Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-11
2003-09-09
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S320000, C544S321000
Reexamination Certificate
active
06617332
ABSTRACT:
The present invention relates to novel natural product derivatives, to processes for their preparation, to pharmaceutical compositions comprising them and to their use in the treatment of disorders in humans or animals.
EP-A-0339596 discloses antibiotics of the formula
which are obtained by cultivating a microorganism of the genus Flexibacter.
Specifically, this publication also describes the following compounds
in which the carbon atom A has the S configuration (TAN-1057A) or the R configuration (TAN-1057B). Y. Funabashi et al.; Tetrahedron 49, 13, 1993 describe the chemical and structural characterization of TAN-1057A and TAN-1057. B. N. Katayama et al.; J. Antibiotics, 46, 606, 1993 report about the taxonomy of TAN-1057-producing organisms and the biological properties of TAN-1057. Total syntheses of TAN-1057 compounds were published by C. Yuan and R. M. Williams in J. Am. Chem. Soc.; 119, 11777, 1997 and A. de Meijere et al. in Eur. J. Org. Chem. 1998, 777. First derivatives of TAN-1057 compounds were described by R. M. Williams in J. Antibiotics; 51, 189, 1998. However, most of the derivatizations relate to the cyclic amidinourea moiety of the molecule. Thus, for example, derivatives of the type
in which R represents Ac, COPh, COOMe, SO
2
Me and CO
2
CH
2
Ph are described.
WO 99/07685, which was published after the date of priority of the present application, discloses derivatives, acylated at the cyclic amidinourea moiety of the molecule and additionally phosphorylated, of the general formula:
in which R
2
represents
Only two derivatizations (J. Antibiotics; 51, 189, 1998) relate to the (S)-&bgr;-homoarginine moiety:
However, these derivatizations resulted in a complete loss of biological activity.
It was the object of the inventors of the present invention to synthesize further derivatives of the TAN-1057 compounds to investigate their biological and/or pharmacological actions. After overcoming difficult synthetic problems, the inventors succeeded in synthesizing further novel compounds which are derivatized in the (S)-&bgr;-homoarginine moiety of TAN 1057, using a novel, generally applicable process, which compounds, surprisingly, have considerably lower toxicity, with comparable activity.
Accordingly, the present invention provides compounds of the general formula:
in which
R
1
represents hydrogen or (C
1
-C
6
)alkyl,
X represents a group of the formula —(CH
2
)
m
—, in which m is 0, 1 or 2,
D is selected from groups of the formulae D
1
to D
3
in which R
2
represents hydrogen or hydroxyl,
R
3
represents hydrogen, or
R
2
and R
3
together form an oxo group,
Y represents a straight-chain or branched (C
1
-C
5
)alkanediyl group in which optionally one carbon atom may be replaced by —O— or —NH— and which may optionally be substituted by hydroxyl or oxo, or represents a group of the formulae below
in which r and s are identical or different and are 0, 1 or 2,
Z represents a group selected from groups of the formulae
in which R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
, R
17
, R
18
and R
19
in each case independently of one another are selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
4
)alkanoyl, t-butoxycarbonyl, benzyloxycarbonyl and benzyl,
Q represents oxygen or sulphur and
pis 1, 2 or 3 and
Het represents a 5- or 6-membered heteroaromatic group having 1 to 4 nitrogen atoms,
except for compounds in which
R
1
represents methyl, m is 1, D represents D
1
, Y represents —(CH
2
)
3
— and Z represents a group of the formula
and pharmaceutically acceptable salts thereof.
The case corresponding to TAN 1057A/B, in which R
1
represents methyl, m is 1, D represents D
1
, Y represents —(CH
2
)
3
— and Z represents a group of the formula
which is excluded from the compounds claimed according to the invention, corresponds to the case in which D represents D
2
, R
2
and R
3
represent hydrogen, R represents methyl, m is 1, Y represents —(CH
2
)
2
— and Z represents a group of the formula
which, as a consequence, is likewise excluded from the compounds according to the invention.
The present invention preferably provides compounds of the general formula:
in which R
1
represents hydrogen or (C
1
-C
6
)alkyl,
X represents a group of the formula —(CH
2
)
m
—, in which m is 0, 1 or 2,
D is selected from groups of the formulae D
1
to D
3
in which R
2
represents hydrogen or hydroxyl,
R
3
represents hydrogen, or
R
2
and R
3
together form an oxo group,
Y represents a straight-chain or branched (C
1
-C
5
)alkanediyl group in which optionally one carbon atom may be replaced by —O— or —NH— and which may optionally be substituted by hydroxyl or oxo, or represents a group of the formulae below
in which r and s are identical or different and are 0, 1 or 2,
Z represents a group selected from groups of the formulae
in which R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
, R
17
, R
18
and R
19
in each case independently of one another are selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
4
)alkanoyl, t-butoxycarbonyl, benzyloxycarbonyl and benzyl,
Q represents oxygen or sulphur and
p is 1, 2 or 3 and
Het represents a 5- or 6-membered heteroaromatic group having 1 to 4 nitrogen atoms,
except for compounds in which
R
1
represents methyl, m is 1, D represents D
1
, Y represents —(CH
2
)
3
— and Z represents a group of the formula
(corresponds to the case in which D represents D
2
, R
2
and R
3
represent hydrogen, R
1
represents methyl, m is 1, Y represents —(CH
2
)
2
— and Z represents a group of the formula
and pharmaceutically acceptable salts thereof.
m in the group of the formula —(CH
2
)
m
— for X is preferably 1 or 2. Accordingly, the group of the formula —(CH
2
)
m
— for X preferably includes a methylene or an ethylene (ethane-1,2-diyl) group. X is particularly preferably a methylene group.
A straight-chain or branched (C
1
-C
5
)alkanediyl group in which optionally one carbon atom may be replaced by —O— or —NH— and which, additionally, may optionally be substituted by hydroxyl or oxo, in the definition of Y includes, for example, straight-chain (C
1
-C
5
)alkanediyl groups, such as methylene, ethylene, propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl. Preference is given to straight-chain (C
1
-C
4
)alkanediyl groups.
A straight-chain or branched (C
1
-C
5
)alkanediyl group in which one carbon atom is replaced by —O— or —NH— and which, additionally, may optionally be substituted by hydroxyl or oxo, in the definition of Y includes, for example, groups of the formulae:
Here, either side of the groups may be attached to Z.
The groups of the formulae
for Y include, for example, symmetrical radicals in which r and s are identical, or asymmetrical radicals; symmetrical radicals in which r and s are 0, i.e. 1,2-phenylene, 1,3-phenylene and 1,4-phenylene, being preferred. Particular preference is given to 1,3- or m-phenylene.
In the general formula (I), Z is selected from groups of the formulae
in which R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
, R
17
, R
18
and R
19
in each case independently of one another are selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
4
)alkanoyl, t-butoxycarbonyl, benzyloxycarbonyl and benzyl,
Q represents oxygen or sulphur and
p is 1, 2, or 3 and
Het represents a 5- or 6-membered heteroaromatic group having 1 to 4 nitrogen atoms.
Among these groups for Z
R
4
, R
5
, R
6
, R
7
and R
17
are as defined above are preferred.
Z is particularly preferably a group of the formula
in which R
4
, R
5
, R
6
and R
7
are as defined above, preferably hydrogen.
In the group of the formula
for Z, Het is advantageously selected from the group consisting of the group of the formulae:
Here, the azoles, i.e. the five-membered unsaturated heterocyclic ring systems having 1 to 4 nitrogen atoms, can be attached either via a carbon or via a nitrogen atom.
Among these radicals, six-memb
Belov Vladimir N.
Brands Michael
de Meijere Armin
Endermann Rainer
Es-Sayed Mazen
Bayer Aktiengesellschaft
Kahsay H
Raymond Richard L.
LandOfFree
Tan-1057 derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Tan-1057 derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Tan-1057 derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3058271