NO971070L - Antivirus nucleoside analogs containing a substituted benzimidazole base attached to a carbocyclic ring - Google Patents

Description

Antiviral nucleoside analogs containing a substituted benzimidazole base attached to a carbocyclic ring

The present invention relates to certain purine nucleoside analogs containing a carbocyclic ring in place of the sugar residue, pharmaceutically acceptable derivatives thereof, and their use in medical therapy, particularly for the treatment of certain viral infections.

Hepatitis B virus (HBV) is a small DNA-containing virus that infects humans. It is a member of the class of closely related viruses known as hepadnaviruses, in which each member selectively infects either mammals or birds, such as the wood-chuck and duck. - Worldwide, HBV is a viral pathogen with major consequences. It is most common in Asian countries, and predominates in sub-Saharan Africa. The virus is etiologically associated with primary hepatocellular carcinoma and is thought to cause 80% of the world's liver cancers. In the United States, more than 10,000 people are hospitalized for HBV disease each year, and an average of 250 die of incurable disease.

The United States currently has a combined estimated 500,000 to 1 million infectious carriers. Chronic active hepatitis will develop in over 25% of carriers, often progressing to cirrhosis. It is estimated that 5,000 people die of HBV-related cirrhosis each year in the United States, and that perhaps 1,000 die of HBV-related liver cancer. Even when a universal HBV vaccine is available, the need for effective anti-HBV compounds will continue. A large pool of persistently infected carriers, estimated at 220 million worldwide, will not benefit from vaccination and will remain at high risk of HBV-induced liver disease. This carrier population serves as a source of infection of susceptible individuals who fall victim to disease especially in endemic areas or high-risk groups such as IV drug abusers and homosexuals. Thus, there is a great need for effective antiviral agents, both to control the chronic infection and to reduce the course of hepatocellular carcinoma.

Clinical effects of infection with HBV vary from headache, fever, malaise, nausea, vomiting, anorexia and diaphragmatic pain. Replication of the virus is normally controlled by the immune system, with a healing process lasting weeks or months in humans, but the infection can be more severe and lead to persistent chronic liver disease as explained above.

In "Viral Infections of Humans" (second edition, Ed., Evans, A.S. (1982) Plenum Publishing Corporation, New York) Chapter 12 describes in detail the etiology of viral hepatitis infections. Among the DNA viruses, the herpes group is the source of many common viral diseases in humans. The group includes cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), herpes simplex virus (HSV) and human herpes virus 6 (HHV6).

Like other herpes viruses, infection with CMV leads to a life-long connection between virus and host, and after a primary infection, the virus can be present for many years. Clinical effects vary from death and severe reduction (microcephaly, hepatosplenomegaly, jaundice, mental impairment) through well-being failure/tendency to chest and ear infections to lack of any obvious disease effect. CMV infection in AIDS patients is a dominant cause of morbidity as it is present in 40 to 80% of the adult population in a latent form and can be reactivated in immunologically compromised patients.

EBV causes infectious mononucleosis and is also thought to be the cause of nasopharyngeal cancer, immunoblastic lymphoma, Burkitt's lymphoma and hairy leukoplakia.

VZV causes chickenpox and shingles. Chickenpox is the primary disease that occurs in a host without immunity. In young children, it is normally a mild disease characterized by a vesicular rash and fever. Shingles is a recurrent form of the disease that occurs in adults who were previously infected with varicella. The clinical manifestations of shingles are neuralgia and a vesicular skin rash that is unilateral and dermatomal in distribution. Spread of inflammation can lead to paralysis or convulsions and coma can occur if the meninges are affected. In immunologically compromised patients, VZV can progress to severe or even fatal disease.

HSV 1 and HSV 2 are some of the most common causes of infection in humans. Many of these viruses are able to remain in the host's neural cells. After infection, individuals are at risk of repeated clinical manifestations of the infection, which can be both physically and psychologically disturbing. HSV infection is often characterized by widespread lesions in the skin, mouth and/or genitals. Primary infections may be subclinical, although they tend to be more severe than infections in individuals previously exposed to the virus. Eye infections with HSV can lead to keratitis or cataracts. Infection in newborns, in immunologically weakened patients and penetration of infection into the central nervous system can develop fatally. HHV6 is the cause of roseola infantum (exanthum subitum) in children, which is characterized by wood fever and the appearance of a rash after the fever has subsided. HHV6 has also been implicated in syndromes with fever and/or rash and pneumonia or hepatitis in immunologically weakened patients.

It has now been found that certain substituted benzimidazole compounds as shown below are useful for the treatment or prophylaxis of certain viral infections. According to the first aspect of the present invention, new compounds of the formulas (I) and (1-1) are provided

where R<1> is H, CH3 or CH2OH; R 2 is H or OH; R<3> is H or OH; or

R 2 and R 3 together form a bond;

R4 is amino, cyclopropylamino, cyclobutylamino, isopropylamino, tert-butylamino or -NR<8>R<9>where R<8>and R<9> together with the nitrogen atom to which they are attached form a 4-, 5- or 6- membered heterocyclic ring; R<5> is H and R<6> and R<7> are Cl, except for the compound (±)-(1R<*>. 2S<*>. 3S<*>, 5S<*>)-5-[ 5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol and provided that at least one of R<1>, R<2> and R3 is or contains

OH;

Preferred compounds of formula (I) and (1-1) are those in which R4 is cyclopropylamino, isopropylamino or tert-butylamino and especially isopropylamino or tert-butylamino.

Preferred compounds of formula (I) and (1-1) are those of formula (IA) or

(IA-1)

where R<2> is H or OH; R4 is amino, cyclopropylamino, isopropylamino, tert-butylamino, especially isopropyl or tert-butylamino, or -NR<8>R<9>where R<8>and R<9> together with the nitrogen atom to which they are attached form a 4- , 5- or 6-membered heterocyclic ring; R<5> is H; and R6 and R<7> are Cl, and except the compound (±)-(1 R<*>, 2S<*>, 3S<*>, 5S<*>)-5-[5,6-dichloro-2 -(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol and pharmaceutically acceptable derivatives thereof.

Particularly preferred compounds of formula (IA) and (IA-1) are those in which R<4> is cyclopropylamino, isopropylamino or tert-butylamino; R<5> is H; and R6 and R<7> are both Cl; and the pharmaceutically acceptable derivatives thereof. It will be clear that the present invention encompasses the particular enantiomers shown in formula (I) and (1-1), including tautomers of the purine, alone and in combination with their mirror image enantiomers. Enantiomers shown in formula (I) are preferred and are preferably provided substantially free of the corresponding enantiomer to the extent that it is generally present in the mixture at less than 10% by weight, preferably less than 5% by weight, even more preferably less than 2% by weight and preferably less than 1% by weight of the corresponding enantiomer calculated on the total weight of the mixture. Enantiomers shown with formula (1-1) are strongly preferred, and are preferably essentially free of the corresponding enantiomer to the extent that it is generally present in the mixture at less than 10% by weight, preferably less than 5% by weight, even less than 2% by weight and preferably less than 1% by weight of the corresponding enantiomer calculated on the total weight of the mixture.

Particularly preferred examples are:

(1R,2S,3S,5S)-5-[5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;

(±)-(1R<*>, 2S<*>, 3S<*>, 5S*)-5-[5,6-dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-3 -(hydroxymethyl)-1,2-cyclopentanediol;

(1R,2S,3S,5S)-5-[5,6-dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;

(1R,2S,3S,5S)-5-[2-(tert-butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; and

(±)-(1R<*>. 2S<*>. 3S<*>, 5S<*>)-5-[2-(tert-butylamino)-5,6-dichloro-1H-benzimidazol-1-yl ]-3-(hydroxymethyl)-1,2-cyclopentanediol;

(1S,2R,3R,5R)-5-[5,6-dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;

(1S,2R,3R,5R)-5-[2-(tert-butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol;

(±)-(1R<*>, 2S<*>, 3S<*>, 5S*)-5-[5,6-dichloro-2-(1-azetidinyl)-1H-benzimidazol-1-yl] -3-(hydroxymethyl)-1,2-cyclopentanediol;

(1R,2S,3S,5S)-5-[5,6-dichloro-2-(1-azetidinyl)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; and

(1S,2R,3R,5R)-5-[5,6-dichloro-2-(1-azetidinyl)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol,

and pharmaceutically acceptable salts thereof.

The compounds of formulas (I) and (1-1) above and their pharmaceutically acceptable derivatives are referred to herein as the compounds according to the invention.

In a further aspect of the invention, the compounds of the invention are provided for use in medical therapy, in particular for the treatment or prophylaxis of viral infections such as herpes virus infections. As of today, the compounds according to the invention have been shown to be active against hepatitis B virus (HBV) and cytomegalovirus (CMV) infections, although early results suggest that the invention could also be active against other herpes virus infections such as EBV , VZV, HSVI and II and HHV6. The compounds according to the present invention are particularly useful for the treatment or prophylaxis of CMV infections. The use of the compounds according to the invention in the preparation of a drug for the treatment of viral infections is also described.

Other viral conditions that can be treated according to the invention are discussed in the introduction above.

In yet another aspect of the present invention there is provided:

a) A method for the treatment or prophylaxis of a hepadnavirus infection such as hepatitis B or a herpes virus infection such as CMV, which comprises

treating individuals with a therapeutically effective amount of a

compound according to the invention.

b) Use of a compound according to the invention in the preparation of a drug for the treatment or prophylaxis of all the above-mentioned

infections or conditions.

By "a pharmaceutically acceptable derivative" is meant any pharmaceutically or pharmacologically acceptable salt, ester or salt of such an ester of a compound according to the invention, or any compound which, after administration to the recipient, is capable of producing (directly or indirectly) a compound according to the invention, or an antivirally active metabolite or residue thereof.

The term heterocyclic ring means a saturated, unsaturated or partially saturated ring containing one or more heteroatoms independently selected from nitrogen, oxygen and sulphur. Examples of such groups include azetidinyl, pyrrolidinyl and piperidinyl.

Preferred esters of the compounds of the invention include carboxylic acid esters in which the non-carbonyl residue of the ester group is selected from straight or branched alkyl chains, e.g. n-propyl, t-butyl, n-butyl, alkyl alkyl (e.g. methoxymethyl), aralkyl (e.g. benzyl), aryloxyalkyl (e.g. phenoxymethyl), aryl (e.g. phenyl optionally substituted with halogen , C 1-4 alkyl or C 1-4 alkoxy or amino); sulfonate esters such as alkyl or aralkylsulfonyl (eg methanesulfonyl); amino acid esters (eg L-valyl or L-isoleucyl); and mono-, di- or triphosphate esters. The phosphate esters can further be esterified with e.g. a C1.20 alcohol or a reactive derivative thereof, or with a 2,3-di(Ce-24)acyl-glycerol.

With respect to the above-described esters, unless otherwise specified, any alkyl radical present suitably contains 1 to 18 carbon atoms, especially 3 to 6 carbon atoms such as the pentanoate. Any aryl residue present in such esters suitably comprises a phenyl group.

Any reference to another of the above compounds also includes a reference to a pharmaceutically acceptable salt thereof.

Physiologically acceptable salts include salts of organic carboxylic acids such as acetic acid, lactic acid, tartaric acid, malic acid, isethionic acid, lactobionic acid, p-aminobenzoic acid and succinic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid and inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid.

The above compounds according to the invention and their pharmaceutically acceptable derivatives can be used in combination with other therapeutic agents for the treatment of the above-mentioned infections or conditions. Examples of such further therapeutic agents include agents effective for the treatment of viral infections or associated conditions such as acyclic nucleosides (eg, acyclovir), immunomodulatory agents such as thymosin, ribonucleotide reductase inhibitors such as 2-acetylpyridine-5-[( 2-chloroanilino)thiocarbonyl)-thiocarbon hydrazone, interferons such as α-interferon, 1-β-D-arabinofuranosyl-5-(1-propynyl)uracil, 3'-azido-3'-deoxythymidine, ribavirin and phosphonoformic acid. The component compounds in such combination therapy can be administered simultaneously, in either separate or combined formulations, or at different times, e.g. in sequence so that a combined effect is achieved.

The compounds of the invention, herein also referred to as the active ingredient, may be administered for therapy by any suitable route including oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal). It will be clear that the preferred route will vary with the condition and age of the recipient, the nature of the infection and the active ingredient selected.

In general, a suitable dose for each of the above conditions will be in the range of 0.01 to 250 mg per kg body weight of the recipient (e.g. a human) per day, preferably in the range of 0.1 to 100 mg per kg body weight per day, and preferably in the range of 1.0 to 20 mg per kg body weight per day. (Unless otherwise stated, all weights of active ingredient are calculated as the parent compound of formula (I); for salts or esters thereof, the weights would be proportionally increased.) The desired dose is preferably presented as two, three, four, five, six or several sub-doses administered at suitable intervals during the day. These sub-doses can be given in unit dose form, e.g. containing 10 to 1,000 mg, preferably 20 to 500 mg and preferably 100 to 400 mg of active ingredient per unit dose form.

Ideally, the active ingredient should be administered so that peak plasma concentrations of the active ingredient from approx. 0.025 to approx. 100 nM, preferably approx. 0.1 to 70 µM, preferably approx. 0.25 to 50 µM. This can e.g. achieved by intravenous injection of a 0.1 to 5% solution of the active ingredient, possibly in saline, or administered orally as a bolus containing approx. 0.1 to approx. 250 mg per kg of the active ingredient. Desired blood levels can be maintained with a continuous infusion that gives approx. 0.01 to approx. 5.0 mg/kg/hour or through interrupted infusions containing approx. 0.4 to approx. 15 mg/kg of the active ingredient.

Although it is possible to provide the active ingredient alone, it is preferred to provide it as a pharmaceutical formulation. The formulations according to the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers for this, and possibly other therapeutic agents. Each carrier must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and not harmful to the patient. Formulations include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The formulations can easily be brought into unit dose form, and can be prepared by all well-known methods in the pharmaceutical field. Such methods include the step of bringing the active compound into contact with the carrier constituting one or more aids. In general, the formulations are prepared by bringing the active ingredient evenly and thoroughly into contact with liquid carriers or finely divided solid carriers or both, and then shaping the product if necessary.

Compositions suitable for transdermal administration may be formulated as defined patches designed to remain in intimate contact with the recipient's epidermis over an extended period of time. Such spots can conveniently contain the active compound 1) in an optionally buffered, aqueous solution or 2) dissolved and/or dispersed in an adhesive or 3) dispersed in a polymer. A suitable concentration of the active compound is approx. 1% to 25%, preferably approx. 3% to 15%. As a special possibility, the active compound can be released from the stain by electro-transport or iontophoresis as generally described in Pharmaceutical Research. 3 (6), 318 (1986).

Formulations according to the present invention suitable for oral administration can be formulated as limited units such as capsules, cachets or

tablets each containing a predetermined amount of the active ingredient; as a powder or granule; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be formulated as a bolus, electuary or paste.

A tablet can be made by compression or molding, possibly with one or more auxiliary ingredients. Compressed tablets can be prepared by pressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granule, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethylcellulose), lubricant, inert diluent, preservative, disintegrant (eg sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose), surfactant or dispersant. Molded tablets can be made by molding in a machine with a mixture of the powdered compound moistened with an inert liquid diluent. The tablets can optionally be coated or coated and can be formulated so that it provides a slow or controlled release of the active ingredient therein by using e.g. hydroxypropylmethylcellulose in varying ratios that provide the desired release profile. Tablets can optionally be produced with an enteric coating which provides release in other parts of the intestine than the stomach.

Suitable formulations for topical oral administration are lozenges comprising the active ingredient in a flavored base, normally sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerol, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Formulations for rectal administration can be made as a suppository with a suitable base comprising e.g. cocoa butter or a salicylate.

Formulations suitable for vaginal administration can be made as pessaries, tampons, creams, gels, pastes, foam or spray formulations which, in addition to the active ingredient, contain such carriers as are well known in the art as suitable.

Suitable formulations for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostatic agents and soluble ingredients which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners. The formulations can be manufactured in unit-dose or multi-dose closed containers, e.g. ampoules and glass, and can be stored in a freeze-dried (lyophilized) state that only requires the addition of the sterile liquid carrier, e.g. water for injections, immediately before use. Extemporaneous injection solutions or suspensions can be prepared from sterile powders, granules and tablets of the previously described type.

Preferred unit dosage formulations are those containing a daily dose or unit, daily subdose as indicated above, or an equivalent fraction thereof, of an active ingredient.

It should be clear that in addition to the components specifically mentioned above, the formulations according to this invention may contain other agents which are common in the field with regard to the relevant type of formulation, e.g. those suitable for oral administration may contain such additional agents as sweetening agents, thickening agents and flavoring agents.

The present invention further includes the following method shown schematically for the production of the compounds according to this invention

Thus, according to a further feature of the present invention, there is provided a process for the preparation of compounds of formula (I) and (1-1) alone or in combination with their mirror-image enantiomers, and their pharmaceutically acceptable derivatives comprising (A) conversion of

or the mirror image enantiomer thereof with

a) either a compound with the formula R<4>CO2H where R<4>is H, C1-4alkyl or C1.4perfluoroalkyl preferably at a higher temperature, or a compound

with the formula R<4>C(OR)3where R<4>is H, C1-4alkyl or C1-4perfluoroalkyl and R is C1-4alkyl, preferably at ambient temperature and in an acidic medium,

which gives a compound of the formula (I) or (1-1) where R 4 is H, or

b) cyanogen bromide to form a compound of formula (I) or (1-1) wherein R 4 is NH 2 ; or

(B)

a) transfer of a compound of formula (I) or (1-1) in which R4 is hydrogen into a further compound of formula (I) or (1-1) in which R4 is

a leaving group, e.g. by treatment with an N-(CI, Br or

l) succinimide while forming a compound in which R<4> is Cl, or Br and

b) transfer of a compound of the formula (I) or (1-1) in which R4 is Cl or Br into a further compound of the formula (I) or (1-1) in which R4 is a

amino group or substituted amino group -NR<8>R<9> as defined above, by treatment with a C1.4alkylamine or di-Ci-4alkylamine or R<8>R<9>NH where R<8> and R<9> is as defined above, or

(C) reaction of a compound of the formula

(wherein R<4>, R<5>, R6 and R<7> are as previously defined) or a functional equivalent

hence with a connection with the formula

wherein R<1>, R2 and R3 are as defined above, and L is a leaving group, e.g. an organosulfonyloxy (e.g. p-toluenesulfonyloxy or methanesulfonyloxy), halogen or triflate (OS02CF3 group), e.g. in the presence of a base such as sodium carbonate or sodium hydride in a solvent such as dimethylformamide, advantageously at a higher temperature, e.g. 80-100°C, forming a compound of formula (I) or (1-1) in which R4 is hydrogen, halogen or NR<8>R<9>; and optionally transferring a compound of the formula (I) or (1-1) into a pharmaceutically acceptable derivative thereof.

Alternatively, the compound of formula (IV) in method (C) above can be replaced with a compound in which the L and R<3-> groups are replaced by a cyclic sulfate group.

All structures shown above are intended to represent the enantiomers shown as well as their mirror image isomers, as well as mixtures thereof. Thus, the present invention is intended to encompass both the racemates and the pure enantiomers, essentially free of mirror image isomers.

A compound of formula (I) or (1-1) can be converted into a pharmaceutically acceptable ester by reaction with a corresponding esterification agent, e.g. a

acid halide or anhydride. The compound of formula (I) or (1-1) including esters thereof can be converted into pharmaceutically acceptable salts thereof in the usual manner, e.g. by treatment with a corresponding acid. An ester or salt of an ester of formula (I) or (1-1) can be transferred in the parent compound, e.g. by hydrolysis.

The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way. The term "active ingredient" used in the examples means a compound of formula (I) or (1-1) or a pharmaceutically acceptable derivative thereof.

Example A

Tablet formulations

The following formulations A and B were prepared by wet granulation of the ingredients with a solution of povidone followed by the addition of magnesium stearate and compression.

Formulation A

Formulation B

Formulation C - The following formulations, D and E, were prepared by direct compression of the blended ingredients. The lactose used in formulation E was of the direct compression type (Dairy Crest - "Zeparox").

Formulation D

Formulation E

Formulation F (controlled release formulation)

The formulation was prepared by wet granulation of the ingredients (below) with a solution of povidone followed by the addition of magnesium stearate and compression.

Example B

Capsule formulations

Formulation A

A capsule formulation was prepared by mixing the ingredients of formulation D in Example A above and filling into a two-part hard gelatin capsule. Formulation B (below) was prepared in a similar manner.

Formulation B

Formulation C

Capsules were prepared by melting macrogol 4000 BP, dispersing the active ingredient in the melt and filling the melt into a two-piece hard gelatin capsule.

Formulation D

Capsules were filled by dispersing the active ingredient in the lecithin and arachis oil and filling the dispersion into soft, elastic gelatin capsules.

Formulation E (controlled release capsule)

The following controlled release capsule formulation was prepared by extruding components a, b and c using an extruder, followed by pelletizing the extrudate and drying. The dried pellets were then coated with release-controlling membrane (d) and filled into a two-part hard gelatin capsule.

Example C

Injectable formulation

Formulation A

The active ingredient was dissolved in most of the water (35 - 40°C) and the pH adjusted to between 4.0 and 7.0 with hydrochloric acid or sodium hydroxide as needed. The batch was then filled to the correct volume with water and filtered through a sterile micropore filter into a sterile 10 ml brown glass bottle (type 1) and sealed with sterile closures and overseals.

Formulation B

Active ingredient 0.125 g

Sterile, pyrogen-free, pH 7 phosphate buffer, ad 25 ml

Example D

Intramuscular injection

The active ingredient was dissolved in the glycofurol. The benzyl alcohol was then added and dissolved and water added to 3 ml. The mixture was then filtered through a sterile micropore filter and sealed in sterile 3 ml brown glass bottles (type 1).

Example E

Syrup

The active ingredient was dissolved in a mixture of the glycerol and most of the purified water. An aqueous solution of the sodium benzoate was then added to the solution, followed by the addition of the sorbitol solution and finally the flavoring agent. The volume was filled up with purified water and mixed well.

Example F

Suppository

<*>The active ingredient was used as a powder in which at least 90% of the particles were 63lm diameter or smaller.

One fifth of Witepsol H15 was melted in a steam jacket pan at 45°C maximum. The active ingredient was sieved through a 200 lm sieve and added to the molten base with mixing using a silverson fitted with a cutting head until a uniform dispersion was achieved. While maintaining the temperature at 45°C, the remaining Witepsol H15 was added to the suspension and stirred to ensure a homogeneous mixture. The entire suspension was passed through a 250lm stainless steel sieve and allowed to cool to 40°C with continuous stirring. At a temperature of 38°C to 40°C, 2.02 g of the mixture was filled into suitable 2 ml plastic molds. The suppositories were allowed to cool to room temperature.

Example G

Pessaries

The above ingredients were mixed directly and pessaries prepared by direct compression of the resulting mixture.

Antivirus testing

1. Anti-HCMV

Human cytomegalovirus (HCMV) is measured in monolayers of MRC5 cells (human embryonic lung) in multiwell dishes. The activity of the compounds is determined in the plaque reduction assay, in which a cell monolayer is infected with a suspension of HCMV. A range of concentrations of the compound to be tested (of known molarity) is then incorporated into the carboxymethyl cellulose overlay. The plaque numbers in each concentration are expressed as a percentage of the control and a dose-response curve is drawn. From this curve, the 50% inhibitory concentration (IC50) is determined.

Anti-HCMV activity

2. Anti-HBV

a. Overview

Anti-HBV activity of the compounds of formula (I) and (1-1)

is determined with a high-throughput measurement for determining efficiency. Supernatants from growing HBV-producing cells (HepG2 2.2.15, P5A cell line) in 96-well plates are applied to microtiter plate wells that have been coated with a specific monoclonal antibody against HBV surface antigen (HBsAg). Virus particles present in the supernatants bind to the antibody and remain immobilized while other debris is removed by washing. These virus particles are then denatured to release HBV DNA chains which are then amplified by the polymerase chain reaction and detected by a colorimetric hybrid capture assay. Quantification is achieved by fitting a standard curve to dilutions of a cell supernatant with known HBV DNA content. By

comparing HBV DNA levels of untreated control cell supernatants with supernatants containing a compound of formula (I) or (1-1) provides a measure of anti-HBV efficacy.

b. Immunoaffinity capture of HBV

HBV producer cells, 2,500 cells/well, were seeded in 96-well culture dishes in RPMI/10% fetal bovine serum/2mM glutamine (RPMI/10/2:). The media were replaced on days 1, 3, 5 and 7 with dilutions of a compound of formula (I) or (1-1) in RPMI/10/2 to a final volume of 150 µl. 50 µl of monoclonal anti-HBsAG mouse antibody (10 µg/ml in PBS) was added to each well of a round-bound microtiter plate. After overnight incubation at 4°C, the solutions were evaporated and replaced with 100 µl of 0.1% BSA in PBS. Samples were incubated for 2 hours at 37°C and washed three times with PBS/0/01% Tween-20 (PBS/T) using a Nunc washer. 10 µl of 0.035% Tween-20 in PBS was then added to all wells with Pro/Pette. Cell supernatants (25 µl) containing extracellular virion DNA were transferred into wells of Pro/Pette; The final Tween concentration is 0.01%. 25 µl HBV standard media dilutions in RPMI/10/2 were added

two rows of wells to serve as an internal standard curve for

quantification, and the plates were sealed and incubated at 4°C overnight.

Samples were washed five times with PBS/T and twice with PBS, the last wash being evaporated. Then 25 µl of 0.09N NaOH/0.01% NP40 was added to each well of Pro/Pette, and the sample wells were sealed and incubated at 37°C for 60 minutes. Samples were then neutralized with 25 µl 0.09N HCl/100 mM tris (pH 8.3).

c. Polymerase chain reaction (PCR)

Polymerase chain reaction (Saiki, R.K. et al., Science, 239 (4839) 487-91 (1988)) was performed on 5 µl samples using a Perkin Eimer PCR kit. PCR is carried out in "MicroAmp tubes" in a final volume of 25 ul. Primers were chosen from conserved regions of the HBV genome, determined by alignment of multiple sequences. A primer is biotinylated at the 5-prime end to facilitate hybrid capture detection of the PCR products. All primers were purchased from Synthecell Corp., Rockville, MD 20850.

d. Hybrid capture detection of PCR products

PCR products were detected with horseradish peroxidase-labeled oligonucleotide probes (Synthecell Corp., Rockville, MD 20850) that hybridize to biotinylated strands of denatured PCR products directly in streptavidin-coated microtiter plate wells using essentially the method of Holodiniy, M. et al.. BioTechniaues, 12 (1) 37-39 (1992). Modifications included the use of 251 PCR reaction volumes and sodium hydroxide denaturation instead of heat. Simultaneous binding of the biotin residue to plate-bound streptavidin during the hybridization serves to "capture" the hybrids. Unbound labeled probes were washed away prior to colorimetric determination of the bound (hybridized) horseradish peroxidase. Amounts of HBV DNA present in the original samples were calculated by comparison with standards. These values were then compared with those from untreated cell cultures to determine the degree of anti-HBV activity.

IC50 (median inhibitory concentration) is the amount of a compound that gives a 50% increase in HBV DNA. The approximate IC 50 for the compounds of Examples 4, 13 and 69 are tabulated.

Example 1

(±)-(1R<*>. 2S<*>. 3S<*>, 5S<*>)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2- cyclopentanediyl diacetate

(±)-(1R<*>, 2S<*>, 3R<*>, 4R<*>)-tert-butyl N-[2,3-dihydroxy-4-(hydroxymethyl)-1-cyclopentyl carbamate (6, 27 g, 25.1 mmol) and 1N hydrochloric acid (50 mL) were stirred overnight. The resulting clear solution was evaporated in vacuo and dried by evaporation of methanol and ethanol to give the hydrochloride of (+)-(1S<*>, 2R<*>, 3S<*>, 5R<*>)-3-amino -5-(hydroxymethyl)-1,2-cyclopentanediol as a solid foam (4.73 g).

The solid foam was vigorously refluxed with triethylamine (7.5 g, 75 mmol), 1,2,4-trichloro-5-nitrobenzene (5.84 g, 25.0 mmol as 97%, Aldrich) and 2-methoxyethanol ( 75 ml) for 24 hours. The resulting black mixture was evaporated to dryness and the residue chromatographed on silica gel and the product eluted with methanol:chloroform/1:10 as a dark orange glassy mass (6.9 g). Crystallization from ethanol-water gave an orange powder (3.00 g) which was stirred with acetic anhydride (3.0 mL) - pyridine (20 mL) at room temperature overnight. Evaporation of the volatiles followed by crystallization from ethyl acetate-hexanes gave the title compound as orange needles (2.82 g, 24%), m.p. 153-156°C; <1>H-NMR (DMSO-d6)8: 8.25 and 7.51 (both s, 1 each, C6H2), 8.07 (d, J=7.8 Hz, 1 , NH), 5.23 and 5.09 (both m, 2, 2 CHO), 4.3 (m, 1, CHN), 4.2-4.0 (m, 2, CH2O), 2.5 -2.35 (m, 2, 2CH), 2.04, 2.03, 2.02 (all s, 9, 3CH3CO), 1.5-1.4 (m, 1, CH).

Anal, calcd for C15H20N2O5Cl2: C, 46.67; H, 4.35; N, 6.05; Cl, 15.31. Found: C, 46.66; H, 4.37; N, 6.02, Cl, 15.38.

Example 2

(+)-(1R<*>, 2S<*>. 3S<*>, 5S*)-3-(acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1 ,2-cyclopentanediyl diacetate

(±)-(1R<*>, 2S<*>, 3S<*>, 5S<*>)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2- cyclopentanediyl diacetate (2.75 g, 5.93 mmol) and Raney nickel (aqueous slurry, Aldrich, 300 mg wet) in isopropanol (250 mL) were shaken under hydrogen (40 x 0.068 atm) in a Parr shaker in 2.25 hours. The catalyst was filtered off with Celite and the filtrate acidified with 98% formic acid (5 mL) and evaporated to an orange oil. The oil was diluted with additional 98% formic acid (45 mL) and the resulting orange solution refluxed for 40 minutes. Volatiles were removed and the remaining dark oil dissolved in chloroform (100 mL). The chloroform solution was washed with saturated aqueous sodium bicarbonate (3x10 mL), dried (sodium sulfate) and evaporated to a foam which was chromatographed on silica gel. The title compound eluted with methanol:chloroform / 3:97 as a white foam from ethyl acetate (2.26 g, 86%);<1>H-NMR(DMSO-d6)5: 8.57, 8.17, 7.97 (all s, 1 each, 3 benzimidazole CH), 5.6 (m, 1, CHO), 5.3-5.1 (m, 2, CHO and CHN), 4.35-4.15 (m, 2, CH2O), 2.6-2.4 (m

overlapped with solvent, 2 CH), 2.10, 2.06, 1.92 (all s) overlapped with 2.0 (m, total 10, 3CH3CO and CH).

Anal, calcd for C19H20N2O6Cl2: C, 51.49; H, 4.55; N, 6.32; Cl, 16.00. Found: C, 51.39; H, 4.58; N, 6.22; Cl, 16.07.

Example 3

(±)-(1 R<*>, 2S<*>, 3S<*>, 5S<*>)-3-(acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazole -1-yl)-1,2-cyclopentanediyl diacetate

(±)-(1R<*>, 2S<*>. 3S<*>, 5S*)-3-(acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1 ,2-cyclopentanediyl diacetate (1.32 g, 2.98 mmol) in dry N,N-dimethylformamide (6 mL) was heated to 60°C. Portions (ca. 1 mmol each) of N-bromosuccinimide (1.59 g, 8.93 mmol) were added over 5 hours. Heating continued for another 4 hours. Volatile components were removed in vacuo and the residue chromatographed on silica gel. The title compound eluted with 1:1 hexane-ethyl acetate as a brown powder (1.1 g, 69%),<1>H-NMR identical to recrystallized sample. Such a sample was recrystallized from ethanol-water to a white powder, m.p. 156-159°C; <1>H-NMR(DMSO-d6)8: 8.34, 7.97 (both s, 1 each, 2 benzimidazole CH), 5.6 (m, 1, OCH), 5 .3 (m, 1, OCH), 5.2-5.0 (m, 1, NCH), 4.4^.2 (m, 2, OCH2), 2.7-2.5 (m, 1 , CH), 2.4-2.0 (m) overlapping 2.1 and 2.07 (both s, total 8, CH2 and 2CH3CO), 1.92 (s, 3, CH3CO); mass spectrum (Cl): 527 (6.6), 525 (45), 523 (100), 521 (65, M+1), 257 (48, M-B).

Anal, calcd for C19Hi9N2O6BrCl2: C, 43.71; H, 3.67; N, 5.37; total halogen as Br, 45.91. Found: C, 43.64; H, 3.63; N, 5.30; total halogen as Br, 45.77.

Example 4

(+)-(1R<*>, 2S<*>, 3S<*>. 5S*)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-( hydroxymethyl)-1,2-cyclopentanediol

(±)-(1R<*>, 2S<*>. 3S<*>, 5S<*>)-3-(acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazole-1 -yl)-1,2-cyclopentanediyl diacetate (600 mg, 1.15 mmol) was added to a stirred mixture of sodium carbonate (122 mg) in water (2 mL)-ethanol (10 mL)-methanol (10 mL) . After 2.5 hours at room temperature, the pH was adjusted to 7 with glacial acetic acid. The volatiles were removed in vacuo and the residue triturated with water (5 mL) and

filtered to give a white solid. Recrystallization of the solid from 1:1 ethanol-methanol gave the title compound as a white powder (282 mg, 62%) m.p. 208-211°C;<1>H-NMR(DMSO-d6)5: 8.23 (s, 1, benzimidazole H7), 7.95 (s, benzimidazole H4), 5.13 (t, J=4 ,1 Hz, 1, CH2OH), 5.03 (d, J=6.2 Hz, 1, OH), 5.0-4.85 (m, 1, H5), 4.71 (d, J= 3.5 Hz, 1, OH), 4.55-4.45 (m, 1, H1), 3.85-3.80 (m, 1, H2), 3.7-3.6 and 3, 55-3.45 (both m, 1 each, OCH 2 ) 2.2-1.95 (m, 3, H 3 and 2H 4 ); mass spectrum (Cl): 395 (M+1).

Anal, calcd for C 12 H 2 N 2 O 2 Cl 2 Br: C, 39.43; H, 3.31; N, 7.07; total halogen as Br, 60.52. Found: C, 39.50; H, 3.33; N, 7.02; total halogen as Br, 60.61.

Example 5

(1a, 3p, 4p)-(3,4-dihydroxy-1-cyclopentyl)methylbenzoate

To a stirred, cooled (0°C) solution of 4-hydroxymethylcyclopentene (J.-P.

Depression and A.E. Green, J. Org. Chem. 1984. 49, 928-931, and references therein) (37.0 g, 276 mmol) in pyridine (450 mL) was added benzoyl chloride (32.1 mL, 276 mmol) over 30 minutes. The resulting mixture was stirred at room temperature for 1.25 hours. Water (50 mL) was added and the volatiles removed in vacuo. The remaining oil was dissolved in chloroform, and the solution was extracted with water and then dried over sodium sulfate. Evaporation of the solvent gave (3-cyclopenten-1-yl)methylbenzoate as a yellow oil (53.94 g, 91%), sufficiently pure for use; 1H-NMR(DMSO-d6)8: 7.98, 7.67, 7.56 (m, 5, C6H5), 5.72 (s, 2, CH=CH), 4.19 (m, 2, OCH 2 ), 2.71 (m, 1, CH), 2.56-2.77 (m, overlapping solvent, 2CH), 2.21-2.14 (m, 2, 2CH).

(3-Cyclopenten-1-yl)methylbenzoate (37.6 g, 0.161 mol) in acetone (200 mL) was added dropwise over 2 hours to a stirred solution of N-methylmorpholine-N-oxide (33.1 g , 60% in water, 0.169 mol), osmium tetroxide (2.5% in t -butanol, Aldrich, 3.0 mL) and acetone (200 mL) at ambient temperature. Stirring continued for another 16 hours. Chloroform (500 mL) and water (150 mL) were added. The organic layer was separated, washed with cold 1N hydrochloric acid (2 x 150 mL) and then with saturated aqueous sodium bicarbonate (100 mL) and dried (MgSO 4 ). Volatiles were removed and the remaining solid crystallized from toluene (200 mL) to give the title compound

as white crystals (26.9 g, 73%), m.p. 92-94°C; <1>H-NMR(DMSO-d6)5: 7.96, 7.65, 7.56 (m, 5 C6H5), 4.38 (d, J=4.1 Hz, 3, 20H), 4.14 (d, J=6.6 Hz, 2, CH2O), 3.90 (m, 2, 2 OCH), 2.58 (m overlapping solvent, CH), 1.75 ( m, 2, 2CH), 1.55 (m, 2, 2CH).

Anal, calcd for C 13 H 16 O 4 : C, 66.09; H, 6.83. Found: C, 66.19; H, 6.86.

Evaporation of the mother liquors gave 10.33 g of white solid containing additional title compound contaminated with (+)-(1_1 3^ 4j -3,4-dihydroxy-1-cyclopentyl)methylbenzoate, ratio approximately 2:3 according to<1 >H-NMR.

Example 6

(3a-ct, 5a, 6a-a)-(tetrahydro-4H-cyclopenta-1,3-2-dioxathiol-5-yl)methylbenzoate S-oxide

Thionyl chloride (6.04 g, 50.8 mmol) was added to a solution of (1β, 3α, 4α)-(3,4-dihydroxy-1-cyclopentyl)methylbenzoate (10.0 g, 42.3 mmol) in carbon tetrachloride (150 ml). The solution was refluxed for 1.5 hours. The solvent was evaporated to return the title compound as a thick oil sufficiently pure for use (see following example). One such sample was recrystallized as a waxy solid from toluene, m.p. 48-57°C; <1>H-NMR(DMSO-d6)5: 7.96, 7.66, 7.52 (m, 5, C6H5), 5.46 and 5.32 (both m, 1 , 2 OCH, due to about 1:1 mixture of isomeric S-oxides), 4.28 (m, 2, OCH2), 2.90 and 2.43 (both m, 1, CH from two isomeric S-oxides) , 2.10 and 1.74 (both m, 4, 4CH).

Anal. calcd for daH₂O₂S: C, 55.31; H, 5.00; S, 11.36. Found: C, 55.41; H, 5.04; S, 11.30.

Example 7

(3a-a, 5a, 6a-a)-(tetrahydro-4H-cyclopenta-1,3-2-dioxathiol-5-yl)methylbenzoate S, S-oxide

(3a-a, 5a, 6a-a)-(tetrahydro-4H-cyclopenta-1,3-2-dioxathiol-5-yl)methyl-benzoate-S-oxide (previous example, 42.3 mmol) was stirred in carbon tetrachloride (40 mL)-acetonitrile (40 mL)-water (60 mL) while sodium metaperiodate (8.98 g, 42.3 meq.) and ruthenium trichloride (44 mg, 0.21 meq.) were added. Additional sodium metaperiodate (179 mg) was added after 30 min to complete the reaction, which

was assessed by TLC (silica gel, methanol:chloroform/1:19, visualized in iodine). After a total of 1.0 hour, methylene chloride (300 ml) was added. The organic layer was separated

from, and the aqueous layer was extracted with additional methylene chloride (300 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (100 mL), then saturated aqueous sodium chloride (100 mL), dried (MgSO 4 ) and evaporated in vacuo to give the title compound as a white powder (12.37 g, 98% ), m.p. 114-119°C;<1>H-NMR(DMSO-d6)5: 8.02, 7.70, 7.55 (all m, 5, C6H5), 5.62 (m, 2, OCH), 4.34 (d, J=5.8 Hz, 2, OCH2), 2.79-2.64 (m, 1, CH), 2.32.2.21 and 1.97-1.79 (m, 4 , 2 CH2).

Anal, calcd for C 10 H 2 SO 3 : C, 52.35; H, 4.73; S, 10.75. Found: C, 52.32; H, 4.73; S, 10.69.

Example 8

(±)-(1 R<*>, 2R<*>, 4S<*>)-2-(5,6-dichloro-1 H -benzimidazol-1 -yl)-4-(hydroxymethyl)-cyclopentanol

Sodium hydride (416 mg, 10.4 meq. as a 60% oil dispersion) was added to a solution of 5,6-dichlorobenzimidazole (L.B. Townsend and G.R. Revankar, Chem. Rev. 1970. 70, 389, and references therein) (1, 50 g, 8.00 mmol) in dry N,N-dimethylformamide (35 mL). The mixture was stirred for 45 minutes at 25°C. (3a-a, 5a, 6a-a)-(tetrahydro-4H-cyclopenta-1,3-2-dioxathiol-5-yl)methylbenzoate S,S-oxide (3.05 g, 10.2 mmol)

(prepared in examples 7, 8 and 9) was added in portions over 5 hours. Stirring was continued overnight at ambient temperature. Volatiles were removed in vacuo and the remaining oil dissolved in 1,4-dioxane (130 mL)-water (10 mL) at reflux with 4M sulfuric acid (2.3 mL). After 10 minutes at reflux, the solution was basified with 5 N sodium hydroxide, heated for an additional hour at 50°C, and then neutralized with additional acid. Evaporation of volatiles in vacuo gave residual solids which were extracted with chloroform to remove unreacted 5,6-dichlorobenzimidazole and then crystallized from ethanol-water to give the title compound as a white powder (2.09 g, 87%). Recrystallization of such a sample from ethanol-water gave the title compound as white granules, m.p. 244-245°C; <1>H-NMR(DMSO-d6)5: 8.47, 8.05, 7.93 (all s, 3, aryl CH), 5.19

(d, J=5.3 Hz, 1, CHOH), 4.71 (t, J=5.3 Hz, 1, CH2OH), 4.6-4.5 (m, 1, NCH), 4, 37-4.25 (m, 1, OCH), 3.4 (m, 2, OCH2), 2.4-2.2 and 1.95-1.62 (m, 5, 5CH).

Anal, calcd for C13H14N2O2Cl2 0.02 C2H5OH: C, 51.85; H, 4.71; N, 9.27; Cl, 23.47. Found: C, 51.87; H, 4.74; N, 9.28; Cl, 23.60.

Example 9

(±)-(1R<*>, 2R<*>. 4S<*>)-4-(acetoxymethyl)-2-(5,6-dichloro-1H-benzimidazol-1-yl) cyclopentyl acetate

(±)-(1 R<*>, 2R<*>, 4S<*>)-2-(5,6-dichloro-1 H -benzimidazol-1-yl)-4-(hydroxymethyl)cyclopentanol (7, 80 g, 25.8 mmol) was dissolved in pyridine (50 mL)-acetic anhydride (50 mL) and the solution was stirred overnight. The volatiles were removed in vacuo and the remaining oil partitioned between methylene chloride (150 mL) and saturated aqueous sodium bicarbonate (100 mL). The organic layer was dried (sodium sulfate) and evaporated to a glassy mass (9.91 g, 99%); <1>H-NMR(DMSO-d6)5: 8.58, 8.08, 7.96 (s , 3, aryl CH), 5.39-5.32 (m, 1, OCH), 5.09-5.04 (m, 1, NCH), 4.11 (d, J=6.6Hz, 2 , OCH2), 2.59-2.50 (m overlapping solvent, CH), 2.41-2.35 (m, 1, CH), 2.17-1.86 (m overlapping 2.06 and 1, 94, both p, total 9, 3CH and 2CH3CO).

Anal, calcd for 0^8^0^12-0.1 CH 2 Cl 2 : C, 52.96; H, 4.70; N, 7.26; Cl, 18.55. Found: C, 52.86; H, 4.74; N, 7.25; Cl, 18.50.

Example 10

(±)-(1 R<*>, 2R<*>, 4S*)-4-(acetoxymethyl)-2-(2-bromo-5,6-dichloro-1 H -benzimidazol-1-yl)-cyclopentyl -acetate

N-Bromosuccinimide (4.54 g, 25.5 mmol) was added to a solution of (±)-(1R<*>, 2R<*>.4S*M-(aethoxymethyl)-2-(5,6- dichloro-1H-benzimidazol-1-yl)-cyclopentyl acetate (8.95 g, 23.2 mmol) in dry N,N-dimethylformamide (46 mL). The solution was maintained at about 70°C (oil bath) in 5 hours. Volatiles were removed in vacuo and the remaining orange syrup was chromatographed on silica gel. The title compound was eluted with chloroform as a light yellow solid (5.14 g, 48%), mp 122-125°C;< 1>H-NMR(DMSO-d6)5: 8.16 (s, 1, benzimidazole H7), 7.95 (s, 1, benzimidazole H4), 5.60-5.55 (m, 1, OCH) , 5.12-5.03 (m, 1, NCH), 4.15 (d, J=6.3Hz, 2, OCH2), 2.66- 2.60 (m, 1, CHCH2), 2, 29-2.14 (m, 3, CH), 2.06 (s, 3, CH3CO), 1.93 (s overlapping with m, 4, CH3CO + CH); mass spectrum {Cl): 469 (5.8 ), 467 (37.5), 465 (95), 463 (54, M+1), 199 (100, M-B).

Anal, calcd for ^ 7H, 7H 2 C\ 2 BtO 4 : C, 43.99; H, 3.69; N, 6.04; total halogen as Br, 51.65. Found: C, 44.06; H, 3.70; N, 5.97; total halogen as Br, 51.74.

Example 11

Analysis of (-)-(1S, 4R)-4-amino-2-cyclopentene-1-methanol and its enantiomer, (+)-(1R, 4S)-4-amino-2-cyclopentene-1-methanol

Samples of the title compounds were characterized by the method of Bruckner, H., Wittner, R., and Godel, H., "Automated Enantioseparation of Amino Acids by Derivitization with o-Phthaldialdehyde and N-Acylated Cysteines", J. Chrom., 476

(1989) 73-82, using o-phthaldialdehyde and N-acetyl-L-cysteine as derivatization reagents. Chromatographic separation using an Optima II ODS 100 x 4.5 mm, 3 µm column (III Supplies Co., Meriden, CT) and gradient elution at 0.9 ml/min using first 100% sodium acetate buffer, 40 mM, pH 6.5, with a linear ramp to 18% acetonitrile over 15 minutes and a subsequent hold at 18% acetonitrile for 15 minutes. Detection was at 338 nm. Samples were dissolved in 0.1 molar borate buffer, pH 10.4. The identity and purity of the samples was established by comparison with authentic standards (see EP 434450 (June 26, 1991)). The retention time for the (1S, RS) isomer was approx. 21 minutes. The retention time for the (1R, 4S) isomer was approx. 22 minutes.

Example 12

(±)-cis-4-amino-2-cyclopentene-1-methanol

A dry 21 three-necked flask was equipped with a mechanical stirrer, thermometer and gas inlet adapter connected to a nitrogen source and apparatus. The flask was purged with nitrogen, immersed in an ice-acetone bath, and lithium aluminum hydride solution in tetrahydrofuran (1.0 molar, 800 mL, 0.80 mol, Aldrich) was added via cannula. Dry tetrahydrofuran (2x15 mL) was used to flush the lithium aluminum hydride solution. When the solution had cooled to 0°C, the slurry of (±)-cis-4-amino-2-cyclopentene-1-carboxylic acid-4-toluenesulfonate salt in tetrahydrofuran was introduced by cannula with good stirring at such a rate that the temperature kept at less than 10°C and moderated the hydrogen evolution (about an hour). The flask was flushed with dry tetrahydrofuran (2x15 mL) and the set-up was replaced with a reflux condenser. The resulting clear, light brown solution was slowly heated to gentle reflux over two hours, at which point it became cloudy. After refluxing overnight (16 hours), the heat bath was lowered, sodium fluoride (136.3 g, 3.25 mol, reagent grade powder) was added, and the condenser was returned to downward distillation. The mixture was distilled to a thin slurry (700 ml distillate total), then cooled in an ice bath. Diethyl ether (dry, 500 mL) was added and the condenser was replaced with a dropping funnel containing water (43 mL, 2.4 mol). The water was added slowly (two hours) with care to control the rate of hydrogen evolution and to keep the temperature at 10±5°C. Meanwhile, water (54 mL) was added to the above-collected distillate, and sufficient additional tetrahydrofuran was added to bring the total volume up to 900 mL (6% H 2 O). The reaction mixture was filtered with suction and the cake displacement washed with tetrahydrofuran (100 ml). A portion of the 6% water-tetrahydrofuran solution (300 mL) was used to slurry wash the cake, which was then returned to the reaction flask. The cake was triturated (25 minutes) in 6% water-tetrahydrofuran (400 ml), filtered and displacement washed with 6% water-tetrahydrofuran (200 ml). The combined filtrates were evaporated to a pale yellow oil under vacuum (44.07 g, 67.8% according to HPLC, see example 3). This oil, which contained pure title compound, water and a trace of tosylate salt, turned dark rapidly under ambient conditions. It immediately reacted to form the N-BOC derivative, a stable, crystalline solid (see the following example). The filter cake was returned to the flask and triturated in methanol (800 mL) for 48 hours. The resulting slurry was filtered under a rubber stopper and the cake was washed with methanol (200 mL). The filtrate was evaporated under vacuum to a yellow solid (56.80 g, 20.9% yield by HPLC; total yield 88.7%).

Example 13

(±)-cis-4-amino-2-cyclopentene-1-methanol

With the procedure from example 12, but in approx. 2 times as large scale (97.40 g, 0.8924 mol of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one) the title compound was obtained as extracts containing the title compound (0.7926 mol, 88.8% of theoretical, taking into account removed aliquots, which was determined by the method in example 11).

Example 14

(±)-cis-tert-butyl N-(4-[hydroxymethyl]-2-cyclopenten-1-yl!)carbamate

The combined tetrahydrofuran extracts from the previous example were concentrated in vacuo to 1.031 g, cooled in an ice water bath, and a mixture of sodium bicarbonate (97.46 g, 1.16 mol) in water (500 mL) was added. This was followed by di-tert-butyl dicarbonate (204.5 g, 0.9501 mol). The mixture was stirred at 5°C for two days. The methanol extracts from the previous example were evaporated to an oily solid (136.64 g) which was added to the mixture. After warming to room temperature, the organic solvents were evaporated under vacuum and the resulting slurry was extracted with hexanes, three portions of methylene chloride, then hexanes again (200 mL each). The organic extracts were evaporated to an oil, which was crystallized from hexanes (ca. 300 mL) to give the title compound (154.15 g, 0.7229 mol). Additional product was obtained by chromatography of the mother liquors (10.5 g, 0.0491 mol, 86.6% of theory from the starting lactam, taking into account removed aliquots).

Example 15

(±)-cis-[4-(4,5-dchloro-2-nitroanilino)-2-cyclopenten-1-yl]methanol

(±)-cis-tert-butyl N-[4-(hydroxymethyl)-2-cyclopenten-1-yl carbamate (50.0 g, 0.230 mol) was stirred in 25% trifluoroacetic acid in methylene chloride (1.5 L) at 0°C for 1.0 hours. Evaporation of volatiles returned the trifluoroacetic acid salt of the amine described in Example 27 as a dark oil. To this oil was added t-butanol (350 mL), potassium carbonate (65 g), and 1,2,4-trichloro-5-nitrobenzene (Aldrich, 54.7 g, 0.230 mol as 97%). The resulting mixture was refluxed

boiled with vigorous stirring for 3 days. Volatiles were removed under vacuum and the residue triturated with methanol. The methanol-soluble material was chromatographed on silica gel. The crude product was eluted with 2% methanol-chloroform to give an orange solid (38.0 g). Crystallization from ethyl acetate-hexanes afforded the title compound as orange crystals (34.0 g, 49%), m.p. 96-98°C;<1>H-NMR(DMDO-d6) and mass spectrum (Cl) consistent with the structure and identical to samples of chiral enantiomers described in Examples 18 and 26.

Anal, calcd for C 12 H 12 N 2 Cl 2 O 3 : C, 47.55; H, 3.99; N. 9,24; Cl, 23.39. Found: C, 47.75; H, 4.10; N, 92.0; Cl, 23.52.

Continued elution of the column gave additional fractions containing the title compound with slightly low Rr impurities. These fractions were pooled with the mother liquor from the above crystallization and recrystallized from ethyl acetate-hexanes to give an additional orange solid (16.7 g) with an identical<1>H-NMR spectrum bringing the total yield to 73%.

Example 16

(±)-(1R<*>, 2S<*>. 3S<*>, 5S<*>)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2- cyclopentanediyl diacetate and

(±)-(1R<*>, 2S<*>, 3R<*>. 5R<*>)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2- cyclopentanediyl diacetate

To a solution of (±)-cis-[4-(4,5-dchloro-2-nitroanilino)-2-cyclopenten-1-yl] methanol (20.0 g, 66.0 mmol) and N-methylmorpholine N -oxide (Aldrich, 60% aqueous solution, 12.0 ml, 69 mmol) in acetone (280 ml) is added osmium tetroxide (2.5% in t-butyl alcohol, Aldrich, 1.24 ml). After stirring at ambient temperature for 18 h, volatiles were removed in vacuo and the residue stirred with pyridine (200 mL)-acetic anhydride (40 mL) for a further 18 h. The solution was evaporated to a thick red oil, which was partitioned between saturated aqueous sodium carbonate and chloroform. The chloroform layer was dried (sodium sulfate) and then evaporated to an oil in vacuo. A mixture of the isomeric title compounds was eluted from a silica gel column with 2% methanol-chloroform and crystallized from ethyl acetate-hexanes (by grafting crystals of the (1R<*>, 2S<*>) isomer prepared by the method of Example 1 ) which gave (±)-(1R<*>, 2S<*>, 3S<*>, 5S<*>)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1 ,2-cyclopentanediyl diacetate as orange crystals (17.4 g, 57%), m.p. 154-156°C;<1>H-NMR(DMDO-d6) identical to the sample described in Example 1.

Further crystallization of the mother liquor contents from ethyl acetate-hexanes gave (±)-(1R<*>. 2S<*>, 3R<*>, 5R<*>)-3-(acetoxymethyl)-5-(4, 5-Dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate as orange crystals (8.82 g, 29%), m.p. 105-107°C;

1 H-NMR(DMDO-d6).

Anal, calcd for C18H20N2CI2O8: C, 46.67; H, 4.35; N, 6.05; Cl, 15.31. Found: C, 46.50; H, 4.33; N, 5.96; Cl, 15.23.

Example 17

(±)-(1R* 2S<*>, 3R<*>, 5R> 3-(acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1 -yl)-1,2 -cyclopentanediyl diacetate

(±)-(1R<*>, 2S<*>. 3R<*>, 5R<*>)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2- cyclopentanediyl diacetate (5.00 g, 10.8 mmol) was stirred in ammonia/methanol (ca. 2 N, 100 mL) at ambient temperature for 18 h. Evaporation of the volatiles in vacuo returned an orange solid (±)-(1R<*>, 2S<*>, 3R<*>, 5R<*>)-5-(4,5-dichloro-2 -nitroanilino)-3-(hydroxymethyl)-1,2-cyclopentanediol with an identical Rf on silica gel TLC plates to the chiral sample described in Example 19. This solid was reduced with Raney nickel/hydrogen (45 x 0.068 atm) in isopropanol (200 mL). The catalyst was filtered off with Celite. The filtrate wash was evaporated to dryness in vacuo. The residue was refluxed in formic acid (96%, 50 ml) for one hour as described in example 2. The remaining oil after the evaporation of the formic acid was dissolved in methanol. The pH was adjusted to 13 with aqueous 5 N sodium hydroxide, and the solution was stirred at ambient temperature for one hour to hydrolyze the formate esters. The pH was adjusted to 7 with 1 N hydrochloric acid and volatiles removed by evaporation in vacuo. Pyridine (100 mL) and acetic anhydride (4 mL) were added to the residue and the mixture was stirred at ambient temperature overnight. Evaporation of volatiles in vacuo followed by chromatography on silica gel with 1% methanol-chloroform gave (±)-(1R<*>, 2S<*>, 3R<*>, 5R<*>)-3-(acetoxymethyl)- 5-(5,6-dichloro-1 H -benzimidazol-1 -yl)-1,2-cyclopentanediyl diacetate as white crystals from ethanol-water (2.6 g, 53%);<1>H-NMR( DMDO-d6i agreement with the structure.(±)-(1R<*>, 2S<*>, 3R<*>, 5R<*>)-3-(acetoxymethyl)-5-

(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (2.5 g, 5.7 mmol) was dissolved in dry dioxane (15 mL) and the solution refluxed, while fresh , recrystallized N-bromosuccinimide (2.10 g, 11.5 mmol) was added in one portion. After 5 minutes of reflux, the red-brown solution was evaporated in vacuo to a red oil. A chloroform solution of this oil was washed with water and then dried (sodium sulfate). The chloroform solution was evaporated to an oil which was chromatographed on silica gel. Product-containing fractions were eluted with 2-4% methanol-chloroform. Crystallization from ethyl acetate-hexanes afforded an off-white solid (1.5 g, 50%);<1>H-NMR(DMDO-d6i consistent with the structure of the title compound. One such sample was re-chromatographed on silica gel eluting with chloroform and gave (±)-(1R<*>, 2S<*>, 3R<*>, 5R<*>)-3-(acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazole -1-yl)-1,2-cyclopentanediyl diacetate as white crystals after crystallization from ethyl acetate-hexanes, mp 166-167°C;<1>H-NMR(DMSO-d6)8: 8,14 and 7, 96 (both s, 1 each, 2 aromatic CH), 5.6-5.35 (m, 3, 2 OCH and NCH), 4.4-4.1 (m, 2, OCH2), 2.8- 2.4 (m overlapping solvent, 2 CH), 2.4-2.1 (m overlapping s at 2.25, total 4, CH and CH3), 2.04 (s, 3, CH3), 1.37 (s, 1, CH 3 );mass spectrum (Cl): 525 (53), 523 (100), 521 (54, M+1).

Anal, calcd for CigHt<g>NzBrCIzOe: C, 43.70; H, 3.67; N, 5.37; total halogen as Cl, 20.37. Found: C, 43.65; H, 3.68; N, 5.35; total halogen as Cl, 20.32.

Example 18

(1S,4R)-[4-(4,5-dichloro-2-nitroanilino)-2-cyclopenten-1-ylmethanol

(-)-(1R,4S)-tert-butyl N-[(4-hydroxymethyl)-2-cyclopenten-1-yl]carbamate

(15.00 g, 70.3 mmol) was transferred by the procedure of Example 1 to (1S, 4R)-[4-(4,5-dichloro-2-nitroanilino)-2-cyclopenten-1-ylmethanol, isolated as a yellow powder after elution from a silica gel column with 1:1 hexanes-chloroform and recrystallization from ethyl acetate-hexanes (9.97 g, 47%), m.p. 94.5-96.5°C;<1>H-NMR(DMSO-d6)8: 8.24 (s, 1, benzimidazole CH), 8.09 (d, J=8.1Hz, 1, NH ), 7.51 (s, 1, benzimidazole CH), 5.95 and 5.85 (both m, 2, CH=CH), 4.9-4.7 (m overlapping t at 4.78, J= 5.1 Hz, total 2, CHN and OH), 3.4 (m, 2, CH2O), 2.80 (m, 1, CH), 2.6-2.4 (m overlapping solvent, CH), 1.5-1.4 (m, 1, CH); mass spectrum

(Cl): 303 (M+1); [α]<20>589+ 199°, [α]20578 + 222°, [α]<20>M6+ 333° (c = 0.267, methanol).

Anal, calcd for C^H^CIAO-IS Q-H^: C, 49.30; H, 4.59; N, 8.79; Cl, 22.25. Found: C, 49.64; H, 4.64; N, 8.68; Cl, 22.10.

Example 19

(1S, 2R, 3R, 5R)-5-(4,5-dichloro-2-nitroanilino)-3-(hydroxymethyl)-1,2-cyclopentanediol and

(1R, 2S, 3R, 5R)-5-(4,5-dichloro-2-nitroanilino)-3-(hydroxymethyl)-1,2-cyclopentanediol

" To a solution of (1S,4R)-[4-(4,5-dichloro-2-nitroanilino)-2-cyclopenten-1-ylmethanol (8.60 g, 27.6 mmol) and N-methylmorpholine N- oxide (Aldrich, 60% aqueous solution, 5.02 ml, 29.0 mmol) in acetone (90 ml) was added osmium tetroxide (Aldrich, 2.5% in t-butyl alcohol, 0.51 ml). stirring at ambient temperature for 18 h, an additional 0.25 mL of 60% aqueous N-methylmorpholine N-oxide was added, and the solution was stirred for another 5 h. Volatiles were evaporated in vacuo, and the residue was recrystallized twice from 95% ethanol to give (1S,2R,3R,5R)-5-(4,5-dichloro-2-nitroanilino)-3-(hydroxymethyl)-1,2-cyclopentanediol as yellow powder (1.78 g, 19%), m.p. 197-199°C;<1>H-NMR(DMSO-d6)5: 8.23, (s, 1, benzimidazole CH), 8.1 (d, J=7.0 Hz, 1, NH), 7.50 (s, 1, benzimidazole CH), 5.02 (d, J=4.9 Hz, 1, OH), 4.74 (t, J=5.1 Hz, 1, CH2OH), 4, 58 (d, J=5.1 Hz, 1, OH), 4.0-3.8 (m, 1, NCH), 3.8-3.7 (m, 2, 2

OCH), 3.5-3.4 (m, 2, CH2O), 2.45-2.25 (m, 1, CH), 2.1-1.9 (m, 1, CH), 1, 4-1.2 (m, 1, CH); mass spectrum (Cl): 337 (M+1), [a]<20>589- 106°, [ct]<20>578- 1 18°, [a]<20>546- 182°

(c = 0.273, methanol).

Anal, calcd for C 2 H 2 CIA: C, 42.75; H, 4.19; N, 8.31; Cl, 21.03. Found: C, 42.84; H, 4.21; N, 8.24; Cl, 21.09.

Chromatography of the mother liquor contents on silica gel gave the (1R, 2S) isomer after elution with 7-8% methanol-chloroform; two recrystallizations from 90% ethanol gave (1R,2S,3R,5R)-5-(4,5-dichloro-2-nitroanilino)-3-(hydroxymethyl)-1,2-cyclopentanediol as a yellow powder (1.57 g, 17%), m.p. 179-181°C; <1>H-NMR(DMSO-d6)6: 8.70 (d, J=7.1 Hz, 1, NH), 8.22 and 7.32 (both s, 1 each , 2 benzimidazole CH), 5.28 (d, J=5.6 Hz, 1, OH), 4.77 (d, J=3.9Hz, 1 OH), 4.45 (t, J=4, 9 Hz, 1, CH2OH), 4.1-3.9 (m, 3, 2 OCH and NCH), 3.6-3.5 and 3.45-3.35 (both m partially overlapping H2O, 2, CH 2 O), 2.45-2.25 (m, 1, CH), 2.1-3.9 (m, 1, CH), 1.35-1.25 (m, 1, CH); mass spectrum (Cl); 337 (M+1); [α]20589- 15.6°, [α]<20>578- 13.2°, [cc]<20>^-4.00° (c = 0.250, methanol).

Anal, calcd for C₂H₂CIA: C, 42.75; H, 4.19; N, 8.31; Cl, 21.03. Found: C, 42.87; H, 4.15; N, 8.30; Cl, 21,14.

Elution with 8-10% methanol-chloroform gave a white solid (2.9 g) whose<1>H-NMR showed ca. 1:1 mixture of the two isomers.

Further elution of the column with 10-20% methanol-chloroform gave fractions containing additional (1S, 2R, 3R, 5R)-5-(4,5-dichloro-2-nitroanilino)-3-(hydroxymethyl)-1,2- cyclopentanediol which crystallized from 90% ethanol as a white powder (2.23 g) bringing the overall yield of this isomer to 43%.

Example 20

(1S, 2R, 3R, 5R)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentane-diyl-diacetate

(1S,4R)-[4-(4,5-dichloro-2-nitroanilino)-2-cyclopenten-1-yl]methanol (3.75 g, 11.1 mmol) was acetylated in pyridine-acetic anhydride as in Example 16. The crude product was eluted from a silica gel column with 2% methanol-chloroform and crystallized from ethyl acetate to give (1S, 2R, 3R, 5R)-3-(acetoxymethyl)-5-(4,5-dichloro-2 -nitroanilino)-1,2-cyclopentanediyl diacetate as a yellow powder (5.13 g, 100%), NMR identical to that of Example 1. One such sample was crystallized from ethyl acetate-hexanes to give the title compound as a yellow powder, m.p. 128-130°C;<1>H-NMR(DMSO-de) and mass spectrum (Cl) identical to that of Example 1; [α]20589-95.8°, [α]<20>578-107°, [oc]2<0>^-165° (c = 0.259, methanol).

Anal, calcd for C18H20N2CI2O8: C, 46.67; H, 4.35; N, 6.05; Cl, 15.31. Found: C, 46.74; H, 4.36; N, 5.96; Cl, 15.38.

Example 21

(1S,2R,3R,5R)-3-(acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentaneyl 1-diacetate

(1S,2R,3R,5R)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate (4.42 g, 9.97 mmol) was transferred to the title compound as with the racemic sample described in Example 2. Crude product was chromatographed on silica gel eluting with 5% methanol-chloroform and the solvents evaporated to give (1S, 2R, 3R, 5R)-3-(acetoxymethyl)-5-( 5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate as an off-white solid foam from ethanol (4.0 g, 90%);<1>H-NMR(DMSO- d6)6 and mass spectrum (Cl) identical to those for the racemate described in example 2; [α]<20>859+ 25.5°, [α]20578 + 26.7°, [α]<20>546+ 30.6° (c = 0.255, methanol).

Anal, calcd for C19H20N2CI2O6: C, 51.49; H, 4.55; N, 6.32; Cl, 16.00. Found: C, 51.33; H, 4.58; N, 16.27; Cl, 15.90.

Example 22

(1S, 2R, 3R, 5R)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol

(1S,2R,3R,5R)-3-(acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (0.96 g, 2, 17 mmol) and sodium carbonate (0.230 g, 2.17 mmol) were stirred in water (3 mL)-ethanol (15 mL)-methanol (15 mL) at ambient temperature for 24 h. The pH was adjusted to 7 with acetic acid, and the volatile components removed in vacuo. The remaining solid was slurried in water (25 mL) and filtered. Recrystallization from 2:1 ethanol-methanol gave (1S, 2R, 3R, 5R)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol as a white powder (408 mg, 60%), m.p. 222-225°C; <1>H-NMR(DMSO-de)5: 8.49, 8.09 and 7.96 (all s, 1 each, 3 benzimidazole CH), 5.04 (d, J= 7.0Hz, 1, OH), 4.87 (t, J=5.1 Hz, 1, CH2OH), 4.8-4.6 (m overlapping d at 4.76, J=4.3Hz, 2 , NCH and OH), 4.25-4.10 (m, 1, OCH), 3.9-3.8 (m, 1, OCH), 3.6-3.45 (m, 2, CH2O) , 2.45-2.25 (m, 1, CH), 2.2-2.0 (m, 1, CH), 1.85-1.65 (m, 1, CH); mass spectrum (Cl): 317 (M+1); [a]<20>589- 12.2°, [a]<20>578- 12 , 9°, [a]<20>546- 14.1° (c = 0.255 methanol).

Anal, calcd for C₂H₂I₂CIA: C, 49.23; H, 4.45; N, 8.83; Cl, 22.36. Found: C, 49.25; H, 4.47; N, 8.83; Cl, 22.46.

Example 23

(1S, 2R, 3R, 5R)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol

(1S,2R,3R,5R)-3-(acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (2.00 g, 4, 51 mmol) was dissolved in dry N,N-dimethylformamide (9 ml) and heated to 90°C. N-Bromosuccinimide (1.62 g, 9.02 mmol) was added in four portions over 5 hours. Volatile components were evaporated in vacuo. The residue was chromatographed on silica gel and the product was eluted with 30-50% ethyl acetate-hexanes as a yellow glassy mass (1.00 g, 43%); <1>H-NMR(DMSO-d6)5 consistent with structure. This sample was deblocked with sodium carbonate (203 mg, 1.9 mmol) in water (3 mL)-ethanol (15 mL)-methanol (15 mL) at ambient temperature for 5 hours. The pH was adjusted to 7 with acetic acid. The solution was evaporated to dryness in vacuo, the residue was triturated with water to give a white powder which was chromatographed. Elution of a silica gel column with 10-12% methanol-chloroform gave (1S, 2R, 3R, 5R)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-( hydroxymethyl)-1,2-cyclopentanediol as white powder after crystallization from 1:1 ethanol-methanol (410 mg, 54%), m.p. 212-215°C;<1>H-NMR(DMSO-d6)5 and mass spectrum identical to those for the racemate described in example 4; [ct]20589 - 31.2°, [α]<20>578- 32.2°, [α]20^ - 37.3° (c = 0.260, methanol).

Anal. calcd for C 2 H 2 N 2 BrCIA: C, 39.43; H, 3.31; N, 7.07; total halogen as Cl, 26.86. Found: C, 39.62; H, 3.37; N, 7.02; total halogen as Cl, 26.75.

Example 24

(1S, 2R, 3R, 5R)-[5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol

(1S,2R,3R,5R)-3-(acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yf)-1,2-cyclopentanediyl diacetate (500 mg, 0.958 mmol) was refluxed in

water:ethanol/2:1 (7.5 mL) with cyclopropylamine (0.66 mL, 9.6 mmol) under nitrogen for 18 h. TLC (silica gel, 10% methanol-chloroform) showed complete conversion to a single spot with a lower Rf than the starting material. 1 N sodium hydroxide (0.96 mL) was added and volatiles were evaporated. The residue was chromatographed on a silica gel flash column. The title compound was eluted with 10% methanol-chloroform

as a colorless glassy mass which solidified from water:ethanol/2:1 (5 mL) to give an off-white powder (207 mg, 59%), m.p. 116-118°C split;<1>H-NMR(DMSO-d6)5 and mass spectrum: identical to those for the enantiomer described in example 74; [α]<20>589- 12.2°, [α]<20>578- 12.5°, [α]<20>M6-13.5° (c = 0.312, methanol).

Ana], calcd for C 16 H 19 N 3 Cl 2 O 3 : C, 51.63; H, 5.15; N, 11.29; Cl, 19.05. Found: C, 51.37; H, 5.10; N, 11.16; Cl, 19.25.

Example 25

(1R,4S)-4-amino-2-cyclopentene-1-methanol

A mixture of (-)-(1S,4R)-4-amino-2-cyclopentene-1-carbolic acid (Chiroscience Ltd., Cambridge, England; 40.00 g, 0.315 mol) in dry tetrahydrofuran (300 mL) was stirred in an ice bath, while 1 M lithium aluminum hydride in tetrahydrofuran (Aldrich, 485 mL) was added over 1.5 h. The temperature during this addition was not allowed to exceed 0°C. The mixture was brought to ambient temperature and then to reflux over one hour and held at reflux for 2.5 hours. The mixture was allowed to cool to ambient temperature and sodium fluoride (89.6 g) was added and stirring continued for another 0.5 h. The mixture was cooled (ice bath) and water (23 ml) added slowly. Stirring was continued for another 0.5 hours. The precipitate was filtered and extracted with 40% methanol-tetrahydrofuran (2 x 300 mL). The filtrate wash was evaporated in vacuo to a colorless oil which darkened rapidly in air and light and was used immediately (Example 16). One such sample was dried at ambient temperature/0.2 mm Hg to a pale yellow oil;<1>H-NMR(DMSO-d6)5 identical to that of the enantiomer described in Example 22, d: 5.67 (m, 2, CH=CH), 3.8-3.7 (m, 1, CHN), 3.32 (d, J=6.0 Hz, overlapped with a broad D20 exchangeable peak centered at 3.18 , CH20, OH , NH2 and H2O in solvent), 2.68-2.56 (m, 1, H-1), 2.28-2.18 (m, 1, 1/2 CH2), 1.08-0.98 (m, 1.1/2 CH 2 ); mass spectrum (Cl): 114 (M+1); [a]20589 + 55.0°, [a]20578 + 58.3°, [a]20546 + 67.4°, [a]<20>436+ 1 19° (c = 0.242, methanol).

Anal, calcd for CeHJNO-0.31 H 2 O: C, 60.69; H, 9.86; N, 11.80. Found: C, 61.12; H, 9.79; N, 11.38.

Example 26

(1R,4S)-[4-(4,5-dichloro-2-nitroanilino)-2-cyclopenten-1-yl]methanol

The filtrate wash from Example 25 was evaporated and t-butanol (400 mL) was added to the remaining oil. This solution was used for condensation with 1,2,4-trichloro-5-nitrobenzene (Aldrich, 71.3 g, 0.315 mol as 97%) by the method from example 10. After evaporation of the volatile components in vacuo, the reaction mixture was chromatographed on a silica gel column and eluted with 1:1 hexanes-ethyl acetate and ethyl acetate. Re-chromatography of the crude product on silica gel was carried out by elution with 4-6% methanol-chloroform. Combined product-containing fractions gave 58 g of a reddish solid after evaporation of the solvents. This solid was recrystallized from ethyl acetate-hexanes to give (1R,4S)-[4-(4,5-dichloro-2-nitroanilino)-2-cyclopenten-1-yl]methanol as a yellow powder (34.5 g, 36% from (-)-(1S,4R)-4-amino-2-cyclopentene-1-carbolic acid); m.p. 95-97°C;<1>H-NMR(DMSO-d6)6 and mass spectrum (Cl) identical to those for the enantiomer described in example 18; [a]<20>589- 195°, [a]<20>578- 217°, [a]<20>^- 326° (c = 0.350, methanol).

Anal, calcd for C^H^^CIA: C, 47.55; H, 3.99; N, 9.24; Cl, 23.39. Found: C, 47.56; H, 4.01; N, 9.25; Cl, 23.30.

Continued elution of the column (above) gave additional yellow powder (18.0 g, 19%) whose<1>NMR showed that there was additional title compound contaminated with ca. 15% (1R,4S)-[4-(2,5-dichloro-4-nitroanilino)-2-cyclopenten-1-yl]methanol.

Example 27

(1R, 2S, 3S, 5S)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate and

(1S, 2R, 3S, 5S)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate and

(1R,4S)-[4-(4,5-dichloro-2-nitroanilino)-1,2-cyclopenten-1-yl]methanol (17.00 g, 56.1 mmol) was hydroxylated, and the mixture of triols was acetylated as in Example 16. The crude, red oil isolated after acetylation was chromatographed on silica gel, and a mixture of the title compounds eluted with 2% methanol-chloroform. Fractional crystallization from ethyl acetate-hexanes gave (1R, 2S, 3S, 5S)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate as yellow needles in two yields (12.78 g, 49%), m.p. 127-128°C;<1>H-NMR(DMSO-d6)5 and mass spectrum (Cl) identical to those for the racemic sample described in Example 1 and the enantiomer described in Example 55; [α]20589 + 106°, [α]<20>57B+119°, [α]<20>546+ 184° (c = 0.275, methanol).

Anal, calcd for C18H20N2CI2O8: C, 46.67; H, 4.35; N, 6.05; Cl, 15.31. Found: C, 46.74; H, 4.40; N, 6.09; Cl, 15.22.

Further fractional crystallization of the mother liquor contents from ethyl acetate-hexanes gave (1S, 2R, 3S, 5S)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl- diacetate as orange crystals (2.45 g, 10%), m.p. 122-124°C;<1>H-NMR(DMSO-d6)8.

Evaporation of combined mother liquors gave a further 9.50 g (40%) of approx. a 1:1 (according to <1>H-NMR) mixture of the title compounds.

Example 28

(1R, 2S, 3S, 5S)-3-(acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate

(1R, 2S, 3S, 5S)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate was converted to the title compound as in Example 2. The crude product after formic acid- treatment was chromatographed on silica gel eluting with 10% ethyl acetate-hexanes. Evaporation of product-containing fractions left (1R, 2S, 3S, 5S)-3-(acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-

1,2-cyclopentanediyl diacetate as a white solid foam from ethyl acetate (1.85 g, 95%);<1>H-NMR(DMSO-d6)5 and mass spectrum (Cl) identical to those for the racemate described in Example 2 and the enantiomer described in Example 56; [α]<20>589- 25.5°, [α]<20>578- 27.0°, [α]20^ - 31.2° (c = 0.333, methanol).

Anal, calcd for C 19 H 20 N 2 Cl 2 O 6 O.1 EtOAc: C, 51.54; H, 4.64; N, 6.20; Cl, 15.68. Found: C, 51.29; H, 4.69; N, 6.19; Cl, 15.91.

Example 29

(1S, 2R, 3S, 5S)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol and

(1R,2S,3S,5S)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol

An approx. 1:1 mixture of (1R, 2S, 3S, 5S)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate and (1S, 2R, 3S , 5S )-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate (4.30 g, 9.28 mmol) was deacetylated with sodium carbonate (97 mg) in 1:1:1 water-ethanol-methanol (100 ml) at ambient temperature for 24 hours. The pH was adjusted to 7 with acetic acid and the volatiles were removed in vacuo. The remaining solid was extracted with methanol. The methanol filtrate was evaporated to dryness in vacuo. The remaining solid was dissolved in ethanol (55 mL)-water (20 mL), adjusted to pH 5-6 with sulfuric acid, and refluxed with iron powder (325 mesh, 99.9%, Aldrich, 5.18 g, 93 meq .) and ferrous sulfate heptahydrate (Aldrich, 98+%, 1.30 g, 4.58 meq.) for 4 hours. The solids were filtered off, and the ethanol-filtrate wash concentrated to an oil. Triethyl orthoformate (55 mL) and methanesulfonic acid (0.05 mL) were added to the oil and the resulting solution stirred at ambient temperature for 18 hours. Evaporation in vacuo returned an oil which was redissolved in 1N hydrochloric acid (50 mL)-dioxane (5 mL). After 2.5 hours the pH was adjusted to 7 with 1N sodium hydroxide and the volatiles evaporated in vacuo. The remaining solid was chromatographed on silica gel. Elution with 10-12% methanol-chloroform gave fractions containing (1S, 2R, 3S, 5S)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl!)-1, 2-Cyclopentanediol which was isolated as white crystals (540 mg, 18%) after crystallization from ethyl acetate-hexanes, m.p. 201-202°C; <1>H-NMR(DMSO-d6)d: 8.42, 8.07 and 7.92 (all s, 1 each, 3 benzimidazole CH), 5.1-4.8 ( m overlapping d at 5.02, J=5.7 Hz, and d at 4.93, J=3.9 Hz, total 3, NCH and 2 OH), 4.54 (t, J=4.8 Hz , 1,OH), 4.2-4.0 (m, 2, 2 OCH), 3.75-3.45 (m, 2, OCH2), 2.4-1.9 (m, 3, CH2 and CH); mass spectrum (Cl): 317 (M+1); [a]<20>589- 61.4°, [oc]20578 - 63.1°, [a]<20>^- 72.9° (c = 0.350, methanol).

Anal, calcd for C 2 H 2 NaCl: C, 49.23; H, 4.45; N, 8.83; Cl, 22.36. Found: C, 49.20; H, 4.45; N, 8.78; Cl, 22.37.

Further elution of the column with 15-20% methanol-chloroform gave fractions containing a mixture of the title compounds followed by fractions containing only (1R, 2S, 3S, 5S)-5-(5,6-dichloro-1H-benzimidazol-1- yl)-3-(hydphoxymethyl)-1,2-cyclopentanediol which was isolated as white crystals (605 mg, 21%) after crystallization from 10% methanol-ethyl acetate, m.p. 221-222°C;<1>H-NMR(DMSO-d6) and mass spectrum (Cl) 317 (M+1); [α]<20>589+ 14.5°, [α]<20>578+ 15.2°, [α]20^ + 16.9° (c = 0.290, methanol).

Anal, calcd for C 2 H 2 NAA: C, 49.23; H, 4.45; N, 8.83; Cl, 22.36. Found: C, 49.29; H, 4.46; N, 8.87; 22,26.

Example 30

(1R,2S,3S,5S)-3-(acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate

(1R,2S,3S,5S)-3-(acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (1.40 g, 2, 94 mmol) was brominated as in example 3. Volatile components were removed in vacuo and the residue chromatographed on silica gel. Crude product eluted with 20-30% hexane-ethyl acetate as a colorless oil. A chloroform solution of the oil was washed with water to remove contaminating succinimide. The chloroform solution was dried (sodium sulfate) and evaporated to dryness in vacuo to give the title compound as a white solid foam from ethanol (760 mg, 50%);<1>H-NMR(DMSO-de) and mass spectrum (Cl) identical to the racemate as described in example 3; [cc]20589+ 43.8°, [α]20578 + 45.2°, [α]20^ + 52.2° (c = 0.345, methanol).

Anal, calcd for C 2 H 2 BrCl 2 -0.05 EtOH: C, 43.74; H, 3.71; N, 5.34; total halogen as Cl, 20.28. Found: C, 43.74; H, 3.69; N, 5.35; total halogen as Cl, 20.41.

Example 31

(1R, 2S, 3S, 5S)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol

(1R,2S,3S,5S)-3-(acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (660 mg, 1.26 mmol ) was deacetylated as in Example 4 to give the title compound as a white powder after crystallization from 1:1 ethanol-methanol (415 mg, 83%), m.p. 213-216°C;<1>H-NMR(DMSO-d6) and mass spectrum (Cl) identical to the racemate described in Example 4; [α]<20>589+ 35.9°, [578<+>36.8°, [α]20546 + 42.1° (c = 0.340, methanol).

Anal, calcd for C^H^r^BrCIA C, 39.43; H, 3.31; N, 7.07; total halogen as Cl, 26.86. Found: C, 39.48; H, 3.29; N, 7.00; total halogen as Cl, 26.90.

Example 32

(1R,2S,3S,5S)-5-[5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol

(1R, 2S, 3S, 5S)-3-(acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (500 mg, 0958 mmol) was refluxed in water:ethanol/2:1 (7.5 mL) with cyclopropylamine (newly opened vial from Aldrich, 0.66 mL, 9.6 mmol) under nitrogen for 18 h. TLC (silica gel, 10% methanol-chloroform) showed complete transfer in a single spot with a lower Rf than the starting material. 1 N sodium hydroxide (0.96 mL) was added and the volatiles evaporated. The residue was chromatographed on a silica gel flash column. The title compound was eluted with 10% methanol-chloroform as a colorless glassy mass which solidified from water:ethanol/2:1 (5 mL) to give a white powder (170 mg, 48%), m.p. 219-220°C;<1>H-NMR(DMSO-d6)5: 7.64 and 7.46 (both s, 2, aromatic CH), 7.11 (m, 1, NH), 5.11 (t, J=4.3 Hz, 1, OH), 4.77 (d, J=7.0Hz, 1, OH), 4.67 (d, J=3.7Hz, 1 OH), 4, 65-4.30 (m, 2, OCH and NCH), 3.85-3.75 (m, 1, OCH), 3.7-3.4 (m, 2, OCH2), 2.85-2 ,70

(m, 1, NCH in cyclopropyl), 2.15-1.80 (m, 3, CH2 and CH in cyclopentane), 0.80-0.50 (m, 4, 2 CH2 in cyclopropyl); mass spectrum (Cl): 372 (M+1); [α]<20>589<+>13.4°, [α]20578+ 15.5°, [α]<20>546+ 16 , 9° (c = 0.277, methanol). (See examples 26-28 and 30).

Anal, calcd for C 2 H 2 NaCl: C, 51.63; H, 5.15; N, 11.29; Cl, 19.05. Found: C, 51.36; H, 5.06; N, 11.25; Cl, 19,16.

Example 33

(1R,2S,3S,5S)-5-[5,6-dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol

(1R, 2S, 3S, 5S)-3-(acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (1.00 g , 1.92 mmol) was refluxed in ethanol (10 mL) with isopropylamine (1.6 mL, Fluka) under nitrogen for 24 h. A second portion of isopropylamine (0.80 mL) was added and reflux continued for another 4 hours. Volatiles were evaporated, the residue was redissolved in ethanol, 1 N sodium hydroxide (1.90 mL) was added, and volatiles were re-evaporated. The residue was chromatographed on a silica gel column. The title compound was eluted with 10% methanol-ethyl acetate as a colorless glassy mass. Evaporation of an ethanol solution gave the title compound as an off-white solid foam (360 mg, 46%). One such sample was solidified by trituration with 95% water-5% methanol, which gave the title compound as a white powder (96%), m.p. 137-138°C;<1>H-NMR(DMSO-d6)5: 7.60 and 7.39 (both s, 2, aromatic CH), 6.64 (d, J=7.4 Hz, 1 , NH), 5.15 (t, J=4.3 Hz, 1, OH), 4.81 (d, J=7.3 Hz, 1, OH), 4.70 (d, J=3, 5 Hz, 1, OH), 4.70-4.50 (m, 1, NCH), 4.50-4.30 (m, 1, OCH), 4.10-4.00 (m, 1, NCH in cyclopropylamino), 3.9-3.75 (m, 1, OCH), 3.70-3.50 (m, 2, OCH2), 2.20-1.80 (m, 3, CH2 and CH in cyclopentane), 1.24 (d, J=6.6 Hz, 6, 2 CH 3 ); mass spectrum (Cl): 374 (M+1); [a]<20>589- 3.72°, [a]20578- 2.60°, [a]<20>M6- 2.23°, [a]20438 - 9.67°, [a]< 20>365-51.7° (c = 0.269, methanol).

(See examples 16-18 and 20).

Anal, calcd for C 16 H 21 N 3 Cl 2 O 3 -1.3 H 2 O: C, 48.32; H, 5.98; N, 10.57; Cl, 17.83. Found: C, 48.08; H, 5.91; N, 10.41; Cl, 18,13.

Example 34

(±)-(1R<*>. 2S<*>, 3S<*>, 5S*)-5-(5,6-dichloro-2-amino-1H-benzimidazol-1-yl)-3-( hydroxymethyl)-1,2-cyclopentanediol

(±)-(1R<*>. 2S<*>, 3S<*>, 5S<*>)-3-(acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1 -yl)-1,2-cyclopentanediyl diacetate (750 mg, 1.44 mmol) was dissolved in ethanol (10 mL). Hydrazine hydrate (55%, 0.41 mL, 7.2 mmol) was added and the solution was refluxed for 2 h. Volatiles were evaporated and the remaining white solid was recrystallized from ethanol-water and stirred with Raney nickel (pre-equilibrated under hydrogen) in methoxyethanol (20 mL) for 30 minutes. The catalyst was filtered off and the filtrate was made weakly basic with aqueous sodium hydroxide to complete the removal of the acetate groups. The solution was neutralized and volatile components evaporated. The remaining solid was recrystallized from ethanol-water to give the title compound as a bright red solid (97 mg, 20%), m.p. 283-284°C split;<1>H-NMR(DMSO-d6)d: 7.61 and 7.30 (both s, 2, aromatic CH), 6.65 (br s, 2, NH2), 5.07 (t, J=4.3 Hz, 1, OH), 4.80 (d, J=7.0 Hz, 1, OH), 4.66 (d, J=3.7Hz, 1, OH), 4.65-4.50 (m, 1, NCH), 4.45-4.30 (m, 1, OCH), 3.90-4.80 (m, 1, OCH), 3, 70-3.40 (two m, 2, OCH 2 ), 2.20-1.80 (m, 3, CH 2 and CH in cyclopentane); mass spectrum (Cl): 332 (M+1), (See Examples 1-3).

Anal, calcd for C 2 H 2 NaCl: C, 47.01; H, 4.55; N, 12.65; Cl, 21.35. Found: C, 46.72; H, 4.60; N, 12.46; Cl, 21.08.

Example 35

(±)-(1 R<*>, 2R<*>, 4S*)-2-(2-cyclopropylamino-5,6-dichloro-1 H -benzimidazol-1-yl)-4-(hydroxymethyl)cyclopentanol

(±)-(1R<*>, 2R<*>, 4S<*>)-4-(acetoxymethyl)-2-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)cyclopentyl- acetate (500 mg, 1.50 mmol) was reacted with cyclopropylamine (0.73 mL) in the same manner as in Example 32. The crude product was chromatographed on silica gel, and the title compound eluted with 5% methanol-ethyl acetate as a colorless glassy mass which crystallized from ethyl acetate-hexanes to a white powder (180 mg, 48%), m.p. 251-253°C;<1>H-NMR(DMSO-d6)5: 7.54 and 7.45 (both s, 2, aromatic CH), 5.04 d, J=5.1Hz, 1, OH ), 4.97 (t, J=4.7Hz, 1, OH), 4.60-4.50 and 4.50-4.30 (both m, 1 each, NCH and OCH), 3.50 ( m, 2, OCH 2 ), 2.80

(m, 1, CH), 2.35-2.10 (m, 1, CH), 2.05-1.80 (m, 3, CH2and CH in cyclopentane), 1.80-1.60 (m , 1, CH), 0.80-0.50 (1 m, 4, 2CH2 in cyclopropyl); mass spectrum (Cl): 356 (M+1). (See examples 5-7).

Anal, calcd for C 2 H 2 NaCl: C, 53.97; H, 5.34; N, 11.80; Cl, 19.91. Found: C, 53.72; H, 5.42; N, 11.52; Cl, 19.64.

Example 36

(±)-(1R<*>, 2S<*>, 3S<*>, 5S*)-5-[5,6-dichloro-2-(cyclobutylamino)-1H-benzimidazol-1-yl]-3 -(hydroxymethyl)-1,2-cyclopentanediol

(±)-(1R<*>, 2S<*>. 3S<*>, 5S<*>)-3-(acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazole-1 -yl)-1,2-cyclopentanediyl diacetate (500 mg, 0.958 mmol) was dissolved in absolute ethanol (7 mL) and cyclobutylamine (0.41 mL, 4.8 mmol) was added. The solution was refluxed under nitrogen for 18 hours. Volatiles were evaporated and the residue was stirred in methanol half-saturated with ammonia at 0°C (20 mL) for 18 hours. Volatiles were removed in vacuo and the residue was crystallized from ethanol-water to give the title compound as a white solid, m.p. 250°C decomp.;<1>H-NMR(DMSO-d6)6: 7.61 and 7.38 (both s, 1 each, aromatic CH), 7.07 (d, J=7.4 Hz, 1, NH), 5.15 (t, J=3.9 Hz, 1, OH), 4.81 (d, J=7.3 Hz, 1, OH), 4.71-4.45 (m overlapping d at 4.71, J=3.5Hz, total 2, OH and NCH), 4.40-4.30 (m, 2, OCH and NCH), 3.82-3.80 (m, 1, OCH), 3.72-3.42 (both m, 1 each, OCH2), 2.32-1.67 (three m, 9, 4CH2 and CH); mass spectrum (Cl): 386 (M+1). (see examples 5-7).

Anal, calcd for C17H21N3CI2O30.15 H2O 0.05 C2H5OH: C, 52.49; H, 5.56; N, 10.74; Cl, 18,12. Found: C, 52.34; H, 5.47; N, 10.52; Cl, 17.99.

Example 37

(±)-(1R<*>. 2S<*>. 3S<*>, 5S<*>)-5-[5,6-dichloro-2-(1-azetidinyl)-1H-benzimidazol-1-yl ]-3-(hydroxymethyl)-1,2-cyclopentanediol

(±)-(1R<*>, 2S<*>. 3S<*>, 5S<*>)-3-(acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazole-1 -yl)-1,2-cyclopentanediyl diacetate (500 mg, 0.958 mmol) was dissolved in ethanol (7 mL). Azetidine (Aldrich, 250 mg, 4.4 mmol as 98%) was added and the solution was refluxed under nitrogen for 48 h. Methanolic ammonia (saturated at 0°C, 20 mL) was added to the cooled solution, and this solution was

stirred for another 18 hours. Volatiles were evaporated, the residue was redissolved in ethanol (10 mL) and 1 N sodium hydroxide (0.96 mL) was added. The volatiles were evaporated and the remaining solids were triturated with water (3 mL) and filtered. Recrystallization of the solid from acetonitrile-methanol gave the title compound as a white powder (146 mg, 41%), m.p. 221-222°C; <1>H-NMR(DMSO-d6)5: 7.78 and 7.53 (both s, 1 each, 2 aromatic CH), 5.05 (t, J=4.3 Hz , 1, OH), 4.91 (d, J=5.3Hz, 1, OH), 4.59 (d, J=3.7Hz, 1, OH), 4.45-4.40 (m, 2, OCH and NCH), 4.25-4.15 (m, 4, 2 CH2N), 3.82-3.79 (m, 1, OCH), 3.66-3.43 (both m, 1 each, OCH 2 ), 2.40-2.32 (m, 2, CH 2 ), 2.03-1.95 (m, 3, CH 2 and NCH); mass spectrum (Cl): 372 (M+1). (See examples 8-10).

Anaj. calcd for C 2 H 2 N 2 C 1 A : C, 51.63; H, 5.14; N, 11.29; Cl, 19.05. Found: C, 51.45; H, 5.10; N, 11.27; Cl, 18.96.

Example 38

(±)-(1R<*>. 2S<*>. 3R<*>, 5R*)-5-[5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3 -(hydroxymethyl)-1,2-cyclopentanediol

(±)-(1R<*>. 2S<*>. 3R<*>, 5R<*>)-3-(acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazole-1 -yl)-1,2-cyclopentanediyl diacetate (Example 39, 1.00 g, 1.87 mmol), cyclopropylamine (Aldrich, 1.7 mL, 24 mmol) and absolute ethanol (10 mL) were refluxed under nitrogen in 48 hours. The reaction was cooled and 1 N sodium hydroxide (1.2 mL) was added. Volatiles were evaporated in vacuo and the remaining oily solid was chromatographed on silica gel. Elution with 5% methanol-ethyl acetate gave fractions containing white powder (200 mg). Recrystallization from 1:1 water-ethanol gave (±)-(1R<*>, 2S<*>, 3R<*>, 5R<*>)-5-[5,6-dichloro-2-(cyclopropylamino)- 1 H -benzimidazol-1 -yl]-3-(hydroxymethyl)-1,2-cyclopentanediol as white crystals (180 mg, 40%; mp >250°C;<1>H-NMR(DMSO-d6)8 : 7.70 (m, 1, NH), 7.62 and 7.39 (both s, 1 each, 2 benzimidazole CH), 5.77 (br s, 1, OH), 5.13 (d, J =5.3 Hz, 1, OH), 4.95-4.80 (m, 1, CHN), 4.48 (t, J=4.7 Hz, 1, CH2OH), 4.2-4, 0 (m, 2, 2 OCH), 3.7-4.0 (m, 2, OCH2), 2.9-2.65 (m, 1, OCH), 2.2-1.8 (m, 3, CH2 and CH); mass spectrum (Cl): 372 (M+1) ) See examples 10-14).

Anal, calcd for C 2 H 2 NaCl: C, 51.63; H, 5.14; N, 11.29; Cl, 19.05. Found: C, 51.53; H, 5.18; N, 11.22; Cl, 18.97.

Example 39

(±)-(1R<*>. 2S<*>, 3R<*>, 5S*)-5-[5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3 -methyl-1,2-cyclopentanediol

Part A. (±)-(1S<*>. 2R<*>. 3R<*>, 5R*)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl )-1,2-cyclopentanediol

(±)-(1R<*>. 2S<*>, 3S<*>, 5S*)-3-(acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1 ,2-cyclopentanediyl diacetate (Example 2, 3.00 g, 6.77 mmol) was dissolved in methanol (100 mL). Methanol saturated with ammonia at 0°C (100 mL) was added and the solution stirred at ambient temperature overnight. Volatiles were evaporated in vacuo and the remaining solid slurried with water and filtered to give the title compound as a brown powder (2.02 g, 94%).

Part B. (±)-(1R<*>. 2S\ 3R<*>, 5S*)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-3-iodo-1,2 -cyclopentanediol

(±)-(1S<*>, 2R<*>, 3R<*>, 5R*)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1 ,2-Cyclopentanediol (part A, 2.00 g, 6.31 mmol) was dissolved in dry DMF (15 mL) under nitrogen and cooled (ice bath), while a solution of methyl triphenoxyphosphonium iodide (Aldrich, 3 .27 g, 6.94 mmol) in dry DMF (15 mL) was added dropwise over 20 min. Stirring was continued in the ice bath for another 30 minutes and then at ambient temperature for 18 hours. Volatile components were evaporated in vacuo, and the remainder chromatographed on silica gel. Product was eluted with 2% methanol-chloroform and after evaporation of the solvents gave a pale yellow powder (750 mg, 28%);<1>H-NMR(DMSO-d6)6: 8.51, 8.08 and 7.97 (all s, 1 each, 3 benzimidazole CH), 5.20 (d, J=6.7Hz, 1, OH), 5.04 (d, J=4.9 Hz, 1, OH), 4.8 -4.6 (m, 1, NCH), 4.3-4.2 (m, 1, OCH), 3.8-3.7 (m, 1, OCH), 3.6-3.4 ( m, 2, CH2I), 2.55-2.40 (m, CH overlapping solvent), 2.35-2.20 (m, 1, CH), 1.75-1.50 (m, 1,

CH).

Part C. (±)-(1R<*>, 2S<*>, 3R<*>, 5S*)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-3-methyl- 1,2-cyclopentanediyl diacetate

(±)-(1R<*>. 2S<*>, 3R<*>, 5S<*>)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-3-iodo-1, 2-Cyclopentanediol (part B, 0.73 g, 1.71 mmol) in ethanol (200 mL) was shaken with 5% Pd on carbon (140 mg) with triethylamine (0.24 mL) under hydrogen (3.4 atm ) on a Parr shaker for 7.5 hours. The catalyst was filtered off (Celite) and the ethanol filtrate evaporated to a white solid. To this solid was added pyridine (15 ml) and acetic anhydride (1.3 ml). The resulting solution was stirred at ambient temperature for 18 hours. The volatiles were evaporated and the remaining oil was dissolved in chloroform (50 mL). The chloroform solution was extracted with aqueous sodium bicarbonate and dried (sodium sulfate). Evaporation of the chloroform returned the title compound as a yellow glassy mass (560 mg, 85%);<1>H-NMR{DMSO-d6)5: 8.61, 8.15 and 7.97 (all s, 1 each , 3 benzimidazole CH), 5.60-5.45 (m, 1, OCH), 5.20-4.94 (m, 2, OCH and NCH), 2.50-2.15 (m, 3, CH2 and CH), 2.09 and 1.95 (both s, 3 each, 2 OAc), 1.20 (d, J=6.5 Hz, 3, CHCHJ.

Part D. (±)-(1R<*>, 2S<*>, 3R<*>. 5S*)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)- 3-methyl-1,2-cyclopentanediyl diacetate

(±)-(1R<*>. 2S<*>, 3R<*>. 5S*)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-3-methyl-1,2 -cyclopentanediyl diacetate (Part C, 550 mg, 1.43 mmol) was dissolved in dry tetrahydrofuran (15 mL). N-Bromosuccinimide (520 mg, 2.92 mmol) was added and the resulting solution refluxed vigorously for 10 minutes. A further portion of N-bromosuccinimide (100 mg) was added and reflux continued for another 5 minutes. At this point, TLC (silica gel plates developed with 5% methanol-chloroform) showed that the starting material had been converted to a UV-absorbing spot with a slightly higher Rf. The reaction mixture was treated by cooling (ice bath) and diluted with chloroform (50 mL). This solution was washed with water and dried (sodium sulfate). Evaporation returned a yellow solid which was chromatographed on silica gel. The title compound was eluted with 5% methanol-chloroform and triturated in ethyl acetate to give a white powder (460 mg, 68%), m.p. 235-236°C split;<1>H-NMR(DMSO-d6)5: 8.38 and 7.97 (both s, 1 each, 2 benzimidazole CH), 5.75-5.65 (m, 1, OCH), 5.2-5.0 (m, 2, OCH and NCH), 2.11 (s) overlapped by 2.2-2.05 (m, total 6, OAc with CH2and CH), 1 .95 (s, 3, OAc), 1.22 (d, J=6.3Hz, 3, CHCl); mass spectrum (Cl): 463 (M+1).

Part E. (±)-(1R<*>. 2S<*>, 3R<*>, 5S<*>)-5-[5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazole-1- yl]-3-methyl-1,2-cyclopentanediol

(±)-(1R<*>. 2S<*>, 3R<*>. 5S*)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-methyl -1,2-cyclopentanediyl diacetate (part D, 350 mg, 0.75 mmol) and cyclopropylamine (Aldrich, 0.53 mL) were refluxed in methoxyethanol (5 mL) for 5 h. 1 N sodium hydroxide solution (0.75 mL) was added to the cooled reaction mixture and volatiles were evaporated in vacuo. The residue was chromatographed on silica gel. Product was eluted with 5% methanol-chloroform. Recrystallization from methanol-ethyl acetate gave (±)-(1R<*>, 2S<*>, 3R<*>, 5S<*>)-5-[5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazole- 1-yl]-3-methyl-1,2-cyclopentanediol as white crystals (170 mg, 64%); m.p. 231r233°C; <1>H-NMR(DMSO-d6)5: 7.48 and 7.39 (both s, 1 each, 2 benzimidazole CH), 7.10 (m, 1, NH), 4.83 (d, J=5.9 Hz, 1, OH), 4.74 (d, J=5.1 Hz, 1, OH), 4.5-4.3 (m, 2, NCH and OCH), 3.7-3.6 (m, 1, OCH), 2.85-2.7 (m, 1, CHNH), 2.1-1.8 (m, 2, CH2 and CH), 1.7 -1.5 (m, 1, CH), 1.16 (d, J=5.4 Hz, 3, CHCK, ), 0.8-0.5 (m, 4, 2 CH 2 i cyclopropyl); mass spectrum (Cl): 356 (M+1). (See examples 1 and 2).

Anal, calcd for C 2 H 2 NaCl: C, 53.95; H, 5.38; N, 11.80; Cl, 19.90. Found: C, 53.75; H, 5.45; N, 11.71; Cl, 19.98.

Example 40

(1R,2S,3S,5S)-5-[2-(tert-butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol

A solution of (1R, 2S, 3S, 5S)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol (500 mg , 1.26 mmol) was stirred in tert-butylamine (Aldrich, 98%, 20 mL) in a Parr bomb held at 148°C (oil bath) for 48 h. The bomb was cooled and the resulting pale yellow solution diluted with ethanol containing 1 N sodium hydroxide (1.2 mL). Volatile constituents were evaporated in vacuo, and the residue was chromatographed on silica gel. The title compound was eluted with 10% methanol-chloroform as a colorless oil. The oil was dissolved in absolute ethanol, evaporated to an oil and triturated with water (3 mL) to give (1R,2S,3S,5S)-5-[2-(tert-butylamino)-5,6-dichloro-1H -benzimidazol-1 -yl]-3-(hydroxymethyl)- 1,2-cyclopentanediol as white powder (303 mg, 61%), m.p.: collapses to glassy mass at 116-150°C;<1>H- NMR(DMSO-d8)5: 7.63 and 7.43 (both s, 2 aromatic CH), 6.15 (s, 1, NH), 5.08 (t, J=4.3 Hz, 1, OH), 4.85 (d, J=7.4 Hz, 1, OH), 4.71 (d, J=3.8 Hz, 1, OH), 4.7-4.5 (m, 1 , NCH), 4.45-4.3 (m, 1, OCH), 3.80 (m, 1, OCH), 3.7-3.4 (m, 2, OCH2), 2.2-1 .85 (m, 3, CH 2 and CH in cyclopentane), 1.47 (s, 9, 3 CH 3 ); mass spectrum (Cl): 388 (M+1); [a]<20>589- 4.0°, [ a] 20576- 4.3°, [a]<20>^-6.0°, [a]<20>436- 22.6°, [ α]<20>365-82.1° (c = 0.420, methanol). (See examples 25-28, 30 and 31.)

Anal, calcd for C17H23N3CI2O3 0.40 H2O: C, 51.63; H, 6.07; N, 10.62; Cl, 17.93. Found: C, 51.50; H, 5.99; N, 10.54; Cl, 17.96.

Example 41

(±)-(1R<*>, 2S<*>, 3S<*>, 5S<*>)-5-[2-(rerr-butylamino)-5,6-dichloro-1H-benzimidazol-1-yl ]-3-(hydroxymethyl)-1,2-cyclopentanediol

A solution of (±)-(1R<*>, 2S<*>. 3S<*>, 5S<*>)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl) -3-(hydroxymethyl)-1,2-cyclopentanediol (750 mg, 1.44 mmol) was stirred in tert-butylamine (Aldrich, 98%, 25 mL) in a Parr bomb maintained at 90°C (oil bath) in 6 days. Volatiles were evaporated in vacuo, the remaining solids refluxed in ethanol (30 ml) with aqueous dimethylamine (Aldrich, 40%, 2 ml) for one hour. Volatile components were evaporated, and the remaining solids chromatographed on silica gel. Elution with 10% methanol-ethyl acetate gave the title compound as a colorless glassy mass. Crystallization from water gave (±)-(1R<*>. 2S<*>, 3S<*>, 5S<*>)-5-[2-(ferr-butylamino)-5,6-dichloro-1H-benzimide -zol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol as a white powder (150 mg, 26%); m.p. 130-132°C;<1>H-NMR(DMSO-d6) identical to that of the enantiomer described in Example 30. (See Examples 1-4.)

Anal, calcd for C17H23N3CI2O3 0.65 H2O 0.07 C2H5OH: C, 51.18; H, 5.94; N, 10.47; Cl, 17.63. Found: C, 51.34; H, 6.06; N, 10.37; Cl, 17.58.

Example 42

(±)-(1R<*>, 2S<*>, 3S<*>, 5S*)-5-[-5,6-dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]- 3-(hydroxymethyl)-1,2-cyclopentanediol

(±)-(1R<*>, 2S<*>, 3S<*>. 5S<*>)-3-(acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazole-1 -yl)-1,2-cyclopentanediyl diacetate (750 mg, 1.44 mmol) was refluxed in ethanol (10 mL) with isopropylamine (1.22 mL, Aldrich) under nitrogen for 18 h. A second portion of isopropylamine (1.22 mL) was added and reflux continued for another 24 hours. Volatiles were evaporated, the residue was redissolved in ethanol, 1 N sodium hydroxide (1.44 mL) was added, and volatiles were evaporated again. The residue was chromatographed on a silica gel column. The title compound was eluted with 10% methanol-chloroform as a colorless glassy mass. The glassy mass was crystallized from ethyl acetate-hexanes to give (±)-(1R<*>, 2S<*>, 3S<*>, 5S<*>)-5-[5,6-dichloro-2-(isopropyl -amino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol as white crystals (305 mg, 57%); m.p. 213-214°C;<1>H-NMR(DMSO-d6) identical to the enantiomer described in example 23. (See examples 1-4.)

Anal, calcd for C 16 H 21 N 3 Cl 2 O 3 : C, 51.35; H, 5.66; N, 11.23; Cl, 18.95. Found: C, 51.27; H, 5.69; N, 11.17; Cl, 18.88.

Claims (15)

1. Compound characterized by formula (I) or (1-1): where R<1> is H, CH3 or CH2 OH; R 2 is H or OH; R 3 is H or OH; or R 2 and R 3 together form a bond; R4 is amino, cyclopropylamino, cyclobutylamino, isopropylamino, tert-butylamino or -NR <8> R <9> where R <8> and R <9> together with the nitrogen atom to which they are bound form a 4-, 5- or 6- membered heterocyclic ring; R<5> is H; and R6 and R7 are Cl, except for the compound (±)-(1R <*> . 2S <*> . 3S <*> , 5S <*> )-5-[5,6-dichloro-2-(cyclopropylamino)- 1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; provided that at least one of R<1> , R2 and R3 is or contains OH; and pharmaceutically acceptable derivatives thereof. 2. Compound according to claim 1, characterized in that R2 is OH. 3. Compound according to claim 2, characterized in that R4 is cyclopropylamino, isopropylamino or tert-butylamino. 4. Compound according to claim 3, characterized by R4 being isopropylamino or tert-butylamino. 5. Compound according to claim 1 characterized by formula (IA) or (IA-1) where R<2> is H or OH; R <4> is amino, cyclopropylamino, isopropylamino, tert-butylamino or -NR <8> R <9> where R <8> and R <9> together with the nitrogen atom to which they are attached form a 4-, 5- or 6-membered heterocyclic ring; R 5 is H; and R6 and R <7> are Cl, except the compound (±)-{1R <*> , 2S <*> , 3S <*> , 5S <*> )-5-[5,6-dichloro-2-( cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol, and pharmaceutically acceptable derivatives thereof. 6. Compound according to claim 5, characterized in that R4 is cyclopropylamino, isopropylamino or tert-butylamino; R<5> is H; R<6> and R7 are both Cl; and the pharmaceutically acceptable derivatives thereof. 7. Compound according to claim 6, characterized in that R4 is isopropylamino or tert-butylamino. 8. Compound according to claim 1, characterized in that it is selected from (1R, 2S, 3S, 5S)-5-[5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3 -(hydroxymethyl)-1,2-cyclopentanediol; (1R,2S,3S,5S)-5-[5,6-dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; (±)-(1R <*> , 2S <*> , 3S <*> . 5S <*> )-5-(5,6-dichloro-2-amino-1H-benzimidazol-1-yl)-3 -(hydroxymethyl)-1,2-cyclopentanediol; (±)-(1 R<*> , 2R<*> , 4S*)-2-(2-cyclopropylamino-5,6-dichloro-1H-benzimidazol-1-yl)-4-(hydroxymethyl)cyclopentanol; (±)-(1R <*> , 2S <*> . 3S <*> , 5S <*> )-5-[5,6-dichloro-2-(cyclobutylamino)-1H-benzimidazol-1-yl] -3-(hydroxymethyl)-1,2-cyclopentanediol; (±)-(1R <*> , 2S <*> , 3S <*> , 5S <*> )-5-[5,6-dichloro-2-(1-azetidinyl)-1H-benzimidazol-1- yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; (±)-(1R <*> , 2S <*> , 3R <*> , 5R <*> )-5-[5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]- 3-hydroxymethyl)-1,2-cyclopentanediol; (±)-(1R <*> , 2S <*> . 3R <*> , 5S <*> )-5-[5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl] -3-methyl-1,2-cyclopentanediol; (1R,2S,3S,5S)-5-[2-(tert-butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; (±)-(1R <*> , 2S <*> , 3S <*> . 5S*)-5-[2-(fe/t-butylamino)-5,6-<Jichloro-1H-benzimidazol-1 -yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; (±)-(1R <*> , 2S <*> . 3S <*> , 5S*)-5-[5,6-dichloro-2(isopropylamino)-1H-benzimidazol-1-yl]-3- (hydroxymethyl)-1,2-cyclopentanediol; (1S,2R,3R,5R)-5-[5,6-dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; (1S,2R,3R,5R)-5-[2-(tert-butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; (+)-(1R <*> , 2S <*> , 3S <*> , 5S*)-5-[5,6-dichloro-2-(1-azetidinyl)-1H-benzimidazol-1-yl] -3-(hydroxymethyl)-1,2-cyclopentanediol; (1R,2S,3S,5S)-5-[5,6-dichloro-2-(1-azetidinyl)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; and (1S,2R,3R,5R)-5-[5,6-dichloro-2-(1-azetidinyl)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol and pharmaceutically acceptable derivatives thereof. 9. Method for treating a herpes virus infection in an individual, characterized by treating the individual with a therapeutically effective amount of at least one compound of the formula (I) or (1-1) (as defined in claim 1) or a pharmaceutically acceptable derivative thereof. 10. Method according to claim 9, characterized in that the herpes virus infection is a cytomegalovirus infection. 11. Method according to claim 9 or 10, characterized in that the compound is selected from (1R,2S,3S,5S)-5-[5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; (1R,2S,3S,5S)-5-[5,6-dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; (±)-(1R <*> , 2S <*> , 3S <*> , 5S <*> )-5-(5,6-dichloro-2-amino-1H-benzimidazol-1-yl)-3 -(hydroxymethyl)-1,2-cyclopentanediol; (±)-(1 R<*> , 2R<*> , 4S*)-2-(2-cyclopropylamino-5,6-dichloro-1H-benzimidazol-1-yl)-4-(hydroxymethyl)cyclopentanol; (±)-(1R <*> , 2S <*> . 3S <*> , 5S <*> )-5-[5,6-dichloro-2-(cyclobutylamino)-1H-benzimidazol-1-yl] -3-(hydroxymethyl)-1,2-cyclopentanediol; (±)-(1R <*> . 2S <*> , 3S <*> , 5S <*> )-5-[5,6-dichloro-2-(1-azetidinyl)-1H-benzimidazol-1- yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; (±)-(1R <*> , 2S <*> , 3R <*> , 5R <*> )-5-[5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl] -3-(hydroxymethyl)-1,2-cyclopentanediol; (±)-(1R <*> . 2S <*> , 3R <*> , 5S <*> )-5-[5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl] -3-methyl-1,2-cyclopentanediol; (1R,2S,3S,5S)-5-[2-(tert-butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; (±)-(1R <*> , 2S <*> , 3S <*> , 5S*)-5-[2-(/erf-butylamino)-5,6-dichloro-1H-benzimidazol-1-yl ]-3-(hydroxymethyl)-1,2-cyclopentanediol; (±)-(1R <*> , 2S <*> , 3S <*> . 5S <*> )-5-[5,6-dichloro-2(isopropylamino)-1H-benzimidazol-1-yl]- 3-(hydroxymethyl)-1,2-cyclopentanediol; (1S,2R,3R,5R)-5-[5,6-dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; (1S,2R,3R,5R)-5-[2-(tert-butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; (+)-(1R <*> , 2S <*> , 3S <*> , 5S <*> )-5-[5,6-dichloro-2-(1-azetidinyl)-1H-benzimidazol-1 - yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; (1R,2S,3S,5S)-5-[5,6-dichloro-2-(1-azetidinyl)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; and (IS, 2R, 3R, 5R)-5-[5,6-dichloro-2-(1-azetidinyl)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol and pharmaceutically acceptable derivatives thereof. 12. Use of one or more of the compounds according to claim 1 in the preparation of a drug for the treatment of viral infections, in particular hepatitis B virus and and cytomegalovirus infections. 13. Pharmaceutical formulations, characterized in that they comprise at least one compound of formula (I) or (1-1) (as defined in claim 1) or a pharmaceutically acceptable derivative thereof, together with at least one pharmaceutically acceptable carrier or excipient. 14. Pharmaceutical formulation according to claim 13, characterized in that the compound is selected from (1R,2S,3S,5S)-5-[5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; (1R,2S,3S,5S)-5-[5,6-dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; (±)-(1R <*> , 2S <*> , 3S <*> , 5S*)-5-(5,6-dichloro-2-amino-1H-benzimidazol-1-yl)-3-( hydroxymethyl)-1,2-cyclopentanediol; (±)-(1 R<*> , 2R<*> , 4S*)-2-(2-cyclopropylamino-5,6-dichloro-1H-benzimidazol-1-yl)-4-(hydroxymethyl)cyclopentanol; (±)-(1R <*> , 2S <*> , 3S <*> , 5S <*> )-5-[5,6-dichloro-2-(cyclobutylamino)-1H-benzimidazol-1-yl] -3-(hydroxymethyl)-1,2-cyclopentanediol; (±)-(1R <*> , 2S <*> , 3S <*> , 5S <*> )-5-[5,6-dichloro-2-(1-azetidinyl)-1H-benzimidazol-1- yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; (±)-(1R <*> , 2S <*> , 3R <*> , 5R*)-5-[5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3 -hydroxymethyl )-1,2-cyclopentanediol; (±)-(1R <*> , 2S <*> . 3R <*> , 5S*)-5-[5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3 -methyl-1,2-cyclopentanediol; (1R,2S,3S,5S)-5-[2-(tert-butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; (±)-(1R <*> , 2S <*> , 3S <*> , 5S <*> )-5-[2-(tert-butylamino)-5,6-dichloro-1H-benzimidazole-1 - yl]-3-(hydroxymethyl)-1,2-cyclopentanediol; (±)-(1R <*> , 2S <*> , 3S <*> , 5S*)-5-[5,6-dichloro-2(isopropylamino)-1H-benzimidazol-1-yl]-3- (hydroxymethyl)-1,2-cyclopentanediol; and pharmaceutically acceptable derivatives thereof. 15. Process for the preparation of compounds of formula (I) and (1-1) (as defined in claim 1) alone or in combination with their mirror image enantiomers, and their pharmaceutically acceptable derivatives, characterized by (A) conversion of or the mirror image enantiomer thereof, med a) either a compound of the formula R<4> CO2 H in which R4 is H, C1 -alkyl or C1-4 -perfluoroalkyl or a compound of the formula R <4> C(OR)3 in which R4 is H, C1 -4 -alkyl or C1.4 -perfluoroalkyl, and R is C1.4 -alkyl, forming a compound of formula (IA) or (IA-1) wherein R<4> is H; or b) cyanogen bromide to form a compound of the formula (IA) or (IA-1) in which R 4 is NH 2 ; (B) a) converting a compound of formula (IA) or (IA-1) in which R 4 is hydrogen into another compound of formula (IA) or (IA-1) in which R<4> is a leaving group; or b) transferring a compound of formula (IA) or (IA-1) in which R <4> is Cl, Br or I into another compound of formula (IA) or (IA-1) in which R <4> is a amino or substituted amino group -NR <8> R <9> as defined above; or (C) reacting a compound of the formula (wherein R<4> , R<5> , R6 and R <7> are as previously defined) or a functional equivalent hence with a compound of formula wherein R<1> , R2 and R3 are as defined above, and L is a leaving group, forming a compound of formula (IA) or (IA-1) wherein R4 is hydrogen, halogen or -NR<8> R <9> and optionally transferring a compound of formula (IA) or (IA-1) into a pharmaceutically acceptable derivative thereof.