CA1243679A - 3-ACYLAMINO-2-OXO-1-AZETIDINYL-.beta.-OXYPROPIONATES - Google Patents

Abstract

GC209 ABSTRACT 3-ACYLAMINO-2-OXO-1-AZETIDINYL-.beta.-OXYPROPIONATES Antibacterial activity is exhibited by (3-acylamino)-2-azetidinones having in the 1-position a group of the formula or a salt or ester thereof wherein R5 and R6 are the same or different and each is hydrogen, halogen, hydroxy, alkoxy, alkylthio, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, (cycloalkyl)-alkyl, (cycloalkenyl)alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl or together R5 and R6 can be ,CZ1Z2 Z1 and Z2 are the same or different and each is hydrogen, alkyl, phenyl, or substituted phenyl; and R7 is hydrogen and R8 is hydrogen, hydroxy, alkoxy, alkanoyloxy, or halogen, or together R7 and R8 can be =CZ1Z2.

Description

367'1'3 3-ACYL~MINO-2-OXO-l-AZETIDINYL-~-OXYPROPIONATES
This in~ention relates to new compounds ~avi~ ths ~ormula I R2 -~
Rl-NH-~ C~R3 1 ¦ l5 17 C - - N- 0~ I-C-COOH , and salts and esters thereo~, which e~hibit antibacterial activity. In formula I and throughout the speci~ication, ~he symbols are as defined below.
R~ is an acyl group derived from a carboxylic acid;
R2 is hydrogen or m~thoxy;
R3 and R4 are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cyclo-alkyl, phenyl, substituted phenyl or a 4, 5, 6 or 7-membered heterocycle (referred to hereina~ter as Rx) or one of R3 and R4 is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalo-methyl, alkoxycarbonyl, 2-phenylethenyl,

2-phenylethynyl, carboxyl, -CH2Xl ~wherein Xl is azido, amino (-NH2), hydroxy, alkanoylamino, phenylcarbonylamino, (substituted phenyl}carbonyl-amino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, cyano, -A-~-NX6X7, -S-X2, or -O-X2 (wherein A, X2, X6 and X7 are as hereinafter defined)], -S-X2 or -0-X2 ~wherein X2 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substi~uted phenyl)alkyl, al~anoyl, phenylalkanoyl, ~substitùted phenyl)alkanoyl, phenylcarbonyl, ~`

~4~675~

(substituted phenyl)carbonyl, or heteroaryl-carbonyl]~ l3 13 -0-C-X~ o~ -S-C 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 ato~ to which they are attached form a cycloalkyl group; and X~ is formyl, alkanoyl, phenylcarbonyl, ~substit~ted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl (NH2-~-), (substituted amino)-carbonyl, or cyano (-C-N)], or -A-C-NX6X7 twherein A is -CH=CH-, -(C~2)n-, -CH2-0-, -CH2-NH-, 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 hydro~en and X7 is amino, subs~ituted amino, acylamino or alkoxy, or X~ and X7 when taken together with the nitrogen atom to which they are attached form a 4, 5, 6 or 7-membered heterocycle):
R5 and R~ are the same or different and each is hydrogen, halogen, hydroxy, alkoxy, alkylthio, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl, phenyl, substituted phenyl, phenylalkyl or (subs~ituted phenyl)alkyl or together R5 and R6 can be SCZlZ2 wherein Zl and Z2 are the same or different and each is hydrogen, alkyl. phenyl, or substituted phenyl: and 6~

R7 is hydcogen and R~ i5 hydrogen, hydeoxy, alkoxy, alkanoyloxy, or halogen, or together R7 and R8 can be ~CZ1Z2 ( 1 Z2 are defined above) or dxo (,0).
Listed below are definitions o~ various terms used to describe the A-lactam~ of this invention.
These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in ~pecific instances) either individually oc as part of a larger group.
The ~erms "alkyl" and "alkoxy" refer to both - straight and branched chain groups. Those groups having 1 to 10 carbon atoms are preferred.
The terms "cycloalkyl" and "cycloalkenyl"
refer to cycloalkyl and cycloalkenyl groups havin~

3,4,5,6 or 7 carbon atoms.
The term "substituted alkyl" refers to alkyl groups substituted with one, or more, azido, amino (-NH2), halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenyloxy, tsub~tituted phenyl)oxy, Rx-oxy, mercapto, alkylthio, phenylthio, (substituted phenyl)thio, alkylsulfinyl, or alkylsulfonyl gruops.
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.
~he term "pcotected carboxyl~' refers to a carboxyl group which has been esterified with a conventional acid pcotecting group. These groups are well known in the art: see, for example, United States patent 4,144,333, issued ~arch 13, 1979.

-~LZ~

The pLeferred protected carboxyl groups are benzyl, benzhydryl, t-butyl, and ~-nitrobenzyl esters.
The term "substituted phenyl" ~eers to a phenyl group substituted with 1, 2 or 3 amino (-NH2), halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to ~ carbon atoms), alkoxy (o~ 1 to 4 carbon atom~), or carboxyl groups.
The expression "a 4,5,6 or ?-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, tri~luoromethyl, al~yl of 1 to 4`
carbons, alkoxy of 1 to 4 carbons, alkylsulfonyl, phenyl, substituted phenyl, ~-furfurylideneamino ~O~,CH,N-( ~ ), benzylideneamino and substituted alkyl groups (wherein the alkyl group has 1 to 4 carbons). One type o~ "4,5,~ or 7-membered heterocycle" is the "heteroaryl" group. The term "heteroaryl" refers to those 4,5,6 or 7-membered heterocycles which are aromatic. Exempla~y 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 unsub6tituted azetinyl, oxetanyl, thietanyl, piperidinyl; piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydLopyLimidinyl, dihyrothiazolyl and hexahydroazepinyl. Exemplary '`

6~7~3 of the substi~uted 4,5,6-or 7-membered heterocycles are l-alkyl-3-azetinyl, 2-oxo-1-imidazolidinyl, 3 alkylsulfonyl-2-oxo-1-imidazolidinyl, 3-benzylimino-2-oxo-1-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-~(alkoxycarbon~l')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-tetrahydeofuranyl, 2,3-dioxo- l-piperazinyl, 2,5-dioxo-1-piperazinyl,

4-alkyl- 2,3-dioxo-1-piperazinyl, and ~-phenyl-2,3-dioxo-l-piperazinyl.
The term "substituted amino" refers ~o a group having the formula -NYlY2 wherein Yl is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, and ~2 is alkyl, phenyl, ~ubstituted phenyl, phenylalkyl, (substituted phenyl)alkyl, hydroxy, cyano, alkoxy, phenylalkoxy, or amino (-NN2)~

~3~7~

The term "acyl" refers to all organic radicals derived from an organic acid (i.e., a carboxyllc acid) by removal of the hydroxyl group. Certain acyl groups are, of course, preferred but this preEerence should not be viewed as a limitation of the scope of this invention. Exemplary acyl groups are those acyl groups which have been used in the past to acylate ~-lactam antibiotics including 6-aminopenicillanic acid and derivatives and 7-aminocephalosporanic acid and derivatives;
see, for example, Cephalosporins and Penicillins, edited by Flynn, Academic Press (1972), German Offenlegungsschrift 2,716,677, published October 10, 1978, Belgian patent 867,994, published December 11, 1978, United States patent 4,152,432, issued May 1, 1979, United States patent 3,971,778, issued July 27, 1976, United States patent 4,172,199, issued October 23, 1979, and British patent 1,348,894, pub-lished March 27, 1974. The following list o~
acyl groups is presented to furkher exemplify the term "acyl"; it shouId not be regarded as limiting that term. Exemplary acyl groups are:
(a) Aliphatic groups having the formula R -C-wherein Ra is alkyl; cycloalkyl; alkoxy; alkenyl;

,, ~, ~ ;;

, :~LZ~3ti~

cycloalkenyl; cyclohexadienyl; or alkyl or alkenyl substituted with one or more halogen, cyanp, nitro, amino, mercapto, alkylthio, or cyanomethyl-thio groups.
(b) Carbocyclic aromatic groups having the formula Rb~_d( CH ) -C-, Rb ~ Re Rb ~ C52-O-C-, Rc Rb ~ O-CH -~-. GC209 Rb ~ S-C~2-ll- or -~H2-S~
wherein n is 0, 1, 2 or 3; Rb, Rc, and Rd each is independently hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon 15 atoms or aminomethyl; and Re is amino, hydroxyl, a carboxyl salt, protected carboxyl, formyloxy, a sulfo salt, a sulfoamino salt, azido, halogen, hydrazino, alkylhydrazino, phenylhydrazino, or [(alkylthio)thioxomethyl]thio.
20Preferred carbocyclic aromatic acyl groups include those having the formula 25HO ~ CH~-C-, 30~ H2 C , :
C~2NH2 : :
``~

, :

-..

:: .
.

~2~13~3 , GC209 _g_ EIO ~ H-C- (Re is pre~erably ~e a carboxyl sal~ or sul~o salt) and ~ C~l-C- (R is pref er~hly a carboxyl salt or sulfo salt).
(c) Heteroaromatic groups having the formula Rf-(CH2)n-C-, Rf CH-C-Re R,-O-CH2-C- , Rf-S-CH2-1- , O O

Rf-C - C- , wherein n is 0, 1, 2 or 3; Re i5 as defined above; and Rf is a substitu~ed or unsubstituted

5-, S- or 7-membered heterocyclic ring containing 1,Z,3 or 4 (preferably 1 or 2) nitrogen, oxygen and sulfur atoms. Exemplary heterocyclic ' -- ~L2~;~6 ~

--10~

rings are thienyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, pyxazinyl, thiazolyl, pyrimidinyl, thiadiazolyl and tetrazolyl. Exemplary substituents are halogen, hydroxyl, nitro, amino, prote~ted amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon akoms, alkoxy of 1 to 4 carbon atoms, or Il .
~OOC-CH-CH~-0-C-NH- .

1~
Preferred heteroaromatic acyl groups include those groups of the above formulas wherein Rf is 2-amino-4-thiazolyl, 2-amino-5-halo-4-~hiazolyl, 4-ami~opyrimidin-2-yl, 5 amino-1,2,4-thiadiazol-3-yl, 2-thienyl, 2-furanyl, or 6-aminopyridin-2-yl.
(d) [~(4-Substituted-2,3-dioxo-1-piper-azinyl)carbonyl]amino]arylacetyl groups having the formula 1 1O~
-C-CH NH-C-N N-Rh R ~
g O O
wherein Rg is an aromatic group (including 2~ carbocyclic aromatics such as those of the rormula Rc Rb~Rd and heteroaromatics as included within the definition of R); and Rh is alkyl, substituted 4367~
. GC209 alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, ~mino or mercapto groups), arylmethyleneamino (i.e., ~N=CH~Rg wherein Rg is as defined above), R
arylcarbonylamino (i.e., ~NH~C~Rg wherein Rg is as de~ined above) or alkylcarbonylamino.
Preferred L [(4-substituted-2,3-dioxo-1-piperazinyl)carbonyl]amino]arylacetyl groups include those wherein Rh is ethyl, phenylmethylene-amino or 2-furylmethyleneamino.
(e) ~Substituted oxyimino)arylacetyl groups having the formula -C-C=N-O-R
g wherein Rg is as defined above and Ri is hydrogen,-alkyl, cycloalkyl, alkylaminocarbonyl, arylamino-carbonyl (i.e., ~C~NH-Rg wherein Rg is as defined above) or substituted alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino, mercapto, alkylthio, aromatic group (as defined by Rg), carboxyl (including salts thereof), amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy(phenylmethoxy)phosphinyl, or dialkoxy-phosphinyl substituents).

.

6'7~

.. .

Preferred ~substituted axyimino)arylacetylgroups include those wherein Rg is 2-amino-4-thiazolyl. Also preferred are those groups wherein Ri is methyl, e-thyl, carboxymethyl, l-carboxy-l-methylethyl, 2,2,2-tri1uoroethyl or l-carboxycyclop.ropyl.
(f~ (Acylamino)arylacetyl groups having the formula 0 O
-C-CH~NH-C-R
Rg where'n Rg lS as defined above and Rj is Rb ~ d ~ (CH2)n-O-, amino, alkylamino, (cyanoalkyl)-amino, amido, alkylamido, (cyanoalkyl)amido, -CH2-NH-C ~ N -CH-CH2-C-NH-CH3, EIO
~02-N ~CH2 -CH2 OH)2 ' ~CH3 OH
,OH OH

~ ' ~ ~ ~ ~_~N -CH ~ or HO ~ C-O O

~4~67~ GC209 .. , O Preferred (acylamino)arylacetyl groups of the above formula include those groups wherein Rj is amino or amido. Also preferred are those groups wherein Rg is phenyl or 2-thienyl, (g) [~[3-Substituted-2-oxo-1-imidazoli-dinyl]carbonyl]amino]arylacetyl groups having the formula o O O C
-C-CH NH-C-N N~Rk Rg CH2 -CH2 wherein Rg is as dsfined above and Rk is hydrogen, alkylsulfonyl, arylmethyleneamino (i.e~, ~N=CH~Rg wherein Rg is as defined above), -C-Rm (wherein Rm is hydrogen, alkyl or halogen substituted alkyl), aromatic group (as defined by Rg above), alkyl or substituted alkyl (wherein tne alkyL group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups).
Preferred ~[3-substituted-2-oxo-1-imidazoli-dinyl]carbonyl]amino]arylacetyl groups of the above formula include those wherein Rg is phenyl or 2-thienyl. Also preferred are those groups wherein Rk is hydrogen, methylsulfonyl, phenyl-methyleneamino or 2-furylmethyleneamino.

. ~ ,, .

~ :, ~ ~3~7~3 The terms "salt" and "salts" refer to basicsalts formed with inorganic and organic bases.
Such salts include ammonium salts, alkali metal salts like sodium and potassium salts (Which are preferred), alkaline earth metal salts like ~he calcium and magnesium salts, salts with organic bases, e.q., dicyclohexyla~ine salt, benzathine, N-methyl-D-glucamine, hydcabamine salts, salts with amino acids like arginine, lysine and the like.
The nontoxic, pharmaceutically acceptable salts are preferred, although other salts are also useful, e.~., in isolating or purifying the product.
The salts are formed in conventional manner by reacting the free acid form of the product with one or more equivalents of the appropriate base providing the desired cation in a solvent or medium in which the salt is insoluble, or in water and removing the water by freeze drying. By neutralizing the salt with an insoluble acid like a cation exchange resin in the hydrogen form (e.~., polystyrene sulfonic acid resin like Dowex 50) or with an aqueous acid and extraction with an organic solvent, e.q., ethyl acetate, dichloromethane or the like, the free acid form can be obtained, and, if desired, another salC formed.

~36'7~

British Application 8320497, published under No. 2125794, discloses ~-lactam antibiotics and intermediates having the ~ormula R2 _9 L ~

~c l o c - COOH

and salts and esters thereof, wher~in RL is hydrogen or acyl, az is hydrogen o~ methoxy, and R3. R4. R5 and R6 are as defined hereinafte~. Additionally. the patent application disclo6es intermediates having the formula R~

- N-O-CH2fHC02alkyl N~l~z wherein Al and A2 are amino protecting groups.
As set forth throughbut this present sPecification~ -~-lactams having in the l-position an ester of the R5 l7 group -O-C -C-COOH are contemplated as an integral part of this invention. Exemplary esters include alkyl, aikenyl, alkynyl, cycloalkyl, ~cycloalkyl)alkyl, Rx-alkyl, trialkylsilylalkyl, mono-, di- or trihaloalkyl, hydroxyalkyl, ~ Z~367~

alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl,diphenylmethoxy- carbonylalkyl, carbamoylalkyl, alkylcarbamoylalkyl, dialkylcarbamoylalkyl, indanyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, Rx-carbonylalkyl, -~H-O-~-Y4 ~wherein Y3 is hydrogen, alkyl or phenyl and Y4 i5 hydeogen, alkyl, cycloalkyl, (cycloalkyl)oxy, phenyl, or alkoxy, or together Y3 and Y4 are -(CH~)2-, O' `
-(CH2)3-, -CH=CH-, or ~ ], and _ IHl Y3 esters. ~ Y3 Hyd~olyzable esters are ~hose esters that can be hydrolyzed ln vivo to give the parent carboxylic acid product; they exhibit the antibiotic acitivity of the parent carboxylic acid. Non-hydrolyzable esters (esters that do not hydrolze in vivo to the parent carboxylic acid) are contemplated foe use in this invention as intermediates: some of them are also active as antibiotics.
I5 l7 ~-Lactams having a -O-C- ~-COOH substituent ~ 6 8 (or an ester or salt thereof) in the l-position and an amino or acylamino substituent in the 3-position contain at laast one chiral center -- the carbon atom (in the 3-position of the B-lactam nucleus) to which the amino or acylamino substituent is attached. This invention is directed to those ~-lactams which have been described above, whe~ein the stereochemistry at the chiral center in the .

, . . .
~' ` . .

~LZ4367~3 3-position of the A-lactam nucleus is the same as the configuration at the carbon atom in the 6-position of naturally occu~ring penicillins (e.q., penicillin G) and as the configuration at the carbon atom in the 7-position of naturally occurring cephamycins, (e.~., cephamycin C).
Also included within the scope of thi6 invention are racemic mixture6 which contain the above-described B-lactams.

The ~-lactams of formula I, and salts thereof, have activity against a range of gram-negati~e and gram-positive organisms. The compounds of this invention can be used as agents to combat bacterial infections ~including urinary tract infections and respiratory infections) in 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 mgJkgJday, 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 a~d cephalo6porins to the site of the infection are also contemplated for use with the novel family of B-lactams of this invention.
Such methods of administration include oral, intravenous, intramuscular, and as a suppository.

~Z~6~9 The ~-lactams of this invention can be prepared from an amino acid having the ~ormula II OH ~R~
NH2-lH - ~ R3 ~ OH

The amino group is first protected with a classical peotacting group (e.q., t-butoxycarbonyl. benzyl-oxycarbonyl. o-nitrophenylsulfenyl, etc.), yielding the compound having the formula Al-NH-fH C~ R3 ~ ~ OH

In formula III, and throughout the specification, the symbol "Al" refers to a nitrogen protecting group. For certain produc~s of formula I, the desired acyl group "Rl" can be used as the protecting group "Al" and thus incorporated a~
the beginning of the reaction sequence.
Reaction of an N-protected amino acid of formula III with a compound baving the formula IV R5 ~7 yields a compound ha~ing the focmula A -NH

¦ l5 l7 O R~ R~

.

~243679 In formula V, and throughout the specification, the symbol Z3 represents a carboxyl p~otecting group.
The hydroxyl group of a compound of Eormula V
is converted to a leaving group using, fo~ example, a classical reagent such as methanesulfonyl chlo~ide lme~hanesulfonyl is referred to hereinafter as "Ms").
The fully protected compond having the formula VI OMs ,R~
Al-NH-CH ~\ R3 ¦ I ~ 7 is cyclized by treatment with base. e.q., potassium carbonate. The reaction is preferably carried out in an organic solvent such as acetone, under reflux conditions, and yields a compound having the formula Al-~H-C~ - C-R
¦ ¦ l5 17 NH-O-C-c-cOOz3 -6 a Alternatively, cyclization of a compound of formula V can be accomplished without first converting the hydroxyl group to a leaving qroup.
Treatment of a compound of formula ~ with triphenylphosphine and diethylazodicarboxylate or carbon tetrachloride, yields a compound of formula VrI.
Both of the methods disclosed above fo~ ring closure of a compound of formula V result in the inversion of the stereochemistry of the R3 an~
R4 substituents.

,.

~;~4~6~

Deprotection of the 3-amino substituent o~ a compound of ~ormula ~II can be accomplished using art-recognized techniques. If, for example, the pro~ecting group is t-butoxycarbonyl, trifluoroacetic acid can be uæed to deprotect the amino group. If the protecting group is benzyloxy-carbonyl, catalytic (e.q., palladium on charcoal~
hydrogena~ion can be used. If the protecting goup is o-nitrophenylsul~enyl, ~-toluenesulfonic acid can be used in combination with ~-thiocresol. The deprotected compound has the foemula NH2-C~ - ~-R3 i I R5 R7 ~C - - N-O-C--C~ -OZ3 and is a key intermediate for preparing the compounds of this invention. The compounds of formula V}II form an integral part of this invention.
Well known acylation techniques can be used to convert a compound of formula VIII to the corresponding compound having the formula Rl-NH-CH C-R3 5 ~7 ~ ~ N-0- - -C-OZ3 .

Exemplary techniques include reaction wit~ a carboxylic acid (Rl-OH) or corresponding carboxylic acid halide or carboxylic acid anhydride. The reactions with a carboxylic acid proceèd most readily in the presence of a carbo-diimide such as dicyclohexylcarbodiimide and a 67~

substance capable of forming a reactive intermediate ln situ such as N-hydroxybenzo-triazole or N-hydroxysuccinimide. In those instances wherein the acyl g~oup (R1) contains reactiYe funct;.onality (such a6 amino or carboxyl groups) it may be necessary to irst protect these functional groups, then carry out the acylation reaction, and finally deprotect the resulting product.
Deprotection of the carboxylic acid group, followed by esterification (if desired), yields the desired products of formula I wherein R2 is hydrogen.
Alternative means are available for converting an intermediate of formula VI r to a product of formula I. For example, a compound of formula VII can be reacted with N-methyl-N-tri-methyl~ilyl-trifluoroacetamide (MSTPA) and a silane such as iodotrimethylsilane to cleave the "AL"
and "Z3" groups to yield the corresponding 3-trimethylsilylamino compound, which can be acylated using the above-described procedures.
The products of formula I wherein R2 is methoxy can be prepared from the corresponding compound of formula VII. Halogenating (preferably chlorinating) the amide nitrogen of a compound of ` formula VII wherein Al is benzyloxycarbonyl, or benzylcarbonyl, yields a compound having the formula X Cl R4 - 1 l5 C7 ~6 R~

~2~6'79 Reagen~s and procedures of N-chlorinating amides are well known in the art. Exemplary reagen~s a~e tert.-butyl hypochlorite, sodium hypochlorite, and chlorine. The reaction can be run in an organic solvent ~e.q., a lower alkanol such as methanol) or in a two phase solvent system (e.q., water/m~thyl-ene chloride) in the presence of a base such as sodium borate decahydrate. The reaction is prefeeably run at a reduced temperature.
Reaction of a compound of foemula X with a methoxylating agent, e.q., an alkali metal methoxide, yields a compound ~in combination with its enantiomer if R3 and R4 are the same or if X is a racemic mixture) having the formula Al-NH-CH - C-R

d l o ~ - ~ - C-OZ3 The reaction can be run in an organic solvent, e.q., a polar organlc solvent such as tetrahydro-furan, at a reduced temperature.
Alternatively, a comeound of formula VII can be converted to a compound of formula XI using a single step procedure. The methoxylating agent can first be mixed with a compound of formula VII and the N-chlorinating reagent then added to the reaction mixture.
Conversion of a compound of formula XI to the desired product of formula I can be accomplished using the procedures described above for the conversion of an inter~ediate of formula VrI to a product of this invsntion.

`
`:
, ~
.:

~Z~136'79 The starting materials of formula II are readily obtainable using art-recognized procedures;
see, for example. SYnthesis, pg. 216 (1979) and J
Orq. Chem., 44:3967 (1979~.
The starting materials of formula IV are obtainable by first reacting a compound having the formula XII l5 R7 C =C-COOalkyl.
~6 with a compound ha~ing the formula XIII alkyl /C=N-OH
alkyl to yield a compound having the formula XIV alkyl aS l7 /C=N-O- f _ CH-COOalkyl alkY~ ~6 or by first eeacting a compound of formula XII with a compound having the formula XV alkyl-O \
/C=N-OH
alkyl to yield a compound having the formula XVI alkyl-O\ R5 l7 /C=N-O-C-CH-COOalkyl .
alkYl ~6 Hydrolysis of a compound of formula XIV or XVI
yields a salt of the corresponding compound having the formula XVII l5 C7 H2N-O-~- ~-COOH

l;Z~3~i ~ 9 Partial hydrolysis of a compound of formula XVI bymeans of HC1 yields a salt having the formula XVIII l5 R7 HCl H2N-O-~- ~H-COOalkyl .

This method i~ advantageous if ~he alkyl ester group is a suitable pcotecting group (Z3).
~efare a carboxyl protecting group ~Z3) can be added to a compound of formula XVII the amino group must firs~ be protected using conventional technigues. The carboxyl protecting group (Z3) can then be added, and the amino protecting group removed to yield the corresponding starting material of formula IV.
Alternatively, a compound of formula XIII or XV can be reacted with a compound having the ~ormula XIX l5 l7 Z4-C-C-COOalkyl wherein Z4 is a leaving group such as chlorine, ~-~oluenesulfonyl or methanesulfonyl to yield a compound having the formula XX alkyl l5 l7 \ C=N-O-C- C-COOalkyl or alkyl R6 R8 XXI alkyl-\ l5 l7 / C~N-O-C- C-COOalkyl or alkyl ~6 R8 Treatment of a compound of formula XX or XXI in the manner described above for the treatment of a compound of formula XIV yields the corresponding stareing material of formula IV.
~ he following examples are specific e~bodiments of this invention.

:LZ~6~9 .

ExamPle 1 (3S-trans)-~3-[~(t-ButYloxY2carbonyllaminol-4-methYl-?-oxo-l-azetidin~lloxYl-B----propanoic acid, diphenvlmethvl ester A) N-Phthalovl-B-aminoxvProPanoic acid A solution of 29.6ml (0.36 mol) of pyridine in 25ml of dry dioxane was dropped into a solution of 26.6g (0.18 mol) of ph~halic anhydride and 25.5g (0.1~ mol~ of ~-aminoxypropanoic acid hydro-chloride in lOOml of dcy dioxane. The mixture was refluxed for 3 to 4 hours and then evaporated in vacuo. The residue was taken up in cold water and adju6ted to pH 8 by the addition of sodlum carbonate. After extraction with chloroform the aqueous phase was acidified with dilute HCl ~o pH 2 and then extracted again several times with chloroform. The combined organic layers were dried with CaS04 and then evaporated in vacuo. The residue was crystallized from hot e~hanol, yielding

7.2g of the ti~le compound, melting point 128-13~C
(dec~
B) N-Phthalo~yl-~-aminoxypropanoic acid, diphenvlmethyl ester A solution of freshly prepared 8.6g (0.044 mol) diphenyldiazomethane in 70ml dioxane was dropped into a solution of 9.5g (0.04 mol) of N-phthaloyl-~-aminoxypropanoic acid in 30ml of dioxane at room temperature. After stirring overnight and concentration in vacuo, the residue was dissolved in chloroform and washed twice with - NaHC03 solution and then with water. Drying over ~Z~3679 CaS04, ~iltration, evaporation of the so}vent invacuo and stirring with petroleum ether (boiling point 40~60C~ yielded l5.0g of the title compound as slightly pink crystals, melting point 11~-118C.

C) B-Aminoxypro~anoic acid~_diPh-enyl~ethyl ester N-Phthaloyl-~-aminoxypeopanoic acid, diphenyl~ethyl ester (16.lg) (0.04 mol) was - dissolved in 80ml of dichloromethane and cooled to ooc. Hydrazine hydrate (3.5ml) (0.072 mol) was added dropwise a~ 0C and stirring was continued for 4 hours at room temperature. The precipitated phthalhydrazide was removed by suction and the filtrate was concentrated in vacuo. The residual oil was dis~olved in ether, insoluble impurities were filtered off and the sol~ent was distilled off again in vacuo to give in quantitative yield a syrup which was used directly in the next step.

D) ~-~2-t5DiPhenYlmethoxy-)carbonyllethyl~
N-l~t-butYloxY)carbonyll-L-threonine hydroxamate A solution of 6.33g (0.03 mol) of dicyclo-hexylcarbodiimide (DCC) in lOml of dry tetrahydro-furan was dropped into a solution of 6.73g ~0.03 mol) of N-~-~(t-butyloxy)carbonyl]-L-threonine, 4.71g (0.03 mol) of l-hydroxybenzotriazole hydrate (HOBT) and 8.33g (0.03 mol) of ~-aminoxypropanoic acid, diphenylmethyl ester in 200ml of dry tetrahydrofuran at 0-5C. The mixture was stirred overnight at eoom temperature. The precipitated dicyclohexylurea was removed by filtration and the filtrate was concentrated in vacuo. The residual ,~
, ,67~31 oil was dissolved in ethyl acetate, insolubledicyclohexylurea was separated by filt~atlon, and the ~iltrate was washed ~ive times With 5% NaEIC03 solution, once with aqueous buffer soiution p~l 4 (citrate) and then with water. Drying over M~S04, ~ollowed by filtration and evaporation ln vacuo gave 12.4g of an oily residue. The oily ~esidue was dissolved in acetonitrile and dried over molecular sieves (3~). The solvent was eemoved in vacuo and the crude oil was used in the next step without any further purification.

E) (3S-trans)-~3-[L~t-ButYloxY~carbonYll-aminol-4-methvl-2-oxo-1-azetidinYlloxYl-~3-Propanoic acid, diPhenylmethvl ester Triphenylphosphine (7.5~g) (0.029 mol) was added to a solution of 12.41g (0.026 mol) o~
0-~2-t(diphenylmethoxy)carbonyllethyl]-~-N-t(t-butyloxy)carbonyl]-L-threonine hydroxamate in 130ml of dry acetonitrile. A solution of 6.04ml (0.043 mol) of triethylamine and 2.81ml (0.029 ml) of carbon tetrachloride in 13ml of dry acetonitrile was added dropwi~e at room temperature and the mixture was stirred overnight. The solvent was removed in vacuo and the residue was dissolved in chloroform, washed twice with aqueous buffer solution pH 4 (citrate), dried over MgSO4, filtered and evaporated in vacuo. The residue was chromatographed on silica gel, eluting with ether/ethyl acetate (2:1). The fractions which did not contain any triphenylphosphine oxide were combined and concentrated in vacuo and purified by ~L2~67~

a second chromatog~aphy on silica gel eluting Withtoluene/ether (3:1). Evaporation of ~he appeopria~e t~actions yave 4.6g of the title compound as a highly viscosou~ oil.
ExamPle 2 ~3S-[3~Z),4B~1-3- r ~ (2-~mino-4-thiazolYl ) -(methoxYiminolacetyllaminol-4-methvl-2-oxo-l-azetidinYlloxYl-~-Propanoic acid, sodium salt A) (3S-transl-~t3-Amino-4-methYl-2-oxo-1-azetidinYl)oxyl-B-Propanoic acid. trifluoroaceta~e salt (3S-trans)-~3-t t ~ lt-Butyloxy)carbonyl]-amino]-4-methyl-2-oxo-1-azetidinyl]oxy]-B-propanoic acid, diphenylmethyl ester (3.~Sg, 8.05 mmol; see example lE) was dissolved in a solution of 1.6ml (1.47 mmol) of anisole in 16ml of trifluoroacetic acid at -10C. The mixture was evaporated ln vacuo (bath temperature 0-5C) 10 minutes later and the residue was stirred with dry ether. The organic layer was separated from the semi-solid p~oduct which was dried in vacuo over P205. yielding l.L7g of the title compound.
B) ~ S-r3~(Z),4~ lL3~ 2-Amino-4-thiaæolYl)-(methoxYimino)acetyllaminol-4-methyl-2-oxo-1-azetidinYlloxyl-~-pro~anoic acid, sodium salt N-~ethyl-N-trimethylsilyltrifluoroacetamide (0.93ml, 5.04 mmol) was added to a suspension of 0.48g (L.59 mmol) of (3S~trans)-~(3-amino-4-methyl-2-oxo-1-azetidinyl)oxy]-~-propanoic acid, ., .. . ' ., .

16~YI

trifluoeoacetate salt in 6ml of dryacetonitrile/tetrahydrofuran (1:1~ at 0C andstirriny was continued for 30 minutes at room temperature. After removing the solvents 1n vacuo, the oily residue was dissolved in 5ml of dry tetrahydrofuran and then added to a mixture o~
Q.51g ~1.59 mmol) of dry ~Z)-2-amino-~-(methoxy-imino)-4-thiazoleacetic acid, l-hydroxybenzo-triazole estee in 5m} of dry tetrahydrofuran at 0C. After stirring overnight and evaporation in vacuo, the residue was taken up in ether, lml of methanol was added, followed by ice-cold water and the pH of the mixture was adjusted to 6.5 by the addition of NaHCO3 solution. The aqueous layer was separated, washed with additional ether and then free2e-dried. Reverse phase chromatography on HP-20 re~in with water as eluent and freeze-drying of the corresponding fractions yielded 210mg of the title compound, melting point >100C, dec.
Example 3 L3S-1 ~(Z1.4~ t~2-Amino-4-thiazolyl~ r (1-carboxY-l-methylethoxy)iminolacetYllaminol-4-methYl-2-oxo-1-azetidin~lloxyl-B-p~opanoic acid, sodium salt N-Meehyl-N-trimethylsilyltrifluoroacetamide (l.Llml, 6,02 mmol) was added to a suspension of 0.57g (1.9 mmol) of (3S-trans)-~(3-amino-4-methyl-2-oxo-1-azetidinyl~oxy]-B-propanoic acid.
trifluoroacetate salt in 6ml of dry acetonitrile/
~etrahydrofuran (1:1) at 0C. After stiLring for 30 minutes at room temperature, the solvents were distilled off in vacuo. The oily residue was dissolved in 5ml of dry tet~ahydrofuran and then .

61-~9.

added at room temperature to a reaction mixture of 0.84g ~1.9 mmol) o~ (Z)-2-amino-~-~(1-diphenyl-methoxycarbonyl-l-methyle~hoxy)imino-4 thiazoleacetic acid, 0.3g(1.9 mmol) of l-hydroxyben20~riazole and 0.39g (1.9 mol~ of dicyclohexylcarbodiimide in lOml of dry tetrahydrdfuran which had been previously stirred for 2 hours at 50C. Stirring was continued for 3 hours at room temperature, the precipitate was filtered off and the solvent was removed in vacuo. The residue was taken up in ether, lml of methanol was added, followed by ice-cold water and the pH of the mixture was adjusted to 6.5 by the addition of NaHC03 solution. The aqueous layer was separated and lS freeze-dried and the resulting [3S-~3~(Z),4~]]-~3-~(2-amino-4-thiazolyl)t(l-diphenylmethoxy-carbonyl-l-methylethoxy)imino]acetyl]aminol-4-methyl-2-oxo-1-azetidinyl]oxy]-~-propanoic acid, sodium salt was chromatographed on HP-20 resin eluting with H20Jacetone. Freeze-drying of ~he appropriate fractons gave a colorless powder which was added to a -10C cold mixture of 3.8ml of trifluoroacetic acid and 0.38ml of anisole. After stirring at room temperature for 30 minutes, the solvent was distilled off in vacuo. Ether and ice-cold water were added and the pH of the mixture was adjusted immediately to 6.5 by the addition of NaHC03 solution. After freeze-drying of the separated aqueous layer, the crude title compound was purified by reverse phase chromaeography on HP-20 resin eluting with water. Free2e-drying of the appropriate fractions gave O.~9g of a colorless solid which decomposed at >110C.

~;~4367~
~- GC209 Example 4(3S-trans~-1[3-[~(PhenYlmethoxYl~arbonyllaminol~
4-methYl-2-oxo-l-azetidinvlloxy]-~-peopanoic acid, methYl ester A) R-AminoxYPro~anoic acid, methvl e~ter, hvdrochloride A 601ution of 37.9g ~0.44 mol) of methyl acrylate in lOOml of dry dioxane was slowly dropped into a mixture of ~L.3g (0.4 mol) of ethylaceto-hydroximate and 2.2g (0.04 mol) of sodium methoxide in 400ml of dry dioxane at 20C. The mixture wa~
stiered for 5 hours a~ room temperature and then concentrated in vacuo. The eesidual li~uid was taken up in dry ether, filtered and fractionated in vacuo. ~he fraction bpl6 100-115C was collected and yielded 53.6g of material. 13.9g (0.10 mol) of this material was dissolved in 20ml of dry dioxane, 1.8ml (0.1 mol) of water was added and ~he mixture was saturated with gaseous hydrochloric acid by slight cooling. The ~lear solution was evaporated in vacuo and the residual oil crystallized after the addition of isopropanol by cooling (-10C).
Ice-cold ether was added with stirring and the hygroscopic, colorle~s crystals were collected by suction and dried in ~acuo over P205~ yielding 129 of the title compound.

B) O- r 2-(Methoxycarbonyl)ethYll-~-N-~(~henyl-methoxv~c~rbonyl ~-L-threonine hYdroxamate A 601ution of 5.07g (0.02 mol) of [(phenyl-methoxy)carbonyl]-L-threonine in 15ml of water was dropped into a solution o~ 4.67g (0.03 mol) cf methyl-R-aminoxypropionate, hydrochloride and the ., '-"~

~ .

~2~ 79 pH of the solution was adjusted to 4 - 5 by simultaneous addition of 2N NaO~I. With pEI control (pH 4 - 5), a solution o~ 4.22g t0.022 mol) oP
N-ethyl-N'-(3-dimethrlaminopropyl)carbodiimide, hydrochloride in 5ml of water was added and stirring was continued for 3 hours. The reaction mixture was extracted with ethyl acetate and the organic layer was washed successively with lN
citeic acid, 5N NaHC03 and water and ~hen dried with CaSo4. Filtration and removal of the sol~ent in vacuo gave a waxy colorless peoduct.
c) (3s-trans)-r r3-l r (PhenYlmethoxY)carbonYll-aminol-4-rnethYl-2-oxo-l-azetidinylloxyl-~-propanoic acid, me~hyl estee Starting from 4.95g (1~ mmol) of 0-~2-(methoxycarbonyl)ethyl]-~-N-t~phenylmethoxy)-carbonyl]-L-threonine hydroxamate. 4.04g (15.4 ~mol) of triphenylphosphine, 3.22ml (23.1 mmol) of ~riethylamine and 1.50ml (15.5 mmol) of carbon tetrachloride the title compound was prepared using the same conditions as in example 1~.
Chromatography of the crude reactio~ product on silica gel (eluting with toluene) gave a colorless high viscosous oil: yield 2.7g.

Example 5 [3s-r3~tz~4~ 3-~ r t2-Amino-4-thiazolyll-(methoxyimino~acetyllaminol-4-methyl-2-oxo-1_ aze~idin~lloxYl-B=ProPanoic acid, methvl ester (35-trans)-~t3-[~tPhenylmethoxy)carbonyl]-amino]-4-methyl-2-oxo-1-azetidinyl]oxy]-B-propanoic acid, methyl ester 0.765g ~2.38 mol) was dissolved in ~Sml of dry dimethylfor~amide and hydrogenated with 0.4g of palladium on charcoal (10%~ as catalyst. ~fter 40 minutes, the catalyst was filtered off and the filtrate was added to a solution of 0.76g (Z. 3a mmol) o~ (Z)-2~amino-5 c-(methoxyimino)-4-thiazoleacetic acid.
l~hydroxybenzotriazole ester in lOml of dry dimethylformamide. The mixture was stirred overnight at ambient temperature. The solvent was removed in vacuo, the residue taken up in ethyl acetate, filtered, washed with 5~ NaHC03 solution and dried over CaS04. Filtration and evaporation in vacuo gave a residue which solidified on stirring with dry ether. Yield 0.46g, melting point >60C, dec.
Example 6 r3S-~3~(Z~ 1-[~3-rL~2-Amino-4-thiazolyl)r(l-caeboxv-l-me~chYlethoxY)iminolacetvllaminol-4-methYl-2-oxo-l-azetidinylloxy~ -propanoic acid, ~0 methYl ester (Z)-2-Amino-~ dipheny}methoxycarbonyl-l-methylethoxy)imino]-4-thiazoleacetic acid (l.OSg, 2.38 mmol), 0.37g (2.38 mmol) of l-hydroxybenæo-triazole and 0.49g (2.38 mmol) of dicyclohexyl-caebodiimide in lOml of dry dimethylformamide were stirred for 2 hours at 50C and the precipitate was removed by suction.
(~S-trans)-tt3-tt(Phenylmethoxy)carbonyll-amino]-4-methyl-2-oxo-1-azetidinyl~oxy~-~-propanoic acid, methyl ester ~0.765g, 2.38 mmol: see example 4~ was hydrogenated in 15ml of dry dimethyl-formamide in the presence of 0.4g o~ palladium on charcoal (10%) as catalyst (ca. 40 minutes). Both filtrates were combined and stirred overnight at ., ~

room tempe~a~ure. ~fter removing the solvent ln vacuo, ~he residue was taken up in ethyl ace~ate, filtered, washed with 5~ NaHC03 ~olution and dried over CaS04. Filtration and eVaporation in vacuo ~ave 1.3g of crude ~3S-~3~(Z),4~]] ~[3-~t~2-amino-4-thiaozlyl)t(l-diphenylmethoxycarbonyl-l-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-l-azetidinyl]oxy]-~-propanoic acid, methyl ester, which was purified by chromatography on silica gel, eluting with ethyl acetate, and yielding 0.96g of material, melting point >55C, dec.
A solution of 2.93ml of ~rifluoroacetic acid and anisole (lO:1) was cooled to -10C and then added to 0.83g (1.33 mmol) of the above azetidine.
After sticring at 0C ~or 15 minutes the solvent was remo~ed in vacuo (bath temperature 5C)~ The residue was taken up in ether and ice-cold water and the pH was adjusted to 6.5 by addition of NaHC03 solution. The aqueous layer was separated, washed with ether and freeze-dried. The crude salt was purified by reversed phase chromatography on HP-20 resin eluting with water/
acetone. Freeze-drying of the appropriate ~ fractions and stirring with dry ether gave 0.395g of the title compound as a eolorless solid, dec.
>56C

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. A process for making a compound of the formula or a pharmaceutically acceptable ester or salt thereof, wherein R1 is an acyl group derived from a carboxylic acid;
R2 is hydrogen or methoxy;
R3 and R4 are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or a 4, 5, 6 or 7-membered heterocycle, or one of R3 and R4 is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, -CH2X1, carboxyl, -S-X2, -O- X2, or ; wherein X1 is azido, amino, hydroxy, alkanoylamino, phenylcarbonylamino, (substituted phenyl)carbonylamino, alkylsulfonyloxy, phenyl-sulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, cyano, , -S-X2 or -O-X2; X2 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, alkanoyl, phenylalkanoyl, (substituted phenyl)-alkanoyl, phenylcarbonyl, (substituted phenyl)-carbonyl, or heteroarylcarbonyl; one of X3 and X4 is hydrogen and the other is hydrogen or alkyl, or X3 and X4 when taken together with the carbon atom to which they are attached form a cycloalkyl group; X5 is formyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino)carbonyl, or cyano; A is -CH=CH-, (CH2)n-, -CH2-O-, -CH2-NH- 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, substituted amino, acylamino 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;
R5 and R6 are the same or different and each is hydrogen, halogen, hydroxy, alkoxy, alkylthio, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, (cycloalkyl)-alkyl, (cycloalkenyl)alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, or R5 and R6 can together be =CZ1Z2;
R7 is hydrogen and R8 is hydrogen, hydroxy, alkoxy, alkanoyloxy, or halogen, or R7 and R8 can together be =CZ1Z2 or oxo (=O); and Z1 and Z2 are the same or different and each is hydrogen, alkyl, phenyl or substituted phenyl;

The term "substituted alkyl" refers to alkyl groups substituted with one, or more, azido, amino (-NH2), halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenyloxy, (substituted phenyl)oxy, Rx-oxy, mercapto, alkylthio, phenylthio, (substituted phenyl)thio, alkylsulfinyl, or alkylsulfonyl groups;
the term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino (-NH2), halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms), or carboxyl groups;
the term "4, 5, 6 or 7-membered heterocycle" refers to azetinyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl, dihydrothiazolyl and hexahydroazepinyl, or one of the above groups substituted with one or more oxo, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons, alkylsulfonyl, phenyl, substituted phenyl, 2-furfurylideneamino, benzylideneamino and substituted alkyl groups of 1 to 4 carbons;
the term "heteroaryl" by itself or as part of another group refers to pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl, and tetrazolyl, or one of the groups substituted with one or more oxo, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons, alkylsulfonyl, phenyl, substituted phenyl, 2-furfurylideneamino, benzylideneamino and substituted alkyl groups of 1 to 4 carbons;
the term "substituted amino" refers to a group having the formula NY1Y2 wherein Y1 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, and Y2 is alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, hydroxy, cyano, alkoxy, phenylalkoxy, or amino (-NH2);
which process comprises A) reacting a compound of the formula (wherein Z3 is a carboxyl protecting group) with a carboxylic acid of the formula R1-OH, or the corresponding carboxylic acid halide or carboxylic acid anhydride, in the presence of dicyclohexylcarbodiimide and either N-hydroxy-benzotriazole or N-hydroxysuccinimide, and thereafter removing the carboxyl protecting group to provide the compounds of formula I where R2 is hydrogen; or, B) reacting a compound of the formula (wherein Prot is an amino protecting group and Z3 is a carboxyl protecting group) with an alkali metal methoxide to provide a compound of the formula removing the amino protecting group and thereafter acylating and removing the carboxyl protecting group from the so-formed compound as described in process (A) to provide the compounds of formula I
wherein R2 is methoxy.

2. A process in accordance with claim 1 wherein R2 is hydrogen.
3. A process in accordance with claim 1 wherein R3 and R4 are each independently hydrogen or alkyl.
4. A process in accordance with claim 1 wherein R3 and R4 are each independently hydrogen or methyl.
5. A process in accordance with claim 1 wherein R5, R6, R7 and R8 are each hydrogen.
6. A process in accordance with claim 1 wherein R1 is and R1 is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxy-cyclopropyl.
7. A process in accordance with claim 1 wherein R1 is 8. A process in accordance with claim 1 wherein R1 is 9. A compound having the formula or a pharmaceutically acceptable ester or salt thereof, wherein R1 is an acyl group derived from a carboxylic acid;
R2 is hydrogen ox methoxy;
R3 and R4 are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or a 4, 5, 6 or 7-membered heterocycle, or one of R3 and R4 is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, -CH2X1, carboxyl, -S-X2, -O-X2, or ; wherein X1 is azido, amino, hydroxy, alkanoylamino, phenylcarbonylamino, (substituted phenyl)carbonylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyl-oxy, phenyl, substituted phenyl, cyano, , -S-X2 or -O-X2; X2 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, alkanoyl, phenylalkanoyl, (substituted phenyl)-alkanoyl, phenylcarbonyl, (substituted phenyl)-carbonyl, or heteroarylcarbonyl; one of X3 and X4 is hydrogen and the other is hydrogen or alkyl, or X3 and X4 when taken together with the carbon atom to which they are attached form a cycloalkyl group; X5 is formyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino)carbonyl, or cyano; A is -CH=CH-, -(CH2)n-, -CH2-O-, -CH2-NH- or -CH2-S-CH2; n is 0, 1 or 2;
and X5 and X7 are the same or different and each is hydrogen, alkyl, phenyl or substituted phenyl, or X6 is hydrogen and X7 is amino, substituted amino, acylamino 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;
R5 and R6 are the same or different and each is hydrogen, halogen, hydroxy, alkoxy, alkylthio, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, (cycloalkyl)-alkyl, (cycloalkenyl)alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, or R5 and R6 can together be =CZ1Z2;
R7 is hydrogen and R8 is hydrogen, hydroxy, alkoxy, alkanoyloxy, or halogen, or R7 and R8 can together be =CZ1Z2 or oxo (=O); and Z1 and Z2 are the same or different and each is hydrogen, alkyl, phenyl or substituted phenyl;

The term "substituted alkyl" refers to alkyl groups substituted with one, or more, azido, amino (-NH2), halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenyloxy, (substituted phenyl)oxy, Rx-oxy, mercapto, alkylthio, phenylthio, (substituted phenyl)thio, alkylsulfinyl, or alkylsulfonyl groups;
the term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino (-NH2), halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms), or carboxyl groups;
the term "4, 5, 6 or 7-membered heterocycle" refers to azetinyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl, dihydrothiazolyl and hexahydroazepinyl, or one of the above groups substituted with one or more oxo, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons, alkylsulfonyl, phenyl, substituted phenyl, 2-furfurylideneamino, benzylideneamino and substituted alkyl groups of 1 to 4 carbons;
the term "heteroaryl" by itself or as part of another group refers to pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl, and tetrazolyl, or one of the groups substituted with one or more oxo, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons, alkylsulfonyl, phenyl, substituted phenyl, 2-furfurylideneamino, benzyl-ideneamino and substituted alkyl groups of 1 to 4 carbons;
the term "substituted amino" refers to a group having the formula NY1Y2 wherein Y1 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, and Y2 is alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phe-nyl)alkyl, hydroxy, cyano, alkoxy, phenylalkoxy, or amino (-NH2), when made by the process of claim 1.
10. A compound of claim 9 wherein R2 is hydro-gen when made by the process of claim 2.
11. A compound of claim 9 wherein R3 and R4 are each independently hydrogen or alkyl when made by the process of claim 3.
12. A compound of claim 9 wherein R3 and R4 are each independently hydrogen or methyl when made by the process of claim 4.
13. A compound of claim 9 wherein R5, R6, R7 and R8 are each hydrogen when made by the process of claim 5.
14. A compound of claim 9 wherein R1 is and Ri is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxy-cyclopropyl when made by the process of claim 6.

15. A compound of claim 9 wherein R1 is when made by the process of claim 7.
16. A compound of claim 9 wherein R1 is when made by the process of claim 8.
17. A compound having the formula or a pharamceutically acceptable ester or salt thereof, wherein R1 is an acyl group derived from a carboxylic acid;
R2 is hydrogen or methoxy;
R3 and R4 are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or a 4, 5, 6 or 7-membered heterocycle, or one of R3 and R4 is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2 phenylethynyl, -CH2X1, carboxyl, -S-X2, -O- X2, or ; wherein X1 is azido, amino, hydroxy, alkanoylamino, phenylcarbonylamino, (substituted phenyl)carbonylamino, alkylsulfonyl-oxy, phenylsulfonyloxy, (substituted phenyl)-sulfonyloxy, phenyl, substituted phenyl, cyano, , -S-X2 or -O-X2; X2 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, alkanoyl, phenylalkanoyl, (substituted phenyl)alkanoyl, phenylcarbonyl, (substitted phenyl)caxbonyl, or heteroarylcarbonyl; one of X3 and X4 is hydrogen and the other is hydrogen or alkyl, or X3 and X4 when taken together with the carbon atom to which they are attached form a cycloalkyl group; X5 is formyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino)carbonyl, or cyano; A is -CH=CH-, -(CH2)n-, -CH2-O-, -CH2-NH- 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, substituted amino, acylamino 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;
R5 and R6 are the same or different and each is hydrogen, halogen, hydroxy, alkoxy, alkylthio, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, (cycloalkyl) alkyl, (cycloalkenyl)alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, or R5 and R6 can together be =CZ1Z2;
R7 is hydrogen and R8 is hydrogen, hydroxy, alkoxy, alkanoyloxy, or halogen, or R7 and R8 can together be =CZ1Z2 or oxo (=O); and Z1 and Z2 are the same or different and each is hydrogen, alkyl, phenyl or substituted phenyl;
the term "substituted alkyl" refers to alkyl groups substituted with one, or more, azido, amino (-NH2), halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenyloxy, (substituted phenyl)oxy, Rx-oxy, mercapto, alkylthio, phenylthio, (substituted phenyl)thio, alkylsulfinyl, or alkylsulfonyl groups;
the term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino (-NH2), halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms), or carboxyl groups;
the term "4, 5, 6 or 7-membered heterocycle"
refers to azetinyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl, dihydrothiazolyl and hexahydroazepinyl, or one of the above groups substituted with one or more oxo, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons, alkylsulfonyl, phenyl, substituted phenyl, 2-furfurylideneamino, benzylideneamino and substituted alkyl groups of 1 to 4 carbons;
the term "heteroaryl" by itself or as part of another group refers to pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl, and tetrazolyl, or one of the groups substituted with one or more oxo, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons, alkylsulfonyl, phenyl, substituted phenyl, 2-furfurylideneamino, benzylideneamino and substituted alkyl groups of 1 to 4 carbons;
the term "substituted amino" refers to a group having the formula NY1Y2 wherein Y1 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, and Y2 is alkyl, phenyl, substituted phenyl, phenylalkyl, (subtituted phenyl)alkyl, hydroxy, cyano, alkoxy, phenylalkoxy, or amino (-NH2).
18. A compound in accordance with claim 17 wherein R2 is hydrogen.
19. A compound in accordance with claim 17 wherein R3 and R4 are each independently hydrogen or alkyl.
20. A compound in accordance with claim 17 wherein R3 and R4 are each independently hydrogen or methyl.
21. A compound in accordance with claim 17 wherein R5, R6, R7 and R8 are each hydrogen.
22. A compound in accordance with claim 17 wherein R1 is and Ri is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxy-cyclopropyl.

23. A compound in accordance with claim 17 where-in R1 is 24. A compound in accordance with claim 17 where-in R1 is A pharmaceutical composition containing a compound of Claim 1 having the formula or a pharmaceutically acceptable ester or salt thereof, wherein R1 is an acyl group derived from a carboxylic acid;
R2 is hydrogen or methoxy;
R3 and R4 are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl phenyl, substituted phenyl or a 4-, 5-, 6- or 7-membered heterocycle, or one of R3 and R4 is hydro-gen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, -CH2X1, carboxyl, -S-X2, -O-X2, or ; wherein X1 is azido, amino, hydroxy, alkanoylamino, phenylcarbonylamino, (substituted phenyl)carbonylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, cyano, , -S-X2 or -O-X2; X2 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phe-nyl)alkyl, alkanoyl, phenylalkanoyl, (substituted phenyl)alkanoyl, phenylcarbonyl, (substituted phe-nyl)carbonyl, or heteroarylcarbonyl; one of X3 and X4 is hydrogen and the other is hydrogen or alkyl, or X3 and X4 when taken together with the carbon atom to which they are attached form a cycloalkyl group; X5 is formyl, alkanoyl, phenylcarbonyl, (sub-stituted phenyl)carbonyl, phenylalkylcarbonyl, (sub-stituted phenyl)alkylcarbonyl, carboxyl, alkoxycar-bonyl, aminocarbonyl, (substituted amino)carbonyl, or cyano; A is -CH=CH-, -(CH2)n-, -CH2-O-, -CH2-NH-or -CH2-S-CH2; n is 0, 1 or 2; and X6 and X7 are the same or different and each is hydrogen, alkyl, phe-nyl or substituted phenyl, or X6 is hydrogen and X7 is amino, substituted amino, acylamino 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;
R5 and R6 are the same or different and each is hydrogen, halogen, hydroxy, alkoxy, alkylthio, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, cyc-loalkenyl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl, phenyl, substituted phenyl, phenylalkyl or (substi-tuted phenyl)alkyl, or R5 and R6 can together be =CZ1Z2;
R7 is hydrogen and R8 is hydrogen, hydroxy, al-koxy, alkanoyloxy, or halogen, or R7 and R8 can to-gether be =CZ1Z2 or oxo (=O); and Z1 and Z2 are the same or different and each is hydrogen, alkyl, phenyl or substituted phenyl;
in admixture with a pharmaceutically acceptable di-luent or carrier therefor.
26. A composition in accordance with claim 25 wherein R2 is hydrogen.
27. A composition in accordance with claim 25 wherein R3 and R4 are each independently hydrogen or alkyl.
28. A composition in accordance with claim 25 wherein R3 and R4 are each independently hydrogen or methyl.
29. A composition in accordance with claim 25 wherein R5, R6, R7 and R8 are each hydrogen.
30. A composition in accordance with claim 25 wherein R1 is and Ri is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxycyclo-propyl.
31. A composition in accordance with claim 25 wherein R1 is 32. A composition in accordance with claim 25 wherein R1 is 33. A composition in accordance with claim 25 which is suitable for oral, intravenous or intra-muscular administration.
34. A composition in accordance with claim 25 which is suitable for administration as a suppository.