Hydroxy derivatives of tylosin and process for their...

Details Hydroxy derivatives of tylosin and process for their... Hydroxy derivatives of tylosin and process for their...

1999-09-10

2001-04-03

Peselev, Elli (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S018500

Reexamination Certificate

active

06211348

ABSTRACT:

TECHNICAL FIELD
International Patent Classification: A 61 K 31/70, C 07 H 17/08
TECHNICAL PROBLEM
The present invention relates to tylosin derivatives, new synthetic products of the macrolide class exhibiting antimicrobial activity. It particularly relates to 12,13-dihydroxy tylosin derivatives of the formula (I)
wherein
R represents O, R
1
represents CHO, CH═NOH or CH(OCH
3
)
2
, R
2
represents H or mycarosyl, R
3
represents N(CH
3
)
2
or NO(CH
3
)
2
, and - - - line represents a single or a double bond, with the proviso that R
3
represents N(CH
3
)
2
when - - - line represents a single bond;
wherein
R represents NOH, R
1
represents CHO or CH(OCH
3
)
2
, R
2
represents H or mycarosyl,
R
3
represents N(CH
3
)
2
or NO(CH
3
)
2
, and - - - line represents a single or a double bond, with the proviso that R
3
represents N(CH
3
)
2
when - - - line represents a single bond;
and to a process for their preparation.
PRIOR ART
It is known that 13-hydroxy derivatives of tylosin have been prepared by the reductive opening of the oxirane ring of 12,13-epoxy tylosin derivative, followed by catalytic hydrogenation, oximation or hydrolysis reactions (A.Narandja, SI 9700281).
According to the known prior art, the introduction of a second hydroxyl group and the formation of a vicinal diol have not been described as yet, therefore 12,13-dihydroxy derivatives of tylosin represent novel, hitherto not described compounds, which is also true of processes for their preparation.
TECHNICAL SOLUTION
It has been found that 12,13-dihydroxy tylosin derivatives of the formula
wherein
R represents O, R
1
represents CHO, CH═NOH or CH(OCH
3
)
2
, R
2
represents H or mycarosyl, R
3
represents N(CH
3
)
2
or NO(CH
3
)
2
, and - - - line represents a single or a double bond, with the proviso that R
3
represents N(CH
3
)
2
when - - - line represents a single bond;
wherein
R represents NOH, R
1
represents CHO or CH(OCH
3
)
2
, R
2
represents H or mycarosyl,
R
3
represents N(CH
3
)
2
or NO(CH
3
)
2
, and - - - line represents a single or a double bond, with the proviso that R
3
represents N(CH
3
)
2
when - - - line represents a single bond;
can be prepared by subjecting a compound of the formula (II)
wherein R represents H or mycarosyl, dissolved in a halogenated hydrocarbon, preferably in methylene chloride, to an oxidation reaction with 3 to 8 equivalents of m-chloroperbenzoic acid within 6 to 20 hours at room temperature, whereupon, optionally,
a compound of formula I, wherein
R represents O, R
1
represents CH(OCH
3
)
2
, R
2
represents H or mycarosyl, R
3
represents NO(CH
3
)
2
, and - - - line represents a double bond, is subjected:
A/ to a reduction of N-oxide with Zn-powder in a mixture of lower C
1
-C
3
-aliphatic alcohol and water under the addition of 3-5% w/v of ammonium chloride at a pH value of 2 to 7, preferably in the range of 5.0 to 5.5 at room temperature within 3 to 6 hours,
or optionally
B/ to a reduction of N-oxide and C
10
-C
11
double bond
B1/ by a catalytic hydrogenation process in an organic solvent, preferably in a lower C
1
-C
3
aliphatic alcohol in the presence of 2 to 5% w/w palladium on charcoal at a hydrogen pressure of 0.2 to 0.5 MPa at room temperature within 5 to 8 hours;
or optionally
B2/ by an electrochemical reduction process in an electrochemical cell with separate anode and cathode compartments, wherein there are used a Hg-basin as a working electrode (cathode), graphite as a counter electrode and a saturated calomel electrode as a reference electrode, in a phosphate buffer (pH=5.4) at a constant potential of −1.4 V towards the saturated calomel electrode at room temperature within 40 minutes and a charge waste of 80 C;
or optionally,
C/ to an oximation reaction with 1 to 8 equivalents of hydroxylamine hydrochloride in pyridine or a lower C
1
-C
3
aliphatic alcohol under the addition of a base (pyridine or Na
2
CO
3
) in a nitrogen stream at room temperature or reflux temperature within 1 to 10 hours,
or optionally,
a compound of formula (I), wherein R represents NOH, R
1
represents CH(OCH
3
)
2
, R
2
represents H or mycarosyl, R
3
represents NO(CH
3
)
2
, and - - - line represents a double bond, is subjected to the reduction of N-oxide according to process A, or optionally, to the reduction of N-oxide and the double bond by the catalytic hydrogenation as described under B1,
or optionally,
a compound of the formula (I), wherein R represents O, R
1
represents CH(OCH
3
)
2
, R
2
represents H or mycarosyl, R
3
represents N(CH
3
)
2
, and - - - line represents a single or a double bond, is subjected to the oximation reaction as described under C,
or optionally,
a compound of formula (I), wherein R represents NOH, R
1
represents CH(OCH
3
)
2
, R
2
represents H or mycarosyl, R
3
represents N(CH
3
)
2
, and - - - line represents a single or a double bond, is subjected to hydrolysis in a mixture of acetonitrile and 0.2 N HCl (2:1) or of acetonitrile and 1% aqueous solution of trifluoroacetic acid (1:2) at room temperature within 2 hours,
or optionally,
a compound of formula (I), wherein R represents O, R
1
represents CHO, R
2
represents H or mycarosyl, R
3
represents N(CH
3
)
2
, and - - - line represents a single or a double bond, is subjected to the oximation reaction as described under C.
According to the present invention the novel compounds are isolated by conventional extraction processes from aqueous alkaline solutions by the use of halogenated hydrocarbons such as methylene chloride, chloroform or tetrachloromethane, and by evaporation to a dry residue.
The reaction course is followed by chromatography on thin layer of silica gel (Merck 60 F
254
) in a solvent system: methylene chloride-methanol-ammonium hydroxide 25% (90:9:1.5, system E), (90:9:0.5, system E1) or chloroform-methanol-ammonium hydroxide 25% (95:15:1.5, system AJ). If appropriate, the separation of the reaction products and the purification of the products for the purpose of spectral analyses are performed on a silica gel column (Merck 60, 230-400 mesh/ASTM, or 60-230 mesh/ASTM in solvent system E, E1 or AJ). The identification of the novel compounds is performed by UV and NMR spectroscopies and by mass analysis.
The novel compounds show antibacterial activity, but can also be used as intermediates for the preparation of new derivatives.


REFERENCES:
patent: 5688924 (1997-11-01), Narandja et al.

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