MXPA98010617A

MXPA98010617A - Cyclopentine compounds substituted useful as inhibitors of neuraminid

Info

Publication number: MXPA98010617A
Application number: MXPA/A/1998/010617A
Authority: MX
Inventors: S Babu Yarlagadda; Chand Pooran; A Montgomery John
Original assignee: S Babu Yarlagadda; Biocryst Pharmaceuticals Inc; Chand Pooran; A Montgomery John
Priority date: 1996-06-14
Filing date: 1998-12-14
Publication date: 1999-09-01

Abstract

Compounds represented by the formula (I), and pharmaceutically acceptable salts thereof, and their method of preparation are provided. The compounds of the above formula are neuraminidase inhibitors against influenza viruses, and can be used in the treatment of patients infected with the influenza virus.

Description

CYCLOPENTAN SUBSTITUTE COMPOUNDS USEFUL AS INHIBITORS OF NEURAMINIDASE DESCRIPTION Technical Field This invention relates to substituted cyclopentane compounds and novel derivatives thereof useful as neuraminidase inhibitors, to pharmaceutical compositions containing said compounds useful for the prevention, treatment or amelioration of viral, bacterial and other infections, and to methods for using such compounds. The present invention also relates to novel intermediates or precursors for producing the novel substituted cyclopentane compounds of the present invention.

Background of the Invention Despite the abundance of information available, influenza remains a potentially devastating disease for humans, lower mammals, and birds. There is no effective vaccine and there is no cure available once the infection has started.

Influenza viruses consist of eight portions of single-stranded RNA, packaged in an orderly fashion inside the virion. Each portion encodes one of the major viral proteins. The replication complex is enclosed in a membrane composed of a matrix protein associated with a lipid bilayer. Embedded in the lipid bilayer there are two surface glycoprotein tips, hemagglutinin (HA) and the enzyme neuraminidase (NA). All the viral genes have been cloned and the three-dimensional structures of the surface glycoproteins have been determined. 5 Influenza viruses continuously experience the antigenic variation of the two surface antigens, HA and NA, to which the neutralizing antigens are directed. For this reason, vaccines and the subject's natural immune system have not been very effective. Attention is now being directed to finding other potential antiviral agents that act in other sites of the virion. This invention is directed to flfc novel compounds that are useful in inhibiting the enzyme from viral surface NA.

In addition, many other organisms carry NA. Many of these organisms that possess NA are also major pathogens of man and / or mammals, including Vibraeo cholerae, Clostridium perfringes, Streptococcus pneumoniae, Arthrobacter sialophilas, and other viruses, such as parainfluenza virus, mumps virus, Newcastle disease virus, avian flu virus, and Sendai virus . The compounds of this The invention also aims to inhibit NA in these organisms.

In viruses, NA exists in the form of a tetramer formed by four subunits approximately spherical and a centrally anchored stem containing a hydrophobic region through which it is embedded in the body's membrane. Different roles for NA have been suggested. The enzyme catalyzes the cleavage of the α-ketosidic linkage between the terminal sialic acid and an adjacent sugar moiety. The elimination of the sialic acid decreases the viscosity and allows the access of the virus to the epithelial cells. NA also destroys the HA receptor in the host cell, thereby allowing elution of the progeny of virus particles from the infected cells. Research indicates that the active site for influenza neuraminidase remains substantially unchanged for most strains of influenza. For example, a comparison of the sequences of the subtypes of influenza A and influenza B shows conserved residues with crucial structural and functional roles. Even though the homology of the sequence is only about 30%, many of the catalytic residues are conserved. In addition, the three-dimensional structures of the neuraminidases of influenza A and B have been determined. The superposition of the different structures shows a remarkable structural similarity of the active site. Since the amino acid residues of the active site are conserved in all known influenza A neuraminidases that have been sequenced so far, an inhibitor can be designed that is effective against different influenza A and / or B neura inidase strains on the basis of to the three-dimensional structure of neuraminidase.

In general, it is thought that the role of NA is for the mobility of the virus both to and from the site of the infections. Compounds that inhibit the activity of neuraminidase can protect a subject from infection and / or cure a subject once the infection has been installed. Another object of the invention is to provide a method for using the compounds of this invention to treat and / or cure viral infections.

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 RESPITATORY TRACT, Vol. 1 (J.S. Oxford, Ed.), CRC Press, 1977, p. 189-205.

Von Itzstein et al. describe cyclohexane analogs of -D-neuraminic acid of formula where: A is O, C or S in Formula (A), and N or C in Formula (b); R1 is C02H, P03H2, N02, S02H, S03H, tetrazolyl-, CH2CH0, CHO, or CH (CH0) 2; R2 is H, OR6, F, Cl, Br, CN, NHR6, SR6 or CH2X, where X is NHR6, halogen, or OR6; R3 and R3 'are H, CN, NHR6, SR6, = N0R6, OR6, guanidino, NR6; R4 is NHR6, SR6, OR6, C02R6, N02, C (R6) 3, CH2C02R6, CH2N02 or CH2NHR6; R5 is CH2YR6, CHYR6CH2YR6 or CHYR6CHYR6CH2YR6; R is H, acyl, alkyl, allyl, or aryl; And it is O, S, NH, or H; and the pharmaceutical salts thereof, useful as antiviral agents.

In addition, in the United States Patent No. 5,453,533 some benzene derivatives are suggested to be inhibitors of influenza virus neuraminidase and several others are described in the US Pat. serial number 08 / 413,886. Yamamoto et al. describe various sialic acid isomers for having neuraminidase inhibitory activity in Synthesis of Sialic Acid isomers With Inhibitory Activity Against Neuraminidase, TETRAHEDRON LETTERS, Vol. 33, No. 39, p. 5791-5794, 1992.

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

However, none of these references describe the cyclopentane derivatives of the present invention.

Compendium of the Invention One aspect of the present invention is directed to compounds represented by the formula: where X is CH2, O or S; R? is H, OH, H2, or OR11; Rg is C02H, S03H, P03H2, N02, the esters thereof, or the salts thereof; 0 S 0 0 II II II »R2 is H, NHCR5, NHCR5, NHS02R5, CNHR5, S02NHR5, CH2SR, 5 'each of R3 and R8 is individually H, (CH2) nC02R10, (CH2) mOR10, CON (R1Q) m, (CH2) nN (R1 £)) m, CH (R10) a / (CH2) n (R10) m, CH2CH (0R10) CH20R10, CH (0R1 ()) CH (0R10) CH20R10, CH20R10, CH (OR1Q) CH2NHR10, CH2CH (OR1Q) CH2NHR10, CH (OR10) CH (OR10) CH2NHR10, or NR1QC (= NR10) N ( R10) a; provided that at least one of R2, R3 and R8 is different from H; R4 is H, (CH2) n0H, (CH2) nNH2, (CH2) nC (= NH) NH2, (CH2) nNHC (= NR7) NH2, < CH2) nCN or (CH2) nN3; R5 is H, lower alkyl, branched chain alkyl, cyclic alkyl or CF3; R7 is H, OH, CN, NH2 or N02; each R10 individually is H, lower alkyl, lower alkylene, branched alkyl, cyclic alkyl, substituted cyclic alkyl, aromatic (CH2) n, substituted aromatic (CH2) n, and when m is 2 both R10 groups may also be interconnected to form a heterocyclic ring with N; R1] L is lower alkyl, branched alkyl, or aromatic (CH2) m; m is 1 or 2; and n is 0-4; and additionally provided that when X is O or S,. and R. is different from CH (OR10) CH (OR10) CH2OR10; and the pharmaceutically acceptable salts thereof.

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

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

Yet another aspect of the present invention with the treatment of influenza virus infection comprising administering to a patient in need thereof a compound as defined above in an amount effective to inhibit influenza virus neuraminidase.

The present invention also has to do with methods for producing the compounds defined above.

Better and Different Ways to Carry Out the Invention One aspect of the present invention is directed to compounds represented by the formula: where X is CH2, 0 or S; R? is H, OH, NH2, or OR11; R9 is C02H, S03H, P03H2, N02, the esters thereof, or the salts thereof; O S 0 O R2 is H, NHCR I5, NHCIR5, NHS02R5, C IINHRg, S02NHR5, C IIH2SR5, OR II CH, SR- .; or each of R3 and R8 is individually H, (CH2) nC02R10, (H2) mOR10. CON (R10) m, (CH2) aN (R10) m CH < R10) m, (CH2) n (R10) m, CH2CH (OR1 (J) CH2OR10, CH (OR10) CH (OR1Q) CH2OR1Q, CH2OR10, CH (0R10) CH2NHR10, CH2CH (OR1Q) CH2NHOR1Q, CH (OR10) CH (OR10) CH2NHR10, or NR1 £) C (= NR10 ) N (R10) m; provided that at least one of R2, R3 and Rg is different from H; R4 is H, (CH2) nOH, (CH2) nNH2, (CH2) nC (= NH) NH2, (CH2) nNHC (= NR7) NH2, (CH2) nCN or (CH2) nN3; R5 is H, lower alkyl, branched chain alkyl, cyclic alkyl or CF3; R7 is H, OH, CN, NH2 O N02; each R10 individually is H, lower alkyl, lower alkylene, aromatic (CH2) n, branched alkyl, cyclic alkyl, substituted cyclic alkyl, substituted (CH2 ^ n aromatic, and when it is 2 both R10 groups may also be interconnected to form a ring heterocyclic with N; Rj ^ is lower alkyl, branched alkyl, or aromatic (CH2) m, m is 1 or 2, and n is 0-4, and further provided that when X is O or S, R3 and R- is different from CH (OR10) CH (OR1Q) CH2OR10; and the pharmaceutically acceptable salts thereof.

About R10 when m = 2, each R10 can be the same or different.

The lower alkyl groups contain from 1 to about 8 carbons, and preferably from 1 to about 3 carbon atoms, and can be straight chain, branched or cyclic saturated aliphatic hydrocarbon groups.

Examples of suitable alkyl groups include methyl, ethyl and propyl. Examples of the branched alkyl groups include isdpropyl and t-butyl. Examples of suitable cyclic aliphatic groups typically contain from 3 to 8 carbon atoms and include cyclopentyl and cyclohexyl. The aromatic or aryl groups are preferably phenyl or alkyl (aralkyl) substituted aromatic groups such as phenyl (C 1 -C 3) alkyl, for example benzyl.

Examples of substituted cycloalkyl groups include cyclic aliphatic groups typically containing from 3 to 8 ring carbon atoms substituted with alkyl groups typically having 1 to 6 carbon atoms and / or hydroxy groups. Usually 1 or 2 substituted groups are present.

The lower alkylene group can be a straight chain, branched or cyclic unsaturated hydrocarbon group and contains from 2 to 8 carbon atoms and preferably 2-3 carbon atoms. Examples of the alkylene groups are vinyl, 1-propenyl, allyl, isopropenyl, 2-methyl-2-propenyl and cyclopentenyl.

Heterocyclic rings with N contain 3 to 7 atoms in the ring. The heterocyclic rings can be substituted, for example, with a lower alkyl group. Examples of suitable heterocyclic groups are pyrrolidino, azetidino, piperidino, 3,4-dideshydropiperidino, 2-methylpiperidino and 2-ethylpiperidino.

The 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, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicyclic, succinic, p-toluene sulfonic, tartaric, acetic, citric, methanesulfonic, formic acids. , benzoic, malonic, naphthalene-2-sulfonic, trifluoroacetic and benzenesulfonic.

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

Examples of the specific compounds within the scope of the present invention are: cis-3- [(methylcarbonylamino) methyl] cyclopentane-carboxylic acid; 3-amino-c-4- (methylcarbonylamino) methyl-r-cyclopentanecarboxylic acid; trans-3- acid. { [(amino) (imino) methyl] amino} -c-4- [(methylcarbonylamino) methyl] cyclopentane-r-carboxylic acid; 4 (3. {[[(amino) (imino) methyl] amino} -3a- [(2-hydroxy-l-methylcarbonyl-amino) ethyl] -l-cyclopentanecarboxylic acid; 3ß-. { [(amino) (imino) methyl] amino} -4a- [(2-hydroxy) (1-methylcarbonylamino) ethyl] cyclopentane-sodium carboxylate; trans-3-amino-trans-l-hydroxy-cis-4 [(hydroxymethyl) (methylcarbonylamino) methyl] cyclopentane-r-carboxylic acid; trans-3- acid. { [(amino) (imino) methyl] amino} -trans-l-hydroxy-cis-4- [(2-hydroxymethyl) (1-methylcarbonylamino) -ethyl] cyclopentane-r-carboxylic acid; 3β-amino-4α- [(1-methylcarbonylamino) (2, 3, 4-trihydroxy) butyl] cyclopentanecarboxylic acid; 3ß- acid. { [(amino) (imino) methyl] amino} -4 a - [(1-methyl-carbonylamino) (2,3,4-trihydroxy) butyl] cyclopentanecarboxylic acid; cis-3- acid. { [(amino) (imino) methyl] amino} -trans-l-hydroxy-trans-4- [(1-methylcarbonylamino) (2-trifluoroethyl-carbonyloxy) ethyl] cyclopentane-r-carboxylic acid; t-3-amino-c-4- [(1-methylcarbonylamino) (2-phenylmethoxy) -ethyl] -t-l-hydroxycyclopentane-r-carboxylic acid; c-3- acid. { [(amino (imino) methyl] amino]} - tl-hydroxy-t-4. (. (methylcarbonylamino) - {[[(methyl) - (methoxy) amino] carbonyl] .methyl] cyclopentane -r-carboxylic acid; 3ß- acid. { [(amino) (imino) methyl] amino} -4 -. { . { 4- [(methoxy) - (ethyl) amino] -1- (methylcarbonylamino-2-oxo.) Butyl.} - cyclopentanecarboxylic; t-3- acid. { [(amino) (imino) methyl] amino} -c-4- [(diethylamino-carbonyl) (methylcarbonylamino) methyl] -t-l-hydroxycyclo-pentane-r-carboxylic acid; t-3-amino-c-4- [(di-n-propylaminocarbonyl) (methylcarbonylamino) methyl] -t-1-hydroxy-cyclopentane-r-carboxylic acid; • 5 t-3- acid. { [(amino) (imino) methyl] amino} -c-4- [di-n-propylaminocarbonyl) (methylcarbonylamino) methyl] -t-hydroxycyclopentane-r-carboxylic acid; c-3- acid. { [(amino) (imino) methyl] amino} -c-4- [di-n-propyl-10-aminocarbonyl) (methylcarbonylamino) methyl] -t-1-hydroxy-cyclopentane-r-carboxylic acid; 3ß- acid. { [(amino) (imino) methyl] amino} -4a- [di-n-propylaminocarbonyl) (methylcarbonylamino) -methyl] cyclopentane-carboxylic acid; 3ß- acid. { [(amino) (imino) ethyl] amino} -4 - [(methylcarbonylamino) (3-pentylaminocarbonyl) methyl] cyclopentanecarboxylic; 3ß- acid. { [(Amino) (imino) methyl] amino} -4 - [(diethylaminocarbonyl) (methylcarbonylamino) methyl] cyclopentanecarboxylic; 3ß-acid. { [(Amino) (imino) methyl] amino} -4a- { [(ethyl) (propyl) - ^ P aminocarbonyl] (methylcarbonylamino) methyl} cyclopentane-carboxylic acid; 3ß-acid. { [(Amino) (imino) methyl] amino} -4a- { [(ethyl) (propyl) -aminocarbonyl] (methylcarbonylamino) methyl} cyclopentanecarboxylic; 30 3ß acid. { [(Amino) (imino) methyl] amino} -4 - [1- (1-methyl-carbonylamino) pent-2-enyl] -cyclopentanecarboxylic acid; 3ß- acid. { [(Amino) (imino) methyl] amino} -4- [1- (1-methyl-35-carbonylamino) pentyl] -cyclopentanecarboxylic acid.

In addition, an exemplary key intermediate, methyl 3-t-butoxycarbonylamino-4-formylcyclopentanecarboxylate 6 (Scheme 4), can be synthesized from methyl 3-hydroxy-4-hydroxymethylcyclopentanecarboxylate 1. (synthesis given in the accompanying pages ). The primary hydroxyl of 1 can be protected with the group TBDMS (t-butyldimethylsilyl); the secondary hydroxyl groups after the reaction of Mitsunobu (Ph3P, DEAD (diethyl azodicarboxylate), NH3) can give the azide 3_; the azide 3 is reduced (H2, Pd / C in the presence of ((t-boc) 20) to give the protected amine 4. The primary hydroxyl can be deprotected and upon oxidation it can give the aldehyde 6. key intermediate.

As shown in Scheme 5, aldehyde 6 can be further coupled with an appropriate allyl or vinyltributyltin compound to introduce the radical for the glycol or glycerol side chain. The scheme has been made with vinyltributyltin. The t-boc group of the compound can be removed (trifluoroacetic acid) to an amine 8 and the amine can be reacted with bis-boc (-0C (= 0) C (CH 3) 3) thiourea to give the protected guanidine 9. The hydroxyl of 9. after the Mitsunobu reaction can give the azide .10; the azide may be reduced to the amine JL, and further acylated with an appropriate alkyl or alkylsulfonyl chloride to give the desired 12. The double bond of an allyl or vinyl group of the side chain in the dihydroxylation catalyzed by osmium could give compound 13., which after additional deprotections could produce the desired objective 14.

After the deprotection step of compound 13, the primary hydroxyl can be converted to a tosyl group (4-CH3 phenyl S02), the conversion of a tosyl group to an azide and the azide to an amine gives the compounds where R3 = CH (OH) CH2NH2, CH (OH) CH (OH) CH2NH2, O CH2CH (OH) CH2NH2.

The synthesis route for preparing the compounds, when R7 is OH, CN, NH2 or N02 is shown in Scheme 6. The amine 8. after the reaction with cyanogen bromide could give the cyanamine JL5; the side chain can be manipulated in the same way as shown in Scheme 5 to give 16; the additional reaction of cyanamine JL6. with hydroxylamine hydrochloride, hydrazine or cyanamide could give the appropriate, which when unprotected can produce the objective.

The reaction of 8. with 2-methyl-l-nitro-2-thio- S | pseudourea leads to 18 (R7 = N02). When R2 is NH-CR6, the compounds of type 12. when reacting with P2S6 or La sson reagent (2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphoethane-2, 4- disulfide) could give the compound .19., which in additional reactions can be converted into the desired objectives.

Other methods to prepare the equivalent of the key intermediate are presented in Schemes 8 and 9. Intermediate 25. can be prepared by two different procedures: i) Scheme 8: Reaction of diethyl malonate with sodium hydride and then cis-1,4-dichloro-2-butene gives 1,1-dimethyl-3-cyclopentene dicarboxylate, which is saponified, decarboxylated and esterified to give the benzylic ester of 3-cyclopentene 22 .. Compound 22. after the reaction with PhI = NTS gives the aziridine 23 .. The aziridine can be opened with bisphenylthiomethane and n-butyl lithium to give 24., and 24. after the reaction with copper oxide and copper chloride could produce 25 .. The compound 25 can be used in Scheme 5 and worked up in the same way as 5 to give the desired objectives. ii) Scheme 9: The cyclopentene ester 22. after a hydroxylation reaction with chloramine-T in the presence of 0s04 gives .26; the isomers are separated. The desired isomer after the reaction with 4-nitrobenzenesulfonyl chloride gives 22, and the ONS group can be displaced with bisphenylthiomethane to give 24. Conversion to 25 occurs as described above.

Scheme 4 aMe R is benzyl, lower alkyl, acetyl, benzylcarbonyl, or lower alkylcarbonyl.

Scheme 5 When R3 = CH (OH) CH2OH 11 Scheme 5 CONT. lower alkyl. 13 R is C (= 0) R5 or S02R5 Scheme 6 When R7 is OH, CN, NH2, or N02 16 1S R is lower alkyl, lower alkylcarbonyl, lower alkylsulfonyl.

Scheme 7 12 19 R ßs lower alkyl.

Scheme 8 HCCHaCl / »**« aH_ fX 8 ~ C ^ H HCCHaCl NC0jMe ^ - 20 21 23 22 T3 ts 24 25 Bn is benzyl. Ts is p-toluenesulfonyl.

Scheme 9 aBn 26 27 Ts 24 It is benzyl. is p-toluenesulfonyl. is 4-nitrophenylsulfonyl, Scheme 10 is H or lower alkyl, The following Scheme 11 illustrates a process for preparing the compounds of Examples 6, 7, 20, 26, 27, 28, and 29 represented by the formula: Example 6 R = guanidine; R '= CH2OH isomer A in C-6 7 R = guanidine; R '= CH2OH isomer B at C-6 0 || OMe 20 R = guanidine; R '= C - CH2CH2N Me 26 R = guanidine; R '= C - N (Et) 2 O II 27 R = guanidine; R '= C - (Pr) 2 0 | 28 R = guanidine; R '= C-N-CH (Et) 2; isomer A H OR II 29 R = guan? D? Na; R '= C-N-CH (Et) 2; isomer B H Scheme 11 The following Scheme 12A or Scheme 12B illustrates a process for preparing the compounds of Examples 16, 17, 19, 24, and 25 represented by the formula: Example OR II 16 R = guanidine; R '= CH20CCF3 or II 17 R = guanidine; R '= CH2OCCF3 O OMe 19 R = guanidine; R '= CN Me OR II 24 R = guanidine; R '= CN (Pr) 2 or 25 R = guanidine; R '= CN (Pr) 2 Scheme 12A 4 The product according to Examples 19, 24 and 25 depends on R? and R2 and the isomeric precursor.

Scheme 12B The product of Examples 16 and 17 depends on the isomer of the precursor.

F - compounds of Examples 6 and 7 F - Iz compounds Examples 26, 27, 28 and 29 F - the compound of Example 20 this of the 20 The following Scheme 13 illustrates a process for preparing the compounds of Examples 8, 9, 21, 22 and 23 represented by the following formula: Example 8 R = NH2, R '= CH20H 9 R = guanidine; R '= CH20H 18 R = NH2, R' = CH2OCH2C6H5 O II 21 R = guanidine; R '= CN (C2H5) 2 O II 22 R = NH2, R '= CN (C3H7) 2 O II 23 R = guanidine, R '= CN (C3H7) 2 Scheme 13 BOC BCC Scheme 13 (cont.) Scheme 13 /cont.l • Scheme 13 (cont.) Example 21 Scheme 13 (cont ..

Example 23 Scheme 13 (cont.) Example 22 (C3H7) 2 The following Scheme 14 illustrates a process for preparing the compounds of Examples 10, 11, 12, 13, 14 and 15 represented by the formula: Scheme 14 Examples 10 or 11) NHBoc, T? A, HgCl you Scheme 15 Scheme 15 illustrates a process for preparing compounds in which X is 0 or S.

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

Example 1 Cis-3- [(methylcarbonylamino) methyl "| cyclopentanecarboxylic acid To a mixture of cis-3- (methoxycarbonyl) -cyclopentanecarboxylic acid [prepared according to the procedure described by Tucjan J.J. Horonowsky and Walter A. Szorek. Can. J. Chem. 66 61-70 (1988); 17.2 g, 0.1 mmol] and triethylamine (10.1 g, 0.1 mmol) in tetrahydrofuran (300 mL) was added ethyl chloroformate (10.9 g, 0.1 mmol) at about -5 °. C over a period of approximately 30 min. The mixture was further stirred for about 15 min at about -5 ° C. The resulting slurry was filtered and the solids were washed with tetrahydrofuran. The combined filtrates were cooled to about 10 ° C and a solution of sodium borohydride (14.5 g, 0.38 mol) was added with stirring in one portion. The mixture was further stirred for about 10 min. and methanol (62 ml) was added dropwise over a period of 1 hour at about 10 ° C. After the addition of methanol was complete, 6 N hydrochloric acid was added slowly until neutralization. The organic layer was collected and the aqueous layer was extracted twice with ether. The combined organic extracts were dried, filtered and concentrated. The residue was dissolved in ether (about 300 ml), and a white solid precipitated which was removed by filtration. The filtrate was concentrated and the residue was passed through a column of silica gel using methanol in chloroform at about 2%. The appropriate fractions were combined and concentrated to give 12.5 g (79%) of methyl cis-3-hydroxymethylcyclopentanecarboxylate.

To a mixture of methyl cis-3-hydroxymethylcyclopentanecarboxylate (4.74 g, 30 mmol) in dry benzene (approximately 250 ml) was added trnylphosphine (7.86 g, 30 mmol), diethyl azodicarboxylate (5.22 g). g, 30 mmol) and hydrazolic acid (2.5 M in toluene, 14.0 mL, 35 mmol). The mixture was stirred at room temperature for approximately 16 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. A precipitate formed upon standing for about 2 hours and was removed by filtration. The filtrate was concentrated and the residue was passed through a column of silica gel using chloroform as eluent. The appropriate fractions were combined and concentrated to give 2.6 g (47%) of methyl cis-3-azidomethyl-cyclopentanecarboxylate.

A mixture of methyl cis-3-azidomethylcyclopentane carboxylate (1.2 g, 6.5 mmol) and 1 N sodium hydroxide (12.0 ml, 12 mmol) was stirred at room temperature for about 8 hours. The alkaline mixture was extracted with chloroform. The aqueous layer was acidified with hydrochloric acid and extracted twice with chloroform. The combined chloroform extracts of the acid mixture were dried over sodium sulfate, filtered and concentrated to give approximately 1.0 g (91%) of cis-3-azidomethylcyclopentanecarboxylic acid.

Analysis: Calculated for C7H1, LN302: C, 49.70; H, 6.55; N, 24.84 Found: C, 49.92; H, 6.49; N, 24.58 A mixture of cis-3-azidomethylcyclopentanecarboxylic acid (0.9 g, 5.3 mmol) in methanol (approximately 30 ml) was hydrogenated at about 50 psi and at room temperature in the presence of 10% Pd on carbon (approx. 40 mg) for approximately 1 hour. The catalyst was removed by filtration and the filtrate was concentrated to a syrup. After dissolving the syrup in dimethylformamide and dichloromethane for acetylation (next step), a little white precipitate formed. The precipitate was collected by filtration, washed with dichloromethane and dried to give cis-3-aminomethylcyclopentanecarboxylic acid as a white powder, mp. 186-188 ° C. The yield of the syrup was 0.7 g (100%). The white solid obtained was approximately 0.35 g. The rest of the substance of the mixture of dimethylformamide and dichloromethane was not recovered, but was used for the acetylation step.

Analysis: Calculated for C7H13N02 • 0, 1H20: C, 57.99; H, 9.18; N, 9.66 Found: C, 57.70; H, 9.01; N, 9.50 To a mixture of cis-3-aminomethylcyclopentanecarboxylic acid (0.2 g, 1.4 mmol) in pyridine (ca. 5 ml) was added acetic anhydride (approximately 1 ml) and the mixture was stirred at approximately 70 ° C for approximately 2 hours. The solvent was removed under reduced pressure, water was added several times and evaporated in vacuo. A viscous, clear oil was obtained and dried in vacuo under reflux of acetone to give 0.25 g (97%) of cis-3- [(methylcarbonylamino) methyl] cyclopentanecarboxylic acid.

Analysis: Calculated for C9H15N03: C, 58.36; H, 8.16; N, 7.56 Found: C, 58.90; H, 7.94; N, 6.90 Example 2 t-3-amino-c-4- (methylcarbonylamino ^ methyl-r-cyclopentanecarbonyl: trifluoroacetic acid [1: 1] (To a mixture of c-2-acetyloxy-c-4-methoxy-15-carbonyl-r-cyclopentanecarboxylic acid [prepared according to the procedure described by Tucjan JJ Horonowsky and Walter A. Szorek, Can. J. Chem. 63 2787- 2797 (1985); 23.4 g, 101.64 mmol] in tetrahydrofuran (approximately 250 ml) and triethylamine (approximately 14.96 ml, 106.7 mmol), Ethyl chloroformate (approximately 10.2 ml, 106.7 mmol) was added over a period of about 5 min. at about 0 ° C. After stirring for 30 ^^ additional minutes at the same temperature, the mixture will ^^ filtered with suction, and the cake was washed with tetrahydrofuran (3 x 10 mi).

Sodium borohydride (15.7 g, 406.56 mmol) was added to the filtrate in one portion. Then methanol (approximately 64 ml) was added dropwise as Over a period of about one hour at about 10 ° C. After stirring for an additional 30 minutes the reaction mixture was quenched carefully with 1 N HCl to pH 7. The solvent was removed in vacuo to obtain a white solid. The solid dissolved in Water (approximately 50 ml) and HCl (1 N) was added to adjust the pH to approximately 6. The solution was homogeneous. The solution was extracted with ethyl acetate (4 x 150 mL). The organic layers were combined and washed with brine (approximately 150 ml) and dried with sodium sulfate. The solvent was removed in vacuo to give a white solid. The white solid was dissolved in ether (approximately 200 ml) and filtered to remove insoluble impurities. The filtrate was concentrated in vacuo to provide 21.5 g (97%) of a mixture of methyl c-4-hydroxycyclopentanecarboxylate, methyl c-3-methylcarbonyloxy-c-4-hydroxymethylcyclopentane-r-carboxylate and c-3 -hydroxy-c-4-hydroxymethyl-cyclopentane-methyl-r-carboxylate.

The above mixture was dissolved in methanol (approximately 200 ml) and a solution of sodium methoxide (approximately 7 ml, 25% by weight in methanol) was added dropwise at room temperature. The reaction mixture was stirred for approximately 90 min. and the solvent was removed in vacuo. The white residue was purified by flash column chromatography. { 20-40% [chloroform / methanol / ammonium hydroxide conc. (80: 18: 2)] in dichloromethane} to provide 13.2 g (76%) of pure methyl c-3-hydroxy-c-4-hydroxymethylcyclopentane-r-carboxylate in the form of a white solid.

To methyl c-3-hydroxy-c-4-hydroxymethylcyclopentane-r-carboxylate (13.2 g, 76.3 mmol), triphenylphosphine (44.5 g, 167.86 mmol) and diethyl azodicarboxylate (27.82) mi, 167.86 mmol) in anhydrous benzene (ca. 800 ml) was added dropwise with stirring under nitrogen at room temperature hydrazoic acid (1 M solution in toluene, 190.75 ml, 190.75 mmol) throughout of a period of approximately 30 min. The reaction mixture was stirred overnight at room temperature and concentrated in vacuo to half the original volume. The solid obtained on standing was removed by filtration and the filtrate was concentrated in vacuo to provide an orange residue. The residue was crystallized from ethyl acetate / hexane to remove triphenylphosphine oxide and 1,2, -ethoxycarbonyl hydrazine. The filtrate was concentrated in vacuo and purified by flash column chromatography (5-25% ethyl acetate in hexane) to provide 8.8 g (52%) of t-3-azido-c-4-azidomethylcyclopentane- methyl r-carboxylate.

To methyl t-3-azido-c-4-azidomethylcyclopentane-r-carboxylate (approximately 8.4 g, 37.5 mmol) was added 1 N sodium hydroxide (112.5 ml, 112.5 mmol) and stirred overnight at room temperature. The reaction mixture was extracted with chloroform (3 x 20 mL). The aqueous layer was acidified to pH 4 using conc. HCl. and extracted with chloroform (4 x 25 ml). The organic layers were combined, dried with magnesium sulfate, filtered through a pad of silica and concentrated in vacuo to obtain 7.58 g (96%) of t-3-azido-c-4-azidomethyl acid. -c-cyclopentane-r-carboxylic acid in the form of a colorless oil.

Analysis: Calculated for C7H10N6O2: C, 40.00; H, 4.80; N, 39.98 Found: C, 40.24; H, 4.88; N, 39.73 To a solution of t-3-azido-c-4-azidomethyl-c-cislopentane-r-carboxylic acid (1.05 g, 5.0 mmol), dicyclohexylcarbodiimide (2.5 g, 12 mmol) and 4-dimethyl -aminopyridine (60 g, 0.5 mmol) in dichloromethane (approximately 25 ml), was added dropwise over a period of about 15 rain, at room temperature t-butanol (0.97 ml, 10 ml). 0 mmol). After stirring at room temperature overnight, the mixture was filtered with suction and the cake was washed with ether (3 x 5 mi). The filtrate was concentrated in vacuo and ether (approximately 25 ml) was added to the residue. The organic layer was washed with cold HCl (1%, 20 mL), saturated sodium bicarbonate (2 x 20 mL), water (20 mL), dried over magnesium sulfate, filtered and the solvent removed under vacuum obtain 2.92 g of an oil. Purification of the crude product by flash column chromatography (ether in 2-5% hexane) provided 0.39 g (29%) of t-3-azido-c-4-azidomethyl-rlt-butoxycarbonyl-cyclopentane as a a colorless oil.

Analysis: Calculated for C1; LH? AN602: C, 49.61; H, 6.81; N, 31.56 Found: C, 49.83; H, 6.76; N, 31.38 To a solution of t-3-azido-c-4-azidomethyl-rlt-butoxycarbonylcyclopentane (0.33 g, 1.22 mmol) in methanol (ca. 10 mL) was added in Pd / C nitrogen (0.1 g, Palladium content of 10%) and the resulting mixture was hydrogenated at approximately 50 psi for approximately 20 min. The hydrogen was evacuated, and upon addition of fresh hydrogen, the resulting mixture was hydrogenated at about 50 psi for about 40 min. The catalyst was removed by filtration through Celite. The filtrate was concentrated in vacuo to give approximately 0.25 g (97%) of t-3-amino-c-4-aminomethyl-r-l-t-butoxycarbonyl-cyclopentane.

To a solution of t-3-amino-c-4-aminomethyl-rlt-butoxycarbonylcyclopentane (0.25 g, 1.22 mmol), in dichloromethane (ca. 10 ml), cooled to 0 ° C is added dropwise with agitation over a period of approximately 5 min. acetic anhydride (0.098 ml, 1.04 mmol). After stirring at 0 ° C for about one hour, the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo to obtain a white solid. The crude product is purified by flash column chromatography. { 30-100% [chloroform / methanol / ammonium hydroxide conc. (80: 18: 2)] in dichloromethane} and provides: 1. t-3-methylcarbonylamino-c-4- (methylcarbonylamino) -methyl-r-t-butoxycarbonyl-cyclopentane, 0.04 g (11%) as a white solid, mp. 170-172 ° C.

Analysis: Calculated for C15H26N204-0.25H20: C, 59.48; H, 8.82; N, 9.25 Found: C, 59.59; H, 8.82; N, 9.17 2. t-3-amino-c-4- (methylcarbonylamino) -methyl-r-l-t-butoxycarbonylcyclopentane, 0.12 g (39%) as a white solid, mp. 86-87 ° C.

Analysis: Calculated for c13H24N203: C, 60.91; H, 9.44; N, 10.93 Found: C, 60.69; H, 9.40; N, 10.87 3. t-3-amino-c-4-aminomethyl-r-l-t-butoxycarbonyl-cyclopentane, 0.05 g (20%) as a colorless oil. The oil was dissolved in dichloromethane (2 mL) and acetic acid (3 equi) was added. The resulting solution was stirred for 15 minutes and the solid obtained was filtered to obtain the product in the form of acetate, mp. 124-127 ° C Analysis: Calculated for C11H22N202 -2C2H402 -0.25H2O: C, 53.16; H, 9.07; N, 8.27 Found: C, 53.34; H, 8.81; N, 8.46 To a solution of t-3-amino-c-4- (methylcarbonylamino) -methyl-rlt-butoxycarbonyl-cyclopentane, (0.09 g, 0.32 mmol) in dichloromethane (approximately 3 mL) was added dropwise acid trifluoroacetic (ca. 0.67 mL, 8.8 mmol) and stirred at room temperature for about 2 h. The solvent was removed in vacuo and the excess trifluoroacetic acid was removed by co-distillation three times in vacuo with dichloromethane (ca. 5 ml) to obtain 0.1 g (99%) of t-3-amino-c-4 acid. - [(Methylcarbonylamino) methyl] -cyclopentane-r-carboxylic acid trifluoroacetic acid in the form of a hygroscopic, tan-colored solid.

Analysis: Calculated for C9H16N203 -CF3C02H: C, 42.04; H, 5.45; N, 8.90 Found: C, 41.75; H, 5.58; N, 8.59 Example 3 Acid t-3-. { [(amino) (imino ^ methyl] amino.}. -c-4- (methylcarbonylamino) ethyl] -cyclopentane-r-carboxylic acid: trifluoroacetic acid [1: 1.25] To a stirred solution of t-3-azido-c-4-azidomethylcyclopentane-r-carboxylic acid from Example 2 (approximately 4.0 g, 19.05 mmol) in dichloromethane (approximately 40 mL) was added liquefied isobutylene (approximately 20 ml), followed by dropwise addition of phosphoric acid (prepared by saturating 2.5 ml of 85% H3P04 with P205) in dichloromethane (2.5 ml) and boron trifluoride etherate (0.9 ml). After stirring the mixture at about -78 ° C for about 2 h at room temperature overnight, water with ice and saturated aqueous NaHCO 3 was added until the mixture became alkaline. The aqueous layer was extracted with dichloromethane (2 x 20 mL). The organic layers were combined, washed with water (20 ml) and brine (20 ml), dried over anhydrous MgSO 4, and concentrated in vacuo to provide 1.7 g of a colorless oil. Purification of the crude product by flash column chromatography (ether in 5-10% hexane) yielded 1.2 g (24%) of t-3-azido-c-4-azidomethyl-r-l-t-butoxycarbonylcyclopentane.

To a solution of t-3-azido-c-4-azidomethyl-rl-t-butoxycarbonylcyclopentane (1.22 g, 4.6 mmol) in methanol (20 mL) was added in Pd / C nitrogen (0.1 g). , palladium content of 10%) and the resulting mixture was hydrogenated at approximately 50 psi for approximately 30 min. The hydrogen was evacuated, and upon addition of fresh hydrogen, the resulting mixture was hydrogenated at about 50 psi for about 30 min. The catalyst was removed by filtration through Celite. The filtrate was concentrated in vacuo to give approximately 0.94 g (96%) of t-3-amino-c-4-aminomethyl-r-l-t-butoxycarbonylcyclopentane.

To a solution of t-3-amino-c-4-aminomethyl-rl-t-butoxycarbonylcyclopentane (0.63 g, 2.95 mmol), in dichloromethane (30 mL), cooled to about -5 ° C anhydride was added acetic acid (0.25 ml, 2.65 mmol) dropwise with stirring over a period of about 5 min. After stirring at 0 ° C for about one hour the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo to obtain a white solid. Purification of the crude product by flash column chromatography. { 30-100% [chloroform / methanol / ammonium hydroxide conc. (80: 18: 2)] in dichloromethane} yield 0.33 g (44%) of t-3-amino-r-l-t-butoxycarbonyl-c-4- (methylcarbonylamino) methylcyclopentane.

To t-3-amino-rlt-butoxycarbonyl-c-4- (methyl-carbonylamino) methylcyclopentane (0.33 g, 1.29 mmol) in dimethylformamide (approximately 5 mL) is added triethylamine (0.63 mL, 4%). 52 mmole) and bis-boctiourea (0.4 g, 1.42 mmol). The resulting mixture was cooled to 0 ° C and mercuric chloride (0.39 g, 1.42 mmol) was added. The resulting mixture was cooled to 0 ° C for about 30 minutes and then at room temperature overnight. Ethyl acetate (approximately 50 ml) was added and the suspension was filtered through Celite. The filtrate was washed with water (2 x 20 ml) and brine (20 ml), the organic layer was dried (MgSO 4), filtered, and the solvent was removed in vacuo to give about 0.7 g of crude product. The crude product was purified by flash column chromatography (30-50% ethyl acetate in hexane) and recrystallized from ether / hexane to obtain 0.51 g (79%) of a colorless oil. The oil was crystallized from petroleum ether to obtain t-3-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} - cis-l-t-butoxycarbonyl-c-4- [(methylcarbonylamino) -methyl] -cyclopentane as a white solid, mp. 145-146 ° C.

Analysis: Calculated for c24H42N407: C, 57, 81; H, 8, 49; N, 11, 24 Found: C, 57, 70; H, 8, 52; N, 10, 98 To a solution of t-3-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -cis-1-t-butoxycarbonyl-c-4- [(methylcarbonylamino) methyl] cyclopentane (0.44 g, 0.88 mmol) in dichloromethane (approximately 9 ml) is added dropwise trifluoroacetic acid (1.7 ml). , 22.1 mmol) and stirred at room temperature for about 1 hour. The solvent is removed in vacuo and the excess trifluoroacetic acid is removed by co-distillation three times in vacuo with dichloromethane (ca. 5 ml) to obtain a white solid. The white solid was triturated with ether and dried in vacuo under reflux of acetone to obtain 0.21 g (67%) of t-3- acid. { [(amino) (imino) methyl] amino} -c-4- [(Methylcarbonylamino) methyl] cyclopentane-r-carboxylic acid trifluoroacetic acid in the form of a hygroscopic solid.

Analysis: Calculated for CgH16N203 • 1.25CF3C02H: C, 39.30; H, 5.04; N, 14.56 Found: C, 39.21; H, 5.29; N, 14.26 Example 4 C-3-f [(amino) (imino) methyl] amino acid} methyl] cyclopentane-r-carboxylic acid To a mixture of c-3-aminomethylcyclopentane-carboxylic acid of Example 1 (0.07 g, 0.5 mmol) and potassium carbonate (0.07 g, 0.5 mmol) in water (approximately 1.5 ml) aminoiminomethanesulfonic acid (0.06 g, 0.5 mmol) was added and the mixture was stirred for about 18 hours at room temperature. A white solid was separated, which was collected by filtration, washed with a small amount of water and dried under vacuum to give 0.04 g (49%) of c-3 acid. { . { [(amino) (imino) methyl] amino} -metil } Cyclopentanecarbonyl in the form of a white powder, mp. 280 ° C (dark).

Example 5 Acid t-3-. { [(amino) (imino) methyl] amino} -c-4-. { [(amino) - (imino methyl] amino.}. methyl.}. cyclopentane-r-carboxylic: dihydrochloride: hydrate: 2-propanol (5: 10: 5: 2) To a stirred solution of the t-3-azido-c-4-azidomethylcyclopentane-r-carboxylic acid from Example 2 (approximately 4.0 g, 19.05 mmol) in dichloromethane (approximately 40 ml) was added liquefied isobutylene (approx. 20 ml), followed by the dropwise addition of phosphoric acid (prepared by saturating 2.5 ml of 85% H3P04 with P205) in dichloromethane (2.5 ml) and boron trifluoride etherate (0.9 ml). After stirring the mixture at about -78 ° C for about 2 h at room temperature overnight, water with ice and saturated aqueous NaHCO 3 was added until the mixture became alkaline. The aqueous layer was extracted with dichloromethane (2 x 20 mL). The organic layers were combined, washed with water (20 ml) and brine (20 ml), dried over anhydrous MgSO 4, and concentrated in vacuo to provide 1.7 g of a colorless oil. Purification of the crude product by flash column chromatography (ether in 5-10% hexane) yielded 1.2 g (24%) of t-3-azido-c-4-azidomethyl-r-l-t-butoxycarbonylcyclopentane.

To a solution of t-3-amino-c-4-aminomethyl-rt-butoxycarbonylcyclopentane (0.32 g, 1.5 mmol) in dimethylformamide (approximately 5 ml) was added triethylamine (1.5 ml, 10.5 mmol). ) and bis-boctiourea (0.91 g, 3.3 mmol). The resulting mixture was cooled to 0 ° C and mercuric chloride (0.9 g, 3.3 mmol) was added. The reaction mixture was stirred at 0 ° C for approximately 30 min. and then at room temperature overnight. Ethyl acetate (approximately 25 ml) was added and the suspension was filtered through Celite. The filtrate was washed with water (2 x 20 mL) and brine (20 mL), the organic layer was dried (MgSO4), filtered, and the solvent was removed in vacuo to give approximately 1.22 g of crude product. The crude product is purified by flash column chromatography (ether in 25-36% hexane) to provide 0.75 g (71%) of a colorless oil. The oil was crystallized from petroleum ether to obtain t-3 ~. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] -amino} -c-4-. { . { t-butoxycarbonylamino) (t-butoxycarbonylimino) -ethyl] amino} methyl } -r-t-butoxycarbonylcyclopentane as a white solid, mp. 152-154 ° C.

Analysis: Calculated for c33H58N6010: C, 56.72; H, 8.37; N, 12.03 Found: C, 56.96; H, 8.51; N, 12.06 A solution of t-3-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -c-4-. { . { t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} methyl } -r-t-butoxycarbonylcyclopentane (0.56 g, 0.88 mmol) in 5N hydrochloric acid (approximately 1 mL) was stirred at room temperature for approximately 2 h. The solvent was removed in vacuo to provide a hygroscopic residue. The residue was washed several times with ether and dried under vacuum at the reflux temperature of acetone to obtain 0.18 g (64%) of t-3- acid. { [(amino) (imino) methyl] -amino} -c-4-. { . { [(amino) (imino) methyl] amino} methyl } Cyclopentane-r-carboxylic acid: dihydrochloride: idrate: 2-propanol (5: 10: 5: 2) in the form of a hygroscopic solid.

Analysis: Calculated for C9H16N203 -2HC1 -H20 • 0.4C3H80: C, 34.29; H, 7.11; N, 23.52 Found: C, 34.38; H, 6.84; N, 23.94 F.W. 272.30 Acid 4ß-. { [(amino) (imino) methyl lamino} -3a-f (2-hydroxy-l-methylcarbonylamino) ethyl] -1-cyclopentanecarboxylic (isomer A in C-6) To a solution of sodium azide (2.12 g, 32.6 mmol) in dimethylformamide (15 ml) cooled to 0 ° C was added dropwise with stirring 4-bromocyclopent-2-enone (DePuy, CH; Isaks, M .; Eilers, KL; Morris, GFJ Org. Chem. 1964. 29, 3503; 3.5 g, 21.7 mmoles) in dimethylformamide (5 ml) over a period of 5 min. The reaction mixture was stirred at 0 ° C for 30 min. and was diluted with ethyl acetate (20 ml). The reaction mixture was washed with water (2 x 20 mL) and brine (20 mL), dried (MgSO4), filtered, and concentrated in vacuo to provide an oily residue. Purification by flash column chromatography (10-15% ethyl acetate in hexane) gave 1.9 g (71%) of 4-azidocyclopent-2-enone as a light yellow oil.

To a solution of diethyl acetamidomalonate (Aldrich, 1.25 g, 5.7 mmol) in ethanol (10 ml) under nitrogen was added freshly cut sodium metal (0.03 g, 1.4 mmol). The reaction mixture was stirred at room temperature until all sodium had dissolved. The reaction mixture was cooled to -40 ° C (dry ice / acetonitrile) and added dropwise over a period of 10 min. a solution of 4-azidopent-2-enone (0, 7 g, 5.7 mmol) in ethanol (5 ml). The reaction mixture was stirred at -40 ° C for 30 min. and quenched with trifluoroacetic acid (0.1 ml, 1.4 mmol). The solvent was removed in vacuo to give a white solid. Purification of the crude product by flash column chromatography (ether in 60% hexane) gave 1.2 g (63%) of trans-3-azido-4- [(methylcarbonylamino) bis (ethoxycarbonyl) methyl] cyclopentanone in shape of a white solid, mp. 121-122 ° C.

Analysis: Calculated for c14H20N406: C, 49.41; H, 5.92; N, 16.46 Found: C, 49.47; H, 5.95; N, 16.48 To a mixture of trans-3-azido-4- [bis (ethoxy-carbonyl) (methylcarbonylamino) methyl] cyclopentanone (8.2 g, 24.1 mmol) in methanol (100 mL) was added sodium borohydride (0, 46 g, 12.1 mmol) in portions over a period of 5 minutes at room temperature. The reaction mixture was further stirred for 10 minutes and then acetic acid (1 ml) was added and the mixture was concentrated. The residue was dissolved in ethyl acetate (100 ml) and washed with water (1 x 100 ml) and brine (1 x 100 ml) and dried (MgSO 4). After filtration, the filtrate was concentrated to give 8.2 g (100%) of 3β-azido-4a- [bis- (ethoxycarbonyl) (methylcarbonylamino) methyl] cyclopentanol, a mixture of isomers, in the form of an oil of light brown.

Analysis: Calculated for c? 4H22N406: C, 49, 12; H, 6, 46; N, 16, 37 Found: C, 49, 16; H, 6, 51; N, 16, 11 A mixture of 3β-azido-4a- [bis (ethoxycarbonyl) - (methylcarbonylamino) methyl] cyclopentanol, a mixture of isomers (8.0 g, 23.4 mmol), and sodium hydroxide (IN, 72.0 ml, 72.0 mmol) was stirred for 16 hours at room temperature. Acetic acid (glacial, 20 ml) was added and the mixture was heated to gentle reflux for 2 hours. The mixture was then extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL) and brine (1 x 100 mL) and dried (MgSO4). After filtration, the filtrate was concentrated and the residue was passed through a column of silica gel using ethyl acetate as eluent to give 4.0 g (63%) of 3β-azido-4a- [(ethoxycarbonyl) (methylcarbonylamino) -methyl] cyclopentanol, a mixture of isomers, in the form of a colorless syrup.

Analysis: Calculated for C1; lH18N404: C, 48.89; H, 6.71; N, 20.72 Found: C, 48.76; H, 6.72; N, 20.65 A mixture of the above alcohol, a mixture of isomers (3.8 g, 14.0 mmol), in ethyl acetate (120 ml) was hydrogenated in the presence of Pd / C (250 mg, Palladium content of 10%). at 40 psi and at room temperature for 16 h. The catalyst was removed by filtration and the filtrate was concentrated to give 2.8 g (82%) of 3β-amino-4 - [(ethoxycarbonyl) (methylcarbonylamino) methyl] -cyclopentanol as a syrup.

To a mixture of 3β-amino-4 - [(ethoxycarbonyl) - (methylcarbonylamino) methyl] cyclopentanol (2.8 g, 11.5 mmol) in dimethylformamide (25 ml) was added triethylamine (4.06 g, 40.02 g. mmoles). The mixture was cooled in an ice bath and bis-boctiourea (3.17 g, 11.5 mmol) was added, stirred for 10 minutes and mercury (II) chloride (3.12 g, 11.5 g) was added. mmoles). The reaction mixture was stirred at the temperature of an ice bath for 1 hour, diluted with ethyl acetate (100 ml), and filtered through Celite. The filtrate was washed with water (1 x 100 mL) and brine (1 x 100 mL) and dried (MgSO4). After filtration, the filtrate was concentrated and the residue was passed through a column of silica gel (100 g) using ethyl acetate as eluent to give 5.0 g (89%) of 3β-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4 - [(ethoxycarbonyl) (methylcarbonylamino) -methyl] cyclopentanol, a mixture of isomers, in the form of a white foam. An analytical sample was prepared by recrystallization from ethyl acetate / hexane.

Analysis: Calculated for C 22 H 36 N 408: C, 54.31; H, 7.87; N, 11.51 Found: C, 54.47; H, 7.95; N, 11.39 To a mixture of 3ß-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4a- [(ethoxycarbonyl) - (methylcarbonylamino) methyl] cyclopentanol (4.02 g, 8.27 mmol) in dichloromethane (75 ml) was added pyridinium chlorochromate (5.3 g, 24.8 mmol) and stirred at room temperature for 16 h. The mixture was diluted with ether, the reaction was filtered through Celite, and the filtrate was concentrated. The residue was passed through a column of silica gel (200 g) using ethyl acetate / hexane (1: 1) as eluent to give: 1. 0.62 g (15%) of isomer A, application of longer route in the CCF in ethyl acetate, in the form of a white powder, mp. 175 ° C. An analytical sample of 3β- was prepared. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4 - [(ethoxycarbonyl) (methylcarbonylamino) methyl] cyclopentanone, isomer A, by recrystallization from ethyl acetate / hexane.

Analysis: Calculated for C22H3g 408: C, 54.53; H, 7.49; N, 11.56 Found: C, 54.50; H, 7.44; N, 11.43 2. 0.1 g (2.5%) of isomer B, application of shorter route in the CCF in ethyl acetate, in the form of a white powder, mp. 139 ° C. An analytical sample of 3β- was prepared. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4 - [(ethoxycarbonyl) (methylcarbonylamino) methyl] cyclopentanone, isomer B, by recrystallization from ethyl acetate / hexane.

Analysis: Calculated for C 22 H 36 N 408: C, 54.53; H, 7.49; N, 11.56 Found: C, 53.94; H, 7.44; N, 11.26 To a mixture of 2-trimethylsilyl-1,3-dithiane (0.67 g, 3.5 mmol) in tetrahydrofuran (6 mL) at 0 ° C was added n-butyl lithium (1.6 M, 2.5 mL). , 3.7 mmol), and the mixture was stirred at 0 ° C for 0.75 h. After cooling the mixture to -42 ° C, a mixture of 4β- was added. { [(t-butoxycarbonyl-amino) (t-butoxycarbonylimino) methyl] amino} -4 - [(ethoxycarbonyl) (methylcarbonylamino) methyl] cyclopentanone, mixture of isomers (0.24 g, 0.5 mmol), in tetrahydrofuran (4 mL) and the mixture was further stirred at -42 ° C for 2 h. The mixture was then quenched with saturated aqueous ammonium chloride (2 mL) and warmed to room temperature. The organic layer was separated, water (5 ml) was added to the aqueous phase and extracted with ethyl acetate (2 x 15 ml). The combined organic layers were washed with water (1 x 20 mL), brine (1 x 20 mL) and dried (MgSO4). After filtration, the filtrate was concentrated and the residue was passed through a column of silica gel (50 g) using ethyl acetate / hexane (1: 2) as eluent to give: 1. 0.15 g (50%) of isomer A, longer application in the CCF in ethyl acetate / hexane (1: 2), in the form of a white powder, mp. 190-191 ° C. An analytical sample of 2- was prepared. { 3ß-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4 - [(ethoxycarbonyl) (methylcarbonylamino) methyl] cyclopentylidene} 1,3-dithiane, isomer A, by recrystallization from ethyl acetate / hexane.

Analysis: Calculated for C2gH42N407S2: C, 53.22; H, 7.21; N, 9.55 Found: C, 53.44; H, 7.27; N, 9.31 2. 0.06 g (20%) of isomer B, application of shorter route in the TLC in ethyl acetate / hexane (1: 2), in the form of a white powder, mp. 185-186 ° C. An analytical sample of 2- was prepared. { 3ß-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4 - [(ethoxycarbonyl) (methylcarbonylamino) methyl] cyclopentylidene} -1,3-dithiane, isomer B, by recrystallization from ethyl acetate / hexane.

Analysis: Calculated for C26H42N407S2: C, 53, 22; H, 7, 21; N, 9, 55 Found: C, 53, 19; H, 7, 20; N, 9, 52 To a solution of 2-. { 3ß-. { [(t-butoxycarbonylamino) - (t-butoxycarbonylimino) methyl] amino} -4a- [(ethoxycarbonyl) - (methylcarbonylamino) methyl] cyclopentylidene} -l, 3-dithiane, isomer A, (1.2 g, 2.0 mmoles), in tetrahydrofuran (40 ml) was added dropwise in nitrogen lithium borohydride (Aldrich, 2 M solution in tetrahydrofuran, 2.0 mi, 4.0 mmol) and 9-borabicyclo [3.3, 1] nonane-lithium hydride (Aldrich, 1 M solution in tetrahydrofuran, 0.2 ml, 0.2 mmol) and the reaction mixture was stirred at room temperature. the room temperature during the night. Three additional portions of lithium borohydride (2 M solution in tetrahydrofuran, 2.0 ml, 4.0 mmol) and 9-borabicyclo- [3, 3, 1] nonane-lithium hydride (1 M solution in tetrahydrofuran, were added. 0.2 ml, 0.2 mmol) over a period of 36 hours. The solution was quenched with 1 N sodium hydroxide (10 mL), brine (10 mL) and stirred for 5 min. The reaction was acidified to pH 4 using glacial acetic acid, ether (20 mL) was added and the aqueous layer was separated. The aqueous layer was extracted with ether (2 x 20 mL), the organic layers were combined, dried and concentrated in vacuo to obtain a crude product. The crude product was purified on a Chromatotron (50-100% ethyl acetate in hexane) to provide 0.34 g (31%) of 2-. { 3ß-. { [(t-butoxy- • carbonylamino) - (t-butoxycarbonylimino) methyl] amino} -4a- [(2-hydroxy) (1-methylcarbonylamino) ethyl] cyclopentylidene} -l, 3-dithiane, isomer A, recrystallized from ether in the form of a white solid, mp. 209-210 ° C.

Analysis: Calculated for C24H40N406S2: C, 52.92; H, 7.40; N, 10.29 Found: C, 53.03; H, 7.30; N, 10.19 To a solution of 2-. { 3ß-. { [(t-butoxycarbonylamino) - (t-butoxycarbonylimino) methyl] amino} -4a- [(2-hydroxy) (1- (methylcarbonylamino) ethyl] cyclopentylidene] -l, 3-dithiane, isomer A (0.23 g, 0.4 mmol), in methanol (6.7 ml) 6 N HCl (0.83 mL, 4.99 mmol) was added and the mixture was stirred at room temperature until all of the starting material disappeared (TLC analysis, ethyl acetate, ~ 3.0 h). under vacuum (water bath temperature ~ 40 ° C) to provide 3β- { [(amino) (imino) -methyl] amino.} -4- [(2-hydroxy) (1-methylcarbonylamino) ethyl] -l- [(3-mercaptopropyl) thiocarbonyl] cyclopentane. {MS (ES + 1) 363.5 [100%, (M + 1).}.

To the above crude product was added water (1.4 ml) and concentrated ammonium hydroxide (1.4 ml) and the reaction was stirred for 3 hours at room temperature. The solvent was removed in vacuo to give 0.6 g of the title compound mixed with salts, MS (ES + 1) 272.4 [100%, (M + 1)].

Example 7 3ß-. { [(amino) (imino) methyl] amino} -4 - [(2-hydroxy) - (1-methyl-carbonylamino) ethyl 1-cyclopentane-sodium carboxylate: diethyl ether: hydrate (12: 4: 3) isomer B To a solution of 2-. { 3ß-. { [(t-butoxycarbonylamino) - (t-butoxycarbonylimino) methyl] amino} -4 - [(ethoxycarbonyl) - (methylcarbonylamino) methyl] cyclopentylidene} -l, 3-dithiane Example 6, isomer A (6.74 g, 11.5 mmol), in ethanol (57.5 ml) and tetrahydrofuran (115 ml) was added 1N sodium hydroxide (23 ml, 23 mmol) ) and water (35 mi). The reaction was stirred at room temperature for 5 h. The tetrahydrofuran was removed in vacuo and the aqueous layer was washed with ethyl acetate (2 x 10 mL) and acidified to pH 5 with glacial acetic acid. The solid obtained was collected by filtration to provide 5.95 g (93%) of 2-. { 3ß-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4ct- [(carboxy) (methylcarbonylamino) methyl] -1-cyclopentylidene} -1,3-dithiane in the form of a white solid.

Analysis: Calculated for C24H38N407S2 -0.5C2H6O-lH2O: C, 50.07; H, 7.23; N, 9.34 Found: C, 50.28; H, 6.85; N, 9.04 To a solution of the above acid (1.12 g, 2.0 mmol) in tetrahydrofuran (20 ml) cooled to 0 ° C was added dropwise with stirring triethylamine (0.32 ml, 2.2 g. mmoles) and ethyl chloroformate (0.21 ml, 2.1 mmol). The reaction mixture was stirred for 1 hour at 0 C. The reaction was filtered through Celite and the cake was washed with tetrahydrofuran (2 x 5 mL). The filtrate was cooled to 0 ° C, sodium borohydride (powder, 0.23 g, 6 mmol) was added and then methanol (1.3 ml) was added dropwise over a period of 1 h. . The reaction mixture was quenched with brine (10 mL) and acidified with glacial acetic acid to pH 5. Ether (10 mL) was added and the organic layer was separated. The aqueous layer was extracted with ether (2 x 10 mL). The organic layers were combined, dried and concentrated in vacuo to provide 1.1 g (100%) of 2-. { 3ß-. { [(t-Butoxycarbonylamino) - (t-butoxycarbonylimino) -methyl] amino} -4 - [(2-hydroxy) (1-methylcarbonylamino)] - 1-cyclopentylidene} -l, 3-ditiano.

To a solution of the above solid (3.67 g, 6.75 mmol) in dimethylformamide (16 mL) was added t-butyl-dimethylchlorosilane (1.15 g, 7.4 mmol) and imidazole (0.92 g, , 5 mmol). The reaction mixture was stirred at room temperature overnight, poured into water (20 ml) and extracted with ether (3 x 20 ml). The organic layers were combined, washed with water (20 ml) and brine (25 ml), dried, and the solvent was removed in vacuo to give 4.4 g of a colorless oil. Purification of the crude product by flash column chromatography (15-25% ethyl acetate in hexane) gave: 1. Isomer A, 2.5 g (57%) as a white solid, mp. 129-130 ° C (Rf = 0.36, ethyl acetate in 25% hexane); MS (ES +) 444.9 [100%, (M + 1) -t-butyl-dimethylsilyl] Analysis: Calculated for C30H54N405S2Si: C, 54, 68; H, 8, 26; N, 8, 50 Found: C, 54.71; H, 8.05; N, 8.61 2. Isomer B, 1, 21 g (27%) of 2-. { 3ß-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4 - [(2- t-Butyldimethylsilyloxy) (1-methylcarbonylamino) ethyl] -cyclopentylidene} -l, 3-dithiane, isomer B in the form of a white solid pf. 94-96 ° C, (Rf = 0.28, ethyl acetate in 25% hexane); MS (ES +) 659, 4 [100%, (M + 1)].

Analysis: Calculated for C30H54N4O5S2Si: C, 54, 68; H, 8, 26; N, 8, 50 Found: C, 55, 06; H, 8, 18; N, 8, 40 To a solution of 1.21 g (27%) of above B-isomer (1.11 g, 1.68 mmol) in methanol (50.4 mL), 6 N HCl (4.2 mL, 25%) was added. 2 mmoles) and the mixture was stirred at room temperature until all the starting material disappeared (TLC analysis, ethyl acetate, ~ 30 h). The solvent was removed in vacuo (water bath temperature ~ 35 ° C) to provide 3β-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4a- [(2-hydroxy) - (1-methylcarbonylamino) ethyl] -1- [(3-mercaptopropyl) thiocarbonyl] cyclopentane. { MS (ES + 1) 563.5 [100%, (M + 1)], 463.5 [80%, (M + 1) -t-butoxycarbonyl], 363.4 [50%, (M + 1) -di-t-butoxycarbonyl]} .

The above crude product was dried in vacuo to remove trace amounts of water and then dissolved in dichloromethane (25 ml). Trifluoroacetic acid (1.29 ml, 16.8 mmol) was added and the mixture was stirred overnight at room temperature. The solvent was removed in vacuo to provide a crude residue of 3β- [(amino) (imino) methyl] amino} -4 - [(2-hydroxy) - (1-methylcarbonylamino) ethyl] -1- [(3-mercaptopropyl) thiocarbonyl] -cyclopentane. { MS (ES + 1) 363.4 [100%, (M + 1)]} .

The above crude residue was dissolved in tetrahydrofuran (8.5 ml), and methanol (4.2 ml) and 1N sodium hydroxide (8.4 ml, 8.4 mmol) were added and the reaction mixture was stirred for 35 minutes at room temperature. Tetrahydrofuran and methanol were removed in vacuo and the aqueous layer was washed with ethyl acetate (2 x 10 mL). The aqueous layer was filtered and the filtrate was acidified to pH 6.5 (1 N HCl). The acidified aqueous layer was washed with ethyl acetate (2 x 10 mL) and concentrated in vacuo to provide 1.3 g of crude product.

The above crude product (1.0 g) was loaded on a column of silica gel (50 g) and eluted with chloroform: methanol: conc. Ammonium hydroxide. (5: 4: 1) (1,000 ml) to separate the organic and inorganic impurities. The column was then eluted with water in 25% 2-propanol to provide 0.21 g (43%) of an oil. The oil was triturated with ethanol / ether and ether (5 x 10 mL) to give the title compound as a white solid, mp. 65 ° C (melts) (Rf = 0.36, water in 25% 2-propanol, TLC plate developed with KMn04 spray).

Analysis: Calculated for C 13 H 19 N 4 N a 04 - 0, 35 C 4 Hlo O - 0.25 H 2 O: C, 45.86; H, 7.14; N, 17.25 Found: C, 46.14; H, 7.50; N, 17.55 Example 8 • CF2C02H .0.5CF3CO2NH4 T-3-amino-t-l-hydroxy-c-4- [(hydroxymethyl) (methylcarbonylamino) methyl] cyclopentane-r-carboxylic acid: trifluoroacetic acid: trifluoroacetate ammonium (1: 1: 0.5) A mixture of trans-3-azido-4- [bis (ethoxycarbonyl) - (methylcarbonylamino) methyl] cyclopentanone (from Example 6, 0.50 g, 1.5 mmol), di-t-butyl dicarbonate (Aldrich, , 39 g, 1.77 mmol), and Pd / C, 10% (0.140 g) in ethyl acetate (25 mL) was hydrogenated at 45 psi for 1 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 0.69 g of crude product. Purification by flash column chromatography (silica gel, 75% ethyl acetate / hexanes) gave a semisolid 1.2 g. Recrystallization of the residue from ether / hexanes gave 0.275 g (45%) of trans-3-t-butyloxycarbonylamino-4- [bis (ethoxycarbonyl) (methylcarbonylamino) methyl] cyclopentanone as a white solid, mp. 135-136 ° C.

Analysis: Calculated for C19H3QN204: C, 55.06; H, 7.30; N, 6.76 Found: C, 54.63; H, 7.17; N, 674 To a stirred solution of bis- (phenylthio) methane (Aldrich, 1.12 g, 4.84 mmol) in tetrahydrofuran (10 ml) at 0 ° C was added dropwise n-butyl lithium (1.6 M) , 3.0 mi, 4.84 immoles). After 30 min. After stirring, the reaction mixture was cooled to -78 ° C and trans-3-t-butyloxycarbonylamino-4- [bis (ethoxycarbonyl) (methylcarbonylamino) methyl] cyclopentanone (0.50 g, 1.2 g) was added dropwise. mmoles) in tetrahydrofuran (6 ml). The reaction mixture was stirred for 1 hour, then quenched with a saturated aqueous solution of ammonium chloride (10 ml). The separated aqueous layer was extracted with ether (4 x 10 mL). The combined organic extracts were washed with brine, dried (MgSO 4), filtered through Celite, and concentrated in vacuo to provide 1.25 g of crude product. Purification by flash column chromatography (silica gel, 75 g, 25% ethyl acetate / hexanes) gave 0.16 g (20%) of c-3- (t-butoxycarbonylamino) -t-4- [bis] (ethoxycarbonyl) (methylcarbonylamino) methyl] -t-1- [bis (phenylthio) methyl] cyclopentan-rl-ol as a white solid, mp. 36-37 ° C.

Analysis: Calculated for C32H42N208S2: C, 59, 42; H, 6, 54; N, 4, 33 Found: C, 59, 64; H, 6, 45; N, 3, 94 A mixture of c-3- (t-butoxycarbonylamino) -t-4- [bis (ethoxycarbonyl) (methylcarbonylamino) methyl] -t-1- [bis (phenylthio) methyl] cyclopentan-rl-ol (0.63 g, 0.97 mmol) and potassium hydroxide (1 N, 3.4 ml, 3.4 mmol) in a 50% aqueous solution of ethanol (24 ml) was stirred at room temperature for 12 h. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in ethyl acetate (12 mL). This reaction mixture was heated to reflux for 1 hour and allowed to cool to room temperature. To this reaction mixture was added glacial acetic acid (0.2 ml, 3.4 mmol). The separated aqueous layer was extracted with ethyl acetate (4 x 10 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered through Celite, and concentrated in vacuo to provide 0.54 g of crude product. Purification by radial CLP (silica gel, 25-50% ethyl acetate / hexanes) gave 0.35 g (63%) of c- 3- (t-butoxycarbonylamino) -t-4- [(ethoxycarbonyl) ( methylcarbonylamino) methyl] -tl- [bis (phenylthio) methyl] cyclopentan-ol-ol in the form of a white solid, mp. 58-59 ° C.

Analysis: Calculated for C2gH38N206S2: C, 60, 60; H, 6, 66; N, 4, 87 Found: C, 60.76; H, 6.79; N, 4.88 To a stirred solution of c-3- (t-butoxycarbonyl-amino) -t-4- [(ethoxycarbonyl) (methylcarbonylamino) methyl] -t-1- [bis (phenylthio) methyl] cyclopentan-rl-ol (0, 17 g, 0.29 mol) in tetrahydrofuran (7 ml) at room temperature was added lithium borohydride (2 M, 0.3 ml, 0.6 mmol). After 12 hours of stirring, the reaction mixture was heated at 50 ° C for 45 min. To this reaction mixture was added 1 N HCl (6 mL). The separated aqueous layer was extracted with ethyl acetate (4 x 5 mL). The combined organic extracts were washed with brine, dried (MgSO 4), filtered through Celite, and concentrated in vacuo to provide 0.16 g of crude product. Purification by radial CLP (silica gel, 50% ethyl acetate / hexanes) gave 0.08 g (50%) of c-3- (t-butoxy-carbonylamino) -t-4- [(2-hydroxy) ) (1-methylcarbonylamino) ethyl] -tl- [bis (phenylthio) methyl] cyclopentan-rl-ol (isomer A) as a white solid, mp. 66-67 ° C.

Analysis: Calculated for C27H36N205S2: C, 60, 88; H, 6, 62; N, 5, 26 Found: C, 60.95; H, 6.94; N, 5.14 To a stirred solution of c-3- (t-butoxycarbonylamino) -t-4- [bis (ethoxycarbonyl) (methylcarbonylamino) methyl] -thyl- [bis (phenylthio) methyl] cyclopentan-rl-ol (0.76 g, 1.2 mmol) in tetrahydrofuran (10 ml) at room temperature was added lithium borohydride (0.03 g, 1.4 mmol). The reaction mixture was refluxed for 12 hours and allowed to cool to room temperature. To this reaction mixture was added 1 N HCl (10 mL). The separated aqueous layer was extracted with ether (4 x 10 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered through Celite, and concentrated in vacuo to provide 0.54 g of crude product. Purification by radial CLP (silica gel, 70% ethyl acetate / hexanes) gave 0.15 g (21%) of c-3- (t-butoxycarbonylamino) -t-4- [(2-hydroxy) ( 1-methylcarbonyl-amino) ethyl] -tl- [bis (phenylthio) methyl] cyclopentan-r-1-ol (isomer B) as a white solid, mp. 176-177 ° C.

Analysis: Calculated for C27H36N205S2: C, 60.88; H, 6.62; N, 5.26 Found: C, 60.85; H, 6.72; N, 5.03 To a stirred solution of a mixture of the isomers A and B of c-3- (t-butoxycarbonylamino) -t-4- [(2-hydroxy) (l-methylcarbonylamino) ethyl] -tl- [bis (phenylthio) - methyl] cyclopentan-rl-ol (5.65 g, 10.6 mmol) in dimethylformamide (100 mL) at -23 ° C was added sodium hydroxide (95%, 0.345 g, 13.8 mmol) and tetrabutylamino iodide (0.40 g, 1.1 mmol). After stirring for 30 minutes, benzyl bromide (2.0 ml, 15 ml) was added dropwise., 8 mmol). The reaction mixture was stirred at -23 ° C for 3 hours, then quenched with glacial acetic acid (2.5 ml) and water (100 ml). The separated aqueous layer was extracted with ethyl acetate (7 x 15 mL). The combined organic extracts were washed with brine, dried (MgSO 4), filtered through Celite, and concentrated in vacuo to provide 9.1 g of crude product. Purification by flash column chromatography (silica gel, 210 g, 50-75% ethyl acetate / hexanes) gave 2.98 g (45%) of c-3- (t-butoxycarbonylamino) -t-4- [(1-methyl-carbonylamino) (2-phenylmethoxy) ethyl] -tl- [bis (phenylthio) -methyl] cyclopentan-rl-ol as a white solid, mp. 52-54 ° C.

Analysis: Calculated for C34H42N2OsS2: C, 65.57; H, 6.79; N, 4.49 Found: C, 65.52; H, 6.80; N, 4.45 A mixture of c-3- (t-butoxycarbonylamino) -t-4- [(1-methylcarbonylamino) (2-phenylmethoxy) ethyl] -t-1- [bis (phenylthio) methyl] cyclopentan-rl-ol (2, 53 g, 4.1 mmol), mercuric oxide (1.90 g, 6.8 mmol), and boron trifluoride etherate (1.1 ml, 8.9 mmol () in a 15% aqueous solution of tetrahydrofuran (70 ml) was stirred at room temperature for 2 h.The reaction mixture was filtered through a pad of Celite and Florisil.The filtrate was concentrated in vacuo to give 2.74 g of the crude product. above in methanol (50 mL) was added iode (1.9 g, 7.5 mmol) and the reaction mixture was heated to 50 ° C. A solution of potassium hydroxide (0%) was added dropwise to this mixture. 71 M / methanol, 50 ml, 35.7 mmol) After 2 hours of stirring at 50 ° C, the reaction mixture was filtered through Celite, the filtrate was concentrated in vacuo and the resulting residue was dissolved in ethyl acetate (30 ml) and water (20 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (4 x 10 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered through Celite, and concentrated under vacuum to provide 3.6 g of crude product. Purification by flash column chromatography (silica gel, 200 g, 50-100% ethyl acetate / hexanes) gave 0.224 g (14%) of the desired hydroxy acid as a white solid. To a solution of the 10 hydroxy acid (0.244 g, 0.56 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (0.86 mL, 11.2 mmol) and the reaction mixture was stirred at room temperature for 12 hours . The reaction mixture was concentrated in vacuo to give a crude product. The purification by flash chromatography (silica gel, 60 g, chloroform / methanol / ammonium hydroxide: 80/18/2) gave 0.241 g of a thick, yellow oil. Trituration of the yellow oil with ether yielded 0.185 g (51%) of t-3-amino-c-4- [(1-methylcarbonylamino) (2-20 phenylmethoxy) ethyl] -tl-hydroxycyclopentane-r-carboxylic acid shape of a tan solid, mp. 37-39 ° C.

Analysis: Calculated for C17H24N205 -C2HF3O-0, 1C2H4F3N02: 25 C, 40.84; H, 4.83; N, 7.58 Found: C, 40.86; H, 5.08; N, 7.90 A mixture of t-3-amino-c-4- [(1-methyl-carbonylamino) (2-phenylmethoxy) ethyl] -t-1-hydroxycyclopentane-30-carboxylic acid (0.09 g, 0.14 mmol) ) and Palladium hydroxide (0.15 g) in ethanol (20 ml) was hydrogenated at 40 psi overnight. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo to give 0.078 crude product. A mixture of the above crude amine and Trifluoroacetic acid (0.2 ml, 2.6 mmol) in dichloromethane (10 ml) was stirred overnight. The mixture was concentrated in vacuo to give 0.08 g of a brown solid which was triturated with ether to give 0.045 g (75%) of the title compound as a tan solid, mp. 83-85 ° C.

Analysis: Calculated for C10H18N205 * C2HF3 ° 2 '°' 5C2H4F3N02: C, 36.67; H, 4.97; N, 8.22 Found: C, 36.40; H, 5.15; N, 7.95 Example 9 Acid t-3-. { [(amino) (imino) methyl] amino} -t-l-hydroxy-c-4- [(2-hydroxymethyl) (1-methylcarbonylamino) ethyl] cyclopentane-r-carboxylic acid: trifluoroacetic acid: diethyl ether [20: 15: 2] (isomer A in C-6) To tris (methylthio) methane (21.27 g, 138 mmol) in tetrahydrofuran (350 ml) at -78 ° C was added dropwise over a period of 10 minutes in nitrogen n-butyl lithium (solution 1, 6 M in hexane, 90 ml, 144 mmol) and stirred at -78 ° C for 40 min. To the anion at -78 ° C was added a solution of 3β- (t-butoxycarbonylamino) -4 - [(ethoxycarbonyl) (methylcarbonylamino) methyl] cyclopentanone from Example 6 (isomer A, 8.34 g, 17.23 mmole) in tetrahydrofuran (50 ml) over a period of 10 minutes and the reaction mixture was stirred at -78 ° C for 1 hour.5 h. The solution was quenched with saturated ammonium chloride (50 ml) and warmed to room temperature, ether (50 ml) was added, and the organic layer was separated. The aqueous layer was extracted with ether (2 x 50 mL), the organic layers were combined, dried over MgSO4 and concentrated in vacuo to provide an oil. The crude oil was dissolved in ethyl acetate (50 ml) and hexane (400 ml) and stored overnight in a freezer. A crystalline solid was filtered off. The mother liquor was purified by flash column chromatography (silica gel, 240 g, 30-45% ethyl acetate in hexane) to obtain 2.7 g (24%) of 3β-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4a- [(ethoxycarbonyl) (methylcarbonylamino) methyl] -l- [(tris-methylthio) -methyl] cyclopentanol as a mixture of isomers.

To a solution of the above mixture (2.69 g, 4.22 mmol), in tetrahydrofuran (42 mL) was added dropwise in nitrogen lithium borohydride (0.74 g, 33.73 mmol) and 9-borabicylo [3, 3,1] nonane-lithium hydride (1 M solution in tetrahydrofuran, 0.84 ml, 0.84 mmol) and the reaction mixture was stirred at room temperature overnight. The solution was quenched with 1 N sodium hydroxide (1 mL), brine (20 mL) and stirred for 5 min. The reaction was acidified to pH 4 using glacial acetic acid. Ether (10 mL) was added and the aqueous layer was separated. The aqueous layer was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (2 x 10 mL), the organic layers were combined, dried and concentrated in vacuo to obtain 3.3 g of a yellow oil. . The oil was purified by flash column chromatography [silica gel (200 g), chloroform: methanol: conc. Ammonium hydroxide. to 10% (80: 18: 2) in dichloromethane] to provide 1.5 g (60%) of t-3-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -c-4- [(2-hydroxy) (1-methylcarbonylamino) ethyl] -tl- [tris (methylthio) methyl] cyclopentan-r-ol, a white solid [Rf = 0.17, chloroform: methanol: ammonium hydroxide conc. 20% (80: 18: 2) in dichloromethane].

To a mixture of the above solid (1.2 g, 2.0 mmol), mercuric chloride (2.02 g, 7.45 mmol) and mercuric oxide (0.65 g, 3.02 mmol) was added methanol / water (46.2 / 3.8 ml) and the reaction mixture was stirred at room temperature for 30 min. The mixture was filtered through a pad of Celite and Florisil (20 g). The cake was washed with methanol (20 mL) and the filtrate was concentrated in vacuo to provide 2.1 g of a white semi-solid. The crude product was purified by flash column chromatography [silica gel (60 g); 75% ethyl acetate in hexane and 10% methanol in ethyl acetate] to provide 0.55 g (55%) of t-4-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} - methyl c-3- [(2-hydroxymethyl) (l-methylcarbonylamino) ethyl] -t-l-hydroxycyclopentane-r-carboxylate in the form of a white solid, mp. 94-96 ° C.

To a solution of the above solid (0.47 g, 0.93 mmol) in tetrahydrofuran (9.3 mL) was added 1 N sodium hydroxide (1.86 mL, 1.86 mmol) and water (7.4 mL). ). The reaction mixture was stirred at room temperature for 1 h.

The tetrahydrofuran was removed in vacuo and the aqueous layer was washed with ether (2 x 10 mL). The aqueous layer was acidified with glacial acetic acid (pH = 5), saturated with sodium chloride and extracted with ethyl acetate (3 x 15 mL). The organic layers were combined and concentrated in vacuo to provide 0.33 g (73%) of crude product which was triturated with ether / hexane to provide t-3- acid. { [(t-butoxy-carbonylamino) (t-butoxycarbonylimino) methyl] amino} -tl-hydroxy-c-4- [(2-hydroxymethyl) (1-methylcarbonylamino) ethyl] -t-1-cyclopentane-r-carboxylic acid (isomer A) as a white solid, mp 238-240 ° C.

Analysis: Calculated for C22H36N4Og: C, 51.63; H, 7.43; N, 11.47 Found: C, 51.31; H, 7.48; N, 11.07 To a solution of t-3- acid. { [(t-butoxycarbonyl-amino) (t-butoxycarbonylimino) methyl] amino} -tl-hydroxy-c- 4- [(hydroxymethyl) (methylcarbonylamino) methyl] cyclopentane-r-carboxylic acid, isomer A (0.2 g, 0.41 mmol), in dichloromethane (10 ml), trifluoroacetic acid ( 0.63 ml, 8.2 mmol) and the reaction is stirred at room temperature overnight. Additional trifluoroacetic acid (0.32 ml, 4.1 mmol) was added and the reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo and traces of excess trifluoroacetic acid were removed in vacuo by co-distilling the residue twice with dichloromethane (10 ml). The residue was dissolved in water (5 ml) and concentrated in vacuo to give an oily residue which was triturated with ether to obtain 0.13 g (83%) of the title compound as a white solid, mp. 162-166 ° C.

Analysis: Calculated for C13H19F3N409 • 0.75C2HF302 • 0.5C4H1Q0: C, 40, 64; H, 5.75; N, 14, 70 Found: C, 40, 77; H, 5.80; N, 14, 67 Example 10 3β-amino-4 - [(1-methylcarbonylamino) (2,3,4-trihydroxy) butyl] cyclopentanecarboxylic acid: trifluoroacetic acid (1: 1) (isomer A in C-6) To 2-trimethylsilyl-1,3-dithiane (Aldrich, 7.88 g, 41.5 mmol) in tetrahydrofuran (100 ml) at 0 ° C was added dropwise over a period of 10 minutes in hydrogen. -butyl lithium (1.6 M solution in hexane, 28.6 ml, 45.7 mmol) and stirred at 0 ° C for 45 min. The anion was cooled to -40 ° C and then a solution of 3ß- (t-butoxycarbonylamino) -4a- [bis (ethoxycarbonyl) (methylcarbonylamino) -methyl] cyclopentanone was added dropwise over a period of 15 minutes. (from Example 8, 4.3 g, 10.4 mmol) in tetrahydrofuran (50 ml). The reaction mixture was stirred at -40 ° C for 5 hours and warmed to -20 ° C. The solution was quenched with saturated ammonium chloride (50 ml) and warmed to room temperature. Ether (20 ml) was added and the organic layer was separated. The aqueous layer was extracted with ether (2 x 25 mL), the organic layers were combined, dried over MgSO4 and concentrated in vacuo to give a crude product. Purification of the crude product by flash column chromatography (silica gel, 320 g, 30-35% ethyl acetate in hexane) gave 3.16 g (59%) of 2-. { 3β- (t-butoxycarbonylamino) -4 - [bis (ethoxycarbonyl) (methylcarbonylamino) methyl] cyclopentylidene} -l, 3-dithiane in the form of a colorless oil which solidifies on drying under vacuum at the reflux temperature of acetone to give a solid, mp. 66-68 ° C.

Analysis: Calculated for C23H3gN207S2: C, 53.47; H, 7.02; N, 5.42 Found: C, 53.50; H, 7.07; N, 5.41 To a solution of 2-. { 3β- (t-butoxycarbonylamino) -4 - [bis (ethoxycarbonyl) (methylcarbonylamino) methyl] cyclopentylidene} -l, 3-dithiane (7.5 g, 14.53 mmol) in ethanol (75 ml) was added 1 N sodium hydroxide (50.9 ml, 50.9 mmol) and water (25 ml) and the mixture of reaction was heated to reflux for 2 h. The reaction was cooled, glacial acetic acid (4.6 ml, 76.3 mmol) was added, the mixture was heated to gentle reflux for 1 hour and stirred at room temperature overnight. The separated solid was collected by filtration, washed with water and dried under vacuum at the reflux temperature of toluene to provide 1.63 g (27%) of a solid. The filtrate was extracted with ethyl acetate (3 x 100 mL), the organic layers were combined, dried and concentrated in vacuo to provide 3.5 g of residue. An analytical sample was prepared by crystallization of the combined solid in ethanol to provide 5.1 g (85%) of 2-. { 3β- (t-butoxycarbonylamino) -4a- [(carboxy) (methylcarbonylamino) methyl] cyclopentylidene} -l, 3-dithiane in the form of a white solid pf. 174-176 ° C.

Analysis: Calculated for C18H28N205S2-0.75H20: C, 50, 27; H, 6, 91; N, 6, 51 Found: C, 50, 03; H, 6, 54; N, 6, 41 To a solution of 2-. { 3β- (t-butoxycarbonylamino) -4 - [(carboxy) (methylcarbonylamino) methyl] cyclopentylidene} 1,3-dithiane (5.13 g, 12.3 mmol) in tetrahydrofuran (120 ml) cooled to 0 ° C was added methyl chloroformate (1 ml, 13.5 mmol) and triethylamine (2.2 ml, 15.4 mmol). The reaction mixture was stirred at 0 ° C for 40 minutes and a cold solution of N, 0-dimethyl-hydroxylane hydrochloride (1.84 g, 18.5 mmol) and triethylamine (3.5 ml, 24.6 mmole) in tetrahydrofuran (5 ml) which had been stirred at 0 ° C for 30 min. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction was filtered through Celite and the cake was washed with tetrahydrofuran (10 mL). To the filtrate was added a cold solution of N, 0-dimethylhydroxylamine hydrochloride (1.84 g, 18.5 mmol) and triethylamine (3.5 mL, 24.66 mmol) in tetrahydrofuran. (5 ml) which had been stirred at 0 ° C for 30 minutes and stirred again overnight at room temperature. The solvent was removed in vacuo and sodium hydroxide (0) was added to the residue., 1 M, 100 ml) and ethyl acetate (100 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 75 mL). The organic layers were combined and washed with brine (100 ml), dried and concentrated in vacuo to provide 4.73 g of the crude amide as a semi-solid. Purification of the crude product by flash column chromatography [200 g, silica gel, 90% ethyl acetate in hexane and chloroform / methanol / ammonium hydroxide % (80: 18: 2) in methylene chloride] gave 4.2 g (74%) of 2-. { 3β- (t-butoxycarbonylamino) -4a-. { (methylcarbonylamino) -. { [(methyl) (methoxy) amino] carbonyl} methyl } Cyclopentylidene } -1.3-ditian. An analytical sample was prepared, mp. 122-126 ° C, as a white solid by recrystallization from ether / hexane, Analysis: Calculated for C20H33N3O5S2: C, 52.26; H, 7.24; N, 9.14 Found: C, 52.34; H, 7.20; N, 9.09 To a solution of 2-. { 3β- (t-butoxycarbonylamino) -4-. { (methylcarbonylamino). { [(methyl) (methoxy) amino] carbonyl} - methyl} Cyclopentylidene } -l, 3-dithiane (0.26 g, 0.57 mmol) in tetrahydrofuran (2.5 ml) cooled to 0 ° C was added dropwise lithium hydride and tri-t-butoxyaluminum (Aldrich, solution 1, 0 M in tetrahydrofuran, 1.4 ml, 1.4 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was carefully quenched with 1 N HCl (1.0 ml, the pH should not fall below 4.0) and stirred for 5 min. Ether (20 mL) and a 1 M aqueous solution of the sodium potassium tartrate salt (10 mL) were added and the reaction mixture was stirred at room temperature for 30 min. The organic layers were separated and the aqueous layer was extracted with ether (2 x 10 mL). The organic layers were combined, washed with brine (20 mL), dried and concentrated in vacuo to provide 0.3 g of a white solid. Purification of the crude product by flash column chromatography (20 g of silica gel, 50-80% ethyl acetate in hexane) gave two isomers (at C-6) of 2-. { 3β- (t-butoxycarbonylamino) -4 - [(formyl) (methylcarbonylamino) methyl] cyclopentylidene} -l, 3-ditiano. 1. 0.09 g (40%) of isomer A in C-6, a white solid, mp. 188-192 ° C (dec.).

Analysis: Calculated for C18H28N204S2: C, 53, 97; H, 7, 05; N, 6, 99 Found: C, 53, 93; H, 7, 09; N, 6, 93 2. 0.08 g (35%) of isomer B in C-6, a white solid, mp. > 180 ° C (dec.).

Analysis: Calculated for C18H28N204S2: C, 53.97; H, 7.05; N, 6.99 Found: C, 54.03; H, 7.05; N, 6.97 To a solution of 2-. { 3β- (t-butoxycarbonylamino) -4 - [(formyl) (methylcarbonylamino) methyl] cyclopentylidene} 1,3-dithiane (0.17 g, 0.43 mmol) in tetrahydrofuran (5 mL) cooled to -78 ° C was added dropwise vinylmagnesium bromide (Aldrich, 1.0 M solution in tetrahydrofuran, 2, 2 mL, 2.2 mmol) and stirred at -78 ° C for 2 hours. The reaction was quenched carefully with saturated aqueous ammonium chloride (5.0 mL). Ether (10 ml) and brine (5 ml) were added and the reaction mixture was allowed to warm to room temperature. The organic layers were separated and the aqueous layer was extracted with ether (2 x 10 mL). The organic layers were combined, washed with brine (20 ml), dried and concentrated in vacuo to provide 0.17 g of crude product as a white solid. Purification of the crude product by flash column chromatography (10 g of silica gel, 50-100% ethyl acetate in hexane) gave 0.06 g (33%) of 2-. { 3β- (t-butoxycarbonylamino) -4 - [(2-hydroxy) (1-methylcarbonylamino) -3-butenyl] cyclopentylidene} -l, 3-dithiane (isomer A in C-6) in the form of a white solid, mp. > 210 ° C (dec.).

Analysis: Calculated for C20H32N2O4S2: C, 56.05; H, 7.53; N, 6.54 Found: C, 56.18; H, 7.50; N, 6.47 To a solution of 2-. { 3β- (t-Butoxycarbonylamino) -4a- [(2-hydroxy) (1-methylcarbonylamino) -3-butenyl] -cyclopentylidene} -l, 3-dithiane (isomer A, 0.55 g, 1.28 mmol) in methanol (19.3 ml) was added with 6 N HCl (3.2 ml, 19.28 mmol) and the mixture was stirred at the ambient temperature until all the starting material disappeared (TLC, ethyl acetate and analysis of MS ~ 20 h). The reaction mixture was cooled to 0 ° C and sodium hydroxide (1.02 g, 25.7 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction was quenched with glacial acetic acid (0.8 mL, 12.85) and concentrated in vacuo to provide a crude residue. To the residue was added ethyl acetate (10 ml) and water (10 ml). The aqueous layer was separated and extracted with ethyl acetate (2 x 10 mL). The organic layers were combined and concentrated in vacuo to provide 0.4 g of crude product.

The above crude product was dissolved in anhydrous methanol (20 ml) and cooled to 0 ° C. A solution of dry HCl in ether (Aldrich, 1.0 M solution, 5 ml) was added and the reaction mixture was stirred overnight. The reaction was quenched with 1N sodium hydroxide in methanol to adjust the pH of the reaction to 6-7, and concentrated in vacuo to obtain a crude residue. The residue was dissolved in water (10 ml) and extracted with dichloromethane (3 x 10 ml). The organic layers were combined, dried and concentrated in vacuo to obtain 0.2 g of crude product. The crude product was purified by flash column chromatography [chloroform / methanol / ammonium hydroxide conc. 10-50% (80: 18: 2) in dichloromethane] to provide 0.12 g (24%) of 3β- (t-butoxycarbonylamino) -4a- [(2-hydroxy) (1-methylcarbonylamino) -3- butenyl] methyl-cyclo-pentanecarboxylate (isomer A in C-6) in the form of oil, MS (ES +) 371.4 [100%, (M + l)] and 353.4 [100%, (M + l) -H20] The above oil (0.1 g, 0.27 mmol) was dissolved in tetrahydrofuran / t-butanol (2 mL, 1: 1) and N-methylmorpholine oxide (50 mg), osmium tetroxide (0.05) was added. % by weight in t-butanol, 0.2 ml) and water (1 ml). The reaction mixture was stirred overnight at room temperature. A saturated aqueous solution of sodium sulfite (2 ml) was added and stirred vigorously for 30 minutes. Brine (2 mL) was added and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried and concentrated in vacuo to obtain 0.1 g of crude product. The crude product was purified by flash column chromatography [methanol in 0, 5, 10, 50, 100% ethyl acetate] to provide 0.06 g (59%) of triol as a semi-solid, MS (ES +) 405 , 4 [100%, (M + l)] and 387.5 [60%, (M + 1) -H20]. To a solution of the above solid (0.06 g, 0.16 mmol) in tetrahydrofuran (1.6 mL) was added 1 N sodium hydroxide (1.0 mL, 1.0 mmol) and stirred at room temperature for 1.5 h. Ether (5 ml) and water (1 ml) were added, and the organic layers were separated. The aqueous layer was washed with ethyl acetate (2 x 5 mL). The aqueous layer was then acidified to pH 5-4 using 1N HCl, saturated with sodium chloride and extracted with ethyl acetate (3 x 5 mL). The organic layers were combined, dried and concentrated in vacuo to provide 0.027 g (43%) of 3ß- (t-butoxycarbonylamino) -A- [(1-methylcarbonylamino) (2, 3, 4-trihydroxy) butyl] Cyclopentane-carboxylic acid (isomer A in C-6) as a white solid, MS (ES +) 391.4 [55%, (M + 1)], 373.6 [40% (M + 1) - H20] and 100% 317.3 [(M + 1) -t-butyl].

To a solution of the above acid [0.027 g, 0.07 mmol) in dichloromethane (1.0 ml) was added trifluoroacetic acid (0.11 ml, 1.4 mmol), and the reaction was stirred at room temperature during the night. Additional trifluoroacetic acid (0.11 ml, 1.4 mmol) was added and the reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo and traces of trifluoroacetic acid were removed in vacuo by co-distilling the residue twice with dichloromethane (10 ml). The residue was dissolved in water (0.5 ml), concentrated in vacuo and dried at the reflux temperature of acetone under vacuum to obtain 0.017 g (60%) of the title compound (isomer A) in the form of a solid to tan, MS (ES +) 291.4 [100% (M + 1)].

Example 11 3ß-amino-4a-f (1-methylcarbonylamino) (2, 3, 4-trihydroxy) butyl] cyclopentanecarboxylic acid: trifluoroacetic acid (1: 2) (isomer B in C-6) To a solution of 2-. { 3β- (-butoxycarbonylamino) -4 - [(formyl) (methylcarbonylamino) methyl] cyclopentylidene} 1,3-dithiane (isomer B in C-6), of Example 10 (0.45 g, 1.13 mmol) in tetrahydrofuran (20 mL) cooled to -78 ° C was added dropwise vinylmagnesium bromide (Aldrich, 1.0 M solution in tetrahydrofuran, 5.6 mL, 5.6 mmol) and stirred at -78 ° C for 1 hour. The reaction was carefully quenched with saturated aqueous ammonium chloride (5%)., 0 mi). Ether (20 ml) and brine (5 ml) were added and the reaction mixture was allowed to warm to room temperature. The organic layers were separated and the aqueous layer was extracted with ether (2 x 10 mL). The organic layers were combined, washed with brine (20 mL), dried and concentrated in vacuo to provide 0.5 g of a white solid. Purification of the crude product by flash column chromatography (10 g of silica gel, 60-100% ethyl acetate in hexane) gave 0.21 g (44%) of 2-. { 3β- (t-butoxycarbonylamino) -4a- [(2-hydroxy) (1-methylcarbonylamino) -3-butenyl] cyclopentylidene} -l, 3-ditian (isomer B in C-6) as a white solid, mp. > 210 ° C (dec.) Analysis: Calculated for C20H32N2O4S2 -0.25H2O: C, 55.46; H, 7.56; N, 6.47. Found: C, 55.20; H, 7.47; N, 6.41 To a solution of 2-. { 3β- (t-butoxycarbonylamino) -4 - [(2-hydroxy) (1-methylcarbonylamino) -3-butenyl] -cyclopentylidene} -l, 3-dithia.o (isomer B in C-6), (0.58 g, 1.36 mmol) in methanol (21 ml) was added 6N HCl (3.4 ml, 20.46 mmol) and the mixture was stirred at room temperature until all the starting material disappeared (~20 h. ). The reaction mixture was cooled to 0 ° C and • added sodium hydroxide (1.1 g, 27.6 mmol) and the The reaction was stirred at room temperature for 1 hour. The reaction was quenched with glacial acetic acid (0.83 mL, 13.79 mmol) and concentrated in vacuo. To the obtained residue was added ethyl acetate (10 ml) and water (10 ml). The aqueous layer was separated and extracted with ethyl acetate (2 x 10 mi). The organic layers were combined and concentrated in vacuo to provide 0.41 g of residue.

The previous crude product was dissolved in methanol • anhydrous (20 ml) and cooled to 0 ° C. A solution was added of dry HCl in ether (Aldrich, 1.0 M solution, 5 ml) and the reaction mixture was stirred overnight. The reaction was quenched with 1N sodium hydroxide in methanol to adjust the pH of the reaction to 6-7, and concentrated in vacuo. The residue was dissolved in water (10 ml) and extracted with dichloromethane (3 x 10 ml). The organic layers were combined, dried and concentrated in vacuo to obtain 0.17 g of crude product. The crude product was purified by flash column chromatography [chloroform / methanol / ammonium hydroxide conc. at 10-50% (80: 18: 2) in dichloromethane] to provide 0.14 g (28%) of 3ß- (t-butoxycarbonylamino) -Aa- [(2-hydroxy) (1-methyl-carbonylamino) -3-butenyl] Methyl cyclopentanecarboxylate (isomer B in C-6) as an oil, MS (ES +) 371.4 [90%, (M + 1)].

The above oil (0.12 g, 0.32 mmol) was dissolved in tetrahydrofuran / t-butanol (2 mL, 1: 1) and N-methylmorpholine oxide (50 mg), osmium tetroxide (0.05) was added. % by weight in t-butanol, 0.2 ml) and water (1 ml). The reaction mixture was stirred overnight at room temperature. A saturated aqueous solution of sodium sulfite (2 ml) was added and stirred vigorously for 30 minutes. Brine (2 mL) was added and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried and concentrated in vacuo to obtain 0.1 g of crude product. The crude product was purified by flash column chromatography [methanol in 0, 5, 10, 50, 100% ethyl acetate] to provide 0.08 g (62%) of the triol as a semi-solid, MS (ES +) 405 , 2 [100%, (M + l)].

To a solution of the above solid (0.08 g, 0.2 mmol) in tetrahydrofuran (2 mL) was added 1 N sodium hydroxide (1.2 mL, 1.2 mmol) and stirred at room temperature for 1 hour. 5 h. Ether (5 ml) and water (2 ml) were added, and the organic layers were separated. The aqueous layer was washed with ethyl acetate (2 x 5 mL). The aqueous layer was then acidified to pH 5-4 using 1N HCl, saturated with sodium chloride and extracted with ethyl acetate (3 x 5 mL). The organic layers were combined, dried and concentrated in vacuo to provide 0.02 g (26%) of 3ß- (t-butoxycarbonylamino) -A- [(1-methylcarbonyl-amino) (2,3,4- trihydroxy) butyl] cyclopentanecarboxylic acid (isomer B in C-6) as a white solid, MS (ES +) 391.4 [20%, (M + l)] and 373.6 [100% (M + 1) ) -H20] To a solution of the above acid (0.02 g, 0.05 mmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.08 mL, 1.1 mmol) and the reaction was stirred at room temperature during the night.

Additional trifluoroacetic acid (0.08 ml, 1.1 mmol) was added and the reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo and traces of trifluoroacetic acid were removed in vacuo by co-distilling the residue twice with dichloromethane (10 ml). The residue was dissolved in water (0.5 ml), concentrated in vacuo and dried at the reflux temperature of acetone under vacuum to obtain 0.02 g (77%) of the title compound as a white solid. toasted color, mp. 58-62 ° C.

Analysis: Calculated for ci2H22N2 ° 5 'C2HF3 ° 2: C, 37.08; H, 4.67; N, 5.40 Found: C, 37.50; H, 4.43; N, 5.28 Example 12 3ß- acid. { [(amino) (imino) methyl] amino} -Aa- [(1-methylcarbonyl-amino) (2,3,4-trihydroxy) butyl] -cyclopentanecarboxylic acid: trifluoroacetic acid (1: 2) (isomer A in Cl, isomer A in C-6-isomer B in C- 7) To a solution of 2-. { 3β- (t-Butoxycarbonylamino-Aa- [(formyl) methylcarbonylamino) -methyl] cyclopentylidene-1,3-dithiane (isomer A in C-6), of Example 10 (1.75 g, 4.4 mmol), in tetrahydrofuran (100 mL) cooled to -78 ° C was added dropwise vinylmagnesium bromide (Aldrich, 1.0 M solution in tetrahydrofuran, 44 mL, 44 mmol) and stirred at -78 ° C for 1 hour. The reaction was quenched carefully with saturated aqueous ammonium chloride (20 mL), ether (100 mL) and brine (20 mL) was added and the reaction mixture was allowed to warm to room temperature. The organic layers were separated and the aqueous layer was extracted with ether (3 x 50 mL) and dichloromethane (100 mL). The organic layers were combined, dried and concentrated in vacuo to provide 2.0 g of a white solid.

To the above solid (2.0 g, 4.4 mmol) dissolved in dimethylformamide (20 mL) was added t-butyl-dimethylsilyl chloride (0.86 g, 5.5 mmol), imidazole (0.6 g, 8 g). , 8 immoles) and 4-dimethylaminopyridine (0.14 g, 0.11 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (20 mL), and extracted with ether (3 x 25 mL), dried and concentrated in vacuo to provide 2.48 g of crude product. Purification of the crude product by flash column chromatography (150 g of silica gel, 10-30% ethyl acetate in hexane) gave the following isomers of 2-. { 3β- (t-butoxycarbonylamino) -4a-. { 2-. { [(t-butyl) (dimethyl) -silyl] oxy} -3-butenil} Cyclopentylidene } -l, 3-ditiano: 1. 0.22 g (9%) of isomer A in C-6, isomer A in C-7 as a white solid, mp 72-76 ° C (dec.).

Analysis: Calculated for C26H46N204S2Si -O, 5H20: C, 56, 59; H, 8, 59; N, 5, 08 Found: C, 56.61; H, 8.47; N, 4.97 2. 0.86 g (36%) of isomer A in C-6, isomer B in C-7 as a white solid, mp 116-118 ° C (dec.).

Analysis: Calculated for C26H46N204S2Si: C, 57.53; H, 8.54; N, 5.16; Found: C, 57.84; H, 8.59; N, 5.23.

To a solution of isomer A in C-6, isomer B in C-7 above (0.58 g, 1.07 mmol) in methanol (16.6 ml) was added 6N HCl (2.8 ml, 16%). 6 mmoles) and the mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0 ° C and sodium hydroxide (0.86 g, 10.7 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction was quenched with glacial acetic acid (0.64 mL, 10.7 mmol) and concentrated in vacuo. To the obtained residue was added 1 N HCl (2.14 ml, 2.14 mmol), ethyl acetate (10 ml) and water (10 ml). The aqueous layer was separated, saturated with sodium chloride and extracted with ethyl acetate (2 x 10 mL). The organic layers were combined and concentrated in vacuo to provide 0.33 g (85%) of crude product.

The above crude product was dissolved in anhydrous methanol (8 ml) and cooled to 0 ° C. A solution of dry HCl in ether (Aldrich, 1.0 M solution, 1.6 ml) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo (bath temperature 25 ° C) to obtain a crude residue of 3β- (t-butoxycarbonylamino) -4a- [(2-hydroxy) (1-methylcarbonylamino) -3-butenyl] cyclopentane methyl carboxylate in the form of an oil, MS (ES +) 371.5 [100%, (M + 1)].

To a solution of the above compound in dichloromethane (8.0 mL) was added trifluoroacetic acid (1.26 mL, 16.4 mmol), and the reaction was stirred at room temperature overnight. Additional trifluoroacetic acid (0.63 ml, 8.2 mmol) was added and the reaction was stirred at room temperature for 1 hour. The solvent was removed in vacuo and traces of trifluoroacetic acid were removed in vacuo by co-distillation of the residue twice with dichloromethane (5 ml). The residue was dissolved in dimethylformamide (5 ml), triethylamine (0.58 ml, 4.1 mmol), 1,3-bis (t-butoxycarbonyl) -2-methyl-2-thioseudourea (0.29 g, 0.98 mmol), and mercuric chloride ( 0.27 g, 0.98 mmol), and the reaction was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (20 mL) and filtered to remove the organic impurities. The filtrate was washed with water (2 x 10 mL) and brine (10 mL), dried and concentrated in vacuo to obtain 0.4 g of crude product. The crude product was purified by flash column chromatography [silica gel (20 g), 40-50% ethyl acetate in hexane] to give the two C-1 isomers of 3β-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} - methyl Aa- [(2-hydroxy) (1-methylcarbonylamino) -3-butenyl] -cyclopentanecarboxylate: 1. 0.15 g (27%) of isomer A in Cl, in the form of a semi-solid, EM (ES +) 495.5 [100%, (M + 1) -H20] and 513.6 [10%, (M + l)]. 2. 0.07 g (13%) of isomer B in C-1, in the form of a semi-solid, MS (ES +) 513.5 [100%, (M + 1)].

The above A isomer (0.15 g, 0.29 mmol) was dissolved in tetrahydrofuran / t-butanol (2 mL, 1: 1) and N-methylmorpholine oxide (50 mg), osmium tetraoxide (a few crystals) and water (1 ml). The reaction mixture was stirred overnight at room temperature. A saturated aqueous solution of sodium sulfite (2 mL) and sodium sulfite (1 g) was added and stirred vigorously for 30 minutes. Brine (2 mL) was added and the aqueous layer was saturated with sodium chloride and extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried and concentrated in vacuo to obtain 0.15 g (94%) of 3β-. { [(t-butoxycarbonyl-amino) (t-butoxycarbonylimino) methyl] amino} -4a- [(1-methyl-carbonylamino) (2,3,4-trihydroxy) util] methyl cyclopentanecarboxylate (isomer A in Cl), MS (ES +) 529.4 [100%, (M + 1) -H20 ] and 547.4 [50%, (M + l)].

To a solution of the above solid (0.15 g, 0.27 mmol) in tetrahydrofuran (1.5 mL) was added 1 N sodium hydroxide (1.4 mL, 1.4 mmol), and stirred at the temperature environment for 2, 0 hours. Ether (2 m) and water (2 ml) were added and the organic layers were separated. The aqueous layer was washed with ether (2 x 5 mL). The aqueous layer was acidified to pH 4 using 1 N HCl, saturated with sodium chloride and extracted with ethyl acetate (3 x 5 mL). The organic layers were combined, dried and concentrated in vacuo to provide 0.13 g (84%) of acid as a white solid. MS (ES +) 515.4 [80%, (M + 1) -H20] and 533.5 [30%, (M + 1)].

To a solution of the above acid (0.13 g, 0.24 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.04 mL, 0.48 mmol) and the reaction was stirred at room temperature for the night. Additional trifluoroacetic acid (0.02 ml, 0.24 mmol) was added and the reaction was stirred at room temperature for 1 hour. The solvent was removed in vacuo and traces of excess trifluoroacetic acid were removed in vacuo by co-distillation of the residue twice with dichloromethane (10 ml). The residue was dissolved in water (1.0 ml), concentrated in vacuo and dried at reflux temperature of acetone in vacuo to obtain 0.07 g (46%) of the title compound as a color solid. toasted, mp 76-80 ° C.

Analysis: Calculated for 13H24N406-2C2HF302: C, 36, 44; H, 4.67; N, 9, 99 Found: C, 36, 81; H, 4, 24; N, 9, 55 Example 13 a? k Acid 3ß-. { [(amino) (imino) methyl] amino} -4ct- [(1-methylcarbonyl-15 amino) (2,3,4-trihydroxy) butyl] -cyclopentanecarboxylic acid: trifluoroacetic acid (1: 2) (isomer B in Cl, isomer A in C-6, isomer B in C -7) 3ß- was dissolved. { [(t-butoxycarbonylamino) (t-20-butoxycarbonylimino) methyl] amino} Methyl 4 - [(2-hydroxy) (1-methylcarbonylamino) -3-butenyl] cyclopentanecarboxylate (isomer B in Cl, from Example 12) (70 mg, 0.14 mmol) in tetrahydrofuran / t-butanol (2 ml) , 1: 1) and N-methylmorpholine oxide (50 mg), tetraoxide osmium (a few crystals) and water (1 ml). The reaction mixture was stirred overnight at room temperature. A saturated aqueous solution of sodium sulfite (2 mL) and sodium sulfite (1 g) was added and stirred vigorously for 30 minutes. Brine (2 ml) was added and the aqueous layer was saturated with sodium chloride and extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried and concentrated in vacuo to obtain 0.07 g (86%) of 3β-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4 - [(1- 35 methylcarbonyl-amino) (2,3,4-trihydroxy) butyl] cyclopentane-carboxylic acid methyl ester (isomer B in Cl), MS (ES +) 547.4 [100%, (M + l )].

To a solution of the above solid (0.07 g, 0.13 mmol) in tetrahydrofuran (1.5 ml) was added 1N sodium hydroxide (0.degree., 64 mL, 0.64 mmol), and stirred at room temperature for 2 hours. Ether (2 ml) and water (2 ml) were added and the organic layers were separated. The aqueous layer was washed with ether (2 x 5 mL). The aqueous layer was acidified to pH 4 using 1 N HCl, saturated with sodium chloride and extracted with ethyl acetate (3 x 5 mL). The organic layers were combined, dried and concentrated in vacuo to provide 0.017 g (26%) of acid as a white solid. MS (ES +) 533.2 [60%, (M + 1)].

To a solution of the above acid (0.017 g, 0.03 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.06 mL, 0.6 mmol) and the reaction was stirred at room temperature overnight . Additional trifluoroacetic acid (0.03 ml, 0.3 mmol) was added and the reaction was stirred at room temperature for 1 hour. The solvent was removed in vacuo and traces of excess trifluoroacetic acid were removed in vacuo by co-distillation of the residue twice with dichloromethane (10 ml). The residue was dissolved in water (1.0 ml), concentrated in vacuo and dried at reflux temperature of the acetone under vacuum to obtain 0.01 g (60%) of the title compound as a solid of color. toasted, mp 124-128 ° C.

Analysis: Calculated for C13H24N406-2C2HF302: C, 36, 44; H, 4.67; N, 10, 00 Found: C, 35, 84; H, 4, 24; N, 10, 51 Example 14 3ß- acid. { [(amino) (imino) methyl] amino} -4"- [(1-methylcarbonyl-15 amino) (2,3,4-trihydroxy) butyl] cyclopentanecarboxylic acid: trifluoroacetic acid (4: 9) (isomer B in C-6, isomer A in Cl. C-7 and / or C-8) To a solution of 2-. { 3β- (t-butoxycarbonylamino) -20 Aa- [(formyl) (methylcarbonylamino) methyl] cyclopentylidene} 1,3-dithiane (isomer B in C-6) (2.58 g, 6.45 mmol) of Example 10 in tetrahydrofuran (64 ml) cooled to -78 ° C was added dropwise vinylmagnesium bromide (Aldrich , • 1.0 M solution in tetrahydrofuran, 64.5 ml, 64.5 mmol) and the mixture was stirred at -78 ° C for 1 hour. The reaction mixture was quenched carefully with saturated aqueous ammonium chloride (20 mL). Ether (100 ml) and brine (20 ml) were added and the reaction mixture was allowed to warm to room temperature. The organic layers are separated and the aqueous layer was extracted with ether (3 x 50 mL). The organic layers were combined, dried and concentrated in vacuo to provide 3.7 g of a white solid.

To the above solid (2.0 g, 4.4 mmol) dissolved in dimethylformamide (30 mL) was added t-butyldimethylsilyl chloride (1.31 g, 8.44 mmol), imidazole (0.92 g, 13.5 mmol) and dimethylaminopyridine (0.21 g, 1.69 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (30 mL) and extracted with ether (3 x 30 mL). The organic layers were combined and washed with water (30 ml) and brine (30 ml), dried and concentrated in vacuo to provide 3.8 g of crude product. Purification of the crude product by flash column chromatography (210 g of silica gel, 25% ethyl acetate in hexane) gave 1.44 g (41%) of 2-. { 3β- (t-butoxycarbonylamino) -Aa- [(1-methyl-carbonylamino) (2- {[[(t-butyl) (dimethyl) silyl] oxy} -3-butenyl] cyclopentylidene}. , 3-dithiane (isomer B in C-6, mixture of isomers in C-7 85:15) in the form of a white solid, mp 76-84 ° C.

Analysis: Calculated for C26H46N204S2Si: C, 57.53; H, 8.54; N, 5.16 Found: C, 57.29; H, 8.52; N, 5.09 To a solution of 2-. { 3β- (t-butoxycarbonylamino) -4a- [(1-methylcarbonylamino) (2- {[[(t-butyl) (dimethyl) silyl] -oxi} -3-butenyl] cyclopentylidene} -l, 3-dithiane (1.4 g, 2.58 mmol) in methanol (39.0 mL) was added with 6 N HCl (6.5 mL, 39.0 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0 ° C and sodium hydroxide (2.07 g, 51.7 mmol) was added and the reaction was stirred at room temperature for 1 hour.

The reaction was quenched with glacial acetic acid (1.6 mL, 27 mmol) and concentrated in vacuo. To the obtained residue was added 1 N HCl (5.2 ml, 5.2 mmol), ethyl acetate (10 ml) and water (20 ml). The aqueous layer was separated, saturated with sodium chloride and extracted with ethyl acetate (2 x 10 mL). The organic layers were combined and concentrated in vacuo to provide 0.68 g (74%) of crude product.

The above crude product was dissolved in anhydrous methanol (19 ml) and cooled to 0 ° C. A solution of dry HCl in ether (Aldrich, 1.0 M solution, 3.8 ml) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo (bath temperature 25 ° C) to obtain methyl 3β- (t-butoxycarbonylamino) -4 - [(2-hydroxy) (1-methylcarbonylamino) -3-butenyl] cyclopentanecarboxylate in form of an oil, MS (ES +) 371.5 [100%, (M + 1)].

To a solution of the above ester in dichloromethane (19 ml) was added trifluoroacetic acid (2.94 ml, 38.0 mmol), and the reaction was stirred at room temperature overnight. Additional trifluoroacetic acid (1.5 ml, 17 mmol) was added and the reaction was stirred at room temperature for 1 hour. The solvent was removed in vacuo and traces of trifluoroacetic acid were removed in vacuo by co-distillation of the residue twice with dichloromethane (5 ml). The residue was dissolved in dimethylformamide (10 mL), and triethylamine (1.4 mL, 10 mmol), 1,3-bis (t-butoxycarbonyl) -2-methyl-2-thioseudourea (0.66 g, 2%) were added. , 28 mmole), and mercuric chloride (0.62 g, 2.28 mmole). The reaction was stirred overnight at room temperature and the reaction mixture was diluted with ethyl acetate (30 mL) and filtered to remove the inorganic impurities. The filtrate was washed with water (2 x 10 mL) and brine (10 mL), dried and concentrated in vacuo to obtain 0.78 g of crude product. The crude product was purified by flash column chromatography [silica gel (40 g), 40-50% ethyl acetate in hexane] to give two isomers of 3β-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] -amino} -4 - [(2-hydroxy) (1-methylcarbonylamino) -3-butenyl] -cyclopentanecarboxylic acid methyl ester: 1. 0.15 g (16%) of isomer A in the form of a semi-solid, MS (ES +) 495.5 [100%, (M + 1) -H20] and 513.6 [30%, (M + l)] . 2. 0.12 g (13%) of isomer B in the form of a semi-solid, MS (ES +) 513.5 [100%, (M + 1)].

The above A isomer (0.13 g, 0.25 mmol) was dissolved in tetrahydrofuran / t-butanol (2 mL, 1: 1) and N-methylmorpholine oxide (50 mg), osmium tetraoxide (a few crystals) and water (1 ml). The reaction mixture was stirred overnight at room temperature. A saturated aqueous solution of sodium sulfite (2 mL) and sodium sulfite (1 g) was added and stirred vigorously for 30 minutes. Brine (2 mL) was added and the aqueous layer was saturated with sodium chloride and extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried and concentrated in vacuo to obtain 0.12 g (92%) of 3β-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4a- [(1-Methyl-carbonylamino) (2,3,4-trihydroxy) butyl] cyclopentane-carboxylic acid methyl ester, MS (ES +) 547.4 [20%, M + 1)] and 529.4 [100 %, (M + 1) -H20].

To a solution of the above solid (0.12 g, 0.23 mmol) in tetrahydrofuran (1 mL) was added 1N sodium hydroxide (1.1 mL, 1.1 mmol), and the mixture was stirred at the temperature environment for 2.0 hours. Ether (2 mL) and water (2 mL) were added, the layers were separated and the aqueous layer was saturated with sodium chloride and extracted with ethyl acetate (3 x 5 mL). The organic layers were combined, dried and concentrated in vacuo to provide 0.033 g (25%) of acid as a white solid. MS (ES +) 515.4 [25%, (M + 1) -H20] and 533.4 [5%, (M + 1)].

To a solution of the above acid (0.033 g, 0.06 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.1 mL, 1.2 mmol) and the reaction was stirred at room temperature overnight . Additional trifluoroacetic acid (0.05 ml, 0.6 mmol) was added and the reaction was stirred at room temperature for 1 hour. The solvent was removed in vacuo and traces of excess trifluoroacetic acid were removed in vacuo by co-distillation of the residue twice with dichloromethane (10 ml). The residue was dissolved in water (1.0 ml), concentrated in vacuo and dried at reflux temperature of acetone under vacuum to obtain 0.018 g (49%) of the title compound as a tan solid, pf. 125-135 ° C.

Analysis: Calculated for C13H24N406 • 2,25C2HF302: C, 35.69; H, 4.49; N, 9.51 Found: C, 36.02; H, 4.19; N, 9.58 Example 15 3ß- acid. { [(amino) (imino) methyl] amino} -Aa- [(1-methylcarbonyl-amino) (2, 3, 4-trihydroxy) butyl] -cyclopentanecarboxylic acid: trifluoroacetic acid (5: 13) (isomer B in C-6, isomer B in Cl, C-7 and / or C-8) E13ß-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} Methyl 4 - [(2-hydroxy) (1-methylcarbonylamino) -3-butenyl] cyclopentanecarboxylate, (isomer B in C-6, isomer B in Cl and C-7, of Example 14) (0.12 g, 0.24 mmol) was dissolved in tetrahydrofuran / t-butanol (2 ml, 1: 1) and N-methylmorpholine oxide (60 mg), osmium tetraoxide (a few crystals) and water (1 ml) were added. The reaction mixture was stirred overnight at room temperature. A saturated aqueous solution of sodium sulfite (2 ml) and sodium sulfite (1 g) were added and the reaction was stirred vigorously for 30 minutes. Brine (2 mL) was added, the aqueous layer was saturated with sodium chloride and extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried and concentrated in vacuo to obtain 0.11 g (87%) of 3β-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} Aa- [(1-methylcarbonylamino) - (2,3,4-trihydroxy) butyl] -cyclopentanecarboxylic acid methyl ester, MS (ES +) 547.5 [100%, M + 1)].

To a solution of the above solid (0.11 g, 0.2 mmol) in tetrahydrofuran (1 mL) was added 1 N sodium hydroxide (1.1 mL, 1.1 mmol), and the mixture was stirred at the temperature environment for 2 hours. Ether (2 ml) and water (2 ml) were added and the organic layers were separated. The aqueous layer was washed with ether (2 x 5 mL). The aqueous layer was acidified to pH 4 using 1 N HCl, saturated with sodium chloride and extracted with ethyl acetate (3 x 5 mL). The organic layers were combined, dried and concentrated in vacuo to provide 0.013 g (12%) of acid as a white solid. MS (ES +) 533.5 [100%, (M + 1)].

To a solution of the above acid (0.013 g, 0.24 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.04 mL, 0.48 mmol) and the reaction was stirred at room temperature overnight . Additional trifluoroacetic acid (0.02 ml, 0.24 mmol) was added and the reaction was stirred at room temperature for 1 hour. The solvent was removed in vacuo and traces of excess trifluoroacetic acid were removed in vacuo by co-distillation of the residue twice with dichloromethane (10 ml). The residue was dissolved in water (1.0 ml), concentrated in vacuo and dried at reflux temperature of acetone in vacuo to obtain 0.01 g of the title compound, mp. 140-145 ° C.

Analysis: Calculated for C13H24N406 • 2, 6C2HF302: C, 34.76; H, 4.26; N, 8.91 Found: C, 34.52; H, 4.20; N, 9.16 Example 16 C-3-f [(amino) (imino) methyl] amino acid} -t-l-hydroxy-t-4- [(1-methylcarbonylamino) (2-trifluoromethylcarbonyloxy) ethyl] -cyclopentane-r-carboxylic acid: trifluoroacetic acid (4: 1) (isomer A in C-6) To a mixture of tris- (methylthio) methane (1.08 g, 7.0 mmol) in tetrahydrofuran (15 mL) at -78 ° C was added n-butyl lithium (1.6 M, 4.4 mL, 7%). , 0 immole) in nitrogen over a period of 2 minutes. The mixture was further stirred for 0.5 hour at this temperature and a mixture of 3β- was added thereto. { [(t-butoxycarbonylamino) - (t-butoxycarbonylimino) methyl] amino} -4a- [(ethoxycarbonyl) - (methylcarbonylamino) methyl] cyclopentanone (isomer A of Example 6, 0.49 g, 1.0 mmol) in tetrahydrofuran (5 ml). The reaction mixture was quenched with a solution of saturated aqueous ammonium chloride (5 ml) after stirring for 1 hour at -78 ° C. The mixture was allowed to warm to room temperature and the organic layer was separated. The aqueous layer was further extracted with ether (10 ml). The combined organic layers were dried (MgSO 4), filtered and the filtrate was concentrated to a syrup, which was purified by passing through a column of silica gel (25 g) using ether / hexane (3: 1) to give 0.42 g (66%) of t-3-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -c-4- [(ethoxycarbonyl) - (methylcarbonylamino) methyl] -t-l- [ris (methylthio) methyl] -cyclopentane-r-ol (isomer A in C-6) as a white solid. An analytical sample was prepared by recrystallization from ether / hexane, mp. 155 ° C (dec.).

Analysis: Calculated for C26H46N408S3: C, 48.88; H, 7.26; N, 8.77 Found: C, 49.00; H, 7.34; N, 8.64 To a solution of the above compound (1.5 g, 2.4 mmol) in tetrahydrofuran (25 mL) was added dropwise in nitrogen lithium borohydride (Aldrich, 0.22 g, 9.6 mmol) and 9-borabicylo [3, 3, 1] nonane-lithium hydride (Aldrich, 1 M solution in tetrahydrofuran, 0.24 ml, 0.24 mmol) and the reaction mixture was stirred at room temperature overnight. More lithium borohydride (0.16 g, 7.2 mmol) and 9-borabicyclo [3, 3, 1] nonane-lithium hydride (Aldrich, 1 M solution in tetrahydrofuran, 0.24 mL, 0.24 was added. Immoles) and the reaction was stirred at room temperature for 4 hours. The reaction was quenched with 1 N sodium hydroxide (3 mL), brine (3 mL) and stirred for 5 minutes. The reaction was acidified to pH 4 using glacial acetic acid. Ether (10 mL) was added and the aqueous layer was separated. The aqueous layer was neutralized with saturated aqueous sodium bicarbonate and extracted with ether (2 x 10 mL). The organic layers were combined, dried and concentrated in vacuo to obtain 1.55 g of a yellow oil. The oil was purified by flash column chromatography [chloroform: methanol: 20% concentrated ammonium hydroxide (80: 18: 2) in dichloromethane]. The oil was crystallized from ether / hexane to provide 0.6 g (42%) of t-3-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -c-4- [(2-hydroxy) (1-methylcarbonylamino) ethyl] -tl- [tris (methylthio) -methyl] cyclopentane-r-ol (isomer A in C-6) as a white solid , pf. 108-112 ° C.

Analysis: Calculated for C24H44N40? S3: C, 48.30; H, 7.43; N, 9.39 Found: C, 48.37; H, 7.49; N, 9.25 To a mixture of the above compound (1.0 g, 1.69 mmol), mercuric chloride (1.69 g, 6.23 mmol) and mercuric oxide (0.48 g, 2.53 mmol) was added methanol / water (40/3 ml) and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was filtered through a pad of celite and Florisil (17 g). The cake was washed with methanol (20 mL) and the filtrate was concentrated in vacuo to give 1.8 g of a white semi-solid. The crude product was purified by flash column chromatography [silica gel (33 g); 75% ethyl acetate in hexane and 10% methanol in ethyl acetate] to provide 0.57 g (68%) of c-3. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -t-l-hydroxy-t-4- [(2-hydroxy) (1-methylcarbonylamino) ethyl] -cyclopentane-methyl-r-carboxylate (isomer A in C-6) as a white solid, mp. 72-74 ° C. [Rf = 0, ¿7, methanol in 5% ethyl acetate].

Analysis: Calculated for 22H38N409: C, 52, 58; H, 7, 62; N, 11, 15 Found: C, 52, 85; H, 7, 82; N, 10, 93 To a solution of the above ester (0.5 g, 1.0 mmol) in tetrahydrofuran (10 mL) was added 1N sodium hydroxide (2.0 mL, 2.0 mmol) and water (3 mL). my). The reaction mixture was stirred at room temperature for 1 hour, the tetrahydrofuran was removed in vacuo and the aqueous layer was made acidic with glacial acetic acid (pH = 5). The aqueous layer was saturated with sodium chloride and extracted with ethyl acetate (5 x 10 mL). The organic layers were combined and concentrated in vacuo to give 0.43 g (88%) of c-3 acid. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -tl-hydroxy-t-4- [(2-hydroxy) (1-methylcarbonylamino) ethyl] -cyclopentane-r-carboxylic acid (isomer A in C-6, as a white solid.) MS (ES +) 489 , 5 [50%, (M + l)].

The above acid (0.29 g, 0.6 mmol) was dissolved in dichloromethane (12 mL), trifluoroacetic acid (0.91 mL, 11.88 mmol) was added and the reaction was stirred at room temperature overnight . Additional trifluoroacetic acid (0.45 ml, 5.9 mmol) was added and the reaction was stirred at room temperature for 1 hour. The solvent was removed in vacuo and traces of excess trifluoroacetic acid were removed in vacuo by co-distillation of the residue twice with dichloromethane (10 ml). The residue was triturated with ether to obtain 0.14 g (56%) of the title compound as a white solid, mp. 148-160 ° C.

Analysis: Calculated for C 13 H 19 F 3 N 40 9 -0, 25 C 2 HF 302: C, 39.28; H, 4.70; N, 13.57 Found: C, 39.34; H, 5.00; N, 13.26 Example 17 Acid c-3-. { [(amino) (imino) methyl] amino} -t-l-hydroxy-t-4- [(1-methylcarbonylamino) (2-trifluoromethylcarbonyloxy) ethyl] -cyclopentane-r-carboxylic acid: trifluoroacetic acid (4: 3) (isomer B in C-6) To tris (methylthio) methane (Aldrich, 18.9 ml, 142 mmol) in tetrahydrofuran (250 ml) at -78 ° C, n-butyl lithium was added dropwise over a period of 10 minutes under nitrogen. 1.6 M solution in hexane, 98 ml, 156 mmol) and stirred at -78 ° C for 40 minutes. The anion at -78 ° C is added a solution of 3β-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4 - [(ethoxycarbonyl) - (methylcarbonylamino) methyl] cyclopentanone, isomer B of Example 6 (8.58 g, 1.7.7 mmol) in tetrahydrofuran (85 ml) dropwise over a period of 10 hours. minutes and the The reaction mixture was stirred at -78 ° C for 1.5 hours. The reaction was quenched with saturated ammonium chloride (50 mL) and warmed to room temperature. Ether (50 mL) was added and the organic layers were combined, dried over MgSO4, and concentrated in vacuo to provide a gross product. Purification of the crude product by flash column chromatography (silica gel, 660 g, 30-50% ethyl acetate in hexane) gave 3.8 g (34%) of t-3. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] -amino} -c-4- [(ethoxycarbonyl) (methylcarbonylamino) methyl] -t- l- [tris (methylthio) methyl] cyclopentane-r-ol (isomer B in C-6) as a white solid, mp. 94-96 ° C.

Analysis: Calculated for C26H 8N ° 8S3: C, 48.88; H, 7.26; N, 8.77 Found: C, 49.08; H, 7.05; N, 8.75 To a solution of the above compound (1.4 g, 2.2 mmol) in tetrahydrofuran (22 mL) was added dropwise in nitrogen lithium borohydride (Aldrich, 0.38 g, 16.43 mmol) and 9-borabicyclo [3, 3, 1] nonane-lithium hydride (Aldrich, 1 M solution in tetrahydrofuran, 0.44 mL, 0.44 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with 1 N sodium hydroxide (3 mL), brine (3 mL) and stirred for 5 minutes. The reaction was acidified to pH 4 using glacial acetic acid, ether (10 ml) was added and the aqueous layer was separated. The aqueous layer was neutralized with saturated aqueous sodium bicarbonate and extracted with ether (2 x 10 mL). The organic layers were combined, dried and concentrated in vacuo to obtain 1.44 g of a yellow oil. The oil was purified by flash column chromatography [chloroform: methanol: 20% concentrated ammonium hydroxide (80: 18: 2) in dichloromethane]. The oil was crystallized from ether / hexane to provide 0.47 g (36%) of t-3-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -c-4- [(2-hydroxy) (1-methylcarbonylamino) ethyl] -tl- [tris (methylthio) -methyl] cyclopentane-r-ol (isomer B in C-6) as a white solid , pf. 108-110 ° C.

Analysis: Calculated for C24H44N407S3: C, 48.30; H, 7.43; N, 9.39 Found: C, 48.58; H, 7.51; N, 9.20 To a mixture of the above compound (0.78 g, 1.32 mmol), mercuric chloride (1.34 g, 4.9 mmol) and mercuric oxide (0.43 g, 1.97 mmol) was added methanol / water (29.5 / 2.5 ml) and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was filtered through a pad of Celite and Florisil (13 g). The cake was washed with methanol (20 mL) and the filtrate was concentrated in vacuo to provide 1.1 g of a white semi-solid. The crude product was purified by flash column chromatography [silica gel (30 g); 75% ethyl acetate in hexane and 10% methanol in ethyl acetate] to provide 0.42 g (63%) of c-3. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) -methyl] amino} -t-l-hydroxy-t-4- [(2-hydroxy) (1-methylcarbonyl-amino) ethyl] cyclopentane-methyl-r-carboxylate (isomer B in C-6) as a white solid, mp. 194-198 ° C.

Analysis: Calculated for C22H38N409 -0.5H20: C, 51.65; H, 7.68; N, 10.95 Found: C, 51.37; H, 7.50; N, 10.93 To a solution of the above ester (0.38 g, 0.76 mmol) in tetrahydrofuran (7.5 ml) was added 1N sodium hydroxide (1.5 ml, 1.5 mmol) and water (2.25 ml). ). The reaction mixture was stirred at room temperature for 1 hour. Tetrahydrofuran was removed in vacuo and the aqueous layer was made acidic with glacial acetic acid (pH = 5). The aqueous layer was saturated with sodium chloride and extracted with ethyl acetate (5 x 10 mL). The organic layers were combined and concentrated in vacuo to provide 0.325 g (87%) of acid. This was triturated with ethyl flB acetate in hexane to provide 0.18 g of c-3-5 acid. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] -amino} -tl-hydroxy-t-4- [(2-hydroxy) (1-methylcarbonyl-amino) ethyl] cyclopentane-r-carboxylic acid (isomer B in C-6, as a white solid.) MS (ES +) 489.4 [100%, (M + 1)]. 10 The above acid (0.15 g, 0.31 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (0.48 mL, 6%) was added. 3 mmole) and the reaction was stirred at room temperature overnight, additional trifluoroacetic acid (0.24 ml, 3.2 mmol) was added and the reaction was stirred at room temperature for 1 hour. The residue was triturated with ethanol / ether to obtain 0.125 g (86%) of the title compound. in the form of a white solid, mp 210-220 ° C.

Analysis: Calculated for C13H19F3N409 -0, 75C2HF302: C, 37.07; H, 4.24; N, 11.93 Found: C, 37.33; H, 4.45; N, 12.22 Example 18 .CF3C02H.l .5CF3C02NH4 T-3-Amino-c-4- [(1-methylcarbonylamino) (2-f-enylmethoxy) ethyl] -t-1-hydroxycyclopentane-r-carboxylic acid: trifluoroacetic acid: trifluoroacetate ammonium (2: 2: 3) ) A mixture of c-3- (t-butoxycarbonylamino) -t-4- [(1-methylcarbonylamino) (2-phenylmethoxy) ethyl] -tl- [bis (phenylthio) methyl] cyclopentane-rl-ol of Example 8 (2 , 53 g, 4.1 mmol), mercuric oxide (1.90 g, 8.8 mmol), and boron trifluoride etherate (1.1 ml, 8.9 mmol) in a 15% aqueous solution of tetrahydrofuran (70 ml) was stirred at room temperature for 2 hours. The reaction mixture was filtered through a pad of Celite and Florisil. The filtrate was concentrated in vacuo to give 2.74 g of the crude product. To the above crude product in methanol (50 ml) was added iodine (1.9 g, 7.5 mmol) and the reaction mixture was heated to 50 ° C. To this mixture was added dropwise a solution of potassium hydroxide (0.71 M / methanol, 50 ml, 35.7 mmol). After 2 hours of stirring at 50 ° C, the reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo and the resulting residue was dissolved in ethyl acetate (30 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (4 x 10 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered through Celite, and concentrated in vacuo to provide 3.6 g of crude product. Purification by flash column chromatography (silica gel, 200 g, 50-100% ethyl acetate / hexanes) gave 0.224 g (14%) of the desired hydroxy acid as a white solid. To a solution of the hydroxy acid (0.244 g, 0.56 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (0.86 mL, 11.2 mmol) and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo to give a crude product. Purification by flash column chromatography (silica gel, 60 g, chloroform / methanol / ammonium hydroxide: 80/18/2) gave 0.241 g of a thick yellow oil. Trituration of the yellow oil with ether gave 0.185 g (51%) of the title compound as a tan solid, mp. 37-39 ° C.

Analysis: Calculated for C17H24 205 -C2HF30 • 1.5C2H4F3N02: C, 40.84; H, 4.83; N, 7.58 Found: C, 40.86; H, 5.08; N, 7.90 Example 19 Acid c-3-. { [(amino) (imino) methyl] amino} -t-l-hydroxy-t-4-. { [(methylcarbonylamino). { [(methyl) (methoxy) amino] carbonyl} -metil } Cyclopentane-r-carboxylic acid: trifluoroacetic acid (1: 1) To a solution of t-3-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] -amino} -c-4- [(ethoxycarbonyl) - (methylcarbonylamino) methyl] -tl- [tris (methyl) methyl] -cyclopentane-r-ol (isomer B in C-6) (from Example 17, 2.1 g, 3 , 3 mmol) in ethanol (4 mL) and tetrahydrofuran (16.5 mL) was added 1N sodium hydroxide (6.6 mL, 6.6 mmol) and water (4 mL) and the reaction mixture was stirred at RT. the room temperature for 2 hours. The tetrahydrofuran was removed in vacuo and the aqueous layer was acidified to pH 4-5 using glacial acetic acid. The solid obtained was collected by filtration and dried under vacuum at the reflux temperature of toluene to provide 1.78 g (87%) of t-3. { [(t-Butoxycarbonylamino) - (t-butoxycarbonylimino) methyl] -amino-c-4- [(carboxy) - (methylcarbonylamino) methyl] -tl- [tris (methylthio) methyl] cyclopentane-r-ol in the form of a solid white, MS (ES +) 611.5.

To a solution of the above acid (0.92 g, 1.5 mmol) in dichloromethane / tetrahydrofuran (12/3 mL) cooled to 0 ° C was added methyl chloroformate (0.13 mL, 1.58 mmol) and triethylamine. (0.25 ml, 1.8 mmol). The reaction mixture was stirred at 0 ° C for 30 minutes and a cold-prepared solution of N, 0-dimethylhydroxylamine hydrochloride (0.22 g, 2.25 mol) and triethylamine (0.42 ml, 3, 0 mmol) in dichloromethane (5 ml) which had been stirred at 0 ° C for 30 minutes. The reaction mixture was allowed to warm to room temperature and was stirred overnight. Ether (20 ml), tetrahydrofuran (50 ml) and sodium hydroxide (20 ml) were added and the organic layer was separated. The organic layer was washed with brine (20 mL), dried and concentrated in vacuo to provide a crude amide as an oil. Purification of the crude product by flash column chromatography (60 g of silica gel, 50-100% ethyl acetate in hexane) gave 0.63 g (64%) of t-3. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -c-4-. { (methylcarbonylamino). { [(methoxy) (methyl) amino] carbonyl} -metil } -t-l- [Tris (methylthio) methyl] -cyclopentane-r-ol as a white solid. An analytical sample was prepared, mp. 200 ° C by crystallization from ether.

Analysis: Calculated for C26H47N508S3: C, 47.76; H, 7.25; N, 10.71 Found: C, 47.96; H, 7.28; N, 10.63 To a mixture of the above compound (0.5 g, 0.77 mmol), mercuric chloride (0.78 g, 2.8 mmoles) and mercuric oxide (0.25 g, 1.15 mmol) were added. methanol / water (16.3 / 1.4 ml) was added, and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was filtered through a pad of Celite and Florisil (7 g). The cake was washed with methanol (20 mL) and the filtrate was concentrated in vacuo to give 1.8 g of a white semi-solid. The crude product was purified by flash column chromatography [silica gel (20 g); 75% ethyl acetate in hexane and 10% methanol in ethyl acetate] to provide 0.35 g (82%) of c-3. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -t-l-hydroxy-t-4-. { (methylcarbonylamino) -. { [(methoxy) (methyl) amino] carbonyl} methyl } methyl cyclopentane-carboxylate in the form of a white solid, mp. 72-74 ° C [Rf = 0.29 and 0.15, ethyl acetate]; MS (ES +) 560.6.

To a solution of the above solid (0.352 g, 0.63 mmol) in tetrahydrofuran (6.3 mL) was added 1 N sodium hydroxide (1.3 mL, 1.3 mmol) and water (5 mL) and the mixture of reaction was stirred at room temperature for 1 hour. Tetrahydrofuran was removed in vacuo and the aqueous layer was washed with ether (2 x 10 mL). The aqueous layer was acidified to pH 5-4 using glacial acetic acid, and saturated with sodium chloride and extracted with ethyl acetate (3 x 10 mL). The organic layer was dried and concentrated in vacuo to provide 0.23 g (67%) of c-4- acid. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -t-l-hydroxy-t-4-. { (methylcarbonylamino). { [(methoxy) (methyl) amino] -carbonyl} methyl } cyclopentane-r-carboxylic acid in the form of a white solid, MS (ES +) 546.6.

To a solution of the above acid (0.18 g, 0.33 mmol) in dichloromethane (6.6 mL) was added trifluoroacetic acid (0.51 mL, 6.6 mmol) and the reaction was stirred at room temperature for the night. Additional trifluoroacetic acid (0.25 ml, 3.3 mmol) was added and the reaction was stirred at room temperature for 1 hour. The solvent was removed in vacuo and traces of excess trifluoroacetic acid were removed in vacuo by co-distillation of the residue twice with dichloromethane (10 ml). The residue was dissolved in water (5 ml) and concentrated in vacuo to obtain 0.14 g (92%) of the title compound as a white solid, mp. 160-161 ° C.

Analysis: Calculated for C13H23N5Og -C2HF202: C, 39.22; H, 5.26; N, 15.25 Found: C, 39.09; H, 5.29; N, 14.95 Example 20 3ß- acid. { [(amino) (imino) methyl l amino} -4 -. { [(methoxy) (methyl) -amino] -1- (methylcarbonylamino) -2-oxo} butyl} Cyclopentanecarboxylic acid: trifluoroacetic acid (1: 1) To a solution of 2-. { 3ß-. { [(t-butoxycarbonylamino) - (t-butoxycarbonylimino) methyl] amino} -4 - [(ethoxycarbonyl) - (methylcarbonylamino) methyl] -l-cyclopentylidene} -l, 3-dithiane of Example 6 (6.74 g, 11.5 mmol) in ethanol (57.5 ml) and tetrahydrofuran (115 ml) was added 1N sodium hydroxide (23 ml, 23 mmol) and water (35 ml) and the reaction mixture was stirred at room temperature for 5 hours. Tetrahydrofuran was removed in vacuo and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The aqueous layer was acidified to pH 5-4 using glacial acetic acid. The obtained solid was collected by filtration and dried under vacuum at the reflux temperature of acetone to give 5.95 g (93%) of 2-. { 3ß-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4 - [(carboxy) (methylcarbonylamino) methyl] -1-cyclopentylidene} -l, 3-dithiane in the form of a white solid. An analytical sample was prepared, mp. 158 ° C by recrystallization from ethanol.

Analysis: Calculated for C 24 H 38 N 407 S 2 - 0, 75 C 2 Hg O: C, 51.63; H, 7.22; N, 9.44 Found: C, 51.70; H, 7.26; N, 9.18 To a solution of the above acid (0.63 g, 1.13 mmol) in dichloromethane / tetrahydrofuran (8/2 mL) cooled to 0 ° C was added methyl chloroformate (0.1 mL, 1.24 mmol) and triethylamine. (0.19 ml, 1.36 mmol). The reaction mixture was stirred at 0 ° C for 30 minutes and a cold solution of N, 0-dimethylhydroxylamine hydrochloride (0.17 g, 1.7 mmol) and triethylamine (0.32 mL, 2.26 mmol) was added. ) in dichloromethane (5 ml) which had been stirred at 0 ° C for 30 minutes. The reaction mixture was allowed to warm to room temperature and was stirred overnight. Brine (5 mL), water (5 mL) and saturated sodium carbonate (5 mL) were added and the organic layer was separated. The organic layer was dried and concentrated in vacuo to provide an oil. Purification of the crude product by flash column chromatography (34 g of silica gel, 50-75% ethyl acetate in hexane) gave 0.48 g (63%) of 2-. { 3ß-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4a- { . { [(methoxy) (methyl) amino] -carbonyl} methyl } cyclopentylidene} -l, 3-ditiano. An analytical sample was prepared, mp. 190-192 ° C by crystallization from ether / hexane.

Analysis: Calculated for C2gH43N507S2: C, 51.89; H, 7.20; N, 11.64 Found: C, 52.32; H, 7.24; N, 11.33 To a solution of the above compound (3.4 g, 5.7 mmol) in tetrahydrofuran (50 mL) was added dropwise vinylmagnesium bromide (Aldrich, 1 M solution in tetrahydrofuran, 33.94 mL, 33.94 mmol) over a period of 10 minutes. The reaction mixture was stirred at room temperature for 10 minutes and quenched with a saturated solution of ammonium chloride and brine (1: 1, 30 ml). Ether (25 mL) was added and the organic layer was separated. The organic layers were combined, dried and concentrated in vacuo to provide an oil. Purification of the crude product by flash column chromatography (180 g of silica gel, 20-70% ethyl acetate in hexane) gave 2.0 g (56%) of 2-. { 3ß-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} - Aa-. { . { 4- [(methoxy) (methyl) amino] -1- (methylcarbonylamino) -2-oxo} butyl} cyclopentylidene} -l, 3-dithiane in the form of a white solid, mp. 99-101 ° C.

Analysis: Calculated for C28H4? N507S3: C, 53.40; H, 7.52; N, 11.12; S, 10.18 Found: C, 53.81; H, 7.48; N, 10.96; s, 10.25 To a solution of the above compound (0.55 g, 0.9 mmol) in methanol (26.4 mL) was added 6N HCl (2.2 mL, 13.0 mmol) and the mixture was stirred at room temperature until all the starting material had disappeared (TLC analysis, ethyl acetate, ~ 30 hours). The reaction mixture was cooled to 0 ° C and sodium hydroxide (0.72 g, 18 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction was quenched with glacial acetic acid (0.5 ml) and concentrated in vacuo to provide a residue. To the residue was added ethyl acetate (10 ml) and water (10 ml). The aqueous layer was separated and extracted with ethyl acetate (10 mL). The organic layers were combined and concentrated in vacuo to provide a crude product. The above crude product was purified by flash column chromatography (50-80% ethyl acetate in hexane) to provide 0.29 g (56%) of 3β-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) -methyl] amino} -4a- { . { 4- [(methoxy) (methyl) amino] -l- (methylcarbonylamino) -2-oxo} butyl} Methyl cyclopentanecarboxylate in the form of an oil. The oil crystallized in 'ether in the form of a white solid.

Analysis: Calculated for C2gH45N509: C, 54.63; H, 7.93; N, 12.25 Found: C, 54.66; H, 7.87; N, 11.94 To a solution of the above ester (0.2 g, 0.35 mmol) in tetrahydrofuran (3.5 mL) was added 1N sodium hydroxide (0.88 mL, 0.88 mmol) and water (2 mL) and The reaction mixture was stirred at room temperature for 2 hours. The tetrahydrofuran was removed in vacuo and water (5 ml) was added. The aqueous layer was washed with ether (2 x 5 mL) and acidified to pH 5-4 using glacial acetic acid. The aqueous layer was saturated with sodium chloride and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried and concentrated in vacuo to provide 0.18 g of the corresponding cyclopentanecarboxylic acid as a white solid, MS (ES +) 558.3 [100%, (M + 1)].

To a solution of the above acid (0.18 g, 0.33 mmol) in dichloromethane (6.6 mL) was added trifluoroacetic acid (0.51 mL, 6.6 mmol) and the reaction was stirred at room temperature for the night. Additional trifluoroacetic acid (0.25 ml, 3.3 mmol) was added and the reaction was stirred at room temperature for 1 hour. The solvent was removed in vacuo, and traces of excess trifluoroacetic acid were removed in vacuo by co-distillation of the residue twice with dichloromethane (10 mL). The residue was washed with ether (2 x 10 mL), precipitated with methanol / ether and dried at reflux temperature of toluene in vacuo to obtain the title compound as a tan solid, mp. 189-192 ° C.

Analysis: Calculated for C15H27N505 -C2HF302: C, 43.31; H, 5.99; N, 14.85 Found: C, 43.38; H, 5.74; N, 14.42 Example 21 C02H Acid t-3-. { [(amino) (imino) methyl] mino} -c-4- (diethylaminocarbonyl) (methylcarbonylamino) methyl] -t-l-hydroxy-cyclopentane-r-carboxylic acid: trifluoroacetic acid (3: 5) To a stirred solution of tris (methylthio) methane (1.6 ml, 12 mmol) in tetrahydrofuran (20 ml) at -78 ° C was added dropwise n-butyl lithium (2.5 M, 5.3 ml, 13.3 mmol). After 30 minutes of stirring, 3β-t-butoxycarbonylamino-4α- [bis (ethoxycarbonyl) - (methylcarbonylamino) methyl] cyclopentanone from Example 8 (1.0 g, 2.4 mmol) in tetrahydrofuran ( 15 mi). The reaction mixture was stirred at -78 ° C for 3 hours, then quenched with a saturated aqueous solution of ammonium chloride (15 ml). The separated aqueous layer was extracted with ether (4 x 10 mL). The combined organic extracts were washed with brine, dried (MgSO 4), filtered through Celite, and concentrated in vacuo to give a crude product. Purification by radial CLP (silica gel, 25-35% ethyl acetate / hexane) gave 0.48 g (35%) of c-3- (t-butoxycarbonylamino) -t-4- [bis- (ethoxycarbonyl ) - (methylcarbonylamino) methyl] -tl- [tris (methylthio) methyl] -cyclopentane-r-ol as a white solid, mp. 98-100 ° C.

Analysis: Calculated for C23H40N2OgS3: C, 48.57; H, 7.09; N, 4.93 Found: C, 48.74; H, 7.00; N, 4.91 To a mixture of the above compound (1.71 g, 3.0 mmol) in ethanol (15 mL) was added 1N sodium hydroxide (15 mL) and heated to reflux for 2 hours. The mixture was acidified with acetic acid and refluxed for 1 hour and concentrated. To the residue was added water (50 ml) and the mixture was extracted with dichloromethane (3 x 50 ml) The combined organic extracts were dried (MgSO 4), filtered and concentrated to give c-3- (t-butoxycarbonylamino) - t-4- [(carboxy) (methylcarbonylamino) -methyl] -tl- [tris (methylthio) methyl] cyclopentane-r-ol (1.2 g, 85%).

To a mixture of the above acid (1.2 g, 2.56 mmol) in tetrahydrofuran (15 mL) at -5 ° C was added triethylamine (0.29 g, 2.8 mmol) and ethyl chloroformate (0.31 g, 2.8 mmol) and stirred for 2.5 hours. To this mixture was then added diethylamine (0.38 g, 5.2 mmol) and stirred at 0 ° C for 1 hour and at room temperature for 3 hours. The mixture was diluted with ethyl acetate (100 ml) and water (75 ml). The organic layer was separated, washed with water (100 ml) and brine (100 ml), and dried (MgSO 4). After filtration, the filtrate was concentrated to give 1.1 g (82%) of c-3- (t-butoxycarbonyl-amino) -t-4- [(diethylaminocarbonyl) (methylcarbonylamino) "methyl] -tl- [ crude tris (methylthio) methyl] cyclopentane-r-ol.

To a mixture of the above crude amide (1.10 g, 2.10 mmol) in a mixture of methanol (12): water (1) (51.0 ml) was added mercury (II) chloride (2.10 g, 7.75 mmol) and mercury oxide (II) (0.69 g, 3.18 mmol) and stirred for 2 hours. The solids were removed by filtration through Celite and washed with dichloromethane (100 ml). Water (100 ml) was added to the filtrate and the organic layer was separated. The aqueous layer was further extracted with dichloromethane (2 x 80 mL). The combined organic layers were dried (MgSO4), filtered and the filtrate was concentrated to give 0.9 g (100%) of a t-3- (t-butoxycarbonylamino) -c-4- [(diethylaminocarbonyl)) syrup. crude methyl (methylcarbonylamino) methyl] -tl-hydroxycyclopentane-r-carboxylate.

A mixture of the above crude ester (0.9 g) in dichloromethane (50 ml) was stirred with trifluoroacetic acid (5.0 ml) for 16 hours. The reaction mixture was concentrated and dried under vacuum to give 0.93 g (100%) of the corresponding t-3-amino-c-4- [(diethylaminocarbonyl) - (methylcarbonylamino) methyl] -tl-hydroxycyclopentane-r- crude methyl carboxylate. This was used as is for the next stage.

To a mixture of the above amine (0.93 g, 2.1 mmol) in dimethylformamide (20 mL) were added triethylamine (1.06 g, 10.5 mmol), N, N'-bis-t-methoxycarbonyl- S-methylisothiourea (0.61 g, 2.1 mmol), and mercury (II) chloride (0.57 g, 2.1 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (100 mL) and filtered through Celite. The filtrate was washed with water (2 x 100 mL), and brine (1 x 100 mL). The organic layer was dried (MgSO 4), filtered and concentrated to a syrup, which was purified by passing through a column of silica gel (50 g) using methanol in 5% ethyl acetate to give 0, 65 g (54%) of t-3-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -c-4- [(Diethylaminocarbonyl) (methylcarbonylamino) methyl] -t-l-hydroxy-cyclopentane-methyl-r-carboxylate in the form of a white powder, mp. > 120 ° C (dec.).

Analysis: Calculated for C2gH45N509: C, 54.63; H, 7.93; N, 12.25 Found: C, 54.56; H, 7.97; N, 12.04 A mixture of the above ester (0.88 g, 0.66 mmol) in 0.1 N sodium hydroxide (13.0 ml, mixture of water-1, tetrahydrofuran-1, ethanol-1) was stirred at room temperature for 2 hours. This was neutralized with acetic acid after filtration through a cotton plug and stirred at room temperature for 16 hours. The obtained precipitated product was collected by filtration, washed with water and dried under vacuum to give 0.33 g (90%) of t-3- acid. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -c-4- [(diethylaminocarbonyl) (methylcarbonylamino) ethyl] -t-1-hydroxycyclopentane-r-carboxylic acid in the form of a white solid, mp. > 235 ° C (dec.).

Analysis: Calculated for C25H43N509: C, 53.85; H, 7.77; N, 12.56 Found: C, 53.74; H, 7.83; N, 12.56 A mixture of t-3- acid. { [(t-butoxycarbonylamino) - (t-butoxycarborylimino) methyl] amino} -c-4- [(diethylamino-carbonyl) (methylcarbonylamino) methyl] -tl-hydroxycyclo-pentane-r-carboxylic acid (0.9 g, 0.16 mmol) in dichloromethane (5.0 ml) was stirred with trifluoroacetic acid (0.5 ml) for 48 hours. It was then concentrated and dried under vacuum to give 0.8 g (90%) of the title compound as a brown powder, mp. 99-103 ° C (dec.).

Analysis: Calculated for C15H27N505 -1, 67C2HF302: C, 40.23; H, 5.27; N, 12.79 Found: C, 40.38; H, 5.28; N, 12.38 Example 22 T-3-amino-c-4- [(di-n-propylaminocarbonyl) - (methylcarbonylamino) methyl] -t-l-hydroxycyclopentane-r-carboxylic acid: trifluoroacetic acid (1: 1) (isomer A in C-6) To a mixture of c-3- (t-butoxycarbonylamino) -t-4- [bis (ethoxycarbonyl) (methylcarbonylamino) ethyl] -t-1- [tris (methylthio) methyl] cyclopentane-r-ol of Example 21 (1 , 46 g, 2.6 mmol) in ethanol (20 ml) and water (10 ml) was added 1N sodium hydroxide (10 ml, 10 mmol) and heated to reflux for 2 hours. The mixture was concentrated in vacuo and acidified with glacial acetic acid (1.0 ml, 17.5 mmol). Ethyl acetate (20 ml) was added to the concentrated product and it was heated to reflux for 1 hour. The layers were separated and the aqueous layer was extracted with ether (4 x 10 mL). The combined organic extracts were washed with brine, dried (MgSO 4), filtered through Celite, and concentrated in vacuo to provide c-3- (t-butoxycarbonylamino) -t-4- [(carboxy) (methylcarbonylamino) methyl] -tl- [tris (methylthio) methyl] cyclopentane-r-ol (0.98 g, 76%).

To a stirred mixture of the above acid (0.97 g, 2.0 mmol) in tetrahydrofuran (25 ml) at 0 ° C was added ethyl chloroformate (2.1 ml, 2.2 mmol) and triethylamine (0.35 g). mi, 2.5 mmol). After stirring for 20 minutes, the reaction mixture was allowed to warm to room temperature, was stirred for an additional 30 minutes, and was stirred. filtered through Celite. The filtrate was concentrated in vacuo to give 0.85 g (100%) of the crude mixed anhydride.

To a mixture of the above mixed anhydride (0.84 g, 10 1.56 mol) in tetrahydrofuran (20 mL) at 0 ° C was added di-n-propylamine (0.6 mL, 4.4 mmol). The reaction mixture was stirred at 0 ° C for 30 minutes and at room temperature for 3 hours. The mixture was diluted with water (10 ml) and the layers separated. The aqueous layer was extracted with ethyl acetate (4 x 10 mL). The combined organic extracts were washed with brine, dried (MgSO 4), filtered through Celite, and concentrated in vacuo to provide 1.0 g of the crude product. Purification by radial CLP (silica gel, 30-50% ethyl acetate / hexane) gave 0.23 g (27%) of c-3- (t-butoxycarbonylamino) -t-4- [(di- n-propylaminocarbonyl) (methylcarbonylamino) methyl] -tl- [tris (methylthio) methyl] cyclopentan-r-ol (isomer A in C-6) in the form of a single isomer.

To a mixture of the above amide (0.17 g, 0.31 mmol) in methanol (16.5 ml) and water (1.5 ml) at room temperature was added mercuric oxide (0.10 g, 0.degree. , 47 mmole) and mercuric chloride (0.31 g, 1.2 mmole). After stirring for 2 hours, the reaction mixture was filtered through a pad of Florisil and Celite. The filtrate was concentrated in vacuo to give 0.26 g of crude product. Purification by radial CLP (silica gel, 50-75% ethyl acetate / hexane) yielded 0.14 g (96%) of t-3- (t-butoxycarbonylamino) -c-4- [(di-n) -propyl-35-aminocarbonyl) (methylcarbonylamino) methyl] -tl-hydroxy-cyclopentane-methyl-carboxylate.

To a mixture of the above ester (0.13 g, 0.29 mmol) in tetrahydrofuran (3.5 ml) and water (2.5 ml) at room temperature was added 1N sodium hydroxide (0.6 ml, 0.6 immoles). The reaction mixture was stirred for 1 hour and concentrated in vacuo. The concentrated product was acidified to pH 5-4 with glacial acetic acid and extracted with ethyl acetate (5 x 10 mL). The combined organic extracts were washed with brine, dried (MgSO 4), filtered through Celite, and concentrated in vacuo to provide 0.13 g (100%) of t-3- (t-butoxycarbonylamino) -c acid. -3- [(di-n-propylaminocarbonyl) - (methylcarbonylamino) methyl] -t-1-hydroxycyclopentane-r-carboxylic acid.

A mixture of the above crude solid (0.13 g, 0.29 mol) in dichloromethane (10 mL) with trifluoroacetic acid (0.45 mL, 5.8 mmol) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give 0.16 g of a thick oil which was triturated with ether to provide 0.083 g (63%) of the title compound as a tan solid, mp. 168-170 ° C.

Analysis: Calculated for ClgH2gN305 -C2HF302: C, 47.26; H, 6.61; N, 9.19 Found: C, 47.47; H, 6.83; N, 9.33 Example 23 • I.25CF3C02H Acid t-3-. { [(amino) (imino) methyl lamino} -c-4- [(di-n-propylaminocarbonyl) (methylcarbonylamino) methyl] -t-hydroxy-cyclopentane-r-carboxylic acid: trifluoroacetic acid (4: 5) To a mixture of c-3- (t-butoxycarbonylamino) -t-4- [bis (ethoxycarbonyl) (methylcarbonylamino) methyl] -tl- [tris (methylthio) methyl] cyclopentane-r-ol of Example 21 (1.46 g, 2.6 mmol) in ethanol (20 ml) and water (10 ml) was added 1N sodium hydroxide (10 ml, 10 mmol) and heated to reflux for 2 hours. The mixture was concentrated in vacuo and acidified with glacial acetic acid (1.0 ml, 17.5 mmol). Ethyl acetate (20 ml) was added to the concentrated product and it was heated to reflux for 1 hour. The layers were separated and the aqueous layer was extracted with ether (4 x 10 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered through Celite, and concentrated in vacuo to provide c-3- (t-butoxycarbonylamino) -t-4- [(carboxy) (methylcarbonylamino) methyl] -tl- [tris (methylthio) methyl] cyclopentane-r-ol (0.98 g, 76%).

To a stirred mixture of the above solid (0.97 g, 2.0 mmol) in tetrahydrofuran (25 ml) at 0 ° C was added ethyl chloroformate (0.21 ml, 2.2 mmol) and triethylamine (0.35 g). mi, 2.5 mmol). After stirring for 20 minutes, the reaction mixture was allowed to warm to room temperature, stir for a further 30 minutes, and filtered through Celite. The filtrate was concentrated in vacuo to give 0.85 g (100%) of the crude mixed anhydride.

To a mixture of the above mixed anhydride (0.84 g, 1.56 mmol) in tetrahydrofuran (20 mL) at 0 ° C was added di-n-propylamine (0.6 mL, 4.4 mmol). The reaction mixture was stirred at 0 ° C for 30 minutes and at room temperature for 3 hours. The mixture was diluted with water (10 ml) and the layers separated. The aqueous layer was extracted with ethyl acetate (4 x 10 mL). The combined organic extracts were washed with brine, dried (MgSO 4), filtered through Celite, and concentrated in vacuo to provide 1.0 g of the crude product. Purification by radial CLP (silica gel, 30-50% ethyl acetate / hexane) gave 0.58 g (68%) of c-3- (t-butoxycarbonylamino) -t-3- [(di-n) -propylaminocarbonyl) (methylcarbonylamino) -tl- [tris (methylthio) methyl] cyclopentan-r-ol.

To a mixture of the above amide (0.34 g, 0.63 mmol) in methanol (16.5 ml) and water (1.5 ml) at room temperature was added mercuric oxide (0.210 g, 0.97 mmol) ) and mercuric chloride (0.64 g, 2.4 mmol). After stirring for 2 hours, the reaction mixture was filtered through a pad of Florisil and Celite. AND? The filtrate was concentrated in vacuo to give 0.44 g of crude product. Purification by radial CLP (silica gel, 50-75% ethyl acetate / hexane) yielded 0.27 g (94%) of t-3- (t-butoxycarbonylamino) -c-4- [(di-n) -propylaminocarbonyl) (methylcarbonylamino) methyl] -tl-hydroxy-cyclopentane-methyl-r-carboxylate.

A mixture of the above ester (0.15 g, 0.32 mmol) in dichloromethane (10 mL) with trifluoroacetic acid (0.5 mL, 6.6 mmol) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give 0.16 g of t-3-amino-c-4- [(di-n-propyl-aminocarbonyl) (methylcarbonylamino) methyl] -tl-hydroxy-cyclopentane-r-carboxylate of methyl in the form of a thick oil.

To a mixture of the above amine (0.16 g, 0.33 mmol) in dimethylformamide (3 mL) was added N, N'-bis-t-butoxycarbonyl-S-methylisothiourea (0.11 g, 0.37 mmol) ), triethylamine (0.3 ml, 2.2 mmol), and mercuric chloride (0.10 g, 0.37 mmol). The reaction mixture was stirred at room temperature for 3 hours. Water (5 ml) was added to this mixture and the layers separated. The organic layer was washed with brine, dried (MgSO 4), filtered through Celite, and concentrated in vacuo to provide 0.22 g of a yellow solid. Purification by radial CLP (silica gel, 50-75% ethyl acetate / hexane) gave 0.13 g (67%) of t-3. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -c-4- [(di-n-propylaminocarbonyl) (methylcarbonylamino) methyl] -t-1-hydroxycyclopentane-methyl-r-carboxylate.

To a mixture of the above compound (0.13 g, 0.22 mmol) in tetrahydrofuran (4 mL) and water (2 mL) at room temperature was added 1 N sodium hydroxide (0.5 mL, 0.5 mmol). ). The reaction mixture was stirred for 2 hours and concentrated in vacuo. The concentrated product was acidified to pH 5-4 with glacial acetic acid and extracted with ethyl acetate (5 x 10 mL). The combined organic extracts were washed with brine, dried (MgSO 4), filtered through Celite, and concentrated in vacuo to provide 0.13 g (100%) of t-3- acid. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} - c-4- [(di-n-propylaminocarbonyl) (methylcarbonylamino) methyl] -t-1-hydroxycyclopentane-r-carboxylic acid.

A mixture of the above acid (0.13 g, 0.22 mmol) and trifluoroacetic acid (0.5 mL, 6.6 mmol) in dichloromethane (10 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give 0.2 g of the crude product. Trituration with ether gave 0.08 g (74%) of the title compound as a tan solid, mp. 153-155 ° C.

Analysis: Calculated for C17H31N505 -1.25C2HF302: C, 44.36; H, 6.16; N, 13.26 Found: C, 44.34; H, 6.17; N, 13.19 Example 24 Acid c-3-. { (amino) (imino) methyl] amino} -t-4- [(di-n-propylaminocarbonyl) (methylcarbonylamino) methyl] -t-1-hydroxy-cyclopentane-r-carboxylic acid: trifluoroacetic acid (1: 1) (isomer A in C-6) To a mixture of t-3-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -c-4- [(ethoxycarbonyl) - (methylcarbonylamino) methyl] -tl- [tris (methylthio) ethyl] -cyclopentan-r-ol (isomer A in C-6) of Example 16 (2.55 g, 4, 0 mmol) in tetrahydrofuran (20 ml) and ethanol (10 ml) was added 1N aqueous sodium hydroxide (7.0 ml, 7.0 mmol) and stirred at room temperature for 4 hours. After neutralization with acetic acid, the mixture was concentrated. Water (50 ml) was added to the residue and it was stirred for 4 hours. The white precipitated product obtained was collected by filtration, washed with water and dried under vacuum at 60 ° C for 24 hours to give 2.1 g (86%) of t-3. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) -methyl] amino} -c-4- [(carboxy) (methylcarbonylamino) methyl] -t-l- [tris (methylthio) methyl] cyclopentan-r-ol (mixture of isomers) in the form of a white solid, mp. 228-230 ° C (dec.) Analysis: Calculated for C24H42N408S3 -H20: 5 C, 45.84; H, 7.05; N, 8.91 Found: C, 45.31; H, 6.64; N, 9.05 To a mixture of the above acid (0.61 g, 1 mmol) in tetrahydrofuran (5 mL) at -5 ° C was added triethylamine (0.1 g, 1 mmol) and ethyl chloroformate (0.11 g, 1 mmol) and stirred for 0.5 h. To this mixture was then added di-n-propylamine (0.1 g, 1 mmol), the mixture was stirred at 0 ° C for 1 hour and at room temperature for 1 hour. The mixture was diluted with ethyl acetate • 15 (40 mi) and water (40 mi). The organic layer was separated, washed with water (50 ml) and brine (50 ml), and dried (MgSO 4). After filtration the filtrate was concentrated and the residue was passed through a column of silica gel (25 g) using ethyl acetate / hexane (1: 1) as Eluent to give 0.37 g (53%) of t-3-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -c-4- [(di-n-propylaminocarbonyl) (methylcarbonylamino) ethyl] -t-l- [tris (methylthio) methyl] cyclopentan-r-ol (isomer A in C-6) • in the form of a white solid, mp. 88-90 ° C. Analysis: Calculated for c30H55N5O7S3: C, 51.92; H, 7.99; N, 10.09 Found: C, 52.15; H, 8.04; N, 9.95 30 To a mixture of the above amide (0.6 g, 0.9 mmol) in a mixture of methanol (12): water (1) (22.0 ml) was added mercuric chloride (II). ) (0.91 g, 3.35 mmol) and mercury (II) oxide (0.3 g, 1.40 mmol) and stirred for 0.5 hours. The solids were removed by filtration through Celite and washed with dichloromethane (50 ml). Water (50 ml) was added to the filtrate and an organic layer was separated. The aqueous layer was further extracted with dichloromethane (2 x 40 mL). The combined organic layers were dried (MgSO4), filtered and the filtrate was concentrated to a syrup, which was purified by passing through a column of silica gel (50 g) using ethyl acetate as eluent to give 0 , 07 g (13%) of c-3-. { [(t-butoxycarbonylamino) (t-butoxycarbonylamino) methyl] amino} -t-4- [(di-n-propylaminocarbonyl) - (methylcarbonylamino) methyl] -t-l-hydroxy-cyclopentane-methyl-carboxylate (isomer A in C-6) as a white solid, mp. 128-130 ° C (dec.).

Analysis: Calculated for C28H4gN50g: C, 56.08; H, 8.23; N, 11.68 Found: C, 56.20; H, 8.10; N, 11.84 A mixture of the above ester (0.13 g, 0.22 mmol) in tetrahydrofuran (2.0 ml) and ethanol (1.0 ml) was stirred with 1 N sodium hydroxide (0.5 ml, 0.5 mmol). ) for 1 hour. This was neutralized with acetic acid and the precipitated product obtained was collected by filtration, washed with water and dried under vacuum to give 0.08 g (67%) of c-3 acid. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) -methyl] amino} -t-4- [(di-n-propylaminocarbonyl) (methylcarbonylamino) methyl] -t-l-hydroxycyclopentane-r-carboxylic acid (isomer A in C-6) in the form of an off-white solid, mp. 225-230 ° C (dec.).

Analysis: Calculated for C27H47N5Og -0.5H2O: C, 54.53; H, 8.13; N, 11.78 Found: C, 54.25; H, 7.90; N, 11.48 A mixture of the above acid (0.66 g, 0.10 mmol) in dichloromethane (4.0 ml) was stirred with trifluoroacetic acid (1.0 ml) for 16 hours. This was then concentrated and dried under vacuum to give 0.04 g (80%) of the title compound as a white solid, mp. 128-130 ° C (dec.).

Analysis: Calculated for C17H31N505 -C2HF302: C, 45.69; H, 6.46; N, 14.02 Found: C, 46.37; H, 6.69; N, 14,13 Example 25 Acid c-3-. { [(amino) (imino) methyl] amino} -t-4- [(di-n-propylaminocarbonyl) (methylcarbonylamino) methyl] -t-1-hydroxy-cyclopentane-r-carboxylic acid: trifluoroacetic acid (1: 1) (isomer B in C-6) To a mixture of t-3-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -c-4- [(di-n-propylaminocarbonyl) (methylcarbonylamino) methyl] -tl- [tris (methylthio) -methyl] cyclopentane-r-ol (isomer B in C-6) which had been isolated as a by-product of the Preparation of isomer A in Example 24 (0.51 g, 0.73 mmol) in a mixture of methanol (12): water (1) (18.0 ml) was added with mercury (II) chloride (0.75 g). g, 2.75 mmol) and mercury (II) oxide (0.24 g, 1.12 mmol) and stirred for 2 hours. The solids were removed by filtration through Celite and washed with dichloromethane (50 ml). Water (50 ml) was added to the filtrate and an organic layer was separated. The aqueous layer was further extracted with dichloromethane (2 x 40 mL). The combined organic layers were dried (MgSO 4), filtered and the filtrate was concentrated to give a white solid, which was recrystallized from ether / hexane to give 0.35 g (80%) of c-3. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -t-4- [(di-n-propylaminocarbonyl) (methylcarbonylamino) methyl] -t-1-hydroxycyclopentane-methyl-r-carboxylate (isomer B in C-6) as a white solid, mp . 170-172 ° C (dec.).

Analysis: Calculated for c28H4gN5Og: C, 56.08; H, 8.23; N, 11.68 Found: C, 55.96; H, 8.29; N, 11.70 To a mixture of the above ester (0.25 g, 0.42 mmol) in tetrahydrofuran (3.0 mL) and ethanol (1.3 mL) was stirred with 1 N sodium hydroxide (1.0 mL, 1.0 immoral) for 2 hours. The solvent was evaporated and the residue was dissolved in water (1 ml) and neutralized with acetic acid. The precipitated product obtained was collected by filtration, washed with water and dried under vacuum to give 0.20 g (79%) of the corresponding acid.

A mixture of the above acid (0.15 g, 0.26 mol) in dichloromethane (10 ml) was stirred with trifluoroacetic acid (1.2 ml) for 16 hours. This was then concentrated and dried under vacuum to give 0.11 g (85%) of the title compound as a white solid, mp. 202-205 ° C (dec.).

Analysis: Calculated for C17H31N505 -C2HF302: C, 45.69; H, 6.46; N, 14.02 Found: C, 45.84; H, 6.51; N, 13.82 Example 26 3β-f [(amino) (imino) and il] amino acid} -4 - [(diethylaminocarbonyl) (methylcarbonylamino) methyl] cyclopentane-> 15 carboxylic (isomer A in C-6) To a mixture of 2-. { 3ß-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4 - [(carboxy) (methylcarbonylamino) methyl] -1-cyclopentylidene} -l, 3-ditian of Example 20 (0.56 g, 1 mmol) in tetrahydrofuran (8 mL) at 0 ° C was added triethylamine (0.11 g, 1.1 mmol) and methyl chloroformate (0.1 g, 1.1 mmol). ) and stirred for 0.5 hour. To this mixture was added after • diethylamine (0.11 g, 1.5 mmol) and stirred at 0 ° C for 1 hour and at room temperature for 1 hour. The mixture was diluted with ethyl acetate (40 ml) and water (40 ml). The organic layer was separated, washed with water (50 ml) and brine (50 ml), and dried (MgSO 4). After filtration, the filtrate was concentrated and the residue was made pass through a column of silica gel (50 g) using ethyl acetate / hexane (1: 1) as eluent to give 0.21 g (34%) of 2-. { 3ß-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4 - [(diethylaminocarbonyl) - (methylcarbonylamino) methyl] -l-cyclopentylidene} -l, 3-ditian in the form of a white solid.

A mixture of the above amide (0.1 g, 0.016 mmol) in 0.5 N HCl in methanol (5.0 mL, 2.5 mmol) was stirred for 24 hours at room temperature and 2 hours at 45 ° C. . To the mixture was added 6.0 N HCl (0.2 ml, 1.2 mmol) and heated at 45 ° C for another 2 hours. The reaction mixture was then concentrated and the residue was stirred with 0.1 N sodium hydroxide (5.0 ml, 0.5 mmol) for 1 hour, concentrated, and again stirred with 1 N sodium hydroxide ( 1.0 ml, 1.0 mmol) for 0.5 hour. This was then filtered through a cotton plug and neutralized with dilute hydrochloric acid to give the title compound mixed with sodium chloride, MS (ES +) 342.3 (M + 1, 100%).

Example 27 3ß- acid. { [(amino) (imino) methyl lamino} -Aa- [(di-n-propylaminocarbonyl) (methylcarbonylamino) methyl] cyclopentanecarboxylic (isomer A in C-6) To a mixture of 2-. { 3ß-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4a- [(carboxy) (methylcarbonylamino) methyl] -l-cyclopentylidene} -l, 3-dithiane (isomer A) of Example 20 (0.56 g, 1 mmol) in tetrahydrofuran (8 mL) at 0 ° C was added triethylamine (0.11 g, 1.1 mmol) and methyl chloroformate. (0.1 g, 1.1 mmol) and stirred for 0.5 h. To this mixture was then added di-n-propylamine (0.15 g, 1.5 mmol) and stirred at 0 ° C for 1 hour and at room temperature for 1 hour. The mixture was diluted with ethyl acetate (40 ml) and water (40 ml). The organic layer was separated, washed with water (50 ml) and brine (50 ml), and dried (MgSO 4). After filtration, the filtrate was concentrated and the residue was passed through a column of silica gel (50 g) using ethyl acetate / hexane (1: 1) as eluent to give 0.22 g (34%) ) of 2-. { 3ß-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4a- [(di-n-propylaminocarbonyl) (methylcarbonylamino) methyl] -1-cyclopentylidene} -1,3-dithiane (isomer A) in the form of a white solid, mp. 125-126 ° C.

Analysis: • Calculated for C30H51N5OgS2: 5 C, 56.14; H, 8.01; N, 10.91 Found: C, 56.72; H, 8.05; N, 10.76 A mixture of the above compound (0.11 g, 0.016 mmol) in 0.5 N HCl in methanol (5.0 mL, 2.5 mmol) was stirred for 24 hours at room temperature and 2 hours at 45 ° C. To the mixture was further added 6.0N hydrochloric acid (0.2 ml, 1.2 mmol) and heated at 45 ° C for another 2 hours. The reaction mixture was concentrated • then and the residue was stirred with 0.1 N sodium hydroxide (5.0 mL, 0.5 mmol) for 1 hour, concentrated, and again stirred with 1 N sodium hydroxide (1.0 mL, 1.0 mmol) for 0.5 hour. This was then filtered through a cotton plug, neutralized with dilute hydrochloric acid and concentrated to give the title compound mixed with sodium chloride, MS (ES +) 370.4 (M + 1, 100%).

Example 28 3ß- acid. { [(amino) (imino) methyl] mino} -4a- [(Methylcarbonylamino) (3-pentylaminocarbonyl) methyl] cyclopentanecarboxylic (isomer A in C-6) To a mixture of 2-. { 3ß-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4a- [(carboxy) (methylcarbonylamino) methyl] -l-cyclopentylidene} -l, 3-di iano (isomer A) of Example 20 (0.56 g, 1 mmol) in tetrahydrofuran (8 ml) at 0 ° C was added triethylamine (0.11 g, 1.1 mmol) and chloroformate methyl (0.1 g, 1.1 mmol) and stirred for 0.5 h. To this mixture was then added 3-pentylamine (0.2 g, 2.3 mmol) and stirred at 0 ° C for 1 hour and at room temperature for 1 hour. The mixture was diluted with ethyl acetate (40 ml) and water (40 ml). The organic layer was separated, washed with water (50 ml) and brine (50 ml), and dried (MgSO 4). After filtration, the filtrate was concentrated and the residue was passed through a column of silica gel (50 g) using ethyl acetate / hexane (1: 1) as eluent to give 0.28 g (45%) ) of 2-. { 3ß-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4a- [(Methylcarbonylamino) - (3-pentylaminocarbonyl) methyl] -l-cyclopentylidene} -l, 3-dithiane (isomer A in C-6) in the form of a white solid, mp. > 230 ° C (dec.).

Analysis: Calculated for C29H4gN5OgS2: C, 55.48; H, 7.86; N, 11.15 Found: C, 55.96; H, 7.92; N, 10.99 A mixture of the above compound (0.1 g, 0.016 mmol) in 0.5 N HCl in methanol (5.0 mL, 2.5 mmol) was stirred for 24 hours at room temperature and 2 hours at 45 ° C. To the mixture was further added 6.0N hydrochloric acid (0.2 ml, 1.2 mmol) and heated at 45 ° C for another 2 hours. The reaction mixture was then concentrated and the residue was stirred with 0.1 N sodium hydroxide (5.0 ml, 0.5 mmol) for 1 hour, concentrated, and again stirred with 1 N sodium hydroxide ( 1.0 ml, 1.0 mmol) for 0.5 hour. This was then filtered through a cotton plug, neutralized with dilute hydrochloric acid and concentrated to give the title compound mixed with sodium chloride, MS (ES +) 356.5 (M + 1, 100%).

Example 29 3ß- acid. { [(amino) (imino) methyl] amino} -Aa- [(methylcarbonyl¬ • amino) (3-pentylaminocarbonyl) methyl] cyclopentanecarboxylic 15 (isomer B in C-6) To a mixture of 2-. { 3ß-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4 - [(carboxy) (methylcarbonylamino) methyl] -l-cyclopentylidene} -l, 3-ditian (isomer A) of Example 20 (0.56 g, 1 mmol) in tetrahydrofuran (8 mL) at 0 ° C was added triethylamine (0.11 g, 1.1 mmol) and methyl chloroformate (0.1 g). , 1.1 mmol) and stirred for 0.5 hour. To this mixture was added after • 3-Pentylamine (0.2 g, 2.3 mmol) and stirred at 0 ° C for 1 hour and at room temperature for 1 hour. The mixture was diluted with ethyl acetate (40 ml) and water (40 ml). The organic layer was separated, washed with water (50 ml) and brine (50 ml), and dried (MgSO 4). After filtration, the filtrate was concentrated and the residue was made pass through a column of silica gel (50 g) using ethyl acetate / hexane (1: 1) as eluent Oara to give 0.06 g (10%) of 2-. { 3ß-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4 - [(Methylcarbonylamino) (3-pentylaminocarbonyl) methyl] -l-cyclopentylidene} - 1,3-dithiane (isomer B in C-6) in the form of a white solid, mp. > 200 ° C (dec.).

Analysis: Calculated for 2gH4gN50gS2: C, 55.48; H, 7.86; N, 11.15 Found: C, 55.21; H, 7.72; N, 11.06 A mixture of the above compound (isomer B, 0.035 g, 0.005 mmol) in 0.5 N HCl in methanol (3.0 ml, 1.5 mmol) was stirred for 24 hours at room temperature and 2 hours at 45 ° C. To the mixture was further added 6.0N hydrochloric acid (0.2 ml, 1.2 mmol) and heated at 45 ° C for another 2 hours. The reaction mixture was then concentrated and stirred with 1 N sodium hydroxide (0.4 ml, 0.4 mmol) for 4 hours. It was then filtered through a cotton plug, neutralized with dilute hydrochloric acid and concentrated to give the title compound mixed with sodium chloride, MS (ES +) 356.4 (M + 1, 100%).

Example 30 3ß- acid. { [(amino) (imino) meti1] amino > -4a- [(diethylaminocarbonyl) (methylcarbonylamino) methyl] cyclopentanecarboxylic (isomer A in C-6, isomer A in C-1) To a mixture of 2-. { 3β- (t-butoxycarbonylamino) -4 - [(carboxy) (methylcarbonylamino) methyl] cyclopentylidene} -1,3-dithiane from Example 10 (10 g, 24.0 mmol) in tetrahydrofuran (150 mL) was added triethylamine (3.03 g, 30.0 mmol), and methyl chloroformate (2.84 g, , 0 mmol) and stirred at room temperature for 1 hour. To this mixture was added diethylamine (4.4 g, 60.0 mmol) and the mixture was stirred for 16 hours. The reaction mixture was diluted with ethyl acetate (200 ml) and washed with water (200 ml). The organic layer was separated, dried (MgSO 4), filtered and concentrated to give 9.1 g (81%) of a mixture of C-6 isomers as a residue. This residue was recrystallized from ethyl acetate to give 1.9 g of 2-. { 3β- (t-butoxycarbonylamino) -Aa- [(diethylaminocarbonyl) - (methylcarbonylamino) methyl] cyclopentylidene-1,3-dithiane (isomer B in C-6).

To the above solid (1.88 g, 4.0 mmol) methanolic hydrochloric acid (100 mL, 0.5 N) was added and stirred for 16 hours at 50 ° C. The mixture was then neutralized with methanolic sodium hydroxide and stirred for 0.5 hour at room temperature. The mixture was concentrated and the residue was passed through a column of silica gel (100 g) using chloroform (90): methanol (9): • ammonium hydroxide (1) as eluent to give 0.6 g (50%) of methyl 3-amino-4 - [(diethylaminocarbonyl) (methylcarbonylamino) -methyl] cyclopentanecarboxylate (isomer B in C-6) in the form of a whitish solid, mp. 95 ° C.

Analysis: 10 Calculated for c15H27N304: C, 57.49; H, 8.68; N, 13.41 Found: C, 57.38; H, 8.63; N, 13.33 To a mixture of the previous amine (0.7 g, 2.23 immoles) in dimethylformamide (13 ml) were added triethylamine (0.81 g, 8.01 mmol), S-methyl-N, N "-bis-t-butoxycarbonyl isothiourea (714 mg, 2.46 mmol) and sodium chloride. mercury (665 mg, 2.46 mmol) and the mixture was stirred at room temperature for 16 hours.

The reaction was diluted with ethyl acetate (100 mL), filtered through Celite and the filtrate was washed with water (2 x 100 mL) and brine (1 x 100 mL). The organic layer was dried (MgSO 4), filtered and the filtrate was • concentrated. The residue was passed through a column silica gel (100 g) using ethyl acetate as eluent. The desired fractions were combined and concentrated to give 0.7 g (56%) of a mixture of isomers. The mixture was recrystallized from ether-hexane three times to give 0.16 g (13%) of t-3β-. { [(t-butyloxycarbonyl-30 amino) (t-tritoxycarbonylimino) methyl] amino} -c-4- [(diethylaminocarbonyl) (methylcarbonylamino) methyl] cyclo-pentane-methylcarboxylate (isomer A in C-6 and C-1) as a white solid, mp. 140 ° C.

Analysis: Calculated for C26H 5N5 ° 8: C, 56.20; H, 8.16; N, 12.60 Found: C, 55.50; H, 8.16; N, 12.48 A mixture of the above ester (0.14 g, 0.25 mmol) in tetrahydrofuran (5 mL) was stirred with sodium hydroxide (1 N, 1.5 mL) at room temperature for 4 hours. The mixture was concentrated, the residue was dissolved in water (2 ml), filtered through a cotton plug and the filtrate was acidified with acetic acid. The obtained precipitated product was collected by filtration, washed with water and dried to give 0.11 g (81%) of the corresponding acid.

A mixture of the above acid (0.08 g, 0.15 mmol) in dichloromethane (5 mL) was stirred with trifluoroacetic acid (1.0 mL) for 16 hours at room temperature. The reaction mixture was concentrated and the residue was washed with ether (2 x 20 mL). The residue was dissolved in methanol and ether was added. The mixture was left in a refrigerator for 24 hours. The solvent was decanted and the residue was washed twice with ether and dried to give 0.06 g of the trifluoroacetic acid salt of the title compound as a white powder, mp. > 110 ° C (dec.).

Analysis: Calculated for ClgH27N504 - CF3COOH: C, 44, 83; H, 6, 20; N, 15, 38 Found: C, 44, 71; H, 6, 37; N, 14, 77 Example 31 Acid3ß-. { [(amino) (imino) methyl] amino} -4a- { [(ethyl) (propyl) -aminocarbonyl] (methylcarbonylamino) methyl} cyclopentanecarboxylic (isomer A in C-6) To a mixture of 2-. { 3ß-. { [(t-butoxycarbonylamino) - (t-butoxycarbonylimino) methyl] amino} -4a- [(carboxy) (methylcarbonylamino) methyl] -l-cyclopentylidene} -l, 3-dithiane (from Example 7 (0.5 g, 0.9 mmol) in tetrahydrofuran (15 mL) was added triethylamine (0.12 g, 1.15 mmol), and methyl chloroformate (0.11 mmol). g, 1.15 mmol) and stirred at room temperature for 1 hour, to this mixture was added ethylpropylamine (0.32 g, 3.6 mmol) and stirred for 3 hours at room temperature. it was diluted with ethyl acetate (70 ml) and washed with water (75 ml) and brine (75 ml) The organic layer was separated, dried (MgSO.sub.4), filtered and concentrated. through a column of silica gel (50 g) using a mixture of ethyl acetate: hexane (1: 1) as eluent to give 0.17 g (30%) of 2-. {3ß- { [ (t-butoxycarbonylamino) (t-butoxycarbonylimino) -methyl] amino.} -4a- [(ethylpropylaminocarbonyl) (methylcarbonylamino) methyl] -l-cyclopentylidene} -l, 3-dithiane (isomer A in C-6) in the form of a white solid, mp 115-116 ° C.

Analysis: Calculated for C2gH4gN5Og: C, 55.48; H, 7.87; N, 11.15 Found: C, 55.60; H, 7.84; N, 11.23 A sample of 0.24 g (43%) of isomer B in C-6 was also isolated in the form of a white solid, mp. 122-123 ° C.

Analysis: Calculated for C29H49N5 ° 6: C, 55.48; H, 7.87; N, 11.15 Found: C, 55.57; H, 7.89; N, 11.21 A mixture of the above isomer (0.14 g, 0.266 mmol) and hydrochloric acid in methanol (0.75 N, 6.0 mL) was stirred at room temperature for 24 hours. The mixture was then neutralized with 1 N sodium hydroxide and 2 drops of additional 1 N sodium hydroxide were added and the mixture was stirred for 2 hours. After neutralization with 1N hydrochloric acid, the mixture was concentrated, the salts were separated by filtration and the filtrate was concentrated. The residue was passed through a column of silica gel (20 g) using ethyl acetate: hexane (3: 1) as eluent to give 0.05 g (39%) of 3β-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4 - [(ethylpropylaminocarbonyl) (methylcarbonylamino) methyl] -1-cyclopentanecarboxylic acid methyl ester (isomer A in C-6).

A mixture of the above ester (0.04 g, 0.07 mmol) and sodium hydroxide (1 N, 0.5 ml) was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (2 mL) and filtered through a cotton plug. The filtrate was neutralized with acetic acid. The precipitated product that formed was collected by filtration, washed with water and dried to give 0.03 g (77%) of 3β-acid. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4a- [(ethylpropylaminocarbonyl) - (methylcarbonylamino) methyl] cyclopentanecarboxylic (isomer A in C-6).

A mixture of the above acid (0.012 g, 0.02 mmol) in dichloromethane (2 mL) was stirred with trifluoroacetic acid (0.2 mL) for 24 hours at room temperature. The reaction mixture was concentrated and evaporated twice with dichloromethane to give the title compound as a residue [MS (ES +): 356.4].

Example 32 Acid3ß-. { [(amino) (imino) methyl] amino} -4a- { [(ethyl) (propyl) - to inocarbonyl] (methylcarbonylamino) ethyl} Cyclopentane-carboxylic acid (isomer B in C-6) A mixture of 2-. { 3ß-. { [(t-butoxycarbonylamino) - (t-butoxycarbonylimino) methyl] amino} -4 - [(ethylpropylaminocarbonyl) (methylcarbonylamino) methyl] -1-cyclopentylidene} -1,3-dithiane (isomer B in C-6) (from Example 31) (0.18 g, 0.288 mmol) and hydrochloric acid in methanol (0.75 N, 6.0 ml) was stirred at room temperature for 24 hours. The mixture was then neutralized with 1 N sodium hydroxide and 2 drops of additional 1 N sodium hydroxide were added and the mixture was stirred for 2 hours. After neutralization with 1 N hydrochloric acid, the mixture was concentrated, the salts were separated by filtration and the filtrate was concentrated. The residue was passed through a column of silica gel (20 g) using ethyl acetate: hexane (3: 1) as eluent to give 0.06 g (36%) of 3β-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -Aa- [(ethylpropylaminocarbonyl) (methylcarbonylamino) methyl] -1-cyclopentanecarboxylic acid methyl ester (isomer B in C-6).

A mixture of the above ester (0.06 g, 0.1 mol) and sodium hydroxide (1 N, 0.5 ml) was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (2 mL) and filtered through a cotton plug. The filtrate was neutralized with acetic acid. The precipitated product that formed was collected by filtration, washed with water and dried to give 0.045 g (80%) of 3β-acid. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -Aa- [(ethylpropylaminocarbonyl) - (methylcarbonylamino) methyl] cyclopentanecarboxylic (isomer B in C-6).

A mixture of the above acid (0.03 g, 0.05 mmol) in dichloromethane (2 mL) was stirred with trifluoroacetic acid (0.3 mL) for 24 hours at room temperature. The reaction mixture was concentrated and evaporated twice with dichloromethane to give the title compound as a residue [MS (ES +): 356.3 (100%)].

Examples 33-64 General preparation of amides through parallel synthesis resulting in a mixture of isomers in C-1 and C-6.

To a mixture of 2-. { 3ß-. { [(t-butoxycarbonylamino) - (t-butoxycarbonylimino) methyl] amino} -4 - [(carboxy) (methylcarbonylamino) methyl] -l-cyclopentylidene} -l, 3-dithiane (from Example 7 (0.093 g, 0.16 mmol) in tetrahydrofuran (3.0 mL) was added triethylamine (35 μL, 0.25 mmol), and methyl chloroformate (20 μL, 0, 25 mmole) and the mixture was stirred at room temperature for 1 hour, to this mixture the appropriate amine (0.8 mmol) was added and the mixture was stirred for 16 hours at room temperature. Ethyl (20 ml) and washed with water (20 ml) The organic layer was separated, dried (MgSO 4), filtered and concentrated.

To this residue was added methanolic hydrochloric acid (4.5 ml, 0.75 N), stirred for 20 hours at room temperature, made basic with sodium hydroxide and stirred for 4 hours at room temperature. The mixture was neutralized again with HCl, concentrated to dryness and stirred with dichloromethane (50 ml) and trifluoroacetic acid (100 ml) for 4 hours. The mixture was then concentrated to dryness and the residue was characterized by mass spectrum analysis. The following amides were isolated by this method: • Example R10 R10 MS (ES +) 5 33 CH3 (CH2) 2Ph 404.4 34 CH3 (CH2) 3CH3 356.4 10 35 C2H5 (CH2) 2Ph 404.4 36 CH3 (CH2) 2Ph 384.4 37 pyrrolidino 340, 5 15 38 (CH2) 2CH3 CH2-cyclopropyl 382.4 • 39 C2H5 (CH2) 0H 358.5 20 40 C2H5 (CH2) 3CH3 370.4 41 CH3 (CH2) 0H 344.2 42 az: etidine 326.4 25 43 H CH (CH3) (C2Hg) 342.3 46 CH3 CH (CH3) 2 342.3 35 47 CH3 (CH2) 2CH3 342.3 48 C2H5 (CH2) 2CH3 356.4 40 49 H CH (C2H5) 2 356.3 50 2H5 C2H5 342.3 51 H CH ( CH 3) 2 328.4 45 52 H CH (CH 3) (CH 2 CH 2 Ph) 418.5 53 H CH (CH 3) [CH 2 CH (CH 3) 2] 370.4 54 H CH (CH 2 OH) C 3 H 7 372.3 55 H CH (CH3) (C4Hg) 370.5 56 H CH (CH 3) [(CH 2) 2 C (OH) 414.6 (CH 3) 2] 57 H CH (CH 3) (CH 2 OCH 3) 358.0 58 H CH (C2H5) (CH2OCH3) 372.0 59 H CH (CH3) (C3H?) 356.0 60 H CH (C2H5) (C3H?) 384.0 61 piperidine 354.0 62 3,4 - dideshidropiperidino 352.0 63 2-methylpiperidino 368.0 64 2-ethylpiperidino 382.0 Example 65 3ß- acid. { [(amino) (imino) methyl] amino} -4 - [l- (1-Methylcarbonylamino) pent-2-enyl] cyclopentanecarboxylic To a suspension of propyltriphenyl-phosphonium bromide (0.28 g, 0.73 mmol) in tetrahydrofuran (10 mL) at -78 ° C was added sodium bis (trimethylsilyl) amide (1 M / tetrahydrofuran, 0.73 mL). , 0.73 mmol) dropwise. After stirring for 10 minutes, the reaction mixture was allowed to warm to 0 ° C, stir for 20 minutes, and cooled to -78 ° C. To this mixture was added 2-. { 3β- (t-butoxycarbonylamino) -4a - [(formyl) (methylcarbonylamino) -methyl] cyclopentylidene} -l, 3-dithiane (0.097 g, 0.24 mmol) (from Example 10) in tetrahydrofuran (6 mL) and the reaction mixture was stirred for 1 hour. Water (10 ml) was added and the layers separated. The aqueous layer was extracted with ether (4 x 10 mL). The combined organic extracts were washed with brine, dried (MgSO 4), filtered through Celite, and concentrated in vacuo to give 0.16 g of crude product. Purification by radial CLP (Si02, 50-75% ethyl acetate / hexanes) gave 0.093 g (91%) of 2-. { 3β- (t-butoxycarbonylamino) -4a- [1- (1-methyl-carbonylamino) pent-2-enyl] cyclopentylidene} -l, 3-dithiane in the form of a white solid, mp. 175-177 ° C.

Analysis: Calculated for C21H34N203S2: C, 59.12; H, 8.03; N, 6.57 Found: C, 59.21; H, 8.04; N, 6.51 To a stirred solution of the above solid (0.64 g, 1.5 mmol) in methanol (44 ml) at room temperature was added 6 N HCl (3.8 ml, 22.8 mmol) and the reaction mixture was stirred. stirred for 25 hours. The reaction mixture was cooled to 0 ° C and sodium hydroxide (1.0 g, 25 mmol) was added. After stirring for 50 minutes at room temperature, the reaction mixture was quenched with glacial acetic acid (0.41 ml, 7.0 mmol) and concentrated in vacuo to provide a residue. To this residue was added ethyl acetate (15 ml) and water (10 ml) and the layers were separated. The aqueous layer was extracted with ethyl acetate (4 x 15 mL). The combined organic extracts were washed with brine, dried (MgSO 4), filtered through Celite, and concentrated in vacuo to give 0.37 g (66%) of 3β- (t-butoxycarbonylamino) -4a- [1] - Methyl (1-methyl-carbonylamino) penty-2-enyl] cyclopentanecarbonylate.

A mixture of the above ester (0.28 g, 0.66 mmol) and trifluoroacetic acid (1.0 ml, 13.0 mmol) in dichloromethane was stirred at room temperature for 5.5 hours. The reaction mixture was concentrated in vacuo to give 0.29 g (100%) of methyl 3β-amino-4 - [1- (methylcarbonylamino) -pent-2-enyl] cyclopentanecarboxylate.

To the mixture of the above amine (0.29 g, 0.66 mmol) in dimethylformamide (7 ml) was added N, N'-bis-t-butoxycarbonyl-S-methylisothiourea (0.24 g, 0.81 mmol) ), triethylamine (3.0 ml, 21.5 mmol), and mercuric chloride (0.22 g, 0.81 mmol). The reaction mixture was stirred at room temperature overnight. To this mixture was added ethyl acetate (20 ml) and water (15 ml) and the layers were separated. The organic layer was washed with brine, dried (MgSO 4), filtered through Celite, and concentrated in vacuo to provide 0.35 g of crude product. Purification by radial CLP (Si02, 50-75% ethyl acetate / hexanes) gave 0.214 g (64%) of 3β-. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} - Methyl aa- [1- (1-methylcarbonylamino) pent-2-enyl] cyclopentanecarboxylate.

To a mixture of the above ester (0.116 g, 0.23 mmol) in tetrahydrofuran (3.5 ml) and water (2 ml) at room temperature was added 1 N NaOH (0.6 ml, 0.6 mmol). The reaction mixture was stirred for 2 hours and concentrated in vacuo. The concentrated product was acidified with glacial acetic acid and extracted with ethyl acetate (4 x 10 mL). The combined organic extracts were washed with brine, dried (MgSO 4), filtered through Celite, and concentrated in vacuo to give 0.114 g (100%) of 3β-acid. { [(t-butoxycarbonylamino) (t-butoxycarbonylimino) methyl] amino} -4 - [1- (1-methylcarbonylamino) -pent-2-enyl] -cyclopentanecarboxylic acid.

A mixture of the above acid (0.114 g, 0.23 mmol) and trifluoroacetic acid (0.35 mL, 4.5 mmol) in dichloromethane (8 mL) was stirred at room temperature for 24 hours. The reaction mixture was concentrated in vacuo to give a crude product. Trituration with ether gave 0.064 g (59%) of the title compound as a tan solid, mp. 62-64 ° C. Analysis: Calculated for C14H24N403 -1.5CF3C02H: C, 43.68; H, 5.50; N, 11.99 Found: C, 43.48; H, 5.84; N, 12.03 Example 66 3ß- acid. { [(amino) (imino) meti1] amino} -4or- [l- (1-methy1-carbonylamino) pentyl] cyclopentanecarboxylic A mixture of Example 65 (0.021 g, 0.045 mmol) and platinum oxide (0.05 g) in ethanol (6 ml) was hydrogenated at 50 psi overnight. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo to give a crude product. Trituration with ether gave 0.020 g (95%) of the title compound as a tan solid, mp. 65-67 ° C.

Analysis: Calculated for C14H26N403 • 1.5CF3C02H: C, 43.50; H, 5.91; N, 11.95 Found: C, 43.63; H, 6.16; N, 12.20 Biochemistry The in vitro analysis is based on the method referred to by von Itzstein et al. (European Patent Application No. 92309634.6). The neuraminidase of the H1N9 strain of influenza was obtained by the method described by Laver et al. Virology 1984, 137, pgs. 314-323. The IC 50 values were measured by a spectrofluorometric technique using the fluorogenic substrate 2 '- (4-methyl-umbelliferyl) -a-D-acetylneuramic acid. This substrate is cleaved by neuraminidase to produce a fluorescent product that can be quantified. The test mixture contains inhibitors at different concentrations (four to six points) and enzyme in MES buffer [(2- (N-morpholino) ethanesulfonic acid]] 32.5 mM, 4 mM CaCl2 at pH 6.5 (total volume = 80) μl) The reaction is initiated by the addition of 20 μl of the substrate to a final concentration of 75 μM After 10 minutes at 37 ° C, 2.4 ml of glycine / 0.1 M NaOH are added (pH = 10, 2) to 0.1 ml of the reaction mixture to terminate the reaction A target is organized with the same substrate solution without enzyme Fluorescence is read using an Aminco-Bowman fluorescence spectrophotometer (excitation: 360 nm and emission: 450 nm) and subtracts the targets from the substrate of the readings The IC50 is calculated by plotting the percentage of inhibition against the concentration of inhibitor, and the determination of each point is made in duplicate.

Crystallography Complexes were prepared between the neuraminidase and the inhibitor molecules by transferring crystals of neuraminidase H1N9 to 2 ml of phosphate buffer solution in which the inhibitor had been dissolved. The concentration of the inhibitor compound was adjusted to be 2 mM. The crystal was allowed to equilibrate in the buffer solution for about 1 day and then was separated from the solution and mounted on a glass capillary for the collection of the X-ray diffraction data. All measurements of the intensity of lightning X were recorded with a Siemens X-100 multi-wire area detector on a Rigaku RU-300 rotary anode generator operating at 100 mA and 50 V and a copper anode. The distance from the crystal to the detector was 160 mm and the detector was compensated to collect the data at 2.4 A. The intensity data were measured in oscillation frames from 0 'Io to 240 s of exposure per frame. Each crystal produced 600-700 frames of data before the radiation deterioration of the crystals prevented the collection of additional data.

The intensity data were processed using the XENGEN program package. The integrated intensities were scaled and interspersed to produce a set of final data that contained only single reflections. The final data sets were complete at a resolution of 2.5 A. All fine-tuning was carried out using the XPLOR program. The starting model for the tuning was the native N9 structure tuned to 2 A. The Fourier difference maps at 2.5 A were calculated using the calculated phases of the tuned model. The analysis of the electron density maps was performed on a workstation for Silicon Graphics indigo Extreme 2 computer graphics using the QUANTA graphics program. The idealized models for the inhibitor molecules were manually adjusted to the different electron densities. These models of • inhibitor were included later in the refined XPLOR.

Biological Data Example No. Inhibition of Influenza Neuraminidase: H1N9 IC50 (μm) l 10 3 115 5 280 6 90 7 3,800 9 600 • 15 10 600 12 7,5 13 4,3 14 40 15 50 20 16 70 17 2,000 19 16 20 8 • 21 1,6 25 23 0,47 24 4,9 25 2,300 263 0,041 Dosage and Formulation The antiviral compounds of this invention can be administered as a treatment for viral infections by any method that produces contact of the site of action of the active agent with the viral neuraminidase in the organism of a human, mammal, bird, or other animal. They can be administered by conventional methods suitable for use in conjunction with drugs, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen administration route and standardized pharmaceutical practice.

The dose administered will, of course, vary depending on 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 degree of the symptoms, the kind of concurrent treatment; the frequency of treatment; and the desired effect. The daily dose of active ingredient can be expected to be about 0.001 to 1,000 milligrams (mg) per kilogram (kg) of body weight, with a dose of 0.1 to about 30 mg / kg being preferred.

The dosage forms (compositions suitable for administration) contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will normally be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

The active ingredient 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 active ingredient can also be administered intranasally (drops in the nose) or by inhalation. Other dosage forms are potentially possible such as transdermal administration, through a patch mechanism or an ointment.

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both the tablets and the capsules can be manufactured in the form of sustained release products to provide a continuous release of the medication over a period of hours. The compressed tablets may 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 may contain colorants and flavors to increase patient acceptance.

In general, suitable carriers for parenteral solutions are water, a suitable oil, physiological saline solution, aqueous dextrose (glucose), and solutions of related sugars and glycols such as propylene glycol or polyethylene glycols. Solutions for parenteral administration preferably contain a salt of the water-soluble active ingredient, suitable stabilizing agents, and, if necessary, buffering substances. Antioxidant agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Citric acid and its salts and the sodium salt of EDTA are also used. In addition, parenteral solutions may contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington, s Pharmaceutical Sciences, Mack Publishing Company, a model reference text in this field.

The pharmaceutical dosage forms suitable for the administration of the compounds according to the present invention can be illustrated as follows: Capsules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules with 100 mg of active ingredient powder, 150 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate, each.

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 gelatin positive displacement pump to form soft gelatin capsules containing 100 mu active ingredient. The capsules are washed and dried.

Tablets A large number of tablets are prepared by conventional methods so that the dosage unit is 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 coatings may be applied to increase palate sensation or delayed absorption.

On the other hand, the compounds of the present invention can be administered in the form of nose drops or a nasal inhaler.

Some 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.

It is also intended that such modifications fall within the scope of the appended claims.

The above description includes all the information considered essential to enable those skilled in the art to put the claimed invention into practice. Because the cited applications can provide useful additional information, these cited substances are incorporated herein by reference in their entirety.

Claims

1. A compound represented by the formula: where X is CH2, O or S R? is H, OH, NH2, or OR11; Rg is C02H, S03H, P03H2, N02, the esters thereof, or the salts thereof; O S O O R2 is H, NHC IR5, NHC IR5, NHSO-, R5, C sNHR5, S0 -NHR5, CH2S «R5, O 8 CH-SR-; Or each of R3 and R8 is individually H, (CH2) nCO2R10, (CH2) mOF.10, CON (R10) m, (CH2) nN (R1Q) m, CH (R10) m, (CH2) n (R10) m, CH2CH (OR10) CH2OR10, CH (OR10) CH (OR10) CH2OR1 £), CH2OR1Q, CH (OR10) CH2NHR10, CH2CH (OR10) CH2NHR1Q, CH (OR1Q) CH (OR10) CH2NHR10, or NR1QC (= NR10) N ( R10) m; provided that at least one of R2, R3 and R8 is different from H; R4 is H, (CH2) nOH, (CH2) nNH2, (CH2) nC (= NH) NH2, (CH2) ßNHC (= NR7) NH2, (CH2) nCN or (CH2) nN3; R5 is H, lower alkyl, branched chain alkyl, cyclic alkyl or CF3; R7 is H, OH, CN, NH2 or N02; R10 is H, lower alkyl, lower alkylene, branched alkyl, cyclic alkyl, substituted cyclic alkyl, aromatic (CH2) n, substituted aromatic (CH2) n, and when m is 2 both R10 groups may also be interconnected to form a heterocyclic ring with N; R? L is lower alkyl, branched alkyl, or aromatic (CH2) m; m is 1 or 2; and n is 0-4; and further provided that when X is 0 or S, R3 and R- is different from CH (OR10) CH (OR10) CH2OR10; and the pharmaceutically acceptable salts thereof.

2. The compound of claim 1, wherein said lower alkyl group contains from 1 to about 8 carbon atoms; and said lower alkylene group contains from 2 to about 8 carbon atoms.

3. The compound of claim 1, wherein said lower alkyl group contains from 1 to about 3 carbon atoms; and said lower alkylene group contains from 2 to 3 carbon atoms.

4. The compound of claim 1, wherein said alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, t-butyl, cyclopentyl, and cyclohexyl, the aromatic group is selected from the group consisting of phenyl, and aromatic groups substituted with I rent; the substituted cycloalkyl group contains 3-8 carbon atoms in the ring and are substituted with 1 or 2 alkyl groups having 1-6 carbon atoms, a hydroxy group or both; and the alkylene group is selected from the group consisting of vinyl, 1-propenyl, allyl, isopropenyl, 2-methyl-2-propenyl and cyclopentenyl-

5. The compound of claim 1, wherein said salt is of an acid selected from the group formed by hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicyclic, succinic, p-toluenosulphonic, tartaric, citric acetic, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, trifluoroacetic acid and benzenesulfonic.

6. The compound of claim 1, wherein said salt is a sodium or ammonium salt.

7. The compound of claim 1, which is cis-3- [(methylcarbonylamino) methyl] cyclopentanecarboxylic acid or a salt thereof.

8. The compound of claim 1, which is trans-3-amino-c-4- (methylcarbonylamino) methyl-r-cyclopentanecarboxylic acid or a salt thereof.

9. The compound of claim 1, which is trans-3- acid. { [(amino) (imino) methyl] amino} -c-4- [(methylcarbonylamino) methyl] cyclopentane-r-carboxylic acid or a salt thereof.

10. The compound of claim 1, which is 4β- acid. { [(amino) (imino) methyl] amino} -3 - [(2-hydroxy-l-ethylcarbonylamino) ethyl] -l-cyclopentanecarboxylic acid or a salt thereof.

11. The compound of claim 1, which is 3β-. { [(amino) (imino) methyl] amino} -4a- [(2-hydroxy) (1-methylcarbonylamino) ethyl] cyclopentane-sodium carboxylate.

12. The compound of claim 1, which is trans-3-amino-trans-l-hydroxy-cis-4 [(hydroxymethyl) (methylcarbonylamino) methyl] cyclopentane-r-carboxylic acid or a salt thereof.

13. The compound of claim 1, which is trans-3- acid. { [(amino) (imino) methyl] amino} -trans-l-hydroxy-cis-4- [(2-hydroxymethyl) (1-methylcarbonylamino) -ethyl] cyclopentane-r-carboxylic acid or a salt thereof.

14. The compound of claim 1, which is 3β-amino-4 - [(1-methylcarbonylamino) (2, 3, 4-trihydroxy) butyl] cyclopentanecarboxylic acid or a salt thereof.

15. The compound of claim 1, which is 3β- acid. { [(amino) (imino) methyl] amino} -4a- [(1-methyl-carbonylamino) (2,3,4-trihydroxy) butyl] cyclopentanecarboxylic acid or a salt thereof.

16. The compound of claim 1, which is cis-3- acid. { [(amino) (imino) methyl] amino} -trans-l-hydroxy-trans-4- [(1-methylcarbonylamino) (2-trifluoromethyl-carbonyloxy) ethyl] cyclopentane-r-carboxylic acid or a salt thereof.

17 The compound of claim 1, which is t-3-amino-c-4- [(1-methylcarbonylamino) (2-f-enylmethoxy) -ethyl] -t-l-hydroxycyclopentane-r-carboxylic acid or a salt thereof.

18. The compound of claim 1, which is c-3 acid. { [(amino (imino) methyl] amino]} - tl-hydroxy-t-4. (. (methylcarbonylamino) - {[[(methyl) - (methoxy) amino] carbonyl] .methyl] cyclopentane -r-carboxylic acid or a salt thereof.

19. The compound of claim 1, which is 3β- acid. { [(amino) (imino) methyl] amino} -4a- { . { 4- [(methoxy) - (methyl) amino] -l- (methylcarbonylamino-2-oxo} -yl} -cyclohentanecarboxylic acid or a salt thereof.

20. The compound of claim 1, which is t-3- acid. { [(amino) (imino) methyl] amino} -c-4- [(diethylaminocarbonyl) (methylcarbonylamino) methyl] -t-1-hydroxycyclopentane-r-carboxylic acid or a salt thereof.

21. The compound of claim 1, which is t-3-amino-c-4- [(di-n-propylaminocarbonyl) (methylcarbonylamino) methyl] -t-l-hydroxycyclopentane-r-carboxylic acid or a salt thereof.

22. The compound of claim 1, which is t-3- acid. { [(amino) (imino) methyl] amino} -c-4- [di-n-propylaminocarbonyl) (methylcarbonylamino) methyl] -t-hydroxycyclopentane-r-carboxylic acid or a salt thereof.

23. The compound of claim 1, which is c-3 acid. { [(amino) (imino) methyl] amino} -c-4- [di-n-propylaminocarbonyl) (methylcarbonylamino) methyl] -t-1-hydroxy-cyclopentane-r-carboxylic acid or a salt thereof.

24. The compound of claim 1, which is 3β- acid. { [(amino) (imino) methyl] amino} -4a- [di-n-propylaminocarbonyl) (methylcarbonylamino) methyl] cyclopentanecarboxylic acid or a salt thereof.

25. The compound of claim 1, which is 3β- acid. { [(amino) (imino) methyl] amino} -Aa- [(Methylcarbonylamino) (3-pentylaminocarbonyl) methyl] cyclopentanecarboxylic acid or a salt thereof.

26. The compound of claim 1, which is 3β- acid. { [(Amino) (imino) methyl] amino} -4a- [(diethylaminocarbonyl) (methylcarbonylamino) methyl] cyclopentanecarboxylic acid or a salt thereof.

27. The compound of claim 1, which is 3β- acid. { [(Amino) (imino) methyl] amino} -4 -. { [(ethyl) (propyl) -aminocarbonyl] (methylcarbonylamino) methyl} cyclopentanecarboxylic acid or a salt thereof.

28. The compound of claim 1, which is 3β- acid. { [(Amino) (imino) methyl] amino} -4a- { [(ethyl) (propyl) -aminocarbonyl] (methylcarbonylamino) methyl} cyclopentanecarboxylic acid or a salt thereof.

29. The compound of claim 1 represented by the formula:

30. The compound of claim 1, which is 3β- acid. { [(Amino) (imino) methyl] amino} -Aa- [1- (1-methyl-carbonylamino) pent-2-enyl] cyclopentanecarboxylic acid or a salt thereof.

31. The compound of claim 1, which is 3β- acid. { [(Amino) (imino) methyl] amino} -4a- [1- (1-methyl-carbonylamino) pentyl] cyclopentanecarboxylic acid or a salt thereof.

32. A composition for inhibiting influenza virus neuraminidase, comprising: a pharmaceutically acceptable carrier and an amount effective to inhibit influenza virus neuraminidase of a compound according to claim 1.

33. A method for inhibiting influenza virus neuraminidase, comprising the step of: administering to a patient in need thereof a composition comprising a pharmaceutically acceptable carrier and an amount effective to inhibit influenza virus neuraminidase of a compound according to Claim 1

34. A method for treating influenza virus infection, comprising the step of: administering to a patient in need thereof a composition comprising a pharmaceutically acceptable carrier and an amount effective to inhibit the influenza virus neuraminidase of a compound according to claim 1.