CA1272726A - 2-oxo-1-(aminocarbonylaminosulfonyl- aminocarbonyl)azetidines - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Intermediate compounds having the formula:

or a salt thereof, are useful in the preparation of related compounds of the formula:

Description

~ 2r'7~.~.~ GCl83a ..

AZETIDINES

B-Lactams having the formula ~C - N-C~-NH-SO~-N -i~-R

O
and salts thereof, have antibacterial activity.
~ In formula I, and throughout the specification, ; lO the symbols are as defined below.

Rl is acyl;
R2 is hydrogen or methoxy;
i R3 and R4 are the same or different and each is hydrogen, alkyl~ alXenyl, alkynyl, cycloalkyl, aryl or a 5,6 or 7-membered heterocycle or one of R3 and R4 is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, ` 2-phenylethynyl, carboxyl, -CH~X1, -S-X2, ~' GCl83a --X2 ~ -O-CI-X~ , -S~C-X4 , or -A-C-NX6X7 ;

X1 is azido, amino (-NH2), hydroxy, alkanoyl-amino, alkylsulfonyloxy, arylsulfonyloxy, aryl, cyano, -S-X2 or -O-X2 , X2 is al~yl, substituted alkyl, aryl, arylalkyl, alkanoyl, substituted alkanoyl, arylcarbonyl or heteroarylcarbonyl;
one of X3 and X4 is hydrogen and the other is hydrogen or alkyl, or X3 and X4 when taken together with the carbon atom to which they are attached form a cycloalkyl group;
X5 is formyl, alkanoyl, arylcarbonyl, arylalkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl (NH2-C-), (substituted amino)carbonyl, or cyano (-C--N) ;
A is -CH=CH-, -CH2-CH=CH-, ~(CH2)~m ~ -(CH2)m,-O-, -(CH2)m,-NH , -(CH2)m,-S-CH2-, or -(CH2)m,-O-CH2-;
~ m is 0~ 1, 2 or 3;
:~ m' is 1 or 2;
X6 and X7 are the same or different and each is hydrogen or alkyl, or X6 is hydrogen and X7 is amino, substituted amino, acylamino or alkoxy;
R5 is hydrogen, alkyl or aryl;
R6 is hydrogen, alkyl, aryl, a 5, 6 or 7-mem~ered heterocycle, -NR7R8, or - (CH2) n~x wherein n is 1,2,3 or 4 and X is halogen, aryl, alkoxy, aryloxy or -NRgRlo ;
R7 and R8 are the same or different and each is hydrogen, alkyl or aryl, or R7 is hydrogen and R~ is a 5,6 or 7-membered heterocycle or -(CH2)n-Y wherein n is 1,2,3 or 4 and Y is alkoxy, amino(-NH2), alkylthio or halogen; and '7~ ;` GC:L8 3a Rg and R1o are the same or different and each is hydrogen or alkyl, or R9 i~ hydrogen and Rlo is a 5,6 or 7-membered heterocycle.
Listed below are definitions of various terms used to describe the ~-lactams of this invention. These definitions apply to the terms as they are used throughout the specifi-cation (unless they are otherwise defined in specific instances) either individually or as part of a larger group.
The terms "alkyl" and "alkoxy" refer to both straight and branched chain groups. Those groups having 1 to 10 carbon atoms are preferred.
The terms "cycloalkyl" and "cycloalkenyl"
refer to cycloalkyl and cycloalkenyl groups - having 3,4,5,6 or 7 carbon atoms.
The terms "alkanoyl", "alkenyl", "alkynyl", "alken-l-yl" and "alkyn-l-yl" refer to both straight and branched chain groups. Those groups ha~ing 2 to 10 carbon atoms are preferred.
The term "halogen" refers to fluorine, chlorine, bromine and iodine.
The term "protected carboxyl" refers to a carboxyl group which has been esterified with a conventional acid protecting group. These groups are well known in the ar~; see, for example, United States patent 4,144,333, issued March 13, 1979. The preferred protected carboxyl groups are benzyl, benzhydryl, t-butyl, and ~-nitrobenzyl esters.
The term "aryl" refers to phenyl and phenyl substituted with 1,2 or 3 amino(-NH2), halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms) or carboxyl 3S groups.

GC183a 7X'~f~;

The expression "a 5, 6 or 7-m~mbered heterocycle" refers to substituted and unsubstituted, aromatic and non-aromatic groups containlng one or more nitrogen~ oxygen or sulfur atoms. Exemplary substituents are oxo(=O), halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons, alkylsulfonyl, phenyl, substituted phenyl, 2-furylmethylenei~ino ( ~ ~, phenylmethyleneimino and substituted alkyl groups (wherein the alkyl group has 1 to 4 carbons).
One type of "5,6 or 7-membered heterocycle" is the "heteroaryl'' group. The term "heteroaryl"
refers to those 5,6 or 7-membered heterocycles which are aromatic. Exemplary heteroaryl groups are substituted and unsubstituted pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl, and tetxazolyl.
Exemplary nonaromatic heterocycles (l.e., fully or partially saturated heterocyclic groups) are substituted and unsubstituted piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl, and dihydro-thiazolyl. Exemplary of the substituted 5, 6 or7-membered heterocycles are 2-oxo-1-imidazolidinyl, 3-alkylsulfonyl-2-oxo-1-imidazolidinyl, 3-benzyl-imino-2-oxo-1-imidazolidinyl, 3-alkyl-2-oxo-1-imidazolidinyl, 3-aryl-2-oxo-1-imidazolidinyl, 3-(2-hydroxyethyl)-2-oxo-1-imidazolidinyl, 3- L (l-methylethylidene)amino]-2-oxo-l-imidazolidin G~183a 3-benzyl-2-oxo-1-imida~olidinyl, 3-(2-aminoethyl)-2-oxo-l-imidazolidinyl, 3-~2-(alkylamino)ethyl~-2-oxo-l--imidazolidinyl, 3-[2-(dialkylamino)ethyl]-2-oxo-l-imidazolidinyl, 3-amino-2-oxo-1-imidazolidinyl, 3-ureido-2-oxo-1-imidazolidinyl, 3-[(alkoxycarbonyl)-amino]-2-oxo-1-imidazolidinyl, 3-[2-~(alkoxycarbonyl)-amino]ethyll-2-oxo-1-imidazolidinyl, 2-oxo-1-pyrrolidinyl, 2-oxo-3-oxazolidinyl, 4-hydroxy-6-methyl-2-pyrimidinyl, 2-oxo-3-pyrroldinyl, 2-oxo-3-tetra-hydrofuranyl, 2,3-dioxo-1-piperazinyl, 2,5-dio~o-1-piperazinyl, 4-alkyl-2,3-dioxo-1-piperazinyl, and 4-phenyl-2,3-dioxo-1-piperazinyl.
The term "substituted alkyl" refers to alkyl groups substituted with one, ox more, azido, amino(-NH2), halogen, hydroxy, carboxy, cyano, alkoxycarbonyl~ aminocarhonyl, alkanoyloxy, alkoxy, aryloxy, a 5,6 or 7-membered heterocycleoxy, mercapto, alkylthio, arylthio, alkylsulfinyl, or alkylsulfonyl groups.
The term "substituted amino" refers to a group having the ormula -NYlY2 wherein Yl is hydrogen, alkyl, aryl, or ary~alkyl, and Y2 is alkyl, aryl, arylalkyl, hydroxy, cyano, alkoxy, phenylalkoxy, or amino(-NH2).
The term "substituted alkanoyl" includes within its scope compounds havin~ the formula o (substituted alkyl)-C- (wherein "substituted alkyl" is de-fined above) and phenylalkanoyl.

~l27~726 ,~ .

, ... ..
The term "acyl" refers to all organic radi-cals de:rived from an organic acid (l.e., a carboxy-lic acid) by removal o the hyd.roxyl group. Cer-tain acyl yroups are~ of course, preferred but this preference should not be viewed as a limitation of the scope of this invention. Exemplary acyl groups are those acyl groups which have been used in the past to acylate ~ lactam antibiotics includins 6-aminopenicillanic acid and derivatives and 7-amino-cephalosporanic acid and derivatives; see, for ex-ample, Cephalosporins and Penicillins, edited by Flynn, Academic Press (1972~, German Offenlegungs-schrift 2,716,677, published October 10r 1978, Bel-gian patent 867,994, published December 11, 1978, Vnited States patent 4,152,432, issued May 1, 1979, United States patent 3,971,77~, issued July 27, 1976, United States patent 4,172,199, issued October 23, 1979, and British patent 1,348,894, published March 27, 1974. The following list of acyl groups is pre-sented to further exemplify the term "acyl"; it should not be regarded as limiting that term. Exemplary acyl groups are:
(a) Aliphatic groups having the formula R -C-wherein Ra is alkyl; cycloalkyl; alkoxy; alkenyl;

~æ ~7Z~ GC183a "
cycloalkenyl; cyclohexadienyl; or alk~l or alkenyl substituted with one or more halogen, cyano, nitro, ~lino, mercapto, alkylthiot or cyanomethyl-tllio groups.
(b) Car~ocyclic aromatic groups having the formula Rc (CH23n~

CH-C- , Re Rb ~Rd ~=7 C~2 c Rb ~ C 2 ~ 72 ~ ~, GClg3a -C~-C- or S

~H2 wherein n is 0, 1, 2 or 3; ~, Rc, and Rd each is independently hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alXyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or aminomethyl; and Re is amino, hydroxyl, a carboxyl salt, protected carboxyl, formyloxy, ; a sulfo salt, a sulfoamino salt~ azido, halogen, hydra~ino, alkylhydrazino, phenylhydrazino, or [(alkylthio)thioxomethyl~thio.
Preferred carbocyclic aromatic acyl groups include those ha~ing the formula .

HO ~

~H2-C-, ~ 2 2 ,:

~z~ GC183a ~ ~ ~9._ HO ~ ~ Re is pre~erab~y : ~e : 5 a carboxyl salt or sulfo salt) and O
~ 7~-C- (Re is preferably Re a carboxyl salt or sulfo salt).
(c) Heteroaromatic groups ha~ing the formula o R~-(CH~)n-C-t Rf-CH-C-; Re O

R E--O--CH2--C-- , ~:, , O
-S-CH2--C- r O O
R~-C -C- ~

wherein n is 0, 1, Z or 3; Re is as defined above; and R~ is a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring contamlng 3n 1,2,3 or 4 (preferably 1 or 2) nitrogen, oxygen ~ and sulfur atoms. Exemplary heterocyclic :;

a 2~92 ,~ GC183a -ln-rings are thienyl, ~uryl, pyrrolyl, pyrid.inyl, pyra~lyl~ pyrazinyl, thiazolyl, thiadiazolyl~
pyrimidinyl ancl tetrazolyl. :Exemplary suhstit:uents are halo~en, hydroxyl, nitro, a~ino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or ; HOOC-CH-C~-O-C-N~-.

Preferred heteroaromatic acyl groups include those groups of the above formulas wherein Rf is 2-amino-4-thiazolyl, 2-amino-5-halo-4-thiazolyl, 4-aminopyrimidin-2-yl, 5-amino-1,2,4-thiadiazol-3-yl, 2-thienyl, ? 2-furanyl, or 6-aminopyridin-2 yl.
(d) [[(4-Substituted-2, 3-dioxo-1-piper-a~inyl)carbonyl~amino~arylacetyl groups ha~ing the ~ormula ~ 20 e '1~
-C-CH-NH-C-N N -Rh Rg O ~ ~O

wherein Rg is an aromatic group (including carbocyclic aromatics such as those of the formula Rc Rb` ~ d 30 and heteroaromatics as included within the definition o Rf); and Rh is alXyl, substituted

2 27 ~; GC183a ~L 7 ~

alkyl (wherein the alkyl group is s-~stituted with one or more halogen, cyano, nitro, aminc or mercapto groups), arylrnethyleneaminQ (i e., ~N=C~-Rg wherein Rg is as defined above), ~ylcarbonylamino (i.e., ~N~~C~Rg wherein Rg is as defined abo~e) or alkylcarbonylamino.
Preferred ~[~4-substituted-2,3-dioxo-1 piperazinyl)carbonyl]amino]arylacetyl groups include those wherein ~ is ethyl, phenylmethylene-amino or 2-furylmethyleneamino.
(e) (Substituted oxyimino)arylacetyl groups ha~ing the formula O
--C--C=N--O-R
Rg wherein R is as defined above and Ri is hydrogen, alkyl, cycloalkyl, alkylaminocarbonyl, arylamino-O
carbonyl (i~e., ~C~NH~Rg wherein Rg is as defined above) or substituted alkyl (wherei~ the alkyl group is substituted with 1 or more halogen, cyano, nitro, amino, mercapto, alkylthio, aromatic group (as defined by Rg), carboxyl (including salts thereof), amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy(phenylmethoxy)phosphinyl, or dialkoxy-phosphinyl substituents)~

~ 7~ GC1~3a Preferred ~substituted oxy ~ino)aryl.ac~tyl group~ include those wherein Rg is 2-amino-4-thia~olyl. Also preferred are those groups wherein Ri is me~lyl, ethyl, carboxymethylt l-carboxy-l-methylethyl or 2,2,2-trifluoroe~hyl.
~ f) (Acylamino)arylacetyl groups having the formula O O
-C-CH~NH-C-R
: Rg wherein R is as deined above and Rj is R

Rb ~ (CH2)n-0-, amino, alkylamino, (cyanoalkyl~-amino, amido, alkylamido, (yanoalkyl)amido, -CH2--NH--C~ -CH-cH2-c-N~-cH3~
.~

HO
~2--N (CX2'-CH2 OH)2, ~CH3 OH OH

~?~ O

~7~7~,~ GC183a Preferred (acylamino) ~rylacetyl groups o~
the above formula include those groups wherein R. is amino or amido. Al~o preferred are those groups wherein Rg i~ pheny~ or 2-thienyl.
s (g) 1 113-Substitu~ed-2-oxo-1-imida~oli-dinyllcar~onyl~amino~arylacetyl groups having the formula R

o ~ ~c~
-C-C~-NH-C-N N-Rk Rg CH CH~

wherein ~g is as defined above and ~ is hydrogen, alkylsulfonyl, arylmethyleneamino (i.e., ~N-CH~Rg wherein Rg is as defined above), -C-Rm (wherein Rm is hydrogen, ~lkyl or halogen substituted alkyl), aromatic group (as defined by Rg above), alkyl or substituted alkyl (wherein the alXyl group is substituted with one or more halogen, cyano, nitro, amlno or mercapto groups).
~ Prefexred ~[3-substituted-2-oxo-1-imida~oli-; ainyl3carbonyl~amino~arylacetyl groups of the a~ove formula include those wherein Rg is phenyl or 2-thienyl. Also preferred are those sroups wherein Rk is hydrogent methylsulfonyl, phenyl-methyleneamino or 2-furylmethyleneamlno.

C183a The compounds oE this invention form basic salts with various inorganic: and organic bases which are also within the scope of this invention.
Such salts include ammonium salts, alkali metal S salts, alkaline earth metal salts, salts with organic bases, e g., dicyclohexylamine, benzathine, N-methyl-D~glucamine, hydrabamine and the like. The pharmaceutically acceptable salts are preferred, although other salts are also useful, e.~, in isolating or purifying the product.
Some of the compounds of this invention may be crystallized or recrystallized from solvents containing water. In these cases water of hydration may be formed. This invention contemplates stoichiometric hydrates as well as compounds containing variable amounts oE water that may be produced by processes such as lyophilization. R R5 1 ~-Lactams having a -C-NH-S02-N ~ C-R6 substituent in the l-position and an acylamino substituent in the 3-position contain at least one chiral center - the carbon atom (in the 3-position of the ~-lactam nucleus) to which the acylamino substituent is attached. This invention is directed to those ~-lactams which have been described above, wherein the stereochemistry at the chiral center in the 3-position of the ~-lactam nucleus is the same as the configuration at the carbon atom in the 6-position of naturally occurring C183a penicillins (e.g., penicillin G) and as the configuration at the carbon atom in the 7-position of naturally occurring cephamycins (e.g., cephamycin C).
Also included within the scope of this invention are racemic mixtures which contain the above-described B-lactams~

1 0 ~I 1~5 1l B-Lactams having a -C-N~-SO2-N - C-R6 substituent in the l-position of the G-lactam nucleus and an acylamino substituent in the

3-position of the ~-lactam nucleus, and salts thereof, have activity against a range of gram-negative and gram-positive organisms.
The compounds of this invention can be used as agents to combat bacterial infections (including urinary tract infections and respiratory infections) in rnammalian species, such as domesticated animals (_ g., dogs, ~ cats, cows, horses, and the li~e) and humans.
- For combating bacterial inections in mammals a compound of this invention can be administered to a mammal in need thereof in an amount of about 1.4 mg/kg/day to about 350 mg/kg/day, preferably about 14 mg/kg/day to about 100 mg/kg/day. ~11 modes of adminis-tration which have been used in the past to 3n deliver penicillins and cephalosporins -to the site of the infection are also contemplated 1~ 7Z~Z~; GC].83a for use with the novel family of ~-lactarns of this invention. Such methods of administration include oral, intravenous, intramuscular, and as a suppos.itory A -C-NH-SO2-N - C-R6 activatlng group can be introduced onto the nitrogen atom of a ~-lactam by reacting a ~-lactam having the formula II

//C NH
O
wherein Al is a nitrogen protecting group, with the appropriate isocyanate having the formula III R5 o O=c=N-so2 -N--C -R6 As the protective group Al ~or amino above, : any of those used for this purpose in the field of ~-lactam or peptide synthesis may conveniently :: be employed. Examp~es of such amino protecting group include aromatic acyl ~roups such as phthaloyl, p-nitrobenzoyl, p-tert-butYlbenzoyl, p-tertbutyl-benzenesulfonyl, henzenesulfonyl, toluenesulronyl, ~7~
GC183a etc., aliphatic acyl groups such as Eormvl, acetyl, propionyl, monochloroacetyl, dichloroacetyl, tri-chloroacetyl, methanesulfonyl, ethanesulfonyl, ~ri-fluoroacetyl, maleyl, succinyl, etc., and esterifled carboxyl groups such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isopropoxy-carbonyl, 2-cyanoethoxycarbonyl, ~ -trichloro-ethoxycarbonyl, ~-trimethylsilylethoxycarbonyl, ~-methylsulfonylethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxy-carbonyl, di-phenylmethyloxycarbonyl, methoxymethyl-oxycarbonyl, acetylmethyloxycarbonyl, isobornyloxy-carbonyl, phenyloxycarbonyl, etc., as well as non-acyl amino-protecting groups such as trityl, 2-nitrophenylthio, benzylidene, 4-nitrobenzylidene, trialkylsilyl, benzyl, p-nitrobenzyl, proton, etc.
The choice of amino-protecting group is not critical in the present invention.
The reaction is preferably run in an organic solvent, e.g., an inert solvent such as tetrahydro-furan or dimethoxyethane, in the presence of a base such as triethylamine or alkyl lithium.
The activating group can also be inserted onto the Formula II ~-lactam in sequential segments.
Thus ~or example, with reference to the activating group as represented ~elow:
O I R ~ o ~ 5l 1!
~ , N ~ R6, (a) (b) (c) there are various methods known in the art by which the sequential portions (a), (b) and (c) above can be added to the Formula II ~-lactam in single or double bond portions or all together.

~7v~ GC183a One such method, which is ~referred ~omPrises first reactina a B-l~çt~ ~f formula II with an isocyanate havina the formula IV
o=C=N-S02- Z

wherein.Z is a leaving group, e.g., a halogen such as chlorine. The reaction is preferably run in an inert organic solvent, ~ , a halocarbon such as dichloromethane, or in : acetonitrile, and yields an intermediate having the formula A -NH R2 =R4 1 ~ C - C-R3 O O
Reaction of an intermediate of formula V
with a RsN~12 amine preferably in the form of a silylated derivative such as with a silyl compound having ,!,' the fon~a ~ Si(CH3)3 R -N
\ Si(CH3j3 `~ yields an intermediate having the formula VII
1 ~ C - C-R
; I 1 3 15 ~C N-l-NH-so2-~-si(CH3)3 :' O

~ 2~ GC183a which can be reacted wi.th an acyl halidehaving the formula VIII R
R6-c-halogen to yield a ~-lactam having the formula 1 ~`C - C-R3 l5 ~C - N-CI-NH-So2 N ~1 6 Alternatively, compounds of formulas VI
and VIII can be first reacted to yield a ~ ~ compound having the formula : X R~
2n (CH3)3-Si-N ICl R6 which can be reacted with a compound of formula V to yield a compound of formula IX.
Sti.ll another procedure for preparing a ~ c~mpound of formula IX wherein R6 is -NR7R8, : comprises reactin~ a compound of formula V
with a urea having the formula XI l5 , R7 HN - C-N
11 ~ R

in the presence of triethylamine.

~ y~ ~ GCl83a .

Deprotection of a compound of formula IXusing conventlonal techni~ues yields thecorrespondiny key intermediate having the formula XII

NH2 ~ -2 4~ R3 R

O~,C N-1_NH_SO2-N_C_R6 , or a salt thereof. The particular deprotection reaction used will, of course, depend on the protecting group ("Al") present. If, for example, Al is a t-butoxycarbonyl protecting group, deprotection can be accomplished by treatment of a compound of formula IX with acid (e.g., formic acid or trifluoroacetic acid). If, for example, Al is a benzyloxy-carbonyl protecting group, deprotection can be accomplished by catalytic hydrogenation of-a compound of formula IX.
Well known acylation techniques can be used to convert an intermediate of formula XII
to a corresponding product of formula I.
It is also evident that the desired acyl group in the Formula I product can also function as the protecting group for the amino group (NH2-) in the Formula XII compound above, or as the Al-group in the Formula II reactant shown previously where Al-is defined as a nitrogen protecting group.
In such cases, there will be no need for removing the Al-protecting group after insertion of the o R5~
-c-NH-so2-N-c R6 activating group.

~2 72 726 GC183a Exemplary techniques include reacti.on of A
compound of Eormula XII with a carboxylic acid (Rl-OH), or corresponding carboxylic acid halide or carhoxylic acid anhydride. The reaction with a carhoxylic acid proceeds most readily in the presence of a carbodiimide such as dicyclohexylcarbodiimide and a substance capable of forming an active ester in situ such as N-hydroxybenzotriazole. In those instances where the acyl group (Rl) contains reactive functionality (such as amino or carboxyl groups) it may be necessary to first protect those functional groups, then carry out the acylation reaction, and finally deprotect the resulting product.
In general terms, the process or preparing the desired compounds therefore comprises reacting a ~-lactam having the formula Ri - NH C C R3 I
~C ~ NH
O
wherein R2, R3 and R4 are as previously defined and Ri is acyl (Rl) as previously defined or the group Ri-NH- is a protected amino group with an isocyanate having the formula R O
~5 11 O= C- N -S02 -N C - R6 or sequential segments thereof wherein R5 and R6 are as prevlously defined, and where Ri-NH- is a `~ protected amino group removing said protecting group and acylating with the appropriate acylating group to form the desired product.

~L2'~72~;
GC18 3a The azetidinQneS of formula II can be prepared utilizing the procedures described in United Kingdom patent application 2,071,650, published September 23, 1981.
The preferred compounds of formula I
are those wherein R3 and R4 are each hydrogen.
Also preferred are those compounds of formula I
wherein R6 is a 5,6 or 7-membexed heterocycle, especially a 4-alkyl-2,3-dioxo-1-piperazinyl group, a 2-oxD-l-imidazolidinyl group, a 3-alkyl-2-o~o-1-imidazolidinyl group or a 3-(substituted alkyl)-2-oxo-1-imidazolidinyl group. Specific groups that are preferred are the 4-ethyl-2,3-dioxo-1-piperazinyl, 3-ethyl-2-oxo-1-imidazolidinyl, and 3-(2-aminoethyl)-2-oxo-l-imidazolidinyl groups. Preferred 3-acylamino groups are those wherein the acyl portion of the group is ~Z)-2-amino-a-(alkoxy-imino)-4--thiazoleacetyl or (Z)-2-amino-~-[I(substituted alkyl)oxy~imino~-4-thiazoleacetyl, especially (Z)-2-amino-a-(methoxyimino)-4-thiazoleacetyl and (Z)-2-amino-a-[(1-carboxy-1 methylethoxy)imino]-4-thiazoleacetyl.
The followiny examples are specific embodiments of this invention.

:~ .

~ 7Z ~2~ GCl a 3a Example 1 ¦3S(Z)]-N~ [~[(Aee-t ~ sul ~ ~
carborlyl]-2-oxo-3-azetidinyl].-2-amino-cL-(_ethoxyim ~ zoleacetamide, dipotassium salt A) (S)-[l-l[¦(Acetylamino)sulfonyl]amino~-carbonyl3-2-oxo~3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt (S)-3-~L(Phenylmethoxy)carbonyl~amino]-2-azetidinone (4.4 g) wassuspended in dry ethyl acetate. The mixture was cooled to -5 C and 3.1 g of chlorosulfonyl isocyanate was dropped in with stirring at such a rate that the temperature did not exceed 0 C.
lS Stirring at 0 C was continued for an addi~ional 20 minutes. After this time 4 g of hexa-methyldisilazane was added and the solution was stirred at ambient temperature for 12 hours. Acetyl chloride (3.2 g) was added and the solution was again stirred for 48 hours.
The ethyl acetate was then washed with water and extracted twice with 50 ml portions of saturated aqueous bicarbonate. The organic layer was discarded and the aqueous phase was treated with 25% hydrochlorie acid until the pH waslØ Extraction with ethyl acetate, drying and evaporation of the solvent yielded

4 g of the title compound in crude form.
~his was dissolved in acetone/water GC183a -~4-the pH was adjusted to 6.5, the solvent was removed ln vacuo and the crysta~l.ine title compound was filtered off with ether. Further purification achieved by HP-20 chromatography (water/acetone 9:1 as eluent) yielded the title compound, melting point 130-135C, dec.

B) [3S~Z)]-N- [l-[[~(Acetylamino)sulfonyl~-amlnoJcarbonyl]-2-oxo-3-azetidinyl]-2-amino-a-(methoxyimino)-4--thiazoleacetamide, dipotassium salt (s ) - [ 1- [ I ~(Acetylamino)sulfonyl]amino]-carbonyl]-2-oxo-3-azetidinyl~carbamic acid, phenylmethyl ester, potassium salt (940 mg) was dissolved in 50 ml of dry dimethylformamide and hydrogenated in the presence of 500 mg of 10% palladium on charcoal for 30 minutes, after which the catalyst was filtered off.
: (Z)-2~Amino-~-(methoxyimino~-4-thiazoleacetic acid ~450 mg), 1 g of dicyclohexylcarbodiimide and 150 mg of ~-hydroxybenzotriazole were added to the filtrate. The solution was stirred overnight, the precipitated urea was filtered off and the solvent was removed in vacuo. The remaining solid was chroma-tographed on HP-20*using water as eluent, and yielded 400 mg of product, melting point 255-260C, dec.~

30 * The terms "HP-20" and "HP-20 resin" refer to macroporcus styrene-divinylbenzene copolymer.

~ ; GC1~3a --~5-E mple 2 ~ Z ~ y__m ~ yl~-amino]carbonyl]-2-oxo-3 azet:idinyl]amino]-1-( amino-4-thiazolyl)-2-oxoethylidene]amino]-oxy]-2-methylpropanoic acid A) 2-[~2-L _-~[~(Acetylamino)sulfonyl]amino]-carbonyl]-2-oxo-3-azetidinyl]amino]-1-(2-amino-4 thiazolyl)-2-oxoethylidene]amino]oxy]-2-: 10 methylpropanoic acid, diphen~lmethyl ester, monopotassium salt (S) - Ll- [ I [ ~Acetylamino)sulfonyl]amino]-carbonyl]-2-oxo-3-azetidinylJcarbamic acid, phenylmethyl ester, potassium salt (1.38 g;
see example lA) was hydrogenated in dry dimethylformamide in the presence of 700 m~
of 10% palladium on charcoal for 30 minutes after which the catalyst was filtered off.
(Z)-2-Amino-~-[~2-(diphenylmethoxy~-1,1-dimethyl-2-oxoethoxy]iminol-4-thiazoleacetic acid (1.32 g), 1.2 g of dicyc.lohexylcarbodiimide : and 150 mg of N-hydroxybenzotriazole were ; added and the solution was stirred Xor 12 ~ hours. The precipitated urea was filtered : 25 off and the solvent was removed in vacuo.
The residue was dissolved in 20 ml of acetone, filtered and poured into 100 ml of ether.
The precipitated title compound was filtered off and dried yielding 2.5 g of material.

GC183a 2~i B) [3S(Z) ~ [2-[[1-[[~(Acetylamino)sulfo~l]-amlno] _ r ~ _]-2-oxo-3-azetidirlyl]aminoJ-l-(2-amino-4-thiazolyl)-2-oxoethylldene]amjno]-oxy~-2-methylpropanoic acid 2-[[[2-~1- E ~ [ (Acetylamino)sulfonyl~aminol-carbonyl~-2-oxo-3-azetidinyl~amino]-1-(2-amino-4-thiazolyl)-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, diphenylmethyl ester, monopotassium salt (2.5 g) was suspended in

5 ml of anisole and cooled to 0C. Trifluoro-acetic acid (12 ml) was slowly dropped in with stirring, maintaining the temperature at 0C.
Af:ter 3.5 hours, the solution was poured into 100 ml of ether, precipitating the desired product. The crude product was filtered off and purified by HP-20 chromatography using water/acetone;(9:1) as eluent and yielding 620 mg of product, melting point 225-230 C,dec.
.

Example 3 [l-[[~[(Chloroacetyl)amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (S)-3-~[(Phenylmethoxy)carbonyl]amino~-2-azetidinone (4.4 g) was su~pended in 150 ml of dry ethyl acetate. The mixture was cooled to -50 C and 3.3 g of chlorosulfonyl isocyanate was added with stirring; stirring was continued without cooling until the temperature reached 0 C. N ~Trimethylsilyl)chloroacetamide (6.0 g) was added and the solution was stirred overnight.

GCla3a The insoluble material was filtered off and the filtrate washed with water. The organic layer was extracted twice with saturated aqueous sodium bicarbonate. The alkaline aqueous layer was acidified to pH 1 with 20%
hydrochloric acid and extracted twice with 150 ml portions of ethyl acetate. The organic layers were combined, dried and evaporated to dryness~ The oily residue was dissolved in 50 ml of acetone and the pH was adjusted to 6.5 by addition of lN potassium hydroxide. The solvent was removed ln vacuo and the crystalline residue filtered with ether, yielding 3.9 g of the title compound.

Example 4 E 3S (R)] N-[2-lll-t[[(Acetylamino)sulfonyl]-amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-~ oxo-l-phenylethyl]-4-ethyl-2,3-dioxo-1-; 20 ~_perazinecarboxamide, potassium salt Following the procedure of example lB, but substituting (R)-~-[t(4-ethYl-2,3-dioxo-l-piperazinyl)carbonyl]amino]benzeneacetic acid for (Z)-2-amino-a (methoxyimino)-4-thiazoleacetic acid, yie ded the title compound meltlng point 160-165C, dec.

.. .. .

~. 2 ;~ GC 183a Exarnple 5 ~ chloroacetyl)amino]-sulfonyl]amino~carbonyl]-2 oxo-3-azetidinyl]--(methoxyimino)-4-thia2Oleacetarnide, potassium salt [l-[~I(Chloroacetyl)amino]sulfonyl]amino~-carbonylJ-2-oxo-3-azetidiny~]carbamic acia, phenyl-methyl ester (1.0 g; see example 3) was slowly added to 20 ml of 40~ HBr in acetic acid at 10C. When the addition was complete the solution was stirred for 5 minutes. Dry diethyl ether (100 ml) was added and the precipitate was filtered off, washed with ether and dried carefully. This compound was dissolved in 50 ml of water, the pH adjusted to 6.5 with lN KOH and the resulting solution freeze-dried. The compound obtained was dissolved in 50 ml of dry dimethylformamide and (Z)-2-amino-~-(methoxyimino)-4-thiazoleacetic acid, 0.04 g of N-hydroxybenzotriazole and 0.76 g dicyclohexylcarbodiimide are added and the solution was stirred overnight at ambient temperature. The precipitated urea was filtered off and the solvent removed in vacuo. The residue was chromatographed using HP-~0 resin (eluent:water), yielding 0.19 g of product, melting point 215-220C.

~7f2~6 GC183a ..

Example 6 ~_ (Z)]~2~ l (2-Amino-4-thiazolyl)-2- ~
[ [ [ I ~chloroacetyl ? amino~5ulfonyl]amino]carbonyl]
_-oxo-3-azetidinyl~amino]-2-oxoe ~ylidene~amino]-oxy]-2-methylpropanoic acid, dipotassium salt I (Chloroacetyl ) amino ] sulfonyl ] amino ] -carbonyl]-2-oxo-3-azetidinyl~carbamic acid, phenylmethyl ester (2.0 g; see example 3) was added at 5C with stirring to 40 ml of 40~
hydrogen bromide in acetic acid; after 5 minutes a clear solution was obtained. Dry ether (200 ml) was slowly dropped in and the precipitate was filtered off, washed with ether and dried carefully. The white powder was then dissolved in 50 ml of water and the pH adjusted to 6.5 and the solution freeze-dried. The compound obtained was dissolved in 100 ml of dry dimethyl-formamide and 2.72 g of (Z)-2-amino-a-[~2-(diphenylmethoxy)-l.l-dimethyl-2-oxoethoxy]-imino~-4-thiazoleacetic acid, 0.08 g N-hydroxy-benzotriazole and 1.52 g of dicyclohexylcarbodiimide was added and the solution was stirred for 12 hours. The precipitate was filtered off and the ; solvent removed in ~cuo. The residue was stirred with 100 ml of dry ether and filtered. The compound was then suspended in 6 ml of anisole and cooled to -15~C. At this point 12 ml of trifluoroacetic acid was dropped in with stirring at such a rate, that the temperature did not exceed -10 C. After completion of the addition, ~ ~ 7~ ~-3~ GC183a .

stirl-ing was continued at -10 C for 2 hours.
Cold ether (200 ml) was added and the precipitated compound was filtered off, washed with ether, dried and dissolved in 50 ml of acetone/water (1:1). The pH was adjusted to 6.5 with lN KOH, the acetone removed 1n vacuo and the remaining aqueous solution freeze-dried, 2.25 g of crude title compound ~as obtained. Purification was achieved by HP-20 chromatography (water eluent), yielding 0.5 g of product, melting point 220-225C, dec.

Example 7 [3S(Z)]-2-[I[1-(2-Amino-4-thiazolyl)-2-~[1-[Il[(methoxyacetyl)amino]sulfonyl]a no]carbonyl~-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]-oxy]-2-methylpropanoic acid, dipotassium salt A) (S)-[l-[l~[(Methoxyacetyl)amino]sulfonyl]-amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl e ter, monopotassium salt (S)-3-~[(Phenylmethoxy)carbonyl]amino~-2-azetidinone (4.4 g) was suspended in 100 ml of dry ethyl acetate. The mixture was cooled to -30 C and 3.12 g of chlorosulfonylisocyanate was added with stirring. ~he cooling was stopped and when the temperature had reached 0C a clear solution was obtained. After 30 minutes at 0 C
13.9 g of N-trimethylsilyl methoxyacetamide were added and stirring was continued for 24 hours at am~ient temperature. After this time GC183a .

the ethyl acetate solution was washed with water,dried and the solvent removecl. The residue was dissolved in acetone/water t~:l) and the pH was adjusted to 6.5 with lN KOH. The acetone was removed ln vacuo and the aqueous solution was free~e dried.

B) [3S(Z)] 2-[[~1-(2-Amino-4-thiazolyl)-2-[rl-[ [ [ r (methoxyacetyl)amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]- -oxo-ethylidene]amino]-oxy~-2-methylpropanoic acid, dipotassium salt (s) ~ [1- [ ~ I I (Methoxyacetyl)amino]sulfonyl]-amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, monopotassium salt (0.43 g) was dissolved in 50 ml of dry dirnethyl-formamide. Palladium on charcoal (10%; 0.25 g) was added and hydrogen was bubbled through for 30 minutes with stirring. The catalyst was filtered off and 0.42 g of (Z)-2-amino-a-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]-imino]-4-thiazoleacetic acid, 0.01 g N-hydroxy-benzotriazole and 0.24 g of dicyclohexylcarbodiimide was added; the solution was stirred at ambient temperature for 12 hours. The precipitate was filtered off and the solvent removed ln vacuo.
The residue was suspended in diethyi ether and the precipitate filtered off (0.76 g~. This compound was suspended in 3 ml o anisole and cooled to -15C; 6 ml of trifluoroacetic acid was slowly dropped in with stirring, so that :
;

l~ 7~æ~ GC183a the temperature did not exceed -10C. After the addition was complete, the temperature was snaintained for 2 hours. Cold diethyl ether (100 ml) was added and the precipitate was filtered off, dried and dissolved in water.
The pH was adjusted to 6.5 by addition of lN KOH
and the solution was chromatographed on HP-20 resin, usiny water as eluent, yielding 200 mg of product, melting point 245-250 C, dec.

Example 8 13$(Z)]-2-Amino-N-Il-[l[I(methoxyacetyl)amino]-sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl~--(methoxyimino)-4-thiazoleacetamide,potassium salt (S)~ [¦[¦(Methoxyacetyl)amino~sulfonyl]-amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, monopotassium salt (O.S g;
see example 7A) was hydrogenated in 30 ml of dry dimethylformamide in the presence of 0.25 g 10% palladium on charcoal for 30 minutes.
The catalyst was filtered off and 0.22 g of (Z)-2-amino--(methoxyimino)-4-thiazoleacetic ~ acid, 0.01 g of N-hydroxybenzotriazole and :~ 0.21 g of dicyclohexylcarbodiimide were added.
~5 The solution was stirred overnight, ~iltered and evaporated to dryness. The residue was chromatographed (HP-20, water as eluent), yielding 0.12 g of product, melting point 170-175C,dec.-GC1~3 Ex~ e 9 f3S~Z)-2~[[~1-(2-Amino-4-tlliazolyl)-2~f[1-ff[(ben~oylamino)sulfonyl]amino]carbonyl]-2-; oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]-oxo~-2-methylpropaI7oic acid, dipotassium salt A) (S)-[l-~¦(Aminosulfonyl)amino]carbonyl]-2-oxo-3-a2etidinyl~carbamic acid, phenylmethyl ester, potassium salt Method I
(S)-(2-Oxo-3-azetidinyl)carbamic acid, phenylmethyl ester (11 g) was dissolved in a mixture of 200 ml of acetonitrile and 50 ml of dichloromethane. The mixture was cooled to -50C and a solution of chlorosulfonyl isocyanate (9 g) in 25 ml of dichloromethane was added with stirring. After warming the mixture to -30C a solution of 6 g of ammonia in 60 ml of acetonitrile was added slowly.
The reaction temperature was raised to -10 C
and finally to 0-5C. The reaction time was 3 hours. The ammonium salt of the title compound precipitated and was filtered by suction (20 g). The crude product was purified by HP-20 chromatography (100-200 mesh) eluting with 2000 ml of water and water/acetone (8:2);
20 ml fractions were taken. The elution was monitored by thin-layer chromatography. From fractions 142-154, 9.3 g of product was obtained by evaporation.

~ ~7v~ c 18 3a -3~-The ammonium salt of the title compound was dissolved in 100 ml of water, layered with 200 ml of ethyl acetate and acidified. After separation and washing of the aqueous layer twice with ethyl acetate, the or~anic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and evaporated to yield 8.1 g of the ~ree acid of the title compound.
Method II
A ~ixture of (S) (2-oxo-3-azetidinyl)carbamic acid, phenylmethyl ester (11 g) in 175 ml of dichloromethane was cooled to -30C. While stirring, 7.7 g of chlorosulfonyl isocyanate in 75 ml dichloromethane was added dropwise within 15 minutes. The temperature of the solution was allowed to rise to 0C over 30 minutes. Subsequently the clear solution was again cooled to -30C and 8.~ g of bis-(tri methylsilyl)amine dissolved in 30 ml of dichloromethane, was dropped in, while passing dry nitrogen through the flask. After an hour the reaction temperature was allowed to rise to -15C and was maintained for an additional 30 minutes. The solvent was distilled off in vacuo, and the residue was triturated with 400 ml of ether to give a solid (16.6 g) which was washed with an additional 20 ml of ether.
From the ethereal motherliquor there was obtained ~ 7X~,~ GC183a a second crop of 4.2 g of product.
The crude mater:ial (18.0 g) along with about 20 g of ~P-20 resin was suspended in 30 ml of water and the mixture was chroma tographed on an HP-20 column eluted with a) 3 L of water; b) 2.5 L of water/acetone (a 2~;
3) 4 L of water/acetone (7:3); d) 6 L of water/
acetone (6:4). Fraction d yielded 6.2 g of the title compound,melting point 150-152 C.
B) (S)-[l-[[~(Benzoylamino)sulfonyl~amino]-carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt (S)-~ (Aminosulfonyl)amino]carbonyl]-2-oxo-3-azetidinyl]carhamic acid, phenylmethyl ester, potassium salt (2.3 g) and 2.2 g of potassium carbonate were stirred in 50 ml of dry dimethylformamide with 5 g of benzoyl chloride and 0.6 g of dimethylaminopyriaine overnight.
The solvent was removed in vacuo and the residue was extracted at pH 1 (aqueous solution) with ethyl acetate. The organic layer was dried and evaporated to dryness. The residue was dissolved in water/acetone (1:9) and the pH adjusted to

6.5 with lN KOH. The acetone was removed in vacuo and the remaining aqueous solution fxeeze-dried.
Purification of the resulting white powder was achieved by HP-20 chromatography using water/
acetone (9:1) as eluent, and yielding 1.1 g of product melting point 96-99C, dec.

~7X,7~; GC183a _36_ C) [3S(2,)~-2-[~[1-~2-Amino~4-thiazolyl)-Z-~[1-~[~(~enzoyl~mino)sulfonyl]amin _ arbonylJ-2-oxo-3-azetidinyl~amino~-2-oxoethy]idene]amino]-oxy]-2-methylpropanoic acid, dipotassium salt (S)-[l-[II(Benzoylamino)sulonyl]amino]-carbonyl]-2-oxo-3-azetidinyl~carbamic acid, phenylmethyl ester, potassium salt (0.5 g) was hydrogenated in 100 ml of dry dimethylformamide in the presence of 0.25 g of 10% palladium on charcoal for 1 hour. The catalyst was filtered off and 0.46 g of (Z)-2-amino-a-[12-(diphenyl-methoxy)-l,l-dimethyl-2-oxoethoxy~imino]-4-thiazoleacetic acid, 0.01 g N-hydroxyben~otriazole and 0.24 g of dicyclohexylcarbodiimide were added and the solution was stirred for 12 hours. The solvent was distilled off in vacuo and the residue was filtered of with 100 ml of ether and dried (0.92 g). This compound was suspended in 2 ml of anisole, cooled to -10 C and 4 ml trifluoroacetic acid was added with stirring. The temperature was main'cained for 5 hours. After this time 100 ml o dry ether was added and the precipitated compound was filtered off, dissolved in 5 ml of water and the pH was adjusted to 6.5 with lN KOH.
2S The resulting aqueous solution was chromatographed on HP~20 resin ~eluting with water) and yielded 0.24 g of product, melting point 225-230C, dec.
, .

~ 7~ GCl83a Example 1() [3S(R)]-N-[2 ~ ~ (Benzoy~amino)Sulfony~la _no]-carbonyl]-2-oxo-3-azetidlnyl]amino]-2-oxo-l-phenylethyl~-4 ethyl-2, dioxo-l-piperazine carboxamide, potassium salt s ) - [ ~ I (Benzoylamino)sulfonyl]amino]-carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt (0.25 g;
see example 9B) was hydrogenated as described in example 9C. (R)-~ (4-Bthyl-2,3-dioxo-l-piperazinyl)carbonyl]amino]benzeneacetic acid (0.17 g), 0.01 g of N-hydroxybenzotriazole and 0.13 g of dicyclohexylcarbodiimide were added to the resulting solution which was stirred overnight. The solvent was distilled off in vacuo and there~due chromatographed using HP-20 resin and water/acetone (l9:1) as eluent, yielding 0.14 g of product, melting point 180-185C, dec.
- E_ample ll l3s (Z? ~-2-Amino-~-[l-~[(benzoylamino)sulfonyl]-amino]carbonyl~-2-oxo-3-azetidinyl] -a- (methoxy-imino)-4-thiazoleacetamide, potassium salt (S)~ [(Benzoylamino)sulfonyl]amino]-carbonyl]-2-oxo-3-azetidinyl~carbamic acid, phenylmethyl ester, potassium salt (0.25 g;
see example 9B) was hydrogenated as described in example 9C. To the resulting solution 0.01 g of N-hydroxybenzotriazole, 0.11 g of (Z)-2-amino-~-(methoxyimino)-4-thiazoleacetic acid and 0.13 g of dicyclohexylcarbodiimide were added. After GC183a

7~7~;

stirring overnight at room temperature~ the solvent was removed ln vacuo and -the residue chromatographed using HP-20 resin and water/acetone (19:1) as eluent, yielding 0.05 y o product, melting point 205 210C.

Example 12 S) - [ 1- [ I [ I (Acetyl)methylamino3sulfonyl~amino]-_arbonyl]-2-oxo-3--azetidinyl]carbamic acid, phenylmethyl ester (S)-3-[~(Phenylmethoxy)carbonyl]amino]-2-azetidinone (2.2 g) was suspended in 100 ml of anhydrous tetrahydrofuxan and cooled to -50 C with stirring. Chlorosulfonylisocyanate (1.56 g) was added and the temperature was maintained at 0 C for 30 minutes. After this time `~ 3.51 g of heptamethyl disilazane was added and stirring at room temperature was continued over-night. Acetyl chloxide (3.14 g) was added and the solution was stirred for an additional 48 hours. The solvent was removed in vacuo, and the residue dissolved in ethyl acetate and extracted twice with 50 ml portions of water. The aqueous layer was discarded and the ethyl acetate solution was dried ~ith Na2SO4 and evaporated to dryness. The residue was dissolved in acetone~water (9:1), the pH adjusted to 6.5 with 1i~ KOH and the acetone removed ln vacuo. The remaining aqueous solution was free~e-dried.
The resulting crude compound (1.9 g) was purified by HP-20 chromatography, yielding 1.03 g of product.

GCI83a _ _s(z)~-2-Amino~N~ 1 I ( 2 -me t~yl.~rop~oyl-) a sulfonyl]amino]carbonYl]-2-oxo-3-azet~dinyl]-__ __ _~
~-(me _oxyimino)-4-thiazoleacetam1de potassium salt (S)-3-ll(Phenylmethoxy)carbonyl]amino]-2-azetidinone (2.2 g~ was suspended in 100 ml of dry ethyl acetate, cooled to -50C and 1.56 g chlorosulfonylisocyanate was added. After 30 minutes at 0C a clear solution was obtained and 4~78 g o~ N-trimethylsilyl 2-methylpropionamide was added and stirring at ambient temperature was continued for 12 hours. The solution was washed with 100 ml of water, dried and evaporated to dryness. The residue was dissolved in water/acetone (1^9) and the pH adjusted to 6.5 with lN KOH. Acetone was removed in vacuo and the remaining aqueous solution freeze-dried, ylelding 0.28 g of compound~ This compound was dissolved in 20 ml of dry dimethylformamide and hydrogenated with 0.1 g of 10% palladium on charcoal for 30 minutes. The catalyst was - -filtered off and 0.1 g of (Z~-2-amino--(me1hoxy-imino)-4-thiazoleacetic acid, 0.01 g of N-hydroxy-benzotriazole and 0.13 g of dicyclohexylcarbodiimide ; 25 were added and the mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue chromatographed on HP-20 resin eluting with H2O/acetone (19:1) and yielding 50 mg of product, melting point ; 30 ~ 185-190C, dec.

~ GC183a - ~ O ~

Example 14 l3S~Z)]-2-~nino-N~ (aminocarbon~l)amino]-sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyL]-~-(me ~ mid~, potassium salt A) S)~ r ~ I I (Aminocarbonyl)amino]sulfonyl]-amino]carbonyl~-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt (S) -3- [ L (Phenylmethoxy)carbonyl~amlno]-2-azetidinone (13.2 g) was suspended in 300 ml of dry tetrahydrofuran at 0C. Chlorosulfonyl-isocyanate (11.1 g) dissolved in 80 ml of dry dichloromethane was dropped in with stirring.
The temperature was maintained with cooling at 0 C for 30 minutes. Trimethylsilyl urea (10.5 g) was added and stirring was continued at room temperature overnight. The solvent was removed in vacuo and 200 ml of methanol was added. The solution was stirred for 30 minutes, the solvent evaporated and the residue treated with 200 ml of ethyl acetate and 100 ml of water. The organic layer was separated, dried and filtered. After removal of the solvent,the oily residue was dissolved in 100 ml of acetone and 10 ml of water, and the pH was adjusted to 6.5 by addition of lN
potassium hydroxide. After evaporation of the solvent, the title compound remaine~. Yield 11.0 g; melting point 120-125 C,dec.

~Z ~ 2~ GC183a B) 13S(Z)]-2-~mino-N~ [[l~(aminocarbonyl)amino]-s_lfonyl]amino~carbonyl~-2-~oxo-3-azetidi.nyl~-u-(methoxyimino)-4-thiazoleace~clnlide~_~_tassiunl sa:Lt (s) - [ 1- ~ [ I ~ ( Aminocarbonyl)amino3sulfonylJ-amino~carbonyl~-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt (1.4 g) was hydrogenated in 100 ml of dry dimethylformamide with 0.7 g of 10% palladium on charcoal as a catalyst. Ater 30 minutes the hydrogenation was completed, the catalyst filtered off and 0.66 g of (Z)-2-amino--(methoxyimino)-4-~hiazole- . i.
acetic acid and 0.2 g of N-hydroxybenzotriazole were added. Dicyclohexylcarbodiimide (720 mg), dissolved in 100 ml of dry dimethylformamide was slowly dropped in with stirring during a period of 10 hours. Stirring was continued for an additional 12 hours. The mixture was cooled to 0C, the precipitated urea filtered off, the solvent removed in vacuo and the residue chroma-tographed on HP-20 resin using water as eluent.
Yield 900 mg; melting point 205-210C, dec.

Example 15 [3s(z)]-2 ~ 2-[~ (Aminocarbonyl)amino]-`
sulfonyllamino3carbonyl]-2-oxo-3-a~etidinyl]amino3-1-(2-amino-4-thiazolyl)-2-oxoethylidene]amino]oxy~-2-methylpropanoic acid, dipotassium salt ~ S) - El- ~ L ~ ~ (Aminocarbonyl)amino~sulfonyl]-amino~carbonyll-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt tl.93 g; see example 14A) was hydro~enated in the presence of 1 g of 10% palladium on charcoal in 200 ml of X ~ ~ GCI83a -~2-dry dimethylformamide or 30 mlnutes. The catalystwas filtered off and 30~ mg of N-~vdrGxy~enzo-triazole alld 2.5 g of (Z)-2-amino-~-LL2~(diphenyl-me-thoxy)-l,l-climethyl-2-oxoethoxy~lmino]-4-thiazoleacetic acid was added. Dicyclohexyl-carbodiimide (1.1 g~, dissolved in 100 ml of dimethylformamide was slo~ly dropped in (10 hours).
When the addition is complete, stirring was contirlued for an additional 10 hours. The solvent was removed in vacuo and the solid residue was suspended in 10 ml of anisole and cooled to 0 C.
At this temperature 20 ml of trifluoroacetic acid was dropped in with stirring. The temperature was maintained at 0 C with cooling. After 3.5 hours, the reaction was complete and the solution was poured in-to 200 ml of ether. The precipitate was filtered off, dried and dissolved in 10 ml of water/acetone (1:1), and the pH was adjusted to 6.5 by the addition of 1 N potassium hydroxide.
The acetone was removed in vacuo and the aqueous phase chromatographedon HP-20 resin using water as eluent. Yield 1.5 g; melting point 258C, dec.

Example 16 13S~R)~-N-I2-[~1-[l[[(Aminocarbonyl)amino]sulfonyl]-amino]carbo~ -2-oxo-3-azetidinyl~amino]-2-oxo-1-phenylethyl]-4-ethyl-2,3-dioxo-1-piperazine-carboxamide,_potassium salt (s) -Il- [ I I I (Aminocarbonyl)amino]sulfonyl~-amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt (1.34 g; see example14A) was hydrogenated with 0.6 g of 10% palladium on charcoal as catalyst in 100 ml 3~

GCI83a -~3~

of dry dirnethylformarnide for 30 minutes. The catalyst was filtered of~ and 1.23 g o (R)-a-I[(4-ethyl-2,3-diQ~o-l-piperazinyl)carbonyl]-amino]benzeneacetic acid and 100 mg of N-hydroxy-benzGtriazole were added. Dicyclohexyl-carbodiimide (0.8 g),in 100 ml of dimethyl-formarnide was dropped in with stirring over a period of 10 hours. Stirring was continued for an additional 10 hours. The solvent was removed ln vacuo and the residue chromatographed on HP-20 resin, using water as eluent. Yield 590 mg; melting point 198C, dec.

Example 17 ~3S(Z)]-2-Amino-a-(methoYyimino)-N-[l-~f¦(methyl-amino)carbonyl]amino]sulfonyl]amino3carbonyl3-2-oxo-3-azetidinyl]-4-thiazoleacetamide, potassium salt A) (S)~[l-~[[~[(Methylamino)carbonyl]amino]sulfonyl]-amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, ~otassium salt ( s) - :f 1~ (~minosulfonyl)amino~carbonyl~-2-o~o-3-azetidinyl~car~amic acid, phenyl-methyl ester, potassium salt (1 g; see example 9A) was dissolved in 20 ml of dry dimethyl-formamide. Methylisocyanate (500 m~,was added and the solution was stirred overnight at ambient temperature. The solvent was removed in vacuo and the residue was treated with acetone/ether (1:1) and filtered. Yield 0.9 g; melting point 153-160C, dec.

GC1~3a -44-~

B) ~ Z)~ 2-Amino-u-(methoxy ~
I [ I [ ~ methylam o)carbonyl] amino] sulfonylJamino]-carbonyl]-'2-'oxo-3-azetidinyl']-4'-'thiazoleacetamide, potassium salt (S) -Il- L [ I I I (Methylamino)carbonyl]amino]-sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-carbamic acid, phenylmethyl ester, potassium salt (437 mg) was hydrogenated in 50 ml of dry dimethyl-formamide in the presence of 200 mg of 10%
palladium on charcoal. After 45 minutes the reaction was complete and the catalyst was filtered off. (5)-2-Amino-~-(methoxyimino)-4-thiazoleacetic acid (220 mg), 50 mg of N-hydroxy-ben~otriazole and 300 mg of dicyclohexylcarbodiimide were added with stirring at ambient temperature.
Stirring was continued for 12 hours, the solution cooled to 0C and the precipitated urea was filtered off. The solvent of the mother liquor ; was removed _ vacuo and the residue was chroma-tographed on HP-20 resin, using water. Yield 305 mg; melting point 220~225C, dec.

~ 7~7~
-~5~

Example 18 ¦3S(R)]-4_E,t~y__N-12~ [ I llmet~ l[(methy~amino)-~ ino~sul'fonyl]'amino3carbonyl] -2-oxo-3-azetidinyl~amino~ ~ 2,3-dioxo-l-pipera~inecarboxamide, potassium salt A) (S)~ Methyl~methylamino~carbonyl]amino3-sulfonyl] mino]carbonyl]-2-oxo-3-azetidinyl]-carbamic acid, phenylme-thyl ester, potassium salt 10(s) -3- [ I tPhenylmethoxy)carbonyl~amino]-2-azetidinone (4.4 g) was suspended in 100 ml of dry tetrahydrofuran and the mixture was cooled to -10C. At this temperature, 1.6 g of chloro-sulfonylisocyanate was added and the reaction mixture was allowed to reach room temperature.
Trimethylsilyl N,N'-dimethylurea (5~2 g) were added '~ and stirring at ambient temperature was continued for 12 hours. The solvent was removed in vacuo and the residue was dissolved in 100 ml of 0 ethyl acetate. The organic solution was washed twice with 50 ml portions of water, with 50 ml of 2 N phosphoric ac~d and with brine. The organic layer wasevaporated to dryness, the~
residue dissolved in water/acetone (1:1) (50 ml).
The pH was adjusted to 6.5 with l N potassium hydroxide. The acetone was removed in vacuo and the aqueous solution ~reeze dried to yield

8 g of crude title compound pure enough for further reactions.

~7~7~6 GC183a _ -~6-~ 3S(R)]-4-Eth l-N-~2-[~1-[[[~methyl[(methyl-Y_ ___ _ amino)carbonyl~aminoJsulfonyllamino _arb~ny1 -2-ox - _ azetidinyl]amino]-2-oxo-1-phenylethyl]-2,3-dioxo-1-piperaz;necarboxamide, potassium salt (s)-~ I [MethylI(methylamino)carbonyl~-amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl~-carbamic acid, phenylmethyl ester, potassium salt (900 mg) was hydrogenated in 50 ml of dry dimethyl-formamide in the presence of 400 mg of 10% palladium on charcoal. The hydrogen uptake ceased after about 30 minutes. The catalyst was filtered off and 700 mg (R)-~-~l(4-ethyl-2,3-dioxo-1-piperazinyl)-carbonyl]amino]benzeneacetic acid, 100 mg of N-hydroxybenzotriazole and 600 mg of dicyclo-hexylcarbodiimide were added with stirring. After 12 hours at ambient temperature, the precipitated urea was filtered of, and the solvent removed in vacuo. The residue was chromatographed on HP-20 resin, using water/acetone (9:1) as eluent.
Yield 700 mg; melting point 177 C, dec.

Example 19 3S~Z)]-2-l[ Il- (2-Amino-4-thiazolyl)-2-[ll-[~[lmethyl-~(methylamino)carbonyl]amino]sulfonyllamino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene~amino~-oxy]-2-methylpropanoic acid, dipotassium salt (s) - ~ Methyl~(methylamino)carbonyl]-amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-carbamic acid, phenylmethyl ester, potassium salt (900 mg; see example18A) was hyarogenated in 50 ml of dry dimethylformamide in the presence of 450 mg of 10~ palladium on charcoal for 30 minutes. The catalyst was filtered off and 1 g CCl~a -~7--of (Z)-2-amino-a-~I2-(dipheny]methoxy)-1,1-dimethyl-~-oxoethoxy3imino]~ thiazoleacetic acid, 100 mg of N-hydroxybenzotriazole and 600 my o~
dicyclohexylcarbodiimide were added with stirring at ambient temperature. After 12 hours, the solution was cooled to 0C and the precipitated urea was filtered off. The solution was evaporated to dryness and the residue was filtered off with 50 ml of ethyl acetate. The crude compound was suspended in 2 ml of anisole, cooled to -5C
and 6 ml of trifluoroacetic acid was dropped in at such a rate that the temperature could be maintained at 0C. After 2 hours, 100 ml of dry ether was added and the precipitate was filtered off, washed with ether and dried. The crude compound was dissolved in 20 ml of water and the pH adjusted to 6.5 with lN potassium hydroxide.
After freeze drying, the crude potassium salt was chromatographed using HP-20 re~in and water as eluent and then freeze-dried. Yield 400 mg;
melting point 220C, dec.

Example 20 [3S(Z))-2-Amino-a-(methoxy _ino~-N-[l-[¦~methyl-~(methylamino)carbonyl]amino]sulfonyl]amino~-carbonyl]-2-oxo-3-azetidinyl3-4-thiazoleacetamide, potassium salt : ( s ) - I 1- ~ L ~ ~ethyl L ( methylamino)carbonyl~
amino]sulfonyl~amino3carbonyl~-2-oxo-3-azetidinyl3-carbamic acid, phenylmethyl ester, potassium salt (440 mg; see example18A) was hydrogenated as described in example 6. (Z)-2-A~ino-a-(methoxyimino)-4-thiazoleacetic acid (220 mg), 50 mg of N-hydroxy-benzotriazole and 250 ml of dicyclohexylcarbodiimide .

~7~7~ GCl8~a ..

were added after removal of the catalyst~ Stirringat ambient tempera-ture was continuecl for 12 hours.
The solvent was removed in vacuo and t:he resldue ~hromatographed on HP-20 resin, using water/acetone (9:1) as eluent. Yield 350 mg (isolated by free~e drying); melting point 192C, dec.

Example 21 __.
[3S (æ) ]-2-[l[1-(2-Amino-4-thiazolyl)-2-~
~[~(dimethylamino)carbonyl]amino~sulfonyl~-amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy~-2-methylpropanoic acid, potassium salt lS A) (S)-~ [(Dimethylamino)carbonyllamino]-sulfonyl]amino]carbonyl~-2-oxo-3-azetidinyl~-carbamic acid, phenylmethyl ester, potassium salt (S)-3-[[(Phenylmethoxy)carbonyl]amino]-2-azetidinone (4.4 g) was suspended in 150 ml of ethyl acetate and cooled to -15 C. Chloro-sulfonylisocyanate (3.0 g) was added and the mixture was stirred at 0C until a clear solution was obtained. N,N-Dimethylurea (2 g) and 2 g of triethylamine were added and stirring was continued overnight. The precipitate was filtered off and the mother liquor washed with two 50 ml portions of water, 50 ml of 2N phosphoric acid and brine.
The solvent was removed in vacuo and the residue was dissolved in 50 ml of water/acetone (1:1).
The pH was adjusted to 6.5 with lN potassium hydroxide. The acetone was removed in vacuo and the aqueous solution was free~e dried. Crude title compound (7 g) was obtained, which was pure enough for further manipulation.

GC183a B) ~3S(Z)]-2-[I¦1 [2-Amino-4-khiazolyl)-2-[¦1-bonyl]amino]sul~onyl~-amlno~carbonyl~-2-oxo-3-azetidinyl~amino]-2-oxoethylidene~amino]oxy]-2-methylpropanoic acid, potassium salt (S)-[l-~ (Dimethylamino)carbonyl]amino]-sulfonyl]amino]carbonyl~-2-oxo-3-azetidinyl]-carbamic acid, phenylmethyl ester, potassi~ salt (451 mg) was dissolved in 50 ml of anhydrous dimethylformamide, 200 ml of 10% palladium on charcoal was added and hydrogen was bubbled throuyh the solution for 45 minutes. The catalyst was filtered off and 450 mg of (Z)-2-amino-~-[I2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]-imino]-4-thiazoleacetic acid, 100 mg of N-hydroxy-benzotriazole and 300 mg of dicyclohexylcarbQdiimide were added and the solution was stirred at ambient temperature for 12 hours. The precipitated urea was filtered off and the solvent removed in vacuo. The residue was chromatographed using HP-20 resin and water/acetone (7:3) as eluent.
The benzhydryl ester of the title compound (600 mg) was isolated by freeze dryingO This compound was suspended in 2 ml of anisole, the mixture cooled to -10 C and 4 ml of trifluoroacetic acid was slowly dropped in, s~ that the temperature did not exceed -5C. When the addition was complete, stirring at -5C was continued for 2 to 5 hours.
The title compound was precipitated by the addition f 100 ml of ether, filtered off, dissolved in 5 ml of water and the p~I adjusted to 6.5 with 2N
potassium hydroxide. The solution was chroma-tographed on HP-20 resin using water as eluent.
Yield 280 mg; melting point 191C, dec.

~ 7~,~; GC183a Example 22 _S(Z)~-2-[[Il-(2-Amino-4-thiaz lyl)-2-1~1-~ I [ I 1 ( 3-ethyl-2-oxo-l-imidazolidinyl)carbonyl]-amino]sulfonyl]amino]carbonyl]-2-o~o-3-azetidinyl~-amino]-2-oxoethylidene]amino]oxy]-2-methyl-propanoic acid, dipotassium salt A~ (S)-~ [ I (3_E yl-2-oxo-1-imidazolidinyl)-carbonyl]amino]sulfonyl]amino]carbonyl]-2-oxc-3-10 _ ~
otassium salt P
(S)-3-ll(Phenylmethoxy)carbonyl]amino]-2-azetidinone (6.6 g) was suspended in 200 ml of anhydrous ethyl acetate and the mixture was cooled to -15C. At this temperature, 5 g of chlorosulfonylisocyanate was added with stirring at 0C until a clear solution was obtained (10 minutes). Triethylamine (4 g) and 5.2 g of l-aminocarbonyl-3-ethylimidazolidin-2-one were added and stirring was continued at room temperature for 12 hours-. The reaction mixture was washed with two 50 ml portions o~ water, 50 ml of 2 N phosphoric acid and brine. The organic phase was evaporated to dryness, the residue dissolvea in lS0 ml oE water/acetone ~ and the pH was adjusted to 6.5 with 1 N
potassium hydroxide. The acetone was distilled off in vacuo and the remaining aqueous solution was free~e dried. The crude title compound --(12.2 g) was pure enough for further reactions.

GCL83a ~ D

) _3S(Z)~-2-~[¦1-(2-Amino-4--thiazolyl)-2-[ Il- f I ~I~(3-ethyl-2-oxo-1-imlda_olidinyl)carbony~3~
amino]sulfonyl]aminoJc_rbonyl]-2-oxo-3-az_t inyll-a o~-2-oxoethylidene]amino]oxy]-2- ethyl-propanoic acid, dipotassium salt (S) ~ [l [l I (3-Ethyl-2-oxo-l-imidazolidinyl) -carbonyl]amino]sulfonyl]amino]carbonyl~-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, ; potassium salt (520 mg) was hydrogenated in S0 ml of anhydrous dimethylformamide in the presence of 200 mg of lO~ palladium on charcoal for 40 minutes. The catalyst was filtered off, 460 mg of (Z~-2-amino~ 2-(diphenylmethoxy)-l,l-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid, lO0 ml of N-hydroxybenzotriazole and 300 mg of dicyclohexylcarbodiimide were added and the solution was stirred overnight. The sol~-ent was distilled off in vacuo and the residue was filtered off with ethyl acetate, suspended in 2 ml of anisole and cooled to -lO C. Trifluoro-acetic acid (4 ml) were dropped in at such a rate that the temperature did not e~ceed -5C. Stirring at this temperature was continued for 2 hours.
After addition of lO0 ml ether, the precipitate ~.~s filtered off, dissolved in lO ml of water, the pH adjusted to 6.5 with 1 N potassium hydroxide and the aqueous solution was chromatographed on HP-20 using water as eluent, and the title compound isolated by freeze drying. Yield 250 mg; melting point 245C, dec.

7,~ GC1~3 -~2-Example 23 _35(Z)]-2-Amino-~-(ethoxylmlno)~[1~[[l[[(3-ethyl-2-oxo-1-imidazolidinyl)carbonyl]amino]-sulfonyl]amino]carbonyl3-2-oxo-3-azetidinyl]-4-thia~oleacetamide, potassium salt (s) - Il- ~ L L I [ ~3-Ethyl-2-oxo-l-imidazolidinyl)-carbonyl]amino]sulfonyl]amino~carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt (520 mg; see example 22~) was hydrogenated in 50 ml of dimethylformamide in the presence of 200 mg of 10% palladium on charcoal for 40 minutes. The catalyst was filtered off and 230 mg of (Z)-2-amino-a-(ethoxyimino)-4-thiazoleacetic acid, lO0 mg of N-hydroxybenzotriazole and 300 mg of dicyclo-hexylcarbodiimide were added. The solution was agitated at room temperature for 12 hours. After this time the solvent was removed ln vacuo and the residue filtered with ethyl acetate. Purifi-cation of the crude compound was accomplishedby HP-20 chromatography using water/acetone (9:1) as eluent, and the title compound isolated by freeze drying. Yield 420 mg; melting point 125 C.
, GC1~3a Example . _ .
~3s (z) ] -~-Amino-N~ l l;I [ L (3-ethyl~2-oxo-1 imidazolidinyl)carbonyl]amino]sulfonyl]amin _ carbonyl]-2-oxo-3-azetidinyl]--(methoxyimino)-4-thiazoleacetamide, potassium salt -Following the procedure of example 23, but replacing (z)-2-amino-~-tethoxyimino)-4-thiazoleaceticiacid by (Z)-2-amino-~-(methoxy-imino)-4-thiazoleacetic acid, yielded 400 mg of the title compound; melting point 176C, dec.

Example 25 [3S(R)]-4-Ethyl-N-I2-~ ( 3-ethyl-2-oxo-1-imidazolidinyl)carbonyl]amino]sulfonyl]amino]-carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxo-1-phenylethyl]-2,3~dioxo-1-piperazinecarboxamide potassium salt (S) -Il- [ [ [L [ (3-Ethyl-2-oxo-1-imidazolidinyl)-carbonyl]amino]sulfonyl~amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester,potassium salt (520 mg; see example22~ was hydrogenated in 50 ml of dimethylformamide in the presence of 200 mg of 10% palladium on charcoal for 40 minutes. After filtration, 330 mg of ~R)-~ (4-ethyl-2,3-dioxo-1-piperazinyl)-carkonyl]amino]benzeneacetic acid, 300 mg of dicyclohexylcarbodiimide and 100 mg of N-hydroxy benzotriazole were added and the solution was stirred for 12 hours at room temperature. The solution was evaporated in vacuo to dryness and the residue filtered with ethyl acetate.

' '' '' GC183a 5~-Purification of the crude compound was achievedby chromatography on HP-20 resin using water/
acetone (9:1) as eluent. Yleld 480 mg; meltiny point 181C, dec.

Example 26 -~3S(Z)]-2-Amino--(metho~yiminO)-N-[l~~ILI(4~
ethyl-2,3-dioxo-1-piperazinyl)carbonyl~amino]
; sulfonyl]amino]carbonyl] 2--_xo-3-azetidinyl]-4-thiazoleacetamide, potassium salt A) (S)-[l-~[ I [I(4-Ethyl-2,3-dioxo-l-piperazinyl) carbonyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt (S)-3-~[(Phenylmethoxy)carbonyl]amino]-2-; azetidinone (4.4 g) was suspended in 200 ml of ethyl acetate and at -15C, 3 g of chloro-sulfonylisocyanate was added with stirring. After 15 minutes at 0C a clear solution was obtained.
2.5 g Triethylamine and 4 g of 1-aminocarbonyl-4-ethyl-2,3-dioxopiperazine was added and stirring was continued for 16 houxs. The mixture was washed with two 50 ml portions of water, 50 ml of 2 N phosphoric acid and brine. After evaporation of the solvent, the residue was dissolved in 100 ml of acetone/water (1~ he pH adjusted to 6.5, the acetone removed and 8 g of crude compound gsolated ~y freeze drying.

.~7~6 GC183a B) L3S(Z)]-2--Amino~ (methoxyi.mino)-N-[l_ I I I I I ( 4-ethy'1-'2,3-'dioxo-1 piperazinyl)carbonylJ-amino~su_fonyl]amino]carbonyll--2~oxo-3-azetidinyl]-4-th:iazoleacetamide, potassium salt (s) - Il- [ I [ I I (4-Ethyl-2,3-dioxo-1-piperazinyl)-carbonyl~amino~sulfonyl~amino3carbonyl~-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt (S48 mg) was hydrogenated in 50 ml of dimethylformamide in the presence o 270 mg of 10% palladium on charcoal for 45 minutes.
To the hydrogenation solution, 210 mg o~ (Z)-2-amino-~-(methoxyimino)-4-thiazoleacetic acid, 50 mg of N-hydrox~benzotriazole and 300 mg of dicyclohexylcarbodiimide were added and the solution was stirred at 20C for 16 hours. The solverlt was removed in vauco, the residue filtered with ethyl acetate and the crude compound was chromatographed on HP-20 resin using water/aceLone (9:1) as eluent. Yield 280 mg.

~ Example ~7 [3S(Z')]-2-[~12-[[1-[[1[(4-Ethyl-2,3-dioxo-1-piperazinyl)carbonyl~amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-1-(2-amino-4-thiazolyl)-2-oxoethylidene)amino~oxy]-2-methylpropanoic acid, dipotassium salt (s) - [1- [ I I [ ~ ( 4-Ethyl-2,3-dioxo-1-piperazinyl)-carbonyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, 3~ potassium salt (548 mg; see example 2~) was hydrogenated in 50 ml of dimethylformamide in the presence of 270 mg of 10~ palladium on charcoal GC183a '7~
56~

for 45 minutes. After removaL of the catalyst, ~50 mg of ~Z)-2-amino--[l2-(diphenylmetho~y)-1,1-dimethyl~2-oxoethoxy]lmino] 4~thiazoleacetic acid, 100 mg of ~-hydroxybenzotriazole and 300 mg of dicyclohexylcarbodiimide were added. The solution was stirred for 16 hours. The solvent was removed in vacuo and the residue was filtered with ethyl acetate. The crude benzhydryl ester of the title compound was suspended in 2 ml of anisole, cooled to -10C and 4 ml of trifluoro-acetic acid was drGpped in with stirring. The temperature was maintained at -5C for 2 hours.
Ether (100 ml) was added and the precipitate was filtered off, dried and dissolved in 5 ml of water, the pH adjusted to 6.5 and the solution chromatographed on HP-20 resin using water as eluent. The title compound (180 mg) was isolated by freeze drying.

Example 28 ~3S(R)]-4-Ethyl-N-[2-[~ [~[tmethylamino)-carbonyllamino]sulfonyl]amino]carbonyl~-2-oxo-3-azetidinyl]amino]-2-oxo-1-phenylethyl-2,3-dioxo-l-piperazlnecarboxamide,_potassium salt (S)-ll-[ll[~(Methylamino)carbonyl~amino]~
sulfonyl]amino]carbonyl~-2-oxo-3-azetldinyll-carbamic acid, phenylmethyl ester, potassium salt (437 mg; see example17A) was hydrogenated in 50 ml of dry dimethylformamide in the presence of 200 mg of 10% palladium on charcoal for 45 minutes. The catalyst was filtered off, 350 mg GC183a of ~R) -a- ~ I (4-ethyl~2,3-dioxo-1-pi~erazinyl)-carbonylJamino~benzeneacetic acid, 50 m~ of N-hydroxybenzotriazole and 300 mg of dicyclo-hexylcarbodiimide were added; the solution was S stirred for 12 hours. After removal of the solvent in vacuo, the residue was chromatographed on HP-20 resin using water/acetone (9:1) as eluent. Yie]d 380 m5; melting point 178-183C,dec.

Example 29 [3S(Z)]-2-[I~1-(2-~mino--4-thiazolyl)-2-~
~ [ I ~ ~ (methylamino)carbonyl]amino]sulfonyl3amino]-carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxo-ethylidene]amino]oxy~-2^methylpropanoic acid, dipotassium salt ~ S) - Il- L [ E ~ [ (Methylamino)carbonyl~amino]-sulfonyl]amino]carbonyl~-2 oxo-3-azetidinyl]-carbamic acid, phenylmethyl ester, potassium salt (437 mg; see example17A) was hydrogenated in 50 ml of dimethylformamide in the presence of 200 mg of 10% palladium on charcoal for 45 minutes. The catalyst was filtered off and 450 mg of (Z~-2-amino-~-~[2-(diphenylmethoxy)~
dimethyl-2-oxoethoxy~imino3-4-thiazoleacetic acid, 50 mg o~ N-hydrocvben~otria ole and 300 mg of dicyclohexylcarbodiimide were added. The solution was stirred overnight, evaporated to dryness, the residue suspended in 2 ml of anisole, cooled to -10C and 4 ml of trifluoro-acetic acid was dropped in. Stirring was ~ ; GC1~3a -~8-continued for 2 hours at -5 C. After addition of 100 ol oE ether, the precipitate was filtered of, dissolved in 5 ml of water, the pH adjusted to 6.5 with 1 N potassium hydroxide and the aqueous solution chromatographed on HP-20 resin using water as eluent. The title compound (280 mg) was isolated by freeze drying, melting point 215-220C, dec Example 30 I3S(Z)]-2-Amino-N-~l-[I~II(dimethylamino)carbonyl]-amino]sulfonyl]amino]carbonyl~-2-oxo-3-azetidinyl~-a-(methoxyimino)--4-`thiazoleacetamide, potassium salt (s) -~1- [ ~ (Dimethylamino)carbonyl]amino]-sulfonyl]amino]carbonyl]-2-oxo-3-aæetidinyl]-carbamic acid, phenylmethyl ester, potassium salt (451 mg; see example 21A) was hydrogenated in 50 ml of dimethylformamide in the presence of 200 mg of 10~ palladium on charcoal for 45 minutes. The catalyst was filtered off and 201 mg of (Z)-2-amino-~-(methoxyimino)-4-thiazoleacetic acid, 50 mg of N-hydroxybenzotriazole and 300 mg of dicyclohexylcarbodiimide were added~ The solution was stirred for 12 hours at ambient temperature. Tne solvent was removed in vacuo and the crystalline residue chromatographed on HP-20 resin using water/acetone (9.5:0~5) as eluent. Yield 2~5 mg; melting-point 201C, dec.

1~7~7~ GC~3a ~ 31 3S(Z)]-2-Amino-~-(methoxyimino)-N-[2-oxo~l-[[[[[(2-oxo-l-pyrrolidinyl)carbonyl]amino]
sulfonyl]amino]carbonyl]-3-azetidinyl]-4-thiazoleacetamide, potassium salt A) (S)-[2-Oxo-1-~ L [[(2-oxo-1-pyrrolldinyl)carbonyl]-amino]sulfonyl]amino]carbonyl]-3- ~
carbamic acid, phenylmethyl ester, potassium salt (S)-3-~[(Phenylmethoxy)carbonyl]amino]-2-azetidinone (3g) was suspended in 100 ml of dry tetrahydrofuran at 0C. Chlorosulfonylisocyanate (2.1 g) was slowly dropped in with stirring while the temperature was maintained at 0C;
after 30 minutes, a clear solution was obtained.
At 0C, 1.7 g of triethylamine and 2.05 g of N-carbamoylpyrrolidone were added. Stirring was continued at ambient temperature for 15 hours.
After this time the precipitate was filtered off and the mother liquor evaporated to dryness.
~- The residue was dissolved in 50 ml of water/acetone (1:1), the pH adjusted to 6.5 with 1 N potassium hydroxide, the acetone removed in vacuo and the xemaining aqueous solution freeze dried yielding 6 g of the title compound.

.
:

~7~ 7~; GC183a ..
-6~-B) 3S(Z)]--2-~nino- -(methoxyimino)-N-~2-oxo_l~
[[[[[(2-oxo~ pyrrolldinyl)carbonyl]arnino~-sulfonyl]amino]carbonyl]-3-azetidinyl]-4-thiazoleacetamide, potassium salt _ ~S)-[2-Oxo~ [[[I(2-oxo-1-pyrrolidinyl)-carbonyl]amino~sulfonyl]amino]carbonyl]-3-azetidinyl~carbamic acid, phenylmethyl ester, potassium salt (1 g) was hydrogenated in dimethyl-formamide using a 10~ palladium on charcoal catalyst. The catalyst was filtered off, and 0.44 g of (Z)-2-amino-~-(methoxyimino)-4-thiazoleacetic aaid, 30 mg N-hydroxybenzotriazole and 0.82 g dicyclohexylcarbodiimide were added to the mother liquor. The solution was stirred overnight, the solvent removed ln vacuo and the residue chromatographed on HP-20 resin (eluting with water) yielding 300 mg of the title compound.

Example 32 [3S(Z)]-2-[¦[1-(2-Amino-4-thiazolyl)-2-oxo-2-L~2-oxo-1-I[~I~(2-oxo=1-pyrroldinyl)carbonyl3-amino]sulfonyl~aminojcarbonyl]-3-azetidlnyl~-amino~ethylidene~amino]oxy~-2-methylpropanoic acid, dipotassium salt (S)-I2-Oxo-1-[Ill[(2-oxo-l-pyrrolidinyl)-carbonyl]amino~sulfonyl]amino]carbonyl]-3-azetidinyl]carbamie acid, phenylmethyl ester, potassium salt (1.5 g; see example 31A) was hydrogenated in dimethylformamide using a 10~
palladium on eharcoal catalyst. The catalyst 2 ~ 3 GC1~3a was filtered off, and 1.47 ~ of (Z)-2-amino-~-~[2{diphenylmethoxyj-1,1-dimethyl-2-oxoethoxy]-lmino]-4-thiazoleacetic acid, 40 mg of N-hyAroxy-benzotriazole and 1.26 g of dicyclohexylcarbodiimide were added to the mother li~uor~ The solution was stirred overnight, the solvent removed ln vacuo and the residue filtered with ether. The residue was suspended in 5 ml of anisole and cooled to -5 C. Trifluoroacetic acid (13 ml) was slowly dropped in with stirring, and after 30 minutes .the crude product was precipitated by the addition of 100 ml of ether and filtered off.
The product was dissolved in 5 ml of water and the pH adjusted to 6.5 with 1 N potassium hydroxide.
Chromatography on HP-20 resin (eluting with water) yielded 500 mg of the title compound, melting point 233C, dec.
:
Example 33 ~3S(R)]-4-Ethyl-2,3-dioxo-N-¦2-oxo-2-[~2-oxo-1-[l[(2-oxo-1-pyrrolidinyl)carbonyl]amino3sulfonyl]
amino]carbonyl~-3-azetidinyl3amino3-1-phenylethyl~-1-: piperazinecarboxamide, potass:ium salt (S)-[2-Oxo-l-l[lCI(2-oxo-l-pyrroldinyl)-carbonyl]amino3sulfonyl3aminolcarbonyl~-3-azetidinyl3carbamic acid, phenylmethyl ester, potassium salt (1 g; see example 31A) was hydrogenated in dimethylformamide using a 10% palladium on charcoal catalyst. The catalyst was filtered off, 0.7 g of (R)-~-[I(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyllamino]benzeneacetic acid, Cl~3a ~62-30 mg of N-hydroxyben~otriazole and 0.82 y of dicyclohexylcarbodiimide were added to the mother liquor, and ~e mixture was s-tirxed overnight at ambient temperature. The solvent was removed ln vacuo and the residue chromatoyraphed on HP--20 resin, eluting with water, to yield 300 mg of the title compound, melting point 186C.

Example 34 ~3S(Z)~-2-Amino-~-(methoxyimino)-N-[2-o o-l-I ~[~[(2-oxo-3-oxazolidinyl)carbonyl]amino]sulfonyl]-amino]carbonyl]-3-azetidinyl] 4-thiazoleacetamide, - potassium salt -A) (S~-[2-Oxo-1-[[[[[(2-oxo-3-oxazolidinyl)-carbonyl~amino~sulfonyl]amino]c rbonyl]-3-azetidinyl~carbamic acid, phenylmethyl ester, potassium salt ` (S)-3-[[(Phenylmethoxy)carbonyl]amino]-2-azetidinone (3.0 g) was suspended in 300 ml of dry tetrahydrofuran and cooled to -70C. Chloro-sulfonylisocyanate (2.3 g) dissolved in 10 ml of dry tetrahydrofuran was dropped in with stirring. The temperature was allowed to rise to 0C and this temperature was maintained for 10 minutes. Afterwards it was cooled to -40C.
Triethylamine (1.65 g) and 1.95 g of N-carbamoyl-2-oxooxazolidine were added. The mixture was stirred at room temperature for 14 hours and the solvent was removed in vacuo. After dis~
solution in ethyl acetate, 100 ml of 2N phosphoric acid was added and extracted three times with ' ~

~ r~ ~ GC183a ..

etllyl acetate. The combined oryanic layers were evaporated in vacuo, the residue was dissolved in 100 ml of acetone/water (1:1) and ~e pH
was adjusted to 6.5 with lN potassium hydroxide.
After removal o~ -the acetone ln vacuo, the aqueous solution was freeze dried yielding 5.2 g of crude product.

B) [3S(Z)]-2- mino-~-(methoxyimino)-N-12-oxo-1--E ~ ~ I [ ( 2-oxo-3-oxazolidinyl)carbonyl]amino]
sulfonyl]amino]carbonyl]~3-azetidinyl]-4-thiazoleacetamide, potassium salt (S) [2-Oxo-1-[~[~[(2-oxo-3-oxazolidinyl)-carbonyl]amino]sulfonyl]amino]carbonyl]-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt (1 g) was hydrogenated in 80 ml ; of dry dimethylformamide using 0 . 5 g of 10 palladium on charcoal as catalyst. After 20 minutes, the hydrogenationwas completed and the catalyst~as filtered off. (Z)-2-~; Amino-~-(methoxyimino)-4-thiazoleacetic acid (0.44 g),30 mg of ~-hydroxyben~otriazole and O.91 g of dicyclohexylcarbodiimide were added to the mother liquor. The solution was stirred 2~ for 12 hours at room temperature, the solvent removed in vacuo and the 1.7 g residue was chromatographed using HP-20 resin and water as eluent, yielding 0.3 g of the title compound, melting point 208c, dec.
Analysis for C14H15KN8OgS2: C: 30.99; H: 2.79;
N: 20.65; S: 11.82; K: 7.21;
Found: C: 30.08; H: 3.13; N: 19.52; S: 10~34;
K: 7.41 1 ~ 7~ i GC183a Exam~ S
_ [3S(R)]~4-Ethyl-2,3-dioxo N-~2-o o-2~[[2-oxo-1-~[~[~(2-oxo-3-oxazolidinyl)carbonyl]amino]
_ _ sulfonyl]amino]carbonyl~-3-azetidinyl]amino]-1-phenylethyl]-l-piperazinecarboxamide, potassium salt (S)-~2-Oxo-l-I~L[~2-oxo-3-oxazolidinyl)-carbonyl]amino]sulfonyl]amino]carbonyl]-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt (1 g; see example 34A) was hydrogenated in 80 ml of dry dimethylformamide using 0.5 g of a 10% palladium on charcoal catalyst. The catalyst was filtered off, 0.7 g of (R)--[~(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]-amino]benzeneacetic acid, 30 mg of N-hydroxybenzo-1~ triazole and 0.91 g of dicyclohexylcarbodiimide - were added to the mother liquor, and the mixture was stirred ~or 14 hours at ambient temperature.
The solvent was removed ln vacuo and the residue chromatographed on HP-20 resin, eluting with water, to yield 0.36 g of the title compound, melting point 187C, dec. `
Analysis for C23H25K~8O11S: C: 41.81; H: 3.81;
N: 16.96; S: 4.85, K: 5.92 Found: C: 40.04; H: 3.93; N: 16.33; S: 4.45; K: 5.59 ~5 7~ GC183a ~65-E ~[3S(Z)]-2-[[[1-(2-Amino-4-thiazolyl)-2-oxo-2-I[2-oxo-1-~[[[~(2-oxo-3-oxazoli ~ _bonyl]-amino]sulfonyl]amlno]carbonyl]-3-azetidinyl]-amino]ethylidene]amino]oxy]-2-methylpropanoic acid, dipotassium salt (S)-[2-Oxo-l-~[~[ L ( 2-oxo-3-oxazolidinyl3-carbonyl]amino~sulfonyl]amino]carbonyl~-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt (1 y; see example 34A) was hydrogenated in 80 ml of dimethylformamide using 0.5 g of a~10% palladium on charcoal catalyst. The catalyst was filtered off, and 0.97 g of (Z)-2-amino-~-L~2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid, 30 mg of N hydroxybenzotriazole and 0.91 g of dicyclohexylcarbodiimide were added to the mother liquor. The solution was stirred for 14 hours and the solvent removed ln vacuo. The residue was suspended in 4 ml of anisole and cooled to -5C. Trifluoroacetic acid (12 ml) was 510wly drapped in with stixring, and after 20 minutes the crude product was precipitated by the addition of 100 ml of ether and filtered off. The product was dissolved in 20 ml of water/acetone (1:1) and the pH adjusted to 6.5 with 1 N potassium hydroxide. Acetone was evaporated, the residue was freeze-dried and the crude product was chxomatography on HP-20 resin to yield 0.28 g of the title compound, melting point 250C, dec.
AnalysiS for Cl7Hl8K2N8olls2 N: 17.17; S: 9.83; K: 11.98 Found: C: 29.54; H: 3.23; N: 16.93; S: 8.97; K: 11.86 ~-7~D~ GC183a Example 37_S(Z)3-2-A_ino-N-[1-[~[[[~3-~2-amlnoethyl)-2_ oxo-l-imidazo ~
amlno]carbonyl] 2-oxo-3-a~etidinyl~ (methoxy-imino)-4-thiazoleaceta _ de, potassium salt (S)-3-~[(Phenylmethoxy)carbonyl]amino]-2-azetidinone (2 g) was suspended in 200 ml of dry tetrahydrofuran and cooled to -70C. Chloro-sulfonylisocyanate ~1.4 g) dissolved in 7 ml of dry tetrahydrofuran was added with stirring.
The temperature was allowed to rise to 0 C
and this temperature was maintained for 10 minutes.
Afterwards it was cooled to -40C, 1.2 g of triethylamine was dropped in and 2.9 g of 1-l2-[(t-butoxycarbonyl)amino3ethyl]-3-carbamoyl-2-oxoimidazolidine was added. This mixture was stirred at room temperature for 14 hours. Following the work-up procedure described in example 34A
yielded 5.4 g of (S)-[1-[[[[~[3-f2-(t-butoxy-carbonylamino)ethyl]-2-oxo-1-imidazolidinyl]-carbonyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-a~etidinyl)carbamic acid, phenylmethyl ester, potassium salt.
The above-prepared compound (2.7 g) was ; 2~ hydrogenated in 250 ml of dry dimethylformamide using 1.4 g of 10~ palladium on charcoal catalyst.
After 30 minutes, the hydrogenation was completed and the catalyst was filtered off. (Z)-2-Amino-~-tmethoxyimino)-4-thiazoleacetic acid (0.95 g), 54 mg of N-hydroxybenzotria~ole and 1.75 g of dicyclohexylcarbodiimide were added to the mother liquor. The solution was stirred for 12 hours at ~ G~1~3a ..

room temperature, the solvent removed ln vacuoand the residue dissolved in 6 ml of anisole and cooled to -5C. Trifluoroacetic acid ~15 ml) was careflllly dropped in with stirring. The temperature was maintained for an additional 3 hours, and the title compound precipitated by the addition of 150 ml of dry ether. The product was filtered and dissolved in 30 ml of water/acetone (1:1), and the pH was adjusted to 6.5 by the addition of lN potassium hydroxide. Acetone was evaporated, the residue free2e-dried and 2.7 g of crude product was chromatographed on HP-20 resin eluting with water, to yield 0.25 g of the title compound, melting point 193C, dec.
Example 38 [3S(Z)]-2-[[[2-[[1-[ I [ ~ ~ [3-(2-Aminoethyl)-2-oxo-l-imidazolidinyl]carbonyl]amino~sulfonyl]-amino]carbonyl]-2-oxo-3-azetidinyl]amino]-1-(2-amino-4-thiazolyl)-2-oxoethylidene]amino]-; oxy]-2-methylpropanoic acid, dipotassium salt ( s ) ~ [1- I [ I [ I I 3~ I 2-(t-Butoxycarbonylamino)-ethyl]-2-oxo-1-imidazolidinyl]carbonyl]amino]-suifonyl]amino]carbonyl]-2-oxo-3-azetidinyl]
carbamic acid, phenylmethyl ester, potassium salt (2.7 g; see example 37) was hydrogenated in dry dimethylformamide using 10% palladium on charcoal as a catalyst. The catalyst was filtered off, and (Z)-2-amino-~ 2-(diphenyl-methoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid (2.1 g), 54 mg of N-hydroxy-benzotriazole and 1.75 g o dicyclohexylcarbodiimide were added to the mother liquor. Following the work-up procedure described in example 37 and GC183a -6~-chromatography on HP-20 resin eluting with water yielded 0.3 g of ~e title compound, melting point 221C, dec.

~xample 39 [3S(Z)]-2-Amino-N-~ [1~[3-(2-hydroxyethyl)-2-oxo-l-imidazolidinyl]carbonyl]amino]sulfonyl]-___ amlno~carbonyl]-2-oxo-3-azetidinyl]-~-(methoxy--- _ ____ imino)-4-thiaæoleacetamide, potassium salt (S)-3-[[(Phenylmethoxy)carbonyl]amino]-2-aæetidinone (1.5 g) was suspended in 100 ml of dry tetrahydrofuran and cooled to -70C. Chloro-sulfonylisocyanate (1.1 g) dissolved in 10 ml of dry tetrahydrofuran was dropped in with stirring.
The temperature was allowed to rise to 0 C
and maintained there for 20 minutes, followed by cooling to -40C. Trie~hylamine (0.9 g) and 2.8 g of 1-carbamoyl-2-oxo-3-[2-[(triphenylmethyl)oxy]-ethyl]imidazolidine were added and the mixture was stirred at room temperature for 14 hours.
The solvent was removed in vacuo and the work-up~
procedure of example 34~ was followed yielding 4.3 g of (S)-~ I [ I ~ ~ 3-(2-hydroxyethyl)-2-oxo-1-imidazolidinyl]carbonyllamino]sulfonyl]amino]-carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt.
The above-prepared compound was hydrogenated in 80 ml of dry dimethylformamide using 0.3 g of 10% palladium on charcoal catalyst. After 30 minutes the hydrogenation was completed and the catalyst was filtered off. (Z)-2-Amino-~-.

GC183a (methoxyimino)-4-thlazoleacetic acid (195 mg), 13 mg of N-hydroxybenzotriazole and 360 my of dicyclohexylcarbodiimide were added to the mother liquor. The solution was stirred for 12 hours at room temperature, the solvent removed ln vacuo and the residue precipitated with ether. Crude product (0.5 g) was purified on HP-20 resin (eluent water/acetone (9.5:0.5)) yielding 30 mg of the title compound,melting point 193C, dec.
Analysis for C16HlgKNgOgS2: C: 32.87; H: 3.28;
N: 21.56; S: 10.97; K: 6.69 Found: C: 31.26;! H: 3.44; N: 18.56; S: 8.86; K: 6.56 Example 40 L3S (Z) ] -2- ¦ [ ~1- (2-A_ ino-4-thiazolyl)-2-~
[ I ~ 3-(2-hydroxyethyl?-2-oxo-1-imidazolidinyl]-carbonyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino~-2-oxoethylidene]amino]oxy] 2-methylpropanoic acid, dipotassium salt (S)-~1-[1[[~3-(2-Hydroxyethyl)-2-oxo-1-imidazolidinyl]carbonyl]amino]sulfonyl]amino]-carbonyl]-2-oxo-3-azetidinyl~carbamic acid, phenylmethyl ester, potassium salt (470 mg; see example 39) was hydrogenated ln 80 ml of dry dimethylformaide using 0.3 g of 10~ palladium on charcoal as a catalyst. After 30 minutes the catalyst was filtered off, and (Z)-2-amino-~-~12-(diphenylmethoxy)-l,l-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid, 13 mgof N-hydroxybenzotriazole and 360 mg of dicyclohexylcarbodiimide were added to the mother liquor. Following the procedure ~ GC183a clescrlbed in example 36 yielded the title compound, melting point 219C, dec.

Example 41 [3s(z~]-2-~~L2-[[~ [l(3-Amino-2-oxo-l-lmidazolidinyl) carbonyl]aminolsulfonyl]amino]car~onyl~-2-oxo-3-azetidinyl]amino]-1-(2-amino-4-thiazo]yl?-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, dipotassium salt A) (S)-~l-[~ 13- L (t-Butoxycarbonyl)~mino]-2-oxo-1-imidazolidinyl]carbonyl]amino]sulfonyl]amino]-carbon~l~-2-oxo-3-azetidinYl]carbamic acid, ~ . _ phenylmethyl ester, potassium salt 15(S)-3-~[(Phenylmethoxy)carbonyl]amino]-2-azetidinone (1.5 g) were suspended in 150 ml of dry tetrahydrofuran and cooled to -60C. Chloro-sulfonylisocyanate (1.1 g) dissolved in 20 ml of dry tetrahydro~uran was dropped in with stirring.
The temperature was allowed to rise to 0 C and this temperatuxe was maintained for 15 minutes and then cooled to -60C. Triethylamine(0.9 g) - and 1.7 g of 1-carbamoyl-3-l(t-butoxycarbonyl)-amino]-2-oxoimidazolidine were added. The mixture was stirred at room temperature for 14 hours and then worked-up usinq the procedure described in example 34, part A, yielding 1.5 g of the title compound.

~'7~ j GCl83a -71~

B) [3S(Z)]-2-[[[2-[~l-[[[[[(3-Amino-2-oxo-1 _ ___ _ _ _ _.__ ~ ~amlno]sulfon~l]amino]-carbonyl]-2-oxo-3-azetidinyl]amino]-l-(2-amino-4 thi.aæolyl)-2-oxoethylidene~amino3Oxy]-2-methyl-propanoic_acid, dipotassium salt (s) - [l-I [ I [ [ [3-I (t-Butoxycarbonyl)amino]-2-oxo-l-imidazolidinyl]carbonyl]amino]sulfonyl~-amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt (0.79 g) was hydrogenated in 60 ml of dry dimethylformamide using 0.4 g of 10% palladium on charcoal catalyst..
After 20 minutes,the hydrogenation was completed and the catalyst was filtered off. (Z)-2-Amino-a-1~2-(diphenylmethoxy)-l~l-dimethyl-2-oxoethoxy]
imino]-4-thiazoleacetic acid (0.63 g), l9 mg of N-hydroxybenzotriazole and 540 mg of dicyclo-hexylcarbodiimide were added to the mother liquor.
Following the procedure described in example 34B, yielded 48 mg of the title compound, melting point 208C, dec.
Example 42 ~3S(Z)]-2-Amino-~-(methoxyimino)-N-[1-[[[[[[3-I(l-methylethylidene)amino]-2-ox -l-imidazolidinyl]-carbon l~amino]sulfonvl]amino]carbonyl~-2-oxo-3-Y
azetidinyl]-4-thiazoleacetamide, potassium salt (S)-11~[~[~[3-[(t-Butoxycarbonyl)amino]-2-oxo-l-imidazolidinyl]carbonyl]amino]sulfonyl]-amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester~ potassium salt (0.7 g; see example 41A) was hydrogenated and then reacted with 0.26 g of (Z)-2-amino-a-(methoxyimino)-4-thiazoleacetic acid following the procedures ~ r~ GC18~a ..

described in example 37B, yieldlng 65 my oE thc title compound, ~elting point 207C, dec.
Analysis for C17~21KN108 2 N: 23.47; S: 10.75; K: 6.55 Found: C: 32.56; H: 3.88; N: 21.37; S: 9.10; K: 7.03 Example 43 ~3S(Z)]-2-Amino-N-~l-f[~[I(3-methyl-2-oxo-l-imidazolidinyl)carbonyl]amino~sulfonyl]amino]-carbonyl]-2-oxo-3-azetidinyl]-a-tmethoxyimino)-4-thiazoleacetamide, potassium salt A) (S)-Ll-[~[~(3-Methyl-2-oxo-1-imidazolidinyl)-carbonyl]amino]sulfonyl3amino]carbonyl]-2~oxo-3-_zetidinyl]carbamic acid, phenylmethyl ester, potassium salt (S)~3-[[(Phenylmethoxy)carbonyl~amino~-2-azetidinone (3.0 g) was suspended in 300 ml of dry tetrahydrofuran and cooled to -70C. Chloro-sulfonylisocyanate (2.1 g) dissolved in 10 ml of dry tetrahydrofuran was dropped in with stirring~ The termperature was allowed to rise to 0C and this temperature was maintained for 10 minutes, the~ cooled to -40C. Triethylamine (1.7 g) and 2.3 g of 1-carbamoyl-3-methyl-2-oxoimida~olidine were added. Following the procedure described in example 34A yielded 4.3 g of the title compound.

~ 7~,~ GC1~3a .

B) [3S(b)]-2-Amino-N-[1-[~[~[(3-methyl-2-oxo 1 imidazolidinyl)_c~ amlno _ulfonyl]amlno]-carbonyl]-2-oxo-3-azetidinyl]-a~(me ~oxyimino ? -4 -t~iazoleacetamide, potassium salt (S)-~1-[~[~[(3-Methyl-2-oxo-1-imidazolidinyl)-carbonyl]amino]sulfonyl]amino]carbonyl~-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt (1.2 g) was hydrogenated in 80 ml of dry dimethylformamide using 0.6 g of 10%
palladium on charcoal as catalyst. After 30 minutes the catalyst was filtered off, and (Z)-2-amino-~-(methoxyimino)-4~thiazoleacetic acid (0.52 g), 32 mg of N-hydroxybenzotriazole and 1.0 g of dicyclohexylcarbodiimidë were added to the mother liquor. The solution was stirred for 13 hours at room temperature and the solvent was then removed in vacuo. The residue was chromatographed on HP-20 resin, eluting with water, to yield 0.120 g of the title compound, melting point 205C,dec.
Analysis for C15H18KNgO8S2: C: 32.43; H: 3.27;
N: 22.69; S: 11.54; K: 7.04 ; Found: C: 30.83; H: 3.44; N: 21.34; S: 10.20; K: 7.30 .

GC183a _7a _ Example 44 ~3s(z)]-2-[[l2-[ll-[~[l[(3-Methyl-2-oxo-l-imidazolidinyl)carbon~l]amino]sulfonyl]amino]-carbonyl]-2-oxo-3-azetidinyl]amino~-1-(2-amino 4-thiazolyl)-2-oxoethylidene]amino]oxy]-2-methyl-propanoic acid,_dipotassium salt ~ S)-~1-[~ (3-Methyl-2-oxo-l-imidazolidinyl)-carbonyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt (1.5 g; see example 43A) was hydrogenated in 80 ml of dry dimethylformamide using 0.8 g of 10~ palladium on charcoal as catalyst. After 30 minutes the catalyst was filtered off and 1.4 g of (Z)-2-amino-~ 2-(diphenylmethoxy)-1,1-dimethyl-2 oxoethoxy]-imino]-4-thiazoleacetic acid, 40 mg of N-hydroxy-benzotriazole and 1.3 g of dicyclohexylcarbodiimide were added to the mother liquor. Following the procedure of ecample 36 yielded 0.5 g of the title compound, melting point 211C, dec.
Analysis for ClgH21K2NgOloS2-N: 18.94; S: 9.63; K: 11.75Found: C: 30.55; H: 3.53; N: 18.12; S: 8.65; K: 10.97 j GC183a E~ le 45 [3S(Y.)]-2-[¦[2-[[1-[[1[[(2 Oxo-l~imidazolidinyl)-carbonyl]amino~sulfonyl]amino]carbon 1]-2-oxo-3-azetidinyl]amino]-1-(2-amino_4-thiazol_1)-2-_oethylidene}amino3Oxy]-2-methylpropanoic acid, dipotassium salt -A) (S)-ll-[l[l[r2-Oxo-3-(triphenylmethyl)-1-imidazolidinvl]carbonvl]amino]sulfonyl]amino]-.. . .
carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt (S)-3-~[(Phenylmethoxy)carbonyl]amino]-2-azetidinone (1.3 g) was suspended in 130 ml of dry tetrahydrofuran and cooled to -70C.- --Chlorosulfonylisocyanate (0.9 g) dissolved in5 ml of dry tetrahydrofuran was dropped in with stirring. The temperature was allowed to rise to 0C and maintained there for 10 minutes, followed by cooling to -40C. Triethylamine (0.8 g) and 0.65 g of 1-carbamoyl-2-oxo-3-(triphenylmethyl)imidazolidine were added and the mixture was worked-up following the procedure described in example 34A ~o yield 3.2 g of the title compound.

7~ C;C183a B) _S(Z)1-2-[l[2-Lll-[[[[~(2-Oxo--l-imidazolldlnyl)-carbony:L]amino~sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-1-(2-amino-'l-thiaæolyl)~Z-oxo-.
ethylidene]amino]oxy]-2-methylpropanoic acld, dipotassium salt (S) - ~ [ 12-Oxo-3- (triphenylmethyl) -1-imidazolidinyl]carbonyl]amino]sulfonyl]amino]-carbonyl]-~-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt (1.5 g) was hydrogenated in 80 ml of dry dimethylformamide using 0.9 g of 10% palladium on charcoal as catalyst. After 30 minutes the catalyst was filtered off and 0.98 g of (Z)-2-amino-a-~[2-(diphenylmethoxy)-l,l-dimethyl-2-oxoethoxy~-imino]-4-thiazoleacetic acid, 27 mg of N-hydroxy-benzotriazole and 0.84 g of dicyclohexylcarbodiimide were added to the mother liquor. Following the procedure of example 36 yielded 0.28 g of the title compound, melting point 228 C, dec.

- Example 46 - -: ~3S(Z)]-2-Amino-N-ll~ I (2-oxo-1-imidazolidinyl)-carbonyl]amino~sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-~ ~methoxyimino)-4-thiazoleacetamide, pot~ssium salt A) (S)-[1-1[~[(2-Oxo-1-imidazolidinyl)carbonyl~-amino~sulfonyl]amino]carbonyl~-2-oxo-3-azetidinyl]-carbamic acid, phenylmethyl ester, potassium salt (S)-~ [l[~2-Oxo-3-(triphenylmethyl)-1-imidazolidinyl]carbonyl]amino]sulfonyl]amino]-carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl estert potassium salt (1.7 g; see example 45A) was treated with 2N phosphoric acid ~ 7~ GC 18 3a and :LN potassium hydroxide following the proceduxe described in exarnple 34A to yield 1.73 g of the title compound.

B) [3S(Z)]-2-Amino-N~ (2-oxo-1-imidazolidinyl)-.
carbonylJamino]sulfonyl~amino]carbonyl]-2-oxo-3-azetidinyl]--(methoxyimino)-4~thiazoleacetamide, potassium salt (s) - [1- L [ ~ ~ I (2-Oxo-l-imidazolidinyl)carbonyl]-amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-carbamic acid, phenylmethyl ester, potassium salt (0.8 g) was hydrogenated in 70 ml of dry dimethylformamide using 0.5 g of 10% palladium on charcoal as catalyst. After 20 minutes the catalyst was filtered off, and (Z)-2-amino--(methoxyimino)-4-thiazoleacetic acid (0.38 g), 27 mg of N-hydroxybenzotriazole and 0.78 g of dicyclohexylcarbodiimide were added to the mother liquor. The solution was stirred for 14 hours at room temperature and the solvent was then ~emoved in vacuo. The residue was chromatographed on ~P-20 resin, to yield 200 mg of the title compound, melting point 216C, dec.

GC183a Example 47~3S(Z)~-2-Amino-N-~l- I [~[[3-(methylsulfonyl)-2-oxo-l-imidazolidinyl]carbonyl]aminoJsulfon~l]-amino]carbonyl]-2-oxo-3-azetidinyl]-~-(methoxy-.
imino)-4-thiazoleacetamide, potassium salt A) (S)-[l~ 3-(Methylsulfonyl-2-oxo-1-imidazolidinyl]carbonyl]amino]sulfonyl]amino]-carbonyl]-2~oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt (S)-3-11(Phenylmethoxy)carbonyl]amino]-2-aæetidinone (3.0!g) was suspended in 300 ml of dry tetrahydrofuran and cooled to -70C.
Chlorosulfonylisocyanate (2.1 g) dissolved in 10 ml of dry tetrahydrofuran was dropped in with stirring. The temperature was allowed to rise to 0C and this temperature was maintained for 10 minutes, then cooled to -40C. Triethyl-amine (1.7 g) and 2.3 g of 1-carbamoyl-3-(methyl-sulfonyl)-2-oxoimidazolidine were added.
Following the procedure described in example 34A
yielded 2.8 g of the title compound.

B) ¦3S(Z)~2-Amino-N-~1-[~ 3-(methylsulfonyl?-2-oxo-l-imidazolidin l]carbonyl]amino]sulfonyl]-- Y
amino]carbonyl-2-oxo-3-azetidinyl~-~-(methoxy-imino)-4-thiazoleacetamide, potassium salt (S)-Il-[~ 3-(Methylsulfonyl)-2-oxo-l-imidazolidinyl~carbonyl]amino~sulfonyl]amino]-carbonyl~ 2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt (1.8 g) was hydrogenated in 300 ml of dry dimethylformamide using 2.0 g of 10% palladium on charcoal as catalyst.

7~; GC183a _79_ After 20 minutes the catalyst was filtered off, and (Z)-2-amino-~ (methoxyimino)-4-thiazoleaceti.c acid (1.1 g), 70 mg of N-hydroxybenzotriazole and 2.0 g of dicyclohexylcarbodiimide were added to the mother liquor. The solution was stirred for 12 hours at room temperature and the solvent was then removed in vacuo. The residue was chromatographed on HP-20 resin, eluting with water/acetone (9:1), to yield 200 mg of the title compound, melting point 204C, dec.

! Example 48 [3S(z)]-2-[I [2-L[l-I ~[[~[3-(Methylsulfonyl)-2-oxo-l-imidazolidinyl]carbonyl]amino]sulfonyl]-_ino]carbonyl]-2-oxo 3-azetidinyl]amino]-1-(2-amino-4-thiazolyl)-2-oxoethylidene~aminol-oxy]-2-methylpropanoic acid, dipotassium salt (S)-~1-[[[¦[~3-(Methylsulfonyl)-2-oxo-1-imidazolidinyl]carbonyl]amino]sulfonyl]aminol-carbonyl~-2-oxo-3-azetidinyllcarbamic acid, phenylmethyl ester, potassium salt (1.5 g;
see example 47A) was hydrogenated in 150 ml of dry dimethylformamide using 0.9 g of 10%
palladium o~ charcoal as catalyst. After 20 minutes the catalyst was filtered off and 1.23~g of (Z)-2-amino~ 2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy3imino]-4-thiazoleacetic acid, 40 mg of N-hydroxybenzotriazole and 1.1 g of dicyclo-hexylcarbodiimide were added to the mother liquor.
3~ Following the procedure of example 36 yielded 180 mg of the title compound, melting point 236 C, dec.

,.

GC183a Exam~le 49 [3S(Z)]-2-Amino N~ I [ I E I ( 3- isopropyl 2-oxo-L-imidazolidinyl)carbonyl]amino]sulfonyl]amino]-carbonyl]-2-oxo-3-azetidinyl]-~-(methoxyimino)-4-thiazoleacetamide, potassium salt A) ( ~ l I 1 I [(3~ propyl-2-oxo-1-imidazolidinyl)-carbonyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, ~henylmethyl ester, potassium salt (S)-3-~[(Phenylmethoxy)carbonyl]amino]-2-azetidinone (3.0~g) was suspended in 300 ml of ; dry tetrahydrofuran and cooled to -70C. Chloro-sulfonylisocyanate (2.1 g) dissolved in 10 ml f dry tetrahydrofuran was dropped in with stirring.
The temperature was allowed to rise to 0C
and tllis temperature was maintained for 10 minutes, then cooled to -40C. Triethylamine (1.7 g) and 2.74 g of 1-carbamoyl-3-isopropyl-2-oxo-imidazolidine were added. Following the procedure described in example 34A yielded 5.9 g of the title compound.
.
B) [3S(Z)3-2-Amino-N-~ [[~L(3-isopropyl-2-; 25 oxo-l-imidazolidinyl)carbonyl~amino~sulfonyl~-amino]carbonyl3-2-oxo-3-azetidinyl]-u-(methoxyimino)-4-thiazoleacetamide, potassium salt (S) - [1- ~ ~ [ [ E (3-Isopropyl-2-oxo-1-imidazolidinyl)-carbonyl]amino]sulfonyl~amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt (1.5 g) was hydrogenated in 150 ml of dry dimethylformamide using 0.8 g of 10%
; palladium on charcoal as catalyst. After 20 minutes GC183a the catalyst was filtered off, and 0~6 g of (Z)--2-amino--(methoxyimino)-4--thiazoleacetic acid, 40 mg of N-hydroxyben7.0triazole and 1.2 y of dicyclohexylcarbodiimide were added to the mother liquor. The solution was stirred for 14 hours at room temperature and the solvent was then removed ln vacuo. The residue was chromatographed on HP-20 resin, eluting with water/acetone (9.25:0.75) to yield 30~ my of~
the title compound, melting point 189C, dec.

~ Example 50 [3S(Z)]-2-[~2-~[1- r [ [ [ [ (3-isopropyl-2-oxo-1-imida~olidinyl)carbonyl]amino]sulfonyl]amino]-.
carbonyl]-2-oxo-3-azetidinyl]amino]-1-(2-amino-4-._ _ thiazoly~-2-oxoethylidene]amino]oxy]-2=methyl-propanoic acid, dipotassium salt (s~ - [1- [ [ [ [ r (3-Methyl-2-oxo-1 imidazolidinyl)-carbonyl]amino]sulonyl]amino]carbonyl~-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester, potassium salt (1.5 g; see example 43A) was hydrogenated in 150 ml of dry dimethylformamide using 0.8 g of 10% palladium on charcoal as catalyst. After 20 minutes the catalyst was filtered off and 1.3 g of (Z)-2-amino--~[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]-imino]-4-thiazoleacetic acid, 40 mg of N-hydroxy-benzotriazole and l.2 g of dicyclohexylcarbodiimide were added to the mother liquor. Following the procedure of example 36 yielded 0.4 g of the title compound, melting point 234C, dec.

Claims (4)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A compound having the formula:

or a salt thereof, wherein R2 is hydrogen or methoxy;
R3 and R4 are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cyc-loalkyl, aryl or a 5, 6 or 7-membered het-erocycle or one of R3 and R4 is hydrogen and the other is azido, halomethyl, dihalo-methyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, X1 is azido, amino, hydroxy, alkanoylamino, alkylsulfonyloxy, arylsulfonyloxy, aryl, cyano, X2 is alkyl, substituted alkyl, aryl, arylal-kyl, alkanoyl, substituted alkanoyl, aryl-carbonyl or heteroarylcarbonyl;

one of X3 and X4 is hydrogen and the other is hydrogen or alkyl, or X3 and X4 when taken together with the carbon atom to which they are attached form a cycloalkyl group;
X5 is formyl, alkanoyl, arylcarbonyl, arylal-kylcarbonyl, carboxyl, alkoxycarbonyl, am-inocarbonyl, (substituted amino)carbonyl, or cyano;
A is m is 0, 1, 2 or 3;
m' is 1 or 2;
X6 and X7 are the same or different and each is hydrogen or alkyl, or X6 is hydrogen and X7 is amino, substituted amino, acylamino or alkoxy;
R5 is hydrogen, alkyl or aryl;
R6 is hydrogen, alkyl, aryl, a 5, 6 or 7-mem-bered heterocycle, wherein n is 1, 2, 3 or 4 and X is halogen, aryl, alkoxy, aryloxy or R7 and R8 are the same or different and each is hydrogen, alkyl or aryl, or R7 is hydro-gen and R8 is a 5, 6 or 7-membered hetero-cycle or wherein n is 1, 2, 3 or 4 and Y is alkoxy, amino, alkylthio or halogen; and R9 and R10 are the same or different and each is hydrogen or alkyl, or R9 is hydrogen and R10 is a 5, 6 or 7-membered heterocycle;
wherein the terms "alkyl" and "alkoxy" refer to groups having 1 to 10 carbon atoms;
the term "cycloalkyl" refers to groups having 3, 4, 5, 6 or 7 carbon atoms;
the terms "alkanoyl", "alkenyl" and "alkynyl"
refer to groups having 2 to 10 carbon at-oms;

the term "aryl" refers to a phenyl or phenyl substituted with 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or carboxyl groups;
the term "substituted alkyl" refers to alkyl groups substituted with one, or more, az-ido, amino, halogen, hydroxy, carboxy, cy-ano, alkoxycarbonyl, aminocarbonyl, alka-noyloxy, alkoxy, aryloxy, a 5, 6 or 7-membered heterocycleoxy, mercapto, alkyl-thio, arylthio, alkylsulfinyl, or alkyl-sulfonyl groups;
the term "substituted alkanoyl" refers to groups having the formula:

(substituted alkyl) the term "substituted amino" refers to a group having the formula wherein Y1 is hydrogen, alkyl, aryl, or arylalkyl, and Y2 is alkyl, aryl, arylalkyl, hydroxy, cy-ano, alkoxy, phenylalkoxy, or amino;
the term "heteroaryl" refers to pyridinyl, fur-anyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4 triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, tri-azinyl, tetrazolyl or one of the above groups substituted with one, or more, hal-ogen, hydroxy, nitro, amino, cyano, tri-fluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylsulfo-nyl, aryl, 2-furylmethyleneimino, phenyl-methyleneimino or substituted alkyl, where-in the alkyl group has 1 to 4 carbon atoms, groups; and the term "5, 6 or 7-membered heterocycle" refers to pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazo-lyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl, tetrazolyl, piperidi-nyl, piperazinyl, imidazolidinyl, oxazoli-dinyl, pyrrolidinyl, tetrahydropyrimidinyl, dihydrothiazolyl, or one of the above groups substituted with one or more oxo, halogen, hydroxy, nitro, amino, cyano, trifluorome-thyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylsulfonyl, aryl,

2-furylmethyleneimino, phenylmethyleneimino, or substituted alkyl, wherein the alkyl group has 1 to 4 carbon atoms, groups.

2 . A composition in accordance with claim 1.
wherein the compound has the formula:

or a salt thereof, wherein R2 is hydrogen or methoxy;
R3 and R4 are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cyc-loalkyl, aryl or a 5, 6 or 7 membered het-erocycle or one of R3 and R4 is hydrogen and the other is azido, halomethyl, dihal-omethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethynyl, 2-phenylethynyl, carboxyl, X1 is azido, amino, hydroxy, alkanoylamino, alkylsulfonyloxy, arylsulfonyloxy, aryl, cyano, X2 is alkyl, substituted alkyl, aryl, arylal-kyl, alkanoyl, substituted alkanoyl, aryl-carbonyl or heteroarylcarbonyl;
one of X3 and X4 is hydrogen and the other is hydrogen or alkyl, or X3 and X4 when taken together with the carbon atom to which they are attached form a cycloalkyl group;
X5 is formyl, alkanoyl, arylcarbonyl, arylal-kylcarbonyl, carboxyl, alkoxycarbonyl, am-inocarbonyl, (substituted amino)carbonyl, or cyano;
A is m is 0, 1, 2 or 3;
m' is 1 or 2;
X6 and X7 are the same or different and each is hydrogen or alkyl, or X6 is hydrogen and X7 is amino, substituted amino, acylamino or alkoxy;
R5 is hydrogen, alkyl or aryl;
R6 is hydrogen, alkyl, aryl, a 5, 6 or 7-mem-bered heterocycle, wherein n is 1, 2, 3 or 4 and X is halogen, aryl, alkoxy, aryloxy or ;
R7 and R8 are the same or different and each is hydrogen, alkyl or aryl, or R7 is hydro-gen and R8 is a 5, 6 or 7-membered hetero-cycle or wherein n is 1, 2, 3 or 4 and Y is alkoxy, amino, alkylthio or halogen; and R9 and R10 are the same or different and each is hydrogen or alkyl, or R9 is hydrogen and R10 is a 5, 6 or 7-membered heterocycle;
wherein the terms "alkyl" and "alkoxy" refer to groups having 1 to 10 carbon atoms;
the term "cycloalkyl" refers to groups having

3, 4, 5, 6 or 7 carbon atoms;
the terms "alkanoyl", "alkenyl" and "alkynyl"
refer to groups having 2 to 10 carbon at-oms;
the term "aryl" refers to a phenyl or phenyl substituted with 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl, alkyl of 1 to

4 carbon atoms, alkoxy of 1 to 4 carbon atoms or carboxyl groups;
the term "substituted alkyl" refers to alkyl groups substituted with one, or more, az-ido, amino, halogen, hydroxy, carboxy, cy-ano, alkoxycarbonyl, aminocarbonyl, alka-noyloxy, alkoxy, aryloxy, a 5, 6 or 7-mem-bered heterocycleoxy, mercapto, alkylthio, arylthio, alkylsulfinyl, or alkylsulfonyl groups;
the term "substituted alkanoyl" refers to groups having the formula:

(substituted alkyl) the term "substituted amino" refers to a group having the formula wherein Y1 is hydrogen, alkyl, aryl, or arylalkyl, and Y2 is alkyl, aryl, arylalkyl, hydroxy, cy-ano, alkoxy, phenylalkoxy, or amino;
the term "heteroaryl" refers to pyridinyl, fur-anyl, pyrrolyl, thienyl, 1,2,3 triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, tri-azinyl, tetrazolyl or one of the above groups substituted with one, or more, hal-ogen, hydroxy, nitro, amino, cyano, tri-fluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylsulfo-nyl, aryl, 2-furylmethyleneimino, phenyl-methyleneimino or substituted alkyl, where-in the alkyl group has 1 to 4 carbon atoms, groups; and the term "a 5, 6 or 7-membered heterocycle" re-fers to pyridinyl, furanyl, pyrrolyl, thi-enyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrim-idinyl, oxazolyl, triazinyl, tetrazolyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydropy-rimidinyl, dihydrothiazolyl, or one of the above groups substituted with one or more oxo, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon at-oms, alkoxy of 1 to 4 carbon atoms, alkyl-sulfonyl, aryl, 2-furylmethyleneimino, phe-nylmethyleneimino, or substituted alkyl, wherein the alkyl group has 1 to 4 carbon atoms, groups.