto-no
Methyl 2-enopyranosonate (20 g, 41.1 mmol) (Z
biral, Erich; Phadtare, S .; Schmid, Walther; Liebi
gs Ann. Chem., 1987, (1), p39-43.
Compound) in anhydrous dimethylformamide (100 ml)
At room temperature to give 4-benzyloxy-n-butyl mesylate (18.
6 g, 72 mmol), sodium hydride (1.7 g, 40.6 mmo
l) was added and stirred at room temperature for 1 hour. Ethyl acetate
(300 ml) and saturated ammonium chloride aqueous solution (150 ml)
Partition, separate the organic layer, and wash with saturated saline (100 ml x 3)
Wash, dry over sodium sulfate and evaporate under reduced pressure to give
The residue was chromatographed (silica gel, ethyl acetate
/ Hexane = 1/2) to give the title compound a yellow oil
I got it. (10.5 g, 39%) IR (CDClThree) νmax: 2929, 1746, 1686, 1513, 1462 cm
-1MS (FAB) m / e 654 ([M + H]+). HRMS (FAB) Calcd for C33H55OTenNSiNa: 676.3493; fo
und 676.3486 ([M + Na] +).1 H NMR (400 MHz, CDClThree) δppm: 7.31-7.35 (3H, m),
7.26-7.29 (2H, m), 5.38 (1H, d, J = 8.8 Hz), 4.51
(2H, s), 4.16-4.27 (2H, m), 4.09-4.15 (2H, m), 4.00
-4.05 (2H, m), 3.78 (3H, s), 3.65-3.75 (3H, m), 3.
48-3.53 (2H, m), 3.22 (3H, s), 2.27 (1H, dd, J = 1
(2.9, 5.1 Hz), 1.95 (3H, s), 1.65-1.76 (3H, m), 1.4
1 (3H, s), 1.31 (3H, s), 0.86 (9H, s), 0.06 (3H,
s), 0.04 (3H, s). [α]D 20 -14.0 ° (c 0.70, CHClThree(Ii) 4-O-acetyl-5-acetylamino-7-O-
(4'-benzyloxy-n-butyl) -3,5-dideoxy
C-8,9-O-isopropylidene-2-O-methyl-D-g
Lysero-D-galacto-non-2-enopyranosonic acid methyl
The compound (4.0 g, 6.12 mmol) obtained in Example 4 (i) was
Dissolve in tetrahydrofuran (100ml) and add 1M
Labutylammonium fluoride-containing tetrahydrofur
Add run (6.12 ml, 6.12 mmol) and stir at 50 ° C for 3 hours
did. The reaction mixture was evaporated under reduced pressure, and the resulting residue was treated with acetic anhydride.
(50 ml) and pyridine (50 ml), and stirred for 3 hours.
Was. After the reaction solution was distilled off under reduced pressure, the residue was azeotropically distilled with toluene. Obtained
The residue is chromatographed (silica gel, methyl chloride
/ Methanol = 20/1) to give the title compound
Obtained as Rufus. (1.73g, 49%) IR (CDClThree) νmax: 2930, 2859, 1742, 1687, 1515 cm
-1. MS (FAB) m / e 582 ([M + H]+). HRMS (FAB) Calcd for C29H44O11N: 582.2914; found
582.2899 ([M + H]+).1 H NMR (400 MHz, CDClThree) δppm: 7.24-7.35 (5H, m),
5.25-5.32 (2H, m), 4.50 (2H, s), 4.21-4.26 (2H, m),
4.13 (1H, dd, J = 8.5, 6.1 Hz), 4.00 (1H, dd, J =
7.1, 1.3 Hz), 3.78 (3H, s), 3.72 (1H, dd, J = 10.
5, 1.3 Hz), 3.60-3.67 (2H, m), 3.57 (1H, dd, J =
5.5, 1.3 Hz), 3.48-3.52 (2H, m), 3.25 (3H, s), 2.36
(1H, dd, J = 12.8, 4.9 Hz), 2.03 (3H, s), 1.92 (3
H, s), 1.88 (1H, dd, J = 12.8, 12.1 Hz), 1.67-1.73
(4H, m), 1.40 (3H, s), 1.32 (3H, s). (Iii) 4-O-acetyl-5-acetylamino-3,5-di
Deoxy-7-O- (4'-hydroxy-n-butyl) -8,
9-O-isopropylidene-2-O-methyl-D-glycero
-D-galacto-non-2-enopyranosonic acid methyl compound obtained in Example 4 (ii) (1.72 g, 2.96 mmol)
Is dissolved in methanol (100 ml) and
Carbon carbon (0.4 g) and then placed in a hydrogen atmosphere.
Then, the mixture was stirred at room temperature for 2 hours. Filter through Celite to remove the residue.
Washed with tanol. The filtrate and washings are obtained after evaporation under reduced pressure.
The residue is chromatographed (silica gel, methyl chloride
/ Methanol = 20/1) to give the title compound
Obtained as Rufus. (1.41g, 97%) IR (CDClThree) νmax: 2929, 1743, 1686, 1518, 1438 cm
-1MS (FAB) m / e 492 ([M + H]+). HRMS (FAB) Calcd for Ctwenty twoH38O11N: 492.2445; found
492.2467 ([M + H]+).1 H NMR (400 MHz, CDClThree) δppm: 5.36 (1H, d, J = 9.5
Hz), 5.27 (1H, ddd, J = 11.7, 10.2, 5.1 Hz), 4.30
(1H, ddd, J = 11.7, 9.5, 9.5 Hz), 4.21-4.29 (1H,
m), 4.15 (1H, dd, J = 8.8, 6.6 Hz), 4.01 (1H, dd,
J = 8.8, 6.6 Hz), 3.80 (3H, s), 3.55-3.75 (6H, m),
3.25 (3H, s), 2.36 (1H, dd, J = 13.2, 5.1 Hz), 2.
05 (3H, s), 1.96 (3H, s), 1.91 (1H, dd, J = 13.2,
11.7 Hz), 1.58-1.81 (4H, m), 1.41 (3H, s), 1.32 (3
H, s). [Α]D 20 -88.6 ° (c 0.35, CHClThree(Iv) 4-O-acetyl-5-acetylamino-3,5-di
Deoxy-8,9-O-isopropylidene-2-O-methyl
-7-O- [4 '-(2 "-nitrophenylselenyl) -n-
Butyl) -D-glycero-D-galacto-non-2-eno
Methyl pyranosone The compound obtained in Example 4 (iii) (1.41 g, 2.86 mmol)
Was dissolved in anhydrous tetrahydrofuran (30 ml), and
2-nitrophenyl selenocyanate (1.30 at room temperature under ambient atmosphere
g, 5.72 mmol), tributylphosphine (1.42 ml, 5.
72 mmol) and stirred at room temperature for 1 hour. Methanol
After the addition, the reaction mixture was evaporated under reduced pressure, and the resulting residue was chromatographed.
Chromatography (silica gel, ethyl acetate / hexane = 1 /
2) to give the title compound (5) as a colorless amorphous
Obtained. (1.90g, 98%) IR (CDClThree) νmax: 2930, 1743, 1686, 1516 cm-1MS (FAB) m / e 677 ([M + H]+). HRMS (FAB) Calcd for C28H41O12NTwo 78Se: 675.1833; f
ound 675.1841 ([M + H] +).1 H NMR (400 MHz, CDClThree) δppm: 8.28 (1H, dd, J = 8.
1, 1.5 Hz), 7.58 (1H, d, J = 7.0, 1.5 Hz), 7.52 (1
H, ddd, J = 8.1, 7.0, 1.5 Hz), 7.29 (1H, d, J = 7.
0, 7.0, 1.5 Hz), 5.23-5.29 (2H, m), 4.22-4.32 (2H,
m), 4.13 (1H, dd, J = 8.6, 6.1 Hz), 4.00 (1H, dd,
J = 8.6, 6.9 Hz), 3.78 (3H, s), 3.64-3.73 (3H, m),
3.56 (1H, dd, J = 5.8, 1.3 Hz), 3.25 (3H, s), 2.9
5-3.06 (2H, m), 2.35 (1H, dd, J = 12.8, 5.0 Hz), 2.
03 (3H, s), 1.94 (3H, s), 1.79-1.95 (5H, m), 1.40
(3H, s), 1.32 (3H, s). (V) 4-O-acetyl-5-acetylamino-7-O- (4 ′
-N-butenyl) -3,5-dideoxy-8,9-O-isoprop
Lopylidene-2-O-methyl-D-glycero-D-galacto
-Methyl non-2-enopyranosonate The compound obtained in Example 4 (iv) (1.89 g, 2.80 mmol)
Was dissolved in tetrahydrofuran (30 ml), and
Hydrogen hydride (30%) (0.64 ml, 5.60 mmol) was added dropwise.
Stirred at warm for 3 hours. After distilling off the reaction solution under reduced pressure, the resulting residue
Chromatography (silica gel, ethyl acetate /
(Xan = 1/1) to give the title compound as a colorless amorphous
As obtained. (1.33g, 99%) IR (CDClThree) νmax: 2928, 1743, 1688, 1516, 1438 cm
-1. MS (FAB) m / e 474 ([M + H]+). HRMS (FAB) Calcd for Ctwenty twoH36OTenN: 474.2339; found
474.2337 ([M + H]+).1 H NMR (400 MHz, CDClThree) δppm: 5.85 (1H, dddd, J =
17.2, 10.2, 6.8, 6.8Hz), 5.24-5.32 (1H, m), 5.23
(1H, d, J = 10.3 Hz), 5.06-5.13 (1H, m), 5.00-5.05
(1H, m), 4.22-4.32 (1H, m), 4.09-4.16 (2H, m), 4.
00 (1H, dd, J = 8.6, 6.8 Hz), 3.79 (3H, s), 3.70 (1
H, dd, J = 9.2, 1.5 Hz), 3.67 (2H, t, J = 7.0 Hz),
3.57 (1H, dd, J = 5.8, 1.5 Hz), 3.25 (3H, s), 2.35
-2.43 (3H, m), 2.04 (3H, s), 1.94 (3H, s), 1.90 (1
H, dd, J = 12.8, 11.7 Hz), 1.41 (3H, s), 1.32 (3H,
s). [α]D 20 -64.9 ° (c 0.70, CHClThree(Vi) 4-O-acetyl-5-acetylamino-7-O-
(4'-n-butenyl) -3,5-dideoxy-2-O-methyl
Ru-D-glycero-D-galacto-non-2-enopyrano
Methyl sonicate Compound (1.30 g, 2.74 mmol) obtained in Example 4 (v)
Dissolve in acetic acid (30 ml) and water (5 ml) and stir at 50 ° C for 3 hours
did. After evaporating the reaction solution under reduced pressure, the obtained residue was chromatographed.
Raffy (silica gel, methylene chloride / methanol = 10 /
1) to give the title compound as a colorless amorphous
Was. (0.80 g, 67%) IR (CDClThree) νmax: 1744, 1682, 1518, 1438 cm-1MS (FAB) m / e 434 ([M + H]+). HRMS (FAB) Calcd for C19H31OTenNNa: 456.1845; foun
d 456.1860 ([M + Na]+).1 H NMR (400 MHz, CDThreeOD) δppm: 5.86 (1H, dddd, J =
17.2, 10.2, 6.8, 6.8 Hz), 5.22 (1H, ddd, J = 11.
5, 10.0, 5.1 Hz), 5.06-5.12 (1H, m), 4.98-5.03 (1
H, m), 4.17 (1H, dd, J = 10.7, 10.0 Hz), 4.03 (1H,
dd, J = 10.7, 1.2 Hz), 3.88 (1H, ddd, J = 8.5, 4.
6, 2.9 Hz), 3.81 (1H, dd, J = 11.4, 2.9 Hz), 3.78
(3H, s), 3.64 (1H, dd, J = 11.4, 4.6 Hz), 3.58 (2
H, t, J = 7.2 Hz), 3.45 (1H, dd, J = 8.5, 1.2 Hz),
2.30-2.40 (3H, m), 1.99 (3H, s), 1.91 (3H, s), 1.7
9 (1H, dd, J = 12.7, 11.5 Hz). (Vii) 4-O-acetyl-5-acetylamino-7-O-
(4'-n-butenyl) -3,5-dideoxy-2-O-methyl
-8,9-O-thiocarbonyl-D-glycero-D-gal
Methyl ct-non-2-enopyranosonate The compound obtained in Example 4 (vi) (800 m
g, 1.85 mmol) in methylene chloride (30 ml).
4-dimethylaminopyridine (518 mg, 4.24 mmol) under cooling,
Add thiophosgene (0.155 ml, 2.04 mmol), and add
Stirred for hours. Methanol was added to the reaction solution, and the mixture was evaporated
Was. The obtained residue is subjected to chromatography (silica gel,
Methylene chloride / methanol = 50/1) to give the title compound
Was obtained as a colorless amorphous. (700 mg, 80%) IR (CDClThree) νmax: 1747, 1692, 1514 cm-1MS (FAB) m / e 476 ([M + H]+). HRMS (FAB) Calcd for C20H30OTenNS: 476.1612; found
476.1590 ([M + H]+).1 H NMR (400 MHz, CDClThree) δppm: 5.82 (1H, dddd, J =
17.2, 10.2, 6.8, 6.8 Hz), 5.42 (1H, d, J = 9.7 H
z), 5.29 (1H, ddd, J = 11.5, 10.0, 5.1 Hz), 5.08-5.
15 (1H, m), 5.04-5.08 (1H, m), 4.95-5.03 (2H, m),
4.72-4.81 (1H, m), 4.26 (1H, dd, J = 10.7, 10.0 H
z), 4.02-4.04 (1H, m), 3.81 (3H, s), 3.62-3.76 (3H,
m), 3.17 (3H, s), 2.43 (1H, dd, J = 12.9. 5.1 H
z), 2.35-2.42 (2H, m), 2.05 (3H, s), 1.96 (3H, s),
1.83 (1H, dd, J = 12.9. 11.7 Hz). (Viii) 4-O-acetyl-5-acetylamino-7-O-
(4'-n-butenyl) -2-O-methyl-3,5,8,9-te
Toradeoxy-D-glycero-D-galacto-non-2-
Methyl enopyranosonate The compound obtained in Example 4 (vii) (700 m
g, 1.47 mmol) in trimethyl phosphite (30 ml)
Then, the mixture was stirred at 110 ° C for 24 hours. After distilling off the reaction solution under reduced pressure,
Azeotrope with ruene and chromatograph the residue obtained.
(Silica gel, ethyl acetate) to give the title compound as colorless
Obtained as amorphous. (0.47 g, 80%) IR (CDClThree) νmax: 1744, 1685, 1518, 1438 cm-1MS (FAB) m / e 400 ([M + H]+). HRMS (FAB) Calcd for C19H29O8NNa: 422.1791; foun
d 422.1810 ([M + Na]+).1 H NMR (400 MHz, CDClThree) δppm: 5.96 (1H, ddd, J =
17.7, 9.9, 7.8 Hz), 5.83 (1H, dddd, J = 17.2, 10.2,
6.8, 6.8 Hz), 5.36 (1H, d, J = 9.3 Hz), 5.22-5.32
(2H, m), 5.06-5.11 (1H, m), 5.00-5.06 (1H, m), 4.1
6-4.26 (1H, m), 3.82-3.86 (1H, m), 3.79 (3H, s), 3.
74-3.81 (1H, m), 3.59 (1H, dd, J = 10.3, 2.6 Hz),
3.56 (1H, ddd, J = 9.0, 7.0, 7.0 Hz), 3.33 (1H, dd
d, J = 9.0, 7.0, 7.0 Hz), 3.23 (3H, s), 2.30-2.40
(3H, m), 2.03 (3H, s), 1.93 (3H, s), 1.90 (1H, dd,
J = 12.8, 11.5 Hz). [Α]D 20 -55.1 ° (c 0.90, CHClThree(Ix) (2S, 4S, 5R, 6R, 2'R) -4-acetoxy-5-
Acetylamino-6- (5 ', 6'-dihydro-2'H-pyran
-2'-yl) -2-methoxy-tetrahydro-pyran-2
-Methyl carboxylate The compound obtained in Example 4 (viii) (0.27
g, 0.73 mmol) in methylene chloride (50 ml).
(Tricyclohexylphosphine) benzylidene lute
(IV) dichloride (8 mg) at room temperature for 24 hours
While stirring. After evaporating the reaction solution under reduced pressure, the obtained residue was chromatographed.
Marked by chromatography (silica gel, ethyl acetate)
The title compound was obtained as a colorless amorphous. (0.25g, 99
%) IR (CDClThree) νmax: 2955, 2929, 2855, 1744, 1684, 15
18, 1438 cm-1MS (FAB) m / e 372 ([M + H]+). HRMS (FAB) Calcd for C17Htwenty fiveO8NNa: 394.1478; found
394.1467 ([M + Na]+).1 H NMR (400 MHz, CDClThree) δppm: 6.00-6.06 (1H, m),
5.69 (1H, dd, J = 10.8, 2.0 Hz), 5.40 (1H, d, J =
8.8 Hz), 5.28 (1H, ddd, J = 11.7, 11.7, 4.8 Hz),
4.32-4.35 (1H, m), 4.18 (1H, ddd, J = 11.7, 10.7,
8.8 Hz), 4.05-4.10 (1H, m), 3.78 (3H, s), 3.68-3.7
4 (1H, m), 3.69 (1H, dd, J = 10.7, 2.0 Hz), 3.25
(3H, s), 2.37 (1H, d, J = 12.7, 4.8 Hz), 2.13-2.22
(1H, m), 2.02 (3H, s), 1.96-2.06 (1H, m), 1.93 (3
H, s), 1.90 (1H, dd, J = 12.7, 11.7 Hz). [Α]D 20 -63.7 ° (c 0.25, CHClThree). (X) (2S, 4S, 5R, 6R, 2'R) -4-acetoxy-5-a
Cetylamino-6- (3 ', 4'-dihydroxy-tetrahi
Dro-pyran-2'-yl) -2-methoxy-tetrahydride
Methyl ropyran-2-carboxylate Compound obtained in Example 4 (ix) (0.38 g, 1.02 mmol)
Was dissolved in acetone (10 ml), t-butanol (2 ml), N-
Methylmorpholine N-oxide 50% aqueous solution (263 mg, 1.1
3 mmol) and osmium tetroxide (1 mg, 0.004 mmol).
Then, the mixture was stirred for 5 hours under ice cooling. The reaction solution was distilled off under reduced pressure to obtain
The residue obtained is chromatographed (silica gel, methyl chloride
(Methylene chloride / methanol = 10/1) to give the title compound
Obtained as morphus. (0.37 g, 87%) IR (CDClThree) νmax: 2928, 2855, 1743, 1684, 1661, 15
19 cm-1. MS (FAB) m / e 406 ([M + H]+). HRMS (FAB) Calcd for C17H27OTenNNa: 428.1533; foun
d 428.1549 ([M + Na]+).1 H NMR (400 MHz, CDClThree) δppm: 5.36 (1H, d, J = 9.
4 Hz), 5.31 (1H, ddd, J = 11.3, 10.3, 5.1 Hz), 4.3
1 (1H, ddd, J = 10.7, 10.3, 9.4 Hz), 4.17-4.22 (1
H, m), 3.96 (1H, dd, J = 9.8, 2.7 Hz), 3.90 (1H, d
dd, J = 10.5, 1.9 Hz), 3.79 (3H, s), 3.77-3.81 (1
H, m), 3.69 (1H, ddd, J = 12.8, 12.6, 2.0 Hz), 3.61
(1H, ddd, J = 11.3, 11.3, 5.1 Hz), 3.61 (1H, dd,
J = 9.8,1.9 Hz), 3.30 (3H, s), 2.58-2.67 (1H, s, b
r), 2.42 (1H, dd, J = 12.8, 5.1 Hz), 2.25-2.34 (1
H, s, br), 1.90-1.97 (1H, m), 2.04 (3H, s), 1.95
(3H, s), 1.90 (1H, d, J = 12.8, 11.3 Hz), 1.78-1.83
(1H, m). (Xi) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5-acetyla
Mino-4-azido-6- (3 ', 4'-diacetoxy-tetra
Hydro-pyran-2'-yl) -5,6-dihydro-4H-py
Methyl run-2-carboxylate The compound obtained in Example 4 (x) (0.36 g,
0.888 mmol) was dissolved in acetic anhydride (3 ml) and acetic acid (1 m
l), sulfuric acid (0.3 ml) was added at room temperature and stirred at the same temperature for 12 hours
did. The reaction mixture was cooled under ice-cooling with ethyl acetate (100 ml) and saturated carbonic acid.
Partitioned into aqueous sodium hydrogen (60 ml). Separate the organic layer
Release, wash with brine (50 ml) and dry over sodium sulfate
After distilling off under reduced pressure, the residue was azeotropically distilled with toluene. The obtained residue
Dissolve in dimethylformamide (0.4 ml) and add sodium azide
Lium (240 mg), Dowex 50W (H+) Resin (240 m
g) was added and the mixture was stirred at 60 ° C. for 2 hours. Filter the reaction solution under reduced pressure
Then, the residue was washed with methanol. The filtrate and washings are distilled under reduced pressure.
After removal, the residue obtained is chromatographed (silica gel).
, Methylene chloride / methanol = 20/1)
The compound was obtained as a colorless amorphous. (220mg, 49%) IR (CDClThree) νmax: 2928, 2855, 2102, 1743, 1680, 15
11 cm-1MS (FAB) m / e 441 ([M + H]+). HRMS (FAB) Calcd for C18Htwenty fourO9NFourK: 479.1181; found
479.1169 ([M + K]+).1 H NMR (400 MHz, CDClThree) δppm: 5.94 (1H, d, J = 2.
6 Hz), 5.85 (1H, d, J = 7.4 Hz), 5.57-5.61 (1H, m)
5.16 (1H, dd, J = 10.0, 3.0 Hz), 4.90 (1H, dd, J =
9.4, 2.6 Hz), 4.70 (1H, dd, J = 10.1, 1.8 Hz), 3.
90 (1H, dd, J = 10.0, 1.8 Hz), 3.87-3.91 (1H, m),
3.78 (3H, s), 3.67-3.73 (1H, m), 3.61 (1H, ddd, J
= 10.1, 9.4, 7.4 Hz), 2.12 (3H, s), 2.08 (3H, s),
2.03-2.11 (1H, m), 2.00 (3H, s), 1.80-1.85 (1H,
m). [α]D 20 + 68.6 ° (c 0.30, CHClThree(Xii) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5-acetyl
Amino-4- (N, N'-bis-t-butyloxycarbonyl
G) Guanidino-6- (3 ', 4'-diacetoxy-tetra
Hydro-pyran-2'-yl) -5,6-dihydro-4H-py
Methyl lan-2-carboxylate Compound obtained in Example 4 (xi) (73 mg, 0.165 mmol)
Is dissolved in ethanol (30 ml) and rinsed under a nitrogen atmosphere.
Catalyst (20 mg) and then replaced with hydrogen
Then, the mixture was stirred at room temperature for 3 hours. The reaction solution was filtered through Celite and filtered.
The product was washed with methanol, and the filtrate and the washing were distilled off under reduced pressure.
The obtained residue was dissolved in dimethylformamide (1 ml),
N, N'-bis-t-butoxycarbonylthiourea (57 mg, 0.20
8 mmol), triethylamine (58 μl, 0.415 mmol),
Mercuric chloride (56 mg, 0.208 mmol) was added at room temperature.
The mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through celite and the residue was filtered.
Washed with ethyl acetate. The filtrate and washings were distilled off under reduced pressure.
The residue obtained is chromatographed (silica gel, hexane
/ Ethyl acetate = 1/1) to give the title compound as a colorless amorph
I got it as an ass. (100mg, 88%) IR (CDClThree) νmax: 2928, 2855, 1730, 1672, 1641, 16
06 cm-1MS (FAB) m / e 657 ([M + H]+). HRMS (FAB) Calcd for C29H44O13NFourNa: 679.2803; fou
nd 679.2826 ([M + Na]+).1 H NMR (400 MHz, CDThreeOD) δppm: 8.61 (1H, d, J = 8.
8 Hz), 6.68 (1H, d, J = 8.1 Hz), 5.83 (1H, d, J =
2.9 Hz), 5.56-5.60 (1H, m), 5.12-5.17 (2H, m), 4.27
(1H, ddd, J = 9.5, 8.8, 8.1 Hz), 4.02 (1H, d, J =
9.5 Hz), 3.92 (1H, dd, J = 11.7, 4.4 Hz), 3.85 (1
H, d, J = 10.3 Hz), 3.78 (3H, s), 3.69-3.73 (1H,
m), 2.10 (3H, s), 2.02-2.09 (1H, m), 2.02 (3H, s),
2.00 (3H, s), 1.76-1.82 (1H, m), 1.50 (18H, s). [Α]D 20 + 0.1 ° (c 0.45, CHClThree). (Xiii) (4S, 5R, 6
R, 2'S, 3'S, 4'R) -5-acetylamino-6- (3 ', 4'
-Diacetoxy-tetrahydro-pyran-2'-yl)-
5,6-dihydro-4-guanidino-4H-pyran-2-cal
Methyl bonate trifluoroacetate Compound obtained in Example 4 (xii) (330 mg, 0.502 mmo
l) in methylene chloride (3 ml) and dissolve in a nitrogen atmosphere.
Rifluoroacetic acid (1 ml) was added, and the mixture was stirred at room temperature for 3 hours.
After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to reverse phase chromatography.
Fee (Cosmosil, water / methanol = 2/1)
The title compound was obtained as a colorless amorphous. (240 mg, 83
%) IR (KBr) νmax: 3340, 3270, 3189, 1746, 1669, 155
0, 1439 cm-1MS (FAB) m / e 457 ([M + H]+). HRMS (FAB) Calcd for C19H29O9NFour : 457.1934; found
457.1957 ([M + H]+).1 H NMR (400 MHz, CDThreeOD) δppm: 5.84 (1H, d, J = 2.
9 Hz), 5.52-5.57 (1H, m), 5.12 (1H, dd, J = 10.3,
2.9 Hz), 4.50 (1H, d, J = 8.8, 2.9 Hz), 4.31 (1H,
dd, J = 9.5, 2.2 Hz), 4.16 (1H, dd, J = 9.5, 8.8 H
z), 3.96 (1H, dd, J = 10.3, 2.2 Hz), 3.85 (1H, ddd,
J = 11.7, 11.0, 4.4 Hz), 3.78 (3H, s), 3.64-3.72
(1H, m), 2.09 (3H, s), 1.99-2.08 (1H, m), 2.01 (3H,
(siv), 1.96 (3H, s), 1.78-1.85 (1H, m). (xiv) (4S, 5R, 6R, 2'R, 3'R, 4'R) -5-acetyl
Amino-5,6-dihydro-6- (3 ', 4'-dihydroxy
-Tetrahydro-pyran-2'-yl) -4-guanidino
-4H-pyran-2-carboxylic acid hydrate The compound obtained in Example 4 (xiii) (235 mg, 0.412 mmo
l) in methanol (3 ml) and add 1M
An aqueous thorium solution (1.65 ml, 1.65 mmol) was added, and the
Stir for 30 minutes. Next, Dowex 50W X8 (H+) Resin
In addition, the pH of the reaction solution was adjusted to 2. Immediately vacuum filtration
Then, the residue was washed with water. The filtrate and washings were distilled off under reduced pressure.
The obtained residue is subjected to reverse layer chromatography (Cosmosil,
Water). After distillation under reduced pressure, the obtained residue is ion-exchanged.
Chromatography (Dowex 50W (H+)resin,
Water, aqueous ammonia) to give the title compound as a colorless
Obtained as fass. (48mg, 83%) IR (KBr) νmax: 3351, 2962, 2927, 1666, 1619, 1403
cm-1MS (FAB) m / e 359 ([M + H]+). HRMS (FAB) Calcd for C14Htwenty threeO7NFour : 359.1566; found
359.1584 ([M + H]+).1 H NMR (400 MHz, DTwoO) δppm: 5.43 (1H, d, J = 2.2
Hz), 4.26 (1H, d, J = 9.5, 2.2 Hz), 4.14 (1H, dd, J
= 11.0, 1.5 Hz), 4.02-4.07 (1H, m), 4.00 (1H, dd,
J = 11.0, 9.5 Hz), 3.78 (1H, dd, J = 10.3, 2.9 H
z), 3.57 (1H, dd, J = 10.3, 1.5 Hz), 3.52-3.57 (1H,
m), 3.38-3.46 (1H, m), 1.69-1.79 (1H, m), 1.85 (3
H, s), 1.57-1.64 (1H, m). [Α]D 20 + 6.0 ° (c 0.40, HTwoO). (Example 5) (4S, 5R, 6R, 2'R, 3'R, 4'R) -5-acetylamino-
4-guanidino-5,6-dihydro-6- (3 ', 4'-dihydrido
Roxy-oxepane-2'-yl) -4H-pyran-2-ca
Rubonic acid trihydrate
【０２８９】[0289]
【化１７】 Embedded image
【０２９０】(i)5−アセチルアミノ−4−O−t−ブチル
ジメチルシリル−3，5−ジデオキシ−8，9−O−イソプ
ロピリデン−2−O−メチル−7−O−（4'−n−ペンテニ
ル）−D−グリセロ−D−ガラクト−ノン−2−エノピラ
ノソン酸メチル 5−アセチルアミノ−3，5−ジデオキシ−8，9−O−イソ
プロピリデン−2−O−メチル−4−O−t−ブチルジメチ
ルシリル−D−グリセロ−D−ガラクト−ノン−2−エノ
ピラノソン酸メチル(10 g, 20.3 mmol）（Zbiral, Eric
h; Phadtare, S.;Schmid, Walther; Liebigs Ann. Che
m., 1987年, (1), p39-43.に記載された化合物）を無水
ジメチルホルムアミド（60 ml）に溶解し、氷冷下水素
化ナトリウム (1.7 g, 40.6 mmol）を加え、室温で15分
攪拌した。続いて室温で1-ブロモ-ペンタ-4-エン（3.28
ｇ、22 mmol）を滴下し、室温で1時間撹拌した。反応液
を酢酸エチル（200 ml）と飽和塩化アンモニウム水溶液
（100 ml）に分配し、有機層を分離し、飽和食塩水（50
ml X 3）で洗浄し、硫酸ナトリウムで乾燥し、減圧留
去後、得られた残査をクロマトグラフィー（シリカゲ
ル、酢酸エチル/ヘキサン＝1/2）に付して標記化合物を
黄色オイルとして得た。（1.40g、12％） IR (CDCl3) νmax： 2931, 2859, 1746, 1684, 1514 cm
-1. MS (FAB) m/e 560 ([M+H]+). HRMS (FAB) Calcd for C27H49O9NSiNa : 582.3074; fou
nd 582.3070 ([M+Na]+).1 H NMR (400 MHz, CDCl3) δppm: 5.85 (1H, m), 5.18
(1H, d, J = 9.8 Hz),5.04 (1H, dd, J = 17.0, 1.6 H
z), 4.96 (1H, dd, J = 10.1, 1.6 Hz), 4.21-4.27 (1
H, m), 4.10-4.18 (2H, m), 4.02 (1H, dd, J = 8.4,
7.0 Hz), 3.95 (1H, dd, J = 9.3, 1.3 Hz), 3.79 (3H,
s), 3.60-3.75 (4H, m), 3.22 (3H, s),2.26 (1H, dd,
J = 12.7, 4.8 Hz), 2.10-2.18 (2H, m), 1.97 (3H,
s), 1.70-1.75 (3H, m), 1.41 (3H, s), 1.32 (3H, s),
0.86 (9H, s), 0.06 (3H, s), 0.05 (3H, s). (ii)4−O−アセチル−5−アセチルアミノ−3，5−ジデ
オキシ−2−O−メチル−7−O−（4'−n−ペンテニル）
−D−グリセロ−D−ガラクト−ノン−2−エノピラノソ
ン酸メチル 実施例５(i)で得られた化合物（1.4 g, 2.5 mmol）をテ
トラヒドロフラン（30ml）に溶解し、室温で１Mテトラ
ブチルアンモニウムフルオライド含有テトラヒドロフラ
ン（2.5 ml, 2.5 mmol）を加え、3時間撹拌した。反応
液を減圧留去し、得られた残査に無水酢酸（30ml）、ピ
リジン（30ml）を加え、室温で3時間攪拌した。反応液
を減圧留去後、トルエンで共沸した。得られた残査に酢
酸（30ml）、蒸留水（10ml）を加え、50℃で4時間撹拌
した。反応液を減圧留去後、トルエンで共沸した。得ら
れた残査をクロマトグラフィー（シリカゲル、塩化メチ
レン/メタノール＝20/1）に付して標記化合物を無色ア
モルファスとして得た。（0.89g、80％） IR (CDCl3)νmax： 3423, 2928, 2855, 1744, 1683, 16
42 cm-1. MS (FAB) m/e 448 ([M+H]+). HRMS (FAB) Calcd for C20H33O10NK : 486.1742; found
486.1738 ([M+K]+).1 H NMR (400 MHz, CDCl3) δppm: 5.84 (1H, dddd, J =
17.0, 10.1, 6.6, 6.6 Hz), 5.42 (1H, d, J = 9.8 H
z), 5.26 (1H, ddd, J = 11.7, 10.7, 5.0 Hz),5.03 (1
H, dd, J = 17.0, 1.6 Hz), 4.96 (1H, dd, J = 10.1,
1.6 Hz), 4.32(1H, ddd, J = 10.7, 10.7, 9.8 Hz), 3.
98-4.03 (1H, m), 3.90 (1H, d, J = 10.7, 1.6 Hz),
3.87 (1H, dd, J = 11.2, 3.6 Hz), 3.80 (3H, s), 3.7
5 (1H, d, J = 11.2, 4.9 Hz), 3.54-3.64 (2H, m), 3.
49 (1H, dd, J = 7.3, 1.6 Hz),3.29 (3H, s), 2.39 (1
H, dd, J = 12.8, 5.0 Hz), 2.12-2.18 (2H, m), 2.04
(3H, s), 1.94 (3H, s), 1.91 (1H, dd, J = 12.8, 11.
7 Hz), 1.67-1.75 (2H, m). (iii)4−O−アセチル−5−アセチルアミノ−3，5−ジデ
オキシ−2−O−メチル−7−O−（4'−n−ペンテニル）
−8，9−O−チオカルボニル−D−グリセロ−D−ガラク
ト−ノン−2−エノピラノソン酸メチル 窒素雰囲気下、実施例５(ii)で得られた化合物（0.82
g, 1.83 mmol）を塩化メチレン（30ml）に溶解し、4-ジ
メチルアミノピリジン（515 mg, 4.21 mmol）を加え、
氷冷下１Mチオホスゲン含有塩化メチレン（2.10 ml, 2.
10 mmol）を加え、氷冷下1時間撹拌した。反応液にメタ
ノールを加え、減圧留去して得られた残査をクロマトグ
ラフィー（シリカゲル、塩化メチレン/メタノール＝50/
1）に付して標記化合物を無色アモルファスとして得
た。（0.84g、94％） MS (FAB) m/e 490 ([M+H]+). HRMS (FAB) Calcd for C21H31O10NSK : 528.1306; foun
d 528.1320 ([M+K]+).1 H NMR (400 MHz, CDCl3) δppm: 5.83 (1H, dddd, J =
17.1, 10.2, 6.4, 6.4 Hz), 5.26-5.32 (3H, m), 5.04
(1H, dd, J = 17.1, 1.8 Hz), 4.94-5.02 (2H, m), 4.
75 (1H, dd, J = 8.0, 7.6 Hz), 4.26 (1H, ddd, J = 1
0.5, 10.4, 10.2 Hz), 3.98-4.00 (1H,m), 3.81 (3H,
s), 3.70 (1H, dd, J = 10.4, 2.1 Hz),3.65 (2H, t, J
= 6.5 Hz), 3.17 (3H, s), 2.43 (1H, dd, J = 12.9,
5.0 Hz),2.09-2.19 (2H, m), 2.05 (3H, s), 1.96 (3H,
s), 1.84 (1H, dd, J = 12.9,11.7 Hz), 1.68-1.80 (2
H, m). (iv)5−アセチルアミノ−2−O−メチル−7−O−（4'−n
−ペンテニル）−3，5，8，9−テトラデオキシ−D−グ
リセロ−D−ガラクト−ノン−2−エノピラノソン酸メチ
ル 窒素雰囲気下、実施例５(iii)で得られた化合物（0.83
g, 1.70 mmol）を亜リン酸トリメチル（30ml）に溶解
し、110℃で24時間撹拌した。反応液を減圧留去後、ト
ルエンで共沸した。得られた残査をメタノールに溶解
し、室温で4.9Mナトリウムメトキシド含有メタノール
（0.035ml、0.17mmol）を滴下し30分撹拌した。、次い
で４M塩酸含有ジオキサン溶液で中和し、反応液を減圧
留去後、得られた残査をクロマトグラフィー（シリカゲ
ル、酢酸エチル）に付して標記化合物を無色アモルファ
スとして得た。（0.30g、48％） IR (Liquid film) (CDCl3)νmax： 3366, 2955, 2939,
1751, 1660, 1535 cm- 1. MS (FAB) m/e 372 ([M+H]+). HRMS (FAB) Calcd for C18H30O7N : 372.2022; found 3
72.2011 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 6.69 (1H, s,br), 5.
82-5.90 (1H, m), 5.76-5.85 (1H, m), 5.35-5.40 (2H,
m), 4.99-5.06 (2H, m), 4.07-4.09 (1H, m),3.94-4.0
1 (1H, m), 3.79 (3H,s), 3.68 (1H, dd, J = 10.2, 2.
8 Hz), 3.63 (1H, ddd, J = 9.3, 6.6, 6.6 Hz), 3.55
(1H, ddd, J = 10.9, 10.3, 5.0 Hz),3.43 (1H, ddd, J
= 9.3, 6.4, 6.4 Hz), 3.24 (3H,s), 2.41 (1H, dd, J
= 13.4, 5.0 Hz), 2.11-2.18 (2H, m), 2.02 (3H, s),
1.68-1.75 (2H, m), 1.65 (1H, dd, J = 13.4, 10.9 H
z). (v)（2S, 4S, 5R, 6R, 2'R）−5−アセチルアミノ−4−
アセトキシ−6−（2', 5', 6', 7'−テトラヒドロ−オ
キセピン−2'−イル）−2−メトキシ−テトラヒドロ−
ピラン−2−カルボン酸メチル 窒素雰囲気下、実施例５(iv)で得られた化合物（0.27
g, 0.73mmol）を塩化メチレン(50 ml)に溶解し、ビス
（トリシクロヘキシルホスフィン）ベンジリデンルテニ
ウム（IV）ジクロライド（8 mg）を加え、室温で24時間
撹拌した。反応液を減圧留去後、得られた残査をクロマ
トグラフィー（シリカゲル、酢酸エチル）に付して標記
化合物を無色アモルファスとして得た。（0.25g、99
％） IR (Liquid film) (CDCl3)νmax： 3359, 2930, 2856,
1751, 1658, 1537 cm- 1. MS (FAB) m/e 344 ([M+H]+). HRMS (FAB) Calcd for C16H26O7N : 344.1709; found 3
44.1699 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 6.86 (1H, s,br), 5.
91-5.99 (1H, m), 5.71-5.77 (1H, m),5.54-5.57 (1H,
m), 4.40-4.44 (1H, m), 4.07-4.14 (1H, m),3.94-4.01
(1H, m), 3.79 (3H, s), 3.62-3.72 (3H, m), 3.25 (3
H, s), 2.44 (1H, dd, J = 13.5, 5.2 Hz), 2.34-2.42
(1H, m), 2.15-2.26 (1H, m), 2.01 (3H, s), 1.89-2.
00 (1H, m), 1.73-1.86 (1H, m),1.69 (1H, dd, J = 1
3.5, 11.0 Hz). (vi)（2S, 4S, 5R, 6R, 2'R）−5−アセチルアミノ−4
−アセトキシ−6−（3'，4'−ジヒドロキシ−オキセパ
ン−2'−イル）−2−メトキシ−3，5，6−トリヒドロ−
4H−ピラン−2−カルボン酸メチル 実施例５(v)で得られた化合物（0.30 g, 0.87mmol）を
アセトン(10 ml)に溶解し、t-ブタノール(2 ml)、N-メ
チルモルホリンN−オキシド50％水溶液（225 mg,0.96mm
ol）を室温で加えたのち、氷冷下四酸化オスミウム（1m
g, 0.004 mmol）を加え、溶液を氷冷下2時間撹拌した。
反応液を減圧留去し、得られた残査をクロマトグラフィ
ー（シリカゲル、塩化メチレン/メタノール＝10/1）に
付して標記化合物を無色アモルファスとして得た。（0.
30g、91％） MS (FAB) m/e 378 ([M+H]+). HRMS (FAB) Calcd for C16H27O9NNa : 400.1583; found
400.1562 ([M+Na]+).1 H NMR (400 MHz, CD3OD) δppm: 3.86-4.03 (5H, m),
3.77 (3H, s), 3.76-3.79 (1H, m), 3.46-3.54 (1H,
m), 3.41 (1H, dd, J = 8.2, 1.5 Hz), 3.34 (3H, s),
2.31 (1H, dd, J = 12.9, 4.9 Hz), 1.99 (3H, s), 1.8
5 (1H, dd, J = 12.9, 11.0 Hz), 1.62-1.70 (4H, m). (vii)（4S, 5R, 6R, 2'S, 3'S, 4'R）−5−アセチルア
ミノ−4−アジド−5，6−ジヒドロ−6−（3'，4'−ジア
セトキシ−オキセパン−2'−イル）−4H−ピラン−2−
カルボン酸メチル 窒素雰囲気下、実施例５(vi)で得られた化合物（0.30
g, 0.795mmol）を無水酢酸（3 ml）に溶解し、酢酸（0.
3 ml）、硫酸（0.3 ml）を室温で加え、同温で12時間撹
拌した。反応液を氷冷下酢酸エチル（30ml）と飽和炭酸
水素ナトリウム水溶液（30ml）に分配した。有機層を分
離し、食塩水（20ml）で洗浄し、硫酸ナトリウムで乾燥
し、減圧留去後、トルエンで共沸した。得られた残査を
ジメチルホルムアミド（0.3 ml）に溶解し、アジ化ナト
リウム（200 mg）、ダウエックス50W（H+）樹脂（200 m
g）を加え、60℃で6時間撹拌した。反応液を減圧濾過
し、濾物をメタノールで洗浄した。濾液、洗液を減圧留
去後、得られた残査をクロマトグラフィー（シリカゲ
ル、塩化メチレン/メタノール＝20/1）に付して標記化
合物を無色アモルファスとして得た。（130mg、36％） IR (Liquid film) (CDCl3)νmax： 3282, 2955, 2098,
1740, 1662, 1545 cm- 1. MS (FAB) m/e 455 ([M+H]+). HRMS (FAB) Calcd for C19H27O9N4 : 455.1778; found
455.1773 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 5.93 (1H, d, J = 2.
6 Hz), 5.71 (1H, d,J = 8.0 Hz), 5.44 (1H, ddd, J =
9.3, 3.9, 2.1 Hz), 5.37 (1H, dd, J = 5.8, 2.1 H
z), 4.61 (1H, dd, J = 9.3, 2.6 Hz), 4.58 (1H, dd,
J = 10.1, 2.2 Hz), 4.07 (1H, ddd, J = 10.1, 9.3,
8.0 Hz), 4.04-4.10 (1H, m), 3.78 (3H,s), 3.70 (1H,
dd, J = 5.8, 2.2 Hz), 3.49 (1H, ddd, J = 12.2, 8.
6, 3.9 Hz), 2.08 (3H, s), 2.06 (3H, s), 2.05 (3H,
s), 1.75-1.88 (4H, m). (viii)（4S, 5R, 6R, 2'S, 3'S, 4'R）−5−アセチルア
ミノ−4−アミノ−5，6−ジヒドロ−6−（3'，4'−ジア
セトキシ−オキセパン−2'−イル）−4H−ピラン−2−
カルボン酸メチル 実施例５(vii)で得られた化合物（0.13 g, 0.286mmo
l）をエタノール（30 ml）に溶解し、窒素雰囲気下リン
ドラー触媒（50mg）を加え、次いで水素雰囲気に置換
し、室温で3時間攪拌した。反応液をセライト濾過し濾
物をメタノールで洗浄した。濾液、洗液を減圧留去後得
られた残査をクロマトグラフィー（シリカゲル、塩化メ
チレン/メタノール＝10/1）に付して標記化合物を無色
アモルファスとして得た。（100mg、81％） IR (Liquid film) (CDCl3)νmax： 2928, 1736, 1682,
1511 cm-1. MS (FAB) m/e 429 ([M+H]+). HRMS (FAB) Calcd for C19H28O9N2K : 467.1432; found
467.1407 ([M+K]+).1 H NMR (400 MHz, CDCl3) δppm: 5.93 (1H, d, J = 2.
5 Hz), 5.55 (1H, d,br, J = 8.8 Hz), 5.44 (1H, m),
5.36 (1H, dd, J = 5.6, 2.2 Hz), 4.22 (1H,dd, J = 1
0.1, 1.8 Hz), 4.08 (1H, ddd, J = 12.2, 5.1, 4.8 H
z), 3.95 (1H,ddd, J = 10.1, 8.8, 8.7 Hz), 3.76 (3
H, s), 3.67 (1H, dd, J = 5.6, 1.8 Hz), 3.62 (1H, d
d, J = 8.7, 2.5 Hz ), 3.45 (1H, ddd, J = 12.2, 8.
6, 3.9 Hz), 2.09 (3H, s), 2.07 (3H, s), 2.05-2.10
(1H, m), 2.05 (3H, s), 1.75-1.88 (3H, m). (ix)（4S, 5R, 6R, 2'S, 3'S, 4'R）−5−アセチルアミ
ノ−4−（N，N'−ビス−t−ブチルオキシカルボニル）
グアニジノ−5，6−ジヒドロ−6−（3'，4'−ジアセト
キシ−オキセパン−2'−イル）−4H−ピラン−2−カル
ボン酸メチル 実施例５(viii)で得られた化合物（92mg, 0.214mmol）
をジメチルホルムアミド(1 ml)に溶解し、N,N'-ビス-t-
ブトキシカルボニルチオ尿素(71 mg, 0.257 mmol)、ト
リエチルアミン（72 μl, 0.514 mmol）、塩化第二水銀
（70 mg, 0.257mmol）を加え、室温で2時間攪拌した。
反応液をセライト濾過し濾物を酢酸エチルで洗浄した。
濾液、洗液を減圧留去後、得られた残査をクロマトグラ
フィー（シリカゲル、ヘキサン/酢酸エチル＝1/1）に付
して標記化合物を無色アモルファスとして得た。（135m
g、94％） IR (Liquid film) (CDCl3)νmax： 2928, 1730, 1687,
1640, 1606, 1568 cm- 1. MS (FAB) m/e 671 ([M+H]+). HRMS (FAB) Calcd for C30H47O13N4 : 671.3140; found
671.3146 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 8.55 (1H, d, br, J
= 8.7 Hz), 6.45 (1H,d, J = 8.2 Hz), 5.82 (1H, d, J
= 2.4 Hz), 5.47 (1H, ddd, J = 9.5, 2.5,1.8 Hz),
5.34 (1H, dd, J = 5.8, 2.5 Hz), 5.10 (1H, ddd, J =
9.4, 8.7, 2.5 Hz), 4.32 (1H, ddd, J = 10.0, 8.7,
8.2 Hz), 4.08-4.13 (1H, m), 4.07 (1H, dd, J = 10.
0, 0.9 Hz), 3.78 (3H, s), 3.61 (1H, dd, J = 5.8,
0.9 Hz),3.49 (1H, ddd, J = 12.2, 8.6, 3.9 Hz), 2.0
9 (3H, s), 2.05 (3H, s), 2.03-2.10 (1H, m), 1.96
(3H, s), 1.80-1.88 (2H, m), 1.70-1.77 (1H, m), 1.4
9 (9H, s), 1.49 (9H, s). （x）（4S, 5R, 6R, 2'S, 3'S, 4'R）−5−アセチルア
ミノ−6−（3'，4'−ジアセトキシ−オキセパン−2'−
イル）−5，6−ジヒドロ−4−グアニジノ−4H−ピラン
−2−カルボン酸メチル トリフルオロ酢酸塩 実施例５(ix)で得られた化合物（130mg, 0.194mmol）を
塩化メチレン（3 ml）に溶解し、窒素雰囲気下トリフル
オロ酢酸（1ml）を加え、室温で3時間攪拌した。反応液
を減圧留去後、得られた残査を逆層クロマトグラフィー
（コスモシル、水/メタノール＝1/1）に付して標記化合
物を無色アモルファスとして得た。（78mg、69％） IR (KBr)νmax： 3341, 3267, 3188, 2957, 1740, 166
9, 1549, cm-1. MS (FAB) m/e 471 ([M+H]+). HRMS (FAB) Calcd for C20H30O9N4K : 509.1650; found
509.1668 ([M+K]+).1 H NMR (500 MHz, CD3OD) δppm: 5.84 (1H, d, J = 2.
5 Hz), 5.39 (1H, ddd, J = 9.5, 4.4, 2.3 Hz), 5.35
(1H, dd, J = 5.9, 2.3 Hz), 4.40-4.45 (1H,m), 4.30
(1H, dd, J = 9.5, 2.3 Hz), 4.27 (1H, dd, J = 9.5,
8.6 Hz), 3.98(1H, ddd, J = 12.4, 5.5, 5.0 Hz), 3.7
8 (1H, dd, J = 5.9, 2.3 Hz), 3.77(3H, s), 3.46 (1
H, ddd, J = 12.4, 8.5, 4.2 Hz), 2.04-2.16 (3H, m),
2.05(3H, s), 2.03 (3H, s), 2.00 (3H, s), 1.75-1.8
8 (3H, m). (xi)（4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルアミ
ノ−5，6−ジヒドロ−6−（3'，4'−ジヒドロキシ−オ
キセパン−2'−イル）−4−グアニジノ−4H−ピラン−2
−カルボン酸、トリフルオロ酢酸塩 実施例５(x)で得られた化合物（70mg, 0.120mmol）をメ
タノール（3 ml）に溶解し、室温で1M水酸化ナトリウム
水溶液（0.479ml, 0.479mmol）を加え、室温で30分攪拌
した。次いでダウエックス50W X8（H+）樹脂を加え、反
応液のpHを2に調整した。ただちに減圧濾過し、水で濾
物を洗浄した。濾液、洗液を減圧留去後、得られた残査
を逆層クロマトグラフィー（コスモシル、水）に付して
標記化合物を無色アモルファスとして得た。（48mg、83
％） IR (Liquid film) (CDCl3)νmax： 2928, 1736, 1682,
1511 cm-1. MS (FAB) m/e 373 ([M+H]+). HRMS (FAB) Calcd for C15H25O7N4 : 373.1724; found
373.1716 ([M+H]+).1 H NMR (500 MHz, CD3OD) δppm: 5.84 (1H, d, J = 2.
6 Hz), 4.39 (1H, dd,J = 8.8, 2.6 Hz), 4.36 (1H, d
d, J = 9.7, 1.5 Hz), 4.30 (1H, dd, J = 9.7, 8.8 H
z), 4.01-4.07 (2H, m), 3.86 (1H, ddd, J = 12.3,
6.2, 6.2 Hz), 3.61 (1H, dd, J = 8.5, 1.5 Hz), 3.44
(1H, ddd, J = 12.3, 7.5, 5.7 Hz), 2.00 (3H, s),
1.87-2.02 (2H, m), 1.59-1.72 (2H, m). (xii)（4S, 5R, 6R, 2'R, 3'R, 4'R）−5―アセチルア
ミノ―5，6―ジヒドロ―6―（3'，4'−ジヒドロキシ―
オキセパン−2'−イル）―4―グアニジノ―4H―ピラン
−2―カルボン酸、三水和物 実施例５(xi)で得られた化合物（35 mg, 0.072 mmol）
をイオン交換クロマトグラフィー（ダウエックス50Ｗ
（H+）樹脂、水、アンモニア水）に付して、凍結乾燥
後、標記化合物を無色アモルファスとして得た。（24m
g、85％）1 H NMR (500 MHz, CD3OD) δppm： 5.51 (1H, d, J =
2.6 Hz), 4.31 (1H, dd, J = 8.8, 2.6 Hz), 4.20 (1H,
dd, J = 9.7, 1.5 Hz), 4.11 (1H, dd, J = 9.7, 8.8
Hz), 3.98-4.02 (2H, m), 3.82 (1H, ddd, J = 12.3,
6.2, 6.2 Hz), 3.53 (1H, dd, J = 8.5, 1.5 Hz), 3.28
(1H, ddd, J = 12.3, 7.5, 5.7 Hz), 1.94 (3H, s),
1.72-1.91 (2H, m), 1.55-1.62 (2H, m). （実施例６） （4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルアミノ−
5，6−ジヒドロ−6−（3'，4'−ジヒドロキシ−テトラ
ヒドロ−ピラン−2'−イル）−4−グアニジノ−4H−ピ
ラン−2−カルボン酸オクタニル トリフルオロ酢酸塩(I) 5-Acetylamino-4-O-t-butyldimethylsilyl-3,5-dideoxy-8,9-O-isopropylidene-2-O-methyl-7-O- (4'- n-pentenyl) -D-glycero-D-galacto-none-2-enopyranosonic acid methyl 5-acetylamino-3,5-dideoxy-8,9-O-isopropylidene-2-O-methyl-4-O- Methyl t-butyldimethylsilyl-D-glycero-D-galacto-non-2-enopyranosonate (10 g, 20.3 mmol) (Zbiral, Eric
h; Phadtare, S .; Schmid, Walther; Liebigs Ann. Che
m., 1987, (1), p39-43.) was dissolved in anhydrous dimethylformamide (60 ml), sodium hydride (1.7 g, 40.6 mmol) was added under ice-cooling, and the mixture was added at room temperature. Stir for 15 minutes. Subsequently, 1-bromo-penta-4-ene (3.28
g, 22 mmol) was added dropwise and stirred at room temperature for 1 hour. The reaction solution was partitioned between ethyl acetate (200 ml) and a saturated aqueous solution of ammonium chloride (100 ml), and the organic layer was separated.
ml 3), dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was chromatographed (silica gel, ethyl acetate / hexane = 1/2) to give the title compound as a yellow oil. Was. (1.40 g, 12%) IR (CDCl 3 ) νmax: 2931, 2859, 1746, 1684, 1514 cm
-1 . MS (FAB) m / e 560 ([M + H] + ). HRMS (FAB) Calcd for C 27 H 49 O 9 NSiNa: 582.3074; fou
nd 582.3070 ([M + Na] +) 1 H NMR (400 MHz, CDCl 3) δppm:. 5.85 (1H, m), 5.18
(1H, d, J = 9.8 Hz), 5.04 (1H, dd, J = 17.0, 1.6 H
z), 4.96 (1H, dd, J = 10.1, 1.6 Hz), 4.21-4.27 (1
H, m), 4.10-4.18 (2H, m), 4.02 (1H, dd, J = 8.4,
7.0 Hz), 3.95 (1H, dd, J = 9.3, 1.3 Hz), 3.79 (3H,
s), 3.60-3.75 (4H, m), 3.22 (3H, s), 2.26 (1H, dd,
J = 12.7, 4.8 Hz), 2.10-2.18 (2H, m), 1.97 (3H,
s), 1.70-1.75 (3H, m), 1.41 (3H, s), 1.32 (3H, s),
0.86 (9H, s), 0.06 (3H, s), 0.05 (3H, s). (Ii) 4-O-acetyl-5-acetylamino-3,5-dideoxy-2-O-methyl-7-O -(4'-n-pentenyl)
-Methyl -D-glycero-D-galacto-non-2-enopyranosonate The compound (1.4 g, 2.5 mmol) obtained in Example 5 (i) was dissolved in tetrahydrofuran (30 ml), and 1M tetrabutylammonium fluoride was added at room temperature. Ride-containing tetrahydrofuran (2.5 ml, 2.5 mmol) was added, and the mixture was stirred for 3 hours. The reaction solution was evaporated under reduced pressure, acetic anhydride (30 ml) and pyridine (30 ml) were added to the obtained residue, and the mixture was stirred at room temperature for 3 hours. After the reaction solution was distilled off under reduced pressure, the residue was azeotropically distilled with toluene. Acetic acid (30 ml) and distilled water (10 ml) were added to the obtained residue, and the mixture was stirred at 50 ° C for 4 hours. After the reaction solution was distilled off under reduced pressure, the residue was azeotropically distilled with toluene. The obtained residue was subjected to chromatography (silica gel, methylene chloride / methanol = 20/1) to give the title compound as a colorless amorphous. (0.89 g, 80%) IR (CDCl 3 ) νmax: 3423, 2928, 2855, 1744, 1683, 16
42 cm -1 .MS (FAB) m / e 448 ([M + H] + ) .HRMS (FAB) Calcd for C 20 H 33 O 10 NK: 486.1742; found
. 486.1738 ([M + K] +) 1 H NMR (400 MHz, CDCl 3) δppm: 5.84 (1H, dddd, J =
17.0, 10.1, 6.6, 6.6 Hz), 5.42 (1H, d, J = 9.8 H
z), 5.26 (1H, ddd, J = 11.7, 10.7, 5.0 Hz), 5.03 (1
H, dd, J = 17.0, 1.6 Hz), 4.96 (1H, dd, J = 10.1,
1.6 Hz), 4.32 (1H, ddd, J = 10.7, 10.7, 9.8 Hz), 3.
98-4.03 (1H, m), 3.90 (1H, d, J = 10.7, 1.6 Hz),
3.87 (1H, dd, J = 11.2, 3.6 Hz), 3.80 (3H, s), 3.7
5 (1H, d, J = 11.2, 4.9 Hz), 3.54-3.64 (2H, m), 3.
49 (1H, dd, J = 7.3, 1.6 Hz), 3.29 (3H, s), 2.39 (1
H, dd, J = 12.8, 5.0 Hz), 2.12-2.18 (2H, m), 2.04
(3H, s), 1.94 (3H, s), 1.91 (1H, dd, J = 12.8, 11.
(7 Hz), 1.67-1.75 (2H, m). (Iii) 4-O-acetyl-5-acetylamino-3,5-dideoxy-2-O-methyl-7-O- (4'-n-pentenyl )
Methyl -8,9-O-thiocarbonyl-D-glycero-D-galacto-non-2-enopyranosonate The compound obtained in Example 5 (ii) (0.82
g, 1.83 mmol) in methylene chloride (30 ml) and 4-dimethylaminopyridine (515 mg, 4.21 mmol) was added.
1M thiophosgene-containing methylene chloride (2.10 ml, 2.
10 mmol) and stirred for 1 hour under ice cooling. Methanol was added to the reaction solution, and the residue obtained by evaporation under reduced pressure was subjected to chromatography (silica gel, methylene chloride / methanol = 50 /
By subjecting it to 1), the title compound was obtained as a colorless amorphous. (0.84 g, 94%) MS (FAB) m / e 490 ([M + H] + ). HRMS (FAB) Calcd for C 21 H 31 O 10 NSK: 528.1306; foun
d 528.1320 ([M + K] +) 1 H NMR (400 MHz, CDCl 3) δppm:. 5.83 (1H, dddd, J =
17.1, 10.2, 6.4, 6.4 Hz), 5.26-5.32 (3H, m), 5.04
(1H, dd, J = 17.1, 1.8 Hz), 4.94-5.02 (2H, m), 4.
75 (1H, dd, J = 8.0, 7.6 Hz), 4.26 (1H, ddd, J = 1
0.5, 10.4, 10.2 Hz), 3.98-4.00 (1H, m), 3.81 (3H,
s), 3.70 (1H, dd, J = 10.4, 2.1 Hz), 3.65 (2H, t, J
= 6.5 Hz), 3.17 (3H, s), 2.43 (1H, dd, J = 12.9,
5.0 Hz), 2.09-2.19 (2H, m), 2.05 (3H, s), 1.96 (3H,
s), 1.84 (1H, dd, J = 12.9,11.7 Hz), 1.68-1.80 (2
H, m). (Iv) 5-acetylamino-2-O-methyl-7-O- (4'-n
-Pentenyl) -3,5,8,9-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosonic acid methyl compound obtained in Example 5 (iii) under nitrogen atmosphere (0.83
g, 1.70 mmol) was dissolved in trimethyl phosphite (30 ml) and stirred at 110 ° C. for 24 hours. After the reaction solution was distilled off under reduced pressure, the residue was azeotropically distilled with toluene. The obtained residue was dissolved in methanol, and methanol (0.035 ml, 0.17 mmol) containing 4.9 M sodium methoxide was added dropwise at room temperature, and the mixture was stirred for 30 minutes. Then, the mixture was neutralized with a 4M hydrochloric acid-containing dioxane solution, the reaction solution was distilled off under reduced pressure, and the obtained residue was subjected to chromatography (silica gel, ethyl acetate) to obtain the title compound as a colorless amorphous. (0.30 g, 48%) IR (Liquid film) (CDCl 3 ) νmax: 3366, 2955, 2939,
.. 1751, 1660, 1535 cm - 1 MS (FAB) m / e 372 ([M + H] +) HRMS (FAB) Calcd for C 18 H 30 O 7 N: 372.2022; found 3
72.2011 ([M + H] + ). 1 H NMR (400 MHz, CDCl 3 ) δppm: 6.69 (1H, s, br), 5.
82-5.90 (1H, m), 5.76-5.85 (1H, m), 5.35-5.40 (2H, m
m), 4.99-5.06 (2H, m), 4.07-4.09 (1H, m), 3.94-4.0
1 (1H, m), 3.79 (3H, s), 3.68 (1H, dd, J = 10.2, 2.
8 Hz), 3.63 (1H, ddd, J = 9.3, 6.6, 6.6 Hz), 3.55
(1H, ddd, J = 10.9, 10.3, 5.0 Hz), 3.43 (1H, ddd, J
= 9.3, 6.4, 6.4 Hz), 3.24 (3H, s), 2.41 (1H, dd, J
= 13.4, 5.0 Hz), 2.11-2.18 (2H, m), 2.02 (3H, s),
1.68-1.75 (2H, m), 1.65 (1H, dd, J = 13.4, 10.9 H
z). (v) (2S, 4S, 5R, 6R, 2'R) -5-acetylamino-4-
Acetoxy-6- (2 ', 5', 6 ', 7'-tetrahydro-oxepin-2'-yl) -2-methoxy-tetrahydro-
Methyl pyran-2-carboxylate The compound obtained in Example 5 (iv) (0.27
g, 0.73 mmol) was dissolved in methylene chloride (50 ml), bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride (8 mg) was added, and the mixture was stirred at room temperature for 24 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to chromatography (silica gel, ethyl acetate) to obtain the title compound as a colorless amorphous. (0.25g, 99
%) IR (Liquid film) (CDCl 3 ) νmax: 3359, 2930, 2856,
1751, 1658, 1537 cm - 1 . MS (FAB) m / e 344 ([M + H] + ) .HRMS (FAB) Calcd for C 16 H 26 O 7 N: 344.1709; found 3
. 44.1699 ([M + H] +) 1 H NMR (400 MHz, CDCl 3) δppm: 6.86 (1H, s, br), 5.
91-5.99 (1H, m), 5.71-5.77 (1H, m), 5.54-5.57 (1H,
m), 4.40-4.44 (1H, m), 4.07-4.14 (1H, m), 3.94-4.01
(1H, m), 3.79 (3H, s), 3.62-3.72 (3H, m), 3.25 (3
H, s), 2.44 (1H, dd, J = 13.5, 5.2 Hz), 2.34-2.42
(1H, m), 2.15-2.26 (1H, m), 2.01 (3H, s), 1.89-2.
00 (1H, m), 1.73-1.86 (1H, m), 1.69 (1H, dd, J = 1
(Vi) (2S, 4S, 5R, 6R, 2'R) -5-acetylamino-4
-Acetoxy-6- (3 ', 4'-dihydroxy-oxepan-2'-yl) -2-methoxy-3,5,6-trihydro-
4H-Methyl pyran-2-carboxylate The compound obtained in Example 5 (v) (0.30 g, 0.87 mmol) was dissolved in acetone (10 ml), and t-butanol (2 ml) and N-methylmorpholine N were dissolved. -50% aqueous solution of oxide (225 mg, 0.96 mm
ol) at room temperature, and then add osmium tetroxide (1m
g, 0.004 mmol) and the solution was stirred for 2 hours under ice cooling.
The reaction solution was distilled off under reduced pressure, and the obtained residue was subjected to chromatography (silica gel, methylene chloride / methanol = 10/1) to obtain the title compound as a colorless amorphous. (0.
MS (FAB) m / e 378 ([M + H] + ). HRMS (FAB) Calcd for C 16 H 27 O 9 NNa: 400.1583; found
. 400.1562 ([M + Na] +) 1 H NMR (400 MHz, CD 3 OD) δppm: 3.86-4.03 (5H, m),
3.77 (3H, s), 3.76-3.79 (1H, m), 3.46-3.54 (1H,
m), 3.41 (1H, dd, J = 8.2, 1.5 Hz), 3.34 (3H, s),
2.31 (1H, dd, J = 12.9, 4.9 Hz), 1.99 (3H, s), 1.8
5 (1H, dd, J = 12.9, 11.0 Hz), 1.62-1.70 (4H, m). (Vii) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5-acetylamino-4-azide -5,6-dihydro-6- (3 ', 4'-diacetoxy-oxepan-2'-yl) -4H-pyran-2-
Methyl carboxylate The compound obtained in Example 5 (vi) (0.30
g, 0.795 mmol) was dissolved in acetic anhydride (3 ml), and acetic acid (0.
3 ml) and sulfuric acid (0.3 ml) were added at room temperature, and the mixture was stirred at the same temperature for 12 hours. The reaction solution was partitioned between ethyl acetate (30 ml) and a saturated aqueous sodium hydrogen carbonate solution (30 ml) under ice cooling. The organic layer was separated, washed with brine (20 ml), dried over sodium sulfate, evaporated in vacuo and azeotroped with toluene. The obtained residue was dissolved in dimethylformamide (0.3 ml), sodium azide (200 mg), Dowex 50W (H + ) resin (200 m
g) was added and stirred at 60 ° C. for 6 hours. The reaction solution was filtered under reduced pressure, and the residue was washed with methanol. After the filtrate and washings were distilled off under reduced pressure, the resulting residue was subjected to chromatography (silica gel, methylene chloride / methanol = 20/1) to obtain the title compound as a colorless amorphous. (130mg, 36%) IR (Liquid film) (CDCl 3 ) νmax: 3282, 2955, 2098,
1740, 1662, 1545 cm - 1 . MS (FAB) m / e 455 ([M + H] + ) .HRMS (FAB) Calcd for C 19 H 27 O 9 N 4 : 455.1778; found
. 455.1773 ([M + H] +) 1 H NMR (400 MHz, CDCl 3) δppm: 5.93 (1H, d, J = 2.
6 Hz), 5.71 (1H, d, J = 8.0 Hz), 5.44 (1H, ddd, J =
9.3, 3.9, 2.1 Hz), 5.37 (1H, dd, J = 5.8, 2.1 H
z), 4.61 (1H, dd, J = 9.3, 2.6 Hz), 4.58 (1H, dd,
J = 10.1, 2.2 Hz), 4.07 (1H, ddd, J = 10.1, 9.3,
8.0 Hz), 4.04-4.10 (1H, m), 3.78 (3H, s), 3.70 (1H,
dd, J = 5.8, 2.2 Hz), 3.49 (1H, ddd, J = 12.2, 8.
6, 3.9 Hz), 2.08 (3H, s), 2.06 (3H, s), 2.05 (3H,
(s), 1.75-1.88 (4H, m). (viii) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5-acetylamino-4-amino-5,6-dihydro-6- (3 ', 4'-diacetoxy-oxepane-2'-yl) -4H-pyran-2-
Methyl carboxylate The compound obtained in Example 5 (vii) (0.13 g, 0.286 mmo)
l) was dissolved in ethanol (30 ml), Lindlar catalyst (50 mg) was added under a nitrogen atmosphere, and then the atmosphere was replaced with a hydrogen atmosphere, followed by stirring at room temperature for 3 hours. The reaction solution was filtered through celite, and the residue was washed with methanol. The residue obtained after evaporating the filtrate and the washings under reduced pressure was subjected to chromatography (silica gel, methylene chloride / methanol = 10/1) to obtain the title compound as a colorless amorphous. (100mg, 81%) IR (Liquid film) (CDCl 3 ) νmax: 2928, 1736, 1682,
1511 cm -1 .MS (FAB) m / e 429 ([M + H] + ) .HRMS (FAB) Calcd for C 19 H 28 O 9 N 2 K: 467.1432; found
. 467.1407 ([M + K] +) 1 H NMR (400 MHz, CDCl 3) δppm: 5.93 (1H, d, J = 2.
5 Hz), 5.55 (1H, d, br, J = 8.8 Hz), 5.44 (1H, m),
5.36 (1H, dd, J = 5.6, 2.2 Hz), 4.22 (1H, dd, J = 1
0.1, 1.8 Hz), 4.08 (1H, ddd, J = 12.2, 5.1, 4.8 H
z), 3.95 (1H, ddd, J = 10.1, 8.8, 8.7 Hz), 3.76 (3
H, s), 3.67 (1H, dd, J = 5.6, 1.8 Hz), 3.62 (1H, d
d, J = 8.7, 2.5 Hz), 3.45 (1H, ddd, J = 12.2, 8.
6, 3.9 Hz), 2.09 (3H, s), 2.07 (3H, s), 2.05-2.10
(1H, m), 2.05 (3H, s), 1.75-1.88 (3H, m). (Ix) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5-acetylamino-4- (N , N'-bis-t-butyloxycarbonyl)
Guanidino-5,6-dihydro-6- (3 ′, 4′-diacetoxy-oxepan-2′-yl) -4H-pyran-2-carboxylate methyl compound The compound obtained in Example 5 (viii) (92 mg, 0.214mmol)
Was dissolved in dimethylformamide (1 ml) and N, N'-bis-t-
Butoxycarbonylthiourea (71 mg, 0.257 mmol), triethylamine (72 μl, 0.514 mmol) and mercuric chloride (70 mg, 0.257 mmol) were added, and the mixture was stirred at room temperature for 2 hours.
The reaction solution was filtered through celite, and the residue was washed with ethyl acetate.
After the filtrate and washings were distilled off under reduced pressure, the resulting residue was subjected to chromatography (silica gel, hexane / ethyl acetate = 1/1) to give the title compound as a colorless amorphous. (135m
g, 94%) IR (Liquid film) (CDCl 3 ) νmax: 2928, 1730, 1687,
1640, 1606, 1568 cm - 1 . MS (FAB) m / e 671 ([M + H] + ) .HRMS (FAB) Calcd for C 30 H 47 O 13 N 4 : 671.3140; found
671.3146 ([M + H] + ). 1 H NMR (400 MHz, CDCl 3 ) δppm: 8.55 (1H, d, br, J
= 8.7 Hz), 6.45 (1H, d, J = 8.2 Hz), 5.82 (1H, d, J
= 2.4 Hz), 5.47 (1H, ddd, J = 9.5, 2.5, 1.8 Hz),
5.34 (1H, dd, J = 5.8, 2.5 Hz), 5.10 (1H, ddd, J =
9.4, 8.7, 2.5 Hz), 4.32 (1H, ddd, J = 10.0, 8.7,
8.2 Hz), 4.08-4.13 (1H, m), 4.07 (1H, dd, J = 10.
0, 0.9 Hz), 3.78 (3H, s), 3.61 (1H, dd, J = 5.8,
0.9 Hz), 3.49 (1H, ddd, J = 12.2, 8.6, 3.9 Hz), 2.0
9 (3H, s), 2.05 (3H, s), 2.03-2.10 (1H, m), 1.96
(3H, s), 1.80-1.88 (2H, m), 1.70-1.77 (1H, m), 1.4
9 (9H, s), 1.49 (9H, s). (X) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5-acetylamino-6- (3 ', 4'-diacetoxy-oxepane −2'−
Yl) -5,6-Dihydro-4-guanidino-4H-pyran-2-carboxylic acid methyl trifluoroacetate The compound (130 mg, 0.194 mmol) obtained in Example 5 (ix) was methylene chloride (3 ml). And trifluoroacetic acid (1 ml) was added under a nitrogen atmosphere, followed by stirring at room temperature for 3 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to reverse layer chromatography (Cosmosil, water / methanol = 1/1) to obtain the title compound as a colorless amorphous. (78 mg, 69%) IR (KBr) νmax: 3341, 3267, 3188, 2957, 1740, 166
.. 9, 1549, cm -1 MS (FAB) m / e 471 ([M + H] +) HRMS (FAB) Calcd for C 20 H 30 O 9 N 4 K: 509.1650; found
. 509.1668 ([M + K] +) 1 H NMR (500 MHz, CD 3 OD) δppm: 5.84 (1H, d, J = 2.
5 Hz), 5.39 (1H, ddd, J = 9.5, 4.4, 2.3 Hz), 5.35
(1H, dd, J = 5.9, 2.3 Hz), 4.40-4.45 (1H, m), 4.30
(1H, dd, J = 9.5, 2.3 Hz), 4.27 (1H, dd, J = 9.5,
8.6 Hz), 3.98 (1H, ddd, J = 12.4, 5.5, 5.0 Hz), 3.7
8 (1H, dd, J = 5.9, 2.3 Hz), 3.77 (3H, s), 3.46 (1
H, ddd, J = 12.4, 8.5, 4.2 Hz), 2.04-2.16 (3H, m),
2.05 (3H, s), 2.03 (3H, s), 2.00 (3H, s), 1.75-1.8
8 (3H, m). (Xi) (4S, 5R, 6R, 2'R, 3'R, 4'R) -5-acetylamino-5,6-dihydro-6- (3 ', 4'- Dihydroxy-oxepane-2'-yl) -4-guanidino-4H-pyran-2
-Carboxylic acid, trifluoroacetate The compound (70 mg, 0.120 mmol) obtained in Example 5 (x) was dissolved in methanol (3 ml), and a 1 M aqueous sodium hydroxide solution (0.479 ml, 0.479 mmol) was added at room temperature. The mixture was stirred at room temperature for 30 minutes. Next, Dowex 50W X8 (H + ) resin was added to adjust the pH of the reaction solution to 2. The mixture was immediately filtered under reduced pressure, and the residue was washed with water. After the filtrate and washings were distilled off under reduced pressure, the resulting residue was subjected to reverse layer chromatography (Cosmosil, water) to obtain the title compound as a colorless amorphous. (48mg, 83
%) IR (Liquid film) (CDCl 3 ) νmax: 2928, 1736, 1682,
1511 cm -1 .MS (FAB) m / e 373 ([M + H] + ) .HRMS (FAB) Calcd for C 15 H 25 O 7 N 4 : 373.1724; found
. 373.1716 ([M + H] +) 1 H NMR (500 MHz, CD 3 OD) δppm: 5.84 (1H, d, J = 2.
6 Hz), 4.39 (1H, dd, J = 8.8, 2.6 Hz), 4.36 (1H, d
d, J = 9.7, 1.5 Hz), 4.30 (1H, dd, J = 9.7, 8.8 H
z), 4.01-4.07 (2H, m), 3.86 (1H, ddd, J = 12.3,
6.2, 6.2 Hz), 3.61 (1H, dd, J = 8.5, 1.5 Hz), 3.44
(1H, ddd, J = 12.3, 7.5, 5.7 Hz), 2.00 (3H, s),
1.87-2.02 (2H, m), 1.59-1.72 (2H, m). (Xii) (4S, 5R, 6R, 2'R, 3'R, 4'R) -5-acetylamino-5,6- Dihydro-6- (3 ', 4'-dihydroxy-
Oxepan-2'-yl) -4-guanidino-4H-pyran-2-carboxylic acid, trihydrate The compound obtained in Example 5 (xi) (35 mg, 0.072 mmol)
To ion exchange chromatography (Dowex 50W
(H +) resin, water, aqueous ammonia) and lyophilization to give the title compound as a colorless amorphous. (24m
g, 85%) 1 H NMR (500 MHz, CD 3 OD) δppm: 5.51 (1H, d, J =
2.6 Hz), 4.31 (1H, dd, J = 8.8, 2.6 Hz), 4.20 (1H,
dd, J = 9.7, 1.5 Hz), 4.11 (1H, dd, J = 9.7, 8.8
Hz), 3.98-4.02 (2H, m), 3.82 (1H, ddd, J = 12.3,
6.2, 6.2 Hz), 3.53 (1H, dd, J = 8.5, 1.5 Hz), 3.28
(1H, ddd, J = 12.3, 7.5, 5.7 Hz), 1.94 (3H, s),
1.72-1.91 (2H, m), 1.55-1.62 (2H, m). (Example 6) (4S, 5R, 6R, 2'R, 3'R, 4'R) -5-acetylamino-
5,6-Dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4-guanidino-4H-pyran-2-carboxylic acid octanyl trifluoroacetate
【０２９１】[0291]
【化１８】 Embedded image
【０２９２】（i）（4S, 5R, 6R, 2'R, 3'R, 4'R）−5
−アセチルアミノ−4−（N，N'−ビス−t−ブチルオキ
シカルボニル）グアニジノ−5，6−ジヒドロ−6−
（3'，4'−ジヒドロキシ−テトラヒドロ−ピラン−2'−
イル）−4H−ピラン−2−カルボン酸メチル 実施例４(xii)で得られた（4S, 5R, 6R, 2'S, 3'S, 4'
R）−5−アセチルアミノ−4−（N，N'−ビス−t−ブチ
ルオキシカルボニル）グアニジノ−6−（3'，4'−ジア
セトキシ−テトラヒドロ−ピラン−2'−イル）−5，6−
ジヒドロ−4H−ピラン−2−カルボン酸メチル（11.7 g,
17.8 mmol）をメタノール（150 ml）に溶解し、窒素雰
囲気下4.9 Ｍナトリウムメトキシド含有メタノール（1
ml, 1 mmol）を加え、室温で1時間攪拌した。4M塩酸含
有1, 4−ジオキサンで中和し、反応液を減圧留去後、得
られた残査をクロマトグラフィー（シリカゲル、塩化メ
チレン/メタノール＝20/1）に付して標記化合物を無色
アモルファスとして得た。（7.2 g、70％） IR (KBr)νmax： 3340, 3270, 3189, 1746, 1669, 155
0, 1439 cm-1. MS (FAB) m/e 573 ([M+H]+). HRMS (FAB) Calcd for C19H29O9N4 : 457.1934; found
457.1957 ([M+H]+).1 H NMR (400 MHz, CD3OD) δppm: 5.89 (1H, d, J = 2.
4Hz), 5.02 (1H, dd,J = 9.8, 2.4 Hz), 4.37 (1H, dd,
J = 10.3, 1.5 Hz), 4.26 (1H, dd, J = 10.3, 9.8 H
z), 4.10-4.13 (1H, m), 3.86 (1H, dd, J = 10.3, 2.9
Hz), 3.78 (3H, s), 3.71 (1H, dd, J = 10.3, 1.5 H
z), 3.64-3.68 (2H, m), 1.94 (3H, s),1.82-1.89 (1H,
m), 1.70-1.76 (1H, m), 1.52 (9H, s), 1.47 (9H,
s). （ii）（4S, 5R, 6R, 2'S, 3'S, 4'R）−5−アセチルア
ミノ−4−（N，N'−ビス−t−ブチルオキシカルボニ
ル）グアニジノ−5，6−ジヒドロ−6−（3'，4'−O−イ
ソプロピリデン−3'，4'−ジオキシ−テトラヒドロ−ピ
ラン−2'−イル）−4H−ピラン−2−カルボン酸メチル 実施例６(i)で得られた化合物（0.30 g, 0.524 mmol）
をアセトン（5 ml）に溶解し、窒素雰囲気下2, 2−ジメ
トキシプロパン（0.4 ml, 3.25 mmol）、p−トルエンス
ルホン酸一水和物（98 mg, 0.52 mmol）を加え、室温で
1時間攪拌した。反応液を酢酸エチル（30 ml）と飽和炭
酸水素ナトリウム水溶液（30 ml）に分配した。有機層
を分離し、食塩水（20ml X 3）で洗浄し、硫酸ナトリウ
ムで乾燥し、減圧留去後、標記化合物を得た。（0.32
g、99％）1H NMR (400 MHz, CDCl3) δppm: 8.58 (1H,
d, J = 8.3 Hz), 6.47 (1H, d,J = 7.3 Hz), 5.83 (1H,
d, J = 2.9 Hz), 5.15 (1H, ddd, J = 7.8, 7.3, 2.9H
z), 4.43-4.46 (1H, m), 4.34 (1H, dd, J = 9.5, 5.1
Hz), 4.25 (1H, ddd, J= 10.3, 8.3, 7.8 Hz), 4.07 (1
H, d, J = 10.3 Hz), 3.89 (1H, ddd, J = 11.7, 11.7,
5.9 Hz), 3.77 (3H, s), 3.59 (1H, ddd, J = 11.7, 1
1.7, 2.9 Hz),3.33 (1H, d, J = 9.5 Hz), 2.08-2.15
(1H, m), 2.05 (3H, s), 1.96-2.04 (1H, m), 1.95 (3
H, s), 1.49 (18H, s), 1.45 (3H, s), 1.38 (3H, s). （iii）（4S, 5R, 6R, 2'S, 3'S, 4'R）−5−アセチル
アミノ−4−（N，N'−ビス−t−ブチルオキシカルボニ
ル）グアニジノ−5，6−ジヒドロ−6−（3'，4'−O−イ
ソプロピリデン−3'，4'−ジオキシ−テトラヒドロ−ピ
ラン−2'−イル）−4H−ピラン−2−カルボン酸オクタ
ニル 実施例６(ii)で得られた化合物（160 mg, 0.267 mmol）
をメタノール（5 ml）に溶解し、室温で1M水酸化カリウ
ム水溶液（0.32 ml, 0.32 mmol）を加え、40℃で30分間
攪拌した。反応液を減圧留去後、トルエンで共沸して得
られた残査を窒素雰囲気下、ジメチルホルムアミド（1.
2 ml）に溶解し、1−ブロモオクタン（181 mg, 0.940 m
mol）を室温にて滴下し、50℃にて3時間攪拌した。反応
液を酢酸エチル（30 ml）と飽和炭酸水素ナトリウム水
溶液（30 ml）に分配した。有機層を分離し、食塩水（2
0ml X 3）で洗浄し、硫酸ナトリウムで乾燥し、減圧留
去後、得られた残査をクロマトグラフィー（シリカゲ
ル、酢酸エチル/ヘキサン＝1/1）に付して標記化合物を
無色アモルファスとして得た。（137 mg、82％） IR (CDCl3)νmax： 2928, 2856, 1727, 1688, 1640, 16
06, 1569 cm-1. MS (FAB) m/e 711 ([M+H]+). HRMS (FAB) Calcd for C35H59O11N4 : 711.4180; found
711.4209 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 8.56 (1H, d, J = 8.
8 Hz), 6.47 (1H, d,J = 8.1 Hz), 5.83 (1H, d, J =
2.9 Hz), 5.15 (1H, ddd, J = 9.5, 8.8, 2.9Hz), 4.42
-4.46 (1H, m), 4.34 (1H, dd, J = 9.5, 4.4 Hz), 4.2
6 (1H, ddd, J= 10.3, 9.5, 8.1 Hz), 4.12-4.18 (2H,
m), 4.07 (1H, d, J = 10.3 Hz), 3.89 (1H, ddd, J =
11.7, 11.0, 5.1 Hz), 3.59 (1H, ddd, J = 12.5, 11.
7, 2.9Hz), 3.34 (1H, d, J = 9.5 Hz), 2.05-2.14 (1
H, m), 1.95-2.02 (1H, m), 1.95 (3H, s), 1.63-1.72
(4H, m), 1.49 (9H, s), 1.48 (9H, s), 1.45 (3H, s),
1.38 (3H, s), 1.22-1.38 (8H, m), 0.88 (3H, t, J =
7.0 Hz). （iv）（4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルア
ミノ−5，6−ジヒドロ−6−（3'，4'−ジヒドロキシ−
テトラヒドロ−ピラン−2'−イル）−4−グアニジノ−4
H−ピラン−2−カルボン酸オクタニル トリフルオロ酢
酸塩 実施例６(iii)で得られた化合物（120 mg, 0.169 mmo
l）を塩化メチレン（3ml）に溶解し、トリフルオロ酢酸
（3 ml）を加え、4時間攪拌した。反応液を減圧留去
後、得られた残査をテトラヒドロフラン（5 ml）に溶解
し、水（1 ml）、トリフルオロ酢酸（0.2 ml）を加え、
3時間攪拌した。反応液を減圧留去後得られた残査を逆
相クロマトグラフィー（コスモシル、水/メタノール＝1
/2）に付して標記化合物を無色アモルファスとして得
た。（90 mg、91％） IR (KBr)νmax： 3342, 3197, 2929, 2858, 1669, 154
9, 1430 cm-1. MS (FAB) m/e 471 ([M+H]+). HRMS (FAB) Calcd for C19H29O9N4 : 471.2819; found
471.2834 ([M+H]+).1 H NMR (400 MHz, CD3OD) δppm: 5.83 (1H, d, J = 2.
9 Hz), 4.49 (1H, dd,J = 8.8, 1.5 Hz), 4.46 (1H, d
d, J = 8.1, 2.9 Hz), 4.17-4.22 (2H, m), 4.17 (1H,
dd, J = 8.8, 8.1 Hz), 4.10-4.13 (1H, m), 3.83 (1H,
dd, J = 9.5,2.9 Hz), 3.72 (1H, dd, J = 9.5, 1.5 H
z), 3.68 (1H, d, J = 7.3 Hz), 3.66-3.70 (2H, m),
1.99 (3H, s), 1.81-1.91 (1H, m), 1.64-1.78 (3H,
m), 1.27-1.42 (10H, m), 0.99 (3H, t, J = 7.0 Hz). [α]D 20 -8.8°(c 0.15, CH3OH). （実施例７） （4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルアミノ−
5，6−ジヒドロ−6−（3'，4'−ジヒドロキシ−テトラ
ヒドロ−ピラン−2'−イル）−4−グアニジノ−4H−ピ
ラン−2−カルボン酸デシル トリフルオロ酢酸塩(I) (4S, 5R, 6R, 2'R, 3'R, 4'R) -5
-Acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) guanidino-5,6-dihydro-6-
(3 ′, 4′-dihydroxy-tetrahydro-pyran-2′-
Myl) -4H-pyran-2-carboxylate (4S, 5R, 6R, 2'S, 3'S, 4 'obtained in Example 4 (xii)
R) -5-Acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) guanidino-6- (3 ', 4'-diacetoxy-tetrahydro-pyran-2'-yl) -5,6 −
Methyl dihydro-4H-pyran-2-carboxylate (11.7 g,
17.8 mmol) was dissolved in methanol (150 ml), and methanol (1 M) containing 4.9 M sodium methoxide was added under a nitrogen atmosphere.
ml, 1 mmol) and stirred at room temperature for 1 hour. The reaction mixture was neutralized with 1,4-dioxane containing 4M hydrochloric acid, and the reaction mixture was evaporated under reduced pressure. The resulting residue was subjected to chromatography (silica gel, methylene chloride / methanol = 20/1) to give the title compound as a colorless amorphous substance. As obtained. (7.2 g, 70%) IR (KBr) νmax: 3340, 3270, 3189, 1746, 1669, 155
0, 1439 cm -1 . MS (FAB) m / e 573 ([M + H] + ). HRMS (FAB) Calcd for C 19 H 29 O 9 N 4 : 457.1934; found
. 457.1957 ([M + H] +) 1 H NMR (400 MHz, CD 3 OD) δppm: 5.89 (1H, d, J = 2.
4Hz), 5.02 (1H, dd, J = 9.8, 2.4 Hz), 4.37 (1H, dd,
J = 10.3, 1.5 Hz), 4.26 (1H, dd, J = 10.3, 9.8 H
z), 4.10-4.13 (1H, m), 3.86 (1H, dd, J = 10.3, 2.9
Hz), 3.78 (3H, s), 3.71 (1H, dd, J = 10.3, 1.5 H
z), 3.64-3.68 (2H, m), 1.94 (3H, s), 1.82-1.89 (1H,
m), 1.70-1.76 (1H, m), 1.52 (9H, s), 1.47 (9H,
s). (ii) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5-acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) guanidino-5,6-dihydro Methyl -6- (3 ', 4'-O-isopropylidene-3', 4'-dioxy-tetrahydro-pyran-2'-yl) -4H-pyran-2-carboxylate Obtained in Example 6 (i) Compound (0.30 g, 0.524 mmol)
Was dissolved in acetone (5 ml), 2,2-dimethoxypropane (0.4 ml, 3.25 mmol) and p-toluenesulfonic acid monohydrate (98 mg, 0.52 mmol) were added under a nitrogen atmosphere.
Stir for 1 hour. The reaction solution was partitioned between ethyl acetate (30 ml) and a saturated aqueous sodium hydrogen carbonate solution (30 ml). The organic layer was separated, washed with brine (20 ml × 3), dried over sodium sulfate, and evaporated under reduced pressure to give the title compound. (0.32
g, 99%) 1 H NMR (400 MHz, CDCl 3 ) δppm: 8.58 (1H,
d, J = 8.3 Hz), 6.47 (1H, d, J = 7.3 Hz), 5.83 (1H,
d, J = 2.9 Hz), 5.15 (1H, ddd, J = 7.8, 7.3, 2.9H
z), 4.43-4.46 (1H, m), 4.34 (1H, dd, J = 9.5, 5.1
Hz), 4.25 (1H, ddd, J = 10.3, 8.3, 7.8 Hz), 4.07 (1
H, d, J = 10.3 Hz), 3.89 (1H, ddd, J = 11.7, 11.7,
5.9 Hz), 3.77 (3H, s), 3.59 (1H, ddd, J = 11.7, 1
1.7, 2.9 Hz), 3.33 (1H, d, J = 9.5 Hz), 2.08-2.15
(1H, m), 2.05 (3H, s), 1.96-2.04 (1H, m), 1.95 (3
H, s), 1.49 (18H, s), 1.45 (3H, s), 1.38 (3H, s). (Iii) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5-acetylamino- 4- (N, N'-bis-t-butyloxycarbonyl) guanidino-5,6-dihydro-6- (3 ', 4'-O-isopropylidene-3', 4'-dioxy-tetrahydro-pyran- Octanyl 2'-yl) -4H-pyran-2-carboxylate Compound obtained in Example 6 (ii) (160 mg, 0.267 mmol)
Was dissolved in methanol (5 ml), 1M aqueous potassium hydroxide solution (0.32 ml, 0.32 mmol) was added at room temperature, and the mixture was stirred at 40 ° C. for 30 minutes. After evaporating the reaction solution under reduced pressure, the residue obtained by azeotropic distillation with toluene was distilled under a nitrogen atmosphere into dimethylformamide (1.
2 ml) and 1-bromooctane (181 mg, 0.940 m
mol) was added dropwise at room temperature and stirred at 50 ° C. for 3 hours. The reaction solution was partitioned between ethyl acetate (30 ml) and a saturated aqueous sodium hydrogen carbonate solution (30 ml). Separate the organic layer and add brine (2
0ml X 3), dried over sodium sulfate, and evaporated under reduced pressure. The resulting residue was subjected to chromatography (silica gel, ethyl acetate / hexane = 1/1) to obtain the title compound as a colorless amorphous. Was. (137 mg, 82%) IR (CDCl 3 ) νmax: 2928, 2856, 1727, 1688, 1640, 16
06, 1569 cm -1 . MS (FAB) m / e 711 ([M + H] + ). HRMS (FAB) Calcd for C 35 H 59 O 11 N 4 : 711.4180; found
. 711.4209 ([M + H] +) 1 H NMR (400 MHz, CDCl 3) δppm: 8.56 (1H, d, J = 8.
8 Hz), 6.47 (1H, d, J = 8.1 Hz), 5.83 (1H, d, J =
2.9 Hz), 5.15 (1H, ddd, J = 9.5, 8.8, 2.9Hz), 4.42
-4.46 (1H, m), 4.34 (1H, dd, J = 9.5, 4.4 Hz), 4.2
6 (1H, ddd, J = 10.3, 9.5, 8.1 Hz), 4.12-4.18 (2H,
m), 4.07 (1H, d, J = 10.3 Hz), 3.89 (1H, ddd, J =
11.7, 11.0, 5.1 Hz), 3.59 (1H, ddd, J = 12.5, 11.
7, 2.9Hz), 3.34 (1H, d, J = 9.5 Hz), 2.05-2.14 (1
H, m), 1.95-2.02 (1H, m), 1.95 (3H, s), 1.63-1.72
(4H, m), 1.49 (9H, s), 1.48 (9H, s), 1.45 (3H, s),
1.38 (3H, s), 1.22-1.38 (8H, m), 0.88 (3H, t, J =
(Iv) (4S, 5R, 6R, 2'R, 3'R, 4'R) -5-acetylamino-5,6-dihydro-6- (3 ', 4'-dihydroxy-
Tetrahydro-pyran-2'-yl) -4-guanidino-4
H-pyran-2-carboxylate octanyl trifluoroacetate Compound obtained in Example 6 (iii) (120 mg, 0.169 mmo
l) was dissolved in methylene chloride (3 ml), trifluoroacetic acid (3 ml) was added, and the mixture was stirred for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was dissolved in tetrahydrofuran (5 ml), and water (1 ml) and trifluoroacetic acid (0.2 ml) were added.
Stir for 3 hours. The residue obtained after evaporating the reaction solution under reduced pressure was subjected to reverse phase chromatography (Cosmosil, water / methanol = 1).
/ 2) to give the title compound as a colorless amorphous. (90 mg, 91%) IR (KBr) νmax: 3342, 3197, 2929, 2858, 1669, 154
9, 1430 cm -1 . MS (FAB) m / e 471 ([M + H] + ) .HRMS (FAB) Calcd for C 19 H 29 O 9 N 4 : 471.2819; found
. 471.2834 ([M + H] +) 1 H NMR (400 MHz, CD3OD) δppm: 5.83 (1H, d, J = 2.
9 Hz), 4.49 (1H, dd, J = 8.8, 1.5 Hz), 4.46 (1H, d
d, J = 8.1, 2.9 Hz), 4.17-4.22 (2H, m), 4.17 (1H,
dd, J = 8.8, 8.1 Hz), 4.10-4.13 (1H, m), 3.83 (1H,
dd, J = 9.5,2.9 Hz), 3.72 (1H, dd, J = 9.5, 1.5 H
z), 3.68 (1H, d, J = 7.3 Hz), 3.66-3.70 (2H, m),
1.99 (3H, s), 1.81-1.91 (1H, m), 1.64-1.78 (3H,
m), 1.27-1.42 (10H, m), 0.99 (3H, t, J = 7.0 Hz). [α] D 20 -8.8 ° (c 0.15, CH 3 OH). (Example 7) (4S, 5R , 6R, 2'R, 3'R, 4'R) -5-acetylamino-
5,6-Dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4-guanidino-4H-pyran-2-carboxylic acid decyl trifluoroacetate
【０２９３】[0293]
【化１９】 Embedded image
【０２９４】（i）（4S, 5R, 6R, 2'S, 3'S, 4'R）−5
−アセチルアミノ−4−（N，N'−ビス−t−ブチルオキ
シカルボニル）グアニジノ−5，6−ジヒドロ−6−
（3'，4'−O−イソプロピリデン−3'，4'−ジオキシ−
テトラヒドロ−ピラン−2'−イル）−4H−ピラン−2−
カルボン酸デシル 実施例６(ii)で得られた（4S, 5R, 6R, 2'S, 3'S, 4'
R）−5−アセチルアミノ−4−（N，N'−ビス−t−ブチ
ルオキシカルボニル）グアニジノ−5，6−ジヒドロ−6
−（3'，4'−O−イソプロピリデン−3'，4'−ジオキシ
−テトラヒドロ−ピラン−2'−イル）−4H−ピラン−2
−カルボン酸メチル（160 mg, 0.267 mmol）をメタノー
ル（5 ml）に溶解し、室温で1M水酸化カリウム水溶液
（0.32 ml, 0.32 mmol）を加え、40℃で30分間攪拌し
た。反応液を減圧留去後、トルエンで共沸して得られた
残査を窒素雰囲気下、ジメチルホルムアミド（1.2 ml）
に溶解し、1−ブロモデカン（208 mg, 0.94 mmol）を室
温にて滴下し、50℃にて3時間攪拌した。反応液を酢酸
エチル（30 ml）と飽和炭酸水素ナトリウム水溶液（30
ml）に分配した。有機層を分離し、食塩水（20ml X 3）
で洗浄し、硫酸ナトリウムで乾燥し、減圧留去後、得ら
れた残査をクロマトグラフィー（シリカゲル、酢酸エチ
ル/ヘキサン＝1/1）に付して標記化合物を無色アモルフ
ァスとして得た。（120 mg、68％） IR (CDCl3)νmax： 2928, 2856, 1727, 1688, 1640, 16
06, 1569 cm-1. MS (FAB) m/e 739 ([M+H]+). HRMS (FAB) Calcd for C37H63O11N4 : 739.4493; found
739.4520 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 8.56 (1H, d, J = 8.
8 Hz), 6.47 (1H, d,J = 8.1 Hz), 5.83 (1H, d, J =
2.9 Hz), 5.15 (1H, ddd, J = 9.5, 8.8, 2.9Hz), 4.42
-4.46 (1H, m), 4.34 (1H, dd, J = 9.5, 4.4 Hz), 4.2
6 (1H, ddd, J= 10.3, 9.5, 8.1 Hz), 4.12-4.18 (2H,
m), 4.07 (1H, d, J = 10.3 Hz), 3.89 (1H, ddd, J =
11.7, 11.0, 5.1 Hz), 3.59 (1H, ddd, J = 12.5, 11.
7, 2.9Hz), 3.34 (1H, d, J = 9.5 Hz), 2.05-2.14 (1
H, m), 1.95-2.02 (1H, m), 1.95 (3H, s), 1.63-1.72
(4H, m), 1.49 (9H, s), 1.48 (9H, s), 1.45 (3H, s),
1.38 (3H, s), 1.22-1.38 (12H, m), 0.88 (3H, t, J =
7.0 Hz).（ii）（4S, 5R, 6R, 2'R, 3'R, 4'R）−5−
アセチルアミノ−5，6−ジヒドロ−6−（3'，4'−ジヒ
ドロキシ−テトラヒドロ−ピラン−2'−イル）−4−グ
アニジノ−4H−ピラン−2−カルボン酸デシル トリフ
ルオロ酢酸塩 実施例７(i)で得られた化合物（105 mg, 0.142 mmol）
を塩化メチレン（3ml）に溶解し、トリフルオロ酢酸（3
ml）を加え、4時間攪拌した。反応液を減圧留去後、得
られた残査をテトラヒドロフラン（5 ml）に溶解し、水
（1 ml）、トリフルオロ酢酸（0.2 ml）を加え、3時間
攪拌した。反応液を減圧留去後得られた残査を逆相クロ
マトグラフィー（コスモシル、水/メタノール＝1/2）に
付して標記化合物を無色アモルファスとして得た。（80
mg、92％） IR (KBr)νmax： 3342, 3197, 2929, 2858, 1669, 154
9, 1430 cm-1. MS (FAB) m/e 499 ([M+H]+). HRMS (FAB) Calcd for C24H43O7N4 : 499.3132; found
499.3136 ([M+H]+).1 H NMR (400 MHz, CD3OD) δppm: 5.83 (1H, d, J = 2.
9 Hz), 4.49 (1H, dd,J = 8.8, 1.5 Hz), 4.46 (1H, d
d, J = 8.1, 2.9 Hz), 4.17-4.22 (2H, m), 4.17 (1H,
dd, J = 8.8, 8.1 Hz), 4.10-4.13 (1H, m), 3.83 (1H,
dd, J = 9.5,2.9 Hz), 3.72 (1H, dd, J = 9.5, 1.5 H
z), 3.68 (1H, d, J = 7.3 Hz), 3.66-3.70 (2H, m),
1.99 (3H, s), 1.81-1.91 (1H, m), 1.64-1.78 (3H,
m), 1.27-1.42 (14H, m), 0.99 (3H, t, J = 7.0 Hz).
[α]D 20 -6.7°(c 0.15, CH3OH). （実施例８） （4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルアミノ−
5，6−ジヒドロ−6−（3'，4'−ジヒドロキシ−テトラ
ヒドロ−ピラン−2'−イル）−4−グアニジノ−4H−ピ
ラン−2−カルボン酸ドデシル トリフルオロ酢酸塩(I) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5
-Acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) guanidino-5,6-dihydro-6-
(3 ′, 4′-O-isopropylidene-3 ′, 4′-dioxy-
Tetrahydro-pyran-2'-yl) -4H-pyran-2-
Decyl carboxylate obtained in Example 6 (ii) (4S, 5R, 6R, 2'S, 3'S, 4 '
R) -5-Acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) guanidino-5,6-dihydro-6
-(3 ', 4'-O-isopropylidene-3', 4'-dioxy-tetrahydro-pyran-2'-yl) -4H-pyran-2
-Methyl carboxylate (160 mg, 0.267 mmol) was dissolved in methanol (5 ml), a 1 M aqueous potassium hydroxide solution (0.32 ml, 0.32 mmol) was added at room temperature, and the mixture was stirred at 40 ° C for 30 minutes. After evaporating the reaction solution under reduced pressure, the residue obtained by azeotropic distillation with toluene was subjected to dimethylformamide (1.2 ml) under a nitrogen atmosphere.
, And 1-bromodecane (208 mg, 0.94 mmol) was added dropwise at room temperature, and the mixture was stirred at 50 ° C for 3 hours. The reaction solution was diluted with ethyl acetate (30 ml) and a saturated aqueous solution of sodium hydrogen carbonate (30 ml).
ml). Separate the organic layer and add brine (20ml x 3)
After drying over sodium sulfate and evaporating under reduced pressure, the obtained residue was subjected to chromatography (silica gel, ethyl acetate / hexane = 1/1) to obtain the title compound as a colorless amorphous. (120 mg, 68%) IR (CDCl 3 ) νmax: 2928, 2856, 1727, 1688, 1640, 16
06, 1569 cm -1 . MS (FAB) m / e 739 ([M + H] + ). HRMS (FAB) Calcd for C 37 H 63 O 11 N 4 : 739.4493; found
. 739.4520 ([M + H] +) 1 H NMR (400 MHz, CDCl 3) δppm: 8.56 (1H, d, J = 8.
8 Hz), 6.47 (1H, d, J = 8.1 Hz), 5.83 (1H, d, J =
2.9 Hz), 5.15 (1H, ddd, J = 9.5, 8.8, 2.9Hz), 4.42
-4.46 (1H, m), 4.34 (1H, dd, J = 9.5, 4.4 Hz), 4.2
6 (1H, ddd, J = 10.3, 9.5, 8.1 Hz), 4.12-4.18 (2H,
m), 4.07 (1H, d, J = 10.3 Hz), 3.89 (1H, ddd, J =
11.7, 11.0, 5.1 Hz), 3.59 (1H, ddd, J = 12.5, 11.
7, 2.9Hz), 3.34 (1H, d, J = 9.5 Hz), 2.05-2.14 (1
H, m), 1.95-2.02 (1H, m), 1.95 (3H, s), 1.63-1.72
(4H, m), 1.49 (9H, s), 1.48 (9H, s), 1.45 (3H, s),
1.38 (3H, s), 1.22-1.38 (12H, m), 0.88 (3H, t, J =
(7.0 Hz). (Ii) (4S, 5R, 6R, 2'R, 3'R, 4'R)
Acetylamino-5,6-dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4-guanidino-4H-pyran-2-carboxylic acid decyl trifluoroacetate Example 7 Compound obtained in (i) (105 mg, 0.142 mmol)
Was dissolved in methylene chloride (3 ml), and trifluoroacetic acid (3
ml) and stirred for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was dissolved in tetrahydrofuran (5 ml), water (1 ml) and trifluoroacetic acid (0.2 ml) were added, and the mixture was stirred for 3 hours. The residue obtained after evaporating the reaction solution under reduced pressure was subjected to reverse phase chromatography (Cosmosil, water / methanol = 1/2) to obtain the title compound as a colorless amorphous. (80
mg, 92%) IR (KBr) νmax: 3342, 3197, 2929, 2858, 1669, 154
9, 1430 cm -1 .MS (FAB) m / e 499 ([M + H] + ) .HRMS (FAB) Calcd for C 24 H 43 O 7 N 4 : 499.3132; found
. 499.3136 ([M + H] +) 1 H NMR (400 MHz, CD 3 OD) δppm: 5.83 (1H, d, J = 2.
9 Hz), 4.49 (1H, dd, J = 8.8, 1.5 Hz), 4.46 (1H, d
d, J = 8.1, 2.9 Hz), 4.17-4.22 (2H, m), 4.17 (1H,
dd, J = 8.8, 8.1 Hz), 4.10-4.13 (1H, m), 3.83 (1H,
dd, J = 9.5,2.9 Hz), 3.72 (1H, dd, J = 9.5, 1.5 H
z), 3.68 (1H, d, J = 7.3 Hz), 3.66-3.70 (2H, m),
1.99 (3H, s), 1.81-1.91 (1H, m), 1.64-1.78 (3H,
m), 1.27-1.42 (14H, m), 0.99 (3H, t, J = 7.0 Hz).
[α] D 20 -6.7 ° (c 0.15, CH 3 OH). (Example 8) (4S, 5R, 6R, 2′R, 3′R, 4′R) -5-acetylamino-
5,6-dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4-guanidino-4H-pyran-2-carboxylic acid dodecyl trifluoroacetate
【０２９５】[0295]
【化２０】 Embedded image
【０２９６】（i）（4S, 5R, 6R, 2'S, 3'S, 4'R）−5
−アセチルアミノ−4−（N，N'−ビス−t−ブチルオキ
シカルボニル）グアニジノ−5，6−ジヒドロ−6−
（3'，4'−O−イソプロピリデン−3'，4'−ジオキシ−
テトラヒドロ−ピラン−2'−イル）−4H−ピラン−2−
カルボン酸ドデシル 実施例６(ii)で得られた化合物（4S, 5R, 6R, 2'S, 3'
S, 4'R）−5−アセチルアミノ−4−（N，N'−ビス−t−
ブチルオキシカルボニル）グアニジノ−5，6−ジヒドロ
−6−（3'，4'−O−イソプロピリデン−3'，4'−ジオキ
シ−テトラヒドロ−ピラン−2'−イル）−4H−ピラン−
2−カルボン酸メチル（160 mg, 0.267 mmol）をメタノ
ール（5 ml）に溶解し、室温で1M水酸化カリウム水溶液
（0.32 ml, 0.32 mmol）を加え、40℃で30分間攪拌し
た。反応液を減圧留去後、トルエンで共沸して得られた
残査を窒素雰囲気下、ジメチルホルムアミド（1.2 ml）
に溶解し、1−ブロモドデカン（234 mg, 0.94 mmol）を
室温にて滴下し、50℃にて3時間攪拌した。反応液を酢
酸エチル（30 ml）と飽和炭酸水素ナトリウム水溶液（3
0 ml）に分配した。有機層を分離し、食塩水（20ml X
3）で洗浄し、硫酸ナトリウムで乾燥し、減圧留去後、
得られた残査をクロマトグラフィー（シリカゲル、酢酸
エチル/ヘキサン＝1/1）に付して標記化合物を無色アモ
ルファスとして得た。（140 mg、68％） IR (CDCl3)νmax： 2928, 2855, 1727, 1687, 1640, 16
06, 1569 cm-1. MS (FAB) m/e 767 ([M+H]+). HRMS (FAB) Calcd for C39H67O11N4 : 767.4807; found
767.4796 ([M+H]+).1H NMR (400 MHz, CDCl3) δppm:
8.56 (1H, d, J = 8.8 Hz), 6.47 (1H, d,J = 8.1 Hz),
5.83 (1H, d, J = 2.9 Hz), 5.15 (1H, ddd, J = 9.5,
8.8, 2.9Hz), 4.42-4.46 (1H, m), 4.34 (1H, dd, J =
9.5, 4.4 Hz), 4.26 (1H, ddd, J= 10.3, 9.5, 8.1 H
z), 4.12-4.18 (2H, m), 4.07 (1H, d, J = 10.3 Hz),
3.89 (1H, ddd, J = 11.7, 11.0, 5.1 Hz), 3.59 (1H,
ddd, J = 12.5, 11.7, 2.9Hz), 3.34 (1H, d, J = 9.5
Hz), 2.05-2.14 (1H, m), 1.95-2.02 (1H, m), 1.95 (3
H, s), 1.63-1.72 (4H, m), 1.49 (9H, s), 1.48 (9H,
s), 1.45 (3H, s),1.38 (3H, s), 1.22-1.38 (16H, m),
0.88 (3H, t, J = 7.0 Hz). [α]D 20 -25.5°(c 0.40, CHCl3). （ii）（4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルア
ミノ−5，6−ジヒドロ−6−（3'，4'−ジヒドロキシ−
テトラヒドロ−ピラン−2'−イル）−4−グアニジノ−4
H−ピラン−2−カルボン酸ドデシル トリフルオロ酢酸
塩 実施例８(i)で得られた化合物（120 mg, 0.156 mmol）
を塩化メチレン（3ml）に溶解し、トリフルオロ酢酸（3
ml）を加え、4時間攪拌した。反応液を減圧留去後、得
られた残査をテトラヒドロフラン（5 ml）に溶解し、水
（1 ml）、トリフルオロ酢酸（0.2 ml）を加え、3時間
攪拌した。反応液を減圧留去後得られた残査を逆相クロ
マトグラフィー（コスモシル、水/メタノール＝1/2）に
付して標記化合物を無色アモルファスとして得た。（85
mg、85％） IR (KBr)νmax： 3342, 3197, 2929, 2858, 1669, 154
9, 1430 cm-1. MS (FAB) m/e 527 ([M+H]+). HRMS (FAB) Calcd for C26H47O7N4 : 527.3445; found
527.3453 ([M+H]+).1 H NMR (400 MHz, CD3OD) δppm: 5.83 (1H, d, J = 2.
9 Hz), 4.49 (1H, dd,J = 8.8, 1.5 Hz), 4.46 (1H, d
d, J = 8.1, 2.9 Hz), 4.17-4.22 (2H, m), 4.17 (1H,
dd, J = 8.8, 8.1 Hz), 4.10-4.13 (1H, m), 3.83 (1H,
dd, J = 9.5,2.9 Hz), 3.72 (1H, dd, J = 9.5, 1.5 H
z), 3.68 (1H, d, J = 7.3 Hz), 3.66-3.70 (2H, m),
1.99 (3H, s), 1.81-1.91 (1H, m), 1.64-1.78 (3H,
m), 1.27-1.42 (18H, m), 0.99 (3H, t, J = 7.0 Hz). [α]D 20 -5.7°(c 0.25, CH3OH). （実施例９） （4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルアミノ−
5，6−ジヒドロ−6−（3'，4'−ジヒドロキシ−テトラ
ヒドロ−ピラン−2'−イル）−4−グアニジノ−4H−ピ
ラン−2−カルボン酸テトラデシル トリフルオロ酢酸
塩(I) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5
-Acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) guanidino-5,6-dihydro-6-
(3 ′, 4′-O-isopropylidene-3 ′, 4′-dioxy-
Tetrahydro-pyran-2'-yl) -4H-pyran-2-
Dodecyl carboxylate Compound (4S, 5R, 6R, 2'S, 3 ') obtained in Example 6 (ii)
S, 4'R) -5-acetylamino-4- (N, N'-bis-t-
(Butyloxycarbonyl) guanidino-5,6-dihydro-6- (3 ', 4'-O-isopropylidene-3', 4'-dioxy-tetrahydro-pyran-2'-yl) -4H-pyran-
Methyl 2-carboxylate (160 mg, 0.267 mmol) was dissolved in methanol (5 ml), a 1 M aqueous potassium hydroxide solution (0.32 ml, 0.32 mmol) was added at room temperature, and the mixture was stirred at 40 ° C for 30 minutes. After evaporating the reaction solution under reduced pressure, the residue obtained by azeotropic distillation with toluene was subjected to dimethylformamide (1.2 ml) under a nitrogen atmosphere.
, And 1-bromododecane (234 mg, 0.94 mmol) was added dropwise at room temperature, and the mixture was stirred at 50 ° C for 3 hours. The reaction solution was diluted with ethyl acetate (30 ml) and a saturated aqueous sodium hydrogen carbonate solution (3.
0 ml). Separate the organic layer and add saline (20 ml X
3), dried over sodium sulfate, distilled off under reduced pressure,
The obtained residue was subjected to chromatography (silica gel, ethyl acetate / hexane = 1/1) to give the title compound as a colorless amorphous. (140 mg, 68%) IR (CDCl 3 ) νmax: 2928, 2855, 1727, 1687, 1640, 16
06, 1569 cm -1 . MS (FAB) m / e 767 ([M + H] + ). HRMS (FAB) Calcd for C 39 H 67 O 11 N 4 : 767.4807; found
767.4796 ([M + H] + ). 1 H NMR (400 MHz, CDCl 3 ) δppm:
8.56 (1H, d, J = 8.8 Hz), 6.47 (1H, d, J = 8.1 Hz),
5.83 (1H, d, J = 2.9 Hz), 5.15 (1H, ddd, J = 9.5,
8.8, 2.9Hz), 4.42-4.46 (1H, m), 4.34 (1H, dd, J =
9.5, 4.4 Hz), 4.26 (1H, ddd, J = 10.3, 9.5, 8.1 H
z), 4.12-4.18 (2H, m), 4.07 (1H, d, J = 10.3 Hz),
3.89 (1H, ddd, J = 11.7, 11.0, 5.1 Hz), 3.59 (1H,
ddd, J = 12.5, 11.7, 2.9Hz), 3.34 (1H, d, J = 9.5
Hz), 2.05-2.14 (1H, m), 1.95-2.02 (1H, m), 1.95 (3
H, s), 1.63-1.72 (4H, m), 1.49 (9H, s), 1.48 (9H,
s), 1.45 (3H, s), 1.38 (3H, s), 1.22-1.38 (16H, m),
0.88 (3H, t, J = 7.0 Hz). [Α] D 20 -25.5 ° (c 0.40, CHCl 3 ). (Ii) (4S, 5R, 6R, 2'R, 3'R, 4'R) -5-acetylamino-5,6-dihydro-6- (3 ', 4'-dihydroxy-
Tetrahydro-pyran-2'-yl) -4-guanidino-4
H-pyran-2-carboxylate dodecyl trifluoroacetate Compound obtained in Example 8 (i) (120 mg, 0.156 mmol)
Was dissolved in methylene chloride (3 ml), and trifluoroacetic acid (3
ml) and stirred for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was dissolved in tetrahydrofuran (5 ml), water (1 ml) and trifluoroacetic acid (0.2 ml) were added, and the mixture was stirred for 3 hours. The residue obtained after evaporating the reaction solution under reduced pressure was subjected to reverse phase chromatography (Cosmosil, water / methanol = 1/2) to obtain the title compound as a colorless amorphous. (85
mg, 85%) IR (KBr) νmax: 3342, 3197, 2929, 2858, 1669, 154
9, 1430 cm -1 .MS (FAB) m / e 527 ([M + H] + ) .HRMS (FAB) Calcd for C 26 H 47 O 7 N 4 : 527.3445; found
. 527.3453 ([M + H] +) 1 H NMR (400 MHz, CD 3 OD) δppm: 5.83 (1H, d, J = 2.
9 Hz), 4.49 (1H, dd, J = 8.8, 1.5 Hz), 4.46 (1H, d
d, J = 8.1, 2.9 Hz), 4.17-4.22 (2H, m), 4.17 (1H,
dd, J = 8.8, 8.1 Hz), 4.10-4.13 (1H, m), 3.83 (1H,
dd, J = 9.5,2.9 Hz), 3.72 (1H, dd, J = 9.5, 1.5 H
z), 3.68 (1H, d, J = 7.3 Hz), 3.66-3.70 (2H, m),
1.99 (3H, s), 1.81-1.91 (1H, m), 1.64-1.78 (3H,
m), 1.27-1.42 (18H, m), 0.99 (3H, t, J = 7.0 Hz). [α] D 20 -5.7 ° (c 0.25, CH 3 OH). (Example 9) (4S, 5R , 6R, 2'R, 3'R, 4'R) -5-acetylamino-
5,6-dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4-guanidino-4H-pyran-2-carboxylic acid tetradecyl trifluoroacetate
【０２９７】[0297]
【化２１】 Embedded image
【０２９８】（i）（4S, 5R, 6R, 2'S, 3'S, 4'R）−5
−アセチルアミノ−4−（N，N'−ビス−t−ブチルオキ
シカルボニル）グアニジノ−5，6−ジヒドロ−6−
（3'，4'−O−イソプロピリデン−3'，4'−ジオキシ−
テトラヒドロ−ピラン−2'−イル）−4H−ピラン−2−
カルボン酸テトラデシル 実施例６(ii)で得られた化合物（4S, 5R, 6R, 2'S, 3'
S, 4'R）−5−アセチルアミノ−4−（N，N'−ビス−t−
ブチルオキシカルボニル）グアニジノ−5，6−ジヒドロ
−6−（3'，4'−O−イソプロピリデン−3'，4'−ジオキ
シ−テトラヒドロ−ピラン−2'−イル）−4H−ピラン−
2−カルボン酸メチル（160 mg, 0.267 mmol）をメタノ
ール（5 ml）に溶解し、室温で1M水酸化カリウム水溶液
（0.32 ml, 0.32 mmol）を加え、40℃で30分間攪拌し
た。反応液を減圧留去後、トルエンで共沸して得られた
残査を窒素雰囲気下、ジメチルホルムアミド（1.2 ml）
に溶解し、1−ブロモテトラデカン（234 mg, 0.94 mmo
l）を室温にて滴下し、50℃にて3時間攪拌した。反応液
を酢酸エチル（30 ml）と飽和炭酸水素ナトリウム水溶
液（30 ml）に分配した。有機層を分離し、食塩水（20m
l X 3）で洗浄し、硫酸ナトリウムで乾燥し、減圧留去
後、得られた残査をクロマトグラフィー（シリカゲル、
酢酸エチル/ヘキサン＝1/1）に付して標記化合物を無色
アモルファスとして得た。（140 mg、66％） IR (CDCl3)νmax： 2928, 2855, 1727, 1687, 1640, 16
06, 1569 cm-1. MS (FAB) m/e 795 ([M+H]+). HRMS (FAB) Calcd for C41H71O11N4 : 795.5119; found
795.5112 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 8.56 (1H, d, J = 8.
8 Hz), 6.47 (1H, d,J = 8.1 Hz), 5.83 (1H, d, J =
2.9 Hz), 5.15 (1H, ddd, J = 9.5, 8.8, 2.9Hz), 4.42
-4.46 (1H, m), 4.34 (1H, dd, J = 9.5, 4.4 Hz), 4.2
6 (1H, ddd, J= 10.3, 9.5, 8.1 Hz), 4.12-4.18 (2H,
m), 4.07 (1H, d, J = 10.3 Hz), 3.89 (1H, ddd, J =
11.7, 11.0, 5.1 Hz), 3.59 (1H, ddd, J = 12.5, 11.
7, 2.9Hz), 3.34 (1H, d, J = 9.5 Hz), 2.05-2.14 (1
H, m), 1.95-2.02 (1H, m), 1.95 (3H, s), 1.63-1.72
(4H, m), 1.49 (9H, s), 1.48 (9H, s), 1.45 (3H, s),
1.38 (3H, s), 1.22-1.38 (20H, m), 0.88 (3H, t, J =
7.0 Hz). [α]D 20 -29.2°(c 0.35, CHCl3). （ii）（4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルア
ミノ−5，6−ジヒドロ−6−（3'，4'−ジヒドロキシ−
テトラヒドロ−ピラン−2'−イル）−4−グアニジノ−4
H−ピラン−2−カルボン酸テトラデシル トリフルオロ
酢酸塩 実施例９(i)で得られた化合物（120 mg, 0.152 mmol）
を塩化メチレン（3ml）に溶解し、トリフルオロ酢酸（3
ml）を加え、4時間攪拌した。反応液を減圧留去後、得
られた残査をテトラヒドロフラン（5 ml）に溶解し、水
（1 ml）、トリフルオロ酢酸（0.2 ml）を加え、3時間
攪拌した。反応液を減圧留去後得られた残査を逆相クロ
マトグラフィー（コスモシル、水/メタノール＝1/2）に
付して標記化合物を無色アモルファスとして得た。（95
mg、94％） IR (KBr)νmax： 3342, 3197, 2929, 2858, 1669, 154
9, 1430 cm-1. MS (FAB) m/e 555 ([M+H]+). HRMS (FAB) Calcd for C28H51O7N4 : 555.3758; found
555.3768 ([M+H]+).1 H NMR (400 MHz, CD3OD) δppm: 5.83 (1H, d, J = 2.
9 Hz), 4.49 (1H, dd,J = 8.8, 1.5 Hz), 4.46 (1H, d
d, J = 8.1, 2.9 Hz), 4.17-4.22 (2H, m), 4.17 (1H,
dd, J = 8.8, 8.1 Hz), 4.10-4.13 (1H, m), 3.83 (1H,
dd, J = 9.5,2.9 Hz), 3.72 (1H, dd, J = 9.5, 1.5 H
z), 3.68 (1H, d, J = 7.3 Hz), 3.66-3.70 (2H, m),
1.99 (3H, s), 1.81-1.91 (1H, m), 1.64-1.78 (3H,
m), 1.27-1.42 (22H, m), 0.99 (3H, t, J = 7.0 Hz). [α]D 20 -2.9°(c 0.45, CH3OH). （実施例１０） （4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルアミノ−
5，6−ジヒドロ−6−（3'，4'−ジヒドロキシ−テトラ
ヒドロ−ピラン−2'−イル）−4−グアニジノ−4H−ピ
ラン−2−カルボン酸ヘキサデシル トリフルオロ酢酸
塩(I) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5
-Acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) guanidino-5,6-dihydro-6-
(3 ′, 4′-O-isopropylidene-3 ′, 4′-dioxy-
Tetrahydro-pyran-2'-yl) -4H-pyran-2-
Tetradecyl carboxylate Compound (4S, 5R, 6R, 2'S, 3 ') obtained in Example 6 (ii)
S, 4'R) -5-acetylamino-4- (N, N'-bis-t-
(Butyloxycarbonyl) guanidino-5,6-dihydro-6- (3 ', 4'-O-isopropylidene-3', 4'-dioxy-tetrahydro-pyran-2'-yl) -4H-pyran-
Methyl 2-carboxylate (160 mg, 0.267 mmol) was dissolved in methanol (5 ml), a 1 M aqueous potassium hydroxide solution (0.32 ml, 0.32 mmol) was added at room temperature, and the mixture was stirred at 40 ° C for 30 minutes. After evaporating the reaction solution under reduced pressure, the residue obtained by azeotropic distillation with toluene was subjected to dimethylformamide (1.2 ml) under a nitrogen atmosphere.
Dissolved in 1-bromotetradecane (234 mg, 0.94 mmo
l) was added dropwise at room temperature and stirred at 50 ° C for 3 hours. The reaction solution was partitioned between ethyl acetate (30 ml) and a saturated aqueous sodium hydrogen carbonate solution (30 ml). Separate the organic layer and add saline (20m
l X 3), dried over sodium sulfate and evaporated under reduced pressure. The residue obtained was chromatographed (silica gel,
The residue was subjected to ethyl acetate / hexane = 1/1) to give the title compound as a colorless amorphous. (140 mg, 66%) IR (CDCl 3 ) νmax: 2928, 2855, 1727, 1687, 1640, 16
06, 1569 cm -1 . MS (FAB) m / e 795 ([M + H] + ). HRMS (FAB) Calcd for C 41 H 71 O 11 N 4 : 795.5119; found
. 795.5112 ([M + H] +) 1 H NMR (400 MHz, CDCl 3) δppm: 8.56 (1H, d, J = 8.
8 Hz), 6.47 (1H, d, J = 8.1 Hz), 5.83 (1H, d, J =
2.9 Hz), 5.15 (1H, ddd, J = 9.5, 8.8, 2.9Hz), 4.42
-4.46 (1H, m), 4.34 (1H, dd, J = 9.5, 4.4 Hz), 4.2
6 (1H, ddd, J = 10.3, 9.5, 8.1 Hz), 4.12-4.18 (2H,
m), 4.07 (1H, d, J = 10.3 Hz), 3.89 (1H, ddd, J =
11.7, 11.0, 5.1 Hz), 3.59 (1H, ddd, J = 12.5, 11.
7, 2.9Hz), 3.34 (1H, d, J = 9.5 Hz), 2.05-2.14 (1
H, m), 1.95-2.02 (1H, m), 1.95 (3H, s), 1.63-1.72
(4H, m), 1.49 (9H, s), 1.48 (9H, s), 1.45 (3H, s),
1.38 (3H, s), 1.22-1.38 (20H, m), 0.88 (3H, t, J =
(Α Hz). [Α] D 20 -29.2 ° (c 0.35, CHCl 3 ). (Ii) (4S, 5R, 6R, 2'R, 3'R, 4'R) -5-acetylamino-5, 6-dihydro-6- (3 ', 4'-dihydroxy-
Tetrahydro-pyran-2'-yl) -4-guanidino-4
H-pyran-2-carboxylate tetradecyl trifluoroacetate Compound obtained in Example 9 (i) (120 mg, 0.152 mmol)
Was dissolved in methylene chloride (3 ml), and trifluoroacetic acid (3
ml) and stirred for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was dissolved in tetrahydrofuran (5 ml), water (1 ml) and trifluoroacetic acid (0.2 ml) were added, and the mixture was stirred for 3 hours. The residue obtained after evaporating the reaction solution under reduced pressure was subjected to reverse phase chromatography (Cosmosil, water / methanol = 1/2) to obtain the title compound as a colorless amorphous. (95
mg, 94%) IR (KBr) νmax: 3342, 3197, 2929, 2858, 1669, 154
9, 1430 cm -1 . MS (FAB) m / e 555 ([M + H] + ) .HRMS (FAB) Calcd for C 28 H 51 O 7 N 4 : 555.3758; found
. 555.3768 ([M + H] +) 1 H NMR (400 MHz, CD3OD) δppm: 5.83 (1H, d, J = 2.
9 Hz), 4.49 (1H, dd, J = 8.8, 1.5 Hz), 4.46 (1H, d
d, J = 8.1, 2.9 Hz), 4.17-4.22 (2H, m), 4.17 (1H,
dd, J = 8.8, 8.1 Hz), 4.10-4.13 (1H, m), 3.83 (1H,
dd, J = 9.5,2.9 Hz), 3.72 (1H, dd, J = 9.5, 1.5 H
z), 3.68 (1H, d, J = 7.3 Hz), 3.66-3.70 (2H, m),
1.99 (3H, s), 1.81-1.91 (1H, m), 1.64-1.78 (3H,
m), 1.27-1.42 (22H, m), 0.99 (3H, t, J = 7.0 Hz). [α] D 20 -2.9 ° (c 0.45, CH 3 OH). (Example 10) (4S, 5R , 6R, 2'R, 3'R, 4'R) -5-acetylamino-
5,6-dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4-guanidino-4H-pyran-2-carboxylic acid hexadecyl trifluoroacetate
【０２９９】[0299]
【化２２】 Embedded image
【０３００】（i）（4S, 5R, 6R, 2'S, 3'S, 4'R）−5
−アセチルアミノ−4−（N，N'−ビス−t−ブチルオキ
シカルボニル）グアニジノ−5，6−ジヒドロ−6−
（3'，4'−O−イソプロピリデン−3'，4'−ジオキシ−
テトラヒドロ−ピラン−2'−イル）−4H−ピラン−2−
カルボン酸ヘキサデシル 実施例６(ii)で得られた化合物（4S, 5R, 6R, 2'S, 3'
S, 4'R）−5−アセチルアミノ−4−（N，N'−ビス−t−
ブチルオキシカルボニル）グアニジノ−5，6−ジヒドロ
−6−（3'，4'−O−イソプロピリデン−3'，4'−ジオキ
シ−テトラヒドロ−ピラン−2'−イル）−4H−ピラン−
2−カルボン酸メチル（160 mg, 0.267 mmol）をメタノ
ール（5 ml）に溶解し、室温で1M水酸化カリウム水溶液
（0.32 ml, 0.32 mmol）を加え、40℃で30分間攪拌し
た。反応液を減圧留去後、トルエンで共沸して得られた
残査を窒素雰囲気下、ジメチルホルムアミド（1.2 ml）
に溶解し、1−ブロモヘキサデカン（194 mg, 0.636 mmo
l）を室温にて滴下し、50℃にて3時間攪拌した。反応液
を酢酸エチル（30 ml）と飽和炭酸水素ナトリウム水溶
液（30 ml）に分配した。有機層を分離し、食塩水（20m
l X 3）で洗浄し、硫酸ナトリウムで乾燥し、減圧留去
後、得られた残査をクロマトグラフィー（シリカゲル、
酢酸エチル/ヘキサン＝1/1）に付して標記化合物を無色
アモルファスとして得た。（100 mg、45％） IR (KBr)νmax： 2928, 2855, 1727, 1687, 1640, 160
6, 1569 cm-1. MS (FAB) m/e 823 ([M+H]+). HRMS (FAB) Calcd for C43H75O11N4 : 823.5432; found
823.5420 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 8.58 (1H, d, J = 8.
3 Hz), 6.47 (1H, d,J = 7.3 Hz), 5.83 (1H, d, J =
2.2 Hz), 5.15 (1H, ddd, J = 7.8, 7.3, 2.2Hz), 4.42
-4.46 (1H, m), 4.34 (1H, dd, J = 9.5, 5.1 Hz), 4.2
6 (1H, ddd, J= 10.3, 8.8, 8.3 Hz), 4.12-4.18 (2H,
m), 4.07 (1H, d, J = 10.3 Hz), 3.89 (1H, ddd, J =
11.7, 11.7, 5.9 Hz), 3.59 (1H, ddd, J = 11.7, 11.
7, 2.9Hz), 3.34 (1H, d, J = 9.5 Hz), 2.05-2.14 (1
H, m), 1.95-2.02 (1H, m), 1.95 (3H, s), 1.63-1.72
(4H, m), 1.49 (9H, s), 1.48 (9H, s), 1.45 (3H, s),
1.38 (3H, s), 1.22-1.38 (24H, m), 0.88 (3H, t, J =
7.0 Hz). [α]D 20 -22.5°(c 0.90, CHCl3). （ii）（4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルア
ミノ−5，6−ジヒドロ−6−（3'，4'−ジヒドロキシ−
テトラヒドロ−ピラン−2'−イル）−4−グアニジノ−4
H−ピラン−2−カルボン酸ヘキサデシル トリフルオロ
酢酸塩 実施例１０(i)で得られた化合物（80 mg, 0.097 mmol）
を塩化メチレン（3ml）に溶解し、トリフルオロ酢酸（3
ml）を加え、4時間攪拌した。反応液を減圧留去後、得
られた残査を、テトラヒドロフラン（5 ml）に溶解し、
水（1 ml）、トリフルオロ酢酸（0.2 ml）を加え、3時
間攪拌した。反応液を減圧留去後得られた残査を逆相ク
ロマトグラフィー（コスモシル、水/メタノール＝1/3）
に付して標記化合物を無色アモルファスとして得た。
（52 mg、77％） IR (KBr)νmax： 3341, 3203, 2925, 2855, 1669, 154
8, 1430 cm-1. MS (FAB) m/e 583 ([M+H]+). HRMS (FAB) Calcd for C30H55O7N4 : 583.4071; found
583.4076 ([M+H]+).1 H NMR (400 MHz, CD3OD) δppm: 5.83 (1H, d, J = 2.
9 Hz), 4.49 (1H, dd,J = 8.8, 1.5 Hz), 4.46 (1H, d
d, J = 8.1, 2.9 Hz), 4.17-4.22 (2H, m), 4.17 (1H,
dd, J = 8.8, 8.1 Hz), 4.10-4.13 (1H, m), 3.83 (1H,
dd, J = 9.5,2.9 Hz), 3.72 (1H, dd, J = 9.5, 1.5 H
z), 3.68 (1H, d, J = 7.3 Hz), 3.66-3.70 (2H, m),
1.99 (3H, s), 1.81-1.91 (1H, m), 1.64-1.78 (3H,
m), 1.27-1.42 (26H, m), 0.99 (3H, t, J = 7.0 Hz). [α]D 20 -2.7°(c 0.40, CH3OH). （実施例１１） （4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルアミノ−
5，6−ジヒドロ−6−（3'，4'−ジヒドロキシ−テトラ
ヒドロ−ピラン−2'−イル）−4−グアニジノ−4H−ピ
ラン−2−カルボン酸オクタデシル トリフルオロ酢酸
塩(I) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5
-Acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) guanidino-5,6-dihydro-6-
(3 ′, 4′-O-isopropylidene-3 ′, 4′-dioxy-
Tetrahydro-pyran-2'-yl) -4H-pyran-2-
Hexadecyl carboxylate Compound (4S, 5R, 6R, 2'S, 3 ') obtained in Example 6 (ii)
S, 4'R) -5-acetylamino-4- (N, N'-bis-t-
(Butyloxycarbonyl) guanidino-5,6-dihydro-6- (3 ', 4'-O-isopropylidene-3', 4'-dioxy-tetrahydro-pyran-2'-yl) -4H-pyran-
Methyl 2-carboxylate (160 mg, 0.267 mmol) was dissolved in methanol (5 ml), a 1 M aqueous potassium hydroxide solution (0.32 ml, 0.32 mmol) was added at room temperature, and the mixture was stirred at 40 ° C for 30 minutes. After evaporating the reaction solution under reduced pressure, the residue obtained by azeotropic distillation with toluene was subjected to dimethylformamide (1.2 ml) under a nitrogen atmosphere.
Dissolved in 1-bromohexadecane (194 mg, 0.636 mmo
l) was added dropwise at room temperature and stirred at 50 ° C for 3 hours. The reaction solution was partitioned between ethyl acetate (30 ml) and a saturated aqueous sodium hydrogen carbonate solution (30 ml). Separate the organic layer and add saline (20m
l X 3), dried over sodium sulfate and evaporated under reduced pressure. The residue obtained was chromatographed (silica gel,
The residue was subjected to ethyl acetate / hexane = 1/1) to give the title compound as a colorless amorphous. (100 mg, 45%) IR (KBr) νmax: 2928, 2855, 1727, 1687, 1640, 160
6, 1569 cm -1 . MS (FAB) m / e 823 ([M + H] + ) .HRMS (FAB) Calcd for C 43 H 75 O 11 N 4 : 823.5432; found
. 823.5420 ([M + H] +) 1 H NMR (400 MHz, CDCl 3) δppm: 8.58 (1H, d, J = 8.
3 Hz), 6.47 (1H, d, J = 7.3 Hz), 5.83 (1H, d, J =
2.2 Hz), 5.15 (1H, ddd, J = 7.8, 7.3, 2.2Hz), 4.42
-4.46 (1H, m), 4.34 (1H, dd, J = 9.5, 5.1 Hz), 4.2
6 (1H, ddd, J = 10.3, 8.8, 8.3 Hz), 4.12-4.18 (2H,
m), 4.07 (1H, d, J = 10.3 Hz), 3.89 (1H, ddd, J =
11.7, 11.7, 5.9 Hz), 3.59 (1H, ddd, J = 11.7, 11.
7, 2.9Hz), 3.34 (1H, d, J = 9.5 Hz), 2.05-2.14 (1
H, m), 1.95-2.02 (1H, m), 1.95 (3H, s), 1.63-1.72
(4H, m), 1.49 (9H, s), 1.48 (9H, s), 1.45 (3H, s),
1.38 (3H, s), 1.22-1.38 (24H, m), 0.88 (3H, t, J =
[Α] D 20 -22.5 ° (c 0.90, CHCl 3 ). (Ii) (4S, 5R, 6R, 2′R, 3′R, 4′R) -5-acetylamino-5, 6-dihydro-6- (3 ', 4'-dihydroxy-
Tetrahydro-pyran-2'-yl) -4-guanidino-4
H-pyran-2-carboxylate hexadecyl trifluoroacetate Compound obtained in Example 10 (i) (80 mg, 0.097 mmol)
Was dissolved in methylene chloride (3 ml), and trifluoroacetic acid (3
ml) and stirred for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was dissolved in tetrahydrofuran (5 ml),
Water (1 ml) and trifluoroacetic acid (0.2 ml) were added, and the mixture was stirred for 3 hours. The residue obtained after evaporating the reaction solution under reduced pressure was subjected to reverse phase chromatography (Cosmosil, water / methanol = 1/3).
To give the title compound as a colorless amorphous.
(52 mg, 77%) IR (KBr) νmax: 3341, 3203, 2925, 2855, 1669, 154
8, 1430 cm -1 . MS (FAB) m / e 583 ([M + H] + ) .HRMS (FAB) Calcd for C 30 H 55 O 7 N 4 : 583.4071; found
. 583.4076 ([M + H] +) 1 H NMR (400 MHz, CD 3 OD) δppm: 5.83 (1H, d, J = 2.
9 Hz), 4.49 (1H, dd, J = 8.8, 1.5 Hz), 4.46 (1H, d
d, J = 8.1, 2.9 Hz), 4.17-4.22 (2H, m), 4.17 (1H,
dd, J = 8.8, 8.1 Hz), 4.10-4.13 (1H, m), 3.83 (1H,
dd, J = 9.5,2.9 Hz), 3.72 (1H, dd, J = 9.5, 1.5 H
z), 3.68 (1H, d, J = 7.3 Hz), 3.66-3.70 (2H, m),
1.99 (3H, s), 1.81-1.91 (1H, m), 1.64-1.78 (3H,
m), 1.27-1.42 (26H, m), 0.99 (3H, t, J = 7.0 Hz). [α] D 20 -2.7 ° (c 0.40, CH 3 OH). (Example 11) (4S, 5R , 6R, 2'R, 3'R, 4'R) -5-acetylamino-
5,6-Dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4-guanidino-4H-pyran-2-carboxylic acid octadecyl trifluoroacetate
【０３０１】[0301]
【化２３】 Embedded image
【０３０２】（i）（4S, 5R, 6R, 2'S, 3'S, 4'R）−5
−アセチルアミノ−4−（N，N'−ビス−t−ブチルオキ
シカルボニル）グアニジノ−5，6−ジヒドロ−6−
（3'，4'−O−イソプロピリデン−3'，4'−ジオキシ−
テトラヒドロ−ピラン−2'−イル）−4H−ピラン−2−
カルボン酸オクタデシル 実施例６(ii)で得られた化合物（4S, 5R, 6R, 2'S, 3'
S, 4'R）−5−アセチルアミノ−4−（N，N'−ビス−t−
ブチルオキシカルボニル）グアニジノ−5，6−ジヒドロ
−6−（3'，4'−O−イソプロピリデン−3'，4'−ジオキ
シ−テトラヒドロ−ピラン−2'−イル）−4H−ピラン−
2−カルボン酸メチル（160 mg, 0.267 mmol）をメタノ
ール（5 ml）に溶解し、室温で1M水酸化カリウム水溶液
（0.32 ml, 0.32 mmol）を加え、40℃で30分間攪拌し
た。反応液を減圧留去後、トルエンで共沸して得られた
残査を窒素雰囲気下、ジメチルホルムアミド（1.2 ml）
に溶解し、1−ブロモオクタデカン（279 mg, 0.82 mmo
l）を室温にて滴下し、50℃にて3時間攪拌した。反応液
を酢酸エチル（30 ml）と飽和炭酸水素ナトリウム水溶
液（30 ml）に分配した。有機層を分離し、食塩水（20m
l X 3）で洗浄し、硫酸ナトリウムで乾燥し、減圧留去
後、得られた残査をクロマトグラフィー（シリカゲル、
酢酸エチル/ヘキサン＝1/1）に付して標記化合物を無色
アモルファスとして得た。（103 mg、45％） IR (CDCl3)νmax： 2928, 2855, 1727, 1687, 1640, 16
06, 1569 cm-1. MS (FAB) m/e 851 ([M+H]+). HRMS (FAB) Calcd for C45H79O11N4 : 851.5746; found
851.5739 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 8.56 (1H, d, J = 8.
8 Hz), 6.47 (1H, d,J = 8.1 Hz), 5.83 (1H, d, J =
2.9 Hz), 5.15 (1H, ddd, J = 9.5, 8.8, 2.9Hz), 4.42
-4.46 (1H, m), 4.34 (1H, dd, J = 9.5, 4.4 Hz), 4.2
6 (1H, ddd, J= 10.3, 9.5, 8.1 Hz), 4.12-4.18 (2H,
m), 4.07 (1H, d, J = 10.3 Hz), 3.89 (1H, ddd, J =
11.7, 11.0, 5.1 Hz), 3.59 (1H, ddd, J = 12.5, 11.
7, 2.9Hz), 3.34 (1H, d, J = 9.5 Hz), 2.05-2.14 (1
H, m), 1.95-2.02 (1H, m), 1.95 (3H, s), 1.63-1.72
(4H, m), 1.49 (9H, s), 1.48 (9H, s), 1.45 (3H, s),
1.38 (3H, s), 1.22-1.38 (28H, m), 0.88 (3H, t, J =
7.0 Hz). [α]D 20 -23.4°(c 0.70, CHCl3). （ii）（4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルア
ミノ−5，6−ジヒドロ−6−（3'，4'−ジヒドロキシ−
テトラヒドロ−ピラン−2'−イル）−4−グアニジノ−4
H−ピラン−2−カルボン酸オクタデシル トリフルオロ
酢酸塩 実施例１１(i)で得られた化合物（80 mg, 0.094 mmol）
を塩化メチレン（3ml）に溶解し、トリフルオロ酢酸（3
ml）を加え、4時間攪拌した。反応液を減圧留去後、得
られた残査をテトラヒドロフラン（5 ml）に溶解し、水
（1 ml）、トリフルオロ酢酸（0.2 ml）を加え、3時間
攪拌した。反応液を減圧留去後得られた残査を逆相クロ
マトグラフィー（コスモシル、水/メタノール＝1/3）に
付して標記化合物を無色アモルファスとして得た。（52
mg、76％） IR (KBr)νmax： 3342, 3197, 2929, 2858, 1669, 154
9, 1430 cm-1. MS (FAB) m/e 611 ([M+H]+). HRMS (FAB) Calcd for C32H59O7N4 : 611.4383; found
611.4393 ([M+H]+).1 H NMR (400 MHz, CD3OD) δppm: 5.83 (1H, d, J = 2.
9 Hz), 4.49 (1H, dd,J = 8.8, 1.5 Hz), 4.46 (1H, d
d, J = 8.1, 2.9 Hz), 4.17-4.22 (2H, m), 4.17 (1H,
dd, J = 8.8, 8.1 Hz), 4.10-4.13 (1H, m), 3.83 (1H,
dd, J = 9.5,2.9 Hz), 3.72 (1H, dd, J = 9.5, 1.5 H
z), 3.68 (1H, d, J = 7.3 Hz), 3.66-3.70 (2H, m),
1.99 (3H, s), 1.81-1.91 (1H, m), 1.64-1.78 (3H,
m), 1.27-1.42 (30H, m), 0.99 (3H, t, J = 7.0 Hz). [α]D 20 -3.0°(c 0.45, CH3OH). （実施例１２） （4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチルアミノ−
6−（4'−n−ブチリルオキシ−3'−ヒドロキシ−テトラ
ヒドロ−ピラン−2'−イル）−5，6−ジヒドロ−4−グ
アニジノ−4H−ピラン−2−カルボン酸 一水和物(I) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5
-Acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) guanidino-5,6-dihydro-6-
(3 ′, 4′-O-isopropylidene-3 ′, 4′-dioxy-
Tetrahydro-pyran-2'-yl) -4H-pyran-2-
Octadecyl carboxylate Compound (4S, 5R, 6R, 2'S, 3 ') obtained in Example 6 (ii)
S, 4'R) -5-acetylamino-4- (N, N'-bis-t-
(Butyloxycarbonyl) guanidino-5,6-dihydro-6- (3 ', 4'-O-isopropylidene-3', 4'-dioxy-tetrahydro-pyran-2'-yl) -4H-pyran-
Methyl 2-carboxylate (160 mg, 0.267 mmol) was dissolved in methanol (5 ml), a 1 M aqueous potassium hydroxide solution (0.32 ml, 0.32 mmol) was added at room temperature, and the mixture was stirred at 40 ° C for 30 minutes. After evaporating the reaction solution under reduced pressure, the residue obtained by azeotropic distillation with toluene was subjected to dimethylformamide (1.2 ml) under a nitrogen atmosphere.
Was dissolved in 1-bromooctadecane (279 mg, 0.82 mmo
l) was added dropwise at room temperature and stirred at 50 ° C for 3 hours. The reaction solution was partitioned between ethyl acetate (30 ml) and a saturated aqueous sodium hydrogen carbonate solution (30 ml). Separate the organic layer and add saline (20m
l X 3), dried over sodium sulfate and evaporated under reduced pressure. The residue obtained was chromatographed (silica gel,
The residue was subjected to ethyl acetate / hexane = 1/1) to give the title compound as a colorless amorphous. (103 mg, 45%) IR (CDCl 3 ) νmax: 2928, 2855, 1727, 1687, 1640, 16
06, 1569 cm -1 . MS (FAB) m / e 851 ([M + H] + ). HRMS (FAB) Calcd for C 45 H 79 O 11 N 4 : 851.5746; found
. 851.5739 ([M + H] +) 1 H NMR (400 MHz, CDCl 3) δppm: 8.56 (1H, d, J = 8.
8 Hz), 6.47 (1H, d, J = 8.1 Hz), 5.83 (1H, d, J =
2.9 Hz), 5.15 (1H, ddd, J = 9.5, 8.8, 2.9Hz), 4.42
-4.46 (1H, m), 4.34 (1H, dd, J = 9.5, 4.4 Hz), 4.2
6 (1H, ddd, J = 10.3, 9.5, 8.1 Hz), 4.12-4.18 (2H,
m), 4.07 (1H, d, J = 10.3 Hz), 3.89 (1H, ddd, J =
11.7, 11.0, 5.1 Hz), 3.59 (1H, ddd, J = 12.5, 11.
7, 2.9Hz), 3.34 (1H, d, J = 9.5 Hz), 2.05-2.14 (1
H, m), 1.95-2.02 (1H, m), 1.95 (3H, s), 1.63-1.72
(4H, m), 1.49 (9H, s), 1.48 (9H, s), 1.45 (3H, s),
1.38 (3H, s), 1.22-1.38 (28H, m), 0.88 (3H, t, J =
(Α Hz). [Α] D 20 -23.4 ° (c 0.70, CHCl 3 ). (Ii) (4S, 5R, 6R, 2'R, 3'R, 4'R) -5-acetylamino-5, 6-dihydro-6- (3 ', 4'-dihydroxy-
Tetrahydro-pyran-2'-yl) -4-guanidino-4
H-pyran-2-carboxylate octadecyl trifluoroacetate Compound obtained in Example 11 (i) (80 mg, 0.094 mmol)
Was dissolved in methylene chloride (3 ml), and trifluoroacetic acid (3
ml) and stirred for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was dissolved in tetrahydrofuran (5 ml), water (1 ml) and trifluoroacetic acid (0.2 ml) were added, and the mixture was stirred for 3 hours. The residue obtained after evaporating the reaction solution under reduced pressure was subjected to reverse phase chromatography (Cosmosil, water / methanol = 1/3) to obtain the title compound as a colorless amorphous. (52
mg, 76%) IR (KBr) νmax: 3342, 3197, 2929, 2858, 1669, 154
9, 1430 cm -1 . MS (FAB) m / e 611 ([M + H] + ) .HRMS (FAB) Calcd for C 32 H 59 O 7 N 4 : 611.4383; found
. 611.4393 ([M + H] +) 1 H NMR (400 MHz, CD 3 OD) δppm: 5.83 (1H, d, J = 2.
9 Hz), 4.49 (1H, dd, J = 8.8, 1.5 Hz), 4.46 (1H, d
d, J = 8.1, 2.9 Hz), 4.17-4.22 (2H, m), 4.17 (1H,
dd, J = 8.8, 8.1 Hz), 4.10-4.13 (1H, m), 3.83 (1H,
dd, J = 9.5,2.9 Hz), 3.72 (1H, dd, J = 9.5, 1.5 H
z), 3.68 (1H, d, J = 7.3 Hz), 3.66-3.70 (2H, m),
1.99 (3H, s), 1.81-1.91 (1H, m), 1.64-1.78 (3H,
m), 1.27-1.42 (30H, m), 0.99 (3H, t, J = 7.0 Hz). [α] D 20 -3.0 ° (c 0.45, CH 3 OH). (Example 12) (4S, 5R , 6R, 2'R, 3'S, 4'R) -5-acetylamino-
6- (4'-n-butyryloxy-3'-hydroxy-tetrahydro-pyran-2'-yl) -5,6-dihydro-4-guanidino-4H-pyran-2-carboxylic acid monohydrate
【０３０３】[0303]
【化２４】 Embedded image
【０３０４】（i）（4S, 5R, 6R, 2'R, 3'R, 4'R）−5
−アセチルアミノ−4−（N，N'−ビス−t−ブチルオキ
シカルボニル）グアニジノ−5，6−ジヒドロ−6−
（3'，4'−ジヒドロキシ−テトラヒドロ−ピラン−2'−
イル）−4H−ピラン−2−カルボン酸ジフェニルメチル 実施例６(i)で得られた化合物（4S, 5R, 6R, 2'R, 3'R,
4'R）−5−アセチルアミノ−4−（N，N'−ビス−t−ブ
チルオキシカルボニル）グアニジノ−5，6−ジヒドロ−
6−（3'，4'−ジヒドロキシ−テトラヒドロ−ピラン−
2'−イル）−4H−ピラン−2−カルボン酸メチル（1.95
g, 3.40 mmol）をメタノール（20 ml）に溶解し、氷冷
下1M水酸化ナトリウム水溶液（4.4 ml, 4.4 mmol）を加
え、30分間攪拌した。反応液に塩化メチレン（60 ml）
を加えた後、塩化メチレン（30 ml）と0.5M希塩酸（10
ml）に分配した。有機層を分離し、ジフェニルジアゾメ
タン（2 g, 10.3 mmol）を室温にて加え、５分間攪拌し
た。反応液を減圧留去後、得られた残査をクロマトグラ
フィー（シリカゲル、塩化メチレン/メタノール＝20/
1）に付して標記化合物を無色アモルファスとして得
た。（2.24 g、89％） IR (KBr)νmax： 3316, 3065, 2978, 2933, 2876, 173
0, 1641, 1612, 1561 cm-1. MS (FAB) m/e 725 ([M+H]+). HRMS (FAB) Calcd for C37H49O11N4 : 725.3398; found
725.3407 ([M+H]+).1 H NMR (400 MHz, CD3OD) δppm: 7.25-7.41 (10H, m),
6.90 (1H, s), 6.04(1H, d, J = 2.6 Hz), 5.05 (1H,
dd, J = 9.2, 2.6 Hz), 4.40 (1H, dd, J = 10.0, 1.0
Hz), 4.29 (1H, dd, J = 10.0, 9.2 Hz), 4.10-4.14 (1
H, m), 3.89 (1H, dd, J = 9.9, 3.0 Hz), 3.72 (1H, d
d, J = 9.9, 1.0 Hz), 3.66-3.69 (2H,m), 2.08-2.15
(1H, m), 1.94 (3H, s), 1.80-1.88 (1H, m), 1.70-1.7
7 (1H,m), 1.52 (9H, s), 1.47 (9H, s). （ii）（4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチルア
ミノ−4−（N，N'−ビス−t−ブチルオキシカルボニ
ル）グアニジノ−6−（4'−n−ブチリルオキシ−3'−ヒ
ドロキシ−テトラヒドロ−ピラン−2'−イル）−5，6−
ジヒドロ−4H−ピラン−2−カルボン酸ジフェニルメチ
ル [4'−アシルオキシ化合物]及び（4S, 5R, 6R, 2'S,
3'R, 4'R）−5−アセチルアミノ−4−（N，N'−ビス−
t−ブチルオキシカルボニル）グアニジノ−6−（3'−n
−ブチリルオキシ−4'−ヒドロキシ−テトラヒドロ−ピ
ラン−2'−イル）−5，6−ジヒドロ−4H−ピラン−2−
カルボン酸ジフェニルメチル [3'−アシルオキシ化合
物] 実施例１２(i)で得られた化合物（124 mg, 0.171 mmo
l）をメタノール（10 ml）に溶解し、室温にてジブチル
チンオキシド（45 mg, 0.179 mmol）を加え、70℃にて2
0分間攪拌した。反応液を減圧留去し、トルエンで共沸
した。得られた残査を真空ポンプで一時間乾燥後、トル
エンに溶解し、窒素雰囲気下、氷冷下ブチリルクロライ
ド（19 μl, 0.179 mmol）、トリエチルアミン（3 μl,
0.022 mmol）を滴下し、同温にて1時間攪拌した。メタ
ノールを加え、反応液を減圧留去後得られた残査をクロ
マトグラフィー（シリカゲル、ヘキサン／酢酸エチル＝
1／1）に付して標記化合物をそれぞれ無色アモルファス
として得た。（4'−アシルオキシ化合物：70 mg、41
％,）（3'−アシルオキシ化合物：26 mg、15％） （4'−アシルオキシ化合物） IR (KBr)νmax： 3317, 3090, 3065, 3033, 2973, 293
4, 2875, 1731, 1641,1611, 1555 cm-1. MS (FAB) m/e 795 ([M+H]+). HRMS (FAB) Calcd for C41H55O12N4 : 795.3816; found
795.3798 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 8.59 (1H, d, J = 8.
8 Hz), 7.26-7.38 (10H, m), 6.92 (1H, s), 6.45 (1H,
d, J = 6.6 Hz), 5.93 (1H, d, J = 2.9 Hz),5.32-5.3
6 (1H, m), 5.14-5.20 (1H, m), 4.28-4.36 (2H, m),
4.06-4.12 (1H,m), 3.81-3.87 (1H, m), 3.57-3.66 (2
H, m), 2.37 (2H, t, J = 7.3 Hz), 2.17 (1H, br), 1.
97 (1H, s), 1.89-1.96 (1H, m), 1.80-1.87 (1H, m),
1.62-1.72 (2H, m), 1.49 (9H, s), 1.49 (9H, s), 0.9
7 (3H, t, J = 7.3 Hz). （3'−アシルオキシ化合物） IR (KBr)νmax： 3314, 3090, 3065, 3033, 2974, 293
4, 2876, 1731, 1642,1611, 1561 cm-1. MS (FAB) m/e 795 ([M+H]+). HRMS (FAB) Calcd for C41H55O12N4 : 795.3816; found
795.3818 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 8.60 (1H, d, J = 9.
5 Hz), 7.25-7.42 (10H, m), 6.92 (1H, s), 5.88 (1H,
d, J = 2.2 Hz), 5.25 (1H, dd, J = 9.8, 2.6 Hz),
5.17 (1H, dd, J = 9.5, 8.8, 2.2 Hz), 4.48-4.53 (1
H, m), 4.34 (1H,ddd, J = 9.5, 8.8, 8.8 Hz), 4.20
(1H, d, J = 9.5 Hz), 3.95-4.00 (1H, m), 3.75-3.86
(2H, m), 2.26 (2H, t, J = 7.3 Hz), 1.99 (3H, s),
1.93-2.00 (1H, m), 1.76-1.82 (1H, m), 1.49 (18H,
s), 1.26 (2H, qt, J = 7.3, 7.3 Hz), 0.78 (3H, t, J
= 7.3 Hz). （iii）（4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチル
アミノ−6−（4'−n−ブチリルオキシ−3'−ヒドロキシ
−テトラヒドロ−ピラン−2'−イル）−5，6−ジヒドロ
−4−グアニジノ−4H−ピラン−2−カルボン酸 一水和
物 実施例１２(ii)で得られた4'−アシルオキシ化合物（70
mg, 0.088 mmol）を塩化メチレン（3ml）に溶解し、ト
リフルオロ酢酸（3 ml）を加え、4時間攪拌した。反応
液を減圧留去後、得られた残査を逆相クロマトグラフィ
ー（コスモシル、水/メタノール＝2/1）に付して標記4'
−n−ブチリルオキシ化合物（１％の3'−n−ブチリルオ
キシ化合物を含有する）を無色アモルファスとして得
た。（30mg、76％） 同様に実施例１２(ii)で得られた3'−アシルオキシ化合
物（40 mg, 0.050 mmol）を塩化メチレン（3ml）に溶解
し、トリフルオロ酢酸（3 ml）を加え、4時間攪拌し
た。反応液を減圧留去後、得られた残査を逆相クロマト
グラフィー（コスモシル、水/メタノール＝2/1）に付し
て標記4'−n−ブチリルオキシ化合物（１％の3'−n−ブ
チリルオキシ化合物を含有する）を無色アモルファスと
して得た。（15 mg、70％） （4'−n−ブチリルオキシ化合物） IR (KBr)νmax： 3336, 2965, 2935, 2876, 1668, 1619
cm-1. MS (FAB) m/e 429 ([M+H]+). HRMS (FAB) Calcd for C18H29O8N4 : 429.1985; found
429.1971 ([M+H]+).1 H NMR (400 MHz, CD3OD) δppm: 5.56 (1H, d, J = 2.
0 Hz), 5.28-5.31 (1H, m), 4.34-4.39 (2H, m), 4.19
(1H, dd, J = 8.8, 8.8 Hz), 4.07 (1H, dd, J= 9.8,
2.9 Hz), 3.75 (1H, ddd, J = 11.7, 10.7, 4.9 Hz),
3.72 (1H, dd, J= 9.8, 1.0 Hz), 3.52 (1H, ddd, J =
11.7, 10.7, 1.0 Hz), 2.38 (1H, t, J= 7.3 Hz), 1.99
(3H, s), 1.90-1.99 (1H, m), 1.76-1.82 (1H, m), 1.
67 (2H,qt, J = 7.3, 7.3 Hz), 0.97 (3H, t, J = 7.3
Hz). Anal. Calcd for C18H28N4O8 : C, 50.46; H, 6.59; N1
3.08. found C, 47.07; H, 6.48; N, 12.03. （実施例１３） （4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチルアミノ−
5，6−ジヒドロ−4−グアニジノ−6−（4'−n−ヘキサ
ノイルオキシ−3'−ヒドロキシ−テトラヒドロ−ピラン
−2'−イル）−4H−ピラン−2−カルボン酸 一水和物(I) (4S, 5R, 6R, 2'R, 3'R, 4'R) -5
-Acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) guanidino-5,6-dihydro-6-
(3 ′, 4′-dihydroxy-tetrahydro-pyran-2′-
Yl) -4H-pyran-2-carboxylate diphenylmethyl Compound obtained in Example 6 (i) (4S, 5R, 6R, 2'R, 3'R,
4'R) -5-acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) guanidino-5,6-dihydro-
6- (3 ', 4'-dihydroxy-tetrahydro-pyran-
Methyl 2'-yl) -4H-pyran-2-carboxylate (1.95
g, 3.40 mmol) was dissolved in methanol (20 ml), a 1 M aqueous sodium hydroxide solution (4.4 ml, 4.4 mmol) was added under ice cooling, and the mixture was stirred for 30 minutes. Methylene chloride (60 ml)
After addition of methylene chloride (30 ml) and 0.5 M dilute hydrochloric acid (10
ml). The organic layer was separated, diphenyldiazomethane (2 g, 10.3 mmol) was added at room temperature, and the mixture was stirred for 5 minutes. After evaporating the reaction solution under reduced pressure, the resulting residue was chromatographed (silica gel, methylene chloride / methanol = 20 /
By subjecting it to 1), the title compound was obtained as a colorless amorphous. (2.24 g, 89%) IR (KBr) νmax: 3316, 3065, 2978, 2933, 2876, 173
0, 1641, 1612, 1561 cm -1 . MS (FAB) m / e 725 ([M + H] + ) .HRMS (FAB) Calcd for C 37 H 49 O 11 N 4 : 725.3398; found
. 725.3407 ([M + H] +) 1 H NMR (400 MHz, CD 3 OD) δppm: 7.25-7.41 (10H, m),
6.90 (1H, s), 6.04 (1H, d, J = 2.6 Hz), 5.05 (1H,
dd, J = 9.2, 2.6 Hz), 4.40 (1H, dd, J = 10.0, 1.0
Hz), 4.29 (1H, dd, J = 10.0, 9.2 Hz), 4.10-4.14 (1
H, m), 3.89 (1H, dd, J = 9.9, 3.0 Hz), 3.72 (1H, d
d, J = 9.9, 1.0 Hz), 3.66-3.69 (2H, m), 2.08-2.15
(1H, m), 1.94 (3H, s), 1.80-1.88 (1H, m), 1.70-1.7
7 (1H, m), 1.52 (9H, s), 1.47 (9H, s). (Ii) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5-acetylamino-4- ( N, N'-bis-t-butyloxycarbonyl) guanidino-6- (4'-n-butyryloxy-3'-hydroxy-tetrahydro-pyran-2'-yl) -5,6-
Diphenylmethyl dihydro-4H-pyran-2-carboxylate [4'-acyloxy compound] and (4S, 5R, 6R, 2'S,
3'R, 4'R) -5-acetylamino-4- (N, N'-bis-
t-butyloxycarbonyl) guanidino-6- (3'-n
-Butyryloxy-4'-hydroxy-tetrahydro-pyran-2'-yl) -5,6-dihydro-4H-pyran-2-
Diphenylmethyl carboxylate [3'-acyloxy compound] The compound obtained in Example 12 (i) (124 mg, 0.171 mmo
l) was dissolved in methanol (10 ml), and dibutyltin oxide (45 mg, 0.179 mmol) was added at room temperature.
Stirred for 0 minutes. The reaction solution was distilled off under reduced pressure and azeotroped with toluene. The obtained residue was dried with a vacuum pump for 1 hour, dissolved in toluene, and butyryl chloride (19 μl, 0.179 mmol) and triethylamine (3 μl,
0.022 mmol) was added dropwise and stirred at the same temperature for 1 hour. Methanol was added, and the reaction mixture was evaporated under reduced pressure. The resulting residue was chromatographed (silica gel, hexane / ethyl acetate =
1/1) to give the title compounds as colorless amorphous materials. (4'-acyloxy compound: 70 mg, 41
%,) (3'-acyloxy compound: 26 mg, 15%) (4'-acyloxy compound) IR (KBr) νmax: 3317, 3090, 3065, 3033, 2973, 293
4, 2875, 1731, 1641,1611, 1555 cm -1 . MS (FAB) m / e 795 ([M + H] + ) .HRMS (FAB) Calcd for C 41 H 55 O 12 N 4 : 795.3816; found
. 795.3798 ([M + H] +) 1 H NMR (400 MHz, CDCl 3) δppm: 8.59 (1H, d, J = 8.
8 Hz), 7.26-7.38 (10H, m), 6.92 (1H, s), 6.45 (1H,
d, J = 6.6 Hz), 5.93 (1H, d, J = 2.9 Hz), 5.32-5.3
6 (1H, m), 5.14-5.20 (1H, m), 4.28-4.36 (2H, m),
4.06-4.12 (1H, m), 3.81-3.87 (1H, m), 3.57-3.66 (2
H, m), 2.37 (2H, t, J = 7.3 Hz), 2.17 (1H, br), 1.
97 (1H, s), 1.89-1.96 (1H, m), 1.80-1.87 (1H, m),
1.62-1.72 (2H, m), 1.49 (9H, s), 1.49 (9H, s), 0.9
7 (3H, t, J = 7.3 Hz). (3'-acyloxy compound) IR (KBr) νmax: 3314, 3090, 3065, 3033, 2974, 293
4, 2876, 1731, 1642,1611, 1561 cm -1 . MS (FAB) m / e 795 ([M + H] + ) .HRMS (FAB) Calcd for C 41 H 55 O 12 N 4 : 795.3816; found
. 795.3818 ([M + H] +) 1 H NMR (400 MHz, CDCl 3) δppm: 8.60 (1H, d, J = 9.
5 Hz), 7.25-7.42 (10H, m), 6.92 (1H, s), 5.88 (1H,
d, J = 2.2 Hz), 5.25 (1H, dd, J = 9.8, 2.6 Hz),
5.17 (1H, dd, J = 9.5, 8.8, 2.2 Hz), 4.48-4.53 (1
H, m), 4.34 (1H, ddd, J = 9.5, 8.8, 8.8 Hz), 4.20
(1H, d, J = 9.5 Hz), 3.95-4.00 (1H, m), 3.75-3.86
(2H, m), 2.26 (2H, t, J = 7.3 Hz), 1.99 (3H, s),
1.93-2.00 (1H, m), 1.76-1.82 (1H, m), 1.49 (18H,
s), 1.26 (2H, qt, J = 7.3, 7.3 Hz), 0.78 (3H, t, J
(7.3 Hz). (Iii) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5-acetylamino-6- (4'-n-butyryloxy-3'-hydroxy-tetrahydro-pyran- 2'-yl) -5,6-dihydro-4-guanidino-4H-pyran-2-carboxylic acid monohydrate 4'-acyloxy compound (70) obtained in Example 12 (ii)
mg, 0.088 mmol) was dissolved in methylene chloride (3 ml), trifluoroacetic acid (3 ml) was added, and the mixture was stirred for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to reverse phase chromatography (Cosmosil, water / methanol = 2/1) to give the title 4 ′
A -n-butyryloxy compound (containing 1% of a 3'-n-butyryloxy compound) was obtained as a colorless amorphous. (30 mg, 76%) Similarly, the 3′-acyloxy compound (40 mg, 0.050 mmol) obtained in Example 12 (ii) was dissolved in methylene chloride (3 ml), and trifluoroacetic acid (3 ml) was added. Stir for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to reverse phase chromatography (Cosmosil, water / methanol = 2/1) to give the title 4'-n-butyryloxy compound (1% of 3'-n- Containing a butyryloxy compound) as a colorless amorphous. (15 mg, 70%) (4'-n-butyryloxy compound) IR (KBr) νmax: 3336, 2965, 2935, 2876, 1668, 1619
cm -1 .MS (FAB) m / e 429 ([M + H] + ) .HRMS (FAB) Calcd for C 18 H 29 O 8 N 4 : 429.1985; found
. 429.1971 ([M + H] +) 1 H NMR (400 MHz, CD 3 OD) δppm: 5.56 (1H, d, J = 2.
0 Hz), 5.28-5.31 (1H, m), 4.34-4.39 (2H, m), 4.19
(1H, dd, J = 8.8, 8.8 Hz), 4.07 (1H, dd, J = 9.8,
2.9 Hz), 3.75 (1H, ddd, J = 11.7, 10.7, 4.9 Hz),
3.72 (1H, dd, J = 9.8, 1.0 Hz), 3.52 (1H, ddd, J =
11.7, 10.7, 1.0 Hz), 2.38 (1H, t, J = 7.3 Hz), 1.99
(3H, s), 1.90-1.99 (1H, m), 1.76-1.82 (1H, m), 1.
67 (2H, qt, J = 7.3, 7.3 Hz), 0.97 (3H, t, J = 7.3
Hz). Anal.Calcd for C 18 H 28 N 4 O 8 : C, 50.46; H, 6.59; N1
3.08. Found C, 47.07; H, 6.48; N, 12.03. (Example 13) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5-acetylamino-
5,6-dihydro-4-guanidino-6- (4'-n-hexanoyloxy-3'-hydroxy-tetrahydro-pyran-2'-yl) -4H-pyran-2-carboxylic acid monohydrate
【０３０５】[0305]
【化２５】 Embedded image
【０３０６】（i）（4S, 5R, 6R, 2'R, 3'S, 4'R）−5
−アセチルアミノ−4−（N，N'−ビス−t−ブチルオキ
シカルボニル）グアニジノ−6−（4'−n−ヘキサノイル
オキシ−3'−ヒドロキシ−テトラヒドロ−ピラン−2'−
イル）−5，6−ジヒドロ−4H−ピラン−2−カルボン酸
ジフェニルメチル [4'−アシルオキシ化合物]及び（4
S, 5R, 6R, 2'S, 3'R, 4'R）−5−アセチルアミノ−4−
（N，N'−ビス−t−ブチルオキシカルボニル）グアニジ
ノ−6−（3'−n−ヘキサノイルオキシ−4'−ヒドロキシ
−テトラヒドロ−ピラン−2'−イル）−5，6−ジヒドロ
−4H−ピラン−2−カルボン酸ジフェニルメチル [3'−
アシルオキシ化合物] 実施例１２(i)で得られた化合物（4S, 5R, 6R, 2'R, 3'
R, 4'R）−5−アセチルアミノ−4−（N，N'−ビス−t−
ブチルオキシカルボニル）グアニジノ−5，6−ジヒドロ
−6−（3'，4'−ジヒドロキシ−テトラヒドロ−ピラン
−2'−イル）−4H−ピラン−2−カルボン酸ジフェニル
メチル（150 mg, 0.207 mmol）をメタノール（10 ml）
に溶解し、室温にてジブチルチンオキシド（54 mg, 0.2
17 mmol）を加え、70℃にて20分間攪拌した。反応液を
減圧留去し、トルエンで共沸した。得られた残査を真空
ポンプで一時間乾燥後、トルエンに溶解し、窒素雰囲気
下、氷冷下ヘキサノイルクロライド（30 μl, 0.217 mm
ol）、トリエチルアミン（3 μl, 0.022 mmol）を滴下
し、同温にて1時間攪拌した。メタノールを加え、反応
液を減圧留去後得られた残査をクロマトグラフィー（シ
リカゲル、ヘキサン／酢酸エチル＝1／1）に付して標記
化合物をそれぞれ無色アモルファスとして得た。（4'−
アシルオキシ化合物：89 mg、51％）（3'−アシルオキ
シ化合物：50 mg、29％） （4'−アシルオキシ化合物） IR (CDCl3)νmax： 3313, 3279, 3264, 2961, 2930, 28
73, 2857, 1727, 1686, 1639, 1606, 1567 cm-1. MS (FAB) m/e 823 ([M+H]+). HRMS (FAB) Calcd for C43H59O12N4 : 823.4130; found
823.4150 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 8.59 (1H, d, J = 8.
8 Hz), 7.26-7.38 (10H, m), 6.92 (1H, s), 6.43 (1H,
d, J = 6.6 Hz), 5.93 (1H, d, J = 2.9 Hz),5.31-5.3
5 (1H, m), 5.14-5.20 (1H, m), 4.28-4.36 (2H, m),
4.06-4.12 (1H,m), 3.81-3.87 (1H, m), 3.57-3.66 (2
H, m), 2.37 (2H, t, J = 7.3 Hz), 2.17 (1H, br), 1.
97 (1H, s), 1.89-1.96 (1H, m), 1.80-1.87 (1H, m),
1.60-1.68 (2H, m), 1.49 (9H, s), 1.49 (9H, s), 1.2
8-1.36 (4H, m), 0.94 (3H, t, J= 7.3 Hz). （4'−アシルオキシ化合物） IR (CDCl3)νmax： 3313, 2980, 2961, 2932, 2874, 17
30, 1686, 1643, 1606, 1572 cm-1. MS (FAB) m/e 823 ([M+H]+). HRMS (FAB) Calcd for C43H59O12N4 : 823.4130; found
823.4151 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 8.60 (1H, d, J = 8.
8 Hz), 7.25-7.42 (10H, m), 6.92 (1H, s), 5.89 (1H,
d, J = 2.2 Hz), 5.25 (1H, dd, J = 10.3, 2.2 Hz),
5.17 (1H, dd, J = 8.8, 8.8, 2.2 Hz), 4.46-4.51 (1
H, m), 4.31 (1H, ddd, J = 10.3, 8.8, 8.8 Hz), 4.18
(1H, d, J = 10.3 Hz), 3.97 (1H, d, J= 10.3 Hz),
3.74-3.85 (1H, m), 2.26-2.32 (2H, m), 1.99 (3H,
s), 1.93-2.00 (1H, m), 1.76-1.82 (1H, m), 1.49 (18
H, s), 1.14-1.28 (6H, m), 0.79 (3H, t, J = 7.3 H
z). （ii）（4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチルア
ミノ−5，6−ジヒドロ−4−グアニジノ−6−（4'−n−
ヘキサノイルオキシ−3'−ヒドロキシ−テトラヒドロ−
ピラン−2'−イル）−4H−ピラン−2−カルボン酸 一水
和物 実施例１３(i)で得られた4'−アシルオキシ化合物（80
mg, 0.097 mmol）を塩化メチレン（3ml）に溶解し、ト
リフルオロ酢酸（3 ml）を加え、4時間攪拌した。反応
液を減圧留去後、得られた残査を逆相クロマトグラフィ
ー（コスモシル、水/メタノール＝1/1）に付して標記4'
−n−ヘキサノイルオキシ化合物（７％の3'−n−ヘキサ
ノイルオキシ化合物を含有する）を無色アモルファスと
して得た。（37 mg、80％） 同様に実施例１３(i)で得られた3'−アシルオキシ化合
物（44 mg, 0.053 mmol）を塩化メチレン（3ml）に溶解
し、トリフルオロ酢酸（3 ml）を加え、4時間攪拌し
た。反応液を減圧留去後、得られた残査を逆相クロマト
グラフィー（コスモシル、水/メタノール＝1/1）に付し
て標記4'−n−ヘキサノイルオキシ化合物（１％の3'−n
−ヘキサノイルオキシ化合物を含有する）を無色アモル
ファスとして得た。（20 mg、79％） IR (KBr)νmax： 3341, 3273, 2959, 2930, 2933, 287
2, 1737, 1658, 1617 cm-1. MS (FAB) m/e 457 ([M+H]+). HRMS (FAB) Calcd for C20H33O8N4 : 457.2298; found
457.2291 ([M+H]+).1 H NMR (400 MHz, CD3OD) δppm: 5.55 (1H, d, J = 2.
9 Hz), 5.28-5.31 (1H, m), 4.34-4.38 (2H, m), 4.19
(1H, dd, J = 8.8, 8.8 Hz), 4.07 (1H, dd, J= 9.5,
2.9 Hz), 3.75 (1H, ddd, J = 11.7, 10.7, 4.9 Hz),
3.72 (1H, dd, J= 9.5, 1.5 Hz), 3.52 (1H, ddd, J =
11.7, 10.7, 1.0 Hz), 2.38 (2H, t, J= 7.3 Hz), 1.99
(3H, s), 1.90-1.99 (1H, m), 1.76-1.82 (1H, m), 1.
60-1.70(2H, m), 1.28-1.40 (4H, m), 0.92 (3H, t, J
= 7.3 Hz). （実施例１４） （4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチルアミノ−
5，6−ジヒドロ−4−グアニジノ−6−（3'−ヒドロキシ
−4'−n−オクタノイルオキシ−テトラヒドロ−ピラン
−2'−イル）−4H−ピラン−2−カルボン酸 一水和物(I) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5
-Acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) guanidino-6- (4'-n-hexanoyloxy-3'-hydroxy-tetrahydro-pyran-2'-
Yl) -5,6-dihydro-4H-pyran-2-carboxylate diphenylmethyl [4′-acyloxy compound] and (4
S, 5R, 6R, 2'S, 3'R, 4'R) -5-acetylamino-4-
(N, N'-bis-t-butyloxycarbonyl) guanidino-6- (3'-n-hexanoyloxy-4'-hydroxy-tetrahydro-pyran-2'-yl) -5,6-dihydro-4H -Diphenylmethyl pyran-2-carboxylate [3'-
Acyloxy compound] Compound (4S, 5R, 6R, 2′R, 3 ′) obtained in Example 12 (i)
R, 4'R) -5-acetylamino-4- (N, N'-bis-t-
(Butyloxycarbonyl) guanidino-5,6-dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4H-pyran-2-carboxylate diphenylmethyl (150 mg, 0.207 mmol) To methanol (10 ml)
And dibutyltin oxide (54 mg, 0.2 mg) at room temperature.
17 mmol) and stirred at 70 ° C. for 20 minutes. The reaction solution was distilled off under reduced pressure and azeotroped with toluene. The obtained residue was dried with a vacuum pump for 1 hour, dissolved in toluene, and hexanoyl chloride (30 μl, 0.217 mm
ol) and triethylamine (3 μl, 0.022 mmol) were added dropwise, and the mixture was stirred at the same temperature for 1 hour. Methanol was added, the reaction solution was evaporated under reduced pressure, and the obtained residue was subjected to chromatography (silica gel, hexane / ethyl acetate = 1/1) to give the title compounds as colorless amorphous materials. (4'-
Acyloxy compound: 89 mg, 51%) (3′-acyloxy compound: 50 mg, 29%) (4′-acyloxy compound) IR (CDCl 3 ) νmax: 3313, 3279, 3264, 2961, 2930, 28
73, 2857, 1727, 1686, 1639, 1606, 1567 cm -1 . MS (FAB) m / e 823 ([M + H] + ) .HRMS (FAB) Calcd for C 43 H 59 O 12 N 4 : 823.4130 ; found
. 823.4150 ([M + H] +) 1 H NMR (400 MHz, CDCl 3) δppm: 8.59 (1H, d, J = 8.
8 Hz), 7.26-7.38 (10H, m), 6.92 (1H, s), 6.43 (1H,
d, J = 6.6 Hz), 5.93 (1H, d, J = 2.9 Hz), 5.31-5.3
5 (1H, m), 5.14-5.20 (1H, m), 4.28-4.36 (2H, m),
4.06-4.12 (1H, m), 3.81-3.87 (1H, m), 3.57-3.66 (2
H, m), 2.37 (2H, t, J = 7.3 Hz), 2.17 (1H, br), 1.
97 (1H, s), 1.89-1.96 (1H, m), 1.80-1.87 (1H, m),
1.60-1.68 (2H, m), 1.49 (9H, s), 1.49 (9H, s), 1.2
8-1.36 (4H, m), 0.94 (3H, t, J = 7.3 Hz) (4'- acyloxy compound) IR (CDCl 3) νmax: . 3313, 2980, 2961, 2932, 2874, 17
30, 1686, 1643, 1606, 1572 cm -1 . MS (FAB) m / e 823 ([M + H] + ) .HRMS (FAB) Calcd for C 43 H 59 O 12 N 4 : 823.4130; found
. 823.4151 ([M + H] +) 1 H NMR (400 MHz, CDCl 3) δppm: 8.60 (1H, d, J = 8.
8 Hz), 7.25-7.42 (10H, m), 6.92 (1H, s), 5.89 (1H,
d, J = 2.2 Hz), 5.25 (1H, dd, J = 10.3, 2.2 Hz),
5.17 (1H, dd, J = 8.8, 8.8, 2.2 Hz), 4.46-4.51 (1
H, m), 4.31 (1H, ddd, J = 10.3, 8.8, 8.8 Hz), 4.18
(1H, d, J = 10.3 Hz), 3.97 (1H, d, J = 10.3 Hz),
3.74-3.85 (1H, m), 2.26-2.32 (2H, m), 1.99 (3H,
s), 1.93-2.00 (1H, m), 1.76-1.82 (1H, m), 1.49 (18
H, s), 1.14-1.28 (6H, m), 0.79 (3H, t, J = 7.3 H
z). (ii) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5-acetylamino-5,6-dihydro-4-guanidino-6- (4'-n-
Hexanoyloxy-3'-hydroxy-tetrahydro-
Pyran-2'-yl) -4H-pyran-2-carboxylic acid monohydrate The 4'-acyloxy compound (80) obtained in Example 13 (i)
mg, 0.097 mmol) was dissolved in methylene chloride (3 ml), trifluoroacetic acid (3 ml) was added, and the mixture was stirred for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to reverse phase chromatography (Cosmosil, water / methanol = 1/1) to give the title 4 ′
A -n-hexanoyloxy compound (containing 7% of 3'-n-hexanoyloxy compound) was obtained as a colorless amorphous. (37 mg, 80%) Similarly, the 3'-acyloxy compound (44 mg, 0.053 mmol) obtained in Example 13 (i) was dissolved in methylene chloride (3 ml), and trifluoroacetic acid (3 ml) was added. And stirred for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to reverse phase chromatography (Cosmosil, water / methanol = 1/1) to give the title 4'-n-hexanoyloxy compound (1% of 3'- n
-Containing a hexanoyloxy compound) as a colorless amorphous. (20 mg, 79%) IR (KBr) νmax: 3341, 3273, 2959, 2930, 2933, 287
2, 1737, 1658, 1617 cm -1 . MS (FAB) m / e 457 ([M + H] + ) .HRMS (FAB) Calcd for C 20 H 33 O 8 N 4 : 457.2298; found
. 457.2291 ([M + H] +) 1 H NMR (400 MHz, CD 3 OD) δppm: 5.55 (1H, d, J = 2.
9 Hz), 5.28-5.31 (1H, m), 4.34-4.38 (2H, m), 4.19
(1H, dd, J = 8.8, 8.8 Hz), 4.07 (1H, dd, J = 9.5,
2.9 Hz), 3.75 (1H, ddd, J = 11.7, 10.7, 4.9 Hz),
3.72 (1H, dd, J = 9.5, 1.5 Hz), 3.52 (1H, ddd, J =
11.7, 10.7, 1.0 Hz), 2.38 (2H, t, J = 7.3 Hz), 1.99
(3H, s), 1.90-1.99 (1H, m), 1.76-1.82 (1H, m), 1.
60-1.70 (2H, m), 1.28-1.40 (4H, m), 0.92 (3H, t, J
(Example 14) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5-acetylamino-
5,6-dihydro-4-guanidino-6- (3'-hydroxy-4'-n-octanoyloxy-tetrahydro-pyran-2'-yl) -4H-pyran-2-carboxylic acid monohydrate
【０３０７】[0307]
【化２６】 Embedded image
【０３０８】（i）（4S, 5R, 6R, 2'R, 3'S, 4'R）−5
−アセチルアミノ−4−（N，N'−ビス−t−ブチルオキ
シカルボニル）グアニジノ−5，6−ジヒドロ−6−（3'
−ヒドロキシ−4'−n−オクタノイルオキシ−テトラヒ
ドロ−ピラン−2'−イル）−4H−ピラン−2−カルボン
酸ジフェニルメチル [4'−アシルオキシ化合物]及び
（4S, 5R, 6R, 2'S, 3'R, 4'R）−5−アセチルアミノ−
4−（N，N'−ビス−t−ブチルオキシカルボニル）グア
ニジノ−5，6−ジヒドロ−6−（4'−ヒドロキシ−3'−n
−オクタノイルオキシ−テトラヒドロ−ピラン−2'−イ
ル）−4H−ピラン−2−カルボン酸ジフェニルメチル
[3'−アシルオキシ化合物] 実施例１２(i)で得られた化合物（4S, 5R, 6R, 2'R, 3'
R, 4'R）−5−アセチルアミノ−4−（N，N'−ビス−t−
ブチルオキシカルボニル）グアニジノ−5，6−ジヒドロ
−6−（3'，4'−ジヒドロキシ−テトラヒドロ−ピラン
−2'−イル）−4H−ピラン−2−カルボン酸ジフェニル
メチル（100 mg, 0.138 mmol）をメタノール（10 ml）
に溶解し、室温にてジブチルチンオキシド（36 mg, 0.1
45 mmol）を加え、70℃にて20分間攪拌した。反応液を
減圧留去し、トルエンで共沸した。得られた残査を真空
ポンプで一時間乾燥後、トルエンに溶解し、窒素雰囲気
下、氷冷下オクタノイルクロライド（25 μl, 0.145 mm
ol）、トリエチルアミン（3 μl, 0.022 mmol）を滴下
し、同温にて1時間攪拌した。メタノールを加え、反応
液を減圧留去後得られた残査をクロマトグラフィー（シ
リカゲル、ヘキサン／酢酸エチル＝1／1）に付して標記
化合物をそれぞれ無色アモルファスとして得た。（4'−
アシルオキシ化合物：60 mg、51％）（3'−アシルオキ
シ化合物：20 mg、17％） （4'−アシルオキシ化合物） IR (KBr)νmax： 3315, 2959, 2931, 2860, 1732, 164
1, 1610, 1555cm-1. MS (FAB) m/e 851 ([M+H]+). HRMS (FAB) Calcd for C45H63O12N4 : 851.4442; found
851.4456 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 8.59 (1H, d, J = 8.
8 Hz), 7.26-7.38 (10H, m), 6.92 (1H, s), 6.43 (1H,
d, J = 6.6 Hz), 5.93 (1H, d, J = 2.9 Hz),5.31-5.3
5 (1H, m), 5.14-5.20 (1H, m), 4.28-4.36 (2H, m),
4.06-4.12 (1H,m), 3.81-3.87 (1H, m), 3.57-3.66 (2
H, m), 2.37 (2H, t, J = 7.3 Hz), 2.17 (1H, br), 1.
97 (1H, s), 1.89-1.96 (1H, m), 1.80-1.87 (1H, m),
1.60-1.68 (2H, m), 1.49 (9H, s), 1.49 (9H, s), 1.2
4-1.36 (8H, m), 0.89 (3H, t, J= 7.3 Hz). （3'−アシルオキシ化合物） IR (CDCl3)νmax： 2958, 2929, 2856, 1729, 1686, 16
42, 1607 cm-1. MS (FAB) m/e 851 ([M+H]+). HRMS (FAB) Calcd for C45H63O12N4 : 851.4442; found
851.4444 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 8.60 (1H, d, J = 8.
8 Hz), 7.25-7.42 (10H, m), 6.92 (1H, s), 5.89 (1H,
d, J = 2.2 Hz), 5.25 (1H, dd, J = 10.3, 2.2 Hz),
5.17 (1H, dd, J = 8.8, 8.8, 2.2 Hz), 4.46-4.51 (1
H, m), 4.31 (1H, ddd, J = 10.3, 8.8, 8.8 Hz), 4.18
(1H, d, J = 10.3 Hz), 3.97 (1H, d, J= 10.3 Hz),
3.74-3.85 (1H, m), 2.26-2.32 (2H, m), 1.99 (3H,
s), 1.93-2.00 (1H, m), 1.76-1.82 (1H, m), 1.49 (18
H, s), 1.14-1.28 (10H, m), 0.79 (3H, t, J = 7.3 H
z). （ii）（4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチルア
ミノ−5，6−ジヒドロ−4−グアニジノ−6−（3'−ヒド
ロキシ−4'−n−オクタノイルオキシ−テトラヒドロ−
ピラン−2'−イル）−4H−ピラン−2−カルボン酸 一水
和物 実施例１４(i)で得られた4'−アシルオキシ化合物（72
mg, 0.084 mmol）を塩化メチレン（3ml）に溶解し、ト
リフルオロ酢酸（1ml）を加え、4時間攪拌した。反応液
を減圧留去後、得られた残査を逆相クロマトグラフィー
（コスモシル、水/メタノール＝1/2）に付して標記4'−
n−オクタノイルオキシ化合物（７％の3'−n−オクタノ
イルオキシ化合物を包含する）を無色アモルファスとし
て得た。（30 mg、70％） 同様に3'−アシルオキシ化合物（20 mg, 0.024 mmol）
を塩化メチレン（3ml）に溶解し、トリフルオロ酢酸（1
ml）を加え、4時間攪拌した。反応液を減圧留去後、得
られた残査を逆相クロマトグラフィー（コスモシル、水
/メタノール＝1/2）に付して標記4'−n−オクタノイル
オキシ化合物（１０％の3'−n−オクタノイルオキシ化
合物を包含する）を無色アモルファスとして得た。（8
mg、67％） IR (KBr)νmax： 3340, 3208, 2929, 2858, 1738, 166
5, 1619 cm-1. MS (FAB) m/e 485 ([M+H]+). HRMS (FAB) Calcd for C22H37O8N4 : 485.2612; found
485.2610 ([M+H]+).1 H NMR (400 MHz, CD3OD) δppm: 5.53 (1H, d, J = 2.
9 Hz), 5.27-5.31 (1H, m), 4.34-4.38 (2H, m), 4.19
(1H, dd, J = 8.8, 8.8 Hz), 4.08 (1H, dd, J= 9.5,
2.9 Hz), 3.75 (1H, ddd, J = 11.7, 10.7, 4.9 Hz),
3.72 (1H, dd, J= 9.5, 1.5 Hz), 3.50 (1H, ddd, J =
11.7, 10.7, 1.0 Hz), 2.39 (2H, t, J= 7.3 Hz), 1.99
(3H, s), 1.90-1.99 (1H, m), 1.76-1.82 (1H, m), 1.
60-1.70(2H, m), 1.28-1.40 (8H, m), 0.90 (3H, t, J
= 7.3 Hz). （実施例１５） （4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチルアミノ−
6−（4'−n−デカノイルオキシ−3'−ヒドロキシ−テト
ラヒドロ−ピラン−2'−イル）−5，6−ジヒドロ−4−
グアニジノ−4H−ピラン−2−カルボン酸 一水和物(I) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5
-Acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) guanidino-5,6-dihydro-6- (3 '
-Hydroxy-4'-n-octanoyloxy-tetrahydro-pyran-2'-yl) -4H-pyran-2-carboxylic acid diphenylmethyl [4'-acyloxy compound] and (4S, 5R, 6R, 2'S, 3 'R, 4'R) -5-acetylamino-
4- (N, N'-bis-t-butyloxycarbonyl) guanidino-5,6-dihydro-6- (4'-hydroxy-3'-n
-Octanoyloxy-tetrahydro-pyran-2'-yl) -4H-pyran-2-carboxylate diphenylmethyl
[3′-Acyloxy compound] The compound (4S, 5R, 6R, 2′R, 3 ′) obtained in Example 12 (i)
R, 4'R) -5-acetylamino-4- (N, N'-bis-t-
(Butyloxycarbonyl) guanidino-5,6-dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4H-pyran-2-carboxylate diphenylmethyl (100 mg, 0.138 mmol) To methanol (10 ml)
And dibutyltin oxide (36 mg, 0.1
45 mmol) and stirred at 70 ° C. for 20 minutes. The reaction solution was distilled off under reduced pressure and azeotroped with toluene. The obtained residue was dried with a vacuum pump for 1 hour, dissolved in toluene, and cooled with octanoyl chloride (25 μl, 0.145 mm
ol) and triethylamine (3 μl, 0.022 mmol) were added dropwise, and the mixture was stirred at the same temperature for 1 hour. Methanol was added, the reaction solution was evaporated under reduced pressure, and the obtained residue was subjected to chromatography (silica gel, hexane / ethyl acetate = 1/1) to give the title compounds as colorless amorphous materials. (4'-
Acyloxy compound: 60 mg, 51%) (3′-acyloxy compound: 20 mg, 17%) (4′-acyloxy compound) IR (KBr) νmax: 3315, 2959, 2931, 2860, 1732, 164
1, 1610, 1555cm -1 . MS (FAB) m / e 851 ([M + H] + ). HRMS (FAB) Calcd for C 45 H 63 O 12 N 4 : 851.4442; found
851.4456 ([M + H] + ). 1 H NMR (400 MHz, CDCl 3 ) δppm: 8.59 (1H, d, J = 8.
8 Hz), 7.26-7.38 (10H, m), 6.92 (1H, s), 6.43 (1H,
d, J = 6.6 Hz), 5.93 (1H, d, J = 2.9 Hz), 5.31-5.3
5 (1H, m), 5.14-5.20 (1H, m), 4.28-4.36 (2H, m),
4.06-4.12 (1H, m), 3.81-3.87 (1H, m), 3.57-3.66 (2
H, m), 2.37 (2H, t, J = 7.3 Hz), 2.17 (1H, br), 1.
97 (1H, s), 1.89-1.96 (1H, m), 1.80-1.87 (1H, m),
1.60-1.68 (2H, m), 1.49 (9H, s), 1.49 (9H, s), 1.2
4-1.36 (8H, m), 0.89 (3H, t, J = 7.3 Hz) (3'- acyloxy compound) IR (CDCl 3) νmax: . 2958, 2929, 2856, 1729, 1686, 16
42, 1607 cm -1 . MS (FAB) m / e 851 ([M + H] + ). HRMS (FAB) Calcd for C 45 H 63 O 12 N 4 : 851.4442; found
. 851.4444 ([M + H] +) 1 H NMR (400 MHz, CDCl 3) δppm: 8.60 (1H, d, J = 8.
8 Hz), 7.25-7.42 (10H, m), 6.92 (1H, s), 5.89 (1H,
d, J = 2.2 Hz), 5.25 (1H, dd, J = 10.3, 2.2 Hz),
5.17 (1H, dd, J = 8.8, 8.8, 2.2 Hz), 4.46-4.51 (1
H, m), 4.31 (1H, ddd, J = 10.3, 8.8, 8.8 Hz), 4.18
(1H, d, J = 10.3 Hz), 3.97 (1H, d, J = 10.3 Hz),
3.74-3.85 (1H, m), 2.26-2.32 (2H, m), 1.99 (3H,
s), 1.93-2.00 (1H, m), 1.76-1.82 (1H, m), 1.49 (18
H, s), 1.14-1.28 (10H, m), 0.79 (3H, t, J = 7.3 H
z). (ii) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5-acetylamino-5,6-dihydro-4-guanidino-6- (3'-hydroxy-4'- n-octanoyloxy-tetrahydro-
Pyran-2'-yl) -4H-pyran-2-carboxylic acid monohydrate 4'-acyloxy compound (72) obtained in Example 14 (i)
mg, 0.084 mmol) was dissolved in methylene chloride (3 ml), trifluoroacetic acid (1 ml) was added, and the mixture was stirred for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to reverse phase chromatography (Cosmosil, water / methanol = 1/2) to give the title 4'-
The n-octanoyloxy compound (including 7% 3'-n-octanoyloxy compound) was obtained as a colorless amorphous. (30 mg, 70%) Similarly, 3'-acyloxy compound (20 mg, 0.024 mmol)
Was dissolved in methylene chloride (3 ml) and trifluoroacetic acid (1
ml) and stirred for 4 hours. After the reaction solution was distilled off under reduced pressure, the resulting residue was subjected to reverse phase chromatography (Cosmosil, water
/ Methanol = 1/2) to give the title 4'-n-octanoyloxy compound (including 10% of the 3'-n-octanoyloxy compound) as a colorless amorphous. (8
mg, 67%) IR (KBr) νmax: 3340, 3208, 2929, 2858, 1738, 166
5, 1619 cm -1 . MS (FAB) m / e 485 ([M + H] + ) .HRMS (FAB) Calcd for C 22 H 37 O 8 N 4 : 485.2612; found
. 485.2610 ([M + H] +) 1 H NMR (400 MHz, CD 3 OD) δppm: 5.53 (1H, d, J = 2.
9 Hz), 5.27-5.31 (1H, m), 4.34-4.38 (2H, m), 4.19
(1H, dd, J = 8.8, 8.8 Hz), 4.08 (1H, dd, J = 9.5,
2.9 Hz), 3.75 (1H, ddd, J = 11.7, 10.7, 4.9 Hz),
3.72 (1H, dd, J = 9.5, 1.5 Hz), 3.50 (1H, ddd, J =
11.7, 10.7, 1.0 Hz), 2.39 (2H, t, J = 7.3 Hz), 1.99
(3H, s), 1.90-1.99 (1H, m), 1.76-1.82 (1H, m), 1.
60-1.70 (2H, m), 1.28-1.40 (8H, m), 0.90 (3H, t, J
(Example 15) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5-acetylamino-
6- (4'-n-decanoyloxy-3'-hydroxy-tetrahydro-pyran-2'-yl) -5,6-dihydro-4-
Guanidino-4H-pyran-2-carboxylic acid monohydrate
【０３０９】[0309]
【化２７】 Embedded image
【０３１０】（i）（4S, 5R, 6R, 2'R, 3'S, 4'R）−5
−アセチルアミノ−4−（N，N'−ビス−t−ブチルオキ
シカルボニル）グアニジノ−6−（4'−n−デカノイルオ
キシ−3'−ヒドロキシ−テトラヒドロ−ピラン−2'−イ
ル）−5，6−ジヒドロ−4H−ピラン−2−カルボン酸ジ
フェニルメチル ［4'−アシルオキシ化合物］及び（4
S, 5R, 6R, 2'S, 3'R, 4'R）−5−アセチルアミノ−4−
（N，N'−ビス−t−ブチルオキシカルボニル）グアニジ
ノ−6−（3'−n−デカノイルオキシ−4'−ヒドロキシ−
テトラヒドロ−ピラン−2'−イル）−5，6−ジヒドロ−
4H−ピラン−2−カルボン酸ジフェニルメチル ［3'−
アシルオキシ化合物］ 実施例１２(i)で得られた化合物（4S, 5R, 6R, 2'R, 3'
R, 4'R）−5−アセチルアミノ−4−（N，N'−ビス−t−
ブチルオキシカルボニル）グアニジノ−5，6−ジヒドロ
−6−（3'，4'−ジヒドロキシ−テトラヒドロ−ピラン
−2'−イル）−4H−ピラン−2−カルボン酸ジフェニル
メチル（158 mg, 0.217 mmol）をメタノール（10 ml）
に溶解し、室温にてジブチルチンオキシド（57 mg, 0.2
28 mmol）を加え、70℃にて20分間攪拌した。反応液を
減圧留去し、トルエンで共沸した。得られた残査を真空
ポンプで一時間乾燥後、トルエンに溶解し、窒素雰囲気
下、氷冷下デカノイルクロライド（47 μl, 0.23 mmo
l）、トリエチルアミン（3μl, 0.022 mmol）を滴下
し、同温にて1時間攪拌した。メタノールを加え、反応
液を減圧留去後得られた残査をクロマトグラフィー（シ
リカゲル、ヘキサン／酢酸エチル＝1／1）に付して標記
化合物をそれぞれ無色アモルファスとして得た。（4'−
アシルオキシ化合物：80 mg、42％）（3'−アシルオキ
シ化合物：68 mg、35％） （4'−アシルオキシ化合物） IR (CDCl3)νmax： 2958, 2928, 2856, 1728, 1686, 16
40, 1606, 1567 cm-1. MS (FAB) m/e 879 ([M+H]+). HRMS (FAB) Calcd for C47H67O12N4 : 879.4755; found
879.4779 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 8.59 (1H, d, J = 8.
8 Hz), 7.26-7.38 (10H, m), 6.92 (1H, s), 6.43 (1H,
d, J = 6.6 Hz), 5.93 (1H, d, J = 2.9 Hz),5.31-5.3
5 (1H, m), 5.14-5.20 (1H, m), 4.28-4.36 (2H, m),
4.06-4.12 (1H,m), 3.81-3.87 (1H, m), 3.57-3.66 (2
H, m), 2.37 (2H, t, J = 7.3 Hz), 2.16 (1H, br), 1.
97 (1H, s), 1.89-1.96 (1H, m), 1.80-1.87 (1H, m),
1.60-1.68 (2H, m), 1.49 (9H, s), 1.49 (9H, s), 1.2
4-1.36 (12H, m), 0.89 (3H, t,J = 7.3 Hz). （4'−アシルオキシ化合物） IR (CDCl3)νmax： 2958, 2928, 2855, 1729, 1686, 16
41, 1605 cm-1. MS (FAB) m/e 879 ([M+H]+). HRMS (FAB) Calcd for C47H67O12N4 : 879.4755; found
879.4745 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 8.59 (1H, d, J = 8.
8 Hz), 7.25-7.42 (10H, m), 6.92 (1H, s), 5.89 (1H,
d, J = 2.2 Hz), 5.24 (1H, dd, J = 10.3, 2.2 Hz),
5.17 (1H, dd, J = 8.8, 8.8, 2.2 Hz), 4.46-4.51 (1
H, m), 4.30 (1H, ddd, J = 10.3, 8.8, 8.8 Hz), 4.17
(1H, d, J = 10.3 Hz), 3.97 (1H, d, J= 10.3 Hz),
3.74-3.85 (1H, m), 2.26-2.32 (2H, m), 1.99 (3H,
s), 1.93-2.00 (1H, m), 1.76-1.82 (1H, m), 1.49 (18
H, s), 1.14-1.28 (14H, m), 0.79 (3H, t, J = 7.3 H
z). （ii）（4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチルア
ミノ−6−（4'−n−デカノイルオキシ−3'−ヒドロキシ
−テトラヒドロ−ピラン−2'−イル）−5，6−ジヒドロ
−4−グアニジノ−4H−ピラン−2−カルボン酸 一水和
物 実施例１５(i)で得られた4'−アシルオキシ化合物（73
mg, 0.080 mmol）を塩化メチレン（3ml）に溶解し、ト
リフルオロ酢酸（2ml）を加え、4時間攪拌した。反応液
を減圧留去後、得られた残査を逆相クロマトグラフィー
（コスモシル、水/メタノール＝1/2）に付して標記4'−
n−デカノイルオキシ化合物（２％の3'−n−デカノイル
オキシ化合物を包含する）を無色アモルファスとして得
た。（37 mg、72％） 同様に実施例１５(i)で得られた3'−アシルオキシ化合
物（60 mg, 0.068 mmol）を塩化メチレン（3ml）に溶解
し、トリフルオロ酢酸（2ml）を加え、4時間攪拌した。
反応液を減圧留去後、得られた残査を逆相クロマトグラ
フィー（コスモシル、水/メタノール＝1/2）に付して標
記4'−n−デカノイルオキシ化合物（２％の3'−n−デカ
ノイルオキシ化合物を包含する）を無色アモルファスと
して得た。（20 mg、55％） IR (KBr)νmax： 3341, 3208, 2927, 2856, 1738, 166
5, 1620 cm-1. MS (FAB) m/e 513 ([M+H]+). HRMS (FAB) Calcd for C24H41O8N4 : 513.2925; found
513.2913 ([M+H]+).1 H NMR (400 MHz, CD3OD) δppm: 5.53 (1H, d, J = 2.
9 Hz), 5.27-5.31 (1H, m), 4.32-4.38 (2H, m), 4.19
(1H, dd, J = 8.8, 8.8 Hz), 4.08 (1H, dd, J= 9.5,
2.9 Hz), 3.75 (1H, ddd, J = 11.7, 10.7, 4.9 Hz),
3.72 (1H, dd, J= 9.5, 1.5 Hz), 3.50 (1H, ddd, J =
11.7, 10.7, 1.0 Hz), 2.39 (2H, t, J= 7.3 Hz), 1.99
(3H, s), 1.90-1.99 (1H, m), 1.76-1.82 (1H, m), 1.
60-1.70(2H, m), 1.28-1.40 (12H, m), 0.90 (3H, t, J
= 7.3 Hz). （実施例１６） （4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチルアミノ−
5，6−ジヒドロ−4−グアニジノ−6−（3'−ヒドロキシ
−4'−n−ラウロイルオキシ−テトラヒドロ−ピラン−
2'−イル）−4H−ピラン−2−カルボン酸 一水和物(I) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5
-Acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) guanidino-6- (4'-n-decanoyloxy-3'-hydroxy-tetrahydro-pyran-2'-yl) -5 Diphenylmethyl 2,6-dihydro-4H-pyran-2-carboxylate [4'-acyloxy compounds] and (4
S, 5R, 6R, 2'S, 3'R, 4'R) -5-acetylamino-4-
(N, N'-bis-t-butyloxycarbonyl) guanidino-6- (3'-n-decanoyloxy-4'-hydroxy-
Tetrahydro-pyran-2'-yl) -5,6-dihydro-
4H-pyran-2-carboxylate diphenylmethyl [3'-
Acyloxy compound] Compound (4S, 5R, 6R, 2′R, 3 ′) obtained in Example 12 (i)
R, 4'R) -5-acetylamino-4- (N, N'-bis-t-
(Butyloxycarbonyl) guanidino-5,6-dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4H-pyran-2-carboxylate diphenylmethyl (158 mg, 0.217 mmol) To methanol (10 ml)
And dibutyltin oxide (57 mg, 0.2 mg) at room temperature.
28 mmol) and stirred at 70 ° C. for 20 minutes. The reaction solution was distilled off under reduced pressure and azeotroped with toluene. The obtained residue was dried with a vacuum pump for 1 hour, dissolved in toluene, and decanoyl chloride (47 μl, 0.23 mmo
l), triethylamine (3 μl, 0.022 mmol) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Methanol was added, the reaction solution was evaporated under reduced pressure, and the obtained residue was subjected to chromatography (silica gel, hexane / ethyl acetate = 1/1) to give the title compounds as colorless amorphous materials. (4'-
Acyloxy compound: 80 mg, 42%) (3′-acyloxy compound: 68 mg, 35%) (4′-acyloxy compound) IR (CDCl 3 ) νmax: 2958, 2928, 2856, 1728, 1686, 16
40, 1606, 1567 cm -1 . MS (FAB) m / e 879 ([M + H] + ) .HRMS (FAB) Calcd for C 47 H 67 O 12 N 4 : 879.4755; found
. 879.4779 ([M + H] +) 1 H NMR (400 MHz, CDCl 3) δppm: 8.59 (1H, d, J = 8.
8 Hz), 7.26-7.38 (10H, m), 6.92 (1H, s), 6.43 (1H,
d, J = 6.6 Hz), 5.93 (1H, d, J = 2.9 Hz), 5.31-5.3
5 (1H, m), 5.14-5.20 (1H, m), 4.28-4.36 (2H, m),
4.06-4.12 (1H, m), 3.81-3.87 (1H, m), 3.57-3.66 (2
H, m), 2.37 (2H, t, J = 7.3 Hz), 2.16 (1H, br), 1.
97 (1H, s), 1.89-1.96 (1H, m), 1.80-1.87 (1H, m),
1.60-1.68 (2H, m), 1.49 (9H, s), 1.49 (9H, s), 1.2
4-1.36 (12H, m), 0.89 (3H, t, J = 7.3 Hz) (4'- acyloxy compound) IR (CDCl 3) νmax: . 2958, 2928, 2855, 1729, 1686, 16
41, 1605 cm -1 . MS (FAB) m / e 879 ([M + H] + ) .HRMS (FAB) Calcd for C 47 H 67 O 12 N 4 : 879.4755; found
. 879.4745 ([M + H] +) 1 H NMR (400 MHz, CDCl 3) δppm: 8.59 (1H, d, J = 8.
8 Hz), 7.25-7.42 (10H, m), 6.92 (1H, s), 5.89 (1H,
d, J = 2.2 Hz), 5.24 (1H, dd, J = 10.3, 2.2 Hz),
5.17 (1H, dd, J = 8.8, 8.8, 2.2 Hz), 4.46-4.51 (1
H, m), 4.30 (1H, ddd, J = 10.3, 8.8, 8.8 Hz), 4.17
(1H, d, J = 10.3 Hz), 3.97 (1H, d, J = 10.3 Hz),
3.74-3.85 (1H, m), 2.26-2.32 (2H, m), 1.99 (3H,
s), 1.93-2.00 (1H, m), 1.76-1.82 (1H, m), 1.49 (18
H, s), 1.14-1.28 (14H, m), 0.79 (3H, t, J = 7.3 H
z). (ii) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5-acetylamino-6- (4'-n-decanoyloxy-3'-hydroxy-tetrahydro-pyran- 2'-yl) -5,6-dihydro-4-guanidino-4H-pyran-2-carboxylic acid monohydrate The 4'-acyloxy compound (73) obtained in Example 15 (i)
mg, 0.080 mmol) was dissolved in methylene chloride (3 ml), trifluoroacetic acid (2 ml) was added, and the mixture was stirred for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to reverse phase chromatography (Cosmosil, water / methanol = 1/2) to give the title 4'-
The n-decanoyloxy compound (including 2% of 3'-n-decanoyloxy compound) was obtained as a colorless amorphous. (37 mg, 72%) Similarly, the 3'-acyloxy compound (60 mg, 0.068 mmol) obtained in Example 15 (i) was dissolved in methylene chloride (3 ml), and trifluoroacetic acid (2 ml) was added. Stir for 4 hours.
After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to reverse phase chromatography (Cosmosil, water / methanol = 1/2) to give the title 4'-n-decanoyloxy compound (2% of 3'- n-decanoyloxy compound) as a colorless amorphous. (20 mg, 55%) IR (KBr) νmax: 3341, 3208, 2927, 2856, 1738, 166
5, 1620 cm -1 . MS (FAB) m / e 513 ([M + H] + ). HRMS (FAB) Calcd for C 24 H 41 O 8 N 4 : 513.2925; found
513.2913 ([M + H] + ). 1 H NMR (400 MHz, CD 3 OD) δppm: 5.53 (1H, d, J = 2.
9 Hz), 5.27-5.31 (1H, m), 4.32-4.38 (2H, m), 4.19
(1H, dd, J = 8.8, 8.8 Hz), 4.08 (1H, dd, J = 9.5,
2.9 Hz), 3.75 (1H, ddd, J = 11.7, 10.7, 4.9 Hz),
3.72 (1H, dd, J = 9.5, 1.5 Hz), 3.50 (1H, ddd, J =
11.7, 10.7, 1.0 Hz), 2.39 (2H, t, J = 7.3 Hz), 1.99
(3H, s), 1.90-1.99 (1H, m), 1.76-1.82 (1H, m), 1.
60-1.70 (2H, m), 1.28-1.40 (12H, m), 0.90 (3H, t, J
(Example 16) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5-acetylamino-
5,6-dihydro-4-guanidino-6- (3'-hydroxy-4'-n-lauroyloxy-tetrahydro-pyran-
2'-yl) -4H-pyran-2-carboxylic acid monohydrate
【０３１１】[0311]
【化２８】 Embedded image
【０３１２】（i）（4S, 5R, 6R, 2'R, 3'S, 4'R）−5
−アセチルアミノ−4−（N，N'−ビス−t−ブチルオキ
シカルボニル）グアニジノ−5，6−ジヒドロ−6−（3'
−ヒドロキシ−4'−n−ラウロイルオキシ−テトラヒド
ロ−ピラン−2'−イル）−4H−ピラン−2−カルボン酸
ジフェニルメチル [4'−アシルオキシ化合物]及び（4
S, 5R, 6R, 2'S, 3'R, 4'R）−5−アセチルアミノ−4−
（N，N'−ビス−t−ブチルオキシカルボニル）グアニジ
ノ−5，6−ジヒドロ−6−（4'−ヒドロキシ−3'−n−ラ
ウロイルオキシ−テトラヒドロ−ピラン−2'−イル）−
4H−ピラン−2−カルボン酸ジフェニルメチル [3'−ア
シルオキシ化合物] 実施例１２(i)で得られた化合物（4S, 5R, 6R, 2'R, 3'
R, 4'R）−5−アセチルアミノ−4−（N，N'−ビス−t−
ブチルオキシカルボニル）グアニジノ−5，6−ジヒドロ
−6−（3'，4'−ジヒドロキシ−テトラヒドロ−ピラン
−2'−イル）−4H−ピラン−2−カルボン酸ジフェニル
メチル（158 mg, 0.217 mmol）をメタノール（10 ml）
に溶解し、室温にてジブチルチンオキシド（57 mg, 0.2
28 mmol）を加え、70℃にて20分間攪拌した。反応液を
減圧留去し、トルエンで共沸した。得られた残査を真空
ポンプで一時間乾燥後、トルエンに溶解し、窒素雰囲気
下、氷冷下ラウロイルクロライド（47 μl, 0.23 mmo
l）、トリエチルアミン（3μl, 0.022 mmol）を滴下
し、同温にて1時間攪拌した。メタノールを加え、反応
液を減圧留去後得られた残査をクロマトグラフィー（シ
リカゲル、ヘキサン／酢酸エチル＝1／1）に付して標記
化合物をそれぞれ無色アモルファスとして得た。（4'−
アシルオキシ化合物：87 mg、44％）（3'−アシルオキ
シ化合物：67 mg、34％） （4'−アシルオキシ化合物） IR (CDCl3)νmax： 2928, 2855, 1730, 1684, 1637, 16
14, 1542 cm-1. MS (FAB) m/e 907 ([M+H]+). HRMS (FAB) Calcd for C49H71O12N4 : 907.5069; found
907.5071 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 8.58 (1H, d, J = 8.
8 Hz), 7.26-7.38 (10H, m), 6.92 (1H, s), 6.43 (1H,
d, J = 6.6 Hz), 5.93 (1H, d, J = 2.9 Hz),5.31-5.3
5 (1H, m), 5.14-5.20 (1H, m), 4.28-4.36 (2H, m),
4.06-4.12 (1H,m), 3.81-3.87 (1H, m), 3.57-3.66 (2
H, m), 2.37 (2H, t, J = 7.3 Hz), 2.14 (1H, br), 1.
97 (1H, s), 1.89-1.96 (1H, m), 1.80-1.87 (1H, m),
1.60-1.68 (2H, m), 1.49 (9H, s), 1.49 (9H, s), 1.2
4-1.36 (16H, m), 0.89 (3H, t,J = 7.3 Hz). （3'−アシルオキシ化合物） IR (CDCl3)νmax： 2928, 2855, 1730, 1687, 1641, 16
06, 1572 cm-1. MS (FAB) m/e 907 ([M+H]+). HRMS (FAB) Calcd for C49H71O12N4 : 907.5069; found
907.5085 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 8.59 (1H, d, J = 8.
8 Hz), 7.25-7.42 (10H, m), 6.92 (1H, s), 5.89 (1H,
d, J = 2.2 Hz), 5.24 (1H, dd, J = 10.3, 2.2 Hz),
5.17 (1H, dd, J = 8.8, 8.8, 2.2 Hz), 4.46-4.51 (1
H, m), 4.33 (1H, ddd, J = 10.3, 8.8, 8.8 Hz), 4.18
(1H, d, J = 10.3 Hz), 3.97 (1H, d, J= 10.3 Hz),
3.76-3.86 (1H, m), 2.26-2.32 (2H, m), 1.99 (3H,
s), 1.93-2.00 (1H, m), 1.76-1.82 (1H, m), 1.49 (18
H, s), 1.12-1.32 (18H, m), 0.88 (3H, t, J = 7.3 H
z). （ii）（4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチルア
ミノ−5，6−ジヒドロ−4−グアニジノ−6−（3'−ヒド
ロキシ−4'−n−ラウロイルオキシ−テトラヒドロ−ピ
ラン−2'−イル）−4H−ピラン−2−カルボン酸 一水和
物 実施例１６(i)で得られた4'−アシルオキシ化合物（77
mg, 0.085 mmol）を塩化メチレン（3ml）に溶解し、ト
リフルオロ酢酸（3ml）を加え、4時間攪拌した。反応液
を減圧留去後、得られた残査を逆相クロマトグラフィー
（コスモシル、水/メタノール＝1/2）に付して標記4'−
n−ラウロイルオキシ化合物（３％の3'−アシルオキシ
化合物を包含する）を無色アモルファスとして得た。
（38 mg、80％） 実施例１６(i)で得られた3'−アシルオキシ化合物（60
mg, 0.066 mmol）を塩化メチレン（3ml）に溶解し、ト
リフルオロ酢酸（3ml）を加え、4時間攪拌した。反応液
を減圧留去後、得られた残査を逆相クロマトグラフィー
（コスモシル、水/メタノール＝1/2）に付して標記4'−
n−ラウロイルオキシ化合物（３％の3'−アシルオキシ
化合物を包含する）を無色アモルファスとして得た。
（21 mg、56％） IR (KBr)νmax： 3341, 3208, 2925, 2854, 1738, 166
5, 1618 cm-1. MS (FAB) m/e 541 ([M+H]+). HRMS (FAB) Calcd for C26H45O8N4 : 541.3237; found
541.3237 ([M+H]+).1 H NMR (400 MHz, CD3OD) δppm: 5.53 (1H, d, J = 2.
9 Hz), 5.27-5.31 (1H, m), 4.32-4.38 (2H, m), 4.19
(1H, dd, J = 8.8, 8.8 Hz), 4.08 (1H, dd, J= 9.5,
2.9 Hz), 3.75 (1H, ddd, J = 11.7, 10.7, 4.9 Hz),
3.72 (1H, dd, J= 9.5, 1.5 Hz), 3.50 (1H, ddd, J =
11.7, 10.7, 1.0 Hz), 2.39 (2H, t, J= 7.3 Hz), 1.99
(3H, s), 1.90-1.99 (1H, m), 1.76-1.82 (1H, m), 1.
60-1.70(2H, m), 1.28-1.40 (16H, m), 0.90 (3H, t, J
= 7.3 Hz). （実施例１７） （4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチルアミノ−
5，6−ジヒドロ−4−グアニジノ−6−（3'−ヒドロキシ
−4'−n−ミリストイルオキシ−テトラヒドロ−ピラン
−2'−イル）−4H−ピラン−2−カルボン酸 一水和物(I) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5
-Acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) guanidino-5,6-dihydro-6- (3 '
-Hydroxy-4'-n-lauroyloxy-tetrahydro-pyran-2'-yl) -4H-pyran-2-carboxylic acid diphenylmethyl [4'-acyloxy compound] and (4
S, 5R, 6R, 2'S, 3'R, 4'R) -5-acetylamino-4-
(N, N'-bis-t-butyloxycarbonyl) guanidino-5,6-dihydro-6- (4'-hydroxy-3'-n-lauroyloxy-tetrahydro-pyran-2'-yl)-
4H-Pyran-2-carboxylate diphenylmethyl [3'-acyloxy compound] The compound obtained in Example 12 (i) (4S, 5R, 6R, 2'R, 3 '
R, 4'R) -5-acetylamino-4- (N, N'-bis-t-
(Butyloxycarbonyl) guanidino-5,6-dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4H-pyran-2-carboxylate diphenylmethyl (158 mg, 0.217 mmol) To methanol (10 ml)
And dibutyltin oxide (57 mg, 0.2 mg) at room temperature.
28 mmol) and stirred at 70 ° C. for 20 minutes. The reaction solution was distilled off under reduced pressure and azeotroped with toluene. The obtained residue was dried with a vacuum pump for 1 hour, dissolved in toluene, and lauroyl chloride (47 μl, 0.23 mmo
l), triethylamine (3 μl, 0.022 mmol) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Methanol was added, the reaction solution was evaporated under reduced pressure, and the obtained residue was subjected to chromatography (silica gel, hexane / ethyl acetate = 1/1) to give the title compounds as colorless amorphous materials. (4'-
Acyloxy compound: 87 mg, 44%) (3′-acyloxy compound: 67 mg, 34%) (4′-acyloxy compound) IR (CDCl 3 ) νmax: 2928, 2855, 1730, 1684, 1637, 16
14, 1542 cm -1 . MS (FAB) m / e 907 ([M + H] + ) .HRMS (FAB) Calcd for C 49 H 71 O 12 N 4 : 907.5069; found
. 907.5071 ([M + H] +) 1 H NMR (400 MHz, CDCl 3) δppm: 8.58 (1H, d, J = 8.
8 Hz), 7.26-7.38 (10H, m), 6.92 (1H, s), 6.43 (1H,
d, J = 6.6 Hz), 5.93 (1H, d, J = 2.9 Hz), 5.31-5.3
5 (1H, m), 5.14-5.20 (1H, m), 4.28-4.36 (2H, m),
4.06-4.12 (1H, m), 3.81-3.87 (1H, m), 3.57-3.66 (2
H, m), 2.37 (2H, t, J = 7.3 Hz), 2.14 (1H, br), 1.
97 (1H, s), 1.89-1.96 (1H, m), 1.80-1.87 (1H, m),
1.60-1.68 (2H, m), 1.49 (9H, s), 1.49 (9H, s), 1.2
4-1.36 (16H, m), 0.89 (3H, t, J = 7.3 Hz) (3'- acyloxy compound) IR (CDCl 3) νmax: . 2928, 2855, 1730, 1687, 1641, 16
06, 1572 cm -1 . MS (FAB) m / e 907 ([M + H] + ) .HRMS (FAB) Calcd for C 49 H 71 O 12 N 4 : 907.5069; found
. 907.5085 ([M + H] +) 1 H NMR (400 MHz, CDCl 3) δppm: 8.59 (1H, d, J = 8.
8 Hz), 7.25-7.42 (10H, m), 6.92 (1H, s), 5.89 (1H,
d, J = 2.2 Hz), 5.24 (1H, dd, J = 10.3, 2.2 Hz),
5.17 (1H, dd, J = 8.8, 8.8, 2.2 Hz), 4.46-4.51 (1
H, m), 4.33 (1H, ddd, J = 10.3, 8.8, 8.8 Hz), 4.18
(1H, d, J = 10.3 Hz), 3.97 (1H, d, J = 10.3 Hz),
3.76-3.86 (1H, m), 2.26-2.32 (2H, m), 1.99 (3H,
s), 1.93-2.00 (1H, m), 1.76-1.82 (1H, m), 1.49 (18
H, s), 1.12-1.32 (18H, m), 0.88 (3H, t, J = 7.3 H
z). (ii) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5-acetylamino-5,6-dihydro-4-guanidino-6- (3'-hydroxy-4'- n-Lauroyloxy-tetrahydro-pyran-2'-yl) -4H-pyran-2-carboxylic acid monohydrate 4'-acyloxy compound (77) obtained in Example 16 (i)
mg, 0.085 mmol) in methylene chloride (3 ml), trifluoroacetic acid (3 ml) was added, and the mixture was stirred for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to reverse phase chromatography (Cosmosil, water / methanol = 1/2) to give the title 4'-
The n-lauroyloxy compound (including 3% of the 3'-acyloxy compound) was obtained as a colorless amorphous.
(38 mg, 80%) The 3'-acyloxy compound (60) obtained in Example 16 (i)
mg, 0.066 mmol) was dissolved in methylene chloride (3 ml), trifluoroacetic acid (3 ml) was added, and the mixture was stirred for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to reverse phase chromatography (Cosmosil, water / methanol = 1/2) to give the title 4'-
The n-lauroyloxy compound (including 3% of the 3'-acyloxy compound) was obtained as a colorless amorphous.
(21 mg, 56%) IR (KBr) νmax: 3341, 3208, 2925, 2854, 1738, 166
5, 1618 cm -1 . MS (FAB) m / e 541 ([M + H] + ). HRMS (FAB) Calcd for C 26 H 45 O 8 N 4 : 541.3237; found
. 541.3237 ([M + H] +) 1 H NMR (400 MHz, CD 3 OD) δppm: 5.53 (1H, d, J = 2.
9 Hz), 5.27-5.31 (1H, m), 4.32-4.38 (2H, m), 4.19
(1H, dd, J = 8.8, 8.8 Hz), 4.08 (1H, dd, J = 9.5,
2.9 Hz), 3.75 (1H, ddd, J = 11.7, 10.7, 4.9 Hz),
3.72 (1H, dd, J = 9.5, 1.5 Hz), 3.50 (1H, ddd, J =
11.7, 10.7, 1.0 Hz), 2.39 (2H, t, J = 7.3 Hz), 1.99
(3H, s), 1.90-1.99 (1H, m), 1.76-1.82 (1H, m), 1.
60-1.70 (2H, m), 1.28-1.40 (16H, m), 0.90 (3H, t, J
(Example 17) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5-acetylamino-
5,6-dihydro-4-guanidino-6- (3'-hydroxy-4'-n-myristoyloxy-tetrahydro-pyran-2'-yl) -4H-pyran-2-carboxylic acid monohydrate
【０３１３】[0313]
【化２９】 Embedded image
【０３１４】（i）（4S, 5R, 6R, 2'R, 3'S, 4'R）−5
−アセチルアミノ−4−（N，N'−ビス−t−ブチルオキ
シカルボニル）グアニジノ−5，6−ジヒドロ−6−（3'
−ヒドロキシ−4'−n−ミリストイルオキシ−テトラヒ
ドロ−ピラン−2'−イル）−4H−ピラン−2−カルボン
酸ジフェニルメチル [4'−アシルオキシ化合物]及び
（4S, 5R, 6R, 2'S, 3'R, 4'R）−5−アセチルアミノ−
4−（N，N'−ビス−t−ブチルオキシカルボニル）グア
ニジノ−5，6−ジヒドロ−6−（4'−ヒドロキシ−3'−n
−ミリストイルオキシ−テトラヒドロ−ピラン−2'−イ
ル）−4H−ピラン−2−カルボン酸ジフェニルメチル
[3'−アシルオキシ化合物] 実施例１２(i)で得られた化合物（4S, 5R, 6R, 2'R, 3'
R, 4'R）−5−アセチルアミノ−4−（N，N'−ビス−t−
ブチルオキシカルボニル）グアニジノ−5，6−ジヒドロ
−6−（3'，4'−ジヒドロキシ−テトラヒドロ−ピラン
−2'−イル）−4H−ピラン−2−カルボン酸ジフェニル
メチル（158 mg, 0.217 mmol）をメタノール（10 ml）
に溶解し、室温にてジブチルチンオキシド（57 mg, 0.2
28 mmol）を加え、70℃にて20分間攪拌した。反応液を
減圧留去し、トルエンで共沸した。得られた残査を真空
ポンプで一時間乾燥後、トルエンに溶解し、窒素雰囲気
下、氷冷下ミリストイルクロライド（62 μl, 0.228 mm
ol）、トリエチルアミン（3 μl, 0.022 mmol）を滴下
し、同温にて1時間攪拌した。メタノールを加え、反応
液を減圧留去後得られた残査をクロマトグラフィー（シ
リカゲル、ヘキサン／酢酸エチル＝1／1）に付して標記
化合物をそれぞれ無色アモルファスとして得た。（4'−
アシルオキシ化合物：98 mg、48％）（3'−アシルオキ
シ化合物：60 mg、29％） （4'−アシルオキシ化合物） IR (CDCl3)νmax： 2957, 2928, 2855, 1727, 1685, 16
39, 1606, 1567 cm-1. MS (FAB) m/e 935 ([M+H]+). HRMS (FAB) Calcd for C51H75O12N4 : 935.5382; found
935.5402 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 8.59 (1H, d, J = 8.
8 Hz), 7.26-7.38 (10H, m), 6.92 (1H, s), 6.43 (1H,
d, J = 6.6 Hz), 5.93 (1H, d, J = 2.9 Hz),5.31-5.3
5 (1H, m), 5.14-5.20 (1H, m), 4.28-4.36 (2H, m),
4.06-4.12 (1H,m), 3.81-3.87 (1H, m), 3.57-3.66 (2
H, m), 2.37 (2H, t, J = 7.3 Hz), 2.18 (1H, br), 1.
97 (1H, s), 1.89-1.96 (1H, m), 1.80-1.87 (1H, m),
1.60-1.68 (2H, m), 1.49 (9H, s), 1.49 (9H, s), 1.2
4-1.36 (20H, m), 0.88 (3H, t,J = 7.3 Hz). （3'−アシルオキシ化合物） IR (CDCl3)νmax： 2956, 2928, 2855, 1727, 1686, 16
43, 1606, 1572 cm-1. MS (FAB) m/e 935 ([M+H]+). HRMS (FAB) Calcd for C51H75O12N4 : 935.5382; found
935.5379 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 8.59 (1H, d, J = 8.
8 Hz), 7.25-7.42 (10H, m), 6.92 (1H, s), 5.89 (1H,
d, J = 2.2 Hz), 5.24 (1H, dd, J = 10.3, 2.2 Hz),
5.17 (1H, dd, J = 8.8, 8.8, 2.2 Hz), 4.46-4.51 (1
H, m), 4.32 (1H, ddd, J = 10.3, 8.8, 8.8 Hz), 4.17
(1H, d, J = 10.3 Hz), 3.97 (1H, d, J= 10.3 Hz),
3.76-3.86 (1H, m), 2.26-2.32 (2H, m), 1.99 (3H,
s), 1.93-2.00 (1H, m), 1.76-1.82 (1H, m), 1.49 (18
H, s), 1.12-1.32 (22H, m), 0.88 (3H, t, J = 7.3 H
z). （ii）（4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチルア
ミノ−5，6−ジヒドロ−4−グアニジノ−6−（3'−ヒド
ロキシ−4'−n−ミリストイルオキシ−テトラヒドロ−
ピラン−2'−イル）−4H−ピラン−2−カルボン酸 一水
和物 実施例１７(i)で得られた4'−アシルオキシ化合物（80
mg, 0.085 mmol）を塩化メチレン（4ml）に溶解し、ト
リフルオロ酢酸（2ml）を加え、4時間攪拌した。反応液
を減圧留去後、得られた残査を逆相クロマトグラフィー
（コスモシル、水/メタノール＝1/5）に付して標記4'−
n−ミリストイルオキシ化合物（１％の3'−n−ミリスト
イルオキシ化合物を包含する）を無色アモルファスとし
て得た。（33 mg、66％） 同様に実施例１７(i)で得られた3'−アシルオキシ化合
物（47 mg, 0.050 mmol）を塩化メチレン（4ml）に溶解
し、トリフルオロ酢酸（2ml）を加え、4時間攪拌した。
反応液を減圧留去後、得られた残査を逆相クロマトグラ
フィー（コスモシル、水/メタノール＝1/5）に付して標
記4'−n−ミリストイルオキシ化合物（１％の3'−n−ミ
リストイルオキシ化合物を包含する）を無色アモルファ
スとして得た。（16 mg、54％） IR (KBr)νmax： 3345, 2925, 2854, 1738, 1665, 1619
cm-1. MS (FAB) m/e 569 ([M+H]+). HRMS (FAB) Calcd for C28H49O8N4 : 569.3550; found
569.3554 ([M+H]+).1 H NMR (400 MHz, CD3OD) δppm: 5.53 (1H, d, J = 2.
9 Hz), 5.27-5.31 (1H, m), 4.32-4.38 (2H, m), 4.19
(1H, dd, J = 8.8, 8.8 Hz), 4.08 (1H, dd, J= 9.5,
2.9 Hz), 3.75 (1H, ddd, J = 11.7, 10.7, 4.9 Hz),
3.72 (1H, dd, J= 9.5, 1.5 Hz), 3.50 (1H, ddd, J =
11.7, 10.7, 1.0 Hz), 2.39 (2H, t, J= 7.3 Hz), 1.99
(3H, s), 1.90-1.99 (1H, m), 1.76-1.82 (1H, m), 1.
60-1.70(2H, m), 1.28-1.40 (20H, m), 0.90 (3H, t, J
= 7.3 Hz). （実施例１８） （4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチルアミノ−
5，6−ジヒドロ−4−グアニジノ−6−（3'−ヒドロキシ
−4'−n−パルミトイルオキシ−テトラヒドロ−ピラン
−2'−イル）−4H−ピラン−2−カルボン酸 一水和物(I) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5
-Acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) guanidino-5,6-dihydro-6- (3 '
-Hydroxy-4'-n-myristoyloxy-tetrahydro-pyran-2'-yl) -4H-pyran-2-carboxylic acid diphenylmethyl [4'-acyloxy compound] and (4S, 5R, 6R, 2'S, 3 ' R, 4'R) -5-acetylamino-
4- (N, N'-bis-t-butyloxycarbonyl) guanidino-5,6-dihydro-6- (4'-hydroxy-3'-n
-Myristoyloxy-tetrahydro-pyran-2'-yl) -4H-pyran-2-carboxylate diphenylmethyl
[3′-Acyloxy compound] The compound (4S, 5R, 6R, 2′R, 3 ′) obtained in Example 12 (i)
R, 4'R) -5-acetylamino-4- (N, N'-bis-t-
(Butyloxycarbonyl) guanidino-5,6-dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4H-pyran-2-carboxylate diphenylmethyl (158 mg, 0.217 mmol) To methanol (10 ml)
And dibutyltin oxide (57 mg, 0.2 mg) at room temperature.
28 mmol) and stirred at 70 ° C. for 20 minutes. The reaction solution was distilled off under reduced pressure and azeotroped with toluene. The obtained residue was dried with a vacuum pump for 1 hour, dissolved in toluene, and cooled under ice-cooling under a nitrogen atmosphere under a nitrogen atmosphere (62 μl, 0.228 mm
ol) and triethylamine (3 μl, 0.022 mmol) were added dropwise, and the mixture was stirred at the same temperature for 1 hour. Methanol was added, the reaction solution was evaporated under reduced pressure, and the obtained residue was subjected to chromatography (silica gel, hexane / ethyl acetate = 1/1) to give the title compounds as colorless amorphous materials. (4'-
Acyloxy compound: 98 mg, 48%) (3′-acyloxy compound: 60 mg, 29%) (4′-acyloxy compound) IR (CDCl 3 ) νmax: 2957, 2928, 2855, 1727, 1685, 16
39, 1606, 1567 cm -1 . MS (FAB) m / e 935 ([M + H] + ) .HRMS (FAB) Calcd for C 51 H 75 O 12 N 4 : 935.5382; found
935.5402 ([M + H] + ). 1 H NMR (400 MHz, CDCl 3 ) δppm: 8.59 (1H, d, J = 8.
8 Hz), 7.26-7.38 (10H, m), 6.92 (1H, s), 6.43 (1H,
d, J = 6.6 Hz), 5.93 (1H, d, J = 2.9 Hz), 5.31-5.3
5 (1H, m), 5.14-5.20 (1H, m), 4.28-4.36 (2H, m),
4.06-4.12 (1H, m), 3.81-3.87 (1H, m), 3.57-3.66 (2
H, m), 2.37 (2H, t, J = 7.3 Hz), 2.18 (1H, br), 1.
97 (1H, s), 1.89-1.96 (1H, m), 1.80-1.87 (1H, m),
1.60-1.68 (2H, m), 1.49 (9H, s), 1.49 (9H, s), 1.2
4-1.36 (20H, m), 0.88 (3H, t, J = 7.3 Hz) (3'- acyloxy compound) IR (CDCl 3) νmax: . 2956, 2928, 2855, 1727, 1686, 16
43, 1606, 1572 cm -1 . MS (FAB) m / e 935 ([M + H] + ) .HRMS (FAB) Calcd for C 51 H 75 O 12 N 4 : 935.5382; found
. 935.5379 ([M + H] +) 1 H NMR (400 MHz, CDCl 3) δppm: 8.59 (1H, d, J = 8.
8 Hz), 7.25-7.42 (10H, m), 6.92 (1H, s), 5.89 (1H,
d, J = 2.2 Hz), 5.24 (1H, dd, J = 10.3, 2.2 Hz),
5.17 (1H, dd, J = 8.8, 8.8, 2.2 Hz), 4.46-4.51 (1
H, m), 4.32 (1H, ddd, J = 10.3, 8.8, 8.8 Hz), 4.17
(1H, d, J = 10.3 Hz), 3.97 (1H, d, J = 10.3 Hz),
3.76-3.86 (1H, m), 2.26-2.32 (2H, m), 1.99 (3H,
s), 1.93-2.00 (1H, m), 1.76-1.82 (1H, m), 1.49 (18
H, s), 1.12-1.32 (22H, m), 0.88 (3H, t, J = 7.3 H
z). (ii) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5-acetylamino-5,6-dihydro-4-guanidino-6- (3'-hydroxy-4'- n-myristoyloxy-tetrahydro-
Pyran-2'-yl) -4H-pyran-2-carboxylic acid monohydrate The 4'-acyloxy compound (80) obtained in Example 17 (i)
mg, 0.085 mmol) in methylene chloride (4 ml), trifluoroacetic acid (2 ml) was added, and the mixture was stirred for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to reverse phase chromatography (Cosmosil, water / methanol = 1/5) to give the title 4'-
The n-myristoyloxy compound (including 1% of 3'-n-myristoyloxy compound) was obtained as a colorless amorphous. (33 mg, 66%) Similarly, the 3′-acyloxy compound (47 mg, 0.050 mmol) obtained in Example 17 (i) was dissolved in methylene chloride (4 ml), and trifluoroacetic acid (2 ml) was added. Stir for 4 hours.
After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to reverse phase chromatography (Cosmosil, water / methanol = 1/5) to give the title 4'-n-myristoyloxy compound (1% of 3'-n -Including myristoyloxy compounds) as a colorless amorphous. (16 mg, 54%) IR (KBr) νmax: 3345, 2925, 2854, 1738, 1665, 1619
cm -1 . MS (FAB) m / e 569 ([M + H] + ). HRMS (FAB) Calcd for C 28 H 49 O 8 N 4 : 569.3550; found
. 569.3554 ([M + H] +) 1 H NMR (400 MHz, CD 3 OD) δppm: 5.53 (1H, d, J = 2.
9 Hz), 5.27-5.31 (1H, m), 4.32-4.38 (2H, m), 4.19
(1H, dd, J = 8.8, 8.8 Hz), 4.08 (1H, dd, J = 9.5,
2.9 Hz), 3.75 (1H, ddd, J = 11.7, 10.7, 4.9 Hz),
3.72 (1H, dd, J = 9.5, 1.5 Hz), 3.50 (1H, ddd, J =
11.7, 10.7, 1.0 Hz), 2.39 (2H, t, J = 7.3 Hz), 1.99
(3H, s), 1.90-1.99 (1H, m), 1.76-1.82 (1H, m), 1.
60-1.70 (2H, m), 1.28-1.40 (20H, m), 0.90 (3H, t, J
(Example 18) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5-acetylamino-
5,6-dihydro-4-guanidino-6- (3'-hydroxy-4'-n-palmitoyloxy-tetrahydro-pyran-2'-yl) -4H-pyran-2-carboxylic acid monohydrate
【０３１５】[0315]
【化３０】 Embedded image
【０３１６】（i）（4S, 5R, 6R, 2'R, 3'S, 4'R）−5
−アセチルアミノ−4−（N，N'−ビス−t−ブチルオキ
シカルボニル）グアニジノ−5，6−ジヒドロ−6−（3'
−ヒドロキシ−4'−n−パルミトイルオキシ−テトラヒ
ドロ−ピラン−2'−イル）−4H−ピラン−2−カルボン
酸ジフェニルメチル [4'−アシルオキシ化合物]及び
（4S, 5R, 6R, 2'S, 3'R, 4'R）−5−アセチルアミノ−
4−（N，N'−ビス−t−ブチルオキシカルボニル）グア
ニジノ−5，6−ジヒドロ−6−（3'−ヒドロキシ−4'−n
−パルミトイルオキシ−テトラヒドロ−ピラン−2'−イ
ル）−4H−ピラン−2−カルボン酸ジフェニルメチル
[3'−アシルオキシ化合物] 実施例１２(i)で得られた化合物（4S, 5R, 6R, 2'R, 3'
R, 4'R）−5−アセチルアミノ−4−（N，N'−ビス−t−
ブチルオキシカルボニル）グアニジノ−5，6−ジヒドロ
−6−（3'，4'−ジヒドロキシ−テトラヒドロ−ピラン
−2'−イル）−4H−ピラン−2−カルボン酸ジフェニル
メチル（158 mg, 0.217 mmol）をメタノール（10 ml）
に溶解し、室温にてジブチルチンオキシド（57 mg, 0.2
28 mmol）を加え、70℃にて20分間攪拌した。反応液を
減圧留去し、トルエンで共沸した。得られた残査を真空
ポンプで一時間乾燥後、トルエンに溶解し、窒素雰囲気
下、氷冷下パルミトイルクロライド（69 μl, 0.228 mm
ol）、トリエチルアミン（3 μl, 0.022 mmol）を滴下
し、同温にて1時間攪拌した。メタノールを加え、反応
液を減圧留去後得られた残査をクロマトグラフィー（シ
リカゲル、ヘキサン／酢酸エチル＝1／1）に付して標記
化合物をそれぞれ無色アモルファスとして得た。（4'−
アシルオキシ化合物：92 mg、44％）（3'−アシルオキ
シ化合物：67 mg、32％） （4'−アシルオキシ化合物） IR (CDCl3)νmax： 2957, 2928, 2855, 1729, 1685, 16
39, 1606, 1567 cm-1. MS (FAB) m/e 963 ([M+H]+). HRMS (FAB) Calcd for C53H79O12N4 : 963.5694; found
963.5689 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 8.58 (1H, d, J = 8.
8 Hz), 7.26-7.38 (10H, m), 6.92 (1H, s), 6.43 (1H,
d, J = 6.6 Hz), 5.93 (1H, d, J = 2.9 Hz),5.31-5.3
5 (1H, m), 5.14-5.20 (1H, m), 4.28-4.36 (2H, m),
4.06-4.12 (1H,m), 3.81-3.87 (1H, m), 3.57-3.66 (2
H, m), 2.37 (2H, t, J = 7.3 Hz), 2.14 (1H, br), 1.
97 (1H, s), 1.89-1.96 (1H, m), 1.80-1.87 (1H, m),
1.60-1.68 (2H, m), 1.49 (9H, s), 1.49 (9H, s), 1.2
4-1.36 (24H, m), 0.88 (3H, t,J = 7.3 Hz). （3'−アシルオキシ化合物） IR (CDCl3)νmax： 2957, 2928, 2855, 1729, 1687, 16
38, 1607 cm-1. MS (FAB) m/e 963 ([M+H]+). HRMS (FAB) Calcd for C53H79O12N4 : 963.5694; found
963.5705 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm: 8.59 (1H, d, J = 8.
8 Hz), 7.25-7.42 (10H, m), 6.92 (1H, s), 5.89 (1H,
d, J = 2.2 Hz), 5.24 (1H, dd, J = 10.3, 2.2 Hz),
5.17 (1H, dd, J = 8.8, 8.8, 2.2 Hz), 4.46-4.51 (1
H, m), 4.33 (1H, ddd, J = 10.3, 8.8, 8.8 Hz), 4.18
(1H, d, J = 10.3 Hz), 3.97 (1H, d, J= 10.3 Hz),
3.76-3.86 (1H, m), 2.26-2.32 (2H, m), 1.99 (3H,
s), 1.93-2.00 (1H, m), 1.76-1.82 (1H, m), 1.49 (18
H, s), 1.12-1.32 (26H, m), 0.88 (3H, t, J = 7.3 H
z). （ii）（4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチルア
ミノ−5，6−ジヒドロ−4−グアニジノ−6−（3'−ヒド
ロキシ−4'−n−パルミトイルオキシ−テトラヒドロ−
ピラン−2'−イル）−4H−ピラン−2−カルボン酸 一水
和物 実施例１８(i)で得られた4'−アシルオキシ化合物（6
5）（85 mg, 0.088 mmol）を塩化メチレン（4ml）に溶
解し、トリフルオロ酢酸（2ml）を加え、4時間攪拌し
た。反応液を減圧留去後、得られた残査を逆相クロマト
グラフィー（コスモシル、水/メタノール＝1/6）に付し
て標記4'−n−パルミトイルオキシ化合物（７％の3'−
アシルオキシ化合物を包含する）を無色アモルファスと
して得た。（35 mg、65％） 同様に実施例１８(i)で得られた3'−アシルオキシ化合
物（66）（60 mg, 0.062 mmol）を塩化メチレン（4ml）
に溶解し、トリフルオロ酢酸（2ml）を加え、4時間攪拌
した。反応液を減圧留去後、得られた残査を逆相クロマ
トグラフィー（コスモシル、水/メタノール＝1/6）に付
して標記4'−n−パルミトイルオキシ化合物（５％の3'
−アシルオキシ化合物を包含する）を無色アモルファス
として得た。（25 mg、66％） IR (KBr)νmax： 3338, 2925, 2853, 1738, 1666, 1618
cm-1. MS (FAB) m/e 597 ([M+H]+). HRMS (FAB) Calcd for C30H53O8N4 : 597.3863; found
597.3850 ([M+H]+).1 H NMR (400 MHz, CD3OD) δppm: 5.53 (1H, d, J = 2.
9 Hz), 5.27-5.31 (1H, m), 4.32-4.38 (2H, m), 4.19
(1H, dd, J = 8.8, 8.8 Hz), 4.08 (1H, dd, J= 9.5,
2.9 Hz), 3.75 (1H, ddd, J = 11.7, 10.7, 4.9 Hz),
3.72 (1H, dd, J= 9.5, 1.5 Hz), 3.50 (1H, ddd, J =
11.7, 10.7, 1.0 Hz), 2.39 (2H, t, J= 7.3 Hz), 1.99
(3H, s), 1.90-1.99 (1H, m), 1.76-1.82 (1H, m), 1.
60-1.70(2H, m), 1.28-1.40 (24H, m), 0.90 (3H, t, J
= 7.3 Hz). （実施例１９） （4S, 5R, 6R, 2'R）−5−アセチルアミノ−5，6−ジヒ
ドロ−6−（4'，5'−ジヒドロキシ−テトラヒドロ−ピ
ラン−2'−イル）−4−グアニジノ−4H−ピラン−2−カ
ルボン酸・水和物(I) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5
-Acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) guanidino-5,6-dihydro-6- (3 '
-Hydroxy-4'-n-palmitoyloxy-tetrahydro-pyran-2'-yl) -4H-pyran-2-carboxylic acid diphenylmethyl [4'-acyloxy compound] and (4S, 5R, 6R, 2'S, 3 ' R, 4'R) -5-acetylamino-
4- (N, N'-bis-t-butyloxycarbonyl) guanidino-5,6-dihydro-6- (3'-hydroxy-4'-n
-Palmitoyloxy-tetrahydro-pyran-2'-yl) -4H-pyran-2-carboxylate diphenylmethyl
[3′-Acyloxy compound] The compound (4S, 5R, 6R, 2′R, 3 ′) obtained in Example 12 (i)
R, 4'R) -5-acetylamino-4- (N, N'-bis-t-
(Butyloxycarbonyl) guanidino-5,6-dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4H-pyran-2-carboxylate diphenylmethyl (158 mg, 0.217 mmol) To methanol (10 ml)
And dibutyltin oxide (57 mg, 0.2 mg) at room temperature.
28 mmol) and stirred at 70 ° C. for 20 minutes. The reaction solution was distilled off under reduced pressure and azeotroped with toluene. The obtained residue was dried with a vacuum pump for 1 hour, dissolved in toluene, and palmitoyl chloride (69 μl, 0.228 mm
ol) and triethylamine (3 μl, 0.022 mmol) were added dropwise, and the mixture was stirred at the same temperature for 1 hour. Methanol was added, the reaction solution was evaporated under reduced pressure, and the obtained residue was subjected to chromatography (silica gel, hexane / ethyl acetate = 1/1) to give the title compounds as colorless amorphous materials. (4'-
Acyloxy compound: 92 mg, 44%) (3′-acyloxy compound: 67 mg, 32%) (4′-acyloxy compound) IR (CDCl 3 ) νmax: 2957, 2928, 2855, 1729, 1685, 16
39, 1606, 1567 cm -1 . MS (FAB) m / e 963 ([M + H] + ) .HRMS (FAB) Calcd for C 53 H 79 O 12 N 4 : 963.5694; found
963.5689 ([M + H] + ). 1 H NMR (400 MHz, CDCl 3 ) δppm: 8.58 (1H, d, J = 8.
8 Hz), 7.26-7.38 (10H, m), 6.92 (1H, s), 6.43 (1H,
d, J = 6.6 Hz), 5.93 (1H, d, J = 2.9 Hz), 5.31-5.3
5 (1H, m), 5.14-5.20 (1H, m), 4.28-4.36 (2H, m),
4.06-4.12 (1H, m), 3.81-3.87 (1H, m), 3.57-3.66 (2
H, m), 2.37 (2H, t, J = 7.3 Hz), 2.14 (1H, br), 1.
97 (1H, s), 1.89-1.96 (1H, m), 1.80-1.87 (1H, m),
1.60-1.68 (2H, m), 1.49 (9H, s), 1.49 (9H, s), 1.2
4-1.36 (24H, m), 0.88 (3H, t, J = 7.3 Hz) (3'- acyloxy compound) IR (CDCl 3) νmax: . 2957, 2928, 2855, 1729, 1687, 16
38, 1607 cm -1 . MS (FAB) m / e 963 ([M + H] + ). HRMS (FAB) Calcd for C 53 H 79 O 12 N 4 : 963.5694; found
963.5705 ([M + H] + ). 1 H NMR (400 MHz, CDCl 3 ) δppm: 8.59 (1H, d, J = 8.
8 Hz), 7.25-7.42 (10H, m), 6.92 (1H, s), 5.89 (1H,
d, J = 2.2 Hz), 5.24 (1H, dd, J = 10.3, 2.2 Hz),
5.17 (1H, dd, J = 8.8, 8.8, 2.2 Hz), 4.46-4.51 (1
H, m), 4.33 (1H, ddd, J = 10.3, 8.8, 8.8 Hz), 4.18
(1H, d, J = 10.3 Hz), 3.97 (1H, d, J = 10.3 Hz),
3.76-3.86 (1H, m), 2.26-2.32 (2H, m), 1.99 (3H,
s), 1.93-2.00 (1H, m), 1.76-1.82 (1H, m), 1.49 (18
H, s), 1.12-1.32 (26H, m), 0.88 (3H, t, J = 7.3 H
z). (ii) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5-acetylamino-5,6-dihydro-4-guanidino-6- (3'-hydroxy-4'- n-palmitoyloxy-tetrahydro-
Pyran-2'-yl) -4H-pyran-2-carboxylic acid monohydrate The 4'-acyloxy compound (6) obtained in Example 18 (i)
5) (85 mg, 0.088 mmol) was dissolved in methylene chloride (4 ml), trifluoroacetic acid (2 ml) was added, and the mixture was stirred for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to reverse phase chromatography (Cosmosil, water / methanol = 1/6) to give the title 4'-n-palmitoyloxy compound (7% of 3'-
(Including acyloxy compounds) as a colorless amorphous. (35 mg, 65%) Similarly, the 3'-acyloxy compound (66) (60 mg, 0.062 mmol) obtained in Example 18 (i) was treated with methylene chloride (4 ml).
And trifluoroacetic acid (2 ml) was added thereto, followed by stirring for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to reverse phase chromatography (Cosmosil, water / methanol = 1/6) to give the title 4'-n-palmitoyloxy compound (5% of 3 '
-Including acyloxy compounds) as a colorless amorphous. (25 mg, 66%) IR (KBr) νmax: 3338, 2925, 2853, 1738, 1666, 1618
.. cm -1 MS (FAB) m / e 597 ([M + H] +) HRMS (FAB) Calcd for C 30 H 53 O 8 N 4: 597.3863; found
. 597.3850 ([M + H] +) 1 H NMR (400 MHz, CD 3 OD) δppm: 5.53 (1H, d, J = 2.
9 Hz), 5.27-5.31 (1H, m), 4.32-4.38 (2H, m), 4.19
(1H, dd, J = 8.8, 8.8 Hz), 4.08 (1H, dd, J = 9.5,
2.9 Hz), 3.75 (1H, ddd, J = 11.7, 10.7, 4.9 Hz),
3.72 (1H, dd, J = 9.5, 1.5 Hz), 3.50 (1H, ddd, J =
11.7, 10.7, 1.0 Hz), 2.39 (2H, t, J = 7.3 Hz), 1.99
(3H, s), 1.90-1.99 (1H, m), 1.76-1.82 (1H, m), 1.
60-1.70 (2H, m), 1.28-1.40 (24H, m), 0.90 (3H, t, J
(Example 19) (4S, 5R, 6R, 2'R) -5-acetylamino-5,6-dihydro-6- (4 ', 5'-dihydroxy-tetrahydro-pyran-2'). -Yl) -4-guanidino-4H-pyran-2-carboxylic acid hydrate
【０３１７】[0317]
【化３１】 Embedded image
【０３１８】(i)5−アセチルアミノ−4−O−t−ブチル
カルボニルオキシ−3，5−ジデオキシ−8，9−O−イソ
プロピリデン−2−O−メチル−D−グリセロ−D−ガラク
ト−ノン−2−エノピラノソン酸メチル 5−アセチルアミノ−4−O−t−ブチルカルボニルオキシ
−3，5−ジデオキシ−8，9−O−イソプロピリデン−2−
O−メチル−D−グリセロ−D−ガラクト−ノン−2−エノ
ピラノソン酸メチル（10.2g、22.10mmol）を90％酢酸水
(100ml)に溶解し、60℃で3時間攪拌した。反応液を減圧
留去後、得られた残渣をトルエンにて共沸(２回)した。
さらに酢酸エチル、ヘキサンを加え粉末化し標記化合物
を無色粉末として得た。（1.79g、92％） TLC（シリカゲル）： Rf = 0.29 (塩化メチレン／メタ
ノール＝10/1).1 H NMR (400 MHz, CD3OD) δppm: 5.22 (1H, ddd, J =
11.7, 11.0, 5.1 Hz),4.20 (1H, dd, J = 11.0, 10.3 H
z), 3.98 (1H, dd, J = 10.3, 1.5 Hz), 3.72-3.85 (5
H, m), 3.60-3.70 (1H, m), 3.51.(1H, d, J = 9.5 H
z), 3.30 (3H, s), 2.41 (1H, dd, J = 12.5, 5.1 Hz),
1.91 (3H, s), 1.72 (1H, dd, J = 12.5,11.7 Hz), 1.
16 (9H, s). (ii)（2S, 4S, 5R, 6R）−5−アセチルアミノ−4−t−
ブチルカルボニルオキシ−6−ホルミル−2−メトキシ−
テトラヒドロ−ピラン−2−カルボン酸メチル 実施例１９(i)で得られた化合物(8.1 g, 19.22 mmol）
をアセトン(80 ml)、蒸留水(20ml)に溶解し、室温で過
ヨウ素酸ナトリウム（16.44ｇ、76.88 mmol）を加え、
同温で1時間攪拌した。反応液を濾過し、濾液を減圧留
去後、得られた残査を酢酸エチルに溶解し飽和重曹水、
飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥し
た。濾過し、炉液を減圧留去後、得られた残査を酢酸エ
チル、ヘキサンにて粉末化し標記化合物を無色粉末とし
て得た。（6.6g、96％） TLC（シリカゲル）： Rf = 0.48 (塩化メチレン／メタ
ノール＝10/1) (iii)（2S, 4S, 5R, 6R）−5−アセチルアミノ−4−t−
ブチルカルボニルオキシ−6−(1'R−1−ヒドロキシ−ブ
ト−3'−エニル)−2−メトキシ−テトラヒドロ−ピラン
−2−カルボン酸メチル [1'R化合物]及び（2S, 4S, 5
R, 6R）−5−アセチルアミノ−4−t−ブチルカルボニル
オキシ−6−(1'S−1−ヒドロキシ−ブト−3'−エニル)
−2−メトキシ−テトラヒドロ−ピラン−2−カルボン酸
メチル [1'S化合物] 窒素雰囲気下、実施例１９(ii)で得られた化合物（8.95
g, 24.9 mmol）を塩化メチレン(100 ml)に溶解し、氷
冷にてアリルトリメチルシラン (7.6 ml, 49.81mmol)を
加え、さらに1規定四塩化チタン・塩化メチレン溶液(30
ml)を滴下し、同温度にて10分、室温にて1時間攪拌し
た。反応液を、氷を浮べた飽和重曹水に加え30分間攪拌
し、塩化メチレンにて抽出した。塩化メチレン層を無水
硫酸ナトリウムにて乾燥し、濾過、濾液を減圧留去し得
られた残渣をシリカゲルクロマトグラフィー（トルエン
/アセトニトリル＝1/1) に付して標記化合物を無色アモ
ルファスとして得た(1'R化合物：5.18 g、52％）(1'S化
合物：2.52 g、25％)。 (1'R化合物） TLC（シリカゲル）: Rf = 0.67 (トルエン/アセトニト
リル＝1/1)1 H NMR (400 MHz, CDCl3) δppm: 5.84-5.99 (2H, m),
5.33 (1H, ddd, J = 11.7, 11.0, 5.1 Hz), 5.03-5.17
(2H, m), 4.32 (1H, d, J = 5.1 Hz), 4.03 (1H, ddd,
j = 10.3, 10.3, 8.1 Hz), 3.81 (3H, s), 3.61-3.69
(1H, m), 3.35 (1H, d, J = 10.3 Hz), 3.27 (3H, s),
2.58-2.68 (1H, m), 2.38 (1H, dd,J = 12.5, 5.1 Hz),
2.25-2.35 (1H, m), 1.98 (1H, dd, J = 12.5, 11.7 H
z), 1.97(3H, s), 1.17 (9H, s). (1'S化合物） TLC（シリカゲル）: Rf = 0.61 (トルエン/アセトニト
リル＝1/1)1 H NMR (400 MHz, CDCl3) δppm: 5.83-5.95 (1H, m),
5.65 (1H, d, J = 8.8Hz), 5.27 (1H, ddd, J = 11.7,
10.3, 5.1 Hz), 5.10-5.20 (2H, m), 4.03 (1H, ddd, J
= 10.3, 10.3, 8.8 Hz), 3.74-3.84 (4H, m), 3.62 (1
H, dd, J = 10.3, 2.2 Hz), 3.27 (3H, s), 2.72 (1H,
d,J = 8.8 Hz), 2.50-2.60 (1H, m), 2.31-2.41 (2H,
m), 1.92 (3H, s), 1.90 (1H, dd, J = 12.5, 11.7 H
z), 1.16 (9H, s). (iv)（2S, 4S, 5R, 6R）−5−アセチルアミノ−4−t−
ブチルカルボニルオキシ−6−(1'R−1−アリルオキシ−
ブト−3'−エニル)−2−メトキシ−テトラヒドロ−ピラ
ン−2−カルボン酸メチル 窒素雰囲気下、実施例１９(iii)で得られた1'R化合物
(1.83ｇ, 4.56 mmol)を塩化メチレン(20ml)、シクロヘ
キサン(40ml)に溶解し、アリル 2,2,2,-トリクロロア
セトイミデート(9.23g, 45.6 mmol)を加え、さらに氷冷
下にてトリフルオロメタンスルホン酸(1ml)を滴下し同
温度にて5時間攪拌した。反応液にピリジン(10ml)を加
え10分間攪拌後、塩化メチレン、水に分配し、有機層を
無水硫酸ナトリウムにて乾燥し、減圧留去後、得られた
残渣をシリカゲルクロマトグラフィー（酢酸エチル/ヘ
キサン=1/3−1/1−2/1）に付して標記化合物を無色アモ
ルファスとして得た。(0.45g、22％) TLC（シリカゲル）：Rf = 0.37 (酢酸エチル:ヘキサン
＝1/1). MS (FAB) m/e 442 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 5.92-6.03 (1H, m),
5.74-5.86 (1H, m), 5.05-5.29 (6H, m),4.33 (1H, dd
d, J = 10.2, 10.2, 10.1 Hz), 4.02-4.14 (2H,m),3.80
(3H, s), 3.46-3.57 (2H, m), 3.27 (3H, s), 2.42-2.
59 (2H, m), 2.33 (1H, dd, J = 12.8, 5.0 Hz), 1.93
(1H, dd, J = 12.8, 11.8 Hz), 1.91 (3H, s), 1.16 (9
H, s). (v)（2S, 4S, 5R, 6R, 2'R）−5−アセチルアミノ−4−
t−ブチルカルボニルオキシ−6−（3'，6'−ジヒドロ−
2'H−ピラン−2'−イル）−2−メトキシ−テトラヒドロ
−ピラン−2−カルボン酸メチル 窒素雰囲気下、実施例１９(iv)で得られた化合物（0.69
g, 1.56 mmol）を塩化メチレン（500 ml）に溶解し、
ビス（トリシクロヘキシルホスフィン）ベンジリデンル
テニウム（IV）ジクロライド（50 mg）を加え、室温で2
4時間撹拌した。反応液を減圧留去後、得られた残渣を
シリカゲルクロマトグラフィー（酢酸エチル/ヘキサン
＝2/1）に付して標記化合物を無色アモルファスとして
得た。（0.52g、80％） TLC（シリカゲル）： Rf = 0.47 (塩化メチレン／メタ
ノール＝10/1) MS (FAB) m/e 414 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 5.80-5.88 (1H, m),
5.67-5.74 (1H, m), 5.39 (1H, d, j = 9.2 Hz), 5.28
(1H, ddd, J = 11.4, 10.6, 5.1 Hz), 4.37 (1H, ddd,
J = 10.3, 10.3, 9.5 Hz), 4.15-4.34 (2H, m), 3.79
(3H, s), 3.59-3.66 (1H, m), 3.46 (1H, dd, J = 10.
3, 1.4 Hz), 3.26 (3H, s), 2.64-2.77(1H, m), 2.38
(1H, dd, J = 12.9, 5.1 Hz), 1.94 (1H, dd, J = 12.
9, 11.4 Hz),1.91 (3H, s), 1.77-1.84 (1H, m), 1.16
(9H, s). (vi)（2S, 4S, 5R, 6R, 2'R）−5−アセチルアミノ−4
−t−ブチルカルボニルオキシ−6−（４'，5'−ジヒド
ロキシ−テトラヒドロ−ピラン−2'−イル）−2−メト
キシ−テトラヒドロ−ピラン−2−カルボン酸メチル
[低極性2'R化合物]及び（2S, 4S, 5R, 6R, 2'R）−5−
アセチルアミノ−4−t−ブチルカルボニルオキシ−6−
（４'，5'−ジヒドロキシ−テトラヒドロ−ピラン−2'
−イル）−2−メトキシ−テトラヒドロ−ピラン−2−カ
ルボン酸メチル [高極性2'R化合物] 実施例１９(v)で得られた化合物（0.51 g, 1.23 mmol）
をアセトン(5 ml)、蒸留水(5 ml)、アセトニトリル(5 m
l)に溶解し、N-メチルモルホリン N-オキシド50％水溶
液（320 mg, 1.38 mmol）、四酸化オスミウム（1mg, 0.
004 mmol）を加え、氷冷下5時間撹拌した。反応液を減
圧留去し、得られた残渣をシリカゲルクロマトグラフィ
ー（塩化メチレン／メタノール＝10/1）に付して標記化
合物をそれぞれアモルファスとして得た(低極性2'R化合
物：345mg、63％)(高極性2'R化合物：162mg、29％)。 （低極性2'R化合物） TLC（シリカゲル）: Rf = 0.19 (トルエン:アセトニト
リル=1/3) MS (FAB) m/e 448 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 5.61 (1H, br), 5.25
(1H, ddd, J = 15.9,11.1, 5.0 Hz), 4.27 (1H, ddd,
J = 10.2, 10.1, 10.0 Hz), 4.29 (1H, d, J= 2.5 Hz),
3.73-3.90 (6H, m), 3.50 (1H, t, J = 10.3 Hz), 3.4
4 (1H, dd,J= 10.3, 1.5 Hz), 3.22 (3H, s), 2.38 (1
H, dd, J = 12.9, 5.0 Hz), 2.13-2.24 (1H, m), 1.69-
2.13 (7H, m),1.15 (9H, s). （高極性2'R化合物） TLC（シリカゲル）: Rf = 0.08 (トルエン:アセトニト
リル=1/3) MS (FAB) m/e 448 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 5.58(1H, d, J = 8.3
Hz), 5.28 (1H, ddd,J = 11.4, 10.5, 5.0 Hz), 4.23
(1H, ddd, J = 10.0, 10.0, 10.0 Hz), 4.03(1H, d, j
= 12.4 Hz), 3.81 (3H, s), 3.67-3.76 (3H, m), 3.51-
3.58 (1H, m), 3.44 (1H, d, J = 12.4 Hz), 3.25 (3H,
s), 1.97 (5H, m), 1.92 (3H, s), 1.86 (1H, dd, J =
12.7, 11.4 Hz), 1.15 (9H, s). (vii)（4S, 5R, 6R, 2'R,）−5−アセチルアミノ−4−
アジド−6−（４'，５'−ジアセトキシ−テトラヒドロ
−ピラン−2'−イル）−5，6−ジヒドロ−4H−ピラン−
2−カルボン酸メチル [低極性2'R化合物] 窒素雰囲気下、実施例１９(vi)で得られた低極性2'R化
合物（345mg、0.771mmol)を酢酸(0.25ml)、無水酢酸(1m
l)に溶解し、氷冷下、濃硫酸(0.2ml)を加え、80℃にて3
時間攪拌した。炭酸ナトリウム(1.5g)、水(7.5ml)、ト
ルエン(7.5ml)の混合2層液を激しく攪拌し、この中に先
の反応液を室温にて注加し30分間攪拌した。トルエン層
を分取し、水層をトルエンにて抽出、トルエン層を集
め、無水硫酸ナトリウムにて乾燥し、減圧留去後、得ら
れた残渣をN,N'-ジメチルホルムアミド（2 ml）に溶解
し、アジ化ナトリウム（345 mg）、ダウエックス50W（H
+）樹脂（345 mg）を加え、70℃で3時間撹拌した。酢酸
エチルにて反応液を希釈し水洗、無水硫酸ナトリウムに
て乾燥し、減圧留去後、得られた残査をクロマトグラフ
ィー（シリカゲル、塩化メチレン/メタノール＝20/1）
に付して標記化合物を無色アメ状として得た。（290m
g、85％） TLC（シリカゲル）：Rf = 0.47 (塩化メチレン/メタノ
ール＝10/1) MS (FAB) m/e 441 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 6.01(1H, d, J = 3.3
Hz), 5.96 (1H, d, J= 6.8 Hz), 5.53 (1H, d, J = 2.
1 Hz), 4.92-5.00 (1H, m), 4.71 (1H, dd, J= 7.7, 3.
2 Hz), 4.47 (1H, dd, J = 8.3, 3.8 Hz), 3.85-3.98
(2H, m), 3.83(3H, s), 3.61-3.74 (2H, m), 1.86 (11
H, m). (viii)（4S, 5R, 6R, 2'R）−5−アセチルアミノ−4−
（N，N'−ビス−t−ブチルオキシカルボニル）グアニジ
ノ−6−（4'，5'−ジアセトキシ−テトラヒドロ−ピラ
ン−2'−イル）−5，6−ジヒドロ−4H−ピラン−2−カ
ルボン酸メチル [低極性2'R化合物] 実施例１９(vii)で得られた化合物（160 mg, 0.363 mmo
l）をエタノール（10ml）に溶解し、窒素雰囲気下リン
ドラー触媒（50 mg）を加え、次いで水素雰囲気に置換
し、室温で3時間攪拌した。反応液をセライト濾過し濾
物をエタノールで洗浄し、濾液、洗液を減圧留去した。
得られた残渣を無水テトラヒドロフラン(10ml)に溶解し
１H−ピラゾール−１−[N,N'−ビス(t−ブトキシカルボ
ニル)]カルボキサミジン (226mg、 0.727mmol)を加え室
温にて終夜攪拌した。反応液を濃縮し、残渣を酢酸エチ
ルにて希釈、1N-塩酸、飽和重曹水、飽和食塩水にて洗
浄、無水硫酸ナトリウムにて乾燥し、減圧留去後、得ら
れた残渣をシリカゲルクロマトグラフィー（ヘキサン/
酢酸エチル＝1/2）に付して標記化合物を無色アモルフ
ァスとして得た。（168mg、70％） TLC（シリカゲル）：Rf = 0.32 (ヘキサン/酢酸エチル
＝1/2) MS (FAB) m/e 657 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 11.39 (1H, s), 8.58
(1H, d, J = 8.7 Hz), 6.49 (1H, d, J = 7.9 Hz), 5.
86 (1H, d, J = 2.8 Hz), 5.53 (1H, d, J = 3.1 Hz),
5.16 (1H, dt, J = 8.8, 2.7 Hz), 4.93-4.97 (1H, m),
4.16-4.25 (1H, m), 4.82-4.96 (3H, m), 3.81 (3H,
s), 3.67 (1H, dd, J = 10.9, 10.8 Hz),2.25-2.39 (1
H, m), 2.12 (3H, s), 1.99 (3H, s), 1.98 (3H, s),
1.74-1.89(1H, m), 1.50 (9H, s), 1.49 (9H, s). (ix)（4S, 5R, 6R, 2'R）−5−アセチルアミノ−5，6−
ジヒドロ−6−（4'，5'−ジヒドロキシ−テトラヒドロ
−ピラン−2'−イル）−4−グアニジノ−4H−ピラン−2
−カルボン酸・水和物 [低極性2'R化合物] 実施例１９(viii)で得られた化合物(81mg、0.123mmol)
をメタノール２mlに溶解し28％ナトリウムメトキシド・
メタノール溶液(0.2ml)を加え室温にて12時間攪拌し
た。さらに反応液に1M水酸化ナトリウム水溶液(150μ
l、0.148mmol)を加え1時間攪拌した。次いで反応液にダ
ウエックス50W×8（H+）樹脂を加え中和した。ただちに
減圧濾過し、水で濾物を洗浄した。濾液、洗液を減圧留
去後、得られた残渣を逆層クロマトグラフィー（コスモ
シル、水/メタノール＝1/1）に付し精製した。得られた
化合物を塩化メチレン(3ml)に懸濁し、トリフルオロ酢
酸(1ml)を加え室温にて12時間攪拌した。減圧留去後、
得られた残渣を逆層クロマトグラフィー（コスモシル、
水）に付して、標記化合物を無色アモルファスとして得
た。（8mg、18％） TLC（シリカゲル）：Rf = 0.24 (t-ブタノール:酢酸:水
=5:1:1) MS (FAB) m/e 359 [M+H]+ 1 H NMR (400 MHz, D2O) δppm: 5.48 (1H, d, J = 2.8
Hz), 4.20 (1H, dd, J= 8.5, 2.8 Hz), 4.05 (1H, d, J
= 2.4 Hz), 3.99(1H, dd, J = 9.3, 8.5 Hz), 3.88 (1
H, dd, J = 9.3, 2.5 Hz), 3.79 (1H, dt, J = 12.0,
2.1 Hz), 3.51-3.64 (2H, m), 3.32 (1H, dd, J = 10.
1, 9.8 Hz), 2.01 (1H, ddd, J = 14.5,12.0, 2.5 Hz),
1.86 (3H, s), 1.58 (1H, ddd, J = 14.5, 3.6, 2.1 H
z). (x)（4S, 5R, 6R, 2'R,）−5−アセチルアミノ−4−ア
ジド−6−（４'，５'−ジアセトキシ−テトラヒドロ−
ピラン−2'−イル）−5，6−ジヒドロ−4H−ピラン−2
−カルボン酸メチル [高極性2'R化合物] 窒素雰囲気下、実施例１９(vi)で得られた高極性2'R化
合物（162mg、0.362mmol)を酢酸(0.25ml)、無水酢酸(1m
l)に溶解し、氷冷下、濃硫酸(0.2ml)を加え、80℃にて3
時間攪拌した。炭酸ナトリウム(1.5g)、水(7.5ml)、ト
ルエン(7.5ml)の混合2層液を激しく攪拌し、この中に先
の反応液を室温にて注加し30分間攪拌した。トルエン層
を分取し、水層をトルエンにて抽出、トルエン層を集
め、無水硫酸ナトリウムにて乾燥し、減圧留去後、得ら
れた残渣をN,N'-ジメチルホルムアミド（2 ml）に溶解
し、アジ化ナトリウム（170 mg）、ダウエックス50W（H
+）樹脂（170 mg）を加え、70℃で3時間撹拌した。酢酸
エチルにて反応液を希釈し水洗、無水硫酸ナトリウムに
て乾燥し、減圧留去後、得られた残査をシリカゲルクロ
マトグラフィー（塩化メチレン/メタノール＝20/1）に
付して標記化合物(13)を無色アメ状物として得た。（86
mg、54％） TLC（シリカゲル）：Rf = 0.46 (塩化メチレン/メタノ
ール＝10/1) MS (FAB) m/e 441 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 6.00(1H, d, J = 3.0
Hz), 5.89 (1H, d, J= 7.6 Hz), 5.17 (1H, brs), 4.9
8-5.07 (1H, m), 4.63 (1H, dd, J = 7.9, 3.1 Hz), 4.
51 (1H, dd, J = 8.5, 3.5 Hz), 4.11 (1H, dd, J = 1
3.0, 1.5 Hz),3.69-3.85 (5H, m), 3.61 (1H, d, J = 1
3.0 Hz), 2.28 (1H, ddd,J = 12.2, 12.1, 12.0 Hz),
2.16 (3H, s), 2.04 (3H, s), 2.03 (3H, s), 1.78-1.8
5 (1H,m). (xi)（4S, 5R, 6R, 2'R）−5−アセチルアミノ−4−
（N，N'−ビス−t−ブチルオキシカルボニル）グアニジ
ノ−6−（4'，5'−ジアセトキシ−テトラヒドロ−ピラ
ン−2'−イル）−5，6−ジヒドロ−4H−ピラン−2−カ
ルボン酸メチル [高極性2'R化合物] 実施例１９(x)で得られた化合物（80 mg, 0.363 mmol）
をエタノール（5 ml）に溶解し、窒素雰囲気下リンドラ
ー触媒（30 mg）を加え、次いで水素雰囲気に置換し、
室温で3時間攪拌した。反応液をセライト濾過し濾物を
エタノールで洗浄し、濾液、洗液を減圧留去した。得ら
れた残渣を無水のテトラヒドロフラン(5ml)に溶解し１H
−ピラゾール−１−[N,N'−ビス(t−ブトキシカルボニ
ル)]カルボキサミジン (85mg、 0.272mmol)を加え室温に
て終夜攪拌した。反応液を濃縮し、残渣を酢酸エチルに
て希釈、1N-塩酸、飽和重曹水、飽和食塩水にて洗浄、
無水硫酸ナトリウムにて乾燥し、減圧留去後、得られた
残渣をクロマトグラフィー（シリカゲル、ヘキサン/酢
酸エチル＝1/2）に付して標記化合物(14)を無色アモル
ファスとして得た。（77mg、65％） TLC（シリカゲル）：Rf = 0.25 (ヘキサン/酢酸エチル
＝1/2) MS (FAB) m/e 657 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 11.38 (1H, s), 8.57
(1H, d, J = 8.6 Hz), 6.48 (1H, d, J = 7.9 Hz), 5.
88 (1H, d, J = 2.7 Hz), 5.10-5.19 (2H, m),4.98-5.0
7 (1H, m), 4.25 (1H, ddd, J = 9.1, 9.1, 8.2 Hz),
4.11 (1H, dd,J = 13.3, 1.9 Hz), 3.97 (1H, d, J = 1
1.1 Hz), 3.80 ( 3H, s), 3.69 (1H, d, J = 11.8 Hz),
3.61 (1H, d, J = 12.7 Hz), 2.83 (1H, ddd, J = 12.
2, 12.1, 12.0 Hz), 2.15 (3H, s), 2.02 (3H, s), 1.9
7 (3H, s), 1.75 (1H, dd, J =12.0, 5.0 Hz), 1.49 (9
H, s), 1.48 (9H, s). (xii)(4S, 5R, 6R, 2'R）−5−アセチルアミノ−5，6−
ジヒドロ−6−（4'，5'−ジヒドロキシ−テトラヒドロ
−ピラン−2'−イル）−4−グアニジノ−4H−ピラン−2
−カルボン酸・水和物 [高極性2'R化合物] 実施例１９(xi)で得られた化合物(77mg、0.117mmol)を
メタノール２mlに溶解し28％ナトリウムメトキシド・メ
タノール溶液(0.2ml)を加え室温にて12時間攪拌した。
さらに反応液に1M水酸化ナトリウム水溶液(140μl、0.1
40mmol)を加え1時間攪拌した。次いで反応液にダウエッ
クス50W×8（H+）樹脂を加え中和した。ただちに減圧濾
過し、水で濾物を洗浄した。濾液、洗液を減圧留去後、
得られた化合物を塩化メチレン(3ml)に懸濁し、トリフ
ルオロ酢酸(1ml)を加え室温にて12時間攪拌した。減圧
留去後、得られた残渣を逆層クロマトグラフィー（コス
モシル、水）に付して、標記化合物を無色アモルファス
として得た。（20mg、48％） TLC（シリカゲル）：Rf = 0.16 (t-ブタノール:酢酸:水
=5:1:1) MS (FAB) m/e 359 [M+H]+ 1 H NMR (400 MHz, D2O) δppm: 5.58 (1H, brs), 4.21
(1H, dd, J = 8.2, 2.5 Hz), 4.03 (1H, dd, J = 9.1,
8.2 Hz), 3.93 (1H, dd, J = 9.1, 2.1 Hz), 3.70-3.79
(2H, m), 3.62 (1H, s), 3.52 (1H, ddd, J = 12.0,
2.3, 2.1 Hz), 3.34 (1H, d, J = 12.0 Hz), 1.82-1.94
(4H, m), 1.46-1.55 (1H, m). （実施例２０） (4S, 5R, 6R, 2'S）−5−アセチルアミノ−5，6−ジヒ
ドロ−6−（4'，5'−ジヒドロキシ−テトラヒドロ−ピ
ラン−2'−イル）−4−グアニジノ−4H−ピラン−2−カ
ルボン酸・水和物(I) 5-acetylamino-4-O-t-butylcarbonyloxy-3,5-dideoxy-8,9-O-isopropylidene-2-O-methyl-D-glycero-D-galacto- Methyl non-2-enopyranosonate 5-acetylamino-4-O-t-butylcarbonyloxy-3,5-dideoxy-8,9-O-isopropylidene-2-
Methyl O-methyl-D-glycero-D-galacto-non-2-enopyranosonate (10.2 g, 22.10 mmol) was added to 90% aqueous acetic acid.
(100 ml) and stirred at 60 ° C. for 3 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was azeotropically distilled (twice) with toluene.
Ethyl acetate and hexane were further added to give a powder, and the title compound was obtained as a colorless powder. (1.79 g, 92%) TLC (silica gel): Rf = 0.29 (methylene chloride / methanol = 10/1). 1 H NMR (400 MHz, CD 3 OD) δ ppm: 5.22 (1H, ddd, J =
11.7, 11.0, 5.1 Hz), 4.20 (1H, dd, J = 11.0, 10.3 H
z), 3.98 (1H, dd, J = 10.3, 1.5 Hz), 3.72-3.85 (5
H, m), 3.60-3.70 (1H, m), 3.51. (1H, d, J = 9.5 H
z), 3.30 (3H, s), 2.41 (1H, dd, J = 12.5, 5.1 Hz),
1.91 (3H, s), 1.72 (1H, dd, J = 12.5,11.7 Hz), 1.
16 (9H, s). (Ii) (2S, 4S, 5R, 6R) -5-acetylamino-4-t-
Butylcarbonyloxy-6-formyl-2-methoxy-
Methyl tetrahydro-pyran-2-carboxylate Compound obtained in Example 19 (i) (8.1 g, 19.22 mmol)
Was dissolved in acetone (80 ml) and distilled water (20 ml), and sodium periodate (16.44 g, 76.88 mmol) was added at room temperature.
The mixture was stirred at the same temperature for 1 hour. The reaction solution was filtered, and the filtrate was distilled off under reduced pressure.
The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration and evaporation of the filtrate under reduced pressure, the resulting residue was triturated with ethyl acetate and hexane to give the title compound as a colorless powder. (6.6 g, 96%) TLC (silica gel): Rf = 0.48 (methylene chloride / methanol = 10/1) (iii) (2S, 4S, 5R, 6R) -5-acetylamino-4-t-
Methyl butylcarbonyloxy-6- (1′R-1-hydroxy-but-3′-enyl) -2-methoxy-tetrahydro-pyran-2-carboxylate [1′R compound] and (2S, 4S, 5
(R, 6R) -5-acetylamino-4-t-butylcarbonyloxy-6- (1'S-1-hydroxy-but-3'-enyl)
Methyl 2-methoxy-tetrahydro-pyran-2-carboxylate [1 ′S compound] The compound obtained in Example 19 (ii) under a nitrogen atmosphere (8.95)
g, 24.9 mmol) was dissolved in methylene chloride (100 ml), and allyltrimethylsilane (7.6 ml, 49.81 mmol) was added thereto under ice-cooling. Further, a 1N titanium tetrachloride / methylene chloride solution (30 ml) was added.
ml) was added dropwise, and the mixture was stirred at the same temperature for 10 minutes and at room temperature for 1 hour. The reaction solution was added to a saturated aqueous sodium bicarbonate solution with ice, stirred for 30 minutes, and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was subjected to silica gel chromatography (toluene
/ Acetonitrile = 1/1) to give the title compound as a colorless amorphous (1′R compound: 5.18 g, 52%) (1 ′S compound: 2.52 g, 25%). (1′R compound) TLC (silica gel): Rf = 0.67 (toluene / acetonitrile = 1/1) 1 H NMR (400 MHz, CDCl 3 ) δppm: 5.84-5.99 (2H, m),
5.33 (1H, ddd, J = 11.7, 11.0, 5.1 Hz), 5.03-5.17
(2H, m), 4.32 (1H, d, J = 5.1 Hz), 4.03 (1H, ddd,
j = 10.3, 10.3, 8.1 Hz), 3.81 (3H, s), 3.61-3.69
(1H, m), 3.35 (1H, d, J = 10.3 Hz), 3.27 (3H, s),
2.58-2.68 (1H, m), 2.38 (1H, dd, J = 12.5, 5.1 Hz),
2.25-2.35 (1H, m), 1.98 (1H, dd, J = 12.5, 11.7 H
. z), 1.97 (3H, s), 1.17 (9H, s) (1'S compound) TLC (silica gel): Rf = 0.61 (toluene / acetonitrile = 1/1) 1 H NMR (400 MHz, CDCl 3) δppm: 5.83-5.95 (1H, m),
5.65 (1H, d, J = 8.8Hz), 5.27 (1H, ddd, J = 11.7,
10.3, 5.1 Hz), 5.10-5.20 (2H, m), 4.03 (1H, ddd, J
= 10.3, 10.3, 8.8 Hz), 3.74-3.84 (4H, m), 3.62 (1
H, dd, J = 10.3, 2.2 Hz), 3.27 (3H, s), 2.72 (1H,
d, J = 8.8 Hz), 2.50-2.60 (1H, m), 2.31-2.41 (2H,
m), 1.92 (3H, s), 1.90 (1H, dd, J = 12.5, 11.7 H
z), 1.16 (9H, s). (iv) (2S, 4S, 5R, 6R) -5-acetylamino-4-t-
Butylcarbonyloxy-6- (1′R-1-allyloxy-
Methyl (but-3'-enyl) -2-methoxy-tetrahydro-pyran-2-carboxylate 1'R compound obtained in Example 19 (iii) under nitrogen atmosphere
(1.83 g, 4.56 mmol) was dissolved in methylene chloride (20 ml) and cyclohexane (40 ml), allyl 2,2,2-trichloroacetimidate (9.23 g, 45.6 mmol) was added, and further under ice cooling. Trifluoromethanesulfonic acid (1 ml) was added dropwise, and the mixture was stirred at the same temperature for 5 hours. Pyridine (10 ml) was added to the reaction solution, and the mixture was stirred for 10 minutes, partitioned between methylene chloride and water, the organic layer was dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The obtained residue was subjected to silica gel chromatography (ethyl acetate / ethyl acetate). Hexane = 1 / 3-1 / 1-2 / 1) to give the title compound as a colorless amorphous. (0.45g, 22%) TLC (silica gel): Rf = 0.37. (Ethyl acetate: hexane = 1/1) MS (FAB ) m / e 442 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm: 5.92-6.03 (1H, m),
5.74-5.86 (1H, m), 5.05-5.29 (6H, m), 4.33 (1H, dd
d, J = 10.2, 10.2, 10.1 Hz), 4.02-4.14 (2H, m), 3.80
(3H, s), 3.46-3.57 (2H, m), 3.27 (3H, s), 2.42-2.
59 (2H, m), 2.33 (1H, dd, J = 12.8, 5.0 Hz), 1.93
(1H, dd, J = 12.8, 11.8 Hz), 1.91 (3H, s), 1.16 (9
H, s). (V) (2S, 4S, 5R, 6R, 2'R) -5-acetylamino-4-
t-butylcarbonyloxy-6- (3 ′, 6′-dihydro-
Methyl 2'H-pyran-2'-yl) -2-methoxy-tetrahydro-pyran-2-carboxylate Compound (0.69) obtained in Example 19 (iv) under a nitrogen atmosphere.
g, 1.56 mmol) in methylene chloride (500 ml),
Add bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride (50 mg) and add
Stir for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to silica gel chromatography (ethyl acetate / hexane = 2/1) to obtain the title compound as a colorless amorphous. (0.52g, 80%) TLC (silica gel): Rf = 0.47 (methylene chloride / methanol = 10/1) MS (FAB ) m / e 414 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm : 5.80-5.88 (1H, m),
5.67-5.74 (1H, m), 5.39 (1H, d, j = 9.2 Hz), 5.28
(1H, ddd, J = 11.4, 10.6, 5.1 Hz), 4.37 (1H, ddd,
J = 10.3, 10.3, 9.5 Hz), 4.15-4.34 (2H, m), 3.79
(3H, s), 3.59-3.66 (1H, m), 3.46 (1H, dd, J = 10.
3, 1.4 Hz), 3.26 (3H, s), 2.64-2.77 (1H, m), 2.38
(1H, dd, J = 12.9, 5.1 Hz), 1.94 (1H, dd, J = 12.
9, 11.4 Hz), 1.91 (3H, s), 1.77-1.84 (1H, m), 1.16
(9H, s). (Vi) (2S, 4S, 5R, 6R, 2'R) -5-acetylamino-4
-T-butylcarbonyloxy-6- (4 ', 5'-dihydroxy-tetrahydro-pyran-2'-yl) -2-methoxy-tetrahydro-pyran-2-carboxylic acid methyl ester
[Low polarity 2'R compound] and (2S, 4S, 5R, 6R, 2'R) -5-
Acetylamino-4-t-butylcarbonyloxy-6-
(4 ', 5'-dihydroxy-tetrahydro-pyran-2'
-Yl) -2-Methoxy-tetrahydro-pyran-2-carboxylate [Highly polar 2'R compound] The compound obtained in Example 19 (v) (0.51 g, 1.23 mmol)
In acetone (5 ml), distilled water (5 ml), acetonitrile (5 m
l), 50% aqueous solution of N-methylmorpholine N-oxide (320 mg, 1.38 mmol), and osmium tetroxide (1 mg, 0.1%).
004 mmol) and stirred under ice cooling for 5 hours. The reaction solution was distilled off under reduced pressure, and the obtained residue was subjected to silica gel chromatography (methylene chloride / methanol = 10/1) to obtain the title compounds as amorphous (low polar 2'R compound: 345 mg, 63%). ) (Highly polar 2'R compound: 162 mg, 29%). (Less polar 2'R compound) TLC (silica gel): Rf = 0.19 (toluene: acetonitrile = 1/3) MS (FAB ) m / e 448 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm : 5.61 (1H, br), 5.25
(1H, ddd, J = 15.9,11.1, 5.0 Hz), 4.27 (1H, ddd,
J = 10.2, 10.1, 10.0 Hz), 4.29 (1H, d, J = 2.5 Hz),
3.73-3.90 (6H, m), 3.50 (1H, t, J = 10.3 Hz), 3.4
4 (1H, dd, J = 10.3, 1.5 Hz), 3.22 (3H, s), 2.38 (1
H, dd, J = 12.9, 5.0 Hz), 2.13-2.24 (1H, m), 1.69-
2.13 (7H, m), 1.15 (9H, s). (Highly polar 2'R compound) TLC (silica gel): Rf = 0.08 (toluene: acetonitrile = 1/3) MS (FAB) m / e 448 [M + H] + 1 H NMR (400 MHz, CDCl 3 ) δppm: 5.58 (1H, d, J = 8.3
Hz), 5.28 (1H, ddd, J = 11.4, 10.5, 5.0 Hz), 4.23
(1H, ddd, J = 10.0, 10.0, 10.0 Hz), 4.03 (1H, d, j
= 12.4 Hz), 3.81 (3H, s), 3.67-3.76 (3H, m), 3.51-
3.58 (1H, m), 3.44 (1H, d, J = 12.4 Hz), 3.25 (3H,
s), 1.97 (5H, m), 1.92 (3H, s), 1.86 (1H, dd, J =
(12.7, 11.4 Hz), 1.15 (9H, s). (Vii) (4S, 5R, 6R, 2'R,)-5-acetylamino-4-
Azido-6- (4 ', 5'-diacetoxy-tetrahydro-pyran-2'-yl) -5,6-dihydro-4H-pyran-
Methyl 2-carboxylate [Low-polarity 2'R compound] Under a nitrogen atmosphere, the low-polarity 2'R compound (345 mg, 0.771 mmol) obtained in Example 19 (vi) was treated with acetic acid (0.25 ml) and acetic anhydride (1 m2).
l), add concentrated sulfuric acid (0.2 ml) under ice cooling, and add
Stirred for hours. A two-layer liquid mixture of sodium carbonate (1.5 g), water (7.5 ml), and toluene (7.5 ml) was vigorously stirred, and the reaction solution was poured into the mixture at room temperature and stirred for 30 minutes. The toluene layer was separated, the aqueous layer was extracted with toluene, the toluene layer was collected, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the obtained residue was added to N, N'-dimethylformamide (2 ml). Dissolve, sodium azide (345 mg), Dowex 50W (H
+ ) Resin (345 mg) was added, and the mixture was stirred at 70 ° C for 3 hours. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resulting residue was chromatographed (silica gel, methylene chloride / methanol = 20/1).
To give the title compound as a colorless candy. (290m
g, 85%) TLC (silica gel): Rf = 0.47 (methylene chloride / methanol = 10/1) MS (FAB ) m / e 441 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm: 6.01 (1H, d, J = 3.3
Hz), 5.96 (1H, d, J = 6.8 Hz), 5.53 (1H, d, J = 2.
1 Hz), 4.92-5.00 (1H, m), 4.71 (1H, dd, J = 7.7, 3.
2 Hz), 4.47 (1H, dd, J = 8.3, 3.8 Hz), 3.85-3.98
(2H, m), 3.83 (3H, s), 3.61-3.74 (2H, m), 1.86 (11
H, m). (Viii) (4S, 5R, 6R, 2'R) -5-acetylamino-4-
(N, N'-bis-t-butyloxycarbonyl) guanidino-6- (4 ', 5'-diacetoxy-tetrahydro-pyran-2'-yl) -5,6-dihydro-4H-pyran-2-carboxylic Methyl acid salt [Low-polarity 2'R compound] The compound obtained in Example 19 (vii) (160 mg, 0.363 mmo
l) was dissolved in ethanol (10 ml), Lindlar catalyst (50 mg) was added under a nitrogen atmosphere, and then the atmosphere was replaced with a hydrogen atmosphere, followed by stirring at room temperature for 3 hours. The reaction solution was filtered through celite, and the residue was washed with ethanol. The filtrate and the washing were distilled off under reduced pressure.
The obtained residue was dissolved in anhydrous tetrahydrofuran (10 ml), 1H-pyrazole-1- [N, N'-bis (t-butoxycarbonyl)] carboxamidine (226 mg, 0.727 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, the residue was diluted with ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. (Hexane /
(Ethyl acetate = 1/2) to give the title compound as a colorless amorphous. (168mg, 70%) TLC (silica gel): Rf = 0.32 (hexane / ethyl acetate = 1/2) MS (FAB ) m / e 657 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm: 11.39 (1H, s), 8.58
(1H, d, J = 8.7 Hz), 6.49 (1H, d, J = 7.9 Hz), 5.
86 (1H, d, J = 2.8 Hz), 5.53 (1H, d, J = 3.1 Hz),
5.16 (1H, dt, J = 8.8, 2.7 Hz), 4.93-4.97 (1H, m),
4.16-4.25 (1H, m), 4.82-4.96 (3H, m), 3.81 (3H,
s), 3.67 (1H, dd, J = 10.9, 10.8 Hz), 2.25-2.39 (1
H, m), 2.12 (3H, s), 1.99 (3H, s), 1.98 (3H, s),
1.74-1.89 (1H, m), 1.50 (9H, s), 1.49 (9H, s). (Ix) (4S, 5R, 6R, 2'R) -5-acetylamino-5,6-
Dihydro-6- (4 ', 5'-dihydroxy-tetrahydro-pyran-2'-yl) -4-guanidino-4H-pyran-2
-Carboxylic acid hydrate [Low polar 2'R compound] The compound obtained in Example 19 (viii) (81 mg, 0.123 mmol)
Was dissolved in 2 ml of methanol, and 28% sodium methoxide
A methanol solution (0.2 ml) was added, and the mixture was stirred at room temperature for 12 hours. Further, add 1M aqueous sodium hydroxide solution (150μ
l, 0.148 mmol) and stirred for 1 hour. Next, Dowex 50W × 8 (H + ) resin was added to the reaction solution for neutralization. The mixture was immediately filtered under reduced pressure, and the residue was washed with water. After the filtrate and the washings were distilled off under reduced pressure, the obtained residue was purified by reverse layer chromatography (Cosmosil, water / methanol = 1/1). The obtained compound was suspended in methylene chloride (3 ml), trifluoroacetic acid (1 ml) was added, and the mixture was stirred at room temperature for 12 hours. After distillation under reduced pressure,
The obtained residue is subjected to reverse layer chromatography (Cosmosil,
Water) to give the title compound as a colorless amorphous. (8 mg, 18%) TLC (silica gel): Rf = 0.24 (t-butanol: acetic acid: water
= 5: 1: 1) MS (FAB) m / e 359 [M + H] + 1 H NMR (400 MHz, D 2 O) δppm: 5.48 (1H, d, J = 2.8
Hz), 4.20 (1H, dd, J = 8.5, 2.8 Hz), 4.05 (1H, d, J
= 2.4 Hz), 3.99 (1H, dd, J = 9.3, 8.5 Hz), 3.88 (1
H, dd, J = 9.3, 2.5 Hz), 3.79 (1H, dt, J = 12.0,
2.1 Hz), 3.51-3.64 (2H, m), 3.32 (1H, dd, J = 10.
1, 9.8 Hz), 2.01 (1H, ddd, J = 14.5,12.0, 2.5 Hz),
1.86 (3H, s), 1.58 (1H, ddd, J = 14.5, 3.6, 2.1 H
z). (x) (4S, 5R, 6R, 2'R,)-5-acetylamino-4-azido-6- (4 ', 5'-diacetoxy-tetrahydro-
Pyran-2'-yl) -5,6-dihydro-4H-pyran-2
-Methyl carboxylate [Highly polar 2'R compound] Under a nitrogen atmosphere, the highly polar 2'R compound (162 mg, 0.362 mmol) obtained in Example 19 (vi) was treated with acetic acid (0.25 ml) and acetic anhydride (1 m2).
l), add concentrated sulfuric acid (0.2 ml) under ice cooling, and add
Stirred for hours. A two-layer liquid mixture of sodium carbonate (1.5 g), water (7.5 ml), and toluene (7.5 ml) was vigorously stirred, and the reaction solution was poured into the mixture at room temperature and stirred for 30 minutes. The toluene layer was separated, the aqueous layer was extracted with toluene, the toluene layer was collected, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the obtained residue was added to N, N'-dimethylformamide (2 ml). Dissolve, sodium azide (170 mg), Dowex 50W (H
+ ) Resin (170 mg) was added and stirred at 70 ° C. for 3 hours. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was subjected to silica gel chromatography (methylene chloride / methanol = 20/1) to give the title compound ( 13) was obtained as a colorless candy. (86
mg, 54%) TLC (silica gel): Rf = 0.46 (methylene chloride / methanol = 10/1) MS (FAB ) m / e 441 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm: 6.00 (1H, d, J = 3.0
Hz), 5.89 (1H, d, J = 7.6 Hz), 5.17 (1H, brs), 4.9
8-5.07 (1H, m), 4.63 (1H, dd, J = 7.9, 3.1 Hz), 4.
51 (1H, dd, J = 8.5, 3.5 Hz), 4.11 (1H, dd, J = 1
3.0, 1.5 Hz), 3.69-3.85 (5H, m), 3.61 (1H, d, J = 1
3.0 Hz), 2.28 (1H, ddd, J = 12.2, 12.1, 12.0 Hz),
2.16 (3H, s), 2.04 (3H, s), 2.03 (3H, s), 1.78-1.8
5 (1H, m). (Xi) (4S, 5R, 6R, 2'R) -5-acetylamino-4-
(N, N'-bis-t-butyloxycarbonyl) guanidino-6- (4 ', 5'-diacetoxy-tetrahydro-pyran-2'-yl) -5,6-dihydro-4H-pyran-2-carboxylic Methyl acid [High polar 2'R compound] The compound obtained in Example 19 (x) (80 mg, 0.363 mmol)
Was dissolved in ethanol (5 ml), Lindlar catalyst (30 mg) was added under a nitrogen atmosphere, and then the atmosphere was replaced with a hydrogen atmosphere.
Stirred at room temperature for 3 hours. The reaction solution was filtered through celite, and the residue was washed with ethanol. The filtrate and the washing were distilled off under reduced pressure. The obtained residue was dissolved in anhydrous tetrahydrofuran (5 ml) and 1H
-Pyrazole-1- [N, N'-bis (t-butoxycarbonyl)] carboxamidine (85 mg, 0.272 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, and the residue was diluted with ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline,
After drying over anhydrous sodium sulfate and evaporating under reduced pressure, the obtained residue was subjected to chromatography (silica gel, hexane / ethyl acetate = 1/2) to obtain the title compound (14) as a colorless amorphous. (77mg, 65%) TLC (silica gel): Rf = 0.25 (hexane / ethyl acetate = 1/2) MS (FAB ) m / e 657 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm: 11.38 (1H, s), 8.57
(1H, d, J = 8.6 Hz), 6.48 (1H, d, J = 7.9 Hz), 5.
88 (1H, d, J = 2.7 Hz), 5.10-5.19 (2H, m), 4.98-5.0
7 (1H, m), 4.25 (1H, ddd, J = 9.1, 9.1, 8.2 Hz),
4.11 (1H, dd, J = 13.3, 1.9 Hz), 3.97 (1H, d, J = 1
1.1 Hz), 3.80 (3H, s), 3.69 (1H, d, J = 11.8 Hz),
3.61 (1H, d, J = 12.7 Hz), 2.83 (1H, ddd, J = 12.
2, 12.1, 12.0 Hz), 2.15 (3H, s), 2.02 (3H, s), 1.9
7 (3H, s), 1.75 (1H, dd, J = 12.0, 5.0 Hz), 1.49 (9
H, s), 1.48 (9H, s). (Xii) (4S, 5R, 6R, 2'R) -5-acetylamino-5,6-
Dihydro-6- (4 ', 5'-dihydroxy-tetrahydro-pyran-2'-yl) -4-guanidino-4H-pyran-2
-Carboxylic acid hydrate [Highly polar 2'R compound] The compound obtained in Example 19 (xi) (77 mg, 0.117 mmol) was dissolved in 2 ml of methanol, and a 28% methanol solution of sodium methoxide (0.2 ml) was obtained. Was added and stirred at room temperature for 12 hours.
Further add 1M aqueous sodium hydroxide solution (140 μl, 0.1
40 mmol) and stirred for 1 hour. Next, Dowex 50W × 8 (H + ) resin was added to the reaction solution for neutralization. The mixture was immediately filtered under reduced pressure, and the residue was washed with water. After evaporating the filtrate and washings under reduced pressure,
The obtained compound was suspended in methylene chloride (3 ml), trifluoroacetic acid (1 ml) was added, and the mixture was stirred at room temperature for 12 hours. After evaporation under reduced pressure, the obtained residue was subjected to reverse layer chromatography (Cosmosil, water) to give the title compound as a colorless amorphous. (20 mg, 48%) TLC (silica gel): Rf = 0.16 (t-butanol: acetic acid: water
= 5: 1: 1) MS (FAB) m / e 359 [M + H] + 1 H NMR (400 MHz, D 2 O) δppm: 5.58 (1H, brs), 4.21
(1H, dd, J = 8.2, 2.5 Hz), 4.03 (1H, dd, J = 9.1,
8.2 Hz), 3.93 (1H, dd, J = 9.1, 2.1 Hz), 3.70-3.79
(2H, m), 3.62 (1H, s), 3.52 (1H, ddd, J = 12.0,
2.3, 2.1 Hz), 3.34 (1H, d, J = 12.0 Hz), 1.82-1.94
(4H, m), 1.46-1.55 (1H, m). (Example 20) (4S, 5R, 6R, 2'S) -5-acetylamino-5,6-dihydro-6- (4 ', 5'- Dihydroxy-tetrahydro-pyran-2'-yl) -4-guanidino-4H-pyran-2-carboxylic acid hydrate
【０３１９】[0319]
【化３２】 Embedded image
【０３２０】(i)（2S, 4S, 5R, 6R）−5−アセチルアミ
ノ−4−t−ブチルカルボニルオキシ−6−(1'S−1−アリ
ルオキシ−ブト−3'−エニル)−2−メトキシ−テトラヒ
ドロ−ピラン−2−カルボン酸メチル 窒素雰囲気下、実施例１９(iii)で得られた化合物（2S,
4S, 5R, 6R）−5−アセチルアミノ−4−t−ブチルカル
ボニルオキシ−6−(1'S−1−ヒドロキシ−ブト−3'−エ
ニル)−2−メトキシ−テトラヒドロ−ピラン−2−カル
ボン酸メチル（1'S化合物）(2.52ｇ, 6.28 mmol)を塩化
メチレン(20ml)、シクロヘキサン(40ml)に溶解し、アリ
ル 2,2,2,-トリクロロアセトイミデート(12.71g, 62.8
mmol)を加え、さらに氷冷下にてトリフルオロメタンス
ルホン酸(1ml)を滴下し同温度にて2時間攪拌した。反応
液にピリジン(1ml)を加え30分間攪拌後、塩化メチレ
ン、水に分配し、有機層を無水硫酸ナトリウムにて乾燥
し、減圧留去後、得られた残渣をシリカゲルクロマトグ
ラフィー（酢酸エチル/ヘキサン=1/5−2/1）に付して標
記化合物を無色アモルファスとして得た。(0.53g、19
％) TLC（シリカゲル）：Rf = 0.44 (酢酸エチル:ヘキサン
＝1/1) MS (FAB) m/e 442 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 5.81-5.99 (2H, m),
5.49 (1H, d, J = 9.0Hz), 5.13-5.29 (4H, m), 5.06
(1H, d, J = 10.0 Hz), 3.90-4.08 (3H, m), 3.79 (3H,
s), 3.66(1H, d, J = 10.7, 2.3 Hz), 3.45-3.51 (1H,
m), 3.29 (3H,s), 2.50-2.57 (2H, m), 2.31(1H, dd,
J = 12.8, 5.1 Hz), 1.91 (3H, s), 1.88 (1H, dd, J =
12.8, 10.2 Hz), 1.15 (9H, s). (ii)（2S, 4S, 5R, 6R, 2'S）−5−アセチルアミノ−4
−t−ブチルカルボニルオキシ−6−（3'，6'−ジヒドロ
−2'H−ピラン−2'−イル）−2−メトキシ−テトラヒド
ロ−ピラン−2−カルボン酸メチル 窒素雰囲気下、実施例２０(i)で得られた化合物（0.53
g, 1.20 mmol）を塩化メチレン（500 ml）に溶解し、ビ
ス（トリシクロヘキシルホスフィン）ベンジリデンルテ
ニウム（IV）ジクロライド（50 mg）を加え、室温で24
時間撹拌した。反応液を減圧留去後、得られた残渣をシ
リカゲルクロマトグラフィー（酢酸エチル/ヘキサン＝2
/1）に付して標記化合物を無色アモルファスとして得
た。（0.32g、65％） TLC（シリカゲル）：Rf = 0.47 (塩化メチレン／メタノ
ール＝10/1) MS (FAB) m/e 414 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 5.83-5.89(1H, m),
5.64-5.70 (1H, m), 5.48 (1H, d, J = 9.6 Hz), 5.24
(1H, ddd, J = 11.5, 10.4, 5.1 Hz), 4.18-4.21 (2H,
m), 4.05 (1H, ddd, J = 10.4, 10.4, 9.8 Hz), 3.79
(3H, s), 3.64-3.73 (1H, m), 3.63 (1H, dd, J = 10.
7, 3.4 Hz), 3.31 (3H, s), 2.45-2.58 (1H, m), 2.32
(1H, dd, J = 12.7, 5.1 Hz), 2.22-2.31 (1H, m), 1.9
2 (3H, s),1.90 (1H, dd, J = 12.7, 11.5 Hz), 1.15
(9H, s). (iii)（2S, 4S, 5R, 6R, 2'S）−5−アセチルアミノ−4
−t−ブチルカルボニルオキシ−6−（４'，5'−ジヒド
ロキシ−テトラヒドロ−ピラン−2'−イル）−2−メト
キシ−テトラヒドロ−ピラン−2−カルボン酸メチル
[低極性2'S化合物]及び（2S, 4S, 5R, 6R, 2'S）−5−
アセチルアミノ−4−t−ブチルカルボニルオキシ−6−
（４'，5'−ジヒドロキシ−テトラヒドロ−ピラン−2'
−イル）−2−メトキシ−テトラヒドロ−ピラン−2−カ
ルボン酸メチル[高極性2'S化合物] 実施例２０(ii)で得られた化合物（0.3 g, 0.726mmol）
をアセトン(2 ml)、蒸留水(2 ml)、アセトニトリル(2 m
l)に溶解し、N-メチルモルホリン N-オキシド50％水溶
液（190 mg, 0.798 mmol）、四酸化オスミウム（1mg,
0.004 mmol）を加え、氷冷下3時間撹拌した。反応液を
減圧留去し、得られた残渣をクロマトグラフィー（シリ
カゲル、塩化メチレン／メタノール＝10/1）に付して標
記化合物(低極性2'S化合物：171mg、53％)(高極性2'S化
合物：133mg、41％)を得た。 （低極性2'S化合物） TLC（シリカゲル）: Rf = 0.31 (塩化メチレン／メタノ
ール＝10/1) MS (FAB) m/e 448 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 5.88(1H, d, J = 9.0
Hz), 5.24 (1H, ddd,J = 11.5, 11.0, 5.1 Hz), 4.23
(1H, brs), 3.63-3.89 (6H, m (3.80 (3H, s)を含む)),
3.66 (1H, dd, J = 10.3, 10.1 Hz), 3.27 (3H, s),
3.06 (1H, brs), 2.68 (1H, d, J = 8.4 Hz), 2.33 (1
H, dd, J = 12.7, 5.1 Hz), 2.21 (1H, dd, J = 14.3,
2.1 Hz), 2.09 (2H, brs), 1.95-2.05 (1H, m), 1.94
(3H, s), 1.85 (1H, dd, J = 12.7, 11.5 Hz), 1.15 (9
H, s). （高極性2'S化合物） TLC（シリカゲル）: Rf = 0.28 (塩化メチレン／メタノ
ール＝10/1) MS (FAB) m/e 448 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 5.67 (1H, d, J = 9.
3 Hz), 5.24 (1H, ddd, J = 11.5, 10.9, 5.1 Hz), 3.9
7-4.08 (2H, m), 3.81 (3H, s), 3.70-3.78 (2H, m),
3.61 (1H, dd, J = 10.7, 3.1 Hz), 3.45-3.53 (2H,
m), 3.26 (3H, m),2.37 (1H, dd, J = 12.8, 5.1 Hz),
1.75-2.25 (8H, m), 1.15 (9H, s). (iv)（4S, 5R, 6R, 2'S,）−5−アセチルアミノ−4−ア
ジド−6−（４'，５'−ジアセトキシ−テ−ピラン−2'
−イル）−5，6−ジヒドロ−4H−ピラン−2−カルボン
酸メチル （低極性2'S化合物） 窒素雰囲気下、実施例２０(iii)で得られた低極性2'S化
合物(171mg、0.382mmol)を酢酸(0.25ml)、無水酢酸(1m
l)に溶解し、氷冷下、濃硫酸(0.2ml)を加え、80℃にて3
時間攪拌した。炭酸ナトリウム(1.5g)、水(8ml)、トル
エン(8ml)の混合2層液を激しく攪拌し、この中に先の反
応液を室温にて注加し30分間攪拌した。トルエン層を分
取し、水層をトルエンにて抽出、トルエン層を集め、無
水硫酸ナトリウムにて乾燥し、減圧留去後、得られた残
渣をN,N'-ジメチルホルムアミド（2ml）に溶解し、アジ
化ナトリウム（170 mg）、ダウエックス50W（H+）樹脂
（170 mg）を加え、70℃で3時間撹拌した。酢酸エチル
にて反応液を希釈し水洗、無水硫酸ナトリウムにて乾燥
し、減圧留去後、得られた残渣をクロマトグラフィー
（シリカゲル、塩化メチレン/メタノール＝20/1）に付
して標記化合物を無色アメ状物として得た。（129mg、7
7％） TLC（シリカゲル）：Rf = 0.49 (塩化メチレン/メタノ
ール＝10/1) MS (FAB) m/e 441 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 6.04 (1H, d, J = 4.
2 Hz), 5.77 (1H, d,J = 8.5 Hz), 5.48 (1H, d, J =
2.9 Hz), 4.89-4.96 (1H, m), 4.41-4.48 (1H,m ), 4.1
9(1H, t, J = 4.4 Hz), 4.08 (1H, d, J = 7.5, 5.2 H
z), 3.96-4.04(1H, m), 3.78-3.91 (4H, m), 3.68 (1H,
t, J = 10.7 Hz), 2.09-2.19 (4H, m), 2.01 (6H, s),
1.75-1.85 (1H,m). (v)（4S, 5R, 6R, 2'S）−5−アセチルアミノ−4−
（N，N'−ビス−t−ブチルオキシカルボニル）グアニジ
ノ−6−（4'，5'−ジアセトキシ−テトラヒドロ−ピラ
ン−2'−イル）−5，6−ジヒドロ−4H−ピラン−2−カ
ルボン酸メチル （低極性2'S化合物） 実施例２０(iv)の化合物（127 mg, 0.288 mmol）をメタ
ノール（5 ml）に溶解し、窒素雰囲気下リンドラー触媒
（50 mg）を加え、次いで水素雰囲気に置換し、室温で2
時間攪拌した。反応液をセライト濾過し濾物をメタノー
ルで洗浄し、濾液、洗液を減圧留去した。得られた残渣
を無水テトラヒドロフラン(2ml)に溶解し１H−ピラゾー
ル−１−[N,N'−ビス(t−ブトキシカルボニル)]カルボ
キサミジン (179mg、 0.577mmol)を加え室温にて12時間
攪拌した。反応液を濃縮し、残渣を酢酸エチルにて希
釈、1N-塩酸、飽和重曹水、飽和食塩水にて洗浄、無水
硫酸ナトリウムにて乾燥し、減圧留去後、得られた残渣
をクロマトグラフィー（シリカゲル、ヘキサン/酢酸エ
チル＝1/2）に付して標記化合物を無色アモルファスと
して得た。（132mg、70％） TLC（シリカゲル）：Rf = 0.33 (ヘキサン/酢酸エチル
＝1/2) MS (FAB) m/e 657 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 11.36 (1H, s), 8.56
(1H, d, J = 8.2 Hz), 6.93 (1H, d, J = 7.2 Hz), 5.
85 (1H, d, J = 2.6 Hz), 5.46 1H, brs), 5.03-5.11
(1H, m), 4.94-5.03 (1H, m), 4.04 (1H, dd, J = 10.
1, 3.0 Hz), 3.82-3.96 (3H, m), 3.81 (3H, s), 3.71
(1H, t, J = 10.7 Hz), 2.30-2.38 (1H, m), 2.12 (3H,
s), 1.90-2.01 (7H, m), 1.50 (9H, m), 1.49 (9H,
s). (vi)(4S, 5R, 6R, 2'S）−5−アセチルアミノ−5，6−
ジヒドロ−6−（4'，5'−ジヒドロキシ−テトラヒドロ
−ピラン−2'−イル）−4−グアニジノ−4H−ピラン−2
−カルボン酸・水和物 （低極性2'S化合物） 実施例２０(v)の化合物(132mg、0.201mmol)をメタノー
ル２mlに溶解し28％ナトリウムメトキシド・メタノール
溶液(0.2ml)を加え室温にて1時間攪拌した。反応液にダ
ウエックス50W×8（H+）樹脂を加え中和し、減圧留去
後、得られた残渣を塩化メチレン(3ml)に溶解し、トリ
フルオロ酢酸(1ml)を加え室温にて12時間攪拌した。反
応液を減圧留去し、得られた残渣を蒸留水(1ml)溶解
し、1M水酸化ナトリウム水溶液(220μl、0.220mmol)を
加え1時間攪拌した。次いで反応液にダウエックス50W×
8（H+）樹脂を加え中和した。ただちに減圧濾過し、水
で濾物を洗浄した。濾液、洗液を減圧留去後、得られた
残渣を逆層クロマトグラフィー（コスモシル、水）に付
して、標記化合物を無色アモルファスとして得た。（46
mg、64％） TLC（シリカゲル）：Rf = 0.29 (t-ブタノール:酢酸:水
=5:1:1) MS (FAB) m/e 359 [M+H]+ 1 H NMR (400 MHz, D2O) δppm: 5.68 (1H, d, J = 4.0
Hz), 4.11-4.22 (4H,m), 3.84-3.92 (1H, m), 3.68-3.7
7 (2H, m), 3.50 (1H, dd, J = 12.3, 8.0 Hz), 1.90-
2.00 (4H, m), 1.77 (1H, dd, J = 12.3, 1.30 Hz). (vii)（4S, 5R, 6R, 2'S,）−5−アセチルアミノ−4−
アジド−6−（４'，５'−ジアセトキシ−テトラヒドロ
−ピラン−2'−イル）−5，6−ジヒドロ−4H−ピラン−
2−カルボン酸メチル （高極性2'S化合物） 窒素雰囲気下、実施例２０(iii)で得られた高極性2'S化
合物（133mg、0.297mmol)を酢酸(0.25ml)、無水酢酸(1m
l)に溶解し、氷冷下、濃硫酸(0.2ml)を加え、80℃にて3
時間攪拌した。炭酸ナトリウム(1.5g)、水(8ml)、トル
エン(8ml)の混合2層液を激しく攪拌し、この中に先の反
応液を室温にて注加し30分間攪拌した。トルエン層を分
取し、水層をトルエンにて抽出、トルエン層を集め、無
水硫酸ナトリウムにて乾燥し、減圧留去後、得られた残
渣をN,N'-ジメチルホルムアミド（2 ml）に溶解し、ア
ジ化ナトリウム（135 mg）、ダウエックス50W（H+）樹
脂（135 mg）を加え、70℃で3時間撹拌した。酢酸エチ
ルにて反応液を希釈し水洗、無水硫酸ナトリウムにて乾
燥し、減圧留去後、得られた残査をクロマトグラフィー
（シリカゲル、塩化メチレン/メタノール＝20/1）に付
して標記化合物を無色アメ状物として得た。（101mg、7
7％） TLC（シリカゲル）：Rf = 0.48 (塩化メチレン/メタノ
ール＝10/1) MS (FAB) m/e 441 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 6.06 (1H, d, J = 4.
7 Hz), 5.83 (1H, d,J = 8.6 Hz), 5.15 (1H, brs), 4.
95-5.04 (1H, m), 4.56-4.64 (1H, m), 4.17-4.25 (2H,
m), 4.07 (1H, dd, J = 13.0, 1.5 Hz), 3.78-3.89 (4
H, m), 3.61 (1H, d, J = 13.0 Hz), 2.15 (3H, s), 1.
96-2.13 (7H, m), 1.89 (1H, ddd, J =12.1, 11.9, 11.
8 Hz). (viii)（4S, 5R, 6R, 2'S）−5−アセチルアミノ−4−
（N，N'−ビス−t−ブチルオキシカルボニル）グアニジ
ノ−6−（4'，5'−ジアセトキシ−テトラヒドロ−ピラ
ン−2'−イル）−5，6−ジヒドロ−4H−ピラン−2−カ
ルボン酸メチル（高極性2'S化合物） 実施例２０(vii)で得られた化合物（100 mg, 0.227 mmo
l）をエタノール（2 ml）に溶解し、窒素雰囲気下リン
ドラー触媒（40 mg）を加え、次いで水素雰囲気に置換
し、室温で5時間攪拌した。反応液をセライト濾過し濾
物をエタノールで洗浄し、濾液、洗液を減圧留去した。
得られた残渣を無水テトラヒドロフラン(2ml)に溶解し
１H−ピラゾール−１−[N,N'−ビス(t−ブトキシカルボ
ニル)]カルボキサミジン (141mg、 0.454mmol)を加え室
温にて12時間攪拌した。反応液を濃縮し、残渣を酢酸エ
チルにて希釈、1N-塩酸、飽和重曹水、飽和食塩水にて
洗浄、無水硫酸ナトリウムにて乾燥し、減圧留去後、得
られた残渣をクロマトグラフィー（シリカゲル、ヘキサ
ン/酢酸エチル＝1/2）に付して標記化合物を無色アモル
ファスとして得た。（70mg、47％） TLC（シリカゲル）：Rf = 0.20 (ヘキサン/酢酸エチル
＝1/2) MS (FAB) m/e 657 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 11.38 (1H, s), 8.54
(1H, d, J = 8.0 Hz), 6.96 (1H, d, J = 6.6 Hz), 5.
92 (1H, d, J = 2.7 Hz), 5.17 (1H, brs), 4.95-5.09
(2H, m), 4.02-4.11 (3H, m), 3.81 (3H, s), 3.71-3.7
7 (1H, m), 3.62 (1H, d, J = 13.2 Hz), 1.91-2.23 (1
1H, m), 1.50 (9H, s), 1.49 (9H, s). (ix)(4S, 5R, 6R, 2'S）−5−アセチルアミノ−5，6−
ジヒドロ−6−（4'，5'−ジヒドロキシ−テトラヒドロ
−ピラン−2'−イル）−4−グアニジノ−4H−ピラン−2
−カルボン酸・水和物 （高極性2'S化合物） 実施例２０(viii)で得られた化合物(70mg、0.073mmol)
をメタノール２mlに溶解し28％ナトリウムメトキシド・
メタノール溶液(0.1ml)を加え室温にて1時間攪拌した。
反応液にダウエックス50W×8（H+）樹脂を加え中和し、
減圧留去後、得られた残渣を塩化メチレン(3ml)に溶解
し、トリフルオロ酢酸(1ml)を加え室温にて12時間攪拌
した。反応液を減圧留去し、得られた残渣を蒸留水(1m
l)溶解し、1M水酸化ナトリウム水溶液(90μl、0.09mmo
l)を加え1時間攪拌した。次いで反応液にダウエックス5
0W×8（H+）樹脂を加え中和した。ただちに減圧濾過
し、水で濾物を洗浄した。濾液、洗液を減圧留去後、得
られた残渣を逆層クロマトグラフィー（コスモシル、
水）に付して、標記化合物を無色アモルファスとして得
た。（26mg、68％） TLC（シリカゲル）：Rf = 0.19 (t-ブタノール:酢酸:水
=5:1:1) MS (FAB) m/e 359 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 5.67 (1H, d, J = 3.
5 Hz), 4.14-4.23 (3H, m), 3.91 (1H, dd, J = 12.7,
2.0 Hz), 3.77-3.83 (1H, m), 3.76 (1H, brs), 3.58-
3.67 (1H, m), 3.51 (1H, d, J = 12.7 Hz), 1.96 (3H,
s), 1.82-1.89(1H, m), 1.75 (1H, ddd, J = 12.1, 1
1.9, 11.6 Hz). （実施例２１） （4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチルアミノ−
5，6−ジヒドロ−6−（3', 4'−ジヒドロキシ−5'，5'
−ジフロロ−テトラヒドロ−ピラン−2'−イル）−4−
グアニジノ−4H−ピラン−2−カルボン酸 水和物(I) (2S, 4S, 5R, 6R) -5-acetylamino-4-t-butylcarbonyloxy-6- (1'S-1-allyloxy-but-3'-enyl) -2-methoxy- Methyl tetrahydro-pyran-2-carboxylate The compound (2S,
4S, 5R, 6R) -5-Acetylamino-4-t-butylcarbonyloxy-6- (1'S-1-hydroxy-but-3'-enyl) -2-methoxy-tetrahydro-pyran-2-carboxylic acid methyl ester (1 ′S compound) (2.52 g, 6.28 mmol) was dissolved in methylene chloride (20 ml) and cyclohexane (40 ml), and allyl 2,2,2-trichloroacetimidate (12.71 g, 62.8
mmol), and trifluoromethanesulfonic acid (1 ml) was added dropwise under ice-cooling, followed by stirring at the same temperature for 2 hours. Pyridine (1 ml) was added to the reaction solution, and the mixture was stirred for 30 minutes, partitioned between methylene chloride and water, the organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (ethyl acetate / ethyl acetate). Hexane = 1 / 5-2 / 1) to give the title compound as a colorless amorphous. (0.53g, 19
%) TLC (silica gel): Rf = 0.44 (ethyl acetate: hexane = 1/1) MS (FAB ) m / e 442 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm: 5.81-5.99 ( 2H, m),
5.49 (1H, d, J = 9.0Hz), 5.13-5.29 (4H, m), 5.06
(1H, d, J = 10.0 Hz), 3.90-4.08 (3H, m), 3.79 (3H,
s), 3.66 (1H, d, J = 10.7, 2.3 Hz), 3.45-3.51 (1H,
m), 3.29 (3H, s), 2.50-2.57 (2H, m), 2.31 (1H, dd,
J = 12.8, 5.1 Hz), 1.91 (3H, s), 1.88 (1H, dd, J =
12.8, 10.2 Hz), 1.15 (9H, s). (Ii) (2S, 4S, 5R, 6R, 2'S) -5-acetylamino-4
-Methyl t-butylcarbonyloxy-6- (3 ', 6'-dihydro-2'H-pyran-2'-yl) -2-methoxy-tetrahydro-pyran-2-carboxylate Example 20 under nitrogen atmosphere. The compound obtained in (i) (0.53
g, 1.20 mmol) in methylene chloride (500 ml), and bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride (50 mg) was added.
Stirred for hours. After evaporating the reaction solution under reduced pressure, the residue obtained was chromatographed on silica gel (ethyl acetate / hexane = 2).
/ 1) to give the title compound as a colorless amorphous. (0.32g, 65%) TLC (silica gel): Rf = 0.47 (methylene chloride / methanol = 10/1) MS (FAB ) m / e 414 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm : 5.83-5.89 (1H, m),
5.64-5.70 (1H, m), 5.48 (1H, d, J = 9.6 Hz), 5.24
(1H, ddd, J = 11.5, 10.4, 5.1 Hz), 4.18-4.21 (2H,
m), 4.05 (1H, ddd, J = 10.4, 10.4, 9.8 Hz), 3.79
(3H, s), 3.64-3.73 (1H, m), 3.63 (1H, dd, J = 10.
7, 3.4 Hz), 3.31 (3H, s), 2.45-2.58 (1H, m), 2.32
(1H, dd, J = 12.7, 5.1 Hz), 2.22-2.31 (1H, m), 1.9
2 (3H, s), 1.90 (1H, dd, J = 12.7, 11.5 Hz), 1.15
(9H, s). (Iii) (2S, 4S, 5R, 6R, 2'S) -5-acetylamino-4
-T-butylcarbonyloxy-6- (4 ', 5'-dihydroxy-tetrahydro-pyran-2'-yl) -2-methoxy-tetrahydro-pyran-2-carboxylic acid methyl ester
[Low polar 2'S compound] and (2S, 4S, 5R, 6R, 2'S) -5-
Acetylamino-4-t-butylcarbonyloxy-6-
(4 ', 5'-dihydroxy-tetrahydro-pyran-2'
-Yl) -2-methoxy-tetrahydro-pyran-2-carboxylate [highly polar 2'S compound] The compound obtained in Example 20 (ii) (0.3 g, 0.726 mmol)
In acetone (2 ml), distilled water (2 ml), acetonitrile (2 m
l), N-methylmorpholine N-oxide 50% aqueous solution (190 mg, 0.798 mmol), osmium tetroxide (1 mg,
0.004 mmol), and the mixture was stirred under ice cooling for 3 hours. The reaction solution was evaporated under reduced pressure, and the obtained residue was subjected to chromatography (silica gel, methylene chloride / methanol = 10/1) to give the title compound (low-polar 2'S compound: 171 mg, 53%) (high-polar 2'S compound: 133 mg, 41%). (Less polar 2'S compound) TLC (silica gel): Rf = 0.31 (methylene chloride / methanol = 10/1) MS (FAB ) m / e 448 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm: 5.88 (1H, d, J = 9.0
Hz), 5.24 (1H, ddd, J = 11.5, 11.0, 5.1 Hz), 4.23
(1H, brs), 3.63-3.89 (6H, m (including 3.80 (3H, s))),
3.66 (1H, dd, J = 10.3, 10.1 Hz), 3.27 (3H, s),
3.06 (1H, brs), 2.68 (1H, d, J = 8.4 Hz), 2.33 (1
H, dd, J = 12.7, 5.1 Hz), 2.21 (1H, dd, J = 14.3,
2.1 Hz), 2.09 (2H, brs), 1.95-2.05 (1H, m), 1.94
(3H, s), 1.85 (1H, dd, J = 12.7, 11.5 Hz), 1.15 (9
(Highly polar 2'S compound) TLC (silica gel): Rf = 0.28 (methylene chloride / methanol = 10/1) MS (FAB) m / e 448 [M + H] + 1 H NMR (400 MHz, CDCl 3 ) δppm: 5.67 (1H, d, J = 9.
3 Hz), 5.24 (1H, ddd, J = 11.5, 10.9, 5.1 Hz), 3.9
7-4.08 (2H, m), 3.81 (3H, s), 3.70-3.78 (2H, m),
3.61 (1H, dd, J = 10.7, 3.1 Hz), 3.45-3.53 (2H,
m), 3.26 (3H, m), 2.37 (1H, dd, J = 12.8, 5.1 Hz),
1.75-2.25 (8H, m), 1.15 (9H, s). (Iv) (4S, 5R, 6R, 2'S,)-5-acetylamino-4-azido-6- (4 ', 5'-diacetoxy- Tepyran-2 '
-Yl) -5,6-dihydro-4H-pyran-2-carboxylate (low-polarity 2'S compound) Under a nitrogen atmosphere, the low-polarity 2'S compound (171 mg, 0.382 mmol) obtained in Example 20 (iii) was added. Acetic acid (0.25 ml), acetic anhydride (1 m
l), add concentrated sulfuric acid (0.2 ml) under ice cooling, and add
Stirred for hours. A two-layer liquid mixture of sodium carbonate (1.5 g), water (8 ml), and toluene (8 ml) was vigorously stirred, and the reaction solution was poured into the mixture at room temperature and stirred for 30 minutes. The toluene layer was separated, the aqueous layer was extracted with toluene, the toluene layer was collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The obtained residue was dissolved in N, N'-dimethylformamide (2 ml). Then, sodium azide (170 mg) and Dowex 50W (H + ) resin (170 mg) were added, and the mixture was stirred at 70 ° C. for 3 hours. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the obtained residue was subjected to chromatography (silica gel, methylene chloride / methanol = 20/1) to give the title compound. Obtained as a colorless candy. (129mg, 7
7%) TLC (silica gel): Rf = 0.49 (methylene chloride / methanol = 10/1) MS (FAB ) m / e 441 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm: 6.04 (1H , d, J = 4.
2 Hz), 5.77 (1H, d, J = 8.5 Hz), 5.48 (1H, d, J =
2.9 Hz), 4.89-4.96 (1H, m), 4.41-4.48 (1H, m), 4.1
9 (1H, t, J = 4.4 Hz), 4.08 (1H, d, J = 7.5, 5.2 H
z), 3.96-4.04 (1H, m), 3.78-3.91 (4H, m), 3.68 (1H,
t, J = 10.7 Hz), 2.09-2.19 (4H, m), 2.01 (6H, s),
1.75-1.85 (1H, m). (V) (4S, 5R, 6R, 2'S) -5-acetylamino-4-
(N, N'-bis-t-butyloxycarbonyl) guanidino-6- (4 ', 5'-diacetoxy-tetrahydro-pyran-2'-yl) -5,6-dihydro-4H-pyran-2-carboxylic Methyl acid (low-polarity 2'S compound) The compound of Example 20 (iv) (127 mg, 0.288 mmol) was dissolved in methanol (5 ml), a Lindlar catalyst (50 mg) was added under a nitrogen atmosphere, and then replaced with a hydrogen atmosphere. And at room temperature 2
Stirred for hours. The reaction solution was filtered through celite, and the residue was washed with methanol. The filtrate and the washing were distilled off under reduced pressure. The obtained residue was dissolved in anhydrous tetrahydrofuran (2 ml), 1H-pyrazole-1- [N, N'-bis (t-butoxycarbonyl)] carboxamidine (179 mg, 0.577 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution is concentrated, the residue is diluted with ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. Silica gel, hexane / ethyl acetate = 1/2) to give the title compound as a colorless amorphous. (132mg, 70%) TLC (silica gel): Rf = 0.33 (hexane / ethyl acetate = 1/2) MS (FAB ) m / e 657 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm: 11.36 (1H, s), 8.56
(1H, d, J = 8.2 Hz), 6.93 (1H, d, J = 7.2 Hz), 5.
85 (1H, d, J = 2.6 Hz), 5.46 1H, brs), 5.03-5.11
(1H, m), 4.94-5.03 (1H, m), 4.04 (1H, dd, J = 10.
1, 3.0 Hz), 3.82-3.96 (3H, m), 3.81 (3H, s), 3.71
(1H, t, J = 10.7 Hz), 2.30-2.38 (1H, m), 2.12 (3H,
s), 1.90-2.01 (7H, m), 1.50 (9H, m), 1.49 (9H,
s). (vi) (4S, 5R, 6R, 2'S) -5-acetylamino-5,6-
Dihydro-6- (4 ', 5'-dihydroxy-tetrahydro-pyran-2'-yl) -4-guanidino-4H-pyran-2
-Carboxylic acid hydrate (low-polarity 2'S compound) The compound of Example 20 (v) (132 mg, 0.201 mmol) was dissolved in 2 ml of methanol, and a 28% methanol solution of sodium methoxide (0.2 ml) was added. Stir for 1 hour. The reaction solution was neutralized by adding Dowex 50W × 8 (H + ) resin, and the residue was dissolved in methylene chloride (3 ml), and trifluoroacetic acid (1 ml) was added. Stirred for hours. The reaction solution was distilled off under reduced pressure, the obtained residue was dissolved in distilled water (1 ml), a 1 M aqueous sodium hydroxide solution (220 µl, 0.220 mmol) was added, and the mixture was stirred for 1 hour. Then add Dowex 50W ×
8 (H + ) resin was added for neutralization. The mixture was immediately filtered under reduced pressure, and the residue was washed with water. After evaporating the filtrate and washings under reduced pressure, the obtained residue was subjected to reverse layer chromatography (Cosmosil, water) to obtain the title compound as a colorless amorphous. (46
mg, 64%) TLC (silica gel): Rf = 0.29 (t-butanol: acetic acid: water
= 5: 1: 1) MS (FAB) m / e 359 [M + H] + 1 H NMR (400 MHz, D 2 O) δppm: 5.68 (1H, d, J = 4.0
Hz), 4.11-4.22 (4H, m), 3.84-3.92 (1H, m), 3.68-3.7
7 (2H, m), 3.50 (1H, dd, J = 12.3, 8.0 Hz), 1.90-
2.00 (4H, m), 1.77 (1H, dd, J = 12.3, 1.30 Hz). (Vii) (4S, 5R, 6R, 2'S,)-5-acetylamino-4-
Azido-6- (4 ', 5'-diacetoxy-tetrahydro-pyran-2'-yl) -5,6-dihydro-4H-pyran-
Methyl 2-carboxylate (highly polar 2'S compound) Under a nitrogen atmosphere, the highly polar 2'S compound (133 mg, 0.297 mmol) obtained in Example 20 (iii) was treated with acetic acid (0.25 ml) and acetic anhydride (1 m2).
l), add concentrated sulfuric acid (0.2 ml) under ice cooling, and add
Stirred for hours. A two-layer liquid mixture of sodium carbonate (1.5 g), water (8 ml), and toluene (8 ml) was vigorously stirred, and the reaction solution was poured into the mixture at room temperature and stirred for 30 minutes. The toluene layer was separated, the aqueous layer was extracted with toluene, the toluene layer was collected, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the obtained residue was added to N, N'-dimethylformamide (2 ml). After dissolution, sodium azide (135 mg) and Dowex 50W (H + ) resin (135 mg) were added, and the mixture was stirred at 70 ° C. for 3 hours. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resulting residue was subjected to chromatography (silica gel, methylene chloride / methanol = 20/1) to give the title compound. Was obtained as a colorless candy. (101mg, 7
7%) TLC (silica gel): Rf = 0.48 (methylene chloride / methanol = 10/1) MS (FAB ) m / e 441 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm: 6.06 (1H , d, J = 4.
7 Hz), 5.83 (1H, d, J = 8.6 Hz), 5.15 (1H, brs), 4.
95-5.04 (1H, m), 4.56-4.64 (1H, m), 4.17-4.25 (2H,
m), 4.07 (1H, dd, J = 13.0, 1.5 Hz), 3.78-3.89 (4
H, m), 3.61 (1H, d, J = 13.0 Hz), 2.15 (3H, s), 1.
96-2.13 (7H, m), 1.89 (1H, ddd, J = 12.1, 11.9, 11.
(8 Hz). (Viii) (4S, 5R, 6R, 2'S) -5-acetylamino-4-
(N, N'-bis-t-butyloxycarbonyl) guanidino-6- (4 ', 5'-diacetoxy-tetrahydro-pyran-2'-yl) -5,6-dihydro-4H-pyran-2-carboxylic Methyl acid salt (highly polar 2'S compound) The compound obtained in Example 20 (vii) (100 mg, 0.227 mmo
l) was dissolved in ethanol (2 ml), a Lindlar catalyst (40 mg) was added under a nitrogen atmosphere, the atmosphere was replaced with a hydrogen atmosphere, and the mixture was stirred at room temperature for 5 hours. The reaction solution was filtered through celite, and the residue was washed with ethanol. The filtrate and the washing were distilled off under reduced pressure.
The obtained residue was dissolved in anhydrous tetrahydrofuran (2 ml), 1H-pyrazole-1- [N, N'-bis (t-butoxycarbonyl)] carboxamidine (141 mg, 0.454 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution is concentrated, the residue is diluted with ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. Silica gel, hexane / ethyl acetate = 1/2) to give the title compound as a colorless amorphous. (70mg, 47%) TLC (silica gel): Rf = 0.20 (hexane / ethyl acetate = 1/2) MS (FAB ) m / e 657 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm: 11.38 (1H, s), 8.54
(1H, d, J = 8.0 Hz), 6.96 (1H, d, J = 6.6 Hz), 5.
92 (1H, d, J = 2.7 Hz), 5.17 (1H, brs), 4.95-5.09
(2H, m), 4.02-4.11 (3H, m), 3.81 (3H, s), 3.71-3.7
7 (1H, m), 3.62 (1H, d, J = 13.2 Hz), 1.91-2.23 (1
(IxH) (1H, m), 1.50 (9H, s), 1.49 (9H, s). (Ix) (4S, 5R, 6R, 2'S) -5-acetylamino-5,6-
Dihydro-6- (4 ', 5'-dihydroxy-tetrahydro-pyran-2'-yl) -4-guanidino-4H-pyran-2
-Carboxylic acid hydrate (highly polar 2'S compound) The compound obtained in Example 20 (viii) (70 mg, 0.073 mmol)
Was dissolved in 2 ml of methanol, and 28% sodium methoxide
A methanol solution (0.1 ml) was added, and the mixture was stirred at room temperature for 1 hour.
Dowex 50W × 8 (H + ) resin was added to the reaction solution to neutralize it,
After evaporation under reduced pressure, the obtained residue was dissolved in methylene chloride (3 ml), trifluoroacetic acid (1 ml) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was distilled off under reduced pressure, and the obtained residue was distilled water (1 m
l) Dissolve, 1M sodium hydroxide aqueous solution (90μl, 0.09mmo
l) was added and stirred for 1 hour. Then add Dowex 5 to the reaction mixture.
0W × 8 (H + ) resin was added for neutralization. The mixture was immediately filtered under reduced pressure, and the residue was washed with water. After the filtrate and washings were distilled off under reduced pressure, the resulting residue was subjected to reverse layer chromatography (Cosmosil,
Water) to give the title compound as a colorless amorphous. (26 mg, 68%) TLC (silica gel): Rf = 0.19 (t-butanol: acetic acid: water
= 5: 1: 1) MS (FAB) m / e 359 [M + H] + 1 H NMR (400 MHz, CDCl 3 ) δppm: 5.67 (1H, d, J = 3.
5 Hz), 4.14-4.23 (3H, m), 3.91 (1H, dd, J = 12.7,
2.0 Hz), 3.77-3.83 (1H, m), 3.76 (1H, brs), 3.58-
3.67 (1H, m), 3.51 (1H, d, J = 12.7 Hz), 1.96 (3H,
s), 1.82-1.89 (1H, m), 1.75 (1H, ddd, J = 12.1, 1
(Example 21, 21) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5-acetylamino-
5,6-dihydro-6- (3 ', 4'-dihydroxy-5', 5 '
-Difluoro-tetrahydro-pyran-2'-yl) -4-
Guanidino-4H-pyran-2-carboxylic acid hydrate
【０３２１】[0321]
【化３３】 Embedded image
【０３２２】(i)2,2-ジフロロ-3-ブテン-1-オール 窒素雰囲気下、氷冷にて乾燥テトラヒドロフラン(100m
l)に水素化アルミニウムリチウム(1.64g、43.3 mmol)を
加え、さらに同温度にて2,2-ジフルオロ-3-ブテン酸エ
チル(5g、33.31 mmol)の乾燥テトラヒドロフラン(30ml)
溶液を滴下し10分間攪拌した。反応温度を室温まで昇温
し2時間攪拌した。氷冷下、反応液に飽和硫酸ナトリウ
ム水溶液(12ml)を加え30分間攪拌し、濾過、濾液を減圧
留去後、減圧蒸留にて精製し標記化合物(b.p.67-71℃ 1
00mmHg)を得た。（2.36g、66％）1 H NMR (400 MHz, CDCl3) δppm: 5.91-6.05 (1H, m),
5.75 (1H, ddd, J = 17.6, 2.2, 2.2 Hz), 5.56 (1H,
d, J = 11.0 Hz), 3.77-3.86 (2H, m), 1.99 (1H, t, J
= 7.0 Hz). (ii)2,2-ジフロロ-3-ブテニル トリフロロメタンスルフ
ォネート 窒素雰囲気下、実施例２１(i)で得られた化合物(1.1g、
10.18 mmol)を乾燥塩化メチレン(20ml)に溶解し、ピリ
ジン(1.65ml、20.35 mmol)を加え氷冷下、無水トリフロ
ロメタンスルホン酸(2.6ml、15.27 mmol)の乾燥塩化メ
チレン(10ml)溶液を滴下し、同温度にて1時間攪拌し
た。反応液に1M塩酸、塩化メチレンを加え１０分間攪拌
し分液、塩化メチレン層を飽和重曹水にて洗浄し、無水
硫酸ナトリウムにて乾燥した。濾過、濃縮し、標記化合
物を油状物として得た。(1.4g)この化合物は精製するこ
と無しに次の工程に使用した。(I) 2,2-Difluoro-3-buten-1-ol In a nitrogen atmosphere, dry tetrahydrofuran (100 m
l) Lithium aluminum hydride (1.64 g, 43.3 mmol) was added, and ethyl tetrahydrofuran (30 ml) of ethyl 2,2-difluoro-3-butenoate (5 g, 33.31 mmol) was further added at the same temperature.
The solution was added dropwise and stirred for 10 minutes. The reaction temperature was raised to room temperature and stirred for 2 hours. Under ice-cooling, a saturated aqueous solution of sodium sulfate (12 ml) was added to the reaction solution, and the mixture was stirred for 30 minutes, filtered, and the filtrate was distilled off under reduced pressure.
00 mmHg). (2.36 g, 66%) 1 H NMR (400 MHz, CDCl 3 ) δppm: 5.91-6.05 (1H, m),
5.75 (1H, ddd, J = 17.6, 2.2, 2.2 Hz), 5.56 (1H,
d, J = 11.0 Hz), 3.77-3.86 (2H, m), 1.99 (1H, t, J
(7.0 Hz). (Ii) 2,2-Difluoro-3-butenyl trifluoromethanesulfonate The compound obtained in Example 21 (i) (1.1 g,
10.18 mmol) was dissolved in dry methylene chloride (20 ml), pyridine (1.65 ml, 20.35 mmol) was added, and a solution of trifluoromethanesulfonic anhydride (2.6 ml, 15.27 mmol) in dry methylene chloride (10 ml) was added under ice cooling. The mixture was added dropwise and stirred at the same temperature for 1 hour. 1M Hydrochloric acid and methylene chloride were added to the reaction solution, and the mixture was stirred for 10 minutes and separated. The methylene chloride layer was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate. Filtration and concentration gave the title compound as an oil. (1.4 g) This compound was used in the next step without purification.
【０３２３】1H NMR (400 MHz, CDCl3) δppm: 5.81-6.
01 (2H, m), 7.71 (1H, d, J = 10.3 Hz), 4.56 (2H,
t, J = 11.0 Hz). (iii) 5−アセチルアミノ−4−O−t−ブチルジメチルシ
リル−3，5−ジデオキシ−8，9−O−イソプロピリデン
−2−O−メチル−7−O−（2',2'−ジフロロ−ブト−3'
−エニル）−D−グリセロ−D−ガラクト−ノン−2−エ
ノピラノソン酸メチル 5−アセチルアミノ−3，5−ジデオキシ−8，9−O−イソ
プロピリデン−2−O−メチル−4−O−t−ブチルジメチ
ルシリル−D−グリセロ−D−ガラクト−ノン−2−エノ
ピラノソン酸メチル(3.72g、7.56mmol)をN,N'-ジメチル
ホルムアミド(20ml)に溶解し、室温にて水素化ナトリウ
ム(660mg、15.12mmol 55％含有)を加え同温度で15分間
攪拌した。氷冷下、実施例２１(ii)で得られた化合物
(2.36g、9.83mmol)のN,N'-ジメチルホルムアミド(4ml)
溶液を滴下し室温にて30分間攪拌した。反応液を酢酸エ
チル、飽和塩化アンモニウム水溶液に分配し、有機層を
水、飽和食塩水にて洗浄した。無水硫酸ナトリウムで乾
燥し、減圧留去後、得られた残渣をシリカゲルクロマト
グラフィー（酢酸エチル/ヘキサン＝1/1）に付して標記
化合物を得た。（2.74g、62％） TLC（シリカゲル）：Rf = 0.71 (ヘキサン/酢酸エチル
＝1/1) MS (FAB) m/e 582 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 5.94-6.12 (1H, m),
5.75 (1H, dd, J = 17.6, 2.9 Hz), 5.53 (1H, d, J =
11.0 Hz), 5.41 (1H, d, J = 8.1 Hz), 4.34-4.46 (1H,
m), 4.18-4.31 (2H, m), 3.97-4.16 (4H, m), 3.87 (1
H, dd, J = 2.2, 2.2 Hz), 3.79 (3H, s), 3.49 (1H, d
dd, J = 10.3, 9.5, 8.8 Hz), 3.20 (3H, s), 2.28 (1
H, dd, J = 12.5, 5.1 Hz), 1.96 (3H, s), 1.56-1.65
(1H, m),1.42 (3H, s), 1.42 (3H, s), 0.86 (9H, s),
0.06 (3H, s), 0.04 (3H, s). (iv)5−アセチルアミノ−3，5−ジデオキシ−8，9−O−
イソプロピリデン−2−O−メチル−7−O−（2',2'−ジ
フロロ−ブト−3'−エニル）−D−グリセロ−D−ガラク
ト−ノン−2−エノピラノソン酸メチル 実施例２１(iii)で得られた化合物（2.74 g、4.71 mmo
l）を乾燥テトラヒドロフラン(30ml)に溶解し、室温で1
Mテトラブチルアンモニウムフロリド含有テトラヒドロ
フラン(6.12 ml, 6.12 mmol)を加え、同温で3時間撹拌
した。反応液を減圧留去後、得られた残渣をシリカゲル
クロマトグラフィー（塩化メチレン/メタノール＝20/1
−10/1）に付して標記化合物を無色アモルファスとして
得た。（2.08g、94％） TLC（シリカゲル）：Rf = 0.44 (塩化メチレン/メタノ
ール＝10/1) MS (FAB) m/e 468 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 5.91-6.08 (2H, m),
5.75 (1H, ddd, J = 2.9, 2.2, 1.8 Hz), 5.54 (1H, d,
J = 11.0 Hz), 4.25-4.36 (1H, m), 3.82-4.22 (6H,
m), 3.79 (3H, s), 3.64-3.78 (2H, m), 3.21 (3H, s),
2.42 (1H, dd,J = 12.5, 5.1 Hz), 2.04 (3H, s), 1.8
9 (1H, br), 1.67 (1H, dd, J = 12.5,11.0 Hz), 1.43
(3H, s), 1.33 (3H, s). (v) 5−アセチルアミノ−４−O−アセチル−3，5−ジデ
オキシ−8，9−O−イソプロピリデン−2−O−メチル−7
−O−（2',2'−ジフロロ−ブト−3'−エニル）−D−グ
リセロ−D−ガラクト−ノン−2−エノピラノソン酸メチ
ル 実施例２１(iv)で得られた化合物(2.08g、4.45mmol)を
無水酢酸(5ml)、ピリジン(5ml)に溶解し3時間攪拌し
た。反応液を減圧留去後、得られた残渣をクロマトグラ
フィー（シリカゲル、塩化メチレン/メタノール＝20/
1）に付して標記化合物を無色アモルファスとして得
た。（1.73g、49％） TLC（シリカゲル）：Rf = 0.57 (塩化メチレン／メタノ
ール＝10/1) MS (FAB) m/e 510 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 5.99-6.13 (1H, m),
5.73-5.79 (1H, m), 5.52 (1H, d, J = 11.0 Hz), 5.32
-5.45 (2H, m), 4.27 (1H, ddd, J = 6.6, 6.6, 5.1 H
z), 3.92-4.18 (5H, m), 3.82 (1H, dd, J = 11.0, 1.5
Hz), 3.80 (3H,s), 3.71 (1H, dd, J = 5.9, 1.5 Hz),
3.25 (3H, s), 2.39 (1H, dd, J = 12.5, 5.1 Hz), 2.
05 (3H, s), 1.95 (3H, s), 1.83 (1H, dd, J = 12.5,
11.7 Hz), 1.41 (3H, s), 1.32 (3H, s). (vi) 5−アセチルアミノ−４−O−アセチル−3，5−ジ
デオキシ−2−O−メチル−7−O−（2',2'−ジフロロ−
ブト−3'−エニル）−D−グリセロ−D−ガラクト−ノン
−2−エノピラノソン酸メチル 実施例２１(vi)で得られた化合物（2.12g、4.16mmol）
を90％酢酸水(20ml)に溶解し、60℃で3時間攪拌した。
反応液を減圧留去後、得られた残査をクロマトグラフィ
ー（シリカゲル、塩化メチレン/メタノール＝10/1）に
付して標記化合物を無色アモルファスとして得た。（1.
79g、92％） TLC（シリカゲル）：Rf = 0.36 (塩化メチレン／メタノ
ール＝10/1) MS (FAB) m/e 470 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 5.94-6.08 (1H, m),
5.76 (1H, ddd, J = 16.8, 2.9, 2.2 Hz), 5.51-5.60
(2H, m), 5.29 (1H, ddd, J = 11.7, 10.3, 5.1Hz), 5.
25 (1H, ddd, J = 10.3, 10.3, 9.5 Hz), 3.75-4.08 (1
0H, m), 3.65 (1H, dd, J = 7.3, 1.5 Hz), 3.28 (3H,
s), 3.18 (1H, br), 2.40 (1H, dd, J =13.2, 5.1 Hz),
2.04 (3H, s), 1.94 (3H, s), 1.87 (1H, dd, J = 13.
2, 11.7Hz). (vii) 5−アセチルアミノ−４−O−アセチル−3，5−ジ
デオキシ−8，9−O−チオカルボニル−2−O−メチル−7
−O−（2',2'−ジフロロ−ブト−3'−エニル）−D−グ
リセロ−D−ガラクト−ノン−2−エノピラノソン酸メチ
ル 窒素雰囲気下、実施例２１(vi)で得られた化合物(1.75
mg、3.73 mmol)を乾燥塩化メチレン(50ml)に溶解し、氷
冷下、4-ジメチルアミノピリジン（1.05g、8.57 mmo
l）、チオホスゲン（0.39ml、4.10 mmol）を加え、氷冷
下1時間撹拌した。反応液にメタノールを加え、減圧留
去した。得られた残渣をシリカゲルクロマトグラフィー
（塩化メチレン/メタノール＝10/1）に付して標記化合
物を無色アモルファスとして得た。（1.89g、99％） TLC（シリカゲル）：Rf = 0.49 (塩化メチレン/メタノ
ール＝10/1) MS (FAB) m/e 512 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 5.91-6.06 (1H, m),
5.76 (1H, ddd, J = 16.8, 2.9, 2.2 Hz), 5.50-5.59
(2H, m), 5.40 (1H, ddd, J = 11.7, 10.3, 5.1Hz), 4.
92-5.05 (2H, m), 4.73-4.83 (1H, m), 3.98-4.19 (3H,
m), 3.82-3.94(2H, m), 3.81 (3H, s), 3.18 (3H, s),
2.47 (1H, dd, J = 12.5, 5.1 Hz), 2.06 (3H, s), 1.
97 (3H, s), 1.79 (1H, dd, J = 12.5, 11.7 Hz). (viii)4−O−アセチル−5−アセチルアミノ−7−O−
（2',2'−ジフロロ−ブト−3'−エニル）−2−O−メチ
ル−3，5，8，9−テトラデオキシ−D−グリセロ−D−ガ
ラクト−ノン−2−エノピラノソン酸メチル 窒素雰囲気下、実施例２１(vii)で得られた化合物(1.87
g、3.66 mmol）を亜リン酸トリメチル（50ml）に溶解
し、12時間加熱還流した。反応液を減圧留去後、トルエ
ンで共沸し、得られた残渣をシリカゲルクロマトグラフ
ィー（塩化メチレン／メタノール＝10/1）に付して標記
化合物を無色アモルファスとして得た。（1.40 g、88
％） TLC（シリカゲル）：Rf = 0.49 (塩化メチレン/メタノ
ール＝10/1) MS (FAB) m/e 436 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 5.89-6.12 (2H, m),
5.72 (1H, ddd, J = 15.4, 2.2, 2.2 Hz), 5.51 (1H,
d, J = 11.0 Hz), 5.28-5.42 (4H, m), 4.11 (1H, ddd,
J = 10.3, 10.3, 9.5 Hz), 4.00 (1H, dd, J = 8.1,
2.9 Hz), 3.79 (3H, s), 3.58-3.78 (3H, m), 3.22 (3
H, s), 2.39 (1H, dd, J = 12.5, 5.1 Hz),2.03 (3H,
s), 1.92 (3H, s), 1.87 (1H, dd, J = 12.5, 11.7 H
z). (ix)（2S, 4S, 5R, 6R, 2'R）−4−O−アセチル−5−ア
セチルアミノ−6−（5'，5'−ジフロロ−,5'，6'−ジヒ
ドロ−2'H−ピラン−2'−イル）−2−メトキシ−テトラ
ヒドロ−ピラン−2−カルボン酸メチル 窒素雰囲気下、実施例２１(viii)で得られた化合物（1.
40 g、1.56 mmol）を乾燥塩化メチレン(150 ml)に溶解
し、ビス（トリシクロヘキシルホスフィン）ベンジリデ
ンルテニウム（IV）ジクロライド（100 mg）を加え、室
温で36時間撹拌した。反応液を減圧留去後、得られた残
渣をシリカゲルクロマトグラフィー（酢酸エチル/ヘキ
サン＝3/1）に付して標記化合物を無色アモルファスと
して得た。（0.80g、57％） TLC（シリカゲル）：Rf = 0.15 (酢酸エチル/ヘキサン
＝2/1) MS (FAB) m/e 408 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 6.23 (1H, d, J = 1
0.3 Hz), 6.03-6.15 (1H, m), 5.38 (1H, d, J = 8.8 H
z), 5.30 (1H, ddd, J = 11.7, 11.0, 5.1 Hz),4.37 (1
H, brs), 4.28 (1H, ddd, J = 11.0, 9.5, 9.5 Hz), 4.
09-4.21 (1H, m), 3.71-3.90 (5H, m), 3.25 (3H, s),
2.40 (1H, dd, J = 13.5, 5.1 Hz), 2.03 (3H, s), 1.8
5-1.99 (4H, m). (x)（2S, 4S, 5R, 6R, 2'R）−4−アセトキシ−5−アセ
チルアミノ−6−（5'，5'−ジフロロ−3'，4'−ジヒド
ロキシ−テトラヒドロ−ピラン−2'−イル）−2−メト
キシ−テトラヒドロ−ピラン−2−カルボン酸メチル 実施例２１(ix)で得られた化合物（512ｍg, 1.26 mmo
l）をアセトン(3 ml)、蒸留水(3 ml)、アセトニトリル
(3 ml)に溶解し、N-メチルモルホリン N-オキシド 50％
水溶液（320 mg, 1.38 mmol）、四酸化オスミウム（1m
g, 0.004 mmol）を加え、室温にて12時間撹拌した。反
応液を減圧留去し、得られた残渣をシリカゲルクロマト
グラフィー（塩化メチレン/メタノール＝10/1）に付し
て標記化合物(36)を得た。(193mg、35％) TLC（シリカゲル）：Rf = 0.33 (塩化メチレン／メタノ
ール＝10/1) MS (FAB) m/e 442 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 5.92 (1H, d, J = 9.
5 Hz), 5.32 (1H, ddd, J = 11.7, 10.3, 5.1 Hz), 3.6
8-4.35 (10H m), 5.52 (1H, d, J = 10.3 Hz),3.28 (3
H, s), 3.13 (1H, d, J = 9.5 Hz), 2.42 (1H, dd, J =
13.2, 5.1 Hz), 2.05 (3H, s), 1.96 (3H, s), 1.90
(1H, dd, J = 13.2, 11.7 Hz). (xi)（4S, 5R, 6R, 2'S,3'S, 4'R）−5−アセチルアミ
ノ−4−アジド−6−（3'，4'−ジアセトキシ−5'，5'−
ジフロロ−テトラヒドロ−ピラン−2'−イル）−5，6−
ジヒドロ−4H−ピラン−2−カルボン酸メチル 窒素雰囲気下、実施例２１(x)で得られた化合物（185m
g、0.419mmol)を酢酸(0.25ml)、無水酢酸(1ml)に溶解
し、氷冷下、濃硫酸(0.2ml)を加え、80℃にて3時間攪拌
した。炭酸ナトリウム(1.5g)、水(10ml)、トルエン(10m
l)の混合2層液を激しく攪拌し、この中に先の反応液を
室温にて注加し30分間攪拌した。トルエン層を分取し、
水層をトルエンにて抽出、トルエン層を集め、無水硫酸
ナトリウムにて乾燥し、減圧留去後、得られた残渣をN,
N'-ジメチルホルムアミド（2 ml）に溶解し、アジ化ナ
トリウム（200 mg）、ダウエックス50W（H+）樹脂（200
mg）を加え、70℃で3時間撹拌した。酢酸エチルにて反
応液を希釈し水洗、無水硫酸ナトリウムにて乾燥し、減
圧留去後、得られた残査をシリカゲルクロマトグラフィ
ー（塩化メチレン/メタノール＝20/1）に付して標記化
合物(37)を無色アメ状物として得た。（144mg、72％） TLC（シリカゲル）：Rf = 0.63 (塩化メチレン/メタノ
ール＝10/1) MS (FAB) m/e 477 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 6.00 (1H, d, J = 2.
9 Hz), 5.81-5.90 (1H, m), 5.68-5.78 (1H, m), 5.32-
5.43 (1H, m), 4.81 (1H, dd, J = 9.5, 2.9 Hz), 4.71
(1H, dd, J = 10.3, 2.2 Hz), 4.02 (1H, dd, J = 12.
5, 11.7 Hz), 3.73-3.91 (5H, m), 3.66 (1H, ddd, J =
10.3, 9.5, 7.3 Hz), 2.17 (3H, s), 2.09 (3H, s),
2.01 (3H, s). (xii)(4S, 5R, 6R, 2'S, 3'S, 4'R）−5−アセチルアミ
ノ−4−（N，N'−ビス−t−ブチルオキシカルボニル）
グアニジノ−6−（3'，4'−ジアセトキシ−5'，5'−ジ
フロロ−テトラヒドロ−ピラン−2'−イル）−5，6−ジ
ヒドロ−4H−ピラン−2−カルボン酸メチル 実施例２１(xi)で得られた化合物（136 mg, 0.285 mmo
l）をエタノール(5 ml)、メタノール(1 ml)に溶解し、
窒素雰囲気下リンドラー触媒（50 mg）を加え、次いで
水素雰囲気に置換し、室温で3時間攪拌した。反応液を
セライト濾過し濾物をメタノールで洗浄し、濾液、洗液
を減圧留去した。得られた残渣を無水テトラヒドロフラ
ン(2ml)に溶解し１H−ピラゾール−１−[N,N'−ビス(t
−ブトキシカルボニル)]カルボキサミジン (177mg、 0.5
71mmol)を加え室温にて終夜攪拌した。反応液を濃縮
し、残渣を酢酸エチルにて希釈、1N-塩酸、飽和重曹
水、飽和食塩水にて洗浄、無水硫酸ナトリウムにて乾燥
し、減圧留去後、得られた残渣をシリカゲルクロマトグ
ラフィー（ヘキサン/酢酸エチル＝1/2）に付して標記化
合物を無色アモルファスとして得た。（127mg、64％） TLC（シリカゲル）：Rf = 0.40 (酢酸エチル：ヘキサン
＝2/1) MS (FAB) m/e 693 [M+H]+ 1 H NMR (400 MHz, CDCl3) δppm: 11.39 (1H, s), 8.63
(1H, d, J = 8.1 Hz), 6.90 (1H, d, J = 6.6 Hz), 5.
84 (1H, d, J = 2.2 Hz), 5.72 (1H, brs), 5.34 (1H,
d, J = 10.3 Hz), 5.15 (1H, ddd, J = 8.8, 8.1, 2.2
Hz), 4.19-4.23(1H, m), 3.75-4.06 (7H, m), 2.15 (3
H, s), 2.03 (3H, s), 2.01 (3H, s), 1.50 (9H, s),
1.49 (9H, s). (xiii)（4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチルア
ミノ−5，6−ジヒドロ−6−（3', 4'−ジヒドロキシ−
5'，5'−ジフロロ−テトラヒドロ−ピラン−2'−イル）
−4−グアニジノ−4H−ピラン−2−カルボン酸 水和物 実施例２１(xii)で得られた化合物(127mg、0.183mmol)
をメタノール3mlに溶解し28％ナトリウムメトキシド・
メタノール溶液(0.1ml)を加え室温にて1時間攪拌した。
反応液にダウエックス50W×8（H+）樹脂を加え中和し、
減圧留去後、得られた残渣を塩化メチレン(3ml)に溶解
し、トリフルオロ酢酸(1ml)を加え室温にて12時間攪拌
した。反応液を減圧留去し、得られた残渣を蒸留水(3m
l)溶解し、1M水酸化ナトリウム水溶液(220μl、0.22mmo
l)を加え1時間攪拌した。次いで反応液にダウエックス5
0W×8（H+）樹脂を加え中和した。ただちに減圧濾過
し、水で濾物を洗浄した。濾液、洗液を減圧留去後、得
られた残渣を逆層クロマトグラフィー（コスモシル、
水）に付して、標記化合物(39)を無色アモルファスとし
て得た。（58mg、80％） TLC（シリカゲル）：Rf = 0.41 (2-プロパノール:酢酸:
水=5:1:1) MS (FAB) m/e 395 [M+H]+ 1 H NMR (400 MHz, D2O) δppm: 5.63 (1H, s), 4.44 (1
H, d, J = 9.5 Hz), 4.33 (1H, d, J = 10.9 Hz), 4.14
-4.29 (3H, m), 3.86 (1H, dd, J = 12.2, 12.5 Hz),
3.65-3.80 (2H, m), 2.02 (3H, s). （実施例２２） （4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルアミノ−
5，6−ジヒドロ−6−（3'，4'−ジヒドロキシ−テトラ
ヒドロ−ピラン−2'−イル）−4−グアニジノ−4H−ピ
ラン−2−カルボン酸メチル 一トリフルオロ酢酸塩
二水和物 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 5.81-6.
01 (2H, m), 7.71 (1H, d, J = 10.3 Hz), 4.56 (2H,
(iii) 5-acetylamino-4-O-t-butyldimethylsilyl-3,5-dideoxy-8,9-O-isopropylidene-2-O-methyl-7-O -(2 ', 2'-Difluoro-but-3'
-Enyl) -D-glycero-D-galacto-non-2-enopyranosonic acid methyl 5-acetylamino-3,5-dideoxy-8,9-O-isopropylidene-2-O-methyl-4-O-t -Butyldimethylsilyl-D-glycero-D-galacto-non-2-enopyranosonic acid methyl (3.72 g, 7.56 mmol) was dissolved in N, N'-dimethylformamide (20 ml), and sodium hydride (660 mg , 15.12 mmol 55%) and stirred at the same temperature for 15 minutes. Compound obtained in Example 21 (ii) under ice cooling
(2.36 g, 9.83 mmol) N, N'-dimethylformamide (4 ml)
The solution was added dropwise and stirred at room temperature for 30 minutes. The reaction solution was partitioned between ethyl acetate and a saturated aqueous ammonium chloride solution, and the organic layer was washed with water and saturated saline. After drying over anhydrous sodium sulfate and evaporating under reduced pressure, the obtained residue was subjected to silica gel chromatography (ethyl acetate / hexane = 1/1) to obtain the title compound. (2.74g, 62%) TLC (silica gel): Rf = 0.71 (hexane / ethyl acetate = 1/1) MS (FAB ) m / e 582 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm : 5.94-6.12 (1H, m),
5.75 (1H, dd, J = 17.6, 2.9 Hz), 5.53 (1H, d, J =
11.0 Hz), 5.41 (1H, d, J = 8.1 Hz), 4.34-4.46 (1H,
m), 4.18-4.31 (2H, m), 3.97-4.16 (4H, m), 3.87 (1
H, dd, J = 2.2, 2.2 Hz), 3.79 (3H, s), 3.49 (1H, d
dd, J = 10.3, 9.5, 8.8 Hz), 3.20 (3H, s), 2.28 (1
H, dd, J = 12.5, 5.1 Hz), 1.96 (3H, s), 1.56-1.65
(1H, m), 1.42 (3H, s), 1.42 (3H, s), 0.86 (9H, s),
0.06 (3H, s), 0.04 (3H, s). (Iv) 5-acetylamino-3,5-dideoxy-8,9-O-
Methyl isopropylidene-2-O-methyl-7-O- (2 ', 2'-difluoro-but-3-3'-enyl) -D-glycero-D-galacto-non-2-enopyranosonate Example 21 (iii) )) (2.74 g, 4.71 mmo
l) in dry tetrahydrofuran (30 ml)
Tetrahydrofuran (6.12 ml, 6.12 mmol) containing M tetrabutylammonium fluoride was added, and the mixture was stirred at the same temperature for 3 hours. After evaporating the reaction solution under reduced pressure, the resulting residue was subjected to silica gel chromatography (methylene chloride / methanol = 20/1).
-10/1) to give the title compound as a colorless amorphous. (2.08g, 94%) TLC (silica gel): Rf = 0.44 (methylene chloride / methanol = 10/1) MS (FAB ) m / e 468 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm : 5.91-6.08 (2H, m),
5.75 (1H, ddd, J = 2.9, 2.2, 1.8 Hz), 5.54 (1H, d,
J = 11.0 Hz), 4.25-4.36 (1H, m), 3.82-4.22 (6H,
m), 3.79 (3H, s), 3.64-3.78 (2H, m), 3.21 (3H, s),
2.42 (1H, dd, J = 12.5, 5.1 Hz), 2.04 (3H, s), 1.8
9 (1H, br), 1.67 (1H, dd, J = 12.5,11.0 Hz), 1.43
(3H, s), 1.33 (3H, s). (V) 5-acetylamino-4-O-acetyl-3,5-dideoxy-8,9-O-isopropylidene-2-O-methyl-7
-O- (2 ', 2'-difluoro-but-3'-enyl) -D-glycero-D-galacto-non-2-enopyranosonic acid methyl compound obtained in Example 21 (iv) (2.08 g, 4.45 mmol) was dissolved in acetic anhydride (5 ml) and pyridine (5 ml) and stirred for 3 hours. After evaporating the reaction solution under reduced pressure, the resulting residue was chromatographed (silica gel, methylene chloride / methanol = 20 /
By subjecting it to 1), the title compound was obtained as a colorless amorphous. (1.73g, 49%) TLC (silica gel): Rf = 0.57 (methylene chloride / methanol = 10/1) MS (FAB ) m / e 510 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm : 5.99-6.13 (1H, m),
5.73-5.79 (1H, m), 5.52 (1H, d, J = 11.0 Hz), 5.32
-5.45 (2H, m), 4.27 (1H, ddd, J = 6.6, 6.6, 5.1 H
z), 3.92-4.18 (5H, m), 3.82 (1H, dd, J = 11.0, 1.5
Hz), 3.80 (3H, s), 3.71 (1H, dd, J = 5.9, 1.5 Hz),
3.25 (3H, s), 2.39 (1H, dd, J = 12.5, 5.1 Hz), 2.
05 (3H, s), 1.95 (3H, s), 1.83 (1H, dd, J = 12.5,
(11.7 Hz), 1.41 (3H, s), 1.32 (3H, s). (Vi) 5-acetylamino-4-O-acetyl-3,5-dideoxy-2-O-methyl-7-O- (2 ', 2'-Difluoro-
Butoh-3'-enyl) -D-glycero-D-galacto-non-2-enopyranosonic acid methyl compound obtained in Example 21 (vi) (2.12 g, 4.16 mmol)
Was dissolved in 90% aqueous acetic acid (20 ml) and stirred at 60 ° C. for 3 hours.
After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to chromatography (silica gel, methylene chloride / methanol = 10/1) to obtain the title compound as a colorless amorphous. (1.
79g, 92%) TLC (silica gel): Rf = 0.36 (methylene chloride / methanol = 10/1) MS (FAB ) m / e 470 [M + H] + 1 H NMR (400 MHz chloride, CDCl 3) δppm: 5.94 -6.08 (1H, m),
5.76 (1H, ddd, J = 16.8, 2.9, 2.2 Hz), 5.51-5.60
(2H, m), 5.29 (1H, ddd, J = 11.7, 10.3, 5.1Hz), 5.
25 (1H, ddd, J = 10.3, 10.3, 9.5 Hz), 3.75-4.08 (1
0H, m), 3.65 (1H, dd, J = 7.3, 1.5 Hz), 3.28 (3H,
s), 3.18 (1H, br), 2.40 (1H, dd, J = 13.2, 5.1 Hz),
2.04 (3H, s), 1.94 (3H, s), 1.87 (1H, dd, J = 13.
(Vii) 5-acetylamino-4-O-acetyl-3,5-dideoxy-8,9-O-thiocarbonyl-2-O-methyl-7
-O- (2 ', 2'-Difluoro-but-3'-enyl) -D-glycero-D-galacto-non-2-enopyranosonic acid methyl Compound obtained in Example 21 (vi) under a nitrogen atmosphere. (1.75
mg, 3.73 mmol) was dissolved in dry methylene chloride (50 ml), and ice-cooled, 4-dimethylaminopyridine (1.05 g, 8.57 mmol
l) and thiophosgene (0.39 ml, 4.10 mmol) were added, and the mixture was stirred for 1 hour under ice cooling. Methanol was added to the reaction solution, and the mixture was distilled off under reduced pressure. The obtained residue was subjected to silica gel chromatography (methylene chloride / methanol = 10/1) to give the title compound as a colorless amorphous. (1.89g, 99%) TLC (silica gel): Rf = 0.49 (methylene chloride / methanol = 10/1) MS (FAB ) m / e 512 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm : 5.91-6.06 (1H, m),
5.76 (1H, ddd, J = 16.8, 2.9, 2.2 Hz), 5.50-5.59
(2H, m), 5.40 (1H, ddd, J = 11.7, 10.3, 5.1Hz), 4.
92-5.05 (2H, m), 4.73-4.83 (1H, m), 3.98-4.19 (3H,
m), 3.82-3.94 (2H, m), 3.81 (3H, s), 3.18 (3H, s),
2.47 (1H, dd, J = 12.5, 5.1 Hz), 2.06 (3H, s), 1.
97 (3H, s), 1.79 (1H, dd, J = 12.5, 11.7 Hz). (Viii) 4-O-acetyl-5-acetylamino-7-O-
Methyl (2 ', 2'-difluoro-but-3'-enyl) -2-O-methyl-3,5,8,9-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosonate Nitrogen In an atmosphere, the compound obtained in Example 21 (vii) (1.87
g, 3.66 mmol) was dissolved in trimethyl phosphite (50 ml) and heated under reflux for 12 hours. After evaporating the reaction solution under reduced pressure, the residue was azeotropically distilled with toluene, and the obtained residue was subjected to silica gel chromatography (methylene chloride / methanol = 10/1) to give the title compound as a colorless amorphous. (1.40 g, 88
%) TLC (silica gel): Rf = 0.49 (methylene chloride / methanol = 10/1) MS (FAB ) m / e 436 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm: 5.89-6.12 ( 2H, m),
5.72 (1H, ddd, J = 15.4, 2.2, 2.2 Hz), 5.51 (1H,
d, J = 11.0 Hz), 5.28-5.42 (4H, m), 4.11 (1H, ddd,
J = 10.3, 10.3, 9.5 Hz), 4.00 (1H, dd, J = 8.1,
2.9 Hz), 3.79 (3H, s), 3.58-3.78 (3H, m), 3.22 (3
H, s), 2.39 (1H, dd, J = 12.5, 5.1 Hz), 2.03 (3H,
s), 1.92 (3H, s), 1.87 (1H, dd, J = 12.5, 11.7 H
z). (ix) (2S, 4S, 5R, 6R, 2'R) -4-O-acetyl-5-acetylamino-6- (5 ', 5'-difluoro-, 5', 6'-dihydro -2'H-pyran-2'-yl) -2-methoxy-tetrahydro-pyran-2-carboxylic acid methyl Under nitrogen atmosphere, the compound obtained in Example 21 (viii) (1.
40 g, 1.56 mmol) was dissolved in dry methylene chloride (150 ml), bis (tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride (100 mg) was added, and the mixture was stirred at room temperature for 36 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to silica gel chromatography (ethyl acetate / hexane = 3/1) to obtain the title compound as a colorless amorphous. (0.80g, 57%) TLC (silica gel): Rf = 0.15 (ethyl acetate / hexane = 2/1) MS (FAB ) m / e 408 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm : 6.23 (1H, d, J = 1
0.3 Hz), 6.03-6.15 (1H, m), 5.38 (1H, d, J = 8.8 H
z), 5.30 (1H, ddd, J = 11.7, 11.0, 5.1 Hz), 4.37 (1
H, brs), 4.28 (1H, ddd, J = 11.0, 9.5, 9.5 Hz), 4.
09-4.21 (1H, m), 3.71-3.90 (5H, m), 3.25 (3H, s),
2.40 (1H, dd, J = 13.5, 5.1 Hz), 2.03 (3H, s), 1.8
5-1.99 (4H, m). (X) (2S, 4S, 5R, 6R, 2'R) -4-acetoxy-5-acetylamino-6- (5 ', 5'-difluoro-3', 4 Methyl '-dihydroxy-tetrahydro-pyran-2'-yl) -2-methoxy-tetrahydro-pyran-2-carboxylate Compound obtained in Example 21 (ix) (512 mg, 1.26 mmo
l) with acetone (3 ml), distilled water (3 ml), acetonitrile
(3 ml) and N-methylmorpholine N-oxide 50%
Aqueous solution (320 mg, 1.38 mmol), osmium tetroxide (1m
g, 0.004 mmol) and stirred at room temperature for 12 hours. The reaction solution was evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (methylene chloride / methanol = 10/1) to obtain the title compound (36). (193mg, 35%) TLC (silica gel): Rf = 0.33 (methylene chloride / methanol = 10/1) MS (FAB ) m / e 442 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm: 5.92 (1H, d, J = 9.
5 Hz), 5.32 (1H, ddd, J = 11.7, 10.3, 5.1 Hz), 3.6
8-4.35 (10H m), 5.52 (1H, d, J = 10.3 Hz), 3.28 (3
H, s), 3.13 (1H, d, J = 9.5 Hz), 2.42 (1H, dd, J =
13.2, 5.1 Hz), 2.05 (3H, s), 1.96 (3H, s), 1.90
(1H, dd, J = 13.2, 11.7 Hz). (Xi) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5-acetylamino-4-azido-6- (3 ', 4'- Diacetoxy-5 ', 5'-
Difluoro-tetrahydro-pyran-2'-yl) -5,6-
Methyl dihydro-4H-pyran-2-carboxylate The compound obtained in Example 21 (x) (185m
g, 0.419 mmol) was dissolved in acetic acid (0.25 ml) and acetic anhydride (1 ml), concentrated sulfuric acid (0.2 ml) was added under ice-cooling, and the mixture was stirred at 80 ° C. for 3 hours. Sodium carbonate (1.5 g), water (10 ml), toluene (10 m
The mixed two-layer liquid obtained in l) was vigorously stirred, and the previous reaction liquid was poured therein at room temperature, followed by stirring for 30 minutes. Separate the toluene layer,
The aqueous layer was extracted with toluene, the toluene layers were collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure.
Dissolved in N'-dimethylformamide (2 ml), sodium azide (200 mg), Dowex 50W (H + ) resin (200
mg) and stirred at 70 ° C. for 3 hours. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was subjected to silica gel chromatography (methylene chloride / methanol = 20/1) to give the title compound ( 37) was obtained as a colorless candy. (144mg, 72%) TLC (silica gel): Rf = 0.63 (methylene chloride / methanol = 10/1) MS (FAB ) m / e 477 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm: 6.00 (1H, d, J = 2.
9 Hz), 5.81-5.90 (1H, m), 5.68-5.78 (1H, m), 5.32-
5.43 (1H, m), 4.81 (1H, dd, J = 9.5, 2.9 Hz), 4.71
(1H, dd, J = 10.3, 2.2 Hz), 4.02 (1H, dd, J = 12.
5, 11.7 Hz), 3.73-3.91 (5H, m), 3.66 (1H, ddd, J =
10.3, 9.5, 7.3 Hz), 2.17 (3H, s), 2.09 (3H, s),
2.01 (3H, s). (Xii) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5-acetylamino-4- (N, N'-bis-t-butyloxycarbonyl)
Methyl guanidino-6- (3 ', 4'-diacetoxy-5', 5'-difluoro-tetrahydro-pyran-2'-yl) -5,6-dihydro-4H-pyran-2-carboxylate Example 21 ( xi) (136 mg, 0.285 mmo
l) in ethanol (5 ml) and methanol (1 ml)
Under a nitrogen atmosphere, a Lindlar catalyst (50 mg) was added, and the atmosphere was replaced with a hydrogen atmosphere, followed by stirring at room temperature for 3 hours. The reaction solution was filtered through celite, and the residue was washed with methanol. The filtrate and the washing were distilled off under reduced pressure. The obtained residue was dissolved in anhydrous tetrahydrofuran (2 ml) and 1H-pyrazole-1- [N, N'-bis (t
-Butoxycarbonyl)] carboxamidine (177 mg, 0.5
(71 mmol) and stirred at room temperature overnight. The reaction solution was concentrated, the residue was diluted with ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. (Hexane / ethyl acetate = 1/2) to give the title compound as a colorless amorphous. (127mg, 64%) TLC (silica gel): Rf = 0.40 (ethyl acetate: hexane = 2/1) MS (FAB ) m / e 693 [M + H] + 1 H NMR (400 MHz, CDCl 3) δppm: 11.39 (1H, s), 8.63
(1H, d, J = 8.1 Hz), 6.90 (1H, d, J = 6.6 Hz), 5.
84 (1H, d, J = 2.2 Hz), 5.72 (1H, brs), 5.34 (1H,
d, J = 10.3 Hz), 5.15 (1H, ddd, J = 8.8, 8.1, 2.2
Hz), 4.19-4.23 (1H, m), 3.75-4.06 (7H, m), 2.15 (3
H, s), 2.03 (3H, s), 2.01 (3H, s), 1.50 (9H, s),
1.49 (9H, s). (Xiii) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5-acetylamino-5,6-dihydro-6- (3 ', 4'-dihydroxy-
5 ', 5'-difluoro-tetrahydro-pyran-2'-yl)
-4-guanidino-4H-pyran-2-carboxylic acid hydrate The compound obtained in Example 21 (xii) (127 mg, 0.183 mmol)
Was dissolved in 3 ml of methanol, and 28% sodium methoxide
A methanol solution (0.1 ml) was added, and the mixture was stirred at room temperature for 1 hour.
Dowex 50W × 8 (H + ) resin was added to the reaction solution to neutralize it,
After evaporation under reduced pressure, the obtained residue was dissolved in methylene chloride (3 ml), trifluoroacetic acid (1 ml) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was distilled off under reduced pressure, and the obtained residue was distilled water (3 m
l) Dissolve, 1M sodium hydroxide aqueous solution (220μl, 0.22mmo
l) was added and stirred for 1 hour. Then add Dowex 5 to the reaction mixture.
0W × 8 (H + ) resin was added for neutralization. The mixture was immediately filtered under reduced pressure, and the residue was washed with water. After the filtrate and washings were distilled off under reduced pressure, the resulting residue was subjected to reverse layer chromatography (Cosmosil,
Water) to give the title compound (39) as a colorless amorphous. (58 mg, 80%) TLC (silica gel): Rf = 0.41 (2-propanol: acetic acid:
Water = 5: 1: 1) MS (FAB) m / e 395 [M + H] + 1 H NMR (400 MHz, D 2 O) δppm: 5.63 (1H, s), 4.44 (1
H, d, J = 9.5 Hz), 4.33 (1H, d, J = 10.9 Hz), 4.14
-4.29 (3H, m), 3.86 (1H, dd, J = 12.2, 12.5 Hz),
3.65-3.80 (2H, m), 2.02 (3H, s). (Example 22) (4S, 5R, 6R, 2'R, 3'R, 4'R) -5-acetylamino-
Methyl 5,6-dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4-guanidino-4H-pyran-2-carboxylate monotrifluoroacetate
Dihydrate
【０３２４】[0324]
【化３４】 Embedded image
【０３２５】実施例６(i)で得られた化合物（4S, 5R, 6
R, 2'R, 3'R, 4'R）−5−アセチルアミノ−4−（N，N'
−ビス−t−ブチルオキシカルボニル）グアニジノ−5，
6−ジヒドロ−6−（3'，4'−ジヒドロキシ−テトラヒド
ロ−ピラン−2'−イル）−4H−ピラン−2−カルボン酸
メチル（80 mg, 0.139 mmol）を塩化メチレン（3ml）に
溶解し、トリフルオロ酢酸（3 ml）を加え、4時間攪拌
した。反応液を減圧留去後得られた残査を逆相クロマト
グラフィー（コスモシル、水/メタノール＝3/1）に付し
て、凍結乾燥後、標記化合物を無色アモルファスとして
得た。（62 mg、85％） IR (KBr)νmax：3346, 3205, 2959, 2930, 2881, 1728,
1670, 1549, 1441 cm -1. MS (FAB) m/e 373 ([M+H]+). HRMS (FAB) Calcd for C15H25O7N4 : 373.1723; found
373.1732 ([M+H]+).1 H NMR (400 MHz, CD3OD) δppm：5.85 (1H, d, J = 2.
9 Hz), 4.48 (1H, dd,J = 8.8, 2.0 Hz), 4.45 (1H, d
d, J = 7.8, 2.9 Hz), 4.16 (1H, dd, J = 8.8, 7.8 H
z), 4.10-4.13 (1H, m), 3.83 (1H, dd, J = 9.8, 2.9
Hz), 3.79 (3H,s), 3.72 (1H, dd, J = 9.8, 2.0 Hz),
3.66-3.70 (2H, m), 1.99 (3H, s), 1.83-1.91 (1H,
m), 1.72-1.77 (1H, m). [α]D 20 -3.9°(c 0.35, CH3OH). （実施例２３） （4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルアミノ−
5，6−ジヒドロ−6−（3'，4'−ジヒドロキシ−テトラ
ヒドロ−ピラン−2'−イル）−4−グアニジノ−4H−ピ
ラン−2−カルボン酸エチル 一トリフルオロ酢酸塩
二水和物The compound (4S, 5R, 6) obtained in Example 6 (i)
R, 2'R, 3'R, 4'R) -5-acetylamino-4- (N, N '
-Bis-t-butyloxycarbonyl) guanidino-5,
6-dihydro-6- (3 ', 4'-dihydroxy-tetrahydrido
Ropyran-2'-yl) -4H-pyran-2-carboxylic acid
Methyl (80 mg, 0.139 mmol) in methylene chloride (3 ml)
Dissolve, add trifluoroacetic acid (3 ml) and stir for 4 hours
did. The residue obtained after evaporating the reaction solution under reduced pressure was subjected to reverse phase chromatography.
Applied to graphy (Cosmosil, water / methanol = 3/1)
After lyophilization, the title compound is converted to a colorless amorphous
Obtained. (62 mg, 85%) IR (KBr) νmax: 3346, 3205, 2959, 2930, 2881, 1728,
1670, 1549, 1441 cm -1MS (FAB) m / e 373 ([M + H]+). HRMS (FAB) Calcd for CFifteenHtwenty fiveO7NFour : 373.1723; found
373.1732 ([M + H]+).1 H NMR (400 MHz, CDThreeOD) δppm: 5.85 (1H, d, J = 2.
9 Hz), 4.48 (1H, dd, J = 8.8, 2.0 Hz), 4.45 (1H, d
d, J = 7.8, 2.9 Hz), 4.16 (1H, dd, J = 8.8, 7.8 H
z), 4.10-4.13 (1H, m), 3.83 (1H, dd, J = 9.8, 2.9
Hz), 3.79 (3H, s), 3.72 (1H, dd, J = 9.8, 2.0 Hz),
3.66-3.70 (2H, m), 1.99 (3H, s), 1.83-1.91 (1H,
m), 1.72-1.77 (1H, m). [α]D 20 -3.9 ° (c 0.35, CHThreeOH). (Example 23) (4S, 5R, 6R, 2'R, 3'R, 4'R) -5-acetylamino-
5,6-dihydro-6- (3 ', 4'-dihydroxy-tetra
Hydro-pyran-2'-yl) -4-guanidino-4H-py
Ethyl run-2-carboxylate monotrifluoroacetate
Dihydrate
【０３２６】[0326]
【化３５】 Embedded image
【０３２７】（i）（4S, 5R, 6R, 2'S, 3'S, 4'R）−5
−アセチルアミノ−4―（N，N'―ビス−t―ブチルオキ
シカルボニル）グアニジノ―5，6―ジヒドロ―6−
（3'，4'−O−イソプロピリデン−3'，4'−ジオキシ−
テトラヒドロ−ピラン−2'−イル）―4H―ピラン−2−
カルボン酸エチル（36） 実施例６(ii)で得られた化合物（4S, 5R, 6R, 2'S, 3'
S, 4'R）−5−アセチルアミノ−4−（N，N'−ビス−t−
ブチルオキシカルボニル）グアニジノ−5，6−ジヒドロ
−6−（3'，4'−O−イソプロピリデン−3'，4'−ジオキ
シ−テトラヒドロ−ピラン−2'−イル）−4H−ピラン−
2−カルボン酸メチル（290 mg, 0.473 mmol）をメタノ
ール（5 ml）に溶解し、室温で1M水酸化カリウム水溶液
（0.56 ml, 0.56 mmol）を加え、40℃で30分間攪拌し
た。反応液を減圧留去後、トルエンで共沸して得られた
残査を窒素雰囲気下、ジメチルホルムアミド（1.2 ml）
に溶解し、ヨウ化エチル（300 mg, 1.92 mmol）を室温
にて滴下し、50℃にて3時間攪拌した。反応液を酢酸エ
チル（30 ml）と飽和炭酸水素ナトリウム水溶液（30 m
l）に分配した。有機層を分離し、食塩水（20ml X 3）
で洗浄し、硫酸ナトリウムで乾燥し、減圧留去後、得ら
れた残査をクロマトグラフィー（シリカゲル、酢酸エチ
ル/ヘキサン＝3/2）に付して標記化合物を無色アモルフ
ァスとして得た。（185 mg、62％） IR (CDCl3) νmax： 2928, 2873, 1727, 1686, 1640, 1
606, 1569 cm-1. MS (FAB) m/e 627 ([M+H]+). HRMS (FAB) Calcd for C29H47O11N4 : 627.3241; found
627.3246 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm： 8.56 (1H, d, J =
8.8 Hz), 6.46 (1H, d,J = 8.1 Hz), 5.80 (1H, d, J =
2.9 Hz), 5.15 (1H, ddd, J = 9.5, 8.8, 2.9Hz), 4.4
2-4.46 (1H, m), 4.34 (1H, dd, J = 9.5, 4.4 Hz), 4.
22-4.29 (1H,m), 4.12-4.20 (2H, m), 4.07 (1H, d, J
= 10.3 Hz), 3.89 (1H, ddd, J = 11.7, 11.0, 5.1 H
z), 3.59 (1H, ddd, J = 12.5, 11.7, 2.9 Hz), 3.34
(1H, d, J= 9.5 Hz), 2.05-2.14 (1H, m), 1.95-2.02
(1H, m), 1.95 (3H, s), 1.50 (9H, s), 1.49 (9H, s),
1.45 (3H, s), 1.38 (3H, s), 1.31 (3H, t, J = 6.8
Hz). [α]D 20 -20.8°(c 0.60, CHCl3). （ii）（4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルア
ミノ−5，6−ジヒドロ−6−（3'，4'−ジヒドロキシ−
テトラヒドロ−ピラン−2'−イル）−4−グアニジノ−4
H−ピラン−2−カルボン酸エチル 一トリフルオロ酢酸
塩 二水和物 実施例２３(i)で得られた化合物（240 mg, 0.383 mmo
l）を塩化メチレン（3ml）に溶解し、トリフルオロ酢酸
（3 ml）を加え、4時間攪拌した。反応液を減圧留去
後、得られた残査をテトラヒドロフラン（5 ml）に溶解
し、水（1 ml）、トリフルオロ酢酸（0.2 ml）を加え、
3時間攪拌した。反応液を減圧留去後得られた残査を逆
相クロマトグラフィー（コスモシル、水/メタノール＝3
/1）に付して、凍結乾燥後、標記化合物を無色アモルフ
ァスとして得た。（171 mg、83％） IR (KBr) νmax 3347, 3196, 2986, 2879, 1670, 1550,
1430 cm-1. MS (FAB) m/e 387 ([M+H]+). HRMS (FAB) Calcd for C16H27O7N4 : 387.1880; found
387.1896 ([M+H]+).1 H NMR (400 MHz, CD3OD) δppm： 5.85 (1H, d, J =
2.9 Hz), 4.48 (1H, dd, J = 8.8, 2.0 Hz), 4.45 (1H,
dd, J = 7.8, 2.9 Hz), 4.25 (3H, q, J = 7.3Hz), 4.
16 (1H, dd, J = 8.8, 7.8 Hz), 4.10-4.13 (1H, m),
3.83 (1H, dd, J= 9.8, 2.9 Hz), 3.72 (1H, dd, J =
9.8, 2.0 Hz), 3.66-3.70 (2H, m), 1.99(3H, s), 1.83
-1.91 (1H, m), 1.72-1.77 (1H, m), 1.30 (3H, t, J =
7.3 Hz). [α]D 20 -2.0°(c 0.70, CH3OH). （実施例２４） （4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルアミノ−
5，6−ジヒドロ−6−（3'，4'−ジヒドロキシ−テトラ
ヒドロ−ピラン−2'−イル）−4−グアニジノ−4H−ピ
ラン−2−カルボン酸ペンチル 一トリフルオロ酢酸塩
二水和物(I) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5
-Acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) guanidino-5,6-dihydro-6-
(3 ′, 4′-O-isopropylidene-3 ′, 4′-dioxy-
Tetrahydro-pyran-2'-yl) -4H-pyran-2-
Ethyl carboxylate (36) Compound (4S, 5R, 6R, 2'S, 3 ') obtained in Example 6 (ii)
S, 4'R) -5-acetylamino-4- (N, N'-bis-t-
(Butyloxycarbonyl) guanidino-5,6-dihydro-6- (3 ', 4'-O-isopropylidene-3', 4'-dioxy-tetrahydro-pyran-2'-yl) -4H-pyran-
Methyl 2-carboxylate (290 mg, 0.473 mmol) was dissolved in methanol (5 ml), a 1 M aqueous potassium hydroxide solution (0.56 ml, 0.56 mmol) was added at room temperature, and the mixture was stirred at 40 ° C for 30 minutes. After evaporating the reaction solution under reduced pressure, the residue obtained by azeotropic distillation with toluene was subjected to dimethylformamide (1.2 ml) under a nitrogen atmosphere.
And ethyl iodide (300 mg, 1.92 mmol) was added dropwise at room temperature, followed by stirring at 50 ° C. for 3 hours. The reaction solution was treated with ethyl acetate (30 ml) and a saturated aqueous sodium hydrogen carbonate solution (30 m
l) Dispensed. Separate the organic layer and add brine (20ml x 3)
After drying over sodium sulfate and evaporating under reduced pressure, the resulting residue was subjected to chromatography (silica gel, ethyl acetate / hexane = 3/2) to obtain the title compound as a colorless amorphous. (185 mg, 62%) IR (CDCl 3 ) νmax: 2928, 2873, 1727, 1686, 1640, 1
606, 1569 cm -1 . MS (FAB) m / e 627 ([M + H] + ). HRMS (FAB) Calcd for C 29 H 47 O 11 N 4 : 627.3241; found
627.3246 ([M + H] + ). 1 H NMR (400 MHz, CDCl 3 ) δppm: 8.56 (1H, d, J =
8.8 Hz), 6.46 (1H, d, J = 8.1 Hz), 5.80 (1H, d, J =
2.9 Hz), 5.15 (1H, ddd, J = 9.5, 8.8, 2.9Hz), 4.4
2-4.46 (1H, m), 4.34 (1H, dd, J = 9.5, 4.4 Hz), 4.
22-4.29 (1H, m), 4.12-4.20 (2H, m), 4.07 (1H, d, J
= 10.3 Hz), 3.89 (1H, ddd, J = 11.7, 11.0, 5.1 H
z), 3.59 (1H, ddd, J = 12.5, 11.7, 2.9 Hz), 3.34
(1H, d, J = 9.5 Hz), 2.05-2.14 (1H, m), 1.95-2.02
(1H, m), 1.95 (3H, s), 1.50 (9H, s), 1.49 (9H, s),
1.45 (3H, s), 1.38 (3H, s), 1.31 (3H, t, J = 6.8
(Α) D 20 -20.8 ° (c 0.60, CHCl 3 ). (Ii) (4S, 5R, 6R, 2'R, 3'R, 4'R) -5-acetylamino-5,6 -Dihydro-6- (3 ', 4'-dihydroxy-
Tetrahydro-pyran-2'-yl) -4-guanidino-4
Ethyl H-pyran-2-carboxylate monotrifluoroacetate dihydrate The compound obtained in Example 23 (i) (240 mg, 0.383 mmo
l) was dissolved in methylene chloride (3 ml), trifluoroacetic acid (3 ml) was added, and the mixture was stirred for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was dissolved in tetrahydrofuran (5 ml), and water (1 ml) and trifluoroacetic acid (0.2 ml) were added.
Stir for 3 hours. The residue obtained after evaporating the reaction solution under reduced pressure was subjected to reverse phase chromatography (cosmosil, water / methanol = 3).
/ 1), and after lyophilization, the title compound was obtained as a colorless amorphous. (171 mg, 83%) IR (KBr) νmax 3347, 3196, 2986, 2879, 1670, 1550,
.. 1430 cm -1 MS (FAB ) m / e 387 ([M + H] +) HRMS (FAB) Calcd for C 16 H 27 O 7 N 4: 387.1880; found
387.1896 ([M + H] + ). 1 H NMR (400 MHz, CD 3 OD) δppm: 5.85 (1H, d, J =
2.9 Hz), 4.48 (1H, dd, J = 8.8, 2.0 Hz), 4.45 (1H,
dd, J = 7.8, 2.9 Hz), 4.25 (3H, q, J = 7.3Hz), 4.
16 (1H, dd, J = 8.8, 7.8 Hz), 4.10-4.13 (1H, m),
3.83 (1H, dd, J = 9.8, 2.9 Hz), 3.72 (1H, dd, J =
9.8, 2.0 Hz), 3.66-3.70 (2H, m), 1.99 (3H, s), 1.83
-1.91 (1H, m), 1.72-1.77 (1H, m), 1.30 (3H, t, J =
[Α] D 20 -2.0 ° (c 0.70, CH 3 OH). (Example 24) (4S, 5R, 6R, 2′R, 3′R, 4′R) -5-acetylamino −
Pentyl 5,6-dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4-guanidino-4H-pyran-2-carboxylate monotrifluoroacetate dihydrate
【０３２８】[0328]
【化３６】 Embedded image
【０３２９】（i）（4S, 5R, 6R, 2'S, 3'S, 4'R）−5
−アセチルアミノ−4―（N，N'―ビス−t―ブチルオキ
シカルボニル）グアニジノ―5，6―ジヒドロ―6−
（3'，4'−O−イソプロピリデン−3'，4'−ジオキシ−
テトラヒドロ−ピラン−2'−イル）―4H―ピラン−2−
カルボン酸ペンチル 実施例６(ii)で得られた化合物（4S, 5R, 6R, 2'S, 3'
S, 4'R）−5−アセチルアミノ−4−（N，N'−ビス−t−
ブチルオキシカルボニル）グアニジノ−5，6−ジヒドロ
−6−（3'，4'−O−イソプロピリデン−3'，4'−ジオキ
シ−テトラヒドロ−ピラン−2'−イル）−4H−ピラン−
2−カルボン酸メチル（200 mg, 0.326 mmol）をメタノ
ール（5 ml）に溶解し、室温で1M水酸化カリウム水溶液
（0.39 ml, 0.39 mmol）を加え、40℃で30分間攪拌し
た。反応液を減圧留去後、トルエンで共沸して得られた
残査を窒素雰囲気下、ジメチルホルムアミド（1.2 ml）
に溶解し、ペンチルブロマイド（200 mg, 1.32 mmol）
を室温にて滴下し、50℃にて3時間攪拌した。反応液を
酢酸エチル（30 ml）と飽和炭酸水素ナトリウム水溶液
（30 ml）に分配した。有機層を分離し、食塩水（20ml
X 3）で洗浄し、硫酸ナトリウムで乾燥し、減圧留去
後、得られた残査をクロマトグラフィー（シリカゲル、
酢酸エチル/ヘキサン＝1/1）に付して標記化合物を無色
アモルファスとして得た。（132 mg、60％） IR (CDCl3) νmax： 2929, 2873, 2856, 1727, 1685, 1
640, 1606, 1569 cm-1. MS (FAB) m/e 627 ([M+H]+). HRMS (FAB) Calcd for C29H47O11N4 : 627.3241; found
627.3246 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm： 8.56 (1H, d, J =
8.8 Hz), 6.47 (1H, d,J = 8.1 Hz), 5.81 (1H, d, J =
2.9 Hz), 5.15 (1H, ddd, J = 9.5, 8.8, 2.9Hz), 4.4
2-4.46 (1H, m), 4.34 (1H, dd, J = 9.5, 4.4 Hz), 4.
17-4.30 (3H,m), 4.07 (1H, d, J = 10.3 Hz), 3.89 (1
H, ddd, J = 11.7, 11.0, 5.1 Hz), 3.59 (1H, ddd, J
= 12.5, 11.7, 2.9 Hz), 3.34 (1H, d, J = 9.5 Hz),
2.05-2.14 (1H, m), 1.95-2.02 (1H, m), 1.95 (3H,
s), 1.50 (9H, s), 1.49 (9H, s),1.45 (3H, s), 1.38
(3H, s), 1.31 (3H, t, J = 6.8 Hz). [α]D 20 -21.9°(c 0.70, CHCl3). （ii）（4S, 5R, 6R, 2'R, 3'R, 4'R）−5−アセチルア
ミノ−5，6−ジヒドロ−6−（3'，4'−ジヒドロキシ−
テトラヒドロ−ピラン−2'−イル）−4−グアニジノ−4
H−ピラン−2−カルボン酸ペンチル 一トリフルオロ酢
酸塩 二水和物 実施例２４(i)で得られた化合物（198 mg, 0.296 mmo
l）を塩化メチレン（3ml）に溶解し、トリフルオロ酢酸
（3 ml）を加え、4時間攪拌した。反応液を減圧留去
後、得られた残査をテトラヒドロフラン（5 ml）に溶解
し、水（1 ml）、トリフルオロ酢酸（0.2 ml）を加え、
3時間攪拌した。反応液を減圧留去後得られた残査を逆
相クロマトグラフィー（コスモシル、水/メタノール＝3
/1）に付して、凍結乾燥後、標記化合物を無色アモルフ
ァスとして得た。（129 mg、75％） IR (KBr) νmax： 3344, 3198, 2961, 2935, 2875, 167
0, 1550, 1467, 1430cm-1. MS (FAB) m/e 429 ([M+H]+). HRMS (FAB) Calcd for C19H33O7N4 : 429.2349; found
429.2324 ([M+H]+).1 H NMR (400 MHz, CD3OD) δppm： 5.85 (1H, d, J =
2.9 Hz), 4.48 (1H, dd, J = 8.8, 2.0 Hz), 4.45 (1H,
dd, J = 7.8, 2.9 Hz), 4.14-4.23 (3H, m), 4.10-4.1
3 (1H, m), 3.83 (1H, dd, J = 9.8, 2.9 Hz), 3.72 (1
H, dd, J = 9.8,2.0 Hz), 3.66-3.70 (2H, m), 1.99 (3
H, s), 1.83-1.91 (1H, m), 1.66-1.78(3H, m), 1.34-
1.41 (4H, m), 0.93 (3H, t, J = 7.3 Hz). Anal. Calcd for C19H32N4O7.C2F3O.2H2O : C, 43.60;
H, 6.45; N, 9.68; F,9.85. found C, 44.51; H, 6.28;
N, 8.50; F, 10.34. [α]D 20 -1.2°(c 0.40, CH3OH). （実施例２５） （4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチルアミノ−
6−（4'−アセトキシ−3'−ヒドロキシ−テトラヒドロ
−ピラン−2'−イル）−5，6―ジヒドロ−4−グアニジ
ノ−4H−ピラン−2−カルボン酸 トリフルオロ酢酸塩
二水和物(I) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5
-Acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) guanidino-5,6-dihydro-6-
(3 ′, 4′-O-isopropylidene-3 ′, 4′-dioxy-
Tetrahydro-pyran-2'-yl) -4H-pyran-2-
Pentyl carboxylate Compound (4S, 5R, 6R, 2'S, 3 ') obtained in Example 6 (ii)
S, 4'R) -5-acetylamino-4- (N, N'-bis-t-
(Butyloxycarbonyl) guanidino-5,6-dihydro-6- (3 ', 4'-O-isopropylidene-3', 4'-dioxy-tetrahydro-pyran-2'-yl) -4H-pyran-
Methyl 2-carboxylate (200 mg, 0.326 mmol) was dissolved in methanol (5 ml), a 1 M aqueous potassium hydroxide solution (0.39 ml, 0.39 mmol) was added at room temperature, and the mixture was stirred at 40 ° C for 30 minutes. After evaporating the reaction solution under reduced pressure, the residue obtained by azeotropic distillation with toluene was subjected to dimethylformamide (1.2 ml) under a nitrogen atmosphere.
And dissolved in pentyl bromide (200 mg, 1.32 mmol)
Was added dropwise at room temperature, and the mixture was stirred at 50 ° C. for 3 hours. The reaction solution was partitioned between ethyl acetate (30 ml) and a saturated aqueous sodium hydrogen carbonate solution (30 ml). Separate the organic layer and add saline (20 ml)
X 3), dried over sodium sulfate and evaporated under reduced pressure. The residue obtained was chromatographed (silica gel,
The residue was subjected to ethyl acetate / hexane = 1/1) to give the title compound as a colorless amorphous. (132 mg, 60%) IR (CDCl 3 ) νmax: 2929, 2873, 2856, 1727, 1685, 1
640, 1606, 1569 cm -1 . MS (FAB) m / e 627 ([M + H] + ). HRMS (FAB) Calcd for C 29 H 47 O 11 N 4 : 627.3241; found
627.3246 ([M + H] + ). 1 H NMR (400 MHz, CDCl 3 ) δppm: 8.56 (1H, d, J =
8.8 Hz), 6.47 (1H, d, J = 8.1 Hz), 5.81 (1H, d, J =
2.9 Hz), 5.15 (1H, ddd, J = 9.5, 8.8, 2.9Hz), 4.4
2-4.46 (1H, m), 4.34 (1H, dd, J = 9.5, 4.4 Hz), 4.
17-4.30 (3H, m), 4.07 (1H, d, J = 10.3 Hz), 3.89 (1
H, ddd, J = 11.7, 11.0, 5.1 Hz), 3.59 (1H, ddd, J
= 12.5, 11.7, 2.9 Hz), 3.34 (1H, d, J = 9.5 Hz),
2.05-2.14 (1H, m), 1.95-2.02 (1H, m), 1.95 (3H,
s), 1.50 (9H, s), 1.49 (9H, s), 1.45 (3H, s), 1.38
(3H, s), 1.31 (3H, t, J = 6.8 Hz). [Α] D 20 -21.9 ° (c 0.70, CHCl 3 ). (Ii) (4S, 5R, 6R, 2'R, 3 ' R, 4'R) -5-acetylamino-5,6-dihydro-6- (3 ', 4'-dihydroxy-
Tetrahydro-pyran-2'-yl) -4-guanidino-4
H-pyran-2-carboxylate pentyl monotrifluoroacetate dihydrate The compound obtained in Example 24 (i) (198 mg, 0.296 mmo
l) was dissolved in methylene chloride (3 ml), trifluoroacetic acid (3 ml) was added, and the mixture was stirred for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was dissolved in tetrahydrofuran (5 ml), and water (1 ml) and trifluoroacetic acid (0.2 ml) were added.
Stir for 3 hours. The residue obtained after evaporating the reaction solution under reduced pressure was subjected to reverse phase chromatography (cosmosil, water / methanol = 3).
/ 1), and after lyophilization, the title compound was obtained as a colorless amorphous. (129 mg, 75%) IR (KBr) νmax: 3344, 3198, 2961, 2935, 2875, 167
0, 1550, 1467, 1430cm -1 . MS (FAB) m / e 429 ([M + H] + ). HRMS (FAB) Calcd for C 19 H 33 O 7 N 4 : 429.2349; found
429.2324 ([M + H] + ). 1 H NMR (400 MHz, CD 3 OD) δppm: 5.85 (1H, d, J =
2.9 Hz), 4.48 (1H, dd, J = 8.8, 2.0 Hz), 4.45 (1H,
dd, J = 7.8, 2.9 Hz), 4.14-4.23 (3H, m), 4.10-4.1
3 (1H, m), 3.83 (1H, dd, J = 9.8, 2.9 Hz), 3.72 (1
H, dd, J = 9.8,2.0 Hz), 3.66-3.70 (2H, m), 1.99 (3
H, s), 1.83-1.91 (1H, m), 1.66-1.78 (3H, m), 1.34-
1.41 (4H, m), 0.93 (3H, t, J = 7.3 Hz). Anal.Calcd for C 19 H 32 N 4 O 7 .C 2 F 3 O.2H 2 O: C, 43.60;
H, 6.45; N, 9.68; F, 9.85.found C, 44.51; H, 6.28;
N, 8.50; F, 10.34. [Α] D 20 -1.2 ° (c 0.40, CH 3 OH). (Example 25) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5- Acetylamino-
6- (4'-acetoxy-3'-hydroxy-tetrahydro-pyran-2'-yl) -5,6-dihydro-4-guanidino-4H-pyran-2-carboxylic acid trifluoroacetate
Dihydrate
【０３３０】[0330]
【化３７】 Embedded image
【０３３１】（i）（4S, 5R, 6R, 2'R, 3'S, 4'R）−5
−アセチルアミノ−4−（N，N'−ビス−t−ブチルオキ
シカルボニル）グアニジノ−6−（4'−アセトキシ−3'
−ヒドロキシ−テトラヒドロ−ピラン−2'−イル）−
5，6―ジヒドロ―4H―ピラン−2−カルボン酸ジフェニ
ルメチル ［4'−アシルオキシ化合物］及び（4S, 5R,
6R, 2'S, 3'R, 4'R）−5−アセチルアミノ−4−（N，N'
−ビス−t−ブチルオキシカルボニル）グアニジノ−6−
（3'−アセトキシ−4'−ヒドロキシ−テトラヒドロ−ピ
ラン−2'−イル）―5，6―ジヒドロ―4H―ピラン−2−
カルボン酸ジフェニルメチル ［3'−アシルオキシ化合
物］ 実施例１２(i)で得られた化合物（4S, 5R, 6R, 2'R, 3'
R, 4'R）−5−アセチルアミノ−4−（N，N'−ビス−t−
ブチルオキシカルボニル）グアニジノ−5，6−ジヒドロ
−6−（3'，4'−ジヒドロキシ−テトラヒドロ−ピラン
−2'−イル）−4H−ピラン−2−カルボン酸ジフェニル
メチル（280 mg, 0.382 mmol）をメタノール（10 ml）
に溶解し、室温にてジブチルチンオキシド（100 mg, 0.
401 mmol）を加え、70℃にて20分間攪拌した。反応液を
減圧留去し、トルエンで共沸した。得られた残査を真空
ポンプで一時間乾燥後、トルエンに溶解し、窒素雰囲気
下、氷冷下アセチルブロマイド（30 μl, 0.401 mmo
l）、トリエチルアミン（6μl, 0.040 mmol）を滴下
し、同温にて1時間攪拌した。メタノールを加え、反応
液を減圧留去後得られた残査をクロマトグラフィー（シ
リカゲル、酢酸エチル）に付して標記化合物をそれぞれ
無色アモルファスとして得た。（4'−アシルオキシ化合
物：180 mg、61％）（3'−アシルオキシ化合物：36 m
g、12％） （4'−アシルオキシ化合物） IR (CDCl3) νmax： 2960, 2928, 2855, 1729, 1684, 1
637, 1604, 1568 cm-1. MS (FAB) m/e 767 ([M+H]+). HRMS (FAB) Calcd for C39H51O12N4 : 767.3503; found
767.3527 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm： 8.59 (1H, d, J =
8.8 Hz), 7.26-7.38 (10H, m), 6.92 (1H, s), 6.43 (1
H, d, J = 6.6 Hz), 5.93 (1H, d, J = 2.9 Hz), 5.31-
5.34 (1H, m), 5.14-5.20 (1H, m), 4.28-4.36 (2H,
m), 4.06-4.12 (1H, m), 3.81-3.87 (1H, m), 3.58-3.6
6 (2H, m), 2.17 (1H, br), 2.13 (3H, s),1.98 (3H,
s), 1.89-1.96 (1H, m), 1.80-1.87 (1H, m), 1.49 (9
H, s), 1.48(9H, s). [α]D 20 -12.8°(c 0.75, CHCl3). （3'−アシルオキシ化合物）1 H NMR (400 MHz, CDCl3) δppm：8.60 (1H, d, J = 9.
5 Hz), 7.25-7.42 (10H, m), 6.92 (1H, s), 5.89 (1H,
d, J = 2.2 Hz), 5.23 (1H, dd, J = 9.8, 2.6 Hz),
5.17 (1H, dd, J = 9.5, 8.8, 2.2 Hz), 4.48-4.53 (1
H, m), 4.34 (1H,ddd, J = 9.5, 8.8, 8.8 Hz), 4.20
(1H, d, J = 9.5 Hz), 3.95-4.00 (1H, m), 3.75-3.86
(2H, m), 2.05 (3H, s), 1.99 (3H, s), 1.93-2.00 (1
H, m), 1.76-1.82 (1H, m), 1.49 (18H, s). （ii）（4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチルア
ミノ−6−（4'−アセトキシ−3'−ヒドロキシ−テトラ
ヒドロ−ピラン−2'−イル）−5，6―ジヒドロ―4−グ
アニジノ−4H―ピラン−2−カルボン酸 トリフルオロ酢
酸塩 二水和物 実施例２５(i)で得られた4'−アシルオキシ化合物（173
mg, 0.225 mmol）を塩化メチレン（3ml）に溶解し、ト
リフルオロ酢酸（3 ml）を加え、4時間攪拌した。反応
液を減圧留去後、得られた残査を逆相クロマトグラフィ
ー（コスモシル、水）に付して、凍結乾燥後、標記4'−
アセトキシ化合物（７％の3'−アセトキシ化合物を包含
する）を無色アモルファスとして得た。（94 mg、81
％） IR (KBr) νmax： 3342, 3197, 2970, 2938, 2878, 172
2, 1668, 1549 cm-1. MS (FAB) m/e 401 ([M+H]+). HRMS (FAB) Calcd for C16H25O8N4 : 401.1672; found
401.1668 ([M+H]+).1 H NMR (400 MHz, CD3OD) δppm： 5.84 (1H, d, J =
2.0 Hz), 5.28-5.31 (1H, m), 4.44-4.51 (2H, m), 4.1
9 (1H, dd, J = 8.8, 8.8 Hz), 4.02 (1H, dd,J = 9.8,
2.9 Hz), 3.77 (1H, ddd, J = 11.7, 10.7, 4.9 Hz),
3.72 (1H, dd,J = 9.8, 1.0 Hz), 3.57 (1H, ddd, J =
11.7, 10.7, 1.0 Hz), 2.10 (3H, s),2.00 (3H, s), 1.
89-1.99 (1H, m), 1.79-1.86 (1H, m). （実施例２６） （4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチルアミノ−
5，6―ジヒドロ−4−グアニジノ−6−（3'−ヒドロキシ
−4'−n−プロピオニルオキシ−テトラヒドロ−ピラン
−2'−イル）−4H−ピラン−2−カルボン酸 三水和物(I) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5
-Acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) guanidino-6- (4'-acetoxy-3 '
-Hydroxy-tetrahydro-pyran-2'-yl)-
Diphenylmethyl 5,6-dihydro-4H-pyran-2-carboxylate [4'-acyloxy compound] and (4S, 5R,
6R, 2'S, 3'R, 4'R) -5-acetylamino-4- (N, N '
-Bis-t-butyloxycarbonyl) guanidino-6-
(3'-acetoxy-4'-hydroxy-tetrahydro-pyran-2'-yl) -5,6-dihydro-4H-pyran-2-
Diphenylmethyl carboxylate [3'-acyloxy compound] Compound (4S, 5R, 6R, 2'R, 3 ') obtained in Example 12 (i)
R, 4'R) -5-acetylamino-4- (N, N'-bis-t-
(Butyloxycarbonyl) guanidino-5,6-dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4H-pyran-2-carboxylate diphenylmethyl (280 mg, 0.382 mmol) To methanol (10 ml)
And dibutyltin oxide (100 mg, 0.
401 mmol) and stirred at 70 ° C. for 20 minutes. The reaction solution was distilled off under reduced pressure and azeotroped with toluene. The obtained residue was dried with a vacuum pump for 1 hour, dissolved in toluene, and acetyl bromide (30 μl, 0.401 mmo
l), triethylamine (6 μl, 0.040 mmol) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Methanol was added, the reaction solution was evaporated under reduced pressure, and the resulting residue was subjected to chromatography (silica gel, ethyl acetate) to give the title compounds as colorless amorphous materials. (4′-acyloxy compound: 180 mg, 61%) (3′-acyloxy compound: 36 m
g, 12%) (4′-acyloxy compound) IR (CDCl 3 ) νmax: 2960, 2928, 2855, 1729, 1684, 1
637, 1604, 1568 cm -1 . MS (FAB) m / e 767 ([M + H] + ) .HRMS (FAB) Calcd for C 39 H 51 O 12 N 4 : 767.3503; found
767.3527 ([M + H] + ). 1 H NMR (400 MHz, CDCl 3 ) δppm: 8.59 (1H, d, J =
8.8 Hz), 7.26-7.38 (10H, m), 6.92 (1H, s), 6.43 (1
H, d, J = 6.6 Hz), 5.93 (1H, d, J = 2.9 Hz), 5.31-
5.34 (1H, m), 5.14-5.20 (1H, m), 4.28-4.36 (2H,
m), 4.06-4.12 (1H, m), 3.81-3.87 (1H, m), 3.58-3.6
6 (2H, m), 2.17 (1H, br), 2.13 (3H, s), 1.98 (3H,
s), 1.89-1.96 (1H, m), 1.80-1.87 (1H, m), 1.49 (9
[Α] D 20 -12.8 ° (c 0.75, CHCl 3 ). (3′-acyloxy compound) 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 8.60 (1H , d, J = 9.
5 Hz), 7.25-7.42 (10H, m), 6.92 (1H, s), 5.89 (1H,
d, J = 2.2 Hz), 5.23 (1H, dd, J = 9.8, 2.6 Hz),
5.17 (1H, dd, J = 9.5, 8.8, 2.2 Hz), 4.48-4.53 (1
H, m), 4.34 (1H, ddd, J = 9.5, 8.8, 8.8 Hz), 4.20
(1H, d, J = 9.5 Hz), 3.95-4.00 (1H, m), 3.75-3.86
(2H, m), 2.05 (3H, s), 1.99 (3H, s), 1.93-2.00 (1
H, m), 1.76-1.82 (1H, m), 1.49 (18H, s). (Ii) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5-acetylamino-6- ( 4'-acetoxy-3'-hydroxy-tetrahydro-pyran-2'-yl) -5,6-dihydro-4-guanidino-4H-pyran-2-carboxylic acid trifluoroacetate dihydrate Example 25 ( The 4'-acyloxy compound (173) obtained in i)
mg, 0.225 mmol) was dissolved in methylene chloride (3 ml), trifluoroacetic acid (3 ml) was added, and the mixture was stirred for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to reverse phase chromatography (Cosmosil, water), lyophilized, and dried under the title 4'-
The acetoxy compound (including 7% of the 3'-acetoxy compound) was obtained as a colorless amorphous. (94 mg, 81
%) IR (KBr) νmax: 3342, 3197, 2970, 2938, 2878, 172
.. 2, 1668, 1549 cm -1 MS (FAB) m / e 401 ([M + H] +) HRMS (FAB) Calcd for C 16 H 25 O 8 N 4: 401.1672; found
401.1668 ([M + H] + ). 1 H NMR (400 MHz, CD 3 OD) δppm: 5.84 (1H, d, J =
2.0 Hz), 5.28-5.31 (1H, m), 4.44-4.51 (2H, m), 4.1
9 (1H, dd, J = 8.8, 8.8 Hz), 4.02 (1H, dd, J = 9.8,
2.9 Hz), 3.77 (1H, ddd, J = 11.7, 10.7, 4.9 Hz),
3.72 (1H, dd, J = 9.8, 1.0 Hz), 3.57 (1H, ddd, J =
11.7, 10.7, 1.0 Hz), 2.10 (3H, s), 2.00 (3H, s), 1.
89-1.99 (1H, m), 1.79-1.86 (1H, m). (Example 26) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5-acetylamino-
5,6-dihydro-4-guanidino-6- (3'-hydroxy-4'-n-propionyloxy-tetrahydro-pyran-2'-yl) -4H-pyran-2-carboxylic acid trihydrate
【０３３２】[0332]
【化３８】 Embedded image
【０３３３】（i）（4S, 5R, 6R, 2'R, 3'S, 4'R）−5
−アセチルアミノ−4−（N，N'−ビス−t−ブチルオキ
シカルボニル）グアニジノ−6−（3'−ヒドロキシ−4'
−n−プロピオニルオキシ−テトラヒドロ−ピラン−2'
−イル）−5，6―ジヒドロ―4H―ピラン−2−カルボン
酸ジフェニルメチル ［4'−アシルオキシ化合物］及び
（4S, 5R, 6R, 2'S, 3'R, 4'R）−5−アセチルアミノ−
4−（N，N'−ビス−t−ブチルオキシカルボニル）グア
ニジノ−6−（4'−ヒドロキシ−3'−n−プロピオニルオ
キシ−テトラヒドロ−ピラン−2'−イル）―5，6―ジヒ
ドロ―4H―ピラン−2−カルボン酸ジフェニルメチル
［3'−アシルオキシ化合物］ 実施例１２(i)で得られた化合物（4S, 5R, 6R, 2'R, 3'
R, 4'R）−5−アセチルアミノ−4−（N，N'−ビス−t−
ブチルオキシカルボニル）グアニジノ−5，6−ジヒドロ
−6−（3'，4'−ジヒドロキシ−テトラヒドロ−ピラン
−2'−イル）−4H−ピラン−2−カルボン酸ジフェニル
メチル（280 mg, 0.382 mmol）をメタノール（10 ml）
に溶解し、室温にてジブチルチンオキシド（100 mg, 0.
401 mmol）を加え、70℃にて20分間攪拌した。反応液を
減圧留去し、トルエンで共沸した。得られた残査を真空
ポンプで一時間乾燥後、トルエンに溶解し、窒素雰囲気
下、氷冷下プロピオニルクロライド（35 μl, 0.401 mm
ol）、トリエチルアミン（6 μl, 0.040 mmol）を滴下
し、同温にて1時間攪拌した。メタノールを加え、反応
液を減圧留去後得られた残査をクロマトグラフィー（シ
リカゲル、酢酸エチル）に付して標記化合物をそれぞれ
無色アモルファスとして得た。（4'−アシルオキシ化合
物：160 mg、53％）（3'−アシルオキシ化合物：75 m
g、25％） （4'−アシルオキシ化合物） IR (CDCl3) νmax： 2982, 2929, 2855, 1728, 1686, 1
640, 1605, 1567 cm-1. MS (FAB) m/e 781 ([M+H]+). HRMS (FAB) Calcd for C40H53O12N4 : 781.3660; found
781.3669 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm： 8.59 (1H, d, J =
8.8 Hz), 7.26-7.38 (10H, m), 6.92 (1H, s), 6.44 (1
H, d, J = 6.6 Hz), 5.93 (1H, d, J = 2.9 Hz), 5.31-
5.34 (1H, m), 5.14-5.20 (1H, m), 4.28-4.36 (2H,
m), 4.07-4.12 (1H, m), 3.81-3.87 (1H, m), 3.58-3.6
6 (2H, m), 2.41 (2H, q, J = 7.3 Hz), 2.15 (1H, b
r), 1.97 (3H, s), 1.89-1.96 (1H, m), 1.80-1.87 (1
H, m), 1.49 (9H, s), 1.48 (9H, s), 1.17 (3H, t, J
= 7.3 Hz). [α]D 20 -14.7°(c 0.35, CHCl3). （3'−アシルオキシ化合物） IR (CDCl3) νmax： 2982, 2929, 2855, 1729, 1686, 1
641, 1605, 1571 cm-1. MS (FAB) m/e 781 ([M+H]+). HRMS (FAB) Calcd for C40H53O12N4 : 781.3660; found
781.3679 ([M+H]+).1 H NMR (400 MHz, CDCl3) δppm： 8.59 (1H, d, J =
9.5 Hz), 7.25-7.42 (10H, m), 6.92 (1H, s), 5.90 (1
H, d, J = 2.2 Hz), 5.24 (1H, dd, J = 9.8, 2.6 Hz),
5.17 (1H, dd, J = 9.5, 8.8, 2.2 Hz), 4.44-4.50 (1
H, m), 4.29 (1H, ddd, J = 9.5, 8.8, 8.8 Hz), 4.16
(1H, d, J = 9.5 Hz), 3.95-4.00 (1H, m), 3.75-3.84
(2H, m), 2.34 (2H, q, J = 7.3 Hz), 1.98 (3H, s),
1.93-2.00(1H, m), 1.76-1.83 (1H, m), 1.49 (18H,
s), 1.10 (3H, t, J = 7.3 Hz). （ii）（4S, 5R, 6R, 2'R, 3'S, 4'R）−5−アセチルア
ミノ−5，6―ジヒドロ−4−グアニジノ−6−（3'−ヒド
ロキシ−4'−n−プロピオニルオキシ−テトラヒドロ−
ピラン−2'−イル）−4H−ピラン−2−カルボン酸 三水
和物 実施例２６(i)で得られた4'−アシルオキシ化合物（163
mg, 0.209 mmol）を塩化メチレン（3ml）に溶解し、ト
リフルオロ酢酸（3 ml）を加え、4時間攪拌した。反応
液を減圧留去後、得られた残査を逆相クロマトグラフィ
ー（コスモシル、水/メタノール＝2/1）に付して、凍結
乾燥後、標記4'−n−プロピオニルオキシ化合物（１％
の3'−アセトキシ化合物を包含する）を無色アモルファ
スとして得た。（60 mg、61％） IR (KBr) νmax： 3342, 3197, 2970, 2938, 2878, 172
2, 1668, 1549 cm-1. MS (FAB) m/e 401 ([M+H]+). HRMS (FAB) Calcd for C16H25O8N4 : 401.1672; found
401.1668 ([M+H]+).1 H NMR (400 MHz, CD3OD) δppm： 5.53 (1H, d, J =
2.0 Hz), 5.28-5.31 (1H, m), 4.34-4.39 (2H, m), 4.1
9 (1H, dd, J = 8.8, 8.8 Hz), 4.07 (1H, dd,J = 9.8,
2.9 Hz), 3.75 (1H, ddd, J = 11.7, 10.7, 4.9 Hz),
3.72 (1H, dd,J = 9.8, 1.0 Hz), 3.52 (1H, ddd, J =
11.7, 10.7, 1.0 Hz), 2.42 (2H, t, J= 7.3 Hz), 1.99
(3H, s), 1.90-1.99 (1H, m), 1.76-1.82 (1H, m), 1.
14 (3H, t, J = 7.3 Hz). Anal. Calcd for C17H26N4O8.3H2O : C, 43.59; H, 6.8
9; N, 11.96; F, 0.00. found C, 44.68; H, 7.19; N,
12.09; F, 0.00. （実施例２７） （４Ｓ，５Ｒ，６Ｒ，２’Ｓ，３’Ｓ，４’Ｒ）−５−
アセチルアミノ−４−アミノ―５，６―ジヒドロ―６−
（３’，４’−Ｏ−ジアセチル−３’，４’−ジオキシ
−テトラヒドロ−ピラン−２’−イル）―４Ｈ―ピラン
−２−カルボン酸メチル(I) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5
-Acetylamino-4- (N, N'-bis-t-butyloxycarbonyl) guanidino-6- (3'-hydroxy-4 '
-N-propionyloxy-tetrahydro-pyran-2 '
-Yl) -5,6-dihydro-4H-pyran-2-carboxylate diphenylmethyl [4'-acyloxy compound] and (4S, 5R, 6R, 2'S, 3'R, 4'R) -5-acetylamino −
4- (N, N'-bis-t-butyloxycarbonyl) guanidino-6- (4'-hydroxy-3'-n-propionyloxy-tetrahydro-pyran-2'-yl) -5,6-dihydro- 4H-Pyran-2-carboxylate diphenylmethyl
[3′-Acyloxy compound] The compound (4S, 5R, 6R, 2′R, 3 ′) obtained in Example 12 (i)
R, 4'R) -5-acetylamino-4- (N, N'-bis-t-
(Butyloxycarbonyl) guanidino-5,6-dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4H-pyran-2-carboxylate diphenylmethyl (280 mg, 0.382 mmol) To methanol (10 ml)
And dibutyltin oxide (100 mg, 0.
401 mmol) and stirred at 70 ° C. for 20 minutes. The reaction solution was distilled off under reduced pressure and azeotroped with toluene. The obtained residue was dried with a vacuum pump for 1 hour, dissolved in toluene, and cooled under ice-cooling under a nitrogen atmosphere with propionyl chloride (35 μl, 0.401 mm
ol) and triethylamine (6 μl, 0.040 mmol) were added dropwise, and the mixture was stirred at the same temperature for 1 hour. Methanol was added, the reaction solution was evaporated under reduced pressure, and the resulting residue was subjected to chromatography (silica gel, ethyl acetate) to give the title compounds as colorless amorphous materials. (4′-acyloxy compound: 160 mg, 53%) (3′-acyloxy compound: 75 m
g, 25%) (4′-acyloxy compound) IR (CDCl 3 ) νmax: 2982, 2929, 2855, 1728, 1686, 1
640, 1605, 1567 cm -1 . MS (FAB) m / e 781 ([M + H] + ) .HRMS (FAB) Calcd for C 40 H 53 O 12 N 4 : 781.3660; found
781.3669 ([M + H] + ). 1 H NMR (400 MHz, CDCl 3 ) δppm: 8.59 (1H, d, J =
8.8 Hz), 7.26-7.38 (10H, m), 6.92 (1H, s), 6.44 (1
H, d, J = 6.6 Hz), 5.93 (1H, d, J = 2.9 Hz), 5.31-
5.34 (1H, m), 5.14-5.20 (1H, m), 4.28-4.36 (2H,
m), 4.07-4.12 (1H, m), 3.81-3.87 (1H, m), 3.58-3.6
6 (2H, m), 2.41 (2H, q, J = 7.3 Hz), 2.15 (1H, b
r), 1.97 (3H, s), 1.89-1.96 (1H, m), 1.80-1.87 (1
H, m), 1.49 (9H, s), 1.48 (9H, s), 1.17 (3H, t, J
[Α] D 20 -14.7 ° (c 0.35, CHCl 3 ). (3′-acyloxy compound) IR (CDCl 3 ) νmax: 2982, 2929, 2855, 1729, 1686, 1
641, 1605, 1571 cm -1 . MS (FAB) m / e 781 ([M + H] + ) .HRMS (FAB) Calcd for C 40 H 53 O 12 N 4 : 781.3660; found
781.3679 ([M + H] + ). 1 H NMR (400 MHz, CDCl 3 ) δppm: 8.59 (1H, d, J =
9.5 Hz), 7.25-7.42 (10H, m), 6.92 (1H, s), 5.90 (1
H, d, J = 2.2 Hz), 5.24 (1H, dd, J = 9.8, 2.6 Hz),
5.17 (1H, dd, J = 9.5, 8.8, 2.2 Hz), 4.44-4.50 (1
H, m), 4.29 (1H, ddd, J = 9.5, 8.8, 8.8 Hz), 4.16
(1H, d, J = 9.5 Hz), 3.95-4.00 (1H, m), 3.75-3.84
(2H, m), 2.34 (2H, q, J = 7.3 Hz), 1.98 (3H, s),
1.93-2.00 (1H, m), 1.76-1.83 (1H, m), 1.49 (18H,
s), 1.10 (3H, t, J = 7.3 Hz). (ii) (4S, 5R, 6R, 2'R, 3'S, 4'R) -5-acetylamino-5,6-dihydro-4-guanidino -6- (3'-hydroxy-4'-n-propionyloxy-tetrahydro-
Pyran-2'-yl) -4H-pyran-2-carboxylic acid trihydrate 4'-acyloxy compound (163) obtained in Example 26 (i)
mg, 0.209 mmol) in methylene chloride (3 ml), trifluoroacetic acid (3 ml) was added, and the mixture was stirred for 4 hours. After evaporating the reaction solution under reduced pressure, the obtained residue was subjected to reverse phase chromatography (Cosmosil, water / methanol = 2/1), lyophilized, and then charged with the title 4′-n-propionyloxy compound (1%
3′-acetoxy compound) was obtained as a colorless amorphous. (60 mg, 61%) IR (KBr) νmax: 3342, 3197, 2970, 2938, 2878, 172
.. 2, 1668, 1549 cm -1 MS (FAB) m / e 401 ([M + H] +) HRMS (FAB) Calcd for C 16 H 25 O 8 N 4: 401.1672; found
401.1668 ([M + H] + ). 1 H NMR (400 MHz, CD 3 OD) δppm: 5.53 (1H, d, J =
2.0 Hz), 5.28-5.31 (1H, m), 4.34-4.39 (2H, m), 4.1
9 (1H, dd, J = 8.8, 8.8 Hz), 4.07 (1H, dd, J = 9.8,
2.9 Hz), 3.75 (1H, ddd, J = 11.7, 10.7, 4.9 Hz),
3.72 (1H, dd, J = 9.8, 1.0 Hz), 3.52 (1H, ddd, J =
11.7, 10.7, 1.0 Hz), 2.42 (2H, t, J = 7.3 Hz), 1.99
(3H, s), 1.90-1.99 (1H, m), 1.76-1.82 (1H, m), 1.
14 (3H, t, J = 7.3 Hz) Anal Calcd for C 17 H 26 N 4 O 8 .3H 2 O:.. C, 43.59; H, 6.8
9; N, 11.96; F, 0.00. Found C, 44.68; H, 7.19; N,
12.09; F, 0.00. (Example 27) (4S, 5R, 6R, 2'S, 3'S, 4'R) -5-
Acetylamino-4-amino-5,6-dihydro-6
Methyl (3 ′, 4′-O-diacetyl-3 ′, 4′-dioxy-tetrahydro-pyran-2′-yl) -4H-pyran-2-carboxylate
【０３３４】[0334]
【化３９】 Embedded image
【０３３５】実施例４(xi)で得られた（４Ｓ，５Ｒ，６
Ｒ，２’Ｓ，３’Ｓ，４’Ｒ）−５−アセチルアミノ−
４−アジド―５，６―ジヒドロ―６−（３’，４’−Ｏ
−ジアセチル−３’，４’−ジオキシ−テトラヒドロ−
ピラン−２’−イル）―４Ｈ―ピラン−２−カルボン酸
メチル（９．０ｇ、２０．４ｍｍｏｌ）を、エタノール
（３００ｍＬ）に溶解し、窒素雰囲気下、リンドラー触
媒（２．４ｇ）を加え、続いて水素雰囲気に置換し、室
温で３時間攪拌した。反応液を濾過し、濾物をエタノー
ル（２００ｍＬ）で洗浄し、濾液と洗液を合わせて減圧
下、溶剤を留去して、粗製の標記目的化合物を得た。得
られた粗製の標記目的化合物をシリカゲルカラムクロマ
トグラフィ−（塩化メチレン：メタノール、１０：１、
ｖ/ｖ）を用いて精製し、標記目的化合物（７．３ｇ、
収率８６％）を白色アモルファスとして得た。 [α]D 22 -4.7° (c 1.30, CH3OH); IR (CDCl3) νmax 3452, 3428, 2956, 2929, 2876, 285
5, 2256, 1741, 1679, 1601, 1512, 1463, 1439, 1373
cm-1;1 H NMR (400 MHz, CD3OD) δ 1.79-1.84 (1H, m), 2.00
(3H, s), 2.02-2.11 (1H, m), 2.09 (3H, s), 2.11 (3
H, s), 3.66-3.76 (2H, m), 3.77 (3H, s), 3.84(1H, d
d, J = 8.5, 2.0 Hz), 3.87-3.92 (2H, m), 4.35 (1H,
dd, J = 9.5, 1.0 Hz), 5.17 (1H, dd, J = 10.5, 2.5
Hz), 5.57-5.61 (1H, m), 5.67-5.72 (1H, m), 5.95 (1
H, d, J = 2.9 Hz); MS (FAB) m/e 415 ([M+H]+); HRMS (FAB) Calcd for C18H26O9N2K : 453.1276; found
453.1255 ([M+K]+). （実施例２８) （４Ｓ，５Ｒ，６Ｒ，２’Ｓ，３’Ｓ，４’Ｒ）−５−
アセチルアミノ−４−アミノ―５，６―ジヒドロ―６−
（３’，４’−Ｏ−ジアセチル−３’，４’−ジオキシ
−テトラヒドロ−フラン−２’−イル）―４Ｈ―ピラン
−２−カルボン酸メチル(4S, 5R, 6) obtained in Example 4 (xi)
R, 2'S, 3'S, 4'R) -5-acetylamino-
4-azido-5,6-dihydro-6- (3 ', 4'-O
-Diacetyl-3 ', 4'-dioxy-tetrahydro-
Methyl pyran-2′-yl) -4H-pyran-2-carboxylate (9.0 g, 20.4 mmol) was dissolved in ethanol (300 mL), and under a nitrogen atmosphere, a Lindlar catalyst (2.4 g) was added. Subsequently, the atmosphere was replaced with a hydrogen atmosphere, and the mixture was stirred at room temperature for 3 hours. The reaction solution was filtered, and the residue was washed with ethanol (200 mL). The filtrate and the washing solution were combined, and the solvent was distilled off under reduced pressure to obtain a crude title compound. The obtained crude title compound was purified by silica gel column chromatography (methylene chloride: methanol, 10: 1,
v / v) to give the title compound (7.3 g,
(86% yield) as a white amorphous. [α] D 22 -4.7 ° (c 1.30, CH 3 OH); IR (CDCl 3 ) ν max 3452, 3428, 2956, 2929, 2876, 285
5, 2256, 1741, 1679, 1601, 1512, 1463, 1439, 1373
cm -1 ; 1 H NMR (400 MHz, CD 3 OD) δ 1.79-1.84 (1H, m), 2.00
(3H, s), 2.02-2.11 (1H, m), 2.09 (3H, s), 2.11 (3
H, s), 3.66-3.76 (2H, m), 3.77 (3H, s), 3.84 (1H, d
d, J = 8.5, 2.0 Hz), 3.87-3.92 (2H, m), 4.35 (1H,
dd, J = 9.5, 1.0 Hz), 5.17 (1H, dd, J = 10.5, 2.5
Hz), 5.57-5.61 (1H, m), 5.67-5.72 (1H, m), 5.95 (1
H, d, J = 2.9 Hz); MS (FAB) m / e 415 ([M + H] + ); HRMS (FAB) Calcd for C 18 H 26 O 9 N 2 K: 453.1276; found
453.1255 ([M + K] + ). (Example 28) (4S, 5R, 6R, 2 ′S, 3 ′S, 4′R) −5
Acetylamino-4-amino-5,6-dihydro-6
Methyl (3 ', 4'-O-diacetyl-3', 4'-dioxy-tetrahydro-furan-2'-yl) -4H-pyran-2-carboxylate
【０３３６】[0336]
【化４０】 Embedded image
【０３３７】実施例１(vii)で得られた（４Ｓ，５Ｒ，
６Ｒ，２’Ｓ，３’Ｓ，４’Ｒ）−５−アセチルアミノ
−４−アジド―５，６―ジヒドロ―６−（３’，４’−
Ｏ−ジアセチル−３’，４’−ジオキシ−テトラヒドロ
−フラン−２’−イル）―４Ｈ―ピラン−２−カルボン
酸メチル（５１０ｍｇ、１．１９ｍｍｏｌ）を、エタノ
ール（５０ｍＬ）に溶解し、窒素雰囲気下、リンドラー
触媒（１７０ｍｇ）を加え、続いて水素雰囲気に置換
し、室温で３時間攪拌した。反応液を濾過し、濾物をエ
タノール（５０ｍＬ）で洗浄し、濾液と洗液を合わせて
減圧下、溶剤を留去して、粗製の標記目的化合物を得
た。得られた粗製の標記目的化合物をシリカゲルカラム
クロマトグラフィ−（塩化メチレン：メタノール、１
０：１、ｖ/ｖ）を用いて精製し、標記目的化合物（４
１０ｇ、収率８５％）を白色アモルファスとして得た。 [α]D 22 -14.1° (c 0.80, CH3OH); IR (CDCl3) νmax 2956, 2927, 2855, 1742, 1682, 154
0, 1508, 1457, 1439, 1371 cm-1;1 H NMR (400 MHz, CDCl3) δ 2.06 (3H, s), 2.08 (3H,
s), 2.09 (3H, s), 3.79 (3H, s), 3.8-3.90 (3H, m),
4.19-4.23 (2H, m), 4.38-4.42 (2H, m), 5.48-5.56
(2H, m), 5.97 (1H, d, J = 1.8 Hz); MS (FAB) m/e 401 ([M+H]+); HRMS (FAB) Calcd for C17H25O9N2 : 401.1560; found
401.1566 ([M+H]+). （実施例２９） （４Ｓ，５Ｒ，６Ｒ，２’Ｓ，３’Ｓ，４’Ｒ）−５−
アセチルアミノ−４−アミノ―５，６―ジヒドロ―６−
（３’，４’−Ｏ−ジアセチル−３’，４’−ジオキシ
−テトラヒドロ−オキセパン−２’−イル）―４Ｈ―ピ
ラン−２−カルボン酸メチル(4S, 5R, 4R) obtained in Example 1 (vii)
6R, 2'S, 3'S, 4'R) -5-acetylamino-4-azido-5,6-dihydro-6- (3 ', 4'-
Methyl O-diacetyl-3 ′, 4′-dioxy-tetrahydro-furan-2′-yl) -4H-pyran-2-carboxylate (510 mg, 1.19 mmol) is dissolved in ethanol (50 mL), and nitrogen atmosphere is added. Under the mixture, a Lindlar catalyst (170 mg) was added, followed by replacing the atmosphere with a hydrogen atmosphere and stirring at room temperature for 3 hours. The reaction solution was filtered, and the residue was washed with ethanol (50 mL). The filtrate and the washing solution were combined, and the solvent was distilled off under reduced pressure to obtain a crude title compound. The obtained crude title compound is purified by silica gel column chromatography (methylene chloride: methanol, 1
0: 1, v / v) to give the title compound (4
(10 g, yield: 85%) as a white amorphous. [α] D 22 -14.1 ° (c 0.80, CH 3 OH); IR (CDCl 3 ) ν max 2956, 2927, 2855, 1742, 1682, 154
0, 1508, 1457, 1439, 1371 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 2.06 (3H, s), 2.08 (3H,
s), 2.09 (3H, s), 3.79 (3H, s), 3.8-3.90 (3H, m),
4.19-4.23 (2H, m), 4.38-4.42 (2H, m), 5.48-5.56
(2H, m), 5.97 (1H, d, J = 1.8 Hz); MS (FAB) m / e 401 ([M + H] + ); HRMS (FAB) Calcd for C 17 H 25 O 9 N 2 : 401.1560; found
401.1566 ([M + H] + ). Example 29 (4S, 5R, 6R, 2 ′S, 3 ′S, 4′R) −5
Acetylamino-4-amino-5,6-dihydro-6
Methyl (3 ', 4'-O-diacetyl-3', 4'-dioxy-tetrahydro-oxepan-2'-yl) -4H-pyran-2-carboxylate
【０３３８】[0338]
【化４１】 Embedded image
【０３３９】実施例５(vii)で得られた（４Ｓ，５Ｒ，
６Ｒ，２’Ｓ，３’Ｓ，４’Ｒ）−５−アセチルアミノ
−４−アジド―５，６―ジヒドロ―６−（３’，４’−
Ｏ−ジアセチル−３’，４’−ジオキシ−テトラヒドロ
− オキセパン−２’−イル）―４Ｈ―ピラン−２−カ
ルボン酸メチル（１３０ｍｇ、０．２８６ｍｍｏｌ）
を、エタノール（３０ｍＬ）に溶解し、窒素雰囲気下、
リンドラー触媒（４０ｍｇ）を加え、続いて水素雰囲気
に置換し、室温で３時間攪拌した。反応液を濾過し、濾
物をエタノール（３０ｍＬ）で洗浄し、濾液と洗液を合
わせて減圧下、溶剤を留去して、粗製の標記目的化合物
を得た。得られた粗製の標記目的化合物をシリカゲルカ
ラムクロマトグラフィ−（塩化メチレン：メタノール、
１０：１、ｖ/ｖ）を用いて精製し、標記目的化合物
（１００ｍｇ、収率８１％）を白色アモルファスとして
得た。 [α]D 22 +27.9° (c 0.60, CH3OH); IR (CDCl3) νmax 2954, 2928, 2876, 2855, 2253, 173
6, 1682, 1511, 1464, 1454, 1438, 1370 cm-1;1 H NMR (400 MHz, CD3OD) δ 1.70-1.90 (3H, m), 2.05
(3H, s), 2.07-2.11 (1H, m), 2.07 (3H, s), 2.09 (3
H, s), 3.45 (1H, ddd, J = 12.3, 8.8, 3.8 Hz), 3.61
(1H, dd, J = 8.8, 1.8 Hz), 3.67 (1H, dd, J = 5.6,
1.8 Hz), 3.76 (3H, s), 4.05-4.10 (1H, m), 4.23 (1
H, dd, J = 10.8, 1.8 Hz), 5.36 (1H, dd, J = 5.6,
2.3 Hz), 5.42-5.47 (1H, m), 5.53-5.57 (1H, m), 5.9
3 (1H, d, J= 2.5 Hz); MS (FAB) m/e 429 ([M+H]+); HRMS (FAB) Calcd for C19H28O9N2K : 467.1432; found
467.1407 ([M+K]+). （試験例１）経口投与による抗インフルエンザ効果−１ ５−６週令のＢａｌｂ／Ｃマウス（メス）に生理食塩水
に溶解した本発明の化合物の溶液２００μＬを投与量が
１３．３μｍｏｌ／ｋｇ（５．０ｍｇ／ｋｇ）となるよ
う経口投与した。その投与から４時間後にクロロホルム
／エーテル（１：１）で充満した麻酔瓶の中でマウスに
麻酔をかけ、そのマウスにインフルエンザウイルスＡ／
ＰＲ／８／３４株（１５００ plaque formation unit
s）を感染させた。感染後、４時間、１７時間、２７時
間、４０時間、５１時間、６４．５時間、７５時間、８
８時間、９９時間後に本発明の化合物の溶液２００μＬ
を投与量が１３．３μｍｏｌ／ｋｇ（５．０ｍｇ／ｋ
ｇ）となるよう経口投与した。感染後２０日までマウス
の生死を観察した。(4S, 5R,
6R, 2'S, 3'S, 4'R) -5-acetylamino-4-azido-5,6-dihydro-6- (3 ', 4'-
O-Diacetyl-3 ', 4'-dioxy-tetrahydro-oxepan-2'-yl) -4H-pyran-2-carboxylate methyl (130 mg, 0.286 mmol)
Is dissolved in ethanol (30 mL), and under a nitrogen atmosphere,
A Lindlar catalyst (40 mg) was added, the atmosphere was replaced with a hydrogen atmosphere, and the mixture was stirred at room temperature for 3 hours. The reaction solution was filtered, and the residue was washed with ethanol (30 mL). The filtrate and the washing solution were combined, and the solvent was distilled off under reduced pressure to obtain a crude title compound. The obtained crude title compound was purified by silica gel column chromatography (methylene chloride: methanol,
(10: 1, v / v) to give the title compound (100 mg, yield 81%) as a white amorphous. [α] D 22 + 27.9 ° (c 0.60, CH 3 OH); IR (CDCl 3 ) ν max 2954, 2928, 2876, 2855, 2253, 173
6, 1682, 1511, 1464, 1454, 1438, 1370 cm -1 ; 1 H NMR (400 MHz, CD 3 OD) δ 1.70-1.90 (3H, m), 2.05
(3H, s), 2.07-2.11 (1H, m), 2.07 (3H, s), 2.09 (3
H, s), 3.45 (1H, ddd, J = 12.3, 8.8, 3.8 Hz), 3.61
(1H, dd, J = 8.8, 1.8 Hz), 3.67 (1H, dd, J = 5.6,
1.8 Hz), 3.76 (3H, s), 4.05-4.10 (1H, m), 4.23 (1
H, dd, J = 10.8, 1.8 Hz), 5.36 (1H, dd, J = 5.6,
2.3 Hz), 5.42-5.47 (1H, m), 5.53-5.57 (1H, m), 5.9
3 (1H, d, J = 2.5 Hz); MS (FAB) m / e 429 ([M + H] + ); HRMS (FAB) Calcd for C 19 H 28 O 9 N 2 K: 467.1432; found
467.1407 ([M + K] + ). (Test Example 1) Anti-Influenza Effect by Oral Administration-1 200 μL of a solution of the compound of the present invention dissolved in physiological saline in Balb / C mice (females) of 5 to 6 weeks old Was orally administered to give a dose of 13.3 μmol / kg (5.0 mg / kg). Four hours after the administration, the mice were anesthetized in an anesthesia bottle filled with chloroform / ether (1: 1), and the mice were given an influenza virus A /
PR / 8/34 shares (1500 plaque formation unit
s) infected. 4 hours, 17 hours, 27 hours, 40 hours, 51 hours, 64.5 hours, 75 hours, 8 hours after infection
After 8 hours and 99 hours, 200 μL of a solution of the compound of the present invention
At a dose of 13.3 μmol / kg (5.0 mg / k
g) orally. The mice were observed for life or death until 20 days after infection.
【０３４０】その結果、非投与マウスが感染後７日まで
に全数が死亡するのに対し、本発明の実施例４の化合物
を経口投与したマウスは感染後２０日の時点でも６２．
５％のマウスが生存していた。 （試験例２）経口投与による抗インフルエンザ効果−２ ５−６週令のＢａｌｂ／Ｃマウス（メス）に生理食塩水
に溶解した本発明のエステル誘導体の溶液２００μＬを
投与量が１４μｍｏｌ／ｋｇとなるよう経口投与した。
その投与から４時間後にクロロホルム／エーテル（１：
１）で充満した麻酔瓶の中でマウスに麻酔をかけ、その
マウスにインフルエンザウイルスＡ／ＰＲ／８／３４株
（１５００ plaque formation units）を感染させた。
感染後、4時間、1６時間、28時間、41時間、54時間、66
時間、74時間、91時間、101時間後に本発明のエステル
誘導体の溶液２００μＬを投与量が１４μｍｏｌ／ｋｇ
となるよう経口投与した。感染後２０日までマウスの生
死を観察した。As a result, all of the non-administered mice died by 7 days after the infection, whereas the mice to which the compound of Example 4 of the present invention was orally administered had the 62.degree.
5% of the mice were alive. (Test Example 2) Anti-Influenza Effect by Oral Administration-2 5 to 6-week-old Balb / C mice (females) were administered with 200 μL of a solution of the ester derivative of the present invention dissolved in physiological saline to give a dose of 14 μmol / kg. Oral administration was performed as follows.
Four hours after the administration, chloroform / ether (1:
Mice were anesthetized in an anesthesia bottle filled with 1), and the mice were infected with influenza virus A / PR / 8/34 strain (1500 plaque formation units).
4 hours, 16 hours, 28 hours, 41 hours, 54 hours, 66 hours after infection
After hours, 74 hours, 91 hours, and 101 hours, 200 μL of the solution of the ester derivative of the present invention was administered at a dose of 14 μmol / kg.
Oral administration was performed so that The mice were observed for life or death until 20 days after infection.
【０３４１】その結果、非投与マウスが感染後８日まで
に全数が死亡するのに対し、本発明の実施例２４及び２
５のエステル誘導体を経口投与したマウスは感染後２０
日の時点でもいずれも７０％のマウスが生存していた。 （試験例３）経鼻投与による抗インフルエンザ効果−１ ５−６週令のＢａｌｂ／Ｃマウス（メス）をクロロホル
ム／エーテル（１：１）で充満した麻酔瓶の中にいれ、
麻酔をかけた。麻酔マウスに生理食塩水に溶解した本発
明のエステル誘導体の溶液５０μＬを投与量が０．３μ
ｍｏｌ／ｋｇとなるよう鼻腔内に滴下投与した。その投
与から２４時間後に同様に麻酔したマウスにインフルエ
ンザウイルスＡ／ＰＲ／８／３４株（５００ plaque f
ormationunits）を感染させた。感染後２０日までマウ
スの生死を観察した。As a result, all of the non-administered mice died by 8 days after infection, whereas those of Examples 24 and 2 of the present invention
Mice to which the 5 ester derivative was orally administered were 20
At the time of day, 70% of the mice were still alive. (Test Example 3) Anti-influenza effect by nasal administration -15 5-6 week old Balb / C mouse (female) was placed in an anesthesia bottle filled with chloroform / ether (1: 1),
Anesthesia was applied. Anesthetized mice were given 50 μL of a solution of the ester derivative of the present invention dissolved in physiological saline at a dose of 0.3 μL.
The solution was administered dropwise to the nasal cavity so as to be mol / kg. Twenty-four hours after the administration, similarly anesthetized mice were inoculated with influenza virus A / PR / 8/34 strain (500 plaque f
ormationunits). The mice were observed for life or death until 20 days after infection.
【０３４２】その結果、非投与マウスが感染後９日まで
に全数が死亡するのに対し、本発明の実施例１１のエス
テル誘導体を経鼻投与したマウスは感染後２０日の時点
でも全数が生存していた。 （試験例４）経鼻投与による抗インフルエンザ効果−２ ５−６週令のＢａｌｂ／Ｃマウス（メス）をクロロホル
ム／エーテル（１：１）で充満した麻酔瓶の中にいれ、
麻酔をかけた。麻酔マウスに生理食塩水に溶解した本発
明のエステル誘導体の溶液５０μＬを投与量が１．０μ
ｍｏｌ／ｋｇとなるよう鼻腔内に滴下投与した。その投
与から７日後に同様に麻酔したマウスにインフルエンザ
ウイルスＡ／ＰＲ／８／３４株（５００ plaque forma
tion units）を感染させた。感染後２０日までマウスの
生死を観察した。As a result, all of the non-administered mice died by 9 days after the infection, whereas all of the mice to which the ester derivative of Example 11 of the present invention was intranasally administered survived 20 days after the infection. Was. (Test Example 4) Anti-influenza effect by nasal administration-2 5-6 week old Balb / C mouse (female) was placed in an anesthesia bottle filled with chloroform / ether (1: 1),
Anesthesia was applied. A dose of 1.0 μL of a solution of the ester derivative of the present invention dissolved in physiological saline was added to an anesthetized mouse.
The solution was administered dropwise to the nasal cavity so as to be mol / kg. Seven days after the administration, the mice anesthetized in the same manner were treated with influenza virus A / PR / 8/34 strain (500 plaque forma
action units) were infected. The mice were observed for life or death until 20 days after infection.
【０３４３】その結果、非投与マウスが感染後９日まで
に全数が死亡するのに対し、本発明の実施例１１のエス
テル誘導体を経鼻投与したマウスは感染後２０日の時点
でも全数が生存していた。 （製剤例１）液剤１ 実施例４の化合物が１０％（W/W）、塩化ベンザルコニ
ウムが０．０４％（W/W）、フェネチルアルコールが
０．４０％（W/W）、精製水が８９．５６％（W/W）とな
るように液剤を調整する。 （製剤例２）液剤２ 実施例４の化合物が１０％（W/W）、塩化ベンザルコニ
ウムが０．０４％（W/W）、ポリエチレングリコール４
００が１０％（W/W）、プロピレングリコールが３０％
（W/W）、精製水が３９．９６％（W/W）となるように液
剤を調整する。 （製剤例３）散剤 実施例４の化合物が４０％（W/W）、ラクトースが６０
％（W/W）となるように散剤を調整する。 （製剤例４）エアゾール剤 実施例４の化合物が１０％（W/W）、レシチンが０．５
％（W/W）、フロン１１が３４．５％（W/W）、フロン１
２が５５％（W/W）となるようにエアゾール剤を調整す
る。 （製剤例５）錠剤 下記処方の粉末を混合し、トウモロコシデンプン糊を用
いて湿式造粒、乾燥した後、打錠機により打錠して、一
錠490ｍｇの錠剤とする。As a result, all of the non-administered mice died by 9 days after the infection, whereas all of the mice to which the ester derivative of Example 11 of the present invention had been intranasally administered survived 20 days after the infection. Was. (Formulation Example 1) Solution 1 The compound of Example 4 is 10% (W / W), benzalkonium chloride is 0.04% (W / W), and phenethyl alcohol is 0.40% (W / W), purification Adjust the solution so that the water is 89.56% (W / W). (Formulation Example 2) Solution 2 10% (W / W) of the compound of Example 4, 0.04% (W / W) of benzalkonium chloride, polyethylene glycol 4
00 is 10% (W / W), propylene glycol is 30%
(W / W), the liquid preparation is adjusted so that the purified water becomes 39.96% (W / W). (Formulation Example 3) Powder 40% (W / W) of the compound of Example 4 and 60 of lactose
Adjust the powder so that it becomes% (W / W). (Formulation Example 4) Aerosol 10% (W / W) of the compound of Example 4 and 0.5 of lecithin
% (W / W), CFC 11 is 34.5% (W / W), CFC 1
The aerosol is adjusted so that 2 becomes 55% (W / W). (Formulation Example 5) Tablet Powder having the following formulation is mixed, wet-granulated using corn starch paste, dried, and then tableted with a tableting machine to give a tablet of 490 mg per tablet.
【０３４４】 尚、所望により、剤皮を塗布することができる。[0344] In addition, a coating can be applied as desired.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 荒井 雅巳 東京都品川区広町１丁目２番58号 三共株 式会社内 (72)発明者 山下 誠 東京都品川区広町１丁目２番58号 三共株 式会社内 Ｆターム(参考） 4C062 AA15 AA18 AA19 BB16 BB19 4C063 AA01 BB01 CC78 CC80 DD75 DD78 EE01 4C086 AA02 AA03 BA07 BA10 GA02 GA16 NA14 ZB33 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Masami Arai 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Makoto Yamashita 1-2-58 Hiromachi, Shinagawa-ku, Tokyo F term in Sankyo Co., Ltd. (reference) 4C062 AA15 AA18 AA19 BB16 BB19 4C063 AA01 BB01 CC78 CC80 DD75 DD78 EE01 4C086 AA02 AA03 BA07 BA10 GA02 GA16 NA14 ZB33
Claims (20)
酸基を示し、 Ｒ3及びＲ4は同一又は異なって水素原子又は炭素数１乃
至４個のアルキル基を示し、 Ｒ5及びＲ6は同一又は異なって水素原子、フッ素原子又
は炭素数１乃至４個のアルキル基を示し、 Ｒ7及びＲ8は同一又は異なって水素原子又は炭素数１乃
至４個のアルキル基を示し、 Ｒ9はフッ素原子で置換されていてもよい炭素数１乃至
４個のアルキル基であり、 Ｒ10は炭素数１乃至４個のアルキルで置換されていても
よいアミノ基又は式−ＮＲ11Ｃ（＝ＮＲ12）Ｒ13（式
中、Ｒ11及びＲ12は同一又は異なって水素原子又は炭素
数１乃至４個のアルキル基を示し、Ｒ13は水素原子、炭
素数１乃至４個のアルキル基又は炭素数１乃至４個のア
ルキル基で置換されていてもよいアミノ基を示す）で表
される基を示し、 ｎは１、２又は３を示し、 ｍは０、１又は２を示す。］で表される化合物、その薬
理上許容されるエステル誘導体又はそれらの薬理上許容
される塩。1. A compound of the general formula [Wherein, R 1 and R 2 represents a hydrogen atom or a hydroxyl group the same or different, R 3 and R 4 are the same or different and each represents a hydrogen atom or a C 1 to 4 alkyl group having a carbon, R 5 and R 6 is the same or different and represents a hydrogen atom, a fluorine atom or an alkyl group having 1 to 4 carbon atoms; R 7 and R 8 are the same or different and represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; 9 is an alkyl group having 1 to 4 carbon atoms which may be substituted by a fluorine atom; R 10 is an amino group which may be substituted by an alkyl having 1 to 4 carbon atoms or a compound represented by the formula -NR 11 C ( ＮＲNR 12 ) R 13 (wherein, R 11 and R 12 are the same or different and each represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R 13 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms) Or an amino group which may be substituted with an alkyl group having 1 to 4 carbon atoms. A group represented by a group), n represents 1, 2 or 3, m represents 0, 1 or 2. Or a pharmacologically acceptable ester derivative thereof or a pharmacologically acceptable salt thereof.
あって水素原子又は水酸基である化合物、その薬理上許
容されるエステル誘導体又はそれらの薬理上許容される
塩。2. The compound according to claim 1, wherein R 1 and R 2 are the same and are a hydrogen atom or a hydroxyl group, a pharmaceutically acceptable ester derivative thereof, or a pharmaceutically acceptable salt thereof.
あって水酸基である化合物、その薬理上許容されるエス
テル誘導体又はそれらの薬理上許容される塩。3. The compound according to claim 1, wherein R 1 and R 2 are the same and are a hydroxyl group, a pharmaceutically acceptable ester derivative thereof, or a pharmaceutically acceptable salt thereof.
において、Ｒ3及びＲ4が、同一又は異なって水素原子又
はメチル基である化合物、その薬理上許容されるエステ
ル誘導体又はそれらの薬理上許容される塩。4. The compound according to claim 1, wherein R 3 and R 4 are the same or different and are a hydrogen atom or a methyl group, a pharmaceutically acceptable ester derivative thereof, or a pharmaceutically acceptable ester derivative thereof. Pharmacologically acceptable salt.
において、Ｒ3及びＲ4が、同一であって水素原子である
化合物、その薬理上許容されるエステル誘導体又はそれ
らの薬理上許容される塩。5. The compound according to claim 1, wherein R 3 and R 4 are the same and are a hydrogen atom, a pharmaceutically acceptable ester derivative thereof, or a pharmaceutically acceptable ester derivative thereof. Salt.
において、Ｒ5及びＲ6が、ｎの繰り返し単位において独
立して、同一又は異なって水素原子又はフッ素原子であ
る化合物、その薬理上許容されるエステル誘導体又はそ
れらの薬理上許容される塩。6. The compound according to any one of claims 1 to 5, wherein R 5 and R 6 are independently the same or different and are hydrogen or fluorine in n repeating units, and their pharmacology. Or a pharmacologically acceptable salt thereof.
において、Ｒ5及びＲ6が、同一であって水素原子である
化合物、その薬理上許容されるエステル誘導体又はそれ
らの薬理上許容される塩。7. The compound according to claim 1, wherein R 5 and R 6 are the same and are a hydrogen atom, a pharmaceutically acceptable ester derivative thereof, or a pharmaceutically acceptable derivative thereof. Salt.
において、ｎが、１または２である化合物、その薬理上
許容されるエステル誘導体又はそれらの薬理上許容され
る塩。8. The compound according to any one of claims 1 to 7, wherein n is 1 or 2, a pharmacologically acceptable ester derivative thereof, or a pharmacologically acceptable salt thereof.
において、ｎが、２である化合物、その薬理上許容され
るエステル誘導体又はそれらの薬理上許容される塩。9. A compound according to any one of claims 1 to 7, wherein n is 2, a pharmacologically acceptable ester derivative thereof, or a pharmacologically acceptable salt thereof.
項において、ｍが、０または１である化合物、その薬理
上許容されるエステル誘導体又はそれらの薬理上許容さ
れる塩。10. The compound according to any one of claims 1 to 9, wherein m is 0 or 1, a pharmacologically acceptable ester derivative thereof, or a pharmacologically acceptable salt thereof.
項において、ｍが、０である化合物、その薬理上許容さ
れるエステル誘導体又はそれらの薬理上許容される塩。11. A compound according to any one of claims 1 to 9, wherein m is 0, a pharmacologically acceptable ester derivative thereof, or a pharmacologically acceptable salt thereof.
一項において、Ｒ7及びＲ8が、ｍの繰り返し単位におい
て独立して、同一又は異なって水素原子又はメチル基で
ある化合物、その薬理上許容されるエステル誘導体又は
それらの薬理上許容される塩。12. The compound according to any one of claims 1 to 11, wherein R 7 and R 8 are independently the same or different hydrogen atoms or methyl groups in the repeating unit of m; Or a pharmacologically acceptable salt thereof.
一項において、Ｒ7及びＲ8が、同一であって水素原子で
ある化合物、その薬理上許容されるエステル誘導体又は
それらの薬理上許容される塩。13. The compound according to any one of claims 1 to 11, wherein R 7 and R 8 are the same and are a hydrogen atom, a pharmaceutically acceptable ester derivative thereof, or a pharmaceutically acceptable ester derivative thereof. Salt.
一項において、Ｒ9が、フッ素原子で置換されていても
よいメチル基である化合物、その薬理上許容されるエス
テル誘導体又はそれらの薬理上許容される塩。14. The compound according to any one of claims 1 to 13, wherein R 9 is a methyl group optionally substituted with a fluorine atom, a pharmaceutically acceptable ester derivative thereof, or a pharmacologic compound thereof. Above acceptable salts.
一項において、Ｒ9が、メチル、ジフルオロメチルまた
はトリフルオロメチル基である化合物、その薬理上許容
されるエステル誘導体又はそれらの薬理上許容される
塩。15. The compound according to any one of claims 1 to 13, wherein R 9 is a methyl, difluoromethyl or trifluoromethyl group, a pharmaceutically acceptable ester derivative thereof or a pharmaceutically acceptable derivative thereof. Salt.
一項において、Ｒ9が、メチル基である化合物、その薬
理上許容されるエステル誘導体又はそれらの薬理上許容
される塩。16. The compound according to any one of claims 1 to 13, wherein R 9 is a methyl group, a pharmaceutically acceptable ester derivative thereof, or a pharmaceutically acceptable salt thereof.
一項において、Ｒ10が、アミノ、メチルアミノ、ジメチ
ルアミノ又は式−ＮＲ11aＣ（＝ＮＲ12a）Ｒ13a（式
中、Ｒ11a及びＲ12aは同一又は異なって水素原子又はメ
チル基を示し、Ｒ13aは水素原子、メチル、アミノ又は
メチルアミノ基を示す）で表される基である化合物、そ
の薬理上許容されるエステル誘導体又はそれらの薬理上
許容される塩。17. The method according to claim 1, wherein R 10 is amino, methylamino, dimethylamino or a compound of the formula —NR 11a C (＝ NR 12a ) R 13a , wherein R 11a and R 11a R 12a is the same or different and represents a hydrogen atom or a methyl group, and R 13a represents a hydrogen atom, methyl, amino or methylamino group), a pharmaceutically acceptable ester derivative thereof or Pharmacologically acceptable salts of
一項において、Ｒ10が、アミノ、メチルアミノ、ジメチ
ルアミノ、ホルムイミドイルアミノ、アセトイミドイル
アミノ又はグアニジノ基である化合物、その薬理上許容
されるエステル誘導体又はそれらの薬理上許容される
塩。18. The compound according to any one of claims 1 to 16, wherein R 10 is an amino, methylamino, dimethylamino, formimidoylamino, acetimidoylamino or guanidino group, or a pharmaceutically acceptable salt thereof. An acceptable ester derivative or a pharmacologically acceptable salt thereof.
一項において、Ｒ10が、グアニジノ基である化合物、そ
の薬理上許容されるエステル誘導体又はそれらの薬理上
許容される塩。19. The compound according to any one of claims 1 to 16, wherein R 10 is a guanidino group, a pharmacologically acceptable ester derivative thereof, or a pharmacologically acceptable salt thereof.
許容されるエステル誘導体又はそれらの薬理上許容され
る塩。 （4S, 5R, 6R, 2'R, 3'R, 4'R）−5―アセチルアミノ―
5，6―ジヒドロ―6―（3', 4'−ジヒドロキシ−テトラ
ヒドロ−フラン−2'−イル）―4―グアニジノ―4H―ピ
ラン−2―カルボン酸、（4S, 5R, 6R, 2'R, 3'R, 4'R）
−5―アセチルアミノ―5，6―ジヒドロ―6―（3', 4'−
ジヒドロキシ−テトラヒドロ−ピラン−2'−イル）―4
―グアニジノ―4H―ピラン−2―カルボン酸、（4S, 5R,
6R, 2'R, 3'R, 4'R）−5―アセチルアミノ―5，6―ジ
ヒドロ―6―（3', 4'−ジヒドロキシ−テトラヒドロ−
オキセパン−2'−イル）―4―グアニジノ―4H―ピラン
−2―カルボン酸、（4S, 5R, 6R, 2'R, 3'R, 4'R）−5
―アセチルアミノ―5，6―ジヒドロ―6―（3', 4'−ジ
ヒドロキシ−テトラヒドロ−ピラン−2'−イル）―4―
グアニジノ―4H―ピラン−2―カルボン酸ブチル、（4S,
5R, 6R, 2'R, 3'R, 4'R）−5―アセチルアミノ―5，6
―ジヒドロ―6―（3', 4'−ジヒドロキシ−テトラヒド
ロ−ピラン−2'−イル）―4―グアニジノ―4H―ピラン
−2―カルボン酸ペンチル、（4S, 5R, 6R, 2'R, 3'R,
4'R）−5―アセチルアミノ―5，6―ジヒドロ―6―（3',
4'−ジヒドロキシ−テトラヒドロ−ピラン−2'−イ
ル）―4―グアニジノ―4H―ピラン−2―カルボン酸ヘキ
シル、（4S, 5R, 6R, 2'R, 3'R, 4'R）−5―アセチルア
ミノ―5，6―ジヒドロ―6―（3', 4'−ジヒドロキシ−
テトラヒドロ−ピラン−2'−イル）―4―グアニジノ―4
H―ピラン−2―カルボン酸オクチル、（4S, 5R, 6R, 2'
R, 3'R, 4'R）−5―アセチルアミノ―5，6―ジヒドロ―
6―（3', 4'−ジヒドロキシ−テトラヒドロ−ピラン−
2'−イル）―4―グアニジノ―4H―ピラン−2―カルボン
酸デシル、（4S, 5R, 6R, 2'R, 3'R, 4'R）−5―アセチ
ルアミノ―5，6―ジヒドロ―6―（3', 4'−ジヒドロキ
シ−テトラヒドロ−ピラン−2'−イル）―4―グアニジ
ノ―4H―ピラン−2―カルボン酸ドデシル、（4S, 5R, 6
R, 2'R, 3'R, 4'R）−5―アセチルアミノ―5，6―ジヒ
ドロ―6―（3', 4'−ジヒドロキシ−テトラヒドロ−ピ
ラン−2'−イル）―4―グアニジノ―4H―ピラン−2―カ
ルボン酸テトラデシル、（4S, 5R, 6R, 2'R, 3'R, 4'
R）−5―アセチルアミノ―5，6―ジヒドロ―6―（3',
4'−ジヒドロキシ−テトラヒドロ−ピラン−2'−イル）
―4―グアニジノ―4H―ピラン−2―カルボン酸ヘキサデ
シル、（4S, 5R, 6R, 2'R, 3'R, 4'R）−5―アセチルア
ミノ―5，6―ジヒドロ―6―（3', 4'−ジヒドロキシ−
テトラヒドロ−ピラン−2'−イル）―4―グアニジノ―4
H―ピラン−2―カルボン酸オクタデシル、及び、（4S,
5R, 6R, 2'R, 3'R, 4'R）−5―アセチルアミノ―5，6―
ジヒドロ―6―（3', 4'−ジヒドロキシ−テトラヒドロ
−ピラン−2'−イル）―4―グアニジノ―4H―ピラン−2
―カルボン酸アイコサニル。20. A compound selected from the following group, a pharmacologically acceptable ester derivative thereof, or a pharmacologically acceptable salt thereof. (4S, 5R, 6R, 2'R, 3'R, 4'R) -5-acetylamino-
5,6-dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-furan-2'-yl) -4-guanidino-4H-pyran-2-carboxylic acid, (4S, 5R, 6R, 2'R , 3'R, 4'R)
-5-acetylamino-5,6-dihydro-6- (3 ', 4'-
Dihydroxy-tetrahydro-pyran-2'-yl) -4
-Guanidino-4H-pyran-2-carboxylic acid, (4S, 5R,
6R, 2'R, 3'R, 4'R) -5-acetylamino-5,6-dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-
Oxepan-2'-yl) -4-guanidino-4H-pyran-2-carboxylic acid, (4S, 5R, 6R, 2'R, 3'R, 4'R) -5
-Acetylamino-5,6-dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4-
Guanidino-4H-pyran-2-carboxylate, (4S,
5R, 6R, 2'R, 3'R, 4'R) -5-acetylamino-5,6
-Dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4-guanidino-4H-pyran-2-carboxylate pentyl, (4S, 5R, 6R, 2'R, 3 'R,
4'R) -5-acetylamino-5,6-dihydro-6- (3 ',
4'-dihydroxy-tetrahydro-pyran-2'-yl) -4-guanidino-4H-pyran-2-carboxylate hexyl, (4S, 5R, 6R, 2'R, 3'R, 4'R) -5 -Acetylamino-5,6-dihydro-6- (3 ', 4'-dihydroxy-
Tetrahydro-pyran-2'-yl) -4-guanidino-4
Octyl H-pyran-2-carboxylate, (4S, 5R, 6R, 2 '
R, 3'R, 4'R) -5-acetylamino-5,6-dihydro-
6- (3 ', 4'-dihydroxy-tetrahydro-pyran-
2'-yl) -4-guanidino-4H-pyran-2-carboxylate decyl, (4S, 5R, 6R, 2'R, 3'R, 4'R) -5-acetylamino-5,6-dihydro -6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4-guanidino-4H-pyran-2-carboxylate dodecyl, (4S, 5R, 6
R, 2'R, 3'R, 4'R) -5-acetylamino-5,6-dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4-guanidino -4H-pyran-2-tetracarboxylic acid tetradecyl, (4S, 5R, 6R, 2'R, 3'R, 4 '
R) -5-Acetylamino-5,6-dihydro-6- (3 ',
4'-dihydroxy-tetrahydro-pyran-2'-yl)
-4-Guanidino-4H-pyran-2-carboxylate hexadecyl, (4S, 5R, 6R, 2'R, 3'R, 4'R) -5-acetylamino-5,6-dihydro-6- (3 ', 4'-dihydroxy-
Tetrahydro-pyran-2'-yl) -4-guanidino-4
Octadecyl H-pyran-2-carboxylate and (4S,
5R, 6R, 2'R, 3'R, 4'R) -5-acetylamino-5,6-
Dihydro-6- (3 ', 4'-dihydroxy-tetrahydro-pyran-2'-yl) -4-guanidino-4H-pyran-2
-Eicosanyl carboxylate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2001147151A JP2002037780A (en) | 2000-05-19 | 2001-05-17 | Sialic acid derivative |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000-147155 | 2000-05-19 | ||
| JP2000147155 | 2000-05-19 | ||
| JP2001147151A JP2002037780A (en) | 2000-05-19 | 2001-05-17 | Sialic acid derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2002037780A true JP2002037780A (en) | 2002-02-06 |
Family
ID=26592171
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2001147151A Pending JP2002037780A (en) | 2000-05-19 | 2001-05-17 | Sialic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2002037780A (en) |
-
2001
- 2001-05-17 JP JP2001147151A patent/JP2002037780A/en active Pending
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