3-deoxy-desmycosin derivatives and process for their...

Details 3-deoxy-desmycosin derivatives and process for their... 3-deoxy-desmycosin derivatives and process for their...

2002-01-28

2003-01-07

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S263000, C549S267000, C549S268000, C536S002000

Reexamination Certificate

active

06504035

ABSTRACT:

TECHNICAL FIELD
International Patent Classification: A 61 K 31/70, C 07 H 17/08
TECHNICAL PROBLEM
The present invention relates to new tylosin derivatives, new synthetic products of the macrolide class exhibiting antimicrobial activity. It particularly relates to 3-deoxy-3-oxo-desmycosin derivatives of the formula (I)
wherein
R represents CHO or CH(OCH
3
)
2
, R
1
and R
2
represent H or acetyl, R
3
represents H or OH, R
4
represents N(CH
3
)
2
or N—O(CH
3
)
2
, the line - - - represents a single or a double bond, the line . . . represents
or a double or a single bond, and the line
represents a double or a single bond, and to derivatives of 3-deoxy-2,3-didehydro-desmycosin of the formula II
wherein
R represents CHO or CH(OCH
3
)
2
, R
1
represents H or OH, R
2
represents N(CH
3
)
2
or N—O(CH
3
)
2
, the line - - - represents a double or a single bond, the line . . . represents
or a single bond, and the
line represents a double or a single bond, and to a process for the preparation thereof.
PRIOR ART
It is known that 13-hydroxy derivatives of tylosin have been prepared by a reductive opening of the oxirane ring (A. Narandja, SI 9700281). It is also known that 10,11,12,13-tetrahydro derivatives of tylosin have been prepared by catalytic hydrogenation of tylosin (A. Narandja, EP 287082 B3). It is also known that 3-deoxy-2,3-didehydro derivatives of tylosin (S. Kageyama, Bull. Chem. Jpn. 65, 3405,1992) as well as 3-deoxy-3-oxo derivatives of 6-O-methyl-erythromycin (A. Agouridas, J. Med. Chem. 41, 4080, 1998) have been prepared.
According to the known prior art, however, neither 3-deoxy-3oxo-derivatives of tylosin class nor 3-deoxy-2,3-didehydro derivatives with exchanged left side of the molecule in C-10 to C-13 positions and processes for the preparation thereof have been described so far.
TECHNICAL SOLUTION
It has been found that derivatives of 3-deoxy-3-oxo-desmycosin of the formula I
wherein
R represents CHO or CH(OCH
3
)
2
, R
1
and R
2
represent H or acetyl, R
3
represents H or OH, R
4
represents N(CH
3
)
2
or N—O(CH
3
)
2
, the line - - - represents a single or a double bond, the line . . . represents
or a double or a single bond, and the line
represents a double or a single bond, and 3-deoxy-2,3-didehydro-derivatives of the formula II
wherein
R represents CHO or CH(OCH
3
)
2
, R
1
represents H or OH, R
2
represents N(CH
3
)
2
or N—O(CH
3
)
2
, the line - - - represents a double or a single bond, the line . . . represents
or a single bond, and the line
represents a double or a single bond, can be prepared starting from a compound of the formula III
wherein R represents H or SO
2
CH
3
and the line - - - represents a double or a single bond.
According to the present invention the compound of formula III, wherein R represents H and the line - - - represents a double bond, is subjected
A/ to an oxidation reaction in a solution of methylene chloride in the presence of 15-28 equivalents of DMSO, 8-14 equivalents of N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide hydrochloride and 8-14 equivalents of pyridine trifluoroacetate within 2-6 hours at a temperature of 10-25° C., whereupon the obtained compound of the formula I, wherein R represents CH(OCH
3
)
2
, R
1
and R
2
represent acetyl, R
3
represents H, R
4
represents N(CH
3
)
2
, the lines - - - and . . . represent double bonds and the line
represents a single bond,
is optionally subjected
B/ to a methanolysis at reflux temperature within 4-6 hours and the obtained compound of the formula I, wherein R represents CH(OCH
3
)
2
, R
1
and R
3
represent H, R
2
represents acetyl, R
4
represents N(CH
3
)
2
, the lines - - - and . . . represent double bonds and the line
represents a single bond,
is optionally subjected
B1/ to an alkaline methanolysis in a mixture of methanol and 25% NH
4
OH (2:1) at 5° C. for a period of 48-60 hours, whereupon the obtained compound of the formula I wherein R represents CH(OCH
3
)
2
, R
1
, R
2
and R
3
represent H, R
4
represents N(CH
3
)
2
, the lines - - - and . . . represent double bonds and the line
represents a single bond,
is optionally subjected
B2/ to a hydrolysis in a mixture of acetonitrile and 1% trifluoroacetic acid (2:3) within 2 hours at room temperature, giving a compound of the formula I, wherein R represents CHO, R
1
, R
2
and R
3
represent H, R
4
represents N(CH
3
)
2
, the lines - - - and . . . represent double bonds and the line
represents a single bond,
or optionally,
a compound of the formula I, wherein R represents CH(OCH
3
)
2
, R
1
and R
2
represent acetyl, R
3
represents H and R
4
represents N(CH
3
)
2
, the lines - - - and . . . represent double bonds and the line
represents a single bond,
is subjected
C/ to a catalytic hydrogenation reaction in the presence of 2-5% Pd/C (w/w) at room temperature within 5-8 hours at a hydrogen pressure of 0.3-0.5 MPa, whereupon the obtained compound of the formula I, wherein R represents CH(OCH
3
)
2
, R
1
and R
2
represent acetyl, R
3
represents H, R
4
represents N(CH
3
)
2
, and the lines - - - , . . . and
represent single bonds, can be optionally subjected to methanolysis or alkaline methanolysis reactions in the manner described under B or B1;
or optionally, it is subjected
D/ to an oxidation reaction in a methylene chloride solution in the presence of 3-6 equivalents of m-chloroperbenzoic acid within 6-10 hours at room temperature, giving a compound of the formula I, wherein R represents CH(OCH
3
)
2
, R
1
and R
2
represent acetyl, R
3
represents H, R
4
represents N—O(CH
3
)
2
, the line - - - represents a double bond, the line . . . represents
and the line
represents a single bond,
or optionally,
a compound of the formula I, wherein R represents CH(OCH
3
)
2
, R
1
and R
3
represent H, R
2
represents acetyl, R
4
represents N—(CH
3
)
2
, the lines - - - and . . . represent double bonds and the line
represents a single bond, is subjected to the oxidation reaction in the manner described under D, and the obtained compound of the formula I, wherein R represents CH(OCH
3
)
2
, R
1
and R
3
represent H, R
2
represents acetyl, R
4
represents N—O(CH
3
)
2
, the line - - - represents a double bond, the line . . . represents
and the line
represents a single bond,
is optionally subjected
to the catalytic hydrogenation reaction in the manner described under C, giving a compound of the formula I, wherein R represents CH(OCH
3
)
2
, R
1
and R
3
represent H, R
2
represents acetyl, R
4
represents N(CH
3
)
2
, the line - - - represents a single bond, the line . . . represents
and the line
represents a single bond,
is optionally subjected
E/ to a reduction reaction with Zn-powder in a solution of EtOH and a 10% aqueous NH
4
OH solution (1:2) under maintaining the pH-value of 5.0-5.5, giving a compound of the formula I, wherein R represents CH(OCH
3
)
2
, R
1
represents H, R
2
represents acetyl, R
3
represents OH, R
4
represents N(CH
3
)
2
, the lines - - - and . . . represent single bonds and the line
represents a double bond,
or optionally,
a compound of the formula I, wherein R represents CH(OCH
3
)
2
, R
1
, R
2
and R
3
represent H, R
4
represents N(CH
3
)
2
, the lines - - - and . . . represent double bonds and the line
represents a single bond, is subjected to the oxidation reaction in the manner described under D, and the obtained compound of the formula I, wherein R represents CH(OCH
3
)
2
, R
1
, R
2
and R
3
represent H, R
4
represents N—O(CH
3
)
2
, the line - - - represents a double bond, the line . . . represents
and the line
represents a single bond,
is optionally subjected
to the catalytic hydrogenation reaction in the manner described under C, giving a compound of the formula I, wherein R represents CH(OCH
3
)
2
, R
1
, R
2
and R
3
represent H, R
4
represents N(CH
3
)
2
, the line - - - represents a single bond, the line . . . represents
and the line
represents a single bond,
or optionally,
to the reduction with Zn-powder in the manner described under E, giving a compound of the formula I, wherein R represents CH

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