CA1188310A - 3-0-demethyl derivatives of the istamycin b series of compounds and their preparation - Google Patents
3-0-demethyl derivatives of the istamycin b series of compounds and their preparationInfo
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- CA1188310A CA1188310A CA000453522A CA453522A CA1188310A CA 1188310 A CA1188310 A CA 1188310A CA 000453522 A CA000453522 A CA 000453522A CA 453522 A CA453522 A CA 453522A CA 1188310 A CA1188310 A CA 1188310A
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Abstract
COMPOUNDS AND THEIR PREPARATION
ABSTRACT OF THE DISCLOSURE
New derivatives of the istamycin B series of compounds are provided, which are 3-0-demethylistamycin Bo, 3-0-demethyl-istamycin B and 3-0-demethyl-2"-N-formimidoylistamycin B repre-sented generally by Formula I or specifically by Formulae Ia, Ib and Ic, respectively. Compound Ia is useful as an intermediate for the preparation of Compounds Ib and Ic and the latter two compounds exhibit a high antibacterial activity against a wide variety of Gram-positive and Gram-negative bacteria and are use-ful antibiotics. Also provided are processes for the prepara-tion of the new derivatives starting from istamycin Bo.
ABSTRACT OF THE DISCLOSURE
New derivatives of the istamycin B series of compounds are provided, which are 3-0-demethylistamycin Bo, 3-0-demethyl-istamycin B and 3-0-demethyl-2"-N-formimidoylistamycin B repre-sented generally by Formula I or specifically by Formulae Ia, Ib and Ic, respectively. Compound Ia is useful as an intermediate for the preparation of Compounds Ib and Ic and the latter two compounds exhibit a high antibacterial activity against a wide variety of Gram-positive and Gram-negative bacteria and are use-ful antibiotics. Also provided are processes for the prepara-tion of the new derivatives starting from istamycin Bo.
Description
33~
BACKGROUNV OF TE~E INVENTION
We have pre~iously discovered a new strain of antino-mycetes, Streptomyces tenjimariensis SS-939 which was deposited in -the Japanese public depository "Fermentation Research Ins-titute" under the deposit number FERM~P 4932 and in the American Type Culture Collection under ATCC Number 31603, and produced by cultivation of said strain several different new aminoglycosidic antibiotic substances, ista-mycin A, istamycin B, istamycin A~ and istamycin Bo (refer to our published Japanese Patent KOKAI No. 145697/80 and No.
43295/81; our published U.K. Patent Application GB 2,048,855A;
and our U.S. Patent No. 4,296,106. Subsequently, we totally synthesized di-N6 , 03-demethylistamycin A and found its antibacterial activity against Pseudomonas aeruginosa to be significantly higher than that of istamycin A. We then con-tinued our studies on istamycin antibiotics with the intention ofconverting istamycin B (which has a higher antibacterial activity than istamycin A) into the 3-O-demethyl derivative thereof, and have now succeeded in synthesizing 3-O-demethyl-istamycin B starting from istamycin BQ, and have found that 3-O-demethylistamycin B is effective against not only Pseudomonas aeruginosa but also a variety of resistant _ .
bacteria. In this series of studies, we have also synthesi.zed 3-O-demethylistamycin Bo and 3-O-demethyl--2"-N-formimidoyl-istamycin B, the former being useful as an intermediate to be converted into 3-O-demethylistamycin B by glycylating the 4-methylamino group thereof, and the latter being a 3-O-demethylistamycin B derivative useful as an antibiotic similarly to formimidoylistamycin B and formimidoylistamycin A (see U.S. Patent No~ 4,382~926) both of which were synthesized by us.
3~
The 3-O-demethylistamycin Bo ? 3-~demethylis'carnycin B
and 3-O~demethyl-2n-N formimidoylis~amycirl B described and claimed herelII have been dlsclosed by us in J. Anti}:)iotics, 33, 1577-1580 ~December 1980), along with details of their prepara-tion and their antibacterial activity, W~3 are aware of UrS~ Pa~en. 4 j25~,421 which discloses c~rtain O-demethylaminoglycosldes and claims those of ~e f ormula Rl 61 f~ NH~2 NH2 ~ O ~
NH2 -(:H3 wherein R L and R2 are ~e same or different and are hydxogen or methyl ~ R3 is hydrogen or an urlsu~stituted or substituted amino~c yl group having 2 to 4 carbon atoms in the acyl moiety, the substituent ~eing selected from hydroxyt formyl and ~arbamoyl; prosrided ~at, when Rl~ R2 and R3 are each hydrogen atoms ~ the methyl~mino group at 'che 4-position i5 not oriented tran~ ~o the hydroxyl group~ a~ the 3~ and 5-positionsO
Alt~ough the aminocyclitol r~ ngs are nl3mbered in. the opposite directiorls in U ~ S ., 4, 255, 421 and in the co~n-pounds di~closed and claim~d herein (compound~ named as 3-o-deme thyl derivatives herein are named as 5-O-demethyl derivatives ther~in~, it may be seen ~at t:he claims of T~.S~
4,255,~21 literally i~clude within their scope two of the ~ree compotmds disclosea and claimed herein, i~ e. 3-Q-demethyl sta~mycin Bo arld 3~0~demethylistamycirl B. However" U,.5.
4 0 255, 421 dc~es not exemplify ~ither 9f these two compounds and, fur the:r ~ neit:hex discloses the starting material necessary for th~3ir preparation nor teaches how the n~cessary starting material may be prepared~ Thus, 3 O-demethylistamycin Bo and 3-O~demethyllstamycin B con~ain a 6'-N-methyl group ~nd a C-l amino group which is cis to the sugar moiety, and the starting material for the demethylat~on reaction ~istamycin Bo herein) must contaln ~hese same groups and configurations. U.Sc 4,255,421, on the o~her hand, discloses as starting materials only antibio~ic compl~x KA~6Ç06 [~he sporarioins; see J.
Antibio~ics~ 32, 187 (197~], at leas~ some of whioh contain a C-l amino group that is cis ~o he sugar moiety, but all of which have a 6'-C~methyl group; antibiotic complex KA-7038 [the sannamycins; see JO Antibiotics~ 32, 1066 (1979)], some of which contain a 69~N-methyl group but all of which have a C-l amino group which is rans to the ~ugar moiety; and fortimicins A and B Isee J. ~ntibiotics, 30, 552 (1977)3, both ~f which have a 6' C-amlno group and a C-l amino gxoup which is rans to the sugar moiety D as well as an additional hydroxyl group on the C-6 position (numbered C 2 herein) which is not present in the compounds claimed herein. ~hus, the sporaricin, sannamycin and fort~micin starting materials dis~losed in U.S.
4,255,421 are not suitahle starting material~ for the prepara-tion of any of the three compounds disclosed and claimed herein, since they have the wrong 6'-substitution and~or the wrong stereo configuxation of the l-amino group, and in ~ome instances have an additional hydroxyl group on the C-6 position~ The starting materials disclosed in U . S . 4, 255 " 421 are products oî fermentation and not synthe'cic products t and there is no disclosure o~ how ~o ob~ain the necess2lry starting material~
for the pxeparation of he compourld disclosed and claimed herein. mus, U.S. 4,255,421 does not contain an enabling dis closure for the prepaxation of the here~n olaimed 3-O-deme~hyl-istamycin Bo~ 3-O-demethylistamycin B or 3 O-demethyl-2"-~-formimidoylistamycin B~
3 1~ !
DETAIL~ DESCRIPTION OF THE INVENTION
_ Accordlng to a first aspect o~ this inventlon, there~ore~ there are provided as new c~mpounds 3-O-demethyl derivatives of istamycln B serles compounds of formula I:
CH3N ~
41~2 Y \
~11 ~1 3t NH2¦ ~ ~ OH (I) 4 ~ OH
CH3N~
whereln R represents a hydrogen atom, a glycyl group or an N-formimidoylglycyl group, and acid addition salts thereof.
Concretely~ the following three compound~ and ~heir a~id addition ~alts ar~ provided:
3-O~Demethylistamycin Bo (R is HJ
3-O~Demethylistamycin B (R i5 H~NCH2CO ~ ) 3~0-Demethyl-21' N-formimiavyli~tamycin B
BACKGROUNV OF TE~E INVENTION
We have pre~iously discovered a new strain of antino-mycetes, Streptomyces tenjimariensis SS-939 which was deposited in -the Japanese public depository "Fermentation Research Ins-titute" under the deposit number FERM~P 4932 and in the American Type Culture Collection under ATCC Number 31603, and produced by cultivation of said strain several different new aminoglycosidic antibiotic substances, ista-mycin A, istamycin B, istamycin A~ and istamycin Bo (refer to our published Japanese Patent KOKAI No. 145697/80 and No.
43295/81; our published U.K. Patent Application GB 2,048,855A;
and our U.S. Patent No. 4,296,106. Subsequently, we totally synthesized di-N6 , 03-demethylistamycin A and found its antibacterial activity against Pseudomonas aeruginosa to be significantly higher than that of istamycin A. We then con-tinued our studies on istamycin antibiotics with the intention ofconverting istamycin B (which has a higher antibacterial activity than istamycin A) into the 3-O-demethyl derivative thereof, and have now succeeded in synthesizing 3-O-demethyl-istamycin B starting from istamycin BQ, and have found that 3-O-demethylistamycin B is effective against not only Pseudomonas aeruginosa but also a variety of resistant _ .
bacteria. In this series of studies, we have also synthesi.zed 3-O-demethylistamycin Bo and 3-O-demethyl--2"-N-formimidoyl-istamycin B, the former being useful as an intermediate to be converted into 3-O-demethylistamycin B by glycylating the 4-methylamino group thereof, and the latter being a 3-O-demethylistamycin B derivative useful as an antibiotic similarly to formimidoylistamycin B and formimidoylistamycin A (see U.S. Patent No~ 4,382~926) both of which were synthesized by us.
3~
The 3-O-demethylistamycin Bo ? 3-~demethylis'carnycin B
and 3-O~demethyl-2n-N formimidoylis~amycirl B described and claimed herelII have been dlsclosed by us in J. Anti}:)iotics, 33, 1577-1580 ~December 1980), along with details of their prepara-tion and their antibacterial activity, W~3 are aware of UrS~ Pa~en. 4 j25~,421 which discloses c~rtain O-demethylaminoglycosldes and claims those of ~e f ormula Rl 61 f~ NH~2 NH2 ~ O ~
NH2 -(:H3 wherein R L and R2 are ~e same or different and are hydxogen or methyl ~ R3 is hydrogen or an urlsu~stituted or substituted amino~c yl group having 2 to 4 carbon atoms in the acyl moiety, the substituent ~eing selected from hydroxyt formyl and ~arbamoyl; prosrided ~at, when Rl~ R2 and R3 are each hydrogen atoms ~ the methyl~mino group at 'che 4-position i5 not oriented tran~ ~o the hydroxyl group~ a~ the 3~ and 5-positionsO
Alt~ough the aminocyclitol r~ ngs are nl3mbered in. the opposite directiorls in U ~ S ., 4, 255, 421 and in the co~n-pounds di~closed and claim~d herein (compound~ named as 3-o-deme thyl derivatives herein are named as 5-O-demethyl derivatives ther~in~, it may be seen ~at t:he claims of T~.S~
4,255,~21 literally i~clude within their scope two of the ~ree compotmds disclosea and claimed herein, i~ e. 3-Q-demethyl sta~mycin Bo arld 3~0~demethylistamycirl B. However" U,.5.
4 0 255, 421 dc~es not exemplify ~ither 9f these two compounds and, fur the:r ~ neit:hex discloses the starting material necessary for th~3ir preparation nor teaches how the n~cessary starting material may be prepared~ Thus, 3 O-demethylistamycin Bo and 3-O~demethyllstamycin B con~ain a 6'-N-methyl group ~nd a C-l amino group which is cis to the sugar moiety, and the starting material for the demethylat~on reaction ~istamycin Bo herein) must contaln ~hese same groups and configurations. U.Sc 4,255,421, on the o~her hand, discloses as starting materials only antibio~ic compl~x KA~6Ç06 [~he sporarioins; see J.
Antibio~ics~ 32, 187 (197~], at leas~ some of whioh contain a C-l amino group that is cis ~o he sugar moiety, but all of which have a 6'-C~methyl group; antibiotic complex KA-7038 [the sannamycins; see JO Antibiotics~ 32, 1066 (1979)], some of which contain a 69~N-methyl group but all of which have a C-l amino group which is rans to the ~ugar moiety; and fortimicins A and B Isee J. ~ntibiotics, 30, 552 (1977)3, both ~f which have a 6' C-amlno group and a C-l amino gxoup which is rans to the sugar moiety D as well as an additional hydroxyl group on the C-6 position (numbered C 2 herein) which is not present in the compounds claimed herein. ~hus, the sporaricin, sannamycin and fort~micin starting materials dis~losed in U.S.
4,255,421 are not suitahle starting material~ for the prepara-tion of any of the three compounds disclosed and claimed herein, since they have the wrong 6'-substitution and~or the wrong stereo configuxation of the l-amino group, and in ~ome instances have an additional hydroxyl group on the C-6 position~ The starting materials disclosed in U . S . 4, 255 " 421 are products oî fermentation and not synthe'cic products t and there is no disclosure o~ how ~o ob~ain the necess2lry starting material~
for the pxeparation of he compourld disclosed and claimed herein. mus, U.S. 4,255,421 does not contain an enabling dis closure for the prepaxation of the here~n olaimed 3-O-deme~hyl-istamycin Bo~ 3-O-demethylistamycin B or 3 O-demethyl-2"-~-formimidoylistamycin B~
3 1~ !
DETAIL~ DESCRIPTION OF THE INVENTION
_ Accordlng to a first aspect o~ this inventlon, there~ore~ there are provided as new c~mpounds 3-O-demethyl derivatives of istamycln B serles compounds of formula I:
CH3N ~
41~2 Y \
~11 ~1 3t NH2¦ ~ ~ OH (I) 4 ~ OH
CH3N~
whereln R represents a hydrogen atom, a glycyl group or an N-formimidoylglycyl group, and acid addition salts thereof.
Concretely~ the following three compound~ and ~heir a~id addition ~alts ar~ provided:
3-O~Demethylistamycin Bo (R is HJ
3-O~Demethylistamycin B (R i5 H~NCH2CO ~ ) 3~0-Demethyl-21' N-formimiavyli~tamycin B
2~ ln t1R ;5 HN=~HNHCH2CO ) .
Physico-chemical properties of the new compounds according to thi5 inYenti~n ~re shown in Table 1.
Physico-chemical properties of the new compounds according to thi5 inYenti~n ~re shown in Table 1.
3~C~
, i~
o o U o . ~
. ~ o C)~
o ~> h ~`I ~d i:: ~ ~
~ ~ ~a _ ~ -z; ~ ~ h Ei h P' u~ -- ~ S a) ~ o ^ ~ ~ ,~ _ J~ ~ ~:J O r I~, Z h I u7 h 3 6~ o ~1 ~ ~ O c~ J
~ ~ ~ ~ S o -- ~ ~ 0C~ ~0 ~ I ~
s ~a) J~ ~0 ~ . . . . ~ ~'~ O
o ~ ~ ~ o * ~ ~ ~ ~ O
a~ ~a td tQ 3 ~ ~L~ ~ ~ tn C~ ~
E~ ~ ~ ~ Sl ~Q
h c~ 3 ~ ~ ~ O O
I ~ ~ O o ~d O ~ a ~
O ~ u~ ~ O h p r~ . . . . . P~
IO ~ 1 0 3 ~ D N0~ O Ul -~ a ~ ~ ~i o ~
_ ~ ~ O
U~ ~ ~
h h ~ o 0 u~
hr I ~ J~ ~ '~ ~) h R:~m ~ ~ 0 ~ a~ + ~o o ~ rd QJ
J~ ~ C~ O N ~ ~: ,~ r-l 3 h J~ ~ O U~ O O* 3~ ~ `-- r1 10 0 t~J a~rl D v~ 3 ~1 3 ~1 c~~ h a~
r~~ ~ ~ ~ ~1 ~ ~_ E~ c~ h L~ ~ ~ #
o I ~ a ~ u~
rO ~ N r-l (~J ~1 I ~ -C)I tO ~ O OD 2~1 3t-- ~ ~
l~ . I (r~ ~ 3 r~
O ~
N O O
S ~ ,_~ ~ O
,1 ~1 o 3 ~ N N
Q~ s a:l d) p~ ) t~a ~
c:l ~ ~: ~ u~ o o~ N _ ~rl ~ Ifl .~ ~ ~ U~~D N ~ O O
E-~ E t) O Q) N ~1 ~ ~r ~ ~P ~ 4 Z Z
a ~ ~ h Lr~ ~ o ~ o r~l I 1~ t~ O I t~l ~ 0 3 \~ L.~ 1~ ~1 O ~ C~ ~ ~ ~ . . . I ~ . 1: :C
I U~ ~ O ~ N ~ e f~ ~ 'OC~ 3 r~1 ~
_ _. _ _ ~
O ~ ~ O O
. ~ 0 O ~ ~- OS ~ U~
rl O ~ h~ 1~ q) h -- ~ I o rJ r~ 3 td ~ ~ ~ ~O S~ C~
hQ. ~ 1~ U:C æ u~
3 h.l::
a~ o ~ p, c> ~ a) ~ d a ~
C~ V
.--1 N
1:
~ .
'~ 3~D
~7--The antibacterial spectra of 3-0-demethylistamycin B~
~esquicarbonate and 3-0-deme~hyl-2"-N-formimidoylistamycin B~
disulphate~rihydrate are shown in Table 2, along with that of istamycln B for comparison purposes.
3~
,1 m O 00 0~ ~ O ~ O O ~D ) ~ ~D ~O
O O O O ~D O O O O ~ O O ~ ~1 C~ J~ V V V V
~n ~ a~
o * ~
~d I C) h Z
_ C~
I u~ o o ao 0 0 s~ O O O ~o ~ O ~D
O ~ --1 C~ S ~O O O O O O O O O I--I O O l~~ r~
J~ O
h ~ ~ v v v v v v v t~ O ~ ~
a~ J~ n ~
Q ~r1 I E~
0 ,D O h ~ C I ~
td rl ~ ~U
h * I
~ ~ ~ ~ o~ o oo 0 ~ a~ o o o ~D ~D O ~D ~
a) ~ ~ ~ ~ t-- ~1 ~ ~ ~ ~ ~ u~ ~ u~ ,~
~ ~ ~ C~ . ~ . . . . . . . . . . .
J~ ~ Q~ O ~ O O O O ~1 ~I C~
~ a ~
~: ~ ~ V V V V V
o, ~
;~1 ~ ~
a) . r-~ o D
~ o~
E~ o ~1 .C U~ C~
~,q Lr~ ~ O E~
~~ O ~ ~ o~ ~ O ~1 ~:
CQ
~ ~ ~ O ~ ~
rlU~ h1~ 0 H 1~ ~ ~ ~ t~l a~ ~ o c> ~ ~ td P~ Z C~
bSh _ ~ ~rl u~ ~ E-~ O b~ æ
h 5 I:L :~ Hr3 ~ CC . Q~
o td Q~ ~> ~ t~ ~ ~i rl O td P~ ~d ~1 ~q ~ ~q ~1 F~ D~ In r-l h _~ : ~ ::S O
::~ ~ ~d ~:: ~ a~ ~1 E~ c) ~r! ~ ~ a) ~ ,Q h h :~
E~ o C~ ~ ~ ~ ~ O ~ ~1 c~
~ O ~ :~ n~ ~q c~ ~ ~ rl O _ - O C~ ~ Lg ~ ~ ~ ~ S
a) ,~ ~ o E~ ~ :~ C) ~ ~ ~ ~1 a~ ~d ~
S: S O ~ r~ ~1 = ,1 S: R Q1 P C4 h c~ q_l rl ~rl ~ O ,5::
~d ~ c~ ~1 c~ c~ ~ ~ O C) O :~ ~q u~ u~ ~: u~ s~ a: a~ c~ ~: W
33~
~1 ~ ~I N o ~
N 1~ 1 t\l~1 ~ 15~ ~1 N L~ r I N ~1 N
N P ~
a~ o ~ o ~ ~I ~) o ~1 ~I N ~~I -i O O O C7 0 .~
0 ~ ~I r-~ r~l r~ t~l N N t-- O H ~: r-l ~1 ~ ~ ~ ~ ~ ~ ~ ¢ CC ~ 3 ~ ~) N ~1 r~l N N N N N ~ ~ ~ t~l N t~
N ~d ~ m S
X ~ ~ ~ El h h ol = ~ = 1~ ~:
S~ a 3~
O~1 0 ~ D O O ~ D O O O LS~ O ~7 rl O L~ O Lr~ N L~ O
r~ r-l H
t~ Lr\ (rS 1~ ~I r~ N L~
O ~ O ~U ~ t~l O ~ N ~ J N 1~ D O
--l 0 N r l r l r 1 N O
~J 1~ r~ N ~ U~
~1 ~1 N ~1 ~\1 H H ~I N H H C~J
N ~) L
~I H rl c~ rro o~ r~ H æ o~
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,, I ~ ~ æ :z ~a ,I c~ ~
O ~ ~ ~ ~ ~ ~ ~ - = = = =
0 ~ C) ~rl S J~ h h 0 O ~ p~ p, C: :~ ~:: ~d b~ _c~ 0 ~q ~ J ~ a) ~ ~ h ~ ~
O r l ~ ~dP~ t~l ~q u~ ,_1 ~ :~ h Ei u~ rl rl cd ~d r-l r-l t~l td cd ~: ~: O
~1 a~ ~ u~ 0 ~ ~ ~ ~ a~ ~
H E~ E~ O O _ h al O O O
.C ~ ~ h u~ u:~ c/~ ~:4 ~ u~ v~u:~ ~t ~ P~
- ~8~3 td O o o o o o h o o o o U~ o ,~ ,1 ~ ~ ~
~ A A V
O
~o U~
OU~ ~ O. ~
O ~ ~ ~ ,, O e ~1 ~
A O
~d ~
. ~ O
L~ ~ S
N . 1~ a O O O O ~D O
O h h r~ ~ h Q :~
S
C) ~ h ~ ~1 ~U t-- O
::~ N O t-- ~i ~1 0 h J:~
O J~
t-- ~1 ~n ~ -d u L:
,~ I p Gq ~ Z
a~ o ~ c~ bO
~, N ~ ~ t~ r\ ~ U:l U~
cq ,J ~ P ~q ~ ~ ~
~ ~ O
~ ~ a) h o o C~ ~
. d h S: S S
~3 C~
O O
e O ~ ~ H H
~1 ~ P~ * * *
The antibacterial spectra data given above clearly demonstrate tha~ 3-0-demethylistamycln B and 3-0-demethyl-2"-N-~ormimidoylistamycln B exhibit a high antibacterial actlvlty against a wide variety of Gram-negative and Gram-posltive bacteria. On the other hand, 3-O~demethylistamycin Bo has a poor antibacterlal activity, but ls use~ul as an intermediate for the preparation of 3-0-demethylistamycin B.
3-0-Demethylistamycln Bo (dicarbonate) 3 3-0-demethyl istamycin B (sesquicarbonate) and 3-0-demethyl-2"-N-formimidoylistamycin B (disulphate trihydrate) are further characterized by their low toxicity. Thus, when the acute toxicity o~ these three compounds was estimated by intra-venous in~ection in mice 3 it was found that all the mice tested tolerated a dose of 160 mg/kg of each compound.
3~0-Demethylistamycin ~0~ 3-O~demethylistamycin B
and 3-O~demethyl-2"-N-~ormimidoylistamycin B according to this invention may be obtained ln the form of the free base, a hydrate or a carbonate thereo~, and more pref~rably in view of their stability they can be converted into a pharmaceutically acceptable acid additlon salt thereof by reacting with a pharmaceutically acceptable acid in a usual mannerO Examples of the pharmaceutically acceptable acids are inorganic acids such as hydrochloricg hydrobromic~
sul~uric, phosphoric and nitric acids and organic acid~
such as acetic~ malic, c~tric~ ascorblc and methanesul~onic acids. The compounds may also exist as salt-hydrates~ e.g.
3-0-demethyl-2"~N-formimidoylistamycin B~disulfat2 trihydxateO
.
83~
3 O-Demethylistamycin Bo of formula Ia:
CH3N--~6'
, i~
o o U o . ~
. ~ o C)~
o ~> h ~`I ~d i:: ~ ~
~ ~ ~a _ ~ -z; ~ ~ h Ei h P' u~ -- ~ S a) ~ o ^ ~ ~ ,~ _ J~ ~ ~:J O r I~, Z h I u7 h 3 6~ o ~1 ~ ~ O c~ J
~ ~ ~ ~ S o -- ~ ~ 0C~ ~0 ~ I ~
s ~a) J~ ~0 ~ . . . . ~ ~'~ O
o ~ ~ ~ o * ~ ~ ~ ~ O
a~ ~a td tQ 3 ~ ~L~ ~ ~ tn C~ ~
E~ ~ ~ ~ Sl ~Q
h c~ 3 ~ ~ ~ O O
I ~ ~ O o ~d O ~ a ~
O ~ u~ ~ O h p r~ . . . . . P~
IO ~ 1 0 3 ~ D N0~ O Ul -~ a ~ ~ ~i o ~
_ ~ ~ O
U~ ~ ~
h h ~ o 0 u~
hr I ~ J~ ~ '~ ~) h R:~m ~ ~ 0 ~ a~ + ~o o ~ rd QJ
J~ ~ C~ O N ~ ~: ,~ r-l 3 h J~ ~ O U~ O O* 3~ ~ `-- r1 10 0 t~J a~rl D v~ 3 ~1 3 ~1 c~~ h a~
r~~ ~ ~ ~ ~1 ~ ~_ E~ c~ h L~ ~ ~ #
o I ~ a ~ u~
rO ~ N r-l (~J ~1 I ~ -C)I tO ~ O OD 2~1 3t-- ~ ~
l~ . I (r~ ~ 3 r~
O ~
N O O
S ~ ,_~ ~ O
,1 ~1 o 3 ~ N N
Q~ s a:l d) p~ ) t~a ~
c:l ~ ~: ~ u~ o o~ N _ ~rl ~ Ifl .~ ~ ~ U~~D N ~ O O
E-~ E t) O Q) N ~1 ~ ~r ~ ~P ~ 4 Z Z
a ~ ~ h Lr~ ~ o ~ o r~l I 1~ t~ O I t~l ~ 0 3 \~ L.~ 1~ ~1 O ~ C~ ~ ~ ~ . . . I ~ . 1: :C
I U~ ~ O ~ N ~ e f~ ~ 'OC~ 3 r~1 ~
_ _. _ _ ~
O ~ ~ O O
. ~ 0 O ~ ~- OS ~ U~
rl O ~ h~ 1~ q) h -- ~ I o rJ r~ 3 td ~ ~ ~ ~O S~ C~
hQ. ~ 1~ U:C æ u~
3 h.l::
a~ o ~ p, c> ~ a) ~ d a ~
C~ V
.--1 N
1:
~ .
'~ 3~D
~7--The antibacterial spectra of 3-0-demethylistamycin B~
~esquicarbonate and 3-0-deme~hyl-2"-N-formimidoylistamycin B~
disulphate~rihydrate are shown in Table 2, along with that of istamycln B for comparison purposes.
3~
,1 m O 00 0~ ~ O ~ O O ~D ) ~ ~D ~O
O O O O ~D O O O O ~ O O ~ ~1 C~ J~ V V V V
~n ~ a~
o * ~
~d I C) h Z
_ C~
I u~ o o ao 0 0 s~ O O O ~o ~ O ~D
O ~ --1 C~ S ~O O O O O O O O O I--I O O l~~ r~
J~ O
h ~ ~ v v v v v v v t~ O ~ ~
a~ J~ n ~
Q ~r1 I E~
0 ,D O h ~ C I ~
td rl ~ ~U
h * I
~ ~ ~ ~ o~ o oo 0 ~ a~ o o o ~D ~D O ~D ~
a) ~ ~ ~ ~ t-- ~1 ~ ~ ~ ~ ~ u~ ~ u~ ,~
~ ~ ~ C~ . ~ . . . . . . . . . . .
J~ ~ Q~ O ~ O O O O ~1 ~I C~
~ a ~
~: ~ ~ V V V V V
o, ~
;~1 ~ ~
a) . r-~ o D
~ o~
E~ o ~1 .C U~ C~
~,q Lr~ ~ O E~
~~ O ~ ~ o~ ~ O ~1 ~:
CQ
~ ~ ~ O ~ ~
rlU~ h1~ 0 H 1~ ~ ~ ~ t~l a~ ~ o c> ~ ~ td P~ Z C~
bSh _ ~ ~rl u~ ~ E-~ O b~ æ
h 5 I:L :~ Hr3 ~ CC . Q~
o td Q~ ~> ~ t~ ~ ~i rl O td P~ ~d ~1 ~q ~ ~q ~1 F~ D~ In r-l h _~ : ~ ::S O
::~ ~ ~d ~:: ~ a~ ~1 E~ c) ~r! ~ ~ a) ~ ,Q h h :~
E~ o C~ ~ ~ ~ ~ O ~ ~1 c~
~ O ~ :~ n~ ~q c~ ~ ~ rl O _ - O C~ ~ Lg ~ ~ ~ ~ S
a) ,~ ~ o E~ ~ :~ C) ~ ~ ~ ~1 a~ ~d ~
S: S O ~ r~ ~1 = ,1 S: R Q1 P C4 h c~ q_l rl ~rl ~ O ,5::
~d ~ c~ ~1 c~ c~ ~ ~ O C) O :~ ~q u~ u~ ~: u~ s~ a: a~ c~ ~: W
33~
~1 ~ ~I N o ~
N 1~ 1 t\l~1 ~ 15~ ~1 N L~ r I N ~1 N
N P ~
a~ o ~ o ~ ~I ~) o ~1 ~I N ~~I -i O O O C7 0 .~
0 ~ ~I r-~ r~l r~ t~l N N t-- O H ~: r-l ~1 ~ ~ ~ ~ ~ ~ ~ ¢ CC ~ 3 ~ ~) N ~1 r~l N N N N N ~ ~ ~ t~l N t~
N ~d ~ m S
X ~ ~ ~ El h h ol = ~ = 1~ ~:
S~ a 3~
O~1 0 ~ D O O ~ D O O O LS~ O ~7 rl O L~ O Lr~ N L~ O
r~ r-l H
t~ Lr\ (rS 1~ ~I r~ N L~
O ~ O ~U ~ t~l O ~ N ~ J N 1~ D O
--l 0 N r l r l r 1 N O
~J 1~ r~ N ~ U~
~1 ~1 N ~1 ~\1 H H ~I N H H C~J
N ~) L
~I H rl c~ rro o~ r~ H æ o~
~D
U~ r~
r ~ a ~~ lO
,, I ~ ~ æ :z ~a ,I c~ ~
O ~ ~ ~ ~ ~ ~ ~ - = = = =
0 ~ C) ~rl S J~ h h 0 O ~ p~ p, C: :~ ~:: ~d b~ _c~ 0 ~q ~ J ~ a) ~ ~ h ~ ~
O r l ~ ~dP~ t~l ~q u~ ,_1 ~ :~ h Ei u~ rl rl cd ~d r-l r-l t~l td cd ~: ~: O
~1 a~ ~ u~ 0 ~ ~ ~ ~ a~ ~
H E~ E~ O O _ h al O O O
.C ~ ~ h u~ u:~ c/~ ~:4 ~ u~ v~u:~ ~t ~ P~
- ~8~3 td O o o o o o h o o o o U~ o ,~ ,1 ~ ~ ~
~ A A V
O
~o U~
OU~ ~ O. ~
O ~ ~ ~ ,, O e ~1 ~
A O
~d ~
. ~ O
L~ ~ S
N . 1~ a O O O O ~D O
O h h r~ ~ h Q :~
S
C) ~ h ~ ~1 ~U t-- O
::~ N O t-- ~i ~1 0 h J:~
O J~
t-- ~1 ~n ~ -d u L:
,~ I p Gq ~ Z
a~ o ~ c~ bO
~, N ~ ~ t~ r\ ~ U:l U~
cq ,J ~ P ~q ~ ~ ~
~ ~ O
~ ~ a) h o o C~ ~
. d h S: S S
~3 C~
O O
e O ~ ~ H H
~1 ~ P~ * * *
The antibacterial spectra data given above clearly demonstrate tha~ 3-0-demethylistamycln B and 3-0-demethyl-2"-N-~ormimidoylistamycln B exhibit a high antibacterial actlvlty against a wide variety of Gram-negative and Gram-posltive bacteria. On the other hand, 3-O~demethylistamycin Bo has a poor antibacterlal activity, but ls use~ul as an intermediate for the preparation of 3-0-demethylistamycin B.
3-0-Demethylistamycln Bo (dicarbonate) 3 3-0-demethyl istamycin B (sesquicarbonate) and 3-0-demethyl-2"-N-formimidoylistamycin B (disulphate trihydrate) are further characterized by their low toxicity. Thus, when the acute toxicity o~ these three compounds was estimated by intra-venous in~ection in mice 3 it was found that all the mice tested tolerated a dose of 160 mg/kg of each compound.
3~0-Demethylistamycin ~0~ 3-O~demethylistamycin B
and 3-O~demethyl-2"-N-~ormimidoylistamycin B according to this invention may be obtained ln the form of the free base, a hydrate or a carbonate thereo~, and more pref~rably in view of their stability they can be converted into a pharmaceutically acceptable acid additlon salt thereof by reacting with a pharmaceutically acceptable acid in a usual mannerO Examples of the pharmaceutically acceptable acids are inorganic acids such as hydrochloricg hydrobromic~
sul~uric, phosphoric and nitric acids and organic acid~
such as acetic~ malic, c~tric~ ascorblc and methanesul~onic acids. The compounds may also exist as salt-hydrates~ e.g.
3-0-demethyl-2"~N-formimidoylistamycin B~disulfat2 trihydxateO
.
83~
3 O-Demethylistamycin Bo of formula Ia:
CH3N--~6'
4' ~
\ 2' \ NH2 O ~i (Ia) 4 ~oH
CH3~
H
may be prepared according to this invention by demethylat-ing at the 3-methoxy group of lstamycin Bo of formula II:
3H ~ 5, 4' ~ '\
2 \ NH2 O ~
(II) 4 ~ 3 in a manne.- known per se. There are several process well-known in the art for demethyla~ion of the methoxy group~
s~ch as ~reatment with hydriodic acid or hydrobromlc acld, treatment wlth a Lewis acid, typlcally a metal halide such .
as aluminium trichloride, aluminium trlbromlde, boron trlchloride, boron ~ribromide, boron trifluoride, zinc dichloride~ zlnc dii~dide or iron trichloride, or treat-ment with an alkali metal such as sodlum ~r lithium (see "The Chemlstry o~ the Ether Linkage", edited by S. Patai, page 21, publlshed by Interscience Publishers Inc. in 1967). A pre~erred process ~or the demethylation reaction to be used here is one wherein istamycln Bo is heated with 48% hydrobromic acid at 90 - 100C in a sealed tube, which can achieve ef~ective demethylation reaction in a short reaction time as described in published U.K. Application GB 2 037 743.
3-0-~emethylistamycin B of formula Ib:
3H ~ 5, 4' ~ \
\ 2~ \NH2 O ~ ~ OH
(Ib) 4\~oH
may be prepared according to thls invention by acylating the 4-methylamino ~roup of 3-0-demethylistamycin Bo o~
~ormula Ia with glycine. In practlce, this is attalned by previously protecting the 1- and 2'-amino groups and the 6'-met~ylamino group of 3-O-demethyli5tamy~in Bo with a conventional monovalen~ amino-protecting group to give a 1-, 2'- and 6Z-N-protected derivative of 3-0-demethylistamycin Bo of Fonnula III, CH3N ~ ' I O ~ ~ OH
R' ~ (III) \ ~ 3 4 ~ OH
I
H
wherein R' represents a conventional mon~valent amino~protecting group, reacting the eompound of Formula tIII) with a convention-ally N-protected glycine whose amino-protecting group is the same as or different from those on the 1-, 2 9~' and 6'-positlons of the compound of Formula ~III), or with a reactive derivative ~h~reof, in an inert sol~ent, at a temperatur~ of from about 0C
to about lOO~C, to acylate the 4-me~hyl~nino group, thuS forming a compound of Formula IV:
CH3NI ~
Rt4 ~ ~ \ NH
9' r~ , ~ OH (IV)
\ 2' \ NH2 O ~i (Ia) 4 ~oH
CH3~
H
may be prepared according to this invention by demethylat-ing at the 3-methoxy group of lstamycin Bo of formula II:
3H ~ 5, 4' ~ '\
2 \ NH2 O ~
(II) 4 ~ 3 in a manne.- known per se. There are several process well-known in the art for demethyla~ion of the methoxy group~
s~ch as ~reatment with hydriodic acid or hydrobromlc acld, treatment wlth a Lewis acid, typlcally a metal halide such .
as aluminium trichloride, aluminium trlbromlde, boron trlchloride, boron ~ribromide, boron trifluoride, zinc dichloride~ zlnc dii~dide or iron trichloride, or treat-ment with an alkali metal such as sodlum ~r lithium (see "The Chemlstry o~ the Ether Linkage", edited by S. Patai, page 21, publlshed by Interscience Publishers Inc. in 1967). A pre~erred process ~or the demethylation reaction to be used here is one wherein istamycln Bo is heated with 48% hydrobromic acid at 90 - 100C in a sealed tube, which can achieve ef~ective demethylation reaction in a short reaction time as described in published U.K. Application GB 2 037 743.
3-0-~emethylistamycin B of formula Ib:
3H ~ 5, 4' ~ \
\ 2~ \NH2 O ~ ~ OH
(Ib) 4\~oH
may be prepared according to thls invention by acylating the 4-methylamino ~roup of 3-0-demethylistamycin Bo o~
~ormula Ia with glycine. In practlce, this is attalned by previously protecting the 1- and 2'-amino groups and the 6'-met~ylamino group of 3-O-demethyli5tamy~in Bo with a conventional monovalen~ amino-protecting group to give a 1-, 2'- and 6Z-N-protected derivative of 3-0-demethylistamycin Bo of Fonnula III, CH3N ~ ' I O ~ ~ OH
R' ~ (III) \ ~ 3 4 ~ OH
I
H
wherein R' represents a conventional mon~valent amino~protecting group, reacting the eompound of Formula tIII) with a convention-ally N-protected glycine whose amino-protecting group is the same as or different from those on the 1-, 2 9~' and 6'-positlons of the compound of Formula ~III), or with a reactive derivative ~h~reof, in an inert sol~ent, at a temperatur~ of from about 0C
to about lOO~C, to acylate the 4-me~hyl~nino group, thuS forming a compound of Formula IV:
CH3NI ~
Rt4 ~ ~ \ NH
9' r~ , ~ OH (IV)
5\
~ ~ 3 4 ~ OH
CH3l /A
COC~2N ~B
~ ~ .
_, .. . . . . _ .
wherein Ri ha~ the same meanlng as defined above, A represents a hydr~gen atom and B repxesen~s a conventional monovalent ~mino~protecting group or A a~d B toge ~er form a conventional divalent amino-protecting gro~p, and then removing all the amino-protecting ~roups on the compound of Formula IV by conventional m~ans to give 3~0-deme~hylistamyeln B of Fonmula Ib~
~ n the ami~o-protection step~ the 1- and 2~-amino groups and th~ 6i methylamino group of 3-0-demethylistamycin Bo of Formula Ia may be simul~ar~eously protected with a monovalent amino-protecting group wi~hout affecting th~ 4-methylamino group thexeof. As an example of a sui~able, conventional mono-valent amino-protecting group, there may be mentioned an alkoxycarbonyl group, particularly having 2-7 carbon atoms, such as tert-butoxycarbonyl a~d ~er~-amyloxy~arbonyl; a ~ycloalkyloxy-carbonyl group, particulaxly 4-7 carbon atoms such as cyclohexyloxycarbonyl; an aralkyloxycarbonyl group such as benzyloxycarbonyl; and an acyl group, partlcularly an alkanoyl group having 2- 7 carbon atoms such as tri-rluoroacetyl and o-nitrophenoxyacetyl. The introduction of such an amino-protecting ~roup may be carried out ln a manner known in the syntheses of peptides, e.g. by using a known amino-protecting group-lntroducing reagent ln the ~orm of an acid halide, an acld azide~ an active ester, an acid anhydrlde, etc. By using such an amino~protecting group-introduclng reagent ln an amount Or 2.5 - 4.0 moles per mole o~ 3-V-demethyll~tamycin Bo~ ~t ~s possible to preferentially ~orm 1,2~ 9 6~trl-N protected 3 0-demethyl-istamycin Bo o~ formula III above due to the dlrference in reactivlty of the respective amlno and methylamlno groups o~ 3-0-demethylistamycln ~0~ Alternatlvely9 132~ ,6'~trl N-protected 3-0 demethylistamycin ~0 o~' ~ormula III may be obtained in a hlgher yleld by reacting 3 0 demethylistamycin 7~' ! ~` i 33~1~
Bo with one molar equlvalent of a divalenk catlon such as those Or divalent transitlon metals such as copper, nickel and cobalt and of zinc (II) to form a metal complex~ and reacting the complex with 3 - 5 moles of an amino-protecting group-introducing reagent 3 followed by removal of the metal cation from the reaction product (see, for example, published U.K. Patent Application No. 2,036,020).
The subsequent glycylation (i.e. acylatlon with glycine) of the 4-methylamino group of the 1,2',6'-tri-N-protected 3-0-demethylistamycin Bo of rormula III may be effected by reacting the compound with glycine or a reactive derivatlve thereof in accordance wlth any of the known N-acylation processes ~or peptide-syntheses such as the dicyclohexylcarbodiimide process, mixed acid anhydride process, azide process, ac~ive ester process, etc. The reaction may be conducted over a temperature range of from about 0C to about 100C in a 501vent such as methanol, dioxane~ acetonitrile or methylene chloride. It i5 preferable for the glycine reagent to have the amino group protected~ and the amlno-protecting group for thls purpose may be the same as or dl~ferent ~rom those on the 1- and 2'-amino groups and on the 6'-methylamino group of 3-0-demethylistamycin Bo and which ls easily removable. Thusg the amino-protecting group ~or protecting khe amino group in the glycine reagen~ may be selected ~rom the above mentloned ~mlno~protectlng groups and some dlvalent amlno-protecting groups such as those of a Schiff base type. The acylation reactlon wlth a glycine reagent is preferably carr~ed out according to ~n act~ve ester process ln an ~383~
organlc ~olvent such as dioxane under heatlng to a temperature of 40 ~ 60C, thus giving a compound of ~ormula IV above.
The removal of the amino-protecting groups on the amino and methylamlno groups o~ the compound of ~ormula IV
may be effected in a known manner, for example, by hydro-genolysis in the presence of palladium9 platinum oxlde>
etc. as catalyst for the removal o~ an aralkyloxycarbonyl group or by hydrolysis in an aqueous solution of trifluoro-acetic acid~ acetic acid~ etc. or a dlluted aqueous acld solution such as a diluted hydrochloric acid for the removal o~ other amino-protecting groups.
3-0-Demethyl-2"-N-formimidoyllstamycin B of ~ ormula Ic:
C~3N ~ -4, ~ .0\
OH
(Ic) ~ ~ H
CH3l COCH2NHCH=NH
may be prepared according to this invent~on by formimidoy-lating the 2"~amino group o~ 3~0-demethylistamycin B o~
~ormula Ib. Thus, for thls purpose~ a 1- 3 2'- and 6'-tri-N-protected derlYatlve of 3~0-demethylistamycin Bo o~
formula III above ls provlded as startlng materlal. The .
31~D
compound of Formula III as reacted wi~h a conventionally N~protected glycine whose amino-protecting group is differ-ent from those on the 1-, 2'- and 6 t -positions of th~
compound of Formula III, or w.ith a reac~ive d~rivative thereof~ ~o acylate ~he 4-methylamino group, thu5 forming a compound of Formula V:
CH3N ~ ' R' 1 4' ~ O
\ 2' \ NH
~b~ ~ O~ (V) 5 ~ ~ 3 CH3~
I /A' COCH2N ~B' wherein R' represents a conventiona:L monovalent amino-protecting group, Al xepresents a hydrogen atom and B~
represents a conven~iDnal mon~valent amin~-protecting group which is differ~nt from R', or A' and B' together form a co~ventional divalent amino-protecting group. Then, the amino-protecting group on the 2"-amino group in the glycine moiety of ~he compound of Formula V is selectively removed and ~he resulting ¢ompound is reacted with an iminoether to convert the 2;'~amino group into an amldine group, thus ~ormlng a compound o~ ~ormula VI:
3~
CH3N ~
R' ~ o \ 7 \ 2' \ NH
~1' ~1 3t IH \o/6~ ~ OH
R~ ~ (VI) 4~oH
CH3l COCH2NHCH=NH
wherein R' has the same meaning as defined above. Finally, the remaining amino-protecting groups on the 1-l 2'- and
~ ~ 3 4 ~ OH
CH3l /A
COC~2N ~B
~ ~ .
_, .. . . . . _ .
wherein Ri ha~ the same meanlng as defined above, A represents a hydr~gen atom and B repxesen~s a conventional monovalent ~mino~protecting group or A a~d B toge ~er form a conventional divalent amino-protecting gro~p, and then removing all the amino-protecting ~roups on the compound of Formula IV by conventional m~ans to give 3~0-deme~hylistamyeln B of Fonmula Ib~
~ n the ami~o-protection step~ the 1- and 2~-amino groups and th~ 6i methylamino group of 3-0-demethylistamycin Bo of Formula Ia may be simul~ar~eously protected with a monovalent amino-protecting group wi~hout affecting th~ 4-methylamino group thexeof. As an example of a sui~able, conventional mono-valent amino-protecting group, there may be mentioned an alkoxycarbonyl group, particularly having 2-7 carbon atoms, such as tert-butoxycarbonyl a~d ~er~-amyloxy~arbonyl; a ~ycloalkyloxy-carbonyl group, particulaxly 4-7 carbon atoms such as cyclohexyloxycarbonyl; an aralkyloxycarbonyl group such as benzyloxycarbonyl; and an acyl group, partlcularly an alkanoyl group having 2- 7 carbon atoms such as tri-rluoroacetyl and o-nitrophenoxyacetyl. The introduction of such an amino-protecting ~roup may be carried out ln a manner known in the syntheses of peptides, e.g. by using a known amino-protecting group-lntroducing reagent ln the ~orm of an acid halide, an acld azide~ an active ester, an acid anhydrlde, etc. By using such an amino~protecting group-introduclng reagent ln an amount Or 2.5 - 4.0 moles per mole o~ 3-V-demethyll~tamycin Bo~ ~t ~s possible to preferentially ~orm 1,2~ 9 6~trl-N protected 3 0-demethyl-istamycin Bo o~ formula III above due to the dlrference in reactivlty of the respective amlno and methylamlno groups o~ 3-0-demethylistamycln ~0~ Alternatlvely9 132~ ,6'~trl N-protected 3-0 demethylistamycin ~0 o~' ~ormula III may be obtained in a hlgher yleld by reacting 3 0 demethylistamycin 7~' ! ~` i 33~1~
Bo with one molar equlvalent of a divalenk catlon such as those Or divalent transitlon metals such as copper, nickel and cobalt and of zinc (II) to form a metal complex~ and reacting the complex with 3 - 5 moles of an amino-protecting group-introducing reagent 3 followed by removal of the metal cation from the reaction product (see, for example, published U.K. Patent Application No. 2,036,020).
The subsequent glycylation (i.e. acylatlon with glycine) of the 4-methylamino group of the 1,2',6'-tri-N-protected 3-0-demethylistamycin Bo of rormula III may be effected by reacting the compound with glycine or a reactive derivatlve thereof in accordance wlth any of the known N-acylation processes ~or peptide-syntheses such as the dicyclohexylcarbodiimide process, mixed acid anhydride process, azide process, ac~ive ester process, etc. The reaction may be conducted over a temperature range of from about 0C to about 100C in a 501vent such as methanol, dioxane~ acetonitrile or methylene chloride. It i5 preferable for the glycine reagent to have the amino group protected~ and the amlno-protecting group for thls purpose may be the same as or dl~ferent ~rom those on the 1- and 2'-amino groups and on the 6'-methylamino group of 3-0-demethylistamycin Bo and which ls easily removable. Thusg the amino-protecting group ~or protecting khe amino group in the glycine reagen~ may be selected ~rom the above mentloned ~mlno~protectlng groups and some dlvalent amlno-protecting groups such as those of a Schiff base type. The acylation reactlon wlth a glycine reagent is preferably carr~ed out according to ~n act~ve ester process ln an ~383~
organlc ~olvent such as dioxane under heatlng to a temperature of 40 ~ 60C, thus giving a compound of ~ormula IV above.
The removal of the amino-protecting groups on the amino and methylamlno groups o~ the compound of ~ormula IV
may be effected in a known manner, for example, by hydro-genolysis in the presence of palladium9 platinum oxlde>
etc. as catalyst for the removal o~ an aralkyloxycarbonyl group or by hydrolysis in an aqueous solution of trifluoro-acetic acid~ acetic acid~ etc. or a dlluted aqueous acld solution such as a diluted hydrochloric acid for the removal o~ other amino-protecting groups.
3-0-Demethyl-2"-N-formimidoyllstamycin B of ~ ormula Ic:
C~3N ~ -4, ~ .0\
OH
(Ic) ~ ~ H
CH3l COCH2NHCH=NH
may be prepared according to this invent~on by formimidoy-lating the 2"~amino group o~ 3~0-demethylistamycin B o~
~ormula Ib. Thus, for thls purpose~ a 1- 3 2'- and 6'-tri-N-protected derlYatlve of 3~0-demethylistamycin Bo o~
formula III above ls provlded as startlng materlal. The .
31~D
compound of Formula III as reacted wi~h a conventionally N~protected glycine whose amino-protecting group is differ-ent from those on the 1-, 2'- and 6 t -positions of th~
compound of Formula III, or w.ith a reac~ive d~rivative thereof~ ~o acylate ~he 4-methylamino group, thu5 forming a compound of Formula V:
CH3N ~ ' R' 1 4' ~ O
\ 2' \ NH
~b~ ~ O~ (V) 5 ~ ~ 3 CH3~
I /A' COCH2N ~B' wherein R' represents a conventiona:L monovalent amino-protecting group, Al xepresents a hydrogen atom and B~
represents a conven~iDnal mon~valent amin~-protecting group which is differ~nt from R', or A' and B' together form a co~ventional divalent amino-protecting group. Then, the amino-protecting group on the 2"-amino group in the glycine moiety of ~he compound of Formula V is selectively removed and ~he resulting ¢ompound is reacted with an iminoether to convert the 2;'~amino group into an amldine group, thus ~ormlng a compound o~ ~ormula VI:
3~
CH3N ~
R' ~ o \ 7 \ 2' \ NH
~1' ~1 3t IH \o/6~ ~ OH
R~ ~ (VI) 4~oH
CH3l COCH2NHCH=NH
wherein R' has the same meaning as defined above. Finally, the remaining amino-protecting groups on the 1-l 2'- and
6'-positions of the compound of` formula VI are removed to yield 3-0-demethyl-2"-N~formimidoylistamycin B of formula Ic.
In one preferred example for ~orming an N-protected intermediate compound of ~ormula V whereln R' is benzyloxy-carbonyl ~roup, A' is hydrogen and B' is tert-butoxycarbonyl ~roup, 1,2'96'-trl-N benæyloxycarbonyl-3-O-demethylistamycin Bo is acylated on the 4-methylamino group with the N~hydroxy-succinimide ester of N-~ert-butoxycarbonylglycine.
According to another prererred embodiment, 1~2' J6' tri-N-tert-butoxycarbonyl-3-0 demethylistamycin Bo is acylated on the 4-methylamlno group with the N~hydroxysuccinimide ester of N-benzyloxycarbonylglyclne~ thus forming an N-protected intermed1ate compound of formula V ln which R' is tert butoxycarbonyl3 Al is hydrogen and B' is benzyloxycarbonyl group.
~311~) In the ~ormimldoylatlon step~ the iminoether reagent to be used may be one ha~ing the general formula:
R"OCH=NH
whereln R" represents a lower alkyl group or an aralkyl group such as benzyl r or an acid addition salt thereo~ such as the hydrochloride or sulfate. The use of an iminoether hydrochloride such as ethylformimidate hydrochloride or benzylformimidate hydrochloride ls preferred. The reactlon may be conducted in an organic solvent such as dioxane or methanol or in an aqueous solutlon at a temperature of below about 30C in a known manner. The resulting compound o ~ormula VI, 1,2',6'-tri~N-protected-3-O-demethyl-2"-N-formimidoylistamycin B, or an acid addition salt thereof, may be purified by a column chromatography using a silica gel or the like~
The remaining amino-protecting groups on the 1- and 2'-amino groups and on the 6'-methylamino group of the compound o~ rormula ~I may be removed by a knowm method as above mentioned~ thus to yield the desired 3-0-demethyl-2"-N-rormimidoylistamycin B of ~ormula Ic.
3-O-Demethylistamycin B and 3-O-demethyl-2t'-N- -~ormimidoylistamycin B of this invention have a high antibacterial activity and are of a low toxicity to animals.
Accordingly, these compounds are useful similarly to the known ant~bacterlal antibiotics and may be formulated into known pharmaceutlcal ~orms and administered ln the same manner as the known antibacterlal antlblotics. According to a further aspect of this inventlong there is provided a pharmaceutlcal composition comprising an ant~bacterially 3~
-~2-e~fectlve amount o~ 3-O-demethylistamycin B or 3-O-demethyl-2"-N~formimidoylist~mycin B, or a pharmaceutically acceptable acld addition salt thereof, ln combination with ~ pharma-ceutically acceptable carrier. It will be appreciated that the actual preferred dosages of the active new compoundS of khls invention used wlll vary according to the particular compound belng used, the particular composition formulated, the mode of appllcation and the particular situs and organism belng treated. Many factors that modify the action of the drug will be taken into account by the skilled in the art, for example, age3 body weight, sex, diet, time of administration, route of adminlstration, rate of excre-tion, drug combinations, reactlon sensitivities and severity of the disease. Optimal application rates for a given set o~ conditions can be ascertained by the skilled ln the art using conventional dosa~e determination tests in view of the above guidellnes.
The ~ollowing Examples ~urther illustrate the pre-paration of the compounds according to this invention.
Example 1 Preparation of 3-O-demethylistamycin Bo , .
Istamycin Bo monocarbonate (500 mg, 1.27 mmol) was dissolved in 48% hydrobromlc acid (50 ml) and the solution was heated ln a sealed tube at 90 - 93C for 4 hours. The reaction solutlon was concentrated to dryness in vacuo and the resldue was di~solved in water (50 ml)O The solutlon was ad~usted to pH 8.5 wlth addition o~ 7M aqueous ammonia and passed through a column (21 x 550 mm) o~ ~OO ml o~
.. . .. _ . , _ _ . _ .. , . _ . . .... . . . . .
3~
*
CM-Sephadex C-25 (NH4-~orm, a product o~ Pharmacla Co., Sweden). The ~olumn was eluted gradlently with 0.15M
aqueous ammonla (1120 ml) and 0.70M aqueous ammonia (1120 ml~, The eluate was collected ln 16 ml-fractions. The rractiOns Nos. B5 to 102 were combined together and concentrated to dryness in vacuo to afford 275 mg o~ a colorless powder of 3-0-demethylistamycin Bo~dicarbonate. Yield ~9%.
Ex~ple ?.
Preparation of 3-O~demeth~listamycin B
3--0-Demethyllstamycln Bo-dicarbonate (150 mg, 0.34 mmol) obtained ln Example 1 was dissolved in rnethanol (12 ml) and to the solution N-benzyloxycarbonyloxysuc-cinlmide (329 mgg 1.34 mmol) was added over 2 hours with stirring and u~der cooling to -10C, and the mixture was stirred for ~urther two hours. The reactlon solution was concentrated in vacuoto form a syrup, which was then dlssolved in chloroform (25 ml). The solutlon was washed with water (8 ml x 2) and the chloroform layer was dehydrated over anhydrous sodium sulfate and concentrated to dryness in vacuo to yield a crude powder of 1,2',6'-tri-N-benzyloxycarbonyl-3-0-demethylistamycin Bo. This powder was dissolved ln dloxane (9 ml) and to the solution were added triethylamine (0.5 ml) and N-(N-benzyloxycarbonyl-glycyloxy)succinlmide (250 mg, 0.82 mmol)~ and the mixture was heated to 55C for 2 hours under stirring~ The reaction solutlon was concentrated ln vacuo and the residue was dissolved in chloroform ~25 ml) and washed with water (8 ml x 2). The chloroform layer was dehydrated over anhydrous sodium sul~ate and concentrated to dryness in vacuo to give * trade mark.
- 2~ -a crude powder ~389 mg). Thls powder was purified by column chromatoKraphy on sllica gel (30 g of Wako gel C-200, a product of Wako Pure Chemical Industries, Ltd., Japan; the column size: 14 x 350 mm) developed with a mixture Or ethyl aceta~e-toluene (5:2 by volume) ~o afford a colorless powder (83 mg) of 1,2'~6'~2"-tetra-N-benzyloxy-carbonyl 3-0-demethylistamycin B. This powder was dissolved in a mixture o~ me~hanol (5 ml)~ water (1 ml) and acetlc acid (0.5 ml) and the solutlon was sub~ected to hydro-genolysis under a hydrogen stream ln the presence of 5%
palladium-carbon (15 mg; a product of Kawaken Flne Chemical Company, Japan) as catalyst at room temperature for 1.5 hours. After the catalyst was removed by flltratlon, the reaction solut.ion was concentrated to dryness in vacuo to yield a crude powder (60.9 mg). A 60 mg portion of the powder was dis~olved ln water (3 ml) and the solutlon was adJusted to pH 8 wlth addition of aqueous ammonia and passed through a column (8 x 95 mm) of 5 ml of Amberlite CG-50 (NH~ form, a product of Rohm & Haas Co., U.S~A.). The column was washed with water (10 ml) and then eluted with 0.2M aqueous ammonia ~70 ml) and o.8M aqueous ammonia (70 ~) ln a manner Or gradient elution. The eluate was collected in 1.4 ml-fractions. The ~ractions Nos. 22- 38 were combined together and concentrated to dryness in vacuo to af~ord a colorless powder (35~5 mg) of 3-O-demethylistamycin B sesquicarbonate. Y~eld: 23~.
* trade mark.
.
Example 3 Preparation o~ 3~0-demethyl-2"-N-formlmidoyl~
3-O-Demethylistamycin Bo-dicarbonate (260 mg, 0.59 mmol3 obtained in Example 1 was dissolved in methanol (24 ml) and to the solution were added triethyl amine (0.32 ml) and 2-(tert-butoxycarbonyloxyimino)-2-phenyl-acetonitrile t433 mg9 1.76 mmol) (BOC-ON, a product of Aldrich Co~, U.S.A.) under stirring and cooling (0-8C), and the mlxture was allowed to stand overnlght. The reactlon solution was concentrated in vacuo and then dissolved in chloroform. The chloroform solution was purified by column chromatography on silica gel (20 g of Wako gel C-200; the column slze: 14 x 250 mm). The column was washed with chloroform (80 ml) and developed with a mixture of chloro~orm-methanol (10:]. by volume), and the eluate was concentrated to dryness to afford a colorless powder (255 mg) of 1, 2 ', 6 ' -tri-N-tert-butoxycarbonyl-3-0-demethylistamycin Bo. Yield: 66%.
This powder (215 mg~ 0.33 mmol) was dissolved in dloxane (7 ml) and there were added to the solution tri-ethylamine (0.Q72 ml) and N-(N benzyloxycarbonylglycyloxy) succlnimide (160 mg, 0.52 ~mol)3 and the mixture ~as maintalned at 5SC ~or 2 hours to hasten ~he reaction.
The reaction solutlon was concentrated in vacuo and puri~ied by column chromatography on sillca ~el (26 o~ Wako gel C-200;
* trade mark.
3~3 the column size: 14 x 310 mm) developed with a mlxture of ethyl acetate-toluene (11:4~ ~o yleld a colorless powder ~197 mg) o~ 2" N-benzyloxycarbonyl-1,2',6'-tri~N-tert-butoxycarbonyl-3-O-demethylistamycln B. Yield: 75%.
This powder (190 mg, 0.23 mmol~ was dissolved in a mlxture of methanol (6 ml) J water (1 ml) and acetic acid (o.05 ml~ and the solution was sub~ected to hydrogenolysis in a hydrogen stream in the presence of 5% palladlum-carbon (30 mg) as catalyst at room temperature for 3 hours. After the catalyst was removed by filtration, the reaction solu-tion was concentrated to dryne~s in vacuo to afford a colorless powder (160 mg) o~ 1,2'~6'-tri-N-tert-butoxy-carbonyl-3-0-demethylistamycin B-monoacetate. Yield: 93%.
This powder (150 mg, 0.20 mmol) was dissolved in a mixture of methanol (27 ml) and water (4 ml), and to ~he solution there was added dropwise over 15 minutes a solution of` benzylformimidate hydrochloride (209 mg~ 1.22 mmol) in methanol (5 ml) under ice-cooling, while the pH of the reaction solution was adJusted to 8.0 - 8.5 by addition of a 0.5N potassium hydroxlde~ The reaction solution was furthe~ stirred ~or 30 minutes under ice-cooling~ then adJusted to pH 4.0 by addltion of lN hydrochloric acid and concentrated in vacuo to give a syrup. The syrup was dis-solved in butanol (50 ml) and the solutlon was washed with water (25 ml x 2). The butanol layer separated was concentrated to dryness in vacuo and th~ residue was 3~
- 27 ~
purlfled by column chromatography on sillca gel (20 g of Wako gel C-200; the column size: 12 x 370 mm) developed with a mixture of chloroform-methanol (4:1 by volume) to yield a colorless powder (63 mg) of 1,2',6'-trl-N-tert-butoxycarbonyl~3-0-demethyl-2"-N-formimidoyllstamycin B.
Yield: 42%.
This powder (63 mg) was dissolved in a90% tri-fluoroacetic acid (2.5 ml) and the solution was allowed to stand for 1.5 hours and then concentrated to dryness in vacuo. The residue was dissolved ln water (2 ml) and the solution was passed through a column (8 x lO mm) of 5 ml of Amberllte IRA-400 (S04 form; a product of Rohm & Haas Co., U.S.A.) to e~fect a salt exchange. The effluent (6 ml) was concentrated to dryness in vacuo to obtain a colorless powder (53 mg) of 3-O-demethyl-2"-N-formimidoyl-istamycln B-disulphate-trihydrate. Yield: 95%.
In one preferred example for ~orming an N-protected intermediate compound of ~ormula V whereln R' is benzyloxy-carbonyl ~roup, A' is hydrogen and B' is tert-butoxycarbonyl ~roup, 1,2'96'-trl-N benæyloxycarbonyl-3-O-demethylistamycin Bo is acylated on the 4-methylamino group with the N~hydroxy-succinimide ester of N-~ert-butoxycarbonylglycine.
According to another prererred embodiment, 1~2' J6' tri-N-tert-butoxycarbonyl-3-0 demethylistamycin Bo is acylated on the 4-methylamlno group with the N~hydroxysuccinimide ester of N-benzyloxycarbonylglyclne~ thus forming an N-protected intermed1ate compound of formula V ln which R' is tert butoxycarbonyl3 Al is hydrogen and B' is benzyloxycarbonyl group.
~311~) In the ~ormimldoylatlon step~ the iminoether reagent to be used may be one ha~ing the general formula:
R"OCH=NH
whereln R" represents a lower alkyl group or an aralkyl group such as benzyl r or an acid addition salt thereo~ such as the hydrochloride or sulfate. The use of an iminoether hydrochloride such as ethylformimidate hydrochloride or benzylformimidate hydrochloride ls preferred. The reactlon may be conducted in an organic solvent such as dioxane or methanol or in an aqueous solutlon at a temperature of below about 30C in a known manner. The resulting compound o ~ormula VI, 1,2',6'-tri~N-protected-3-O-demethyl-2"-N-formimidoylistamycin B, or an acid addition salt thereof, may be purified by a column chromatography using a silica gel or the like~
The remaining amino-protecting groups on the 1- and 2'-amino groups and on the 6'-methylamino group of the compound o~ rormula ~I may be removed by a knowm method as above mentioned~ thus to yield the desired 3-0-demethyl-2"-N-rormimidoylistamycin B of ~ormula Ic.
3-O-Demethylistamycin B and 3-O-demethyl-2t'-N- -~ormimidoylistamycin B of this invention have a high antibacterial activity and are of a low toxicity to animals.
Accordingly, these compounds are useful similarly to the known ant~bacterlal antibiotics and may be formulated into known pharmaceutlcal ~orms and administered ln the same manner as the known antibacterlal antlblotics. According to a further aspect of this inventlong there is provided a pharmaceutlcal composition comprising an ant~bacterially 3~
-~2-e~fectlve amount o~ 3-O-demethylistamycin B or 3-O-demethyl-2"-N~formimidoylist~mycin B, or a pharmaceutically acceptable acld addition salt thereof, ln combination with ~ pharma-ceutically acceptable carrier. It will be appreciated that the actual preferred dosages of the active new compoundS of khls invention used wlll vary according to the particular compound belng used, the particular composition formulated, the mode of appllcation and the particular situs and organism belng treated. Many factors that modify the action of the drug will be taken into account by the skilled in the art, for example, age3 body weight, sex, diet, time of administration, route of adminlstration, rate of excre-tion, drug combinations, reactlon sensitivities and severity of the disease. Optimal application rates for a given set o~ conditions can be ascertained by the skilled ln the art using conventional dosa~e determination tests in view of the above guidellnes.
The ~ollowing Examples ~urther illustrate the pre-paration of the compounds according to this invention.
Example 1 Preparation of 3-O-demethylistamycin Bo , .
Istamycin Bo monocarbonate (500 mg, 1.27 mmol) was dissolved in 48% hydrobromlc acid (50 ml) and the solution was heated ln a sealed tube at 90 - 93C for 4 hours. The reaction solutlon was concentrated to dryness in vacuo and the resldue was di~solved in water (50 ml)O The solutlon was ad~usted to pH 8.5 wlth addition o~ 7M aqueous ammonia and passed through a column (21 x 550 mm) o~ ~OO ml o~
.. . .. _ . , _ _ . _ .. , . _ . . .... . . . . .
3~
*
CM-Sephadex C-25 (NH4-~orm, a product o~ Pharmacla Co., Sweden). The ~olumn was eluted gradlently with 0.15M
aqueous ammonla (1120 ml) and 0.70M aqueous ammonia (1120 ml~, The eluate was collected ln 16 ml-fractions. The rractiOns Nos. B5 to 102 were combined together and concentrated to dryness in vacuo to afford 275 mg o~ a colorless powder of 3-0-demethylistamycin Bo~dicarbonate. Yield ~9%.
Ex~ple ?.
Preparation of 3-O~demeth~listamycin B
3--0-Demethyllstamycln Bo-dicarbonate (150 mg, 0.34 mmol) obtained ln Example 1 was dissolved in rnethanol (12 ml) and to the solution N-benzyloxycarbonyloxysuc-cinlmide (329 mgg 1.34 mmol) was added over 2 hours with stirring and u~der cooling to -10C, and the mixture was stirred for ~urther two hours. The reactlon solution was concentrated in vacuoto form a syrup, which was then dlssolved in chloroform (25 ml). The solutlon was washed with water (8 ml x 2) and the chloroform layer was dehydrated over anhydrous sodium sulfate and concentrated to dryness in vacuo to yield a crude powder of 1,2',6'-tri-N-benzyloxycarbonyl-3-0-demethylistamycin Bo. This powder was dissolved ln dloxane (9 ml) and to the solution were added triethylamine (0.5 ml) and N-(N-benzyloxycarbonyl-glycyloxy)succinlmide (250 mg, 0.82 mmol)~ and the mixture was heated to 55C for 2 hours under stirring~ The reaction solutlon was concentrated ln vacuo and the residue was dissolved in chloroform ~25 ml) and washed with water (8 ml x 2). The chloroform layer was dehydrated over anhydrous sodium sul~ate and concentrated to dryness in vacuo to give * trade mark.
- 2~ -a crude powder ~389 mg). Thls powder was purified by column chromatoKraphy on sllica gel (30 g of Wako gel C-200, a product of Wako Pure Chemical Industries, Ltd., Japan; the column size: 14 x 350 mm) developed with a mixture Or ethyl aceta~e-toluene (5:2 by volume) ~o afford a colorless powder (83 mg) of 1,2'~6'~2"-tetra-N-benzyloxy-carbonyl 3-0-demethylistamycin B. This powder was dissolved in a mixture o~ me~hanol (5 ml)~ water (1 ml) and acetlc acid (0.5 ml) and the solutlon was sub~ected to hydro-genolysis under a hydrogen stream ln the presence of 5%
palladium-carbon (15 mg; a product of Kawaken Flne Chemical Company, Japan) as catalyst at room temperature for 1.5 hours. After the catalyst was removed by flltratlon, the reaction solut.ion was concentrated to dryness in vacuo to yield a crude powder (60.9 mg). A 60 mg portion of the powder was dis~olved ln water (3 ml) and the solutlon was adJusted to pH 8 wlth addition of aqueous ammonia and passed through a column (8 x 95 mm) of 5 ml of Amberlite CG-50 (NH~ form, a product of Rohm & Haas Co., U.S~A.). The column was washed with water (10 ml) and then eluted with 0.2M aqueous ammonia ~70 ml) and o.8M aqueous ammonia (70 ~) ln a manner Or gradient elution. The eluate was collected in 1.4 ml-fractions. The ~ractions Nos. 22- 38 were combined together and concentrated to dryness in vacuo to af~ord a colorless powder (35~5 mg) of 3-O-demethylistamycin B sesquicarbonate. Y~eld: 23~.
* trade mark.
.
Example 3 Preparation o~ 3~0-demethyl-2"-N-formlmidoyl~
3-O-Demethylistamycin Bo-dicarbonate (260 mg, 0.59 mmol3 obtained in Example 1 was dissolved in methanol (24 ml) and to the solution were added triethyl amine (0.32 ml) and 2-(tert-butoxycarbonyloxyimino)-2-phenyl-acetonitrile t433 mg9 1.76 mmol) (BOC-ON, a product of Aldrich Co~, U.S.A.) under stirring and cooling (0-8C), and the mlxture was allowed to stand overnlght. The reactlon solution was concentrated in vacuo and then dissolved in chloroform. The chloroform solution was purified by column chromatography on silica gel (20 g of Wako gel C-200; the column slze: 14 x 250 mm). The column was washed with chloroform (80 ml) and developed with a mixture of chloro~orm-methanol (10:]. by volume), and the eluate was concentrated to dryness to afford a colorless powder (255 mg) of 1, 2 ', 6 ' -tri-N-tert-butoxycarbonyl-3-0-demethylistamycin Bo. Yield: 66%.
This powder (215 mg~ 0.33 mmol) was dissolved in dloxane (7 ml) and there were added to the solution tri-ethylamine (0.Q72 ml) and N-(N benzyloxycarbonylglycyloxy) succlnimide (160 mg, 0.52 ~mol)3 and the mixture ~as maintalned at 5SC ~or 2 hours to hasten ~he reaction.
The reaction solutlon was concentrated in vacuo and puri~ied by column chromatography on sillca ~el (26 o~ Wako gel C-200;
* trade mark.
3~3 the column size: 14 x 310 mm) developed with a mlxture of ethyl acetate-toluene (11:4~ ~o yleld a colorless powder ~197 mg) o~ 2" N-benzyloxycarbonyl-1,2',6'-tri~N-tert-butoxycarbonyl-3-O-demethylistamycln B. Yield: 75%.
This powder (190 mg, 0.23 mmol~ was dissolved in a mlxture of methanol (6 ml) J water (1 ml) and acetic acid (o.05 ml~ and the solution was sub~ected to hydrogenolysis in a hydrogen stream in the presence of 5% palladlum-carbon (30 mg) as catalyst at room temperature for 3 hours. After the catalyst was removed by filtration, the reaction solu-tion was concentrated to dryne~s in vacuo to afford a colorless powder (160 mg) o~ 1,2'~6'-tri-N-tert-butoxy-carbonyl-3-0-demethylistamycin B-monoacetate. Yield: 93%.
This powder (150 mg, 0.20 mmol) was dissolved in a mixture of methanol (27 ml) and water (4 ml), and to ~he solution there was added dropwise over 15 minutes a solution of` benzylformimidate hydrochloride (209 mg~ 1.22 mmol) in methanol (5 ml) under ice-cooling, while the pH of the reaction solution was adJusted to 8.0 - 8.5 by addition of a 0.5N potassium hydroxlde~ The reaction solution was furthe~ stirred ~or 30 minutes under ice-cooling~ then adJusted to pH 4.0 by addltion of lN hydrochloric acid and concentrated in vacuo to give a syrup. The syrup was dis-solved in butanol (50 ml) and the solutlon was washed with water (25 ml x 2). The butanol layer separated was concentrated to dryness in vacuo and th~ residue was 3~
- 27 ~
purlfled by column chromatography on sillca gel (20 g of Wako gel C-200; the column size: 12 x 370 mm) developed with a mixture of chloroform-methanol (4:1 by volume) to yield a colorless powder (63 mg) of 1,2',6'-trl-N-tert-butoxycarbonyl~3-0-demethyl-2"-N-formimidoyllstamycin B.
Yield: 42%.
This powder (63 mg) was dissolved in a90% tri-fluoroacetic acid (2.5 ml) and the solution was allowed to stand for 1.5 hours and then concentrated to dryness in vacuo. The residue was dissolved ln water (2 ml) and the solution was passed through a column (8 x lO mm) of 5 ml of Amberllte IRA-400 (S04 form; a product of Rohm & Haas Co., U.S.A.) to e~fect a salt exchange. The effluent (6 ml) was concentrated to dryness in vacuo to obtain a colorless powder (53 mg) of 3-O-demethyl-2"-N-formimidoyl-istamycln B-disulphate-trihydrate. Yield: 95%.
Claims (2)
1. A process for the preparation of 3-0-demethyl-2"-N-formimidoylistamycin B of Formula Ic:
(Ic) or an acid addition salt or salt-hydrate thereof, which comprises reacting a 1-, 2'- and 6'-tri-N-protected 3-0-demethylistamycin B0 of formula III:
(III) wherein R' represents a conventional monovalent amino-protecting group with a conventionally N-protected glycine whose amino-protecting group is one different from those on the 1-, 2'- and 6'-positions of the compound of Formula III or with a reactive derivative thereof, in an inert solvent, at a temperature of from about 0°C to about 100°C, to acylate the 4-methylamino group, thus forming a compound of Formula V:
(V) wherein R' has the same meaning as defined above, A' represents a hydrogen atom and B' represents a con-ventional monovalent amino-protecting group which is different from R', or A' and B' together form a con-ventional divalent amino-protecting group, selectively removing the amino-protecting group on the 2"-amino group in the glycine moiety of the compound of Formula V, reacting the resulting compound with an iminoether, in an inert solvent, at a temperature below about 30°C, to convert the 2"-amino group into an amidine group, thus forming a compound of Formula VI:
(VI) wherein R' has the same meaning as defined above, and then removing the remaining amino protecting groups on the 1-, 2'- and 6'-positions of the compound of Formula VI to give 3-0-demethyl-2"-formimidoylistamycin B of Formula Ic.
(Ic) or an acid addition salt or salt-hydrate thereof, which comprises reacting a 1-, 2'- and 6'-tri-N-protected 3-0-demethylistamycin B0 of formula III:
(III) wherein R' represents a conventional monovalent amino-protecting group with a conventionally N-protected glycine whose amino-protecting group is one different from those on the 1-, 2'- and 6'-positions of the compound of Formula III or with a reactive derivative thereof, in an inert solvent, at a temperature of from about 0°C to about 100°C, to acylate the 4-methylamino group, thus forming a compound of Formula V:
(V) wherein R' has the same meaning as defined above, A' represents a hydrogen atom and B' represents a con-ventional monovalent amino-protecting group which is different from R', or A' and B' together form a con-ventional divalent amino-protecting group, selectively removing the amino-protecting group on the 2"-amino group in the glycine moiety of the compound of Formula V, reacting the resulting compound with an iminoether, in an inert solvent, at a temperature below about 30°C, to convert the 2"-amino group into an amidine group, thus forming a compound of Formula VI:
(VI) wherein R' has the same meaning as defined above, and then removing the remaining amino protecting groups on the 1-, 2'- and 6'-positions of the compound of Formula VI to give 3-0-demethyl-2"-formimidoylistamycin B of Formula Ic.
2. The compound 3-0-demethyl-2"-N-formimidoylistamycin B, or a pharmaceutically acceptable acid addition salt or salt-hydrate thereof, whenever prepared or produced by the process of claim 1 or an obvious chemical equivalent thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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JP125334/80 | 1980-09-11 | ||
JP55125334A JPS5750996A (en) | 1980-09-11 | 1980-09-11 | 3-o-demthylistamycin b derivative |
CA000385579A CA1188313A (en) | 1980-09-11 | 1981-09-10 | 3-0-demethyl derivatives of the istamycin b series of compounds and their preparation |
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CA000453522A Division CA1188310A (en) | 1980-09-11 | 1984-05-03 | 3-0-demethyl derivatives of the istamycin b series of compounds and their preparation |
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CA000453522A Division CA1188310A (en) | 1980-09-11 | 1984-05-03 | 3-0-demethyl derivatives of the istamycin b series of compounds and their preparation |
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CA000453522A Expired CA1188310A (en) | 1980-09-11 | 1984-05-03 | 3-0-demethyl derivatives of the istamycin b series of compounds and their preparation |
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CA000453521A Expired CA1188309A (en) | 1980-09-11 | 1984-05-03 | 3-0-demethyl derivatives of the istamycin b series of compounds and their preparation |
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1984
- 1984-05-03 CA CA000453521A patent/CA1188309A/en not_active Expired
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