PH26959A - Digestive tract contractile motion stimulate - Google Patents

Description

oo 26959

The present invention relates to a stimulnnt for contractile motion of the digestive tract of mammals.

PRIOR ART

The digestive tract consists of the stomach, the duodenum, the small intestine, etc., and plays an important role in the digestion of food taken from the mouth. The contructile motion of the digestive tract is essential in order to perform the digestion smoothly, In a healthy man, the autonomous nerve system and digestive tract hormones function effective- 1y to induce contraction of the digestive tract not only immediately after the intake of foods but also in a state where the digestive tract is empty, when such contraction has been considered absent. The movement in such empty digestive tract is transmitted from the stomach to the duodenum and to the small in- testine, and plays an important role for cleaning the digestive tract, thus preparing for next intake of foods (Z. Itoh, "Iden", 33, 29, 1979). } A stimulant for contraction of the digestive tract is expected to induce a normal movement of the digestive tract, in a human with weakened function of the dipestive tract, thereby na healthy body being maintained. :

CL

Motilin is already known as a digentive tract hormone for stimulating the contraction of the di- gestive tract. This substance is a peptide, con- } sisting of 22 amino acids and extracted by J. Ce.

Brown in 1966 from the mucous membrane nf a pig ‘tuo- denum (J. Ce. Brown et al., Gastroenterology, 50, 333, 1966), and is already synthesized chemically (B. wunsch et al., Zeitschrift fur Waturfoisch, 28¢, 235, 1973).

PROBLEM TO BE RISOLVID BY THE PREGENT

IHVENTION

However the supply of motilin by extraction from natural substance or by chemical synthesis is not sufficient, and has not been possible in a large amount.

MEANS FOR SOLVING THE PROBLEI

In the course of a survey for providing a substance capable of stimulating the contraction of the digestive tract and adapted for a large supply, "the present inventors have synthesized various deri- vatives from antibiotic erythromycin a, B, Cy D and

F and have found that said derivatives have a strong stimulating effect on the contraction of the digestive tract. .

Based on this finding, the present inventors have made intensive efforts and have reached the present invention.

The present invention provides: ‘ 5 A digestive tract contractile motion ~timulant containing a compound, or a salt therenf, reprasented by the general formula: 1 a - R

RO [7 ’ 1 0 0 CH 3 13 . 7 CH,

Pe , i RT oR

CH 2 > 0 ci, 2

Litt 0 + OR" cu 3 wherein rH stands for a hydrogen atom or an acyl radical which may be substituted; rR” stands for a hy- drogen atom, an acyl or alkyl radical which may be substituted; Rr stands for a hydrogen atom or a me-

I thyl radicnlj Rr etands for a hydrogen atom or a hy- droxy radical; rR? stands for the formula ’ RP 7 15 .=N \ ge :

wherein R® stands for a hydrogen atom, a lower al- kyl or cycloalkyl radical, R® stonds for a hydrogen atom, a lower alkyl, cycloalkyl, lower alkenyl or lower alkynyl radical which may be substituted, or

R® and R® form a cyclic alkylamino radical together with the adjacent nitrogen atom) or the formula . rd nl X=

N gf (wherein 4 stands for a lower alkyl radical, each of R® and rf, which may be the same or different, - 10 stands for a lower alkyl, cycloalkyl, lower alkenyl or lower alkynyl radical which may be substituted, } or R® and rd form a cyclic alkylamino radical toge- - ther with the adjacent nitrogen atom, and X~ stands . . for an anion)j and when R™ is the formula : R ; 5 / ya ~N I . A Re stands for the formula:

gH Ch pt?

CH cit n_Y 2 6 11 2 12

N

13 wherein, Z stands for the formula

I AN oR? or (wherein Rg stands for a hydrogen atom, an acyl or 5 alkyl radical which may be substituted, and g® stands for a hydrogen atom, an acyl radical of a lower car- boxylic acid or an alkyl radical which may be substi- : tuted by an alkylthio radical), the formula 11 12 / cn 4 3

OR H

: 10 (wherein rR’ stands for a hydrogen atom, an acyl or alkyl radical which may be substituted), po XK

N11 12/0, 11 12 or O 5

CH CH Ny” 3 0 3 : 8 . 8 (wherein Y stands for the formula B-R~ wherein R -—b -

N \ N\

S= 0, C=0, C= ~~ J Ve or the formula 9

NN ~~ R .C 7

N oY } 9 0. wherein each of RZ and R, which moy be the same or different, stands for a hydrogen atom or an alkyl . radical, or constitutes a cyclic alkyl radical with - 9 10 the adjacent carbon atom, or either of R- and R js a hydrogen atom, an alkyl radical br an aryl radical while the other is a dinlkylamino radical), . 11 12 . .

R and R both stand for hydrogen atoms or both } taken together form a chemical bond, or the formula: : CH 3 cl 0 CH 5 £ok > 11 0 5! / 12 wherein Z' stands for the formula \11 XK ot CH 3

(wherein rH stands for a hydrogen atom, an n~cyl or } alkyl radical which may be substituted), or when Rr"

Cn is the formula ©" / : -N — Rr°%, x A

N Ng

R

5S stands for the formula: ptt CH nt? ~~ - CH

CH 0 3 - . 3 / 11 4 13 13 wherein gH, gH? and 7 have the same meanings as de- ; fined above, the formula:

CH

: 3 . } . CH . . 0 : 34 2

CH, 11 ” zt 12 wherein 7%! has the same meaning as defined above, or the formula: cH 3 . 0

A H

Cc 3 : 2%0 11

Z

: 12 wherein % has the same meaning as defined above, and

Rr’ stands for a hydrogen atom or low alkylj with 1 proviso that each of rR, Rr, RY, rR, and R® is not a hydrogen atom at the same time, when R® is a dime~ . : 11 12 thylamino radical, both of R and R taken together form a chemical bond and Rr’ is a methyl radical; and each of 2h, Rr, r* and r3 is not a hydrogen atom at the same time, when R® is » dimethylamino radical and R> is a methyl radicals

DESCPIPTION OF THE PREFERRED EHBODIHENTS

The acyl radical represented by Rr! in the foregoing formula can be 2a carboxylic acyl, n sul- fonic acyl, a phosphorous acyl or a phosphoric acyle ; 2 55 7 } 15 The acyl radical represented by Ry R” or R in the foregoing formula can he a carboxylic acyl or a sulfonic acyl.

The carboxylic acyl is an acyl radical derived from a carboxylic acid, which can be a monocarboxylic or polycarboxylic acid, and a satnrated or unsatu- rated cnrboxylic acid.

As the monocarboxylic acid radical, a sotn- rated or unsaturated acyl radical containing 1 to 20 carbon atoms (such as formyl, acetyl, propionyl butyryl, isobutyryl, valeryl, isovaleryl, hexmnmoyl, pivaloyl, lauroyl, myristoyl, palmitoyl, stenroyl, ’ acryloyl, propioloyl, methacryloyl etc.) or an aryl carboxylic acid radical are preferred. The aryl car-— boxylic acid include bennene carboxylic acid, naph~ thalene carboxylic acid nnd the like.

As the polycarboxylic acyl radical, a dicar- boxylic acyl radical, which can be a saturated or unsaturated acyl radical containing 2 to 6 carbon atoms, which may optionally be esterified, such an oxalo, carboxyacetyl, 3-carhoxyrropionyl, c¢is-3- } carboxy acryloyl, trans=S-carbovyacryloyl, cis-methyl~— 3-carboxyacryloyl, etc, ore preferred.

The sulfonic acyl is an acyl radical derived from a sulfonic acid, represented for example by the general formula rs, - wherein ptt stands for an alkyl, aryl or aralkyl radical. The alkyl radical preferably contains for example 1 to 6 carbon atoms, and may be linear or branched. DIxamples of the al- kyl radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. bxamples of the aryl radical include phenyl and naphthyl. The aryl radical may have a substituent and examples of said substituent include a lower alkyl radical (such as methyl), a lower al- . 5 koxy radical (such as methoxy), a halogen aton (such as. fluorine, chlorine, and bromine), a nitro radical, a carboxy radical, etc.

An example of said aralkyl in 2-phenethyl.

The phosphorous acyl is an acyl radical derived from phosphorous acid, represented, for example, by the general formula \ #1 50p-

I

) wherein gto stands for a hydrogen atom, an alkyl, aryl or aralkyl radical. The alkyl radical prefere . 15 ably contains for example, 1 to 6 carbon atoms and can be linear or branched. Examples of the alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Examples of the aryl radical include phe=- 120 nyl, tolyl and naphthyl.

The aralkyl radical can be an aryl alkyl radical, wherein the aryl can be the above-men-— tioned aryl, while the alkyl preferably contains 1 to 3 carbon atoms, and there can be mentioned, for example, methyl, ethyl or propyl.

The phosphoric acyl is an acyl radical de- rived from phosphoric acid, represented, for exnmple, by a general formula (r*%0) ro- wherein RL has the same meaning as Rr, The substituent in the acyl radical which may be substituted, represented hy wt,

R°, Rr and Rr’, can be, for example, a halogen atom, an alkoxy or alkylthio radical. lxamples of the halogen atoms are chlorine, bromine, fluorine and iodine. is the alkoxy radical, there can be mentioned, ’ 15 radicals containing 1 to 4 carbon atoms, such as me- thoxy, ethoxy, propoxy and butoxye

As the alkylthio radical, there can be men- tioned radicals containing, 1 to li carbon ntoms, such as, methylthio, ethylthio, propylthio, isopro- pylthio, butylthio, irobutylthio, sec-butylthio and tert-butylthio.

The lower carboxylic acyl radicnl represented by g® in the foregoing formula can be a monacarboxy- rd lic acyl or polycarboxylic acyl radical containing 1 to 6 carbon atoms, such as, formyl, acetyl, pro-

: pionyl, butyryl isobutyryl, valeryl, isovaleryl, hexanoyl, oxalo, carboxyacetyl or 3-carboxypro- pionyl,

In the foregoing formula, the alkyl radical in the alkyl radical which may be substituted, re= presented by r°, R%, R or Rr’, preferably contains 1 to 3 carbon atoms, and can be linear or branched. } Examples of the alkyl radicals include methyl, ethyl, } propyl and isopropyl. The gnbstituent is preferably an alkoxy radical containing 1 to 3 carbon atoms or an alkoxyalkoxy radical containing 2 to 6 carbon atoms and examples of the alkoxy radicals include methoxy, ethoxy and propoxy, while examples of the alkoxyalkoxy radicals include methoxyethoxy, methoxy-— propoxyy methoxybutoxy, methoxypentyloxy, ethoxy- : ethoxy, ethoxypropoxy, ethoxybutoxy and propoXypro- . Co pPOXYe

In the foregoing formula, the alkyl radical which is represented by g® and may have an alkylthio ; 20 substituent can be methyl. The alkylthio as the substituent may include a radical represented by } the general formula - 217 : wherein R is a lower alkyl radical. The lower al-

kyl radical preferably contains 1 to 3 carbon atoms, such as methyl, ethyl or propyl.

In the foregoing formula, the ~1kyl radical represented by gS may contain 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, and examples thereof include methyl, ethyl and propyl.

In the foregoing formula, the aryl radical represented by i? is, for example, phenyl, tolyl or naphthyl.

In the foregoing formnls, the alkyl radical containing 1 tn 6 carbon atoms, represented by R2 and R10, can be linear or branched, and examples thereof inclivle methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl., Among these preferrad is a linear or . branched radical containing 1 to 3 carbon atoms, such as methyl, ethyl, propyl or isopropyl.

In the foregoing formula, the carbon chain represented by Rr? and gC for forming a cyclic al- . 20 kyl together with the carbon atom in the acetal bond may have 4 to 5 carbon atoms, including tetramethylene, . pentamecthylene, etc in the foregoing formula, the aryl radical represented by rR? and 10 is, for example, phenyl, tolyl or naphthyl.

In the foregoing formula, the dialkylamino radical represented by r’ and 10 is represented by the general formula a2?) wherein at ntands for a lower alkyl radical. The lower alkyl radical may contain 1 to 3 carbon atoms, such ns methyl, ethyl : or propyl.

In the foregoing formula, the lower alkyl radical represented by rR” or RY contains preferably 7 1 to 6 carbon atoms and examples thereof include me-= ’ 10 thyl, ethyl, propyl, isopropyl butyl, isobutyl, sec= . butyl, pentyl, isopentyl and hexyle

As to Rr? in the foregoing formula, the lower alkyl radical represented by R® or rf which may have substituents contains preferably 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyly isopropyl, butyl, isobutyl, pentyl and hexyl. - In the foregoing formula, substituted or unsubstituted cycloalkyl represented by RP, r® or af may contain 3 to 7 carbon atoms, and examples there— of include cyclpropyl, cyclobutyl, cyclopentyl, cy~ clohexyl, cycloheptyls preferably those having 4 to 6 carbon atoms, namely cyclobutyly cyclopentyl and cyclohexyls

The lower alkenyl radical which may be substi=- tuted, represented by r® or rf, contains preferably

2 to 6 carbon atoms, and examples thereof inclnde : vinyl, allyl, 2-butenyl, methylallyl, 3-butenyl, 2- pentenyl, h-pentenyl, and S-hexenyle : The lower alkynyl radical which may be substi- : 5 tuted, represented by R® or rf, contains preferably to 6 carbon ntoms, and examples thereof include ethy- : nyl, propargyl, 2-butyn-1-yl, 3-putyn-l-yl, Z=-butyne 2~yl, 1-pentyn-3-y1, 3-pentym-1yl, hopentyn-2-yl, and } 3-hexyn-1-yle , 10 The substituents in the foregoing alkyl, cyselo=- ) alkyl, alkenyl and alkynyl radicals, pach of which may be substituted, include, for example, hydroxyl, 05 _g-eyolontkyly Cooro™TY Le Cyl LKOXY Cy _jyalkoxy=

C,_zmalkyls Cy _goy ol onlkyloxys Cp? TYLOXY Choro” aralkyloxy, Cy _jyikylthios C5 _gosoloatkylthios Ce 10” arylthio, C,_yprratkylthios amino, monoCy _jalkylamino, di-C,_jnlkylamino, C5_govelralkylamino, Cg10PTYY~ } amino, C,_yprralkylamines azido, nitro, halogen, } cyano, carboxy C, _yrlkoxycarbonyl, Cy oPryLioxy— carbonyl, C5_geyelonlkyloxyearbonyty C,)_ppRralkyloxy= carbonyl (CO in these carbonyl groups may be aceta- lyzed) Cy _gatkanoyly formyloxy, Cc, _yalkyloulfinyl,

Cg_qooryloviinyly c, jalkylsulfonyl, CgyoFyleul- fonyl, C, y5atkanoyloxys sul fo, carbamoyly carbamoyl which may be substituted, carbamoyloxy, carbamoyloxy which may be substituted, formylamino, Cc, _ylkanoyl= : amino, Cy of tyloarbonylanine, Cy _jalkoxycarbonyl- amino, Cy peralkyloxycarbonylanine, OX0y EPOXY, thioxo, culfonamido, heterocyclic radical, hetevo- ' 5 cyclic thio, heterocyclic carbonylamino, heterocyclic oxy, heterocyclic amino, Cy _palkoxyearboxycarbenyloxy,

C,._yalkylsulfonyloxy, Cg _ppRTylsulfonyloxy, sul fo- . amino, sulfamoylamino, ureido, and silylexy.

The alkyl having cycloalkyl aryl, Cy _yPlkyl and the alkyl having a group containing heterocyclic radical, which may substitute to alkyl, alkenyl al- kynyl or cycloalkyl mentioned above, may have fur- : ther substituents. Examples of such substituents are hydroxy, C,_yalkyl (which may have substituents, and the substituent in this case is the same as the snbs- tituents in the alkyl as described above; the radical containing C,_y2kyl as hereinafter mentioned may also have the same substituent), Cy alkoxy Cy y~ alkylthio, amino, C,_palkylamino, di(c,_jalkylomino,

Cg 102Tylamino, azido, nitro, halogen, oxo, Cyano, carboxy, Ci alkoxycarbonyl, CgqgTyloxycarbonyl,

Cy.galkanoyl, Cy .gnlkanoyloxy, sulfo, carbamoyl, substituted carbamoyl, carbhamoyloXy , C,_yalkanoyl- amino, ¢, yalkoxycarbonylamino and sulfonamido.

Examples of the substituent in the foregoing aryl and heterocyclic radicals which may substi~- tuted include hydroxy, Cy ytd Cgo10™TY Cs 6” cycloalkyl, halogen, carboxy, sulfn, Cy _ylkoxys

Cc, _rlEyLthics nitro, ¢, _jynlkoxycarbonyly amino, monoC, _,alkylamines di-C) _jalkylamino, Cy _yrlkanoyl- amino, CguyoPryLoxys C,y_q Pr eLkY Le Cpp_y pray OXY

Cg ponryLaminos Cy pr alkylamines cyano, Cg try oxycarbonyl, Cy paralkyloxyonrbonyls Cy _gatkanoyle

Cy _galkanoyloxys carbamoyl, carbamoyl which may be ‘ 10 substituted, carbamoyloxy which mny be substituted, c, _ylkoxycarbonyl- amino and 0X0.

The alkyl, the radical containing Cy KYL or the aryl group which is the substituent in the foregoing aryl and heterocyclic radical which may be substituted may further have substituents, and as the substituents the same substituents as the alkyl and aryl radicals as described above may be included.

The number of the aubstituents on the fore- going respective radicals is preferably 1 to 3o ’ These substituents will be described in de- . tail below.

Examples of Cy _yalkyl radical as the substi- tuent include methyl, ethyl, propyl, isopropyly butyl, isobutyl, sec-butyl and tert-butyl.

Examples of C,_goyclonlkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclo- j hexyl. fixamples of Ce_10”TY radicals include phenyl and naphthyl. pxamples of Cy proxy radical include methoxy, ethoxy, Propoxys isopropoxy, butoxy and tert-butoxy. fxamples of C,_goycloalkyloxy radicals include cyclopropyloxy, cyclopentyloxy and cyclohexyloxye

Examples of Cg qoryloxy radicals include phenoxy and naphtyloxye.

Lxamples of Cp pra tkyloxy radical include benzyloXy, ?-phenethyloxy and l-phenethyloxye ’ gxnmples of Cy po Lkylthio radicals include methylthio, ethvlthio, propylthio and butylthio.

Exomples of o,_goyeloatkylthio radicals in-~ clude cyclopropylthio, cyclopentylthio and cyclo~ hexylthio.

Examples of Cgoyo?Tylthie radical include phenylthio and naphtyglthio. nxamples of C,_ypnratkylthio radicals in- clude benzylthioy 2-phenethylthio and 1-phenethylthio. sxamples of monoC, _,rlkylamino radicals in- clude methylamino, ethylamino, propylanino, is0- propylamino, butylamino, jsobutylamino and tert-

it butylaminoe

Examples of dig, _jalkylamine radicals in- clude dimethylamino, diethylamino, Aipropytaminn, dibutylamino, H-methyl-li~ethylamino, H-ne thyl-n-= propylamino and N-methyl-N-butylamino. pxamples of G,_geyelonthkylaning radicals in=- : clude cyclopropylamino, cyvelobutylamino, cyclopentyl- amino and cyclohexylamino. ixnmples of Cgoypnrylomine radicals include anilino and the like.

Examnles of G,_pprrntkylamine radicals include benrzylamino, 2-phenethylamino and 1-phenethylamino. mxamples of halogen atoms include fluorine, . chlorine, bromine and iodine. sxampler of Oy alkoxycarbonyl radicals in- clude ma thoxycarbonyl, ethoxycarbonyl, propoxycir= bonyl, isopropoxycarbonyl, putoxy carbonyls tert- butoxycarbonyl and isobutoxycarbonyle

Example of Cg_qoaryLoxyonrbonst radicals include phenoxycarbonyl and the like.

Examples of G4_geycloaliyloxyearbonyl radi-

Lo cals include cyclopropyloxycarbonyl, cyclobntylo<y= carbonyl, cyslopantyloxyearhonyl and cychohexyloxy-— carbonyl.

Examples of C,_gparalkyloxyearbonyl radicals

. include benzyloxycarbonyl, l-phenetyloxycarbonyl and 2- phenetyloxycarbonyl.

Examples of C, —galkanoyl radicals include formyl, ' acetyl, propionyl, butyryl and pivaloyl. ‘ Examples of C, _gelkenoyloxy radicals include for- myloxy, acetoxy, butyryloxy, plvaloyloxy, pentanoyloxy, hexenoyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy, de- canoyloxy, undecanoyloxy, dodecanoyloxy, tridecanoyloxy, tetradecanoyloxy snd pentadecanoyloxy.

Examples of substituted carbemoyl radicals include

N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-ethylcarba- : moyl, N,N-diethylcarbamoyl, N-phenylearbsmoyl, pyrrolidino- i carbonyl, plperidinocarbonyl, piperazinocarbonyl, morpho- linocarboryl and N-benzylcarbemoyl. ) 15 Examples of substituted carbamoyloxy radicals in- tL clude N-methylcarbemoyloxy, N, N-dimethylcarbamoyloxy, N- : ethylcarbamoyloxy, N-benzylcarbanoyloxyy N,N-dibenzylcarba- moyloxy, N-benzylcarbemoyloxy, N,N-dibenzylcarbamoyloxy and - N-phenylcarbamoyloxys

Examples of Cy —421kenoylemino radicals include for=- mylamino, acetamido, propionemido and butyrylamino.

Example of C,_,,arylcarbonylemino radicals include i benzemido and the like, - Examples of C, ~alkoxycarbornylamino radicals include methoxycarbony lamino, ethoxycarbony lamino, butoxycarbonyl-~ emino and tert-butoxycarbonylemino,

Examples of Cro aralkyloxycarbonylamino radical . include benzyloxycarbonylamino, 4-methoxybenzyloxycar- bonylamino, 4-nitrobenzylexycarbonylamino and 4-chloro- benzyloxycarbonylemino,

Exemples of sulfonamido radicals include methane- sulforylamino, ethanesulfonylemino, butanesulforylamino, benzenesulfonylemino, toluenesulfonylamino, napthalene- sulfonylemino, trifluoromethanesulfonylemino, 2-chloro- ethanesulfonylamino and 2,2,2-trifluoromethanesulfonylamino.

Heterocyclic radicals include cyclic groups contain- ing 1 to 5 nitrogen atoms, oxygen atoms, sulfur atoms and examples thereof are pyrrolidinyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isooxazolyl, iso- thiezolyl, thiazolyl, piperidinyl, pyridyl, pyridazinyl, pyrazinyl, piperadinyl, pyrimidinyl, pyranyl, tetrahydro- : pyranyl, tetrahydrofuryl, indolyl, quinolyl, 1,3,4soxadis- zolyl, thieno/?,3-d/pyridyl} 1,2,3~thiadiazolyl, 1,3,4- thiadiszolyl, 1,2,3=-triazolyl, 1,2,4-triazolyl, 1,3,4- triazolyl, tetrazolyl, 1,3-dioxoranyl, tetrazolo/1,5-h/- pyridazinyl, benzothiazolyl, benzooxazolyl, benzoimidazoryl, benzothienyl end morpholinyls »

As a heterocyclic thio, heterocyclic oxy, hetero- cyclic amino and heterocyclic carbonylamino radicals, there can be mentioned radicals having the shove heterocyclic - PD -

radicals bonded to sulfur atom, oxygen atom, nitrogen atom or carbonylamino radical, respectively.

Examples of Cy —4Alkylsulfonyloxy radicals in- clude methanesulfonoyloxy, ethanesulfonyloxy and butane- sulfonyloxy.

Examples of C_)erylsulfonyloxy radicals include benzenesulfonyloxy and toluenesulfonyloxy. r Examples of silyloxy radicals include trimethyl- ” silyloxy, t-butyldimethylsilyloxy and t-butyldiphenyl~- silyloxye. .

Examples of Cy ~42lkylsulphymyl radicals include : methylsulfinyl, ethylsulfinyl, propylsulfinyl smd butyl- sulfinyl.

Examples of Co_108¥yisulfinyl radicals include phenylsulfinyl and naphtylsulfinyl.

Examples of Cy ~48lkylsulfonyl radicals include methanesulfonyl, ethanesulfonyl end butanesulfonyl.

Examples of Ce_q0aTYy 18ulfonyl radicals include benzenesulfonyl and toluenesulfonyl,

Examples of Cy —421koxycarbonyloxy radicals include methoxycarbonyloxy, ethoxycarbonyloxy snd tert-butoxy- carbonyloxy.

Further specific examples of the foregoing res- pective radicals include chloromethyl, bromomethyl, iodo- methyl, trifluoromethyl, chloroethyl, bromoethyl, iodo=- 7

: to chloropropyl, hydroxymethyl, hydroxyethyl, hydroxypro- : pyl, 2-hydroxy-2-phenylethyl, cyclopropylmethyl, cyclo~- butylmethyl, cyclopentylmethyl, cyclohexylmethyl, 7 cyclohexylethyl, 3.chlorocyclobutylmethyl, benzyl, h-

chlorobenzyl, 4-nitrobenzyl, h-methoxybonzyl, 2,l-di- methoxybenzyl, 3, b-dimethnxybenzyl, 4-methylbenzyl, 2-

. ethoxyethyl, 2-(2,2,2~trifluoroethoxy)ethyl, methoxymethyl,

: 2,2-dimethoxyethyl, 2,2-diethoxyethyl, cyclopropylmethoxy- - methyl, cyclobutylmethoxymethyl, 2-cyclopropylmethoxyethyl, ‘ 10 2-cyclobutylmethoxyethyl, 2-benzyloxyethyl, Z~benzyloxy=-

‘ propyl, 2-phanoxyethyl, 2-(2-phenethoxy)ethyl, 3-phenyl- propyl, methylthiomethyl, 2-methylthioethyl, 2-phenyl= thioethyl, 2-benzylthioethyl, 2-butylthioethyl, cyclohexyl- thiomethyl, 2-(l-pyridylthio)ethyl, aminomethyl, amino-

ethyl, 2-methylaminoethyl, 2-tert-butylaminoethyl, 2-dime= : thylaminocethyl, z-dimethylaminopropyl, 2-cyclohexylamino~ ethyl, 2-henzylaminoethyl, 2-azidoethyl, nitromethyl, 2- nitroethyl, cyanomethyl, 2-cyanoethyl, li-cyanobutyl, car- boxymethyl, 2-carboxyethyl, ethoxycarbonylmethyl, phenoxy- carbonylmethyl, cyclopentyloxycarbonylmethyl, acetylmethyl, penzoylmethyl, 4-chlorobenzoylmethyl, 3-(L4-bromobenzoyl)~ propyl, 3-methoxybenzoylmethyl, 2-formyloxyethyl, 2-methyl- sulfinylethyl, 2-phenylsulfinylethyl, 2-methylsulfonylethyl, 3-phenylsulfonylpropyl, 2-acetoxyethyl, heacetoxybutyl, ~ 2h ~ .

pivaloyloxymethyl, 3-sulfopropyl, carbamoylmethyl, 3-~ earbamoylpropyl, pyrrolidinocarbonylmethyl, 2-(N-ethyl- benzylemino Jethyl, 2-(2~-oxopyrrolidine ethyl, 2-formyl- eminoethyl, 3-formylaminopropyl, 3-trifluoroscetamido-

Co 5 propyl, 2-benzamidoethyl, 3-tert-butoxycarbonylaminopro- pyl, benzyloxycarbonylaminopropyl, 2,3-epoxypropyl, 2- . thioacetamidoethyl, 3-sulfosminopropyl, 2-(1, 3-d1oxoran- 2-y1)ethyl, 2-, 3-, A-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-pyridyl propyl, furfulyl, 3-(2-furyl)allyl, 3-(2- furyl)propyl, 2-(2-pyranyloxy)ethyl, 2-(3-indolyl)ethyl, 3-(1-4indolyl)-propyl, 3-(2-benzimidazolyl)propyl, 2-mor=- : pholinoethyl, (3-isoxazolyl)methyl, 2-(2-pyridylthio)- ethyl, 2-(2-benzthiazolyl )ethyl, 2-(2-pyrimidinylthio )~- ethyl, 2-(2-aminoethylthio)ethyl, 2-isonicotinoylemino- ethyl, 2-thenoylaminoethyl, 2-furoylaminoethyl, 2-(tert= butoxycarbonyloxy Jethyl, 3-(tert-butoxycarbonyloxy)propyl, o-methylsulfonyloxyethyl, 2-(p-toluenesulfonyloxy Jethyl, 2-tert-butytdimethylsilyloxy ethyl, sulfosminomethyl, 2- (sulfoaminoethyl, ureidomethyl, 2-ureidoethyl, sulfemoyl- aminanethyl, 2-sulfemoyleminoethyl and (2-methoxyethoxy)- methyl,

Examples of more preferable substituents in the . lower alkyl, cycloalkyl, lower alkenyl end lower alkynyl ‘ radicals which may be substituted include halogen atoms (such as chlorine, bromine, iodine and fluorine), lower alkoxy groups having 1 to 4 carbon atoms (such as me- thoxy, ethoxy, propoXy, isopropoxy, and butoxy), lower alkylthio radicals having 1 to I, carbon atoms (such as methylthio, ethylthio, propylthio, and butylthio), aryl radicals (such as phenyl, tolyl, naphthyl, etc.)y hy- droxy radical, alkoxycarbonyloxy radicals (such as tert- butoxycarbonyloxy), aralkyloxycarbonyloxy radicals (such as benzyloxycarbonyloxy), amino, substituted amino radi- cals (such as dimethylamino, and diethylamino}, hetero- : 10 cyclic radicals (cyclic amino) (rvuch as morpholino, pi- peridino, pyrrolidino, and p-oxypyrrolidinon), acyloxy radicals 1 to 3 carbon atoms (such as formyloxy acetoxy and triflucroacetoxy), acylamino radicals having 1 to 3 carbon atoms (such as acetamido, and trifluoroacet- amido), carboxy, lower (Cy) alkoxycarbonyl radicals (such as me thoxycarbonyl, ethoxycarbonyl, and butoxy- carbonyl), carbamoyl, substituted carbamoyl radicals (such as dimethylcarbamoyl and diethylcarbamoyl), sulfo and others. .

In the foregoing formula, as the carbon chain represented by RP and RC or rd and R® for forming a nitrogen containing cyclic alkylamino together with the nitrogen atom on the Zt.position, those have 3 to 6 carbon atoms such as trimethylene, tetramethylene, pen= tamethylens, and hexamethylene are included. } In the foreghing formula, examples of the anions represented by X- include halogen ions (such as iodide ion, bromo ion and chloro jon), sulfate ion, phosphate ion, nitrate ion, methanesulfate ion, p-~tolylsulfate ) ion, benzenesulfate ion, hydroxyl ion and organic car- . boxylate ion (such as oxalate ion, maleate ion, fumarate 10m, succinate ion, citrate jon, lactate ion, trifluoro- acetate ion, lactobionate ion, acetate ion, propinate ion and ethylsuééinate ion),

In the compound (1) of the present invention, it is preferable that gr? is a hydrogen atom; rR: is a hydrogen atom or an alkyl carboxylic acyl radical having 1 to 5 carbon atoms; Rr’ is a hydrogen atom, sn alkyl carboxylic acyl radical having 1 to 5 carbon atoms, =n alkyl sulfonic acyl radical having 1 to 5 carbon atoms; or an alkylthio- methyl radical having 1 to 5 carbon atoms; rR is a methyl radical; ®t is a hydrogen atom; Z is the formula

C aR wherein each of Rr and g® is a hydrogen atom, an alkyl carboxylic acyl radical having 1 to 5 carbon atoms or an : 20 alkyl sulfonic acyl radicel having 1 to 5 carbon atoms, or rR and r® from

CH

~ NN / 3 =o D=s “s=0 B—m or OC pL ? ’ J / J NN

CH

3 as Yj; each of re and R® 1s an slkyl radical having 1 to 3 carbon atoms, or rl and R® form a cyclic alkyl radicals rt is an unsubstituted or substituted alkyl radical have ing 1 to 5 carbon atoms, an alkenyl or alkynyl radical 2 to 6 carbon atoms.

It is further preferable that at least one of R’ and r® is an alkyl carboxylic acyl or alkylthiomethyl radical, each of which has 1 to 5 carbon atoms, or Y is

CH, \ \ N73 \=s, $220, B--Ph oT ¢ , / ss / / \

CH

3 when re and R® are alkyl radicals having 1 to 3 carbon atoms and form a tertiary smino radical as R%, and each of rR and Rr is an hydrogen atom or an alkyl carboxylic acyl having 1 to 5 carbon atoms, Furthermore, at least one of Rr and re is preferably an alkyl carboxylic acyl radical having 1 to 5 carbon atoms, an allkylthiomethyl : radical having 1 to 5 carbon atoms or an alkyl sulfonic acyl radical having 1 to 5 carbon atoms, or Y is prefer- ably ~ CH \ \ \ NN 3 s 20 J=5, S=0, B~ph or ¢ , s 7 ZN , ot . - pg -

when Rt is a carboxylic acyl radical having 1 to 5 carbon atoms and BR is a hydrogen atom. when RY is a quaternary ammonium salt, it is preferable that both Rr? and r® are hydrogen, or at least one of Rr’ and r® ig an alkyl acyl radical have ing 1 to 5 carbon atoms or an alkyl sulfonic acyl radical.

In the compound (1) of the present invention,

R® is preferable to be a quaternary ammonium salt.

Particularly, it is preferably that 4 and R® form together with adjacent nitrogen Atom a cyclic alkyl- amino radical of 5 to 7 members such as pyrrolidine, piperidine, hexamethyleneimine and the like, or both : | rd and R® areuvalkyl radicals having 1 to 5 carbon atoms and rf is an alkyl radical having 1 to 5 car=- : bon atoms, an alkenyl or alkynyl radical having 2 to i Co § carbon atoms. When they have a substituent, it is . N particularly preferable to be hydroxy, carboxy, Cyn alkoxycarbonyl, halogen, cyano, 0, _g-cycloalkyl and : 20 so on. As X of the quaternary ammonium salt, there are preferably mentioned chlorine, bromine and iodine. } The compound (1) of the present invention can be prepared according to the following method. . A compound which may be protected, represented by the following formula, is reacted with an acylat— ing, alkylating, boronating, carbonating, sulfinylating or ketalizing agent, followed by the removal of pro- : tection, if necessary, whereby the compound [I7 con be prepared:

HO 2

At 0 ~ CH : 3

CH

3 3 cH, 3 - 4 OR cH CHR 3 | 2 Cli 0 oT of

CH

3 wherein RB and R® have the seme meanings as defined above,

A! represents the formula: aL ai

R

CH cu_—| © 3 3 / b . 7 12 a3 (wherein 2" represent the formula

Cl 7 124 ary oH oH or the formula

NIL 12 CH 7 HO have the same meanings as defined above) or the formila:

CH

3

CH CH

3 3

HO _ T 0 ci, J 3

A compound represented by the following formula or its shlt

CH

3 - o rlo R® £37 ~ 0 cH cH 2 3N1o 3 0 / HoTE NL cn ’ ZN 3 13 CH ong) 3 ~ 3 oo OR: h cil hd HR cn 0 3

Ire 2 4h OR” 0

Cliz wherein rt, ®, R, 2? anda R® have the same meanings, 741" represents the formula

HHL CH

5 6 2

OR OR

J

(wherein R’ and r® have the same meanings as defined above), the formula : 2 oo un 1 oy

Ls pa

OR H

(vherein R' has the same meaning as defined above) or the formula ‘ : an : y pd (wherein Y has the same meaning es defined above), is } treated under a cyclic condition, whereby a compound or ite salt, represented by the following formula, can be : 10 prepared; . H cn, CH °K 2 3 10 0. 3 0 / 6 ~Len one 3 13 CH or> cus” 2 CH en, Rr" ’

CH ' 3 2 lp OR® 0

CH

3 / i wherein RY, rR’, Rr, r*, R® and R"'have the same mean- ings as defined above,

The compound /1_/ can be prepared by subjecting a compound represented by the following formula to N- i 5 alkylation, N~alkenylation or N-alkynylation reactiolN;

R'o_ rR? £7 :

H,C 3 5 3 : 0

Z NL CH

3 on, City 3 ° OR

OC

Cli v

CH, R LL cil, (Ny 2 0 OR

CH

3 i 2 3 4 wherein Ay Ry R"y R” and R™ have the same meanings as defined above, R® represents -H-R® (wherein RP) has the pame meaning as defined above) or the formila d

R pe

TC i R® pd (wherein RY and R® have the same meanings as defined above ).

The compound AT can be prepared by subjecting : the compound 7 to a already known reaction, namely by ! reacting with an acylating, alkylating, boronating, car- bonating, sulfinylating or ketalyzing agent, followed by the removal of protection, if necessary.

The acylating agent employable in the acylation is a reactive derivative of a carboxylic acid capable of in- troducing a carboxylic acid radical, such as an gcid halide, an acid enhydride, an smide compound, an active ester or €. an active thioester, Examples of such reactive deriva- tives are as follows: (1) Acid halide

Examples of such acid halides are acid chloride and acid bromide. (2) Acid anhydride } Examples of such acid anhydrides include mixed an- hydrides of monoalkyl carbonic acid, mixed anhydrides of aliphatic carboxylic acide such as acetic acid, pivalie acid, valeric acid, isovaleric acid, trichloroacetic acid etec,, mixed anhydrides of aromatic carboxylic acids such as benzoic acid, and symmetric acid anhydride. (3) Amide compound

An examples of such anide compounds, there can be ee —————— CL ————— ee eer eee errr used compounds wherein an acyl radical is bonded to a nitrogen stom in a ring, such as a pyrazole, imidazole, 4-subptituted imidazole, dimethylpyrazole or benzotri- azole. . 5 (4) Active ester

Examples of such active esters include methyl ester, ethyl ester, methoxymethyl ester, propargyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, trichloro- phenyl ester, pentachlorophenyl ester, mesylphenyl ester, and esters with l-hydroxy-lH-2-pyridone, N-hydroxysuceinin. mide. or N-hydroxyphthalimide. (5) Active thioester .

Examples of such active thioesters include thio- esters with heterocyclic thiols such as 2-pyridylthio or 2-benzothiazolylthiod, : The above-mentioned reactive derivatives sre suit- ably selected according to the kind of the carboxylic . acid.

In case a reactive derivative of a polycarboxylic acid is employed es the acylating agent, carboxyl radi- ‘ cals, except one, are preferably protected in the form of esters,

The acylating egent can also be a reactive deri- vative of a sulfonic acid capable of introducing a sul- ~ 25 fornic acyl radical, for example an acid halide such as

\ methanesulfonyl chloride, benzylsulfonyl chloride or or paratoluene sulfonyl chloride, or a symmetric acid anhydride such as methane sulfonic anhydride or para- toluene sulfonic anhydride.

In the alkylation, the alkylating employable for the alkylation at the 4"- or ll-position can for example be a corresponding alkyl halide (for exnmple chloride, bromide or iodide), and that employable for the alkylation at the 12- position can for example be dimethyl sulfoxide.

Example of the boronating agents employable in the boronation reaction are alkylboric acids (such as ethyl-boric acid) and arylboric acids (such as phenyl- boric acid).

Examples of the carbonating agents employable in the carbonation reaction are ethylene carbonate, carbonyl diimidazole and thiocarbonyl diimidazole.

Examples of the sulfinylating agents employable in the sulfinylation reaction is ethylene sulfite.

Bxamples of the ketalyzing agents employable in the ketalyzation reaction are 2-methoxypropane, 2,2- dimethoxypropane, lyl-dimethoxycyclohexane, NyN-dime~ : thylformamide dimethylacetal, and N,H-dimethylaceta— mide dimethylacetal.

In case of amploying a reactive derivative of a carboxylic acid as the acylating agent in the acylation re- action, the amount of said acylating agent varies according - 36 ~

SR

Ce ———————————— ————————— to the mumber of acyl radicals to be introduced.

The solvent to be employed in the acylatiom is not limited as along as it does not react with the acylat- ing egent, but is preferably dichloromethane, ether, py=- ridine, chloroform or the like, Exsmples of bases are , tertiary amines such as triethylamine, diisopropylethyl=- anine and tribenzylemine, end inorganic salts such es potassium carbonate, The reaction temperature is about 0°c. to 80°C.,, end the reaction time is about 10 mimtes to 2 weeks,

In case of employing a reactive derivative of a sul~ fonic acld as the acylating agent in the acylation reaction, the amount of the acylating agent varies according to the mmber of acyl radicals to be introduced,

Examples of the solvents to be employed in the acyla— . tion are pyridine, chlorefory, ether amd dichloromethane,

Exemples of the bases are tertiary amines such as pyridine, tribenzylemine and diisopropylethylamine. The reaction tem- perature is about 0°C, to 50°C., end the reaction time is } 20 about 10 minutes to 2 days.

The amount of alkylating agent in the alkylation reaction varies according to the mumber of alkyl radicals to be introduced.

Examples of the solvents to be employed in the gl~ kylation reaction are chloroform, dimethyl sulfoxide, di-

methyl formamide, ether and ethamol. The reaction tem- perature is about 0%c. to 80°C. , and the reaction time 418 about 15 mimtes to 1 week, Examples of the base to be employed in the alkylation at the 4" - or 11- position are tertiary amines such as diisopropylethyl- amine or pyridine, sodium hydride snd potassium hydride.

In the boronation reaction, the boronating agent is preferably employed in an equivalent amount or in ex- ) cess (2°~ 3 times in molar ratio), Examples of the sol~ vents to be employed in the boronation reaction are ben- zene, toluene and ether. The reaction temperature is about 80°C. to 130°C., end the reaction time is about 1 hour to % hours.

In the carbonation reaction, the carbonating agent is preferably employed in a 2.10 times excess emount, in moler ratio, according to the kind thereof, Examples of the solvent to be employed in the carbonation reaction are benzene and toluene, The reaction temperature is about 25°C. to 130°C., end the resction time 1s about 30 mimites to 1 days.

In cage of employing ethylene carbonate as the car- bonating sgent in the carbonation reaction, the base to be employed can be an inorganic salt such as potassium car- ~ bonatee

In the sulfinylation reaction, the sulfinylating ee ——————————— er errs agent is preferably employed in a small excess (2-3 times in moler ratio). Examples of the solvents to be employed in the sulfinylation are methanol and ethanol,

The reaction temperature is about 20°¢c, to 30%. , and the reaction time is about 2 days to 3 days. The base to be employed in said sulfinylation cen be an inorganic salt such as potassium carbonate.

The ketalization reaction should preferably be car- ried out sccording to the ketal exchange reaction by us- ing the compound of the corresponding formulae rR OR RO rR r10 OR r0 (wherein rR and rH have the smme meanings as defined above, R represents a lower alkyl radical such as methyl, ethyl) as the ketalyzing agent, As the reaction solvent . B 15 there can be employed halogenated hydrocarbons such ag chloroform, ethers such as tetrahydrofuran, snd amides such as dimethylformamide, and it is also possible to use the ketalyzing agent itself os the solvent. Although the ketalating agent may be used usually in slight excess (about 2 times mols) to a great excess (about 100 times mols )y but the amount is preferably 2 to 4 times excess in the case of the latter ketalyzing agent. As the catalyst a strong acid salt of pyridine (such as pyridinium chlo- ride), etc.s is preferably used. Particularly in the case of the present compound, the combination of the latter ketalyzing sgent and pyridinium chloride is preferred,

The reaction may be conducted preferably at a temperature of oc. to the boiling point of the solvent, more prefer- ably at around room temperature (about 15%. to 25° ¢.).

The reaction time may be fram several hours to 72 hours, usually about 12 to 24 hours.

In the above-mentioned reactions of the compound [27 which may be protected, the order of reactivity of hydroxyl radicals on the 2"~, 4"-, 11= and 12- positions is 21) av 1 11)) 120

In the following there are explained the cases of . introducing a carboxylic acyl radicals In case of acyla- tion at the 2'-position only, a chloroform solution of the compound /2_/ is egitated with an acylating agent in a small excess (about 2 times in molar ratio) and a base in ’ a small excess (about 3 times in molar ratio). The re~ action is completed in a short time at room temperature, and the desired compound is obtained by purification by silica gel chromatography. ) In case of acylation at the 4"- position only, a com- pound subjected to the acetylation at the 2'-position as explained above is agitated with an acylating sgent and a base in large excess for 15 mimites to overnight at room temperature, then treated in the usual mammer end purified by silica gel chromatography to obtain a 2'-0- : acetyl-4'~0-acylated compound. - The desired compound ) 5 is obtained by allowing a methanolic solution of the oo above-mentioned compound to stand for 1 to 2 days at room temperature, and distilling off methanol under a reduced pressure, followed by purification by silica gel : chromatography.

Re 10 In case of acylation at the 11- position only, a - 2'_0-gcetyl=4"-formylated campound obtained in the above~ explained manner is agitated with large excesses of an

Co - acylating agent and a base for several hours to several : days at room temperature to about 70°C. to obtain a 2'~ - 15 O-acetyl~4"-formyl-l1l-acylated compound, which is then . . : heated under reflux for about 3 hours to 3 days in methanol a : to obtain the desired compound. : In case of acylation at the 12-position only, a

Co 21=0~acetylated compound obtained in the above~explained oe 20 manner 18 agitated overnight with trimethylchlorosilame and tribenzylamine and treated in the usual manner to ob- tain a 2'-O-acetyl-1ll, 4"-d1-0O-silylated compound, A di- . chloroethane solution of the compound is agitated with large excesses of en acylating agent amd a base for two deys at 75 ~ 80° C. to obtain a 2'-O-acetyl-11, 4"-di-0-

s811y1-12~-0~acylated compound, which is treated in the } usuel manner end subjected to methenolysis to obtain the

CL desired compound, in In the following, there will explained the case of introducing an alkyl radical, In case of alkylation at the 4"-position only, a compound of which the 2'~position is acetylated in the above-explained manner is dissolved

Lo in dichloromethane, added with an alkylating agent and a base under cooling with ice, and is let to stand for 30 mimites at room temperature to obtain a 2'-0O-acetyl-4"-0- alkylated compound. This compound is dissolved in metha- i nol, then is let to stand for one day at room temperature, and the reaction solution is concentrated under a reduced pressure and is purified by silica gel chromatography to obtain the desired compound, : In case of alkylation at the 1l-position only, the : compound 27 is reacted with excessive amounts of benzyl- oxycerbonyl chloride and sodium hydrogen carbonate, amd 5% CL the 3'~dimethylemino radical are protected by, in the lat- oo 20 ter case, by methyl radical of it by the acyl. It is then dissolved in dimethylformemide and reacted with =n alkylat=- oo ing agent and a base under cooking with ice. The product } is then dissolved in water and ethamol, then subjected to hydrogenolysis in the presence of a palladium—-carbon cata- lyst, and hydrogenated in the presence of formaldehyde to

: obtain the desired compound. : In case of alkylation at the 12-position only, a . compound, of which the 2'-, 4"- and ll-position are i acetylated in the above-explained manner, is dissolved in dimethyl sulfoxide and is let to stand, with a large excess of acetic anhydride, for 96 hours to 1 week at oo room temperature, The reaction solution is then concen~ . trated under a reduced pressure, and purified by silica

Lo gel chromatography, and the obtained compound is dissolved . 10 in methanol and heated with lithium hydroxide at 50° C. for 4 hours to obtain the desired compound.

Preferred examples of the protecting radicals are } acetyl for the 2'-position, formyl and silyl for the 4'- ) position, ond acetyl and silyl for the 1l-position.

A compound [27 having a protective radicals can be

CL prepsred in processes similar to that explained above, : If thus prepared compound 7 has a protective - ) radicals, they may be removed if necessary. The removal - of the protective radical can be suitably achieved in the usual monner, for example, by a method using a base (al- oo kaline hydrolysis), a method using hydrazine or a re- . | duction method, according to the kind of the protective

Bp radicals, In the method using a base, there can be em- : ployed, depending on the kind of the protective radicals and other conditions, for example, a hydroxide of an slka~

Lo line metal such as sodium, potassium or lithium or an

So alkali earth metal such as calcium or magnesium, an in- . organic base “such as a carbonate, a metal alkoxide, an organic amine, an organic base such as quaternary esm- moniwm salt, or a basic ion exchange resin. If the me- ; thod using a base is conducted in the presence of a sol=- } vent, said solvent is usually a hydrophilic organic sol- vent, water or a mixture thereof, . The reduction method is conducted, for example, in the presence of a reducing metal catalyst, depending on the kind of protective radicals and other conditions, and ) the examples of such catalyst employable in catalytic re- duction include platimm catalysts such as platimm sponge; platimm asbestos, platirmm black, platinum oxide and col- : 15 loidal platinum: palladium catalysts such as palladium sponge, palladium black, palladium oxide, palladium on barium sulfate, palladium on barium carbonate, palladium on activated carbon, colloidal palladium and palladium on

So silica gel; reduced nickel, nickel oxide, Raney nickel and . 20 Urushibara nickels The reduction method is usually con- - ducted in a solvent, which is usually composed of mm al- cohol such as methanol, ethanol, propyl alcohol or iso- propyl alcohol, or ethyl acetate, . The method using a base or the reeuction method oo 25 is usually conducted under cooling or under heating,

In the reaction in which the compound 37 is

Co treated under acidic conditions to prepare the compound } [4 7, there can be employed, for acidification, en or- oo genic acid such as acetic acid, pyridinium chloride or

Co 5 pyridinium paratoluene sulfonate, oo The reaction temperature is about 0°C. to 30°C., the reaction time is about 30 mimites to 1 hour, and the range of pH in reaction is 1 to 6, The solvent employable in the reaction is, for example, acetic acid, chldraform, di- chloromethane or ether, and the reaction is preferably : conducted under agitation, - By subjecting a compound 57 which corresponds +o oo the compound /5_/ in which R° is a formula ~NH-RP (wherein

RP is the same meaning as defined above) to N-alkylation, . y 15 N-alkenylation or N-alkynylation, a compound /1!/ which - ’ corresponds to the compound nT in which R® is the formula a ab : - -N ’

Nee - {wherein RP and RC have the same meanings as defined above) ’ can be prepared,

Co 20 The reaction is carried out by reacting a corres- : ponding ketone or aldehyde to the compound 57 under the reduction conditions, As the reduction conditions, cata-

lytic reduction can be used /see R. K. Clark Jr. and

Co M. Flyfelder, ANTIBIOTICS AND CHPMOTHERAPY, 7, 483 (1957)/. The catalyst usable therefor may be those ns described in the previous item of reductive deprotection, : S particularly preferable being palladium black, palladium, carbon, and Raney nickel. The reaction can be preferably

Ct carried out in alcohols (such ps methanol and ethanol),

LL ethers (such as tetrahydrofuran and dimethoxyethane) and aqueous mixtures thereof, In the presence of hydrogen gas, under ice cooling to about 80°, preferably around room tem- oo perature, - As the reduction condition, reduction by use of a . metal hydride may also be used, As the metal hydride so- dium borohydride, sodium cysnoborohydride are preferred, . 15 The reaction is carried out preferably in a solvent . : such as alcohols (e.g, methanol and ethanol), ethers (e.g.

Co tetrahydrofuran and dimethoxyethme), nitriles (e.g. nceto- . nitrile) and aqueous mixtures thereof, more preferably while 3 } maintaining the pH of the reaction mixture at neutral to

CL | 20 weakly acidic (pH about 3 to 6), and it is preferable for control of the pH, to add a buffer solution or mineral scid (such as hydrochloric acid ), an orgamic acid (such a8 acetic acid) or an aqueous solution thereof, rd The amount of the metal hydride used is varied, de- ’ 25 pending on the carbonyl compound used, but it is a slight

Lo - 46 -

excess over to about 100 times the theoretical amount, preferably a slight excess to about 10 times thercof, and it is added suitably with the progress of the re- action, - 5 The reaction is carried out at abort -20°C. to

Co 80%C., preferably at about 0°C. to 30° c. oo The compound a7 cm also be synthesized by allow-

So ing the compound 55 to react with, for exsmple, corres- : ponding alkyl, alkenyl or alkynyl halide, mm ester, tri- oxonium salt, etce., in the presence of a bese. : Examples of the bases include sodium hydroxide, - potassium hydroxide, sodium hydrogen carbonate, potassium - carbonate, butyl lithium phenyl lithium and sodium hy-

Lo dride.

Examples of the halogen atoms in the halide in- clude chlorine, bromine and iodine, particularly prefer- on ably iodine.

LC . Examples of the esters include a sulfate ester and the like, : 20 Typical exmmples of the trioxonium salts include : | trimethyloxonium fluoroborate, triethyloxonium fluoroborate, iE etd.

The reaction reagents are each about 1 to 100 mol equivalent, preferably about 2 to 25 mol equivalent per 1 : 25 mol of the starting compound,

Co /

’

Co Examples of the solvents to be used in the re~ 3 action include preferably halogenated hydrocarbons (such - as chloroform and dichloromethane), ethers (such as ethyl. : - ether and tetrahydrofuran), esters (such ns ethyl acetate )y alcohols (such as methanol and ethanol), ete.

The reaction is carried out under ice cooling (about 0° C.) To the hoiling point of the solvent (to about 100° ¢,), preferably at room temperature (about 15° oo to 25° ¢.) about 80°C,

The reaction time is about 2 to 48 hours.

By subjecting the above compound /1'/ to Nealkyla- - tion, N-alkenylation or N-alkymylation reaction (quarter- ; nary ammoniating reaction), a campound /1'/ which cor-

Co responds to a compound /1_/ in which R® is the forma ae nN 15 ot —r°, x

N . ) | (wherein 4, R® RT and X- have the same meaning as defined " above) can be prepared. . 3 : Examples of the reagents to be used in the reaction

Co inelude corresponding alkyl, slkenyl or alkynyl halides, i N 20 esters, trioxonium salts, etc.

To Examples of the halogen atoms in the halides in- 3 clude chlorine, bromine and iodine, particularly prefer-

Co ably iodine. : - Examples of the esters include a sulfate ester and the likes. - Typical examples of the trioxonjum salts include oe 5 trimethyloxonium fluoroborate, triethyloxonium fluoro- - borate, etc. = The reaction reagent is used in an amount of about 1 to 100 mol equivalent, preferably about 2 to 25 mol h equivalent per one mol of the sterting compound. : - 10 The solvent to be used in the reaction include, for example, halogenated hydrocarbons (such ps chloro- form and dichloromethane), ethers (such as ethyl ether and tetrahydrofuran), esters (such as ethyl acetate), al- cohols (such as methenol end ethanol), etc.

The reaction is carried out under ice cooling (about - 0° C.) to the boiling point of the solvent (about 100° C.), . ‘ preferably at roam temperature (about 15° to 25° C.) to oo about 80° C. - The reaction time is about 2 to 48 hours, : 20 The quaternization can be conducted before or after

Co the foregoing acylation reaction and the like, preferably i; thereafter,

From the reaction mixture, after carrying out op~ tionally washing with aqueous sodium carbonate, or asueous sodium chloride, drying or concentration, the product can a ~- 49 -

: . . : | JS ‘ be isolated by filtration of the precipitate formed by addition of an ether to obtain the desired products as a salt of the anion from the reagent used in quaterni-

BN Co zation, : E 5 When the reaction mixture is subjected to colum . chromatography with silica gel or ion exchange resin, us- ing, for example, a mixture of chloroform-methanol added . with conc. aqueous ammonia, a compound with hydroxide ion ) (oH-) as the anion can be obtained,

The anions of the compound thus obtained cen be . exchanged with other anions by a conventional means. - The starting compound 57 cen be prepared by

Co treating, for example, de-(N-methyl)erythromycin A or bis- [de (N-methyl) erythromycin A /E. H. Flynn, et.al., Journal of the American Chemical Society, 77, 3104 (1955), Japanese

Leid-open Patent Application No. 9129/1972/ under acidic - conditions, ol The compound [1.7 thus obtained can be isolated and - i purified in per se already known methods, for example con- oo 20 centration, pH alteration, solvent-transformation, solvent - extraction, lyophilization, crystallization, recrystalli-

CL zation, distillation, chromatography etc, : Fhe compound HJ may form a salt with an acid,

Examples of such acids include organic acids (for example, ethylsuccinic acid, glycopeptonic acid, stearic acid, pro- /

Ce pionie acid, succinic acid, lactic acid, trifluoroacetie acid, acetic acid, methemesulfonic acid, paratoluenesul- fonic acid, and benzenesulfonic ncid) and mineral acids (for example, sulfuric acid, hydrochloric acid, hydrio- dic acid, phosphoric acid, nitric acid).

The raw material for preparing the compound NJ co can be prepared, for example, by methods reported by We

Slawinsld et al., Journal of the Royal Hetherlands Chemical : Society, 94 236, 1975; V. C. Stephens ot at., Antibiotie oo 10 Annual, 1958-1959, 346; P. H, Jones et al., Journal of oC Medicinal Chemistry, 15, 631, 1972; J. Trdenier et al., : Journal of Organic Chemistry, 39, 2495, 1974; A. Bonpszek et al., Roczniki Chemi, 43 763, 1969; C. VW. Pettinga et nl., oo Journal of the American Chemical Society, 76, 569, 1954; - 15 P, Fo Wiley et nal., Journal of the American Chemienl So=- ciety, 79, 6074, 1957; J. Majer et al., Journal of the

So American Chemical Society, 99, 1620, 1977; and J, R, Martin et al., Journal of Antibioties, 35, 426, 1982 or similar - methods, or by subjecting the compounds deseribed in the

BE 20 above-mentioned references to the above-described process

Ce or the conventional known mesms, - On the other hand, the starting compounds enhydro- } ~ erythromycin A can be prepared according to the methods : reported by P. Kurath, et ale, Experientia, 27, 362 (1971),

K. Krowichki and A, Zemojski, The Journal of Antibiotics,

. rd 26, 569 (1973), whije 9-dihydroerythromyein A 6,9- . epoxide and 9-dihydroerythromycin B 6,9-epoxide can be

Co prepared according to the methods reported in Japanese ~ Laid-open Patent Application No. 1588/1974, i 5 The compound [7 or its salt has an excellent effect on stimulating the gastrointestinal contraction, a Also, no lethal case was observed vhen the compound (55) described later is orally administered to mouse at a dose of 2300 mg/kg. Accordingly, the compound /1_/ be consi- ) 10 dered to be low in toxicity.

The compound 7 shows an excellent effect for oo stimilating the gastrointestinal contraction with a low toxicity, and the preparation of the present invention } containing the compound AJ can therefore be utilized af a gastrointestinal contractive motion stimulant for the therapy of digestive malfunctions (nemses, vomiting, want of apetite in gastritis, gastric ulcer, duodenal ulcer, diseases in gallbladder and biliary tract, etc.) so in memale (mouse, rat, dog, cow, pig, mam, etc. ). oo 20 The digestive tract contractive motion stimulent of the present invention can be administered orally or non- oo orally to the above-mentioned mammals, The daily dose thereof, in case of oral administration, is ca. 0,0001- 100 mg/kg in the form of the compound AWA and, in case of non-oral administration, for example, intravenous in-

Co - 52 = jection, is ca, 0.00001-10 mg/kg. . For example, a compound (32, to be explained later, induces an extremely strong contraction in the stomach, duodemum and smell intestine in dog, by an in- travenous administration of a dose of 1.0 mg/kg. The i contractile motion is comparable to the strongest one in

Co the gastro~intestinal contraction in normal dog. Also a reduced dose in the order of 3 ug/kg induces, indtead : continuous strong contraction, a contractile motion of ‘ 10 an identical pattern with that of the natural contraction inter digestive state, a The digestive tract contractile motion stimulant : of the present invention can be formed into various pre- oo parations, containing the compound 7 and additional

BE 15 components, such as emulsion, hydrated mixture, tablet, ” ; solution, powder, pgramiles, capsule, pill etc, Said addi- n - tional components include pharmacologicelly permitted . vehicle, disintegrator, lubricant, binder, dispersant, - ” plasticizer etc, As examples of the additional components, the examples of vehicles are lactose, glucose snd white : suger; those of disintegrators are starch, sodium algi- nl nate, agar powder and carboxymethyl cellulose caleciumg ) those of lubricents are magnesium stearate, tale and

J liquid paraffin; those of binders are syrup, gelatin so~ lution, ethanol and polyvinyl alcohol; those of dispersants are methyl cellulose, ethyl cellulose and shellac; and those of plasticizers are glycerin and starch oo These preparations can be obtained by methods

Ll usually employed in the field of pharmaceuticals, . 5 The present invention will now be clarified co in further detail by reference examples and examples, oo but the present invention is not limited thereby. : PREFERRED EMBODIMENTS OF THE INVENTION

The gastrointestinal motion was measured in " 10 the following manner (7. Itoh, Nihon Heikatsu-kin - Gakkai Zasshi, 13, 33, 1976). A crossbreed adult

Co dog of a weight of 10-15 kg wasn anesthetized and the oo abdominal cavity was opened, and force transducers “ were chronically sutured on the serosa of the gastro- : 15 .intestinal tract such as gastric body, gastric antrum, a. i duodenum, jejunum, etc. in directions capable of re- cording the contraction of circular muscles. The lead wires were extracted from the back and fixed to the skin. The experiment could be started about 5 oo 20 days after recovery from such operation, and a dog : prepared in this manner can be subjected to experiments - for about 6 months. The force transducer, when sub- ‘ pd jected to a bending stress by the contraction of the gastrointestinal tract where the transducer is sutured, - - 5h = allows Lo record the wave form correnponding to the applied force, on a pen-recording oscillograph, and this method allows to measure the nature and magnitude of the contraction. © 5 The dog was maintained in an experimental

Co cage, and the wave form of contraction can be imme- oo diately recorded by connecting the wires of the transducer to the polygraph. The rastrointestinal : contractive motion can be divided, from the pattern ‘ 10 of contraction, into the one in a period after food : intake and it in an interdigestive period. The ex- . periments were conducted, during the interdigestive oo period and in an inactive period lacking the con-

Co traction in the stomach. The sample was injected through a silicone tube placed in advance in the - puperior vena cava over 10 seconds. cn The sample was dissolved in physiological

Co Co saline to a total volume of 10 ml. and was slowly oo injected intravenously for a period of ca. 10 : 20 seconds.

The gastrointestinal motor stimulating acti=- - } vity (GMSA) is summarized in Table lo

Br ———————— TU

CE Y ’ ; , . | . 2 Lhd } oo, 3 + + { + oo I { ! 3 1 n | 18) MN od ast \ | © © : . ' od = ad | i = : r = ez z s “ a | : 1 mS : wo _ ; on 8 5 “ ~ Al Tm Oo 3 o rq oO © on 0 _, } = © \ mom mom om mom om

Ed try . Oo © ~

Co jad jos] MN . © tr al . 5 oN Q : } Oo oo 0 Q 0 Sn An uD Pn : 5 o pm © i vob © wn

Fee] moon 0 mom © . o . NN ui 2 8 8 oN a

MN “vy oO Q o o me MN 0 ty 0} 5p] oO mo [1a Q nO nN MN . 9 ol jae} gon mom tr . Pom ml © tv © om oo om

Q

~ 0 . ny . : a . £y . : oy . 3

Co : 0 —— on . Hl om moomoo 3 mom oo o . oq. . Se 00

So ac ~~ ~~ ~~ ~~ ~~ ~~ : 8 —~ —~ + In Ww © Oo . 0 nn ON Hl a NY MN [@] ~ ~~ ~~ ~~ rr ~~ ~~ ~

- ’ - py - oo Hs 1 + + t + 1 : nn ™ tn a od 3 =3

Cee SI) B.D

HY \/ .o- m 1 = cs = = = : ao 3 od - 5 J id o IS on i) fee] 0 3 wo TL 0 0 £1 3 NO Mn Nn . ha t bi 3 0 v3 rd oo » 3 m > © 3s oo d o © , ° mo. ~ NC o a 1 2 i" ° | Va < SON

Oo oe

S ol 5 2, /\ : < mi 0 i o . 2 aA + O 0 : iH 2 3) 1

OL in od 0

O fr; 05 Ss] 0 oO {2° ; OO jae] wd

N B—0 : 3s a © m it te 3] mt me 28 nN : Ne << tr [31 ™ a +] jer] Ty rd Irs wi - o . ° oo 0, = ~~ ~~ ~~ ~~ ~~ ~~ g 1 0 [oy on ~~ © a Mm Ya a) nN =+ nN : 0 ~ ~ ~~ ~~ ~~ ~~

—_— —

Et } tod : } 5 + 1 + J - . co ’ I] - . . NNN

So : jaat jan] ad . D0 © . ®/ . ml = o = = = =

Q

Sn 0 } jos a [4 tre ir © jae] 0 23] o . © : = oO) / NN =~ 0 M0 n\ nN . H 03 © a Ts : je} o MD i$ ©

CL 4 mm ma 5 oO

Bi £ OO = ah oO

So o 3 oO io o 0 ™ Q vi . 1 oO X © > oo [a ~~ nN 0 ol oN ’ jae] ve vi oO Q q ™ Oo ry ry r © A 3 Mm MN nN MN m Ny nN tn a vd mn 3 t rd 0 m vy €y it © wy 3 oO © wh . 0 o —O ~ : oN LIN © ~~. D—0 Sl om om mt mm mom ~ . tr tO . 2 m : \

Ce mom ~{ : m he] in re ot ire in . © 9. . Oe : 0.0 ~~ ~~ ~~ ~~ ~~ ~~

E = ~ 0d 4 in 0 o- 0O nn nN tn nn

: i] id . 5 : $ + : t+ in @, ~ - 8] - } NNN ON Nn MN

Co CES A. -! oom om od a5 © | © © i © rn © . Nd ~~ \ o ® o/ \/ . [+] °c = : ] 1 1

Co 0 : o [ad tr ag! tm jo] @ . - 3 wo ) 0 in 3 : 0 ra EAR mn

Ma a

BE | © MO o “wy

CL fa] md = o in

CL ~~ - 2 = Q = } oC Oo nN ) ~ : tre : . "3 —0 ot

So =] le) N77 Bom my 3

Co ot hy oe o - & ! a © — md Mm

Ty id 0

Lo Wa 0 3 o =O oN = } \ om ©3 it it ue . oO oN : (EI =! . 0 IY TD

IN

2: oO

NE

. Ea) o oO . ©) [a — Jo] rv re me Ty ! - © } 53 = #

Oo ° 2, 0 ~~ ~~ ~~ ~~ [Ea oO oN 0 o nO wv) o~ - 0 ~~ ~r ~~ ~~ oo —- 59

. oo - <4 2 t t } : tS + + ‘4 tn . ry I. EY . mn : JR3] t oe et wooo ow ¥s ae ry ry ry i ry

N yd © ® : m = \ / \/ . pc = ‘5 . 1 1 ! d Mi aki ml tre tri © a } w! MY of tr nf + © pO o o © x ry 9 of M = = ov / ad [A ~~ . © i «J - OQ © nN rd + >

Co Oo 2a) le} [5 fa ae

Hl The 4 © 5 txt ot tr

Et od od © © : NN \D oi } oO — \ oO — © al re ret sed asd ir

NT

© at il [Ta meri Fy eee UY . ie] ) by : oO rod

Lo ny \0 i m™m n "he mt ire tr rt o 5. ‘ o 3 ~~ Lan fe) ~~ ~~ ~

E = 3 un [ [ol : oO o- to. o~ C- : wn ~~ ~s ~~ ~.s

BC — oo & : : I foe] OQ @®@ © ®

EY m oO mo

MIN Nn oN . MH om om © Ho : 4000 0 ©

NN 5 @/ ® o = _ J @® z = ° 3

A

. A

B: ~ xl m = ™ Hl : " MO oo , i Hoo. © mF [= nd MN 9) 3 = "9 oa 3S 0 3 AC ~ Hl oo we © oS i QO >

CL mon a) i : 3 g Hf = i 8 )

SE " Oo

E S—\ o —C fr ©

Co ~

Nn o om mo = = = . NN ry — ©) . ret [9] °° n

L hai - ~ ml mw t= = = o [« 0 |] eo] ~ ~ ~ wm g=l © ~ a o o © © x ®

°o, oo oA Hn He mo

NA ol MN Nid nN MN e+] - mE EH BE MBBS oO © 5 OV © Oo © ® ® ® “ 7 7 7 o i 1 ! » al o 3 , ’ a 4 gq nN EI he r © 3 NL 8 5 mo po wn wa = = o 3 5 } S o oO 0 2 - < oo 1 © o

Lo - 1 )

Co Oo in

Al by - m ' nn MN : = £1 iE i 5

Co - ao" ag"

C i. 0 “N m= © “@ . 4 —0O 0 o.

NY —o ~N . 0 pi is . Ha ¢

Co o oOo

UG

5 ~ 3 tn = = - E oo 3 7 > ) oo fu ~ > “a g o 4 > o he & Zz o ~ ~ ~

— — _— tL C4 , 0 } } . a 3 + © 8 in n TY

IY t= im in da Th oN oN of

Lv OO oO oO 0 oN

NN J

© 5 = = i [+] { 1 1 =z

Cg Mg : nS a od Oo a oO NY o oe] I ’ rel 3 Ie] ’ 3 « NT 3 85 Cw = ml m o ny 1 { © : — OO fa i a) Te wp ~~ m C oO : gl 5 40 5 5 :

A 0 od oo mw mm =] m oO oO \ oO © / fd Jn

LATE © —*3 " 8 ©) od : ny, Ww. Mm m m m I 1m at : ~ . - m in m m 3 . g* * ~~ . oo =

AZ ~1 ~ ~ ~ g nO ™~ © on c AD oN a on

Oo ~~ ~~’ ~~ ~ ]

< . 1 + i + : © ® oO = H © =

In nn . - fm no nN . nn

PN = wo Tey

INT © © - i ® @ @ ® w ! = ’ 1 . o { s a 8 NM 03 :

Po Lo LN le} QO 9 Oo = 0 i in m m ° FE © Ya & 1 oO MN {© 2 = AN © a Ry <2 - oN 0 ”

EH Ld 1 © Yi 1d

I$) “ (% = fs m m i . 0 — \ [@) = OQ . y 0 at 0 —_ © NL J+] je] 3 ©

Oo om ny 0 14

Am —~ ~ o [2] je x ° ; 8.

QO ~~ ~~ ~~ ~~ a, 0 o ~ oy n

B= oO Q Oo Oo 0 —- ~~ —~ ~ ] ~~ ~~ ~~’ ~r - Blt -

<¢ a Posts mw © B ® © : tH a Hl PD m © Mm © mn

NNN NON WN non

He og MH © gE MN 0B © UO © NN oD © ~~ NN \1|/ \|/ A SN 4 : ® 5 8 8 @® { « = = = = } [5 7 7 A 1 ol 3! oN 3 on ©

A dz 8 a mo I x "Heo ow

B® © bi 0 8 8&8 8 © J oO AY Q oO oO oO 1 di o ge t= o m Oo OO © + - OO

Al © Oo 17 oo 0 ge } £4 o 0

My mn - 3 3 wn - wd LN 50 0 0 MO OB iH o —0 in oS mH oO Oo 0 __O of Na. of ~ HH

O oo .m a

Ya Oy ~ ES) Es mom mom ~ m a mo ox om x §. 0 ~~ 2,0 + ~~ ~~ NSA 82 © in WwW WW oO Oo 0 ~ © oO © © HA o ~ ~ A A A at St NS NS i 1 } $ a

D oO tt By @ a’ © a’ © me ©

Mm oO m oO m 0 m 8

Mm KN MON NNN Nn nN oa Hon oo im ad oi

OO UU UU BD Ub LB LL OLLB DO @® ® @® ® < = = = = ' ~ ! 1 1 ! oN ~ 3 ° I. 0 o 3 bi B=

A © MY a 0 a NS 3d , Nn ox ay 0 mn oe] =} [+] & is 8 ro Oo — ¢ © :

Oo oO . } 1 a ; } © :

I] Jo MN @] © 1 NY ’ ’ a bd 2) < © mm 1s et [ oO - iN \O ” " 0 oO x = mo wm w= 0 oO \ o © pd 1 | 0 —0 . [554 oO a , . oo a ™ wt m mt =

Ye) } } [2] 3 . x mw 22] ml jar] o g° * 00 ~~ ~~ ~~ ~~ . B= [a oN NN Eo

La] + ~ —~ 0 [a ~~ [a] ~~ . oO ~ ~~ ~ ~~ .

‘ nN ~~ oN © fe © nN Mm oN m0 1 td 1d + i oO oO oO oO 0 oN 0 ol a=} jo] +2] 0 xd oO oO Uo oO

MN Nn nN Nn © > . id jo] xd i [2] » o 6 © Om o NN / ~

N/ ON / \N/ @® « = = = = x 1 1 1 1 ° ol

S PN m8 = oy j5e4 . oo 5 Oz

Hl od =~ MO © ° i 0 I" o el m i tw 0 oO — O © ! oN — O oO J 1 q [] 3 : m o 0 © : mn . «<2 Ch NM

Bt ad ad 3 0 -

In wd o-{ o == Y Ee] ww ml ol —_F

C N a . 1 yar 1s 0 —t w 1 oN .

OO ui a ee] m to b+ ny 0 i

Mom . ~ ~ tri 24 ml . mn 8 0 ~ ~~ ~~ ~~ 0 [ns oa <t 0 8 = —~f — 0 ol - 0 ~ —- — pu

Q ~r ~~ ~r ~r - 67 = N

+1 3 5 & . o oN oa wm HW 8 8 a 8 ® i om <W ~ Co

Ov © 0 o oN

Mon MN [\V NON om om i wd mom oO

Oo OO © oO 8 oO ° J © = = = 1 r 1 ~ . 0; © JL MO 4 wd mo = 0 0 - tg 0 orl o 8 My . +H in oO ud 0 o © od tm mt m ~ qo © g 1 oO Lo © 40 a. oO . = [ay Co ! a i " : . a © i

S Oo ~ : 1 jad == ) oO o © ~ \ 5 ba pe wm m

Ja¥ " ' 0 alo

Ny [$9] © ad © & id tn

Wav. ol : : . oN orm ~m ow jas] [e] - og Fo] xt fe] o q - © 00 ~~ ~~ ~~ : a2 fo} o <Q 8 N NM 0 ~4 — - oO ~r ~~ ~~ mete

CH i. © 3 Clg _ Cig X

I

® vi R aig (N, | 7 .

HO

~ 0 )

HO > Clty oil ty cil : OCH y 2° i © 3 0 OH ' Gil,

Compound nL

Nee Rx® GHEA (85) CH, >) -e : (86) C,H, IQ ee . (87) (CH,),CH Ie ++ 5 (88) (CH) 5Clly 10 ree : (115) CH, CH=CH, Br @ ve (116) CH, C= CH Br @ +e

J

TABLE 1"

CH CH CH

3 ’ 3

Ho oy” < CH, i ) 11 A 0 0 0 % CH j 12 3

A 1 ci ’ CH J 3 3

TG ocH “lis CH ” o 3 3 0 —ol

CH

3 - Compound Noe z GMSA *h HE 12 + : OH H CH 3 *5 N12 on + . CH 3 *6 11 12 + - \ , CH 0 3 eimai ein A Se eee ie Ae re Aa eetiAe TL. Aet rr . 5 In Tables 1, 1' and 1", ++++, +++, ++ and + of

GMSA respectively indicate that the minimum effective : concentration required for inducing a gastrointes- tinal contractive motion in dog, comparable to the spontaneous one in the interdigestive period is in a range of 0.01-0.1 pe/kes 0.1~10 pe/kes 10-30 pe/ke and 30-50 pe/kgs respectively. (*1) The numbers of compounds correspond to

: a those in the reference examples.

The process for preparing the compounds ree= presented by *2, *5 and *( is described in reference,

Cl J. Tadanier et al., Journal of Organic Chemistry 39, 2hgs, 1974,

The process for preparing the compounds re- presented by *3 is described in a reference, W. Slawvine ski et nl., Journal of the Royal Hdtherlands Chemical

Society 9%, 236, 1975. . 10 The process for preparing the compounds repre- sented by *4 is described in a reference, P. Kurath, et al., Experientia, 27, 362, 1971.

REFERENCE EXAMPLE 1 5 : 250 mg of 2t'-O-acetyl=8,9-anhydroerythromycin

A 6,9-hemiketal (compound 1) (V. C. Stephens et Al.,

Te Antibiotics Annual, 1958-1959, 346) was dissolved in . 2 ml of dry pyridine, and 0.3 ml of acetyl chloride was added at a time at room temperature and under . vigorous agitation. After agitation for 15 minutes, 20 ml of ethyl acetate was added. The obtained ethyl acetate solution was washed with the saturated aqueous solution of sodium hydrogen carbonate, then with the . saturated aqueous solution of sodium chloride, then : dried with anhydrous sodium sulfate, and the solvent } 25 was distilled off to obtain a crude products

The crude product was purified by silica gel } column chromatography (developed with a 50:1:0.01 ! mixed solvent of chloroform, methanol and concentrated “ aqueous ammonia) to obtain 100 mg (yield 38%) of 2',4'"= -7 = he ) 'aaD ORIGINAL 9

Lo

; di-Owacetyl~8,9-—anhydroerythromycin A 6,9~hemiw : | ketal (compound 2) as white powder,

REFERENCE EXAMPLE 2 : 303 mg of the compound 1, 0.3 ml of propionyl chloride and 2 ml of dry pyridine were employed in the process of Example 1 to obtain 143 mg (yield 4Ah%) oC of 2',0-acetyl-4"-0-propionyl-8,9-anhydroerythromycin

A 6,9-hemiketal (compound 3) as white powder. : REFERENCE EXAMPLE 3 w 10 303 mg of the compound 1 was dissolved in 1 ml of dry pyridine and agitated overnight with 0,07 ml of benzoyl chloride. Thereafter the same process as in Reference Example 1 was adopted to obtain 127 . mg (yield 37%) of 2'=O-acetyl-4"-O-benzoyl~8,9-anhy~ . 15 droerythromycin A 6,9~hemiketal (compound 4) in white powder.

REFERENCE EXAMPLE UL

} 100 mg of the compound 2 obtained in Reference

Example 1 was dissolved in 2 ml of methanecl, and - . 20 agitated overnight at room temperature. A crude pro- duct, obtained by distilling off the solvent, vas : purified by silica gel column chromatography (deve~ - loped by a 50:1:0.01 mixture of chloroform, methanol . Ca

: and concentrated aqueous ammonia) to obtain 35 mg. (yield 37%) of W'-O-acetyl-8,9-anhydroerythromycin

A 6,9-hemiketal (compound 5) in white powder. : REFERENCE EXAMPLE 5 143 mg of the compound 3 obtained in Reference

So Example 2 was dissolved in 2 ml of methanol, and pro- i cessed in the same manner ae in Reference Example Lk to : obtain 83 mg (yield 61%) of 4"-O-propionyl-8,9=anhy= droerythromycin A 6,9~hemiketal (compound 6) in white powder.

REFERENCE EXAMPLE 6 127 mg of the compound 4 obtained in Reference

Example 3 was dissolved in 2 ml of methanol, and was processed in the same manner as in Reference Example ) 15 L to obtain 92 mg (yield 77%) of 4"-0O-benzoyl-8,9- anhydroerythromycin A 6,9-hemiketal (compound 7) in white powder.

REFERENCE EXAMPLE 7 : 59 mg of 2'-O~acetyl-4"-O-formyl-8,9-anhydro- i 20 erythromycin A 6,9-hemiketal (compound 8) (J. Tadanier et al., Journal of Organic Chemistry, 39, 2495, 1974) was dissolved in 1 ml of methanol, and was processed in the same manner as in Reference Example 4 to obw= tain 29 mg of 4-0-formyl-8,9-anhydroerythronycin A

6,9-hemiketal (compound 9) in white powder.

REFERENCE EXAMPLE 8 303 mg of the compound 1 was dissolved in 20 ml of dry pyridine, and 0.3 ml of crotonyl chloride was added at a time under vigorous agitation at room tem- perature. After agitation for 15 minutes, 30 ml, of ) ethyl acetate was added, The obtain ethyl acetate so-

Jjution was washed with the saturated aqueous solution of sodium hydrogen carbonate and with the saturated aqueous solution of sodium chloride, then dried with anhydrous sodium sulfate and the solvent was distilled : off. : The obtained residue was dissolved in 2 ml of : methanol, and agitated overnight at room temperature.

A crude product obtained by removing the solvent by distillation was purified by silica gel column chro- matography (developed with a 50:1:0.01 mixture of chloroform, methanol and concentrated aqueous am— monia) to obtain 31 mg (yield 10%) of 4"-O-crotonyl- 8,9~anhydroerythromycin A, 7,9=-hemiketal (compound 10) : in white powder,

REFERENCE EXAMPLE 9 205 mg of the compound 1, 2 ml of dry 0.3 ml . of butyryl chloride were processed in the same manner

: as in Reference Example 8 to obtain 18 mg (yield 8%) of 4"-O-butyryl-8,9-anhydroerythromycin A 6,9- 2 hemiketal (compound 11) in white powder,

REFERENCE EXAMPLE 10 303 mg of the compound 1, 2 ml of dry pyridine ) and O.%t ml of isovaleryl chloride were processed in the same manner as in Reference Example 8 to obtain - 40 mg (yield 12%) of 4"~O-isovaleryl-8,9-~anhydroery~ thromycin A §,9~hemiketal (compound 12) in white pow- i 10 der. ) REFERENCE EXAMPLE 11 303 mg of the compound 1, 2 ml of dry pyridine, - and O.4 ml of ethylmalonyl chloride were processed in the same manner as in Reference Example 8 to obtain . 15 4O mg (yield 12%) of A4"-O~ethylmalonyl-8,9~anhydro- : erythromycin A 6,9~hemiketal (compound 13) in white : powder. “ 205 mg of the compound 1 was dissolved in 1 ml of dry pyridine, and agitated for 4 days at room tem=— ‘perature with 0.25 ml of acetic anhydride. The mix- ture was diluted with 30 ml of ethyl acetate, then washed with the saturated aqueous solution of sodium hydrogen carbonate and the saturated aqueous solution of sodium chloride, and dried with anhydrous so- . dium sulfate. The residue, obtained by distilling off the solvent, was dissolved in 1 ml of methanol oo and agitated overnight at room temperature. A crude product, obtained by removing the solvent by distil. : lation, was purified with silica gel column chroma= . tography (developed with a 50:1:0.01 mixture of chloroform,

Lo methanol and concentrated aqueous ammonia water to obw tain 129 mg (yield 60%) of 11,4"-~di-O-acetyl-8,9-anhy- droerythromycin A 6,9-hemiketal (compound 14) in white powder,

REFERENCE EXAMPLE 13

Co 205 mg of the compound 1, 1 ml of dry pyridine and 0.25 ml of propionic anhydride were processed in } 15 the same manner as in Reference Example 12 to obtain 105 mg (yield 47%) of 11,4"-di~O-propionyl-8,9~anhy- droerythromycin A 6,9-hemiketal (compound 15) in white powders.

REFERENCE EXAMPLE 1h 205 mg of the compound 1 was dissolved in 1 - 20 ml of dry pyridine, and agitated with 0.5 ml of buty=- ric anhydride for 7 days at room temperature. It was thereafter processed in the same manner as Re- ference Example 12 to obtain 113 mg (yield 40%) of 11,4"-di-O-butyryl-8,9-anhydroerythromycin A 6,9 hemiketal (compound 16) in white powder.

REFERENCE EXAMPLE 15 . 205 mg of the compound 1 was dissolved in 1 ml of dry pyridine, and agitated with 0.5 ml of ben- zoyl chloride for 3 days at room temperature. The mixture was then processed in the same manner as in

Example 12 to obtain 107 mg (yield 35%) of 11,4"edi-

O-benzoylerythromycin A 6,9-hemiketal (compound 17) in white powder.

REFERENCE EXAMPLE 16 « 184 mg of the compound 1 was dissolved in 2 ml of dry pyridine, and agitated with W4O mg of benzyl- sulfonyl chloride for 5 hours at room temperature.

The mixture was then diluted with 30 ml of ethyl acetate, washed with the saturated aqueous solution of sodium hydrogen carbonate and with the saturated aqueous solution of sodium chloride, and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent by distillation was dissolved in 2 ml of methanol, and agitated overnight at room temperature. A crude product obtained by removing the solvent by distillation was purified by silica gel column chromatography (developed by a 50:1:0.01 mixture of chloroform, methanol and concentrated aqueous ammonia) to obtain 127 mg (yield 51%) of 11,4"-di-0-benzylsulfonyl-8,9-anhydroerythromycin

A 6,9~hemiketal (compound 18) in white powder.

REFERENCE EXAMPLE 17 oT 5 227 mg of the compound 1 was dissolved in 2 ml of dry pyridine, and agitated with 527 mg of para- toluenesulfonyl chloride for 2 days at 50°C. The mixture was processed in the same manner as in Re- ference Example 16 to obtain 81 mg (yield 26%) of 11,4"=di-0-paratoluenesul fonyl-8,9-anhydroerythromycin

A 6,9-hemiketal (compound 19) in white powder.

REFERENCE EXAMPLE 18 9 g of 8,9-anhydroerythromycin A 6,9=hemiketal cyclic-1l1l,12~carbonate (compound 20) (W. Slawinski et al., Journal of the Royal Netherlands Chemical

Society, 94, 236, 1975) was dissolved in 100 ml of chloroform and agitated with 4 ml of pyridine and 3 ml of mcetic anhydride for 45 minutes at room tem- perature, This reaction solution was washed with the saturated aqueous solution of sodium hydrogen carbonate and with the saturated aqueous solution of sodium chloride, then dried with anhydrous sodium sulfate, and the solvent was distilled off to obtain white powder of 21-0-acetyl~8,9~anhydroerythromycin A 649~ nemiketal cyclic-11,12-carbonate (compound 21) quan~ tatively in substantially pure state,

REFERENCE EXAMPLE 19 235 mg of the compound 21 obtained in Example 18 was dissolved in 1 ml of dry pyridine, and agim tated with 0.5 ml butyric anhydride for 2 days at room temperature. The reaction solution was diluted with 30 ml of ethyl acetate, then washed with the saturated aqueous solution of sodium hydrogen carbon- ate and with the saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and the solvent was distilled off to obtain a crude product.

The crude product was purified by silica gel column chromatography (developed by a 50:1t -0.01 mix- ture of chloroform, methanol and concentrated aqueous ammonia) to obtain 78 mg (yield 31%) of 2'=0O-acetyl- 4"-0O=butyryl-8,9-anhydroerythromycin A 6,9~-hemiketal= cyclic~ll,12-carbonate (compound 22) in white powder.

REFERENCE EXAMPLE 20 59 mg of the compound 22 obtained in Reference

Example 19 was dissolved in 1 ml of methanol, and agitated overnight at room temperature. A crude pro- duct obtained by removing the solvent by distillation was purified by silica gel column chromatography (de-

veloped by a 50:1:0.01 mixture of chloroform, me- thanol and concentrated aqueous ammonia) to obtain 40 mg (yield 72%) of 4"-O-butyryl-8,9-anhydroery- thromycin A 6,9-hemiketal-cyclic-11l,12~carbonate (compound 23) in white powder.

REFERENCE EXAMPLE 21 79 mg of 11~O-methanesulfonyl=2'=0O-acetyl-4"~ 0-formyl~8,9-anhydroerythrémycin A 6,9-hemiketal (compound 24) (J. Tadaniel et al., Journal of Organic

Chemistry, 39, 2495, 1974) was dissolved in 1 ml of methanol, and agitated overnight at room temperature,

A crude product obtained by removing the solvent by distillation was purified by silica gel column chro~ matography (developed by a 50:1:0.01 mixture of chloroform, methanol and concentrated aqueous am- monia) to obtain 40 mg (geld 52%) of 1l-O-methanesul- fonyl—-l4"-0~formyl-8,9~anhydroerythromyecin A 649~hemi~ ketal (compound 25) in white powder,

REFERENCE EXAMPLE 22 150 mg of the compound 1 was dissolved in 2 ml of dry pyridine, and 46 ul of methanesulfonyl chloride was added thereto under agitation and under cooling with ice. After completion of the addition, agita- tion was continued for 1 hour under cooling with ice,

and then for 2 hours at room temperature. The same process as in Example 16 was thereafter conducted to obtain 123 mg (yield 78%) of 11,4"'~di-O-methane~ sulfonyl-8,9~anhydroerythromycin A 6,9~hemiketal (compound 26) in which powder, .

Low mass (SIMS) m/e : 872 (M + H)+

The structure, specific rotatory power and

NMR spectrum values of the compounds obtained in Re~ ference Example 1 to 22 are summarized in Tables 2 and 3.

TABLE —

CH CH . 3 to 3

Zo en. [No | CH 5. 3 0 : RO ~ NL cH ae 3 “Nn

Hy) 3 cH,

OCH

CH, ~ cil, 2 0 3 0 AN oR?

Compound CH, 6 2h

Noa . gt rR g RR /[q/p (el.0,cHCl3) ee ee eters ee ete ete te 2 co H BH =4h4.4°

CH, CH, CO 3 CH;CO Cl;CH,CO H H ~46.0° (c 0.5) b CH, CO PhCO H H =56,2° i 5 H CH;CO H H =h3.4° + 0 6 H CH3CH,,CO H H -38.0 7 H PhCO H H ~59.2° 9 H CHO H H -h1.8° 0 oO 10 H i. ~N H H =h3.4 3 . 0 : 11 H CH,CH,,CH,,CO H H =33.4

CH

12 H 2d H H =35.0° cH, 3 0 0 13 H J) H H -34,8°

Et0

»

I

TABLE 2-continued

CH CH cH 3 plo Ny 3 iH < cn

C

So No 3 0 ~ CH 6 3

ROO cn

H,C 3 oH / 3 OCH, 2 © SH CH

CH 3 3 3 0 0” OR®

CH

3

Compound 1 2 5 6 24

No. ® 0&0 =z [Ay (er-oacucty) 14 H CH CO CH,CO H -21.4° 1 -25.6° 5 H CH, CH,CO CH,CH,,CO H -25.6 16 v Ci : a) 21 2 N°

H CHy #,CH,CO CH, CH ,,CH,,CO H -25.h 17 H PhCoO, PhCO H -50.0°

H . o 18 H PhCH, SO, PhCH,SO,, 37.6 o on oH ~9.0° 19 H CH, 2 3 2 0 N -33.6° 1 21 CH;CO H >=0 33,6 22 CH.CO CH,CH,CH,CO > =0 -h1,2° 3 37272 ~ ° v 0 23 H CH CH, CH, CO >=0 42.6 25 H CHO CH,SO,, H =32.4° 26 H CH,4S0, CH,S0 H ~34.8°

Tn Table 3, Ph is phenyl and Et is Thy TT ssn em

The numbers of compounds correspond to those in the Reference

Examples.

~~

Jao] nl ~ - oo 8 nN ~~’ . - o wn Q ~~ . oO 0 - ~~ ~~ . ~ N ~~ oJ Jo] lal La}

Nn [9 2+] © - Hn 0 << : og —~ - ~

Q ~ ry ~~ 1} 1 wn ao in == ir] =z + - Mn a = ° = - - 2+] t~ ~~ o = ~~ - - ~~ py - ~~ ” le) © Q o i £ . on oO ~~

Ny ny oO . . mn » — © 0 un ~~~ ~~ oN » ' ~~ ~ ~ mn mm mM ee se mn

Mn mon Nn nA MY MN of wn MN * - - - jes} jos} ve g oO « 0 o a 0 0 oO NN ¢ WM Nr ~~ = 0 a on © 4 ww Oo an A eo) » w O OO = . \ \ g| « © . . . +s © \ o| wn 4 oN ow [ mi > eo oO oe ~l 2 I ne a" *” oo oO Q == Oo 1 - 0 © © £0 bg > nf oO no = [20 oO s 8 ~~

Jos] eo] gf ee Mn Nn nn oN \0 qa wn ny nn Inn inn in ~s . * . . 0 ° . . > 0 A AHA HA — x= { “| 5

Ne q| ~ ' ol

A 0 -

Lo ml xl vw : <4] =| cc oO MN +4 mn oo [a

E4} =) «NN Non MY MN MN nN Nn . 1] © . . . . o ° . . ml = No oN NNN oN oN oN

Nn = 1 -

MN

~~ j=]

MN

- 0 ~~ nn FA nN oN 2 n Mn

LJ NN Ny NN Ny MN 4 * 0 * 0 * » 0. * 9 MM Nn ny NN La

N

» 0 = o

Q aN tN 0 On Oo \ [2d] ~ 8 .

Q

~~

Q \

Jo] 0 0 - - ~~ ~~ js] o je! 0 ~ ol Q - - ~~ * 0 : 0 oo jo2] wo * ~

Lg ny ~~ o- un ao - ~~ . 4 0 = o¥ . . » ~~ ~ ~ MN + Q Oo = > NN ~~ a .e Ny Pe] oi " ne » ot n ir wa od [3 > ~~ OO 0 o vw HB an NN . e A £1 ~~ — 0 fo] 0 « Oa ¢ 2 0 <4 ~~ o Ps co | i ’ ‘ Oo 9 ol 1 31 er - ~~ = ~ ws =e} 4 oO me o a ~ 8g ni 0 A oe . - ~~ «QO - LO ~~ 0 - Mn 3A n © Joo] ~~ ~~ oO - ~~ @ - MN

Nn i * of 0 4 ~~ ~ NN 0 0 ~r 4 wn mow

HA) ® - 13 *Q Nr ri NN 0 LA oN ke - ot 0 ~~ ~ * ~~ un O [=] se tO e mo — © + on 0 0 nN 0 MN (3 Q - nee 1 - oo 1 + Oo * a ££ oO n uw 8 se £5 ol ~ [SY ~ Nr [1a o [ea] 1 wn nN joo] > m oe Ey oO Q OQ ~| Ww o= 0 . 5 * 0

Of $+ << o- oN =| Oo nl © o f [6] IB] § Q oo] 1 ’ oJ [TET oN) = £ o 0 0 Q = gl oO + Ay 0 a4 ) 2+

Ql ~~ : oS ol Hi

Oo] S| - tn [Sg o- | 0 Nn oN 0 0 O 0 \O 1 wn wn tn n in ny mn mn wn ny NN IN IN

I+] ~ ¢ . ° ° 0 ° . . a + 0 . . rl © ~~ ~ ~~ rt [al ~ ~ — [a] oe He wl “of = = 1

Oo} ~r{ oo § °

PN ~ 0] . » = 0 ' [4] 3 - Qo ml mM) 0 an ~ Q o 0 uN nN © aN VOW Ns] g og] XE] oN Nn NN MN a Mn My [a4] oN NNN Io el =] od ° . . . . . . ° . « eo ¢ a 1| © [aV] o oJ 3") ol a od o ol NNN NNN 0 m= el

Mm l= 1 ® - . £ 0" Ma o jo] . ~ o 2] [15 > - . 0 ol nN oJ ol 4 o ~~ MN oO LIAN + ~~ Nn 0 0 nN Nn nN nN 0 nN NNN Q

Ld 0 9 * * * » * 0 * * & 0 * 0

B nN MN NN ©" Nn La My Nn MN NNN ND ] 7 u = + nn .

Q

«t 0 oO - = Nn 3 5 8 l= 3M Nn +4 nO o. © Nn ~H OMNI a 2 — — — ~ ~ + ~ ~ i NNN = 8

Q =] 0 -

REFERENCE EXAMPLE 23 200 mg of 8,9-anhydroerythromycin A 6,9~hemi- ketal (compound 27) (V. C. Stephens et al., Antibiotics

Annual, 1958-1959, 346) was dissolved in 3.h ml, of . 5 CHC1,, then added with 0.22 ml of anhydrous pyridine

A and 0.34 ml of butyric anhydride, and was allowed to stand for 20 minutes at room temperature. The re- action solution was diluted with 20 ml of CHCL 5s and washed with 20 ml of the saturated aqueous solution of sodium hydrogen carbonate and 20 ml of water. The

CHCl, layer was dried with anhydrous sodium sulfate, and concentrated under a reduced pressure to obtain . a colorless glass-like substance. ¥aid substance was purified by silica gel column chromatography, utiliz- ing a developing mixed solvent of CHC: CH 0H: conc.

NH, OH = 40:1:0.01, to obtain 209 mg (yield 95.2%) of 2'-0-butyryl-8,9~anhydroerythromycin A 6,9~hemiketal (compound 28) in white powder.

Rf value: 0.36 (CHC 2 CH OH: conce NH) OH = 10: 1:0.01) Carrier:silica gel (Merck, West Germany), High mass: 785.4936 (calcd. for Cyq Hoy NOy 5 785,4921),

The same. carrier was employed also in the thin layer chromatography in the following Examples.

REFERENCE EXAMPLE 24 200 mg of 21'-0-acetyl-8,9-anhydrodrythromycin

. A 6,9-hemiketal (compound 29) (V. C. Stephens et.al.

Antibiotics Annual, 1958-1959, 346) was dissolved in 4 ml. of anhydrous pyridine, and added with 0.12 ml of methanesulfonyl chloride under cooling with ice.

After 30 minutes, the same process as that for pro- ducing the compound 28 was conducted to obtain a : colorless glass-like substance. This substance was dissolved, without purification in 8 ml of methanol and was let to stand at room temperature. After one day, the reaction solution was concentrated under re~ duced pressure to obtain a colorless glass-like subs tance. This substance was purified by silica gel column chromatography, utilizing a mixed developing solvent of CHC1,:CH, OH: conc. NH, OH = %30:1:0.01, to obs tain 116 mg (yield 52.3%) of 4"~O=methanesul fonyl~8,9~ anhydroerythromycin A 6,9-hemiketal (compound 20) in white powder,

Rf value: 0.20 (CH Clg: CH OH: conc. NH), OH = 1031s 0.01), high mass: 793,427 (caled. for C3gHgp N01, 88 793,427).

REFERENCE EXAMPLE 25 300 mg of 21wO~acetyl-i"-0-formy1-8,9~anhydro- erythromycin A 6,9-hemiketal (compound 31) (=compound 8) (Journal of The Chemical Society, 39, 2495, 1974) was dissolved in 8.1 ml of CHCl, and heated under re~ flux with 5 mg of 4-dimethylaminopyridine, 15 ml of triethylamine and 1.2 ml of acetic anhydride. The reaction mixture was cooled to room temperature after 3 days, and the same process as that for ob- taining the compound 28 was conducted to obtain a pale yellow glass~like substance. This substance was dissolved, without purification, in 12 mlxf methanol and heated under reflux. The solution was cooled to room temperature after 3 days and concentrated under reduced pressure to obtain a pale yellow glass-like substance. This substance was purified by silica gel i column chromatography, utilizing a developing solvent system of CHC, 2 CH, OH: conc, NH, OH = 50:1:0,01, to obtain 136 mg (yield L44.5%) of 11,12-di-O-acetyl-8,9~ anhydroerythromycin A 6,9~hemiketal (compound 32) in white powder.

Rf value: 0.15 (CHCl, :CH,iconc. NH)OH = 10:1: 0.01), low mass: M + 799, high mass: 799.4703 (calcd. for

Cly1HgoNO 4° 799.4713).

REFERENCE EXAMPLE 26 300 mg of the compound 31 was dissolved in 8.1 ml of CHCL,y then added with 5 mg of lY-dimethylamino- pyridine, 2.2 ml of triethylamine and 2.2 ml of pro- pionic anhydride, and processed in the same manner as in the preparation of the compound 32 to obtain 68 mg mg (yield 21.5%) of 11,12-di-O~propionyl-8,9~anhydro-

erythromycin A 6,9-hemiketal (compound 33) in white powder.

Rf value: 0.16 (CHCL 5: CH OH: conc. NH OH = 10:1 0.01), high mass: 827.502 (calcd. for CyyzflozNOy 4,2 827.502).

REFERENCE EXAMPLE 27 300 mg of the compound 31 was dissolved in 8.1 ml of CHCl 5s then added with 5 mg of h-dimethylamino- pyridine, 2.2 ml of triethylamine and 2.6 ml of buty- ric anhydride, and processed in the same manner as in the preparation of the compound 32 to obtain 141 mg (yield 43.2%) of 11,12-di~O=butyryl-8,9~anhydroery~ thromycin A 6,9-hemiketal (compound 34) in white pow- der.

Rf value: O/i8 LCHCL, 1 CH OH: conc. NH, OH=10:1 0.01), low mass: M+855, high mass: 855.5343 (calcd. for C,H NO, 1, 8855.5339)

REFERENCE EXAMPLE 28 1.0 g of the compound 31 was dissolved in 10 ml of toluene, and heated under reflux with 929 mg of thiocarbonyl diimidazole. The solution was cooled to room temperature after 4 hours and processed in the same manner as in the preparation of the compound 28 to obtain a yellow glass-like substance. The ob= tained glass-like substance was purified by silica ] gel column chromatography, utilizing a developing solvent system of CHCL,:CH OHzconc. Nit) OH=100:1¢ 0.01, to obtain 373 mg (yield 36.0%) of 2'~O-acetyl- 4eO-formyl-8,9-anhydroerythromycin A 6,9~-hemiketalw~ cyclic~11,12-thiocarbonate (compound 35) in white powder.

Rf value: 0.45 (CHC1,:CHyOHzconCo NH, OH = 10:1: 0.01), high mass: 827.4091 (caled. for Cy HgcNO),S: 827.4121).

REFERENCE EXAMPLE 29 100 mg of the compound 35 was dissolved in k ml of methanol and heated under reflux. After 3 days, the solution was cooled to room temperature, and con- ’ 15 centrated under reduced pressure to obtain a color ’ less glass-like substance. The obtained glass-like substance was purified by silica gel column chromato- graphy, utilizing a developing solvent system of

CHC: CH,OH: conc. NH) OH=50:1:0.01, to obtain 63 mg (yield 68.8%) of 8,9-anhydroerythromycin A 6,9-~hemi= ketal-cyclic=1ll,12~thiocarbonate (compound 36) in white powder.

Rf yalue: 0.20 (CHC1 5: CH OH3 conc. NH), OH = 1021:0.01) high pase 757.4061 (calcd. for C3gHg3N0y 8+ 757.407).

REFERENCE EXAMPLE 30 170 mg of the compound 27 was dissolved in l.1 ml of methanol, then added with 21% mg of potassium carbonate and 27 © of ethylene sulfite and agitated i at room temperature. After 2 days, the solution was processed in the same manner as in the preparation of the compound 28 to obtain a colorless glass-like substance. The obtained glass~like substance was purified by silica gel column chromatography, utiliz- ing a developing solvent system of CHCL 5: CH OH: conco

NH, OH = 10:1:0.01, to obtain 72 mg (yield 39.8%) of 8,9-anhydroerythromycin A 6,9-hemiketal~11,12-sulfite (compound 37) in white powder.

Rf. value: 0.09 (CHC1 4: CH OH: conc. NH, 0H=1031:0.01), high mass: 761.401 (calcd. for CpHgaN0 382761401)

REFERENCE EXAMPLE 31 200 mg of the compound 29 was dissolved in 10 ml of benzene, and heated under reflux with 32 mg of 7 phenyl-boric acid. The solution was cooled to room temperature after 2 hours and processed in the same manner as in the preparation of the compound 28 to obtain 216 mg (yield 97.8%) of 2'-O~acetyl=8,9=anhy- droerythromycin A 6,9~hemiketal-11,12~phenylboronate : (compound 38) in white powder.

This compound was so pure that it did not re- quire purification.

Rf value: 0.40 (CHCl 5: CH OH: conc, NH, OH = 10:1:0,01). : REFERENCE EXAMPLE 32 216 mg of the compound 38 obtained in Reference

Example 31 was dissolved in 8.6 ml of methanol and was let to stand at room temperature. After 1 day, the solution was concentrated under a reduced pres- sure to obtain a colorless glass-like substance. The obtained glass-like substance was purified by silica gel column chromatography, utilizing a developing solvent system of CHC1,:CH, OH: conc. NH, OH = 50:1:0,01,

Co to obtain 199 mg (yield 97.0%) of 8,9-anhydroerythro= mycin A 6,9-hemiketal~11,12-phenylboronate (compound 39) in white powder.

Rf value: 0.40 (CHC1:CH;OH: conc NH, OR = 10:1:0.01).

REFERENCE EXAMPLE 33 1.40 g. of the compound 29 was dissolved in 14 ml of dry pyridine, then added with 1,1 ml of chloro~ trimethylsilane and was let to stand at room tempera- ture. After 2 hours, the solution was processed in the same manner as in the preparation of the compound . 28 to obtain 1.50 g (yield 90.0%) of 2'=O-acetyl=-

11,4"-di-O-trimethylsilyl=-8,9~anliydroerythromycin A 6,9-hemiketal (compound 40) as a colorless glass- like substance.

Rf value: 0.43 (CHC152CH5OH: conc. NH, OH = 10:1:0.01).

REFERENCE EXAMPLE 34 : 750 mg of the compound 40 was dissolved in 3 ml, of 1,2~dichloromethane, then added with 2.40 g of tri- benzylamine and 0.72 ml of acetyl chloride under cool ing, and, after cooling 10 minutes, heated at 75° under agitation. After 3 days, the solution was processed in the same manner as in the preparation of the com- pound 28 to obtain a pale yellow solid substance. The obtained solid substance was dissolved, without puri- fication, in 30 ml of methanol and heated at 50° op

The solution was cooled to room temperature after 1 day and concentrated under a reduced pressure to ob- ' taln a pale yellow solid substance. The obtained so- 1id substance was purified by silica gel column chro 2p matography, utilizing a developing solvent system of

CHC1 53 CH, OH: conce. NH, OH = 50:1:0.,01, to obtain 163 mg. (yield 25.9%) of 12-O-acetyl-8,9-anhydroerythromycin A, 6,9-~hemiketal (compound 41) as white powder,

RE value: 0.15 (CHCl,:CH,OHiconc. NH, OH = 10:1:0.01), high mass: 757,460 (calcd. for C3qtgpNOy 33

757.460).

REFERENCE EXAMPLE 35 800 mg of the compound 40 was dissolved in 3.2 ml of 1,2-dichloroethane, then added with 2.56 g of tribenzylamine and 0.85 ml of propionyl chloride under

Lo cooling, and, after 10 minutes, heated at 75°¢. under agitation. After 3 days, the solution was processed in the same manner as in the preparation of the com- pound 30 to obtain 273 mg (yield 39. % of 12-O-pro- pionyl-8,9-anhydroerythromycin A 6,9-hemiketal (com pound 42) as white powder.

Rf value: 0.17 (CHC1 CH OH conc. NH, OH = 10:1:0.01), high mass: 771.476 (calcd. for ChollggNOy 3: 271.476).

REFERENCE EXAMPLE 36 400 mg of the compound 29 was dissolved in 0.8 ml of dichloromethane, then added with 0.2 ml of N,N~ : diisopropylethylamine and 0.22 ml of methoxyethoxy methyl chloride under cooling, and after 10 minutes, was let to stand at room temperature. After 3 hours, the same process as in the preparation of the compound 28 as conducted to obtain a colorless glass-like subs~ tance. The obtained glass-like substance was purified by silica gel column chromatography, utilizing a de~ veloping solvent system of CHC1:CH,OH: conc. NH, OH = . on =

100:1:0.01, to obtain 250 mg (yield 56.0%) of 2'-10- acetyl-4"-O-methoxyethoxymethyl-8,9~anhydroerythro- mycin A 6,9-hemiketal (compound 43) as white powder.

Rf value 0.43 (CHC1,2CH OH: conc. NH, OH = 10:1:0.01), high mass: 845.513 (calcd. for CyzHogNOy 5° 845.513). . | REFERENCE EXAMPLE 37 150 mg of the compound 43 obtained in Example 36 was dissolved in 6 ml of methanol and was let to stand at room temperature. After one day, the re- action solution was concentrated under reduced pres- sure to obtain a colorless glass-like substance. The obtained glass-like substance was purified by silica gel column chromatography, utilizing a developing solvent system of CHC1,:CH,OHzconc. NH) OH = 30:1:0.01, to obtain 85 mg (yield 59.6%) of 4"-O-methoxy-ethoxy- me thyl-8,9~anhydroerythromycin A 6,9~hemiketal (com- pound 4h) in white powder.

Rf value: 0.27 (CHC1 ;CH OH: conc. NH, OH = 10:1:0.01), high mass: 803,502 (calcd. for Ch HozNOy 2 803,502),

The structure, specific rotatory power and NMR spectrum of the compounds obtained in Reference Exam- ples 23 - 37 are summarized in Tables Lb and 5s

Fan} . ny ~ . 0

Re] 0 -

Q

A of . at °o 0 o o o o

NN + ww Oo oO oO o o

N\] 0 ° Q © * 0 .

B53 253 5 8 3 t 1 1 1 1 % Y o 0

Q oN

Q 0 jee 0 oO ao m 1 me nog on =] > om © ny © 03 "nN 0 js] ©

MN 1 i ~ Sono hoo 8 rE 3 o INN ~ 8 © ww © ) in 8 3 oe © =

Ty oJ i>] 3S oY Cu 4 © N Ml om om mS = = ~ oO jo] MNO be Y [$} aol tn rq oS wr © v3 © . m Nn tN <4 rt i 3 0 3 oi" © \ o =O a" oJ tn Q ol mo) om aT: A BE - 53] tre 5 0

NN oo ~ mo 3) NY — [on] o oO oh : [+4 . } oO 0 oJ 34 Q ~ &] © ~ oo a= =~ j=l oA irs td x © 0

NN ol 0 o 8. 00 22 © © oN Mn 2 nn 0

EB ANN nn Oy MN

Oo

~~

HN ri . 0 wn 0 [Jd lo} . ~~ : —-{ wn ol ° ~r QO ol

MN ~~ ~ o o o i 0 0 0 © 0 of Oo al Ov NN FO

MN ° . ° . . 9 ® ’ wl Qo + Q nN nN oO IF © Ny wn 0 CNY ONY MN

J 1 1 i Corr ' oO oO

Q al wo! Om 4 sd NOD mon 9 { oon 0 y 0 3 © © ~~ a, £ r=] dg oO [27 ny

MN i 1 4 rs ! m m f= 0 t 8 5 a : : 9 oA" 0 o go 3 8 4 o 5 je] ~~ c Sony, MN hot ot p le) 4 i tom Mom @ + i oJ oO ~ gl © / = 0 oO 5 0 ~ nN AS 4 mi tr Or! %5 I) e a) ie]

Fa m © 2 =] © oon < 5g ) oom + ol Dv

B= oN th oO ¢ O ™ i" [a oY oN ) + jae] ~ 2] 8 o — © ™ m me m Mm om ooo Ad \ jae oN NE d oO 0 pod mw oO ~ DO je]

N NM QO OO |u a ~ my om 0 nd © rd 0 — moog Rk oO a) BO fH MN q “9

Oo ow 0 0 >

Dm ow

Q oO Q bo 0 oO © £5 g oy jee] ny Mm [ates o i = = £0 [&] m 0 [&] 2 a ] nn oO wo ow ono + o ® g © 0 ° ~ 5 oo 0 £2, 2 oo oQ oN Q ~ Oo yt no g nN [a nN FF Ft Fe o 0 oa +4 EA

» ~~ . ~~ jae] — m Ny i pa . N - n Mn - 0 ~ Hw ~r | DD ~

Poe] oO oon ~ » nN 00 - . ~ = a) =) 8, + - io in oO Q io 5 =<

Q = 9 8 4 0 0 Q oo od i 1 © oN mn . — = 1 tg = 3 - LD ~~ 0 al Oo I ~~ . > » an] 0 —~ —~ ~~ ee ~ in nl ~ ~~ mm = 2 4 mon Ny mom MN mo 0 '

Ne - nN ne Mm Nn - 0 [} - « © es 00 MN

WB ~~ ~~’ 8 B nw eH

SQ X 7 o ~~ 00 ~ FF OO © oO ”m S oo ov FO ’

OS oo =~ ° ee & 0 Oo =

Ce Nw oN o-oo a 8B a A 1 arom 0 nF nN = 1 Magy noe A nd « o MN oe 3d nw © oe 0 oo 0 gon 2 5 8 S oO © ~~ O 8 @ 0 oo 0 Oo 0 2 i i ome 1 0 Nm ~~} @ = nN ~ TT = 3 S 5 A oJ m m A non O . © a ©

PL} gl] mT £0 ~ n ol ~] o «o = + go FT in oO nn adn 0 o] UU Mm Nn Nom MN Nn NAN Mn = 0 oe» se 8 + e 8» © ¢ oo eo & 0 8 A mm mom MMM nn nn . nn] = el ™ in} © = <q) of

Hq 5 = 3 ol SI nw eo © © + ow oo oH mo Nw

No WN EE EE EB A NE TEA LA WL I 3 of eo oe Ta + se 8 ee 0 © Zl © oa No NNN ANNAN A lt mtn = z 1 =

A . ~~ tn

MN nl] HA Ww Mm aN © © © © xr KM or In NO ~~ nnn Hh FF In WR InN th WO InN Inn IN . ol +¢ oe « oe oo +» ee so + 0 2 oA A A “gH A MHA HA AAA 0 g 0 ¢ mol © © on MF Ino Bo OAT £2 © Aon MoT Mm Rm om FF oO

REFERENCE EXAMPLE 38 300 mg of the compound 27 was dissolved in 3 ml of dry pyridine, and added with 0.4 ml of acetic anhydride. The reaction mixture was heated at 50°C, for 24 hours. The reaction solution as poured into ml of the cold saturated aqueous solution of so- dium hydrogen carbonate, and the resulting product was extracted with chloroform (3 x 10 ml). The extracting solution was dried with anhydrous sodium sulfate, and 10 the solvent was removed under reduced pressure to ob~ a crude product. This product was purified by silica gel column chromatography (Merck Art 7734 silica gel 20 g; eluting solvent chloroform-methanol /50: 1)7 to obtain 290 mg of 11,2' 4" =tri-O-acetyl-8,9-anhydroery- thromycin A 6,9-hemiketal (compound h5) as white powder.

Rf value: 0.38 (CHC 5: CH OH = 20:1).

REFERENCE EXAMPLE 39 290 mg of the compound 45 obtained in Reference

Ee 20 Example 38 was dissolved in 3 ml of dry dimethyl sul- foxide, and added with 1 ml. of acetic anhydride,

The reaction mixture was let to stand for 96 hours at room temperature. The reaction solution was cone centrated under reduced pressure ({2 mm Hg), and - | t

! the residue was dissolved in 20 ml of chloroform.

The obtained chloroform solution was washed with 10 ml of the saturated aqueous solution of sodium hydrogen carbonate, then dried with anhydrous sodium sulfate, and the solvent was distilled off under re- duced pressure. The crude produce was purified by silica gel column chromatography (Merci Art 773h silica gel 20 g.; eluting solvent chloroform-methanol (50:1)), to obtain 173 mg of 11,2',4t-tri-O-acetyl~12~ } 10 O-methylthiomethyl-8,9~anhydroerythromycin A 6,9~hemie ketal (compound 46) as white powder.

Rf value: 0.39 (CHCL 4: CH, 0H = 20:1). } Lo. REFERENCE EXAMPLE 40 173 mg of the compound 46 obtained in Reference ’ 15 Example 39 was dissolved in 5 ml of methanol, and added with 20 mg of lithium hydroxide. The reaction solution was heated at 50°¢. for & hours under agita- tion. After concentration under a reduced pressure, the residue was dissolved in 20 ml of chloroform, : 20 The chloroform solution was washed with 10 ml of water, then was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pres— sure. The crude product was purified by silica gel column chromatography (Merck Art 7734 silica gel 15 g; eluting solvent chloroform-methanol (30:1), to obtain 118 mg of 12-0-methylthiomethyl~8,9=~anhydro- erythromycin A 6,9-hemiketal (compound 47) was white powder,

Rf value: 0.16 (CHCL 52 CH OH = 10:1).

REFERENCE EXAMPLE 41 300 mg of the compound 8 was dissolved in 3 ml of dry pyridine, and added with 0.3 ml of acetic an- hydride. The mixture was heated at 50°¢. for 24 hours. The reaction solution was poured into 10 ml of the cold saturated aqueous solution of sodium hy- drogen carbonate, and the resulting product was ex- : tracted with chloroform (3 x 10 ml). The extracting solution was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. This product was purified by silica gel column chromatography [Merck Art 7734 silica gel 20 g, eluting solvent :chloroform-methanol : (50:1)7 to obtain 195 mg of 11,2'=di~O-acetyl-h"- 0-formyl-8,9~anhydroerythromycin A 6,9~hemiketal (compound 48) as white powder.

Rf value: 0.37 (CHC15: CH, = 10:1) high mass: 827,4680 (calcd. for Cy Hg gO, 52827. 4663) -

REFERENCE EXAMPLE 42 195 mg of the compound 48 obtained in Example

41 was dissolved in 5 ml of methanol, and the so- lution was heated under reflux for 1 hour. Then the solvent was distilled off under a reduced pres- ‘ sure to obtain a crude product. This product was purified by silica gel column chromatography (Merck

Re Art 773h silica gel 20 go. eluting solvent:chloroform- : methanol (30:1)) to obtain 155 mg of 11-0~ncetyl-h"= 0-formyl-8,9-anhydroerythromycin A 6,9-hemiketal (com- pound 49) as white powder.

Rf value: 0.28 (CHCL 2 CH CH, CH = 10:1)

REFERENCE LXAMPLE 43 210 mg of the compound 48 obtained in Reference

Example 41 was dissolved in 5 ml of methanol, and the ' solution was heated under reflux for 4s hours. Then the solvent was distilled off under reduced pressure to obtain a crude product. This product was purified by silica gel column chromatography (Merck Art 773h silica gel 20 g. eluting solvent:chloroform-mathanol (30:1) to obtain 158 mg of 11-O-acetyl-B8,9-anhydro- erythromycin A6,9-hemiketal (compound 50) as white . powder.

Rf value: 0.21 (cHo1 20H ON = 10:1).

REFERENCE EXAMPLE 44 155 mg of the compound 49 obtained in Reference

: Example 42 was processed in the same manner as in

Example 43 to obtain 115 mg of 11-O~ac#tyl-8,9- anhydroerythromycin A 6,9~hemiketal (compound 50) : as white powder.

REFERENCE EXAMPLE Ls : 300 mg of the compound 8 was dissolved in 3 ml of dry pyridine, and added with 0.3 ml of acetic an- hydride. The reaction mixture was heated at 50°C. for 2h hours. The reaction solution was poured into 10 ml of the cold saturated aqueous solution of so- dium hydrogen carbonate, and the resulting product . wae extracted with chloroform (3 x 10 ml). The ex~ tract was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 5 ml of methanol, and hanted under reflux for 45 hours. The solvent was distilled off under reduced pressure, and the residue was puri- fied by silica gel column chromatography ta obtain 156 mg of 11~0-acetyl~8,9-anhydroerythromycin A 6,9~ hemiketal (compound 50) as white powder.

REFERENCE EXAMPLE 46 300 mg of the compound 8 and 0.3 ml of propionic } anhydride were réacted according to the method of Re- ference Example 45, and the protection was removed with methanol. The crude product was purified by silica gel column chromatography (Merck Art 7734 silica gel 20 g. eluting solventechloroform-methanol (30:1)) to obtain 152 mg of 11-0~propionyl-8,9~an~ hydroerythromycin A 6,9=-hemiketal {compound 51) as white powder.

Rf value: 0.21 (CHC 2 CH, OH) = 10:1)

REFERENCE NUMERAL 47 300 mg of the compound 8 and 0.3 ml of butyric anhydride were reacted and after removal of the pro- tection according to the process of Reference Example 4s, 4 crude product was obtained. This product was purified by silica gel column chromatography (Merck

Art 7734 silica gel 20 g. eluting solvent:chloroform=~ methanol (30:1) to obtain 146 mg of 11-0-butyryl-8,9~ anhydroerythromycin A 6,9-hemiketal (compound 52) as

Co white powder.

Rf valuet 0.21 (CHC1,* CH, OH = 10:1)

REFERENCE EXAMPLE 48 300 mg of the compound 8 and 0.3 ml of benzoyl chloride were reacted and after removal of the pro- tection according to the process of Reference Example 45, a crude product was obtained. This product was purified by silica gel column chromatography (Merck

Art 7730 silica gel 20 g. eluting solvent:chloro—~ form-methanol (30:1)) to obtain 155 mg of 11-O-ben~- zoyl-8,9~anhydroerythromycin A 6,9-~hemiketal (com=~ pound 53) as white powder.

Rf value: 0.20 (CHC1 5: CH OH = 10:1)

REFERENCE EXAMPLE 49 : 200 mg of erythromycin A was dissolved in 2 ml of CHCL5s then added with 78 ul of 2-methoxypropene and 64 mg of pyridinium chloride and let to stand at room temperature. After 1 day, the reaction so= lution was diluted with 20 ml of CHCL 4 and washed with 20 ml of the saturated aqueous solution of so- dium hydrogen carbonate and 20 ml of water. The

CHCl layer was dried with anhydrtous sodium sulfated and concentrated under a reduced pressure to obtain a colorless glass-like substance. The obtained glass— like substance was purified by silica gel column chro- matography, utilizing a developing solvent system of

CHCL 4: ClizOHz conc. NH, OH = 30:1:0.01, to obtain 194 mg (94.0%) of 11,12-0-isopropylidene~8,9~anhydroery- thromycin A 6,9~hemiketal (compound Sk) as colorless powder.

Rf value: O.1lh (CHCL,:CHIIz conc. NH), Ol = 10:1:0.01) high mass: 755.4856 (calcd. for Chollggh0y 23755: 4815) oe - 105 -

) The structure, specific rotatory power and

NMR spectrum of the compounds obtained in Examples 38-49 are summarized in Tables 6 and 7.

~

MN fo 0 je2} 0 . ” o : . . 0 o ° 0 o 0 0 o — Ow 0 0 0 \D © ot * ° * ° © » ° LJ ol 0 ~ © Nn 0 © oO ~ Nn od SU J] - i t 1 1 ! 1 1 1 . mn oJ 3

S oJ 0 jae] = nn 0 © ™ mn mn 0 a] ry a=] jx} brs : AN oy 5 o) oO 0 Mn oJ

AA ui oa 0 MNO Oo © ES

No nN Oo MN Q / pe Oo oO 3 © oF nN oO o [0] oO Q Q Q oa 0 wy PY © OQ Q © l&] jan} oO 05 © + Nn Mo nO oN 1 mi mooi on a a MN ry 0 oO [$] oO ja] x

Oo, rd © MN 2 \ © =

MN NN 5 © ry oo oO 3 =O 0 oO o \ oJ © ©

Oo or M\ pn iT Oo Q < el: mom mom om i [&) oo [&] © 03 a LAA © mo 3 td oo oO © ) un 0 $0 vom —t me oO Q Q : oO 0 © on nom om } jas] jae] jas]

Pb ry © |] o 8. = n tc. 0 on © HH § + 2 Fr oF nn In

~~

NN

— oO 0 0 - oO

I" 0

Oo

O ol + 9 ~r oO +

UATE] n ' ) we

T) 0 0 © ~ © g

Ny i m % of i og © wo oJ @ gl © © om 0 al \ mo < S 8 q O 8 oA = Mm oO 0 / N Li 8 5 wo 0 © - ¥ = EAN o © £3 rv: of il 8 oO oO Po 0 o on 2 a .] ] +h © he Dy ° . IE] Q m ty 1 0 <q oO - wi £

I rd + o

Nn +H jas] 0 o = © © \ 5

O al [2d

Nan 0 mt m n

NY m1 ad o ire O—0 H 0 ~ 4

Oo © > 0 ny, Ww MN go

Mom om ® a 0 ™g n 5 “tO £2

LB

~ om O mm ml joel © - \O ty © © - un a o © o E+ 0 g 8 , ° 3 0 0 a8 2 MN = d + g n in © oO oq £2 0 Ee

» ~~ rg - ~~

MN 0 = i ~ Oo 22] ~ . 0 " Lb) - ~ al - 0 oO a =

A ~~’ Oo . Ny = oJ oN — o oo —~ ¢ mw © . 0 oJ

MN 0 Mm nN T wd De o B i un Q j2) ~

Oo z= ~~ << Q 0 + lo] OQ 'a i o i ! S = ~ 4 ~~ —~ = * 3 ~ ~ em mm A + © ' ~ i Im oN ~ Rn mn se. oe ~ oe y oe « ww 0 u ~ tm = © 0 My tt oH im im i ~~ ~ BH 0 OO Me KN MN MN wn oo n OA ~ 0 - - : ~~ oO OO . Nn ~~ 0 0 8 0 ON NO X oO nN ad in A Non io . - = MO ee eH A + al oe - Hn e ©O * ° ‘ :

MND m0 oo NA o- mom oe On o @ 0 oO DD ~~ Wn on 0 oN 0 © 8 ~~ Hu O00 Om Nm < UU << m

L QO Oo MN BO Qo Oo oO Q Oo ~ Pr] 1 1 1 e O ! 1 1 1 1 t a > - +H += om oo = = ~~ ~ a Oo oN A No AA od + A A ~ 49 jo] . 0

A = ~ } 0 nN m Ld 0 un . - ~’ NN 8 Qo *

BQ = Ny ml 5 5 n on - Nn WO In InN Ww i ~ A Nn MON IN ml e = ° °° 2 ld A AM a8 E 1 MN MOM ny Nn

Bod b> <a ~~ = ~~ ~~’ \0 2 > 0

A 5 ~ . & © ol o 2 2 MN < = . on Oo oO 0 +H +4 + ™ = ol oN ay ol MNO MN nN mo! = i . «oe oo «a sled = al J on Noo alo 1 0n 3

Jz m [a] § ~~ a ~ 2B ™ ) » a 0 o~ o& o~ © © © © lu ~ tN [1a in un n mn on nn nto > . . . . . ° » . o| ©

T fi ~ dt ft A A AA Ag 0 wt 0 h i o~ i ° 3 ~ . Q 0 9 T 2 2 2 A % RIS a= * 3 Fn nn nH g =] 3 +4

REFERENCE EXAMPLE 50 100 mg of the compound 27 was dissolved in 1 ml of chloroform and stirred for 2 hours with addi- : tion of 40 ul of methyl iodide. After most of the solvent was distilled off, 5 ml of ether was added and the precipitate formed was filtered. The preci- pitate was washed with ether and dried to obtain 65 mg (yield 54%) of 8,9~-anhydroerythromycin A 6,9-hemi~ ketal methyl iodide (compound 55) in white powder.

REFERENEBE EXAMPLE 51

By using 30 mg of the compound 32 and 15 pi of methyl iodide, the same processing as in Reference

Example 50 was conducted to obtain 18 mg (yield 51%) of 11,12-di-O-acetyl-8,9-anhydroerythromycin A 649~ hemiketal methyl iodide (compound 56) in white powder,

REFERENCE EXAMPLE 52

By using 79 mg of 11,0-methanesul fonyl-8,9~an~ hydroerythromycin A 6,9-hemiketal (compound 57) and 29 ul of methyl iodide, the same processing as in Re- ference Example 50 was conducted to obtain in 55 mg (yield 58%) of 11~0-methanesul fonyl-8,9~anhydroery=- thromycin A 6,9-~hemiketal methyl iodide (compound 58) in white powder.

REFERENCE EXAMPLE 53

By using 78 mg of the compound 25 and 59 ul of methyl iodide, the same processing as in Reference

Example 50 was conducted to obtain 67 mg (yield 7453) of 11~O-methane~-sul fonyl-""-g-Lormyl-8,9-anhydroery- thromycin A 6,9-hemiketal methyl iodide (compound 59) in pale yellow powder.

REFERENCE EXAMPLE Sh 200 mg of the compound 27 was dissolved in 4 pr of chloroform, then 0.5 ml of ethyl iodide was added thereto and the mixture was refluxed for 20 hours.

After most of the solvent was distilled off under re- duced pressure, 10 ml of ether was added and a preci- pitate formed was filtered. The precipitate was washed with ether and dried to obtain 145 mg (yield 60%) of 8,9-anhydroerythromycin A 6,9-hemiketal ethyl : jodide (compound 60) in white powder.

REFERENCE EXAMPLE 53 200 mg of the compound 27 was dissolved in 4 ml of chloroform, then 0.5 ml of propyl jodide was added thereto and the mixture was refluxed for 48 hours.

After the same processing as in Reference Example Sl, } 120 mg (yield 48%) of 8,9-anhydroerythromycin A 649 hemiketal propyl iodide (compound 61) was obtained in white powder, .

REFERENCE EXAMPLE 56 200 mg of the compound (1) and 0.2 ml of methyl iodide were employed to carry out the same processing as in Reference Example 50. As the re- sult, 154 mg (yield 65%) of 2'-O-acetyl-8,9-anhydro~ erythromycin A 6,9~hemiketal methyl iodide (compound 62) was obtained in white powder,

The structural formulae of the compounds ob= tained Reference 50 to 56 and their physical properties ) are shown in Table 8 and Table 9, respectively, v lH HoH HH

CM my i nm nn wlg gg 8 BE § #5 F . ml] © vO bv LL 0 no o| JO SN SN NE BM wl 5 8 8 B no B

Hoo

Sn

Po] oO oO 8 © oO ae mlm nom om omomom - Oo 4 on om mm on Oo

Toe \ © [a . ol®@ =, Ln AN Na i / © o oO oO © : =] S — TY 0 nn 0 bl mn oO = mp Moy nm i malo ™ mom

Sleo Oo OO © , a 0 0 - . og 5 ry 3 ) © nN o } AR o LE

SNC oN Mm tod } Mm 3 - 8 / o a) o . WC 5 ~ © te, © =] ST TT I ; ee} . oO 0 © 0 = . o 8 n Ww © oo © HH « of in mn mn 0 00 8

O oO 3

~~ . - o ~~ MN

Hoo » no ~ 0 - - > ~~ ~~ nw un nN td - pe) ”» MN —~ 0" I od - = 0 eI id @ NN un A 0 > no - . Q ~~ 0 Oo MN mn 0

Q oO oO = HB ! 0 QO 0 3 - Q ~~ 1 1 ol NO : ~~ ~ No OQ ~~ Q mM ~~ ~~ ~~ - ~ 0 MN ~~ Nn Noy On A a oa 1 9 St ~ nr pd ~ ~~ pd Q OQ ~ OO

Q Q . TER «0 O 0 0 OO MN MN aN MN

Ee] a on O I A ~ NRA a a ~~ A g] » 0 . ss O + O . « UO 0 0 « O = ~~ ~ ON ~~ nN ~~ MN 00 ~~ ~~ ~ oN o 3 d=

Bl MN . » 0 ~ aN o- Nn = 4 oQ <Q he

LL] + NN = in NN MN 81 3 . . . . . * . £ ? Ny Ny Lan MN La MN Mm » - ol] Mn @ “a mM = Q ~~ =A I > ~~ ~~ ~~ ~~ ~~ ~~ tx = -3 od hos joo] wn 4 om oh ao On 1 0 oN On mo Mn oO, ~ WO ~ 0 oN - . ” * - ® - o ”~ . ” 0 ”- . -~ nN MN NN 0n nn Non Nn No 0 Nn Noa hd Nt Ad So Sr ~~ Ad

Mm = - m . 4

E+ ~~ ol

MN

- 0 ~ [on] ao QQ nn <0 QQ . n mn nn tn wn n tn n tn ~ 0 * . . . . ° . 2 ~ ~ ~ r+ [a — — lal 1 0 1 ~~ ~~ ~~ ~~~ ~~ ~~ ~~ nN MN o nN jos} Jo] 22] . 4 © t 0 Oo oo [ed o Qo Q a . o vv +4 OO od My oo O oQ nt NO NM

Ae] jax] si oi LI: « o oo ° 0 nn 0 NO 4 O oO oO + OO 0 o o o «oJ oJ aN a - 1 ” t - 1 - - 1 ~ = 0 1 Qo Oo oO Q ~ O oO 1 O rf ss N\ . La ¢ MN . nn oN ee Ny .

Hh Da) —~ NN NN Ng Ma NAN NA 8d ING " > 0 ™ i ™ I" ™ n ™~ it ~ n 2,0 0 To ol} 0 ol o 1B of {T, ol see ee Ge ge ge gee . . 0 0 in 0 oO on Q ~ oJ

Bom wn tn mn in 0 0 0

Q

R oO

REFERENCE EXAMPLE 57 100 mg of the compound 27 was dissolved in 2 : ml of dry ether and added with 73 pl nf diisopropyl-

A ethylamine and 33 ul of valeryl chloride at 0°. The mixture was warmed to room temperature, and stirred for 15 minutes at the same temperature, followédg by dilution with addition of 25 ml of ethyl acetate.

This was washed with the saturated aqueous modium hy- drogen carbonate and saturated aqueous sodium chlo- ) ride solution, followed by drying over anhydrous so . dium sulfate, The crude produce obtained by evapora- . tion of the solvent was purified by silica gel chro- matography (developing solvent:chloroform-methanol- conc. aqueous ammonia (20:1:0.01) to obtain 96 mg (yield 86%) of 21—-0-valeryl-8,9-anhydroerythromycin

A 6,9-hemiketal (compound 63) in white powder.

REFERENCE EXAMPLE 58

By using 50 mg of the compound 27, 37 Pr of diigo- propylethylamine and 20 ul of hexanoyl chloride, the same processing as in Reference Example 57 was con- ducted to obtain 53 mg (yield 94%) of 2'-O-hexanoyl- 8,9-anhydroerythromycin A 6,9-hemiketal (compound 6h) in white powder.

By using 100 mg of the compound 27, 73 pl of diisopropylethylamine and 93 mg of arachidonyl chlo- - 115 =~ [ 9 »,

BAD ORIGINASR EAL 9)

ride, the same processing as in Reference Example 57 was conducted to obtain 104 mg (yield 73%) of 2'- 0O-arachidonyl-8,9-anhydroerythromycin A 6,9-hemi- detal (compound 65) in white powder.

REFERENCE EXAMPLE 60

By using 100 mg of the compound 274 73 pl of di- jsopropylethylamine and 34 ml of isovalery chloride, the same processing as in Reference Example 57 was conducted to obtain 100 mg (yield 89%) of 2'-~O-iso- valeryl-8,9-anhydroerythromycin A 6,9~hemiketal (com= pound 66) in white powder.

REFERENCE EXAMPLE 61 . By using 100 mg of the compound 27, 73 pL of di~- isopropylethylamine and 27 pt of crotonyl chloride, the same processing as in Reference Example 57 was conducted to obtain 87 mg (yield 79%) of 2'~O-crotonyl- 8,9~anhydroerythromycin A 6,9-hemiketal (compound 67) in white powder.

REFERENCE EXAMPLE 62

By using 100 mg of the compound 27, 73 pt of di- isopropylethylamine and 33 pL of benzoyl chloride, the same processing as in Reference Example 57 was conducted to obtain 87 mg (yield 75%) of 2'-O-~benzoyl-

8,9-anhydroerythromycin A 6,9~hemiketal (compound 68) in white powder,

REFERENCE EXAMPLE 63 200 mg of the compound 27 was dissolved in L ml of chloroform and 150 pt of diisopropylethylamine was added thereto. After the mixture was heated to s0°¢c., 32 pL of methanesulfonyl chloride was added : thereto and the mixture was stirred for 25 minutes, followed further by addition of 20 pL of methanesul- fonyl chloride. After stirring for 15 minutes, the mixture was cooled to room temperature and diluted with 30 ml of ethyl acetate. This was washed with gaturated aqueous sodium hydrogen carbonate and satu=- rated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent was purified by silica gel chromatography (developing solventichloroform— methanol-conc. aqueous ammonia (60 : 1 : 0.01) to ob= tain 53 mg of 2'-O-methanesulfonyl-8,9~anhydroery- . thromycin A 6,9-hemiketal (compound 69) (yield 24%) “and 52 mg (yield 21%) of 11,2'~di-O-methanesulfonyl- 8,9-anhydroerythtomycin A 6,9-hemiketal (compound 70).

REFERENCE EXAMPLE 64 100 mg of the compound 27 was dissolved in 1 ml of dry pyridine, added with 0.3 ml of diphenyl- chlorophosphate and the mixture was stirred over- night. The mixture was diluted with 20 ml of ethyl acetate and the solution washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride solution and was dried over anhydrous sodium sulfate and the solvent was evaporas ted. The crude product obtained was purified by silica gel chromatography [developing solvent:chloro- formme thanol-conc. aqueous ammonia (10:1:0.01)7 to obtain 43 mg (yield 33%) of 2(-0-diphenylphosphoryl- 8,9-anhydroerythromyein A 6,9-hemiketal {compound 71) in white powder.

REFERENCE EXAMPLE 65

Using 100 mg of the compound 27, 1 ml of py- : ridine and 0.2 ml of diethylchlorophosphate, the same processing as in Reference Zxample 64 was con~ ducted to obtain 25 mg (yield 21%) of 2t'-0~diethylphos- phoryl-8,9-anhydroerythromycin A 6,9-hemiketal (com= pound 72) in white powder.

REFERENCE EXAMPLE 66 157 mg of the compound (8) was dissolved in 1 ml of dry pyridine, added with 0.2 ml of valeric acid

Co } anhydride and the mixture was stirred at 50° Ce for

2 weeks. After the mixture was cooled to room tem- perature, it was diluted with 30 ml of ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride so- "5 lution and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue obtained was dissolved in 6 ml of methanol, followed by stirring at 50° ¢. for 3 hours. After cooling to room tem— perature and addition of 0.4 ml of 5% aquecus sodium : 10 hydrogen carbonate solution the mixture was further i | stirred for 6 hours. After concentration to a volume : of about 2 ml, the concentrate was diluted with 30 ml of ethyl acetate and washed with saturated aqueous godium chloride solution, followed by drying over an- hydrous sodium sulfate, The crude product obtained by evaporation of the solvent was purified by silica gel chromatography [developing solvent:chloroform— methanol-conc. aqueous ammonia (10:1:0.1)) to obtain 91 mg (yield 57%) of 11-0-valery~8,9-anhydroerythro- mycin A 6,9~hemiketal (compound 73) in white powder.

REFERENCE EXAMPLE 67

By using 157 mg of the compound 8, 1 ml of : dry pyridine and 0.2 ml of hexanoic acid anhydride, the same processing as in Reference Example 66 was conducted to obtain.98 mg (yield 60%) of 11-O~hexa- - 119 ~- a noyl-8,9-anhydroerythromycin A 6,9~hemiketal (come pound 74) in white powder.

The structural formulae, specific rotatory powers and NMR spectrum values of the compounds ob tained in Reference Examples 57-67 shown in Table 10. ra \

~~~ ~~ o joa] . 3 ~~ mp -

INE \ 8 ray x Oo wn on [3 £4 o « O 0 ~~! QQ \0 * r=] un gl © -—poreeo 0 ae 4 © . ~~

Jo] of MN a] oe . “| a ©] 0 WW © - OO > © MON mn = *« oe 8 0 “of § MN Nn ~~} = 0 ~ = zl ~~ i 1] ml Ww ~] =» n - J nn Mm in + © . Nl Noy oN [}) sa 0 & oo 0 = ov ou a ow 7

MN

~~ . a Jos} a £3 Mm bd nom 0 0 in te . \ oD] QO o a eo 9

Coe o f- =] A A A ~+ + 3 ) OQ = Mog

Do ol LA. a H lo

A = q o mj o <| ~

Et m 10 [aN tre [AA : My 5 = oy A na © in NAB © MN elo oo oo oo 0 ol © nN oo FF nN

NN 0,3 se eo 0 0° 2» . 4 co | = a on oO © 4 oO oO =O ol] mm Mm a Mm» — — ror tr { o on = oN 3 Bo Ng fomomom om : N

C8 OH mo a —~Y - MN Nn . moog 0 ln

OO © 8 H

X Mm SF AH ~ ~~ ~~ x I : NOON NOD oo oo .

UO OO oO mom 3 8 85 8 3 he 8 83 8 8 8 dg 8. 0 © 0, Mm Fn Oo

E OW DV WOW WO

J mm ! nN Nn - - » ~~ 1 ~~ wu 0 it . 2] ~ ~ Oo :

NN 1 > — — ”

X . £8 ~ . » 8 ~~ i ~N Ny ~~ na Nn . + - .“ wo un e EB NN Ne . 5 | momo . © o OO = w 0 NO ee : » 0 oO Oo £ : ~] 0 Aco mm — ] ~~ i

Al of a ! - o : ol — :

Slo 0 nF BIN uy ‘| = + MON RN NY oy al © . * » « ° . . *

J MY MY tn Nn NN [AA : “n ™ ’ ~ ' gl ~ ; z ml

Z

1] = ml wv 1 rt at oJ Q QO OO Mm © oO Cc os © a MA Mn NN 1a) = 0 . * . [] 9 . = od od ~N oN oJ ol ©} .

MY . f= . nN = { ir Nn

MN © Hn - ‘ i jas} © o ~~ © c- Ww Oo eof © MNO hn! ~~ in InN nN nnn mn ol oO © . » . ° 0 ° of oO = — ~~ —t ~t ~~ - 2 O MN | ! o = mo joo i

Al om - © oN 0 al B/N a o oO ~~ , ! m — nN My <i ml 3 £4 [&) Mn O

My - a 3 jar} MN no 0 5 het NN, » 0 0 o o o © 0 } © »< 0 nN oo 4 $+ 2 0 & . MN . © . ° * ° 1 + on Fo oN Oo e-

MN ol 1 Noo FF FN —~ ee) o o - 1 I 1 1 1 I ry -— ! \ nN 1 MN oO jae] MN mo © ~~ |] £ oN oN -t

Non a Q moe ~~ oi NOM oi tn mom om om Do oJ 0 D— © ~~ = oN Oo InN Q S aboot na |) ~r i m To Q

Oo

Now ~~ ~~

Nona jas] od Pe 2] £8 Dv oO 9D ny ol Nr ~ ~ oO oO oO oO Oo m © 0 ©] a My jas] jae] 5

QO

2, 0 0 oN 0 A NM =

E= © vo ~~ o

REFERENCE EXAMPLE 68 1.00 g of de(ll-methyl) erythromycin A (re- re ference: Japanese Laid-open PatentApplication No. 9129/1972) was dissolved in 5 ml of glacial acetic acid and the solution was stirred for 1 hour. The : reaction mixture was poured into 20 ml of ice-cooled conc. aqueous ammonia. The mixture was extracted 3 times with 10 ml of chloroform. The chloroform so- lution was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.

The residue was purified by silica gel chromatography [developing solvent:chloroform-methanol~conc, aqueous ammonia (10:1:0.1)7 to obtain 830 mg (yield 85%) of de- (N-methyl)-8,9-anhydroerythromycin A 6,9-hemiketal (compound 75) in white powder.

REFERENCE EXAMPLE 69 930 mg of bis-/de(N-methyl)/erythromycin A (re-~ ) ference: Japanese Laid-open PatentApplication Nos 9129/ : 1972) was processed in the same manner as in Reference

Example 68 to obtain 770 mg (yield 85%) of bis [de (N= methyl/-8,9-anhydroerythromycin A 6,9-hemiketal (com= pound 76) in white powder.

REFERENCE EXAMPLE 70 #00 mg of ethyl-nor<erythromycin A [Teference:

R. K. Clark, Jr. et al. Antibiotics and Chemothera- py VII, 483, (1957)7 was processed in the same man- ner as in Reference Example 68 to obtain 327 mg (yield 84%) of ethyl-nor-8,9-anhydroerythromycin A 6,9~hemiketal (compound 77) in white powder,

REFERENCE EXAMPLE 71 168 gm of butyl-nor-erythromycin A [reference:

R. K. Clark, Jr. et al. Antibiotics and Chemotherapy

VII, L383, (1957) was processed in the same manner as in Reference Example 68 to obtain 99 mg (yield 60%) of butyl-nor-8,9-anhydroerythromycin A 6,9~hemiketal (compound 78) in white powder,

REFERENCE EXAMPLE 72 88 mg of the compound 77 wae dissolved in 2 ml of chloroform, then 1 ml of ethyl iodide was added thereto and the mixture was stirred at 80°c. for 1k hours. After most of the solvent was evaporated under reduced pressure, 5 ml of ether was added and the pre- cipitate formed was filtered. The precipitate was washed with ether and dried to obtain 72 mg (yield 67%) of ethyl-nor-8,9-anhydroerythromycin A 6,9-hemiketal ethyl iodide (compound 79) in white powder.

REFERENCE EXAMPLE 73 376 mg of the compound 76 was dissolved in 5 ml of methanol. 138 mg of sodium hydrogen carbon- ate and 1.0 ml of l,4-dibromobubhane were added, and the mixture was stirred at 50°C. for 8 hours. The reaction mixture was diluted with 30 ml of ethyl acetate, and washed with water and saturated aqueous sodium chloride solution. The ethyl acetate solution was dried over anhydrous sodium sulfate and the sol- : : vent was evaporated under reduced pressure. The re- ‘ sidue was purified by silica gel column chromatogra- phy /€luant: chloroform-methanol-conc. aqueous ammonia (10:1:0.1)7 to obtain 158 mg (yield 39%) of de(dimethyl- amino)=3'=pyrrolidino~8,9~anhydroerythromycin A 8,9~ hemiketal (compound 80) in white powder.

REFERENCE EXAMPLE 74

By using 63 mg of the compound 80 and 0.1 ml of methyl iodide, the same processing as in Reference

Example 50 was conducted to obtain 70 mg (yield 93%) : of de(dimethylamino)=3'-pyrrolidino-8,9-anhydroery- thromycin A 6,9-hemiketal methyl iodide (compound 81) : 20 | in white powder.

REFERENCE EXAMPLE 75 120 mg of the compound 27 was dissolved in 1 ml of chloroform, then 0.5 ml of 2-bromoethanol and 0.5 ml of diisopropylethylamine were added thereto and the mixture was stirred for 2 days. After evaporation of the solvent, 5 ml of ether was added and the precipitate formed was filtered. The pre— cipitate was washed with 10 ml of ether and dried to obtain 119 mg (yield 84%) of 8,9-anhydroerythro- mycin A 6,9~hemiketal 2-hydroyxyethyl bromide (com- pound 82) in white powder.

REFERENCE EXAMPLE 76 150 mg of the compound 27 was dissolved in 1 ml of chloroform, then 0.5 ml of allylbromide and 0.25 ml of diisopropylethylamine were added thereto and the mixture was stirred for 1 day. After evaporation of the solvent, 5 ml of ether was added and a precipitate : formed was filtered. The precipitate was washed with 10 ml of ether and dried to obtain 134 mg (yield 76%) of 8,9-anhydroerythromycin A 6,9-hemiketal allyl bromide (compound 83) in white powder.

The structural formulasé;, specific rotatory powers and NMR spectrum values of the compounds ob- tained in Reference Examples 68 to 76 areshown in

Table 11.

. To ' ~~ ~~ wm +» tm UA ] La - \ © - n . > 1 — ~~ ~~ ~ - M MN - MN gl o Ne i Ned 0 fo] 0 0 mW od 0 Nn ©) OU A . = 0 © =O ol © ~ ~ ~ ~~ Ns : a) H : “al @ oy 0 o| = + oN +2 . * © al ol “0 £4 + ~~ ol 4 ng MN w - n un ~~ of ml ~~ My 0 MY = o . » . = wl MY Ny La

QO

J

" MN ow 0 : MN “3 2D ” 0 © = © Ny Ny . — oO a a Oo > un © o~ \O : 3 3 i004 a . . * qs o [3 - - oO 5 0 2a] [ay ; jas} 0 © 3 ty 0 ~~ 0 ~~ nN . 0 oN Aa} + nN os 4 on) » ~~ * — 0 oO o » ~~ ~N\ oO \O Q - oO = on ta 3 m3 ry ol \ ° oJ Qn t D> 1 0 oO 0 1 0 ol Mn [S$] MN -~ 0 - . oy p> oy a No oO oJ A Oo . ord 2) . Q og oY 0 od ™ 3 ~ HH ™ — 4 * Q oO Lv —0 © [3] ¢ m9 Mn a \{ A J el I 2s m ri in nn I Nn as) wo on ol oN ~ re oO = 0 0D \ / NN / = = 0 oe

A 0 in \0 e-

EZ ~~ ~~ o~ oO

~~ . ~ Jax} » Nn ~ od - jae} . o 0 © > ~~ - ~~ i Ld NN n 0 — o MN oO Qo nN 0 moo » NM [a] 8g] ~— 0 A oO fA [&} ’ = O = 0 0a 0 ~~ ar ~~ ~ 0 4 ~ el] 0 NN A) oS oN oO

Al . * al] o a MY > \ Hl ~~ +] ol Mm

Q - 2¢ 0 0 <Q \Q nl ~~ NN Ny Ny o . * . g 5 My MN LAA o =f! © = a NY £2 a og MN My 0 jar] id Q 0 0 |S] —

MN Jas] ’ 4 MN NY pi 0 v1 —~ Oo 0 0 Oo © o rt oO ~ in in mn . M4 . . ° ~ F ~ ~~ ~ od Mm © oQ we

MY NN i joo] © © oO ~~ o Q ~~ / oO Ny Q ~ 0 fe °o | 0 jan} ¢« O

NM o 3 OO C- o Q NM , jos! o 2 NT oJ MN By 0 a 1 © 1 jas] 1 © ’ \ d © |] o MN - MN MN - no NAa9 Na o Na 9 . . 9 .

My oN od N, A ~ . MN, : 8 58 a6 ol od ov! . 5 OO oo ®, ol ©, ol wo, ol of 4 4 ~~ ~~ ~~ } nl Oo 0 ml x w tam . . on in in

A joe] oi t fm 5 s 5 oY Sh

NJ | AN4 = = = o od =e

Qo 0 «Q on £20 [ns oo Oo

B 0

OQ

~~ ~~ Fan ~~ + ro) md Bs) o Nn 0 0 [i] - > - = 0 ~~ 9 ~ n ~~ gl - A > MN -0 24 © no ao NO ng un dN oN 0 MN ~ QA = nN =n

Q 4 © £2 oo Zo

Stn ~~ ~~ ~~ r a te © ox = on sla fea Ny i + ° . © ‘oo al nn ™ a 3] 2] ~ om nl] wv oS. 3 ~ ~~ Ny Ny NN . mi o * . ° ’ ’ =| = NY NY nN ” =o

J fA ’ ~~ . a=) [a he] . Qo un =e] Ky 0 . = MN — tN wn nm

EE 5 m O . ° 9 ‘ rf 0 [=>] = ~t —~ —

Co + mM 0 J i} ofl m no [a ¢ 3 = : — . a Oo (a “ y 3 Oo He oO ~~ oO ~ Qo

Mm : / oO 4 0 = . <q wm © — £4 +s O eo O OO 2 » Nn o ~~ om OWN nn : ni x x oi oo a oO £5 9 0 ron Pn [ES]

J 44 NM - MN - MC - " rf oy oC NO oO jo] oO Q H . 0 a MN oe oO \ o ox Ne ~ ™ ~ P no 0 [3] ol © 5 © NL Ge : Nn 3 jae] oy , © od uw?" . Boom m © od x 5 $4 m m oJ ® 3 i a © 4 oN I} a3 jas] £3 ©

NN HY nN [Y) 0 MY on 3 md = jog] ja od ol © Nn WO © ® @ >= @ = 5

QO .

Po ~~ od nN : 8g = oO o0 [se] oO . 5]

of chloroform, then 0.7 ml of propyl iodide was added thereto, and the mixture wes heated under re- ’ flux for 2 days. After evaporation of the solvent, ml of ather was added and the precipitate formed 5 was filtered. The precipitate was washed with 10 ml of ether and dried to obtain 87 mg (yield 70%) of 9-dihydroerythromycin A 6,9-epoxide propyl iodide (compound 87) in white powder.

REFERENCE EXAMPLE 80 100 mg of the compound 84 was dissolved in 1 ml of chloroform, then 1,0 ml of butyl iodide was added thereto, and the mixture was heated under re=- flux for 1 days. After evaporation of the solvent, . 5 ml of ether was added and the precipitate formed was filtered. The precipitate was washed with 10 ml of ether and dried to obtain 95 mg (yield 76%) of 9- dihydroerythromycin A 6,9~epoxide propyl iodide (com- pound 88) in white powder.

The structural formulae, specific rotatory . oT 20 powers and NMR spectrum values of the compound obtained in Reference Examples 77 to 80 are shown in Table 12.

—~ nA ' o

Nn} ~~ alm 0 Ny ~A - 0 o~ 0 gl «— "nm "ny MN MN 0, Q . » * ¢

I MY MY Nn )

Q

[)] 1 . =o = ~ NN © > . “0 ~~ ~~ ~~ Fa g mi 11d jo=] je] o 0 Ww 0 . 2 » - - - 41 ~~ MN aol od od © 0 Q [i] [}} Q ~~ 3) = = =a 2] o = = on =z n = } 1 I ) = - - - - oo i MY NY 0 MN —= - ~r rt ~~ ~~ © 218% 8S v © — . . . . ry la NY MN . wr Mm

Sm bel a nw io \ | < wi q 2 7 xt 2 [&) MN 0 i . La] Oo 2 Hl © > oO mlP o o . 0 Q o © . +3 we ' 0" ~ 9 SN a hy 2 1 on o © ° . a 5 ol 0 in oO O = J ~ MN [Ia <4 o [aN 1 | 1 ! 3 i) 0 0 od . m ~~ = =O =o G,

My oN MN [==] w= 0 © 0 n

QO OO La £3

Hom om oT 0 7 N © jaxi wn oon

My tr oJ a jan] od 0 od

[3] ry oO ol 0 © yr © o gq. 0 0 in 0 © 87 0 oD 0 o0 0 [sb]

REFERENCE EXAMPLE g] 200 mg of the compound 27 was dissolved in 4 ml of chloroform, then 0,3 ml of benzyl chloride was added thereto and the mixture was heated under reflux for 48 hours. Subsequently, the same processing as in Reference

Co Example 54 was conducted to obtain 122 mg (yield 527) of - : 8, 9-anhydroeyythromycin A 6,9-hemiketal benzyl chloride (compound 89) in white powder.

REFERENCE EXAMPLE g2 200 mg of the compound 57 was dissolved in 4 ml of chloroform, then 0.5 ml of ethyl iodide was added thereto and the mixture was heated under reflux for 20 hours. Sub- sequently, the same processing as in Reference Example 54 was conducted to obtain 134 mg (yield 56%) of 8,9-snhydro- erythromycin A 6,9-hemiketal ethyl iodide (compound 90) in pale yellow powder. : REFERENCE EXAMPLE g3 200 mg of the compound 57 was dissolved in 4 ml of chloroform, then 0.5 ml of ethyl iodide was added thereto end the mixture was heated under reflux for 20 hours. Sub- sequently, the same processing ag in Reference Example 54 was conducted to obtain 126 mg (yield 52%) of 11-O-mesyl- 8, 9-anhydroerythromycin A 6,9~hemiketnl ethyl iodide (com~ : pound 91) in pale yellow powder, i

200 mg of the compound 57 wag dissolved in 4 ml of chloroform, then 0.5 ml of ethyl iodide was added thereto and the mixture was heated under reflux for 20 : | 5 hours, Subsequently, the same processing as in Reference

Exomple 54 was conducted to obtain 126 mg (yield 597) of ; 11-0-mesyl-8,3-anhydroerythromycin A 6,9-hemiketal ethyl iodide (compound 91) in pale yellow powder.

REFERENCE EXAMPLE g4 200 mg of the compound 27 was dissolved in 4 ml of chloroform, then 0.5 ml of ethyl bromide wns added there- to and the mixture was heated under reflux for 48 hours.

Subsequently, the same processing as in Reference Fxample 54 was conducted to obtain 189 mg (yield 82%) of 8,9- anhydroerythromycin A 6,9-hemiketal ethyl bromide (com- pound 92) in white powder,

The structural formulae, specific rotatory powers and MMR spectrum values of the compounds obtained in Re- ference Exomples 81-84 are shown in Table 13.

~~ - $s] - Ny un MN jar] - ry 0 © CoN £3 Of Q

Ay = QQ ™ LY} ~~ ~~] © ~ ry oad ~r in [] IE [\ ~~ NY MN ol © 4 0 3 = . £2 in Ne oJ - nl] +» 0 su «0 . ol o o~ Nn MN . ~~

J - £1] ~~ ’ of i

I” n{ - ol ©w a3) ~~ 4 ~~ |p 0 ~| © MY MY Hy ny dl = . . . 9 sO NN ty toy Ny : <a = ry g = i] ~~ +1 iT ol wo [+] - 24 0 on ~~ o0 on . vl] ~~ O . LE] — oJ ° 0 * 0 ml o MN © ry ia) i

Ny ~~

Ti

MN

- on lo |] On 0 tn 0 0 tn @ ~~ . a . °

Li t ~ ef ~ — i= od

NN i 0" MY jee] n,m vi gd oO ~ \ t © is] a I. 2 ce joa] \ © 3 td = lo] Q 0 © »

O Q Oo oO Q

Ny Oo OQ ° \0 3 . on oJ ~~ ml 10 ol @ ¢ * °

QO, ind 0 0 o~ ~ = ry ol 0 od ny la 3] MY ~~ 1 ! 1 1 oq wo PY MN of [] wd od = [5] ro - MN . ® © Oo =O 4

Oo ~~ 4

San be © + i. -

Nn ig wl jas] NN B— > MN IN o Oo a

Fort 1 =

L of a vd in oJ 0) in ra i m hd ri «ol ad © oJ m3 © ! ow ©

My NY

Td aot > nd ong ol ov ml Q oO ir 0 0 ! pe] 8. 0 0 ON Oo ~t NN iz oo ON oa on a8

Oo [db] +

By use of 68 mg of anhydroerythromycin A (com- pound 93) [reference: P. Kurath, et al., Experientis, 27, : 362 (1971) end 0,2 ml of ethyl iodide, the smme process- ing as Reference Example 54 was conducted to obtain 69 mg of anhydroerythromycin A ethyl iodide (compound 94) in white powder (yield 75%).

By use of 105 mg of the compound (93) end 0,3 ml of propyl iodide, the same processing as Reference Fxam-— ple 55 was conducted to obtain 93 mg of anhydroerythro- mycin A propyl iodide (compound 95) in pale yellow pow-— der (yield 72%).

REFERENCE EXAMPLE 87

By use of 105 mg of the compound (93) and 0.5 ml of benzyl chloride, the same processing ss Reference Exam- ple 55 was conducted to obtain anhydroerythromycin A ben- zyl chloride (compound 96) in a yield of 75%.

The structural formulae, specific rotatory powers and MMR of the compounds obtained in Reference Examples 85 to 87 shown in Table 14,

¢ ~ { m ~~ oO t s+] . X [1a . © n - : . ~ 4 o ' © = ' ~~ £3, 8 } uy ©. ! oy i ~~ o ; of 4 : « > te “alo , - 0 . £7 . gl - fo os oO fa] ov tn oN rd {

Pw 0 . . . : of = to Hy ty : 0, 3 .

Pe! . 0] - ) . try | . m . = { =z : 1 : oO wm | { > A : wm w 1 o a AO - a Q = ! ed 3) tS ne 2 Iv 1" A

D-= 85 «0 IO

Oo © J zl A oe o 318 © a wo LID £4 ¢ ae '

PN a . of 3 3 = = 3 4 o Oo OO Q Q o © MO MD Py = eo 13 °o 3 [I

Oo ny ©» = [gh] «QQ Le) nN Q ty NY ri a O Bal - ~ & © © wb to Ie 1 oO oO AK . , . . ; a " 0 © PM, Pe MN,

P . "8 N_ 5 20 oo ol |v, ol 5, ol i) - 0 5 J ~~ NI | ~ © oO 0 ed . oe - = ty £L

LN © 0g ot jar o a4 a} MY 3 ry > 0 ° 8. oo = in \0 . Rm an on on £ oO © re

REFERENCE EXAMPLE 68 ‘ 206 mg of the compound 76 was dissolved in 3 ml of methanol, then 76 mg of sodium hydrogen carbonate md 0.5 ml of ethyl iodide were added thereto, nnd the mix- ture was stirred at 50° C. overnight. This remction mixture was diluted with 30 ml of ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride solution, The ethyl acetate solution was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure.

The residue was purified by silica gel column chromago- graphy (developing solvent: chloroform-methanol-conc, equeous ammonia (50:1:0,1) to obtain 98 mg (yield 449) of diethyl-dinor-8,9-mhydroerythromyecin A 6,9-hemiketal (compound 98).

REFERENCE EXAMPLE gg

By using 550 mg of the compound 76, 1-6 ml of 1,5~ dibramopentane and 202 mg of sodium hydrogen carbonate, the same processing as in Reference Example 73 was con~

Co 20 ducted to obtain 327 mg (yield 54%) of de(dimethylemino)- 3! ~-plperidy1-8,9~anhydroerythromycin ‘A 6,9-hemiketal coy pound 99) in white powder,

REFERENCE EXAMPLE 90

By using 78 mg of the compound 97 end 1 ml of ethyl iodide, the same processing ss in Reference Example T2 wes conducted to obtain 15 mg (yield 16%) of diethyl- dinor-8, 9-unhydroerythromycin A 6,9-hemiketal ethyl iodide (compound 100) in pale yellow powder,

REFERENCE EXAMPLE 9)

By using 93 mg of the compound 80 and 1 ml of ethyl iodide, the same processing as in Reference Fxample 72 was conducted to obtain 94 mg (yield 84%) of de(dime- thylamino )-3'-pyrrolidino-8,9-anhydroerythromyein A 6,9~ hemiketal ethyl iodide (eompound 101) in pale yellow powder,

REFERENCE EXAMPLE 92 83 mg of the compound 99 and 0.5 ml of methyl iodide were dissolved in 0.5 ml of chloroform, and stirred at 40%. for 9 hours. Thereafter, the seme processing as in

Example 50 was conducted to obtain 84 mg (yield 85%) of de~ (dimethylamino )-3'-piperidino-~g, 9-anhydroery thramycin A 6,9- hemiketal methyl iodide (compound 102) in pale yellow pow- } der,

REFERENCE EXAMPLE ,

By using 94 mg of the compound 99 and 1 ml of ethyl : iodide, the same processing as in Reference Exemple 72 wns conducted to obtain 33 mg (yield 29%) of de(dimethylemino)-

31~piperidino-8, 9-anhydroerythromycin A 6,9-hemiketal } ethyl iodide (compound 103) in pale yellow povder.

REFERENCE EXAMPLE 94

By using 50 mg of the compound 27 and 0,6 ml of propargyl bromide, the same processing as in Reference

Example 50 was conducted to obtain 52 mg (yi eld 89%) of 8, 9~enhydroerythromycin A 6,9~hemiketal propargyl bromide (compound 104) in white powder,

REFERENCE EXAMPLE 95

By using 111 mg of the compound 32 and 0,12 ml of propargyl bromide, the same processing as in Reference ~ Exemple 50 was conducted to obtain 111 mg (yield 87 %) 3 of 11,12-di-O-acety1-8,9-anhydroerythromycin A 6,9-hemi- ketol propargyl bromide (compound 105) in white powder,

The structural formulas, specific rotatory powers and MYR spectrum values of the compounds obtained in Re- ference Examples 88-95 are shown in Table 15,

~~ + = 0 > —~ . 0 0 ~~ -— ~~ ~~ ~~ ~~ ia} MN MN a .n a n ~ I. ~ Gn © Oo

I” © 0 © an mn mn o no Nn Nn Nn n 8} © 0 © 0 0 © of rr ~~ ~ = ~ nd o ®

I

~ af sl ~~ <q ey 0 0 in in oon g - 0 Ny NY MY MY nN * ° ° . 0 *

M5 1 a My NY rN +? = of i ’. of = : rd ™ . . [3

Co - . ‘ Red ; : - © \0 0 oo 0 0 wm mn [InN ny in uy x tx S| A 4 ' aA + he r ~ r ba © - od oO = 8 0 bi oO MY [Ta oO oO — jer] —_ £3 53} o 0 ~~ 0 A 2% A oN % oN My ~~ = 231 oS NY oO [# eo 4 eo oo 4 ss ° : « oo} © t~ OU FO MND dt Oo £4 oO = alo NE Nn oJ Nal a ~ 9 1 © [NS 1 rom © 3 io om wl - al - od - oy ol © > Gob NO N LO NL 9 Nol No [I . . MY 0 - : " 0 3 ~ — ~~, MN, HIN : ~

[4] — ml o £2 0 of 5 ol ol 5 .° Sol Got Te Ze Ty

Nat © in © 3 nN LU © H u3 - I 05 “ MN — oo o i “in i" © mm oO ol in aa] NT

Ti nd [a “In ~ © oO = jae! 0 <

Mo NN / Je = = = wT = + ™ a] tre ml tr m o §. 00 o~ es) on oO ~ pol on Io on oO o 6 ~ — ] 0 0

NN

—~ tig ~ . ~~ tx MYM i ro 0 * e\D — " - u nn ee + - un - el) cf 0n - NM Me ov - oJ mE Ne > © ~ ~~ Q ~~ Oven + = 0 Qa =a OO OoO=O 0 = 0 a = 0 DUE MN 0 MN MY 1 MN 1A \ ~r - 0 0 - 0 ~An=- O

B g mo 0 NO ~My . od ©v ~~ ~~ ~~ ns — Ns ev of Kk o NY 0 ~ 3 0 ol] © ~~ oJ Oo Onl . =] + . . . «0 o oO MM 0 af oJ MN . 4 . ’ “0 ~~

Td gl Mm =~ -

Hl oo QQ 0 aon on

Pll mn NN oy NY © Q . ° . . ov] 8B ty Hy 0 NY oy OO 0 Jd ml = “a — © a) - QQ | x) rt n nN i [Ta ry

Nt » ° ° » ” @ ~ et ol el = o 1

MN

8 mr nN 0 a © i Jas] nr wv QC

Bl ne ee \ 8 mS © ig 0 ~~ ~~ ~~ ~~ a o © oo = o o uf om . 3 © 8 ec O nD o oO oo Oo @ o- NY . MN . Ny ’ NY ~ kA oN ast nd ~~ Oo oO ° 1 © on oO MNO nO oO MN f; 0 0 I 1 I ie ml wd ol [a] - of - oN - od - ’ m © Hop NL 9 nO ol LQ NO * -- ° q . - . & wh win 9 ) ~ ~, MN, NA + + © © oo iN ol Ne of ) ol © ol

CR SN I I= I — J = oo oO oO \ Oo } © MY \ joo]

Hy © a © © ® jas] 4 rd |] . w- aa] = m [&] m 0

Q Mm nn ® o um nN my Ll ll m 0 xy ol © [&) 0 po] in ny 1 I tg oy NN nl ~ =i va © wo om om : ® \@ ,° OO =

MN ast m jas} [221 rt ©

Q

© o g ® NN MN =a un 0 0 oO Q oO Oo [TA ~~ 4 [al r— g c © - 1h2 =~

REFERENCE EXAMPLE 96 120 mg of 11-O-methylerythromycin A (reference

Japenese Isid-open Patent Publication No, 192294/1982) was dissolved in 6 ml of glacial acetic acid and the so- lution was stirred for one and a half hours, The re- : action mixture was poured into 15 ml of ice-cooled conc. aqueous gmonia. This mixture was extracted 3 times with m1 of chloroform. This chloroform solution was dried over anhydrous sodium sulfate, end the solvent was eva- ) 10 porated under reduced pressure, The residue wns purified by silica gel chromatography (developing solvent-chloro- form-methenol-conc, squeous ammonia (20:1:0,01)) to obtain 95 mg (yield 75%) of 11-O-methyl-8,9-anhydroerythromycin

A 6,9-hemiketal (compound 106) in vhite powder.

REFERENCE EXAMPLE 97 125 mg of 11-O-ethylerythromycin A (reference:

Japenese laid-open Patent Publication No. 192294/1982) was treated in the same mammer as in Reference Exemple 96 to obtain 102 mg (yield 84%) of 11-O-ethyl-8,9-anhydro- erythromycin A 6,9-hemiketal (compound 107) in white pow- der.

REFERENCE EXAMPLE 9g 120 mg of the compound 48 was dissolved in 3.2 ml of chloroform, then added with 2 mg of A-dimethylaminopy-

ridine, 0.86 ml of triethylamine and 0.86 ml of pro- pionic anhydride, snd heated under reflux for 3 days.

The reaction mixture was cooled to room temperature and the same process as that for obtaining the compound 28 was conducted to obtain a pale yellow glass-like subs- tance, This substnnce was dissolved, without purifica- tion, in 6 ml of methenol, snd heated under reflux for 3 days. The solution was cooled to room temperature and concentrated under reduced pressure to obtain a pale yellow glass-like substence. This substance was purified by silica gel column chromatography, utilizing a develop- ing solvent system of chloroform-methenol-cone. aqueous ammorda = 50:1:0,01, to obtain 65 mg (yield 55%) of 11-0- propionyl-12-0-acetyl-8,9-anhydroerythromycin A 6,9-hemi- ketal (compound 108) in white powder.

Rf value: 0,16 {chloroform methanol:cone. aqueous ammonia = 10:1:0,01), low mass: M + 813, high mass: 813.486 (calcd, for C,,H NO) : 813.487).

REFERENCE EXAMPLE 99 120 mg of the compound 48 was dissolved in 3,2 ml of chloroform, then added with 2 mg of 4-dimethylamino- pyridine, 0.86 ml of triethylamine and 0,86 ml of butyric anhydride, and processed in the same manner as in the preparation of the compound 108 to obtain 75 mg (yield 67%) of 11-0-butyryl-12+<0-acetyl-8,9~anhydroerythromycin

A 6,9~ hemiketal (compound 109) in white powders

Rf value: 0.16 (chloroform-methanol-conce aqueous ammonia = 10:1:0.01), low mass: I + 827, high mass: 827.502 (calcd. for Cy 3H, 3N0y yy: 827.502) 0

REFERENCE EXAMPLE 100 100 mg of the compound 32 was dissolved in 1 ml of chloroform and heated under reflux for 2 days with addition of 0.5 ml of ethyl bromide. Thereafter, the same processing as in Reference Lxample 50 was conducted to obtain 98 mg (yield 86%) of 11,12-di-0~ acetyl-8,9~anhydroerythromycin A 6,9-hemiketal ethyl, bromide (compound 110) in white powders

REFERENCE EXAMPLE 101 150 mg of the compound 27 was dissolved in 1 ml of chloroform, them 1 ml of bromoacetate and 0.5 ml. of diisopropylethylamine were added thereto and the mixture was stirred for 6 hours. After evaporation of the solvent, 5 ml of ether was added and the pre- cipitate formed was filtered. The precipitate was washed with 10 ml of ether and dried to obtain 145 mg (yield 80 %) of 8,9~-anhydroerythromycin A 649~hemi-- . ketal methoxycarbonyl methyl bromide (compound 111) in white powder. ~~ v4 ~ 145 -

} REFERENCE EXAMPLE 102 150 mg of the compound 27 was dissolved in 1 : ml of chloroform, then 200 mg of bromoacetic acid and 0.5 ml of diisopropylethylamine were added there- to and the mixture was heated under reflux for 6 hours. After evaporation of the solvent 5 ml of ether was added and the precipitate formed was fil. tered. The precipitate was washed with 10 ml of ether and dried to obtain 127 mg (yield 71%) of 8,9-anhydro- erythromycin A 6,9-hemiketal carboxymethyl bromide (compound 112) in white powder.

REFERENCE EXAMPLE 103 150 mg of the compound 27 was dissolved in 1 ml of chloroform, then 0.5 ml of monofluorcethyl bro- mide was added thereto and the mixture was heated under reflux for 5 days. Subsequently, the same pro- } cessing as in Reference Example 75 was conducted to obtain 135 mg (yield 76%) of 8,9-anhydroerythromycin

A 6,9-hemiketal (2-fluoroethyl bromide (compound 13) ) 20 in white powder. - REFERENCE EXAMPLE 104 150 mg of the compound 27 was dissolved in 1 " ml of chloroform, then 0.5 ml of bromoacetonitrile was added thereto and the mixture was allowed to stand at room temperature for 5 hours. Subsequently, the same processing as in Reference Example 75 was con- ducted to obtain 165 mg (yield 94%) of 8,9-anhydro- erythromycin A 6,9-hemiketal cyanomethyl bromide (com= pound 114) in white powder.

The structural formulae, specific rotatory powers and NMR spectrum values of the compounds obtained in

Reference Examples 96-104 are shown in Table 16.

IO 1 5

- —~ ~~ ~ ~

Jest Jor] Jas] jas] . ~~ MN MN NN nn 2 - - - - : c 0 0 0 0 © ~~ ~~ ~~ ~r > —~ on Nn o nN 0 + Oo Oo oo wn » . . se ~~ MN a) oN nN ~~ ~~ ~~ ~n ~~ 0n Q Mn Mm 0 MN 0 ha 0A . = = eid oo <q I << rd << <x O o Qo © QQ QQ QO Mm : £1 fr An 10 1 0 t 1A

Fe ~ OO Oo oO a0 NO . a oO or a rd ~~ No ~ ~~

[2] fy fo jas] . om . a -

Hw \D 0 bet oJ 0 @ | LA MN NY Nn Ny le . . . . .

MN NY MN MN Nn 3 : 5 NY : 2] 9 0 {~~

Oo 1a 2 [Oo 0 - 0 ~~ on o MN on oS = oN on MN NN od - 2 Q T . ° . ° = 0) of oJ nl MM = 1

MN

: —

RH

SE o R 3 « ] ut AA] H 2 fo . . 0 . 5 ne “ 2 ~ 4 ~~ — ~~ jag} 1 0 NY on ~d Oo joo] " © o ~~ —~ o oO 0 ~~ B ~~ © MO NF 0 Me Mm NH ¢ 0 oO co HH OO r+ °° OO ¢ QO 0 OO [a] 0 og OU ol 0 oO mm 0 mm oN Mn

Q MY of ym | 0 aw ~ UO ft ’ 123] i mI “4 by 1D © { 1 ©

I=] © HHH << - 3 - oF . 0 - m FN Om NO own oO N_O nN oO NO

P= yd Ny OL 3 noe 0 . Me Ae Ne . El 0 ol 2,00 Poort IN HIN, HOR, AH ~ - “ aha : ol vl ol oo ol © 31 of jes} —_ 5 \ Oo O o i. DO jae] J] 3 © od oN ol on m © No A ~~ ~~ ~~ ~~ Tn

MY [AA [AY ° hy 83 > og & 5 5 Teg My © oO ol ~ ~ ~~ ~ ~ xn oo I

Zl or 5% bad 9 © : “ i. ®/ od 3 z= 0 0 oN Q Q m jas] ol © © jag] uN nN md jae] a! in ol 0 fas] NN jas] oO [64 wd ol Oo Q im oO 0 0 © g

Oo 0 o~- © on ~ 2 0 oO Oo o Q ~ 8 ” — — ~ ri ~~

. » 2 . © > ~~ 0 0 ~~ — ~~ ~~ n 0 a 0 Q ° a e] oO Oo N o NY MN Gal a pr] a a 2) © . » 0 © 0 > 0 ~r ~ ~~ . a 0 md 31a lu o~ se] oC R o nN 1 MN o

Slo » » . HN = nN My NN o[? gi = 8 » oli o od » nla [Ne esl ov in 0 in " =| ha MN n\ [1a¥ o = = . » * NM = MN MM MN

Nn : oH . * tn tn in ° 0 0 . 0 — 3 — ~~ —

My tm x 3 Mm O 1 : £3 ot] 0 nO . 3 0 ~d J nN o ° + ~~ i o far] Qo ~~ o on o ~~ e iT © o 2} a: 0 sm 5 — ' oO Oo « O wv oO g “MN

NN om od MN 1 = fe) o © Io Mo ig tu W = = of © 1 oO © Ne 0 a} Hob | - I - N * o_O : ot o bd - he H a alo a 0 nO Ae

EH [8] 0 @ Qe me MN oo — " In oP = NN, NS MN, A A 1

PY 9 a a 2, ol ol o! ol ol! ol 13, ol 4 - : oe gr & get Ne

MN — m o =

D m 0 nN H he be m a OA m m >» » tt — © et Fx A © Q Q - oO MN oO oO td = oi Cu B TR EL no ©

Co dO mY dN dw HY EE wl] ee 4 0 jo] oO OV oO uv Lvov HD oO / J / \ / \e \z e/ \d = = = > oN ~ mm od mn wt ~ jo] joo] oe = fod . o gs —~ a IY 2,2 ~~ ~~ ~ 3 g ~~ — la —t ©

O

- 149 f

REFERENCE EXAMPLE 105

By using 200 mg of 9-dihydroerythromycin A 6,9- epoxide (compound 84) (reference: Japanese Laid-Open patent Publication No. 1588/1972) and 0.5 ml of allyl bromide, the same processing as in Reference Example 50 was conducted to obtain 190 mg of 9-dihydroerythro- mycin A 6,9-epoxide allyl bromide (compound 115 in white powders

REFERENCE EXAMPLE 106

By using 200 mg of 9-dihydroerythromycin A 6,9- epoxide (compound 84) and 0.5 ml of propargyl bromide, the same processing as in Reference Example 50 was } conducted to obtain 195 mg (yield 84%) of 9-dihydro- erythromycin A 6,9~-epoxide propargyl bromide (compound 116) in white powder.

The structural formulae, specific rotatory . powers and NMR spectrum values of the compounds ob- tained in Reference Examples 105 and 106 are shown in

Table 17. i

7 a a (eo ] af —~ ol i rl Ny 3 . gl w ad ~~ 0 o- . of © NY a3) = * . o| O a © 31 = ol MN > = ~~

Lae] 0 ft] = pl wn ’ of ~ 0 oO ol] o [al ao of = . ’

DO 0 7 0"n [oY £4 x) = m 2 a = [Ya AD 21 m an 3 © nom = \ ol Oo my \ oO 00 oO -— i

Za 5 n ~ / 3D — MN 5 . Pa © 5 > tre oO o 0 ) aff 3 + ow

PE . Q m 9 1 oO ol 0 ~ = + oo! ~— 0 = = aS 5 oJ t I jas] “a 0 nN ~ 1 > =) “ 5 o = © oO mo fd Bs oO fd TY) —10D 0 =

SQ JO No ya wd & Po ol Hl © © oN oJ wn jas] © © o 8. 0 0 wn 0

R= ~ — fu — — 0

REFERENCE EXAMPLE 107

S05 mg of the compound 75 was dissolved in 5 ml of methanol, then 121 mg of sodium hydrogen car- bonate and 68.5 ul of allyl bromide were added thereto, and the mixture was stirred at 50° Ce. for two hours. This reaction mixture was diluted with 35 ml of ethyl acetate, and the solution was washed with a saturated aqueous sodium hydrogen carbonate and a saturated aqueous sodium chloride solution.

The ethyl acetate solution was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluant: chloroform-metha- nol-cone¢., aqueous ammonia (10:1:0.1) to obtain 72 mg (yield 67%) of allyl-nor-8,9-anhydroerythromycin A 6,9-hemiketal (compound 117) in white powder.

REFERENCE EXAMPLE 108

By using 105 mg of the compound 75, 25 mg of so- dium hydrogen carbonate and 14.7 pr of propargyl bro- mide, the same processing as in Reference DBxample 107 was conducted to obtain 66 mg (yield 60%) of propar~ gyl-nor=8,9~-anhydroerythromycin A 6,9-hemiketal (com- pound 118) in white powder. 105 mg of the compound 75 was dispersed in 1 ml of methanol, then 0.29 ml of diisopropylethylamine ’ and 0.29 ml of l-iodopropane were added thereto, and the mixture was stirred at 50°¢. for 22 hours. : This reaction mixture was diluted with 20 ml of : 5 ethyl acetate, and the solution was washed with a saturated aqueous sodium hydrogen carbonate and a saturated aqueous sodium chloride solution. The ethyl acetate solution was dried over anhydrous so~ dium sulfate and the solvent was evaporated under re- duced pressure. The residue was purified by silica gel column chromatography (eluant: chloroform-methanol- conc. aqueous ammonia (50:1:0.1) to obtain 84 mg (yield 75%) of propyl-nor-8,9-anhydroerythromycin A 6,9~hemi~ ketal ‘compound 119) in white powder. : REFERENCE EXAMPLE 110

By using 105 mg of the compound 75, 0,26 ml, of diisopropylethylamine and 0.21 ml of bromoethanol, the same processing as in Reference Example 109 was conducted to obtain 94 mg (yield 8U4%) of 2-hydroxyethyl- 20° nor-8,9~anhydroerythromycin M 6,9~-hemiketal (compound 120) in white powder.

REFERENCE EXAMPLE 111 ‘

By using 351 mg of the compound 75, 0.87 ml of diisopropylethylamine and 2 ml of 2-iodopropane, the

Ea same processing as in Reference Example 109 was conducted to obtain 101 mg (yield 27%) of isopro- pyl-nor-8,9-anhydroerythromycin A 6,9~hemiketal (compound 121) in white powder.

REFERENCE EXAMPLE 112

By using 351 mg of the compound 75, 0.87 ml of diisopropylethylamine and 2.2 ml of isobutyl bro- mide, the same processing as in Reference Example 109 was conducted to obtain 52 mg (yield 14%) of iso~ butyl-nor-8,9-anhydroerythromycin A 6,9-hemiketal ( compound 122) in white powder.

REFERENCE EXAMPLE 113 1.0 g of the compound 76 was dispersed in 10 } ml of methanol, to this 2.5 ml of diisopropylethyl- amine and 1.3 ml of allyl bromide were added, and the mixture was stirred at 50°C. for 40 minutes. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromato-

Co graphy (eluant: chloroform-methanol-conc, aqueous ammonia (50:1:0,1) to obtain 337 mg (yield 30%) of diallyl-dinor-8,9-anhydroerythromycin A 6,9-hemi=- ketal (compound 123) in white powder and 256 mg (yield 24%) of allyl-dinor-8,9-anhydroerythromycin

A 6,9-hemiketal (compound 124) in white powder.

REFERENCE EXAMPLE 11h : 500 mg of the compound 76 was dispersed in 5 ml of methanol, to this were added 0.6% ml of diisb- propylethylamine and 0.33 ml of propargyl bromide, and the mixture was stirred at s0°c. for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromato= graphy (eluant: chloroform-methanol-conc. aqueous ammonia (100:1:10.1)) to obtain 114 mg (yield 21%) of dipropargyl-dinor-8,9-anhydroerythromycin A 6,9~ hemiketal (compound 125) in white powder and 252 mg (yiald 45%) of propargyl-dinor-8,9-anhydroerythromycin

A 6,9~hemiketal (compound 126) in white powder.

RUFERENCE EXAMPLE 115

By using 256 mg of the compound 124, 0.61 ml of diisopropylethylamine and 0.31 ml of propargyl bromide, the same processing as in Reference Example 109 was conducted to obtain 207 mg (yield 77%) of

Neallyl-N-propargyl-dinor-8,9-anhydroerythromycin

A 6,9~hemiketal {compound 127) in white powder.

REFERENCE EXAMPLE 116

By using 100 mg of the compound 117 and 0.1 ml of allyl bromide, the same processing as in Re ’ ference Example S50 wés conducted to obtain 110 mg

(yield 94%) of allyl-nor-8,9-anhydroerythromycin A 6,9-hemiketal allyl bromide (compound 128) in white powder.

REFERENCE EXAMPLE 117

By using 100 mg of the compound 117 and 0.1 ml of propargyl bromide, the same processing as in

Reference Lxample 50 was conducted to obtain 102 mg (yield 85%) of allyl-nor~8,9-anhydroerythromycin A 6,9-hemiketal propargyl bromide (compound 129} in white powder. . REFERENCE EXAMPLE 118 : By using 61 mg of the compound 118 and 0,1 ml of propargyl bromide, the same processing as in Re- ference Example 50 was conducted to obtain 51 mg (yield 72%) of propargyl-nor-8,9-anhydroerythromycin A 6,9 hemiketal propargyl bromide (compound 130) in white power.

REFERENCE EXAMPLE 119

By using 99 mg of the compound 123 and 0.1 ml of allyl bromide, the same processing as in Reference

Example 50 was conducted to obtain 16 mg (yield 1h%) of diallyl-dinor-8,9-anhydroerythromycin A 6,9~hemi- ketal allyl bromide (compound 131) in white powder.

REFERLHCE EXAMPLE 120 61 mg of the compound 123 was dissolved 1 ml of methanol, then 12 mg of sodium hydrogen carw- bonate and 81.9 pl of propargyl bromide were added thereto, and the mixture thereof was stirred at room

N . temperature for 3 days. The same processing as in

IE Reference Example 50 was hereinafter conducted to ob- tain 32 mg (yield 39%) of diallyl-dinor~8,9~anhydroery- thromycin A 6,9~hemiketal propargyl bromide (compound 132) in white powder.

REFERENCE EXAMPLE 121

By using 101 mg of the compound 126, 24 mg of sodium hydrogen carbonate and 0.1 ml of propargyl bro- ) mide, the same processing as in Reference Example 120 was conducted to obtain 38 mg (yield 30%) of dipro- pargyl-dinor-8,9-anhydroerythromycig A 6,9~hemiketal propargyl bromide (compound 133) in white powder pro- pargyl bromide (compound 133) in white powder.

By using 50 mg of the compound 121, and 0,1 ml of iodomethane, the same processing as in Reference

Example 50 was conducted to obtain 52 mg (yield 86%) of 8,9~anhydroerythromycin A 6,9-hemiketnl isopropyl iodide (compound 134) in white powder.

REFERINCE EXAMPLE 123

By using 29 mg of the compound 122, and Oh ml of iodomethane, the same processing As in Reference

Example S50 was conducted to obtain 30 mg (yield 86%) of 8,9-anhydroerythromycin A 6,9-hemiketal isopropyl iodide (compound 135) in white powder.

REFERENCE EXAMPLE 124 150 mg of the compound 27 was dissolved in 3 . ml of chloroform, then 1 ml of butyl iodide was added thereto and the mixture was heated under reflux for % days. The same processing as in Reference Example 50 was hereinafter conducted, to obtain 12 mg (yield 64%) of 8,9~anhydroerythromycin A 6,9~hemiketal butyl fodide (esmpound 136) in white powder.

REFERENCE EXAMPLE 1235 150 mg of the compound 27 was dissolved in 2 ml of chloroform, then 0.3 ml of cyclopropylmethyl bromide was added thereto and the mixture was heated under reflux for 2 days. The same processing as in

Reference Example 50 was hereinafter conducted to ob~ tain 145 mg (yield 81%) of 8,9~anhydroerythromycin

A 6,9-hemiketal cyclopropyl-methyl bromide {compound é

137) in white powder.

REFERENCE EXAMPLE 126 150 mg of the compound 27 was dissolved in 2 ml of chloroform, then 0.5 ml of crotyl bromide was added thereto and the mixture was allowed to stand at room temperature for 6 hours. The same processing as in Reference Fxample 50 was hereinafter conducted to obtain 175 mg (yield 98%) of 8,9-anhydroerythromycin

A 6,9-hemiketal crotyl bromide (compound 138) in white powder.

REFERENCE EXAMPLE 127 ’ 150 mg of the compound 27 was dissolved in 1.5 ml of chloroform, then 0.5 ml of 2,3~dibromopropene was added thereto and the mixture was allowed to stand at room temperature for 1 day. The same processing as in Reference Example 50 was hereinafter conducted to obtain 111 mg (yield 58%) of 8,9~anhydroerythromy- cin A 6,9-hemiketal 2-bromoallyl bromide (compound 139) in white powder.

REFERENCE EXAMPLE 128 150 mg of the compound 27 was dissolved in 3 ml of chloroform, then 0.5 ml of propargyl chloride was added thereto and the mixture thereof was heated under reflux for 1 dry. The same processing as in

Reference Example 50 was conducted to obtain 156 mg (yield 94%) of 8,9-anhydroerythromycin A 6,9-hemi= ketal propargyl chloride (compound 140) in white powders.

The structural formulae, specific rotatory powers and NMR spectrum values of the compounds ob- tained in Reference Example 108-129 are shown in

Table 18.

i ~~ ~~

NY nN — ~ ba on In

RK © © le. ~

Nn [a] 0 [¢4 y © | 0 [=] ~ ~~ ry OO ~~ ~~ ~~ ~~ foal os] ~~ ~~

Ny nm joo] J] ~~ - - MN MN mn 0 n - - = - - v 0 0 0 ° * - - = vi @ ©

Elm = z = = [<1 Ke} 1 | =z = elo] = : - } ! ~~ " MY r = ol - ~ NY MN =I ~ 3 al © on nN [18% = a). —~ MY oN uN sl . . + o oO al od a “o £ 1 £2 o] olin

P - ni n Nn \D 0 wy ~~ rn MM AA 0 lo © ° . a & 5] MY 1a ny MN

Q

J a — .

J]

NY nN - \D0 o- | O- ue ey 0 n in nn nn 0 ~~ 9 ° * * wg og of i. - ov © md

So my 1 0 0 ~~ oO rq = oO | 2 = -

Mm £1 mm o In 3 “3 3 5 — My ~~ MN

Ei [oF ~ © ol n rl o rr rt me ol i 3 0 3 0 © ~~ © © 5 > ~~ ~~ 0 ~r } = ~ al o o o 0 ny S ~ oJ oN = o jo 3 S 5 J 3 “ ol © Q 2 o \ Gy 3 4 T " il 1 1 ' 22] wo

EK ’ © - / N wf —e AN jee] } ° n ; 4 9 9 2 5 0 .r3 a on il o N =i lil rr a 5 © tS 0

MN o MY ol a) nd 1a) ol wd a bi ax! id 28 wd J 0 rd ry > 0 © O oO = \ m= = [aot o = 3 eo 0 an ©

Oo » ~ 4 N ©: 0 ri 1 1 ~ ’ £ =

Q

© ~

Pp - 161 -

~ ~

HN

A

© n 0 ~~ ~~ tn ~~ NY . +» -

J mn . © - > ® + = 8] © 4 - 24 0 ! . nl -

NM ~~ ~~ ~~ ~ ofl © ~~ MN [oA nN MM

StH [a dy ~ fe 4 Q [3] 0 0 © 0 £2 oJ) 0 0 Nn n > . © © oO © oO on ~~ ~ ~~ ~t “vo 8 31 ~ fa] 33 4] BY ol ~ ol v 0 on No No

Of ~r Ny Mm MN MN MN nl o ° @ 0 . . = " MN My MY KY ml oOo = “le ~~ 1I3 [72% o » o~ \0 O~ Oo O-

QO 0 ny my un um my = ~ 9 0 ° 9 . o @ — [al rt ~ Las! ol =

MN Mo = 3 moO oo 3] 0 ry

MN

9 3] MN 0 mm © jas] oO ty [a oO \ ~ Oo ~~ ~ ~~ ~~ «m o ~~ ~~ MY IN [AD AR 2 Q oO oO 1a} od -

El 1 Ha ° ~~ 0 0 oO 0 ; AR 8 2% [a nN ol © NN ~~ m = ~~ ~~ © o o oO [& £> oN 0 0 =t = od

RA < 2 ° : a ~~, | © AR arty £3 o =O » A ' ! \ o Q ol NN . QO a

MN od +d ~N ~~ Of wo 3 wnt tn oJ 3 “5 A 5 mi © oJ =

I. ~~ moo 209 ho ii sg jas] wd 0 ii wv © 0 oO

MY od 0 [4] |&) oJ mi 0 joe] m3 ol 74 om © © 3) to © 5 a © / 0 NJ N\/ ‘3 =} . oe on Ny = In \n oO 0 oy oJ Of ao oJ [sed 1 & al oH . 8

Q

— . — a . * 0) oO

OO nN

PY on n © © ~~’

Nt ~~ — td . Te Ny — MY - + - 0 jo] [0] - © ~ © gl > Qo = — = = nd =, i 0 i -

Qf ~~ ~~ - MY

Al uv [18 tn ~~

Al HN ri ~ ©] © 0 oo C- > = a «© [a] +2 . . “| c ~ EN My 8 = fa] ~~ +n ol]

LH] oo pl wv 0] ~ 0 0 on © MN a) 53) r= ° . . = O Mm MN nN = fo ~~ ’ aed

Mm : - n

Nd do 2g o~- on N 3 ol" AN TN 0 : rs £3 5 oO ~~ — —t

My 5 ml o 0 [AAY 0 m o oi 1 oO © oy ~~ ~~ ~~ ~~ [al oO oO MN 223 jas ° ri oO o 9 o I. ~~ 2 on 20 mq 2 A ol © 6 0 & YN - nN + ~t ~~. ~~ 5g = on o 0 o © Nn © t 0 ~~ © 0 °

MN — 3 MN . a] MY od ol

Oo =O | 1 { i oO \ o o

S10 Nw 0 mw 0 oO NB nN = © od os o 9 0 Et © ty ir Te md 3) bry 0 113 io J PP trl Il © oe lt

[3] © o © ) 0) of In 3 0 of oi ti as] wv rhs to

Mm © © ty ~r © mn © jz ed ™ od ‘ g o- oO 0

Qo © od oJ on 2, 0 ~{ ~ I 8 = . o ry rand - —~ mn " 0 |&) oO tO } 1 a . 0) ©

[5] ~~ ~~ ~~ = yo ~~ Lo i 0

Pp Ny - ( ts - nl . lo mn - . ‘bh ~ ol . ~ © L o = = 8, 0 = =

Ay 1 ! 4, - — ~~ — - 0 MY 0 2] a AA of ~ oO « O ~~’ 4) @ oN Mn noo } a «oJ 0 [2] Mn on oS + . |S] 0 oO ° sO HN ~~ ~r ~~ ol

Pan 3

MN

[9 #0

Oj ~~ o| ©

Qd = wl OQ Oo 3 \O I \O . 1 = NY MN NY ml = ° . . . ° =n Hy [XY MY NY NY = — [set

NY

” n ~

Q On od on 0 0 o =! mn nn tn un

QO 1 ° . . 0 0 ~ ~ ~ " ~ " oO —~t { 1 4 1

H ry no pe J od 0 a NJ 0 . o MY oO m Jaz] ry i QO rd 0 Oo Oo — © — — ~~ . Oo O 2 jae] jae) fa | MM MN MY oO Oo = 0 tr oR MN 1 oO 1 ol © 0 ja] 3 ir < © D ~~ ~~ EN 0 wD © . MY J ~ ~~ joa} ry ol o o oc o o © je} n "\ MnO + =f lo ™ 0 . . 0 © oO my 0 0 0 ®, IY ~ ot a or | 1 | ! 1 1

J oO oO © \ =

C oO QO © ® ® am £4 4 f i !

M\ jae jas] m m m oN © ar] ty 0 od NY —~ Be H ™ \ J ~~ ~~ on m 8 0 ry 3 od 3 5 oH mi 0 mi wre 0 —~ ol 5 py AB a Te

N ry a yl |S] —~ mi nN BD ~ mn NB

MN Ja] [] og J 3 ~ joe} [&} jos] 3 © od O io fo ty wD © ~— ad ~~ 0

Nt 0 \ / I \ / 7 \ / = = [21 ad = d § * oO ot oy NY = o 0 MY Mm NN tn 0 2,0 rt a ~~ — rt &

Oo © - 16h = a ~~ ~~ 0 oO 2 : o 10 Fn

N n A i a © oO

Sr

Nt ~~ ~~

Fa m o : : \o 0 — \0 - - + o-~ n 0 o un - - o - oJ a gl > al o o , el ® = = pl o = = = 0 = 1 T d=) 3 : - - n ~All wn Aa ~ ol & ~~ ~~

I on oy = st — al ol “al x ’ A .

Oo NM ry ra fq ~~ + 3 ol 0 d fl © 0 a ~ nl ~ aN MN EN © . 2 ° pe te FN gl 5 ’ m :

Zl 1 fra ~N td "2 on on - 0 in in ° ~~ 0 0 ° = r4 rd —- o 1

Ee g NO © £! _ 3 . a (3) x Mn hn 0 2] o 3] 0 Oo * joe] 3 5 — < fa Oo ty 3 1 5 i

Hl eo m 5 2 © m m Q jo + ~ =~ o & MN MN Yall Bo je ° oa] xd NN . © oO 3 S| © oD oa

Gl ¢ DN

AN 1 i 5 \ o © aA mow oO © + - oO tn OD

Oo Qo 0 e] oom NN nl © fH id ~~ od m

MN te id Ov < a 0 a o al / ~~ ~~ ~~ jar] ~~ " Pe] GY © 10 fas hy o 3 ol

Oo oa © jee] 0 asl ™ ~ |] ~~ > ~~ oO = = = ® ® ® g 3 nn 0 o~ oo © rN rN

Be ~~! —t [= 9 0 a ~~ Fan

Q 0 mn ' . MY oO « [R] NY 0 © 0 © ~~ 0 © ~~ Lg xy ~~ ~~ \0 tos] 2} ~~ - 0 0 + n »- - £3 - n 0

Q Nd - - © b> LH] od Of

O4 = Q o . 0 o = = = 0 1 led = [+] - 1 1 ja | ry - - ~~ Ww ~~ nN 0m

[0] $4 ~~ Nr = 0 SoM =F \O ~—t NY oJ * » . “2 Oo tN NY HY 8 jo

Hl] —~ +1 : Of Mm . ‘ o > 2 4} 0 4 ON mn] MY LA Mm

QO . ¢ * ml = 1a) ay NN =| 9 =i 3

Io : ~~ jas]

MM

- 0 QO 0 m mn um in ? 9 o .

Q ~! et ef o = © 1 o MN Nid o j=} Td wi Oo ’ ord 0 nN 0 + jas} gl [&] NN a yr, —= Oo jee} © vy t — ~~ ~~ ~~

QQ oO o jae] 4 joe] — o ° OQ oO © —~ PMY MN MN 3 o m3 ui ae] a hr} " of 0 © ©

Le) re = ~ ~ =~ <4 t A £4 iS > od 0 oO o ot NN m \D al oQ [®] 5 ~~ on © ee wv] al al oJ 1 I

Mn 8 -(\ =o

Nn 0 © oO 4 id ry —— 5 3] [i]

Wa 2 > m m © j&] oY ol o Oo CL ©

Es] © oO ol 2 5 2 el © fn act 4 oO a i nom oN —~ 3 —~ © ~~ i

MN 0 tn al Nn 0 jae] oJ 3 i od ol j&] & [] 0 wD asl ™ ~ 3} ~~ ~~ ~— oO : = = = g

OO oO Oo» Oo a, © MN NY =< . g8 = ~ rt r4

Q

REFERENCE EXAMPLE 129 73.5 mg of the compound 32 was dissolved in 0.8 ml of methanol, and 0,2 ml of water was added thereto, followed by addition of 66.4 mg of ClizCO0Na. 3050. The reaction mixture was heated at 50° Cey and stirred after 26 mg of iodine was added thereto.

In order to maintain the pH of the reaction mixture. at 8 to 9, O.4 ml portions of 1N aqueous sodium hy- droxide solution were added thereto after 10 minutes, 30 minutes and 1 hour, respectively, and the stirring was further continued for 1 hour. The solution was thereafter poured into 100 ml of dilute aqueous am- monia and the resultant product was extracted with chloroform. The extract was washed with dilute . aqueous ammonia and dried with anhydrous sodium sule fate. Thereafter, the solvent was distilled off under reduced pressure. The residue was purified by silica a gel column chromatography [eluant chleroform-methanole conc. aqueous ammonia (15:1:0.1)/to obtain S51 mg (yield 70%) of 11,12-di-O-acetyl~de-li-methyl-8,9-an- hydroerythromycin A 6,9-hemiketal {compound 1h1) in white powders i By using 79 mg of the compound 141, 0,17 ml of diisopropylethylamine sand 0.16 ml of indomnrthane, the same processing as in Reference Example 109 was conducted to obtain 30 mg (yield 37%) of 11,12-di-0- acetyl-N-ethyl-nor-8,9~anhydroerythromycin A 6,9~ hemiketal (compound 142) in white powder.

REFERENCE EXAMPLE 131

By using 500 mg of the compound 20, 468 mg of

Cli;COONa~3H,,0 and 170 mg of iodine, the same process- ing as in Reference Example 129 was conducted to ob= tain 413 mg (yield 84%) of de-l-methyl-8,9-anhydro= erythromycin A 6,9-henmiketal cyclic 11,l2-carbonate {compound 143) in white powder.

REFERENCE EXAMPLE 132

By using 350 mg of the compound 143, 0.84 ml of ¢ diisopropylethylamine and 0,77 ml of iodoethane, the same processing as in Reference Example 109 was con- ducted to obtain 254 mg (yield 69%) of N-ethyl-nor- 8,9~anhydroerythromycin A 6,9-~hemiketal cyclic 11,12 carbonate (compound 144) in white powder.

REFERENCE EXAMPLE 133

By using 24.8 mg of 8,9~anhydroerythromycin B ’ 6,9-hemiketal (reference: P. Kurath, et al., Expe- rientia, 27, 362, 1971) and 0.2 mk of bromoethaneq the same processing as in Reference Example 100 was conducted to obtain 20 mg (yield 69%) of 8,9-anhy- droerythromycin B 6,9-hemiketal ethyl bromide (com- pound 145) in white powder.

REFERENCE EXAMPLE 134

By using 24.7 mg of 8,9-anhydroerythromycin B 6,9~hemiketal and 0.05 ml of propargyl bromide, the same processing as in Reference Example 50 was con- ducted to obtain 24 mg (yield 83%) of 8,9-anhydroery- thromycin B 6,9~hemiketal propargyl bromide (compound - 10 146) in white powder.

REFERENCE EXAMPLE 135

By using 50 mg of the compound 54% and 0.3 ml of propargyl bromide, the same processing as in Re- ference Example 50 was conducted to obtain Sh mg (yield 93%) of 11,12-O-isopropylidene-8,9-anhydroery=~ thromycin A 6,9-hemiketal propargyl bromide (compound 147) in white powder,

REFERENCE EXAMPLE 136

By using 50 mg of the compound 39 and 0.3 ml of propargyl bromide, the same processing as in Rew ference Example S50 was conducted to obtain 55 mg (yield 96%) of 8,9-anhydroerythromycin A 6,9~hemiketal 11,12-phenylboronate .propargyl bromide (compound 148)

in white powder, . i

REFERENCE EXAMPLE 137

By using 100 mg of the compound 20 and 0.3 a ml of propargyl bromide, the same processing as in

Reference Example 50 was conducted to obtain 108 mg (yield 93%) of 8,9¢anhydroerythromycin A 6,9~hemi~ ketal 11,12-cyclic~carbonate propargyl bromide (com- pound 149) in white powder.

REFERENCE EXAMPLE 138

By using 100 mg of the compound 37 and 0.3 ml of propargyl bromide, the same processing as in Re- ference Example 50 was conducted to obtain 107 mg (yield 93%) of 8,9-anhydroerythromycin A 6,9-hemiketal 11,12-sulfite propargyl bromide (compound 150) in white powder.

REFERENCE EXAMPLE 139 100 mg of the compound 8 was dissolved in 2ml of dry dimethyl sulfoxide, and to this, were added 1 ml of acetic anhydride and 0.3 ml of acetic acid.

The reaction mixture was allowed to stand for 1 day at room temperature. Thereafter, the same processing as in Reference Example 39 was conducted to obtain 65 mg (yield 56%) of 2'-O-acetyl-U"~O-formyl-11,12-0~ methylthiomethyl-8,9-anhydroerythromycin A 6,9-hemi-

ketal (compound 151) in white powder.

REFERENCE EXAMPLE 140 150 mg of the compound 151 was dissolved in 6 ml of methanol, and to this, was added 1 ml of conc. aqueous ammonia. The reaction mixture was heated, for 2 days under reflux. Thereafter, the same process-— ing as in Reference Example 40 was conducted to ob- tain 105 mg (yield 76i%) of 11,12~di~0-methylthiomethyl- 8,9~anhydroerythromycin A 6,9-hemiketal (compound 152) in white powder.

REFERENCE EXAMPLE 141

By using 100 mg of the compound 152 and 0.2 ml of propargylbromide, the same processing as in

Reference Example 50 was conducted to obtain 98 mg (yield 86%) of 11,12-di~O-methylthiomethyl-8,9~-anhy~ droerythromycin A 6,9~hemiketal propargyl bromide (compound 153) in white powder.

REFERENCE EXANPLE 142 i 99 mg of the compound 1 was dissolved in 3 ml of chloroform, then 0.5 ml of propargyl bromide was added thereto and the mixture was allowed to stand at room temperature for 3 hours. The same process— ing as in Reference Example 50 was hereinafter con-

- ducted to obtain 76 mg (yield 66%) of 2'=O-acetyl- 8,9~anhydroerythromycin A 6,9-hemiketal (compound 154) in white powder.

The structural formulae, specific rotatory powers and NHR spectrum values of the compounds ob=- tained in Reference Examples 129-142 are shown in

Table 19.

~~ ~~ ~~ ~~ ~~ oO tn IO in n . - I] ~ od — © 0 0 © 28] jae] wi me ol oO © 0 0

Set” No a Ag ~ + nN 0 0 a 0 pS © 0 © 0 * Q " ° © o- — o Oo — ~ ey to ' 1 1 t

In 1

Nn mq Nn <a] . oo nt om J bd m3 Do oom on oO = = = = ~~ ol «J o 0 nN ~ tid Oo oy ND

A wm 4 0 MN 3 oO +3 fm oO 0 ~ oO Q Q : o " + = < ~ tg m Oo Q om 5] > 0 Ia) © oO © 32 i f 3 Ry © ae] 0 Q Q Q Q = i i 1 i \ o " 2 2 : gq wd m o © oO CO mm 0) © . LAE NY

Mop oJ mn m j=] n ns ~

Jo ry joa] i] mt 3 — o oy + 0 + + 3 +4 = — — ~t r=

. i . : ~~

S| zg = 3 z ~ o Oo Q ae) . " Nn [1a MN ol = fas b=] = . ~ oO 0 oO 0 - Ag Nt? hg —? = . ! ol o o . Q o nl © 0 oN + ~~ . ° * . ot = R go 4 &, 1 1 1 T ® 0 . 8 ° x5 s5 48 & | I I nN oO © 0

Qa Non NM NN nw mom Nn =o = oad momo . > 0 OO © OU o OV UO © © oO - 1 \N1/ \l/ \l/ \I/ g = = =/ = } nN

E “ on ® ® = @ ® © = © £ oO ia} . © = MN © oO = . - i ve CO oO ~~ o a : nN 1 5} -~ © ~ m x } : = x MY a = nN on JIN —4 -

Ed < 3 © © £ : NJ 1

MN

’ boo] o Oo © Mm © \ 7 \ 7 \ : o’ Q Qo i 1 o Q i i. 3 nN a} = x ‘ Ca > 55 p o 5 moa Tn mom

Ny = = = Eo) _ . oF f= = to es . . mn 0 o- «QQ ' a I = = +

~~

Q ~~ ~~ ~~ — ~~ « v a2} jae] MN non ~ Q oO — (a) [lo

NY nN 0 0 NN ol wi i oom ig ~ oO 0 a © ©

St St ~~ ag Ne + : od o o o o 0 o \O = oN \0 od ~~ . ° ’ 0 ° i an ~~ o~ 2 oy 0; al Mn monn

NX | 1 1 1 1 ‘ ® m 0 mid £4 od

[3] 0 Non m oO ~~ Can il | MN fil © © ol jas} *D o NN J Mon nd |] 0 NN nN

Q woo on ood ~~ ~~ mg jes 3 4 Oo 0 oO Do = = noo 0 os oy \ / \| / \ | / £3 nN NY 0 = = = 0 v nd oO ? 5 8 ® ® ® ~~ |S) MY o ~ Oo IN ~~ Lh] [o))] Oo ~~ MN A tn

O 22] Te 3 1S] o Ln Oo Lv v3 ed ry |] ra [2] m ~” wy } NNN <x on joe] jas] jor] £4 -t Uv 40 " rm Oo o o [&] an

Ly

MN oO Q joo] 3 o © i i \ © a NN NY MN

AN © J N J ~ 8 85 9 nN non i ? 1 i [ZR jas mi at Oo ol oF

Dg > OD a 8 wi 5 + MN 2 o 3 0 . . oJ jx

[24] on] jaa! [8] jae] ml ~ © ~ ot las] 4 ml m ° on Oo ~ ol ny o rd wn nnn = ~ ~ ot A

~~ ~~ 3e] oO « . MN

La jas] 0 ol ~~

Nt

Eu o of A : oJ - 0 ~~

NT

& : £4 m jaa} oO fi © nm BN Of ' 3 wl i

[3] ry © ) \ | / - ®@ o = od

MN .

Wo 0 » 3 LO o My ° id + 3s] © D NY m oO } kad |] i ~~ oO os on a © ot © 4 . [ep] mM “or § 3 3 3 0" m oO jas] i O nN

M jae] 5 o =O i © \N\ o

N nl 0

MN jab 1] i ty — 73 © Ld

Ny nF Td nr m } a . i he [a oO ™ b ° I of n 0 wy = 4

TABLE 19(b)

Compound

No. RHR spectrum d value ppm 8-Me 3N.-0OMe (Bp, 3H) (5,311) Others (solvent) 14 1.59 3.34 1.99 (OAc, s, 3H), 2.03 (OAc s, 3H) 2.h2 (3'-NMe, s,3H) (cpel,) 3 142 1.60 3.34 1.99(0Ac, s,31), 2.03(0Ac, 5,3) 2.23 (3'-llg, 5,30) (coel,) 143 1.62 3.35 2.42 (3'-lle,s,31) (cnel,) 144 1.61 3,35 2.23% (3'-NMe, s,3H) (cnely) 145 1.58 3.38 2.1h (3'-NMe,, 8,61) (cp50D) 4 . 146 1.58 3.39 3.25 (3'-NMe,, 8,61) (¢n50D) 147 1.62 3.39 \ Cli 1.38 ( Cc 15,611) (CD50D)

ZN cn 3 3.27 (3'-liMe,, 5,61) 148 1.62 3.39 3.28(3 "Nie, , 5,611) (cp,0D) ?.%3-7.8 (ph, My, 5H) 149 1.61 3.53 © 3.37(3'-lHe, 5,61) (cDel,) 150 1.57 3439 3.39(3" -NH8, 54611) (CD50D) 151 1.58 3.36 2,04(2"-Chec, 5,3H), (cDel,) 2.27(3' -NMs, 5,6H), 8.19(L"-CHOSs, 111) 152 1.58 2.35 2.22(11-SCH_, 8, 3H), (CDC) oh (12-5CH2, &,31) 2.29(3"~NMe2, 8,61)

ee TABLE 19(b)-continued

Compound ~~ _____ NMR spectrum J value ppm

No. 8-Me 3"-0Me (s, 31) (5, 31) Others (solvent) 153 1.58 3,39 2.22 (SCH, 5,61), (€D;0P) © 3.25(3"=MMe 8, 6H) 15h 1.56 2.38 » 2,20 (2'-0Ac, s, 3H), (cp;0D) 2,32 (3'-lite,, sy 6H)

REFERENCE EXAMPLE 143 150 mg of the compound 84 was dissolved in 3 ml of ehloroform, then 0.5 ml of propargyl chloride was added thereto and the mixture was heated under reflux for 1 day. Thereafter, the same processing as in Re- ference Example 50 was conducted to obtain 1h2 mg (yield 86%) of 9~dihydroerythromycin A 6,9-epoxide propargyl chloride (compound 155) in white powder.

REFERENCE EXAMPLE 144

By using 143 mg of the compound 84, 27 ml of acetic anhydride end 31 pL of pyridine, the same pro- cessing as in Reference Example 23 was conducted to obtain 125 mg (yield 83%) of 2'-acetyl-9-dihydroery- thromycin A 6,9-epoxide (compound 156) in white powders : 150 mg of the compound 84 was dissolved in 3 ml of chloroform, then 0.5 ml of benzyl chloride was added thereto and the mixture was heated under re- flux for 38 hours. Thereafter, the same processing as in Reference Fxample 50 vas conductad to obtain 155 mg (yield 81%) of a-dihydroerythromycin A 6,9~ epoxide benzyl chloride (eampound 157) in white powder. . '

REFERENCE EXAMPLE 146 150 mg of the compound 84 was dissolved in 3 ml of chloroform, then 0.5 ml of 1-bromo->~fluoro— ethane was added thereto and the mixture was heated under reflux for 7 days. Thereafter, the same pro- cessing as in Reference Fxample 50 was conducted to obtain 66 mg (yield 37%) of 9-dihydroerythromycin A 6,9-epoxide 2-fluoroethyl bromide (compound 158) in pale yellow powder.

REFERENCE EXAMPLE 147 150 mg of the compound 84 was dissolved in 3 ml of chlornform, then 0.5 ml of eyclopropylmethyl bromide was added thereto and the mixture was heated "under reflux for 38 hours. Thereafter, the same pro- cessing as in Reference Example 50 was conducted to nd obtain 153 mg (yield 865) of 9-dihydroerythromycin

A 6,9-epoxide cyclopropylmethyl bromide (compound 159) in white powder,

REFERENCE EXAMPLE 148 150 mg of the compound 84 was dissolved in 3 ml of chloroform, then 0.5 ml of 3-butenyl hromide } was added thereto and the mixture was heated under reflux for 38 hours. Therenfter, the same process-— ing as in Reference Fxarmple 50 was conducted to ob- tain 113 mg (yield 633) of 9-dihydroerythromycin A 6,9-epoxide 3-butenyl bromide (compound 160) in white powder.

REFERANCE BXAIPLE 119 125 mg of the compound 156 was dissolved in 3 ml of chloroform,, then 0.5 ml of propargyl bromide was added thereto and the mixture was allowed to stand at room temperature for 3 hours. Thereafter, the same processing as in Reference mxample 50 was conducted to : obtain 114 mg (yield 7%:) of 2'-N-acetyjl-9-dihydro-

erythromycin A 6,9-epoxide propargyl bromide (com= " pound 161) in white powder.

The structural formulae, specific rotatory powers and NMR spectrum valnes of the compounds ob- tained in Reference Examples 143-149 are shown in

Table 20,

y — . foe)

MN

- un - ~~ 0 : 0 =]

Qo Q ~~ t Ny a =- ed [1 oO ~~ [5] ~ 0 £4 © g Q OO — . 2) [op] ny + e

Oo nl © o . =) ao "la “2 [5 - 0 o- un Ny ~ NY A) My

LH o v ° fa] = MN MY My

S

0 ! of = 2] MN n £ 2 ~~ 53) 0 a oN © © 0 oe — aN oN ~ wv 0d * . a a] 2 " oN MN we EE = o bp J ls} a

O vd Mm ©

Oo

Qo —~ oJ ~ oO joel oO [1aY Oo 9 = in 0 o 0 : 5 ~ 4m + Ww = m [ay YA 0 4 a 2 = iw nN .

Et r o> - 3 mn -3 © i > lo 1 1 1 °

NN 1 4 ¥ =o ol ph 2 ® Q ox] al Hy od ri © [os JES © © o N 85 me O On tre oy tr 8 Uf nN £1 1] v1 nN, © 0 Mn od

MN MY oJ ~~ ul wi oom ~ 0rd io 8 5 [$] 7) Uy © \ / \l/ = © mm jee] < jos] - . o 3 oe in 0D o> oo tn 1 in 7 —~ rt - og o } oO

’ ~~ [ie]

MY

. - 0 ~~ - o ©

Oo <g

Al » 7

Ol - ~~] o of < ~~ gle : Oo rd 134 oy . g 0 — - i a 0 0 \0 o> 0 “n} Ny 1 a) J

Lh) [4 [] . .

Ny ry NY [a 2] 1 5] 2m 0 © od wn el] ~~ .

Zl rz] w - n ~ un MN NY nn a 0 ~~ ol

NM oJ . ® . Q m O ty aa My ia) oO =

Ni > oO z

ND MN . of i wl 5 © 3 Hs = ol ~~ +» o jez]

IS] x oO : © A % % %

[3] - u d i ; <t 0 ° ° » °

MY 0 ol 2 o- o- oJ on a] nN » ny NY NY tn © My MN, © ' 1 1 1 9 Ao © 2 & ol

Et on o ~ 0 o o oN / i @ ~ NA ® D @ © t fo a NB 03 t 84 rel fu

Oo ©) m mM m I] md mi Qo MY Fy [$] 0 nom oN o J be = i oO © ©

Mm Mm od Noy al MN My 0 M0 : md jas] I mom om tom art dod > 0 Uo Oo ©» Yo Dw 0 ~ tm tre fr x o g © QO fo) OQ ~~

Qo ny in Oo 0 a= — a [= —~

Oo [$1

J BN . .

REFERENCE EXAMPLE 150

By using 64 mg of 6-O-methylerythromycin A (reference: S. lorimoto, et al., J. Antibiotics, 37, 187, 1984) and 0.1 ml of propargyl bromide, the same processing as in Reference pxample 50 was con- ducted to obtain 73 mg (yield 984) of 6-O-methylery- thromycin A propargyl bromide (compound 162) in white powder.

REFERENCE EXAMPLE 151 200 mg of erythromycin A was dissolved in 3 ml of chloroform, then 0.3 ml of ethyl iodide was added thereto and the mixture was heated under reflux for 20 hours. Thereafter, the same processing as in

Reference Example 54 was conducted to obtain 150 mg (yield 62%) of erythromyéin A ethyl iodide (compound 163) in pale yellow powder.

REFERENCE EXANPLE 152 100 mg of erythromycin A was dissolved in 2 ml of chloroform, then 0.2 ml of allyl bromide was added thereto and the mixture was stirred at room temperature for 5 hours. Thereafter, the same pro- cessing as in Reference Example 50 was conducted to \ obtain 97 mg (yield 83%) of erythromycin A allyl bro-

mide (compound 164).

REFERENCE EXAMPLE 153 200 mg of erythromycin A was dissolved in 3 ml of chloroform, then 0.2 ml of propargyl bromide was added thereto and the mixture was stirred at } room temperature for 3 hours. Thereafter, the same processing as in Reference Bxample Sh was conducted to obtain 202 mg (yield 874) of erythromycin A pro- pargyl bromide (compound 165) in white powder.

The structural formulae, specific rotatory ol powers and NHR spectrum values of the compounds ob~- tained in Reference fixamples 150-153 are shown in

Table 21.

» . © ~~ =m "I \O =» ~ wn ~

Aik . Qo] 0 =a

NNT oO nie . oo [12 ~A 8] jo

OQ]

I jas! © I a - — | © \O in nn 0

Gg {~~ MN La MN MN > Q . . ° 2 = MN aN Ny : = |3 oo gm . 13 . R +3

QO ~~ 2 |\D n| » n or = 0 0 Oo 0 O- ® =o ~ aH oN = ° . . . nd = 0m Ny My MN o Ny MN or 74 0D

AND » a 0 — =z MNO yo oi Q / Nn 8S tn — o oy 4 o oc oo o ao! My ry moO = “Wo 3 0 im O oo” ° : ° 0 9 © oO 3 BN, = D- MN ©

AN © © TT m wr . t 1 1 = oy o NIH

J 4h] Q

Jos] - 3! [$4 — Ny 0 ir

Q 0) $4 $4 $e

NY > m [am m m 22] © ry

Oo d Nom m bs i oa] 0D — 6 ae

OO © © 3 ml 0 oO 1 oN 9 ©

Ho m™ in

HI mon © oon © oJ © of oJ wo ml = © 0 — oy

Yl 8 om om om o g © ol MN at un 0 0 0 \0 \O 0 [Thad — r~ ~~ i

EB oO oO

REFERENCE EXAMPLE 15h 50 mg of the compound 9 was dissolved in 1 ml of chloroform, then 0.2 ml of methyl iodide was added thereto and the mixture was stirred at room temperature for 3 hours. Thereafter, the same pro=- cessing as in Reference gxample 50 was conducted to : obtain 49 mg (yield 83%) of W"'-0-formyl-8,9-anhydro- erythromycin A 6,9-hemiketal methyl iodide (compound 166) in pale yellow powder.

REFERENCE EXAMPLE 155 50 mg of the compound 9 was dissolved in 2 ml of chloroform, then 0.5 ml of ethyl iodide was added thereto and the mixture was heated under reflux for 20 hours. Subsequently, the same processing as in

Reference Example 50 was conducted to obtain 38 mg (yield 13%) of W"-O-formyl=8,9-anhydroerythromycin

A 649~-hemiketal ethyl iodide (compound 167) in pale yellow powder.

REFERENCE EXAMPLE 156 50 mg of the compound 9 was dissolved in 2 ml of chloroform, then 0.5 ml of propyl iodide was added thereto and the mixture was heated under reflux for U8 hours. Subsequently, the same processing as in Re- ference Example 50 was conducted to obtain 3h mg,

(yield 56%) of W"-0-formyl-8,9-anhydroerythromycin

A 6,9-hemiketal propyl iodide (compound 168) in pale yellow powder.

REFERENCE EXAMPLE 157 50 mg of the compound 9 was dissolved in 1 ml of chloroform, 0.2 ml of propargyl bromide war added and the mixture was stirred at room temperature for 3 hours. Subsequently, the same processing as in

Reference Example 50 was conducted to obtain 51 mg. (yield 87%) of W"'-0O-formyl-8,9-anhydroerythromycin A 6,9-hemiketal propargyl bromide (compound 169) in white powder,

REFERENCE EXAMPLE 158 50 mg of the compound 9 was dissolved in 1 ml of chloroform, then 0.2 ml of allyl bromide was added thereto and the mixture was stirred at room tempera- ture for 5 hours. Subsequently, the same processing as in Reference Example 50 was conducted to obtain 47 mg (yield 80%) of h"-O-formyl-8,9-arhydroerythro- mycin A 6,9~hemiketal allyl bromide (compound 170) in white powder.

REFERLNCE EXAMPLE 159 / 50 mg of the compound 50 was processed in the same manner as in Reference iixample 15h to obtain } 50 mg (yield 84%) of 11-O-acetyl-8,9-anhydroery- thromycin A 6,9~hemiketal methyl iodide (compound 171) in pale yellow powder.

REFERENCE EXAMPLE 160 50 mg of the compound 50 was processed in the same manner as in Reference Fxamplel55 to obtain 39 mg (yield 65%) of 1l~O-acetyl-8,9~anhydroerythromycin

A 6,9~hemiketal ethyl iodide (compound 172) in pale yellow powder.

REFERENCE EXAMPLE161 « . 50 mg of the compound 50 was processed in the same manner as in Reference Example 156 to obtain 33 mg (yield 54%) of 11-O-acetyl-8,9-anhydroerythromycin

A 6,9-hemiketal propyl iodide (compound 173) in pale yellow powders

REFERENCE EXAMPLE 162 50 mg of the compound 50 was processed in the same manner as in Reference Example 157 to obtain 49 mg (yield 84%) of 11-O-acetyl-8,9-anhydroerythromycin

A 6,9-hemiketal propargyl bromide (compound 174) in : white powder.

REFERENCE EXAMPLE 163 50 mg of the compound 50 was processed in the

. ' same manner as in Reference Hxample 162 to obtain 46 mg (yield 79%) of 11-O-acetyl-8,9-anhydroerythro- mycin A 6,9-hemiketal allyl bromide (compound 175) in white powder.

REFERLNCE EXAMPLE 164 50 mg of the compound 25 was dissolved in 1 ml of chloroform, then 0,2 ml of propargyl bromide was added thereto and the mixture was stirred at room temperature for 3 hours. Thereafter, the same pro- cessing as in Reference Example 50 was conducted to obtain 4h mg (yield 77%) of 4"-O-formyl-ll-O-mesyl- 8,9-anhydroerythromycin A 6,9-hemiketal propargyl bro~ mide (compound 176) in white powder.

REFERENCE LXAMPLE 165 50 mg of the compound 57 was dissolved in 2 ml of chloroform, then 0.3 ml of ethyl iodide was added thereto and the mixture was heated under reflux for hours. Subsequently, the same processing as in

Reference Example 50 was conducted to obtain 39 mg 20 (yield 66%) of 11~0O-mesyl-8,9-anhydroerythromycin A 6,9-hemiketal ethyl iodide (compound 177) in pale yellow powders.

REFERENCE EXAIPLE 166 oe 50 mg of the compound 57 was dissolved in 2 ml of chloroform, then 0.3 ml of propyl iodide was added thereto and the mixture was heated under re- flux for "#8 hours. Subsequently, the same proceass- ing as in Reference Example 54 wrs conducted to ob- tain 34% mg (yield 56%) of 11-O-mesyl-8,9-anhydro- erythromycin A 6,9-hemiketal propyl iodide (compound 178) in pale yellow powder,

The structural formulne, specific rotatory powers and NMR spectrum values of the compounds oh- tained in Reference Rxamples 154-166 are shown in

Table 22.

~~ ~~ ~~ ~~ ~ 7] jae! m3 je] ml ~~ — [a —~ [a] [a] Jo] . ~ - ”" LJ] ” Ny tn 0 mn 0 n - 0n - L > - »

Oo O Oo QQ Q -~ wd jazi 3 3 = © 0” © 0 © QO 0 <¢

Qo Q Q Q Q Q

Q Mf # [= | on | 1 £3 nz Ny 2 me MN oN = ~~ + [J [So oF 0-3 [5 4 . QO 00 ~r QO vr OO Nr or ~~ 00 ~~ Of ~~ ~~ 0

QO ~~

MN to a ey 0 - . ~~ 0 ~ ~ ~~ 2 —~ x © 8 @ <1 -3 -=t to [LA £2 a . ° © . ° . jolt <Q mn HN NY Ny My MY 0 = ‘ 3 0 — © > ~~ og <3 © \0 ot oN Oo — «Q Nn = NY ri a NN ~ ol ow * . . + ° . g [2 ty toy MN NN NN [38 - a ~ pN +» © @ 2 ~~ 0 ie .

NY oo ~ = 0

Ed ~~ on [oa] on ON on Oo

MN tn mn mn mn un 0 id 9 . 0 ° 9 °

Ed 9 ~~ i 4 ~~ 4 4 (a) on ry nN 0 nl 3 oO i) 0 0 = wl v .

Le NYE) oO 7 y— ® wd PY MN on < © 3 je] 0 0 o o o al O lo} Vv 3 © 3 Q + = oO Oo ol | al 0 % 0 * Q .

Bln a ow ~ 4 Oo 3 oy oy = 2 NN, © MN MN Ia rn 0 ~ m ol ia) oO or) ° ! 1 1 ! 1 <t ui T ~

Ei Dd Dm 1 ol

NY NY ~rt ~ [a8] jas] 0 0 5 $4 ~4 +4 La] + m Mm 4 . ol a -— (S) oO =O \ i oO 4 jes} oO . 0 or ~~ of 0 i oS o = ) Um) in - OQ 0 oo NOE A Te dW : 1 v1 jen 2 2 |] ~ © © 0 © © Ty m

MN

31 oO oN Q ~ tri jae] tr m re 0

QQ Oo QQ oO Oo ri je} 3 m3 ig 0 ry © 0 © 0 eel - \ £

So . Oo 0 \D O- oQ a Oo ~ : 47 \O 0 \0 \0 o- o-

B — — — ot — 4

Q

~ : ~~ ~~ ~~ ~~ 24] ~~ ~~ ~~ ml 3 jo] 3s ~ mi jos]

Jos} MY MA MN My MN Mm . fe - - - - - - 0n » > 0] wn 0n w wn n n - ~~ - - - - - Q - ~ mn © Q Oo L 1} ard 0 0

Q 0 <q be] “1 = >a 0 = = fa Q Q Q Q oo © OQ OQ 8 © oOo! Oo ~t 1! Q 1 clot X10 F0 £1 or ~~ ed ~ MO nz Ney NA 49 ord 0 rq ort * ri ord od * * rd g 0 oJ NN ~r oJ ~r oJ er NANr OO) wr NY Ny ©

QO ~~ 3 od

Al ND os 51 - wn ~~ oo oQ JN) [3d —~ C- C- © MM haY m Ny + NY LAY w= . . © . ° . . jo |] NY ny MN 0 NY NN Hy

Al © 0 [)] a nn] 6d

Q il un on o- + tn o [ce]

Mo r —~ 3 — al ~ r =a. ° * ° ° » . . =n Ny LADY My NY MY NY NY ~~ : on . ~~ > ol

LAY

Tin - OO Oo OO Q —~ Q Q

Q mm MN — m 0 \0 \0 \O \0 0 \0 = oe oo ~ o ° ° 0 ° . °

A 0 MO A ~ 4 ~~ ~ [a] [= rt 3 = 13

Slo =) a) 0 oh o ol / S S ~ Oo o —

J ue 2] - ral © © Hn ~ +1 " + xmmlo o Q 0 ° o o ] 3 m xd al o + \0 + on -=t 0 <q oO « © . 0 ° o © . £1 NM Ny | ] ha 3 ol 0 0 o- ry 10 ~ rf — rt od o oJ

A 3] I ) i 1 1 i i i e . ol

My —0 ~ od o

N\ 4 54 jo] 4 od +4 t4 m mM m He 1

N

Mm mod i 2g Hl MAN 3 mn 8 8 Ana BS AE nN 28) ja] 3 tT Of MY mm |] © 0 0 [84 = 0 [Ea [AR

LAA} MN MN [AD Mm 3 4] 3 a 5 1 jo] © 0 0 0 0 Su ol oN al 0 Q OQ Oo oO Oo ™~ © |) 0 [sh] tn 40] 1

Q i 1 om Jas] ml my 1 © mi jab o o 3 0 co 0 ol MY 3 uN 0 ©

QT o~ [a o~ C- ~~ [8 8 la) — 1 — —t rd x

Q o-

EXAMPLE 1

A capsule preparalion is formed by suffi- ciently mixing the following components of the fol- lowing amounts and filling the same in a No, 3 cap= sule: 11,12-di~0O-acetyl-8,9~anhydro~ mycin A-6,9-hemiketal [Compound (32)7 1.5 mg

Lactobionic acid 0.75 mg

Lactose 96.25 mg . Magnesium stearate 1 mg } per capsule 99.5 mg

For an adult, 1 to 2 capsules are given three times a day before each meal.

EXAMPLE 2

The following components of the following amounts are formed as a flat tablet, with slanted edges, of a diameter of 6.5 mm. according to the

Japanese Pharmacopoeia, General Rule 14, Table Pre- paration:

11,12-di-0-acetyl-8,9-anhydroery- thromycin A-6,9-hemiketal /Com— pound (32)7 2.5 mg

Lactobionic acid 1.25 mg

Lactose 72.25 mg

Corn starch 30 mg

Hydroxypropyl cellulose 3 mg

Magnesium stearate 0.5 mg per tablet 109.5 mg

Ce ——————————————————

For an adult, a tablet is given three times a day before each meal.

EXAMPLE 3

The following components of the following amounts are dissolved in distilled water for in- . 15 jection, then filtered by a Millipore filter, and lyophilized. An intravenous injection preparation is prepared, at use, by dissolving thus lyophilized product in distilled water for injection to a total volume of 5 ml: ee ———————————————ae 11,12-di-0-acetyl-8,9~anhydroery- thromycin A-6,9~hemiketal /Compound 32)7 2 mg

Lactobionic acid 1 mg

Mannitol ’ _ 150 mg oo 155 mg

For an adult, this preparation is divided into 10 portions, and three administrations are given a day, one portion each time.

EXAMPLE 4

A capsule preparation is formed by sufficient~ ly mixing the following components of the following amounts and filling the same in a No. 3 capsule? ee ——— ee —————— 11-O-methanesulfonyl~8,9-anhydroery=- thromycin A-6,9-hemiketal /Com— pound (57) 1.5 mg

Lactobionic acid 0,75 mg

Lactose 96.25 mg

Magnesium stearate 1 mg per capsule 99.5 mg eee

For an adult, 1 to 2 capsules are given three : times a day before each meal.

EXAMPLE 5

The following components of the following amounts are formed as a flat tablet, with slanted edges, of a diameter of 6.5 mm, according to the

Japanese Pharmacopoeia, General Rule 14, Table Pre-~ paration: f ee ————— 11-0-methanesulfonyl-8,9~anhydro- erythromycin A~-8,9-hemiketal [Compound (57)7 2.5 mg

Lactobionic acid 1.25 mg lactose 72.25 mg

Corn starch 30 mg

Hydroxypropyl cellulose 3 mg

Magnesium stearate 00,5 mg per tablet 109.5 mg

For an adult, a tablet is given three times a day before each meal,

EXAMPLE 6

The following components of the following amounts are dissolved in distilled water for in- . 15 jection, then filtered by a Millipore filter, and lyophilized. An intravenous injection preparation is prepared, at use, by dissolving thus lyophilized . product in distilled water for injection to a total volume of 5 ml:

Co ——— 11-0-methanesul fonyl-8,9~anhydro~ erythromycin A-6,9-hemiketal [Compound (57)7 2 mg

Lactobionic acid 1 mg

Mannitol ‘ 150 mg . A153 mg y

For an adult, this preparation is dividdd into 10 portions, and three administrations are given a day, one portion each time.

EXAMPLE 7 8,9~anhydroerythromycin A 649~ 0.5 mg hemiketal-methyliodide [Compound (55)7

Lactose : 96.25 mg

Magnesium stearate 1 mg per capsule 96.75 mg

Ce ————————————————

A capsule preparation is formed by sufficient- 1y mixing the above components of the above amounts and filling the same in a No. 3 capsule,

For an adult, 1 to 2 capsules are given three : times a day before each meal.

EXAMPLE 8 i 8,9-anhydroerythromycin A~6,9- hemiketal-ethyliodidd /Compound (60)7 0.2 mg

Lactose 72.25 mg

Corn starch 30 mg - Rydroxypropyl cellulose 2 mg - Magnesium stéarate - ____0e5 mg per capsule 105.95 mg

The above components of the above amounts are formed as a flat table, with slated edges, of a diameter of 6.5 mm, according to the Japanese » Pharmacopoeia, General Rule 14, Table Preparation.

For an adult, a tablet is given three times a day before each meal,

EXAMPLE 9 i ————————————— 11-0O-methanesulfonyl-l"=0~formyl-8,9- anhydroerythromycin A-6,9-hemi- ketal [Compound (25)7 ' 2.5 mg

Lactobionic acid 1.25 mg : Lactose 72.25 mg

Corn starch 30 mg

Hydroxypropyl cellulose 3 mg

Magnesium stearate 0.5 mg per capsule 109.5 mg . The above components of the above amounts are formed as a flat table, with slanted edges, of a dia~ meter of 6.5 mm, according to the Japanese Pharmaco- poeia, General Rule 1h, TabletPreparation. : For an adult, a tablet is given three times a day before Bach metal.

As described hereinbefore, the compound 7 has an excellent effect of stimulating the gastro- intenstinal contractive motion, and the preparation of the present invention containing this compound can be advantageously used as a digestive tract con- tractile motion stimulant.

Claims (14)

WHAT IS CLAIMED IS:

1. A therapeutic method of stimulating di- gestive tract contractile motion in mammals which comprises administering orally or non-prally to mam- mals in need of such treatment an effective amount of a digestive tract contractile motion stimulant composition comprising a pharmaceutics1ly acceptable carrier and an effective digestive contractile motion stimulating amount of a compound having the formulas Le ptt il lo oo Ri? Rr” CH 0 H3C— 10 WY — CH : Z : ts 1 cH oii, A 3 3 ! 0 : OCH CH 3 3 if 3 cH ° 3 20 0" OR cH 3 wherein rR is selected from the group consisting of: a hydrogen atom, an acyl radical of C,_gnliphatic carboxylic acid, a Ch_12 aroyl radical, a Cig alkylsulfonyl radical,

a 12 dialkyloxyphosphoryl radical, and a Cy, pydiaryloxyphosphoryl radical; RZ is selected from the group consisting of: a hydrogen atom, Co 5 a Cy 6 alkanoyl radical which may be substie tuted by C13 alkoxycarbonyl radical, a Cg.12 aroyl radical, ’ a C126 alkylsulfonyl radical, a Ce 12 arylsulfonyl radical, a C,_poaralkylsulfonyl radical, and a C13 alkyl radical which may be substituted ’ by Cog alkoxy radical; wherein 7 stands for the formula: 11 12 cH 5) 6 > OR OR wherein Rr is selected from the group consisting of: a hydrogen atom, a Ci1-6 alkanoyl radical, a Ceo1o aroyl radical, a Ci 6 alkylsulfonyl radical, a Ce_12 arylsulfonyl radical, a C20 aralkylsulfonyl radical, and a C3 alkyl radical which may be substituted by Cin alkylthio radical, and g® j= selected from the group consisting of a hydrogen atom, a C6 alkanoyl radical; and a Cy 3 alkyl radical which may be unsubsti-~ tuted by Cy alkylthio radical, or wherein 7 stands for the formula: A cH 3 OH H or 2 stands for the formula: . 11 12 : . 0 0 Ny” wherein Y stands for the formula Ber (wherein 0 stands for Co_12 aryl radical) hN ~N ~N C= 0, S=0, C=38, 7 A 7s or the formula: 9 ~~ R C NN AY . 9 10 . wherein each of R’ and R , which may be the same or different, stands for a hydrogen atom or a Ci6 alkyl radical; ,

b R -N NN RS wherein R° is selected from the group consisting of: a hydrogen atom and a C16 alkyl radical; and wherein R® is selected from the group consisting of: a hydrogen atom, ) a Cyst alkyl radical which may be substituted with one or more hydroxyl radicals, * 10 a Cs g alkenyl radical, and a Cig alkynyl radical; } or together RP and R® from a C_goyclic al= kylamino radical together with the adjacent nitrogen atom; or ‘ 15 R? stands for the formula d / * -i + ~R%,X"

rf . d . e f . wherein R™ 18 Cy 6 alkyl radical, and R and Ry which may be the same or different are selected from the group consisting of: / ~ 20h ~ a hydrogen atom, a C6 alkyl rodical which may be substituted by hydroxyl radical, carboxy radical, cyano radical, or halogen, a C,_geyeloalkyl radi- cal, or a Cy gnikoxycarbonyl radical; a Cr 20 aralkyl radical; . a Cs g alkynyl radical; or together R® and rf form a Cour cyclic alkylamino radical with the adjacent nitrogen atom; X stands for an anion; and ptt and r'? each represent a hydrogen atom or both taken together to form a chemical bande

2. The method of Claim 1, wherein the digestive tract contractile motion stimulant compound is selected from the group consisting of: 8,9-anhydroerythromycin A 6,9~hemiketal methyl iodide, 8,9-~anhydroerythromy- cin A 6,9-hemiketal 2-hydroxyethyl bronide, 8,9-an- hydroerythromycin A 6,9-hemiketnl allyl bromide, 8,9- anhydroerythromycin A 6,9-hemiketal benzyl chlorides 8,9-anhydroerythromycin A 6,9-hemiketal ethyl bro-~ mide, diethyl-dinor-anhydroerythromycin A 649-hemi- ketal, 8,9-anhdroerythromycin A propargyl bromide, 211yl-nor-8,9-anhydroerythromycin A 6,9-hemiketal and 8,9-anhydroerythromycin A 6,9-hemiketal propar- : 25 gyl chlorides .

3, The method of Claim 1, wherein rt in the digestive tract contractile motion stimulant com=- pound is a hydrogen atom or an acyl radical of Cy 5 aliphatic carboxylic acid.

4. The method of Claim 1, wherein R® in the digestive tract contractile motion stimulant compound i ; ka adi is a hydrogen atomy a C15 alkanoyl radical or C15 alkylsul fonyl radical.

5. The method of Claim 1, wherein 7 in the digestive tract contractile motion stimulant compound has the formula: \11 1 cl : / 3 OR OR wherein each of Ry and R, are independently selected from the group consisting of hydrogen atom, and Cis alkanoyl radical.

6. The method of Claim 1, wherein Y in the digestive tract contractile motion stimulant compound is selected from the group consisting of: cl 73 §= 0, C=0, C=5, B-Ph and ’ - CH - 3

7. The method of Claim 1, wherein B® in the digestive tract contractile motion stimulant comnound has the formula: h R 7 N NRC . b . . . Cc . wherein R is a Cy to Ce radical and R° is a Cy to Cg alkyl radical which may be substi- tuted with one or more hydroxyl radicals.

8. The method of Claim 1, wherein RY in the digestive tract contractile motion stimulent compound is N-methyl-H-ethylamino radical,

9. The method of Claim 1, wherain RR? in the : digestive tract contractile motion stimulant compound has the formula: . oF -N *—R®, X~ : rf d . . e f wherein R is a Cy¢ alkyl radicesl, and R™ and R, which may be the same or different hre selected from the group consisting of: ’ a hydrogen atom, a Cy 6 alkyl radical which may be substituted by hydroxyl radical, carboxy radical, cyano radical, halogen, C35 cycloalkyl radical, or Cy 3 alkoxycarbonyl radical; a C20 aralkyl radical; a C,_¢ alkenyl radical; and a Cy 6 alkynyl radical; or together R® and rf form a Cg 7 cyclic alkyl- smino radical with the adjacent nitrogen atom; and X stands for an anion.

10. The method of Claim 1, wherein rf in the : digestive tract contractile motion stimulant com- pound is Cog alkenyl or C56 alkynyl radical.

11. The method of Claim 1, wherein RE and rf form a Con cyclic alkylamino radical with the adjacent nitrogen atom.

12. The method of Claim 1, wherein a di-~ gestive tract contractile motion stimulant composi- tion additionally comprises one or more of the phar- maceutically acceptable additional components selected from the group consisting of vehicle, di- sintegrator, lubricant, binder, dispersant and plasticizer.

13. The methdd of Claim 1, wherein the effec—

iy gE Ted LL ’ mw 26959

. “ tive amount of the digertive contractile motion stimulating compound of formula (1) for oral admi- nistration to a mammal in need of such treatment is in the range of from about 0.0001 to 100 mg/kg in a form diluted or compounded with pharmaceutically i acceptable carries or diluents.

14. The method of Claim 1, wherein the effec tive amount of the digestive contractile motion sti- mulating compound for oral administration to a mammal in need of such treatment is in the range of from . wbout 0.00001 to 10 mg/kg in a form diluted or com- ’ } pounded with pharmaceutically acceptable carriers or diluents. SATOSHI OMURA ZEN ITOH Inventors / - 209 ~