B-lactam-like chaperone inhibitors

Details B-lactam-like chaperone inhibitors B-lactam-like chaperone inhibitors

1999-02-19

2002-12-17

Berch, Mark L (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S194000, C514S195000, C514S197000, C540S205000, C540S301000, C540S302000, C540S310000, C540S347000, C540S215000, C548S201000, C436S547000, C435S091500, C435S091500

Reexamination Certificate

active

06495539

ABSTRACT:

TECHNICAL FIELD
The invention relates to antibiotics. Novel &bgr;-lactams of the invention and compositions containing them inhibit or prevent bacterial growth and/or attachment to host tissue.
BACKGROUND ART
&bgr;-Lactam antibiotics, such as the penicillins, are known in the art. As use of these and other antibiotics has become more prevalent, resistant strains of bacteria have emerged and the need to develop new antibiotics has become apparent. The present invention is directed to a novel class of &bgr;-lactam compounds which are effective against bacterial infection, colonization and/or growth in any environment in which such prevention or inhibition is desirable.
Periplasmic chaperones are required for assembly of virulence associated pili in pathogenic, gram-negative bacteria. Pili occur on the surface of these bacteria and allow the bacteria to colonize host tissue and give rise to infections. The pili are protein fibers that present adhesions that attach to receptors that are found in the host.
The development of compounds that interfere with bacterial protein secretions constitutes an attractive approach to overcome wide-spread bacterial resistance to existing antibiotics.
The contents of all publications and U.S. patents and patent applications referred to hereinafter are hereby incorporated by reference to the extent necessary to understand or complete the disclosure of the present invention and to the same extent as though each were individually so incorporated.
DISCLOSURE OF THE INVENTION
The invention is directed generally to compounds of the formula
and the salts, esters and amides thereof
wherein Z
is S, SO, SO
2
or O;
each of R
1
, R
2
and R
3
is independently h or substituted or unsubstituted alkyl (1-10C), substituted or unsubstituted acyl (2-11C), substituted or unsubstituted aryl (6-14C), substituted or unsubstituted arylcarbonyl (7-15C), substituted or unsubstituted arylalkyl (7-15C) wherein substituents on any alkyl or acyl moiety are selected from the group consisting of halo and RO, wherein R is H or alkyl (1-6C), and any substituents on any aryl moiety are selected from the group consisting of halo, —CN, CF
3
and RO, where R is H or alkyl with the proviso that R
1
cannot be H and R
1
and R
3
are not identical
wherein in formula (1), the B ring may contain one double bond that is located between positions 2 and 3, in formula (2), the B ring may contain one double bond that can be located between positions 2 and 3 or positions 3 and 4.
The A and B rings have been numbered for the purpose of this application. This numbering may vary from that of IUPAC. The named compounds employ numbering consistent with IUPAC which may vary from the internal numbering scheme for the A and B rings.
In additional aspects, the invention is directed to methods to inhibit or prevent bacterial growth using the compounds of the invention, to antibodies specific for them and to antimicrobial compositions, including pharmaceutical compositions containing these compounds.
Further, the compounds of the invention are useful as scaffolds for the generation of libraries using combinatorial techniques. The libraries would be screened for desirable prospects using assays, those for antichaperone activity or antimicrobial activity.
MODES OF CARRYING OUT THE INVENTION
The present invention provides novel class of &bgr;-lactams which are effective in treating or preventing bacterial infections. Without intending to be bound by any theory, applicants believe that the compounds of the invention exert their effects by interfering with the function of chaperones required for the assembly of pili from pilus subunits in diverse Gram-negative bacteria. Such interference is particularly effective since the formation of pili is essential to bacterial pathogenicity and since the production of pilus subunits in the absence of chaperones is known to be directly toxic.
The novel compounds of the invention comprise (1S,2R,5S)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid and its derivatives, the corresponding compounds where S is replaced by O or by SO or SO
2
, and their six-membered ring analogs.
The active forms of the compounds of the invention are those wherein the chirality of the nitrogen at position 1 is “S”, the chirality of the carbon at position 2 is “R”, the chirality of the carbon at position 5 is “S”, and the chirality of the carbon at position 6 is “R” in the specific parent compound described above. The same stereochemistry is retained in the analogous compounds and derivatives although the designation of the chirality at each position may be different depending on the specific substitutions made. Accordingly, the appropriate stereoisomer can be determined by referring to formula (1). As long as this stereochemical form is present, the formulation will be active. The invention, of course, includes racemic mixtures which include this stereoisomer as well as mixtures of the various diastereomers, as long as this particular form is included.
Included in such derivatives are the salts, especially pharmaceutically acceptable salts.
Salts of carboxylic acids include those derived from inorganic bases such as the sodium, potassium, lithium, ammonium, calcium, magnesium, zinc, aluminum, and iron salts and the like, as well as those derived from organic, especially nontoxic, bases such as the primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins. Examples of such compounds capable of forming salts are isopropyl amine, trimethyl amine, triethyl amine, 2-dimethyl aminoethanol, dicyclohexyl amine, amino acids such as lysine, arginine and histidine, caffeine, procaine, betaene, theobromine, purines, piperazines, and the like.
As the compounds of the invention may themselves contain amino groups, the acid addition salts are also included in the scope of the invention. Such acid addition salts can be formed from inorganic acids such as hydrochloric, sulfuric, and phosphoric acid or from organic acids such as acetic, propionic, glutamic, glutaric, as well as acid ion-exchange resins.
The compounds of formula (1) including (1a) and (1b) may also be in esterified form. Typically, the esters are prepared from a hydrocarbyl alcohol. By “hydrocarbyl” is meant a monovalent substituent containing only carbon and hydrogen which may be straight or branched chain, saturated or unsaturated, aromatic or nonaromatic or both and can be cyclic or noncyclic. Thus, hydrocarbyl alcohol of 1-10C could include cyclopentyl ethyl alcohol, 2-pentanyl alcohol, 3-butynyl alcohol, 2,4-dimethyl hexyl alcohol, benzyl alcohol and the like. Particularly preferred are alkyl alcohols. “Alkyl” refers to a saturated straight or branched chain hydrocarbon which may, if it contains a sufficient number of carbon atoms, be cyclic or contain a cyclic portion. Typical examples include methyl, ethyl, t-butyl, cyclohexyl and the like. The alkyl esters of the compounds of formula are particularly preferred, especially alkyl esters wherein the alcohol contains 1-4C.
Suitable embodiments of R
1
, R
2
and R
3
include substituted or unsubstituted alkyl (1-10C), substituted or unsubstituted acyl (2-11C), substituted or unsubstituted aryl (6-14C), substituted or unsubstituted pyridyl, substituted or unsubstituted arylcarbonyl (7-15C), substituted or unsubstituted arylalkyl (7-15C) wherein substituents on any alkyl moiety are selected from the group consisting of halo, and RO, wherein R is H or alkyl (1-6C) and substituents on any aryl moiety are selected from the group consisting of halo, RO, where R is H or alkyl, and —CN and CF
3
. Particularly preferred are embodiments wherein R
1
is unsubstituted phenyl carbonyl or substituted phenyl carbonyl wherein said substituents are selected from the group consisting of lower alkyl (1-4C) and halo.
Embodiments wherein R
2
is alkyl (1-6C) or H are also preferred.
Also preferred are embodiments having formula (1a) wherein Z is S.
Also preferred are embodiments having formula (1a

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