Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
  • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D257/04—Five-membered rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
  • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
  • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
  • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
  • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
  • C07D501/36—Methylene radicals, substituted by sulfur atoms

Definitions

• This invention relates to cephalosporin compounds having antibacterial activity, processes for their preparation, pharmaceutical compositions containing them and intermediates for preparing them.
• the compounds are characterized by having at the 3-position a sulfamidoethyl substituted tetrazole group.
• Exemplary of the compounds of this invention are those represented by the following structural formula: Formula I in which R represents a pharmaceutically acceptable acyl group known to be of utility as a substituent on the 7-amino group in the structures of known or prior art cephalosporins or on the 6-amino group in the structures of known or prior art penicillins.
• acyl substituents are: wherein:
• the 4-carboxylic acid group of the compounds of Formula I may be readily esterified by methods well known to the art.
• These esters include, for example, simple alkyl and aryl esters as well as esters . which are easily cleaved, within the body, to the parent acid such as indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl and thienylglycyloxymethyl esters and others.
• A is COOH
• this group may be similarly esterified. All such ester derivatives'are included within the scope of this invention.
• alkali metal salts such as the sodium or potassium'salts (for example using sodium or potassium 2-ethyl hexanoate), ammonium salts, organic amine salts such as those with procaine or dibenzylethylenediamine.
• cephalosporin modifications can be made by known synthetic procedures such as introduction of an a-methoxy group at position 7, preferably at the stage of the 7-aminocephalosporanic acid reactants disclosed below (IV), prior to N-acylation.
• Optical isomers are also possible such as with the.mandeloyl or phenylglycyl substituents at 7. The D-forms of these subgeneric groups are preferred.
• the compounds of this invention are most conveniently prepared by a displacement of the acetoxy group of a known 7-acylaminocephalosporanic acid (II) by 1-(2-sulfamidoethyl)-1,4-dihydro-5H-tetrazole-5-thione (III).
• a similar displacement with the thione can be run on 7-aminocephalosporanic acid to give 7-amino-3-[l-(2-sulfamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (IV) which may then be N-acylated as known to the art as described above.
• Suitable protective groups may be used in either method as is known to the art (see “Protective Groups in Organic Chemistry”, J.F.W. McOmie, Plenum Press, 1973, Chapters 2 and 3 for use of amino, carboxy, sulfo or hydroxyl protective groups).
• t-butyl (for COOH) or t-butoxycarbonyl (for NH 2 ) groups are easily removed by treatment with trifluoroacetic acid.
• the invention also includes the alkali metal and ammonium salts of the compound of Formula III.
• Certain compounds of Formula I have shown antibacterial activity against both Gram positive and Gram negative bacteria with minimum inhibitory concentrations (MIC's) in vitro from 0.4 to 200 ⁇ g/ml.
• sodium salt (B) are:
• Compound A gave an ED50 in mice of 0 .26 against E. coli as well as 0.195 mg/kg against Kleb. pneumo. (s.c.).
• compositions having antibacterial activity which comprise a pharmaceutical carrier containing an active quantity of a compound of Formula I as well as methods of combatting bacterial infections by administering such a composition to an infected animal or human host in a nontoxic amount sufficient to combat such infections are also objects of this invention.
• the administration which, of course, should be of a non-toxic quantity of a compound of Formula I may be orally or by parenteral injection such as subcutaneously, intramuscularly or intravenously.
• the injection of suitably prepared sterile solutions or suspensions containing an effective, nontoxic amount of the new cephalosporin compound is the preferred route of administration.
• the compounds of Formula I are preferably formulated and administered in the same manner as other prior art cephalosporins such as cephazolin or cephalothin.
• the dosage regimen preferably comprises administration, preferably by injection, of an active but nontoxic quantity of a compound of Formula I selected from the dosage unit range of from about 250 mg. to 600 mg. with the total daily dosage regimen being from about 750 mg. to 6 g.
• the precise dosages are dependent upon the age and weight of the subject and on the susceptibility of the infection being treated in each individual. These can be determined by those skilled in the art based on the data disclosed herein compared with that available to the art attained with the known cephalosporins outlined herebefore.
• Triethylamine (1.0 g., 0.01 mol) was added to a suspension of 1.73 g. (0.005 mol) of the above tetrazole hydrochloride in 50 ml. of dry tetrahydrofuran. The suspension was cooled to 0° C. At that temperature 0.885 g. (0.005 mol) of N-tert-butylsulfamoyl chloride in 40 ml. of dry tetrahydrofuran was added. After 30 minutes of stirring, the triethylamine hydrochloride was separated by filtration. The filtrate was evaporated to dryness.
• the tert-butyl compound (51.5 g.) was added to 500 ml. of trifluoroacetic acid and 250 ml. of m-dimethoxybenzene. The mixture was stirred at room temperature for 3 hours then stripped of the trifluoroacetic acid in vacuo. The dimethoxybenzene solution was diluted with 1.5 1. of ether to give a yellow precipitate. The solid was chromatographed on silica using 50:50 acetone/chloroform as eluant. The product-coataining eluate was stripped. The residue was triturated with 100 ml.
• the sulfamido intermediate (25.55 g., 0.065 mol) was suspended in 300 ml. of'dry methanol and treated with 17 ml. of 25%'sodium methoxide in methanol at room temperature with stirring. The methanol was stripped off in vacuo and the residue dissolved in 300 ml. of water. After filtering, the aqueous solution (pH 9.0) was extracted with ethyl acetate and then adjusted to pH 7.5 with dilute hydrochloric acid and again extracted with ethyl acetate.
• the aqueous layer was applied to an XAD-4 column (a nonionic resin which is a crosslinked copolymer of styrenedivinylbenzene) and eluted first with water and then 50% aqueous methanol.
• the methanol was stripped in vacuo from the pooled product-containing fractions.
• the remaining aqueous solution was treated with dilute hydrochloric acid to a pH of 1.5 and then extracted with ethyl acetate. After drying (MgSO 4 ) the extracts, the ethyl acetate was removed in vacuo to give a residue which was dissolved in dry methanol and adjusted to pH of 7.0 with 12.5% sodium methoxide in methanol.
• the solution is lyophilized to give 7-(D-a-amino-4-hydroxyphenylacetamido)-3-[1-(2-sulfamidoethyl)tetrazole-5-ylthiomethyl]-3-cephem-4-carboxylic acid.
• Similar treatment of the t-boc derivatives of the 7-DL-(a-aminophenylacetamido)cephalosporanic acid gives the corresponding 7-DL-( ⁇ -aminophenylacetamido)-3-[1-(2-sulfamidoethyl)tetrazole-5-ylthiomethyl]-3-cephem-4-carboxylic acid.
• the product-containing effluent is evaporated-to dryness to give a residue which is dissolved in a small amount of water and lyophilized to give 7-trifluoromethyl- thioacetamido-3-[1-(2-sulfamidoethyl)tetrazole-5-ylthio- methyl]-3-cephem-4-carboxylic acid sodium salt.
• Substituting 7-(2-thienylacetamido)-cephalosporanic acid gives 7-(2- thienylacetamido)-3-[1-(2-sulfamidoethyl)tetrazole-5-ylthio- methyl)-3-cephem-4-carboxylic acid sodium salt.
• An injectable pharmaceutical composition is formed by adding sterile saline solution (2 ml.) to 500 mg. of the product of Example 1. This material is injected parenterally four times daily to a human patient infected with susceptible bacteria. Other compounds of this invention may be similarly used.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Communicable Diseases (AREA)
• Pharmacology & Pharmacy (AREA)
• Oncology (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Cephalosporin Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

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• 1977
  • 1977-06-09 US US05/805,197 patent/US4117123A/en not_active Expired - Lifetime
• 1978
  • 1978-06-05 JP JP53068753A patent/JPS6053028B2/ja not_active Expired
  • 1978-06-09 EP EP78300031A patent/EP0000100B1/fr not_active Expired
  • 1978-06-09 EP EP80200252A patent/EP0018669B1/fr not_active Expired
  • 1978-06-09 DE DE7878300031T patent/DE2861592D1/de not_active Expired

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