WO1986005784A1

WO1986005784A1 - Antibiotics and preparation containing same

Info

Publication number: WO1986005784A1
Application number: PCT/JP1985/000160
Authority: WO
Inventors: Hiroshi Shimadzu; Susumu Shinagawa; Isao Minamida
Original assignee: Takeda Chemical Industries, Ltd.
Priority date: 1985-04-03
Filing date: 1985-04-03
Publication date: 1986-10-09
Also published as: JPS61257973A

Abstract

Compounds represented by general formula (I) (wherein R1 and R2, which may be the same or different, each represents hydrogen or an organic residue via a carbon atom or -SO2-, X represents (II), (III), (IV), (V), (wherein R4 represents hydrogen, hydroxy, halogen or an organic residue via a carbon, nitrogen, oxygen, or sulfur atom, R5 represents a divalent group via two carbon atoms which may optionally be substituted, $(1,4)$- is bound to the p-position of the benzene ring with respect to R1O-, and $(1,4)$- is bound to the m-position with respect to R1O-), R6 represents carboxy, a group derived from carboxy, or a delta-lactone together with -OH in position 7 or 13, and Y represents -CO- or (VI) (wherein R7 forms a 5-membered ring together with -OR1 when R1 represents an organic residue via a carbon atom), provided that X does not represent (VII), when R1 and R2 each represents H, R6 represents methoxycarbonyl, and Y represents -CO-, and that X does not represent (VIII) when R represents methyl, R2 is hydrogen, R6 is methoxycarbonyl, and Y is -CO-) and salts thereof have excellent antibacterial activity, and can be used as antibacterial agent.

Description

Specification

Antibiotics and preparations

Technical field

The present invention relates to a novel ansamycin antibiotic having an antibacterial activity and a preparation containing the same.

Conventional technology

As an ansamycin antibiotic having an antibacterial action, for example, Damavaricin D is known [Journal of Antibiotics, Vol. 29, No. 201]. ~ 203 (1976)].

Disclosure of the invention

The tansamycin antibiotic TAN-528A is produced and accumulated by culturing Streptomyces sp.

It is.

Thus, the present inventors synthesized various derivatives using the antibiotic TAN-528A as a raw material, and examined the pharmacological action thereof. As a result, they found that the derivatives had excellent antibacterial activity.

The present inventors have further studied based on these findings and completed the present invention.

The present invention relates to (I) a compound represented by the general formula: [1]

CH ₃ CH ₃ CH ₃ R ⁶

[Wherein R ¹ and R ² are the same or different and are each a hydrogen or carbon atom or

Haichi

formula

A halogen or an organic residue via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom; R ⁵ represents a divalent group via two carbon atoms which may have a substituent; This indicates that A— is bonded to the para-position of the 1 ^ 0 group of the benzene ring, and that Reiichi is bonded to the meta-position of the R group of the benzene ring in Formula [1]. R ⁶ is a group which can be derived from carboxy, carboxyl, or a group which can be derived from a 7- or 13-position mono-OH. That 0 H taractones may be formed, Y is one CO— or one? One (where

R ⁷

R ⁷ indicates that R ¹ forms a 5-membered ring with one OR ¹ where an organic residue through a carbon atom. )). Where R ¹ and R ² are hydrogen, R ⁶ is methoxycarbonyl and Y is — C 0 —

X is not when R ¹ is methyl and R ² is hydrogen and R ^{6 is}

, Tf CH:

0

X is when ,,, and are methoxycarbonyl and Y is —C 0—

S-CH _;

Ύ

0

is not. Or a salt thereof, and

(Ii) An antibacterial agent containing the compound [1] or a salt thereof.

In the above formula, as the organic residue via the carbon atom represented by R ¹ or R ² , those having a molecular weight of up to 400 are preferable, and examples thereof include, for example, alkyl, alkenyl, alkynyl, aralkyl, acyl, and alkyloxy groups. Luponyl and the like, which may have 1 to 3 substituents.

In the above formula, as the organic residue via one S 0 ₂ — represented by R ¹ or R ² , one having a molecular weight of up to 300 is preferable, and for example, for example, a compound of the formula R ³ —S 0 ₂ — ( Wherein R ³ represents an alkyl, aryl or heterocyclic ring; These may have 1 to 3 substituents. ).

In the above formula, as the organic residue via the carbon atom represented by, those having a molecular weight of up to 200 are preferable, and examples thereof include alkyl, alkenyl, alkynyl, acyl, alkoxycarbonyl, and acylboxycarbonyl. And these may have 1 to 3 substituents.

In the above formula, as the organic residue via the nitrogen atom represented by R ⁴ , those having a molecular weight of up to 300 are preferable, and examples thereof include, for example, amino, secondary amino, and tertiary amino rings. Tertiary amino, etc., which may have 1 to 3 substituents.

Examples of the secondary amino include monoalkylamino, dicycloalkylamino, monoarylamino, monoalkylamino, and the like.

Examples of the tertiary amino include dialkylamino, dicycloalkylamino, diarylamino, diaralkylamino, X-alkyl-1: \ ^: — arylamino, —alkiryl N-aralkylamino, and the like. No.

Examples of the tertiary amino forming the ring include morpholino, pyrrolidino, piperazino, hexamethyleneimino and the like.

These primary amino, secondary amino, tertiary amino, and tertiary amino forming a ring may have 1 to 3 substituents.

In the above formula, as the organic residue via the oxygen atom represented by R ⁴ , those having a molecular weight of up to 200 are preferable, and examples thereof include, for example, alkoxy, acyloxy, alkyloxycarbonyloxy, and aralkyloxy. Carbonyloxy, alkylsulfonyloxy, arylsulfonyloxy, etc. These may have 1 to 3 substituents.

In the above formula, as the organic residue via the sulfur atom represented by R ⁺ , those having a molecular weight of up to 500 are preferable.

R ³ ′ -S (O) n- (wherein, R ³ ′ represents alkyl, aryl, aralkyl, heterocycle, or heterocyclic alkyl, which has 1 to 3 substituents. N represents an integer of 0 to 2. Examples of the group include: In the above formula, examples of the halogen represented by R ⁺ include fluorine, chlorine, bromine, and iodine.

In the above formula, the divalent group via two carbon atoms which may have a substituent represented by R ⁵ is preferably a group having a molecular weight of up to 300, and is preferably a group having a molecular weight of up to 300 via the two carbon atoms. Examples of the divalent group include ortho-to-phenylene, ortho-naphthylene, vinylene, ethylene and the like, and these may have a 1-3 value substituent.

In the above formula, as a group which can be derived from Karubokin represented by R ^6; or, preferably has a molecular weight of up to 200, examples of which example esters, such as § mi de, and the like.

Examples of the ester include an alkyl ester, an aryl ester, an aralkyl acetyl, an alkoxyalkyl ester, an acyloxy alkyl ester, and the like. These have 1 to 3 substituents. b good ₀

Examples of the amide include ammonia, monoalkylamine, dialkylamin, penoarylamine, diallylamine, penoaralkylamine, dialkylamine, N-alkyl-N-arylamine, and N-alkyl. — Amides with amines such as N-aralkylamine and cyclic amine, which may have 1 to 3 substituents.

In the above formula, the 5-membered ring formed between R ⁷ and one OR ¹ has a partial structural formula

Is represented as In the partial structural formula, R ¹ ′ is, for example, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclohexyl, phenyl, benzyl, etc., and R ⁷ ′ is, for example, acetyl or acetyl. Examples include propionyl, benzoyl, nitrile, ethoxycarbonyl, methoxycarbonyl, ethylsulfonyl, methylsulfonyl, phenylsulfonyl, tolynisulfonyl, a nitro group, and carboxy. -In the above general formula, alkyl refers to alkyl in alkoxy, alkyl in alkyloxy, alkyl in alkoxy, alkyl in carbonyl, alkyl in alkylsulfonyloxy, alkyl in monoalkylamino, alkyl in dialkylamino, N— Alkyl-N-arylamino and N-alkyl-alkyl in N-aralkylamino, alkyl in alkyl esters, alkyl in alkoxyalkyl esters, alkyl in monoalkylamines, alkyl in dialkylamines, N-alkyl-N- Alkyl in arylamine, N-alkyl-alkyl in N-alkylalkylamine is preferably, for example, one having 1 to 20 carbon atoms. Additionally having a carbon number of 1-8 is more preferable. The alkyl may be straight-chain or branched. Specific examples of the alkyl include, for example, methyl, ethyl, propyl, isopropyl, and petit. , Isobutyl, sec-butyl, te-butyl, pentyl, hexyl, heptyl, octyl, nonyl, 2-ethylhexyl, decyl, pendecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, octadecyl, Nonadecyl and eicosyl are examples.

In the above general formula, alkenyl preferably has 2 ^ 6 carbon atoms. Specific examples of the alkenyl include, for example, vinyl, aryl, isopropyl, methallyl, 1,1-dimethylaryl, 2-butenyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 5-hexenyl and the like. Can be

In the above general formula, alkynyl having 2 to 6 carbon atoms is preferable, and specific examples thereof include ethynyl, propargyl, 2-butyn-11-yl, and 3-butyn-11-yl. , 3 —butin 1 -yl, 1 —pentin 1 -yl, 3 —pentin 1 -yl, 4 —pentin 2 -yl, 3 —hexine 1 -yl Can be

In the above general formula, cycloalkyl preferably has 3 to 3 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In the above general formula, as acyl or in acyloxycarbonyl: as acyl in acyloxy, acyl in acyloxy, or acyl in acyloxyalkyl ester, for example, alkyl or alkenyl corresponding to R ¹ or R ² Examples include phenyl, alkynyl, and aryl corresponding to R ³ (described below), and an acyl group obtained by introducing a carbonyl group or an oxycarbonyl group into a heterocyclic ring, and acetyl, propionyl, and butyryl. Heterocyclic carbonyls such as alkylcarbonyl, such as carbonyl, hexanoyl, heptanyl, octanoyl, and decanol; arylcarbonyl, such as benzoyl and naphthoyl; thiophenecarbonyl, furancarbonyl, and pyridinecarbonyl. Alkoxycarbonyl groups such as, methoxycarbonyl and ethoxycarbonyl; Wenoki Examples include aryloxycarbonyl groups such as cyclocarbonyl and naphthyloxycarbonyl, and arylalkoxycarbonyl groups such as benzyloxycarbonyl.

In the above general formula, as aryl, aryl in arylsulfonyloxy, aryl in monoarylamino, aryl in diarylamino, aryl in N-alkyl-1 aryl in N-arylamino, aryl in aryl ester. Examples of aryl in monoarylamine, aryl in diarylamine, and aryl in N-alkyl-N-arylamine include, for example, phenyl and naphthyl. And the like.

In the above general formula, examples of the heterocyclic ring represented by R ³ include phenyl, furyl, pyridyl and the like.

In the above general formula, the heterocyclic ring represented by R ³ ′ or the heterocyclic ring in the heterocyclic alkyl includes, for example, chenyl, furyl, pyridyl, and an oxygen atom, a sulfur atom, and a heteroatom such as a nitrogen atom. And 5- to 8-membered rings or bonding rings having a bond on a carbon atom, such as 2 — or 3 — pyrrolyl, 2 — or 3 — furyl, 2 — or 3 — phenyl, 2 — Or 3—pyrrolidinyl, 2—, 3— or 4-pyridyl, N—one oxide 2—, 3—or 4—pyridyl, 2—, 3— or 4-piperidinyl, 2—, 3— Or 4-pyranyl, 2-, 3- or 4-thioviranyl, pyrazinyl, 2-, 4-one or 5-thiazolyl, 2-, 4-one or 5-oxazolyl, 3-, 4_ or 5-isothiazolyl, 3 —, 4 mono or 5 — iso Oxazolyl, 2—, 4— or 5— imidazolyl, 3—, 4— or 5—pyrazolyl, 3— or 4 monopyridazinyl, N—oxydoh 3— or 4—pyridazinyl, 2—, 4 1 or 5 —Pyrimidinyl, N-oxydoxide 2—, 4 — or 5 —pyrimidin Nil, piperazinyl, 4 mono or 5— (1,2,3—thiadiazolyl), 3 mono or 5— (1,2,4—thiadiazolyl), 1,3,4—thiadiazolyl, 1,2,5—thiadiazolyl, 4—or 5— (1,2,3—oxaziazolyl), 3—or 5— (1,2,4-oxaziazolyl), 1,3,4—oxoxadiazolyl, 1,2,5—oxaziazolyl, 1, 2, 3 — or

2, 4 — triazolyl, 1 H— or 2 H—tetrazolyl, pyrido [2,

3—d] pyrimidyl, benzopyranyl, 1,8—, 1,5—, 1,6—, 1,7—, 2,7—or 2,6—naphthyridyl, quinolyl, thieno [2,3 — D] Pyridyl is commonly used.

In the above general formula, aralkyl is defined as aralkyl in aralkyloxycarbonyl, aralkyl in N-alkyl-N-aralkylamine, aralkyl in diaralkylamino, aralkyl in diaralkylamino, and N-aralkyl-1N. Examples of aralkyl in aralkylamino, aralkyl in aralkyl ester, aralkyl in monoaralkylamine, and aralkyl in diaralkylamine include, for example, benzyl, 2-phenethyl and the like. Examples thereof include morpholino, pyrrolidino, piperazino, hexamethyleneimino and the like.

The above alkyl group, alkenyl group, alkynyl group, acyl group, secondary amino, tertiary amino, tertiary amino, secondary amine, tertiary amine or ring forming a ring The formed tertiary amine may have a substituent. Examples of such a substituent include a hydroxyl group, a C ₃ -cycloalkyl group (which may have a substituent), C _B - _{1 0} § Li - Le group, C ₊ alkoxy group, C ₃ (which may have a substituent.) - ₊ alkoxy group, C ₃ - ₆ cycloalkyl Ruokishi group, C s-i. Ariruokishi group, 〇 ₇ - _{1 2} Ararukiruokishi group, C 1 - ₊ Arukiruchio group, 〇 ₃ - ₆ cycloalkylthio group, C ₆ - ₁₀ § Li - thio group,

G ₇ — ₁₂ aralkylthio, amino, mono C ₊ alkylamino, di

C ₊ Arukiruamino groups, C 3 - ₆ consequent opening Arukiruamino group, Rei_6- _{1 0} Ariru amino group, 〇 ₇ - ₁₂ Ararukiruamino group, azido group, nitro port group Nono androgenic atom, Shiano group, carboxy groups, C alkoxycarbonyl groups, C ₂ - ₅ Ashiruo alkoxycarbonyl group, C _e - ₁₀ § Li - Ruo alkoxycarbonyl group, C ₃ - ₈ Shikuroa Ruki Ruo alkoxycarbonyl group, C ₇ - ₁₂ § Lal kill O alkoxycarbonyl group, d - ₅ Arukanoiru groups, C ₂ - ₅ alkanoylamino Noi Ruo alkoxy group, a sulfo group, Karubamo I group, substituted force Rubamoiru group, Chiokarupamoiru group, a substituted Chiokarubamoi group, forces Rubamoiruokishi group, a substituted Scarpa乇Iruokishi group, Futaruimi de groups, C Arukanoiruami de group, 〇 ₈ - ₁₀ § reel § sill Ami de group.

Alkoxycarbonyl § amino 'group, 〇 ₇ - ₁₂ § Lal Kill O alkoxycarbonyl § amino group, Okiso group, an epoxy group, Chiokiso group, sulfonamide de group, a Hajime Tamaki (which may have a substituent.) Examples include a heterocyclic thio group, a heterocyclic oxy group, and a heterocyclic amino group.

Examples of the above-mentioned alkyl, alkenyl, alkynyl and aryl groups which may be substituted on the cycloalkyl group, aryl and heterocyclic groups may be, for example, a hydroxyl group. , § alkoxy group, C ₊ alkylthio group, Amino group, mono C Arukiruami amino group, di C Arukiruamino group, 〇 ₈ - ₁₀ § Li one Ruamino group, azido group, two preparative mouth Nono androgenic atom, Shiano group, a carboxy group , C _t-+ alkoxy one carboxy alkenyl groups, C 6- ₁₀ § Li - Ruo alkoxycarbonyl groups, C Al force Noiru group,

C ₂ one _s Al force Noiruokin group, a sulfo group, a force Luba乇I group, substituted force Rubamoi group, forces Rubamoiruokishi group, a substituted force Rubamoiruokishi group, C i - ₄ alkanol Iruami de group, C _t - ₊ alkoxy one Karuboniruami And a sulfonamide group. Examples of the groups which may be substituted on the above-mentioned alkoxy, alkoxycarbonyl, alkoxycarbonyloxy, acyloxycarbonyl, acyloxy, alkyl ester, alkylsulfonyloxy, alkoxyalkyl ester and acyloxyalkyl ester include: For example, a hydroxyl group, C _t - ₄ § Rukokin, C alkylthio group, Amino group, mono C ^ Arukiruamino group, di C _t - ₊ Arukiruamino group, 〇 ₆ - _{1 0} § Li - Ruamino group, C ₇ - _{1 2} Ararukiru Amino Group, nitro group, halogen atom, carboxy group, C-alkoxy-propanol group, C-alkynyl group, Ci-5-alkyloxy group, sulfo group, lbamoyl group, substitution rubamoyl group, lbamoyloxy group , Substitution power rubamoyloxy group, C alkanoylamide group and the like.

Aryl, aralkyl, aralkyl, aralkyl esters, aralkyl esters, aralkyl esters in the above-mentioned aryl, aryl esters, monoarylamines, diarylamines, N-alkyl-N-arylamines. Min, diaralkylamine, N-alkyl-aralkyl in N-aralkylamine, a heterocyclic ring represented by R ³ ′, and a group which may be substituted by a heterocyclic alkyl heterocyclic ring include, for example, a hydroxyl group, an alkyl group group (which may have a substituent), (which may have a substituent) C ₈ one _{1 0} Ariru group, C ₃ - _s consequent opening alkyl group Roh, androgenic atom, a carboxyl group, a sulfo group , § alkoxy groups, C alkylthio group, two preparative port groups, C _t-+ alkoxy - carboxymethyl group, an amino group, a mono C - ₄ alkylamino amino group, di C - ₄ alkylamino groups, C Rukanoiruami de group, 〇 ₈ - _{1 0} § Li - Ruokishi group, 0 ₇ - _{1 2} Araru kill group, C ₇ - _{1 2} Ararukiruokishi group, C ₆ - _{1 0} Ariruamino group, C ₇ - _{1 2} § Rarukiruami amino group, Shiano group, 〇 ₈ - _{1 2} § reel O alkoxycarbonyl group, C ^?

2 aralkyloxycarbonyl group, C alkenyl group, C 2-5 alkanoyloxy group, benzyl group, substituted carpamoyl group, substituted carbamoyloxy group, C ₄ alkoxy-carbonylamino group, etc. Can be The above-mentioned aryls in rusulfonyloxy, represented by R ³

- As a group which may be substituted on Le and heterocyclic, such as C [- ₊ § alkyl group, C ₆ - ₁₀ § Li - Le group Nono androgenic atom, C ₊ alkoxy group, a nitro group, C ₃ -e Sik port alkyl groups, C, - ₊ alkylthio groups, C alkoxy Ichiriki Lupo alkenyl groups, C ₅ Al force Roh I group, and the like.

Examples of the divalent substituent may have the groups represented by R ^5, was example, if hydroxyl Bruno, androgenic, C ie alkyl group, 0 ₃ - ₆ consequent opening alkyl, Ce-io § Li 'Lumpur group , C alkoxy, C t -alkylthio, amino, mono C ₊ alkylamino, di C alkylamino, azide, ditro, cyano, carboxy, C ₄ alkoxy-carbonyl, C alkyl I le group, C ₂ one ₅ Arca Noi Ruo alkoxy group, a sulfo group, a force Rubamoiru group, Cal Bamoiruokishi group, C _t-+ Al force Noiruami de group, etc. Okiso group like et be.

These substituents will be described in detail below. ·

Examples of the C- ₄ alkyl group as a substituent include methyl, ethyl, propyl; isopropyl, butylisobuty), sec-butyl, tert-butyl, and the like.

C ₃ - _beta, for example cyclopropyl cycloalkyl group, Shikuropuchi Le, cyclopentyl, cyclohexylene, etc. cyclohexyl force

Examples of C 0 aryl groups include phenyl and naphthyl.

〇 ₇ - ₁₀ The Ararukiru group such as benzyl, 1 Fuenechiru, 2-phenethyl, 1 - Fuwenirupuropiru, 2 Fuwenirupuropiru, 3-phenylene pulp outlet pills,

Examples of C alkoxy groups include methoxy, ethoxy.propoxy, isopropoxy, butoxy and tert-butoxy.

C ₃ - 8 cycloalkyl § Ruki Ruo carboxymethyl The group for example cyclopropyl O key And cyclohexyloxy,

. Examples of aryloxy groups include phenoxy and naphthoxy.

C ₇ - ₁ The ₂ Ararukiruokishi groups such Benjiruokishi, 2 Hue Nechiruokishi is,

Examples of CL- ₊ alkylthio groups include methylthio, ethylthio, propylthio, and butylthio.

C ₃ - ₆ cycloalkylthio The group e.g. cyclopropylthio, such as cyclohexylthio to shea click port,

C ₆ - _{1 0} The § Li one thio group such as phenylthio, etc.,

C. 7 - i The ₂ Ararukiruchio group e.g. benzylthio and mono C Arukiruami amino group as, for example Mechiruami Bruno, Echirua amino, propylamino, Puchiruamino like,

Examples of the dialkylamino group include dimethylamino, getylamino, dipropylamino, dibutylamino, and the like.

C ₃ - ₆ consequent opening Arukiruami amino group as, for example consequent Ό Puropiruami Bruno, cyclohexane, etc. Kishiruami Bruno is,

C _G -t 0 arylamino groups include, for example, anilino,

The C ₇ one _{1 2} Ararukiruamino groups such Benjiruamino, such as 2-Hue Nechiruami Bruno is,

Examples of halogen atoms include fluorine, chlorine, bromine, and iodine.

Examples of C alkoxy-carbonyl groups include methoxycarbonyl, ethoxyquincarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, and the like.

C ₈ - _t. Examples of aryloxycarbonyl groups include phenoxycarbonyl, C ₃ - ₆ consequent opening alkyl O carboxymethyl The group e.g. consequent opening flop port pills O alkoxycarbonyl, hexyl O alkoxycarbonyl or the like to the consequent opening '

Examples of the C ₇ -L 2 aralkyloxycarbonyl group include benzyloxycarbonyl and the like.

d-5 alkanoyl groups include, for example, formyl, acetyl, propionyl, butyryl phenol, pivalyl, etc.

Alkanoyloxy groups include, for example, formyloxy, acetoxy, butyryloxy, bivaloyloxy and the like.

Examples of the substituent groups include N-methylcarbamoyl,, N-dimethylcarbamoyl, N-ethylcarbamoyl, N-phenylcarbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl, morpholinocarbonyl and the like. But,

Examples of substituted thiolvamoyl groups include —methylthio lvamoyl.

Examples of the substituent groups include N-methylcarbamoyloxy, N, -dimethylcarbamoyloxy, and M-ethylcarbamoyloxy.

Examples of the C ₊ alkanoylamide group include formylamino, acetoamide, propionamide, and butyrylamide.

C ₆ - _{1 0} § Li - The Ruashiruami de group e.g. Benzuami Donado Ca

Examples of the C alkoxy-carbonylamino group include methoxycarbonylamino, ethoxycarbonylamino, tert-butoxycarbonylamino, and the like.

C ₇ - _1, such as ₂ § Lal Kill O carboxymethyl The carbonylamino group for example benzyl Ruo alkoxycarbonyl § Mino is,

Examples of the optionally substituted C alkyl group include, for example, methoxymethyl , 2-Methoxyxetil, hydroxymethyl, fluoromethyl, trifluoromethyl, difluoromethyl, carboxymethyl, ethoxycarbonylmethyl, potassium benzyl, cyanoethyl, acetylmethyl, etc.

Examples of the heterocyclic group include a cyclic group containing one to four nitrogen atoms, one oxygen atom and one sulfur atom, such as pyrrolidino, 2-pyrrolyl, 3-pyrrolidinyl,

3 — pyrazolyl, 2 — imidazolyl, 2 — furyl, 2 — phenyl, 2- oxosazolyl, 3 — isoxazolyl, 4 — isothiazolyl, 4-thiazolyl, piperidino, 2 — pyridyl, 3 — pyridyl Jill, 4—pyridyl, piperazino, 2—pyrimidinyl, 5—pyrimidinyl, 2—viranyl, 2—tetrahydropyranil, 2—tetrahidrofril, 3—indrillyl, 2—quinolyl, 1 , 3,

4 —Oxaziazolu 2 —Ir, Thieno [2,3—d] pyridyl 6 —Ir, 1, 2, 3 —Thiadiazolu 4 —Iro, 1,3,4: —Thiadiazole— 2-yl, 1, 2, 3, 4-tetrasol-1-5-yl, 4, 5-jihi draw 1, 3-dioxo-1-2-yl.

More specifically,

R ¹⁰ — or R ²⁰ — — as well: Hid, Coxy, Methoxy, Ethkin, Proboxy, Isop σ-Poxy, Butoxy, Isobutoxy, Bentiloxy, Isopentyloxy, Hexyloxy, Hepti / Roxy, Octyloxy, nonyloxy, decyloxy, pendecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy, hexadesiloxy, octadecyloxy, cyclopropyl methoxy, methoxy methoxy, methoxy ethoxy, 2-clocloethoxy , 2 — Fluoroethoxyquin, 2, 2, 2 — Trifluoroethoxy, 3 — Clopropoxy, 2 — Hydroxyethoxy, 4-Hydroxybutoxy, 2 — Cyanethoxy, 3 — Cyanpropoxy, 3, 3-die Tokin Propoxy, 2-Phono Xietokin, aryloxy, crotyloxy, benzyloxy, ρ-xylyloxy, 4 Benzyloxy, 3-fluorobenzyloxy, 412-trobenzoyloxy, phenethyloxy, cinnamyloxy, cyclopentyloquin, cyclohexyloxy, 2-oxopropoxy, phenacyloxy, 2'-, 3'- and 4'-methylphen Nasiloxy, 4 'monoclophenasiloxy, 2'-, 3'- and 4'-methoxyphenasiloxy, 4'12-trophenasiloxy, 3'-nitro-phenasiloxy, (2-tetrahydrobilanyl) Methoxy, 4, 5 —Dihidro 1, 3 —Dioxol — 2 —Ilmethoxy-1 2 —Furfuryloxy, 2- (2-furyl) ethoxy, 3-Tenyloxy, 2- (2-Cenyl) ethyloxy, Perholinoetkin, Piperi Dinoethoxy, pyrrolidinoethoxy, floylmethoxy, tenylmethoxy, 2—Quinolyl methoxy, 2- (5,6-Benzo-1,4-dioxanyl) methoxy, methoxycarbonyl methoxy, sorbamoyl methoxy, methoxycarboxy, isopropyloxycarbonyloxy, pheno Xycarbonyloxy, benzyloxycarbonyloxy, bivaloyloxycarbonyloxy, acetoxy, propionyloxy, butyryloxy, isoptyryloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, dexanoyloxy, decanyloxy, decanyloxy, decanoloxy, decanolyl , Tetradecanoyloxy, hexadenoyloxy, octadecanyloxy, pivaloyloxy, cy σpropanoyloxy, cy σbutanoyloxy, cyclope Nantanoloxy, cyclohexanoyloxy, acryloyloxy, crotonyloxy, benzoyloxy, naphthyloxy, phenylacetyloxy, 2-methoxybenzoyloxy, 2-methylbenzoyloxy, 4-methylbenzoyloxy, 4-fluroxy O-benzoyloxy, 3-phenylpropionyloxy, cinnamoyloxy, chloroacetyloxy, promoacetyloxy, 3-chloropropanoyloxy, 4-chlorobutyryloxy, methyl Toxiacetyloxy, 3_ethoxypropanoyloxy, phenoxyacetyloxy, 4-phenyloxybutyryloxy, 8—acetoxyoctanoyloxy, cyanoacetyloxy, 4-nitrobenzoyloxy, 3-methoxycarbonyl Propanoyl, 3 -ethoxycarbonylacryloyloxy, 5-ethoxyethoxycarbonylpentanoyloxy, azidoacetoxy, floyloxy, tenyloxy, 2-phenolicyloxy, 2-picolyloxy, 3-picolyloxy, 4 —Picolyloxy, 4-cyclohexylbutyryloxy, 2 —naphthylacetyloxy, phenylpropynyloxy, 2 —thiophenecarbonyloxy, 3 —thiophenecarbonyloxy, 2 —furancarbonyloxy, 3 —furancarboxy Leoxy, methylsulfonyloxy, ethylsulfonyloxy, isopropylsulfonyloxy, butylsulfonyloxy, 3-chloropropylsulfonyloxy, phenylsulfonyloxy, ρ-trilus; Midophenylsulfonyloxy, — — trifluoroacetamidylsulfonyloxy, 4-aminophenylsulfonyloxy, 4-monophenylphenylsulfonyloxy, 4-butylphenylsulfonyl Roxy, '1 -Fluorophenylsulfonyloxy, 4 — Iodophenylsulfonyloxy, 3, 2,' I-Dichlorophenylsulfonyloxy, 2 —Naphthylsulfonyloxy, 2 —Thiophopensulfonyloxy, 5 —Methyl-2 —Chemophensulfonyloquine, methoxycarbonyloxy Si, ethoxycarboxy, isopropoxycarbonyloxy, butoxycarbonyloxy, hexyloxycarbonyl, 2-cycloethylcarbonyloxy, aryloxycarbonyloxy, benzyloxycarbonyloxy, pheno Xycarbonyloxy, 4 12-trophinoxycarbonyloxy, cyclohexyloxycarbonyloxy and the like.

Specific examples of R include, for example, hydrogen, hydroxy, halogen, and methyl. L-tyl, ethyl, propyl, isopropyl, butyl, amino, methylamino, dimethylamino, ethylamino, getylamino, propylamino, dipropylamino, butylamino, dibutylamino, hexylamino, hexylamino Xylamino, cyclopropylamino, dicyclopropylamino, cyclobutylamino, dicyclobutylamino, cyclopentylamino, dicyclopentylamino, cyclohexylamino, dicyclohexylamino, phenylamino , Diphenylamino, benzylamino, dibenzylamino, dimethylamino, phenylamino, diethylamino, phenylamino, methyl-benzylamino, benzylamino, morpholino , Pipera Zino, N'-methylbiperazino, N'-ethylbiperazino, di

— (2—Hydroxyshetyl) amino, G (2—ethoxyxethyl) amino, Di (2—methoxyxethyl) amino, G (carboxymethyl) amino, Jetiru (ethoxycarbonylmethyl) Amino, Gee (2-ethylamchiethyl) Amino, Gee (2—ethylaminetyl) 5 Amino, Gee (2—ethylethylamine) G- (2-phenylethyl) amino, di- (2-benzylethyl) amino, g- (2-nitroethyl) amino, di- (2-chloroethyl) amino, di-1 (2-) Carboxyethyl) amino, di (3-oxoptyl) amino, g (2-acetoxicetyl) amino, di-1 (2-sulfoethyl) amino, gee (2—powerbamoylethyl) ami0ノ、ジ一（Ν 1-Dimethylcarbamoylethyl) amino, G- (2-hydroxycarbamoyloxyethyl) amino, di- (Ν.Ν-dimethylcarbamoyloxyethyl) amino, di- (2-acetamy) (Ethyl) amino, methoxy, ethoxy, propoxy.butoxy, 2-hydroxyethoxy, 2-methoxyethoxy, 2-methylthioethoxy, 2-aminoaminoethoxy, 2-methylaminoethoxy, 2-dimethylaminoethoxy. 2-phenylamino-ethoxy, 2-benzylamino-ethoxy, 3-nitropropoxy, 3-clopropoxy, 2-carboxyethoxy, 2-acetoethoxy, 3-oxobutoxy, 2-ethoxycarbonylethoxy, 2-sulphoethoxy, 2-rubamoyl ethoxy, 2-dimethylamino ethoxy, 2-dimethylaminoxetoxy , 2-dimethylaminocarbamoyloxyethoxy, 2-acetamidoethoxy, acetate, propiolyloxy, petit-mouth, hydroxyacetoxy, methoxyacetoxy, methylthioacetoxy, glycyloxy, methylaminoacetate Toxic, dimethylaminoacetoxy, phenylaminoacetoxy, benzylaminoacetoxy, nitroacetoxy, chloroacetoxy, succinoquine, ethoxycarbonylacetoxy, 4-oxovaleroxy, acetoethoxyacetoxy, 3-sulfo Loporioloxy, rubamoylacetoxy, M-dimethylcarbamoylacetoxy, acetamidoacetoxy, benzoyloxy, methoxycarbonyloxy, ethoxyquinylcarbonyl, propoxycarbonyloxy, butoxycarbonyloxy, 2,2,2- Tri-mouth ethoxycarbonyloxy, benzyloxycarbonyloxy, methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, butylsulfonyloxy, phenylsulfonyloxy, P-toluenesulfonyl Quinine, 4-chloro succinylsulfonyloxy, 3, -i-dic σ'cophenylsulfonyloxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, iso-butylthio, sec —butylthio, t er t—butylthio Benzylthio, phenylthio, naphthylthio, furylthio, pyridylthio, (5-methyl-1,3,4—thiadiazol-2-yl) thio, [5_ (2-dimethylaminoethyl) 1-1,3,4—thio Asiazol 2 —yl] thio, (3,4 —thiadiazole-2 —yl) thios 1-methyl-1 H—tetrazol-1 5 —yl) thio, [1 — (2 —Hid σ-kissetil) 1 1 H—Tetrazol—5—yl] thio, [1— (2—Dimethylaminoethyl) 1 1Η—Tetrazol-1 5—yl] thio, (1—Sul) 1- (2-Sulfoethyl) -1H-Tetrazol-5- (yl) thio, (1-Carboxymethyl-1H-tetrazo) Lou 5 —yl) thio, [1 — (2-carboxyethyl) — 1 H-tetrazole—δ-yl] thio, (2 —methyl-2 Η— 1,2,3,5-tetrazole-1 4 — Yl) thio, (4-Methyl-1 4 Η— 1, 2, 4 — Triazo-Lou 3 — yl) thio, (4, 5 — Dimethyl—4 Η— 1, 2, 4 -triazo — Lou 3 — (Yl) thio, (1,2,3—thiadiazol-5—yl) thio, (3-hydroxy-4-1, carboxy-1,2, thiazol-5—yl) thio, (4-methyl-1,1, 3 — thiazo-l- 2- (yl) thio, (4-carboxymethyl)-3-thiazole-2-yl) thio, (5-methyl-1, 3, 4) L-5-yl) thio, 2-hid pi-xethylthio, 2-methoxethylthio, 2-phenylethylthio, 2-methylthioethylthio, 2-phenylmercaptoethylthio, 2-aminoethylthio , 2-Methylaminoethylthio, 2-dimethylaminoethylthio, 2-benzylamino. -Ethylthio. 2-phenylaminoethylthio, 2-carboxyethylthio,

2-Etoquinol-Lupirylethylthio, 2-Acetoxicetylthio, 2-Sulphoethylthio, 2-Lubamoylethylthio, 2-Dimethylcarbamoylthio, 2-Lubamoyloxethylthiol, 2 -Dimethylcarbazyloxy, 2-acetamidoethylthio, 2-ethoxycarbonylaminoethylthio, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, iso-butylsulfinyl, sec-butylsulfinyl , Tert-butylsulfinyl, benzylsulfinyl, phenylsulfinyl, naphthylsulfinyl, furylsulfinyl, pyridylsulfinyl, (5-methyl-1,3,4-thiadiazol-2-yl) sulfinyl, [5- (2 —Dimethylaminoethyl)

-1, 3, 4 -thiadiazol 2-yl disulfinyl, (1, 3, 4 -th Asiazol-2—yl) sulfinyl, (1—methyl-1H—tetrazol—5—yl) sulfinyl, [1—1 (2—hydroxyxethyl) -1H—tetrazol—5—yl ] Sulfinyl, [1 — (2-dimethylamino) -1 1 H-tetrazol-5-yl] sulfinyl, (1-sulfomethyl — 1 H-tetrazol-5-yl) sulfinyl, [1-(2 —sulfetiyl) Le) 1 1-H-Tetrazol-5-yl] sulfinyl, (1-Carboxymethyl-1H-tetorazol-5-yl) sulfinyl, [1— (2—carboxicetyl) -1H-tetrazole 5—yl] sulfinyl, (2—methylol 2 H—1,2,3,5—tetorazol—41-yl) sulfinyl, (4-methyl-4H—1,2,4—triazole—3 — (Yl) sulfinyl, (4,

5—Dimethyl-4H—1,2,4-triazole-3-yl) sulfinyl (1,2,3—thiadiazole-5-yl) sulfinyl, (3—hydroxy-4 monocarboxy-1) , 2—Thiazol-5-yl) sulfinyl, (4-methyl-1, 3-thiazo-lu-2-yl) sulfinyl, (4-Carboxymethyl-1, 3 —kiazo-lu-2-yl) sulfinyl, ( 5—Methyl

1, 3, 4 — oxaziazo-lu 5 — yl) sulfinyl, 2 — hydroxyethylsulfinyl, 2 — methoxysulfinyl. 2 — phenylethylsulfinyl, 2 — methylthioethylsulfinyl, 2 — phenylmercapto 2-ethylaminosulfinyl, 2-aminoaminosulfinyl, 2-methylaminoethylsulfinyl, 2-dimethylaminoethylsulfinyl,

2 Benzylaminoethylsulfinyl, 2-phenylaminoethylsulfinyl, 2-carboxyethylsulfinyl, 2-ethoxycarbonylsulfinyl, 2-acetoxysulfylsulfinyl, 2-sulfoethylsulfinyl, 2—caprolvayluele Tylsulfinyl, 2-dimethylcarbamoylsulfinyl, 2-carbamyloxysulfinyl, 2-dimethylcarbamoyloxysulfinyl, 2-acetamidoe Tylsulfinyl, 2-ethoxyethoxycarbonylaminoethylsulfinyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, benzylsulfonyl, Phenylsulfonyl, naphthylsulfonyl, furylsulfonyl, pyridylsulfonyl,

(5-Methyl-1,3,4-thiadiazol-2-yl) sulfonyl, [5- (2-dimethylaminoethyl) 1-1,3,4—thiadiazoyl-2-yl] sulfonyl, (1,3, 4 —Thiadiazol-2-yl) sulfonyl, (1-methyl-1-yl-1Η-tetrazol-5-yl) sulfonyl, [1— (2—hydroxicetyl) —1Η—tetrazol—5—yl ] Sulfonyl, [1- (2-dimethylaminoethyl) -1-i-tetrathrol-5-yl] sulfonyl, (1-sulfomethyl-1-tetrathrazol-5-yl) sulfonyl, [1-1- (2-sulfoethyl) ) -1 1Η-Tetrazol-5-yl] sulfonyl, (1 一 -ruboxymethyl-1 1- テ totrazol-5-yl) sulfonyl, [1 — (2 一 carboquinethyl) —1Η- テ totrazo Ru—5—yl] sulfonyl (2-Methyl-2 2—1,2,3,5—Tetrazol-4-yl) sulfonyl, (4-Methyl-4 4— and 2.4—Triazo-lu-3-yl) sulfonyl, (4,5— Dimethyl '1 Η— 1,2,4 — triazo--3-yl-3 —yl) sulfonyl, (1,2,3 —thiadiazol-5 —yl) sulfonyl, (3 —hydroxy 4 — Garboxy 1,2-thiazole-5-yl) sulfonyl, (4-methyl-1, 3-thiazo-lu-2-yl) sulfonyl, (4-carboxymethyl-1,3 -thiazo-lu-2-yl) ) Sulfonyl, (5-Methyl-1,3,4-oxoxadiazole-5-yl) sulfonyl, 2—Hydroxitytylsulfonyl, 2—Methoxyshetylsulfonyl, 2—Phenylethylsulfonyl, 2— Methylthioethylsulfonyl, 2-phenylmercaptoe Rusuru Honiru, 2 - § Mi Noe chill sulfonyl, 2 - Mechiruami Noechirusuruhoni 1, 2-dimethylaminoethylsulfonyl, 2-benzylaminoethylsulfonyl, 2-phenylaminoethylsulfonyl, 2-carboxyethylsulfonyl, 2-ethoxycarbenylethylsulfonyl, 2-acetoxyethylsulfonyl, 2 —Sulfonylethylsulfonyl, 2-dibutyl-5-ethylsulfonyl, 2-dimethylcarbamoylsulfonyl, 2-carbamoyloxshetylsulfonyl, 2-dimethylcarbamoyloxysulfonyl, 2-acetamidoethyl Sulfonyl, 2-ethoxycarbonylaminomethylsulfonyl and the like can be mentioned.

As R ⁵ , specifically, for example, 1,2-phenylene, 4-methyl-1,0-l, 2-phenylene, 5-methyl-11,2-phenylene, 4-ethylene

1,2-phenylene, 5-ethyl-1,2-phenylene, 4-methoxy-1,2-phenylene, 5-methoxy-1,2-phenylene, 4-chloro-1,2'-phenyl Len, 5-chloro-1,2-phenylene, 4-amino1,2-maenylene, 5-amino1,2-phenylene, 4-nitro-1,2-phenylene

15-, 5-nitro-1, 2-phenylene, 4-methoxycarbonyl-1,1,2-phenylene;; -methoxycarbonyl-1, 2 -phenylene, 4 1, '2-phenylene, 5-carboxy-1,2-phenylene, 4-dimethylamino-1,2-phenylene, 5-dimethylamino-1,2-phenylene, 4-acetamido 2—Fenerene, 5—acetamid 1, 2—

20 Phenylene, 4-hydroxy-1, 2, 2-phenylene, 5-hydroxy1,

2-phenylene, 4, 5-dimethyl-1,2-phenylene, 4,5-dichloroa-1,2-phenylene, 2,3-naphthalene, 6-chloro-2,3-naphthalene, 7 —Chloro-2,3-naphthylene, vinylene, 1,2-dimethylvinylene, ethylene, 1,2-dimethylethylene, and the like.

25 The R ^8, specifically, for example carboxy, main butoxycarbonyl, ethoxycarbonyl, propyl O alkoxycarbonyl, butyl O propoxycarbonyl two , Methoxymethoxycarbonyl, 2-methoxyethoxycarbonyl, 1-methoxyethoxycarbonyl, methylthiomethoxycarbonyl, 2-methylthioethoxycarbonyl, acedoxymethoxycarbonyl, 1-acetomethoxycarbonyl, 1-ethoxy Quincarbonyloxyethoxycarbonyl, ethoxycarbonyloxymethoxycarbonyl, bivaloyloxymethoxycarbonyl, 1-pivaloyloxyethoxycarbonyl, aryloxycarbonyl, 2,2,2—tricycloethylethylo Xycarbonyl, phenoxycarbonyl, 4-methoxyphenyloxycarbonyl, 2,4-dimethoxyphenyloxycarbonyl, 412-nitrophenyloxycarbonyl, 2,4-dinitrophenyl Niloxycarbonyl, benzyloxy Carbonyl, 2,2-dinitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 2-aminoaminocarbonyl, 2- Dimethylaminoethyloxycarbonyl, 2-methylsulfonylethyloxycarbonyl, 2-trimethylsilylethyloxycarbonyl, 2-di-cyanoethyloxycarbonyl, 2-diethyloxycarbonyl, L-vinyl, methylamino carbonyl, dimethylamino carbonyl; les, ethylamino carbonyl, getylamino carbonyl, propylamino carbonyl, dipropylamino carbonyl, butylamino carbonyl, dibutylamino carbonyl, Kisilaminocarbonyl Dihexylaminocarbonyl, cyclopropylaminocarbonyl, dicyclopropylaminocarbonyl, cyclobutylaminocarbonyl, dicyclobutylaminocarbonyl, cyclopentylaminocarbonyl, dicyclopentylaminocarbonyl, hexahexylaminocarbonyl, dihexylaminocarbonyl, dicyclohexylaminocarbonyl Minocarbonyl, phenylaminocarbonyl, diphenylaminocarbonyl, benzylaminocarbonyl, dibenzylaminocarbonyl, N-methyl X-phenylamino carbonyl, X-ethyl-X-phenylamino carbonyl, morpholino-X-carbonyl, pyrrolidine-N-carbonyl, piperidine-N-carbonyl, piperazine-N-carbonyl, N'-Methylbiperazine N-carbonyl, carboxymethylaminocarbonyl, ethoxycarbonylmethylaminocarbonyl, ruboxshetylamino carbonyl, carbonyl, ethoxycarbonylethylaminocarbonyl, 2 —Hydroxyquinethylaminocarbonyl dicarbonyl (2-hydroxyhexyl) aminocarbonyl, 2-aminoethylaminocarbonyl, G- (2-aminoethyl) aminocarbonyl, 3-aminopropylamino Carbonyl, 2-methoxyhexyl 0-aminocarbonyl, 2-methoxyhexylaminocarbonyl It is like we are.

Preferred specific examples of the compound [〖] of the present invention are shown below.

25-demethylthio-1 25-methylsulfonyl-1 TAN-528A (TA-528A sulfone),

δ 25—demethylthio-25-methylsulfinyl—T AN— 528 A (T

Λ X 528 Α sulfokind) (isomer a),

25-demethylthio-l25-methylsulfuric acid TAX-528A (TAN --- 528A sulfoxide) (isomer b),

25-Demethylthio-1 25-phenylthio-1 TAN- 528 A, 0 2 δ-Demethylthio-1 25-propylthio-1 TA-1 528 A,

TAX- 528 A easier tons (R ^G forming a easy tons ring),

T A: — 528 A carboxylic acid,

1 9 — Demethoxy 1 9 Hydroxy TAN — 528 A,

1 9—Demethoxy 1 9 1 Ethoxy T A Ν— 528 A,

5 1 9—Demethoxy 1 9—Hexyloxy—T AN— 528 A,

1 9-demethoxy- 19-heptyloxy TAN- 528 A, 1 I 9-demethoxy 19-heptyloxy TAN-528A lactone,

1 9-demethoxy 19- (2-chloroethoxy) -TAN-528A, 19-demethoxy- 19- (2,3-epoxypropyloxy) -TAN-528A,

5 1 9-demethoxy-1 9-aryloxy TAN— 528 A,

1 9—Demethoxy-1 9— ρ—Xyloxy 1 TAN— 528Α, 19-Demethoxy 1 9— (2-Phenylethoxy) 1 TAN-528 A, 19—Demethoxy 1 19-Panasiloxy 1 TAN— 528 A, 19-demethoxy 1 9—phenacyloxy TAN— 528 A aldo 丄 0 —

1 9-demethoxy 2 1 1-dehydro-doxy 1 9, 2 1 —bis-fuesyloxy-TA 1 528 A,

1 9—Demethoxy— 1 9 Lumbamoyloxy TAN-528 A, '19 —Demethoxy — 19 9-acetoxy — TAN— 528 A, ·

1δ 1 9—Demethoxy-1 9—Hexanoyloxy T AN— 528Α,

1 9 Demethoxy 1 9 —Benzoyloxy TAN— 528 A, 19 —Demethoxy. 19 9 p-Tosyloxy TA 1 528 A, 1 9 .Demethoxy 1 2 1 — Dehydroxy 1 19, 2 1 — bis-p — to siloxy AM— 528 A,

20 1 9—Demethoxy 19 1 p-Tosyloxy T AN-528A lactone

1 9-demethoxy 1 9-phenoxycarbonyloxy T A N— 528A,

1 9—Demethoxy 2 1 —Dehydroxy 1 9, 2 1 —Bis-phenoxycarbonyloxy T A N— 528 A,

25 19—Demethoxy 19—Hydroxy T AN—528A lactone,

1 9—Demethoxy 19-Acetoxy T AN—528A lactone, 5 2 5 —Demethylthio-1 25, '2 4 —Venzothiazino TAX— 528 A,

25-demethylthio-25-hydroquinone T A Ν-528A, 25-demethylthio-25-methoxy-TAN-528A,

25-Demethylthio-1 25-Hydro T AN— 528 A,

δ 25-demethylthio-l 25-dimethylaminomethyl-T AN-528Α,

25-Demethylthio-1-25-pyrrolidinomethyl-TAN-528A, 25-Demethylthio-25-hydroxymethyl-TAN-528A, 25-Demethylthio-25-node TAN-528A,

1 9—Demethoxy 1 9— (3-Hydroxypropyl quinone) TAN0-528A,

1 9 —Demethoxine 1 9— (2-Phenokinetokin) -TAN— 528

A,

19-Demethoxy-1-19-cyclopropylmethoxy-TA A-528A The compound [1] of the present invention can be produced, for example, by the method described below5.

In the general formula [1: a compound in which R ¹ is hydrogen and Y is CO-: a compound in which the general formula: 1 is an organic residue via a carbon atom and Y is -CO- 3 "a can be prepared by subjecting to elimination reaction of the organic residue through a carbon atom _c

As the reaction, when the organic residue via the carbon atom is an alkyl, alkenyl, or alkynyl which may have a substituent, the compound [3] may be subjected to a reaction known per se, ₂ performed by reaction with a reagent or basic reagent

Examples of the acidic reagent used include pentahydrohalic acids such as hydroiodic acid and hydrobromic acid, Lewis acids such as anhydrous trimethylsilane, anhydrous aluminum chloride, boron trifluoride and boron tribromide. , And as a basic reagent Is a power such as lithium iodide, magnesium iodide, sodium or lithium thiolate, lithium thiophenolate or the like, or a magnesium salt, especially Lewis acid, especially anhydrous Aluminum chloride is preferred. In general, the reaction is preferably carried out in a solvent, and the solvent may be a halogenated hydrocarbon such as dichloromethane, an ether such as ether or tetrahydrofuran, or an aromatic hydrocarbon such as benzene, toluene, or xylene. However, when anhydrous aluminum chloride is used, benzene, toluene, xylene and the like are preferable. The reaction temperature is appropriately selected from the range of about −70 ° C. to 150 ° C. When using anhydrous aluminum chloride, the reaction temperature is selected from the range of about 50 ° C. to 120 ° C. Is good. The reaction time is about 0.1 to 10 hours.

When the organic residue via the carbon atom is a substituted or unsubstituted acyl group or an acyloxycarbonyl, the compound [3] is converted to an acid [eg, Mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc., and strong organic acids such as trifluor σ-acetic acid, toluenesulfonic acid, methanesulfonic acid, etc. or bases [(row, sodium carbonate, calcium carbonate) , Sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, etc.] or tert-butoxy potassium, lithium iodide, lithium propyl. When the base is used as the reaction reagent, if the reaction is performed in an anhydrous solvent, if necessary, add water to the reaction solution or transfer the reaction solution to water. After opening, acid (eg, Acid, and collecting the product After the neutralized or acidified with, etc. 胙 acid).

Examples of the solvent include lower alcohols such as methanol and ethanol, polar nonprotonic solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphorotriamide, or a mixture thereof. A mixed solvent of water is frequently used. The reaction temperature is not about -10 and 100 ° C, preferably about 1-5 It is not 7 0 '.

R ¹ is also a carbon atom in the general formula: 1] properly: or - S 0 ₂ - compound is an organic residue through a [4], R ¹ of the general formula [1] is hydrogen, Y is - The compound can be produced by introducing an organic residue via a carbon atom or 1 S 0 ₂ — into a compound [5] that is CO— and, if necessary, subjecting the obtained compound to a cyclization reaction. Examples of the introduction reaction include an alkylation reaction, an alkenylation reaction, an alkynylation reaction, an acylation reaction, and a sulfonylation reaction.

The alkylation, alkenylation or alkynylation reaction can be carried out by a method known per se or a method analogous thereto. As the alkyl, alkenyl or alkynylating agent to be used in the reaction, the corresponding alkyl, alkenyl or alkynyl halide (eg, chloride, bromide, oxide, etc.) is most preferred, but other than that. Dialkyl sulfate, alkyl sulfate, etc. 0 Used as appropriate.

The amount of the alkyl, alkenyl or alkynylating agent to be used depends on the reactivity and the like, but is usually in the range of about 1 to 100 moles per mole of the compound: 5; High halides (eg, benzyl halide, phenacylharadono, σ-genoketone, logenog, acid, arylaryl, propargylhalide, which generally has substituents, generally alk; le, alkenyl, or alkynylyo 5 to 10 times mol in the case of amide, etc., about 10 to 20 times when bromide is used, and about 10 to 50 times when chloride is used. Molar amounts are used. '

The solvent used in the alkyl, alkenyl or alkynylation reaction is not particularly limited as long as it can dissolve the reaction reagent in a relatively good manner. Examples thereof include alcohols such as methanol and ethanol, and dimethyl ether. Tell, Ethers such as tetrahydrofuran and dimethoxetane; ketones such as acetone and methylethylketone; amides such as dimethylformamide and dimethylacetamide; dimethylsulfoxide and sulfolane; Examples include halogenated hydrocarbons such as sulfoxides and sulfones, dichloromethane, chloroform, and aromatic hydrocarbons such as benzene, toluene, and xylene. Of these, methanol is preferred.

The reaction temperature may be about −10 ° C. to 50, and the reaction time may be about 1 to 24 hours.

In this reaction, silver salts such as silver oxide and bases (eg, inorganic bases such as carbonated lime, alkali metal alcohols such as sodium methylate and lithium methylate, triethylamine, pyridine, dimethylamide) The reaction rate can be increased and the yield can be improved by coexisting an amine such as pyridine. In addition, crown ethers (eg, 18-crown-6), quaternary ammonium salts (eg, tetraethylammonium chloride, benzyltri'methylammonium chloride, cetyltrimethylammonium chloride) C) In this case, the reaction may be carried out not only in the above-mentioned solvents but also in a mixed two-phase system of these solvents and water. Further, as is often used, especially when chloride is used as a reaction reagent, it is preferable to add an iodide ion source such as potassium iodide or sodium iodide to the reaction system.

The alkylation reaction can also be performed using a diazoalkane such as diazomethane as a reaction reagent. The reaction is carried out in a solvent such as alcohols (eg, methanol), ethers (eg, getyl ether, tetrahydrofuran, etc.), and ester solvents (eg, ethyl citrate). Preferably, boron trifluoride, fluoroboron or the like may be added as a reaction accelerator. The reaction is—20 ° C to 30 ° C. Performed at a temperature of C. The alkylation reaction can also be carried out with 0-alkyl-X, -disubstituted isourea (eg,

0- methyl, 0- Echiru, 0- benzyl -: ^\, τ '- dicyclohexyl Kishiruiso urea, etc.) can also be a carried out as a reaction reagent. Examples of the solvent include ethers (eg, tetrahydrofuran, didioxane, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride), esters (eg, ethyl acetate, etc.), aromatic hydrocarbons Hydrogen (eg, benzene, toluene, xylene, etc.) is used. The reaction temperature is about 40 ° C to 150 ° C.

The alkylation and alkenylation reaction can also be carried out by reacting a compound [5] with a reactive reagent having an unsaturated bond [eg, argens (eg, isobutylene, methyl acrylate, ethyl acrylate, acrylate). The reaction can also be performed by reacting lonitrile, methacrylonitrile, etc.), or alkyne granules (eg, methyl propiolate, cyanoacetylene, etc.). The reaction is carried out in a solvent [eg, ether (eg, diethyl ether, dioxane, tetrahydrofuran, etc.), halogenated hydrocarbon (eg, dichloromethane, etc.)], acid (eg, sulfuric acid, etc.), Bases [eg, alkali metal alkoxides (eg, sodium methylate, etc.), tertiary amines (eg,. \ '-Methylmo,' refolin, etc.), quaternary ammonium salts (eg, benzyltrimethyl) Such as ammonium hydroxide). The reaction temperature is about 120 to 50 ⁼ C.

As the acylating agent used in the acylation reaction, acyl halide is preferable. As the halogen, bromine and chlorine are preferred because they are simple. The amount of the acylating agent to be used is preferably an equimolar amount or more, and more preferably i. The solvent used for the acylation reaction is not particularly limited as long as it can dissolve the compound [5] and the acylating agent, but is preferably a solvent such as methylene chloride, chloroform, tetrahydrofuran, and dioxane. And so on. The reaction temperature is about --30 to 25 ° C and the reaction time Is about 0.1 to 3 hours. Also, by coexisting amines such as triethylamine. Pyridine and dimethylamino pyridine in the present reaction system, side reactions can be suppressed and the yield can be improved.

0 H

I

In the general formula [1], Y is a group represented by the formula C— (where R ⁷ is as defined above)

R ⁷

You. The compound [6] which is a group represented by the formula (1) is a compound [4] wherein Y is —CO— and R ¹ is an α-keto group—nitrile group, and —alkoxycarbonyl group, , Or an alkyl group having a monosulfonyl group or a carboxy group (which may be further substituted but has at least one hydrogen atom) [7] by intramolecular aldol condensation. it can.

The intramolecular aldol condensation reaction can proceed only by dissolving it in an organic solvent, especially benzene, phenol, and dichloromethane. The catalyst is accelerated by using a catalytic amount of a base such as triethylamine or benzylamine as a catalyst. Is done. Silica gel or molecular sieve may be used as a catalyst. The reaction is advantageously carried out at room temperature, the reaction time depending on the starting material: 7] and the structure of the base, but generally requires about Q.24 to 24 hours.

The compound [8] in which R ² is a carbon atom or an organic residue via —S 0 ₂ — in the general formula [1] is different from the compound [9] in which R ² is hydrogen in the general formula [1] by a carbon atom or — It can be produced by reacting a compound capable of introducing an organic residue via —SO ₂ —. Examples of the introduction reaction include an alkylation reaction, an alkenylation reaction, an alkynylation reaction, an acylation reaction, and a sulfonylation reaction. The reaction reagent, reaction conditions, and the like in the introduction reaction are the same as those in the production of compound [4] from compound [5] described above, but more severe conditions are often required. In that case Use excessive amounts of reagents, raise the reaction temperature, and increase the reaction time.

In the general formula [1], the compound [10] in which R ⁺ is an organic residue via a sulfur atom and η = 1, 2 is a compound [11] in which the general formula [1] is -S—R ³ ′ ] To an oxidation reaction. As the oxidizing agent, meta-chloro α-perbenzoic acid, sodium metaperiodide, etc. are used. When the compound where η = 1 is desired, about 1 equivalent or slightly more than about 1 equivalent is used. When a compound where η = 2 is desired, it is preferable to use about 2 equivalents or more of the oxidizing agent. As a solvent for the reaction, a solvent which dissolves the compound [10] and the oxidizing agent is desirable. When using methachloroperbenzoic acid as the oxidizing agent, usually, dichloromethane, chloroform, ethyl acetate, methanol and the like are used. It is preferably used. When sodium metaperiodate is used as the oxidizing agent, a mixed solvent with water is preferable. When a compound having a reaction temperature of η = 1 is produced, the reaction is carried out at a low temperature to room temperature, usually at about −30 ° to 25 ° C., and the reaction time is about Ο..Γ to 24 hours. When the compound where n = 2 is produced, it is carried out at a slightly higher temperature than the above, usually at about 0 to 100 ° C. When producing a compound in which n = 2, a compound in which n = 1 in the compound: 102 may be used instead of the compound [1 1 =]. In this case, the amount of the oxidizing agent should be about 1 equivalent or more.

Compound = 1 1], the compound [1 0] R ³ 'and n = 1 compound in the - S- compound or a metal salt thereof represented by H, can be produced by substitution reaction with § Mi emissions salt Can be. — When S—H is used, it is desirable to coexist tertiary amines such as triethylamine and diisopropylethylamine. It is preferable to use about 1 equivalent or more of S—H or a salt thereof, and the solvent for the reaction is not particularly limited. Usually, dichloromethane, ethyl acetate, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, and the like are used. It is preferably used. Reaction temperature, The time is a force that changes depending on the structure of compound [10] and n = 1 and the structure of R ³ '-S—H or a salt thereof.

One 20 ° to 100 °. In C, the reaction time is about 0.1 to 24 hours. The progress of the reaction can be monitored by thin layer chromatography (TLC) or the like.

The compound [1 2] in which R ⁺ is hydrogen in the general formula [1] is obtained by subjecting the compound [1 1] (supra) in which R ⁺ is -S— in the general formula [1] to a desulfurization reaction. It can be manufactured by the following. Examples of the desulfurizing agent include organic compounds such as Raney Nigel and triptyl hydride and trivalent organic phosphorus compounds such as triphenylphosphine, trimethylphosphite and triethylphosphite. The amount of desulfurizing agent used is about 1 equivalent or more when using an organic tin compound or a trivalent organic phosphorus compound. When Raney-Nigel is used, the amount used depends on its activity. A desirable method is to observe the reaction status by TLC while introducing a small amount of Raney nickel into the reaction system, and if the raw material remains, add Raney nickel further, and do not use excess Raney nickel. is there. As a solvent used in the desulfurization reaction, for example, when Raney nickel is used, methanol, ethanol and the like are used, and when an organic tin and an organic phosphorus compound are used, acetone, benzene, toluene and the like are preferably used. used. The reaction temperature in the desulfurization reaction is about 30 to 100 ° C, and the reaction time is about 0.5 to 24 hours.

In the general formula [1], the compound [13] in which R ⁺ is hydroxy is, for example, a by-product when the dehydration reaction and the substitution reaction at the 25-position proceed in the same system, or as a compound [ 11] with sodium borohydride. The amount of sodium borohydride is about 1 to δ-fold molar amount, and tetrahydrofuran and dioxane are used as solvents. Etc. are preferably used. The reaction temperature is generally about 25 ° to 100 ° C., and the reaction time is often about 0.1 to 3 hours.

Compound [14] in which R ⁺ is a halogen in general formula [1] can be produced by subjecting compound [12] in which R ⁴ is H in general formula [1] to a halogenation reaction. it can. As the halogenating agent used in the halogenation reaction, for example, wherein CH ₂ = N rather S _"8 X type, R ⁸ is C _t - in ₊ the lower alk Kill group or N rather ₈ to form a ring X may represent a halogen such as chlorine, bromine or iodine), followed by reaction with manganese dioxide, followed by reaction with manganese dioxide. The lower alkyl of -4 includes, for example, methyl, ethyl, η-propyl, isopropyl, η-butyl, isoptyl, t-butyl, etc., as the ring formed by <^ 8:ぺ Lysine, · Hexamethyleneimine and the like.

The amount of the methylene salt and manganese dioxide used is excessive, usually about 2 to 1 μm. As a solvent used for the halogenation, for example, acetonitrile is used in the reaction with methyleneimmonium salt, and in the reaction with manganese dioxide, for example, dichloromethane or the like is used. The reaction temperature is about 50 to 100 ° C for the reaction with the former, the reaction time is about G.5 to 10 hours, and those for the reaction with the latter are about —10 ° to 30 °. About 1 to 24 hours at C.

A compound in which R ⁴ is an organic residue via a carbon atom in the general formula [1].

[15] can be produced by subjecting a compound [12] in which R ⁺ is hydrogen in the general formula [1] to an organic residue introduction reaction via a carbon atom. The reaction for introducing an organic residue through the carbon atom includes, for example, CH 2 = N <8 X (wherein, R ⁸ and X have the same meanings as described above), and react with a methyleneimmonium salt represented by Reaction. When using a methylene indium salt, an excess amount, usually about 2 to 10 times, is used, and acetonitrile is often used as a solvent. The reaction temperature is about 50 to 100 ° C, and the reaction time is often about 0.5 to 10 hours. The thus obtained amino-substituted methyl derivative can be easily converted to a hydroxy-substituted methyl derivative if desired. When the Mannich reaction is used, it can be carried out in the same manner as a technique known in the field of rifamycin. Such techniques include those described in N. Maggi, V. Arioli and P. Sensi, Journal of Medicinal Chemistry, 8_790 (1965). .

In the general formula [1], the compound [I 6] in which R is an organic residue group via a nitrogen atom is a compound [12] in which R ⁴ is hydrogen in the general formula [1]. It can be produced by subjecting to a residue introduction reaction. The reaction for introducing an organic residue also via the nitrogen atom can be carried out in the same manner as in the art known in the field of rifamycin and its analogous compound tribomycin. Examples of the technology include the technology described in the following document.

W. Kump and H. Bickel, Helv. Chim. Acta., 56, 2348 (1973), H. Bickel, F. n'usel, W. ump and L. Neipp, Antimicrobial Agents and Chemotherapy, 3 5 2 (1967), P. Bellomo, M. B rufani, E. Marchi, G. Mascellani, W.

Melloni, L. Montecchi and L. Stanzani, Journal of

Medicinal Chemistry, 20, 1287 (1977). The compound [17] in which R ⁺ is an organic residue through an oxygen atom in the general formula [1:] is a compound [13] in which R ⁺ is a hydroxyl group in the general formula [1] is an organic residue through an oxygen atom. The reaction for introducing an organic residue via an oxygen atom, which can be produced by subjecting to an introduction reaction, includes an alkylation reaction, an acylation reaction, a sulfonylation reaction, and an alkyloxycarbonylation reaction. The alkylation reaction, acylation reaction and sulfonylation reaction can be carried out under the same conditions as those for the conversion reaction from compound [5] to compound [4]. In the alkylation reaction, a diazo compound can also be used as an alkylating agent. The alkyloxycarbonylation reaction can be carried out under the same conditions by using an alkyloxycarbonyl compound instead of the aryl halide used in the acylation reaction.

-X is the formula in General Formula 1:

0

Compound [18] is a compound represented by the general formula [

0

Is R ³ ′ —S—wherein { ³ } has the same meaning as described above. Is a compound of the general formula

SH

Η ₂ Ν. [1 9]

[Wherein, R ⁵ has the same meaning as described above. To the compound [1 9] The compound can be produced by subjecting the obtained compound to a reduction reaction, if necessary.

The reaction of the compound [10] with the compound [19] is a cyclization reaction in which a dehydration condensation reaction at the 24 position and a substitution reaction at the 25 position occur simultaneously. The reaction reagent used in the reaction is a compound having an amino group and a thiol group at two adjacent carbon atoms in the molecule. The amount of the reaction reagent is generally used in excess, and is often used in an amount of about 1 to 10 moles per mole of the compound [10]. Examples of the solvent used in the reaction include dichloromethane, chloroform and the like. The reaction temperature is about 130 ° to 50 ° C, and the reaction time is about 0.5 to 10 hours.

The reduction reaction is performed by bringing compound [18] into contact with a reducing agent. As the reducing agent, for example, high Dorosarufuai preparative sodium _{_{_{(Na 2 S 2 0 4)}}} , such as Asukorubin acid and the like, which normally excess is used. As the solvent used for the reduction reaction, for example, ethyl acetate, ethanol, methanol, tetrahydrofuran, dioxane and the like can be mentioned. The reaction temperature is about 0 to 50 ° C, and the reaction time is about 0.1 to 1 hour.

General formula [1] in R ⁶ are the 7-position or one 3-position of 0 and rings that are formed one C 0-, Compound [2 0], in the general formula [1] R ^e is a carboxylic acid ester can be prepared by subjecting a compound [2 1] or the compound R ^B is a carboxylic acid [2 2] lactone ring formation reaction. The lactone ring formation reaction is an intramolecular dealcoholation reaction when the compound [21] is used, and an intramolecular dehydration reaction when the compound [22] is used. The lactonizing agent used in the reaction includes, for example, mineral acids such as hydrochloric acid and sulfuric acid, organic acids such as methanesulfonic acid and ρ-toluenesulfonic acid, inorganic bases such as sodium hydroxide and hydroxide rim, and triethyl acetate. Amin, benzylamine, pyri Examples include organic bases such as gin and piperidine, but in some cases the process proceeds simply by ripening. The amount of the lactonizing agent used may be a catalytic amount or a solvent amount, and the solvent used in the reaction may be, for example, dichloromethane, chloroform, ethanol when using an organic acid or an organic base. When methanol or the like uses a mineral acid or inorganic base, ethanol or methanol

It is desirable to use The reaction temperature is about 0 ° to 100 °. (The reaction time is about 0.1 to 10 hours.

The compound [22] in which R ⁶ is carboxy in the general formula [1] is a compound [22] in which R ^B is a carboxylic acid ester in the general formula [1]. 21] to a hydrolysis reaction. The hydrolysis reaction can be carried out under the same conditions as ordinary ester hydrolysis reactions obvious to those skilled in the art. That is, generally, water, alcohols (eg, methanol, ethanol, propanol, butanol, diethylene glycol, 2-methoxyethanol, etc.), ketones (eg, acetone) ), Ethers (eg, tetrahydrofuran, dioxane, dimethoxetane, etc.), amides (eg, dimethylformamide, dimethylacetamide, hexamethylphosphoro Solvents (eg, triamide), sulfoxides (eg, dimethyl sulfoxide), sulfones (eg, sulfolane), and sulfonic acids (eg, formic acid, folic acid, etc.) (single or mixed solvents) ) Medium acid (eg, mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, organic acid such as paratoluenesulfonic acid, strong acid ion exchange resin, etc.) or base (eg, sodium hydroxide, water Oxidizing power ゥWater, carbonated sodium, sodium hydrogencarbonate, barium hydroxide, sodium hydroxide, sodium methoxide, ammonia, etc.). preferable. The amount of the base is about 1 to 10 moles, preferably about 1.2 to 4 moles. The reaction temperature and time largely depend on the type of alcohol component in the ester group, but are not about 120 to 70 ° C, respectively, preferably about -5 ° C, -30 and about 0.1 to 24 hours, preferably about 0.1 to 3 hours.

In the general formula [1], R ⁸ is a group that can be derived from carboxy, for example, a compound [21] which is a carboxylic acid ester, and a compound [23] which is an amide. It can be produced by subjecting it to a transesterification reaction or an amidation reaction in [21]. Alternatively, the lactone compound of compound [20] can be opened with an alcohol and an amine to produce compound [21] and compound [23], respectively.

That is, the compound [22] of the compound [22]. The conversion to [21] can be achieved by (a) condensing compound [22] with the corresponding alcohol component by the action of an acid catalyst or a condensing agent, or (mouth) compound [22] or its carboxyl group. By reacting the salt in the above with an alkylating agent. In (ii), the reaction is usually carried out in a solvent. Examples of the solvent used include ethers (eg, dimethyl ether, tetrahydrofuran, dimethoxetane), aromatic hydrocarbons (eg, 'benzene, toluene, etc.). , Halogenated hydrocarbons (eg, carbon tetrachloride, etc.) The (lower) alcohol component itself may be used as a solvent. Acid catalysts or condensing agents that can be used include hydrochloric acid, sulfuric acid, phosphorus Mineral acids such as acids, organic acids such as benzenesulfonic acid, toluenesulfonic acid, etc., boron trifluoride, ferrous sulfate, Lewis acids such as anhydrous aluminum chloride, thionyl chloride, acetyl chloride, cuprate formate, chlorosulfone Acid, acid chlorides such as toluenesulfonic acid chloride, acid anhydrides such as trifluoroacetic anhydride, 2,2-dimethoxypro And acetal solvents such as dimethylformamide, dimethylacetate, etc. These acid catalysts or condensing agents can be used in most cases in catalytic amounts (0.01 to 0.1 equivalents relative to compound [22]). The reaction temperature may be about 110-fold to about 110-fold, and the reaction temperature may be about 120-140 ° C (: preferably about 110-500 ° C). It is.

When a salt of a carboxylic acid (compound [22]) is used in (mouth), the salt may be a metal salt such as a sodium salt, a potassium salt, a calcium salt, a copper salt, a silver salt, or a triethyl ammonium salt. Trialkylamines or quaternary ammonium salts such as pyridinium salts and tetraethylammonium salts are preferred. These salts may be prepared before the esterification reaction, and may be a base corresponding to the solution of compound [22]. (If necessary, isonitriles [eg, hexyl hexyl isonitrile, etc.] may be added as a dehydrating agent) or the base hydrolysis reaction solution in (a) may be used as it is. Alternatively, those produced in the reaction solution may be used. The alkylation reaction is preferably carried out in a solvent such as water, alcohols (eg, ethanol), ketones (eg, acetone), ethers (eg, methyl ether, tetrahydrogen). Sigma furan, dioxane, etc.), amides (eg, dimethylformamide, dimethylacetamide, hexamethyl phosphorotriamide, etc.), sulfoxides (eg, dimethylsulfoxide, etc.), aromatics Examples include hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (clean, dichloromethane, etc.), and these may be used alone or mixed to form a homogeneous or heterogeneous reaction system. Can. Examples of the alkylating agent to be used include alkyl halides which may have a substituent (eg, chlorine, bromine, iodine, etc. as halogens: eg, methyl iodide, benzyl chloride, benzyl chloride, benzyl chloride, hexyl chloride). , Trityl bromide, phenacyl bromide, etc.), dialkyl sulfates (eg, dimethyl sulfate, getyl sulfate, etc.), trialkyl phosphinates (eg, trimethyl phosphate), trialkyl oxodimethyl salts (eg, triethyl) Oxonium tetrafluoroborate, etc.), phenol ethers (eg, butyl isopropenyl ether, etc.)

-Acetates (eg, vinyl acetate, etc.), isobutylene (with catalyst And sulfuric acid is preferred), and diazoalkanes (eg, diazomethane. Phenyldiazomethane, diphenyldiazomethane, etc.).

The amount of the base used relative to the starting carboxylic acid is in the range of about 1 to 100 molar equivalents, preferably about 1 to 25 molar equivalents, and the alkylating agent (here, alkyl halide, dialkyl sulfate, etc.) is correspondingly used. Is used in an amount of about 0.8 to 120 molar equivalents, preferably about 1 to 30 molar equivalents. Further, the alkylation reaction may be carried out by adding a quaternary anidium compound as a so-called phase transfer catalyst (for example, the same as described above).

When using enol ethers, enol acetates, or isobutylene as the alkylating agent, a carboxylic acid (compound [22] is selected as the starting material. In these cases, the alkylating agent is the compound [22] The reaction may be carried out at room temperature, but the reaction proceeds at room temperature. Temperature, or a catalyst (eg, sulfuric acid, toluenesulfonic acid, acetic acid [mercury, tert-ethylamine], etc.) may be added.

When diazoal carboxylic acid is used as an alkylating agent, the progress of the reaction can be controlled by an appropriate method (eg, thin-layer chromatography), since the diazoalkane itself may be unstable in the reaction solvent. It is advisable to use reagents that are necessary and sufficient for the reaction while tracing with various colors. The reaction proceeds well at a temperature of about 0 to 30 ° C, but if necessary, it may be heated or heated (up to about 40-50 ° C) or a catalyst (eg, methanol, triethanol, etc.). (For example, boron fluoride).

Further, the target compound [21] can also be obtained by transesterification of a certain compound [21]. In this reaction, the compound [21] (preferably R ₆ = C 0 CH ₃ ) is reacted with an alcohol corresponding to a desired ester, or another ester or orthoester containing the same in the presence of an acid catalyst. As the acid catalyst, inorganic acids such as hydrobromic acid and sulfuric acid and perchloric acid, and organic acids such as benzenesulfonic acid, toluenesulfonic acid and methanesulfonic acid are preferred. The reaction is carried out at room temperature to 200 ° C. (preferably at room temperature to 130 ° C.).

The amidation reaction of an ester form (compound [21]) or a lactone form (compound [20]) is carried out according to the general amidation of an ester, to a compound [21] or a compound [20]. And the desired amino compound, ie, ammonia (which can be introduced into the reaction system in the form of gaseous ammonia, concentrated aqueous ammonia, ammonia solution, ammonium chloride and bases) or amines, (Eg, methanol, ethanol, etc.), ethers (eg, tetrahydrofuran, etc.), sulfoxides (eg, dimethylsulfoxide, etc.) polar solvents or mixed solvents containing these solvents It is preferable to carry out the reaction by medium reaction. If necessary, base catalysts such as aluminum chloride, sodium methoxide, dimethylaminopyridine, and DBU (1,8-diazabicyclo [5,4,0] -7-indene) can be used. The addition promotes the progress of the reaction and is sometimes preferred. The reaction proceeds at a temperature within the range from room temperature to the boiling point of the solvent. <For example, the amines may be ripened to a temperature of about 180 using amines themselves as a reaction medium. . General. In the formula [1], X is represented by the formula (wherein, R ⁺ has the same meaning as described above.

0H. ) Is a compound of the general formula [1] wherein X is (-

0

R has the same meaning as described above. ) Can be produced by subjecting compound [25] to a reduction reaction. As a reagent for the reduction reaction, ascorbic acid The compound can be produced under the same conditions as in the above-mentioned reaction for producing the reduced form of the compound [18].

The target compound [1] thus obtained can be isolated and purified by a method known per se, such as concentration, solvent extraction, chromatography, crystallization, recrystallization and the like.

The compound [1] of the present invention may act with a base to form a salt. Examples of the base include inorganic bases such as sodium, potassium, lithium, calcium, magnesium, and ammonia, and organic bases such as pyridine, collidine, triethylamine, and triethanolamine. ·.

When the compound [1] of the present invention is obtained in a free form, it may be formed into a salt using a conventional means, and the compound obtained as a salt may be converted into a free form using a conventional means. .

The compound [1] may form an inner salt, which is also included in the present invention. '

Each of the stereoisomers of the compound [i] can be used alone or in a mixture as a medicament.

The compound [1] thus obtained is useful as a medicine, and has antibacterial activity against, for example, certain gram-positive and gram-negative bacteria.

Next, the biological properties of compound [1] will be described.

Among the compounds of the present invention [1], representative compounds of M. tuberculosis

Table 1 shows the antibacterial activity against (Mycobacterium tuberculos is H37Rv). The minimum inhibitory concentration (MIC) was measured after 2 weeks of culture at 37 ° C by a dilution method using Kirchina medium supplemented with 5% bovine serum. table 1

The toxicity of the compound [1] of the present invention is low.

As described above, the compound [1] of the present invention or a salt thereof exhibits antibacterial activity against certain gram-positive bacteria and gram-negative bacteria, and is also low in toxicity, thereby causing infection by bacteria. It can be used as a bacterial infection therapeutic or antibacterial agent for the treatment of bacterial infections in mammals (eg, mice, rats, dogs, cows, pigs, humans, etc.).

The daily dose of the compound [1: or a salt thereof is about 1200 mg / kg, more preferably about 10 to δ0 mg / kg of the compound [1: Is administered by mixing the compound [1] or a pharmaceutically acceptable salt thereof with a suitable pharmaceutically acceptable carrier, excipient, or diluent by conventional means. It can be administered orally in the form of granules, capsules, drops, or the like, or it can be formulated by conventional means, for example, into injections, and compounded into sterile carriers manufactured by conventional means. It can be administered orally.

When producing the above oral preparations, for example, tablets, a binder (eg, hydroxypropyl propyl cellulose, hydroxypropyl methylcellulose, macro Gol, etc.), disintegrants (eg, starch, carboxymethylcellulose calcium, etc.), emollients (eg, lactose, starch, etc.), lubricants (eg, magnesium stearate, talc, etc.) They can be appropriately blended.

In addition, when preparing parenteral preparations such as injections, use isotonic agents (eg, glucose, D-sorbitol, D-mannitol, sodium chloride, etc.), preservatives (eg, benzyl alcohol, cuprate butanol) , Para-hydroxybenzoate, propyl para-benzoate, etc.) and buffers (eg, phosphate buffer, sodium acetate buffer, etc.) can be appropriately added.

The antibiotic TAN-528A, which is a raw material compound used in the method of the present invention, is obtained by culturing an antibiotic TAN-528A producing bacterium belonging to the genus Streptomyces in a culture medium, and adding the antibiotic TAN-528A to the culture. It can be produced by accumulating and accumulating and collecting it. Specific examples of the producing bacteria include Streptom ces al bolongus C-46366 strain. The microorganism can be obtained from the Fermentation Research Institute (ίF 0, Osaka, Japan). It was deposited under the accession number IF 0 14280 on August 5, 1983 at 183-85, Jusanhoncho, Yodogawa-ku, Ishikawa. In addition, the microorganism was submitted to the Research Institute of Microorganisms and Technology (FRI, 1-3-1 Higashi-Yatabe-cho, Tsukuba-gun, Ibaraki, Japan) at the Institute of Industrial Technology, Ministry of International Trade and Industry of Japan in August 1983. Deposited on the 9th as accession number FERM 7—7198.

BEST MODE FOR CARRYING OUT THE INVENTION

Next, the content of the present invention will be described in more detail with reference to Reference Examples and Examples, which do not limit the present invention. In addition, the percentage in the medium is% by weight / volume unless otherwise specified. Reference example 1

Glucose 2%, soluble starch 3%, corn steep liquor 1%, raw Soy flour 1%, Peputo down 0.5%, Ma CI 0.3% after CaC 0 Put ₃ 0.5% (pH 7.0) or Ranaru medium 500ml to 2 J2 Yozaka necked flask, and sterilized 125 ° C, 25 min, scan The cells were inoculated with Treptomyces' Arbolongs C-146366 (FERMP-7198, IF014280) and cultured on a reciprocating shaker at 28 ° C for 2 days. 1.5 J2 of the resulting seed culture was transferred to a 50-volume stainless steel tank containing 30 J2 of the same composition as the above seed medium, and cultured at 28 ° C for 2 days with aeration and agitation (aeration of 100 J2; agitation at 280 rpm) Min). 5 Jg of the resulting seed culture was inoculated into a 200 J2 tank containing 100% of the main culture medium consisting of 3% glycerol, 0.5% meat extract, 0.5% NaC, and 0.5% peptone (pH 7.0). Aeration and agitation culture (aeration 100%; agitation 200 revolutions / minute) was performed for 2 days.

The resulting culture solution :) was filtered using Hyflo Supercell (4.5Kg), the filtrate (80.2) was extracted with PH 3 using ethyl acetate (40J2 X 2), and the extract was extracted with 2% hydrogen carbonate. After washing with sodium water (40βΧ2), concentrating the ethyl acetate layer, washing the concentrated solution (820 ml) with water, then concentrating the ethyl acetate layer, adding n-hexane to the concentrate and precipitating, A coarse powder (1.16 g) was obtained. The coarse powder (丄 .9 g) obtained in the same manner was subjected to force ram chromatography on a gel (95 g). The fraction eluted with ethyl acetate: toluene (6: 4) was concentrated to dryness to obtain TAM-528A (683 mg). This powder was subjected to column chromatography with Sephadex LH-20 (340 ml), and the fraction containing the antibiotic TAN-528A eluted with ethyl acetate was concentrated to give a crystalline powder of the antibiotic TAN-528A. (506 mg) was obtained.

The physicochemical properties of the antibiotic TAN-528A obtained above are as follows.

(1) Appearance; orange yellow crystalline powder

(2) Melting point: 161-163 ° C (decomposition point) (3) Specific ^{_{^{rotation; [o;] 2 D 5}}} 910. ± 100 °

(c = 0.10 in chloroform)

(4) pKa 'value; 8.75 (titration method)

(5) Molecular weight measurement: 746 (M + 3H) + (S I MS method)

743 (M ⁺ ) (EI-MS method)

(6) Elemental Ki value; (%)

Actual value, C: 61.20, H; 6.72, N; 1.89,

0; 26.11, S; 4.48,

Calculated value, C; 61.36, H; 6.64, N; 1.88,

0; 25.81, S; 4.31

(7) molecular formula (molecular _{_{weight); - C 38 H + a}} N 0 i 2 S (743.865).

(8) Ultraviolet absorption spectrum; in methanol. .Lambda. 218 ± _{2 nm} (E = 485 245, 270, 350ηπι (shoulder), 0 ± 3 nm (El = 60 ± 10)

(9) Infrared absorption spectrum;

The main peaks are as follows.

3450, 2970, 2930, 2880, 1730, 1670, 1620, 1560, 1460, 1405, 1370, 1290, 1250, 1200, 1165, 1140, 1105, 1050, 1035, 980, 925, 880, 820, 780, 750, 735, 630cm ^_1.

(10) CMR spectrum (100MHz);

At least the following signals are observed.

195.19, 183.19, 180.41, 172.85, 164.40, 162.73, 161.98, 147.46, 144.54, 142.89, 140.70, 139.45, 137.09, 131.79,

128.97 (s), 128.97 (d), 127.71, 123.89, 109.06, 82.79, 76.57, 73.14, 70.00, 62.86, 51.78, 46.92, 41.93, 38.80, 38.37, 36.96, 20.55, 18.90, 17.47, 16.04, 15.65, 12.09, 9.21, 9.10 (where s represents singlet and d represents doublet, respectively).

(11) solubility; ·

Easily soluble, acetate, ethyl acetate, dichloromethane, dimethyl sulfoxide,

Poorly soluble, water, hexane

(12) color reaction;

Positive knock-on, magnesium acetate reaction

'' Negative, ninhydrin, dragendorf, Ehrlich reaction

(13) Stability; stable in organic solvents ·

(U) Thin layer chromatography; Silica gel HF _{25 +} (Merck, West Germany) Solvent system Rf value

Ethyl acetate: methanol 0.62

(50: 1)

Zic D rometan: methanol 0.44

(9: 1)

Example 1 Dihydro-TAN-528A (TAN-528A hydroquinone)

TA - a 528 A 148 mg dissolved in acetic acid Echiru (AcO Et) 20ml, this _{_{_{3% Na 2 S 2 0 4}}} - stirring by addition of water 10 ml. The AcOEt layer was washed with water, dried over anhydrous Na ₂ SO ₄ , AcOEt was distilled off under reduced pressure, and the residue was collected by filtration with hexane to obtain the title compound. Yield 124 mg. Melting point: 158-160 ° C Element I ¹ loaf value C ₃₈ H ₅₁ N 0 ₁₂ S 1Z2H ₂₀

Calculated: C 60.46; H 6.94; 1.86; S 4.25

Found: C 60.50; H 6.87; 1.88; S 4.28

Example 2 Preparation of 25-demethylthio-25-methylsulfonyl-TAN-528A:

674 mg of TAN-528A was dissolved in 30 ml of dichloromethane, cooled to 0 ° C, 172 mg of m-chloroperbenzoic acid was added, and the mixture was stirred for 30 minutes. Dichloromethane was distilled off under reduced pressure, and the residue was extracted with 100 mL of AcOEt. The AcOEt solution was washed with water, dried over anhydrous Na ₂ S 04, concentrated under reduced pressure, and the residue was collected by filtration with hexane to give 660 mg of yellow. A powder was obtained. This was dissolved in a small amount of AcO Et and adsorbed on a force column of a silica gel (30 g) pretreated with 1% oxalic acid-AcOEt in advance, and AcOEt-11-hexane (4: 6) was added. and developed with a solvent, washed with water gathered eluted fractions of 190ml from 121 ml, Shi preparative Iro by hardening dried over anhydrous Na ₂ S 0 ₄燦後, and evaporated to remove the Ac 0 Et to n- key. San ll¼g The title compound was obtained. Melting point: 165-168. C, [] ^² _D ² Na 718.9. _{(c = 0.18, CHC 1 3} ), SI MS m / e :( ^ 3) + 778, MR (90 Hz, CDC) <5: 0.75, 0.78, 0.86 & 1.20 ( each 311, (1,6.5), 2.04, 2.17 & 2, 27 (each 3H, s), 2.4- 2.7 ( ~2H, m), 2.81 (lH, m), 3.28 (3H, s, 25 - S 0 2 CH 3), 3.3-3.8 ( ~ 5H.br.ni), 3.70 & 3.83 (311, 3 each), 4.0-4.3 (2H, m), 0.80 (lH, d, 9Hz), 5.80 (lH, dd 16,9Hz), 6.o2 ( lH, d, 10Hz), 7.07 (lH, dd 16,10Hz), 8.73 (lH, s), 11.73 (lH, s)

Elemental analysis value C ₃₈ H _{+ 9} NO ₁ S

Calculated: C 58.83; H 6.36; 1.81; S 4.13

Found: C 58.96; H 6.39; N 1.95; S 4.32 Example 3 Preparation of 25-demethylthio-l25-methylsulfinyl TAN-528A:

The eluted fractions from 240 ml to 350 ml were collected and washed with water and dried over anhydrous Na ₂ S 0 ₊ in silica gel column chromatography in Example 2, and the solvent was distilled off under reduced pressure to obtain a powder with hexane and collected by filtration. . This was reprecipitated from AcOEt-n-hexane to give 113 mg of the title compound as an orange crystalline powder. Mp: 161 to 164 ^{_{^{Te, [a] 2 D 2 +}}} 726.1 ° (c = 0.18, CHC 1 3), SI MS m / e: (M + l) Ten 760, (M + 2) + 761, (M + 3) + 762, NMR (90MHz, CDC 1 3) <5: 0.76, 0.78, 0.86 & 1.18 ( each 3H, d, 6.5Hz), 1.98 , 2.15 & 2.27 ( each 3H's), 2.3-2.8 (~2H, m) , 2.85 (lH, m), 3.13 (3H, s, 25- S 0 CH 3), 3.4-3.7 (2H, m), 3.70 (3H, s), 3.8 (~ 3H, br.), 3.84 (3H , s), 3.9-4.2 (2H ₍ ra), δ .85 (1H, d, 8Hz) ' ₍ 5.76 (lH, dd 16, 7Hz), 6.42 (1H, d.lOHz), 7.02 (lH, dd 16,10Hz), 8.68 (iH, s), 11.89 (lH, s)

Elemental Ki value C ₃₈ H _{+ s} N'0 ₁₃ S

; Calculated value: C 60.07; H 6.50; 1.84; S 4.22

Found: C 60.34; H 6.58; N 1.95; S 4.49

Example 4 25-Demethylthio-1 25-methylsulfinyl-T AN—

Preparation of 528A (isomer of the sulfoxide moiety of the compound of Example 3):

The eluate fractions from 460 ml to 610 ml were collected by the silylation gel column chromatography in Example 2, and n-hexane was distilled off under reduced pressure. The AcOEt solution was washed with water and dried over anhydrous Na ₂ S 0 ₊ . Ac0Et was distilled off under reduced pressure, and the thus-obtained orange crystals were collected by filtration and recrystallized from Ac0Et to obtain 192 mg of the title compound. Mp: 186 ~ 189 ° C, ^{_{^{[Do] 2 D 2 + 778.9 ° (}}} c = 0.18, CHC 1 3), SI MS m / e: (Mr 1) ⁺ 760, (M + 2) ⁺ 761, (M + 3) 10 762, NR (90 Hz, CD Cl ₃ ) 5: 0.76, 0.80, 0.84, 1.23 (3H, d, 6.5 each) Hz), 2.05, 2.20 & 2.24 (3H, s each), 2.4-2.7 (~ 2H, m), 2.83 (lH, m), 3.26 (3H, s, 25-SO CHs), 3.4-3.7 (2H, m), 3.72 & 3.83 (3H, s), 4.0-4.3 (2H, m), 5.75 (lH, d, 9Hz), 5.82 (lH, dd 9,16Hz), 6.53 (lH, d, 11Hz), 7.22 (1H, dd 11,16Hz), 8.80 (lH, s), 11.89 (lH, s)

Elemental analysis value C ₃₈ H ₄₉ NO ₁₃ S

Calculated: C 60.07; H 6.50; N 1.84; S 4.22

Found: C 80.11; H 6.56; N 1.80; S 4.31

Example 5 Preparation of 25-demethylthio-25-phenylthio-TAN-528A

223 mg of TAN-528A was dissolved in 30 ml of MeOH, cooled to 0 ° C, and 78 mg of m-chloroperbenzoic acid was added, followed by stirring for 2 hours. — The eOH was distilled off under reduced pressure, extracted with 50 ml of AcOEt, washed with water and dried over anhydrous Na ₂ S 0 ₊ .

AcOEt was distilled off and the residue was triturated with hexane and collected by filtration. Of 245 mg of this powder, 120 mg was dissolved in AcOEt iOml, cooled to 10 ° C, added with 22 mg of thiophenol and 0.28 ml of 10% triethylamine-AcOEt, and stirred for 30 minutes with TC. AcO and extracted with Et 50 ml acidified with an added N- hydrochloric acid. the AcOEt layer was Inui燦with washed with water anhydrous Na ₂ SC was distilled off under reduced pressure, the residue was dissolved in a small amount of CHG1 _3, a column of silica gel (8 g) Placing, were collected by filtration CHC 1 ₃ collecting fractions eluted expanded from 85ml to U5ml in CHC 1 ₃ as a powder with hexane f was distilled off under reduced pressure and the residue to give the title compound. yield 59 mg.

Mp: 151 ~ 153 ° C (decomposition), SI MS m / e: (M + 2) + 807, NMR (90MHz, CD Cl 3) <5: 1.80 (3H, s, - C Dan _3), 2.02 (3H , s, -CH ₃ ), 2.30 (3H, s, -CH ₃ ), 3.70 (3H, s, -OCH ₃ ), 3.82 (3H, s, -0CH ₃ ), 7.24 (5H, s, -C ₆ H ₅ ) Elemental analysis value C ₊₃ H ₅₁ NO ₁₂ S

Calculated: C 64.08; H 6.37; 1.73; S 3.98

Obtained: C 63.6δ; H 6.04; N 1.57; S 3.53

Example 6 Preparation of 25-demethylthio-25-propylthio-TAN-528A:

223 mg of TAN-528A was dissolved in 10 ml of dichloromethane, cooled to 110 ° C, 57 mg of m-chloroperbenzoic acid was added, and the mixture was stirred for 30 minutes. Dichloromethane (50 ml) was added and the mixture was washed with water. The dichloromethane layer was washed with water and dried over anhydrous Na ₂ SO ₄ , dichloromethane was distilled off under reduced pressure, and the residue was collected with hexane. Dissolve the powder in 20 ml of dichloromethane, cool to 10 ° C, add 1.18 of propanediol 25J2 and 0.88 ml of 10% triethylamine dichloromethane, stir at 0 for 1 hour, distill off dichloromethane and remove the residue to the residue. And 20 mL of 0.1N HCl were added, and the AcOEt layer was separated, washed with a 1% aqueous ferric chloride solution, then with water, and dried over anhydrous Na ₂ S 0 ₊ .

The AcOEt was distilled off under reduced pressure 'to the residue is dissolved in a small amount of CH C1 ₃ adsorbed on a column of silica force gel (6 g), and developed with -1% MeO H- CHC 1 ₃ solvent system, 30 m The eluted fractions from 1 to 55 mi were collected, concentrated under reduced pressure, and the residue was collected by n-hexane. Re-precipitation with Ac0Et-n-hexane gave 109 mg of the title compound.

Melting point: U8 ~ 150 ° C (decomposition)

Elemental analysis value C ₊ . H ₅₃ N 0 ₁₂ S

Calculated: C 62.24; H 6.92; 1.81; S 4.15

Found: C 62.06; H 7.02; N 1.85; S 4.27

NMROOMHz, CD C) (5: 2.02 (3H, s, -CH 3), 2.20 (3H, s, -CH 3), 2.28 (3H, s, -CH 3), 3.70 (3H, s, -0CH 3 ), 3.82 (3H, s, -0CH ₃ ), 0.70 (3H, t, -S-CH2CH2CH3), 1.50 (2H, m, -S-CH2-CH2CH3)

-, 1

Five

Example 製造 Preparation of T AN—528Α lactone (condensation of carboxylic acid at 10-position and hydroxyl-block at 7-position):

Dissolve 446 mg of TAN-528A in 20 ml of tetrahydrofuran. After cooling to C, 1.2 ml of N-NaOH was added and stirred at 0 ° C for 20 minutes. The reaction solution was neutralized with 12 ml of 0.1 N-HC1 and extracted with 100 ml of AcOEt. The AcOEt layer was washed with water, dried over anhydrous Na ₂ S 0 ₊ and concentrated under reduced pressure. The residue was force ram chromatography using silica force gel small amount of dissolved in CH C 1 ₃ 8 g - is carried out for, and eluted with _{'1% MeO H- CHC 1 3} , eluted fractions from 25ml to 57ml The mixture was concentrated under reduced pressure, and the residue was collected by filtration with hexane to obtain the title compound.

10 Yield 141 mg. Mp 172 ~ n5 ° C, [] 2 D 5 + 857.9 ° (c = 0.14, CHC 1 3), SI MS mZe: (M tens 3) + 714, NMR (90MHz , CD Cl 3) <5: 2.08 ( 3H, s, -CH ₃ ), 2.20 (3H, s, -CH ₃ ), 2.25 (3H, s, -CH ₃ ), 2.30 (3H, s, -CH ₃ ), 3.80 (3H, s, -0CH ₃ ).

Elemental analysis value C ₃₇ H _{+ 5} NO _lt S

Calculated: C 62.43; H 6.37; 1.97; S 4.50

Found: C 62.70; H 6.39; 2.24; S 4.98

Example 8 TAN—528 A lactone (an isomer having a different lactonization position from that of Example 7; a carboxylic acid at position 10 and a hydroxyl group at position 13 condensed)

20

Manufacturing:

The eluted fractions ranging from 89 ml to 120 ml were collected by the silica gel gel chromatography in Example 7, concentrated under reduced pressure, and the residue was triturated with hexane as a powder to obtain the title compound. Yield 152mg. Mp:. 259~263 ° C [α] + 920.8 ° (c = 0.12, CHC 1 3), SI MS

twenty five

m / e: (M + 3) ⁺ 714, NMR (90 MHz, CD Cl ₃ ) 5: 2.08 (3H, s, -CH ₃ ), _{2.16 (3H, s, -CH 3} ), 2.26 (3H, s, -CHo), 2.35 (3H, s, -CH 3), 3.82 (3H, s, -O-CHs)

Elemental Xin value as C ₃₇ H ₅ N 0 _lt S

Calculated: C 62.43; H 6.37; N 1.97; S 4.50

Found: C 62.34; H 6.40; N 2.37; S 4.53

Example 9 Production of TAN-528A-10-carboxylic acid:

297 mg of TAN-528A was dissolved in 10 ml of ethanol, cooled to 0 ° C, 2 ml of N-NaOH was added, and the mixture was stirred at room temperature for 40 minutes. Then, 2 ml of N—HC1 was added for neutralization, ethanol was distilled off under reduced pressure, and the mixture was extracted with 50 ml of AcOEt. The AcOEt layer was washed with water, dried over anhydrous Na ₂ S 0 ₊ , and AcOEt was distilled off under reduced pressure. The residue was dissolved in a small amount of CHC 1 ₃ adsorbed on silica gel force ram (silica force gel _{6 g), CHC 1 3 -} 011- Water (270: 24: 1) from the solvent system deployment city 40ml of Elution fractions up to 60 ml were collected and concentrated under reduced pressure, and the residue was dissolved in 150 ml of ACOE. The A c 0 and dried E t solution in the washing after anhydrous N a ₂ S 0 _+, AcOEt also was distilled off under reduced pressure, was collected by Iro in the powder residue AcOEt- Echirueteru to give the title compound. Yield 110mg. Mp: n6 ~ 178 ° C,: α] 2 + 956.2 ° (c = 0.16, CHC1 3), SI MS me: (M- 2) + 731, 1 H - NR (90 Hz, CD Cl 3) <5 : 2.00 (3H, s, -CH 3), 2.20 (3H, s, -CH 3), 2.26 (3H, s, -CH 3), 2.38 (3H, s, -CH 3), 3.82 (3H, s , -0CH ₃ )

Elemental Xin value C ₃₇ H _{+ 7} N 0 ₁₂ S · 1Z2H ₂₀

Calculated: C 60.15; H 6.55; N 1.89; S 4.34

Found: C 60.21; H 6.44; N 1.97; S 4.56

Example 10 Preparation of 19-demethoxy-19-hydroxy-TAN-528A: — Οδ—

3.51 g of well-milled anhydrous aluminum chloride was suspended in benzene, 2.00 g of TAN-528A was added thereto, and the mixture was ripened and refluxed for 1 hour in an oil bath, and then G.55 g of anhydrous aluminum chloride was added. The mixture was refluxed for aging. After allowing to cool, the reaction solution was poured into 3 N hydrochloric acid, 400 ml of ethyl ether was added to separate the layers, the aqueous layer was further extracted with ether (100 ml × 4), the organic layers were combined, washed with saturated saline, and dried (MgS 0 ₊₎ was concentrated to dryness to give a red-orange solid 1.70g. This was subjected to silica gel gel column chromatography (ζό45 mm x 600 mm, column preparation and elution with 0.5% oxalic acid-containing ethyl acetate, and the eluate was diluted with water and the solvent was distilled off). 976 mg of the title compound were obtained. Also, 377 mg of the starting compound

10 Collected.

Molecular weight: SI MS m / e: ( M + 3) + 732

E. I. M / e M +: 729

UV and visible spectrum: 221 (ε = 42080), 368 (ε = 6420)

IR v cm ^-1 : 3450, 1655 (sh), 1640 (sh), 1620, 1480, 1380, max

0), r,

L Elemental analysis value C ₃₇ H ₇ N 0 ₁₂ S. 1 / 2H ₂₀

Calculated value C 60.15; H 6.55; 1.90; S 4.34

Found C 60.19; H 6.59; N 1.87; S 4.43

Example 11 Preparation of 19-demethoxy-19-hexyloxy-TAN-528A5:

1 9—Demethoxy 1 9—Hydroxy TAN—Dissolve 47.6 mg of TAN-528A in methanol, add 15 mg of silver oxide, stir for 30 minutes, add 83.5 mg of hexyl iodide and room temperature. Stir for 45 minutes. The reaction solution was filtered, concentrated to dryness, and the residue was subjected to preparative TLC (Merck Art NO. 5715, 200 x 2000 dragons, 2 sheets, developing solvent: Cloth form / acetone = 2/1). Was eluted with chloroform / methanol = 6/1, and the eluate was filtered and evaporated to dryness under reduced pressure to obtain 30.8 mg of the desired product. This was reprecipitated from acetone-hexane to obtain 16.2 mg of the pure title compound.

Melting point: i33 ~ 135 ° C (decomposition) ''

5 NMR (90 Hz, CD Cl ₃ ) <5: 0.7-0.9 (12H, m), 1.21 (3H, d, J = 6.5Hz),

1.28C6H.br.s), 1.70 (2H, m) ₎ 2.00 (3H ₍ s), 2.17 (3H, s), 2.28 (3H, s),

2.35 (311, 3), 2.5-2.7 (lH, m), 2.83 (1H, dd, J = 2.5Hz & ca.2.5Hz), 3.4-3.65 (2H, m), 3.70 (3H, s), 3.8 -4.3 (4H, in, 19-OCH2-, 9-H, 11-H), 4.10 (disappears with lH, s, addition of heavy water), 4.38 (lH, dJ = 7, disappears with addition of heavy water),. 67 (lH, d, J = 9Hz, disappeared by adding heavy water), 5.76 (1H, d, J = 9Ηζ),

5.77 (1H, dd, J = 15Hz & 8Hz), 6.42 (1H, d, J = 11Hz), 6.95 (lH, dd, J = 15Hz & 11Hz), 8.38 (lH, s, disappeared by adding heavy water), 12.00 (1H, s, disappeared by adding heavy water)

Element value C ₊₃ H ₅₃ N0 ₁₂ SI / 2H2O

5 Calculated: C, 62. '75; H.7.35; N.1.70

Found: C, 62.81; H.7.36; N.1.80 Example 12-23

In the same manner as in Example 1i, the corresponding 19-demethoxy-19-alkyloxy-1 TAN-528A was obtained using the following alkyl iodide or alkyl bromide, respectively.

Example 12 19—Demethoxy—19— (2-Etoquinone) TAN—

528A

Alkylating agent: 2-k σσ-ethylpromide

_{NMR (90MHz, CDC 1 3)} δ: 0.80, 0.93, 1.00 ( each 3H, d, J = 6.5Ηζ) , 1.23 (3H, d, J = 6.5Hz)) 2.07, 2.13, 2.27, 2.33 ( each 3H, s),. 2.71 (iH, d, J = 3Hz), 3.3-3.6 (2H, ni) ₎ 3.6- 4.0 (4H, m, 19-0CH ₂ CH ₂ C1), 3.83 (3H, s), 4.1-4.4 (2H, ni m), 5.65 (lH, d, J = 11Hz), 5.77 (lH, dd, j = 15Hz & 6Hz), 6.38 (-lH, d, J = llHz), 7.20 (lH, dd, J-15Hz & 11Hz) ), 8.10 (1H, s, disappeared by adding heavy water), 12.17 (lH, s, disappeared by adding heavy water)

Example 13 19-demethoxy-19-p-xylyloxy-TAN-528A Alkylating agent: p-xylyl bromide

N MR (90 Hz, CD C ") ό, 0.85-0.95 (9Η, m), 1.23 (3Η, d, J = 6.5Hz), 2.03, 2.20, 2.23, 2.36, 2.39 (3H, s), 2.85 (1Η, br.s), 3.35- 3.65 (2H, m), 3.70 (3H, s), 3.7-.9 (ca.4ΙΙ, ιη), 5.75 (1H, d, J = 12Hz), 5.80 ( lH ₍ dd, J = 15Hz & 9Hz), 6.43 (1H, d, J = 10Hz), ca.7.0 (1H, m, 4-H), 7.21, 7.30 (2H, d J = 9Hz each), 8.37 ( lH, s), 12.0CiH.br)

Example 14 19-Demethoxy 19-aryloxy-TAN-528A Alkylating agent: allyl iodide

Melting point: U6 ~ i48 ° C

_{N MR (90MHz, CDC 1 3} ) <5: 0, 73, 0.79, 0.87 J.22 ( each 3H, d, J = 6.5) , 2.00,2.18,2.25,2.37 (! Each 3 1, 3), 2.83 (lH.dd, J-2.5Hz & ca.2.5

Hz), 3.35-3.65 (2H, m) _> 3.70 (3H, s), 4.0-4.75 (ca.7H, m, CH ₂ = CH- CH ₂ -0, 9-H, 11-H, 0HX3), 5.15-5.45 (2H, m, CH ₂ = CHCH ₂₀ ), 5.65-

6.3 (3H, tn, CH2 = CHCH 2 0, 15-, 5-H), 6.41 (1H, dd, J = 10Hz & 1.5 Hz), 6.95 (lH.dd, J = 15Hz & 10Hz), 8.34 (111, s, disappeared by adding heavy water), 12.00 (lH, s, disappeared by adding heavy water)

Elemental _analysis value C ₊₀ H ₅₁ N 0 ₁₂ S

Calculated value C 62.40; H 6.68; 1.82

Found C 62.15; H 6.68; N 1.89.

Example 15 19-Demethoxy-19-Ethoxy-TAN-528A

Alkylating agent: iodide chill

Melting point: 1_54 ~ 156 ° C (decomposition)

_{NMROOMHz, CDC 1 3) <5} : 0.73, 0.79, 0.87 (. Each 3H d, J = 6.5Ηζ), il- 1.3 (3H, m) (1.33 (3H) d, J = 6.5Hz) 19-CH 3 CH ₂ 0), 2.00, 2.17, 2.24, 2.37 (311, 3 each), 2.83 (1H, dd, J = 2.5Hz & ca.2.5Hz), 3.35-3.7 (2H, m), 3.70 (3H, s ), 3.8- 4.3 (4H, m , "l9 -CH 3 CH 2 0, 9-H, 11-H), 4.07 (lH, s, disappeared in heavy water pressure), SSdH.dJ ^ SHz, disappeared heavy water addition ),

4.63 (iH, d, J = 9 Hz, disappeared by adding heavy water), 5.70 (lH, dd, J = iOHz & 1.5 Hz), 5.77 (lH, dd, J = 15 Hz & 9 Hz), 6.42 (lH, d, J = 11Hz), 6.95 (LH.dd, J = 15Hz & 11Hz), 8.37 (disappears when 1H, s, heavy water is added), 12.00 (disappears when 1H, s, heavy water is added)

Element analysis value C ₃₃ HwNO ₁₂ S

Calculated value C 61.81; H 6.78; 1.85

Found C 62.05; H 6.95; 1.93

Example 16 19—Demethoxine 19—Power Rubamoyl Methoxy TAN—

528A

Alkylating agent: 2-deacetamide

Melting point: 167-170 ° C (decomposition) MR (90MHz, CD Cl ₃ ) 5: 0.7- 0.9 (9H, m), 1.15-1.3 (3H, m),

2.00, 2.18, 2.28, 2.40 (each 3H, s), 2.85 (1H, dd, J = 2.5Hz & 2Hz), 3.4-3.8 (ca.2H, m), 3.70 (3H, s), 4.0-4.3 ( ca.2H, m), 4.24, 4.58 ( each 111, (1,] = 15112,11 ₂ ^ 0 ^ ₂ 0 -), 4.3- 4.7 & .2} 1,1) ^1>, disappeared in heavy water addition) , 5.76 (iH, dd, J = 15Hz & 11Hz), 5.82 (1H, d, J = 11Hz), ca.6.0, ca.6.9

Og "lH, br, ₂ NCO-), 6.42 (aH, ci, J = 10Hz), 6.95 (1H, d, J = 15Hz & 10Hz), 8.37 (lH, s, dissipated by adding heavy water), 12.08 (lH, br.s, disappeared by adding heavy water) Elemental analysis value C ₃₉ H ₅₀ N ₂ O ₁₃ S · 3 / 2H ₂₀

Calculated C 57.55; H 6.56; N 3.44

Found C 57.28; H 6.37; N 3.39

Example Γ7 19-Demethoxy-19-Panasiloxy-TAN-528A Alkylating agent: Panacil bromide

Melting point: 149-150 ⁼ C ...

MR (90MHz, CD Cl ₃ ) 5: 0.69, 0.77, 0 · 86 (each 3H, d, J = 7.5Hz), 1.22 (3H, d, J-6.5Hz), 1.97, 2.18 (each 3H, br s), 2.27, 2.37 (3H, s each),

2.28 (lH, br.s), 3.35-3.6δ (2Η, m), 3.70 (3H.s), 4.0 KlH, br.s, disappeared by adding heavy water), 4.1—4.3 (2H, m), 4.37 ( lH, d, J = 7.5 Hz, disappeared by adding heavy water), 4.62 (lH, d, J = 9 Hz, disappeared by adding heavy water), 5.01, 5.75 (1H, d, J = 16 Hz each), o.6-6.0 (2H, m) ₎ 6.42 (1H, br .d, J = 10Hz), 6.9.5 (lH, dd, J = ΙδΗζ & 10Hz), 7.4--7.7 (3H, m), 7.85-8.0 (2H, m ), 8.34 (dissipated by adding lH, s, heavy water), 12.00 (dissipated by adding iH, s, heavy water)

As elemental folding value _{_{_{C 45 H 53 N 0 13 S}}} · H 2 0

Calculated value C 62.41; H 6.40; N 1.62

Found C 62.44; H 6.24; N 1.73

Example 18 19—Demethoxy 19-Panasiloxy TAN—528

A aldol (obtained simultaneously with the compound of Example 17) NR (90 MHz, CDC l ₃ ) <5: 0.70, 0.74, 0.87, 1.22 (each 3H, d, J = 6.5 Hz), i.6G (ca.2H, br, disappeared by adding heavy water), 1.96, 2.17 ( 3H, br.s), 2.21, 2.34 (3H, s), 2.82 (lH, br.s), 3.3-3.5 (2H, m), 3.69 (3H, s), 4.06 (lH, s, heavy water .05- 4.30 (2Η, Μ), 4.42 (lH, d, J = 6HZ, disappeared with heavy water), SS lH.dJ-lQHz, disappeared with heavy water), .64 (lH, d ,

J = 10Hz), 5.50 (lH, s, disappeared by adding heavy water, 17-Og), 5.73 (lH, s, ^ COCH), o.77 (lH, dd, J = 16Hz & 9Hz), 6.41 (1H, d, J = 10Hz), 6.97 (1H, dd, J = 16Hz & 10Hz), 7.3-7.7 (3H, m), 7.8-7.95 (2H, m), 8.50 (lH, s, disappeared by adding heavy water), 11.2— 11.6 (disappears when IH, br, heavy water is added)

Example 19 19-demethoxy 21-dehydroxy 19,21-bis

—Panasiloxy—T A Ν—528 mg (obtained simultaneously with the compounds of Examples 17 and 18)

_{NxMR (90MHz, CDC 1 3)} δ: 0.67 (3H, d, J = 6Hz), 0.77, 0.89 ( each 3 (1, J = 7Hz) , 1.23 (3H, d, J = 6.5Hz), 1.6 (ca .2H, br), 2.00, 2.16 (each 3H; br.s), 2.35, 2.40 (each 3H, s), 2.82 (1H, r.s), 3.35-3.65 (2H, m),

3.71 (3H, s), 4.05-4.3δ (2Η, (η), 4.43 (1H, d, J = 8Hz) .4.67 (lH, d, J = 9Hz), 5.08, 5.25, 5.64, 5.72 (each 1H , d, J = 16 Hz), 5.70 (lH, d, J = 101I), 5.85 (iH, dd, J = loHz & 10 Hz), 6.41 (1H, d, J = 11 Hz), 6.91 (lH.dd, J = 15Hz & 11Hz), 7.4- 7.7 (6H, m), 7.85-8.l (4H, m), 8.60 (IH.s)

Example 20 19-Demethoxy-191- (2-Phenoxhetoxy) -TA

N-528A

Alkylating agent: 2-phenolic acid

Melting point: 133-135. C

NMR (90 MHz, CD Cl ₃ ) (5: 0.73, 0.80, 0.88 (each 3H.d, J = 6.5 Hz),

1.2-1.3 (3H, m), 2.01, 2.18 (3Η, br.s), 2.67, 2.71 (3H, s), 2.83ClH, br.s), 3.4-3.6δ (2Η, m), 3.70 (3H, s), 4.06 (1H, s, disappeared by adding heavy water), 4.05 4.5 (711, 111, and 111 minutes are heavy water Addition), 4.63 (lH, d, J = 8 Hz, disappearance with heavy water addition), 5.73 (lH, d, J = llHz), 5.80 (lH, dd, J = 14 Hz & 9 Hz), 6.43 (lH, br. d, J = llHz), 6.8 7.1 (4H, m), 7.2-7. (2H, m), 8.36 (disappears when adding lH, s, heavy water), 12.00 (disappears when adding lH, s, heavy water)

As elemental忻値_{_{_{C 45 H 5S NO 13 S ·}}} 1 / 2H 2 0

Calculated value C 62.92; H 6.57; N 1.63

Found C 63.04; H 6.56; N 1.63

Example 21 19-demethoxy-19- (2,3-epoxypropoxy)

TAN-528 A

Alkylating agent: Epibrohydrin

Melting point: 150 ~ 52 ° C (decomposition)

NMR (90 MHz, CD Cl ₃ ) 5: 0.70, 0.79, 0.87, 1.22 (each 3H, d, J = 6.5 Hz), 1.7 (ca.2H, disappeared by adding br. Heavy water), 2.01, 2.19 (each 3H, br.s), 2.29, 2.37 (3H, s), 2.6-2.7 (1Η, πι), 2.8-2.9 (2Ή, m), 3.2-3.6 (3H, m),

3.70 (3H, s), 4.05 (disappears when iH, s, heavy water is added), 4.1-4.7 (6H, m, of which 2 min ': disappears when heavy water is added), .73 (lH, br.d, J = 10Hz), 5.80 (lH, dd, J = 15Hz. & SHz), 6.42 (lH, br.d, J-lOIIz), 6.95 (111, dd, J = 15Hz & 10Hz), 8.35 (lH, s, heavy water Disappeared by addition), 12.01 (disappeared by adding lH, br. Heavy water)

Elemental Xin value as C ₊₀ H ₅₁ N 0 ₁₃ S

Calculated C 61.13; H 6.54; N 1.78

"Measured C 60.89; H 6.53; N 1.81

Example 22 19-demethoxy-19-heptyloxy-TAN-528A Alkylating agent: heptyl bromide

Melting point: 129 ~; L31 ° C

_{NMR (90MHz, CDC 1 3)} <5: 0.73 (3H, d, J = 6. δΗζ), 0.79 (3H, d, J = 7.53), 0.87. 1.23 (3H, d, J = 7Hz each), 0.87 (3H, tJ = ca.7Hz, terminal of heptyl group-C3), 1.2-1.4 (8H, br. 1.65 (ca.2H, br, disappeared by addition of heavy water), 1.73 (2H, m, / 3 / (^ ₂ ) of heptyl group) 2.01, 2.18 (3H, br.s ), 2.24, 2.37 (3H, s). 2.83 (lH, br.s), 3.35-3.6 (2H, m) ₎ 3.7- .3 (4H, m, 9-H, 11-H, a-C day ₂ ),

4.08 (lH, s, disappeared by adding heavy water), 4.38aH, d, J = 8 Hz, disappeared by adding heavy water), 4.64 (lH, d, J = 9 Hz, disappeared by adding heavy water), 5.73 (lH, d, J = 11Hz), 5.77 (1H, dd, J = 15.5Hz & 10Hz), 6.2 (1H, br.d, J = 10Hz), 6.93 (lH, dd, J = 15.5Hz & 10Hz), 8.34 (lH , s, disappeared by adding heavy water), 11.97 (1H, s, disappeared by adding heavy water)

As Elemental analysis _{_{_{C 4 H ei N0 12 S ·}}} 1 / 2H 2 0

Calculated value C 63.14; H 7.47; N 1.67

Found C 62.74; H 7.34; 1.93

Example 23 19—Demethoxy—19—Heptyloxy TAN—528A lactone

Obtained simultaneously with the compound of Example 22.

Melting point: 〖61 ~ 163 ° C

. \ MR (90MHz, CDC 1 3) (5:. 0.80, 0.92, 1.00, 1.22 ( each 3H, d J = 6.5 Hz) , 0.90 (3H, t, J = ca.7Hz, terminal C ₃ heptyl ), 1.2-1.4 (8H, br, methyleneproton of heptyl group), 1.5-1.8 (2H, m, -heptone of heptyl group), 2.07, 2.13 (3H, br.s), 2.25 , 2 · 34 (3H, s), 2.70 (ca.4H, m, 6-H, 8-H, 12-H, 14-H), 3.4-4.4 (ca.7H, m, of which 1H Disappears upon addition of heavy water, α-proton of heptyl group, 7-1_, 10-H, 11-H, 13-Η), 5.67 (lH, d, J = 12Hz) ₍ ..5.79 (lH, dd ₎ J-15Hz & 6Hz), 6.35 (lH, d, J = 10Hz), 7.24 (lH, dd, J = 15Hz & 10Hz), 8.13 (lH, s, disappeared by adding heavy water), 12.13 (lH, s, heavy water Disappears on addition) As elemental folding value _{_{C +3 H 57 NO nS · 2}} H 2 0

Calculated value C 62.08; H 7.39; 1.68

Found C 62.03; H 7.39; N 1.65

Example 24 Preparation of 19-demethoxy 19-acetoxy TAN-528A:

42,2 mg of 19-demethoxy 19-hydroxy TAN-528A was dissolved in 5 ml of methylene chloride, and 9.5 mg of acetyl chloride and then 7.O mg of triethylamine were added with stirring at room temperature. After stirring for 10 minutes, about 5 ml of water was added, and the organic layer was separated, washed with water, dried (MgS O ₊ ), and concentrated to dryness to obtain 40.3 mg of a red-orange solid, which was prepared preparatively. Purification by one TLC (developing solvent: hexane Zacetone = 1/1) gave 22.9 mg of the title compound.

Melting point: 170-173 ° C (decomposition)

_{MR (90MHz, CD C1 3)} (5: 0.73, 0.80, 0.83, 1.23 ( each 3H, d, J = 6.5 Hz ), 1.8 (ca.2H, br, disappeared in heavy water addition), 1.97, 2.20 (each 3H , br. s), 2.16

(3H, s, CH ₃ C0-0) ₍ 2.26, 2.38 (3H, s each), 2.83 (lH, br.s), 3.35-3,7 (2H, m), 4.0-4.3δ (2Η, ιη ), 4.06 (, s, disappeared by adding heavy water), 4.2 (lH, d, J = 7 Hz, disappeared by adding heavy water), 4.65 (lH.d, J = 9 Hz, disappeared by adding heavy water), 5.72 (lH .d, J = llHz), 5.77 (lH, dd, J = 15Hz & 8Hz), 6.2 (1H, d, J = 10Hz), 6.93 (lH, dd, J-15Hz & 10Hz), 8.33 (111 , s, disappeared by adding heavy water), 11.07

(iH.br.s, disappeared by adding heavy water)

As elemental fold value _{_{_{C 33 H 49 NO 13 S ·}}} Ή 2 0

Calculated value C 59.30; Η6.51; Ν1.77

Found C 59.61; Η6.72; Ν1.76

Example 25-31

In the same manner as in Example 2, 19-demethoxy—19—hydroxy— TAN-528A is reacted with asilyl chloride or sulfonyl chloride in the presence of triethylamine or dimethylaminopyridine to give the corresponding 19-demethoxy--19-asiloxy- or -19-sulfonyloxy-TAN-528A. Obtained.

Example 25 19-Demethoxy-19-benzoyloxy TAN-528A Acylating agent: benzoyl chloride

Base: Triethylamine

Melting point: i71-174 ° C (decomposition)

_{NMR (90MHz, CDC 1 3)} δ: 0.75, 0.77, 0.87 ( each 3 H, d, J = 6.5Ηζ ), 1.15- 1.3 (ca.5H, m), 1.88 (. 3H, br s), 2.19 ( 6H, r.s), 2.37 (3H, s),

2.5-2.7 (ca.2H, m), 2.83 (1H, br.s, 10-H), 3.- 3.85 (2H, m), 3.70 (3H, s), 4.06 (lH, s, heavy water added Disappeared), .05-4.3 (2H, tn), 4.4-4.8 (disappeared by adding 2H, 'br, heavy water), 5.77 (iH, dd, J = 16Hz & 8Hz), 5.85 (lH, d, J = 8Hz ), 6.42 (lH, d, J = 10.5Hz), 6.93 (1H, dd, J = 16Hz & 10.5Hz), 7.35-7.75 (3H, m) ', 8.00-8.35 (2H, m), 8.39 (iH , s, disappeared by adding heavy water),

12.1Q (disappears when lH, s, heavy water is added)

Elemental analysis value C _{+ +} H ₅₁ NO ₁₃ S

Calculated value C 63.37; H 6.16; 1.68

Found C 63.40; H 6.38; 1.60

Example 26 19-demethoxy-19-prolyloxy-TAN-528A

Base: Triethylamine

Melting point: 138 ~ 140 ° C

NMROOMHz, CD Cl ₃ ) <5: 0.72, 0.77 (each 3H, d, J = 7Hz), 0.86, 1.22 (each 3H, d, J = 6.5Hz), ca. 0.90 (3H, t, J = unknown, terminal C Dan ₃ forces Puroiru group),

1.15—1.4 (ca.5H, in),: L.68 (2H, quiiitet, J = 7Hz, 1.95, 2.19 (each 3H, br.s), 2.13, 2.37 (each 3H, s),

2.50 (2H, t, J = 7 Hz, α-methyleneproton of the propyl group), 2.82 (1Η, br.s), 3.4-3.6o (2H, m), 3.70 (3H, s), 4.04 ( 1H, s, disappeared by adding heavy water), 4.05-4.3 (2H ₎ m), 4.40 (lH, d, J = 7Ηζ, disappeared by adding heavy water), 4.63 (lH, d, J = 8Hz, disappeared by adding heavy water) ), 5.73 (lH, d, J = 10Hz) ₎ 5.76 (lH, dd, J = 15)

Hz & 9Hz), 6.40 (lH, d, J = llHz), 6.92 (1H, dd, J = 15Hz & 11Hz), 8.33 (1H, s, disappeared by adding heavy water), 12.04 (1Η, s, heavy water added) Disappeared)

As elemental忻修_{_{_{C +3 H 57 N 0 13 S}}} · 2 H 2 0

Calculated value C 59.78; H 7.12; N 1.62

Found C 59.59; H 6.83; N 1.52

Example 27 19-Demethoxy-19-toluenesulfonyloxy-TAN

-.528 A

ΎSilting agent: Ρ— Tosyl σ-lid

Base: dimethylaminopyridine (or triethylamine) Melting point: 16Q-163 ° C (decomposition)

_{N MR (90MHz, CDC 1 3} ) <5: 0.80 (6H, d, J - 6.5Hz), O.SKSH.d, J =

6.5Hz), 1.23 (3Η, (ί, J = 6.5Hz), 1.64 (ca.2H, br), 1.77, 2.18 (each; m, br.s), 2.34, 2.37 (each 3H, s), 2 . 6 (3H, s, 25 -SCH 3), 2.84 (. 1H, br s), 3.35-3.7 (2H, m), 3.70 (3H, s), 3.98 (lH, s), 4.0 - 4.3 (2H , ra), 4.45 (lH, d, J = '7Hz), 4.67 (lH, d, J = 8Hz), 5.79 (1H, dd, J = 16Hz & 9Hz),

5.93 (lH, d, J = 10Hz), 6.42 (lH ₍ d, J = llHz), 6.92 (1H, dd, J = 16Hz & 11Hz), 7.32, 7.78 (2H, d, J = 8Hz each), 8.31 (lH, s), 12.08 (iH, s) Elemental Q value C _{+ ÷} H ₅₃ N 0 ₁₄ S 2

Calculated value C 59.78; H 6.04; N 1.58

Found C 59.74; H 6.17; N 1.49

Example 28 19—Demethoxy 21—Dehydroxy—19, 21—Bi S-1p—Tosyloxy-1 TAN—528A

The acylating agent and base are the same as in Example 27

Melting point: 157 ~ 160 ° C (decomposition)

NMROOMHz.CD Cl ₃ ) 5: 0.74 (6H.t, J = 6.5Hz), 0.86 (3H, d, J =

7.5Hz), 1.23 (3H, d, J = 6.5Hz), 1.64 (ca.3H, br), 1.77 (3H, br.s),

1.83 (3H, s), 2.19 (3H, br.s), 2.32 (3H, s), 2.46 (6H, s), 2.82 (lH, br.s), 3.70 (3H, s), 3.35-.3.7 (2H, m), 4.12 (lH, s), 4.1-4.3 (2H, m), 4.45 (lH, d, J = 8Hz) ₍ 4.70 (1H, d, J = 9Hz), 5.79 (lH, dd, J = 15Hz &

8Hz), 5.84 (lH, d, J = llHz), 6.40 (1H, d, J = 10Hz), 6.86 (1H, dd, J = 15Hz & 10Hz), 7.30, 7.35, 7.73, 7.77 (2H, d each) , J = 8Hz), 8.53 (1H, s)

Elemental Xin value as C ₅₁ H ₅₃ NO ₁₈ S ₃

Calculated value C 59.00; H 5.73; .1.35

Found C 59.21; H δ.97; N 1.32-Example 29 19-demethoxy 19-tosyloxy-TAN-528A

Croton

(It is obtained simultaneously with the compound of Example 27 or 28.)

X MR (90MHz, CD Cl ₃ ) 5: 0.85, 0.93, 1.02, i.20 (each 3H, d, J-6.5 Hz), 1.77, 2.10 (each 3H, br.s), 2.37 (6H, s) , 2.47 (3H, s), 2.6-2.75 (ca.3H, m), 3.45-4.35 (ca.6H, m), 5.75 (lH, dd, J = 16Hz & 9Hz),

5.76 (lH, d ₍ J = llHz), 6.37 (1H, dd, J = 11Hz & 2Hz), 7.20 (1H, dd, J = 16Hz & UHz), 7.34, 7.79 (2H, d, J = 8Hz each) , 8.04 (lH, s), 12.27 (1H, s)

Example 30 19-demethoxy-19-phenyloxycarbonyloxy

TAN-528 A

Acylating agent: phenyl chloroformate Base: Triethylamine

Melting point: 158-161 ° C (decomposition)

_{NMR (90MHz, CDC 1 3)} 5: 0.71, 0.79, 0.87, 1.23 ( each 3H, d, J = 6.5 Hz ), 1.75 (ca.2H.br), 2.01, 2.13 (. Each 3H, br s), 2.30, 2.38 (each 3H, s), 2.83 (lH, br.s), 2.5-2.7 (ca.2H, m), 3.35-3.7 (2H, m), 3.70 (3H, s),

4.05 (lH, s), 4.0-4.35 (2H, m), 4.42 (lH, d, J-7Hz), 4.65 (1H, d, j = 8 Hz)., 5.71 (lH, d, J = 10Hz) ₍ 5.77 (1H, dd, J = 15Hz & 8Hz), 6.40 (lH, d, J = UHz), 6.93 (lH, dd, J = 15Hz & 11Hz), 7.34 (5H, s), 8.31 (lH, s ), 12.10 (lH, s)

Elemental analysis value C "H ₅₁ NO · 1 / 2H ₂₀

Calculated value C 61.55 H 6.10; N 1.63

Found C 61.62; H 6.32; N 1.61

Example 31'i.9-Demethoxy-21-dehydrodroxy-l 19,21-bisulfonyloxylponyloxy-TA-528A (obtained simultaneously with the compound of Example 30)

X MR (90MHz, CD C 1 3) <5: 0.71, 0.80, 0.87 (.. Each 3H d J = 6.5Hz), 1.2 -1.35 (ca.5H, m), 1.6 (ca.2Η, br), 2.05, 2.19 (3H, br.s), 2.37, 2.40 (311, 3), 2.83 (lH, br.s), 3.35-3.7 (2H, m), 3.70 (3H, s), 4.03 (lH , s), 4.0-4.35 (2H, m), 4.45 (1H, d, J = 7.5Hz), 4.67 (lH, d, J = 8.5Hz), 5.73 (1H, d, J = llHz), 5.80 ( iH, dd, J = 15Hz & 9Ήζ), 6.43 (1H, d, J = llHz), 6.93 (lH, dd, J = 15Hz & 11Hz), 7.33, 7.40 (5H, s), 8.47 (lH, s )

Example 32 Production of T AN—52SA lactone:

52.8 mg of TAN-528A was dissolved in 5 ml of acetone and stirred at room temperature. To this, 1.42 ml of a 0.05 N sodium hydroxide solution in methanol was added. After stirring for 30 minutes, the reaction mixture is concentrated to dryness, and the residue is prepared. The product was subjected to TLC (developing solvent: hexane / acetone = 1/1) to obtain 34.1 mg of the title compound. This product is considered to be the same as the lactone obtained in Example 8.

Melting point: 266-269 ° C (decomposition)

MR (90MHz, CDC l ₃ ) <5: 0.80, 0.90, 0.99, 1.20 (311, (1, J-6.5 Hz), 2.07, 2.12, 2.27, 2.36 (3H, s), 2.4-2.8 (ca .3H, m), 2.70 (iH.d, J = 3Hz), 3.52 (lH, dd, J = 9Hz & 2Hz), 3.70 (1H, d, J = 8Hz), 3.7 (ca, 3H, l) r , Vanishes when heavy water is added), 3.82 (3H, s), 3.97 (1H, dd, J = 2.5Hz & ca.2.5Hz), 4.30 (1Η, (1 (1, J = 9Hz & 5Hz, 7-day) , 5.65 (1H, d, J = 10 Hz), 5.77 (lH, dd, J = 16 Hz & 7 Hz), 6.37 (lH, d, J = 11 Hz), 7.23 (1H, dd, J = 16 Hz & 11 Hz), 8.12 (1H, s, disappeared by adding heavy water), 12.15 (lH, s, disappeared by adding heavy water)

MS (m / z): 711 (M ⁺ ), 693, 675, 664, 646, 628, 610

Elemental folding value _{_{'C 37 H + 5 MOHS'}} 1 / 2H ' as ₂ 0'

Calculated C 61.65; H 6.43; N 1.94

Found C 61.70; H 6.50; 1.89.

Example 33 Production of TAN-528A lactone:

79 mg of TAN-528A was dissolved in 5 ml of pyridine, and the mixture was refluxed for 3 hours in an oil bath. The reaction solution was concentrated to dryness, and the residue was subjected to preparative TLC to obtain 17.3 mg of the title compound. (In addition, 28.8 mg of raw material compound was recovered.)

This product was found to have the same melting point and NMR as the lactone obtained in Example 32.

Example 34 Production of T AN—528A lactone:

Dissolve 20 mg of TAN-528A in 4 ml of dichloromethane, add 9% of piperidine and stir at room temperature overnight. The reaction solution was worked up according to Example 32 to obtain 15.2 mg of the title compound. This product is compatible with the TAN-528A lactone obtained in Example 32 and the melting point.

N MR

Example 35 Preparation of 19-demethoxy-19-hydr σ-xi T A — 528 A lactone:

Using 57.0 mg of 19-demethoxy-19-hydroxy-TAN-528A, the reaction was carried out in the same manner as in Example 32 to obtain 20.2 mg of the title compound.

Melting point: 184-187 ° C

_{N MR (90MHz, CDC 1 3} ) δ: 0.76, 0.93, 1.03, 1.20 ( each 3H, d, J = 6.5Hz) , 2.04, 2.13, 2.20, 2.40 ( each 3H, s), 2.5- 2.8 ( ca. 3H, m), 2.74 (lH, d, J = 3 Hz), 3.62 (iH, dd, J = 9 Hz & 3 Hz), 3.6—3.8 (1H, br.dissipated by adding heavy water), 3.72 (lH, d ₍ J = 9Hz), 3.97 (lH, dd, J = 2.5Hz & ca.2.5Hz), 4.13 (ca.2H, d, J = .7Hz, disappeared by adding heavy water), .23 (1H, dd, J- 9Hz & 5Hz, 7-), 5.Do (lH, d, J = 10Hz), 5.74 (lH, dd, J = 15Hz & 6Hz), 6.39 (lH, d, J = 10Hz), 7.23 (lH, dd, J = 15Hz & 10Hz), 8.19 (1H, s, disappeared by adding heavy water), 12.n (lH, br, disappeared by adding heavy water)

Elemental Ki value C

As OHS · 1 / 2Η ₂ 0

Subtracted value C 61.18; H 6.27; 1.98

Found C 61.30; H 6.25; X 1.97

Example 36 Preparation of 19-demethoxy-19-acetoxy-TAN-528A lactone:

To a solution of 19-demethoxy-19-hydroxy-TAN-25.5 mg in acetone (ca.3 ml) was added 0.69 ml of a 0.05N sodium hydroxide in methanol solution. After stirring for 10 minutes, the solvent was distilled off under reduced pressure, the residue was dissolved in 4 ml of THF, and 4 mg of acetyl chloride was added thereto and stirred for 10 minutes. Then, the reaction solution was poured into 5 ml of 1% aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated saline and dried, and the solvent was distilled off. The residue was subjected to TiV TLC (developing solvent: hexane / acetone = i / l) to obtain 8.1 mg of the title compound.

Melting point: 186 ~ 189 ° C

NMR (90 Hz, CD Cl ₃ ) <5: 0.78, 0 JO (3H, d, J = 6.5 Hz each), 0.99 (3H, d, J = 7 Hz), 1.20 (3H, d, J = 6.5 Hz) , 2.02, 2.10 (each 3H, br.s), 2.14 (3H, s,

CH ₃ C0-0-) ₍ 2.23, 2.36 (3H, s each), 2.5-2.7 (ca.4H.m), 3.5-4.35 (1H of 6H, m disappears by adding heavy water), 5.65 (lH, d, J = 10Hz), 5.76 (1H, dd, J = 15Hz & 8Hz), 6.36 (lH, d, J = llHz), 7.20 (1H, dd, J = 15Hz & 11Hz), 8.07 (lH, s, 12.20 (lH, s, disappeared by adding heavy water)

As elemental圻値_{_{_{C 38 H 45 N0 12 S ·}}} 1 / 2H 2 0

Calculated C 60.95; H 6.19; 1.87

Found C 60.71; H 6.48; N 1.81

At the same time, 4.5 mg of 19-demethoxy-19-acetoxy-TAN-528A was obtained.

Example 37 Preparation of 25-detylthio 24-24-doxy-24,25-benzothiazino — Τ Λ — 528 A:

59 Jmg of 2-demethylthio-25-methylsulfinyl TAN-528A was dissolved in 5 mi of dichloromethane, and the mixture was stirred under ice cooling. To this, 0-aminothiophenol 12. (kg and triethylamine 9.5 mg) were added sequentially, and the mixture was stirred for 30 minutes. Then, 5.8 mg of 0-aminothiophenol was added, and the mixture was stirred for 30 minutes at room temperature. the poured into water, and later partial solution was added Q.1N hydrochloric acid Q.9Ml, the organic layer is washed with water, dried distilled off (MgS 0 ₄₎ and the solvent, preparative TL C (developing solvent residue: Hexane / acetone = 1/1), and the band with an Rf value of around 0.6 was scraped and eluted to obtain 11.6 mg of the title compound.

Melting point: 183-185 ° C (decomposition) N ^T R (90 MHz, CDC l ₃ ) <5: 0.53, 0.61, 0.82, 1.25 (each 3H, d, J = 6.5 Hz), 1.83, 2.25, 2.32 (each 3H, s), .73 (1H, d , J = 2.5Hz), 3.3-3.6 (2H, m), 3.66, 3.94 (3H, s), 4.0-4.3 (2H, m), 4.45 (lH, d, J = 7Hz), 4.63 (1H, d, J = 8Hz), 5.55 (lH, d, J = 10Hz), 5.78 (lH, dd, J = 15Hz & 8Hz).

6.aH, d, J = lliiz), 7.06 (lH, dd, J = 15Hz & 11Hz), 7.35-7.55 (3H, m), 7.75-7.95 (1H ₍ IR) ₍ 8.41 (1H, S), 12.84 (1H, S)

MS (m / z): 802 (M ⁺ ), 784, 770, 766, 752, 734

Element value C + sHwNsO S 'HzO

Calculated value C 62.91; H 6.38; N 3.41

Found C 62.99; H 6.27; 3.49

Example 38 In the preparative TLC of Example 37, a band having an Rf value of around 0.1 was scraped off and eluted with 25-demethylthio-1.25-hydroxy TAN-528A to obtain 11.7 mg of the title compound. .

Melting point: 165 ~ L67 ° C

MR (90MHz, CDC 5: 0.76, 0.79, 0.83, 1.23 (each 3H, dJ = 6.5 Hz), 2.02, 2.19, 2.26 (each 3H, s), 2.4—2.7 (ca.3H, m), 2.84 ( 3.4-3.65 (2H, m), 3.74, 3.84 (each 3H, s). 3.95-4.3 (2H, m), 4.45 (ca. 2H, hr, disappeared by adding heavy water), 5.80 (1H, dd, J = ΙδΗζ & 8Hz), 5.83 (iH, d ₍ J = 10Hz), 6.52 (lH, d, J = UHz), 7.26 (1H, dd, J = loHz & 11Hz), 8.52 (lH , s, disappeared by adding heavy water), 12.19 (lH, s, disappeared by adding heavy water)

MS (m / z): 713 (M +), 695, 677, 663, 659, 645, 627

As elemental圻値_{_{_{C 37 H 47 N 0 13 ·}}} H 2 0

Calculated value C 60.73; H 6.75; N 1.91; S 0.00

Found C 60.75; H 6.61; N 2.04; S 0.00 Example 39 Preparation of 25-demethylthio-l24-deoxo-l24,25-benzothiazino-TAN-528A and 25-demethylthio-l25-hydroxy-TAN-528A:

The reaction was carried out in the same manner as in Examples 37 and 38 using 114.4 mg of 25-demethylthio-25-methylsulfinyl TAN-528A to obtain 26.9 mg of a benzothiazino compound and 60.lmg of a hydroxy compound.

This benzothiazino compound was found to have the same melting point and N MR as that obtained in Example 37. The melting point and NMR of this hydroxy compound were the same as those obtained in Example 38.

Example 40 25-Demethylthio-15-hydroxy-TAN-528A

102 mg of TAN-528A was dissolved in 4 ml of THF, 14 mg of sodium borohydride was added, and the mixture was heated under reflux with stirring for 1 hour. Pour the reaction mixture into cold water, add about 5 ml of 1 N hydrochloric acid, extract with chloroform, wash the extract with water, dry it, evaporate the solvent, and remove the residue with Breparative TLC (developing solvent: chloroform / acetone = 2 / 1) to obtain 10.img of the title compound, and 18.1 mg of TAN-528A was recovered.

This product was found to be similar to the compound obtained in Example 38 in melting point and NR.

Example 41 Preparation of 25-Demethylthio-25-Methoxy-TAN-528A:

37.5 mg of 25-demethylthio-125-hydroxy TAN-528A was dissolved in 5 ml of dichloromethane, and about 0.7 ml of a diazomethane ether solution was added thereto. After 10 minutes, the reaction solution was concentrated to dryness. This was subjected to preparative TLC (developing solvent: hexane / aceton = 1/1), and a yellow-orange band with an Rf of 0.7 was scraped off and eluted to obtain 28 mg of the title compound.

Melting point: 155-157 ° C _{NR (90MHz, CDC 1 3)} 5: 0.7δ (3Η, d, J = 7Hz), 0.80, 0.83,1.22 ( each 3H, d, J = 6.4Hz) , 1.99, 2.17, 2.25 ( each 3H, s) , 丄 .8 to 2.8 (5 to 6H, m of which 1 to 2H disappear by addition of heavy water), 2.85 (lH, br.s), 3.4-3.7 (2H, m), 3.70, 3.84 (3H, s for each ), 4.03 (3H, s), 3.9-4.7 (3H of 5H, m disappeared by adding heavy hydrogen), 5.73 (lH, dd, J = 16Hz & 8Hz), 5.82 (lH, d, J = 9Hz), 6.37 (1

H, d, J = 10Hz), 6.92 (lH, dd, J-16Hz & 11Hz), 7.73 (1H, s, disappeared by adding heavy water), 12.18 (lH, br.s, disappeared by adding heavy water)

As Elemental analysis _{_{_{C 38 H 43 NO 13 · H}}} 2 0

Calculated C 61.20; H 6.89; N 1.88

Found C 60.98; H 7.06; N 1.93

Example 42 Preparation of 25-demethylthio-l25-hydro-TAN-528A: TA-528AlOlmg was dissolved in 15 ml of ethanol, to which ethanol of a Raney-Nii gel (type W-2) was added. The suspension (230 mg by dry weight) was added, and the mixture was refluxed for 3 hours while stirring. The reaction solution was filtered, and the filtrate was concentrated to dryness. The residue was subjected to preparative TLC (developing solvent: chloroform / acetone = 2/1) to obtain 10.3 mg of the title compound. 14.2 mg of {{λ'-52δ} was also recovered.

Physical properties of the title compound:

_{MR (90MHz, CDC 1 3)} 5: 0.75 (3H, d, J - 6.5Hz), 0.80 (3H, d, J = 7Hz), 0.88, 1.22 ( each 311, (1, ₁ '= 6.51 {2) , 2.06, 2.15, 2.27 (3H, s each), 1.8-

2.7 (4H, m) _> 2.83 (lH, br.s), 3.4-3.6 (3H, m of lH is lost by adding heavy water), 3.73, 3.84 (311,3), 3.9-4.5 (5H, m of 3m disappeared by adding heavy water), 5.75 (lH, d, J = 10Hz), 5.78 (1H, dd, J = 15Hz & 9Hz), 6.42 (lH, d, J = 10Hz), 7.25 (lH , dd, J = 15Hz & 10Hz), 7.69 (lH, s), 8.56 (lH, s, disappeared with heavy water), 11.99 (111, s, disappeared with heavy water)

Example 43 25-Demethylthio-1-25-dimethylaminomethyl-TAN — Production of 528A:

25-Demethylthio-25-Hydroxy-TAN-528 A 155 mg of acetonitrile (7 ml) solution was added to a solution of Etsenzamoser Salt (CH ₂ (10) θ

-NMe ₂ -I) (55 mg) was added, and the mixture was refluxed on an oil bath under dehumidification and stirring. Four hours later, 30 mg of the reagent was added, and the mixture was refluxed for another 2 hours. After the reaction solution was concentrated to dryness, ethyl acetate and water were added thereto for liquid separation. The acid ethyl layer was washed with brine and dried, and the solvent was distilled off to dryness to obtain 144 mg of a yellow-orange solid. This was subjected to preparative TLC (developing solvent: chloroform / methanol = 11/1), and a brown band having an Rf value of 0.4 was scraped and eluted to obtain 47.7 mg of the title compound.

NMR (90 MHz, CD Cl ₃ ) 5: 0.75, 0.79, 0.90, 1.17 (3H, d, J = 6.5 Hz each), 2.04 (3H, s), 2.17 (ca.12H.br.s), 2.85 (lH , br.s), 3.3-3.7 (ca.5H, m, of which 1H disappears with the addition of heavy water), 3.70 (3H, s), 3.83 (3H, s), 3.8-4.6 (ca.5H, m, Of which, 3H disappears by adding heavy water), 5.76 (lH, dd, J = 9 Hz & 16 Hz), 5.88 (lH, d, J = llHz), 6.42 (1H, d, J = 11 Hz), 7.02 (1H, dd) , J = llHz & 16Hz)

λί S (SI MS) m, / e: (M10 3) ⁺ 757

Example 44 Preparation of 25-demethylthio-25-dimethylaminomethyl-TAN-528A:

65.7 mg of 25-demethylthio-125-hydro-TAN-528A was dissolved in 5 mU of THF, and formalin 502 and dimethylamine (50% aqueous solution) 40, "β were added, followed by stirring at room temperature overnight. The reaction mixture was poured into a mixture of ethyl ethyl-water and 0.1 H C1 was added to adjust the aqueous layer to about 6. The organic layer was dried and dried to obtain 60.3 mg of a solid. The residue was subjected to preparative TLC (developing solvent: black formaldehyde = 12/1), and the brown band was scraped and eluted to give 5.1 mg of the title compound, which was analyzed by TLC and NMR in Example 43. Product. Example 45 Preparation of 25-demethylthio-25- (1-pyrrolidinomethyl) -TAN-528A:

Using pyrrolidine in place of dimethylamine of Example 44, 4.1 mg of the title compound was obtained from 67.8 mg of 25-demethylthio-l25-hydro-TAN-528A.

_{NMR (90MHz, CD Gl 3)} (5: 0.7-1.0 (9 HmMeX 3), 1.20 (3H, d, J = 6.5, Me), 2.05 (3H, s, Me), 2.27 (3H, s, Me) , 1.9-2.2 (4H, m, pyrrolidiao methylenex 2), 3.6- 3.9 (4H, m, pyrrolidino

methyleneX2), 3.69 (3H, s, Me), 3.83 (3H, s, Me)

Example 46 2o-Demethylthio-15-hydroxymethyl-TAN-

Production of 528A:

Crude 25.1-demethylthio-l25-dimethylaminomethyl-TAN-528A 45. Omg was left in the air at room temperature for 10 minutes, and then subjected to preparative TLC (developing solvent: Kuguchi σ form // methanol = 11Ζ1) Then, a red band having an Rf value of 0.3 was scraped off and eluted to obtain 6.4 mg of the title compound.

_{MR (90MHz, CDC 1 3)} δ: 0.75 - 0.95 (9H, m), 1.13 (3H, d, J = 6Hz), 2.01, 2.14 ( each 3H, br.s), 2.24 (3H , s), 1.8 -2.7 (ca.5H.ni), 2.77 (111, br.s), 3.66 (3H, s), 3.73 (2H, s), 3.80 (3H ₍ s), 3.3-4.5 (ca.6H.m) , 5.5-6.0 (2H, m) _> 6.37 (111, d, J = 9Hz), 7.1-7.4 (1H, m)

MS (E.I.) 727 (M ⁺ ), 713, 695, 677, 663, 659

Example 47 Preparation of 25-demethylthio-25-ode-TAN-528A: 2δ-demethylthio-125-hydro-TAN-528Α li 3.2 mg was dissolved in acetonitrile 6 ml, and the mixture was dissolved in Ethylene Moser. 39 mg of a salt was added, and the mixture was refluxed for 2 hours. An additional 59 mg of the reagent was added, and the mixture was further refluxed for 1 hour. After the reaction product was concentrated to dryness, a mixture of ethyl acetate and water was added, and the mixture was separated. After washing with water, drying and drying, 99.6 mg of a brown solid was obtained. Dissolve this in 6 ml of dichloromethane, add 4 ml of diacid, and dioxide Manganese lOOmg was added and stirred at room temperature overnight. The solid was washed with water containing 590 mg of sodium hydrogen carbonate, dried and dried to obtain 90.4 mg of a brown powder. This was subjected to Preparative TLC (developing solvent: hexane / acetone = 5/6), and the yellow-orange band having an Rf value of 0.3 was scraped off and eluted to obtain 18.8 mg of the title compound.

NMR (90 MHz, CD Cl ₃ ) <5: 0.74, 0.79, 0.89, 1.17 (each 3H, d, J = 6.5 Hz), 2.03, 2.17, 2.27 (each 3H, s), 2.87 (1H, r.s) , 3.35- 3.6 (2H, m), 3.71, 3.84 (3H, s each), 4.0—4.8 (5H, m, 3H disappears by adding heavy water), 5.74 (lH, dd, J = 15Hz & 8Hz) , 5.76 (1H, d, J = 9 Hz), 6.45 (lH, d, J = U Hz), 6.99 (lH, dd, J = 15 Hz & 11 Hz), 8.35 (1H, s, disappeared by adding heavy water), 1 1.85 (disappears when lH, s, heavy water is added)

MS (SI MS & E.I.) 823 (M ⁺ ), 697

Industrial applicability

The compound [1] of the present invention or a salt thereof has excellent antibacterial activity and can be used as an antibacterial agent. '

Claims

The scope of the claims

1. General formula ο

/ H

0 with OH

Is an organic residue via S 0 ₂ —, X is a formula,

Tan- -R ⁺ , ；，八

OH

OH or a formula (where R * is hydrogen, hydroxy)

A halogen or an organic residue via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom; R ⁵ represents a divalent group via two carbon atoms which may have a substituent; A— is bonded to the para-position of the R group of the ring, and the bond is bonded to the meta-position of the R 1 group of the benzene ring in the formula, respectively. R ^B is derived from carboxy, carboxy Group or a delta lactone between 1-OH and 7- or 13-position

0 H

Y ′: or — C 0 — or 1 C — (where R ⁷ is

R ⁷

When R ¹ is an organic residue via a carbon atom, it indicates that it forms a 5-membered ring together with 10 R ¹ . )). However, when R ¹ and R ² are hydrogen, R ⁶ is methoxycarbonyl and Y is —CO—

0

,

X is not R ¹ is methyl, R ² is hydrogen and R ⁶ is

騸,, CH:

0

义

When Y is —C 0— in methoxycarbonyl, X is

Ύ, S— CH _: 0

is not. Compound represented by: or a salt thereof _c

2. General formula

Wherein R and R ² are the same or different and each is hydrogen or carbon atom or

Ha—

Expression

A halogen or an organic residue via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom; R ⁵ represents a divalent group via two carbon atoms which may have a substituent; A- is bonded to the para-position of the R group of the ring, and 騸-is bonded to the meta-position of the R group of the benzene ring in the formula, respectively. R ⁸ is a group that can be derived from carboxy, carboxine or a delta lactone between —OH and 7- or 13-position

0 H

That Y is — C 0 — or — C one (where R ⁷ is

R ⁷

When R ¹ is an organic residue via a carbon atom, -0 indicates that it forms a 5-membered ring together with R ¹ . )). However, when R ife and R ² are hydrogen, R ⁶ is methoxycarbonyl and Y is —CO— X is not R ¹ is methyl, R ² is hydrogen and R ⁶ is

When Y is one C 0— in methoxycarbonyl, X is

is not. ] An antibacterial agent containing a compound represented by the formula (I) or a salt thereof (