CA1285954C - Hydrazide derivatives of monocyclic .beta.-lactam antibiotics - Google Patents

Abstract

ABSTRACT This invention relates to compounds of the formula: wherein R1 and R2 are each independently hy-drogen or alkyl of 1 to 4 carbon atoms, or R1 and R2 together with the carbon atom to which they are attached form a cycloalkyl ring; R3 is hydrogen or alkyl; R4 is hydrogen or alkyl; and R5 is selected from a variety of substituents. These compounds are valuable for use as intermed-iates in the preparation of compounds of the formula: and pharmaceutically acceptable salts thereof, which are themselves useful in that they possess antibacterial activity.

Description

12~35~354 ` GC227 HYDRAZIDE DERIVATIVES OF MONOCYCLIC
~-LACTAM ANTIBIOTICS

Compounds having the formula IRl R2 R3 R4 o-C-~ -N- N-R5 N l_6 - 7 H2N ~ C~ NH ~ -SO3H ~
and pharmaceutically acceptable salts thereof t have antibacterial activity. In formula I, and throughout the specification, the symbols are as defined below.
R1 and R2 are each independently hydrogen or Alkyl of 1 to 4 carbon atoms, or Rl and R2 together with the carbon atom to which they are attached form a cycloalkyl ring;
R3 is hydrogen or alkyl;
R4 is hydrogen or alkyl, and R5 is hydrogen, alkyl, phenyl, substituted phenyl, a 4,5,6 or 7-membered heterocycle (hereinafter referred to as Rx), phenylalkyl, (substituted phenyl)alkyl, o Rx-alkyl, -e-NHYl [wherein Yl is hydrogen, alkyl, phenyl, substituted phenyl, methylcarbonyl, tri-fluoromethylcarbonyl, phenylcarbonyl, (substitutedpheny})carbonyl, carboxymethyl, methylsulfonyl, phenylsulfonyl, (substituted phenyl)sulfonyl, :~ aminocarbonyl, aminocarbonylamino, aminoethyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, phenylcarbonylamino, (subs~ituted phenyl)carbonyl-S
~ : amino, l-pyrrolidinyl, or l-piperidinyl], -~-NHYl, : ~ ~ O
Y2 [wherein Y2 is hydrogen, alkyl, phenyl, substituted phenyl, Rx, alkoxy, formyl, carbonyl, , .
:, :

;~ ~

- . .

.: , . , aminocarbonyl, aminocarbothio, methylaminocarbonyl, methylaminocarbothio, trifluoromethyl, phenyl-methyl, (substituted phenyl)methyl, phenyloxy-methyl, (substituted phenyl)oxymethyl, cyano-methyl, hydroxymethyl, alkoxymethyl, aminomethyl,methylcarbonylaminomethyl, aminocarbonylaminomethyl, methylsulfonylaminomethyl, carboxymethyl, amino-carbonylmethyl, alkoxycarbonylmethyl, Rx-alkyl, hydroxyaminocarbonylmethyl, or azidomethyl], -~-Y2, -~-Y3 [wherein Y3 is amino, alkyl, alkyl-thio, carboxythio, alkoxycarbonylthio, or amino-carbonylthio], -SO2-Y4 [wherein Y4 is alkyl, amino, hydroxyamino, alkoxyamino, methylcarbonylamino, or O
phenylcarbonylamino], -SO3H or -~-OY5 [wherein Y5 is hydrogen or alkyl and Y6 is hydrogen, alkyl, carboxymethyl, or aminocarbonylmethyl]; or together R4 and R5 are =CH-Y7 wherein Y7 is phenyl or substituted phenyl;
R6 and R7 are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cyclo-alkyl, phenyl, substituted phenyl or Rx, or one of R6 and R~ is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxy-carbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -C~2Xl [wherein Xl is azido, amino (-NH2), hydroxy, alkanoylamino, phenylcarbonyl-: 30 amino, (substituted phenyl)carbonyl- amino, alkyl-sulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, , . . , . . , , . . - . . .............. - . .

- . : .
, ~as~

cyano, -A-C-NX6X7' -S~X2, or -0-X2 (wherein A, X2, X6 and X7 are as hereinafter defined)], -S-X2 or --X2 [wherein X2 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (sub-stituted phenyl)alkyl, alkanoyl, phenylalkanoyl, ~substituted phenyl)alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, or heteroaryl-carbonyl] -o-c-x4 or -S-f-x4 ~wherein 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; and X5 is formyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkyl-carbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl (N~2-C-), (substituted amino)carbonyl, or cyano (-C_N)], or -A-C-NX6X7 (wherein A is -C~=C~-, (CH2)n~, -CH2-O-, -CH2-N~-, or -CH2-S-CH2-, n is 0, 1 or 2, and X6 and X7 are the same or different and each is hydrogen, alkyl, phenyl or substituted phenyl, or X6 is hydrogen and X7 is amino, sub-stituted amino, alkanoylamino or alkoxy, or X6 and X7 when taken together with the nitrogen atom to : which they are attached form a 4, 5, 6 or 7-membered heterocycle).
Listed below are definitions of various terms used to describe ~-lactams of this ;~ invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific .

, ~ . - - . - - : . - -12~S~S~

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 l to lO carbon atoms are preferred.
The term "cycloalkyl" refers to cycloalkyl groups having 3,4,5,6 or 7 carbon atoms~
The term "substituted alkyl" refers to alkyl groups substituted with one, or more, azido, amino (-N~2), halogen, hydroxy, carboxy, cyano, alkoxy-carbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenyloxy, (substituted phenyl)oxy, Rx-oxy, mercapto, alkylthio, phenylthio, (substituted phenyl)thio, alkylsulfinyl, or alkylsulfonyl groups.
The terms "alkanoyl", "alkenyl", and "alkynyl" refer to both straight and branched chain groups. Those groups having 2 to 10 carbon atoms are preferred.
The terms "halogen" and "halo" refer to fluorine, chlorine, bromine and iodine.
The term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino (-N~2), halogen, hydroxyl, trifluoromethyl, alkyl (of l to 4 carbon atoms), alkoxy (of l to 4 carbon atoms), or carboxyl groups.
The expression "a 4,5,6 or 7-membered heterocycle" (referred to as ''Rx'') refers to substituted and unsubstituted, aromatic and non-aromatic groups containing one or more nitrogen, oxygen or sulfur atoms. Exemplary substituents are oxo (=0), halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons, alkylsulfonyl, phenyl, substituted phenyl, 2-furfurylideneamino . ~ , . . . . .
~ ~ ' ,-. .
-: -~5~5~

_5_ GC227 O~r_CH=N-( ~ ), benzylideneimino and substituted alkyl groups (wherein the alkyl group has 1 to 4 carbons). One type of "4,5,6 or 7-membered S heterocycle" is the "heteroaryl`' group. The term "heteroaryl" refers to those 4,5,6 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 tetrazolyl. Exemplary nonaromatic heterocycles (i.e., fully or partially saturated heterocyclic groups) are substituted and unsubstituted azetinyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl, dihyrothiazolyl and hexahydroazepinyl. Exemplary of the substituted 4,5,6 or 7-membered heterocycles are 1-alkyl-3-azetinyl, 2-oxo-1-imidazolidinyl, 3-alkylsulfonyl-2-oxo-l-imidazolidinyl, 3-benzylimino-2-oxo-l-imidazolidinyl, 3-alkyl-2-oxo-1-imidazolidinyl, 3-phenyl (or substituted phenyl)-2-oxo-1-imidazolidinyl, 3-benzyl-2-oxo-1-imidazolidinyl, 3-(2-aminoethyl)-2-oxo-1-imidazolidinyl, 3-amino-2-oxo-1-imidazolidinyl, 3-[(alkoxycarbonyl)amino]-2-oxo-1-imidazolidinyl, 3-[2-[(alkoxycarbonyl)-amino]ethyl]-2-oxo-1-imidazolidinyl, 2-oxo-1-pyrrolidinyl, 2-oxo-3-oxazolidinyl, 4-hydroxy-6-methyl-2-pyrimidinyl, 2-oxo-1-hexahydroazepinyl, 2-oxo-3-pyrrolidinyl, 2-oxo-3-tetrahydrofuranyl, 2,3-dioxo-1-piperazinyl, 2,5-dioxo-1-piperazinyl, 4-alkyl-2,3-dioxo-1-piperazinyl, and 4-phenyl-2,3-dioxo-1-piperazinyl.

~ ' ~, ! , . . .

128595.~

The term "substituted amino" refers to a group having the formula -NZlZ2 wherein Zl is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, and Z2 5 is alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, hydroxy, cyano, alkoxy, phenylalkoxy, or amino ~-NH2).
The terms "salt" and "salts`', when used to describe the ~-lactams of this invention, refer to basic salts formed with inorganic and organic bases. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts, alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases, e.g., dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, hydrabamine salts, salts with amino acids like arginine, lysine and the like.
Pharmaceutically acceptable salts are preferred.
Salts of an azetidinone-l-sulfonic acid are formed by reacting the free acid form of the sulfonate with one or more eguivalents of an appropriate base providing the desired cation in water or in a solvent mixture containing water.
The salt is isolated by removal of solvent in vacuo or, in the case of water, by lyophilization.
The free acid of the sulfonate is formed by treating an azetidinone-l-sulfonic acid salt with an insoluble sulfonic acid such as a cation exchange resin in the hydrogen form (e.g. a poly styrene sulfonic acid resin like Dowex 50).
Alternatively, salts may be formed by cation interchange. A salt of a ~-lactam compound soluble in an organic solvent is combined with a salt containing the desired cation, also soluble in the :
~.. . ... . . . .
. . , ' ` ~ , ' ` ' -~ ~ .

3595~

same solvent system. The solvent system is chosen so that the formed salt is much less soluble than either of the added salts and thus precipitates from the medium and is collected.

The ~-lactams of formula I, and pharmaceutically acceptable salts thereof, have activity against gram-negative organisms. The compounds of this invention can be used as agents to combat bacterial infections (including urinary tract infections and respiratory infections) in mammalian species, such as domesticated animals (e.q., dogs, cats, cows, horses, and the like) and humans.
For combating bacterial infections 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. All modes of administration which have been used in the past to deliver penicillins and cephalosporins to the site of the infection are also contemplated for use with ~-lactams of this invention. Such methods of administration include oral, intravenous, intra-muscular, and as a suppository.
The compounds of this invention can be prepared using a variety of procedures. One method utilizes as a starting material the known mono-~ ~ cyclic ~-lactam antibiotics having the formula ::

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

~X~S95~

II1~ ,,2 ~ -C-~-OH
/~ ~S~ ~ F 6_ -~7 and salts thereof. Compounds of formula II are described in the literature; see, for example, United Kingdom patent application 2071650, published September 23, 1981. Reaction of a compound of formula II with a hydrazide having the formula III l3 l4 EN-N -R5, or a salt thereof, in the presence of a coupling agent, yields the desired products of formula I.
If the starting material of formula II is an inner salt (-SO3H in the l-position), it is preferable to first treat the compound with one equivalent of a base (e.a., tributylamine or trioctylamine) to form the salt of the sulfonic acid. Preferably, the reaction is run in the presence of a substance capable of forming a reactive intermediate in situ, such as N-hydroxybenzotriazole and/or a catalyst such as dimethylaminopyridine, using a coupling agent such as dicyclohexylcarbodiimide.
Exemplary solvents which can be used for the reaction are dimethylformamide, tetrahydrofuran, dichloromethane or mixtures thereof.
Alternatively, the compounds of this invention can be prepared by acylating a compound having the formula :~:

., , ., - : ~ . : , .
: , . , - ~ : : -~2~5~5~

_g_ IV 2 R6, ~R7 ~ N-S03H

or a salt thereof, with a carboxylic acid having the formula V R1 R2 ~3 14 /O~ N-N-R5 N O
~ o Well-known acylation procedures can be used for the reaction. Exemplary techniques include the use of a carboxylic acid of formula V or a corresponding carboxylic acid halide or carboxylic acid anhydride. The reaction with a carboxylic acid proceeds most readily in the presence of a carbodiimide such as dicyclohexylcarbodiimide and a substance capable of forming a reactive inter-mediate in situ such as N-hydroxybenzotriazole or N-hydroxysuccinimide.
Compounds of formula V are novel compounds, and as such, form an integral part of this invention. They can be prepared by reacting ~2-amino-4-thiazolyl)glyoxylic acid, which has the formula Nl ~ C-C-O~
/ S
; H2N
with a compound having the formula ,.~ ...... . . . . . . . . .... . . . . .

,,:
: : - . : . . .

12~5~5~

VII Rl R2 13 R4 H2N-O-~C-N- ~-R5, or a salt thereof. The reaction proceeds best in water and in mixtures of water and organic solvents, such as methanol, ethanol, tetrahydro-furan or dioxane.
Reactants of formula VII can be prepared by reacting a compound having the formula VIII R

~ -O-~-C-OH

lS or ~I-O~-halo with a hydrazide having the formula to yield the corresponding compound having the formula X [~N-O-C/-~;-N-N-R5 .
: 30 If an acid reactant of formula VIII is used, a suitable coupling agent, such as dicyclohexylcarbo-diimide, should be present. Alternatively, an acid of formula VIII can be activated by formation of a mixed anhydride. If an acid halide , . . ,,, , ,: ~
, . . . ~ . . ' . , :
' ', ''. '., , , ~. , .

~2~5~3~
GC2~7 derivative of formula IX is used, a suitable base should be present. The hydrazides of formula X
can be deprotected using standard methodology to yield the desired reactants of formula VII.
Exemplary deprotecting agents are hydrazine and methylhydrazine.
Hydrazine derivatives of formula III, and methods for their preparation, are well known in the literature. Reviews of their synthesis can be found in Smith, "The Chemistry of Open-Chain organic Nitrogen Compounds", Vols. I ~ II, Benjamin, Inc., New York, Amsterdam, 1966; Muller, "Methoden der Organischen Chemie" (Houben-Weyl), Vol. 10/2, Georg Thieme Verlag Stuttgart, 1967;
Sandler and Karo, "Organic Functional Group Preparations", Vol. 1, Academic Press, New York, 1968; and Timberlake and Stowell, "The Chemistry of ~ydrazo, Azo, and Azoxy Groups", ed. S.Patai, part 1, Interscience, New York, 1975.
Reactants of formula IV are described in United Kingdom patent application 2071650, published September 23, 1981.
The compounds of this invention (both the pharmaceutical products of formula I and the intermediates of formula V) contain an imino group (-~-) and can exist as syn or anti isomers or as N-mixtures of both. All of these isomeric forms are within the scope of this invention. The syn isomers are preferred, however, because that isomeric form has superior activity.
Whether the pharmaceutical products of formula I are prepared from a starting compound of formula II or from a starting compound of formula ~5 V, the isomerism of the starting material will determine the isomerism of the product. In lX~5~5~

preparing a compound of formula V, the ratio of syn/anti will depend on the reaction conditions.
If the reaction of compounds of formula VI and VII
is run at room temperature, the ratio of syn/anti will be favorable to the obtaining of the syn isomer. Lowering the reaction temperature increases the ratio of syn/anti, but slows the reaction. Raising the reaction temperature decreases the ratio of syn/anti, but speeds the reaction. Separation of the syn and anti isomers can be accomplished using fractional crystalliza-tion.
Alternative methodology for preparing the compounds of this invention will be apparent to the practitioner of this invention. For example, those compounds of formula I wherein R4 and R5 are =C~-Y7 can be prepared by reacting the corres-ponding compound of formula I wherein R4 and R5 are each hydrogen with the appropriate benzaldehyde.
The following examples are specific embodiments of this invention.

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

~28595~i Example 1 [3S-[3a(Z),4~]]-3-[[(2-Amino-4-thiazolyl)[[l,1-dimethyl-2-[2-[(1,l-dimethylethoxy)carbonyl]-hydrazino]-2-oxoethoxy]imino]acetyl3amino]-4-S methyl-2-oxo-1-azetidinesulfonic acid, mono-potassium salt ~3S-[3~(Z),4~]]-3-[[(2-Amino-4-thiazolyl)-[(l-carboxy-l-methylethoxy)imino]acetyl}amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (2.18 g), 0.93 g of tributylamine, 0.1 g of N-hydroxybenzo-triazole and 0.05 g of dimethylaminopyridine were dissolved in 30 ml of dimethylformamide, and 1.06 g of N,N-dicyclohexylcarbodiimide was added.
After stirring for 30 minutes, a solution of lS 0.66 g of [(1,1-dimethylethoxy)carbonyl~hydrazine in S ml of dimethylformamide was added. Stirring overnight at room ~emperature, filtering off the formed dicyclohexylurea and distilling off the solvent yielded an oily residue which was dissolved in acetone (30 ml) an~ filtered. To the filtrate were added 30 ml of ether and a solution of 1.7 g of potassium perfluorobutanesulfonate in 10 ml of acetone. Crude product (1.8 g) was obtained a`s a precipitate. Purification was by column chromatography on ~P-20*, using water and water/tetrahydrofuran (9:1) as eluents, and yielded 1.3 g of the title compound, melting point 258C.
IR (KBr): 1765 cm 1 (~-lactam carbonyl) H-NMR (200 M~z, DMSO-d6**): ~ = 1.38 (m, l5H); 3.68 ~m,l~); 4.5 (dd, lH); 6.78 (s, lH); 7.28 (s, broad, 2H); 8.75 (s, broad lH); 9.13 (s, broad, lH); 9.28 (d, broad, lH) ppm ------____ *HP-20: macroreticular styrene-divinylbenzene copolymer, Mitsubishi Chemical Industries, Ltd.
:
**DMS0-d6: deuterated dimethylsulfoxide :

i~85~S ~

Exam~le 2 [3S- [3a ( Z ), 4~ ] ] -3- [ ~ [ [2-[2-(Aminocarbonyl)hydrazino]-1,1-dimethyl-2-oxoethyl]imino](2-amino-4-thiazolyl)-acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, monopotassium salt [3S-[3~(Z),4~]]-3-[[(2-Amino-4-thiazolyl)-[(l-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-l-azetidinesulfonic acid (2.18 g) and 0.93 g of tributylamine in 20 ml of dimethyl-formamide were stirred at room temperature andO.1 g of N-hydroxybenzotriazole and 0.05 g of dimethylaminopyridine were added followed by 1.06 g of N,N-dicyclohexylcarbodiimide in 5 ml of dimethylformamide. After stirring for 30 minutes, a solution of 0.6 g of (aminocarbonyl~hydrazine, hydrochloride and 0.93 g of tributylamine in 15 ml of dimethylformamide wcre added. Stirring at room temperature overnight, filtering off the formed dicyclohexylurea and evaporating the dimethyl-formamide of the filtrate yielded a residue whichwas dissolved in 30 ml of acetone/tetrahydrofuran (1:1) and fi}tered. After adding 3.4 g of potassium perfluorobutanesulfonate in 15 ml of acetone, the filtrate formcd a precipitate of 2.7 g crude product. This was purified by column chromatography on HP-20, using water as eluent, and yielding 1.3 g of the title compound, melting point 245C, after freeze drying.
IR (XBr): 1763 cm 1 (~-lactam carbonyl) H-NMR (200 MHz, DMSO-d6): ~ = 1.38 (d, 6H); 1.40 (d, 3H); 3.65 (m, lH); 4.53 (dd, lH); 5.98 (s, broad, 2H); 6.80 (s, lH); 7.23 (s, broad, 2H) 7.75 (s, lH); 9.25 (d, 2H); 9.35 (s, lH) ppm ~:
.

~285~35~

Example 3 [3S-[3~(Z),4~]]-3-[[(2-Amino-4-thiazolyl)[[2-[2-(aminothioxomethyl)hydrazino-1,1-dimethyl-2-oxoethoxy]imino]acetyl]amino]-4-methyl-2-oxo-1-S azetidinesulfonic acid, monoPotassium salt [3S- [ 3a ( Z ), 4~ ] ~ -3- [ [ ( 2-Amino-4-thiazolyl)-[(l-carboxy-l-methylethoxy)imino]a~-etyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (2.18 g), 0.93 g of tributylamine, 0.1 g of N-hydroxy-benzotriazole and 0.05 g of dimethylaminopyridine were dissolved in 30 ml of dimethylformamide and 1.06 g of N,N-dicyclohexylcarbodiimide in 5 ml of dimethylformamide was added. After stirring for 15 minutes at room temperature, 0.46 g of (amino-thioxomethyl)hydrazine in 10 ml of dimethylform-amide was added and stirring was continued for 6 hours. ~ormed dicyclohexylurea (0.98 g) was filtered off and the dimethylformamide of the filtrate was distilled off in vacuo. The oily residue was dissolved in 50 ml of acetone, filtered and after adding a solution of 1.7 g of potassium perfluorobutanesulfonate in 10 ml of acetone, crude product separated from the solution. It was washed with ether and purified by column chromatography on HP-20 using water as eluent and yielding 1.3 g of the title compound, melting point 215C (dec).
IR (KBr): 1765 cm (~-lactam carbonyl) H-NMR (200 MHz, DMSO-d6): ~ = 1.35 (s, 6H)i 1.40 (d, 3H); 3.63 (m, lH); 4.52 (dd, lH); 6.80 (s, lH); 6.95 (s, lH); 7.30 (s, broad, 2H); 8.00 (s, lH); 9.18 (d, lH); 9.38 (s, lH); 9.68 (s, lH) ppm . .: : . . . : , . . .

~2~5954 Example 4 [3S-[3a(Z),4~]]-3-[[[[2-(2-Acetylhydrazino)-l,l-dimethyl-2-oxoethoxy]imino](2-amino-4-thiazolyl)-acetyl]amino)-4-methyl-2-oxo-1-azetidinesulfonic acid, monopotassium salt ~ 3S-[3a(Z),4~]]-3-[[(2-Amino-4-thiazolyl)-[(l-carboxy-l-methy}ethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (2.18 q) and 0.93 g of tributylamine were dissolved in 20 ml of dimethylformamide and stirred at room temperature.
N-Hydroxybenzotriazole (0.1 g) and 0.05 g of dimethylaminopyridine were added followed by a solution of 1.06 g of N,N-dicyclohexylcarbodiimide in 10 ml of dimethylformamide. After 20 minutes stirring, a solution of 0.3 g of acetylhydrazine in S ml of dimethylformamide was added. After 5 hours, the formed dicyclohexylurea was filtered off and the dimethylformamide of the filtrate was distilled off in vacuo. The oily residue was dissolved in 30 ml of acetone, filtered and a solution of 1.7 g of potassium perfluorobutane-sulfonate in 10 ml of acetone was added. Crude product (1.7 g) was obtained as a precipitate, washed with ether, dried and purified by column chromatography on HP-20 using water as an eluent and yielding 0.8 g of the title compound, melting point 241C (dec).
IR ~KBr): 1760 cm 1 (~-lactam carbonyl) H-NMR (200 MHz, DMSO-d6): ~ = 1.38 (s, 6H); 1.40 (d, 3H); 1.83 (s, 3R); 3.68 (m, lH); 4.53 (dd, lH); 6.80 (s, lH)i 7.28 (s, 2H); 9.15 (s, broad, lH); 9.28 (d, lH); 9.73 (s, broad, lH) ppm : ' ~ :

::::

- - - , .. . . . .

~.2~595~ -ExamPle 5 [3S-[3~(Z),4~]]-3-[[(2-Amino-4-thiazolyl)[[2-[2-(2-furanylcarbonyl)hydrazino]-1,1-dimethyl-2-oxo-ethoxy]imino]acetyl]amino]-4-methyl-2-oxo-1-azetidineculfonic acid, monoPotassium salt [3S-[3a(Z),4~]]-3-[[(2-Amino-4-thiazolyl)-[(1-carboxy-l-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (2.18 g), O.93 g of tributylamine, 0.1 g of N-hydroxybenzo-triazole and 0.05 g of dimethylaminopyridine were dissolved in 30 ml of dimethylformamide. After adding 1.06 g of N,N-dicyclohexylcarbodiimide and stirring at room temperature for 20 minutes, a solution of 0.75 g of (2-furanylcarbonyl)hydrazine in 5 ml of dimethylformamide was added. Overnight stirring followed by filtering off the formed dicyclohexylurea and distilling off the dimethyl-formamide of the filtrate yielded an oily residue. It was dissolved in 50 ml of acetone, filtered and to the solution was added 1.7 g of potassium perfluorobutanesulfonate and 20 ml of ether yielding a precipitate of the crude product (2.4 g). Purification by HP-20 column chromato-graphy using water as eluent yielded 1.5 g of the title compound, melting point 255C (dec).
IR (KBr): 1763 cm 1 (~-lactam carbonyl) H-NMR (200 MNH, DMSO-d6): ~ = 1.45 (dd, 9H); 3.68 (m, lH); 4.51 (dd, lH); 6.60 (m, lH); 6.85 (s, lH); 7.23 (d, lH); 7.28 (s, lH); 7.85 (s, lH);
30 9.31 (d, broad, lH); 9.41 (s, broad, lH); 10.25 (s, broad, lH) ppm .-. . , .:

. .

128~954 Example 6 [3S-[3~(Z),4~]]-3-[[(2-Amino-4-thiazolyl)[(2-(formylhydrazino)-l,l-dimethyl-2-oxoethoxy]-imino]acetyl]amino-4-methyl-2-oxo-1-azetidine-sulfonic acid, monoPotassium salt [3S-t3a(Z),4~]]-3-[[(2-Amino-4-thiazolyl)-[(l-carboxy-l-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-l-azetidinesulfonic acid (1.09 g), 0.88 g of trioctylamine, 0.05 g of N-hydroxy-benzotriazole and 0.025 g of dimethylaminopyridine were dissolved in 50 ml of tetrahydrofuran. After adding a solution of 0.55 g of N,N-dicyclohexyl-carbodiimide in lO ml of tetrahydrofuran and stirring for 30 minutes at room temperature, a solution of 0.15 g of formylhydrazine in 10 ml of tetrahydrofuran was added. Overnight stirring was followed by filtering.off the formed dicyclohexylurea and the addition of O.85 g of potassium perfluoro-butanesulfonate to the filtrate to give crude product as a precipitate. This was recrystallized from methanol/isopropanol to give 0.9 g of the title compound, melting point 254C (dec).
IR (KBr): 1762 cm 1 (~-lactam carbonyl) H-NMR (200 MHz, DMSO-d6): ~ = 1.40 (dd, 9H); 3.68 (m, lH); 4.52 (dd, lH); 6.58 (s, lH); 7.30 (s, 2H); 8.03 (s, 1~); 9.25 (s, broad, lH); 9.28 (d, broad, lH); 9.90 (s, broad, lH) ppm ' ~ ~

~285~5~

Example 7 [3S-[3~(Z),4~]]-3-[[(2-Amino-4-thiazolyl)[[2-[2-[[(aminocarbonyl)amino]acetyl]hydrazino]-l,1-dimethyl-2-oxoethoxy]imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, monoPotassium salt [3S-[3a(Z),4~]]-3-[[(2-Amino-4-thiazolyl)-[(l-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (1.09 g), 0.47 g of tributylamine, 0.05 g of N-hydroxybenzo-triazole and 0.025 g of dimethylaminopyridine were dissolved in 30 ml of dimethylformamide. N,N-Di-cyclohexylcarbodiimide (0.55 g) was added and, after stirring for 20 minutes, a solution of 0.35 g of [[(aminocarbonyl)amino]acetyl]hydrazine in 20 ml of dimethylformamide was added. Stirring overnight, filtering off the formed dicyclohexylurea and distilling off the dimethylformamide of the filtrate yielded a residue which was dissolved in 30 ml of tetrahydrofuran/methanol (2:1) and filtered. To the filtrate was added a solution of 0.85 g of potassium perfluorobutanesulfonate in 10 ml of acetone. Crude product was obtained as a precipitate (1.3 g). Purification by column chromatography on H~-20 using water as an eluent yielded the title compound, melting point 205C
(dec)-IR (KBr): 1760 cm 1 (~-lactam carbonyl) H-NMR (200 MHz, DMSO-d6) ~ = 1.40 (dd, 9H); 3.65 (m, 3H); 4.52 (dd, lH); 5.63 (s, 2H); 6.28 (t, lH); 6.80 (s, lH); 7.80 (s, 2H); 9.25 (s, lH);
9.30 (d, lH); 9.80 (s, lH) ppm . , .
.. . . . . .

1;~859s~

Exam~le 8 [3S-[3a(Z),4~]]-3-[[(2-Amino-4-thiazolyl)[[1,1-dimethyl-2-[2-(methylsulfonyl)hydrazino]-2-oxo-ethoxy]imino)acetyl]amino~-4-methyl-2-oxo-1-azetidinesulfonic acid, mono~otassium saltt3S-~3~(Z),4~]]-3-[[(2-Amino-4-thiazolyl)-[(l-carboxy-l-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (2.18 g), 0.93 g of tributylamine, 0.1 g of N-hydroxybenzo-triazole and 0.05 g of dimethylaminopyridine weredissolved in 30 ml of dimethylformamide. A
solution of 1.06 g of N,N-dicyclohexylcarbodiimide in 5 ml of dimethylformamide was added, and after 20 minutes stirring at room temperature, a solution of 0.60 g of (methylsulfonyl~hydrazine in 8 ml of dimethylformamide was dropped in. After stirring for 5 hours, the formed dicyclohexylurea was filtered off, the dimethylformamide of the filtrate was distilled off and the residue was dissolved in 20 ml of acetone and filtered. A
solution of 1.7 g of potassium perfluorobutane-sulfonate in 15 ml of acetone was added. A
precipitate of 1.8 g of crude product was obtained and purified by column chromatography on HP-20 using water as eluent and yielding 1.2 g of the title compound, melting point 235C (dec).
IR (KBr): 1760 cm 1 (~-lactam carbonyl) H-NMR (200 MHz, DMSO-d6): ~ = 1.40 ~dd, 9H); 2.90 (s, 3H); 3.66 (m, lH); 4.5 (dd, lH); 6.78 (s, lH);
7.26 (s, 2H); 9.06 (d, lH); 9.43 (s, broad, lH);
9.78-(s, broad, lH); ppm .

::
, - -S95~

Exam~le 9 [3S-[3a(Z),4~]]-3-[[[[(2-(2-Phenylhydrazino)-l,l-dimethyl-2-oxoethoxy]imino](2-amino-4-thiazolyl)-acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, mono~otassium salt __ [3S-[3~(Z)`,4~]]-3-[[(2-Amino-4-thiazolyl)-[(l-carboxy-l-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (2.18 g), 0.93 g of tributylamine, 0.1 g of N-hydroxybenzo-triazole and O.OS g of dimethylaminopyridine were dissolved in 30 ml of dimethylformamide and a solution of 1.06 g of N,N-dicyclohexy}carbodiimide was added. After stirring for 20 minutes at room temperature, a solution of 0.54 g of phenyl-hydrazine in 5 ml of dimethylformamide was droppedin. Stirring for 4 hours, filtering off the formed dicyclohexylurea and distilling off the dimethyl-formamide of the filtrate yielded a residue which was dissolved in 20 ml of tetrahydrofuran and filtered. To the filtrate was added 1.7 g of potassium perfluorobutanesulfonate and 20 ml of ether yielding 1.8 g of the title compound as a precipitate, melting ~oint 223C (dec).
IR (RBr): 1762 cm 1 (~-lactam carbonyl) lH-NMR ~200 MHz, DMSO-d6): 8 = 1.43 (m, 9H); 3.73 (m, 1~); 4.53 (dd, lH); 6.63 (t, lH); 6.75 (d, 2H); 6.88 (s, lH); 7.30 (s, lH); 7.73 (s, lH);
9.25 (s, broad, lH); 9.45 (d, lH); ppm 3595~

Exam~le 10 [3S-[3a(Z),4~] ]-3-[ [ [ [2-[2-(Cyanoacetyl)hydrazino]-1,1-dimethyl-2-oxoethoxy]imino](2-amino-4-thiazolyl)-acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic S acid, monoPotassium salt [3S-[3~(Z),4~]]-3-~[(2-Amino-4-thiazolyl)-[(l-carboxy-l-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (2.18 g), 0.93 g of tributylamine, 0.1 g of N-hydroxybenzo-triazole and 0.05 g of dimethylaminopyridine were dissolved in 30 ml of dimethylformamide. A
solution of 1.06 g of N,N-dicyclohexylcarbodiimide in 5 ml of dimethylformamide was added and after stirring for 20 minutes, a solution of 0.5 g of (cyanoacetyl)hydrazine in 50 ml of dimethylform-amide was added. Stirring overnight at room temperature, filtration and distilling off the dimethylformamide of the filtrate yielded an oily residue. It was dissolved in 20 ml of methanol, filtered and to the filtrate a solution of 1.7 g of potassium perfluorobutanesulfonate in 10 ml of acetone was added. Crude product was obtained as a precipitate. Purification by column chromato-graphy on HP-20 using water as an eluent yielded the title compound, melting point 223C (dec).
IR (KBr): 2235 cm 1 ~cyano); 1765 cm 1 (~-lactam carbonyl) H-NMR (200 MHz, DMSO-d6): ~ = 1.41 (m, 9H); 3.70 (m, lH); 3.73 (s, 2H); 4.51 (dd, 1~); 6.83 (s, ; 30 lH); 7.30 (s, 2H); 9.28 (d, lH); 9.33 (s, broad, lH); 9.73 (d, broad, A~); 10.30 (s, broad, lH); ppm .

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

;'35 ~

Example 11 [ 3S- [3a ( Z ), 4~ ] ] -3- [ [ [ 12- [2- (Aminooxyacetyl)-hydrazino]-l,l-dimethyl-2-oxoethoxy]imino]( 2-amino-4-thiazolyl)acetyl]amino]-4-methyl-2-oxo-l-azetidinesulfonic acid, monoPotassium salt [3S-[3~(Z),4~]]-3-[[(2-Amino-4-thiazolyl)-~(l-carboxy-l-methylethoxy)imino]acetyl~amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (2.18 g), 0.93 g of tributylamine, 0.1 g of N-hydroxybenzo-triazole and 0.05 g of dimethylaminopyridine were stirred at room temperature in 30 ml of dimethyl-formamide. A solution of 1.06 g of N,N-dicyclo-hexylcarbodiimide in 5 ml of dimethylformamide was added and, after stirring for 20 minutes, a solution of 0.5 g of (aminooxoacetyl)hydrazine in 20 ml of dimethylformamide was added. Stirring overnight, filtering off the formed dicyclohexyl-urea and distilling off the dimethylformamide of the filtrate yielded a residue which was dissolved in 30 ml of tetrahydrofuran/methanol (3:1). After filtration, a solution of 1.7 g of potassium perfluorobutanesulfonate in 20 ml of acetone was added. Crude product was obtained as a precipi-tate. Purification by column chromatography on HP-20 u~ing water as eluent yielded 1.6 g of the title compound, melting point 148C (dec).
IR (RBr): 1768 1 (~-lactam carbonyl) H-NMR (200 MHz DMSO-d6): ~ = 1.45 (m, 9H); 3.68 (m, lH); 4.52 (dd, lH); 6.83 (s, lH); 7.28 (s, 2H~ 8.00 (d, broad, 2~); 9.30 ~d, broad, 2~; ppm :

.

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

lZ~35~35~

Exam~le 12 [3S-[3a(Z),4~]]-3-[[~2-Amino-s-thiazolyl)[[2-hydrazino-l,l-dimethyl-2-oxoethoxy]imino]acetyl]-amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, and the trifluoroacetate salt thereof Method I
A) [35-~3a(Z),4~]]-3-[[(2-Amino-4-thiazolyl)[[2-[2-(triphenylmethyl)hydrazino]-1,1-dimethyl-2-oxo-ethoxy]imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, monoDotassium salt [3S-[3a(Z),4~]]-3-[[(2-Amino-4-thiazolyl)-t(l-carboxy-l-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (2.18 g), 0.1 g of N-hydroxybenzotriazole, 0.05 g of dimethyl-aminopyridine and 0.93 g of tributylamine were dissolved in 20 ml of dimethylformamide. With stirring, a solution of 1.1 g of N,N-dicyclohexyl-carbodiimide in 10 ml of dimethylformamide was added. After stirring at room temperature for 15 minutes, a solution of 1.55 g of (triphenylmethyl)-hydrazine, hydrochloride and 0.93 g of tributyl-amine in 20 ml of dimethylformamide were added.
Stirring overnight, filtering off the formed dicyclohexylurea and distilling off the dimethyl-formamide of the filtrate yielded a residue whichwas dissolved in 20 ml of acetone and filtered.
To the filtrate was added 150 ml of ether and a solution of 3.40 g of potassium perfluorobutane-sulfonate in 30 ml of aceonte. Crude product was obtained as a precipitate (2.2 g). Purification by column chromatography on HP-20 using water and water/tetrahydrofuran (9:1) as eluents yielded the :

.

. . ~ ,. . .
. .

1.2~5'~

title compound, melting point 182-184C (dec).
IR (KBr): 1760 cm~l (~-lactam carbonyl) H-NMR (200 MHz, DMSO-d6): ~ = 1.10 (d, 6H); 1.38 (d, 3H); 3.63 (m, lH); 4.38 (dd, lH); 5.78 (d, lH); 6.58 (s, lH); 7.33 (m, 17H); 8.00 (d, lH);
9.25 (d, lH)i ppm B) [3S-[3a(Z),4~]]-3-[[(2-Amino-4-thiazolyl)~[2-hydrazino-l,l-dimethyl-2-oxoethoxy]imino]acetyl]-aminol-4-methyl-2-oxo-1-azetidinesulfonic acid [3S-[3a(Z),4~]]-3-~[(2-Amino-4-thiazolyl)-[[2-t2-(triphenylmethyl)hydrazino]-1,1-dimethyl-2-oxo-ethoxy]imino~acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, monopotassium salt (0.8 g) was suspended in 20 ml of dichloromethane. At 0C, with stirring, 10 ml of formic acid (98%) was added. After continuous stirring for 20 minutes, the clear solution was transferred into 100 ml of ether. A precipitate of the formic acid salt of the title compound and potassium formiate were obtained. The precipitate was stirred in 30 ml of acetonitrile and 5 ml of N-Methyl-N-(trimethyl-; silyl)trifluoroacetamide was added. Stirring for 10 minutes, filtration and the addition of 5 ml of methanol to the filtrate yielded the title compound as a crystalline precipitate.
IR (KBr): 1762 cm 1 (~-lactam carbonyl) H-NMR (200 M~z, DMSO-d6): ~ = 1.38 (m, 9H); 3.68 (m, lH); 4.5 (dd, lH); 6.80 (s, lH); 7.30 (m, broad, 4H); 9.1S (s, broad, lH); 9.38 (d, broad, lH); ppm si~

Method II
[3S-[3~(Z),4~]]-3-[[(2-Amino-4-thiazolyl)[[2-hydrazino-1,1-dimethyl-2-oxoethoxy]imino]acetyl]-amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, trifluoroacetate salt (1:2) [3S-[3a(Z),4~]]-3-[[(2-Amino-4-thiazolyl)-[[1,1-dimethylethoxy)carbonyl]hydrazino~-2-oxo-ethoxy]imino]acetyl]amino]-~-methyl-2-oxo-l-azetidinesulfonic acid, monopotassium salt (10 g) was dissolved in 30 ml of dichloromethane and added dropwise to 60 ml of trifluoroacetic acid with stirring at -10C. After 20 minutes of stirring, the reaction was complete. The addition of 200 ml of ether to the solution precipitated 7.8 g of the title compound, melting point 220C, (dec)-Exam~le 13 [3S-[3a(Z),4~]]-3-[[(2-Amino-4-thiazolyl)[[1,1-dimethyl-2-[2-(2-pyridinyl)hydrazino]-2-oxoethoxy]-imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, mono~otassium salt [3S-[3a(Z),4~]]-3-[[~2-Amino-4-thiazolyl)-[(l-carboxy-l-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (1.04 g), 0.05 g of N-hydroxybenzotriazole, 0.025 g of dimethylaminopyridine and 0. as g of trioctylamine were dissolved in 20 ml of dimethylformamide.
N,N-Dicyclohexylcarbodiimide (0.55 g) in lO ml of tetrahydrofuran was added. Stirring for 15 minutes at room temperature, followed by the addition of 0.3 g of (2-pyridinyl)hydrazine in 5 ml of dimethylformamide and overnight stirring completed the reaction. Dicyclohexylurea was filtered off, the solvents of the filtrate were distilled off and the residue was dissolved in :
:

,. , ., . ~. ,~ . , , . , . : . :, 1~5~35~

20 ml of tetrahydrofuran and filtered.
Potassium perfluorobutanesulfonate (0.85 g) was added, stirring for 5 minutes followed by the addition of 10 ml of ether formed crude product as a precipitate (0.9 g). Purification by column chromatography on HP-20 yielded the title compound, melting point 205-207C ~dec).
IR (KBr): 1762 cm 1 (~-lactam carbonyl) lH-NMR (200 MHz, DMSO-d6): ~ = 1.40 (dd, 9H); 3.65 (m, lH); 4.53 (dd, lH); 6.65 (m, 2~); 6.84 (s, 1~); 7.30 (s, 2H); 7.43 (t, 1~); 8.00 (d, 1~);
8.18 (s, lH); 9.35 (s, lH); 9.40 (d, lH); ppm ExamDle 14 ~3S-[3a(Z),4~]]-3-[[[[2-[2-(3-Pyridinylcarbonyl)-hydrazino]-l,l-dimethyl-2-oxoethoxy]imino](2-amino-4-thiazolyl)acetyl]amino]-4-methyl-2-oxo-1-azetidine-sulfonic acid,, mono~otassium salt ~3S-[3a(Z),4~]]-3-t[(2-Amino-4-thiazolyl)-[(1-carboxy-1-methylethoxy~imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (2.18 g), 0.93 g of tributylamine, 0.1 g of N-hydroxybenzo-triazole and 0.05 g of dimethylaminopyridine in 30 ml of dimethylformamide were stirred and a solution of 1.06 q of N,N-dicyclohexylcarbodiimide in 10 ml of dimethylformamide was dropped in.
After 30 minutes, a solution of 0.68 g of (3-pyridinyl-carbonyl)hydrazine in 10 ml of dimethylformamide was added. Stirring overnight, filtering off the dicyclohexylurea, and stripping off the dimethyl-formamide of the filtrate yielded a residue which was ~issolved in 30 ml of acetone. After adding 1.7 g of potassium perfluorobutanesulfonate in 20 ml of acetone, the title compound was obtained . : ~ . . . :

~2~5~ t as a precipitate (1.8 g), melting point 243C
(dec).
IR (KBr): 1760 cm 1 (~-lactam carbonyl) lH-NMR (200 MHz, DMSO-d6): ~ = 1.44 (dd, 9H); 3.70 (m, lH); 4.53 (dd, lH); 6.85 (s, lH); 7.28 (s, 2~); 7.51 (m, lH); 8.20 (m, lH); 8.73 (~, lH);
9.01 (d, lH); 9.30 (d, lH); 9.S0 (s, lH); 10.63 (s, broad, lH); ppm Exam~le 15 [3S-t3a(Z),4~]]-3-[[(2-Amino-4-thiazolyl)[[2-[2-(aminocarbonyl)-2-methylhydrazino]-1,1-dimethyl-2-oxoethoxy]imino]acetyl~amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, mono~otassium salt t3S- [3a (Z),4~]]-3-t[(2-Amino-4-thiazolyl)-t(1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (1.09 g), 0.47 g of tributylamine, 0.05 g of N-hydroxybenzo-triazole and 0.025 g of dimethylaminopyridine were dissolved in 15 ml of dimethylformamide. After adding a solution of O.S5 g of N,N-dicyclohexyl-carbodiimide in 5 ml of dimethylformamide and stirring at room temperature for 15 minutes, a solution of 0.4 g of 2-(aminocarbonyl)-2-methyl-hydrazine and 0.47 g of tributylamine in 10 ml of tetrahydrofuran was added. Overnight stirring, filtering off the dicyclohexylurea and distilling off the æolvents of the filtrate yielded a residue which was dissolved in 20 ml of tetrahydrofuran and filtered. To the filtrate was added a solution of 0.85 g of potassium perfluorobutane-sulfonate in 20 ml of tetrahydrofuran and S0 ml of ether. Crude product ~1.1 g) was obtained as a precipitate. Purification by column chromatography ' - . , -.~ , . - . .

.. . .

~28595~

on HP-20 yielded the title compound, melting point 203-205C (dec).
IR (KBr): 1762 cm 1 (~-lactam carbonyl) lH-NMR (200 MHz, DMSO-d6): ~ = 1.36 (s, 6H); 1.40 (d, 3H); 2.93 (s, 3H); 3.65 (m, lH); 4.53 (dd, lH); 6.08 (s, broad, 2H); 6.78 (s, lH); 7.23 (s, 2H); 9.25 (d, lH); 9.78 (s, lH); ppm Example 16 t3S-~3a(Z),4,~]~-3-[[(2-Amino-4-thiazolyl)[[2-[2-[(methylamino)carbonyl]hydrazino]-1,1-dimethyl-2-oxoethoxy]imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, mono~otassium salt [3S-[3~(Z),4~]]-3-[[(2-Amino-4-thiazolyl)-[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (1.09 g), 0.47 g of tributylamine, 0.05 g of N-hydroxybenzo-triazole and 0.025 g of dimethylaminopyridine were dissolved in 20 ml of dimethylformamide. N,N-Di-cyclohexylcarbodiimide (0.55 g) was added, andafter 20 minutes stirring at room temperature a solution of 0.28 g of [(methylamino)carbonyl]-hydrazine, hydrochloride and 0.4 g of tributylamine in 20 ml of dimethylformamide was also added.
Overnight stirring, filtering off the dicyclo-hexylurea and distilling off the dimethylformamide of the filtrate yielded a residue, which was dissolved in 30 ml of dimethylformamide and filtered. To the filtrate was added a solution of 1.7 g of potassium perfluorobutanesulfonate in 20 ml of acetone. Crude product (1.1 g~ was obtained as a precipitate. Purification by column chromatography on HP-20 using water as an eluent yielded the title compound, melting-point 218C
3s (dec)-, .:. .
-: . - , , - . , -i.~8595~

IR (KBr): 1760 cm 1 (~-lactam carbonyl) H-NMR (200 MHz, DMSO-d6): ~ = 1.36 (d, 6H); 1.39 (d, 3H); 2.51 (d, 2H); 3.66 (m, lH); 4.52 (dd, lH); 5.65 (d, broad, lH); 6.80 (s, lH); 7.28 (s, 2H); 7.86 (s, lH); 9.23 (s, lH); 9.33 (d, lH); ppm Exam~le 17 [3S-~3~( æ ), 4~]]-3-~(2-Amino-4-thiazolyl)[[2-[2-[(methylamino)thiozomethyl]hydrazino]-l,l-dimethyl-2-oxoethoxy]imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, monoDotassium salt [3S-t3atZ),4~]]-3-t~(2-Amino-4-thiazolyl)-[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (1.09 g), 0.05 g of N-hydroxybenzotriazole, 0.025 g of dimethylaminopyridine and 0.88 g of trioctylamine were dissolved in 50 ml of of tetrahydrofuran and 0.55 g of N,N-dicyclohexylcarbodiimide was added.
After stirring for 30 minutes at room temperature, 0.27 g of [(methylamino)thioxomethyl]hydrazine in 20 ml of tetrahydrofuran was added. Overnight stirring, filtering off the formed dicyclohexyl-urea and adding 0.85 g of potassium perfluoro-butanesulfonate in 15 ml of acetone to the filtrate formed crude product as a precipitate.
Adding ether yielded a second crop. (Total 1.1 g). Purification by column chromatography on HP-20 using water as an eluent yielded the title compound, melting point 206-208C, (dec).
IR (KBr): 1760 cm 1 (~-lactam carbonyl) H-NMR (200 MHz, DMSO-d6): ~ = 1.38 (d, 6H); 1 40 (d, 3H); 2.85 (d, 3H); 3.68 (m, lH); 4.52 (dd, lH); 6.79 (d, broad, lH); 6.89 (s, lH); 7.33 (s, 2H); 9.28 (d, lH); 9.46 (s, broad, lH); 9.53 (s, broad, lH); ppm ~ ~:

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

~S~5~

Example 18 [3S-[3~(Z),4~]]-3-[[(2-Amino-4-thiazolyl)[[2-[2-[imino(methylthio)methyl]hydrazino]-1,1-dimethyl-2-oxoethoxy]imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, monoPotassium salt [3s-[3~Z),4~]]-3-[[(2-Amino-4-thiazolyl)-[(l-carboxy-l-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (2.18 g), 0.93 g of tributylamine, 0.-1 g of N-hydroxybenzo-triazole and 0.05 g of dimethylaminopyridine were dissolved in 30 ml of dimethylformamide. N,N-Di-cyclohexylcarbodiimide (1.06 g) in 5 ml of dimethyl-formamide was added and, after stirring for 20 minutes, a solution of 1.17 g of [imino(methyl-thio)methyl]hydrazine, hydrogen iodide salt and0.93 g of tributylamine in 15 ml of dimethyl-formamide was also added. Continuous stirring overnight at 5C, filtering off the dicyclohexyl-urea and distilling off the dimethylformamide of the filtrate yielded an oily residue. The residue was dissolved in 30 ml of tetrahydrofuran and 5 ml of methanol, filtered and a solution of 3.4 g of potassium perfluorobutanesulfonate in 20 ml of acetone was added. Crude product (1.2 g) was obtained as a precipitate. Purification by column chromatography on ~P-20 using water as an eluent yielded 1.4 g of the title compound, melting point 208C,(dec).
IR (KBr): 1765 cm (~-lactam carbonyl) 30 lH-NMR (200 MHz, DMSO-d6): ~ = 1.36 (d, 6H); 1.40 (d, 3H); 2,28 (s, 3H); 3.68 (m, lH); 4.51 (dd, lH); 6.38 (s, broad, 2H); 6.81 (s, lH); 7.28 (s, 2H); 9.06 (s, broad, lH); 9.40 (d, broad, lH); ppm . - . , . ~ . .: . - . .
~- . ~ -: . . . : . ~ . . .

~S~5'~

Exam~le 19 [3s-~3a(z)~4~]]-3-t~(2-Amino-g-thiazolyl)~2-~2 taminothioxomethyl)hydrazino]-i~l-dimethyl-2 ethoxy]imino]acetyl~amino-4-methyl-2-oxo-1-S azetidinesulfonic acid, mono~otassium saltt3S-t3a(Z),4a]]-3- r ~ ( 2-Amino-4-thiazolyl)-t(l-carboxy-l-methyiethoxy)imino~acetyl]a~ino]-4-methyl-2-oxo-1-azetidinesulfonic acid (0.66 g), 0.3 g of tributylamine, 0.26 g of N-hydroxybenzo-triazole and 0.01 g of dimethylaminopyridine weredissolved in 10 ml of dimethylformamide and a soiution of 0.33 g of N,N-dicyclohexylcarbodiimide in S ml of dimethylforma~;de was added. After stirring for 20 minutes at room temperature, a solution of 0.28 g of (aminothio~omethyl~-hydrazine in 10 ml of dimethylformamide was also added. Stirring was continued for 24 hours, formed dicyclohexylurea was filtcred off and the dimethylformamide of the filtrate was distilled off. The residue was dissolved in 20 ml tetra-hydrofuran~methanol (1:1), filtered and a solution of 0.51 g of potassium perfluorobutanesulfonate i~
S ml of methanol was added followed ~y 20 ml of ether. The re~ultant prccipitate of crude product was purified by column chromatography on Hæ-20 using water as an eluent and yieldins 0.8 g of the title compound, melting point 218C, (dec).
IR (KBr): 1768 cm 1 (~-lactam carbonyl) 1H-NMR (200 M~z, DMSO-d6) ~ = 1.23 (d, 3H); 1.35 (d, 6R); 4.05 (m, l~)i S.10 (m, lH); 6.80 (s, 1~);
6.g3 (s, broad, lH, CSN~2); 7.33 (s, broad, 2H);
8.10 (s, broad, lH, CSN~2), 9.14 (d, broad, lH);
9.40 (s, broad, 1~); 9.65 (s, broad, lH); ppm * Trade Mark .
., ~ - , ~ , . - ~, ~3S95 ~

ExamDle 2 0 t3S- [3a ( Z ), 4~ ~ ] ~3~ t ~ ( 2-Amino-4-thiazolyl ) [ E2- [2-[ 3, 4-bis (acetyloxy)benzoyl]hydrazino]-l,1-dimethyl-2-oxoethoxy]imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, mono~otassium saltt3S-~3~(Z),4~]~-3-~(2-Amino-4-thiazolyl)-~2-hydrazino-1,1-dimcthyl-2-oxoethoxy]imino]-acet~l]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, trifluoroacetate salt (1:2) (~.36 g) and 1.47 g of tributylamine were dissolvcd in 15 ml of dimethylformamide. At 0C, with stirring, a solution of 0.75 g of 3,4-(diacetyl-oxy)benzoyl chloride in S ml of dimethylform~;de was dropped in. After stirring for 3 hours, the dimethylformamide was distilled off and the residue was dissolved in 20 ml of tetrahydrofuran and filtered. To the filtrate was added 2.75 g of potassiu~ perfluorobutanesulfonate. After stirring for 10 minutes, 20 ml of ether was added and crude product was obtained as a precipitate.
This was purified by liguid chromatography on XAD-2* using water and water/tetrahydrofuan (9.5:O.S) as eluents, yielding 1.1 g of the title compound, melting point 221C (dec).
IR (K3r): 176~ cm 1 (~-lactam carbonyl) ~-NMR (200 MEz, DMSO-d6) ~ ~ 1.41 (d, 3~); 1.48 (d, 6E); 2.29 (s, 6~); 3.70 (m, lE); 4.06 (dd, 1~); 6.85 (s, lE); 7.26 (s, 2~); 7.40 (d, lE);
7.81 (m, 2~); 9.30 (d, 1~); 9.48 (s, 1~); 10.49 (s, 1~); ppm _____ :~ :
*XAD-2: macroreticular styrenë-divinylbenzene c~pclymer, Rohm and ~aas Company * Trade tqark ' - - - ' . ' ' : : ' . .
: . . .
- . -. .. . .
- .
: .. . .

~ 2~35~35~

Example 21 [3S-[3~(Z),4~]]-3-[[(2-Amino-4-thiazolyl)[[l,l-dimethyl-2-[2-[(2-amino-4-thiazolyl)acetyl]-hydrazino]-2-oxoethoxy]imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, monopotassium salt [3S-[3a(Z),4~]]-3-[[(2-Amino-4-thiazolyl)-~ carboxy-l-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (1.09 g), 0.47 g of tributylamine, 0.1 g of N-hydroxybenzo-triazole and 0.05 g of dimethylaminopyridine weredissolved in 10 ml of dimethylformamide and 0.54 g of N,N-dicyclohexylcarbodiimide was added. After stirring for 20 minutes at room temperature, O.45 g of [(2-amino-4-thiazolyl)acetyl]hydrazine was added. Overnight stirring, filtration from the formed dicyclohexylurea and distilling of the dimethylformamide of the filtrate yielded a residue. It was dissolved in 10 ml of tetrahydro-furan, filtered again and 1.7 g of potassium perfluorobutanesulfonate and 10 ml of ether were added to the filtrate yielding a precipitate. The crude product was purified by column chromatography on ~P-20 using water as an eluent, yielding 0.67 g of the title compound, melting point 147C (dec).
IR (KBr): 1765 cm 1 (~-lactam carbonyl) H-NMR (200 MHz, DMSO-d6) ~ = 1.43 (2d, 9H); 3.30 (d, 2~); 3.71 (m, lH); 4.51 (dd, lH); 6.31 (s, lH); 6.80 (s, lH); 6.82 (s, 2H); 7.26 (s, 2H);
30 9.28 (s, broad, 3~); 9.77 (s, broad, lH); ppm .
: . -~X~595~

_35 GC227 Example 22 [3S-[3~(Z),4~]]-3-[[(2-Amino-~-thiazolyl)[[2-[2-[(2,3-dihydroxyphenyl)methylene]hydrazino]-1,1-dimethyl-2-oxoethoxy]imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, monopotassium salt, dimethYlformamide (1:2) t3S- [3a (Z),4~]]-3-[[(2-Amino-4-thiazolyl)-[[2-hydrazino-1,1-dimethyl-2-oxoethoxy~imino]-acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, trifluoroacetate salt (1:2) (0.68 g) and 0.37 g of tributylamine were dissolved in 10 ml of dimethylformamide. A solution of 0.14 g of 2,3-dihydroxybenzaldehyde in 10 ml of dimethylformamide was added. Ater stirring for 12 hours, the solution was filtered and the dimethylformamide filtrate was distilled off. The residue was dissolved in 30 ml of methanol and a solution of 1.1 g of potassium perfluorobutanesulfonate in 20 ml of methanol was added. The title compound (0.45 g) was obtained as a crystalline precipitate, melting point 199C (dec).
IR (KBr): 1770 cm 1 (~-lactam carbonyl) H-NMR (200 MHz, DMSO-d6) ~: 1.42 (d, 3H); 1.50 (d, 6H); 3.80 (m, 1~); 4.50 (m, lH); 4.68 (s, broad, 2H); 6.65-7.00 (m, 4H); 7.25 (s, broad, 2H); 4.49 (s, lH); 9.43 (d, 2H); 10.99 (s, lH); ppm - . . . . ......................... . .
, -. - , : - - -. . . . . . . .

~2~5~5~

Example 23 [3S-[3~(Z),4~]]-3-[[(2-Amino-4-thiazolyl)[[2-[2-[(3,4-dihydroxyphenyl)methyiene]hydrazino]-1,1-dimethyl-2-oxoethoxy]imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, mono-Potassium salt _ ~ 3S-[3a(Z),4~]]-3-[[(2-Amino-4-thiazolyl)-[[2-hydrazino-1,1-dimethyl-2-oxoethoxy]imino]-acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, trifluoroacetate salt (1:2) (0.68 g) and 0.37 g of tributylamine were dissolved in 15 ml of dimethylformamide. To this solution was added 1 g of molecular sieves (3 angstroms) together with 0.14 g of 3,4-dihydroxybenzaldehyde. After stirring for 8 hours at room temperature, the solution was filtered and the filtrate was distilled off. The residue was dissolved in methanol and filtered again. To the filtrate was added 1.1 g of potassium perfluorobutanesulfonate and 10 ml of diethyl ether. Crude product was obtained as a precipitate. Purification by liquid chromatography on XAD-2 using water and water/
methanol (9.7:0.3) as eluents yielded 0.8 g of the title compound, melting point 258C (dec).
IR (~Br): 1768 cm 1 (~-lactam carbonyl) H-NMR (200 M~z, DMS0-d6) ~: 1.41 (d, 3H); 1.46 (s, 6H); 3.38 (s, broad, 2H); 3.78 (m, lH); 4.51 (dd, lH); 6.75 (m, lH); 6.83 (s, lH); 6.90 (m, lH); 7.25 (s, broad, 2H); 8.13 (s, lH); 9.45 (s, broad, lH); 10.40 (s, broad, lH); ppm .

.. , .. . ~ ~ . ~ . .

;~, ,: ' .

~2S595~

Example 24 (Z)-2-Amino-a-[[l,1-dimethyl-2-[2-[(1,1-dimethyl-ethoxy)carbonyl]hydrazino]-2-oxoethoxy]imino]acetic acid A) 1-[2-[(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-oxy]-2-methyl-1-oxopropyl]-2-[(1,1-dimethylethoxy)-carbonyll 2-[(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-oxyJ-2-methylpropanoyl chloride (34.5 g) was dissolved in 200 ml of dichloromethane. At 0C, with stirring, a solution of 17 g of [(l,l-dimethyl-ethoxy)carbonyl]hydrazine and 13 g of triethylamine in 80 ml of dichloromethane was added. After stirring overnight, 300 ml of ice water was added, and after stirring for 5 minutes, the organic phase was separated and extracted with 100 ml of 5%
sodium bicarbonate solution and then with 100 ml of water. After drying over sodium sulfate, the dichloromethane was evaporated. The oily residue crystallized after several hours, yielding 42.4 g of white crystals.
IR (XBr): 1800 cm 1 (carbonyl phthalimido) 1740 cm 1 (carbonyl ester) lH-NMR (90 MHz, DMSO-d6): ~ = 1.34 (s, 9~); 1.50 (s, 6~); 7.93 (s, 4~); 8.81 (s, broad, lH); 9.69 (s, 1~); ppm B) 1-[2-(Aminooxy)-2-methyl-1-oxopropyl]-2-[(t-butYloxy)carbonyl]hvdrazide 1-~2-[(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)oxy]-2-methyl-1-oxopropyl]-2-[(1,l-dimethyl-ethoxy)carbonyl] (18.2 g) was dissolved in 200 ml of dichloromethane and at 0C a solution of 2.3 g of N-methylhydrazine was added dropwise in 300 ml .

lX8595~

of dichloromethane. After 4 hours stirring, the reaction mixture was filtered and the dichloro-methane of the filtrate was evaporated yielding an oily residue of the title compound (24.2 g), which crystallized after standing im the cold.
H-NMR (90 MHz, DMSO-d6): ~ = 1.30 (s, 9H?; 1.46 (s, 6H); 5.95 (s, broad, 2H); 8.59 (s, broad, lH);
9.35 (s, broad, lH); ppm 10 C) (Z)-2-Amino-a-t[1,1-dimethyl-2-[2-[(1,1-dimethylethoxy)carbonyl]hydrazino]-2-oxoethoxy]-iminolacetic acid (Z)-2-Amino-4-thiazoleglyoxylic acid ~1.72 g) was suspended in 30 ml of water/tetra-hydrofuran (1:1) and 2.33 g of 1-[2-(aminooxy)-2-methyl-1-oxopropyl~-2-[(t-butyloxy)carbonyl]-hydrazine was added; the pH was adj~sted to 5.6 with sodi~m bicarbonate. Stirring overnight' formed a clear solution. The dimethylformamide was evaporated and the water solution was adjusted to p~ 2 with 2 N phosphoric acid at 5~C. Crude product was obtained as an oily precipitate which crystallized after treat~ent with ether.
Recrystallization from dimethylformamide/iso-propanol yielded 3.2 g of white crystals, meltingpoint 195C (dec).
IR (KBr): 1730 cm 1 H-NMR (90 MRz, DMSO-d6) ~ = 1.41 (d + s, l5H);
6.92 (s, lH); 7.27 (s, broad, 2H); 8.00 (s, broad, 30 lH); 8.71 (s, broad, lH); 9.15 (s, broad, lH) ::

~::

-. . . . . .

12~59~i~

Example 25 [3S-[3a(Z),4~]]-3-[[(2-Amino-4-thiazolyl)[[2-(2,2-dimethylhydrazino)-1,1-dimethyl-2-oxo-ethoxy]imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, mono~otassium salt [3S-[3a(Z),4~]]-3-[[(2-Amino-4-thiazolyl)-[(l-carboxy-l-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (1.09 g), 0.47 g of tributylamine, 0.05 g of N-hydroxy-benzotriazole and 0.005 g of 4-dimethylamino-pyridine were dissolved in 10 ml of dimethyl-formamide. With stirring, 0.6 g of dicyclo-hexylcarbodiimide was added in 5 ml of dimethyl-formamide. After 20 minutes stirring at room temperature, a solution o 0.15 g of 1,1-dimethyl-hydrazine in 5 ml of dimethylformamide was added.
Stirring overnight, filtering off the formed dicyclohexylurea and distilltng off the dimethyl-formamide of the filtrate yielded an oily residue. It was dissolved in 25 ml of acetone and 0.85 g of potassium perfluorobutanesulfonate was added. Crude product was obtained as a precipitate and purified by column chromatography on ~P-20 using water as an eluent. The product had a melting point of 242C (dec).

Exam~le 26 [3S-[3a(Z),4~]]-3-t[2-Amino-4-thiazolyl)[[2-[2-(l-pyridinylacetyl)hydrazino]-1,1-dimethyl-2-oxoethoxy]imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, inner salt [3S-[3a(Z),4~]]-3-[[(2-Amino-4-thiazolyl)-[~l-carboxy-l-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (2.18 g), 0.93 g of tributylamine, 0.1 g of N-hydroxybenzo-.

. :. ~......... . :

~Z~S'~3~

triazole and 0.05 g of 4-dimethylaminopyridine were dissolved in 20 ml of dimethylformamide and a solution of 1.06 g of dicyclohexylcarbodiimide in 5 ml of dimethylformamide was added. After stirring for 15 minutes at room temperature, a solution of 0.94 g Girard Reagent P in 20 ml of dimethylformamide was added. After 3 hours of stirring, formed dicyclohexylurea was filtered off and the dimethylformamide of the filtrate was distilled off. Addition of 50 ml of tetrahydro-furan to the residue yielded 1.8 g of crude product, which was purified by column chromato-graphy on HP-20 using water as an eluent, yielding 0.63 g of product, melting point 235C.
ExamDle 27 [3S-[3a(Z),4~]]-3-1[(2-Amino-4-thiazolyl)[[2-[2-[3,4-bis(hydroxy)benzoyl]hydrazino]-1,1-dimethyl-2-oxoethoxy]imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, mono~otassium salt A) 1-13,4-bis(Acetyloxy)benzoyl]-2-[(t-butyloxy)-carbonvl1hvdrazine ~(t-Butyloxy)carbonyl]hydrazine (1.32 g) and 1.01 g of triethylamine were dissolved in lS ml o dichloromethane. At 0C, 2.5 g of 3,4-(diacetyl-oxy)benzoyl chloride dissolved in 10 ml of dichloro-methane was dropped in with stirring. After 2 hours, the dichloromethane was twice extracted with ice water (50 ml portions). The organic layer was dried over sodium sulfate and the ~ solvent evaporated, yielding 2.9 g of the title -~ compound as a white crystalline material, melting ~ 35 point 78-82C.

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

~3S'~35~

B) 1-[3,4-bis(Hydroxy)benzoyl]-2-[(t-butyloxy)-carbonYl hYdrazine 1-[3,4-bis(Acetyloxy)benzoyl]-2-[(t-butyl-oxy)carbonyl]hydrazine (2.6 g) was dissolved in 50 ml of methanol and 5 ml of water. At oC~
ammonia (gas) was bubbled into the solution for 10 minutes. After standing overnight in a refrigerator, the solution was evaporated, and to the remaining oil, 10 ml of dichloromethane was added. This yielded 1.5 g of the title compound, melting point 148C.

C) [3,4-bis(Acetyloxy)benzoyl]hydrazine, trifluoroacetate salt 1-[3,4-bis(~ydroxy)benzoyl]-2-[(t-butyloxy)-carbonyl hydrazine (1.4 gj was stirred in 10 ml of trifluoroacetic acid for 30 minuteg at 5C. The title compound was obtained as a precipitate, which was isolated and washed three times with 10 ml of portions of diethyl ester (anhydrous);
melting point 173C.

D) [35-t3a(Z),4~]]-3-t[(2-Amino-4-thiazolyl)[t2-t2-t3,4-bis(hydroxy)benzoyl}hydrazino]-1,1-dimethyl-2-oxoethoxy]imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic aci~ opotassium salt __ t3,4-bis(Acetyloxy)benzoyl]hydrazine, trifluoroacetate salt was coupled with [3S-[3a(Z), 4~]]-3-[[(2-amino-4-thiazolyl)[(l-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-l-azetidinesulfonic acid using tributylamine, N-hydroxybenzotriazole, dimethylaminopyridine, dicyclohexylcarbodiimide, and potassium perfluoro-butanesulfonate, using the procedure described in 12~35954 previous examples, yielding the title compound, melting point 247C (dec).
H-NMR (200 MHz, DMSO-d6) ~ = 1.38 (d, 3H); 1.42 (d, 6H); 3.35 (s, broad, 2H (H0-)); 3.69 (m, lH);
4.05 (dd, lH); 6.75 (d, lH); 7.25 (m, 3H); 9.32 (d+s, 2H); 10.01 (s, broad, 1~); ppm.
IR(KBr): 1780cm 1 (~-lactam carbonyl) Exam~le 28 t3S-t3a(Z),4~]]-3-tt(2-Amino-4-thiazolyl)[[2-t2-t3,4-bis(hydroxy)benzoyl]hydrazino]-1,1-dimethyl-2-oxoethoxy]imino]acetyl]amino]-4-tt(aminocarbonyl)methyl]thio]-2-oxo-1-azetidine-sulfonic acid, mono~otassium salt Following the procedure of example 27, but substituting [3S-t3a(Z),4~]~-3-tt(2-amino-4-thiazolyl)[(l-carboxy-l-methylethoxy)imino]-acetyl]amino]-4-[t(aminocarbonyl)methyl]thio-2-oxo-1-azetidinesulfonic acid for [3S-[3a(Z),4~]]-3-[[(2-amino-4-thiazolyl)t(l-carboxy-l-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid, yielded the title compound.
Additional compounds falling within the scope of this invention are set forth below.

:::
::

~: :

I Rl R2 R3 R4 0- ~ - N - N-R5 6_ _R7 -~-NH ~ N-S03H , 2N d/

Formula I
Rl/R2 R3 R4/R5 R6 R7 H/H H R -~-NH2 H CH3 H -~-NH2 c~3 H

~ H -q-N~2 ~ CH3 CH3/H H H -C-~-OH H CH3 CH3/~ -NH-N~2 ~ c~3 CH3/CH3 H H -~-N~-~-NH2 H CH3 CH3/C~3 H H -~-NH2 -S-CH2-~C-NH2 H
o 3/CH3 H H -~-NH-CH2- -OH H CH3 O O
CH3/CH3 H H -C-CH2-~-NH2 H CH3 O O
CH3/CH3 H H -~-CH2-C-OH H CH3 O O
Il l CH3/CH3 H H -C-CH2-NH- ~-CH3 H CH3 :

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

~Z85~S~

_44_ GC227 Rl/R2 R3 R4/R5 6 7 o Ol O

CH3/CH3 H H -c-NH-cH2-cH2-NH2 H CH3 OH

CH3/CH3 H H -C-CH2 ~ H H CH3 IH

H/H H H -C ~ H CH3 H
~H

CH3/CH3 H H -C-CH3-O ~ OH H CH3 0~

CH3/CH3 H H -C-NH-NH-~ ~ H H CH3 ~OR

CH3/CH3 H H ~ OH H CH3 OH

CR3/C~3 H =CH ~ H H C~3 O~H

H =CH ~ OH H CH3 H
CH3/CH3 H =C ~ OH H3 H
~H

CH3/CH3 H =CH ~ OH -S-CH2-C-NH2 H
, - , ........ . .. . , ........ :
.':'.'.: - . ' - . ' . .' - .'. .. , : ,. . -

Claims

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

1. A compound having the formula:

wherein R1 and R2 are each independently hy-drogen or alkyl of 1 to 4 carbon atoms, or R1 and R2 together with the carbon atom to which they are attached form a cycloalkyl ring;
R3 is hydrogen or alkyl;
R4 is hydrogen or alkyl; and R5 is hydrogen, alkyl, phenyl, sub-stituted phenyl, a 4, 5, 6 or 7-membered heterocycle, phenyl alkyl, (substituted phenyl)alkyl, (4, 5, 6 or 7-membered heterocyc-, le)alkyl, , , , , , -SO2-Y4, -SO3H or , together R4 and -SO3H or , together R4 and R5 are =CH-Y7; wherein Y1 is hydrogen, alkyl, phenyl, substituted phenyl, methyl-carbonyl, trifluoromethyl-carbonyl, phenylcarbonyl, (substituted phenyl)carbo-nyl, carboxymethyl, methyl-sulfonyl, phenylsulfonyl, (substituted phenyl)sulfo-nyl, aminocarbonyl, amino-carbonylamino, aminoethyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, phenylcarbonylamino, (sub-stituted phenyl)carbonylam-ino, 1-pyrrolidinyl or 1-piperidinyl;
Y2 is hydrogen, alkyl, phenyl, substituted phenyl, a 4, 5, 6 or 7-membered heterocycle, alkoxy, formyl, carbonyl, aminocarbonyl, aminocarbo-thio, methylaminocarbonyl, methylaminocarbothio, tri-fluoromethyl, phenylmethyl, (substituted phenyl)methyl, phenyloxymethyl, (substitu-ted phenyl)oxymethyl, cyano-methyl, hydroxymethyl, alk-oxymethyl, aminomethyl, me-thylcarbonylaminomethyl, am-inocarbonylaminomethyl, me-thylsulfonylaminomethyl, carboxymethyl, aminocarbo-nylmethyl, alkoxycarbonylme-thyl, (4, 5, 6 or 7-membered heterocycle)alkyl, hydroxya-minocarbonylmethyl, or az-idomethyl;
Y3 is amino, alkyl, alkylthio, carboxythio, alkoxycarbonyl-thio or aminocarbonylthio;
Y4 is alkyl, amino, hydroxyam-ino, alkoxyamino, methylcar-bonylamino, or phenylcarbo-nylamino;
Y5 is hydrogen or alkyl;
Y6 is hydrogen, alkyl, carboxy-methyl, or aminocarbonylme-thyl; and Y7 is phenyl or substituted phenyl:

wherein the term "substituted phenyl" means a phenyl group 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;
and the term "a 4, 5, 6, or 7-membered heterocycle"
means pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl, tetrazolyl, azetinyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, imidazolylidinyl, oxazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl, dihydrothiazolyl or hexahydroazepinyl or one of the above groups substituted with one or more oxo, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylsulfonyl, phenyl, substituted phenyl, 2-furylimino, benzylimino or substituted alkyl, wherein the alkyl group has 1 to 4 carbon atoms, groups.

2. A compound in accordance with claim 1 wherein R1 and R2 are each methyl.