SE435062B - PROCEDURE FOR THE PREPARATION OF NEW CEPHALOSPORINES - Google Patents

PROCEDURE FOR THE PREPARATION OF NEW CEPHALOSPORINES

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Publication number
SE435062B
SE435062B SE7808204A SE7808204A SE435062B SE 435062 B SE435062 B SE 435062B SE 7808204 A SE7808204 A SE 7808204A SE 7808204 A SE7808204 A SE 7808204A SE 435062 B SE435062 B SE 435062B
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SE
Sweden
Prior art keywords
dioxo
piperazinocarbonylamino
methyl
cephem
carboxylic acid
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Application number
SE7808204A
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Swedish (sv)
Other versions
SE7808204L (en
Inventor
I Saikawa
S Takano
C Yoshida
O Takashima
K Momonoi
S Kuroda
M Komatsu
T Yasuda
Y Kodama
Original Assignee
Toyama Chemical Co Ltd
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Priority claimed from JP5066374A external-priority patent/JPS539238B2/ja
Priority claimed from JP5225474A external-priority patent/JPS539239B2/ja
Priority claimed from JP6078774A external-priority patent/JPS539240B2/ja
Priority claimed from JP9199674A external-priority patent/JPS5123284A/en
Priority claimed from JP10995474A external-priority patent/JPS5139687A/en
Priority claimed from JP14249974A external-priority patent/JPS5170788A/en
Priority claimed from JP50037207A external-priority patent/JPS51113890A/en
Application filed by Toyama Chemical Co Ltd filed Critical Toyama Chemical Co Ltd
Publication of SE7808204L publication Critical patent/SE7808204L/en
Publication of SE435062B publication Critical patent/SE435062B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cephalosporin Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

1508064 N-Piperazinocarbonyl-amino acid derivatives TOYAMA CHEMICAL CO Ltd 28 April 1975 [13 Aug 1974 28 Oct 1974 17 Feb 1975] 15360/77 Divided out of 1508062 Heading C2C Novel compounds I and salts and carboxyl derivatives thereof (R is an amino acid residue; R<SP>2</SP> and R<SP>3</SP> are H or alkyl and R<SP>2</SP> and R<SP>3</SP> are both linked to the same carbon atom; and A is H or an optionally substituted alkyl, alkenyl, aryl or aralkyl group) are prepared by reaction of a compound II NH 2 RCOOR<SP>1</SP> (III) (R<SP>1</SP> is H or a cation) with a reactive derivative of a compound IV

Description

?80820h~? resistenta bakterier, som f n ofta isoleras från många kliniksjuk- hus. De har benägenhet att hydrolyseras med ß-laktamas, som produ- ceras av många läkemedelsresistenta bakterier. ? 80820h ~? resistant bacteria, which are currently often isolated from many clinic hospitals. They tend to be hydrolyzed with β-lactamase, which is produced by many drug-resistant bacteria.

I ändamål att erhålla penicilliner och cefalosporiner utan nämnda olägenheter har omfattande forskning utförts för att finna nya föreningar med formeln (I), vilka framställes genom att man binder gruppen vari A, X, Y, R2, R3, n och m har den i det följande angivna betyd- elsen med aminogruppen i acylgruppen av penicilliner och cefalo- sporiner. Det har visat sig att dessa föreningar på ett tillfreds~ ställande sätt tillgodoser nämnda ändamål och uppvisar synnerligen värdefulla terapeutiska egenskaper.In order to obtain penicillins and cephalosporins without the aforementioned disadvantages, extensive research has been carried out to find new compounds of formula (I) which are prepared by binding the group wherein A, X, Y, R 2, R 3, n and m have it in the the following given meaning with the amino group in the acyl group of penicillins and cephalosporins. It has been found that these compounds satisfactorily serve the said purposes and exhibit extremely valuable therapeutic properties.

Det är ett ändamål med uppfinningen att framställa nya cefa- losporiner med en mono- eller dioxo-piperazino(tio)karbonylaminogrupp i molekylen med ett brett antibakteriellt spektrum, hög resistens mot¿ß-laktamas producerad av bakterier och effektiv antibakteriell aktivitet mot kliniska isolat av bakterier.It is an object of the invention to produce novel cephalosporins having a mono- or dioxo-piperazino (ten) carbonylamino group in the molecule with a broad antibacterial spectrum, high resistance to β-lactamase produced by bacteria and effective antibacterial activity against clinical isolates of bacteria.

Andra ändamål och fördelar enligt uppfinningen framgår av den följande beskrivningen.Other objects and advantages of the invention will become apparent from the following description.

Föreningarna enligt uppfinningen är cefalosporiner med den allmänna formeln L (X)n A-N N-o-NH-ca-coua S r ' (I) W u å; N / CHZR 0 x (R2R3)m ' coonl 'I80820lP7 vari R5 är Cl_8-alkyl, tienyl, fenyl eller hydroxifenyl, Rl är en väte- atom, en alkalimetallatom, en ftalidylgrupp, en metoximetylgrupp, en valeryloximetylgrupp, en isopropoximetylgrupp eller en pivaloyloximetyL~ grupp; n är l eller 2; X är syre och de n X-en är bundna i varje kom- bination vid 2-, 3- och 5-ställningarna i piperazinringen; m är 4 - n; varje par av R2 och R3 är bundna till samma kolatom och m par av R2 och R3, som kan vara lika eller olika, betecknar individuellt väte eller Cl_8-alkyl; A betecknar väte eller C2_4-alkenyl, fenyl, lägre alkylsulfonyl, Cl_4-acylkarbamoyl eller N-(lägre alkyl)-aminokarbonyl, eller en Cl_l2-alkylgrupp, som kan vara substituerad med klor, hydroxi eller karboxi, eller en Cl_18-acylgrupp eller en lägre alkoxikarbonyl- grupp; Y är en syre- eller svavelatom; och R4 är väte, azido, pyridinium, lägre alkoxi, Cl_4-acyloxi, karbamoyloxi, lägre alkoxitiokarbonyltio, lägre alkyltio (vilken lägre alkyltiogrupp kan vara substituerad med karboxi), eller någon av grupperna oxazolyltio, tiazolyltio, tiazo~ linyltio, imidazolyltio, pyridazinyltio, pyrimidinyltio, oxadiazolyltio, tiadiazolyltio, triazolyltio, tetrazolyltio, piperazinyltiokarbonyltio, isoxazolylkarbonyltio, (pyridyl-l-oxid)tio eller (5-oxo-2,5-dihydro- l,2,4-triazinyl)tio, som kan vara substituerade med lägre alkyl- I formeln (I) är Rs C1_8-alkyl, såsom metyl, etyl, etylpropyl, butyl, pentyl, hexyl, heptyl, oxktyl; tienyl; fenyl; eller hydroxi- fenyl.The compounds of the invention are cephalosporins of the general formula L (X) n A-N N-o-NH-ca-coua S r '(I) W u å; Wherein R 5 is C 1-8 alkyl, thienyl, phenyl or hydroxyphenyl, R 1 is a hydrogen atom, an alkali metal atom, a phthalidyl group, a methoxymethyl group, a valeryloxymethyl group, an isopropoxyimethyllo group or ~ group; n is 1 or 2; X is oxygen and the n Xs are bonded in each combination at the 2-, 3- and 5-positions of the piperazine ring; m is 4 - n; each pair of R 2 and R 3 is attached to the same carbon atom and m pairs of R 2 and R 3, which may be the same or different, represent individual hydrogen or C 1-8 alkyl; A represents hydrogen or C 2-4 alkenyl, phenyl, lower alkylsulfonyl, C 1-4 acylcarbamoyl or N- (lower alkyl) aminocarbonyl, or a C 1-2 alkyl group, which may be substituted by chlorine, hydroxy or carboxy, or a C 1-18 acyl group or a lower alkoxycarbonyl group; Y is an oxygen or sulfur atom; and R 4 is hydrogen, azido, pyridinium, lower alkoxy, C 1-4 acyloxy, carbamoyloxy, lower alkoxythiocarbonylthio, lower alkylthio (which lower alkylthio group may be substituted by carboxy), or any of the groups oxazolylthio, thiazolylthio, thiothiolylidyl pyrimidinylthio, oxadiazolylthio, thiadiazolylthio, triazolylthio, tetrazolylthio, piperazinylthiocarbonylthio, isoxazolylcarbonylthio, (pyridyl-1-oxide) thio or (5-oxo-2,5-dihydro-1,2,4-triazinyl) thio, which may be lower alkyl - In formula (I), R 5 is C 1-8 alkyl, such as methyl, ethyl, ethylpropyl, butyl, pentyl, hexyl, heptyl, oxytyl; thienyl; phenyl; or hydroxyphenyl.

I formeln (I) är R1 väte, en esterbildande grupp eller en katjon med förmåga att bilda ett icke-toxiskt salt. Den esterbildande gruppen kan vara någon av dem som använts i samband med föreningar av cefalosporintyp. Nämnda esterbildande grupper utgöres närmare bestämt av (1) esterbildande grupper med förmåga att avlägsnas genom katalytisk reduktion, kemisk reduktion eller behandling under milda betingelser, såsom arylsulfonylalkylgrupper, exempelvis toluen-sul- fonetyl, etc; substituerade eller osubstituerade aralkylgrupper, såsom bensyl, 4-nitrobensyl, difenylmetyl, trityl, 3,5-di(tert.-bu- tyl)-4-hydroxibensyl, etc; substituerade eller osubstituerade alkylgrupper, såsom tert.-butyl, trikloretyl, etc; fenacyl, alkoxi- a1kyl,sàsom metoximetyl, etc; och osubstituerade eller alkyl- substituerade cykliska aminoalkylgrupper, såsom piperidinoetylf 4-metylpiperidinoetyl, morfolinoetyl, pyrrolidinoetyl, etc; (2) esterbildande grupper med förmåga att med lätthet avlägsnas med hjälp av enzymer i en levande kropp, såsom acyloxialkyl, pivaloyloximetyl, etc; en ftalídgrupp; och en indanylgrupp.In formula (I), R 1 is hydrogen, an ester-forming group or a cation capable of forming a non-toxic salt. The ester-forming group may be one of those used in connection with cephalosporin-type compounds. More specifically, said ester-forming groups are (1) ester-forming groups capable of being removed by catalytic reduction, chemical reduction or treatment under mild conditions, such as arylsulfonylalkyl groups, for example toluene-sulfonethyl, etc .; substituted or unsubstituted aralkyl groups such as benzyl, 4-nitrobenzyl, diphenylmethyl, trityl, 3,5-di (tert-butyl) -4-hydroxybenzyl, etc .; substituted or unsubstituted alkyl groups such as tert-butyl, trichlorethyl, etc .; phenacyl, alkoxyalkyl, such as methoxymethyl, etc .; and unsubstituted or alkyl-substituted cyclic aminoalkyl groups such as piperidinoethyl or 4-methylpiperidinoethyl, morpholinoethyl, pyrrolidinoethyl, etc .; (2) ester-forming groups capable of being readily removed by enzymes in a living body, such as acyloxyalkyl, pivaloyloxymethyl, etc .; a phthalide group; and an indanyl group.

Exemplen pà de esterbildande grupperna enligt (1) och (2) äri enbart typiska och andra exempel finner man i de amerikanska patent- ..-w ...__ 7808204-7 4 skrifterna 3 499 909, 3 573 296 och 3 641 018 och DE-OS 2 301 014, 2 253 287 och 2 337 105 kan användas enligt uppfinningen. Katjoner med förmåga att bilda icke-toxiska salter omfattar sådana katjoner som tidigare nämnts i samband med föreningar av cefalosporintyp.The examples of the ester-forming groups according to (1) and (2) are only typical and other examples are found in U.S. Pat. Nos. 3,499,909, 3,573,296 and 3,641,018. and DE-OS 2,301,014, 2,253,287 and 2,337,105 can be used according to the invention. Cations capable of forming non-toxic salts include those previously mentioned in connection with cephalosporin-type compounds.

Salterna omfattar alkalimetallsalter, såsom natriumsalt, kaliumsalt, etc; jordalkalimetallsalter, såsom kalciumsalt, magnesiumsalt, etc; ammoniumsalt; och salter med kvävehaltiga organiska baser, såsom prokain, dibensylamin, N-bensyl-ß-fenetylamin, 1-efenamin, N,N- dibensyletylendiamin, etc. I I formeln (I) betecknar m par av R2 och R3, som kan vara lika eller olika, individuellt väte, C1_8-alkyl, såsom metyl, etyl, propyl, pentyl, hexyl, heptyl, oktyl.The salts include alkali metal salts, such as sodium salt, potassium salt, etc .; alkaline earth metal salts such as calcium salt, magnesium salt, etc .; ammonium salt; and salts with nitrogen-containing organic bases, such as procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-phenenamine, N, N-dibenzylethylenediamine, etc. II Formula (I) represents m pairs of R 2 and R 3, which may be the same or various, individual hydrogen, C 1-8 alkyl, such as methyl, ethyl, propyl, pentyl, hexyl, heptyl, octyl.

I formeln (I).betecknar A väte; C2_4-alkenyl, såsom vinyl, propenyl, butenyl; fenyl; lägre alkylsulfonyl, såsom metansulfonyl, etansulfonyl, propansulfonyl; C1_4-acylkarbonyl, såsom N-acetyl- karbamoyl, N-propionylkarbamoyl, N-butyrylkarbamoyl; eller N-(lägre alkyl)-aminokarbonyl, såsom N-metylaminokarbonyl, N-etylaminokar- bonyl, N-propylaminokarbonyl, N-butylaminokarbonyl; eller C1_12- -alkyl, såsom metyl, etyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, oktyl, dodecyl, eller liknande (vilken C1_12-alkylgrupp kan vara substituerad med klor, hydroxi eller karboxi); C1_18-acyl, såsom formyl, acetyl, propionyl, isovaleryl, kaproyl, önantoyl, kapryloyl, palmitoyl, steroyl, akroloyl, cyklohexankarbonyl, bensoyl, fenylglycyl, furoyl, tenoyl eller liknande; eller lägre alkoxikar- bonyl, såsom metoxikarbonyl, etoxikarbonyl, propoxikarbonyl, butoxi- karbonyl.In formula (I), A represents hydrogen; C 2-4 alkenyl, such as vinyl, propenyl, butenyl; phenyl; lower alkylsulfonyl, such as methanesulfonyl, ethanesulfonyl, propanesulfonyl; C 1-4 acylcarbonyl, such as N-acetylcarbamoyl, N-propionylcarbamoyl, N-butyrylcarbamoyl; or N- (lower alkyl) aminocarbonyl, such as N-methylaminocarbonyl, N-ethylaminocarbonyl, N-propylaminocarbonyl, N-butylaminocarbonyl; or C 1-12 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, dodecyl, or the like (which C 1-12 alkyl group may be substituted with chlorine, hydroxy or carboxy); C1-18 acyl, such as formyl, acetyl, propionyl, isovaleryl, caproyl, onantoyl, capryloyl, palmitoyl, steroyl, acroloyl, cyclohexanecarbonyl, benzoyl, phenylglycyl, furoyl, tenoyl or the like; or lower alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl.

I den allmänna formeln (L) är vidare R4 väte, azido, pyridi- nium, lägre alkoxi, såsom metoxi, etoxi, propoxi, etc; C1_4-acyloxi, såsom acetyloxi, propionyloxi, butyryloxi; karbamoyloxí; lägre alkoxitiokarbonyltío, såsom metoxitiokarbonyltio, etoxikarbonyltío, butoxitiokarbonyltio; lägre alkyltio, såsom metyltio, etyltio, propyltio, etc (nämnda lägre alkyltiogrupp kan vara substituerad med karboxi); eller oxazolyltio, tiazolyltio, tiazolinyltio, imi- dazolyltio, pyridiazinyltio, pyrimidinyltio, oxadiazolyltio, tiadiazo- lyltio, triazolyltio, tetrazolyltio, piperazinyltio- karbonyltio, isoxazolylkarbonyltio, (pyridin-1-oxi-2-yl)-tio eller '(5-oxo-2,5-dihydro-1,2,4-triazinyl)tio, som kan vara substituerade med lägre alkyl.In the general formula (L) further, R 4 is hydrogen, azido, pyridinium, lower alkoxy, such as methoxy, ethoxy, propoxy, etc .; C 1-4 acyloxy, such as acetyloxy, propionyloxy, butyryloxy; carbamoyloxy; lower alkoxythiocarbonylthio, such as methoxythiocarbonylthio, ethoxycarbonylthio, butoxytiocarbonylthio; lower alkylthio such as methylthio, ethylthio, propylthio, etc. (said lower alkylthio group may be substituted with carboxy); or oxazolylthio, thiazolylthio, thiazolinylthio, imidazolylthio, pyridiazinylthio, pyrimidinylthio, oxadiazolylthio, thiadiazolylthio, triazolylthio, tetrazolylthio, piperazinylthiocarbonylthio (oxo-2-yl) oxy-2-oxy-2-oxy-1-oxy-1-oxy-2-yl -2,5-dihydro-1,2,4-triazinyl) thio, which may be substituted by lower alkyl.

Nämnda föreningar med formeln (I) enligt uppfinningen uppvisar optiska isomerer och samtliga D-isomerer, L-isomerer och racemiska föreningar avses ligga inom ramen för uppfinningen. 7808204-7 5 Såsom exempel på särskilt lämpliga föreningar med formeln (I) kan nämnas följande: o ~ . s A-N n-c-slfl-cfl-coran (Ia) W g å; linècnzn" (3233) ' ° 1 3 coon o .>\ \ . s Å-fl H Pf-Ü-gafi-Ch-COÉIH L, ' (Ib) W " 'ä N , ca R _ o R 2 [R2a3\ Û l * *" '3 coon f~ .a-n I za-o-z-zfl-og-comgïfS u (Ic) c/è/ t! q O RD 0 N / CHZR (äêeä-z . cooal o A-N rr-(IJI-razæ-on-cown-J/:KS L, (ia) 5 N ,/ CH R 027! o R O 2 (RZPÄZ ' ' coonl e ?80820h-7 0 o ' A-N N-c-NH-cH-CONH S L, (Ie) yßy " '5 N ,/ cH2R 2 3 ° R o (R R ) 1 2 COOR vari R1, R2, R3, R4, RS oçh A har den angivna betydelsen.Said compounds of formula (I) according to the invention have optical isomers and all D-isomers, L-isomers and racemic compounds are intended to be within the scope of the invention. 7808204-7 As examples of particularly suitable compounds of formula (I) may be mentioned the following: o ~. s A-N n-c-sl fl- c fl- coran (Ia) W g å; linècnzn "(3233) '° 1 3 coon o.> \ \. s Å-fl H Pf-Ü-ga fi- Ch-COÉIH L,' (Ib) W" 'ä N, ca R _ o R 2 [R2a3 \ Û l * * "'3 coon f ~ .an I za-oz-z fl- og-comgïfS u (Ic) c / è / t! Q O RD 0 N / CHZR (äêeä-z. Cooal o AN rr- (IJI-razæ-on-cown-J /: KS L, (ia) 5 N, / CH R 027! O RO 2 (RZPÄZ '' coonl e? 80820h-7 0 o 'AN Nc-NH-cH-CONH SL, (Ie) yßy "'5 N, / cH2R 2 3 ° R o (RR) 1 2 COOR wherein R1, R2, R3, R4, RS and A have the specified meaning.

Enligt uppfinningen framställes föreningarna med formeln (I) medelst ett förfarande, varvid man (1) omsätter en förening med den allmänna formeln R7-NH-en-coNHf:L:r'S U ' Rs - 0 N ,/ cuan - (II) cqonll med ett reaktionsbenäget derivat i gruppen -C-OH Y (i det följande benämnd "(tio)karboxígrupp") av föreningen med den allmänna formeln (X n f%\.According to the invention, the compounds of formula (I) are prepared by a process, wherein (1) reacting a compound of the general formula R7-NH-en-coNHf: L: r'S U 'Rs - 0 N, / cuan - (II) with a reaction-prone derivative of the group -C-OH Y (hereinafter referred to as "(ten) carboxy group") of the compound of the general formula (X nf% \).

A-N Z , -3-on I (III) Y 2 3 (R R >m eller (2) omsätter en förening med den allmänna formeln R?-HN*:l:T”S u-Ä N ,/ CHÉR - (IV) o coonll med en förening med den allmänna formeln r A-N N-c-NH-ca-con d ' - (V) W ll l 5 Il 2 3 Y R ° (R R )m eller med ett reaktionsbenäget derivat i gruppen -C-OH O (i det följande benämnd "karboxígrupp") 7808204-7 av föreningen med formeln (V), eller (3) omsätter en förening med den allmänna formeln ,"fT\ I ' A-5 r-c-ra-ca-Conn 5 (VI) xL¥ 3 äs N ,/ cnas o )~ coonll med en förening med den allmänna formeln Rsu (VII) eller med en pyridin.AN Z, -3-on I (III) Y 2 3 (RR> m or (2) converts a compound of the general formula R? -HN *: 1: T "S u-Ä N, / CHÉR - (IV ) o compound with a compound of the general formula r AN Nc-NH-ca-con d '- (V) W ll l 5 Il 2 3 YR ° (RR) m or with a reaction-prone derivative in the group -C-OH O (hereinafter referred to as "carboxy group") 7808204-7 of the compound of formula (V), or (3) reacting a compound of the general formula, "fT \ I 'A-5 rc-ra-ca-Conn 5 (VI ) xL ¥ 3 äs N, / cnas o) ~ coonll with a compound of the general formula Rsu (VII) or with a pyridine.

I nämnda formler (II) - (VIII) har R5, R2, R3, A, x, Y, m och n den angivna betydelsen; R11 är väte, en konventionell salt- bildande katjon använd inom detta arbetsområde eller en konventio- nell karboxiskyddande grupp använd inom detta område; och R7 är väte eller en konventionell silyl- eller fosforskyddande grupp med för- måga att med lätthet avlägsnas genom behandling med H20 eller en alkohol. konventionella saltbildande katjoner representerade av R11 inkluderar katjoner med förmåga att bilda ett icke-toxiskt salt, såsom nämnts ovan i samband med R1, och en katjon med förmåga att bilda ett salt med andra kvävehaltiga organiska baser, såsom trimetylamin, trietylamín, tributylamin, pyridin, dimetylanilin, N-metylpiperidin, N-metylmorfolin, dietylamin, dicyklohexylamin, etc.In said formulas (II) - (VIII), R 5, R 2, R 3, A, x, Y, m and n have the meaning given; R 11 is hydrogen, a conventional salt-forming cation used in this field of work or a conventional carboxy-protecting group used in this field; and R 7 is hydrogen or a conventional silyl or phosphorus protecting group capable of being easily removed by treatment with H 2 O or an alcohol. conventional salt-forming cations represented by R 11 include cations capable of forming a non-toxic salt, as mentioned above in connection with R 1, and a cation capable of forming a salt with other nitrogen-containing organic bases, such as trimethylamine, triethylamine, tributylamine, pyridine, dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, etc.

En konventionell karboxiskyddande grupp inkluderar en esterbildande grupp, såsom nämnts i samband med R1, och en konventionell silyl- eller forsforskyddande grupp med förmåga att med lätthet avlägsnas genom behandling med H20 eller en alkohol, såsom (CH3)3Sí-, 0% CHO\_ [:::O/,eP-, CšHâo,,P-, etc.A conventional carboxy protecting group includes an ester-forming group, as mentioned in connection with R 1, and a conventional silyl or rapeseed protecting group capable of being easily removed by treatment with H 2 O or an alcohol, such as (CH 3) 3 Si-, 0% CHO [::: O /, eP-, CšHâo ,, P-, etc.

En konventionell silyl- eller fosforskyddande grupp representerad av R7 är av samma typ som nämnts i samband med R 1.A conventional silyl or phosphorus protecting group represented by R 7 is of the same type as mentioned in connection with R 1.

I formeln (VI) är B en substituent med förmåga att med lätt- het ersättas av ett nukleofilt medel och inkluderar exempelvis halogenatomer, såsom klor, brom, etc; lägre alkanoyloxi, såsom formyloxi, acetoxi, propionyloxi, butyryloxi, pivaloyloxi, etc; arylkarbonyloxi, såsom bensoyloxi, naftoyloxi, etc; arylkarbonyltio, såsom bensoyltio, naftoyltio, etc; karbamoyloxi; heteroaromatiska amin-N-oxid-tiogrupper med en tiogrupp på den kolatom som ligger i grannställning till N-oxidgruppen i molekylen, såsom pyrídin-1-oxid- -2-yltio. pyridazin-1-oxid-6-yltio, etc. var och en av de för B ...WH _. .__ . _. -. .._...-f ..,.. _.. ...»,_ _.........._. __.__..........,_ _.. '7808204-7 nämnda grupperna kan vara substituerade med sådana substituenter som exempelvis halogen, nitro, alkoxi, alkyltio, acyl etc.In formula (VI), B is a substituent capable of being easily replaced by a nucleophilic agent and includes, for example, halogen atoms such as chlorine, bromine, etc .; lower alkanoyloxy, such as formyloxy, acetoxy, propionyloxy, butyryloxy, pivaloyloxy, etc .; arylcarbonyloxy, such as benzooyloxy, naphthoyloxy, etc .; arylcarbonylthio, such as benzoylthio, naphthoylthio, etc .; carbamoyloxy; heteroaromatic amine N-oxide thio groups having a thio group on the carbon atom adjacent to the N-oxide group in the molecule, such as pyridin-1-oxide--2-yltio. pyridazin-1-oxide-6-ylthio, etc. each of those for B ... WH _. .__. _. -. .._...- f .., .. _ .. ... », _ _.........._. The groups mentioned may be substituted by such substituents as, for example, halogen, nitro, alkoxy, alkylthio, acyl, etc.

I formeln (VII) betecknar R8 azido eller en lägre alkyliE=~ grupp (som kan vara substituerad med karboxi) eller oxalyltío, tiazolyltio, tíazolynyltio, imidazolyltio, pyridazínyltío, pyrimidi- nyltio, oxadiazolyltio, tiazolyltio, triazolyltio, tetrazolyltio, piperazinyltiokarbonyltio, isoxazolylkarbonyltio, (pyridyl-1-oxid)tio eller (5-oxo-2,5~dihydro-1,2,4-triazinyl)tio, vilka kan vara sub- stituerade med lägre alkyl.In the formula (VII), R 8 represents azido or a lower alkyl group (which may be substituted by carboxy) or oxalylthio, thiazolylthio, thiazolynylthio, imidazolylthio, pyridazinylthio, pyrimidinylthio, oxadiazolylthio, thiazolylthiozylethylthiolazyl (pyridyl-1-oxide) thio or (5-oxo-2,5-dihydro-1,2,4-triazinyl) thio, which may be substituted with lower alkyl.

I formeln (VII) är M väte, en alkalimetall eller en jordalkali~ metall.In formula (VII), M is hydrogen, an alkali metal or an alkaline earth metal.

Såsom förening (II) kan man använda varje D-isomer, L-isomer eller racemisk förening.As compound (II) one can use any D-isomer, L-isomer or racemic compound.

Såsom reaktionsbenäget derivat av (tio)karboxígrupper i föreningen med formeln (VIII) använder man ett reaktionsbenäget derivat av en karbonsyra, som vanligen användes vid syntes av syra- amidföreningar. Exempel på reaktionsbenägna derivat är syrahalider, syraazider, syracyanider, blandade syraanhydrider, aktiva estrar, aktiva aminer, etc. Särskilt lämpliga exempel därpå är syrahalider såsom syraklorider, syrabromider, etc; och aktiva estrar såsom cyanometylester, triklormetylester, etc.As the reaction-derivative of (ten) carboxy groups in the compound of formula (VIII), a reaction-derivative of a carboxylic acid is commonly used in the synthesis of acid amide compounds. Examples of reactive derivatives are acid halides, acid azides, syracyanides, mixed acid anhydrides, active esters, active amines, etc. Particularly suitable examples thereof are acid halides such as acid chlorides, acid bromides, etc .; and active esters such as cyanomethyl ester, trichloromethyl ester, etc.

Det reaktionsbenägna derivatet av (tio)karboxigruppen i före- ningen med formeln (III) kan med lätthet erhållas genom att man omsätter exempelvis en oxopiperazin med formeln (VIII), syntetiserad enligt i det följande angivna litteraturreferenser, med fosgen, tio- fosgen, triklormetylester av klormyrsyra eller liknande, (X)n Å-N (XII 9 (n-Rïflm vari A, X, R2, R3, m och n har den ovan angivna betydelsen.The reactive derivative of the (ten) carboxy group in the compound of formula (III) can be easily obtained by reacting, for example, an oxopiperazine of formula (VIII), synthesized according to the literature references given below, with phosgene, thiophosgene, trichloromethyl ester of chloroformic acid or the like, (X) n Å-N (XII 9 (n-R 1 m) wherein A, X, R 2, R 3, m and n have the meaning given above.

Litteraturreferenser: V G Granik, Khim~Farm. Zh, I(4), 16-19 (1967) (Russ); Samuel R Aspinall, J Am Chem Soc, 62, 1202-4 (1940); Kuniyoshi Masuzawa, Pharm Bull (Japan), åâ, 2078-2081 (1966); Arthur P Phillips, Ger 1135472, augusti 30 (1962); J L Riebsomer, J Org Chem, lä, 68 - 73 (1950); Jongkee, Rec trav Chim, gl, 305; 780820lv7 Patric T Izzo, J Am Chem Soc, ål, 4668-4670 (1959); och B H Chase & A M Downes, J Chem Soc, 3874-3877 (1953).Literature references: V G Granik, Khim ~ Farm. Zh, I (4), 16-19 (1967) (Russ); Samuel R Aspinall, J Am Chem Soc, 62, 1202-4 (1940); Kuniyoshi Masuzawa, Pharm Bull (Japan), åâ, 2078-2081 (1966); Arthur P Phillips, Ger 1135472, August 30 (1962); J L Riebsomer, J Org Chem, lä, 68-73 (1950); Jongkee, Rec trav Chim, gl, 305; 780820lv7 Patric T Izzo, J Am Chem Soc, eel, 4668-4670 (1959); and B H Chase & A M Downes, J Chem Soc, 3874-3877 (1953).

Konkreta exempel på föreningar med formeln (VIII) och det reaktionsbenägna derivatet av (tio)karboxigruppen av föreningen med formeln (III) är sammanställda i tabell I resp tabell II. '7808204-7 10 Tabell I.Concrete examples of compounds of formula (VIII) and the reaction-prone derivative of the (ten) carboxy group of the compound of formula (III) are summarized in Table I and Table II, respectively. '7808204-7 10 Table I.

(X) fihn _ AN I-.TH (11:11) m smäupwqkr :R Förening (omkristallisaticns- ,n _1) lösningsmedel) *“m 0 ío Vc=o 540 ,_1¿ 136% (fi ) '31 O] VNH 3450 - 5250 O C: ' kßkbuïlkï ' __ - \)_ ' QQ 3 143°c/1 mm Hg C-O HN\_§5 oljeartat material \ë3¿ ÉÉCO ' 5209 0 lšqlflpunkiß 122 - _ \\_\ 12500/2 mm Hg- QCZO 1550 - 1630 m: 1:1' >_' l4O ~ lli~lOC VHB 3250» 3l7Û CH§ o C143 m: 85 - 86% (nu: - x/Cm; 560 - 1620 ' - :Pm C115 o cfizícc-zcgfg JC=O 1710, 1640 \ “ 105 - 1oe°c (fxcczt) _13: 111m #00, 3190 1f4 , 16" JO 112 - 113°c ¶( (j > Vczo J 5 ö CH3COH IH ' QNH ÉÉÖO, 3329 \_J o JH, 1-s-ïo 1630 4 129 - 13o°c (m1) J _ H ' ClCH2CQíø}Hi NH S210 78082014-7 O O Vczo 10-30-1630 ,_1-_- 134 - 135 c (ma) ) _ 012011001; :om m; :280 \._/ 0 VC=O 1070, 1040 96 - 9700 (00%) v _ CH3(CH¿)1_5CI~1¿f;0::U1ïH :.".~1 2200 o Vego 1000, 1020 14' eo - 61°c (1013) v 01:5(c1æ2)5c1a¿00;: :m 3250 0 . o Uczo 1000, 1620 14/ I 83 _ 84 c (IPB) v 011502112) ácsëco-zL/rra NH 3250 0 o VM, 1060, 1620 14 99 - 100 0 (0014) __ CHB (CHQ Ä :CFQCCÉTJJH Y EL 3:50 0 x/'æo 1070, 1020 203 - 205% (191) 0 »Lzo 1040, 1600 h” 91 - 93% (m) ” @'ÜÛH f? JNH 3250 I 0 w: 1050 1020 P4 146 - 111290 (121) ° O ' 01 3 -0011 fm ?200 0 o VC=O 1000, 1020 4 110 - 120 c (111) 0111 O\ 0021 H VHB 3200 01130 0 J 11 Vzo 1070, 1000 01150 001: :rn 102 - 18500 (nu) U Vw 2200 78082011-7 12 -z-:aben I (form) c1 0 16=n, 1620 , .(X) fi hn _ AN I-.TH (11:11) m smäupwqkr: R Compound (recrystallization, n _1) solvent) * “m 0 ío Vc = o 540, _1¿ 136% (fi) '31 O] VNH 3450 - 5250 OC: 'kßkbuïlkï' __ - \) _ 'QQ 3 143 ° c / 1 mm Hg CO HN \ _§5 oljeartat material \ ë3¿ ÉÉCO' 5209 0 lšql fl punkiß 122 - _ \\ _ \ 12500/2 mm Hg- QCZO 1550 - 1630 m: 1: 1 '> _' l4O ~ lli ~ lOC VHB 3250 »3l7Û CH§ o C143 m: 85 - 86% (nu: - x / Cm; 560 - 1620 '-: Pm C115 o c fi zícc-zcgfg JC = O 1710, 1640 \ “105 - 1oe ° c (fxcczt) _13: 111m # 00, 3190 1f4, 16" JO 112 - 113 ° c ¶ ((j> Vczo J 5 ö CH3COH IH ' QNH ÉÉÖO, 3329 \ _J o JH, 1-s-ïo 1630 4 129 - 13o ° c (m1) J _ H 'ClCH2CQíø} Hi NH S210 78082014-7 OO Vczo 10-30-1630, _1 -_- 134 - 135 c (ma)) _ 012011001;: om m;: 280 \ ._ / 0 VC = O 1070, 1040 96 - 9700 (00%) v _ CH3 (CH¿) 1_5CI ~ 1¿f; 0 :: U1ïH :. ". ~ 1 2200 o Vego 1000, 1020 14 'eo - 61 ° c (1013) v 01: 5 (c1æ2) 5c1a¿00 ;:: m 3250 0. O Uczo 1000, 1620 14 / I 83 _ 84 c (IPB) v 011502112) ácsëco-zL / rra NH 3250 0 o VM, 1060, 1620 14 99 - 100 0 (0014) __ CHB (CHQ Ä: CFQCCÉTJJH Y EL 3:50 0 x / 'æo 1070, 1020 203 - 205% (191) 0 »Lzo 1040, 1600 h” 91 - 93% (m) ”@' ÜÛH f? JNH 3250 I 0 w: 1050 1020 P4 146 - 111290 (121) ° O '01 3 -0011 fm? 200 0 o VC = O 1000, 1020 4 110 - 120 c (111) 0111 O \ 0021 H VHB 3200 01130 0 J 11 Vzo 1070, 1000 01150 001:: rn 102 - 18500 (nu) U Vw 2200 78082011-7 12 -z-: aben I (form) c1 0 16 = n, 1620,.

Cl@CCIfLd_IïE1 cljaazåat material VHB PCO cs=/0 60 ( C) ) VÉ=0 1620, 1630 “- 124 - 12 c Û CHBCOILTTH _ ' . VNH _ :E25 0 VC=O IÉÖO 7 O _¿_{" 167 - 168°c (ßton) VH ïzoo C¿5“°2 1_}“¶ y{¿0?¿< 1"1o. 11-0 0 VC=0 1»9o, 1650, / O cflšccxšcèfi NH \__J 76 - 179% <@> o 0 1660, 1é_o ,4 as - 88 c (acoßt) V @1c:~zcozrwna NH mo. :zco / 61 - 82 c ([ ]> _ ___ CH-ÅÉHEÛCCÉLÅÄH Ü JFH ,¿"\Û, IÅ-ZÛ o yß=0 16=ø, 1620 . ,_( 139 - 19o°c (IBA) - (cH;)3cäsca¿-fl¥_yfi VNH "zæo O O. o \)C=O 1560 $~< 136 - 138 C ) - ~ ,. vïrfrt 1n1_;¿= (aceton) »hg _ 1 o Jczo 1ßïo _ 1130 I oljeartat mate rial cH3(cH¿)¿cH¿-quøyfl NH ,z7o 0 Jim 32 S0 cH3(cH¿;¿cn2-H HH °13eaT*a* material vß=0 1650 - 1430 L! 13 Tabell I (íorts.) 78108201» - 7 O / -ïiáflcfl “mig-ra NH , 2 r. c. L__< . _ . _ olgeartat mater1a¿ \/C:O lé-ïn - lezo 5 o 2,0 las - 1630 f_( Hffiroklcrid 'I I xnl n*- \__J oljearüat material oljeartat material 3 'LJ^ OM JC=0 1720, löao f: ' ' - 'nån _ \:¿}¿H¿ONL-FH o}3eartat mate__ßl »NH 3_Oo o JH; 1-320 koknunkt " ' I 'ÜÉN NH lO4-ÜC/4 film Hg VEH :ZFE I 'ïfi _ VCZO l'ê_v ¿¿TCH2_N :H oljeartat material VNH ;:,O .« \__J f - TO ,,.__. , ,.._.__.. "- .....3((»H2)ZL..___ Ux-jafl oljearüat maïerial oljcartat material VNH 'Lif-OG - 'S-ÉOC oljeartat material O ÛÉÉZ\ r-fl? rf 1 'H ä /vflßlígßhä-:Lflfl øljeartat material vaoszoa-7 14 Tabell I (for-bs.) y l o _ C=0 1620 CH3(CH2)4CH2_N\_JI;H Oljeârtat fllaïërial JHH 7.270 (àñ ¶ \/(;=0 1620 " ' 't 't 't ' l cfiycflzgcfiâ-:Lræfi “gear a ma erla VM; 3270 Q x/Cæ 1620 _ w _, oljeartat material _ cf15(cH2)6cH¿-l1U1.H Jm ;.270 få VC=O 1620 rñ ° _ I. .L - _. gH3(C1-12)lOCH¿_;;\_J NH olgeartat mauerlal y/NH ;270 0% _ } Jcro 1620 , , 1' f f t 'l _ QNQNH o Jear a me. erla VNH 3300 Q CHS' Jczo 1630 _ _* __ oljeartat material __ c1«:5(cf12)¿cfl¿-.«1\_J=.1H y/Im .uoo O \ _ _ »è_O laïo CH3(CH2)¿CH2_1: m; ølgeartat matenal " F” - VNH ïšoo CH3 0 , JC=O 1.530 cfïflcflfizcnzq: UH oljeartat material L* VNH ÉÉOO CH5 - o 0 Who 1630 M 157 - 1s8°c <[l ]> O cng-r-Lrm U Jim 3300 15 Tabell I (for-ts.) vsoezou-7 Q CH: vczo 1700 H NCO_Q*flE oljeartat material vän 5400 _ 3:50 f- \_._/ 0 kokpunkt _ 183 - 185°c/2 mm ag V@=0 1620 HOCH«Ch2-N JH L 1./ Q \/C:O lÖE-Û V " '-=~ t ma' r' ' cH¿=cHcH¿-H YH °* '°r at te lal VNH 3300 x \_../ 0 _ _ VC=0 1620 CH¿=CHcH_N fp olgeartat mater1al J I NH 3300 CH5 0 \§__\ JC=O 1.540 CHc=ggH2_N 35 oljeartat material V “ I “*“ NH 3300 CH3 0 “ _ v _ \)(~=Q lönO _ CH=CHCH¿_N '53 olgeartat ma1er1al ) fifl I | \'_' Jl-ÃMD š CHE /_ 3 0 _ + _ VC=0 1020 FÅ '_ \ ol3ear.at mater1al V ~_¶ q_Jmu¿¿~q_}ni NH 200 184 - 1&5°c (utan) ï/QZQ 1590 - 1650 3100, ÉOÉO 177 - 17@°u (namn) VCSO 1cso _ 1550 \}TJ}I 3190 . 3050 78082011-7 16 ...t Tabell I (forts.) (3 I. l”"\ cæg-nuzzii 142 - 1Hs°c (m) 1630 ~ l{2O ,, 'VHB :zoo o O I 2 Jczo 1660 - 1220 @-f~~-_u NH 2o9°o (Iaf-A v52 _ I _ J _ 1 »HH 1230 o o o Q _ VC=@ 1695, :sec \ f _ 158 c (121) J ca;-1L_yH HH 3220 o o VC=0 1730 - =;o Cfl3CÛuvfl2-H2~§Ldfl oljeartat material JNH () () ¶1_1V (0113 kct-nunn 166 _ 167°c ([0]) 01 0 0 _ 1680, Lëšo n n» -ïM--u ) x) 'zfxgo Cnjonzfikøfin NH 1:, ) _ O O Q VC=O 1780, l1'O _ 1.! ge _ 1oo°c ({ j) ¿ _ñ _f oH¿cH¿cH24í_}ua 0 \;H ; I o o vC=@ 1695, Leïo \ 1.! 111 - 113°: (cola) J _n_ ___ oH3(cz¿;¿cH¿-aL_}n¶ NH ;<«o, :-:» 0 0 cH3(c§2)3cH¿-4í_}n¶ IL()i1 1oo°c (Kpm) 5900, ïlco ¥-¥ :z __: '11 cH3(cM2)4cn9 .1_¿ I 111 - 115°c (IPB) I 1700, 1eao aøoo, :zoo vaoazoa-7 17 Tabell I (forts.) 0 0 V~_0 1700, 1:60 ' 1.1 112 - 115°c < vu) V _ cH3 O' O O \C._.O _-./ÛO, IÖÉÛ 1.4 116 - 120 0 (122) Q cH5;ca,-1 nu ~ ~ \_/ O O o \)C=Q 1580, låiš _ __ 156 - 137 C V CH2=CnunÅ_:-;.\_J;.:í (acetøn) :E { 0 0 1 202 - 2o4°c (:P1) ~ Vyn- ï~2fl° 0 0 VC=O 1700 - 1650 1.¿ 128 - 129°c (ston) ~ _ _ c1cH cH-: NH V33 :200 - :lG0 2 6 \__/ u *H 127 - 12&°c <1c0Lt) J ”T” I O O v 'I 0 _: .lo cH=-I :E 146 - 1h7°C < )« ” \-< [0] Jyw =200, :1c0 01:: HI NH 18:* - lOJ C (EÜÜIÉ) V23; ÛTÉO, Qš>~cn¿n NH 96 - 90°c än O (IIfA-u-hexan) 780820lv7 143 - L-6°C (:P¿) 210 - 2:2°c Gæmn ' 132 - 53% (IÉOH) |.J (\'\ (n m 3170 98 _ 1:o°c :H th \)l a, ä r-c LH ll É w' I (cH;)¿cHoH (cH3)¿cHocH(:33)2 ACOEt = CH3COOCH2CH3 td f+ O I!! ll CHz-CI-POH J C 780820h-7 19 Tabell II ' (XW. /_{}\ 1 Reaktionsbenägna derivat av zk-í-I TI- .1 (III) \ \ (Rïnï), _ ä . . F l.~k ,_ . A-L.. Cl @ CCIfLd_IïE1 cljaazåat material VHB PCO cs = / 0 60 (C)) VÉ = 0 1620, 1630 “- 124 - 12 c Û CHBCOILTTH _ '. VNH _: E25 0 VC = O IÉÖO 7 O _¿_ {"167 - 168 ° c (ßton) VH ïzoo C¿5“ ° 2 1 _} “¶ y {¿0? ¿<1" 1o. 11-0 0 VC = 0 1 »9o, 1650, / O c fl šccxšcè fi NH \ __ J 76 - 179% <@> o 0 1660, 1é_o, 4 as - 88 c (acoßt) V @ 1c: ~ zcozrwna NH mo. : zco / 61 - 82 c ([]> _ ___ CH-ÅÉHEÛCCÉLÅÄH Ü JFH, ¿"\ Û, IÅ-ZÛ o yß = 0 16 = ø, 1620., _ (139 - 19o ° c (IBA) - ( cH;) 3cäsca¿- fl ¥ _ y fi VNH "zæo O O. o \) C = O 1560 $ ~ <136 - 138 C) - ~,. vïrfrt 1n1_; ¿= (acetone) »hg _ 1 o Jczo 1ßïo _ 1130 I oljeartat mate rial cH3 (cH¿) ¿cH¿-quøy fl NH, z7o 0 Jim 32 S0 cH3 (cH¿; ¿cn2-H HH ° 13eaT * a * material vß = 0 1650 - 1430 L! 13 Tabell I (íorts.) 78108201 »- 7 O / -ïiá fl c fl“ mig-ra NH, 2 rc L __ <. _. _ olgeartat mater1a¿ \ / C: O lé -ïn - lezo 5 o 2,0 las - 1630 f_ (Hf fi roklcrid 'II xnl n * - \ __ J oljearüat material oljeartat material 3' LJ ^ OM JC = 0 1720, löao f: '' - 'nån _ \: ¿} ¿H¿ONL-FH o} 3eartat mate__ßl »NH 3_Oo o JH; 1-320 koknunkt" 'I' ÜÉN NH lO4-ÜC / 4 film Hg VEH: ZFE I 'ï fi _ VCZO l'ê_v ¿¿TCH2_N: H oljeartat material VNH;:, O. «\ __ J f - TO ,, .__.,, .._.__ .." - ..... 3 ((»H2) ZL ..___ Ux-ja fl oljearüat maïerial oljcartat material VNH 'Lif-OG -' S-ÉOC oily material O ÛÉÉZ \ r- fl? rf 1 'H ä / v fl ßlígßhä-: Lfl fl øljeartat material vaoszoa-7 14 Table I (for-bs.) ylo _ C = 0 1620 CH3 (CH2) 4CH2_N \ _JI; H Oljeârtat fl laïërial JHH 7.270 (àñ ¶ \ / (; = 0 1620 "'' t 't' t 'l c fi yc fl zgc fi â-: Lræ fi“ gear a ma erla VM; 3270 Q x / Cæ 1620 _ w _, oily material _ cf15 (cH2) 6cH¿-l1U1.H Jm; .270 få VC = O 1620 rñ ° _ I. .L - _. gH3 (C1-12) lOCH¿ _ ;; \ _ J NH olgeartat mauerlal y / NH; 270 0% _} Jcro 1620,, 1 'f f t' l _ QNQNH o Jear a me. erla VNH 3300 Q CHS 'Jczo 1630 _ _ * __ oljeartat material __ c1 «: 5 (cf12) ¿c fl¿ -.« 1 \ _ J = .1H y / Im .uoo O \ _ _ »è_O laïo CH3 (CH2) ¿CH2_1: m; ølgeartat matenal "F” - VNH ïšoo CH3 0, JC = O 1,530 cfï fl c flfi zcnzq: UH oljeartat material L * VNH ÉÉOO CH5 - o 0 Who 1630 M 157 - 1s8 ° c <[l]> O cng-r-Lrm U Jim 3300 Table I (for-ts.) Vsoezou-7 Q CH: vczo 1700 H NCO_Q * fl E oily material friend 5400 _ 3:50 f- \ _._ / 0 boiling point _ 183 - 185 ° c / 2 mm ag V @ = 0 1620 HOCH «Ch2-N JH L 1. / Q \ / C: O lÖE-Û V" '- = ~ t ma' r '' cH¿ = cHcH¿-H YH ° * '° r at te lal VNH 3300 x \ _ .. / 0 _ _ VC = 0 1620 CH¿ = CHcH_N fp olgeartat mater1al JI NH 3300 CH5 0 \ § __ \ JC = O 1.540 CHc = ggH2_N 35 oljeartat material V “I“ * “NH 3300 CH3 0 “_ v _ \) (~ = Q lönO _ CH = CHCH¿_N '53 olgeartat ma1er1al) fifl I | \ '_' Jl-ÃMD š CHE / _ 3 0 _ + _ VC = 0 1020 FÅ '_ \ ol3ear.at mater1al V ~ _¶ q_Jmu¿¿ ~ q_} ni NH 200 184 - 1 & 5 ° c (utan) ï / QZQ 1590 - 1650 3100, ÉOÉO 177 - 17 @ ° u (name) VCSO 1cso _ 1550 \} TJ} I 3190. 3050 78082011-7 16 ... t Table I (cont.) (3 I. l ”" \ cæg-nuzzii 142 - 1Hs ° c (m) 1630 ~ l {2O ,, 'VHB: zoo o OI 2 Jczo 1660 - 1220 @ -f ~~ -_u NH 2o9 ° o (Iaf-A v52 _ I _ J _ 1 »HH 1230 ooo Q _ VC = @ 1695,: sec \ f _ 158 c (121) J ca; -1L_yH HH 3220 oo VC = 0 1730 - =; o C fl3 CÛuv fl2- H2 ~ §Ld fl oljeartat material JNH () () ¶1_1V (0113 kct-nunn 166 _ 167 ° c ([0]) 01 0 0 _ 1680, Lëšo nn » -ïM - u) x) 'zfxgo Cnjonz fi kø fi n NH 1 :,) _ OOQ VC = O 1780, l1'O _ 1.! ge _ 1oo ° c ({j) ¿_ñ _f oH¿cH¿cH24í_} ua 0 \; H; I oo vC = @ 1695, Leïo \ 1.! 111 - 113 °: (cola) J _n_ ___ oH3 (cz¿; ¿cH¿-aL_} n¶ NH; <«o,: -:» 0 0 cH3 (c§2) 3cH¿-4í_} n¶ IL () i1 1oo ° c (Kpm) 5900, ïlco ¥ - ¥: z __: '11 cH3 (cM2) 4cn9 .1_¿ I 111 - 115 ° c (IPB) I 1700, 1eao aøoo,: zoo vaoazoa-7 17 Table I (cont.) 0 0 V ~ _0 1700, 1:60 '1.1 112 - 115 ° c <vu) V _ cH3 O' OO \ C ._. O _-./ÛO, IÖÉÛ 1.4 116 - 120 0 (122) Q cH5; ca, -1 nu ~ ~ \ _ / OO o \) C = Q 1580, låiš _ __ 156 - 137 CV CH2 = CnunÅ _: -;. \ _ J;.: Í (acetøn): E {0 0 1 202 - 2o4 ° c (: P1) ~ Vyn- ï ~ 2 fl ° 0 0 VC = O 1700 - 1650 1.¿ 128 - 129 ° c (ston) ~ _ _ c1cH cH-: NH V33: 200 -: lG0 2 6 \ __ / u * H 127 - 12 & ° c <1c0Lt) J ”T” IOO v ' I 0 _: .lo cH = -I: E 146 - 1h7 ° C <) «” \ - <[0] Jyw = 200,: 1c0 01 :: HI NH 18: * - 10J C (EÜÜIÉ) V23; ÛTÉO, Qš> ~ cn¿n NH 96 - 90 ° c än O (IIfA-u-hexane) 780820lv7 143 - L-6 ° C (: P¿) 210 - 2: 2 ° c Gæmn '132 - 53% ( IÉOH) | .J (\ '\ (nm 3170 98 _ 1: o ° c: H th \) la, ä rc LH ll É w' I (cH;) ¿cHoH (cH3) ¿cHocH (: 33) 2 ACOEt = CH3COOCH2CH3 td f + OI !! ll CHz-CI-POH JC 780820h-7 19 Table II '(XW. / _ {} \ 1 Reaction-prone derivatives of zk-í-I TI- .1 (III) \ \ (Rïnï ), _ ä.. F l. ~ k, _. AL ..

Fbrenmg ešârïšâaï I R (Cm 1 o ~ -M P4 \-'-¿=O 1790, 1.1.1, 1,-, 0: * _05* l ' rtdc material Cn/"O lbd 01 0 gea ° 1640 0 Vfs=o 1790, // n _ n- | 0105200-11300001 1750 - -WÛ s Q V;=Q 1790, 012050041 1-0001 1750 - 30! 0 3:0 1710, 1:22. ' ,-/( , ï wwprvfi ) _<:H..00-N 11-0001 " 1040 i "'“; "' 2 l; i \._/ l § 1 1 (_) lrffll-O, l f-»urclf ) 0z;-.«':<,-1f_¿í-I-00c1 1600 - 2240 ' JA.) 1--2 5 t: x-J _ I , I 0 x-Czo 17.110, t Ä n fi, x czašícfig) 4cH2c0-nun-c001 16-00 - 1-...0 | 1 l 0 vf, 1790, 171: , g 1-1 n 9 0114011- )._.0ri 00-0 rI-rzocl 1040 ä å' Å 1 ß \_./ I ?80820h-7 20 Tabell II (forts. ) I 0 VC=0 1790, 1730, " oljeartat material t @0o-N 0-0001 1640 I 0 VC=O 1740, 1600, l fw " I @-00-n 11-00-31 1630 L) . o' VH, 1740, 1540 ,_z " 01@00-N 11-000 LJ 0 z 4/ H vC=O 1730, 1650 0H¿@ 00-1: :z-cocl ' L! 0H~0 0 a \ FJ 0z-:30@c0-:fp;t-0001 " VC=O 17,20, 1640 0H3o “ 01 o <1 J " VH) 17.20.1640 , 01 900-11417-0001 1 1 011; 0 10:73 17-90, 11-10, ' II 011300-17 11-0001 1640 \__/ o VCZO 1790, 1700 f- ~ f* f1~ n xfl- 1 w JH3UO2"PI\_JI\I”@O'»J1. :Dog 1/20, l-wo O vfl-:O 1.790, , 01150011110-11 0-2001 1720 - 1600 21 Tabell II (for:s.) vsoszoa-7 I 0 Jczo lvao, 1120, @r¿_rqCO_¿ïf'4/H_UCC]_ oljeartat material 1550 v ° \._/ O »QZO 1750, 1720, '_41 Il r caïcfizoco-N H-cocl 1040 1 \_J 0 v@=O 1740 - 1720, [__-a Il f (cH;)=ccoocH¿-3 N-coc1 lø70 .I J \__/ P N vQ=O 790, 1vzo o / ' " JC=Q lïwo, 1720 cï=,cH2)¿cH¿-N H-coc1 0 cfl (CH ) cv =(-íncccl " V « 1730 1*2" 3 2 2 -2'\;{ C=Û ' ' V CHZ: I 1 o Q _ _>p I J " C39 1.190, 1.111 ' cH1(fH2)6cH¿-1 U-cocl / p; smä1tpunkt ' o 115 - 116°c J A , (sönderdelning) Cm 17-710, ICÉO 11 x- 0,1 2' I1\_I C P (ur ) o CH; 1 . 1 1n&_§-c@c1 kristall JCSO 1730, 1670 C H; 7808204-7 22 Tabell II (fax-ts.) o M HN N-0001 kristall 90-9 1720, lêáo >_/ CHB 7 smältpmulzt 1,, 0k40H2co0cH¿cH3 59 f GOOC VV=3 1710 - 1., , Hwxdy-0001 (ur IPE) 1660 smältpu. t O>ŶCH3 98 - 100 C v 1725 C \ / _ 0:0 HN N-0001 (ur ÜÉÜ) 0 ' \__/ Û CHB _ . ñ f, olgeartat matez-lal \-C=o 1710, lcgO 0 1-l cH3c0-N N-coc1 \__/ 1790,¶17: 1 0 $~\ <:>»§Hco-N¿_;-cocl 0 cs;-n n-coc1 171" , 1530 >_\ H Vczg 1730 1650 cs3(cH¿)2cH¿-qkdp-coc1 ' ° 7 H \C=o 1730, 1:50 mnæn41:Lum1 J¿\_.1 0 " yß=Ü 1720, 1f1o 23 Tabell II (fortsu) 780820lf-7 O fl oljeartat material '3-_-O 1/73» l 9 CH3 (CHQ )-¿;CšI¿-I~J\~'n-CCL1. 0 1 , _ _ . r " \"C___o l/ác, _"'¿O š (CHB ) -zcïczgcxïßrwïï-c oc 1 i 0 .f _- i; Lï- w n -'C:O 171.1, .uti-Û CH3(CH2)¿Cr-^-I*ï L-z-OCI 1 i i l O n i 1 frn ' ,' -P - m _: - MX E-_-_~___O ..1,\., ..--- z cH3(cp¿)5vfl¿-f. N-Ncl E i O _) u, - - - ï v \ n (T ___ m 1 " 'C=0 1.4.1, .zl-O Cflš (C112 i é -l42-r.\_i..-'..0C.. i 0 : i \ n i .1 f- n *j , M: ärm å “.-C=O lfcu, -WW CH3(CH2;lOH.~ ng. -J.1... i z i š o . , f n \:=0 ' __Q .Fbrenmg ešârïšâaï IR (Cm 1 o ~ -M P4 \ -'- ¿= O 1790, 1.1.1, 1, -, 0: * _05 * l 'rtdc material Cn / "O lbd 01 0 gea ° 1640 0 Vfs = o 1790, // n _ n- | 0105200-11300001 1750 - -WÛ s QV; = Q 1790, 012050041 1-0001 1750 - 30! 0 3: 0 1710, 1:22. ', - / (, ï wwprv fi ) _ <: H..00-N 11-0001 "1040 i" '“;"' 2 l; i \ ._ / l § 1 1 (_) lrf fl l-O, l f- »urclf) 0z; - . «': <, - 1f_¿í-I-00c1 1600 - 2240' JA.) 1--2 5 t: xJ _ I, I 0 x-Czo 17.110, t Ä n fi, x czašíc fi g) 4cH2c0-nun -c001 16-00 - 1 -... 0 | 1 l 0 vf, 1790, 171:, g 1-1 n 9 0114011-) ._. 0ri 00-0 rI-rzocl 1040 ä å 'Å 1 ß \ _. / I? 80820h-7 20 Table II (cont. .) I 0 VC = 0 1790, 1730, "oily material t @ 0o-N 0-0001 1640 I 0 VC = O 1740, 1600, l fw" I @ -00-n 11-00-31 1630 L). o 'VH, 1740, 1540, _z "01 @ 00-N 11-000 LJ 0 z 4 / H vC = O 1730, 1650 0H¿ @ 00-1:: z-cocl' L! 0H ~ 0 0 a \ FJ 0z-: 30 @ c0-: fp; t-0001 "VC = O 17,20, 1640 0H3o" 01 o <1 J "VH) 17.20.1640, 01 900-11417-0001 1 1 011; 0 10: 73 17-90, 11-10, 'II 011300-17 11-0001 1640 \ __ / o VCZO 1790, 1700 f- ~ f * f1 ~ n x fl- 1 w JH3UO2 "PI \ _JI \ I” @O' » J1. : Dog 1/20, l-wo O vfl-: O 1.790,, 01150011110-11 0-2001 1720 - 1600 21 Table II (for: s.) Vsoszoa-7 I 0 Jczo lvao, 1120, @ r¿_rqCO_¿ ïf'4 / H_UCC] _ oljeartat material 1550 v ° \ ._ / O »QZO 1750, 1720, '_41 Il r caïc fi zoco-N H-cocl 1040 1 \ _J 0 v @ = O 1740 - 1720, [__- a Il f (cH;) = ccoocH¿-3 N-coc1 lø70 .IJ \ __ / PN vQ = O 790, 1vzo o / '"JC = Q lïwo, 1720 cï =, cH2) ¿cH¿-N H-coc1 0 c fl (CH) cv = (- íncccl "V« 1730 1 * 2 "3 2 2 -2 '\; {C = Û' 'V CHZ: I 1 o Q _ _> p IJ" C39 1.190, 1.111' cH1 (fH2) 6cH¿-1 U-cocl / p; melting point 'o 115 - 116 ° c YES, (decomposition) Cm 17-710, ICÉO 11 x- 0,1 2' I1 \ _I CP (ur) o CH ; 1. 1 1n & _§-c @ c1 crystal JCSO 1730, 1670 CH; 7808204-7 22 Table II (fax-ts.) O M HN N-0001 crystal 90-9 1720, léáo> _ / CHB 7 melts 1, , 0k40H2co0cH¿cH3 59 f GOOC VV = 3 1710 - 1.,, Hwxdy-0001 (from IPE) 1660 smeltpu. T O> ŶCH3 98 - 100 C v 1725 C \ / _ 0: 0 HN N-0001 ( ur ÜÉÜ) 0 '\ __ / Û CHB _. ñ f, olgeartat matez-lal \ -C = o 1710, lcgO 0 1-l cH3c0-N N-coc1 \ __ / 1790, ¶17: 1 0 $ ~ \ <:> »§Hco- N¿ _; - cocl 0 cs; -n n-coc1 171 ", 1530> _ \ H Vczg 1730 1650 cs3 (cH¿) 2cH¿-qkdp-coc1 '° 7 H \ C = o 1730, 1:50 mnæn41 : Lum1 J¿ \ _. 1 0 "yß = Ü 1720, 1f1o 23 Table II (cont.) 780820lf-7 O fl oily material '3 -_- O 1/73» l 9 CH3 (CHQ) -¿; CšI¿ -I ~ J \ ~'n-CCL1. 0 1, _ _. r "\" C ___ o l / ác, _ "'¿O š (CHB) -zcïczgcxïßrwïï-c oc 1 i 0 .f _- i; Lï- wn -'C: O 171.1, .uti-Û CH3 (CH2) ¿Cr - ^ - I * ï Lz-OCI 1 iil O ni 1 frn ',' -P - m _: - MX E -_-_ ~ ___ O ..1, \., ..--- z cH3 ( cp¿) 5v fl¿- f. N-Ncl E i O _) u, - - - ï v \ n (T ___ m 1 "'C = 0 1.4.1, .zl-O C fl š (C112 i é -l42 -r. \ _ i ..- '.. 0C .. i 0: i \ ni .1 f- n * j, M: ärm å “.-C = O lfcu, -WW CH3 (CH2; lOH. ~ ng . -J.1 ... izi š o., Fn \: = 0 '__Q.

IH Nuz-ï-cocl ¿ i ~ i i , o C22 i _, p å \ ß | 1 . v - :_ 1 a \ _' .XL-Iaf "Opï 9 i \'C=Q 17/*1 -Mf--O i Cflj (C112 ,:_.L.fI2-fl\_;.-, J.. t Q s cH3(c112)¿c:12-n :z-cocl u .Qczo 1720, .Lao E I C 780~820lr7 24 Tabell II (forts.) o n cfgunz)¿cfæ¿-1.L¿=-coc; ol j eartat material 1730 , 1650 C35 OMG smältpunxt \) ,,,_ 1,: m, Næocl los - 1o7°c c=o 1-»0- -LO \_J o _ _ @_Cq *I n cow olgeartat material VC=O 1720, 1,545 ¿2-l\_J'- ._ Û CH: “ "' V voo rm H Neo-N zf-cocl c=0 ' _ j 2 \_,- C: u JC=O l7;oy Hocnzcfiz-:qjï-coc: ' 1550 _ 1530 o Y 'l _ n " VC=O 1720, 1640 cfifcncflå-å-.Ufl--ocl o I f: Jå-xr '1 1 n .IH Nuz-ï-cocl ¿i ~ i i, o C22 i _, p å \ ß | 1. v -: _ 1 a \ _ '.XL-Iaf "Opï 9 i \' C = Q 17 / * 1 -Mf - O i C fl j (C112,: _. L.fI2- fl \ _; .-, J .. t Q s cH3 (c112) ¿c: 12-n: z-cocl u .Qczo 1720, .Lao EIC 780 ~ 820lr7 24 Table II (cont.) On cfgunz) ¿cfæ¿-1.L¿ = -coc; ol j eartat material 1730, 1650 C35 OMG smältpunxt \) ,,, _ 1 ,: m, Næocl los - 1o7 ° cc = o 1- »0- -LO \ _J o _ _ @_Cq * I n cow olgeartat material VC = O 1720, 1,545 ¿2-l \ _J'- ._ Û CH: “" 'V voo rm H Neo-N zf-cocl c = 0' _ j 2 \ _, - C: u JC = O l7; oy Hocnzc fi z-: qjï-coc: '1550 _ 1530 o Y' l _ n "VC = O 1720, 1640 c fi fcnc fl å-å-.U fl-- ocl o I f: Jå-xr '1 1 n.

CE.3=CHïH-1L/rï-I,GC+ Qczo 1730, 3:50 CHš o C k* .. .. ; ._ Hzïclé-Lun-coc* »ho 17:e, L-:eo CH-j 25 Tabell II (forts.) 780-82-014-7 cæïcn 0 'H W-\ cncug-n¥_g-c*c1 (trans-) oljeartat material Vc=o 1.720, l-ÜÉO \ /-\ O N-CHQ-IÉ N-CCCl \_J \._J smälfpunkr 1so°c (sönderdelning) VC-0 0 / -lšov CH3CO-N N-COCl oljeartat material 1H_O 1,_c _1¿ -- -CI 0 0 -_ ä' \)C=O IFÉÛ, _ lÛ, <::fco-N n-cocl " _,_ f 4.010 0 O Vczo 1790, CH3-N N-cccl " ¶_lo f:;o 0 O Qš§~ H fifliï focl JC=o l7:4' C _ :___-I 1 u ,, 2 l,\í_-f' 'm0 - -_20 0 smältpugkt O 0 94-950 , W §_¿ (sönderdelning) \C=0 ;»:0, -220 cH=-N N-cool (ur Cfiïclï" J \_J 3t¿o) O »O CllzCOOCííaCííï-ÉLJ ff-Cb-'fl oljeartat material 0C=@ h.CE.3 = CH 2 H-1L / r 1 -I, GC + Qczo 1730, 3:50 CH 2 o C k * .. ..; ._ Hzïclé-Lun-coc * »ho 17: e, L-: eo CH-j 25 Table II (cont.) 780-82-014-7 cæïcn 0 'H W- \ cncug-n ¥ _g-c * c1 (trans-) oily material Vc = o 1.720, l-ÜÉO \ / - \ O N-CHQ-IÉ N-CCCl \ _J \ ._ J melting point 1so ° c (decomposition) VC-0 0 / -lšov CH3CO-N N-COCl oily material 1H_O 1, _c _1¿ - -CI 0 0 -_ ä '\) C = O IFÉÛ, _ lÛ, <:: fco-N n-cocl "_, _ f 4,010 0 O Vczo 1790 , CH3-N N-cccl "¶_lo f:; o 0 O Qš§ ~ H fifl iï focl JC = o l7: 4 'C _: ___- I 1 u ,, 2 l, \ í_-f' 'm0 - -_20 0 smeltpugkt O 0 94-950, W §_¿ (decomposition) \ C = 0; »: 0, -220 cH = -N N-cool (ur C fi ïclï" J \ _J 3t¿o) O »O CllzCOOCííaCííï -ÉLJ ff-Cb-'fl oily material 0C = @ h.

Q' c) - ~, :":o, F; \\\ ~! O 26 vaoazon-v Tabell II (forts.) 0 O smältpunkt ' 9 --=O M ¶ 95 - 96°c c=o * ~ - cï-:ïcï-Û-z: n-ccc: (sënaeraelning) l _ \-J . (ur AcOBu) 0 O . oljeartat material L? CH c;~:~c1~:~-:r sr-cccl wo - :är 3 C t \_/ __ t d o _ - . ÄH; " \)c=o 'fïfiä cf15(cfi2)¿cfl2-@r\__/..-coc1 0 O smältpunkg V H' 130 - 131 c C: 1720, :sec (cH3)2cH-z-ïLJ:.f-~:o:1 _ (sände rdelning) 0 0 .l Vc-o lzfëo; W P oljeartat material - bd5(C:í2)-:-Cn2-;I\_í.;-COC1. :_20 __ 'Mif o ' V :a f ~.\ O n C=O _ O' ; c:~:3(c:1'2)4c:»z¿-;LÉ:ï-coc1 :zo - š o c Vczo Jae, I " s cH.¿(f;;:2;5cH¿-:I\_/:t-coc1 '520 - QX; n l x/Czo 520, E cflycfiggczïz-:ruïï-"ocl :zo - s 0 o _ V .= “ 1775 \ ' kristall C O ' cnfczzcag-:Lrvl-cccl l 1660 - ?80820lf-7 kristall oljeartat material 'smältpunkt 65 - 70°C CH3C52' (sünderdelning) -7ï«1 \ CHI smëltpunkt Ci f) loo'- 1o1°c_ -jczo 1-35, lg; CH_¿:,_- ;_CgCl (sbnderdelnzng) i c FX, f ?Å¿*(7 smältpunkt ) N _ ____ 1 fälg-Lavl 180 - 181°c Mgïg -- vw:- ~ C Üëgfiy smältpunkg ) (š,--PU¿-r:¥_;::-c cl 160 " 165 C 'who 11:e, 1-370 O /°_\ Uzíl >¿w-/ oljeartat material \Jc=0 1 PC, lïïO. clïuflrfffLfu-:z rv-fml ' 1110 7808204-'7 28 'u Tabell II (forts.) L %L\ smältpugkš 185 - 1 7 C _ , sr=r»__;:-c1oc1 , (Sönderfælning) Vc-io 1720, 1090 O e a Gig-jens. ' 1 *Jc-o 1750, Hw 3_C L U i 1710 - iaeê O 0 ' Q “_ ,--.\ \ CH? C:0 174179 Qššr-C32-N U-CCCl " ' ;-/ ' 1710, l 75 O Anm. 'Et¿G = CH§CH2OCH2CH§ Aase-i = cH3coo(cH¿)5c1-:3 Föreningarna med formeln (V) kan med lätthet erhållas genom omsättning av exempelvis ett salt med en alkalimetall, en jordalkali- metall eller en kvävehaltig organisk bas av en aminosyra (IX) (vilken som helst D-isomer, L-isomer eller racemisk förening) med den allmänna formeln HZN-R-coon (IX) vari R har den ovan angivna betydelsen, med ett reaktionsbenäget deri- vat i (tio)karboxigruppen av en förening med formeln (III) i ett lös» ningsmedel, som är inert mot reaktionen, i närvaro av ett syrabindande medel. Särskilt lämpliga exempel på föreningar med formeln (V) är D-isomerer, L-isomerer och racemiska föreningar av följande föreningar: d-(4-acetyl-2-oxo-1-piperazinokarbonylamino)-fenylättiksyra; a-(4-kloracetyl-2-oxo-l-piperazínokarbonylamino)-fenylättiksyra; a~(4-dikloracetyl-2-oxo-l-piperazinokarbonylamino)~fenylättiksyra; a-(4-palmitoyl-2-oxo-l-piperazinokarbonylamino)-fenylättiksyra; 7-808204-7 29 a-(4-kaprcyl-2-oxo-1-piperazinokarbonylamino)-fenylättiksyra; a-(4-kapryloyl-2-oxø-1-piperazinokarbcnylamino)-fenylättiksyra; a-(4-enantoyl-2-oxo-1-piperazinokarbonylamino)-fenylättiksyra; a-(4-cyk¿ohexankarbonyl-2-oxo-1-píperazinokarbonylamino)~fenylätti¿s¿ra a-(4-benscyl-2-oxo-1-piparazinokarbonylamino)-fenylättiksyra; a~(4-p-klorbensoyl-2-oxo-1-piperazinokarbonylamino)-fenylättiksyra; a-(4-p-metoxibensoyl-2-øxø-1-piperazinokarbenylamino}-fenylättiksyra; a-[4-(3,4,5-trimetoxibensoyl)-2-oxo-l-piparazinokarbcnylaminc]-fenyl~ ättiksyra; a-[4-(2,4-diklqrbensoyl)-2-oxo-1-piperazinckarbonylamino]-fenylättik~ syra; a-(4~acetyl-3-metyl-2-oxo-l-piparazinokarbonylamino)-fenylättiksyra; a-(4-netansulfonyl-2-oxo-1-piparazinokarbcnylamíno)-fenylättiksyra; a-(4-acetylaminokarbonyl-2-oxo-1-piparazinokarbonylamino)-fenyl- ättiksyra; a-(4-fenylaminokarbonyl-2-oxo-1-piperazinokarbonylamino)-fenylättik- syra; a-(4-etoxikarbonyl-2-oxo-l-piperazinokarbcnylamino)-fenylättiksyra; a-(4-pivaloyloximetyl-2-oxo-l-piperazinokarbonylamino)-fenylättiksyra; a-(4-n-hexyl-2-oxo-1-piperazinokarbonylamino)-fenylättiksyra; a-(¿-n-butyl-2-oxo-1-piperazinokarbonylamino)-fenylättiksyra; a-(4-n-butyl-6-mezyl-2-oxo-1-piperazinokarbonylaminc)-fenylättiksyra; a-(4-n-aktyl-2-oxo-1-piperazinokarbonylamino)-fenylëttiksyra; a-(3-oxo-1-piperazinokarbonylamino)-fenylättiksyra; a-(2,5-dimetyl-3-oxo-1-piperazinokarbonylamino)-fenylättiksyra; a-(5-metyl-3-oxo-1-piperazinokarbonylamino)-fenylätfiksyra; a-(2-etozikarbonylmetyl-3-oxo-1-píperazinokarbonylauino)-fenylättik- syra; a-( -mezyl-3-oxo-l-piperazinøkarbonylamino)-fenylättissyra; a-(4-ace:yl-2-metyl-3-oxo-l-píperazinokarbonylaminc)-fenylättiksyra; a-(4-fenylaminokarbonyl-3-oxo-1-piperazinokarbonylamino)-feny1ättik- syra; a-(4-me:yl-3-oxo-1-piperazinokarbonylamino)-fenylättixsyra; a-(4~n-butyl-3-oxo~l~piperazinokarbonylamino)-fenylättiksyra; a-(4-etyl-3-oxo-1-piperazinokarbonylamino)-fenylättixsyra; a-(4-isopropyl-3-oxc-1-piperazinokarbonylamino)-fenylättiksyra; a-(4-n-pentyl-3~oxo-1-piperazinckarbonylamino)-fenylättiksyra; a-(4-isopentyl-3~oxo-1-piparazinokarbonylamino)-fenylättiksyra; a-(4-n-hexyl-3-oxo-1-piperazinokarbonylamino)-fenyläztiksyra; 780820ls-'7 30 a-(4-n-heptyl-3-oxo-l-piparazinokarbonylamino)-fenylättiksyra; a-(4-n-oktyl-3-oxo-1-piparazinokarbonylamino)-fenylättiksyra; a-(4-n-dodecyl-3-oxo-1-piperazinokarbonylamino)-feny_ättiks;ra; a-(4-cyklopentyl-3-øxo-1-piperazinokarbonylaminc)-fenylättiksyra; a-(2-metyl-4-n-butyl-3-oxo-1-piperazinokarbonylamino)-fenyläztiksyrag a-(4-n-butyl-5-metyl-3-oxo-l~piperazinokarbonylamino)-fenylëttiksyrag a-(4-n-butyl-6-metyl-3-oxo-1-piperazinokarbonylamino)-fenylëttiksyra; x-(2-fenyl-3-oxo-1-piperazinokarbonylamino)-fenylättiksyra; a-(4-bensyl-3-oxo-1-piperazinokarbonylamino)-fenylättiksyra; a~( -karbamoyl-2-meïyi-3-oxo-l-piperazinokarbonylamíno)-fenylättiksyra; a-(4-B-hyäroxietyl-3-oxo-1-piparazinokarbcnylamino)-fenylättiksyra; a-(4-allyl-3-oxo-l-piperazinokarbonylamino)-fenylättiksyra; a-(4~a-metylallyl-3-oxo-l-piparazinokarbonylamino)-fenyläïïiksyraç a-(4-6-metylallyl-3-oxo-1-piperazinokarbonylamin )~fenylät1iksyra; a-[44firans-2-butenyl)-3-Oxo-1-piperazinokarbonï-amino]-fenylättiksyra; a-(4-morfolinometyl-3-oxo-1-piperazinokarbbnylamino)-fenylätziksyra; a-(4-etyl-3-oxo-l-piperazinokarbonylamino)-propionsyra; a-(4-acetyl-2,5-dioxo-1-piperazinokarbonylamino)-fenylätt a-(4-bensoyl-2,5-åioxo-l-piparazinokarbonylamíno)-fenylättiksyra; a-(4-metyl-2,5-dioxo-1-piperazinokarbonylamino)-fenylättiksyra; a-(4-bensyl-2,5-dioxo-1-piperazinokarbonylamino)-fenylättiksyra; a-(4-metyl-2,3-dioxo-1-piperazinokarbonylaminoJ-fenylättiks"ra; a-(4-acetoxietyl-2,3-dioxo-1-piperazinokarbonylamino)-fenyläztiksyra; i“syra; a-(4~etyl-2,3-dioxo-1-piparazinokarbonylamino)-fenylättiksy-a; a-(4-n~propyl-2,3-dioxo-1-piperazinokarbonylamino)-fenylättiksyra; a-(4~n-butyl-2,3-dioxo-1-piperazinokarbonylamino)-fenyläïtiksyra; a-(4-isopropyl-2,3-dioxo-1-piperazinokarbonylamino)-fenyläztiksyra; a-(4-nfpentyl-2,3-dioxo-l-piperazinokarbonylamino)-fenylättiksyra; a-(4-n-hexyl-2,3-dioxo-1-piperazinøkarbonylaminó)-fenylättiksyra; a-(4-n-heptyl-2,3-dioxo-l-piperazinokarbonylamino)-fenylättiksyra; a-(4-n-oktyl-2,3-dioxo-1-piperazinokarbonylamino)-fenylätt* I a-(4-allyl-2,3-dioxo-1-piperazinokarbonylamino)-fenylättiksyra; a-(4-fenyl-2,3-dioxo-1-piperazinøkarbonylaminø)-fenylättiksgra; äsyra; a-(4-B-kloretyl-2,3-dioxo-l-piperazinokarbonylamino)-fenyläïtiksyra; a-(4-pyrrolidinoetyl-2,3-dioxo-1-piperazinokarbonylamino)-fen'l"ttik- syra; a-(4-metyl-2,3-dioxo-l-piparazinokarbonylamino)-p-hydroxife:ylättik- syra; a-(4-etyl-2,3~dioxofl-piperazinokarbonylamino)-p-hydroxifenylättiksyra:¿ _-..-..-_._ ._ .-.___ _ 'zeoszoa-v 31 a-(5-metyl-4-etyl-2,3-dioxo-I-piperazinokarbonylamino)-fenylättiksyra; a-(¿,6-dimetyl-2,3-dioxo-1-piperazinokarbonylamino)-fenylättikeyra; c-(4-etyl-2,3-dioxo-l-piparazinotiokarbonylamino)-fenylätfiíksyra; a-(¿-metyl-2,3-dioxo-l-piperazinokarbonylamino)-1,4-cyklohexadienyl« ätziksyra; a-(4-etyl-2,3-dioxo-l-piperazinokarbonylamino)-1,4-cyklohexadienyl- ätfiksyra; d-(4-n~propyl-2,3-dioxo-l-piperazinokarbonylamino)-1,4-cyklohexadienyl- ätziksyra; u-(4-n-butyl-2,3-dioxo-1-piperazinokarbonylamino)-l,4-cyklohexadienyl- ättiksyra; a-(4-metyl-2,3-dioxo-l-piperazinokarbonylamino)-2-tienylättikeyra; a-(4-etyl-2,3-dioxo-l-piperazinokarbonylamino)-2-tienylättiksyra; a-(¿~n-propyl-2,3-dioxo-l-piperazinokarbonylamino)-2-ïienylättiksyra; a~(4-n-butyl-2,3-dioxo-l-piperazinokarbonylamino)-2-tienylättiksyra; a-(2,2-pentametylen-3,5-diozo-1-piperazinokarbonylamino)-fenylättik- syra; I a-(4-bensyl-2,2-pentametylen~3,5-dioxo-l-piperazinokarbonylamino)- -fenylättiksyra; a-(4~fi,ß,8-trikloretoxikarbonyl-2,2-pentametylen-3,5-dioxo-l-pipera- zin karbonylamino)-fenylättiksyra; a~(3,5-di xo-l-piperazinokarbonylamino)-fenylättiksyra; d-(2-metyl-2-fenyl-3,5-dioxo-l-piperazinokarbonylamino)-fenylättixsyra; a-(4-bensyl-2-metyl-3,5-dioxo-l-piperazinokarbonylamino)-fenylë1tik- syra; a-(4-mety1~2,3-dioxo-1-piperazinokarbonylamino)-fenylättiksyra.Q 'c) - ~,: ": o, F; \\\ ~! O 26 vaoazon-v Table II (cont.) 0 O melting point' 9 - = OM ¶ 95 - 96 ° cc = o * ~ - cï-: ïcï-Û-z: n-ccc: (sënaeraelning) l _ \ -J. (ur AcOBu) 0 O. oljeartat material L? CH c; ~: ~ c1 ~: ~ -: r sr-cccl wo -: är 3 C t \ _ / __ tdo _ -. ÄH; "\) c = o 'fï fi ä cf15 (c fi2) ¿c fl2- @ r \ __ / ..- coc1 0 O smältpunkg VH' 130 - 131 c C : 1720,: sec (cH3) 2cH-z-ïLJ: .f- ~: o: 1 _ (sände rdelning) 0 0 .l Vc-o lzfëo; W P oily material - bd5 (C: í2) -: - Cn2-; I \ _í.; - COC1. : _20 __ 'Mif o' V: a f ~. \ O n C = O _ O '; c: ~: 3 (c: 1'2) 4c: »z¿-; LÉ: ï-coc1: zo - š oc Vczo Jae, I" s cH.¿ (f ;;: 2; 5cH¿-: I \ _ /: t-coc1 '520 - QX; nlx / Czo 520, E c fl yc fi ggczïz-: ruïï- "ocl: zo - s 0 o _ V. =“ 1775 \' kristall CO 'cnfczzcag-: Lrvl-cccl l 1660 - 80820lf-7 crystal oily material 'melting point 65-70 ° C CH3C52' (decomposition) -7ï «1 \ CHI melting point Ci f) loo'- 1o1 ° c_ -jczo 1-35, lg; CH_¿:, _-; _CgCl (sbnderdelnzng) ic FX, f? Å¿ * (7 melting point) N _ ____ 1 rim-Lavl 180 - 181 ° c Mgïg - vw: - ~ C Üëg fi y melting point) (š, - -PU¿-r: ¥ _; :: - c cl 160 "165 C 'who 11: e, 1-370 O / ° _ \ Uzíl> ¿w- / oljeartat material \ Jc = 0 1 PC, lïïO. Clïu fl rfffLfu -: z rv-fml '1110 7808204-'7 28' u Table II (cont.) L% L \ smältpugkš 185 - 1 7 C _, sr = r »__;: - c1oc1, (Sönderfælning) Vc-io 1720 , 1090 O ea Gig-jens. '1 * Jc-o 1750, Hw 3_C LU i 1710 - iaeê O 0' Q “_, -. \ \ CH? C: 0 174179 Qššr-C32-N U-CCCl" Note: The compounds of formula (V) can be easily obtained by reacting a salt, for example, with a salt, for example, 1710, 1710, 1 75 O Note: Et = G = CH§CH2OCH2CH§ Aase-i = cH3coo (cH¿) 5c1-: 3 with an alkali metal, an alkaline earth metal or a nitrogen-containing organic base of an amino acid (IX) (any D-isomer, L-isomer or racemic compound) having the general formula HZN-R-coon (IX) wherein R has the as defined above, with a reaction-prone derivative in the (ten) carboxy group of a compound of formula (III) in a solvent inert to the reaction in the presence of an acid scavenger. Particularly suitable examples of compounds of formula (V) are D-isomers, L-isomers and racemic compounds of the following compounds: d- (4-acetyl-2-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-chloroacetyl-2-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-dichloroacetyl-2-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-palmitoyl-2-oxo-1-piperazinocarbonylamino) -phenylacetic acid; 7-808204-7 29 α- (4-Capryl-2-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-Capryloyl-2-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-enantoyl-2-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-cyclohexanecarbonyl-2-oxo-1-piperazinocarbonylamino) -phenylacetic acid α- (4-benzyl-2-oxo-1-piparazinocarbonylamino) -phenylacetic acid; α- (4-p-chlorobenzoyl-2-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-p-methoxybenzoyl-2-oxo-1-piperazinocarbenylamino} -phenylacetic acid; α- [4- (3,4,5-trimethoxybenzoyl) -2-oxo-1-piparazinocarbonylamine] -phenyl-acetic acid; [4- (2,4-Dichlorobenzoyl) -2-oxo-1-piperazinecarbonylamino] -phenylacetic acid; α- (4-acetyl-3-methyl-2-oxo-1-piparazinocarbonylamino) -phenylacetic acid; α- (4 -Nethanesulfonyl-2-oxo-1-piparazinocarbonylamino) -phenylacetic acid; α- (4-acetylaminocarbonyl-2-oxo-1-piparazinocarbonylamino) -phenyl-acetic acid; α- (4-phenylaminocarbonyl-2-oxo-1-piperazinocarbon) phenylacetic acid; α- (4-ethoxycarbonyl-2-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-pivaloyloxymethyl-2-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-n-hexyl-2 -oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (α-n-butyl-2-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-n-butyl-6-mezyl-2-oxo-1-piperazinocarbonylamino ) -phenylacetic acid; α- (4-n-actyl-2-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (3-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (2,5-dimethyl-3-oxo -1-piperazinocarbo nylamino) -phenylacetic acid; α- (5-methyl-3-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (2-Ethocycarbonylmethyl-3-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (-methyl-3-oxo-1-piperazinecarbonylamino) -phenylacetic acid; α- (4-acetyl-2-methyl-3-oxo-1-piperazinocarbonylamine) -phenylacetic acid; α- (4-phenylaminocarbonyl-3-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-methyl-3-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-n-butyl-3-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-ethyl-3-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-isopropyl-3-oxc-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-n-pentyl-3-oxo-1-piperazinecarbonylamino) -phenylacetic acid; α- (4-isopentyl-3-oxo-1-piparazinocarbonylamino) -phenylacetic acid; α- (4-n-hexyl-3-oxo-1-piperazinocarbonylamino) -phenylacetic acid; Α- (4-n-heptyl-3-oxo-1-piparazinocarbonylamino) -phenylacetic acid; α- (4-n-octyl-3-oxo-1-piparazinocarbonylamino) -phenylacetic acid; α- (4-n-dodecyl-3-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-cyclopentyl-3-exo-1-piperazinocarbonylamine) -phenylacetic acid; α- (2-Methyl-4-n-butyl-3-oxo-1-piperazinocarbonylamino) -phenylacetic acid α- (4-n-butyl-5-methyl-3-oxo-1-piperazinocarbonylamino) -phenylacetic acid a- (4 -n-butyl-6-methyl-3-oxo-1-piperazinocarbonylamino) -phenylacetic acid; x- (2-phenyl-3-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-Benzyl-3-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (-carbamoyl-2-methyl-3-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-β-hydroxyethyl-3-oxo-1-piparazinocarbonylamino) -phenylacetic acid; α- (4-allyl-3-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-α-methylallyl-3-oxo-1-piparazinocarbonylamino) -phenylacetic acid α- (4-6-methylallyl-3-oxo-1-piperazinocarbonylamine) -phenylacetic acid; α- [44-trans-2-butenyl) -3-oxo-1-piperazinocarbonylamino] -phenylacetic acid; α- (4-Morpholinomethyl-3-oxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-ethyl-3-oxo-1-piperazinocarbonylamino) -propionic acid; α- (4-Acetyl-2,5-dioxo-1-piperazinocarbonylamino) -phenylate α- (4-benzoyl-2,5-dioxo-1-piparazinocarbonylamino) -phenylacetic acid; α- (4-methyl-2,5-dioxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-Benzyl-2,5-dioxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino] -phenylacetic acid; α- (4-acetoxyethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid; i- acid; α- (4- ethyl 2,3-dioxo-1-piparazinocarbonylamino) -phenylacetic acid α- (4-n-propyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-n-butyl-2, 3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-isopropyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-n-pentyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid ; α- (4-n-hexyl-2,3-dioxo-1-piperazinecarbonylamino) -phenylacetic acid; α- (4-n-heptyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid; a- (4- n-Octyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylate * I α- (4-allyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-phenyl-2,3-dioxo -1-piperazinocarbonylamino) -phenylacetic acid; α- (4-β-chloroethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-pyrrolidinoethyl-2,3-dioxo-1-piperazinocarbonylamino) - phenylacetic acid; α- (4-methyl-2,3-dioxo-1-piparazinocarbonylamino) -p-hy droxife: ylacetic acid; α- (4-ethyl-2,3-dioxofl-piperazinocarbonylamino) -p-hydroxyphenylacetic acid: α-β-β-α-β-α-β-α-β-5-methyl -4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (β, 6-dimethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid; c- (4-ethyl-2,3-dioxo-1-piparazinothiocarbonylamino) -phenylacetic acid; α- (β-methyl-2,3-dioxo-1-piperazinocarbonylamino) -1,4-cyclohexadienyl-acetic acid; α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -1,4-cyclohexadienyl acetic acid; d- (4-n-propyl-2,3-dioxo-1-piperazinocarbonylamino) -1,4-cyclohexadienyl-acetic acid; u- (4-n-butyl-2,3-dioxo-1-piperazinocarbonylamino) -1,4-cyclohexadienyl acetic acid; α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -2-thienylacetic acid; α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -2-thienylacetic acid; α- (β-n-propyl-2,3-dioxo-1-piperazinocarbonylamino) -2-phenylacetic acid; α- (4-n-butyl-2,3-dioxo-1-piperazinocarbonylamino) -2-thienylacetic acid; α- (2,2-pentamethylene-3,5-diozo-1-piperazinocarbonylamino) -phenylacetic acid; In α- (4-benzyl-2,2-pentamethylene-3,5-dioxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4 -, β, 8-Trichloroethoxycarbonyl-2,2-pentamethylene-3,5-dioxo-1-piperazine carbonylamino) -phenylacetic acid; α- (3,5-di xo-1-piperazinocarbonylamino) -phenylacetic acid; d- (2-methyl-2-phenyl-3,5-dioxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-Benzyl-2-methyl-3,5-dioxo-1-piperazinocarbonylamino) -phenylacetic acid; α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid.

Såsom reaktionsbenäget derivat i karboxigruppen av föreningen med formeln (V) använder man ett reaktionsbenäget derivat av en kar- bonsyra, som normalt användes vid syntes av syraamider. Sådana reaktionsbenägna derivafi omfattar exempelvis syrahalider, syraanhyd- rider, blandade syraanhydrider med organiska eller oorganiska syror, aktiva syraamider, syracyanider, aktiva estrar, etc. Syraklorider, blandade syraanhydrider och aktiva syraamider är särskilt lämpliga.As the reaction-derivative in the carboxy group of the compound of formula (V), there is used a reaction-derivative of a carboxylic acid which is normally used in the synthesis of acid amides. Such reactive derivatives include, for example, acid halides, acid anhydrides, mixed acid anhydrides with organic or inorganic acids, active acid amides, syracyanides, active esters, etc. Acid chlorides, mixed acid anhydrides and active acid amides are particularly suitable.

Exempel på de blandade syraanhydriderna är blandade syraanhydrider med subetituerade ättiksyror, alkylkolsyror, arylkolsyror och aralkyl- kolsyror; exempel på de aktiva estrarna är cyanometylestrar, substi- tuerade fenylestrar, och exempel på de aktiva syraamiderna är H-acy1sacka~ N,N-dicyklohexyl-N-acyl- estrar, etc.; riner, N-acylimidazoler, N-acylbensoylamider, substituerade bensylestrar, substituerade tienyl- f 78082014-7 32 karbamider, H-acylsulfonamider, etc.Examples of the mixed acid anhydrides are mixed acid anhydrides with substituted acetic acids, alkyl carboxylic acids, aryl carboxylic acids and aralkyl carboxylic acids; examples of the active esters are cyanomethyl esters, substituted phenyl esters, and examples of the active acid amides are H-acylsacka-N, N-dicyclohexyl-N-acyl esters, etc .; rhines, N-acylimidazoles, N-acylbenzoylamides, substituted benzyl esters, substituted thienyl carbamides, H-acylsulfonamides, etc.

Föreningar med formeln (VI) kan erhållas enligt exempelvis förfarande (l) eller (2). Vissa av de föreningar som erhålles eni;¿. förfarande (3) kan vidare användas såsom utgângsmaterial vid samm förfarande. Vilken som helst av D-, L- och raceniska föreningar med formeln (VI) kan_användas. tföringsformer av förfarandena (1), (2) och (3) förklaras nä... are i det följande.Compounds of formula (VI) may be obtained according to, for example, process (1) or (2). Some of the compounds obtained eni; ¿. process (3) can further be used as starting material in the same process. Any of the D-, L- and racenic compounds of formula (VI) may be used. embodiments of methods (1), (2) and (3) are explained in more detail below.

Förfarandsna 1) och (2) kan utföras under i huvudsak samma betingelser. Detta innebär att föreningen med formeln (II) eller (ïï} löses eller suspenderas i minst ett inert lösningsmedel, valt bland exempelvis vatten, aceton, tetrahydrofuran, dioxan, acetonitril, dimetylformamid, metanol, etanol, metoxietanol, dietyleter, isopropyl- eter, bensen, toluen, metylenklorid, kloroform, etylacetat, metyliso- butylketon och liknande; Den erhållna lösningen eller suspensionen oms"ttes med ett reaktionsbenäget derivat av föreningen med formeln (III) eller med föreningen med formeln (V) eller ett reaktionsbenäget derivat i karboxigruppen av föreningen med formeln (V) i närvaro av eller frånvaro av en bas vid en temperatur mellan -60 och +80°C, företrädesvis mellan -40 och +30°C. Reaktionstiden ligger normalt mellan fem minuter och fem tinnar. Exempel på i nämnda reaktion använda baser omfattar oorganiska baser, såsom alkalimetallhydroxider, alkalimetallvätekarbonater, alkalimetallkarbonater, alkalimetall- acetater, etc.; tertiära aminer, såsom trimetylanin, trietylamin, tributylanin, pyridin, N-metylpiperidin, N-metylmorfolin, lutidin, kollidin, etc.; och sekundära aminer, såsom dicyklohexylamin, dietyl- amin, etc. När föreningarna med formeln (V) användes i form av en fri syra eller ett salt vid förfarande (2), kan detta utföras i när- varo av ett dehydratiserande kondensationsmedel, såsom N,N-dicyklo- hexylkarbodiimid, N-cyklohexyl-N'-morfolinoetylkarbodiimid, N,N'- -dietylkarbodiimid, N,N'-karbonyl-(2-metylimidazol), en trialkylester av fosforsyra, etylester av polyfosforsyra, fosforoxiklorid, fosfor- triklorid, 2-klor-1,3,2-dioxafosfolan eller oxazolylklorid. Salterna av föreningen med formeln (V) omfattar alkalimetallsalter, jordalkali- metallsalter, ammoniumsalter och salter med organiska baser, såsom trimetylamin, dicyklohexylamin och liknande.Processes 1) and (2) can be carried out under essentially the same conditions. This means that the compound of formula (II) or (II) is dissolved or suspended in at least one inert solvent selected from, for example, water, acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, methanol, ethanol, methoxyethanol, diethyl ether, isopropyl ether, benzene , toluene, methylene chloride, chloroform, ethyl acetate, methyl isobutyl ketone and the like; The resulting solution or suspension is reacted with a reaction derivative of the compound of formula (III) or with the compound of formula (V) or a reaction derivative in the carboxy group of the compound of the formula (V) in the presence or absence of a base at a temperature between -60 and + 80 ° C, preferably between -40 and + 30 ° C. The reaction time is normally between five minutes and five peaks. bases used include inorganic bases such as alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali metal acetates, etc .; tertiary amines such as trimethylanine, triethylamine , tributylanine, pyridine, N-methylpiperidine, N-methylmorpholine, lutidine, collidine, etc .; and secondary amines, such as dicyclohexylamine, diethylamine, etc. When the compounds of formula (V) are used in the form of a free acid or a salt in process (2), this may be carried out in the presence of a dehydrating condensing agent, such as N , N-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N, N'-diethylcarbodiimide, N, N'-carbonyl- (2-methylimidazole), a trialkyl ester of phosphoric acid, ethyl ester of polyphosphoric acid, trichloride, 2-chloro-1,3,2-dioxaphospholane or oxazolyl chloride. The salts of the compound of formula (V) include alkali metal salts, alkaline earth metal salts, ammonium salts and salts with organic bases such as trimethylamine, dicyclohexylamine and the like.

Förfarande (3) kan utföras på i det följande angivet sätt.Method (3) can be performed in the manner indicated below.

Här B i formeln (VI) uppvisar en grupp annan än en hetero- aromatisk_H-ozidtiogrupp med en tïogrupp på den kolatom som före- 'I80820lv-7 33 ligger i grannställning till I-oxidgruppen i molekylen, omsatte: föreningen med formeln (VI) med föreningen med formeln (VII) eller en tertiär amin i minst ett lösningsmedel, valt bland exempelvis vatten, metanol, etanol, propanol, isopropanol, butanol, aceton, metyletylketon, metylisobutylketon, tetrahydrofuran, dioxan, aceto- nitril, etylacetat, metoxietanol, dimetozietan, dimetylformamid, dimetylsulfoxid, diklormetan, kloroforn, en dikloretan och liknande.Here B in formula (VI) has a group other than a heteroaromatic -H-ozidiothio group having a thio group on the carbon atom which is adjacent to the I-oxide group in the molecule, reacted: the compound of formula (VI) with the compound of formula (VII) or a tertiary amine in at least one solvent, selected from, for example, water, methanol, ethanol, propanol, isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dioxane, acetonitrile, ethyl acetate, methoxyethanol, dimethoethanol , dimethylformamide, dimethylsulfoxide, dichloromethane, chlorophore, a dichloroethane and the like.

Nämnda reaktion utföres företrädesvis i ett kraftigt polärt lösnings- medel, såsom vatten eller liknande. I detta fall upprätthålles pH i reaktionsblandningen företrädesvis vid 2 - lO, särskilt 4 - 8. Bet önskade pH-värdet kan inställas genom tillsats av en buffertlösning, såsom natriumfosfat. Reaktionsbetingelserna utföres vanligen vid O - l0O°C under en tidrymd av några tinnar upp till lO timmar.Said reaction is preferably carried out in a strongly polar solvent, such as water or the like. In this case, the pH of the reaction mixture is preferably maintained at 2 to 10, especially 4 to 8. The desired pH can be adjusted by adding a buffer solution, such as sodium phosphate. The reaction conditions are usually carried out at 0 to 10 ° C for a period of a few hours up to 10 hours.

B i formeln (VI) är en heteroaromatisk N-oxidtiogrupp med en tiogrupp på den kolatom som föreligger i grannställning till N-oxid- när gruppen i molekylen, omsättes föreningen med formeln (VI) med före- ningen med formeln (VII) i nämnda lösningsmedel i närvaro av en koppar(II)-förening. Denna reaktion är särskilt användbar när en alkohol användes, exempelvis metylalkohol, etylalkohol, propylalkonol, isopropylalkohol, n-butylalkohol, bensylalkohol, etylenglykol eller liknande, såsom föreningen med formeln (VII). I detta fall reaktionen elegant även vid användning av alkoholen själv i Koppar(II)-föreningarna använda vid förlöper överskott såsom reaktionsmedium. detta förfarande omfattar organiska och oorganiska sådana, såsom koppar(II)- klorid, -bromid, -fluorid, -nitrat, -sulfat, -borat, -fosfat, -cyanid, -formiat, -acetat, -propionat, -citrat, -tartrat, -bensoat, -sali- cylat och liknande. Mängden använd koppar(II)-förening är före- trädesvis l/2 mol per mol förening med formeln (VI). Reaktionstem- peraturen och reaktionstiden kan varieras alltefter karaktären av föreningen med formeln (VI), koppar(II)-föreningen och föreningen med formeln (VII), ehuru de vanligen väljes inom intervallet O - 10000 resp. nâgra minuter till några dagar.B in formula (VI) is a heteroaromatic N-oxide thio group having a thio group on the carbon atom adjacent to the N-oxide- when the group in the molecule, the compound of formula (VI) is reacted with the compound of formula (VII) in said solvent in the presence of a copper (II) compound. This reaction is particularly useful when an alcohol is used, for example, methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, n-butyl alcohol, benzyl alcohol, ethylene glycol or the like, such as the compound of formula (VII). In this case the reaction is elegant even when using the alcohol itself in the Copper (II) compounds used in the precursor excess as the reaction medium. this process comprises organic and inorganic ones such as copper (II) chloride, bromide, fluoride, nitrate, sulphate, borate, phosphate, cyanide, formate, acetate, propionate, citrate, tartrate, benzoate, salicylate and the like. The amount of copper (II) compound used is preferably 1/2 mole per mole of compound of formula (VI). The reaction temperature and the reaction time may be varied according to the nature of the compound of formula (VI), the copper (II) compound and the compound of formula (VII), although they are usually selected in the range 0 to 10000 and a few minutes to a few days.

De reaktionsbetingelser som tillämpas vid förfarandena (l), (2) och (3) är icke begränsade till de ovan nämnda och kan varieras allt- efter karaktären av reaktanterna.The reaction conditions applied to processes (1), (2) and (3) are not limited to those mentioned above and may be varied according to the nature of the reactants.

De icke-toxiska salterna med formeln (I), vari Rl är en salt- bildande katjon, kan med lätthet erhållas enligt en sedvanlig procedur ¶ ur föreningarna med formeln (I), vari El är väte eller en blockerande ETUPP- 78082014-7 34 Cefalosporínerna kan således med lätthet erhållas enligt något av förfarandena (1), (2) och (3).The non-toxic salts of formula (I), wherein R1 is a salt-forming cation, can be easily obtained according to a customary procedure ¶ from the compounds of formula (I), wherein E1 is hydrogen or a blocking ETUPP- 78082014-7 34 Thus, the cephalosporins can be easily obtained by any of the methods (1), (2) and (3).

Föreliggande cefalosporiner omfattar konkret följande föreningar, men är icke begränsade därtill: 7-[D(-)-a-(4*metyl-2,3-dioxo-l-piperazinokarbonylamino)-fenylacetamidu: ~3-metyl-A3-cefem-4-karbonsyra, 7-[D(~)-H-(4-etyl-2,3-dioxo-1-piperazínokarbonylamino)-íenylaceïamidc:- -3~metyl-A3-cefem-4-karbonsyra, 7-[D(-)-a-(4-n-prcpyl-2,3-dioxo-1-piperazinøkarbonylamino)-fenylacet- amid0]-3-metyl-A3-cefem-4-karbonsyra, ' 7-[D(-)-a-(4-n-butyl~2,3-dioxo-1-piperazinokarbonylamino)-fenylacet- &mid0]-3-metyl-A3-cefem-4-karbonsyra, 7-[D(-)~a-(4-n-pentyl-2,3-dioxo-1-piperazinokarbonylamino)-fenylacet- amido]-3-metyl-A3-cefem-4-karbonsyra, 7-[D(-)-a-(4-n-hexyl-2,3-díoxo-l-piperazinckarbcn*lamino)-fenylacet~ amido]-3-metyl-A3-cefem-4-karbonsyra, 7-[D(-)-a-(4-n-heptyl-2,3-dioxo-l-píperazinokarbonylamíno)-fenylacet~ amido]-3-metyl-A -cefemf4-karbonsyra, 7-[D(-)-a-(4-n-oktyl-2,3~dioxo-1-piperazinokarbonylamino)-fenylacet~ amido]-3-metyl-A3-cefem-4-karbonsyra, 7-[D(-)-a-(4-metyl-2,3-dioxo-1-piperazinokarbonylamino)-feny1acet- amido]-3-acetoximetyl-A3-cefem-4-karbonsyra, 7-[D(-)-a-(4~n-propyl-2,3-dioxo-l-piperazinokarbonylamino)-feny1ace:~ amido]-3-acetoximetyl-A ~cefem-4-karbonsyra, 7-[D(-)-a-(4-etyl-2,3-dioxo-1-piperazinokarbonylamino)-fenylacetamidoÉ- -3-acetoximetyl-A -cefem-4-karbonsyra, 7-[D(-)-a-(4-isopropyl-2,3-dioxo-l-piperazínokarbonylemino)-fenylacet- amiäo]-3-acetoximetyl-A -cefem-4-karbonsyra, 7-[D(-)-a-(4-etyl-2,3-dioxo-1-piperazinotiokarbonylamino)-fenylacet- amido]-3-acetoximetyl-A -cefem-4-karbonsyra, 7-[D(-)-a-(4-metyl-2,3-dioxo-1-piperazinotiokarbonylemino)-fenylacet~ amiäo]-3-ecetoximetyl-A3-cefemf4-karbonsyra, 7-[D(-)-a-(4-metyl-2,3-díoxo-1-piperazinokarbonylamino)-fenylacet- amido]-3-[2-(5-metyl-1,3,4-tiadiazolyl)-tiometyl]-A3-cefem-4-karbonsfra 7-[D(-)-a-(4-etyl-2,3-dioxo-l-piperazinokarbonylaminc)-fenylacetamido1- -3-[2-(5-metyl-l,3,4-tiadiazolyl)-tiometyl]-A3-ceíem-4-karbonsyra, 7-[D(-)-a-(4-n-propyl-2,3-dioxo-1-piperazinokarbonylamino)-fenylacet- amído]-3-[2-(5-metyl-1,3,4-tiadiazolyl)-tiometyl]-A3-eefem-4-karbon- syra, 7808201! - 7 35 7-[D(-)-a-(4-n-butyl-2,3-dioxo-1-piperazinokarbonylëmino)-fenylacet- amiao]-3-[2-(5-mety1-1, 3, fz-tiadiaz olyl) -ziome :yl yv-cefem-zz-xarbøn- . syra-v 7-[D(-)~a-(4-fenyl-2,3-dicxø-l-piperazinckarbonylamino)-fenylacetamiic¿ -3-[2-(5-metyl-1,3,4-tiadiazolyl)-tiømetyl]-A3-cefem-4-karbonsyra, 7-[D(-)-a~(4-metyl-2,3-dioxo-1-piperazinckarbonylamino)-fenylacetamidcI -3-[5-(1-metyl-1,2,3,4-tetrazolyl)-tiometyl]-A3-cafe:-4-karbonsyra, 7-[D(-)~a-(4-etyl-6-metyl-2,3-dioxo-1-piparazinokarbcnylamino)-feny1~ acetamido]-3-[5-(l-metyl-l,2,3,4-tetrazolyl)-tiometyl]-A3-cefem-4- -karbønsyra, 7-[D(-)-a-(4,6-dimetyl-2,3-dioxo-1-piperazinokarbcnylamino)-fenylac;1- amido]-3-[5-(l~mety1-1,2,3,4-tetrazolyl)-tiømetyl]-A3-cefem-4-karbon- syra, ' 7-[D(-)-a-(4-fenyl-2,3-dioxo-1-piperazinokarbonylamigo)-fenylacet- amiäo]-3-[5-(l~metyI-1,2,3,4-tetrazolyl)-tiometyl]-A5-cefem-4-karbcn- syra, 7-[D(-)-a-(4-metyl-2,3-dicxo-1-piperazinokarbonylamino)-fenylacet- amiäo]-3-[5-(1,3,4-tiadiazolyl)-tiometyl1-A3-cefem-4-karbonsyra, 7-[D(-)-a-(4-etyl-2,3-dioxo-l-piperazinøkarbonylamino)-fenylacet- amiäo]-3-[5-(1,3,4-üiadiazolyl)-üiomefiyl}-A3-cefem-4-karbonsyra, 7-fD(-)-a-(4-metyl-2,3-dioxo-1-piparazinokarbonylamino)-fenylacet- amido]-3-[2-(1-metyl-1,3,4-triazolyl)-ticmetyl]-A3-cefem-4-karbonsyra, 7-[D(-)-a-(4~etyl-2,3-dioxo-1-piperazinokarbonylamino}~fenylacetamido]- -3-[2-(1-metyl-1,3,4-triazolyl)-tiometyl]-A3~cefem-4-karbonsyra, 7-[D(-)~a-(4-fenyl-2,3-dioxø-1-piperazinokarbonylamino)-fenylacet- amido]-3-[2-(1-metylel,3,4-triazclyl)-1iometyl]-A3-cefem-4-karbonsyra, 7-[D(-)-a-(4-metyl-2,3-dioxo-l-piperazinokarbonylamino)-propionamido]- -3-acetoximetyl-A3-cefem-4-karbonsyra, 7-[D(-)-a-(4-metyl-2,3-dioxo-l-piperazinokarbonylamino)-p-hydroxi- fenylacètamido]-3-[5-(1-metyl-1,2,3,4-teïrazolyl)-tiometyl]-A3-cefem- -4-karbonsyra, 7-[D(-)-a-(4-metyl-2,3-dioxo-l-piperazinokarbonylamino)-feny1acet~ amido]-3-azidometyl-A -cefem-4-karbonsyra, 7-[D(-)-a-(4-etyl-2,3-dioxo-1-piperazinckarbonylamino)-fenylacetamido}- -3-[5-(1-metyl-1,2,3,4-tetrazolyl)-tiometyl]-A3-cefem-á-karbonsyra, 7-[D(-}-a-(4-metyl~2,3-dioxo-l-piparazinokarbonylamino)-fanylacet~ amiäo]-3-[5-(1-metyl-1,2,3,4-tetrazolyl)-tiometyl]-A3-cefem-4-karbon- syra, 7-[D(~)-a-(4-metyl-2,3-dioxo-1-piperazinokarbonylamino)-fenylacet- amido]-3-É2-(1,3,4-triazolyl)-tiometyl]-A3-cefem-4-karbonsyra, 7808204 '-7 36 7-[D(-)-a-(4-metyl-2,3-äioxo-I-piperazinokarbonylamino)-fenylacet- amidø]-3-[5-(1,2,3,4-tetrazolyl)-tiometyl1-A3-cefem-4-karbonsyra, 7-[D(-)-a-(4-etyl-2,3-dioxo-l-piperazinokarbonylamino)-feny1acet- amido]-3-[S-(1,2,3,4-tetrazolyl)-tiometyl]-A3-cefem-4-karbons§ra, 7-[D(-)-a-(4-metyl-2,3-diozo+l-piperazinckarbonylamino)-fenylacet- amiåo]-3-[2-(5-metyl-1,3,4-oxadiazolyl)-tiometyl]-A3-cefem-4-karbon- syra, 7-[D(-)-a-(4~metyl-2,3-dioxo-1-piperazinokarbonylamino)-fenylacet- amído]-3-[3-(2,6-dimetyl-5-øxo-2,Bfdihydro-1,2,4-triazinyl)-tiometyl}- -A -cefem-4-karbónsyra, 1 7-[D(-)-a-(4-etyl-2,3-dioxo-l-piperazinokarbonylaminø)-fenylacetamido]- -3-[2-(4-metyloxazolyl)-tiometyl]~A3-cefem-4~karbonsyra, 7-[3(-)-a-(4-metyl-2,3-dioxo-1-píperazinckarbonylaminp)-fenylacæ1- amido]-3-[2-(44metyltiazolyl)-tiometyl]-A3-cefem-4-karbonsyra, 7-[D(-)-a-(4-etyl-2,3-dioxo-1-piperazinokarbonylamino)-fenylace1- amido1-3-[2-(pyridyl-l-bxid)-tiometyl]-A3-cefem-4-karbonsyra, 7-[D(-)-a-(4-metyl-2,3-dioxo-l-piperazinokarbonylaminø)-feny1ace:- amiåo]-3-(2-tiazolinyltiometyl)-A3-cefem-4-karbonsyra, 7-[D(-)-"-(4-mefiyl-2,3-dioxo-l-piperazinokarbonylamino)-fe;ylaceï- amido]-3-[2-(l-meïylimidazolyl)-tiømetyl]-A3-cefem-4-karbonsyra, 7-[D(~)-a-(4-metyl-2,3-díoxo-1-piperazinokarbonylaminc}-fenylace:- amido]-3-(2-pyrimidinyltiometyl)-A3-cefemr4-karbonsyra, 7-[D(-)-a~(¿-etyl-2,3-âioxo-1-piperazinokarbonylaminc)-fenylace:- amído]~3-[3-(6-metylpyridazinyl)-tiometyl]-A3-cefem-4-karbonsyra, 7-[D(-)-a-(4-metyl-2,3-diøxo-1-piperazinokarbonylamincš~fenylacæï- amiáo]-3-[l-(4-metylpiperazino)-tiokarbonyltiometyl]-å5-cefem-4- -karbonsyra, 7-[D(-)-a-(4-metyl-2,3-dioxo-1-piperazinokarbonylaminc)-fenyla:æt~ amiåo]-3-[5-(3-metylisoxazolyl)-karbonyltiometyl]-A3-:efem-4~karëon- syra, 7-[D(-)-a-(4-metyl-2,3-dioxo-l-piperazinokarbonylaminc)-fenylace:- amido]-3-etoxitiokarbonyltiometyl-A3-cefem-4-karbonsyra, 7~[D(-)-a-(4-etoxikarbonyl-2-oxo-1-piperazinokarbonylazino)-fe:ylace:- amiâo]-3-metyl-A3-cefem-4-karbonsyra, metoximetyl-7-[D(~)-Q-(4-metyl-2,3-dioxo-l-piperazinokarbonylamino)- -fenylacetamido]-3~metyl-A3-cefem-4-karboxylat, etc. if?80820h-7 37 Tester avseende känsligheten hos typiska föreningar enligt uppfinningen visas i det följande. (1) Minsta inhiberande koncentrationer (NIC) för föreningarna mo olika standardstammar visas i tabellerna III och IV.The present cephalosporins specifically include, but are not limited to, the following compounds: 7- [D (-) - α- (4 * methyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamidu: 33-methyl-33-cephem 4-Carboxylic acid, 7- [D (~) -H- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -enylacetamide] -3-methyl-A3-cephem-4-carboxylic acid, 7- [D (-) - α- (4-n-propyl-2,3-dioxo-1-piperazinecarbonylamino) -phenylacetamide] -3-methyl-A3-cephem-4-carboxylic acid, 7- [D (-) - α- (4-n-Butyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamide- [3] -methyl-33-cephem-4-carboxylic acid, 7- [D (-) -α- (4- n-pentyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3-methyl-A3-cephem-4-carboxylic acid, 7- [D (-) - α- (4-n-hexyl-2 , 3-dioxo-1-piperazinecarbonylamino) -phenylacetamido] -3-methyl-A3-cephem-4-carboxylic acid, 7- [D (-) - α- (4-n-heptyl-2,3- dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3-methyl-α-cephem-4-carboxylic acid, 7- [D (-) - α- (4-n-octyl-2,3-dioxo-1-piperazinocarbonylamino) - phenylacetamido] -3-methyl-α3-cephem-4-carboxylic acid, 7- [D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbon ylamino) -phenylacetamido] -3-acetoxymethyl-33-cephem-4-carboxylic acid, 7- [D (-) - α- (4-n-propyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylace: Amido] -3-acetoxymethyl-A-cephem-4-carboxylic acid, 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido--3-acetoxymethyl-A -cephem-4-carboxylic acid, 7- [D (-) - α- (4-isopropyl-2,3-dioxo-1-piperazinocarbonylemino) -phenylacetamino] -3-acetoxymethyl-A -cephem-4-carboxylic acid, 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinothiocarbonylamino) -phenylacetamido] -3-acetoxymethyl-A-cephem-4-carboxylic acid, 7- [D (-) -α- (4-methyl-2,3-dioxo-1-piperazinothiocarbonylemino) -phenylacetamino] -3-ecethoxymethyl-N3-cephem-4-carboxylic acid, 7- [D (-) - α- (4-methyl-2 , 3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3- [2- (5-methyl-1,3,4-thiadiazolyl) -thiomethyl] -A3-cephem-4-carbonic acid 7- [D (- ) -α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamine) -phenylacetamido] -3- [2- (5-methyl-1,3,4-thiadiazolyl) -thiomethyl] -A3-cesium-4 -carboxylic acid, 7- [D (-) - α- (4-n-propyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3- [2- (5-m ethyl-1,3,4-thiadiazolyl) -thiomethyl] -A3-ephem-4-carboxylic acid, 7808201; 7- [7- (D) - α- (4-n-butyl-2,3-dioxo-1-piperazinocarbonylemino) -phenylacetamino] -3- [2- (5-methyl-1,3,3, fz-thiadiazolyl) -ziomethyl-yv-cephem-zz-xarbøn-. Acid-α 7- [D (-) - α- (4-phenyl-2,3-dioxo-1-piperazinecarbonylamino) -phenylacetamic acid -3- [2- (5-methyl-1,3,4-thiadiazolyl) -thiomethyl] -A3-cephem-4-carboxylic acid, 7- [D (-) - α- (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) -phenylacetamide] -3- [5- (1-methyl- 1,2,3,4-tetrazolyl) -thiomethyl] -A3-caffe: -4-carboxylic acid, 7- [D (-) -α- (4-ethyl-6-methyl-2,3-dioxo-1- piparazinocarbonylamino) -phenyl-acetamido] -3- [5- (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl] -A3-cephem-4-carboxylic acid, 7- [D (-) - a - (4,6-Dimethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylac; 1-amido] -3- [5- (1-methyl-1,2,3,4-tetrazolyl) -thymethyl] - A3-cephem-4-carboxylic acid, 7- [D (-) - α- (4-phenyl-2,3-dioxo-1-piperazinocarbonylamigo) -phenylacetamino] -3- [5- (1- Methyl-1,2,3,4-tetrazolyl) -thiomethyl] -α5-cephem-4-carboxylic acid, 7- [D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino ) -phenylacetamino] -3- [5- (1,3,4-thiadiazolyl) -thiomethyl] -β-cephem-4-carboxylic acid, 7- [D (-) - α- (4-ethyl-2,3 -dioxo-1-piperazinecarbonylamino) -phenylacetamino] -3- [5- (1,3,4-uladiazolyl) -omioyl} -A3-cephem-4-carboxylic acid, 7-fD (-) - a - (4-Methyl-2,3-dioxo-1-piparazinocarbonylamino) -phenylacetamido] -3- [2- (1-methyl-1,3,4-triazolyl) -ticmethyl] -A3-cephem-4- carboxylic acid, 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino} -phenylacetamido] -3- [2- (1-methyl-1,3,4-triazolyl) -thiomethyl] -A3-cephem-4-carboxylic acid, 7- [D (-) -α- (4-phenyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3- [2- (1 -methylene, 3,4-triazclyl) -1iomethyl] -A3-cephem-4-carboxylic acid, 7- [D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -propionamido] - -3-acetoxymethyl-33-cephem-4-carboxylic acid, 7- [D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido] -3- [5 - (1-methyl-1,2,3,4-thyrazolyl) -thiomethyl] -A3-cephem-4-carboxylic acid, 7- [D (-) - α- (4-methyl-2,3-dioxo- 1-piperazinocarbonylamino) -phenylacetamido] -3-azidomethyl-α-cephem-4-carboxylic acid, 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinecarbonylamino) -phenylacetamido} - -3- [5- (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl] -α3-cephem-α-carboxylic acid, 7- [D (-} - α- (4-methyl-2 , 3-dioxo-1-piparazinocarbonylamino) -phanylacetamino] -3- [5- (1-me Tyl-1,2,3,4-tetrazolyl) -thiomethyl] -A3-cephem-4-carboxylic acid, 7- [D (~) -α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino ) -phenylacetamido] -3-E2- (1,3,4-triazolyl) -thiomethyl] -A3-cephem-4-carboxylic acid, 7808204 '-7 7- [D (-) - α- (4- methyl 2,3-oxo-1-piperazinocarbonylamino) -phenylacetamido] -3- [5- (1,2,3,4-tetrazolyl) -thiomethyl] -N-3-cephem-4-carboxylic acid, 7- [D ( -) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3- [S- (1,2,3,4-tetrazolyl) -thiomethyl] -A3-cephem- 4-Carboxylic acid, 7- [D (-) - α- (4-methyl-2,3-diozo + 1-piperazinecarbonylamino) -phenylacetamino] -3- [2- (5-methyl-1,3 , 4-oxadiazolyl) -thiomethyl] -A3-cephem-4-carboxylic acid, 7- [D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] - 3- [3- (2,6-Dimethyl-5-oxo-2,2-dihydro-1,2,4-triazinyl) -thiomethyl} -A-cephem-4-carboxylic acid, 1 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3- [2- (4-methyloxazolyl) -thiomethyl] -A3-cephem-4-carboxylic acid, 7- [3 (- ) -α- (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) -phenylacetylamido] -3- [2- (44-methylthiazolyl) -thiomethyl] -A3-cephem-4-carboxylic acid, 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacylamido] -3- [2- (pyridyl- 1-Oxide) -thiomethyl] -A3-cephem-4-carboxylic acid, 7- [D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylase: - amino] -3- (2-Thiazolinylthiomethyl) -A3-cephem-4-carboxylic acid, 7- [D (-) - "- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -phylacylamide] -3- [ 2- (1-methylimidazolyl) -thiomethyl] -A3-cephem-4-carboxylic acid, 7- [D (~) -α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamine} -phenylacetamido] -3- (2-pyrimidinylthiomethyl) -A3-cephemr4-carboxylic acid, 7- [D (-) - α- (β-ethyl-2,3-oxo-1-piperazinocarbonylamine) -phenylacetamide]-3- [ 3- (6-methylpyridazinyl) -thiomethyl] -A3-cephem-4-carboxylic acid, 7- [D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylaminophen-phenylaceaamino] -3 - [1- (4-methylpiperazino) -thiocarbonylthiomethyl] -α-5-cephem-4-carboxylic acid, 7- [D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamine) -phenyla: Ethylamino] -3- [5- (3-methylisoxazolyl) carbonylthiomethyl] -A3-: ephem-4-caronic acid, 7- [D (-) - α- (4-methyl-2,3-dioxo -l-piperazinok carbonylamine) -phenylacetamido] -3-ethoxythiocarbonylthiomethyl-3 3-cephem-4-carboxylic acid, 7 - [D (-) - α- (4-ethoxycarbonyl-2-oxo-1-piperazinocarbonyllazino) -pheylase: - amino] -3-methyl-33-cephem-4-carbonic acid, methoxymethyl-7- [D (~) -Q- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3-methyl -A3-cephem-4-carboxylate, etc. according to 80820h-7 37 Tests regarding the sensitivity of typical compounds according to the invention are shown in the following. (1) Minimum inhibitory concentrations (NIC) for the compounds mo different standard strains are shown in Tables III and IV.

Den minsta inhiberande koncentrationen (MIG) bestämdes enligt 1.11 en plattmetod som beskrives i "Chemoterapy" (Japan), vol. 16 (1968), 93-99. Det använda kulturmediet var en hjärtinfusionsagar (pä 7,4). nntale: celler per platta i ympämnet var lO4 (106 celler/ml). -u @ OQO O 1 \ _ . . _ 735 \z 2.» 03 00~ 5 n. A S H v Gäøfioflßäuv @® w ,U\|E_60Nm0fi.¶w 550.0 _ _ 0 _ P 0 __... 00~ 00~A 5A hå 500038 mä 0:8 _ z \ - .Hz ) U M V v ^ :ssfisknv ælæ. fiwrmm» EQ00«__H0IZ,\ _ x . _ _ zuz w OO 1. 3 I .w 2800 0 ü _ _ Éflofimwmu 00000090 z 0.2 v 03 _08 A S4 v P2 v »šfiffiš wx/Åfl æscßaàß . 30000 _ v m. Éfišfiwefimuwuv n 00000 z 0 @ . .H SH 00~ A »mä N. á v lesfipfln -m0 0fi\» 3 V . iFNWI 000050200 7. ,. _ _ .Illlll (f: h. >~Dfi I.. . _. QJTH _ _ aoom r.:....»:c m 0 :æccfiwâšem Efiz ,.fi _00 .cáoccc mflflflmhnm |wmwflm 2 _. . mwcoeowswwm |oflwsmmuw ao n.The minimum inhibitory concentration (MIG) was determined according to 1.11 a plate method described in "Chemotherapy" (Japan), vol. 16 (1968), 93-99. The culture medium used was a cardiac infusion agar (at 7.4). nntale: cells per plate in the inoculum were 10 4 (106 cells / ml). -u @ OQO O 1 \ _. . _ 735 \ z 2. » 03 00 ~ 5 n. ASH v Gäø fi o fl ßäuv @ ® w, U \ | E_60Nm0 fi.¶ w 550.0 _ _ 0 _ P 0 __... 00 ~ 00 ~ A 5A hå 500038 mä 0: 8 _ z \ - .Hz) UMV v ^: ss fi sknv ælæ. fi wrmm »EQ00« __ H0IZ, \ _ x. _ _ zuz w OO 1. 3 I .w 2800 0 ü _ _ É fl o fi mwmu 00000090 z 0.2 v 03 _08 A S4 v P2 v »š fi f fi š wx / Å fl æscßaàß. 30000 _ v m. É fi š fi we fi muwuv n 00000 z 0 @. .H SH 00 ~ A »mä N. á v les fi p fl n -m0 0fi \» 3 V. iFNWI 000050200 7.,. _ _ .Illlll (f: h.> ~ D fi I ... _. QJTH _ _ aoom r.:.... »: cm 0: æcc fi wâšem E fi z, .fi _00 .cáoccc m flflfl mhnm | wmw fl m 2 _.. Mwcoeowswwm | o fl wsmmuw ao n.

Q - 8.- 7 S: .fiaoßmä 7808201» - 7 fi=u _ _ wzcsu o >Tu åzflæmmuiwzmfl »U .\JA. zlz m.. Eöome E50; :imo _ 3 3 ln 1-4 N\ 59 mmg m w~mmooo= \o www .i w 1 z|z m J mzovmumaooz zwmo \ ufi N If\ I* '\ Q Q az co 1 « Q _ O fiww x=@øuo~=u.“wz / \1/. W fia .æzoomumzouz =~mu.m@ G ï o. Q nzooo Q nu mmoovø~mo»m+z mmm wf, w *åooæuzzoæwlfimmu Q v ^.m»p°wV >H fiflunæa '-10 vaoazou-7 m=ø __ qzooo M S4 v Eno å 2.6 v 2.5 v =-_f_.m~=.\.. æzwflo :U/fil %w§;_ f¿wk 1 ==ou=o==^x=f zmmumzu w\ @1ß O D m=w 3¿ .H1 mm i o n m fiz,ï&__ä.m2wmz c @ I I N. u. u KH. _ _ t. . z..z 4mm»nAm.mzoumomzooawßzmmu mw v\ø o 0 , ßzooo 0 M~.m >m.H mm fl.o vv ~>.o «@J-m~m@1m+z mww . Q zfßg m»mH@.mzoomomzo@_w1wmmo <@ ï Q 0 ^.fi;L@@v >H Hfiozua vsoazoa-7 Emo ozooo o Toy \ . _. J . . ..z...u_.fo .vo.__æ.\ , i o V _. o V .L 2 EL o V o» o V __* ___, HQL» ošoooowwo.zoëwJzwzommo _.. V3/ o o ®ooo _ Amiowzmoo V2 \o @ ® o, 4 få Eno .S o . .. \ u V w ß o V F H offšooomomzoozwlzm=o C C .ßzooo o @ n.. \ å . . -moooo EïWfzNfl _] J \ - NH Ä N oofi EL o V mo o o. mzoomomzooom »mmoumo vä c : Ömïoï å ïooå. #2 .mflmnuwmn Eowmw hwmhmø wmwflm soc mdmhio mSmflflMmP m¥Pmu hmw dm>flfi øfl> Hwuofl wwflfimëmfi äflwåmnnw Eowmm mmwnm nfiøfihoflmmmo Soo fiflflosmmwosßflnvmfl .flfivoflmwmuefiflhvmz ".En< veoszoa-7 . _ wzooo 0m.H .on @w.o V @~.o v. m =|w»wm~:04w+J _o mmw \|,« . .. mu.||.z w\ mzoumømzouz zfmo . l o c w ßzoov o fi>q \. . «.. . 1 fiz4-nm:u|\%z fi MW ~1, nu H oc~ wu Ü ^;.^, \ ,wv f:= zzouzçzzoøz z~=@ :L r . ï, O 0 ^.m«Lc@v >~ flficnsa 7808204-7 43 Minszs inhiberande koncsntrationerna (IIC) för föreningarna mc: kliniska isclat av bakterier visas i tabell V och VI.Q - 8.- 7 S: .fi aoßmä 7808201 »- 7 fi = u _ _ wzcsu o> Tu åz fl æmmuiwzm fl» U. \ JA. zlz m .. Eöome E50; : imo _ 3 3 ln 1-4 N \ 59 mmg mw ~ mmooo = \ o www .iw 1 z | zm J mzovmumaooz zwmo \ u fi N If \ I * '\ QQ az co 1 «Q _ O fi ww x = @ øuo ~ = u. “wz / \ 1 /. W fi a .æzoomumzouz = ~ mu.m @ G ï o. Q nzooo Q nu mmoovø ~ mo »m + z mmm wf, w * åooæuzzoæwl fi mmu Q v ^ .m» p ° wV> H fifl unæa '-10 vaoazou-7 m = ø __ qzooo M S4 v Eno å 2.6 v 2.5 v = -_ f_.m ~ =. \ .. æzw fl o: U / fi l% w§; _ f¿wk 1 == ou = o == ^ x = f zmmumzu w \ @ 1ß OD m = w 3¿ .H1 mm ionm fi z, ï & __ ä.m2wmz c @ II N. u. u KH. _ _ t.. z..z 4mm »nAm.mzoumomzooawßzmmu mw v \ ø o 0, ßzooo 0 M ~ .m> m.H mm fl. o vv ~> .o« @ J-m ~ m @ 1m + z mww. Q zfßg m »mH @ .mzoomomzo @ _w1wmmo <@ ï Q 0 ^ .fi; L @@ v> H H fi ozua vsoazoa-7 Emo ozooo o Toy \. _. J. . ..z ... u_.fo .vo .__ æ. \, i o V _. o V .L 2 EL o V o »o V __ * ___, HQL» ošoooowwo.zoëwJzwzommo _ .. V3 / o o ®ooo _ Amiowzmoo V2 \ o @ ® o, 4 få Eno .S o. .. \ u V w ß o V F H offšooomomzoozwlzm = o C C .ßzooo o @ n .. \ å. . -moooo EïWfzN fl _] J \ - NH Ä N oo fi EL o V mo o o. mzoomomzooom »mmoumo vä c: Ömïoï å ïooå. # 2 .m al mnuwmn Eowmw hwmhmø wmw fl m Soc mdmhio MSM flfl MMP m ¥ Pmu HMW dm> flfi O fl> Hwuo al ww flfi MEM FI A fl wåmnnw Eowmm mmwnm n f O fi ho al mmmol Soo fiflfl osmmwosß al NVM al .flfi vivo al mwmue fifl hvmz ".A <veoszoa-7. _ Wzooo 0m.H .ON @wo V @ ~. o v. m = | w »wm ~: 04w + J _o mmw \ |,«. .. mu. || .zw \ mzoumømzouz zfmo. locw ßzoov o fi> q \.. «... 1 fi z4-nm : u | \% z fi MW ~ 1, nu H oc ~ wu Ü ^;. ^, \, wv f: = zzouzçzzoøz z ~ = @: L r. ï, O 0 ^ .m «Lc @ v> ~ ins cnsa 7808204-7 43 Minszs inhibitory concentrations (IICs) for the compounds mc: clinical isolates of bacteria are shown in Tables V and VI.

MIC bestämdes på samma sätt som enligt föregående sskticn (1).The MIC was determined in the same manner as in the previous section (1).

HH 7808204~7 mïo »AA Nino .kl SA å; 3A å: å; mono å _. wïo Tho iho .ÉA ÉA 92 få Éß om; Sto mo _.HH 7808204 ~ 7 mïo »AA Nino .kl SA å; 3A å: å; mono å _. wïo Tho iho .ÉA ÉA 92 få Éß om; Sto mo _.

TÅ om: om; Eko 3A. omá ...må coin .EJ än: .B _. 93 om¿ 34 who 2.» 92A Qho 3.4 om; Eno No __ om Sá ma; 3A 3A om; om; 3A 3A 3A S _. om ww.H wm.H w>.o. mH.m @m.~ æ>.o æ>.o om.H .æw.o om H: wsfinmuwm müo Tov wov ïoV ïo V ïo V ïo V o To V Yo V ïo. V sfifinoüfiwo Lo wov vov qovmëo QoV QoV QoV voV voV w 1. l _ w 34 .To v ïov ïoV . ïov ïo V .ïo V ïo V .wo V To V _ nwwmfiwmw I å män 34 å; 3.» 3A åá Bum 3.» EA fiïnmwmwmwmw må Th. To Nà då šoæ ä.. 013m n: 55 o: oæâ m: oäw oz fi/ wfiqmawm. l/ nsopzs m:vcoooa>s;noæ _ //////// l/l.TÅ om: om; Eco 3A. omá ... må coin .EJ än: .B _. 93 om¿ 34 who 2. » 92A Qho 3.4 om; Eno No __ om Sá ma; 3A 3A om; if; 3A 3A 3A S _. om ww.H wm.H w> .o. mH.m @ m. ~ æ> .o æ> .o om.H .æw.o om H: ws fi nmuwm müo Tov wov ïoV ïo V ïo V ïo V o To V Yo V ïo. V s fifi noü fi wo Lo wov vov qovmëo QoV QoV QoV voV voV w 1. l _ w 34 .To v ïov ïoV. ïov ïo V .ïo V ïo V .wo V To V _ nwwm fi wmw I å men 34 å; 3. » 3A åá Bum 3. » EA fi ïnmwmwmwmw må Th. To Nà då šoæ ä .. 013m n: 55 o: oæâ m: oäw oz fi / w fi qmawm. l / nsopzs m: vcoooa> s; noæ _ //////// l / l.

H|H> Hfimßmä 78082011-7 H5 mlH > Hflcßdà. 3 ff. 26 oi ...a 9,; .Lä .lá é _. w. A cow m.. 3 w 9% å MHJU. a. P. . w 3 ._ fl.. fifz fuiw f_.w fišz 2: ~ï.; _.» fi_.n _; = 0.3 93 .fld 03A 9: ...sin A34. wwá 0.... É wnfinwfiå mm.@ cam mH.n nH.n Oofi oß wH.m mH.m -.M zfiuflhøflmwmu 2.» oi å; å; å än» 3A åä Qmá m l. m ß QS Tua 35 om _ å QS mWw QS U mßšfi Q Éß ä; ma 93 Sá å; .Hm fiflšmwmfiwflwm vi Nå må Ta HSM zu åâ ä .Nim ä müß z. Hmä zu f. wfinqïwm Hfioo :Éfiåuvsuwm Hb ?80820h-7 mwozflwsnmm wmsoaouswmm m... mxå om _. my: mmzo .min ms; om om ._ mm mdfl om mad mfim mono ms; om om _. om mo om om mm om o oS mo ._ oofi om . . oofi ooH om oofi ooH oom No ._ mo mw om mN mm . o . mm m. 3 ooH G _. om .om . ooH om m. 3 om _ . o oom oo .E womäåm oow A ooN A oow A oom A oom A. oom A oow A oow A nmfinodmowo oow ooN .A oom A ooN A ooN A ooN A oo ooN A I w. u . flfivoflmmmo .L oo. A ooN A ooN A _ ooN A ooN A oow A oo . oom. A Lsååmo oom A oom A . oow A oow A oom. A ooo A oo... A oom. A :momwwwæmwmm ïæ Emm zo mmmw zo S2 oo du” zo zo mäm .oo ...H3 ä. mfiowfiom mlH> Hfimßma 780820144 Lt?- Élo 1 1 of co __... o... :o ._ vw. ~ 1 1 sfi. .:h .: :.. Mi. = v.. M . ~ ...ä . o i.. . o å: cc. cc. 2,3 ; ._ HA. . o. m. . NH mm oom. com som cow mm ._ n~.w m.wH m.ma om om om Om Am . u~.w mm mw OCH OOH GOA oow Om HQ wflwümnnm S . N QS 92. oom A oow A oow. A oo... A fiåhoflwmv å; 25 S6 oom A ooo A oom A ooN A w. l.H | H> H fi mßmä 78082011-7 H5 mlH> H fl cßdà. 3 ff. 26 oi ... a 9 ,; .Lä .lá é _. w. A cow m .. 3 w 9% å MHJU. a. P.. w 3 ._ fl .. fi fz fuiw f_.w fi šz 2: ~ ï .; _. » fi_. n _; = 0.3 93 .fl d 03A 9: ... sin A34. wwá 0 .... É wn fi nw fi å mm. @ cam mH.n nH.n Oo fi oß wH.m mH.m -.M z fi u fl hø fl mwmu 2. » oi å; å; å än »3A åä Qmá m l. m ß QS Tua 35 om _ å QS mWw QS U mßš fi Q Éß ä; ma 93 Sá å; .Hm fifl šmwm fi w fl wm vi Now must Ta HSM zu åâ ä .Nim ä müß z. Hmä zu f. W fi nqïwm H fi oo: É fi åuvsuwm Hb? 80820h-7 mwoz fl wsnmm wmsoaouswmm m ... mxå om _. my: mmzo .min ms; om om ._ mm md fl om mad m fi m mono ms; if if _. om mo om om mm om o oS mo ._ oo fi om. . oo fi ooH om oo fi ooH uncle No ._ mo mw om mN mm. o. mm m. 3 ooH G _. if if . ooH at m. 3 at _. o uncle oo .E womäåm oow A ooN A oow A uncle A uncle A. uncle A oow A oow A nm fi nodmowo oow ooN .A uncle A ooN A ooN A ooN A oo ooN A I w. u. flfi vo fl mmmo .L oo. A ooN A ooN A _ ooN A ooN A oow A oo. uncle. A Lsååmo oom A oom A. oow A oow A uncle. A ooo A oo ... A oom. A: momwwwæmwmm ïæ Emm zo mmmw zo S2 oo du ”zo zo mäm .oo ... H3 ä. M fi ow fi om mlH> H fi mßma 780820144 Lt? - Élo 1 1 of co __... o ...: o ._ vw. ~ 1 1 s fi. .: h.:: .. Mi. = v .. M. ~ ... ä. o i ... o å: cc. cc. 2.3; ._ HA. . if. . NH mm oom. com som cow mm ._ n ~ .w m.wH m.ma om om om Om Am. u ~ .w mm mw AND OOH GOA oow Om HQ w fl wümnnm S. N QS 92. oom A oow A oow. A oo ... A fi åho fl wmv å; 25 S6 uncle A ooo A uncle A ooN A w. L.

. M Û. ...JJ »m5 so.. A os... A osm A cow A :fipoflmwwu Ü. xšdflhømi J. .J :H ÃÃ. 001. A os.. N ä. _ Å. A cwomfiwoamwwo ._ f i . F. T f C _.. ß f; ._ .IEÜHHÜNQ .Hm :U Hæoo av rafiw zu wlm m|w m|æ alm wflwflwhwm .Wfimfloflmoca .Äfåmßmam mwoøfiwsnwm wmnoäoøäwwm IIII-llllnll-Inlll w|H> .mfiwßma 118 780820h~? mlH> Hflmßda mïm mmíf. Üïm mfifln .Le ._ .uwfio mdïm “Mmmm mmfw Nm ._ mmÜm w.O wmïn æmJu Hw ._ ßïo .Sá 3% 2A QBÉ wšnwnmm om om @m.H MH.m gflohmwwwwwmw wflššdš mnwflwnwm mmwwmmm. 780820ls-7 49 Det framgår av tabellerna att föreliggande föreningar upp- visar ett bredare antibakteriellt spektrum och en utomordentlig antibakteriell aktivitet mot icke endast Pseudomonas aeruginosa, Klebsiella pneumoniae och Proteus-arter, utan även mot resistenta bakterier, än vad som uppvisas av kontrollsubstansen cefaloglycin, dvs föreningar med en aminogrupp i acylgruppens W-ställning.. M Û. ... JJ »m5 so .. A os ... A osm A cow A: fi po fl mwwu Ü. Xšd fl hømi J. .J: H ÃÃ. 001. A os .. N ä. _ Å. A cwom fi woamwwo ._ f i. F. T f C _ .. ß f; ._ .IEÜHHÜNQ .Hm: U Hæoo av ra fi w zu wlm m | w m | æ alm w fl w fl whwm .W fi m fl o fl moca .Äfåmßmam mwoø fi wsnwm wmnoäoøäwwm IIII-llllnll-Inlll w ~ H8> 8. mlH> H fl mßda mïm mmíf. Üïm m fifl n .Le ._ .uw fi o mdïm “Mmmm mmfw Nm ._ mmÜm w.O wmïn æmJu Hw ._ ßïo .Sá 3% 2A QBÉ wšnwnmm om om @ m.H MH.m g fl ohmwwwwwmw w fl šwwm. 780820ls-7 49 It appears from the tables that the present compounds show a broader antibacterial spectrum and an excellent antibacterial activity against not only Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus species, but also against resistant bacteria, than those shown by the control substance cephaloglycin. i.e. compounds with an amino group in the W position of the acyl group.

Föreningarna med formeln (Ie) uppvisar särskilt goda effek- ter.The compounds of formula (Ie) show particularly good effects.

Föreliggande föreningar har i allmänhet låg toxicitet.The present compounds generally have low toxicity.

Föreningarna med formeln (I) kan administreras icke endast i form av fria syror, utan även i form av icke-toxiska salter eller fysiologiskt godtagbara estrar. Vidare användes de föreningar vilka föreligger i form av fysiologiskt icke godtagbara estrar normalt först efter att ha överförts till de fria syrorna eller icke-toxiska salter genom eliminering av den esterbildande gruppen enligt konventionell teknik.The compounds of formula (I) may be administered not only in the form of free acids, but also in the form of non-toxic salts or physiologically acceptable esters. Furthermore, those compounds which are in the form of physiologically unacceptable esters are normally used only after being converted to the free acids or non-toxic salts by eliminating the ester-forming group according to conventional techniques.

Föreningarna enligt uppfinningen kan administreras till ' människa och djur efter beredning i en fysiologiskt lämplig form, såsom tablett, kapsel, syrup, injektionskomposition eller liknande, såsom vanligen är fallet med läkemedel av penicillin- och cefalo- sporíntyp.The compounds of the invention may be administered to humans and animals after preparation in a physiologically suitable form, such as tablet, capsule, syrup, injection composition or the like, as is usually the case with penicillin and cephalosporin type drugs.

Uppfinningen åskàdliggöres närmare medelst följande exempel, vari de angivna temperaturerna avser Celsius-grader. I de följande tabellerna betecknar "m.p“ smältpunkt, "decomp.“ sönderdelning och “yield“ utbyte.The invention is further illustrated by the following examples, in which the temperatures indicated refer to degrees Celsius. In the following tables, "m.p" denotes melting point, "decomp." Decomposition and "yield" yield.

Exempel 1 En suspension av 4,0 g monohydrat av 7-[D(-) acetamido]-3-metyl-A3-cefem-4-karbonsyra i 60 ml tetrahydrofuran -N-aminofenyl- innehållande 20 volymprocent vatten, inställdes på pH 8,0 - 8,5 genom gradvis tillsats av trietylamin under omröring för bildning av en lösning, som därefter kyldes till 00. Denna lösning försattes gradvis med 2,5 g kristaller av 4-metyl-2,3-dioxo-1-piperazino- karbonylklorid under 10 minuter. Under denna period upprätthölls pH i reaktionslösningen vid 7,5 - 8,0 genom gradvis tillsats av trietylamin. Blandningen omsattes 15 minuter vid 0 - 5°, medan pH upprätthölls vid 7,5 - 8,0. Efter omsättningen omrördes reaktions- vätskan tillsammans med 60 ml dietyleter och 70 ml vatten och vattenskiktet avskildes. Det erhållna vattenskiktet tvättades med 30 ml etylacetat, kyldes till 0 - 5° och inställdes på pH 1,5 genom tillsats av utspädd saltsyra för avsättning av vita krista11er_ 7808204-7 50 Dessa tillvaratogs genom filtrering, tvättades tillräckligt med, vatten och torkades för bildning av 4,7 g vita kristaller av 7-[D(-)-N-(4-metyl~2,3-dioxo-1-piperazinokarbonylamíno)-fenyl- acetamidfikß-metyl-A?-cefem-4-karbonsyra med smältpunkten 185 - 1860 (sönderdelning), utbyte 86%.Example 1 A suspension of 4.0 g of monohydrate of 7- [D (-) acetamido] -3-methyl-A3-cephem-4-carboxylic acid in 60 ml of tetrahydrofuran -N-aminophenyl- containing 20% by volume of water, was adjusted to pH 8 0 - 8.5 by gradual addition of triethylamine with stirring to give a solution, which was then cooled to 0 DEG C. This solution was gradually added with 2.5 g of crystals of 4-methyl-2,3-dioxo-1-piperazino- carbonyl chloride for 10 minutes. During this period, the pH of the reaction solution was maintained at 7.5 - 8.0 by the gradual addition of triethylamine. The mixture was reacted for 15 minutes at 0-5 °, while maintaining the pH at 7.5-8.0. After the reaction, the reaction liquid was stirred together with 60 ml of diethyl ether and 70 ml of water, and the aqueous layer was separated. The resulting aqueous layer was washed with 30 ml of ethyl acetate, cooled to 0-5 ° and adjusted to pH 1.5 by adding dilute hydrochloric acid to deposit white crystals. These were collected by filtration, washed sufficiently, water and dried to give of 4.7 g of white crystals of 7- [D (-) - N- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -phenyl-acetamide fi kß-methyl-A? -cephem-4-carbonic acid with melting point 185 - 1860 (decomposition), yield 86%.

IR (KBr) cm'1: Q C=O 1770 - 1760 (laktam), 1720 - 1660 (-coN< , -cooH). g NMR (aö-nmso) fr-värdem 0,1 (m, a), 0,56 (m, a), 2,62 (SH, s), 4,26 - 4,37 (2H, dd), 5,05 (1H, d), 6,1 (2H, bs), 6,47 (zu, bs), 6,63 (za, s), 7,05 (sn, s), 8,02 (an, s). ' Nämnda försök upprepades, men med det undantaget att 4-metyl- -2,3-dioxo-1-piperazinokarbonylkloriden ersattes av de reaktions- benägna derivat av föreningar med formeln (III) som anges i tabell XXI för bildning av de däri angivna produkterna. Strukturen för dessa bekräftades med IÉ och NMR. 780820194? 51 _ ._ R o> ufvfiæ .UoOnH ^.;E3uvvV .;.ë :ooo m o, o Û .wJ LJ. X w .\ »mo \ ü \J J N N w Sooå = +34 omoïmo w .àzoomooozouïz zëmo fmoo mo va* _ I O O .o o R m.Oæ ofimfiæ .ooømfi ^.meoowuv .m.E mooo o o O 1 Lïa/Nšfml fmo \z 7, - m Too. .o z :o m. å n. ozoomomzoofz zkmowmofmo olo ovlo :TE å. 02 wåufn .OCQOA AÄWEOUUUV .ala 203% O .IR (KBr) cm -1: Q C = O 1770 - 1760 (lactam), 1720 - 1660 (-coN <, -cooH). g NMR (δ δ-nm 50) δ values 0.1 (m, a), 0.56 (m, a), 2.62 (SH, s), 4.26 - 4.37 (2H, dd), 5.05 (1H, d), 6.1 (2H, bs), 6.47 (zu, bs), 6.63 (za, s), 7.05 (sn, s), 8.02 (an , s). Said experiment was repeated, but with the exception that the 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced by the reaction-prone derivatives of compounds of formula (III) given in Table XXI to give the products listed therein. . The structure of these was confirmed by IE and NMR. 780820194? 51 _ ._ R o> ufv fi æ .UoOnH ^ .; E3uvvV.;. Ë: ooo m o, o Û .wJ LJ. X w. \ »Mo \ ü \ JJNN w Sooå = +34 omoïmo w .àzoomooozouïz zëmo fmoo mo va * _ IOO .oo R m.Oæ o fi m fi æ .ooøm fi ^ .meoowuv .mE mooo oo O 1 Lïa / Nšfml fmo \ z 7, - m Too. .o z: o m. å n. ozoomomzoofz zkmowmofmo olo ovlo: TE å. 02 wåufn .OCQOA AÄWEOUUUV .ala 203% O.

MEJ \ Z fiärwmfl! mzoozo:zooåglmooowzo c »w O O 1A 1 va ~ Såå Moxwoonoßooo G O Päwohnfi AHHHV flflmøiow ømë cwmcfiflmnæw >ß Påfinww Pwwmnonmnoflpzmmm .HvOm Hflwflme 760ß20h~7 52 Exemnel 2. (1) En lösning av 0,92 g 1-n-pentyl-2,3-dioxo-piçerazin i 15 ml vattenfri dioxan försattes med 1,1 ml trietylamin och 1,08 g trimetyl- silylklorid. Den erhållna blandningen omrördes 20 tizmar vid rums- temperatur för bildning av trietylaminhydroklorid. Ienna hydrcklorid avskildes genom filtrering och filtratet nedfördes vid 0 - 5° droppvis i en lösning av 0,6 g fosgen i 10 ml vattenfri tetrahydrofuran. Den erhållna blandningen omsattes 30 minuter vid 5 - 100 och två timmar vid rumstemperatur.- Lösningsmedlet avlägsnades genom destillation under reducerat tryck för bildning av 1,21 g blekgul, oljeartad 4-n- -pentyl-2,3-dioxo-1-piperazinokarbonylklorid. na (file) mfl; o C=O 1790, 1720 - 1665. (2) En suspension av 1,70 g monohydrat av 7-[D(-)-a-aminofeny1acet- amido]-3-mety1-A3-cefem-4-karbonsyra i 50 ml tetrahydrofuran, inne- hållande 20 volymprocent vatten, inställdes på pH 8,0 - 8,5 genom tillsats av trietylamin under omröring för bildning av en lösning.MEJ \ Z fi ärwm fl! mzoozo: zooåglmooowzo c »w OO 1A 1 va ~ Såå Moxwoonoßooo GO Päwohn fi AHHHV flfl møiow ømë cwmc fifl mnæw> ß På fi nww Pwwmnonmno fl pzmmm .HvOm H flem n-2 x 2 (7). .3-Dioxo-piçerazine in 15 ml of anhydrous dioxane was added with 1.1 ml of triethylamine and 1.08 g of trimethylsilyl chloride. The resulting mixture was stirred for 20 hours at room temperature to give triethylamine hydrochloride. One hydrochloride was separated by filtration and the filtrate was dropped at 0-5 ° dropwise into a solution of 0.6 g of phosgene in 10 ml of anhydrous tetrahydrofuran. The resulting mixture was reacted for 30 minutes at 5-100 and two hours at room temperature. The solvent was removed by distillation under reduced pressure to give 1.21 g of pale yellow, oily 4-n-pentyl-2,3-dioxo-1-piperazinocarbonyl chloride. . na (file) mfl; o C = O 1790, 1720 - 1665. (2) A suspension of 1.70 g of monohydrate of 7- [D (-) - α-aminophenylacetamido] -3-methyl-A3-cephem-4-carboxylic acid in 50 ml of tetrahydrofuran, containing 20% by volume of water, was adjusted to pH 8.0 - 8.5 by adding triethylamine with stirring to form a solution.

Under denna period upprätthölls pH i lösningen vid 7,5 - 8,0 genom tillsats av trietylamin. Den erhållna blandade lösningen omsattes en timme vid 0 - 50 och därefter två timmar vid 5 - 100, medan pH uppratthöiis vid 7,5 - 8,0. efter omsättningen aviagsnåaes tetra- hydrofuranen genom destillation under reducerat tryck och återstoden löstes i 20 ml vatten och tvättades två gånger med 20 ml etylacetat.During this period, the pH of the solution was maintained at 7.5 - 8.0 by the addition of triethylamine. The resulting mixed solution was reacted for one hour at 0-50 and then two hours at 5-100, while maintaining the pH at 7.5-8.0. after the reaction, the tetrahydrofuran was removed by distillation under reduced pressure, and the residue was dissolved in 20 ml of water and washed twice with 20 ml of ethyl acetate.

Vattenskiktet försattes med 40 ml etylacetat och inställdes på ett pH av 1,5 genom gradvis tillsats av utspädd saltsyra under iskylning.The aqueous layer was added with 40 ml of ethyl acetate and adjusted to a pH of 1.5 by gradually adding dilute hydrochloric acid under ice-cooling.

Etylacetatskiktet avskildes, tvättades med vatten och torkades över vattenfritt magnesiumsulfat. 10 ml etylacetatlösning, innehållande 0,75 g natrium-2-etylhexanoat nedfördes droppvis i skiktet vid 0 - 5° för avsättning av vita kristaller. Dessa tillvaratogs genom filt- rering och tvättades med et"1acetat och därefter med 1,95 g natrium- salt av 7-[D(-)-a-(4-n-pentyl-2,3-dioxo-1-piperazinokarbonylanino)- -fenylacetamido]-3-metyl-¿3-cefem-4-karbonsyra med szältpunkten 164 - 166° (sönderdelning), utbyte 75 %.The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate. 10 ml of ethyl acetate solution containing 0.75 g of sodium 2-ethylhexanoate was dropped dropwise into the layer at 0-5 ° to deposit white crystals. These were collected by filtration and washed with an acetate and then with 1.95 g of sodium salt of 7- [D (-) - α- (4-n-pentyl-2,3-dioxo-1-piperazinocarbonylanino)). - -phenylacetamido] -3-methyl-β-cephem-4-carboxylic acid, m.p. 164 DEG-166 DEG (dec.), yield 75%.

IR (KBr) cm_l: 0 C=0 1750 (laktam), 1720 - 1660 (-COHII), 1590 (-coo@).IR (KBr) cm -1: 0 C = 0 1750 (lactam), 1720 - 1660 (-COHII), 1590 (-coo®).

NHR (dö-DMSO + D20) 2'-värden:_ 2,58 (5H, s), 4,33 (1H, s), 4,49 (1H, d), 5,17 (1H, d), 6,10 (2H, bs), 6,42 - 6,57 (6H, m), 8,09 (3H, s), 8,60 ~ 8,90 (6H, bs), 9,12 (3H, t).NHR (do-DMSO + D 2 O) 2 'values: 2.58 (5H, s), 4.33 (1H, s), 4.49 (1H, d), 5.17 (1H, d), 6.10 (2H, bs), 6.42 - 6.57 (6H, m), 8.09 (3H, s), 8.60 ~ 8.90 (6H, bs), 9.12 (3H, t).

Nämnda försök upprepedes, men med det undantaget att 4-n-pentyl- -2,3-dioxo-1-piperazinokarbonylkloriden ersattes av de reaktions- 7808204-7 53 ' benägna derivat av föreningar med formeln III) som ang-es i tabell XXII för ”oildning av de däri angivna produlcfierna. StruL-:turen fä:- dessa “oekräftades med IR och IIIJIR. 7808-201; ~ 7 54 R ær øamfiz .oovmfi ^.mEoowvv .a.ë \@zo@w O mm: . wav \.z|¿» «\ wl, w >@f|||mz@@=@:zov|z z|~:vQ^wmuv :U .u ÖVLQ ¶ -é E Hv@@|ax;z|~mo@^~m@vmm@ @Y¿w ß mv ufimflæ .ooæmfi ^.asoowøV .m.E æzooo RÅM mm@4wwz \|/ _ « a :zoo=omzoo|z ,z1~mum^Nmov::ø 0 aïß w^1Va fioo@|zw1z|w:@@^~moVwmo K >.>> uaoqæ .oooofl ^.aEoumuv .avi flzooo _ _ 0 mmo4w+zmQA . nu \1/ « w wí mzøømomzoolz zlwmo Ammovxmo mY4w |^|vn fioov|z1;z|~:o«^~=ov«mo qwlßv QhÅSfi-Cnnnfi ^HHHv Qfieåacw øæš zouzflflosnm >a »a>@nvc eomscosacafiæxsom »ll .HHNN fifioßma 7808204-7 55 u ~.@> @fimH> .oo>mH I mmfi ^.@e@@mvv .@.a mzoou O »mo4m+zmmm m@w m mzo@=@mzou«m11ø»Nmo«^Navymao Ho@@|Ãw1z-~m@fi^~m@vmm@ vuk .wak Q -Alva - ß >> @H@H> .mamma 1 mwfi ^.@§o0w@v .@.s mzcou o _ wm@4mrzm% HQo@|a|ßw@@@~=JmmJ xl/ x _ c . m mzo@m@mzo@1z z|o@o~møF=@ mwn o ll YL AE ^.m@hoMv HHNN Hfiußmä 7808204-7 56- Exemnel 3 . 0 Med användning av en hydrcklorid av metoximetylestern av 7-[D- (-)-a-aminofenylacetamido]-3-metyl-A3-cefem-4-karbonsyra och 0,65 g 4-metyl-2,3-dioxo-1-piperazinokarbonylklorid upprepades försöket enligt exempel 1 för bildning av 1,6 g metoximetylester av 7-[D(-)- -a-(4-metyl-2,3-dioxo-l-piperazinokarbonylamino)-fenylacetamido]- -3-metyl-A3-cefem-4-karbonsyra med smältpunkten 146 - l48° (sönder- delning), utbyte 86 %. 0 Ia (ice-r) mfl: 0 0:0 1770 (iaktam), 1710 (fester), 1680 - isoo . (-coz-I<) .Said experiment was repeated, but with the exception that the 4-n-pentyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced by the reaction-prone derivatives of compounds of formula III) given in Table XXII for 'oilding of the produlcs specified therein. StruL-: tur få: - these “were not confirmed with IR and IIIJIR. 7808-201; ~ 7 54 R ær øam fi z .oovm fi ^ .mEoowvv .a.ë \ @ zo @ w O mm:. wav \ .z | ¿»« \ wl, w> @f ||| mz @@ = @: zov | zz | ~: vQ ^ wmuv: U .u ÖVLQ ¶ -é E Hv @@ | ax; z | ~ mo @ ^ ~ m @ vmm @ @ Y¿w ß mv u fi m fl æ .ooæm fi ^ .asoowøV .mE æzooo RÅM mm @ 4wwz \ | / _ «a: zoo = omzoo | z, z1 ~ mum ^ Nmov :: ø 0 aïß w ^ 1Va fi oo @ | zw1z | w: @@ ^ ~ moVwmo K>. >> uaoqæ .oooo fl ^ .aEoumuv .avi fl zooo _ _ 0 mmo4w + zmQA. nu \ 1 / «w wí mzøømomzoolz zlwmo Ammovxmo mY4w | ^ | vn fi oov | z1; z | ~: o« ^ ~ = ov «mo qwlßv QhÅS fi- Cnnn fi ^ HHHv Q fi eåacw øæš zouz flfl osnm> lfi e» a » .HHNN fifi oßma 7808204-7 55 u ~. @> @ Fi mH> .oo> mH I mm fi ^. @ E @@ mvv. @. A mzoou O »mo4m + zmmm m @ wm mzo @ = @ mzou« m11ø »Nmo «^ Navymao Ho @@ | Ãw1z- ~ m @ fi ^ ~ m @ vmm @ vuk .wak Q -Alva - ß >> @ H @ H> .mamma 1 mw fi ^. @ §O0w @ v. @. S mzcou o _ wm @ 4mrzm% HQo @ | a | ßw @@@ ~ = JmmJ xl / x _ c. m mzo @ m @ mzo @ 1z z | o @ o ~ møF = @ mwn o ll YL AE ^.m@hoMv HHNN H fi ußmä 7808204-7 56- Exemnel 3. Using a hydrochloride of the methoxymethyl ester of 7- [D- (-) - α-aminophenylacetamido] -3-methyl-A3-cephem-4-carboxylic acid and 0.65 g of 4-methyl-2,3-dioxo-1 -piperazinocarbonyl chloride The experiment of Example 1 was repeated to give 1.6 g of methoxymethyl ester of 7- [D (-) - -α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3-methyl -A3-cephem-4-carboxylic acid, m.p. 146-148 ° (dec.), Yield 86%. 0 Ia (ice-r) mfl: 0 0: 0 1770 (iaktam), 1710 (fester), 1680 - isoo. (-coz-I <).

Exemnel 4.Example 4.

En suspension av 0,20 g 7-[D(-)-a-aminofenylacetamido]-3- -acetoximetyl-A3-cefem-4-karbonsyra i l5 ml vattenfri klorofcrm för- sattes med 0,17 ml trietylamin under omröring för bildning av en lösning, som därefter kyldes till 0°. Denna lösning försattes med 0,ll.g 4-metyl-2,3-dicxo-l-piperazinokarbonylklorid och den erhållna blandningen omsattes två timmar vid rumstemperatur. Efter omsätt- ningen indunstades reaktionsvätskan under reducerat tryck och åter- stoden löstes i 15 ml vatten. Den erhållna lösningen tvättades med 10 ml etylacetat. Vattenskiktet försattes med 20 ml etylacetat och inställdes på pH 1,5 genom tillsats av 2N saltsyra under iskylning.A suspension of 0.20 g of 7- [D (-) - α-aminophenylacetamido] -3- -acetoxymethyl-33-cephem-4-carboxylic acid in 15 ml of anhydrous chloroform was added with 0.17 ml of triethylamine with stirring to give of a solution, which was then cooled to 0 °. This solution was charged with 0.1 g of 4-methyl-2,3-dicxo-1-piperazinocarbonyl chloride and the resulting mixture was reacted for two hours at room temperature. After the reaction, the reaction liquid was evaporated under reduced pressure, and the residue was dissolved in 15 ml of water. The resulting solution was washed with 10 ml of ethyl acetate. The aqueous layer was added with 20 ml of ethyl acetate and adjusted to pH 1.5 by adding 2N hydrochloric acid under ice-cooling.

Etylacetatskiktet avskildes, tvättades successivt med vatten och mättad natriumkloridlösning och tcrkades över magnesiumsulfat. Lösnings- medlet avlägsnades genom destillation under reducerat tryck för bild- ning av 0,22 g vita kristaller av 7-[D(-)-a-(4-metyl-2,3-dioxo-l- -piperazinokarbonylamino)-fenylacetamido]-3-acetoximetyl-A3-cefem-4- -karbonsyra med smältpunkten 1750 (sönderdelning), utbyte 76 %.The ethyl acetate layer was separated, washed successively with water and saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure to give 0.22 g of white crystals of 7- [D (-) - α- (4-methyl-2,3-dioxo-1--piperazinocarbonylamino) -phenylacetamido] -3-acetoxymethyl-A3-cephem-4-carboxylic acid, m.p. 1750 (dec.), Yield 76%.

IR (KBr) cm"l: J 0:0 1770 (laktam), 1720 - 1650 (-CON:I, -COOH). :mm (aö-nmso) r-väraen: 0,23 (in, a), o,63 (in, a), 2,65 (SH: 5): 4:32 (IH: (1): (ln: (1): 5:05 (lHJ (n: 5121 (ZH: Ûl)¶ 6,15 (2H, bs),,6,40 (2H, bs), 6,57 (2H, bs), 7,0 (3H, s), 8,0 (3H, s).IR (KBr) cm -1: J 0: 0 1770 (lactam), 1720 - 1650 (-CON: 1, -COOH).: Mm (α-nmso) r-vein: 0.23 (in, a), o, 63 (in, a), 2.65 (SH: 5): 4:32 (1H: (1): (ln: (1): 5:05 (1HJ (n: 5121) (ZH: Ûl)) 6.15 (2H, bs), 6.40 (2H, bs), 6.57 (2H, bs), 7.0 (3H, s), 8.0 (3H, s).

Nämnda försök upprepades, men med det undantaget att 4-metyl- -2,3-dioxo-l-piperazinokarbonylkloriden ersattes av de reaktionsbenägna derivat av föreningar med formeln (III) som anges i tabell XXIII för bildning av de däri angivna produkterna. Strukturen för dessa bekräf- tades med IR och NMB. veoszoa-1 -u R Nm vflofiæ .ooowfi ^.msoovuV..m.E moou _» b _ ..o.ïz.l_._»:o_o.14:; n. u. _ \ .šoo::o_ z- _ w- ._ _ fQFQI:ozoo=o__zoo|z ,z|:o.. A mir; VL . i o o o o 175 & mæ oflofiæ .ocmofi ^.oEouøuv .a.E mooo o .n N o w) w n moooo mo z w) m 33-: zfäào wgmzoomoozoolzïzlwmo :o oïo o o -TE u, ïmw 33.» .ooofi ...oeoomov .mä :ooo . _ n N O ïl/ N V n fmoooo moo/WZÄ 1., N N n Sooš ”Tæumofmwo m mzoozoowooonïz _ zloo .mošo ooio o_ o :TE »xšöhm AHHHV flfiwënow umë Qmwmfidmnnm >m ën>fihøø Pwmmnmnwmowvzmom llillllllllilll .HHHNN fifionßfi 78082011-7 58 R ~.o@ flflwfih _oo«nH.^.@Eo@@@v .@.e¶ moøø O \|/ \ mm0ouo~mo.n+z.4» \|/ M HowO|z zlwmø wL|:|1mzoomo=zmo1z 2- nu Qvnm _ I o o «^-v@ å. mm saga .oomafl fmæonmøv .mas m N moow Q mmw HJÛQ aw;z wmommo moøoo mo \»zmfi - .f 1 1_ f Amw mzoømo=zwo»Ã zlmmommu Qv1w vfß O o -#5 ^.mP~°«v HHHxx Hflwpma ?80820l+-? 59 Nämnda 7-[D(-)-d-(4-metyl-2,3-dioxo-1-piperazinokarbonylanino)- -fenylacetamido]-3-acetoxínetyl-A -cefem-4-karbonsyra med smält; akten 1750 (sönderdelning) omkristalliserades ur vattenhaltig acetcn för bildning av vita kristaller med en smältpunkt av 198 - 2000 (sönder- delning).Said experiment was repeated, but with the exception that the 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced by the reactive derivatives of compounds of formula (III) given in Table XXIII to give the products listed therein. The structure of these was confirmed by IR and NMB. veoszoa-1 -u R Nm v fl o fi æ .ooow fi ^ .msoovuV..m.E moou _ »b _ ..o.ïz.l _._»: o_o.14 :; n. u. _ \ .šoo :: o_ z- _ w- ._ _ fQFQI: ozoo = o__zoo | z, z |: o .. A mir; VL. i o o o o 175 & mæ o fl o fi æ .ocmo fi ^ .oEouøuv .a.E mooo o .n N o w) w n moooo mo z w) m 33-: zfäào wgmzoomoozoolzïzlwmo: o oïo o o -TE u, ïmw 33. » .ooo fi ... oeoomov .mä: ooo. _ n NO ïl / NV n fmoooo moo / WZÄ 1., NN n Sooš ”Tæumofmwo m mzoozoowooonïz _ zloo .mošo ooio o_ o: TE» xšöhm AHHHV flfi wënow umë Qmwm fi dmnnm> m ën> lfim. R ~ .o @ flfl w fi h _oo «nH. ^. @ Eo @@@ v. @. E¶ moøø O \ | / \ mm0ouo ~ mo.n + z.4» \ | / M HowO | z zlwmø wL |: | 1mzoomo = zmo1z 2- nu Qvnm _ I oo «^ -v @ å. Mm saga .ooma fl fmæonmøv .mas m N moow Q mmw HJÛQ aw; z wmommo moøoo mo \» zm fi - .f 1 1_ f Amw mzoømo = zwo »Ã zlmmommu Qv1w vfß O o - # 5 ^ .mP ~ °« v HHHxx H fl wpma? 80820l + -? 59 - The 7- [D (-) - d- (4-methyl-2,3-dioxo-1-piperazinocarbonylanino) -phenylacetamido] -3-acetoxynethyl-A -cephem-4-carbonic acid with melt; file 1750 (decomposition) was recrystallized from aqueous acetane to give white crystals, m.p. 198 DEG-2000 DEG C. (decomposition).

Exemnel 5 (l) En lösning av 28,2 g natriumsalt av D(-)-fenylglycin i 150 ml vatten försattes med 200 ml etylacetat och l8,2 g trietylamin och den erhållna blandningen kvldes till 00. 34,3 g 4-metyl-2,3-dioxo-l-piperazinokarbonylklorid under 15 :inuter Denna blandning försattes med och blandningen omsattee 15 minuter via 5 _ 1o°. veeeenexirfes ev- skildes och inställdes på pH 0,5 genom tillsats av 2N saltsyra under iskylning för avsättning av kristaller. Dessa tillvaratogs genom filtrering och torkades för bildning av 42 g vita kristaller av D(-)- -a~(4-metyl-2,3-dioxo-l-piperazinokarbonylamino)-fenylättiksyra med ' smältpunkten l95° (sönderdelning).Example 5 (1) A solution of 28.2 g of sodium salt of D (-) - phenylglycine in 150 ml of water was added with 200 ml of ethyl acetate and 18.2 g of triethylamine and the resulting mixture was cooled to 00. 34.3 g of 4-methyl -2,3-dioxo-1-piperazinocarbonyl chloride for 15 minutes This mixture was added and the mixture was reacted for 15 minutes at 5 DEG-100 DEG. veeeenexirfes was evaporated and adjusted to pH 0.5 by the addition of 2N hydrochloric acid under ice-cooling to deposit crystals. These were collected by filtration and dried to give 42 g of white crystals of D (-) - -α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid, m.p. 195 ° (dec.).

In (ner) emf1= o C=Q 1700, 1660.In (ner) emf1 = o C = Q 1700, 1660.

Enn (dö-Dnso) 1'-värden: 0,1 (in, a), 2,65 (sn, s), 4,50 (in, e), 6,10 (an, be), 6,50 (2H, be), 7,o (3H, e). ' (2) En suspension i 15 ml vattenfri metylenklorid av 0,31 g D(-)- -a-(4-netyl~2,3-dioxo-l-piperazinokarbonylamino)-fenylättiksyra, erhållen enligt (1) ovan, försattes med 0,11 g N-metylmorfolin under omröring för bildning av en lösning, som därefter kyldes till -206.Enn (do-Dnso) 1 'values: 0.1 (in, a), 2.65 (sn, s), 4.50 (in, e), 6.10 (an, be), 6.50 (2H, be), 7.0 (3H, e). (2) A suspension in 15 ml of anhydrous methylene chloride of 0.31 g of D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid, obtained according to (1) above, was added with 0.11 g of N-methylmorpholine with stirring to give a solution, which was then cooled to -206.

Denna lösning försattes med 3 ml vattenfri metylenkloridlösning, inne- hållande 0,l3 g etylklorkarbonat och den bildade blandningen omsattes 60 minuter mellan -10 och 200 för bildning av en blandad syraanhydrid.This solution was added with 3 ml of anhydrous methylene chloride solution containing 0.1 g of ethyl chlorocarbonate and the resulting mixture was reacted for 60 minutes between -10 and 200 to give a mixed acid anhydride.

I den bildade syraanhydriden nedfördes droppvis en lösning, erhållen genom tillsats av 0,50 ml trietylamin till en suspension i 5 ml metanol av 0,41 g 7-amino-3-[2-(5-metyl-l,3,4-tiadiazolyl -tiometyl]- -A3-cefem-4-karbonsyra. Efter tillsatsen omsattes den erhållna bland- ningen 30 minuter mellan -50 och -30°, 30 minuter mellan -30 och -20°, 60 minuter mellan -20 och 0° och 30 minuter vid rumstemperatur. Reak- tionsvätskan koncentrerades under reducerat tryck och koncentratet löstes i 10 ml vatten, tvättades med 5 ml etylacetat, försattes med lö ml etylacetat och inställdes på pH 1,5 genom tillsats av 23 salt- syra under iskylning. Olösliga substanser avskildes genom filtrering och etylacetatskiktet avskildes, tvättades successivt med vatten och mättad natriumkloridlösning, torkades över magnesiumsulfat och be- friades från lösningsmedlet genom destillation under reducerat tryck 7808204-7 60' för bildning av 0,58 g blekgula kristaller av 7-[3(-)-a-(4-:etyl- -_,3-dicxo-1-piperazinokarbonylamino)-fenylacetamido]-3-[2-(5-metyl- -1,3,4-tiadiazolyl)-tiometyl]-A3-cefem-4-karbonsyra med smältpu"¿ten 16c° (eönaeraeining), utbyte 91 få.In the acid anhydride formed, a solution obtained by adding 0.50 ml of triethylamine to a suspension in 5 ml of methanol of 0.41 g of 7-amino-3- [2- (5-methyl-1,3,4- thiadiazolyl-thiomethyl] -A3-cephem-4-carboxylic acid After the addition, the resulting mixture was reacted for 30 minutes between -50 and -30 °, 30 minutes between -30 and -20 °, 60 minutes between -20 and 0 ° and 30 minutes at room temperature The reaction liquid was concentrated under reduced pressure and the concentrate was dissolved in 10 ml of water, washed with 5 ml of ethyl acetate, added with 1 ml of ethyl acetate and adjusted to pH 1.5 by adding 23 hydrochloric acid under ice-cooling. substances were separated by filtration and the ethyl acetate layer was separated, washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate and freed from the solvent by distillation under reduced pressure 7808204-7 60 'to give 0.58 g of pale yellow crystals of 7- [3 ( -) - α- (4-: ethyl-, 1,3-dicxo-1-piperazinocarbo nylamino) -phenylacetamido] -3- [2- (5-methyl--1,3,4-thiadiazolyl) -thiomethyl] -A3-cephem-4-carboxylic acid with melting point 16c ° (ionic compound), yield 91 g .

Ia (ïær) C114: 0 6:9 1780 (lakfian), 1650 - 1720 (-oo:::, --^ooH).Ia (ïær) C114: 0 6: 9 1780 (lak fi an), 1650 - 1720 (-oo :::, - ^ ooH).

ILWLR (dš-DEIISO) f-värden: 0,2 (ll-I, d), 0,6 (ll-I, d), 2,60 ï, S), 4,35 (IH, q), 4,40 (ll-I, d), 5,0 (IH, ä), 5,70 (23, 2.), 5,10 i: b5)1 6125 "' 6155 (23: ZH: bs)s 7:0 (3H1 5): 7930 (3H9 5)- Nämnda försök upprepades, men med det undantaget att 3(-)-a- -(4-metyl-2,3-dioxo-l-piperazinokarbønylamino)-fenylättiksyran er- sattes av de föreningar med formeln (V) som anges i tabell XZIV för bildning av de däri angivna produkterna. Strukturen för dessa ekräftades med IR och NW . 7808204-7 61 u w.ww ofimfiæ .oowva ^.@Eoovov .;.5 S090 RAW \|/ « J F u wwmo \z 1 \ zmïæw U :mo mzooooošáoofzvkoïfl :oo A N13 ...oo o o O 175 _ v fil/ v. . u. .U .n *WOOCIJIHQJUÅQ Zl TU .EU v :SO i O O m få oÉÄ .ooïå Tosoooov .oé mooo o @ \ w u šo m šo -Wi Ä loqlflno. m mzoomomzoolzlzfwmoNmonmo , oïo 175 mooomoæzoolz zkmo mo. mo o o R ä. 33.» óoofi foeoowov .oé mooo o @ W W DV m» mo . \ A læà. wvsvwlmzoomošonïzïvW/MT Nmošo o o -TE í fil) V \\ WOOUIUEZOOIWQ gglårovmu OïO |ß1VQ wfvflßwohm ^>v dfimëhou ømä wflflfiwnmm ÅWHNN flamâma ._ __- .......f-........__...-__..__..__......._,-~,._.. _ _ .ILWLR (dš-DEIISO) f-values: 0.2 (11-I, d), 0.6 (11-I, d), 2.60 ï, S), 4.35 (1H, q), 4 40 (11-I, d), 5.0 (1H, ä), 5.70 (23, 2.), 5.10 i: b5) 1 6125 "'6155 (23: ZH: bs) s 7 : 0 (3H1 5): 7930 (3H9 5) - Said experiment was repeated, but with the exception that 3 (-) - α- - (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid was replaced of the compounds of formula (V) listed in Table XZIV to give the products listed therein, the structure of which was confirmed by IR and NW. 7808204-7 61 u w.ww o fi m fi æ .oowva ^. @ Eoovov.;. 5 S090 RAW \ | / «JF u wwmo \ z 1 \ zmïæw U: mo mzooooošáoofzvkoï fl: oo A N13 ... oo oo O 175 _ v fi l / v.. U. .U .n * WOOCIJIHQJUÅQ Zl TU .EU v: SO i OO m få oÉÄ .ooïå Tosoooov .oé mooo o @ \ wu šo m šo -Wi Ä loql fl no. m mzoomomzoolzlzfwmoNmonmo, oïo 175 mooomoæzoolz zkmo mo. mo oo R ä. 33. » óoo fi foeoowov .oé mooo o @ WW DV m »mo. \ A læà. wvsvwlmzoomošonïzïvW / MT Nmošo oo -TE í fi l) V \\ WOOUIUEZOOIWQ gglårovmu OïO | ß1VQ wfv fl ßwohm ^> wm >m n>. ..... f -........__...-__..__..__......._, - ~, ._ .. _ _.

'I80820h-7 62 nu mm fiwï .UOSH fmsoumuv .nä nl moov o . @ ¶ 1 u d \ šv . /aQšQÄfzM \J :mig w mzoozv=zoo|zïz.@ . o Q :TE © møovmfd _ ïl/ \| _2032 z O Q o .A15 Awmvhowflv >HNN Hfimnfaæ __, .....--_.._.__:...._...__._... __. _ . 7808204 - 7 63 Exemuel 5 Hed användning av 0,3 g D(-)-a-(4-metyl-2,3-dioxo-l-piperazino- karbonylamino)-fenylättiksyra och 0,33 g 7-amino-3-[5-(1-metyl-l,2,3,4- ~tetrazolyl)-tiometyl]-A3-cefem-4-karbonsyra upprepades försöket enligt exempel 5 för bildning av 0,5 g 7-[D(-)-a-(Å-metyl-2,3-dí0x0- -l-piperazinokarbonylamino)-fenylacetamido]-3-[E-(1-metyl-1,2,3,4- -tetrazolyl)-tiometyl]-A3-cefem~4-karbonsyra med smältpunkten 161 - 163° (sönesrasining), utbyte 76 9%.'I80820h-7 62 nu mm fi wï .UOSH fmsoumuv .nä nl moov o. @ ¶ 1 u d \ šv. / aQšQÄfzM \ J: mig w mzoozv = zoo | zïz. @. o Q: TE © møovmfd _ ïl / \ | _2032 z O Q o .A15 Awmvhow fl v> HNN H fi mnfaæ __, ..... - _.._.__: ...._...__._... __. _. 7808204 - 7 63 Exemuel 5 Hed use of 0.3 g D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid and 0.33 g 7-amino-3- [5- (1-Methyl-1,2,3,4-tetrazolyl) -thiomethyl] -A3-cephem-4-carboxylic acid The experiment of Example 5 was repeated to give 0.5 g of 7- [D (-) - α- (α-methyl-2,3-dioxo- -1-piperazinocarbonylamino) -phenylacetamido] -3- [E- (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl] -A3-cephem ~ 4-Carboxylic acid with melting point 161 - 163 ° (sonar rasining), yield 76 9%.

Ia (nujsl) exil; q 0:0 1775 (lastas), 1720 - -COOH). W EEE? (de-DPIXSO) f-värden: 0,02 (IH, d), 0,34 (lH, d), 2,48 (an, s), 4,17 (in, q), 4,26 (m, a),s4,92 (in, a), 5,66 (an, s), 6,o1(5H, s), 6,35 (4H, s), 7,ø (3H, s).Ia (nujsl) exile; q 0: 0 1775 (lastas), 1720 - -COOH). W EEE? (de-DPIXSO) f values: 0.02 (1H, d), 0.34 (1H, d), 2.48 (an, s), 4.17 (in, q), 4.26 (m , a), s 4.92 (in, a), 5.66 (an, s), 6.01 (5H, s), 6.35 (4H, s), 7.10 (3H, s).

Nämnda försök upprepades, men med det undantaget att D(-)-a- -( 4-metyl-2 , S-dioxo-l-piperaz inokarbonylamino ) -f enyläït iksyran er- sattes av de föreningar med formeln (V) som anges i tabell XXV för St 1660 (-coN< , bildning av de däri angivna produkterna. bekräftades med IR och NHR. *kturen för dessa n 7808204-7 64 m ammäæxo awfiaflo fiozseoš Ana Qoaämen A ua::æ>:s øflaoflxzoflæåcë flnu:o@»fl> x Ü ®.<> zfvwä .ocrcfi ^.zEcc:1v .;.E w=w :egg A z 2,: 31:, .¶______,_..|_~_.o F; , _. r «,/ I _ .|\ .| , ælz rm? -:zo,.=..:=,_c.v __cc,._ï:zo,.. zíå O O O O 175 -TE m R wo øamfiæ .oomwfi ^.mEøoæuv .m.e So _ _ 7 L» å. zooo oí © Éo mk 35 m :|c.mo \\§ à vl/ M _ »Iz \ z:lz m mzoomomzoo|ßY¿z| mo moocmomzoolz znwmo O , vlæ o fTš O I Û x 93 33.» _0005 ^¿=_o0@3_¿._= _ * få ¶ L” »vmwöoo o »mo G9 mä, Z x< .4A+z _ \ W n m|¿%. ø»m@@|:zoo:o:zoø1Å%L%|w:om:u mooozuzzoonzf mnfmoßmo o o A v al: h E | I. 2. I. | Fzßdoam ^>v øfiwähom øwä mnfiflmnmm .>xx Hawnøa 7808204-7 65 Exembel 7.Said experiment was repeated, but with the exception that D (-) - α- - (4-methyl-2,5-dioxo-1-piperazine inocarbonylamino) -phenylate acid was replaced by the compounds of formula (V) indicated in Table XXV for St 1660 (-coN <, formation of the products specified therein. was confirmed by IR and NHR. * kturen for these n 7808204-7 64 m ammäæxo aw fi a fl o fi ozseoš Ana Qoaämen A ua :: æ>: s ø fl ao fl xzo fl nu: o @ »fl> x Ü ®. <> zfvwä .ocrc fi ^ .zEcc: 1v.;. E w = w: egg A z 2 ,: 31 :, .¶ ______, _ .. | _ ~ _.o F ;, _. r «, / I _. | \. |, ælz rm? -: zo,. = ..: =, _ c.v __cc, ._ ï: zo, .. zíå OOOO 175 -TE m R wo øam fi æ .oomw fi ^ .mEøoæuv .me So _ _ 7 L »å. zooo oí © Éo mk 35 m: | c.mo \\ § à vl / M _» Iz \ z: lz m mzoomomzoo | ßY¿z | mo moocmomzoolz znwmo O, vlæ o fTš OI Û x 93 33. »_0005 ^¿=_o0@3_¿._= _ * få ¶ L” »vmwöoo o» mo G9 mä, Z x <.4A + z _ \ W nm | ¿%. Ø »m @@ |: zoo: o: zoø1Å% L% | w: om: u mooozuzzoonzf mnfmoßmo oo A v al: h E | I. 2. I. | Fzßdoam ^> v ø fi wähom øwä mn fifl mnmm. > xx Hawnøa 7808204-7 65 Example 7.

Hed användning av 0,30 g D(-)-a-(4~metyl-2,3-dioxo-l-piperazinc- karbonylamino)-fenylättiksyra och 0,34 g 7-amino~3-[5-(l,3,4-tiadi:- zolyl)~tiometyl]-A3-cefem-4-karbonsyra upprepades försöket enligt exempel 5 för bildning av 0,47 g 7-[D(-)-a-(4-mety1~2,3-dioxo-l- -piperazinokarbonylamino)-fenylacetamido]-3-[5-(l,3,4-tiadíazolyl - ~tiometyl]-A3~eefem-4-karbonsyra med smältpunkten 158 - 1590 (sönder- delning), utbyte 71,5 %.Use 0.30 g of D (-) - α- (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) -phenylacetic acid and 0.34 g of 7-amino-3- [5- (1, 3,4-thiadi: -zolyl) -thiomethyl] -A3-cephem-4-carboxylic acid The experiment of Example 5 was repeated to give 0.47 g of 7- [D (-) - α- (4-methyl-2,3,3 -dioxo-1- -piperazinocarbonylamino) -phenylacetamido] -3- [5- (1,3,4-thiadiazolyl-thiomethyl] -A3-ephem-4-carboxylic acid, m.p. 158-1590 (dec.), yield 71 , 5%.

IR (nnjol) cm"l: Q -coon).IR (nnjol) cm -1 (Q -coon).

Nämnda försök upprepades, men med det undantaget att D(-)-a- 0:0 1775 (iaxtam), 1720 - 1660 (-coN<1, -(4-metyl-2,3-dioxo-1-piperazinokarbonylamino)-fenylättiksyran er- sattes av D(~)-d-(4-etyl-2,3-dioxo-1-piperazinokarbonylamino)-fenyl- ättiksyra för bildning av 7-[D(-)-a-(4-etyl-2,3-dioxo-l-piperazino- karbonylamino)-fenylacetamido]-3-[5-(1,3,4-tiadiazolyl)-tiometyl]- -53-cefem-4-karbonsyra med smältpunkten 1230 (sönderdelning), utbyte 64,5 %.Said experiment was repeated, but with the exception that D (-) - α- 0: 0 1775 (iaxtham), 1720 - 1660 (-coN <1, - (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) - the phenylacetic acid was replaced by D (~) -d- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenyl-acetic acid to give 7- [D (-) - α- (4-ethyl-2 , 3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3- [5- (1,3,4-thiadiazolyl) -thiomethyl] -53-cephem-4-carboxylic acid, m.p. 1230 (dec.), Yield 64 , 5%.

Exemnel 8.Example 8.

Med användning av 0,31 g D(-)~d-(4-metyl-2,3-dioxo-l-pipera- zinokarbonylamino)-fenylättiksyra och 0,39 g 7-aminQ-3-[2-(l-metyl- -1,3,4-triazolyl)-tiometyl]-A3-cefem-4-karbonsyra upprepades försöket enligt exempel 5, men med det undantaget att metanolen ersattes av vattenfri metylenklcrid, för framställning av 0,43 g 7~[D(-)-a-(4- -metyl-2,3-dioxo-1-piperazinokarbonylamino)-fenylaeetamido]-3-[2-(1- -metyl-1,3,4-triazolyl)-tiometyl]-A3-cefem-4-karbonsyra, utbyte 70 %.Using 0.31 g of D (-) - d- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid and 0.39 g of 7-aminoQ-3- [2- (1- methyl-1,3,3-triazolyl) -thiomethyl] -A3-cephem-4-carboxylic acid The experiment of Example 5 was repeated, but with the exception that the methanol was replaced by anhydrous methylene chloride, to give 0.43 g of 7 ~ [D (-) - α- (4-Methyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylaethamido] -3- [2- (1-methyl-1,3,4-triazolyl) -thiomethyl] -A3 -cephem-4-carbonic acid, yield 70%.

In (nujoi) cm'1= v C=0 1780 (iakzam), 1720 - 1650 (-coN=:, -COOH).In (nujoi) cm -1 = v C = 0 1780 (iakzam), 1720 - 1650 (-coN = :, -COOH).

Nämnda försök upprepades, men med det undantaget att D(-)-a- -(4-metyl-2,3-dioxo-l-piperazinokarbonylamino)-fenylättiksyran er- sattes av de föreningar med formeln (V) som anges i tabell XXVI för bildning av de däri angivna produkterna. Strukturen för dessa bekräf- tades med IR och NMR. 7808204-7 66 mtš 33» .oowma foaooooo .oá få z mooo o @ o o~mo|__/\fz \ o offilw. wpmoooomomzooxmnz @1 mooomowooooå o O.Said experiment was repeated, but with the exception that D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid was replaced by the compounds of formula (V) given in Table XXVI for the formation of the products specified therein. The structure of these was confirmed by IR and NMR. 7808204-7 66 mtš 33 ».oowma foaooooo .oá få z mooo o @ o o ~ mo | __ / \ fz \ o of fi lw. wpmoooomomzooxmnz @ 1 mooomowooooå o O.

. Qío .A15 o ITS m x móo 33» .ooïà Tošëooo .oé mo v» mooo o 1 awmoÄfzš o_H_\|__ ß n. :zoomëzooå wïfioooooo ._ oÄo 175 EOOUIOSZOOIZ »T m0 _ Q. o lxÉ Puflbø Ohm CC flflwënoæ .æmë wflwnoæmm 7808-204 - 7 67 Exempel 9 Försöket enligt exempel 5 upprepades, men med det undantaget att D(-)-M4(4-metyl-2,3-dioxo-1-piperazinokarbonylamino)-fenyl- ättiksyran ersattes av de föreningar med formeln (V) som anges i tabell XXVII för bildning av de däri angivna produkterna. Struk- turen för dessa bekräftades med IR och NMR; 78082011-7 68 .m w M mooo a\o @ iof; f__1wflooo-ñ\fogi_fi f W» v. @ zlz f =zoo=oo=,_oo-zYLz!A=o :ooomošooåUT»mo o o :TE »TS mao .m mwmmfizAo O. , Ü .flíä w äoomomzoolhñznwowmooo mooomo=zoo|z\mLJz|NowM=o . o o< o :TE :TE mooo @ . o . wo .w w ëo wmmoÅz 1/ O . \ æfil/É mouw mzoomoæzoolzïzàoomooo ooooomooozonïoooloo35 o Q o :TE lTš Ésoobw ^>v Cfloëaow øuë mnfizoswh .HH>Nx fiaoßdä 780820114 69 W mooo m O @ ö \mo.= ä w mvlmwzmgw »:, .\ , \|, \ z11= "w_ .1:z@@=v=z@u|zr¿ |ß=u ==@v=@==Q@|;,1m- :Q o Q |^|vQ |^-,@ moou mwu www _ O m mmu.fl 4 z«|= _ w 1||,:=ovmomzoU|ß z»o@æz@@ :U mooomøzzou-zvfmloomzooflmo 0 0 |^|vn |^|vQ :ocg ._ w n. Q \ _, o , .I . \|I/ J. .Wl/ 1 .. Qío .A15 o ITS mx móo 33 ».ooïà Tošëooo .oé mo v» mooo o 1 awmoÄfzš o_H_ \ | __ ß n.: Zoomëzooå wï fi oooooo ._ oÄo 175 EOOUIOSZOOIZ »T m0 _ Q. o lxÉ Pu ë wm n. Example 9808-204 - 7 67 Example 9 The experiment of Example 5 was repeated, but with the exception that D (-) - M4 (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -phenyl-acetic acid was replaced by the compounds with formula (V) given in Table XXVII to give the products listed therein. The structure of these was confirmed by IR and NMR; 78082011-7 68 .m w M mooo a \ o @ iof; f__1w fl ooo-ñ \ fogi_ fi f W »v. @ zlz f = zoo = oo =, _ oo-zYLz! A = o: ooomošooåUT» mo oo: TE »TS mao .m mwmm fi zAo O., Ü .fl íä w äoomomzoolhñznwowmooo. | z \ mLJz | NowM = o. o o <o: TE: TE mooo @. o. wo .w w ëo wmmoÅz 1 / O. \ æ fi l / É mouw mzoomoæzoolzïzàoomooo ooooomooozonïoooloo35 o Q o: TE lTš Ésoobw ^> v C fl oogaow øuë mn fi zoswh .HH> Nx fi aoßdä 780820114 69 W mooo m O @ öv \ mo.,. z11 = "w_ .1: z @@ = v = z @ u | zr¿ | ß = u == @ v = @ == Q @ |;, 1m-: Q o Q | ^ | vQ | ^ -, @ moou mwu www _ O m mmu. fl 4 z «| = _ w 1 ||,: = ovmomzoU | ß z» o @ æz @@: U mooomøzzou-zvfmloomzoo fl mo 0 0 | ^ | vn | ^ | vQ: ocg ._ w n. Q \ _, o, .I. \ | I / J. .Wl / 1.

|= = N N _ .\, r \ m2o@=@mzo@«= Z- m@~=@ m@@@m@:=@@|z zxhmßfimu Z L m mwu mYL »^|V= -TE ^.w@~o«v HH>xw fifiwnwa '7808204-7 70 oooo o J o.) moo w wwmo mälw r o 73 o lå å! A l l I fl J I lf! www _ zfz wïmzoomozzoo z oo .oo mooomomooo zvwn; o.. :o o o o o o_ |^|vQ ufinvm mooo o o n w N o © o o .-=o.__\ fi.. .äTWfzMm l o o , w» zlz o mzoomomzo o- å .oooomomooo o -ofzm o o o o -TE A15 mooo o moo w owmoÅfz @ mfllflm wLNm. mzoooooozoolzrxzlowoowmo o :TVn @ W) 1 n EOOOEOEZOOIZ z|omorZo _ O -TS ^.wPHomv HH>MN Hfioßma 7808204-7 Exernnel 10 .| = = NN _. \, R \ m2o @ = @ mzo @ «= Z- m @ ~ = @ m @@@ m @: = @@ | z zxhmß fi mu ZL m mwu mYL» ^ | V = -TE ^ .w @ ~ o «v HH> xw fifi wnwa '7808204-7 70 oooo o J o.) moo w wwmo mälw ro 73 o lå å! A l l I fl J I lf! www _ zfz wïmzoomozzoo z oo .oo mooomomooo zvwn; o ..: ooooo o_ | ^ | vQ u fi nvm mooo oonw N o © oo .- = o .__ \ fi .. .äTWfzMm loo, w »zlz o mzoomomzo o- å .oooomomooo o -ofzm oooo -TE A15 mooo o moo w owmoÅfz @ m fl l fl m wLNm. mzoooooozoolzrxzlowoowmo o: TVn @ W) 1 n EOOOEOEZOOIZ z | omorZo _ O -TS ^ .wPHomv HH> MN H fi oßma 7808204-7 Exernnel 10.

Försöket enligt erempel 6 upprepades, men med det undantaget att D(-)~a-(4-metyl-2,3-dioxo~l~piperazinokarbonylamino)-fenylättik- syran ersatües av de föreningar med formeln (V) som anges i tabell XXVIII för bildning av de däri angivna produkterna. dessa bekräfïades med IR och NHR.The experiment of Example 6 was repeated, but with the exception that D (-) - α- (4-methyl-2,3-dioxol-1-piperazinocarbonylamino) -phenylacetic acid is replaced by the compounds of formula (V) given in Table XXVIII for the formation of the products specified therein. these were confirmed by IR and NHR.

Strukturen för _ __ .._........_.,-._._,, ...._..l.....__.._..._ _..«f- i -- - .-.v......- 'I80820lv7 72 36 _ :ooo 1 K ZLJ, afro. vi..- \o s., ._ _. / . .flslz finxåf. __zoc:c:_,5o|_,~.fo2|...:u :ZPšflšvzfozz... __,_.:,.:s o c :TE :Aim »mo . zäføwmßooäwz o @ m; , .c ,|\ . \|/ ,1\ \ ælk. KR mzoomomzoofz zhomnmo mooomoE__oo|z\/z|wom«mo ï o o åxå älva m o m» mooo o @ ÜOJ z\ mmmofixfz .v \ _. |/_,_1 »R Eöomošoolzwßzloommo .oooooooomzoolzJTooåo .Z .Z . m V||\ Vik _ o o :TE ITE fimäwohfi CC cfluëhow dä: wflflfimnwm .HHHÉOÜ .fiflmnma 7808204-7 “zu :saw . ___. , _ ___. Ö z _+;f=:._ 2. ._ \i/ _ w«»= rm =zoU=@==cO1z«|w| :U o 175 3 _ _\ \ f K ICC Cïcšïpclmrxßinmc .O |^|.@ \ .The structure of _ __ .._........_., -._._ ,, ...._ .. l .....__.._..._ _ .. « f- i - - .-. v ......- 'I80820lv7 72 36 _: ooo 1 K ZLJ, afro. vi ..- \ o s., ._ _. /. .fl slz fi nxåf. __zoc: c: _, 5o | _, ~ .fo2 | ...: u: ZPš fl švzfozz ... __, _.:,.: s o c: TE: Aim »mo. zäføwmßooäwz o @ m; , .c, | \. \ | /, 1 \ \ ælk. KR mzoomomzoofz zhomnmo mooomoE__oo | z \ / z | wom «mo ï o o åxå älva m o m» mooo o @ ÜOJ z \ mmmo fi xfz .v \ _. | / _, _ 1 »R Eöomošoolzwßzloommo .oooooooomzoolzJTooåo .Z .Z. m V || \ Vik _ o o: TE ITE fi mäwoh fi CC c fl uëhow dä: w flflfi mnwm .HHHÉOÜ .fifl mnma 7808204-7 “zu: saw. ___. , _ ___. Ö z _ +; f =: ._ 2. ._ \ i / _ w «» = rm = zoU = @ == cO1z «| w | : U o 175 3 _ _ \ \ f K ICC Cïcšïpclmrxßinmc .O | ^ |. @ \.

Hsu _ :com ..=äw~E_\»zew% mmm. w. _ \r» :za @ I LI- .me v:u=zov-z f|ou=2o@«:u =::;=w:z:u|=\-ø|c@=z:v :_ 2 G VIK VIK o o |^|vn |^|.@ mmo mooø L» q \f o O O. g #@¿$.\z wß J « 4 #1 1 = =|.z .fi1_ =zouma=z@@|z z|«:@>:@ =oo@:u=:ou»= =|_:@~m@ .U O \ -Alva «^|_m flimvhoäv HHHÉCm .mmondfi 7808204-7 74" mao ~æ EOOO O _) 19 (o b zlz w I mzoomomzo o|zvLzfoom=o mooomowozoo oåwJTooNmH.. . o. ovt .IA .l l I. v Q _\ oåonnoo mooo o z.\ wwmowzmflw _ lo © o w 1%. o mzoomomzoolzlš mooomošooJbïhE o io 1 ^ 1 v o A | v o m mg mooo o ä /äommowfi @ .o @ ælz o mzoomomzonïzflzkooomfioo moooofioo=éoo|ofimg|3595 åio -TE fmvfiowv HHHÉUfi Hfimndå. 780820h-7 75 Exemnel 11. (1) En suspensicn av 0,9 g D(-)-a-alanin i 15 ml vatten försattes med 2,05 g trietylazin för upplösning av D(-)-a-alanin i vatten och den bildade lösningen kyldes till OO. Lösningen försattes med 2,3 g 4-metyl-2,3-dioxo-l~piperazinokarbonylklorid under 15 minuter, var- efter omsättning utfördes under 30 minuters iskylning. Utspädd salt- syra sattes till reaktionsprodukten för inställning av pH på 2,0.Hsu _: com .. = äw ~ E _ \ »zew% mmm. w. _ \ r »: za @ I LI- .me v: u = zov-z f | ou = 2o @«: u = ::; = w: z: u | = \ - ø | c @ = z : v: _ 2 G VIK VIK oo | ^ | vn | ^ |. @ mmo mooø L »q \ fo O O. g # @ ¿$. \ z wß J« 4 # 1 1 = = | .z .fi1_ = zouma = z @@ | zz | «: @>: @ = oo @: u =: ou» = = | _: @ ~ m @ .UO \ -Alva «^ | _m fl imvhoäv HHHÉCm .mmond fi 7808204-7 74 "mao ~ æ EOOO O _) 19 (ob zlz w I mzoomomzo o | zvLzfoom = o mooomowozoo oåwJTooNmH ... o. ovt .IA .ll I. v Q _ \ oåonnoo mooo o z. \ wwmowzm fl w _ lo © ow 1 %. o mzoomomzoolzlš mooomošooJbïhE o io 1 ^ 1 vo A | vom mg mooo o ä / äommow fi @ .o @ ælz o mzoomomzonïz fl zkooom fi oo moooo fi oo = éoo | o fi mg | 3595 åio -TE fmv fiem H 20 H8 fi ow HH. ) A suspension of 0.9 g of D (-) - α-alanine in 15 ml of water was added with 2.05 g of triethylazine to dissolve D (-) - α-alanine in water and the resulting solution was cooled to 0 DEG C. The solution was added with 2.3 g of 4-methyl-2,3-dioxo-1-piperazinocarbonyl chloride for 15 minutes, after which reaction was carried out under ice-cooling for 30 minutes. Dilute hydrochloric acid was added to the reaction product for adjustment of v pH of 2.0.

Vattnet avlägsnades genom destillation under reducerat tryck och 30 ml aceton sattes till blandninven varefte olösliva substanser avfilt- :z I b i rerades. Den erhållna acetonlösningen försattes med 10 ml aceton- lösning och 1,6 g natriumsalt av 2-etylhexansyra och de avsatta kris- tallerna tillvaratogs genom filtrering och torkades för bildning av 2,1 g natriumsalt av D(-)-a-(4-metyl-2,3-dioxo-1-piperazinokarbonyl- amino)-propionsyra med smältpunkten 115 - ll8° (sönderdelning), utbyte 78,5 %.The water was removed by distillation under reduced pressure, and 30 ml of acetone was added to the mixture, after which insoluble substances were filtered off. The resulting acetone solution was added with 10 ml of acetone solution and 1.6 g of sodium salt of 2-ethylhexanoic acid, and the deposited crystals were collected by filtration and dried to give 2.1 g of sodium salt of D (-) - α- (4- methyl 2,3-dioxo-1-piperazinocarbonylamino) -propionic acid, m.p. 115 DEG-188 DEG C. (decomposition), yield 78.5%.

IR (mr) and; 0 0:0 1700, 1660, 1600 (-c011<, _0009). (2) Försöket enligt exempel 8 upprepades för framställning av 7-[D(-)-a-(4-metyl-2,3-di0x0~l-piperazinokarbonylaminc)-pr0pionamid0]- -3-acetoximetyl-A -cefem~4-karbonsï-a ur natriumsaltet av D(-)-a- -(4~mety1-2,3-dioxo-1-piperazinokarbonylamino)-propionsyra och 7-amino- -3-acetoximetyl-A3-cefem-4-karbonsyra. Den erhållna produkten löstes i 20 ml aceton och en lösning av 0,65 g natriumsalt av 2-etylhexan- syra i 5 ml aceton sattes till den erhållna lösningen. De avsatta kristallerna tillvaratogs genom filtrering och torkades för bildning av 1,2 g natriumsalt av 7-[D(-)-a-(4-metyl-2,3-diox0-l-piperazin0- karbonylamino)-propionamido]-3-acetcximetyl-A -cefem-4-karbonsyra med smaitpunkeen 195° (sönaeraeining), utbyte 67,7 74.IR (mr) and; 0 0: 0 1700, 1660, 1600 (-c011 <, _0009). (2) The experiment of Example 8 was repeated to prepare 7- [D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamine) -propionamide] -3-acetoxymethyl-A -cephem-4 -carbonyl-α from the sodium salt of D (-) - α- - (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -propionic acid and 7-amino--3-acetoxymethyl-33-cephem-4-carboxylic acid. The resulting product was dissolved in 20 ml of acetone and a solution of 0.65 g of sodium salt of 2-ethylhexanoic acid in 5 ml of acetone was added to the resulting solution. The deposited crystals were collected by filtration and dried to give 1.2 g of sodium salt of 7- [D (-) - α- (4-methyl-2,3-dioxo-1-piperazino-carbonylamino) -propionamido] -3- acetimethyl-A -cephem-4-carboxylic acid with melting point 195 ° (sonar unit), yield 67.7 74.

IR (icar) crfï: o 0:0 1780 (innan), 1710 - 1660 (-c011:), 1600 (4009).IR (icar) crf1: 0: 0 1780 (inside), 1710 - 1660 (-c011 :), 1600 (4009).

Exemnel 12. _ Försöket enligt exempel 8 upprepades för bildning av ?-[D(-)- -d-(4-metyl-2,3-dioxo-1-piperazinokarbonylamino)~p-hydr0xifenylacet- amido]-3~[5-(1-metyl-1,2,3,4~tetrazoly1)-tiometyl]-¿3-eefem-4-karb0n- syra ur 7-amino-3-[5-(1-metyl-1,2,3,4-tetrazolyl)-ti0metyl]-A3-cefem- -4~karb0nsyra och D(-)-a-(4-metyl-2,3-dioxo-l-piperazinokarbonyl- amino)-p-hydroxifenylättiksyra. smznæpunkt (sanaeraeining) 147 - 149°, utbyte 62,0 7,.Example 12. The experiment of Example 8 was repeated to give? - [D (-) - -d- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido] -3- [5 - (1-Methyl-1,2,3,4-tetrazolyl) -thiomethyl] -β-ephem-4-carboxylic acid from 7-amino-3- [5- (1-methyl-1,2,3 , 4-tetrazolyl) -thymethyl] -A3-cephem-4-carboxylic acid and D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetic acid. melting point (sanaeraeining) 147 - 149 °, yield 62.0 7 ,.

IR (rar) 6m'1= 0 C=0 1766 <1aetam>, 1720 - 1660 <-c0N -COOH). 780820lv7 76' Pâ samma sätt erhölls 7-[D(-)-a-(4-etyl-2,3-diox0-l-piperazino- kar-0nylamino)-p-hydroxifenylacetamido]-3-[5-(1-metyl-l,2,3,¿-tetra- solyl)-tiometyl]-A3-cefem-4-karbonsyra med smältpunkten l88 - l90° (sönåerdelning), utbyte 80,7 %, ur 7-amino-3-[5-(l-metyl-l,2,3,4- -tetrazolyl)-tiometyl]-A3-cefem-4-karbonsyra och D(-)-a-(4-etyl-2,3- Jdicxo-l-piperazinokarbonylamino)-p-hydroxifenylättiksyra.IR (rar) 6m '1 = 0 C = 0 1766 <1aetam>, 1720 - 1660 (-CON -COOH). 780820lv7 76 'In a similar manner, 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarc-phenylamino) -p-hydroxyphenylacetamido] -3- [5- (1- methyl 1,2,3,3-tetrasolyl) -thiomethyl] -A3-cephem-4-carboxylic acid, m.p. 188 DEG-190 DEG (solar division), yield 80.7%, from 7-amino-3- [5 - (1-methyl-1,2,3,4--tetrazolyl) -thiomethyl] -A3-cephem-4-carboxylic acid and D (-) - α- (4-ethyl-2,3-β-dioxo-1-piperazinocarbonylamino ) -p-hydroxyphenylacetic acid.

Exemnel 13 Försöket enligt exempel 5 upprepades för framställning av 7-[D(-)-a-(4-metyl-2,3-dicxo-l-piperazinokarbonylamino)-fenylacet- amidc]-3-azidometyl-A3-oefem-4-karbonsyra ur D(-)-a-(4-metyl-2,3- -dicxo-l~piperazinokarbonylamino)-fenylättiksyra och 7-anino-3- -azidometyl~A3-cefemf4~karbonsyra. smärfipumr: (sanaeraelning) 185 - 188°, utbyte 68,0 t Ia (nar) Curl; 0 w, 1775 (lakt-m), 1720 - 1660 (-c0::<, 2090.Example 13 The experiment of Example 5 was repeated to prepare 7- [D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamide] -3-azidomethyl-A3-ophem-4 -carboxylic acid from D (-) - α- (4-methyl-2,3--dioxo-1-piperazinocarbonylamino) -phenylacetic acid and 7-anino-3-azidomethyl-33-cephem-4-carboxylic acid. smär fi pumr: (sanaeraelning) 185 - 188 °, yield 68.0 t Ia (nar) Curl; 0 w, 1775 (lakt-m), 1720 - 1660 (-c0 :: <, 2090.

-CCOH).-CCOH).

Q É3 Exennel 14. , I 10 ml fosforsyrabuffertlösning med pH 6,3 suspenderaies 0,57 g 7-[D(-)-a-(4-etyl-2,3-dioxo-1-piperazinokarbonylamino)-íenyl- acetamido]-3-acetoximetyl-A -cefem-4-karbonsyra och 0,07 g natrium- vätekarbonat löstes däri. Lösningen försattes därefter med 0,12 g l-metyl-5-nerkapto-l,2,3,4-tetrazol för upplösning av denna däri och lösningen omsettes 24 timmar, medan pH upprätthölls vid 6,5 - 6,7 med användning av utspädd saltsyra och natriumvätekarbonat. Efter omsättningen kyldes reaktionsblandningen och inställdes på pi 5,0 genom tillsats av utspädd saltsyra. Reaktionsvätskan tvättades med en tillräcklig mängd etylacetat, varefter vattenskiktet avskildes och in tälldes på pH 1,5 genom tillsats av utspädd saltsyra. De avsatta kristallerna tillvaratogs genom filtrering och torkades, varef kristallerna tvättades med etylacetat för bildning av 0,40 g 7-[D(-)- -a-(4-etyl-2,3-dioxo-l-piperezinokarbonylamino)-fenylacetamido]-3- -[S-(l-metyl-1,2,3,4-tetrazolyl)-tiometyl]-A3-cefem-4-karbonsyra med smältpunkten 163 - 1650 (sönderdelníng), utbyte 74,5 %. m (zcsr) carl; 0 0:0 1775 (laktam), 1720 - 1660 (-co:::, _0003). :man (aö-Dnso) fr-varaern 0,18 (in, va), 0,55 (m, d), 2,64 (521, s), 4,3 (1H, q), 4,4 (m, a), 5,0(1H, d). 5,75 (an, s), 6,05 (5H, 5); 693 ' 618 (6H)| 8:92 (BH, t)- På samma sätt erhölls de i tabell XXIX angivna produkterna ur 7-[D(-)-a-(4-metyl-2,3-dioxo-l-piperazinokarbonyl)-fenylacetamido]- -3-acetoxinetyl-A -cefem-4-karbonsyra eller 7-[D(-)-a~(4-ety1-2,3- -dioxo-l-piperazincxarbonyl -cefem~4-karbcnsyra och de âäri. bekräftaâes med IR och NHR. 7808204-7 7 amino)-fenylacefamíäo]-3-aceïozimetyl-A* föreningar med fsrmeln (VIE) som anges Samtliga produkter var D(-)-isomerer och strukturen för dessa 78-08204-7 'vs a m.æs wfimfiz .uoomfl 1 mmfl ^.QEoovov .ß.E mooo 1 O nu flm/.wmomoåfz Ö zíz ro .\ .Il oåoomowozoïzï/ookmo z z I .o o u oi? ofiooš .ooomä Toeooooo .oá m mooo o @ 1 o mo o N m? »o šo í glo zoo/MZ _ ./ Älz oLHmzoomomzoo»zï ziwmo »mo vi , o o a. .om oÉï.. .oooS 1 wfi Tosooooo .oé \ m šo mo, mooo _ »ho _ o mo z/z z _ oNmoÅwrHm. w) 4_\ __ __! mzoomomzoolz zßmo :Iis 2 Z w QIO Puflš 09% ^HH>v flfiwëmom mmš mnflfløhmh .NHNN .mammas 7808-2044 79 K mm øfiwfih .voomfi I maa ^.aEoumuv .m.E \å,.fl J mo. \í/S 2 4fiæfi:o-m+mmQm \|, w_ « 1: a k 0 fmzooflomzøolz Z|«mc>2u Zitiz .IIZ c vïß O O R m.mß cfim«> .uomofl I nwa ^.msoowøv .m.E ¶ I \m øwmmoooz o mww mmfi\z/w 2 flfl. \ __ X f _ \a,|q =rf= 312 m *šçšëåçïz z.iv æwßv fi «.w> flflwfifi .ooomfi a mßfi ^.@s°@@uv .@.e m moøo o 0 flz#w§84Nß:fi w» M 21.2 w\.|1|:zo@=@:zo@|z 21 nu Qvxm I Emfi\Z/= zlilz ^.n@AoHv xfixx Hfimnfiæ ?80820lr'7 ao' u oáß odwï .ooowfl | EA foeoowoo .mä oïo o mooo . o o _ « |=|Yw~=oÅ+z|fl @ 7/ J .__ .lflfmmo »mo Iz F11!oåoomomzoofzïzåmošo . o o & m.mw vamfiæ .U wo | mm ^.aEoomvv..a.E \ mmoo o .ëo/ _ mooo o zå I: _. o o O D .á m=o&l ®o~_.=o-\_,z_N\_\ O w) a m A2 Ymo \ _ o f \ l__=o.o_=o__2oo|= _,T...=o i, O w ï Q o o o o a ßšo Swï .ooofl .. m3 fosoooov .o.e. :ooo o flfl/ _ ä. o/ 35 æoäooooxoocwzâ ou 3 a 2.; zlz .@< mzoomooozoofz »Tao o .moïnømnv MHxN .Sands 780820-4-7 81 a >.wo oHoH> .oowofi 1 oofi ^.oEooooo .o.e mOOU m2 O © \.\ Ur \.Z \||./ z SZOOEOEZOO|Z zlwmo QIO a m.o> oH@H> .oooofl 1 »od A oeoomov .o.e o o Q mooo o mmu zww wkmo \\z fimwfi umgw.mzoomomzoo|Åw@w|~moßmo o o w w o.ßo oHofi> .ooßmfl 1 omfi ^.osoo@ov .o.s . lm N mooo o mßy Q É vm,:Pfi¶z \ W» o [mo :Z m»mmm1:zoo:o:zoo|zv1z|.oo _ o ,o ^.wo»omo xHxx Hfioowo 'N0820lf-7 82 R oåmo .Äofin .moms | mßH fzsouowv :Ta :osv . f o Am~__“.-~\~HwJ1 «“>__~... \%.Q.-.q» ~wmwW_ zlz :n ,«mwJw.ß=@ z moon \o © ^wwvw~mo-m+z|A\ . \|, ~ z fixšfi __=a.a_s=_ou==v ,._,T...=.\. . o\ o _ xr) ._ ~ 21.12 fw r\:!:zcu=c=zou|z 2|f=v.=u :J o 0 x m.~> fifiwflä .uovmfi f mod ^.@so@@@v .@.s z & wo gaf» ßuo._._wfl L mwfl fmëoomvv :TE moon z o O _ H. vwåvwfzmm O 1 fl 2 k =zo0zUmzoo|z z1.=u _ m V14 mao o o 2 m@|^_<@: 2 wav ^.mP~o@v xHNx Hflmßfla 7808204-7 83 & H.m@ øfiwfiæ .uømæfl ^.@so@@øv .@.E O mooo Ziø __ O O ,fOmNm@4m+z mww z m5 :axx ma! Éoomumzøofvwßzlnmu _ o o w o|z mzw|w|Afl|; «m@ x @.«@ wfiwfifi .vømæfi ^.@soU»@v .@.E m EOOO o o mmo-m:»zlwwm=@,m+z mww »|/ « (k m Efløomomzovlvfiv» 21.5 o Aa Û = .\ =zw|o1af|m|«mu .R æx. øfiæf» .oowæfi a mæfi Ömsouwcv .mš zoom hzfmo \ z \» w mzoumomzoøfz z|wm@ xx øw o Mza: A.wp~o«v xfixx Hfiwnma 7808204-7 84 g m.«@ vfiwfifi .oomæfl | Hmfi ^.@so@@@V .@.e w moov Û N IJ _ \O @ .:@.=v@v=@=o=m»ziA\ \:/ « m =zo@=@=zo@|z 2» :U vam o ^.mPho%v NHNN Hfimßma m = J Q =zm|Uo^=o.:Q 7808201: -7 85 Exemnel 15 .QE3 Example 14, In 10 ml of pH 6.3 phosphoric acid buffer solution 0.57 g of 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -enyl] acetamido] are suspended. -3-Acetoxymethyl-A-cephem-4-carboxylic acid and 0.07 g of sodium bicarbonate were dissolved therein. The solution was then added with 0.12 g of 1-methyl-5-nerkapto-1,2,3,4-tetrazole to dissolve it therein and the solution was reacted for 24 hours while maintaining the pH at 6.5 - 6.7 using dilute hydrochloric acid and sodium bicarbonate. After the reaction, the reaction mixture was cooled and adjusted to pi 5.0 by adding dilute hydrochloric acid. The reaction liquid was washed with a sufficient amount of ethyl acetate, after which the aqueous layer was separated and adjusted to pH 1.5 by adding dilute hydrochloric acid. The deposited crystals were collected by filtration and dried, after which the crystals were washed with ethyl acetate to give 0.40 g of 7- [D (-) - -α- (4-ethyl-2,3-dioxo-1-piperezinocarbonylamino) -phenylacetamido]. -3- - [S- (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl] -A3-cephem-4-carboxylic acid, m.p. 163-1650 (dec.), Yield 74.5%. m (zcsr) carl; 0 0: 0 1775 (lactam), 1720 - 1660 (-co :::, _0003). : man (α-Dnso) fr product 0.18 (in, va), 0.55 (m, d), 2.64 (521, s), 4.3 (1H, q), 4.4 ( m, a), 5.0 (1H, d). 5.75 (an, s), 6.05 (5H, 5); 693 '618 (6H) | 8:92 (BH, t) - Similarly, the products listed in Table XXIX were obtained from 7- [D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonyl) -phenylacetamido] - - 3-Acetoxymethyl-α-cephem-4-carboxylic acid or 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinecarbonyl-cephem-4-carboxylic acid and those confirmed by IR and NHR. 7808204-7 7 amino) -phenylacaphamyl] -3-acetoisomethyl-A * compounds of the formula (VIE) indicated All products were D (-) isomers and the structure of these 78-08204-7 'vs a m. æs w fi m fi z .uoom fl 1 mm fl ^ .QEoovov .ß.E mooo 1 O nu fl m / .wmomoåfz Ö zíz ro. \ .Il oåoomowozoïzï / ookmo zz I .oou oi? o fi ooš .ooomä Toeooooo .oá m mooo o @ 1 o mo o N m? »O šo í glo zoo / MZ _ ./ Älz oLHmzoomomzoo» zï ziwmo »mo vi, oo a. .Om oÉï .. .oooS 1 w fi Tosooooo .oé \ m šo mo, mooo _» ho _ o mo z / zz _ oNmoÅwrHm. w) 4_ \ __ __! mzoomomzoolz zßmo: Iis 2 Z w QIO Pu fl š 09% ^ HH> v flfi wëmom mmš mn flfl øhmh .NHNN .mammas 7808-2044 79 K mm ø fi w fi h .voom fi I maa ^ .aEoumuv .m.E \ å ,. fl J mo. \ í / S 2 4fi æ fi: o-m + mmQm \ |, w_ «1: ak 0 fmzoo fl omzøolz Z |« mc> 2u Zitiz .IIZ c vïß OOR m.mß c fi m «> .uomo fl I nwa ^ .msoowøv .mE ¶ I \ m øwmmoooz o mww mm fi \ z / w 2 flfl. \ __ X f _ \ a, | q = rf = 312 m * šçšëåçïz z.iv æwßv fi «.w> flfl w fifi .ooom fi a mß fi ^. @ S ° @@ uv. @. Em moøo o 0 fl z # w§ 84Nß: fi w »M 21.2 w \. | 1 |: zo @ = @: zo @ | z 21 nu Qvxm I Em fi \ Z / = zlilz ^.n@AoHv x fi xx H fi mn fi æ? 80820lr'7 ao 'u oáß odwï. ooow fl | EA foeoowoo .mä oïo o mooo. o o _ «| = | Yw ~ = oÅ + z | fl @ 7 / J .__ .l fl fmmo» mo Iz F11! oåoomomzoofzïzåmošo. o o & m.mw vam fi æ .U wo | mm ^ .aEoomvv..a.E \ mmoo o .ëo / _ mooo o zå I: _. oo OD .á m = o & l ®o ~ _. = o - \ _, z_N \ _ \ O w) am A2 Ymo \ _ of \ l __ = o.o_ = o__2oo | = _, T ... = oi, O w ï Q ooooa ßšo Swï .ooo fl .. m3 fosoooov .oe : ooo o flfl / _ ä. o / 35 æoäooooxoocwzâ ou 3 a 2 .; zlz. @ <mzoomooozoofz »Tao o .moïnømnv MHxN .Sands 780820-4-7 81 a> .wo oHoH> .oowo fi 1 oo fi ^ .oEooooo .oe mOOU m2 O © \. \ Ur \ .Z \ || ./ z SZOOEOEZOO | Z zlwmo QIO a mo> oH @ H> .oooo fl 1 »od A oeoomov .oe oo Q mooo o mmu zww wkmo \\ z fi mw fi umgw.mzoomomzoo|Åw@w|~moßmo ooww o.ßo oHo fi>. ooßm fl 1 at fi ^.osoo@ov .os. lm N mooo o mßy Q É vm,: P fi¶ z \ W »o [mo: Z m» mmm1: zoo: o: zoo | zv1z | .oo _ o, o ^ .wo »omo xHxx H fi oowo 'N0820lf-7 82 R oåmo .Äo fi n .moms | mßH fzsouowv: Ta: etc. fo Am ~ __ “.- ~ \ ~ HwJ1« “> __ ~ ... \%. Q .-. q» ~ wmwW_ zlz: n, «mwJw.ß = @ z moon \ o © ^ wwvw ~ mo- m + z | A \. \ |, ~ z fi xš fi __ = a.a_s = _ou == v, ._, T ... =. \. . o \ o _ xr) ._ ~ 21.12 fw r \:!: zcu = c = zou | z 2 | f = v. = u: J o 0 x m. ~> fifi w fl ä .uovm fi f mod ^. @ so @ @@ v. @. sz & wo gaf »ßuo ._._ w fl L mw fl fmëoomvv: TE moon zo O _ H. vwåvwfzmm O 1 fl 2 k = zo0zUmzoo | z z1. = u _ m V14 mao oo 2 m @ | ^ _ <@: 2 wav ^.mP~o@v xHNx H fl mß fl a 7808204-7 83 & Hm @ ø fi w fi æ .uømæ fl ^. @ So @@øv. @. EO mooo Ziø __ OO, fOmNm @ 4m + z mww z m5 : axx ma! Éoomumzøofvwßzlnmu _ o o w o | z mzw | w | A fl |; «M @ x @.« @ W fi w fifi .vømæ fi ^. @ SoU »@v. @. E m EOOO oo mmo-m:» zlwwm = @, m + z mww »| /« (km E fl øomomzovlv fi v »21.5 o Aa Û =. \ = zw | o1af | m | «mu .R æx. ø fi æf» .oowæ fi a mæ fi Ömsouwcv .mš zoom hzfmo \ z \ »w mzoumomzoøfz z | wm @ xx øw o Mza: A.wp ~ o« v x fi xx H fi wnma 7808204-7 84 g m. «@ V fi w fifi .oomæ fl | Hm fi ^. @ So @@@ V. @. Ew moov Û N IJ _ \ O @.: @. = V @ v = @ = o = m» ziA \ \: / «m = zo @ = @ = zo @ | z 2»: U vam o ^ .mPho% v NHNN H fi mßma m = JQ = zm | Uo ^ = o.: Q 7808201: -7 85 Exemnel 15 .

I lO ml vatten suspenderades 1,15 g 7-[D(-)-a-(4-ety1-2,3- -dioxo-l-piperazinokarbonylamino)-fenylaoetamido]-3-aoetoximetyl-L ~ cefem-4~karbonsyra och 0,17 g natriumvätekarbonat löstes däri, var- efter 0,48 g pyridin och 4,1 g kaliumtiocyanat tillsattes. Den er- hållna blandningen omsattes fem timmar vid 60°, medan pH i blandningen upprätthölls vid 6,0 - 6,5 genom tillsats av utspädd saltsyra eller atriumvätekarbonat. Efter omsättningen tillsattes 20 ml vatten för utspädning av reaxtionsblandningen, som tillräckligt tvättades med kloroform. Vattenskiktet avskildes och inställdes på pH 1,5 genom tillsats av utspädd saltsyra. De avsatta kristallerna tillvaratogs genom filtrering, torkades och tvättades med aceton för bildning av 1,04 g (utbyte 79,6 %) tiocyansyrasalt av 7-[D(-)-d-(4-etyl-2,3-dioxo- -l-piperazinokarbonylamino)-fenylacetamido]~3~pyridinometyl-A3-cefem- -4-karbonsyrabetain med smältpunkten (sönderdelning) l55 - l60°, vilken produkt har formeln okip - cfl3CH2”t__;-coNHcHcoNH-;::í:;_ CW"v _ 1' CHZ-N _' [:] 9 coon scnïïj Ia (rer) cm'1= o 0:0 1780 (laktam), 1720 - 1660 (-coN::).In 10 ml of water was suspended 1.15 g of 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylaoetamido] -3-aethoxymethyl-L-cephem-4-carboxylic acid and 0.17 g of sodium bicarbonate was dissolved therein, after which 0.48 g of pyridine and 4.1 g of potassium thiocyanate were added. The resulting mixture was reacted for five hours at 60 °, while the pH of the mixture was maintained at 6.0 - 6.5 by the addition of dilute hydrochloric acid or atrium bicarbonate. After the reaction, 20 ml of water were added to dilute the reaction mixture, which was sufficiently washed with chloroform. The aqueous layer was separated and adjusted to pH 1.5 by the addition of dilute hydrochloric acid. The deposited crystals were collected by filtration, dried and washed with acetone to give 1.04 g (yield 79.6%) of thiocyanoic acid salt of 7- [D (-) - d- (4-ethyl-2,3-dioxo- 1-piperazinocarbonylamino) -phenylacetamido] -3-pyridinomethyl-33-cephem-4-carboxylic acid betaine with melting point (decomposition) l55 - 160 °, which product has the formula okip - c CH3 CH2 "t __; - coNHcHcoNH -; CW "v _ 1 'CHZ-N _' [:] 9 coon scnïïj Ia (rer) cm'1 = o 0: 0 1780 (lactam), 1720 - 1660 (-coN: :).

.QSCN 2040..QSCN 2040.

Pâ samma sätt erhölls tiooyansyrasaltet av 7-[D(-)-a-(4-metyl- -2,3-dioxo-l-piperazinokarbonylamino)-fenylacetamido]-3-pyridino- metyl-A3-cefem-4-karbonsyrabetain ur 7-[D(-)-a-(4-metyl-2,3-dioxo-l- -piperazinokarbonylamino)-fenylacetamido]-3-aoetoximetyl-A -cefem-4- -karbonsyra och pyridin, vilken produkt har formeln q*4P Q cd;-N\_;tcorHcHooNH _;:L W §»~\ O 0 .LÉT/ (ïn2-1-ï'\-___=_/ coon scN\) smäitpunxz (sdnderdeining) 180 - 185°, utbyte 82,0 %.Similarly, the thiooic acid salt of 7- [D (-) - α- (4-methyl--2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3-pyridinomethyl-A3-cephem-4-carboxylic acid betaine was obtained from 7- [D (-) - α- (4-methyl-2,3-dioxo-1--piperazinocarbonylamino) -phenylacetamido] -3-aethoxymethyl-α -cephem-4-carboxylic acid and pyridine, which product has the formula q * 4P Q cd; -N \ _; tcorHcHooNH _ ;: LW § »~ \ O 0 .LÉT / (ïn2-1-ï '\ -___ = _ / coon scN \) smäitpunxz (sdnderdeining) 180 - 185 °, yield 82.0%.

Pâ konventionellt sätt behandlades dessa båda produkter med ett jonbytarharrs för bildning av den önskade 7-[D(-)~d-(4-etyi-2,3- -dioxo-l-píperazinokarbonylamino)-fenylacetamido]-3-pyridinometyl- -A3-cefem-4-karbonsyrabetainen och 7e[D(-)-a-(4-metyl-2,3-dioxo-l- -piperazinokarbonylamino)-fenylaoetamido]-3-pyridinometyl-A -cefem-4- _ _, _- ___ a-nf-a-v- - 78082011-7 I 86 -karbonsyrabetainen.Conventionally, these two products were treated with an ion exchange resin to give the desired 7- [D (-) - d- (4-ethyl-2,3--dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3-pyridinomethyl- A3-cephem-4-carboxylic acid betaine and 7e [D (-) - α- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylaoetamido] -3-pyridinomethyl-A-cephem-4- _- ___ a-nf-av- - 78082011-7 I 86 -carbonic acid betaine.

Exennel 16. _ _ I 85 nl vattenfri metanol löstes 1,5 g natriumsalt av 7-fD(-)- -a-(4-etyl-2,3-dioxo-1-piperazinckarbonylamino)-fenylacetamidc]-3- -[2-(pyridyl-l-oxid)-tiometyl]-53-cefem-4-karbonsyra. Den erhållna lösningen försattes med 0,65 g vattenfri koppar(II)klcrid och den bildade blandningen omrördes 15 minuter vid rumstemperatur och cm- sattes 14 timmar vid 50°. Efter omsättningen fördes svavelvätegas genom rsaktionslösningen under 20 minuters iskylning. De bildade olösliga substanserna avfiltrerades och filtratet koncentrerades vätekarbonatlösning och de olösliga substanserna avfiltrerades, var- efter utspädd saltsyra sattes till filtratet för inställning av pH på 6,5. Filtratet tvättades med 3 x 10 ml etylacetat, varefter vattenskiktet avskildes bch.inställdes på pH 1,8 genc:_tillsats av utspädd saltsyra, De avsatta kristallerna tillvaratcgs genom filt- rering, torkades under reducerat tryck och tvättades :ed 20 :l etylacetat/kloroform (volym l:l) för bildning av 0,40 g 7-[3(-)-a- -(4-etyl~2,3-díoxo-l-piperazinckarbonylamino)-fenylacetamidc]-3- -metoximetyl-A3-cefem-4-karbonsyra med smältpunkten 152 - 156° (sönderdelning), utbyte 30,5 %.Example 16. In 85 .mu.l of anhydrous methanol was dissolved 1.5 g of sodium salt of 7- [D (-) - -α- (4-ethyl-2,3-dioxo-1-piperazinecarbonylamino) -phenylacetamide] -3- - [ 2- (pyridyl-1-oxide) -thiomethyl] -53-cephem-4-carboxylic acid. The resulting solution was charged with 0.65 g of anhydrous copper (II) chloride and the resulting mixture was stirred for 15 minutes at room temperature and allowed to stand for 14 hours at 50 °. After the reaction, hydrogen sulfide gas was passed through the reaction solution under ice-cooling for 20 minutes. The insoluble substances formed were filtered off and the filtrate was concentrated to hydrogen carbonate solution and the insoluble substances were filtered off, after which dilute hydrochloric acid was added to the filtrate to adjust the pH to 6.5. The filtrate was washed with 3 x 10 ml of ethyl acetate, after which the aqueous layer was separated and adjusted to pH 1.8 by the addition of dilute hydrochloric acid. The deposited crystals were collected by filtration, dried under reduced pressure and washed with 20 l of ethyl acetate / chloroform. (volume 1: 1) to give 0.40 g of 7- [3 (-) - α- (4-ethyl-2,3-dioxo-1-piperazinecarbonylamino) -phenylacetamide] -3-methoxymethyl-A3- cephem-4-carboxylic acid, m.p. 152 DEG-156 DEG (decomposition), yield 30.5%.

:R (Ksr) 9:51: 4 0:0 1770 (iakfam), 1700 (-coc:-:), lasa -cozr :en (aó-nnzso) f-väraen: 0,13 (in, a), 0,53 (Li-z, a), 2,51 (en, s), 4,31 (121, a), 4,41 (in, a), 4,96 (in, a), 5,32 (za, s), 6,10 (an, be), 6,33 (2H, 2H, 22, ba), 6,79 (3H,~s), 8,89 (33, t).: R (Ksr) 9:51: 4 0: 0 1770 (iakfam), 1700 (-coc: - :), lasa -cozr: en (aó-nnzso) f-väraen: 0.13 (in, a), 0.53 (Li-z, a), 2.51 (en, s), 4.31 (121, a), 4.41 (in, a), 4.96 (in, a), 5.32 (za, s), 6.10 (an, be), 6.33 (2H, 2H, 22, ba), 6.79 (3H, ~s), 8.89 (33, t).

Ezennel 17. I -f I ' En lösning av 3,2 g D(-)-a-(4-etyl-2,3-dioxo-l-piperazino- karbonylamino)-fenylättiksyra i 20 ml vattenfri metylenkloríd och 5 nl ; aimefiyizformamia försattes med 1,33 g Nnw-aimefylaniiir.. Den erhållna ' blandningen kyldes till mellan -15 och -l0° och en lösning av l,l4 g etylklorkarbonat i 5 ml vattenfri metylenklorid sattes droppvis till nämnda blandning under fem minuter. Blandningen omsattes EG minuter vid nämnda temperatur.Ezennel 17. A solution of 3.2 g of D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid in 20 ml of anhydrous methylene chloride and 5 nl; The resulting mixture was charged with 1.33 g of Nnw-amethylphenyl. The resulting mixture was cooled to between -15 and -10 ° and a solution of 1.4 g of ethyl chlorocarbonate in 5 ml of anhydrous methylene chloride was added dropwise to said mixture over five minutes. The mixture was reacted for EG minutes at said temperature.

Separat försattes en suspension av 3,28 g 7-amino-3-[5-(l- -metyl-1,2,3,4-tetrazolyl)-tiometyl]-A3-cefem-4-karbcnsyra i 65 ml vattenfri acetonitril med 3,04 g N,0-bis(trimetylsilyl)-acetamid för bildning av en lösning. Denna kyldes till -20° och hälldes i.nämnda I reaktionsblandning. Blandningen omsattes 60 minuter mellan -10 och § -50 och 60.minuter vid 5 - l0°. 3 ter omsättningen försattes reak- 'NOBZOß-'I 87 tionsblandningen med 5 ml metanol och blandningen befriades från olösliga beståndsdelar genom filtrering. Lösningsmedlet avlägsnades genom destillaticn under reducerat tryck. Återstoden löstes i et blandat lösningsmedel, omfattande 100 ml vatten och 50 ml etylacetat och den erhållna lösningen inställdes på ett pH av 7,5 - 8,0 genom tillsats av natriumvätekarbonat, varefter vattenskiktet försattes med 80 m tylacetat och 20 ml aceton och den erhållna lösningen inställdes på p ,5 genom tillsats av utspädd saltsyra. Det organiska skiktet avskildes, tvâ tades tillräckligt med vatten och lösningsmedlet av- l e H l lägsnades ur etylacetat genom destillation under reducerat tryck. Återstcden löstes i 15 ml aceton och denna lösning försattes med 60 ml 2~propanol under omröring för avsättning av vita kristaller. Is avskilda kristallerna tillvaratogs genom filtrering, tvättades till- rack-ligt med z-propanoi och torkade-s för bildning av 5,26 g 7-[D(-)- -a-(4-etyl-2,3-dioxo-l-piperazinokarbonylamino)-fenylacetamido]-3- -[5-(l-metyl-l,2,3,4-tetrazolyl)-tiometyl]-A3-cefem-4-karbonsyra med smäifpmmten 163 - 1ss° (sanaeraeining), utbyte 83,6 7:. strukturen för denna förening bekräftades med IR och NMB.Separately, a suspension of 3.28 g of 7-amino-3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -A3-cephem-4-carboxylic acid was added to 65 ml of anhydrous acetonitrile. with 3.04 g of N, O-bis (trimethylsilyl) -acetamide to give a solution. This was cooled to -20 ° and poured into the reaction mixture. The mixture was reacted for 60 minutes between -10 and § -50 and 60 minutes at 5 - 10 °. After the reaction, the reaction mixture was added to the reaction mixture with 5 ml of methanol and the mixture was freed from insoluble constituents by filtration. The solvent was removed through the distillate under reduced pressure. The residue was dissolved in a mixed solvent comprising 100 ml of water and 50 ml of ethyl acetate, and the resulting solution was adjusted to a pH of 7.5 - 8.0 by adding sodium bicarbonate, after which the aqueous layer was added with 80 ml of ethyl acetate and 20 ml of acetone, and the resulting the solution was adjusted to p, 5 by the addition of dilute hydrochloric acid. The organic layer was separated, washed sufficiently with water and the solvent was removed from ethyl acetate by distillation under reduced pressure. The residue was dissolved in 15 ml of acetone and this solution was added with 60 ml of 2-propanol with stirring to deposit white crystals. The ice-separated crystals were collected by filtration, washed thoroughly with z-propanol and dried to give 5.26 g of 7- [D (-) - -α- (4-ethyl-2,3-dioxo- 1-piperazinocarbonylamino) -phenylacetamido] -3- - [5- (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl] -A3-cephem-4-carboxylic acid with a melting point of 163 DEG-16 DEG (sanitary unit), yield 83.6 7 :. the structure of this compound was confirmed by IR and NMB.

Nämnda procedur upprepades, men med det undantaget att D(-)-a-(4-etyl-2;3-dioxo-l-piperazinokarbonylamino)-fenyl- ättiksyra ersattes med de reaktionsbenägna derivaten av föreningar med formeln (V) i tabell XXX för bildning av ifrågavarande före- ningar. Strukturen för varje förening bekräftades med IR och Nhi.Said procedure was repeated, but with the exception that D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenyl-acetic acid was replaced by the reaction-prone derivatives of compounds of formula (V) in Table XXX for the formation of the associations in question. The structure of each compound was confirmed by IR and Nhi.

Tabell XXX.Table XXX.

~Förening medt fozmeln QV) Pr°dukt o<->- n<->- Q 0 men Ncormcrzcocn my: NcoNHcHconm-- *Prš 3 | ' I “ e e t: m.p. (decomp.)l6l-l63°C, yield 85.8% D(-)- i n(-)- _ 0 /0 §}-få rg . cxzšcnzr Ncomzçncoox _ cigarr; , councncoms-[í 3-1: _ f H25 :N ° oon (I: n on “5 m.p. (decomn.) 188-l90°C, yield ?5.5% _ 7808204-7 88 Tabell XXX (forts.~ Förening medt fozmeln QV) Pr ° dukt o <-> - n <-> - Q 0 men Ncormcrzcocn my: NcoNHcHconm-- * Prš 3 | 'I “e e t: m.p. (decomp.) l6l-l63 ° C, yield 85.8% D (-) - i n (-) - _ 0/0 §} -få rg. cxzšcnzr Ncomzçncoox _ cigar; , councncoms- [í 3-1: _ f H25: N ° oon (I: n on “5 m.p. (decomn.) 188-l90 ° C, yield? 5.5% _ 7808204-7 88 Table XXX (cont.

R m.m> @fl@fi» .pvwwfl 1 =N~ ^.ufioo@vv .@.s m . mw .mccs o ax /zàmš \ :IA @ \||/ __ @\»||«mzouwc=aoc«z zfwmownmmovmmu @ ¶mcoomomzoo|z\|»z«mmownwmuvwnu z||.= .R m.m> @ fl @ fi ».pvww fl 1 = N ~ ^ .u fi oo @ vv. @. S m. mw .mccs o ax / zàmš \: IA @ \ ||| / __ @ \ »||« mzouwc = aoc «z zfwmownmmovmmu @ ¶mcoomomzoo | z \ |» z «mmownwmuvwnu z ||. =.

I ï o c o ,d lfilvu . |^|vu & c.4ß wflmflfi .pumwfi 1 Nwfl ^.@=°o@@v .@.fi m. . I mw mono , 2 _ o . .f . z\ /:|m~mu. \w@fim@¶ mæw . , www.. . \||/ . \.|l/ tifnz w =zco=u=zcø|z z|~=v~^~:ovm=o =ooo=u:zov|z ~»m=o~^wmoVmmo ¶ ^w1¿d cvlßo |^|vn.I ï o c o, d l fi lvu. | ^ | vu & c.4ß w fl m flfi .pumw fi 1 Nw fl ^. @ = ° o @@ v. @. fi m. I mw mono, 2 _ o. .f. z \ /: | m ~ mu. \ w @ fi m @ ¶ mæw. , www ... \ ||| \. | l / tifnz w = zco = u = zcø | zz | ~ = v ~ ^ ~: ovm = o = ooo = u: zov | z ~ »m = o ~ ^ wmoVmmo ¶ ^ w1¿d cvlßo | ^ | vn.

»Alva vsoezoa-1 89,-_ Exemnel 18.»Alva vsoezoa-1 89, -_ Exemnel 18.

Med användning av 3,1 g D(~)-a-(4-etyl-2,3-dioxo-l-piperazino- karbonylamino)-fenylättiksyra och 3,0 g 7-emino-3-[5-(l,2,3-trie vlji -tiometyl]-A3-cefem-4-karbonsyra upprepades försöket enligt exempelïf för bildning av 4,5 g 7-[D(~-)-d-(4-ety1-2,3-a1oxo-1-piperezinokarbo- nylamino)-fenylaeetamido]-3-[5-(1,2,3-triazolyl)-tiometyl]-A3-cefem- -4-karbonsyra med smältpunkten 177 - 1800 (sönderdelning), utbyte 76,7 få. i ~ Ia (mr) mfl: acw 17?o (iaxtam), 1703 (moon), 1680, 1667 (-coN<). “ Exemnel 19.Using 3.1 g of D (~) -α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid and 3.0 g of 7-emino-3- [5- (1, 2,3-Trifluorom-thiomethyl] -A3-cephem-4-carboxylic acid The experiment was repeated according to the example to give 4.5 g of 7- [D (~ -) - d- (4-ethyl-2,3-alkoxo- 1-piperezinocarbonylamino) -phenylaethamido] -3- [5- (1,2,3-triazolyl) -thiomethyl] -A3-cephem--4-carboxylic acid, m.p. 177 DEG-1800 DEG C. (decomposition), yield 76.7 g . i ~ Ia (mr) mfl: acw 17? o (iaxtam), 1703 (moon), 1680, 1667 (-coN <). “Exemnel 19.

Hed användning av 1,9 g D(~)-a-(4-etyl-2,3-dioxo-l-piperazino- karbonylamino)-fenylättiksyra och 2,2 g 7-amino-3-[5-(l,3,4-tiadia- zolyl)~tiometyl]-A3-cefem-4-karbonsyra upprepades försöket enligt exempel 17 för bildning av 3,1 g 7-[D(-)-a-(4-etyl-2,3-dioxo-l-pipera- zinokarbonylamino)-fenylacetamido]-3-[5-(1,3,4-tiadiazolyl)-tiometyl]~ -A3-cefem-4-karbonsyra med smältpunkten 165 - l70° (sönderdelning), utbyte 82 %. m (mr) cnfl: 1 Czo ms (laktam), 1705 ßcoon), 1685, 1675 (-coN<).Use 1.9 g of D (~) -α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid and 2.2 g of 7-amino-3- [5- (1, 3,4-Thiadiazolyl) -thiomethyl] -A3-cephem-4-carboxylic acid The experiment of Example 17 was repeated to give 3.1 g of 7- [D (-) - α- (4-ethyl-2,3- dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3- [5- (1,3,4-thiadiazolyl) -thiomethyl] -A3-cephem-4-carboxylic acid, m.p. 165 DEG-170 DEG C. (decomposition), yield 82 %. m (mr) cnfl: 1 Czo ms (lactam), 1705 ßcoon), 1685, 1675 (-coN <).

Exemnel 120- Hed användning av 1,5 g D(-)-m-(4-etyl-2,3-dioxo-l-piperazino- karbonylemino)-p-hydroxifenylättiksyra och 1,5 g 7-amino-3-[5-(2-metyl- -1,3,4-tíadíazolyl)-tiometyl]-A3-cefem-4-karbonsyra upprepades försöket enligt exempel 17 för bildning av'2,3 g 7-[D(+)-a-(4-etyl-2,3-diøxo- -1-piperazinokarbønylamino)-p-hydroxifenylacetanido]-3-[S-(2-metyl- -1,3,4-tiadiazolyl)-tiometyl]-A3-cefem~4~karbonsyra med smältpunkten 172-l77° (sönderdelning), utbyte 77,7 %.Example 120- Use 1.5 g of D (-) - m- (4-ethyl-2,3-dioxo-1-piperazinocarbonylemino) -p-hydroxyphenylacetic acid and 1.5 g of 7-amino-3- [ 5- (2-Methyl--1,3,4-thiadiazolyl) -thiomethyl] -A3-cephem-4-carboxylic acid The procedure of Example 17 was repeated to give 2.3 g of 7- [D (+) - α- (4-Ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetanido] -3- [S- (2-methyl-1,3,3-thiadiazolyl) -thiomethyl] -A3-cephem-4 Carboxylic acid, m.p. 172-177 ° (dec.), yield 77.7%.

In (Kßr) cm"1= .Qczo 1780 (iaktam), 1710 t-coon), 1685, 1672 ß-CON i ) , ' På samma sätt framställdes föreningarna i tabell XXXI ur D(-)-a-(4-etyl-2,3-dioxo-1-piperazinokarbonylemino)-fenylättiksyra eller D(-)~æ-(4-etyl-2,3-dioxo-l-piperazinokarbonylamino)-p-hydroXi- fenylättiksyra och de i tabell XXXI angivna föreningarna med formeln IV. Strukturen bekräftades med hjälp av IR och NMR. 78082044 90 Tabell XXKI _fi._zw..xmmfiuvmwzw m ÜQ. 3.3» .ooof | 03 Åànëäzw, :Ta ...ásfmzuvflwzu _ :acw _. _. .fi m.. /__.|w~ :u \ \o .fl z . 1 NI» ¶ . . ?.|.~ w =zoo=u=:cs|=. z|m=o»=c krnff . c Ho _ :^|v= u m.~> øflwflæ .oomßfl 1 HßH_^.@fi°»~@v ;@.E ß N. . . . - :O =w :cos m=um=w ¶ :evo c _ . =\ ,:|m~mv|fiw»/zfffl. Hmßw z\z/Qfwmmv \\ Z «o www: Q\»||1=zco=u=zcu|z\1»V|N=@m=u __ _ .«|1,~ L på rv V fibfl L Q Q |^|vA vflßwohm ^>Hv Qfimëhow øwë wnflfimfimä _ 78082011-7 91 x ß.>> Uñofih .pußwfl | mæfi ^.;E0@@:w .L.ß _:=w. .flw :saw W .v C _ Mu ..C :\ @fim«;QI\\ z|wfl Rwfi \|; , ~ = @fim~mQ|\\ z@@@, :1s1¿_ m zzcumuxzcofz mlmwcßzu 211.1 m\; wow .. . ï/ i _ o U 1^|v: m c.w@ vflmfia .o0H@H I wmfi ^.QEo»@@V .@.: m: m\~. N- . m »N N N.In (Kßr) cm -1 = .Qczo 1780 (iactam), 1710 t-coon), 1685, 1672 ß-CON i), 'In the same way, the compounds in Table XXXI were prepared from D (-) - a- (4- ethyl 2,3-dioxo-1-piperazinocarbonylemino) -phenylacetic acid or D (-) - ε- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxy-phenylacetic acid and the compounds listed in Table XXXI with the formula IV The structure was confirmed by IR and NMR 78082044 90 Table XXKI _fi._ zw..xmm fi uvmwzw m ÜQ. 3.3 ».ooof | 03 Åànëäzw,: Ta ... ásfmzuv fl wzu _: acw _. _. .fi m .. /__.|w~: u \ \ o .fl z. 1 NI »¶..?. |. ~. w w zoo = u =: cs | =. z | m = o» = c krnff. c Ho _: ^ | v = u m. ~> Ø fl w fl æ .oomß fl 1 HßH _ ^. @ Fi ° »~ @ v; @. E ß N.... -: O = w: cos m = um = w ¶: evo c _. = \,: | m ~ mv | fi w »/ zff fl. Hmßw z \ z / Qfwmmv \\ Z« o www: Q \ »|| 1 = zco = u = zcu | z \ 1» V | N = @ m = u __ _. «| 1, ~ L på rv V fi b fl LQQ | ^ | vA v fl ßwohm ^> Hv Q fi mëhow øwë wn flfi m fi mä _ 78082011-7 91 x ß. >> Uño fi h .pußw fl | mæ fi ^ .; E0 @@: w .L.ß _: = w. .fl w: saw W .v C _ Mu ..C: \ @ fi m «; QI \\ z | w fl Rw fi \ |;, ~ = @ fi m ~ mQ | \\ z @@@,: 1s1¿_ m zzcumuxzcofz mlmwcßzu 211.1 m \; wow ... ï / i _ o U 1 ^ | v: m c.w @ v fl m fi a .o0H @ H I wm fi ^ .QEo »@@ V. @ .: m: m \ ~. N-. m »N N N.

:U ,_:ö vw :cam :C ¶ m; ^ auv fw mosa ._ _ .r | _ =\ 4fimm=Q|\\ = šc æww . : =\_/»w«w9f\w z:%% .% u , w¿oQ=Q;¿c¿|;w|»¿»m:Jf=@. __ __ ¶ \r:xfzwm w w Z r v > r - f f . f] w% w wlß o o »Alva ...o :åh måcfq... .Coæfivfi 1 mcfi Aßšcuiå ITE «:u==v _ mçøu :ß Tabell XXXI šfnrts.) =\z,, mmzu vw/= c æm@m = =| .Ar , xx, « » _ , .ulili IWHCHVICWNUZVOI: 4... .S3 .IC . p - . ï c .C |^|VQ ?80820h-7 92 Tabell IDCXI (forts . a @.m@ øfimflfi .päßfi 1 wafi ^.:fiouwuv¶.:.e mccw mc . Û _ ßmocøommofämv/211% Amv \||/ _ ü , @v»|||m=ovmQmzou-= =|@:uf=@ _ , vlß O C :Anya moon wmoouommo »\ z.:fl .\w:||zmm m. a odæ cfiwf» .ocsofl Aåucumfivv .aš :osv . . C wmuomzv \\ Mwläw æwwm . .w \ f J n . . n\r|||=;su:umzeo|z. z|@:vÅ=o c ua |^|vm 2000 m Q moowmo \\ 3 \ _ mm; m veoezou-7 93 Exemnel 21.: U, _: ö vw: cam: C ¶ m; ^ auv fw mosa ._ _ .r | _ = \ 4fi mm = Q | \\ = šc æww. : = \ _ / »W« w9f \ w z: %%.% U, w¿oQ = Q; ¿c¿ |; w | »¿» m: Jf = @. __ __ ¶ \ r: xfzwm w w Z r v> r - f f. f] w% w wlß oo »Alva ... o: åh måcfq .... .Coæ fi v fi 1 mc fi Aßšcuiå ITE«: u == v _ mçøu: ß Table XXXI šfnrts.) = \ z ,, mmzu vw / = c æm @ m = = | | .Ar, xx, «» _, .ulili IWHCHVICWNUZVOI: 4 .... .S3 .IC. p -. ï c .C | ^ | VQ? 80820h-7 92 Table IDCXI (cont. a @ .m @ ø fi m flfi .päß fi 1 wa fi ^ .: fi ouwuv¶.:. e mccw mc. Û _ ßmocøommofämv / 211% Amv \ || / _ ü, @v »||| m = ovmQmzou- = = | @: uf = @ _, vlß OC: Anya moon wmoouommo» \ z .: fl. \ w: || zmm m. a odæ c fi wf ». ocso fl Aåucum fi vv .aš: osv.. C wmuomzv \\ Mwläw æwwm. .w \ f J n.. n \ r ||| =; su: umzeo | z. z | @: vÅ = oc ua | ^ | vm 2000 m Q moowmo \\ 3 \ _ mm; m veoezou-7 93 Exemnel 21.

I ett blandat lösningsmedel bestående av 80 ml vatten och 40 ml etylacetat suspenderades 4,0 Q 7-[D(-)-:-aminofenylacetamido]- -3-acetoximetyl-A3-cefem-4-karbonsyra och 1,55 g vattenfri t kalium- karbona* löstes sedan däri under iskylning.In a mixed solvent consisting of 80 ml of water and 40 ml of ethyl acetate was suspended 4.0 Q 7- [D (-) -: - aminophenylacetamido] -3-acetoxymethyl-A3-cephem-4-carboxylic acid and 1.55 g of anhydrous t potassium carbon * was then dissolved therein under ice-cooling.

Denna lösning försattes under 15 minuter vid O-5° :ed 7,3 g 4-(a-hydroxietyl)-2,3-dioxo-l-piperazinokarbcnvlklorid och den bildad blandningen omsättes 30 minuter vid 10-l5°. Efter reaktionen avskilda vattenskiktet, 100 ml acetonitril sattes till vattenskiktet och den bildade lösningen inställdes på pH 1,5 genom tillsats av utspädd saltsyra och mättades med natriumklorid. Aeezenitrilskiktet avskildes tvättades med 2 x 30 ml mättad lösning av natriumklorid och torkades under reducerat tryck. återstoden löstes 1 ett blandat lösningsmedel, omfattande 50 ml aceton och 10 ml etanol och olösliga beståndsdelar avskildes. 100 ml isopropylalkohol sattes till den bildade lösningen och koncentrerades till 2/3 av vätskevolymen. Se avskilda kristaller- na tillvaratogs genom filtrering, tvättades :ed isopropylalkohol och torxaaes för bilaning ev 4,5 e 7-[1>(-)-z-:-(e-hyaroxietyJJ-z,3- -dioxo-l-piperazinokarbonylamino-fenylaeetanido]-3-acetoximetyl-A3- -cefem-4-karbonsyra med smältpunkten 142-l4¿° (sönderdelning), utbyte 76,3 ïê. _ m (zcsr) ctrl: JM 1770 (iektem), ivos b-coon), iaao, less <-CON<>.This solution was added for 15 minutes at 0-5 °: 7.3 g of 4- (α-hydroxyethyl) -2,3-dioxo-1-piperazinocarbonyl chloride and the resulting mixture was reacted for 30 minutes at 10-15 °. After the reaction, the aqueous layer was separated, 100 ml of acetonitrile was added to the aqueous layer, and the resulting solution was adjusted to pH 1.5 by adding dilute hydrochloric acid and saturated with sodium chloride. The acetonitrile layer was separated, washed with 2 x 30 ml of saturated sodium chloride solution and dried under reduced pressure. the residue was dissolved in a mixed solvent comprising 50 ml of acetone and 10 ml of ethanol and insoluble constituents were separated. 100 ml of isopropyl alcohol was added to the resulting solution and concentrated to 2/3 of the liquid volume. See separated crystals were collected by filtration, washed with isopropyl alcohol and torxed to give 4.5 g of 7- [1> (-) - z - :-( e-hyaroxietJJ-z, 3-dioxo-1-piperazinocarbonylamino -phenylaethanido] -3-acetoxymethyl-33- -cephem-4-carboxylic acid, m.p. 142-14 ° (dec.), yield 76.3 μm (zcsr) ctrl: JM 1770 (ectam), ivos b-coon ), iaao, less <-CON <>.

Nämnda procedur upprepades, men med det undantaget att 7-[D- (-)-a-aminofenylaeetamido]-3-aeetoximetyl-A3-2efem-4-karbonsyran er- 'sattes med föreningarna med formeln (II) enligt tabell XZXII för bildning av respektive föreningar enligt tabell XXXII. Strukturen för varje förening bekräftades med IR och NMR. ?80820læ-7 94 Tabell XXXII _R w.:w wfiafih .oonzfi I flàfi ^.uäouoøv .u.§ m _ :w :oss få :QS »Ra w.~=..f\ z \o Q . n* m _ o .___ :l _ Lhflmšö..M..Eo..|,_.11_:uwfivmzqcu w. /zzw =u|_/\/\w m 2112 _ .w _ UT; 4.. _. . _. .Tlz _ w llmzøomofl.. o o »Tä ä o.mm wfiwflæ .coßmfi | mmfi ^.aecuwuv .a.e _ mosa _ :o _ ä? mc . _ O _ . »moouowmuäfü Q _ mšcacwmo W/znrflo _ w :zcfivmfiuflfåoolfiïzlmzomæco: _ _ _ fwïmzofihozmm QIO |^|va »xäzšm HH :Hmsfiow .owë wnflnmnmm 7008-204-7 95 Tabell XXXII (forts ...w cáw. 33» .u i; - 92 Azhucuww; Û N. ~ - :w :cow .E . ...\_._ _ wN.,_u|_N./~,M 14% O . . \ \|/ . rfilá ß Lllmmeguvzumzøulz ”Tflæßomwmßvonm . .r - ï/ ..._ c :Alva :vi .. :C00 finæwmolwz \o _» .z mmmä m6 m9 umowmwm. .ïí __... '7808204-7 96 Exemoel 22. (1) En lösning av 0,63 g D(-)-m-(4-etyl-2,3-dioxo-l-piperazin:- karbonylamino)-fenylättiksyra i 10 ml vattenfri metylenklorid fär» sattes med 0,5 g oxalylklorid och en droppe N,N-dimetylformamii och den erhållna blandningen omsattes 30 minuter vid rumstemperatur.Said procedure was repeated, but with the exception that 7- [D- (-) - α-aminophenylaethamido] -3-aethoxymethyl-A3-2efem-4-carboxylic acid was replaced with the compounds of formula (II) according to Table XZXII to give of the respective compounds according to Table XXXII. The structure of each compound was confirmed by IR and NMR. ? 80820læ-7 94 Table XXXII _R w.:w w fi a fi h .oonz fi I fl à fi ^ .uäouoøv .u.§ m _: w: oss få: QS »Ra w. ~ = .. f \ z \ o Q. n * m _ o .___: l _ Lh fl mšö..M..Eo .. |, _. 11_: uw fi vmzqcu w. / zzw = u | _ / \ / \ w m 2112 _ .w _ UT; 4 .. _. . _. .Tlz _ w llmzøomo fl .. o o »Tä ä o.mm w fi w fl æ .coßm fi | mm fi ^ .aecuwuv .a.e _ mosa _: o _ ä? mc. _ O _. »Moouowmuäfü Q _ mšcacwmo W / znr fl o _ w: zc fi vm fi u fl fåool fi ïzlmzomæco: _ _ _ fwïmzo fi hozmm QIO | ^ | va» xäzšm HH: Hms fi ow .owë wn fl nmnmm 33 ... 208-204. ; - 92 Azhucuww; Û N. ~ -: w: cow .E. ... \ _._ _ wN., _ U | _N./~,M 14% O.. \ \ | /. R fi lá ß Lllmmeguvzumzøulz ” T fl æßomwmßvonm. .R - ï / ..._ c: Alva: vi ..: C00 fi næwmolwz \ o _ ».z mmmä m6 m9 umowmwm. .Ïí __... '7808204-7 96 Exemoel 22. (1) En solution of 0.63 g of D (-) - m- (4-ethyl-2,3-dioxo-1-piperazine: carbonylamino) -phenylacetic acid in 10 ml of anhydrous methylene chloride was added with 0.5 g of oxalyl chloride and one drop N, N-dimethylformamide and the resulting mixture were reacted for 30 minutes at room temperature.

Efter omsättning avlägsnades lösningsmedlet genom destillation under reducerat tryck. Återstoden tvättades med vattenfri bensen för hild- ning av 0,6 g D(-)-d-(4-etyl-2,3-dioxo-l-piperazinokarbonylamino)- -fenylacetylklorid med smältpunkten ll2-ll6° (sönderdelning), utbyte saa sä). I ' .After reaction, the solvent was removed by distillation under reduced pressure. The residue was washed with anhydrous benzene to give 0.6 g of D (-) - d- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetyl chloride, m.p. 112-116 ° (dec.), Yield saa sä). I '.

IR (zoar) mfl: 131m 3280 QC=O 1790, 1595 - (2) En suspension av 0,27 g 7-aminocefalosporansyra i 6 ml vattenfri metanol försattes med 0,24 g trietylamin. Den bildade lösningen kyldes till -400 och lösningen försattes med en lösnin av 5 ml vattenfri metylenklorid, innehållande 0,34 g D(-)-a-(¿- -etyl-2,3-dioxo-1-piperazinokarbonylamino)-fenylacetylklorid och temperaturen i reaktionsvätskan höjdes så småningom till rumstempera- tur under en timme. Efter omsättningen avskildes lösningsmedlet genom destillation under reducerat tryck. Återstoden chargerades i 20 ml vatten och den bildade lösningen tvättades med 2 x 5 ml etyl- acetat. Vattenskiktet försattes med 20 ml etylacetat och lösningen inställdes på pH 1,5 genom tillsats av 2N saltsyra under omröring.IR (zoar) etc The resulting solution was cooled to -400 and the solution was added with a solution of 5 ml of anhydrous methylene chloride containing 0.34 g of D (-) - α- (β-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetyl chloride and the temperature of the reaction liquid was eventually raised to room temperature for one hour. After the reaction, the solvent was separated by distillation under reduced pressure. The residue was charged to 20 ml of water and the resulting solution was washed with ethyl acetate (2 x 5 ml). The aqueous layer was added with 20 ml of ethyl acetate and the solution was adjusted to pH 1.5 by adding 2N hydrochloric acid with stirring.

Det organiska skiktet avskildes, tvättades med mättad natriumklorid- lösning, torkades över vattenfritt magnesiumsulfat och lösningszedlet avlägsnades genom destillation under reducerat tryck för bildning av 453 mg 7-[D(-)-a-(4-etyl-2,3-dioxo-1-piperazinokarbonylamino)-fenyl- acetamido]-3-acetoximetyl-A3-cefem-4-karbonsyra ned smältpunkten 165-l66° (sönderdelning), tbyte 79,0 %. _ På samma sätt erhölls 7-[D(-)-a-(4-etyl-2,3-dioxo-l-pi;erazino- karbonylamino)-p-hydroxifenylacetamido]-3-acetoxinetyl-A3-cefe:-4- -karbonsyra med smältpunkten 168-1740 (sönderdelning), utbyte Te,3 É ur D(-)-a-(4-etyl-2,3-dioxo-I-piperazinokarbonylamino)-p-hydroxifenyl- acetylklorid och 7-aminooefalosporansyra.The organic layer was separated, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solution was removed by distillation under reduced pressure to give 453 mg of 7- [D (-) - α- (4-ethyl-2,3-dioxo- 1-piperazinocarbonylamino) -phenyl-acetamido] -3-acetoxymethyl-33-cephem-4-carboxylic acid down melting point 165-166 ° (decomposition), yield 79.0%. There was thus obtained 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-pi; erazinocarbonylamino) -p-hydroxyphenylacetamido] -3-acetoxymethyl-A3-cefe: -4 - -Carboxylic acid, m.p. 168-1740 (decomposition), yield Te, 3 É of D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenyl acetyl chloride and 7-aminoeophalosporanic acid .

Exemnel 23. ' Med användning av D(-)-m-(4-etyl-2,3-dioxo-l-piperazinokarbo- nylamino)-fenylättiksyra och 7-amino-3-karbamoyloximetyl-A3-cefem-4- -karbonsyra upprepades försöket enligt exempel 17 för bildning av 7-[D(-)¿a-(4-etyl-2,3-dioxo-1-piperazinokarbonylamino)-fenylacet- amido]-3Jkarbamoyloximetyl-A3-cefem-4-karbonsyra med snältpunkten_ 175-l80° (sönderdelning), utbyte 68,0 %. 7808204 ° 7 97 eIR (ICBr) cm"l= ÜNHZ 3450, 3350 àcoz-:n 3300 - flc=o 1778,_171o, isvo På samma sätt erhöll man 7-D(-)-a-(4-etyl-2,3-dioxo-l-pipera- zinokarbonylamino)-p-hydroxifenylacetamido-3-karbamoyloximetyl-¿3- -cefem-4~karbonsyra med smältpunkten l78¥l82° (sönderdelning), utbyte 65,0 %, ur D(-)-a-(4-etyl-2,3-dioxo-1-piperazinokarbonylamino)-p- -hydroxifenylättiksyra och 7-amino-3-karbamoyloxímetyl-A3-cefem-4- ~karbonsyra. ' Exemnel 24. (1) En lösning av 0,32 g D(-)-a-(4-etyl-2,3-dioxo-l-piperazino- karbonylamino)-fenylättiksyra i 15 ml metylenklorid försattes med 0,1 g N-metylmorfolin. Den bildade lösningen kyldes till -200 och lösningen försattes med 0,11 g etylklorkarbonat i 2 ml metylenklorid och den erhållna lösningen underkastades omsättning vid en tempera- tur mellan -10 och -20° under en timme. Reaktionsblandningen för- sattes därefter droppvis med en lösning av 0,44 g benshydrylester av 7-amino-3-karbamoyloximetyl~A3~cefem-4-karbonsyra i 5 ml metylen- klorid vid -20°. Den erhållna lösningen underkastades omsättning mellan -10 och -20° under 1,5 timmar och temperaturen höjdes till rumstemperatur. Lösningsmedlet avlägsnades genom destillation under reducerat tryck och återstoden löstes i 15 ml etylacetat. Den erhållna lösningen tvättades i tur och ordning med lO ml vatten, 5%-ig (vikt) natriumvätekarbonatlösning och mättad natriumkloridlösning och torka- des över vattenfritt magnesiumsulfat. återstoden renades medelst pelarkromatografering (silikagel/kloroform) för bildning av 0,53 g benshydrylester av 7-{D(-)-a-(4-etyl-2,3-dioxo-l-piperazinokarbonyl- amino)-fenylacetamido]-3-karbamoyloximetyl-A -cefem-4-karbonsyra med emaitpmncten 12o-12s° (szsnaeraelning), 'utbyte 71,6 m (ie-r) em-l: 911112 3480, 3380 i :Jconn 33oo üc=o 1780, 1718, 1680 NMR (cnciyïvaraen: -o,1 (in, a), 2,05 (1n, e), 2,64 (ISH, bs), 3,19 (in, s), 4,2o (an, m), 4,86 (IH, d), 5,20 (an, s), men (2H,ebs), 6,1 (2H. m), 613"6¶9 m)1 899 (3Hs Ü)- (2) En lösning av 0,2 g benshydrylester av 7-[D(-)-d-(4- -etyl-2,3-dioxo-l-piperazinokarbonylamino)-fenylacetamido]-3-karba- moyloximetyl-A3-cefem-4-karbonsyra i 5 ml anisol försattes med 5 ml trifluorättiksyra under iskylning och den bildade blandade lösningen 18-08204-7 98 omsattes 30 minuter under iskylning. Efter omsättningen avlägsnades lösningsmedlet genom destillation under reducerat tryck. Ãterstoden löstes i 15 ml etylacetat, den bildade lösningen försattes med 10 ml vatten och den bildade lösningen inställdes på pH 7,5 genom tillsats av natriumvätekarbonatlösning under omröring. Vattenskiktet avsxil- des, sattes till 20 ml etylacetat och inställdes på pH 2,0 genom tillsats av ZN saltsyra. Det organiska skiktet avskildes, tvättades i tur och ordning med vatten och mättad natriumkloridlösning och torkades över va tenfritt magnesiumsulfatÄ Lösningsmedlet avlägsna- des genom destillation under reducerat tryck för avsättning av kri- staller. De avsatta kristallerna tillvaratogs genom filtrering för bildning av 0,13 g 7-[D(-)-a-(4-etyl-2,3-dioxo-1-piperazinokarbonyl- amino)-fenylacetamido]-3-karbamoyloximetyl-A3-cefem~4-karbonsyra, smaitpurmt 175-18o° (senda-delning), utbyte 83,8 9%. m (mr) til: vmaz mo, 3350, VCONHZ 3300, ¿)C=O 1778, 1710, 1670 WMR (dó-DMS0)'ï värden: 0,15 (1H, d), 0,55 (in, a), 2,50 (53, b), 347 (Zfif 5)- 4123 (2H, m), 4,95 (m, a), 5,29 (zñ, 0.), 6,10¶(2H, m), 6,25-5,90 (53, m), 8,9 (3H, t).Example 23. Using D (-) - m- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid and 7-amino-3-carbamoyloxymethyl-A3-cephem-4-carboxylic acid the experiment of Example 17 was repeated to give 7- [D (-) α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3-carbamoyloxymethyl-33-cephem-4-carbonic acid with the melting point_ 175-180 ° (dec.), Yield 68.0%. 7808204 ° 7 97 eIR (ICBr) cm -1 = ÜNHZ 3450, 3350 acoz-: n 3300 - fl c = o 1778, _171o, isvo Similarly, 7-D (-) - α- (4-ethyl-2) was obtained , 3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido-3-carbamoyloxymethyl-β-cephem-4-carboxylic acid, m.p. 178 DEG-108 DEG C. (decomposition), yield 65.0%, from D (-) -α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -β-hydroxyphenylacetic acid and 7-amino-3-carbamoyloxymethyl-33-cephem-4-carboxylic acid. Example 24. (1) A solution of 0.32 g of D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid in 15 ml of methylene chloride was added with 0.1 g of N-methylmorpholine. The resulting solution was cooled to -200 and the solution was added with 0.11 g of ethyl chlorocarbonate in 2 ml of methylene chloride and the resulting solution was subjected to reaction at a temperature between -10 and -20 ° for one hour.The reaction mixture was then added dropwise with a solution of 0.44 g of benzhydryl ester of 7-amino-3-carbamoyloxymethyl-33-cephem-4-carboxylic acid in 5 ml of methylene chloride at -20 °. The solution was subjected to reaction between -10 and -20 ° for 1.5 hours and the temperature was raised to room temperature. The solvent was removed by distillation under reduced pressure and the residue was dissolved in 15 ml of ethyl acetate. The resulting solution was washed successively with 10 ml of water, 5% (w / w) sodium bicarbonate solution and saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. the residue was purified by column chromatography (silica gel / chloroform) to give 0.53 g of benzhydryl ester of 7- {D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3 -carbamoyloxymethyl-A -cephem-4-carboxylic acid having an emission point of 120 DEG-12 DEG C. (yield), yield 71.6 m (ie - r) cm @ -1: 911112 3480, 3380 in: Jconn 3300 üc = o 1780, 1718, 1680 NMR (cnciivarians: -o, 1 (in, a), 2.05 (1n, e), 2.64 (ISH, bs), 3.19 (in, s), 4.2o (an, m) , 4.86 (1H, d), 5.20 (an, s), men (2H, ebs), 6.1 (2H, m), 613 "6¶9 m) 1,899 (3Hs Ü) - ( 2) A solution of 0.2 g of benzhydryl ester of 7- [D (-) - d- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3-carbamoyl oxymethyl-A3-cephem -4-Carboxylic acid in 5 ml of anisole was added with 5 ml of trifluoroacetic acid under ice-cooling and the resulting mixed solution was reacted for 30 minutes under ice-cooling.After the reaction the solvent was removed by distillation under reduced pressure, the residue was dissolved in 15 ml of ethyl acetate, the formed solution was added 10 ml of water and the resulting solution was adjusted to pH 7.5 by adding sodium bicarbonate solution with stirring. The aqueous layer was filtered off, added to 20 ml of ethyl acetate and adjusted to pH 2.0 by adding ZN hydrochloric acid. The organic layer was separated, washed successively with water and saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to deposit crystals. The deposited crystals were collected by filtration to give 0.13 g of 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3-carbamoyloxymethyl-A3- cefem ~ 4-carboxylic acid, melting point 175-18 ° (transmitter division), yield 83.8 9%. m (mr) til: vmaz mo, 3350, VCONHZ 3300, ¿) C = O 1778, 1710, 1670 WMR (dó-DMS0) 'ï values: 0.15 (1H, d), 0.55 (in, a ), 2.50 (53, b), 347 (Z fi f 5) - 4123 (2H, m), 4.95 (m, a), 5.29 (zñ, 0.), 6.10¶ (2H, m), 6.25-5.90 (53, m), 8.9 (3H, t).

Exemoel 25. karbonylíåiíï)É:::;::t::t:,32 g D(-)_a_(?_etylT2'3_diaxo_l_piperazin°' E yra 1 15 ml vattenfri metylenklorid för- SaÜg@$ med 0,1 g Nëmetylmorfolin. Den bildade lösningen kyldes till :ïylííïlÉïíšaïíísdïídbíïdiïínåïf ílTlï i 1 och -20° under en timme Reakt' -n : e.l°sn1n§en äásaïtes mellan -lo H ¿ ¶ . . ionslosningen försattes droppvis med eï šosnlng av 0,45 E ßïß,B-triklâretylester av 7-amino-3-[5-(1_megy1- ;1:,r;å'í;:eï:âä°lišíffâíïïííïïš? i i m1 och -200 under en timme l" ' anaaue losnlfigen ämsattes mellan -lo ¿_ , _0Sningsmedlet aviagsnaaes genom destilla- Elfítunder feduferat firY°k,"aterstoden tvättades successivt med 5%-ig fl ) natriumvatekarbonatlosning och med mättad natriumkloridlös- nlflå Och torkades därefter över_va tenfritt magnesiumsulfat. Lösnings- medlet avläšsnades genom destillation urder reduce t 'r ck h t i ' ^ 'få Tv OC ° r.. , staden renades medelst pelarkromatografering (silikagel,ybensen/:t:1_ É 7 t IQ ~ a .1 - I ace at) ÉOT blldnlnš av 0,53 g ß,3,5-trifiloretylester av 7-[D(_)- vaoozon-7 a -1-{4~etYl~2,3-dioxo-l-piperazinokarbonylamino)-fenylacetamido]-3- -[5-(1-metyl-l,2,3,4-tetrazolyl)-tiometyl}-A3-cefem-4-karbonsyra med Smälïpunkfißn 125-1350 (sönderdelning), utbyte 69,6 %.Exemoel 25. carbonylíåiíï) É :::; :: t :: t:, 32 g D (-) _ a _ (? _ EthylT2'3_diaxo_l_piperazine ° 'E yra 1 15 ml anhydrous methylene chloride for- SaÜg @ $ with 0.1 g Nëmethylmorpholine The solution formed was cooled to: ïylííïlÉïíšaïíísdïídbíïdiïínåïf ílTlï for 1 and -20 ° for one hour B-Trichlorethyl ethyl of 7-amino-3- [5- (1-methyl-; 1:, r; å'í;: eï: âä ° lišíffâíïïííïïš? Ii m1 and -200 for one hour l '' anaaue losnl nl gene was converted between -lo The solvent was removed by distillation. The residue was washed successively with 5% sodium bicarbonate solution and saturated sodium chloride solution. The mixture was then dried over anhydrous magnesium sulfate. The solvent was reduced. ck hti '^' få Tv OC ° r .., the city was purified by column chromatography (silica gel, ybenzene /: t: 1_ É 7 t IQ ~ a .1 - I ace at) ÉOT blldnlnš av 0,53 g ß, 3, 5-tri oret loretyl ester of 7- [D (_) -vazone-7α-1- {4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3- - [5- (1-methyl-1,2 , 3,4-tetrazolyl) -thiomethyl} -A3-cephem-4-carboxylic acid with Smälïpunk fi ßn 125-1350 (decomposition), yield 69.6%.

IR (KBr) cnfl: QC=O 1780, 1715, 1630. (2) En lösning av 0,5 5 B,3,B-trikloretylester av 7-[D(-)-a- -(d-etyl-2,3-dioxo-l-piperazinokarbonylamino)-fenylacetamido]-3-[5- -(1-metyl-l,2,3,4-tetrazolyl)-tiometyl]-A3-cefem-4-karbonsyra försat- tes med 0,5 g zinkstoft och 0,5 ml ättiksyra och den bildade bland- ningen omsattes 1,5 timmar. Efter omsättningen underkastades vätskan "sellaite"-filtrering och filtratet befriades från lösningsmedlet genom destillation under reducerat tryck. Återstoden löstes i 15 ml vatten och den erhållna lösningen inställdes på pH 1,5 genom till- sats av 2N saltsyra för avsättning av kristaller. De avsatta kri- stallerna tillvaratogs genom filtrering, torkades och tvättades med etylacetat för bildning av 7-[D(-)-a-(4-etyl-2,3-dioxo-l-piperazino- karbonylamino)-fenylacetamido]-3-[S-(l-metyl-l,2,3,4-tetrazoly1)_ -tiometyl]-A3-cefem-4-karbonsyra med smältpunkten*l63-l65° (sönder- delning), utbyte 82,1 %.IR (KBr) cnfl: QC = 0 1780, 1715, 1630. (2) A solution of 0.5 B, 3,3-B-trichloroethyl ester of 7- [D (-) - α- - (d-ethyl-2 , 3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3- [5- - (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl] -A3-cephem-4-carboxylic acid was added with 0 , 5 g of zinc dust and 0.5 ml of acetic acid and the resulting mixture was reacted for 1.5 hours. After the reaction, the liquid was subjected to "sellaite" filtration, and the filtrate was freed from the solvent by distillation under reduced pressure. The residue was dissolved in 15 ml of water and the resulting solution was adjusted to pH 1.5 by adding 2N hydrochloric acid to deposit crystals. The deposited crystals were collected by filtration, dried and washed with ethyl acetate to give 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3- [S- (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl] -A3-cephem-4-carboxylic acid, m.p. * 1.63-165 ° (dec.), Yield 82.1%.

Exempel 26 10,0 g D(-)-w-(4-etyl-2,3-dioxo-1-piperazinokarbonylamino)- -p-hydroxifenylättiksyra suspenderades i 60 ml vattenfri metylen- klorid och 6,81 g trimetylsilylklorid sattes till denna suspension.Example 26 10.0 g of D (-) - w- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetic acid was suspended in 60 ml of anhydrous methylene chloride and 6.81 g of trimethylsilyl chloride was added thereto. suspension.

Blandningen kyldes till 50, varefter man droppvis tillsatte 6,04 g trietylamin vid samma temperatur under 15 minuter och omrördes blandningen 90 minuter vid 10 - 150, dvs tills reaktionen var full- bordad. Reaktionsblandningen kyldes till -20°, försattes med 2,18 g dimetylformamid och 3,25 9 triklormetylklorformiat tillsattes droppvis under en tidrymd av 15 minuter. Den erhållna blandningen omsattes 120 minuter vid samma temperatur.The mixture was cooled to 50, then 6.04 g of triethylamine was added dropwise at the same temperature for 15 minutes and the mixture was stirred for 90 minutes at 10-150, ie until the reaction was complete. The reaction mixture was cooled to -20 °, added with 2.18 g of dimethylformamide and 3.25 g of trichloromethylchloroformate was added dropwise over a period of 15 minutes. The resulting mixture was reacted for 120 minutes at the same temperature.

Separat suspenderades 10,0 g 7-amino-3-[5-(1-metyl-1,2,3,4- -tetrazolyl)tiometyl]-A3-cefem-4-karbonsyra i 90 ml vattenfri metylenklorid och 8,62 g trimetylsilylklorid sattes till suspensionen under iskylning. Blandningen försattes dropnvis med 7,40 g tri- etylamin under en tidrymd av 20 minuter, fick omsättas 60 minuter vid samma temperatur och sattes sedan droppvis till den ovan nämnda reaktionsblandningen vid -15 till -100 under en tídrymd av 30 minu- ter och tilläts reagera vid samma temperatur under 90 minuter.Separately, 10.0 g of 7-amino-3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -A3-cephem-4-carboxylic acid was suspended in 90 ml of anhydrous methylene chloride and 8.62 g of trimethylsilyl chloride was added to the suspension under ice-cooling. The mixture was added dropwise with 7.40 g of triethylamine over a period of 20 minutes, allowed to react for 60 minutes at the same temperature and then added dropwise to the above-mentioned reaction mixture at -15 to -100 over a period of 30 minutes and allowed react at the same temperature for 90 minutes.

Reaktionstemperaturen höjdes sedan till 0° och 6,69 9 metanol sattes till reaktionsblandningen.The reaction temperature was then raised to 0 ° and 6.69 g of methanol was added to the reaction mixture.

Blandningen omsattes ytterligare 30 minuter vid Oo och 78082-'04-7 100 hälldes i 280 ml av en vattenlösning, innehållande 10,0 g natrium- vätekarbonat. Den bildade lösningen separerades i ett vattenskikt och ett organiskt skikt. Det organiska skiktet extraherades med 20 ml 3%-ig NaHCO3-vattenlösning och extraktet sattes till nämnda vattenskikt. Den kombinerade vattenlösningen försattes med 130 ml acetonitril. Efter inställning av blandningens pH på 5,0 genom tillsats av 6N HCl och tillsats av 4 g aktivt kol filtrerades den.The mixture was reacted for an additional 30 minutes at 0 ° C and poured into 280 ml of an aqueous solution containing 10.0 g of sodium bicarbonate. The resulting solution was separated into an aqueous layer and an organic layer. The organic layer was extracted with 20 ml of 3% aqueous NaHCO 3 solution and the extract was added to said aqueous layer. The combined aqueous solution was added with 130 ml of acetonitrile. After adjusting the pH of the mixture to 5.0 by adding 6N HCl and adding 4 g of activated carbon, it was filtered.

Filtratet upphettades till 40°, inställdes på pH 2,0 genom tillsats av 6N HCl, omrördes 120 minuter vid 350 och 60 minuter vid 250 samt kyldes sedan med is för avsättning av kristaller. De ut- skilda kristallerna tillvaratogs genom filtrering, tvättades med 20 ml 20%-ig acetonitrillösning i vatten och torkades för bildning av kristaller av 7-[D(-)-W*(4-etylf2,3-dioxo-1-piperazinokarbonyl- amino)-p-hydroxifenyl-acetamido]-3-[5-(1-metyl-1,2,3,4-tetra- zolyl)tiometyl]-A3-cefem-4-karbonsyra, med smältpunkten 170 - 171° (sönderdelning), utbyte 78,3 %.The filtrate was heated to 40 °, adjusted to pH 2.0 by the addition of 6N HCl, stirred for 120 minutes at 350 and 60 minutes at 250 and then cooled with ice to deposit crystals. The separated crystals were collected by filtration, washed with 20 ml of 20% acetonitrile solution in water and dried to give crystals of 7- [D (-) - W * (4-ethylph2,3-dioxo-1-piperazinocarbonyl). amino) -p-hydroxyphenyl-acetamido] -3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -A3-cephem-4-carboxylic acid, m.p. 170-171 ° ( decomposition), yield 78.3%.

NMR (dö-aceton + D20) T'-värde: 8,9 (3H, t), 6,8 - 6,3 (4H, m), 6,2 - 5,9 (7H, m), 5,78 (ZH, ABq), 5,04 (1H, d), 4,58 (1H, S), 4,31 (1H, Ö), 3,08 (4H, A2B2q).NMR (do-acetone + D 2 O) T 'value: 8.9 (3H, t), 6.8 - 6.3 (4H, m), 6.2 - 5.9 (7H, m), δ, 78 (ZH, ABq), 5.04 (1H, d), 4.58 (1H, S), 4.31 (1H, Ö), 3.08 (4H, A2B2q).

Exempel 27 I en blandning av 25 ml vattenfri metylenklorid och 6 ml dimetylformamid löstes 3,44 g natriumsalt av D(-)-flL(4-etyl-2- -oxo-1-piperazínokarbonylamino)-p-hydroxifenylättiksyra och en droppe N-metylmorfolin tillsattes. Den bildade lösningen kyldes till mellan -15 och -100. Lösningen försattes droppvis med 1,14 g etylklorkarbonat under en tidrymd av fem minuter och reaktions- blandningen utfördes en timme vid en temperatur av -15 till -100.Example 27 In a mixture of 25 ml of anhydrous methylene chloride and 6 ml of dimethylformamide was dissolved 3.44 g of sodium salt of D (-) - fl L (4-ethyl-2-oxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetic acid and a drop of N- methylmorpholine was added. The resulting solution was cooled to between -15 and -100. The solution was added dropwise with 1.14 g of ethyl chlorocarbonate over a period of five minutes and the reaction mixture was carried out for one hour at a temperature of -15 to -100.

Därefter tillsattes 1,22 ml N,0-bis(trimetylsilyl)-acetamid och den erhållna blandningen kyldes till -20°l Separat suspenderades 3,28 g 7~amino-3-[5-(1-metyl-1,2,3,4- -tetrazolyl)tiometyl]-A3-cefem-4-karbonsyra i 50 ml metylenklorid och 3,66 ml N,0-bis(trimetylsilyl)4acetamid tillsattes för bild- ning av en lösning, som därefter kyldes till -20°. Denna lösning sattes till nämnda blandning, kyld till -200, och den erhållna blandningen omsattes två timmar vid -15 till -10° och därefter -5 till 0° under tvâ timmar.Then 1.22 ml of N, O-bis (trimethylsilyl) -acetamide were added and the resulting mixture was cooled to -20 °. Separately, 3.28 g of 7-amino-3- [5- (1-methyl-1,2) was suspended. 3,4-Tetrazolyl) thiomethyl] -A3-cephem-4-carboxylic acid in 50 ml of methylene chloride and 3.66 ml of N, O-bis (trimethylsilyl) 4-acetamide were added to give a solution, which was then cooled to -20 ml. °. This solution was added to said mixture, cooled to -200, and the resulting mixture was reacted for two hours at -15 to -10 ° and then -5 to 0 ° for two hours.

Efter omsättning avdestillerades lösningsmedlet och åter- 78082011-7 101 stoden försattes med 30 ml mättad natriumkloridlösning och 50 ml acetonitril och_den erhållna blandningen omrördes en timme, var- efter natriumvätekarbonat tillsattes för inställning av pH på 3,0.After reaction, the solvent was distilled off and the residue was added with 30 ml of saturated sodium chloride solution and 50 ml of acetonitrile, and the resulting mixture was stirred for one hour, after which sodium bicarbonate was added to adjust the pH to 3.0.

Acetonitrilskiktet tvättades med en mättad natriumkloridlösning i vatten och lösningsmedlet avdestillerades. Eter sattes till äter- stoden och blandningen filtrerades för bildning av 3,3 g (utbyte 52,1 %) 7-[D-(-)-W-(4-etyl-2-oxo-1-piperazinokarbonylamino)-p- -hydroxifenylacetamido]-3-[5-(1-metyl-1,2,3,4-tetrazolyl)tiometyll- -A?-cefem-4-karbonsyra, med smältpunkten 120 - 123° (sönderdelning. 1 IR (Kur) cm' = ~/ 1770, 1715 - 1660.The acetonitrile layer was washed with a saturated aqueous sodium chloride solution and the solvent was distilled off. Ether was added to the ether column and the mixture was filtered to give 3.3 g (yield 52.1%) of 7- [D - (-) - N- (4-ethyl-2-oxo-1-piperazinocarbonylamino) -p- -hydroxyphenylacetamido] -3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -N-cephem-4-carboxylic acid, m.p. 120 DEG-123 DEG (decomposition. 1 IR (Cure) cm '= ~ / 1770, 1715 - 1660.

C=O Föreningar med formeln (V) utvaldes och omsattes med 7-amino- -3-metyl-A3-cefem-4-karbonsyra på ovan beskrivet sätt för bildning av följande föreningar: 7-[D(-)-w-(4-n-butyl-3,6-dimetyl-2-oxo-1-piperazinokarbonyl- amino)fenylacetamido]-3-metyl-A?-cefem-4-karbonsyra, smältpunkt: 120 - 1250 (sönderdelning) Ia (Kßr) cm"= VC=O 1775, 1720, 1700, 1680; 7-[D(-)-N-(4-n-butyl~3,3,6-trimetyl-2-oxo-1-piperazinokar- bonylamino)fenylacetamido]-3-metyl-A?-cefem-4-karbonsyra, smältpunkt: 125 - 128° (sönderdelning) IR (Klar) cm"1= 9C=O 1780, 1720 i- 1660.C = O Compounds of formula (V) were selected and reacted with 7-amino--3-methyl-A3-cephem-4-carboxylic acid as described above to give the following compounds: 7- [D (-) - w- ( 4-n-butyl-3,6-dimethyl-2-oxo-1-piperazinocarbonylamino) phenylacetamido] -3-methyl-N, -cephem-4-carboxylic acid, melting point: 120 - 1250 (decomposition) Ia (Kßr) cm -1 = VC = O 1775, 1720, 1700, 1680; 7- [D (-) - N- (4-n-butyl-3,3,6-trimethyl-2-oxo-1-piperazinocarbonylamino) phenylacetamido ] -3-methyl-N-cephem-4-carboxylic acid, melting point: 125 - 128 ° (decomposition) IR (Clear) cm -1 = 9C = 0 1780, 1720 i-1660.

Exempel 28 (1) I 20 ml vattenfri metylenklorid suspenderades 1,72 g 2,3-dioxo-1-piperazinättiksyra och man tillsatte droppvis 2,38 g trimetylsilylklorid och 2,22 g trietylamin i nämnd ordning vid rums- temperatur, varefter den bildade blandningen omsattes 1,5 timmar vid samma temperatur. Reaktionsblandningen kyldes till -500 och 1,0 g triklormetylklorformiat tillsattes droppvis, varefter lös- ningen omsattes 1,5 timmar vid samma temperatur. Reaktionsbland- ningen kyldes till -500 och 1,0 g triklormetylklorformiat tillsattes droppvis, varefter lösningen omsattes 30 minuter vid samma tem- peratur och en timme vid -300. Temperaturen i lösningen höjdes till rumstemperatur under en timme för fullbordande av reaktionen.Example 28 (1) In 20 ml of anhydrous methylene chloride was suspended 1.72 g of 2,3-dioxo-1-piperazineacetic acid and 2.38 g of trimethylsilyl chloride and 2.22 g of triethylamine were added dropwise in that order at room temperature, after which the the mixture was reacted for 1.5 hours at the same temperature. The reaction mixture was cooled to -500 and 1.0 g of trichloromethyl chloroformate was added dropwise, after which the solution was reacted for 1.5 hours at the same temperature. The reaction mixture was cooled to -500 and 1.0 g of trichloromethyl chloroformate was added dropwise, after which the solution was reacted for 30 minutes at the same temperature and one hour at -300. The temperature of the solution was raised to room temperature for one hour to complete the reaction.

Lösningsmedlet avdestillerades under reducerat tryck för bildning av kristaller.The solvent was distilled off under reduced pressure to give crystals.

Separat suspenderades 1,5 g D(-)-M-aminofenylättiksyra i 30 ml vattenfri metylenklorid, som droppvis försattes med 2,4 g trimetylsilylklorid och 2,1 g trietylamin i nämnd ordning vid rumstemperatur. Vid nämnda temperatur omsattes den bildade reak- vaoazou-7 102 tionsblandningen en timme för ástadkommande av fullständig sily- lering. Reaktionslösningen kyldes därefter till -400 och försattes droppvis med en lösning de ovan erhållna kristallerna i 40 ml vattenfri metylenklorid. Den bildade blandningen omsattes 30 minuter vid nämnda temperatur och en timme vid Oo, varefter temperaturen i blandningen höjdes till rumstemperatur under 30 minuter för fullbordande av reaktionen. . Z Efter avslutad reaktion nedfördes reaktionslösningen i 30 ml vatten och pH i den bildade lösningen inställdes på 1,0 med 2N saltsyra. Efter förvaring under bildning av separata skikt uttogs det organiska skiktet och 30 ml vatten sattes till detta, varefter pH däri inställdes på 8,0 med mättad natriumvätekarbonatlösning i vatten. Den erhållna blandningen förvarades och det utskilda vatten- skiktet uttogs och försattes med 30 ml etylacetat, varefter 2N saltsyra tillsattes för inställning av pH på 1,0. Den erhållna blandningen förvarades och det utskilda organiska skiktet uttogs, tvättades med 20 ml mättad natriumkloridlösning i vatten och tor- kades därefter på vattenfritt magnesiumsulfat. Lösningsmedlet avdestillerades under reducerat tryck och återstoden behandlades med dietyleter för bildning av 3,0 g (utbyte 85 %) vita kristal- ler av D(-)-w-(4-karboximetyl-2,3-dixo-1-piperazínokarbonylamino) fenylättiksyra med smältpunkten 70 - 750. 1* QNH :son QC=O 1270 z-coon), 1710 - 1685 (-coN <) NMR (dö-DMSO) ppm-värden; 3,45 - 4,30 (414, m >cH2 x z) IR (Klar) cm' 4,17 (zu, s;cra2), 5,38 (m, a, -j-cn), 7,40 (SH, s, aromatisk proton), 9,80 (m, a, :NHL (2) I 30 ml vattenfri metylenklorid suspenderades 3,49 g D(-)-N-(4-karboximetyl-2,3-dioxo-1 ättiksyra och 1,1 g N-metylmorfolin tillsattes vid rumstemperatur -piperazinokarbonylamino)fenyl- och den bildade blandningen omsattes 30 minuter vid denna tempera- tur. Reaktionslösningen kyldes till -40° och 1,1 g etylkloracetat -200 och en timme vid 00. Reaktionsblandningen kyldes därefter till -500.Separately, 1.5 g of D (-) - M-aminophenylacetic acid was suspended in 30 ml of anhydrous methylene chloride, which was added dropwise with 2.4 g of trimethylsilyl chloride and 2.1 g of triethylamine in that order at room temperature. At said temperature, the formed reaction mixture was reacted for one hour to effect complete silylation. The reaction solution was then cooled to -400 and the crystals obtained above were added dropwise to a solution in 40 ml of anhydrous methylene chloride. The resulting mixture was reacted for 30 minutes at said temperature and one hour at 0 ° C, after which the temperature of the mixture was raised to room temperature for 30 minutes to complete the reaction. . After completion of the reaction, the reaction solution was immersed in 30 ml of water and the pH of the resulting solution was adjusted to 1.0 with 2N hydrochloric acid. After storage to form separate layers, the organic layer was removed and 30 ml of water was added thereto, after which the pH was adjusted to 8.0 with saturated aqueous sodium bicarbonate solution. The resulting mixture was stored and the separated aqueous layer was removed and added with 30 ml of ethyl acetate, after which 2N hydrochloric acid was added to adjust the pH to 1.0. The resulting mixture was stored and the separated organic layer was taken out, washed with 20 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was treated with diethyl ether to give 3.0 g (yield 85%) of white crystals of D (-) - w- (4-carboxymethyl-2,3-dixo-1-piperazinocarbonylamino) phenylacetic acid with melting point 70 - 750. 1 * QNH: son QC = O 1270 z-coon), 1710 - 1685 (-coN <) NMR (die-DMSO) ppm values; 3.45 - 4.30 (414, m> cH2 xz) IR (Clear) cm -1 4.17 (zu, s; cra2), 5.38 (m, a, -j-cn), 7.40 ( SH, s, aromatic proton), 9.80 (m, a,: NHL (2) In 30 ml of anhydrous methylene chloride was suspended 3.49 g of D (-) - N- (4-carboxymethyl-2,3-dioxo-1 acetic acid and 1.1 g of N-methylmorpholine were added at room temperature (piperazinocarbonylamino) phenyl and the resulting mixture was reacted for 30 minutes at this temperature, the reaction solution was cooled to -40 ° and 1.1 g of ethyl chloroacetate -200 and one hour at 0 DEG. The reaction mixture was then cooled to -500.

Lösningen försattes droppvis med 3,73 g trietylaminsalt av tillsattes, varefter lösningen omsattes 30 minuter vid 7-amino-3-acetoximetyl-A3-cefem-4-karbonsyra i 20 ml vattenfri metylenklorid, medan temperaturen upprätthölls vid -400, och den 7808204-'7 103 bildade lösningen omsattes 30 minuter vid* -400 och en timme vid OO, varefter lösningsmedlet avdestillerades under reducerat tryck och återstoden försattes med 30 ml vatten och 30 ml etyl- acetat. pH i den erhållna blandningen inställdes på 8,0 med natrium- vätekarbonat. Vattenskiktet avskildes, försattes med 30 ml metylen- klorid och pH däri inställdes pà 1,0 med 2N saltsyra. Det avskilda organiska skiktet uttogs, tvättades med 20 ml mättad natriumklorid- lösning, torkades över vattenfritt magnesiumsulfat och destillerades under reducerat tryck för eliminering av lösningsmedlet. Den bildade återstoden renades genom pelarkromatografering (eluering med bensen/etylacetat) för bildning av 2,1 g (utbyte 34,8 %) vita kristaller av 7-[D(-)-N-(4-karboximetyl-2,3-dioxo-1-piperazino- karbonylamino)-fenylacetamido]-3-acetoximetyl-A3-cefem-4-karbonsyra med en smältpunkt av 185 - 1900 (sönderdelning)1 1 Omid 3300 QC=O 1775, 1720 - 1665 In (Ksr) cm'1= Föreningar med formeln (IV) och reaktionsbenägna derivat av föreningarna med formeln (V) utvaldes och omsattes pà ovan angivet sätt för bildning av följande föreningar: 7-{P(-)-N-[4-(2-karboxietyl)-2,3-dioxo-1-piperazinokarbonyl- amino]fenylacetamidoj-3-acetoximetyl-A3-cefem-4-karbonsyra smältpunkt; 150 - 1s5° (sönaeraeining) IR (rer) cnffl 0C=O 1773 (lakt-am), 1720 - 1685 (-coN<); 7-[D(-)-W-(4-karboximetyl-2,3-dioxo-1-piperazinokarbonyl- amino)fenylacetamido]-3-[5-(1-metyl-1,2,3,4-tetrazolyl)tiometyl]- -A3~cefem-4-karbonsyra,W 0 smäitpunkt: 170 - 17s° (sönderdelning) IR (Kßr) m4: 0C=O 1770 (iaktam), w 1720 - 1680 (-CON<); 7-in(-)-ß-[4-(2-karboxietyl)-2,3-dioxo-1-piperazinokarbonyl- amino]fenylacetamid%-3-[5-(1-metgl-1,2,3,4-tetrazolyl)tiometyl]- -A;-cefem-4-karbonsyra, smältpunkt: 162 - 1650 (sönderdelning) IR (xßr) cm'1= 0C=o 1770 (lax-ram), 1710 - 1680 (-CON ); 7-{_n (-1 -w- [4- (a-karboxipropyl) -2 , a-dioxo-wpiperazinokarbo- nylamino]fenylacetamido}-3-[5-(1emetyl-1,2,3,4-tetrazolyl)tiometyll- -A?-cefem-4-karbonsyra, ~ 78082011' 7 104 smältpunkt: 1450 (sönderdelníng) IR (Kßr) cmq: 0 1775 (laktam), 1720 - 1680 (-CON ).The solution was added dropwise with 3.73 g of triethylamine salt was added, after which the solution was reacted for 30 minutes at 7-amino-3-acetoxymethyl-A3-cephem-4-carboxylic acid in 20 ml of anhydrous methylene chloride, while maintaining the temperature at -400, and the 7808204- The solution formed was reacted for 30 minutes at -400 and one hour at 0 DEG C., after which the solvent was distilled off under reduced pressure and the residue was added with 30 ml of water and 30 ml of ethyl acetate. The pH of the resulting mixture was adjusted to 8.0 with sodium bicarbonate. The aqueous layer was separated, added with 30 ml of methylene chloride and the pH therein was adjusted to 1.0 with 2N hydrochloric acid. The separated organic layer was removed, washed with 20 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulfate and distilled under reduced pressure to eliminate the solvent. The residue formed was purified by column chromatography (eluting with benzene / ethyl acetate) to give 2.1 g (yield 34.8%) of white crystals of 7- [D (-) - N- (4-carboxymethyl-2,3-dioxo -1-piperazinocarbonylamino) -phenylacetamido] -3-acetoxymethyl-33-cephem-4-carboxylic acid, m.p. 185 DEG-1900 DEG C. (decomposition) 1 = Compounds of formula (IV) and reaction derivatives of the compounds of formula (V) were selected and reacted in the above manner to give the following compounds: 7- {P (-) - N- [4- (2-carboxyethyl) - 2,3-dioxo-1-piperazinocarbonylamino] phenylacetamido-3-acetoxymethyl-33-cephem-4-carboxylic acid melting point; 150-15 ° (solar unit) IR (rer) cnf fl 0C = O 1773 (lactam-am), 1720 - 1685 (-coN <); 7- [D (-) - N- (4-carboxymethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -A3-cephem-4-carboxylic acid, W 0 melting point: 170 - 17s ° (decomposition) IR (Kßr) m 4: OC = O 1770 (lactam), w 1720 - 1680 (-CON <); 7-in (-) - β- [4- (2-carboxyethyl) -2,3-dioxo-1-piperazinocarbonylamino] phenylacetamide% -3- [5- (1-methyl] -1,2,3,4 -tetrazolyl) thiomethyl] -A-cephem-4-carboxylic acid, melting point: 162 - 1650 (decomposition) IR (xßr) cm -1 = OC = o 1770 (salmon frame), 1710 - 1680 (-CON); 7 - {_ n (-1-N- [4- (α-carboxypropyl) -2, α-dioxo-piperazinocarbonylamino] phenylacetamido} -3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl-α-β-cephem-4-carboxylic acid, melting point: 1450 (decomposition) IR (Kßr) cm-1: 1775 (lactam), 1720 - 1680 (-CON).

C=O Exempel 29 Föreningar med formeln (V), (IV) eller(VI) och reaktions- benägna derivat av föreningar med formeln (III) eller (V) eller föreningar med formeln (VII) utvaldes och omsattes på i exemplen avseende förfarandena (1), (2) och (3) beskrivet sätt för bildning av följande föreningar: 7-[D(-)-W-(4-n-butylaminokarbonyl-2,3-dioxo-1-piperazino- karbonylamino)fenylacetamido]-3-[S-(1-metyl-1,2;3,4-tetrazolyl)tio- metyl]-A3-cefem-4-karbonsyra, smältpunkt: 144° (sönderdelning); 7-[D(-)-w-(4-etyl-2,3-dioxo-1-piperazino-karbonylamino)fe- nylacetamido]-3-n-propyltiometyl-A?-cefem-4-karbonsyra, smältpunkt: 155 - 1570 (sönderdelníng; 7-[D(-)-N-(4-etyl-2,3-dioxo-1-piperazinokarbonylamino)fenyl-' acetamido]-3-karboximetyltiometyl-A3-cefem-4-karbonsyra, smältpunkt: 135 - 137° (sönderdelning); _ ftalidyl-7-[D(-)-N-(4-etyl-2,3-diogo-1-piperazinokarbonyl- amino)-p-hydroxifenylacetamído1-3-[S-(1-metyl-1,2,3,4-tetrazolyl)- tiometyl]-A?-cefem-4-karboxylat, smältpunkt: 152 - 1550 (sönderdelning) IR (mer) cm'1= JNH 3330 c=O 1780, 1715, 1670; 7-[D(-)-W-(4-etyl-2,3-dioxo-1-piperazinokarbonylamíno)-2- -tienylacetamido]-3-[5-(1-metyl-1,2,3,4-tetrazolyl)tiometyl]-A§- -cefem-4-karbonsyra, smältpunkt: 160 - 162° (sönderdelning) :R (mar) cm'1=x)c=o 1770 1710 - 1660; 7-[D(-)4W-(4-ß-kloretyl-2,3-dioxo-1-piperazino-karbonylamino)- -p-hydroxifenylacetamido]-3-[5-(1-metyl-1,2,3,4-tetrazolyl)tio- metyl]-A?-cefem-4-karbonsyra, smältpunkt: 193 - 1950 (sönderdelning); 7-[D(-)-W-(4-allyl-2,3-dioxo-1-piperzino-karbonylamino)-p- -hydroxifenylacetamido]-3-[S-(1-metyl-1,2,3,4-tetrazolyl)tiometyl]- -A;-cefem-4-karbonsyra, smältpunkt: 183 - 1850 (sönderdelning); 7-[D(-)-N-(2,3-dioxo-1-piperazinokarbonylamíno)-fenylaceta- vaoàzoa-7 105 mido]-3-[5-(1-metyl-1,2,3,4-tetrazolyl)-tiometyl]-A?-cefem-4- -karbonsyra, smältpunkt: 153 - 1570 (sönderdelníng); n-pentyl-7-[D(-)-w-(4-etyl-2,3-dioxo-1-piperazino-karbonyl- amino)-p-hydroxifenylacetamido]-3-[5-(1-metyl-1,2,3,4-tetrazolyl) tiometyl]-Aë-cefem-4-karboxylat, smältpunkt: 105 - 11o° (sönaerdelning) valeryloximety1-7-[D(-)-N-(4-etyl-2,3-dioxo~1-piperazino- karbonylamino)-p-hydroxifenylacetamido]-3-[S-(1-metyl-1,2,3,4- tetrazolyl)tiometyl]-A?-cefem-4-karboxylat, smältpunkt: 105 - 110°'(sönderdelning); pivaloyloximetyl-7-[D(-)-N-(4~etyl-2,3-dioxo-1-piperazino- karbonylamino)-p-hydroxifenylacetamido]-3-[5-(1~metyl-1,2,3,4- -tetrazolyl)tiometyl]-A?-cefem-4-karboxylat, shältpunkt: 110 * 1150 (sönderdelning); isopropoxímetyl-7-[D(-)-N-(4-etyl-2,3-dioxo-1-piperazíno- karbønylamino)-p-hydroxifenylacetamidol-3-[5-(1-metyl-1,2,3,4- -tetrazolyl)tiometyl]-A?-cefem-4-karboxylat, smältpunkt: 115 - 1200 (sönderdelning.C = 0 Example 29 Compounds of formula (V), (IV) or (VI) and reactive derivatives of compounds of formula (III) or (V) or compounds of formula (VII) were selected and reacted in the examples for the procedures (1), (2) and (3) described methods for the formation of the following compounds: 7- [D (-) - N- (4-n-butylaminocarbonyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -3- [S- (1-methyl-1,2; 3,4-tetrazolyl) thiomethyl] -A3-cephem-4-carboxylic acid, melting point: 144 ° (decomposition); 7- [D (-) - w- (4-ethyl-2,3-dioxo-1-piperazino-carbonylamino) phenylacetamido] -3-n-propylthiomethyl-N, -cephem-4-carboxylic acid, m.p .: 155 1570 (decomposition; 7- [D (-) - N- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenyl] acetamido] -3-carboxymethylthiomethyl-33-cephem-4-carboxylic acid, m.p .: 135 - 137 ° (decomposition); - Phthalidyl-7- [D (-) - N- (4-ethyl-2,3-diogo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamidol] -3- [S- (1 -methyl-1,2,3,4-tetrazolyl) -thiomethyl] -N-cephem-4-carboxylate, melting point: 152 - 1550 (decomposition) IR (more) cm -1 = JNH 3330 c = O 1780, 1715 , 1670; 7- [D (-) - N- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -2-thienylacetamido] -3- [5- (1-methyl-1,2,3 , 4-tetrazolyl) thiomethyl] -A§- -cephem-4-carboxylic acid, melting point: 160 - 162 ° (decomposition): R (mar) cm -1 = x) c = o 1770 1710 - 1660; 7- [D (-) 4W- (4-β-chloroethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido] -3- [5- (1-methyl-1,2,3 , 4-tetrazolyl) thiomethyl] -N-cephem-4-carboxylic acid, m.p .: 193 - 1950 (decomposition); 7- [D (-) - N- (4-allyl-2,3-dioxo-1-piperzinocarbonylamino) -β-hydroxyphenylacetamido] -3- [S- (1-methyl-1,2,3, 4-tetrazolyl) thiomethyl] -N-cephem-4-carboxylic acid, m.p .: 183-1850 (dec.); 7- [D (-) - N- (2,3-dioxo-1-piperazinocarbonylamino) -phenylacetavavoazo-7 105 mido] -3- [5- (1-methyl-1,2,3,4-tetrazolyl ) -thiomethyl] -N-cephem-4-carboxylic acid, m.p .: 153-1570 (dec.); n-pentyl-7- [D (-) - w- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido] -3- [5- (1-methyl-1 , 2,3,4-tetrazolyl) thiomethyl] -α-cephem-4-carboxylate, melting point: 105-110 ° (son division) valeryloxymethyl- 7- [D (-) - N- (4-ethyl-2,3- dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido] -3- [S- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -N-cephem-4-carboxylate, m.p .: 105 - 110 ° '(decomposition); pivaloyloxymethyl-7- [D (-) - N- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido] -3- [5- (1-methyl-1,2,3 , 4-tetrazolyl) thiomethyl] -N-cephem-4-carboxylate, melting point: 110 * 1150 (decomposition); isopropoxymethyl-7- [D (-) - N- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamidol-3- [5- (1-methyl-1,2,3, 4-tetrazolyl) thiomethyl] -N-cephem-4-carboxylate, m.p .: 115-1200 (dec.

Claims (14)

1. 7808204-7 106 PATENTKRAV l. Förfarande för framställning av en förening med den allmänna formeln (X)n' . ' 3 _ A-N N-o-nH-ca-coua--f j 1, (I) try ä åg Å-N\f¿»_CH2R 0 (RZR3),,, . ' çoonl vari R5 är Cl_8-alkyl, tienyl, fenyl eller hydroxifenyl; Rl är en väte- atom, en alkalimetallatom, en ftalidylgrupp, en metoximetylgrupp, en valeryloximetylgrupp, en isopropoximetylgrupp eller en pivaloyloximetyl- grupp; n är l eller 2; X är syre och defn X-en är bundna i varje kom- bination vid 2-, 3- och 5-ställningarna i oiperazinringen; m är 4 - n; varje par av R2 och R3 är bundna till samma kolatom och m par av R2 och R3, som kan vara lika eller olika, betecknar individuellt väte eller Cl_8-alkyl; A betecknar väte eller C2_4-alkenyl, fenyl, lägre alkylsulfonyl, Cl_4-acylkarbamoyl eller N-(lägre alkyl)-aminokarbonyl, eller en Cl_l2-alkylgrupp, som kan vara substituerad med klor, hydroxi eller karboxi, eller en Cl_l8-acylgrupp eller en lägre alkoxikarbonyl- grupp; Y är en syre- eller svavelatom; och R4 är väte, azido, pyridi- nium, lägre alkoxi, Cl_4-acylori, karbamoyloxi, lägre alkoxitiokarbonyl~ tio, lägre alkyltio (vilken lägre alkyltiogrupp kan vara substituerad med karboxi), eller någon av grupperna oxazolyltio, tiazolyltio, tia- zolinvltio,_imidazolyltio, pyridazinyltio, pyrimidinyltio, oxadiazolyl- tio, tiadiazolyltio, triazolyltio, tetrazolyltio, piperazinyltiokar- bonyltio, isoxazolylkarbonyltio, (pyridyl-1-oxid)tio eller (5-oxo~2,5- dihydro-1,2,4-triazinyl)tio, som kan vara substituerade med lägre alkyl, k ä n n e t e c k n a t därav, att man (l) omsätter en förening med den allmänna formeln RHÉH-os-corxnïs u I ' Rs -_ 0 N /_ cnzn - (n) _ _ ç _ - - Qonll 7808204 - 7 107 vari R4 och Rs har den angivna betydelsen; Rll är väte, en konven- tionell saltbildande katjon, vilken användes inom detta område, eller en konventionell karboxiskyddande grupp, vilken användes inom detta område; och R7 är väte eller en konventionell silyl- eller fos- forskyddande grupp med förmåga att med lätthet avlägsnas genom behand- ling med H20 eller en alkohol, med ett reaktionsbenäget derivat i tiokarboxigruppen av en förening med den allmänna formeln 1 A-N N-c-on - (III) vari A, X, Y, R2, R3, m och n har den angivna betydelsen, eller (2) omsätter en förening med den allmänna formeln 7_- al? S > _ . R lg N\T;l~CHaRn I -. (IV) § coonll vari Rll, R4 och R7 har den angivna betydelsen, med en förening med den allmänna formeln (X)n rPW A-N N- -NH-CH-c-oH_ (v) H | n . 2 3 Y R5 o \ (R R ) m vari A, R2, R3, R5, X, Y, m och n har den angivna betydelsen, eller med ett reaktionsbenäget derivat i'karboxigruppen av en förening med formeln (V), eller (3) omsätter en förening med den allmänna formeln . (X)n _» S A-N N-H-NH-en-coun-alïw” (If) I 2 Y H5 N.,/ CHZB * ' (R R3> ° 11 m _ COOR 7808204-7 108 vari A, Rl, R2, R3, Rs, X, Y, m och n har den angivna betydelsen, och B är en substituent med förmåga att med lätthet ersättas av ett nukleofilt medel, med en förening med den allmänna formeln Ram (VIII) vari ä är väte, eller en alkalimetall- eller jordalkalimetallatom; och R är azido, lägre alkoxi, lägre alkyltio (nämnda lägre alkyltio- grupp kan vara substituerad med karboxi) eller en av gruppena oxazo- lyltio, tiazolyltio, tiazolinyltio, imidazolyltio, pyridazinyltio, pyrimidinyltio, oxadiazolyltio, tiadiazolyltio, triazolyltio, tetra- zolyltio, piperazinyltiokarbonyltio, isoxazolyltiokarbonyltio, (pyridyl-l-oxid)-tio eller (5-oxo-2,5-dihydro-l,2,4-triazinyltio, som eventuellt kan vara substituerad med en lägre alkylgrupp eller med pyridin. “H1. 7808204-7 106 CLAIMS 1. A process for the preparation of a compound of general formula (X) n '. '3 _ A-N N-o-nH-ca-coua - f j 1, (I) try ä åg Å-N \ f¿ »_CH2R 0 (RZR3) ,,,. wherein R 5 is C 1-8 alkyl, thienyl, phenyl or hydroxyphenyl; R 1 is a hydrogen atom, an alkali metal atom, a phthalidyl group, a methoxymethyl group, a valeryloxymethyl group, an isopropoxymethyl group or a pivaloyloxymethyl group; n is 1 or 2; X is oxygen and the def X is bonded in each combination at the 2-, 3- and 5-positions of the oiperazine ring; m is 4 - n; each pair of R 2 and R 3 is attached to the same carbon atom and m pairs of R 2 and R 3, which may be the same or different, represent individual hydrogen or C 1-8 alkyl; A represents hydrogen or C 2-4 alkenyl, phenyl, lower alkylsulfonyl, C 1-4 acylcarbamoyl or N- (lower alkyl) aminocarbonyl, or a C 1-2 alkyl group, which may be substituted by chlorine, hydroxy or carboxy, or a C 1-8 acyl group or a lower alkoxycarbonyl group; Y is an oxygen or sulfur atom; and R 4 is hydrogen, azido, pyridinium, lower alkoxy, C 1-4 acylori, carbamoyloxy, lower alkoxythiocarbonyl-thio, lower alkylthio (which lower alkylthio group may be substituted by carboxy), or any of the groups oxazolylthio, thiazolylthio, thiazolinvio Imidazolylthio, pyridazinylthio, pyrimidinylthio, oxadiazolylthio, thiadiazolylthio, triazolylthio, tetrazolylthio, piperazinylthiocarbonylthio, isoxazolylcarbonylthio, (pyridyl-1-oxide) thio or (5-hydroxy-2,5-2,5-oxo-2,5) thio, which may be substituted by lower alkyl, characterized in that (l) reacting a compound of the general formula RHÉH-os-corxnïs u I 'Rs -_ 0 N / _ cnzn - (n) _ _ ç _ - - Qonll 7808204 - 7 107 wherein R 4 and R 5 have the indicated meaning; R 11 is hydrogen, a conventional salt-forming cation used in this field, or a conventional carboxy-protecting group used in this field; and R 7 is hydrogen or a conventional silyl or phosphorus protecting group capable of being easily removed by treatment with H 2 O or an alcohol, having a reaction-derivative in the thiocarboxy group of a compound of the general formula 1 AN Nc-on - ( III) wherein A, X, Y, R 2, R 3, m and n have the given meaning, or (2) a compound of the general formula 7_-a1? S> _. R lg N \ T; l ~ CHaRn I -. (IV) § coon11 wherein R11, R4 and R7 have the meaning given, with a compound of the general formula (X) n rPW A-N N- -NH-CH-c-oH_ (v) H | n. Y R 5 o (RR) m wherein A, R 2, R 3, R 5, X, Y, m and n have the meaning given, or with a reaction-prone derivative in the carboxy group of a compound of formula (V), or ( 3) reactes a compound of the general formula. (X) n _ »S AN NH-NH-en-coun-alïw” (If) I 2 Y H5 N., / CHZB * '(R R3> ° 11 m _ COOR 7808204-7 108 vari A, R1, R 2, R 3, R 5, R 5, X, Y, m and n have the indicated meaning, and B is a substituent capable of being easily replaced by a nucleophilic agent, with a compound of the general formula Ram (VIII) wherein ä is hydrogen, or an alkali metal or alkaline earth metal atom, and R is azido, lower alkoxy, lower alkylthio (said lower alkylthio group may be substituted by carboxy) or one of the groups oxazolylthio, thiazolylthio, thiazolinylthio, imidazolylthio, pyridazinylthiothiothio, thio , triazolylthio, tetrazolylthio, piperazinylthiocarbonylthio, isoxazolylthiocarbonylthio, (pyridyl-1-oxide) -thio or (5-oxo-2,5-dihydro-1,2,4-triazinylthio, which may be optionally substituted with a lower alkyl group or with pyridine. ”H 2. Förfarande enligt patentkravet l, k ä n n e t e c k n a t därav, att den erhållna föreningen är 7-[D(*)-uf(4-etyl-2,3-dioxo- -l-piperazinokarbonylamino)-fenylacetamido]-3-[5-(l,3,4-tiadiazo1yl)~ tiometyll-rš-cefemr4-karbonsyra eller ett icke-toxiskt salt därav.Process according to Claim 1, characterized in that the compound obtained is 7- [D (*) - uf (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3- [5 - (1,3,4-thiadiazolyl) -thiomethyl] -r-cephemr4-carboxylic acid or a non-toxic salt thereof. 3. Eörfarande enligt patentkravet l, k ä n n e t e c k n a t därav, att den erhållna föreningen är 7-[D(-)~a-(4-ety1-2,3-dioxo- -l-piperazinokarbonylamino)-fenylacetamido1-3-[2-(5-metyl-l,3,4- tiadiazolyl)-tiometyl]-rå-Cefem-4-karbonsyra eller ett icke-toxiskt salt därav.Process according to Claim 1, characterized in that the compound obtained is 7- [D (-) - α- (4-ethyl-2,3-dioxo- -1-piperazinocarbonylamino) -phenylacetamido] -3- [2 - (5-methyl-1,3,4-thiadiazolyl) -thiomethyl]-crude Cephem-4-carboxylic acid or a non-toxic salt thereof. 4. Förfarande enligt patentkravet l, k ä n n e t e c k n a t därav, att den erhållna föreningen är 7-[D(-)-a-(4-etyl-2,3-dioxo- -1-piperazinokarbonylamino)-fenylacetamido]-3-[2-(l+metyl-l,3,4- triazolyl)-tiometyl]-¿š~cefemf4-karbonsyra eller ett icke-toxiskt salt därav. ¿Process according to Claim 1, characterized in that the compound obtained is 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3- [ 2- (1 + methyl-1,3,4-triazolyl) -thiomethyl] -β-cephem-4-carboxylic acid or a non-toxic salt thereof. ¿ 5. Förfarande enligt patentkravet l, k ä n n e t e c k n a t därav, att den erhållna.föreningen är 7-[D(-)-a-(4-etyl-2,3-dioxo-l- piperazinokarbonylamino)-fenylacetamido]-3-açetoximetyl-¿š-cefem-4- karbonsyra eller ett icke-toxiskt salt därav.5. A process according to claim 1, characterized in that the obtained compound is 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3-acetoxymethyl -¿Š-cephem-4-carboxylic acid or a non-toxic salt thereof. 6. Förfarande enligt patentkravet l, k ä-n n e t e c k n a t därav, att den erhållna föreningen är 7~[D(-)-d-(4-mety1-2,3-dioxo- -l-piperazinokarbonylamino)-p-hydroxifenyl-acetamido]-3-[5-(l-metyl- -l,2,3,4-tetrazolyl)-tiometyl]-¿š-cefem-4-karbonsyra eller ett icke- toxiskt salt därav. I ' 7808204-7 1096. A process according to claim 1, characterized in that the obtained compound is 7 - [D (-) - d- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenyl-acetamido ] -3- [5- (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl] -β-cephem-4-carboxylic acid or a non-toxic salt thereof. I '7808204-7 109 7. Förfarande enligt patentkravet 1, k ä n n e t e c k n a t därav, att den erhållna föreningen är 7-[D(-)-uf(4-etyl-2,3-dioxo- -l-piperazinokarbonylamino)-fenylacetamido]-3-[5-(l-metyl-l,2,3,4- tetrazolyl)-tiometyl]-¿§-cefem-4-karbonsyra eller ett icke-toxiskt. salt därav.Process according to Claim 1, characterized in that the compound obtained is 7- [D (-) - uf (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido] -3- [5 - (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl] -β-cephem-4-carboxylic acid or a non-toxic. salt thereof. 8. Förfarande enligt patentkravet l, k ä n n e t e c k n a t därav, att den erhållna föreningen är 7-[D(-)-af(4-etyl-2,3-dioxo- -l-piperazinokarbonylamino)-p-hydroxifenylacetamido]-3-[5-(l-metyl- -l,2,3,4-tetrazolyl)-tiometyl]-<3-cefem-4-karbonsyra eller ett icke- toxiskt salt därav. _Process according to Claim 1, characterized in that the compound obtained is 7- [D (-) - af (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido] -3- [5- (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl]-<3-cephem-4-carboxylic acid or a non-toxic salt thereof. _ 9. Förfarande enligt patentkravet l, k ä n n e t e c k n a t därav, att den erhållna föreningen är 7-[D(-)-a-(4-etyl-2,3-dioxo- -l-piperazinokarbonylamino)-p-hydroxifenylfacetamido]-3-[2-(5-metyl- -l,3,4-tiadiazolyl)-tiometyl]-¿§-cefemr4-karbonsyra eller ett icke- toxiskt salt därav.Process according to Claim 1, characterized in that the compound obtained is 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylphacetamido] -3 - [2- (5-methyl-1,3,4-thiadiazolyl) -thiomethyl] -β-cephemr4-carboxylic acid or a non-toxic salt thereof. 10. Förfarande enligt patentkravet 1, k ätn n e t e c k n a t därav, att den erhållna föreningen är 7-[D(-)-ur(4-etyl-2,3-dioxo-l- piperazinokarbonylamino)-p-hydroxifenylacetamido]-3-acetoximetyl-Aê- cefem-4-karbonsyra eller ett icke-toxiekt salt därav.10. A process according to claim 1, characterized in that the compound obtained is 7- [D (-) - ur (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido] -3-acetoxymethyl -Aê- cephem-4-carboxylic acid or a non-toxic salt thereof. 11. ll. Förfarande enligt patentkravet l, k ä n n e t e c k n a t därav, att den erhållna föreningen är 7-[D(-)-G-(4-etyl-2,3-dioxo-l- piperazinokarbonylamino)-p-hydroxifenylacetamido]-3-karbamoyloximetyl- -¿š-cefem-4-karbonsyra eller ett icke-toxiskt salt därav.11. ll. Process according to Claim 1, characterized in that the compound obtained is 7- [D (-) - G- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido] -3-carbamoyloxymethyl- -¿Š-cephem-4-carboxylic acid or a non-toxic salt thereof. 12. Förfarande enligt patentkravet 1, k ä n n e t e c k n a t därav, att A är etyl, R5 är hydroxifenyl och R4 är 2-(5-metyl-l,3,4- tiadiazolyl)-tio.12. A process according to claim 1, characterized in that A is ethyl, R 5 is hydroxyphenyl and R 4 is 2- (5-methyl-1,3,4-thiadiazolyl) -thio. 13. Förfarande enligt patentkravet 1, k ä n n e t e c k n a t därav, att A är etyl, Rs är hydrokifenyl och R4 är acetoxi.13. A process according to claim 1, characterized in that A is ethyl, R 5 is hydroxyphenyl and R 4 is acetoxy. 14. Förfarande enligt patentkravet 1, k ä n n e t e c.k n a t därav, att A är etyl, R5 är hydroxifenyl och R4 är karbamoyloxi.14. A process according to claim 1, characterized in that A is ethyl, R 5 is hydroxyphenyl and R 4 is carbamoyloxy.
SE7808204A 1974-05-09 1978-07-27 PROCEDURE FOR THE PREPARATION OF NEW CEPHALOSPORINES SE435062B (en)

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Families Citing this family (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2528079A1 (en) * 1975-06-24 1977-01-20 Bayer Ag PENICILLIN, THE METHOD FOR MANUFACTURING IT AND THEIR USE AS A MEDICINAL PRODUCT
CH624958A5 (en) * 1975-06-24 1981-08-31 Bayer Ag Process for the preparation of beta-lactam compounds
FR2338046A2 (en) * 1976-01-19 1977-08-12 Toyama Chemical Co Ltd Broad-spectrum cephalosporin antibiotics resistant to beta-lactamase - 7-(alpha-(4pethyl-2,3-dioxo-piperazinocarbonylamino)-para-hydroxy- phenylacetamido)-ceph-3-em-4-carboxylic acids
JPS6026800B2 (en) * 1976-01-22 1985-06-25 富山化学工業株式会社 Novel 7α-methoxycephalosporins and their production method
JPS52106883A (en) * 1976-02-13 1977-09-07 Toyama Chem Co Ltd Novel penicillins and cephalosporins
JPS5331690A (en) * 1976-09-01 1978-03-25 Shionogi & Co Ltd Oxadithiacephalosporins
DE2831568C2 (en) * 1977-07-23 1985-01-10 Toyama Chemical Co. Ltd., Tokio / Tokyo 7 α-Methoxycephalosporins and methods for making the same
DE2810083A1 (en) * 1978-03-08 1979-09-20 Bayer Ag BETA-LACTAM COMPOUNDS
DE2813771A1 (en) * 1978-03-30 1979-10-11 Bayer Ag BETA-LACTAM COMPOUNDS
DE2817228A1 (en) * 1978-04-20 1979-10-31 Bayer Ag PROCESS FOR MANUFACTURING SEMI-SYNTHETIC BETA-LACTAMANTIBIOTICS
EP0015240A1 (en) * 1979-02-16 1980-09-03 Ciba-Geigy Ag Azacyclyl (thio) ureidoacetyl compounds and their preparation
CA1209477A (en) * 1981-03-26 1986-08-12 Bruce E. Haeger Composition of matter comprising a lyophilized preparation of a penicillin derivative
CA1200239A (en) * 1981-03-30 1986-02-04 Donald C. Boop Process for preparing 6-¬d-(-)-alpha-(4-c1-c4 alkyl- 2,3-dioxo-1-piperazinocarbonyl-amino)- phenylacetamido|penicillanic acid
JPS57118587A (en) * 1981-11-26 1982-07-23 Toyama Chem Co Ltd Novel penicillin
BG46664A1 (en) * 1985-08-16 1990-02-15 Druzhestven N Izsledovatelski Method for preparing of 6- /d (-)- alpha- (4- ethyl- 2, 3- dioxo- 1- piperazine carbonylamino)- phenylacetamido/- penicillanic acid
DE3619562A1 (en) * 1986-06-11 1987-12-17 Basf Ag METHOD FOR PRODUCING 2,3-DIOXO-4-OXICARBONYLPIPERAZINE DERIVATIVES, NEW 2,3-DIOXO-4-OXICARBONYLPIPERAZINE DERIVATIVES AND THE USE THEREOF
US5859012A (en) * 1996-04-03 1999-01-12 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
USRE39921E1 (en) 1999-10-07 2007-11-13 Smithkline Beecham Corporation Chemical compounds
GB9923748D0 (en) 1999-10-07 1999-12-08 Glaxo Group Ltd Chemical compounds
GB0025354D0 (en) 2000-10-17 2000-11-29 Glaxo Group Ltd Chemical compounds
ES2335092T3 (en) * 2001-08-24 2010-03-22 Yale University PIPERAZINONA COMPOUNDS AS ANTITUMOR AND ANTICANCER AGENTS.
GB0203022D0 (en) 2002-02-08 2002-03-27 Glaxo Group Ltd Chemical compounds
GB0203020D0 (en) 2002-02-08 2002-03-27 Glaxo Group Ltd Chemical compounds
US7482365B2 (en) 2002-02-08 2009-01-27 Glaxo Group Limited Piperidylcarboxamide derivatives and their use in the treatment of tachykinin-mediated diseases
CN101611040A (en) * 2007-01-31 2009-12-23 富山化学工业株式会社 The novel crystal of piperacillin sodium
PE20120010A1 (en) 2008-10-31 2012-02-07 Shionogi & Co CEPHALOSPORINS THAT HAVE A CATECOL GROUP
WO2011125966A1 (en) 2010-04-05 2011-10-13 塩野義製薬株式会社 Cephem compound having pseudo-catechol group
CA2795322A1 (en) 2010-04-05 2011-10-13 Shionogi & Co., Ltd. Cephem compound having catechol group
US9085589B2 (en) 2010-04-28 2015-07-21 Shionogi & Co., Ltd. Cephem derivative
JP6006201B2 (en) 2011-04-28 2016-10-12 塩野義製薬株式会社 Novel cephem compounds having catechol or pseudo-catechol structure
US9242999B2 (en) 2011-06-27 2016-01-26 Shionogi & Co., Ltd. Cephem compound having pyridinium group
CN110746445B (en) * 2019-10-16 2021-03-16 深圳海关食品检验检疫技术中心 Preparation method of cefoperazone deuterated internal standard substance

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1770620A1 (en) * 1968-06-12 1971-11-11 Bayer Ag New penicillins
DE2104580C3 (en) * 1971-02-01 1981-04-02 Bayer Ag, 5090 Leverkusen Acylureidopenicillins
DE2025415C3 (en) * 1970-05-25 1981-01-22 Bayer Ag, 5090 Leverkusen Process for the preparation of cyclic acylureido penicillins
US3741962A (en) 1971-05-21 1973-06-26 Squibb & Sons Inc Alpha-thioureidocephalosporanic acid compounds
BE790440A (en) * 1971-10-23 1973-04-24 Bayer Ag
BE794886A (en) * 1972-02-22 1973-08-02 Pfizer 6- (ALPHA- (OMEGA-GUANIDINOALCANOYLAMINO) ACYLAMINO) -PENICILLANIC ACIDS
CH570407A5 (en) * 1972-03-29 1975-12-15 Ciba Geigy Ag
AR204813A1 (en) * 1972-05-08 1976-03-05 Yamanouchi Pharma Co Ltd PROCESS FOR THE PREPARATION OF AMPYLICIN DERIVATIVES
AR208171A1 (en) 1972-09-29 1976-12-09 Ciba Geigy Ag PROCEDURE FOR OBTAINING NEW DERIVATIVES OF CEF-3-EM-4-CARBOXYL ACID

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