Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-10-26
2003-10-07
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C560S076000, C560S155000, C560S171000, C560S190000, C546S235000, C546S349000, C548S300100
Reexamination Certificate
active
06630510
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to compounds which have metallo-&bgr;-lactamase inhibitory characteristics. The invention also relates to methods of preparing, pharmaceutical compositions and uses of the compounds.
Metallo-&bgr;-lactamases are bacterial enzymes which confer resistance to virtually all clinically relevant &bgr;-lactam antibiotics, including carbapenems and jeopardize the future use of all such agents. The increased treatment of infections with carbapenems and other &bgr;-lactam antibiotics may lead to the proliferation of clinical bacterial strains which are able to produce metallo-&bgr;-lactamases and thus resist the effects of &bgr;-lactam antibiotics. In fact, metallo-&bgr;-lactamases have now been identified in a number of pathogenic bacterial species including
Bacillus cereus, Bacteroides fragilis, Aeromonas hydrophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Serratia marcescens, Stenotrophomonas maltophilia, Shigella flexneri, Legionella gormanii, Chryseobacterium meningosepticum, Chryseobacterium indologenes, Acinetobacter baumannii, Citrobacter freundii
, and
Aeromonas veronii.
Accordingly, there is an increasing need for agents which when combined with a &bgr;-lactam antibiotic, e.g. imipenem, will restore the effectiveness of the &bgr;-lactam antibiotics and which are at the same time relatively free from undesirable side effects.
WO 98/17639, 97/30027, 98/40056, 98/39311 and 97/10225 teach certain beta-thiopropionyl-amino acid derivatives and their use as inhibitory agents against metallo-&bgr;-lactamases. Goto et. al.,
Biol. Pharm. Bull.
20, 1136 (1997), Payne et. al.,
FEMS Microbiology Letters
157, 171 (1997), Payne et al.,
Antimicrob. Agents Chemother.
41, 135 (1997), Page et. al.,
Chem. Commun.
1609 (1998) and Page et al.,
Biochem. J.
331, 703 (1998) also disclose certain thiols and thioesters as metallo-&bgr;-lactamase inhibitors. Additionally, Toney et al.,
Chemistry and Biology
5, 185 (1998), Fastrez et al.,
Tetrahedron Lett.
36, 9313 (1995), Schofield et al.,
Tetrahedron
53, 7275 (1997), Schofield et. al.,
Bioorg. & Med. Chem. Lett.
6, 2455 (1996) and WO 97/19681 disclose other metallo-&bgr;-lactamase inhibitors. However, the above noted references do not teach the compounds of the instant invention.
Other references which disclosed the general state of the art are Bush et al.,
Antimicrob. Agents Chemother.
41, 223 (1997); Livermore, D. M.
J. Antimicrob. Chemother.
1998, 41 (Suppl. D), 25; Bush, K.
Clin. Infect. Dis.
1998, 27 (Suppl 1), S48; Livermore, D. M.
J. Antimicrob. Chemother.
1997, 39, 673 and Payne, D. J.
J. Med. Microbiol.
1993, 39, 93.
SUMMARY OF THE INVENTION
This invention relates to novel substituted succinic acid metallo-&bgr;-lactamase inhibitors, which are useful potentiators of &bgr;-lactam antibiotics. Accordingly, the present invention provides a method of treating bacterial infections in animals or humans which comprises administering, together with a &bgr;-lactam antibiotic, a therapeutically effective amount of a compound of formula I:
including pharmaceutically acceptable salts, prodrugs, anhydrides, and solvates thereof, wherein:
M
1
and M
2
are independently selected from:
(a) Hydrogen,
(b) Pharmaceutically acceptable cation,
(c) Pharmaceutically acceptable esterifying group; and
(d) A negative charge;
R
1
and R
2
are independently selected from the following:
(a) Hydrogen, provided that R
1
and R
2
are not hydrogen at the same time;
(b) a C
1
to C
16
straight, branched or unsaturated alkyl group substituted with 0 to 2 R
q
groups and substituted with 0 to 3 R
x
groups and optionally interrupted by one of the following O, S, SO
2
, —C(O)—,
(c) —C(O)—NR
a
—, —CO
2
—;
(c) a group of the formula:
wherein
—A— represents a single bond, C
1
to C
8
straight, branched or unsaturated alkyl group optionally substituted with 1 to 2 R
x
groups and optionally interrupted by one of the following O, S, SO
2
, —C(O)—, —C(O)—NR
a
—, —CO
2
—;
represents:
(1) a C
6
to C
14
aryl group;
(2) a C
3
to C
10
alicyclic group;
(3) a C
3
to C
14
heteroaryl group, which contains 1 to 3 heteroatoms, 0 to 3 of which heteroatoms are nitrogen and 0 to 1 of which are oxygen or sulfur;
(4) a C
3
to C
10
heterocyclic group, which contains 1 to 2 heteroatoms, 0 to 1 of which heteroatoms are nitrogen, and 0 to 2 of which are oxygen or sulfur; or
(d) a group of the formula:
wherein:
—A— is as defined above;
A′ is a single bond, O, S, or a C
1
to C
6
straight, branched or unsaturated alkyl group optionally substituted with 1-2 R
x
groups and optionally interrupted by one of the following groups O, S, SO
2
, —C(O)—, —C(O)—NR
a
—, —CO
2
—;
are independently selected from:
(1) a C
6
to C
10
aryl group;
(2) a C
3
to C
8
alicyclic group;
(3) a C
2
to C
9
heteroaryl group, which contains 1 to 3 heteroatoms, 0 to 3 of which heteroatoms are nitrogen and 0 to 1 of which are oxygen or sulfur;
(4) a C
3
to C
8
heterocyclic group, which contains 1 to 2 heteroatoms, 0 to 1 of which heteroatoms are nitrogen, and 0 to 2 of which are oxygen or sulfur;
provided that at least one R
q
group is present in R
1
or R
2
and that when more than one R
q
is present the total number of cationic nitrogen atoms does not exceed 8; the total number of cationic nitrogen atoms can be charged balanced by M
1
and/or M
2
or by M
1
and/or M
2
in combination with an appropriate number of Y
−
; wherein:
R
q
is —E—Q
+
Y
−
;
Y
−
is a pharmaceutically acceptable anionic group;
E is —(CH
2
)
m
—X—(CH
2
)
n
—;
m is 0 to 6;
n is 0 to 6 (but when E is attached to an aromatic ring n is 1-6);
X is a bond, O, S, SO
2
, —C(O)—, —C(O)—N(R
a
)—, —C(O)O—, —CH═CH— or —C≡C—, provided that when X is O, S, —C(O)—N(R
a
)— or —C(O)O—, then n is 2 to 6
and Q
+
, attached to the (CH
2
)
n
terminus of E is:
(1) a cationic group selected from the following:
wherein:
R
u
and R
v
are independently hydrogen or C
1-6
alkyl optionally substituted with 1 to 2 R
y
;
R
w
is hydrogen or C
1-6
alkyl optionally substituted with 1 to 2 R
x
;
R
u
and R
v
when bonded to the same nitrogen atom may together be a C
3-6
alkyl radical, which when taken together with the intervening atoms form a ring;
Two R
u
groups on separate nitrogen atoms may together comprise a C
2-5
alkyl radical, which when taken together with the intervening atoms form a ring;
R
u
, R
v
and R
w
when bonded to the same nitrogen atom may together form a C
6-10
tertiary alkyl radical, which with N
+
forms a bicyclic ring;
(2) A dicationic group:
wherein:
E
1
is —(CH
2
)
p
—Z—(CH
2
)
r
—;
p and r are independently 1 to 4;
Z is a bond, O, S, SO
2
, —C(O)—, —C(O)O—**, —CH═CH—, —C≡C—, or
Provided that when Z is O or S, p is 2 to 4 and r is 2 to 4 and when Z is
or —C(O)O—**, r is 2 to 4;
wherein ** denotes the atom which is bonded to the —(CH
2
)
r
— moiety of E
1
above;
Q
1
is selected from the following:
Q
2
is selected from the following:
R
u
, R
v
and R
w
are independently selected and defined as above,
And in addition, in the case where two R
u
groups on separate nitrogen atoms are joined to form a ring as defined above, two R
v
groups on the same two separate nitrogen atoms may also comprise a C
1-5
alkyl radical to form together with the intervening atoms a bicyclic ring; an example of such is:
(3) A tricationic group selected from the following:
wherein:
Each E
1
is as defined above, but selected independently;
Each Q
1
is as defined above, but selected independently;
Each Q
2
is as defined above, but selected independently;
R
u
, R
v
and R
w
are defined as in the definition of Q
+
item (2) above and selected independently; or
(4) A tetracationic group selected from the following:
wherein:
Each E
1
is as defined above, but selected independently;
Each Q
1
is as defined above, but selected independently;
Each Q
2
is as defined above, but selected independently;
R
u
, R
v
and R
w
are defined as in the defin
Balkovec James M.
Greenlee Mark L.
Olson Steven H.
Rouen Gregory P.
Ayler Sylvia A.
Balasubramanian Venkataraman
Camara Valerie J.
Daniel Mark R.
Merck & Co. , Inc.
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