Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-04-06
2001-10-02
Berch, Mark L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S350000
Reexamination Certificate
active
06297231
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a novel stabilized form of carbapenem antibiotics, compositions and methods thereof. The compounds can be used in the treatment of infectious diseases, including gram positive and negative, aerobic and anaerobic bacteria. The compounds provide good stability against beta-lactamases, and a favorable duration of action.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1
illustrates the stabilization of carbapenem, Compound A at 5° C. A plot of % dimers versus time for Compound A in the presence of sodium carbonate and sodium hydroxide is provided. The plot of % dimers formed versus time in the presence of sodium carbonate exhibits about 5% dimer formation after about 8 hours at a pH of 7.5.
SUMMARY OF THE INVENTION
The present invention relates to a novel stabilized compound of formula I:
or a pharmaceutically acceptable salt, prodrug or hydrate thereof, wherein:
B is selected from a group consisting of H, CN,
substituted or unsubstituted, straight or branch chain, bivalent C
1-6
alkyl, C
2-6
alkenyl, C
3-6
cycloalkyl or C
1-6
alkyl-X—C
1-6
alkyl wherein X is O, S, NH, or N(C
1-6
alkyl), wherein said alkyl, alkenyl and alkenyl is optionally substituted with 1 to 3 groups selected from the group consisting of
or R
2
,
X is selected from the group consisting of O or NH,
R
3
is selected from the group consisting of amino or heterocyclic amine group, each of which can be unsubstituted or substituted with
unsubstituted or substituted heterocyclic group, C
1-6
alkyl, aryl, heteroaryl, hydroxy(C
1-6
)alkyl, carbamoyloxy(C
1-6
)alkyl,
R
4
and R
5
independently are selected from the group consisting of H, hydroxy(C
1-6
)alkyl, CN, amino, carbamoyl, carbamoyl(C
1-6
)alkyl, cyano(C
1-6
)alkyl, mono- or di-(C
1-6
)alkylcarbamoyl, carbamoyloxy, ureido, amino(C
1-6
)alkyl, carbamoyloxy(C
1-6
)alkyl, mono- or di-(C
1-6
)alkylcarbamoyl-(C
1-6
)alkyl, ureido(C
1-6
)alkyl,
and
wherein
is an unsubstituted or substituted 3 to 6 membered heterocyclic ring which can contain additional hetero atoms, with the proviso that R
4
and R
5
cannot be hydrogen at the same time,
R
2
is selected from the group consisting of hydroxy(C
1-6
)alkyl, carbamoyloxy, OH, NR
6
SO
2
R
6
, N(R
6
)
2
,
R
6
is selected from the group consisting of hydrogen or C1-6 alkyl,
R
20
and R
21
are independently selected from the group consisting of H, C
1-5
alkyl, C
3-5
alkenyl, aralkyl group having 1 to 3 carbon atoms in its alkyl moiety, a substituted C
1-5
alkyl, pyridyl or R
20
and R
21
are taken together to represent an alkylene chain or alkylene chain via an oxygen atom, a sulfur atom or a (C2-C3)alkyl-substituted nitrogen atom to form, together with the adjacent nitrogen atom a substituted or unsubstituted 3 to 7 membered cyclic amino group which may contain double bond(s) in its ring, a substituted or unsubstituted guanidyl group of the formula
R
7
is selected from the group consisting of hydrogen, C
1-6
alkyl, a protected or unprotected OH group, a C
1-6
alkoxy, an unsubstituted or (C1-3)alkyl-substituted hydrazino group or a group of the formula —NHOR
8
wherein R8 is a hydrogen atom, a protecting group for a hydroxyl group or a C
1-6
alkyl,
R1 is selected from the group consisting of H or C
1-6
alkyl.
The compounds are distinctly more stable than carbapenem compounds such as meropenem with respect to intermolecular dimerization degradation (See Takeuchi et al.,
Chem. Pharm. Bull
. 43(4), 689-692 (1995), regarding degradates of meropenem) See also Kim, S H et al., Res. Com. Mol. Path. & Pharm., 90(3), 347-362 (1995), regarding DA-1131; lnoue K. et al., Antimicro. Agts & Chemo., 39(10), 2331-2336 (1995), regarding BO-2727 and Lee H. W. et al., J. Antibiotics, 48(9), 1046-1048 (1995). The compounds can be used in the treatment of infectious diseases, including gram positive and negative, aerobic and anaerobic bacteria. The compounds provide good stability against beta-lactamases, and a favorable duration of action. Compound I is a carbapenem antibiotic that is particularly useful for intravenous and intramuscular administration.
REFERENCES:
patent: 4943569 (1990-07-01), Sunagawa
patent: 0 007 614 (1980-02-01), None
patent: 0 072 014 (1983-02-01), None
patent: WO 94/14811 (1994-07-01), None
Y. Takeuchi et al.,Chem. Pharm.. Bull., 43(4), pp. 689-692 (1995).
S. H. Kim et al.,Res. Com.. Mol. Path. & Pharm., 90(3), pp. 347-362 (1995).
K. Inque et al.,Antimicro. Agts., &Chemo., 39(10), pp. 2331-2336 (1995).
H-W. Lee, et al.,J. Antibiotics, 48(9), pp. 1046-1048 (1995).
N.Ohtake et al.,J. Antibiotics, 50(7); pp. 598-613 (1997).
C-H Oh et al.,J. Antibiotics, 47(1); pp. 126-128 (1994).
Y. Iso et al., J.Antibiotics,49(2); pp. 199-209 (1996).
Almarsson Orn
Kaufman Michael J.
Stong John D.
Williams John M.
Ayler Sylvia A.
Berch Mark L.
Daniel Mark R.
Merck & Co. , Inc.
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