Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-01-26
2002-12-03
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S307000, C540S312000
Reexamination Certificate
active
06489316
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to 6-(spirocyclopropyl)-penicillanic acid 4,4-dioxides and non-toxic pharmaceutically acceptable salts thereof, useful as beta-lactamase inhibitors. The present 6-(spirocyclopropyl)-penicillanic acid 4,4-dioxides and pharmaceutical compositions thereof are useful as beta-lactamase inhibitors and as beta-lactamase inhibitors in combination with other beta-lactam antibiotics for use in humans and animals. The present invention also provides certain novel intermediates and processes for the preparation of the penicillanic acid 4,4-dioxide beta-lactamase inhibitors.
2. Description of the Prior Art
A well-known and widely used class of antibacterial compounds are the beta-lactam antibiotics. These antibiotics are characterized by the common structural unit, 2-azetidinone (beta-lactam) moiety. When this moiety is fused to a thiazolidone ring, the corresponding compounds are referred to generically as penicillins and when the fused ring is a dihydrothiazine ring, the compounds are referred to as cephalosporins. Typical examples of penicillins include penicillin G, penicillin V, ampicillin and amoxicillin and typical examples of cephalosporins include cefazolin, cephalexin, and cephalothin, all of which are commonly used clinically.
Despite the wide use of the beta-lactam antibiotics as valuable chemotherapeutic agents against pathogenic microorganisms, emerging resistance against beta-lactam antibiotics has limited their application. Pathogenic microorganisms produce beta-lactamase enzymes, which in turn inactivate conventional beta-lactam antibiotics which include penicillins and cephalosporins. Beta-lactamases are enzymes which cleave the beta-lactam ring of penicillins and cephalosporins, causing the antibiotic to lose its antibacterial activity. The use of a beta-lactamase inhibitor in combination with a beta-lactam drug potentiates the effectiveness of the requisite antibiotic against the resistant or partially resistant microorganisms. The principle of potentiation by beta-lactamase inhibitors is discussed by H. C. Neu, “Antibiotic Inhibitors of Bacterial Cell Wall Biosynthesis”, D. T. Tipper ed. Pergaman Press, 1987, pp. 241-259.
The various beta-lactamase enzymes may be categorized according to structural similarities, or biochemical function with respect to their ability to hydrolyze certain beta-lactam antibiotics. Beta-lactamase enzymes of group 1 (class C), group 2 (class A) and group 4 hydrolyze predominantly cephalosporins and/or penicillins by utilizing the amino acid serine at their active site. Beta-lactamases of group 3 (class B) known as metallo-beta-lactamases utilize a metal ion (commonly zinc) as the beta-lactam hydrolyzing functionality. Metallo-beta-lactamases can hydrolyze penicillin, cephalosporin and carbapenem classes of antibiotics. The currently marketed beta-lactamase inhibitors(clavulanic acid, sulbactam, and tazobactam) are clinically effective against class A beta-lactam enzymes. A detailed explanation of the classification of beta-lactamase enzymes is described in K. Bush, G. A. Jacoby, and A. A. Medeiros in “Antimicrobial Agents and Chemotherapy”, Vol. 39, 1995, pages 1211-1233.
Certain spirocyclopropyl penicillanic acid derivatives are disclosed: Sheehan, J. C., Chacko, E., Lo, Y. S., Ponzi, D. R., Sato, E.,
J.Org. Chem.,
43, No 25, 1978, 4856; Campbell, M. M., Harcus, R. G.,
Tetrahedron Letters
, No 16, 1979, 1441; and Arrowsmith, J. E., Greengrass, C. W., Newman, M. J.,
Tetrahedron,
39, 1983, 2469.
The novel 6-(spirocyclopropyl)penicillanic acid 4,4-dioxides of the present invention exhibit broad spectrum inhibitory activity against beta-lactamases of different classes, and in particular inhibitory activity against group 1 (class C) and group 2 (class A).
SUMMARY OF THE INVENTION
The invention relates to novel compounds selected from those of the general Formula (I):
wherein:
R
1
, R
2
, R
3
, and R
4
are independently selected from H, —OH and —OR
6
;
R
5
is selected from hydrogen, an alkali metal cation, an alkaline earth metal cation, ammonium, tetraalkylammonium, alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 12 carbon atoms, aralkyl of 7 to 20 carbon atoms, aryl of 6 to 12 carbon atoms and moieties of the formulae:
R
6
is selected from alkyl of 1 to 12 carbon atoms optionally substituted with alkoxy, halogen, dialkylamino, -Oalkyloalkyl, and 1 or 2 phenyl groups; cycloalkyl of 3 to 10 carbon atoms; alkenyl of 2 to 12 carbon atoms; alkyloxacyclopropyl of 3 to 12 carbon atoms; aryl of 6 to 12 carbon atoms; heteroaryl having 5 or 6 ring atoms; bicyclic heteroaryl having 8 to 20 ring atoms; heteroarylalkyl having 5 or 6 ring atoms; and —SiR
12
R
13
R
14
;
n is an integer of 1 to 3;
R
7
is selected from alkyl of 1 to 12 carbon atoms; cycloalkyl of 3 to 10 carbon atoms; aralkyl of 7 to 20 carbon atoms; and aryl of 6 to 12 carbon atoms;
R
8
, R
9
, R
10
and R
11
are independently selected from alkyl of 1 to 12 carbon atoms;
R
12
R
13
and R
14
are independently selected from alkyl of 1 to 12 carbon atoms optionally substituted with —OCOR
7
, —CO
2
R
7
, alkenyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 10 carbon atoms;and aryl of 6 to 12 carbon atoms; optionally two of R
12
, R
13
, and R
14
taken together with the silicon atom to which they are attached form a cyclic ring of 5 or 6 ring atoms;
provided that at least one of R
1
, R
2
, R
3
, and R
4
is hydrogen;
or a pharmaceutically acceptable salt thereof.
Among the preferred compounds of Formula (I) of this invention are those in the subgroups, and pharmaceutically acceptable salts thereof:
a) R
5
is selected from H, sodium, lithium and potassium;
b) R
5
is selected from aralkyl of 7 to 20 carbon atoms,
c) R
5
is selected from H, Na, Li, K,
R
1
is selected from —OCH
3
, —OCH
2
CH
2
OCH
3
, —OCH
2
CH
2
Cl, —OCH
2
CH
2
N(CH
3
)
2
, —O—cyclohexyl, —OC(CH
3
)
2
CH
2
CH
3
, —OCH═CHCH
3
, —OCH
2
(tetrahydrofuran), —OCH
2
CH
2
OCH
2
CH
2
OCH
2
CH
3
, —OSi(CH
3
)
2
t-butyl, —OSi(CH
3
)
2
phenyl, —OSi(CH
3
)
2
CH
2
CH═CH
2
, —OSi(CH
3
)
2
CH
2
CH
3
, —OSi(CH
3
)
2
-propyl, OSi(CH
3
)
2
CH═CH
2
, —OSi(CH
3
)
2
CH
2
CH
2
OCOCH
3
, —OSi(phenyl)
3
, —OCH
2
CH═CH
2
, —O-t-butyl, —OCH(phenyl)
2
—OSiMe
2
(cyclohexyl)
d) R
6
is selected from alkyl of 1 to 12 carbon atoms optionally substituted with alkoxy, halogen, dialkylamino, -Oalkyloalkyl, and 1 or 2 phenyl groups; cycloalkyl of 3 to 10 carbon atoms; alkenyl of 2 to 12 carbon atoms; alkyloxacyclopropyl of 3 to 12 carbon atoms; aryl of 6 to 12 carbon atoms; heteroaryl having 5 or 6 ring atoms; bicyclic heteroaryl having 8 to 20 ring atoms; heteroarylalkyl having 5 or 6 ring atoms;
e) R
6
is —SiR
12
R
13
R
14
;
Among the more preferred compounds of Formula (I) of this invention are those in the subgroups, and pharmaceutically acceptable salts thereof:
a) R
1
is —OR
6
;
R
2
, R
3
, and R
4
are H;
R
5
is selected from H, Na, Li, K,
b) R
2
is —OR
6
;
R
1
, R
3
, and R
4
are H;
R
5
is selected from H, Na, Li, K,
c) R
3
is —OR
6
;
R
1
, R
2,
and R
4
are H;
R
5
is selected from H, Na, Li, K,
d) R
4
is —OR
6
;
R
1
, R
2
, and R
3
are H;
R
5
is selected from H, Na, Li, K,
e) R
5
is selected from H, Na, Li, K,
R
6
is independently selected from —CH
3
, —CH
2
CH
2
OCH
3
, —CH
2
CH
2
Cl, —CH
2
CH
2
N(CH
3
)
2
, —cyclohexyl,
—C(CH
3
)
2
CH
2
CH
3
, —CH═CHCH
3
, —CH
2
(tetrahydrofuran), —CH
2
CH
2
OCH
2
CH
2
OCH
2
CH
3
, —Si(CH
3
)
2
t-butyl, —Si(CH
3
)
2
phenyl, —Si(CH
3
)
2
CH
2
CH═CH
2
, —Si(CH
3
)
2
CH
2
CH
3
, —Si(CH
3
)
2
i-propyl, —Si(CH
3
)
2
CH═CH
2
, —Si(CH
3
)
2
CH
2
CH
2
OCOCH
3
, —Si(phenyl)
3
, —CH
2
CH═CH
2
, —t-butyl, —CH(phenyl)
2
, —SiMe
2
(cyclohexyl), furanyl, pyrazolyl, thienyl, dihydroindolyl, dihydrooxazolyl, dihydropyrimidinyl, benzofuranyl, imidazolyl, pyridyl, tetrazolyl, triazolyl, piperazinyl, indolyl, oxazolyl, piperidinyl, dihydrobenzimidazolyl, tetrahydrofuranyl, benzoxazolyl, isooxazolyl, pyrrolyl, dihydrotriazolyl, and tetrahydrothienyl
Prashad Amarnauth S.
Sandanayaka Vincent P.
American Cyanamid Company
McKenzie Thomas
Moran Daniel B.
Shah Mukund J.
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