Background of the Invention Despite the wealth of information available, influenza remains a potentially devastating disease of man, lower mammals, and birds. No effective vaccine exists and no cure is available once the infection has been initiated.

Influenza viruses consist of eight pieces of single stranded RNA, packaged in orderly fashion within the virion. Each piece codes for one of the major viral proteins. The replication complex is enclosed with a membrane composed of matrix protein associated with a lipid bilayer. Embedded in the lipid bilayer are two surface glycoprotein spikes, hemagglutinin (HA) and the enzyme neuraminidase (NA). All of the viral genes have been cloned and the three-dimensional structures of the surface glycoproteins have been determined.

Influenza viruses continually undergo antigenic variation in the two surface antigens, HA and NA, toward which neutralizing antibodies are directed. For this reason, vaccines and a subject's natural immune system have not been very effective. Attention is now being directed to finding other potential antiviral agents acting at other sites of the virion. This invention is directed to novel compounds which are useful in inhibiting the viral surface enzyme NA.

Furthermore, many other organisms carry NA. Many of these NA-possessing organisms are also major pathogens of man and/or mammals, including Vibrio cholera, Clostridium perfringen, Streptococcus pneumoniae, Arthrobacter sialophilas, and other viruses, such as parainfluenza virus, mumps virus, Newcastle disease virus, fowl plague virus, and Sendai virus. Compounds of this invention are also directed to inhibiting NA of these organisms.

In viruses, NA exists as a tetramer made of four roughly spherical subunits and a

ceiiLrauy-amacnea stalK containing a nyaropnomc region by wnicn it is embedded in the organism's membrane. Several roles have been suggested for NA. The enzyme catalyzes cleavage of the a-ketosidic linkage between terminal sialic acid and an adjacent sugar residue.

Removal of the sialic acid lowers the viscosity and permits access of the virus to the epithelial cells. NA also destroys the HA receptor on the host cell, thus allowing elution of progeny virus particles from infected cells.

Research indicates that the active site for influenza neuraminidase remains substantially unchanged for the major strains of influenza. For example, a comparison of sequences from influenza A subtypes and influenza B shows conserved residues with crucial structural and functional roles. Even though the sequence homology is only about 30%, many of the catalytic residues are conserved. Furthermore, the three-dimensional structures of influenza A and B neuraminidases have been determined. Superposition of the various structures shows remarkable structural similarity of the active site. Since the active site amino acid residues are conserved in all known influenza A neuraminidases that have been sequenced so far, an inhibitor that is effective against different strains of influenza A and/or B neuraminidase can be designed based on the three-dimensional structure of a neuraminidase.

In general, the role of NA is thought to be for the mobility of the virus both to and from the site of infections. Compounds that inhibit neuraminidase's activity may protect a subject from infection and/or cure a subject once infection has set in. It is a further object of this invention to provide a method of using compounds of this invention for treating and/or curing a viral infection.

Analogs of neuraminic acid, such as 2-deoxy-2, 3-didehydro-N-acetylneuraminic acid (DANA) and its derivatives are known to inhibit HA in vitro ; however, these compounds are inactive in vivo, Palese and Schulman, in CHEMOPROPHYLAXIS AND VIRUS INFECTION OF THE UPPER RESPIRATORY TRACT, Vol. 1 (J. S. Oxford, Ed.), CRC Press, 1977, at PS 189-205.

Von Itzstein et al. describes cyclohexane analogs of a-D-neuraminic acid of the formula (a)

wnerem : A is O, C or S in Formula (a), and N or C in Formula (b) ; Rl is CO2H, PO3H2, NO2, SO2H, SO3H, tetrazolyl-, CH2CHO, CHO, or CH (CHO) 2 ; R2 is H, OR6, F, Cl, Br, CN, NHR6, SR6 or CH2X, where X is NHR6 halogen, OR6 ; R3 and R3 are H, CN, NHR6, SR6, =NOR6, OR', guanidino, NW ; R4 is NHR6, SR6, oR6, C02R, NO2, C (R6) 3, CH2CO2R, CH2NO2 or CH2NHR6 ; R5 is CH2YR6, CHYR6CH2YR6 or CHYR6CHYR6CH2YR6 ; R6 is H, acyl, alkyl, allyl, or aryl ; Y is O, S, NH, or H ; and pharmaceutical salts thereof, useful as antiviral agents.

In addition, certain benzene derivatives are suggested in U. S. patent 5, 453, 533 as being inhibitors of influenza virus neuraminidase and various others are disclosed in U. S. Patent No.

5, 602, 277. Yamamoto et al. describe various sialic acid isomers as having inhibitory activity against neuraminidase in Synthesis of Sialic Acid Isomers With Inhibitory Activity Against Neuraminidase, TETRAHEDRON LETTERS, Vol. 33, No. 39, pp. 5791-5794, 1992.

WO 96/26933 to Gilead Sciences, Inc. describes certain 6-membered ring compounds as possible inhibitors of neuraminidase.

WO 99/14191 to BioCryst Pharmaceuticals, Inc., the assignee of the present application, and WO 99/582999 to Abbott Laboratories, Inc. describe various pyrrolidine compounds as possible inhibitors of neuraminidase. WO 95/54290 to Abbott Laboratories, Inc. describes certain cyclopentane or cyclopentene derivatives as possible inhibitors of neuraminidase.

More importantly, in WO 97/47194 and WO 99/33781 to BioCryst Pharmaceuticals, Inc. are disclosed a number of cyclopentane and cyclopentene derivatives as being inhibitors of influenza virus neuraminidase.

However, none of these disclose the cyclopentane and cyclopentene derivatives of the present invention which are useful as prodrugs.

Summary of Invention An aspect of the present invention relates to compounds represented by the formulae : (A) or (B) #NHC(O)CH2NH2 # CH2CO2R5 OC(O)- N # C(O)R'5 R5 R5" -(CH2)nOC(O)R5, , , , - (CH2) nOR5- (CH2) n-N-R6 , or; each R2 and R3 individually is H, (CH2) mOH,-C (O) OR,-C (O) R5,-C (O) SR, (CH2) m-C (O)- 10 NR5R'5, -O-C(O)-O-R5, an amino acid and/or a dipeptide ;

each Rs, R'5 and Rs"is independently H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, alkynyl, substituted alkenyl, substituted alkynyl, heterocycle, substituted heterocycle, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, or-CH2CO2 alkyl ; and wherein R5 can also be (dialkyl) CO alkyl ; R6 is each R7 and R'7 individually is alkyl, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl ; Rs is alkyl, or halo substituted alkyl ; n=1-5 and m=0-4 ; and pharmaceutically acceptable salts thereof.

The present invention is also concerned with compositions for inhibiting influenza virus neuraminidase comprising a pharmaceutically acceptable carrier and an amount effective for inhibiting influenza virus neuraminidase of a compound as defined above.

A further aspect of the present invention involves a method for inhibiting influenza virus that comprises administering to a patient in need thereof a compound as defined above in an amount effective for inhibiting influenza virus neuraminidase.

A still further aspect of the present invention is concerned with treating influenza virus infection comprising administering to a patient in need thereof a compound as defined above in an amount effective for inhibiting influenza virus neuraminidase.

A process (referred to as process 1) aspect of the present invention for preparing compounds represented by formula A comprising the following steps : a. Reacting a lactam such as 2-azabicyclo [2. 2. 1] hept-5-en-3-one with an alcohol in the presence of an acid followed by reacting with a suitable anhydride or halide (e. g. chloride) and a base such as trialkylamine to give the corresponding alkoxycarbonyl protected amine- cyclopentene carboxylate (Scheme 1 shows BOC anhydride) ; 2. Reacting the compound from step 1 with an alkyl-nitrobutane/trialkylamine combination and phenylisocyanate to provide a cycloadduct ; or reacting the compound from step 1 with an ethylbutyrohydroximinoxyl halide and a trialkylamine to provide a cycloadduct ; 3. Converting the cycloadduct from step 2 to the corresponding amine ; 4. Acylating the amine from step 3 to provide the corresponding acylamine compound ; 5. Reacting the product from step 4 with an acid to provide the corresponding amine compound ; 6. Reacting the product from step 5 to provide the corresponding guanylated compound ; and optionally 7. Hydrolyzing the product from step 6 to obtain the corresponding acid.

A further aspect of the present invention (referred to as process 2) relates to preparing compounds represented by formula B comprising the following steps : 1. Reacting a lactam with an alcohol in the presence of an acid followed by reacting with a suitable anhydride or halide and a base such as trialkylamine to give the corresponding alkoxycarbonyl protected amine-cyclopentene carboxylate ; 2. Reacting the compound from step 1 with an alkyl-nitrobutane/trialkylamine combination and phenylisocyanate to provide a cycloadduct ; or reacting the compound from

step 1 with an ethylbutyrohydroximinoxyl halide and a trialkylamine to provide a cycloadduct ; 3. Converting the cycloadduct from step 2 to the corresponding amine ; 4. Acylating the amine from step 3 to provide the corresponding acylamine compound ; 5. Reacting the product from step 4 with an alkanesulphonyl halide to provide the corresponding O-SO2 alkyl derivative ; 6. Treating the product from step 5 with a base to provide the corresponding unsaturated compound ; 7. Treating the product from step 6 with an acid to provide the corresponding amine ; and 8. Reacting the product from step 7 to provide the corresponding guanylated compound.

Still further aspects of the present invention (referred to as process 3) relates to forming ester prodrugs of structure A or structure B which comprises : 1. Reacting a guanylated compound obtained from one of the above-disclosed processes 1 or 2 with a base to provide the corresponding salt ; 2. Reacting the product from step 1 with RiX wherein X is a halide to provide the desired product.

Another aspect of the present invention (referred to as process 4) relates to forming ester prodrugs of structure A or structure B which comprises : 1. Hydrolyzing a compound obtained from step 4 of process 1 above or step 6 of process 2 above with a base to give the corresponding salt ; 2. Reacting the product from step 1 with RiX wherein X is a halide ; 3. Hydrolyzing the product from step 2 to provide the corresponding amine ; and 4. Reacting the product from step 3 to provide the corresponding guanylated compound.

A still further aspect of the present invention (referred to as process 5) relates to forming ester prodrugs of structure A or structure B which comprises :

1. Converting a compound obtained from step 4 of process 1 above or step 6 of process 2 above to the corresponding acid ; 2. Reacting the product from step 1 with RlOH in the presence of a coupling agent to provide the corresponding ester ; 3. Hydrolyzing the product from step 2 to provide the corresponding amine ; and 4. Reacting the product from step 3 to provide the corresponding guanylated compound.

Another aspect of the present invention (referred to as process 6) relates to forming ester prodrugs of structure A or structure B which comprises : 1. Reacting the product from step 1 of process 4 or 5 with an alkylchloroformate in the presence of a base to form a mixed anhydride ; 2. Reacting the product from step 1 with ROH ; 3. Hydrolyzing the product from step 2 to provide the corresponding amine ; and 4. Reacting the product from step 3 to provide the corresponding guanylated compound.

A further aspect of the present invention (referred to as process 7) related to forming ester prodrugs of structure A or structure B which comprises : 1. Converting the cycloadduct (e. g. isooxazoline derivative) to its corresponding alkali salt by reacting with a base ; 2. Reacting the product from step 1 with RiX or with RlOH in the presence of a coupling agent to form the corresponding ester. X is a halide ; 3. Hydrogenating the product from step 2 ; 4. Acetylating the product from step 3 ; 5. Hydrolyzing the product from step 4 to provide the corresponding amine ; and 6. Reacting the product from step 5 to provide the corresponding guanylated compound.

A still further aspect of the present invention (referred to as process 8) relates to forming esters of prodrugs of structure A or structure B which comprises : 1. Reacting the product from step 5 of process 1 or the product from step 7 of process 2 with a protected guanylated agent ; 2. Hydrolyzing the product from step 1 to provide the corresponding acid ; 3. Converting the product from step 2 to the corresponding ester ; 4. Removing the protecting group.

Another process aspect of the present invention (referred to as process 9) relates to preparing prodrugs of formula A or formula B which comprises : 1. Reacting the product from step 5 of process 1 or the product from step 7 of process 2 with a cyanogen halide to provide the corresponding cyanamine ; and 2. Reacting the product from step 1 with a hydroxylamine.

Another process aspect of the present invention (referred to as process 10) relates to preparing prodrugs of formula A or formula B which comprises : 1. Reacting the product from step 5 of process 1 or the product from step 7 of process 2 with a guanylating agent ; or reacting the product from step 6 of process 1 or step 8 of process 2 with an alcohol ; 2. Reacting the product from step 1 with R90 C (O) X or RsO C (O) C6H4NO2 in the presence of a base.

Another process of the present invention (referred to as process 11) relates to preparing compounds represented by formula A or formula B which comprises : 1. Reacting the product from step 5 of process 1 or the product from step 7 of process 2 with a guanylating agent.

A still further process of the present invention (referred to as process 12) relates to preparing compounds represented by formula A or formula B which comprises : 1. Converting the product from step 1 of process 10 to an amide ; and 2. Reacting the product from step 1 with an amino acid.

Furthermore, when disubstituted guanidine and ester prodrugs of structures A and B are desired, about 2 equivalents of the reactive reagents are employed.

5 Preferred Embodiments for Carrying Out Invention The present invention relates to compounds represented by the formulae : (A) or (B) R5 Rs" (CH2) nOC (O) Rs , , , (CH2) nORs (CH2) n-N-R6 , or ; each R2 and R3 individually is H, (CH2) mOH,-C (O) OR,-C (O) R5,-C (O) SR, (CH2) m-C (O)- 15 NR5R'5, -O-C(O)-O-R5, an amino acid and/or a dipeptide ; (CHt) n (CHt) n -C-C-O-C(O)R"5 -C-C-O-C(O)-O-R"5 Rs 1 R5 1 , or R4 is H, OH,-OC (O)-Rs,-OC (O)-N-Rs (R's),-O-C (O)-O-Rs ; 5 each Rs, R'5 and R 5 is independently H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, alkynyl, substituted alkenyl, substituted alkynyl, heterocycle, substituted heterocycle, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, or-CH2CO2 alkyl ; and wherein Rs can also be (dialkyl) CO alkyl ; 10 R6 is 0 N N O=#=O, -N## N O=#=O S O=## O2 O , , , , or O # -N## # O 15 each R7 and R'7 individually is alkyl, aralkyl, substituted aralkyl, cycloalkyl, substituted cycloalkyl ; Rs is alkyl, or halo substituted alkyl ;

n=1-5 and m=0-4 ; and pharmaceutically acceptable salts thereof.

Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.

The term"alkyl"refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms. The expression"lower alkyl"refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.

The terms"substituted alkyl","substituted alkenyl"or"substituted alkynyl"refer to an alkyl, alkenyl or alkynyl group substituted by, for example, one to four substituents, such as halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkyloxy, heterocylooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamine, aroylamino, aralkanoylamino, substututed alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e. g. S02NHz), substituted sulfonamido, nitro, cyano, carboxy, carbamyl (e. g. CONH2) substituted carbamyl (e. g. CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where noted above where the substituent is further substituted it will be with halogen, alkyl, alkoxy, aryl or aralkyl.

The term"halogen"or"halo"refers to fluorine, chlorine, bromine and iodine.

The term"aryl"refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may be substituted.

The term"arallcyl"or"alkylaryl"refers to an aryl group bonded directly through an alkyl group, such as benzyl or phenethyl.

The term"substituted aryl"or"substituted alkylaryl"refers to an aryl group or alkylaryl group substituted by, for example, one to four substituents such as alkyl ; substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, cycloalkyloxy, heterocycloooxy, alkanol, alkanoyloxy, amino, alkylamino, aralkylamino, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyclothio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkysulfonyl, sulfonamido, aryloxy and the like. The substituent may be further substituted by halo, hydroxy, alkyl, allcoxy, aryl, substituted aryl, substituted allcyl or aralkyl."Substituted benzyl"refers to a benzyl group substituted by, for example, any of the groups listed above for substituted aryl.

The term"cycloallcyl"refers to optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocyclic ring. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and adamantyl. Exemplary substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.

The terms"heterocycle","heterocyclic"and"heterocyclo"refer to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-

oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1, 3-dixolane and tetrahydro-1, 1- dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, and triazolyl, and the like.

Exemplary bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopridyl, furopyridinyl (such as furo [2, 3-c] pyridinyl, furo [3, 1-b] pyridinyl, or furo [2, 3-b] pyridinyl), dihydroisoindolyl, diyhydroquinazolinyl (such as 3, 4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzothrazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl, and the lilce.

Exemplary substituents include one or more alkyl groups as described above or one or more groups described above as alkyl substituents.

The term"heteroatoms"shall include oxygen, sulfur and nitrogen.

The term"amino acid"means any naturally occurring amino acid including D and L amino acids. The term"dipeptide"means a di-amino acid containing two linked naturally occurring amino D and L acids.

Within the above-described definitions, certain embodiments are preferred. Preferred alkyl groups are lower alkyl groups containing 1 to about 8 carbon, and more preferably 1 to about 5 carbon atoms, and can be straight, branched-chain or cyclic saturated aliphatic hydrocarbon groups.

Examples of suitable alkyl groups include methyl, ethyl and propyl. Examples of branched alkyl groups include isopropyl and t-butyl. An example of a suitable alkylaryl group

is phenethyl. Examples of suitable cycloalkyl groups typically contain 3-8 carbon atoms and include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The aromatic or aryl groups are preferably phenyl or alkyl substituted aromatic groups (aralkyl) such as phenyl Ci-3alkyl such as benzyl.

The N-heterocyclic rings preferably contain 3-7 atoms in the ring and a heteroatom such as N, S or O in the ring. Examples of suitable preferred heterocyclic groups are pyrrolidino, azetidino, piperidino, 3, 4-didehydropiperidino, 2-methylpiperidino and 2- ethylpiperidino. In addition, the above substitutions can include halo such as F, Cl, Br, lower alkyl, lower alkoxy and halo substituted lower alkoxy.

Examples of suitable amino acids are L-Ala, L-Val, L-Isoleu, L-Phe, Gly and L-Leu.

Examples of suitable dipeptides are L-Ala-L-Ala and Gly-Gly.

Preferred groups for R7 and R'7 are CH3, C2H5, n-C3H7 and n-C4Hs and most preferred groups for R7 and R'7 are C2Hs and n-C3H7.

Preferred groups for Rs are CH3, CaHs and C3H7 and most preferred is CH3.

Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from pharmaceutically acceptable, inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic, trifluoroacetic and benzenesulphonic acids.

Salts derived from appropriate bases include alkali such as sodium and ammonia.

It is of course understood that the compounds of the present invention relate to all optical isomers and stereo-isomers at the various possible atoms of the molecule.

The following schemes illustrate methods for preparing compounds of the present invention. In order to facilitate an understanding of the present invention, the methods will be discussed with respect to preparing various preferred compounds of the present invention.

The synthesis of these compounds is illustrated by taldng the examples, wherein R7=R'7=C2H5 ; and Rs=CHs in structures A and B The synthesis of the starting materials for prodrugs in given in Schemes 1 and 2.

Synthesis of the precursors for structure A : SCHEME 1 : The starting material, Lactam (1,-, +, or racemic mixture) is heated at reflux temperature with methanolic HC1. The solvent is evaporated'and the residue is washed with ether to give methyl 4-amino-2-cyclopenten-1-carboxylate hydrochloride, which is further reacted with di- tert-butyl dicarbonate and triethylamine to give methyl 4-tert-butoxycarbonylamino-2- cyclopenten-l-carboxylate (2). Compound (2) is reacted with 2-ethyl-1- nitrobutane/triethylamine and phenylisocyanate to give the cycloadduct (3). Cycloadduct (3) may also be obtained by the reaction of (2) with 2-ethylbutyrohydroximinoxyl chloride and triethylamine. The desired isomer is separated and is hydrogenated in the presence of a catalyst to give the corresponding amine, which is acetylated with acetic anhydride to give methyl 3- (1'-acetylamino-2'-ethyl) butyl-4-tert-butoxycarbonylamino-2-hydroxycyclopentane- 1-carboxylate (4). Cycloadduct (3) can be converted to the amine using chemical reduction also. Compound (4) is treated with HC1 to give the corresponding amine (5), which is guanylated with pyrazole carboxamidine to give the guanidine derivative. The ester is hydrolyzed to acid to give the desired compound (6). Other guanylating agents, such as S- methylthiourea, cyanamide, amino-iminomethane sulphonic acid also may be used for the guanylation.

Synthesis of the precursors for structure B : SCHEME 2 : Compound (4) is reacted with methanesulphonyl chloride to give the-O-SO2CH3 derivative, which is then treated with a base to give the double bond compound (7). Acid treatment of (7) provides amine (8), which is then guanylated to give the product (9) using standard guanylation procedures.

Synthesis of the ester prodrugs of structure A : SCHEME 3 : In structure A, when R2=R3=H ; R7=R'7=C2Hs ; R4=OH ; Rs=CH3 ; and Ri=alliyl, substituted alkyl, cycloalkyl, acylalkyl, or acyloxyalliyl, etc.

These compounds are prepared by using one of the following methods : i) Compound (6) is reacted with a base (for example, sodium or potassium hydroxide) to give the corresponding salt, which is further reacted with RiX, where Ri is as described above and X is Cl, Br, or I to give the corresponding target 11.

ii) Compound (4) on base hydrolysis gives the corresponding salt (12), which is further reacted with RiX to give (13). RiX is the same as described in the above method.

Compound (13) on acid hydrolysis produces amine (14), which is reacted with a guanylating agent to give the target (11). iii) Compound (4) is converted to the acid corresponding to the compound (12), which is reacted with R1OH in the presence of a coupling agent, such as N, N'- dicyclohexylcabodiimide (DCC), 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide, N, N'- diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or methiodide to give the ester (13). The ester is further converted to (11) using the procedures described above. iv) The corresponding acid of compound (12) also is converted to a mixed anhydride, using methyl or ethyl chloroformate in the presence of a base, such as triethylamine. The resultant mixed anhydride is reacted with RlOH to give compound (13), which is further converted to (11). v) Compounds of the type (11) are also prepared from the isooxazoline derivative (3). Compound (3) is converted to the alkali salt (15) with a base and further reacted with RiX to give the ester (16). Compound (16) on hydrogenation in the presence of a catalyst, followed by acetylation gives (13), which is further converted to (11) as described above. vi) The corresponding acid of (15) also is reacted with R1OH in the presence of a coupling agent, such as N, N'-dicyclohexylcabodiimide (DCC), 1-cyclohexyl-3- (2- morpholinoethyl) carbodiimide, N, N'-diisopropylcarbodiimide (DIC), 1- (3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or methiodide to give (16), which is further converted to (11). vii) Amine (5) is reacted with a protected guanylating agent such as H3CS-C- (NHBoc) =Nboc, Boc protected pyrazole carboxamidine, triazole carboxamidine, or 4- nitropyrazole carboxamidine to give protected guanylated derivative (17). Some catalyst, such as acetic acid, HgCl2, ZnCl2, etc. may be desirable for the reaction. The ester is hydrolyzed to acid (18), and converted to ester (19) following one of the above mentioned methods.

Removal of the Boc group is achieved by using H+ (HC1, trifluoroacetic acid, etc.) and the target (11) is obtained. viii) Amine (5) also is reacted with a protected guanylating agent such as H3CS-C- (NHCbz) =NCbz, Cbz protected pyrazole carboxamidine, triazole carboxamidine, or 4- nitropyrazole carboxamidine to give protected guanylated derivative (20). Some catalyst, such as acetic acid, HgC12, ZnCl2, etc. may be desirable for the reaction. The ester is hydrolyzed to acid (21), and converted to ester (22) following one of the above mentioned methods.

Removal of Cbz group is achieved by hydrogenation and the target (11) is obtained.

ix) Any other standard method for converting acid to ester may be used for these reactions.

The desired RiX or R1OH are either commercially available, or are prepared according to the literature procedures.

Other compounds in the series, when R7 and R'7 are other than ethyl also are prepared following the same procedures.

Synthesis of ester prodrugs of structure B : These compounds are prepared the same way as described above using the intermediates with a double bond from Scheme 2.

Synthesis of guanidine and ester prodrugs of structure A : SCHEME 4 a. In structure A, Ri = CH3 ; R2=OH ; R3=H ; Ra = OH ; R7=R'7=C2Hs ; Rs=CH3 Compound (5) is reacted with cyanogen bromide to give corresponding cyanamine (23), which on reaction with hydroxyl amine gives the target (24). b. In structure A, Ri = CH3 ; R3=H ; R4=OH ; R7=R7=C2Hs ; Rs=CH3 ; R2= C (0) OR9, and Rs=alkyl, substituted alkyl, cycloalkyl, phenyl, substituted phenyl, alkoxycarbonylalkyl, substituted alkoxycarbonylalkyl, etc.

These compounds are prepared by one of the following method : i) Compound (25) is prepared from either (5) by reacting with a guanylating agent, such as pyrazole carboxamidine, triazole carboxamidine, 4-nitropyazole carboxamidine or amino-iminomethanesulphonic acid or by esterification of compound (6) with methanol.

Compound (25) further reacts with 1 equivalent of R90C (O) Cl or R90C (O) OC6H4-NO2 (p) in the presence of a base to give the desired target (26). ii) Compound (26) is prepared from (5) also by reacting with one equivalent of appropriately substituted guanylating agent as shown in Scheme 4. Substituted guanylating agents are prepared from the literature procedures. In some cases, a catalyst, such as HgCl2, ZnCl2, acetic acid, etc. may be desired for the reaction.

Other standard literature procedures for the conversion of amine to a carbamate also

may be used. c. In structure A, Ri=CH3 ; R3=H ; R4=OH ; R7=R'7=C2H5 ; Rs=CH3 ; R2=peptide.

These compounds (27) are prepared from the standard methods of amides preparation from amine (25) and the desired amino acid in the presence of a coupling agent.

In place of Ri as CH3, any other ester also can be used for the preparation of the desired targets.

In place of R7=R'7=C2Hs, another alkyl group containing compounds may be prepared using the same methods.

Synthesis of guanidine and ester prodrugs of structure B : These compounds are prepared the same way as discussed above using the intermediates from Scheme 2 with a double bond.

Synthesis of di-substituted guanidine and ester prodrugs of structures A and B : These compounds are prepared the same way as given in Scheme 4 using 2 equivalents of the reagents.

Synthesis of guanidine prodrugs of structures A and B : These compounds are prepared the same way as given in Scheme 4. The esters obtained are hydrolyzed with a base, acid, methanol/water/triethylamine mixture or any other appropriate saponification reagent.

WO 01/62242 SCHEME-1 BocHN LOOCH3 HN-CO @ BocHN COOCH3 PhNCO, Et3N, : HCI/MeOH # 2-ethyl-1-nitrobutane, # ii) Boc anhydride, # Benzene/Toluene #O triethylamine, or Chloro-oxime, TEA Dichloromethane (2) (70%) (3) (92%) BocHN COOCH3 i) H2, PtO2, MeOH HCl/Ether N2N COOCH3 and HCI # # # # ii) Et3N, Ac2O, OH Dichoromethane NHCOCH3 OH (67%) (4) (5) NHCOCH3 HN=j » NH2 i) Pyrazole carboxamidine HCl, # COOH Diisopropylethylamine, DMF NH, « ii) NaOH ou (50%) NHCOCH3 (6) SCHEME-2 SCHEME-3

BocHN COONa/K BocHN COOR1 H2N COOR1 ### # ## # # # - OH OH OH NHCOCH3 NHCOCH3 NHCOCH3 (12) (13) (14) BocHN COONa/K BocHN COOR (3) # # # # O O # (13) # (11) #=N #=N (15) (16) SCHEME-3 (Contnd) BocN=-NHBoc BocH=-NHboc BocN=-NHBoc NH COOCH3 NH COOH NH COOR1 @ '', (5) # # # # # # # 3 (11) OH OH OH NHCOCH3 NHCOCH3 NHCOCH3 (17) (18) (19) CbzN=NHCbz CbzN=-NHCbz CbzN=-NHCbz NH, COOCH3 oh # zu -31. OH # OH # OH NHCOCH3 NHCOCH3 NHCOCH3 (20) (21) (22) Cbz= Benzyloxycarbonyl SCHEME-4 HN=-NHOH NCHN COOCH3 COOCH3. NH CO@ (5) # # # # # OH NHCOCH3 OH NHCOCH3 (23) (24) NH=-NH2 HN=-NHC(O)OR9 # # NH COOCH3 NH COOCH3 (5) or (6) # # # # # Reagent # OH OU NHCOCH3 NHCOCH3 (25) (26) Reagent= R9OC(O)Cl, or R9OC(O)OC6H4-NO2(p)) H3CS-C (=NH) NHC (O) OR9, (5) # (26) N- O2N # N #N ,or #N N N N NH=-NHC(O)OR9 HN=-NHC(O)OR9 HN=-NHC9o0OR9 HN=-NH2 NH=-NH-maino acid NH COOCH3 NH COOCH3 # Amino acid and a OH OH coupling agent/8 OH NHCOCH3 NHCOCH3 (25) (27)

The following are examples of illustrative compounds according to the present invention.

Methyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (1'-acetylamino-2'-ethyl) butyl-4- [ (N-ethoxycarbonyl-amino- imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate ; Ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-benzyloxy- carbonylaminoimino) methyl] amino-2-hydroxycyclopentan-l-carboxylate ; Ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-methoxycarbonyl amino- imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate ; Ethyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (1'-acetylamino-2'-ethyl) butyl-4- [ (N-tert-butoxycarbo- nylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate ; Ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-ethoxycarbonyl-amino- imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate ; Methyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4- [ (N-acetyloxy- methoxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate ; Methyl (1s, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl)buty1-4[(N-acetyloxy- methoxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate ; Ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-trimethylacetyl- oxymethoxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate ; Ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-(α-trimeth yl- acetyloxyethoxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate ;

Ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-2, 2, 2-trichloro- ethoxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate ; Ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-3, 2, 2-trifluoro- ethoxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate ; Ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-(2'-L-amino prop- anoylamino)-imino] methylamino-2-hydroxycyclopentan-1-carboxylate ; Methyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-(2'-L-amino - propanoylamino)-imino] methylamino-2-hydroxycyclopentan-1-carboxylate ; Methyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4- [N- (2'-L-amino-3'- phenylpropanoylamino)-imino] methylamino-2-hydroxycyclopentan-1-carboxylate ; (lS, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4- (amino-imino) methyl- amino-2- (3'- methylbutanoyl) hydroxycyclopentan-l-carboxylic acid ; (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-(amino-imino)me thylamino-2-n- hexanolyoxyclopentan-1-carboxlic acid ;

(1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-benzyloxyca rbonyl- amino- imino) methyl] amino-2-hydroxycyclopentan-1-carboxylic acid ; (1S, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4- [ (N-methoxycarbonyl- amino- imino) methyl] amino-2-hydroxycyclopentan-1-carboxylic acid ; (1S, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4- [ (N-tert-butoxycarbonyl- amino- imino) methyl] amino-2-hydroxycyclopentan-1-carboxylic acid ; (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-ethoxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-l-carboxylic acid ; (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-aceyloxymet holxy- carbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylic acid ; (1S, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(u-acetyloxyethoxy-carbonylamino- imino) methyl] amino-2-hydroxycyclopentan-1-carboxylic acid ; (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-trimethylacetyloxy- methoxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylic acid ; (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-Acetylamino-2'-ethyl) butyl-4-[(N-(u-trimethylacetyloxy- ethoxycarbonylamino-imino) methyl] ainino-2-hydroxycyclopentan-1-carboxylic acid ; (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(2'-L-aminopop anoly- amino- iminomethyl] amino-2-hydroxycyclopentan-1-carboxylic acid ;

Ethyl (lS, 2S, 3R, 4R, 1'S)- (-)-3- (1'-acetylamino-2'-ethyl) butyl-4- [ (N-acetyloxymeth- oxycarbonylamino-N'-acetyloxymethoxycarbonylimino) methyl] amino-2-hydroxy-cyclopentan- 1-carboxylate ; (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-Acetylamino-2'-ethyl) butyl-4-[(N-acetyloxymethoxy- carbonylamino-N'-acetyloxymethoxycarbonylimino) methyl] amino-2-hydroxy-cyclopentan-1- carboxylic acid ; Ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-2, 2, 2-trifluoro- ethoxycarbonylamino-N'-2, 2, 2-trifluoroethoxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate ; Ethyl (lS, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-ethoxycarbonyl-amino-N'- ethoxycarbonylimino) methyl] amino-2-hydroxycyclopentan-1-carboxylate ; Ethyl (1S, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(hydroxylamino- imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate ; (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(hydroxylamino -imino) methyl] amino-2-hydroxycyclopentan-1-carboxylic acid ; 1- [ (4'-Aminomethylcarbonylamino) benzoyloxymethyl] (1S, 2S, 3R, 4R, 1'S)- (-)-3- (1'- acetylamino-2'-ethyl) butyl-4- (amino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate ; 1- [ (4'-Aminomethylcarbonyloxy) benzoyloxymethyl] (1S, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetylamino- 2'-ethyl) butyl-4-(amino-imino) methyl] amino-2-hydroxycyclopentan-l-carboxylate ; n-Hexyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4- (amino-imino) methyl] amino- 2-hydroxycyclopentan-1-carboxylate ;

2-Methylpropyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4- (amino- imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate ; a- (Ethoxycarbonyloxy) ethyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (1'-acetylamino-2'-ethyl)- butyl-4- (amino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate ; a-Acetyloxyethyl (lS, 2S, 3R, 4R, 1'S)- (-)-3- (1'-acetylamino-2'-ethyl) butyl-4- (amino- imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate ; tert-Butylcarbonyloxomethyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetylamino-2'-ethyl)- butyl-4- (amino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate ; a- (methoxycarbonyloxy) ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4- (amino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate ; and a- (iso-Propyloxycarbonyloxy) ethyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4- (amino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate.

The following non-limiting examples are presented to further illustrate the present invention.

Example 1 Methyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-ethoxycarbonylamino- imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate 0

1A : 1-Benzyloxycarbonyl-2-methyl-2-thiopseudourea To a mixture of 2-methyl-2-thiopseudourea sulfate (27. 8 g, 100 mmol), water (20 mL) and benzyl chloroformate (17. 0 g, 100 mmol) at 5 °C was added 40% aqueous sodium hydroxide dropwise until the pH became neutral. The mixture was diluted with dichloromethane (50 mL). Additional benzyl chloroformate (17. 0 g, 100 mmol) was added portion wise over a period of 0. 5 h maintaining the pH of the mixture neutral with the addition of 40% NaOH.

The mixture was stirred for an additional 0. 5 hours and the organic layer was separated. The aqueous layer was extracted with dichloromethane (3 times) after diluting with water. The combined organic layers were dried and after filtration, the filtrate was concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give : i) 1, 3-Bis (benzyloxycarbonyl)-2-methyl-2-thiopseudourea (14. 0 g, 19 %). ii) l-Benzyloxycarbonyl-2-methyl-2-thiopseudourea (24. 0 g, 53 %) 1B : 1-Benzyloxycarbonyl-3-ethoxycarbonyl-2-methyl-2-thiopseudour ea To a solution of l-benzyloxycarbonyl-2-methyl-2-thiopseudourea (1A, 1. 0 g, 4. 46 mmol)) in dichloromethane (20 mL) were added triethylamine (1. 85 mL, 13. 4 mmol) and ethyl chloroformate (1. 45 g, 13. 4 mmol) and stirred for 1 hour. The solution was washed with water, the organic layer was separated, concentrated and purified on silica gel column using hexane : ethyl acetate as an eluent to give 1. 30g (99%) of 1B.

1C : Methyl (l S, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-ethoxy carbonylamino-N'-benzyloxycarbonylimino) methyl] amino-2-hydroxycyclopentan-1- carboxylate To a solution of methyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4-amino-2- hydroxycyclopentan-1-carboxylate trifluoroacetate (1. 03 g, 2. 5 mmol, disclosed in WO 99/33781) in dimethyl formamide (20 mL) were added triethylamine (1. 22 mL, 8. 75 mmol), 1- benzyloxycarbonyl-3-ethoxycarbonyl-2-methyl-2-thiopseudourea (1B, 1. 30 g, 4. 4 mmol) and mercury (II) chloride (1. 2 g, 4. 4 mmol) and the mixture was stirred for 2 hours. After dilution with ethyl acetate (50 mL), the mixture was filtered and the filtrate was washed with water and brine. The organic layer was dried, filtered and the filtrate concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 1. 0 g (73 %) of 1C. 1 : To a solution of methyl (1S, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N- ethoxycarbonylamino-N'-benzyloxycarbonylimino) methyl] amino-2-hydroxycyclo-pentan-l- carboxylate (1C, 1. 0 g, 1. 8 mmol) in methanol (50 mL) and water (5 mL) were added 5 drops of HC1 and 10% Pd/C (200 mg) and the mixture was hydrogenated at 40 psi for 16 h. After removing the catalyst by filtration, the filtrate was concentrated and the residue was taken in ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated, dried, filtered and concentrated. The residue was purified on silica gel column using chloroform : methanol as an eluent to give 0. 7 g (93%) of 1.

Anal. calcd. for Cl9H34N406 : % C 55. 06 % H 8. 27 % N 13. 52 Found : % C 54. 61 % H8. 07 % N 13. 48 MS (ES+) : 416. 0 (M+1) Example 2 Ethyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-benzyloxy- carbonylamino-imino) methyl] amino-2-hydroxycyclopentan-l-carboxylate 2A : 1-Benzyloxycarbonyl-3-tert-butoxycarbonyl-2-methyl-2-thiopse udourea To a solution of 1-benyzyloxycarbonyl-2-methyl-2-thiopseudourea (1A, 5. 0 g, 22. 0 mmol)) in dichloromethane (100 mL) were added triethylamine (9 mL, 66. 0 mmol) and di-tert-butyl dicarbonate (14. 4 g, 66. 0 mmol) and stirred for 16 h. The solution was washed with water ; the organic layer was separated, concentrated and purified on silica gel column using hexane : ethyl acetate as an eluent to give 3. 8 g (53 %) of 2A.

2B : Ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-tert-butoxy- carbonylamino-N'-benzyloxycarbonylimino) methyl] amino-2-hydroxycyclopentan-1- carboxylate To a solution of ethyl (1S, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-amino-2- hydroxycyclopentan-1-carboxylate trifluoroacetate (4. 5 g, 10. 5 mmol, given in WO 99/33781) in dimethyl formamide (50 mL) were added triethylamine (5. 1 mL, 36. 7 mmol), 1- benzyloxycarbonyl-3-tert-butoxycarbonyl-2-methyl-2-thiopseud ourea (2A, 3. 4 g, 10. 5 mmol) and mercury (II) chloride (2. 85 g, 10. 5 mmol) and the mixture was stirred for 2 h. After dilution with ethyl acetate (250 mL), the mixture was filtered and the filtrate was washed with water and brine. The organic layer was dried, filtered and the filtrate concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 3. 2 g (51 %) of 2B. 2 : To a solution of ethyl (1S, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-tert- butoxycarbonylamino-N'-benzyloxycarbonylimino) methyl] amino-2-hydroxycyclo-pentan-l- carboxylate (2B, 1. 2 g, 2. 0 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid

(4. 0 mL) and was stirred for 4 h. After concentration, the residue was taken in ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated, dried, filtered and concentrated. The residue was purified on silica gel column using chloroform : methanol as an eluent to give 0. 80 g (81 %) of 2.

Anal. calcd. for C2sH3sN406 : % C 61. 21 % H 7. 81 % N 11. 42 Found : % C 61. 23 % H 7. 73 % N 11. 50 MS (ES+) : 491. 6 (M + 1) Example 3 Ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-methoxycarbonyl amino-imino) methyl] amino 2-hydroxycyclopentan-1-carboxylate 3A : 1-Benzyloxycarbonyl-3-methoxycarbonyl-2-methyl-2-thiopseudou rea To a solution of 1-benzyloxycarbonyl-2-methyl-2-thiopseudourea (1A, 5. 0 g, 22. 0 mmol) in dichloromethane (100 mL) were added triethylamine (9 mL, 66. 0 mmol) and methyl chloroformate (6. 2 g, 66. 0 mmol) and stirred for 16 h. The solution was washed with water ; the organic layer was separated, concentrated and purified on silica gel column using hexane : ethyl acetate as an eluent to give 2. 8 g (45 %) of 3A.

3B : Ethyl (l S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-methoxy- crbonylamino-N'-benzyloxycarbonylimino) methyl] amino-2-hydroxycyclopentan-1- carboxylate To a solution of ethyl (1S, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-amino-2- hydroxycyclopentan-1-carboxylate trifluoroacetate (3. 9 g, 9. 2 mmol, given in WO 99/33781) in dimethyl formamide (40 mL) were added triethylamine (4. 5 mL, 32. 2 mmol), 1- benzyloxycarbonyl-3-methoxycarbonyl-2-methyl-2-thiopseudoure a (3A, 2. 6 g, 9. 2 mmol) and mercury (II) chloride (2. 5 g, 9. 2 mmol) and the mixture was stirred for 2 h. After dilution with ethyl acetate (200 mL), the mixture was filtered and the filtrate was washed with water and brine. The organic layer was dried, filtered and the filtrate concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 1. 9 g (37%) of 3B.

3 : To a solution of ethyl (1S, 2S, 3R, 4R, l')- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4- [ (N- methoxycarbonylamino-N'-benzyloxycarbonylimino) methyl] amino-2-hydroxycyclo-pentan-l- carboxylate (1C, 1. 6 g, 2. 9 mmol) in ethanol (27 mL) and water (3 mL) were added 5 drops of

HC1 and 10% Pd/C (100 mg) and the mixture was hydrogenated at 40 psi for 2 h. After removing the catalyst by filtration, the filtrate was concentrated and the residue was taken in ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated, dried, filtered and concentrated. The residue was purified on silica gel column using chloroform : methanol as an eluent to give 0. 8 g (66%) of 3.

Anal. calcd. for Ci9H34N406'0. CHO : % C 53. 89 % H 8. 33 %N 13. 23 Found : % C 53. 98 % H 8. 06 % N 13. 10 MS (ES+) : 415. 7 (M+1) Example 4 Ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-tert-butoxycarbo- nylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate To a solution of ethyl (1S, (2S,3R,4R,1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-t ert- butoxycarbonylamino-N'-benzyloxycarbonylimino) methyl] amino-2-hydroxycyclopentan-1- carboxylate (2B, 2. 8 g, 4. 7 mmol) in ethanol (40 mL) and water (4 mL) were added 5 drops of HC1 and 10% Pd/C (200 mg) and the mixture was hydrogenated at 40 psi for 2 h. After removing the catalyst by filtration, the filtrate was concentrated and the residue was taken in ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated, dried, filtered and concentrated. The residue was purified on silica gel column using chloroform : methanol as an eluent to give 1. 5 g (70%) of 4.

Anal. calcd. forC22H4oN406 : % C 57. 87 % H 8. 83 % N 12. 27 Found : % C 57. 88 %H 8. 83 %N 12. 09 MS (ES+) : 457. 4 (M + 1)

Example 5 Ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-ethoxycarbonyl-amino- imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate 5A : Ethyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-ethjyoxycar bo- nylamino-N'-benzyloxycarbonylimino) methyl] amino-2-hydroxycyclopentan-1-carboxylate To a solution of ethyl (1S, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-amino-2- hydroxycyclopentan-1-carboxylate trifluoroacetate (3. 9 g, 9. 1 mmol, given in WO 99/33781) in dimethyl formamide (40 mL) were added triethylamine (4. 4 mL, 31. 9 mmol), 1- benzyloxycarbonyl-2-ethoxycaronyl-2-methyl-2-thiopseudourea (1B, 2. 7 g, 9. 1 mmol) and mercury (II) chloride (2. 5 g, 9. 1 mmol) and the mixture was stirred for 2 h. After dilution with ethyl acetate (200 mL), the mixture was filtered and the filtrate was washed with water and brine. The organic layer was dried, filtered and the filtrate concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 3. 5 g (68 %) of 5A. 5 : To a solution of ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N- ethoxycarbonylamino-N'-benzyloxycarbonylimino) methyl] amino-2-hydroxycyclopentan-1- carboxylate (5A, 2. 0 g, 3. 5 mmol) in ethanol (40 mL) and water (4 mL) were added 5 drops of HC1 and 10 % Pd/C (200 mg) and the mixture was hydrogenated at 40 psi for 3 h. After removing the catalyst by filtration, the filtrate was concentrated and the residue was taken in ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated, dried, filtered and concentrated. The residue was purified on silica gel column using chloroform : methanol as an eluent to give 0. 7 g (47%) of 5.

Anal. calcd. for C20H36N406 : % C 56. 06 % H 8. 07 % N 13. 07 Found : %C 55. 77 % H 8. 43 % N 12. 99 M S (ES+) : 429. 5 (M + 1)

Example 6 Methyl (1S,2S,3R,4R,1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[( N-acetylox- methoxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate zozo HN-\rA HN= NH, C xCOOCH3 oh NH 6A : Methyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-benzylox- carbonylamino-N'-tert-butoxycarbonylimino) methyl] amino-2-hydroxycyclopentan-1- carboxylate To a solution of methyl (1S, 2S, 3R, 4R, l'6)- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4-amino-2- hydroxycyclopentan-l-carboxylate trifluoroacetate (5. 9 g, 14. 3 mmol, given in WO 99/33781) in dimethyl formamide (50 mL) were added triethylamine (7. 0 mL, 50. 1 mmol), 1- benzyloxycarbonyl-3-tert-butoxycarbonyl-2-methyl-2-thiopseud ourea (1B, 5. 2 g, 15. 7 mmol) and mercury (II) chloride (4. 3 g,, 15. 7 mmol) and the mixture was stirred for 2 h. After dilution with ethyl acetate (200 mL), the mixture was filtered and the filtrate was washed with water and brine. The organic layer was dried, filtered and the filtrate concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 6. 8 g (82%) of 6A.

6B : Methyl (l S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-benzyloxy- carbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate To a solution of methyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-ter- <BR> <BR> butoxycarbonylamino-N'-benzyloxycarbonylimino) methyl] amino-2-hydroxycyclopentan-1- carboxylate (6A, 6. 8 g, 11. 7 mmol) in dichloromethane (120 mL) was added trifluoroacetic acid (16. 0 mL) and was stirred for 4 h. After concentration, the residue was taken in ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated, dried, filtered and concentrated. The residue was purified on silica gel column using chloroform : methanol as an eluent to give 4. 5 g (80%) of 6B.

6C : Methyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-benzyloxy- carbonylamino-N'-acetyloxymethoxycarbonylimino) methyl] amino-2-hydroxycyclopentan- 1-carboxylate

To a solution of methyl (1S, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N- benzyloxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate (6B, 0. 48 g, 1 mmol) in hexamethylphosphoramide (6. 0 mL) was added acetyloxymethyl 4-nitrophenyl carbonate (0. 76 g, 3. 0 mmol, prepared by using the method disclosed in Alexander et al. J. Med. Chem. 1988, 31, 318-322) and heated at 45 °C for 16 h. An additional amount of acetyloxymethyl 4-nitrophenyl carbonate (0. 25 g, 1 mmol) was added to the reaction mixture and again heated at 45 °C for 8 h. The mixture was cooled and diluted with water. After saturating with salt, the mixture was extracted with ethyl acetate (3 X). The combined organic extracts were washed with water and brine and dried. After filtration, the filtrate was concentrated and the residue was purified on silica gel column using ethyl acetate : hexane as an eluent to give 0. 25 g (42%) of 6C. 6 : To a solution of methyl (IS, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N- benzyloxycarbonylamino-N'-acetyloxymethoxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate (6C, 0. 25 g, 0. 42 mmol) in methanol (8 mL) and water (2 mL) was added 10% Pd/C (50 mg) and the mixture was hydrogenated at 40 psi for 2 h. After removing the catalyst by filtration, the filtrate was concentrated and the residue was purified on silica gel column using chloroform : methanol as an eluent to give 0. 095 g (49%) of 6.

Anal. calcd. for C20H34N4OsH2O : % C 50. 41 % H 7. 61 % N 11. 76 Found : % C 50. 63 % H7. 40 % N 11. 69 MS (ES+) : 459. 4 (M+1) Example 7 Methyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-acetyloxy- methoxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate 7A : Methyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-benzyloxy- carbonylamino)-N'- (a-acetyloxyethoxycarbonylimino) methyl] amino-2-hydroxy- cyclopentan-1-carboxylate To a solution of methyl (IS, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N- benzyloxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate (6B, 0. 48 g, 1 mmol) in hexamethylphosphoramide (6. 0 mL) was added a-acetyloxyethyl 4-nitrophenyl

carbonate (0. 8 g, 3. 0 mmol, prepared by using the method disclosed in Alexander et al. J. Med. Chem. 1988, 31, 318-322) and heated at 45 °C for 16 h. An additional amount of a- acetyloxymethyl 4-nitrophenyl carbonate (0. 27 g, 1 mmol) was added to the reaction mixture and again heated at 45 °C for 8 h. The mixture was cooled and diluted with water. Agter saturating with salt, the mixture was extracted with ethyl acetate (3 X). The combined organic extracts were washed with water and brine and dried. After filtration, the filtrate was concentrated and the residue was purified on silica gel column using ethyl acetate : hexane as an eluent to give 0. 32 g (53 %) of 7A. 7 : To a solution of methyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N- benzyloxycarbonylamino)-N'- (a-acetyloxymethoxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate (7A, 0. 32 g, 0. 53 mmol) in methanol (8 mL) and water (2 mL) was added 10% Pd/C (60 mg) and the mixture was hydrogenated at 40 psi for 2 h. After removing the catalyst by filtration, the filtrate was concentrated and the residue was purified on silica gel column using chloroform : methanol as an eluent to give 0. 12 g (48 %) of 7.

Anal. calcd. for GlH36N4OsH2O : % C 51. 42 % H 7. 81 % N 11. 42 Found : % C 51. 54 % H7. 48 % N 11. 26 MS (ES+) : 473. 2 (M+1) Example 8 Ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-acetyloxymeth- oxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate 8A : Ethyl (lS, 25, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-benzyloxy- carbonylamino-N'-acetyloxymethoxycarbonylimino) methyl] amino-2-hydroxycyclopentan- 1-carboxylate To a solution of ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N- benzyloxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-l-carboxylate (example 2, 0. 5 g, 1 mmol) in hexamethylphosphoramide (6. 0 mL) was added acetyloxymethyl 4- nitrophenyl carbonate (0. 76 g, 3. 0 mmol, prepared by using the method disclosed in Alexander et al. J. Med. Chem. 1988, 31, 318-322) and heated at 45 °C for 16 h. An additional amount of acetyloxymethyl 4-nitrophenyl carbonate (0. 25 g, 1 mmol) was added to the reaction mixture and again heated at 45 °C for 8 h. The mixture was cooled and diluted with water.

After saturating with salt, the mixture was extracted with ethyl acetate (3 X). The combined organic extracts were washed with water and brine and dried. After filtration, the filtrate was concentrated and the residue was purified on silica gel column using ethyl acetate : hexane as an eluent to give 0. 32 g (53 %) of 8A.

8 : To a solution of methyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N- benzyloxycarbonylamino-N'-acetyloxymethoxycarbonylimino) methyl] amino-2-hydroxy- cyclopentan-l-carboxylate (8A, 0. 32 g, 0. 53 mmol) in ethanol (20 mL) and water (5 mL) was added 10% Pd/C (50 mg) and the mixture was hydrogenated at 40 psi for 2 h. After removing the catalyst by filtration, the filtrate was concentrated and the residue was purified on silica gel column using chloroform : methanol as an eluent to give 0. 22 g (88 %) of 8.

Anal. calcd. for GlH36N4Os : %C 53. 37 % H 7. 67 % N 11. 85 Found : % C 53. 50 % H 7. 63 % N 11. 68 MS (ES+) : 472. 9 (M+1) Example 9 Ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N (a-acetyloxyeth- oxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate O CH3 H O O O CH3 N # # # NH# O } OH H'', OU NHAs 9A : Ethyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-benzyloxy- carbonylamino)-N'- (oc-acetyloxyethoxycarbonylimino) metliyl] amino-2-hydroxy- cyclopentan-1-carboxylate To a solution of ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N- benzyloxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate (example 2, 0. 49 g, 1 mmol) in hexamethylphosphoramide (6. 0 mL) was added a-acetyloxyethyl 4- nitrophenyl carbonate (0. 8 g, 3. 0 mmol, prepared by using the method disclosed in Alexander et al. J. Med. Chem. 1988, 31, 318-322) and heated at 45 °C for 16 h. An additional amount of a-acetyloxymethyl 4-nitrophenyl carbonate (0. 27 g, 1 mmol) was added to the reaction mixture and again heated at 45 °C for 8 h. The mixture was cooled and diluted with water. After saturating with salt, the mixture was extracted with ethyl acetate (3 X). The combined organic extracts were washed with water and brine and dried. After filtration, the filtrate was

concentrated and the residue was purified on silica gel column using ethyl acetate : hexane as an eluent to give 0. 32 g (52%) of 9A.

9 : To a solution of ethyl (1S, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N- benzyloxycarbonylamino)-N'- (a-acetyloxyethoxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate (9A, 0. 32 g, 0. 52 mmol) in ethanol (20 mL) and water (5 mL) was added 10% Pd/C (60 mg) and the mixture was hydrogenated at 40 psi for 2 h. After removing the catalyst by filtration, the filtrate was concentrated and the residue was purified on silica gel column using chloroform : methanol as an eluent to give 0. 2 g (79 %) of 9.

Anal. calcd. for C22H38N4O8 : % C 54. 30 % H 7. 87 % N 11. 51 Found : % C 53. 97 % H 7. 74 % N 11. 26 MS (ES+) : 487. 1 (M+ 1) Example 10 Ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-trimethylacetyl- oxymethoxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate O O H # # NNN#O## # O # H _-_ H N COOED ou --'NHAo 10A : Trimethylacetyloxymethyl 4-nitrophenyl carbonate A mixture of iodomethyl 4-nitrophenyl carbonate (8. 4 g, 26. 0 mmol, prepared from literature method : Alexender et al. J. Med Chem. 1988, 31, 318-322) and mercuric pivalate (12. 0 g, 30 mmol, prepared from literature method : Bunce J. Org. Chem. 1972, 37, 664-669) in benzene (240 mL) was heated at reflux temperature for 1 h. The reaction mixture was concentrated and ether (100 mL) was added to the residue and left at room temperature for 16 h. The precipitate was removed by filtration and the filtrate after concentration was purified on silica gel column using ethyl acetate : hexane as an eluent to give 5. 0 g (64%) of 10A. 10B : Ethyl (1S, 2S,3R,4R,$1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-b enzyloxy- carbonylamino)-N'- (trimetliylacetyloxymethoxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate To a solution of ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N- benzyloxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate (example 2, 0. 49 g, 1 mmol) in hexamethylphosphoramide (6. 0 mL) was added trimethylacetyloxymethyl 4-nitrophenyl carbonate (10A, 0. 9 g, 3. 0 mmol) and heated at 45 °C for 16 h. An additional amount of trimethylacetyloxymethyl 4-nitrophenyl carbonate (0. 3 g, 1 mmol) was added to the reaction mixture and again heated at 45 °C for 8 h. The mixture was

cooled and diluted with water. After saturating with salt, the mixture was extracted with ethyl acetate (3 X). The combined organic extracts were washed with water and brine and dried.

After filtration, the filtrate was concentrated and the residue was purified on silica gel column using ethyl acetate : hexane as an eluent to give 0. 13 g (20%) of 10B.

10 : To a solution of ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N- benzyloxycarbonylamino)-N'- (trimethylacetyloxymethoxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate (10B, 0. 13 g, 0. 21 mmol) in ethanol (8 mL) and water (2 mL) was added 10% Pd/C (30 mg) and the mixture was hydrogenated at 40 psi for 2 h. After removing the catalyst by filtration, the filtrate was concentrated and the residue was purified on silica gel column using chloroform : methanol as an eluent to give 0. 05 g (45%) of 10.

Anal. calcd. for C24H42N4Os0. 5H2O : % C 55. 05 % H 8. 28 % N 10. 70 Found : % C 55. 30 %H8. 14 % N 10. 40 MS (ES+) : 515. 4 (M+1) Example 11 Ethyl (1S, 2S, 3R, 4R, 1'S)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-(ot-trimethyl- acetyloxyethoxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-l-carboxylate 11A : Ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-benzyloxy- carbonylamino)-N'- methyl] amino-2- hydroxycyclopentan-1-carboxylate To a solution of ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N- benzyloxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate (example 2, 0. 49 g, 1 mmol) in hexamethylphosphoramide (6. 0 mL) was added a-acetyloxyethyl 4- nitrophenyl carbonate (0. 8 g, 3. 0 mmol, prepared by using the method disclosed in Alexander et al. J. Med. Chem. 1988, 31, 318-322) and heated at 45 °C for 16 h. An additional amount of a-acetyloxymethyl 4-nitrophenyl carbonate (0. 27 g, 1 mmol) was added to the reaction mixture and again heated at 45 °C for 8 h. The mixture was cooled and diluted with water.

After saturating with salt, the mixture was extracted with ethyl acetate (3 X). The combined organic extracts were washed with water and brine and dried. After filtration, the filtrate was concentrated and the residue was purified on silica gel column using ethyl acetate : hexane as an eluent to give 0. 12 g (18%) of 11A.

11 : To a solution of ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N- benzyloxycarbonylamino)-N'- (a-trimethylacetyloxyethoxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate (11A, 0. 12 g, 0. 18 mmol) in ethanol (10 mL) and water (2 mL) was added 10% Pd/C (40 mg) and the mixture was hydrogenated at 40 psi for 2 h. After removing the catalyst by filtration, the filtrate was concentrated and the residue was purified on silica gel column using chloroform : methanol as an eluent to give 0. 045 g (46 %) of 11.

Anal. calcd. for C2sH44N4Os0. 5H2O : % C 55. 85 % H 8. 44 % N 10. 42 Found : % C 56. 03 % H 8. 24 % N 10. 17 MS (ES+) : 529. 4 (M+1) Example 12 Ethyl (1S, 2S,3R,4R,$1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-p henylacetyloxy- methoxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate 12A : Phenylacetyloxymethyl 4-nitrophenyl carbonate A mixture of iodomethyl 4-nitrophenyl carbonate (15. 0 g, 46. 0 mmol, prepared from literature method : Alexender et al. J. Med. Chem. 1988, 31, 318-322) and mercuric phenyl acetate (30. 0 g, 64 mmol, prepared from literature method : Bunce J. Org. Chem. 1972, 37, 664-669) in benzene (500 mL) was heated at reflux temperature for 20 h. The reaction mixture was concentrated and the residue was purified on silica gel column using ethyl acetate : hexane as an eluent to give 3. 0 g (20%) of 12A. 12B : Ethyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-benzyloxy- carbonylamino)-N'-(phenylacetyloxymethoxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate To a solution of ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N- benzyloxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate (example 2, 0. 49 g, 1 mmol) in hexamethylphosphoramide (6. 0 mL) was added phenylacetyloxymethyl 4-nitrophenyl carbonate (12A, 0. 99 g, 3. 0 mmol) and heated at 45 °C for 16 h. An additional amount of trimethylacetyloxymethyl 4-nitrophenyl carbonate (0. 33 g, 1 mmol) was added to the reaction mixture and again heated at 45 °C for 8 h. The mixture was cooled and diluted

with water. After saturating with salt, the mixture was extracted with ethyl acetate (3 X). The combined organic extracts were washed with water and brine and dried. After filtration, the filtrate was concentrated and the residue was purified on silica gel column using ethyl acetate : hexane as an eluent to give 0. 17 g (25 %) of 12B.

12 : To a solution of ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N- benzyloxycarbonylamino)-N'- (phenylacetyloxymethoxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate (12B, 0. 16 g, 0. 23 mmol) in ethanol (8 mL) and water (2 mL) was added 10% Pd/C (30 mg) and the mixture was hydrogenated at 40 psi for 2 h. After removing the catalyst by filtration, the filtrate was concentrated and the residue was purified on silica gel column using chloroform : methanol as an eluent to give 0. 1 g (79 %) of 12.

Anal. calcd. for C27H4oN40s : % C 59. 11 % H 7. 35 % N 10. 21 Found : % C 59. 09 % H7. 32 %N 9.83 MS (ES+) : 549. 4 (M+1) Example 13 Ethyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-2, 2, 2-trichloro- ethoxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate 13A : Ethyl (1S,2S,3R,4R,$1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[ (N-tert-butoxy- carbonylamino-N'-2, 2, 2-trichloroethoxycarbonylimino) methyl] amino-2-liydroxy- cyclopentan-1-carboxylate To a mixture of ethyl (1S, 2S, 3R, 4R, 1'59-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-tert- butoxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate (example 4, 0. 65 g, 1. 42 mmol) in dichloromethane (25 mL) and aqueous saturated sodium bicarbonate (40 mL) was added 2, 2, 2-trichloroethyl chloroformate (0. 25 mL, 1. 8 mmol) and stirred for 2 h at room temperature. The organic layer was separated, and the aqueous layer was extracted further with dichloromethane. The combined organic layers were dried, filtered and concentrated to give 0. 88 g of the crude product 13A.

13. To a solution of ethyl (lS, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-tert- butoxycarbonylamino-N'-2, 2, 2-trichloroethoxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate (13A, 0. 88 g, 1. 42 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (4. 0 mL) and was stirred for 4 h. After concentration, the residue was taken in ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated, dried, filtered and concentrated. The residue was purified on silica gel column using chloroform : methanol as an eluent to give 0. 4 g (53 %) of 13.

Anal. calcd. for C20H33N406C13 : % C 45. 17 % H 6. 25 % N 10. 53 Found : % C 45. 30 % H 6. 29 % N 10. 33 MS (ES+) : 533. 2 (M+ 1) Example 14 Ethyl (lS, 2S,3R,4R,$1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-2 , 2, 2-trifluoro- ethoxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate 14A : 1-tert-Butoxycarbonyl-2-methyl-2-thiopseudourea To a mixture of 2-methyl-2-thiopseudourea sulfate (2. 78 g, 10 mmol) in dichloromethane (100 mL) and saturated aqueous sodium bicarbonate (100 mL) was added di-tert-butyl dicarbonate (2. 18 g, 10 mmol) and the mixture was stirred for 4 h. The organic layer was separated and concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 2. 5 g (65 %) of 14A.

14B : 1-tert-Butoxycarbonyl-3- (2, 2, 2-trifluoroethoxy) carbonyl-2-methyl-2-thio- pseudourea To a solution of 2, 2, 2-trifluoroethanol (3. 22 g, 32. 2 mmol) in dichloromethane (25 mL) was added ethyl chlorothioformate (5. 0 g, 40. 0 mmol) over a period of 2 min., followed by drop wise addition of FeCl3 in nitromethane (0. 35 g FeCl3 in 0. 7 mL nitromethane) over a period of 5 min. The reaction mixture was further stirred for 0. 5 h, and diluted with dichloromethane (100 mL). The mixture was washed with 1N HC1 (100 mL) and water (4 X 100 mL), and

organic layer separated and dried. After filtration, the filtrate was concentrated to give 6. 7 g of the residue of 2, 2, 2-trifluoroethyl ethylthioformate. To this residue were added 1, 2- dichloroethane (50 mL) and sulfuryl chloride (15. 0 mL) and the solution was heated at gentle reflux for 7 h and then stirred at room temperature for 16 h. The reaction mixture was divided into 2 parts. One part of this mixture was added portion wise over a period of 1 h, to a stirred mixture of l-te7t-butoxycarbonyl-2-methyl-2-thiopseudourea (14A, 2. 5 g, 13. 1 mmol) in dichloromethane (100 mL) and aqueous sodium bicarbonate (100 mL), while maintaining the pH of the mixture basic by adding 40 % sodium hydroxide. The reaction mixture was further stirred for 1 h and the organic layer was separated. After drying, it was filtered and the filtrate was concentrated and the residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 2. 4 g (58%) of 14B.

14C : Ethyl (lS, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-tert-butoxy- carbonylamino-N'-2, 2, 2-trifluoroethoxycarbonylimino) methyl] amino-2-hydroxy- cyclopentan-l-carboxylate To a solution of ethyl (1S, 2S, 3R, 4R, l')- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4-amino-2- hydroxycyclopentan-1-carboxylate trifluoroacetate (0. 85 g, 2 mmol, disclosed in WO 99/33781) in dimethyl formamide (20 mL) were added triethylamine (1. 4 mL, 10. 0 mmol), 1- tert-butoxycarbonyl-3- (2, 2, 2-trifluoroethoxycarbonyl)-2-methyl-2-thiopseudo- urea (14B, 0. 76 g, 2. 4 mmol) and mercury (II) chloride (0. 65 g, 2. 4 mmol) and the mixture was stirred for 2 h.

After dilution with ethyl acetate (100 mL), the mixture was filtered and the filtrate was washed with water and brine. The organic layer was dried, filtered and the filtrate concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 32 g (27%) of 14C.

14. To a solution of ethyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4- [ (N-tert- butoxycarbonylamino-N'-2, 2, 2-trifluoroethoxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate (14C, 0. 32 g, 0. 54 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1. 0 mL) and was stirred for 3 h. After concentration, the residue was taken in ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated, dried, filtered and concentrated. The residue was purified on silica gel column using chloroform : methanol as an eluent to give 0. 2 g (77%) of 14.

Anal. calcd. for C20H33N406F3 : % C 45. 40 % H 5. 63 % N 9. 21 Found : %C 44. 90 % H5. 56 % N 8. 91 MS (ES+) : 483. 3 (M+ 1) Example 15 Ethyl (lS, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4->-(2'-L-amino-3'- phenylpropanoylamino)-imino] methylamino-2-hydroxycyclopentan-1-carboxylate

15A : Ethyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-(2'-L-maino -3'- phenyl) propanoylamino)-N'-(benzyloxycarbonylimino) methyl] amino-2-hydroxy- cyclopentan-1-carboxylate To a solution of N-benzyloxycarbonyl L-phenylalanine (0. 26 g, 0. 87 mmol) in ethyl acetate (20 mL) was added 1, l'-carbonyldiimidazole (0. 14 g, 0. 87 mmol) and the mixture was stirred for 0. 25 h. To this solution was added N-hydroxysuccinimide (0. 1 g, 0. 87 mmol) and stirred for 2 h. The reaction mixture was washed with water and the organic layer separated, dried, filtered and concentrated to give 0. 34 g of N-benzyloxycarbonyl L-phenylalanine succinimido ester.

To a mixture of ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N- (benzyloxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-l-carboxylate (example 2, 0. 33 g, 0. 67 mmol) in dichloromethane (20 mL) and saturated aqueous sodium bicarbonate (20 mL) was added above prepared N-benzyloxycarbonyl L-phenylalanine succinimido ester (0. 34 g, 0. 87 mmol) and the mixture was stirred for 16 h at room temperature. The organic layer was separated, aqueous layer was further extracted with dichloromethane (20 mL) and the combined organic layers were dried. After filtration, the filtrate was concentrated and the residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 41 g (79%) of 15a. 15 : To a solution of ethyl (1S, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[N-(2'-L- amino-3'-phenyl) propanoylamino)-N'- (benzyloxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate (15A, 0. 41 g, 0. 53 mmol) in ethanol (22 mL) and water (6 mL) was added 10 % Pd/C (60 mg) and cone. HCl (3 drops) and the mixture was hydrogenated at 40 psi for 1 h. The mixture was passed through a pad of Celite and silica gel, and the filtrate was concentrated and dried to give 0. 3 g (89%) of 15.

Anal. calcd. for C26H4lNsOs2H C1N2. 5H20 : % C 50. 24 % H 7. 78 % N 11. 27 Found : % C 50. 49 % H 7. 51 % N 10. 85 MS (ES+) : 504. 4 (M + 1) Example 16 Ethyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[N-(2'-L-aminoprop- anoylamino)-imino] methylamino-2-hydroxycyclopentan-1-carboxylate

16A : Ethyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4- [N- (21-L-amino- propanoylamino)-N'-(benzyloxycarbonylimino) methyl] amino-2-hydroxycyclo- pentan-1- carboxylate To a solution of N-benzyloxycarbonyl L-alanine (0. 19 g, 0. 87 mmol) in ethyl acetate (20 mL) was added 1, l'-carbonyldiimidazole (0. 14 g, 0. 87 mmol) and the mixture was stirred for 0. 25 h. To this solution was added N-hydroxysuccinimide (0. 1 g, 0. 87 mmol) and stirred for 2 h.

The reaction mixture was washed with water and the organic layer separated, dried, filtered and concentrated to give 0. 28 g of N-benzyloxycarbonyl L-alanine succinimido ester. To a mixture of ethyl (lys, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[N- (benzyloxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate (example 2, 0. 33 g, 0. 67 mmol) in dichloromethane (20 mL) and saturated aqueous sodium bicarbonate (20 mL) was added above prepared N-benzyloxycarbonyl L-alanine succinimido ester (0. 28 g, 0. 87 mmol) and the mixture was stirred for 16 h at room temperature. The organic layer was separated, aqueous layer was further extracted with dichloromethane (20 mL) and the combined organic layers were dried. After filtration, the filtrate was concentrated and the residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 37 g (79%) of 16A. 16 : To a solution of ethyl (1S, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[N-(2'-L- aminopropanoylamino)-N'- (benzyloxycarbonylimino) methyl] amino-2-hydroxycyclopentan-l- carboxylate (16A, 0. 37 g, 0. 53 mmol) in ethanol (24 mL) and water (6 mL) was added 10% Pd/C (50 mg) and conc. HCl (3 drops) and the mixture was hydrogenated at 40 psi for 1 h. The mixture was passed through a pad of Celite and silica gel, and the filtrate was concentrated and dried to give 0. 26 g (84%) of 16.

Anal. calcd. ofr CH20H27N5O5#2CHCl#2H2O#C2H5OH : % C 45. 36 %H 8. 48 %N 12. 02 Found : % C 45. 52 % H 8. 04 % N 12. 14 MS (ES+) : 428. 1 (M+1) Example 17 Ethyl (15, 2S, 3R, 41e, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(2'-L-amino-3'- methylpentanoylamino)-imino] methylamino-2-hydroxycyclopentan-1-carboxylate

17A : Ethyl (IS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[N-(2'-L-amino- <BR> <BR> 3'methylpentanoylamino)-N'-(benzyloxycarbonylimino) methyl] amino-2-hydroxy-<BR> <BR> <BR> <BR> <BR> <BR> <BR> cyclopentan-1-carboxylate To a solution of N-benzyloxycarbonyl L-isoleucine (0. 3 g, 1. 12 mmol) in ethyl acetate (20 mL) was added 1, 1'-cabonyldiimidazole (0. 9 g, 1. 12 mmol) and the mixture was stirred for 0. 25 h. To this solution was added N-hydroxysuccinimide (0. 13 g, 1. 12 mmol) and stirred for 2 h. The reaction mixture was washed with water and the organic layer separated, dried, filtered and concentrated to give 0. 41 g of N-benzyloxycarbonyl L-isoleucine succinimido ester. To a mixture of ethyl (1S, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[N- (benzyloxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate (example 2, 0. 37 g, 0. 75 mmol) in dichloromethane (20 mL) and saturated aqueous sodium bicarbonate (20 mL) was added above prepared N-benzyloxycarbonyl L-isoleucine succinimido ester (0. 41 g, 1. 12 mmol) and the mixture was stirred for 16 h at room temperature. The organic layer was separated, aqueous layer was further extracted with dichloromethane (20 mL) and the combined organic layers were dried. After filtration, the filtrate was concentrated and the residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 45 g (81 %) of 17A. 17 : To a solution of ethyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (1'-acetylamino-2'-ethyl) butyl-4- [N- (2'-L- amino-3'methylpentanoylamino)-N'- (benzyloxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate (17A, 0. 31 g, 0. 42 mmol) in ethanol (24 mL) and water (6 mL) was added 10 % Pd/C (50 mg) and cone. HC1 (3 drops) and the mixture was hydrogenated at 40 psi for 1 h. The mixture was passed through a pad of Celite and silica gel, and the filtrate was concentrated and dried to give 0. 23 g (84%) of 17.

Anal. calcd. for C23H43 N5O5#3HCl#1.5C2H5OH : % C 48. 18% H 8. 32 % N 10. 81 Found : % C 48. 25 % H 8. 38 % N 10. 77 MS (ES+) : 470. 5 (M+1) Example 18 Methyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-(2'-L-amino - propanoylamino)-imino] methylamino-2-hydroxycyclopentan-1-carboxylate

18A : Methyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[N-(2'-L- aminopropanoylamino)-N'- (benzyloxycarbonylimino) methyl] amino-2-hydroxycyclo pentan-1-carboxylate To a solution of N-benzyloxycarbonyl L-alanine (0. 23 g, 1. 0 mmol) in ethyl acetate (20 mL) was added 1, I'-carbonyldiimidazole (0. 16 g, 1. 0 mmol) and the mixture was stirred for 0. 25 h. To this solution was added N-hydroxysuccinimide (0. 12 g, 1. 0 mmol) and stirred for 2 h.

The reaction mixture was washed with water and the organic layer separated, dried, filtered and concentrated to give 0. 32 g of N-benzyloxycarbonyl L-alanine succinimido ester.

To a mixture of methyl (1S, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[N- (benzyloxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate (example 6B, 0. 32 g, 0. 67 mmol) in dichloromethane (20 mL) and saturated aqueous sodium bicarbonate (20 mL) was added above prepared N-benzyloxycarbonyl L-alanine succinimido ester (0. 32 g, 0. 87 mmol) and the mixture was stirred for 16 h at room temperature. The organic layer was separated, aqueous layer was further extracted with dichloromethane (20 mL) and the combined organic layers were dried. After filtration, the filtrate was concentrated and the residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 31 g (68%) of 18A.

18 : To a solution of methyl (1S, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[N-(2'- L-aminopropanoylamino)-N'- (benzyloxycarbonylimino) methyl] amino-2-hydroxy-cyclopentan- 1-carboxylate (18A, 0. 3 g, 0. 44 mmol) in ethanol (24 mL) and water (6 mL) was added 10% Pd/C (60 mg) and conc. HC1 (3 drops) and the mixture was hydrogenated at 40 psi for 1 h.

The mixture was passed through a pad of Celite and silica gel, and the filtrate was concentrated and dried to give 0. 13 g (53 %) of 18.

Anal. calcd. for GsH3sNsOs3HCl1. 5H2O : % C 41. 50 % H 7. 51 % N 12. 74 Found : %C 41. 60 % H7. 38 % N 12. 64 MS (ES+) : 414. 4 (M+1) Example 19 Methyl (lS, 2S, 3R,4R,1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-(2'-L -amino-3'- phenylpropanoylamino)-imino] methylamino-2-hydroxycyclopentan-1-carboxylate

19A : Methyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[N-(2'-L-amino-3'- phenylpropanoylamino)-N'- (benzyloxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate To a solution of N-benzyloxycarbonyl L-phenylalanine (0. 0. 3 g, 1. 0 mmol) in ethyl acetate (20 mL) was added 1, 1'-carbonyldiimidazole (0. 16 g, 1. 0 mmol) and the mixture was stirred for 0. 25 h. To this solution was added N-hydroxysuccinimide (0. 12 g, 1. 0 mmol) and stirred for 2 h. The reaction mixture was washed with water and the organic layer separated, dried, filtered and concentrated to give 0. 39 g of N-benzyloxycarbonyl L-phenylalanine succinimido ester. To a mixture of methyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4- [N- (benzyloxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate (example 6B, 0. 32 g, 0. 67 mmol) in dichloromethane (20 mL) and saturated aqueous sodium bicarbonate (20 mL) was added above prepared N-benzyloxycarbonyl L-phenylalanine succinimido ester (0. 39 g, 1. 0 mmol) and the mixture was stirred for 16 h at room temperature. The organic layer was separated, aqueous layer was further extracted with dichloromethane (20 mL) and the combined organic layers were dried. After filtration, the filtrate was concentrated and the residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 18 g (35%) of l9A. 19 : To a solution of methyl (1S, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[N-(2'- L-maino-3'-phenylpropanoylamino)-N'-(benzyloxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate (19A, 0. 18 g, 0. 23 mmol) in ethanol (16 mL) and water (4 mL) was added 10% Pd/C (40 mg) and conc. HC1 (2 drops) and the mixture was hydrogenated at 40 psi for 1 h. The mixture was passed through a pad of Celite and silica gel, and the filtrate was concentrated and dried to give 0. 1 g (64 %) of 19.

Anal. calcd. for C2sH3sNsOst3HCl*4H20 : % C 44. 75 % H 7. 51 % N 10. 44 Found : % C 45. 24 %H7. 10 %N10. 30 MS (ES+) : 490. 7 (M+1) Example 20 <BR> <BR> (l S, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-(amino-imino) methyl-amino-2- (3'-methylbutanoyl) hydroxycyclopentan-1-carboxylic acid

20A : 1, 3-Bis (benzyloxycarbonyl)-2-methyl-2-thiopseudourea To a mixture of 2-methyl-2-thiopseudourea sulfate (27. 8 g, 100 mmol), water (20 mL) and benzyl chloroformate (17. 0 g, 100 mmol) at 5 °C was added 40% aqueous sodium hydroxide drop wise till pH became neutral. The mixture was diluted with dichloromethane (50 mL).

Additional benzyl chloroformate (17. 0 g, 100 mmol) was added portion wise over a period of 0. 5 h maintaining the pH of the mixture neutral with the addition of 40 % NaOH. The mixture was stirred for additional 0. 5 h and the organic layer was separated. The aqueous layer was extracted with dichloromethane (3 X) after diluting with water. The combined organic layers were dried and after filtration, the filtrate was concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give : i) 1, 3-Bis (benzyloxycarbonyl)-2-methyl-2-thiopseudourea (14. 0 g, 19%). ii) l-Benzyloxycarbonyl-2-methyl-2-thiopseudourea (24. 0 g, 53%) 20B : (lS, 2S, 3R, 4R, 1'- (-)-3- (1'-Acetylamino-2'-ethyl) butyl-4-tert-butoxycarbonyl- amino-2-hydroxycyclopentan-1-carboxylic acid To a solution of methyl (lys, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-tert- butoxycarbonylamino-2-hydroxycyclopentan-1-carboxylate (27. 7 g, 69. 3 mmol, given in WO 99/33781) in methanol (350 mL) and water (35 mL) was added lithium hydroxide (5. 9 g, 140 mmol) and stirred for 1 h. The reaction mixture was concentrated to half, and acidified with acetic acid and stirred for 2 h. The precipitate was collected by filtration, washed with water and dried to give 19. 0 g (71 %) of 20B.

20C : Benzyl (l S, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-tert-butoxy- carbonylamino-2-hydroxycyclopentan-1-carboxylate To a solution of 1S, 2S, 3R, 4R, 1'S)- (-)-3- (1'-acetylamino-2'-ethyl) butyl-4-tert-butoxy- carbonylamino-2-hydroxycyclopentan-1-carboxylic acid (20B, 15. 0 g, 38. 9 mmol) in dichloromethane (300 mL) was added l, l'-carbonyldiimidazole (6. 34 g, 38. 9 mmol) and stirred for 1 h. To this solution was then added benzyl alcohol (12. 0 mL, 116 mmol) and the mixture was further stirred for 2 h. The reaction mixture was washed with water and brine, organic layer was dried, filtered and concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 16. 2 g (87%) of 20C.

20D : Benzyl (1S, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-tert-butoxy- carbonylamino-2- (3'-methylbutanoyloxy) cyclopentan-l-carboxylate To a solution of benzyl IS, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-tert- butoxycarbonylamino-2-hydroxycyclopentan-l-carboxylate (20C, 0. 71 g, 1. 5 mmol) in pyridine (20 mL) were added isovaleryl chloride (0. 73 mL, 6. 0 mmol) and 4- (dimethylamino) pyridine (18 mg, 0. 15 mmol) and stirred for 1 h. The reaction mixture was extracted with ethyl acetate (2 X) after dilution with water. The combined organic extracts were washed with water (1 X), 0. 2 N HC1 (2 X), water (1 X) and brine (1 X) and dried. After filtration, the filtrate was concentrated and the residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 7 g (83 %) of 20D.

20E : Benzyl (IS, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-(N-benzyloxy- carbonylamino-N'-benzyloxycarbonylimino)-2- (3'-methylbutanoyloxy) cyclopentan-1- carboxylate To a solution of benzyl (lys, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-tert- butoxycarbonylamino-2- (3'-methylbutanoyloxy) cyclopentan-l-carboxylate (20D, 0. 7 g, 1. 25 mmol) in dichloromethane ( (50 mL) was added trifluoroacetic acid (3. 5 mL) and stirred for 2 h. The solvent was evaporated, the residue was co-evaporated with ether (2 X) and washed with ether-hexane and dried. The residue was then dissolved in dimethyl formamide (5 mL) and to this solution were added triethylamine (0. 87 mL, 6. 25 mmol), 1, 3- bis (benzyloxycarbonyl)-2-methyl-2-thiopseudourea (20A, 0. 45 g, 1. 25 mmol) and mercury (II) chloride (0. 34 g, 1. 25 mmol) and the mixture was stirred for 2 h. After dilution with ethyl acetate (25 mL), the mixture was filtered and the filtrate was washed with water and brine.

The organic layer was dried, filtered and the filtrate concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 5 g (52So) of 20E.

20 : To a solution of benzyl (1S, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-(N- benzyloxycarbonylamino-N'-benzyloxycarbonylimino)-2- (3'-methylbutanoyloxy) cyclo- pentan- 1-carboxylate (20E, 0. 35 g, 0. 45 mmol) in ethanol (30 mL) and water (7 mL) were added 4 drops of HC1 and 10% Pd/C (70 mg) and the mixture was hydrogenated at 40 psi for 1 h. The mixture was filtered through a pad of Celite and silica gel and the filtrate was concentrated and dried to give 0. 12 g (52%) of 20.

Anal. calcd. for C20H36N4O5#2HCl#1.5H2O : %C 46. 87 %H 8. 06 % N 10. 93 Found : % C 47. 06 % H7. 80 % N 10. 93 MS (ES+) : 413. 3 (M+1)

Example 21 (lS, 2S, 3R, 4R, 1'- (-)-3- (1'-acetylamino-2'-etliyl) butyl-4- (amino-imino) methylamino-2-n- hexanoyloxycyclopentan-1-carboxylic acid 21A : Benzyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-tert-butoxy- carbonylamino-2-n-hexanoyloxycyclopentan-1-carboxylate To a solution of benzyl 1S, 2S, 3R, 4R, 1'S)- (-)-3- (1'-acetylamino-2'-ethyl) butyl-4-tert- butoxycarbonylamino-2-hydroxycyclopentan-l-carboxylate (20C, 0. 71 g, 1. 5 mmol) in pyridine (20 mL) were added n-hexanoyl chloride (0. 85 mL, 6. 0 mmol) and 4- (dimethylamino) pyridine (18 mg, 0. 15 mmol) and stirred for 2 h. The reaction mixture was extracted with ethyl acetate (2 X) after dilution with water. The combined organic extracts were washed with water (1 X), 0. 2 N HC1 (2 X), water (1 X) and brine (1 X) and dried. After filtration, the filtrate was concentrated and the residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 78 g (90%) of 21A.

21B : Benzyl (l S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-(N-benzyloxy- carbonylamino-N'-benzyloxycarbonylimino)-2-n-hexanoyloxycycl opentan-1-carboxylate To a solution of benzyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-tert- butoxycarbonylamino-2- (3'-methylbutanoyloxy) cyclopentan-l-carboxylate (21A, 0. 78 g, 1. 35 mmol) in dichloromethane ( (50 mL) was added trifluoroacetic acid (3. 5 mL) and stirred for 2 h. The solvent was evaporated, the residue was co-evaporated with ether (2 X) and washed with ether-hexane and dried. The residue was then dissolved in dimethyl formamide (8 mL) and to this solution were added triethylamine (1. 4 mL, 10. 0 mmol), 1, 3-bis (benzyloxycarbonyl)-2-methyl-2-thiopseudourea (20A, 0. 48 g, 1. 35 mmol) and mercury (II) chloride (0. 36 g, 1. 35 mmol) and the mixture was stirred for 2 h. After dilution with ethyl acetate (25 mL), the mixture was filtered and the filtrate was washed with water and brine.

The organic layer was dried, filtered and the filtrate concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 53 g (50%) of 21B.

21 : To a solution of benzyl (lS, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-(N- benzyloxycarbonylamino-N'-benzyloxycarbonylimino)-2-n-hexano yloxycyclopentan-1-

carboxylate (21B, 0. 32 g, 0. 40 mmol) in ethanol (30 mL) and water (7 mL) were added 4 drops of HCl and 10% Pd/C (70 mg) and the mixture was hydrogenated at 40 psi for 1 h. The mixture was filtered through a pad of Celite and silica gel and the filtrate was concentrated and dried to give 0. 14 g (66%) of 21.

Anal. calcd. for C21H38N4O5#2HCl#H2O : % C 48. 74 % H 8. 18 % N 10. 83 Found : %C 48. 72 %H 8. 22 %N 10. 58 MS (ES+) : 427. 3 (M+1) Example 22 (1S,2S,3R,4R,1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[( N-benzyloxycarbonyl- amino- imino) methyl] amino-2-hydroxycyclopentan-1-carboxylic acid A mixture of ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N- benzyloxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate (example 2, 0. 32 g, 0. 65 mmol) in methanol (3 mL) and 1N sodium hydroxide (1. 5 mL) was stirred at room temperature for 2 h. The reaction mixture was neutralized with 1N HC1. The precipitate was collected by filtration, washed with water and dried to give 0. 18 g (60%) of 22.

Anal. calcd. ofr C23h34N4O6 : % C 59. 72 % H 7. 41 % N 12. 11 Found : % C 59. 55 %H 7. 22 % N 11. 94 MS (ES+) : 463. 5 (M+1) Example 23 (1S,2S,3R,4R,1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[( N-methoxycarbonyl- amino- imino) methyl] amino-2-hydroxycyclopentan-1-carboxylic acid

A mixture of ethyl (1S, 2S,3R,4R,1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-et hoxy- carbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate (example 3, 0. 6 g, 1. 45 mmol) in methanol (3 mL) and 1N sodium hydroxide (1. 5 mL) was stirred at room temperature for 2 h. The reaction mixture was neutralized with 1N HC1, concentrated and the residue was suspended in water. The precipitate was collected by filtration, washed with water and dried to give 0. 17 g (30 %) of 23.

Anal. calcd. for CmH3oN406. 0. 25H20 : % C 52. 23 %H 7. 73 % N 14. 33 Found : % C51. 98 %H 7. 66 % N 14. 22 MS (ES+) : 387. 3 (M+ 1) Example 24 (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-tert-butoxycarbonyl-amino- imino) methyl] amino-2-hydroxycyclopentan-1-carboxylic acid A mixture of ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-tert- butoxyoxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-l-carboxylate (example 4, 0. 56 g, 1. 23 mmol) in methanol (3 mL) and IN sodium hydroxide (2. 5 mL) was stirred at room temperature for 3 h. The reaction mixture was neutralized with IN HCl, concentrated and the residue was suspended in water. The precipitate was collected by filtration, washed with water and dried to give 0. 25 g (47%) of 24.

Anal. calcd. for C20H36N4O6#0.5H2O : % C 54. 90 % H 8. 29 % N 12. 81 Found : %C 54. 49 %H 8. 44 % N 12. 75 MS (ES+) : 430. 1 (M+1)

Example 25 (lS, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-ethoxycarbonylamino-imino) methyl]amiono-2-hydroxycyclopentan-1-carhoxylic acid 25A : Benzyl (lS, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4- (N-benzyloxy- carbonylamino-N'-ethoxycarbonylimino)-2-hydroxycyclopentan-1 -carboxylate To a solution of benzyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-tert- butoxycarbonylamino-2-hydroxycyclopentan-l-carboxylate (example 20C, 1. 0 g, 2. 10 mmol) in dichloromethane ((25 mL) was added trifluoroacetic acid (6. 0 mL) and stirred for 2 h. The solvent was evaporated, the residue was washed with ether-hexane and dried. The residue was then dissolved in dimethyl formamide (10 mL) and to this solution were added triethylamine (1. 46 mL, 10. 5 mmol), 1-benzyloxycarbonyl-3-ethoxycarbonyl-2-methyl-2- thiopseudourea (1B, 0. 93 g, 3. 15 mmol) and mercury (II) chloride (0. 85 g, 3. 15 mmol) and the mixture was stirred for 16 h. After dilution with ethyl acetate (50 mL), the mixture was filtered and the filtrate was washed with water and brine. The organic layer was dried, filtered and the filtrate was concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 1. 0 g (76%) of 25A.

25 : To a solution of benzyl (1S, 2S, 3R, 4R, l'S)- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4- (N- benzyloxycarbonylamino-N'-ethoxycarbonylimino)-2-hydroxycycl opentan-1-carboxylate (25A, 0. 51 g, 0. 82 mmol) in ethanol (18 mL) and water (2 mL) were added 4 drops of HCl and 10% Pd/C (100 mg) and the mixture was hydrogenated at 40 psi for 16 h. The mixture was filtered through a pad of Celite and silica gel and the filtrate was concentrated and the residue was purified on silica gel column using chloroform (7) : methanol (3) : ammonium hydroxide (0. 2) mixture as an eluent to give 0. 27 g (82%) of 25.

Anal. calcd. for ClsH32N406-0. 5H2O : % C 52. 80 %H 8. 12 % N 13. 68 Found : %C 52. 91 % H 7. 91 % N 13. 61 MS (ES+) : 401. 2 (M+1) Example 26 (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-acetyloxymetlloxy- carbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylic acid

26A : Benzyl (IS, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-amino-2-hydro- xycyclopentan-1-carboxylate To a mixture of benzyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (1'-acetylamino-2'-ethyl) butyl-4-tert- butoxycarbonylamino-2-hydroxycyclopentan-1-carboxylate (10. 3 g, 21. 6 mmol) in THF (100 mL) and ether (300 mL) was added 7. 5N HCl in ether (40 mL, 300 mmol)) and the mixture was stirred at room temperature for 16 h. The solvent was removed, the residue was suspended in ether-hexane mixture and the precipitate was collected by filtration, washed with ether-hexane and dried to give 8. 6 g (96%) of 26A as hydrochloride.

26B : Benzyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-benzyl- <BR> <BR> oxycarbonylamino-N'-teXt-butoxycarbonylimino) methyl] amino-2-hydroxycyclo-pentan-1- carboxylate To a solution of benzyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4-amino-2- hydroxycyclopentan-1-carboxylate hydrochloride (26A, 6. 1 g, 14. 8 mmole) in dimethyl formamide (60 mL) were added triethylamine (7. 4 mL, 53. 2 mmol), 1-benzyloxy-carbonyl-3- tert-butoxycarbonyl-2-methyl-2-thiopseudourea (2A, 5. 1 g, 15. 8 mmol) and mercury (II) chloride (4. 3 g, 15. 8 mmol) and the mixture was stirred for 2 h. After dilution with ethyl acetate (250 mL), the mixture was filtered and the filtrate was washed with water and brine.

The organic layer was dried, filtered and the filtrate concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 6. 4 g (66%) of 26B.

26C : Benzyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-benzyl- oxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate To a solution of benzyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-tert- butoxycarbonylamino-N'-benzyloxycarbonylimino) methyl] amino-2-hydroxy- cyclopentan-1- carboxylate (26B, 6. 4 g, 9. 8 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (18. 0 mL) and was stirred for 4 h. After concentration, the residue was taken in ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated, dried, filtered and concentrated. The residue was purified on silica gel column using chloroform : methanol as an eluent to give 4. 8 g (89%) of 26C.

26D : Benzyl (IS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-benzyloxy

carbonylamino-N'-acetyloxymethoxycarbonylimino) methyl] amino-2-hydroxycyclo- pentan- 1-carboxylate To a solution of benzyl (lys, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N- benzyloxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-l-carboxylate (26C, 0. 55 g, 1. 0 mmol) in hexamethylphosphoramide (5. 0 mL) was added acetyloxymethyl 4-nitrophenyl carbonate (0. 76 g, 3. 0 mmol, prepared by using the method disclosed in Alexander et al. J. Med. Chem. 1988, 31, 318-322) and heated at 45 °C for 16 h. An additional amount of acetyloxymethyl 4-nitrophenyl carbonate (0. 25 g, 1 mmol) was added to the reaction mixture and again heated at 45 °C for 8 h. The mixture was cooled and diluted with water. After saturating with salt, the mixture was extracted with ethyl acetate (3 X). The combined organic extracts were washed with water and brine and dried. After filtration, the filtrate was concentrated and the residue was purified on silica gel column using ethyl acetate : hexane as an eluent to give 0. 37 g (55 %) of 26D.

26 : To a solution of benzyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N- benzyloxycarbonylamino-N'-acetyloxymethoxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate (26D, 0. 32 g, 0. 48 mmol) in ethanol (40 mL) and water (13 mL) was added 10% Pd/C (70 mg) and the mixture was hydrogenated at 40 psi for 2 h. After removing the catalyst by filtration, the filtrate was concentrated and the residue was purified on silica gel column using chloroform : methanol as an eluent to give 0. 15 g (70%) of 26.

Anal. calcd. for C19H32N4O8: %C 51. 34 % H 7. 26 % N 12. 60 Found : % C 51. 50 % H 7. 14 % N 12. 15 MS (ES+) : 445. 5 (M+ 1) Example 27 (lS, 2S, 3R, 4R, 1'S)- (-)-3- (1'-acetylamino-2'-ethyl) butyl-4- [ (a-acetyloxyethoxy- carbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylic acid I HN OH OH OH CHO 27A : Benzyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-benzyloxy- carbonylamino)-N'- (1-acetyloxyethoxycarbonylimino) methyl] amino-2-hydroxy- cyclopentan-1-carboxylate To a solution of benzyl (1S, 2S, 3R, 4R, l'S) (-)-3- (l'-acetylamino-2'-ethyl) butyl-4- [ (N- benzyloxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate (example 26C, 0. 55 g, 1. 0 mmol) in hexamethylphosphoramide (5. 0 mL) was added a-acetyloxyethyl 4- nitrophenyl carbonate (0. 8 g, 3. 0 mmol, prepared by using the literature ref. : Alexander et al.

J. Med. Chem. 1988, 31, 318-322) and heated at 45 °C for 16 h. Additional amount of a- acetyloxymethyl 4-nitrophenyl carbonate (0. 27 g, 1 mmol) was added to the reaction mixture and again heated at 45 °C for 8 h. The mixture was cooled and diluted with water. After saturating with salt, the mixture was extracted with ethyl acetate (3 X). The combined organic extracts were washed with water and brine and dried. After filtration, the filtrate was concentrated and the residue was purified on silica gel column using ethyl acetate : hexane as an eluent to give 0. 4 g (58 %) of 27A.

27 : To a solution of benzyl (lys, 2S, 3R, 4R,1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N- benzyloxycarbonylamino)-N'- (a-acetyloxymethoxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate (27A, 0. 35 g, 0. 51 mmol) in ethanol (20 mL) and water (5 mL) was added 10% Pd/C (70 mg) and the mixture was hydrogenated at 40 psi for 2 h. After removing the catalyst by filtration, the filtrate was concentrated and the residue was purified on silica gel column using chloroform : methanol as an eluent to give 0. 14 g (60%) of 27.

Anal. calcd. for C20H34N4Os. 0. 5H2O : % C 51. 38 % H 7. 55 % N 11. 98 Found : % C 51. 74 % H 7. 42 % N 11. 70 MS (ES+) : 459. 2 (M+1) Example 28 (lS, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-trimethylacetyloxy- methoxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylic acid HN COON N OH NHAc 28A : Benzyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-benzyloxy- carbonylamino)-N'-(l-trimethylacetyloxymethoxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate To a solution of benzyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N- benzyloxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate (example 26C, 0. 83 g, 1. 5 mmol) in hexamethylphosphoramide (10. 0 mL) was added trimethylacetyloxymethyl 4-nitrophenyl carbonate (example 10A, 0. 9 g, 3. 0 mmol) and heated at 45 °C for 16 h. Additional amount of trimethylacetyloxymethyl 4-nitrophenyl carbonate (0. 3 g, 1 mmol) was added to the reaction mixture and again heated at 45 °C for 8 h. The mixture was cooled and diluted with water. After saturating with salt, the mixture was extracted with ethyl acetate (3 X). The combined organic extracts were washed with water and brine and dried. After filtration, the filtrate was concentrated and the residue was purified on silica gel column using ethyl acetate : hexane as an eluent to give 0. 22 g (20 %) of 28A.

28 : To a solution of benzyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N- benzyloxycarbonylamino)-N'- (l-trimethylacetyloxymethoxycarbonylimino) methyl]- amino-2- hydroxycyclopentan-1-carboxylate (28A, 0. 21 g, 0. 31 mmol) in ethanol (20 mL) and water (5 mL) was added 10% Pd/C (40 mg) and the mixture was hydrogenated at 40 psi for 2 h. After removing the catalyst by filtration, the filtrate was concentrated and the residue was purified on silica gel column using chloroform : methanol as an eluent to give 0. 1 g (66 %) of 28.

Anal. calcd. for C22H3sN4Os. H2O : % C 52. 37 % H 7. 99 % N 11. 10 Found : % C 52. 27 % H7. 92 % N 10. 72 MS (ES+) : 487. 5 (M+1) Example 29 (1S, 2S, 3R, 4R, I'S)- (-)-3- (l'-Acetylamino-2'-ethyl) butyl-4-[(N-(α-trimethylacetyloxy- ethoxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-l-carboxylic acid 0 CH3 0 HN N O O # HN COOH wOH NHAc 29A : Benzyl (l S, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-benzyloxy- carbonylamino)-N'- (oc-trimethylacetyloxyethoxycarbonylimino) methyl] amino-2- hydroxycyclopentan-l-carboxylate To a solution of benzyl (1S, 2S, 3R, 4R, l- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4- [ (N- benzyloxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-l-carboxylate (example 26C, 0. 55 g, 1. 0 mmol) in hexamethylphosphoramide (6. 0 mL) was added a- trimethylacetyloxyethyl 4-nitrophenyl carbonate (0. 8 g, 3. 0 mmol, prepared by using the method disclosed in Alexander et al. J. Med. Chem. 1988, 31, 318-322) and heated at 45 °C for 16 h. An additional amount of a-trimethylacetyloxymethyl 4-nitrophenyl carbonate (0. 27 g, 1 mmol) was added to the reaction mixture and again heated at 45 °C for 8 h. The mixture was cooled and diluted with water. After saturating with salt, the mixture was extracted with ethyl acetate (3 X). The combined organic extracts were washed with water and brine and dried. After filtration, the filtrate was concentrated and the residue was purified on silica gel column using ethyl acetate : hexane as an eluent to give 0. 15 g (20%) of 29A. 29 : To a solution of benzyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N- benzyloxycarbonylamino)-N'- (a-trimethylacetyloxyethoxycarbonylimino) methyl]- amino-2- hydroxycyclopentan-1-carboxylate (29A, 0. 15 g, 0. 21 mmol) in ethanol (12 mL) and water (3 mL) was added 10% Pd/C (40 mg) and the mixture was hydrogenated at 40 psi for 2 h. After

removing the catalyst by filtration, the filtrate was concentrated and the residue was purified on silica gel column using chloroform : methanol as an eluent to give 0. 055 g (52%) of 29.

Anal. calcd. for C23H40N4Os0. 5H2O : % C 54. 21 % H 8. 11 %N 10. 99 Found : % C 54. 55 %H8. 01 % N 11. 02 MS (ES+) : 501. 5 (M+1) Example 30 (1S, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-phenylacetyloxymeth- oxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylic acid 30A : Benzyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-benzyloxy- carbonylamino)-N'- (phenylacetyloxymethoxycarbonylimino) methyl] amino-2-hydro- xycyclopentan-1-carboxylate To a solution of benzyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N- benzyloxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate (example 26C, 0. 83 g, 1. 5 mmol) in hexamethylphosphoramide (10. 0 mL) was added phenylacetyloxymethyl 4-nitrophenyl carbonate (example 12A, 0. 99 g, 3. 0 mmol) and heated at 45 °C for 16 h. An additional amount of phenylacetyloxymethyl 4-nitrophenyl carbonate (0. 33 g, 1 mmol) was added to the reaction mixture and again heated at 45 °C for 8 h. The mixture was cooled and diluted with water. After saturating with salt, the mixture was extracted with ethyl acetate (3 X). The combined organic extracts were washed with water and brine and dried. After filtration, the filtrate was concentrated and the residue was purified on silica gel column using ethyl acetate : hexane as an eluent to give 0. 0. 35 g (31 %) of 30A.

30 : To a solution of benzyl (1S, 2S, 3R, 4R, l- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4- [ (N- benzyloxycarbonylamino)-N'- (phenylacetyloxymethoxycarbonylimino) methyl]- amino-2- hydroxycyclopentan-1-carboxylate (30A, 0. 34 g, 0. 45 mmol) in ethanol (28 mL) and water (7 mL) was added 10% Pd/C (70 mg) and the mixture was hydrogenated at 40 psi for 2 h. After removing the catalyst by filtration, the filtrate was concentrated and the residue was purified on silica gel column using chloroform : methanol as an eluent to give 0. 11 g (47 %) of 30.

Anal. calcd. for C2sH36N4Os0. 5H2O : % C 56. 72 % H 7. 04 % N 10. 58 Found : % C 56. 76 %H 7. 03 % N 10. 39 MS (ES+) : 521. 5 (M+1)

Example 31 <BR> <BR> (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(2'-L-amino-3'-phenyl- propanoylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylic acid 31A : Benzyl (lS, 2S, 3R, 4R, 1'5y)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[N-(2'-L- <BR> <BR> benzyloxycarbonylamino-3'-phenylpropanoylamino)-N'- (benzyloxycarbonylimino)-<BR> <BR> <BR> <BR> <BR> <BR> methyl] amino-2-hydroxycyclopentan-1-carboxylate To a solution of N-benzyloxycarbonyl L-phenylalanine (0. 26 g, 0. 87 mmol) in ethyl acetate (20 mL) was added 1, 1'-carbonyldiimidazole (0. 14 g, 0. 87 mmol) and the mixture was stirred for 0. 25 h. To this solution was added N-hydroxysuccinimide (0. 1 g, 0. 87 mmol) and stirred for 2 h. The reaction mixture was washed with water and the organic layer separated, dried, filtered and concentrated to give 0. 34 g of N-benzyloxycarbonyl L-phenylalanine succinimido ester.

To a mixture of benzyl (lys, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[N- (benzyloxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate (example 26C, 0. 37 g, 0. 67 mmol) in dichloromethane (20 mL) and saturated aqueous sodium bicarbonate (20 mL) was added above prepared N-benzyloxycarbonyl L-phenylalanine succinimido ester (0. 34 g, 0. 87 mmol) and the mixture was stirred for 16 h at room temperature. The organic layer was separated, aqueous layer was further extracted with dichloromethane (20 mL) and the combined organic layers were dried. After filtration, the filtrate was concentrated and the residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 29 g (62%) of 31A.

31 : To a solution of benzyl (1S, 2S, 3R, 4R, I'S)- (-)-3- (l.'-acetylamino-2'-ethyl) butyl-4- [N- (2'-L- benzyloxycarbonylamino-3'-phenylpropanoylamino)-N'- (benzyloxycarbonyl- imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate (31A, 0. 29 g, 0. 41 mmol) in ethanol (22 mL) and water (6 mL) was added 10% Pd/C (50 mg) and cone. HCl (3 drops) and the mixture was hydrogenated at 40 psi for 1 h.. The mixture was passed through a pad of Celite and silica gel, and the filtrate was concentrated and dried to give 0. 19 g (66 %) of 31.

Anal. calcd. for C24H37NsOs2HCl3H2O*C2HsOH : % C 48. 15 % H 7. 77 % N 10. 80

Found : %C 48. 27 %H 7. 30'%N 10. 86 MS (ES+) : 476. 5 (M+1) Example 32 <BR> <BR> (1S, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(2'-L-aminopropanoyl-amino- iminomethyl] amino-2-hydroxycyclopentan-1-carboxylic acid 32A : Benzyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-(2'-L- benzyloxycarbonylaminopropanoylamino)-N'-(benzyloxycarbonyli mino) methyl]-amino-2-<BR> hydroxycyclopentan-1-carboxylate To a solution of N-benzyloxycarbonyl L-alanine (0. 22 g, 1. 0 mmol) in ethyl acetate (20 mL) was added 1, l'-carbonyldiimidazole (0. 16 g, 1. 0 mmol) and the mixture was stirred for 0. 25 h. To this solution was added N-hydroxysuccinimide (0. 11 g, 1. 0 mmol) and stirred for 2 h.

The reaction mixture was washed with water and the organic layer separated, dried, filtered and concentrated to give 0. 32 g of N-benzyloxycarbonyl L-alanine succinimido ester.

To a mixture of benzyl (1S, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[N- (benzyloxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate (example 26C, 0. 44 g, 0. 8 mmol) in dichloromethane (20 mL) and saturated aqueous sodium bicarbonate (20 mL) was added above prepared N-benzyloxycarbonyl L-alanine succinimido ester (0. 32 g, 1. 0 mmol) and the mixture was stirred for 16 h at room temperature. The organic layer was separated, aqueous layer was further extracted with dichloromethane (20 mL) and the combined organic layers were dried. After filtration, the filtrate was concentrated and the residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 0. 3 g (60%) of 32A. 32 : To a solution of benzyl (1S, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[N-(2'-L- benzyloxycarbonylaminopropanoylamino)-N'- (benzyloxycarbonylimino) methyl]- amino-2- hydroxy-cyclopentan-l-carboxylate (32A, 0. 3 g, 0. 48 mmol) in ethanol (24 mL) and water (6 mL) was added 10% Pd/C (50 mg) and conc. HCl (3 drops) and the mixture was hydrogenated at 40 psi for 1 h. The mixture was passed through a pad of Celite and silica gel, and the filtrate was concentrated and dried to give 0. 22 g (86%) of 32.

Anal. calcd. for C18H33N5O5#2HCl#2H2O#0.5C2H5OH : % C 42. 93 % H 7. 96 % N 13. 18 Found : % C 42. 45 % H 7. 53 % N 13. 02 M S (ES+) : 400. 4 (M + 1) Example 33 <BR> <BR> (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(2'-L-amino-3'-methylpen- tanoylamino-iminomethyl] amino-2-hydroxycyclopentan-1-carboxylic acid 33A : Benzyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[N-(2'-L- benzyloxycarbonylamino-3'-methylpentanoylamino)-N'- (benzyloxycarbonylimino)- methyl] amino-2-hydroxy- cyclopentan-1-carboxylate To a solution of N-benzyloxycarbonyl L-isoleucine (0. 22 g, 0. 82mmol) in ethyl acetate (20 mL) was added 1, l'-carbonyldiimidazole (0. 13 g, 0. 82 mmol) and the mixture was stirred for 0. 25 h. To this solution was added N-hydroxysuccinimide (0. 09 g, 0. 82 mmol) and stirred for 2 h. The reaction mixture was washed with water and the organic layer separated, dried, filtered and concentrated to give 0. 3 g of N-benzyloxycarbonyl L-isoleucine succinimido ester.

To a mixture of benzyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N- (benzyloxycarbonylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate (example 26C, 0. 3 g, 0. 54 mmol) in dichloromethane (20 mL) and saturated aqueous sodium bicarbonate (20 mL) was added above prepared N-benzyloxycarbonyl L-isoleucine succinimido ester (0. 3 g, 0. 82 mmol) and the mixture was stirred for 16 h at room temperature. The organic layer was separated, aqueous layer was further extracted with dichloromethane (20 mL) and the combined organic layers were dried. After filtration, the filtrate was concentrated and the residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 4 g (93 %) of 33A.

33 : To a solution of benzyl (1S, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[N-(2'-L- benzyloxycarbonylamino-3'-methylpentanoylamino)-N'- (benzyloxycarbonyl- imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate (33A, 0. 4 g, 0. 5 mmol) in ethanol (24 mL) and water (6 mL) was added 10% Pd/C (100 mg) and conc. HCl (3 drops) and the mixture was hydrogenated at 40 psi for 1 h. The mixture was passed through a pad of Celite

and silica gel, and the filtrate was concentrated and dried to give 0. 12 g (36 %) of 33.

Anal. calcd. for C21H39N5O5#4HCl#4H2O : % C 38. 25 % H 7. 79 % N 10. 62 Found : % C38. 53 % H7. 63 % N 10. 23 MS (ES+) : 442. 5 (M+1) Example 34 Ethyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-acetyloxymeth- oxycarbonylamino-N'-acetyloxymethoxycarbonylimino) methyl] amino-2-hydroxy- cyclopentan-1-carboxylate 34A : 1, 3-Bis (acetyloxymethoxycarbonyl)-2-methyl-2-thiopseudourea A mixture of acetyloxymethyl chloroformate (1. 71 g, 11. 2 mmol, prepared from a literature procedure : Folkmann et al. Synthesis, 1990, 1159-1166) and 2-methyl-2-thiopseudourea sulfate (1. 6 g, 5. 6 mmol) in dichloromethane (10 mL) and aqueous saturated sodium bicarbonate (10 mL) was stirred at room temperature for 16 h. The organic layer was separated, washed with water, and dried. After filtration, the filtrate was concentrated and the residue was purified by silica gel column using Hexane : ethyl acetate as an eluent to give 0. 66 g (36%) of 34A.

34 : To a solution of ethyl (1S, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-amino-2- hydroxycyclopentan-1-carboxylate trifluoroacetate (0. 3 g, 0. 71 mmole, disclosed in WO 99/33781) in dimethyl formamide (10 mL) were added triethylamine (0. 32 mL, 2. 3 mmol), 1, 3-bis (acetyloxymethoxycarbonyl)-2-methyl-2-thiopseudourea (34A, 0. 23 g, 0. 71 mmol) and mercury (II) chloride (0. 19 g, 0. 71 mmol) and the mixture was stirred for 2 h. After dilution with ethyl acetate (50 mL), the mixture was filtered and the filtrate was washed with water and brine. The organic layer was dried, filtered and the filtrate concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 2 g (48 %) of 34.

Anal. calcd. for C25H40N4O12 : %C 51.01, %H 6.84 %N 9. 51 Found : % C 51. 34 % H 7. 20 % N 9. 12 MS (ES+) : 589. 6 (M+1)

Example 35 (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N-acetyloxyme thoxy- carbonylamino-N'-acetyloxymethoxycarbonylimino) methyl] amino-2-hydroxy- cyclopentan- 1-carboxylic acid 35A : Benzyl (l S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-acetyloxy- methoxycarbonylamino-N'-acetyloxymethoxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate To a solution of benzyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-amino-2- hydroxycyclopentan-1-carboxylate hydrochloride (26A, 0. 41 g, 1. 1 mmol) in dimethyl formamide (10 mL) were added triethylamine (0. 45 mL, 3. 3 mmol), 1, 1'- bis (acetyloxymethoxycarbonyl)-2-methyl-2-thiopseudourea (34A, 0. 35 g, 1. 1 mmol) and mercury (II) chloride (0. 3 g, 1. 1 mmol) and the mixture was stirred for 2 h. After dilution with ethyl acetate (50 mL), the mixture was filtered and the filtrate was washed with water and brine. The organic layer was dried, filtered and the filtrate concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 15 g (21 %) of 35A.

35 : To a solution of benzyl (1S, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N- acetyloxymethoxycarbonylamino-N'-acetyloxymethoxycarbonylimi no) methyl]- ainino-2- hydroxycyclopentan-1-carboxylate (35A, 0. 15 g, 0. 23 mmol) in ethanol (16 mL) and water (4 mL) was added 10 % Pd/C (50 mg) and the mixture was hydrogenated at 40 psi for 1 h. The mixture was passed through a pad of Celite and silica gel, and the filtrate was concentrated and dried to give 0. 056g (42%) of 35.

Anal. calcd. for C23H36N4012. H20 : % C 47. 74 % H 6. 62 % N 9. 68 Found : %C 48. 17 % H 6. 63 % N 9. 50 MS (ES+) : 561. 5 (M+ 1)

Example 36 Ethyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(N-2, 2, 2-trifluoro- ethoxycarbonylamino-N'-2, 2, 2-trifluoroethoxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate 36A : 1, 3-Bis (2, 2, 2-trifluoroethoxycarbonyl)-2-methyl-2-thiopseudourea To a solution of 2, 2, 2-trifluoroethanol (3. 22 g, 32. 2 mmol) in dichloromethane (25 mL) was added ethyl chlorothioformate (5. 0 g, 40 mmol) over a period of 2 min., followed by dropwise addition of FeCl3 in nitromethane (0. 35 g FeCl3 in 0. 7 mL nitromethane) over a period of 5 min. The reaction mixture was further stirred for 0. 5 h, and diluted with dichloromethane (100 mL). The mixture was washed with 1N HCl (100 mL) and water (4 X 100 mL), and organic layer separated and dried. After filtration, the filtrate was concentrated to give 6. 7 g of the residue of 2, 2, 2-trifluoroethyl ethylthioformate. To this residue were added 1, 2- dichloroethane (50 mL) and sulfuryl chloride (15. 0 mL) and the solution was heated at gentle reflux for 7 h and then stirred at room temperature for 16 h.

One fourth part of this reaction mixture was added portion wise, over a period of 1 h, to a stirred mixture of 2-methyl-2-thiopseudourea sulfate (2. 0 g, 7. 2 mmol) in dichloromethane (100 mL) and aqueous sodium bicarbonate (100 mL), while maintaining the pH of the mixture basic by adding 40 % sodium hydroxide. The reaction mixture was further stirred for 1 h and the organic layer was separated. After drying, it was filtered and the filtrate was concentrated and the residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 4 g (16%) of 36A.

36 : To a solution of ethyl (1S, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-amino-2- hydroxycyclopentan-1-carboxylate trifluoroacetate (0. 43 g, 1. 0 mmol, given in WO 99/33781) in dimethyl formamide (10 mL) were added triethylamine (0. 49 mL, 3. 5 mmol), 1, 3-bis (2, 2, 2- trifluoroethoxycarbonyl)-2-methyl-2-thiopseudourea (36A, 0. 34 g, 1. 0 mmol) and mercury (II) chloride (0. 27 g, 1. 0 mmol) and the mixture was stirred for 2 h. After dilution with ethyl acetate (50 mL), the mixture was filtered and the filtrate was washed with water and brine.

The organic layer was dried, filtered and the filtrate concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 1 g (16%) of 36.

Anal. calcd. for C23H34N4O8F6 : % C 45. 40 % H 5. 63 % N 9. 21 Found : % C 44. 90 %H 5. 56 %N 8. 91 MS (ES+) : 609. 3 (M+1) Example 37 Ethyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4- [ (N-ethoxycarbonyl- amino- N'-ethoxycarbonylimino) methyl] amino-2-hydroxycyclopentan-1-carboxylate EtO2CNnNHCO2Et NH CO2CH3 #OH ) NHAc 37A : 1, 3-Bis (ethoxycarbonyl)-2-methyl-2-thiopseudourea 2-Methyl-2-thiopseudourea sulfate (15. 0 g, 53. 9 mmol) was suspended in 20 mL of water and cooled to 5°C. Ethyl chloroformate (29. 2 g, 269 mmol) was added and the mixture was stirred for 5 min. Sodium hydroxide (25 %, w/w) was added dropwise until pH reached 8. The white solid was collected by filtration and dried to give 22. 8 g (88%) of 37A.

37 : To a solution of methyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4-amino-2- hydroxycyclopentan-1-carboxylate trifluoroacetate (0. 62 g, 1. 5 mmol, given in WO 99/33781) in dimethyl formamide (15 mL) were added triethylamine (0. 62 mL, 4. 5 mmol), 1, 3-bis- (ethoxycarbonyl)-2-methyl-2-thiopseudourea (37A, 0. 35 g, 1. 5 mmol) and mercury (II) chloride (0. 41 g, 1. 5 mmol) and the mixture was stirred for 2 h. After dilution with ethyl acetate (100 mL), the mixture was filtered and the filtrate was washed with water and brine. The organic layer was dried, filtered and the filtrate concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 3 g (41 %) of 37.

Anal. calcd. for C22H38N4O8 : % C 54. 31 % H 7. 87 % N 11. 51 Found : % C 54. 51 %H 7. 96 % N 11. 40 MS (ES+) : 487. 6 (MA1) Example 38 Ethyl (l S, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(hydroxylamino- imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate

HN-OH HN=t NH,,"%COOCH, /\ COH NHAc 38A : Ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl) butyl-4-amino-2- hydroxycyclopentan-1-carboxylate To a mixture of ethyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (1'-acetylamino-2'-ethyl) butyl-4-tert- butoxycarbonylamino-2-hydroxycyclopentan-1-carboxylate (20. 0 g, 48. 2 mmol) in THF (200 mL) and ether (600 mL) was added 7. 5N HCl in ether (80 mL, 600 mmol)) and the mixture was stirred at room temperature for 16 h. The solvent was removed, the residue was suspended in ether-hexane mixture and the precipitate was collected by filtration, washed with ether-hexane and dried to give 16 g (94%) of 38A as hydrochloride.

38B : Ethyl (lS, 2S, 3R, 4R, 1'S)- (-)-3- (1'-acetylamino-2'-ethyl) butyl-4-cyanamino-2- hydroxycyclopentan-l-carboxylate To a solution of ethyl (1S, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-amino-2- hydroxycyclopentan-l-carboxylate hydrochloride (38A, 0. 7 g, 2. 0 mmole) in dimethyl acetamide (5 mL) were added triethylamine (0. 35 mL, 2. 5 mmol) followed by 1- cyanoimidazole (0. 32 g, 3. 4 mmol) after 15 min. stirring at room temperature. The reaction mixture was further stirred for 6 h at 100 °C. After cooling, the reaction mixture was diluted with water and extracted (3 X) with ethyl acetate. The combined organic layers were dried, filtered and the filtrate concentrated to give 0. 6 g of crude 38B.

38 : A mixture of hydroxylamine hydrochloride (1. 4 g, 20 mmol) and sodium carbonate (1. 06 g, 10 mmol) in methanol (15 mL) was stirred at room temperature for 0. 5 h. The solid was removed by filtration and the filtrate was added to the previously obtained crude 38B and was stirred at room temperature for 24 h. The reaction mixture was concentrated and the residue was suspended in a mixture of chloroform : methanol (1 : 1). The solid was removed by filtration, the filtrate concentrated and the residue was purified by silica gel column using chloroform (80) : methanol (18) : ammonium hydroxide (2) mixture as an eluent to give 40 mg (5%) of 38.

Anal. calcd. for Cl7H32N4Os2. 5H2O0. 25NH4Cl : % C 47. 39 % H 8. 89 % N 13. 82 Found : % C 47. 11 % H 7. 92 % N 14. 06 MS (ES+) : 373. 4 (M+1)

Example 39 <BR> <BR> (l S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-[(hydroxylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylic acid 39A : Benzyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-cyanamino-2- hydroxycyclopentan-1-carboxylate To a solution of benzyl (1S, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-amino-2- hydroxycyclopentan-1-carboxylate hydrochloride (26A, 0. 83 g, 2. 0 mmole) in dimethyl acetamide (5 mL) were added triethylamine (0. 35 mL, 2. 5 mmol) followed by 1- cyanoimidazole (0. 32 g, 3. 4 mmol) after 15 min. stirring at room temperature. The reaction mixture was further stirred for 6 h at 100 °C. After cooling, the reaction mixture was diluted with water and extracted (3 X) with ethyl acetate. The combined organic layers were dried, filtered and the filtrate concentrated to give 0. 7 g of crude 39A.

39B : Benzyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (I'-acetylamino-2'-ethyl) butyl-4- [ (hydroxyl- amino- imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate A mixture of hydroxylamine hydrochloride (1. 4 g, 20 mmol) and sodium carbonate (1. 06 g, 10 mmol) in methanol (15 mL) was stirred at room temperature for 0. 5 h. The solid was removed by filtration and the filtrate was added to the previously obtained crude 39A and was stirred at room temperature for 24 h. The reaction mixture was concentrated and the residue was suspended in a mixture of chloroform : methanol (1 : 1). The solid was removed by filtration, the filtrate concentrated and the residue was purified by silica gel column using chloroform (80) : methanol (18) : ammonium hydroxide (2) mixture as an eluent to give 0. 2 g (23%) of 39B.

39 : To a solution of benzyl (lys, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4- [(hydroxylamino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate (39B, 0. 2 g, 0. 46 mmol) in methanol (16 mL) and water (4 mL) was added 10% Pd/C (40 mg) and the mixture was hydrogenated at 40 psi for 1 h. The mixture was passed through a pad of Celite and silica gel, and the filtrate was concentrated and dried to give 0. 04 g (25%) of 39.

Anal. calcd. for CisH2sN40s'2HCl'H20 : % C 41. 38 % H 7. 41 % N 12. 87

Found : %C 40. 35 % H7. 34 % N 13. 27 MS (ES+) : 345. 1 (M+1) Example 40 40 : 1- [ (4'-Aminomethylcarbonylamino) benzoyloxymethyl] (lS, 2S, 3R, 4R, 1'S)- (-)-3- (l'- acetylamino-2'-ethyl) butyl-4- (amino-imino) methyl] amino-2-hydroxycyclo- pentan--1- carboxylate 40A : 4- [N- (Benzyloxycarbonyl) glycylamino] benzoic acid : Methyl chloroformate (1. 8 mL, 23. 3 mmol) was added to a mixture of N- benzyloxycarbonylglycine (5. 0 g, 23. 9 mmol) and triethylamine (3. 35 mL, 24. 2 mmol) in THF (60 mL) at-20 °C over a period of 10 min. and further stirred for 20 min. To this mixture was then added, a solution of 4-aminobenzoic acid (3. 28 g, 23. 9 mmol) and triethylamine (3. 35 mL, 24. 2 mmol) in THF (45 mL) drop wise and stirred at the same temperature for 1 h. The mixture was brought to room temperature and stirred for 16 h, which was then concentrated and the residue was dissolved in 50% acetic acid (30 mL) and cooled. Water (180 mL) was added and the precipitate was collected by filtration to give 1. 9 g (24%) of 40A. 40B : Chloromethyl 4- [N- (benzyloxycarbonyl) glycylamino] benzoate : A solution of chloromethyl chlorosulfate (0. 8 g, 4. 8 mmol) in dichloromethane (4. 0 mL) was added to a mixture of 4-[N-(benzyloxycarbonyl) glycylamino] benzoic acid (40A, 1. 12 g, 3. 42 mmol), sodium bicarbonate (1. 26 g, 15. 0 mmol) and tetrabutylammonium hydrogensulfate (0. 2 g, 0. 59 mmol) in dichloromethane (20 mL) and water (20 mL) drop wise over a period of 5 min. and the mixture was stirred for 3 h. Organic phase was separated and the aqueous phase was extracted with dichloromethane (2 X). The combined organic phases were concentrated. The residue was taken in ethyl acetate, washed with brine and dried. After filtration, the filtrate was concentrated and the residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 1. 0 g (78%) of 40B.

40C : 1 [ (4'-N-Benzyloxocarbonylaminomethylcarbonylamino) benzoyloxymethyl] (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-tert-butoxycarbonylamino-2-<BR> hydroxycyclopentan-1-carboxylate

A mixture of chloromethyl 4- [N- (benzyloxycarbonyl) glycylamino] benzoate (40B, 1. 0 g, 2. 6 mmol) and sodium iodide (2. 25 g, 15 mmol) in acetone (20 mL) was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure, the residue was taken in dichloromethane (40 mL), washed with 5 % sodium thiosulfate and water. The organic layer was dried and filtered. The filtrate on concentration gave 1. 2 g of a brown residue. The residue was dissolved in dimethyl acetamide (10 mL) and added to a mixture of (15, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-(tert-butoxyzarbo-nylamino)-2- hydroxycyclopentan-1-carboxylic acid (20B, 0. 77 g, 2. 0 mmol) and diisopropylamine (0. 26 g, 2. 6 mmol) in dimethyl acetamide (30 mL) at 0 °C. The reaction mixture was further stirred for 2 h at this temperature and diluted with water and ethyl acetate. Organic layer was separated, aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with sodium bicarbonate, water and brine and dried. After filtration, the filtrate was concentrated, and the residue was purified on silica gel column using hexane : ethyl acetate as eluent to give 0. 9 g (61 %) of 40C.

40D : 1- [ (4'-Benzyloxycarbonylaminomethylcarbonylamino) benzoyloxymethyl] <BR> <BR> (lS, 2S, 3R, 4R, 1'S)- (-)-3- (1'-acetylamino-2'-ethyl) butyl-4- (N-benzyloxycarbonyl- amino-N'- benzyloxycarbonylimino) methyl] amino-2-hydroxycyclopentan-1-carboxylate To a mixture of 1- [ (4'-benzyloxycarbonylaminomethylcarbonylamino) benzoyloxy- methyl] (1S, 2S, 3R, 4R, 1'S)- (-)-3- (1'-acetylamino-2'-ethyl) butyl-4-tert-butoxycarbonyl- amino-2- hydroxy. cyclopentan- 1-carboxylate (40C, 1. 1 g, 1. 5 mmol) in dichloromethane (75 mL) was added trifluoroacetic acid (7. 0 mL) and stirred for 16 h. The solvent was evaporated and the residue was stirred with ether and hexane. The supernatent was decanted and the residue was dried under reduced pressure and dissolved in dimethyl formamide (20 mL). To this solution were added triethylamine (1. 05 mL, 7. 5 mmol), 1, 3-bis- (benzyloxycarbonyl)-2-methyl-2- thiopseudourea (20A, 0. 65 g, 1. 8 mmol) and mercury (II) chloride (0. 49 g, 1. 8 mmol) and stirred for 2 h. After dilution with ethyl acetate (100 mL), the mixture was filtered and the filtrate was washed with water and brine. The organic layer was dried, filtered and the filtrate concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 16 g (11 %) of 40D.

40 : To a solution of 1- [ (4'-benzyloxycarbonylaminomethylcarbonylamino) benzoyl- oxymethyl (1S, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-(N-benzyloxy- <BR> <BR> carbonylamino-N'-benzyloxycarbonylimino) methyl] amino-2-hydroxycyclopentan-l-carboxylate (40D, 0. 11 g, 0. 12 mmol) in ethanol (8 mL) and water (2 mL) was added 10% Pd/C (25 mg) and conc. HCl (2 drops) and the mixture was hydrogenated at 40 psi for 1 h. The mixture was passed through a pad of Celite and silica gel, and the filtrate was concentrated and dried to give 0. 064 g (71 %) of 40.

Anal. calcd. for C2sH3sN607-3HCl-3H2OC2HsOH : % C 43. 58 % H 7. 18 % N 11. 29 Found : % C 43. 24 % H 6. 48 % N 11. 48

MS (ES+) : 535. 6 (M+1) Example 41 41 : 1-[(4'-Aminomethylcarbonyloxy) benzoyloxymethyl] (l S, 2S, 3R, 4R, 1'S)-(-)-3-(1'- acetylamino-2'-ethyl) butyl-4- (amino-imino) methyl] amino-2-hydroxycyclopentan-1- carboxylate 41A : 4-[N-(Benzyloxycarbonyl) glycyloxy] benzoic acid : Isobutyl chloroformate (3. 1 mL, 23. 3 mmol) was added to a mixture of N- benzyloxycarbonylglycine (5. 0 g, 23. 9 mmol) and triethylamine (3. 35 mL, 24. 2 mmol) in THF (60 mL) at-20 °C over a period of 10 min. and further stirred for 20 min. To this mixture was then added, a solution of 4-hydroxybenzoic acid (3. 28 g, 23. 9 mmol) and triethylamine (3. 35 mL, 24. 2 mmol) in THF (45 mL) drop wise and stirred at the same temperature for 1 h. The mixture was brought to room temperature and stirred for 16 h, which was then concentrated and the residue was dissolved in 50 % acetic acid (30 mL) and cooled. Water (180 mL) was added and the precipitate was collected by filtration to give 1. 9 g (24%) of 41A.

41B : Chloromethyl 4- [N- (benzyloxycarbonyl) glycyloxy] benzoate : A solution of chloromethyl chlorosulfate (1. 2 g, 7. 4 mmol) in dichloromethane (4. 0 mL) was added to a mixture of 4- [N- (benzyloxycarbonyl) glycyloxy] benzoic acid (41A, 1. 75 g, 5. 3 mmol), sodium bicarbonate (2. 0 g, 23. 8 mmol) and tetrabutylammonium hydrogensulfate (0. 23 g, 0. 7 mmol) in dichloromethane (20 mL) and water (20 mL) drop wise over a period of 5 min. and the mixture was stirred for 3 h. Organic phase was separated and the aqueous phase was extracted with dichloromethane (2 X). The combined organic phases were concentrated.

The residue was taken in ethyl acetate, washed with brine and dried. After filtration, the filtrate was concentrated and the residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 2. 0 g (98 %) of 41B.

41C : 1 [ (4'-N-Benzyloxycarbonylaminomethylcarbonyloxy) benzoyloxymethyl] (lS, 2S, 3R, 4R, 1'S)- (-)-3- (1'-acetylamino-2'-ethyl) butyl-4-tert-butoxycarbonylamino-2-<BR> hydroxycyclopentan-1-carboxylate

A mixture of chloromethyl 4- [N- (benzyloxycarbonyl) glycyloxy] benzoate (41B, 2. 0 g, 5. 3 mmol) and sodium iodide (4. 5 g, 30. 0 mmol) in acetone (30 mL) was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure, the residue was taken in dichloromethane (80 mL), washed with 5 % sodium thiosulfate and water. The organic layer was dried and filtered. The filtrate on concentration gave 2. 4 g of a brown residue. The residue (1. 55 g, 3. 3 mmol) was dissolved in dimethyl acetamide (10 mL) and added to a mixture of (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-(tert- butoxycarbonylamino)-2-hydroxycyclopentan-l-carboxylic acid (20B, 1. 16 g, 3. 0 mmol) and diisopropylamine (0. 0. 33 g, 3. 3 mmol) in dimethyl acetamide (30 mL) at 0 °C. The reaction mixture was further stirred for 2 h at this temperature and diluted with water and ethyl acetate.

Organic layer was separated, aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with sodium bicarbonate, water and brine and dried. After filtration, the filtrate was concentrated, and the residue was purified on silica gel column using hexane : ethyl acetate as eluent to give 1. 6 g (73 %) of 41C.

41D : 1- [ (4'-N-Benzyloxycarbonylaminomethylcarbonyloxy) benzoyloxymethyl] (lS, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetylamino-2'-ethyl) butyl-4- (N-benzyloxycarbonyl- amino-N'- benzyloxycarbonylimino) methyl] amino-2-hydroxycyclopentan-1-carboxylate To a mixture of 1- [ (4'-benzyloxycarbonylaminomethylcarbonyloxy) benzoyloxymethyl] (15, 25, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-tert-butoxycarbonylamino-2- hydroxycyclopentan-1-carboxylate (40C, 1. 22 g, 1. 7 mmol) in dichloromethane (75 mL) was added trifluoroacetic acid (7. 0 mL) and stirred for 16 h. The solvent was evaporated and the residue was stirred with ether and hexane. The supernatent was decanted and the residue was dried under reduced pressure and dissolved in dimethyl formamide (20 mL). To this solution were added triethylamine (1. 0 mL, 7. 0 mmol), 1, 3-bis- (benzyloxy- carbonyl)-2-methyl-2- thiopseudourea (20A, 0. 73 g, 2. 05 mmol) and mercury (II) chloride (0. 56 g, 2. 05 mmol) and stirred for 2 h. After dilution with ethyl acetate (100 mL), the mixture was filtered and the filtrate was washed with water and brine. The organic layer was dried, filtered and the filtrate concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 11 g (7%) of 41D.

41 : To a solution of 1- [ (4'-benzyloxycarbonylaminomethylearbonyloxy) benzoyloxy-methyl] (1S, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-(N-benzyloxycarbonyl-amino-N'- benzyloxycarbonylimino) methyl] amino-2-hydroxycyclopentan-l-carboxylate (41D, 0. 11 g, 0. 12 mmol) in ethanol (8 mL) and water (2 mL) was added 10 % Pd/C (25 mg) and conc. HCl (2 drops) and the mixture was hydrogenated at 40 psi for 1 h. The mixture was passed through a pad of Celite and silica gel, and the filtrate was concentrated and dried to give 0. 06 g (70%) of 41.

Anal. calcd. for C2sH37NsOs5HCl*3. 5H2OC2HsOH : % C 39. 21 % H 6. 70 % N 8. 89 Found : % C 39. 33 % H 6. 19 % N 8. 25 MS (ES+) : 536. 7 (M+l)

Example 42 42 : n-Hexyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-(amino- imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate 42A : n-Hexyl (1S, 25, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-tert-butoxy- carbonylamino-2-hydroxycyclopentan-1-carboxylate To a mixture of (1S, (2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-tert-buto y- carbonylamino-2-hydroxycyclopentan-1-carboxylic acid (20B, 1. 5 g, 3. 9 mmol) in dichloromethane (40 mL) was added 1, l'-carbonyldiimidazole (1. 3 g, 7. 6 mmol) and stirred at room temperature for 2 h. To this mixture was then added n-hexanol (1. 46 mL, 11. 6 mmol) and the reaction mixture was stirred for 16 h. After dilution with water, the reaction mixture was extracted with dichloromethane (2 X). The combined organic layers were dried, filtered and concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 1. 1 g (60%) of 42A.

42B : n-Hexyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-(N-benzyl- oxycarbonylamino-N'-benzyloxycarbonylimino) methyl] amino-2-hydroxycyclo-pentan-1- carboxylate To a mixture of n-hexyl (15, 25, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-tert- butoxycarbonylamino-2-hydroxycyclopentan-1-carboxylate (42A, 1. 0 g, 2. 1 mmol) in ether (30 mL) and THF (10 mL) was added 7. 5N HC1 in ether (4. 0 mL, 30 mmol) and the mixture was stirred at room temperature for 16 h. After concentration, the residue was suspended in ether- hexane and the solid was collected by filtration, washed with a mixture of ether-hexane and dried to give 0. 78 g (90%) of amine as hydrochloride. Amine was dissolved in dimethyl formamide (20 mL). To this solution were added triethylamine (0. 94 mL, 6. 7 mmol), 1, 3-bis- (benzyloxycarbonyl)-2-methyl-2-thiopseudo-urea (20A, 0. 82 g, 2. 3 mmol) and mercury (II) chloride (0. 62 g, 2. 3 mmol) and stirred for 2 h. After dilution with ethyl acetate (100 mL), the mixture was filtered and the filtrate was washed with water and brine. The organic layer was dried, filtered and the filtrate concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 73 g (56%) of 42B. 42 : To a solution of n-hexyl (1S, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-(N- benzyloxycarbonylamino-N'-benzyloxycarbonylimino) methyl] amino-2-hydroxycyclo pentan-1- carboxylate (42B, 0. 73 g, 1. 1 mmol) in ethanol (40 mL) and water (5 mL) was added 10% Pd/C (100 mg) and conc. HC1 (2 drops) and the mixture was hydrogenated at 40 psi for 1 h.

The mixture was passed through a pad of Celite and silica gel, and the filtrate was concentrated and dried to give 0. 42 g (88%) of 42.

Anal. calcd. for GlH40N404HCl1. 5H2O : % C 52. 98 % H 9. 31 % N 11. 76 Found : %C 52. 84 %H8. 93 % N 11. 85 MS (ES+) : 413. 2 (M + 1) Example 43 43 : 2-Methylpropyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-(amino- imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate 43A : 2-Methylpropyl (lS, 2S, 3R, 4R, 1'S)- (-)-3- (1'-acetylamino-2'-ethyl) butyl-4-tert- butoxycarbonylamino-2-hydroxycyclopentan-1-carboxylate To a mixture of (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-tert-butoxy- carbonylamino-2-hydroxycyclopentan-1-carboxylic acid (20B, 1. 5 g, 3. 9 mmol) in dichloromethane (40 mL) was added 1, l'-carbonyldiimidazole (1. 3 g, 7. 6 mmol) and stirred at room temperature for 2 h. To this mixture was then added 2-methylpropanol (1. 1 mL, 11. 6 mmol) and the reaction mixture was stirred for 16 h. After dilution with water, the reaction mixture was extracted with dichloromethane (2 X). The combined organic layers were dried, filtered and concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 91 g (53%) of 43A.

43B : 2-Methylpropyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-(N- benzyloxycarbonylamino-N'-benzyloxycarbonylimino) methyl] amino-2-hydroxy- cyclopentan-1-carboxylate To a mixture of 2-methylpropyl (15, 25, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-tert- butoxycarbonylamino-2-hydroxycyclopentan-l-carboxylate (43A, 0. 91 g, 2. 0 mmol) in ether (30 mL) and THF (10 mL) was added 7. 5N HCl in ether (4. 0 mL, 30 mmol) and the mixture was stirred at room temperature for 16 h. After concentration, the residue was suspended in ether-hexane and the solid was collected by filtration, washed with a mixture of ether-hexane and dried to give 0. 8 g (99%) of amine as hydrochloride. The amine was dissolved in dimethyl formamide (20 mL). To this solution were added triethylamine (0. 97 mL, 7. 0 mmol), 1, 3-bis (benzyloxycarbonyl)-2-methyl-2-thiopseudo- urea (20A, 0. 86 g, 2. 4 mmol) and mercury (II) chloride (0. 65 g, 2. 4 mmol) and stirred for 2 h. After dilution with ethyl acetate (100 mL), the mixture was filtered and the filtrate was washed with water and brine. The organic layer was dried, filtered and the filtrate concentrated. The residue was purified on

silica gel column using hexane : ethyl acetate as an eluent to give 0. 68 g (50%) of 43B.

43 : To a solution of 2-methylpropyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (1'-acetylamino-2'-ethyl)- butyl- 4- (N-benzyloxycarbonylamino-N'-benzyloxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate (43B, 0. 68 g, 1. 0 mmol) in ethanol (40 mL) and water (5 mL) was added 10% Pd/C (100 mg) and the mixture was hydrogenated at 40 psi for 1 h. The mixture was passed through a pad of Celite and silica gel, and the filtrate was concentrated and dried to give 0. 25 g (57%) of 43.

Anal. calcd. for C19H36N4O4#2.75H2O : % C 52. 57 % H 9. 63 %N 12. 90 Found : % C 52. 17 %H8. 76 % N 13. 00 MS (ES+) : 385. 3 (M+l) Example 44 44 : (x-(Ethoxycarbonyloxy) ethyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl)-butyl-4- (amino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate 44A : a- (Ethoxycarbonyloxy) ethyl (1S,2S,3R,4R,1'S)-(-)-3-(1'-acethylamino-2'-ethyl)-buty1- 4-tert-butoxycarbonylamino-2-hydroxycyclopentan-1-carboxylat e 1-Iodoethyl ethyl carbonate (1. 27 g, 5. 2 mmol ; prepared from that disclosed in Svahn et al. J. Med. Chem. 1986, 29, 448-453 ; Fujimoto et al. J. Antibiotics 1987, XL, 370-384) was added to a mixture of (1S, 25, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl)-butyl-4-tert- butoxycarbonylamin)-2-hydroxycyclopentan-l-carboxylic acid (20B, 1. 0 g, 2. 6 mmol) and diisopropylamine (0. 0. 53 g, 5. 2 mmol) in dimethyl acetamide (30 mL) at 0 °C. The reaction mixture was further stirred for 2 h at this temperature and diluted with water and ethyl acetate. The organic layer was separated, aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with sodium bicarbonate, water and brine and dried. After filtration, the filtrate was concentrated, and the residue was purified on silica gel column using hexane : ethyl acetate as eluent to give 0. 9 g (68%) of 44A.

44B : a- (Ethoxycarbonyloxy) ethyl (1S, 2S, 3R,4R,$1'S)-(-)-3-(1'-acethylamino-2'-ethyl)-buty- 4-[(N-benzyloxycarbonylamino-N'-benzyloxycarbonylimino)methy l]amino-2- hydroxycyclopentan-l-carboxylate To a mixture of oc- (ethoxycarbonyloxy) ethyl (lys, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-

ethyl) butyl-4-tert-butoxycarbonylamino-2-hydroxycyclopentan-l-carb oxylate (44A, 0. 9 g, 1. 8 mmol) in ether (30 mL) and THF (10 mL) was added 7. 5N HC1 in ether (4. 0 mL, 30 mmol) and the mixture was stirred at room temperature for 16 h. After concentration, the residue was suspended in ether-hexane and the solid was collected by filtration, washed with a mixture of ether-hexane and dried to give 0. 79 g (99%) of amine as hydrochloride. The amine was dissolved in dimethyl formamide (20 mL). To this solution were added triethylamine (0. 88 mL, 6. 3 mmol), 1, 3-bis- (benzyloxycarbonyl)-2-methyl-2-thiopseudourea (20A, 0. 76 g, 2. 1 mmol) and mercury (II) chloride (0. 59 g, 2. 1 mmol) and stirred for 2 h. After dilution with ethyl acetate (100 mL), the mixture was filtered and the filtrate was washed with water and brine. The organic layer was dried, filtered and the filtrate concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 84 g (65 %) of 44B. 44 : To a solution of oc- (ethoxycarbonyloxy) ethyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetyl- amino-2'- ethyl) butyl-4- (N-benzyloxycarbonylamino-N'-benzyloxycarbonylimino)- methyl] amino-2- hydroxycyclopentan-1-carboxylate (44B, 0. 84 g, 1. 1 mmol) in ethanol (40 mL) and water (5 mL) was added 10% Pd/C (100 mg) and the mixture was hydrogenated at 40 psi for 1 h. The mixture was passed through a pad of Celite and silica gel, and the filtrate was concentrated and dried to give 0. 25 g (49%) of 44.

Anal. calcd. for C20H36N407. H20 : % C 51. 93 %H 8. 28 %N 12. 11 Found : %C 51. 68 % H 8. 11 % N 12. 05 MS (ES+) : 444. 9 (M+1) Example 45 45 : a-Acetyloxyethyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-(amino- imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate 45A : a-Acetyloxyethyl (lS, 2S, 3R, 4R, 1'S- (-)-3- (1'-acetylamino-2'-ethyl) butyl-4-tert- butoxycarbonylamino-2-hydroxycyclopentan-1-carboxylate 1-Iodoethyl acetate (1. 1 g, 5. 2 mmol ; prepared from that disclosed in Svahn et al. J. Med. Chem. 1986, 29, 448-453 ; Fujimoto et al. J. Antibiotics 1987, XL, 370-384) was added to a mixture of (1S, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-tert-butoxyzarbonylamino- 2-hydroxycyclopentan-1-carboxylic acid (20B, 1. 0 g, 2. 6 mmol) and diisopropylamine (0. 53 g, 5. 2 mmol) in dimethyl acetamide (30 mL) at 0 °C. The reaction mixture was further stirred for 2 h at this temperature and diluted with water and ethyl acetate. Organic layer was

separated, aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with sodium bicarbonate, water and brine and dried. After filtration, the filtrate was concentrated, and the residue was purified on silica gel column using hexane : ethyl acetate as eluent to give 0. 7 g (57%) of 45A. 45B : a-Acetyloxyethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-[(N- benzyloxycarbonylamino-N'-benzyloxycarbonylimino) methyl] amino-2-hydroxy- cyclopentan-1-carboxylate To a mixture of α-acetyloxyethyl (1S,2S,3R,4R,1'S)-(-)-3-(1'-acethylamino-2'-ethyl)buty1-4-te rt- butoxycarbonylamino-2-hydroxycyclopentan-l-carboxylate (45A, 0. 7 g, 1. 5 mmol) in ether (30 mL) and THF (10 mL) was added 7. 5N HC1 in ether (4. 0 mL, 30 mmol) and the mixture was stirred at room temperature for 16 h. After concentration, the residue was suspended in ether- hexane and the solid was collected by fitration, washed with a mixture of ether-hexane and dried to give 0. 61 g (99%) of amine as hydrochloride. Amine was dissolved in dimethyl formamide (20 mL). To this solution were added triethylamine (0. 73 mL, 5. 3 mmol), 1, 3-bis- (benzyloxycarbonyl)-2-methyl-2-thiopseudo-urea (20A, 0. 64 g, 1. 8 mmol) and mercury (II) chloride (0. 49 g, 1. 8 mmol) and stirred for 2 h. After dilution with ethyl acetate (100 mL), the mixture was filtered and the filtrate was washed with water and brine. The organic layer was dried, filtered and the filtrate concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 47 g (46%) of 45B.

45 : To a solution of (x-acetyloxyethyl (1S, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl- 4- (N-benzyloxycarbonylamino-N'-benzyloxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate (45B, 0. 47 g, 0. 69 mmol) in ethanol (40 mL) and water (5 mL) was added 10% Pd/C (100 mg) and the mixture was hydrogenated at 40 psi for 1 h. The mixture was passed through a pad of Celite and silica gel, and the filtrate was concentrated and dried to give 0. 15 g (48 %) of 45.

Anal. calcd. for ClsH34N406@2H2O : % C 50. 65 % H 8. 50 % N 12. 44 Found : % C 50. 38 % H 7. 62 % N 11. 79 MS (ES+) : 415. 4 (M+1) Example 46 46 : tert-Butylcarbonyloxomethyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetylamino-2'-ethyl)- butyl- 4-(amino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate

46A : tert-Butylcarbonyloxymethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl)-butyl- 4-te7t-butoxycarbonylamino-2-hydroxycyclopentan-1-carboxylat e lodomethyl pivalate (0. 74 g, 5. 2 mmol ; prepared from the literature references : svahn et al. J. Med. Chem. 1986, 29, 448-453 ; Fujimoto et al. J. antibiotics 1987, XL, 370-384) was added to a mixture of (1S, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-tert- butoxycarbonylamino-2-hydroxycyclopentan-l-carboxylic acid (20B, 1. 0 g, 2. 6 mmol) and diisopropylamine (0. 53 g, 5. 2 mmol) in dimethyl acetamide (30 mL) at 0 °C. The reaction mixture was further stirred for 2 h at this temperature and diluted with water and ethyl acetate. Organic layer was separated, aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with sodium bicarbonate, water and brine and dried. After filtration, the filtrate was concentrated, and the residue was purified on silica gel column using hexane : ethyl acetate as eluent to give 0. 7 g (59%) of 46A.

46B : tert-Butylcarbonyloxymethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl)- butyl-4- (N-benzyloxycarbonylamino-N'-benzyloxycarbonylimino) methyl] amino-2- hydroxycyclopentan-1-carboxylate To a mixture of tert-butylcarbonyloxymethyl (lS, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'- ethyl) butyl-4-tert-butoxycarbonylamino-2-hydroxycyclopentan-1-carb oxylate (46A, 0. 7 g, 1. 5 mmol) in ether (30 mL) and THF (10 mL) was added 7. 5N HC1 in ether (4. 0 mL, 30 mmol) and the mixture was stirred at room temperature for 16 h. After concentration, the residue was suspended in ether-hexane and the solid was collected by fitration, washed with a mixture of ether-hexane and dried to give 0. 61 g (99%) of amine as hydrochloride. Amine was dissolved in dimethyl formamide (20 mL). To this solution were added triethylamine (0. 73 mL, 5. 3 mmol), 1, 3-bis- (benzyloxycarbonyl)-2-methyl-2-thiopseudourea (20A, 0. 64 g, 1. 8 mmol) and mercury (II) chloride (0. 49 g, 1. 8 mmol) and stirred for 2 h. After dilution with ethyl acetate (100 mL), the mixture was filtered and the filtrate was washed with water and brine. The organic layer was dried, filtered and the filtrate concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 54 g (50% of 46B. 46 : To a solution of tert-butylcarbonyloxymethyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetyl amino-2'- ethyl) butyl-4- (N-benzyloxycarbonylamino-N'-benzyloxycarbonylimino)- methyl] amino-2- hydroxycyclopentan-1-carboxylate (46B, 0. 54 g, 0. 76 mmol) in ethanol (40 mL) and water (5 mL) was added 10% Pd/C (100 mg) and the mixture was hydrogenated at 40 psi for 1 h. The mixture was passed through a pad of Celite and silica gel, and the filtrate was concentrated and dried to give 0. 10 g (26 %) of 46.

Anal. calcd. for GlH3sN406O3. 5H2O : % C 49. 88 % H 8. 97. % N 11. 08 Found : %C 50. 11 % H 7. 99 % N 11. 09 MS (ES+) : 443. 0 (M+1)

Example 47 47 : a- (methoxycarbonyloxy) ethyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl)-butyl- 4-(amino-imino) methyl] amino-2-hydroxycyclopentan-1-carboxylate 47A : a- (methoxycarbonyloxy) ethyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl- 4-tert-butoxycarbonylamino-2-hydroxycyclopentan-1-carboxylat e 1-Iodoethyl methyl carbonate (1. 22 g, 5. 2 mmol ; prepared from the literature references : svahn et al. J. Med. Chem. 1986, 29, 448-453 ; Fujimoto et al. J. antibiotics 1987, XL, 370- 384) was added to a mixture of (1S, 2S, 3R, 4R, l'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-tert- butoxycarbonylamino-2-hydroxycyclopentan-l-carboxylic acid (20B, 1. 0 g, 2. 6 mmol) and diisopropylamine (0. 53 g, 5. 2 mmol) in dimethyl acetamide (30 mL) at 0 °C. The reaction mixture was further stirred for 2 h at this temperature and diluted with water and ethyl acetate. Organic layer was separated, aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with sodium bicarbonate, water and brine and dried. After filtration, the filtrate was concentrated, and the residue was purified on silica gel column using hexane : ethyl acetate as eluent to give 0. 67 g (54%) of 47A.

47B : a- (Methoxycarbonyloxy) ethyl (lS, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl- <BR> <BR> 4- (N-benzyloxycarbonylamino-N'-benzyloxycarbonylimino) methyl]- amino-2-<BR> <BR> <BR> <BR> <BR> hydroxycyclopentan-1-carboxylate To a mixture of a- (methoxycarbonyloxy) ethyl (lS, 2S, 3R, 4R, l'S)- (-)-3- (l'-acetylamino-2'- ethyl) butyl-4-tert-butoxycarbonylamino-2-hydroxycyclopentan-l-carb oxylate (47A, 0. 67 g, 1. 4 mmol) in ether (30 mL) and THF (10 mL) was added 7. 5N HC1 in ether (4. 0 mL, 30 mmol) and the mixture was stirred at room temperature for 16 h. After concentration, the residue was suspended in ether-hexane and the solid was collected by filtration, washed with a mixture of ether-hexane and dried to give 0. 57 g (99%) of amine as hydrochloride. Amine was dissolved in dimethyl formamide (20 mL). To this solution were added triethylamine (0. 69 mL, 4. 9 mmol), 1, 3-bis- (benzyloxycarbonyl)-2-methyl-2-thiopseudourea (20A, 0. 6 g, 1. 7 mmol) and mercury (II) chloride (0. 46 g, 1. 7 mmol) and stirred for 2 h. After dilution with ethyl acetate (100 mL), the mixture was filtered and the filtrate was washed with water and brine. The organic layer was dried, filtered and the filtrate concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 49 g (50%) of 47B.

47 : To a solution of α-(methoxycarbonyloxy)ethyl (1S,2S,3R,4R,1'S)-(-)-3-(1'-acethyl-amino- 2'-ethyl) butyl-4- (N-benzyloxycarbonylamino-N'-benzyloxycarbonylimino)-methyl] amino-2- hydroxyclopentan-1-caboxylate (47B, 0. 48 g, 0. 7 mmol) in ethanol (40 mL) and water (5 mL) was added 10% Pd/C (100 mg) and the mixture was hydrogenated at 40 psi for 1 h. The mixture was passed through a pad of Celite and silica gel, and the filtrate was concentrated and dried to give 0. 13 g (40%) of 47.

Anal. calcd. for C19H34N4O7#2H2O: %C 48. 92 %H 8. 21 % N 12. 01 Found : %C 48. 48 % H 7. 82 % N 12. 89 MS (ES+) : 431. 4 (M+1)

Example 48 48 : a-(iso-Propyloxycarbonyloxy) ethyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (1'-acetylamino-2'- ethyl) butyl-4-(amino-imino)methyl]amino-2-hydroxycyclopentan-1-car boxylate 48A : a- (iso-Propyloxycarbonyloxy) ethyl (lS, 2S, 3R, 4R, 1'5)-(-)-3-(1'-acetylamino-2'- ethyl) butyl-4-tert-butoxycarbonylamino-2-hydroxycyclopentan-1-carb oxylate 1-Iodoethyl iso-propyl carbonate (1. 4 g, 5. 2 mmol ; prepared from the literature references : svahn et al. J. Med. Chem. 1986, 29, 448-453 ; Fujimoto et al. J. antibiotics 1987, XL, 370- 384) was added to a mixture of (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetylamino-2'-ethyl) butyl-4-tert- butoxycarbonylamino-2-hydroxycyclopentan-1-carboxylic acid (20B, 1. 0 g, 2. 6 mmol) and diisopropylamine (0. 53 g, 5. 2 mmol) in dimethyl acetamide (30 mL) at 0 °C. The reaction mixture was further stirred for 2 h at this temperature and diluted with water and ethyl acetate.

Organic layer was separated, aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with sodium bicarbonate, water and brine and dried. After filtration, the filtrate was concentrated, and the residue was purified on silica gel column using hexane : ethyl acetate as eluent to give 0. 81 g (62%) of 48A.

48B : oc-(iso-Propyloxycarbonyloxy) ethyl (1S, 2S, 3R, 4R, 1'S)- (-)-3- (l'-acetylamino-2'- ethyl) butyl-4-(N-benzyloxycarbonylamino-N'-benzyloxycaronylimino)m ethyl]- amino-2- hydroxycyclopentan-1-carboxylate To a mixture of a- (iso-propyloxycarbonyloxy) ethyl (1S, 2S, 3R, 4R, 1'S)-(-)-3-(1'-acetyl-amino- 2'-ethyl) butyl-4-tert-butoxycarbonylamino-2-hydroxycyclopentan-l-carb oxylate (48A, 0. 81 g, 1. 6 mmol) in ether (30 mL) and THF (10 mL) was added 7. 5N HC1 in ether (4. 0 mL, 30 mmol) and the mixture was stirred at room temperature for 16 h. After concentration, the residue was suspended in ether-hexane and the solid was collected by filtration, washed with a mixture of ether-hexane and dried to give 0. 7 g, (99%) of amine as hydrochloride. Amine was dissolved in dimethyl formamide (20 mL). To this solution were added triethylamine (0. 78 mL, 5. 6 mmol), 1, 3-bis- (benzyloxycarbonyl)-2-methyl-2-thiopseudourea (20A, 0. 69 g, 1. 9 mmol) and mercury (II) chloride (0. 52 g, 1. 9 mmol) and stirred for 2 h. After dilution with ethyl acetate (100 mL), the mixture was filtered and the filtrate was washed with water and brine. The organic layer was dried, filtered and the filtrate concentrated. The residue was purified on silica gel column using hexane : ethyl acetate as an eluent to give 0. 78 g (67%) of 48B.

48 : To a solution of o-(iso-propyloxycarbonyloxy) ethyl (1S, 2S, 3R, 4R, 1'6)- (-)-3- (1'-

acetylamino-2'-ethyl) butyl-4- (N-benzyloxycarbonylamino-N'-benzyloxycarbonylimino)- methyl] amino-2-hydroxycyclopentan-1-carboxylate (48B, 0. 48 g, 0. 66 mmol) in ethanol (40 mL) and water (5 mL) was added 10% Pd/C (100 mg) and the mixture was hydrogenated at 40 psi for 1 h. The mixture was passed through a pad of Celite and silica gel, and the filtrate was concentrated and dried to give 0. 17 g (52%) of 48.

Anal. calcd. for GlH3sN407O2H2O : % C 51. 00 % H 8. 56 % N 11. 33 Found : %C 49. 72 % H 8. 05 % N 12. 06 Compounds of the present invention are useful as prodrugs for substituted cyclopentane and substituted cyclopentene compounds which are useful as neuraminidase inhibitors, or as active neuraminidase inhibitors themselves.

For the purposes of this disclosure, the term"prodrug"denotes a derivative of cyclopentane or cyclopentene, which derivative, when administered to a warm-blooded animal, "cleaves"in such a manner as to release the active drug form at its target site or sites of activity. The enzymatic and/or chemical hydrolytic"cleavage"of the compounds of the instant invention occurs in a manner such that the active drug form is released while the remaining "cleaved"moiety remains nontoxic and is metabolized in such a manner that nontoxic, virologically inert products are produced.

The prodrug compounds of the present invention can be used to treat any condition for which the parent cyclopentane or cyclopentene containing drug, medicament or pharmaceutical is useful for. The prodrugs may be administered in low amounts relative to the amounts of neuraminidase inhibitor that would ordinarily be administered.

Dosage and Formulation The compounds of this invention can be administered as treatment for viral infections by any means that produces contact of the active agent's site of action with the viral neuraminidase in the body of a human, mammal, bird, or other animal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration ; the age, health and weight of the recipient ; the nature and extent of the symptoms, the kind of concurrent treatment ; the frequency of treatment ; and the effect desired.

A daily dosage of active ingredient can be expected to be about 0. 001 to 1000 milligram (mg) per kilogram (kg) of body weight, with the preferred dose being 0. 1 to about 30 mg/kg.

Dosage forms (compositions suitable for administration) contain from about 1 mg to about 500 mg of prodrug per unit. In these pharmaceutical compositions, the compound of the present invention will ordinarily be present in an amount of about 0. 5-95 % by weight based on the total weight of the composition.

The prodrug can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms. The prodrug can also be administered intranasally (nose drops) or by inhalation of a drug powder mist. Other dosage forms are potentially possible such as administration transdermally, via a patch mechanism or ointment.

Gelatin capsules contain the prodrug and powdered carriers, such as lactose, starch, cellulose derivatives, biocompatible polymers, magnesium stearate, stearic acid, and the like.

Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. They may also contain buffering agents, surfactants and preservatives. Liquid oral products can be developed to have sustained-release properties.

They may also contain cyclodextrin derivatives to enhance the solubility of the active ingredient and to promote its oral uptake.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and, if necessary, buffering agents.

Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl-or propylparaben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company and in the Handbook of Pharmaceuticals Excipients, American Pharmaceutical Association, both standard reference texts in this field.

Useful pharmaceutical dosage forms for administration of the compounds according to the present invention can be illustrated as follows :

Hard Shell Capsules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered prodrug, 150 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate.

Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The prodrug can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.

Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg of active ingredient, 0. 2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98. 8 mg of lactose.

Appropriate aqueous and non-aqueous coatings may be applied to increase palatability improve elegance and stability or delay absorption.

Immediate Release Tablets/Capsules These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication.

The prodrug is mixed in a liquid containing ingredient such as sugar, gelatin, pectin, and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.

Moreover, the compounds of the present invention can be administered in the form of nose drops, metered dose nasal or buccal inhalers. The drug is delivered from a nasal solution as a fine mist or from a powder as an aerosol.

Various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.

The foregoing disclosure includes all the information deemed essential to enable those skilled in the art to practice the claimed invention. Because the cited applications may provide further useful information, these cited materials are hereby incorporated by reference in their entirety.