CA1192542A - Deformyltylosin derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The invention as disclosed relates to deformyltylosin derivatives of the formula wherein A is a , -CH=CH- or -CH2-CH3 - group, R1 is a hydrogen atom, or lower alkanoyl or aryl-lower alkanoyl group, X1 and X2 are hydrogen atoms or are connected to form a valence bond, Y1 and Y2 are hydrogen atoms or are connected to form a valence bond, Q1 is a hydrogen atom or methyl group, Q2 is a hydrogen atom or wherein R2 is a hydrogen atom or lower alkanoyl group, R is a hydrogen atom or

Description

This invention relates to novel deformyltylosin derivatives. More particularly this invention rela~es to compounds of the ormul ( H~' ~H~Ql OH N(CH~ ) 2 0~) 0 ~;2 <~ ~ \A r~l3

2~
y~ 1 ~}~
~2 (~2 ^ ()--23 ~H~

wherein A is a ~CH2-CH-, CH=CH- or -CH2-CH2- group, bRl Rl is a hydrogen atom, lower alkanoyl or aryl lower alXanoyl group, Xl and X~ each represent a hydrogen atom or are connected to form a valence bond, Yl and Y~ axe connected to form a valence bond or each represent a hydrogen atom, Ql i5 a hydrogen atom or methyl group, Q2 is a hydrogen atom or a C~
0~
30 - O ~ ~ OR2 group, wherein ~2 is a hydrogen ~3~0 0CH3 5~

atom or lower alka~oyl grv~p, R is a hydrogen atom or a 0~3 ~ - OR~ group, wherein R3 is a hydrogen CH ~

atom or a C2 5 alkanoyl group, R~ is a hydrogen a~om or a C2 6 alkanoyl group, and when R3 is not a hydrogen atom, R4 i~ not a hydrogen atom, or a phar~aceu~ically acceptable sal~ thereof.
The salt hereinabove i8 ~ pharmaceutically acceptable salt.
Preferred examples of the salt are inorganic salts such as the hydrochloride, sulfate or phospha~e, or organic salts such as the aceta~e, propionate, tartra-te, citrate, succinate, malater aspartate or glutamate. Other non-toxic salts are also included.
The novel compounds [1] have strong antibacterial activities as compared with the prior known antibiotic tylosin, and also have enhanced antibacterial activities against all macrolide an~ibiotic-resistant strains such as macrolide-resistant A group strains (clinical isolates of erythro~ycin, oleandomycin and 16 membered macrolide antibiotic resistant strains), B group strains and C group strains. Especially the said novel compounds have higher blood levels as compared with known tylosin.
` The antibiotics [1] of ~he present invention will be expected to show an excellent clinical infectlous therapeutic effect. Furthermore, the present antibiotics are useful for veterinary use or feed additives.
In the course o studying novel derivatives o.
16-membered antibiotics, we have found ~hat deformyltylosin or its derivatives prepared by deformylation of ~ylosin or its derivatives uslng ~(C6H5)3P]3RhCl have strong antibacterial activity

3.

as ~ompared with tylosin, and moreover show a superior antibacterial ac~ivity against macrolide antibiotics rasis~ant strains~ and further show higher blood levels.
We have also found that the compound showing such activities can be derived from the macrolide antibiotics having the structure of ~ H0 CZI 1 ~ ( CH 3 ) 2 10 0=~ ~> O ~

thereby to complete the present invention.
The compound Ll~ of the present invention can be produced by the following processes:

Process A: A compound wherein A is -CH2-FH-, Xl and OH
X2 are connected to form a valence bond, Yl and Y2 are connected to form a valence bond, Ql is a hydrogen atom, Q2 is a mysinosyl group, R is a mycarosyl group, i~e. l9-deformyltylosin of the formula 2 s CH ~ ~H v C)~ N ( ~ 3 ) 2 ()}-I

~ -~-01~3 ~ \ C~3 ~H3 ~ ~ 0~

,j~ C~7 ~ ' 3 G~ \~

H0~ ~ [ 1 a ~ ` \
H 3C~/ 0( ~1~ CH 3 is produced by the following methodu Tylosin is deformyla~ed by chlorotris (triphenylphosphine) rhodium, [(C~H5)3P]3RhCl in an inert organic solvent under heating.
A preferred example of an inert organic solvent is benzene. Heating is performed under reflux condition.
The reaction can be checked by silica gel thin layer chromatography and the reaction can be ~erminated by disappearance of the tarting material tylosin in the reaction mixture.
The product ~la~ can be obtained from the reactlon mixture by extracting diluted acid 6uch as diluted hydrochloric acid, adjusting the pH of the extract to pH 9 - 10 by adding aqueous alkali such as aqueous ammonia, then extracting with a water immiscible organic solvent such as chloroform and evaporating off the solvent. Further purification is perfor~d by any conventional isolatlon and purification pr~cedures for macrolide antibiotics, for example by chro~atography such as on silica gel, active alumina or an adsorption resin.

Process B: A compound wherein A is -CH2-fH-, Xl and OH
X2 are conn~cted to form a valence bond, Yl and Y2 are connected to form a valence bond, Ql is a hydrogen 2S atom, Q2 is a mysinosyl yroup and R is a /~\
~ ~ OR91 group in which R31 is a C~ 5 30 O~
~ 3 alkanoyl group and R41 is a C2 ~ alkanoyl group, i~e~, a compound of the formula 5.
C~ CH3 C~ C~3)2 C)R3~

O~ O ~ /_ O {H-~ -OR41 ~ ~3 ~ C~l3 {lb]
~ ~ 0 ~ ~H3 <

H~4~ Cll H~CO OCH~ [lb~
wherein R31 and R41 have the sa~e meaning~ as hereinaboveO
The compound [lb~ i~ prepared by reacting tylosin, or tylosin with the 4"'~hydroxyl group protected, with an ~liphatic carboxylic acid anhydride in the presence of an inorganic base to obtain a compound of the formula ~ \ // ~ ,)2' j/ H3C`~i O

,~CH;~ < 12~

3 ~--O ~ O ~

R50~4" ~0 \ ( CH3 c2]
H .. CC! OC`H ~

.~ ~

wherein R5 is a lower alkanoyl or halo-lower alkanoyl group and R31 is ~ C2 5 alkanoyl group, and reacting the compound [2~ with an aliphatic carboxylic acid anhydride in the presence of a tertiary org~nic amine in an inert organic solvent under heating to prepare a compound of the formula CH3 r--~H0~31 ~ ~(~H ~ ~R3~

0 ~ ~ 0 - < ~ 0 ~ ~R
~ H3 \ ~H3C~3 ~< ,~ O

~ 3 h C ~,,~ /- 0 13 R50~ O CH3 ~
~13CO' ~)~ 3 wherein R41 is a C2 6 alkanoyl group and R31 and R5 have the same meanings as hereinabove, and treating the compound L3~ with a methanol or et~anol solution of ammonia to remoYe the protective groups at positions -3, -20 and -4"', then removing the protective group at position -2' by treatment in methanol under heating ~o obtain a compound of the ~ormula ~ 3 --CHO Cl~l N ( CH3 ) 2 OR3 =< >~ ~ ~ OR~-~ ~OH
~ C~l~ <
H3 ~ o ~ ~ 0 14]

H ~ 0 ~ CH3 H~0 O~H~

7.

wherein R31 and R41 have the same meanings as hereinbefore, then subjecting the compound [4] to deformylation using L(C6H5)3P]3RhCl in an inert organic solvent under heatingO
The compound [4] is prepared from tylosin, or tylosin with the 4"'-hydroxyl group protected, by the method descri~ed in British Patent Publication No.
~,031,418 ~, 2 3 0 Process C: A compound wherein A is -CH2-~H-~ Xl and OH
X2 are connec~ed to form a valence bond, Yl 2nd Y2 are connected to form a valence bond, Q1 is a hydrogen atom, Q2 is a mysinosyl group, and R is 15 0~

OR~l in which R41 is a C2_6 C~13 alkanoyl group, i.e. ~ compound [lc~ of the formula C~ 7' C~ q C)H N ( CH 3 ) z ~H

~ o_(H~ OR.41 >/ H~ O

OH
~ CH. . <
~/ \
H ~C ~ ~ ~ 1 c HO~ ~--35 H~CO OCH~

wherein R41 i~ a C2_6 alkan~yl g~oup-8.

The compou~d [1~ is produced by reactlng tylosin, or tylo in with the 4"' -hydroxyl group pxotected, with alipha~ic carbox~ acid anhydride in the presence of an inorganic base to prepare a compound of the formula ~3 - -C}~ORs 1 OR .41 N i CH3~2 ~H

_<)\/' >r CH 3 3 \ ~ 0 ~ ~2']

R~O~--0 H CO OCH~
wherein R5 is a lower alkanoyl or halo-lower alkanoyl group and R~l has the same meaning as hereinbefore, and treating the compound C2'~ wit~ a methanol or ethanol solution of ammonia to remove the pro~ective groups at positions-3, -20 and -4"', then removing the pro~e~tive group at position 2' by trea~ment in ~ethanol under heating to obtain a compound of the formula CH .' C~HO OH 1~ ( CH3 ) 2 ~1 $ i/ ~ ~0~ ~--/~ CH~
H~C o ~ o" [5 ~ ~ CH3 H ~CO C)CH ~

~3~
. . .

wherein R~l has the sam~ meaning as h~reinbefore, and deformylating th~ compound [5] with ~(C6H5)3P]3RhCl in an inert ~rganic solvent under heatiny.

Proce~s D: ~ comp~und wher~in A i5 -CH2~H- in which R12 is a lower alkanoyl group, Xl and X2 are connected to form a valence bond, Yl and Y2 are connected to form a valence bond, Ql is a hydrog~n a~om~
Q2 is a mysino~yl group, and R is 0~31 ~ ~ in which R31 i~ a C2_5 0 ~
~ 3 alkanoyl group and R41 is a C2_6 alka~oyl group, i.e., a compound of the formula C~H3 C~H3 C~ H3~2 OR31 ~ ~ ~ 3"

0~ ~ O ~ ~ O--~ ~ OR4 ORl,~
~r C~3 <
// \ ~ lld]

~ G ~\0/~=
HO~ _~ CH 3 H3~0 OCH3 The compound ~ld~ is produced as follows. A
compound in which the 2'~ or 4"' - hydroxyl grvup may optionally be protected, of the formula ~,, C~7 C~3 ~R~ N(cH3)2 o~

O -~ ~ o--~ ~ O--~OH

~ ~3 ;~ ~A3 <

10 3~-G ~\c~
~80 ~ ~~ 0 16]
~3~ C~H~ ~ ~H3 wherein R6 i6 a hydrogen atom or an R61 gxoup, wherein R~l is a lower alkanoyl group, R8 i~ a hydrogen atom or an R5 group, wherein R5 is a lower alkanoyl or halo-lower alkanoyl group, is acylated with an aliphatic carboxylic acid halide in ~he presence of a tertiary organic amine in an inert organic solvent to obtain a compound of the formula -Ch CH3 OR~ {~I3)2 OH

~ ~\~ (~OR3 ~/ \ CH 3 C~ 3 '<~ 3/~ 0~ 12 ~H3 ~

H3C o ~\o/~= 17]
35 R8~ ~--O ~

~P1 3f;~0 O~

1~. .

12' R31~ R61 and R8 have the same meanings as hereinbefore, then the said compound [7J i5 acyla~ed wi~h an aliphatic carboxylic acid anhydride in ~he presence of base under hea~ing to ob~ain a compound of the formula CH3 ~ 3 OR61 N (CH3~2 OR31 ~ o ~ ~ O _ ~ 0~41 ORl2 >~ (::~3 <

H~C o \~ ~ lB]
~80 ~ )~ O
~ C~H3 H3CO O ~ 3 ein R12' R3~ R~l and R8 have the same meanings as hereinbefore, then the said compound L83 is treated with methanolic or ethanolic ammonia to remove the prot~ctive group for position-4"', and the protective group at position-2' is removed by heating in methanol.

Process E: A compound wherein A is -cH2-cH-Ln which R12 is a lower alkanoyl group, Xl and X2 are connected to form a valence bond, Yl and Y2 are connected to form a valenc~ bond, Ql is a hydrogen atom, Q2 i5 a mysinosyl group, R is 0~
,~
~ ~OR41 ~ in which R41 is a 12.

C2 6 alkanoyl 910Up, i-e~, a compound of the formula ~ 'H ~ O~ ~ ( Cl ~ 3)2 O =~ O--( ~ OR
< ~) ~H 3 C) ~ 3 ~< ~ORl~

0 /~ CH 3 <
O
HD~ O CH3 lle~
5 ~I CO OC~
wherein R12 and R41 have th~ same meanings as herainbefore.
The compound Cle~ is produced by treating the compound C7'~ with ammonia in methanol or Pthanol to remove the protective group at position-4"' of the compound [7'~ (a compound ~D~ in ~he proces~ D wherein R31 is R~l), and treating in methanol under heating ts remove the protective group at positlon-2'O
A compound [le~ wherein R12 and R41 are not identical groups can be prepared by treating the compound [2'3 with ammonia in methanol or ethanol within a reaction time for not removing the protective group at position-4"', to remove the protective groups at positions 3 and -20 to prepare a compound of the formul~

3 .

~3 _ ~HO OR41 ~ ( C~13 )2 OH

~ '~ C3~04~oR4 ,~ ~C ~' O ~ ~

,~ CH 3 <

10H3C~ /~
R5C)~>-- O
H3CO \ OCH3 wherein R5 i~ a lower alkanoyl or halo-lower alkanoyl group and R41 has the ~ame meaning as hereinbefore, then acylating the said compound [9~ with a lower aliphatic carboxylic acid halid~ in an inert organic ~olvent in the presence of a tertiary organic amine to obtain a compound of the for~ula CHO OR~l N ( ~3 ) 2 OH

2~ 0~ ~ `~ 0~/~ ~OR4 Rl2 ~H3 ,~ CH 3 1~13C ~ o]

R50~
3~~_ ~ `C~13 H 3C0 O~H3 ~ ~ ' 14.

wherein ~12~ R41 and R5 have the same meanings as hereinbefore, and treating the said compound ~10~ with ammonia in methanol or ethanol or remove the protective group at position=4"', further treating in methanol under heating to remove the pro~ective group at position-2' to prepare a compou~d of the formula - CH 3 CHO C)H 1~ ) 2 o S ~-- ~\ ~ ~ / OR4 "> OR 12 ~ ClH~3 <~
:H3C o \~o/~=
HO~ \~
~3CO CH 3 wherein R12 and R41 have the same meanings as hereinbefore, and then deformylating the compound [113 with L[C6H5)3P33RhCl in an inert ~rganic solvent under heating.
Process F: A compound wherein A is -CH=CH , Xl and X2 are connected to form a valence bond, Yl and Y~ are connected to form a valence bond, ~ is a mysinosyl group, ~3 /'~
R is ~ ~ OR~l wherein R41 is a 0~
C~3 C2 6 alkanoyl group, R3 is a hydrogen atom or an R31 group in which R31 is a C2 5 alkanoyl group, i,e., a co~pound of the formula .

~3~2 C}-l ~ CH 3 OH N ( C~1 3 ) 2 OR 3 s ~ O ~ ~U-~

/>-c`H3 t C~ llf]
O
~ CH3 H 3CO OC~H 3 wherein R3 and R41 have the Rame meanings a~
hereinbefore.
The compound ~lf~ is prepared by reactin~ the oompound [ld~ or [le] with an alcoholate in alcohol.
Examples of the alcoholate are C~30Na, C2H50Na and others. The reaction proceeds at room temperature;
however if the reaction rate is slow, it can be heated~
and its end point is marked by disappearance of the compound [ld] or ~le] as detected by s.ilica gel thin layer chromatography.
The compound [lf~ can be obtained by the ~ame isola ion method as for ~he compound ~la] in the process A.

Process ~: A compound wherein A i~ -CH2-fH-, Xl ~nd O~I
X2 are connected to form a valence bond, Yl and Y~
are connected to form a valence bond, Ql i~ a hydrogsn atom, Q2 is a mysinosyl group and R is a hydrogen atom, i~e. l9-deformyl-4'-demycarosyltylo~inO

1~ .

The above compound of khe formula CH3 ~I3 (:~H ~(~3 )2 ~ ~ V ~ )H
~ H3C~/ 0 // ~ ~H3 0 ,~ C~3 <

H() ~ 0 CH
H CO OCH~

i~ prepared by deformylating 4'~demycarosyltylosin wi~h ~(c6H5)3pJ3~hcl in an inert org~nic solYentO

4'-demycarosyltylosin can be prepared by ~0 hydrochloric acid hydrolysi~ of tylo~in. ~ _tibiot. ~nd Chemoth., 11. 328 (1961)~.
. _.
Deformylation of 4'-demycarosyltylosin can be performed by the ~ame process as in the process A
hereinbefore.
The compound ~lg] san be isolated and purified by the same procedure~ as in process A hereinbefor~O

Process H~ A compound wherein A is -CH2~1H~ 11 is ~11 a lower alkanoyl or aryl-lower alkanoyl group), Xl and X2 are connected to form a valence bond, Y1 ~nd Y~
are con~ected to form a valence bolld 7 Ql is a hydrogen atom, Q2 i~ ~ my~ino~yl group and R is a hydrogen atom, iOe. a compound o~ the formula 17 .

C~ 3 CH 3 ~ O ~ N~C~3)2 ~< > ~ 4~H

~ ~3C ~ ~ ~ CH3 0~11 >~CH3 <

0 H3C,~_o ~\ o H(:)~( 4 ~' ~ O
llh]

wherein Rll has the same meaning as hereinbefore.
ThP compound [lh~ is prepared by reacting 4'-demycarosyltylosin with a lower aliphatic carboxy~ic acid anhydride in an inert ~rganic ~olv~nt to prepare a co~pound of the ormula ~ ~ O - ~ OR6 ~ 0~1 /~ r~H3 ~3C ~ O ~ \ ~ ~ O 112 ~0~

~3~ ~C~3 ~3 wherein R61 is a lower alkanoyl group, reacting the said compound [12] with a lower aliphatic c~rbo~ylic acid halide or aryl lower aliphatic carboxylic acid halide to prepare a compound of the f~rmula : . .
. . .

r CH~ 6i l~l(CH3 ) ~

/~ -~ 0~61 ~ H3~ 0 ,~0~11 ,~ CH

0 H3C o '~4\\a~
O- l ~3 ~ 3co ~H3 1~3 wherein Rll and R~l have the same meanings as hereinbefore, treating the compound ~13~ in methanol under heating to remove the protective gxoups at positlons-2' and -4', then removing the p~ote~tive group at posi~ion-4"' in ammonia ~aturated methanol to prepare a compound ~143 of the formula CH 3 ~ ~HO 01~ h ( ~ 3 ) 2 oc~ / ~-~3C~
~ ~ ORll ~ 3 <

~ 0/ 114 HO~r/~ ~--O
C~0CH3 C~3 19 .

wherein Rl1 has the ~ame meaning as hereinbefore, and deformylating the compound [14] with ~ (C6H5) 3P]3RhCl in an inert organic ~olvent under heat ing .
Or alternately, the compound [14] can be prepared by reacting 4'~demycarosyltylQsin with a lower aliphatic carboxylic acid halide in an inert organic ~olvent in the presence of a tertiary organic amine to prepare a compound of the formula 0 ~CH0 ~ ~CH3)~

o \ ~ O ~ OR
,D ~3C~ ~C~I~
~ ~O:R
3 <

3 o \~0 RllO~ ?- C~3 ~15 ~ 3CO Cx~H3 wherein Rll has the same meaning as hereinbefore, then treating the co~pound [153 by the same procedure as for the above compound C13]. 2 3 Process I. A compound wherein A i~ -CH2-~H-, Xl and ~
X~ are connec~ed to orm a valence ~ond, Yl and Y2 are connect~d to form ~ val nce bond, Ql is a hydrogen O ~ ~H3 ~ \~OR21 atom, Q2 is )~/ (R~l is a lower H3CO OC~J3 2~.

alkanoyl group) and R is a hydrogen atom, i.e. a co~pound o the formula 0 ~ CH3 ~ -,) O ~ O
R~10 (~ ~-- o l ~li ~ 3~ OC`H 3 wherein R21 has the same meaning a~ hereinbeforeO
The compound Cli] is prepared by reacting the compound ~12~ with a lower aliphatic carboxylic acid halide in an inert organic solvent in the presence of a tertiary organic amine to prepare a compound of the formula "~ Ci~O OR. ~1 N ( C~13~2 O D \ ~ 0 ~ ~ OR61 // H3(:~-< O~3 <~ 3~ OH
~ CH s ~ 116]

R210 ~

~3C0 ~H3 r~
~6'~

wherein R21 and R61 ha~e the same ~eanings as hereinbefore, removing the protective group at positions-2' and -4' by treating with methanol under heating to prepare a compound of the formula C~
rCH~) OH I~'(CH~ )Z

O =~ O ~ OH
,~ H3~ ~ C~13 /~ OH
~ CH3 <

~ ~1`\0 .210~"' )~O
C~ 3 H3CO~ O~H3 wherein R21 has the s2me meaning as he~einbefore, then deformylating the compound ~17~ with ~(C6H5)3P]3RhCl in an inert organic solvent.

Process J: A compound wherein A is CH2-CH~, (R12 is a lower alkanoyl group), Xl a~d X2 are connected to form a valence bond, Yl and Y2 are connected to form a valence bond, Ql is a hydrogen atom, Q2 is - CH
~ 3 ~ OR21 (R21 i~ a lower alka~oyl group) and R i5 a hydrogen atom, i.e. a compound of the formula r~
22 .

CH3 ~H3 ~H N(C~3 )2 ~ ~ O ~; OH

ORl2 ~`H 3 <
H ~ ~ o ~ ]
R210~(~9"' )--~ ~CH

wherein R12 and R21 have the same meanings E~S
hereinbef ore c The compound [l j ~ is produced by acylating the compound Elg~ or compound Elh]. in which Rll is a lower 20 alkanoyl group with a lower aliphatic carboxylic acid anhydride in the presence o a base to prepare a compound of the f ormula 6:~H 3 CH 3 01~2~ N ( ~ 7 ~\ /~

'~ ~ ORl2 \
j~ CH3 H3C~o ~\ o ~2~ 83 ~3 ~0 C~H 3 ~-~3 ~
wherein R12 and ~21 are lower alkanoyl groups, then removing the protective gxoups at positions-2' and ~4' in methanol under heating.
Process K: A compound wherein A i5 -CH=CH-, Xl and X2 are connected to form a valence b~nd, Yl and Y2 are connected to form a valence bond, Ql is a hydrogen atom, Q2 is a mysinosyl group and R is a hydrogen atom, i.e~
l9~deformyl-2, 3~didehydxo-3-dehydroxy-4'-demycarosyltylosin of the formula CH3 C~H~ OH r'i(~l3 ) 2 >/ ~3C o CH
~>
>~ CH 3 20 ~ ~ U~ ~ ~lk]

H~CO OCH3 The compound ~lk3 is produced by reacting the compound ~lh] wherein Rll is a lower alkanoyl group with an alcoholate in an alcoholic solvent. Examples of alcoholates are CH30Na, C2H50Na and others. The reaction proceeds at room temperatl~re, however heating is effective if the reaction rate is slow, The reaction can be traced by thin layer chromatography and is terminated by checking the disappearaIIce of the starting compound Clh].
Isolation o the compound Llk3 iB performed by th~ same procedures as ~or isolation of the compound Cla3 in process A hereinbefore.

r 24 .

- Process L: A compound wherein A is -CE~2 ~H, Xl and H

X2~ Yl and Y2 are hydro~en atoms, Ql is a hydrogen atom, Q2 is a my6inosyl group, and R is a hydrogen atom, iOe, l9-deformyl-4'-demycarosyl~10, 11, 12, 13-tetrahydrotylosin of the formula 0 ~ ] ~CH~)2 ,~ CH 3-~ 0 <~1 ~ OH
~CH3 ~<

H 3C/ o ' ~\
HO~ O ~ ~ tll ]
~ / ~3 The compound Cll~ is produced by reducing the compound C lg ] .
The compound ~lg] is reducad at positions-10, -11, -12 and -13 by catalytic reduction wi~h a heavy metal catalyst such as platinum oxide, palladium/carbon or Raney Nickel in methanol or ethanol at room temperature.
Reaction is traced by thin layer chromatography and is terminated by checking the disappearance of compound ~lg].
Compound Lll] is isolated by drying in vacuo after filtration of the catalyst.
ProcesQ Ms A compound wherein A is -CH2-C~2-, Xl, X2, Yl, Y2 and Ql are hydrogen atoms, Q2 is a mysinosyl group, and R is a hydrogen atom, iOe.
l9-deformyl-3~dehydroxy-4' demycarosyl~10~ 11, 12, 13-t~trahydrotylosin of the formula ?

;tJ~
25 .

('H ~ )H N ( CH 3 ) Oc<~ O~ 0}~
H3~
/ \ 6~3 ~1 ~
1~ C~13 ~I C~ o>~
3 ~
HO~ CH 3 [lm]
~3~0 ~C~3 The compound ~lm] i8 produced by reducing the compound ~lk]. Reduction of the compound [lk] can be p~rformed by the same procedure as that used in process L
hereinabove.

Proce~s N: A compound wherein A is -CH2-fH-, Xl and X2 are connected to $orm a valence b4nd, Yl and Y2 are connected to form a valence bond, and Ql' Q2 and R
are hydrogen atomsr i.e. 19 deformyl-4'~demycarosyl-23-demysinosyltyLosin o~ the formula ~H3 CH~ OH I~ (cH3 ) 2 H 3 C~~ ~CH 3 /

~(~ 23 ~
~3 26 .

The compound ~ln] i~ produced by deformylating 4'-demycarosyl-23-demysinosyltylosin with ~(C6H5)3P]3RhCl in an inert or~anic solvent under heating.
S 4'-demycarosyl 23-demysinosyltylo~in is prepared by hydrochloric acid hydroly~i~ o~ 4'-demycaro~yltylosin CTetrahedron Letters, 4737 (1970)3.
The above defor~ylation and i~olation and purifica~ion can be performed by ~he same procedure as described in the process A hereinbefore.
Process O: A eompound wherein A is -CH2-~H2-, X
~1 and X2 are connected to form a valence bond, Yl and Y2 are connected to form a valen~e bond, Ql is a methyl group, Q2 is a my6ino~yl group, and R is a hydroqen atom, i.e. 20-deoxo-4'demycarosyltylosin of the formula C~ 19 20 3 r ~1~ 0~ N(C~3 ) 2 ~ ~9 \ C/~ ~OH

,~CH 3 <

H3C~o ~I~o>~

( \ O ~ [lo~
~( CH

The compound ~lo~ i5 produced b~ reducing the C~O
group at position-l9 of tylosin to a CH20H group, 35 exchanging the CH20H group to a CH3 group to prepare 20-deoxotylosin, and de-4'-mycarosylating the obtained 20-deoxotylosin with diluted acid.

S~f~

Alternatively, the compound [lo~ can be prepared by previous 4'-demycarosylation of tylosin and followed by reduction of the CHO group at position-l9 to the CH20H
group.
Minimum inhibitory concentration of ~he products is ~hown in Table 1.
The following example~ illustrate the process of the pre~ent invention.
Rf values in the examples are, if not ~pecified, measured by the following carrier an~ developers.
Carrier: Merck, silica gel 60 Art 5721.
Developer: A; n-hexane - benzene ~ acetone -ethyl acetate - ~ethanol (90 . ~0 ~ 25 . 60 : 30~.
B; chloroform - metha~ol - acetic acid - water ~80 : 7 : 7 5 1) E mple 1 l9-deformyltylosin:
[(C5H5)3PJ3RhCl (2.1 g) was added to tylosin (1.83 g~ dissolved in benzene (50 ml) and refluxed for 6 hours. The reaction mixture was filtered and the filtrate was extracted twice with 0.1 N hydrochloric acid (50 ml). The aqueous layer was adjusted to pH 9 by adding aqueous am~onia and extracted with chloroform (lOQ ml), The extract was dried with anhydrous ~agnesium ~ulfate and dried in vacuo to obtain the product (1l15 g)~
TLCs RfA = 0.23, RfB = 0.24 Mass spectrum (m/~): 887 (M ), 743, 725, 553, 510, 3~2, 3~1, 191, 175, 17~, 1~5.
NMR spectrum (100 MHz, CDC13). disappearance of proton in aldehyde~
Example 2 3"-acetyl-19-d~formyl ~"~isovaleryltylosinO
C(C6~5)3P]3~hCl ~1 9) was added to a solution of 3"-acetyl-4"-isovaleryltylosin ¦1 g) dis~olved in b~nzene (20 ml) and refluxed for 6 hours~ The reaction Unable to recognize this page.

~9 .

mixture was filtered and the filtrate was dried up in vacuo. The residue was purified by silica gel column chromatography using benzene - acetone (& 1) to obtain 3"-acetyl-l9~deformyl~4"-isovaleryltylosin (700 mg).
S TLC: RfA = 0~53~ RfB = 0078 Mass spectrum tm/e): 1013 (M ), 912 ~M -101) 362, 271, 211, 191, lgO, 175, 17~, 173, 16~.
NMR spectrum (100 MH~, CDC13~: 1.77 (12-CH3), 2.00 (3" OAc~.
~ process for production of the above 3"-acetyl 4" isovaleryl-tylosin is described in British Patent publication ~o. 2031418 A.

3, 3", 4"-triacetyl-19-deformyltylosin and 3", 4"~diacetyl-19~deformyl-2, 3-didehydro-3-dehydroxytylosin:
Asetic anhydride (1.5 ml~ was added to a solution of l9-deformyl tylosi~ (950 mg~ dissolved in dry pyridine 20 (10 ml) and heated at 100C for 70 hoursO ~he reaction mixture was concentrated in vacuo and extracted with chloroform (50 ml). The chloroform layer was wa~hed with 0.1 N- HCl, water ~nd diluted aqueous ammonia, dried with anhydrous magnesium sulfate and dried up in vacuo.
25 C2H50~a ~70 mg) was added to a solution of the residue dissolved in ethanol (20 ml~, stirred ~or one hour at room temperature and dried up in vacuo. ~he residue was dissolv~d in methanol saturated with aMmOllia ( 20 ml ) and stirred for 6 hours at room temperature. Water (50 ml~
was added to the reaction mixture and extracted with chloroform (50 ml), The chloroform layer was dehydrated, dri~d up in vacuo, dissolved in methanol (20 ml) and reflu~ed for 16 hours. The reaction mixture was dried up in vacuo to yield the crude product (1.05 g) which was purified by silica gel column chromatography using benzene - ac~tone (6 . 1) to obtain 3, 3", 4"~triace~yl~
l9-deformyltylosin (350 mg) and 3", 4"~diacetyl~
19-deformyl-2,3-didehydro~3-dehydroxytylosin (280 mg).

t~
30~

3, 3", 4"-triacetyl-19~deformyltylosin:
TLC: RfA = 0 49~ Rf~ = O. 76 3", 4"-diacetyl-19 deformyl -2, 3-didehydro-3-dehdroxy~ylosin:
TLC: RfA - 0.52, Rf~ = 0.77 Mass spectrum (m/e): 953 ~M ), 894, 834/ 725, 709, 535, 53~, ~92, 40~, 344, 229, 191, 17~, 17~.
EtOH
10Uv : 215, 7285 nm.
max 4"-butyryl-19-deformyltylosin~
C(C6H5)3P~3RhC1 (200 mg) was added to a solution of 4"-butyryltylosin (200 mg) dissolved in benzene ~ ml) and refluxed for 6 hour~. The reac~ion mixture was filtered and the filtrate was dried up in vacuo. The re~idue was purified by silica gel. thin layer chromatography using benzene - acetone (6 : 1) to yield 20 4"-butyryl-19-deformyltylosin (133 mg3.
TLC: rf~ = 0~44 Mass spectrum (m/e): 957 (M ~, 870 (M ~87~, ~69, 852, 851, 743, 725, 553, 535, 363, 300, 215, 190, 1~, 173.
The above 4"-butyryltylosin is prepar~d by the process di~closed i~ British Patent publication ~o.
2031~
Referential example:
4' demycarosyltylosin~
Tylosin (5 g) dissolved in 1 ~-HCl (100 ml) was ~tirred for 22 hour~ at room temperatureO The reaction mixture wa~ adjusted to pH 9 by adding 10~ sQdium hydroxide a~d extracted twice and chloroform tlOO ml)~
The chloroform layer was dehydrated with anhydrous magnesium sulfate and dried up in vacuo to o~tain crude 4'-demycarosyltylosin (4~4 g) which was purified by silica gel column chromatography ~sing benzene ~ acetone to yield the purified product (3.8 g).
TLC: RfA = 0~02, RfB = 0.17 Mass spectru~ (m/e): 771 (M ), 754, 581, 3~0, lgl, 175, 174.

l9-deformyl-4'demycarosyltylosin:
[(C6H5)3P~3RhCl (5.25 mg~ was added to a solution of 4"-demycarosyltylosin ~4 g) dissolved in benzene (100 ml) and refluxed for 6 hours. The reaction mixture was filtered and the filtrate was extracted three times with 1 ~-HCl (50 ml). The aqueous layex was adjusted at pH 9 by adding 10~ NaOH and extracted twice with chloro~orm ~100 ml). The chloroform lay~r was dehydra~ed and dried up in vacuo to obtain the crude product (3.2 g) which was purified by silica gel cQlumn chromatography using benzene - acetonP tl ~ 1~ to yield purified l9-deformyl~4'demycarosyltylosin (1.8 g).
TLC~ RfA = 0-04~ RfB = 0.29 Mass spectrum (m/e): 743 (M ~, 725, 553, 510, 36~, 191, 174.
NMR spectrum (100 MHz, CDC13): 1.79 (12-CH3~, 2~45 ~3 '-~(CE~3) 2~' 3-45 (2"'=OCH3), 3.61 (3~ OCH3)o disappearance ~ of pro~on in aldehyde.
EtOH
UV : = 282~2 nm ( max - 22100) max Example 6 l9-deformyl-2,3-didehydro-3-dehydroxy-4'~demycarosyltylosin:
Acetic anhydride (5 ml) was added to l9-deformyl-4'-demycarosyltylosin (3 g) dissolved in dry pyxidine 35 (10 ml) and reacted at 70~C for 14 hoursO l'ha xeaction mixture wa~ poured into ice-water and adjusted ~o pH 9.5 by adding 10~ NaOH. Th~ precipitate was filtered to

5~
`~ 32.

obtain crude 3, 2', 4', 4"'-tetraacetyl-19-deformyl-4'-demycarosyltylosin (3.~ g~. This was dissolved in methanol (25 ~1~, 2.8~ CH30Na (5 ml) was added, the mixture was s~irred for 1. 5 hours a~ room temperature, 5 acetic acid (0.157 ml) was added and ~he ~ix~ure was refluxed for 20 hours. The reaction mixture was dried up in vacuo. Chloroform ~100 mg) was added to the re~idue and washed with diluted aqueous ammonia (pH 9)~ The dehydrated chlorofor~ layer was dried up in vauo~
10 C2H50Na (675 mg) was added to the residue dissolved in ethanol (30 ml) and reacted at 70C for 18 hour~. The reaction mixture was dried up and chloroform (100 ml) was added to the residue, then washed with water. The dehydrated chloroform layer was dried up to obtain the 15 crude product (2.3 g~. The crude substance wa~ purified by silica gel column chromatography using benzene -acetone ~2 ~ 1~ to yield the product (1.5 g).
TLC RfA = 0.06, RfB = 0.32 Mas~ spectrum (m/e): 725 tM ), 707, 535, 344, 191, 175, 174.
NMR spectrum Iloo MHz, CDC13)~ 1.80 (12-CH3), 2.50 ~3'-N(CH3)2~, 3.49 (2"' OCH3), 3.61 (3"'-OCH3).
~tOH
UV : = 214O5 nm ( = 19800), 285.2 nm max ( - 19200).
Exal~lple ?
l9~deformyl~ demycaro~yl~23~demysino~yltylosin 4'~demycarosyltylosin ~2 g) di solved in 0.2 N-~Cl (12 ml) was adjusted to pH 1~8 by adding 1 ~-HCl and reacted at 90C for 72 hours, The r~action mix~ure was adjusted to pH 9 by adding 10% ~aOH and extracted twi~e with chloroform (50 ml)~ The chloroform layer wa~
dehydrated and dried up in vacuo to obtain a crude powder (1~5 g~ which wa6 dissolved in benzene (15 ml).

s~
33.

[(C6H5)3P]3RhCl (2 g) was added and the mixture was refluxed ror 6 hours. The reaction mixture was filtered and the filtrate was extracted twice with l N-HC1 ~50 ml). The a~ueous layer was adjusted at pH 9 with lO~
NaOH and e.x~racted three times with chlorofo~ (50 ml)O
The extrac~ was dehydrated and dried up in vacuo to obtain the crude powder (l.O g). The crude powder was purified by silica gel column chromatography using chloroform -methanol (ll : l) to elute l9-deformyl-4'-demycarosyl-tylosin and l9 deformyl-4'-demycarosyl- 23-de~ysinosyl-tylosin, in this orderO Each corresponding fractions wer~
collected and dried up in vacuo to yield l9-deformyl~
4'-demycarosyltylosin ~200 mg3 and 19 deformyl-4'-de~ycarosyl-23-demysinosyltylosin (316 mg), TLC: RfA = 0-04~ RfB ~ 0.19 ~ass spectrum (m/e), 569 (M ~, 379 (M -l90), l9~, 174, 173.
NMR spectrum (100 MHz, CDCl3): 1.82 (12 CH3), 2.51 C3' N~CH3)2].
EtOH
UV ~ = 283.0 nm ( = 2070~).
max l9-deformyl-4'-demycarosyl 3-phenylacetyltylosin:
Acetic anhydride (8 ml) was added to 4'-demycarosyltylosin t4 y) dissolved in acetone (20 ml) and stirred for 3 hours at room temperature. The reaction mixture was adjusted to pH 9 with aqueous ammonia and extracted with chloroform (100 ml)O The extract was washed with water, dehydrated and dried up in vacuo to obtain crude 2', 4'-diacetyl-4'-demycarosyltylosln.
[TLC: RfA = 0 44~ RfB = 0 83] (4-28 g)~
Phenylacetylchloride (3.6 ml) was added to a ~olution of the crude material dissolved in dry pyridine (20 ml) and stirred at 40C for 17 hours~ The reaction mixture was poured into cold water (400 ml), adjusted to pH 9.0 with aqueous ammonia and extracted with chloroform ",~ ~
;~,.",~

34.

(100 ml). The extract was washed with dilu~ed aqueous NaOH, diluted HCl, water and diluted aqueous ammonia and dried up in vacuo after dehydration. The residue was dissolved in ammonia saturated with methanol (20 ml), stirred for 3 hours at roo~ temperature, poured into water (100 ml), ~hen extrac~ed with chloroform (100 ml). The chloroform layer was dehydrated, dried ~p in vacuo and refluxed with methanol (50 ml) for 17 hours.
After checking the removal of the protective 10 group at positions-2' and -4' by TLC, the reac~ion mixture was dried up in vacuo, dissolved in benzene (70 ml) and washed ~nce with water. The benzene layer ~as dehydrated with anhydrous magnesium sulfate and C(C6~5~3P]3~hCl (3.6 g~ was added thereto, then 15 heated at 80~C for 6 hours. I'he filtrate was extracted three times with 1 N-HCl ~100 ml). The extract was neutralized with 10~ aqueous NaOH to adjust ~he pH to 9.0, and extr~cted three times with chloroform (100 ml). The chloroform layer was dehydrated, and dried up in vacuo.
20 The residue was purifi~d by silica gel column chrom~tography using chloroform - methanol (20 ~ 1) to yield the product (404 mg).
TLC: RfR = 0-37 Mass spectrum (m/e) n 661 (M ), 725, 535, 190, ~5 175, 174, 173.
NMR spectrum (100 MHz, CDC13): 1.79 tl2~CH3), 2.50 [3~-NtcH3)2~ 3~45 (2'"-OCH3), 3,60 (3l-l OCH3, ~CH2-ph), 7.26 (ph)-IR tKBr tablet): 1596 cm (ph)o Example 9 3,4~ diacetyl-19-deformyl-4'-demycarosyltylosin:
3, 2', 4', 4"'-tetraacetyl-l9~deformyl-35 4' demycarosyltylosin (100 mg) obtai~ed in Example 5dissolved in methanol l10 ml~ was refluxed for 16 hours.
The reaction mi~ture was dried up in ~acuo and the residue was purified by alumina column chromatography using - benzene - ethyl acetate ~1 : 1) to o~ain the product (8~.7mg).
TLC: RfB = 0'37 Mass ~pectrum (m/e): 827 (M~), 767, 594, 535, 3~5, 3~4, 217, 190, 174, 173.
NMR spectrum (100 MHz, CDC13): 2-06 t3-OAc), 2011 (4"'-OAc), 20A9 [3'-N~C~3)2~' 3-44 (2i"-OCH3), 3051 ~3"'-OCH3).
Example 10 3-acetyl-19-deformyl-4'-demycarosyltylosin:
In example 7, phenylace~ylchloride (6.3 ml~ was replaced by acetylchlorlde (1.84 ml) to pxoduce the product (362 mg)~
TLC R~B = 0.27 Mass spectrum (m/~): 785 (M ), 725, 535, 421, 405, 362, 345, 3~4, 190, 17~, 173.
Example 11 l9-deformyl-4'-demycarosyl-3-propionyltylosin:
In example 7, phenylacetylchloride (6.3 ml~ was replaced by propionylchloride (2~25 ml) to produce the product (412 mg)~
TLC: RfB = 0,31 Mass spectrum (m/e): 799 (M ~, 725~ 535, 435, 419, 362, 345, 344r 19~t 174, Example 12 3-bu~yryl-19-deformyl-4'~demycarosyltylosinc In example 7~ phenylacetylchlorlde (6.3 ml) was replaced by butyrylcllloride ( 2 . 69 ) to produce ~he product:
(523 mg)~
35 TLC: R~B 3 0-33 Mass 3pec~rum (m/e). 813 ~M ), 725, 535, 449~
433~ 362, 3~5, 344, 1~0, 174, Example 13 4"'-butyryl-19~deformyl-4'~demycarosyltylosin:
Dry pyridine (0.26 ml) was added to a olution of 2 , 4'-diacetyl-4'-demycarosyltylosin (1.28 g3 obtained in Example 7 dissolved in dry dichloromethane ~lO ml), butyrylchloride (0.31 ml~ was added and the mi~tuxe was ~tirred for one hour at room temperature. Chloroform ~20 ml) was added to the reaction ~ixture~ The aqueous layer was adjusted ~o pH 9 by adding aqueous a~monia and æhaken to extract. The chloroorm layer was washed with diluted ~Cl, water ~nd diluted ~aOH, dehydrated and dried in vacuo. Th~ r4sidue was dissolved in methanol ~20 ml), refluxed for 16 hours and dried up in vacuo, The residue was dissolYed in chloroform (20 ml), wash~d with diluted lS aqueous NaOH and water, dehydrated and dried up in vacuo.
The residue was dissolved in benzene (25 ml), [(C6H5)3P~3RhC1 ~1.3 g) wa~ added and heated at 80~C for 6 hours. The reaction mixtur~ was $iltered, and the filtrate was dried up in vacuo to obtain the crude product, which was purified by ~ilica gel column chromatography using chloroform - methanol (20 : l) to produce the purified product (620 mg).
B
Mass spectrum (m/e): 813 ~M ), 640, 623, 622, 568, 553, 552, 362, 245, l90, 174, 173.
NMR spectrum (100 MHz, CDCl3).
2.49[3l-N(CH3)~3, 3.4 (2'"-OCH3), 3.51 ~3'"-OCH3)~
Example 14 l9-deformyl lOI ll, 12, 13~tetrahydro-3-dehydroxy-4'-demycaro yltylosin:
l9-deformyl-2,3-didehydro 3-dehydroxy- .
4'-demycarosyltylo~in (lOO mg) obtained in Example 5 was dis~olved in methanol ~4 ml). 5~ Pd~carbon catalyst (50 mg) was added thereto and the above compound was 6ubjected to catalytic reduction or 8 hours at room 37.

temperature. The reaction mixture was filtered to remove - the catalyst and the filtrate wa~ dried up in vacuo to produce the product (85 my~0 TLC: RfB = 0-31 Ma~s spectrllm (m/e): 731 ~M ), 541, (M -191), 350, 191, 175, 174.
UV: no absorption.
Exam~e 15 l9~deformyl-10, 11, 12, 13-tetrahydro-4'-demycarosyltylosin:
l9-deformyl-4'-d~mycarosyltylosin (100 mg) obtained in Example 4 was dis~olved in ethanol (5 ml). 5%
Pd-~arbon catalyst (50 mg) was added ~hereto, and the above compound was subjected to catalytic reduction for 6 hours at room temperature~ The reac~ion mi~ture was filtered to remove the catalyst, and the filtrate was dried up in vacuo to produce th~ product (90 mg)0 TLC~ RfB = 0O20 Mass spectrum (m/e3: 747 ~M 3, 557, (M -191~, 366, 191, 175, 174.
W : no absorption.
E mple l 20-deoxo 4'-demycaro yltylosin:
Tylosin (5 g) was dissolved in a mixture (150 ml~
of 0.2 M phosphate buffer ~pH 7~5~ - methanol (1 : 1).
NaBH4 ~150 mg) dis~olved in the ~ame mixture (10 ml) was added thereto, and the mixture wa~ stixred for 105 hours at room temperature, then its pH was adjusted to 9.5 by adding diluted aqueous ammonia and the reartion mixture 30 was extracted with chloroform (100 ml)~ The chlorofoxm layer was washed with water, dehydrated with anhydrous magnesium sulfate and dried up in vacuo to obtain a crude 20-dihydrotylosin [UV: max = 2~3 n~ RfB ~ 015], The said product wa~ di~ olved in pyridi~e ~20 ml). Tosylchloride (1.25 g) was added thereto, and the mixture was stirred for 16 hour~ at room temperature.
Concentrated ammonia (~ ml) was added to the reaction 38.

mixture, stirred for 15 minutes, and the reaction mixture was then poured in~o water (500 ml) and extracted with chloroform (100 ml). The.chloroform layer was wa~hed with water, diluted HCl, water and diluted aqueous ammonia, in this order, dPhydrated with anhydrous magnesium ~ulfate and dried up in vacuo. The thu6 obtained powder (3.3 g) was dissolved in ethylene glycol dimethyl ether t30 ml). Sodium iodide ~203 g) and zi~c powder (2 g~ ~ere added thereto and refluxed for 3 hours~ The xeaction mixture was filtered to remove zinc powderO Water (100 ml~ was added to the filtrate, and the mixture was adjusted to pH 9.5 by adding diluted ammonia and extracted with chloroform (100 mg). The chloroform layer was washed with water, dehydrated with ma~nesium sulfate and dried up in vacuo to obtain the crude 20-deoxo-4'-demycarosyl-tylosin tRf~ = 0.24)~
The crude product di ssolved i~ 0. 5 N-HCl ( ~0 ml ) was stirred for 18 hours at room temperature. The reac~ion mixture was adjusted to pH 9.5 with ~queous ammonia and extracted with chloroorm (100 ~1). The chloroform layer was washed with water, dehydrated with magnesium sul~ate and dried up in vacuo to obtain a ~rude powd~r (2.2 9) of 20-deoxo-4'-demy~arosyltylosin. The powder was purified by silica gel column chromatogr~phy using chloroform ~ methanol (15 : 1) to yield the purified product (780 mg).
TLC: RfB = 0.32 EtOH
UV . ~ 283 nm ( = 19700).
30max Mass spectrum (m/e): 757 (M ), 739, 612, 567, 3g4, 393, 377, 359, 358, 190, 174, 173.
NMR ~pectrum tlOO MHz, CDC13): 1u79 (12-CH3~, 2.51 C3'-~(cH3)2]~ 3-42 and 3.49 (OC~3), disappearance of aldehyde peak.
~, 'i';
-r J

Claims (16)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the production of a compound of the formula wherein A is a , -CH=CH- or -CH2-CH2- group, R1 is a hydrogen atom, lower alkanoyl or aryl lower alkanoyl group, X1 and X2 each represent a hydrogen atom or are connected to form a valence bond, Y1 and Y2 are connected to form a valence bond or each represent a hydrogen atom, Q1 is a hydrogen atom or methyl group, Q2 is a hydrogen atom or a group, wherein R2 is a hydrogen atom or lower alkanoyl group, R is a hydrogen atom or 40.
group, wherein R3 is a hydrogen atom or a C2-5 alkanoyl group, R4 is a hydrogen atom or a C2-6 alkanoyl group and when R3 is not a hydrogen atom, R4 is not a hydrogen atom, or a pharmaceutically acceptable salt thereof, which comprises carrying out one of the following procedures:
(A) when it is desired to produce a compound of the above formula wherein A is X1 and X2 are connected to form a valence bond, Y1 and Y2 are connected to form a valence bond, Q1 is a hydrogen atom, Q2 is a hydrogen atom or a group, in which R2 is a hydrogen atom or a lower alkanoyl group, and R is a hydrogen atom or a group, in which R3 is a hydrogen atom or a (C2-C5) alkanoyl group and R4 is a hydrogen atom or a (C2-C6) alkanoyl group, and when R3 is not a hydrogen atom, R4 is not a hydrogen atom, deformylating a compound of the formula 41.

wherein R1, R and Q2 have the same meanings as hereinbefore, with tris (triphenylphosphine)rhodium chloride in an inert organic solvent under heating;
(B) when it is desired to produce a compound of the first-mentioned formula hereinabove wherein A is in which R12 is a lower alkanoyl group, X1 and X2 are connected to form a valence bond, Y1 and Y2 are connected to form a valence bond, Q1 is a hydrogen atom, Q2 is a mysinosyl group, and R is in which R31 is a (C2-C5) alkanoyl group and R41 is a (C2-C6) alkanoyl group, acylating a compound of formula 42.

wherein R6 is a hydrogen atom or an R61 group, in which R61 is a lower alkanoyl group, R8 is a hydrogen atom or an R5 group, in which R5 is a lower alkanoyl or halo-lower alkanoyl group, with an aliphatic carboxylic acid halide in the presence of a tertiary organic amine in an inert organic solvent to obtain a compound of the formula 43.

whereing R12, R41, R61 and R8 have the same meanings as hereinbefore, acylating the said compound of formula (7) with an aliphatic carboxylic acid anhydride in the presence of a base under heating to obtain a compound of the formula wherein R12, R31, R41, R61 and R8 have the same meanings as hereinbefore, then treating the said compound of formula (8) with methanolic or ethanolic ammonia to remove the protective group at position 4"', and removing the protective group at position 2' under heating in methanol;
(C) when it is desired to produce a compound of the first mentioned formula hereinabove wherein A is -CH=CH-, X1 and X2 are connected to form a valence bond, Y1 and Y2 are connected to form a valence bond, Q1 is a hydrogen atom, Q2 is a mysinosyl group, and R

is a hydrogen atom or a group in 44.
which R3 is a hydrogen atom or a (C2-C5) alkanoyl group and R41 is a (C2-C6) alkanoyl group, reacting a compound of the formula wherein R12 is a lower alkanoyl group and R has the same meaning as hereinbefore, with an alcoholate in an alcoholic solvent;
(D) when it is desired to produce a compound of the first-mentioned formula hereinbefore wherein A is in which R12 is a lower alkanoyl group, X1 and X2 are connected to form a valence bond, Y1 and Y2 are connected to form a valence bond, Q1 is a hydrogen atom, Q2 is a group wherein R21 is a lower alkanoyl group, and R is a hydrogen atom, acylating a compound of the formula 45.

wherein R1 is a hydrogen atom or an R12 group wherein R12 has the same meaning as hereinbefore, with a lower aliphatic carboxylic anhydride in the presence of a base to obtain a compound of the formula wherein R12 and R21 are lower alkanoyl groups, and then removing the protective groups at positions-2' and -4' in methanol under heating;

46.

(E) when it is desired to produce a compound of the first mentioned formula hereinabove wherein A is X1, X2, Y1 and Y2 are hydrogen atoms, Q1 is a hydrogen atom, Q2 is a mysinosyl group, and R
is a hydrogen atom, reducing a compound of the formula [1g]

at positions -10, -11, -12 and -13 by catalytic reduction with a heavy metal catalyst;
(F) when it is desired to produce a compound of the first-mentioned formula hereinabove wherein A is -CH2-CH2-, X1, X2, Y1, Y2 and Q1 are hydrogen atoms, Q2 is a mysinosyl group, and R is a hydrogen atom, reducing a compound of the formula [1k]

47.

at positions -2, -3, -10, -11, -12, and -13 by catalytic reduction with a heavy metal catalyst; or (G) when it is desired to produce a compound of the first-mentioned formula hereinabove wherein A is X1 and X2 are connected to form a valence bond, Y1 and Y2 are connected to form a valence bond, Q1 is a methyl group, Q2 is a mysinosyl group, and R
is a hydrogen atom, i.e., a compound of the formula reducing the CHO group at position -19 of tylosin to a CH2OH group, exchanging the CH2OH group to a CH3 group to obtain 20-deoxotylosin, and de-4'-mycarosylating the said 20-deoxotylosin with diluted acid; and where desired, forming a pharmaceutically acceptable salt of the compound so produced.

2. A process for the production of a compound of the formula 48.

wherein R1 is a hydrogen atom, or a lower alkanoyl or aryl-lower alkanoyl group, R is a hydrogen atom or a group in which R3 is a hydrogen atom or a (C2-C5) alkanoyl group, and R4 is a hydrogen atom or a (C2-C6) alkanoyl group, and when R3 is not a hydrogen atom, R4 is not a hydrogen atom;

Q2 is a hydrogen atom or a group in which R2 is a hydrogen atom or a lower alkanoyl group;
or a nontoxic, pharmaceutically acceptable salt thereof;
which comprises deformylating a compound of the formula 49.

wherein R1, R and Q2 have the same meanings as hereinbefore, with tris (triphenylphosphine)rhodium chloride in an inert organic solvent under heating; and when desired, forming a pharmaceutically acceptable salt of the first-mentioned compound so produced.

3. A process for the production of a compound of the formula where R12 is a lower alkanoyl group, R31 is a (C2-C5) alkanoyl group and R41 is a (C2-C6) alkanoyl group or a nontoxic, pharmaceutically acceptable salt thereof; which comprises acylating a compound of formula 50.

wherein R6 is a hydrogen atom or an R61 group, in which R61 is a lower alkanoyl group, R8 is a hydrogen atom or an R5 group, in which R5 is a lower alkanoyl or halo-lower alkanoyl group, with an aliphatic carboxylic acid halide in the presence of a tertiary organic amine in an inert organic solvent to obtain a compound of the formula 51.

wherein R12, R41, R61 and R8 have the same meanings as hereinbefore, acylating the said compound of formula (7) with an aliphatic carboxylic acid anhydride in the presence of a base under heating to obtain a compound of the formula [8]

wherein R12, R31, R41, R61 and R8 have the same meanings as hereinbefore, then treating the said compound of formula (8) with methanolic or ethanolic ammonia to remove the protective group at position 4'", and removing the protective group at position 2' under heating in methanol; and where desired, forming a nontoxic, pharmaceutically acceptable salt of the compound of formula (ld) so produced.

4. A process for the production of a compound of the formula 51a.

52.

wherein R is a hydrogen atom or a group in which R3 is a hydrogen atom or a (C2-C5) alkanoyl group and R41 is a (C2-C6) alkanoyl group, or a nontoxic pharmaceutically acceptable salt thereof;
which comprises reacting a compound of the formula where R12 is a lower alkanoyl group and R has the same meaning as hereinbefore, with an alcoholate in an alcoholic solvent; and where desired, forming a nontoxic, pharmaceutically acceptable salt of the first-mentioned compound so produced.

5. A process for the production of a compound of the formula 53.

wherein R21 and R12 are lower alkanoyl groups; or a nontoxic pharmaceutically acceptable salt thereof; which comprises acylating a compound of the formula wherein R1 is a hydrogen atom or an R12 group wherein R12 has the same meaning as hereinbefore, with a lower aliphatic carboxylic anhydride in the presence of a base to obtain a compound of the formula 54.

wherein R12 and R21 are lower alkanoyl groups, and then removing the protective groups at positions-2' and -4' in methanol under heating; and where desired, forming a nontoxic, pharmaceutically acceptable salt of the aforesaid compound of formula (lj) so produced.

6. A process for the production of a compound of the formula or a nontoxic, pharmaceutically acceptable salt thereof;
which comprises reducing a compound of the formula 55.

at positions -10, -11, -12 and 13 by catalytic reduction with a heavy metal catalyst; and where desired forming a nontoxic, pharmaceutically acceptable salt of the compound of formula (11) so produced.

7. A process for the production of a compound of the formula or a nontoxic, pharmaceutically acceptable salt thereof, which comprises reducing a compound of the formula 56.

at positions -2, 3, -10, -11, 12 and -13 by catalytic reduction with a heavy metal catalyst; and where desired, forming a nontoxic pharmaceutically acceptable salt of the compound of formula [lm] so produced.

8. A process for the production of a compound of the formula 57.

or a nontoxic, pharmaceutically acceptable salt thereof;
which comprises reducing the CHO group at position -19 of tylosin to a CH2OH group, exchanging the CH2OH group to a CH3 group to obtain 20-deoxotylosin, and de-4'-mycarosylating the said 20-deoxotylosin with diluted acid; and where desired, forming a nontoxic, pharmaceutically acceptable salt of the compound of formula [lo] so produced.

9. A compound of the formula wherein A is a -CH=CH- or -CH2-CH2- group, R1 is a hydrogen atom, lower alkanoyl or aryl lower alkanoyl group, X1 and X2 each represent a hydrogen atom or are connected to form a valence bond, Y1 and Y2 are connected to form a valence bond or each represent a hydrogen atom, Q1 is a hydrogen atom or methyl group, Q2 is a hydrogen atom or a group, wherein R2 is a 58.

hydrogen atom or lower alkanoyl group, R is a hydrogen atom or group, wherein R3 is a hydrogen atom or a C2-5 alkanoyl group, R4 is a hydrogen atom or a C2-6 alkanoyl group, and when R3 is not a hydrogen atom, R4 is not a hydrogen atom, or a pharmaceutically acceptable salt thereof, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

10. A compound of the formula wherein R1 is a hydrogen atom, or a lower alkanoyl or aryl-lower alkanoyl group, R is a hydrogen atom or a group, R3 is a hydrogen atom 59.

or a (C2-C5) alkanoyl group and R4 is a hydrogen atom or a (C2-C6) alkanoyl group, and when R3 is not a hydrogen atom, R4 is not a hydrogen atom, Q is a hydrogen atom or a group, R2 is a hydrogen atom atom or a lower alkanoyl group, or a nontoxic, pharmaceutically acceptable salt thereof, when prepared by the process of claim 2 or by an obvious chemical equivalent thereof.

11. A compound of the formula [ld]

wherein R12 is a lower alkanoyl group, R31 is a (C2-C5) alkanoyl group, and R41 is a (C2-C6) alkanoyl group, or a nontoxic pharmaceutically acceptable salt thereof, when prepared by the process of claim 3 or by an obvious chemical equivalent thereof.

12. A compound of the formula wherein R is a hydrogen atom or a group, R3 is a hydrogen atom or a (C2-C5) alkanoyl group, and R41 is a (C2-C6) alkanoyl group, or a nontoxic, pharmaceutically acceptable salt thereof, when prepared by the process of claim 4 or by an obvious chemical equivalent thereof.

13. A compound of the formula [1j]

61.

wherein R21 is a lower alkanoyl group, or a nontoxic, pharmaceutically acceptable salt thereof, when prepared by the process of claim 5 or by an obvious chemical equivalent thereof.

14. A compound of the formula [ll]

or a nontoxic, pharmaceutically acceptable salt thereof, when prepared by the process of claim 6 or by an obvious chemical equivalent thereof.

15. A compound of the formula [lm]

62.

or a nontoxic, pharmaceutically acceptable salt thereof, when prepared by the process of claim 7 or by an obvious chemical equivalent thereof.

16. A compound of the formula [lo]

or a nontoxic, pharmaceutically acceptable salt thereof, when prepared by the process of claim 8 or by an obvious chemical equivalent thereof.