CZ71297A3 - Antiviral nucleoside analogs containing substituted benzimidazole base being attached to a carbocyclic ring, process of their preparation, pharmaceutical composition containing thereof and use - Google Patents

Abstract

Antiviral nucleoside analogues contain a substituted benzimidazole base attached to a carbocyclic ring in place of the conventional sugar residue. In formulae (I) and (I-1), 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; R<4> 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, excluding the compound (+/-)-(1R*, 2S*, 3S*, 5S*)-5-[5,6-Dichloro-2-(cyclopropylamino)-1<u>H</u>-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol and provided that at least one of R<1>, R<2> and R<3> is or contains OH. The compounds have activity against herpes virus especially cytomegalovirus and also hepatitis B virus infections.

Description

The invention relates to certain pure nucleoside analogs containing a carbocyclic ring instead of a sugar moiety, pharmaceutically acceptable derivatives thereof, a process for the preparation of these compounds, pharmaceutical compositions and their use in medical treatment, in particular for the treatment of certain viral infections.

BACKGROUND OF THE INVENTION

Hepatitis B virus (HBV) is a small DNA virus that infects humans. It is a member of a class of closely related viruses known as hepadnaviruses, each of which selectively infects either mammals or flying hosts such as woodchuck and ducks.

Worldwide, the HBV viral pathogen is of major importance. It is most common in Asian countries and prevalent in sub-Saharan Africa. The virus is etiologically associated with primary hepatocellular carcinoma and is thought to cause 80% of liver cancer worldwide. In the United States, more than ten thousand people are hospitalized annually with HBV disease, with an average of 250 dying from a severe course of the disease.

In the United States, the pool currently under review includes between 500,000 and 1 million carriers of infection. Chronic active hepatitis will develop in more than 25% of the carriers and often goes into cirrhosis. It has been found that 5,000 people die in the United States each year from HBV-associated cirrhosis and about 1,000 deaths are attributable to HBV-associated liver cancer. Although a universal HBV vaccine is available, there is no need for effective anti-HBV compounds. A large number of persistent infected carriers, assessed worldwide at 220 million, will not benefit from vaccination and will continue to be at high risk for HBV-induced liver disease. This carrier population serves as a source of infection for susceptible individuals to continue the incidence of cases of disease, particularly in endemic areas or high-risk groups such as people abusing IV drug group and homosexuals. Thus, there is a great need for effective antiviral agents, both to control chronic infection and to reduce the progression of hepatocellular carcinoma.

The clinical effects of HBV infection include a wide range from headache, fever, nausea, nausea, vomiting, anorexia and abdominal pain. Virus replication is usually controlled by an immune response with convalescence in the last weeks or months in humans, but infection can be much more severe and lead to persistent chronic liver disease as mentioned above.

In Viral Infections of Humans (Second Edition, Ed., Evans, A. S. (1982) Plenum Publishing Corporation, New York), Chapter 12 details in detail the etiology of viral hepatitis infections.

From DNA viruses, the herpes group is the source of many common viral diseases in humans. This group includes cytomegalovirus (CMV), Epsten-Barr virus (EBV), varicella zoster virus (VZV), herpes simplex virus (HSV) and human herpes virus 6 (HHV6).

Infection with other herpes viruses usually leads to long-term association of the virus and the host with CMV, and after the primary infection, the virus can remain silent for many years. Clinical effects range from death and macroscopic disease (microcephaly, hepatosplenemegaly, jaundice, mental retardation) through failure to develop, susceptibility to cervical and ear infections to loss of any apparent manifestation of the disease. CMV infection in AIDS patients is the predominant cause of morbidity since 40 to 80% of the adult population is present in a latent form and may be reactivated in immunocompromised patients.

EBV causes mononucleosis infections and is also considered to be a causative agent of nasopharyngeal cancer, immunoblastic lymphoma, Burkitt's lymphoma, and hair leukoplakia.

VZV causes chickenpox and shingles. Chickenpox is the primary disease occurring in the host without immunity. In young children, mild disease is usually characterized by vesicular rash and fever. Shingles is a recurrent form of the disease that occurs in adults who were previously infected with varicella. Clinical manifestations of shingles include neuralgia and a vesicular skin rash that has unilateral and dermatomal distribution. The spread of inflammation can lead to paralysis or convulsions and coma if meninges are affected. VZV can disseminate and cause severe or even fatal disease in immunodeficiency scientists.

HSV 1 and HSV 2 are among the most common infectious agents in humans. Most of these viruses are able to persist in host neural cells. After infection, individuals are at risk of recurrence of clinical manifestation of infection, which can be both psychologically and psychologically stressful. HSV infection is often characterized by widespread lesions of the skin, mouth and / or genitals. Primary infections may be subclinical, although they tend to be more dangerous than infections in individuals pre-exposed to the virus. Eye infections with HSV can lead to keratitis or cataracts. Infections in newborns in immunosuppressed patients or infections into the central nervous system can be fatal. HHV6 is a causative agent of roseola infants (exanthum subitum) in children, which is characterized by fever and the occurrence of a rash following a decrease in fever. HHV6 has also been implicated in fever and / or rash syndromes and pneumonia or hapatitis in immunocompromised patients.

SUMMARY OF THE INVENTION

It has been found that certain substituted benzimidazole compounds as described below are useful for the treatment or prophylaxis of certain viral infections.

In a first aspect, the present invention relates to compounds of formulas I and 1-1:

in which :

R1 is hydrogen, CH3 or C1-4OH;

is H or OH, R 6 is H or OH, or R 6 and R 6 together form a bond;

R ⁴ is an amino group, a cyclopropylamino group, a cyclobutylamino group, an isopropylamino group, a tert-butylamino group, or an -NR R group wherein R and R together with the nitrogen atom to which they are attached form a 4 or 6-membered heterocyclic ring;

R is hydrogen, and

R ° and R 'are Cl, excluding the compound (±) ^_ (lR *, 2S *, 3S *, 5S *) - 5- [5,6-dichloro-2- (cyclopropylamino) -lH-benzimidazol-l- yl] -3- (hydroxymethyl) -1,2-cyclopentanediol and with the proviso that at least one of R, R and R is or contains OH;

Preferred compounds of formulas I and I-1 are those in which R 1 is a cyclopropylamino group, an isopropylamino group or a tert-butylamino group, and in particular an isopropylamino group or a tert -butylamino group.

Preferred compounds of formulas I and 1-1 of the invention are compounds of formulas IA or IA-1:

(IA)

(IA-I) in which:

R is hydrogen or OH, r 4 is amino, cyclopropylamino, isopropylamino, tert-butylamino, especially isopropyl or tert-butylamino, or - Nr 8r 9, wherein r 8 and R 8 together with the nitrogen atom to which they are attached form a 4,5 or 6-membered heterocyclic ring;

R 6 is hydrogen, and

R 1 and R ² are chlorine, with the exception of (+) - (IR *, 2S *, 3S *, 5S *) -5- [5,6-dichloro-2- (cyclopropylamino)] 7

ΙΗ-Benzimidazol-1-yl] -3- (hydroxymethyl) -1,2-cyclopentanediol and pharmaceutically acceptable derivatives thereof.

Particularly preferred compounds of formulas IA and IA-1 are those wherein the cyclopropylamino group, the isopropylamino group or the tert-butylamino group is hydrogen and R 0 and R ⁷ are both chlorine, and pharmaceutically acceptable derivatives thereof. It is to be understood that the present invention encompasses the individual enantiomers represented by Formulas I and I-1, including the purine tautomers, alone and in combination with their mirror enantiomers. The enantiomers represented by formula I are preferred and are preferably provided substantially free of the corresponding enantiomer to a range that is generally in admixture with less than 10% w / w. more preferably less than 2% most preferably less than 1% of the corresponding enantiomer based on the total weight of the composition. The enantiomers represented by Formula I-1 are mostly preferred and are preferably provided substantially free of the corresponding enantiomer to a range that is generally in admixture with less than 10% w / w, preferably less than 5% w / w. %, preferably less than 2% w / w. and most preferably less than 1% w / w. of the corresponding enantiomer based on the total weight of the mixture.

Particularly preferred examples of compounds of the present invention 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) -4-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] -1,2-cyclopentanediol;

(+) - (1R *, 2S *, 3S *, 5S *) -5- [2- (t-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) -4-benzimidazol-1-yl] -3- (hydroxymethyl) -1,2-cyclopentanediol, and their pharmaceutically acceptable salts.

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

Another aspect of the invention is to provide compounds of the invention for use in medical therapy, in particular for the treatment or prophylaxis of viral infections such as herpes virus infections. Currently, the compounds of the invention have been found to be active against hepatitis B virus (HBV) and cytomegalovirus (CMVj infections), although recent results suggest that the invention could also be effective against other herpes virus infections such as EBV, VZV, HSVI and II and HHV6 The compounds of the present invention are particularly useful in the treatment or prophylaxis of CMV infections The use of the compounds of the invention in the preparation of a medicament for the treatment of viral infections is also described.

Other viral conditions that can be treated in accordance with the invention have been discussed in the introduction herein.

According to another aspect, the present invention is within the scope of the present invention:

(A) A method of treating or prophylaxis of a hepadnavirus infection such as hepatitis B or a herpes viral infection such as CMV comprising treating a subject with a therapeutically effective amount of a compound of the invention.

(B) Use of a compound of the invention for the manufacture of a medicament for the treatment or prophylaxis of any of the above infections or conditions.

By pharmaceutically acceptable derivative is meant any pharmaceutically or pharmaceutically acceptable salt, ester or salt of such an ester of a compound of the invention, or any compound which upon administration to a recipient is capable of providing (directly or indirectly) a compound of the invention or an antiviral 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 sulfur. Examples of such groups include azetidinyl, pyrrolidinyl and piperidinyl.

Preferred esters of the compounds of the invention include esters of carboxylic acids in which the non-carbonyl group of the ester moiety is selected from straight or branched chain alkyl groups such as n-propyl, tert-butyl, n-butyl, alkoxyalkyl (e.g. methoxymethyl), aralkyl (e.g. benzyl), aryloxyalkyl (e.g. phenoxymethyl), aryl (e.g. phenyl optionally substituted by halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy) carbon atoms or amino group); sulfonate esters such as alkyl- or aralkylsulfonyl (e.g. methanesulfonyl); amino acid esters (eg, L-valyl or L-isoleucyl); and mono-, di- or triphosphate esters. The phosphate esters may further be esterified, for example, with a C 1 -C 20 alcohol or reactive derivatives thereof, or 2,3-di (C 8-24) acylglycerol.

With respect to the above esters, unless otherwise stated, any alkyl group present contains 1 to 18 carbon atoms, especially 3 to 6 carbon atoms, such as pentanoate. Any aryl group present in such esters preferably includes a phenyl group.

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

Physiologically acceptable salts include salts of organic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic, p-aminobenzoic and succinic acids; 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 of the invention and their pharmaceutically acceptable derivatives can be used in combination with other therapeutic agents for the treatment of the above infections or conditions. Examples of such other therapeutic agents include agents that are effective for treating viral infections or conditions associated therewith such as acyclic nucleosides (eg, acyclovir), immunomodulatory agents such as thymosin, ribonucleotide reductase inhibitors such as 2-acetylpyridine-5 - [(2 (chloroanilino) thiocarbonyl) thiocarbonohydrazone, interferons such as α-interferon, 1-PD-arabinofuranosyl-5- (1-propynyl) uracil,

3´-azido-3´-deoxythymidine, ribavirin and phosphoric acid. The component compounds of such combination therapy may be administered simultaneously, either in separate or combined formulations, or at different times, for example sequentially, to achieve a combined effect.

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

In general, a suitable dose for each of the above conditions will be in the range of 0.01 to 250 milligrams per kilogram of body weight of the recipient (e.g., human) per day, preferably in the range of 0.1 to 100 milligrams per kilogram of body weight per day, 0 to 20 milligrams per kilogram of body weight per day. (Unless otherwise indicated, all weights of the active ingredient are calculated as the parent, or sometimes referred to as the parent compound of Formula I; for salts or esters thereof, weights will be increased accordingly). The desired dose is preferably present as two, three, four, six or more sub-doses administered during the day at appropriate intervals. These sub-doses may be administered in unit dosage forms, for example, containing 10 to 1000 milligrams, preferably 20 to 500 milligrams, and most preferably 100 to 400 milligrams of active ingredient per unit dosage form.

Ideally, the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.025 to about 100 μΜ, preferably about 0.1 to 70 μΜ, most preferably about 0.25 to 50 μΜ. This may be achieved, for example, by intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or by oral administration of a bolus containing about 0.1 to about 250 milligrams of active ingredient per kilogram of body weight (mg / kg). Desired blood levels may be maintained by continuous infusion to provide about 0.01 to about 5.0 mg / kg / hour or by intermittent infusions containing about 0.4 to about 15 mg / kg of active ingredient.

While it is possible for the active ingredient to be administered alone, it is preferably present in the pharmaceutical formulation. The formulations of the present invention comprise at least one active ingredient as defined above together with one or more pharmaceutically acceptable carriers thereof and optionally other therapeutic agents. Each carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and not injuring 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 may conveniently be presented in unit dosage form and may be prepared by methods well known in the art of framation.

Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by homogenously and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

Compositions suitable for transdermal administration may be presented as separate patches adapted to achieve intimate contact with the epidermis of the recipient for an extended period of time. Such patches preferably contain the active compound (1) in an optionally buffered, aqueous solution or (2) dissolved and / or dispersed in the adhesive or (3) dispersed in the polymer. A suitable concentration of active compound is about 1% to 25%, preferably about 3% to 15%. One possibility is that the active compound can be delivered from the patch by electrotransport or iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; 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 may also be presented as a bolus, electuary or paste.

A tablet may be made by compression or injection, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable tabletting machine in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g. povidone, cross-linked carboxymethylcellulose), a surfactant or dispersant. Injection tablets may be made by injecting a mixture of a powdered compound moistened with an inert liquid diluent on a suitable injection machine. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient used therein, for example, hydroxypropylcellulose in varying proportions to provide the desired release profile. The tablets may optionally be provided with an enteric coating to provide release in parts of the digestive tract other than the stomach.

Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and oral lavages comprising the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition 1 active ingredient such carriers as are known in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injectable solutions which may contain antioxidants, buffers, bacteriostats and agents that render the formulation isotonic with the blood of the intended recipient; aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit dose or in multi-dose sealed containers such as ampoules and vials and may be stored in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use. Magistra liter injectable solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose as indicated above, or a suitable fraction thereof, of the active ingredient.

It is to be understood that in addition to the ingredients individually mentioned above, the formulations of this invention may contain other agents conventional in the art due to the type of formulation concerned, for example, formulations suitable for oral administration may contain such agents as sweeteners, thickeners and flavoring agents.

The present invention further includes a process for preparing the compounds of the present invention, which is schematically illustrated in the following scheme.

Bases such as K ₂ CO ₃ or triethylamine

->

Solvent such as t-butane dioxane, dimethylformamide (where L is a leaving group such as halogen, especially chlorine)

R ⁵

1) R ⁴ CO ₂ H, heat.

(for R ⁴ = H, alkyl, perfluoroalkyl) (Π) -► (I)

2) N-halosuccinimide (for R ⁴ = halogen)

3) cyanogen bromide (for R ⁴ = NH ₂ )

In another aspect, the present invention relates to a process for the preparation of compounds of formulas I and I-1 alone or in combination with their mirror enantiomers and pharmaceutically acceptable derivatives thereof, comprising (A) reacting a compound of formula II:

or a mirror enantiomer thereof, (a) either with a compound of formula r ⁴ co ₂ h wherein R ⁴ is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl, preferably at elevated temperature, or a compound of formula

R ⁴ C (OR) ₃ wherein R ⁴ is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl and

R is an alkyl group having 1 to 4 carbon atoms, preferably at ambient temperature and in an acidic medium, to form a compound of formula I or 1-1 wherein R ⁴ is hydrogen, or (b) with cyanobromide to form a compound of formula I or I -1, wherein R ⁴ is NH ₂ ; or (B) (a) converting a compound of formula I or 1-1 wherein R ⁴ is hydrogen to another compound of formula I or 1-1 wherein R 6 is a leaving group, for example by treatment with N- (C1, Br or I) succinimide to form a compound wherein R ⁴ is chloro or bromo, and (b) converting a compound of formula I or I-1, wherein R ⁴ is Cl or Br, to another compound of formula I or I-1, wherein R ⁴ is og an amino group or a substituted amino group -NR R as defined above, by treatment with a C 1 -C 4 alkylamine or a C 1 -C 4 -alkylamino group, or R 4 R 4 NH, wherein R 6 and R 6 are as defined above or (C) reacting a compound of formula III:

(wherein R ⁴ , R ⁶ , r 6 and R 6 are as defined above) or a functional equivalent thereof, with a compound of formula IV;

wherein R, R and R are as defined above and L is a leaving group such as an organosulfonyloxy group (e.g. p-toluenesulfonyloxy or methanesulfonyloxy), halogen or a triflate group (i.e. OSO ₂ CF ₃ group), for example in the presence of a base such as sodium carbonate or sodium hydride in a solvent such as dimethylformamide, preferably at an elevated temperature, for example at 80 ° C to 100 ° C, to form a compound of formula I or I-1 wherein R 6 is hydrogen, halogen or NR 6 R 6 and optionally converting the compound of Formula I or 1-1 to a pharmaceutically acceptable derivative thereof.

Alternatively, in method (C) above, the compound q of formula IV may be replaced by a compound in which the groups L and R are replaced by a cyclic sulfate group.

All of the above structures are intended to exemplify the represented enantiomers as well as their mirror isomers, as well as mixtures thereof. The present invention also encompasses both racemates and pure enantiomers substantially free of their mirror isomers.

The compounds of formulas I and I-1 can be converted to a pharmaceutically acceptable ester by reaction with a suitable esterifying agent, for example, an acid chloride or anhydride. The compound of formula (I) or (I-1), including its esters, may be converted to their pharmaceutically acceptable salts in a conventional manner, for example by treatment with a suitable acid. The ester or ester salt of formula I or I-1 can be converted to the parent compound by, for example, hydrolysis.

DETAILED DESCRIPTION OF THE INVENTION

In the following examples, the antiviral nucleoxide analogs containing a substituted benzimidazole base attached to the carbocyclic ring of the invention and the process for their preparation are described in more detail and are not intended to limit the scope of the present invention. The term active ingredient as used in the examples means a compound of Formula I or I-1 or a pharmaceutically acceptable derivative thereof.

ExampleA

Tablet formulations

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

Formulation A

mg / tablet mg / tablet (a) the active ingredient 250 250 (b) lactose 210 26 (c) Povidone B.P. 15 Dec 9 (d) sodium starch glycolate 20 May 12 (e) magnesium stearate 5 3

Formulation B 500 300 (a) the active ingredient mg / tablet 250 mg / tablet 250 (b) lactose 150 - (c) Avicel PH 101 60 26 (d) Povidone B.P. 15 Dec 9 (e) sodium starch glycolate 20 May 12 (f) magnesium stearate 5 3 500 300

Formulation C mg / tablet active ingredient 100 ALIGN! lactose 200 starch 50 Povidone 5 magnesium stearate 4

359

The following Formulations D and E were prepared by direct compression of the mixed components. The lactose used in formulation E was of directly compressible type (Dairy Crest-Zeparox).

Formulation D mg / tablet active ingredient 250 pregelatinized starch NF15 150

400

Formulation E mg / tablet active ingredient 250 lactose 150

Avicel 100

500

Formulation F (controlled release formulation)

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

mg / tablet (a) the active ingredient 500 (b) hydroxypropylmethylcellulose 112 (Methocel K4M Premium) (c) lactose B.P. 53 (d) Povidone B.P.C. 28 (e) magnesium stearate 7

700

Example Β

Capsule formulations

Formulation A

A capsule formulation was prepared by mixing the ingredients of Formulation D in Example 1 and filling into two-piece hard

gelatin capsules. Formulation B in a similar manner. (infra) was ready Formulation B mg / capsule (a) the active ingredient 250 (b) lactose B.P. 143 (c) sodium starch glycolate 23 (d) magnesium stearate 2 420 Formulation C mg / capsule (a) the active ingredient 250 (b) Macrogol 4000 BP 350

600

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

Formulation D mg / capsule active ingredient 250 lecithin 100 peanut oil 100

450

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

Formulation E (controlled release capsules)

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

mg / capsule (a) the active ingredient 250 (b) microcrystalline cellulose 125 (c) lactose BP 125 (d) ethylcellulose 13

513

Example C

Injectable formulation

Formulation A active ingredient 0.200 g hydrochloric acid solution, 1.0 µm q.s. to pH 4.0 to 7.0 sterile water q.s. to 10 ml

The active ingredient was dissolved in most 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 is then topped up with water and filtered through a sterile microporous filter into sterile 10 ml amber glass vials (type 1) and sealed with sterile caps and seals placed over them.

Formulation B active ingredient steryl, pyrogen-free, pH 7 phosphate oufr

Example D

Intramuscular injection active ingredient benzyl alcohol glycofurol water for injections

0,125 g

q.s. to 25 ml

0.20 g 0.10 g 1.45 g

q.s. up to 3,00 ml

The active ingredient is dissolved in glycofurol. Benzyl alcohol is then added and dissolved and water is added to 3 ml. The mixture is then filtered through a sterile micropore filter and sealed into sterile amber vials (type 1).

Example E Syrup active ingredient 0.2500 G sorbitol solution 1,5000 G glycerol 2,0000 G sodium benzoate 0.0050 G flavor, peaches 17.42.3169 0.0125 ml cleaned water q.s. to 5,000 ml

The active ingredient is dissolved in a mixture of glycerol and most of the purified water. An aqueous solution of sodium benzoate is then added to the solution, followed by the addition of a sorbitol solution and finally flavoring. Adjust the volume in purified water and mix well.

Example F

Suppositories

active ingredient (631m) mg / lace 250 hardened fat, BP Dynamit-Nobel) (Vitepsol H15 1770 2020

* The active ingredient was used as a powder in which at least 90% of the particles were 631 m in diameter or less.

One fifth of Vitepsol H15 is melted in a steam jacket at 45 ° C (maximum). The active ingredient is sieved through

2001 mesh and added to the molten base with stirring, using a silverson equipped with a cutting head, until a smooth dispersion is achieved. While maintaining the mixture at 45 ° C, Vitepsol H15 is added to the suspension and mixed until a homogeneous mixture is obtained. The entire suspension is passed through a 2501 m stainless steel sieve and, while stirring is continued, allowed to cool to 40 ° C. At 38-40 ° C, 2.02 g of the mixture is filled into suitable 2 ml plastic molds. The suppositories are allowed to cool to room temperature.

Example G

Pessary mg / pessary active ingredient (631 m) 250 anhydrous dextroza 380 potato starch 363 magnesium stearate 7

1000

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

Antiviral efficiency tests

1. Anti-HCMV

Human cytomegalovirus (HCMV) is evaluated in monolayers of MRC5 cells (human embryo lungs) in multi-well dishes. The activity of the compounds is determined in an assay as well as a decrease in plaque activity in which the cell monolayer is infected with HCMV suspension. The concentration range of the test compound (known molarity) is then incorporated into the carboxymethylcellulose overlay. The plaque numbers of each concentration are expressed as percent of control and a dose response curve is plotted. From this curve, 50% inhibitory concentration (IC 50) is determined.

Anti-HCMV activity

Compound IC 50 (m) Ex

2. Anti-HBV a: Overview:

The anti-HBV activity of the compounds of Formulas I and 1-1 was determined using a high-capacity assay to evaluate efficacy. Supernatants from growth HBV-producing cells (HepG2 2.2.15, P5A cell line) in 96-well plates were applied to wells of a microtiter plate that were coated with a specific monoclonal antibody to HBV surface antigen (HBsAg). The viral particles present in the supernatants bind to the antibody and remain immobilized while other residues are removed by washing. These virus particles are then denatured to release the HBV DNA strands, which are subsequently amplified by the polymerase chain reaction and detected by a colorimetric assay and hybrid capture. Quantification is achieved by comparing a standard curve to dilutions of cell supernatant with known HBV DNA content.

Comparing HBV DNA levels of untreated control cell supernatants with supernatants containing a compound of Formula I or 1-1, a measure of anti-HBV activity is obtained.

b. Immunoaffinity capture of HBV:

HBV production cells, 2500 cells / well, were seeded in 96-well culture dishes in RPMI / 10% fetal bovine serum / 2 mM glutamine (RPMI / 10/2). Media was replaced on 1st, 3rd, 5th. and day 7 with dilutions of the compound of Formula I or 1-1 in RPMI / 10/2 to a final volume of 150 μΐ. Fifteen μΐ of mouse monoclonal anti-HBsAG antibody (10 µg / ml in PBS) was added to each well of a round bottom microtiter plate. After overnight incubation at 4 ° C, the solutions were aspirated and replaced with 100 μΐ 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 Nunc Vasher. Dest μΐ 0.035% Tween 20 in PBS was then added to all wells using Pro / Pette. Cell supernatants (25 μΐ) containing extracellular virion DNA were transferred to the wells using Pro / Pete; the final Tween concentration is 0.01%. Twenty-five μΐ HBV standard copper dilutions in RPMI / 10/2 were added to two rows of wells to serve as an internal standard curve for quantitation and the plates were capped and incubated at 4 ° C overnight. Samples were washed 5 times with PBS / T and 2 times with PBS, the last wash was aspirated. Then, 25 μΐ 0.09N NaOH / 0.01% NP40 was added to each well with Pro / Pette and the sample wells were capped and incubated at 37 ° C for 60 minutes. The samples were then neutralized with 25 μΐ 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 with a 5 μΐ sample using a Perkin Elmer PCR kit. PCR is performed in MicroAmp tubes with a final volume of 25 μΐ. Primers were selected from conserved regions in the HBV genome as determined by aligning several sequences. One primer is biotinylated to

5-prime ends to facilitate detection of hybrid capture capture of PCR products. All primers were purchased from Synthecell Corp., Rockville, MD 20580.

d. Hybrid capture detection of PCR products:

PCR products were delegated with horseradish peroxidase labeled oligonucleotide probes (Synthecell Corp., Rockville, MD 20850) that hybridize to biotinylated strands of denatured PCR products directly in streptavidin-coated wells of the microtiter plate, using essentially the method of Holodini M. et al. Bio-Techniques, 12 (1) 37-39 (1992). Modifications include the use of 251 PCR reaction volumes and denaturing with sodium hydroxide instead of heat. The simultaneous binding of the biotin moiety to streptavidin-coated plates during hybridization serves to capture the hybrids. Unbound labeled probes were washed prior to colorimetric determination of bound (hybridized) horseradish peroxidase. The amounts of HBV DNA present in the original samples were calculated by comparison with standards. These values were then compared to those obtained from untreated cell cultures to determine the extent of anti-HBV activity.

IC 50 (mean inhibitory concentration) is the amount of compound that produces a 50% reduction in HBV DNA. Approximately IC 50 of the compounds of Examples 4, 13 and 69 are tabulated.

Anti-HCMV activity

Compound ^IC 50 (μΜ) in pr. , 4 0,74, 2.5 ex. . 32 1,3, 0.79 ex. 33 0,44, 0.50 in pr. 40 2,0, 1.4 in pr. 41 0,4, 0.40

ganciclovir (control) 1.1 (mean of 10 values).

Example 1 (±) - (1R *, 2S *, 3S *, 5S *) - 3- (Acetoxymethyl) -5- (4,5-dichloro-2-nitroanilino) -1,2-cyclopentanediyl diacetate (+) - ( IR *, 2S *, 3S *, 5S *) - tert -Butyl N- [2,3-dihydroxy-4- (hydroxymethyl) -1-cyclopentyl] carbamate (6.27 g, 25.1 mmol) and 1 N hydrochloric acid (50 mL) was stirred overnight. The resulting clear solution was concentrated in vacuo and dried by evaporation of methanol and ethanol to give (±) - (IR *, 2S *, 3S *, 5S *) -3-amino-5- (hydroxymethyl) -1,2-cyclopentanediol hydrochloride as a solid foam (4.73 g). This 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 ral) for 24 hours. The resulting black mixture was evaporated to dryness and the residue was chromatographed on silica gel and the product eluted with methanol / chloroform 1:10 as a dark orange glass (6.9 g). Crystallization from ethanol-water gave an orange powder (3.00 g) which was stirred in acetic anhydride (3.0 mL) -pyridine (20 mL) at ambient temperature overnight. Evaporation of the volatiles followed by crystallization from ethyl acetate-hexanes gave the title compound as orange needles (2.82 g, 24%), mp 153-156 ° C; 1 H-NMR (DMSO-d 6) δ: 8.25 and 7.51 (both s, 1 each, C ₆ H ₂ ), 8.07 (d, J = 7.8 Hz, 1, NH), δ , 23 and 5.09 (both m, 2.2 CHO), 4.3 (m, 1, CHN), 4.2-4.0 (m, 2, CH ₂ O), 2.5-2, 35 (m, 2,2CH), 2.04, 2.03, 2.02 (all s, 9, 3CH ₃ CO), 1.5-1.4 (m, 1, CH).

Elemental analysis for C ₃₃ H ₂ O ₂ qN «; C1 _2:

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 suspension, Aldrich, 300 mg wet) in isopropanol (250 mL) was shaken under a hydrogen atmosphere (280 kPa - 40 psi) on a Parr shaker for 2.25 hours. The catalyst was filtered through Celite, and the filtrate was acidified with 98% formic acid (5 mL) and concentrated to an orange oil. The oil was diluted with an additional 98% formic acid (45 mL) and the resulting orange solution was refluxed for 40 min. The volatiles were removed and the remaining dark oil was dissolved in chloroform (100 mL). The chloroform solution was washed with saturated aqueous sodium bicarbonate (3 x 10 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 of ethyl acetate (2.26 g, 86%); ¹ H-NMR (DMSO-d ₆ ) δ: 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, CHO), 2.6-2.4 (m overlapping solvent, 2 CH), 2.10, 2.06, 1.92 ( all s) overlapped at 2.0 (m, total 10, 3CH ₃ CO and CH).

Elemental analysis for ^C 19 ^H 20 ^N 2 ^C1 2 ° ^6: calculated 51.49% C, 4.55% H, 6.32% N, 16.00% Cl found 51.39% C, 4.58% H N 6.22% 16.07% Cl.

Example 3 (+) - (1R *, 2S *, 3S *, 5S *) - 3- (Acetoxymethyl) -5- (2-bromo-5,6-dichloro-1H-benzimidazol-1-yl) -1,2- cyclopentanediyl diacetate (+) - (IR *, 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 Ν, Ν-dimethylformamide (6 mL) was heated to 60 ° C. Add portions (about 1 mmol each) of N-bromosuccinimide (1.59 g, 8.93 mmol) over 5 hours. Heating is continued for an additional 4 hours. The volatiles were removed in vacuo and the residue was chromatographed on silica gel. The title compound was eluted with 1: 1 hexane-ethyl acetate as a tan powder (1.1 g, 69%). @ 1 H-NMR consistent with recrystallized sample. The sample was recrystallized from ethanol-water to a white powder, mp 156-159 ° C; ¹ H-NMR (DMSO-d ₆ ) δ: 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), 4.4-4.2 (m, 2, OCH ₂ ), 2.7-2.5 (m, 1, CH), 2.4 -2.0 (m) overlapping 2.1 and 2.07 (both s, total 8, _CH2 and CO 2 CH _3), 1.92 (s, 3, j CO-CH), 1.92 (s, 3 CH 2 CO 2; mass spectrum (CI): 527 (6.6), 525 (45), 523 (100), 521 (65, M + 1), 257 (48, MB). Elemental analysis for C- _L pH ₁ pN ₂ OgBrCl ₂ :

calculated: 43.71% C, 3.67% H, 5.37% N, total halogen as Br 45.91% found 43.64% C, 3.63% H, 5.30% N, total halogen as Br 45.77%.

Example 4 (+) - (1R *, 2S *, 3S *, 5S *) -5- (2-Bromo-5,6-dichloro-1 H -benzoimidazol-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 (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 was triturated with water (5 mL) and filtered. A white solid is obtained. Recrystallization of the solid from 1: 1 ethanol-methanol gave the title compound as a white powder (282 mg, 62%), mp 208-211 ° C; @ 1 H-NMR (DMSO-d6) .delta .: 8.23 (s, 1, benzimidazole H7), 7.95 (s, benzimidazole H4), 5.13 (t, J = 4.1 Hz, 1.0-0.2 ₎ 0Η), 5.03 (d, J = 6.2 Hz, 1, OH), 5.0-4.85 (m, 1, H 5), 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, (CH ₂ ), 2.2-1.95 (m, 3, H 3 and 2H 4); mass spectrum (CI): 395 (M + 1).

Elemental analysis for C £ £ 3H- gN 0gCl ₂ Br _2:

calculated: 39.43% C, 3.31% H, 7.07% N, total halogen as Br 60.52%.

found 39.50% C, 3.33% H, 7.02% N, total allogene as Br 60.61%.

Example 5 (Ια, 3β, 4β) - (3,4-Dihydroxy-1-cyclopentyl) methylbenzoate

To a stirred, cold (0 ° C) solution of 4-hydroxymethylcyclopentene (J.-P.Depres and A.E.Green,

J.Org.Chem. 1984, 49, 928-931 and references cited 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 was added and the volatiles were removed in vacuo. The residual 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) methyl benzoate as a yellow oil (53.94 g, 91%) sufficiently pure for use; 1 H-NMR (DMSO-d 6) δ: 7.98, 7.67, 7.56 (m, 5, C ₆ H ₅ ), 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, 2CH).

(3-Cyclopenten-1-yl) methyl benzoate (37.6 g, 0.161 mol) in acetone (200 mL) was added dropwise over 2 hours to a stirred solution of N-methyl chlorofolin-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 room temperature. Stirring was continued for a further 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 saturated aqueous sodium bicarbonate (100 mL) and dried (MgSO 4). The volatiles were removed and the residual solid crystallized from toluene (200 mL) to give the title compound as white crystals (26.9 g, 73%). mp 92-94 ° C; ¹H-NMR (DMSO-d _6): 7.96,

7.65, 7.56 (m, 5, _{C6 H5),} 4.38 (d, J = 4 Hz, 2, 20H), 4.14 (d, J = 6.6Hz, 2, CH ₂ O), 3.90 (m, 2 OCH), 2.58 (m overlapping solvent, CH), 1.75 (m, 2, 2CH), 1.55 (m, 2,

2CH).

H, 6.83; Found: C, 66.19; H, 6.86.

Concentration of the mother liquors yielded 10.33 g of a white solid containing another title compound contaminated with (+) - (1, 3, 4, 4) - (3,4-dihydroxy-1-cyclopentyl) methyl benzoate, approximately 2: 3 ratio @ 1 H-NMR.

Example 6 (3a-a, 5a, 6a-a) - (Tetrahydro-4H-cyclopenta-1,3,2-dioxathiol-5-yl) methyl benzoate-S-oxide

Thionyl chloride (6.04 g, 50.8 mmol) was added to a solution of (1β, 3a, 4a) - (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. Evaporation of the solvent gave the title compound as a thick oil sufficiently pure for use (see the following example). The sample crystallizes as a waxy solid from toluene, mp 48-57 ° C; ¹ H-NMR (DMSO-d 6) δ: 7.96, 7.66, 7.52 (m, 5, C 8 H 4), 5.46 and 5.32 (both m, 1.2 OCH, thanks to about 1 : 1 mixture of isomeric S-oxides), 4.28 (m, 2, OCH 2), 2.90 and 2.43 (both m, 1, CH of two isomeric S-oxides), 2.10 and 1.74 (both m, 4, 4CH).

Elemental analysis for ^C 13 ^H 14 ° 5 ^S: Calculated ^: 55.31% C, 5.00% H, 11.36% S Found: 55.41% C, 5.04% H, 11.30% S.

Example 7 (3a-a, 5a, 6a-a) - (Tetrahydro-4H-cyclopenta-1,3,2-dioxathiol-5-yl) methyl benzoate-S, S-dioxide (3a-a, 5a, 6a-a) 1- (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). ml) - water (60 ml) with the addition of sodium meta periodate (8.98 g, 42.3 meq) and ruthenium chloride (44 mg, 0.21 meq). After 30 min, additional sodium metaperiodate (179 mg) was added until the reaction was complete by TLC (silica gel, methanol: chloroform / 1:19, visualized in iodine). After a total of 1.0 h, methylene chloride (300 mL) was added. The organic layer was separated and the aqueous layer was extracted with additional methylene chloride (300 mL). The combined organic layers were washed with saturated sodium bicarbonate (100 mL), then saturated aqueous sodium chloride (100 mL), dried (MgSO 4) and concentrated in vacuo to give the title compound as a white powder (12.37 g, 98%), m.p. 114-119 ° C; 1 H-NMR (DMSO-d ₆ ) δ: 8.02, 7.70, 7.55 (all m, 5, C ₆ H ₅ ), 5.62 (m, 2, OCH), 4.34 (d , J = 5.8 Hz, 2 0CH _2), 2.79-2.64 (m,

1, CH), 2.32-2.21 and 1.97-1.79 (m, 4.2 CH ₂ ).

Elemental analysis for C ^ HH ^ SOO::

C, 52.35; H, 4.73; S, 10.75. Found: C, 52.32; H, 4.73;

Example 8 (+) - (1R *, 2R *, 4S *) - 2- (5,6-Dichloro-1H-benzimidazol-1-yl) 4- (hydroxymethyl) cyclopentanol

Sodium hydride (416 mg, 10.4 meq as an oil dispersion) was added to a solution of 5,6-dichlorobenzimidazole (LBTownsend and GRRevankar, Chem. Rev. 1970, 70, 389, and references cited therein) (1.50 g, 8.00 mmol) in dry Ν, Ν-dimethylformamide (35 mL). The mixture was stirred at 25 ° C for 45 minutes. (3a-a, 5a,

6α-α- (tetrahydro-4H-cyclopenta-1,3,2-dioxathiol-5-yl) methylbenzoate-S, S-dioxide (3.05 g, 10.2 mmol) (prepared in Examples 7, 8 and 9) ). Stirring was continued overnight at room temperature. The volatiles were removed in vacuo and the residual oil was dissolved in 1,4-dioxane (130 mL) -water (10 mL) under reflux with 4M sulfuric acid (2.3 mL). After 10 minutes at reflux, the solution was basified with 5N sodium hydroxide, heated at 50 ° C for an additional hour, and then neutralized with additional acid. Evaporation in vacuo gave a solid as a residue which was 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 the sample from ethanol-water gave the title compound as white granules, mp 244-245 ° C; @ 1 H-NMR (DMSO-d6) .delta. 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, CH ₂ 0H), 4.6-4.5 (m, 1, NCH), 4.37-4.25 (m, 1, OCH _3), 3.41 (m, 2 0CH ₂₎ 2.4-2.2 and 1.95-1.62 (m, 5.5CH).

Elemental analysis for C ^ H ^ ₃ 4 N ₂ O ₂ C1 ₂ .0,02C ₂ H = OH:

calculated: C, 51.85; H, 4.71; N, 9.27; Cl, 23.47. Found: C, 51.87; H, 4.74; N, 9.28.

Example 9 (+) - (1R *, 2R *, 4S *) -4- (Acetoxymethyl) -2- (5,6-dichloro-1H-benzimidazol-1-yl) cyclopentyl acetate (+) - (1R *, 2R *, 4S *) - 2- (5,6-Dichloro-1H-benzimidazol-1-yl) 4- (hydroxymethyl) cyclopentanol (7.80 g, 25.8 mmol) was dissolved in pyridine (50 mL) -acetanhydride (50 mL). ml) and the solution was stirred overnight. The volatiles were removed in vacuo and the residual oil was partitioned between methylene chloride (150 mL) and saturated aqueous sodium bicarbonate (100 mL). The organic layer was dried (sodium sulfate) and evaporated to give the glassy material (9.91 g, 99%); ¹ H-NMR (DMSO-d ₆ ) δ: 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 = 6.6 Hz, 2.0CH ₂ ), 2.59-2.50 (m excess solvent, CH),

2.41 to 2.35 (m, 1, CH), 2.17 to 1.86 (m overlapping 2.06 and 1.95, both s, total 9, 3CH and 2CH ₃ CO).

Elemental analysis for C 17 H 17 N ₂ O ₂ Cl ₂ · 0 · 1 CH 2 Cl 2:

calculated: 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 (±) - (1R *, 2R *, 4S *) -4- (Acetoxymethyl) -2- (2-bromo-5,6-dichloro-1H-benzimidazol-1-yl) -cyclopentylacetate

N-Bromosuccinimide (4.54 g, 25.5 mmol) was added to a solution of (+) - (1R *, 2R *, 4S *) -4- (acetoxymethyl) -2- (5,6-dichloro-1H-benzimidazole- 1-yl) cyclopentylacetate (8.95 g, 23.2 mmol) in dry N, N-dimethylformamide (46 mL). The solution is maintained at about 70 ° C (oil bath) for 5 hours. The volatiles were removed in vacuo and the remaining orange syrup was chromatographed on silica gel. The title compound was eluted with chloroform as a pale yellow solid (5.14 g, 48%), m.p. Mp 122-125 ° C; @ 1 H-NMR (DMSO-d6) .delta .: 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 = 6.3 Hz, OCH ₂ ), 2.66-2.60 (m, 1, CHCH ₂ ), 2.29-2.14 (m, 3, CH) , 2.06 (s, 3, CH 2 CO), 1.93 (with overlapping sm, 4, CH ₃ CO + CH); mass spectrum (CI): 469 (5.8), 467 (37.5), 465 (95), 463 (54, M + 1), 199 (100, MB).

Elemental analysis for C £ £ -7 H ₂ N ₂ Cl ₂ BrO _4:

calculated: 43.99% C, 3.69% H, 6.04% N, total halogen as Br 51.65%, found 44.06% C, 3.70% H, 5.97% N, 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, V., Vittner, R., and Godeel, A., Enantiated Enantioseparation of Amino Acids by Derivatization with O-Phthaldehyde and N-Acylated Cysteines, J. Chrom. Use of o-phthalialdehyde and N-acetyl-L-cysteine as derivatizing agents. Chromatographic separation uses an Optima II ODS 100 x 4.5 mm, a 3 gm column (III Supplies Co., Meriden, CT) and a gradient elution at 0.9 mL / min using 100% sodium acetate buffer, 40 mM, pH 6.5, with a linear ramp to 18% acetonitrile over 15 minutes followed by holding to 18% acetonitrile for 15 minutes. Detection was at 338 nm. The samples were dissolved in 0.1 molar borate buffer, pH 10.4. The identity and purity of the samples were evaluated by comparison with authentic standards (see EP 434450 (June 26, 1991)). The retention time (1S, RS) of the isomer was about 21 minutes. The retention time of the (1S, 4S) -isomer was about 22 minutes.

Example 12 (+) - cis-4-Amino-2-cyclopentene-1-methanol

The dry, 21-liter, three-necked flask was equipped with a mechanical stirrer, a thermometer with a gas inlet connected to a nitrogen source, and a septum. The flask was purged with nitrogen, immersed in an ice-acetone bath, and a solution of lithium aluminum hydride in tetrahydrofuran (1.0 molar, 800 mL, 0.80 mol, Aldrich) was added via cannula. Dry tetrahydrofuran (2 x 15 mL) was used to rinse into a lithium aluminum hydride solution.

When the solution was cooled to 0 ° C, the (+) - cis-4-amino-2-cyclopenene-1-carboxylic acid 4-toluenesulfonate salt in tetrahydrofuran was added via cannula with good stirring at such a rate that the temperature was maintained at less than 10 ° C. ° C and a slight hydrogen evolution was maintained (about one hour). The flask was rinsed with dry tetrahydrofuran (2 x 15 mL) and the septum was replaced with a reflux condenser. The resulting clear, light amber solution was slowly warmed to gentle reflux over two hours, then became cloudy. After refluxing overnight (16 hours) the heating bath was removed, sodium fluoride (136.3 g, 3.25 mol, reagent grade powder) was added and the condenser was replaced by downstream distillation. The mixture was distilled into a thick slurry (700 ml of distillate collected), then cooled in an ice bath. Diethyl ether (500 mL, dry) was added and the condenser was replaced by a dropping funnel containing water (43 mL, 2.4 mol). Water was added very slowly (two hours) with careful control of the rate of hydrogen evolution and maintaining the temperature at 10 + 5 ° C. Water (54 mL) was added to the above distillate and an amount of tetrahydrofuran was added sufficient to adjust the total volume to 900 mL (6% H 2 O). The reaction mixture was suction filtered and the cake was washed with tetrahydrofuran (100 mL). A portion of a 6% water-tetrahydrofuran solution (300 mL) was used to wash the cake slurry, which was then returned to the reaction flask. The cake was triturated (25 minutes) in 6% water-tetrahydrofuran (400 mL), filtered and washed with 6% water-tetrahydrofuran (200 mL). The combined filtrates were concentrated to a pale yellow oil in vacuo (44.07 g, 67.8% by HPLC, see Example 3). This oil, containing the pure title compound and traces of the tosylate salt, rapidly darkens under ambient conditions. It was 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 cap and the cake was then washed with methanol (200 mL). The filtrate was concentrated in vacuo to give a yellow solid (56.80 g, 20.9% yield by HPLC; total yield 88.7%).

Example 13 (-) - cis -4-Amino-2-cyclopentene-1-methanol

By the method of Example 12 but on about twice the scale (97.40 g, 0.8924 mol of (+) - 2-azabicyclo [2.2.1] hept-5-en-3-om) the title compound was obtained as extracts containing the title compound (0.7926 mol, 88.8% of theory, followed by removal of the fractions as determined by the method of 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 1031 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, 0.905 mol). The mixture was stirred at 5 ° C for two days. The methanol extracts of 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 in vacuo and the resulting slurry was extracted with hexanes, three portions of methylene chloride, again hexanes (200 mL each). The organic extracts were evaporated to an oil which was crystallized from hexanes (about 300 mL) to give the title compound (154.15 g,

0.7229 mol). Further product was obtained by chromatography of the mother liquors (10.5 g, 0.0491 mol, 86.6% of theory from the starting lactam followed by removal of portions).

Example 15 (+) - cis- [4- (4,5-Dichloro-2-nitroanilino) -2-cyclopenten-1-yl] methanol (+) - cis-tert. Butyl N- (4- [hydroxymethyl) -2-cyclopentenl-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 hour . Evaporation of the volatiles gave the trifluoroacetic acid salt of the amine described in Example 27 as a dark oil. To this oil was added tert-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 with vigorous stirring for 3 days. The volatiles were removed in vacuo 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 gave the title compound as orange crystals (34.0 g, 49%), m.p. 96-98 ° C; @ 1 H-NMR (DMSO-d6) and mass spectrum (Cl) were consistent with structure and consistent with the chiral enantiomer samples described in Examples 18 and 26.

Elemental analysis for (2 ^ 2 ^ 12 ^ 2 ^ 2 ^ 3 'calculated C 47.55, H 3.99, N 9.24, Cl 23.39 found C 47.75, 4.10 % H, 9.20% N, 23.52% Cl.

Continued elution from the column gave additional fractions containing the title compound with a small amount of impurities with low R R. These fractions were combined with the mother liquor from the above crystallization and recrystallized from ethyl acetate-hexanes to give additional orange solids (16.7 g), having the same 1 H-NMR spectrum and giving a total yield of 73%.

Example 16 (+) - (1R *, 2S *, 3S *, 5S *) -3- (Acetoxymethyl) -5- (4,5-dichloro-2-nitroanilino) -1,2-cyclopentanediyl diacetate and (+) - (IR) *, 2S *, 3R *, 5R *) - 3- (acetoxymethyl) -5- (4,5-dichloro-2-nitroanilino) -1,2-cyclopentanediyl diacetate

To a solution of (+) cis- [4- (4,5-dichloro-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) was added osmium tetroxide (2.5% in tert-butyl alcohol, Aldrich, 1.24 mL). After stirring at ambient temperature for 18 hours, the volatiles were removed in vacuo and the residue was stirred with pyridine (200 mL) acetic anhydride (40 mL) for an additional 18 hours. The solution was concentrated to a thick red oil, which was partitioned between saturated aqueous sodium carbonate and chloroform. The chloroform layer was dried (sodium sulfate) and then concentrated to an oil under vacuum. The mixture of isomeric title compounds was eluted from the silica gel column with 2% methanol-chloroform and crystallized from ethyl acetate-hexanes (seeded with crystals (IR *, 2S *) - isomers prepared according to Example 1) to afford (+) - (IR *, 2S *, 3S *, 5S *) - 3- (acetoxymethyl) -5- (4,5-dichloro-2-nitroanilino) -1,2-cyclopentanediyl diacetate as orange crystals (17.4 g, 57%), mp Mp 154-156 ° C; @ 1 H-NMR (DMSO-d6) consistent with the spectrum of the sample described in Example 1.

Continuous crystallization of the mother liquor from ethyl acetate-hexanes gives (+) - (IR *, 2S *, 3R *, 5R *) - 3- (acetoxy-46-methyl) -5- (4,5-dichloro-2-nitroanilino) -1 2-cyclopentanediyl diacetate as orange crystals (8.82 g, 29%), mp 105-107 ° C; ¹ H-NMR (DMSO-d ₆ ).

Elemental analysis for C ^ gHHO o CC ^O ^:

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- (+) - (IR *, 2S *, 3R *, 5R *) -3- (Acetoxymethyl) -5- (4,5-dichloro-2-nitroanilino) -1,2-cyclopeirtanedi diacetate (5.00 g, 10, 8 mmol) was stirred in ammonia / methanol (about 2N, 100 mL) at ambient temperature for 18 hours. The volatiles were removed in vacuo to give an orange solid residue of (+) - (IR *, 2S *, 3R *, 5R *) - 5- (4,5-dichloro-2-nitroanilino) -3- (hydroxymethyl) -1 2-cyclopentanediyl diol having the same on silica gel TLC plates as the chiral sample described in Example 19. This solid was reduced with Raney nickel / hydrogen (315 kPa-45 psi) in isopropanol (200 mL). The catalyst was filtered off through celite. Washing of the filtrate 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 oil remaining after evaporation of the formic acid was dissolved in methanol. The pH was adjusted to 13 with aqueous 5N sodium hydroxide and the solution was stirred at ambient temperature for one hour to hydrate the formate esters. The pH was adjusted to 7 with 1N hydrochloric acid and the volatiles were removed in vacuo. Pyridine (100 mL) and acetic anhydride (4 mL) were added to the residue, and the mixture was stirred at room temperature overnight. The volatiles were removed in vacuo followed by silica gel chromatography with 1% methanol-chloroform to give (+) - (IR *, 2S *, 3R *, 5R *) - 3- (acetoxymethyl) -5- (5,6-dichloro) -1H-benzimidazol-1-yl) -1,2-cyclopentanediyl diacetate as white crystals from ethanol-water (2.6 g, 53%). @ 1 H-NMR (DMSO-d6) was consistent with the structure: (+) - (1R, 2S *, 3R *, 5R *) - 3 (Acetoxymethyl) -5- (5,6-dichloro-1H-benzimidazole-1) -yl) -1,2-cyclopentanediyl diacetate (2.5 g, 5.7 mmol) was dissolved in dry dioxane (15 mL) and the solution was refluxed with sudden addition of freshly recrystallized N-bromosuccinimide (2.10 g, 11.5 mmol) . After refluxing for 5 minutes, the reddish-brown solution was evaporated in vacuo to a red oil. The chloroform solution of this oil was washed with water and then dried (sodium sulfate). The chloroform solution was concentrated to an oil which was chromatographed on silica gel. Product containing fractions were eluted with 2-4% methanol-chloroform. Crystallization from ethyl acetate-hexanes gave an off-white solid (1.5 g, 50%); @ 1 H-NMR (DMSO-d6) was consistent with the structure of the title compound. The sample was re-chromatographed on silica gel eluting with chloroform to give (+) - (IR *, 2S *, 3R *, 5R *) - 3- (cetoxymethyl) -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-d 6) δ: 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, OCH ₂ ), 2.8-2.4 (m overlapping solvent, 2CH), 2.4-2.1 (m, overlapping at 2.25, total 4, CH and CH ₃ ), 2.04 (s, 3, CH ₃ ), 1.37 (s, 1, CH ₃ ); mass spectrum (CI): 525 (53), 523 (100), 521 (54, M + 1).

Elemental analysis for ^C 19 ^H 19 ^N 2 ^BrCl 2 ^O 6 ^: calculated C 43.70, H 3.67, N 5.37, total halogen as Cl 20.37%, found C 43.65, 3 68% H, 5.35% N, total halogen as Cl 20.32%.

Example 18 (IS, 4R) - [4- (4,5-Dichloro-2-nitroanilino) -2-cyclopentenl-yl] methanol (-) - (1R, 4S) -tert-butyl-N- [4-hydroxymethyl] (2-cyclopenten-1-yl) carbamate (15.00 g, 70.3 mmol) was converted to (IS, 4R) - [4- (4,5-dichloro-2-nitroanilino) -2-cyclopentene- 1-yl] methanol, isolated as a yellow powder after elution from a silica gel column using 1: 1 hexanes-chloroform to recover a solid from ethyl acetate-hexanes (9.97 g, 47%), mp 94.5-96, 5 ° C; 1 H-NMR (DMSO-d 6) δ: 8.24 (s, 1, benzimidazole CH), 8.09 (d, J = 8.1 Hz, 1, NH), 7.51 (s, 1, benzimidazole CH), 5.95 and 5.85 (both m, 2, CH = CH), 4.9-4.7 (m exceeding 4.78, J = 5.1 Hz, total 2, CHN and OH ), 3.4 (m, 2, CH ₂ O), 2.80 (m, 1, CH), 2.6-2.4 (m overlapping solvent, CH), 1.5-1.4 (m 1, CH); mass spectrum (CI): 303 (M + l): [a] ^^^^ + 199 °, [a] ^2θ 578+ ²²² °, [a] ²⁰⁵⁴⁶ + 333 ° (c = 0.267, methanol).

Elemental Analysis for ^C 12 ^H 12 ^N 2 ^Cl 2 ° 3 · ⁰ ' ^18C 6 ^H 14 ^:

calculated 49,30 % C, 4.59 % H, 8.79 % N, 22.25 % Cl found 49.64 % C, 4.64 % H, 8.68 % N, 22.10 % Cl Example 1 and d 19 Dec

(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) 5-Dichloro-2-nitroanilino) -3- (hydroxymethyl)

1,2-cyclopentanediol

To a solution of (IS, 4R) - [4- (4,5-dichloro-2-nitroanilino) -2-cyclopenten-1-yl] methanol (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 tert-butyl alcohol, 0.51 mL). After stirring at room temperature for 18 hours, an additional 0.25 mL of 60% aqueous N-oxide N-methylmorpholine was added and the solution stirred for an additional 5 hours. The volatile material was evaporated in vacuo and the residue crystallized twice from 95% ethanol to give (1S, 2R, 3R, 5R) -5- (4,5-dichloro-2-nitroanilino) -3- (hydroxymethyl) -1, 2-cyclopentanediol as a yellow powder (1.78 g, 19%), mp 197-199 ° C; 1 H-NMR (CDCl 3) δ: 8.23 (s, 1, benzimidazole CH), 8.1 (d, J = 7.0Hz, 1, NH), 7.50 (s, 1, benzimidazole CH), 5 02 (d, J = 4.9Hz, 1, OH), 4.74 (t, J = 5 Hz, 1, CH ₂ OH), 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, CH ₂ O) 2.45-2.25 (m, 1, CH), 2.1-1.9 (m, 1, CH), 1.4-1.2 (m, 1, CH); mass spectrum (CI): 337 (M + 1); [α] ^2θ 589-106 °, [a] ^{20 of} 57 g-118 [a] ² θ546-182 ° (c = 0.273, methanol).

Elemental analysis for ^C 12 ^H 14 ^N 2 ^C1 2 ° ^5: Calculated 42.75% C 4.19% H 8.31% N 21.03% Cl found 42.84% C, 4.21% H N, 8.24%, 21.09% Cl.

Chromatography of the mother liquor content on silica gel gives the (IR, 2S) -isomer eluting with 7-8% methanol-chloroform; two 90% ethanol resolidifications give (IR, 2S, 3R, 5R) -5- (4,5-dichloro-2-nitroanilino) -3- (hydroxymethyl)

1,2-cyclopentanediol as a yellow powder (1.57 g, 17%), mp 179-181 ° C; ¹ H-NMR (DMSO-d 6) δ: 8.70 (d, J = 7.1 Hz, 1, NH), 8.22 and 7.32 (both s, each, 1, 2 benzimidazole CH), 5.28 (d, J = 5.6Hz, 1, OH), 4.77 (d, J = 3.9Hz, 1 OH), 4.45 (t, J = 4.9, 1, CH ₂ 0H)

4.1-3.9 (m, 3, 2 OCH and NCH), 3.6-3.5 and 3.45-3.35 (both m partially overlapping H ₂ 0, 2, CH ₂ 0), 2.45 -2.25 (m, 1, CH).

2.1-3.9 (m, 1, CH); 1.35-1.25 (m, 1, CH); mass spectrum (CI): 337 (M + 1); [a] ²⁰ 5g9-15,6 °, [a] ²⁰ 57 g-13.2 °, [a] ² ~ θ546 4.00 ° (c = 0.250, methanol).

Elemental analysis for ^C 12 ^H 14 ^N 2 ^C1 2 ° ^5: Calculated 42.75% C 4.19% H 8.31% N 21.03% Cl found 42.87% C, 4.15% H N, 8.30; Cl, 21.14.

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

Continued elution of the column with 10-20% methanol-chloroform afforded a fraction containing additional (1S, 2R, 3R, 5R) -5- (4,5-dichloro-2-nitroanilino) -3- (hydroxymethyl) -1,2-cyclopentanediol which solidified from 90% ethanol to a white powder (2.23 g) to give an overall yield of this isomer of 43%.

Example 20 (1S, 2R, 3R, 5R) -3- (Acetoxymethyl) -5- (4,5-dichloro-2-nitroanilino) -1,2-cyclopentanediyl diacetate (1S, 4R) - [4- (4,5) (Dichloroanilino) -2-cyclopeten-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 silica gel column with 2% methanol-chloroform and solidified from ethyl acetate to afford (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. Crystallization of the sample from ethyl acetate-hexanes gave the title compound as a yellow powder, mp 128-130 ° C; 1 H-NMR (DMSO-d 6) and mass spectrum (Cl) identical to those of Example 1; [α] ^{2 _} θ589 95.8 °, [α] ² θ578-107 °, [α] ² θ546-165 ° (c = 0.259, methanol).

Elemental Analysis Found ^: C, 46.67; H, 4.35; N, 6.05; Cl, 15.31. Found: C, 46.74; H, 4.36; % N, 15.38% Cl.

Example 21 (1S, 2R, 3R, 5R) -3- (Acetoxymethyl) -5- (5,6-dichloro-6-benzimidazol-1-yl) -1,2-cyclopentanediyl diacetate (1S, 2R, 3R, 5R) - 3- (Acetyloxymethyl) -5- (4,5-dichloro-2-nitroanilino) -1,2-cyclopentanediyl diacetate (4.42 g, 9.97 mmol) was converted to the title compound as well as the racemic sample described in Example 2. The crude product was chromatographed on silica gel eluting with 5% methanol-chloroform and evaporation of the solvents gave (1S, 2R, 3R, 5R) -3- (acetoxymethyl) -5- (5,6-dichloro-1H-benzimidazol-1-yl) - 1,2-cyclopentanediyl diacetate as an off-white solid foam of ethanol (4.0 g, 90%);

1 H-NMR (DMSO-d 6) and mass spectrum (CI) identical to the spectra of the racemate described in Example 2; [a] ^ gg + 25.5 '[a] ² ° + 57 g 26.7 °, [a] ² θ546 + 30.6 ° (c = 0.255, methanol).

Elementary analysis for:

calculated: 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) was stirred in water (3 mL) -ethanol (15 mL) -methanol (15 mL) at ambient temperature for 24 hours. The pH was adjusted to 7 with acetic acid and the volatiles were removed in vacuo. The residual solid was stirred in water (25 mL) and filtered. Resolidification from 2: 1 ethanol-methanol gives (1S, 2R, 3R, 5R) -5- (5,6-dichloro-1H-benzimidazol-1-yl) -3- (hydroxymethyl) -1,2-cyclopentanediol as a white powder (408 mg, 60%), mp 222-225 ° C; ¹ H-NMR (DMSO-d ₆ ) δ: 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 Hz, 1, CH ₂ 0H), 4.8-4.6 (m overlapping d at 4.76, J = 4.3 Hz, 2, NCH and OH ), 4.25-4.10 (m, 1, OCH), 3.9-3.8 (m, 1, OCH), 3.6-3.45 (m, 2, CH ₂ O), 2 , 45-2.25 (m, 1, CH), 2.2-2.0 (m, 1, CH), 1.85-1.65 (m, 1, CH); mass spectrum (CI): 317 (M + 1); [α] 589-12,2 ^2θ °, [α] 578-12,9 ^2θ °, [a] 546-14,1 ^2θ ° (c = 0.255, methanol).

Elemental analysis for C ₇₂ H ₇₄ N ₂ Cl ₂ O ₃ :

calculated: 49.23% C, 4.45% H, 8.83% N, 22.36% Cl found 49.25% C, 4.47% H, 8.83% N, 22.46% Cl.

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. The volatiles were removed under vacuum. The residue was chromatographed on silica gel and the product eluted with 30-50% ethyl acetate-hexanes as a yellow glass (1.00 g, 43%); 1 H-NMR (DMSO-d 6) was consistent with the structure. This sample was unblocked with sodium carbonate (203 mg, 1.9 mmol) in water (3 mL) -ethanol (15 mL) -methanol (5 mL) at room temperature for 5 hours. The pH was adjusted to 7 with acetic acid. The solution was evaporated to dryness in vacuo and the residue was triturated with water to give a white powder which was chromatographed. Elution on a silica gel column with 10-12% methanol-chloroform gave (IS, 2R, 3R, 5R) -5- (2-bromo-5,6-dichloro-1H-benzimidazolyl) -3- (hydroxymethyl) -1,2- cyclopentanediol as a white powder after solidification from 1: 1 ethanol-methanol (410 mg, 54%), mp 212-215 ° C; 1 H-NMR (DMSO-d 6) and mass spectrum are identical to those of the racemate described in Example 4 ; [a] 58 931> 2 °, [α] ² θ5γ ₈ -32.3 °, [a] 54 g ² DEG-37.3 DEG (c = 0.260, methanol).

Elemental analysis for ^: calculated 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 (IS, 2R, 3R, 5R) -5- [5,6-Dichloro-2- (cyclopropylamino) -1H-benzimidazol-1-yl] -3- (hydroxymethyl) -1,2-cyclopentanediol (IS, 2R, 3R, 5R) -3-Acetoxymethyl) -5- (2-bromo-5,6-dichloro-1H-benzimidazol-1-yl) -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 hours. TLC (silica gel, 10% methanol-chloroform) showed complete conversion to a single spot with a lower Rj? than the starting material. 1N sodium hydroxide (0.96 ml) was added and the volatiles were evaporated. The residue is chromatographed on a silica gel flash column. The title compound eluted with 10% methanol-chloroform as a colorless glass which solidified from water: ethanol / 2: 1 to give an off-white powder (207 mg, 59%), m.p. 116-118 ° C dec. ;

@ 1 H-NMR (DMSO-d6) .delta. And mass spectrum were consistent with the spectra

The o-enantiomer described in Example 74; [a] ^ gg LZ, 2 °, [α] 5 °, [α] ² θ546 ^-12, 5 ° (c = 0.312, methanol).

Elemental analysis for ^C 16 ^H 19 ^N 3 ^C 12 ° 3 ^: calculated C 51.63, H 5.15, N 11.29, 19.05 Cl 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-carboxylic acid (Chiroscience Ltd., Cambridge, England; 40.00 g, 0.315 mol) in dry tetrahydrofuran (300 mL) is stirred for ice bath and IM lithium aluminum hydride in tetrahydrofuran (Aldrich, 485 mL) was added over 1.5 hours. The temperature did not exceed 0 ° C during this addition. The mixture was allowed to warm to room temperature and then refluxed for one hour and maintained at reflux for 2.5 hours. The mixture was allowed to cool to room temperature and sodium fluoride (89.6 g) was added and stirring was continued for a further 0.5 hours. The mixture was cooled (ice bath) and water was slowly added. Stirring was continued for an additional 0.5 hour. The precipitate was filtered off and extracted with 40% methanol-tetrahydrofuran (2 x 300 mL). The filtrate wash is concentrated in vacuo to a colorless oil which rapidly darkens in air and light and is used immediately (Example 16). Its sample is dried at room temperature / 0.02 MPa (0.2 mm Hg) to a pale yellow oil; 1 H-NMR (DMSO-d 6) consistent with the spectrum 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 by broad D2O-exchangeable peak centered at 3.18, CH2O, OH, NH2 and _H2 O in solvent), 2.68-2.56 (m, 1, H), 2.28-2.18 (m,

1, 1/2 CH ₂ ), 1.08-0.98 (m, 1, 1/1 CH ₂ ); mass spectrum (CI): 114 (M + 1); [a] ²⁰ + 55.0 ° 5g9, [a] ²⁰⁵⁷⁸ + 58.3 °, [a] ²⁰⁵⁴⁶ + 67.4 °, [α] ² θ436 + 119 ° (c = 0.242, methanol).

*

Elemental analysis for C C ^H ^NO. 0.31H ₂ 0:

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 wash filtrate of Example 25 was concentrated and tert-butanol (400 mL) was added to the residual oil. This solution was used for condensation with 1,2,4-trichloro-5-nitrobenzene (Aldrich, 71.3 g, 0.315 mol as 97%) according to the method of Example 10. The reaction mixture after evaporation of the volatiles in vacuo was chromatographed on silica gel. column eluting with 1: 1 hexanes-ethyl acetate and ethyl acetate. The crude product was chromatographed on silica gel, eluting with 4-6% methanol-chloroform. The combined product containing fractions yielded 58 grams of a reddish solid by evaporation of the solvents. This solid was resolidified 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%)). % of (-) (1S, 4R) -4-amino-2-cyclopentene-1-carboxylic acid) mp 95-97 ° C; 1 H-NMR (DMSO-d 6) and mass spectrum (Cl) are identical to spectra of the enantiomer described in Example 18, [α] ^2θ 589-195 °, [α] ^2θ 578-217 °, [α] ^2θ 546-326 ° (c = 0.350, methanol).

Elemental analysis for C ^ H ^ _{2 2} C1 ₂ N ₂ O _3:

calculated: 47.55% C, 3.99% H, 9.24% N, 23.39% Cl found 47.56% C, 4.01% H, 9.25% N, 23.30% Cl.

Continued elution of the column (above) yielded another yellow powder (18.0 g, 19%) with 1 H-NMR showing it was another title compound contaminated with about 15% (1R, 4S) - [4- (2,5- dichloro-4-anilino) -2-cyclopenten-1-yl] methanol.

Example 27 (1R, 2S, 3S, 5S) -3- (Acetoxymethyl) -5- (4,5-dichloro-2-nixroanilino)

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

1,2-Cyclopentanediyl diacetate (IR, 4S) - [4- (4,5-Dichloro-2-nitroanilino) -2-cyclopentenyl] methanol (17.00 g, 56.1 mmol) is hydroxylated and the mixture of trioles is treated with The red crude oil isolated after acetylation was chromatographed on silica gel and the mixture of the title compounds eluted with 2% methanol-chloroform. Fraction crystallization from ethyl acetate-hexanes gives (IR, 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%), mp 127-128 ° C; (1 H-NMR (d 6)) and mass spectrum (CI) are identical to the racemic sample described in Example 1 and the enantiomer described in Example 55; [α] ^2θ 589+ ¹⁰⁶ °, [α] ^2θ 578 + 119 ^ο , [α] ²⁰ 546 + 184 ° (c = 0.275, methanol).

Elemental analysis for ^C 18 ^H 20 ^N 2 ^C1 2 ° 8 'calculated 46.67% C, 4.35% H, 6.05% N, 15.31% Cl found 46.74% C, 4.40% H N, 6.09; 15.22% Cl.

Continued fractional crystallization of the mother liquors from ethyl acetate-hexanes afforded (1S, 2R, 3S, 5S) -3- (acetoxymethyl) -5- (4,5-dichloro-2-nitroanilino)

1,2-cyclopentanediyl diacetate as orange crystals (2.45 g, 10%), mp 122-124 ° C; ¹ H-NMR (DMSO-d ₆ ).

Evaporation of the mother liquors afforded an additional 9.50 g (40%) of an approximately 1: 1 (by 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 (IR, 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 formic acid product was chromatographed on silica gel eluting with 10% ethyl acetate. -hexanes. Evaporation of the product-containing fractions gave (IR, 2S, 3S, 5S) -3- (acetoxymethyl) -5- (5,6-dichloro-1H-benzimidazol-1-yl) -1,2-cyclopentanediyl diacetate as a white foam from m.p. ethyl acetate (1.85 g, 95%); 1 H-NMR (DMSO-d 6) and mass spectrum (Cl) identical to those of the racemate described in Example 2 and the enantiomer described in Example 56;

[α] 2 ° 589-25.5 °, [α] ^2θ 578-27.0 °, [α] ²⁰ -31.2 ° (c = 0.333, methanol).

Elemental analysis for CH gHH Q Q ^ ^O ^ · 0.1 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 (IR, 2S, 3S, 5S) -5- (5,6-dichloro-1H-benzimidazol-1-yl) -3- (hydroxymethyl) -1,2-cyclopentanediol

About 1: 1 (IR, 2S, 3S, 5S) -3- (acetoxymethyl) -5- (4,558 dichloro-2-nitroanilino) -1,2-cyclopentanediyl diacetate and (1S, 2R, 3S, 5S) -3- (acetoxymethyl) -5- (4,5-dichloro-2-anilino) -1,2-cyclopentanediyl diacetate (4.30, 9.28 mmol) was deacetylated with sodium carbonate (97 mg) in 1: 1: 1 water-ethanol-methanol (100 mL) at room temperature for 24 hours. The pH was adjusted to 7 with acetic acid and the volatiles were removed in vacuo. The residual solid was extracted with methanol. The methanol filtrate was evaporated to dryness in vacuo. The residual solid was dissolved in ethanol (55 mL) -water (20 mL), adjusted to pH 5-6 with sulfuric acid and refluxed with iron powder (0.043 mm, 99.9%, Aldrich, 5.18 g, 93 mL). mekv.) and ferrous sulfate heptahydrate (Aldrich, 98 +%),

1.30 g, 4.58 meq) for 4 hours. The solids were filtered off and the ethanol filtrate was concentrated to an oil. To the oil was added triethyl orthoformate (55 mL) and methanesulfonic acid (0.05 mL), and the resulting solution was stirred at ambient temperature for 18 hours. Concentration in vacuo afforded 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 were removed in vacuo. The residual solids are 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 (CDCl 3): 8.42, 8.07 and 7.92 (all s, 1 each, 3 benzimidazole CH),

5.1-4 (m overlapping d at 5.02, J = 5.7Hz and d at 4.93, J = 3.9Hz, total 3, NCH and 2 OH), 4.54 (t, J = 4.8Hz) , 1, OH)

4.2- 4.0 (m, 2,2 OCH), 3.75-3.45 (m, 2 0CH _2), 2.4-1.9 (m, 3, _CH2 and CH); mass spectrum (CI): 317 (M + 1); ^ία] 589- ² ° ^{61 '4} °' ί «] ^2θ 578- ^{63 '10>} [«] ^2θ -72.9 ° (c = 0.350, methanol).

Elementary analysis for:

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.

Continued elution of the column with 15-20% methanol-chloroform gave a fraction 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 (hydroxymethyl) -1,2-cyclopentadiol, which was isolated as white crystals (605 mg, 21%) by crystallization from 10% methanol-ethyl acetate, mp 221-22 ° C; 1 H-NMR (DMSO-d 6) and mass spectrum (CI) 317 (M + 1); [a] ² ® ^ gg + 14.5 °, [a] ² 7 g ^ ® + 15.2 °, [α] ² θ346 + 16.9 ° (c = 0.290, methanol).

Elemental analysis for Cj ^H H ^ ^^ C ^C ^ ^ ^ ^ ': C, 49.23; H, 4.45; N, 8.83; Cl, 22.36. Found: C, 49.29; H, N, 8.87; Cl, 22.26.

Example 30 (IR, 2S, 3S, 5S) -3- (Acetoxymethyl) -5- (2-bromo-5,6-dichloro-1H-benzimidazol-1-yl) -1,2-cyclopentanediyl diacetate (IR, 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. Volatiles The residue is chromatographed on silica gel. The crude product was eluted with 20-30% hexane-ethyl acetate as a colorless oil. The chloroform oil solution was washed with water to remove contaminating succinimide. The chloroform solution was dried (sodium sulfate) and evaporated to dryness to give the title compound as a white solid foam from ethanol (760 mg, 50%); @ 1 H-NMR (DMSO-d6) and mass spectrum (CI) identical to the racemate described in Example 3; [α] ^ ⁺ ^^ θ589, 8 °, [a] ² ₇ § θ5 + 45.2 °, [a] ² ^^ ^ ₄ + 52.2 ° ^(c = 0.345, methanol).

Elemental analysis for C- ^H-j^^ClCClCO 0,0 · 0.05EtOH:

calculated: 43.74% C, 3.71% H, 5.34% C, 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 afford the title compound as a white powder after solidification from 1: 1 ethanol-methanol (415 mg, 83%), mp 213-216 ° C; 1 H-NMR (d 6) and mass spectrum (CI) identical to those of the racemate described in Example 4; [a] ²⁰ 5 g ₉ + 35.9 °, [a] ² ° + ₅₇ g 36.8 °, [a] ²⁰⁵⁴⁶ + 42.1 ° (c = 0.340, methanol).

Elemental analysis for ^C 13 ^H 21 ^N 2 ^BrCl 2 ° 3 ^: calculated C 39.43, H 3.31, N 7.07, total halogen as Cl 26.86% found C 39.38, 29% H, 7.00% N, total halogen as Cl 26.90%.

Example 32 (1R, 2S, 3S, 5S) -5- [5,6-Dichloro-2- (cyclopropylamino) -1-benzimidazol-1-yl] -3- (hydroxymethyl) -1,2-cyclopentanediol (IR, 2S, 3S, 5S) -3- (Acetoxymethyl) -5- (2-bromo-5,6-dichloro-benzimidazol-1-yl) -1,2-cyclopentanediyl diacetate (500 mg,

0.958 mmol) was refluxed in water: ethanol / 2: 1 (7.5 mL) with cyclopropylamine (freshly opened vial from Aldrich, 0.66 mL, 9.6 mmol) under nitrogen for 18 hours. TLC (silica gel, 10% methanol-chloroform) shows complete conversion to a single spot with lower Rj? than the starting material. 1N sodium hydroxide (0.96 ml) was added and the volatiles were evaporated. The residue is chromatographed on a silica gel flash column. The title compound was eluted with 10% methanol-chloroform as a colorless glass that solidified from water: ethanol / 2: 1 (5 mL) to give a white powder (170 mg, 48%), mp 219-220 ° C; ¹ H-NMR (DMSO-d 6) δ: 7.64 and 7.46 (both s, 2, aromatic CH), 7.11 (m, 1, NH), 5.11 (t, J = 4.3Hz) 1.77 (d, J = 7.0 Hz, 1, OH), 4.67 (d, J = 3.7 Hz, 1, OH), 4.65-4.30 (m, 2, OCH and NCH), 3.85-3.75 (m, 1, OCH), 3.7-3.4 (m, 2.0CH), 2.85-2.70 (m, 1, NCH) cyclopropyl), 2.15-1.80 (m, 3, CH 2 and CH cyclopentane), 0.80-0.50 (m, 4, 2 CH 2 cyclopropyl); mass spectrum (CI): 372 (M + 1); [α] ²⁰⁵⁸⁹ + 13.4 °, [a] ²⁰⁵⁷⁸ + 15.5 °, [a] ²⁰⁵⁴⁶ + 16.9 ° (c = 0.277, methanol). [See Examples 26-28 and 30].

Elemental analysis for ^C 16 ^H 19 ^N 3 ^Cl 2 ° 3 ^: calculated 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 (IR, 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) reflux in ethanol (10 mL) with isopropylamine (1.6 mL, Fluka) under nitrogen for 24 hours Add a second portion of isopropylamine (0.80 mL) and continue refluxing for an additional 4 hours. Dissolve in ethanol, add 1N sodium hydroxide (1.90 mL), evaporate the volatiles again, chromatograph the residue on a silica gel column, eluting with 10% methanol-ethyl acetate as a colorless glass. off-white foam (360 mg, 46%) Its sample solidified upon trituration with 95% water-5% methanol to give the title compound as a white powder (96%), mp 137-138 ° C; ¹ H-NMR (DMSO) -d ₆ ) d 7.60 and 7.39 (ref as, 2, aromatic CH), 6.64 (d, J = 7.4Hz, 1, NH), 5.14 (t, J = 4.3Hz, 1, OH), 4.81 (d, J = 7.3Hz, 1, OH), 4.70 (d, J = 3.5Hz, 1, OH), 4.70 (d, J = 3.5Hz, 1, OH), 4.70-4, 50 (m, 1, NCH), 4.50-4.30 (m, 1, OCH), 4.10-4.00 (m, 1 NCH cyclopropylamino), 3.9-3.75 (m, 1 , OCH), 3.70-3.50 (m, 2,

OCH ₂ ), 2.20-1.80 (m, 3, VH ₂ and cyclopentane CH), 1.24 (d, J = 6.6 Hz, 6.2 CH ₃ ); mass spectrum (CI): 374 (M + 1); [α] ^2θ 589-3.72 °, [α] ^2θ 578-2.60 °, [α] ^2θ 546 ~ 51.7 °) (c = 0.269, methanol). [See Examples 16-18 and 20].

Elemental analysis for C-gH ₂ £ - ^ N ₃ O ₃ Cl ₂ O ₂ .1,3H:

calculated: 48.32% C, 5.98% H, 10.57% N, 17.83% Cl found 48.08% C, 5.91% H, 10.41% N, 18.13% Cl.

Example 34 (+) - (1R *, 2S *, 3S *, 5S *) -5- (5,6-Dichloro-2-amino-1H-benzimidazol-1-yl) -3- (hydroxymethyl) -1,2- cyclopentanediol (±) (IR *, 2S *, 3S *, 5S *) -3- (Acetoxymethyl) -5- (2-bromo-5,6-dichloro-1H-benzimidazol-1-yl) -1,2- Dissolve cyclopentanediyl diacetate (750 mg, 1.44 mmol) in ethanol (10 mL). Hydrazine hydrate (55%, 0.41 mL, 7.2 mmol) was added and the solution was refluxed for 2 hours. The volatiles were evaporated and the residual solid was resolidified 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 slightly basified with aqueous sodium hydroxide to completely remove the acetate groups. The solution was neutralized and the volatiles were evaporated. The residual solid was recrystallized from ethanol-water to give the title compound as a light pink solid (97 mg, 20%), m.p.

283-284 ° C (dec.); ¹ H-NMR (DMSO-d 6) δ: 7.61 and 7.30 (both s, 2, aromatic CH), 6.65 (bs, 2, NH ₂ ), 5.07 (t, J = 4, 3Hz, 1

OH), 4.80 (d, J = 7.0 Hz, 1, OH), 4.66 (d, J = 3.7 Hz, 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 0CH ₂₎ 2.20-1.80 (m, 3, _CH2 and CH of cyclopentane); mass spectrum (CI): 332 (M + 1) [See Examples 1-3].

Elemental analysis for ^ 13 ^ 5 ^ 301 ^ 3:

calculated: 47.01% C, 4.55% H, 12.65% N, 21.35% Cl found 46.72% C, 4.60% H, 12.46% N, 21.08% Cl.

Example 35 (+) - (1R *, 2R *, 4S *) - 2- (2-Cyclopropylamino-5,6-dichloro-1H-benzimidazol-1-yl) -4- (hydroxymethyl) cyclopentanol (+) - (IR *, 2R *, 4S *) -4- (Acetoxymethyl) -2- (2-bromo-5,6-dichloro-1H-benzimidazol-1-yl) cyclopentylacetate (500 mg, 1.50 mmol) was treated with cyclopropylamine (0.70 mL) according to Example 32. The crude product is chromatographed on silica gel and the title compound is eluted with 5% methanol-ethyl acetate as a colorless glass which solidifies from ethyl acetate-hexanes to a white powder (180 mg, 48%), mp 251-253 ° C; ¹ H-NMR (DMSO-d ₆ ) δ: 7.54 and 7.45 (both s, 2, aromatic CH), 5.04 (d, J = 5.1 Hz, 1, OH), 4.97 (t, J = 4.7 Hz, 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, CH), 2.35-2, 10 (m, 1, CH), 2.05 to 1.80 (m, 3, _CH2 and CH of cyclopentane), 1.80-1.60 (m, 1, CH), 0.80-0.50 (1 m, 4, 2CH2 cyclopropyl); mass spectrum (CI): 356 (M + 1). [See Examples 5-7].

Elemental analysis for ^C 16 ^H 19 ^N 3 ^Cl 2 ° 2 ^: calculated C 53.97, H 5.34, N 11.80, C 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-benzimidazol-1-yl) -1,2 -cyclopentane di 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. The volatiles were evaporated and the residue was stirred in methanol half saturated with ammonia at 0 ° C (20 mL) for 18 hours. The volatiles were removed in vacuo and the residue crystallized from ethanol-water to give the title compound as a white solid, m.p. 250 ° C dec .; @ 1 H-NMR (DMSO-d6) .delta .: 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 = 3.5 Hz, 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 (CI): 386 (M + 1). [See Examples 5-7]. Elemental analysis for C17H27N3Cl2O3.0.15 ^ 0.0, O5C2H5OH: Calculated: 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-benzimidazol-1-yl) -1 Dissolve 2-cyclopentanediyl diacetate (500 mg, 0.958 mmol) in ethanol (7 mL). Azetidine (Aldrich, 250 mg, 4.4 mmol as 98%) was added and the solution was refluxed under nitrogen for 48 hours. Methanolic ammonia (saturated at 0 ° C, 20 mL) was added to the cooled solution, and this solution was stirred for an additional 18 hours. The 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 residual solid was triturated with water (3 mL) and filtered. Resolidification of the solid from acetonitrile-methanol gave the title compound as a white powder (146 g, 41%), mp 221-222 ° C; 1 H-NMR (DMSO-d 6) δ: 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 = 5.3 Hz, 1, OH), 4.59 (d, J = 3.7 Hz, 1, OH), 4.45-4.40 (m, 2, OCH and NCH), 4.25-4.15 (m, 4.2 CH ₂ N), 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, _CH2 and NCH); mass spectrum (CI): 372 (M + 1) [See Examples 8-10].

Elemental analysis for ^C 16 ^H 19 ^N 3 ^Cl 2 ° 3 'calculated C 51.63, H 5.14, N 11.29, 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-cyclopentadiol (+) - (1R *, 2S *, 3R *, 5R *) - 3- (Acetoxymethyl) -5- (2-bromo-5,6-dichloro-1H-benzimidazol-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 for 48 hours. The reaction mixture was cooled and 1N sodium hydroxide (1.2 mL) was added. The volatiles were evaporated in vacuo and the residual oily solid was chromatographed on silica gel. Elution with 5% methanol-ethyl acetate gave fractions containing a white powder (200 mg). Recrystallization from 1: 1 water-ethanol gave (+/-) - (IR *, 2S *, 3R *, 5R *) - 5- [5,6-dichloro-2- (cyclopropylamino) -1H-benzimidazol-1-yl] -3- (hydroxymethyl) 1,2-cyclopentanediol as white crystals (180 mg, 40%); mp > 250 ° C; ¹ H-NMR (DMSO-d ₆ ) δ: 7.70 (m, 1, NH), 7.62 and 7.39 (both s, each, 2 benzimidazole CH), 5.77 (bs, 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, CH ₂ OH), 4.2-4.0 (m, 2.2 OCH), 3.7-4.0 (m, 2, OCH ₂ ), 2.9-2.65 (m, 1, OCH) ), 2.2-1.8 (m, 3, _CH2 and CH); mass spectrum (CI): 372 (M + 1). [See Examples 10-14].

Elemental analysis for ^C 16 ^H 19 ^N 3 ^Cl 2 ° 3 ^: calculated 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:

(±) - (IS *, 2R *, 3R *, 5R *) - 5- (5,6-Dichloro-1H-benzimidazol-1-yl) -3- (hydroxymethyl) -1,2-cyclopentanediol (+) - 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 aminoac was added at 0 ° C (100 mL) and the solution was stirred at room temperature overnight. The volatiles were evaporated in vacuo and the remaining solid was stirred with water and filtered to give the title compound as a tan powder (2.02 g, 94%).

Part B:

(+) -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 A solution of methyltriphenoxyphosphonium iodide (Aldrich, 3.27 g, 6.94 mmol) in dry DMF (15 mL) was added dropwise over 20 minutes. Stirring was continued on an ice bath for an additional 30 minutes and then at room temperature for 18 hours. The volatiles were evaporated in vacuo and the residue chromatographed on silica gel. The product was eluted with 2% methanol-chloroform to give, after evaporation of the solvents, a pale yellow powder (750 mg, 28%); ¹ H-NMR (DMSO-d ₆ ) δ: 8.51, 8.08 and 7.97 (all s, 1 each, 3 benzimidazole CH), 5.20 (d, J = 6.7 Hz, 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, _CH2), 2.55-2.40 (m, CH overlapping solvent), 2.35 -2.20 (m, 1, CH); 1.75-1.50 (m, 1, CH).

Part C:

(+) -5- (5,6-Dichloro-1H-benzimidazol-1-yl) -3-methyl-1,2cyclopentanediyl diacetate (+) - (1R *, 2S *, 3R *, 5R *) - 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 (350 kPa - 50 psi) on a Parr shaker for 7.5 hours. The catalyst was filtered off (Celite) and the ethanol filtrate was 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 room temperature for 18 hours. The volatiles were evaporated and the residual oil dissolved! in chloroform (50 mL). The chloroform solution was extracted with aqueous sodium bicarbonate and dried (sodium sulfate). Evaporation of chloroform gave the title compound as a yellow glass (560 mg, 85%); ¹ H-NMR (DMSO-d ₆ ) δ: 8.61, 8.15 and 7.97 (all s, each, 3 benzimidazole CH), 5.60-5.45 (m, 1, OCH), 5 , 20-4,95 (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, CH _3).

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-benzoimidazol-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 was stirred vigorously for 10 minutes. An additional portion of N-bromosuccinimide (100 mg) was added and reflux continued for a further 5 minutes. Here, TLC (silica gel plates developed with 5% methanol-chloroform) shows that the starting material was converted to a UV-absorbing spot with a slightly higher Rf. The reaction was quenched by cooling (ice bath) and diluted with chloroform (50 mL). This solution was washed with water and dried (sodium sulfate). Evaporation gave 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%), mp 235-236 ° C dec .; ¹ H-NMR (DMSO-d 6) δ: 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) exceeding 2.2-2.05 (m, total 6, OAc with CH ₂ and CH), 1.95 (s, 3, OAC ), 1.22 (d, J = 6.3 Hz, 3, CH _3); mass spectrum (CI): 463 (M + 1).

Part E:

(+) - (1R *, 2S *, 3R *, 5S *) - 5- [5,6-Dichloro-2- (cyclopropylamino) -1H-benzimidazol-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 hours. 1N sodium hydroxide (0.75 ml) was added to the cooled reaction mixture and the volatiles were evaporated. under vacuum. The residue is chromatographed on silica gel. The product was eluted with 5% methanol-chloroform. Recrystallization from methanol-ethyl acetate gave (+) - (IR *, 2S *, 3R *, 5S *) -5- [5,6-dichloro-2- (cyclopropylamino) -1H-benzimidazol-1-yl] -3-methyl -1,2-cyclopentanediol as white crystals (170 mg, 64%); m.p. Mp 231-233 ° C;

1 H-NMR (DMSO-d 6) δ: 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 Δ (m, 1, OCH), 2.85-2.7 (m, 1, CHNH), 2.1-1.8 (m, 2, CH ₂ and CH), 1.7-1.5 (m, 1, CH), 1.16 (d, J = 5.4 Hz, 3, CH _3), 0.8 to 0.5 (m, 4, 2 _CH2 of cyclopropyl); mass spectrum (CI): 356 (M + 1). [See Examples 1 and 2].

Elemental analysis for C 6 H £ ₁₉ N ₃ O ₂ C1 _2:

calculated: 53.95% C, 5.38% H, 11.80% N, 19.90% Cl found 53.75% C, 5.45% H, 11.71% N, 19.98% Cl.

Example 40 (1R, 2S, 3S, 5S) -5- [2- (t-Butylamino) -5,6-dichloro-1H-benzimidazol-1-yl] -3- (hydroxymethyl) -1,2-cyclopentanediol

(IR, 2S, 3S, 5S) -5- (2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl) -3- (hydroxymethyl-1,2-cyclopentanediol) solution (500 mg, 1.26 mmol) The mixture was stirred in tert-butylamine (Aldrich, 98%, 20 mL) in a Parr bomb maintained at 148 ° C (oil bath) for 48 hours, cooled, and the resulting pale yellow solution diluted with ethanol containing 1N sodium hydroxide (1.2 mL). The volatiles were evaporated in vacuo and the residue was chromatographed on silica gel, eluting with 10% methanol-chloroform as a colorless oil, dissolved in absolute ethanol, concentrated to an oil and triturated with water (3 mL) to give the title compound. (IR, 2S, 3S, 5S) -5- [tert -Butylamino] -5,6-dichloro-1H-benzimidazol-1-yl] -3- (hydroxymethyl) -1,2-cyclopentanediol as a white powder (303 mg, 61 %), mp at 116-150 ° C collapse on glass; ¹ H-NMR (DMSO-d 6) δ: 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, OCH ₂ ),

2.2-1.85 (m, 3, CH ₂ and CH cyclopentane), 1.47 (s, 9.3 CH-j);

mass spectrum (CI): 388 (M + 1); [α] ² ₈ 9 θ5 ^-4, 0 °, [a] 578-4,3 ^2θ °, [a] 546-6,0 ^2θ °, [a] 436-22,6 ^2θ °, [α] ^2θ 365-82.1 ° (c = 0.420, methanol). [See Examples 25-28, 30 and 31]. Elemental analysis for C ₁₇ H ₂₃ N ₃ Cl ₂ O ₃ · 0.40H ₂ O: calculated C 51.63, H 6.07, N 10.62, Cl 17.93 found 51.50 % C, H 5.99, N 10.54, Cl 17.96.

Example 41 (+) - (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-bromo-5,6-dichloro-1H-benzimidazol-1-yl) -3- (hydroxymethyl) -1,2- of 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 for 6 days).

The volatiles were evaporated in vacuo and the remaining solids were refluxed in ethanol (30 mL) with aqueous dimethylamine (ALdrich, 40%, 2 mL) for one hour. The volatiles were evaporated and the remaining solid was chromatographed on silica gel. Elution with 10% methanol-ethyl acetate gave the title compound as a colorless glass. Solidification from water gave (+) - (1R *, 2S *, 3S *, 5S *) -5- [2- (tert-butylamino) -5,6-dichloro-1H-benzimidazol-1-yl] -3- ( hydroxymethyl) -1,2-cyclopentanediol as a white powder (150 mg, 26%); m.p. 130-132 ° C;

@ 1 H-NMR (DMSO-d6) .delta. Consistent with the spectrum of the enantiomer described in Example 30. [See Examples 1-4].

Elemental analysis for Ο ₄ γΗ23Νβϋΐ2θ3 · 0.0.07 C2H3OH: calculated 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-benzimidazol-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 hours, a second portion of isopropylamine (1.22 mL) was added and refluxing continued The volatiles were evaporated, the residue was redissolved in ethanol, 1 N sodium hydroxide (1.44 mL) was added, and the volatiles were re-evaporated The residue was chromatographed on a silica gel column eluting with 10% methanol. The glass was crystallized from ethyl acetate-hexanes to give (+) - (IR *, 2S *, 3S *, 5S *) - 5- [5,6-dichloro-2- (isopropylamino) -1H-benzimidazole- 1-yl] -3- (hydroxymethyl) -1,2-cyclopentanediol as white crystals (305 mg, 57%), mp 213-214 ° C, ¹ H-NMR (DMSO-d 6) consistent with spectrum em enantiomer described in Example 23. [See Examples 1-4]. Elemental analysis for ^C 16 ^H 21 ^N 3 ^C1 2 ° ^3: calculated 51.35% C, 5.66% H, 11.23% N, 18.95% Cl Found: 51.27% C, 5.69% H N, 11.17%, 18.88% Cl.

Claims (15)

A compound of formula I or 1-1 Z. θ Z θ 0150Q in which: r! is hydrogen, CH ₃ or CH ₂ OH; R ² is H or OH, is H or OH, or R and R together form a bond; R ⁴ is amino, cyclopropylamino, cyclobutylamino, isopropylamino, A tert-butylamino group or -NR R, where R and R together with the nitrogen atom to which they are attached form 4, 5 or A 6-membered heterocyclic ring; is hydrogen, and r ⁶ and R ² are chlorine except (+) - (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, R and R is or comprises OH and pharmaceutically acceptable derivatives thereof. > 2 A compound according to claim 1, wherein R is OH. A compound according to claim 2, wherein R ⁴ is cyclopropylamino, isopropylamino or tert-butylamino. A compound according to claim 3, wherein R ⁴ is an isopropylamino group or a tert-butylamino group. A compound according to claim 1 of formula IA or IA-1: in which : is hydrogen or OH, R 6 is an amino group, a cyclopropylamino group, an isopropylamino group, a tert-butylamino group, in particular an isopropyl group or a tert-butylamino group, or -NR ° R, where R and R 6 are R 6 ^; together with the nitrogen atom to which they are attached form a 4, 5 or 6-membered heterocyclic ring; R5 is hydrogen, and R6 and R ² are chlorine, except (+) - (lR *, 2S *, 3S *, 5S *) - 5- [5,6-dichloro-2- (cyclopropylamino) -lH-benzimidazole -1-yl] -3- (hydroxymethyl) -1,2-cyclopentanediol and pharmaceutically acceptable derivatives thereof. 6. A compound according to claim 5 wherein R is cyclopropylamino, isopropylamino or tert-butylamino; R ^J is hydrogen and R ° and R 'are both chlorine atoms and pharmaceutically acceptable derivatives thereof. A compound according to claim 6, wherein R 1 is an isopropylamino group or a tert-butylamino group. A compound according to claim 1, selected from the group consisting of: (1R, 2S, 3S, 5S) -5- [5,6-dichloro-2- (cyclopropylamino) -1H-benzimidazol-1-yl] -3- (hydroxymethyl) -1,2-cyclopentanediol, (IR, 2S, 3S, 5S) -5- [5,6-dichloro-2- (isopropylamino) -1H-benzimidazol-1-yl] -3- (hydroxymethyl) -1,2-cyclopentanediol, (+) - (IR *, 2S *), 3S *, 5S *) - 5- [5,6-dichloro-2-amino-1H-benzimidazol-1-yl] -3- (hydroxymethyl) -1,2-cyclopentanediol, (+) - (IR *, 2R *, 4S *) - 2- (2-cyclopropylamino-5,6-dichloro-1H-benzimidazol-1-yl) -4- (hydroxymethyl) -1,2-cyclopentanediol, (+) - (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, (+) - (IR) *, 2S *, 3S *, 5S *) -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- (hydroxymethyl) -1,2-cyclopentanediol, (1R, 2S, 3S, 5S) -5- [2- (t-butylamino) -5,6-dichloro-1H-benzimidazol-1-yl] -1,2-cyclopentanediol, (+) - (1R *, 2S *, 3S *, 5S *) -5- [2- (tert-butylamino) -5,6-dichloro-1H-benzimidazol-1-yl] -3- (hydroxymethyl) -1,2-cyclopentanediol, (+) - (IR *, 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-t-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, (IR, 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. A method of treating herpes viral infections in a subject, comprising treating the subject with a therapeutically effective amount of at least one compound of Formula I or 1-1 according to claim 1, or a pharmaceutically acceptable derivative thereof. The method of claim 9, wherein the herpes viral infection is a cytomegalovirus infection. The method of claim 9 or 10, wherein said compound is selected from the group consisting of (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, (+) - (1R *, 2R *, 4S *) - 2- (2-cyclopropylamino-5,6-dichloro-1H-benzimidazol-1-yl) -4- (hydroxymethyl) -1, 2-cyclopentanediol, (+) - (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 *, 3S *, 5S *) - 5- [5,6-dichloro-2- (cyclopropylamino) -1H-benzimidazole-1- yl] -3- (hydroxymethyl) -1,2-cyclopentanediol, (+) - (1R *, 2S *, 3R *, 5S *) - 5- [5,6-dichloro-2- (cyclopropylamino) -1H-benzimidazole -1-yl] -3- (hydroxymethyl) -1,2-cyclopentanediol, (IR, 2S, 3S, 5S) -5- [2- (t-butylamino) -5,6-dichloro-1H-benzimidazol-1-yl] -1,2-cyclopentanediol, (+) - (IR *, 2S *) , 3S *, 5S *) - 5- [2- (t-butylamino) -5,6-dichloro-1H-benzimidazol-1-yl] -3- (hydroxymethyl) -1,2-cyclopentanediol, (+) - (IR) *, 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, (IS, 2R, 3R, 5R) ) -5- [2-tert-Butylamino-5,6-dichloro-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, (IR, 2S, 3S, 5S) -5- [5,6-dichloro-2- (1-azetidinyl) -1H-benzimidazol-1-yl] -3- (hydroxymethyl) -1,2-cyclopentanediol, (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. Use of one or more compounds according to claim 1 for the preparation of a medicament for the treatment of viral infections, in particular hepatitis B virus and cytomegalovirus infection. Pharmaceutical formulations comprising at least one compound of formula (I) or (I-1) according to claim 1 and not a pharmaceutically acceptable derivative thereof together with at least one pharmaceutically acceptable carrier or excipient. 14. The pharmaceutical formulation of claim 13 wherein said compound is selected from the group consisting of: (1R, 2S, 3S, 5S) -5- [5,6-dichloro-2- (cyclopropylamino) -1H-benzimidazol-1-yl] -3- (hydroxymethyl) -1,2-cyclopentanediol, (IR, 2S, 3S, 5S) -5- [5,6-dichloro-2- (isopropylamino) -1H80 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, (+) - (IR *, 2R *) , 4S *) - 2- (2-cyclopropylamino-5,6-dichloro-1H-benzimidazol-1-yl) -4- (hydroxymethyl) -1,2-cyclopentanediol, (+) - (IR *, 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, (+) - ( IR *, 2S *, 3S *, 5S *) -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- (hydroxymethyl) -1,2-cyclopentanediol (1R, 2S, 3S, 5S) -5- [2- (t-butylamino) -5,6-dichloro-1H-benzimidazol-1-yl] -1,2-cyclopentanediol, (+) - (1R *, 2S *, 3S *, 5S *) -5- [2- (t-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 and their pharmaceutically acceptable derivatives. A process for the preparation of compounds of formulas I and 1-1 according to claim 1, alone or in combination with their mirror enantiomers and pharmaceutically acceptable derivatives thereof, comprising (A) reacting a compound of formula II: or a mirror enantiomer thereof, (a) either with a compound of the formula: ^R4 _CO2 H wherein ^R4 is hydrogen, alkyl having 1 to 4 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms, or a compound of the formula: R ⁴ C (OR) ₃ wherein R ⁴ is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 perfluoroalkyl. carbon atoms, and R is an alkyl group having 1 to 4 carbon atoms, to form a compound of formula I or 1-1 wherein R ⁴ is hydrogen, or (b) or with cyanobromide to form a compound of formula IA or IA-1 wherein R ⁴ is NH ₂ or (B) (a) converting a compound of Formula IA or IA-1 wherein R ⁴ is hydrogen to another compound of Formula IA or IA-1 wherein R ⁴ is a leaving group, or (b) converting a compound of Formula IA or IA-1, wherein R ⁴ is a chlorine or bromine atom or iodine to another compound of formula IA or IA-1, wherein R ⁴ is an amino group or an 8-9 substituted amino group -NR R or (C) by reaction of a compound of formula III: (ΠΙ) (where R ⁴ , r ⁵ , r ⁶ and R ² are as defined above) or a functional equivalent thereof, with a compound of formula IV: (IV) wherein R ¹ , R ² and R ² are as defined above and L is a leaving group to form a compound of formula IA or IA-1 wherein hydrogen, halogen or NR ^{8 is} R ⁹ and optionally converting a compound of formula I or 1 -1 to a pharmaceutically acceptable derivative thereof. Represented by: Dr. Miloš Všetečka