Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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:
2 3
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.
2 3
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~-
CH 3 CH 3
~ ~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 30 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
CH3 CH3
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.
2 3
Proce~s D: ~ comp~und wher~in A i5 -CH2~H- in which
OR12
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
1R1 2
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 CH 3
,~ 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.
2 3
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
2 3
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'~
2 1
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.
2 3
Process J: A compound wherein A is CH2-CH~, (R12 is a
2 5 1H 1 2
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
H3CO 0 CH3
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
H 3CO OCH 3 3
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
0 OCH3
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.
2 3
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
0 OCH3
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
350
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,
173
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,
173 0
36
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
