United States Patent (19) 11) Patent Number: 4,562,073 Micetich Et Al

United States Patent (19) 11) Patent Number: 4,562,073 Micetich et al. 45) Date of Patent: * Dec. 31, 1985

(54) PENICILLIN DERIVATIVES Attorney, Agent, or Firm-Murray, Whisenhunt and 75 Inventors: Ronald G. Micetich, Alberta, Ferguson Canada; Shigeru Yamabe, Kobe, 57 ABSTRACT Japan; Motoaki Tanaka, Tokushima, Japan; Makoto Kajitani, Tokushima, A penicillin derivative represented by the following Japan; Tomio Yamazaki, Tokushima, formula Japan; Naobumi Ishida, Tokushima, Japan O O 73 Assignee: Taiho Pharmaceutical Company N7 Limited, Tokyo, Japan S CH2-N a R CH3 * Notice: The portion of the term of this patent N R2 subsequent to Jul. 16, 2002 has been COOR3 disclaimed. 21) Appl. No.: 519,491 wherein R1 is hydrogen or trialkylsilyl; R2 is hydrogen, 22 Filed: Aug. 1, 1983 trialkylsilyl or COOR2' wherein R2' is hydrogen, C1-18 alkyl, C2-7 alkoxymethyl, C3-8 alkylcarbonyloxymethyl, 30 Foreign Application Priority Data C4-9 alkylcarbonyloxyethyl, (C5-7 cycloalkyl)car Dec. 24, 1982 JP Japan ...... 57-233967 bonyloxymethyl, C9-14 benzylcarbonyloxyalkyl, C3-8 Feb. 10, 1983 JP Japan ...... 58-2200 alkoxycarbonylmethyl, C4-9 alkoxycarbonylethyl, phthalidyl, crotonolacton-4-yl, y-butyrolacton-4-yl, 51 Int. Cl...... CO7D 499/00; A61K 31/425 halogenated C-6 alkyl substituted with 1 to 3 halogen 52 U.S. Cl...... 424/114; 260/245.2 R; atoms, C1-6 alkoxy- or nitro-substituted or unsubstituted 514/192 benzyl, benzhydryl, tetrahydropyranyl, dimethylami 58 Field of Search ...... 260/245.2 R, 245.2 T; noethyl, dimethylchlorosilyl, trichlorosilyl, (5-sub 424/270, 271, 114; 514/192 stituted C1-6 alkyl or phenyl or unsubstituted-2-oxo-1,3- 56 References Cited dioxoden-4-yl)methyl, C8-13 benzoyloxyalkyl or group U.S. PATENT DOCUMENTS for forming a pharmaceutically acceptable salt; and R3 4,331,677 5/1982 Foglio et al...... 260/245.2 R has the same meaning as above R2'. Primary Examiner-Nicholas S. Rizzo 18 Claims, No Drawings 4,562,073 1 2 can increase the antimicrobial activity of the 6-lactam PENCILLN DERVATIVES type antibiotic. Examples of antibiotics which can be used conjointly This invention relates to penicillin derivatives and to with the compounds of the present invention are 3-lac a process for preparing them. tam antibiotics which exhibit antibacterial action Of the commercially available antibiotics, g-lactam against gram-positive or gram-negative bacteria and type antibiotics having a 6-lactam ring, namely penicil which include commonly used penicillins such as ampi lins and cephalosporins, are best known and frequently cillin, amoxicillin, hetacillin, ciclacillin, mecillinam, used. Although widely used as useful chemotherapeutic carbenicillin, sulbenicillin, ticarcillin, piperacillin, apal drugs, the G-lactam type antibiotics can not achieve 10 cillin, methicillin, mezlocillin and salts thereof; esters of satisfactory effects against some types of microorgan penicillins such as bacampicillin, carindacillin, talam isms because of resistance of the microorganism to the picillin, carfecillin and pivmecillinam; cephalosporins p-lactam type antibiotics. The resistance thereof are such as cephaloridine, cephalothin, cephapirin, ceph usually attributable to £8-lactanase produced by the acetrile, cefazolin, cephalexin, cefradine, cefotiam, cefa microorganism. The B-lactamase is an enzyme which 15 mandole, cefuroxime, cefoxitin, cefnetazole, cefsulo acts to cleave the S-lactam ring of the g-lactan type din, cefoperazone, cefotaxime, ceftizoxime, cefnenox antibiotic, thereby causing the antibiotic to lose its anti ime, latamoxef, cefaclor, cefroxadine, cefatrizine, cefa microbial activity. For this reason, the action of 3-lacta droxil, cephaloglycin, and salts thereof. The A3-lactam mase must be eliminated or inhibited so as to enable the antibiotics are usually used in an amount of about 0.1 to f3-lactam type antibiotic to produce satisfactory effects. 20 about 10 parts by weight, preferably about 0.2 to about The elimination or inhibition of the G-lactamase activity 5 parts by weight, per part by weight of the compound can be achieved by g-lactamase inhibitors, which are of the invention. used conjointly with the g-lactam type antibiotic to Examples of the trialkylsilyl groups represented by increase the antimicrobial activity of the antibiotic. R1 and R2 in the formula (I) include trialkylsilyl having It is an object of the present invention to provide 25 straight-chain or branched-chain C1-6 alkyl such as novel compounds having 6-lactamase inhibitory action. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pen It is another object of the invention to provide pro tyl, hexyl, and the like. cesses for preparing the same. Examples of the group R2" of COOR2" represented by It is a further object of the invention to provide a R2 in the formula (I) include; C1-18 alkyl such as methyl, 30 ethyl, propyl, isopropyl, tert-butyl, pentyl, hexyl, decyl, pharmaceutical composition having excellent 3-lacta undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl and mase inhibitory action. like straight- or branched-chain alkyl; C2-7 alkox It is an additional object of the invention to provide ymethyl such as methoxymethyl, ethoxymethyl, propy compositions which, when combined with 3-lactam loxymethyl, isopropyloxymethyl, butoxymethyl and type antibiotics, can increase the antibacterial activity 35 hexyloxymethyl; C3-8 alkylcarbonyloxymethyl such as of the antibiotics. methylcarbonyloxymethyl, ethylcarbonyloxymethyl, The penicillin derivatives of the present invention are butylcarbonyloxymethyl and hexylcarbonyloxymethyl; represented by the formula C4-9 alkylcarbonyloxyethyl such as methylcarbonylox yethyl, ethylcarbonyloxyethyl, butylcarbonyloxyethyl O O (I) and pivaloyloxyethyl; (C5-7 cycloalkyl)carbonylox N 7 N N ymethyl such as cyclopentylcarbonyloxymethyl, cy clohexylcarbonyloxymethyl and cycloheptylcar S H-N R bonyloxymethyl; C9-14 benzylcarbonyloxyalkyl such as CH3 benzylcarbonyloxymethyl, benzylcarbonyloxyethyl, a N w R2 O w 45 benzylcarbonyloxypropyl and benzylcarbonyloxybutyl; COOR3 C3-8 alkoxycarbonylmethyl such as methoxycarbonyl methyl, ethoxycarbonylmethyl, propyloxycarbonyl wherein R1 is hydrogen or trialkylsilyl, R2 is hydrogen, methyl and hexyloxycarbonylmethyl; C4-9 alkoxycar trialkylsilyl or COOR2' wherein R2' is hydrogen, C1-18 bonylethyl such as methoxycarbonylethyl, ethoxycar alkyl, C2-7 alkoxymethyl, C3-8 alkylcarbonyloxymethyl, 50 bonylethyl, propyloxycarbonylethyl, butoxycar C49 alkylcarbonyloxyethyl, (C5-7 cycloalkyl)car bonylethyl and hexyloxycarbonylethyl; halogenated bonyloxymethyl, C9-14 benzylcarbonyloxyalkyl, C3-8 C1-6 alkyl substituted with 1 to 3 halogen atoms such as alkoxycarbonylmethyl, C4-9 alkoxycarbonylethyl, chloromethyl, 2,2-dibromoethyl and trichloroethyl; phthalidyl, crotonolacton-4-yl, y-butyrolacton-4-yl, C1-6 alkoxy- or nitro-substituted or unsubstituted benzyl halogenated C1-6 alkyl substituted with 1 to 3 halogen 55 such as p-methoxybenzyl, p-ethoxybenzyl, o-nitroben atoms, C1-6 alkoxy- or nitro-substituted or unsubstituted zyl and p-nitrobenzyl; (5-substituted C1-6 alkyl or benzyl, benzhydryl, tetrahydropyranyl, dimethylami phenyl O unsubstituted-2-oxo-1,3-dioxoden-4- noethyl, dimethylchlorosilyl, trichlorosily, (5-sub yl)methyl such as (2-oxo-1,3-dioxoden-4-yl)methyl, (5- stituted C1-6 alkyi or phenyl or unsubstituted-2-oxo-1,3- methyl-2-oxo-1,3-dioxoden-4-yl)methyl and (5-phenyl dioxoden-4-yl)methyl, C8-13 benzoyloxyalkyl and group 60 2-oxo-1,3-dioxoden-4-yl)methyl; Cs-13 benzoyloxyalkyl for forming a pharmaceutically acceptable salt; and R3 such as benzoyloxymethyl, benzoyloxyethyl, ben has the same meaning as R2'. zoyloxypropyl and benzoyloxybutyl; etc. The penicillin derivatives of the present invention are Examples of the groups represented by R3 in the all novel compounds and have 6-lactamase inhibitory formula (I) are the same as those exemplified in respect properties, hence useful as S-lactamase inhibitory 65 of the group R2'. agents. The ester residues represented by R2' and R3 include The penicillin derivatives of the invention, when used both carboxyl-protecting groups acceptable in the syn in combination with a known f3-lactam type antibiotic, thesis of penicillin compounds and pharmaceutically 4,562,073 3 4. acceptable ester residues. A pharmaceutically accept described in Japanese Unexamined Patent Publication able ester having such residue is an ester which is easily No. 81380/1974 and H. E. Flynn, "Cephalosporins and hydrolyzed in vivo and which is a non-poisonous ester Penicillins, Chemistry and Biology' (published in 1972 capable of rapidly decomposing in the blood or tissue of by Academic Press). Specific examples thereof are humans, thereby producing the corresponding acid of ethyl, propyl, tert-butyl, trichloroethyl and like substi the formula () in which R3 is hydrogen atom. Gener tuted or unsubstituted alkyl groups; benzyl, diphenyl ally in the synthesis of penicillin compounds, ester methyl, p-nitrobenzyl and like substituted or unsubsti protecting groups are used in the art to protect penicil tuted aralkyl groups; acetoxymethyl, acetoxyethyl, pro lin carboxyl groups or other carboxyl groups. While it pionyloxyethyl, pivaloyloxyethyl, pivaloyloxypropyl, is difficult to determine which ester-protecting group 10 benzyloxymethyl, benzyloxyethyl, benzylcarbonylox should be used, consideration are usually given to select esters in which the protecting group per se is suffi ymethyl, cyclohexylcarbonyloxymethyl and like acyl ciently stable in the reaction and which does not permit oxyalkyl groups, methoxymethyl, ethoxymethyl, ben cleavage of the g-lactam ring in removal of the ester zyloxymethyl and like alkoxyalkyl groups; and other protecting groups. Most commonly used as such ester- 15 groups such as tetrahydropyranyl, dimethylaminoethyl, protecting groups are p-nitrobenzyl group, benzhydryl dimethylchlorosilyl, trichlorosilyl and like groups. group, trichloroethyl group, trichlorosilyl group, tetra The steps (A) and (B) of the foregoing process will be hydropyranyl group, etc. Examples of the pharmaceuti described below in detail. cally acceptable ester groups are phthalidyl, crotono Step (A) lacton-4-yl, y-butyrolacton-4-yl, (2-oxo-1,3-dioxoden-4- yl)methyl, etc. 20 A penicillanic acid derivative of the formula (II) is Examples of the group for forming a pharmaceuti reacted with an acetylene derivative of the formula (III) cally acceptable salt represented by R2' and R3 in the to provide a compound of the formula (IV). The reac formula (I) include; sodium, potassium, lithium, or like tion is conducted in a suitable solvent by reacting a alkali metal atoms; calcium, magnesium or like alkaline known penicillanic acid derivative of the formula (II) earth metal atoms; cyclohexylamine, trimethylamine, 25 with a known acetylene derivative of the formula (III) diethanolamine or like organic amine; arginine, lysine or in an amount of about 1 to about 50 moles, preferably like basic amino acid residues; ammonium residues, etc. about 1 to about 10 moles, per mole of the derivative of The penicillin derivatives of the present invention the formula (II). - having the formula (I) can be prepared by the processes The solvents useful in the reaction are not particu ... as shown in reaction equations given below. The pro larly limited and include any of those which do not cesses differ according to the kind of the groups repre adversely affect the reaction. Specific examples of the s sented by R1 and R2. solvents are an acetylene derivative of the formula (III) as used in excess amount or benzene, toluene, xylene Reaction Equation 35 and like aromatic hydrocarbons, tetrahydrofuran, diox O O ane or like ethers, acetone and like polar organic sol vents; etc. These solvents are used singly or in mixture. The reaction proceeds usually at a temperature of be S CH2N3 RCECR5 (III) tween about 50 C. and a boiling point of the solvent, or W. Step (A) G 40 at a temperature of less than 200° C. in a sealed reactor, N and goes to completion in about 2 to about 72 hours. -o? YCOOR4 Depending upon the kind of the penicillin carboxyl (II) protecting group represented by R4, the compounds of O O the formula (IV) obtained in step (A) may be esters of 45 the penicillin derivatives of the present invention hav N 7 N N ing the formula (I). The compounds of the formula (IV) S H-N R are preferably subjected to de-esterification to form a CH derivative of the formula (I-a) in which R3 is hydrogen N R5 Step B which, in turn, is converted into a pharmaceutically w 50 acceptable salt or ester thereof as in the following step COOR4 (B). The compound of the formula (IV) can also be (IV) made into an ester of the formula (I-a) by the conven tional ester interchange reaction in the step (B).

55 Step (B) The compound of the formula (IV) is subjected to de-esterification without or after isolation from the reaction mixture obtained in step (A), whereby a peni cillin derivative of the formula (I-a) in which R3 is hy drogen is obtained. (I-a) As the de-esterification method, reduction, hydroly sis, treatment with an acid and like method can be en In the foregoing formulae, R1 and R3 are as defined ployed for converting the carboxyl-protecting group to above, R4 is penicillin carboxyl-protecting group and carboxyl group. For example, if the carboxyl-protecting R5 is trialkylsilyl or COOR2' wherein R2' is as defined 65 group is an active ester, the reaction frequently pro above. ceeds with ease under mild hydrolysis conditions or by Examples of the penicillin carboxyl protecting group merely bringing the ester into contact with water. The expressed by R4 include known groups such as those reduction method is employed when the carboxyl 4,562,073 5 6 protecting group is trichloroethylbenzyl, p-nitrobenzyl, ing a metal azide with a known derivative of penicil diphenylmethyl or the like. Treatment with an acid is adopted when the carboxyl-protecting group is 4 lanic acid of the formula methoxybenzyl, tert-butyl, trityl, diphenylmethyl, me thoxymethyl, tetrahydropyranyl or the like. S H2X (V) The reduction can be conducted by treating the ester of the formula (IV) with a mixture of (a) zinc, zinc CH3 amalgam or like metal and/or chromium chloride, chro o? W mium acetate or like chromium salt and (b) formic acid, COOR4 acetic acid or like acid. Alternatively, the reduction can 10 be conducted with use of a catalyst in hydrogen atomos wherein X represents chlorine atom or bromine atom phere in a solvent. Examples of the catalysts are plati and R4 is as defined above, oxydizing the reaction mix num, platinum oxide, palladium, palladium oxide, pal ture and subjecting the resulting compound to de ladium-barium sulfate, palladium-calcium carbonate, esterification. palladium-carbon, nickel oxide, Raney-nickel, etc. The 15 solvents are not particularly limited so far as they do not The foregoing method will be described below in adversely affect the reaction, and include methanol, detail. The reaction between the compound of the for ethanol and like alcohols; tetrahydrofuran, dioxane and mula (V) and the metal azide is conducted in a suitable like ethers; ethyl acetate and like esters; acetic acid and solvent by using the metal azide in an amount of about like fatty acids; and a mixture of these organic solvents 20 and water. 1 to about 50 moles, preferably about 1 to about 10 The acids useful for eliminating the carboxyl-protect moles, per mole of the compound of the formula (V). ing group of the ester of the formula (I-a) are formic Examples of the metal azides which can be used include acid, acetic acid and like lower fatty acids; trichloroace those commonly used, such as sodium azide, potassium tic acid, trifluoroacetic acid and like trihalogenated 25 azide and like azides of alkali metals, and barium azide acetic acids; hydrochloric acid, hydrofluoric acid and and like azides of alkaline earth metals. Useful solvents like hydrohalogenic acids; p-toluene-sulfonic acid, tri are not particularly limited as far as they do not ad fluoromethane-sulfonic acid and like organic sulfonic acids; and a mixture of these. In this reaction, when the versely affect the reaction. Examples of useful solvents acid used is in a liquid state and acts also as a solvent, it 30 are dimethylformamide, ethyl acetate, acetone, dichlo is not necessary to use other solvents. However, di romethane, tetrahydrofuran, dioxane, methanol, etha methylformamide, dichloromethane, chloroform, tetra nol and like organic solvents. These organic solvents hydrofuran, acetone and like solvents which do not can be used singly or in mixtures. Also a mixture of such adversely affect the reaction may be used. solvent and water is usable. The reaction proceeds at a The penicillin derivative of the present invention 35 having the formula (I-a) in which R3 is hydrogen can be temperature of usually about -20 to about 100° C., transformed by the salt-forming reaction or esterifica preferably about 0 to about 100° C. The resulting prod tion commonly employed in the art into a pharmaceuti uct can be used in subsequent oxidation without isola cally acceptable salt or ester as contemplated. tion, or alternatively after isolation and purification by a If the ester residue is, for example, 3-phthalidyl, conventional method. The oxidation subsequent to the crotonolacton-4-yl, y-butyrolacton-4-yl or like group, azide-forming reaction is conducted by using an oxidiz the penicillin derivative of the formula (IV) can be alkylated by using 3-halogenated phthalide, 4 ing agent commonly employed such as permanganic halogenated crotonolactone, 4-halogenated-y- acid, periodic acid, peracetic acid, performic acid, tri butyrolactone or the like. Suitable halogens of the fore 45 fluoroperacetic acid, perbenzoic acid, m-chloroperben going halides include chlorine, bromine, iodine, etc. zoic acid, hydrogen peroxide, etc. The oxidizing agent The reaction is carried out by dissolving the salt of the can be used in large excess, and may be employed pref penicillin derivative of the formula (IV) in N,N-dime thylformamide or like suitable polar organic solvent and erably in an amount of about 1 to about 2 moles per adding an approximately equimolecular amount of a 50 mole of the starting compound. The oxidation is carried halide to the solution. The reaction temperature ranges out usually in a suitable solvent. Useful solvents include from about 0 to about 100° C., preferably from about any of those which do not adversely affect the oxidation 15 to about 35° C. Suitable salts of the penicillin deriva reaction such as chloroform, pyridine, tetrahydrofuran, tive to be used in the esterification are salts of sodium, dioxane, methylene chloride, carbon tetrachloride, potassium or like alkali metals; salts of triethylamine, 55 acetic acid, formic acid, dimethylformamide, water, etc. ethyldiisopropylamine, N-ethylpiperidine, N,N-dime thylaniline, N-methylmorpholine or like tertiary The oxidation is performed at a temperature which is amines, etc. After completion of the reaction, the con not particularly limited but generally ranges from room templated product can be easily separated by the con temperature to cooling temperature, preferably about 0. ventional method and also can be purified, when re 60 to about 30' C. quired, by recrystallization, thin layer chromatography, The compound thus obtained is subjected to de column chromatography or like method. esterification whereby the compound of the formula The compound of the formula (II) to be used as the (II) can be produced. The de-esterification is effected starting material in the step (A) is a novel compound under the same conditions as shown in the reaction undisclosed in literture and can be synthesized by the 65 method described in Japanese Patent Application No. scheme of the step (B). The process for preparing the 69142/1982 (relating to an invention accomplished by compound of the formula (II) is described in detail in us). The disclosed method comprises the steps of react reference examples to be set forth later. 4,562,073 7 8 the formula (I). More preferably the ester of the formula Reaction Equation-2 (VI) is subjected to de-esterification as in the step (B) so that the compound is transformed to a penicillin deriva tive of the present invention during the formula (I-b) in which R3 is hydrogen which is converted, when re CH2N3 quired, in the conventional manner into a pharmaceuti CH3 cally acceptable salt thereof or ester thereofas conten o? N w from FFF plated. COOR4 R'CECR5'(III) Step (C) O Step (D) (II) The compound of the formula (VI) is subjected to de-esterification after or without isolation from the reaction product obtained in the step (C), whereby a O O penicillin derivative of the formula (I-b) in which R3 is N 7 N N 15 hydrogen is produced. The de-esterification is carried S H-N out under the same conditions as those described above CH3 in respect of the step (B). o? N w R6 The compound of the formula (VI) can be prepared H COOR4 20 by the process in the step (C) and also by the process to be set forth below in step (E). (VI) Step (E)

O O The compound of the formula (IV) obtained in the 25 step (A) as shown in Reaction Equation-1 wherein at N 7 N N least one of R1 and R5 is trialkylsilyl, namely the com S CH2-N R1 SteSp pound of the formula (IV), is subjected to reaction for n CH3 removing the trialkylsily in the presence of potassium "iro2 N V R5 fluoride after or without isolation from the reaction . COOR4 Step (E) 30 product obtained in the step (A), whereby a compound of the formula (VI) is produced. The trialkylsilyl r (IV) removing reaction is conducted in a suitable solvent by O O using potassium fluoride in an amount of over about 1 N 7 N N mole, preferably about 1 mole, and a catalyst in an S CH2a-N -x 35 amount of about 1/50 to about 1/10 mole, both per mole CH3 of the compound of the formula (IV). Useful as the N R6 catalyst is a phase transfer catalyst such as quaternary o21 w ammonium salt, crown ether or the like. Examples of COOR3 useful solvents are any suitable solvents which do not (I-b) adversely affect the reaction and which include ben zene, toluene, xylene or like aromatic hydrocarbons; In the foregoing formulae, R4 is as defined above, R' acetonitrile, N,N-dimethylformamide, dimethylsulfox and Rs' are the same groups as those represented by R1 ide or like non-protonic polar solvents; etc. The reac and R5 and at least one of them is trialkylsilyl group, and tion temperature and reaction time are appropriately R6 represents hydrogen or COOR2 wherein R2' is as 45 determined. Generally the reaction is performed at a defined above. temperature in the range of room temperature to about The compound of the formula (I) wherein at least one of R1 and R2 is hydrogen atom, namely the compound 100 C., and completes in about 1 to about 10 hours. of the formula (I-b), can be prepared by the process shown above in Reaction Equation-2. The steps in the 50 Reaction Equation-3 process are set forth below in detail. O O Step (C) The compound of the formula (II) is reacted with a S CH2N3 CH2=CHR7 (VII) compound of the formula (III) in a solvent such as 55 CH3 Step (F) G dichloromethane, dichloroethane, chloroform or like o?a N YCOOR4 halogenated hydrocarbons. During this reaction, reac tion for removing the trialkylsilyl group proceeds at the (II) same time, whereby a compound of the formula (VI) is produced. Useful solvents are not particularly limited as O O far as they are halogenated hydrocarbons. The reaction N7 N conditions including the reaction temperature, the pro S H2-N - portions of the reagents to be used and the reaction time are similar to those in the step (A). nCH Step (G) e. Depending upon the kind of the penicillin carboxyl 65 o? N protecting group represented by R4, the compound of H booR4 the formula (VI) thus obtained may be the product as (VIII) contemplated, i.e., an ester of the penicillin derivative of 4,562,073 10 -continued reaction product obtained in the step (F), whereby a Reaction Equation-3 penicillin derivative of the formula (I-c) in which R3 is O O hydrogen is produced. The reaction conditions for de N N7 5 esterification are the same as those described in the step S CH2-N - (B). NCH After completion of the reaction in each step, the a N contemplated compound producible in each step can be o21 bOOR; isolated from the reaction product or, when required, 10 can be purified by the conventional method such as (I-c) recrystallization method, thin-layer chromatography, In the foregoing formulae, R4 is as defined above, and column chromatography or the like. R7 represents acyloxy group. The penicillin derivative of the present invention is Examples of the acyloxy groups represented by R7 is mixed with the 3-lactam type antibiotic substance to are lower acyloxy groups having 2 to 5 carbon atoms form a preparation which is orally or parenterally ad such as acetoxy, propionyloxy, butyryloxy, valleryloxy or like aliphatic acyloxy groups and benzoyloxy or like ministered. Alternatively, the present compound and a aromatic acyloxy groups, etc. suitable antibiotic can be separately administered. Thus The compound of the formula (I) wherein R1 and R2 20 the derivatives of the formula (I) can be used for treat are hydrogen atoms, namely the compound of the for ing infectious disease of human beings and other ani mula (I-c), can be produced by the process as shown mals. above in Reaction Equation-3. The composition of the present invention may be The steps (F) and (G) in Reaction Equation-3 will be made into tablets, pills, capsules, granules, powders, described below in detail. 25 syrups, lozenges, solutions, suspensions, etc. for oral Step (F) administration and aqueous, suspending or water-solu The penicillanic acid derivative of the formula (II) is ble preparations for intravenous, subcutaneous or intra reacted with a vinyl derivative of the formula (VII) muscular injections. while reaction for removing the acyloxy group repre Carriers useful in formulating the preparations are sented by R7 in the formula (VII) is carried out, 30 commonly used pharmaceutically acceptable non-toxic whereby a compound of the formula (VIII) is prepared. carriers such as gelatin, lactose, starch, magnesium stea The reaction between the penicillanic acid derivative of the formula (II) and the vinyl derivative of the formula rate, talc, vegetable oil, animal oil, polyalkylene glycol, (VII) is conducted in the presence of or in the absence etc. The carrier may be used with other additives such of a suitable solvent by using the vinyl derivative of the 35 as diluents, binders, buffer agents, preservatives, glazes, formula (VII) in an amount of at least about 1 mole, disintegrators, coating agents, etc. preferably from 1 to about 200 moles, per mole of the The daily dose of the preparation can be appropri derivative of the formula (II), whereby there occurs ately determined and is not particularly limited. Prefer simultaneously the acyloxy-removing reaction. The solvents which can be used are not particularly limited 0 ably the daily dose is such that the total amount of the as far as they do not adversely affect the reaction. Spe present compound and G-lactam antibiotic is about 1 to cific examples thereof are benzene, toluene, xylene or about 200 mg/Kg body weight for oral administration like aromatic hydrocarbons, tetrahydrofuran, dioxane and about 1 to about 100 mg/Kg body weight for paren or like ethers, etc. The reaction is effected at a tempera teral administration. ture ranging from about 50° C. to a boiling point of the 45 The present invention will be described below in solvent, or a temperature of less than 200 C. in a sealed more detail with reference to examples given below. reactor, and is completed in about 2 to about 72 hours. Depending on the kind of the penicillin carboxyl REFERENCE EXAMPLE 1. protecting group represented by R4 in the formula (VIII), the compound of the formula (VIII) thus ob- 50 Preparation of benzhydryl tained may be the product as contemplated, namely the 243-azidiomethyl-2a-methylpenam-3a-carboxylate ester of the penicillin derivative of the forumla (). More A solution of 5.00 g of sodium azide in 53 ml of water preferably the compound of the formula (VIII) thus was added to a solution of benzhydryl 2,3-chlorometh prepared is subjected to de-esterification as in the step yl-2a-methylpenam-3o-carboxylate (5.13 g) in dimeth (G) so that the compound is converted by the conven- 55 tional method into a penicillin derivative of the formula ylformamide (155 ml). The mixture was stirred at room (I-c) wherein R3 is hydrogen which, in turn, is trans temperature for 4 hours. The resulting reaction mixture formed by the conventional method into a pharmaceuti was poured into cooled water and the mixture was cally acceptable salt thereof or ester thereofas contem extracted with ethyl acetate. The ethyl acetate layer plated. The compound of the formula (VIII) can be 60 was washed with water, dried over magnesium sulfate made into a pharmaceutically acceptable salt thereof or and concentrated to provide 4.87 g of the contemplated ester thereof as contemplated by conducting an ester product as oil in 93% yield. interchange or salt-forming reaction in the conventional Infrared absorption spectrum (nujol) umax (cm): male. 2120, 1812, 1765 Step (G) 65 Nuclear magnetic resonance spectrum (CDCl3) 67 The compound of the formula (VIII) is subjected to (ppm): 1.30 (3H, s), 3.25 (2H, m), 3.42 (1H, d), 3.63 (1H, de-esterification after or without isolation from the d), 4.75 (1H, s), 4.76 (1H, m), 7.00 (1H, s), 7.40 (10H, s) 4,562,073 11 12 2A-(5-ethoxycarbonyl-1,2,3-triazol-1-yl)methyl-2a REFERENCE EXAMPLE 2 methylpenam-3a-carboxylate-1,1-dioxide in amorphous Preparation of benzhydryl form (Compound 2) in 27% yield. 26-azidomethyl-2a-methylpenam-3a-carboxylate Infrared absorption spectrum (KBr) umax (cm1): 1,1-dioxide 1795, 1755, 1727 To a solution of benzhydryl 243-azidomethyl-2a Nuclear magnetic resonance spectrum (CDCl3) 8 methylpenam-3a-carboxylate (7.03 g) in a mixture of (ppm): 1.39 (3H, s), 1.39 (3H, t), 3.48-3.60 (2H, m), 4.39 acetic acid (240 ml) and water (40 ml) was added potas (2H, q), 4.58-4.70 (1H, m), 5.11 (1H, s), 5.14 (1H, d), sium permanganate (6.02 g) over a period of more than 5.25 (1H, d), 5.31 (1H, d), 5.56 (1H, d), 7.54 (2H, d), 8.09 1 hour. The mixture was stirred at room temperature for 10 (1H, s), 8.25 (2H, d). 2.5 hours. The resulting reaction mixture was diluted There was obtained as a second eluted product 1.6 g with ice water. The precipitate was collected by filtra of p-nitrobenzyl 2A3-(4-ethoxycarbonyl-1,2,3-triazol-1- tion, and washed with water. The resulting product was yl)methyl-2a-methylpenam-3a-carboxylate-1,1-dioxide dissolved in ethyl acetate and the solution was washed in amorphous form (Compound 1) in 62% yield. with an aqueous solution of sodium hydrogencarbonate 15 Infrared absorption spectrum (KBr) vmax (cm): and dried over magnesium sulfate. Concentration gave 1800, 1760 (sh), 1733 5.48g of the contemplated product in 72% yield. Nuclear magnetic resonance spectrum (CDCl3) 8 Infrared absorption spectrum (nujol) vmax (cm"): (ppm): 1.34 (3H, s), 1.41 (3H, t), 3.50-3.65 (2H, m), 4.42 2120, 1812, 1765 Nuclear magnetic resonance spectrum (CDCl3) 8 20 (2H, q), 4.60-4.75 (2H, m), 5.09 (2H, s), 5.36 (2H, s), 7.59 (ppm): 1.18 (3H, s), 3.50 (2H, d), 3.72 (1H, d), 3.93 (1H, (2H, d), 8.28 (2H, d), 8.30 (1H, s) d), 4.60 (1H, m), 4.65 (1H, s), 7.00 (1H, s), 7.36 (10H, s) EXAMPLE 2 Preparation of p-nitrobenzyl 2p3-(4-methoxycarbo REFERENCE EXAMPLE 3 nyl-1,2,3-triazol-1-yl)methyl-2a-methylpenam-3a-car Preparation of p-nitrobenzyl 25 boxylate-1,1-dioxide (Compound 3) and p-nitrobenzyl 2,3-azidomethyl-2a-methylpenam-3a-carboxylate 2f}-(5-methoxycarbonyl-1,2,3-triazol-1-yl)methyl-2a The procedure of Reference Example 1 was repeated methylpenam-3a-carboxylate-1,1-dioxide (Compound ... with the exception of using as the starting material p 4) nitrobenzyl 2p3-chloromethyl-2a-methylpenan-3ol-car 30 The contemplated product was synthesized in the boxylate, affording the above contemplated compound. same manner as in Example 1 and eluted by column Infrared absorption spectrum (KBr) vmax (cm): chromatography on silica gel. There was obtained as a ... 2120, 1798. 1760 first eluted product p-nitrobenzyl 2f}-(5-methoxycarbo Nuclear magnetic resonance spectrum (CDCl3) 8 nyl-1,2,3-triazol-1-yl)methyl-2a-methylpenam-3a-car (ppm): 1.40 (3H, s), 3.12 (1H, dd), 3.50 (2H, s), 3.62 (1H, 35 boxylate-1,1-dioxide in amorphous form (Compound 4) dd), 4.83 (1H, s), 5.29 (2H, s), 5.36 (1H, dd), 7.56 (2H, d), in 26% yield. ... 8.26 (2H, d) Infrared absorption spectrum (KBr) umax (cm): REFERENCE EXAMPLE 4 1795, 1727 Preparation of p-nitrobenzyl Nuclear magnetic resonance spectrum (CDCl3) 8 2,3-azidomethyl-2a-methylpenam-3a-carboxylate-1,1- (ppm): 1.39 (3H, s), 3.45-3.60 (2H, m), 3.94 (3H, s), dioxide 4.58-4.70 (1H, m), 5.09 (1H, s), 5.10-5.64 (4H, m), 7.54 (2H, d), 8.10 (1H, s), 8.25 (2H, d). The procedure of Reference Example 2 was followed There was obtained as a second eluted product p with the exception of using as the starting material p nitrobenzyl 2p3-(4-methoxycarbonyl-1,2,3-triazol-1- nitrobenzyl 2A-azidomethyl-2a-methylpenam-3a-car 45 yl)methyl-2a-methylpenam-3a-carboxylate-1,1-dioxide boxylate, giving the above contemplated compound. in amorphous form (Compound 3) in 61% yield. Infrared absorption spectrum (KBr) vmax (cm): Infrared absorption spectrum (KBr) vmax (cm): 2120, 1770 1798, 1730 Nuclear magnetic resonance spectrum (CDCl3) 8 Nuclear magnetic resonance spectrum (CDCl3) 8 (ppm): 1.42 (3H, s), 3.45-3.60 (2H, m), 3.75 (1H, d), 3.96 50 (ppm): 1.33 (3H, s), 3.48-3.68 (2H, m), 3.96 (3H, s), (1H, d), 4.56-4.75 (1H, m), 4.64 (1H, s), 5.33 (2H, s), 7.56 4.56-4.76 (2H, m) 5.09 (2H, s), 5.36 (2H, s), 7.60 (2H, d), (2H, d), 8.26 (2H, d) 8.28 (2H, d), 8.30 (1H, s). EXAMPLE 1. EXAMPLE 3 Preparation of p-nitrobenzyl 2£3-(4-ethoxycarbonyl-1,2,3-triazol-1-yl)methyl-2a 55 Preparation of benzhydryl methylpenam-3a-carboxylate-1,1-dioxide (Compound 2.É.-(4-methoxycarbonyl-1,2,3-triazol-1-yl)methyl-2a 1) and p-nitrobenzyl methylpenam-3a-carboxylate-1,1-dioxide (Compound 2,6-(5-ethoxycarbonyl-1,2,3-triazol-1-yl)methyl-2a 5) and benzhydryl methylpenam-3a-carboxylate-1,1-dioxide (Compound 2.É.-(5-methoxycarbonyl-1,2,3-triazol-1-yl)methyl-2a 2) methylpenam-3a-carboxylate-1,1-dioxide (Compound A 2.1 g quantity of p-nitrobenzyl 2A3-azidomethyl-2a 6) methylpenam-3a-carboxylate-1,1-dioxide and 0.63 g of The contemplated product was synthesized in the ethyl propiolate in 62 ml of benzene were refluxed with same manner as in Example 1 and eluted by column stirring under nitrogen atmosphere for 37 hours. The 65 chromatography on silica gel. First there was eluted solvent was removed by distillation and the residue was benzhydryl 243-(5-methoxycarbonyl-1,2,3-triazol-1- subjected to column chromatography on silica gel to yl)methyl-2a-methylpenan-3ol-carboxylate-1,1-dioxide produce as a first eluted product 0.7 g of p-nitrobenzyl (Compound 6) in 18% yield. 4,562,073 13 14 Infrared absorption spectrum (KBr) umax (cm): Infrared absorption spectrum (KBr) vmax (cm): 1800, 1727 1798, 1726 Nuclear magnetic resonance spectrum (CDCl3) 8 Nuclear magnetic resonance spectrum (DMSO-d6) 8 (ppm): 1.20 (3H, s), 3.44-3.58 (2H, m), 3.91 (3H, s), (ppm): 1.31 (3H, t), 1.42 (3H, s), 3.31 (1H, dd), 3.73 (1H, 4.50-4.65 (1H, m), 5.24 (1H, d), 5.25 (1H, s), 5.45 (1H, 5 dd), 4.32 (2H, q), 4.75-5.38 (4H, m), 8.76 (1H, s) d), 6.91 (1H, s), 7.20-7.40 (10H, m), 8.08 (1H, s). Secondly there was eluted benzhydryl 26-(4-methox EXAMPLE 6 ycarbonyl-1,2,3-triazol-1-yl)methyl-2a-methylpenam Preparation of chloromethyl 3a-carboxylate-1,1-dioxide (compound 5) in 60% yield. 26-(4-ethoxycarbonyl-1,2,3-triazol-1-yl)methyl-2a Infrared absorption spectrum (KBr) vmax (cm): 10 methylpenam-3a-carboxylate-1,1-dioxide (Compound 1803, 1727 9) Nuclear magnetic resonance spectrum (CDCl3) 8 A 2.2 g quantity of sodium hydrogencarbonate and (ppm): 1.05 (3H, s), 3.48-3.62 (2H, m), 3.95 (3H, s), 0.2 g of tetrabutylammonium hydrogensulfate were 4.55-4.75 (2H, m), 5.11 (2H, bs), 7.02 (1H, s), 7.20-7.50 added with stirring at a temperature of less than 10 C. (10H, m), 8.25 (1H, s). 15 to 2.4 g of 2,3-(4-ethoxycarbonyl-1,2,3-triazol-1- EXAMPLE 4 yl)methyl-2a-methylpenam-3a-carboxylic acid-1,1- Preparation of sodium dioxide, 13.5 ml of dichloromethane and 13.5 ml of 2.É.-(4-ethoxycarbonyl-1,2,3-triazol-1-yl)methyl-2a water. To the mixture was dropwise added at the same 20 temperature 1.25g of chloromethyl chlorosulfonate and methylpenam-3o-carboxylate-1,1-dioxide (Compound the resulting mixture was stirred at room temperature 7) for 30 minutes. The organic layer was separated, Hydrogenation was conducted at a low pressure and washed once with water and dried over magnesium at room temperature by using 15 ml of ethyl acetate, 15 sulfate. The solvent was removed by distillation and the ml of water, 340 mg of p-nitrobenzyl 26-(4-ethoxycar 25 residue was purified by column chromatography on bonyl-1,2,3-triazol-1-yl)methyl-2a-methylpenan-3a silica gel, giving 2.2 g of the contemplated compound in carboxylate-1,1-dioxide, 60 mg of 10% palladium char amorphous form in 81% yield. coal and 110 mg of sodium hydrogencarbonate. After Infrared absorption spectrum (KBr) umax (cm): completion of absorption of hydrogen, the reaction 1798, 1723 mixture was filtered to separate the aqueous layer 30 Nuclear magnetic resonance spectrum (CDCl3) 5 which was washed with benzene. The aqueous solution (ppm): 1.42 (3H, t), 1.48 (3H, s), 3.52-3.65 (2H, m), 4.36 was concentrated at reduced pressure and the concen (2H, q), 4.60-4.78 (2H, m), 5.10 (2H, s), 5.73 (1H, d), trate was subjected to column chromatography using an 5.90 (1H, d), 8.31 (1H, s) MCI gel, CHP-20 P (product of Mitsubishi Kasei Co., EXAMPLE 7 Ltd., Japan) to conduct gradient elution with a water 35 10% acetone water mixture. The eluate thus obtained Preparation of iodomethyl was freeze-dried to afford 200 mg of the contemplated 2,3-(4-ethoxycarbonyl-1,2,3-triazol-1-yl)methyl-2a product (Compound 7) as white powder in 76% yield. methylpenam-3a-carboxylate-1,1-dioxide (Compound The white powder decomposed at a temperature of 10) more than 180 C. 40 A 1.73 g quantity of chloromethyl 2,6-(4-ethoxycar Infrared absorption spectrum (KBr) umax (cm): bonyl-1,2,3-triazol-1-yl)methyl-2a-methylpenam-3a 1782, 1720 carboxylic acid-1,1-dioxide and 1.3 g of sodium iodide Nuclear magnetic resonance spectrum (D2O) 8 were stirred in 3.4 ml of acetone at room temperature (ppm): 1.39 (3H, t), 1.46 (3H, s), 3.45 (1H, dd), 3.72 (1H, for 18 hours. To the reaction mixture was added 2.9 ml did), 4.44 (2H, q), 4.50 (1H, s), 4.96-5.10 (1H, m), 5.18 45 of water and the pH of the resulting mixture was ad (1H, d), 5.42 (1H, d), 8.72 (1H, s) justed to 7 to 8 with an aqueous solution of sodium hydrogencarbonate. After addition of 2.9 ml of water, EXAMPLE 5 the mixture was decolorized with an aqueous solution Preparation of of 0.5M sodium thiosulfate, extracted with dichloro 2f}-(4-ethoxycarbonyl-1,2,3-triazol-1-yl)methyl-2a 50 methane, washed with water and dried over magnesium methylpenam-3o-carboxylic acid-1,1-dioxide sulfate. The solvent was removed by distillation and 1.9 (Compound 8) g of the contemplated compound was prepared in amor Hydrogenation was conducted at room temperature phous form in 90% yeild. and at a pressure of 3 atm. by using 4.2 g of p-nitroben 55 Infrared absorption spectrum (KBr) vmax (cm): zyl 2A3-(4-ethoxycarbonyl-1,2,3-triazol-1-yl)methyl-2a 1798, 1725 methylpenam-3a-carboxylate-1,1-dioxide, 1.4 g of so Nuclear magnetic resonance spectrum (CDCl3) 8 dium hydrogencarbonate, 800 mg of 10% palladium (ppm): 1.43 (3H, t), 1.49 (3H, s), 3.52-3.68 (2H, m), 4.43 charcoal, 100 ml of ethyl acetate and 100 ml of water. (2H, q), 4.59-4.78 (2H, m), 5.09 (2H, s), 5.96 (1H, d), After completion of absorption of hydrogen, the reac 60 6.07 (1H, d), 8.32 (1H, s) tion mixture was filtered and the aqueous layer was EXAMPLE 8 separated and washed with benzene. The pH of the Preparation of sodium aqueous layer was adjusted to 1 to 2 with hydrochloric 2p3-(5-ethoxycarbonyl-1,2,3-triazol-1-yl)methyl-2a acid. The aqueous layer was extracted with ethyl ace methylpenan-3ol-carboxylate-1,1-dioxide (Compound tate and the extract was dried over magnesium sulfate. 65 The solvent was distilled off and 3.0 g of the contem 11) plated compound was produced in amorphous form in A 220 mg of the contemplated compound was pre 97% yield. pared in the form of white powder in the same manner 4,562,073 15 16 as in Example 4 from 0.34 g of p-nitrobenzyl 243-(5- pound 14) and 0.9 g of p-nitrobenzyl 2a-methyl-2?6-5- ethoxycarbonyl-1,2,3-triazol-1-yl)methyl-2a-methylpe (p-nitrobenzyloxycarbonyl)-1,2,3-triazol-1-yl)me nam-3o-carboxylate-1,1-dioxide in 83% yield. thylpenam-3a-carboxylate-1,1-dioxide (Compound 15) The white powder thus obtained decomposed at a both in amorphous form. temperature of over 180° C. 5 Compound 14 Infrared absorption spectrum (KBr) umax (cm): Infrared absorption spectrum (KBr) vmax (cm): 1788, 1736 1800, 1740 Nuclear magnetic resonance spectrum (D2O) 8 Nuclear magnetic resonance spectrum (CDCl3) 6 (ppm): 1.39 (3H, t), 1.43 (3H, s), 3.40 (1H, dd), 3.71 (1H, (ppm): 1.34 (3H, s), 3.3-3.8 (2H, m), 4.67 (1H, s), dd), 4.46 (2H, q), 4.57 (1H, s), 4.96-5.05 (1H, m), 5.40 O 4.60–4.76 (1H, m) 5.12 (2H, s), 5.37 (2H, s), 5.48 (2H, s), (1H, d), 5.82 (1H, d), 8.34 (1H, s) 7.5-7.7 (4H, m), 8.1-8.3 (4H, m), 8.37 (1H, s). Compound 15 EXAMPLE 9 Infrared absorption spectrum (KBr) vmax (cm): Preparation of sodium 1800, 1740 2,3-(4-methoxycarbonyl-1,2,3-triazol-1-yl)methyl-2a 15 Nuclear magnetic resonance spectrum (CDCl3) 8 methylpenam-3a-carboxylate-1,1-dioxide (Compound (ppm): 1.41 (3H, s), 3.3-3.7 (2H, m), 4.6-4.7 (1H, m), 12) 5.07 (1H, s), 5.1-5.6 (4H, m), 5.46 (2H, s), 7.4-7.7 (4H, A 0.18 g quantity of the contemplated product was m), 8.15 (1H, s), 8.1-8.4 (4H, m) prepared as white powder in the same manner as in Example 4 from 0.3 g of p-nitrobenzyl 2p3-(4-methox 20 EXAMPLE 12 ycarbonyl-1,2,3-triazol-1-yl)methyl-2a-methylpenam Preparation of dipotassium 3a-carboxylate-1,1-dioxide in 78% yield. 2.É.-(4-carboxy-1,2,3-triazol-1-yl)methyl-2a-methylpe The white powder thus obtained decomposed at a nam-3a-carboxylate-1,1-dioxide (Compound 16) temperature of over 184 C. Hydrogenation was conducted in 100 ml of ethyl Infrared absorption spectrum (KBr) umax (cm): 25 acetate and 100 ml of water at room temperature for 1 1782, 1730 hour by using 3.6 g of p-nitrobenzyl 2a-methyl-2,3-4- Nuclear magnetic resonance spectrum (D2O) 6 (p-nitrobenzyloxycarbonyl)-1,2,3-triazol-1-yl)me (ppm): 1.46 (3H, s), 3.45 (1H, dd), 3.73 (1H, dd), 3.97 thylpenam-3a-carboxylate-1,1-dioxide, 2.0 g sodium (3H, s), 4.50 (1H, s), 4.81 (2H, s), 4.98-5.10 (1H, m), 5.18 hydrogencarbonate and 0.68 g of 10% palladium char (1H, d), 5.42 (1H, d), 8.72 (1H, s) 30 coal, catalyst. Thereafter the aqueous layer was sepa EXAMPLE 10 rated and was washed once with ethyl acetate, and the pH thereof was adjusted to 1.5 to 1.7 with 6N hydro Preparation of sodium chloric acid. The aqueous solution was saturated with 2,6-(5-methoxycarbonyl-1,2,3-triazol-1-yl)methyl-2a sodium chloride and extracted a few times with ethyl methylpenam-3a-carboxylate-1,1-dioxide (Compound 35 acetate. The ethyl acetate solutions thus formed were 13) collected and dried over magnesium sulfate. The sol A 0.19 g quantity of the contemplated compound was vent was distilled off at reduced pressure to provide as - prepared as white powder in the same manner as in the residue a foamed product of 2.6-(4-carboxy-1,2,3- ... Example 4 from 0.3 g of p-nitrobenzyl 2.É.-(5-methox triazol-1-yl)methyl-2a-methylpenam-3a-carboxylic ; yoarbonyl-1,2,3-triazol-1-yl)methyl-2a-methylpenan acid-1,1-dioxide. .3a-carboxylate-1,1-dioxide in 82% yield. A 2 g quantity of the 2A3-(4-carboxy-1,2,3-triazol-1- The white powder thus obtained decomposed at a yl)methyl-2a-methylpenam-3a-carboxylic acid-1,1- temperature of over 180 C. dioxide was dissolved in 20 ml of butanol. To the solu Infrared absorption spectrum (KBr) vmax (cm): 45 tion was added a solution of potassium 2-ethyl hexano 1778, 1730 ate in butanol, and the mixture was stirred awhile at Nuclear magnetic resonance spectrum (D2O) 8 room temperature. The precipitate was filtered to give (ppm): 1.41 (3H, s), 3.41 (1H, dd), 3.71 (1H, dd), 3.98 2.0 g of white solids having a melting point of over 178 (3H, s), 4.56 (1H, s), 4.95-5.08 (1H, m), 5.40 (1H, d), 5.83 C. (decomposition). (1H, d), 8.34 (1H, s) Infrared absorption spectrum (KBr) umax (cm): 50 1780, 1610 EXAMPLE 11 Nuclear magnetic resonance spectrum (D2O) 8 Proparation of p-nitrobenzyl (ppm): 1.47 (3H, s), 3.49 (1H, dd), 3.77 (1H, dd), 4.53 2a-methyl-2,6-4-(p-nitrobenzyloxycarbonyl)-1,2,3- (1H, s), 5.0–5.1 (1H, m), 5.16 (1H, d), 5.41 (1H, d), 8.47 triazol-1-yl)methylpenam-3a-carboxylate-1,1-dioxide (1H, s) (Compound 14) and p-nitrobenzyl 55 2a-methyl-2,3-5-(p-nitrobenzyloxycarbonyl)-1,2,3- EXAMPLE 13 triazol-1-yl)methylpenam-3a-carboxylate-1,1-dioxide Preparation of dipotassium (Compound 15) 243-(5-carboxy-1,2,3-triazol-1-yl)methyl-2a-methylpe A 4 g quantity of p-nitrobenzyl 2g-adidiomethyl-2a 60 nam-3a-carboxylate-1,1-dioxide (Compound 17) methylpenam-3a-carboxylate-1,1-dioxide and 8.2 g of White solid of the contemplated compound with a p-nitrobenzyl acetylene carboxylate in 100 ml of ben melting point of over 175 C. (decomposition) was pre zene were refluxed under nitrogen atmosphere for 12 pared in the same manner as in Example 12 by using hours. The solvent was distilled off at reduced pressure. p-nitrobenzyl 2a-methyl-2,3-5-(p-nitrobenzyloxycar The residue was subjected to column chromatography 65 bonyl)-1,2,3-triazol-1-yl)methylpenam-3a-carboxylate on silica gel to provide 3.6 g of p-nitrobenzyl 2a-meth 1,1-dioxide. yl-2,3-4-(p-nitrobenzyloxycarbonyl)-1,2,3-triazol-1- Infrared absorption spectrum (KBr) umax (cm): yl)methylpenam-3a-carboxylate-1,1-dioxide (Com 1780, 1610 4,562,073 17 18 Nuclear magnetic resonance spectrum (D2O) 8 (ppm): 1.40 (3H, s), 3.43 (1H, dd), 3.71 (1H, dd), 4.58 EXAMPLE 17 (1H, s), 4.9-5.1 (1H, m), 5.36 (1H, d), 5.93 (1H, d), 8.04 Preparation of benzhydryl (1H, s) 2a-methyl-2,3-(1,2,3-triazol-1-yl)methylpenam-3a-car EXAMPLE 1.4 boxylate-1,1-dioxide (Compound 21) Preparation of benzhydryl A 133 mg quantity of benzhydryl 2a-methyl-2,3-(4- 26-(4-carboxy-1,2,3-triazol-1-yl)methyl-2a-methylpe trimethylsilyl-1,2,3-triazol-1-yl)methylpenam-3a-car nam-3a-carboxylate-1,1-dioxide (Compound 18) boxylate-1,1-dioxide, 3.26 g of 18-crown 10 6(1,4,7,10,13,16-hexaoxacyclooctadecane) and 15.8 mg A 0.5 g quantity of benzhydryl 2f}-azidomethyl-2a methylpenam-3a-carboxylate-1,1-dioxide and 0.083 g of of potassium fluoride were stirred in 0.7 ml of N,N- acetylenecarboxylic acid were stirred in 2 ml of dichlo dimethylformamide at 50 to 60° C. for 5.5 hours. The romethane at room temperature under nitrogen atmo reaction mixture was poured into excess iced water and sphere for 24 hours. The solvent was removed by distil 15 the mixture was extracted a few times with ethyl ace lation at reduced pressure and to the residue oil was tate. The ethyl acetate extracts were collected and dried added benzene. The insolubles were filtered off and to over magnesium sulfate. The solvent was distilled off at the residue was added hexane to deposit crystals which reduced pressure and the residue was purified by col umn chromatography on silica gel, whereby a white were collected by filtration. Thus there was produced 20 0.23g of white crystals which melt at 120° to 121 C. product was given which has a melting point of 206 to Infrared absorption spectrum (KBr) vmax (cm): 208 C. (decomposition). 1805, 1745 Infrared absorption spectrum (KBr) umax (cm): Nuclear magnetic resonance spectrum (CDCl3) 8 1800, 1760 (ppm): 1.07 (3H, s), 3.2–3.8 (2H, m), 4.5-4.7 (1H, m), 25 Nuclear magnetic resonance spectrum (CDCl3) 6 4.69 (1H, s), 5.12 (2H, bs), 7.02 (1H, s), 7.1-7.6 (10H, m), (ppm): 1.05 (3H, s), 3.3-3.7 (2H, m), 4.5-4.7 (1H, m), 8.33 (1H, s) 4.65 (1H, s), 5.10 (2H, AB-q), 7.00 (1H, s), 7.3-7.5 (10H, EXAMPLE 1.5 m), 7.73 (1H, s) Preparation of disodium 30 EXAMPLE 1.8 2,3-(4-carboxly-1,2,3-triazol-1-yl)methyl-2a-methylpe Preparation of benzhydryl nam-3a-carboxylate-1,1-dioxide (Compound 19) 2a-methyl-2,3-(1,2,3-triazol-1-yl)methylpenan-3o-car Hydrogenation was conducted in 10 ml of ethyl ace boxylate-1,1-dioxide (Compound 21) tate and 10 ml of water at room temperature for 30 35 minutes by using 49 mg of benzhydryl 2A-(4-carboxly A 500 mg quantity of benzhydryl 2p3-azidomethyl 1,2,3-triazol-1-yl)methyl-2a-methylpenam-3a-carboxy 2a-methylpenam-3a-carboxylate-1,1-dioxide, 335 mg of late-1,1-dioxide, 15 ml of 10% palladium charcoal and trimethylsilylacetylene and 2 ml of methylene chloride 24 mg of sodium hydrogencarbonate. The aqueous were reacted in a sealed reactor at 95 C. for 20 hours. layer was separated from the reaction mixture and The reaction mixture was concentrated at reduced pres washed with ethyl acetate, and was purified with an sure and the residue was purified by column chroma MCI gel, CHP-20P (product of Mitsubishi Kasei Co., tography on silica gel to provide white solids having a Ltd., Japan). After freeze-drying, there was obtained a melting point of 203 to 204' C. (decomposition). white amorphous product having a melting point of Fast atomic bombardment mass spectrum method: 220 to 250 C. (decomposition). 45 m/e=467(M+) The values of the infrared absorption spectrum and The values of the infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound nuclear magnetic resonance spectrum of te compound thus obtained were similar to those of Compound 16 thus obtained were identical with those of Compound prepared in Example 12. 50 21 obtained in Example 17. EXAMPLE 16 EXAMPLE 9 Preparation of benzhydryl Preparation of benzhydryl 2a-methyl-2,3-(4-trimethylsilyl-1,2,3-triazol-1-yl)me 2a-methyl-2,3-(1,2,3-triazol-1-yl)methylpenam-3o-car thylpenam-3a-carboxylate-1,1-dioxide (Compound 20) 55 boxylate-1,1-dioxide (Compound 21) A 150 mg quantity of benzhydryl 2p3-azidomethyl 2a-methylpenam-3a-carboxylate-1,1-dioxide was re A 200 mg quantity of benzhydryl 2p3-azidomethyl acted in a sealed reactor with 300 mg of trimethylsily 2a-methylpenam-3a-carboxylate-1,1-dioxide was re lacetylene at 90° to 95 C. for 20 hours. The reaction acted with 10 ml of vinyl acetate in a sealed reactor at mixture was concentrated at reduced pressure, giving 60 100' to 110' C. for 30 hours. The reaction mixture was 170 mg of white crystals which melt at 172” to 175' C. concentrated at reduced pressure. The residue was Infrared absorption spectrum (KBr) vmax (cm): crystallized with cooled chloroform. 1805, 1755 The white crystals thus obtained were found to have Nuclear magnetic resonance spectrum (CDCl3) 8 65 a melting point (decomposition) and the values of the (ppm): 0.32 (9H, s), 1.05 (3H, s), 3.3-3.7 (2H, m), 4.5-4.7 nuclear magnetic resonance spectrum which were all (1H, m), 4.65 (1H, s), 5.08 (2H, AB-q), 7.00 (1H, s), identical with the values of Compound 21 obtained in 7.3-7.5 (10H, m), 7.67 (1H, s) Example 17. 4,562,073 19 of Mitsubishi Kasei Co., Ltd., Japan). After freeze-dry EXAMPLE 20 ing, there was obtained an amorphous product having a Preparation of sodium melting point of over 170° C. (decomposition). 2a-methyl-2,3-(1,2,3-triazol-1-yl)methylpenan-3ol-car Infrared absorption spectrum (KBr) vmax (cm): boxylate-1,1-dioxide (Compound 22) 5 1780, 1630 Hydrogenation was conducted in 10 ml of ethyl ace Nuclear magnetic resonance spectrum (D2O) 8 tate and 10 ml of water at room temperature for 30 (ppm): 0.32 (9H, s), 1.38 (3H, s), 3.1-3.7 (2H, m), 4.46 minutes by using 45 mg of benzhydryl 2a-methyl-2,3- (1H, s), 4.9-5.0 (1H, m), 5.23 (2H, AB-q), 8.16 (1H, s) (1,2,3-triazol-1-yl)methylpenan-3ol-carboxylate-1,1- The compounds obtained in some of the examples dioxide, 15 mg of 10% palladium charcoal and 16 mg of O were checked for 8-lactamase inhibitory activity and sodium hydrogencarbonate. The aqueous layer was antibacterial activity. separated from the reaction mixture and washed once (1) Test for £3-lactamase inhibitory activity with ethyl acetate. The aqueous solution was then puri The inhibitory activity against penicillinase (3-lacta fied with an MCI gel, CHP-20P (product of Mitsubishi mase) from Bacillus SP was measured by microiodome Kasei Co., Ltd., Japan). After freeze-drying, there was 15 try Tanpakushitsu Kakusan Koso (Protein Nucleic obtained an amorphous product with a melting point of Acid Enzyme), vol. 23, No. 5, pp.391-400 (1978) using over 170° C. (decomposition). a penicillin G as a substrate. Table 1 given below shows Infrared absorption spectrum (KBr) vmax (cm): the results. TABLE 1. 1780, 1630 20 Nuclear magnetic resonance spectrum (D2O) 8 Compound 50%. Inhibitory Concentration (ppm): 1.41 (3H, s), 3.45 (1H, dd), 3.72 (1H, dd), 4.48 Compound 7 5.4 x 10-8M (1H, s), 4.96-5.10 (1H, m), 5.25 (2H, AB-q), 7.85 (1H, d), Compound 11 3.4 x 10-7 M 8.13 (1H, d) Compound 12 4.9 x 108M Compound 13 3.0 x 10-7M EXAMPLE 21 25 Compound 16 6.0 x 10-7 M Compound 17 1.7 x 10-6M Preparation of p-nitrobenzyl Compound 22 6.9 x 10-7 M 2a-methyl-2,3-(1,2,3-triazol-1-yl)methylpenam-3a-car Compound 24 5.1 x 10-7 M boxylate-1,1-dioxide (Compound 23) A 1.02 g quantity of p-nitrobenzyl 2A3-azidonethyl 30 (2) Test for antibacterial activity 2a-methylpenam-3a-carboxylate-1,1-dioxide was re (1) Effects by amplicillin as combined with the acted with 50 ml of vinyl acetate in a sealed reactor at present compound 100 to 110° C. for 30 hours. The reaction mixture was The compounds of the present invention and amplicil concentrated at reduced pressure and the residue was lin, each singly used, were checked for minimal inhibi purified by column chromatography on silica gel, giv 35 tory concentration (MIC) against the bacteria listed in ing 0.73 g of the contemplated compound in amorphous Table 2 given below by micro-broth dilution method form in 67% yield which melts at 182 to 184 C. (“American Journal Clinical Pathology' published in Infrared absorption spectrum (KBr) umax (cm): 1980, vol. 73, No. 3, pp. 374 to 379). The MIC of ampi 1800, 1760 cillin as combined with the present compound (10 Nuclear magnetic resonance spectrum (CDCl3) 5 40 g/ml) was measured against the same bacteria. In the (ppm): 1.26 (3H, s), 3.5-3.6 (2, Hm), 4.66 (1H, s), 4.6-4.7 method, the bacteria cultivated in Mueller Hinton (1H, m) 5.07 (2H, s), 5.36 (2H, s), 7.61 (2H, d), 7.74 (1H, Broth (product of DIFCO) and diluted to 107 CFU/ml d), 7.80 (1H, d), 8.28 (2H, d) were inoculated into the same medium containing ampi EXAMPLE 22 cillin and the present compound in a specific concentra 45 tion, and incubated at 37 C. for 20 hours. Thereafter Preparation of sodium the growth of the microorganisms was observed to 2a-methyl-2p3-(4-trimethylsilyl-1,2,3-triazol-1-yl)me determine the minimal inhibitory concentration (MIC) thylpenam-3a-carboxylate-1,1-dioxide (Compound 24) for rendering the inoculated medium free from turbid Hydrogenation was performed in 15 ml of ethyl ace ity. The present compounds, singly used, turned out to tate and 15 ml of water at room temperature for 30 50 be all more than 25 g/ml in MIC. The bacteria as used minutes by using 200 mg of benzhydryl 2a-methyl-2p3 in the test were those capable of producing (3-lactamase, (4-trimethylsilyl-1,2,3-triazol-1-yl)methylpenam-3a among which the bacteria marked * in the table are carboxylate-1,1-dioxide, 50 mg of 10% palladium char those collected from the living body of human hosts and coal and 98 mg of sodium hydrogencarbonate. The the others are a stock culture. aqueous layer was removed from the reaction mixture 55 In Table 2, the present compounds are shown by the and washed once with ethyl acetate. The aqueous solu compound number. tion was purified with an MCI gel, CHP-20P (product TABLE 2 MC ml Test Ampicillin Present Compound (combined with anpicillin) Bacteria (singly used) 7 1. 12 3 16 17 22 24 S. aureus 25 0.1 0.2 0.2 0.2 0.2 0.78 0.2 0.78 S-54 S. aureus 25 O. O.2 0.2 0.2 0.2 0.78 O. 0.39 ATCC 90124 E. coli 400 6.25 25 3.13 6.25 6.25 0.05 3.13 100 TH-13 E. coli 400 6.25 12.5 3.3 6.25 3.3 6.25 6.25 50 TH-397 4,562,073 21 22 TABLE 2-continued MC ml Test Ampicillin Present Compound (combined with ampicillin) Bacteria (singly used) 7 12 13 6 7 22 24 P. mirabilis 400 1.56 0.78 0.78 0.78 0.78 0.39 O.78 25 12 P. vulgaris 00 0.78 0.78 0.39 0.39 156 1.56 0.78 1.56 ID OX-9 S. narcescens 400 2.5 25 2.5 25 6.25 1.56 3.13 100 TH-05

(2) Effects by antibiotics as combined with the present compound The compounds of the present invention, ampicillin, Preparation Example 2 mecillinam, piperacillin and cephalexin, each singly 15 Anoxycillin 100 mg used, were also tested for minimal inhibitory concentra- und 6 38 E. tion against 30 strains of coliform bacilli collected from Corn starch 490 M the living body of humans. The MIC of each antibiotic Hydroxypropyl methyl cellulose 10 mg as combined with the present compound (10 ug/ml) Total 1000 mg was likewise measured. Table 3 to 6 indicate the results' (amount per dose) in which MIC50 and MIC70 indicate the minimal inhibi tory concentration for inhibiting the growth of 50% The above ingredients are formulated in the propor and 70% respectively of the strains. The MICs of the tions listed above into granules. present compounds singly used were all more than 25 25 Flg/ml. TABLE 3 30 Strains of Ampicillin Present compound as combined with amplicillin coriform bacilii singly used Comp. 7 Comp. 1 Comp. 16 Comp. 17 Comp. 22 MIC50 (ug/ml) 400 6.25 50 6.25 25 3.3 MIC70 (ug/ml) 400 50 100 6.25 OO 6.25

TABLE 4 30 Strains of Mecilinan Present compound as combined with mecillinam coriform bacili singly used Comp. 7 Comp. 11 Comp. 16 Comp. 17 Comp. 22 MIC50 (ug/ml) 3.13 0.2 0.2 0,1 0.05 0.1 MIC70 (ug/ml) 12.5 0.39 0.39 0.1 0.39 0.2

TABLE 5 30 Strains of Piperacillin Present compound as combined with piperacillin coriform bacili singly used Comp. 7 Comp. 11 Comp. 16 Comp. 17 Comp. 22 MIC50 (ug/ml) 50 1.56 6.2S 1.56 6.25 1.56 MIC70 (ug/ml) 200 6.25 25 3.3 50 1.56

TABLE 6 30 Strains of Cephalexin Present compound as combined with cephalexin coriform bacili singly used Comp. 7 Comp. 11 Comp. 16 Comp. 7 Comp. 22 MIC50 (ig/ml) 25 12.5 12.5 6.25 3.13 2.5 MIC70 (ug/ml) 100 OO 100 25 12.5 50 Given below are examples of preparation of the pres- 55 ent antibacterial compositions. Preparation Example 3 Pivmecilinam 70 mg Compound 17 70 mg Preparation Example 1 Lactose 33 mg Ampicillin 200 mg 60 Crystalline cellulose 15 mg Compound 22 200 mg Magnesium stearate 3 mg Lactose 100 mg Talc 4 mg Crystalline cellulose 57 mg Corn starch 15 mg Magnesium stearate 3 mg Hydroxypropyl methyl cellulose 10 mg Total 560 mg Total 220 mg (amount per capsule) 65 (amount per tablet) The above ingredients are formulated in the propor- The above ingredients are formulated in the propor tions listed above into a capsule. tions listed above into a tablet. 4,562,073 24 the carboxyl group and a member selected from the group consisting of cyclohexylamine, trimethylamine, Preparation Example 4 diethanolamine, arginine and lysine. Compound 22 120 mg Hydroxypropyl cellulose 3 mg 11. The penicillin derivative as defined in claim 1 Corn starch 25 mg wherein R1 and R2 are hydrogen. Magnesium stearate 2ng 12. The penicillin derivative as defined in claim 1 Total 150 mg wherein R1 is hydrogen and R2 is -COOR2'. (amount per tablet) 13. The penicillin derivative as defined in claim 12 wherein R2' is C1-18 alkyl. The above ingredients are formulated in the propor O 14. The penicillin derivative as defined in claim 1 tions listed above into a tablet. wherein R2 is trialkylsilyl. We claim: 15. A pharmaceutical composition useful for treating 1. A penicillin derivative represented by the follow bacterial infections in mammals, said composition com ing formula prising (A) a 3-lactam antibiotic and (B) a compound of 5 the formula

N N O O "N 7 N N S CH2-N R 20 S CH-N a N R 2 CH3 o? Li'sYoOOR; N R2 o? COOR3 wherein R1 is hydrogen or trialkylsily; R2 is hydrogen, trialkylsilyl or COOR2' wherein R2' is hydrogen, C1-18 25 wherein R1 is hydrogen or trialkylsily; R2 is hydrogen, alkyl, C2-7 alkoxymethyl, C3-8 alkylcarbonyloxymethyl, trialkylsilyl or COOR2' wherein R2' is hydrogen, C1-18 C4-9 alkylcarbonyloxyethyl, (C5-7 cycloalkyl)car alkyl, C2-7 alkoxymethyl, C3-8 alkylcarbonyloxymethyl, bonyloxymethyl, C9-14 benzylcarbonyloxyalkyl, C3-8 C4-9 alkylcarbonyloxyethyl, (C5-7 cycloalkyl)car alkoxycarbonylmethyl, C4-9 alkoxycarbonylethyl, bonyloxymethyl, C9-14 benzylcarbonyloxyalkyl, C3-8 phthalidyl, crotonolacton-4-yl, y-butyrolacton-4-yl, 30 alkoxycarbonylmethyl, C4-9 alkoxycarbonylethyl, halogenated C1-6 alkyl substituted with 1 to 3 halogen phthalidyl, crotonolacton-4-yl, y-butyrolacton-4-yl, atoms, C1-6 alkoxy- or nitro-substituted or unsubstituted halogenated C1-6 alkyl substituted with 1 to 3 halogen benzyl, benzhydryl, tetrahydropyranyl, dimethylami atoms, C1-6 alkoxy- or nitro-substituted or unsubstituted noethyl, dimethylchlorosilyl, trichlorosilyl, (5-sub benzyl, benzhydryl, tetrahydropyranyl, dimethylami stituted C1-6 alkyl or phenyl or unsubstituted-2-oxo-1,3- 35 noethyl, dimethylchlorosilyl, trichlorosilyl, (5-sub dioxoden-4-yl)methyl, C8-13 benzoyloxyalkyl or group stituted C1-6 alkyl or phenyl or unsubstituted-2-oxo-1,3- for forming a pharmaceutically acceptable salt; and R3 dioxoden-4-yl)methyl, C8-13 benzoyloxyalkyl or group has the same meaning as above R2'. for forming a pharmaceutically acceptable salt; and R3 2. The penicillin derivative as defined in claim 1 has the same meaning as above R2', the weight ratio of wherein R3 is C2-7 alkoxymethyl. (A)/(B) being 0.1 to 10, said £8-lactam antibiotics being 3. The penicillin derivative as defined in claim 1 selected from the group consisting of ampicillin, amox wherein R3 is C3-8 alkylcarbonyloxymethyl, C4-9 alkyl icillin, hetacillin, cicladillin, mecillinam, carbenicillin, carbonyloxyethyl, (C5-7 cycloalkyl)carbonyloxymethyl, sulbenicillin, ticarcillin, piperacillin, apalcillin, methicil C9-14 benzylcarbonyloxyalkyl or C8-13 benzoyloxyalkyl. lin, mezlocillin, bacampicillin, carindacillin, talampicil 4. The penicillin derivative as defined in claim 1 45 wherein R3 is C3-8 alkoxycarbonylmethyl or C4-9 alkox lin, carfecillin and pivnecillinam, cephaloridine, cepha ycarbonylethyl. lothin, cephapirin, cephacetrile, cefazolin, cephalexin, 5. The penicillin derivative as defined in claim 1 cefraidine, cefotiam, cefamandole, cefuroxime, cefoxi wherein R3 is phthalidyl. tin, cefmetazole, cefsulodin, cefoperazone, cefotaxime, 6. The penicillin derivative as defined in claim 1 50 ceftizoxime, cefimenoxime, latamoxef, cefaclor, cefroxa wherein R3 is crotonolacton-4-yl and y-butyrolacton dine, cefatrizine, cefadroxil and cephaloglycin; and 4-yl. pharmaceutically acceptable salts thereof. 7. The penicillin derivative as defined in claim 1 16. A method of treating a bacterial infection in a wherein R3 is (5-substituted C1-6 alkyl or phenyl or mammal subject, said method comprising administering unsubstituted-2-oxo-1,3-dioxoden-4-yl)methyl. 55 to said subject (A) a 3-lactam antibiotic and (B) a com 8. The penicillin derivative as defined in claim 1 pound of the formula wherein R3 is a group for forming a pharmaceutically acceptable salt. O O 9. The penicillin derivative as defined in claim 1 N N wherein R3 is C1-6 alkyl or halogenated C1-6 alkyl substi R tuted with 1 to 3 halogen atoms, C1-6 alkoxy- or nitro S CH-N substituted or unsubstituted benzyl, benzhydryl, tetra 2 hydropyranyl, dimethylchlorosilyl and trichlorosilyl. o?L'S N COOR; -. 10. The penicillin derivative as defined in claim 8 wherein the group for forming a pharmaceutically ac 65 ceptable salt represented by R3 is alkali metal atom, wherein R1 is hydrogen or trialkylsilyl; R2 is hydrogen, alkaline earth metal atom or ammonium, or the group trialkylsilyl or COOR2' wherein R2' is hydrogen, C1-18 COOR3 represents a carboxylic acid salt formed from alkyl, C2-7 alkoxymethyl, C3-8 alkylcarbonyloxymethyl, 4,562,073 25 26 C4-9 alkylcarbonyloxyethyl, (C5-7 cycloalkyl)car moxef, cefaclor, cefroxadine, cefatrizine, cefadroxil and bonyloxymethyl, C9-4 benzylcarbonyloxyalkyl, C3-8 cephaloglycin; and pharmaceutically acceptable salts alkoxycarbonylmethyl, C4-9 alkoxycarbonylethyl, thereof. phthalidyl, crotonolacton-4-yl, y-butyrolacton-4-yl, 17. The penicillin derivative as defined in claim 11 halogenated C1-6 alkyl substituted with 1 to 3 halogen wherein R3 is C3-8 alkylcarbonyloxymethyl, hydrogen, atoms, C1-6 alkoxy- or nitro-substituted or unsubstituted C4-9 alkylcarbonyloxyethyl, (CS-7 cycloalkyl)-car benzyl, benzhydryl, tetrahydropyranyl, dimethylami bonyloxymethyl, C9-14 benzylcarbonyloxyalkyl, C3-8 noethyl, dimethylchlorosilyl, trichlorosilyl, (5-sub alkoxycarbonylmethyl, C4-9 alkoxycarbonylethyl, stituted C1-6 alkyl or phenyl or unsubstituted-2-oxo-1,3- phthalidyl, crotonolacton-4-yl, y-butyrolacton-4-yl, dioxoden-4-yl)methyl, C8-13 benzoyloxyalkyl or group 10 (5-substituted C1-6 alkyl or phenyl or unsubstituted-2- for forming a pharmaceutically acceptable salt; and R3 oxo-1,3-dioxoden-4-yl)methyl, C8-13 benzoyloxyalkyl or has the same meaning as above R2', the weight ratio of group for forming a pharmaceutically acceptable salt. (A)/(B) administered being 0.1 to 10, said 6-lactam 18. The penicillin derivative as defined in claim 12 antibiotics being selected from the group consisting of wherein R3 is C3-8 alkylcarbonyloxymethyl, hydrogen, ampicillin, amoxicillin, hetacillin, ciclacillin, mecilli 15 C4-9 alkylcarbonyloxyethyl, (C5-7 cycloalkyl)-car nam, carbenicillin, sulbenicillin, ticarcillin, piperacillin, bonyloxymethyl, C9-14 benzylcarbonyloxyalkyl, C3-8 apalcillin, methicillin, mezlocillin, bacampicillin, carin alkoxycarbonylmethyl, C4-9 alkoxycarbonylethyl, dacillin, talampicillin, carfecillin and pivmecillinam, phthalidyl, crotonolacton-4-yl, y-butyrolacton-4-yl, cephaloridine, cephalothin, cephapirin, cephacetrile, (5-substituted C1-6 alkyl or phenyl or unsubstituted-2- cefazolin, cephalexin, cefradine, cefotiam, cefamandole, 20 oxo-1,3-dioxoden-4-yl)methyl, C8-13 benzoyloxyalkyl or cefuroxime, cefoxitin, cefnetazole, cefsulodin, cefoper group for forming a pharmaceutically acceptable salt. azone, cefotaxime, ceftizoxime, cefimenoxime, lata x 2k

65 UNITED STATES PATENT AND TRADEMARK OFFICE

CERTIFICATE EXTENDING PATENT TERM UNDER 35 U.S.C. S 156

PATENT NO. : 4,562,073 DATED : December 31, 1985 INVENTOR(S) : Ronald G. Micetich et al. PATENT OWNER : Taiho Pharmaceutical Company

This is to certify that there has been presented to the

COMMISSIONER OF PATENTS AND TRADEMARKS an application under 35 U.S.C. S 156 for an extension of the patent term. Since it appears that the requirements of the law have been met, this certificate extends the term of the patent for the period of

1,344 DAYS from the original expiration date of the patent, June 6, 2003, subject to the requirements of 35 U.S.C. S 41, with all rights pertaining thereto as provided by 35 U.S.C. S 156(b).

I have caused the seal of the Patent and Trademark Office to be affixed this 25th day of April 1996. (3-40%- Bruce A. Lehman Assistant Secretary of Commerce and Commissioner of Patents and Trademarks