Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1992-06-12
1994-02-15
Cintins, Marianne M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540302, C07D47700
Patent
active
052867218
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds and pharmaceutically acceptable salts thereof.
More particularly, it relates to novel 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds and pharmaceutically acceptable salts thereof, which have antimicrobial activity.
INDUSTRIAL APPLICABILITY
Accordingly, the object of the present invention is to provide novel 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds and pharmaceutically acceptable salts thereof, which are highly active against a number of pathogenic microorganisms and are useful as antimicrobial agents.
DISCLOSURE OF INVENTION
The object 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds are novel and can be represented by the following general formula: ##STR3## in which
R.sup.1 is carboxy, COO.sup.-- or protected carboxy,
R.sup.2 is hydroxy(lower)alkyl or protected hydroxy(lower)alkyl,
R.sup.8 is hydrogen or lower alkyl,
Z is a group of the formula: ##STR4## wherein
R.sup.3 is hydrogen; lower alkyl or lower alkenyl, each of which is optionally substituted by the group consisting of lower alkoxy, carbamoyl, hydroxy, halogen, mono(or di)(lower)alkylcarbamoyl, mono(or di)(lower)alkenylcarbamoyl, mono(or bis)-[hydroxy(lower)alkyl]carbamoyl, optionally substituted cyclic-aminocarbonyl, acylamino, ureido, optionally substituted heterocyclic-carbonylamino, carbamoyloxy, mono(or di)(lower)alkylcarbamoyloxy, lower alkylthio, halo(lower)alkylthio, optionally substituted heterocyclicthio, optionally substituted heterocyclic group, optionally substituted aryl, and acyl;
R.sup.9 is hydrogen or lower alkyl, and
R.sup.10 is lower alkyl,
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include;
a salt with a base such as an inorganic base salt, for example, an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt, for example, an organic amine salt (e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.);
a salt with an acid such as inorganic acid addition e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, etc.);
a salt with a basic or acidic amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.); intermolecular quaternary salt and the like.
Such intermolecular quaternary salt can be prepared when R.sup.3 is, for example, pyridyl(lower)alkyl (e.g. 3-pyridylmethyl, etc.) or imidazolyl(lower)alkyl (e.g. imidazol-1-ylmethyl, etc.) and the ring nitrogen atom is further substituted by a suitable substituent such as lower alkyl (e.g. methyl, etc.). In such a case preferable counter anion may be halide (e.g. chloride, etc.).
In the object compound (I) and the intermediary compounds mentioned below, it is to be understood that there may be one or more stereo-isomeric pair(s) such as optical isomers due to asymmetric carbon atom(s), and such isomers are also included within the scope of the present invention.
According to the present invention, the object compound (I) or pharmaceutically acceptable salts thereof can be prepared by the processes as illustrated by the following reaction schemes. ##STR5## in which
R.sup.1, R.sup.2, R.sup.3, R.sup.8, R.sup.9, R.sup.10 and Z are each as defined above,
R.sub.a.sup.1 is protected carboxy,
R.sub.a.sup.2 is protected hydroxy(lower)alkyl,
R.sub.b.sup.2 is hydroxy(lower)alkyl, and
R.sup.4 is lower alkyl or ar(lower)alkyl.
The starting compounds used in the above Processes may be new and can be prepared, for example, by the methods as shown in the following. ##STR6## in which
R.sup.1, R.sub.a.sup.1, R.sup.2, R.sub.a.sup.2, R.sub.b.sup.2, R.sup.3, R.sup.4, R.sup.8, R.sup.9, R.sup.10 are each as defined above,
R.sup.5 and R.sup.6 are each
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Chiba Toshiyuki
Hattori Kohji
Kuroda Satoru
Murata Masayoshi
Ohtake Hiroaki
Cintins Marianne M.
Coole Rebecca
Fujisawa Pharmaceutical Co. Ltd.
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