Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
  • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
  • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
  • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • 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
  • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

• novel heterocyclic compositions of the invention have the formula wherein R is selected from the group consisting of lower alkyl and aryl optionally substituted with at least one member of the group consisting of chlorine, fluorine, nitro, amino and lower alkyl and a tertiary alkyl group, R. is selected from the group consisting of hydrogen, lower alkyl, carboxyl, lower alkoxycarbonyl, 3
• an alkali metal, alkaline earth metal or amine salt of carboxyl a carbamyl, cyano, an amino and chlorine, R is selected from the group consisting of hydrogen, cy-
• the term lower is intended to mean I to 4 carbon atoms.
• R is lower alkyl, phenyl or naphthyl optionally substituted with one or more of chlorine, fluorine, nitro, amino or lower alkyl, preferably 2,6-dichlorophenyl or tertiary alkyl such as adamantyl, R. is hydrogen, lower alkyl, COOY where Y is hydrogen, lower alkyl, alkali metal, alkaline earth metal or an amino group, carbamoyl, cyano, amino or chlorine and R is hydrogen.
• CN amino, lower aralkoxycarbonylamino, lower alkyl, lower alkoxycarbonyl, phenyl, lower aralkyl such as benzyl and carbamoyl optionally substituted on the nitrogen atom with lower alkyl or phenyl
• X may be hydrogen, OH or lower alkanoyloxy such as acetoxy, or -CI-l X together with the -COOH group may form and
• U is an amide forming group such as -NI-l saccharinyl, succinimido, phthalimido or a group OY.
• Y is hydrogen, alkali metal, alkaline earth metal or amine salts, an ester group such as tri(lower) alkylsilyl, di(lower)alkylmonohalosilyl, benzyl, phenacyl or lower alkyl.
• alkyl or alkanoyl is intended to mean 1 to 4 carbon atoms.
• the compounds of formula I may be prepared by several different methods, each of which is an application of a method known in the art for the preparation of penicillins and cephalosporins. According to a feature of the invention. the compounds of formula I are prepared by reacting a salt, ester of a fi-aminopenicillanic or 7-aminocephalosporanic acid compound of the formula:-
• R, R, HHCLR are as defined above or an active functional derivative thereof suitable as an acylating agent for a primary amino group.
• active functional derivatives include the corresponding carboxylic acid chlorides, bromides, acid anhydrides, including mixed anhydrides.
• benzimidazole benzotriazole and their substituted derivatives can be used.
• the ester, salt or amide of the product obtained by the aforesaid processes may be converted by methods known per se into the corresponding penicillanic or cephalosporanic acids.
• a silyl (e.g. trialkylsilyl) ester of the starting material of formula IV or V is employed as reactant, the esterifying group can be readily hydrolyzed to yield the corresponding acid compound of formula 1.
• Another method of the invention for preparing the compounds of general formula 1 comprises reacting an acid of the formula A-COOH wherein A is the group:-
• R, R, and R are as defined above) having reactive groups in the radical A suitably protected.
• the group protecting the carboxyl radical or hydroxy radical when present in the 6-isocyanatopenicillanic or 7-isocyanatocephalosporanic reactant is a dior trialkylsilyl group which can readily be removed from the resultant product by hydrolysis.
• the reac tion between the carboxylic acid of formula A-COOH and isocyanate of formula OCNQ is preferably carried out in an inert organic solvent medium such as toluene, dichloromethane or benzonitrile.
• an organic base for example a substituted imidazole, may serve as catalyst.
• the reaction proceeds according to the reaction scheme illustrated below for penicillanic acid derivatives, for example with a protecting ester group:
• E is a group protecting the carboxyl group during the reaction and is removed, for example by hydrolysis, after the reaction.
• A-Me Hal or A-Me"A wherein A is as defined above, Me is a metal atom such as lithium, sodium or magnesium, the numeral l or ll indicating its valency, and Hal is a halogen (preferably chlorine or bromine) atom followed by hydrolyzing the intermediate product obtained to remove the metal ion, and any hydrolyzable group protecting the carboxyl group.
• the reaction is carried out in an anhydrous organic solvent medium under conditions favoring a reaction of the Grignard, Reformatsky or analogous type.
• the group W in the starting material may be introduced on the amino group of the o-aminopenicillanic acid or 7-aminocephalosporanic acid derivative concurrently with the protection of the carboxyl group and hydroxyl group or afterwards.
• W is a tri(lower) alkylsilyl group.
• W is an easily removable group, the reaction of such compounds with phosgene proceeds much more smoothly under the same reaction conditions than is the case when W is a hydrogen atom.
• the reaction with phosgene'must be carried out in a dry. inert organic solvent medium having regard to the reactivity of the resulting isocyanato groups. Toluene and methylene chloride or mixtures thereof are particularly suitable.
• an organic base can be added to bind the hydrogen chloride formed.
• this base is a tertiary amine such as triethylamine which does not react with the isocyanato function.
• the reaction is preferably carried out at very low temperatures. preferably -40C.
• nitrile oxides can be prepared by known methods, as described by Grundmann, Quilico et al., See e.g. Synthesis 1970, 344 and Experienta 26, H6) (1970) and references cited herein.
• the reaction with n-butyllithium in the presence of tetramethyleendiamine (TMEDA) can be carried out in aprotic solvents such as toluene or tetrahydrofuran.
• Route 1 enables the greatest variation in the desired compounds. In some cases. the group R1 has been changed into another group. e.g.
• the other processes comprise l) a-halogenation of compounds of formula VI optionally followed by reaction with a nucleophilic agent.
• Examples of new compounds of formula VI which can be prepared by the depicted scheme are those EMJ -CH CH OH ble to those of penicillin G and they have special activities against gram positive organism and have. more- Buli/TMEDA a; CO2 H3O R I.) i li -ca COOI-I oxidation over, a good activity against penicillin resistant Staphy- 25 lococci, especially the compounds in which R repre sents the 2,6-dichlorophenyl group.
• R is hydrogen or methyl.
• R is hydrogen and Q is the group of formula II or III in which X represents an acetoxy group, and salts of such compounds.
• the compounds according to the invention are preferably employed for therapeutic purposes in the form of a non-toxic pharmaceutically acceptable salt such as the sodium, potassium or calcium salt.
• a non-toxic pharmaceutically acceptable salt such as the sodium, potassium or calcium salt.
• Other salts that may be used include the non-toxic, suitably crystaline salts with organic bases such as amines, for example tri(lower)alkylamines, procaine and dibenzylamine.
• novel antibacterial compositions of the invention are comprised of a bactericidally effective amount of a 40 compound of formula I and a pharmaceutical carrier.
• compositions may be in the form of liquid preparation such as solutions, suspensions, dispersions or emulsions or in solid form such as powders, capsules or tablets.
• One or more other therapeutics may be 45 added to the said compositions.
• effective amount as used herein in relation to the described compounds means an amount which is sufficient to destroy or inhibit the growth of susceptible microorganism when administered in the usual manner or an amount which is sufficient to control the growth of bacteria.
• the magnitude of an effective amount can be easily determined by those in the art through standard procedures for determining the relative activity of antibacterial agents, when utilized against susceptible organisms via the various available routs of administration.
• Suitable carriers and excipients may be any convenient physiologically acceptable ingredient which can serve to facilitate administration of the therapeutically active compound.
• Carriers may provide some ancillary function such as that of a diluent, flavor-masking agent, binding agent. action delaying agent, stabilizer, and the like.
• Illustrative carriers include water which can contain gelatin, acacia. algenate, dextran, polyvinylpyrrolidine, sodium carboxymethyl cellulose. or the like, aqueous ethanol, syrup, isotonic saline. isotonic glucose, starch, lactose, or any other such material commonly used in the pharmaceutical and veterinary industry.
• the novel method of killing bacteria comprises contacting bacteria with a bactericidal amount of a compound of formula 1.
• the compounds When administered to warmblooded animals, the compounds may be administered for example topically or parenterally.
• the usual daily dose is to 100 mg/kg depending upon the method of administration and the specific compound.
• the reaction mixture was then poured into a mixture of 20 ml of water and 20 ml of diethyl ether with icecooling, the pH being maintained at 6.8.
• the aqueous layer was washed again with 30 ml of diethyl ether and the aqueous layer was acidified to pH 1.5 after addition of ml of diethyl ether.
• the aqueous layer was washed again with 30 ml of diethyl ether and the combined organic layers were washed once with 20 ml of acidified ice-water at pH 1.5 and then with 20 ml of ice-water.
• EXAMPLE ll Sodium salt of 6- 3-( 2 ,6-dich1orophenyl )isoxazole-S-yl]acetamido) penicillanic acid
• a three-necked vessel of 250 ml was equipped with a thermometer, a good condenser and dropping funnel and the reaction was carried out under nitrogen.
• 220 ml of dichloromethane and 2.72 g 10 mmol) of 3-(2,6- dichlorophenyl)isoxazol-S-ylacetic acid were introduced into the vessel.
• the desired product was completely removed from the aqueous layer and the col- COONa lected organic layers were washed with a small amount of ice-water and then dried over anhydrous magnesium sulfate, filtered and concentrated to some extent in vacuo at 0C.
• the ice-bath was removed and the reaction mixture was stirred for another two hours at room temperature. Then it was poured into a mixture of ml of water and 30 ml of diethyl ether with ice cooling while the pH was kept at 7.0. The aqueous layer was washed with another portion of diethyl ether (30 ml) and ethyl acetate (30 ml). After addition of 50 ml of ethyl acetate, the aqueous layer was acidified to pH [.7 and the layers were separated and the aqueous layer was extracted again with 50 ml of ethyl acetate.
• the combined ethyl acetate layers were washed once with acidified ice-water at pH L5 and twice with icewater. After separation, drying over magnesium sulfate and treatment with Norit, the ethyl acetate layer was concentrated to about one third of its volume and then sodium a-ethylcapronate was added. The precipitated sodium salt was washed once with ethyl acetate and twice with n-hexane and after filtration dried in vacuo to obtain 438 mg (0.8 mmoles 44%) of the sodium salt of 7-[ 3-( 2,6-dichlorophenyl)-isoxazol-5-yl 1- acetamido-cephalosporanic acid. According to TLC, the compound was pure.
• the P being tained at 7.0.
• the aqueous layer was washed once wi h maintained at 7.
• the aqueous layer was extracted twice 20 ml of ethyl acetate and once with diethyl ether (20 e With 50 1111 Of ie hyl therml).
• After addition of 50 ml of diethyl ether and 10 ml of aqueous layer the pH was brought to 1.7.
• the aqueous ethyl acetate the pH was brought to 4.
• the layers were layer was extracted once again with 30 ml of ethyl aceseparated and the aqueous layer was extracted twice tate and then these layers were combined and washed with 50 ml of diethyl ether.
• the combined organic layonce with 20 ml of acidified ice-water (pH 1.7) and ers were washed with ice-water and dried over magneonce with normal ice-water (20 ml). After drying over sium sulfate.
• the penicillin was extracted from water with diethyl ether and the 50 lution in ether was washed with a small volume of icewater, treated with activated charcoal, dried over anhydrous magnesium sulfate and concentrated in vacuo to some extent at 0C.
• reaction mixture was stirred for a few minutes at 0C followed by removal of the ice-bath. Stirring was continued for 1 hour at room temperature and then 0.6 ml (5 mmol) of quinoline were added followed by the drop-wise introduction of a solution of approximately 4.5 mmol of 3-(2.4,6-trimethyl)phenyl-4-methyl-isoxazol-5-yl-acetyl chloride (in about 90% purity prepared from 1.3 g (5 mmol) of the corresponding carboxylic acid) in 10 ml of dry dichloromethane at 5C. After a few minutes additional stirring at room temperature, the reaction mixture was poured in ice water. The pH was raised to 7 and the layers were separated.
• the water-layer containing according to thin-layer chromatograms one main reaction product (a small amount of 7-amino-cephalosporanic acid) and a small amount of a by product (possibly the ri -isomer of the desired product), was washed twice with diethyl ether. The organic layers were discarded and the water-layer was successively extracted at pH 5.0. 4.5 and 4.0 with diethyl ether. The extract of pH 4.0 contained only the desired main product.
• Example 1X Using the procedure of Example 1X, a reaction was carried out between 1.3 g (5 mmol) Of 3-(2,4,6- trimethyl) phenyl-4-rnethyl-isoxazol-S-yl-acetic acid dissolved in 25 ml of dry dichloromethane and 5.04 pl mmol of trimethylsilyl 7-iso-cyanato-desacetoxycephalosporanate dissolved in 9 ml of toluene in the presence of about 0.05 ml of N-vinyl-imidazole (catalyst). The addition of the solution of the isocyanate in toluene took about 20 min. Evolution of carbon dioxide was already noticeable after 5 min.
• the acetone solution was somewhat concentrated in vacuo and subsequently seeded. After crystallization had subsided. the flask was placed in the refrigerator. The next day the crystals were recovered by filtration, were washed with cold acetone and diethyl ether and dried in vacuo to constant weight to obtain 1.7 g of the sodium salt of 7 [3-(2.4.6-trimethyl)phenyl-4 -methyl-isoxazoI-5- yllacetamido desacetoxycephalosporanic acid. The structure was confirmed by IR and PMR spectra. According to PMR spectra and thin-layer chromatograms. the final product was contaminated only by a very small amount of acetone and a small amount of N,N'-didesacetoxycephalosporanic acid urea.
• the layers were separated and the water-layer was purified by extraction with diethyl ether.
• the organic layers were discarded and the water-layer at pH 3.0 was extracted with a lzl mixture of diethyl ether and ethyl acetate.
• the combined extracts were washed with icedwater, dried over anhydrous magnesium sulfate, filtered and completely evaporated in vacuo. The resulting. slightly yellowish solid 1.1 g) was examined by IR and PMR.
• the product contained the desired 6- ⁇ [3- (2,6-dichloro )phenyl-4-carbamyl-isoxazol-S- yl]acetamido penicillanic acid and also minor amounts of N,N'-di-penicillanic acid urea and the starting carboxylic acid.
• the crude product was repeatedly extracted with cold-dry diethyl ether in which the urea is slightly soluble.
• the ethereal extract was mixed with iced water buffered to pH 7 and the greater part of the starting carboxylic acid was removed from the water-layer at pH 4.5.
• the water-layer was repeatedly extracted at between pH 4.5 and pH 3.5 with mixtures of much diethyl ether and small but gradually increased amounts of ethyl acetate. Extracts free from the starting carboxylic acid. the urea and degradation products were combined and after the usual manipulations were completely evaporated in vacuo. The resulting colorless solid was dried to constant weight to obtain 350 mg of product. According to thin-layer chromatograms, IR and PMR spectra the final product was pure except for the presence of slight residual amounts of ethyl acetate and diethyl ether. The IR spectrum (KBr disc). complicated by the monomer-dimen feature, i.a.
• EXAMPLE XV Sodium salt of 6- ⁇ l3-(2,6-dichloro)phenyl-4-cyano-isoxazol-5- yllacetamido l penicillanic acid.
• the penicillin was removed from water by extraction with diethyl ether at pH 3.3 and the ethereal extract was washed with iced water. dried over anhydrous magnesium sulfate. filtered and evaporated in vacuo.
• the residual oil was dissolved in about 3 ml of dry ethyl acetate followed by the addition of about 0.6 mmol of sodium a-ethylcapronate dissolved in a small volume of ethyl acetate. Addition of dry diethyl ether resulted in a slightly colored precipitate which was recovered by filtration, was washed with cold diethyl ether and dried in vacuo to constant weight to obtain l8O mg.
• the final product was examined as usual and it contained the sodium salt of 6- ⁇ [3-(2.6- dichloro)phenyl-4-cyano-isoxazol-S-yl]acetamido penicillanic acid and slight amounts of a degradation product and of sodium a'ethylcapronate.
• the IR spectrum of the final product (KBr disc) exhibited i.a. absorptions at 2280 (C a N), 1778 (carbonyl B-lactam). I690 (carbonyl amide), I610 (carbonyl carboxylate ion) and I 1400 cm (isoxazole ring absorptions).
• the penicillin was extracted from water by two extractions with diethyl ether. one performed at pH 5.5 and the other at pH 4.0. The extracts were separatedly washed with iced water. dried over anhydrous magnesium sulfate. filtered and completely evaporated in vacuo to obtain yields of 700 and 300 mg. respectively. Both products gave satisfactory IR spectra and contained according to thin-layer chromatography only one penicillin. Since the sample obtained by extraction at pH 5.5 was contaminated by the starting acetic acid derivative, it was dissolved in ether followed by addition of sodium a-ethylcapronate.
• the obtained sodium salt (350 mg) of 6- ⁇ [3-( l )adamantyl-isoxazol-S- yl]acetamido ⁇ penicillanic acid was pure except for a slight amount of residual sodium a-ethylcapronate. According to a PMR spectrum the second product was pure except for a slight amount of diethyl ether (about 4.0% by weight).
• the reaction product was cooled down to 0C followed by the addition of a few ml of cold acetone containing enough water to hydrolyze the silylester. Next. the mixture was completely evaporated in vacuo in the cold and the residue was dissolved in 75 ml of a cold 1:] mixture of diethyl ether and ethyl acetate. Since it was intended to use this penicillin for the preparation of the penicillin of Example XVIII, the isolation procedure was not aimed at the isolation of the product in a substantially pure state but instead directed at the isolation of as much as possible of the desired product. Therefore, the solution was mixed with 70 ml of iced water buffered to pH 7.
• the well stirred mixture was acidified to pH 5.8 and transferred to a separatory funnel.
• the water-layer was removed and discarded since it contained the by product N.N'-di-penicillanic acid urea and merely traces of the desired product.
• the organic layer was then washed twice with slightly acidic ice-cold water and once with a small amount of neutral water. The organic layer, in this way completely freed from the urea and the catalyst, was dried over anhydrous magnesium sulfate, filtered and completely evaporated in the cold.
• the colored filtrate was concentrated in vacuo at 0C to a volume of about 25 ml and I00 ml of iced water were added and the mixture was brought to pH 7.0. The layers were separated and the colored organic layer was discarded.
• the solution of the desired compound in water was purified by two extractions with a 1:1 mixture of ethyl acetate and diethyl ether. The resulting, practically colorless solution in water was acidified to pH 4.7 and was extracted twice with an excess volume of ethyl acetate. The water layer was discarded and the combined ethyl acetate layers were washed twice with a small amount of iced water.
• the precipitated sodium salt of the said penicillin was recovered by filtration and was repeatedly washed with dry ether. After drying, this product weighed 134 mg. The product was examined in the usual manner. Not counting adhering water (much less than in the case of the free penicillanic acid) the purity of the sodium salt was estimated to be about 80-85% since it contained about 5% by weight of a degradation product and l0- l5% by weight of sodium a-ethylcapronate.
• the reaction mixture was additionally stirred for one hour at 70 to 60C.
• the sequence of reaction was completed by the dropwise addition of a solution of L16 g (3.7 mmol) of trimethylsilyl 6-isocyanato-penicillanate in ID ml of dry toluene whereby the reaction temperature was not allowed to rise above 55C.
• the reaction mixture was then COOH stirred at C for min. and the reaction mixture and dilute hydrochloric acid were slowly and simultaneously poured into a well stirred and icy-cold mixture of 50 ml of diethyl ether and 50 ml of water of pH 4. Then the pH ofthe mixture was raised to 7 and the layers were separated.
• the water layer was again extracted with 50 ml of ether at pH 7 and the organic layers were discarded.
• the water layer was extracted three times with ether successively at pH 5.0. 4.5 and 4.3 and once extracted with a 1:1 mixture of ethyl acetate and diethyl ether at pH 4.3
• Thin-layer chromatography showed that the water layer no longer contained the desired penicillin accompanied with small amounts of sulphur containing impurities and that the first three ethereal extracts contained 6- ⁇ a-carbamyl-[3-(2,6- dichloro)phenyl-isoazol-S-yl]acetamidolpenicillanic acid in a substantially pure state.
• the resulting layers were separated and the water-layer for purification once extracted with 30 ml of diethyl ether and once with 30 ml of ethyl acetate.
• the combined organic layers and the water-layer were inspected by thin-layer chromatography (detection of sulphur containing compounds) with as eluent a 98:2 mixture of diethylether and formic acid.
• the combined organic layer did not contain such compounds and was discarded.
• the chromatogram of the water-layer showed four wellseparated spots, three minor ones and one major spot. The minor spots were attributed respectively to degradation product(s). to N,N'-dipenicillanylurea and to n-butyI-carbonamido-penicillanic acid.
• the Rf-values of the latter two spots were found to be equal to the Rfvalues of the actual peniciilins.
• the water-layer was extracted at pH 4.9 and pH 3.6 with 30 ml of diethyl ether, which resulted in complete removal of the desired compound from the water-layer.
• the remainder and part of the third compound (presumably n-butylpenicillin) were removed by extraction at pH 3.3 with a 2:1 mixture of diethyl ether and ethylacetate.
• this layer was repeatedly washed with iced water of pH 4.6, which resulted in another (the third) almost clean extract and a number of washings still containing considerable amounts of the desired product.
• the fourth extract was obtained by extraction of the combined washings at pH 6.0 with ethyl acetate. The four extracts were combined, washed with iced water, dried on anhydrous magnesium sulfate, filtered and concentrated in vacuo. The concentrated solution of the desired compound in ethyl acetate was treated with a concentrated solution of sodium a-ethyl capronate in ethyl acetate. The sodium salt of the penicillin was precipitated from this addition of dry diethyl ether.
• the precipitate was collected by filtration, washed with diethyl ether and dried to constant weight, to obtain 580 mg of the sodium salt of 6- ⁇ a-(N-phenyl)carbamyI-[3- (2.6-dichloro)phenyl-isoxazol-S-yl] acetamido penicillanic acid.
• the final product was inspected by thinlayer chromatography, IR spectra and PMR spectra, which confirmed the alleged structure and indicated the impurities of the final product: some sodium a-ethyl capronate and a slight amount of degradation product(s).
• mice ED.-,..mg/kg in experiments with mice.
• Example 1111 Example V Example III Inf. i.p. i.p. i.p. i.p. Ther. i.p. s.c. p.o. i.p. s.c. p.o. i.p. s.c. p.o.
• Example IV Example VII
• Example IX Example XI Inf. i.p. i.p. i.p. i.p. i.p.
• Example Vll Example IX Example XI Thor. i.p. sc. p.o. irp. s.c. p.o. i.p. s.ci p.o. i.p. s.c. p.o.
• miceinfection admini- ED in mg/kg Dicloxagroup way stration Tested compound cillin A i.p. itp. 21.5-46.5 2l.5
• Peak blood levels of the two drugs were reached after l hour with the tested compound giving levels of 5.4 lg/ml and dicloxacillin 27 ug/ml. After 4 hours. these levels were 2.2 pig/ml and 7.1 ag/ml respectively. Dicloxacillin was almost completely bound to serum protein whereas the tested compound appeared to be bound to the extent of about 50%. Thus, the amount of free drug in the serum was of the same order. However, the M.I.C. values for the tested compound were approximately 5 l0 times less so that the overall result was better and this was reflected in the in vivo results.
• EXAMPLE XXV EXAMPLE XXVIII Syrups were prepared from the compounds obtained according to Examples l-XXIV by mixing the following ingredients:
• EXAMPLE XXX Tablets were prepared in the usual way containing as active ingredient the compounds of Examples l XXIV. The components of the tablets are listed below:

Landscapes

• 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)

Priority Applications (1)

Applications Claiming Priority (1)

Related Child Applications (1)

Publications (1)

Family

ID=10466394

Family Applications (1)

Country Status (14)

Cited By (9)

Families Citing this family (4)

Citations (2)

• 1970
  • 1970-11-06 GB GB5304070A patent/GB1364453A/en not_active Expired
• 1971
  • 1971-11-03 US US195482A patent/US3891635A/en not_active Expired - Lifetime
  • 1971-11-05 ES ES396720A patent/ES396720A1/es not_active Expired
  • 1971-11-05 DE DE19712166468 patent/DE2166468A1/de active Pending
  • 1971-11-05 JP JP46088177A patent/JPS5212200B1/ja active Pending
  • 1971-11-05 CA CA126,985A patent/CA983920A/en not_active Expired
  • 1971-11-05 DE DE2155081A patent/DE2155081B2/de active Granted
  • 1971-11-05 ZA ZA717433A patent/ZA717433B/xx unknown
  • 1971-11-05 DE DE19712166467 patent/DE2166467A1/de active Pending
  • 1971-11-05 AU AU35431/71A patent/AU463230B2/en not_active Expired
  • 1971-11-05 CH CH1616271A patent/CH573436A5/xx not_active IP Right Cessation
  • 1971-11-05 HU HUKO2471A patent/HU162822B/hu unknown
  • 1971-11-05 FR FR7139822A patent/FR2112504B1/fr not_active Expired
  • 1971-11-05 SU SU1713952A patent/SU520050A3/ru active
  • 1971-11-05 NL NL717115231A patent/NL150117B/xx unknown
  • 1971-11-05 CH CH1400275A patent/CH572935A5/xx not_active IP Right Cessation
  • 1971-11-05 CH CH1400375A patent/CH572936A5/xx not_active IP Right Cessation
  • 1971-11-05 BE BE775012A patent/BE775012A/xx unknown
• 1974
  • 1974-03-01 ES ES423795A patent/ES423795A1/es not_active Expired

Patent Citations (2)

Also Published As

Similar Documents