CA2036190A1 - 1-carba (dethia) cephalosporin antibiotics - Google Patents

Abstract

Abstract 1-Carba(1-dethia)cephem antibacterial agents possessing a 3-(substituted or unsubstituted)thiazolo group are provided. Further provided is a method for treating bacterial infections in man and other animals and a pharmaceutical formulation utilizing said 1-carba(1-dethia)cephems.

Description

'2~3~

1-CARBA(DETHIA)CEPHALOSPORIN ANTIBIOTICS

In the field of antibacterial therapy, the need for new chemotherapeutic agents is one that will never extinguish. Mutant strains resistant to existing antibacterial agents are encountered frequently. To meet this need, considerable research effort continues to focus on such new agents.
The present invention provides various 3-(substituted or unsubstituted)thiazolo-l-carba(l-dethia)-cephems (i.e., l-carba(1-dethia)cephalosporins) useful as antibacterial agents against both gram-negative and gram-positive bacteria. The present invention provides 7~-(acylamino-1-carba(1-dethia) 3-substituted-3-cephem-4-carboxylic acids wherein the group at the 3-position is a 4-thiazole ring optionally substituted in the 2-position by nitro, cyano, phenyl, amino, halo, C1-C6 alkyl, C1-C6 substituted alkyl, an optionally-substi-tuted heterocyclic ring, substituted phenyl, or an acyl group. Also provided are novel 7-amino intermediates useful in the preparation of the compounds of the present invention. Also provided is a pharmaceutical 2 ~ 9 ~

formulation utilizing the compounds of the present invention and a method for treating antibacterial infections in man an other animals.
The present invention provides compounds of Formula (1):

Rl-N
,~ X (1) wherein X i9 a group selected from amino, halo, cyano, lS hydrogen, nitro, C1-C6 alkyl, C1-C6 substituted alkyl, a C3 to C6 heterocyclic ring containing 1, 2, or 3 nitrogen atoms and 0 or 1 sulfur or oxygen atoms, said ring optionally substituted by one or more groups selected from halo, nitro, hydroxy, C1-C6 alkyl, or Cl-C6 substituted alkyl;
phenyl, substituted phenyl or an acyl group of the formula O
Il R"C-, wherein R" is C1-C6 alkyl, C1-C6 substituted alkyl, phenyl, or substituted phenyl;
R3 is hydrogen, C1-C4 alkoxy, or a group of the formula -NHCH0; and R1 is an acyl group of the formula R2-C-, wherein R2 is hydrogen; Cl-C6 alkyl, C1-C6 alkyl substituted by cyano, carboxy, halogen, amino, C1-C4 alkoxy, Cl-C4 alkylthio, or trifluoromethylthio; a phenyl or substituted phenyl group represented by the formula a a''' ~

wherein a and a' independently are hydrogen, halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkanoyloxy, C1-C4 alkyl, C1-C4 alkylthio, amino, mono- or di(C1-C4 alkyl)amino, C1-C4 alkanoylamino, C1-C4 alkylsulfonylamino, carboxy, carbamoyl, hydroxymethyl, amino-methyl, or carboxymethyl;
a group represented by the formula <,~(Z)m- CH2--wherein a and a' have the same meanings as defined above, Z is 0 or S, and m is 0 or 1;
. .
a heteroarylmethyl group represented by the formula R~-CH2-wherein R1 is thienyl, furyl, benæothienyl, benzofuryl, indolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, and such heteroaryl groups substituted by 2~5~

amino, hydroxy, halogen, C1-C4 alkyl, Cl-C4 alkoxy, C1-C4 alkylsulfonylamino;
a substituted methyl group represented by the formula Q

wherein R2 is cyclohex-1,4-dienyl, or a phenyl group or substituted phenyl group represented by the formula a a~

wherein a and a' have the above defined meanings, or R2 is Rl as defined above, and Q is hydroxy, Cl-C4 alkanoyloxy, carboxy sulfo, or amino;
or R2 is a keto group or an oximino-substituted group represented by the formulae O N

wherein R3 is R1 or R2 as defined above and R4 is hydrogen, C1-C4 alkyl, or a group repre-sented by the formula :

-C-(CH2 ~nCOR5 b' wherein b and b' independently are hydrogen, or C1-C3 alkyl, and b and b' when taken together with the carbon to which they are bonded form a 3- to 6-membered carbocyclic ring, R5 is hydroxy, C1-C4 alkoxy, amino, C1-C4 alkyl-amino, or di(C1-C4 alkyl)amino, and n is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.
In the above Formula (1), one preferred R2 group is a keto group or an oximino-substituted group represented by the formulae O N

wherein R3 is Rl or R2 as defined above and R4 is hydrogen, Cl-C4 alkyl, or a group repre-sented by the formula b -C- ( CH2 ~nCORs wherein b and b' independently are hydrogen, : or Cl-C3 alkyl, and b and b' when taken together with the carbon to which they are bonded form 2~3~9~

a 3- to 6-membered carbocyclic ring, R5 y, C1 C4 alkoxy, amino, C1-C alkyl amino, or di(C1-C4 alkyl)amino, and n is 0, 1, 2, or 3.

A preferred Rl group is (2-aminothiazol-4-yl)methoximinoacetyl.
A further preferred R2 group is a substituted methyl group represented by the formula Rp-CH-Q
wherein R2 is cyclohex-1,4-dienyl, or a phenyl group or substituted phenyl group represented by the formula a ~ ~
<~ \~
a' ~

wherein a and a' have the above defined meanings, or R2 is R1 as defined above, and Q is hydroxy, C1-C4 alkanoyloxy, carboxy, sulfo, or amino.

A preferred R1 group is D-phenyl-glycyl.
As a further aspect of the present invention, there are provided intermediates of Formula (2) 2~3~

R1 b~
O ~ ~ X (2) wherein: Rl' is hydrogen or an amino protecting group;
R4 is hydrogen or a carboxy protecting group;
R3' is hydrogen, Cl-C4 alkoxy, or a group of the formula -NHCHO; and X is a group selected from amino, halo, cyano, hydrogen, nitro, Cl-C6 alkyl, Cl-C6 substituted alkyl, a C3 to C6 heterocyclic ring containing 1, 2, or 3 nitrogens and 0, or 1 sulfur or oxygen atoms, said ring optionally substituted by one or more groups selected from halo, nitro, hydroxy, Cl-C6 alkyl, or Cl-C6 substituted alkyl;
phenyl, substituted phenyl, or an acyl group of the formula o : R' " C-, wherein R " ' is Cl-C6 alkyl, Cl-C6 substituted ` alkyl, phenyl, or substituted phenyl. The compounds of formula (2) are useful as intermediates to the anti-bacterial agents of formula (1) In the above Formula (1), the term "Cl to C6 alkyl" denotes such radicals as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, tert-amyl, hexyl and the like. The preferred "Cl to C6alkyl" group is methyl.

The term "C1 to C6 substituted alkyl" denotes the above Cl to C6 alkyl groups that are substituted by one or two halogen, hydroxy, protected hydroxy, amino, protected amino, Cl to C7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carbamoyloxy, cyano, methylsulfonylamino, C1 to C4 alkoxy, phenyl, sub-stituted phenyl, or a C3 to C6 heterocyclic ring containing l, 2, or 3 nitrogen atoms and O or 1 sulfur or oxygen atoms, said ring optionally substituted by one or more groups selected from halo, nitro, hydroxy, or C1-C6 alkyl. The substituted alkyl groups may be substituted once or twice with the same or with different substituents.
Examples of the above substituted alkyl groups include cyanomethyl, nitromethyl, hydroxymethyl, trityl-oxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, allyloxycarbonylmethyl, allyloxycarbonylaminomethyl, carbamoyloxymethyl, methoxymethyl, ethoxymethyl, t-butoxy methyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, 6-hydroxyhexyl, 2,4-dichloro(n-butyl), 2-amino(iso-propyl), 2-carbamoyloxyethyl chloroethyl, bromoethyl, fluoroethyl, iodoethyl, chloropropyl, bromopropyl, fluoropropyl, iodopropyl, phenylmethyl, phenylethyl, phenyl (3-pyridyl)methyl, phenyl(3-pyridyl)ethyl, and the like.
The term "C1 to Cg alkoxy" as used hereindenotes groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups.
The term "substituted phenyl" as used herein denotes a phenyl group substituted with one or two moieties chosen from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, C1 to C6 alkyl, C1 to C~ alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, aminomethyl, protected aminomethyl, trifluoromethyl or N-(methylsulfonylamino).
Examples of the term "substituted phenyl"
include a mono- or di(halo)phenyl group such as 4-chloro-phenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromo-phenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl and the like; a mono- or di(hydroxy)phenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 3-or 4-nitrophenyl; a cyanophenyl group, for example, 4-cyanophenyl; a mono- or di(lower alkyl)phenyl group such as 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl, 4-(iso-propyl)phenyl, 4-ethylphenyl, 3-~n-propyl)phenyl and the like; a mono- or di(alkoxy)phenyl group, for example, 2,6-dimethoxyphenyl, 4-methoxyphenyl, 3-ethoxy-phenyl, 4-(iso-propoxy)phenyl, 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 3- or 4- tri-fluoromethylphenyl; a mono- or dicarboxyphenyl or (protected carboxy)phenyl group such as 4-carboxyphenyl or 2,4-di(protected carboxy)phenyl; a mono- or di-(hydroxymethyl)phenyl or (protected hydroxymethyl)-phenyl such as 3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)-phenyl or (protected aminomethyl)phenyl such as 2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)-phenyl; or a mono- or di(N-(methylsulfonylaminol)phenyl such as 3-(N-(methylsulfonylamino))phenyl. Also, the 9 ~

term "substituted phenyl" represents disubstituted phenyl groups wherein the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl and the like. Preferred substituted phenyl groups include the 2- and 3-trifluoromethylphenyl, the 4-hydroxyphenyl, the 2-aminomethylphenyl and the 3-(N-(methylsulfonylamino))phenyl groups.
The terms "halo" and "halogen" refer to the fluoro, chloro, bromo or iodo groups.
The term "pharmaceutically-acceptable salt"
encompasses those salts that form with the carboxylate anions and includes salts formed with the organic and inorganic cations discussed above. Furthermore, the term includes salts that form by standard acid-base reactions with basic groups (such as amino groups) and organic or inorganic acids. Such acids include hydro-chloric, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D-glutamic, d-camphoric, glutaric, phthalic, tartaric, lauric, stearic, salicyclic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic, and like acids.
The term "carboxy-protecting group" as used herein refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound.
Examples of such carboxylic acid protecting groups 2 ~

include 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxy-benzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylene-dioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4 "-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, ~-(trimethylsilyl)ethyl, ~-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-1-en-3-yl, and like moieties. The species of carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the condition of subsequent reaction(s) on other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. In particular, it is important not to subject the carboxy-protected molecule to stxong nucleophilic bases or reductive conditions employing highly activated metal catalysts such as Raney nickel. (Such harsh removal conditions are also to be avoided when removing amino-protecting groups discussed below.) A preferred carboxylic acid protecting group is the allyl group. Similar carboxy-protecting groups used in the cephalosporin, penicillin and peptide arts can also be used to protect a carboxy group substituents~
Further examples of these groups are found in E. Haslam, "Protective Groups in Organic Chemistry", J.G.W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1981, Chapter 5.

~ $ ~

X-79~7A - 12 -A related term is "protected carboxy", which refers to a carboxy group substituted with one of the above carboxy-protecting groups.
The term "amino-protecting group" as used herein refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups on the compound. Examples of such amino-protecting groups include the formyl group, the trityl group, the t-butoxycarbonyl group, the phthalimido group, the trichloroacetyl group, the chloroacetyl, bromoacetyl and iodoacetyl groups, urethane-type blocking groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 2-(4-xenyl)iso-propoxycar-bonyl, l,l-diphenyleth-1-yloxycarbonyl, 1,1-diphenyl-prop-l-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-~p-toluyI)prop-2-yloxycarbonyl, cyclopentanyloxy-carbonyl, 1-methylcyclopentanyloxycarbonyl, cyclo-hexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)-ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, 9-fluorenyl-methoxycarbonyl ("FMOC"), 2-(trimethylsilyl)ethoxy-carbonyl, allyloxycarbonyl, l-(trimethylsilylmethyl)-prop-l-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxy-carbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropyl-2 ~

methoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl, iso-bornyloxycarbonyl, 1-piperidyloxycarbonyl and the like;
the benzoylmethylsulfonyl group, the 2-(nitro)phenyl-sulfenyl group, the diphenylphosphine oxide group and like amino-protecting groups. The species of amino-protecting group employed is not critical so long as the derivatized amino group is stable to the condition of subsequent reaction(s) on other positions of the mole-cule and can be removed at the appropriate point without disrupting the remainder of the molecule. Preferred amino-protecting groups are the allyloxycarbonyl, the t-butoxycarbonyl, and the trityl groups. Similar amino-protecting groups used in the cephalosporin, penicillin and peptide art are also embraced by the above terms. Further examples of groups referred to by the above terms are described by J.W. Barton, "Pro-tective Groups In Organic Chemistry", J.G.W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 2, and T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1981, Chapter 7.
The related term "protected amino" defines an amino group substituted with an amino-protecting group dis-cussed above.
In Formulae (1) and (2) above, when X is a C3-C6 heterocyclic ring containing 1, 2, or 3 nitrogen atoms and 0 or 1 sulfur or oxygen atoms, (i.e., a heterocyclic ring containing from 3 to 6 carbon atoms, 1, 2, or 3 nitrogen atoms and 0 or 1 sulfur or oxygen atoms) said ring optionally substituted by one or more halo, nitro, hydroxy, C1-Cff alkyl, or Cl-C6 substituted alkyl groups, examples of such rings include pyrrolyl, furanyl, 4-nitrothiazol-2-yl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, morpholinyl, oxazolyl, thiazolyl, 203~3~

thiadiazolyl, oxadiazolyl, l-methyl-3-pyridyl, 2-methyl-3-pyridyl, 3-methyl-4-nitro-imidazol-2-yl, and the like.
One intermediate (VI) can be prepared according to the following Scheme (A) OCH2CNH~

~L Cf~
CO2CH2 ~NO2 I~i, ~ OCH2CN
H~ ~
l CH2 o _N~ 11 OCH2CH, co2CH2 ~N2 l ~U) OCH2CNH~

~N ~ tOCH2CH3 2 5 C02CH2 ~N2 o l~lU~

3 0 ~ OCH*
N~,_~
OCH2CH~
~OCH*H3 ~ [V) CO2CH2 ~3No7 ' :

~3~

X-7967A - lS -o OCH2CN~ ~

FIN~ j~CH~ (V) CO2CH2 ~NO~
I~v~

+ ~CH2CNH~

~N~CI12Elr ~Vl) C0*H2 aNO2 I ~vi~

According to Scheme A, p-NO2 benzyl-7~-phenoxy-acetylamino-l-carba(l-dethia)-3-trifluoromethanesulfonyl-oxy-3-cephem-4-carboxylate (which can be prepared according to the method of Evans et al., U.S. Patent No. 4,673,737, incorporated herein by reference) is reacted with a compound of the formula CH2=C(OCH2CH3)-(Sn(X)3), wherein X is methyl or n-butyl, LiCl, and . - (CH3CN~2PdCl2 in a polar organic solvent, preferably N,N'-dimethylformamide to provide (II~. Further details of this type of transformation can be found in Cook et al. U.S. Patent No. 4,855,418, incorporated herein by reference. Compound (II~ can then be converted to the 3-(2-bromo-1,1-diethoxyethyl~ compound (III) with Br2/CCl4 in ethanol/CH2Cl2 using a base such as 2,6-lutidine.
Reactions (iii) and (iv) depict a methodwhereby the 7-phenoxyacetyl group may be replaced by the t-butoxycarbonyl group. First, compound (III) is ~.

~3~

acylated with di-tert-butoxydicarbonate in the presence of a base such as dimethylaminopyridine.
Secondly, the phenoxyacetyl group is displaced with a base such as LioH in a polar solvent such as tetrahydrofuran. Further description of this exchange can be found in Blaszczak et al., European Patent Appli-cation No. 88306996.5.
Finally, the 3-bromomethylcarbonyl compound (VI) can then be prepared from compound V by an acid catalyzed hydrolysis reaction with, for example, acetic acid in acetonitrile/water.
Compounds of Formula (1) can then be made from intermediate (VI) above by the following Scheme (B):

ol + OCH2CNH~r~

--N~ CH2Bt ( Vl ) COqCU2 aNO2 'I (vi) ~ OCH2CNH ~
p ~ ~ ~v~) COqCH2 ~NO2 (V~i) + OCH2CNH~

O

I

2 ~3 ~
X-7967A - 17 - ~

R1-NH ~
~ N ~ ~ X

In the above step (vi), the 3-(2-substituted) thiazolo compounds may be synthesized by reaction of intermediate (VI) with a compound of the formula S

Il H2N-C-X, wherein X is as defined in Formula 1, above. Thus, with the desired 3-(2-substituted thiazol-4-yl) sub-stituent in place, and with the de-esterification of the 4-p-nitrobenzyl ester occasionally occurring under the previously defined reaction conditions, the 4-carboxy position may be re-esterified to the 4-allyl ester using allyl bromide, NaI, (CH3CH2CH2CH2)4NHS04, and NaHCO3 in N,N'-dimethylformamide. If deesterifi-cation does not occur under these conditions, the p-nitrobenzyl protecting group may be removed by zinc reduction in a solvent mixture of N,N'-dimethyl-formamide/tetrahydrofuran/acetic acid or N,N'-dimethyl-formamide/tetrahydrofuran in HCl and reesterified as described above to the 4-allyl ester. The resulting amino protected, carboxy protected "nucleus" (i.e., formula (2)) can then be treated with p-toluenesulfonic acid H2O or trifluoroacetic acid to remove the 7-t-butoxycarbonyl group to provide the 7-amino 4-carboxy 2~3~

protected intermediate. Further, the 7-amino group can then be acylated with an activated form of the desired R1 substituent using standard procedures well-known in the ~-lactam art. Finally, all remaining amino and~or carboxy protecting groups can then be removed using conventional methodology.
The 7~-acylamino-7~-substituted-l-carbacephalo-sporins represented by Formula (1) wherein R3 is C1-C~
alkoxy can be prepared according to the method described by Koppel, U.S. Patent No. 3,994,885, incorporated herein by reference.
T~e 7~-formamido substituted compounds wherein R3 is -NHCHO can be obtained by the method described by Millner, U.S. Patent No. 4,539,159 incorporated herein by reference. According to this method, a 7~-acylamino-or 7~-protected amino-7~-methylthio-substituted 1-carbacephalosporin is reacted with anhydrous ammonia or an ammonium salt in the presence of mercuric acetate to form the corresponding 7~-amino derivative. The latter is formylated to the 7a-formamido derivative.
One skilled in the art will appreciate that although the above manipulations utilized phenoxyacetyl and t-butyloxycarbonyl as amino protecting groups and the p-nitrobenzyl group as carboxy-protecting group, there are many which would be equally efficacious.
The 1-carbacephalosporins provided by the invention form salts with suitable bases, in partic-ular, the pharmaceutically-acceptable, non-toxic salts.
The C-4 carboxy group of the 1-carbacephalosporin can form salts with the alkali and alkaline earth metal hydroxides, carbonates and bicarbonates. Examples of such pharmaceutically-acceptable salts are the sodium, 2~6~ ~

potassium, calcium and magnesium salts. Salts also may be formed with amines such as dibenzylamine, cyclohexyl-amine, triethylamine, ethanolamine, di-ethanolamine and like amines. Likewise, when the 1-carbacephalosporin is substituted by two or more carboxy groups, di- and tri-salts are obtained by conventional salt-forming methods.
The pharmaceutically-acceptable, non-toxic salts can be useful forms of the antibiotics for pre-paring antibiotic formulations.
This invention also provides a method for - treating infectious diseases in man and other animals caused by bacteria and pharmaceutical formulations suitable for administration in the treatment method.
The therapeutic method of this invention comprises administering to man or other animals an antibiotically effective non-toxic dose of a compound represented by Formula (1) or a pharmaceutically acceptable salt thereof.
An antibiotically effective amount is an amount between about 25 mg and about 2 grams. The compound or salt may be administered in a single . dose or in multiple doses throughout the day. Treat-ment may continue for a week to ten days or longer depending upon the duration of the infection. The particular dose and regimen can depend on such factors as the weight and age of the patient, the particular causative organism, the severity of the infection, the general health of the patient, and the tolerance of the individual to the antibiotic.

9 ~

The l-carbacephalosporins may be administered parenterally, orally, subcutaneously or rectally. AS
with other ~-lactam antibiotics, the method of this invention may be used prophylactically to prevent infections after exposure or before possible exposure, e.g., preoperatively. The antibiotic 1-carbaceph-alosporins may be administered by conventional methods, e.g., in capsules, tablets, by syringe, or by intra-venous drip.
The pharmaceutical formulations of the inven-tion comprise an antibiotically effective non-toxic amount of a l-carbacephalosporin represented by Formula (1) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Formulations for oral administration include capsules, tablets, lozenges and liquid suspensions.
The antibiotic or a salt thereof in the form of a dry powder can be encapsulated in gelatin capsules for oral use. The antibiotic may also be blended with an excipient, e.g., a stabilizer, prior to filling.
Capsules may contain between about 100 mg and about 500 mg to provide unit dosage formulations.
Tablets containing between about 100 mg and 500 mg of the antibiotic or a pharmaceutically accept-able salt thereof can be formulated by conventionalmeanæ and may contain in addition a binding agent, disintegrating agent, stabilizing agent, antioxidant, etc.
Liquid preparations of the antibiotic may be prepared for infant and geriatric use. Pediatric sus-pensions can be formulated with the antibiotic oral 2 ~ 3 ~

excipients such as suspending agents, flavoring agents, stabilizers and the like. Solutions of the antibiotics likewise may be formulated with solubilizing agents, flavoring agents, sugar, water, etc.
Parenteral formulations of the antibiotics for injection are formulated with Water-for-Injection, Ringer's solution, physiological saline or glucose solution. The antibiotic also may be administered in an intravenous fluid by the drip method.
For parenteral use, the antibiotic or a phar-maceutically acceptable salt thereof, can be made up preferably in dry crystalline powder form or as a lyophilized powder and filled into vials. Such vials may contain between about 100 mg and about 2 grams of antibiotic per vial.
The following Experimental Section provides further examples of the various aspects of the present invention but is not to be construed as limiting the scope therefor.
Experimental Section . Preparation 1 p-Nitrobenzyl 7~-phenoxyacetylamido-1-carba(l-dethia)-3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylate The title compound can be prepared according to the method of Evans and Sjogren, U.S. Patent No.
4,673,737, incorporated herein by reference.

~3~

PreParation 2 Trimethyl(l-ethoxy-e~hen-l-yl)stannane (Ref: Organometallics, Vol. 1, No. 6, 1982, J.
Soderquist) A 19.18 ml (14.48 g, 200.36 mmol) sample of ethoxyethylene was dissolved in 100 ml of tetrahydrofuran, cooled to -78C, and treated with a solution of t-butyl-lithium (94.1 ml, 150.56 mmol, 1.6M) over 20 min. under argon. The reaction mixture was then allowed to warm to 0C over 35 min. and added via cannula to a -78C
solution of 20.0 g (100.4 mmol) of chlorotrimethyi-stannane in 40 ml of tetrahydrofuran and allowed to warm to room temperature gradually. After an additional 50 min., the mixture was guenched with saturated NH4Cl solution (400 ml) and extracted with diethyl ether (500 ml). The ether solution was then dried over anhydrous Na2SO4, filtered and concentrated to provide the crude product as a yellowish liquid (23.8 g; 100%). The crude product was then distilled at 40-41C and about 4 mm Hg to provide 12.05 g of the title compound.

lH NMR (300 MHz, CDCl3) ~4.65 (s, lH), 4.10 (s, lH), 3.70 (g, 2H), 1.25 (t, 3H~, and 0.18 (s, 9H).

2 ~

Preparation 3 p-Nitrobenzyl 7~-phenoxyacetylamino-1-carba(l-dethia)-3-(l-ethoxy-ethen-1-yl)-3-cephem-4-carboxylate.

A 1.0 g (1.77 mmol) sample of the title compound of Preparation 1, a 0.142 g (3.34 mmol) sample of lithium chloride, and a 0.043 g (0.167 mmol) sample of dichloropalladium (II) diacetonitrilate were dissolved in 3 ml of dimethylformamide and treated with 0.435 g (1.84 mmol) of trimethyl (l-ethoxy-ethen-l-yl)stannane.
The reaction was then gently warmed with a hot air gun for about 10 seconds, and allowed to stir at room temperature for about one hour. The reaction mixture was poured into 100 ml 1:1 mixture of ethyl acetate/
diethyl ether and 100 ml 10:1 mixture Brine/satd.
NaHCO3 solution. Organics were separated and dried over Na2SO4, filtered, and concentrated ln vacuo. Resultant crude dark oil was then diluted with 2 ml CH2Cl2 and 5 ml diethyl ether and 20 ml of hexane. A dark oil again resulted. Supernatant was decanted and to it was added an additional 40 ml hexane. Desired precipitated as a solid which was filtered and washed with hexane and dried to give 87 mg of the desired compound. The dark oil was chromatographed on 50 g of silica gel using 15-25% ethyl acetate/CH2Cl2 as eluent. The resulting product fractions were concentrated ln vacuo and treated with ~0 ml Et2O to provide 550 mg of the title compound (total yield 637 mg, 74%).

~3~L~

lH NMR: (300 MHz, CDC13) ~8.20 (d, J= 9Hz, 2H), 7.60 (d, J= 9Hz, 2H), 7.35 (t, J= 8Hz, 2H), 7.10 (m, 2H~, 6.90 (d, J= 8Ez, 2H), 5.45 (dd, J= 5,7Hz, lH), 5.37 (AB, 2H), 4.58 (S, 2H), 4.21 (d, J= 3 Hz, lH), 4.18 (d, J= 3Hz, lH), 3.95 (m, lH), 3.75 (m, 2H), 2~70 (dd, J= 4, 18Hz, lH), 2.30 (m, lH), 2.05 (m, lH), 1.50 (m, lH) and 1.25 (t, J= 7Hz, 3H) IR: (CHCl3) 3028, 1772, 1734, 1691, 1524, 1496, 1389, 1299, 1277, and 1207 cm 1 MS: m/e 521 (M ) Analysis Calculated for C27H27N3O8:
Calc.: C, 62.18i H, 5.22; N, 8.06;
Found: C, 62.43; H, 5.36; N, 8.30.

Preparation 4 p-Nitrobenzyl 7~-phenoxyacetylamino-1-carba(l-dethia)-3-(2-bromo-1,1-diethoxyethyl)-3-cephem-4-carboxylate A 570 mg sample of the material from Prepara-tion 4 was dissolved in 4.5 ml of ethanol/2 ml of CH2Cl2 and cooled to 0C. The solution was then treated with 0.153 ml (1.312 mmol) of 2,6-lutidine and 1.1 ml (1.1 mmol) of a 1.0 M Br2/CCl4 solution. The resulting mixture was then poured into a mixture of saturated sodium bicarbonate solution and 1:1 ethyl acetate/diethyl ether. The organic layer was separated, dried over 2 ~ 3 i~

anhydrous Na2S0~, filtered, and concentrated to provide a yellow foam which was used directly in the next step.
A 25 mg sample of the above product was purified over a silica gel (2.5 g) column using 7%
ethyl acetate/CH2Cl2 as eluent to provide 20 mg of the title compound.

lH NMR (300 NHz, CDCl3) ~8.23 (d, J= 9Hz, 2H), 7.60 (d, J= 9Hz, 2H) 7.35 (t, J= 8Hz, 2H), 7.10 (m, 2H), 6.95 (d, J= 8Hz, 2H), 5.35 (AB, 2H) 5.32 (dd, J= 5, 7Hz, lH), 4.58 (s, 2H), 3.95 (m, lH) 3.3-3.6 (2m, 4H), 2.48 (dd, J= 2, 16Hz, lH), 2.20 (m, lH) 2.05 (m, lH) 1.45 (m, lH) 1.16 (t, J= 4Hz, 3H) and 1.10 (t, J= 4Hz, 3H) IR: (CHCl3) 3019, 1772, 1751, 1749, 1695, 1349, 1290, }206 and 1073 cm 1 MS: m/e 646 (M + 1) Analysis Calculated for CpgH32N309Br:
Calc.: C, 53.88; H, 4.99; N, 6.50;
Found: C, 53.59; H, 4.75; N, 6.77.
., Preparation 5 p-Nitrobenzyl 7~-phenoxyacetyl-t-butyloxycarbonylamino-l-carba(l-dethia)-3-(2-bromo-1,1-diethoxy)-3-cephem-4-carboxylate A 700 mg sample of the product of preparation 4 ~as dissolved in 10 ml of CH2C12 at room temperature 2 ~ 3 ~

and treated with 0.256 ml (1.126 mmol) of di-tert-butyl dicarbonate, followed by 132 mg (1.08 mmol) of 4-dimethylaminopyridine and stirring for 30 min. An additional 50 ~1 of di-tert-butyl dicarbonate was added and the reaction stirred for about 30 min. The reaction mixture was chromatographed directly over a silica gel column (40 g) using 20-30% ethyl acetate/CH2Cl2 as eluent to provide 730 mg (90.5%) of the title compound.

lH NMR: (300 MHz, CDCl3) ~8.23 (d, J= 9Hz, 2H), 7.62 (d, J= 9Hz, 2H), 7.30 (t, J= 8Hz, 2H), 7.0 (m, 2H), 6.95 (d, J= 8Hz, 2H~, 5.70 (d, J= 4Hz, lH~, 5.35 (AB, 2H), 5.18 (d, J= 3Hz, 2H), 3.86 (m, lH), 3.35-3.7 (m, 4H), 2.5 (dd, J= 2, 18Hz, lH), 2.18 (m, lH), 1.85 (m, lH) 1.55 (s, 9H) 1.50 (m, lH) 1.16 (t, J= 4Hz, 3H) and 1.10 (t, J= 4Hz, 3H) IR: (CHCl3) 3019, 1791, 1747, 1349, 1226, 1205, and 1145 cm~l MS: m/e 672 (M -OC4Hg) Analysis Calculated for C34H40N3O11Br:
Calc.: C, 54.70; H, 5.40; N, 5.63;
Found: C, 53.55; H, 4.48, N, 6.42.

2~3~9~

Preparation 6 p-Nitrobenzyl 7~-t-butyloxycarbonylamino-1-carba (l-dethia)-3-(2-bromo-1,1-diethoxyethyl-3-cephem-4-carboxylate A 750 mg (O.957 mmol) sample of the product of Preparation 5 was dissolved in 8 ml of tetrahydro-furan, treated with 0.85 ml (0.85 mmol) of 1.0 M
lithium hydroxide soln. and sonicated. A further 0.155 ml portion of lithium hydroxide was added and sonication continued for 30 min. The reaction mixture was then poured into 50 ml of saturated sodium bicarbonate/75 ml ethyl acetate solution. The organic phase was separated and dried over anhydrous Na2 S04, filtered, and concen-trated to provide 410 mg of the product as a foam after column chromatography over silica gel (8% ethyl acetate/
CH2Cl2 ) -The above chromatography provided 176 mg of starting material which was re-submitted to the above conditions to obtain 102 mg of the title compound.
Total yield = 512 mg (86.6%).

1~ NMR: (300 MHz, CDCl3) ~8.23 (d, J= 9Hz, 2H), 7.61 (d, J= 9Hz, 2H), 5.35 (AB, 2H), 5.01 (m, lH), 5.09 (m, lH), 3.85 (m, lH), 3.3-3.6 (m, 4H), 2.47 (dd, J= 2, 16Hz, lH), 2.20 (m, lH), 2.10 (m, lH), 1.43 (s, 9H), 1.12 (t, J= 4Hz, 3H), and 1.08 (t, J= 4Hz, 3H) IR: (CHCl3) 1769, 1741, 1716, 1524, 1349, 1224, 1207, and 1160 cm 1 ~ ~ 3 ~

MS: 611 (M ) Analysis Calculated for C2 6H3~N3OgBr:
Calc.: C, 50.99; H, 5.60; N, 6.86;
Found: C, 51.99; H, 5.16; N, 7.67.

Preparation 7 p-Nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-bromomethylcarbonyl)-3-cephem-4-carboxylate A 125 mg (0.204 mmol) sample of the product of Preparation 6 was dissolved in 1.2 ml of acetonitrile/
0.25 ml of acetic acid/0.05 ml H2O and stirred for about 2 hours. The reaction mixture was then poured into ~50 ml) saturated sodium bicarbonate solution/(100 ml) 1:1 ethyl acetate/diethyl ether solution. The organic phase was separated, dried over anhydrous Na2SO4, filtered, and concentrated to provide 111 mg (about 100%) of the title compound as a white solid.

1H NMR: (300 MHz, CDCl3) ~8.20 (d, J= 9Hz, 2H), 7.62 (d, J= 9Hz, 2H), 5.33 (AB, 2H), 5.28 (dd, J= 4,7Hz, lH), 5.25 (d, J= 4Hz, lH), 4.03 (AB, 2H), 3.87 (m, lH), 2.80 (dd, J= 4,18Hz, lH), 2.45 (m, lH), 2.13 (m, lH) 1.57 (m, lH), and 1.4 (s, 9H) IR: (CHCl3) 3019, 1782, 1718, 1525, 1369, 1291, and 1159 cm 1 MS: m/e 480 (M+-C4Hg) Analysis Calculated for C22H24N3O8Br:
Calc.: C, 49.08; H, 4.49; N, 7.81;
Found: C, 49.29; H, 4.64; N, 7.62.

ExamPle 1 7~-t-butoxycarbonylamino-1-carba(1-dethia)-3-(2-phenyl-thiazolo)-3-cephem-4-carboxylic acid A 75 mg (0.140 mmol) sample of p-nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(1-dethia)-3-bromo-methylcarbonyl)-3-cephem-4-carboxylate (Preparation 7) was dissolved in 1.5 ml of isopropanol and 1 ml of 1,1,2-trichloroethane, followed by the addition of 20 mg (0.146 mmol) of phenylthiocarbamate. The reaction mixture was then heated to about 65C for 1.5 hours.
The reaction mixture was concentrated ln vacuo and treated with 3 ml of diethyl ether/4 ml hexane. The resulting solid (85% yield) was dried to provide the title compound.
Example 2 7,B-t-butoxycarbonylamino-l-carba(l-dethia)-3-(2-(4-NO2-- 3-methylimidazol-2-yl)-thiazol-4-yl-3-cephem-4-carboxylic acid A 127 mg sample of p-nitrobenzyl 7~-t-butoxy-carbonylamino-1-carba(1-dethia)-3-bromomethylcarbonyl-4-carboxylic acid was reacted with 4-NO2-3-methyl imidazolo thiocarbamate in a manner analogous to that of Example 1. Column chromatography ethylacetate/CH2Cl2 with a trace of acetic acid provided 85 mg of the title compound.

Example 3 p-Nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-(phenyl)(2-pyridyl)methylthiazol-4-yl)-3-cephem-4-carboxylate The title compound was prepared in a manner analogous to that of Example 1 (without deesterification) utilizing phenyl-2-pyridylthiocarbamate 710 mg (97.3%) lH NMR: (300 MHz, CDC13) ~8.60 (dd, J= 4, 9Hz, lH), 8.05 (d, J= 9Hz, 2H), 7.60 (m, 9H), 5.83 (d, J= 4Hz, lH), 5.15 (m, 3H), 4.70 (m, lH), 3.90 (m, lH), 2.92 (dd, J= 4, 18Hz, lH), 2.50 (m, lH), 2.20 (m, lH) 1.70 (m, lH) and 1.~8 (s~ 9H) Example 4 7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-phenylthiazol-4-yl)-3-cephem-4-carboxylic acid A 430 mg (0.746 mmol) sample of p-nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-phenyl-thiazol-4-yl)-3-cephem-4-carboxylate was dissolved in 5 ml dimethylformamide/6 ml tetrahydrofuran/4 ml acetic acid along with 200 mg (2.98 mmol) of Zn. Upon comple-tion, the reaction mixture was diluted with CH2Cl2 and filtered through filter (celite) aid. The organic phase was then washed sequentially with H2O, lN HCl, and NaHCO3 solution. The NaHCO3 solution was layered with CH2Cl2, acidified to a pH of 2. The CH2Cl2 layer was separated and the aqueous portion extracted with CH2C12.

2 ~ a The combined CH2Cl2 portions were dried over anhydrous Na2SO4, filtered, and concentrated. Crystallization over diethyl ether/hexane provided 270 mg (82.3%) of the title compound.

Example 5 p-Nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-aminothiazol-4-yl)-3-cephem-4-carboxylate A 600 mg (1.115 mmol) sample of p-nitrobenzyl-7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(bromo-methylcarbonyl)-3-cephem-4-carboxylate was dissolved in 15 ml of isopropanol/10 ml 1,1,2-trichloroethane along with 0.146 ~1.25 mmol) of 2,6-lutidine followed by 88.4 15 mg (1.16 mmol) of thiourea. -Workup analogous to that described above provided 220 mg of the title compound.

lH NMR: (300 MHz, CDCl3) 88.22 (m, 2H), 6.90 (m, lH), 6.58 (m, lH) 6.10 (s, 2H) 5.35 (m, 3H), 3.85 (m, lH), 2.85 (m, lH), 2.58 ~m, lH), 2.40 (m, lH), 1.80 (m, lH), and 1.45 (s, 9H) ExamPle 6 p-Nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-(2,3-dihydroxyphenyl)thiazol-4-yl)-3-cephem-4-carboxylate In a manner analogous to preceding examples, 3,4-dihydroxyphenylthiocarbamate was utilized to provide the title compound (380 mg).

2~3~

lH NMR: (300 ~Hz, CDCl3) ~7.90 (m, 2H), 7.40 (m, lH), 7.12 (m, 3H), 6.98 (s, lH), 6.84 (m, lH), 5.20 (m, 4H), 4.05 (m, lH), 2.84 (dd, J= 4, 18Hz, 1~) 2.35 (m, lH), 2.15 (m, lH), 1.75 (m, lH), and 1.45 (s, 9H) Example 7 p-Nitrobenzyl 7~-t-butoxycarbonyl-l-carba(l-dethia)-3-(2-(2,3-di-(t-butyldimethylsilyloxy)phenyl)thiazol-4-yl~-3-cephem-4-carboxylate A 370 mg sample of the compound produced in Example 6 above was dissolved in 4 ml of dimethyl-formamide and treated with 184 mg of t-butyldimethyl-silylchloride and 85 mg of imidazole and stirred for about 24 hours. An additional 180 mg of t-butyl-dimethylsilyl chloride and 90 mg of imidazole were added and the solution stirred an additional 24 hours.
The reaction mixture was then diluted with 100 ml of ethyl acetate and 100 ml of H2O. The organic phase was separated and washed with lO0 ml of saturated NaHCO3 solution. The organic phase was then dried over anhydrous Na2SO4 and purified over (50 g) silica gel using ethyl acetate as eluent. Further chromatography over silica gel (25% ethyl acetate/hexane) provided 320 mg of p-nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(1-dethia)-3-(3,4-di(t-butyldimethylsilyloxy)-phenylthiazol-4-yl-3-cephem-4-carboxylate.

H NMR: (300 MHz, CDCl3) ~8.0 (d, J= 9Hz, 2H), 7.32 (m, 2H), 7.22 (d, J= 9Hz, 2H), 7.05 (s, lH), 6.80 (m, lH), 5.28 (AB, 2H), 5.22 (m, lH), 5.05 (m, lH~, 3.95 tm, lH), 2.95 (dd J= 4, 18Hz, lH), 2.55 (m, lH), 2.20 (m, lH), 1.70 (m, lH), 1.42 (s, 9H) 1.0 (s, 9H), 0.97 (s, 9H), 0.23 (s, 6H), and 0.20 (s, 6H) Example 8 Allyl 7~-t-butoxycarbonylamino-1-carba(1-dethia)-3-(2-(2,3-di-(t-butyldimethylsilyloxy)phenyl)-3-cephem-4-carboxylate A. Removal of p-nitrobenzyl ester A 320 mg (0.382 mmol) sample of the title compound from Example 7 was dissolved in 2.5 ml of dimethylformamide/3 ml of tetrahydrofuran and 2.5 ml of acetic acid, treated with 100 mg (1.53 mmol) of Zn dust and stirred for 20 min. The reaction mixture was then treated with an additional 1 ml of acetic acid and 100 mg of Zn. After lh, the reaction mixture was filtered, diluted with ethyl acetate and washed with water. The organic phase was then dried and concentrated in vacuo azeotroping any remaining dimethylformamide away with toluene (5 times) to provide the title compound as a foam (220 mg, 82%) (some desilylation occurred)~
B. Formation of allyl ester A 215 mg (0.306 mmol) sample of the product from part A above is reacted with allyl bromide in 2 ~

dimethylformamide in the presence of tetra-n-butyl-ammonium hydrogen sulfate, sodium bicarbonate and sodium iodide to provide the title compound.

Example 9 Allyl 7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-phenylthiazol-4-yl)-3-cephem-4-carboxylate A 103 mg 0.234 mmol) sample of 7~-t-butoxy-carbonylamino-1-carba(l-dethia)-3-(2-phenylthiazol-4-yl)-3-cephem-4-carboxylic acid, prepared according to the foregoing examples, was dissolved in a small amount of N,N-dimethylformamide, treated with 60 mg (0.70 mmol) of NaHC03 and stirred for 10 min. The reaction mixture 15 was then treated with 83 mg (0.246 mmol) of tetra-n-butylammonium hydrogen sulfate, allowed to stir for 10 min., followed by treatment with 26 ~1 (0.294 mmol) of allyl bromide (followed by a additional 10~1) and 109 mg (0.725 mmol) of NaI. After stirring at room temperature overnight, the reaction mixture was poured into 30 ml of saturated NaHC03 solution and 50 ml of ethyl acetate. The organic phase was separated and washed (2x30 ml) with 0.5 N HCl solution, dried over anhydrous Na2 S04, filtered and concentrated ln vacuo to 25 provide the title compound. (100 mg, 89.3%, isolated as a solid from diethyl ether/hexane.) lH NMR: (300 MHz, CDCl3) ~7.90 (m, 2H), 7.40 (m, 3H), 7.15 (s, lH), 5.78 (m, lH), 5.10 (m, 4H), 4.65 (ABX, 2H), 30 3.90 (m, lH), 2.95 (dd, J= 4, 18Hz, lH), 2.50 (m, lH), 2.20 (m, lH), 1.70 (m, lH) and 1.45 (s, 9H).
.

.

~ 3 IR: (CHCl3) 1769, 1718, 1506, 1369, 1248, and 1161 cm 1 MS: m/e 482 (M + 1) AnalysiS Calculated for C2sH27N3sS:
Calc.: C, 62.35; H, 5.65; N, 8.73;
Found: C, 64.23; H, 5.81; N, 8.93.

Examples 10-18 According to the general methodolo~y of Example 9 and the preceding Examples, the followin~
compounds were prepared.

10. Allyl 7~-t-butoxycarbonylamino-l-carba-(1-dethia)-3-[2-(5-nitrothiazol-2-yl)thiazol-4-yl]-3-cephem-4-carboxylate lH NNR: (300 MHz, CDCl3) ~8.55 (s, lH), 7.43 (s, lH), 5.85 (m, lH), 5.25 (m, 3H), 5.10 (m, lH), 4.75 (ABX, 2H), 4.95 (m, lH), 2.98 (dd, J= 4, 18Hz, lH), 2.55 (m, lH), 2.23 (m, lH), 1.70 (m, lH) and 1.45 (s, 9H) IR: (CHCl3) 2976, 1772, 1719, 1390, 1351, 1251, and 1159 cm 1 MS: m/e 534 (M + 1) Analysis Calculated for C22H23NsO7S2:
Calc.: C, 49.52; H, 4.35; N, 13.13;
Found: C, 50.90; H, 4.33; N, 13.23.

11. Allyl 7~-t-butoxycarbonylamino-1-carba-(l-dethia)-3-[2-(4-fluorophenyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, C~C13) ~7.90 (m, 2H), 7.19 (s, lH), 7.12 (m, 2H), 5.8 (m, lH), 5.15 (m, 4H), 4.70 (ABX, 2H), 3.90 (m, lH), 2.95 (dd J= 4, 18Hz, lH), 2.50 (m, lH), 2.20 (m, lH), 1.70 (m, lH), and 1.45 (s, 9H) IR: (KBr) 3019, 2977, 1770, 1719, 1393, 1336, and 1157 cm MS: m/e 499 (M ) Analysis Calculated for C25H26N3O5SF:
Calc.: C, 60.10; H, 5.25; N, 8.41;
Found: C, 62.52; H, 5.57; N, 8.42.

12. Allyl 7~-t-butoxycarbonylamino-1-carba-(l-dethia)-3-[2-(4-pyridyl)thiazol-4-yl]-3-cephem-4-carboxylate ; 1H NMR: (300 MHz, CDCl3) ~8.72 ((d, J= 9Hz, 2H), 7.75 (d, J= 9Hz, 2H), 7.30 (s, lH), 5.80 (m, lH), 5.20 (m, 4H), 4.70 (ABX, 2H), 3.95 (m, lH), 3.0 (dd J= 4, 18Hz, lH), 2.58 (m, lH), 2.25 (m, lH), 2.25 (m, lH), 1.75 (m, lH), and 1.50 (s, 9H) IR: (CHCl3) 3020, 1771, 1718, 1505, 1393, 1348, 1248, and 1161 cm 1 ~3~

MS: m~e 482 (M ) A~alysis Calculated for C2~H2GN~O5S --Calc.: C, 59.74; H, 5.43; N, 11.61;
Found: C, 58.47; H, 5.23; N, 11.25.

13. Allyl 7~-t-butoxycarbonylamino-1-carba-(l-dethia)-3-[2-(3-methyl-4-nitroimidazol-2-yl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~8.10 (s, lH), 7.40 (s, lH), 5.62 (m, lH), 5.25 (m, 3H), 5.08 (d, J= 8Hz, lH), 4.70 (d, J= 6Hz, 2H), 4.48 (s, 3H), 3.95 (m, lH), 3.0 (dd J= 4, 18Hz, lH), 2.58 (m, lH), 2.25 (m, lH), 1.75 (m, lH), and 1.48 ~s, 9H) IR: (CHCl3) 3018, 1772, 1719, 1530, 1472, 1365, 1270, and 1161 cm 1 MS: m/e 530 (M ) 14. Allyl 7~-t-butoxycarbonylamino-1-carba-(l-dethia)-3-[2-(1,1-(2-pyridyl)(phenyl)methyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~8.60 (d, J= 4Hz, lH) 7.63 (t, J- 9Hz, lH), 7.30 (m, 5H), 7.18 (m, 2H), 7.13 (s, lH), 7.11 (6, lH), 5.86 (s, lH), 5.85 (s, lH), 5.65 (m, lH), 5.10 (m, 4H), 4.53 (d, J= 6Hz, lH), 4.47 (d J= 6Hz, lH), 4.28 (dd, J= 5, 15Hz, lH), 4.20 (dd, J= 5, 15Hz, lH), 3.88 (m, lH), 2.90 ~m, lH), 2.45 (m, lH), and 1.45 (s, 9H) 2 ~

IR: (CHCl3) 3019, 1769, 1718, 1496, 1393, 1369, 1247,and 1160 cm 1 MS: m/e 572 (M+) Analysis Calculated for C3lH32N40sS:
Calc.: C, 65.02; H, 5.63; N, 9.78;
Found: C, 65.01; H, 5.60; N, 9.52.

15. Allyl 7~-t-butoxycarbonylamino-1-carba-(l-dethia)-3-[2-(p-nitrophenyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~8.30 (d, J= 9Hz, 2H) 8.05 (d, 15 J= 9H~, 2H) 7.30 (s, lHl, 5.80 (m, lH), 5.20 (m, 4H), 4.68 (ABX, 2H), 3.g5 (m, lH), 3.0 (dd J= 4, 18Hz, lH), 2.55 (m, lH), 2.25 (m, lH), 1.70 (m, lH), and 1.45 (s, 9H) 20 IR: (CHCl3) 3020, 1771, 1719, 1525, 1348, 1248, and 1161 cm MS: m/e 527 (M + 1) Analysis Calculated for C25H26N407S;
Calc.: C, 57.03; H, 4.98; N, 10.64;
Fou~d: C, 57.48; H, 4.82; N, 11.33.

16. ~llyl 7~-t-butoxycarbonylamino-1-carba-30 (1-dethia)-3-[2-(3,4-(t-butyldimethylsilyloxy)phenyl)-thiazol-4-yl]-3-cephem-4-carboxylate 2 ~ L `3 ~

lH NMR: (300 MHz, CDCl3~ ~7.35 (m, 2H), 7.05 (s, lH), 6.85 (d, J= 9Hz, lH), 5.75 (m, lH), 5.15 (m, 4H), 4.65 (ABX, 2H), 3.90 (m, lH), 2.95 (dd J= 4, 18Hz, lH~, 2.48 (m, lH), 2.18 (m, lH), 1.70 (m, lH), 1.45 (s, 9H), 1.02 (s, 9H), 1.0 (s, 9H), 0.24 (s, 6H), and 0.21 (s, 6H) IR: (CHCl3) 2931, 1768, 1718, 1520, 1472, 1392, 1297, 1254 and 1161 cm 1 10 MS: m/e 742 (M + 1) Analysis Calculated for C37H55N307SSi2:
Calc.: C, 59.89; H, 7.47; N, 5.66;
Found: C, 62.22; H, 7.57; N, 5.65.
17. Allyl 7~-t-butoxycarbonylamino-1-carba-(l-dethia)-3-[2-(2-furenyl)thiazol-4-yl]-3-cephem-4-carboxylate 20 lH NMR: (300 MHz, CDCl3) ~7.48 (d, J= 2Hz, lH), 7.10 (s, lH), 6.95 (m, lH), 6.5 ~m, lH), 5.80 (m, lH), 5.15 (m, 4H), 4.68 (ABX, 2H), 3.90 (m, lH), 2.95 (dd J= 4, 18Hz, lH), 2.S0 (m, lH), 2.20 (m, lH), 1.70 (m, lH), and 1.45 (s, 9H) IR: (CHCl3) 3019, 1770, 1718, 1502, 1393, 1249, and 1160 cm MS: m/e 472 (M+ + 1) Analysis Calculated for C2 3H25N3O6S:
Calc.: C, 58.59; H, 5.34; N, 8.91;
Found: C, 59.83; H, 5.27; N, 8.41.

2 ~

18. Allyl 7~-t-butoxycarbonylamino-1-carba-(l-dethia)-3-[2-(3-pyridyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~9.1 (d, J= 2Hz, lH), 8.65 (d, J= 4Hz lH), 8.18 (m, lH), 7.38 (m, lH), 7.22 (s, lH), 5.80 (m, lH), 5.2 (m, 4H), 4.70 (ABX, 2H), 3.95 (m, lH), 3.0 (dd J= 4, 18Hz, lH), 2.52 (m, lH), 2.20 (m, lH), 1.70 (m, lH), and 1.48 (s, 9H) IR: (CHCl3) 3025, 1771, 1717, 1602, 1246, and 1162 cm 1 MS: m/e 482 (M ) Analysis Calculated for C24H26N4O5S:
Calc.: C, 59.74; H, 5.43; N, 11.61, Found: C, 59.90; H, 5.62; N, 11.63.

19. Allyl 7~-t-butoxycarbonylamino-1-carba-20 (1-dethia)-3-[2-(allyloxycarbonylamino)thiazol-4-yl]-3-cephem-4-carboxylate In a procedure analogous to Example 9 above, the title compound was prepared in 38% yield.

25 lH NNR: (300 MHz, CDCl3) ~8.70 (s, lH), 5.90 (m, 2H), 5.30 (m, 6H), 4.72 (d, J= 6Hz, 2H), 4.65 (d, J= 6Hz, 2H) 4.90 (m, lH), 3.85 (dd J= 4, 18Hz, lH), 2.38 (m, lH), 2.10 (m, lH), and 1.45 (æ, 9H) 30 IR: (CHCl3) 3018, 1769, 1722, 1549, 1237, and 1207 cm 1 MS: m/e 504 (M ) 2 ~

Analysis Calculated for C23H28N4O7S:
Calc.: C, 54.75; H, 5.59; N, ll.10;
Found: C, 54.93; H, 5.31; N, 11.94.

Coproduced in this reaction was allyl 7~-t-butoxy-carbonylamino-l-carba(l-dethia)-3-[2-[(allyloxy-carbonyl)(allyl)]amino]-thiazol-4-yl-3-cephem-4-carboxylate (45%).

lH NMR: (300 MHz, CDCl3) ~6.80 (s, lH), 5.90 (m, 2H), 5.25 (m, 5H), 5.05 (d, J= 8Hz, lH), 4.78 (d, J= 6Hz, 2H), 4.65 (d, J= 6Hz, 2H), 3.87 (m, lH), 2.88 (dd J= 4, 18Hz, lH), 2.40 (m, lH), 2.15 (m, lH), 1.65 (m, lH), and 1.45 (s, 9H) IR: (CHCl3) 3020, 1768, 1712, 1504, 1393, 1242, and 1157 cm~l MS: m/e 544 (M ) Analysis Calculated for C26H32N4O7S:
Calc.: C, 57.34; H, 5.92; N, 10.29;
- Found: C, 57.08; H, 5.86; N, 10.09.

It was subsequently discovered that the use of NaH in l-molar eguivalency as base resulted in the desired mono-allylated product.

~ ~ 3 ~

Example 20 Allyl 7~-[(2-allyloxycarbonylaminothiazol-4-yl)-Z-methoximinoacetylamino]-1-carba(l-dethia)-3-[2-(4-fluorophenyl)thiazol-4-yl]-3-cephem-4-carboxylate A. Deprotection An 80 mg (O.16 mmol) sample of allyl 7~-t-butoxycarbonylamino-l-carba(l-dethia)-3-[2-(4-fluoro-phenyl)thiazol-4-yl]-3-cephem-4-carboxylate was dis-solved in 1 ml of CH2C12 and 1 ml of trifluoroacetic acid. The solution was concentrated ln vacuo to provide a foam which was again treated with trifluroracetic acid and concentrated out of acetonitrile. From the resulting foam (CH2Cl2/diethyl ether/hexane) was obtained a tan solid.
B. Acylation In another container, a 46 mg (0.16 mmol) sample of (2-allyloxycarbonylaminothiazol-4-yl)-Z-methoximino acetic acid was dissovled in a small amount of CH2Cl2 and treated with 28 mg (0.16 mmol) of 2-chloro-4,6-dimethoxytria2ene and cooled to 0C. The reaction mixture was then diluted with an additional 1 ml of CH2Cl2 and treated with 19 ~1 (0.168 mmol) of N-methylmorpholine and stirred for about 40 min.
An additional 19 ~1 g N-methylmorpholine was added, followed by addition of the product from Part A, above, using about 2 ml of CH2Cl2 as wash. After 2 hours, the reaction mixture was concentrated ln vacuo and purified by column chromatography (silica gel, 30-40% ethyl acetate/CH2Cl2) to provide 42 mg of the title compound.

2~3~

lH NMR: (300 MHz, CDCl3) ~9.38 (s, lH), 7.90 (m, 2H), 7.20 (s, lH), 7.12 (m, 2H), 5.85 (m, 3H), 5.25 (m, 4H), 4.70 (m, 4H), 4.10 (m, lH), 4.05 (s, 3H), 3.05 (dd, J= 4, 18Hz, lH), 2.60 (m, lH), 2.30 (m, lH), and 1.95 (m, lH) Examples 21-30 ~The following compounds were prepared in a manner analogous to that used in Example 20.
21. Allyl 7~-[(2-allyloxycarbonylamino-thiazol-4-yl)-Z-methoximinoacetylamino]-l-carba(l-dethia)-3-[(2-phenyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~9.40 (s, lH), 7.90 (m, 3H), 7.40 (m, 2H), 7.20 (s, lH), 7.10 (s, lH), 5.95 (m, lH), 5.80 (m, lH), 5.60 (m, lH), 5.20 (m, 4H), 4.70 (m, 4H), 4.10 (m, lH), 4.05 (s, 3H), 3.0 (dd J= 4, 18Hz, lH), 20 2.60 (m, lH), 2.30 (m, lH), and 1.95 (m, lH) 22. Allyl 7~-[2-(allyloxycarbonylamino-thiazol-4-yl)-Z-methoximinoacetylamino]-l-carba(l-dethia)-3-[(pyridyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~9.55 (s, lH), 9.10 (s, lH), 8.65 (d, J= 6Hz, lH) 8.20 (d, J= 9Hz, lH), 8.05 (s, lH), 7.38 (m, lH), 7.30 (s, lH), 7.10 (s, lH), 5.95 ~m, lH), 5.80 (m, lH), 5.75 (m, lH), 5.25 (m, 4H), 4.70 ~m, 4H), 30 4.10 (m, lH), 4.05 (s, 3H), 3.0 (dd J= 4, 18Hz, lH), 2.60 (m, lH), 2.30 (m, lH), and 1.95 (m, lH) 2~3~

23. Allyl 7~-[2-(allyloxycarbonylamino-thiazol-4-yl]-Z-methoximinoacetylamino]-l-carba(l-dethia)-3-[(1-methyl-2-pyridyl)thiazol-4-yl]-3-cephem-4-carboxylate iodide A 58 mg sample of the title compound of Example 22 was dissolved in 0.9 ml of N,N-dimethyl-formamide and treated with 17~1 (0.278 mmol) of methyl-iodide. Crystallization by addition of diethyl ether/
hexane to the reaction mixture provided 56 mg (95%
yield) of the title compound.

lH NMR: (300 MHz, CDCl3) ~9.15 (s, lH), 8.80 (d, J= 9Hz, lH), 8.70 (d, J= 6Hz, lH), 8.10 (m, lH), 7.70 (s, lH), 7.60 (d, J= 9Hz, lH), 7.25, (s, lH), 5.95 (m, lH), 5.75 (m, lH), 5.55 (m, lH), 5.25 (m, 4H), 4.65 (m, 4H), 4.35 (s, 3H), 4.05 (m, lH), 3.95 (s, lH), 3.05 (dd J= 4, 18Hz, lH), 2.55 (m, lH), 2.10 (m, lH), and 1.85 (m, lH) 24. Allyl 7~-[2-(allyloxycarbonylamino-thiazol-4-yl]-Z-methoximinoacetylamino]-l-carba(l-dethia)-3-[2-[5-nitrothiazol-4-yl]thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl~) ~9.30 (s, lH), 8.55 (s, lH), 7.80 (s, lH), 7.45 (s, lH), 7.15 (s, lH), 5.90 ~m, 2H), 5.70 (m, lH), 5.30 (m, 4H), 4.70 (m, 4H), 4.10 (m, lH), 4.05 (s, 3H), 3.0 (dd J= 4, 18Hz, lH), 2.60 (m, lH), and 1.90 (m, lH) (using p-toluenesulfonic acid H2O in place of trifluoroacetic acid) 2~6~ ~

25. Allyl 7~-[(2-triphenylmethylaminothiazol-4-yl)-Z-triphenylmethoximinoacetylamino]-l-carba(1-dethia~-3-[2-[4-nitro-3-methylimidazol-2-yl]thiazol-4-yl-3-cephem-4-carboxylate (using p-toluenesulfonic acid H2O in place of trifluor~acetic acid) lH NMR: (300 MHz, CDCl3) ~8.05 (s, lH), 7.25 (m, 30H), 6.62 (s, H), 6.58 (d, J= 6Hz, lH), 6.43 (s, lH), 5.85 (m, lH), 5.45 (m, lH), 5.20 (m, 2H), 4.70 (m, 2H), 4.40 (s, 3H), 4.0 (m, lH), 2.58 (dd, J= 4, 18Hz, lH), 2.35, (m, lH), 2.10 (m, lH), and 1.45 (m, lH) 26. Allyl 7~-[(2-allyloxycarbonylamino-thiazol-4-yl]-Z-methoximinoacetylamino]-1-carba(1-dethia)-3-[2-[(phenyl)(2-pyridyl)methyl]thiazol-4-yl]-3-cephem-4-carboxylate ~H NMR: (300 MHz, CDCl3) ~9.60 (s, lH), 8.60 (d, J=
4Hz, lH), 8.05 (s, lH), 7.60 (m, lH), 7.25 (m, 5H), 7.20 (m, lH), 7.12 (s, lH), 7.0, (s, lH), 5.80 (m, 3H), 5.20 (m, 4H), 4.50 (m, 4H), 4.10 (m, lH), 4.0 (s, 3H), 2.90 (m, lH), 2.50 (m, lH), 2.20 (m, lH), and 1.90 (m, lH) 2~3~

27. Allyl 7~-[(2-allyloxycarbonylamino-thiazol-4-yl-Z-methoximinoacetylamino]-l-carba(l-dethia)-3-[2-(4-nitrophenyl)thiazol-4-yl]-3-cephem-4-carboxylate (using p-toluenesulfonic acid-H2O instead of trifluoroacetic acid) lH NMR: (300 MHz, CDCl3) ~9.60 (s, lH), 8.25 (d, J= 8Hz, 2H), 8.18 (s, lH), 8.05 (d, J= 8Hz, 2H), 7.35 (s, lH), 7.05, (s, lH), 5.90 (m, 3H), 5.25 (m, 4H), 4.70 (m, 4H), 4.15 (m, lH), 4.05 (s, 3H), 3.0 (dd, J= 4, 18Hz, lH), 2.60 (m, lH), 2.30 (m, lH), and 1.95 (m, lH) 28. Allyl 7~-[(2-allyloxycarbonylamino-thiazol-4-yl]-Z-methoximinoacetylamino]-l-carba(1-dethia)-3-[2-allyloxycarbonylaminothiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~9.60 (s, lH), 8.52 (s, lH), 8.10 (s, lH), 7.02 (s, lH), 6.80 (s, lH), 5.90 (m, 3H), 5.70 (m, lH), 5.25 (m, 6H), 4.70 (m, 6H), 4.05 (m, lH), 4.0 (s, 3H), 2.88 (dd, J= 4, 18Hz, lH), 2.43 (m, lH), 2.20 (m, lH), and 1.90 (m, lH) 29. Allyl 7~-[(2-allyloxycarbonylamino-thiazol-4-yl]-Z-methoximinoacetylamino]-l-carba(l-dethia)-3-[2-(3,4-(t-butyldimethylsilyl)oxy)phenyl-thiazol-4-yl]-3-cephem-4-carboxylate 2 ~ 3 ~

lH NMR: (300 MHz, CDCl3) ~9.45 (s, lH), 7.95 (s, lH), 7.35 (m, 2H), 7.12 (s, lH), 6.84 (m, lH), 5.95 (m, lH), 5.75 (m, 2H), 5.25 (m, 4H), 4.65 (m, 4H), 4.10 (m, lH), 4.02 (s, 3H), 3.0 (dd, J= 4, 18Hz, lH), 2.55 (m, lH), 2.25 (m, lH), 1.90 (m, lH), 1.0 (s, 9H), 0.97 (s, 9H), 0.23 (s, 6H), and 0.18 (s, 6H) 30. Allyl 7~-~(2-allyloxycarbonylamino-thiazol-4-yl)-Z-methoximinoacetylamino]-l-carba(l-10 dethia)-3-[2-(2-furyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~9.55 (s, lH), 8.05 (s, lH), 7.48 (s, lH), 7.15 (s, lH), 7.05 (s, lH), 6.95 (m, lH), 15 6.52 (m, lH), 5.85 (m, 3H), 5.25 (m, 4H), 4.70 (m, 4H), 4.10 (m, lH), 4.02 (s, 3H), 3.0 (dd, J= 4, 18Hz, lH), 2.55 (m, lH), 2.25 (m, lH) and 1.95 (m, lH) Example 31 Sodium 7~-[(2-aminothiazol-4-yl)-Z-methox-iminoacetylamino]-l-carba(l-dethia)-3-[2-(2-phenyl)-thiazol-4-yl]-3-cephem-4-carboxylate A 27 mg (0.0417 mmol) sample of allyl 7~-t(2-allyloxycarbonylaminothiazol-4-yl)-Z-methoximino-acetylamino]-1-carba(l-dethia)-3-[2-(phenyl)thiazol-4-yl]-3-cephem-4-carboxylate was dissolved in 1.5 ml of CH2Cl2, treated with 0.878 mg (0.0013 mmol) of bis triphenylphosphine Pd(II) dichloride and 6 ~1 (0.0917 mmol) of tri-n-butyltinhydride and stirred for 10 min.

~ ~ 3 ~

The reaction mixture was then treated with an additional 5.0 ~l of tri-n-butyltinhydride. After 10 min., the reaction mixture was quenched with a solution of 10 ~l concentrated HCl in 0.5 ml of CH3CN. The resulting mixture was treated with 10 ml of diethyl ether and 10 ml hexane and centrifuged (2X). The resulting solid was dried under vacuum to provide 16.0 mg of the free acid of the title compound (93% pure by HPLC) in 73.7%
yield.
A 130 mg (0.248 mmol) of the above was suspended in about 7 ml H20 and 2 ml CH3CN. A solution of 25 mg (0.297 mmol) of NaHC03 in 1.5 ml of H20 was prepared and added. The resulting solution was sonicated and passed through an HP20SS column eluting with 8% CH3CN-18%
CH3CN/H20. The desired fractions were concentrated and the resulting title compound washed with diethylether/
hexane to provide 125 mg (99.8% pure).

1H NMR: (300 MHz, d6-DMSO) ~9.2 (d, J= 9Hz, 2H), 7.85 (m, 2H), 7.65 (s, lH), 7.40 (m, 3~), 7.15 (s, 2H), 6.70 (s, lH), 5.25 (m, lH), 3.80 (s, 3H), 3.75 (m, lH), 2.95 (dd, J= 4, 18Hz, lH), 2.35 (m, lH), 1.90 (m, lH), and 1.70 (m, lH).

IR (KBr): 3500-3100, 1733, 1648, 1591, 1557, 1539, 1405 and 1376 cm MS: m/e 547 (M + 1) Analysis calculated for c23Hl9N6oss2Na:
Calc.: C, 50.54; H, 3.50; N, 15.38;
Found: C, 50.33; H, 3.76; N, 15.17.

2~3 r~ 1 ~ 3~

Examples 32-38 Examples 32-38 were prepared by methodology analogous to that of Example 31.

32. Sodium 7~-~(2-aminothiazol-4-yl)-Z-methoximinoacetylamino]-l-carba(l-dethia)-3-[2-(2-furyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, d6-DMSO) ~9.25 (d, J= 9Hz, lH), 7.80 (s, lH), 7.65 (s, lH), 7.20 (s, 2H), 6.95 (m, lH), 6.70 (s, lH), 6.60 (m, lH), 5.25 (m, lH),3.80 (s, 3H), 3.75 (m, lH), 3.85, (dd, J= 4, 18Hz, lH), 2.32 (m, lE), 1.85 (m, lH) and 1.65 (m, lH) IR (KBr): 3500-3200, 1744, 1647, 1595, 1538, 1404, 1383 and 1035 cm MS: m/e 537 (M + 1) Analysis calculated for C2lHl7N6O6S2Na:
Calc.: C, 47.01; H, 3.19; N, 15.66;
Found: C, 41.14; H, 2.95; N, 11.02.
.-- Residue: 12.74%

33. 7~-[(2-Aminothiazol-4-yl)-Z-hydroxy-iminoacetylamino]-l-carba(l-dethia)-3-[2-(4-nitro-3-methylimidazol-2-yl)thiazol-4-yl]-3-cephem-4-carboxylic acid 2~3~

H NMR: (300 MHz, d6-DMSO) ~9.15 (d, J= 9Hz, lH), 8.15 (s, lH), 7.88 (s, lH), 7.08 (s, 2H), 6.65 (s,lH), 5.40 (m, lH), 4.30 (s, 3H), 3.80 (m, lH), 3.90 (dd, J= 4, 18Hz, lH), 2.38 (m, lH), 1.95 (m, lH) and 1.7~ (m, lH) IR (KBr): 3500-3100, 1754, 1617, 1528, 1397, 1365, 1339, 1268 and 1209 cm 1 MS: m/e 560 (M + 1) Analysis calculated for C2 oH17Ns7 S2 Calc.: C, 42.93; H, 3.06; N, 22.53;
Found: C, 42.47; H, 3.38; N, 20.77.

34. 7~-[(2-aminothiazol-4-yl)-Z-methox-iminoacetylamino]-l-carba(1-dethia)-3-[2-(1-methyl-3-pyridyl)thiazol-4-yl]-3-cephem-4-carboxylic acid 1H NMR: (300 MHz, D2O) ~9.30 ~s, lH), 8.90 (d, J= 8Hz, lH), 8.78, (d, J= 6Hz, lH), 8.10 (m, lH), 7.65 ~s, lH), 6.95 (s, lH), 5.50, (d, J= 6Hz, lH), 4.45 (s, 3H), 4.10 (m, lH), 4.0 (s, 3H), 3.95, (m, lH), 2.58 (m, lH), 2.20 (m, lH), and 1.80 (m, lH) IR (KBr): 3200, 1758, 1674, 1532, 1384, 1203, and 1168 cm~1 MS: m/e 540 (M + 1) 35. Sodium 7~-[(2-aminothiazol-4-yl)-Z-methoximinoacetylamino~-1-carba(1-dethia)-3-[2-(4-nitro-phenyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, d6-DMSO) ~9.25 (d, J= 9Hz, lH), 8.25 (d, J= 9Hz, 2H), 8.15 (d, J= 9Hz, 2H), 7.85 (s, lH), 7.15 (s, 2H), 6.72 (s, lH), 5.25 (m, lH), 3.80 (s, 3H), 3.75 (m, lH), 2.95 (dd, J= 4, 18Hz, lH), 2.40 (m, lH), 1.90 (m, lH), and 1.70 (m, lH) IR (KBr): 3400-3200, 1733, 1649, 1594, 1523, 1402, 1345, 1050 and 851 cm 1 MS: m/e 592 (M + 1) Analysis calculated for C23H18N7O7S2Na:
Calc.: C, 46.70; H, 3.07; H, 16.57;
Found: C, 46.06; H, 3.05; N, 15.75.
Residue: 5.84%
36. 7~-[(2-aminothiazol-4-yl)-4-methox-iminoacetylamino]-l-carba(l-dethia)-3-[2-(5-nitro-thiazol-2-yl)thiazol-4-yl]-3-cephem-4-carboxylic acid 25 lH NMR: (300 MHz, d6-DMSO) ~9.35 (d, J= 9Hz, lH), 8.90 (s, lH), 8.02 (s, lH), 7.40 (s, 2H), 6.78 (s, lH), 5.45 (m, lH), 3.90 (m, lH), 3.80 (s, 3H), 2.95 (dd, J= 4, 18Hz, lH), 2.40 (m, lH), 2.0 (m, lH), and 1.70 (m, lH) 30 IR (KBr): 3419, 1764, 1629, 1524, and 1350 cm 1 MS: m/e 532 (M - C2 ) ~ ~ ,C~

Analysis calculated for C20Hl6N8O7S3:
Calc.: C, 41.66; H, 2.80; N, 19.43;
Found: C, 41.38; H, 2.90; N, 17.16.

S 37. 7~-[(2-aminothiazol-4-yl)-Z-methoximino-acetylamino]-l-carba(l-dethia)-3-[2-(4-fluorophenyl)-thiazol-4-yl]-3-cephem-4-carboxylic acid lH NMR: (300 MHz, d6-DNSO~ ~9.45 (d, J~ 9Hz, lH), 7.95 (m, 2H), 7.65 (s, lH), 7.35 (m, 2H), 6.83 (s, lH), 5.50 (m, lH), 3.95 (m, lH), 3.90 (s, 3H), 2.95 (m, lH), 2.40 (m, lH), 2.0 (m, lH), and 1.75 (m, lH) IR (KBr): 3400-3000, 1762, 1673, 1631, 1517, 1389, 1234, and 1046 cm 1 MS: m/e 543 (M + 1) Analysis calculated for C23H1gN6O5S2F:
Calc.: C, 50.92; H, 3.53; N, 15.49;
Found: C, 48.53; H, 3.66; N, 13.87.

38. 7~-[(2-aminothiazol-4-yl)-Z-methox-iminoacetylamino]-l-carba(1-dethia)-3-[2-(phenyl)(2-pyridyl)methyl)thiazol-4-yl]-3-cephem-4-carboxylic acid H NMR: (300 MHz, d6-DMSO) ~9.28 (d, J= 9Hz, lH), 8.50 (d, J= 4Hæ, lH), 7.70 (m, lH), 7.50 (s, lH), 7.45 (m, lH), 7.25 (m, 8H), 6.72 (s, lH), 5.90 (s, lH), 5.40 (m, lH), 3.80 (s, 3~), 2.85 (dd, J= 4, 18Hz, lH), 2.30 (m, lH), 1.90 (m, lH), and 1.65 (m, lH) `' ,c~ q~

IR (KBr): 3400-3000, 1758, 1671, 1619, 1589, 1532, and 1379 cm 1 MS: m/e 616 (M + 1) Analysis calculated for C29H25N705S2:
Calc.: C, 56.57; H, 4.09; H, 15.93;
Found: C, 55.11; H, 4.09; N, 15.30.

Example 39 Sodium 7~-[(2-aminothiazol-4-yl)-Z-methox-iminoacetylamino]-l-carba(l-dethia)-3-(2-aminothiazol-4-yl)-3-cephem-4-carboxylate 1H NMR: (300 MHz, d6-DMS0) 89.20 (d, J= 9Hz, lH), 7.15 (s, 2H~, 6.70 (s, lH), 6.60 (s, 2H), 6.55 (s, lH), 5.20 (m, lH), 3.78 (s, 3H), 3.62 (s, lH), 2.64 (dd J= 4, 18Hz, lH), 2.15 (m, lH), 1.75 (m, lH) and 1.60 (m, lH) IR (KBr): 3500-3100, 1744, 1661, 1607, 1591, 1527, 1382, 1350, and 1034 cm 1 . MS: m/e 485 (M ) Analysis calculated for C17H~6N705S2Na:
Calc.: C, 42.06; H, 3.32; N, 20.20;
Found: C, 42.38; H, 3.33; N, 18.59.

- 2~3~

Exam~le 40 Sodium 7~-~(2-aminothiazol-4-yl)-Z-methox-iminoacetylamino]-l-carba(l-dethia)-3-[2-(3,4-dihydroxy-phenyl)thiazol-4-yl]-3-cephem-4-carboxylate 1H NMR: (300 MHz, d6-DMSO) ~9.50 (s, lH), 9.25 (d, J= 9Hz, lH), 7.48 (m, lH), 7.28 (m, lH), 7.15 (m, 3H), 6.75 (d, J= 8Hz, lH), 6.70 (s, lH), 5.25 (m, lH), 3.80 (s, 3H), 3.72 (m, lH), 2.90, (dd, J= 4, 18 Hz, lH), 2.35 (m, lH), 1.88 (m, lH), and 1.65 (m, lH) IR (KBr): 3341, 3226, 2223, 1648, 1628, 1600, 1587, 1365, 1253, and 1159 cm 1 +

15 MS: m/e 579 (M + 1) Analysis calculated for C23H1gN6O7S2Na:
Calc.: C, 47.75; H, 3.31; N, 14.55;
Found: C, 42.41; H, 3.24; N, 12.35.
Residue: 7.69%

Exam~le 41 7~-(D-phenylglycylamino)-l-carba(l-dethia)-25 3-(2-aminothiazol-4-yl)-3-cephem-4-carboxylic acid H NMR: (300 MHz, D20) 87.60 (m, 5H), 6.60 (s, lH), 5.50 ~(d, J= 4Hz, lH), 5.22 (s, lH), 4.0 (m, lH), 2.70 (dd, J= 4, 18Hz, lH), 2.35 (m, lH), 1.78 (m, lH) and 1.35 (m, lH) q ~ Q`

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Claims (9)

1. A compound of Formula (1):

(1) wherein X is a group selected from amino, halo, cyano, hydrogen, nitro, C1-C6 alkyl, C1-C6 substituted alkyl, a C3 to C6 heterocyclic ring containing 1, 2, or 3 nitrogen atoms and O or 1 sulfur or oxygen atoms, said ring optionally substituted by one or more groups selected from halo, nitro, hydroxy, C1-C6 alkyl or C1-C6 substituted alkyl;
phenyl, substituted phenyl, or an acyl group of the formula , wherein R" is C1-C6 alkyl, C1-C6 substituted alkyl, phenyl, or substituted phenyl;
R3 is hydrogen, C1-C4 alkoxy, or a group of the formula -NHCHO; and R1 is an acyl group of the formula , wherein R" is hydrogen; C1-C6 alkyl, C1-C6 alkyl substituted by cyano, carboxy, halogen, amino, C1-C4 alkoxy, C1-C4 alkylthio, or trifluoromethylthio; a X-7967A (EPO) - 58 -phenyl or substituted phenyl group represented by the formula wherein a and a' independently are hydrogen, halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkanoyloxy, C1-C4 alkyl, C1-C4 alkylthio, amino, mono- or di(C1-C4 alkyl)amino, C1-C4 alkanoylamino, C1-C4 alkylsulfonylamino, carboxy, carbamoyl, hydroxymethyl, amino-methyl, or carboxymethyl;
a group represented by the formula wherein a and a' have the same meanings as defined above, Z is O or S, and m is O or 1;
a heteroarylmethyl group represented by the formula wherein R1 is thienyl, furyl, benzothienyl, benzofuryl, indolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, and such heteroaryl groups substituted by amino, hydroxy, halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 alkylsulfonylamino;

X-7967A (EPO) - 59 -a substituted methyl group represented by the formula wherein R2 is cyclohex-1,4-dienyl, or a phenyl group or substituted phenyl group represented by the formula wherein a and a' have the above defined meanings, or R2 is R1 as defined above, and Q is hydroxy, C1-C4 alkanoyloxy, carboxy, sulfo, or amino;
or R2 is a keto group or an oximino-substituted group represented by the formulae wherein R3 is R1 or R2 as defined above and R4 is hydrogen, C1-C4 alkyl, or a group repre-sented by the formula X-7967A (EPO) - 60 - wherein b and b' independently are hydrogen, or C1-C3 alkyl, and b and b' when taken together with the carbon to which they are bonded form a 3- to 6-membered carbocyclic ring, R5 is hydroxy, C1-C4 alkoxy, amino, C1-C4 alkylamino, or di(C1-C4 alkyl)amino; and n is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.

2. A compound of Claim 1 wherein R2 is a substituted methyl group represented by the formula wherein R2 is cyclohex-1,4-dienyl, or a phenyl group or substituted phenyl group represented by the formula wherein a and a' independently are hydrogen, halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkan-oyloxy, C1-C4 alkyl, C1-C4 alkylthio, amino, X-7967A (EPO) - 61 -mono- or di(C1-C4 alkyl) amino, C1-C4 alkanoyl-amino, C1-C4 alkylsulfonyl amino, carboxy, carbamoyl, hydroxymethyl, aminomethyl, or carboxymethyl; or R2 is thienyl, furyl, benzothienyl, benzofuryl, indolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, and such heteroaryl groups substituted by amino, hydroxy, halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 alkyl-sulfonylamino; and Q is hydroxy, C1-C4 alkanoyloxy, carboxy, sulfo, or amino.

3. A compound of Claim 2 wherein R2 is phenyl and Q is amino.

4. A compound of Claim 1 wherein R2 is a keto group or an oximino-substituted group represented by the formulae wherein R3 is hydrogen; C1-C6 alkyl, C1-C6 alkyl substituted by cyano, carboxy, halogen, amino, C1-C4 alkoxy, C1-C4 alkylthio, or trifluoromethylthio; cyclohex-1,4-dienyl, or a phenyl or substituted phenyl group represented by the formula X-7967A (EPO) - 62 -wherein a and a' independently are hydrogen, halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkanoyloxy, C1-C4 alkyl, C1-C4 alkylthio, amino, mono- or di(C1-C4 alkyl)amino, C1-C4 alkanoylamino, C1-C4 alkylsulfonylamino, carboxy, carbamoyl, hydroxymethyl, amino-methyl, or carboxymethyl;
a group represented by the formula wherein a and a' have the same meanings as defined above, Z is O or S, and m is O or 1;
or R3 is thienyl, furyl, benzothienyl, benzofuryl, indolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadia-zolyl, and such heteroaryl groups substituted by amino, hydroxy, halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 alkylsulfonylamino; and R4 is hydrogen, C1-C4 alkyl, or a group repre-sented by the formula wherein b and b' independently are hydrogen, or C1-C3 alkyl, and b and b' when taken together with the carbon to which they are bonded form a 3- to 6-membered carbocyclic ring, and R5 is hydroxy, C1-C4 alkoxy, amino, X-7967A (EPO) - 63 -C1-C4 alkylamino, or di(C1-C4 alkyl)amino and n is 0, 1, 2, or 3.

5. A compound of Claim 4, wherein R3 is 2-aminothiazol-4-yl.

6. A compound of Claim 5 wherein R4 is methyl.

7. A compound of Formula (2):

(2) wherein R1 is hydrogen or an amino protecting group;
R4 is hydrogen or a carboxy protecting group; X is selected from the group consisting of amino, halo, cyano, hydrogen, nitro, C1-C6 alkyl, C1-C6 substituted alkyl, a C3 to C6 heterocyclic ring containing 1, 2, or 3 nitrogen atoms and O or 1 sulfur or oxygen atoms, said ring optionally substituted by one or more groups selected from halo, nitro, hydroxy, C1-C6 alkyl, or C1-C6 substituted alkyl; phenyl, substituted phenyl, or an acyl group of the formula , wherein R''' is C1-C6 alkyl, C1-C6 substituted alkyl, phenyl, or substituted phenyl; and R3 is hydrogen, C1-C4 alkoxy, or a group of the formula -NHCHO.

X-7967A (EPO) - 64 -

8. A pharmaceutical formulation comprising as an active ingredient a compound as claimed in any one of Claims 1 to 6 or a pharmaceutically acceptable salt thereof, associated with one or more pharmaceuti-cally acceptable carriers, excipients, or diluents therefor.

9. A compound as claimed in any of Claims 1 to 6 or a pharmaceutically acceptable salt thereof for use as an antibiotic agent.