Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-07-25
1999-07-20
Berch, Mark L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540222, C07D50156, A61K 31545
Patent
active
059256320
DESCRIPTION:
BRIEF SUMMARY
THE PRESENT INVENTION RELATES TO CEPHALOSPORIN DERIVATIVES OF THE GENERAL
FORMULA I ##STR2## wherein R.sup.1 is hydrogen, lower alkyl, aralkyl, cycloalkyl, R.sup.3 CO-- or --C(R.sup.4 R.sup.5)CO.sub.2 R.sup.6 ; where R.sup.4 and R.sup.5 are each independently hydrogen or lower alkyl, or R.sup.4 and R.sup.5 taken together form a cycloalkyl group; R.sup.3 is hydrogen or lower alkyl and R.sup.6 is hydrogen, lower alkyl, lower alkenyl or a carboxylic acid protecting group. cyclobutyl-methyl, cyclopentyl-methyl or cyclohexyl-methyl; salts of said compounds and hydrates of the compounds of formula I and of their esters and salts.
In above compounds of formula I the substituent in position 3 can be present in the E-form formula Ia or in the Z-form formula Ib ##STR3##
In a particular embodiment of the compounds of formula I n is 1. Moreover R.sup.1 is preferably hydrogen or cyclopentyl. X is preferably CH. The compounds of the formula I are preferably in the Z-form at the oximino group and E-form for the substitutent in position 3.
Preferred compounds of formula I include: oct-2-ene-2-carboxylic acid, ##STR4## carboxylic acid and ##STR5## 2-carboxylic acid. ##STR6##
The invention also relates to pharmaceutical compositions and methods of use of the above.
As used herein, the term "lower alkyl" refers to both straight and branched chain saturated hydrocarbon groups having 1 to 8 and preferably 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, tertiary butyl and the like.
By the term "aralkyl" is meant an alkyl group containing an aryl group. It is a hydrocarbon group having both aromatic and aliphatic structures, that is, a hydrocarbon group in which a lower alkyl hydrogen atom is substituted by a monocyclic aryl group, e.g., phenyl, tolyl, etc.
By the term "cycloalkyl" is meant a 3-7 membered saturated carbocyclic moiety, e.g., cyclopropyl, cyclobutyl, cyclohexyl, etc.
As used herein, "lower alkenyl" refers to unsubstituted or substituted hydrocarbon chain radicals having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, and having at least one olefinic double bond, e.g. allyl, vinyl etc.
The term "carboxylic acid protecting group" refers to protecting groups conventionally used to replace the acidic proton of a carboxylic acid. Examples of such groups are benzyhydryl, t-butyl, p-nitrobenzyl, p-methoxybenzyl and allyl.
As used herein pharmaceutically acceptable salts useful in this invention include salts derived from metals, the ammonium salt, quaternary ammonium salts derived from organic bases and amino acid salts. Examples of preferred metal salts are those derived from the alkali metals, for example, lithium (Li.sup.+), sodium (Na.sup.+) and potassium (K.sup.+), and from the alkaline earth metals, for example, calcium (Ca.sup.++) and magnesium (Mg.sup.++), although cationic forms of other metals, such as iron (Fe.sup.++ or Fe.sup.+++), aluminium (Al.sup.+++), and zinc (Zn.sup.++) are within the scope of this invention. Examples of quaternary ammonium salts derived from organic bases include tetramethylammonium (N.sup.+ (CH.sub.3).sub.4), tetraethylammonium (N.sup.+ (CH.sub.2 CH.sub.3).sub.4), benzyltrimethylammonium (N.sup.+ (C.sub.6 H.sub.5 CH.sub.2)(CH.sub.3).sub.3), phenyltriethylammonium (N.sup.+ (C.sub.6 H.sub.5)(CH.sub.2 CH.sub.3).sub.3), and the like, etc. Those salts derived from amines include salts with N-ethyl-piperidine, procaine, dibenzylamine, N,N'-dibenzylethylenediamine, alkylamines or dialkylamines as well as salts with amino acids such as, for example, salts with arginine or lysine.
As readily hydrolyzable esters of the compounds of formula I there are to be understood compounds of formula I, the carboxy group(s) of which (for example, the 2-carboxy group) is/are present in the form of readily hydrolyzable ester groups. Examples of such esters, which can be of the conventional type, are the lower alkanoyloxy-alkyl esters (e.g., the acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl ester), the lower alkoxycarbonyloxyalkyl esters (e.g., t
REFERENCES:
patent: 5523400 (1996-06-01), Wei et al.
Heinze-Krauss Ingrid
Richter Hans
Berch Mark L.
Hoffmann-La Roche Inc.
Johnston George W.
Kass Alan P.
Rocha-Tramaloni Patricia S.
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