CA1224151A - Penicillin derivatives and process for preparation of the same - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

A pharmaceutical composition useful for treating bacterial infections in mammals which comprises (A) a .beta.-lactam antibiotic and (B) a compound of the formula

Description

This invention relates to penicillin deriva-tives and in particular -to a pharmaceu-tical composition useful for treating bacterial injections in mammals comprising a syenergistic mixture of the penicillin derivatives and a lactam anbitiobic.

of the commercially available antibiotics, ~-lactam type antibiotics having a a-lactam ring, namely penicillins and cephalosporins, are best known and frequently used. Although widely used as useful chemotherapeutic drugs, the ~ -lactam type antibiotics canno-t achieve sa-tisfactory effects against some types of microorganisms because of resistance of the microorganism to the ~-lactam type antibiotics. The resistance thereof are usually at-tributable to ~ -lactamase produced by the micro-organism. The ~-lactamse is an enzyme which acts to cleave the ~ -lactam ring of the ~ -lactam type antibiotic, thereby causing the antibiotic to lose its antimicrobial activity.
For this reason, the action of ~-lactamase must be elimina-ted or inhibited so as to enable the ~ -lactam -type anti-biotic or produce satisfactory effects. The elimina-tion or inhibi-tion of -the ~ -lactamase activity can be achieved by -lactamase inhibitors, which are used cojointly with the ~ -lactam type antibiotic to increase the antimicrobial activity of the antibiotic.

This application is a divisional application of copending application No. 434,044 filed August 8, 1983.

In the copending application No. 434,044 there are provided novel compounds having p -lastamse inhibitory action and their preparation.

The present invention provides a pharmaceutical composition having excellent a -lactarnase inhibitory action, which when combined with ~ -lactam type antibiotics, `

: .
' ~2~5~

can increase the antibacterial aetivity of the an-tibio-tics.

The copending applieation No. 434,044 there are provided penicillin derivatives represented by the formula N = N
O O ~ R
~ ~ ~C112-r~ ~113 (I) ~ N - ~
O "COOR
~ 3 wherein Rl is hydrogen or trialkylsilyl, R2 i5 hydrogen, trialkylsilyl or COOR2' wherein R2' is hydrogen, Cl_l8 alkyl, C2 7 alkoxymethyl, C3_8 alkylearbonyloxymethyl, C4 9 alkylcarbonyloxyethyl, (C5_7 eyeloalkyl)earbonyloxymethyl, C9_l4 benzylearbonyloxyalkyl, C3_8 alkoxyearbonylmethyl, C4_9 alkoxyearbonylethyl, phthalidyl, .

;

: 35 `~:

. . ~ ' I' .

, ~ ~ . ' . . I , .

cro~onolacton-4-yl, ~-butyrolacton-4-yl, halogenated Cl 6 alkyl sul~stituted witll 1 ~o 3 halogen atoms, Cl 6 alkoxy- or nitro-substltuted or unsubstituted benzyl, benzhydryl, te~rahydropyranyl, dimethylaminoethyl, dimethylchlorosllyl, trichlorosilyl, (5-substituted Cl 6 alkyl or phenyl or unsubstituted-2-oxo-1,3-dioxoden-4-yl)methyl, C8_13 benzoyloxyalkyl and group for forming a pharmaceutically acceptable salt; and R3 has the same meaning as R2'.
The penicillin derivatives of the copendillg application are all novel compounds and have ~ -lactamase inhibitory properties, hence useful as ~ -lastamase inhibi--tory agents.
In accord~lce with the present invention penicillin deri-vatives of the copending application when used in combination with aknown ~-lactam type antibiotic, can increase the antimicrobial activity oE-the ~-lactam type antibiotic.
Examples of antibiotics which can be used cojointly with the compounds of the copending applica-tion are ~-lactam antibiotics which exhibit antibacterial ac~ion against gram-positive or gram-nega~ive bacteria and which include commonly used penicillins such ..
as ampicillin, amoxicillin, hetacillin, ciclacillin, mecillinam, carbenicillin, sulbenicillin, ticarcillin, piperacillin, apalcillin, methicillin, mezlocillin .

- -, ~ .
,,-: ,-. . ~
- i '-- ,: ~ ,:
~. .. ' . ' ., ~ .

4 12~41~1 an~ salts thereo~; esters oE penicillins such as bacaml~icillin, carindaeillin, talampicillin, car~ecillin and pivmecillinam; cephalosporins such as cepl~aloridine, cephalothin, cephapirin, cephacetrile, cefazolin, cephalexin, ceEradine, cefotiam, eeamandole, cefuroxime, ceEoxitin, eefmetazole, ce~sulodin, eefoperazone, cefotaxime, eeftizoxime, cefmenoxime, latamoxef, ce~aclor, cefroxadine, cefatrizine, ceadroxil, eephaloglyein, and salts thereoE. The R-lactam antibiotics are usually used in an amount of about 0.1 to about 10 parts by weight, preferably about 0.2 to about S parts by welght, per part by weight of the compound of the invention.
Examples oE the trialkylsilyl groups represented by Rl and R2 in the ~ormula tI) inelude trialkylsilyl having straight-chain or branehed-chain Cl 6 alkyl sueh as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, and the like.
Examples oE the group R2' oE COOR2' represented ~y R2 in the Eormula (I) include; Cl_l8 alkyl such as methyl, ethyl, propyl, isopropyl, tert-butyl, pentyl, hexyl, decyl, undecyl, dodeeyl, tetradeeyl, hexadeeyl, : octadecyl and like straight- or branched-chain alkyl;
C2 7 alkoxymethyl such as methoxymethyl, ethoxymethyl, propyloxymethyl, isopropyloxymethyl, butoxymethyl and hexyloxymethyl; C3 8 alkylcarbonyloxymethyl such as , - .

. ,,, ". ~ ' r _ S _ methylcarbonyloxymethyl, ethylcarbonyloxymetllyl, butylcarborlyloxymethyl and hexylcarbonyloxyme~llyl;
C~ 9 alkylcarbonyloxyetllyl such as methylcarbonyloxy-ethyl, ethylcarbonyloxyethyl, butylcarbonyloxyethyl and pivaloyloxyethyl; (C5 7 cycloalkyl)carbonyloxymethyl such as cyclopentylcarbonyloxymethyl, cyclohexyl-carbonyloxymethyl and cycloheptylcarbonyloxymethyl;
Cg 1~ benzylcarbonyloxyalkyl such as benzylcarbonyloxy-methyl, benzylcarbonyloxyethyl, benzylcarbonyloxypropyl o and benzylcarbonyloxybutyl; C3_8 alkoxycarbonylmethyl such as meLhoxycarbonylmethyl, ethoxycarbonylmethyl, propyloxycarbonylmethyl and hexyloxycarbonylmethyl;
C~ g alkoxycarbonylethyl such as methoxycarbonylethyl, ethoxycarbonylethyl, propyloxycarbonylethyl, butoxy-carbonylethyl and hexyloxycarbonylethyl; halogenatedCl 6 alkyl substituted with 1 to 3 halogen atoms such as chloromethyl, 2,2-dibromoethyl and trichloroethyl;
Cl 6 alkoxy- or nitro-su~stituted or unsubstituted benzyl such as p-methoxybenzyl, p-ethoxybenzyl, o-nitrobenzyl and p-nitrobenzyl; (5-substituted Cl 6 alkyl or phenyl or unsubstituted-2-oxo-1,3-dioxoden-4-yl)methyl such as (2-oxo-1,3-dioxoden-4-yl)methyl;
(5-methyl-2-oxo-1,3-dioxoden-~i-yl)methyl and (5-phenyl-

2-oxo-1,3-dioxoden-4-yl)methyl; C8 13 benzoyloxyalkyl 2S sucll as benzoyloxymethyl, benzoyloxyethyl, benzoyloxy-. ~

'~ , "' ` ~

_ 6 ~ 1~4~

propyl arld benzoyloxybutyl; etc.
Examples o~ the groups represented by R3 in ~he formula (I) are the same as those exempliied in respect of the group R2'.
The ester residues represented l~y R2' and R3 include bo~h carboxyl-protecting groups acceptable in the synthesis of penicillin compounds and pharmaceutically acceptable ester residues. A pharmaceutically acceptable ester having such residue is an ester which is easily hydrolyzed in vivo and which is a non-poisonous ester capable oE rapidly decomposing in the blood or tlssue of humans, thereby producing the corresponding aci~ of the ~ormula (I) in which R3 is hydrogen atom. Generally in the synthesis of penicillin compounds, ester-protecting lS groups are used in the art to protec~ penicillin carbo~yl groups or othex carboxyl groups. While it is dif~icult to ~etermine which ester-protecting group should be used, consideration are usually given to select esters in which the protecting group per se is suficiently stable in the reaction and which does not permlt cleavage of the ~-lactam ring in removal of the ester-protecting groups.
Mos~ commonly used as such ester-protecting groups are p-nitrobenzyl group, benzhydryl group, trichloroethyl group, trichlorosilyl group, tetrahydropyranyl graup, etc. Examples of the pharmaceutically acceptable ester ., : ,,., . . - . ~: . :

. :. . :

- 7 ~

~roups are pllthalidyl, crotonolacton-4-yl, y-butyro-lac~on-~-yl, (2-oxo-1,3-dioxoden-4-yl)metllyl, etc, Examples of the group for forming a pllarma-ceu~ically acceptable salt represented by R2' and R3 in tlle formula (I) include; sodium, potassium, lithium, or like alkali metal a~oms; calcium, magnesium or like alkaline eart~ metal atoms; cyclohexylamine, trimethyl~
amine, die~hanolamine or like tlle organic amine residues;
al~inine, lysine or like basic amino acid residues;
ammonium residues, etc.
The penicillin derivatives having the formula (I) can be prepared by the process as shown in reaction equations given below. The pro-cesses differ according to the kind of the groups represented by Rl and R2.
Reaction EquatIon-l . ' .
O O
~l ~CLl2 3 RlC 3 CR5 (III) F / ~C~.,3 Step (A) "COOR~

(II) .

:

- ' :

., . ~

. . . , :
. . -.

.. :. ;. ~.
.. . .. ;

- 8 ~ 4~

N N
I --~Rl C~l2 N ~ R5 Clt Step (B) ~ N
o ~ "COOR~

(IV) N N
o o I +R
~ ~ ~ C112-N ~ R5 C}I
.. ~ N ~
o ~ `COOR3 (I-a) In the foregoing formulae, Rl and R3 are as deEined above, R4 is penicillin carboxyl-protecting ;~ 5 group and R5 is trialkylsilyl or COOR2' wherein R2 7 ~:~ . i5 as defined above.
. Examples oE the peni.clllin carboxyl protecting group expressed by R4 include known groups such as those described in Japanese Unexamined Patent Publication No.81380/1974 and ll.E. Flynn, "Cephalosporins and Penicillins, Chemlstry and Biology" (published in 1972 by Academic Press). 5peci~ic examples thereo~ are ethyl, propyl, tert-butyl, trichloroe~hyl alid like substi~uted or unsubstituted alkyl groups; benzyl, :
- :

-- , :." - ;, 9 ~ 4~

diphenyl me~hyl, p-ni~robenzyl and lilce substituted or unsu~sti~uted arallcyl groups; acetoxymethyl, acetoxyethyl, propionyloxyethyl, pivaloyloxyethyl, pivaloyloxypropyl, benzyloxyme~hyl, benzyloxye~hyl, benzylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and like acyloxyalkyl groups, methoxyme~hyl, etl~oxy-methyl, benzyloxymethyl and like alko~yalkyl groups;
and other groups such as tetrahydropyranyl, dimethyl-aminoethyl, dimethylchlorosilyl, ~richlorosilyl and like groups.
The s~eps (A) and (~) oE the Eoregoing process will be described below in detail.
_tep (~) A penicillanic acid derivative oE the formula (II) is reacted with an acetylene derivative oE the ormula (III) to provide a compound oE t!~e formula (IV).
The reaction is conducted in a suitable solvent by reacting a known penicillanic acid derivative oE the Eo-rmula (II) with a known acetylene derivative oE the Eorlnula (III) in an amoun~ oE about 1 ~o a~out 50 moles, preerably about 1 ~o about 10 moles, per mole oE the derivative of the Eormula (II).
The solvents use~ul in the reaction are not particularly limited and include any oE tho~e which do no~ adversely afEect the reaction. SpeciEic e~amples i .

, : " ' ,.
, ,-, ~ " .. . ... .

.:

_ 10 ~ ~2~5~

oE tlle solvents are an acetylene derivative o the ~orlnula (III) as used in excess amount or benzene, toluene, xylene and like aromatic hydrocarbons, tetra-hydrofuran, dioxane or like ethers, acetone and like polar organic solvents; etc. These solvents are used singly or in mixture. The reaction proceeds usually at a temperature o~ between about 50C and a boiling point of the solvent, or at a temperature of less than 200C
in a sealed reactor, and goes to completion in about 2 to about 72 hours.
Depending upon the kind oE the penicillin carboxyl protectlng group represented by R~, the com-pounds of the formula (IV) obtained in step (A) may be esters oE the penicillin derivatives oE the present invention having the formula (I). The compounds oE
the formula (IV) are preerably subjected to de-esteriEicatlon to orm a derivative o~ the formula (I-a) itl which R3 is hydrogen which, in turn, is converted into a pharmaceutically acceptable salt or ester thereof as in the ollowing step (B). The compound oE the formula (IV) can also be made into an ester oE the formula (I-a) by the conventional ester interchange reaction in thè
step (B).
Step (B) The compound o~ tbe Eormula (IV) i9 subjected : : , : . ~
: ,.

. :' ' '.; ~ :. " , :

~ 5~
to de-esterification without or after isolation ~rom tlle reaction mixture obtained itl ste~) (A), wllereby a penicillin derivative o~ the ~ormula (I~a) in which R3 is hydrogen is obtained.
As the de-esterification method, reduction, hydrolysis, treatment wi~h an acid and like method can be employed Eor converting the carboxyl-protecting group to carboxyl group. For example, if the carboxyl-protecting group is an active ester, the reactlon Erequently proceeds . 10 with ease under mild hydrolysis conditions or by merely bringing the ester lnto contact with water. The reduction method is employed wllen the carboxyl-protecting group is ; trichloroethylbenzyl, p-nitrobenzyl, diphenylmethyl or t~le like. Treatment with an acid is adopted when the lS carboxyl-protectlng group is 4-methoxybenzyl, tert-butyl, trityl, diphenylmethyl, methoxymethyl, tetrahydropyranyl or the like.
The reductian can be conducted by treating the ester o~ the formula (IV) witll a mixture o~ (a) zinc, zinc-amalgam or like metal and/or chromium chloride, chromium acetate or like chromium salt and (b) ~o~mic acid, acetic acid or like acid. Alternatively, the reduction can be conducted with use of a catalyst in hydrogen atomosphere in a solvent. Examples o~ the catalysts are platinum, platinum oxide, palladium, .. . .
. .,,:
.: ., ~ ;~.,, ~ 2~S~
palladium oxide, palladium-barium sulfate, palladium-calciuln carbonate, palladium-carbon, nickel oxide, L~aney-nickel, etc. llle solvents are not particularly lin~ited so far as they do not adversely afEect the reaction, and include methanol, ethanol and like alcohols; tetrahydrofuran, dioxane and like ethers;
ethyl acetate and like esters; acetic acid and like fatty acids; and a mixture o these organic solvents and water.
lo The acids useful for eliminating the carboxyl-protecting group of the ester o the formula (I-a) are formic acid, acetic acid and like lower fatty acids;
tricllloroacetic acid, trifluoroacetic acid and like trihalogenated acetic acids; hydrochloric acid, hydro-fluoric acid and like hydrohalogenic acids; p-toluene-; sulfonic acid, trifluoromethane-sulfonic acid and like organic sulfonic acids; and a mixture oE these.
In this reaction, when tbe acid used is in~a liquid state and acts also as a solvent, it is not necessary to use other solvents ~lowever, dlmethylformamide, dichloromethane, chloroorm, tetrahydrouran, acetone and like solvents which do not adversely affec~ the reaction may be used.
lhe penicillin derivative of the present invention having the formula (I-a) in which R3 is ., "'. . , ~

_ 13 ~ ~4~

hydrogen can be transformed by the salt-Eorming reaction or esterification commonly employed in the art into a pharmaceutically acceptable salt or ester as contemplated.
If the ester residue is, for example,

3-phthalidyl, crotonolacton-4-yl, y-butyrolacton-4-yl or like group, the penicillin derivative oE the ~ormula (IV) can be alkylated by using 3-halogenated phthalide,

4-halogenated crotonolactone, 4-halogenated-y-butyrolactone or the like. Suitable halogens of the foregoing halides include chlorine, bromine, iodine, etc. rhe reaction is carried out by dissolving ~he salL oE the penicillin derivative oE the formula (I~) in N,N-dimethylformamide or like suitable polar organic solvent and addlng an approximately equimolecular amount oE a halide to the solution. The reaction temperature ranges ~rom about 0 to about 100C, preferably from about 15 to about 35C. Suitable salts oE the penicillln derivative to be used in tlle esterification are salts oE
sodiuln, potassium or like alkali metals; salts of tri-ethylamine, ethyldiisopropylamine, N-ethylplperidine, N,N-dimethylaniline, N-methylmorpholine or like tertiary amines, etc. AEter completion oE the reaction, the contemplated product can be easily separated by the con-; ventional method and also can be purified, when required, by recrys~allization, thin layer chromatography, columnchromatography or like method.

'^

. ~-~ ' ' ~ 2Z~

Tlle compound of the formula (II) to be use~ as the starting material in the step (~) .is a llovel compound undisclosed in litera-ture and can be synthesized by a method com-prising the steps of reacting a metal azidewith a known derivative of penicillanic acid oE the formula C~12~C
3 (V) . O ~COOR4 wherein X represents chlorine atom or bromine atom and R4 is as defined above, oxydizing the reaction mixture and sub~jecting the resulting compound to de-esterification.
The foregoing method will be clescribed below in detail. The reaction between the compound oE the Eorlllula (V) and the metal azide is conduc~ed in a suitable solvent by using the metal azide in an amount o~ about l to about 50 moles, preEerably about l to about 10 moles, per mole of the compound o~ the Eormula (V). Examples o the metal azides which can be used include those commonly used, such as sodium azide, potassium azide and like azides o~ alkali metals, and : .: . .... . . .
.. . .. .

1 5 - ~224~

barium azide ancl like azides oE allcaline earth métals.
Useful solven~s-are not particularly limi~ed as far as they do not adversely affect the reaction. ~xanlples o useEul solvents are dimethylformamide, ethyl acetate, acetone, dichloromethane, tetrahydrofuran, dioxane, methanol, ethanol and like organic solvents. These Organic solvents can be used singly or in mi-xtures.
Also a mixture of such solvent and water is usable.
The reaction proceeds at a temperature of usually about . 10 -20 to about 100C, preEerably about 0 to about 100C.
The resulting product can be used in subsequent oxidation without isolation, or alternatively after isolation and puriEica~ion by a conventional method. The oxidation ~ subsequent to the azid~-forming raaction is conducted - 15 by using an oxidizing agent commonly employed such as permanganic acid, periodic acid, peracetic acid, performic acid, trifluoroperacetic acid, perbenzoic acid, m-chloroperbenzoic acid, hydrogen peroxide, etc.
The oxidizing agent can be used in large excess, and may be e~ployed preferably in an amount oE about 1 to about 2 moles per mole of the starting compound. The oxidation is carried out usually in a suitable solvent. Useful solvents include any of those which do not adversely aEfect tl~e oxidation reaction such as chloroform, z5 pyridine, tetrahydrofuran, dioxane, methylene chloride~

,. i . .. ... ....-. - : .

" " :.,~''' ' ,-, ' , ' : ' --- 1 6 - ~22~15~

carbon tetrachloride, acetic acid, ormic acid, dimethyl-fo~ alnide, water, etc. The oxidation i5 performed at a temperature which is not particularly lilnited but generally ranges from room temperature to cooling tem-perature, preferably about 0 to about 30C.
The compound thus obtained is subjected to de-esterificaTtion whereby the compound of the formula (II) can be produced. The de-esterification is effected under the same conditions as shown in the reaction scheme o the step (B). The process or preparing the compound o the formula (II) ls described in detail ln reEerence examples ~o be set forth later.

.

~ .

. . ; .,; ~ . . , .,: ~:.~ .. .

`' ' ~ :: ' "!:, ' ' : " ' : ' ' ' ' ~ 17 ~2~4~

React:iorl E~lua~ion-2 O O

,L'~ ` Cll Rl ' C - CR5 ' tIII ' ) O `COOR4 11 \ S~ep (C) (II) \
Nc N
C1~2~

C~l R6 .. ,~N1~

(VI) N N
'~ C ~i 2 - N~, 1 ~

C~l / St:ep (D) O ~COOR4 Step (E) . . (IV~ ) N----N
'' 00 ~S~ CII 2 L--~ ~` Cll t ~COOR3 (I-b) .: . ~ .. . :. .
. :.:. .

., . :.,: . ~
. . .
:. ~.,, . :~., In the Eoregoing ~orlnulae, R4 is as deEined above, Rl' and U5' are the same groups as those represented by Rl and R5 and at least one o them is trialkylsilyl group, and R~ represents hydrogen or COOR2' wherein R2' is as deEined above.
The compound of the ormula tI~ wherein at least one o~ Rl and R2 is hydrogen atom, namely the colnpound of the formula (I-b), can be prepared by the process sllown above in Reaction Equation-2. The steps in the process are set forth below in detail.
Step (C) The compound of the formula (II) is reacted with a compound oE the Eonnula (III') in a solvent such as dichloromethane, dichloroethane, chloroforln or like halogenated hydrocarbons. During this reaction, reaction for removing the trialkylsilyl group proceeds ; at the same time, whereby a compound oE the ~ormula (VI) is produced. Useful solvents are no~ particularly limited as Ear as they are halogenated hydrocarbons.
The reaction conditions including the reaction tem-perature, the proportions oE the reagents to be used and the reaction time are similar to those in the step (A)~.
Depending upon the kind of the penicillin carboxyl-protecting group represented by R~, the compound oE the formula ~VI) thus obtained may be the product as , .. , . -.

. .. -: ~.- , ,: :.
- ". ~',., ~ ,, ~
: .
.-.: :

1 9 ~ 4~

contemplated, i.e., an ester aE the penicillin derivati~e oE tlle ~ormula (I~ ore preEerably the ester of the ~ormula (VI) is subjected to de-esterifica~ion as in ~he stey (B) so that the compound is trans~ormed to a penicillin deriva~ive oE the present invention having the formula (I-b) in which R3 is hydrogen which is converted, when required, in the conventional manner into a pharmaceutically acceptable salt thereof or ester thereof as contemplated.
Step (D) The compound oE the Eormula (VI) is subjected to de-esterification after or without isolation from the reaction product obtained in the step (C), whereby a penicillin derivative oE the Eormula (I-b) in which R3 is hydrogen is produced. The de-esterlEication is carried out under the same conditions as those descrlbed above in respect of the step (B).
The compound oE the Eormu;la (VI) can be preyared by the process ln the step (C) and also by the process to be set forth below in a step (E).
Step (E) The compound oE the formula (IV) obtained in tlle step (A) as shown in Reaction Equation-l wherein at least one of Rl and R5 is trialkylsilyl, namely the com-Z5 yound oE the formula (IV'I, Is sub~ected o reaction Eor . :
.
\

-: . , ~: ~ .~ : ..

20 ~ 2~15~

removing the trialkylsilyl in the presence oE potassium Eluoride after or without isolation ~rom the reaction product obtained in the step t~), whereby a compound oE tlle ~ormula (VI) is produced. The trialkylsilyl~
removing reaction is conducted in a s~itable solvent by using potassium fluoride in an amount o over about 1 rnole, preerably about 1 mole, and a catalyst in an amount o about 1/50 to abou~ l/lQ mole, both per mole o the compound of the ormula (IV). Useul as the . 10 catalyst is a phase transer catalyst such as quaternary ammonium salt, crown etheL or the like. Examples oE
useful solvents are any suitable solvents which do not adversely affect the reaction and which include benzene, toluene, xylene or like aromatic hydrocarbons; aceto-nitrile, N,N-dimethylormamide, dimethylsuloxide or like non-protonic polar solvents; etc. The reaction temperature ànd reaction time are appropriately determine~. Generally the reaction is perormed at a temperature in the range o room temperature to about 100C, and completes ln about 1 to about 10 hours.
.

. . .
. 25 -'-_ 21 - ~2~5~

Reaction Equation-3 O O

~ C113 C112 = C~IR7 (~II) O 1 ~COOR4 Step (F) (II) N N
~ ~ ~C~ 2 J
Step (G) r~ C~13 ,I N ~
O/' ¦ "COOR

(VIII) N =

~ CH3 o ~ ~COOR3 Il (I-c) In the oregoing formulae, R4 is as deined above, and R7 represents acyloxy group.

Examples of the acyloxy groups rep-resented by R7 are lower acyloxy groups having 2 to 5 carbon atoms such as acetoxy, propionyloxy, butyryloxy, ~aleryloxy or like aliphatic acyloxy groups and benzoyloxy or like ' ,, ~ . .

. ` '~ " .

~ 22 ~ 5~

aromatic acyloxy groups, etc.
The compound of the ormula (I) wherein Rl and R2 are llydrogen atoms, namely the compound o~ the ~ormula (I~c), can be produced by the process as sho~n above in Reaction Equation~3.
The steps (F) and (G) in Reaction Equation~3 will be described below in detail.
Step (F) The penicillanic acid derivative of tlle formula (II) is reacted with a vinyl derivative oE the formula (VII) wllile reaction for removing the acyloxy group represented by R7 in the formula (VII) is carried out, whereby a compound of tbe formula (VIII) is prepared.
The reaction between the penicillanic acid derivative of the formula (II) and the vinyl derivative o~ the formula (VII) is conducted in the presence o or in the absence o~ a suitable solvent by using the vinyl derivative of the formula (VII) in an amount o at least about 1 mole, preferably about 1 to about 200 moles, per mole of tlle derivative oE the iormula (II)~ whereby there occurs simultaneously tlle acyloxy-removing reaction.
The solvents which can be used are not particularly limlted as far as they do not adversely affect the reaction. Specific examples thereof are benzene, toluene, xylene or like aromatlc hydrocarbons, tetra-<

, ' ~ ~

,~

,:

- 23 ~ ~224~

hydrofuran, dioxane or like ethers, etc. T~e reaction is effected at a temperature ranging from about 50C
to a boiling point of the solvent, or a temperat~lre oE
less than 200C in a sealed reactor, and is completed in about 2 to about 72 hours. Depending on the kind of the penicillin carboxyl-protecting group represented by R4 in the formula (VIII3, the compound of the formula (VIII) thus obtained may be the product as contemplated, naulely the ester of the penicillin derivative oE the formula (I). More preferably the compound o the formula (VIII) thus prepared is subjected to de-esterification as in the step (G) so that the compound is converted by the conventional method into a penicillin derivative of the formula (I-c) wherein R3 is hydrogen which, in turn, is transformed by the conventional method into a pharma-ceutically acceptable salt thereof or ester thereof a3 contemplated. The compound of the formula (VIII) can be made into a pharmaceutically acceptable salt thereoE or ester thereoE as contemplated by conducting an ester interchange or salt-forming reaction in the conventionai manner (~) The compound of ~he formula ~VIII) ls subjected to de-esterification after or without isolation ~rom the reactlon product obtaLned in the step (F), whereby .
~, .. .
.
.,.. ; . ~ -,:
~-,. -~.
~ '~ '.';.' `

_ 2l~ 2~1S~
a penicillin derivative oE the formula (I-c) in wllich R3 is llydrogen is produced. The reac~ion conditions for de-esterification are the same as those described in the step (B).
After comple~ion of the reaction in each step, the contemplated compound producible in each step can be isolated ~rom the reaction product or, when required, can be purified by the conventional method such as recrystallization method, thin-layer chroma~ography, column chromatography or the like.
The penicillin derivative of ~he present invention Ls mixed with the ~-lactam type antibiotic ` substance to form a preparation which is orally or parenterally administered. Alternatively, the present compound and a suitable antibiotlc can ~e separately administered. Thus the derivatives of tlle formula (I) can be used for treating inectious disease of human beings and other animals.
Tlle composition oE the present invention may be made into tablets, pills, capsules, granules, powders, syrups, lozenges, solutions, suspensions, etc. for oral administration and aqueous, suspending or water-soluble preparations for intravenous, subcutaneous or in~ramuscular injections.
Carriers useful in formulating the preparations ... .
.. . - :,. . . .
~:, ., ' . , . . . .
", . . : , . . .
~ . .~ .
.,.,. ~ , .

_ 25 - ~2~

are commonly used pharmaceutically accepta~le non-toxic carriers such as gelatin, lactose, starch, magnesium stearate, talc, vegetable oil, animal oil, polyalkylene ~lycol, etc. The carrier may be used with other additives such as diluents, binders, buEfer agents, preservatives, glazes, disintegrators, coating agents, etc.
The daily dose of the preparation can be appropriately determined and is not particularly limited.
Pre~erably the daily dose is such that the total amount o~ tlle present compound and ~-lactam antibiotic is about 1 to about 200 mg/Kg body weight for oral administration and about 1 to about 100 mg/Kg body weight Eor parenteral administration.
The present invention will be described below in more detail with reEerence to examples given below.
- Reference Example 1 Preparation of benzhydryl 2~-azidomethyl-2~-methylpenam-3a-carboxylate A solution of 5.00 g oE sodium azide in 53 ml oE water was added to a solution o~ benzhydryl 2~-chloro-methyl-2~-methylpenam-3~-carboxylate (5.13 g) ln dimethyl-Eormamide (155 ml). Tlle mixture was stirre~ at room tem-perature ~or 4 hours. The resulting reac~ion mixture was poured into cooled water and the mixture wa~ extracted with ethyl acetate. The ethyl acetate layer was washed , ~
.: ;

_ 26 - 12Z~

wi~h water, dried over magnesium sul~ate and concentrated to provide ~.87 g of the contemplated p~oduct as o-Ll in 93 % yield.
Infrared absorption spectrum (Nujol, a trademark) vmax (cm lj: 2120, 1812, 1765 Nuclear magnetic resonance spectrum (CDC13) (pprn): 1.30 (31~, s), 3.25 (2~1, m), 3.42 (lH, d), 3.63 (1~1, d), 4.75 (1~1, s), 4.76 (1~1, m), 7.00 ~IH, s), 7.40 (lO~t, s) Reference Example 2 Pre~aration of benzhydryl 2~-azidomethyl-~ ~methylpenam-3a-carboxylate l,l-dioxide To a solution of benzhydryl 2~-azidomethyl-2a-methylpenam-3-carboxylate (7.03 g) in a mixture of acetic acid (240 ~1) and water (~0 mlj was added potassium permanganate (6.02 g) over a period of mor~ than 1 hour, The mixture was stirred at room ternperature for 2.5 hours.
The resultlng reaction mLxture was diluted Wittl Lce water.
; 20 Tlle precipitate was collected by filtration, and washed with water. The resulting product was dissolved in ethyl acetate and the solution was washed with an aqueous solution of sodium hydrogencarbonate and dried over m~nesium sulate.~ Concentration gave 5.48 g of~tbe contemplat9d product in 72 % yield.

.
:
;'' ' ~ ~

~, ., , :~; : ., . ~ .; ....
. ... .
, ,. :: ;
". , :. ;: :, ..
. .. . . . .
.: ~ , .. .

27 - ~IL2~ ~L5~L

Infrared absorption spectrum (nujol) \)max (cm 1): 2120, 1812, 1765 Nuclear magnetic resonance spectrwn (CDC13) ~ (ppm): 1.18 (3tl, s), 3.50 (211, d), 3.72 ~ , d), 3.93 ~1~1, d), 4.60 (1ll, m), 4.65 (11l, s), 7.00 (11~1, s), 7.36 (lOtl, s) Reference Example 3 Preparation of p-nitrobenzyl 2~-azidometllyl-2a-10 metllylpenarll-3a-carboxylate The procedure oE Reference Example 1 was repeated witll the exception of using as the starting material p-nitrobenzyl 21~-chloromethyl-2a-methylpenam-3a-carboxylate, affording the above contemplated compound 15 Infrared absorption spectrum (KBr) vmax (cm~l): 2120, 1798, 1760 Nuclear magnetic resonance spectrum (C~C13) (ppm~ : 1.40(3~l, s), 3.12 (1~l, dd), 3.50(21l, s), 3.6Z (1ll, dd), 4.83(ltl, s), 5.29 (211, s),

5.36(1~l, dd), 7.56 (2H, d), 8.26(2~1, d) Reference Example 4 Preparation~of p-nitrobenzyl 213-azidomethyI-2a-25 methylpenam-3a-carboxylate-1,1-dioxide ;, ~ ;, :: ' .

, , . , . -.: - . , :
:, , _ 28 - ~2~

The yrocedure oE ReEerence ~xample 2 was ~ollowed with the exception oE using as the ~arting material p-nitrobenzyl 2~-azidomethyl-2a-methylpenam-3a-carboxylate, giving the above contemplated compound.
ln~rared absorption spectrum (KBr) vmax (cm 1): 212Q, 1770 Nuclear magnetic resonance spectrum (CDC13) (ppm): 1.42 (31~, s), 3.45-3.60 (2~1, m~, 3.75 (111, d), 3.96 (lH, d), 4.56-4.75 (1~1, m), 4.64 (1~1, s), 5.33 (2~t, s), 7.56 (211, d), 8.26 (2~1, d) Example 1 Preparation o~ p-nitrobenzyl 2~-(4-ethoxycarbonyl-1,2,3-triazol-1-yl)methyl-2a-methylpenam-3a-carboxylate-1,1-dioxide (Compound 1) and p-nitrobenzyl 2~-(5-ethoxy-carbonyl-1,2j3-triazol-1-yl)methyl-2a-methylpenam-3a-carboxylate-l,l-dioxide (Compound 2~
A 2.1 g quantity oE p-nitrobenæyl 2~-azido-methyl-2a-methylpenam-3a-carboxylate-1,1-dioxide and 0.63 g oE ethyl propiolate in 62 ml oE benzene were refluxed with stirring under nitrogen atmosphere for 37 hours. The solvent was removed by distillation and the residue was subjected to column chromatography on silica gei to produce as a Eirst eluted product 0.7 g .... ...
. .
.

- 29 - ~2~5~

of p-nitrobenzyl 213-t5-ethoxycarl~onyl-l,2,3-triazol-l-yl)methyl-2(x-metl~ylpenam-3a-carboxylate-l,l-dioxide in amorphous form (Compound 2) in 27 % yield.
Infrared al~sorption spectrum (KBr) vmax (cm 1): 1795, 1755, 1727 Nuclear magnetic resonance spectrum tCDCl3) (ppm) : 1.39 (311, s), l.39(3H, t), 3.48-3.60 (211, m),4.39 (21l, q), 4.58-4.70 (lll"n),5.11 (lll, s), 5.14 (lll, d), 5.25(lll, d), 5.31 (111, d), 5.56(111, d), 7.54 (2~1, d), 8.09(lH, s), 8.25 (211, d).
There was obtained as a second eluted product l.6 g of p-nitrobenzyl 213-(4-ethoxycarbonyl-1,2,3-triazol-l-y1)methyl-2a-methylpenam-3a-carboxylate-l,l-dioxide in amorphous form (Compound 1) in 62 % yield.
Infrared al~sorption spectrum (KUr) vmax (cm 1): 1800, 1760 (sh), 1733 20 Nucleclr magnetic resonance spectrum (cDcl3) (ppm) : 1.34 (3~1j s), 1.41(311, t), 3.50-3.65 (2H, m), 4.42 ~211, q), 4.60-4.75 (2~1, m), 5.09 (211, s), 5.36 (211, s), 7.59 (2H, d), 8.28 (2119 d), 8.30 (lH, s) .
.

.-~ .
. , ::
::
.... ~.
.. ~ .... .. ~ ,, -. ~ .,:. . ,. ... :. .

_ 30 ~ 4~1 Example 2 Preparation of p-nitrobenzyl 2~-(4-methoxycarbonyl-1,2,3-triazol-l-yl)methyl-2a-methylpena,n-3c,-carbOxylate-l,1-dioxide (Compound 3) and p-nitrobenzyl 2~-(5-me~hoxy-carbonyl-1,2,3-triazol-1-yl)methyl-2a-methylpenam-~ -carboxylate-l,l-dioxide (Compound 4) T~e con~emplat~d product was synthesized ln the same manner as in Example 1 and eluted by column chromatography on silica gel. There was obtained as 10 a Eirst eluted product p-nitrobenzyl 2~~(5-methoxy-carbonyl-1,2,3-trlazol-1-yl)methyl-2~-methylpenam-3a-carboxylate-l,l-dioxide in amorphous form (Compound 4) in 26 % yield.
Inrared absorption spectrum (KBr) 15vmax.(cm~l): 1795, 1727 . Nuclear magnetic resonance spectrum (CDC13) : : ~ (ppm) : 1.39 (3~1, s), 3.~5-3.60 ~211, m), 3.94 (311, s), 4.58-4.70 (111, m), 5.09 (111, 9), 5.10-5.64 (411, m), 7.54 (211, d), 8.10 (lH, s), 8.25 (211, d).
There was ob~ained as a second eluted produc.t p-nitrobenzyl 2~-(4-methoxycarbonyl-1,2,3-triazol-1-yl)-. methyl-2a-snethylpenam-3~-carboxylate-1,1-dio~ide in alllorpllous ~orm (Compound 3) in 61 % yi.eld.

., ,. ,, :

:~ , . . ,: :.
::
:.. , , "

_ 3l - ~2~4~

InErared absorption spectrum (ICBr) Vma~ (cm ): 1798, 1730 Nuclear magnetic resonance spectrum (CDCl3) ~ (ppm): 1.33 (311, s), 3.48-3.68 (211, m), 3.96 (311, s), 4.56-~.76 (2~1, m) 5.09 (2~1, s), 5.36 (211) g), 7.60 (2~1, d), 8.28 (211, d), 8.30 (l~1, s).
Example 3 Preparatlon of benzhydryl 2~-(4-mett~oxycarbonyl-l,2,3-triazol-l-yl)methyl-2a-methylpenam-3-carboxylate-1,1-dioxide (Compound 5) and benzbydryl 2~-(5-methoxy-carbonyl-l,2,3-triazol-l-yl)methyl-2a-methylpenam-3a-carboxylate-l,l-dioxide (Compound 6) The contemplated product was synthesized in the same manner as ih Example l and eluted by column chrol11atography on silica gel~ First there was eluted benzhydryl 2~-(5-methoxycarbonyl-l,2,3-triazol-l-yl)-methyl-2a-1l1ethylpenam-3~-carboxylate-l,l-diaxide (Comyound 6) in 18 % yield.
In~rared absorption spectrum (KBr) vmax (cm~l): 1800, 1727 Nuclear magnetic resonance spectrum (CDCl3) ~ (ppm) : 1.20 (311, sj, 3.~4-3.58 (211, m), 3.91 (111, s)j 4.50-4.65 (111, m), ' . "
.

, ~ ,;.', ~; , . ~
. .~
: ~ " - , . ' .~ . .

_ 32 -~4~51 5.2~ (11l, d), 5.25 (1~l, s), S.45 (11l, d), 6.91 (1~1, s), 7.20-7.40 (10ll, m), 8.08 (1~1, s).
Secondly there was eluted benzhydryl 2~-(4-methoxycarbonyl~1,2,3-trlazol-1-yl)methyl-2~-methylpena~-3~-carboxylate l,l-dioxide (compound 5) in 60 % yield.
Infrared absorption spectrum (KBr) vmax (cm 1): 1803, 1727 . 10 Nuclear ma~netic resonance spectrum (CDC13) (ppm) : 1.05 (3~1, s), 3.48-3.62 (211, m), 3.95 (3~1, s), 4.55-4.75 (211, m), 5.11 (211, bs), 7.02 (11-1, s), . 7.20-7.50 (10~l, m), 8.25 (111, s).
Example 4 Preparation of sodium 2~-(4-ethoxycarbonyl-1,2,3-triazol-l-yl)methyl-2a-methylpenam-3a-carboxylate l,l-dioxide (Compound 7) ~Iydrogenation was conducted at a low pressure and at room temperature by using 15 ml of ethyl acetate, lS ml of water, 340 mg of p-nitrobenzyl 2~-(4-ethoxy-carbonyl-1,2,3-triazol-1 yl)methyl-2a-methylpenam-3a-carboxylate-l,l-dioxide, 60 mg of 10 % palladium charcoal and 110 mg o~ sodium hydrogencarbonate. ~fter completion of absorption of hydrogen, the reaction mixture was . . . , ... ~ .. ...... ...... ..... .. . ... .. .... , . , .. _.. ............

:., ~

-.. . ~ ,.. -.
. . . .
.,: ..

- 33 ~

filtered to separate tlle aqueous layer which was washed wi~ll benzene. The aqu~ous solution was concentrated at reducecl pressure and the concentrate was subjected to column chrpmatography uslng an MCI gel, CHP-20 P
5 (a trademark of Mitsubishi Kasei Co., Ltd., Japan) to conduct gradient elution with a water-10 % acetotle water mixture. ~he eluate thus obtained was ~reeze-dried to afford 200 m~ of the contemplated product (Compound 7) as white powder in 76 % yield. The white powder decomposed at a temperature o~ more than 180C.
InErared absorption spectrum (KBr) vmax (cm 1): 1782, 1720 Nuclear magnetic resonance spectrum (D20) ~ (ppm) : 1.39 (311, t), 1.46 (31i, s), lS 3.45 (lH, dd), 3.72 (1ll, dd), 4.4~ (2~1, q), 4.50 (1ll, s), 4.96-S.10 (lH, m), 5.18 (lH, d), 5.42 (1ll, d), 8.72 (lH, s) Example 5 , 20Preparation of 2~ -etlloxycarbonyl-1,2,3-triazol-1-yl)-methyl-2~-methylpenam-3a-carboxylic acid-l,l-dioxide (Compound 8) llydrogenation was conducted at room temperature and at a pressure o~ 3 atm. by using 4.2 g of p-nitro-benzyl 2~-~4-ethoxycarbonyl-1,2~3-trlazol-1-yl)methyl-,. ~
.
.. .. ~ .
: :, _ 3~ 5~

2a-methylpenaln-3a-carboxylate-l~l-dioxide~ 1.4 g oE
so~ium hydrogencarbonate, 800 mg of 10 % palladium charcoal, 100 ml oE ethyl acetate and 100 ml oE water.
A~ter completion o absorption of hydrogen, the reaction mixture was ~iltered and the aqueous layer was separated and washed with benzene. The pH of the aqueous layer was adjusted to 1 to 2 with hydrochloric acid. The aqueous layer was extracted with ethyl acetat~ and the extract was dried over magnesium sulEate. The solvent was distilled oEE and 3.0 g of the contempl~ted compound was produced in amorphous fornt in 97 % yield.
InErared absorption spectr~n (KBr) ~ max (cm 1): 1798, 1726 Nuclear magnetic resonance spectrum (DMS0-d6) ~ (ppm) : 1.31 (311, t), 1.42 (3tl, s), 3.31 (111, dd), 3.73 (111, dd), 4.32 (211, q), 4.75-5.38 (411, m), 8.76 (1~1, s) Exarnl~le 6 Z0 Preparation of chloromethyl 2~-(4-ethoxycarbonyl 1,2,3-triazol-l-yl)methyl-2a-methylpenam-3a-carboxylate-l,l-dioxide (Compound 9) ~ 2.2 g quantity o~ sodium hydrogencarbonate and 0.2 g oE tetrabutylammonium hydrogensul~ate were added with stirring at a temperature oE less than 10C

-., . .-.

...
. : . " ... .

_ 35 - ~2~5~

to 2.4 g of 2~-(4-ethoxycarbonyl-1,2,3~triazol-1-yl)-methyl-2ct-methylpenam-3c~-carboxylie acid-l,l-dioxi~e, 13.5 ml oE ~ichloromethane and 13.5 ml o~ water. To tlle mixture was dropwise added at the same temperature 1.25 ~ o~ chloromethyl chlorosulfonate and the resulting mixture was s~irred at room temperature for 30 minutes.
The organic layer was separa~ed, washed once with water and dried over magnesium sulfate. The solvent was removed by distillation and the resi~ue was purified by column chromatograp~y on sllica gel, giving 2.2 g o~ the con-templated compound in amorphous form ln 81 % yield.
Infrared absorption spectrum (KBr) max (cm 1~ 1798, 1723 Nuclear magnetic resonance spectrum (CDC13) ~ (ppm) : 1.42 (3~l, t), 1.48 (3~l, s), 3.52-3.65 (21l, m), 4.36 (2~1, q), 4.60-4.73 (211, m), 5.10 (211, s~, 5.73 (11l, d), 5.90 (lll, d), 8.31 (111, s) Example 7 Prepara~ion of iodomethyl 2~-(4-ethoxycarbonyl-1,2,3-triazol-l-yl)methyl-2ct-methylpenam-3a-carboxyla~e-l,l-dioxide (Compound 10) A 1~73 g quantity o~ chloromethyl 2~-(4-ethoxycarbonyl-1,2,3-triazol-1-yl)methy1-2a-methylpenam-... .. .

36 - ~L22~

3C~-carboxylic acid~ dioxide and 1.3 g oE sodium iodide were stirred in 3.4 ml o acetone at room temperature ~or l8 l1ours. To the reaction mixture was added 2.9 ml oE
wa~er and the p~1 oE tlle resul~ing mixture wa~: adjusted 5 to 7 to 8 with an aqueous solution of sodium hydrogen-carbonate. AEter addition of 2.9 ml of water, the mixture was decolorized with an aqueous solution of 0.5 M sodium thiosulfate, extracted with dichloro-met11ane, waslled with water and dried over magnesium lO sulfate. Tlle solvent was removed by dlstillation and l.9 g of the contemplated compound was prepared in amorphous ~orm in 90 % yeild.
Infrared absorption spectrum (KBr) vmax (cm l) 1798, 1725 15 Nuclear ma~netic resonance spectrum (CDCl3) (ppm) : 1.42 (3~1, t), l.49 (3~1, s), 3.52-3 68 t211. m), 4~43 (211, q), 4.59-4.78 (2~1, m), 5.09 (2~1, s), ..
5.96 (l}1, d), 6.07 (ll1, d), 8.32 (l~1, s) Example 8 Preparation oE sodium 213-(S-ethoxycarbonyl-1,2,3-triazol-l~yl)methyl-2a-methylpenam-3cL-carboxylate~
dioxide (Compound ll) A 220 mg o~ the contemplated compound was .. ,.~ .. . .
.; ~ ., . ~
: ,, -:
-~~ - 37 ~ ~2415~

prepared in tlle Eorm oE white powder ln th~ same manner as in Exalllple ~t ~Lom 0.34 g o~ p-nitrobenzyl 2~-t5~
ethoxycarbonyl-1,2,3-trlazol-1-yl)methyl-2~-methylpenam-3a-carboxylate-1,1-dioxide in 83 % yield.
The white powder thus obtalned decomposed at a temperature of over 180C.
InErared absorption spectrum (KBr) vmaX (cm~l): 1788, 1736 Nuclear magnetic resonance spectrum ~D20) ~ (ppm) : 1.39 (3H, t), 1.43 (311, s), 3.40 (1}l, dd), 3.71 (11l, dd), 4.46 (211, q), 4.57 (1}~, s), 4.96-5.05 (lll, m), 5.40 (1ll, d), 5.82 (1~l, d), 8.34 (l~l, s) Example 9 Preparation oE sodium 2~-(4-methoxycarbonyl-1,2,3-triazvl-l-yl)methyl-2a-methylpenam-3a-carboY~ylatP-l,1-dioxide (Compound 12) A 0.18 g quan~i~y oE the contemplated product was prepared as white powder in the same manner as in Example 4 Erom 0.3 g of p-nitrobenzyl 2M-(4-methoxy-carbonyl-1,2,3-triazol-1-yl)methyl-2a-methylpenam-3a- `
carboxylate-l,l-dioxide in 78 % yield.
The white powder thus obtain~d decomposed at a tempera~ure o~ over 184C.

~.. . .
: ,,. , '`

- 38 ~

Ir~Erared absorption spectrum (KBr) vmax (cm 1): 1782, 1730 Nuclear magnetic resonance spectrum (D2~) ~ (ppm) ~ 6 (31l, s~, 3.~5 (1ll, dd), 3.73 (lH, dd), 3.97 (311, s), .50 (1~1, s), ~.81 (2~1, s), 4.98-5.10 (1~l, m), 5.18 (1~l, d), 5.42 (111, d), 8.72 (11l, s) Example 10 Preparation of sodium 2~-(S-me~hoxycarbonyl-1,2,3-trlazol-l-yl)methyl-2a-methylpenam-3a-carboxylate-1,1-dioxlde (Compound 13) . A 0.19 g quantity o~ the con~èmplated compound was prepared as whi~e powder in the same manner as in Example 4 from 0.3 g o~ p-nitrobenzyl 2~-(5-methoxy-carbonyl-1,2,3-triazol-1-yl)me~hyl-2~-methylpenam-~ -carboxylate-l,l-dioxide in 82 % yield.
The white yowder thus obtained decomposed at a temperature of over 180C.
Infrared absorption spectrum (K~r) vmax (cm l) 1778, 1730 Nuclear magnetic resonance spectrum (D20) (ppm) ~ l (3~1, s), 3.41 (1ll, dd), 3.71 (1ll, dd), 3.98 (311, s), 4.56 (1ll, s), 4.95-5.08 (11l, m), 5.40 (1~l, d), 5.83 (11l, d), a.34 (1~l, s) , ~ ~ .

- :.. . : - : :
.. . .
: , . . - ;
... ~ . .. . .
.. ,. .. ~ . .
.. . . .

3 9 ~ 2Z4151 E~ample ll Proparation of p-nitrobenzyl 2~-methyl-2~3-[4-(p-nitro-benzyloxycarbonyl)~l,2,3-triazol-l-yl]methylpenam-30-carboxylate-l,l-dioxide (Compound l~) and p-nitrobenzyl 2a-methyl-213-C5-(p-nitrobenzyloxycarbonyl)-l,2,3-triazol-l-yl~methylpenam-3x-carboxylate-l,l-dioxide (Compound l5) A 4 g quantity of p-nitrobenzyl 2~-adidomethyl-2a-methylpenam-3a-carboxylate-l,l-dioxide and 8.2 g o ; lO p-nitrobenzyl acetylene carboxylate in lO0 ml oE benzene were reEluxed under nitrogen atmosphere Eor l2 hours.
The solven~ was distilled of~ at reduced pressure.
Tlle residue was sub~ected to column chromatograyhy on silica gel to provide 3 . 6 g of p-nitrobenzyl 2~-methyl-213-C4-(p-nitrobenzyloxycarbonyl)-l,2,3-tria~ol-l-yl]
methylpenam-3a-carboxylate-l,l-dioxide (Compound 14) and 0.9 g o p-nitrobenzyl 2a-methyl-213-C5-(p-nitro-benzyloxycarbonyl)-l,2,3-triazol-l-yl~metllylpenam-3~-carboxyla~e-l,l-dioxide (Compound 15) botll in amorphous form.
Compound 14 Infrared absorption spectrum (KBr) vmax (cm l) l800, l740 ; 25 ' -- _ 40 - ~2~

Nuclear magnetic resonance spectrum (CDC13) (ppm): 1.34 t311, s), 3.3-3.8 (211, m), 4.67 (111, s), 4.60-4.76 (1ll, m) 5.12 (2~1, s), 5.37 (2~t, s), 5.48 (211, s), 7.5-7.7 (4~1, m), 8.1-8.3 (41l, m), 8.37 (111, s), Compound 15 Infrared absorption spectrum (KBr) ` vmax (cm 1): 1800, 1740 Nuclear magnetic resonance spectrum (CDC13) (ppm): 1.41 (3EI, s), 3.3-3.7 (211, m), 4.6-4.7 (lll, m), 5.07 (1ll, s), 5.1-5.6 (41l, m), 5.46 (211, s~, 7.4-7.7 (41l, m), 8.15 (1~l, s), 15 8.1-8.4 (411, m) ; Example 12 Preparation o dipo~assium 2~-(4-carboxy-1,2t3-rlazol-l-yl)metbyl-2a-methylpenam-3a-carboxylate l,l-dioxide ~Compound 16) llydrogena~ion was conducted in 100 ml of ~: ethyl acetate and 100 ml oE water at room temperature or 1 hour by using 3.6 g o p-nitrobenzyl 2a~methyl-2~-C4-(p-nitrobenzyloxycarbonyl)-1,2,3-triazol.-1-yl)]-metllylpenam-3a-carboxylate-1,1-dioxide, 2.0 g sodium hydrogencarbonate and 0.68 g of 10 % palladium charcoal, .
.: :
.~ .

. ;~
' , ~ 22~

catalys~. Thereafter the aqueous layer was separated and was waslled once with ethyl acetate, and the pll thereo~ was adjusted to 1.5 to 1.7 with 6 N llydrochlorlc acid. The aqueous solution was saturated witll soclium S chloride and extracted a few times wi~h e~hyl acetate.
The ethyl acetate solutions thus formed were collected and dried over magnesium sulfate. The solvent was distilled off at reduced pressure to provide as the residue a ~oamed product oE 2~-(4-carboxy-1,2,3-o triazol-l-yl)methyl-2a-methylpenam-3a-carboxylic acid-l,l-dioxide.
A 2 g quantity of the 2~-(4-carboxy-1,2,3-trlazol-l-yl)methyl-2a-methylpenam-3a-carboxylic acid-l,l-dioxide was dissolved in 20 ml o~ butanol.
To the solution was added a solution o~ potasslum 2-ethyl hexanoate in butanol, and the mixture was stirred awhile at room temperature. The precipitate was filtered to give 2.0 g oE white solids having a melting point oE over 178C (decomposition).
In~rared absorption spectrum (KBr) vmax (cm ): 1780, 1610 Nuclear magnetic resonance spectrum (D20) (ppm) : 1.47 (3~1, s), 3.49 (1~l, dd), 3.77 (lH, dd), 4.53 (lH, s), 5.0-5.1 (lH, m), 5.16 (lH, d), 5.41 (lH, d), 8.47 (1~l, s) .. . .
: ,, , :, , . . ' - ~2 - ~Z~15~

Example 13 Preparatiorl of dipotassium 2~-(5-earboxy-1,2,3-triazol-l-yl)nlethyl-2a-methylpenam-3a-carboxyl~te l,l-dioxide (Compound 17) White solid of the eontemplated eompound with a melting point of over 175C (deeomposition) was prepared in the same manner as in Example 12 by using p-nitrobenzyl 2a-methyl-2~-[5-~p-nitrobenzyloxycarbonyl)-1,2,3-triazol-1-yl]methylpenam-3a-carboxylate-1,1-dioxicle.
InErared absorption speetrum (KBr) vmax (cm 1): 1780, 1610 Nuclear magnetic resonance speetrum (D2O) tppm) : 1.40 (311, s), 3.43 tl~l, dd), 3.71 (11-1, dd), 4.58 (lH, s)~
4.9-5.1 (1~1, m), 5.36 (lH, d), 5.93 (111, d), 8.04 (l~l,-s) Example 14 Preparation oE benzhydryl 2~-(4-carboxy-1,2,3-triazol-l-yl)methyl-2c~-methylpenam-3a-carboxylate-1,l-dioxide (Compound 18) A 0.5 g quantity of benzhydryl 2~-azidomethyl-2a-methylpenam-3a-carboxylate-1,1-dioxide and 0.083 g of acetyleneearboxylie acid were s~irred in 2 ml oE diehloro-methane at room temperature`under nitrogen atmosphere for 24 hours. rhe solvent was removed by distillation at . ,~

.
~' ', ' .' ..

~ 3 ~L%2~

reduced pressure and to ~he residual oil was added benzene The insolubles were filtered off and to the residue was added hexane to deposit crystals which were collected by filtration. Thus ~here was produced 0.23 g of white crystals wllich melt at 120 to 121C.
Infrared absorption spectrum (KBr) vmaX (cm~l): 1805, 1745 Nuclear magnetic resonance spectrum (CDC13~
~ (ppm): 1.07 (311, s), 3.2-3.8 (211, m), 4.5-4.7 (1~1, m), 4.69 (1ll, s), 5.12 (2~1, bs), 7.02 (lll, s), 7~1-7.6 (10~l, m), 8.33 (111, s) .Example 15 Preparation of disodium 2~-(4-carboxly-1,2,3-triazol-1-yl)methyl-2a-me~hylpenam-3a-carboxylate-1,1-dioxide (Compound 19) llydrogenation was conducted in 10 ml o~ ethyl acetate and 10 ml of water at room temperature for 30 minutes by using 49 mg of benæhydryl 2~-(4-carboxly-1,2,3-~riaæol-1-yl)methyl-2a-methylpenam-3a-carboxylate-1,1-dioxide, 15 ml of 10 % palladium charcoal and 24 mg of sodium hydrogencarbonate ~he aqueous layer was separated from the reaction mixture and washed with ethyl acetate, and was purified with an MCI gel, CIIP-20P (product oE Mitsubishi Kasei Co., ~td., Japan).

.~ ..
.. . .

.
:
- . .

l~4 ~2~4~5~

.~fter Ereeze-dryin~, there was obtained a white amorpllou~ product having a melting point of 220 to 250C (decomposition).
The values of the infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound thus obtained were similar to those of Compound 16 prepared in Example 12.
Example 16 Preparation of benzhydryl 2a-methyl-2~-(4-trimethylsilyl-1,2,3-triazol-1-yl)methylpenam-3a-carboxylate-1,1-dioxide (Compound 20) ~ 150 mg quantity of benzhydryl 2~-azidome~hyl-2a-methylpenam-3a-carboxylate-1,1-dioxide was reacted in a sealed reactor with 300 mg of trimethylsilylacetylene at 90 to 95C for 20 hours. The reactlon mixture was concen~ra~ed at reduced pressure, giving 17Q mg of white crystals which melt at 172 to 175C.
It~frared a~sorption spectrum (KBr) .
vmax (cm 1): 1805, 1755 Nuclear magnetic resonance spectrum (CDC13) (ppm) : 0.32 (9~1, s), 1.05 (311, s), 3.3-3.7 (2~1, m), 4.5~4.7 (111, m), 4.65 (111, s), 5.08 (2~1, AB~q), 7.00 (11l, s), 7.3-7.5 (10ll, m), 7.67 (1~, s) ,... ~, ,' ,'' . .' ' ~5 - ~ ~2~L5~

~xample 17 Preparation oE benzhydryl 2a-methyl-2~-(1,2,3-triazol-l-yl)methylpenam-3a-carboxylate~ dioxide (Compound 21) A 133 mg quantity of benzhydryl 2a-methyl-2B-(4-trime~llylsilyl-1,2,3-triazol-1-yl)methylpenam-3a-carboxylate-l,l-dloxide, 3.26 g of 18-crown-6(1,~,7,10, 13,16-hexaoxacyclooctadecane) and 15.8 mg of potassium fluoride were stirred in 0.7 ml o~ N,N-dimethylformamide at S0 to 60C for 5.5 hours. The reaction mixture was lo poured into excess iced water and the mixture was extracted a few times with ethyl acetate. 'rhe ethyl acetate extracts were collected and dried over magnesium sulfate. ~he solvent was distilled off at reduced pressure and the residue was puri~ied by column chromato-graphy on silica gel, whereby a whi~e proudct was givenwhich has a melting point o~ 206 to 208C (decomposition).
InErared absorption spec~rum ~KBr) - ~nax (cm 1): 1800, 1760 Nuclear magnetic resonance spectrum (CDC13) 20 ~ (pp~) : 1.05 (3~1, s), 3.3-3.7 (211, m), 4.5-4.7 (11l, m), 4.65 (1~l, s), 5.10 (2~1, AB-q), 7.00~(1ll, s), 7.3-7.5 (lOH, m), 7.73 (1~l, s) .
` 25 , .

- - .. -- ... . . ~ ~ .

_ 46 ~ 5 Example 18 Preparation oE benzhydryl 2a-methyl-2r3-(1,2,3-triazol-l-yl)methylpenatll-3a-car~oxylate-1,1-dioxide (Compound 21) A 500 mg quantity oE benzhydryl 2~-azidomethyl-5 2a-1nethylpenam-3a-carboxylate-l,l-dioxide, 335 mg of trimethylsilylacetylene and 2 ml oE methylene chloride were reacted in a sealed reactor a~ 95C or 20 hours.
The reaction mixture was concentrated at reduced pressure and the residue was purified by column chromato~
graphy on silica gel to provide white solid~ havirlg a melting point oE 203 to 204~C (decomposltion).
Fast atomic bombardment mass spectrum method m/e=4G7(M ) The values of the infrared absorption spectrum and nuclear magnetic resonance spectrum oE te compound - . thus obtained were identical with those of Compo~nd 21 obtained in Example 17.
; Example 19 Preparation oE benzhydryl 2a-methyl-2~(1,2,3-triazol-20 1-yl)methylpenam-3a-carboxylate-1,1-dioxide (Comp,ound 21) A 200 mg quantity of benzhydryl 2~-azidomethyl-2a-methylpenam-3a-car~oxylate-l~l-dioxide was reacted ,.
with 10 ml of vinyl ace~ate in a sealed reactor at 100 to 110C for 30 hours, The reaction mixture was concentrated at reduced pressure. The residue was crystallized with cooled chloroform.

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The white crystals thus obtained were Eound to llave a melting poin~ (decoMposition) and tlle values of the nuclear magnetic resonancé spectrum which were all idetltical with the values of Compound 21 obtained in E~ample 17.
Example 20 Preparation of sodium 2a-methyl-2~ 2~3-triazol-l-yl) methylpenam-3~-carboxylate-1,1-dioxide (Compound 22) ~Iydrogenation was conducted in 10 ml of ethyl acetate and 10 ml of water at room temperature for 30 minutes by using 45 mg o benzhydryl 2a-methyl-2R-(1,2,3-triazol-1-yl)methylpenam-3a-carboxylate-1,1-dioxide, 15 mg oE 10 % palladium charcoal and 16 mg of sodium hydrogencarbonate, The aqueous layer was separated ~rom the reaction mlxture and washed once wlth ethyl acetate, The aqueous solution was then purified with an MCI gel, CIIP-Z0P (product of Mitsubishi Kasel Co., Ltd., Jayan). AEter freeze-drying, there.was obtained an ; amorphous product with a melting point of over 170C
(decomposition).
Infrared a~sorption spectrum (KBr) vmax (cm 1): 1780, 1630 ..
Nuclear magnetic resonance spectrum (D20) : ~ (ppm~: 1.41 (3}1, s), 3.45 (1~l, dd), 3.72 (1~l, dd), 4.48 ~1~l, s), . ~

, . ; , ~ :' .. . . ..
. . , -. ''. ', ., ~ ,.. :, -:,, :' ' 4.96-5.10 (111, m), 5.25 (211, AB-q), 7.85 (1ll, d), ; 8.13 (lH, d) E~ample 21 Preparation of p-nitrobenzyl 2~-methyl-2~-(1,2,3-triazol-l-yl)methylpenam-3a-carboxylate-1,1-dioxide (Compound 23) A 1.02 g quantity of p-nitrobenzyl 2~-azido-. me~hyl-2a-methylpenam-3a-carboxylate-1,1-dioxide was reacted wit~l 50 ml of vinyl acetate in a sealed reactor at 100 to 110C for 30 hours. The reaction mix~ure was concentrated at reduced pressure and the residue was purified by column chromatography on silica gel, giving 0.73 g of ~he contempla~ed compound in amorpl~ous form : 15 in 67 % yield which melts at 182 to 184C.
Infrared absorptlon spectrum (KBr) vma~ (cm 1): 1800, 1760 Nuclear ma~netic resonance spectrum.(CDC13) ~ (ppm): 1.26 (311, 9), 3.5-3.6 (2~1, m), 4.66 (111, s), 4.6-4.7 (1~l, m) 5.07 (2EI, s), 5.36 (2ll, s), 7.61 (21l, d), 7.74 (111, d),:
7.80 (1~1, d), 8.28 (211, d) ' ' .

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- . . : .:
: .

_ ~9 ~ 51 Example 22 Preparation oE sodium 2~-methyl-2~-(4-trimethylsilyl-1 ,2,3-tri:azol-1-yl)methylpenaln-3c~-carboxylate-1 ,1-dioxide ~Compound 24) ~Iydrogenation was per~ormed in 15 ml of ethyl acetate and 15 ml of water at room temperature for 30 minutes by using 200 mg of benzhydryl 2a-methyl-2~-(4-trimethylsilyl-1,2,3-triazol-1-yl)methylpenam-3~-carboxyla~e-l,l-dioxide, 50 mg of 10 % palladium charcoal and 98 mg of sodium llydrogencarbonate. ~he aqueous layer was removed Erom the reaction mixture and washe~ once with ethyl acetate. The aqueous solution was purified with an MCI gel, CtlP-20P (product of Mitsubishi Kasei Co., Ltd., Japan). After freeze-drying, there was obtained an amorphous product having a melting point oE over 170C (decomposition).
Infrared al~sorption spectrum (KBr) ~max (cm 1): 1780, 1630 Nuclear magnetic resonance spectrum (D20) ~ (ppm) : 0.32 (9~l, s), 1.38 (3ll, s), 3.1-3.7 (2~l, m), 4.46 (ltl, s), 4.9-5.0 (1~1, m), 5.23 (211, ~B-q), 8.16 (1~l, s) ,. ,~ .. ... .
.- ~
-, ,, ~.~ . .
, - 50 ~

The compounds obtained in some oE the examples were checked for ~-lactamase inhibitory activity and antibacterial activity.
tl) Test ~or ~-lactamase lnhibitory activity The inhibitory activity a~ainst penicillinase (~-lactamase) from Bacillus SP was measured by micro-iodometry Tanpakushitsu Kakusan Koso (Proteln Nucleic Acid Enzyme), vol. 23, No.5, pp 391-400 (1978) using a penicillin G as a substrate. Table l given below shows . 10 the results.
Table 1 Compound 50 % Inhibitory Concentration Compound 7 $,4 x 10 8M
" 11 3.4 x 10 7M
" 12 4.9 x 10 8M
" 13 3.0 x 10-7~
" 16 6.0 x 10 7M
" 17 1.7 x 10 6~l " 22 6.9 x 10 7M
" 24 5.1 x 10 M
(2) Test ~or antibacterial actlvity 1) EE~ects by ampicillin as combined with t~le present compound The compounds of the present invention and ampicillin, each singly u:ed, were checked for minimel .
.

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~2 inllibitory concentration ~MIC) against the bacteria lis~ed in Table 2 given below by micro-brotll diluti.on mek~lod ("American Journal Clinical Pathology" publislled in 1980, vol. 73, No.3, pp 374 to 379); The MIC of ampicillin as combined with the present compound (10 ~g/ml) was measured against the same bacteria.
In the method, the ~acteria cultivated in Mueller Hinton Broth (product of DIFCO) and diluted to 1~7 CFU/ml were inoculated into the same medium containing ampicillin and the present compound in a specific concentration, and incubated at 37C for 20 hours. Thereafter the growth o~ the microorganisms was observed to determine the minimal inhibitory concentration (MIC) for rendering the inoculated medium Eree from turbidity. Tlle present compounds, singly used, turned out to be all more than 25 ~g/ml in MIC. The bacteria as used in the test were those capable of producing ~-lactamase, among which the bacteria marked * in the table are those collected from the living body oE human hosts and the others are a stock culture.
In Table 2, the present compounds are shown by the compound number.

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2) EE~ects ^by antibiotics as combined with the present colnpound The compounds o~ the present inventlon, ampicillin, mecillinam, piperacillin and cephalexin, each singly used, were also tested for minimal inhibitory concentration against 30 strains o~ coliform bacilli collected rom the living body o~ humans. The MIC oE
each antibiotic as combined with the present compound (10 ~g/ml) was likewise measured. Table 3 to 6 indicate the results in which MIC50 and MIC70 indica~e ~he minimal inhibitory concentration Eor inhibiting the growth o 50 % and 70 % respectively oE the strains. The MICs oE
the present compounds singly used were all more than 25 ~g/ml.

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Given below are examples of preparation oE
the preserlt antibacterial cornposi~ions~
Preparation E~aMple 1 ~mpicillin 200 mg Compound 22 200 mg Lac~ose 100 mg Crystalline cellulose 57 mg ~agnesium steara~e 3 mg Total 560 mg .. 10 (amount per capsule) The above ingredients are formulated in the proportions lis~ed above into a capsule.
Preparation Example 2 Amoxycillin 100 mg Compound 16 70 mg Lactose 330 mg Corn starch 490 mg llydroxypropyl methyl cellulose 10 mg Total 1000 mg (amount per dose) The above ingredients are formulated in the proportions listed above into granules.
Preparation Example 3 ; Pivmecillinam 70 mg Compound 17 ~70 mg :: .

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Lac~ose 33 mg Crystalline cellulose lS mg Magnesium stearate 3 mg Talc 4 mg Corn starch 15 mg ~Iydroxypropyl methyl cellulose10 mg Total 220 mg (amount per tablet) The above ingredients are formulated in the proportions listed above into a tablet.
Preparation Example 4 Compound 22 120 mg ~Iydroxypropyl cellulose 3 mg Corn starch 25 mg Magnesium stearate 2 mg Total 150 mg (amount per table~) The above ingredients are formulated in the proportions listed above into a tablet.

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Claims (15)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A pharmaceutical composition useful for treating bacterial infections in mammals which comprises (A) a .beta.-lactam antibiotic and (B) a compound of the formula (I) wherein R1 is hydroqen or trialkylsilyl; R2 is hydrogen, trialkylsilyl or COOR2' wherein R2' is hydrogen, C1-18 alkyl, C2-7 alkoxymethyl, C3-8 alkylcarbonyloxymethyl, C4-9 alkylcarbonyloxyethyl, (C5-7 cycloalkyl)carbonyloxymethyl, C9-14 benzylcarbonyloxyalkyl, C3-8 alkoxycarbonylmethyl C4-9 alkoxycarbonylethyl, phthalidyl, crotonolacton-4-yl, .gamma.-butyrolacton-4-yl, halogena-ted C1-6 alkyl substituted with 1 to 3 halogen atoms, C1-6 alkoxy- or nitro-substituted or unsubstituted benzyl, benzhydryl, tetrahydropyranyl, di-methylaminoethyl, dimethylchlorosilyl, trichlorosilyl, (5-substituted C1-6 alkyl or phenyl or unsubstituted-2-oxo-1, 3-dioxoden-4-yl)methyl, C8-13 benzoyloxyalkyl or group for forming a pharmaceutically acceptable salt; and R3 has the same meaning as above R2', the weight ratio of (A)/(B) being 0.1 to 10, said .beta.-lactam antibiotics being selected from the group consisting of penicillins such as ampicillin, amoxicillin, hetacillin, ciclacillin mecillinam, carbeni-cillin, sulbenicillin, ticarcillin, piperacillin, apal-cillin, methicillin, mezlocillin, bacampicillin, carinda-cillin, talampicillin, carfecillin and pivmecillinam;
cephalosporine such as cephaloridine, cephalothin, cepha-pirin, cephacetrile, cefazolin, cephalexin, cefradine, cefotiam, cefamandole, cefuroxime, cefoxitin, cefmetazole, cefsulodin, cefoperazone, cefotaxime, ceftizoxime, cefmen-oxime, latamoxef, cefaclor, cefroxadine, cefatrizine, cefadroxil and cephaloglycin; and pharmaceutically accept-able salts thereof.

2. The pharmaceutical composition as defined in claim 1 wherein R3 is C2-7 alkoxymethyl.

3. The pharmaceutical composition as defined in claim 1 wherein R3 is C3-8 alkylcarbonyloxymethyl, C4-9 alkylcarbonyloxyethyl, (C5-7 cycloalkyl)carbonyloxymethyl, C 14 benzylcarbonyloxyalkyl or C8-13 benzoyloxyalkyl.

4. The pharmaceutical composition as defined in claim 1 wherein R3 is C3-8 alkoxycarbonylmethyl or C4-9 alkoxycarbonylethyl.

5. The pharmaceutical composition as defined in claim 1 wherein R3 is phthalidyl.

6. The pharmaceutical composition as defined in claim 1 wherein R3 is crotonolacton-4-yl and .gamma. -butyrolac-ton-4-yl.

7. The pharmaceutical composition as defined in claim 1 wherein R3 is (5-substituted C1-6 alkyl or phenyl or unsubstituted-2-oxo-1,3-dioxoden-4-yl)methyl.

8. The pharmaceutical composition as defined in claim 1 wherein R3 is a group for forming a pharmaceutically acceptable salt.

9. The pharmaceutical compsotion as defined in claim 1 wherein R3 is Cl 6 alkyl or halogenated C1-6 alkyl substituted with 1 to 3 halogen atoms, C1-6 alkoxy- or nitro-substituted or unsubstituted benzyl, benzhydryl, tetrahydropyranyl, dimethylchlorosilyl and trichlorosilyl.

10. The pharmaceutical composition as defined in claim 8 wherein the group for forming a pharmaceutically acceptable salt represented by R3 is alkali metal atom, alkaline earth metal atom, organic amine residue, basic amino acid residue or ammonium residue.

11. The pharmaceutical composition as defined in claim 1 wherein R1 and R2 are hydrogen.

12. The pharmaceutical composition as defined in claim 1 wherein R1 is hydrogen and R2 is -COOR2'.

13. The pharmaceutical composition as defined in claim 12 wherein R2' is C1-18 alkyl.

14. The pharmaceutical composition as defined in claim 11 or 12 wherein R3 is C3-8 alkylcarbonyloxymethyl, hydrogen, C4-9 alkylcarbonyloxyethyl, (C5-7 cycloalkyl)-carbonyloxymethyl, C9-14 benzylcarbonyloxyalkyl, C3-8 alkoxycarbonylmethyl, C4-9 alkoxycarbonylethyl, phthalidyl, crotonolacton-4-yl, .gamma.-butyrolacton-4-yl, (5-substituted C1-6 alkyl or phenyl or unsubstituted-2-oxo-1,3-dioxoden-4-yl)-methyl, C8-13 benzoyloxyalkyl or group for forming a pharmaceutically acceptable salt.

15. The pharmaceutical composition as defined in claim 1 wherein R2 is trialkylsilyl.