HU211577A9 - Therapeutic nucleosides - Google Patents

Description

The present invention relates to purine nucleoside analogues containing, at the sugar unit site, an unsaturated carbon ring, to pharmaceutically acceptable percentages thereof, and to their use in medical treatment, in particular for the treatment of viral infections.

AIDS (Acquired Immune Deficiency Syndrome) is a disease that results in weakening or damage to the immune system, which predisposes the patient to fatal opportunistic infections. Typically, AIDS is associated with worsening depletion of T-cells, especially the helper-inducing subgroup carrying the OKT ⁴ surface marker.

Human Immunodeficiency Virus (HIV) has been reproducibly isolated from patients with or with frequent symptoms of AIDS. HIV is cytopathic, it appears to infect and kill, in particular, T-cells carrying the OKT ⁴ marker, and it has become common to recognize that HIV is a causative agent of AIDS.

Since realizing that HIV is a causative agent of AIDS, many anti-HIV chemotherapeutic agents have been proposed that may be effective in treating people with AIDS. For example, U.S. Pat. No. 4,724,232, 3'-azido-3'-deoxythymidine (zidovudine) and pharmaceutically acceptable derivatives thereof, and their use in the treatment of human retroviral infections, including AIDS and related clinical conditions. disclosed. Vince et al. (Antiviral Research, 9 (1/2), 120 (1988)) disclose certain carbon ring nucleoside analogues and their use against HIV. Also reported is (±) -9- [cis-4- (hydroxymethyl) -2-cyclopentenyl] guanine (NSC-614,846), also known as carbovir (Second International Conference on Antiviral Research, Williamsburg, VA). April 10-14, 1988]. Hepatitis B virus (HBV) is a pathogenic virus with major consequences worldwide. It is very common in Asian countries and is widespread in sub-Saharan Africa. The virus is pathologically related to primary hepatocellular carcinoma and is thought to be responsible for 80% of the world's liver cancer. In the United States, more than tens of thousands of people are hospitalized each year for HBV disease, with an average of 250 dying from acute illness.

At present, it is estimated that there are about 500,000 to 1,000,000 infectious persons in the United States. About 25% of infectious agents develop chronic active hepatitis, and the disease often develops to cirrhosis. It is estimated that approximately 5,000 people die each year from HBV-related cirrhosis in the United States, and probably 1,000 from HBV-related liver cancer. Even if a universal vaccine effective against HBV is available, it will be necessary to use HBV-effective compounds. It is estimated that there is a steady supply of infected carriers around 220,000,000 people worldwide.

they are not helped by vaccination, they are still at high risk of HBV-induced liver disease. This carrier population is a source of infection for susceptible individuals, maintaining the disease in particular in epidemic areas or high-risk groups, such as intravenous drug users and homosexuals. Thus, there is a great need for effective antiviral agents, which are effective against both chronic infections and reduce the progression of the disease to hepatocellular carcinoma.

Clinical signs of HBV infection include headache, fever, malaise, nausea, vomiting, loss of appetite and abdominal pain. Viral replication is usually regulated by the immune response, and it can take weeks or months for a person to recover, but the infection can sometimes be more severe and lead to permanent chronic liver disease, as outlined above.

Viral Infections of Humans [Second Edition, Ed. Evans, A.S (1982) Plenum Publishing Corporation,

New York], Chapter 12, details the etiology of viral hepatitis infections.

Hepatitis B virus (HBV) is a small DNA virus that infects humans. A member of a closely related class of viruses known as hepadnavirus, each member of which is capable of selectively infecting a mammalian or fowl host, such as marmot and duck. Recent insights into the replication mechanism of the hepadnaviral genome indicate the importance of reverse transcription of the RNA intermediate, corroborating the assumption that reverse transcriptase is a reasonable chemotherapeutic target.

It has now been found that certain purine nucleoside analogs containing the unsaturated carbon ring referred to below are useful in the treatment of viral infections such as hepatitis B and retroviral infections, particularly AIDS.

In one aspect, the invention relates to novel compounds of formula I wherein R ³ is hydrogen or C 1-6 alkyl; R ⁶ is C 3 -C 8 cycloalkyl (preferably C 3 -C 6 cycloalkyl such as cyclopropyl, cyclobutyl or cyclopentyl) and R ⁷ is hydrogen or C 1-6 branched or unbranched alkyl (e.g., methyl or ethyl) or their compounds. and pharmaceutically acceptable derivatives thereof.

Most preferred are the isomers in which the hydroxyl group in the formula (I) is in the cis position with respect to the purine. It is to be understood that the invention encompasses the individual enantiomer of the compounds of formula I as well as all or part of the racemic mixtures of such enantiomers, even if the exact structure depicted relates to an enantiomer.

Preferred examples of compounds of formula I are: a) (-) - cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol and mixtures of a racemic or partially resolvable compound with the (+) - cis enantiomer

HU 211 577 A9

b) (-) - cis -4- [2-amino-6- (cyclopropylmethylamino) -9-purin-9-yl] -2-cyclopentene-1-methanol and racemic or (+) - cis mixtures partially enantiomerically resolved

These compounds are particularly advantageous in that they reach high levels in the central nervous system, where manifestation of HIV infections is particularly debilitating.

The above compounds of formula (I) and their pharmaceutically acceptable derivatives are hereinafter referred to as the compounds of the invention.

In one aspect of the invention, the use of the compounds of the invention in medical treatment is particularly directed to the treatment of retroviral infections or hepatitis B virus infections.

Retroviral infections that can be treated or prevented by the invention include human retrovirus infections such as human immunodeficiency virus (HIV), HIV-1, HIV-2, and human T-cell lymphotropic virus (HLTV), such as HTLV-I or HTLV-II. . The compounds of the invention are particularly useful in AIDS and clinically related conditions such as AIDS-related complex (ARC), advanced generalized lymphadenopathy (PGL), AIDS-related neurological conditions such as multiple sclerosis or tropical paraparesis (partial paralysis) and anti-HIV antibody- positive and HIV positive conditions and thrombocytopenia purpura. The compounds of the invention may also be used to treat or prevent psoriasis.

The compounds of the present invention are particularly useful for the treatment of asymptomatic infections or diseases caused by or associated with human retroviruses in humans. In a further aspect, the invention relates to:

a) a method of treating retroviral infections and hepatitis B virus infections comprising treating a subject in need thereof with a therapeutically effective amount of a compound of the invention; and

b) use of the compounds of the invention in the manufacture of a medicament for the treatment of any of the aforementioned infections or conditions.

The term "pharmaceutically acceptable derivative" means the pharmaceutically acceptable salt, ester or ester of a compound of the invention or any other compound which, upon administration to a subject to be treated, directly or indirectly becomes such a compound of the invention or an antiviral metabolite or residue thereof. salt.

Preferred esters of the compounds of the invention include those with carboxylic acids in which the non-carbonyl moiety of the ester group is a straight or branched alkyl group such as η-propyl, tert-butyl or n-butyl; alkoxyalkyl (e.g., methoxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenoxymethyl), aryl (e.g., optionally halogen, (C1 -C4) alkoxy, (C1 -C4) alkoxy or amino) substituted phenyl); sulfonate esters, such as alkyl or aralkylsulfonyl esters (e.g., methanesulfonyl); amino acid esters (e.g., L-valyl or L-isoleucyl ester); and mono-, di- or triphosphate esters. The phosphate esters may be further esterified, for example with a C 1 -C 20 alcohol or a reactive derivative thereof, or with a 2,3-di (C 6 -C 24 acyl) glycerol.

In the above-described esters, unless otherwise noted, alkyl units preferably contain from 1 to 18 carbon atoms, more preferably from 1 to 4 carbon atoms. The aryl units preferably contain a phenyl group.

Any reference to the above compounds also includes a reference to their pharmaceutically acceptable salts.

Pharmaceutically acceptable salts of the compounds of the present invention and their pharmaceutically acceptable derivatives include, for example, salts with a base, such as salts with a suitable base such as alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium) and ammonium salts; the NW + 4 salts (where W is C 1-4 alkyl). Physiologically acceptable salts of the hydrogen atom or the amino group include organic carboxylic acids such as acetic acid, lactic acid, tartaric acid, malic acid, isethionic acid, lactobionic acid and succinic acid; salts of organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Physiologically acceptable salts of hydroxyl-containing compounds include combinations of the anion of said compound with a suitable cation such as Na ⁺ , NH4 ⁺ and NW4 * (where W is C1-C4 alkyl).

The compounds of the present invention and their pharmaceutically acceptable derivatives may also be used in combination with other therapeutic agents to treat the above infections and conditions. Such additional therapeutic agents include therapeutic agents effective to treat viral infections and related conditions, such as 3'-azido-3'-deoxythymidine (zidovudine), 2 ', 3'-dideoxynucleosides such as 2', 3'-dideoxycytidine, 2 ', 3'-dideoxyadenosine and 2', 3'-dideoxyinosine, cyclic nucleosides (e.g. acyclovir), interferons such as α-interferon, renal secretion inhibitors such as probenicid, nucleoside transport inhibitors such as dipyridamole, dilazep , myo-, lido- or soluflazine or hexobendin, and immunomodulators such as ^; rleukin II and granulocyte macrophage colony stimulating cells, throat, soluble CD ₄ or its genetically engineered derivatives and phosphonic formic acid. The active ingredients of such a combination therapy component may be administered simultaneously, in separate or combined formulations, or at different times, for example sequentially, to achieve the combined effect.

The compounds of the invention, hereinafter referred to as the active ingredient, may be administered for therapeutic purposes by any suitable route, e.g.

A9 is administered orally, rectally, nasally, topically (including oral and sublingual routes), vaginally and parenterally (including subcutaneous, intramuscular, intravenous and intradermal). It will be appreciated that the preferred route of administration will depend upon the condition and age of the patient, the nature of the infection and the active ingredient selected.

For the treatment of the aforementioned conditions (e.g., AIDS), the patient (e.g., human) will generally be administered 3.0-120 mg / kg body weight / day, preferably 6-90 mg / kg body weight / day, more preferably 15-60 mg / kg body weight. kg / day is the appropriate dose. The desired dose is preferably administered in the form of two, three, four, five, six or more sub-doses at appropriate intervals throughout the day. Subdoses may be administered in unit dosage form, for example, 10-1500 mg, preferably 20-1000 mg, more preferably 50-700 mg of active ingredient per unit dose.

Ideally, the active ingredient is administered such that the peak plasma concentration of the active ingredient is about 175 pmol / l, preferably about 2-50 pmol / l, more preferably about 3-30 g / l. This may be achieved, for example, by intravenous injection of a 0.1-5% solution of the active ingredient, optionally in saline, or by oral administration of a large pill containing about 1-100 mg / kg of the active ingredient. The desired blood level can be maintained by administering about 0.01-5.0 mg of active ingredient per kg per hour by continuous infusion or about 0.4-15 mg of active ingredient per kg by continuous infusion.

Although the active ingredient may be administered alone, it is preferably administered in the form of a pharmaceutical composition. The pharmaceutical compositions of the present invention comprise at least one active ingredient as defined above and one or more pharmaceutically acceptable carriers and, optionally, other therapeutic agents. All carriers should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient. The compositions may be administered by oral, rectal, nasal, topical (including oral and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) routes. The compositions are conveniently presented in unit dosage form by any of the methods well known in the art of pharmacy. Such methods include operations such as mixing the active ingredient with a carrier which comprises one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately admixing the active ingredient with the liquid or finely divided solid carrier, or both, and then, if desired, shaping the product.

Formulations for oral administration may be presented in discrete units, for example capsules or tablets, each containing a predetermined amount of the active ingredient, and may be in the form of powders or granules, solutions or suspensions in an aqueous or non-aqueous solvent, or emulsions. The active ingredient may also be formulated as a large pill, electuary or paste.

The tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be formulated with a free-flowing active ingredient such as powder or granules, optionally with a binder (e.g. povidone, gelatin, hydroxypropylmethylcellulose), a glidant, an inert diluent, a preservative, a disintegrant, e.g. , cross-linked povidone, cross-linked sodium carboxymethylcellulose), a surfactant or a dispersant is pressed on a suitable apparatus.

Molded tablets may be made by pouring a powdered active ingredient moistened with an inert liquid diluent into a suitable device. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient, e.g., in varying proportions, to provide the desired release profile of hydroxypropylmethylcellulose. The tablets may optionally be enteric-coated to release the active ingredient, not in the stomach, but in the intestine.

Formulations for topical administration in the mouth include lozenges containing the active ingredient in a flavored base, usually sucrose and acacia or tragacanth, lozenges containing the active ingredient in an inert base such as gelatin and glycerol or sucrose and acacia, the active ingredient is contained in a suitable liquid carrier.

Formulations for rectal administration may be presented as suppositories with appropriate ingredients, for example, cocoa butter or salicylate.

Formulations for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are conventionally employed in the preparation of such compositions.

Formulations for parenteral administration include aqueous and non-aqueous isotonic sterile injectable solutions, which may further contain antioxidant, buffering, bacteriostatic and other solutes which render the composition isotonic with the blood of the subject being treated; aqueous and non-aqueous sterile suspensions, which may also contain suspending and thickening agents. The formulations may be presented in unit dosage form or in a multi-dose sealed container, such as ampoules and vials, and may be stored in a freeze-dried (lyophilized) state, in which case only sterile liquid vehicle such as water for injection is suitable. Immediately before use, injection solutions and suspensions may be prepared from sterile powders, granules and tablets as described above.

Unit dose formulations containing the active ingredient in a daily dose or in a lower dose are preferred.

This is a suitable or a suitable fragment of A9 as described above.

The compounds of the invention may also be formulated into veterinary compositions, for example, by methods well known in the art.

In addition to the ingredients specifically mentioned above, the compositions of the invention may contain other ingredients commonly used in compositions of this type, such as sweeteners, thickeners, and flavoring agents in compositions for oral administration.

The present invention further provides a process for the preparation of the compounds of the present invention and pharmaceutically acceptable derivatives thereof which comprises:

A) a compound of formula II in the formula

R ³ is as defined above, Z is a precursor of the group -NR ⁶ R ⁷ as defined in formula (I) - with a reagent or under conditions in which the precursor group Z is converted to the desired R ² group, or

B) a compound of Formula III: wherein

R ⁶ and R ⁷ are as defined above, R ⁸ is hydrogen or boiled and R ⁹ is a C 1 -C 6 acyl group (e.g. formyl or acetyl) - or a pharmaceutically acceptable derivative of the imidazole ring in the desired compound of formula I or an agent for the formation thereof

i) converting a resulting compound of formula I into a pharmaceutically acceptable derivative, or ii) converting a resulting derivative of compound of formula I into the parent compound or another derivative of the compound.

Process A can be carried out in any conventional manner, for example by reacting a compound of formula II wherein Z is a leaving group (e.g., a halogen such as chlorine) with a suitable amine or amine hydrochloride to introduce the above substituted amino group under reflux. under reflux or at a temperature in excess of 50 ° C, preferably in the presence of an organic solvent such as methanol or ethanol.

Process B may be carried out, for example, by reacting a compound of formula III with formic acid or a reactive derivative thereof (e.g. triethyl orthoformate or diethoxymethyl acetate) in the presence of a solvent such as dimethylacetamide or dimethylformamide at elevated temperature, preferably 75-90 ° C. temperature. This reaction is conveniently carried out by adding a slightly more than an equivalent amount of a strong anhydrous acid, for example 1.1 equivalents of ethanesulfonic acid / l equivalents of compound (III), in which case a lower temperature (e.g. 25 ° C) is used.

For example, the compounds of formula II used as starting materials in process A may be prepared, for example, by first cyclizing a compound of formula III in a manner analogous to that described in process B above.

Other reagents may also be used as substituents for R ^{3 of} formula (I) for the cyclization of compounds of formula (III) to carry compounds other than hydrogen. For example, triethyl or trimethyl orthoacetate may be used with acetic anhydride at 70-120 ° C for several hours. Thus, a compound containing a methyl group as R ^{3 is} obtained. (See HC Koppel and RK Robinson; J. Org. Chem. 1958, 1457.)

Alternatively, for example, (1R, 4S) -9- (4-hydroxymethyl-2-cyclopentyl) -guanine prepared from arysteromycin may be prepared according to Australian Patent Application AU-A-28671/89 (incorporated herein by reference). ).

The compounds of formula (I) may be converted into a pharmaceutically acceptable ester by reaction with a suitable esterifying agent, such as an acid halide or an anhydride. The compounds of formula (I), including their esters, may be converted into their pharmaceutically acceptable salts in conventional manner, for example by reaction with the appropriate acid. An ester or salt of a compound of formula (I) may be converted to the parent compound by, for example, hydrolysis.

Enantiomers of the compounds of formula I can be resolved or isolated by conventional means, for example, by chromatographic separation of diastereomeric esters prepared by acylation of the hydroxy group of the cyclopentenyl unit with an optically active carboxylic acid derivative such as naproxen (J. Org. Chem., 1986, 51, 1287). The cyclopentyl precursor of the compound of formula (III) may also be resolved by fractional crystallization of its salts with optically active carboxylic acids (e.g. dibenzoylD-tartaric acid), or alternatively, by enzymatic resolution as described in J. Med. Chem. 30, 746 (1987) and J. Med. Chem. 28, 1385 (1985).

The invention is further illustrated by the following non-limiting examples. The term "active ingredient" in the examples refers to compounds of formula (I) and pharmaceutically acceptable derivatives.

Example 1 (±) -cis-4 - [(2-Amino-4-chloro-6-pyrimidinyl) amino] 2-cyclopenten-1-methanol

14.88 g, 0.073 mole of cis-4-acetamidocyclopent-2-ene methyl acetate, 46.19 g, 0.146 mole of barium hydroxide octahydrate, prepared as described in United States Patent 4,268,672. and a mixture of water (300 ml) was refluxed under nitrogen for 18 hours. The resulting solution was neutralized with carbon dioxide. The precipitate was washed with water and then with ethanol. The filtrate was combined with the wash solution and evaporated to a syrup to give 11.16 g of syrup with 23.91 g, 0.146 mol of amino-4,6-dichloropyrimidine and 30.5 ml, 0.219 mol of triethylamine in 100 ml of boiling 1L. -butanol for 1.5 hours

A9 condensate. 1N Sodium hydroxide (73 mL) was added and the mixture was evaporated to dryness and the resulting solid was taken up in chloroform (200 mL). The unresponsive

The 2-amino-4,6-dichloropyrimidine was filtered off and washed with 100 ml of chloroform. The chloroform filtrate washer was evaporated and the residue was chromatographed on a silica gel column. Further pyrimidine starting material was eluted with 2.5% methanol-chloroform. The title compound was eluted with 3.5% methanol-chloroform as an off-white solid foam. Yield: 15.90 g (91%).

1 H-NMR (Me ₂ SO-d ₆ ): δ 1.15-1.28 and 2.26-2.41 (2m,

2, CH ₂ ); 2.60-2.71 (m, 1,1'-H); 3.4 (m overlapping H ₂ O, C ₂ OH); 4.625 (t, J = 5.3, 1, CH ₂ OH); 4.95 (broad s, 1, CH-N); 5.67-5.87 (m, 2, CH = CH);

6.38 (bs, 1, NH ₂ ); 7.12 (bs, 1, NH); MS (Cl) M + 1, 241,243.

Analysis results for C | ₀ H ₁₃ N ₄ OC10.2 H ₂ O:

Calculated: C, 48.99; H, 5.55; N, 22.85; Cl, 14.46.

Found: C, 49.10; H, 5.57; N, 22.81.

Cl% = 14.40.

Example 2 (+) - Cis-4 - {[2-Amino-6-chloro-5- (4-chlorophenyl) azo / 4-pyrimidinyl] amino} -2-cyclopenten-1-methanol

11.58 g (48.1 mmol) of (±) cis -4 - [(2-amino-4-chloro-6-pyrimidinyl) amino] -2-cyclopentene-1-methanol prepared according to Example 1; Sodium acetate trihydrate (g) was dissolved in glacial acetic acid (225 ml) and water (225 ml). From 4-chlorobenzene diazonium chloride (6.74 g, 52.8 moles) in 4-chloroaniline, 14.7 ml concentrated hydrochloric acid, 52 ml water and 4.01 g (58.2 mmoles) of sodium nitrite. A cold solution of 0-5 ° C is prepared in 47 ml of water. This cold solution is added to the first solution for 5 minutes. After 18 hours, the resulting yellow precipitate was filtered off, washed with water and extracted with ethanol. Yield: 12.56 g (69%) as a dark yellow powder. M.p. 218-220 ° C (dec.).

1 H-NMR (Me ₂ SO-d ₆ ): δ 10.25 (d, 1, NH); 7.69 and

7.54 (both d, J = 8.9, C ₆ H ₄ ) overlap 7.6 (broad, 6, NH ₂ ); 5.80-5.95 (m, 2, CH = CH); 5.24 (m, 1, CHN); 4.75 (t, 1, CH ₂ OH); 3.41 (t, 2, CH ₂ OH); 2.75 (m, 1, CH); 2.41 (m, 1, CH); 1.441.53 (m, 1, CH).

Analysis results Calculated for C ₆ H ₁₆ N ₆ Cl ₂ O: C, 50.67; H, 4.25; N, 22.16.

Cl, 18.70 Found: C, 50.59; H, 4.29; N, 22.10;

Cl% = 18.66

Example 3 (+) - Cis-4 - {(2,5-Diamino-4-chloro-6-pyrimidinyl) amino] -2-cyclopenten-1-methanol 11.67 g of the title compound of Example 2 are obtained. It is suspended in 235 ml of ethanol, 30 ml of glacial acetic acid and 235 ml of water. The mixture was heated under reflux under nitrogen. 13.5 g of zinc powder are added in small portions over 30 minutes, during which time the compound dissolves. The reaction mixture was heated for an additional 20 minutes, then excess zinc was filtered off from the hot solution and washed with ethanol. The filtrates were evaporated and the residue was purified on a silica gel column using 1 L of chloroform and 1.8 L of 4: 1 chloroform: methanol. The product-containing fractions were combined and the solvent removed in vacuo. 11.2 g of the title compound are obtained in the form of a reddish-orange oil in more than 100% yield. Another small amount of the reaction gave a pure product as a pale yellow solid (76% yield).

1 H-NMR (Me ₂ SO-d ₆ ): δ 1.29 and 2.39 (m, 2, CH ₂ );

2.69 (t, 1,1'-H); 3.37 (d, 2, CH ₂ OH); 3.91 (wide,

2, NH ₂ ); 4.60 (broad, m, 1, CH ₂ OH); 5.02 (m, l,

CHNH); 5.56 (broad s, 2, NH ₂ ); 5.74 (m, 1, = CH);

5.86 (m, 1, = CH); 6.36 (d, 1, CHNH).

Example 4 (±) -Cis-4- (2-Amino-6-chloro-9H-purin-9-yl) -2-cyclopenten-1-methanol

9.7 g of the title compound of Example 3 are dissolved in 100 g of diethoxymethyl acetate and the solution is refluxed for 2 days. The solvent was removed under high vacuum at 50 ° C and 40 ml of dioxane and 60 ml of 0.5 N hydrochloric acid were added to the residue. The mixture was stirred at room temperature for 1.25 hours and then cooled. The reaction mixture was then neutralized to pH 7 with cold 5N sodium hydroxide and extracted several times with chloroform / methanol (3: 1). The organic phases were dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography over silica gel using 2% methanol in chloroform as eluent. yielding 46%

3.7 g of the title compound are obtained. M.p. 138-139 ° C.

1 H-NMR (Me ₂ SO-d ₆ ): δ 1.63 and 2.61 (m, 2, CH ₂ );

2.87 (m, 1,1'-H); 3.44 (d, 2, CH ₂ OH); 5.44 (m, 1,

CH-N); 5.89 (m, 1, = CH); 6.14 (m, 1, = CH); 6.82 (bs, 2, NH ₂ ); 8.02 (s, 1.8-H); (CH ₂ OH) not visible - below the H ₂ O peak). UV: pH 1 λ max 315 (E 7370); 218 (26200); λ shoulder 239.5 (5650). pH 7.4 λ max 307 (E 8000); 245.5 (4,600); 223 (26400).

MS (EI) 265 267 (m) (CI) 266, 268 (m + 1). Analysis results for C || H | According to the formula ₂ N ₅ C1O, 2 H ₂ O:

Found: C, 43.79; H, 5.35; N, 23.21; Cl, 11.75;

Found: C, 43.67; H, 5.29. N, 23.05.

Cl, 11.70.

Example 5 (+) - Cis-4-1,2-Amino-6- (cyclopropylamino) -9H-purin-9-yl) -2-cyclopentene-1-methanol 0.50 g of the title compound of Example 4 is obtained. Dissolve in 40 ml of ethanol and add 0.65 ml of 5 equivalents of cyclopropylamine. The mixture was refluxed under nitrogen for 6 hours. A further 0.65 ml of cyclopropylamine was added and the mixture was refluxed for a further 5.5 hours. The solvent was evaporated and 25 ml of chloroform and 5 ml of saturated sodium bicarbonate solution were added to the residue. The aqueous phase was extracted several times with chloroform and the resulting crude product was purified on a silica gel column. Elution was carried out with 3% methanol-ethyl acetate to give (±) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purine-9- (0.43 g) in 80% yield. il] -2-cyclopentene n-1-methanol is obtained. This product was recrystallized from acetonitrile to give 0.30 g of a white powder. The product thus obtained is collapsed between 93-130 ° C and melts at 165 ° C.

1 H-NMR (Me ₂ SO-d ₆ ): δ 0.56 and 0.63 (2m, 4, 2-cyclopropyl CH 2; 1.56 and 2.60 (2m, 2, cyclopentenylCH ₂ ), 2.85 ( m, 1,1'-H); 3.02 (m, 1, cyclopropyl C 1 -NH); 3.43 (m, 2, CH ₂ OH); 4.71 (t, 1, CH ₂ OH). );

5.40 (m, 1, 4'-H); 5.77 (s, 2, NH ₂ ), overlapping 5.84 (m, 1, = CH); 6.09 (m, 1, = CH); 7.23 (d, 1, NWCH), 7.58 (s, 1, purin-8-Η); MS (Cl) 287 (m + 1) UV: pH 1: λ max 296 (E 14000), 255 (10700), pH

7.0: λ max 284 (15900); 259 (9200); pH 13 λ max 284 (15800), 259 (9100).

Analysis results for C | ₄ H | _g N ₆ O0.25 H ₂ O:

Found: C, 57.82; H, 6.41; N, 28.90; Found: C, 57.84; H, 6.45; N, 28.86.

Example 6 (±) -Cis-4- (2-Atnino-6-cyclopentylamino-9H-purin9-yl) -2-2-cyclopentene-1-methanol

0.53 g (2 mmol) of (±) cis-4- (2-amino-6-chloro-9Z / -purin-9-yl) -2-cyclopentene-1-methanol (2.00 g) prepared in Example 4. A solution of triethylamine (20 mmol), cyclopentylamine (267 mg, 3.1 mmol) and ethanol (10 mL) was heated at reflux for 9 hours. The solution was then allowed to cool to room temperature and 2 mL of 1.0 N sodium hydroxide was added. The crude product obtained by concentrating the solution was purified on a silica gel column using 5% methanol in chloroform as eluent. Yield: 0.430 g (68.4%). A sample was purified by crystallization from a mixture of ethanol and acetonitrile to give an off-white powder, m.p. 143-146 ° C.

1 H-NMR (Me ₂ SO-d ₆ ): δ 7.60 (s, 1H, purine H-8), 7.00 (br m, 1H, NH), 6.10 and 5.86 (m, 2H , CH = CH), 5.77 (br s, 2H, NH3, 5.39 (m, 1H, NCH cyclopentene), 4.76 (br s, 1H, OH), 4.53 (br m, 1H, NCH), 3.44 (m, 2H, OCH, 2.87 (m. IH, CH), 2.62-2.54 (m, IH, 0.5 _CH2 cyclopentene ring), 1.89 (br m, 2H, cyclopentyl CH 3, 1.70-1.48 (broad m, 7H, 0.5 CH ₂ cyclopentene ring, ₃ CH ₃₎ . Analysis for C ₆ H ₂₂ N ₆ O 0.25 H ₂ O:

Found: C, 60.26; H, 7.11; N, 26.35; Found: C, 60.43; H, 7; 16; N, 26.27.

60.37, 7.17, 26.25

Example 7 (±) -cis-4- [2-Amino-6- (cyclopropylmethylamino) 9H-purin-9-yl) -2-cyclopentene-1-methanol

0.53 g (2 mmol) of (±) -cis-4- (2-amino-6-chloro-9H-purin-9-yl) -2-cyclopenten-1-methanol (0.8477 g) prepared in Example 4. . 12 mmol of N-methyl-N-cyclopropylamine (Kari Industries, Aurora, OH) and 20 ml of methanol were placed in a Parr bomb and kept at 62 ° C for 5 hours. The solution was evaporated and diluted with ethanol, then adjusted to pH 12 with 1.0 N sodium hydroxide. This solution was evaporated and the residue was chromatographed on a silica gel column using 3% methanol in chloroform as eluent. Yield: 0.547 g (91.2%). A sample of the product was recrystallized from aqueous ethanol to give a white powder, m.p. 130-131 ° C. 1 H-NMR (Me ₂ SO-d ₆ ): δ 7.61 (s, 1H, purine H-8), 6.10 (m, 1H, CH =), 5.84 (m, 1H, CH = ), 5.7 (wide s,

2H, NH3; 5.40 (m, 1H, CHN), 4.70 (broad t, 1H,

OH), 3.43 (m, 2H, CH ₂ OH), 3.24 (broad s, 4H,

CH ₃ , NCH cyclopropyl), 2.85 (m, 1H, CH), 2,662.57 and 1.61-1.51 (m, 2, cyclopentenyl CH 3, 0.900.65 (m, 4H, 2CH ₂ from cyclopropyl). .

Analytical results based on the formula Ci ₅ H ₂₀ N ₆ O-0.5 H ₂ O:

Found: C, 58.24; H, 6.84; N, 27.16; Found: C, 58.15; H, 6.86; N, 27.14.

Example 8 (+) - Cis-4- (2-Amino-6-cyclobutylamino-9H-purin9-yl) -1,2-cyclopentene-methanol

0.53 g (2 mmol) of (±) cis -4- (2-amino-6-chloro-9 H -purin-9-yl) -2-cyclopentene-1-methanol prepared in Example 4 and 1.387 g. A solution of cyclobutylamine (19.5 mmol) in methanol (15 mL) was heated in an oil flask at 70-75 ° C for 29 hours. The solution was cooled to room temperature and 2 mL of 1.0 N sodium hydroxide was added. The solution is then concentrated and the residue is chromatographed on silica gel. The title compound was eluted with chloroform containing 5% methanol. Yield: 457 mg (75.7%), a colorless foam which solidified to a white powder in acetonitrile. Melting point: 181-183 ° C.

1 H-NMR (DMSO-d 6: δ 7.59 (s, 1H, purine H 8), 7.38 (br m, 1H, NH), 6.10 (m, 1H, 0.5 HC = CH), 5.84 (m overlap, broad s, 5.76, 3H, 0.5 CH = CH, NHJ,

5.36 (m, 1H, NCH cyclopentene), 4.73 (t, overlap, broad m, J = 5.2, 2H, OH, NCH cyclobutane), 3.42 (m, 2H, OCH3, 2.83 (br m, 1H, CH), 2.55 (m, DMSO overlap, 1/2 CH ₂ cyclopentene), 2.20-1.95 (br m, 4H, 2CH ₂ , cyclobutane), 1.58 ( m, 3, CH ₂ , cyclobutane, O, 5CH ₂ cyclopentene).

Calcd for C ₂₀ H _l5 N ₆ O Calculated: C% = 59.98, H% = 6.71, N% = 27.98; Found: C, 60.05; H, 6.73; N, 27.91.

Example 9 (±) -Cis {4- [2-Amino-6- (cyclopmpylamino) -9H-pururin-9-yl] -2-cyclopenten-1-yl} methyl acetate

400 mg (1.5 mmol) of (+) 7 prepared according to Example 5

OJ! 211,577 A9 Cis-4- (2-Amino-6-cyclopropylamino-9H-purin-9-yl) 2-cyclopenten-1-methanol, 228 mg, 2.2 mmol acetic anhydride and 8.4 mg, 6, 9x10 ² mmol 4-N, N-dimethylaminopyridine was dissolved in 12 ml dry Ν, Ν-dimethylformamide and the solution was stirred at room temperature overnight. The solution is then concentrated under high vacuum and the residue is applied to a silica gel column eluted with 5% methanol in chloroform. Yield: 240 mg (48.7%), diluted with ethanol and foamed under high vacuum. 1 H-NMR (DMSO-d ₆ ): δ 7.52 (s, 1H, purine H8), 7.28 (d, J = 4.5, 1H, NH), 6.07 and 5.94 (m , 2H, HC = CH),

5.81 (br, 2H, _NH2), 5.39 (br m, 1H, NCH), 4.06 (m, 2H, _OCH2), 3.02 (br m, 2H, CH, NCH cyclopropane) 2.65 (m, 1H, 0,5CH ₂ cyclopentene), 1.98 (s, 3H, _CH3), 1.56 (m, 1H, 0,5CH ₂ cyclopentene), 0.61 (m, 4H , 2CH ₂ cyclopropane).

Calcd for _{C] 6} H ₂₀ N ₂ O ₆ based on H ₂ 0 0.4 0.015 EtOH formula:

Found: C, 57.16; H, 6.39; N, 24.54;

found:

C% = 56.88, 56.82,

H, 6.32, 6.32,

N, 24.81. 24.78

Example 10 (±) -Cis {4- [2-Amino-6- (cyclopropylmethylamino) 9H-purin-9-yl] -2-cyclopenten-1-yl} methyl acetate 0.30 g 1 mmol of (±) cis-4- [2-amino-6- (cyclopropylmethylamino) -9H-purin9-yl) -2-cyclopentene-1-methanol prepared in Example 7, 0.204 g, A solution of acetic anhydride (2 mmol) and N, N-dimethylaminopyridine (0.005 g, 0.04 mmol) in Ν, Ν-dimethylformamide (10 mL) was stirred at room temperature overnight under a nitrogen atmosphere. Water (1 ml) was added to the solution, stirred for an additional 1 hour and then concentrated under high vacuum. The residual oil was partitioned between 5 mL of saturated sodium bicarbonate solution and 3 x 50 mL of chloroform. The combined chloroform extracts were dried over magnesium sulfate, the solvent was evaporated, and the residue was chromatographed on silica gel. The title compound was eluted with chloroform containing 4% methanol and foamed with ethanol under high vacuum. Yield: 0.330 g (93%). 1 H-NMR (DMSO-d ₆ ): δ 7.59 (s, 1, H-8), 6.10 and 5.90 (2m, 2, CH = CH), 5.80 (bs, 2 , NH ₂ ), 5.40 (br m, 1, CH-N), 4.05 (d, J = 6.1, 2.0, CH ₂ ), 3.30-3.20 (m, overlapping s 3 , At 23, divide by 4, CH-N-Me), 3.10 (broad m, 1, CH), 2.75-2.60 (m, 1.0.5 CH ₂ ), 1.98 ( s, 3H, COCH ₃ ), 1.65-1.50 (m, 1.0.5 CH ₂ ).

Analysis results for C | ₇ H ₂₂ N ₆ O ₂ 0.45 H ₂ OO, 05

Calculated for EtOH: C, 58.21; H, 6.63; N, 23.82; Found: C, 58.15; H, 6.60; N, 23.91.

58.09, 6.61, 23.83.

Example 11 A sample of (±) -cis-4- {2-amino-6- (cyclopropylethylamino) -9H-pururin-9-yl} -2-cyclopenten-1-methanol is prepared. 60 as follows. 18.44 g, 0.323 mol of cyclopropylamine. 45.6 g. A mixture of 0.33 mol of potassium carbonate and 250 ml of dry diethyl ether was stirred vigorously in an ice bath while 50 ml of 0.36 mol of trifluoroacetic anhydride were added dropwise over 30 minutes. Then ice water (20 ml) was added, the ether layer was separated and dried over magnesium sulfate.

Concentration of the solution gave 51.1 g of a pale yellow liquid. A solution of this liquid (15.3 g, about 0.1 mol) in dry acetone (250 ml) was added together with 46.8 g (0.30 mol) of ethyl iodide and heated in an oil bath to 70 ° C. 16.8 g, 0.300 eq. powdered potassium hydroxide was added. Stirring was continued at 70 ° C for a further 30 minutes and then excess ethyl iodide and acetone were evaporated. Water (100 mL) was added to the residue, and the resulting solution was heated to reflux (110 ° C oil bath) for 15 minutes and refluxed for 5 minutes. The solution was then cooled to 25 ° C. saturated with sodium chloride and extracted with diethyl ether (3 x 100 mL). The ethereal solution was dried over magnesium sulfate and evaporated to give 4.86 g (57%) of a pale yellow oil.

1 H-NMR (DMSO-d ₆ ): δ 7.74 (q, J = 6.0, 2,

NCH ₂ CH ₃ ), 2.2-2.08 (m, 1, CHN), 1.97 (broad s,

NH + * H ₂ O), 1.19 (t, J = 6.0, 3, NCH ₂ CH ₃ ), 1.9-1.3 (m, 4, 2CH ₂ ).

1.26 g of this sample of N-cyclopropyl-N-ethylamine were treated with (±) - (cis) 4- (2-amino-6-chloro-9 H) 544 mg (2.00 mmol) prepared in Example 4. -purin-9-yl) -2-cyclopentene-1-methanol in methanol (16 ml) was kept in a Parr bomb at 75 ° C for 11.5 hours. Then 1.5 ml of 1N sodium hydroxide was added and the solution was evaporated to dryness. The residue is chromatographed on silica gel. The title compound was eluted with 4% methanol in chloroform, and the resulting pale yellow glass was crystallized from acetonitrile to give 298 mg (47%) of melting point 152-154 ° C.

1 H-NMR (DMSO-d ₆ ): δ 7.64 (s, 1H, purine H-8), 6.11 and 5.88 (m, 2, HC = CH), 5.80 (broad s, 2, NH ₂ ), 5.42 (m, 1, NCH cyclopentene), 4.75 (t, J = 4.8, 1, OH), 3.94 (m, 2, NCH ₂ ), 3.45 (m, 2, OCH ₂ ), 3.05 (m, 1, NCH cyclopropane), 2.87 (broad m, 1, CH), 2.60 (m. DMSO overlap, 0.5CH ₂ cyclopentene). 1.56 (m, 1, O5CH ₂ cyclopentene), 1.10 (t, J = 6.9, _CH3), 0.85 and 0.65 (m, 4, 2 CH _2).

Analysis: Calculated for C ₆ H ₂₂ N ₆ O: C, 61.13; H, 7.05; N, 26.73; Found: C, 61.06; H, 7.07; N, 26.66.

Example 12 (±) -Cis-14- [2-Amino-6- (cyclopmpylamino) -9H-pururin-9-yl] -2-cyclopenten-1-yl} methyl-L-valinate trifluoroacetate

N-butyloxycarbonyl-L-valine (1.200 g, 5.19 mmol) and 0.562 g. N, N-dicyclohexylcarbodiimide (2.73 mmol) was stirred in dry methylene chloride (46 mL) for 40 min. The mixture is filtered, the precipitate is washed with 8 ml of methylene chloride, and the combined filtrate and washings are dried to dryness. The remaining white solid (anhydride) was added in two portions to (±) -cis-4- [2-amino-6- (cyclopropylamino) -9A / purine (572 mg, 2.00 mmol). -9-yl] -2-cyclopenten-1-methanol, 19 ml of dry Ν, Ν-dimethylformamide and 20 mg, 0.16 mmol of 4-N, N-dimethylaminopyridine. After stirring at 25 ° C under nitrogen for 69 hours, water (0.3 mL) was added. The solution was evaporated to dryness and the residue partitioned between chloroform and water (2.5 mmol) containing sodium bicarbonate. The aqueous phase was extracted with chloroform and partitioned between water. The aqueous phase is extracted with chloroform, the combined organic phases are dried over magnesium sulfate and filtered. Elution with 4% methanol in chloroform gave 520 mg of the title compound as a blocked derivative with N-butyloxycarbonyl as a white foam.

1 H-NMR (Me ₂ SO-d ₆ ): δ 7.62 (s, 1, purine H-8), 7.30 (d, J = 3.9, 1, NH cyclopropylamine), 7, 16 (d, J = 7.9, 1, CHN), 6.08 and 5.95 (m, 2, HC = CH), 5.83 (bs, 2, NH ₂ ), 5.42 (bs) m, 1, NCH), 4.13 (d, J = 6.3, 2, OCH ₂ ), 3.82 (t, J = 7.4, 1, valyl NCH), 3.08 (broad m, 2, CH cyclopentene, CH cyclopropane), 2.69 (m, 1.0.5CH ₂ cyclopentene), 1.97 (m, 1, CHMe ₂ ), 1.60 (m, 1, 0.5CH _2). cyclopentene)

1.37 (s, 9, C (CH) ₃ ), 0.88-0.79 (overlapping d, 6, CH (Ctf) ₃ ) ₂ ), 0.64 and 0.59 (m, 4, 2CH). ₂ cyclopropane).

From this derivative, 510 mg, -25 ml

Dissolve in a 1: 3 mixture of trifluoroacetic acid / methylene chloride and stir at 25 ° C for 30 minutes. The solution was evaporated to give the title compound as a yellow foam (745 mg). 1 H-NMR (DMSO-d 6): δ 9.85 (br m, 1, NH), 8.37 (br m, 3, NH ₃ +), 8.01 (br s, 1, purine H-8 )

7.57 (br s, 2, NH ₂ ), 6.17 and 6.02 (m, 2, HC = CH), 5.48 (m, 1, NCH cyclopenten), 4.26 (m, overlapping, broad solvent, OCH ₂ ), 3.94 (broad m, overlapping solvent, valyl CH), 3.17 (m, 1, CH), 2.92,68 (broad m, 2, cyclopropyl CHN, 0.5CH _2). cyclopentene), 2.14 (m, 1, CHMe ₂ ), 1.66 (m, 1, 0.5CH ₂ cyclopentene), 0.94 (m, 8, CHMe ₂ , CH ₂ cyclopropane), 0.78 ( m, 2, cyclopropyl CH ₂ ).

Analysis for C _I9 H ₂₇ N ₇ O ₂ O 8 3.8 H ₂ O

According to the formula CF ₃ CO ₂ H:

Found: C, 38.35; H, 3.92; N, 11.77. Found: C, 38.25; H, 3.79; N, 11.80.

Example 13 (±) -cis-4- [2-Amino-6- (cyclobutylmethylamino) 9H-purin-9-yl] -2-cyclopenten-1-methanol N-cyclobutyl-N-methylamine prepare a sample as follows. 5.00 g, 68.9 mmol of cyclobutylamine and

Potassium carbonate (13.3 g, 96.5 mmol) in dry diethyl ether (250 mL) was stirred vigorously in an ice bath under a nitrogen atmosphere while trifluoroacetic anhydride (10.7 mL) was added dropwise over 20 min. To the mixture was added ice water (20 ml), the ether layer was separated and dried over magnesium sulfate.

then concentrated to a colorless liquid. The resulting liquid (11.50 g) was dissolved in dry acetone (170 mL) along with methyl iodide (40 g, 0.28 mole) and heated to 40 ° C. To the mixture was then added 16 g, 0.28 equivalents of powdered potassium hydroxide, and the mixture was stirred for an additional 45 minutes at 40 ° C. The excess methyl iodide and the acetone were evaporated and 75 ml of water were added to the resulting liquid and solid. The resulting solution was refluxed in an oil bath at 110 ° C for 15 minutes and refluxed for 5 minutes. The solution was then cooled to 25 ° C, saturated with sodium chloride, extracted with diethyl ether (3 x 150 mL), dried over magnesium sulfate and evaporated. This gave 3.72 g (64%) of a colorless oil, 1 H-NMR (CDCl ₃ ): δ 3.25-3.15 (m, 1, CHN), 2.34 (s,

3, NCH ₃ ), 2.27-2.03 (m, 2, 2CH), 1.8-1.6 (m, 4,

CH ₂ and 2CH).

From this sample of N-cyclobutyl-N-methylamine, 510 mg, 6.0 mmol of 544 mg, 2.00 mmol of (±) - (cis) -4- (2-amino- 6-Chloro-9H-purin-9-yl) -2-cyclopentene-1-methanol in methanol (16 ml) was kept in a Parr bomb at 65 ° C for 5.5 hours. To the solution was then added 2 ml of 1N sodium hydroxide and evaporated to dryness. The residue is chromatographed on silica gel. The title compound was eluted from silica gel with chloroform containing 10% methanol. Acetonitrile gave 528 mg (84%) of the title compound as a pale yellow solid foam. 1 H-NMR (DMSO-d 6): δ 7.62 (s, 1, purine H-8), 6.156.07 (m, 1, = CH), 6.0-5.7 (m, 4, = CH, NH ₂ and cyclobutyl CHN), 5.5-5.3 (m, 1, CHN), 4.77 (t, J = 5.3, 1, OH), 3.42 (m, 2, CW). ₂ OH), 3.27 (s, H ₂ O interlaced, N-CH ₃ ), 2.85 (m, 1, H-1 '), 2.7-2.5 (m, 1.0) , 5 cyclopentyl CH ₂ ), 2.4-2.0 (m, 4, 2 cyclobutyl CH ₂ ), 1.7-1.4 (m, 3, 0.5 cyclopentyl CH ₂ and cyclobutyl CH ₂ ).

Analysis results for C | ₆ H ₂₂ N ₆ OO, 03 H ₂ OO, 05 CH ₃ CH

Found: C, 60.08; H, 7.12; N, 26.33; Found: C, 60.02; H, 7.10; N, 26.30.

59.97, 7.13, 26.26.

Example 14 (+) - Cis - (4- [2-Amino-6- (cyclopropylmethylamino) 9H-purin-9-yl] -2-cyclopenten-1-yl) methyl-L-valinate trifluoroacetate

A mixture of 1.09 g (5.0 mmol) of N-butyloxycarbonyl-L-valine and 0.515 g (2.5 mmol) of N, N-dicyclohexylcarbodiimide in 15 ml of dry methylene chloride is stirred for 1 hour. The mixture was filtered, the precipitate was washed with methylene chloride (10 mL), the filtrate and the washings were combined and evaporated to dryness. To the residue was added (600) (±) -cis-4- [2-amino-6- (cyclopropylmethylamino) -9 H -purin-9-yl] -2- (0.600 g, 2 mmol). cyclopentene-1-methanol, 15 ml of dry Ν, Ν-dimethylformamide and 5 mg, 0.04 mmol of 4-N, N-dimethylaminopyridine. After stirring at room temperature under nitrogen for 16 hours, water (1 mL) was added and the solution

The concentrate was concentrated in vacuo. The residual oil was partitioned between 2 mL of 0.1 N sodium hydroxide and 3 x 50 mL of chloroform. The combined chloroform extracts were dried over magnesium sulfate, the solvent was evaporated and the residue was chromatographed on silica gel. The eluent was chloroform containing 5% methanol. 0.750 g of the title compound is obtained in 75% yield as a derivative blocked with N-butyloxycarbonyl.

1 H-NMR (DMSO-d ₆ ): δ 7.62 (s, 1, H-8), 7.15 (d, J =

8.2, 1, NH), 6.10 and 5.90 (2m, 2, CH = CH), 5.79 (br s, 2, NH ₂ ), 5.40 (br m, 1, CH N), 4.10 (d, J = 6.4, 2, CH ₂ -O), 3.80 (m, 1 val CH-N),

3.30-3.15 (m, overlapping at 3.23, total 4, CHN-Me), 3.10-3.0 (broad m, 1, CH), 2.75-2.55 ( m.

1, 0.5CH ₂ ), 2.05-1.85 (m, 1, CH ₂ Me ₂ ), 1.70-1.50 (m, 1, 0.5CH ₂ ), 1.34 (m , 9, CMe ₃ ), 0.90-0.60 (m,

10, CHMe ₂ and cyclopropyl CH ₂ ).

A sample (0.74 g, 1.5 mmol) of this sample was dissolved in 25 ml of 1: 3 trifluoroacetic acid / methylene chloride, stirred at 25 ° C under nitrogen for 30 minutes and then concentrated to give 87% yield. 0.957 g of the title compound is obtained in the form of a yellow foam.

1 H-NMR (DMSO-d ₆ ): δ 8.38 (br s, 3, NH ₃ +), 8.0 (s, 1, H-8), 7.80-7.10 (br m, 2, NH ₂ ), 6.18 and

6.0 (2m, 2, CH = CH), 5.48 (m, 1, CH-N), 4.26 (broad d, J = 6.5, H ₂ O overlapped, CH ₂ -O) ), 3.93 (br m, 1, CH-N valyl), 3.55 (br s, 3, N-Me),

3.20-3.10 (broad m, 2, CH and cyclopropyl CH-N),

2.79-2.69 (m, 1, 0.5CH ₂ ), 2.20-2.05 (m, 1,

CWMe ₂ ), 1.67-1.60 (m, 1.0, 5CH ₂ ), 1.10-0.90 (m.

10, 2CH ₃ and 2 cyclopropyl CH ₂ ).

Analysis calculated for C ₂₀ H ₂₉ N ₇ O ₂ 1.0 H ₂ O 4, 4 EtOH-2.60 CF ₃ CO ₂ H: C, 42.64; H, 4.95; = 13.39;

Found: C, 42.63; H, 4.9; N, 13.42.

Example 75 (±) -Cis-4- [2-Amino-6- (cyclooctylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol

(±) -cis-4- (2-amino-6-chloro-9 H -purin-9-yl) -2-cyclopenten-1-methanol (0.549 g), cyclooctylamine (0.762 g, 6 mmol) and A mixture of 15 ml of ethanol was refluxed under nitrogen for 20 hours. To the mixture was added 2 ml of 1N sodium hydroxide and the solvent was evaporated. The residual oil was chromatographed on silica gel. The title compound was eluted with 5% methanol in chloroform and crystallized from a mixture of acetonitrile and methanol. Yield: 0.623 g (87%) as a white powder. Melting point: 171-173 ° C.

1 H-NMR (DMSO-d ₆ ); δ 7.60 (s, 1H, H-8), 6.90 (m, 1,

NH), 6.10 and 5.85 (2m, 2, CH = CH), 5.75 (broad s,

2, NH ₂ ), 5.40 (m, 1, CHN), 4.76 (t, J = 5.1, 1, OH),

4.30 (br m, 1, CH-N), 3.45 (m, 2, CH ₂ -O),

2.85 (br m, 1, CH), 2.70-2.55 (m, 1, 1/2 CH ₂ ),

1.85-1.40 (br m, 14: 7 CH ₂ and 1/2 CH _2).

Analysis results for C | _{According to the} formula ₉ H 2 _Cl N ₆ O:

Calculated: C, 64.02. H, 7.92; N, 23.58; Found: C, 64.11; H; = 7.97, N% = 23.51.

Example 16 (+) - Cis-4- [2-Amino-6- (cyclopropylamino) -8-methyl-9H-purin-9-yl) -2-cyclopenten-1-methanol

1.12 g (4.38 mmol) of (±) -cis-4 - [(2,5-diamino-4-chloro-6-pyrimidinyl) amino] 2-cyclopenten-1-methanol prepared in Example 3 A mixture of ml, Ν-dimethylformamide (5 mL) and trimethyl orthoacetate (30 mL) and ethanesulfonic acid (0.66 g, 5.7 mmol) was stirred at 70 ° C for 3 days. The resulting solution was evaporated to give a yellow syrup. To this was added acetic anhydride (20 ml) and the resulting solution was refluxed for 2.5 hours. The resulting dark solution was evaporated to a syrup and the syrup was dissolved in 50 ml of 1N hydrochloric acid. After 24 hours, the pH was adjusted to 6 with sodium hydroxide and most of the water was evaporated. The crude product obtained is extracted into chloroform containing 20% isopropyl alcohol. This solution was dried over magnesium sulfate and the solvent was evaporated. 0.30 g of (±) -cis -4- (2-amino-6-chloro-8-methyl-9H-purin-9-yl) -2-cyclopentene-1-methanol remain as a pale yellow glass. Its structure was identified by 1 H NMR. This sample was dissolved in 10 mL of methanol and stirred in a Parr bomb with 1 mL of cyclopropylamine at 70 ° C for 12 hours. After evaporation and chromatography on silica gel, the title compound is eluted with 5% methanol in chloroform. 136 mg of a cream solid foam are obtained.

1 H-NMR (DMSO-d ₆ ): δ 7.13 (d, J = 4.6, 1, NH), 6.02 and 5.84 (both m, 2, CH = CH), 5.68 -5.56 (m, 3, NH ₂ and CH-N), 4.85 (t, 1, CH ₂ OH), 3.53 (m, 2, C ₁₂ OH), 3.02 (m , 1, CH-N of cyclopropyl), 2.88 (m, I, CH), 2.5 (m, overlapping solvent, 0.5 cyclopentyl CH ₂ ), 1.72 (m, 0.5) cyclopentyl CH ₂ ), 0.7-0.5 (m, 4, 2 cyclopropyl CH ₂ ).

Calcd for _{C] 5} H ₂₀ N ₆ OO 25

CH ₃ OH according to the formula 0,65 H ₂ O:

Found: C, 57.23; H, 7.02; N, 26.26; Found: C, 57.55; H, 6.99; N, 25.95.

Example 17 1- (c) -4- [2-Amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol

The title compound of Example 5 (0.600 g, 2.00 mmol) was dissolved in 12 mL of 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H) -pyrimidinone (Aldrich). To the solution, cooled to -10 ° C, was stirred with 0.76 mL. Phosphoryl chloride (8.0 mmol) was added. After 3 minutes, cold water (100 mL) was added and the resulting solution was neutralized with 3M ammonium hydroxide. The neutralized solution was diluted to 1 L with water and applied to a 2.5 x 20 cm DEAE Sephadex A25 (Pharmacia) column previously equilibrated with 50 mM ammonium bicarbonate solution. The column was first washed with 4 L of 50 mM ammonium bicarbonate. The (±) cis -4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol-5'-monophosphate is then eluted.

I0

A9 with a gradient of increasing concentration of ammonium bicarbonate of 50 to 300 mmol / l, the total volume of eluent being 2 liters. The nucleotide-containing fractions were evaporated to remove the ammonium bicarbonate. We get a white powder. The yield was 71% by UV absorbance and the product gave a peak by HPLC (see below). 1.4 mmol of nucleotide was dissolved in 20 mL of water and 1000 IU of Crotalus atrox (Sigma) snake venom 5'-nucleotidase (EC 3.1.3.5) was added. The solution was incubated at 37 ° C for 22 hours, and additional 1000 IU of enzyme was added. The incubation was continued for another 3 days. HPLC analysis was performed on a 0.4 x 10 cm Whatman Partisii 10 strong anion exchange column, eluting with a gradient of ammonium phosphate, 20 mM to 1M, pH 5.5, 5% methanol, UV detection 284 nm. The assay showed that at this point 50% of the starting nucleotide was dephosphorylated to nucleoside. The mixture was again applied to a DEAE Sephadex column of the type described above. Elution with 4 L of 50 mM ammonium bicarbonate gave fractions containing the title compound. The residual water was evaporated to give a white powder. This material was further purified by chromatography on silica gel (eluent: methanol: chloroform = 1: 9). This gives a colorless glassy material. This material was solidified in acetonitrile to give (-) - cis -4- [2-amino-6- (cyclopropylamino) -9H-purin9-yl] -2-cyclopentene-1-methanol as a white gum, m.p. It is dried at 66 DEG C. to a solid foam. 260 mg of product are obtained in a yield of 86% from the racemate; product Ή NMR _(DMSO-d6) and mass spectrum identical with those of the racemate (title compound of Example 5); [cc] § -59.7 ', [α] ₄ ² 3 ° ₆ -127.8', [α] ₃ ² 6 ° ₅ -218, Γ, (c = 0.15, methanol).

Analysis results for C | ₄ H | on the basis _of N ₆ O 0.8 H ₂ O wherein:

Found: C, 55.91; H, 6.57; N, 27.94; Found: C, 56.05; H, 6.65; N, 27.88.

Further elution of the aforementioned Sephadex column with 2 liters of a gradient of ammonium bicarbonate at a concentration of 50 to 300 mM, yields 5'-monophosphate (see Example 19) which is stable to 5'-nucleotidase.

Example 18 (-) - Cis-4- [2-Amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol-5'-monophosphate Example 17 (0.35 g, 1.2 mmol) was dissolved in 5 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H) -pyrimidinone (Aldrich). The solution was cooled to -10 DEG C. and 0.43 mL (4.6 mmol) of phosphoryl chloride (Aldrich) was added with stirring. After 3 minutes, cold water (20 ml) was added and the mixture was neutralized with 3M ammonium hydroxide. The ion exchange chromatography was carried out as described in Example 17 to give, after evaporation of the water, the diammonium salt of the nucleotide as a white powder (95% yield by UV analysis). HPLC analysis as described in Example 17 shows the presence of a peak; UV λ max nM (0.1 M HCl): 254, 297; (pH 7 phosphate buffer): 259, 284; (0.1 M NaOH): 259, 284. The base / phosphate ratio was determined as 1.0 / 1.3 Ames, B. (Methods in Enzymology 8, 115 (1966)). [ «] § -69.9 ', [a] $ - 73 O \ [j & -84.0 ° (c = 0.52, MeOH: H ₂ O / 4: 1).

Example 19 (+) - Cis-4- [2-Amino-6- (cyclopmpylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol 5'-monophosphate The DEAE described in Example 17 After incubation of the Sephadex column with 5'nucleotidase eluting with 2 L of a gradient of 50 to 300 mM ammonium bicarbonate, nucleotide-containing fractions are obtained from which the water is evaporated. so it is

The title diammonium salt was obtained as a white powder in 56% relative to the title compound. HPLC analysis as described in Example 17 yielded a single peak. UV λ max nM (0.1 M HCl): 254, 297; (pH 7 phosphate buffer): 259. 284; (0.1 M NaOH): 259, 284. The base / phosphate ratio is 1.0 / 0.98. [α] D +62.0 ', [α] D +65.2', [α] D + 75.0 °, (c = 0.54, MeOH: H ₂ O / 4: 1).

Example 20 (+) - Cis-4- [2-Amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol From the title compound of Example 19, 0.67 mmol was dissolved in ml of water and 3000 g of calf intestine

NO alkaline phosphatase (EC 3.1.3.1, BoehringerMannheim) is added. The solution is incubated at 37 ° C for 19 hours and then subjected to HPLC analysis as described in Example 17, which shows that the nucleotide is completely dephosphorylated. The solution is evaporated to dryness and the resulting solid is extracted with 100 ml of ethanol under reflux. The ethanol-soluble substances were adsorbed onto silica gel and applied to a silica gel column. The title compound was eluted with methanol: chloroform (1: 9). Evaporation of a solution of acetonitrile in ethanol afforded 164 mg (79%) of a white solid foam. 1 H-NMR (DMSO-d ₆ ) and mass spectrum data are identical to those of the racemate (title compound of Example 5). [a] ® +58.7 ', [a] ₄₃ + 126.2 ° 6 ° [a] ² ₃ 6 ₅ ° + 217.5 ° (c = 0.10, methanol).

Analysis calculated for C ₁₄ Hi ₈ N ₆ OO, H ₂ 60 OO 15 EtOH formula:% C = 56.49, H% = 6.66, N% = 27.64; Found: C, 56.60; H, 6.63; N, 27.55.

Example 27 Preparation of (-) - cis -4- [2-Amino-6- (cyclopropylmethylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol. A solution of 00 g (6.50 mmol) was dissolved in 20 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (Aldrich). The solution was cooled to -10 ° C and stirred at 2.28 L

A9 mL, 24.0 mmol of phosphoryl chloride was added. After 3 minutes, add 80 ml of cold water and extract with 3 x 80 ml of chloroform. The aqueous phase was diluted with 400 mL of ethanol and adjusted to pH 6 with saturated aqueous sodium hydroxide. The precipitated inorganic salts are filtered off. The filtrate was further diluted with ethanol to a volume of 1 liter and the pH adjusted to 8 by addition of additional sodium hydroxide. The resulting precipitate was filtered off and dried, yielding 4.0% (±) -cis -4- [2-amino-6- (cyclopropylmethylamino) -9H-purin-9-yl] 2-cyclopentene in 62% yield. l-methanol-5'-monophosphate was obtained in the form of a white powder (quantification by UV absorption); HPLC analysis as described in Example 17 showed one peak. This racemic 5'-monophosphate is dissolved in 200 ml of water and 5000 IU of Crotalus atrox 5'-nucleotidase (EC 3.1.3.5, Sigma) is added. The mixture was incubated at 37 ° C for 10 days and then analyzed by HPLC as in Example 17. The assay showed that 50% of the starting nucleotide was dephosphorylated to the nucleoside. These were separated on a DEAE Sephadex A25 (Pharmacia) column, previously equilibrated with 5 x 14 cm, 50 mM ammonium bicarbonate. The title compound was eluted with 2 L of 50 mM ammonium bicarbonate. The eluate is evaporated, the white powder obtained is dissolved in methanol, adsorbed on silica gel and applied to a silica gel column. The title compound was eluted with 1: 9 methanol: chloroform to give a colorless glass. Concentration of the acetonitrile solution of the product gave a white solid foam which was dried at 40 psi of phosphorus pentoxide. This gave 649 mg (72%) of the racemate. The product had 1 H-NMR (DMSO-d ₆ ) and mass spectral data identical to the racemate (title compound of Example 7). [a] D -48.0 ', [a] ² 3 _{4 6} ° -97.1 °, [a] ² ₃ 6 ₅ ° -149 °, (c = 0.14, methanol).

Analysis results for C | ₅ H ₂₀ N ₆ O 0.10 CH ₃ CN:

Found: C, 59.96; H, 6.72; N, 28.06; Found: C, 59.93; H, 6.76; N, 28.03.

The Sephadex column was further eluted with 2 L of 100 mM ammonium bicarbonate followed by 2 L of 20 mM ammonium bicarbonate to give 5'-monophosphate (see Example 22) which was 5 '. -stable against nucleotidase.

Example 22 (+) - Cis-4- [2-Amino-6- (cyclopmpylmethylamino) 9H-purin-9-yl] -2-cyclopentene-1-methanol

Fractions containing the nucleotide eluted from the Sephadex column described in Example 21 were pooled and 4800 IU of calf intestinal alkaline phosphatase (EC 3.1.3.1, Boehringer Mannheim) was added. The solution was incubated at 25 ° C for 18 hours and then subjected to HPLC analysis for total dephosphorylation of the nucleotide. The solution was evaporated to dryness and the resulting solid was extracted with 100 ml of ethanol under reflux. Ethanol soluble materials were adsorbed onto silica gel and applied to a silica gel column. The title compound was eluted from the column using a 1: 9 mixture of methanol and chloroform to give a colorless glass. Concentration of the acetonitrile solution gave a white solid foam which was dried at 40 psi of phosphorus pentoxidone. This gave 659 mg (73%) of the racemate. The product Ή NMR _(DMSO-d6) and mass spectrum identical with those of the racemate (title compound of Example 7). [a] D +47.0 ', [a] ² ₄ &+93.0', [a] ² ₃ 6 ₅ ° +141.3 '(c = 0.11. MeOH).

Analysis results for C | According to the formula ₅ H ₂₀ N ₆ O O 1 CH ₃ CN:

Found: C, 59.95; H, 6.72; N, 28.06; Found: C, 59.92; H, 6.80; N, 27.96.

Example 23 (1S, 4R) -4-Amino-2-cyclopentene-1-methanol-dibenzoyl-D-tartrate (±) -cis-4-Acetamido-cyclopent-2-enylmethyl acetate is hydrolyzed with barium hydroxide. as described in Example 1. The resulting syrup ((±) -4-amino-2-cyclopenten-1-methanol) acetic acid salt) was converted to the free base by stirring with excess Amberlite IRA-400 (OH ') resin in water. The resin was filtered off, washed with water, the combined filtrate and washings were evaporated and the resulting pale yellow syrup dried in portions by evaporation with added ethanol. 2.26 g (20.0 mmol) of the amine thus obtained and 3.62 g (10.0 mmol) of dibenzoyl-D-tartaric acid (Aldrich, 99%) are dissolved in 35 ml of hot absolute ethanol. To the solution is added boiling acetonitrile (about 150 mL) until the cloud point is reached and the solution is allowed to cool slowly to room temperature. The white needles formed are recrystallized three times from the same solvent combination. This gave 1.07 g (37%) of the title compound as white plates. The product has a melting point of 160-162 ° C. [<x] D +66.9 ', [a] ² 3 _{4 6} +165 °, [α] ² 6 _{3 5} +325 DEG (c = 0.28, methanol). X-ray crystallography of this salt enabled the absolute configuration of the cation to be recorded in the knowledge of the known dianion configuration of D-dibenzoyl tartaric acid. This salt crystallized in the space group C2 with a C _{6 H] 2} NO cation and L / 2C | _{g with} H, ₄ O ₈ dianion as an asymmetric unit.

Calcd for C ₆ H || NO I / 2 | basis (C ₈ H ₈ O _I4) wherein:

Found: C, 61.63; H, 6.21; N, 4.79; Found: C, 61.56; H, 6.24; N, 4.74.

Example 24 (1R, 4S) -4-Amino-2-cyclopentene-1-methanol-dibenzoyl-L-tartrate

The title salt was prepared exactly as described in Example 23 and crystallized except that dibenzoyl L-tartaric acid was used. Recrystallization from ethanol / acetonitrile (3x) gave the title compound (1.00 g, 34%) as white plates. 160-162 ° C; [α] D -68.2 °, [α] ₄ ² 3 ° ₆ -169 ', [α] ₃ ² 6 ^θ 5 -333 °, (c = 0.24, methanol).

Analysis results for C ₆ H ₁₁ NO 2/2 (C ₁₈ H ₄ O ₈ ):

Found: C, 61.63; H, 6.21; N, 4.79; Found: C, 61.59; H, 6.2! N, 4.76.

Example 25 (+) - Cis-N- [4-chloro-5-formamido-6 - [(4-hydroxymethyl) -2-cyclopenten-1-yl] amino] -2-pyrimidinyl] acetamide

N- (5-amino-4,6-dichloropyrimidin-2-yl) -acetamide (J. Org. Chem. 40, 3141 (1975)) was formylated so that 0.75 g, 3.4 mmol, above To a solution of compound (20) in acetic anhydride (20 ml) was added 96% formic acid (20 ml) and the resulting solution was stirred at 25 ° C for 1 hour and concentrated to give 0.77 g of N- (4,6-dichloro-5) in 91% yield. Formamide (2-pyrimidinyl) -acetamide was obtained as a tan powder and its structure was confirmed by 1 H-NMR and mass spectral data 840 mg (3.37 mmol) of a tan powder, 940 mg, 8.2 mmol (±) -. Cis-4-amino-2-cyclopentene-1-methanol and 0.80 g, 8.0 mmol of triethylamine in 50 ml of ethanol were kept in an oil bath at 70-80 ° C under nitrogen for 50 minutes and evaporated to give a dark oil. The title compound was eluted with 5% methanol-chloroform to give 840 mg of a peach solid foam. Recrystallization gave 575 mg (52%) of a white granular product, m.p. 189-193 ° C.

1 H-NMR (DMSO-d 6: δ 10.23 (broad, 1.0, NtfAc),

9.3 (broad, 1.0, N77CHO), 8.15 and 7.90 (both s, total 1.0, HC = O from two conformers, peaks merging at 60 ° C), 7.42 and 7 , 22 (both d, J = 8.3, total 1.0, CH-N / 7 from two conformers, peaks merged at 60 ° C), 5.9 and 5.7 (both m, 2.0, CH = CH), 5.05 (m, 1, CH-N),

4.73 (m, 1, OH), 3.39 (m, 2, C ₁₂ OH); 2.72 (m, 1, CH), 2.40 (m, 1, 1/2 CH ₂ ), 1.36 (m, 1, 1/2 CH ₂ ). Analysis results for C | ₃ Hi ₆ N ₅ O ₃ Cl:

Found: C, 47.93; H, 4.95;

N, 21.50; Cl, 10.88;

Found: C, 47.99; H, 4.96;

N, 21.42; Cl, 10.96.

Example 26 (±) -Cis-4-1,2-Amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol 0.91 g of the title compound of Example 25 is obtained. 2.79 mmol was dissolved in 1 mL of dry DMF. Triethyl orthoformate (10 mL) and ethanesulfonic acid (0.29 mL, 3.4 mmol) were added and the solution was heated at 65 ° C for 24 hours. The solution was then evaporated to a syrup, dissolved in 15 mL of 1 hydrogen chloride and stirred for 3 hours. The pH of the mixture was adjusted to 7 with 5N sodium hydroxide and the resulting mixture (oil formed) was extracted with 3 x 100 mL of a 1: 3 mixture of isopropanol: chloroform. The combined organic layers were dried over magnesium sulfate and evaporated. 0.93 g of a red glassy material is obtained. The resulting glassy material was dissolved in methanol (20 mL) and kept in a Parr bomb at 70 ° C for 18 hours with cyclopropylamine (2 mL). The resulting solution was evaporated and the resulting dark glassy material was adsorbed onto silica gel. Elution was carried out with 7% methanol / ethyl acetate. This gave 148 mg (19%) of the title compound as a white powder which was triturated with acetonitrile. 1 H NMR (DMSO-d ₆ ) of the product obtained is identical to that of the title compound of Example 5.

The product of Example 23 is converted to the product of Examples 17 or 21 in the same manner (using N-methyl-N-cyclopropylamine in the final step).

Example 27 (+) - (1R, 4S) -cis-N- [4-Chloro-5-formamido-6 - ([4- (hydroxymethyl) -2-cyclopenten-1-yl] amino) -2 -pyrimidinyl acetamide

2.76 g (9.02 mmol) of (1S, 4R) -4-amino-2-cyclopentene-1-methanol-dibenzoyl-D-tartrate prepared in Example 23 are dissolved in 20 ml of water and 65 ml of the hydroxyl form are obtained. Amberlite LA-400 was applied to a column packed with anion exchange resin. Wash the column with water. The alkaline fractions were combined and evaporated to an oil, the oil was evaporated in absolute ethanol and dried at 66.7 Pa. 1.2 g of (1S, 4R) -4-amino-2-cyclopenten-1-methanol are obtained in the form of a pale yellow oil which darkens rapidly in air. Use immediately. The oil was dissolved in ethanol (5 mL) and N- (4,6-dichloro-5-formamido-2-pyrimidinyl) acetamide (2.07 g, 8.31 mmol) prepared in Example 25 and 2.50 g (24%) were added. To a solution containing 8 mmol triethylamine. The resulting dark solution was heated under a nitrogen atmosphere in an oil bath at 75-80 ° C for 50 minutes. The solution was evaporated to a syrup and applied to a silica gel column.

The title compound was eluted with 3-5% methanol-chloroform. This gave 1.59 g (54%) of a pale yellow solid foam with HNMR identical to that of the crystallized sample. Such a sample was crystallized from ethanol to give white granules having a melting point of 194-195 ° C, 1 HNMR (DMSO-d 6) identical to that of the title compound of Example 25; [α] p + 2.7 °, [α] ₅ ² 7 ° ₈ + 3.6 °, [α] ₅ ² 4 ^θ 6 + 2.9 ′, [α] ₄ ^2θ 6-2.5 °, [α] ₃ ² θ ₅ −41.2 ′.

Example 28 (-) - (1S, 4R) -Cis (2-Amino-6-chloro-9H-purin-9-yl) -2-cyclopenten-7-methanol

A solution of the title compound of Example 27 (1.15 g, 3.53 mmol) in diethoxymethyl acetate (45 mL) was heated at reflux under nitrogen for 3.5 hours. The resulting pale yellow solution was concentrated to a yellow syrup at 66.7 Pa. The syrup was stirred with 50 ml of 1N hydrochloric acid for 1 hour. The solution was neutralized with sodium bicarbonate. and evaporate to dryness. The residual solid was extracted with methanol and the methanol soluble material was applied to a silica gel column. The column was eluted from the column with 10% methanol-ethyl acetate. Yield: 730 mg (78%) of a pale yellow solid foam. 1 H NMR (DMSO-d ₆ ) identical to racemate (title compound of Example 4);

(?) -114.9 ° (c = 0.26, MeOH).

Example 29 (-) - (1S, 4R) -cis-4- [2-Amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol. The title compound (560 mg, 2.11 mmol) in methanol (12 ml) was treated with cyclopropylamine (2.4 ml) in a Parr bomb at 78 ° C for 17 hours. The solvent was evaporated and the residue was chromatographed on silica gel. The title compound was eluted with 5-7% methanol in ethyl acetate. 367 mg (59%) of a colorless solid foam were obtained. The product 'HNMR (DMSO-dJ data is identical to that of Example 17; [α] D -59.0' (c = 0.28, MeOH), confirming the absolute configuration of the title compound of Example 17.

Example 30 (1S, 4R) -4-Amino-2-cyclopentene-1-methanol-dibenzoyl-D-tartrate

44.0 g, 0.400 moles of 2-azabicyclo [2.2.1] hept-5-en-3-one [Daluge and Vince, J. Org. Chem. 43, 2311 (1978) and U.S. Patent 4,268,672] are stirred in 0.5 L of 2N methanolic hydrogen chloride at 25 ° C for 1.5 hours. The volatiles were evaporated to give (±) -cis-methyl-4-amino-2-cyclopentene-1-carboxylate hydrochloride (71.1 g) as an off-white powder. A sample of the resulting powder was triturated with diethyl ether to give a white powder, m.p. 92.5-95 ° C. [J. Org. Chem. 46, 3271 (1981), m.p. 82-83 'C);

1 H-NMR (DMSO-d ₆ ): δ 8.25 (bs, 3, NH, ⁺ ), 6.1 and 5.9 (both m, 2, CH = CH), 3.64 (s) overlap

3.75-3.6 (m, total 4, OMe and CH), 2.65-2.45 and 2.05-1.85 (both m, 2, _CH2).

Analysis C7HnNO _2HCl formula:

Found: C, 47.33; H, 6.81;

N, 7.89; Cl, 19.96;

Found: C, 47.41; H, 6.84;

N, 7.85; Cl, 19.89.

(±) -cis-methyl-4-amino-2-cyclopentene-1-carboxylate hydrochloride (17.7 g, 0.100 mol) and diisobutylaluminum hydride (0.500 mol) in hexane (1M) in 200 ml hexane reflux for 6 hours. The resulting solution was cooled and 10 mL of 1M aqueous ammonium chloride was added followed by 200 mL of methanol. The mixture was refluxed for 30 minutes and magnesium sulfate (10 g) was added. The solids were filtered and washed with additional methanol. The solution obtained by combining the filtrate and the washing liquid was evaporated to give a

15.5 g of a dark oil are obtained; 1 H-NMR (DMSO-d ₆ ) of the oil is identical to that of (±) -4-amino-2-cyclopenten-1-methanol prepared in Example 23. Such a sample was purified by chromatography on silica gel (ElOH: CHCl ₃ : NH ₄ OH / 10: 90: 1) and then crystallized with dibenzoyl-D-tartaric acid (title compound of Example 23).

Example 31 (-) - (1S, 4R) -cis- (2-Amino-6-chloro-9H-purin-9-yl) -2-cyclopentene-methanol A (±) -cis-4- ( 2,6-Diamino-9H-purin-9-yl) -2-cyclopenten-1-methanol 1.50 g (5.65 mmol) (±) - (1α, 4α) -4- (2-amino-6- A mixture of chloro-9-purin-9-yl) -2-cyclopenten-1-methanol and 1.35 ml of ammonia was stirred in a Parr bomb for 48 hours at 70 ° C. The crude product obtained by evaporation of the mixture was purified on a silica gel column eluting with chloroform containing 107c methanol. 1.27 g (91%) of product are obtained which is crystallized from acetonitrile / methanol to give white granules, m.p. 145-147 ° C. 1 H-NMR (Me ₂ SO-d ₆ ): δ 7.59 (s, 1, purine H-8), 6.60 (bs, 2, NH ₂ ), 6.09 and 5.85 (both m , 2,

CH = CH), 5.71 (br s, 2, NH ₂ ), 5.36 (m, 1, CHN), 4.71 (t, J = 5.4, 1, OH), 3.50- 3.35 (m, 2,

CH ₂ -O), 2.85 (m, 1, Η-Γ), 2.60 and 1.57 (both m, 2, CH ₂ ).

Analysis for C | basis _I4 H N O ₆ Calculated:% C = 53.65, H% = 5.73, N% = 34.13; Found: C, 53.79; H, 5.79; N, 34.00.

(1R, 4S) -9- (4-Hydroxymethyl-2-cyclopentenyl) -guanine

1.26 g (5.12 mmol) of (±) -cis-4- (2,6-Diamino-9H-purin-9-yl) -2-cyclopenten-1-methanol (514 mL, 0.02 mol / l) Dissolve in pH 7.4 potassium phosphate buffer with 16.4 x 10 4 units of bovine intestinal adenosine deaminase (adenosine amino hydrolase EC 3.5.4.4, Boehringer Mannheim). After 6.5 hours at 25 ° C, an equal volume of methanol was added. The solution was evaporated to dryness and the resulting solid was extracted with hot methanol (4 x 100 mL). The contents of the methanolic extract were adsorbed onto silica gel and applied to a silica gel column packed with 10% methanol in chloroform. Elution with 400 ml of 10% methanol in chloroform gave 0.66 g of unreacted starting material. Crystallization from methanol / acetonitrile gave 0.38 g (+) - cis-4- (2,6-diamino-9 H -purin-9-yl) -2-cyclopenten-1-methanol as granules, m.p. 178 C. The 'HNMR (Me ₂ SO-d ₆ )' data is identical to that of the starting material. [α] D +85.1 '(c = 0.19, methanol). The column was then eluted with 300 ml of chloroform containing 20-25% methanol to give 0.62 g of a white powder upon evaporation of the eluate. This powder was recrystallized from water to give 0.56 g (84%) of the title compound as white needles. The product has a melting point of> 320 ”C.

HU 211 577 A9

1 H-NMR (Me ₂ SO-d ₆ ): δ 10.54 (bs, 1, NHC = 0),

7.59 (s, 1, H-8), 6.43 (broad s, 2, NH ₂ ), 6.1 and 5.8 (both m, 2, CH = CH), 5.3 (m, 1, CH-N), 4.73 (t, J = 5.3, 1, OH), 3.43 (t, J = 5.6, 2, CH ₂ -O),

2.8-2.6 (m, I, H-4 '), 2.65-2.55 and 1.60-1.50 (both m, 2, CH ₂ );

[α] D -96.3 ° (c = 0.11 0.01 n NaOH: MeOH / 2: 3;

[α] D = -63.9 °, (c = 0.16, MeOH).

Analysis results for Οι, Η ^^ Ο ^ Ο ,? H ₂ O:

Found: C, 50.84; H, 5.59; N, 26.95; Found: C, 50.90; H, 5.63; N, 26.83.

C.

(1S, 4R) - [4- (2-Amino-1,6-dihydro-6-oxo-9H-purin-9-yl) -2-cyclopenten-1-yl] methyl acetate

(1R, 4S) -9- (4-Hydroxymethyl-2-cyclopentenyl) -guanine (150 mg, 0.607 mmol), freshly distilled acetic anhydride (65 mg, 0.161 mmol), 4-dimethylaminopyridine (3 mg) and dry dimethyl (5 ml). formamide mixture was stirred under a nitrogen atmosphere for 2 days. The solvent was evaporated and the residue was applied to a silica gel column. The title compound was eluted with chloroform containing 10% methanol to give a waxy white solid. This material was crystallized from ethanol to give 123 mg (70%) of a white powder, m.p. 274-279 ° C. 1 H-NMR (DMSO-d ₆ ): δ 10.55 (bs, 1, NHCO),

7.55 (s, 1, purine H-8), 6.42 (broad s, 2, NH ₂ ), 6.06 and 5.94 (both m, 2, CH = CH), 5.34 (m , 1, CH-N), 4.07 (d, J = 6.0.2, CH ₂ O), 3.05 (m, 1, CH),

2.6 and 1.55 (both m, 2, _CH2), 1.98 (s, 3, COCHj).

Analysis for C | basis 3H _IS N ₅ O ₃ Calculated: C% = 53.97, H% = 5.23, N% = 24.21;

Found: C, 53.85; H, 5.25; N, 24.12.

D.

(-) - (1S, 4R) -Cis- (2-Amino-6-chloro-9H-purin-9-yl) -2-cyclopentene-1-methanol mg, 0.17 mmol (1S, 4R) - [4- (2-Amino-1,6-dihydro-6-oxo-9H-purin-9-yl) -2-cyclopenten-1-yl] methyl acetate, 2 mL of phosphoryl chloride and 38 μΙΙ, Ν-diethyl- the aniline mixture was refluxed for 3 minutes. The volatiles were evaporated and 5 ml of ice water was added to the residual oil. The solution was neutralized and extracted with methylene chloride (3 x 20 mL). The methylene chloride phases are dried over magnesium sulfate and evaporated. The crude product obtained is chromatographed on silica gel, eluting with 5% methanol in chloroform. After recrystallization from ethyl acetate, (1S, 4R) - [4- (2-amino-6-chloro-9H-purin-9-yl) -2-cyclopenten-1-yl] methyl acetate is obtained as pale yellow crystals. m.p. 124-127 ° C.

1 H-NMR (DMSO-d ₆ ): δ 8.01 (s, 1, purine H-8), 6.90 (s, 2, NH ₂ ), 6.11 and 5.99 (both m, 2 , CH = CH),

5.46 (m, 1, CH-N), 4.06 (d, J = 6.2, 2, CH ₂ O), 3.1 (m, 1, CH-N), 2.7 and 1 , 65 (both m, 2, CH ₂ ),

1.98 (s, 3, CH, CO).

Deacetylation in ammonia-methanol gave the title compound of Example 28.

Example 32 [Cis-4- (2-Amino-6- (cyclopropylamino) -9H-purin9-yl) -2-cyclopenten-1-yl] methyl-R-2,3-bis (hexadecanoyloxy) ) propyl hydrogen phosphate

A solution of La-dipalmitoylphosphatidylcholine (Sigma) (150 mg, 0.2 mmol) in chloroform (6 ml) was treated with (+) - cis-4- (2-amino-6- (cyclopropylamino) 9H, 300 mg, 1.03 mmol). -purin-9-yl) -2-cyclopentene-1-methanol, 1.0 mg 185 units / mg Streptomyces-derived phospholipase Dt (Sigma), type VII, and 1.5 ml of pH 4.5 buffer (250 mM CaCl ₂ , 200 mM NaOAc, 0.1 N hydrochloric acid adjusted to pH 4.5). The resulting biphasic mixture was stirred at 45 ° C (oil bath) for 1 hour. The layers were separated and the aqueous layer was extracted with chloroform (3 x 6 mL). The combined organic layers were washed with 1 N hydrochloric acid, dried and evaporated. Such a sample was purified by eluting from two columns of silica gel eluting with 12% methanol in chloroform to give 120 mg (47%) of the title compound. This material solidified using a mixture of ethyl acetate and acetonitrile to form a pale yellow powder. 155-157 ° C.

1 H-NMR (CD 3 CD-CDCl 3): δ 7.78 (s, overlapping solvent, purine H-8), 6.12 and 5.88 (m, 2, HC = CH), 5.53 (m, 1 , CHN cyclopentene), 5.22 (m, 1, CO ₂ CH), 4.37 (dd, J = 3, 12; 1, 0.5 POCtf ₂ glycerol), 4.12 (m, 1.0, 5 POC ( ₂ glycerol), 3.42 (m, 4, OCH ₂ glycerol, OCH ₂ ), 3.11 (broad m, 1, CH), 2.90 (m, 1, NCH),

2.78 (m, 1, 0.5 CH ₂ cyclopentene), 2.27 (m, 4, 2 CH ₂ CO ₂ ), 1.70 (m, 1, 0.5 CH ₂ cyclopentane), 1.56 ( br m, 4, 2C // ₂ CH ₂ CO _2), 1.27 (br m, 38, 24 CH _2), 0.88 (m, 6, 2CH _3), 0.83 (m, 2, CH ₂ cyclopropyl), 0.60 (m, 2, CH ₂ cyclopropyl).

Calcd for C 4 H _{9 g5} N ₆ O ₈ P-2.4 H ₂ O wherein:

Calculated: C, 61.28; H, 9.42.

N, 8.75; P, 3.22; Found: C, 60.97; H, 9.12;

N, 8.78; P, 2.96.

Example 33 [Cis-4- (2-Amino-6- (cyclopropylamino) -9H-purin9-yl) -2-cyclopenten-1-yl] -ethyl-R-2,3-bis (hexanoyloxy) -propyl -hidmgén phosphate

A solution of L-α-dicaproyl phosphatidylcholine (Sigma) (300 mg, 0.66 mmol) in chloroform (15 mL) was treated with 378 mg

1.32 mmol (±) -cis-4 - [(2-amino) -6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol, 1.04 mg, 185 units / mg specific activity phospholipase VII from Streptomyces type VII (Sigma) and pH 4.5 =

Buffer 4.5 (250 mM CaCl ₂ and 200 mM NaOAc, adjusted to pH 4.5 with hydrogen chloride) and 3 ml chloroform was added. The resulting biphasic mixture was stirred at 45 ° C (oil bath) for 4 hours. Thereafter, the phases are separated 15

The organic layer was washed with 2 x 4 mL of IN hydrochloric acid. The combined aqueous layers were washed with chloroform (10 mL). The combined organic layers were dried over magnesium sulfate and evaporated. The residue was applied to a silica gel column, and the title compound was eluted from the column with 16% methanol-chloroform, and the eluate was evaporated to give a fine yellow powder. This material was dissolved in ethanol (3x50 mL) and evaporated, then dried under high vacuum to give 103 mg (21%) of a pale yellow powder, m.p. 182-185 ° C.

1 H-NMR (DMSO-d ₆ ): δ 7.61 (s, 1, purine H 8), 7.22 (broad s, 1, NH), 6.09 (m, 1.0.5 CH = CH) , 5.89 (m, overlapping broad at s 5.83, 3, 0.5 CH = CH, NH ₂ ),

5.41 (br m, 1, CHN), 5.09 (br m, 1, CO ₂ CH), 4.30 (dd, J = 2.7, 12; 1, 0.5 POCW ₂ , glycerol) , 4.08 (m, 1, 0.5 POCH ₂ , glycerol), 3.80 (wide m, overlapping wide m at 3.75, 4, OCH ₂ glycerol, OCH ₂ ), 3.02 (wide m , 2, CH, NCH cyclopropyl), 2.65 (m, 1.0.5 CH ₂ , cyclopentene), 2.23 (+, J = 7.5, 4, 2 CH ₂ CO ₂ ), 1.48 (br m, 5, 2 C7 / _{2 CH2 CO2,} 0.5 _CH2 cyclopentene), 1.23 [br m, 8, 2 _{(CH2) 2],} 0.84 (m, 6, 2CH ₃ ), 0.67 and 0.58 (m, 4, 2 CH ₂ cyclopropyl).

Calcd for C29H ₄₅ N ₆ O 3.9 _g P-H ₂ O, 0.2 CHC1 ₃ O, EtOH O5 Calculated: C% = 48.00, H% = 7.33;

N, 11.46; Cl, 2.9; Found: C, 48.65; H, 6.61;

N, 10.81; Cl, 2.5.

The procedure of the previous example is described by Satoshi Shuto et al.

(Tetrahedron Letters, 28, (2) 199-202 (1987)).

The Example

Tablet preparations

The following formulations A, B and C are prepared by wet granulating the ingredients with povidone solution, then adding magnesium stearate and pressing.

The Composition

mg / tablet (a) Active substance 250 250 (b) Lactose Β. P. 210 26 (c) Povidon Β. P. 15 9 (d) Sodium starch glycolate 20 12 (e) Magnesium stearate 5 500 3 300

Formulation B mg / tablet

(a) Active substance 250 250 (b) Lactose Β. P. 150 (c) Avicel PH 101 60 26 (d) Povidon Β. P. 15 9 (e) Sodium starch glycolate 20 12 (f) Magnesium stearate 5 500 3 300

C Preparation

agent mg / tabletla 100 Lactose 200 Starch 50 povidone 5 Magnesium stearate 4 359

The following formulations D and E are prepared by direct compression of the mixed components. Lactose used in formulation E is a direct compression type (Dairy Crest - "Zeparox").

D Preparation

agent Pregelatinised starch NF15 mg / tablet 250 150 400 E Preparation mg / tablet agent 250 Lactose 150 Avicel 100 500

Preparation F (controlled release)

The formulation is prepared by wet granulation of the following ingredients with povidone solution followed by extrusion with magnesium stearate.

mg / tablet (a) Active ingredient 500 (b) Hydroxypropylmethylcellulose (Methocel K4M Premium) 112 (c) Lactose B.P. 53 (d) Povidon Β. P. 28 (e) Magnesium stearate 7

700

The release of the active ingredient takes about 6-8 hours and is complete after 12 hours.

Example B

Preparation of capsules

The preparation

The capsule composition is prepared by mixing the ingredients of Preparation D of Example A above and filling them in two-piece hard gelatine capsules. Preparation B below was prepared in a similar manner.

Preparation B mg / capsule (a) Active ingredient 250 (b) Lactose Β. P. 143 (c) Sodium starch glycolate 25 (d) Magnesium stearate 2

420

Formulation C mg / capsule (a) Active ingredient 250 (b) Macrogol 4000 Β. P. 350

60o

Capsules of Formulation C are prepared by melting Macrogol 4000 B.P., dispersing the active ingredient in the melt, and filling the melt into two-piece hard gelatin capsules.

Formulation D mg / capsule

Active substance 50

Lecithin 100

Peanut oil 100

450

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

This preparation (controlled release capsule)

The following capsules, which provide controlled release of the active ingredient, are prepared by extruding components a, b and c using an extruder, forming the extrudate into spheres and drying. The dried pellets are then coated with release membrane (d) and filled into two-piece hard gelatine capsules.

mg / capsule (a) Active ingredient 250 (b) Microcrystalline cellulose 125 (c) Lactose Β. P. 125 (d) Ethyl cellulose 13

5Ϊ3

Example C

Injectable preparations

The preparation

Active ingredient 0.200 g

0.1 M hydrochloric acid solution or 0.1 M sodium hydroxide solution, pH 4.0 to 7.0 Sterile water made up to 10 ml

The active ingredient is dissolved in most of the water at 35-40 ° C, and the pH of the solution is adjusted to 4.0 to 7.0 using hydrochloric acid or sodium hydroxide as needed. The mixture was then filled with water to the desired volume and filtered through sterile micropone filters into sterile 10 ml amber glass vials (type 1), sealed and sealed.

Preparation B.

Active ingredient 0.125 g

Sterile, pyrogen-free pH 7 phosphate buffer supplemented to 25 ml

Example D

Intramuscular injection

Active ingredient 0.20 g

Benzyl alcohol 0.10 g

Glycofurol 75 1.45 g

Water for injections to make up to 3.00 ml The active substance is dissolved in glycofurol. Benzyl alcohol is then added and dissolved in the solution, and the volume is adjusted to 3 ml with water. The mixture was then filtered through a sterile micropore filter and sealed in sterile 3 ml amber glass vials (type 1).

Example E Syrup

Active ingredient 0.25 g

Sorbitol solution 1.50 g

Glycerin 2.00 g

Sodium benzoate 0.005 g

Peach aroma 17.42.3169 0.0125 ml

Purified water to make up to 5.00 ml

The active ingredient is dissolved in a mixture of glycerol and purified water. An aqueous solution of sodium benzoate is added to the above solution, followed by the addition of the sorbitol solution and finally the aroma. The mixture was made up to volume with water and mixed well.

F Example

Cone mg / Cone

Active ingredient (631 m) * 250

Hard Fat, BP (Witepsol H15 - Dynamit Nobel) 1770

2020

1/5 of Witepsol H15 is melted in a vapor jacketed vessel at a temperature of up to 45 ° C. The active ingredient is sieved through a 200 μιτι sieve and mixed with the molten stock, with Silverson fitted with a cutting head, and mixing is continued until a smooth dispersion is obtained. While maintaining the temperature of the mixture at 45 ° C, the remaining Witepsol H15 is added to the suspension and stirred until homogeneous. The whole suspension was passed through a 250 μιη stainless steel sieve with constant stirring and allowed to cool to 40 ° C. When the suspension reaches 38-40 ° C, it is filled into a suitable 2 ml plastic mold per 2.02 g. Allow the suppositories to cool to room temperature.

Example G

Pesszjáriumok mg / pessary Active ingredient (631 m) 250 Dextrose anhydrate 380 potato starch 363 Magnesium stearate 7 1000 The above ingredients are blended directly and by direct pressing of the mixture make pessaries-

us.

* The active ingredient is used as a powder with at least 90% of the particles up to a diameter of 631 m

HU 211 577 A9

Antiviral activity is in dispute

The anli-HIV activity of the compound of Example 5 was assayed in MT ₄ cells by Averett DR [J. Virol. Methods. 23: 263-276 (1989). From an average of thirteen determinations, the IC _{50 was found} to be 21 ± 12 pmol / l. The compound of Example 17 has an IC ₅₀

3.6 pmol / l (mean of 2 determinations).

Claims (20)

A compound of formula I wherein R ³ is hydrogen or C 1-6 alkyl; R ⁶ is C 3 -C 8 cycloalkyl, and R ⁷ is hydrogen, or straight or branched C 1 -C 6 alkyl, and a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof. A compound of formula (I), ester or salt thereof according to claim 1, wherein R ³ is hydrogen, R ⁶ is C 3 -C 6 cycloalkyl, and R ⁷ is methyl or hydrogen. The compound of claim 2, wherein R ⁶ is cyclopropyl. A compound of formula (I) according to claim 1, which is (-) - cis -4- [2-amino-6- (cyclo] opropylamino) -9H-purine-9-yl] -2-cyclopentene -1-methanol, (-) - cis-4- [2-amino-6- (cyclopropylmethylamino) 9H-purin-9-yl] -2-cyclopentene-1-methanol or their (±) -cis racemic or partially resolved mixtures thereof with enantiomers. 5. (±) -cis-4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopenten-1-methanol. 6. (-) - cis -4- [2-Amino-6- (cyclopropylamino) -9-purin-9-yl] -2-cyclopenten-1-methanol. A pharmaceutically acceptable salt of the compound of claim 5 or 6. A pharmaceutically acceptable ester of a compound according to claim 5 or 6. A compound of formula (I) according to claim 1, wherein the pharmaceutically acceptable ester is a mono-, di- or triphosphate ester, or a pharmaceutically acceptable salt thereof. A compound of formula (I) according to claim 1, wherein the pharmaceutically acceptable ester is L-valinate or a salt thereof. A compound according to claim 3, an ester or a salt thereof. wherein the pharmaceutically acceptable ester is a mono-, di- or triphosphate ester, or a pharmaceutically acceptable salt thereof. A compound of formula I wherein R ⁷ is hydrogen, R ⁶ is cyclopropyl, and R ³ is hydrogen, or a pharmaceutically acceptable salt thereof. A compound of formula (I) wherein R ⁷ is methyl, R ⁶ is cyclopropyl and R ³ is hydrogen, or a pharmaceutically acceptable salt thereof. A tablet or capsule containing the compound of claim 12. A tablet or capsule containing the compound of claim 13. 16. (±) -cis-4- [2-amino-6- (cyclopropylmethylamino) -9 H -purin-9-yl] -2-cyclopenten-1-methanol. 17. (-) - cis -4- [2-Amino-6- (cyclopropylmethylamino) -9 H -purin-9-yl] -2-cyclopenten-1-methanol. 18. Pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier. A composition according to claim 18, wherein the compound of formula (I) is: (-) - cis -4- [2-amino-6- (cyclopropylamino) -9 N -purin9-yl] -2-cyclopenten-1-methanol, or (-) - cis -4- [2-amino -6- (cyclopropylmethylamino) 9H-purin-9-yl] -2-cyclopentene-1-methanol, or a racemic or partially resolved mixture thereof with its (±) -cis enantiomers. 20. A tablet or capsule containing 50-700 mg of a compound according to claim 5 or 6, or a pharmaceutically acceptable salt or pharmaceutically acceptable ester thereof.