KR940008290B1 - Lankacidin derivatives and production thereof - Google Patents

Abstract

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Description

Method for preparing lancassidine derivatives

The present invention relates to a novel lancassidine derivative having a bactericidal action and a preparation method thereof.

Lancadine is produced by culturing a strain belonging to the genus Streptomyces and has the following general formula (iii) or (ii).

이고 R^b가 COCH₃인 일반식(ⅰ)의 화합물이고, 란카시디놀은 식중 R^a가

이고 R^b가 H인 일반식(ⅰ)의 화합물이며, 란카시클리놀은 식중 R^c가 H인 일반식(ⅱ)의 화합물이고, 란카시클리놀 A는 식중 R^c가 COCH₃인 일반식(ⅱ)의 화합물이다.Lancacidin A is a compound of formula wherein R ^a is 0 and R ^b is COCH ₃ , and Lancacidin C is a compound of formula wherein R ^a is 0 and R ^b is H. , Lancassinol A is R ^a

And R ^b is a COCH ₃ Compound (ⅰ), is that wherein R is ^a play kasidi

Is a compound of formula (VII) wherein R ^b is H, and lancasslinol is a compound of formula (ii) wherein R ^c is H, and lancasslinol A is a compound of formula R ^c is COCH ₃ (Ii).

Among the derivatives of lancassidine described above, for example, esters at positions 8- and / or 14 of lancassidine C [Acta Cryst., B27, p. 236 (1971); J. Antibiotics, 26, P. 647 (1973)], 3-amino modified derivatives (Antimicrobial Agents and Chemotherapy, 25, pp, 226-233 (1984)) and acyloxy derivatives at 8- and / or 14-positions The Journal of Antibiotics, 26, p. 647 (1973) is known.

As mentioned above, lancassidines have been prepared but the present invention relates to the preparation of novel derivatives of these lancassidines.

The present inventors have synthesized various derivatives from the above-described lancassidines and studied their pharmaceutical functions, and found that these derivatives have excellent pharmaceutical functions.

The present inventors earnestly examined and completed the present invention based on this finding.

The present invention relates to a compound represented by the following general formula [1] or a salt thereof, and a preparation method thereof;

(Z는 산소원자 또는 황원자를 나타내고, R⁵는 탄소원자를 통한 유기성잔기를 나타낸다)로 나타내질 수 있는 기를 나타내거나, 또는 (ⅱ) R¹및 R²가 함께 일반식 =

(식중 R⁶은 아실, 설포닐 또는 알콕시카르보닐을 나타내고, R⁷은 저급알킬을 나타낸다)로 나타내질 수 있는 기를 나타내고, R³및 R⁴는 각각 히드록실, 할로겐, 아지도 또는 산소원자, 황원자 또는 질소원자를 통한 유기성잔기를 나타낸다 ;[Wherein, (i) one of R ¹ and R ² represents a hydrogen atom, and the other is a general formula

(Z represents an oxygen atom or a sulfur atom, R ⁵ represents an organic residue through a carbon atom), or (ii) R ¹ and R ² together represent a general formula =

Wherein R ⁶ represents acyl, sulfonyl or alkoxycarbonyl and R ⁷ represents lower alkyl, R ³ and R ⁴ each represent a hydroxyl, halogen, azido or oxygen atom, Organic residues through a sulfur atom or a nitrogen atom;

, -COCH₃, -COCOCH₂CH₃, -

Provided that R ¹ represents a hydrogen atom and R ² represents -COCOCH ₃ ,

, -COCH ₃ , -COCOCH ₂ CH ₃ ,-

(R⁸은 1~13 탄소원자를 갖는 직쇄알킬을 나타낸다)로 나타내질 수 있는 기를 나타내면, R³은 히드록실 또는 일반식 -OCOR⁹(R⁹는 알킬, 알케닐, 아르알킬, 아릴, 3-피리딜, -CF₃, m-브로모페닐 또는 -CH₂CH₂COOH를 나타낸다)로 나타내질 수 있는 기 이외의 기를 나타내고, R⁴는 히드록실 또는 일반식 -OCOR⁹(R⁹는 상기 정의와 동일)로 나타내질 수 있는 기 이외의 기를 나타내거나 또는 R³및 R⁴모두 포르밀옥시 이외의 기를 나타내고, R¹이 수소원자를 나타내고, R²가 -COCOCH₃를 나타내고 R⁴가 -OCOCH₃를 나타내면 R³은 염소, -OSO₂CH₃또는

CH₃이외의 기를 나타내고, R¹이 수소원자를 나타내고, R²가 -COCOCH₃를 나타내고 R³이 -OCH₃를 나타내면 R⁴는 -OCH₃가 아니다.]Or general formula

(R ⁸ represents straight chain alkyl having 1 to 13 carbon atoms), R ³ represents hydroxyl or of the general formula —OCOR ⁹ (R ⁹ represents alkyl, alkenyl, aralkyl, aryl, 3- Group other than the group which may be represented by pyridyl, -CF ₃ , m-bromophenyl or -CH ₂ CH ₂ COOH, and R ⁴ is hydroxyl or of the general formula -OCOR ⁹ (R ⁹ is the above definition Or R ³ and R ⁴ both represent groups other than formyloxy, R ¹ represents a hydrogen atom, R ² represents -COCOCH ₃ and R ⁴ represents -OCOCH ₃ represents R ³ is chlorine, -OSO ₂ CH ₃ or

Represents a group other than CH _3, R ¹ is a hydrogen atom, R ² represents a -COCOCH ^₃ R ₃ a represents an -OCH ₃ R ⁴ are not -OCH _3.]

In the above general formula, the organic residue through the carbon atom which may be represented by R ⁵ preferably has a molecular weight of 400 or less, alkyl, cycloalkyl, alkanoyl, alkenyl, alkynyl, which may have 1-3 substituents. An aryl or heterocycle group can be illustrated.

Examples of the acyl group which may be represented by R ⁶ in the general formula may include a group which may be represented by the general formula —CO—R ¹⁰ (R ¹⁰ represents alkyl, aralkyl or aryl).

In the formula, the sulfonyl group which may be represented by R ⁶ may be exemplified by the group represented by the general formula —SO ₂ —R ¹¹ (R ¹¹ represents alkyl, aralkyl or aryl).

In the above formulae, examples of the alkoxy carbonyl group which may be represented by R ⁶ may include a group which may be represented by the general formula —COO—R ¹² (R ¹² represents alkyl, aralkyl or aryl).

(R¹⁵및 R¹⁶은 각각 수소 또는 탄소원자를 통한 유기성 잔기로 나타낸다), 일반식

(R¹⁷및 R¹⁸은 각각 수소 또는 탄소원자를 통한 유기성 잔기를 나타낸다), 일반식

(R¹⁹는 수소 또는 탄소원자를 통한 유기성 잔기를 나타낸다), 일반식 -OSO₂R²⁰(R²⁰은 알킬 또는 아릴을 나타낸다), 일반식 -OR²¹(R²¹은 탄소원자를 통한 유기성 잔기를 나타낸다) 및 일반식

(R²², R²³및 R²⁴는 각각 알킬 또는 페닐을 나타낸다)으로 나타내질 수 있는 기를 예시할 수 있다.Wherein, the organic moiety through the oxygen atom, which may be represented by R ³ and R ⁴ , may be represented by the general formula —OCOOR ¹³ or —OCOSR ¹³ (R ¹³ and R ¹³ represent the organic moiety through the carbon atom) or general formula —OCOR. ¹⁴ (R ¹⁴ represents an organic moiety through hydrogen or a carbon atom),

(R ¹⁵ and R ¹⁶ are each represented by an organic moiety through hydrogen or a carbon atom)

(R ¹⁷ and R ¹⁸ each represent an organic moiety through hydrogen or a carbon atom)

(R ¹⁹ represents an organic moiety through hydrogen or a carbon atom), general formula -OSO ₂ R ²⁰ (R ²⁰ represents alkyl or aryl), general formula -OR ²¹ (R ²¹ represents an organic moiety through a carbon atom) And general formula

Illustrative groups can be represented by (R ²² , R ²³ and R ²⁴ each represent alkyl or phenyl).

In the above formula, the organic moiety through the carbon atom represented by R ^{13 to 19} and R ²¹ preferably has a molecular weight of 400 or less, for example, alkyl, cycloalkyl, alkenyl, alkynyl, which may have 1-3 substituents. , Aryl or heterocycle.

In the above formula, the organic residue through the sulfur atom represented by R ³ and R ⁴ is represented by the formula -SR ²⁵ (R ²⁵ is alkyl, cycloalkyl, alkenyl, alkynyl, aryl or heterocycle having a molecular weight of 400 or less optionally with substituents). Group may be exemplified.

(R²⁶및 R²⁷은 각각 수소원자, 임의로 치환체를 가질 수 있는 분자량 400 이하의 알킬, 아릴, 헤테로사이클기, 아실, 설포닐 또는 포스포릴을 나타낸다)로 나타내질 수 있는 기를 예시할 수 있다.Wherein the general formulas represented by R ³ and R ⁴

And R ²⁶ and R ²⁷ each represent a hydrogen atom, optionally an alkyl, aryl, heterocycle group, acyl, sulfonyl or phosphoryl having a molecular weight of 400 or less which may have a substituent.

Examples of the acyl group represented by R ²⁶ and R ²⁷ include those similar to the acyl moiety (-COR ¹⁴ ) of the group represented by the general formula -OCOR ¹⁴ described above.

In R ¹³ to R ²⁷ described above, R ¹³ is halogen, tetrazolylthio, thiadiazolylthio, phenylthio, C _1-3 alkylthio, pyrenylcarbonyloxy or C _1-3 alkanoylaminomethylcarbonyl C _1-3 alkyl, or phenyl, which may be substituted by oxy, R ¹³ is di-C _1-3 alkylaminoethyl or thiadiazolylthiomethyl, R ¹⁴ is hydrogen or halogen, azido, tetrazolylthio Methyl, thiadiazolylthiomethyl, di-C _1-3 alkylamino-C _1-3 alkylthio, mono or di-C _1-3 alkylamino, piperazino, halogeno or C _1-3 alkylamino, mor poly furnace, a mono- or di -C _{1 ~ 3} is optionally substituted C _{1 ~ 3} alkyl, or phenyl, by alkyl-amino, R ¹⁵ and R ¹⁶ are each hydrogen, or C _{1 ~ 3} alkoxy, halogen, pyridyl Amino, di-C _1-3 alkylaminopiperidino, pyridyl, tetrazolylthio or carboxyl-substituted C _1-3 alkyl, or phenyl Or cyclohexyl, or R ¹⁵ and R ¹⁶ together with adjacent nitrogen atoms form morpholino, piperazino or piperidino, and R ¹⁷ and R ¹⁸ together with adjacent nitrogen atoms are morpholino, piperidino Or forms piperazino and R ¹⁹ is hydrogen, C _1-3 alkyl or benzyl, R ²⁰ is C _1-3 alkyl, R ²¹ is C _1-3 alkoxy, C _1-3 alkoxy-C _1-3 is alkyloxy or C _{1 ~ 3} alkyl thio a C _{1 ~ 3} alkyl substituted by, R ^22, R ²³ and R ²⁴ are each C _{1 ~ 4} alkyl, R ²⁵ is phenyl, tetrazolyl, thiadiazolyl, Dia It is preferred to be zolyl, oxazolyl or triazolyl, and R ²⁶ and R ²⁷ are each hydrogen, C _2-5 alkanoyl or tosyl.

The alkyl group in each group description mentioned above preferably has 1-20, more preferably 1-8 carbon atoms. These alkyl groups may be straight or branched chains, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, 2-ethylhexyl, Decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, octadecyl, nonadecyl and eicosyl.

The cycloalkyl group in each group description described above preferably has 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The alkenyl group in each group description above preferably has 2 to 6 carbon atoms, for example vinyl, allyl, isopropenyl, metalyl, 1, 1-dimethylallyl, 2-butenyl, 3- Butenyl, 2-pentenyl and 5-hexenyl.

The alkynyl group in each group description mentioned above preferably has 2-6 carbon atoms, for example ethynyl, propargyl, 2-butyn-1-yl, 3-butyn-1-yl, 3- Butyn-2-yl, 1-pentyn-3-yl, 3-pentyn-1-yl, 4-pentyn-2-yl and 3-hexyn-1-yl.

As the aryl group in each group description mentioned above, phenyl and naphthyl can be illustrated.

As the heterocycle group in each group description mentioned above, a 5 to 8 membered ring containing 1 to 4 hetero atoms such as an oxygen atom, a sulfur atom or a nitrogen atom may be mentioned, for example thienyl, furyl, pyrrolyl , Pyridyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 4 -Thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 3, 4-tria Zolyl, tetrazolyl, N-oxido-pyridyl, pyrimidinyl, N-oxido-pyrimidinyl, pyridazinyl, pyrazinyl, N-oxido-pyridazinyl, benzofuryl, benzodiazolyl, benz Oxazolyl, triazinyl, tetrazolo [1, 5-b] pyridazinyl, triazolo [4, 5-b] pyridazinyl, oxoimidazinyl, thioxotriazinyl, pyrrolidinyl, piperidinyl, Pyranyl, thiopyranyl, 1, 4-oxadinyl, Lepolynyl, 1, 4-thiadinyl, 1, 3-thiazinyl, piperazinyl, benzoimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl , Indolinyl, quinoliginyl, 1, 8-naphthyridinyl, furinyl, putridinyl, dibenzofuranyl, carbazolyl, acryldinyl, phenanthridinyl, phenazinyl, phenothiazinyl, phenoxazinyl And so on.

The arallyl group in each group description above preferably has 7 to 12 carbon atoms, for example benzyl, 2-phenethyl, 1-phenethyl, benzhydryl and trityl.

These aralkyl groups may have 1 to 3 substituents such as halogen, nitro and C _1-4 alkyl. Examples of substituted aralkyl groups are 4-chlorobenzyl, 4-nitrobenzyl, 2, 4-dimethoxybenzyl, 3, 4-dimethylbenzyl, 4-methylbenzyl and the like.

The lower alkyl group represented by R ⁷ described above preferably has 1 to 4 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl.

Substituents of the above optionally substituted alkyl, cycloalkyl, alkenyl and alkynyl include hydroxyl, C _3-6 cycloalkyl, C _6-10 aryl, C _1-4 alkoxy, C _3-6 cycloalkyloxy, C _6-10 aryloxy, C _7-12 aralkyloxy, C _1-4 alkylthio, C _3-6 cycloalkylthio, C _6-10 arylthio, C _7-12 aralkylthio, amino, mono-C _{1 -4} alkylamino, di-C _1-4 alkylamino, C _3-6 cycloalkylamino, C _6-10 arylamino, C _7-12 aralkylamino, azido, nitro, halogen, cyano, carboxy, C _1-4 alkoxycarbonyl, C _6-10 aryloxycarbonyl, C _3-6 cycloalkyloxycarbonyl, C _7-12 aralkyloxycarbonyl, C _1-5 alkanoyl, formylthio, C _{1 ~ 4} alkylsulfinyl, C _6-10 arylsulfinyl, C _1-4 alkylsulfonyl, C _6-10 arylsulfonyl, C _1-15 alkanoyloxy, sulfo, carbamoyl, optionally substituted carbamoyl, Carbamoyloxy, optionally substituted carbamoyloxy, formylamido, C _1-4 alkanoyl amido, C _6-10 arylcarbonyl amido, C _1-4 alkoxycarbonylamino, C _7-12 aralkyloxycarbonylamino, oxo, epoxy, thioxo, sulfonamido, Heterocycle group, heterocyclethio, heterocyclecarbonylamino, heterocycleoxy, heterocycleamino, C _1-4 alkoxycarbonyloxy, di-C _1-4 alkyl-postinothioylamino, di-C _6-10 Aryl-phosphinothioylamino, hydroxyimino, C _1-4 alkoxyimino, C _1-4 alkylsulfonyloxy, C _6-10 arylselfonyloxy, thiocarbonylthio, optionally substituted thiocarbamoylthio And silyloxy.

The heterocycle group of the group comprising a cycloalkyl, aryl, alkyl or heterocycle group of a group comprising C _1-4 alkyl optionally substituted on the alkyl, alkenyl, alkynyl or cycloalkyl described above may optionally further have a substituent. have.

These substituents include hydroxy, C _1-4 alkyl (optionally substituted, substituents are similar to those mentioned above for alkyl; the C _1-4 alkyl-containing groups described below may optionally have similar substituents), C _{1 -4} alkoxy, C _1-4 alkylthio, amino, C _1-4 alkylamino, di-C _1-4 alkylamino, C _6-10 arylamino, azido, nitro, halogen, oxo, cyano, carboxy, C _1-4 alkoxycarbonyl, C _6-10 aryloxycarbonyl, C _1-5 alkanoyl, C _1-5 alkanoyloxy, sulfo, carbamoyl, substituted carbamoyl, carbamoyloxy, C _1-4 alkanoyl amido, C _1-4 alkoxycarbonylamino, sulfonamide, etc. can be illustrated.

Substituents of the above optionally substituted aryl and heterocycle groups include hydroxyl, C _1-4 alkyl, C _6-10 aryl, C _3-6 cycloalkyl, halogen, carboxyl, sulfo, C _1-4 alkoxy, C _1-4 alkylthio, nitro, C _1-4 alkoxycarbonyl, amino, mono-C _1-4 alkylamino, di-C _1-4 alkylamino, C _1-4 alkanoylamido, C _6-10 aryl Oxy, C _7-12 aralkyl, C _7-12 aralkylkilloxy, C _6-10 arylamino, C _7-12 aralkylamino, cyano, C _6-12 aryloxycarbonyl, C _7-12 ar an alkyloxycarbonyl, C _{1 ~ 5} alkanoyl, C _{2 ~ 5} alkanoyloxy, carbamoyl, optionally substituted carbamoyl, optionally substituted carbamoyl oxy, C _{1 ~ 4} alkoxy-carbonyl-amino and oxo It can be illustrated.

Alkyl, which is a substituent of the above-mentioned optionally substituted aryl and heterocycle groups, C _1-4 alkyl or groups containing aryl groups, may further have substituents similar to those described above as substituents of alkyl and aryl groups.

Preferably the number of substituents in each group mentioned above is 1-3.

These substituents are described in more detail below.

Examples of the C _1-4 alkyl that is a substituent include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl and t-butyl.

Examples of C _3-6 cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclopentyl and cyclohexyl.

Examples of C _6-10 aryl are phenyl and naphthyl.

Examples of C _1-4 alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy and t-butoxy.

Examples of C _3-6 cycloalkyloxy groups are cyclopropyloxy, cyclopentyloxy and cyclohexyloxy.

Examples of C _8-10 aryloxy groups are phenoxy and naphthyloxy.

Examples of C _7-12 aralkyloxy groups are benzyloxy, 2-phenethyloxy and 1-phenenyloxy.

Examples of C _1-4 alkylthio groups are methylthio, ethylthio, propylthio and butylthio.

Examples of C _3-6 cycloalkylthio groups are cyclopropylthio, cyclopentylthio and cyclohexylthio.

Examples of C _6-10 arylthio groups are phenylthio and naphthylthio.

Examples of C _7-12 aralkylthio groups are benzylthio, 2-phenethylthio and 1-phenethylthio.

Examples of mono-C _1-4 alkylamino groups are methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino and t-butylamino.

Examples of di-C _1-4 alkylamino groups are dimethylamino, diethylamino, dipropylamino, dibutylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino and N-methyl-N- Butylamino.

Examples of C _3-6 cycloalkylamino groups are cyclopropylamino, cyclopentylamino and cyclohexylamino.

An example of a C _6-10 arylamino group is anilino.

Examples of C _7-12 aralkylamino groups are benzylamino, 2-phenethylamino and 1-phenethylamino.

Examples of halogens are fluorine, chlorine, bromine and iodine.

Examples of C _1-4 alkoxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl and isobutoxy carbonyl.

An example of a C _6-10 aryloxycarbonyl group is phenoxycarbonyl.

Examples of the C _3-6 cycloalkyloxycarbonyl group are cyclopropyloxycarbonyl, cyclopentyloxycarbonyl and cyclohexyloxycarbonyl.

Examples of C _7-12 aralkyloxycarbonyl groups are benzyloxycarbonyl, 1-phenethyloxycarbonyl and 2-phenethyloxycarbonyl.

Examples of C _1-5 alkanoyl groups are formyl, acetyl, propionyl, butyryl and pivaloyl.

Examples of C _1-15 alkanoyloxy groups include formyloxy, acetoxy, butyryloxy, pivaloyloxy, pentanoyloxy, hexanooxy, heptanoyloxy, octanoyloxy, nonanoyloxy, decanoyl Oxy, undecanoyloxy, dodecanoyloxy, tridecanoyloxy, tetradecanoyloxy and pentadecanoyloxy.

Examples of substituted carbamoyl groups are N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-ethylcarbamoyl, N, N-diethylcarbamoyl, N-phenylcarbamoyl, pyrroli Dinocarbamoyl, piperidinocarbamoyl, piperazinocarbamoyl, morpholinocarbamoyl and N-benzylcarbamoyl.

Examples of substituted carbamoyloxy groups are N-methylcarbamoyloxy, N, N-dimethylcarbamoyloxy, N-ethylcarbamoyloxy, N-benzylcarbamoyloxy, N, N-dibenzylcar Barmoyloxy and N-phenylcarbamoyloxy.

Examples of C _1-4 alkanoyl amido groups are formyl amido, acetamido, propionamido and butyrylamido.

An example of a C _6-10 arylcarbonylamido group is benzemido.

Examples of C _1-4 alkoxycarbonylamino groups are methoxycarbonylamino, ethoxycarbonylamino, butoxycarbonylamino and t-butoxycarbonylamino.

Examples of C _7-12 aralkyloxycarbonylamino groups are benzyloxycarbonylamino, 4-methoxybenzyloxycarbonylamino, 4-nitrobenzyloxycarbonylamino and 4-chlorobenzyloxycarbonylamino.

Examples of sulfonamido groups include methanesulfonylamino, ethanesulfonylamino, butanesulfonylamino, benzenesulfonylamino, toluenesulfonylamino, naphthalenesulfonylamino, trifluoromethanesulfonylamino, 2-chloroethanesulfonyl Amino and 2, 2, 2-trifluoromethanesulfonylamino.

As the heterocyclic group, a cycle group containing 1 to 5 nitrogen atoms, oxygen atoms and sulfur atoms may be mentioned, and pyrrolidinyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, Isothiazolyl, thiazolyl, piperidinyl, pyridyl, piperazinyl, pyrimidinyl, pyranyl, tetrahydropyranyl, tetrahydrofuryl, indolyl, quinolyl, 1, 3, 4-oxadiazolyl, Thieno [2, 3-d] pyridyl, 1, 2, 3-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 3, 4-triazolyl, tetrazolyl, 4, 5-dihydro-1, 3-thioxolyl, tetrazolo [1, 5-b] pyridazyl, benzothiazolyl, benzoxazolyl, benzimidazolyl And benzothienyl.

As the heterocyclethio, heterocycleoxy, heterocycleamino and heterocyclecarbonylamino groups, mention may be made of groups in which the heterocycle ring is formed by being bonded to a sulfur atom, an oxygen atom, a nitrogen atom or a carbonylamino group, respectively.

Examples of di-C _1-4 alkylphosphinothioylamino groups are dimethylphosphinothioylamino and diethylphosphinothioylamino.

Examples of the alkoxyimino group are methoxyimino, ethoxyimino, 2-fluoroethoxyimino, carboxyethoxyimino, 1-carboxy-1-methylethoxyimino, 2, 2, 2-trichloroethyloxycarbo Neylmethoxy, 1- (2, 2, 2-trichloroethyloxycarbonyl) -1-methylethoxyimino, (2-aminothiazol-4-yl) methoxyimino and (1H-imidazol-4- (1) methoxyimino.

Examples of C _1-4 alkylsulfonyloxy groups are methanesulfonyloxy, ethanesulfonyloxy and butanesulfonyloxy.

Examples of C _6-10 arylsulfonyloxy groups are benzenesolfonyloxy and toluenesulfonyloxy.

An example of a di-C _6-10 arylphosphinothioylamino group is diphenylphosphinothioylamino.

Examples of substituted thiocarbamoylthio groups are N-methylthiocarbamoylthio, N, N-dimethylthiocarbamoylthio, N-ethylthiocarbamoylthio, N-benzylthiocarbamoylthio, N , N-dibenzylthiocarbamoylthio and N-phenylthiocarbamoylthio.

Examples of silyloxy groups are trimethylsilyloxy, t-butyldimethylsilyloxy and t-butyldiphenylsilyloxy.

Examples of C _1-4 alkylsulfinyl groups are methylsulfinyl, ethylsulfinyl, propylsulfinyl and butylsulfinyl.

Examples of C _6-10 arylsulfinyl groups are phenylsulfinyl and naphthylsulfinyl.

Examples of C _1-4 alkylsulfonyl groups are methanesulfonyl, ethanesulfonyl and butanesulfonyl.

Examples of C _6-10 arylsulfonyl groups are benzenesulfonyl and toluenesulfonyl.

Examples of C _1-4 alkoxycarbonyloxy groups are methoxycarbonyloxy, ethoxycarbonyloxy and t-butoxycarbonyloxy.

The description of each group described above is given in more detail below.

(Z 및 R⁵는 상기 정의와 동일하다)로 나타내지고, 식중 R⁵가 예를들어, 일반식 -C(=O)R^5A(R^5B(R^5B는 임의로 할로겐에 의해 치환된 C_1~5알킬 또는 할로겐에 의해 치환될 수 있는 알킬 또는 아릴 또는 산소 도는 황원자를 통한 헤테로사이클기이다), -CH(Y^A)R^5C(Y^A는 히드록실, C_2~8알카노일옥시, 임의로 할로겐-치환된 C_1~3알콕시카르보닐, 헤테로사이클아미노카르보닐, 할로겐 또는 C_1~3알콕시카르보닐, C_2~5알카노일 또는 아릴설포닐에 의해 치환될 수 있는 아미노 또는 히드록시카르보닐, 알킬설포닐옥시, 아릴설포닐옥시, 트리-C_1~3-알킬실릴옥시, 아릴티오, C_1~3알킬티오, 알킬설포닐, 아지도 또는 황원자를 통한 헤테로사이클기이고, R^5C는 황원자를 통한 헤테로사이클기, 아릴옥시, 아릴 또는 할로겐에 의해 치환될 수 있는 C_1~3알킬이다),One of R ¹ and R ² is hydrogen and the other is of general formula

(Z and R ⁵ are the same as the above definition), wherein R ⁵ is, for example, the general formula -C (= O) R ^5A (R ^5B (R ^5B is optionally substituted by halogen C _{1 ~) 5} is an alkyl group or an alkyl or aryl or heteroaryl through a sulfur atom, an oxygen turning which may be substituted by a halogen ^{cycle), -CH (Y a) R} 5C (Y a is hydroxyl, C _{2 ~ 8} alkanoyloxy, optionally halogen -substituted C _{1 ~ 3} alkoxycarbonyl, heterocyclic amino carbonyl, halogen or C _{1 ~ 3} alkoxycarbonyl, C _{2 ~ 5} alkanoyl or arylsulfonyl amino or hydroxy which may be substituted by hydroxy carbonyl, Alkylsulfonyloxy, arylsulfonyloxy, tri-C _1-3 alkylsilyloxy, arylthio, C _1-3 alkylthio, alkylsulfonyl, azido or a heterocycle group via a sulfur atom, R ^5C is a sulfur atom Is C _1-3 alkyl which may be substituted by heterocycle, aryloxy, aryl or halogen via

로 나타내지는 기의 예는 아세틸, 1-티옥소에틸, 클로로아세틸, 2-클로로-1-티옥소에틸, 브로모아세틸, 2-브로모-1-티옥소에틸, 요오도아세틸, 2-요오도-1-티옥소에틸, 메톡시아세틸, 2-메톡시-1-티옥소에틸, 에톡시아세틸, 2-에톡시-1-티옥소에틸, 페녹시아세틸, 2-페녹시-1-티옥시에틸, 벤질옥시아세틸, 2-벤질옥시-1-티옥소에틸, 4-클로로페녹시아세틸, 2-(4-클로로페녹시)-1-티옥소에틸, 4-히드록시페녹시아세틸, 2-(4-히드록시페녹시)-1-티옥소에틸, 4-아세톡시페녹시아세틸, 2-(4-아세톡시페녹시)-1-티옥소에틸, 페닐아세틸, 2-페닐-1-티옥소에틸, 4-히드록시페닐아세틸, 2-(4-히드록시페닐)-1-티옥소에틸, 3, 4-디히드록시페닐아세틸, 2-(3, 4-디히드록시페닐)-1-티옥소에틸, 4-아세톡시페닐아세틸, 2-(4-아세톡시페닐)아세틸, 2-(4-아세톡시페닐)-1-티옥소에틸, 3, 4-디아세톡시페닐아세틸, 20(3, 4-디아세톡시페닐)-1-티옥소에틸, 3, 4, 5-트리아세톡시페닐아세틸, 2-(3, 4, 5-트리아세톡시페닐)-1-티옥소에틸, 2-아미노메틸페닐아세틸, 2-(2-아미노메틸페닐)-1-티옥소에틸, 2-디메틸아미노설포닐페닐아세틸, 2-(3-디메틸아미노설포닐페닐)-1-티옥소에틸, 3-아미노설포닐메틸페닐아세틸, 2-(3-아미노설포닐메틸페닐)-1-티옥소에틸, 3-메탄설포닐아미노페닐아세틸, 2-(3-메탄설포닐아미노페닐)-1-티옥소에틸, (1, 2-옥사졸-3-일)아세틸, 2-(1, 2-옥사졸-3-일)-티옥소에틸, (1, 2-옥사졸-5-일)아세틸, 2-(1, 2-옥사졸-5-일)-1-티옥소에틸, (1H-아마디졸-4-일)아세틸, 2-(1H-이미다졸-4-일)-티옥소에틸, (1H-피라졸-4-일)아세틸, 2-(1H-피라졸-4-일)-1-티옥소에틸, (5-아미노-1, 2, 4-티아디아졸-3-일)아세틸, 2-(5-아미노-1, 2, 4-티아디아졸-3-일)-1-티옥소에틸, 2-티에닐아세틸, 2-(2-티에닐)-1-티옥소에틸, 2-푸릴아세틸, 2-(2-푸릴)-1-티옥소에틸, (1H-테트라졸-1-일)아세틸, 2-(1H-테트라졸-1-일)-1-티옥소에틸, (티아졸-4-일)아세틸, 2-(티아졸-4-일)-1-티옥소에틸, (2-아미노티아졸-4-일)아세틸, 2-(2-아미노티아졸-4-일)-1-티옥소에틸, (2-클로로아세틸아미노티아졸-4-일)아세틸, 2-(2-클로로아세틸아미노티아졸-4-일)-1-티옥소에틸, 시아노아세틸, 2-시아노-1-티옥소에틸, 메틸티오아세틸, 2-메틸티오-1-티옥소에틸, 에틸티오아세틸, 2-에틸티오-1-티옥소에틸, 페닐티오아세틸, 2-페닐티오-1-티옥소에틸, 트리플루오로메틸티오아세틸, 2-트리플루오로메틸티오-1-티옥소에틸, 디플루오로메틸티오아세틸, 2-디플루오로메틸티오-1-티옥소에틸, 시아노메틸티오아세틸, 2-시아노메틸티오-1-티옥소에틸, 4-피리딜티오아세틸, 2-(4-피리딜티오)-1-티옥소에틸, (1-메틸-1H-트리아졸-2-일)티오아세틸, 2-(1-메틸-1H-트리아졸-2-일)티오-1-티옥소에틸, (1, 5-디메틸-1H-1, 3, 4-트리아졸-2-일)티오아세틸, 2-(1, 5-디메틸, 1H-1, 3, 4-트리아졸-2-일)티오-1-티옥소에틸, (1-메틸-1H-테트라졸-5-일)티오아세틸, 2-(1-메틸-1H-테트라졸-5-일)티오-1-티옥소에틸, [1-(2-디메틸아미노에틸)-1H-테트라졸-5-일]티오아세틸, 2-[2-(1-디메틸아미노에틸)-1H-테트라졸-5-일]티오-1-티옥소에틸, [1-(3-디메틸아미노프로필)-1H-테트라졸-5-일]티오아세틸, 2-[1-(3-디메틸아미노프로필)-1H-테트라졸-5-일]티오-1-티옥소에틸, [1-(2-히드록시에틸)-1H-테트라졸-5-일]티오아세틸, 2-[1-(2-히드록시에틸)-1H-테트라졸-5-일]티오-1-티옥소에틸, (1-카르복시메틸-1H-테트라졸-5-일)티오아세틸, 2-(1-카르복시메틸-1H-테트라졸-5-일)티오-1-티옥소에틸, (1-설포메틸-1H-테트라졸-5-일)티오아세틸, 2-(1-설포메틸-1H-테트라졸-5-일)티오-1-티옥소에틸, (5-메틸-1, 3, 4-티아디아졸-2-일)티오아세틸, 2-(5-메틸-1, 3, 4-티아디아졸-2-일)티오-1-티옥소에틸, [5-(2-디메틸아미노에틸)-1, 3, 4-티아디아졸-2-일]티오아세틸, 2-[5-(2-디메틸아미노에틸)-1, 3, 4-티아졸-2-일]티오-1-티옥소에틸, (5-메톡시에틸-1, 3, 4-티아디아졸-2-일)티오아세틸, 2-(5-메톡시메틸-1, 3, 4-티아디아졸-2-일)티오-1-티옥소에틸, (5-메탄설포닐메틸-1, 3, 4-티아디아졸-2-일)티오아세틸, 2-(5-메탄설포닐메틸-1, 3, 4-티아디아졸-2-일)티오-1-티옥소에틸, (3-메틸-1, 2, 3-티아디아졸-5-일)티오아세틸, 2-(3-메틸-1, 2, 4-티아티아졸-5-일)티오-1-티옥소에틸, (1, 2, 3-티아디아졸-5-일)티오아세틸, 2-(1, 2, 3-티아디아졸-5-일)티오-1-티옥소에틸, 2-아미노에틸티오아세틸, 2-(2-아미노에틸티오)-1-티올-1-티옥소에틸, 2-(2, 2, 2-트리클로로에틸옥시카르보닐아미노)에틸티오아세틸, 2-[2-(2, 2, 2-트리클로로에틸옥시카르보닐아미노)에틸]티오-1-티옥소에틸, 2-아미노비닐티오아세틸, 2-(2-아미노비닐)티오-1-티옥소에틸, 2-(2, 2, 2-트리클로로에틸옥시카르보닐아미노)비닐티오아세틸, 2-[2-(2, 2, 2, -트리클로로에틸옥시카르보닐아미노비닐]티오-1-티옥소에틸, (2-아미노-2-카르복시)에틸티오아세틸, 2-[(2-아미노-2-카르복시)에틸]티오-1-티옥소에틸, [3-(2-아미노-2-카르복시)에틸-1H-이미다졸-2-일]티오아세틸, 2-[3-(2-아미노-2-카르복시)에틸-1H-이미다졸-2-일]티오-1-티옥소에틸, (4-카르복시-3-히드록시-1, 2-티아졸-5-일)티오아세틸, 2-(4-카르복시-3-히드록시-1, 2-티아졸-5-일)티오-1-티옥소에틸, (1-아미노-1H-테트라졸-5-일)티오아세틸, 2-(1-아미노-1H-테트라졸-5-일)티오-1-티옥소에틸, (1-디메틸아미노-1H-테트라졸-5-일)티오아세틸, 2-(1-디메틸아미노-1H-테트라졸-5-일)티오-1-티옥소에틸, [1-(1H-테트라졸-5-일)메틸-1H-테트라졸-5-일]티오아세틸, 2-[1-(1H-테트라졸-5-일)메틸-1H-테트라졸-5-일]티오-1-티옥소에틸, (6-히드록시-4-메틸-5, 6-디히드로-1, 2, 4-트리아진-5-온-3-일)티오아세틸, 2-(6-히드록시-4-메틸-5, 6-디히드로-1, 2, 4-트리아진-5-온-3-일)티오-1-티옥소에틸, [5-(2-아미노-2-카르복실에틸)-1H-이미다졸-2-일]티오아세틸, 2-[5-(아미노-2-카르복실에틸)-1H-이미다졸-2-일]티오-1-티옥소에틸, [5-(2-아미노-2-카르복시에틸)-1, 3, 4-티아졸-2-일]티오아세틸, 2-[5-(2-아미노-2-카르복시에틸)-1, 3, 4-티아디아졸-2-일]티오-1-티옥소에틸, (2-아미노-1, 3, 4-티아디아졸-5-일)티오아세틸, 2-(2-아미노-1, 3, 4-티아디아졸-5-일)티오-1-티옥소에틸, (4, 5-디카르복시-1H-이미다졸-2-일)티오아세틸, 2-(4, 5-디카르복시-1H-이미다졸-2-일)티오-1-티옥소에틸, (5-아미노-4-카르복시-1-메틸-1H-이미다졸-2-일)티오아세틸, 2-(5-아미노-4-카르복시-1-메틸-1H-이미다졸-1-일)티오-1-티옥소에틸, (테트라졸로[1, 5-b]피리다닐-6-일)티오아세틸, (2-카르바모일-2-플루오로비닐티오)아세틸, (2-카르바모일-2-플루오로비닐티오)-1-티옥소에틸, 2-(테트라졸로(1, 5-b]피리다진-6-일)티오-1-티옥소에틸, 1, 2-티옥소프로프리, 2-옥소-1-티옥소프로필, 1, 2-디옥소부틸, 2-옥소-1-티옥소부틸, 1, 2-디옥소펜틸, 2-옥소-1-티옥소펜틸, (1, 2-디옥소-3-페닐)프로필, 3-페닐-2-옥소-1-티옥소프로필, (1, 2-디옥소-2-페닐)에틸, (2-옥소-2-페닐-티옥소)에틸, 1, 2-디옥소-2-(티아졸-4-일)에틸, 2-옥소-2-(티아졸-4-일)-1-티옥소에틸, 2-(2-아미노티아졸-4-일)-1, 2-디옥소에틸, 2-(2-아미노티아졸-4-일)-2-옥소-1-티옥소에틸, 2-(2-클로로아세틸아미노티아졸-4-일)-1, 2-디옥소에틸, 2-(2-클로로아세틸아미노티아졸-4-일)-2-옥소-1-티옥소에틸, 2-(5-아미노-1, 2, 4-티아디아졸-3-일)-1, 2-디옥소에틸, 2-(5-아미노-1, 2, 4-티아디아졸-3-일)-옥소-1-티옥소에틸, 3-브로모-1, 2-디옥소프로필, 3-브로모-2-옥소-1-티옥소프로필, 2-(벤족티아졸-2-일)티오-1, 2-디옥소프로필, 3-(벤조티아졸-2-일)티오-2-옥소-1-티옥소프로필, 3-(벤조티아졸-2-일)티오-1, 2-디옥소프로필, 3-(벤족사졸-2-일)티오-2-옥소-1-티옥소프로필, 3-메틸티오-1, 2-디옥소프로필, 3-메틸티오-2-옥소-1-티옥소프로필, 3-에틸티오-1, 2-디옥소프로필, 3-에틸티오-2-옥소-1-티옥소프로필, 3-(2-피리딜)디옥소프로필, 3-페닐티오-2-옥소-1-티옥소프로필, 3-(피리딜)티오-1, 2-디옥소프로필, 3-(2-피리딜)티오-2-옥소-1-티옥소프로필, 3-(4-피리딜)티오-1, 2-디옥소프로필, 3-(4-피리딜)티오-2-옥소-티옥소프로필, 3-(1-메틸-1, 3, 4-트리아졸-2-일)티오-1, 2-디옥소프로필, 3-(1-메틸-1H-1, 3, 4-트리아졸-2-일)티오-2-옥소-1-티옥소프로필, 3-[1-(2-디메틸아미노에틸)-1H-테트라졸-5-일]티오-1, 2-디옥소프로필, 3-[1-(2-디메틸아미노에틸)-1H-테트라졸-5-일]티오-2-옥소-1-티옥소프로필, 2-히드록시-3-(2-피리딜)티오프로피오닐, 2-히드록시-3-(2-피리딜)티오-1-티옥소프로필, 2-히드록시-3-(4-피리딜)티오프로피로닐, 2-히드록시-2-(4-피리딜)티오-1-티옥소프로필, 3-[1-(2-디메틸아미노에틸)-1H-테트라졸-5-일]티오-2-히드록시프로피오닐, 2-[1-(디메틸아미노에틸)-1H-테트라졸-5-일]티오-2-히드록시-1-티옥소프로필, 2-히드록시-3-페닐티오프로피오닐, 2-히드록시-3-페닐티오-1-티옥소프로필, 3-에틸티오-2-히드록시프로피오닐, 3-에틸티오-2-히드록시-1-티옥소프로필, 3-(2-벤조티아졸릴)티오-2-히드록시프로피오닐, 2-(2-벤조티아졸릴)티오-2-히드록시프로피오닐-1-티옥소프로필, 2-히드록시-1-티옥소프로필, 2-히드록시-3-(4-메틸-4H-1, 2, 4-트리아졸-3-일)티오프로피오닐, 2-히드록시-3-(4-메틸-4H-1, 2, 4-트리아졸-3-일)티오프로피오닐-1-티옥소프로필, 2-아세톡시-3-(2-피리딜)티오프로피오닐, 2-아세톡시-3-(2-피리딜)티오-1-티옥소프로필, 2-아세톡시-3-(4-피리딜)티오프로피오닐, 2-아세톡시-3-(4-피리딜)티오-1-티옥소프로필, 2-프로피오닐옥시-3-(2-피리딜)티오프로피오닐, 2-프로피오닐옥시-3-(2-피리딜)티오-1-티옥소프로필, 2-벤조일옥시-3-(2-피리딜티오-1-티옥소프로필, 2-벤조일옥시-3-(2-피리딜)티오-1-티옥소프로필, 2-벤조일옥시-3-(4-피리딜)티오프로피로일, 2-벤조일옥시-3-(4-피리딜)티오-1-티옥소프로필, 2-아세톡시-3-[1-(2-디메틸아미노에틸)-1H-테트라졸-5-일]-티오프로피오닐, 2-아세톡시-3-[1-(2-디메틸아미노에틸)-1H-테트라졸-5-일]티오-1-티옥소프로필, 2-아세톡시-3-에틸티오프로피오닐, 2-아세톡시-3-에틸티오-1-티옥소프로필, 2-아세톡시-3-(4-메틸-4H-1, 2, 4-트리아졸-3-일)티오프로피오닐, 2-아세톡시-3-(4-메틸-4H-1, 2, 4-트리아졸-3-일)티오-1-티옥소프로필, 2-메탄설포닐옥시-3-(2-피리딜)티오프로피오닐, 2-메탄설포닐옥시-3-(2-피리딜)티오-1-티옥소프로필, 2-메탄설포닐옥시-3-(4-피리딜)티오프로피오닐, 2-메탄설포닐옥시-3-(4-피리딜)티오-1-티옥소프로필, 3-(2-피리딜)티오-2-P-톨루엔설포닐옥시프로피오닐, 3-(2-피리딜)티오-2-P-톨루엔설포닐옥시-1-티옥소프로필, 3-(4-피리딜)티오-1-P-톨루엔설포닐옥시프로피오닐, 3-(4-피리딜)티오-2-P-톨루엔설포닐옥시-1-티옥소프로필, 3-[1-(2-디메틸아미노에틸)-1H-테트라졸-5-일]티오-2-메탄설포닐옥시프로피오닐, 3-[1-(2-디메틸아미노에틸)(-9-1-테트라졸-5-일]티오-2-메탄설포닐옥시-1-티옥소프로필, 3-[1-(2-디메틸아미노에틸)-1H-테트라졸-5-일]티오-2-P-톨루엔설포닐옥시프로피오닐, 3-[1-(2-디메틸아미노에틸(-1H테트라졸-5-일]티오-2-P톨루엔설포닐옥시-1-티옥소프로필, 3-에틸티오-2-메탄설포닐옥시프로피오닐, 3-에틸티오-2-메탄설포닐옥시-1-티옥소프로필, 2-메탄설포닐옥시-3-페닐티오프로피오닐, 2-메탄설포닐옥시-3-페닐티오-1-티옥소프로필, 2-요오드-3-메틸티오프로피오닐, 2-요오도-3-메틸티오-1-티옥소프로필, 3-에틸티오-2-요오도프로피오닐, 3-에틸티오-2-요오드-1-티옥소프로필, 2-요오도-3-페닐티오프로피오닐, 2-요오드-3-페닐티오-1-티옥소프로필, 2-요오도-3-(2-피리딜티오)프로피오닐, 2-요오도-3-(2-피리딜티오)-1-티옥소프로필, 2-요오도-(4-피리딜)티오-1-티옥소프로필, 3-[1-(2-디메틸아미노에틸-1H-테트라졸-5-일]티오-2-요오도프로피오닐, 3-[1-(2-디메틸아미노에틸-1H-테트라졸-5-일]티오-2-요오도-1-티옥소프로필, 2-요오도-3-(4-메틸-4H-1, 2, 4-트리아졸-3-일)티오프로피오닐, 2-요오도-3-(4-메틸-4H-1, 2, 4-트리아졸-3-일)티오-1-티옥소프로필, 3-(2-벤조티아졸릴)티오-2-요오도프로피오닐, 3-(2-벤조티아졸릴)티오-2-요오도-1-티옥소프로필, 2-요오도-3-(2-벤조사졸릴)티오프로피오닐, 2-요오도-3-(2-벤족사졸릴)티오-1-티옥소프로필, 2, 3-비스(에틸티오)프로피오닐, 2, 3-비스(에틸티오-1-(티옥소프로필, 3-에틸티오-2-(2-피리딜)티오프로피오닐, 3-에틸티오-2-(2-피리딜)티오-1-티옥소프로필, 3-에틸티오-2-(4-피리딜)티오프로피오닐, 3-에틸티오-2-(4-피리딜)티오-1-티옥소프로필, 2-메틸티오-3-(2-피리딜)티오프로피오닐, 2-메틸티오-3-(2-피리딜)티오-1-티옥소프로필, 2, 3-비스(2-피리딜)티오프로피오닐, 2, 3-비스(2-피리딜)티오-1-티옥소프로필, 2, 3-비스(4-피리딜)티오프로피오닐, 2, 3-비스(4-피리딜)티오-1-티옥소프로필, 2-(2-피리딜)티오-3-(4-피리딜)티오프로피오닐, 2-(2-피리딜)티오-3-(4-피리딜)티오-1-티오프로필, 2-[1-(2-디메틸아미노에틸)-1H-테트라졸-5-일]티오-3-(2-피리딜)티오프로피오닐, 2-[1-(2-디메틸아미노에틸)-1H-테트라졸-5-일]티오-3-(2-피리딜)티오-1-티옥소프로필, 2-(4-메틸-1H-1, 2, 4-트리아졸-3-일)티오-3-(2-피리딜)티오프로피오닐, 2-(4-메틸-1H-1, 2, 4-트리아졸-3-일)티오-1-티옥소프로필, 2-(2-아미노에틸)티오-3-페닐티오프로피오닐, 2-(2-아미노에틸)티오-3-페닐티오-1-티옥소프로필, 3-[1-(2-디메틸아미노에틸-1H-테트라졸-5-일]티오-2-(2-피리딜)티오프로피오닐, 3-[1-(2-디메틸아미노에틸)-1H-테트라졸-5-일]티오-2-(2-피리딜)티오-1-티옥소프로필, 2-아지도-3-메틸티오프로피오닐, 2-아지도-3-메틸티오-1-티옥소프로필, 2-아지도-3-에틸티오프로피오닐, 2-아지도-3-에틸티오-1-티옥소프로필, 2-아지도-3-페닐티오프로피오닐, 2-아지도-3-페닐티오-1-티옥소프로필, 2-아지도-3-(2-피리딜)티오프로피오닐, 2-아지도-3-(2-피리딜)티오-1-티옥소프로필, 2-아지도-3-(4-피리딜)티오프로피오닐, 2-아지도-3-(4-피리딜)티오-1-티옥소프로필, 2-아지도-3-[1-(2-디메틸아미노에틸)-1H-테트라졸-5-일]티오프로피오닐, 2-아지도-3-[1-(2-디메틸아미노에틸)-1H-테트라졸-5-일]-티오-1-티옥소프로필, 2-아지도-3-[4-메틸-4H-1, 2, 4-트리아졸-3-일]티오프로피오닐, 2-아지도-3-[4-메틸-4H-1, 2, 4-트리아졸-3-일]티오-1-티옥소프로필, 2-아지도-3-(2-벤조티아졸릴)티오프로피오닐, 2-아지도-3-(2-벤조티아졸릴)티오-1-티옥소프로필, 2-아지도-3-(2-벤족사졸릴)티오프로피오닐, 2-아지도-3-(2-벤족사졸릴)티오-1-티옥소프로필, 2-아지도-3-에톡시카르보닐메틸티오프로피오닐, 2-아지도-3-에톡시카르보닐메틸티오-1-티옥소프로필, 2-아미노-3-에틸티오프로피오닐, 2-아미노-3-에틸티오-1-티옥소프로필, 2-아미노-3-(2-메톡시에틸)티오프로피오닐, 2-아미노-3-(2-메톡시에틸)티오-1-티옥소프로필, 2-아미노-3-페닐티오프로피오닐, 2-아미노-3-페닐티오-1-티옥소프로필, 2-아미노-3-(2-피리딜)티오프로피오닐, 2-아미노-3-(2-피리딜)티오-1-티옥소프로필, 2-아미노-3-(4-피리딜)피오프로피오닐, 2-아미노-3-(4-피리딜)티오-1-티옥소프로필, 2-아미노-3-[1-(2-디메틸아미노에틸)-1H-테트라졸-5-일]티오프로피오닐, 2-아미노-3-[1-(2-디메틸아미노에틸)-1H-테트라졸-5-일]티오-1-티옥소프로필, 2-아미노-3-[메톡시메틸-1, 3, 4-티아디아졸-2-일]티오프로피오닐, 2-아미노-3-[5-메톡시메틸-1, 3, 4-티아졸-2-일]티오-1-티옥소프로필, 2-아미노-3-[1-(2-히드록시에틸)-1H-테트라졸-5-일]티오프로피오닐, 2-아미노-3-[1-(2-히드록시에틸)-1H-테트라졸-5-일]티오-1-티옥소프로필, 2-아세틸아미노-3-에틸티오프로피오닐, 2-아세틸아미노-3-에틸티오-1-티옥소프로필, 2-아세틸아미노-3-페닐티오카르보닐, 2-아세틸아미노-3-페닐티오-1-티옥소프로필, 2-아세틸아미노-3-(2-피리딜)티오프로피오닐, 2-아세틸아미노-3-(2-피리딜)티오-1-티옥소프로필, 2-메탄설포닐아미노-3-(2-피리딜)티오프로피오닐, 2-메탄설포닐아미노-3-(2-피리딜)티오-1-티옥소프로필, 2-메틸아미노-3-(4-피리딜)티오프로피오닐, 2-메틸아미노-3-(4-피리딜)티오-1-티오소프로필, 2-벤질아미노-3-(4-피리딜)티오프로피오닐, 2-벤질아미노-3-(4-피리딜)티오-1-티옥소프로필, 2-디메틸아미노-3-[1-(2-디메틸아미노에틸)-1H-테트라졸-5-일]티오프로피오닐, 2-디메틸아미노-3-[1-(2-디메틸아미노에틸)-1H-테트라졸-5-일]티오-1-티옥소프로필, 2-(N-아세틸-N-메틸)아미노-3-(5-메탄설포닐메틸-1, 3, 4-티아디아졸-2-일)티오프로피오닐, 2-(N-아세틸-N-메틸)아미노-3-(5-메탄설포닐메틸-1, 3, 4-티아디아졸-2-일)티오-1-티옥소프로필, 2-디페닐포스피노티오일아미노-3-(2-피리딜)티오프로피오닐, 2-디페닐포스피노티오일아미노-3-(2-피리딜)티오-1-티옥소프로필, 3-(2-피리딜)티오-2-P-톨루엔설포닐아미노프로피오닐, 3-(2-피리딜)티오-2-P-톨루엔설포닐아미노-1-티옥소프로필, 2-(4-에틸-2, 3-디옥소-1-피페라진카르보닐아미노)-3-메틸티오프로피오닐, 2-(4-에틸-2, 3-디옥소-1-피페라진키르보닐아미노)-3-메틸티오-1-티옥소프로필, 3-아지도-1, 2-디옥소프로필, 3-아지도-2-옥소-1-티옥소프로필, 3-아미노-1, 2-디옥소프로필, 3-아미노-2-옥소-1-티옥소프로필, 3-아세틸아미노-1, 2-디옥소프로필, 3-아세틸아미노-2-옥소-1-티옥소프로필, 3-메틸아미노-1, 2-디옥소프로필, 3-메틸아미노-2-옥소-1-티옥소프로필, 3-디메틸아미노-1, 2-디옥소프로필, 3-디메틸아미노-2-옥소-1-티옥소프로필, 3-에틸아미노-1, 2-디옥소프로필, 3-에틸아미노-2-옥소-1-티옥소프로필, 3-(N-아세틸-N-에틸)아미노-1, 2-디옥소프로필, 3-(N-아세틸-N-에틸)아미노-2-옥소-1-티옥소프로필, 3-(N-에틸-N-메탄설포닐)아미노-1, 2-디옥소프로필, 3-(N-에틸-2-메탄설포닐)아미노-2-옥소-1-티옥소프로필, 3-벤질아미노-1, 2-디옥소프로필, 3-벤질아미노-2-옥소-1-티옥소프로필, 3-(4-에틸-2, 3-디옥소-1-피페라진카르보닐아미노)-1, 2-디옥소프로필, 3-(4-에틸-2, 3-디옥소-1-피페라진카르보닐아미노)-2-옥소-1-티옥소프로필, 3-P-톨루엔설포닐아미노-1, 2-디옥소프로필, 3-P-톨루엔설포닐아미노-2-옥소-1-티오소프로필, 3-(N-벤질옥시카르보닐-N-메틸)아미노-1, 2-디옥소프로필, 3-(N-벤질옥시카르보닐-N-메틸)아미노-2-옥소-1-티옥소프로필, 3-포르밀아미노-1, 2-디옥소프로필, 3-포르밀아미노-2-옥소-1-티옥소프로필, 3-아세틸아미노-2-히드록시프로피오닐, 3-아세틸아미노-2-히드록시-1-티옥소프로필, 3-에틸아미노-2-히드록시프로피오닐, 3-에틸아미노-2-히드록시-1-티옥소프로필, 3-(N-에틸-N-프로피오닐)아미노-2-히드록시프로피오닐, 3-(N-에틸-N-프로피오닐)아미노-2-히드록시-1-티옥소프로필, 3-벤질아미노-2-히드록시프로피오닐, 3-벤질아미노-2-히드록시-1-티옥소프로필, 2-히드록시-3-아닐리노프로피오닐, 2-히드록시-3-아닐리노-1-티옥소프로필, 3-벤질옥시카르보닐아미노-2-히드록시프로피오닐, 3-벤질옥시카르보닐아미노-2-히드록시-1-티옥소프로필, 2-히드록시-3-(N-메틸-N-메탄설포닐)아미노프로피오닐, 2-히드록시-3-(N-메틸-N-메탄설포닐)아미노-1-티옥소프로필, 3-(N-벤질-N-메탄설포닐)아미노-2-히드록시프로피오닐, 3-(N-벤질-N-메탄설포닐)아미노-2-히드록시-1-티옥소프로필, 3-(5-카르복시이미다졸-4-일)카르보닐아미노-2-히드록시프로피오닐, 3-(5-카르복시이미다졸-4-일)카르보닐아미노-2-히드록시-1-티옥소프로필, 2-히드록시-3-(4-히드록시-6-메틸피리딘-3-일)카르보닐아미노프로피오닐, 2-히드록시-3-(4-히드록시-6-메틸피리딘-3-일)카르보닐아미노-1-티옥소프로필, 2-아세톡시-3-아세틸아미노프로피오닐, 2-아세톡시-3-아세틸아미노-1-티옥소프로필, 3-아세틸아미노-2-프로피오닐옥시프로피오닐, 3-아세틸아미노-2-프로피오닐옥시-1-티옥소프로필, 2-아세톡시-3-디메톡시아미노프로피오닐, 2-아세톡시-3-디메톡시아미노-1-티옥소프로필, 2-벤질옥시-3-메틸아미노프로피오닐, 2-벤질옥시-3-메틸아미노-1-티옥소프로필, 3-벤질아미노-2-헵타노일옥시프로피오닐, 3-벤질아미노-2-헵타노일옥시-1-티옥소프로필, 2-페닐아세톡시-3-아닐리노프로피오닐, 2-페닐아세톡시-3-아닐리노-1-티옥소프로필, 2-벤질옥시-3-메탄설포닐아미노프로피오닐, 2-벤질옥시-3-메탄설포닐아미노-1-티옥소프로필, 3-(N-메틸-N-P-톨루엔설포닐)아미노-2-페녹시아세톡시프로피오닐, 3-(N-메틸-N-P-톨루엔설포닐)아미노-2-페녹시아세톡시-1-티옥소프로필, 2-아세톡시-3-(N-에틸-N-포르밀)아미노프로피오닐, 2-아세톡시-3-(N-에틸-N-포르밀)아미노-1-티옥소프로필, 3-[N-(4-에틸-2, 3-디옥소피페라진-1-카르보닐)-N-메틸]아미노-2-이소부티릴옥시프로피오닐, 3-(N-(4-에틸-2, 3-디옥소피페라진-1-카르보닐)-N-메틸]아미노-2-이소부티릴옥시-1-티옥소프로필, 3-아세틸아미노-2-메탄설포닐옥시프로피오닐, 3-아세틸아미노-2-메탄솔포닐옥시-1-티옥소프로필, 3-아세틸아미노-2-P-톨루엔설포닐옥시프로피오닐, 3-아세틸아미노-2-P-톨루엔설포닐옥시-1-티옥소프로필, 2-메탄설포닐옥시-3-프로피오닐아미노프로피오닐, 2-메탄설포닐옥시-3-프로피오닐아미노-1-티옥소프로필, 3-벤질아미노-2-메탄설포닐옥시프로피오닐, 3-벤질아미노-2-메탄설포닐옥시-1-티옥소프로필, 2-메탄설포닐옥시-3-메틸아미노프로피오닐, 2-메탄설포닐옥시-3-메틸아미노-1-티옥소프로필, 3-에틸아미노-2-메탄설포닐옥시프로피오닐, 3-에틸아미노-2-메탄설포닐옥시-1-티옥프로필, 3-디메틸아미노-2-P-톨루엔설포닐옥시프로피오닐, 3-디메틸아미노-2-P-톨루엔설포닐옥시-1-티옥소프로필, 2-메탄설포닐옥시-3-(4-모르폴리노)프로피오닐, 2-메탄설포닐옥시-3-(4-모르폴리노)-1-티옥소프로필, 3-(N-에틸-N-메틸)아미노-2-메탄설포닐옥시프로피오닐, 3-(N-에틸-N-메틸)아미노-2-메탄설포닐옥시-1-티옥소프로필, 3-메탄설포닐아미노-2-메탄설포닐옥시프로피오닐, 3-메탄설포닐아미노-2-메탄설포닐옥시-1-티옥소프로필, 3-벤질옥시카르보닐아미노-2-메탄설포닐옥시-1-티옥소프로필, 2-메탄설포닐옥시-3-(2-티오펜설포닐)아미노-1-티옥소프로필, 2-아세틸아미노-2-요오도프로피오닐, 3-아세틸아미노-2-요오도-1-티옥소프로필, 2-요오도-3-프로피오닐아미노프로피오닐, 2-요오도-3-프로피오닐아미노-1-티옥소프로필, 3-벤조일아미노-2-요오도프로피오닐, 3-벤조일아미노-2-요오도-1-티옥소프로필, 3-벤질아미노-2-요오도프로피오닐, 3-벤질아미노-2-요오도-1-티옥소프로필, 2-요오도-3-메틸아미노프로피오닐, 2-요오도-3-메틸아미노-1-티옥소프로필, 3-에틸아미노-2-요오도프로피오닐, 3-에틸아미노-2-요오도-1-티옥소프로필, 3-디에틸아미노-2-요오도프로피오닐, 3-디에틸아미노-2-요오도-1-티옥소프로필, 2-요오도-3-피페리디노프로피오닐, 2-요오도-3-피페리디노-1-티옥소프로필, 2-요오도-3-피롤리디노프로피오닐, 2-요오도-3-피롤리디노-1-티옥소프로필, 2-요오도-3-(4-메틸-1-피페라지닐)프로피오닐, 2-요오도-3-(4-메틸-1-티옥소프로필, 3-(4-아세틸-1-피페라지닐)-2-요오도프로피오닐, 3-(4-아세틸-1-피페라지닐)-2-요오도-1-티옥소프로필, 2-요오도-3-(N-메탄설포닐-N-메틸)아미노프로피오닐, 2-요오도-3-(N-메탄설포닐-N-메틸)아미노-1-티옥소프로필, 3-아세틸아미노-2-아지도프로피오닐, 3-아세틸-2-아지도-1-티옥소프로필, 2-아지도-3-프로피오닐아미노프로피오닐, 2-아지도-3-프로피오닐아미노-1-티옥소프로필, 2-아지도-3-(N-벤조일-N-메틸)아미노프로피오닐, 2-아지도-3-(N-벤조일-N-메틸)아미노-1-티옥소프로필, 2-아지도-3-디에틸아미노프로피오닐, 2-아지도-3-디에틸아미노-1-티옥소프로필, 2-아지도-3-메탄설포닐아미노프로피오닐, 2-아지도-3-메탄설포닐아미노-1-티옥소프로필, 2, 3-디아미노-1-옥소프로필, 2, 3-디아미노프로피오닐, 2-아미노-3-디메틸아미노프로피오닐, 2-아미노-3-디메틸아미노-1-티옥소프로필, 3-아세틸아미노-2-아미노프로피오닐, 3-아세틸아세틸-2-아미노-1-티옥소프로필, 2-아미노-3-벤질옥시카르보닐아미노프로피오닐, 2-아미노-3-벤질옥시카르보닐아미노-1-티옥소프로필, 2-아미노-3-P-톨루엔설포닐아미노프로피오닐, 2-아미노-3-P-톨루엔설포닐아미노-1-티옥소프로필, 2-아미노-3-(N-벤질-N-에틸)아미노프로피오닐, 2-아미노-3-(N-벤질-N-에틸)아미노-1-티옥소프로필, 2, 3-비스아세틸아미노프로피오닐, 2, 3-비스아세틸아미노-1-티옥소프로필, 3-아세틸아미노-2-디메틸아미노프로피오닐, 3-아세틸아미노-2-디메틸아미노-1-티옥소프로필, 3-아세틸아미노-2-벤질옥시카르보닐아미노프로피오닐, 3-아세틸아미노-2-벤질옥시카르보닐아미노-1-티옥소프로필, 3-에틸아미노프로피오닐, 3-에틸아미노-2-메틸아미노-1-티옥소프로필, 2-메탄설포닐아미노-3-모르폴리노프로피오닐, 2-메탄설포닐아미노-3-모르폴리노-1-티옥소프로필, 2-디에틸아미노아미노-3-메탄설포닐아미노프로피오닐, 2-디에틸아미노-3-메탄설포닐아미노-1-티옥소프로필, 3-벤질아미노-2-프로피오닐아미노프로피오닐, 3-벤질아미노-2-프로피오닐아미노-1-티옥소프로필, 3-아세틸아미노-2-에틸티오프로피오닐, 3-아세틸아미노-2-에틸티오-1-티옥소프로필, 3-아세틸아미노-2-(피리딜)티오프로피오닐, 3-아세틸아미노-2-(2-피리딜)티오-1-티옥소프로필, 3-디메틸아미노-2-(2-피리딜)티오프로피오닐, 3-디메틸아미노-2-(2-피리딜)티오-1-티옥소프로필, 3-에틸아미노-2-(4-피리딜)티오프로피오닐, 3-에틸아미노-2-(4-피리딜)티오-1-티옥소프로필, 2-[1-(2-디메틸아미노에틸-1H-테트라졸-5-일]티오-3-메탄설포닐아미노프로피오닐, 2-[1-(2-디메틸아미노에틸)-1H-테트라졸-5-일]티오-3-메탄설포닐아미노-1-티옥소프로필, 2-페닐티오-3-피롤리디노프로피오닐, 2-페닐티오-3-피롤리디노프로피오닐, 2-페닐티오-3-피롤리디노-3-피롤리디노프로필오닐, 2-페닐티오-3-피롤리디노-3-피롤리디노-1-티옥소프로필, 3-벤조일아미노-2-(4-메틸-4H-1, 2, 4-트리아졸-3-일)티오프로피오닐, 3-벤조일아미노-2-(4-메틸-4H-1, 2, 4-트리아졸-3-일)티오-1-티옥소프로필, 2-히드록시아미노-3-(2-피리딜)티오프로피오닐, 2-히드록시이미노-3-(2-피리딜)티오-1-티옥소프로필, 2-메톡시이미노-3-[(2-피리딜)티오]프로피오닐, 2-메톡시 이미노-3-(2-피리딜)티오-1-티옥소프로필, 2-히드록시 이미노-3-[(4-피리딜)티오]프로피오닐, 2-히드록시 이미노-3-(4-피리딜)티오-1-티옥소프로필, 2-메톡시이미노-3-[(4-피리딜)티오]프로피오닐, 2-메톡시이미노-3-(4-피리딜)티오-1-티옥소프로필, 2-(2-아미노 티아졸-4-일)-2-히드록시이미노아세틸, 2-(2-아미노 티아졸-4-일)-2-히드록시이미노-1-티옥소에틸, 2-(2-아미노티아졸-4-일)-2-메톡시이미노 아세틸, 2-(2-아미노 티아졸-4-일)-2-메톡시 이미노-1-티옥소 에틸, 2-(5-아미노-1, 2, 4-티아디아졸-3-일)-2-메톡시 이미노 아세틸, 2-(5-아미노-1, 2, 4-티아디아졸-3-일)-2-메톡시 이미노-1-티옥소 에틸, 2-(5-아미노-5-클로로티아졸-4-일)-2-메톡시 이미노 아세틸, 2-(5-아미노-5-클로로 티아졸-4-일)-2-메톡시 이미노-1-티옥소 에틸, 2-(2-아미노 티아졸-4-일)-2-카르복시메톡시이미노 아세틸, 2-(2-이미노티아졸-4-일)-2-카르복시 메톡시 이미노-1-티옥소 에틸, 2-(2-아미노 티아졸-4-일)-2-(1-카르복시-1-메틸 에톡시 이미노)아세틸, 2-(2-아미노 티아졸-4-일)-2-(1-카르복시-1-메틸 에톡시 이미노)-1-티옥소 에틸, 2-(2-아미노 티아졸-4-일)-2-(1H-이미다졸-4-일)메톡시 이미노 아세틸, 2-(2-아미노 티아졸-4-일)-2-(1H-이미다졸-4-일)메톡시 이미노-1-티옥소 에틸, 2-(2-아미노 티아졸-4-일)-2-(2-플루오로 에톡시)이미노 아세틸, 2-(2-아미노 티아졸-4-일(-2-(2-플루오로 에톡시)이미노-1-티옥소 에틸, 2-히드록시프로피오닐, 2-히드록시-1-티옥소프로필, 2-히드록시-2-페닐 아세틸, 2-히드록시-2-페닐-1-티옥소 에틸, 2-히드록시-3-[(1-메틸-1H-1, 3, 4-2-페닐-1-티옥소 에틸, 2-히드록시이미노프로피오닐, 2-히드록시 이미노-1-티옥소프로필, 2-메톡시이미노프로피오닐, 2-메톡시 이미노-1-티옥소프로필, 2-히드록시-3-[(1-메틸-1H-1, 3, 4-트리아졸-2-일)티오]프로피오닐, 2-히드록시-3-(1-메틸-1H-1, 3, 4-트리아졸-2-일)티오-1-티옥소프로필, 2-히드록시-3-[(1-메틸-1H-테트라졸-5-일)티오]프로피오닐, 2-히드록시-3-(1-메틸-1H-테트라졸-5-일)티오-1-티옥소프로필, 2-히드록시-3-[5-(2-디메틸 아미노 에틸)-1, 3, 4-티아디아졸-2-일]티오프로피오닐, 2-히드록시-3-[[5-(2-디메틸 아미노 에틸)-1, 3, 4-티아디아졸-2-일]티오]-1-티옥소프로필, 2-히드록시-2-[4-(2-아미노-2-카르복시 에톡시 카르보닐 아니모)페닐]아세틸, 2-히드록시-2-[4-(2-아미노-2-카르복시에톡시카르보닐아미노)페닐]아세틸, 2-히드록시-2-[4-(2-아미노-2-카르복시에톡시카르보닐아미노)페닐]-1-티옥소 에틸, 2-포르밀옥시프로피오닐, 2-포르밀옥시-1-티옥소프로필, 2-아세톡시프로피오닐, 2-아세톡시-1-티옥소프로필, 2-프로피오닐옥시프로피오닐, 프로피로닐옥시-1-티옥소프로필, 3-옥타노일옥시프로피오닐, 3-옥타노일 옥시-1-티옥소프로필, α-프로밀옥시-2-페닐-1-티옥소 에틸, 2-포르밀옥시-2-페닐-1-티옥소 에틸, 2-아세톡시-3-(2-피리딜)티오-1-티옥소프로필, 2-아세톡시-3-(4-피리딜티오)프로피오닐, 2-아세톡시-3-(4-피리딜)티오-1-티옥소프로필, 2-아세톡시-3-(페닐티오)프로피오닐, 2-아세톡시-3-페닐-1-티옥소프로필, α-아세톡시페닐아세틸, 2-아세톡시-2-페닐-1-티옥소프로필, 2-메탄설포닐옥시프로피오닐옥시프로피오닐, 2-메탄설포닐옥시-1-티옥소프로필, 2-(4-톨루엔설포닐옥시)프로피오닐, 2-(4-톨루엔설포닐옥시)-1-티옥소프로필, 2-클로로프로피오닐, 2-클로로-1-티옥소프로필, 2-브로모프로피오닐, 2-브로모-1-티옥소프로필, 2-요오도프로피오닐, 2-요오도-1-티옥소프로필, 2-(에틸티오)-프로피오닐, 2-메틸티오-1-티옥소프로필, 2-(메틸티오)프로피오닐, 2-에틸티오-1-티옥소프로필, 2-(페닐티오)프로피오닐, 2-페닐티오-1-티옥소프로필, 2-(2-피리딜티오)프로피오닐, 2-(2-피리딜티오)-1-티옥소프로필, 2-(4-피리딜티오)프로피오닐, 2-(4-피리딜티오)-1-티옥소프로필, 2-[(1-메틸-1H-1, 3, 4-트리아졸-2-일)티오]프로피오닐, 2-[(1-메틸-1H-1, 3, 4-트리아졸-2-일)티오]-1-티옥소프로필, 2-[[1-(2-디메틸 아미노 에틸)-1H-테트라졸-5-일]티오]프로피오닐, 2-[[1-(2-디메틸 아미노 에틸)-1H-테트라졸-5-일]티오]-1-티옥소프로필, α-메틸 티오페닐 아세틸, 2-메틸티오-2-페닐-1-티옥소 에틸, 2-(2-아미노 티아졸-4-일)-2-(메틸티오)아세틸, 2-(2-아미노 티아졸-4-일)-2-메틸티오-1-티옥소 에틸, 2-(N-메틸티오 카르바모일티오)프로피오닐, 2-(N-에틸 티오카르바모일티오)프로피오닐, 2-아지도프로피오닐, 2-아지도-1-티옥소프로필, α-아지도페닐 아세틸, 2-아지도-2-페닐-1-티옥소 에틸, 2-아지도-2-(4-히드록시 페닐)아세틸, 2-아지도-2-(4-히드록시페닐)-1-티옥소 에틸, 2-아미노 프로피오닐, 2-아미노-1-티옥소프로필, α-아미노 페닐 아세틸, 2-아미노-2-페닐-1-티옥소 에틸, 2-아미노-2-(4-히드록시 페닐)아세틸, 2-아미노-2-(4-히드록시 페닐)-4-티옥소 에틸, 2-아미노-2-(3, 4-디히드록시 페닐)아세틸, 2-아미노-2-(3, 4-디히드록시 페닐)-1-티옥소 에틸, 2-아미노-2-(20아미노 티아졸-4-일)아세틸, 2-아미노-2-(2-아미노 티아졸-4-일)-1-티옥소 에틸, 2-아미노-2-(3-벤조티에닐)아세틸, 2-아미노-2-(3-벤조티에닐)-1-티옥소 에틸, 2-아미노-2-(2-나프틸아세틸, 2-아미노-2-(2-나프틸)-1-티옥소 에틸, 2-아미노-2-(3-에탄설포닐아미노페닐)아세틸, 2-아미노-2-(3-에탄설포닐 아미노 페닐)-1-티옥소 에틸, 2-(4-에틸-2, 3-디옥소 피페라진-1-카르보닐 아미노)-2-페닐 아세틸, 2-(4-에틸-2, 3-디옥소 피페라진-1-카르보닐 아미노)-2-페닐-1-티옥소 에틸, 2-(4-에틸-2, 3-디옥소 피페라진-1-카르보닐 아미노)-2-(4-히드록시 페닐)아세틸, 2-(4-에틸-2, 3-디옥소 피페라진-1-카르보닐 아미노)-2-(4-히드록시 페닐)-1-티옥소 에틸, 2-포르밀아미노-2-페닐 아세틸, 2-포르밀 아미노-2-페닐-1-티옥소 에틸, 2-(2-아미노 티아졸-4-일)-2-포르밀 아미노 아세틸, 2-(2-아미노 티아졸-4-일)-2-포르밀 아미노-1-티옥소 에틸, 2-아세틸 아미노프로피오닐, 2-아세틸 아미노-1-티옥소프로필, 2-프로피오닐 아미노 프로피오닐, 2-프로피오닐 아미노-1-티옥소프로필, 2-부티릴 아미노 프로피오닐, 2-부티릴 아미노-1-티옥소프로필, 2-벤질 옥시카르보닐 아미노프로피오닐, 2-벤질 옥시카르보닐 아미노-1-티옥소프로필, 2-(p-톨루엔 설포닐 아미노)프로피오닐, 2-(p-톨루엔 설포닐 아미노)-1-티옥소프로필, 2-(디페닐 포스피노티오일 아미노)프로피오닐, 2-(디페닐 포스피노 티오일 아미노)-1-티옥소프로필, 2-(4-에틸-2, 3-디옥소 피페라진-1-카르보닐 아미노)-2-(3, 4-디히드록 시페닐)아세틸, 2-(4-에틸-2, 3-디옥소 피페라진-1-카르보닐 아미노-2-(3, 4-디히드록시 페닐)-1-티옥소 에틸, 2-(4-에틸-2, 3-디옥소 피페라진-1-카르보닐 아미노)-3-히드록시부티릴, 2-(4-에틸-2, 3-디옥소 피페라진-1-카르보닐 아미노)-3-히드록시-1-티옥소 부틸, 2-(5-카르복시-1H-이미다졸-4-일)카르보닐 아미노-2-페닐 아세틸, 2-(5-카르복시-1H-이미다졸-4-일)카르보닐 아미노-2-페닐-1-티옥소 에틸, 2-(4-히드록시-6-메틸 피리딘-3-일)카르보닐 아미노-2-(4-히드록시 페닐)아세틸, 2-(4-히드록시-6-메틸 피리딘-3-일)카르보닐 아미노-2-(4-히드록시 페닐)-1-티옥소 에틸, 2-카르복시-2-페닐 아세틸, 2-카르복시-2-페닐-1-티옥소 에틸, 2-설포-2-페닐 아세틸, 2-설포-2-페닐-1-티옥소 에틸, 2-카르복시-2-(4-히드록시 페닐)아세틸, 2-카르복시-2-(4-히드록시 페닐)-1-티옥소 에틸, 2-카르복시-2-(3, 4-디아세톡시페닐)아세틸, 2-카르복시-2-(3, 4-디아세톡시페닐)-1-티옥소 에틸, 2-(4-히드록시페닐)-2-설포 아세틸, 2-(4-히드록시페닐)-2-설포-1-티옥소 에틸, 2-(3, 4-디히드록시페닐)-2-설포 아세틸, 2-(3, 4-디히드록시페닐)-2-설포-1-티옥소 에틸, 2-(4-클로로 페닐)-2-설포-1-티옥소 에틸, 2-(4-메톡시 페닐)-2-설포 아세틸, 2-(4-메톡시 페닐)-2-설포-1-티옥소 에틸, 2-(4-아세틸 아미노 페닐)-2-카르복시아세틸, 2-(4-아세틸 아미노 페닐)-2-카르복시-1-티옥소 에틸, 벤조일, 페닐-1-티오카르보닐, (2-아미노티아졸-4-일)카르보닐, (2-아미노 티아졸-4-일)-1-티옥소 메틸, 아크릴로일, 비닐(티오카르보닐)(3-에톡시카르보닐)아크릴로일, 2-에톡시카르보닐-1-티옥소알릴, 카프릴로일, 1-티옥소헥실, 시클로 헥산카르보닐, 시클로헥산-티오카르보닐, (5-아미노-1, 2, 4-티아디아졸-3-일)-1-티옥소 메틸, 시클로프로판카르보닐, 시클로프로판티오카르보닐, 시클로부탄카르보닐, 시클로부탄티오카르보닐, 시클로펜탄카르보닐, 시클로펜탄티오카르보닐, 시클로-3-헥센카르보닐, 시클로-3-헥센-티오카르보닐, 시클로-1, 4-헥산디엔카르보닐, 시클로-1, 4-시클로헥사디엔-티오카르보닐, 3, 3-디클로로 아크릴로일, 2, 2-디클로로 비닐-티오카르보닐, 2-(2-아미노 티아졸-4-일)-3-클로로 아크릴로일, 2-(2-아미노 티아졸-4-일)-3-클로로 비닐-티오카르보닐, 2-(2-아미노 티아졸-4-일)-3-브로모 아크릴로일, 2-(2-아미노 티아졸-4-일)-3-브로모비닐-티오카르보닐, 2-히드라조노-2-(2-아미노 티아졸-4-일)아세틸, 2-히드라조노-2-(2-아미노 티아졸-4-일)-1-티옥소 에틸, 2-트리 메틸실릴옥시프로피오닐, 2-트리메틸실리옥시-1-티옥소프로필, 2-t-부틸디메틸실리옥시프로피오닐, 2-t-부틸디메틸실릴옥시-2-티옥소프로필, 2-페닐설피닐프로피오닐, 2-페닐설피닐-1-티옥소프로필, 2-벤젠설포닐프로피오닐, 2-벤젠설포닐-1-티옥소프로필 등이다.-R^5D(R^5DIs aryl, C_{5 ~ 7}Cycloalkyl or heterocycle group), -C (= NOR^5ER^5F(R^5EIs hydroxyl or C_{1 to 3}Alkoxy and R^5FIs a heterocycle group via a sulfur group, optionally substituted with halogen_{1 to 3}Alkyl) or -CY^B= CH₂(Y is hydrogen, C_{2 ~ 5}Alkanoyloxy, C_1-5Alkoxycarbonyloxy or tri-C_{1 to 3}In the case of a group represented by

Examples of groups represented by acetyl,  1-thioxoethyl,  Chloroacetyl,  2-chloro-1-thioxoethyl,  Bromoacetyl,  2-bromo-1-thioxoethyl,  Iodoacetyl,  2-iodo-1-thioxoethyl,  Methoxyacetyl,  2-methoxy-1-thioxoethyl,  Ethoxyacetyl,  2-ethoxy-1-thioxoethyl,  Phenoxyacetyl,  2-phenoxy-1-thioxyethyl,  Benzyloxyacetyl,  2-benzyloxy-1-thioxoethyl,  4-chlorophenoxyacetyl,  2- (4-chlorophenoxy) -1-thioxoethyl,  4-hydroxyphenoxyacetyl,  2- (4-hydroxyphenoxy) -1-thioxoethyl,  4-acetoxyphenoxyacetyl,  2- (4-acetoxyphenoxy) -1-thioxoethyl,  Phenylacetyl,  2-phenyl-1-thioxoethyl,  4-hydroxyphenylacetyl,  2- (4-hydroxyphenyl) -1-thioxoethyl,  3,  4-dihydroxyphenylacetyl,  2- (3,  4-dihydroxyphenyl) -1-thioxoethyl,  4-acetoxyphenylacetyl,  2- (4-acetoxyphenyl) acetyl,  2- (4-acetoxyphenyl) -1-thioxoethyl,  3,  4-diacetoxyphenylacetyl,  20 (3,  4-diacetoxyphenyl) -1-thioxoethyl,  3,  4,  5-triacetoxyphenylacetyl,  2- (3,  4,  5-triacetoxyphenyl) -1-thioxoethyl,  2-aminomethylphenylacetyl,  2- (2-aminomethylphenyl) -1-thioxoethyl,  2-dimethylaminosulfonylphenylacetyl,  2- (3-dimethylaminosulfonylphenyl) -1-thioxoethyl,  3-aminosulfonylmethylphenylacetyl,  2- (3-aminosulfonylmethylphenyl) -1-thioxoethyl,  3-methanesulfonylaminophenylacetyl,  2- (3-methanesulfonylaminophenyl) -1-thioxoethyl,  (One,  2-oxazol-3-yl) acetyl,  2- (1,  2-oxazol-3-yl) -thioxoethyl,  (One,  2-oxazol-5-yl) acetyl,  2- (1,  2-oxazol-5-yl) -1-thioxoethyl,  (1H-adizol-4-yl) acetyl  2- (1H-imidazol-4-yl) -thioxoethyl,  (1H-pyrazol-4-yl) acetyl,  2- (1H-pyrazol-4-yl) -1-thioxoethyl,  (5-amino-1,  2,  4-thiadiazol-3-yl) acetyl,  2- (5-amino-1,  2,  4-thiadiazol-3-yl) -1-thioxoethyl,  2-thienylacetyl,  2- (2-thienyl) -1-thioxoethyl,  2-furylacetyl,  2- (2-furyl) -1-thioxoethyl,  (1H-tetrazol-1-yl) acetyl,  2- (1H-tetrazol-1-yl) -1-thioxoethyl,  (Thiazol-4-yl) acetyl,  2- (thiazol-4-yl) -1-thioxoethyl,  (2-aminothiazol-4-yl) acetyl,  2- (2-aminothiazol-4-yl) -1-thioxoethyl,  (2-chloroacetylaminothiazol-4-yl) acetyl,  2- (2-chloroacetylaminothiazol-4-yl) -1-thioxoethyl,  Cyanoacetyl,  2-cyano-1-thioxoethyl,  Methylthioacetyl,  2-methylthio-1-thioxoethyl,  Ethylthioacetyl,  2-ethylthio-1-thioxoethyl,  Phenylthioacetyl,  2-phenylthio-1-thioxoethyl,  Trifluoromethylthioacetyl,  2-trifluoromethylthio-1-thioxoethyl,  Difluoromethylthioacetyl,  2-difluoromethylthio-1-thioxoethyl,  Cyanomethylthioacetyl,  2-cyanomethylthio-1-thioxoethyl,  4-pyridylthioacetyl,  2- (4-pyridylthio) -1-thioxoethyl,  (1-methyl-1H-triazol-2-yl) thioacetyl,  2- (1-methyl-1H-triazol-2-yl) thio-1-thioxoethyl,  (One,  5-dimethyl-1H-1,  3,  4-triazol-2-yl) thioacetyl,  2- (1,  5-dimethyl,  1H-1,  3,  4-triazol-2-yl) thio-1-thioxoethyl,  (1-methyl-1H-tetrazol-5-yl) thioacetyl,  2- (1-methyl-1H-tetrazol-5-yl) thio-1-thioxoethyl,  [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thioacetyl,  2- [2- (1-dimethylaminoethyl) -1H-tetrazol-5-yl] thio-1-thioxoethyl,  [1- (3-dimethylaminopropyl) -1H-tetrazol-5-yl] thioacetyl,  2- [1- (3-dimethylaminopropyl) -1H-tetrazol-5-yl] thio-1-thioxoethyl,  [1- (2-hydroxyethyl) -1H-tetrazol-5-yl] thioacetyl,  2- [1- (2-hydroxyethyl) -1H-tetrazol-5-yl] thio-1-thioxoethyl,  (1-carboxymethyl-1H-tetrazol-5-yl) thioacetyl,  2- (1-carboxymethyl-1H-tetrazol-5-yl) thio-1-thioxoethyl,  (1-sulfomethyl-1H-tetrazol-5-yl) thioacetyl,  2- (1-sulfomethyl-1H-tetrazol-5-yl) thio-1-thioxoethyl,  (5-methyl-1,  3,  4-thiadiazol-2-yl) thioacetyl,  2- (5-methyl-1,  3,  4-thiadiazol-2-yl) thio-1-thioxoethyl,  [5- (2-dimethylaminoethyl) -1,  3,  4-thiadiazol-2-yl] thioacetyl,  2- [5- (2-dimethylaminoethyl) -1,  3,  4-thiazol-2-yl] thio-1-thioxoethyl,  (5-methoxyethyl-1,  3,  4-thiadiazol-2-yl) thioacetyl,  2- (5-methoxymethyl-1,  3,  4-thiadiazol-2-yl) thio-1-thioxoethyl,  (5-methanesulfonylmethyl-1,  3,  4-thiadiazol-2-yl) thioacetyl,  2- (5-methanesulfonylmethyl-1,  3,  4-thiadiazol-2-yl) thio-1-thioxoethyl,  (3-methyl-1,  2,  3-thiadiazol-5-yl) thioacetyl,  2- (3-methyl-1,  2,  4-thiathiazol-5-yl) thio-1-thioxoethyl,  (One,  2,  3-thiadiazol-5-yl) thioacetyl,  2- (1,  2,  3-thiadiazol-5-yl) thio-1-thioxoethyl,  2-aminoethylthioacetyl,  2- (2-aminoethylthio) -1-thiol-1-thioxoethyl,  2- (2,  2,  2-trichloroethyloxycarbonylamino) ethylthioacetyl,  2- [2- (2,  2,  2-trichloroethyloxycarbonylamino) ethyl] thio-1-thioxoethyl,  2-aminovinylthioacetyl,  2- (2-aminovinyl) thio-1-thioxoethyl,  2- (2,  2,  2-trichloroethyloxycarbonylamino) vinylthioacetyl,  2- [2- (2,  2,  2,  -Trichloroethyloxycarbonylaminovinyl] thio-1-thioxoethyl,  (2-amino-2-carboxy) ethylthioacetyl,  2-[(2-amino-2-carboxy) ethyl] thio-1-thioxoethyl,  [3- (2-amino-2-carboxy) ethyl-1H-imidazol-2-yl] thioacetyl,  2- [3- (2-amino-2-carboxy) ethyl-1H-imidazol-2-yl] thio-1-thioxoethyl,  (4-carboxy-3-hydroxy-1,  2-thiazol-5-yl) thioacetyl,  2- (4-carboxy-3-hydroxy-1,  2-thiazol-5-yl) thio-1-thioxoethyl,  (1-amino-1H-tetrazol-5-yl) thioacetyl,  2- (1-amino-1H-tetrazol-5-yl) thio-1-thioxoethyl,  (1-dimethylamino-1H-tetrazol-5-yl) thioacetyl,  2- (1-dimethylamino-1H-tetrazol-5-yl) thio-1-thioxoethyl,  [1- (1H-tetrazol-5-yl) methyl-1H-tetrazol-5-yl] thioacetyl,  2- [1- (1H-tetrazol-5-yl) methyl-1H-tetrazol-5-yl] thio-1-thioxoethyl,  (6-hydroxy-4-methyl-5,  6-dihydro-1,  2,  4-triazine-5-one-3-yl) thioacetyl,  2- (6-hydroxy-4-methyl-5,  6-dihydro-1,  2,  4-triazine-5-one-3-yl) thio-1-thioxoethyl,  [5- (2-amino-2-carboxyethyl) -1H-imidazol-2-yl] thioacetyl,  2- [5- (amino-2-carboxyethyl) -1H-imidazol-2-yl] thio-1-thioxoethyl,  [5- (2-amino-2-carboxyethyl) -1,  3,  4-thiazol-2-yl] thioacetyl,  2- [5- (2-amino-2-carboxyethyl) -1,  3,  4-thiadiazol-2-yl] thio-1-thioxoethyl,  (2-amino-1,  3,  4-thiadiazol-5-yl) thioacetyl,  2- (2-amino-1,  3,  4-thiadiazol-5-yl) thio-1-thioxoethyl,  (4,  5-dicarboxy-1H-imidazol-2-yl) thioacetyl,  2- (4,  5-dicarboxy-1H-imidazol-2-yl) thio-1-thioxoethyl,  (5-amino-4-carboxy-1-methyl-1H-imidazol-2-yl) thioacetyl,  2- (5-amino-4-carboxy-1-methyl-1H-imidazol-1-yl) thio-1-thioxoethyl,  Tetrazolo [1,  5-b] pyridanyl-6-yl) thioacetyl,  (2-carbamoyl-2-fluorovinylthio) acetyl,  (2-carbamoyl-2-fluorovinylthio) -1-thioxoethyl,  2- (tetrazolo (1,  5-b] pyridazin-6-yl) thio-1-thioxoethyl,  One,  2-thioxoproprile,  2-oxo-1-thioxopropyl,  One,  2-dioxobutyl,  2-oxo-1-thioxobutyl,  One,  2-dioxopentyl,  2-oxo-1-thioxopentyl,  (One,  2-dioxo-3-phenyl) propyl,  3-phenyl-2-oxo-1-thioxopropyl,  (One,  2-dioxo-2-phenyl) ethyl,  (2-oxo-2-phenyl-thioxo) ethyl,  One,  2-dioxo-2- (thiazol-4-yl) ethyl,  2-oxo-2- (thiazol-4-yl) -1-thioxoethyl,  2- (2-aminothiazol-4-yl) -1,  2-dioxoethyl,  2- (2-aminothiazol-4-yl) -2-oxo-1-thioxoethyl,  2- (2-chloroacetylaminothiazol-4-yl) -1,  2-dioxoethyl,  2- (2-chloroacetylaminothiazol-4-yl) -2-oxo-1-thioxoethyl,  2- (5-amino-1,  2,  4-thiadiazol-3-yl) -1,  2-dioxoethyl,  2- (5-amino-1,  2,  4-thiadiazol-3-yl) -oxo-1-thioxoethyl,  3-bromo-1,  2-dioxopropyl,  3-bromo-2-oxo-1-thioxopropyl,  2- (benzoxazol-2-yl) thio-1,  2-dioxopropyl,  3- (benzothiazol-2-yl) thio-2-oxo-1-thioxopropyl,  3- (benzothiazol-2-yl) thio-1,  2-dioxopropyl,  3- (benzoxazol-2-yl) thio-2-oxo-1-thioxopropyl,  3-methylthio-1,  2-dioxopropyl,  3-methylthio-2-oxo-1-thioxopropyl,  3-ethylthio-1,  2-dioxopropyl,  3-ethylthio-2-oxo-1-thioxopropyl,  3- (2-pyridyl) dioxopropyl,  3-phenylthio-2-oxo-1-thioxopropyl,  3- (pyridyl) thio-1,  2-dioxopropyl,  3- (2-pyridyl) thio-2-oxo-1-thioxopropyl,  3- (4-pyridyl) thio-1,  2-dioxopropyl,  3- (4-pyridyl) thio-2-oxo-thioxopropyl,  3- (1-methyl-1,  3,  4-triazol-2-yl) thio-1,  2-dioxopropyl,  3- (1-methyl-1H-1,  3,  4-triazol-2-yl) thio-2-oxo-1-thioxopropyl,  3- [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thio-1,  2-dioxopropyl,  3- [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thio-2-oxo-1-thioxopropyl,  2-hydroxy-3- (2-pyridyl) thiopropionyl,  2-hydroxy-3- (2-pyridyl) thio-1-thioxopropyl,  2-hydroxy-3- (4-pyridyl) thiopropyronyl,  2-hydroxy-2- (4-pyridyl) thio-1-thioxopropyl,  3- [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thio-2-hydroxypropionyl,  2- [1- (dimethylaminoethyl) -1H-tetrazol-5-yl] thio-2-hydroxy-1-thioxopropyl,  2-hydroxy-3-phenylthiopropionyl,  2-hydroxy-3-phenylthio-1-thioxopropyl,  3-ethylthio-2-hydroxypropionyl,  3-ethylthio-2-hydroxy-1-thioxopropyl,  3- (2-benzothiazolyl) thio-2-hydroxypropionyl,  2- (2-benzothiazolyl) thio-2-hydroxypropionyl-1-thioxopropyl,  2-hydroxy-1-thioxopropyl,  2-hydroxy-3- (4-methyl-4H-1,  2,  4-triazol-3-yl) thiopropionyl,  2-hydroxy-3- (4-methyl-4H-1,  2,  4-triazol-3-yl) thiopropionyl-1-thioxopropyl,  2-acetoxy-3- (2-pyridyl) thiopropionyl,  2-acetoxy-3- (2-pyridyl) thio-1-thioxopropyl,  2-acetoxy-3- (4-pyridyl) thiopropionyl,  2-acetoxy-3- (4-pyridyl) thio-1-thioxopropyl,  2-propionyloxy-3- (2-pyridyl) thiopropionyl,  2-propionyloxy-3- (2-pyridyl) thio-1-thioxopropyl,  2-benzoyloxy-3- (2-pyridylthio-1-thioxopropyl,  2-benzoyloxy-3- (2-pyridyl) thio-1-thioxopropyl,  2-benzoyloxy-3- (4-pyridyl) thiopropyloyl,  2-benzoyloxy-3- (4-pyridyl) thio-1-thioxopropyl,  2-acetoxy-3- [1- (2-dimethylaminoethyl) -1 H-tetrazol-5-yl] -thiopropionyl,  2-acetoxy-3- [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thio-1-thioxopropyl,  2-acetoxy-3-ethylthiopropionyl,  2-acetoxy-3-ethylthio-1-thioxopropyl,  2-acetoxy-3- (4-methyl-4H-1,  2,  4-triazol-3-yl) thiopropionyl,  2-acetoxy-3- (4-methyl-4H-1,  2,  4-triazol-3-yl) thio-1-thioxopropyl,  2-methanesulfonyloxy-3- (2-pyridyl) thiopropionyl,  2-methanesulfonyloxy-3- (2-pyridyl) thio-1-thioxopropyl,  2-methanesulfonyloxy-3- (4-pyridyl) thiopropionyl,  2-methanesulfonyloxy-3- (4-pyridyl) thio-1-thioxopropyl,  3- (2-pyridyl) thio-2-P-toluenesulfonyloxypropionyl,  3- (2-pyridyl) thio-2-P-toluenesulfonyloxy-1-thioxopropyl,  3- (4-pyridyl) thio-1-P-toluenesulfonyloxypropionyl,  3- (4-pyridyl) thio-2-P-toluenesulfonyloxy-1-thioxopropyl,  3- [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thio-2-methanesulfonyloxypropionyl,  3- [1- (2-dimethylaminoethyl) (-9-1-tetrazol-5-yl] thio-2-methanesulfonyloxy-1-thioxopropyl,  3- [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thio-2-P-toluenesulfonyloxypropionyl,  3- [1- (2-dimethylaminoethyl (-1Htetrazol-5-yl) thio-2-Ptoluenesulfonyloxy-1-thioxopropyl,  3-ethylthio-2-methanesulfonyloxypropionyl,  3-ethylthio-2-methanesulfonyloxy-1-thioxopropyl,  2-methanesulfonyloxy-3-phenylthiopropionyl,  2-methanesulfonyloxy-3-phenylthio-1-thioxopropyl,  2-iodine-3-methylthiopropionyl,  2-iodo-3-methylthio-1-thioxopropyl,  3-ethylthio-2-iodopropionyl,  3-ethylthio-2-iodine-1-thioxopropyl,  2-iodo-3-phenylthiopropionyl,  2-iodine-3-phenylthio-1-thioxopropyl,  2-iodo-3- (2-pyridylthio) propionyl,  2-iodo-3- (2-pyridylthio) -1-thioxopropyl,  2-iodo- (4-pyridyl) thio-1-thioxopropyl,  3- [1- (2-dimethylaminoethyl-1H-tetrazol-5-yl] thio-2-iodopropionyl,  3- [1- (2-dimethylaminoethyl-1H-tetrazol-5-yl] thio-2-iodo-1-thioxopropyl,  2-iodo-3- (4-methyl-4H-1,  2,  4-triazol-3-yl) thiopropionyl,  2-iodo-3- (4-methyl-4H-1,  2,  4-triazol-3-yl) thio-1-thioxopropyl,  3- (2-benzothiazolyl) thio-2-iodopropionyl,  3- (2-benzothiazolyl) thio-2-iodo-1-thioxopropyl,  2-iodo-3- (2-benzosazolyl) thiopropionyl,  2-iodo-3- (2-benzoxazolyl) thio-1-thioxopropyl,  2,  3-bis (ethylthio) propionyl,  2,  3-bis (ethylthio-1- (thioxopropyl,  3-ethylthio-2- (2-pyridyl) thiopropionyl,  3-ethylthio-2- (2-pyridyl) thio-1-thioxopropyl,  3-ethylthio-2- (4-pyridyl) thiopropionyl,  3-ethylthio-2- (4-pyridyl) thio-1-thioxopropyl,  2-methylthio-3- (2-pyridyl) thiopropionyl,  2-methylthio-3- (2-pyridyl) thio-1-thioxopropyl,  2,  3-bis (2-pyridyl) thiopropionyl,  2,  3-bis (2-pyridyl) thio-1-thioxopropyl,  2,  3-bis (4-pyridyl) thiopropionyl,  2,  3-bis (4-pyridyl) thio-1-thioxopropyl,  2- (2-pyridyl) thio-3- (4-pyridyl) thiopropionyl,  2- (2-pyridyl) thio-3- (4-pyridyl) thio-1-thiopropyl,  2- [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thio-3- (2-pyridyl) thiopropionyl,  2- [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thio-3- (2-pyridyl) thio-1-thioxopropyl,  2- (4-methyl-1H-1,  2,  4-triazol-3-yl) thio-3- (2-pyridyl) thiopropionyl,  2- (4-methyl-1H-1,  2,  4-triazol-3-yl) thio-1-thioxopropyl,  2- (2-aminoethyl) thio-3-phenylthiopropionyl,  2- (2-aminoethyl) thio-3-phenylthio-1-thioxopropyl,  3- [1- (2-dimethylaminoethyl-1H-tetrazol-5-yl] thio-2- (2-pyridyl) thiopropionyl,  3- [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thio-2- (2-pyridyl) thio-1-thioxopropyl,  2-azido-3-methylthiopropionyl,  2-azido-3-methylthio-1-thioxopropyl,  2-azido-3-ethylthiopropionyl,  2-azido-3-ethylthio-1-thioxopropyl,  2-azido-3-phenylthiopropionyl,  2-azido-3-phenylthio-1-thioxopropyl,  2-azido-3- (2-pyridyl) thiopropionyl,  2-azido-3- (2-pyridyl) thio-1-thioxopropyl,  2-azido-3- (4-pyridyl) thiopropionyl,  2-azido-3- (4-pyridyl) thio-1-thioxopropyl,  2-azido-3- [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thiopropionyl,  2-azido-3- [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] -thio-1-thioxopropyl,  2-azido-3- [4-methyl-4H-1,  2,  4-triazol-3-yl] thiopropionyl,  2-azido-3- [4-methyl-4H-1,  2,  4-triazol-3-yl] thio-1-thioxopropyl,  2-azido-3- (2-benzothiazolyl) thiopropionyl,  2-azido-3- (2-benzothiazolyl) thio-1-thioxopropyl,  2-azido-3- (2-benzoxazolyl) thiopropionyl,  2-azido-3- (2-benzoxazolyl) thio-1-thioxopropyl,  2-azido-3-ethoxycarbonylmethylthiopropionyl,  2-azido-3-ethoxycarbonylmethylthio-1-thioxopropyl,  2-amino-3-ethylthiopropionyl,  2-amino-3-ethylthio-1-thioxopropyl,  2-amino-3- (2-methoxyethyl) thiopropionyl,  2-amino-3- (2-methoxyethyl) thio-1-thioxopropyl,  2-amino-3-phenylthiopropionyl,  2-amino-3-phenylthio-1-thioxopropyl,  2-amino-3- (2-pyridyl) thiopropionyl,  2-amino-3- (2-pyridyl) thio-1-thioxopropyl,  2-amino-3- (4-pyridyl) pyoproiononyl,  2-amino-3- (4-pyridyl) thio-1-thioxopropyl,  2-amino-3- [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thiopropionyl,  2-amino-3- [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thio-1-thioxopropyl,  2-amino-3- [methoxymethyl-1,  3,  4-thiadiazol-2-yl] thiopropionyl,  2-amino-3- [5-methoxymethyl-1,  3,  4-thiazol-2-yl] thio-1-thioxopropyl,  2-amino-3- [1- (2-hydroxyethyl) -1H-tetrazol-5-yl] thiopropionyl,  2-amino-3- [1- (2-hydroxyethyl) -1H-tetrazol-5-yl] thio-1-thioxopropyl,  2-acetylamino-3-ethylthiopropionyl,  2-acetylamino-3-ethylthio-1-thioxopropyl,  2-acetylamino-3-phenylthiocarbonyl,  2-acetylamino-3-phenylthio-1-thioxopropyl,  2-acetylamino-3- (2-pyridyl) thiopropionyl,  2-acetylamino-3- (2-pyridyl) thio-1-thioxopropyl,  2-methanesulfonylamino-3- (2-pyridyl) thiopropionyl,  2-methanesulfonylamino-3- (2-pyridyl) thio-1-thioxopropyl,  2-methylamino-3- (4-pyridyl) thiopropionyl,  2-methylamino-3- (4-pyridyl) thio-1-thiosopropyl,  2-benzylamino-3- (4-pyridyl) thiopropionyl,  2-benzylamino-3- (4-pyridyl) thio-1-thioxopropyl,  2-dimethylamino-3- [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thiopropionyl,  2-dimethylamino-3- [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thio-1-thioxopropyl,  2- (N-acetyl-N-methyl) amino-3- (5-methanesulfonylmethyl-1,  3,  4-thiadiazol-2-yl) thiopropionyl,  2- (N-acetyl-N-methyl) amino-3- (5-methanesulfonylmethyl-1,  3,  4-thiadiazol-2-yl) thio-1-thioxopropyl,  2-diphenylphosphinothioylamino-3- (2-pyridyl) thiopropionyl,  2-diphenylphosphinothioylamino-3- (2-pyridyl) thio-1-thioxopropyl,  3- (2-pyridyl) thio-2-P-toluenesulfonylaminopropionyl,  3- (2-pyridyl) thio-2-P-toluenesulfonylamino-1-thioxopropyl,  2- (4-ethyl-2,  3-dioxo-1-piperazinecarbonylamino) -3-methylthiopropionyl,  2- (4-ethyl-2,  3-dioxo-1-piperazinylcarbonylamino) -3-methylthio-1-thioxopropyl,  3-azido-1,  2-dioxopropyl,  3-azido-2-oxo-1-thioxopropyl,  3-amino-1,  2-dioxopropyl,  3-amino-2-oxo-1-thioxopropyl,  3-acetylamino-1,  2-dioxopropyl,  3-acetylamino-2-oxo-1-thioxopropyl,  3-methylamino-1,  2-dioxopropyl,  3-methylamino-2-oxo-1-thioxopropyl,  3-dimethylamino-1,  2-dioxopropyl,  3-dimethylamino-2-oxo-1-thioxopropyl,  3-ethylamino-1,  2-dioxopropyl,  3-ethylamino-2-oxo-1-thioxopropyl,  3- (N-acetyl-N-ethyl) amino-1,  2-dioxopropyl,  3- (N-acetyl-N-ethyl) amino-2-oxo-1-thioxopropyl,  3- (N-ethyl-N-methanesulfonyl) amino-1,  2-dioxopropyl,  3- (N-ethyl-2-methanesulfonyl) amino-2-oxo-1-thioxopropyl,  3-benzylamino-1,  2-dioxopropyl,  3-benzylamino-2-oxo-1-thioxopropyl,  3- (4-ethyl-2,  3-dioxo-1-piperazinecarbonylamino) -1,  2-dioxopropyl,  3- (4-ethyl-2,  3-dioxo-1-piperazinecarbonylamino) -2-oxo-1-thioxopropyl,  3-P-toluenesulfonylamino-1,  2-dioxopropyl,  3-P-toluenesulfonylamino-2-oxo-1-thiosopropyl,  3- (N-benzyloxycarbonyl-N-methyl) amino-1,  2-dioxopropyl,  3- (N-benzyloxycarbonyl-N-methyl) amino-2-oxo-1-thioxopropyl,  3-formylamino-1,  2-dioxopropyl,  3-formylamino-2-oxo-1-thioxopropyl,  3-acetylamino-2-hydroxypropionyl,  3-acetylamino-2-hydroxy-1-thioxopropyl,  3-ethylamino-2-hydroxypropionyl,  3-ethylamino-2-hydroxy-1-thioxopropyl,  3- (N-ethyl-N-propionyl) amino-2-hydroxypropionyl,  3- (N-ethyl-N-propionyl) amino-2-hydroxy-1-thioxopropyl,  3-benzylamino-2-hydroxypropionyl,  3-benzylamino-2-hydroxy-1-thioxopropyl,  2-hydroxy-3-anilinopropionyl,  2-hydroxy-3-anilino-1-thioxopropyl,  3-benzyloxycarbonylamino-2-hydroxypropionyl,  3-benzyloxycarbonylamino-2-hydroxy-1-thioxopropyl,  2-hydroxy-3- (N-methyl-N-methanesulfonyl) aminopropionyl,  2-hydroxy-3- (N-methyl-N-methanesulfonyl) amino-1-thioxopropyl,  3- (N-benzyl-N-methanesulfonyl) amino-2-hydroxypropionyl,  3- (N-benzyl-N-methanesulfonyl) amino-2-hydroxy-1-thioxopropyl,  3- (5-carboxyimidazol-4-yl) carbonylamino-2-hydroxypropionyl,  3- (5-carboxyimidazol-4-yl) carbonylamino-2-hydroxy-1-thioxopropyl,  2-hydroxy-3- (4-hydroxy-6-methylpyridin-3-yl) carbonylaminopropionyl,  2-hydroxy-3- (4-hydroxy-6-methylpyridin-3-yl) carbonylamino-1-thioxopropyl,  2-acetoxy-3-acetylaminopropionyl,  2-acetoxy-3-acetylamino-1-thioxopropyl,  3-acetylamino-2-propionyloxypropionyl,  3-acetylamino-2-propionyloxy-1-thioxopropyl,  2-acetoxy-3-dimethoxyaminopropionyl,  2-acetoxy-3-dimethoxyamino-1-thioxopropyl,  2-benzyloxy-3-methylaminopropionyl,  2-benzyloxy-3-methylamino-1-thioxopropyl,  3-benzylamino-2-heptanoyloxypropionyl,  3-benzylamino-2-heptanoyloxy-1-thioxopropyl,  2-phenylacetoxy-3-anilinopropionyl,  2-phenylacetoxy-3-anilino-1-thioxopropyl,  2-benzyloxy-3-methanesulfonylaminopropionyl,  2-benzyloxy-3-methanesulfonylamino-1-thioxopropyl,  3- (N-methyl-N-P-toluenesulfonyl) amino-2-phenoxycetoxypropionyl,  3- (N-methyl-N-P-toluenesulfonyl) amino-2-phenoxycetoxy-1-thioxopropyl,  2-acetoxy-3- (N-ethyl-N-formyl) aminopropionyl,  2-acetoxy-3- (N-ethyl-N-formyl) amino-1-thioxopropyl,  3- [N- (4-ethyl-2,  3-dioxopiperazin-1-carbonyl) -N-methyl] amino-2-isobutyryloxypropionyl,  3- (N- (4-ethyl-2,  3-dioxopiperazin-1-carbonyl) -N-methyl] amino-2-isobutyryloxy-1-thioxopropyl,  3-acetylamino-2-methanesulfonyloxypropionyl,  3-acetylamino-2-methanesulfonyloxy-1-thioxopropyl,  3-acetylamino-2-P-toluenesulfonyloxypropionyl,  3-acetylamino-2-P-toluenesulfonyloxy-1-thioxopropyl,  2-methanesulfonyloxy-3-propionylaminopropionyl,  2-methanesulfonyloxy-3-propionylamino-1-thioxopropyl,  3-benzylamino-2-methanesulfonyloxypropionyl,  3-benzylamino-2-methanesulfonyloxy-1-thioxopropyl,  2-methanesulfonyloxy-3-methylaminopropionyl,  2-methanesulfonyloxy-3-methylamino-1-thioxopropyl,  3-ethylamino-2-methanesulfonyloxypropionyl,  3-ethylamino-2-methanesulfonyloxy-1-thiopropyl,  3-dimethylamino-2-P-toluenesulfonyloxypropionyl,  3-dimethylamino-2-P-toluenesulfonyloxy-1-thioxopropyl,  2-methanesulfonyloxy-3- (4-morpholino) propionyl,  2-methanesulfonyloxy-3- (4-morpholino) -1-thioxopropyl,  3- (N-ethyl-N-methyl) amino-2-methanesulfonyloxypropionyl,  3- (N-ethyl-N-methyl) amino-2-methanesulfonyloxy-1-thioxopropyl,  3-methanesulfonylamino-2-methanesulfonyloxypropionyl,  3-methanesulfonylamino-2-methanesulfonyloxy-1-thioxopropyl,  3-benzyloxycarbonylamino-2-methanesulfonyloxy-1-thioxopropyl,  2-methanesulfonyloxy-3- (2-thiophensulfonyl) amino-1-thioxopropyl,  2-acetylamino-2-iodopropionyl,  3-acetylamino-2-iodo-1-thioxopropyl,  2-iodo-3-propionylaminopropionyl,  2-iodo-3-propionylamino-1-thioxopropyl,  3-benzoylamino-2-iodopropionyl,  3-benzoylamino-2-iodo-1-thioxopropyl,  3-benzylamino-2-iodopropionyl,  3-benzylamino-2-iodo-1-thioxopropyl,  2-iodo-3-methylaminopropionyl,  2-iodo-3-methylamino-1-thioxopropyl,  3-ethylamino-2-iodopropionyl,  3-ethylamino-2-iodo-1-thioxopropyl,  3-diethylamino-2-iodopropionyl,  3-diethylamino-2-iodo-1-thioxopropyl,  2-iodo-3-piperidinopropionyl,  2-iodo-3-piperidino-1-thioxopropyl,  2-iodo-3-pyrrolidinopropionyl,  2-iodo-3-pyrrolidino-1-thioxopropyl,  2-iodo-3- (4-methyl-1-piperazinyl) propionyl,  2-iodo-3- (4-methyl-1-thioxopropyl,  3- (4-acetyl-1-piperazinyl) -2-iodopropionyl,  3- (4-acetyl-1-piperazinyl) -2-iodo-1-thioxopropyl,  2-iodo-3- (N-methanesulfonyl-N-methyl) aminopropionyl,  2-iodo-3- (N-methanesulfonyl-N-methyl) amino-1-thioxopropyl,  3-acetylamino-2-azidopropionyl,  3-acetyl-2-azido-1-thioxopropyl,  2-azido-3-propionylaminopropionyl,  2-azido-3-propionylamino-1-thioxopropyl,  2-azido-3- (N-benzoyl-N-methyl) aminopropionyl,  2-azido-3- (N-benzoyl-N-methyl) amino-1-thioxopropyl,  2-azido-3-diethylaminopropionyl,  2-azido-3-diethylamino-1-thioxopropyl,  2-azido-3-methanesulfonylaminopropionyl,  2-azido-3-methanesulfonylamino-1-thioxopropyl,  2,  3-diamino-1-oxopropyl,  2,  3-diaminopropionyl,  2-amino-3-dimethylaminopropionyl,  2-amino-3-dimethylamino-1-thioxopropyl,  3-acetylamino-2-aminopropionyl,  3-acetylacetyl-2-amino-1-thioxopropyl,  2-amino-3-benzyloxycarbonylaminopropionyl,  2-amino-3-benzyloxycarbonylamino-1-thioxopropyl,  2-amino-3-P-toluenesulfonylaminopropionyl,  2-amino-3-P-toluenesulfonylamino-1-thioxopropyl,  2-amino-3- (N-benzyl-N-ethyl) aminopropionyl,  2-amino-3- (N-benzyl-N-ethyl) amino-1-thioxopropyl,  2,  3-bisacetylaminopropionyl,  2,  3-bisacetylamino-1-thioxopropyl,  3-acetylamino-2-dimethylaminopropionyl,  3-acetylamino-2-dimethylamino-1-thioxopropyl,  3-acetylamino-2-benzyloxycarbonylaminopropionyl,  3-acetylamino-2-benzyloxycarbonylamino-1-thioxopropyl,  3-ethylaminopropionyl,  3-ethylamino-2-methylamino-1-thioxopropyl,  2-methanesulfonylamino-3-morpholinopropionyl,  2-methanesulfonylamino-3-morpholino-1-thioxopropyl,  2-diethylaminoamino-3-methanesulfonylaminopropionyl,  2-diethylamino-3-methanesulfonylamino-1-thioxopropyl,  3-benzylamino-2-propionylaminopropionyl,  3-benzylamino-2-propionylamino-1-thioxopropyl,  3-acetylamino-2-ethylthiopropionyl,  3-acetylamino-2-ethylthio-1-thioxopropyl,  3-acetylamino-2- (pyridyl) thiopropionyl,  3-acetylamino-2- (2-pyridyl) thio-1-thioxopropyl,  3-dimethylamino-2- (2-pyridyl) thiopropionyl,  3-dimethylamino-2- (2-pyridyl) thio-1-thioxopropyl,  3-ethylamino-2- (4-pyridyl) thiopropionyl,  3-ethylamino-2- (4-pyridyl) thio-1-thioxopropyl,  2- [1- (2-dimethylaminoethyl-1H-tetrazol-5-yl] thio-3-methanesulfonylaminopropionyl,  2- [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thio-3-methanesulfonylamino-1-thioxopropyl,  2-phenylthio-3-pyrrolidinopropionyl,  2-phenylthio-3-pyrrolidinopropionyl,  2-phenylthio-3-pyrrolidino-3-pyrrolidinopropylonyl,  2-phenylthio-3-pyrrolidino-3-pyrrolidino-1-thioxopropyl,  3-benzoylamino-2- (4-methyl-4H-1,  2,  4-triazol-3-yl) thiopropionyl,  3-benzoylamino-2- (4-methyl-4H-1,  2,  4-triazol-3-yl) thio-1-thioxopropyl,  2-hydroxyamino-3- (2-pyridyl) thiopropionyl,  2-hydroxyimino-3- (2-pyridyl) thio-1-thioxopropyl,  2-methoxyimino-3-[(2-pyridyl) thio] propionyl,  2-methoxy imino-3- (2-pyridyl) thio-1-thioxopropyl,  2-hydroxy imino-3-[(4-pyridyl) thio] propionyl,  2-hydroxy imino-3- (4-pyridyl) thio-1-thioxopropyl,  2-methoxyimino-3-[(4-pyridyl) thio] propionyl,  2-methoxyimino-3- (4-pyridyl) thio-1-thioxopropyl,  2- (2-amino thiazol-4-yl) -2-hydroxyiminoacetyl,  2- (2-amino thiazol-4-yl) -2-hydroxyimino-1-thioxoethyl,  2- (2-aminothiazol-4-yl) -2-methoxyimino acetyl,  2- (2-amino thiazol-4-yl) -2-methoxy imino-1-thioxo ethyl,  2- (5-amino-1,  2,  4-thiadiazol-3-yl) -2-methoxy imino acetyl,  2- (5-amino-1,  2,  4-thiadiazol-3-yl) -2-methoxy imino-1-thioxo ethyl,  2- (5-amino-5-chlorothiazol-4-yl) -2-methoxy imino acetyl,  2- (5-amino-5-chlorothiazol-4-yl) -2-methoxy imino-1-thioxo ethyl,  2- (2-amino thiazol-4-yl) -2-carboxymethoxyimino acetyl,  2- (2-iminothiazol-4-yl) -2-carboxy methoxy imino-1-thioxo ethyl,  2- (2-amino thiazol-4-yl) -2- (1-carboxy-1-methyl ethoxy imino) acetyl,  2- (2-amino thiazol-4-yl) -2- (1-carboxy-1-methyl ethoxy imino) -1-thioxo ethyl,  2- (2-amino thiazol-4-yl) -2- (1H-imidazol-4-yl) methoxy imino acetyl,  2- (2-amino thiazol-4-yl) -2- (1H-imidazol-4-yl) methoxy imino-1-thioxo ethyl,  2- (2-amino thiazol-4-yl) -2- (2-fluoro ethoxy) imino acetyl,  2- (2-amino thiazol-4-yl (-2- (2-fluoro ethoxy) imino-1-thioxo ethyl,  2-hydroxypropionyl,  2-hydroxy-1-thioxopropyl,  2-hydroxy-2-phenyl acetyl,  2-hydroxy-2-phenyl-1-thioxoethyl,  2-hydroxy-3-[(1-methyl-1H-1,  3,  4-2-phenyl-1-thioxoethyl,  2-hydroxyiminopropionyl,  2-hydroxy imino-1-thioxopropyl,  2-methoxyiminopropionyl,  2-methoxy imino-1-thioxopropyl,  2-hydroxy-3-[(1-methyl-1H-1,  3,  4-triazol-2-yl) thio] propionyl,  2-hydroxy-3- (1-methyl-1H-1,  3,  4-triazol-2-yl) thio-1-thioxopropyl,  2-hydroxy-3-[(1-methyl-1H-tetrazol-5-yl) thio] propionyl,  2-hydroxy-3- (1-methyl-1H-tetrazol-5-yl) thio-1-thioxopropyl,  2-hydroxy-3- [5- (2-dimethyl amino ethyl) -1,  3,  4-thiadiazol-2-yl] thiopropionyl,  2-hydroxy-3-[[5- (2-dimethyl amino ethyl) -1,  3,  4-thiadiazol-2-yl] thio] -1-thioxopropyl,  2-hydroxy-2- [4- (2-amino-2-carboxy ethoxy carbonyl animo) phenyl] acetyl,  2-hydroxy-2- [4- (2-amino-2-carboxyethoxycarbonylamino) phenyl] acetyl,  2-hydroxy-2- [4- (2-amino-2-carboxyethoxycarbonylamino) phenyl] -1-thioxo ethyl,  2-formyloxypropionyl,  2-formyloxy-1-thioxopropyl,  2-acetoxypropionyl,  2-acetoxy-1-thioxopropyl,  2-propionyloxypropionyl,  Propionyloxy-1-thioxopropyl,  3-octanoyloxypropionyl,  3-octanoyl oxy-1-thioxopropyl,  α-propyloxy-2-phenyl-1-thioxoethyl,  2-formyloxy-2-phenyl-1-thioxoethyl,  2-acetoxy-3- (2-pyridyl) thio-1-thioxopropyl,  2-acetoxy-3- (4-pyridylthio) propionyl,  2-acetoxy-3- (4-pyridyl) thio-1-thioxopropyl,  2-acetoxy-3- (phenylthio) propionyl,  2-acetoxy-3-phenyl-1-thioxopropyl,  α-acetoxyphenylacetyl,  2-acetoxy-2-phenyl-1-thioxopropyl,  2-methanesulfonyloxypropionyloxypropionyl,  2-methanesulfonyloxy-1-thioxopropyl,  2- (4-toluenesulfonyloxy) propionyl,  2- (4-toluenesulfonyloxy) -1-thioxopropyl,  2-chloropropionyl,  2-chloro-1-thioxopropyl,  2-bromopropionyl,  2-bromo-1-thioxopropyl,  2-iodopropionyl,  2-iodo-1-thioxopropyl,  2- (ethylthio) -propionyl,  2-methylthio-1-thioxopropyl,  2- (methylthio) propionyl,  2-ethylthio-1-thioxopropyl,  2- (phenylthio) propionyl,  2-phenylthio-1-thioxopropyl,  2- (2-pyridylthio) propionyl,  2- (2-pyridylthio) -1-thioxopropyl,  2- (4-pyridylthio) propionyl,  2- (4-pyridylthio) -1-thioxopropyl,  2-[(1-methyl-1H-1,  3,  4-triazol-2-yl) thio] propionyl,  2-[(1-methyl-1H-1,  3,  4-triazol-2-yl) thio] -1-thioxopropyl,  2-[[1- (2-dimethyl amino ethyl) -1H-tetrazol-5-yl] thio] propionyl,  2-[[1- (2-dimethyl amino ethyl) -1H-tetrazol-5-yl] thio] -1-thioxopropyl,  α-methyl thiophenyl acetyl,  2-methylthio-2-phenyl-1-thioxoethyl,  2- (2-amino thiazol-4-yl) -2- (methylthio) acetyl,  2- (2-amino thiazol-4-yl) -2-methylthio-1-thioxo ethyl,  2- (N-methylthio carbamoylthio) propionyl,  2- (N-ethyl thiocarbamoylthio) propionyl,  2-azidopropionyl,  2-azido-1-thioxopropyl,  α-azidophenyl acetyl,  2-azido-2-phenyl-1-thioxoethyl,  2-azido-2- (4-hydroxy phenyl) acetyl,  2-azido-2- (4-hydroxyphenyl) -1-thioxoethyl,  2-amino propionyl,  2-amino-1-thioxopropyl,  α-amino phenyl acetyl,  2-amino-2-phenyl-1-thioxoethyl,  2-amino-2- (4-hydroxy phenyl) acetyl,  2-amino-2- (4-hydroxy phenyl) -4-thioxoethyl,  2-amino-2- (3,  4-dihydroxy phenyl) acetyl,  2-amino-2- (3,  4-dihydroxy phenyl) -1-thioxoethyl,  2-amino-2- (20amino thiazol-4-yl) acetyl,  2-amino-2- (2-amino thiazol-4-yl) -1-thioxo ethyl,  2-amino-2- (3-benzothienyl) acetyl,  2-amino-2- (3-benzothienyl) -1-thioxo ethyl,  2-amino-2- (2-naphthylacetyl,  2-amino-2- (2-naphthyl) -1-thioxo ethyl,  2-amino-2- (3-ethanesulfonylaminophenyl) acetyl,  2-amino-2- (3-ethanesulfonyl amino phenyl) -1-thioxo ethyl,  2- (4-ethyl-2,  3-dioxo piperazine-1-carbonyl amino) -2-phenyl acetyl,  2- (4-ethyl-2,  3-dioxopiperazin-1-carbonyl amino) -2-phenyl-1-thioxoethyl,  2- (4-ethyl-2,  3-dioxo piperazine-1-carbonyl amino) -2- (4-hydroxy phenyl) acetyl,  2- (4-ethyl-2,  3-dioxo piperazine-1-carbonyl amino) -2- (4-hydroxy phenyl) -1-thioxo ethyl,  2-formylamino-2-phenyl acetyl,  2-formyl amino-2-phenyl-1-thioxoethyl,  2- (2-amino thiazol-4-yl) -2-formyl amino acetyl,  2- (2-amino thiazol-4-yl) -2-formyl amino-1-thioxo ethyl,  2-acetyl aminopropionyl,  2-acetyl amino-1-thioxopropyl,  2-propionyl amino propionyl,  2-propionyl amino-1-thioxopropyl,  2-butyryl amino propionyl,  2-butyryl amino-1-thioxopropyl,  2-benzyl oxycarbonyl aminopropionyl,  2-benzyl oxycarbonyl amino-1-thioxopropyl,  2- (p-toluene sulfonyl amino) propionyl,  2- (p-toluene sulfonyl amino) -1-thioxopropyl,  2- (diphenyl phosphinothioyl amino) propionyl,  2- (diphenyl phosphino thioyl amino) -1-thioxopropyl,  2- (4-ethyl-2,  3-dioxo piperazine-1-carbonyl amino) -2- (3,  4-dihydroxyphenyl) acetyl,  2- (4-ethyl-2,  3-dioxo piperazine-1-carbonyl amino-2- (3,  4-dihydroxy phenyl) -1-thioxoethyl,  2- (4-ethyl-2,  3-dioxo piperazine-1-carbonyl amino) -3-hydroxybutyryl,  2- (4-ethyl-2,  3-dioxo piperazine-1-carbonyl amino) -3-hydroxy-1-thioxo butyl,  2- (5-carboxy-1H-imidazol-4-yl) carbonyl amino-2-phenyl acetyl,  2- (5-carboxy-1H-imidazol-4-yl) carbonyl amino-2-phenyl-1-thioxoethyl,  2- (4-hydroxy-6-methyl pyridin-3-yl) carbonyl amino-2- (4-hydroxy phenyl) acetyl,  2- (4-hydroxy-6-methyl pyridin-3-yl) carbonyl amino-2- (4-hydroxy phenyl) -1-thioxo ethyl,  2-carboxy-2-phenyl acetyl,  2-carboxy-2-phenyl-1-thioxoethyl,  2-sulfo-2-phenyl acetyl,  2-sulfo-2-phenyl-1-thioxoethyl,  2-carboxy-2- (4-hydroxy phenyl) acetyl,  2-carboxy-2- (4-hydroxy phenyl) -1-thioxoethyl,  2-carboxy-2- (3,  4-diacetoxyphenyl) acetyl,  2-carboxy-2- (3,  4-diacetoxyphenyl) -1-thioxoethyl,  2- (4-hydroxyphenyl) -2-sulfo acetyl,  2- (4-hydroxyphenyl) -2-sulfo-1-thioxoethyl,  2- (3,  4-dihydroxyphenyl) -2-sulfo acetyl,  2- (3,  4-dihydroxyphenyl) -2-sulfo-1-thioxoethyl,  2- (4-chlorophenyl) -2-sulfo-1-thioxoethyl,  2- (4-methoxy phenyl) -2-sulfo acetyl,  2- (4-methoxy phenyl) -2-sulfo-1-thioxoethyl,  2- (4-acetyl amino phenyl) -2-carboxyacetyl,  2- (4-acetyl amino phenyl) -2-carboxy-1-thioxo ethyl,  Benzoyl,  Phenyl-1-thiocarbonyl,  (2-aminothiazol-4-yl) carbonyl,  (2-amino thiazol-4-yl) -1-thioxo methyl,  Acryloyl,  Vinyl (thiocarbonyl) (3-ethoxycarbonyl) acryloyl,  2-ethoxycarbonyl-1-thioxoallyl,  Capryloyl,  1-thioxohexyl,  Cyclo hexanecarbonyl,  Cyclohexane-thiocarbonyl,  (5-amino-1,  2,  4-thiadiazol-3-yl) -1-thioxo methyl,  Cyclopropanecarbonyl,  Cyclopropanethiocarbonyl,  Cyclobutanecarbonyl,  Cyclobutanethiocarbonyl,  Cyclopentanecarbonyl,  Cyclopentanethiocarbonyl,  Cyclo-3-hexenecarbonyl,  Cyclo-3-hexene-thiocarbonyl,  Cyclo-1,  4-hexanedienecarbonyl,  Cyclo-1,  4-cyclohexadiene-thiocarbonyl,  3,  3-dichloro acryloyl,  2,  2-dichloro vinyl-thiocarbonyl,  2- (2-amino thiazol-4-yl) -3-chloro acryloyl,  2- (2-amino thiazol-4-yl) -3-chloro vinyl-thiocarbonyl,  2- (2-amino thiazol-4-yl) -3-bromo acryloyl,  2- (2-amino thiazol-4-yl) -3-bromovinyl-thiocarbonyl,  2-hydrazono-2- (2-amino thiazol-4-yl) acetyl,  2-hydrazono-2- (2-amino thiazol-4-yl) -1-thioxo ethyl,  2-trimethylsilyloxypropionyl,  2-trimethylsiloxy-1-thioxopropyl,  2-t-butyldimethylsilyloxypropionyl,  2-t-butyldimethylsilyloxy-2-thioxopropyl,  2-phenylsulfinylpropionyl,  2-phenylsulfinyl-1-thioxopropyl,  2-benzenesulfonylpropionyl,  2-benzenesulfonyl-1-thioxopropyl and the like.

In the above-mentioned R ^5A to R ^5F , Y ^A and Y ^B , R ^5A is C _1-3 alkyl, R ^5B is triazolylthio, tetrazolylthio, pyridylthio which may be substituted by dimethyl amino ethyl, methyl or amino And a heterocycle group through sulfur, consisting of thiazolylthio, Y ^A is hydroxyl or benzothiazol-2-ylthio, R ^5C is pyridin-2-ylthio methyl or methyl, and R ^5D is cyclohexyl , Phenyl or 2-amino thiazol-4-yl, R ^5E is hydroxyl or methoxyl, R ^5F is pyridin-2- ^ylthiomethyl , Y ^B is acetyloxy or t-butoxycarbonyloxy It is preferable.

(R⁶과 R⁷은 상기 정의와 동일하다)을 나타내는 경우에, R⁶의 실질적인 예는 아세틸, 프로필, 부티릴, 피발로일, 펜타노일, 헥사노일, 메탄설포닐, 톨루엔설포닐, 벤젠 설포닐, 메톡시카르보닐, 에톡시카르보닐, 이소부톡시카르보닐 및 벤질옥시카르보닐이며, R⁷의 실질적인 예는 메틸, 에틸, 프로필 및 부틸이다.General formula with R ¹ and R ² =

When R ⁶ and R ⁷ are the same as defined above, practical examples of R ⁶ include acetyl, propyl, butyryl, pivaloyl, pentanoyl, hexanoyl, methanesulfonyl, toluenesulfonyl, benzene Sulfonyl, methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl and benzyloxycarbonyl, and practical examples of R ⁷ are methyl, ethyl, propyl and butyl.

Substantial examples of R ³ or R ⁴ include hydroxyl, chlorine, bromine, iodine, azido, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, t-butoxycar Carbonyloxy, phenoxycarbonyloxy, benzyloxycarbonyloxy, 4-nitrobenzyloxycarbonyloxy, 2,4-dinitrobenzyloxycarbonyloxy, 4-methoxybenzyloxycarbonyloxy, 3, 4- Dimethoxybenzyloxycarbonyloxy, 2, 2, 2-trichloro ethoxycarbonyloxy, methoxymethoxycarbonyloxy, 2-methoxyethoxycarbonyloxy, 1-methoxy ethoxycarbonyloxy, Methylthiomethoxycarbonyloxy, 2-methylthioethoxycarbonyloxy, acetoxymethoxy cicarbonyloxy, 1-acetoxyethoxycarbonyloxy, pivaloyloxymethoxycarbonyloxy, 2-pivalo Ethoxycarbonyloxy, allyloxycarbonyloxy, 4-methoxyphenoxycarbonyloxy, 2, 4-dimeth Methoxyphenoxycarbonyloxy, 2-aminoethoxycarbonyloxy, 2-dimethyl amino ethoxycarbonyloxy, 2-methanesulfonyl ethoxycarbonyloxy, 2-trimethylsilylethoxycarbonyloxy, 2-cya Noethoxycarbonyloxy, 2-nitroethoxycarbonyloxy, ethoxycarbonylmethoxycarbonyloxy, chloromethoxycarbonyloxy, iodomethoxycarbonyloxy, [[1- (2-dimethyl amino Ethyl) -1H-tetrazol-5-yl] thio] methoxycarbonyloxy, [[1- (3-dimethyl amino propyl) -1H-tetrazol-5-yl] thio] methoxycarbonyloxy, [ (1-methyl-1H-tetrazol-5-yl) thio] methoxycarbonyloxy, [(4-methyl-4H-1, 2,4-triazol-3-yl) thio] methoxycarbonyloxy , [[5- (2-dimethyl aminoethyl) -1, 3, 4-triazol-2-yl) thio] methoxycarbonyloxy, [(5-methyl-1, 3, 4-thiadiazole- 2-yl) thio] methoxycarbonyloxy, [(4, 5-dimethylthiazol-2-yl) thio] methoxy carbonyl C, [(4,5-dimethyloxazol-2-yl) thio] methoxycarbonyloxy, [(3-methyl-1, 2, 4-thiadiazol-5-yl) thio] methoxycarbonyl Oxy, [(1,2,3-thiadiazol-5-yl) thio] methoxycarbonyloxy, [(1H-1,2,3-triazol-5-yl) thio] methoxycarbonyloxy , [(1-methyl-1H-imidazol-2-yl) thio] methoxycarbonyloxy, [(2-methyl-2H-1, 2,4-triazol-3-yl) thio] methoxycar Carbonyloxy, (2-pyrimidinylthio) methoxycarbonyloxy, (2-benzthiazolthio) methoxycarbonyloxy, (2-benzimidazolthio) methoxycarbonyloxy, (2-benzoxazole Thio) methoxycarbonyloxy, [(1,2,4-triazin-3-yl) thio] methoxycarbonyloxy, [(4-carboxy-3-hydroxy-1,2-thiazole-5 -Yl) thio] methoxycarboroxy, [(6-methyl pyridazine-1-oxide-3-yl) thio] methoxycarbonyloxy, [(N-oxido-2-pyridyl) thio] Methoxycarbonyloxy, (2-amino ethylthio) methoxycarbonyloxy, (2-acetyl amino ethylthio) methoxycarbonyloxy, (2-dimethyl amino ethylthio) methoxycarbonyloxy, (N-aceto imino-3-pyrrolidinothio) methoxycarbonyloxy, (phenyl Thio) methoxycarbonyloxy, (4-pyridylthio) methoxycarbonyloxy, formyloxy, acetoxy, propionyloxy, butylyloxy, isobutylyloxy, pentanoyloxy, hexanoyloxy, heptane Crudeoxy, pivaloyloxy, cyclopropanecarbonyloxy, cyclobutanecarbonyloxy, cyclopentanecarbonyloxy, cyclohexanecarbonyloxy, cycloheptancarbonyloxy, acryloyloxy, crotonoyloxy, benzoyloxy , Phenylacetyloxy, 2-methoxybenzoyloxy, 2-methylbenzoyloxy, 4-methylbenzoyloxy, 4-fluorobenzoyloxy, 3-phenylpropionyloxy, cinnamoyloxy, chloroacetoxy, bromoacetoxy , 3-chloropropanoloxy, 4-chlorobutyryloxy, Methoxyacetoxy, 3-ethoxypropanoyloxy, phenoxycetoxy, 4-phenoxybutylyloxy, cyano acetoxy, 4-nitro benzoyloxy, pentachloro phenoxycarbonyloxy, 2, 4, 5-trichlorophenoxy cycarbonyloxy, [(5-methoxymethyl-1, 3, 4-thiadiazol-2-yl) thio] methoxycarbonyloxy, (ethylthio) methoxycarbonyloxy, (3,4-dihydro-2H-pyran-2-carbonyloxy) methoxycarbonyloxy, (acetylaminocarbonyloxy) methoxycarbonyloxy, (2-dimethylaminoethylthio) carbonyloxy, [ (5-methoxymethyl-1, 3, 4-thiadiazol-2-yl) thio] methoxycarbonyloxy, (2-acetylamino ethylthio) methoxycarbonyloxy, 3-methoxycarbonylprop Panoyloxy, 3-ethoxycarbonyloxy, azido acetoxy, 2-thienyl acetoxy, 2-pyridinecarbonyloxy, 3-pyridinecarbonyloxy, 4-pyridinecarbonyloxy, 4-cyclohexylbuty Ryloxy, 2-nap Acetylacetyloxy, 2-thiophencarbonyloxy, 3-thiophencarbonyloxy, 2-furancarbonyloxy, 3-furancarbonyloxy, (3-dimethylamino) propanoyloxy, (3-methylthio Propanoyloxy, (3-methanesulfonyl) propanoyloxy, 2-pyridinecarbonyloxy, 3-pyridinecarbonyloxy, 4-pyridinecarbonyloxy, 2-aminopropanoyloxy, 3-amino Propanoyloxy, α-aminophenylacetyloxy, 2-amino-4-carboxybutylyloxy, 2-amino-5-carboxypentanoyloxy, 2-amino-3-mercaptopropanoyloxy, amino acetoxy , 2, 5-diaminopentanoyloxy, 2-[(N-acetyl-N-methyl) amino] propanoyloxy, 2-[(N-butyryl-N-methyl) amino] acetoxy, iodo Acetoxy, [(1-methyl-1H-tetrazol-5-yl) thio] acetoxy, [[1- (2-dimethylamino ethyl) -1H-tetrazol-5-yl] thio] acetoxy, [ (5-methyl-1, 3, 4-thiadiazol-2-yl) thio] acetoxy, [(4-methyl-4H-1, 2,4-triazol-3-yl) thio] acetoxy, [(2-dimethylaminoethyl) thio] acetoxy, dihydroxyphosphinyloxy, dimethylphosphonoxy, diethylphosphonoxy, dipropylphosph Phonooxy, diisopropylphosphonoxy, diisobutylphosphonoxy, di-t-butylphosphonoxy, dipentylphosphonoxy, dihexylphosphonoxy, dicyclopropylphosphonoxy, dicyclobutylphosphonoxy , Dicyclopentylphosphonoxy, [(2-dimethyl amino ethyl) thio] acetoxy, [[1- (2-hydroxyethyl) -1H-tetrazol-5-yl] thio] aceto group, [[ 5-methoxymethyl-1, 3, 4-thiadiazol-2-yl] thio] acetoxy, [[5- (2-diethylphosphonoethyl) thio-1, 3, 4-thiadiazole- 2-yl] thio] acetoxy, [(2-diethylaminoethyl) thio] acetoxy, dimethyl aminoacetoxy, diethyl amino acetoxy, N'-methyl piperazino acetoxy, N '-(2- Pyridyl) piperazino acetoxy, (2-chloroethylamino) acetoxy, ( 2-fluoroethylamino) acetoxy, n-propylaminoacetoxy, di-iso-propylaminoacetoxy, (2-hydroxyethylamino) acetoxy, iso-propylaminoacetoxy, morpholinoacetoxy, 4-methylaminobutyryloxy, N '-(4-pyridyl) piperazino acetoxy, (N-acetyl-N-methylamino) acetoxy, 3-dimethylaminopropanoyloxy, 4-dimethylaminobuty Ryloxy, dicyclo hexylphosphonoxy, diphenylphosphonoxy, dibenzylphosphonoxy, divinylphosphonoxy, diallylphosphonoxy, di-2-butenylphosphonoxy, bis-4-chlorophenyl Phosphonoxy, bis-4-methoxyphenylphosphonoxy, bis-4-aminophenylphosphonoxy, bis-4-nitrophenylphosphonoxy, bis-4-methoxycapbonylphenylphosphonoxy, bis-4 -Acetoxyphenylphosphonoxy, bis-3, 4-diacetoxyphosphonoxy, bis-4-chlorobenzylphosphonoxy, bis-4-acet aminobenzylphospho Oxy, bis (methoxymethyl) phosphonoxy, bis (2-methoxyethyl) phosphonoxy, bis (2-methylthioethyl) phosphonoxy, bis (2-dimethylaminoethyl) phosphonoxy, bis ( 3-dimethylaminopropyl) phosphonoxy, bis (ethoxycarbonylmethyl) phosphonoxy, bis (2-methanesulfonyl amino ethyl) phosphonoxy, bis (2-chloroethyl) phosphonoxy, methane sulfonyl Oxy, ethanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy, naphthalenesulfonyloxy, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, Heptylthio, octylthio, phenylthio, 4-methylphenylthio, benzylthio, 2-phenyl ethylthio, trifluoromethylthio, difluoromethylthio, 2-amino ethylthio, 2- (2, 2, 2- Trichloroethoxycarbonyl amino) ethylthio, methoxycarbonyl methylthio, ethoxycarbonyl methylthio, carboxy Tylthio, 3-dimethyl amino propylthio, 2-hydroxy ethylthio, 2-chloro ethylthio, 2-cyano ethylthio, 2-methoxycarbonylethylthio, 2-ethoxycarbonyl ethylthio, 2- Carboxyethylthio, 3-amino propylthio, 2-acetylaminovinylthio, 2- (2, 2, 2-trichloro ethoxy carbonyl amino) vinylthio, 2-amino-2-carboxy ethylthio, 2-fluoro Ro-2-carbamoylvinylthio, methoxymethylthio, 2-methoxy ethylthio, 2-methylthio methylthio, 2-methanesulfonyl ethylthio, 2-pyrrolidinylthio, 2-carbamoyl- 3-pyrrolidinylthio, 2-morpholinylcarbonyl-3-pyrrolidinylthio, N-aceto imino-3-pyrrolidinylthio, N- (N-methylaceto imino) -3-pyrroli Dinylthio, 4-dimethyl amino phenylthio, 3-amino phenylthio, 4-hydroxy phenylthio, 4-carboxymethylthio phenylthio, 4-carbamoyl phenylthio, 4-metalsulfonyl amino phenyl tee , 2-sulfoethylthio, 2-pyridylthio, 4-pyridylthio, (2-amino thiazol-4-yl) methylthio, (1-methyl-1H-1, 3, 4-triazole-2 -Yl) thio, (5-amino-1-methyl-1H-1, 3, 4-triazol-2-yl) thio, (1-methyl-1H-tetrazol-5-yl) thio, [1- (2-dimethyl amino ethyl) -1H-tetrazol-5-yl] thio, [1- (3-dimethyl amino propyl) -1H-tetrazol-5-yl] thio, [1- (2-hydroxyethyl ) -1H-tetrazol-5-yl] thio, [1- (3-hydroxypropyl) -1H-tetrazol-5-yl] thio, [1- (2-amino ethyl) -1H-tetrazol- 5-yl] thio, [1- (2-acetamido ethyl) -1H-tetrazol-5-yl] thio, [1- (2-methyl amino ethyl) -1H-tetrazol-5-yl] thio , [1- (2-ethylaminoethyl) -1H-tetrazol-5-yl] thio, [1- (2-formylaminoethyl) -1H-tetrazol-5-yl] thio, (1-carboxy Methyl-1H-tetrazol-5-yl) thio, [1- (2-carboxyethyl-1H-tetrazol-5-yl] thio, (1-sulfomethyl-1H-tetrazol-5-yl) thio, [1- (2-sulfoethyl) -1H-tetrazol-5-yl] tea , [(1-amino-1H-tetrazol-5-yl] thio, [(1-dimethylamino-1H-tetrazol-5-yl] thio, (1-methoxymethyl-1H-tetrazol-5- Il] thio, (1-methylthiomethyl-1H-tetrazol-5-yl) thio, [1-ethyl (hydro) phosphonomethyl-1H-tetrazol-5-yl] thio, (1-diethylforce Phonomethyl-1H-tetrazol-5-yl) thio, (1-carbamoylmethyl-1H-tetrazol-5-yl) thio, (1-dimethylcarbamoyl-1H-tetrazol-5-yl) Thio, (5-carboxy-1-methyl-1H-1, 3, 4-triazol-2-yl) thio, (5-carbamoyl-1-methyl-1H-1, 3, 4-triazole- 2-yl) thio, (5-methoxymethyl-1, 3, 4-thiadiazol-2-yl) thio, (5-methylthiomethyl-1, 3, 4-thiadiazol-2-yl) Thio, (5-methanesulfonylmethyl-1, 3, 4-thiadiazol-2-yl) thio, [5- (2-dimethylaminoethyl) -1, 3, 4-thiadiazol-2-yl ] Thio, [5- (3-dimethylaminopropyl) -1, 3, 4-thiadiazol-2-yl] thio, [(5-carboxymethyl-1, 3, 4-thiadiazol-2-yl ] Thio, [(5-methoxycarbonylmethyl-1, 3, 4- Adiazol-2-yl] thio, [(5-carbamoylmethyl-1, 3, 4-thiadiazol-2-yl] thio, (5-dimethylcarbamoylmethyl-1, 3, 4-thia Diazol-2-yl) thio, (5-trifluoromethyl-1, 3, 4-thiadiazol-2-yl) thio, (5-amino-1, 3, 4-thiadiazol-2- Yl) thio, (5-methoxycarbonylamino-1, 3, 4-thiadiazol-2-yl) thio, [5- (2-dihydrophosphonoethyl) thio-1, 3, 4-thia Diazol-2-yl] thio, [5- (2-diethylphosphonoethyl) thio-1, 3, 4-thiadiazol-2-yl] thio, (3-methyl, 1, 2, 4- Thiadiazol-2-yl) thio, (1, 3, 4-thiadiazol-2-yl) thio, (1, 2, 3-thiadiazol-5-yl) thio, (1-methyl-1H -Imidazol-2-yl) thio, (4, 5-dimethyloxazol-2-yl) thio, (4-methylthiazol-2-yl) thio, (5-methylthiazol-2-yl) thio , (4, 5-dimethylthiazol-2-yl) thio, (1H-1, 3, 4-triazol-2-yl) thio, (1H-1, 2, 3-triazol-5-yl) Thio, (1-methyl-1H-1, 2, 4-triazol-5-yl) thio, (1-ethyl-1H-1, 2, 4-triazol-3-yl) thio, ( 2-pyridyl) thio, (5, 6-dimethyl-1, 2, 4-triazin-3-yl) thio, (2-benzothiazolyl) thio, [4- (2-amino-2-carboxyethyl ) -1H-imidazol-2-yl] thio, (4-carboxy-3-hydroxyisothiazol-5-yl) thio, (6-hydroxy-4-methyl-4, 5-dihydro-tri Azine-5-one-3-yl) thio, 5- (2-amino-2-carboxyethyl) -1, 3, 4-thiadiazol-2-yl) thio, (4, 5-dicarboxy-1H -Imidazol-2-yl) thio, (5-amino-4-carboxy-1-methyl-1H-imidazol-2-yl) thio, (tetrazolo [1, 5-b] pyridazyl) thio, ( 6-methylpyridazine-1-oxydo-3-yl) thio, (N-oxido-2-pyridyl) thio, (3-methoxypyridazin-1-oxydo-6-yl) thio, ( Benzoxazol-2-yl) thio, (benzoimidazol-2-yl) thio, (5-carboxymethyl-4-methylthiazol-2-yl) thio, methoxy, ethoxy, propoxy, isopropoxy , Butoxy, isobutoxy, s-butoxy, t-butoxy, hexyloxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy , Phenoxy, benzyloxy, 2-phenylethyloxy, 2-aminoethoxy, 2-dimethylaminoethoxy, ethoxycarbonylmethoxy, 2-hydroxyethoxy, 2-cyanoethoxy, methoxy Methoxy, (2-methoxyethoxy) methoxy, 2-methoxyethoxy, 2-methylthioethoxy, carboxymethoxymethoxy, methoxycarbonylmethoxymethoxy, carbamoylmethoxymethoxy , N, N-dimethylcarbamoylmethoxymethoxy, (2-methylthioethoxy) methoxy, (2-methanesulfonylethoxy) methoxy, (2-dimethylaminoethoxy) methoxy, (3 -Dimethylaminopropoxy) methoxy, (2-phenoxyethoxy) methoxy, (2-allyloxyethoxy) methoxy, (2-cyclopropoxyethoxy) methoxy, [(2-pyridyloxy ) Ethoxy] methoxy, [2- (2-pyridylthio) ethoxy] methoxy, [2- [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thioethoxy] Methoxy, amino, dimethylamino, diethylamino, methylamino, ethylamino, propylamino, dipro Amino, isopropylamino, diisopropylamino, butylamino, dibutylamino, isobutylamino, diisobutylamino, s-butylamino, t-butylamino, di-t-butylamino, pyrrolidino, piperi Dino, piperazino, morpholino, benzylamino, anilino, N-benzyl-N-methylamino, N-methylanilino, N-benzyl-N-ethylamino, acetylamino, propionylamino, butyrylamino , Isobutyrylamino, pentanoylamino, N-pentanoylamino, pivaloylamino, cyclobutanecarbonylamino, cyclohexaneamino, cycloheptanamino, N-acetyl-N-methylamino, N-methyl-N- Propanoylamino, N-acetyl-N-ethylamino, N-ethyl-N-propanoylamino, 2-pyrimidinylamino, bis (2-hydroxyethyl) amino, bis (2-ethoxyethyl) Amino, bis (2-methoxyethyl) amino, bis (carboxymethyl) amino, N-ethyl-N-ethoxycarbonylamino, Bis (2-ethylthioethyl) amino, bis (2-dimethylaminoethyl) amino, bis (3-oxobutyl) amino, bis (2-acetoxyethyl) amino, bis (2-carbamoylethyl) amino, 2-thiophenecarbonylamino, 2-furancarbonylamino, (2-aminothiadiazol-4-yl) carbonylamino, benzylcarbonylamino, 4-hydroxybenzylcarbonylamino, 2-thienylacetyl Amino, 3-thienylacetylamino, (2-aminothiazol-4-yl) acetylamino, 2- (2-aminothiazol-4-yl) -2-oxoacetylamino, 2- (2-aminothia Zol-4-yl) -2-methoxyiminoacetylamino, 2- (2-amino-5-chlorothiazol-4-yl) -2-methoxyiminoacetylamino, 2- (5-amino-1, 2, 4-thiadiazol-3-yl) -2-methoxyiminoacetylamino, 2- (2-aminothiazol-4-yl) -2-carboxymethoxyiminoacetylamino, 2- (2-amino Thiazol-4-yl) -2- (1-carboxy-1-methyl) ethoxyiminoacetylamino, 2- (2-aminothia Zol-4-yl) -2- (2-fluoroethoxyimino) acetylamino, [2- (2-aminothiazol-4-yl) -2- (1H-imidazol-4-yl) methoxy Mino] acetylamino, 2- (4-ethyl-2, 3-dioxo-1-piperazincarbonylamino) -2-phenylacetylamino, 2- (4-ethyl-2, 3-dioxo-1- Piperazinecarbonylamino) -2- (4-hydroxyphenyl) acetylamino, 2-formylamino-2-phenylacetylamino, 2- (4-ethyl-2, 3-dioxo-1-piperazincar Carbonylamino) -2- (3,4-dihydroxyphenyl) acetylamino, 2- (4-ethyl-2,3-dioxo-1-piperazinecarbonylamino) -3-hydroxybutyrylamino, 2- (5-carboxy-1H-imidazol-4-yl) carbonylamino-2-phenylacetylamino, methoxycarbonylamino, ethoxycarbonylamino, isobutyloxycarbonylamino, benzyloxycarbonylamino , t-butyloxycarbonylamino, (2, 2, 2-trichloroethoxy) carbonylamino, 4-methoxybenzyloxycarbonylamino, 4-meth Ciphenoxycarbonylamino, methanesulfonylamino, benzenesulfonylamino, p-toluenesulfonylamino, 2-thiophensulfonylamino, (5-methylthiophen-2-yl) sulfonylamino, 4-chloro Benzenesulfonylamino, 3, 4-dichlorobenzenesulfonylamino, 4-acetamidobenzenesulfonylamino, dimethylphosphonoamino, diethylphosphono amino, dipropylphosphonoamino, diphenylphosphonoamino, dibenzyl Phosphonoamino, trimethylsilyloxy, t-butyldimethylsilyloxy, t-butyldiphenylsilyloxy, N-methylcarbamoyloxy, N-propylcarbamoyloxy, N-phenylcarbamoyloxy, N-e Oxycarbamoylmethylcarbamoyloxy, N-chloromethylcarbamoyloxy, N- (2-chloroethyl) carbamoyloxy, N-iodomethylcarbamoyloxy, N- (2-iodoethyl ) Carbamoyloxy, N- [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thiomethylcarbamoyloxy, N- [2- [1- (2-dimeth Tylaminoethyl) -1H-tetrazol-5-yl] thioethyl] carbamoyloxy, N- [1- (3-dimethylaminopropyl) -1H-tetrazol-5-yl] thiomethylcarbamoyloxy , N- [2- [1- (3-dimethylaminopropyl) -1H-tetrazol-5-yl] thioethyl] carbamoyloxy, N- (1-methyl-1H-tetrazol-5-yl) Thiomethylcarbamoyloxy, N- [2- (1-methyl-1H-tetrazol-5-yl) thioethyl] carbamoyloxy, N- (4-methyl-4H-1, 2, 4-tria Zol-3-yl) thiomethylcarbamoyloxy, N- [2- (4-methyl-4H-1, 2,4-triazol-3-yl) thioethyl] carbamoyloxy, N- [5 -(2-dimethylaminoethyl) 1, 3, 4-thiadiazol-2-yl] thiomethylcarbamoyloxy, N- [2- [5- (2-dimethylaminoethyl) 1, 3, 4- Thiadiazol-2-yl] thioethyl] carbamoyloxy, N- (5-methyl-1, 3, 4-thiazol-2-yl) thiomethylcarbamoyloxy, N- [2- (5 -Methyl-1, 3, 4-thiadiazol-2-yl) thioethyl] carbamoyloxy, N- (4, 5-dimethylthiazol-2-yl) thiomethylcarbamoyloxy, N- [ 2- (4, 5 -Dimethylthiazol-2-yl) thioethyl] carbamoyloxy, N- (4, 5-dimethyloxazol-2-yl) thiomethylcarbamoyloxy, N- [2- (4, 5-dimethyl Oxazol-2-yl) thioethyl] carbamoyloxy, N- (3-methyl, 1, 2, 4-thiadiazol-5-yl) thiomethylcarbamoyloxy, N- [2- (3 -Methyl-1, 2, 4-thiadiazol-5-yl) thioethyl] carbamoyloxy, N- (1, 2, 3-thiazol-5-yl) thiomethylcarbamoyloxy, N- [2- (1, 2, 3-thiazol-5-yl) thioethyl] carbamoyloxy, N- (1H-1, 2, 3-triazol-5-yl) thiomethylcarbamoyloxy, N- [2- (1H-1, 2, 3-triazol-5-yl) thioethyl] carbamoyloxy, N- (1-methyl-1H-imidazol-2-yl) thiomethylcarbamoyl Oxy, N- [2- (1-methyl-1H-imidazol-2-yl) thioethyl] carbamoyloxy, N- (2-methyl-2H-1, 2, 4-triazol-3-yl ) Thiomethylcarbamoyloxy, N- [2- (2-methyl-2H-1, 2,4-triazol-3-yl) thioethyl] carbamoyloxy, N- (2-pyrimidinyl) Thiomethylcarbamoyloxy, N- [2- (2-pyri Diyl) thioethyl] carbamoyloxy, N- (2-benzthiazolyl) thiomethylcarbamoyloxy, N- [2- (2-benzthiazolyl) thioethyl] carbamoyloxy, N- (2 -Benzimidazolyl) thiomethylcarbamoyloxy, N- [2- (2-benzimidazolyl) thioethyl] carbamoyloxy, N- (benzoxazolyl) thiomethylcarbamoyloxy, N- [2- (2-benzoxazolyl) thioethyl] carbamoyloxy, N-[(1,2,4-triazin-3-yl) thiomethyl] carbamoyloxy, N- [2- (1 , 2, 4-triazin-3-yl) thioethyl] carbamoyloxy, N-[(4-carboxy-3-hydroxy-isothiazol-5-yl) thiomethyl] carbamoyloxy, N -[2- (4-carboxy-3-hydroxy-1, 2-thiazol-5-yl) thioethyl] carbamoyloxy, N-[(6-methylpyridazine-1-oxide-3- Yl) thiomethyl] carbamoyloxy, N,-[2- (6-methylpyridazine-1-oxide-3-yl) thioethyl] carbamoyloxy, N-[(N-oxido-2 -Pyridyl) thiomethyl] carbamoyloxy, N- [2-oxido-2-pyridyl) thioethyl] car Barmoyloxy, N-[(2-aminoethyl) thiomethyl] carbamoyloxy, N- [2- (2-aminoethyl) thioethyl] carbamoyloxy, N-[(2-acetylaminoethyl) Thiomethyl] carbamoyloxy, N- [2- (2-acetylaminoethyl) thioethyl] carbamoyloxy, N-[(2-dimethylaminoethyl) thiomethyl] carbamoyloxy, N- [2 -(2-dimethylaminoethyl) thioethyl] carbamoyloxy, N-[(2-formimidoaminoethyl) thiomethyl] carbamoyloxy, N- [2- (2-formimidoaminoethyl) thioethyl ] Carbamoyloxy, N-[(N-acetoimino-3-pyrrolidinyl) thiomethyl] carbamoyloxy, N- [2- (N-acetoimino-3-pyrrolidinyl) thioethyl] car Barmoyloxy, N- (phenylthiomethyl) carbamoyloxy, N- [2- (phenylthio) ethyl] carbamoyloxy, N-[(4-pyridyl) thiomethyl] carbamoyloxy, N -[2- (4-pyridyl) thioethyl] carbamoyloxy, N-ethylcarbamoyloxy, N-iso-propylcarbamoyloxy, Nn-butylcar Lebamoyloxy, Nt-butylcarbamoyloxy, N-cyclohexylcarbamoyloxy, N, N-dimethylcarbamoyloxy, N, N-diethylcarbamoyloxy, N, N-dipropylcarba Moyloxy, N, N-dibutylcarbamoyloxy, N-ethyl-N-methylcarbamoyloxy, N-benzyl-N-methylcarbamoyloxy, pyrrolidinocarbonyloxy, piperidinocarbonyl Oxy, morpholinocarbonyloxy, N'-methylpiperazinocarbonyloxy, N'-acetylpiperazinocarbonyloxy, N-methyl-thiocarbamoyloxy, N-ethyl-thiocarbamoyloxy , N-phenyl-thiocarbamoyloxy, piperazinocarbamoyloxy, N- (2-dimethylaminoethylcarbamoyloxy, N '-(2-pyridyl) piperazinocarbamoyloxy, car Barmoyloxy, N- [2- (N'-methyl) piperazinoethyl] carbamoyloxy, [N '-(2-dimethylaminoethyl) piperazino)] carbamoyloxy, N- (3 -Pyridylmethyl) carbamoyloxy, [N '-(2-hydroxye) ) Piperazino] carbamoyloxy, N- [2- (2-pyridyl) ethyl] carbamoyloxy, N- (2-pyridylmethyl) carbamoyloxy, N- (4-pyridylmethyl ) Carbamoyloxy, (4-piperidinopiperidino) carbamoyloxy, (N'-benzylpiperazino) carbamoyloxy, N '-(4-pyridyl) piperazinocarbamoyl Oxy, [N '-(morpholinocarbonylmethyl) piperazino] carbamoyloxy, [N'-(pyridinocarbonylmethyl) piperazino] carbamoyloxy, [N '-(isopropyl Aminocarbonylmethyl) piperazino] carbamoyloxy, N- [2- (2-pyridyl) aminoethyl] carbamoyloxy, [N '-(2-pyridylmethyl) piperazino] carba Moyloxy, N- (1-carboxyethyl) carbamoyloxy, N- (3-carboxypropyl) carbamoyloxy and the like.

In R <^1> and R <^2> of compound (I), as R <^5> , substituted alkanoyl, (alpha) -hydroxyalkyl, More preferably, C _1-5 alkanoyl can be illustrated. As R ⁶ , C _1-5 alkanoyl, and R ⁷ may be preferably C _1-4 lower alkyl.

R ³ is represented by the general formula —OCOOR ¹³ (R ¹³ is the same as defined above), —OCOSR ^{13 ′} (R ^{13 ′} is the same defined above), —OCOR ¹⁴ (R ¹⁴ is the same defined above), and Groups represented by -OCONR ¹⁵ R ¹⁶ (R ¹⁵ and R ¹⁶ are the same as defined above) are preferred.

In the aforementioned OR ¹³ and SR ^{13 '} , C _1-4 lower alkyloxy is more preferable as OR ¹³ , and ω-C _2-4 lower alkanoylaminoalkylthio is more preferable as SR ^13' .

R ¹⁴ is preferably hydrogen, C _1-4 lower alkyl or alkyl whose terminal is substituted by di (C _1-4 alkyl) amino or heterocycle group (thiadiazole, tetrazole, etc.) and optionally has an intermediate sulfur atom. .

R ¹⁵ and R ¹⁶ are each preferably C _1-5 lower alkyl or a nitrogen-containing heterocycle group (piperidine, pyrrolidine, piperazine, etc.) which may have substituents (lower alkyl, pyridyl, etc.) To form.

R ⁴ is especially hydroxy or C _1-4 lower alkanoyloxy (acetyloxy and the like).

Compound [1] of the present invention is, for example, alkylated, acylated, hydrolyzed, thioamidated, halogenated, azylated, and / or an oxygen atom, a sulfur atom or the like. It can be prepared by a reaction for introducing an organic residue through a nitrogen atom.

[Wherein R ^{1 '} , R ^2' , R ^{3 '} and R ^4' are the same as or can be converted to R ¹ , R ² , R ³ and R ⁴ , respectively.]

More specifically, the compound represented by the following general formula [1-2] is alkylated to obtain a compound of the general formula [2], and the compound of [2] is acylated and then hydrolyzed or Or (ii) acylating after hydrolysis to obtain a compound of the following general formula [1-3], or acylating a compound of the following general formula [3], thioamidating and alkylating, if necessary, to the following general Compounds are obtained by obtaining a compound of the formula [1-4] or by reacting a compound represented by the following general formula [1-6] with halogen, azide or introducing an organic moiety through an oxygen atom, a sulfur atom or a nitrogen atom. [1] is prepared.

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ^{1 ′} , R ^{3 ′} , R ^{2 ′} and R ^{4 ′} are the same as the above definition.]

Where R ¹ and R ² together are general formula =

Compound [1-2], which is a compound of formula [1], which represents a group of (R ⁶ and R ⁷ are the same as defined above), can be prepared, for example, according to the following reaction step:

가 피루보일아미노인 일반식[1]의 화합물, 즉 화합물[4]를 환원시켜 2'-히드록시 화합물[5]를 수득하고, 이를 아실화, 설포닐화 또는 알콕시카르보닐화하여 화합물[6]을 수득하고, 이를 티오아미드화하여 화합물[2]를 수득하고, 이 화합물[2]를 알킬화하거나, 또는 화합물[4]를 티오아미드화하여 화합물[7]을 수득하고, 이를 환원시켜 화합물[8]을 수득하고, 이를 아실화, 설포닐화 또는 알콕시화하여 화합물[2]를 수득하고 이를 알킬화함으로써 화합물[1-2]를 수득한다.Food

Is a pyruboylamino compound, i.e., compound [4], which is reduced to give 2'-hydroxy compound [5], which is acylated, sulfonylated or alkoxycarbonylated to give compound [6]. ] To thioamide to obtain compound [2], to alkylate this compound [2], or to thioamide of compound [4] to give compound [7], which is reduced to compound [ 8] is obtained, which is acylated, sulfonylated or alkoxylated to give compound [2], which is then alkylated to give compound [1-2].

Reduction reaction to compound [4]-> compound [5] or reduction to compound [7]-compound [8] is preferably carried out by contacting the starting material with a boron hydride compound. Examples of the boron hydride compound include sodium borohydride, lithium borohydride or sodium cyanoborohydride. In general, the reaction is preferably alcohol (eg methanol, ethanol), ether (eg tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, 2-methoxyethylether) or these solvents In a solvent such as a mixture of water and water. It is not advisable to use excess reaction reagents, as there are other positions that can cause reactions with the reagents (e.g., 18-position), and are generally used even if the volume consumed by the reaction with the solvent is later taken Preference is given to using about 1 to 2 times the theoretical volume. The reaction temperature is appropriately selected from about -70 ° C to room temperature, preferably from about -30 ° C to about 0 ° C. The reaction time is about 1 minute to 3 hours.

The reaction of compound [5]-compound [6] or acylation, sulfonylation or alkoxycarbonylation to compound [8]-compound [2] can be performed by a well-known method or a similar method.

As an acylating agent used in an acylation reaction, the acyl halide containing the acyl group represented by R <^6> , an acid anhydride, etc. can be illustrated. The sulfonylating agent for the sulfonylation reaction can be exemplified by sulfonyl halide or sulfonic acid containing a sulfonyl group represented by R ⁶ . Examples of the alkoxycarbonylating agent for the alkoxycarbonylation reaction include alkoxycarbonyl halides or bicarbonate esters containing an alkoxycarbonyl group represented by R ⁶ . As the halogen in the above halide, bromine and chlorine are particularly preferred. The amount of reagent is equimolar or more, preferably about 1 to 5 molar equivalents. When acid anhydride is used as the acylating agent in the acylation reaction described above, it can be used in excess. As the reaction solvent, any compound capable of dissolving the compound [5] or the compound [8] and the reaction reagent can be used. Preferably, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, dioxane, N, N- Dimethylformamido, N, N-dimethylacetamido, dimethylsulfoxide, hexamethylphosphorotriamide, pyridine, etc. can be illustrated. Reaction temperature is about -50-30 degreeC, and reaction time is about 0.1-24 hours. By allowing amines such as triethylamine, dimethylaminopyridine, pyridine, N, N-dimethylaniline, N, N-diethylaniline to coexist in the reaction system, it is possible to control possible side reactions while shortening the reaction time and increasing the yield. .

The reaction to compound [6] → compound [2] or the thioamidation reaction to compound [4] → compound [7] can be carried out, for example, by using phosphorus pentasulphide or Lawerson's reagents. Can be. Laweson reagents include 2, 4-bis (4-methoxyphenyl) -1, 3-dithia-2, 4-diphosphetane-2, 4-disulfide, 2, 4-bis (4-phenoxy Phenyl) -1, 3-dithia-2, 4-diphosphetane-2, 4-disulfide, 2, 4-bis (4-methylthiophenyl) -1, 3-dithia-2, 4-dipot Spentane-2, 4-disulfide, 2, 4-bis (4-phenylthiophenyl) -1, 3-dithia-2, 4-diphosphetane-2, 4-disulfide, etc. can be illustrated. . The amount of the reaction reagent is generally about 0.5 to 30 molar equivalents, but when the reaction is carried out at a high temperature, an amount of about 0.5 to 3 molar equivalents is preferred. Dichloromethane, tetrahydrofuran, 1, 4-dioxane, hexamethylphosphorotriamide, pyridine, etc. can be illustrated as a reaction solvent. Reaction temperature is about 20-110 degreeC, and reaction time is about 0.1-24 hours.

The alkylation reaction from compound [2] to compound [1-2] is carried out by contacting compound [2] with an alkylating agent. Examples of the reagent used are alkyl halides such as alkyl halides such as alkyl iodide, alkyl bromide and alkyl chloride, dialkyl sulfuric acid, Meerwein reagent and the like. The amount of reagent used in the reaction is 1 molar equivalent to excess, preferably about 3 molar equivalents to fruit, when the reagent is an alkhalilide or dialkyl sulfuric acid. When using Meerwin's reagent, it is preferable to use about 1 to 2 molar equivalents. Examples of the solvent used in the reaction include dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, and the like, and when alkyl halide or dialkyl sulfate is used as the alkylating agent, sodium bicarbonate, sodium carbonate, potassium bicarbonate or potassium carbonate It is preferable to make inorganic bases, such as these, coexist, and also to coexist with the above-mentioned solvent in order to melt | dissolve such inorganic bases. The reaction time is about 0.5 hours to 10 days. The use of Meerwin's reagent as an alkylating agent proceeds rapidly and completes in about 5 hours. In addition, the use of Meerwin's reagent as an alkylating agent yields a salt of compound [1-2]. In the case of separating compound [1-2], a base (e.g., sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, It is necessary to neutralize the salt using sodium hydrogen phosphate, potassium dihydrogen phosphate, sodium acetate and the like).

The acylation reaction of compound [1-2] can be performed by contacting compound [1-2] with the acylating agent containing the group represented by R <^5> . Examples of acylating agents are acid halides, mixed acid anhydrides, active esters, and the like, and acid chlorides and acid bromide are particularly preferably used. The amount of acid halide is about 1 to 3 molar equivalents. The reaction is preferably carried out in a solvent. Examples of the solvent include acetic anhydrides such as methyl acetate, ethyl acetate, propyl acetate and butyl acetate, halogenated hydrocarbons such as dichloromethane and chloroform, ethyl ether, 1,4-dioxane, Ethers such as tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, hexamethylphosphorotriamide and the like. Reaction temperature is about 0-80 degreeC, and it is convenient to carry out near room temperature. The reaction time is about 1 to 24 hours. Subsequent hydrolysis reaction can proceed by adding water after completion of the acylation reaction described above, and in some cases can complete the hydrolysis in the presence of moisture contained in the solvent used for the acylation reaction. In the case of adding water, the volume is, for example, 1 to 10 molar equivalents. The reaction temperature for obtaining the desired result is about 0 to 50 ° C, and the reaction time is about 1 to 24 hours.

By-products formed when the compound [1-3] is prepared from the compound [1-2] described above can be removed by a known method such as chromatography, recrystallization, and reprecipitation.

In order to acylate compound [3], and to thioamideize the acylated compound, if necessary, to prepare compound [1-4], the compound [1-2] is first acid-hydrolyzed and then the resulting compound [ 3] acylated.

The acid hydrolysis reaction of compound [1-2] can be carried out using an inorganic acid (eg, hydrochloric acid, sulfuric acid, bromic acid, iodic acid, fluoric acid, nitric acid, perchloric acid, chromic acid, periodic acid) in the presence of water or It is carried out by contact with an organic acid (eg methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid). The reaction is preferably carried out in an organic solvent in order to dissolve compound [1-2]. Examples of the solvent used may include acetone, tetrahydrofuran, 1, 4-dioxane, dichloromethane, chloroform, dichloroethane, methanol, ethanol and the like. Reaction temperature is about 0 to about 50 degreeC, and it is convenient to carry out reaction at room temperature. The reaction time varies depending on the reaction temperature, the acid concentration and the type of organic solvent used, and is 0.5 to 24 hours. Compound [1-3] is prepared by acylating the compound [3], which is produced by acid hydrolysis of compound [1-2] and is preferably unseparated. In more detail, the preferred method produces compound [1-3] by allowing acylating agent to coexist when acid hydrolyzing compound [1-2] and immediately acylating compound [3].

The acylation reaction of compound [3] can be carried out similarly to the acylation reaction of compound [1-2].

In the case where the compound obtained by the acylation is thioamidated as necessary, the reaction can be carried out similarly to the reaction for thioamidating the compound [6] or compound [4] described above.

Among the compounds [1-3], for example, the following compounds [9] to [44] can also be produced by the 3-position conversion reaction.

Acylation or sulfonylation of compound [5]-compound [9] or [10], compound [22]-compound [23] or [24] and compound [33]-compound [34] or compound [35] The reaction can be carried out under similar conditions as those of the above-mentioned conversion from compound [5] to compound [6].

The reduction reaction of compound [20]-compound [22] and compound [32]-compound [33] can be carried out similarly to the conversion reaction with compound [4]-compound [5] mentioned above.

Compound [10; R = methyl or tolyl] → compound [11], compound [24; R '= methyl or tolyl] → compound [25] and compound [35; R "= methyl or tolyl] → iodide reaction of the compound [36] can be performed by a well-known method. Examples of the iodide agent are potassium metal salts, such as sodium iodide and potassium iodide, and generally about 1 mol equivalent or its The above is preferably used in an amount of about 1 to 5 molar equivalents The reaction is preferably a solvent such as acetone, methyl ethyl ketone, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetace With amide, dimethylsulfoxide and hexamethylphosphorotriamide, when acetone is used as the solvent, the reaction is mostly carried out under reflux N, N-dimethylformamide or N, N-dimethylacetamide The reaction usually proceeds at low temperatures, where the reaction time varies depending on the amount of the iodide, the type of solvent and the reaction temperature, typically about 1 to 24 hours.

In the conversion reaction of compound [11]-compound [12], compound [19]-compound [20], compound [25]-compound [26] and compound [36]-compound [37], thiol or its salt is used. . In the case of using a thiol, the reaction is carried out by allowing a base such as organic amines such as triethylamine, diisopropylamine and pyridine or inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and potassium hydrogen carbonate to coexist. You can get good results by letting this go smoothly. The amount of the reaction reagent is usually about 1 molar equivalent to 5 molar equivalents, and when using a thiol salt, about 1 to 2 molar equivalents are sufficient. The reaction is carried out in a solvent. As the solvent, for example, tetrahydrofuran, 1, 4-dioxane, ethanol, methanol, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, hexamethylphosphorotriamide, aceto Nitrile, nitromethane and the like are often used. Reaction temperature is about -30-50 degreeC. Usually, it is preferable to start the reaction to cool and to heat it to room temperature, since abrupt reactions can be avoided. The reaction time is about 1 minute to 24 hours.

Azide reactions of compound [11] → compound [15], compound [25] → compound [27], compound [19] → compound [30] and compound [36] → compound [38] are generally azide The alkali metal salt of hydrogen azide such as sodium or potassium azide is used under similar conditions to the conversion reaction to thiol described above. In addition, when using the solvent which does not melt | dissolve the alkali metal salt of hydrogen azide well, it is preferable to make water coexist in a reaction system. Reaction temperature is about 0-100 degreeC, and reaction time is about 10 minutes-24 hours.

As the oxidizing agent for the oxidation reaction of the compound [12]-compound [13], for example, metachloroperbenzoic acid, sodium meta-periodide and the like are preferably used in an amount of about 1 molar equivalent. As the reaction solvent, those capable of dissolving compound [12] and an oxidizing agent are preferably used. When meta-perchlorobenzoic acid is used as the oxidizing agent, for example, dichloromethane, chloroform, ethyl acetate methanol or ethanol is preferably used. When sodium meta-periodide is used as the oxidizing agent, a mixed solvent containing water is preferably used. The reaction temperature is considerably lower than room temperature, usually about -30 ° to 25 ° C, and the reaction time is about 0.1 to 24 hours.

The conversion of compound [13] to compound [14] can be carried out by heating so that sulfinic acid is evaporated. The reaction is carried out in a solvent such as benzene, toluene, xylene and the like. In sulfinic acid formed by decomposition of Compounds [13] and [14], good results can be obtained by allowing the reagents that trap sulfinic acid to coexist in the reaction system. Examples of sulfinic acid trapping agents are trimethyl phosphite, triethyl phosphite, triisopropyl phosphite, tributyl phosphite, triphenyl phosphine, tributyl phosphine and the like, and preferably about 1 to 10 molar equivalents are used. You can get the result. Reaction temperature is about 80-120 degreeC, and reaction time is about 0.5-24 hours.

The conversion reaction of compound [15]-compound [16], compound [27]-compound [28], compound [30]-compound [31] and compound [38]-compound [39] can be carried out by reducing an azide group. Can be. Methods for reducing azide groups to amino groups are well known, for example a) catalytic reduction with a Lindlar catalyst, b) 1, 3-propanedithiol and triethylamine, c) trivalent A phosphorus compound is allowed to react, and a product is hydrolyzed (Standinger reaction), d) a method using chromium chloride (Cr (II) Cl ₂ ], and e) reduction by zinc-acetic acid. In the method a), the azide compound is stirred at room temperature under a hydrogen stream using a Lindler catalyst. Examples of the solvent used are ethyl acetate, benzene, ethanol, methanol and the like. The reaction time varies depending on the amount and activity of the catalyst used, but is usually about 1 to 24 hours. In method b), about 1-3 molar equivalents of 1, 3-propanedithiol or triethylamine are used and the reaction system is stirred for about 1 to 24 hours. As the reaction solvent, for example, methanol, ethanol, dichloromethane, chloroform, tetrahydrofuran, ethyl acetate or a mixed solvent thereof are used. In method c), a trivalent phosphorus compound (eg, triphenylphosphine, trimethylphosphite, triethylphosphite, etc.) is reacted with an azide compound and hydrochloric acid is used to decompose the generated iminophosphoran. . Synthesis, 1985, p. 202]. At this time, for example, benzene is used as the solvent. In method d) chromium chloride was dissolved in 0.6 M hydrochloric acid, the solution was added dropwise to the azide compound dissolved in acetone and the mixture was stirred at 0 ° C. for 5 minutes [The Journal of Antibiotic, 38, 477 (1985)]. The zide compound is reduced to an amino compound. In method e), excess zinc and acetic acid are used for reduction, acetic acid may also be used as a solvent, or other solvents (eg, dichloromethane, chloroform, ethyl acetate, etc.) may be used, and the reaction temperature is about 0 to It is 50 degreeC and reaction time is about 1 minute-24 hours.

The conversion of compound [16]-compound [17], compound [28]-compound [29], compound [31]-compound [32] and compound [39]-compound [40] can be carried out by a known method. have. That is, the amino compound is alkylated using an alkylating agent such as alkyl chloride, alkyl bromide, alkyl iodide or alkyl sulfuric acid. The amount of alkylating agent is mostly about 1 to 3 equivalents. Although all solvents can be used, ethanol, methanol, etc. are used preferably. The reaction temperature is generally high in many cases, usually about 50-100 ° C. The reaction time is about 1 to 24 hours. Under these reaction conditions, N-dialkyl compounds are sometimes produced as by-products. When the formation of these N-dialkyl compounds is undesirable, the N-monoalkyl compounds can be obtained by reductive alkylation with aldehydes. In this case, the aldehyde compound is reacted with cooling near room temperature and the resulting imino compound is reduced by using a reducing agent such as sodium cyanoborohydride to obtain a monoalkyl compound. The amount of aldehyde is about 1 to 3 molar equivalents, and the amount of sodium cyanoborohydride is preferably about 1 to 3 times the theoretical amount. Methanol, ethanol, tetrahydrofuran, etc. are used as a reaction solvent, and reaction time is about 0.1 to 24 hours. In acylation, sulfonyl 롸 or phosphinothioylation reactions, the reaction can be carried out using a corresponding halide (a less expensive and convenient chloride) under conditions similar to the conversion of compound [5] to compound [6], but also This can also be done by the Schotten-Baumann reaction which allows water and organic bases to coexist with the solvent.

The conversion of compound [4] to compound [18] can be carried out by reacting chlorotrimethylsilane in the presence of a base. For this purpose, it is sufficient to use about 1 to 1.5 molar equivalents of chlorotrimethylsilane, and for example, triethylamine or diisopropylethylamine is preferably used as the base. The amount of base is about 1-1.5 molar equivalents is sufficient. The reaction is preferably carried out in a solvent such as dichloromethane, chloroform or dichloroethane. The reaction is preferably carried out at about 0 to 50 ° C, particularly conveniently at room temperature. The reaction time is about 1-5 hours.

The conversion reaction of compound [18] to compound [19] can be carried out by reacting N-bromosuccinimide with compound [18]. It is sufficient to use about 1-1.5 molar equivalents of N-bromosuccinimide, and the reaction proceeds smoothly even under ice cooling. As the reaction solvent, for example, dichloromethane, chloroform or dichloroethane is preferably used. Reaction temperature is about -50-0 degreeC, and reaction time is about 1-60 minutes.

The conversion reaction between compound [20]-compound [21] and compound [32]-compound [41] is carried out by reacting hydroxylamine or O-substituted hydroxylamine. The amount of these reagents is usually preferably about 1 to 3 molar equivalents. If they are in the form of salts with acids, such as hydrochloride, sulfate, etc., it is preferable to add an equimolar amount of base (eg pyridine or triethylamine) and react in free form. Preferred examples of the reaction solvent are methanol, ethanol, tetrahydrofuran, 1, 4-dioxane or an aqueous mixture thereof. The reaction temperature is about 0 to 50 ° C, preferably room temperature, and the reaction time is about 1 to 24 hours.

The conversion of compound [4] to compound [42] or [43] is carried out by reacting a bicarbonate ester or an acid anhydride in the presence of a base. The amount of bicarbonate ester or acid anhydride is typically about 1-5 molar equivalents. Examples of the base are triethylamine or diisopropylethylamine, and their amount is usually about 1 to 5 molar equivalents. Examples of the reaction solvent are dichloromethane, chloroform or dichloroethane, and the reaction proceeds rapidly when about 1 molar equivalent of 4-N, N-dimethylaminopyridine is present as an acylation promoter in the reaction system. The reaction temperature is about −50 to 50 ° C., and the reaction time is about 1 to 24 hours.

The conversion of compound [19] to compound [44] can be carried out by reacting with about 1 to 1.5 molar equivalents of thiourea. As the reaction solvent, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, 1, 4-dioxane and an aqueous mixture thereof are preferably used. The presence of an inorganic base such as sodium hydrogen carbonate in an equimolar reaction system is preferable in most cases because the reaction proceeds rapidly without producing by-products. The reaction temperature is about 0 to 50 ° C., preferably around room temperature, and the reaction time is about 0.1 to 5 hours.

인 일반식[1]의 화합물, 즉 화합물[45]는 대응 3-아미노 화합물[1-3]을 티오아미드화 함으로써 제조할 수 있다. 화합물[1-3]→화합물[45]의 전환반응은 상술한 화합물[6]→화합물[2]와 비슷한 방법으로 수행할 수 있다.Where one of R ¹ and R ² is hydrogen and the other

The compound of phosphorus general formula [1], that is, compound [45], can be produced by thioamideizing the corresponding 3-amino compound [1-3]. The conversion reaction of compound [1-3] to compound [45] can be carried out by a method similar to that of compound [6] to compound [2].

In addition, the conversion reactions for the corresponding 3-amido compounds described above are also applicable for 3-thioamido compounds, through which other derivatives can be prepared.

In the formula, the compound of the general formula [1], that is, the compound [46], wherein R ³ and / or R ⁴ is hydroxyl, is, for example, carboxylic acid ester, carboxylic acid ester, phosphate ester, sulfonic acid ester Or by leaving off the ether compound.

When carboxylic acid esters or carboxylic acid esters are used for the purpose of leaving, ie in other words they are intended to be introduced as protecting groups of the hydroxyl groups of R ³ and / or R ⁴ , the leaving reaction is more easily carried out. can do. Examples of such carboxylic acid esters and carboxylic acid esters include benzyloxycarbonyloxy, 2, 2, 2-trachloroethoxycarbonyloxy, aryloxycarbonyloxy, chloroacetyloxy and the like, as well as literatures such as Theodora W. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York, 1981.

Ethers are typically difficult to remove. Thus, when ether is used to obtain a hydroxyl compound, the ether can be used only as a protecting group. Examples of such ether compounds include those described in the above-mentioned documents in addition to trimethylsilyl ether, t-butyldimethylsilyl ether, t-butyldiphenyl ether, methyl ether, methoxyethoxy ether and the like.

The removal reaction of the carboxylic acid ester, the carboxylic acid ester, the phosphoric acid ester or the sulfonic acid ester can be carried out by a known method or a similar method. In more detail, the reaction is a hydrolysis reaction and can be carried out under conditions similar to known ester hydrolysis reactions. That is, hydrolysis generally involves water, alcohols (e.g. methanol, ethanol, propanol, butanol, diethylene glycol, 2-methoxyethanol, etc.), ketones (e.g. acetone, etc.), ethers (e.g. tetrahydrofuran, di Oxane, dimethoxyethane, etc.), amide (e.g., dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, etc.), sulfoxide (e.g., dimethyl sulfoxide, etc.), sulfone (e.g., sulfolane), carboxyl Acid (eg, hydrochloric acid, bromic acid, inorganic acids such as reduced acid, organic acids such as p-toluenesulfonic acid, strong acid ion-exchange) in a solvent (such as formic acid, acetic acid, and the like) Resin or the like) or a base (e.g., sodium hydroxide, potassium hydroxide, potassium carbonate, sodium hydrogen carbonate, barium hydroxide, calcium carbonate, sodium methoxide, ammonia, etc.), and hydrolysis using a base is preferred. . The amount of base is about 1-10 moles, preferably about 1.2-4 moles. The reaction temperature and time are highly dependent on the kind of acyl moiety of the ester group used, and are about -20 to 70 ° C, preferably -5 to 30 ° C, and about 0.1 to 24 hours, preferably about 0.1 to 3 hours. .

When an ether compound is used as a protecting group of a hydroxyl group, it can remove by a well-known method. In more detail, when silyl groups such as trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl are used as protecting groups, the silyl group may be a fluorine-containing compound (e.g., potassium fluoride, sodium fluoride, tetra- n-butylammonium fluoride). The reaction is carried out optionally in the presence of water in solvents such as tetrahydrofuran, dioxane, methanol and ethanol. The amount of fluorine ion-containing compound is about 1 to 10 times mole, preferably about 1 to 2 times mole. Reaction temperature and time are respectively -20-100 degreeC, Preferably it is about -5-30 degreeC, It is about 0.1-24 hours, Preferably it is about 0.1-10 hours. Removal of these silyl groups is carried out by contacting them with inorganic acids such as hydrochloric acid and sulfuric acid or organic acids such as methanesulfonic acid and toluenesulfonic acid. In most cases, the reaction is carried out using a solvent such as ethanol, methanol, terahydrofuran, dioxane or acetone which is mixed with water in the presence of water. In most cases a catalytic amount of acid is sufficient for this purpose, but optionally an excess is used. The reaction temperature is about -5 to 100 ° C, preferably about 0 to 30 ° C, and the reaction time is about 0.1 to 24 hours, preferably about 0.1 to 2 hours. In the case of using an ether-containing compound such as methoxymethyl or methoxyethoxy as the protecting group, it can be removed by contact with the above-mentioned acid. When methyl or benzyl is used as the protecting group, it can be removed by contacting with iodotrimethylsilane. The amount of iodotrimethylsilane is about 1-10 moles, preferably about 1-3 moles. The reaction is carried out in solvents such as chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, dioxane and acetone. The reaction temperature is about -50 to 100 ° C, preferably about -20 to 30 ° C, and the reaction time is about 0.1 to 24 hours, preferably about 0.1 to 10 hours.

In the case where the general formula R ³ in [1] a pentanoyl oxy, iso-pentanoyl oxy, butyryl oxy, isobutyryl oxy or propionyloxy, an enzyme having an action of converting an acyloxy group of R ³ to hydroxyl groups The acyloxy group of R ³ can be converted to a hydroxyl group by contacting with the compound. An enzyme may be exemplified by a deacylated esterase produced from a strain belonging to the genus Bacillus and capable of producing the enzyme. Examples of the microorganisms belonging to the genus Bacillus include Bacillus megathelium. This method is described, for example, in The Journal of Antibiotics, 28, 390 (1975).

When R ⁴ of the general formula [1] is acetoxy, propionyloxy or butyryloxy, the acyloxy group of R ⁴ is contacted with an enzyme capable of converting the acyloxy group of R ⁴ to the hydroxy group with the compound. Can be converted to practical skills. This method is described in detail in US Pat. No. 3,691,181 and US Pat. No. 3,676,300.

The enzyme is preferably purified, but if not purified, the culture broth of the microorganism or the culture broth is filtered, centrifuged, sonicated, French-pressure treated, osmotic shock, freeze-thaw, alumina- Enzyme-containing substances such as solutions, mycelium or crushed mycelium obtained by appropriate physicochemical methods such as grinding, bacterial enzymatic treatment or treatment with a surfactant or organic solvent can be used, and immobilized enzymes can also be used. The concentration of the starting material in the reaction system in which the above-described enzyme or enzyme-containing material and the starting material are in contact is about 10 ⁻⁴ to 1 mol / l, more preferably about 10 ⁻³ to 10 ⁻¹ mol / l. The amount of the enzyme or enzyme-containing substance is about 0.1-100 mg / ml, more preferably about 0.5-50 mg / ml, based on the amount of enzyme.

The above reaction is about 0.1 to 48 hours, more preferably about 4 to 10, more preferably about 5 to 8 pH, and about 0 to 60 ℃, more preferably about 20 to 40 ℃ Do this for 0.1 to 24 hours.

A compound of formula [1], in which R ³ and / or R ⁴ is chlorine, ie compound [47], for example, reacts with chlorine with a compound [46] wherein R ³ and / or R ⁴ is hydroxy It can be prepared by allowing oxy to be substituted with chlorine. As the chlorinating agent, thionyl chloride can be conveniently used, and it is preferable to allow the base for capturing hydrogen chloride generated to coexist. The amount of thionyl chloride is about 1-1.5 molar equivalents is sufficient. Examples of bases are pyridine, picoline, lutidine, dimethylaniline, diethylaniline, triethylamine, diisopropylethylamine and the like, and the amount is preferably similar to that of thionylchloride. The reaction is carried out in a solvent, preferably dichloromethane, chloroform, dichloroethane. The reaction temperature is about -50 to 30 ° C, particularly preferably -30 to 0 ° C. The reaction time is about 0.1 to 3 hours.

Compounds of the general formula [1], in which R ³ and / or R ⁴ is bromine, ie compound [48], for example, can be substituted with thionyl bromide instead of thionyl chloride used for the conversion of compound [46] to compound [47]. Or by using alkali metal bromide in place of the alkali metal iodide used for conversion of the compound [49] to compound [50] described later.

Compounds of the general formula [1], in which R ³ and / or R ⁴ is iodine, i.e. compound [50], can be prepared by treating compound [49] similar to the conversion reaction of compound [10] to compound [11] described above. Can be.

Compounds of the general formula [1], in which R ³ and / or R ⁴ is azido, ie compound [51], can be prepared by treating compound [50] similarly to the conversion reaction of compound [11] to compound [15] described above. Can be.

The following is a method for preparing the compound of the general formula [1], wherein R ³ and / or R ⁴ is an organic moiety through an oxygen atom.

R ³ and / or R ⁴ is OCOOR ¹³ in the general formula (1) compound, the compound [52], and R ³ and / or R ⁴ is OCOR ¹⁴ in the general formula the compounds of the compound [1] of [53] is an example For example, it can be prepared by treating compound [46] similarly to the conversion reaction of compound [5] to compound [6] described above.

등인 것이다. 그 염으로는 소듐염이 바람직하다. 반응은 바람직하게는 메탄올, 에탄올, 테트라히드로푸란, N, N-디메틸포름아미드, N, N-디메틸아세토아미드, 디메틸설폭시드, 아세토니트릴 등의 유기용매에서 실시한다. 티올 또는 그 염의 양은 바람직하게는 약 1~5몰 당량이고, 반응 온도는 약 0~50℃이고, 반응 시간은 약 1분~약 10시간이다.Compound [52 '], wherein R ³ and / or R ⁴ is a compound of formula [1], wherein OCOSR ^13' is prepared, for example, by reacting compound [52] with a thiol represented by formula HSR ³ or a salt thereof can do. In the reaction, the compound [52] is preferably in an activated form, for example R ^{13 '} .

Etc. As the salt, sodium salt is preferable. The reaction is preferably carried out in organic solvents such as methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetoamide, dimethyl sulfoxide and acetonitrile. The amount of thiol or salt thereof is preferably about 1 to 5 molar equivalents, the reaction temperature is about 0 to 50 ° C., and the reaction time is about 1 minute to about 10 hours.

^'인 일반식[1]의 화합물인 화합물[54]와 식중 R³및/또는 R⁴가

인 일반식[1]의 화합물인 화합물[55]는 예를들어 일반식 OCN-R¹⁵로 나타내지는 이소시아네이트 또는 일반식 SCN-R¹⁷로 나타내지는 이소티오시아네이트와 화합물[46]을 반응시켜 제조할 수 있다. 반응은 바람직하게는 디클로로메탄, 클로로포름, 1, 2-디클로로에탄, 테트라히드로푸란, 1, 4-디옥산, 아세토니트릴, N, N-디메틸포름아미드 또는 N, N-디메틸아세트아미드 등에서 실시한다. 이소시아네이트 또는 이소티오시아네이트의 양은 바람직하게는 약 1~10몰 당량이고, 반응 온도는 약 0~150℃이고 반응 시간은 약 10분~48시간이다. 반응계에 예를들어, 약 0.1~5몰 당량의 염화아연, 브롬화아연, 요오드화아연, 염화구리(Ⅰ) 또는 디-n-부틸틴디라우레이트가 공존하도록 하면, 반응 시간을 단축시키는 이들의 촉매작용에 의해 반응 온도가 낮아질 수 있다.R ³ and / or R ⁴ is

^'Of the formula (1) compound, the compound [54] and wherein R ³ and / or R ⁴ of

Compound [55], which is a compound of the general formula [1], is prepared by reacting an isocyanate represented by the general formula OCN-R ¹⁵ or an isothiocyanate represented by the general formula SCN-R ¹⁷ with the compound [46]. can do. The reaction is preferably carried out in dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, 1, 4-dioxane, acetonitrile, N, N-dimethylformamide or N, N-dimethylacetamide and the like. The amount of isocyanate or isothiocyanate is preferably about 1 to 10 molar equivalents, the reaction temperature is about 0 to 150 ° C. and the reaction time is about 10 minutes to 48 hours. In the reaction system, for example, about 0.1 to 5 molar equivalents of zinc chloride, zinc bromide, zinc iodide, copper chloride (I), or di-n-butyltin dilaurate coexist, thereby reducing their reaction time. The reaction temperature can be lowered.

Compound [54] can also be prepared by reacting compound [52] with a compound represented by the general formula HNR ¹⁵ R ¹⁶ . Compound [52] used in this reaction is preferably an activated form of R ^{13 '} such as C ₆ Cl ₅ , 2, 4, 5-C ₆ H ₂ Cl _3, and the like. The reaction is preferably carried out in organic solvents such as dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, 1, 4-dioxane and acetonitrile. Water may be allowed to coexist in the solvent. The amount of amine is preferably about 1 to 10 molar equivalents. The reaction temperature and time vary depending on the amine and are about 0-100 ° C. and about 1 minute to about 168 hours, respectively.

인 일반식[1]의 화합물, 즉 화합물[56]은 예를들면 화합물[46]을 포스포-에스테르화시킴으로써 제조할 수 있다. 포스포-에스테르화제로는 예를들어 디(알킬, 알케닐, 알키닐, 헤테로사이클고리, 시클로알킬, 아릴 또는 아르알킬)포스포클로리데이트를 편리하게 사용할 수 있다. 포스포-에스테르화제의 양은 약 1~20몰 당량이며, 또한 용매로서 염기를 이용함으로써 좋은 결과를 얻을 수 있다. 염기의 전형적인 예는 피리딘이다. 개시단계의 반응 온도는 약 -70~50℃이고, 점차 상승시켜 약 -30~-10℃의 온도에서 수시간 유지함으로써 좋은 결과를 얻는다. 포스포클로리데이트는 N-클로로숙신이미드와 디에스테르 포스파이트를 반응시켜 제조할 수 있다.R ³ and / or R ⁴ is

The compound of phosphorus general formula [1], ie compound [56], can be prepared, for example, by phospho-esterifying compound [46]. As the phospho-esterifying agent, for example, di (alkyl, alkenyl, alkynyl, heterocycle ring, cycloalkyl, aryl or aralkyl) phosphochlorate may be conveniently used. The amount of the phospho-esterifying agent is about 1 to 20 molar equivalents, and good results can be obtained by using a base as a solvent. Typical examples of bases are pyridine. The reaction temperature in the initiation step is about -70 to 50 ° C, and gradually increases to obtain good results by holding at a temperature of about -30 to -10 ° C for several hours. Phosphochlorate can be prepared by reacting N-chlorosuccinimide with diester phosphite.

Compounds of the general formula [1], ie, compound [49], wherein R ³ and / or R ⁴ is OSO ₂ R ²⁰ , for example, are similar to compounds [5] to compound [10]. ] Can be prepared by treatment.

Compounds of the general formula [1], ie, compound [57], wherein R ³ and / or R ⁴ is OR ²¹ may be prepared, for example, by etherifying compound [46] or by substitution reaction of compound [50]. The etherification reaction can in most cases be carried out as alkylation, alkenylation, alkynylation or cycloalkylation.

Alkylation, alkenylation, alkynylation or cycloalkylation reactions can be carried out according to known methods or similar methods. Alkylating agents, alkenylating agents, alkynylating agents and cycloalkylating agents may most preferably refer to the corresponding alkyl, alkenyl, alkynyl and cycloalkyl halides (e.g. chloride, bromide, etc.), respectively, but dialkylsulfuric acid, Alkyl sulfate etc. can also be conveniently used.

The amounts of these alkylating agents, alkenylating agents, alkynylating agents and cycloalkylating agents vary, for example, depending on their reactivity, but are usually 1 to 100 times mole relative to compound [46], preferably for example When using high halides (e.g., optionally substituted benzyl halides, phenacyl halides, halogeno ketones, halogeno-acetic acid, allyl halides, propargyl halides or generally alkyl, alkenyl or alkynyl iodides, etc.) The amount is about 1 to 10 times mole, and when bromide is used, the amount is generally about 1 to 20 times mole, and when chloride is used, the amount is about 1 to 50 times mole.

The solvent used for alkylation, alkenylation or alkynylation only needs to dissolve the reagents used well, for example, alcohols such as methanol and ethanol, ethers such as diethyl ether, tetrahydrofuran and dimethoxyethane, acetone and methyl Ketones such as ethyl ketone, amides such as dimethylformamide, dimethylacetamide, sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, hydrocarbon halides such as dichloromethane and chloroform and aromatic hydrocarbons such as benzene, toluene and xylene to be. The reaction temperature is about −10 to 50 ° C., and the reaction time is about 1 to 24 hours.

Silver salts such as silver oxide or bases (for example, inorganic bases such as potassium carbonate, alkali metal alcoholates such as sodium methylate and lithium methylate, amines such as triethylamine, diisopropylethylamine, pyridine, and dimethylaminopyridine) Coexistence in the reaction system can increase the reaction rate and thereby improve the yield. On the other hand, to achieve this object more advantageously, crown ethers (eg, 18-crown-6) or quaternary ammonium salts (eg, tetraethylammonium chloride, benzyltrimethylammonium chloride, acetyltrimethylammonium chloride, etc.) may be added to the reaction system. In this case the reaction can be carried out in a two-phase system of the solution and water. In addition, good results can be obtained by adding a source of iodide, such as potassium iodide and sodium iodide, to the reaction system as is often the case with chloride as a reagent.

The alkylation reaction can also be carried out using diazoalkanes such as diazomethane as the reagent. This reaction can be preferably carried out in a solvent such as alcohol (e.g. methanol), ether (e.g. diethyl ether, tetrahydrofuran) and ester (e.g. ethyl acetate, etc.), For example, boron trifluoride or fluoro-boron may be added. The reaction is carried out at -20 ~ 30 ℃.

The alkylation reaction is also carried out using O-alkyl-N, N'-disubstituted isoureas (e.g. O-methyl, O-ethyl, O-benzyl-N, N'-dicyclohexylurea, etc.) as reaction reagents. can do. Examples of solvents are ethers (e.g. tetrahydrofuran, dioxane, etc.), halogenated hydrocarbons (e.g. dichloromethane, chloroform and carbon tetrachloride), esters (e.g. ethyl acetate, etc.) or aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.). )to be. Reaction temperature is about 40-150 degreeC.

The alkylation and alkenylation reactions can also be carried out by reaction reagents having reactive unsaturated bonds [eg, alkene (eg isobutylene, methylacrylate, ethylacrylate, acrylonitrile, methacrylonitrile, etc.), alkyne (eg methyl Propiolate, cyanoacetylene, etc.)] can be carried out by reacting with compound [46]. These reactions are preferably carried out in acids (e.g. sulfuric acid, etc.) or bases [e.g., in solvents (e.g. ethers (e.g. diethylether, dioxane, tetrahydrofuran, etc.), halogenated hydrocarbons (e.g. dichloromethane, etc.)). , Alkali metal alkoxide (eg, sodium methylate), tertiary amine (eg, N-methylmorpholine, etc.) or quaternary ammonium salt (eg, benzyltrimethyl ammonium hydroxide, etc.). Reaction temperature is about -20-50 degreeC.

Substitution reaction using compound [50] can be performed using alkanol, alkenol, alkynol, cycloalkanol, an arylhydroxy compound, a heterocycle hydroxy compound, and an alkyl metal or its amine salt. It is preferable to use counter salts to enhance the nucleophilicity of these alcohols and hydroxy compounds. The amount of these alcohols or hydroxy compounds is usually 1 to 100 molar equivalents, and in the case of simple alcohols such as methanol and ethanol, it can also be used as a solvent. Any solvent can be used as long as it dissolves the compound [50] and the reaction reagent well, but alcohols such as methanol and ethanol, acetone, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, and dimethyl sulfoxide It is preferable to use a solvent having a high polarity such as a seed or sulfolane because good results can be obtained. Reaction temperature is about -10-100 degreeC, and reaction time is 1-24 hours.

A silver salt such as silver oxide or an alkali metal alcoholate or amine can be present in the reaction system to increase the reaction rate to increase the yield. Similar results are obtained by adding crown ethers or phase-transfer catalysts.

The compound of formula [1], that is, compound [58], wherein R ³ and / or R ⁴ is OSiR ²² R ²³ R ²⁴ can be prepared by silyl-ether ester of compound [46]. The silyl-etherification reaction conditions are substantially the same as the etherification reaction conditions of compound [46]-compound [57], and silyl halide (especially chloride) is preferably used as the silyl-etherification agent. The amount of the silyl-etherating agent should be about 1 to 3 molar equivalents, and a good result is obtained if an appropriate amount of base is present in the reaction system. Examples of the base include triethylamine, diisopropylethylamine, imidazole and the like. As the reaction solvent, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, sulfolane, hexamethyl phosphorotriamide and the like are preferably used. The reaction temperature is about -30 to 50 ° C, preferably about 0 to 25 ° C, and the reaction time is about 1 to 10 hours.

Compounds of the general formula [1], wherein R ³ and / or R ⁴ is an organic moiety through a sulfur atom, are prepared by the method shown below. Compounds of the general formula [1], in which R ³ and / or R ⁴ is SR ²⁵ , ie compound [59], are treated, for example, with compound [50] similar to the conversion of compound [11] to compound [12] described above. Can be prepared.

The compound of the general formula [1], wherein R ³ and / or R ⁴ is a nitrogen atom, is prepared by the following method.

Compounds of the general formula [1], in which R ³ and / or R ⁴ is NR ²⁶ R ²⁷ , ie compound [60] are for example reduced compounds [51] to which R ³ and / or R ⁴ are amine groups [61] can be obtained, which can be prepared by alkylation, if necessary, followed by alkylation or acylation or sulfonylation or phosphorylation. This conversion method can be carried out similarly to the conversion reaction of the compound [15]-compound [16]-compound [17] described above. The phosphorylation reaction of the compound [61] or an N-alkyl derivative thereof can be carried out by 46] → can be carried out similarly to phosphorylation of compound [56].

Compound [60] can be prepared by substitution reaction of an amine or an alkyl metal salt of compound [50]. The conditions required in this case are almost similar to those of the substitution reaction with alcohols or hydroxyl derivatives of compound [50], but generally with amines and the reaction is carried out under milder conditions because of its high nucleophilicity.

As starting materials used in the process of the present invention, mention may be made, for example, of those described in US Pat. No. 3,625,055, which may be prepared according to methods analogous to those described in these documents.

Compound [1] thus obtained can be separated and purified by known methods such as concentration, solvent-extraction, chromatography, crystallization, recrystallization, and the like.

Compound [1] of the present invention can form a salt by the action of a base when having an acid group such as carboxylic acid, sulfonic acid or phosphoric acid in the R ¹ to R ⁴ position. Examples of the base may include inorganic bases such as sodium, potassium, lithium, calcium, magnesium, and ammonia and organic bases such as pyridine, collidine, triethylamine, and triethanolamine.

In addition, in the case of having a basic group such as an amino group or a substituted amino group in the R ¹ to R ⁴ position, the compound [1] may be in the form of an acid addition salt. Such acid addition salts include hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, phosphate, benzoate, maleate, fumarate, succinate, tartrate, citrate, oxalate, glyoxylate, aspartate Mention may be made of laginate, methanesulfonate, 1, 2-ethanedisulfonate, benzenesulfonate and the like.

When compound [1] is obtained in free form, it can be converted into the salt by a known method, or, conversely, when obtained in salt form, it can be converted into free form by a known method.

Compound [1] may optionally form an internal salt, all of which are included in the present invention.

The spatial isomers of compound [1] can be used as bactericides independently or as a suitable mixture thereof.

Compound [1] thus obtained shows strong bactericidal activity against gram positive bacteria and some gram negative bacteria. Compound [1] is macrolide-resistant Staphylococcus aureus and methicillin. It shows strong bactericidal action against Sepam-resistant Staphylococcus aureus (MRSA) and is well absorbed into the digestive tract and is stable in vivo. Compound [1] has bactericidal activity against the genus Mycoplasma. On the other hand, the toxicity of compound [1] is low.

As described above, the compound [1] of the present invention has excellent bactericidal action and its toxicity is low. Therefore, it can be used as an antimicrobial agent for the treatment of bacterial infections in animals (e.g. poultry, sheep, dogs, cats, rabbits, cows, horses, monkeys, humans) and for the treatment of animals infected with asterococcus, while It can also be used as an additive to a sample to protect it from infection or to promote their growth.

The daily dose of Compound [1] or its salts depends on the method of administration, the species of animal to be administered and the purpose of administration, but is generally about 0.01 to 1000 mg / kg, more preferably about 0.1 to 300 mg, in view of Compound [1]. / kg.

Compound [1] or a pharmaceutically acceptable salt thereof can be administered orally in the form of, for example, tablets, granules, capsules, drops, etc., prepared by mixing in a known manner with suitable pharmaceutically acceptable carriers, excipients and diluents. Or parenteral administration in the form of injections prepared by insertion into sterile carriers.

In preparing such oral pharmaceutical preparations, such as tablets, suitable binders (e.g., hydroxylpropyl cellulose, hydroxypropylmethyl cellulose, macrogol, etc.), disintegrants (e.g. starch, calcium carboxymethylcellulose, etc.), excipients (e.g. , Lactose, starch, etc.), lubricants (eg, magnesium stearate, talc, etc.) and the like.

In preparing parenteral preparations such as injections, isotonic agents (e.g., glucose, D-sorbitol, D-mannitol, sodium chloride, etc.), preservatives (e.g., benzyl alcohol, chlorobutanol, methyl p-oxybenzoate, propyl p) -Oxybenzoate, etc.), a buffer (for example, a phosphate buffer, sodium acetate buffer, etc.), etc. can be suitably formulated.

EXAMPLE

The following Reference Examples and Examples illustrate the invention in more detail. The abbreviations used in Tables 1-9 of the Reference Examples and Examples have the following meanings:

All NMR data of the Reference Examples and Examples were measured by 90 MHz in CDCl ₃ unless otherwise noted.

A note of "DM" indicates that NMR was measured in DMSO-D ⁶ in addition to CDCl ₃ .

"NA" represents the ambiguous proton in the signal. IR data were measured using KBr and expressed in cm ⁻¹ .

Reference Example 1

Preparation of Lancacidin C 8, 14-Diacetate

In 50 ml of pyridine, 5.0 g of lancassidin A was dissolved. 25 ml of acetic anhydride was added to the solution. The mixture was stirred at rt for 2 h. The product was left overnight at room temperature and 600 ml of ice water was added. The precipitate formed was collected by filtration and dissolved in ether. The ether layer was separated, dried over MgSO ₄ and the ether was distilled off. The residue was cooled to give crystals. The crystals were collected by filtration, washed with ether and dried to afford 3.148 g of the title compound.

NMR (90 MHz, CDCl ₃ ) δ: 1.30 (d, 3H, J = 8 Hz), 1.37 (s, 3H), 1.54 (s, 3H), 1.89 (s, 3H), 2.01 (s, 3H), 2.04 ( s, 3H), 2.16-2.60 (m, 5H), 2.44 (s, 3H), 4.40 (dt, 1H, J = 12 Hz & 3 Hz), 4.70 (d, 1H, J = 14 Hz), 5.05 (q, 1H , J = 8 Hz, 5.20-5.87 (m, 6H), 6.26 (d, 1H, J = 14 Hz), 8.06 (d, 1H, J = 10 Hz).

IR (KBr): 3410, 1735, 1730, 1710, 1685, 1235 cm ^-1 .

Reference Example 2

Preparation of 3- (2-hydroxypropionamido) -lancon 8, 14-diacetate (lancassidinol 8, 14-diacetate)

5.5 g of Lancacidin C-8, 14-diacetate was dissolved in 250 ml of methanol, the solution was cooled with ice water, and a solution of 120 mg of sodium borohydride dissolved in 15 ml of methanol was added dropwise and stirred at the same temperature for 30 minutes. It was. 1 ml of acetic acid was added to the mixture, and methanol was distilled off to obtain crystals. The crystals were dissolved in ethyl acetate (about 150 ml), washed with water and dried.

The solvent was distilled off and the residue was subjected to column chromatography [250 g of silica gel, solvent: ethyl acetate-benzene (2: 1)] to give 1.5827 g of the title compound (isomer of large Rf value, 2'-L-compound). ), 1.7803 g of the title compound (small Rf isomer, estimated 2'-D-compound) and 1.7344 g of the title compound (2'-DL-compound) were obtained.

2 '-(L) -compound:

NMR (90 MHz, CDCl ₃ ) δ: 1.30 (d, 3H, J = 7 Hz), 1.37 (s, 3H), 1.40 (d, 3H, J = 7 Hz), 1.54 (s, 3H), 1.88 (s, 3H ), 2.02 (s, 3H), 2.04 (s, 3H), 2.17-2.60 (m, 5H), 3.67 (s, 1H), 4.21 (q, 1H, J = 7 Hz), 4.28-4.56 (m, 1H) ), 4.72 (d, 1H, J = 10 Hz), 5.05 (q, 1H, J = 7 Hz), 5.20 to 5.90 (m, 6H), 6.29 (d, 1H, J = 14 Hz), 7.66 (q, 1H, J = 10 Hz).

IR (KBr): 3380, 1750, 1730, 1715, 1680, 1250 cm ^-1 .

2 '-(D) Compound:

NMR (90 MHz, CDCl ₃ ) δ: 1.24 to 1.49 (m, 9H), 1.55 (s, 3H), 1.88 (s, 3H), 2.03 (s, 3H), 2.05 (s, 3H), 2.16 to 2.60 ( m, 5H), 3.70 (s, 1H), 4.10 to 4.55 (m, 2H), 4.70 (d, 1H, J = 10 Hz), 5.03 (q, 1H, J = 7 Hz), 5.22 to 5.88 (m, 6H ), 6.30 (d, 1H, J = 14 Hz), 7.66 (d, 1H, J = 10 Hz).

IR (KBr): 3400, 1740, 1725, 1715, 1670, 1245 cm ^-1 .

Reference Example 3

Preparation of 3- (2-hydroxypropionamido) -lancon 14-acetate (lancassidinol 14-acetate)

20.2 g of lancassidin A was dissolved in 500 ml of methanol. The solution was cooled with ice water and 600 mg of sodium borohydride dissolved in 60 ml of methanol was added dropwise under stirring and stirred for 40 minutes. To the mixture was added 2 ml of acetic acid and methanol was distilled off to obtain crystals which were dissolved in ethyl acetate-tetrahydrofuran (2: 1, about 600 ml), washed with water and dried over MgSO ₄ . The solvent was evaporated to give crystals. A mixture of ethyl acetate and ether (1: 2) was added to the crystals, and the crystals were collected by filtration, washed with the same solvent mixture and dried to give 19.4 g of the title compound (a 1: 1 mixture of isomers in the 2'-position). It was.

NMR (90 MHz, CDCl ₃ -DMSO-d ₆ ) δ: 1.25 to 1.50 (m, 9H), 1.53 (s, 3H), 1.87 (s, 3H), 2.02 (s, 3H), 2.2 to 2.6 (m, 5H), 3.8 to 4.3 (m, 2H), 4.45 (m, 1H), 4.69 (m, 1H), 5.25 to 5.85 (m, 6H), 6.30 (d, 1H, J = 14 Hz), 7.82 & 7.87 ( D, 1H, J = 10 Hz respectively).

IR (KBr): 1740, 1720 (sh.), 1706, 1634, 1234, 1010, 956 cm ^-1

Reference Example 4

Preparation of 3- (2-acetoxypropionamido) -lancon 8, 14-diacetate (lancassidiol 2 ', 8, 14-triacetate)

19.3 g of 3- (2-hydroxypropionamido) -lancon 14-acetate was dissolved in 140 ml of pyridine. 70 ml of acetic anhydride was added to the solution. The mixture was stirred for 4 hours and left standing at room temperature. The reaction mixture was poured into ice water (about 1.3 L) and filtered to collect precipitate. The precipitate was dissolved in ethyl acetate-tetrahydrofuran (small amount). The aqueous layer was discarded and the organic layer was dried over MgSO ₄ and concentrated. Ether was added to the concentrate, the vessel was scraped to form crystals, and a mixture of ether-hexane (1: 1, about 200 ml) was added thereto. The crystals were collected by filtration, washed with the same solvent system and dried to give 18.3 g of the title compound (about 1: 1 mixture of isomers in 2′-position). The NMR, IR and TLC data of this product are the same as those of the compounds obtained in Reference Examples 5 and 6 below.

Reference Example 5

Preparation of 3- (2- (L) -acetoxypropionamido) -lancon 8, 14-diacetate (lancassidinol 2′-8, 14-triacetate):

1.019 g of 3- (2- (L) -hydroxy-propionamido) -rancon 8, 14-diacetate (isomer showing large Rf value) was dissolved in 10 ml of pyridine. 5 ml of acetic anhydride was added to the solution, and the mixture was stirred for 2.5 hours. The mixture was left at room temperature overnight and then poured into ice water (about 80 ml). The resulting precipitate was collected by filtration and redissolved in ethyl acetate-ether. The aqueous layer was discarded and the organic layer was dried over MgSO ₄ . The solvent was distilled off to leave crystals, to which ether was added, collected by filtration and dried to give 950.1 mg of the title compound.

Melting point: 209-211 degreeC (decomposition).

NMR (90 MHz, CDCl ₃ ) δ: 1.30 (d, J = 7 Hz, 17-Me), 1.42 (s, 2-Me), 1.46 (d, J = 7 Hz, 2′-Me), 1.54 (s, 11 -Me), 1.88 (s, 5-Me), 2.02 & 2.04 (s, 8-OAc, 14-OAc), 2.1-2.7 (m, 9-H ₂ , 15-H ₂ , 17-H), 2.19 (s, 2'-OAc), 4.42 (m, 16-H), 4.67 (d, J = 11 Hz, 4-Me), 4.9-5.9 (m, 2'-H, 8-H, 3-H , 6-H, 7-H, 10-H, 13-H, 14-H), 6.27 (d, J = 15 Hz, 12-H), 7.36 (d, J = 10 Hz, NH).

IR (KBr): 3430, 1730, 1705, 1675, 1500, 1368, 1240, 1022cm ^-1

Reference Example 6

Preparation of 3- (2- (D) -acetoxypropionamido) -lancon 8, 14-diacetate

Performed in the same manner as in Reference Example 5 using 0.995 g of 3- (20- (D) -hydroxypropionamido) -rancon 8, 14-diacetate (isomer represented by small Rf value) obtained in Reference Example 2. This gave 745.1 mg of the title compound.

Melting Point: 163 ~ 165 ℃

NMR (90 MHz, CDCl ₃ ) δ: 1.30 (d, J = 7 Hz, 17-Me), 1.33 (s, 2-Me), 1.40 (d, = 7 Hz, 2′-Me), 1.53 (s, 11- Me), 1.86 (s, 5-Me), 2.00 & 2.03 (s, 8-OAc, 14-OAc), 2.1-2.7 (m, 9-H ₂ , 15-H ₂ , 17-H), 2.23 (s, 2'-OAc), 4.37 (m, 16-H), 4.67 (d, J = 11 Hz, 4-H), 4.9-5.9 (m, 2'-H, 8-H, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.28 (d, J = 15 Hz, 12-H), 7.18 (d, J = 10 Hz, NH).

IR (KBr): 3430, 1730, 1706, 1684, 1506, 1366, 1240, 1020, 960cm ^-1

Reference Example 7

Preparation of Lancacidin C 8-benzyl Carbonate

495 mg of lancassidin C was dissolved in 4.5 ml of pyridine. The solution was cooled with ice water, stirred and 0.343 ml of carbobenzoxylchloride was added. Stirred at the same temperature for 30 minutes and at room temperature for 1.5 hours. The product was left at room temperature overnight, ice water (about 50 ml) was added and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with 1N HCl and water and then dried over MgSO ₄ . The solvent was distilled off, and the residue was subjected to silica gel (50 g) column chromatography [eluent: ethyl acetate-chloroform (1: 1)], and the eluate fractions were collected by 10 g. The twelfth to eighteenth fractions were combined and concentrated to give 71.65 mg of the title compound, an oily product, which was crystallized by standing in a freezer.

Melting Point: 185 ~ 187 ℃ (Decomposition)

NMR (90 MHz, CDCl ₃ ) δ: 1.29 (d, J = 7 Hz, 17-Me), 1.35 (s, 2-Me), 1.52 (s, 11-Me), 1.88 (s, 5-Me), 2.1 ~ 2.7 (m, 9-H ₂ , 15-H ₂ , 17-H), 2.43 (s, COCOCH ₃ ), 4.07 (m, 8-H), 4.41 (m, 16-H), 4.66 (d, J = 11 Hz, 4-H), 5.11 (s, C ₆ H ₅ CH ₂ ), 5.1 to 5.8 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H ), 6.30 (d, J = 15 Hz, 12-H), 7.32 (s, C ₆ H ₅ ), 8.05 (d, J = 10 Hz, NH)

IR (KBr): 1738, 1708, 1680, 1500, 1314, 1252, 1136, 962 cm ^-1

[α] _D ²⁴ -161.8 ° (c = 0.555, CHCl ₃ )

Reference Example 8

Preparation of Lancacidin C8-Benzyl Carbonate

The 22nd to 23rd fractions obtained in the column chromatography performed in Reference Example 7 were combined and concentrated to give 65.15 mg of the title compound, an oily product, which was left to freezer and crystallized.

Melting Point: 182 ~ 184 ℃ (Decomposition)

NMR (90 MHz, CDCl ₃ ) δ: 1.24 (d, J = 7 Hz, 17-Me), 1.36 (s, 2-Me), 1.54 (s, 11-Me), 1.88 (s, 5-Me), 2.0 ~ 2.7 (m, 9-H ₂ , 15-H ₂ , 17-H), 2.44 (s, COCOCH ₃ ), 4.2-5.1 (m, 16-H, 4-H, 13-H, 8-H, 14-H), 5.11 (s, C ₆ H ₅ CH ₂ ), 5.1-6.0 (m, 3-H, 6-H, 7-H, 10-H), 6.14 (d, J = 15 Hz, 12- H), 7.33 (s, C ₆ H ₅ ), 8.06 (d, J = 10 Hz, NH).

IR (KBr): 1740, 1706, 1682, 1380, 1354, 1256, 1162, 1000, 960 cm ^-1

[α] _D ²⁴ -140.9 ° (c = 0.46, CHCl ₃ )

Reference Example 9

Preparation of Lancacidin C8, 14-bischloroacetate

459 mg of Lancassidin C was suspended in 10 ml of dichloromethane. To the suspension was added 366 mg 4-dimethylaminopyridine and 513 mg monochloroacetic anhydride. The mixture was stirred at rt for 8.5 h and left overnight. The product was washed with water and dried over MgSO ₄ . Dichloromethane was evaporated to give crystals. Ether was added to the crystals, and insoluble crystals were filtered off. The filtrate was concentrated. The concentrate was TLC-Plate manufactured by Merck. Art. No. 5715, 20 × 20 cm, plate, developing solvent: ethyl acetate-hexane (2: 1)] was purified by permanent TLC to give 3.9 mg of the title compound as a colorless oily product.

NMR (90 MHz, CDCl ₃ ) δ: 1.31 (d, J = 7 Hz, 17-Me), 1.38 (s, 2-Me), 1.53 (s, 11-Me), 1.90 (s, 5-Me), 2.2 ˜2.7 (m, 9-H ₂ , 15-H ₂ , 17-H), 2.45 (s, COCOCH ₃ ), 0.01 & 4.03 (s, ClCH ₂ x 2), 4.43 (m, 16-H), 4.72 (d, J = 10 Hz, 4-H), 5.0 to 6.1 (m, 8-H, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.32 ( d, J = 15 Hz, 12-H), 8.05 (d, J = 10 Hz, NH).

IR (KBr): 1740, 1704, 1680, 1252, 1160, 960cm ^-1

Reference Example 10

Preparation of Lancacidin A 8-benzoate

501 mg of Lancassidin A was dissolved in 5 ml of pyridine. 0.174 ml of benzoyl chloride was added dropwise to the solution with stirring under ice cooling. After 5 minutes the ice water bath was removed and the mixture was stirred at room temperature. After 35 minutes, 0.087 ml of benzoyl chloride was further added, and further stirred for 30 minutes. The product was poured into ice water and the resulting precipitate was extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with 1N HCl and NaCl aqueous solution and dried over MgSO ₄ . The solvent was distilled off to leave crystals, to which a mixture of ether and petroleum ether (1: 1) was added. The crystals were collected by filtration, washed with the same solvent and dried to give 476.8 mg of the title compound.

Melting Point: 221 ~ 223 ℃ (Decomposition)

NMR (90 MHz, CDCl ₃ ) δ: 1.32 (d, J = 7 Hz, 17-Me), 1.38 (s, 2-Me), 1.59 (s, 11-Me), 1.92 (s, 5-Me), 2.02 (s, OAc), 2.2-2.7 (m, 9-H ₂ , 15-H ₂ , 17-H), 2.43 (s, COCOCH ₃ ), 4.32 (m, 16-H), 4.73 (d, J = 11 Hz, 4-H), 5.2-5.9 (m, 8-H, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.32 (d, J = 15 Hz, 12-H), ˜7.5 (m, 3H, C ₆ H ₅ ), ˜8.1 (m, 3H, C ₆ H ₅ , NH).

IR (KBr): 1708, 1356, 1270, 1240, 1112, 952 cm ^-1

[α] _D ²⁴ -124.2 ° (c = 0.48, CHCl ₃ )

Reference Example 11

Preparation of Esterase for 14-O-Deacylation

Apply Streptomyces Locay in a 40 liter container. Volubilis No. 5 L of T-2636 (IFO 12507, FERM P-6155) (culture was described in the example published in Tokugo Sho 47-20959) was added and 20 L of 95% ethanol was added. The mixture was thoroughly mixed and left at 10 ° C. or lower for 12 hours. The supernatant was removed using siphon to obtain a slurry containing white precipitate and released product. This slurry was centrifuged (5-10 degreeC, 2000 * g or more). The soil-like material thus obtained was dried for 1 day in a vacuum at 10 DEG C (50 mu Hg or less) to obtain an off-white enzyme preparation.

Reference Example 12

Preparation of Lancassidin C

102 mg of lancassidin A was dissolved in 200 ml of methanol. 80 ml of 2.0 g of an aqueous solution of the enzyme obtained in Reference Example 11 was added thereto. The mixture was stirred at rt for 35 min and methanol was distilled off. The residue was extracted with isobutyl ketone-tetrahydrofuran (1: 1). The extract was dried over MgSO ₄ and the solvent was distilled off. Ether was added to the residue to give a white powdery crystalline material which was filtered and dried to yield 24.85 mg of the title compound. NMR, IR and TLC of this product are the same as those of the lancassidin C obtained by the fermentation method.

Reference Example 13

Preparation of Lancacidin C-8-acetate

In a mixture of 20 ml of methanol and 10 ml of tetrahydrofuran, 109 mg of lancassidine C 8, 14-diacetate was dissolved. 80 ml of an aqueous solution of 2.0 g of enzyme obtained in Reference Example 11 was added to the solution, and the mixture was stirred at room temperature for 50 minutes. Methanol and tetrahydrofuran were distilled off and the residue was extracted with chloroform-acetone. The organic layer was dried over MgSO ₄ and the solvent was distilled off. The residue was chromatographed on silica gel (60 g), eluted with ethyl acetate-chloroform (2: 1) and eluted with 8 g of each fraction. The 25th to 36th fractions were combined and the solvent was distilled off to give 42.2 mg of the title compound as white crystals.

NMR (90 MHz, CDCl ₃ ) δ: 1.28 (d, J = 7 Hz, 17-Me), 1.37 (s, 2-Me), 1.55 (s, 11-Me), 1.90 (s, 5-Me), 2.03 (s, OAc), 2.2-2.6 (m, 9-H ₂ , 15-H ₂ , 17-H), 2.43 (s, COCOCH ₃ ), 4.33 (m, 14-H), 4.43 (m, 16- H), 4.70 (d, J = 11 Hz, 4-H), 5.05 (m, 8-H), 5.2-5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H ), 6.15 (d, J = 15 Hz, 12-H), 8.07 (d, J = 10 Hz, NH).

IR (KBr): 3475, 1728, 1706, 1672, 1256, 1234 (sh.), 1012, 960 cm ^-1

Reference Example 14

Preparation of Lancacidin C:

To a mixture of 10 ml of dichloromethane and 1 ml of acetic acid was dissolved 405 mg of lancassidine C8, 14-bis (2, 2, 2-trichloro ethylcarbonate). The solution was added 810 mg of zinc powder and the mixture was stirred at room temperature for 5 hours. Ethyl acetate was added to the product, the insoluble material was filtered off using a filter and the filtrate was concentrated. The concentrate was subjected to silica gel (50 g) column chromatography [eluent: tetrahydrofuran-chloroform (1: 2)], and the eluate was fractionated by 10 g. The 20th to 28th fractions were combined and the solvent was distilled off. Ether was added to the residue and the vessel walls were scraped to give 45.5 mg of the title compound. This product is identical in lancassidine C obtained by fermentation in NMR, IR and TLC.

Reference Example 15

Preparation of Lancassidin C

In 1 ml of tetrahydrofuran 60.4 mg of lancassidine C 8, 14-bistrimethylsilylether was dissolved. 0.3 ml of 1N-HCl was added to the solution, and the mixture was stirred at room temperature for 10 minutes. Ethyl acetate was added to the product, washed successively with water, aqueous sodium bicarbonate solution and brine, dried over MgSO ₄ and distilled off the solvent to give 50.5 mg of the title compound. This product is identical in lancassidine C and NMR, IR and TLC obtained by fermentation.

Reference Example 16

Preparation of Lancassidin C

20.6 mg of lancassidine C 8, 14-bis (dimethyl-t-butylsilylether) was dissolved in 0.5 ml of tetrahydrofuran. 0.1 ml of 2N-HCl was added to the solution, and the mixture was stirred at room temperature for 2.5 hours. Ethyl acetate was added to the product, washed successively with water, aqueous sodium bicarbonate solution and brine, dried over MgSO ₄ and the solvent was distilled off. The residue was purified by permanent TLC using TLC-plate (Merck, Art. No. 5715, 20 × 20 cm, field solvent: ethyl acetate) to give 17.4 mg of the title compound. This product is identical in lancassidine C and NMR, IR and TLC obtained by fermentation.

Reference Example 17

Preparation of 8-dehydroxy-8-chloro-lancassidin A

501 mg of Lancassidin A was dissolved in 5 ml of dichloromethane. 89 μl of pyridine was added to the solution and the mixture was cooled to 0 ° C. 80.2 μl of thionyl chloride was added dropwise to the resulting mixture. The mixture was stirred at the same temperature for 30 minutes, to which ice water was added and extracted with dichloromethane. The extract was dried over MgSO ₄ and the solvent was distilled off. The residue was subjected to silica gel (50 g) column chromatography [eluent: ethyl acetate-chloroform (1: 4)], and the eluate was fractionated by 15 g. The 11th to 23rd fractions were combined and the solvent was distilled off. Ether was added to the residue to separate the crystals, and ether-petroleum ether (1: 2) was added. The crystals were collected by filtration and dried to give 339.9 mg of the title compound as a crystal.

NMR (90 MHz, CDCl ₃ ) δ: 1.30 (d, J = 7 Hz, 17-Me), 1.37 (s, 2-Me), 1.56 (s, 11-Me), 1.91 (s, 5-Me), 2.02 (s, OAc), 2.1 to 2.8 (m, 15-H ₂ , 17-H, 9-H ₂ ), 2.45 (s, COCOCH ₃ ), 4.14 (m, 8-H), 4.42 (m, 16- H), 4.71 (d, J = 11 Hz, 4-H), 5.2-5.9 (m, 3-H, 6-H, 10-H, 13-H, 14-H), 6.26 (d, J = 15 Hz 12-H), 8.6 (d, J = 10 Hz, NH).

IR (KBr): 3380, 1740, 1708, 1700 (sh.), 1506, 1356, 1256, 1224, 1138, 946cm ^-1

Mass m / s: 519 (M ⁺ ), 483 (M ⁺ -36 (HCl)), 459 (M ⁺ -60 (AcOH)), 423 (M ⁺ -36-60)

Reference Example 18

Preparation of Bis [3- (2- (D) -hydroxy-pyropyionamido) -lancon 8, 14-diacetate-2 '-(O) -yl] sulfone

86.7 mg of 3- (2- (D) -hydroxypropionamido) -rancon 8, 14-diacetate were dissolved in 0.5 ml of pyridine. To the solution was added 12.7 μl of thionyl chloride under ice cooling and the mixture was stirred for 20 minutes. Ice water was added to the product, and the resulting precipitate was collected by filtration and recrystallized with ethyl acetate-ether to give 60.1 mg of the title compound.

Melting Point: 182 ~ 183 ℃

NMR (90MHz, CDCl ₃ ) δ: 1.20 ~ 1.67 (m, 12H), 1.87 (s, 3H), 2.02 (s, 3H), 2.04 (s, 3H), 2.15 ~ 2.60 (m, 5H), 4.60 ~ 5.90 (m, 10H), 6.28 (d, 1H, J = 14 Hz), 7.40-7.70 (m, 1H).

IR (KBr): 3420, 1730, 1715, 1690, 1245cm ^-1

Reference Example 19

Preparation of 2- (2, 2, 2-trichloroethoxycarbonyl) phenylacetyl chloride

1) 5.0 g of phenylmalonic acid was suspended in 80 ml of dichloromethane. To the suspension was added 4.25 g of 2, 2, 2-trichloroethanol. 5.8 g of dicyclohexylcarbodiimide was added little by little with stirring under ice-cooling. Stir for 20 minutes at the same temperature and 3 hours at room temperature. The precipitate formed was filtered off and the precipitate was washed with a small amount of dichloromethane. The filtrate was washed with water and extracted with aqueous sodium hydrogen carbonate solution. The aqueous layer was acidified with 1N-HCl and ethyl acetate extracted. The extract was washed with brine, dried over MgSO ₄ and the solvent was distilled off. Chloroform was added to the residue and the precipitated phenylmalonic acid was filtered off. The filtrate was concentrated to give 3.2 g of crude phenylmalonic acid mono (2, 2, 2-trichloroethyl) ester.

NMR (60 MHz, CDCl ₃ ) δ: 4.78 (s, 3H), 7.37 (s, 5H), 9.5 (br., 1H).

2) 3.2 g of the phenylmalonic acid mono (2, 2, 2-trichloroethyl) ester was dissolved in 12 ml of thionyl chloride. The solution was stirred at 50 ° C. for 1 hour and refluxed for 30 minutes. The reaction solution was concentrated and the distillate was removed with a vacuum pump (bad temperature: 140 ° C.) to give 2.4 g of the title compound, an orange oily product.

NMR (60 MHz, CDCl ₃ ) δ: 4.80 (s, 2H), 5.13 (s, H), 7.40 (s, 5H).

Reference Example 20

Preparation of D (-)-2- (2, 2, 2-trichloroethoxycarbonylamino) phenylacetylchloride

0.88 g of D (-)-2- (2, 2, 2-trichloroethoxycarbonylamino) phenylacetic acid was suspended in 12 ml of dichloromethane. To the suspension was added dropwise N, N-dimethylformamide and 0.6 ml of oxalylchloride under ice-cooling with stirring. The mixture was stirred at the same temperature for 10 minutes and at room temperature for 20 minutes and concentrated to yield 1.0 g of the crude product of the title compound as a yellow orange oily substance.

NMR (60 MHz, CDCl ₃ ) δ: 4.77 (s, 2H), 5.62 (br. D, 1H, J = 7 Hz), 5.9 (br., 1H), 7.42 (s, 5H)

Example 1

Preparation of Lancadine C 8, 14- (2, 2, 2-trichloroethyl) carbonate:

459 mg of Lancassidin C was dissolved in 4.5 ml of pyridine. 0.413 ml of chloroformic acid 2, 2, 2-trichloroethyl ester was added dropwise to the solution while stirring. The mixture was stirred for 1 hour, poured into 50 ml of ice water and extracted with ethyl acetate. After washing the extract with water, 1N HCl and then dried over MgSO _4. The solvent was distilled off. Ether is added to the residue and allowed to cool to form crystals. A mixture of ether and petroleum ether (1: 1) was added, filtered to collect crystals and dried to afford 411.4 mg of the title compound.

Melting Point: 188 ~ 190 ℃ (Decomposition)

NMR (90 MHz, CDCl ₃ ) δ: 1.30 (d, J = 7 Hz, 17-Me), 1.38 (s, 2-Me), 1.56 (s, 11-Me), 1.90 (s, 5-Me), 2.2 ~ 2.7 (m, 9-H ₂ , 15-H ₂ , 17-H), 2.43 (s, COCOCH ₃ ), 4.45 (m, 16-H), 4.65 ~ 5.2 (m, 4-H, 8-H ), 4.73 (s, CCl ₃ CH ₂ x 2), 5.2 to 5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.35 (H, d , J = 15 Hz, 12-H), 8.05 (d, J = 10 Hz, NH).

IR (KBr): 1754, 1712, 1690, 1380, 1246 cm ^-1

Example 2

Preparation of Lancacidin A 8- (2, 2, 2-trichloroethylcarbonate):

501 mg of Lancassidin A was dissolved in 5 ml of pyridine. To the solution was added 0.206 ml of 2, 2, 2-trichloroethyl chloroformate dropwise with stirring under ice cooling. The mixture was stirred at the same temperature for 5 minutes and at room temperature for 70 minutes. 0.103 ml of 2, 2, 2-trichloroethyl chloroformate was added and stirred for 30 minutes. The product was poured into ice water and extracted with ethyl acetate. The extract was washed sequentially with 1N-HCl and brine and dried over MgSO ₄ . The solvent was distilled off. Ether was added to the residue and the crystals were separated by cooling. A mixture of ether and petroleum ether (1: 1) was added, filtered to collect crystals and dried to yield 429 mg of the title compound.

Melting Point: 214 ~ 216 ℃ (Decomposition)

NMR (90 MHz, CDCl ₃ ) δ: 1.30 (d, J = 7 Hz, 17-Me), 1.37 (s, 2-Me), 1.54 (s, 11-Me), 1.89 (s, 5-Me), 2.00 (s, OAc), 2.2 to 2.7 (m, 9-H ₂ , 15-H ₂ , 17-H), 2.43 (s, COCOCH ₃ ), 4.40 (m, 16-H), ˜4.7 (m, 4 -H), 4.73 (s, CCl ₃ CH ₂ ), ~ 4.95 (m, 8-H), 5.2-5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.27 (d, J = 15 Hz, 12-H), 8.05 (d, J = 10 Hz, NH).

IR (KBr): 1746, 1706, 1684, 1376, 1358, 1242, 946cm ^-1

[α] _D ²⁴ -185.6 ° (c = 0.555, CHCl ₃ )

Example 3

Preparation of Lancacidin A 8-dibenzylphosphate:

5.24 g of dibenzyl phosphite was dissolved in 40 ml of benzene. 2.67 g of N-chlorosuccinimide was added to the solution, and the mixture was stirred under nitrogen atmosphere for 2 hours. Insoluble material was decanted and benzene was distilled off. The residue was added at −60 ° C. to a solution of 1.003 g of Lancacidin A dissolved in 25 ml of pyridine. The mixture was raised to -20 ° C over 30 minutes. The mixture was stirred at −20 ° C. for 2.5 hours, poured into 100 ml of ice water, and extracted with ethyl acetate. The extract was washed sequentially with 2N-HCl, water, aqueous sodium hydrogen carbonate solution, water and salt solution, and dried over Na ₂ SO ₄ . The solvent was distilled off and the residue was subjected to silica gel column chromatography [eluent: ethyl acetate-hexane (1: 1) and ethyl acetate-benzene (1: 1)]. The eluate containing the desired product was concentrated and the residue was crystallized from ether to give 1.2747 g of the title compound.

Melting Point: 179 ° C (Decomposition)

NMR (90MHz, CDCl ₃ ) δ: 1.30 (d, J = 7Hz, 3H), 1.37 (s, 3H), 1.50 (s, 3H), 1.83 (s, 3H), 2.00 (s, 3H), 2.15 ~ 2.60 (m, 5H), 2.46 (s, 3H), 4.27 ~ 4.76 (m, 3H), 4.98 (d, J = 9Hz, 2H), 5.01 (d, J = 9Hz, 2H), 4.95 ~ 5.80 (m , 6H), 6.22 (d, J = 15 Hz, 1H), 7.30 (s, 5H), 7.31 (s, 5H), 8.07 (br. D, J = 10 Hz, 1H).

IR (KBr): 1755, 1735, 1715, 1695, 1245, 1010 cm ^-1 .

[α] _D ²⁴ -159.6 ° (c = 0.535, CHCl ₃ )

Example 4

Preparation of Lancadine A 8-diethylphosphate:

The reaction was carried out similarly to Example 3, except that diethyl phosphite was used instead of the dibenzyl phosphite of Example 3 to obtain the title compound.

Yield: 85.5%, Melting Point: 151 ~ 152 ℃

NMR (90MHz, CDCl ₃ ) δ: 1.27 (d, J = 7Hz, 3H), 1.28 (t, J = 7Hz, 6H), 1.38 (s, 3H), 1.54 (s, 3H), 1.90 (s, 3H ), 2.01 (s, 3H), 2.02 ~ 2.70 (m, 5H), 2.45 (s, 3H), 3.88 ~ 4.80 (m, 7H), 5.15 ~ 5.85 (m, 6H), 6.25 (d, J = 15Hz , 1H), 8.09 (br. D, J = 10 Hz, 1H).

IR (KBr): 1735, 1715, 1690, 1265, 1245, 1015 cm ^-1

[α] _D ²⁴ -203.6 ° (c = 0.47, CHCl ₃ )

Example 5

Preparation of Lancacidin A 8-Dimethylphosphate:

The reaction was carried out in the same manner as in Example 3, but using the dimethyl phosphite instead of the dibenzyl phosphite of Example 3 to obtain the title compound.

Yield: 92.1%, Melting Point: 138 ~ 140 ℃

NMR (90MHz, CDCl ₃ ) δ: 1.30 (d, J = 7Hz, 3H), 1.37 (s, 3H), 1.54 (s, 3H), 1.91 (s, 3H), 2.01 (s, 3H), 2.20 ~ 2.70 (m, 5H), 2.44 (s, 3H), 3.68 (d, J = 12 Hz, 3H), 3.70 (d, J = 12 Hz, 3H), 4.30-4.83 (m, 3H), 5.20-5.90 (m , 6H), 6.26 (d, J = 15 Hz, 1 H), 8.10 (br. D, J = 10 Hz, 1 H).

IR (KBr): 1735, 1715, 1690, 1245, 1010 cm ^-1

[α] _D ²⁴ -216.8 ° (c = 0.5, CHCl ₃ )

Example 6

Preparation of Lancacidin A 8-diphenylphosphate:

The title compound was obtained by carrying out the reaction similar to Example 3 using commercially available diphenyl phosphorochlorate.

Yield: 85.9%, Melting point: 153 ~ 154 ℃ (decomposition)

NMR (90MHz, CDCl ₃ ) δ: 1.29 (d, J = 7Hz, 3H), 1.35 (s, 3H), 1.51 (s, 3H), 1.84 (s, 3H), 2.00 (s, 3H), 2.15 ~ 2.65 (m, 5H), 2.47 (s, 3H), 4.25-4.95 (m, 3H), 5.15-5.85 (m, 6H), 6.23 (d, J = 15 Hz, 1H), 7.00-7.50 (m, 10H ), 8.08 (br. D, J = 10 Hz, 1H).

[α] _D ²⁴ -161.6 ° (c = 0.485, CHCl ₃ )

Example 7

Preparation of Lancadine C 8-acetate-14-dibenzylphosphate:

The title compound was obtained (yield 37.9%) by carrying out a reaction similar to that of Example 3 using lancassidin C-8-acetate instead of lancassidin A of Example 3. The product was purified by recrystallization (solvent: AcOEt-Et ₂ O) without column chromatography because it was unstable with silica gel.

Melting Point: 137 ~ 138 ℃

NMR (90MHz, CDCl ₃ ) δ: 1.16 (d, J = 7Hz, 3H), 1.35 (s, 3H), 1.48 (s, 3H), 1.87 (s, 3H), 2.04 (s, 3H), 2.20 ~ 2.60 (m, 5H), 2.43 (s, 3H), 4.20 to 5.85 (m, 9H), 4.96 (d, J = 8 Hz, 2H), 5.01 (d, J = 8 Hz, 2H), 6.18 (d, J = 15 Hz, 1H), 7.31 (s, 5H), 7.34 (s, 5H), 8.05 (br. D, J = 10 Hz, 1H).

IR (KBr): 1730, 1710, 1690, 1240, 1010, 965 cm ^-1 .

[α] _D ²⁴ -119.4 '(c = 0.515, CHCl ₃ )

Example 8

Preparation of Lancacidin C 8-acetate-14-diethylphosphate:

The title compound was obtained by performing the reaction similar to Example 3 using diethyl phosphite and lancassidine C-8-acetate instead of the dibenzyl phosphite and lancassidin A of Example 3 (yield 51.8). %). This product was purified by recrystallization (solvent: AcOEt-Et ₂ O) without column chromatography because it was unstable with silica gel.

Melting Point: 163 ~ 164 ℃

NMR (90MHz, CDCl ₃ ) δ: 1.20 ~ 1.40 (m, 12H), 1.56 (s, 3H), 1.90 (s, 3H), 2.05 (s, 3H), 2.25 ~ 2.60 (m, 5H), 2.45 ( s, 3H), 3.87-5.90 (m, 13H), 6.30 (d, J = 15 Hz, 1H), 8.06 (br. d, J = 10 Hz, 1H).

IR (KBr): 1735, 1715, 1695, 1265, 1245, 1035, 970 cm ^-1

[α] _D ²⁴ -173.7 ° (c = 0.505, CHCl ₃ )

Example 9

Preparation of Lancacidin C 8, 14-bis (dibenzylphosphate):

The title compound was obtained by performing the reaction similar to Example 3 using lancasidine C instead of lancassidin A of Example 3 (yield 72.8%). The product was purified by recrystallization (solvent: Et ₂ O) without column chromatography because it was unstable with silica gel.

Melting Point: 120 ~ 122 ℃

NMR (90 MHz, CDCl ₃ ) δ: 1.15 (d, J = 7 Hz, 3H), 1.34 (s, 3H), 1.43 (s, 3H), 1.81 (s, 3H), 2.05-2.60 (m, 5H), 2.45 (s, 3H), 4.20 to 5.85 (m, 17H), 6.13 (d, J = 15Hz, 1H), 7.30 (s, 10H), 7.32 (s, 10H), 8.06 (br. D, J = 10Hz , 1H).

IR (KBr): 1750, 1715, 1690, 1265, 1010 cm ^-1

[α] _D ²⁴ -82.8 ° (c = 0.495, CHCl ₃ )

Example 10

Preparation of Lancacidin C 8, 14-bis (diethylphosphate):

The title compound was obtained by performing the reaction similar to Example 3 using diethyl phosphite and lancassidin C instead of the dibenzyl phosphite and lancassidin A of Example 3 (yield 51.1%). This product was purified by recrystallization (solvent: Et ₂ O) without column chromatography because it was unstable with silica gel.

Melting Point: 153 ~ 154 ℃

NMR (90MHz, CDCl ₃ ) δ: 1.10 ~ 1.45 (m, 18H), 1.54 (s, 3H), 1.90 (s, 3H), 2.20 ~ 2.70 (m, 5H), 2.44 (s, 3H), 3.85 ~ 4.28 (m, 8H), 4.28-5.90 (m, 9H), 6.25 (d, J = 15 Hz, 1H), 8.08 (br. D, J = 10 Hz, 1H).

IR (KBr): 1755, 1715, 1690, 1260, 1035, 990cm ^-1

[α] _D ²⁴ -140.8 ° (c = 0.495, EtOH)

Example 11

Preparation of Lancacidin C 8, 14-bis (2-methoxyethoxymethylether):

To 459 mg of lancassidine C was added 10 ml of dichloromethane, 0.523 ml of N, N-diisopropylethylamine and 0.343 ml of 2-methoxyethoxymethylchloride. The mixture was stirred at rt for 7.5 h and left overnight. Dichloromethane was added to the mixture, washed with brine and dried over MgSO ₄ . The solvent was distilled off and the residue was subjected to silica gel (50 g) column chromatography [eluent: ethyl acetate-hexane (2: 1)]. The eluate was fractionated by 10 g and the 18th to 28th fractions were combined and concentrated to give 419 mg of the title compound as an oily product.

NMR (90 MHz, CDCl ₃ ) δ: 1.25 (d, J = 7 Hz, 17-Me), 1.37 (s, 2-Me), 1.53 (s, 11-Me), 1.90 (s, 5-Me), 2.2 ~ 2.7 (m, 9-H ₂ , 15-H ₂ , 17-H), 2.43 (s, COCOCH ₃ ), 3.36 (s, OMe x 2), 3.62 (A ₂ , B ₂ , OCH ₂ CH ₂ O x 2), 3.9-4.9 (m, 8-H, 14-H, 16-H, 4-H), 4.70 (s, OCH ₂ O x 2), 5.2-5.8 (m, 3-H, 6- H, 7-H, 10-H, 13-H), 6.12 (d, J = 16 Hz, 12-H), 8.06 (d, J = 10 Hz, NH).

IR (KBr): 1744, 1706, 1680, 1498, 1354, 1256, 1132, 1100, 1038 cm ^-1 .

Example 12

Preparation of Lancadine A 8- (2-methoxyethoxymethylether):

159.7 mg of the title compound were obtained by performing a reaction similar to Example 11 using 230 mg of lancassidin A instead of lancassidin C of Example 11. The product was further purified by recrystallization with chloroform-hexane (yield 105.5 mg).

Melting Point: 130 ~ 131 ℃

NMR (90 MHz, CDCl ₃ ) δ: 1.30 (d, J = 6.5 Hz, 17-Me), 1.37 (s, 2-Me), 1.52 (s, 11-Me), 1.89 (s, 5-Me), 2.01 (s, OAc), 2.2 ~ 2.55 (m, 9-H ₂ , 15-H ₂ , 17-H), 2.44 (s, COCOCH ₃ ), 3.35 (s, OMe), 3.45 ~ 3.8 (m, OCH ₂ CH ₂ O), 4.02 (m, 8-H), 4.37 (m, 16-H), 4.65 (d, J = 11 Hz, 4-H), 4.70 (s, OCH ₂ O), 5.2-5.85 ( m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.27 (d, J = 15 Hz, 12-H), 8.07 (d, J = 10 Hz, NH) .

IR (KBr): 3420, 2940, 1755 (sh.), 1735, 1715, 1685, 1510, 1355, 1235, 1145, 1110, 1080, 1045, 1030 (sh.), 1020, 975 cm ^-1 .

Example 13

Preparation of Lancadine A 8-methoxymethylether:

276.7 mg of the title compound were obtained by performing the reaction similar to Example 11 using 230 mg of lancassidin A and methoxymethyl chloride, respectively, in place of the lancastidine C and 2-methoxyethoxymethyl chloride of Example 11 It was. This compound was recrystallized from chloroform-ether to give 147.2 mg of purified compound.

Melting Point: 200 ~ 202 ℃

NMR (90 MHz, CDCl ₃ ) δ: 1.30 (d, J = 6.5 Hz, 17-Me), 1.37 (s, 2-Me), 1.48 (s, 11-Me), 1.89 (s, 5-Me), 2.01 (s, OAc), 2.2 ~ 2.55 (m, 9-H ₂ , 15-H ₂ , 17-H), 2.43 (s, COCOCH ₃ ), 3.32 (s, OME), 3.97 (m, 8-H ), 4.44 (s, 16-H), 4.57 & 4.64 (A Bq, J = 10 Hz, OCH ₂ O), 4.67 (d, J = 11 Hz, 4-H), 5.25-5.85 (s, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.29 (d, J = 15 Hz, 12-H), 8.06 (d, J = 10 Hz, NH).

IR (KBr): 3400, 2950, 1750 (sh.), 1730, 1710, 1690, 1510, 1440, 1360, 1320, 1240, 1150, 1100, 1070, 1040, 1020, 960, 910, 745 cm ^-1 .

Example 14

Preparation of Lancacidin C 8, 14-Ditrimethylsilyl Ether:

13.79 g of Lancacidin C was dissolved in 120 ml of N, N-dimethylformamide and the solution was cooled with ice water. To the solution, 10.46 ml of triethylamine and 9.52 ml of chlorotrimethylsilane were added dropwise under stirring. The mixture was stirred at the same temperature for 3 hours, further added 2.0 ml of triethylamine and stirred at the same temperature for 1 hour. Ether was added to the product, washed successively with water and brine and dried over MgSO ₄ . The solvent was distilled off and the residue was subjected to silica gel column chromatography [eluent: ethyl acetate-hexane (1: 1)]. The desired fractions were combined and concentrated to give 17.0 g of the title compound.

NMR (90MHz, CDCl ₃ ) δ: 0.01 (s, 18H), 1.25 (d, J = 7Hz, 3H), 1.36 (s, 3H), 1.88 (s, 3H), 2.10 ~ 2.60 (m, 5-H ), 2.43 (s, 3H), 3.90 to 4.55 (m, 3H), 4.70 (d, J = 10 Hz, 1H), 5.19 to 5.85 (m, 5H), 6.05 (d, J = 15 Hz, 1H), 8.10 (d, J = 10 Hz, 1H).

IR (KBr): 1750, 1710, 1695 cm ^-1 .

Example 15

Preparation of Lancadine C 8, 14-bis (dimethyl-t-butylsilylether):

9.19 g of lancassidine C was dissolved in 50 ml of N, N-dimethylformamide and the solution was cooled with ice water. 4.08 g imidazole and 6.78 g t-butyldimethylchlorosilane were added to the solution under stirring and stirred at the same temperature for 10 minutes and at room temperature for 1 hour. Ether was added to the product and the mixture was washed sequentially with water, 1N-HCl and brine and dried over MgSO ₄ .

The solvent was distilled off to give 13.8 g of the title compound which was further purified by reprecipitation from chloroform-petroleum ether.

Melting Point: 218 ~ 220 ℃

NMR (90 MHz, CDCl ₃ ) δ: 0.00 (s, 12H), 0.82 (s, 18H), 1.20 (d, J = 6 Hz, 3H), 1.33 (s, 3H), 1.48 (s, 3H), 1.86 ( s, 3H), 2.00-2.60 (m, 5H), 2.40 (m, 3H), 3.80-4.70 (m, 4H), 5.00-5.83 (s, 5H), 6.00 (d, J = 15 Hz, 1H), 8.06 (d, J = 10 Hz, H).

IR (KBr): 1755, 1715, 1690, 1060 cm ^-1 .

Example 16

Lancassinol 8, 14-bis (2, 2, 2-trichloroethyl) carbonate [2 '-(L) isomer] and Lancassinol 8, 14-bis (2, 2, 2-trichloroethyl ) Preparation of Carbonate [2 '-(D) Isomer] (Designation of coordination of 2'-position is temporary hypothetical, and the same is true in later examples)

810 mg of lancassidine C 8, 14-bis (2, 2, 2-trichloroethyl) carbonate was dissolved in 10 ml of tetrahydrofuran. 10 ml of methanol was added to the solution, stirred under cooling, 12.0 mg of sodium borohydride was added, and further stirred at the same temperature for 20 minutes. 0.1 ml of acetic acid was added to the product and the solvent was distilled off. The residue was subjected to silica gel (50 g) column chromatography [eluent: ethyl acetate-chloroform (1: 1)], and the eluate was fractionated by 10 g. The 15-20th fractions were combined and concentrated to give 188.4 mg of the title compound [2 '-(L) isomer], and the 25-40 fractions were combined and concentrated to yield 316.9 mg of the title compound [2'-(D) isomer). Was obtained and 151.5 mg of their mixture was obtained by combining and concentrating the 21st to 24th fractions.

2 '-(L) -isomer: Melting point: 172 ~ 174 ° C (decomposition)

NMR (90 MHz, CDCl ₃ ) δ: 1.30 (d, J = 7 Hz, 17-Me), 1.40 (s, 2-Me), 1.43 (d, J = 7 Hz, 2′-Me), 1.57 (s, 11 -Me), 1.89 (s, 5-Me), 2.2 to 2.7 (m, 9-H ₂ , 15-H ₂ , 17-H), 4.26 (q, J = 7 Hz, 2'-Me), 4.45 ( m, 16-H), 4.6-5.2 (m, 4-H, 8-H), 4.74 (s, CCl ₃ CH ₂ × 2), 5.2-5.9 (m, 3-H, 6-H, 7- H, 10-H, 13-H, 14-H), 6.35 (d, J = 15 Hz, 12-H), 7.55 (d, J = 10 Hz, NH).

IR (KBr): 1746, 1708, 1652, 1376, 1244, 812 cm ^-1 .

[α] _D ²⁴ -140.2 ° (c = 0.565, CHCl ₃ )

2 '-(D) -isomer: Melting point: 152 ~ 154 ℃ (decomposition)

NMR (90 MHz, CDCl ₃ ) δ: 1.23 (d, J = 7 Hz, 17-Me), 1.40 (s, 2-Me), 1.40 (d, J = 7 Hz, 2′-Me), 1.57 (s, 11 -Me), 1.89 (s, 5-Me), 2.2-2.7 (m, 9-H ₂ , 15-H ₂ , 17-H), 4.23 (q, J = 7 Hz, 2'-Me), 4.45 ( m, 16-H), 4.6-5.2 (m, 4-H, 8-H), 4.76 (s, CCl ₃ CH ₂ × 2), 5.2-5.9 (m, 3-H, 6-H, 7- H, 10-H, 13-H, 14-H), 6.37 (d, J = 15 Hz, 12-H), 7.46 (d, J = 10 Hz, NH).

IR (KBr): 1752, 1705, 1654, 1376, 1242, 936, 814 cm ^-1 .

[α] _D ²⁴ -133.6 ° (c = 0.59, CHCl ₃ )

Example 17

Preparation of 0 (2 ') acetyl lancassidiol 8, 14-bis (2, 2, 2-trichloroethyl) carbonate [2'-(L) isomer]

1.132 g of lancassidinol 8, 14-bis (2, 2, 2-trichloroethyl) carbonate [2 '-(L) isomer] was dissolved in 7.45 ml of pyridine. 3.73 ml of acetic anhydride was added to the solution, and the mixture was stirred at room temperature for 2.5 hours and left overnight. The product was poured into ice water (about 100 ml) and extracted with ethyl acetate.

The extract was washed sequentially with 1N-HCl and water and dried over MgSO ₄ . The solvent was distilled off and a small amount of ether was added to the residue to crystallize. Petroleum ether was added to the product, filtered to collect crystals and dried to yield 1.0723 g of the title compound.

Melting Point: 194 ~ 196 ℃ (Decomposition)

NMR (90 MHz, CDCl ₃ ) δ: 1.30 (d, J = 7 Hz, 17-Me), 1.42 (s, 2-Me), 1.45 (d, J = 7 Hz, 2′-Me), 1.55 (s, 11 -Me), 1.88 (s, 5-Me), 2.19 (s, OAc), 2.2-2.8 (m, 9-H ₂ , 15-H ₂ , 17-H), 4.45 (m, 16-H), 4.6 to 5.1 (m, 4-H, 8-H), 4.74 (s, CCL ₃ CH ₂ × 2), 5.13 (q, J = 7 Hz, 2'-H), 5.3 to 6.0 (m, 3-H , 6-H, 7-H, 10-H, 13-H, 14-H), 6.35 (d, J = 15 Hz, 12-H), 7.36 (d, J = 10 Hz, NH).

IR (KBr): 1740, 1706, 1668, 1370, 1276, 1244, 958, 932, 808 cm ^-1 .

[α] _D ²⁴ -125 ° (c = 0.525, CHCl ₃ )

Example 18

Preparation of 0 (2 ')-acetyl lancassidinol 8, 14-bis (2, 2, 2-trichloroethyl) carbonate [2'-(D) isomer]

2.0233 g of the reaction was carried out in the same manner as in Example 17 using 2.029 g of lancassidiol-8, 14-bis (2, 2, 2-trichloroethyl) carbonate [2 '-(D) isomer]. g of the title compound were obtained.

Melting Point: 150 ~ 152 ℃ (Decomposition)

NMR (90 MHz, CDCl ₃ ) δ: 1.28 (d, J = 7 Hz, 17-Me), 1.35 (s, 2-Me), 1.41 (d, J = 7 Hz, 2′-Me), 1.56 (s, 11 -Me), 1.88 (s, 5-Me), 2.23 (s, OAc), 2.2-2.8 (m, 9-H ₂ , 15-H ₂ , 17-H), 4.41 (m, 16-H), 4.6 to 5.2 (m, 4-H, 8-H), 4.74 (s, CCl ₃ CH ₂ × 2), 5.19 (q, J = 7 Hz, 2'-H), 5.2 to 6.0 (m, 3-H , 6-H, 7-H, 10-H, 13-H, 14-H), 6.35 (d, J = 15 Hz, 12-H), 7.24 (d, J = 10 Hz, NH).

IR (KBr): 1746, 1700, 1676, 1368, 1240, 1070, 936, 808 cm ^-1 .

[α] _D ²⁴ -100.2 ° (c = 0.505, CHCl ₃ )

Example 19

Preparation of 3- (2-oxo-1-thioxo) propylamino-lancon 8, 14-diacetate:

54.3 mg of lancassidine C 8, 14-diacetate was dissolved in 2 ml of dichloromethane. To the solution was added 72.8 μl of pyridine and 450 mg of phosphorus pentasulfide. The mixture was stirred at rt, after 70 min supplemented with 150 mg phosphorus pentasulfide and further stirred for 7 h. Dichloromethane was added to the product and the insoluble material was filtered off. The filtrate was concentrated and permanent TLC [ed. Merck, Art. No. 5715 20 × 20 cm, 2 plates, developing solvent: ethyl acetate-chloroform (1: 4)] yielded 27.3 mg of the title compound.

Melting Point: 219 ~ 221 ℃ (Decomposition)

NMR (90 MHz, CDCl ₃ ) δ: 1.33 (d, J = 7 Hz, 17-Me), 1.39 (s, 2-Me), 1.56 (s, 11-Me), 1.96 (s, 5-Me), 2.01 & 2.03 (s, 8-OAc, 14-OAc), 2.2-2.6 (m, 9-H ₂ , 15-H ₂ , 17-H), 2.64 (s, CSCOCH ₃ ), 4.43 (m, 16- H), 4.70 (d, J = 10 Hz, 4-H), 5.06 (m, 8-H), 5.25-6.2 (m, 3-H, 6-H, 7-H, 10-H, 13-H , 14-H), 6.30 (d, J = 15 Hz, 12-H), 10.00 (d, J = 10 Hz, NH).

IR (KBr): 1728, 1706, 1368, 1240, 1208, 1014, 960 cm ^-1 .

Example 20

Preparation of 3- (2- (L) -acetoxy-1-thioxo) propylamino-lancon 8, 14-diacetate

117.4 mg of 3- (2- (L) -acetoxypropionamide) -lancon 8, 14-diacetate were dissolved in 4 ml of dichloromethane. 16.2 μl of pyridine and 100 mg of phosphorus pentasulfide were added to the solution, and the mixture was stirred at room temperature. After 15 minutes and 3 hours, 100 mg of phosphorus pentasulfide, respectively, was added to the product.

After 4.5 hours, dichloromethane was added to the mixture and the insoluble material was filtered off. The filtrate was concentrated and the concentrate was purified by silica gel (30 g) column chromatography [eluent: ethyl acetate-chloroform (1: 4)], and the eluate was fractionated by 5 g. The 18th-25th fractions were combined and concentrated to give 31.1 mg of the title compound.

Melting Point: 241 ~ 243 ℃ (Decomposition)

NMR (90 MHz, CDCl ₃ ) δ: 1.33 (d, J = 7 Hz, 17-Me), 1.43 (s, 2-Me), 1.56 (s, 11-Me), 1.59 (d, J = 7 Hz, 2 ′ -Me), 1.95 (s, 5-Me), 2.03 (s, 9-OAc, 14-OAc), 2.20 (s-2'-OAc), 2.2-2.6 (m, 9-H ₂ , 15-H ₂ , 17-H), 4.43 (m, 16-H), 4.63 (d, J = 11 Hz, 4-H), 4.9-6.3 (m, 2'-H, 8-H, 3-H, 6- H, 7-H, 10-H, 13-H, 14-H), 6.27 (d, J = 15 Hz, 12-H), 9.23 (d, J = 9 Hz, NH).

IR (KBr): 3360, 1758, 1734, 1708, 1370, 1240 cm ^-1 .

Example 21

Preparation of 3- (2- (D) -acetoxy-1-thioxo) propylamino-lancon 8, 14-diacetate

The reaction was carried out in the same manner as in Example 20 using 117.4 mg of 3- (2- (D) -acetoxypropionamide) lancon 8, 14-diacetate to give 17.6 g of the title compound.

Melting Point: 155 ~ 157 ℃ (Decomposition)

NMR (90 MHz, CDCl ₃ ) δ: 1.32 (d, J = 7 Hz, 17-Me), 1.33 (s, 2-Me), 1.53 (d, J = 7 Hz, 2′-Me), 1.55 (s, 11 -Me), 1.95 (s, 5-Me), 2.01 & 2.03 (s, 8-OAc, 14-OAc), 2.2-2.7 (m, 9-H ₂ , 15-H ₂ , 17-H), 2.27 (s, 2'-OAc), 4.40 (m, 16-H), 4.68 (d, J = 12Hz, 4-H), 4.9 ~ 6.3 (m, 2'-H, 8-H, 3-H , 6-H, 7-H, 10-H, 13-H, 14-H), 6.27 (d, J = 15 Hz, 12-H), 8.95 (d, J = 9 Hz, NH).

IR (KBr): 1735, 1704, 1365, 1238 cm ^-1 .

Example 22

Preparation of 3- (2- (DL) -acetoxy-1-thioxo) propylamino-lancon 8, 14-diacetate

9.63 g of 3- (2- (DL) -acetoxypropionamido) -rancon 8, 14-diacetate was dissolved in 328 ml of pyridine. 8.2 g of phosphorus pentasulfide was added to the solution, and the mixture was stirred at 110 ° C. for 9 hours. The pyridine was distilled off and dichloromethane (ca. 500 g) was added to the residue to liberate the residue, and the insoluble material was filtered off using cotton. The filtrate was concentrated and the concentrate was purified by silica gel (250 g) column chromatography (eluent: ethyl acetate-chloroform (1: 4)). The desired fractions were combined and concentrated to give crystals and ether was added. Filtration collected and dried crystals to yield 3.136 g of the title compound.

Example 23

3- (2- (L) -hydroxy-1-thioxo) propylamino-lancon 8, 14-diacetate and 3- (2- (D) -hydroxy-1-thioxo) propylamino-lancon 8 , 14-diacetate

158.5 mg of the title compound [2 '-(L) isomer], 281.2 by similar procedure to Example 16 using 603 mg of 3- (2-oxo-1-thioxo) propylamino-lancon 8, 14-diacetate mg of the title compound [2 '-(D) isomer] and 136.8 mg of these mixtures were obtained.

2 '-(L) isomer, melting point 220 ~ 222 ℃ (decomposition)

NMR (90 MHz, CDCl ₃ ) δ: 1.32 (d, J = 7 Hz, 17-Me), 1.40 (s, 2-Me), 1.53 (d, J = 7 Hz, 2′-Me), 1.55 (s, 11 -Me), 1.96 (s, 5-Me), 2.01 & 2.03 (s, 8-OAc, 14-OAc), 2.2-2.7 (m, 9-H ₂ , 15-H ₂ , 17-H), 3.40 (d, J = 5 Hz, OH), 4.3 to 4.7 (m, 16-H, 2'-H), 4.73 (d, J = 11 Hz, 4-H), 5.04 (m, 8-H), 5.2 ~ 6.4 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.28 (d, J = 15 Hz, 12-H), 9.40 (d, J = 10 Hz , NH).

IR (KBr): 3320, 1728, 1706, 1495, 1360, 1240, 1014, 960 cm ^-1 .

[α] _D ²⁵ -352.9 ° (c = 0.505, CHCl ₃ )

2 '-(D) isomer, melting point 157 ~ 159 ℃

NMR (90 MHz, CDCl ₃ ) δ: 1.32 (d, J = 7 Hz, 17-Me), 1.40 (s, 2-Me), 1.49 (d, J = 7 Hz, 2′-Me), 1.56 (s, 11 -Me), 1.96 (s, 5-Me), 2.02 & 2.03 (s, 8-OAc, 14-OAc), 2.2-2.7 (m, 9-H ₂ , 15-H ₂ , 17-H), 3.47 (d, J = 5 Hz, OH), 4.32 (m, 16-H), 4.6 (m, 2'-H), 4.73 (d, J = 11 Hz, 4-H), 5.06 (m, 8- H), 5.25 to 6.4 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.31 (d, J = 15 Hz, 12-H), 9.37 (d , J = 10 Hz, NH).

IR (KBr): 1728, 1708, 1496, 1368, 1240, 1014, 958 cm ^-1 .

[α] _D ²⁵ -314.5 ° (c = 0.525, CHCl ₃ )

Example 24

Preparation of 3- (2-oxo-1-thioxo) propylamino-lancon 8, 14-bis (2, 2, 2-trichloroethyl) carbonate:

810 mg of lancassidine C 8, 14-bis (2, 2, 2-trichloroethyl) carbonate was dissolved in 20 ml of pyridine. 500 mg of phosphorus pentasulfide was added to the solution, and the mixture was stirred at 85 ° C. for 75 minutes. Pyridine was distilled off. Dichloromethane (about 50 ml) was added to the residue, the mixture was liberated well and the insoluble material was filtered off using cotton. The filtrate was concentrated, the concentrate was purified by silica gel (50 g) column chromatography [eluent: ethyl acetate-chloroform (1:10)], and the eluate was fractionated by 10 g. The ninth to fourteenth fractions were combined, concentrated, crystallized and dried by addition of a small amount of ether to yield 203.2 mg of the title compound.

Melting Point: 190 ~ 192 ℃ (Decomposition)

NMR (90 MHz, CDCl ₃ ) δ: 1.33 (d, J = 7 Hz, 17-Me), 1.39 (s, 2-Me), 1.56 (s, 11-Me), 1.95 (s, 5-Me), 2.2 ~ 2.7 (m, 9-H ₂ , 15-H ₂ , 14-H), 2.64 (s, CSCOCH ₃ ), 4.46 (m, 16-H), 4.5 ~ 5.2 (m, 4-H, 8-H ), 4.72 (s, CCl ₃ CH ₂ × 2), 5.2 to 6.2 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.36 (d, J = 15 Hz, 12-H), 9.96 (d, J = 9 Hz, NH).

IR (KBr): 1756, 1708, 1378, 1248, 1210 cm ^-1 .

Example 25

3- (2- (L) -hydroxy-1-thioxo) propylamino-lancon 8, 14-bis (2, 2, 2-trichloroethyl) carbonate and 3- (2- (D)- Preparation of hydroxyl-1-thioxo) -propylamino-lancon 8, 14-bis (2, 2, 2-trichloroethyl) carbonate

The reaction was carried out in the same manner as in Example 16 using 1.68 g of 3- (2-oxo-1-thioxo) propylamino-lancon 8, 14-bis (2, 2, 2-trichloroethyl) carbonate This gave 480 mg of the title compound [2 '-(L) isomer] and 839 mg of the title compound [2'-(D) isomer].

2 '-(L) isomer, melting point 155 ~ 157 ℃ (decomposition)

NMR (90 MHz, CDCl ₃ ) δ: 1.32 (d, J = 7 Hz, 17-Me), 1.42 (s, 2-Me), 1.53 (d, J = 7 Hz, 2′-Me), 1.57 (s, 11 -Me), 1.97 (s, 5-Me), 2.1 to 2.8 (m, 9-H ₂ , 15-H ₂ , 17-H), 2.94 (d, J = 5 Hz, OH), 4.3 to 5.2 (m , 16-H, 4-H, 8-H, 2'-H), 4.74 (s, CCl ₃ CH ₂ × 2), 5.2-6.35 (m, 3-H, 6-H, 7-H, 10 -H, 13-H, 14-H), 6.36 (d, J = 15 Hz, 12-H), 9.32 (d, J = 10 Hz, NH).

IR (KBr): 1758, 1714, 1508, 1380, 1248, 940, 820 cm ^-1 .

2 '-(D) isomer, melting point 178 ~ 180 ℃ (decomposition)

NMR (90 MHz, CDCl ₃ ) δ: 1.32 (d, J = 7 Hz, 17-Me), 1.42 (s, 2-Me), 1.50 (d, J = 7 Hz, 2′-Me), 1.57 (s, 11 -Me), 1.97 (s, 5-Me), 2.1 to 2.8 (m, 9-H ₂ , 15-H ₂ , 17-H), 3.06 (d, J = 5 Hz, OH), 4.3 to 5.2 (m , 16-H, 4-H, 8-H, 2'-H), 4.74 (s, CCl ₃ CH ₂ × 2), 5.2-6.35 (m, 3-H, 6-H, 7-H, 10 -H, 13-H, 14-H), 6.37 (d, J = 15 Hz, 12-H), 9.32 (d, J = 10 Hz, NH).

IR (KBr): 1754, 1708, 1502, 1380, 1244, 940, 818 cm ^-1 .

Example 26

Preparation of 3- (2- (L) -acetoxy-1-thioxo) propylamino-lancon 8, 14- (2, 2, 2-trichloroethyl) carbonate

Example 17 using 397 mg of 3- (2- (L) -hydroxy-1-thioxo) propylamino-lancon 8, 14-bis (2, 2, 2-trichloroethyl) carbonate Similarly, 387 mg of the title compound were obtained by carrying out the reaction.

Melting Point: 137 ~ 139 ℃

NMR (90 MHz, CDCl ₃ ) δ: 1.35 (d, J = 7 Hz, 17-Me), 1.46 (s, 2-Me), 1.59 (s, 11-Me), 1.62 (d, J = 7 Hz, 2 ' -Me), 1.98 (s, 5-Me), 2.22 (s, OAc), 2.2 to 2.8 (m, 9-H ₂ , 15-H ₂ , 17-H), 4.3 to 5.2 (m, 16-H , 4-H, 8-H, 2'-H), 4.74 (s, CCl ₃ CH ₂ × 2), 5.2-6.3 (m, 3-H, 6-H, 7-H, 10-H, 13 -H, 14-H), 6.36 (d, J = 15 Hz, 12-H), 9.22 (d, J = 10 Hz, NH).

IR (KBr): 1756, 1710, 1506, 1376, 1244, 1046, 940 cm ^-1 .

[α] _D ²⁴ -202 ° (c = 0.5, CHCl ₃ )

Example 27

Preparation of 3- (2- (D) -acetoxy-1-thioxo) propylamino-lancon 8, 14- (2, 2, 2-trichloroethyl) carbonate

Similar to Example 17 using 754 mg of 3- (2- (D) -hydroxy-1-thioxo) propylamino-lancon 8, 14-bis (2, 2, 2-trichloroethyl) carbonate 728 mg of the title compound were obtained by carrying out the reaction.

Melting Point: 194 ~ 196 ℃ (Decomposition)

NMR (90 MHz, CDCl ₃ ) δ: 1.31 (d, J = 7 Hz, 17-Me), 1.35 (s, 2-Me), 1.54 (d, J = 7 Hz, 2′-Me), 1.58 (s, 11 -Me), 1.96 (s, 5-Me), 2.26 (s, OAc), 2.0 to 2.7 (m, 9-H ₂ , 15-H ₂ , 17-H), 4.3 to 5.2 (m, 16-H , 4-H, 8-H, 2'-H), 4.74 (s, CCl ₃ CH ₂ × 2), 5.2-6.4 (m, 3-H, 6-H, 7-H, 10-H, 13 -H, 14-H), 6.36 (d, J = 15 Hz, 12-H), 8.95 (d, J = 10 Hz, NH).

IR (KBr): 1748, 1710, 1374, 1244, 1044, 934, 816 cm ^-1 .

[α] _D ²⁴ -173.3 ° (c = 0.505, CHCl ₃ )

Example 28

Preparation of 3- (2-oxo-1-thioxo) propylamino-lancon 14-acetate-8- (2, 2, 2-trichloroethyl) carbonate:

270.7 mg of the title compound were obtained by carrying out the reaction similar to Example 24 using 1.354 g of lancassidin A 8- (2, 2, 2-trichloroethyl) carbonate.

Melting Point: 237 ~ 238 ℃ (Decomposition)

NMR (90 MHz, CDCl ₃ ) δ: 1.33 (d, J = 7 Hz, 17-Me), 1.40 (s, 2-Me), 1.57 (s, 11-Me), 1.96 (s, 5-Me), 2.02 (s, OAc), 2.2 to 2.7 (m, 9-H ₂ , 15-H ₂ , 17-H), 2.64 (s, CSCOCH ₃ ), 4.44 (m, 16-H), ˜4.7 (m, 4 -H), 4.73 (s, CCl ₃ CH ₂ × 2), -5.0 (m, 8-H), 5.2-6.2 (m, 3-H, 6-H, 7-H, 10-H, 13- H, 14-H), 6.28 (d, J = 15 Hz, 12-H), 9.98 (d, J = 9 Hz, NH).

IR (KBr): 1742, 1706, 1494, 1378, 1244, 1208, 954 cm ^-1 .

[α] _D ²⁴ -305.0 ° (c = 0.48, CHCl ₃ )

Example 29

3- (2- (L) -hydroxy-thioxo) propylamino-lancon 14-acetate-8- (2, 2, 2-trichloroethyl) carbonate and 3- (2- (D) -hydrate Preparation of Roxy-Tioxo) propylamino-Rancon 14-Acetate-8- (2, 2, 2-Trichloroethyl) carbonate:

The reaction was carried out similarly to Example 16 using 3.511 g of 3- (2-oxo-1-thioxo) propylamino-lancon 14-acetate-8- (2, 2, 2-trichloroethyl) carbonate. This gave 1.0942 g of the title compound [2 '-(L) isomer], 1.0811 g of the title compound [2'-(D) isomer] and 725.7 mg of a mixture thereof.

2 '-(L) isomer, melting point 206-208 ° C (decomposition)

NMR (90 MHz, CDCl ₃ ) δ: 1.32 (d, J = 7 Hz, 17-Me), 1.41 (s, 2-Me), 1.53 (d, J = 7 Hz, 2′-Me), 1.57 (s, 11 -Me), 1.97 (s, 5-Me), 2.02 (s, OAc), 2.2-2.7 (m, 9-H ₂ , 15-H ₂ , 17-H), 3.05 (d, J = 5 Hz, OH ), 4.3 to 5.2 (m, 16-H, 4-H, 8-H, 2'-H), 4.74 (s, CCl ₃ CH ₂ ), 5.2 to 6.35 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.28 (d, J = 15 Hz, 12-H), 9.35 (d, J = 9 Hz, NH).

IR (KBr): 1748, 1706, 1500, 1372, 1244, 958 (sh.), 940 cm ^-1 .

[α] _D ²⁴ -251.8 ° (c = 0.51, CHCl ₃ )

2'-isomer, melting point 214-216 ° C (decomposition)

NMR (90 MHz, CDCl ₃ ) δ: 1.31 (d, J = 7 Hz, 17-Me), 1.41 (s, 2-Me), 1.50 (d, J = 7 Hz, 2′-Me), 1.56 (s, 11 -Me), 1.97 (s, 5-Me), 2.02 (s, OAc), 2.2-2.7 (m, 9-H ₂ , 15-H ₂ , 17-H), 3.16 (d, J = 5 Hz, OH ), 4.3 to 5.2 (m, 16-H, 4-H, 8-H, 2'-H), 4.73 (s, CCl ₃ CH ₂ ), 5.2 to 6.35 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.29 (d, J = 14 Hz, 12-H), 9.33 (d, J = 9 Hz, NH).

IR (KBr): 1754, 1728, 1706, 1498, 1374, 1240, 960 (sh.), 944 cm ^-1 .

[α] _D ²³ -259.7 ° (c = 0.595, CHCl ₃ )

Example 30

Preparation of 3- (2- (L) -acetoxy-1-thioxo) propylamino-lancon 14-acetate-8- (2, 2, 2-trichloroethyl) carbonate

Example 17, using 972.6 mg of 3- (2- (L) -hydroxy-thioxo) propylamino-lancon 14-acetate-8- (2, 2, 2-trichloroethyl) carbonate The reaction was carried out in a similar manner to give 839.9 mg of the title compound.

Melting Point: 188 ~ 190 ℃ (Decomposition)

NMR (90 MHz, CDCl ₃ ) δ: 1.33 (d, J = 7 Hz, 17-Me), 1.45 (s, 2-Me), 1.58 (s, 11-Me), 1.62 (d, J = 7 Hz, 2 ' -Me), 1.98 (s, 5-Me), 2.03 (s, 14-OAc), 2.2-2.7 (m, 9-H ₂ , 15-H ₂ , 17-H), 2.23 (s, 2'- OAc), 4.3 to 5.2 (m, 16-H, 4-H, 8-H, 2'-H), 4.76 (s, CCl ₃ CH ₂ ), 5.2 to 6.3 (m, 3-H, 6-H , 7-H, 10-H, 13-H, 14-H), 6.24 (d, J = 15 Hz, 12-H), 9.25 (d, J = 9 Hz, NH).

IR (KBr): 1752, 1730 (sh.), 1704, 1380, 1366, 1270 (sh.), 1240, 1218 (sh.) Cm ^-1 .

[α] _D ²⁵ -252.0 ° (c = 0.49, CHCl ₃ )

Example 31

Preparation of 3- (2- (D) -acetoxy-1-thioxo) propylamino-lancon 14-acetate-8- (2, 2, 2-trichloroethyl) carbonate

Example 17 using 973.6 mg of 3- (2- (D) -hydroxy-1-thioxo) propylamino-lancon 14-acetate-8- (2, 2, 2-trichloroethyl) carbonate 915.2 mg of the title compound were obtained by the similar procedure.

Melting Point: 222 ~ 224 ℃ (Decomposition)

NMR (90 MHz, CDCl ₃ ) δ: 1.32 (d, J = 7 Hz, 17-Me), 1.35 (s, 2-Me), 1.54 (d, J = 7 Hz, 2′-Me), 1.58 (s, 11 -Me), 1.97 (s, 5-Me), 2.02 (s, 14-OAc), 2.2-2.7 (m, 9-H ₂ , 15-H ₂ , 17-H), 2.27 (s, 2'- OAc), 4.3 to 5.2 (m, 16-H, 4-H, 8-H, 2'-H), 4.74 (s, CCl3CH2), 5.2 to 6.3 (m, 3-H, 6-H, 7- H, 10-H, 13-H, 14-H), 6.28 (d, J = 15 Hz, 12-H), 8.98 (d, J = 10 Hz, NH).

IR (KBr): 1746, 1706, 1508, 1368, 1278, 1242, 1044, 940 cm ^-1 .

[α] D ²⁵ -217.1 ° (c = 0.515, CHCl3)

Example 32

Preparation of 3-phenoxyacetamido-rancon 8, 14-diacetate

60.3 mg of 3- (2- (DL) -acetoxy-1-thioxo) propylamino-lancon 8, 14-diacetate was dissolved in 1 ml of dichloromethane. To the solution was added 19.0 mg of triethyloxonium tetrafluoroborate. The mixture was stirred at rt for 70 min and 15.4 μl of phenoxyacetyl chloride and 0.1 ml of water were added. The product was stirred vigorously at room temperature, extracted with dichloromethane, the extract was washed with brine and dried over MgSO 4. The solvent was distilled off and the residue was purified by permanent TLC [plate: Merck, Art. No. 5715, 20 × 20 cm, 2 plates, developing solvent: ethyl acetate-chloroform (1: 4)] afforded 15.5 mg of the title compound.

Melting Point: 217 ~ 218 ℃ (Decomposition)

NMR (90 MHz, CDCl 3) δ: 1.29 (d, J = 7 Hz, 17-Me), 1.30 (s, 2-Me), 1.53 (s, 11-Me), 1.90 (s, 5-Me), 2.00 & 2.03 (s, 8-OAc, 14-OAc), 2.2-2.7 (m, 9-H2, 15-H2, 17-H), 4.37 (m, 16-H), 4.49 (s, OCH2CO), 4.68 (d, J = 11 Hz, 4-H), 5.06 (m, 8-H), 5.2-6.2 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H ), 6.27 (d, J = 15 Hz, 12-H), ˜7.0 & ˜7.35 (m, C6H5, respectively), 7.82 (d, J = 10 Hz, NH).

IR (KBr): 1732, 1708, 1368, 1240 cm ^-1 .

Mass m / e: 607 (M ⁺ ), 563 (M ⁺ -44 (CO2)), 447 (M ⁺ -60 (AcOH)), 503 (M ⁺ -60-44), 487 (M ⁺ -60- 60), 443 (M ⁺ -60-60-44)

Example 33

Preparation of 3- (2- (DL) -acetoxy-1-ethylthiopropylidene) amino-lancon 8, 14-diacetate

180.9 mg of 3- (2- (DL) -acetoxy-1-thioxo) propylamino-lancon 8, 14-diacetate was dissolved in 3 ml of dichloromethane. 68.4 mg of triethyloxonium tetrafluoroborate was added to the solution, and the mixture was stirred for 130 minutes. To the product was added 1.8 ml of an aqueous solution of 93.6 mg NaH 2 PO 4 .2H 2 O and 117.6 mg Na 2 HPO 4.

The mixture was shaken and extracted with dichloromethane.

The dichloromethane layer was washed with brine, dried over MgSO 4 and concentrated to give 158.7 mg of the title compound as a solid foam.

IR (KBr): 1740, 1712, 1370, 1240, 1020, 962 cm ^-1 .

Example 34

Preparation of 3-phenoxyacetamido-rancon 8, 14-bis (2, 2, 2-trichloroethyl) carbonate

Example 32, using 87.0 mg of 3- (2- (D) -acetoxy-1-thioxo) propylamino-lancon 8, 14-bis (2, 2, 2-trichloroethyl) carbonate The reaction was carried out similarly to give 13.2 mg of the title compound as an oil.

NMR (90MHz, CDCl3) δ: 1.23 (d, J = 7Hz, 17-Me), 1.32 (s, 2-Me), 1.59 (H, 11-Me), 1.92 (s, 5-Me), 2.2 ~ 2.8 (m, 9-H2, 15-H2, 17-H), 4.42 (m, 16-H), 4.50 (s, OCH2CO), 4.6-5.2 (m, 4-H, 8-H), 4.74 ( s, CCl3CH2 × 2), 5.2 to 5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.15 (d, J = 15 Hz, 12-H) , ˜7.0 & 7.3 (m, C 6 H 5), 7.84 (d, J = 10 Hz, NH).

IR (KBr): 1748, 1706, 1676, 1504, 1486, 1374, 1242, 1200, 958, 940 cm ^-1 .

Example 35

Preparation of 3-phenoxyacetamido-rancon 8, 14-bis (2, 2, 2-trichloroethyl) carbonate

Example 32 using 87.0 mg of 3- (2- (L) -acetoxy-1-thioxo) propylamino-lancon 8, 14-bis (2, 2, 2-trichloroethyl) carbonate Similarly, 14.9 mg of the title compound as an oil was obtained by carrying out the reaction.

This product is identical in TLC, IR and NMR data with the compound obtained in Example 34.

Example 36

Preparation of 3-phenoxyacetamido-rancon 8, 14-bis (2, 2, 2-trichloroethyl) carbonate

Example 32, using 584.8 mg of 3- (2- (DL) -acetoxy-1-thioxo) propylamino-lancon 8, 14-bis (2, 2, 2-trichloroethyl) carbonate Similar reactions yielded 131.4 mg of the title compound (instead of TLC separation, silica gel chromatography was performed).

This product is consistent with the product obtained in Example 34 in TLC, IR and NMR data.

Example 37

Preparation of 3- [2- (2, 2, 2-trichloroethoxycarbonyl) phenylacetamido] rancon 8, 14-bis (2, 2, 2-trichloroethyl) carbonate

163 mg of 3- (2- (DL) -acetoxy by reaction similar to Example 36 using 2- (2, 2, 2-trichloroethoxycarbonyl) phenylacetyl chloride instead of phenoxyacetyl chloride 26.0 mg of the title compound were obtained from -1-thioxo) propylamino-rancon 8, 14-bis (2, 2, 2-trichloroethyl) carbonate.

NMR (90 MHz, CDCl 3) δ: 1.18 & 1.21 (3H, d, J = 6.5 Hz, 17-Me respectively), 1.27 & 1.34 (3H, s, 2-Me each), 1.56 (3H, s, 11-Me ), 1.85 & 1.86 (3H, s, 5-Me respectively), 2.25-2.7 (5H, m, 9-H2, 15-H2, 17-H), 4.2-4.8 (2H, m, 4-H, 16 -H), 4.66 (1H, s, C6H5CH), 4.74 & 4.79 (6H, s, CCl3CH2 x 3), 4.98 (1H, m, 8-H), 5.25-5.7 (6H, m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.12 & 6.13 (1H, d, J = 15 Hz, 12-H), 7.40 (5H, br.s, C6H5), 7.4 & 7.73 (1H, respectively d, J = 10 Hz, NH).

IR (KBr): 1755, 1710, 1680, 1500, 1450, 1380, 1250, 1140, 1070, 965, 945, 815, 720 cm ^-1 .

Example 38

Preparation of 3- (2- (DL) -acetoxy-1-methylthio propylidene) amino-lancon 14-diacetate

6.03 g of 3- (2- (DL) -acetoxy-1-thioxo) propylamino-lancon 8, 14-diacetate was dissolved in 200 ml of tetrahydrofuran. To the solution was added 100 ml of an aqueous solution of 6.23 ml of methyl iodide, 2.12 g of Na 2 CO 3 and 2.77 g of benzyltrimethylammonium iodide and the mixture was stirred at room temperature. After 67 hours, 6.23 ml of methyl iodide was added to the mixture. After 91 hours the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO 4, the solvent was distilled off to obtain crystals, and a small amount of ether was added thereto to complete the crystallization, ether-petroleum ether (1: 2) was added followed by filtration to collect the crystals. It was. The crystals were washed with the same solvent to afford 2.2588 g of the title compound. The filtrate was concentrated to give 3.6589 g of the title compound as a solid.

Crystalline substance, melting point 190 ~ 192 ℃ (decomposition)

IR (KBr): 1724, 1620, 1362, 1232, 1010, 958 cm ^-1 .

Example 39

Preparation of 3- (2- (L) -acetoxy-1-methylthiopropylidene) amino-lancon 14-acetate-8- (2, 2, 2-trichloroethyl) carbonate

Example 38 using 73.7 mg of 3- (2- (L) -acetoxy-1-thioxo) propylamino-lancon 14-acetate-8- (2, 2, 2-trichloroethyl) carbonate The reaction was carried out in a similar manner to give 31.3 mg of the title compound as an oil.

IR (KBr): 1740, 1618, 1366, 1238, 1010, 956, 940 cm ^-1 .

Example 40

Preparation of 3-phenoxyacetamido-rancon 14-acetate-8- (2, 2, 2-trichloroethyl) carbonate

Example 32 using 73.7 mg of 3- (2- (D) -acetoxy-1-thioxo) propylamino-lancon 14-acetate-8- (2, 2, 2-trichloroethyl) carbonate The reaction was carried out in a similar manner to give 11.5 mg of the title compound.

NMR (90 MHz, CDCl 3) δ: 1.30 (d, J = 7 Hz, 17-Me), 1.32 (s, 2-Me), 1.57 (s, 11-Me), 1.93 (s, 5-Me), 2.01 ( s, OAc), 2.1 to 2.7 (m, 9-H2, 15-H2, 17-H), 4.50 (s, C6H5OCH2), 4.2 to 5.15 (m, 16-H, 4-H, 8-H) , 4.74 (s, CCl3CH2), 5.15 ~ 6.0 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.28 (d, J = 15Hz, 12-H ), ˜7.0 & 7.3 (m, C 6 H 5), 7.85 (d, J = 9 Hz, NH).

IR (KBr): 1750, 1708, 1678, 1488, 1376, 1244, 960, 944 cm ^-1 .

Example 41

Preparation of 3- [D-(-)-2- (4-ethyl-2, 3-dioxo-1-piperazinecarboxamide) phenylacetamido] rancon 8, 14-diacetate

The reaction was carried out in the same manner as in Example 32 using D-(-)-2- (4-ethyl-2, 3-dioxo-1-piperazinecarboxamide) phenylacetyl chloride to give 60.3 mg of 3- (2 2.9 mg of the title compound were obtained from-(DL) -acetoxy-1-thioxo) propylamino-lancon 8, 14-diacetate.

NMR (90MHz, CDCl3) δ: 1.01 (s, 2-Me), 1.20 (t, J = 7.5Hz, NCH2CH3), 1.21 (d, J = 7Hz, 17-Me), 1.52 (s, 11-Me) , 1.84 (s, 5-Me), 2.00 & 2.04 (s, 8-OAc, 14-OAc), 2.15-2.6 (9-H2, 15-H2, 17-H), 3.51 (q, J = 7.5 Hz, NCH2CH3), 3.4 ~ 3.7 & 3.95 ~ 4.15 (m, NCH2CH2N), 4.29 (m, 16-H), 4.66 (d, J = 11Hz, 4-H), 5.07 (m, 8-H), 5.1 ~ 5.85 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H, C6H5CH), 6.26 (d, J = 15 Hz, 12-H), 6.93 (d, J = 10 Hz, 3-NH), 7.39 (br. S. C6H5), 9.95 (d, J = 6 Hz, C6H5CHNHCO).

IR (KBr): 1725 (sh.), 1712, 1680 (sh.), 150 0, 1370, 1240, 1175, 1015, 960 cm ^-1 .

Example 42

Preparation of 3- (2-oxo-1-thioxo) propylamino-lancon 14-acetate-8-benzoate:

The reaction was carried out in the same manner as in Example 24 using 5.369 g of lancassidine C-14-acetate-8-benzoate to yield 1.0653 g of the title compound.

Melting Point: 247 ~ 249 ℃ (Decomposition)

NMR (90 MHz, CDCl 3) δ: 1.35 (d, J = 7 Hz, 17-Me), 1.40 (s, 2-Me), 1.60 (s, 11-Me), 1.98 (s, 5-Me), 2.02 ( s, OAc), 2.2 to 2.7 (m, 9-H2, 15-H2, 17-H), 2.64 (s, CSCOCH3), 4.45 (m, 16-H), 4.73 (d, J = 11 Hz, 4- H), 5.2 to 6.2 (m, 8-H, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.33 (d, J = 15 Hz, 12-H) , ~ 7.5 & 8.05 (m, C6H5, respectively), 9.98 (d, J = 9 Hz, NH).

IR (KBr): 1730 (sh.), 1712, 1495, 1355, 1274, 1244, 1212, 1112, 960 cm ^-1 .

[α] D ²⁶ -261.7 ° (c = 0.525, CHCl3)

Example 43

Preparation of 3-phenoxyacetamido-rancon 8, 14-diacetate

31.6 mg of 3- (2- (DL) -acetoxy-1-ethylthiopropylidene) amino-lancon 8, 14-acetate was dissolved in 1 ml of ethyl acetate. 7.7 μl of phenoxyacetyl chloride was added to the solution, and the mixture was stirred at room temperature for 250 minutes. Ethyl acetate was added to the product, washed with brine and concentrated with MgSO 4.

Ethyl acetate was distilled off and the residue was purified by permanent TLC [plates: Merck, Art. No 5715, 20 × 20 cm, 2 plates, developing solvent: ethyl acetate-chloroform (1: 4)] to give 5.4 mg of the title compound. This product is consistent with the compound obtained in Example 32 in TLC, IR and NMR data.

Example 44

Preparation of 3-phenylacetamido-Rancon 8, 14-diacetate:

The title compound was obtained by carrying out the reaction similarly to Example 43 using phenylacetyl chloride. (Yield: 10%).

NMR (90 MHz, CDCl 3) δ: 1.22 (d, J = 7 Hz, 17-Me), 1.25 (s, 2-Me), 1.52 (s, 11-Me), 1.86 (s, 5-Me), 2.00 & 2.04 (s, 8-OAc, 14-OAc), 2.15-2.6 (m, 9-H2, 15-H2, 17-H), 3.57 (s, C6H5CH2), 4.32 (m, 16-H), 4.57 (d, J = 12 Hz, 4-H), 5.05 (m, 8-H), 5.2-5.85 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H ), 6.23 (d, J = 15 Hz, 12-H), 6.63 (d, J = 10 Hz, NH), 7.30 (s, C6H5).

IR (KBr): 1726, 1705, 1488, 1365, 1236, 1015, 956 cm ^-1 .

Example 45

Preparation of 3-phenylthioacetamido-rancon 8, 14-diacetate:

The title compound was obtained by yielding the reaction similar to Example 43 using phenylthioacetyl chloride (yield: 21%).

Melting Point: 125 ~ 128 ℃

NMR (90 MHz, CDCl 3) δ: 1.09 (s, 2-Me), 1.28 (d, J = 7 Hz, 17-Me), 1.53 (s, 11-Me), 1.85 (s, 5-Me), 2.01 & 2.05 (s, 8-OAc, 14-OAc), 2.2-2.7 (m, 9-H2, 15-H2, 17-H), 3.53 & 3.75 (ABq, J = 17 Hz, SCH), 4.33 (m, 16-H), 4.56 (d, J = 11 Hz, 4-H), 5.07 (m, 8-H), 5.2-5.85 (m, 3-H, 6-H, 7-H, 10-H, 13 -H, 14-H), 6.26 (d, J = 15 Hz, 12-H), 7.25 (m, C6H5), 7.95 (d, J = 10 Hz, NH).

IR (KBr): 1732, 1708, 1365, 1238, 1016 cm ^-1 .

Example 46

Preparation of 3- (3-ethoxycarbonylacrylamido) -rancon 8, 14-diacetate:

The title compound was obtained (yield: 20%) by reaction similar to Example 43 using 3-ethoxycarbonylacryl chloride.

NMR (90 MHz, CDCl 3) δ: 1.30 & 1.32 (t, J = 7 Hz, CH 3 CH 2), 1.31 (d, J = 7 Hz, 17-Me), 1.41 (s, 2-Me), 1.54 (s, 11- Me), 1.90 (s, 5-Me), 2.03 & 2.04 (s, 8-OAc, 14-OAc), 2.2-2.7 (m, 9-H2, 15-H2, 17-H), 4.23 & 4.26 (Q, J = 7Hz, CH3CH2), ~ 4.4 (m, 16-H), 4.67 (d, J = 11Hz, 4-H), 5.07 (m, 8-H), 5.2 ~ 6.0 (m, 3 -H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.28 (d, J = 15 Hz, 12-H), 6.74 & 6.93 (ABq, J = 15 Hz, CO COO) , 6.99 (d, J = 10 Hz, NH).

IR (KBr): 1724, 1710 (sh.), 1672, 1362, 1296, 1238, 1020 cm ^-1 .

Example 47

Preparation of 3-benzamido-rancon 8, 14-diacetate:

The title compound was obtained by the reaction similar to Example 43 using benzoyl chloride (yield: 9%).

NMR (90 MHz, CDCl 3) δ: 1.27 (d, J = 7 Hz, 17-Me), 1.36 (s, 2-Me), 1.57 (s, 11-Me), 1.97 (s, 5-Me), 2.02 & 2.03 (s, 8-OAc, 14-OAc), 2.2 ~ 2.6 (m, 9-H2, 15-H2, 17-H), 4.43 (m, 16-H), 4.76 (d, J = 11Hz, 4 -H), 5.07 (m, 8-H), 5.2-6.1 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.28 (d, J = 15 Hz, 12-H), ˜7.5 & ˜8.1 (m, C6H5, respectively), 7.82 (d, J = 9 Hz, NH).

IR (KBr): 1728, 1708, 1368, 1240, 1020 cm ^-1 .

Example 48

Preparation of 3-chloroacetamido-rancon 8, 14-diacetate:

The title compound was obtained by the reaction similar to Example 43 using chloroacetyl chloride (yield: 35%).

NMR (90 MHz, CDCl 3) δ: 1.31 (d, J = 7 Hz, 17-Me), 1.41 (s, 2-Me), 1.54 (s, 11-Me), 1.88 (s, 5-Me), 2.01 & 2.03 (s, 8-OAc, 14-OAc), 2.15-2.6 (m, 9-H2, 15-H2, 17-H), 4.01 (s, ClCH2), 4.40 (m, 16-H), 4.70 (d, J = 11 Hz, 4-H), 5.05 (m, 8-H), 5.2-6.1 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H ), 6.28 (d, J = 15 Hz, 12-H), 7.81 (d, J = 10 Hz, NH).

IR (KBr): 1728, 1704, 1668, 1504, 1368, 1238, 1012, 958 cm ^-1 .

Example 49

Preparation of 3- (difluoromethylthio acetamido) -lancon 8, 14-diacetate

The title compound was obtained (yield: 15%) by reaction similar to Example 43 using difluoromethylthioacetyl chloride.

NMR (90 MHz, CDCl 3) δ: 1.31 (d, J = 7 Hz, 17-Me), 1.37 (s, 2-Me), 1.55 (s, 11-Me), 1.88 (s, 5-Me), 2.02 & 2.04 (s, 8-OAc, 14-OAc), 2.1-2.6 (m, 9-H2, 15-H2, 17-H), 3.46 (s, COCH2S), 4.43 (m, 16-H), 4.70 (d, J = 11 Hz, 4-H), 5.08 (m, 8-H), 5.2-5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H ), 6.28 (d, J = 15 Hz, 12-H), 6.90 (t, J = 54 Hz, CHF2), 7.61 (d, J = 9 Hz, NH).

IR (KBr): 1730, 1712, 1670, 1368, 1240, 1060, 1020 cm ^-1 .

Example 50

Preparation of 3- (2-chloroacetylaminothiazol-4-yl) acetamido-rancon 8, 14-diacetate:

The reaction was carried out similarly to Example 43 using (2-chloroacetylaminothiazol-4-yl) acetylchloride hydrochloride and using a mixture of tetrahydrofuran and ethyl acetate (1: 2) as the reaction solvent. The compound was obtained (yield 17%).

NMR (90 MHz, CDCl 3) δ: 1.27 (d, J = 7 Hz, 17-Me), 1.28 (s, 2-Me), 1.53 (s, 11-Me), 1.85 (s, 5-Me), 2.01 & 2.03 (s, 8-OAc, 14-OAc), 2.1-2.7 (m, 9-H2, 15-H2, 17-H), 3.53 & 3.80 (ABq, thiazole-CH2), 4.30 (s, ClCH2 ), 4.35 (m, 16-H), 4.67 (d, J = 11 Hz, 4-H), 5.05 (m, 8-H), 5.2-5.9 (m, 3-H, 6-H, 7-H , 10-H, 13-H, 14-H), 6.27 (d, J = 15 Hz, 12-H), 6.97 (s, thiazole-5-H), 8.00 (d, J = 9 Hz, NH).

IR (KBr): 1728, 1706, 1542, 1368, 1236 cm ^-1 .

Example 51

Preparation of 3-n-hexanoylamino-lancon 8, 14-diacetate:

The title compound was obtained by the reaction similar to Example 43 using n-hexanoyl chloride (yield: 4%).

NMR (90MHz, CDCl3) δ: 0.87 (t, J = 6Hz, CH3 (CH2) 4CO), 1.1 ~ 1.8 (m, CH3 (CH2) 3CH2CO), 1.30 (d, J = 7Hz, 17-Me), 1.40 (s, 2-Me), 1.54 (s, 11-Me), 1.88 (s, 5-Me), 2.03 & 2.05 (s, 8-OAc, 14-OAc), 2.05 to 2.55 (m, 9- H2, 15-H2, 17-H, CH2CONH), 4.40 (m, 16-H), 4.65 (d, J = 11 Hz, 4-H), 5.07 (m, 8-H), 5.2-5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.25 (d, J = 14 Hz, 12-H), 6.55 (d, J = 10 Hz, NH).

IR (KBr): 3430, 2920, 1730, 1710 (sh.), 1660, 1365, 1230, 1100, 1010, 955 cm ^-1 .

Example 52

Preparation of 3-cyclohexylcarboxamido-rancon 8, 14-diacetate:

The reaction was carried out in the same manner as in Example 43 using cyclohexanecarboxylic acid chloride to give the title compound (yield: 9%).

NMR (90MHz, CDCl3) δ: 1.28 (d, J = 7Hz, 17-Me), 1.37 (s, 2-Me), 1.54 (s, 11-Me), 1.86 (s, 5-Me), 1.1 ~ 2.0 (m, cyclohexyl-CH2 × 5), 2.01 & 2.03 (s, 8-OAc, 14-OAc, respectively), 2.2-2.6 (m, 9-H2, 15-H2, 17-H, cyclohexyl-CH2 ), 4.39 (m, 16-H), 4.63 (d, J = 11 Hz, 4-H), 5.06 (m, 8-H), 5.25-6.10 (m, 3-H, 6-H, 7-H) , 10-H, 13-H, 14-H), 6.28 (d, J = 15 Hz, 12-H), 6.62 (d, J = 10 Hz, NH).

IR (KBr): 3440, 2940, 1740, 1710 (sh.), 1640, 1370, 1240, 1020, 965 cm ^-1 .

Example 53

Preparation of 3- (2- (thienyl) acetamido-rancon 8, 14-diacetate:

The title compound was obtained (yield: 19%) by carrying out a reaction similar to Example 43 using (2-thienyl) acetyl chloride.

NMR (90 MHz, CDCl 3) δ: 1.23 (d, J = 7 Hz, 17-Me), 1.29 (s, 2-Me), 1.52 (s, 11-Me), 1.86 (s, 5-Me), 1.99 & 20.03 (s, 8-OAc, 14-OAc), 2.15-2.6 (m, 9-H2, 15-H2, 17-H), 3.75 (s, CH2CON), 4.33 (m, 16-H), 4.58 (d, J = 11 Hz, 4-H), 5.05 (m, 8-H), 5.2-5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H ), 6.24 (d, J = 15 Hz, 12-H), 6.79 (d, J = 10 Hz, NH), 6.9-7.1 & 7.2-7.3 (m, thienyl-H3, respectively).

IR (KBr): 3440, 1730, 1710, 1670, 1500, 1370, 1240, 1020, 965 cm ^-1 .

Example 54

Preparation of 3- [D-(-)-2- (4-ethyl-2, 3-dioxo-1-piperazinecarboxamido) phenylacetamido] -rancon 8, 14-diacetate:

The title compound was obtained by carrying out the reaction similar to Example 43 using D (-)-2- (4-ethyl-2, 3-dioxo-1-piperazinecarboxamido) phenylacetyl chloride (yield: 8%). The product is consistent in the TLC, IR and NMR data with the compound obtained in Example 41.

Example 55

Preparation of 3- [D-(-)-2- (2, 2, 2-trichloroethoxycarbonylamino) phenylacetamido] -rancon 8, 14-diacetate:

The title compound was obtained (yield: 10%) by carrying out a reaction similar to Example 43 using D (-)-2- (2, 2, 2-trichloroethoxycarbonylamino) phenylacetyl chloride.

NMR (90 MHz, CDCl 3) δ: 0.90 (s, 2-Me), 1.23 (d, J = 6.5 Hz, 17-Me), 1.53 (s, 11-Me), 1.88 (s, 5-Me), 2.00 & 2.05 (s, 8-OAc, 14-OAc), 2.15-2.55 (m, 9-H2, 15-H2, 17-H), 4.27 (m, 16-H), 4.65 (d, J = 11 Hz , 4-H), 4.62 & 4.74 (d, J = 15 Hz, CCl3CH2), 4.95-5.2 (m, 8-H, C6H5CH), 5.25-5.85 (m, 3-H, 6-H, 7-H , 10-H, 13-H, 14-H), 6.26 (d, J = 15 Hz, 12-H), 6.49 (br. D, J = 7 Hz, NHCOOCH2), 6.95 (br. D, J = 10 Hz, C6H5CHCONH), 7.39 (br. S, C6H5).

IR (KBr): 3415, 1735, 1710, 1680, 1490, 1370, 1240, 1020, 960 cm ^-1 .

Example 56

Preparation of 3- [2- (2, 2, 2-trichloroethoxycarbonyl) phenylacetamido] -rancon 8, 14-diacetate:

The title compound was obtained (yield: 21%) by carrying out a reaction similar to Example 32 using 2- (2, 2, 2-trichloroethoxycarbonyl) phenylacetylchloride.

NMR (90 MHz, CDCl 3) δ: 1.28 (s, 2-Me), 1.28 (d, J = 7.5 Hz, 17-Me), 1.52 (s, 11-Me), 1.84 (s, 5-Me), 2.00 & 2.03 (s, 8-OAc, 14-OAc), 2.2-2.6 (m, 9-H2, 15-H2, 17-H), 4.38 (m, 16-H), 4.39 (s, C6H5CH) ~ 4.7 (m, 4-H), 4.81 (s, CCl3CH2), 5.05 (m, 8-H), 5.25 ~ 5.95 (m, 3-H, 6-H, 7-H, 10-H, 13-H , 14-H), 6.27 (d, J = 15 Hz, 12-H), 7.43 (br. S, C6H5), 7.69 (d, J = 10 Hz, NH).

IR (KBr): 3420, 2940, 1740, 1710, 1680, 1500, 1370, 1245, 1140, 1020, 965, 720 cm ^-1 .

Example 57

Preparation of 3-chloroacetamido-rancon 8, 14-diacetate.

2.144 g of 3- (2- (DL) -acetoxy-1-methylthiopropylidene) amino-lancon 8, 14-diacetate in 34.7 ml of ethyl acetate, 17.4 ml of tetrahydrofuran and 0.277 ml of chloroacetyl Chloride was added. The mixture was stirred at rt for 6.5 h, ethyl acetate was added, washed with brine and dried over MgSO 4. The solvent was distilled off and the residue was subjected to silica gel (120 g) column chromatography [eluent: ethyl acetate-chloroform (1: 4)]. The desired fractions were combined and concentrated to give 523 mg of the title compound. This product was obtained from Example 48 and TLC. Matches in IR and NMR data.

Example 58

Preparation of 3-phenoxyacetamido-rancon 8, 14-diacetate:

60.3 mg of 3- (2- (DL) -acetoxy-1-thioxy) propylamino-lancon 8, 14-diacetate was dissolved in 1 ml of dichloromethane. 17.8 mg trimethyloxonium tetrafluoroborate was added to the solution, and the mixture was stirred at room temperature for 30 minutes. To the product was added 15.4 μl of phenoxyacetyl chloride and 0.1 ml of water and 1.4 mg of the title compound was obtained by vigorously stirring the mixture at room temperature for 200 min and running similar to Example 32. This product is consistent with the product obtained in Example 32 in TLC, IR and NMR data.

Example 59

Preparation of 3- [2- [1- (2-dimethylaminoethyl) -1 H-tetrazol-5-yl] thio] acetamido-rancon 8, 14-diacetate:

55.0 mg of 3-chloroacetamido-rancon 8, 14-diacetate was dissolved in 1 ml of N, N-dimethylformamide. To the solution was added 17.3 mg of [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thiol, 8.09 μl of pyridine and 16.6 mg of potassium iodide, and the mixture was stirred at 50 ° C. for 3 hours. After cooling, water was added, extracted with ethyl acetate and dried over MgSO 4. The solvent was distilled off and the residue was subjected to silica gel column chromatography [eluent: ethyl acetate-methanol (5: 1)]. The desired fractions were combined and concentrated to give 59.6 mg of the title compound.

NMR (90 MHz, CDCl 3) δ: 1.27 (d, J = 7 Hz, 17-Me), 1.30 (s, 2-Me), 1.53 (s, 11-Me), 1.84 (s, 5-Me), 2.01 & 2.03 (s, 8-OAc, 14-OAc), 2.1 to 2.6 (m, 9-H2, 15-H2, 17-H), 2.25 (s, NMe2), 2.75 (t, J = 6 Hz, CH2NMe2) , 3.88 & 4.08 (ABq, J = 15 Hz, SCH2CO), 4.35 (t, J = 6 Hz, tetrazole-CH2)-4.4 (m, 16-H), 4.63 (d, J = 11 Hz, 4-H), 5.05 (m, 8-H), 5.2 ~ 6.1 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.25 (d, J = 15Hz, 12- H), 7.58 (d, J = 10 Hz, NH),

IR (KBr): 3440, 1724, 1704, 1618, 1366, 1236, 1014 cm ^-1 .

Example 60

Preparation of 3- [2- (4-methyl-4H-1, 2, 4-triazol-3-yl) thio] acetamido-rancon 8, 14-diacetate:

The title compound was obtained (yield: 48%) by carrying out a reaction similar to Example 59 using (4-methyl-4H-1, 2, 4-triazol-3-yl) thiol.

NMR (90 MHz, CDCl 3) δ: 1.26 (d, J = 7 Hz, 17-Me), 1.35 (s, 2-Me), 1.51 (s, 11-Me), 1.82 (s, 5-Me), 2.00 & 2.04 (s, 8-OAc, 14-OAc), 2.1-2.6 (m, 9-H2, 15-H2, 17-H), 3.58 (s, triazole-Me), 3.76 & 4.05 (ABq, J = 15 Hz, SCH2CO), 4.35 (m, 16-H), 4.61 (d, J = 11 Hz, 4-H), 5.05 (m, 8-H), 5.2-5.9 (m, 3-H, 6-H , 7-H, 10-H, 13-H, 14-H), 6.25 (d, J = 15 Hz, 12-H), 7.76 (d, J = 9 Hz, NH), 8.13 (s, triazole-H ).

IR (KBr): 1732, 1712 (sh.), 1666, 1508, 1370, 1244, 1020, 960 cm ^-1 .

Example 61

Preparation of 3- [2- (4-pyridyl) thio] acetamido-rancon 8, 14-diacetate:

The reaction was carried out in the same manner as in Example 59 using 4-pyridyl thiol to give the title compound (Yield: 57%).

NMR (90 MHz, CDCl 3) δ: 1.09 (s, 2-Me), 1.26 (s, J = 7 Hz, 17-Me), 1.53 (s, 11-Me), 1.87 (s, 5-Me), 2.00 & 2.04 (s, 8-OAc, 14-OAc), 2.1-2.7 (m, 9-H2, 15-H2, 17-H), 3.57 & 3.80 (ABq, J = 17 Hz, SCH2CO), 4.33 (m, 16-H), 4.54 (d, J = 11 Hz, 4-H), 5.05 (m, 8-H), 5.2-5.9 (m, 3-H, 6-H, 7-H, 10-H, 13 -H, 14-H), 6.24 (d, J = 15 Hz, 12-H), 7.14 & 8.39 (ABq, J = 6 Hz, pyridine-H4), 7.80 (d, J = 9 Hz, NH).

IR (KBr): 1730, 1710, 1670, 1574, 1498, 1370, 1240, 1028, 960 cm ^-1 .

Example 62

Preparation of 3-([(4-carboxy-3-hydroxy-1, 2-thiazol-5-yl) thio] acetamido-rancon 8, 14-diacetate:

55.0 mg of 3-chloroacetamido-lantone 8, 14-diacetate was dissolved in 1 ml of N, N-dimethylformamide. To the solution was added 24.3 mg of (4-carboxy-3-hydroxy-1, 2-thiazol-5-yl) thiol trisodium salt and 16.6 mg potassium iodide. The mixture was stirred at 60 ° C. for 30 minutes. N and N-dimethylformamide were distilled off under reduced pressure. Chloroform was added to the residue, washed with 1N hydrochloric acid and dried over MgSO 4. Chloroform was distilled off and the residue was reversed-phase TLC [plate: Merck, Art, No. 15424, 10 × 10 cm, 2 plates, developing solvent: methanol-water (5: 1)] gave 33.12 mg of the title compound.

IR (KBr): 1728, 1660, 1368, 1236, 1018, 958 cm ^-1 .

Example 63

Preparation of 3- [2- (5-methoxymethyl-1, 3, 4-thiadiazol-2-yl) thio] acetamido-rancon 8, 14-diacetate:

The title compound was obtained (yield: 41%) by carrying out a reaction similar to Example 59 using (5-methoxymethyl-1, 3, 4-thiadiazol-5-yl) thiol.

NMR (90 MHz, CDCl 3) δ: 1.25 (d, J = 7 Hz, 17-Me), 1.34 (s, 2-Me), 1.53 (s, 11-Me), 1.84 (s, 5-Me), 1.99 & 2.03 (s, 8-OAc, 14-OAc), 2.1-2.6 (m, 9-H2, 15-H2, 17-H), 3.42 (s, CH2OCH3), 3.97 (s, COCH2S), 4.35 (m , 16-H), 4.67 (d, J = 11 Hz, 4-H), 4.77 (s, CH2OCH3), 5.05 (m, 8-H), 5.2-5.9 (m, 3-H, 6-H, 7 -H, 10-H, 13-H, 14-H), 6.25 (d, J = 15 Hz, 12-H), 7.73 (d, J = 9 Hz, NH).

IR (KBr): 1728, 1710, 1674, 1366, 1240, 1018, 960 cm ^-1 .

Example 64

Preparation of 3- [2- (5-methanesulfonylmethyl-1, 3, 4-thiadiazol-2-yl) thio] acetamido-rancon 8, 14-diacetate:

The title compound was obtained (yield: 55%) by carrying out a reaction similar to Example 59 using (5-methanesulfonyl-1, 3, 4-thiadiazol-2-yl) thiol.

NMR (90 MHz, CDCl 3) δ: 1.24 (d, J = 7 Hz, 17-Me), 1.29 (s, 2-Me), 1.51 (s, 11-Me), 1.83 (s, 5-Me), 2.00 & 2.03 (s, 8-OAc, 14-OAc), 2.1-2.6 (m, 9-H2, 15-H2, 17-H), 2.97 (s, CH3SO2), 4.01 (s, COCH2S), 4.36 (m , 16-H), 4.60 (d, J = 11 Hz, 4-H), 4.70 (s, CH2SO2), 5.05 (m, 8-H), 5.2-5.85 (m, 3-H, 6-H, 7 -H, 10-H, 13-H, 14-H), 6.25 (d, J = 15 Hz, 12-H), 7.62 (d, J = 10 Hz, NH).

IR (KBr): 1726, 1708 (sh.), 1660, 1362, 1312, 1240, 1140 cm ^-1 .

Example 65

Preparation of 3- [2- [1- (2-hydroxyethyl) -1H-tetrazol-5-yl] thio] acetamido-rancon 8, 14-diacetate:

The title compound was obtained (yield: 70%) by carrying out a reaction similar to Example 59 using [1- (2-hydroxyethyl) -1H-tetrazol-5-yl] thiol.

NMR (90 MHz, CDCl 3) δ: 1.23 (d, J = 7 Hz, 17-Me), 1.30 (s, 2-Me), 1.50 (s, 11-Me), 1.80 (s, 5-Me), 2.00 & 2.03 (s, 8-OAc, 14-OAc), 2.1 to 2.6 (m, 9-H2, 15-H2, 17-H), 3.88 & 4.10 (ABq, J = 15 Hz, COCH2s) to 4.0 (m, CH2CH2OH)-4.4 (m, CH2CH2OH), 4.58 (d, J = 11 Hz, 4-H), 5.0 (m, 8-H), 5.2-5.8 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.25 (d, J = 15 Hz, 12-H), 7.50 (d, J = 10 Hz, NH).

IR (KBr): 1724, 1706, 1656, 1366, 1240, 1016, 956 cm ^-1 .

Example 66

Preparation of 3- (2-aminothiazol-4-yl) acetamido-rancon 8, 14-diacetate:

108.5 mg of 3- (2-chloroacetylaminothiazol-4-yl) acetamido-rancon 8, 14-diacetate was dissolved in 5 ml of tetrahydrofuran. 5 ml of water and 20.3 mg of sodium N-methyldithiocarbamate were added to the solution, and the mixture was stirred at room temperature for 90 minutes and extracted with ethyl acetate. The extract was washed with brine and dried over MgSO 4. The residue was subjected to permanent TLC [plates: Merck products, Art, No. 5715, 20 × 20 cm, 2 plates, developing solvent: tetrahydrofuran-chloroform (1: 1)] to give 34.5 mg of the title compound.

NMR (90 MHz, CDCl 3 -DMSO-d 6 (3: 1)) δ: 1.25 (d, J = 7 Hz, 17-Me), 1.31 (s, 2-Me), 1.50 (s, 11-Me), 1.79 ( s, 5-Me), 1.99 & 2.02 (s, 8-OAc, 14-OAc, respectively) 2.1-2.7 (m, 9-H2, 15-H2, 17-H), 3.39 (thiazole-CH2), 4.52 (m, 16-H), 4.73 (d, J = 11 Hz, 4-H), 5.02 (m, 8-H), 5.2-5.8 (m, 3-H, 6-H, 7-H, 10 -H, 13-H, 14-H), 6.22 (s, thiazole-5-H), 6.29 (d, J = 15 Hz, 12-H), 6.32 (br. S, NH2), 7.70 (d, J = 9 Hz, NH).

IR (KBr): 1730, 1710, 1658, 1514, 1368, 1240 cm ^-1 .

Example 67

Preparation of 3- [D (-)-2-amito-phenylacetamido] -rancon 8, 14-diacetate:

330.6 mg of 3-D (-)-2- (2, 2, 2-trichloroethoxycarbonylamino) phenylacetamido] -rancon 8, 1-diacetate was dissolved in 15 ml of ethyl acetate. To the solution was added 2.8 ml of acetic acid and 1.25 g of zinc powder, and the mixture was stirred at room temperature overnight. The precipitate was filtered off using a filter. The filtrate was washed with brine and dried over MgSO 4. The solvent was distilled off and the residue was subjected to silica gel chromatography [2.5 × 38 cm, eluent: chloroform-acetone (9: 1) and chloroform-acetone (2: 1)]. The desired fractions were combined and concentrated to give 85.0 mg of the title compound.

NMR (90 MHz, CDCl 3) δ: 1.23 (s, 2-Me), 1.27 (d, J = 6.5 Hz, 17-Me), 1.53 (s, 11-Me), 1.84 (s, 5-Me), 2.00 & 2.03 (s, 8-OAc, 14-OAc), 2.1-2.6 (m, 9-H2, 15-H2, 17-H), 4.37 (m, 16-H), 4.68 (d, J = 11 Hz , 4-H), 5.07 (m, 8-H), 5.2-5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H, C6H5CH), 6.28 ( d, J = 15 Hz, 12-H), 7.32 (br. s, C6H5), 7.83 (br. d, J = 10 Hz, NH).

IR (KBr): 3415, 1735, 1715, 1675, 1500, 1370, 1250, 1025, 965, 750 cm ^-1 .

Example 68

Preparation of 3- (2-carboxy-phenylacetamido) -lancon 8, 14-diacetate:

38.3 mg of 3- [2- (2,2,2-trichloroethoxycarbonyl) -phenylacetamido] rancon 8, 14-diacetate was dissolved in 1.5 ml of dichloromethane. 50 μl of acetic acid and 43 mg of zinc powder were added to the solution, and the mixture was stirred at room temperature. After 2 and 5 hours, 50 μl of acetic acid and 42 mg of a cotton powder were further added. After 8 hours the precipitate was filtered off using a filter. The filtrate was washed with dichloromethane, which was washed sequentially with dilute aqueous sodium hydrogen carbonate solution and water and then dried over MgSO 4. Dichloromethane was distilled off.

The residue is permanent TLC plate [Merck, Art. No. 5715, 20 × 20 cm, 2 plates, developing solvent: chloroform-methanol (4: 1)] gave 10.6 mg of the title compound.

NMR (90 MHz, CDCl 3) δ: 1.15 to 1.35 (m, 17-Me, 2-Me), 1.50 (s, 11-Me), 1.83 (s, 5-Me), 1.98 & 2.02 (s, 8-, respectively) OAc, 14-OAc), 2.25-2.6 (m, 9-H2, 15-H2, 17-H), 4.3-4.45 (m, 16-H), 4.47 & 4.50 (s, C5H5CH), 4.60 (br d.J = 11 Hz, 4-H), 5.06 (m, 8-H), 5.25-5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H ), 6.25 (d, J = 15 Hz, 12-H), 7.37 (s, C6H5), 7.65 (d, J = 10 Hz, NH), 9.7 (br., -COOH).

IR (KBr): 3400, 2930, 1730, 1710, 1670, 1370, 1300, 1250, 1235, 1015, 960 cm ^-1 .

Example 69

Preparation of 3- (2-acetoxyacrylamido) -rancon 8, 14-diacetate:

54.3 mg of lancassidine C 8, 14-diacetate was dissolved in 1 ml of dichloromethane. To the solution was added 13.9 μl triethylamine, 18.9 μl acetic anhydride and 12.2 mg 4- (N, N-dimethylamino) pyridine. The mixture was stirred at rt for 9 h and left at rt overnight. Dichloromethane was added to the product, washed sequentially with 2 ml of 0.5 N hydrochloric acid and brine and dried over MgSO 4. Dichloromethane was distilled off and the residue was permanent TLC plate [Merck, Art. No. 5715, 20 × 20 cm, 2 plates, developing solvent: ethyl acetate-chloroform (1: 4)] gave 13.9 mg of the title compound.

NMR (90 MHz, CDCl 3) δ: 1.29 (d, J = 7 Hz, 17-Me), 1.38 (s, 2-Me), 1.54 (s, 11-Me), 1.89 (s, 5-Me), 2.02 & 2.04 (s, 8-OAc, 14-OAc), 2.2-2.7 (m, 9-H2, 15-H2, 17-H), 2.33 (s, 2'-OAc), 4.39 (m, 16-H ), 4.67 (d. J = 11 Hz, 4-H), 5.07 (m, 8-H), 5.2-6.2 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H = CH 2), 6.27 (d. J = 15 Hz, 12-H), 7.35 (d, J = 10 Hz, NH).

IR (KBr): 1738, 1712, 1372, 1244, 1172, 1022 cm ^-1 .

Example 70

Preparation of 3- (2-t-butoxycarbonyloxyacrylamido) -rancon 8, 14-diacetate:

1.086 g of lancassidine c 8, 14-diacetate was dissolved in 20 ml of dichloromethane. The solution was cooled to -30-20 C. To the solution was added 0.278 ml of triethylamine, 0.918 ml of di-t-butyl bicarbonate and 244 mg of 4- (N, N-dimethylamino) pyridine, the mixture was stirred for 8.5 hours, dichloromethane was added Washed sequentially with 40 ml 0.5 N hydrochloric acid and brine and dried over MgSO 4. Dichloromethane was distilled off and the residue was purified by silica gel (250 g) column chromatography [eluent: ethyl acetate-chloroform (1: 4)] and the eluate was partitioned by 20 g. The 49-78 fractions were combined and concentrated to afford crystals, to which nucleic acid was added and dried to afford 747.6 mg of the title compound.

Melting point 199-201 degreeC (decomposition).

NMR (90 MHz, CDCl 3) δ: 1.30 (d, J = 7 Hz, 17-Me), 1.40 (s, 2-Me), 1.53 (s, Bu ^t , 11-Me), 1.90 (s, 5-Me) , 2.01 & 2.03 (s, 8-OAc, 14-OAc, respectively), 2.2-2.7 (m, 9-H2, 15-H2, 17-H), 4.40 (m, 16-H), 4.72 (d.J = 11 Hz, 4-H), 5.2-6.1 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H = CH2), 6.28 (d. J = 15 Hz, 12 -H), 7.35 (d, J = 10 Hz, NH).

IR (KBr): 3400, 1748, 1728, 1706, 1504, 1368, 1240, 1146 cm ^-1 .

[α] D ^23.5 -169.4 ° (c = 0.595, CHCl 3)

Mass m / e: 643 (M ⁺ ), 543 (M ⁺ -101 (COOBu ^t )), 483 (M ⁺ -101-60 (AcOH)), 440 (M ⁺ -101-60-44 (CO2)) , 423 (M ⁺ -101-60-60), 380 (M ⁺ -101-60-60-44).

Example 71

(Iii) 3- (2-t-butoxycarbonyloxyacrylamido) -lancon 14-acetate-8-t-butylcarbonate and (ii) 3- (2-t-butoxycarbonyloxyacrylic Preparation of Amido) -Rancon 14-Acetate:

50.1 mg of lancassidin A was dissolved in 1 ml of dichloromethane. Cool the solution with ice water and 13.9 μl triethylamine. 45.9 μl of di-t-butylcarbonate and 12.2 mg of 4- (N, N-dimethylamino) pyridine were added and stirred for 55 minutes. Dichloromethane was added to the mixture, washed successively with 2 ml of 0.5 N hydrochloric acid and brine and dried over MgSO 4. Dichloromethane was distilled off and the residue was permanent TLC plate [Merck, Art. No. 5715, 20 × 20 cm, 2 plates developing solvent: ethyl acetate-hexane (2: 1)] to give 14.3 mg of the title compound (VII) and 17.4 mg of the title compound (ii).

Compound (i):

NMR (90 MHz, CDCl 3) δ: 1.29 (d, J = 7 Hz, 17-Me), 1.39 (s, 2-Me), 1.46 (s, 8-OCOOBu ^t ), 1.52 (s, 11-Me, 2 ′ -OCOOBu ^t ), 1.88 (s, 5-Me), 2.01 (s, OAc), 2.2-2.7 (m, 9-H2, 15-H2, 17-H), 4.39 (m, 16-H), 4.69 (d.J = 11Hz, 4-H), 4.86 (m, 8-H), 5.2 ~ 6.1 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H = CH 2), 7.34 (d, J = 9 Hz, NH).

IR (KBr): 1758 (sh.), 1738, 1710, 1368, 1276, 1252, 1146 cm ^-1 .

Compound (ii):

NMR (90 MHz, CDCl 3) δ: 1.28 (d, J = 7 Hz, 17-Me), 1.39 (s, 2-Me), 1.53 (s, 11-Me, Bu ^t ), 1.89 (s, 5-Me) , 2.01 (s, OAc), 2.2-2.6 (m, 9-H2, 15-H2, 17-H), -4.1 (m, 8-H), 4.40 (m, 16-H), 4.66 (d. J = 11Hz, 4-H), 5.2 ~ 6.1 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H = CH2), 6.26 (d. J = 14Hz, 12-H), 7.36 (d, J = 9 Hz, NH).

IR (KBr): 1756, 1734 (sh.), 1708, 1642, 1508, 1372, 1244, 1146 cm ^-1 .

Example 72

Preparation of 3- (2-acetoxyacrylamido) -rancon 8, 14-bis (2, 2, 2-trichloroethyl) carbonate:

Dissolve 810 mg of Lancacidin C 8, 14-bis (2, 2, 2-trichloroethyl) carbonate in 6 ml of pyridine, cool the solution with ice water and 122 mg of 4- (N, N-dimethylamino Pyridine and 3 ml of acetic anhydride were added. The mixture was stirred for 3 hours, poured into ice water and extracted with ethyl acetate. The extract was washed sequentially with 1N hydrochloric acid and aqueous NaCl solution and cooled with MgSO 4. The solvent was distilled off, and the residue was purified by silica gel (130 g) column chromatography [eluent: ethyl acetate-hexane (1: 1)], and the eluate was fractionated by 10 g. The 23rd-26th fractions were combined and concentrated to give 267.1 mg of the title compound.

NMR (90MHz, CDCl3) δ: 1.31 (d, J = 7Hz, 17-Me), 1.40 (s, 2-Me), 1.57 (s, 11-Me), 2.33 (s, OAc), 2.2 ~ 2.7 ( m, 9-H2, 15-H2, 17-H), 4.45 (m, 16-H) to 4.7 (m, 4-H), 4.75 (s, CCl3CH2 x 2) to 5.0 (m, 8-H) , 5.2 to 6.4 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 5.37 & 6.02 (d. J = 2 Hz, = CH2), 6.35 (d J = 15 Hz, 12-H), 7.35 (d, J = 9 Hz, NH).

IR (KBr): 1750, 1704, 1680, 1374, 1240, 1164, 810 cm ^-1 .

Example 73

Preparation of 3- (2- (L) -iodinepropionamido) -lancon 8, 14-diacetate and 3- (2- (D) -iodopropionamido) -lancon 8, 14-diacetate:

230.7 mg of bis [3- (2- (D) -hydroxypropionamido) rancon 8, 14-diacetate-2 '(O) -yl] sulfone was dissolved in 5 ml of acetone. 300 mg of iodine and sodium were added to the solution and refluxed for 22.5 hours. Acetone was distilled off, ethyl acetate was added to the residue, washed successively with water and aqueous NaCl solution, and dried over Na 2 SO 4. Ethyl acetate was distilled off from the product. The residue was subjected to silica gel column chromatography [eluent: ethyl acetate-benzene (1: 2) and telacetate-benzene (2: 1)]. The desired fractions were combined and concentrated to give 59.2 mg of the title compound (2 '-(L) compound and 35.7 mg of the title compound (2'-(D) compound).

2 '-(L) Compound:

NMR (90MHz, CDCl3) δ: 1.31 (d, 3H, J = 7Hz), 1.47 (s, 3H), 1.54 (s, 3H), 1.87 (s, 3H), 1.95 (d, 3H, J = 8Hz) , 2.01 (s, 3H), 2.03 (s, 3H), 2.20 to 2.55 (m, 5H), 4.30 to 4.80 (m, 3H), 4.90 to 5.88 (m, 7H), 6.27 (d, 1H, J = 15 Hz), 7.02 (d, 1H, J = 10 Hz).

IR (KBr): 1735, 1715, 1670, 1240 cm ^-1 .

2 '-(D) Compound:

NMR (90 MHz, CDCl 3) δ: 1.31 (d, 3H, J = 7 Hz), 1.42 (s, 3H), 1.54 (s, 3H), 1.87 (s, 3H), 1.95 (d, 3H, J = 6 Hz) , 2.01 (s, 3H), 2.04 (s, 3H), 2.20 to 2.55 (m, 5H), 4.25 to 4.80 (m, 3H), 4.90 to 5.87 (m, 7H), 6.27 (d, 1H, J = 14 Hz), 7.10 (d, 1H, J = 10 Hz).

IR (KBr): 1740, 1715, 1680, 1240 cm ^-1 .

Example 74

Preparation of 3- (2- (DL) -p-toluenesulfonyloxypropionamido) -lancon 8, 14-diacetate:

273.8 mg of 3- (2- (DL) -lancon 8, 14-diacetate were dissolved in 1 ml of pyridine, 104.9 mg of p-toluenesulfonyl chloride was added to the solution under ice-cooling The mixture was stirred for 15 minutes After further stirring at room temperature for 21 hours, 133.5 mg of p-toluenesulfonyl chloride was added and further stirred for 2 hours, iced water was added to the product, extracted with ethyl acetate, and the extract was sequentially extracted with 1N hydrochloric acid and aqueous NaCl solution. Washed and dried over Na 2 SO 4 The solvent was distilled off The residue was subjected to silica gel column chromatography [ethylacetate-benzene (1: 2)] The desired fractions were combined and concentrated to give 198.9 mg of the title compound.

NMR (90MHz, CDCl3) δ: 1.23 ~ 1.50 (m, 6H), 1.54 (s, 3H), 1.70 ~ 1.90 (m, 6H), 2.02 (s, 3H), 2.03 (s, 3H), 2.20 ~ 2.60 (m, 5H), 4.30-5.90 (m, 10H), 6.30 (d, 1H, J = 14 Hz), 7.30-7.94 (m, 5H).

IR (KBr): 1740, 1720, 1685, 1245 cm ^-1 .

Example 75

Preparation of 3- (2- (L) -iodopropionamido) -lancon 8, 14-diacetate and 3- (2- (D) -iododopropionamido) -lancon 8, 14-diacetate:

199 mg of 3- (2- (DL) -p-toluenesulfonyloxypropionamido) -rancon 8, 14-diacetate was dissolved in 5 ml of acetone. To the solution was added sodium iodide to 127.8 mg, the mixture was refluxed for 3.5 hours and the acetone was distilled off. Ethyl acetate was added to the residue, washed successively with water and aqueous NaCl solution, and dried over Na 2 SO 4. The solvent was distilled off and the residue was subjected to silica gel column chromatography [eluent: ethyl acetate-benzene (1: 2)]. 111.9 mg of the title compound (2 '-(L) compound) and 62.4 mg of the title compound (2'-(D) compound) were obtained by combining and concentrating the desired fractions. These compounds are consistent in TLC, IR and NMR data with the compound obtained in Example 73, respectively.

Example 76

Preparation of 3- (2- (DL) -methanesulfonyloxypropionamido) -lancon 8, 14-diacetate:

1.09 g of 3- (2- (DL) -hydroxypropionamido) -rancon 8, 14-diacetate was dissolved in 2 ml of dichloromethane. To the solution was added 0.32 ml of pyridine and 0.31 ml of methanesulfonylchloride under ice cooling and the mixture was stirred for 15 minutes. The product was stirred at room temperature for 1 hour, ice water was added and extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid and aqueous NaCl solution and dried over Na 2 SO 4. The solvent was distilled off and the residue was subjected to silica gel column chromatography [eluent: ethyl acetate-benzene (1: 1)]. The desired fractions were combined and concentrated to give 998 mg of the title compound.

NMR (90MHz, CDCl3) δ: 1.25 ~ 1.66 (m, 12H), 1.87 (s, 3H), 2.02 (s, 3H), 2.03 (s, 3H), 2.16 ~ 2.60 (m, 5H), 3.03 (s , 1H), 3.18 (s, 2H), 4.30 ~ 4.56 (m, 1H), 4.70 (d, 1H, J = 10Hz), 4.90 ~ 5.90 (m, 8H), 6.26 (d, 1H, J = 15Hz) , 7.43-77.7 (m, 1 H).

IR (KBr): 1740, 1715, 1690, 1240 cm ^-1 .

Example 77

Preparation of 3- (2- (L) -iodinepropionamido) -lancon 8, 14-diacetate and 3- (2- (D) -iodinepropionamido) -lancon 8, 14-diacetate:

2.8 g of the title compound (2 '-(L) compound) by carrying out the reaction with 4.4 g of 3- (2- (DL) -methanesulfonyloxypropionamido) -rancon 8, 14-diacetate; 1.5 g of the title compound (2 '-(D) compound) were obtained. These products are consistent in the TLC, IR and NMR data with the compound obtained in Example 73.

Example 78

Preparation of 3- (2- (DL) -trimethylsilyloxypropionamido) -lancon 8, 14-diacetate:

109.1 mg 3- (2- (DL) -hydroxypropionamido) -rancon 8, 14-diacetate was dissolved in 1 ml of dichloromethane. 33.5 μl of triethylamine and 30.5 μl of chlorotrimethylsilane were added to the solution, and the mixture was stirred at room temperature for 20 minutes. Ice water was added to the product, extracted with dichloromethane, dried over Na 2 SO 4 and the solvent was distilled off. The residue was subjected to silica gel column chromatography [eluent: ethyl acetate-hexane (1: 1)]. The desired fractions were combined and concentrated to give 117 mg of the title compound.

NMR (90MHz, CDCl3) δ: 0.21 (s, 3.6H), 0.26 (s, 5.4H), 1.25 ~ 1.50 (m, 9H), 1.59 (s, 3H), 1.92 (s, 3H), 2.06 (s , 3H), 2.08 (s, 3H), 2.20-2.65 (m, 5H), 4.10-5.90 (m, 10H), 6.33 (d, 1H, J = 15 Hz), 7.75-8.06 (m, 1H).

IR (KBr): 1740, 1710, 1680, 1240 cm ^-1 .

Example 79

Preparation of 3- (2-phenylthiopropionamido) -lancon 8, 14-diacetate:

54.6 mg of 3- (2- (DL) -hydroxypropionamido) -rancon 8, 14-diacetate was dissolved in 0.1 ml of pyridine. 74 μl tributylphosphine and 65.5 mg diphenyldisulfite were added to the solution, the mixture was stirred at room temperature for 19 hours, and 40.8 mg by silica gel column chromatography [eluent: ethyl acetate-benzene (1: 2)]. The title compound was obtained.

NMR (90 MHz, CDCl3) δ: 1.25 to 1.86 (m, 15H), 2.01 (s, 3H), 2.06 (s, 3H), 2.15 to 2.60 (m, 5H), 3.66 to 4.02 (m, 1H), 4.20 ~ 4.55 (m, 2H), 4.90-5.83 (m, 7H), 6.26 (d, 1H, J = 14 Hz), 7.12-7.45 (m, 5H), 7.56-7.80 (m, 1H).

IR (KBr): 1735, 1715, 1675, 1240 cm ^-1 .

Example 80

Preparation of 3- (2- (DL) -phenylthiopropionamido) -lancon 8, 14-diacetate:

168 mg of sodium hydride (purity 60%) and 0.43 ml of thiophenol are added to 2 ml of ethanol, the mixture is cooled with ice water and 2.18 g of 3- (2- (DL) -methane dissolved in 14 ml of tetrahydrofuran Sulfonyloxypropionamido) -rancon 8, 14-diacetate was added dropwise under stirring. The whole mixture was stirred at rt for 2 h, aqueous NaCl solution was added and extracted with ethyl acetate. The organic layer was washed with aqueous NaCl solution and dried over Na 2 SO 4. The solvent was distilled off and the residue was subjected to silica gel column chromatography [eluent: ethyl acetate-hexane (1: 1)]. The desired fractions were combined and concentrated to yield 1.785 g of the title compound. This product is consistent with the compound obtained in Example 79 in TLC, IR and NMR data.

Example 81

Preparation of 3- (2- (DL) -methanesulfonyloxypropionamido) -lancon 8, 14-ditrimethylsilylether:

1.38 g of lancassidine C 8, 14-ditrimethylsilylether was dissolved in a mixture of 10 ml tetrahydrofuran and 10 ml methanol. 25.9 mg of boron hydride was added to the solution by stirring under ice cooling, and the mixture was stirred at the same temperature for 10 minutes. The solvent was distilled off to give crude 3- (2- (DL) -hydroxypropionamido) -lancon 8, 14-ditrimethylsilylether, which was dissolved in 7 ml of pyridine. 0.53 ml of methanesulfonyl chloride was added to the solution with stirring at 0 ° C. The mixture was further stirred for 70 minutes, poured into ice water and extracted with ethyl acetate. The organic layer was dried over Na 2 SO 4. The solvent was distilled off and the residue was subjected to silica gel column chromatography [eluent: ethyl acetate-benzene (1: 2)]. The desired fractions were combined and concentrated to give 330 mg of the title compound.

NMR (90 MHz, CDCl 3) δ: 0.10 (s, 18H), 1.2 to 1.7 (m, 12H), 1.87 (s, 3H), 2.1 to 2.6 (m, 5H), 3.14 & 3.17 (s, 3H, respectively), 3.8-4.45 (m, 4H), 4.9-6.1 (m, 8H), 7.53 (d, 1H, J = 10 Hz).

IR (KBr): 1750, 1710, 1515, 1360, 1260, 1175 cm ^-1 .

Example 82

(3- (2- (L) -iodopropionamido) -lancon 8, 14-ditrimethylsilylether and 3- (2- (D) -iodopropionamido) -lancon 8, 14-ditrimethyl Preparation of Silyl Ether:

136.8 mg of 3- (2- (DL) -methanesulfonyloxypropionamido) -rancon 8, 14-ditrimethylsilyl ether was dissolved in 2 ml of acetone. 111 mg sodium iodide was added to the solution and the mixture was refluxed for 4 hours. After cooling, the precipitate was filtered off and the filtrate was concentrated. The concentrate was subjected to silica gel column chromatography [eluent: ethyl acetate-hexane (1: 2)]. The desired fractions were combined and concentrated to give 61.8 mg of the title compound (2 '-(L) compound) and 42,7 mg of the title compound (2'-(D) compound).

2 '-(L) Compound:

NMR (90 MHz, CDCl 3) δ: 0.01 (s, 18H), 1.25 (d, 3H, J = 7 Hz), 1.49 (s, 3H), 1.52 (s, 3H), 1.88 (s, 3H), 1.96 (d , 3H, J = 7Hz), 2.10 ~ 2.70 (m, 5H) m, 3.80 ~ 4.70 (m, 5H), 5.10 ~ 5.80 (m, 5H), 6.00 (d, 1H, J = 15Hz), 7.03 (d , 1H, J = 10 Hz).

IR (KBr): 1760, 1720, 1675, 1255, 1070, 845 cm ^-1 .

2 '-(D) Compound:

NMR (90 MHz, CDCl 3) δ: 0.01 (s, 18H), 1.25 (d, 3H, J = 7 Hz), 1.42 (s, 3H), 1.53 (s, 3H), 1.87 (s, 3H), 1.92 (d , 3H, J = 7Hz), 2.05-2.60 (m, 5H), 3.85-4.70 (m, 5H), 5.12-5.85 (m, 5H), 6.00 (d, 1H, J = 15Hz), 7.15 (d, 1H, J = 10 Hz).

IR (KBr): 1755, 1715, 1675, 1255, 1045, 845 cm ^-1 .

Example 83

Preparation of 3- (2-trimethylsilyloxyacrylamido) -lancon 8, 14-diacetate:

1.08 g of lancassidine C 8, 14-diacetate was dissolved in 4 ml of dichloromethane. 0.42 ml of triethylamine and 0.32 ml of chlorotrimethylsilane were dissolved in the solution, and the mixture was stirred at room temperature for 2 hours. The resulting precipitate was filtered off. Dichloromethane was added to the filtrate, washed sequentially with cold water and aqueous NaCl solution, and dried over Na 2 SO 4. The solvent was removed upstream and the residue was dissolved in 2 ml of dichloromethane. 20 ml of petroleum ether was added to the solution to give 1.17 g of the needle-like title compound. '

Melting Point 190 ~ 191.5 ℃

NMR (90 MHz, CDCl 3) δ: 0.30 (s, SiMe 3), 1.30 (d, J = 7 Hz, 17-Me), 1.39 (s, 2-Me), 1.55 (s, 11-Me), 1.90 (s, 5-Me), 2.02 & 2.04 (s, OAc × 2), 2.2 to 2.6 (m, 9-H2, 15-H2, 17-H), 4.40 (m, 16-H), 4.59 & 5.50 (each d, J = 2Hz, 3'-H2), 4.71 (d, J = 11Hz, 4-H), 5.07 (s, 8-H), 5.2 ~ 5.9 (m, 3-H, 6-H, 7- H, 10-H, 13-H, 14-H), 6.28 (d, J = 15 Hz, 12-H), 7.88 (d, J = 10 Hz, NH).

IR (KBr): 3410, 1742, 1712, 1496, 1374, 1250, 856 cm ^-1 .

[α] D ²⁶ -201.0 ° (c = 0.505, CHCl3)

Example 84

Preparation of 3- (3-brom-2-oxopropionamido) -lancon 8, 14-diacetate:

1.23 g of 3- (2-trimethylsilyloxyacrylate) -lancon 8, 14-diacetate was dissolved in 20 ml of dichloromethane. 0.427 g of N-bromosuccinimide was added to the solution little by little and stirred for 10 minutes. To the resulting mixture was added 20 ml of dichloromethane. The mixture was washed with water and aqueous NaCl solution and dried over Na 2 SO 4. Dichloromethane was distilled off and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate-hexane (1: 2) and ethyl acetate-hexane (2: 3)) inactivated with 10% water. The desired fractions were combined and concentrated to give 622.8 mg of the title compound.

NMR (90MHz, CDCl3) δ: 1.31 (d, 3H, J = 7Hz), 1.38 (s, 3H), 1.53 (s, 3H), 1.88 (s, 3H), 2.01 (s, 3H), 2.03 (s , 3H), 2.15 to 2.55 (m, 5H), 4.36 (d, 1H, J = 14 Hz), 4.54 (d, 1H, J = 14 Hz), 4.70 (d, 1H, J = 11 Hz), 4.93 to 5.83 ( m, 7H), 6.27 (d, 1H, J = 15 Hz), 8.10 (d, 1H, J = 10 Hz).

IR (KBr): 1740, 1720, 1700, 1245 cm ^-1 .

Example 85

Preparation of 3- (2- (DL) -methanesulfonyloxypropionamido) -lancon 8, 14-bis (dimethyl-t-butylsilylether):

7.5 g of the title compound were obtained by carrying out the reaction similarly to Example 81 using 13.8 g of Lancaside C 8, 14-bis (dimethyl-t-butylsilylate).

207-208 degreeC (chloroform petroleum ether)

NMR (90MHz, CDCl3) δ: 0.00 (s, 6H), 0.04 (s, 6H), 0.85 (s, 9H), 0.88 (s, 9H), 1.20 (d, 3H, J = 6Hz), 1.40 (s , 3H), 1.50 (s, 3H), 1.54-1.67 (m, 3H), 1.89 (s, 3H), 2.05-2.60 (m, 5H), 3.04 & 3.08 (s, 3H), 3.80-4.70 ( m, 4H), 4.95-5.89 (m, 6H), 6.00 (d, 1H, J = 15 Hz), 7.59 (d, 1H, J = 10 Hz).

IR (KBr): 1745, 1710, 1060 cm ^-1 .

[α] D ²⁶ -111.9 ° (c = 0.52, CHCl3)

Example 86

3- (2- (L) -iodopropionamido) -lancon 8, 14-bis (dimethyl-t-butylsilylether) and 3- (2- (D) -iodopropionamido) -lancon 8 , 14-bis (dimethyl-t-butylsilyl ether)

9536 mg of reaction was carried out in the same manner as in Example 82 using 1.536 g of 3- (2- (DL) -methanesulfonyloxypropionamido) -rancon 8, 14-bis (dimethyl-t-butylsilylether) The title compound (2 '-(L) compound) and 501 mg of the title compound (2'-(D) compound) were obtained. 2 '(L) compound, melting point 175 ° C (decomposition) (ethyl acetate-hexane):

NMR (90 MHz, CDCl 3) δ: 0.00 (s, 12H), 0.83 (s, 9H), 0.85 (s, 9H), 1.25 (d, 3H, J = 6Hz), 1.48 (s, 3H), 1.52 (s , 3H), 1.85 (s, 3H), 1.96 (d, 3H, J = 7Hz), 2.05 ~ 2.50 (m, 5H), 3.80 ~ 4.70 (m, 5H), 5.00 ~ 5.80 (m, 5H), 6.00 (d, 1H, J = 15 Hz), 7.06 (d, 1H, J = 10 Hz).

IR (KBr): 1745, 1715, 1675, 1065 cm ^-1 .

[α] D ²³ -105.7 ° (c = 0.525, CHCl3)

2 ′-(D) compound, melting point 185 ° C. (decomposition) (ethyl acetate-hexane):

NMR (90 MHz, CDCl 3) δ: 0.03 (s, 12H), 0.85 (s, 9H), 0.87 (s, 9H), 1.24 (d, 3H, J = 7 Hz), 1.40 (s, 3H), 1.54 (s , 3H), 1.87 (s, 3H), 1.98 (d, 3H, J = 7 Hz), 2.00-2.60 (m, 5H), 3.90-4.75 (m, 5H), 5.15-5.86 (m, 5H), 6.00 (d, 1H, J = 15 Hz), 7.20 (d, 1H, J = 9 Hz).

IR (KBr): 1745, 1705, 1675, 1065 cm ^-1 .

[α] D ²³ -73.6 ° (c = 0.525, CHCl3)

Example 87

Preparation of 3- (2- (DL) -benzenesulfinylpropionamido) -lancon 8, 14-diacetate:

Dissolve 1.60 g of 3- (2- (DL) -phenylthiopropionamido) -rancon 8, 14-diacetate in 6 ml of dichloromethane, cool the solution with ice water and replace 649.3 mg of m-chloroperbenzoic acid. Was added. The mixture was stirred for 30 minutes, 61.8 mg more m-chloroperbenzoic acid was added and the whole mixture was stirred for another 15 minutes. The resulting precipitate was filtered off and the filtrate was washed with aqueous sodium bicarbonate solution and aqueous NaCl solution and dried over Na 2 SO 4. Dichloromethane was filtered off and the residue was subjected to silica gel column chromatography [eluent: ethyl acetate-hexane (2: 1) and ethyl acetate). The desired fractions were combined and concentrated to give 1.39 g of the title compound.

NMR (90MHz, CDCl3) δ: 1.20 ~ 1.90 (m, 15H), 2.01 (s, 3H), 2.08 (s, 3H), 2.16 ~ 2.60 (m, 5H), 3.26 ~ 3.70 (m, 1H), 4.26 ~ 4.56 (m, 1H), 4.70 (d, 1H, J = 11 Hz), 4.93-5.90 (m, 7H), 6.26 (d, 1H, J = 14 Hz), 7.20-7.72 (m, 6H).

IR (KBr): 1735, 1715, 1670 cm ^-1 .

Example 88

3- (2- (DL) -benzenesulfinylpropionamido) -lancon 8, 14-diacetate and 3- (2- (DL) -benzenesulfonylpropionamido) -lancon 8, 14-diacetate Produce :

199.2 mg of title by conducting a reaction similar to Example 87 using 238.7 mg of 3- (2- (DL) -phenylthiopropionamido) -lancon 8, 14-diacetate and 127 mg of m-chloroperbenzoic acid Compound (sulfoxide compound, this product is consistent with TLC, NMR and IR data with compound obtained in Example 87) and 50 mg of title compound (sulfone compound) were obtained.

Sulfone compounds:

NMR (90MHz, CDCl3) δ: 1.25 ~ 1.90 (m, 15H), 2.00 ~ 2.15 (m, 6H), 2.19 ~ 2.60 (m, 5H), 3.73 ~ 4.03 (m, 1H), 4.30 ~ 4.60 (m, 1H), 4.63-4.90 (m, 1H), 4.92-5.90 (m, 7H), 6.30 (d, 1H, J = 15 Hz), 7.23-9.90 (m, 6H).

IR (KBr): 1740, 1725, 1715, 1680, 1240 cm ^-1 .

Example 89

Preparation of 3-Acrylamido-Rancon 8, 14-Diacetate:

1.10 g of 3- (2- (DL) -benzenesulfinylpropionamido) lancon 8, 14-diacetate and 1.0 ml of trimethylphosphite were refluxed in 30 ml of xylene for 30 minutes. Xylene was distilled off and the residue was subjected to silica gel column chromatography [eluent: ethyl acetate-hexane (2: 1) and ethyl acetate). The desired fractions were combined and concentrated to give 402.9 mg of the title compound.

NMR (90MHz, CDCl3) δ: 1.30 (d, 3H, J-7Hz), 1.41 (s, 3H), 1.55 (s, 3H), 1.90 (s, 3H), 2.01 (s, 3H), 2.03 (s , 3H), 2.20-2.55 (m, 5H), 4.25-4.50 (m, 1H), 4.70 (d, 1H, J = 10 Hz), 4.93-5.53 (m, 8H), 6.13-6.40 (m, 2H) , 6.72 (d, 1H, J = 10 Hz).

IR (KBr): 1740, 1720, 1680, 1240 cm ^-1 .

Example 90

Preparation of 3- (2 (DL) -N-methylthiocarbamoylthio propionamido) -lancon 8, 14-diacetate:

98.3 mg of 3- (2- (L) -iodopropionamido) -rancon 8, 14-diacetate were dissolved in 1.5 ml tetrahydrofuran. To the solution was added 21.3 mg of sodium N-methyldithiocarbamate dissolved in 0.5 ml of water. The mixture was stirred for 40 minutes at room temperature and extracted with ethyl acetate. The extract was washed with aqueous NaCl solution and dried over Na 2 SO 4. The solvent was distilled off and the residue was subjected to silica gel column chromatography [eluent: ethyl acetate-benzene (1: 2)]. The desired fractions were combined and concentrated to give 83.3 mg of the title compound.

NMR (90 MHz, CDCl 3) δ: 1.28 (d, 3H, J = 7 Hz), 1.39 (s, 3H), 1.51 (d, 3H, J = 8 Hz), 1.52 (s, 3H), 1.85 (s, 3H) , 2.25 to 2.55 (m, 5H), 3.16 (s, 1.5H), 3.22 (s, 1.5H), 4.27 to 4.78 (m, 3H), 4.90 to 5.90 (m, 7H), 6.26 (d, 1H, J = 15 Hz), 7.50 (d, 1H, J = 10 Hz), 8.60 (br. S, 1H).

Example 91

3- (2- (L)-(benzothiazol-2-yl) thio-propionamido] -lancon 8, 14-diacetate and 3 [2- (D)-(benzothiazol-2-yl) Preparation of Thio-Propionamido] -Rancon 8, 14-Diacetate:

A mixture of 31.2 mg of 3- (2- (DL) -methanesulfonyloxypropionamido) -lancon 8, 14-diacetate and 10.4 mg of 2-mercaptobenzothiazole sodium was mixed with 0,5 ml of tetrahydrofuran. It was refluxed for 3.5 hours. After cooling the resulting mixture, ethyl acetate was added, washed successively with water and aqueous NaCl solution and dried over Na 2 SO 4. The solvent was distilled off and the residue was taken up in a permanent TLC plate [Merck, Art. No. 5715, 20 × 20 cm, developing solvent: ethyl acetate-hexane {1: 1)] to separate 13.4 mg of the title compound (2 '-(L) compound) and 7.8 mg of the title compound (2'-(D)). Compound).

2 '-(L) compound, melting point 178-180 ° C (AcOEt-Et2O):

NMR (90 MHz, CDCl 3) δ: 1.14 (s, 3H), 1.16 (d, 3H, J = 7 Hz), 1.51 (s, 3H), 1.61 (d, 3H, J = 7 Hz), 1.86 (s, 3H) , 2.00 (s, 3H), 2.05 (s, 3H), 2.10 ~ 2.55 (m, 5H), 4.15 ~ 4.40 (m, 1H), 4.50 ~ 4.80 (m, 2H), 4.90 ~ 5.80 (m, 7H) , 6.23 (d, 1H, J = 15 Hz), 7.17-8.10 (m, 5H).

IR (KBr): 1740, 1715, 1680, 1245cm ^-1

2 '-(D) compound, melting point 151-152 占 폚 (AcOEt-Et2O):

NMR (90 MHz, CDCl 3) δ: 1.27 (d, 3H, J = 7 Hz), 1.34 (s, 3H), 1.49 (s, 3H), 1.61 (d, 3H, J = 8 Hz), 1.81 (s, 3H) , 2.00 (s, 3H), 2.03 (s, 3H), 2.15 to 2.55 (m, 5H), 4.33 (br. D, 2H, J = 12 Hz), 4.65 (q, 1H, J = 8 Hz), 4.80 to 5.80 (m, 7H), 6.20 (d, 1H, J = 14 Hz), 7.20-8.20 (m, 5H).

IR (KBr): 1735, 1715, 1665, 1240 cm ^-1 .

Example 92

3- [2- (L)-(benzothiazol-2-yl) thio-propionamido] -lancon 8, 14-diacetate and 3- [2- (D)-(benzothiazol-2-yl Preparation of Thio-Propionamido] -Rancon 8, 14-Diacetate:

65.5 mg of 3- (2- (L) -iodopropionamido) -rancon 8, 14-diacetate were dissolved in 1 ml of tetrahydrofuran. To the solution was added 28.4 mg of 2-mercaptobenzothiazole sodium. The mixture was stirred at rt for 40 min. Ethyl acetate was added to the resulting mixture, washed successively with water and brine and dried over Na 2 SO 4. The solvent was distilled off and the residue was subjected to silica gel column chromatography [eluent: ethyl acetate-hexane (1: 1)]. The desired fractions were combined and concentrated to yield 3.7 mg of the title compound (2 '-(L) compound) and 57.4 mg of the title compound (2'-(D) compound). These products are consistent in TLC, NMR and IR data with the product obtained in Example 91.

Example 93

3- [2- (L)-(benzothiazol-2-yl) thio-propionamido] -lancon 8, 14- diacetate and 3- [2- (D)-(benzothiazol-2-yl Preparation of Thio-Propionamido] -Rancon 8, 14-Diacetate:

61.4 mg of the title compound (2 ′-(L)) was reacted in the same manner as in Example 92 using 65.6 mg of 3- (2- (D) -iodopropionamido) -rancon 8, 14-diacetate. -Compound) and 5.8 mg of the title compound (2 '-(D) -compound) were obtained. These products are identical in TLC, NMR and IR data with the product obtained in Example 91.

Example 94

3- [2- (L)-(benzoxazol-2-yl) thio-propionamido] -lancon 8, 14-diacetate and 3- [2- (D)-(benzoxazol-2-yl) thio Preparation of Propionamido-Lancon 8, 14-Diacetate:

22.7 mg of 2-mercaptobenzoxazole was dissolved in 1 ml of tetrahydrofuran. 6 mg of sodium hydride (about 60%) was added to the solution, the mixture was stirred for 5 minutes, 65.6 mg of 3- (2- (L) -iodopropionamido) -lancon 8, 14-diacetate was added and 30 minutes Further stirred. Ethyl acetate was added to the resulting mixture, washed successively with water and aqueous NaCl solution, and dried over Na 2 SO 4. The solvent was distilled off and the residue was permanent TLC plate [Merck, Art. No. 5715, 20 × 20 cm, developing solvent: ethyl acetate-benzene (1: 2)] to separate 5.1 mg of the title compound (2 '-(L) compound) and 52.1 mg of the title compound (2'-(D)). Compound).

2 '-(L) compound, melting | fusing point 188-190 degreeC (AcOEt-Et2O):

NMR (90 MHz, CDCl 3) δ: 1.16 (d, 3H, J = 6 Hz), 1.19 (s, 3H), 1.52 (s, 3H), 1.63 (d, 3H, J = 8 Hz), 1.86 (s, 3H) , 2.00 (s, 3H), 2.06 (s, 3H), 2.10 to 2.55 (m, 5H), 4.30 (dt, 1H, J = 12 Hz & 3 Hz), 4.46 (q, 1H, J = 8 Hz), 4.66 ( s, 1H, J = 12Hz, 4.90 ~ 5.80 (m, 7H), 6.25 (d, 1H, J = 15Hz), 7.10 ~ 7.70 (m, 4H), 7.93 (d, 1H, J = 10Hz),

IR (KBr): 1740, 1715, 1680, 1240 cm ^-1 .

2 '-(D) compound, melting point 191-192 캜 (AcOEt-Et2O):

NMR (90 MHz, CDCl 3) δ: 1.25 (d, 3H, J = 6 Hz), 1.35 (s, 3H), 1.50 (s, 3H), 1.65 (d, 3H, J = 7 Hz), 1.88 (s, 3H) , 2.00 (s, 3H), 2.03 (s, 3H), 2.13-2.53 (m, 5H). 4.25-4.63 (m, 3H), 4.80-5.80 (m, 7H), 6.20 (d, 1H, J = 15 Hz), 7.10-7.72 (m, 4H), 8.09 (d, 1H, J = 10 Hz).

IR (KBr): 1740, 1715, 1665, 1245 cm ^-1 .

Example 95

3- [2- (L)-(benzoxazol-2-yl) thio-propionamido] -lancon 8, 14-diacetate and 3- [2- (D)-(benzoxazol-2-yl) thio Preparation of Propionamido-Rancon 8, 14-Diacetate:

45.8 mg of the title compound (2 ′-(L)) was subjected to a reaction similar to Example 94 using 65.6 mg of 3- (2- (D) -iodopropionamido) -rancon 8, 14-diacetate. Compound) and 9.1 mg of the title compound (2 '-(D) compound) were obtained. These products were identical in TLC, IR and NMR data with the product obtained in Example 94.

Example 96

Preparation of 3- [2- (D)-(benzoimidazol-2-yl) thio propionamido] -lancon 8, 14-diacetate:

41.5 by reaction similar to Example 94 using 22.5 mg 2-mercaptobenzoimidazole and 65.6 mg 3- (2- (L) -iodopropionamido) -rancon 8, 14-diacetate mg of the title compound were obtained.

Melting point 158-160 degreeC (AcOEt-Et2O).

NMR (90 MHz, CDCl 3) δ: 1.29 (d, 3H, J = 7 Hz), 1.36 (s, 3H), 1.48 (s, 3H), 1.57 (d, 3H, J = 8 Hz), 1.80 (s, 3H) , 2.00 (s, 3H), 2.03 (s, 3H), 2.15 ~ 2.55 (m, 5H), 4.15 ~ 4.53 (m, 3H), 4.82 ~ 5.80 (m, 7H), 6.20 (d, 1H, J = 15 Hz), 7.10-7.85 (m, 4H), 8.10 (d, 1H, J = 10 Hz), 10.40 (br. S, 1H).

IR (KBr): 1740, 1715, 1670, 1240 cm ^-1 .

Example 97

Preparation of 3- [2- (L)-(benzoimidazol-2-yl) thio-propionamido) -lancon 8, 14-diacetate:

43.0 by reaction similar to Example 94 using 22.5 mg 2-mercaptobenzoimidazole and 65.6 mg 3- (2- (D) -iodopropionamido) -rancon 8, 14-diacetate mg of the title compound were obtained.

Melting point 156-157 degreeC (Et2O-petroleum ether).

NMR (90 MHz, CDCl 3) δ: 1.10 (s, 3H), 1.22 (d, 3H, J = 7 Hz), 1.50 (s, 3H), 1.57 (d, 3H, J = 8 Hz), 1.86 (s, 3H) , 2.01 (s, 3H), 2.04 (s, 3H), 2.05 to 2.55 (m, 5H), 4.10 to 4.43 (m, 2H), 4.65 (d, 1H, J = 11 Hz), 4.90 to 5.80 (m, 7H), 6.20 (d, 1H, J = 15 Hz), 7.00-7.80 (m, 4H), 8,01 (d, 1H, J = 10 Hz), 11.05 (br. S, 1H).

IR (KBr): 1730, 1715, 1660, 1240 cm ^-1 .

Example 98

Preparation of 3- [2- (D)-(benzothiazol-2-yl) thio-propionamido] -rancon:

61.8 mg of 3- (2- (L) -iodopropionamido) -rancon 8, 14-tetrimethylsilylether was dissolved in 1 ml of ditrahydrofuran. 25.1 mg of 2-mercaptobenzothiazole sodium was added to the solution, the mixture was stirred for 30 minutes, 0.3 ml of 1N hydrochloric acid was added, stirred for 10 minutes, and then extracted with ethyl acetate. The extract was washed sequentially with water, aqueous sodium hydrogen carbonate solution and aqueous NaCl solution and dried over Na 2 SO 4. The solvent was distilled off and the residue was subjected to silica gel column chromatography [eluent: ethyl acetate]. The desired fractions were combined and concentrated to give 52.0 mg of the title compound.

NMR (90MHz, CDCl3) δ: 1.30 (s, 3H), 1.45 (s, 3H), 1.60 (d, 3H, J = 7Hz), 1.80 (s, 3H), 2.00 ~ 2.60 (m, 5H), 3.80 ~ 4.50 (m, 4H), 4.65 (q, 1H, J = 7 Hz), 5.05-5.85 (m, 5H), 6.06 (d, 1H, J = 16 Hz), 7.15-8.15 (m, 5H).

IR (KBr): 3400 (br.), 1750, 1710, 1670 cm ^-1 .

Example 99

Preparation of 3- [2- (D)-(benzothiazol-2-yl) thio-propionamido] -lancon 8, 14-bis (dimethyl-t-butylsilylether):

114.4 mg of the title compound by reaction similar to Example 92 using 120 mg of 3- (2- (L) -iodopropionamido) -rancon 8, 14-bis (dimethyl-t-butylsilylether) Obtained.

NMR (90 MHz, CDCl 3) δ: 0.00 (s, 12H), 0.80 (s, 9H), 1.13 (d, 3H, J = 7Hz), 1.26 (s, 3H), 1.43 (s, 3H), 1.59 (d , 3H, J = 7Hz), 1.79 (s, 3H), 1.95 ~ 2.60 (m, 5H), 3.70 ~ 4.80 (m, 5H), 5.00 ~ 5.80 (m, 5H), 5.90 (d, 1H, J = 15 Hz), 7.15 to 8.10 (m, 5H).

IR (KBr): 1755, 1710, 1680, 1060 cm ^-1 .

[α] D ²⁴ -91.7 ° (c = 0.605, CHCl3)

Example 100

3- [2- (L)-(benzothiazol-2-yl) thio-propionamido] -lancon 8, 14-bis (dimethyl-t-butylsilylether) and 3- [2- (D)- Preparation of (benzothiazol-2-yl) thiopropionamido] -lancon 8, 14-bis (dimethyl-t-butylsilyl ether):

114.3 mg of the title compound by reaction similar to Example 92 using 120 mg of 3- (2- (D) -iodopropionamido) -rancon 8, 14-bis (dimethyl-t-butylsilylether) (2 '-(L) compound) and 12.2 mg of the title compound (2'-(D) compound (the product is consistent with TLC, IR and NMR data with the product obtained in Example 99).

2 '-(L) compound, melting | fusing point 192-194 degreeC (CHCl3-petroleum ether):

NMR (90 MHz, CDCl 3) δ: -0.06 (s, 3H), 0.00 (s, 9H), 0.78 (s, 9H), 0.86 (s, 9H), 1.01 (d, 3H, J = 7 Hz), 1.07 ( s, 3H), 1.45 (s, 3H), 1.58 (d, 3H, J = 7 Hz), 1.83 (s, 3H), 1.95-2.60 (m, 5H), 3.80-4.80 (m, 5H), 5.00- 5.80 (m, 5H), 5.93 (d, 1H, J = 15 Hz), 7.09-8.15 (m, 5H).

IR (KBr): 1745, 1715, 1685, 1070 cm ^-1 .

[α] D ²⁴ -183.8 ° (c = 0.474, CHCl3)

Example 101

3- [2- (L) -benzoxazol-2-yl) thio-propionamido] -lancon 8, 14-bis (dimethyl-t-butylsilylether) and 3- (2- (D)-(benzone Preparation of Sazol-2-yl) thio-propionamido] -lancon 8, 14-bis (dimethyl-t-butylsilylether):

22.7 mg of the title compound by reaction similar to Example 94 using 120 mg of 3- (2- (L) -iodopropionamido) -rancon 8, 14-bis (dimethyl-t-butylsilylether) (2 '-(L) compound) and 98.7 mg of the title compound (2'-(D) compound) were obtained.

2 '-(L) compound, melting | fusing point 198-199 degreeC (CHCl3-petroleum ether):

NMR (90 MHz, CDCl 3) δ: -0.04 (s, 3H), 0.00 (s, 9H), 0.79 (s, 9H), 0.83 (s, 9H), 1.06 (d, 3H, J = 7 Hz), 1.13 ( s, 3H), 1.48 (s, 3H), 1.62 (d, 3H, J = 7 Hz), 1.84 (s, 3H), 1.95-2.60 (m, 5H), 3.80-4.70 (m, 5H), 5.05- 5.80 (m, 5H), 5.92 (d, 1H, J = 15 Hz), 7.10-7.70 (m, 4H), 7.90 (d, 1H, J = 10 Hz).

IR (KBr): 1755, 1710, 1680, 1060 cm ^-1 .

[β] D ²⁵ -175.7 ° (c = 0.56, CHCl3)

2 '-(D) -compound, melting point 192 ~ 192 ° C (CHCl3-petroleum ether):

NMR (90 MHz, CDCl 3) δ: 0.00 (s, 3H), 0.01 (s, 6H), 0.02 (s, 3H), 0.83 (s, 9H), 0.85 (s, 9H), 1.16 (d, 3H, J = 7 Hz), 1.33 (s, 3H), 1.46 (s, 3H), 1.67 (d, 3H, J = 7 Hz), 1.84 (s, 3H), 2.00-2.60 (m, 5H), 3.75-4.65 (m , 5H), 5.00-0.80 (m, 5H), 5.96 (d, 1H, J = 16 Hz), 7.10-7.80 (m, 4H), 8.10 (d, 1H, J = 10 Hz).

IR (KBr): 1755, 1705, 1660, 1065 cm ^-1 .

[α] D ²⁴ + 57.2 ° (c = 0.465, CHCl3)

Example 102

3- [2- (L)-(benzoxazol-2-yl) thio-propionamido] -lancon 8, 14-bis (dimethyl-t-butylsilylether) and 3- [2- (D)-( Preparation of benzoxazol-2-yl) -thio-propionamido] -lancon 8, 14-bis (dimethyl-t-butylsilyl ether):

101.4 mg of the title compound by reaction similar to Example 94 using 120 mg of 3- (2- (D) -iodopropionamido) -rancon 8, 14-bis (dimethyl-t-butylsilylether) (2 '-(L) compound) and 20.9 mg of the title compound (2'-(D) compound) were obtained. These products are identical in TLC, IR and NMR data with the compounds obtained in Example 101.

Example 103

Preparation of 3- [2- (D)-(benzoimidazol-2-yl) thio-propionamido] -lancon 8, 14-bis (dimethyl-t-butylsilylether).

Example 94 using 33.8 mg 2-mercaptobenzoimidazole and 120 mg 3- (2- (L) -iodopropionamido) -lancon 8, 14-bis (dimethyl-t-butylsilylether) The reaction was carried out similarly to yield 86.5 mg of the title compound.

Melting Point 175 ~ 176 ℃ (AcOEt)

NMR (90MHz, CDCl3) δ: 0.00 (s, 9H), 0.03 (s, 3H), 0.83 (s, 18H), 1.18 (d, 3H, J = 6Hz), 1.33 (s, 3H), 1.46 (s , 3H), 1.56 (d, 3H, J = 7 Hz), 1.81 (s, 3H), 2.00-2.65 (m, 5H), 3.75-4.60 (m, 5H), 5.00-5.80 (m, 5H), 5.90 (d, 1H, J = 15 Hz), 7.05-7.25 (m, 2H), 7.36-77.6 (m, 2H), 8.03 (d, 1H, J = 9 Hz), 8.15 (br. s, 1H).

IR (KBr): 1750, 1710, 1660, 1065 cm ^-1 .

[α] D ²⁵ -45.4 ° (c = 0.485, CHCl3)

Example 104

Preparation of 3- [2- (L)-(benzoimidazol-2-yl) thio-propionamido] -lancon 8, 14-bis (dimethyl-t-butylsilylether).

Example 94 using 33.8 mg 2-mercaptobenzoimidazole and 120 mg 3- (2- (D) -iodopropionamido) -lancon 8, 14-bis (dimethyl-t-butylsilylether) The reaction was carried out similarly to yield 69.2 mg of the title compound.

Melting Point 200 ° C (Decomposition) (AcOEt)

NMR (90 MHz, CDCl 3) δ: 0.00 (s, 12H), 0.79 (s, 9H), 0.82 (s, 9H), 1.01 (s, 3H), 1.09 (d, 3H, J = 7Hz), 1.46 (s , 3H), 1.54 (d, 3H, J = 7 Hz), 1.83 (s, 3H), 1.90-2.70 (m, 5H), 3.80-4.75 (m, 5H), 4.95-5.75 (m, 5H), 5.90 (d, 1H, J = 15 Hz), 6.96-7.75 (m, 2H), 7.33-77.6 (m, 2H), 7.96 (d, 1H, J = 10 Hz), 8.16 (br. s, 1H).

IR (KBr): 1745, 1715, 1660, 1065 cm ^-1 .

[α] D ²⁵ -189.5 ° (c = 0.465, CHCl3)

Example 105

Preparation of 3- [2- (D)-(2-pyridylthio) propionamido] -lancon 8, 14-bis (dimethyl-t-butylsilylether):

Example 94 and 25.5 mg 2-mercaptopyridine and 120.5 mg 3- (2- (L) -iodopropionamido) -rancon 8, 14-bis (dimethyl-t-butylsilylether) Similar reactions yielded 46.4 mg of the title compound.

Melting point 190-191 ° C. (CHCl 3 -petroleum ether).

NMR (90 MHz, CDCl 3) δ: 0.00 (s, 3H), 0.03 (s, 9H), 0.77 (s, 9H), 0.80 (s, 9H), 1.13 (d, 3H, J = 6Hz), 1.18 (s , 3H), 1.44 (s, 3H), 1.50 (d, 3H, J = 7Hz), 1.77 (s, 3H), 1.90 ~ 2.55 (m, 5H), 3.75 ~ 4.65 (m, 5H), 5.00 ~ 5.80 (m, 5H), 5.90 (d, 1H, J = 15 Hz), 6.84-7.63 (m, 3H), 8.13 (d, 1H, J = 10 Hz), 8.43-8.55 (m, 1H).

IR (KBr): 1755, 1720, 1675, 1065 cm ^-1 .

[α] D ²⁴ + 15.5 ° (c = 0.54, CHCl3)

Example 106

Preparation of 3- [2- (L)-(2-pyridylthio) propionamido] -lancon 8, 14-bis (dimethyl-t-butylsilylether):

Example 94 and 25.6 mg 2-mercaptopyridine and 120.1 mg 3- (2- (D) -iodopropionamido) -rancon 8, 14-bis (dimethyl-t-butylsilylether) Similarly, 99.1 mg of the title compound was obtained by carrying out the reaction.

Melting point 221-222 ° C (ACOET-hexane).

NMR (90 MHz, CDCl 3) δ: -0.02 (s, 3H), 0.02 (s, 9H), 0.82 (s, 9H), 0.86 (s, 9H), 1.10 (d, 3H, J = 6 Hz), 1.12 ( s, 3H), 1.49 (s, 3H), 1.55 (d, 3H, J = 7Hz), 1.85 (s, 3H), 2.00 ~ 2.60 (m, 5H), 3.85 ~ 4.64 (m, 5H), 5.05 ~ 5.80 (m, 5H), 5.92 (d, 1H, J = 15 Hz), 6.85-7.60 (m, 3H), 8.02 (d, 1H, J = 10 Hz), 8.43-8.56 (m, 1H).

IR (KBr): 1745, 1715, 1680, 1065 cm ^-1 .

[α] D ²⁵ -163.2 ° (c = 0.53, CHCl3)

Example 107

Preparation of 3- [2- (D)-(benzothiazol-2-yl) thio-1-thioxo] propylamino-lancon 8, 14-bis (dimethyl-t-butylsilylether):

662.4 mg of 3- [2- (D)-(benzothiazol-2-yl) thio-propionamido] -rancon 8, 14-bis (dimethyl-t-butylsilylether) was dissolved in 4 ml of pyridine. . 0.4 g of phosphorus pentasulfide was added to the solution, and the mixture was stirred at 90 ° C. for 6 hours. Pyridine was distilled off and the residue was subjected to silica gel column chromatography [eluent: ethyl acetate-hexane (1: 5)]. The desired fractions were combined and concentrated and the concentrates were permanent TLC plate [Merck, Art. No. 5715 20 × 20 cm, developing solvent: ethyl acetate-hexane (1: 5)] afforded 42.5 g of the title compound.

NMR (90 MHz, CDCl 3) δ: 0.00 (s, 3H), 0.03 (s, 9H), 0.83 (s, 9H), 0.88 (s, 9H), 1.15 (d, 3H, J = 7 Hz), 1.19 (s , 3H), 1.31 (d, 3H, J = 7 Hz), 1.50 (s, 3H), 1.94 (s, 3H), 2.00 to 2.50 (m, 5H), 3.80 to 4.70 (m, 5H), 4.95 to 6.40 (m, 6H), 7.15-8.00 (m, 4H), 9.66 (d, 1H, J = 9 Hz).

IR (KBr): 1760, 1715, 1260, 1065 cm ^-1 .

Example 108

Preparation of 3- (2- (D) -azidopropionamido) -lancon 8, 14-bis (dimethyl-t-butylsilyl ether):

1.0 g of 3- (2- (L) -iodopropionamido) -rancon 8, 14-bis (dimethyl-t-butylsilylether) was dissolved in 15 ml of N, N-dimethylformamide. 122 mg of sodium azide was added to the solution. The mixture was stirred at 0 ° C. for 1 hour and at room temperature for 30 minutes and poured into ice water. The resulting precipitate was collected by filtration and dissolved in ethyl acetate. The organic layer was separated from the aqueous layer and dried over Na 2 SO 4. The ethyl acetate solution was concentrated and chloroform and petroleum ether were added to the concentrate to give 603.3 mg of the title compound. The filtrate was concentrated and silica gel column chromatography [eluent: ethyl acetate-hexane (1: 3)] further gave 167.4 mg of the title compound.

Melting Point: 197 ~ 198 ℃ (CHCl3-Petroleum Ether)

NMR (90 MHz, CDCl 3) δ: 0.00 (s, 3H), 0.03 (s, 9H), 0.85 (s, 9H), 0.86 (s, 9H), 1.22 (d, 2H, J = 7Hz), 1.38 (s , 3H), 1.46 (d, 3H, J = 7 Hz), 1.53 (s, 3H), 1.73 (s, 3H), 1.95 to 2.55 (m, 5H), 3.75 to 4.65 (m, 5H), 5.00 to 5.75 (m, 5H), 5.90 (d, 1H, J = 15 Hz), 7.40 (d, 1H, J = 10 Hz).

IR (KBr): 2140, 1750, 1710, 1680, 1060 cm ^-1 .

[α] D ²⁵ -128.4 ° (c = 0.54, CHCl3)

Example 109

Preparation of 3- (2- (L) -azidopropionamido) -lancon 8, 14-bis (dimethyl-t-butylsilylether):

400.4 mg of 3- (2- (D) -iodopropionamido) -rancon 8, 14-bis (dimethyl-t-butylsilylether) was used to carry out the reaction similar to Example 108 (by reprecipitation). No purification) 300.3 mg of the title compound were obtained.

NMR (90 MHz, CDCl 3) δ: 0.00 (s, 3H), 0.03 (s, 6H), 0.05 (s, 3H), 0.73 (s, 9H), 0.75 (s, 9H), 1.12 (d, 3H, J = 7 Hz), 1.25 (s, 3H), 1.39 (s, 3H), 1.43 (d, 3H, J = 7 Hz), 1.75 (s, 3H), 2.00-2.55 (m, 5H), 3.80-4.64 (m , 5H), 5.00-0.80 (m, 5H), 5.90 (d, 1H, J = 15 Hz), 7.45 (d, 1H, J = 10 Hz).

IR (KBr): 2110, 1755, 1715, 1680, 1065 cm ^-1 .

[α] D ²⁵ -88.3 ° (c = 0.48, CHCl3)

Example 110

Preparation of 3- (2- (D) -aminopropionamido) -lancon 8, 14-bis (dimethyl-t-butylsilylether):

To 71.9 mg 3- (2- (D) -azidopropionamido) -rancon 8, 14-bis (dimethyl-t-butylsilylether) was added 0.5 ml of methanol and 0.5 ml dichloromethane.

20.1 μl of 1, 3-propanedithiol and 27.9 μl triethylamine were added to the mixture. The whole mixture was stirred at rt overnight. The solvent was distilled off and the residue was permanent TLC plate [Merck, Art, No. 5715 20 × 20 cm, developing solvent: acetone-benzene (1: 1)] to give 30.5 mg of the title compound.

Melting point 165-166 캜 (AcOEt-petroleum ether).

IR (KBr): 1710, 1250, 1060, 834 cm ^-1 .

Example 111

Preparation of 3- (2- (D) -aminopropionamido) -lancon 8, 14-bis (dimethyl-t-butylsilylether):

71.5 mg of 3- (2- (D) -azidopropionamido) -rancon 8, 14-bis (dimethyl-t-butylsilylether) was dissolved in 2 ml of benzene. 35.1 mg of Lindler catalyst was added to the solution, and the mixture was stirred at room temperature under a hydrogen atmosphere for 19 hours, followed by 5 times of 35 mg of Lindler catalyst. The catalyst was filtered off and the filtrate was subjected to silica gel column chromatography [eluent: acetone-benzene (2: 3)]. The desired fractions were combined and concentrated to give 71.3 mg of the title compound. This product is consistent with the data obtained in Example 110 in the data of TLC, IR and NMR.

Example 112

Preparation of 3- (2- (L) -aminopropionamido) -lancon 8, 14-bis- (dimethyl-t-butylsilylether):

28.8 mg of title by carrying out a reaction similar to Example 111 using 71.7 mg of 3- (2- (L) -azidopropionamido) -ralcon 8, 14-bis (dimethyl-t-butylsilylether) The compound was obtained.

IR (KBr): 1716, 1256, 1068, 840 cm ^-1 .

Example 113

Preparation of 3- (2- (D) -acetylaminopropionamido) -lancon 8, 14-bis (dimethyl-t-butylsilylether):

65.4 mg of 3- (2- (D) -aminopropionamido) -rancon 8, 14-bis (dimethyl-t-butylsilylether) was dissolved in 1 ml of pyridine. 0.5 ml of acetic anhydride was added to the solution while cooling with ice water and stirred for 22 minutes at the same temperature. The solvent was distilled off and the residue was washed with a permanent TLC plate [Merck, Art, No. 5715. 20 × 20 cm, developing solvent: acetone-benzene (1: 3)] to give 63.5 mg of the title compound.

Melting point: 207-209 ° C. (HCCl 3 -petroleum ether).

NMR (90 MHz, CDCl 3) δ: 0.00 (s, 3H), 0.01 (s, 9H), 0.90 (s, 9H), 0.92 (s, 9H), 1.28 (d, 3H, J = 6Hz), 1.42 (s , 3H), 1.47 (d, 3H, J = 7 Hz), 1.59 (s, 3H), 1.91 (s, 3H), 2.04 (s, 3H), 2.05-2.70 (m, 5H), 3.95-4.75 (m , 5H), 5.10-5.90 (m, 5H), 6.00 (d, 1H, J = 15 Hz), 6.43 (d, 1H, J = 6 Hz), 7.09 (d, 1H, J = 10 Hz).

IR (KBr): 3430, 1745, 1710, 1680, 1660, 1060 cm ^-1 .

[α] D ²⁴ -112.8 ° (c = 0.485, CHCl3)

Example 114

Preparation of 3- (2- (L) -acetylaminopropionamido) -lancon 8, 14-bis (dimethyl-t-butylsilylether):

27.1 mg of the title compound by reaction similar to Example 113 using 28.6 mg of 3- (2- (L) -aminopropionamido) -rancon 8, 14-bis (dimethyl-t-butylsilylether) Obtained.

NMR (90 MHz, CDCl 3) δ: 0.00 (s, 3H), 0.03 (s, 3H), 0.83 (s, 9H), 0.85 (s, 9H), 1.20 (d, 3H, J = 6 Hz), 1.31 (d , 3H, J = 7Hz), 1.36 (s, 3H), 1.51 (s, 3H), 1.85 (s, 3H), 2.00 (s, 3H), 2.05 ~ 2.63 (m, 5H), 3.85 ~ 4.70 (m , 5H), 5.10 to 5.83 (m, 5H), 6.00 (d, 1H, 15 Hz), 6.31 (d, 1H, J = 7 Hz), 7.10 (d, 1H, J = 10 Hz).

IR (KBr): 3450, 1755, 1715, 1680, 1660, 1065 cm ^-1 .

Example 115

Preparation of 3- (2- (L) -azidopropionamido) -lancon 8, 14-diacetate:

745.7 mg of the title compound were obtained by reaction similar to Example 108 using 983.7 mg of 3- (2- (D) -iodopropionamido) rancon 8, 14-diacetate.

NMR (90 MHz, CDCl 3) δ: 1.30 (s, 3H, J = 7 Hz), 1.38 (s, 3H), 1.53 (d, 3H, J = 7 Hz), 1.54 (s, 3H), 1.87 (s, 3H) , 2.01 (s, 3H), 2.04 (s, 3H), 2.20-2.60 (m, 5H), 4.11 (q, 1H, J = 7 Hz), 4.40 (dt, 1H, J = 12 Hz & 3 Hz), 4.68 ( d, 1H, J = 11 Hz, 4.93-5.85 (m, 7H), 6.27 (d, 1H, J = 15 Hz), 7.50 (d, 1H, J = 10 Hz).

IR (KBr): 2120, 1740, 1715, 1685, 1240 cm ^-1 .

[α] D ²⁵ -161.8 ° (c = 1.05, HCl 3)

Example 116

Preparation of 3- (2- (D) -azidopropionamido) rancon 8, 14-diacetate:

The reaction was carried out in the same manner as in Example 108 using 1.311 g of 3- (2- (L) -iodopropionamido) -rancon 8, 14-diacetate to afford 1.0205 g of the title compound.

Melting point: 193 ° C. (acOEt-Et 2 O).

NMR (90 MHz, CDCl 3) δ: 1.31 (d, 3H, J = 7 Hz), 1.38 (s, 3H), 1.46 (d, 3H, J = 7 Hz), 1.54 (s, 3H), 1.87 (s, 3H) , 2.02 (s, 3H), 2.04 (s, 3H), 2.20-2.60 (m, 5H), 4.09 (q, 1H, J = 7Hz), 4.40 (dt, 1H, J = 12Hz & 3Hz), 4.67 ( d, 1H, J = 11 Hz, 4.93-8.84 (m, 7H), 6.28 (d, 1H, J = 15 Hz), 7.50 (d, 1H, J = 10 Hz).

IR (KBr): 2120, 1735, 1715, 1685, 1240 cm ^-1 .

[α] D ²⁵ -180.0 ° (c = 0.55, CHCl3)

Example 117

Preparation of 3- (2- (D) -aminopropionamido) -lancon 8, 14-diacetate:

465.2 mg of the title compound were obtained by reaction similar to Example 111 using 540.4 mg of 3- (2- (D) -azidopropionamido) -rancon 8, 14-diacetate.

Melting point: 162-163 ° C. (AcOEt-Et 2 O).

NMR (90 MHz, CDCl 3) δ: 1.25 (d, 3H, J = 7 Hz), 1.27 (d, 3H, J = 7 Hz), 1.35 (s, 3H), 1.52 (s, 3H), 1.56 (s, 2H) , 1.86 (s, 3H), 1.98 (s, 3H), 2.00 (s, 3H), 2.15 to 2.55 (m, 5H), 3.45 (q, 1H, J = 7 Hz), 4.33 (dt, 1H, J = 12 Hz & 3 Hz), 4.70 (d, 1H, J = 11 Hz), 4.92-5.83 (m, 7H), 6.26 (d, 1H, J = 15 Hz), 8.06 (d, 1H, J = 10 Hz).

IR (KBr): 1735, 1720, 1670, 1240 cm ^-1 .

[α] D ²⁵ -238.3 ° (c = 0.46, CHCl3)

Example 118

Preparation of 3- (2- (L) -aminopropionamido) -lancon 8, 14-diacetate:

333.1 mg of the title compound were obtained by carrying out a reaction similar to Example 111 using 525.6 mg of 3- (2- (L) -azidopropionamido) -rancon 8, 14-diacetate.

Melting point: 149-150 ° C. (AcOEt).

NMR (90 MHz, CDCl 3) δ: 1.30 (d, 3H, J = 7 Hz), 1.33 (d, 3H, J = 7 Hz), 1.38 (s, 3H), 1.55 (s, 3H), 1.64 (s, 2H) , 2.01 (s, 3H), 2.03 (s, 3H), 2.20 to 2.55 (m, 5H), 3.46 (q, 1H, J = 7 Hz), 4.39 (dt, 1H, J = 12 Hz & 3 Hz), 4, 72 (d, 1H, J = 11 Hz), 4.93-5.85 (m, 7H), 6.27 (d, 1H, J = 15 Hz), 8.15 (d, 1H, J = 10 Hz).

IR (KBr): 1735, 1715, 1670, 1250 cm ^-1 .

[α] D ²⁵ -231.1 ° (c = 0.505, CHCl3)

Example 119

Preparation of 3- (2- (D) -acetylaminopropionamido) -lancon 8, 14-diacetate:

The reaction was carried out in the same manner as in Example 113 using 97.5 mg of 3- (2- (D) -aminopropionamido) -rancon 8, 14-diacetate to give 101.1 mg of the title compound.

Melting Point: 173 ~ 174 ℃ (AcOEt-Et2O)

NMR (90 MHz, CDCl 3) δ: 1.28 (d, 3H, J = 7 Hz), 1.37 (d, 3H, J = 7 Hz), 1.37 (s, 3H), 1.54 (s, 3H), 1.82 (s, 3H) , 2.02 (s, 6H), 2.04 (s, 3H), 2.20-2.60 (m, 5H)), 4.26-4.75 (m, 3H), 4.90-5.85 (m, 7H), 6.23 (d, 1H, J) = 7 Hz), 6.26 (d, 1H, J = 15 Hz). 7.10 (d, 1 H, J = 10 Hz).

IR (KBr): 1735, 1715, 1660, 1245 cm ^-1 .

[α] D ²⁵ -167.0 ° (c = 0.525, CHCl3)

Example 120

Preparation of 3- (2-L) -acetylaminopropionamido) -lancon 8, 14-diacetate:

122.8 mg of the title compound were obtained by reaction similar to Example 113 using 109.3 mg of 3- (2- (L) -aminopropionamido) -lancon 8, 14-diacetate.

NMR (90 MHz, CDCl 3) δ: 1.28 (d, 6H, J = 7 Hz), 1.38 (s, 3H), 1.53 (s, 3H), 1.84 (s, 3H), 1.98 (s, 3H), 2.00 (s , 3H), 2.03 (s, 3H), 2.15 ~ 2.60 (m, 5H), 4.25 ~ 4.70 (m, 3H), 4.91 ~ 5.85 (m, 7H), 6.26 (d, 1H, J = 15Hz), 6.74 (d, 1H, J = 7 Hz), 7.13 (d, 1H, J = 10 Hz).

IR (KBr): 1740, 1715, 1665, 1240 cm ^-1 .

[α] D ²⁴ -207.0 ° (c = 0.56, CHCl3)

Example 121

Preparation of 3- (2- (D) -propionylaminopropionamido) -lancon 8, 14-diacetate:

115.2 mg of the title compound were obtained by reaction similar to Example 113 using 109.1 mg of 3- (2- (D) -aminopropionamido) -lancon 8, 14-diacetate and propionic anhydride.

Melting Point: 188 ~ 189 ° C (AcOEt).

NMR (90 MHz, CDCl 3) δ: 1.15 (t, 3H, J = 7 Hz), 1.28 (d, 3H, J = 7 Hz), 1.37 (d, 3H, J = 7 Hz), 1.37 (s, 3H), 1.53 ( s, 3H), 1.86 (s, 3H), 2.01 (s, 3H), 2.03 (s, 3H), 2.13-2.55 (m, 7H), 4.27-4.75 (m, 3H), 4.91-5.85 (m, 7H), 6.14 (d, 1H, J = 8 Hz), 6.23 (d, 1H, J = 15 Hz), 7.12 (d, 1H, J = 10 Hz).

IR (KBr): 1740, 1715, 1665, 1245 cm ^-1 .

[α] D ²⁵ -154.1 ° (c = 0.56, CHCl3)

Example 122

Preparation of 3- (2- (L) -propionylaminopropionamido) -lancon 8, 14-diacetate:

122.3 mg of the title compound were obtained by reaction similar to Example 113 using 108.9 mg of 3- (2- (L) -aminopropionamido) -lancon 8, 14-diacetate and propionic anhydride.

NMR (90 MHz, CDCl 3) δ: 1.13 (t, 3H, J = 7 Hz), 1.28 (d, 6H, J = 7 Hz), 1.38 (s, 3H), 1.53 (s, 3H), 1.85 (s, 3H) , 2.00 (s, 3H), 2.03 (s, 3H), 2.10 ~ 2.60 (m, 7H), 4.30 ~ 4.80 (m, 3H), 4.93 ~ 5.85 (m, 7H), 6.27 (d, 1H, J = 15 Hz), 6.52 (d, 1H, J = 8 Hz), 7.15 (d, 1H, J = 10 Hz).

IR (KBr): 1740, 1720, 1670, 1245 cm ^-1 .

[α] D ²⁵ -209.2 ° (c = 0.545, CHCl3)

Example 123

Preparation of 3- (2- (D) -n-butyrylaminopropionamido) -lancon 8, 14-diacetate:

119.7 mg of the title compound were obtained by reaction similar to Example 113 using 109.1 mg of 3- (2- (D) -aminopropionamido) -lancon 8, 14-diacetate and n-butyric anhydride. .

Melting Point: 188 ~ 189 ° C (AcOEt).

NMR (90MHz, CDCl3) δ: 0.92 (t, 3H, J = 7Hz), 1.27 (d, 3H, J = 7Hz), 1.34 (d, 3H, J = 7Hz), 1.37 (s, 3H), 1.50 ~ 1.85 (m, 2H), 1.53 (s, 3H), 1.86 (s, 3H), 2.01 (s, 3H), 2.03-2.55 (m, 7H), 2.04 (s, 3H), 4.25-4.75 (m, 3H), 4.90-5.50 (m, 7H), 6.06 (d, 1H, J = 7 Hz), 6.25 (d, 1H, J = 15 Hz), 7.10 (d, 1H, J = 10 Hz).

IR (KBr): 1740, 1715, 1665, 1245 cm ^-1 .

[α] D ²⁵ -155.7 ° (c = 0.535, CHCl3)

Example 124

Preparation of 3- (2- (L) -n-butyrylaminopropionamido) -lancon 8, 14-diacetate:

128.1 mg of the title compound were obtained by reaction similar to Example 113 using 109.4 mg of 3- (2- (L) -aminopropionamido) -lancon 8, 14-diacetate and n-butyric anhydride. .

NMR (90 MHz, CDCl 3) δ: 0.91 (t, 3H, J = 7 Hz), 1.29 (α, 6H, J = 7 Hz), 1.38 (s, 3H), 1.50 to 1.90 (m, 2H), 1.54 (s, 3H), 1.86 (s, 3H), 2.00-2.55 (m, 7H), 2.01 (s, 3H), 2.03 (s, 3H), 4.27-4.74 (m, 3H), 4.91-5.85 (m, 7H) , 6.23 (d, 1H, J = 8 Hz), 6.25 (d, 1H, J = 15 Hz), 7.05 (d, 1H, J = 10 Hz).

IR (KBr): 1740, 1715, 1665, 1240 cm ^-1 .

[α] D ²⁵ -192.2 ° (c = 0.475, HCl 3)

Example 125

Preparation of 3- (2- (D) -benzyloxycarbonylaminopropionamido) -lancon 8, 14-diacetate:

109.3 mg of 3- (2- (D) -aminopropionamido) -rancon 8, 4-diacetate was dissolved in 2 ml of benzene. 31.2 μl of carbobenzoxyl chloride and 22 μl of 10N-sodium hydroxide aqueous solution were added dropwise to the solution while stirring under ice cooling with ice water. The mixture was stirred at rt for 5 min and extracted with ethyl acetate. The extract was washed with aqueous NaCl solution and dried over Na 2 SO 4. The solvent was distilled off and the residue was subjected to silica gel column chromatography [eluent: ethyl acetate]. The desired fractions were combined and concentrated to give 114.4 mg of the title compound.

Melting point: 185 ~ 186 ° C. (AcOEt).

NMR (90 MHz, CDCl 3) δ: 1.26 (d, 3H, J = 7 Hz), 1.33 (s, 3H), 1.36 (d, 3H, J = 7 Hz), 1.52 (s, 3H), 1.84 (s, 3H) , 2.00 (s, 3H), 2.02 (s, 3H), 2.13 ~ 2.55 (m, 5H), 4.16 (q, 1H, J = 7Hz), 4.20 ~ 4.50 (m, 1H), 4.63 (d, 1H, J = 11 Hz), 4.90-5.85 (m, 9H), 6.23 (d, 1H, J = 15 Hz), 7.16 (d, 1H, J = 10 Hz), 7.31 (s, 5H).

IR (KBr): 735, 1715, 1250 cm ^-1 .

[α] D ²⁵ -151.1 ° (c = 0.47, CHCl3)

Example 126

Preparation of 3- (2- (L) -benzyloxycarbonylaminopropionamido) -lancon 8, 14-diacetate:

133.8 mg of the title by reaction in 109.1 mg of 3- (2- (L) -aminopropionamido) -lancon 8, 14-diacetate and in the same manner as in Example 125 using dichloromethane as solvent The compound was obtained.

NMR (90 MHz, CDCl 3) δ: 1.26 (d, 3H, J = 7 Hz), 1.32 (d, 3H, J = 7 Hz), 1.34 (s, 3H), 1.53 (s, 3H), 1.84 (s, 3H) , 2.01 (s, 3H), 2.03 (s, 3H), 2.15 to 2.50 (m, 5H), 4.15 (q, 1H, J = 7 Hz), 4.25 to 4.50 (m, 1H), 4.65 (d, 1H, J = 11 Hz), 4.90-5.80 (m, 9H), 6.26 (d, 1H, J = 15 Hz), 7.11 (d, 1H, J = 10 Hz), 7.30 (s, 5H).

IR (KBr): 1735, 1720, 1245 cm ^-1 .

[α] D ²⁵ -175.2 ° (c = 0.52, CHCl3)

Example 127

Preparation of 3- (2- (D) -p-toluenesulfonylaminopropionamido) -lancon 8, 14-diacetate:

Dissolve 109.2 mg of 3- (2- (D) -aminopropionamido) -rancon 8, 14-diacetate in 1 ml of pyridine. 46.6 mg of p-toluenesulfonyl chloride was added to the solution and the mixture was stirred for 30 minutes. Pyridine was distilled off. Ethyl acetate was added to the residue, washed successively with water, 1N hydrochloric acid and aqueous NaCl solution and dried over Na 2 SO 4. The solvent was distilled off and the residue was subjected to silica gel column chromatography [eluent: ethyl acetate-hexane (2: 1)]. The desired fractions were combined and concentrated to give 89.4 mg of the title compound.

Melting point: 193 ~ 194 ° C (AcOEt).

NMR (90 MHz, CDCl 3) δ: 1.25 (d, 3H, J = 7 Hz), 1.27 (d, 3H, J = 7 Hz), 1.36 (s, 3H), 1.79 (s, 3H), 2.00 (s, 3H) , 2.03 (s, 3H), 2.15 to 2.55 (m, 5H), 2.35 (s, 3H), 3.75 (folder, 1H, J = 7Hz), 4.26 to 4.70 (m, 2H), 4.90 to 5.85 (m , 7H), 6.25 (d, 1H, J = 15 Hz), 7.20 (d, 2H, J = 8 Hz), 7.40 (d, 1H, J = 10 Hz), 7.68 (d, 2H, J = 8 Hz).

IR (KBr): 1730, 1715, 1240 cm ^-1 .

[α] D ²⁵ -138.3 ° (c = 0.475, CHCl3)

Example 128

Preparation of 3- (2- (L) -p-toluenesulfonylaminopropionamido) -lancon 8, 14-diacetate:

94.2 mg of the title compound were obtained by reaction similar to Example 127 using 109.4 mg of 3- (2- (L) -aminopropionamido) -rancon 8, 14-diacetate.

Melting point: 174-175 ° C. (AcOEt).

NMR (90 MHz, CDCl 3) δ: 1.21 (s, 3H), 1.25 (d, 3H, J = 7 Hz), 1.29 (d, 3H, J = 7 Hz), 1.52 (s, 3H), 1.82 (s, 3H) , 2.01 (s, 3H), 2.03 (s, 3H), 2.15 to 2.55 (m, 5H), 2.38 (s, 3H), 3.78 (folder, 1H, J = 7 Hz), 4.25 to 4.65 (m, 2H ), 4.90 to 5.85 (m, 7H), 6.24 (d, 1H, J = 15 Hz), 7.06 (d, 1H, J = 10 Hz), 7.24 (d, 2H, J = 8 Hz), 7.73 (d, 2H, J = 9 Hz).

IR (KBr): 1740, 1715, 1245 cm ^-1 .

[α] D ²⁵ -205.9 ° (c = 0.49, CHCl3)

Example 129

Preparation of 3- (2- (D) -diphenylphosphinothioylaminopropionamido) -lancon 8, 14-diacetate:

108.4 mg of 3- (2- (D) -aminopropionamido) -rancon 8, 14-diacetate were dissolved in 0.5 ml of chloroform. 83.7 μl triethylamine was added to the solution.

A solution of 102.1 mg of diphenylphosphinothioyl chloride dissolved in 0.5 ml of chloroform was added dropwise to the mixture and stirred for 1 hour. Ethyl acetate was added to the product. The mixture was washed sequentially with 1N hydrochloric acid, water, aqueous sodium hydrogen carbonate solution and aqueous NaCl solution and dried over Na 2 SO 4. The solvent was distilled off and the residue was subjected to silica gel column chromatography [eluent: ethyl acetate-hexane (1: 1)]. The desired fractions were combined and concentrated to give 96.0 mg of the title compound.

NMR (90MHz, CDCl3) δ: 1.28 (d, 3H, J = 7Hz), 1.36 (s, 3H), 1.38 (d, 3H, J = 7Hz), 1.54 (s, 3H), 1.86 (s, 3H) , 2.01 (s, 3H), 2.03 (s, 3H), 2.15 to 2.55 (m, 5H), 3.41 (dd, 1H, J = 6 Hz & 9 Hz), 3.70 to 4.20 (m, 1H), 4.30 to 4.55 ( m, 1H), 4.67 (d, 1H, J = 8 Hz), 4.90 to 5.85 (m, 7 Hz), 6.27 (d, 1H, J = 5 Hz), 7.20 to 7.60 (m, 7H), 7.70 to 8.15 (m , 4H).

IR (KBr): 1735, 1715, 1680, 1240 cm ^-1 .

[α] D ²⁶ -131.4 ° (c = 0.455, CHCl3)

Example 130

Preparation of 3- (2- (L) -diphenylphosphinothioylaminopropionamido) -lancon 8, 14-diacetate:

102.1 mg of the title compound were obtained by conducting a reaction similar to Example 129 using 109.2 mg of 3- (2- (L) -aminopropionamido) -rancon 8, 14-diacetate.

NMR (90 MHz, CDCl 3) δ: 1.30 (d, 3H, J = 7 Hz), 1.33 (d, 3H, J = 7 Hz), 1.38 (s, 3H), 1.53 (s, 3H), 1.85 (s, 3H) , 2.01 (s, 3H), 2.04 (s, 3H), 2.15 to 2.55 (m, 5H), 3.43 (dd, 1H, J = 5 Hz & 9 Hz), 3.65 to 4.20 (m, 1H), 4.25 to 4.50 ( m, 1H), 4.65 (d, 1H, J = 10 Hz), 4.90 to 5.85 (m, 7H), 6.25 (d, 1H, J = 15 Hz), 7.16 (d, 1H, J = 10 Hz), 7.27 to 7.56 (m, 6H), 7.70-8.15 (m, 4H).

IR (KBr): 1740, 1715, 1680, 1240 cm ^-1 .

[α] D ²⁶ -161.5 ° (c = 0.48, CHCl3)

Example 131

Preparation of 3- (2- (D) -1ethylthiopropionamido) -lancon 8, 14-diacetate:

The reaction was carried out in the same manner as in Example 94 using 164.3 mg of 3- (2- (L) -iodopropionamido) -lancon 8, 14-diacetate and ethanethiol to give 99.5 mg of the title compound.

Melting Point: 183 ~ 184 ℃ (AcOEt-Et2O)

NMR (90 MHz, CDCl 3) δ: 1.21 (t, 3H, J = 7 Hz), 1.32 (d, 3H, J = 7 Hz), 1.38 (d, 3H, J = 7 Hz), 1.39 (s, 3H), 1.56 ( s, 3H), 1.79 (s, 3H), 2.03 (s, 3H), 2.05 (s, 3H), 2.20 to 2.70 (m, 7H), 3.42 (q, 1H, J = 7 Hz), 4.42 (dt, 1H, J = 3Hz & 12Hz) M, 4.70 (br.d, 1H, J = 11Hz), 4.94 ~ 5.86 (m, 7H), 6.28 (d, 1H, J = 15Hz), 7.71 (d, 1H, J = 10 Hz).

IR (KBr): 1740, 1710, 1675, 1245 cm ^-1 .

[α] D ²² -150.0 ° (c = 0.48, CHCl3)

Example 132

Preparation of 3- (2- (L) -ethylthiopropionamido) -lancon 8, 14-diacetate:

93.1 mg of the title compound were obtained by reaction similar to Example 94 using 164.9 mg of 3- (2- (D) -iodopropionamido) -rancon 8, 14-diacetate and ethanethiol.

Melting point: 178-179 ° C. (Et 2 O).

NMR (90 MHz, CDCl 3) δ: 1.20 (t, 3H, J = 7 Hz), 1.32 (d, 3H, J = 7 Hz), 1.40 (s, 3H), 1.46 (d, 3H, J = 7 Hz), 1.54 ( s, 3H), 1.88 (s, 3H), 2.02 (s, 3H), 2.04 (s, 3H), 2.16-2.60 (m, 7H), 2.39 (dt, 1H, J = 3 Hz & 12 Hz), 3.36 ( q, 1H, J = 7 Hz, 4.70 (br. d, 1H, J = 11 Hz), 4.93 to 5.84 (m, 7H), 6.26 (d, 1H, J = 15 Hz), 7.76 (d, 1H, J = 10 Hz).

IR (KBr): 1740, 1710, 1675, 1240 cm ^-1 .

[α] D ²² -213.7 ° (c = 0.49, CHCl3)

Example 133

Preparation of 3- [3- (benzothiazol-2-yl) -thio-2-oxopropionamido] -lancon 8-acetate:

187.0 mg of 3- (3-bromo-2-oxopropionamido) -rancon 8, 14-diacetate was dissolved in 1 ml of tetrahydrofuran. To the solution was added 69.1 mg of 2-mercaptobenzothiazole sodium at 0 ° C. and the mixture was stirred at the same temperature for 15 minutes, ethyl acetate was added and washed with water and aqueous NaCl solution. The raw document was dried over Na 2 SO 4, the solvent was distilled off, and the residue was subjected to silica gel column chromatography [eluent: ethyl acetate-hexane (1: 1) and ethyl acetate-hexane (2: 1)]. The desired fractions were combined and concentrated to yield 80.1 mg of 2, 9,14-diacetate compound which was dissolved in 5 ml of tetrahydrofuran. To the solution was added 30 ml of an aqueous solution containing 10 ml of methanol and 1.4 g of enzyme obtained in Reference Example 11, and the mixture was stirred for 40 minutes. The resulting mixture was extracted with 60 ml of chloroform. The organic layer was washed with aqueous NaCl solution and dried over Na 2 SO 4. The solvent was distilled off and the residue was reversed-phase permanent TLC plate [Merck, Art. No. 15424, 10 × 20 cm, developing solvent: methanol-water (4: 1)] gave 25.1 mg of the title compound.

NMR (90 MHz, CDCl 3) δ: 1.23 (d, 3H, J = 7 Hz), 1.41 (s, 3H), 1.56 (s, 3H), 1.67 (br.s, 1H), 1.96 (s, 3H), 2.07 (s, 3H), 2.15 to 2.60 (m, 5H), 4.15 to 4.76 (m, 5H), 4.90 to 5.92 (m, 6H), 6.13 (d, 1H, J = 15 Hz), 7.20 to 7.82 (m, 4H), 8.23 (d, 1H, J = 10 Hz).

IR (KBr): 3400, 1735, 1710, 1250 cm ^-1 .

[α] D ²⁴ -112.1 ° (c = 0.14, EtOH)

Example 134

Preparation of 3- [3- (benzoxazol-2-yl) thio-2-oxopropionamido] -lancon 8, 14-diacetate:

3- (3-Bromo-2-oxopropionamido) -lancon 8, 14-diacetate was prepared from 307.4 mg of 3- (2-trimethylsilyloxyacrylamido) -lancon 8, 14-diacetate. . On the other hand, 113.7 mg of 2-mercaptobenzoxazole was dissolved in 1 ml of tetrahydrofuran. 2 ml of sodium hydride (purity 60%) was added dropwise to the solution mixture and the mixture was stirred for 5 minutes. To the product was added 2 ml of tetrahydrofuran containing the 3'-bromo compound prepared above, the mixture was stirred for 15 minutes, diluted with ethyl acetate and washed sequentially with water and brine. The resulting solution was dried over Na 2 SO 4 and the solvent was distilled off. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate-hexane (1: 1)) The desired fractions were combined and concentrated to give 168.1 mg of the title compound.

NMR (90 MHz, CDCl 3) δ: 1.37 (d, 1H, J = 7 Hz), 1.41 (s, 3H), 1.55 (s, 3H), 1.93 (s, 3H), 2.03 (s, 3H), 2.05 (s , 3H), 2.2 ~ 2.6 (m, 5H), 4.50 (m, 1H), 4.65 (s, 2H), 4.70 (d, 1H, J = 11Hz), 5.05 (m, 1H), 5.2 ~ 5.9 (m , 6H), 6.28 (d, 1H, J = 15 Hz), 7.15-7.6 (m, 4H), 8.09 (d, 1H, J = 10 Hz).

IR (KBr): 1735, 1715, 1695, 1505, 1245 cm ^-1 .

Example 135

Preparation of 3- [3- (pyridin-2-yl) -thio-2-oxopropionamido] -lancon 8-acetate:

54.0 mg of 2-mercaptopyridine was dissolved in 4 ml of tetrahydrofuran, cooled with ice water, 19.5 mg of sodium hydride (in oil, 60%) was added and stirred for 5 minutes. To the mixture was added 249.1 mg of 3- (3-bromo-2-oxopropionamido) -rancon 8, 14-diacetate, and further stirred for 10 minutes. Ethyl acetate was added, washed successively with water and aqueous NaCl solution and dried over N 2 SO 4. The solvent was distilled off and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate-hexane (1: 1)) The desired fractions were combined and concentrated to give 123.7 mg of crude 8, 14-diacetate. The product was dissolved in 5 ml of methanol and 40 ml of an aqueous solution containing 2.5 g of enzyme prepared in Reference Example 11 was added The mixture was stirred for 30 minutes and extracted with chloroform The extract was washed with aqueous NaCl solution and dried over Na 2 SO 4. The solvent was distilled off and the residue was purified by silica gel column chromatography [eluent: ethyl acetate-hexane (2: 1)] with 10% water, and the desired fractions were combined and concentrated to give 73.6 mg of the title compound. .

Melting Point: 145 ~ 146 ℃ (Et2O)

NMR (90 MHz, CDCl 3) δ: 1.23 (d, 3H, J = 7 Hz), 1.41 (s, 3H), 1.55 (g, 3H), 1.72 (br.s, 1H), 1.93 (s, 3H), 2.05 (s, 3H), 2.15 to 2.55 (m, 5H), 4.15 to 4.80 (m, 5H), 4.93 to 5.91 (m, 6H), 6.15 (d, 1H, J = 15 Hz), 6.84 to 7.55 (m, 3H), 7.99-8.20 (m, 2H).

IR (KBr): 3400, 1730, 1710, 1690, 1260 cm ^-1 .

[α] D ^23.5 -136.8 ° (c = 0.345, EtOH)

In a similar manner as above, the 3'-substituted thio-8, 14-diacetate was reacted with a sodium salt of thiol with 3- (3-bromo-2-oxopropionamido) -rancon 8, 14-diacetate. Was obtained and hydrolyzed using the enzyme prepared in Reference Example 11 to obtain 3- (3-substituted thio-2-oxopropionamido) -lancon 8-acetate shown in Examples 136 to 139.

Example 136

Preparation of 3- (3-phenylthio-2-oxopropionamido) -lancon 8-acetate:

Total yield: 8%

Melting Point: 164 ~ 165 ℃ (AcOEt)

NMR (90 MHz, CDCl 3) δ: 1.25 (d, 3H, J = 7 Hz), 1.34 (s, 3H), 1.58 (s, 3H), 1.63 (br.s, 1H), 1.90 (s, 3H), 2.05 (s, 3H), 2.15 to 2.55 (m, 5H), 4.01 (d, 1H, J = 14 Hz), 4.18 (d, 1H, J = 14 Hz), 4.20 to 4.56 (m, 2H), 4.68 (br, d, 1H, J = 11 Hz, 4.93-5.91 (m, 6H), 6.13 (d, 1H, J = 15 Hz), 7.5-7.50 (m, 5H), 8.03 (d, 1H, J = 10 Hz).

IR (KBr): 3400, 1730, 1710, 1690, 1260 cm ^-1 .

[α] D ²³ -117.4 ° (c = 0.155, EtOH)

Example 137

Preparation of 3- (3-ethylthio-2-oxopropionamido) -lancon 8-acetate:

Total yield: 14%

Melting Point: 191 ° C (Decomposition) (Et2O)

NMR (90 MHz, CDCl 3) δ: 1.21 (t, 3H, J = 7 Hz), 1.25 (d, 3H, J = 7 Hz), 1.39 (s, 3H), 1.55 (s, 3H), 1.82 (br, s, 1H), 1.89 (s, 3H), 2.04 (s, 3H), 2.15 ~ 2.63 (m, 7H), 3.55 (d, 1H, J = 13Hz), 3.69 (d, 1H, J = 13Hz), 4.20 ~ 4.55 (m, 2H), 4.72 (br. D, 1H, J = 11 Hz), 4.92-5.91 (m, 6H), 6.13 (d, 1H, J = 15 Hz), 8.08 (d, 1H, J = 10 Hz) .

IR (KBr): 3400, 1730, 1710, 1680, 1260 cm ^-1 .

[α] D ²⁴ -162.6 ° (c = 0.115, EtOH)

Example 138

Preparation of 3- [3- [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thio-2-oxopropionamido] -lancon 8-acetate

Total yield: 20%

Hexamethylphosphoramide (HMPA) was used as the solvent of the 3'-thiation reaction and the reaction was performed at room temperature.

NMR (90 MHz, CDCl 3) δ: 1.23 (d, 3H, J = 7 Hz), 1.40 (s, 3H), 1.54 (s, 3H), 1.89 (s, 3H), ˜2.0 (br. S, 1H), 2.04 (s, 3H), 2.25 (s, 6H), 2.15 ~ 2.55 (m, 5H), 2.75 (t, 2H, J = 6Hz), 4.15 ~ 4.80 (m, 7H), 4.93 ~ 5.90 (m, 6H ), 6.15 (d, 1H, J = 15 Hz), 8.06 (d, 1H, J = 10 Hz).

IR (KBr): 3400, 1735, 1710, 1260 cm ^-1 .

[α] D ²⁴ -121.8 ° (c = 0.385, EtOH)

Example 139

Preparation of 3- [3- [1-methyl-1H-1, 3, 4-triazol-2-yl] thio-2-oxopropionamido] -lancon 8-acetate:

Total yield: 11%

(Ethanol-tetrahydrofuran was used as the solvent of the 3'-thiolation reaction.)

NMR (90 MHz, CDCl 3) δ: 1.23 (d, 3H, J = 7 Hz), 1.40 (s, 3H), 1.54 (s, 3H), 1.88 (s, 3H), 2.04 (s, 3H), ˜21 ( br.s, 1H), 2.15 to 2.55 (m, 5H), 3.64 (s, 3H), 4.16 to 4.70 (m, 5H), 4.92 to 5.90 (m, 6H), 6.12 (d, 1H, J = 15 Hz ), 8.05 (d, 1H, J = 10 Hz), 8.10 (s, 1H).

IR (KBr): 3400, 1740, 1715, 1265 cm ^-1 .

[α] D ²³ -132.1 ° (c = 0.215, EtOH)

Example 140

Preparation of 3- (2-aminothiazol-4-yl) carboxamido-lancon 8, 14-diacetate:

499.5 mg of 3- (3-bromo-2-oxopropionamido) -rancon 8, 14-diacetate was dissolved in 5 ml of N, N-dimethylformamide. To this was added 74.0 mg thiourea. The mixture was stirred for 1.5 hours and diluted with ethyl acetate. The resulting mixture was washed sequentially with aqueous sodium bicarbonate brine and dried over Na 2 SO 4. The solvent was distilled off and the residue was subjected to silica gel column chromatography [eluent: ethyl acetate-hexane (2: 1)]. The desired fractions were combined and concentrated to give 263.0 mg of the title compound.

Melting point: 206 ° C. (decomposition) (AcOEt).

NMR (90 MHz, CDCl3-DMSO-d6) δ: 1.25 (d, 3H, J = 7 Hz), 1.39 (s, 3H), 1.51 (s, 3H), 1.82 (s, 3H), 1.99 (s, 3H) , 2.01 (s, 3H), 2.15 to 2.60 (m, 5H), 4.53 to 5.80 (m, 9H), 6.30 (d, 1H, J = 15 Hz), 6.93 (br.s, 2H), 7.94 (s, 1H), 8.05 (d, 1H, J = 10 Hz).

IR (KBr): 3400, 1735, 1715, 1245 cm ^-1 .

[α] D ²⁴ -84.9 ° (c = 0.485, EtOH)

Example 141

Preparation of 3- [3- (pyridin-2-yl) thio-2-hydroxyiminopropionamido] -lancon 8, 14-diacetate:

66.0 mg of 3- [3- (pyridin-2-yl) -thio-2-oxopropionamido] -rancon 8, 14-diacetate was dissolved in 1 ml of methanol. To the solution was added 8.0 mg of hydroxylamine-hydrochloride and 8.9 μl of pyridine and the mixture was stirred. After 30 and 70 minutes, respectively, 9 μl of pyridine was replenished and after 170 minutes 7,7 mg of hydroxylamine hydrochloride was added and the entire mixture was stirred for a total of 4 hours. To this was added ethyl acetate, washed successively with water and aqueous NaCl solution and dried over Na 2 SO 4. The solvent was distilled off and the residue was separated by TLC plate (Merck, Art. No. 5715, 20 × 20 cm, developing solvent: ethyl acetate-hexane (1: 1)) to obtain 47.3 mg of the title compound.

NMR (90 MHz, CDCl 3) δ: 1.26 (d, 3H, J = 7 Hz), 1.37 (s, 3H), 1.52 (s, 3H), 1.88 (s, 3H), 2.00 (s, 3H), 2.03 (s , 3H), 2.15 to 2.55 (m, 5H), 4.20 (s, 2H), 4.25 to 4.50 (m, 1H), 4.70 (br.d, 1H, J = 10 Hz), 4.90 to 5.95 (m, 7H) , 6.25 (d, 1H, J = 15 Hz), 6.93-77.6 (m, 3H), 8.01 (br. D, 1H, J = 10 Hz), 8.40 (m, 1H).

IR (KBr): 3400, 1735, 1710, 1675, 1240 cm ^-1 .

[α] D ²¹ -112.8 ° (c = 0.54, CHCl3)

Example 142

Preparation of 3- [3- (pyridin-2-yl) thio-2-methoxyiminopropionamido] -lancon 8, 14-diacetate

Similar to Example 141 using 65.9 mg of 3- [3- (pyridin-2-yl) thio-2-oxopropionamido] -lancon 8, 14-diacetate and o-methyl-hydroxylamine hydrochloride The reaction gave 40.8 mg of the title compound.

Melting Point: 175-177 ℃ (Et2O)

NMR (90 MHz, CDCl 3) δ: 1.30 (d, 3H, J = 7 Hz), 1.39 (s, 3H), 1.55 (s, 3H), 1.89 (s, 3H), 2.03 (s, 3H), 2.05 (s , 3H), 2.15 to 2.55 (m, 5H), 4.03 (s, 3H), 4.27 (s, 2H), 4.30 to 4.53 (m, 1H), 4.73 (br. D, 1H, J = 11 Hz), 4.95 ~ 5.85 (m, 7H), 6.27 (d, 1H, J = 15 Hz), 6.86-7.55 (m, 3H), 7.68 (br. D, 1H, J = 10 Hz), 8.38 (m, 1H).

IR (KBr): 1735, 1710, 1680, 1240 cm ^-1 .

[α] D ²² -108.9 ° (c = 0.485, CHCl3)

Example 143

3- [3- (pyridin-2-yl) thio-2- (L) -hydroxypropionamido] -lancon 8, 14-diacetate and 3- [3- (pyridin-2-yl) thio-2 Preparation of-(D) -hydroxypropionamido] -Rancon 8, 14-Diacetate:

580.4 mg of 3- [3- (pyridin-2-yl) thio-2-oxopropionamido] -rancon 8, 14-diacetate was dissolved in 10 ml of methanol. 0.5 ml of a methanol solution containing 10.4 mg of sodium borohydride was added dropwise under stirring, and the mixture was stirred for 15 minutes. The solvent was distilled off and the residue was subjected to silica gel column chromatography [eluent: ethyl acetate-hexane (2: 1)]. The desired fractions were combined and concentrated to give 409.6 mg of the title compound (2 '-(DL) compound). 52.2 mg of this product was purified by TLC plate [Merck, Art. No. 5715, 20 × 20 cm, developing solvent: ethyl acetate-hexane (1: 2)] to separate 23.4 mg of the title compound (2 '-(L)) and 21.5 mg of the title compound (2'-(D) Compound).

2 '-(L) Compound:

NMR (90 MHz, CDCl 3) δ: 1.26 (d, 3H, J = 7 Hz), 1.36 (s, 3H), 1.54 (s, 3H), 1.90 (s, 3H), 2.01 (s, 3H), 2.04 (s , 3H), 2.15 to 2.55 (m, 5H), 2.56 (d, 2H, J = 4 Hz), 4.22 to 4.55 (m, 2H), 4.73 (br. D, 1H, J = 11 Hz), 4.93 to 5.54 ( m, 7H), 6.26 (d, 1H, J = 15 Hz), 7.00-7,80 (m, 3H), 8.16 (br.d, 1H, J = 10 Hz), 8.40 (m, 1H), ~ 7.80 ( br.s, 1H).

IR (KBr): 3400, 1735, 1715, 1680, 1245 cm ^-1 .

[α] D ^22.5 -229.1 ° (c = 0.485, CHCl3)

2 '-(D) Compound:

NMR (90 MHz, CDCl 3) δ: 1.27 (d, 3H, J = 7 Hz), 1.42 (s, 3H), 1.53 (s, 3H), 1.89 (s, 3H), 2.02 (s, 3H), 2.04 (s , 3H), 2.15 to 2.55 (m, 5H), 3.40 (dd, 1H, J = 5 Hz & 15 Hz), 3.56 (dd, 1H, J = 4 Hz & 15 Hz), 4.27 to 4.58 (m, 2H), 4.72 ( br, d, 1H, J = 11 Hz, 4.90-5.85 (m, 7H), 6.23 (d, 1H, J = 15 Hz), 6.99-7.60 (m, 3H), 7.16 (br. d, 1H, J = 10 Hz), 8.37 (m, 1 H), ~ 7.90 (br. S, 1 H).

IR (KBr): 3400, 1735, 1715, 1670, 1240 cm ^-1 .

[α] D ^22.5 + 14.5 ° (c = 0.47, CHCl3)

Example 144

Preparation of 3- (3-bromo-2-methoxyiminopropionamido) -lancon 8, 14-diacetate:

5.9 mg by carrying out a reaction similar to Example 141 using 62.8 mg of 3- (3-bromo-2-oxopropionamido) -rancon 8, 14-diacetate and O-methyl-hydroxylamine hydrochloride The title compound was obtained.

NMR (90MHz, CDCl3) δ: 1.31 (d, 3H, J = 7Hz), 1.41 (s, 3H), 1.54 (s, 3H), 1.89 (s, 3H), 2.01 (s, 3H), 2.03 (s , 3H), 2.20 to 2.55 (m, 5H), 4.02 to 4.55 (m, 4H), 4.72 (br.d, 1H, J = 10 Hz), 4.93 to 5.81 (m, 7H), 6.25 (d, 1H, J = 15 Hz), 7.83 (br. D, 1H, J = 10 Hz).

IR (KBr): 1735, 1710, 1240 cm ^-1 .

Mass m / e: 652 (M ⁺ +2), 650 (M ⁺ ).

Example 145

3- (3-phenylthio-2- (L) -hydroxypropionamido) -lancon 8, 14-diacetate and 3- (3-phenylthio-2- (D) -hydroxypropionamido)- Preparation of Lancon 8, 14-diacetate:

112.3 mg of the title compound (2 ′-(L)) was subjected to a reaction similar to Example 143 using 429.2 mg of 3- (3-phenylthio-2-oxopropionamido) -lancon 8, 14-diacetate. Compound) and 84.1 mg of the title compound (2 '-(D) compound) were obtained.

NMR (90 MHz, CDCl 3) δ: 1.28 (d, 3H, J = 7 Hz), 1.36 (s, 3H), 1.53 (s, 3H), 1.67 (br.s, 1H), 1.86 (s, 3H), 2.01 (s, 3H), 2.03 (s, 3H), 2.15 to 2.55 (m, 5H), 2.96 to 3.65 (m, 2H), 4.00 to 4.50 (m, 2H), 4.68 (br. d, 1H, J = 11 Hz), 4.90-5.85 (m, 7H), 6.26 (d, 1H, J = 15 Hz), 7.15-7.46 (m, 5H), 7.84 (br. D, 1H, J = 10 Hz).

IR (KBr): 3420, 1740, 1715, 1245 cm ^-1 .

[α] D ²¹ -204.7 ° (c = 0.53, CHCl3)

2 '-(D) compound,

Melting Point: 177 ~ 178 ℃ (AcOEt-Et O):

NMR (90 MHz, CDCl 3) δ: 1.28 (d, 3H, J = 7 Hz), 1.37 (s, 3H), 1.54 (s, 3H), 1.86 (s, 3H), ˜2.0 (br. S, 1H), 2.02 (s, 3H), 2.05 (s, 3H), 2.15 to 2.55 (m, 5H), 2.99 (dd, 1H, J = 9 Hz & 15 Hz), 3.55 (dd, 1H, J = 4 Hz & 15 Hz), 4.05 ~ 4.52 (m, 2H), 4.70 (br.d, 1H, J = 11 Hz), 4.96-5.85 (m, 7H), 6.26 (d, 1H, J = 15 Hz), 7/12-7.50 (m, 5H ), 7.87 (br. D, 1 H, J = 10 Hz).

IR (KBr): 3420, 1740, 1715, 1670, 1245 cm ^-1 .

[α] D ²¹ -165.5 ° (c = 0.475, CHCl3)

Example 146

Preparation of 3- (2-oxo-1-thiooxopropylamino) -lancon 14-acetate 8-diethylphosphate:

96.3 mg of Lancacidin A 8-diethylphosphate and 15.1 mg of phosphorus pentasulfide were reacted at 50 ° C. for 19 hours in 0.5 ml of pyridine. Pyridine was distilled off. Dichloromethane was added to the residue and the insoluble material was filtered off. The filtrate was concentrated and TLC plate [Merck, Art. No. 5715 20 × 20 cm, 2 plates, developing solvent: ethyl acetate-hexane (1: 1)] gave 10.2 mg of the title compound.

NMR (90MHz, CDCl3) δ: 1.20 ~ 1.45 (m, 12H), 1.55 (s, 3H), 1.97 (s, 3H), 2.02 (s, 3H), 2.20 ~ 2.65 (m, 5H), 2.65 (s , 3H), 3.89-4.27 (m, 4H), 4.32-4.82 (m, 3H), 5.20-6.36 (m, 7H), 10.01 (br. D, 1H, J = 10 Hz).

IR (KBr): 1740, 1715, 1270, 1245, 1015 cm ^-1 .

Example 147

Preparation of 3- (2- (DL) -hydroxypropionamido) -lancon 14-acetate 8-diethylphosphate:

817.1 mg of the title compound were obtained by carrying out a reaction similar to Example 143 using 956.7 mg of lancassidin A diethylphosphate.

NMR (90MHz, CDCl3) δ: 1.20 ~ 1.50 (m, 15H), 1.55 (s, 3H), 1.88 (s, 3H), 2.02 (s, 3H), ~ 2.0 (br.s, 1H), 2.15 ~ 2.70 (m, 5H), 3.85 to 4.85 (m, 8H), 5.20 to 5.90 (m, 6H), 6.26 (d, 1H, J = 15 Hz), 7.67 (br. D, to 0.5H, J = 10 Hz) , 7.78 (br. D, ˜0.5H, J = 10 Hz).

IR (KBr): 3400, 1740, 1715, 1675, 1245, 1010 cm ^-1 .

Example 148

Preparation of 3- (2- (DL) -n-octanoyloxypropionamido) -lancon 14-acetate 8-diethylphosphate:

64.8 mg of 3- (2- (DL) -hydroxypropionamido) -rancon 14-acetate 8-diethylphosphate was dissolved in 0.5 ml of pyridine. To the solution was stirred dropwise with ice water and 0.1 ml of n-octanoylchloride was added dropwise and stirred for further 15 minutes. Ice water was added to the product, and the mixture was extracted with ethyl acetate. The extract was washed sequentially with 1N hydrochloric acid, aqueous NaCl solution, aqueous sodium hydrogen carbonate solution and aqueous NaCl solution and dried over Na 2 SO 4. The solvent was distilled off and the residue was subjected to silica gel column chromatography [eluent: chloroform-ethyl acetate (2: 1)]. The desired fractions were combined and concentrated to give 77.0 mg of the title compound.

NMR (90MHz, CDCl3) δ: 0.87 (~ t, 3H), 1.15 ~ 2.75 (m, 29H), 1.55 (s, 3H), 1.89 (s, 3H), 2.02 (s, 3H), 3.90 ~ 4.85 ( m, 7H), 5.10 to 5.90 (m, 7H), 6.25 (d, 1H, J = 15 Hz), 7.29 (br, d, ˜0.5H, J = 10 Hz), 7.45 (br. d, ˜0.5H, J = 10 Hz).

IR (KBr): 2940, ˜1720 (br.), 1260 (br.), ˜1000 (br.) Cm ⁻¹ .

Example 149

Preparation of 8-dehydroxy-8-iodolancassidin A:

5.01 g of lancassidin A was dissolved in 50 ml of N, N-dimethylformamide. To the solution was added 1.82 ml of pyridine and 1.72 ml of methanesulfonyl chloride and the mixture was stirred for 1 hour. 3.735 g of potassium iodide was added to the product, stirred at 60 ° C. for 20 minutes, poured into 500 ml of ice water, and extracted with ethyl acetate (250 ml × 2). The extract was washed with water and dried over MgSO 4. The solvent was distilled off and the residue was subjected to silica gel (100 g) column chromatography [eluent: ethyl acetate-chloroform (1:10)]. The desired fractions were combined and concentrated. A small amount of ether was added to the concentrate to crystallize, and ether-petroleum ether (1: 2) was added followed by filtration to collect the crystals. The crystals were washed with the same solvent system and dried to yield 2.3431 g of the title compound. NMR at 400 MHz revealed the product to be a mixture of three components.

NMR (90 MHz, CDCl 3) δ: (only data of the principal component is shown)

1.28 (d, J = 7 Hz, 17-Me), 1.37 (s, 2-Me), 1.51 (s, 11-Me), 1.88 (s, 5-Me), 2.00 (s, OAc), 2.2 to 2.6 (m, 3H, 15-H2 17-H), 2.43 (s, COCOCH3), 2.8 (m, 2H, 9-H2), -4.3 (m, 16-H, 8-H), 4.68 (d, J = 11 Hz, 4-H), 5.1-6.0 (m, 6H, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.23 (d, J = 15 Hz, 12-H), 8.05 (d, J = 10 Hz, NH).

IR (KBr): 3380, 1740, 1708, 1690, 1510, 1358, 1224, 1136, 948 cm ^-1 .

Mass m / e: 552 (M ⁺ -59 (AcO)), 484 (M ⁺ -127 (I)), 483 (M ⁺ -128 (HI)), 424 (M ⁺ -127-60 (AcOH)) , 423 (M ⁺ -128-60).

Example 150

Preparation of 8-dehydroxy-8-azido-lancassidin A:

3.055 g of 8-dehydroxy-8-iodo-lancadine A was dissolved in 50 ml of N, N-dimethylformamide. 390 mg of sodium azide was added to the solution, and the mixture was stirred for 80 minutes. The resulting mixture was poured into ice water, sodium chloride was added, extracted with ethyl acetate and dried over MgSO 4. The solvent was distilled off and the residue was subjected to silica gel (120 g) column chromatography [eluent: ethyl acetate-hexane (1: 1)]. The eluate was fractionated by 13 g, the 19th to 31st fractions were combined, concentrated, and a small amount of ether was added to crystallize and ether-petroleum ether (1: 2) was added thereto. The mixture was filtered to collect crystals, washed with the same solvent system and dried to yield 1.3184 g of the title compound.

NMR (90 MHz, CDCl 3) δ: 1.32 (d, J = 7 Hz, 17-Me), 1.37 (s, 2-Me), 1.49 (s, 11-Me), 1.89 (s, 5-Me), 2.01 ( s, OAc), 2.2 to 2.8 (m, 15-H2, 9-H2, 17-H), 2.44 (s, COCOCH3), 4.43 (m, 16-H) to 4.6 (m, 8-H), 4.77 (d, J = 11 Hz, 4-H), 5.2-6.1 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.25 & 6.32 & 6.35 (each 1H, d, respectively 2: 3: 1, J = 15 Hz, 12-H), 8.09 (d, J = 9 Hz, NH).

IR (KBr): 2100, 1728, 1706, 1688, 1502, 1352, 1232, 1134 cm ^-1 .

Example 151

Preparation of 8-dehydroxy-8-[[1- (2-dimethylaminoethyl) 1H-tetrazol-5-yl] thio] -lancassidin A:

208 mg of [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thiol and 44.0 mg of sodium hydride (in oil, 60%) were dissolved in 10 ml of hexamethylphosphoramide under heating. After cooling, 611 mg of 8-dehydroxy-8-iodo-lancadine A was added to the solution, the mixture was stirred at room temperature for 14 hours, an aqueous NaCl solution was added, and extracted with ethyl acetate. The extract was dried over MgSO 4. The solvent was distilled off and the residue was subjected to silica gel (300 g) column chromatography [eluent: ethyl acetate-ethanol (10: 1)]. The desired fractions were combined and concentrated to give 273.9 mg of the title compound (low polar isomer: estimated 8-position β compound) and 113.9 mg of the title compound (high polar isomer: 8-position α compound). Obtained.

Β compound at 8-position:

NMR (90 MHz, CDCl 3) δ: 1.33 (d, J = 7 Hz, 17-Me), 1.37 (s. 2-Me), 1.52 (s, 11-Me), 1.88 (s, 5-Me), 2.01 ( s, OAc), 2.1 to 2.5 (m, 3H, 15-H2, 17-H), 2.25 (s, NMe2), 2.43 (s, COCOCH3), 2.5 to 2.9 (m, 2H, 9-H2), 2.73 (t, J = 7 Hz, CH2NMe2), 4.30 (t, J = 7 Hz, tetrazol-CH2) to 4.4 (m, 16-H), 4.72 (d, J = 11 Hz, 4-H), 4.95 (m, 8-H), 5.3-5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.35 (d, J = 15 Hz, 12-H), 8.07 (d, J = 10 Hz, NH).

IR (KBr): 1728, 1708, 1688, 1356, 1240 cm ^-1 .

Α-compound at 8-position:

NMR (90 MHz, CDCl 3) δ: 1.31 (d, J = 7 Hz, 17-Me), 1.37 (s, 2-Me), 1.55 (s, 11-Me), 1.85 (s, 5-Me), 2.01 ( s, OAc), 2.1 to 2.5 (m, 15-H2, 17-H), 2.24 (s, NMe2), 2.43 (s, COCOCH3), 2.5 to 2.8 (m, 9-H2), 2.73 (t, J = 7 Hz, CH2NMe2), 4.30 (t, J = 7 Hz, tetrazole -CH2) to 4.3 (m, 16-H, 8-H), 4.70 (d, J = 11 Hz, 4-H), 5.2 to 5.9 ( m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.29 (d, J = 15 Hz, 12-H), 8.06 (d, J = 10 Hz, NH) .

IR (KBr): 1728, 1708, 1688, 1356, 1240 cm ^-1 .

In a similar manner to the above, the sodium salt of thiol was reacted with 7-dehydroxy-8-iodo-lancadine to give 8-dehydroxy-8-substituted-thio-lancacidine shown in Examples 152-161. Obtained.

Example 152

Preparation of 8-dehydroxy-8- (4-pyridylthio) -lancassidin A:

The reaction was carried out at 0 ° C. for 4 hours using N, N-dimethylformamide-tetrahydrofuran (1: 2) as the reaction solvent.

Yield 58%.

NMR (90 MHz, CDCl 3) δ: 1.30 (d, J = 7 Hz, 17-Me), 1.41 (s, 2-Me), 1.53 (s, 11-Me), 1.92 (s, 5-Me), 2.01 ( s, OAc), 2.1 to 2.5 (m, 15-H2, 17-H), 2.41 (s, COCOCH3), 2.5 to 2.8 (m, 9-H2) to 4.4 (m, 16-H, 8-H) , 4.70 (d, J = 11 Hz, 4-H), 5.3-6.25 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.35 (d, J = 15 Hz, 12-H) -7.1 (br., Pyridine-H2), 8.05 (d, J = 9 Hz, NH)-8.1 (br., Pyridine -H2).

IR (KBr): 1724, 1708, 1682, 1572, 1354, 1236 cm ^-1 .

Mass m / e: 594 (M ⁺ ), 550 (M ⁺ -44 (CO2)), 5.34 (M ⁺ -60 (AcOH)), 490 (M ⁺ -44-60), 483 (M ⁺ -111) .

Example 153

Preparation of 8-dehydroxy-8-[[1- (3-dimethylaminopropyl) -1H-tetrazol-5-yl] thio] -lancassidin A:

8-β-compound (estimated): yield 50%.

NMR (90 MHz, CDCl 3) δ: 1.38 (d, J = 7 Hz, 1 7-Me), 1.38 (s, 2-Me), 1.53 (s, 11-Me), 1.89 (s, 5-Me), 2.02 (s, OAc), 1.8 to 2.9 (m, CH2CH2N, 15-H2, 17-H, 9-H2), 2.20 (s, NMe2), 2.44 (s, COCOCH3), 4.27 (t, J = 7 Hz, tetra Sol -CH2)-4.4 (m, 16-H), 4.72 (d, J = 11 Hz, 4-H), 4.98 (m, 8-H), 5.3-5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.35 (d, J = 15 Hz, 12-H), 8.05 (d, J-10 Hz, MH).

IR (KBr): 1726, 1706, 1682, 1498, 1356, 1234, 950 cm ^-1 .

8-α-compound (estimated): yield 14%.

NMR (90 MHz, CDCl 3) δ: Data different from that of 8-β-compound 1.31 (d, J = 7 Hz, 17-Me), 1.85 (s, 5-Me), 2.18 (s, NMe 2), 6.31 (d, J = 15 Hz, 12-H).

IR (KBr): 1726, 1706, 1682, 1498, 1356, 1234, 950 cm ^-1 .

Example 154

Preparation of 8-dehydroxy-8- (1-methyl-1H-tetrazol-5-yl) thio-lancassidin A:

Reaction was performed overnight at 0-5 degreeC using N and N- dimethylformamide as a reaction solvent.

Yield 44%.

NMR (90 MHz, CDCl 3) δ: 1.31 (d, J = 6.5 Hz, 17-Me), 1.37 (s, 2-Me), 1.54 (s, 11-Me), 1.89 (s, 5-Me), 2.02 (s, OAc), 2.25-2.85 (m, 9-H2, 15-H2, 17-H), 2.43 (s, COCOCH3), 3.90 (s, tetrazol-CH3), 4.44 (m, 16-H) , 4.72 (d, J = 11 Hz, 4-H), 4.97 (br., 8-H), 5.3-5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.35 (d, J, 15 Hz, 12-H), 8.06 (d, J = 10 Hz, NH).

IR (KBr); 3400, 2950, 1730, 1715, 1690, 1500, 1450, 1360, 1240, 1170, 1140, 1015, 955, 750 cm ^-1 .

Example 155

Preparation of 8-dehydroxy-8- (5-methyl-1, 3, 4-thiazol-2-yl) thio-lancassidin A:

The reaction was carried out at room temperature for 1 hour.

Yield 37%.

NMR (90 MHz, CDCl 3) δ: 1.32 (d, 6.5 Hz, 17-Me), 1.47 (s, 2-Me), 1.52 (s, 11-Me), 1.90 (s, 5-Me), 2.01 (s , OAc), 2.2-2.8 (m, 9-H2, 15-H2, 17-H), 2.43 (s, COCOCH3), 2.68 (s, thiazole-CH3), 4.43 (m, 16-H), 4.72 (d, J = 11 Hz, 4-H), 4.83 (m, 8-H), 5.3-6.15 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H ), 6.35 (d, J = 15 Hz, 12-H), 8.07 (d, J = 10 Hz, NH).

IR (KBr): 3385, 2930, 1730, 1710, 1685, 1500, 1445 (sh), 1430, 1355, 1230, 1135, 1055, 1010, 950 cm ^-1 .

Example 156

Preparation of 8-dehydroxy-8-phenylthio-lancadine A:

The reaction was carried out using N, N-dimethylformamide as a reaction solvent at 0 ° C. for 30 minutes and at room temperature for 45 minutes. Yield 12%.

NMR (90 MHz, CDCl 3) δ: 1.33 (d, J = 6 Hz, 17-Me), 1.36 (s, 2-Me), 1.50 (s, 11-Me), 1.89 (s, 5-Me), 2.02 ( s, OAc), 2.2 to 2.8 (m, 9-H2, 15-H2, 17-H), 2.43 (s, COCOCH3), 4.22 (m, 8-H), 4.31 (m, 16-H), 4.73 (d, J = 11 Hz, 4-H), 5.3-6.25 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.48 (d, J = 15 Hz 12-H), 7.1-7.75 (m, C6H5), 8.06 (d, J = 10 Hz, NH).

IR (KBr): 3490, 2930, 1750 (sh.), 1730, 1710, 1685, 1500, 1360, 1235, 1160 (sh.), 1140, 1010, 950, 740 cm ^-1 .

Example 157

Preparation of 8-dehydroxy-8- [5- (2-dimethylaminoethyl) -1, 3, 4-thiadiazol-2-yl] thio-lancassidin A:

8-β-compound (estimated): yield 12%.

NMR (90 MHz, CDCl 3) δ: 1.32 (d, J = 6.5 Hz, 17-Me), 1.37 (s, 2-Me), 1.52 (s, 11-Me), 1.90 (s, 5-Me), 2.03 (s, OAc), 2.27 (s, NMe2), 2.43 (s, COCOCH3), 2.2 to 2.8 (m, 9-H2, 15-H2, 17-H), 2.59 (t, J = 6.5 Hz, CH2NMe2) , 3.14 (t, J = 6.5 Hz, thiazole-CH2), 4.42 (m, 16-H), 4.76 (d, J = 11 Hz, 4-H), 4.86 (m, 8-H), 5.3-6.1 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.34 (d, J = 15 Hz, 12-H), 8.05 (d, J = 10 Hz, NH ).

IR (KBr): 3380, 2940, 1745, 1705, 1685, 1500, 1450, 1375, 1360, 1260, 1160, 1140, 1055, 1010, 960, 745 cm ^-1 .

8-α-compound (estimated): yield 2%.

NMR (90 MHz, CDCl 3) δ: 1.30 (d, J = 6.5 Hz, 17-Me), 1.37 (s, 2-Me), 1.55 (s, 11-Me), 1.87 (s, 5-Me), 2.02 (s, OAc), 2.27 (s, NMe2), 2.43 (s, COCOCH3), 2.2 to 2.8 (m, 9-H2, 15-H2, 17-H), 2.61 (t, J = 6.5 Hz, CH2NMe2) , 3.16 (t, J = 6.5 Hz, thiazole-CH2), 4.06 (m, 8-H), 4.41 (m, 16-H), 4.68 (d, J = 11 Hz, 4-H), 5.25-6.0 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.28 (d, J = 15 Hz, 12-H), 8.05 (d, J = 10 Hz, NH ).

IR (KBr): 3400, 2925, 2860, 1730, 1705, 1680, 1495, 1450, 1365, 1230, 1135, 1055, 1010, 950 cm ^-1 .

Example 158

Preparation of 8-dehydroxy-8- (4, 5-dimethylthiazol-2-yl) thio-lancassidin A

The reaction was carried out using N, N-dimethylformamide as a reaction solvent at 0 ° C. for 1 hour and at room temperature for 1 hour. Yield 17%.

NMR (90 MHz, CDCl 3) δ: 1.32 (d, J = 6.5 Hz, 17-Me), 1.38 (s, 2-Me), 1.51 (s, 11-Me), 1.90 (s, 5-Me), 2.03 (s, OAc), 2.26 (s, thiazole -CH3x2), 2.44 (s, COCOCH3), 2.2-2.7 (m, 9-H2, 15-H2, 17-H), 4.42 (m, 16-H) , 4.62 (m, 8-H), 4.73 (d, J = 11 Hz, 4-H), 5.3-5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14 -H), 6.05 (d, J = 15 Hz, 6-H), 6.37 (d, J = 15 Hz, 12-H), 8.06 (d, J = 10 Hz, NH).

IR (KBr): 3380, 2930, 1730, 1710, 1685, 1500, 1440, 1430 (sh.), 1355, 1230, 1160, 1135, 1010, 950 cm ^-1 .

Example 159

Preparation of 8-dehydroxy-8- (4, 5-dimethyloxazol-2-yl) thio-lancassidin A

The reaction was carried out at 0 ° C. for 1 hour using N, N-dimethylformamide as the reaction solvent.

Yield 12%.

NMR (90 MHz, CDCl 3) δ: 1.33 (d, J = 6.5 Hz, 17-Me), 1.38 (s, 2-Me), 1.52 (s, 11-Me), 1.89 (s, 5-Me), 2.03 (s, 6H, OAc, oxazole -CH3), 2.18 (s, oxazole -CH3), 2.2-2.75 (m, 9-H2, 15-H2, 17-H), 2.44 (s, COCOCH3), 4.42 (m, 16-H), 4.56 (m, 8-H), 4.74 (d, J = 10 Hz, 4-H), 5.3-6.05 (m, 3-H, 6-H, 7-H, 10- H, 13-H, 14-H), 6.35 (d, J = 15 Hz, 12-H), 8.05 (d, H = 10 Hz, NH).

IR (KBr): 3400 (br.), 2930, 1730, 1710, 1690, 1500, 1360, 1235, 1140, 1020, 955 cm ⁻¹ .

Example 160

Preparation of 8-dehydroxy-8- (1-dimethylamino-1H-tetrazol-5-yl) thio-lancassidin A:

The reaction was carried out at room temperature for 3 hours using N, N-dimethylformamide as the reaction solvent.

Yield 45%, Melting Point: 14 ~ 146 ℃

(Decomposition) (CHCl3-Et2O-hexane)

NMR (90 MHz, CDCl 3) δ: 1.32 (d, J = 6.5 Hz, 17-Me), 1.37 (s, 2-Me), 1.53 (s, 11-Me), 1.90 (s, 5-Me), 2.01 (s, OAc), 2.2-2.85 (m, 9-H2, 15-H2, 17-H), 2.43 (s, COCOCH3), 2.94 (s, NMe2), 4.43 (m, 16-H), 4.69 ( d, J = 11 Hz, 4-H), 4.95 (m, 8-H), 5.3-5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H) , 6.32 (d, J = 15 Hz, 12-H), 8.02 (d, J = 10 Hz, NH).

IR (KBr): 3400, 2980, 2940, 1730, 1710, 1685, 1500, 1440, 1350, 1230, 1155, 1135, 1065, 1010, 950, 745 cm ^-1 .

Example 161

Preparation of 8-dehydroxy-8- (1-ethyl-1H-1, 2, 4-triazol-3-yl) thio-lancassidin A:

The reaction was carried out for 3 hours by ice-cooling using N, N-dimethylformamide as a reaction solvent.

Yield 42%.

NMR (90 MHz, CDCl 3) δ: 1.33 (d, J = 6.5 Hz, 17-Me), 1.37 (s, 2-Me), 1.47 (t, J = 7.5 Hz, NCH 2 CH 3), 1.52 (s, 11-Me ), 1.88 (s, 5-Me), 2.02 (s, OAc), 2.2 to 2.75 (m, 9-H2, 15-H2, 17-H), 2.43 (s, COCOCH3), 4.13 (q, J = 7.5 Hz, NCH2CH3), 4.44 (m, 16-H), 4.73 (d, J = 10 Hz, 4-H), 4.73 (m, 8-H), 5.3-5.95 (m, 3-H, 6-H , 7-H, 10-H, 13-H, 14-H), 6.37 (d, J = 15 Hz, 12-H), 7.95 (s, triazole-H), 8.05 (d, J = 10 Hz, NH ).

IR (KBr): 3380, 2975, 2925, 1720, 1700, 1680, 1490, 1435, 1350, 1230, 1130, 1050, 1005, 945 cm ^-1 .

Example 162

Preparation of Lancadine C 8- (2, 2, 2-trichloroethylcarbonate):

135.3 mg of lancassidin A 8- (2, 2, 2-trichloroethylcarbonate) was dissolved in 20 ml of tetrahydrofuran and 20 ml of methanol was added. 40 ml of an aqueous solution containing 2.7 g of enzyme obtained in Reference Example 11 was added to the mixture, followed by stirring at room temperature for 50 minutes. The resulting mixture was extracted with 80 ml of chloroform. The chloroform layer was washed with aqueous NaCl solution and dried over MgSO 4. Chloroform was distilled off. A small amount of ether was added to the residue and the mixture was left to crystallize and ether-petroleum ether (1: 1) was added. The crystals were collected by filtration and dried to yield 82.9 mg of the title compound.

Melting point 209-211 degreeC (decomposition).

NMR (90MHz, CDCl3) δ: 1.28 (d, J = 7Hz3, 17-Me), 1.38 (s, 2-Me), 1.57 (s, 11-Me), 1.91 (s, 5-Me), 2.2 ~ 2.7 (m, 9-H2, 15-H2, 17-H), 2.43 (s, COCOCH3) to 4.4 (m, 16-H, 14-H) to 4.7 (m, 4-H), 4.73 (s, CCl3CH2), 4.97 (m, 8-H), 5.15-5.95 (m, 3-H, 6-H, 7-H, 10-H, 13-H), 6.18 (d, J = 15 Hz, 12-H ), 8.07 (d, J = 10 Hz, NH).

IR (KBr): 1748, 1704, 1674 (sh.), 1376, 1244, 954 cm ^-1 .

[α] D ²⁵ -183.8 ° (c = 0.495, CHCl 3)

The corresponding 14-hydroxy compound of Example 163-221 was obtained by deacetylating 14-acetate using an enzyme in a similar manner as above.

Example 163

Preparation of 3- (2-oxo-1-thioxopropylamino) -lancon-8-acetate:

Yield 94%. Melting Point: 201 ~ 203 ℃

NMR (90 MHz, CDCl 3) δ: 1.27 (d, J = 7 Hz, 17-Me), 1.41 (s, 2-Me), 1.56 (s, 11, Me), 1.95 (s, 5-Me), 2.03 ( s, OAc) 2.2-2.6 (m, 9-H2, 15-H2, 17-H), 2.63 (s, CSCOCH3), 3.72 (m, 14-OH), 4.32 (m, 14-H), 4.43 ( m, 16-H), 4.69 (d, J = 11 Hz, 4-H), 5.04 (m, 8-H), 5.2-6.15 (m, 3-H, 6-H, 7-H, 10-H , 13-H, 6.15 (d, J = 15 Hz, 12-H), 9.98 (d, J = 10 Hz, NH).

IR (KBr): 3330, 1740, 1708, 1494, 1378, 1350, 1262, 1210, 1026, 964 cm ^-1 .

[α] D ²⁵ -409.1 ° (c = 0.47, CHCl3)

Example 164

3- (2-oxo-1-thioxopropylamino) -lancon 8- (2, 2, 2-trichloroethylcarbonate)

The reaction was carried out at room temperature for 45 minutes and at 37 ° C. for 200 minutes and purified by silica gel column chromatography. Yield 80%.

Melting Point: 177 ~ 179 ℃

NMR (90MHz, CDCl3) δ: 1.28 (d, J = 7Hz, 17-Me), 1.39 (s, 2-Me), 1.57 (s, 11, Me), 1.96 (s, 5-Me), 2.2 ~ 2.7 (m, 9-H2, 15-H2, 17-H), 2.64 (s, CSCOCH3) to 4.4 (m, 16-H, 14-H) to 4.7 (m, 4-H), 4.73 (s, CCl3CH2), 4.96 (m, 8-H), 5.2-6.15 (m, 3-H, 6-H, 7-H, 10-H, 13-H), 6.17 (d, J = 15 Hz, 12-H ), 9.98 (d, J = 10 Hz, NH).

IR (KBr): 1752, 1706, 1378, 1248, 1208, 960 cm ^-1 .

[α] D ²⁵ -321.8 ° (c = 0.485, CHCl3)

Example 165

3- (2- (L) -hydroxy-1-thioxopropylamino) -lancon 8-acetate:

Yield 61%. Melting Point: 213 ~ 214 ℃ (Decomposition)

NMR (90 MHz, CDCl3-DMSO-d 6 (4: 1)) δ: 1.25 (d, J = 7 Hz, 17-Me), 1.37 (s, 2-Me), 1.48 (d, J = 7 Hz, 2′- Me), 1.53 (s, 11-Me), 1.92 (s, 5-Me), 2.01 (s, OAc), 2.1 to 2.7 (m, 9-H2, 15-H2, 17-H), 4.1 to 4.6 (m, 2'-H, 14-H) to 4.5 (m, 16-H), 4.78 (d, J = 11 Hz, 4-H), 4.99 (m, 8-H), 5.15 to 6.35 (m, 3-H, 6-H, 7-H, 10-H, 13-H), 6.13 (d, J = 15 Hz, 12-H), 9.77 (d, J = 10 Hz, NH).

IR (KBr): 1730, 1710, 1500, 1372, 1260, 1064, 1020, 996, 964 cm ^-1 .

[α] D ²⁵ -366.0 ° (c = 0.52, CHCl3)

Example 166

3- (2- (D) -hydroxy-1-thioxopropylamino) -lancon 8-acetate)

Yield 81%. Melting Point: 156 ~ 158 ℃ (Decomposition)

NMR (90 MHz, CDCl 3 -DMSO-d 6 (4: 1)) δ: 1.25 (d, J = 7 Hz, 17-Me), 1.40 (d, J = 7H, 2′-Me), 1.41 (s, 2- Me), 1.55 (s, 11-Me), 1.93 (s, 5-Me), 2.02 (s, OAc), 2.1 to 2.7 (m, 9-H2, 15-H2, 17-H), 4.1 to 4.7 (m, 2'-H, 14-H, 16-H), 4.75 (d, J = 11 Hz, 4-H), 5.03 (m, 8-H), 5.1-6.3 (m, 3-H, 6 -H, 7-H, 10-H, 13-H), 6.14 (d, J = 15 Hz, 12-H), 9.85 (d, J = 10 Hz, NH).

IR (KBr): 3520, 3300, 1730, 1702, 1498, 1374, 1260 (sh.), 1248, 1064, 958 cm ^-1 .

[α] D ²⁵ -272.6 ° (c = 0.53, CHCl3)

Example 167

3- [2- [1- (2-Dimethylaminoethyl) -1 H-tetrazol-5-yl] thio] acetamido-rancon 8-acetate:

The reaction was carried out at 37 ° C. for 4.5 hours and at room temperature for 14 hours using 40 times the enzyme (weight) of 14-acetate and purified by TLC.

Yield 15%.

NMR (90 MHz, CDCl 3) δ: 1.22 (d, J = 7 Hz, 17-Me), 1.29 (s, 2-Me), 1.53 (s, 11-Me), 1.84 (s, 5-Me), 2.03 ( s, OAc), 2.1 to 2.6 (m, 9-H2, 17-H), 2.24 (s, NMe2), 2.73 (t, J = 7 Hz, CH2NMe2), 3.84 & 4.04 (ABq, J = 15 Hz, SCH2CO) ˜4.3 (m, 16-H, 14-H), 4.31 (t, J = 7 Hz, tetrazol-CH2), 4.59 (d, J = 11 Hz, 4-H), 5.05 (m, 8-H), 5.2 to 5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H), 6.13 (d, J = 15 Hz, 12-H), 7.56 (d, J = 9 Hz, NH) .

IR (KBr): 1728, 1702, 1666, 1620, 1366, 1250, 1012, 954 cm ^-1 .

Example 168

3- [2- (4-Methyl-4H-1, 2, 4-triazol-3-yl) thio] acetamido-rancon 8-acetate:

The reaction was carried out at 37 ° C. for 15 hours and purified by TLC. Yield 19%.

NMR (90 MHz, CDCl 3) δ: 1.27 (d, J = 7 Hz, 17-Me), 1.35 (s, 2-Me), 1.53 (s, 11-Me), 1.83 (s, 5-Me), 2.04 ( s, OAc), 2.1 to 2.6 (m, 9-H2, 15-H2, 17-H), 3.57 (s, triazole-CH3), 3.74 & 4.02 (ABq, J = 15 Hz, SCH2CO) to 4.4 (m , 16-H, 14-H), 4.59 (d, J = 10 Hz, 4-H) to 5.05 (m, 8-H), 5.2 to 6.0 (m, 3-H, 6-H), 7-H , 10-H, 13-H), 6.12 (d, J = 15 Hz, 12-H), 6.95 (s, triazole-H), 7.74 (d, J = 10 Hz, NH).

IR (KBr): 1730, 1708, 1660, 1508, 1370, 1250, 1020, 960 cm ^-1 .

Example 169

3- [2- (4-pyridyl) thio] acetamido-rancon 8-acetate:

The reaction was carried out at 37 ° C. for 15.5 hours and purified by TLC. Yield 42%

NMR (90 MHz, CDCl 3) δ: 1.10 (s, 2-Me), 1.18 (d, J = 7 Hz, 2-Me), 1.52 (s, 11-Me), 1.86 (s, 5-Me), 2.04 ( s, OAc), 2.1-2.6 (m, 9-H2, 15-H2, 17-H), 3.57 & 3.78 (ABq, J = 17 Hz, SCH2CO)-4.3 (m, 16-H, 14-H), 4.50 (d, J = 12 Hz, 4-H), 5.05 (m, 8-H), 5.2-5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H), 6.12 (d, J = 15 Hz, 12-H), 7.14 (d, J = 6 Hz, pyridine-H2), 7.81 (d, J = 10 Hz, NH), 8.38 (m, pyridine-H2).

IR (KBr): 1726, 1702, 1652, 1578, 1498, 1370, 1252, 1014, 960 cm ^-1 .

Example 170

3- (2-Difluoromethylthio) acetamido-rancon 8-acetate:

Purification was carried out by TLC.

Yield 49%

NMR (90 MHz, CDCl 3) δ: 1.25 (d, J = 7 Hz, 17-Me), 1.38 (s, 2-Me), 1.53 (s, 11-Me), 1.87 (s, 5-Me), 2.03 ( s, OAc), 2.1 to 2.6 (m, 9-H2, 17-H), 3.47 (s, SCH2CO) to 4.0 (m, 16-H, 14-H), 4.67 (d, J = 11 Hz, 4- H), 5.05 (m, 8-H), 5.2-5.9 (m, 3H, 6-H, 7-H, 10-H, 13-H), 6.15 (d, J = 15 Hz, 12-H), 6.87 (t, J = 56 Hz, CHF2), 7.58 (d, J = 10 Hz, NH).

IR (KBr): 1732, 1706, 1664, 1502, 1372, 1254, 1060, 1020, 960 cm ^-1 .

Example 171

3- [2- (5-methanesulfonylmethyl-1, 3, 4-thiadiazol-2-yl) thio] acetamido-rancon 8-acetate:

The reaction was carried out at 37 ° C. for 20 hours and purified by TLC. Yield 26%.

NMR (90 MHz, CDCl 3) δ: 1.20 (d, J = 7 Hz, 17-Me), 1.30 (s, 2-Me), 1.53 (s, 11-Me), 1.83 (s, 5-Me), 2.04 ( s, OAc), 2.1 to 2.6 (m, 9-H2, 15-H2, 17-H), 2.99 (s, SO2CH3), 4.02 (s, SCH2CO) to 4.4 (m, 14-H, 16-H, ), 4.62 (d, J = 11 Hz, 4-H), 4.70- (s, thiadiazole -CH2), 5.05 (m, 8-H), 5.2-5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H), 6.13 (d, J = 15 Hz, 12-H), 7.62 (d, J = 10 Hz, NH).

IR (KBr): 1728, 1710, 1664, 1368, 1312, 1260, 1140, 964 cm ^-1 .

Example 172

3- [2- [1- (2-hydroxyethyl) -1H-tetrazol-5-yl] thio] acetamino-lancon 8-acetate:

The reaction was carried out at 37 ° C. for 16 hours and purified by TLC. Yield 18%.

NMR (90 MHz, CDCl 3) δ: 1.22 (d, J = 7 Hz, 17-Me), 1.32 (s, 2-Me), 1.53 (s, 11-Me), 1.82 (s, 5-Me), 2.04 ( s, OAC), 2.1 to 2.6 (m, 9-H2, 15-H2, 17-H), 3.88 & 4.12 (ABq, J = 15 Hz, SCH2CO) to 4.1 (m, CH2CH2OH) to 4.4 (m, 14- H, 16-H, tetrazol-CH2), 4.55 (d, J = 12 Hz, 4-H), 5.03 (m, 8-H), 5.2-5.9 (m, 3-H, 6-H, 7- H, 10-H, 13-H), 6.15 (d, J = 15 Hz, 12-H), 7.52 (d, J = 10 Hz, NH).

IR (KBr): 1730, 1708, 1662, 1372, 1252, 1060, 1018, 960 cm ^-1 .

Example 173

3- [2- (2-aminothiazol-4-yl) acetamido] rancon 8-acetate:

The reaction was carried out at 37 ° C. for 7.5 hours and purified by TLC. Yield 30%.

NMR (90 MHz, CDCl 3) δ: 1.20 (d, J = 7 Hz, 17-Me), 1.30 (s, 2-Me), 1.53 (s, 11-Me), 1.85 (s, 5-Me), 2.03 ( s, OAc), 2.1-2.6 (m, 9-H2, 15-H2, 17-H), 3.45 (s, thiazole-CH2), 4.37 (m, 14-H, 16-H), 4.65 (d , J = 12 Hz, 4-H), 5.05 (m, 8-H), 5.2-5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H), 6.13 (d, J = 15 Hz, 12-H), 6.28 (s, thiazole -H), 7.18 (d, J = 10 Hz, NH).

IR (KBr): 1736, 1710, 1630, 1512, 1260, 1246 cm ^-1 .

Example 174

8-dehydroxy-8-iodo-lancassidin C:

Purification was carried out by silica gel column. Yield 75%. Melting Point: 150 ℃ (Decomposition)

NMR (90 MHz, CDCl 3) δ: 1.23 (d, J = 7 Hz, 17-Me) 1.40 (s, 2-Me), 1.51 & 1.54 (s, 3H, 11-Me, respectively), 1.88 (s, 5-Me ), 2.1 to 2.4 (m, 3H, 15-H2, 17-H), 2.43 (s, COCOCH3), 2.5 to 3.0 (m, 2H, 9-H2) to 4.3 (m, 3H, 16-H, 8) -H, 4-H), 4.63 (d, J = 11 Hz, 4-H), 5.0-6.0 (m, 5H, 3-H, 6-H, 7-H, 10-H, 13-H), 6.12 & 6.22 (D, 1H, J = 15 Hz, 12-H), 8.07 (d, J = 9 Hz, NH).

IR (KBr): 3560, 3410, 1700, 1676, 1494, 1358, 1262, 1138, 1000, 960 cm ^-1 .

Example 175

8-dehydroxy-8-[[1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thio] -lancassidin C (8-β-compound)

The reaction was carried out at 37 ° C. for 20 hours, and purified by silica gel column chromatography. Yield 29%.

NMR (90 MHz, CDCl 3) δ: 1.28 (d, J = 7 Hz, 17-Me), 1.38 (s, 2-Me), 1.53 (s, 11-Me), 1.88 (s, 5-Me), 2.26 ( s, NMe2) to 2.3 (m, 15-H2, 17-H), 2.75 (t, J = 7 Hz, CH2NMe2) to 2.75 (m, 9-H2), 4.31 (t, J = 7 Hz, tetrazole -CH2 ) To 4.4 (m, 14-H, 16-H), 4.72 (d, J = 11 Hz, 4-H), 4.93 (m, 8-H), 5.25 to 6.0 (m, 3-H, 6-H , 7-H, 10-H, 13-H), 6.22 (d, J = 15 Hz, 12-H), 8.03 (d, J = 10 Hz, NH).

IR (KBr): 1740, 1708, 1686, 1502, 1452, 1386, 1358, 1258 cm ^-1 .

Example 176

8-dehydroxy-8-[[1- (2-dimethylaminoethyl-1H-tetrazol-5-yl] thio] -lancassidin C (8-α-compound)

The reaction was carried out at 37 ° C. for 3 hours and at room temperature for 14 hours, and then purified by silica gel column chromatography. Yield 52%.

NMR (90 MHz, CDCl 3) δ: 1.25 (d, J = 7 Hz, 17-Me), 1.37 (5, 2-Me), 1.55 (s, 11-Me), 1.84 (s, 5-Me), 2.23 ( s, NMe2) to 2.3 (m, 15-H2, 17-H), 2.43 (s, COCOCH3, 2.73 (t, J = 7 Hz, CH2NMe2) to 2.8 (m, 9-H2), 4.30 (t, J = 7 Hz, tetrazole -CH2) to 4.3 (m, 14-H, 8-H) to 4.4 (m, 16-H), 5.2 to 6.0 (m, 3-H, 6-H, 7-H, 10- H, 13-H), 6.17 (d, J = 15 Hz, 12-H), 8.07 (d, J = 10 Hz, NH).

IR (KBr): 1740, 1706, 1682, 1500, 1448, 1386, 1356, 1258 cm ^-1 .

Example 177

8-dehydroxy-8-[[1- (3-dimethylaminopropyl) -1H-tetrazol-5-yl] thio] -lancassidin C (8-β-compound):

The reaction was carried out at room temperature for 22.5 hours and purified by silica gel column chromatography. Yield 63%.

NMR (90 MHz, CDCl 3) δ: 1.28 (d, J = 7 Hz, 17-Me), 1.38 (s, 2-Me), 1.53 (s, 11-Me), 1.88 (s, 5-Me). 1.9 to 2.8 (m, CH2CH2NMe2, 15-H, 17-H, 9-H2), 2.20 (s, NMe2), 2.44 (s, COCOCH3), 4.28 (t, J = 7 Hz, tetrazole -CH2) to 4.45 (m, 16-H, 14-H), 4.73 (d, J = 11 Hz, 4-H), 4.94 (m, 8-H), 5.2-6.0 (m, 3-H, 6-H, 7- H, 10-H, 13-H), 6.21 (d, J = 15 Hz, 12-H), 8.07 (d, J = 10 Hz, NH).

IR (KBr): 3380, 1742, 1706, 1686, 1500, 1450, 1384, 1356, 1258cn- ¹ .

Example 178

8-dehydroxy-8-[[1- (3-dimethylaminopropyl) -1H-tetrazol-5-yl] thio) -lancadine (8-α-compound):

The reaction was carried out at room temperature for 5 hours and purified by silica gel column chromatography. Yield 65%.

NMR (90MHz, CDCl3) δ: 1.26 (d, J = 7Hz, 17-Me), 1.38 (s, 2-Me), 1.53 (s, 11-Me), 1.88 (s, 5-Me), 1.9 ~ 2.8 (m, CH2CH2NMe2, 15-H2, 17-H, 9-H2), 2.19 (s, NMe2), 2.44 (s, COCOCH3), 4.28 (t, J = 7 Hz, tetrazole -CH2) to 4.45 (m , 16-H, 14-H), 4.73 (d, J = 11 Hz, 4-H), 4.94 (m, 8-H), 5.2-6.0 (m, 3-H, 6-H, 7-H, 10-H, 13-H), 6.17 (d, J = 15 Hz, 12-H), 8.07 (d, J = 10 Hz, NH).

IR (KBr): 3380, 1742, 1706, 1686, 1500, 1450, 1384, 1356, 1258 cm ^-1 .

Example 179

8-Dehydroxy-8-azido-lancassidin C:

Purification by silica gel column chromatography. Yield 82%.

NMR (90MHz, CDCl3) δ: 1.26 (d, J = 7Hz, 17-Me), 1.38 (s, 2-Me), 1.49 (s, 11-Me), 1.89 (s, 5-Me), 2.1 ~ 2.8 (m, 15-H2, 9-H2, 17-H), 2.44 (s, COCOCH3), 4.0 to 5.0 (m, 16-H, 8-H, 14-H, 4-H), 5.1 to 6.0 (m, 3-H, 6-H, 7-H, 10-H, 13-H), 6.14 & 6.19 & 6.23 (d, 1H, respectively, 2: 3: 1, J = 15Hz, 12-H) , 8.08 (d, J = 10 Hz, NH).

IR (KBr): 2110, 1744, 1708, 1686, 1504, 1354, 1256, 962 cm ^-1 .

Example 180

8-dehydroxy-8-chloro-lancassidin C:

Purification by silica gel column chromatography. Yield 91%.

NMR (90 MHz, DMSO-d 6 -CDCl 3 (1: 1)) δ: 1.22 (d, J = 7 Hz, 17-Me), 1.32 (s, 2-Me), 1.50 (s, 11-Me), 1.79 ( s, 5-Me), 1.95 to 2.8 (m, 15-H2, 17-H, 9-H2), 2.28 (s, COCOCH3), 4.22 (m, 8-H, 14-H) to 4.6 (m, 16-H), 4.82 (d, J = 11 Hz, 4-H), 5.1 to 5.8 (m, 3-H, 6-H, 7-H, 10-H, 13-H), 6.10 (d, J = 15 Hz, 12-H), 8.04 (d, J = 9 Hz, NH).

IR (KBr): 3410, 1702, 1674, 1488, 1352, 1260, 1134, 998, 960 cm ^-1 .

Example 181

3- (2- (L) -azidopropionamido) -rancon 8-acetate:

Purification by silica gel column chromatography. Yield 91%. Melting Point: 202 ° C (Decomposition) (AcOEt-Et2O)

NMR (90 MHz, CDCl 3) δ: 1.25 (d, 3H, J = 7 Hz), 1.37 (s, 3H), 1.52 (d, 3H, J = 7 Hz), 1.53 (s, 3H), 1.70 to 1.85 (m, 1H), 1.86 (s, 3H), 2.04 (s, 3H), 2.15 to 2.55 (m, 5H), 4.00 (q, 1H, J = 7 Hz), 4.10 to 4.75 (m, 3H), 4.90 to 5.90 ( m, 7H), 6.12 (d, 1H, J = 15 Hz), 7.47 (d, 1H, J = 10 Hz).

IR (KBr): 3410, 2140, 1740, 1710, 1660, 1250 cm ^-1 .

[α] D ²⁵ -167.5 ° (c = 0.48, CHCl3)

Example 182

3- (2- (D) -azidopropionamido) -rancon 8-acetate:

Purification by silica gel column chromatography. Yield 88%. Melting Point: 195 ~ 196 ℃ (AcOEt-Et2O)

NMR (90 MHz, CDCl 3) δ: 1.26 (d, 3H, J = 7 Hz), 1.40 (s, 3H), 1.45 (d, 3H, J = 7 Hz), 1.55 (s, 3H), 1.70 to 1.85 (m, 1H), 1.87 (s, 3H), 2.05 (s, 3H), 2.18-2.60 (m, 5H), 4.08 (q, 1H, J = 7 Hz), 4.20-4.72 (m, 3H), 4.90-5.90 ( m, 7H), 6.13 (d, 1H, J = 15 Hz), 7.48 (d, 1H, J = 10 Hz).

IR (KBr): 3400, 2110, 1760, 1740, 1715, 1660, 1260 cm ^-1 .

[α] D ²⁵ -197.0 ° (c = 0.495, CHCl 3)

Example 183

3- (2- (L) -acetylaminopropionamido) -lancon 8-acetate:

The reaction was carried out at 37 DEG C for 4.5 hours using 30-fold (weight) enzyme of 14-acetate and purified by silica gel column chromatography. Yield 36%.

NMR (90 MHz, CDCl 3) δ: 1.23 (d, 3H, J = 7 Hz), 1.29 (d, 3H, J = 7 Hz), 1.39 (s, 3H), 1.53 (s, 3H), 1.85 (s, 3H) , 1.99 (s, 3H), 2.04 (s, 3H), 2.00-2.60 (m, 6H), 4.20-4.75 (m, 3H), 4.90-5.90 (m, 7H), 6.13 (d, 1H, J = 15 Hz), 6.39 (d, 1H, J = 7 Hz), 7.06 (d, 1H, J = 10 Hz).

IR (KBr): 3400, 1740, 1715, 1665, 1255 cm ^-1 .

[α] D ²⁶ -172.8 ° (c = 0.125, EtOH)

Example 184

3- (2- (D) -acetylaminopropionamido) -lancon 8-acetate:

The reaction was carried out at room temperature for 7 hours and purified by silica gel column chromatography. Yield 68%. Melting Point: 192 ~ 193 ℃ (MeOH)

NMR (90 MHz, CDCl 3) δ: 1.23 (d, 3H, J = 7 Hz), 1.38 (d, 3H, J = 7 Hz), 1.38 (s, 3H), 1.54 (s, 3H), 1.62 (s, 1H) m 1.86 (s, 3H), 2.01 (s, 3H), 2.04 (s, 3H), 2.15-2.55 (m, 5H), 4.20-4.70 (m, 3H), 4.91-5.91 (m, 7H), 6.10 (d, 1H, J = 7 Hz), 6.13 (d, 1H, J = 15 Hz), 7.06 (d, 1H, J = 10 Hz).

IR (KBr): 3450, 1730, 1710, 1660, 1255 cm ^-1 .

[α] D ²⁶ -140.4 ^x (c = 0.535, EtOH)

Example 185

3- (2- (L) -butyrylaminopropionamido) -lancon 8-acetate:

Purification by silica gel column chromatography. Yield 98%.

NMR (90 MHz, CDCl 3) δ: 0.91 (t, 3H, J = 7 Hz), 1.23 (d, 3H, J = 7 Hz), 1.29 (d, 3H, J = 7 Hz), 1.38 (s, 3H), 1.54 ( s, 3H), 1.45-1.90 (m, 2H), 1.86 (s, 3H), 2.04 (s, 3H), 2.06-2.60 (m, 8H), 4.20-4.76 (m, 4H), 4.90-5.90 ( m, 7H), 6.13 (d, 1H, J = 15 Hz), 6.35 (d, 1H, J = 8 Hz), 7.08 (d, 1H, J = 10 Hz).

IR (KBr): 3400, 1740, 1715, 1660, 1255 cm ^-1 .

[α] D ²⁵ -177.8 ° (c = 0.445, EtOH)

Example 186

3- (2- (D) -butyrylaminopropionamido) -lancon 8-acetate:

Purification by silica gel column chromatography. Yield is quantitative.

Melting Point: 199`200 ℃ (AcOEt)

NMR (90 MHz, CDCl 3) δ: 0.91 (t, 3H, J = 7 Hz), 1.22 (d, 3H, J = 7 Hz), 1.38 (s, 3H), 1.39 (d, 3H, J = 7 Hz), 1.54 ( s, 3H), 1.50-.90 (m, 3H), 1.86 (s, 3H), 2.04 (s, 3H), 2.10-2.55 (m, 7H), 4.15-4.72 (m, 4H), 4.90-5.90 (m, 7H), 6.11 (d, 1H, J = 8 Hz), 6.13 (d, 1H, 15 Hz), 7.10 (d, 1H, J = 10 Hz).

IR (KBr): 3400, 1730, 1710, 1645, 1260 cm ^-1 .

[α] D ²⁵ -130.2 ° (c = 0.5, EtOH)

Example 187

3- (2- (L) -benzyloxycarbonylaminopropionamido) -lancon 8-acetate:

The reaction was carried out overnight at room temperature and purified by TLC. Yield 51%.

NMR (90 MHz, CDCl 3) δ: 1.24 (s, 3H), 1.30 (d, 3H, J = 7 Hz), 1.31 (d, 3H, J = 7 Hz), 1.54 (s, 3H), 1.76 (br.s, 2H), 1.86 (s, 3H), 2.04 (s, 3H), 2.10-2.55 (m, 5H), 4.04-4.70 (m, 4H), 4.90-5.90 (m, 7H), 5.10 (s, 2H) , 6.10 (d, 1H, J = 15 Hz), 7.05 (d, 1H, J = 10 Hz), 7.31 (s, 5H).

IR (KBr): 3420, 1730, 1715, 1250cm ^-1

[α] D ²⁵ -125.2 ° (c = 0.735, EtOH)

Example 188

3- (2- (D) -benzyloxycarbonylaminopropionamido) -lancon 8-acetate:

The reaction was carried out overnight at room temperature. Yield 100%.

Melting Point: 191 ~ 192 ℃ (AcEt)

NMR (90MHz, CDCl3) δ: 1.23 (d, 3H, J = 7Hz), 1.35 (s, 3H), 1.39 (d, 3H, J = 7Hz), 1.54 (s, 3H), 1.64 (s, 2H) , 1.86 (s, 3H), 2.04 (s, 3H), 2.15 to 2.50 (m, 5H), 4.06 to 4.70 (m, 4H), 4.90 to 5.90 (m, 7H), 5.11 (s, 2H), 6.10 (d, 1H, J = 15 Hz), 7.13 (d, 1H, J = 10 Hz), 7.33 (s, 5H).

IR (KBr): 3370, 1730, 1710, 1645, 1245 cm ^-1 .

[α] D ²⁵ -130.3 ° (c = 0.495, EtOH)

Example 189

3- (2- (L) -p-toluenesulfonylaminopropionamido) -lancon 8-acetate:

The reaction was carried out at room temperature for 24 hours using 60 times (weight) enzyme of 14-acetate and separated by TLC. Yield 48%.

Melting Point: 182 ~ 183 ℃ (AcOEt).

NMR (90 MHz, CDCl 3) δ: 1.23 (d, 6H, J = 7 Hz), 1.26 (s, 3H), 1.52 (s, 3H), 1.81 (s, 3H), 1.90 (br. S, 2H), 2.04 (s, 3H), 2.10 to 2.55 (m, 5H), 2.38 (s, 3H), 3.78 (folder, 1H, J = 7 Hz), 4.15 to 4.65 (m, 3H), 4.90 to 5.90 (m, 7H ), 6.13 (d, 1H, J = 15 Hz), 7.10-7.40 (m, 3H), 7.73 (d, 2H, J = 8 Hz).

IR (KBr): 3400, 1740, 1715, 1670, 1260 cm ^-1 .

[α] d ²⁵ -164.2 ° (c = 0.095, EtOH)

Example 190

3- (2- (D) -p-toluenesulfonylaminopropionamido) -lancon 8-acetate:

The reaction was carried out at room temperature for 21 hours using 40-fold (weight) enzyme of 14-acetate, and purified by silica gel column chromatography. Yield 82%.

Melting Point: 198 ~ 199 ℃ (AcOEt)

NMR (90 MHz, CDCl3- (CD3) 2C = 0) δ: 1.22 (d, 3H, J = 7 Hz), 1.26 (d, 3H, J = 7 Hz), 1.39 (s, 3H), 1.54 (s, 3H) , 1.81 (s, 3H), 2.14 (s, 3H), 2.10 ~ 2.55 (m, 5H), 2.52 (s, 1H), 3.32 (d, 1H, J = 4Hz), 3.76 (pentagon, 1H, J = 7 Hz), 4.10-4.76 (m, 3H), 4.90-5.90 (m, 7H), 6.14 (d, 1H, J = 15 Hz), 6.34 (d, 1H, J = Hz), 7.27 (d, 2H, J = 8 Hz), 7.72 (d, 2H, J = 8 Hz).

IR (KBr): 3420, 1730, 1715, 1660, 1260 cm ^-1 .

[α] D ²⁵ -119.5 ° (c = 0.4, EtOH)

Example 191

3- (2- (L) -diphenylphosphinothioylaminopropionamido) -lancon 8-acetate:

The reaction was carried out at room temperature for 28 hours using 40 times the weight of enzyme of 14 acetate, and separated by TLC. Yield 40%.

NMR (90 MHz, CDCl 3) δ: 1.23 (d, 3H, J = 7 Hz), 1.28 (d, 3H, J = 7 Hz), 1.34 (s, 3H), 1.53 (s, 3H), 1.84 (s, 3H) , 1.95 (br. S, 1H), 2.04 (s, 3H), 2.10 to 2.55 (m, 5H), 3.50 (dd, 1H, J = 5 Hz & 9 Hz), 3.70 to 4.70 (m, 4H), 4.90 to 5.90 (m, 7H), 6.14 (d, 1H, J = 15 Hz), 7.17 (d, 1H, J = 10 Hz), 7.30-7.55 (m, 6H), 7.70-8.15 (m, 4H).

IR (KBr): 3400, 1740, 1710, 1665, 1255 cm ^-1 .

[α] D ²⁵ -117.9 ° (c = 0.655, EtOH)

Example 192

3- (2- (D) -diphenylphosphinothioylaminopropionamido) -lancon 8-acetate:

The reaction was carried out at room temperature for 17 hours using 40 times the enzyme weight of 14-acetate. Yield 74%.

NMR (90 MHz, DMSO-d6) δ: 1.22 (d, 3H, J = 7 Hz), 1.26 (d, 3H, J = 7 Hz), 1.32 (s, 3H), 1.55 (s, 3H), 1.70 (s, 3H), 2.00 (s, 3H), 2.20-2.60 (m, 6H), 3.60-5.90 (m, 12-H), 6.13 (d, 1H, J = 15 Hz), 7.35-7.62 (m, 6H), 7.66-8.13 (m, 5 H).

IR (KBr): 3390, 1740, 1710, 1650, 1255 cm ^-1 .

[α] D ²⁴ -97.0 ° (c = 0.44, DMF)

Example 193

3- [3- (benzoxazol-2-yl) thio-2-oxopropionamido] -lancon 8-acetate:

Purification by silica gel column chromatography inactivated with 10% water and further purification using a reverse phase TLC plate. Yield 44%.

NMR (90 MHz, CDCl 3) δ: 1.23 (d, 3H, J = 7 Hz), 1.41 (s, 3H), 1.56 (s, 3H), 1.65 (br, s, 1H), 1.92 (s, 3H), 2.06 (s, 3H), 2.15 to 2.55 (m, 5H), 4.10 to 4.80 (m, 4H), 4.95 to 5.92 (m, 6H), 6.12 (d, 1H, J = 15 Hz), 7.15 to 7.60 (m, 4H), 8.10 (d, 1H, J = 10 Hz).

IR (KBr): 3490, 1725, 1700, 1680, 1235 cm ^-1 .

[α] D ²⁵ -114.3 ° (c = 0.2275, CHCl3)

Example 194

3- (2-Aminothiazol-4-yl) carboxamido-lancon 8-acetate:

Purification by silica gel column chromatography. Yield 97%, Melting Point: 182 ~ 184 ℃ (CHCl3)

NMR (90 MHz, CDCl 3) δ: 1.25 (d, 3H, J = 7 Hz), 1.43 (s, 3H), 1.55 (s, 3H), 1.75 (br.s, 1H), 1.90 (s, 3H), 2.04 (s, 3H), 2.15 to 2.50 (m, 5H), 4.20 to 5.92 (m, 11H), 6.13 (d, 1H, J = 15 Hz), 7.32 (s, 1H), 8.10 (d, 1H, J = 10 Hz).

IR (KBr): 3400, 1730, 1715, 1250 cm ^-1 .

[α] D ^24.5 -77.7 ° (c = 0.44, EtOH)

Example 195

3- (2- (D) -Ethylthiopropionamido) -Rancon 8-acetate:

Purification by TLC. Yield 87%.

NMR (90 MHz, CDCl 3) δ: 1.22 (t, 3H, J = 7 Hz), 1.28 (d, 3H, J = 7 Hz), 1.39 (d, 3H, J = 7 Hz), 1.40 (s, 3H), 1.54 ( s, 3H), 1.86 (s, 3H), 2.03 (s, 3H) to 2.1 (br.s, 1H), 2.15 to 2.67 (m, 7H), 3.38 (q, 1H, J = 7 Hz), 4.20 to 4.83 (m, 3H), 4.92-5.53 (m, 6H), 6.15 (d, 1H, J = 15 Hz), 7.73 (d, 1H, J = 10 Hz).

IR (KBr): 3420, 1740, 1715, 1670, 1255 cm ^-1 .

[α] D ²⁴ -135.4 ° (c = 0.435, EtOH)

Example 196

3- (2- (L) -ethylthiopropionamido) -lancon 8-acetate:

Purification by TLC. Yield 68%.

Melting Point: 1709 ~ 180 ℃ (Et2O)

NMR (90 MHz, CDCl 3) δ: 1.20 (t, 3H, J = 7), 1.25 (d, 3H, J = 7 Hz), 1.39 (s, 3H), 1.47 (d, 3H, J = 7 Hz), 1.54 ( s, 3H), 1.88 (s, 3H), 2.04 (s, 3H), 2.16-2.60 (m, 7H), 3.36 (q, 1H, J = 7 Hz), 4.20-4.80 (m, 3H), 4.94- 5.93 (m, 6H), 6.16 (d, 1H, J = 15 Hz), 7.80 (d, 1H, J = 10 Hz).

IR (KBr): 3420, 1740, 1715, 1670, 1255 cm ^-1 .

[α] D ²⁴ -193.3 ° (c = 0.36, EtOH)

Example 197

3- [3- (pyridin-2-yl) thio-2-hydroxyiminopropionamido] -lancon 8-acetate:

Purification by silica gel column chromatography. Yield 73%.

NMR (90 MHz, CDCl 3) δ: 1.22 (d, 3H, J = 7 Hz), 1.39 (s, 3H), 1.54 (s, 3H), 1.89 (s, 3H) to 2.0 (br, s. 1H), 2.05 (s, 3H), 2.15 to 2.55 (m, 5H), 4.22 (s, 2H), 4.15 to 4.56 (m, 2H), 4.72 (br. d, 1H, J = 10 Hz), 4.90 to 5.53 (m, 6H), 6.15 (d, 1H, J = 15 Hz), 6.95 to 7.85 (m, 3H), 8.01 (br. D, 1H, J = 10 Hz), 8.40 (m, 1H) to 11.5 (br.s, 1H ).

IR (KBr): 3400, 1740, 1710, 1670, 1260 cm ^-1 .

[α] D ²¹ -120.0 ° (c = 0.365, EtOH)

Example 198

Preparation of 3- [3- (pyridin-2-yl) thio-2-methoxyiminopropionamido] -lancon 8-acetate:

Purification by silica gel column chromatography. Yield 78%.

NMR (90 MHz, CDCl 3) δ: 1.23 (d, 3H, J = 7 Hz), 1.38 (s, 3H), 1.55 (s, 3H), 1.66 (br.s, 1H), 1.89 (s, 3H), 2.05 (s, 3H), 2.15 to 2.55 (m, 5H), 4.03 (s, 3H), 4.26 (s, 2H), 4.20 to 4.55 (m, 2H), 4.72 (br. d, 1H, J = 11 Hz) , 4.93-5.92 (m, 6H), 6.15 (d, 1H, J = 15 Hz), 6.85-7.55 (m, 3H), 7.76 (br. D, 1H, J = 10 Hz), 8.38 (m, 1H).

IR (KBr): 3400, 1740, 1715, 1680, 1260 cm ^-1 .

[α] D ²² -163.1 ° (c = 0.065, EtOH)

Example 199

Preparation of 3- [3-pyridin-2-yl) thio-2- (L) -hydroxypropionamido] -lancon 8-acetate:

The reaction was carried out using 2 '-(DL) compound, and the product was separated by TLC. Yield 31%.

NMR (90MHz, CDCl3) δ: 1.21 (d, 3H, J = 7Hz), 1.36 (s, 3H), 1.55 (s, 3H), 1.90 (s, 3H), 2.15 (s, 3H) ~ 1.7 (br s, 2H), 2.15 to 2.55 (m, 5H), 3.57 (d, 2H, J = 4 Hz), 4.16 to 4.56 (m, 3H), 4.75 (br. d, 1H, J = 11 Hz), 4.95 to 5.95 (m, 6H), 6.16 (d, 1H, J = 15 Hz), 7.02-77.7 (m, 3H), 8.19 (br. D, 1H, J = 10 Hz), 8.45 (m, 1H).

IR (KBr): 3400, 1740, 1710, 1670, 1260 cm ^-1 .

[α] D ²¹ -213.6 ° (c = 0.11, EtOH)

Example 200

3- [3- (pyridin-2-yl) thio-2- (D) -hydroxypropionamido] -lancon 8-acetate:

The reaction was carried out using a 2 '-(DL) compound, and the product was separated by TLC. Yield 33%.

NMR (90 MHz, CDCl 3) δ: 1.23 (d, 3H, J = 7 Hz), 1.42 (s, 3H), 1.55 (s, 3H), ˜1.80 (br.s, 2H), 1.89 (s, 3H), 2.05 (s, 3H), 2.15 ~ 2.55 (m, 5H), 3.30 ~ 3.70 (m, 2H), 4.15 ~ 4.58 (m, 3H), 4.72 (br. D, 1H, J = 11Hz), 4.95 ~ 5.95 (m, 6H), 6.14 (d, 1H, J = 15 Hz), 7.00-7.70 (m, 3H), 8.16 (br. d, 1H, J = 10 Hz), 8.10 (m, 1H).

IR (KBr): 3400, 1740, 1710, 1670, 1255 cm ^-1 .

[α] D ²¹ -64.3 ° (c = 0.185, EtOH)

Example 201

Lancacidin C 8-dibenzylphosphate:

The reaction was carried out at room temperature and purified by silica gel column chromatography.

Yield: 68%

Melting Point: 194 ° C (Decomposition) (AcOEt)

NMR (90MHz, CDCl3) δ: 1.24 (d, 3H, J = 7Hz), 1.37 (s, 3H), 1.49 (s, 3H), 1.83 (s, 3H), 2.15 ~ 2.65 (m, 6H), 2.45 (s, 3H), 4.15 to 4.80 (m, 4H), 4.97 (d, 2H, J = 8 Hz), 5.01 (d, 2H, J = 8 Hz), 5.05 to 5.90 (m, 5H), 6.10 (d, 1H, J = 15 Hz), 7.29 (s, 5H), 7.31 (s, 5H), 8.11 (br. D, 1H, J = 10 Hz).

IR (KBr): 3425, 1755, 1715, 1695, 1265, 1000 cm ^-1 .

[α] D ²⁴ -157.6 ° (c = 0.49, CHCl3)

Example 202

Lancacidin C 8-diethylphosphate:

The reaction was carried out at 35 ° C. for 1 hour and purified by silica gel column chromatography.

Yield: 79%

Melting Point: 194 ° C (Decomposition) (AcOEt-Et2O)

NMR (90MHz, CDCl3) δ: 1.20 ~ 1.40 (m, 12H), 1.54 (s, 3H), 1.79 (br.s, 1H), 1.90 (s, 3H), 2.20 ~ 2.70 (m, 5H), 2.45 (s, 3H), 2.87 to 4.80 (m, 8H), 5.15 to 5.53 (m, 5H), 6.13 (d, 1H, J = 15H), 8.09 (br. d, 1H, J = 10 Hz).

IR (KBr): 3400, 1745, 1710, 1680, 1260, 1005 cm ^-1 .

[α] D ²⁴ -193.7 ° (c = 0.46, EtOH)

Example 203

Lancacidin C 8-dimethylphosphate

Purification by silica gel column chromatography.

Yield: 95%

Melting Point: 173 ° C (Decomposition) (AcOEt)

NMR (90MHz, CDCl3) δ: 1.26 (d, 3H, J = 7Hz), 1.37 (s, 3H), 1.54 (s, 3H), 1.90 (s, 3H), 2.15 ~ 2.70 (m, 5H), 2.45 (s, 3H), 2.84 (br. s, 1H), 3.69 (d, 3H, J = 12 Hz), 3.74 (d, 3H, J = 12 Hz), 4.20 to 4.85 (m, 4H), 5.15 to 5.98 ( m, 5H), 6.13 (d, 1H, J = 15 Hz), 8.15 (br. d, 1H, J = 10 Hz).

IR (KBr): 3410, 1755, 1715, 1690, 1265, 1015 cm ^-1 .

[α] D ²⁴ -222.0 ° (c = 0.5, CHCl3)

Example 204

3- (2-Oxo-1-thioxopropylamino) -lancon 8-diethylphosphate:

The reaction was carried out at 37 ° C. for 2 hours and purified by silica gel column chromatography.

Yield: 89%

NMR (90 MHz, CDCl 3) δ: 1.20 to 1.45 (m, 12H), 1.56 (s, 3H), 1.96 (s, 3H), 2.05 (br.s, 1H), 2.16 to 2.65 (m, 5H), 2.65 (m, 3H), 3.88 to 4.80 (m, 8H), 5.15 to 6.25 (m, 6H), 10.01 (br. d, 1H, J = 10 Hz).

IR (KBr): 3420, 1755, 1710, 1265, 1010 cm ^-1 .

[α] D ²⁴ -303.0 ° (c = 0.1, EtOH)

Example 205

3- (2- (DL) -n-octanoyloxypropionamido) -lancon 8-diethylphosphate:

The reaction was carried out overnight at 30 ° C. for 2 hours at room temperature and purified by TLC.

Yield: 64%

NMR (90 MHz, CDCl 3) δ: 0.87 (~ t, 3H), 1.15 to 1.95 (m, 34H), 2.10 to 2.70 (m, 8H), 3.85 to 4.80 (m, 8H), 5.05 to 5.95 (m, 6H ), 6.12 (d, 1H, J = 15 Hz), 7.30 (br, d, ˜0.5H, J = 10 Hz), 7.45 (br. D, ˜0.5H, J = 10 Hz).

IR (KBr): 3430, 2945, 1750, 1710, 1685, 1265, 1035, 1010 cm ^-1 .

Example 206

3- (2- (DL) -hydroxypropionamido) -lancon 8-diethylphosphate:

Purification by silica gel column chromatography.

Yield: 85%

NMR (90 MHz, CDCl 3) δ: 1.15 to 1.50 (m, 15H), 1.54 (s, 3H), 1.88 (s, 3H), 2.10 to 2.68 (m, 6H), 3.49 (br. S, 1H), 3.88 ~ 4.80 (m, 9H), 5.15-5.95 (m, 5H), 6.13 (d, 3H, J = 15 Hz), 7.57 (br. D, ~ 0.5H, J = 10 Hz), 7.73 (br. D, ~ 0.5H, J = 10 Hz).

IR (KBr): 3420, 1750, 1715, 1655, 1265, 1040, 1010 cm ^-1 .

Example 207

3-cyclohexylcarboxamido-rancon 8-acetate:

The reaction was carried out overnight at room temperature and purified by TLC.

Yield: 25%

Melting Point: 169 ~ 172 ℃

NMR (90MHz, CDCl3) δ: 1.23 (d, J = 7Hz, 17-Me), 1.37 (s, 2-Me), 1.54 (s, 11-Me), 1.87 (s, 5-Me), 1.2 ~ 2.0 (m, cyclohexyl-CH2 x 5), 2.04 (s, OAc), 2.2-2.6 (m, 9-H2, 15-H2, 17-H, cyclohexyl-CH), 4.3-4.5 (m, 14 -H, 16-H), 4.64 (d, J = 11 Hz, 4-H), 5.06 (m, 8H), 5.15-5.95 (m, 3-H, 6-H, 7-H, 10-H, 13-H), 6.16 (d, J = 15 Hz, 12-H), 6.60 (d, J = 10 Hz, NH).

IR (KBr): 3450, 2930, 1735, 1705, 1650, 1495, 1450, 1370, 1245, 1015, 960, 745 cm ^-1 .

Example 208

3- (2-thienyl) acetamido-rancon 8-acetate:

The reaction was carried out overnight at room temperature and purified by TLC.

Yield: 43%

Melting Point: 187 ~ 189 ℃ (Decomposition)

NMR (90 MHz, CDCl 3) δ: 1.18 (d, J = 6.5 Hz, 17-Me), 1.30 (s, 2-Me), 1.53 (s, 11-Me), 1.87 (s, 5-Me), 1.74 (br. s, OH), 2.04 (s, OAc), 2.15 to 2.55 (m, 9-H2, 15-H2, 17-H), 3.75 (s, thiophene-CH2), 4.15 to 4.45 (m, 14-H, 16-H), 4.58 (d, J = 11 Hz, 4-H), 5.03 (m, 8-H), 5.15-5.9 (m, 3-H, 6-H, 7-H, 10 -H, 13-H), 6.11 (d, J = 15 Hz, 12-H), 6.79 (d, J = 10 Hz, NH), 6.95-7.1 (m, 2H, thiophene-H2), 7.2-7.3 ( m, 1H, thiophene-H).

IR (KBr): 3430 (sh.), 3390, 1735, 1710, 1650, 1375, 1265, 1240, 1020, 965 cm ^-1 .

Example 209

3- [D (-)-2- (4-ethyl-2, 3-dioxo-1-piperazine carboxamido) phenylacetamido] -rancon 8-acetate:

The reaction was carried out overnight at room temperature and purified by TLC.

Yield: 24%

Melting Point: 166 ~ 169 ℃

NMR (90 MHz, CDCl 3) δ: 1.01 (s, 2-Me), 1.16 (d, J = 7 Hz, 17-Me), 1.20 (t, J = 7.5 Hz, CH 2 CH 3), 1.52 (s, 11-Me) , 1.71 (br. S, OH), 1.84 (s, 5-Me), 2.05 (s, OAc), 2.1 to 2.55 (m, 9-H2, 15-H2, 17-H), 3.53 (q, J = 7.5 Hz, CH2CH3), 3.4-3.6 & 3.95-4.15 (m, 2H each, piperazine -H4), 4.15-4.45 (m, 14-H, 16-H), 4.64 (d, J = 11 Hz, 4-H), 5.06 (m, 8-H), 5.25-5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H, C6H5CH), 6.14 (d, J = 15 Hz 12-H), 6.93 (d, J = 10 Hz, 3-NH), 7.38 (br. S, C6H5), 9.93 (d, J = 6 Hz, C6H5CHNH).

IR (KBr): 3420 (br.), 1710, 1680, 1500, 1370, 1250, 1185, 1015, 960 cm ^-1 .

Example 210

3- [D (-)-2- (2, 2, 2-trichloroethoxycarbonylamino) phenylacetamido] -rancon 8-acetate:

The reaction was carried out at 33 ° C. for 20 hours and purified by TLC.

Yield: 25%

Melting Point: 147 ~ 150 ℃

NMR (90 MHz, CDCl 3) δ: 0.85 (s, 2-Me), 1.17 (d, J = 6.5 Hz, 17-Me), 1.52 (s, 11-Me), 1.59 (s, OH), 1.87 (s , 5-Me), 2.04 (s, OAc), 2.15 to 2.55 (m, 9-H2, 17-H), 4.15 to 4.55 (m, 14-H, 16-H), 4.63 (d, J = 11 Hz , 4-H), 4.57 & 4.73 (ABq, J = 12 Hz, CCl3CH2), 4.9-5.2 (m, 8-H, C5H5CH), 5.3-5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H), 6.12 (d, J = 15 Hz, 12-H), 6.47 (br, d, J = 7 Hz, NHCOO), 6.91 (br, J = 10 Hz, 3-NH), 7.37 ( br.s, C6H5).

IR (KBr): 3415 (br.), 1735, 1710, 1680, 1495, 1370, 1250, 1060, 1020, 960, 745, 720, 695 cm ^-1 .

Example 211

3- [D (-)-2-aminophenylacetamido] -rancon 8-acetate:

The reaction was carried out at 30 to 35 ° C. for 22 hours and purified by TLC.

Yield: 27%

Melting Point 135 ~ 137 ℃

NMR (90 MHz, CDCl 3) δ: 1.21 (s, 2-Me), 1.21 (d, J = 6.5 Hz, 17-Me), 1.53 (s, 11-Me), 1.83 (s, 5-Me), 1.7 ~ 2.01 (br., OH, NH2), 2.03 (s, OAc), 2.15-2.45 (m, 9-H2, 15-H2, 17-H), 4.25-4.5 (m, 14-H, 16-H ), 4.68 (d, J = 11 Hz, 4-H), 5.07 (m, 8-H), 5.2-5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H, C6H5CH), 6.15 (d, J = 15 Hz, 12-H), 7.31 (s, C6H5), 7.79 (br. D, J = 10 Hz, NH).

IR (KBr): 3400 (br.), 1735, 1705, 1670, 1490, 1370, 1245, 1020, 960 cm ^-1 .

Example 212

Lancadine C 8- (2-methoxyethoxymethylether):

Purification by silica gel column chromatography.

Yield: 99%

Melting Point: 168 ~ 170 ℃ (CHCl3-hexane)

NMR (90 MHz, CDCl 3) δ: 1.25 (d, J = 6.5 Hz, 17-Me), 1.34 (s, 2-Me), 1.47 (s, 11-Me), 1.89 (s, 5-Me), 2.2 ~ 2.55 (m, 9-H2, 15-H2, 17-H), 2.45 (s, COCOCH3), 3.35 (s, CH2CH2OCH3), 3.45-3.8 (m, CH2CH2OCH3), 4.01 (m, 8-H), 4.3 ~ 4.55 (m, 14-H, 16-H), 4.66 (d, J = 11Hz, 4-H), 4.71 (s, OCH2O), 5.2 ~ 5.95 (m, 3-H, 6-H, 7 -H, 10-H, 13-H), 6.16 (d, J = 15 Hz, 12-H), 8.07 (d, J = 10 Hz, NH).

IR (KBr): 3470, 3375, 2940, 2890, 1745, 1705, 1670, 1515, 1505 (sh.), 1450, 1350, 1255, 1130, 1100, 1085, 1060, 1035, 1015, 980, 960cm ^-1 .

Example 213

Lancacidin C 8-methoxymethylether:

Purification by silica gel column chromatography.

Yield: 77%

Melting Point: 197 ~ 199 ℃ (Decomposition)

NMR (90 MHz, CDCl 3) δ: 1.23 (d, J = 6.5 Hz, 17-Me), 1.35 (s, 2-Me), 1.48 (s, 11-Me), 1.51 (s, OH), 1.90 (s , 5-Me), 2.2-2.55 (m, 9-H2, 15-H2, 17-H), 2.43 (s, COCOCH3), 3.32 (s, CHsOCH3), 3.96 (m, 8-H), 4.25- 4.55 (m, 14-H, 16-H), 4.57 & 4.64 (ABq, J = 10 Hz, CH2OCH3), 4.65 (d, J = 11 Hz, 4-H), 5.2-5.9 (m, 3-H, 6 -H, 7-H, 10-H, 13-H), 6.15 (d, J = 15 Hz, 12-H), 8.06 (d, d = 10 Hz, NH).

IR (KBr): 3450, 3375, 2930, 1745, 1725 (sh.), 1705, 1670, 1505, 1350, 1250, 1220, 1140, 1090, 1060, 1020, 960 cm ^-1 .

Example 214

3-dehydroxy-8- (1-methyl-1H-tetrazol-5-yl) thio-lancassidin C:

The reaction was carried out at room temperature for 20 hours and subjected to silica gel column chromatography.

Yield: 74%

Melting Point: 182 ~ 184 ℃ (CHCl3-Et2O)

NMR (90 MHz, CDCl 3) δ: 1.27 (d, J = 6.5 Hz, 17-Me), 1.37 (s, 2-Me), 1.53 (s, 11-Me), 1.90 (s, 5-Me), 2.2 ~ 2.85 (m, 9-H2, 15-H2, 17-H), 2.44 (s, COCOCH3), 3.91 (s, tetrazol -CH3), 4.25-4.5 (m, 14-H), 4.47 (m, 16-H), 4.72 (d, J = 10 Hz, 4-H), 4.85 to 5.05 (m, 8-H), 5.3 to 60. (m, 3-H, 6-H, 7-H, 10- H, 13-H), 6.22 (d, J = 15.5 Hz, 12-H, 8,07 (d, J = 11 Hz, NH).

IR (KBr): 3460, 1745, 1705, 1665, 1605, 1380, 1350, 1250, 1160, 1150, 1130, 1055, 1010, 960 cm ^-1 .

Example 215

8-dehydroxy-8- (5-methyl-1,3,4-thiadiazolyl) thio-lancassidin C:

The reaction was carried out overnight at room temperature and purified by TLC.

Yield: 85%

Melting Point: 142-144 ° C (CHCl3-Et2O-C6H14)

NMR (90 MHz, CDCl 3) δ: 1.27 (d, J = 6.5 Hz, 17-Me), 1.37 (s, 2-Me), 1.50 (s, 11-Me), 1.90 (s, 5-Me), 2.2 2.8 (m, 9-H2, 15-H2, 17-H), 2.44 (s, COCOCH3), 2.66 (s, thiadiazole-CH3), 4.25-4.6 (m, 14-H, 16-H) , 4.71 (d, J = 11 Hz, 4-H), 4.7-4.9 (m, 8-H), 5.3-6.1 (m, 3-H, 6-H, 7-H, 10-H, 13-H ), 6.22 (d, J = 15 Hz, 12-H), 8.07 (d, J = 10 Hz, NH).

IR (KBr): 3450 (br.), 1735, 1700, 1675, 1490, 1370, 1350, 1250, 1130, 1050, 955 cm ^-1 .

Example 216

8-dehydroxy-8-phenylthio-lancassidin C:

The reaction was carried out overnight at room temperature and purified by TLC.

Yield: 70%

NMR (90 MHz, CDCl 3) δ: 1.27 (d, J = 6.5 Hz, 17-Me), 1.37 (s, 2-Me), 1.52 (s, 11-Me), 1.64 (br., OH), 1.92 ( s, 5-Me), 2.2 to 2.7 (m, 9-H2, 15-H2, 17-H), 2.45 (s, COCOCH3), 4.2 to 4.6 (m, 8-H, 14-H, 16-H ), 4.74 (d, J = 11 Hz, 4-H), 5.3 to 5.6 (m, 3-H, 7-H, 10-H, 13-H), 6.15 (d, J = 15 Hz, 6-H) , 6.28 (d, J = 15 Hz, 12-H), 7.15-7.45 (m, C6H5), 8.10 (d, J = 10 Hz, NH).

IR (KBr): 3400, 2930, 1750, 1710, 1680, 1505, 1455, 1440, 1360, 1260, 1225, 1160, 1140, 1060, 1005, 965, 745 cm ^-1 .

Example 217

8-dehydroxy-8- [5- (2-dimethylaminoethyl) -1,3,4-thiadiazol-2-yl] thio-lancassidin C:

The reaction was carried out overnight at room temperature and purified by TLC.

Yield: 47%

NMR (90 MHz, CDCl 3) δ: 1.26 (d, J = 6.5 Hz, 17-Me), 1.37 (s, 2-Me), 1.52 (s, 11-Me), 1.89 (s, 5-Me), 2.07 (br., OH), 2.26 (s, NMe2), 2.2 to 2.8 (m, 9-H2, 15-H2, 17-H), 2.43 (s, COCOCH3), 2.60 (t, J = 6.5 Hz, CH2NMe2 ), 3.15 (t, J, 6.5 Hz, thiadiazole-CH2), 4.2 to 4.55 (m, 14-H, 16-H), 4.70 (d, J = 11 Hz, 4-H), 4.78 (m, 8-H), 5.3-6.1 (m, 3-H, 6-H, 7-H, 10-H, 13-H), 6.22 (d, J = 15 Hz, 12-H), 8.06 (d, J = 10 Hz, NH).

IR (KBr): 3380, 2940, 1745, 1705, 1685, 1500, 1450, 1375, 1360, 1260, 1160, 1140, 1055, 1010, 960, 745 cm ^-1 .

Example 218

8-dehydroxy-8- (4,5-dimethylthiazol-2-yl) thio-lancassidin C:

Purification was carried out by TLC.

Yield: 61%

NMR (90 MHz, CDCl 3) δ: 1.27 (d, J = 6.5 Hz, 17-Me), 1.37 (s, 2-Me), 1.51 (s, 11-Me), 1.7-1.9 (br., OH), 1.89 (s, 5-Me), 2.2-2.75 (m, 9-H2, 15-H2, 17-H), 2.25 (s, thiazole-CH3 x 2), 2.43 (s, COCOCH3), 4.3-4.6 (m, 8-H, 14-H, 16-H), 4.73 (d, J = 11 Hz, 4-H), 5.3-5.95 (m, 3-H, 7-H, 10-H, 13-H ), 6.03 (d, J = 15 Hz, 6-H), 6.22 (d, J = 15 Hz, 12-H), 8.06 (d, J = 10 Hz, NH).

IR (KBr): 3380, 2910, 1740, 1700, 1680, 1490, 1360 (sh.), 1350, 1250, 1155, 1125, 1050, 1005, 955 cm ^-1 .

Example 219

8-dehydroxy-8- (4,5-dimethyloxazol-2-yl) thio-lancassidin C:

Purification was carried out by TLC.

Yield: 64%

NMR (90 MHz, CDCl 3) δ: 1.27 (d, J = 6.5 Hz, 17-Me), 1.37 (s, 2-Me), 1.51 (s, 11-Me), 1.76 (brs., OH), 1.88 ( s, 5-Me), 2.01 & 2.17 (s, oxazole -CH3 x 2, respectively), 2.2-2.75 (m, 9-H2, 15-H2, 17-H), 2.43 (s, COCOCH3), 4.2- 4.55 (m, 14-H, 16-H), 4.65 (m, 8-H), 4.72 (d, J = 10 Hz, 4-H), 5.3-6.05 (m, 3-H, 6-H, 7 -H, 10-H, 13-H), 6.22 (d, J = 15 Hz, 12-H), 8.05 (d, J = 10 Hz, NH).

IR (KBr): 3400, 2930, 1750, 1710, 1690, 1500, 1450, 1360, 1260, 1225, 1185, 1165, 1140, 1060, 1010, 965, 745 cm ^-1 .

Example 220

8-dehydroxy-8- (1-dimethylamino-1H-tetrazol-5-yl) thio-lancassidin C:

The reaction was carried out at room temperature for 5.5 hours.

Yield: 78%

NMR (90 MHz, CDCl 3) δ: 1.27 (d, J = 6.5 Hz, 17-Me), 1.38 (s, 2-Me), 2.54 (s, 11-Me), 1.90 (s, 5-Me), ~ 2.0 (br., OH), 2.2 to 2.85 (m, 9-H2, 15-H2, 17-H), 2.44 (s, COCOCH3), 2.95 (s, NMe2), 4.2 to 4.55 (m, 14-H , 16-H), 4.72 (d, J = 11 Hz, 4-H), 4.98 (m, 8-H), 5.3-6.0 (m, 3-H, 6-H, 7-H, 10-H, 13-H), 6.23 (d, J = 15 Hz, 12-H), 8.07 (d, J = 10 Hz, NH).

IR (KBr): 3390, 2980, 2930, 1745, 1710, 1685, 1500, 1440, 1380, 1355, 1250, 1220, 1160, 1135, 1055, 1010, 960, 745 cm ^-1 .

Example 221

8-dehydroxy-8- (1-ethyl-1H-1, 2, 4-triazol-3-yl) thio-lancassidin C:

Purification was carried out by TLC.

Yield: 81%

Melting Point: 139 ~ 141 ℃ (Decomposition) (CHCl3-Et2O-C6H14)

NMR (90 MHz, CDCl 3) δ: 1.27 (d, J = 6.5 Hz, 17-Me), 1.37 (s, 2-Me), 1.46 (t, J = 7.5 Hz, CH 2 CH 3), 1.52 (s, 11-Me ), 1.87 (s, 5-Me), 2.2 to 2.75 (m, 9-H2, 15-H2, 17-H, OH), 2.43 (s, COCOCH3), 4.13 (q, J = 7,5 Hz, CH2CH3 ), 4.3 to 4.6 (m, 14-H, 16-H), 4.73 (d, J = 10 Hz, 4-H), 4.73 (m, 8-H), 5.3 to 6.1 (m, 3-H, 6) -H, 7-H, 10-H, 13-H), 6.23 (d, J = 15 Hz, 12-H), 7.97 (s, triazole-H), 8.07 (d, J = 10 Hz, NH).

IR (KBr): 3390, 2980, 2925, 1740, 1700, 1680, 1495, 1445, 1350, 1255, 1130, 1055, 1005, 955 cm ^-1 .

Example 222

Preparation of 3- (2- (L) -aminopropionamido) -lancon 8-acetate:

81.4 mg of 3- (2- (L) -azido propionamido) -rancon 8-acetate was dissolved in 3 ml of acetone. 82 mg of Lindler catalyst was added to the solution. The mixture was stirred under hydrogen atmosphere for 1.5 h. Acetone was distilled off. To the residue was added 2 ml of ethanol and 40 mg of Lindler catalyst. The mixture was stirred for 2.5 h under hydrogen atmosphere and filtered using a filter aid (Celite). The filtrate was concentrated and silica gel column chromatography [eluent: ethyl acetate-methanol (6: 1)]. The desired fractions were combined and concentrated to give 63.6 mg of the title compound.

Melting Point: 178 ~ 179 ° C (AcOEt).

NMR (90 MHz, CDCl 3) δ: 1.24 (d, 3H, J = 7 Hz), 1.33 (d, 3H, J = 7 Hz), 1.37 (s, 3H), 1.55 (s, 3H), 1.76 (br.s, 3H), 1.88 (s, 3H), 2.04 (s, 3H), 2.15 to 2.53 (m, 5H), 3.47 (q, 1H, J = 7 Hz), 4.10 to 4.80 (m, 3H), 4.95 to 5.53 ( m, 7H), 6.15 (d, 1H, J = 15 Hz), 8.18 (d, 1H, J = 10 Hz).

IR (KBr): 3400, 1735, 1710, 1660, 1260 cm ^-1 .

[α] D ²⁵ -212.9 ° (c = 0.465, EtOH)

Example 223

Preparation of 3- (2- (D-aminopropionamido) -rancon 8-acetate:

101.0 mg of 3- (2- (D) -azidopropionamido) -rancon 8-acetate was dissolved in 2 ml of dichloromethane. 102 mg of Lindler catalyst was added to the solution, and the mixture was stirred for 160 minutes in a hydrogen atmosphere. The product was supplemented with 0.5 ml of ethanol and 200 mg of Lindler catalyst and the mixture was further stirred under hydrogen atmosphere for 1 hour. The catalyst was filtered off and the filtrate was concentrated. The concentrate was subjected to silica gel column chromatography [eluent: ethyl acetate-methanol (6: 1)]. The desired fractions were combined and concentrated to give 85.4 mg of the title compound.

Melting point: 169 ° C. (AcOEt).

NMR (90 MHz, CDCl 3) δ: 1.23 (d, 3H, J = 7 Hz), 1.29 (d, 3H, J = 7 Hz), 1.38 (s, 3H), 1.55 (s, 3H), 1.82 (s, 3H) , 2.04 (s, 3H), 2.12 (s, 3H), 2.10 to 2.60 (m, 5H), 3.49 (q, 1H, J = 7 Hz), 4.15 to 4.80 (m, 3H), 4.90 to 5.91 (m, 7H), 6.13 (d, 1H, J = 15 Hz), 7.99 (d, 1H, J = 10 Hz).

IR (KBr): 3410, 1730, 1710, 1655, 1250 cm ^-1 .

[α] D ²⁵ -145.5 ° (c = 0.53, EtOH)

Example 224

Preparation of 3-phenoxyacetamido-rancon:

54.5 mg of 3-phenoxyacetamido-rancon 8, 14-bis (2, 2, 2-trichloroethylcarbonate) were dissolved in 1.25 ml of dichloromethane. To the solution was added 0.125 ml of acetic acid and 109 mg of zinc powder. After 190 minutes, 109 mg of zinc powder was replenished, and after 265 minutes, 1 ml of dichloromethane was replenished. Stir for a total of 385 minutes. Precipitation was removed by filtration of the product with a filter aid (Celite). The filtrate was washed with ethyl acetate and concentrated. The concentrate was TLC plate [Merck, art. No 5715, 20 × 20 cm, 2 plates, developing solvent: tetrahydrofuran-chloroform (1: 1)] to give 17.1 mg of the title compound.

NMR (90MHz, CDCl3) δ: 1.23 (d, J = 7Hz, 17-H), 1.30 (s, 2-Me), 1.53 (s, 11-Me), 1.90 (s, 5-Me), 2.1 ~ 2.5 (m, 9-H2, 15-H2, 17-H), 4.07 (m, 8-H) to 4.4 (m, 14-H, 16-H), 4.48 (s, COCH2O), 4.64 (d, J = 10Hz, 4-H), 5.1 ~ 5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H), 6.13 (d, J = 15Hz, 12-H) ~ 6.95 And 7.3 (m, C6H5), 7.85 (d, J = 9 Hz, NH).

IR (KBr): 1742, 1704, 1668 1506, 1488, 1256, 1008, 960 cm ^-1 .

Example 225

Preparation of 3-phenoxyacetamido-rancon 14-acetate:

59,6 mg of the title compound was reacted in a similar manner to Example 224 using 144.8 mg of 3-phenoxyacetamido-rancon 14-acetate 8- (2, 2, 2-trichloroethyl carbonate). Obtained.

Melting point 128 ° C. (CHCl 3).

NMR (90 MHz, CDCl 3) δ: 1.27 (d, J = 7 Hz, 17-Me), 1.30 (s, 2-Me), 1.53 (s, 11-Me), 190 (s, 5-Me), 2.01 ( s, OAc), 2.15 to 2.7 (m, 9-H2, 15-H2, 17-H) to 4.1 (m, 8-H), 4.37 (m, 16-H), 4.48 (s, COCH2O), 4.65 (d, J = 11H, 4-H), 5.2-5.85 (m, 3-H, 6-H, 7-H, 10-H, 13-H, 14-H), 6.26 (d, J = 15 Hz , 12-H), ˜7.0 and 7.3 (m, C 6 H 5), 7.87 (d, J = 10 Hz, NH).

IR (KBr): 1728, 1706, 1674, 1504, 1488, 1236, 1008 cm ^-1 .

Example 226

Preparation of 3- (2-acetoxyacrylamido) -rancon:

206.5 mg of 3- (2-acetoxyacrylamido) -rancon 8, 14-bis (2, 2, 2-trichloroethyl carbonate) was used to react 36.5 mg of The title compound was obtained.

NMR (90MHz, CDCl3) δ: 1.22 (d, J = 7Hz, 17-Me) ~ 1.40 (s, 2-Me), 1.54 (s, 11-Me), 1.89 (s, 5-Me), 2.2 ~ 2.7 (m, 9-H2, 15-H2, 17-H), 2.32 (s, OAc) to 4.06 (m, 8-H) to 4.4 (m, 14-H, 16-H), 4.62 (d, J = 10H, 4-H), 5.2 to 5.9 (m, 3-H, 6-H, 7-H, 10-H, 13-H), 5.35 and 6.01 (d, J = 2 Hz, = CH2, respectively) , 6.13 (d, J = 15 Hz, 12-H), 7.41 (d, J = 10 Hz, NH).

IR (KBr): 1744, 1704, 1500, 1258, 1168, 1012 cm ^-1 .

Example 227

Preparation of 3-[(2-carboxy) -phenylacetamido] -rancon:

73.2 mg of 3- [2- (2,2,2-trichloroethoxycarbonyl) -phenylacetamido] -rancon 8,14-bis (2,2,2-trichloroethyl carbonate) The reaction was carried out similarly to Example 224, to give 21.7 mg of the title compound.

NMR (90 MHz, CD3OD) δ: 0.92 (d, J = 6.5 Hz, 17-Me), 0.93 (s, 2-Me), 1.21 (s, 11-Me), 1.49 (s, 5-Me), 1.8 ~ 2.3 (m, 9H2, 15-H2, 17-H), 3.71 (m, 8-H), 3.95-4.6 (m, 4-H, 14-H, 16-H), 4.95-5.5 (m, 3-H, 6-H, 7-H, 10-H, 13-H), 5.89 (d, J = 15 Hz, 12-H), 6.9-7.1 and 7.2-7.4 (m, C6H5).

IR (KBr): 3420, 1740, 1710, 1650, 1510, 1370, 1255, 1010, 960 cm ^-1 .

Example 228

Preparation of 3-[(2- (D)-(benzothiazol-2-yl) thio-1-thioxo] propylamino-lancone:

42.4 mg of 3- [2- (D)-(benzothiazol-2-yl) -thio-1-thioxo] propylamino-lancon 8, 14-bis (dimethyl-t-butyl) in 1 ml tetrahydrofuran Silyl ether) was dissolved. 0.15 ml of 2N hydrochloric acid was added to the solution. The mixture was stirred for 2.5 hours and concentrated. The concentrate was TLC plate [Merck, Art. No. 5715, 20 × 20 cm, developing solvent, ethyl acetate-hexane (2: 1)] gave 19 mg of the title compound.

NMR (90 MHz, CDCl 3) δ: 1.16 (d, 3H, J = 7 Hz), 1.21 (s, 3H), 1.51 (s, 3H), 1.78 (d, 3H, J = 7 Hz), 1.80 (br.s, 2H), 1.90 (s, 3H), 2.10 to 2.50 (m, 5H), 3.80 to 4.60 (m, 4H), 4.95 to 6.35 (m, 7H), 7.15 to 8.00 (m, 4H), 9.65 (d, 1H, J = 10 Hz).

IR (KBr): 3430, 1750, 1710, 1260 cm ^-1 .

[α] D ²⁵ -271.6 ° (c = 0.44, CHCl3)

Example 229

Preparation of 3- [2- (L)-(benzothiazol-2-yl) thio-propylamido] -lancon:

99.7 mg 3- [2- (L)-(benzothiazol-2-yl) thio-propionamido] -lancon 8, 14-bis (dimethyl-t-butylsilylether) in 1.5 ml of tetrahydrofuran Was dissolved. 0.36 ml of 2N hydrochloric acid was added to the solution, and the mixture was stirred for 2 hours and extracted with ethyl acetate. The extract was washed sequentially with water, aqueous sodium bicarbonate solution and brine. The product was dried over Na 2 SO 4 and concentrated. The concentrate was purified by TLC plate (Merck, Art. No. 5715, 20 × 20 cm, developing solvent: ethyl acetate) to give 53.6 mg of the title compound.

Melting point 139-140 ° C. (AcOEt-petroleum ether).

NMR (90 MHz, CDCl 3) δ: 1.08 (d, 3H, J = 6 Hz), 1.01 (s, 3H), 1.50 (s, 3H), 1.60 (d, 3H, J = 7 Hz), 1.86 (s, 3H) , 2.00 to 2.60 (m, 7H), 3.85 to 4.80 (m, 5H), 5.10 to 5.90 (m, 5H), 6.10 (d, 1H, J = 15 Hz), 7.15 to 8.10 (m, 5H).

IR (KBr): 3400, 1745, 1710, 1664 cm ^-1 .

[α] D ²⁴ -267.0 ° (c = 0.525, MeOH)

The compounds of Examples 230 to 237 were obtained by carrying out a reaction similar to the above using the corresponding 8, 14-bis (dimethyl-t-butylsilylether).

Example 230

3- [2- (D)-(benzoxazol-2-yl) -thio-propionamido] -rancon:

Yield 78%.

NMR (90 MHz, CDCl 3) δ: 1.16 (d, 3H, J = 7 Hz), 1.32 (s, 3H), 1.47 (s, 3H), 1.63 (d, 3H, J = 7 Hz), 1.82 (s, 3H) , 2.05 to 2.80 (m, 7H), 3.80 to 4.65 (m, 5H), 5.05 to 5.90 (m, 5H), 6.06 (d, 1H, J = 15 Hz), 7.10 to 7.80 (n1, 4H), 8.10 ( d, 1H, J = 10 Hz).

IR (KBr): 3400, 1745, 1710, 1670 cm ^-1 .

[α] D 2 ⁴ + 48.6 ° (c = 0.51, EtOH).

[Example 231]

3- [2- (L)-(benzoxazol-2-yl) thio-propionamido] -rancon:

Yield 71%.

Melting Point: 142 ~ 144 ℃ (AcOEt)

NMR (90 MHz, CD3COCD3) δ: 1.05 (d, 3H, J = 7 Hz), 1.01 (s, 3H), 1.50 (s, 3H), 1.62 (d, 3H, J = 7 Hz), 1.82 (s, 3H) , 2.00 to 2.60 (m, 5H), 2.76 (s, 2H), 4.00 to 4.85 (m, 5H), 5.10 to 5.80 (m, 5H), 6.18 (d, 1H, J = 15 Hz), 7.20 to 7.70 ( m, 4H), 7.83 (d, 1H, J = 11 Hz).

IR (KBr): 3400, 1745, 1715, 1660 cm ^-1 .

[α] D 2 ⁴ -226.5 ° (c = 0.54, EtOH).

Example 232

3- [2- (D)-(benzoimidazol-2-yl) thio-propionamido] -lancon:

Yield 64%.

NMR (90 MHz, CD3COCD3) δ: 1.23 (d, 3H, J = 6 Hz), 1.36 (s, 3H), 1.46 (s, 3H), 1.55 (d, 3H, J = 7 Hz), 1.76 (s, 3H) , 1.95-2.65 (m, 5H), 2.93 (br.s, 2H), 3.70-4.75 (m, 5H), 5.00-5.80 (m, 5H), 6.10 (d, 1H, = 15 Hz), 7.00-7.25 (m, 2H), 7.35-77.7 (m, 2H), 8.48 (d, 1H, J = 10 Hz), 11.50 (br. s, 1H).

IR (KBr): 3400, 1750, 1710, 1665 cm ^-1 .

Example 233

3- [2- (L)-(benzoimidazol-2-yl) thio-propionamido] -lancon:

Yield 41%.

NMR (90 MHz, CD3COCD3) δ: 1.03 (d, 3H, J = 7 Hz), 1.04 (s, 3H), 1.50 (s, 3H), 1.53 (d, 3H, J = 7 Hz), 1.82 (s, 3H) , 2.00 to 2.70 (m, 5H), 2.80 (s, 2H), 3.70 to 4.90 (m, 5H), 5.15 to 5.80 (m, 5H), 6.15 (d, 1H, J = 15 Hz), 7.00 to 7.22 ( m, 2H), 7.23-7.80 (m, 2H), 8.28 (d, 1H, J = 10 Hz), 11.53 (br. s, 1H).

IR (KBr): 3400, 1740, 1710, 1660 cm ^-1 .

[α] D 2 ⁴ -163.3 ° (c = 0.40, EtOH).

Example 234

3- [2- (D)-(pyridin-2-yl) thio-propionamido] -lancon:

Yield 61%.

NMR (90 MHz, CDCl 3) δ: 1.20 (d, 3H, J = 7 Hz), 1.25 (s, 3H), 1.50 (s, 3H), 1.52 (d, 3H, J = 7 Hz), 1.72 (br.s, 2H), 1.83 (s, 3H), 2.05 ~ 2.50 (m, 5H), 3.84 ~ 4.60 (m, 5H), 5.10 ~ 5.90 (m, 5H), 6.10 (d, 1H, J-15Hz), 6.90 ~ 7.60 (m, 3H), 8.26 (d, 1H, J = 10 Hz), 8.45-8.60 (m, 1H).

IR (Neat): 3400 (br.), 1740, 1710, 1660 cm ^-1 .

[α] D 2 ⁴ + 12.1 ° (c = 0.77, EtOH).

Example 235

3- [2- (L)-(pyridin-2-yl) -thio-propionamido] -lancon:

Yield 59%.

Melting Point: 187 ° C (Decomposition) (AcOEt-C6H14)

NMR (90 MHz, DMSO-d6) δ: 1.10 (s, 3H), 1.14 (d, 3H, J = 6 Hz), 1.45 (s, 3H), 1.46 (d, 3H, J = 7 Hz), 1.95 to 2.50 ( m, 5H), 3.85-4.90 (m, 7H), 5.00-5.75 (m, 5H), 6.08 (d, 1H, J = 15 Hz), 6.95-7.70 (m, 3H), 8.03 (d, 1H, J = 10 Hz), 8.45-8.55 (m, 1H).

IR (KBr): 3400 (br.), 1750, 1715, 1660 cm ^-1 .

[α] D ²⁵ -252.6 ° (c = 0.53, EtOH).

Example 236

3- (2- (D) -azidopropionido) -rancon:

Yield 68%.

Melting Point: 186-188 ° C (Decomposition) (AcOEt)

NMR (90 MHz, CDCl 3) δ: 1.25 (d, 3H, J = 6 Hz), 1.38 (s, 3H), 1.46 (d, 3H, J = 7 Hz), 1.52 (s, 3H), 1.85 (s, 3H) , 2.10-2.80 (m, 7H), 3.90-4.75 (m, 5H), 5.10-5.90 (m, 5H), 6.13 (d, 1H, J = 15 Hz), 7.51 (d, 1H, J = 10 Hz).

IR (CHCl 3): 3400, 2120, 1740, 1710, 1680 cm ^-1.

[α] D 2 4 ^o5 -220.4 ° (c = 0.55, EtOH).

Example 237

3- (2- (L) -azidopropionamido) -Rancon:

Yield 60%.

Melting Point: 192 ~ 194 ℃ (Decomposition) (AcOEt)

NMR (90 MHz, CDCl 3) δ: 1.25 (d, 3H, J = 6 Hz), 1.39 (s, 3H), 1.53 (d, 3H, J = 7 Hz), 1.54 (s, 3H), 1.89 (s, 5H) , 2.10-2.65 (m, 5H), 3.90-4.75 (m, 5H), 5.10-5.90 (m, 5H), 6.15 (d, 1H, J = 15 Hz), 7.50 (d, 1H, J = 10 Hz).

IR (KBr): 3350 (br.), 2130, 1755, 1710, 1655 cm ^-1 .

[α] D ^23.5 -173.3 ° (c = 0.45, EtOH).

Example 238

Preparation of Lancassidin A 8-dihydrodiene phosphate:

76.3 mg of lancassidin A 8-dibenzylphosphate was dissolved in 5 ml of dichloromethane. To the solution was added 33.0 μl trimethylsilyl bromide under a nitrogen atmosphere and the mixture was concentrated by stirring for 20 minutes. The product was reversed-phase TLC plate [Merck, Art. No. 15424, 10 × 20 cm, developing solvent; Methanol-water-tetrahydrofuran (10: 10: 1) to afford 36.9 mg of the title compound.

NMR (90 MHz, DMSO-d 6 -CDCl 3 -D 2 O) δ: 1.25 (d, 3H, J = 6 Hz), 1.34 (s, 3H), 1.48 (s, 3H), 1.80 (s, 3H), 1.98 (s, 3H), 2.5 to 2.65 (m, 5H), 2.39 (s, 3H), 4.45 to 4.90 (m, 3H), 5.05 to 5.80 (m, 6H), 6.30 (d, 1H, J = 15 Hz), 8.10 ( br, d, 1H, J = 10 Hz).

IR (KBr): 3400, 1735, 1715, 1695, 1245, 1015 cm ^-1 .

Example 239

Preparation of Lancacidin A 8-Formate:

251 mg of Lancacidin A was dissolved in 2.5 ml of N, N-dimethylformamide. To the solution was added 89 mg of pyridine and 126 mg of methanesulfonyl chloride in turn under stirring. The mixture was stirred for 1.5 h, ethyl acetate was added and washed with aqueous NaCl solution. The product was dried over MgSO 4 and the solvent was distilled off to give 294 mg of yellow crystalline solid material which was recrystallized from chloroform-ether-hexane to give 152 mg of the title compound as pale yellow crystals.

Melting point 214-215 degreeC (decomposition).

NMR (90MHz, CDCl3) δ: 1.31 (3H, d, J = 6.5Hz), 1.37 (3H, s), 1.56 (3H, s), 1.90 (3H, s), 2.01 (3H, s), 2.2 ~ 2.6 (5H, m), 4.41 (1H, m), 4.71 (1H, d, J = 10 Hz), 5.17 (1H, m), 5.25-5.9 (6H, m), 6.29 (1H, J = 15 Hz), 8.03 (1 H, s), 8.08 (1 H, d, J = 10 Hz).

IR (KBr): 3410, 2930, 1720 (sh.), 1705, 1685, 1495, 1440, 1370, 1350, 1310, 1260, 1240 (sh.), 1230, 1170, 1135, 1015, 965, 940, 860 , 810cm ^-1 .

Example 240

Preparation of Lancadine A 8-Chloromethyl Carbonate:

4.5 g of 130 g of lancassidine A was dissolved in 150 ml of dichloromethane, stirred under ice-cooling, and dissolved in 7.1 g of chloromethyl chloroformate (containing about 15% dichloromethyl chloroformate) and dichloromethane (40 ml). Pyridine was added sequentially and stirred at room temperature for 30 minutes. 200 ml of chloroform was added to the product, which was washed sequentially with water (100 ml × 2), 0.1 N-HCl (100 ml), water (100 ml), dilute aqueous sodium hydrogen carbonate solution (100 ml) and water. The product was dried over MgSO 4 and the solvent was distilled off. The residue was subjected to silica gel (300 g) column chromatography [eluent: chloroform-ethyl acetate (20: 1, and 15: 1)]. Eluates containing the title compound were divided into three groups in the elution order. Each group was concentrated to give the foamed title compound.

Ether (about 70 ml) was added to Fraction 3 obtained above and left to allow crystals to precipitate. The crystals were collected by filtration and dried to give 609 mg of the title compound as purified.

Melting point 195-196 ° C (decomposition).

NMR (90 MHz, CDCl 3) δ: 1.30 (3H, d, J = 6.5 Hz), 1.37 (3H, s), 1.55 (3H, s), 1.90 (3H, s), 2.03 (3H, s). 2.2-2.65 (5H, m), 2.44 (3H, s), 4.40 (1H, m), 4.72 (1H, d, J = 10 Hz), 4.95 (1H, m), 5.2-5.85 (8H, m), 6.27 (1H, doublet, J = 14.5 Hz), 8.06 (1H, doublet, J = 10 Hz).

IR (KBr): 3400, 1760, 1710, 1680, 1510, 1440, 1355, 1235, 1155, 1130, 1100, 1020, 940 cm ^-1 .

Example 241

Preparation of Lancadine A 8-Methylthiomethyl Ether:

501 mg of Lancacidin A was dissolved in 10 ml of 1, 2-dichloromethane, and 0.261 ml of 3-iso-propylethylamine and 0.126 ml of chloromethyl methylsulphide were added. The mixture was stirred at reflux for 19 h. Cool, dichloromethane was added, washed with aqueous NaCl aqueous solution and dried over MgSO 4. The solvent was distilled off. The residue was subjected to silica gel (100 g) column chromatography [eluent: ethyl acetate-chloroform (1: 4)], and the eluate was fractionated by 15 g. The 26th to 37th fractions were combined and concentrated to give 161.9 mg of the title compound as white crystals.

Melting Point 175 ~ 177 ℃

NMR (90 MHz, CDCl 3) δ: 1.31 (3H, d, J = 7 Hz), 1.38 (3H, s), 1.54 (3H, s), 1.92 (3H, s), 2.02 (3H, 2), 2.13 (3H , s), 2.2 to 2.6 (5H, m), 2.44 (3H, s), 4.11 (1H, m), 4.41 (1H, m), 4.50 and 4.72 (2H, ABq, J = 12 Hz), 4.70 (1H , d, J = 11 Hz), 5.25-5.9 (6H, m), 6.28 (1H, d, J = 15 Hz), 8.09 (1H, d).

IR (KBr): 1720 (sh.), 1706 (sh.), 1686 (sh.), 1354, 1238, 1050, 954 cm ^-1 .

Example 242

Preparation of Lancadine A 8-iodomethyl Carbonate:

의 에틸 아세테이트를 가하고, 19.3g의 Na2S2O3를 함유하는 300ml의 물, 200ml의 물, 200ml의 물 및 200ml의 NaCl 수용액으로 차례로 세척하고 MgSO4로 건조시켰다. 용매를 증류 제거하고, 잔류물을 실리카겔(320g) 컬럼 크로마토그래피[용리액 : 클로로포름-에틸 아세테이트(30 : 1, 그리고 20 : 1)]하였다. 표제 화합물을 함유하는 분획을 농축하여 13.8g의 황색 거품성 물질을 수득하고 에테르(약 100ml)를 가하였다. 혼합물을 방치하여 결정을 분리해내고, 이를 여과하여 수집하고 건조시킴으로써 9.5g의 표제 화합물을 수득하였다. 이 화합물은 약 5%의 8-클로로메틸 카르보네이트 및 8-디클로로 메틸 카르보네이트를 함유하는 것으로 밝혀졌다. 다음 실시예에서는, 이 화합물을 정제하지 않은 채로 사용한다.Crude lancassidine A 8-chloromethyl carbonate (8.2 g of fraction 1 + 5.5 g of fraction 2) was dissolved in 120 ml of acetonitrile. To the solution was added 11.2 g of sodium iodide. The mixture is stirred at 50-60 ° C. for 3 hours, 1.5

Ethyl acetate was added and washed sequentially with 300 ml of water containing 19.3 g of Na 2 S 2 O 3, 200 ml of water, 200 ml of water and 200 ml of NaCl aqueous solution and dried over MgSO 4. The solvent was distilled off and the residue was subjected to silica gel (320 g) column chromatography [eluent: chloroform-ethyl acetate (30: 1, and 20: 1)]. Fractions containing the title compound were concentrated to give 13.8 g of yellow foamy material and ether (about 100 ml) was added. The mixture was left to separate the crystals, which were collected by filtration and dried to yield 9.5 g of the title compound. This compound was found to contain about 5% of 8-chloromethyl carbonate and 8-dichloro methyl carbonate. In the following examples, this compound is used without purification.

Melting point: 147-149 ° C. (decomposition).

NMR (90 MHz, CDCl 3) δ: 1.32 (3H, d, J = 6.Hz), 1.37 (3H, s), 1.54 (3H, s), 1.90 (3H, s), 2.01 (3H, s), 2.2 ~ 2.65 (5H, m), 2.44 (3H, s), 4.41 (1H, m), 4.71 (1H, d, J = 10 Hz), 4.96 (1H, m), 5.22-6.0 (6H, m), 5.91 (2H, s), 6.27 (1H, d, J = 15 Hz), 8.06 (1H, d, J = 9 Hz).

IR (KBr): 3400, 1760, 1680, 1510, 1360, 1280, 1235, 1220, 1160, 1135, 1070, 1020, 930 cm ^-1 .

Example 243

Preparation of 8-dehydroxy-8-acetylamino-lancassidin C:

(1) 3.6 g of 8-dehydroxy-8-azido-lancadine A was dissolved in a mixture of 100 ml of tetrahydrofuran and 50 ml of methanol. 120 mg of sodium borohydride was added to the solution with stirring at −20 ° C. and stirred for another 20 minutes. 0.24 ml of acetic acid was added to the product and the solvent was distilled off. The residue was dissolved in 400 ml of ethyl acetate, washed with water, 5% aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution and saturated aqueous NaCl solution and dried over MgSO 4. The solvent was distilled off and the residue was purified by silica gel (250 g) column chromatography [eluent: ethyl acetate-chloroform (1: 4, and 1: 1)] to 729 mg of 8-dehydroxy-8-azido-lancasidinol. A [2 '-(L) -isomer] and 1.29 g of 8-dehydroxy-8-azido-lancassidiol A [2'-(D) -isomer] were obtained.

2 '-(L) -isomer;

NMR (90 MHz, CDCl 3) δ: 1.30 (3H, d, J = 6 Hz), 1.38 (3H, d, J = 6 Hz), 1.40 (3H, s), 1.50 (3H, s), 1.88 (3H, s) , 2.03 (3H, s), 2.2 to 2.7 (5H, m), 4.0 to 4.7 (4H, m), 4.75 (1H, d, J = 10.5 Hz), 5.2 to 6.0 (6H, m), 6.32 (1H) , d, J = 15 Hz), 7.65 (1H, d, J = 10.5 Hz).

IR (KBr): 3380, 3250, 2980, 2940, 2100, 1730, 1705, 1640, 1520 cm ^-1 .

2 '-(D) -isomer:

NMR (90 MHz, CDCl 3) δ: 1.30 (3H, d, J = 6 Hz), 1.39 (3H, d, J = 6 Hz), 1.40 (3H, s), 1.49 (3H, s), 1.87 (3H, s) , 2.03 (3H, s), 2.2 to 2.8 (5H, m), 4.0 to 4.7 (4H, m), 4.76 (1H, d, J = 10.5 Hz), 5.3 to 6.0 (6H, m), 6.32 (1H) , d, J = 15 Hz), 7.53 (1H, d, J = 10.5 Hz).

IR (KBr): 3400, 2990, 2940, 2100, 1730, 1705, 1640, 1500 cm ^-1 .

(2) 1.20 g of 8-dehydroxy-8-azido-lancassinol A [2 '-(D) -isomer] was dissolved in 15 ml of N, N-dimethylformamide. 0.32 g imidazole and 0.69 g t-butyldimethylsilyl chloride were added to the solution, the mixture was stirred for 14 hours, 200 ml of ethyl acetate was added, followed by water, 1N-HCl, water, 5% aqueous sodium hydrogen carbonate solution. Washed sequentially with water, saturated aqueous NaCl solution and dried over MaSO 4. The solvent was distilled off and the residue was purified by silica gel (260 g) column chromatography [eluent: ethyl acetate-chloroform (1: 20)] to give 1.22 g of 8-dehydroxy-8-azido-O (2 ')-t. -Butyldimethylsilyl-lancassidiol A [2 '-(D) -isomer] was obtained.

NMR (90 MHz, CDCl3) δ: 1.00 (9H, s), 1.20-1.34 (6H, d, x 3), 1.38 (3H, s), 1.90 (3H, s), 2.03 (3H, s), 2.2- 2.8 (5H, m), 4.0 to 4.71 (3H, m), 4.78 (1H, d, J = 10.5 Hz), 5.2 to 6.2 (6H, m), 6.29 and 6.33 (1H, d, J = 15 Hz) , 7.75 (1H, doublet, J = 9 Hz).

IR (KBr): 3400, 2930, 2850, 2100, 1730, 1710, 1670, 1490 cm ^-1 .

(3) 1.20 g of 8-dehydroxy-8-azido-O (2 ')-t-butyldimethylsilyl-lancassinol A [2'-(D)-in a mixture of 20 ml of acetone and 10 ml of acetic acid. Isomers] were dissolved. 2.0 g of zinc powder was added to the urine solution, and the mixture was stirred for 20 minutes. Insoluble material was filtered off and the filtrate was concentrated. The concentrate was dissolved in 300 ml of tetrahydrofuran-ethyl acetate (1: 4) mixture and washed sequentially with water, 5% aqueous sodium hydrogen carbonate solution, water, saturated aqueous ammonium chloride solution and saturated brine. The product was dried over MgSO 4 and the solvent was distilled off. The residue was purified by silica gel (90 g) column chromatography [methanol-chloroform (1: 20)] to give 492 mg of 8-dehydroxy-8-amino-O (2 ')-t-butyldimethylsilyl-lancassinol A [2 '-(D) -isomer] was obtained.

NMR (90 MHz, CDCl 3) δ: 1.00 (9H, s), 1.29 (3H, d, J = 7.5 Hz), 1.32 (3H, d, J = 7.5 Hz), 1.38 (3H, s), 1.53 (3H, s), 1.88 (3H, s), 2.00 (3H, s), 2.1 to 3.0 (7H, m), 4.00 (1H, br.s), 4.25 (1H, q, J = 6.8 Hz), 4.3 to 4.5 (1H, m), 4.75 (1H, d, J = 9 Hz), 5.2-6.2 (6H, m), 6.33 (1H, d, J = 15 Hz), 7.73 (1H, d, J = 10.5 Hz).

IR (KBr): 3410, 2940, 2860, 1730, 1710, 1670, 1500 cm ^-1 .

(4) 470 mg of 8-dehydroxy-8-amino-O (2 ')-t-butyldimethyl-lancassinol A [2'-(D) -isomer] was dissolved in 3 ml of pyridine. 2 ml of acetic anhydride was added to the solution, and the mixture was stirred for 1 hour and concentrated. The concentrate was dissolved in 200 ml of ethyl acetate and the solution was washed sequentially with 1N-HCl, water, 5%, aqueous sodium hydrogen carbonate solution, water and saturated brine and dried over MgSO 4. The solvent was distilled off to give 429 mg of 8-dehydroxy-8-acetyl amino-O (2 ')-t-butyl dimethylsilyl-lancassinol A [2'-(D) -isomer].

NMR (90 MHz, CDCl 3) δ: 1.00 (9H, s), 1.29 (3H, d, J = 7.5 Hz), 1.32 (3H, d, J = 7.5 Hz), 1.38 (3H, s), 1.53 (3H, s), 1.89 (3H, s), 2.03 (6H, s), 2.2 to 2.9 (5H, m), 4.23 (1H, q, J = 6.8 Hz), 4.40 (1H, dt, J = 3 and 12 Hz) , 4.70 (1H, d, J = 12 Hz), 4.7--5.0 (1H, m), 5.2--6.0 (7H, m), 6.28 (1H, d, J = 15 Hz), 7.73 (1H, d, J = 11 Hz ).

IR (KBr): 3410, 2860, 1730, 1710, 1660, 1500 cm ^-1 .

(5) 200 mg of 8-acetylamino-O (2 ')-t-butyldimethylsilyl-lancassinol A [2'-(D) -isomer] was dissolved in 5 ml of tetrahydrofuran. 5 ml of 2N-HCl was added to the solution, the mixture was stirred for 3 hours, 60 ml of ethyl acetate was added, washed sequentially with water, 5% aqueous sodium bicarbonate solution, water and saturated aqueous NaCl solution and dried over MgSO 4. The solvent was distilled off. The residue was purified by silica gel (28 g) column chromatography [eluent: methanol-chloroform (1: 20, and 1: 10)] to 56 mg of 8-dehydroxy-8-acetylamino-lancassinol A [2 '-(D ) -Isomer] was obtained.

NMR (90 MHz, CDCl 3) δ: 1.27 (3H, d, J = 6 Hz), 1.31 (3H, d, J = 7 Hz), 1.40 (3H, s), 1.51 (3H, s), 1.83 (3H, s) , 2.03 (6H, s), 2.2--2.7 (5H, m), 4.1--4.3 (1H, m), 4.40 (1H, dt, J = 3 and 15 Hz), 4.65 (1H, d, J = 12 Hz), 4.7-5.0 (1H, m), 5.3-6.2 (7H, m), 6.30 (1H, d, J = 15 Hz), 7.61 (1H, d, J = 7 Hz).

(6) 56 mg of 8-dehydroxy-8-acetylamino-lancassinol A [2 '-(D) -isomer] was dissolved in 0.5 ml of dimethyl sulfoxide. 0.5 ml of acetic anhydride was added to the solution and stirred for 30 hours. 60 ml of ethyl acetate was added to the mixture, washed successively with water, 5% aqueous sodium hydrogen carbonate solution, water and saturated salt solution and dried over MgSO 4. The solvent was distilled off and the residue was subjected to silica gel (35 g) column chromatography [eluent: methanol-chloroform (1:20)] to give 46 mg of 8-dehydroxy-8-acetylamino-lancadine A.

NMR (90MHz, CDCl3) δ: 1.30 (3H, d, J = 6Hz), 1.36 (3H, s), 1.52 (3H, s), 1.88 (3H, s), 1.96 (3H, s), 2.01 (3H , s), 2.2 to 2.7 (5H, m), 2.45 (3H, s), 4.43 (1H, dt, J = 3 and 12 Hz), 4.67 (1H, d, J = 10.5 Hz), 4.7 to 5.0 (1H) m), 5.2-6.0 (7H, m), 6.31 (1H, d, J = 15 Hz), 6.02 (1H, d, J = 10.5 Hz).

IR (KBr): 3380, 2990, 2940, 1720 (sh.), 1710, 1660, 1510 cm ^-1 .

(7) Esterase prepared in Reference Example 11, in which 46 mg of 8-dehydroxy-8-acetylamino-lancadine A was dissolved in a mixture of 5 ml of tetrahydrofuran and 5 ml of methanol, and dissolved in 10 ml of water. (1.0 g) of solution was added and the mixture was stirred for 2.5 h. The product was extracted with 20 ml of chloroform. The organic layer was washed with saturated brine and dried over MgSO 4. The solvent was distilled off and the residue was subjected to silica gel (30 g) column chromatography [eluent: methanol-chloroform (1:20)] to give 27 g of the title compound.

NMR (90MHz, CDCl3) δ: 1.27 (3H, d, J = 6Hz), 1.38 (3H, s), 1.52 (3H, s), 1.90 (3H, s), 2.00 (3H, s), 2.2 ~ 2.6 (5H, m), 2.45 (3H, s), 4.1-4.6 (2H, m), 4.65 (1H, d, J = 10.5 Hz), 4.7-5.0 (1H, m), 5.2-6.0 (6H, m ), 6.18 (1H, d, J = 15 Hz), 8.05 (1H, d, J = 10.5 Hz).

IR (KBr): 3380, 2980, 2925, 1715, 1700, 1670, 1510 cm ^-1 .

Example 244

Preparation of 8-dehydroxy-8-p-toluenesulfonylamino-lancassidin C:

(1) Dissolve 180 mg of 8-dehydroxy-8-amino-O (2 ') t-butyldimethylsilyl-lancassinol A [2'-(D) -isomer] in 6 ml of dichloromethane and 36 mg of Pyridine and 57 mg of p-toluenesulfonyl chloride were added and the mixture was stirred for 18 hours. 70 ml of ethyl acetate was added to the product, washed successively with 5% aqueous sodium hydrogen carbonate solution, water, 1N-HCl and saturated brine and dried over MgSO 4. The solvent was distilled off and the residue was purified by silica gel (70 g) column chromatography [eluent: methanol-chloroform (1: 20)] to 143 mg of 8-dehydroxy-8-p-toluenesulfonylamino-O (2 '). -t-butyldimethylsilyl-lancassidiol A [2 '-(D) -isomer] was obtained.

NMR (90 MHz, CDCl 3) δ: 100 (9H, s), 1.28 (3H, d, J = 6 Hz), 1.33 (3H, s,), 1.39 (H, d, J = 7 Hz), 1.46 (3H, s ), 1.75 (3H, s), 2.01 (3H, s), 2.2-2.7 (5H, m), 2.40 (3H, s), 4.1-4.5 (3H, m), 4.69 (1H, d, J = 10.5 Hz), 5.2-5.9 (7H, m), 6.32 (1H, d, J = 15 Hz), 7.1-7.3 (2H, m), 7.6-7.8 (3H, m)

IR (KBr): 3420, 2940, 2850, 1740, 1710, 1680, 1500 cm ^-1 .

(2) Example 244 using 8-dehydroxy-8-p-toluenesulfonylamino-O (2 ')-t-butyldimethylsilyl-lancassinol A [2'-(D) -isomer] The following compounds were obtained by carrying out the reaction similarly to (5).

8-dehydroxy-8-p-toluenesulfonylamino-lancassinol A [2 '-(D) -isomer]:

NMR (90 MHz, CDCl 3) δ: 1.30 (3H, d, J = 6 Hz), 1.40 (3H, s), 1.42 (3H, d, J = 7 Hz), 1.44 (3H, s), 1.78 (3H, s) , 2.02 (3H, s), 2.2-2.7 (5H, m), 2.40 (3H, s), 4.1-4.4 (2H, m), 4.68 (1H, d, J = 10.5 Hz), 5.2-5.6 (8H m), 6.35 (1H, d, J = 15 Hz), 7.2-7.5 (3H, m), 7.04-7.9 (2H, m).

IR (KBr): 3400, 2940, 1730 (sh.), 1625 cm ^-1 .

Dehydroxy-8-p-toluenesulfonylamino-lancadine A:

NMR (90MHz, CDCl3) δ: 1.28 (3H, d, J = 6Hz), 1.33 (3H, s), 1.43 (3H, s), 1.70 (3H, s), 2.01 (3H, s), 2.40 (3H , s), 2.50 (3H, s), 4.37 (1H, dt, J = 3 and 12 Hz), 4.65 (1H, d, J = 10.5 Hz), 5.2-6.2 (8H, m), 6.83 (1H, d , J = 15 Hz), 7.2-7.4 (2H, m), 7.6-8.1 (3H, m).

8-dehydroxy-8-p-toluenesulfonylamino-lancassidin C:

NMR (90MHz, CDCl3) δ: 1.25 (3H, d, J = 6Hz), 1.33 (3H, s), 1.43 (3H, s), 1.71 (3H, s), 2.1 ~ 2.7 (5H, m), 2.40 (3H, m), 2.48 (3H, s), 4.1-4.6 (2H, m), 4.62 (1H, d, J = 10.5 Hz), 5.1-6.0 (7H, m), 6.28 (1H, d, J = 15 Hz), 7.2-7.4 (2H, m), 7.6-7.8 (2H, m), 7.95 (1H, d, J = 10.5 Hz).

IR (KBr): 3400, 2910, 1740, 1705, 1680, 1500 cm ^-1 .

Example 245

Preparation of Lancacidin A 8-chloroacetate:

의 에틸 아세테이트를 가하였다. 혼합물을 물, 5% 탄산수소나트륨 수용액 1N-HCl, 물 및 NaCl 포화 수용액으로 차례로 세척하고 MgSO4로 건조시켰다. 용매를 증류 제거하였다. 잔류물에 200ml의 이소프로필 에테르를 가하였다. 혼합물을 방치하고 결정을 분리해냈다. 여과하여 결정을 수집하고 전조시킴으로써 21.8g의 표제 화합물을 수득하였다.20 g of lancassidine A was dissolved in 250 ml of N, N-dimethylacetamide and 5 ml of chloroacetyl chloride was added dropwise with stirring. The mixture is stirred at room temperature for 2.5 hours, 1

Ethyl acetate was added. The mixture was washed sequentially with water, 5% aqueous sodium hydrogen carbonate solution 1N-HCl, water and saturated aqueous NaCl solution and dried over MgSO 4. The solvent was distilled off. 200 ml of isopropyl ether was added to the residue. The mixture was left to stand and the crystals separated. Filtration collected and precursord the crystals to yield 21.8 g of the title compound.

Melting point: 192-198 ° C. (decomposition).

NMR (90 MHz, CDCl 3) δ: 1.30 (3H, 3, J = 6 Hz), 1.38 (3H, s), 1.56 (3H, s), 1.90 (3H, s), 2.02 (3H, s), 2.44 (3H , s), 2.2 to 2.7 (5H, m), 4.03 (2H, s), 4.42 (1H, dt, J = 3 and 12 Hz), 4.72 (1H, d, J = 10.5 Hz), 5.0 to 5.9 (7H) m), 6.28 (1H, d, J = 15 Hz), 8.07 (1H, d, J = 10.5 Hz).

IR (KBr): 3400, 2960. 2870, 1740, 1710, 1510 cm ^-1 .

Example 246

Preparation of Lancacidin A 8-phenyl Carbonate:

501 mg of Lancassidin A was dissolved in 5 ml of pyridine. 0.188 ml of phenyl chloroformate was added dropwise to the solution while stirring under ice cooling. The mixture was stirred at the same temperature for 5 minutes and at room temperature for 75 minutes. Ice water was added to the product, and extracted with ethyl acetate. The extract solution was washed sequentially with 1N-HCl and brine, dried over MgSO 4 and the solvent was distilled off. Ether is added to the residue to allow for crystallization. To this was added ether-petroleum ether (1: 1), filtered to collect crystals and dried to give 473.9 mg of the title compound.

Melting Point: 220 ~ 222 ℃ (Decomposition)

NMR (90MHz, CDCl3) δ: 1.32 (3H, d, J = 7Hz), 1.40 (3H, s), 1.59 (3H, s), 1.95 (3H, s), 2.04 (3H, s), 2.2 ~ 2.8 (5H, m), 2.47 (3H, s), 4.43 (1H, m), 4.75 (1H, d, J = 11 Hz), 5.03 (1H, m), 5.2-6.0 (6H, m), 6.32 (1H) , d, J = 15 Hz), 7.1-7.55 (5H, m), 8.10 (1H, d, J = 10 Hz).

IR (KBr): 1740, 1706, 1684, 1354, 1240, 1208, 952 cm ^-1 .

In the same manner as in Example 246, the following compounds were prepared.

Example 247

Lancassinol A 8-methylcarbonate, melting point 215-216 ° C. (decomposition)

NMR (90MHz, CDCl3) δ: 1.32 (3H, d, J = 7Hz), 1.39 (3H, s), 1.56 (3H, s), 1.91 (3H, s), 2.04 (3H, s), 2.2 ~ 2.6 (5H, m), 3.78 (3H, s), 4.44 (1H, m), 4.74 (4H, d, J = 11 Hz), 4.93 (1H, m), 5.2-5.9 (6H, m), 6.31 (1H) , d, J = 15 Hz), 8.09 (1H, d, J = 10 Hz).

IR (KBr): 1740, 1706, 1684, 1500, 1440, 1356, 1260, 948 cm ^--1 .

Example 248

Lancacidin A 8-pentachlorophenylcarbonate, melting point 185-187 degreeC (decomposition)

NMR (90MHz, CDCl3) δ: 1.31 (3H, d, J = 7Hz), 1.38 (3H, s), 1.59 (3H, s), 1.94 (3H, s), 2.03 (3H, s), 2.15 ~ 2.8 (5H, m), 2.46 (3H, s), 4.43 (1H, m), 4.74 (1H, d, J = 11 Hz), 5.05 (1H, m), 5.2-5.95 (6H, m), 6.30 (1H) , d, J = 15 Hz), 8.10 (1H, d, J = 10 Hz).

IR (KBr): 1780 (sh.), 1756, 1710, 1688, 1360, 1240 cm ^-1 .

Example 249

Preparation of Lancacidin A 8-azidoacetate:

200 mg of lancassidin A 8-iodoacetate was dissolved in 10 ml of N, N-dimethylformamide. 40 mg of sodium azide was added to the solution, and the mixture was stirred at room temperature for 1 hour. 50 ml of ethyl acetate was added to the resulting mixture, washed with water 1N-HCl, water and saturated brine and dried over MgSO 4. The solvent was distilled off and the residue was subjected to silica gel (70 g) column chromatography [eluent: ethyl acetate-chloroform (1: 20, and 1: 10)] to give 110 mg of the title compound.

Melting point: 186-191 ° C. (decomposition).

NMR (90MHz, CDCl3) δ: 1.32 (3H, d, J = 6Hz), 1.40 (3H, s), 1.57 (3H, s), 1.92 (3H, s), 2.03 (3H, s), 2.1 ~ 2.7 (5H, m), 2.47 (3H, s), 3.87 (2H, s), 4.43 (1H, dt, J = 3 and 12 Hz), 4.74 (1H, d, J = 10.5 Hz), 5.0 to 5.9 (7H) m), 6.32 (1H, d, J = 15 Hz), 8.10 (1H, d, H = 10.5 Hz).

IR (KBr): 3400, 2100, 1735, 1710, 1685, 1500 cm ^-1 .

Example 250

Preparation of 3- (2'-methoxyiminopropionamido) -lancon 14-acetate 8-iodoacetate

In 20 ml of tetrahydrofuran, 500 mg of lancassidine A 8-iodoacetate was dissolved. 190 mg of O-methyl-hydroxylamine hydrochloride and 320 mg of sodium carbonate were added to the solution, and the mixture was stirred at room temperature for 21 hours. 100 ml of ethyl acetate was added to the resulting mixture, washed successively with water, saturated aqueous ammonium chloride solution, water and saturated brine and dried over MgSO 4. The solvent was distilled off and the residue was subjected to silica gel (70 g) column chromatography [eluent: hexane-ethyl acetate (2: 1)} to give 390 mg of the title compound.

Melting Point: 138 ~ 141 ° C.

NMR (90 MHz, CDCl 3) δ: 1.31 (3H, d, J = 6 Hz), 1.41 (3H, s), 1.57 (3H, s), 1.90 (3H, s), 2.00 (3H, s), 2.03 (3H , s), 2.1 to 2.7 (5H, m), 3.68 (2H, s), 4.03 (3H, s), 4.40 (1H, dt, J = 3 and 12 Hz), 4.76 (1H, d, J = 1.05 Hz ), 4.9 to 5.9 (7H, m), 6.30 (1H, d, J = 15 Hz), 7.89 (1H, d, J = 10.5 Hz).

IR (KBr): 3400, 2940, 1725, 1670, 1500 cm ^-1 .

Example 251

Preparation of Lancacidin A 8-iodoacetate:

10 g of lancassidin A 8-chloroacetate was dissolved in 300 ml of acetonitrile. 10 g of sodium iodide was added to the solution and the mixture was stirred at 55 ° C. for 18 hours. Acetonitrile was distilled off. 600 ml of ethyl acetate was added to the residue, which was washed sequentially with water, aqueous sodium thiosulfate solution, water and saturated aqueous NaCl solution and dried over MgSO 4. The solvent was distilled off. 110 ml of ether was added to the residue and the crystals precipitated. The crystals were collected by filtration and dried to yield 8.9 g of the title compound.

Melting point: 191-197 ° C (decomposition).

NMR (90MHz, CDCl3) δ: 1.30 (3H, d, J = 6Hz), 1.38 (3H, s), 1.57 (3H, s), 1.90 (3H, s), 2.03 (3H, s), 2.1 ~ 2.7 (5H, m), 2.46 (3H, s), 3.67 (2H, s), 4.40 (1H, dt, J = 3 and 12 Hz), 4.71 (1H, d, J = 10.5 Hz), 4.9-5.9 (7H m), 6.28 (1H, d, J = 15 Hz), 8.08 (1H, d, J = 10.5 Hz).

IR (KBr): 3400, 2940, 1725, 1675, 1500 cm ^-1 .

Example 252

Preparation of Lancacidin A 8-N-phenyl Carbamate:

300.6 mg of Lancassidin A was dissolved in 6 ml of dichloromethane. To the solution was added 180 mg of zinc chloride and 0.131 g of phenyl isocyanate. The mixture was stirred at rt for 19 h. Dichloromethane was added to the resulting mixture, and the insoluble material was decanted off. The liquid was concentrated, silica gel (75 g) column chromatography [eluent: ethyl acetylamino-chloroform (1:10)], and the eluate were fractionated by 20 g. The 34th to 43rd fractions were combined and concentrated to give crystals, ether was added, crystals were collected by leisure, washed with ether and dried to give 121.1 mg of the title compound as white crystals.

Melting point: 231-232 ° C. (decomposition).

NMR (90MHz, CDCl3) δ: 1.31 (3H, d, J = 7Hz), 1.37 (3H, s), 1.55 (3H, s), 1.89 (3H, s), 2.02 (3H, s), 2.2 ~ 2.6 (5H, m), 2.44 (3H, s), 4.40 (1H, m), 4.70 (1H, d, J = 11 Hz), 5.05 (1H, m), 5.25-5.9 (6H, m), 6.28 (1H) , d, J = 15 Hz), 6.73 (1H, br.s), 6.9-7.5 (5H, m), 8.05 (1H, d, J = 10 Hz).

IR (KBr): 1724 (sh.), 1706, 1682, 1514, 1438, 1236 (sh.), 1220 cm ^-1 .

The compound shown in Table 1 was obtained by carrying out the reaction similar to Example 252 using the lancassidin A as starting material.

TABLE 1

Example 262

Preparation of O (8) -morpholinocarbonyl lancassidine A:

476.1 mg of lancassidin A 8-pentachlorophenyl carbonate was dissolved in 6 ml of dichloromethane. 0.104 ml of morpholine was added to the solution, and the mixture was stirred at room temperature for 2 hours. Dichloromethane was added to the resulting mixture, and the solution was washed with water and dried over MgSO 4. The solvent was distilled off and the residue was subjected to silica gel (100 g) column chromatography [eluent: ethyl acetate-chloroform (1: 4), and ethyl acetate-chloroform (1: 1)].

The eluate was concentrated. A small amount of ethe was added to the concentrate to crystallize, ether-petroleum ether (1: 1) was added and the crystals collected and dried to give 313.0 mg of the title compound as white crystals.

Melting point 223-225 ° C. (decomposition).

NMR (90MHz, CDCl3) δ: 1.31 (3H, d, J = 7Hz), 1.38 (3H, s), 1.56 (3H, s), 1.91 (3H, s), 2.03 (3H, s), 2.2 ~ 2.7 (5H, m), 2.46 (3H, s), ~ 3.6 (8H, m), 4.43 (1H, m), 4.71 (1H, d, J = 11 Hz), 5.02 (1H, m), 5.25-5.9 ( 6H, m), 6.32 (1H, d, J = 15 Hz), 8.07 (1H, d, J = 10 Hz).

IR (KBr): 1750 (sh), 1730 (sh), 1710, 1695, 1426, 1360, 1238, 1132, 954 cm ^-1 .

The compound shown in Table 2 was obtained by carrying out the reaction in a similar manner as in Example 262 using lancassidin A 8-pentachlorophenyl carbonate as starting material.

TABLE 2

Example 283

Preparation of Lancacidin A 8- (1-methyl-1H-tetrazol-5-yl) thioacetate:

200 mg of 1-methyl-1H-tetrazol-5-thiol was dissolved in 2 ml of N, N-dimethylformamide. 24 mg of sodium hydride (60%) was added to the solution, which was stirred for 10 minutes at room temperature. 500 mg of Lancassidin A 8-chloroacetate dissolved in 2 ml of N, N-dimethylformamide was added dropwise to the mixture over 5 minutes. The mixture was further stirred for 30 minutes. 50 ml of ethyl acetate was added to the resulting mixture, and the mixture was washed sequentially with water, 1N-HCl, water and saturated brine and dried over MgSO 4. The solvent was distilled off and the residue was subjected to silica gel (60 g) column chromatography [eluent: ethyl acetate-chloroform (1: 4, and 1: 2)] to give 560 mg of the title compound.

131 ~ 139 ℃

NMR (90MHz, CDCl3) δ: 1.31 (3H, d, J = 6Hz), 1.40 (3H, s), 1.57 (3H, s), 1.92 (3H, s), 2.03 (3H, s), 2.2 ~ 2.7 (5H, m), 2.47 (3H, s), 3.97 (3H, s), 4.13 (2H, s), 4.43 (1H, dt, J = 3 and 12 Hz), 4.72 (1H, d, J = 10.5 Hz ), 4.9 to 5.9 (7H, m), 6.28 (1H, d, J = 15 Hz), 8.08 (1H, d, J = 10.5 Hz).

IR (KBr): 3400, 2990, 2940, 1730, 1710, 1685, 1500 cm ^-1 .

The compounds shown in Table 3 were obtained by carrying out the reaction in the same manner as in Example 283, using lancassidin A 8-chloroacetate as starting material.

TABLE 3

Example 290

Preparation of Lancadine A 8-diethylaminoacetate:

In 30 ml of tetrahydrofuran, 1.0 g of lancassidine A 8-iodoacetate was dissolved. 0.5 ml of diethylamine was added to the solution, the mixture was stirred for 1.5 hours, 200 ml of ethyl acetate was added, washed sequentially with water and saturated brine and dried over MgSO 4. The solvent was distilled off and the residue was subjected to silica gel (75 g) column chromatography [eluent: ethyl acetate-chloroform (1: 1)] to give 800 mg of the title compound.

Melting point 183 ℃

NMR (90 MHz, CDCl 3) δ: 1.02 (6H, t, J = 7 Hz), 1.30 (3H, 3, J = 6 Hz), 1.35 (3H, s), 1.88 (3H, s), 2.00 (3H, s) , 2.1 to 2.7 (5H, m), 2.43 (3H, s), 2.63 (4H, q, J = 7 Hz), 3.30 (2H, s), 4.40 (1H, dt, J = 3 and 12 Hz), 4.69 ( 1H, d, J = 10.5 Hz), 5.0-5.9 (7H, m), 6.28 (1H, d, J = 15 Hz), 8.07 (1H, d, J = 10.5 Hz).

IR (KBr): 3400, 2975, 2940, 1730, 1710, 1685, 1505 cm ^-1 .

The compounds shown in Table 4 were obtained by carrying out a reaction similar to Example 290, using lancassidin A 8-iodoacetate as starting material.

TABLE 4

Example 303

Preparation of 8-dehydroxy-8-[[1- (2-hydroxyethyl) -1H-tetrazol-5-yl] thio] -lancassidin A:

In 4 ml of N, N-dimethylformamide, 100 mg of 8-dehydroxy-8-iodolancadine and 70.0 mg of 1- (2-hydroxyethyl) -1H-tetrazol-5-thiol were dissolved.

To the solution was added 16.0 mg sodium hydride, the mixture was stirred for 5 hours, ice water was added and extracted with ethyl acetate. The organic layer was dried over MgSO 4. The solvent was distilled off and the residue was purified by silica gel column chromatography to obtain 79.8 mg of the title compound (low polar isomer: estimated 8-β-compound) and 6.1 mg of the title compound (high polar isomer: 8- estimated as α-compound.

8-β compound:

NMR (90MHz, CDCl3) δ: 1.33 (3H, d, J = 6.5Hz), 1.39 (3H, s), 1.53 (3H, s), 1.89 (3H, s), 2.02 (3H, s), 2.2 ~ 2.8 (5H, m), 2.44 (3H, s), 4.0-4.2 (2H, m), 4.36 (2H, t, J = 5 Hz), 4.43 (1H, m), 4.72 (1H, d, J = 11 Hz ), 4.9 to 5.05 (1H, m), 5.3 to 5.9 (6H, m), 6.35 (1H, d, J = 15 Hz), 8.06 (1H, q, J = 10 Hz).

IR (KBr): 3480, 2430, 1725, 1705, 1680, 1510, 1490, 1450, 1380, 1355, 1235, 1135, 1055, 1010, 950, 740 cm ^-1 .

8-α compound:

NMR (90MHz, CDCl3) δ: 1.30 (3H, d, J = 6.5Hz), 1.37 (3H, s), 1.55 (3H, s), 1.85 (3H, s), 2.02 (3H, s), 2.2 ~ 2.8 (5H, m), 2.44 (3H, s) m, 3,95-4.2 (3H, m), 4.3-4.55 (3H, m), 4.73 (1H, d, J = 11 Hz), 5.25-5.9 ( 6H, m), 6.29 (1H, d, J = 14 Hz), 8.06 (1H, d, J = 9 Hz).

The compounds shown in Table 3 were obtained by carrying out the reaction in a similar manner to Example 303 using 8-dehydroxy-8-iodolancassidin A as starting material.

TABLE 5

Example 308

Preparation of Lancacidin A-8 [(2-dimethylaminoethyl) thio] methyl carbonate and Lancadine A 8- [S- (2-dimethylaminoethyl)] thiocarbonate:

178 mg sodium hydride (60%) was added to 22 ml methanol. After the exothermic reaction and foaming was completed, 316 mg of 2-dimethylaminoethane thiol hydrochloride was added to the solution, and the mixture was stirred for 10 minutes. To the resulting mixture was added 1.46 g of lancastidine A 8-iodo methyl carbonate obtained in Example 242, and the mixture was further stirred for 1 hour. 500 ml of ethyl acetate was added to the product, washed with brine (100 ml × 3) and dried over MgSO 4. The solvent was distilled off and the residue was purified by silica gel (300 g) column chromatography [eluent: methanol-ethyl acetate (1: 20)] to give 698,5 mg of the title compound (methyl carbonate compound) and 83.4 mg of the title compound. (Thiocarbonate compound) was obtained.

Methyl carbonate compound, melting point 99-101 ° C. (decomposition):

NMR (90MHz, CDCl3) δ: 1.31 (3H, d, J = 6.5Hz), 1.37 (3H, s), 1.55 (3H, s), 1.90 (3H, s), 2.02 (2H, s), 2.2 ~ 2.65 (7H, m), 2.26 (6H, s), 2.45 (3H, s), 2.75-2.9 (2H, m), 4.40 (1H, m), 4.72 (1H, d, J = 11 Hz), 4.93 ( 1H, m), 5.21 (2H, s), 5.2-5.85 (6H, m), 6.29 (1H, d, J = 15 Hz), 8.07 (1H, d, J = 10 Hz).

IR (KBr): 3380, 2940, 1740, 1705, 1685, 1500, 1450, 1355, 1330, 1230, 1135, 1010, 960, 925 cm ^-1 .

Thiocarbonate compound, melting | fusing point 190-191 degreeC (decomposition):

NMR (90 MHz, CDCl 3) δ: 1.31 (3H, d, J = 6.5 Hz), 1.38 (3H, s), 1.55 (3H, s), 1.90 (3H, s), 2.03 (3H, s), 2.27 ( 6H, s), 2.2-2.65 (7H, m), 2.45 (3H, s), 2.9-3.05 (2H, m), 4.40 (1H, m), 4.70 (1H, d, J = 11 Hz), 5.13 ( 1H, m), 5.2-5.85 (6H, m). 6.28 (1H, d, J = 15 Hz), 8.06 (1H, d, J = 10 Hz).

IR (KBr): 3390, 2935, 1725, 1705, 1685, 1500, 1450, 1355, 1135, 1235, 1010, 940 cm ^-1 .

As starting material, the reaction shown in Table 6 was obtained by carrying out the reaction in a similar manner as in Example 308 using lancassidin A 8-iodomethyl carbonate.

TABLE 6

Example 315

Preparation of Lancacidin A 8-N- [2-[[1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thio] ethyl] carbamate:

121.3 mg of lancassidine A 8-N- (chloroethyl) carbamate was dissolved in 2 ml of N, N-dimethylformamide. To the solution was added 34.6 mg of 1- (2-dimethylaminoethyl) -1H-tetrazol-5-thiol, 33.2 mg of potassium iodide and 0.0162 ml of pyridine. The mixture was stirred at 60 ° C. for 1 hour, 80 ° C. for 1 hour and 100 ° C. for 3 hours. The solvent was distilled off under reduced pressure. A small amount of chloroform and ethyl acetate was added to the residue, washed with aqueous NaCl solution and dried over MgSO 4. The solvent was distilled off and the residue was purified by silica gel (25 g) column chromatography [eluent: ethanol-ethyl acetate (1: 1-)] to give 62.3 mg of the title compound as an oily substance.

NMR (90MHz, CDCl3) δ: 1.30 (3H, d, J = 7Hz), 1.36 (3H, s), 1.53 (3H, s), 1.88 (3H, s), 2.00 (3H, s), 2.15 ~ 2.6 (5H, m), 2.27 (6H, s), 2.43 (3H, s), 2.80 (2H, t, J = 6 Hz), ~ 3.45 (4H, m), 4.32 (2H, t, J = 6 Hz), -4.4 (1H, m), 4.70 (1H, d, J = 11 Hz), 4.93 (1H, m), 5.2-5.9 (7H, m). 6.28 (1H, doublet, J = 15 Hz), 8.04 (1H, doublet, J = 10 Hz).

IR (KBr): 1724 (sh.), 1710, 1686 (sh.), 1500, 1356, 1242, 1136 cm ^-1 .

Example 317

Preparation of Lancadine A 8- (3, 4-dihydro-2H-pyran-2-carbonyloxy) methyl carbonate:

97.5 mg of sodium 3,4-dihydro-2H-pyran-2-carboxylate was suspended in 5 ml of N, N-dimethylacetamide. To the suspension was added 342.5 mg of lancassidin A 8-iodomethyl carbonate and stirred for 1 hour. 200 ml of ethyl acetate was added to the mixture, washed with brine (50 ml × 4) and dried over MgSO 4. The solvent was distilled off and the residue was subjected to silica gel (180 Gg) column chromatography [eluent: ethyl acetate-chloroform (1:10)] to give 305.8 mg of the title compound.

NMR (90 MHz, CDCl 2) δ: 1.31 (3H, d, J = 6.5 Hz), 1.40 (3H, s), 1.56 (3H, s), 1.92 (3H, s), 2.04 (7H, br, s), 2.2 to 2.65 (5H, m), 2.47 (3H, s), 4.43 (1H, m), 4.5 to 4.65 (1H, m), 4.72 (1H, d, J = 11 Hz), 4.7 to 4.85 (1H, m ), 4.95 (1 H, m), 5.25-5.9 (6 H, m). 5.85 (2H, s), 6.30 (1H, d, J = 15 Hz), 6.42 (1H, d, J = 6 Hz), 8.11 (1H, d, J = 10 Hz).

IR (KBr): 1750, 1730 (sh.), 1710, 1685, 1500, 1360, 1240, 1150, 1070, 1010, 940 cm ^-1 .

Example 319

Preparation of Lancadine A 8- (4-dimethylamino) butyrate:

500 mg of Lancassidin A was dissolved in 30 ml of dichloromethane. To the solution was added 481.3 mg 4- (dimethylamino) butyrate hydrochloride, 353,5 mg triethylamine, 1.09 g dicyclohexyl carbodiimide and 318 mg zinc chloride, and the mixture was stirred for 1.5 hours. To the mixture was further added 160 mg 4- (dimethylamino) butyrate hydrochloride, 117 mg triethylamine, 363 mg dicyclohexylcarbodiimide and 106 mg zinc chloride. The resulting mixture was further stirred for 1 hour and filtered. The solid portion was washed with 100 ml of chloroform. The filtrate and washes were combined, washed with water (100 ml × 3) and dried over MgSO 4. The solvent was distilled off and the residue was subjected to silica gel (180 g) column chromatography [eluent: methanol-chloroform (1:25, and 1: 8)] to give 251.7 mg of the title compound as a white powder product.

NMR (90MHz, CDCl3) δ: 1.30 (3H, d, J = 7Hz), 1.37 (3H, s), 1.54 (3H, s), 1.90 (3H, s), 1.7 ~ 1.95 (2H, m), 2.02 (3H, s), 2.24 (6H, s), 2.2 to 2.55 (9H, m), 2.44 (3H, s), 4.40 (1H, m), 4.70 (1H, d, J = 11 Hz), 5.07 (1H , m), 5.25-5.9 (6H, m). 6.29 (1H, d, J = 15 Hz), 8.07 (1H, d, J = 10 Hz).

IR (KBr): 3400, 2940, 1725, 1710, 1690, 1500, 1360, 1230, 1160, 1135, 1015, 690 cm ^-1 .

Example 322

Preparation of Lancadine A 8-N- (3-carboxypropyl) carbamate:

72 mg of sodium hydride (60%) was added to 37.5 ml of methanol. After the foaming and exothermic reaction was complete, 201 mg of 4-aminobutyric acid and 342 mg of lancassidin A 8-iodinemethyl carbonate were added to the mixture and stirred for 1.5 hours. The product was concentrated and 100 ml of chloroform was added. The mixture was washed sequentially with dilute phosphoric acid and water and dried over MgSO 4. The solvent was distilled off and the residue was subjected to silica gel (100 g) column chromatography [eluent: methanol-chloroform (1: 20, and 1: 10)] to give 231 mg of the title compound.

Melting point 179-181 degreeC (decomposition).

NMR (90 MHz, CDCl 3) δ: 1.30 (3H, d, J = 6.5 Hz), 1.37 (3H, s), 1.53 (3H, s), 1.89 (3H, s), 1.85 to 2.1 (2H, m), 2.02 (3H, s), 2.2 to 2.6 (7H, m), 2.45 (1H, s), 3.23 (2H, dd, J = 6.5 and 6.5 Hz), 4.41 (1H, m), 4.69 (1H, d, J = 11 Hz), 4.8-5.2 (2H, m), 5.3-5.9 (6H, m), 6.28 (1H, d, J = 15 Hz), 8.07 (1H, d, J = 10 Hz).

IR (KBr): 3380, 2940, 1730 (sh.), 1710, 1690 (sh.), 1510, 1360, 1230, 1160, 1135, 1010, 960 cm ^-1 .

A mixture of Example 316 in a reaction similar to Example 315, a compound of Example 318 in a reaction similar to Example 317, and a compound of Examples 320 and 321 in a reaction similar to Example 319, with Example 322 Similar reactions yielded the compounds of Example 323, which are shown in Table 7.

TABLE 7

Example 324

Preparation of tancassidin C 8-N-methyl carbamate:

The esterase of Reference Example 11 (2.2 g) dissolved in a mixture of 24.3 ml of tetrahydrofuran and 24.3 ml of methanol, dissolved in 135.5 mg of lancassidin A 8-N-methyl carbamate and dissolved in 48.6 ml of water. ) Solution was added. The whole mixture was stirred for 1 hour and extracted with 47.2 ml of chloroform. The organic layer was washed with aqueous NaCl solution and dried over MgSO 4. The solvent was removed upstream, the residue was purified by silica gel (25 g) column chromatography-eluent: ethyl acetate] and the eluate was fractionated by 5 g. The 12th to 17th fractions were combined and distilled to yield 77.4 mg of the title compound.

NMR (90MHz, CDCl3) δ: 1.26 (3H, d, J = 7Hz), 1.37 (3H, s), 1.54 (3H, s), 1.89 (3H, s), 2.2 ~ 2.6 (5H, m), 2.44 (3H, s), 2.77 (3H, d, J = 5 Hz), ~ 4.3 (1H, m), 4.42 (1H, m), 4.69 (1H, d, J = 11 Hz), ~ 4.7 (1H, m) , 5.2-5.95 (5H, m), 6.17 (3H, d, J = 15 Hz), 8.06 (1H, d, J = 10 Hz).

IR (KBr): 1720 (sh.), 1704, 1682 (sh.), 1500, 1254, 1130, 960 cm ^-1 .

The reaction was carried out in a similar manner to Example 324 using the corresponding lancassidin A 8-derivative as starting material to afford the compounds shown in Table 8. In Example 404, the compound obtained in Example 250 was used as the starting material.

TABLE 8

R ¹ : ^{* 1} = 3 = CH ₃ (= NOCH ₃ ) CONH

Example 408

Preparation of O (8)-(4-methylpiperazino) carbonyl lancassidin A hydrochloride:

200 mg of O (8)-(4-methylpiperazino) carbonyl lancassidin A was dissolved in 6.4 ml of tetrahydrofuran. 0.139 ml of 1N-HCl was added to the solution and left for 10 minutes. The solvent was distilled off and the remaining material such as glass was treated with ether and triturated. The powdery product was collected by filtration and dried to yield 203.7 mg of the title compound.

NMR (90MHz, CDCl ₃ ) δ: 1.31 (3H, d, J = 7Hz), 1.38 (3H, s), 1.55 (3H, s), 1.90 (3H, s), 2.02 (3H, s), 2.1 ~ 2.65 (5H, m), 2.44 (3H, s), 2.83 (3H, s), 3.15 (4H, br,), 4.0 (4H, br.), 4.43 (1H, m), 4.72 (1H, d, J = 11 Hz), 5.00 (1H, m), 5.2-5.9 (6H, m), 6.28 (1H, d, J = 15 Hz), 8.07 (1H, d, J = 10 Hz).

IR (KBr): 1740 (sh.), 1720 (sh.), 1700, 1460 (sh.), 1420, 1254, 962 cm ^-1 .

Each of the hydrochlorides shown in Table 9 were obtained by running analogously to Example 408 using amino derivatives of the corresponding lancassidin A or C derivatives as starting materials.

TABLE 9

Claims (62)

A method for producing a compound of formula (2) or a salt thereof, wherein the compound of formula (1-2) is alkylated.

[The above formula, R ³ is C _{1 ~ 4} alkyl--OCOO ① ② ω-C _{2 ~ 4} a C _{1 ~ 4} alkyl--OCOS, ③ -OCOR ¹⁴ (wherein, R ¹⁴ to groping alkanoylamino is the terminal ⓐ di (C _{1 ~ 4} alkyl) amino or ⓑ oxygen, sulfur or C _{1 ~ 4} alkyl group) containing 1 to 4 nitrogen heteroatoms and optionally substituted with 5 ~ 8-membered heterocycle having an intermediate sulfur atom, or ④ - OCONR ¹⁵ R ¹⁶ , wherein R ¹⁵ and R ¹⁶ are each C _1-5 alkyl groups or together form a heterocycle group containing a nitrogen atom which may be substituted with ⓐ C _1-4 alkyl or ⓑ pyridyl; R ⁴ is a hydroxy or C _1-4 alkanoyloxy group; R ⁶ is C _1-5 alkanoyl; R ⁷ is a C _1-4 alkyl group]

[Wherein R ³ , R ⁴ , and R ⁶ are each as defined above or can be converted to them] A method for producing a compound of formula (1-3), wherein the compound of formula (2) is acylated and then hydrolyzed.

[The above formula, R ³ is C _{1 ~ 4} alkyl--OCOO ① ② ω-C _2-4 alkyl the -OCOS-C _{1 ~ 4,} ③ -OCOR ¹⁴ (wherein, R ¹⁴ to groping alkanoylamino is the terminal ⓐ di (C _{1 ~ 4} alkyl) amino or ⓑ oxygen, sulfur or C _{1 ~ 4} alkyl group) containing 1 to 4 nitrogen heteroatoms and optionally substituted with 5 ~ 8-membered heterocycle having an intermediate sulfur atom, or ④ - OCONR ¹⁵ R ¹⁶ , wherein R ¹⁵ and R ¹⁶ are each C _1-5 alkyl groups or together form a heterocycle group containing a nitrogen atom which may be substituted with ⓐ C _1-4 alkyl or ⓑ pyridyl; R ⁴ is a hydroxy or C _1-4 alkanoyloxy group; R ⁶ is a C _1-5 alkanoyl group or α-hydroxy C _1-4 alkyl group]

[Wherein, R ³ and R ⁴ are each as defined above or can be converted to them: R ⁶ is C _1-5 alkanoyl and R ⁷ is C _1-4 alkyl group] A process for producing a compound of formula (1), characterized in that thioamidation and alkylation as necessary after acylating the compound of formula (3).

[Wherein R ¹ is ① one of these is a hydrogen atom and the other is a formula

(Wherein Z is an oxygen atom or a sulfur atom; R ⁵ is a C _1-5 alkanoyl group or an α-hydroxy C _1-4 alkyl group) or

(Wherein R 6 is a C _1-5 alkanoyl group; R ⁷ is a C _1-4 alkyl group); R ³ is C _{1 ~ 4} alkyl--OCOO ① ② ω-C _{2 ~ 4} alkyl, -OCOS-C _{1 ~ 4} by groping alkanoylamino ③ -OCOR ¹⁴ (wherein, R ¹⁴ is a terminal ⓐ di (C _1-4 alkyl) amino or a C _1-4 alkyl group containing 1-4 oxygen, sulfur or nitrogen heteroatoms and optionally substituted with a 5-8 membered heterocycle group having an intermediate sulfur atom, or ④-OCONR ¹⁵ R ¹⁶ (Wherein R ¹⁵ and R ¹⁶ are each C _1-5 alkyl group or together form a heterocycle group containing a nitrogen atom which may be substituted with ⓐ C _1-4 alkyl or ⓑ pyridyl); R ⁴ is hydroxy or C _1-4 alkanoyloxy group]

[Wherein R ³ and R ⁴ are each the same as defined above or can be converted into them] The compound of formula (1-6) is represented by formula XCOR ^{14 '} wherein R ^14' contains _1-4 di-C ( _4- alkyl) amino or ⓑ oxygen, sulfur or nitrogen heteroatoms at A C _1-4 alkyl group substituted with a 5-8 membered heterocycle group having an intermediate sulfur atom, or a C _1-4 alkyloxy group; X is a halogen). Method for preparing the compound.

[Wherein R ¹ is ① one of these is a hydrogen atom and the other is a formula

(Wherein Z is an oxygen atom or a sulfur atom; R ⁵ is a C _1-5 alkanoyl group or an α-hydroxy C _1-4 alkyl group) or

(Wherein R 6 ^{is a} C _1-5 alkanoyl group; R ⁷ is a C _1-4 alkyl group); R ³ is R ⁴ are each formula -OCOOR ¹³ group or a group represented by the formula -OCOR ¹⁴ a (wherein, R ¹³ is C _{1 ~ 4} alkyl group) (wherein, R ¹⁴ is a terminal ⓐ di (C _{1 ~ 4} alkyl) amino Or ⓑ a C _1-4 alkyl group containing 1 to 4 oxygen, sulfur or nitrogen heteroatoms and optionally substituted with a 5-8 membered heterocycle group having an intermediate sulfur atom; R ⁴ also includes hydroxy or C _1-4 alkanoyloxy groups]

[Wherein R ¹ and R ² are each as defined above; R ^{3 '} and R ^4' are each a hydroxy group or an alkanoyloxy group and at least one of R ^{3 '} and R ^4' is a hydroxy group] 5. A compound according to claim 4, wherein one of R ¹ and R ² is a hydrogen atom and the other is a formula

(Wherein Z is an oxygen atom or a sulfur atom; R ⁵ is a C _1-5 alkanoyl group or an α-hydroxy C _1-4 alkyl group). The compound of claim 6, wherein R ⁵ is of the formula —C (═O) R ^5A , wherein R ^5A is C _1-3 alkyl which may be substituted by halogen, or a heterocycle group via an aryl or sulfur atom, CH ₂ -R ^5B (R ^5B is C _1-5 alkyl optionally substituted by halogen or alkyl which may be substituted by halogen, or aryl or heterocycle group via oxygen or sulfur atom), -CH (Y ^A ) R ^5C (Y ^A is hydroxyl, C _2-8 alkanoyloxy, optionally halogen-substituted C _1-3 alkoxycarbonyl, heterocycle aminocarbonyl, halogen, or C _1-3 alkoxycarbonyl, C _{2 ~} Amino which may be substituted by ₅ alkanoyl or arylsulfonyl, or hydroxy carbonyl, alkylsulfonyloxy, arylsulfonyloxy, tri-C _1-3 alkylsilyloxy, arylthio, C _1-3 alkyl Thio, alkylsulfonyl, azido, or a heterocycle group via a sulfur atom, R ^5C is a heterocycle group via a sulfur atom, aryljade Is a C _1-3 alkyl group which may be substituted by aryl or halogen), -R ^5D (R ^5D is an aryl, C _5-7 cycloalkyl or heterocycle group), -C (= NOR ^5E ) R ^5F (R ^5E is hydroxyl or C _1-3 alkoxy, R ^5F is a heterocycle group via a sulfur atom, C _1-3 alkyl optionally substituted by halogen) or -CY ^B = CH ₂ (Y ^B is hydrogen, C _2-5 alkanoyloxy, C _1-5 alcoholcycarbonyloxy or tri-C1-3 alkylsilyl). 8. The method of claim 7, wherein R ^5A is C _1-3 alkyl. 8. The heterocycle group according to claim 7, wherein R ^5B is a heterocycle group via a sulfur atom, consisting of triazolylthio, tetrazolylthio, pyridylthio and thiazolyl thio, which may be substituted by dimethylaminoethyl, methyl or amino. Way. 8. The method of claim 7, wherein Y ^A is hydroxyl or benzothiazol-2-ylthio and R ^5C is pyridin-2- ^ylthiomethyl or methyl. 8. The method of claim 7, wherein R ^5D is cyclohexyl, phenyl or 2-aminothiazol-4-yl. 8. The method of claim 7, wherein R ^5E is hydroxyl or methoxy and R ^5F is pyridin-2- ^ylthiomethyl . 8. The method of claim 7, wherein Y ^B is acetyloxy or t-butoxycarbonyloxy. 7. The method of claim 6 wherein Z is sulfur and R ⁵ is acetyl. 7. The method of claim 6 wherein Z is oxygen and R ⁵ is acetyl. 5. The compound of claim 4, wherein R ³ and R ⁴ are each hydroxyl, halogen, azide or a general formula: —OCOOR ¹³ wherein R ¹³ is an organic moiety via carbon, —OCOSR ^{15 ′} wherein R ^{13 ′} is Same as R ¹³ ), -OCOR ¹⁴ (wherein R ¹⁴ is an organic phase residue through carbon), -OCONR ¹⁵ R ¹⁶ (wherein R ¹⁴ and R ¹⁶ are each hydrogen or organic residue through carbon). -OCSNR ¹⁷ R ¹⁸ (where R ¹⁷ and R ¹⁸ are each organic residues via hydrogen or carbon), -OPO (OR ^1- ) ₂ (where R ^{1 ~} are organic residues via hydrogen or carbon), -OSO ₂ R ²⁰ (wherein R ^-0 is alkyl or aryl), -OR ²¹ (wherein R ²¹ is an organic moiety through carbon), -OSiR ²² R ²³ R ²⁴ (wherein R ²² , R ²³ , R ²⁴ is Each is alkyl or aryl, -SR ²⁵ (wherein R ²⁵ is an alkyl, cycloalkyl, alkenyl, alkynyl, aryl or heterocycle group which may have substituents), or NR ²⁶ R ²⁷ (where R ²⁶ and R ²⁷ is a group represented by hydrogen, alkyl, aryl, heterocycle group, acyl, sulfonyl or phosphoryl, which may each have a substituent. 18. The compound of claim 16 wherein R ^{13 '} is halogen, tetrazolylthio, thiadiazolylthio, phenylthio, C _1-3 alkylthio, pyrenylcarbonyloxy or C _1-3 alkanoylaminomethylcarbonyloxy C _1-3 alkyl, or phenyl which may be substituted. 18. The process of claim 16, wherein R ^{13 '} is di-C _1-3 alkylaminoethyl or thiadiazolylthiomethyl. 18. The compound of claim 16, wherein R ¹⁴ is halogen, still tetrazolylthiomethyl, thiadiazolylthiomethyl, di-C _1-3 alkylamino-C _1-3 alkylthio, mono- or di-C _1-3 alkylamino. , Piperazino, hydroxyl or C _1-3 alkylamino, morpholino, mono- or di C _1-3 alkylamino which may be substituted by C _1-3 alkylamino, or phenyl. 18. The compound of claim 16, wherein R ¹⁵ and R ¹⁶ are each hydrogen or C _1-3 alkoxycarbonyl, halogen, pyridylamino, di-C _1-3 alkylamino piperidino, pyridyl, tetrazolylthio or carboxyl. C _1-3 alkyl, or phenyl or cyclohexyl, which may be substituted by a carboxyl, or R ¹⁵ and R ¹⁶ together with adjacent nitrogen atoms to form morpholino, piperazino, or piperidino Way. 17. The method of claim 16, wherein R ¹⁷ and R ¹⁸ together with adjacent nitrogen atoms form morpholino, piperidino or piperazino. 17. The process of claim 16, wherein R ¹⁹ is hydrogen C _1-3 alkyl or benzyl. The method of claim 16, wherein R ²⁰ is C _1-3 alkyl or phenyl. 17. The method of claim 16, wherein the compound is C _1-3 alkyl, C _1-3 alkoxy C _1-3 alkyloxy, or C _1-3 alkyl substituted with C _1-3 alkylthio. The method of claim 16 wherein R ²² , R ²³ and R ²⁴ are each C _1-4 alkyl. 17. The method of claim 16, wherein R ²⁵ is phenyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl or triazolyl. 17. The method of claim 16, wherein R ²⁶ and R ²⁷ are each hydrogen, C _1-5 alkanoyl or tosyl. 7. The method of claim 6, wherein R ¹ is 2-oxo-1-thioxo-propyl and R ³ and R ⁴ are acetyloxy or hydroxyl, respectively. 9. The method of claim 8, wherein R ³ is acetyloxy and R ⁴ hydroxyl. ^10. The method of claim 9, wherein R ^5B is pyridylthio, R ³ is acetyloxy and R ⁴ is hydroxyl. The method of claim 10 wherein Y ^A is hydroxyl, R ^5C is pyridylthiomethyl, and R ³ and R ⁴ are acetyloxy. 20. The method of claim 19, wherein R ¹⁴ is di-C _1-3 alkylaminomethyl, R ⁴ is hydroxy and R ¹ is pyruboyl. 21. The method of claim 20, wherein R ¹⁵ and R ^{16 form} 2-pyridyl- or 4-methyl-piperadino, R ⁴ is hydroxyl or acetoxy and R ¹ is pyruboyl. 29. The method of claim 28, wherein 3- (2-oxo-1-thioxo propylamino) -lancon 8-acetate is prepared. 8. Process according to claim 7, characterized in that 3- (2-acetoxyacrylamino) -rancon 8, 14-diacetate is prepared. 6. The method of claim 5, wherein lancassidin C 8-dimethylaminoacetate is prepared. 6. The method of claim 5, wherein lancassidin C 8-dimethylaminoacetate is prepared. 6. The process of claim 5, wherein lancassidin A 8-[(2-dimethylaminoethyl) thio] methylcarbonate is prepared. 6. The process of claim 5, wherein lancassidin C 8-[(2-dimethylaminoethyl) thio] methylcarbonate is prepared. A method for producing a compound of formula (1-3), characterized in that it is acylated after hydrolysis of the compound of formula (2).

[The above formula, R ³ is C _{1 ~ 4} alkyl--OCOO ①, ② ω-C _{2 ~ 4} a C _{1 ~ 4} alkyl--OCOS, substituted alkanoylamino ③ -OCOR ¹⁴ (wherein, R ¹⁴ is the terminal the ⓐ di (C _{1 ~ 4} alkyl) amino or ⓑ oxygen, sulfur or C _{1 ~ 4} alkyl group) containing 1 to 4 nitrogen heteroatoms and optionally substituted with 5 ~ 8-membered heterocycle having an intermediate sulfur atom, or ④ -OCONR ¹⁵ R ¹⁶ , wherein R ¹⁵ and R ¹⁶ are each C _1-4 alkyl groups or together form a heterocycle group containing a nitrogen atom which may be substituted with ⓐ C _1-4 alkyl or ⓑ pyridyl; R ⁴ is a hydroxy or C _1-4 alkanoyloxy group; R ⁶ is a C _1-5 alkanoyl group or α-hydroxy C _1-4 alkyl group]

[Wherein, R ³ and R ⁴ are each as defined above or can be converted to them; R ⁶ is a C _1-4 alkanoyl group; R ⁷ is a C _1-4 alkyl group] Characterized by reacting a compound of formula (1-6) with a compound of formula T = C = NR ¹⁵ , wherein T is O or S atom; R ¹⁵ is an organic moiety through hydrogen or carbon atom Compound of formula (1) and preparation method.

[Wherein, R ¹ and R ² are one of:

(Wherein Z is an oxygen atom or a sulfur atom; R ⁵ is a C _1-5 alkanoyl group or an α-hydroxy C _1-4 alkyl group) or

(Wherein R ⁶ is a C _1-5 alkanoyl group; R ⁷ is a C _1-4 alkyl group); R ³ and R ⁴ are each a group of the formula -OCONR ¹⁵ R ¹⁶ (where R ¹⁵ and R ¹⁶ are each an organic moiety through hydrogen or a carbon atom) or a formula -OCSNR ¹⁷ R ¹⁸ (where R ¹⁷ and R ¹⁸ are each Hydrogen or an organic moiety via a carbon atom), and R ^{4 also} comprises a hydroxy or C _1-4 alkanoyloxy group]

[Wherein, R ⁴ and R ² are each as defined above; R ^{3 '} and R ^4' are each a hydroxy group or an alkanoyloxy group and at least one of R ^{3 '} and R ^4' is a hydroxy group] A compound of formula (1-6) is reacted with a compound of formula XCOOR ^{13 '} wherein X is halogen; R ^13' is C ₆ Cl ₅ or 2, 4, 5-C ₆ H ₂ Cl ₃ A process for preparing a compound of formula (1), wherein the compound is reacted with a compound of the formulas HNR ¹⁵ , R ¹⁶ , wherein R ¹⁵ and R ¹⁶ are each an organic moiety through hydrogen or a carbon atom.

[Wherein, R ¹ and R ² are one of:

(Wherein Z is an oxygen atom or a sulfur atom; R ⁵ is a C _1-5 alkanoyl group or an α-hydroxy C _1-4 alkyl group) or

(Wherein R ⁶ is a C _1-5 alkanoyl group; R ⁷ is a C _1-4 alkyl group); R ³ and R ⁴ are each a group of the formula -OCONR ¹⁵ R ¹⁶ , wherein R ¹⁵ and R ¹⁶ are each an organic moiety through hydrogen or a carbon atom, and R ⁴ is also a hydroxy or C _1-4 alkanoyloxy group It includes]

[Wherein R ¹ and R ² are each as defined above; R ^{3 '} and R ^4' are each a hydroxy group or an alkanoyloxy group and at least one of R ^{3 '} and R ^4' is a hydroxy group] The compound of formula (1-6) is represented by the compound of formula HSR ^{13 ′} (wherein R ^{13 ′} is CHCl ₂ , C ₆ Cl ₅ , 2, 4, 5-C ₆ H ₂ Cl ₃ , or CH ₂ I). A process for producing a compound of formula (1), characterized in that for reaction.

[Wherein, R ¹ and R ² are one of:

(Wherein Z is an oxygen atom or a sulfur atom; R ⁵ is a C _1-5 alkanoyl group or an α-hydroxy C _1-4 alkyl group) or

(Wherein R ⁶ is a C _1-5 alkanoyl group; R ⁷ is a C _1-4 alkyl group); R ³ and R ⁴ are each a group of the formula -OCONR ¹³ (wherein SR ^{13 '} is a ω-C _2-4 alkanoyl amino alkylthio group), and R ⁴ is also a hydroxy or C _1-4 alkanoyloxy group It includes]

[Wherein R ¹ and R ² are each as defined above; R ^{3 '} and R ^4' are each a hydroxy group or an alkanoyloxy group and at least one of R ^{3 '} and R ^4' is a hydroxy group] 6. The method of claim 5 wherein Z is sulfur and R ⁵ is acetyl. 47. The method of claim 46, wherein Z is sulfur and R ⁵ is acetyl. 48. The method of claim 47, wherein Z is sulfur and R ⁵ is acetyl. 49. The method of claim 48, wherein Z is sulfur and R ⁵ is acetyl. 6. The method of claim 5 wherein Z is oxygen and R ⁵ is acetyl. 47. The method of claim 46, wherein Z is oxygen and R ⁵ is acetyl. 48. The method of claim 47, wherein Z is oxygen and R ⁵ is acetyl. 49. The method of claim 48, wherein Z is oxygen and R ⁵ is acetyl. 6. A compound according to claim 5, wherein R ¹⁴ is halogen, azido, tetrazolylthiomethyl, thiadiazolylthiomethyl, di-C _1-3 alkylamino-C _1-3 alkylthio, mono- or di-C _1-3. characterized in that the or di-C _{1 ~ 3} C _{1 ~ 3} alkyl, or phenyl which may be substituted by an alkylamino-alkylamino, piperazino, hydroxyl or C _{1 ~ 3} alkyl amino, morpholino, mono . 47. The compound of claim 46, wherein R ¹⁵ and R ¹⁶ are each hydrogen or C _1-3 alkoxycarbonyl, halogen, pyridylamino, di-C _1-3 alkylamino piperidino, pyridyl, tetrazolylthio or carr C _1-3 alkyl, or phenyl or cyclohexyl, which may be substituted by a carboxyl, or R ¹⁵ and R ¹⁶ together with adjacent nitrogen atoms to form morpholino, piperazino, or piperadino Way. 48. The compound of claim 47, wherein R ¹⁵ and R ¹⁶ are each hydrogen or C _1-3 alkoxycarbonyl, halogen, pyridylamino, di-C _1-3 alkylamino piperidino, pyridyl, tetrazolylthio or carr C _1-3 alkyl, or phenyl or cyclohexyl, which may be substituted by a carboxyl, or R ¹⁵ and R ¹⁶ together with adjacent nitrogen atoms to form morpholino, piperazino, or piperidino Way. 47. The method of claim 46, wherein R ¹⁷ and R ¹⁸ together with adjacent nitrogen atoms form morpholino, piperidino or piperazino. 48. The method of claim 47, wherein R ¹⁷ and R ¹⁸ together with adjacent nitrogen atoms form morpholino, piperidino or piperazino. 59. The method of claim 57, wherein R ¹⁴ is di-C _1-3 alkylaminomethyl, R ⁴ is hydroxy and R ¹ is pyruboyl. 59. The method of claim 58, wherein R ¹⁵ and R ^{16 form} 2-pyridyl or 4-methyl-piperadino, R ⁴ is hydroxyl or acetoxy and R ¹ is pyruboyl. 60. The method of claim 59, wherein R ¹⁵ and R ^{16 form} 2-pyridyl or 4-methyl-piperadino, R ⁴ is hydroxyl or acetoxy and R ¹ is pyruboyl. 48. The process of claim 47, wherein O (8)-[(4-2-pyridylpiperadino] carbonyl-lancassidin A is prepared. 48. The process of claim 47, wherein O (8)-[4- (2-pyridyl) piperazino] carbonyl-lancassidin A is prepared. 48. The process of claim 47, wherein O (8)-(4-benzylpiperazino) carbonyl-lancassidin C is prepared. 48. The process of claim 47, wherein O (8)-(4-benzylpiperadino) carbonyl-lancadine C hydrochloride is prepared.