Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1989-07-21
1992-01-07
Rizzo, Nicholas S.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540222, 540226, C07D50120, A61K 31545
Patent
active
050792423
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is directed to certain 7-beta-[2-(2-amino-4-thiazolyl)-(Z)-2-(chloromethylene)acetamido]-3-[(subs tituted)methyl]ceph-3-em-4-carboxylic acids, pharmaceutically-acceptable salts thereof and conventional in vivo hydrolyzable esters thereof. These compounds are valuable as broad spectrum antibacterial agents, particularly useful for the systemic treatment of bacterial infections in man and other mammals; and, in the acid or salt form, as topical or industrial antibacterial agents.
The present invention employs a substantial number of the same 7-amino-3-(substituted)methyl]ceph-3-em-4-carboxylic acid precursors as those employed by Nagakura et al., published Japanese application 61-037788, in the synthesis of certain 7-beta-[D-2-((4-ethyl-2,3- dioxo-1-piperazino)carbonylamino)-alpha-2-(4-hydroxyphenyl)acetamido]-3-[( substituted)methyl]-3-cephem-4-carboxylic acids. Japanese published applications 58-164593 and 60-11490 describe 7-[2-(2-amino-4- thiazolyl)-2-(chloromethylene)acetamido]-3-methylceph-3-em-4-carboxylic acid and a number of analogs substituted on 3-methyl with a variety of diaza- and polyaza-heteroarylthio groups.
SUMMARY OF THE INVENTION
The present invention is directed to antibacterial cephem compounds having the formula ##STR1## wherein R is hydrogen or a radical forming a group which is hydrolyzable under physiological conditions; ##STR2## R.sup.1 and R.sup.2 are taken separately, and R.sup.1 is hydrogen, halogen, hydroxy, (C.sub.1 -C.sub.4)-alkoxy or (C.sub.1 -C.sub.4)alkyl, and and form a methylenedioxo group; R.sup.1, R.sup.2 and R.sup.3 is other than hydrogen, halogen or (C.sub.1 -C.sub.4)alkyl; NHCOR.sup.4 ; substituted with halogen; and pharmaceutically-acceptable cationic salt when R is hydrogen.
The term halogen, as used herein, refers to fluoro, chloro and bromo groups. Alkyl groups are straight chain or branched.
Pharmaceutically-acceptable acid addition salts include, but are not limited to, those with hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, citric acid, maleic acid, succinic acid, benzenesulfonic acid, p-toluenesulfonic acid, 2-naphthalenesulfonic acid and methanesulfonic acid. Pharmaceutically-acceptable cationic salts include, but are not limited to, those of sodium, potassium, calcium, N,N'-dibenzylethylenediamine, N-methylglucamine (meglumine) and diethanolamine. The preferred cationic salts are those of potassium and sodium.
The reference to esters which are hydrolyzable under physiological conditions refers to those esters frequently referred to as in vivo hydrolyzable esters or "pro-drugs". Such esters are now as well-known and common in the penicillin art as pharmaceutically-acceptable salts. Such esters are generally used to enhance oral absorption, but in any event are readily hydrolyzed in vivo to the parent acid. The more preferred ester forming radicals are those wherein R is: The most preferred radicals are pivaloyloxymethyl and 1-(ethoxycarbonyloxy)ethyl.
Because of their ease of preparation and excellent antibacterial activity, preferred compounds have Y as 3-fluoro-4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3-carboxy-4-hydroxyphenyl, 5-chloro-2-thienyl, 5-(aminomethyl)-2-thienyl, 1,1-dioxo-3-thiolanylthio or cis-1-oxo-3-thiolanylthio.
The present invention is also directed to corresponding pharmaceutical compositions and a method of treating bacterial infections in mammals, including man.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is readily carried out. The compounds of the formula (I) are best formed by coupling formylated side chain acid of the formula ##STR3## with a 7-aminocephem compound of the formula ##STR4## where R and Y are as defined above, to form an intermediate compound of the formula ##STR5## which, with or without isolation, is deformylated under mild solvolysis conditions to form the desired compound of the formula (I). When R is an ester group, said group can be already in place in the intermediate (IV) or alternatively introduced after coupling (and usua
REFERENCES:
patent: 4500716 (1985-02-01), Kinast
patent: 4634697 (1987-01-01), Hamashima
patent: 4647658 (1987-03-01), Hamashima et al.
patent: 4912212 (1990-03-01), Ochiai et al.
Chemical Abstracts 110:75164(e) (1989) Abstracting JP 63211287 dated Sep. 2, 1988, application 87/43,100 dated 2/27/87.
Brokke Mervin E.
Lumb J. Trevor
Pfizer Inc.
Richardson Peter C.
Rizzo Nicholas S.
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