NO166184B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE N9-CYCLOPENTYL-SUBSTITUTED ADENIN DERIVATIVES. - Google Patents

Description

The present invention relates to the production of new therapeutically active N9-cyclopentyl-substituted adenine derivatives. The new compounds are effective adenine receptor agonists.

The compounds produced according to the invention are effective as adenosine, especially adenosine-2 (A-2), receptor ligands useful in mammals as adenosine receptor agonists, especially as adenosine-2 (A-2) receptor agonists.

Said advantageous properties make the compounds produced according to the invention useful for the treatment of conditions in mammals which show a response to selective adenosine receptor stimulation, especially adenosine-2 receptor stimulation, e.g. cardiovascular conditions, such as hypertension, thrombosis and arteriosclerosis, and also conditions of the central nervous system including psychotic conditions such as schizophrenia, or convulsive conditions such as epilepsy.

The compounds produced according to the invention are structurally related to the natural product aristeromycin, which is described e.g. in J. Org. Chem. 51, 1287-1293 (1986) and the publications to which reference is made and which is described in the literature as a carbocyclic analogue of adenosine.

More specifically, the present invention is directed to the preparation of the compounds of formula 1

wherein R, R 3 and R*5 are independently hydrogen or hydroxy, provided that at least one of R, R<3> and R<5> is hydroxy; R<1> means hydrogen or C5~C7-cycloalkyl substituted with N-pyrrolyl; R<2> means hydrogen, halogen, -SR' where R<*> stands for C3-C4-alkenyl or phenyl-C1-C4-alkyl, or -N(R<9>)R'' where R<9> means hydrogen or C1-C4-alkyl and R'' means phenyl-Ci-C4-alkyl where phenyl is unsubstituted or substituted by halogen, C1-C4- alkoxy, carboxy-C1-C4-alkyl, C1-C6- alkoxycarbonyl-C1 -C4-alkyl, N,N-di-C1-C4-alkyl-carbamoyl-C1-C4-alkyl or carboxy-C1-C4-alkoxy; pyridyl C 1 -C 4 alkyl, naphthyl C 1 -C 4 alkyl, C 5 -C 7 cycloalkyl C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl; or phenyl which is unsubstituted or substituted by C 1 -C 4 alkoxycarbonyl, R<4> means hydroxymethyl provided that R<2> does not mean hydrogen; or R<4> means -CONHR<6> where R<6> means C1-C4-alkyl, C3-C6-cycloalkyl or hydroxy-C1-C4-alkyl; pharmaceutically acceptable ester derivatives thereof in which free hydroxy groups are esterified in the form of a pharmaceutically acceptable ester; and salts thereof.

The invention is also directed to the preparation of the compounds of formula I in which all substituents have the meanings indicated above, except that ^<9> stands exclusively for hydrogen.

A particular embodiment of the invention relates to the preparation of the compounds of formula I indicated above in which R<4> stands for -CONHR<6>, and R, R<1>, R<2>, R3, R5, R6, R<9>, m and Ra have the meanings given above; pharmaceutically acceptable ester derivatives thereof as indicated above; and pharmaceutically acceptable salts thereof.

Another particular embodiment relates to the preparation of the compounds of formula I in which R<4> stands for hydroxymethyl, with the prerequisite for R<2> stated above.

The general definitions used here have the following meaning within the scope of the present invention.

The term "lower" used above and in the following in connection with organic residues or compounds, defines such with up to 4, and advantageously one or two carbon atoms.

Halogen is preferably chlorine, but can also be fluorine, bromine or iodine.

Cycloalkyl preferably stands for 3 to 6 ring-membered cycloalkyl, i.e. C3-C6 cycloalkyl. Cs-Ci-cycloalkyl stands for cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl in the group R<6>.

Cycloalkyl-Ci-C4-alkyl preferably stands for (cyclopentyl or cyclohexyl)-Ci-C4-alkyl, advantageously 1- or 2-(cyclopentyl or cyclohexyl)-ethyl, -propyl or -butyl.

Hydroxy-C1-C4-alkyl preferably stands for 2-, 3- or 4-hydroxy-C2-C4-alkyl, preferably hydroxyethyl.

Pyridyl preferably stands for 2-, 3- or 4-pyridyl, advantageously 2- or 3-pyridyl.

The pharmaceutically acceptable ester derivatives in which one or more free hydroxy groups are esterified in the form of a pharmaceutically acceptable ester are particularly esters which can be converted by solvolysis under physiological conditions to the compounds of formula I containing free hydroxy groups. Preferred as mentioned pharmaceutically acceptable esters are straight chain or branched lower alkanoic acid esters, e.g. acetic acid, isobutyric acid, pivaloic acid esters; lower alkoxy-lower acanic acid esters, e.g. methoxyacetic acid, 3-ethocypropionic acid esters; arylcarboxylic acid esters, e.g. benzoic acid esters, nicotinic acid esters; carbamic acid and N-mono- or N,N-di-lower alkylcarbamic acid esters (carbamates), e.g. N-mono- or N,N-diethylcarbamic acid or N-mono- or N,N-dimethylcarbamic acid esters.

Pharmaceutically acceptable salts are generally acid addition salts, which are preferably of pharmaceutically acceptable inorganic or organic acids, such as strong mineral acids, e.g. hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric, phosphoric or nitric acid; aliphatic or aromatic carboxylic or sulphonic acids, e.g. formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, gluconic acid, citric acid, maleic acid, fumaric acid, pyruvic acid, phenylacetic acid, benzoic acid, 4-aminobenzoic acid, anthraniic acid, 4-hydroxybenzoic acid, salicylic acid, 4-aminosalicylic acid, pamoic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid, cyclohexylsulfamic acid; or ascorbic acid. For compounds containing a free carboxy group, salts are also derived from bases, e.g. alkali metal salts such as sodium salt.

The new compounds produced according to the invention are active in in vitro and in vivo experimental systems according to the state of the art and show indications of adenosine receptor agonist activity in mammals.

The adenosine receptor agonists produced according to the invention are useful in mammals, including humans, for the treatment of disease states in the central nervous system, especially psychoses such as schizophrenia, and cardiovascular diseases, especially hypertension and thrombosis.

The above-mentioned properties can be demonstrated by in vitro and in vivo experiments, preferably using mammals, e.g. rats, dogs, monkeys or isolated organs, tissues and preparations thereof. Said compounds can be used in vitro in the form of solutions, e.g. preferably aqueous solutions, and in vivo either enterally or parenterally, advantageously orally or intravenously, e.g. in gelatin capsules, as starch suspensions or in aqueous solutions. The dose in vitro can vary between 10-3 molar and 10-<9> molar concentrations. The dose in vivo may vary between 0.001 and 25 mg/kg/day, preferably between 0.0025 and 10 mg/kg/day depending on the compound and the method of administration.

Adenosine-2 (A-2) receptor binding properties, indicative of adenosine-2 receptor agonist activity for the compounds prepared according to the invention are determined in vitro by determining their ability to inhibit the specific binding of <3>H-5'-N -ethylcarboxamidoadenosine (<3>H-NECA), e.g. essentially as described by R.F. Bruns et al., Mol. Pharma-col. 529 , 331 (1986 ), in striatum membrane preparations from the corpus striatum of male Sprague-Dawley rats. The concentration of a particular compound required to replace the specific binding of 4 nM <3>H-NECA is determined in the presence of 40 nM cyclopentyadenosine.

Adenosine 1 (A-I) receptor binding properties of the compounds of formula I indicative of adenosine 1 receptor agonist activity are determined, e.g. essentially according to R.F. Bruns et al. in Proe. Nati. Acad. Pollock. U.S.A 77, 5547 (1980 ), by determining their ability to inhibit the specific binding of <3>H-cyclohexyladenosine (<3>H-CHA) in rat iron membrane preparations from male Sprague-Dawley rats The concentration of a particular compound required to displace the specific binding of 1 nM <3>H-CHA is determined.

Selectivity for the adenosine-2 (A2) receptor can be determined by comparing the relative potency of the two adenosine receptor assays.

As an indication of in vivo adenosine receptor agonist activity, the hypotensive activity of the compounds of formula I as well as their effect on heart rate can be measured in normotensive or spontaneously hypertensive rats by intravenous or oral administration.

Typically, the blood pressure-reducing effect in normotensive rats can be determined as follows: Adult male rats weighing 300-400 g are anesthetized using "Inactin" (100 mg/kg, i.p.). A femoral artery and an opposite vein are cannulated for direct blood pressure measurement and i.v. drug administration. The animals are given a 15 minute period for equilibration before examination. Vehicle (1 ml/kg, i.v.) is administered over a period of 30 seconds followed by a 0.3 ml portion of saline administered over a period of 30 seconds. Changes in diastolic blood pressure are recorded using a Beckman polygraph while heart rate is recorded using the blood pressure pulse. The test compound is administered in the same way as the vehicle and a dose-response curve is established. Percentage changes in heart rate and blood pressure are recorded.

The blood pressure lowering effect in the spontaneously hypertensive rat is determined after oral administration. The compounds of formula I which are selective as adenosine-2 receptor agonists effectively lower blood pressure without any significant effect on heart rate.

Antipsychotic activity can be demonstrated e.g. by measuring the inhibition of "one-way conditioned avoidance" or "Sidman avoidance" in the rat, or by measuring the antagonism of the behavioral stimulant effects of apomorphine.

Antithrombotic activity can be demonstrated by measuring the inhibition of collagen-induced platelet aggregation.

Illustrative compounds of formula I show IC5Q values in the adenosine-2 receptor binding assay in the range of 5 x 10-<6 > to 2 x 10~<®>M; the compounds also show hypotensive activity in anesthetized normotensive rats at a dose of 0.0025 to 0.035 mg/kg i.v. and in the spontaneously hypertensive rat at a dose of 3 to 10 mg/kg p.o.

The compound of formula I and the indicated derivatives thereof are prepared according to the invention by using methods which include: a) for compounds of formula I in which R, R<1>, R<2>, R<3>, R<4> and R <5 >has the meaning given under formula I, provided that one of R and R<5> means hydroxy, condensation of a compound of formula III where R<1> and R<2> have the meaning defined under formula I, with a compound of formula IV

wherein R<3> and R<4> have the meaning defined under formula I, in the presence of a strong base and, if necessary, separation of any resulting isomers; or

b) for compounds of formula I where R, R<1>, R<2>, R<3>, R<4> and R5 have the meaning defined under formula I, condensation of a

compound of formula V

wherein X represents a leaving group; R, R<2>, R<3>, R<4> and R^ have the meaning defined under formula I, with a compound of formula Via

where R<1> has the meaning defined under formula I; or

c) for compounds of formula I in which R<2> stands for -SR' or

-N(R<9>)R'', condensation of a compound of formula VII

where R, R<1>, R<3>, R<4> and R<5> have the meaning defined under formula I, and X stands for a leaving group, with either a compound of formula Via where R'* has the meaning defined under formula I, or with a compound of formula VIb or a reactive alkali metal salt derivative thereof wherein R' has the meaning defined under formula I; or with a compound of formula VIc where R'' and R<9> have the meaning defined under formula I; and, if desired, (1) hydrolyzing a resulting compound of formula I, wherein R<2> means -N(R<9>)R<*>' and R'* is C 1 -C 4 alkoxycarbonyl-C 1 -C 1 -alkylphenyl-C 1 -C 1 -alkyl, to obtain another compound of formula I where R<2> means -N(R<9>)R<*>' and R'' is carboxy-C1-C4~ alkylphenyl-C^-C4~alkyl, or (2) reaction of a resulting compound of formula I, where R<2> stands for —N(R9)R' ' and R'' is carboxy-C1-C4-alkyl- phenyl-C₁-C₄-alkyl, with a C₁-C₄-alkanol to obtain another compound of formula I, where R<2> means —N( R₄ )R' ' and R' ' is C₄- C5-Alkoxycarbonyl-C1-C4-alkylphenyl-C1-C4-alkyl, or (3) reacting a resulting compound of formula I wherein R<2> means halogen, with sodium hydrogen sulphide and then with a compound X'-R' , where R<*> is as defined under formula I and X' means halogen, to obtain another compound of formula I where R<2> means —SR', where R' is as defined under formula I;

and, if further required in any of the above-mentioned methods, temporary protection of any interfering reactive groups in the starting materials and then subsequent removal of the protecting groups to obtain a resulting compound of formula I; and, if desired, converting a resulting free compound into a salt or a resulting salt into a free compound or into another salt and, if desired, separating any resulting mixture of isomers or racemates into the individual isomers or racemates, and if necessary, resolution of a racemate in the optical antipodes.

A leaving group in the above processes stands in particular for halogen, for example chlorine, bromine or iodine, aliphatic or aromatically substituted sulphonyloxy, e.g. methylsulfonyloxy or 4-methylphenylsulfonyloxy (tosyloxy), or aliphatically substituted thio, e.g. lower alkylthio such as methylthio.

In starting compounds and intermediates which are converted to the compounds of formula I as described above, functional groups present, such as amino and hydroxy, are optionally protected by means of conventional protecting groups which are common in preparative organic chemistry. Protected amino and hydroxy groups are those that can be converted under mild conditions into free amino and hydroxy groups without destroying the molecular lattice or causing unwanted side reactions to take place.

Well-known protecting groups that fulfill these conditions and their introduction and removal are e.g. described in J.F.W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London, New York 1973, T.W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1984.

For example, a hydroxy group can be protected in the form of esters, e.g. as acyl derivatives such as lower alkanoyl-, ben/.y 1 oxycarbonyl 1 - or lower alkoxycarbonyl esters, or such hydroxy group may be protected in the form of ethers, e.g. such as 2-tetrahydropyranyl, trityl or benzyl ethers.

Hydroxy groups on neighboring carbon atoms can also be protected, e.g. in the form of ketals or acetals, such as isopropylidene or benzylidene derivatives.

In a resulting protected compound of formula I or an intermediate, in which one or more of the functional groups are protected, the protected functional groups, e.g. hydroxy groups, are released in a manner known per se, e.g. by means of solvolysis, especially hydrolysis with acid, or by hydrogenolysis.

The production according to the invention of the compounds of formula I according to method a) which includes opening of an epoxide ring is preferably carried out in a polar solvent such as dimethylformamide and at an elevated temperature, advantageously at a temperature varying from 50 to 125°C. The reactive organometallic derivative, e.g. The lithium, sodium or potassium derivative of the starting material of formula III is preferably prepared in situ by reacting a compound of formula III with a correspondingly strong base such as sodium, potassium or lithium hydride or amide in a polar anhydrous solvent such as dimethylformamide, advantageously at room temperature .

Method a) is preferred for compounds of formula I in which R<2> stands for hydrogen or halogen.

Starting materials of formula III (adenine and derivatives thereof) can be prepared by methods known in the art for the synthesis and derivatization of purines, e.g. as stated in Barton and Ellis, "Comprehensive Organic Chemls-try" Volume 4, pages 499-518.

Starting materials of formula IV are either known in the art or are preferably prepared as indicated below. A more specific embodiment relates to the compounds of formula IVa, especially the compounds of formula IVa in which R4 stands for -CONHR<6> as defined above.

A cyclopentene derivative VIII, in which R<4> has the meaning given above, can be hydroxylated, e.g. with selenium dioxide in organic solvents such as tetrahydrofuran and dimethoxyethane, preferably at reflux temperature, so that the hydroxy-substituted cyclopentane derivative of formula IX is obtained. Epoxidation of the cyclopentane derivatives of either formula VIII or IX, e.g. with m-chloroperbenzoic acid in a solvent such as dichloromethane at room temperature, gives a corresponding epoxide: of formula IV in which R<3> stands for hydrogen or in which R<3> stands for hydroxy (of formula IVa above).

The epoxidation of the cyclopentene derivatives can also be carried out under Sharpless epoxidation conditions with t-butyl hydroperoxide, preferably in the presence of vanadium or titanium catalysts, such as vanadyl acetylacetonate or titanium tetraisopropoxide. Asymmetric epoxidation for kinetic resolution of the epoxides into optically active isomers can similarly be carried out in the presence of e.g. a diester of d- or l-tartaric acid, as described in Pure and Applied Chemistry 55, 589 (1983). The production of the compounds of formula I by method b) which includes the displacement of a cleavable group X (e.g. chlorine) in a compound of formula V by means of an amine of formula Via is preferably carried out at elevated temperature, e.g. at a temperature varying from 75 to 150<*>C, with an excess of the amine, in the absence or presence of a solvent, especially a polar solvent such ■as methanol or dimethylformamide, or under elevated pressure, or in the presence of a base such such as triethylamine. The starting materials of formula V in which R<2> stands for hydrogen or halogen can advantageously be prepared by condensing a compound of formula X

in which X, R and R<2->R^ have the meaning given for compounds of formula V, optionally in partially protected form, with formic acid or a mixture of formic acid and anhydric anhydride, with a lower alkyl carboxylic acid ester of a di-lower alkyl oxymotanol or with a tri-lower alkyl orthoformate, and if necessary, release of any protected hydroxy groups.

The condensation is preferably carried out by reacting a compound of formula X with a tri-lower alkyl orthoformate such as triethyl orthoformate in a polar solvent such as dimethylacetamide in the presence of an acid such as concentrated hydrochloric acid, preferably at room temperature.

The intermediates of formula X can be prepared by condensing e.g. a compound of formula XI

wherein R<2> has the meaning given for formula V, with a compound of formula XII

wherein R, R<3>, R<4> and R<5> have the meaning defined above, e.g. by the general methods described in J. Am. Chem. Soc. 91, 3075 (1969) and J. Org. Chem. 45, 531 (1980), preferably in the presence of a solvent such as triethylamine.

The compounds of formula XI and XII can in turn be prepared by methods known in the art, e.g. the compounds of formula XII can be prepared according to Tetrahedron Letters 22, 2331 (1981) or J. Org. Chem. 45, 531 (1980).

The starting materials of formula V in which R<2> stands for -SR' or -N(R<9>)r", and X stands for a leaving group, can for example be prepared by reacting a compound of formula V in which X stands for hydroxy (or as its oxotautomer) with a halogenating agent such as phosphorus oxychloride.

The intermediates of formula V in which X stands for hydroxy can in turn be prepared by first converting a compound of formula V, or a protected derivative thereof, in which X and R<2> both stand for chlorine, into a compound of formula V in which X stands for hydroxy and R2 stands for chlorine by hydrolysis with acid and subsequent conversion of said intermediate, using the methodology as described e.g. for method b), to a compound of formula V in which X stands for hydroxy and R<2> stands for -SR<*> or -N(R<q>)R"

The production of the compounds of formula I by method c) which includes displacement of the cleavable group X (e.g. chlorine) in a compound of formula VII by means of an amine of the formula Via or VIc is carried out essentially as described above under method b). The displacement by means of a mercaptan of the formula VIb is preferably carried out in the presence of a strong base, e.g. an alkali metal hydroxide such as sodium hydroxide.

The starting materials of formula Via, VIb and VIc are either known or are prepared using methods known in the art and which are described herein.

The starting materials of formula VII can be prepared e.g. substantially as described under method a), by reacting the corresponding substituted purine derivatives with an epoxide of the formula IV.

The compounds of formula I or intermediates leading to these can be converted into other compounds of formula I or corresponding intermediates using chemical methodology known in the art and as shown herein.

The compounds of formula I in which R<2> stands for halogen, e.g. chlorine, can be converted according to method c) as described above to compounds of formula I in which R<2> stands for -NHR'.

The conversion of compounds of formula I containing free hydroxy groups into ester derivatives thereof can be carried out by condensation with a corresponding carboxylic acid, advantageously as a reactive functional derivative thereof, according to acylation

(esterification) methods which are well known; in the field of technology.

Depending on the choice of starting materials and methods, the new compounds may exist in the form of one of the possible isomers, e.g. as diastereomers, as optical isomers (antipodes) as racemates, or as mixtures thereof.

In the event that diastereomeric mixtures of the above compounds or intermediates are obtained, these can be separated into the individual racemic or optically active isomers by methods which are known per se, e.g. by fractional distillation, crystallization or chromatography.

The racemic products of formula I or basic intermediates can be resolved into the optical antipodes, e.g. by separation of diastereomeric salts thereof, e.g. by fractional crystallization of d- or l-(tartrate, dibenzoyl tartrate, mandelate or camphor sulphonate) salts.

Advantageously, the most active antipode of the compounds of formula I is isolated.

Finally, the compounds of formula I are obtained either in free form or as a salt thereof. For example, any resulting free base can be converted to a corresponding acid addition salt, preferably using a pharmaceutically acceptable acid or an anion exchange preparation, or resulting salts can be converted to the corresponding free bases, for example, using a stronger base, such as a metal or ammonium hydroxide, or an optional basic salt, e.g. an alkali metal hydroxide or carbonate, or a cation exchange preparation. These or other salts, e.g. the picrates, can also be used for the purification of the obtained bases; the bases are then first converted into salts. On the basis of the close relationship between the free compounds and the compounds in the form of their salts, when a compound is mentioned in the present context, a corresponding salt is also understood, provided that this is possible or suitable under the conditions.

The compounds, including their salts, can also be obtained in the form of hydrates, or include other solvents used for the crystallization.

The following examples shall illustrate the invention. Unless otherwise stated, all evaporations are carried out under reduced pressure, preferably between 2 and 13 kPa. The structure of the final products, intermediates and starting materials is confirmed by analytical methods, e.g. microanalysis and spectroscopic characterization (e.g. MS,

IR, NMR).

The numbering of the positions on adenine and/or purine rings is as conventionally used in the art (eg Merck Index, tenth edition).

Unless otherwise stated, the end products are preferably isolated as the free base by crystallization from a mixture of an alcohol (methanol, ethanol or isopropanol) and ethyl ether.

Example 1: 2.58 g of adenine is added to a suspension of 1.2 g of sodium hydride (60%, washed with dry ether) in 20 ml of dry dimethylformamide. After stirring for 10 minutes at room temperature, the resulting mixture is treated with a solution of 4.9 g of 2-α-hydroxy-3-oc-4-α-epoxy-cyclopentane-1-3-N-ethylcarboxamide in 30 ml of dry dimethylformamide, heated to 105 <*>C for 18 hours, then cool to room temperature. The reaction mixture is quenched with water and concentrated under vacuum. The crude product is purified by reverse-phase chromatography using 120 g of reverse-phase octadecylsilane (C^g)-bonded silica gel so that a) 2-a-4-a-dihydroxy-3e-(9-adenyl)-cyclopentan-le-N is obtained -ethylcarboxamide, melting point 250-253°C, and b) 2-a-3-a-dihydroxy-4-3-(9-adenyl)-cyclopentane-1-p-N-ethylcarboxamide which is recrystallized from methanol, m.p.

208.5-209°C; NMR(CD 3 OD): 8.36 (1H,s); 8.18 (1H,s); 4.5 (lH.dd); 4.28 (lH.dd).

The starting material is prepared as follows: 15 g of 3-cyclopentene-1-N-ethylcarboxamide is added to a mixture of 750 ml of dry tetrahydrofuran and 375 ml of dry dimethoxyethane, followed by 12 g of selenium dioxide at room temperature. After the reaction is heated to 70°C with mechanical stirring overnight and cooled to room temperature, the resulting solution is filtered through Celite. The filtrate is concentrated under vacuum and the residue is chromatographed on 400 g of silica gel using 45% methanol in ethyl acetate as eluent so that 2-a-hydroxy-3-cyclopentene-1-e-N-ethylcarboxamide is obtained, m.p. 48-50'C.

A solution of 4.6 g of 2-α-hydroxy-3-cyclopentene-1-p-N-ethylcarboxamide, 10.24 g of m-chloroperbenzoic acid and 70 ml of dichloromethane is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the residue is distributed between ether and water. The aqueous layer is concentrated in vacuo to obtain 2-cx-hydroxy-3-a-4-cx-epoxy-cyclopentane-1-e-N-ethylcarboxamide, m.p. 83-85°C.

In a similar way, the following is produced:

c ) 2-a-3-o.-dihydroxy-4-e-[9-(2-chloroadenyl)]-cyclopentane-1-p-N-ethylcarboxamide, m.p. 233-237°C; NMR((CD30D); 8.34 (1H.s); 4.43 (1H.dd); 4.25 (1H.t); d) 3-a-hydroxy-4-e-(9-adenyl)-cyclopentane-1-P-N-ethylcarboxamide , sm.p. 282-285°C; NMR(CD 3 OD): 8.17 (1H.s); 8.15 (lH.s); 4.7 (lH.s); e) 2-α-3-α-dihydroxy-4-β-(9-adenyl)-cyclopentane-1-β-N-cyclopropylcarboxamide, m.p. 218-220°C; NMR (CD 3 OD ): 8.20 (1H.s); 4-17 (lH.dd); 4.25 (lH.h); f) 2-a-4-a-dihydroxy-3-p-(9-adenyl)-cyclopentane-1-p-N-cyclopropylcarboxamide, m.p. above 250'C; g) 3-c-hydroxy-4-3-[9-(2-chloroadenyl)]-cyclopentane-1-a-N-ethylcarboxamide, m.p. 197-200*C; NMR(CD 3 OD): 8.1 (1H.s);

4.13 (lH.q).

The starting material for compounds c and d, trans-3,4-epoxy-cyclopentane-1-N-ethylcarboxamide, is prepared by epoxidation of 3-cyclopentene-1-N-ethylcarboxamide with m-chloroperbenzoic acid followed by chromatographic purification on silica gel (using 296 methanol in ethyl acetate as eluent).

Example 2:

a) A stirred mixture of 58 mg of 2-a-3-a-dihydroxy-4-e-[9-(2-chloroadenyl)]-cyclopentane-1-e-N-ethylcarboxamide and 1.5 ml

freshly distilled 2-phenylethylamine heated to 130°C for 14 hours and cooled to room temperature. Excess 2-phenylethylamine is removed under vacuum and the residue triturated with ether. The solid obtained after filtration is recrystallized from methanol to obtain 2-a-3- α-dihydroxy-4-β-[2-(2-phenylethylamino)-9-adenyl]-cyclopentane-1-β-N-ethylcarboxamide, <s>m.p. 234-236-C; NMR(CD3OD): 7.9 (1H .s); 4.46 (1H,t); 4.33 (1H.t).

In a similar way, the following is produced:

b ) 3-a-hydroxy-4-e-[2-(2-phenylethylamino)-9-adenyl]cyclopentane-1-e-ethylcarboxamide, m.p. 220-224<*>C; NMR(CD 3 OD): 7.73 (1H.s); 3.22 (2H,q): 2.91 (2H,t); 2.48 (2H,t); c) 2-a-4-oc-dihydroxy-3-3-[2-(2-phenylethylamino)-9-adenyl]-cyclopentane-1-e-N-ethylcarboxamide, m.p. 224-226°C;

NMR(CD 3 OD): 7.8 (1H,s); 4.25 (lH.dd);

d) 2-o<-3-Oi-dihydroxy-4-e-[2-(2-pyridylethylamino)-9-adenyl]-

cyclopentane-1-e-N-ethylcarboxamide; NMR(CD 3 OD): 7.93 (1H.s); 4.47 (lH.h); 4.37 (lH.h).

Example 3: To a suspension of 241 mg of sodium hydride (60#, washed with dry ether) in 8 ml of dry dimethylformamide, 932 mg of 2-chloroadenine is added. After stirring for 10 minutes at room temperature, the resulting mixture is treated with 800 mg of 1-3-hydroxymethyl-2-cx-hydroxy-3-oc-epoxycyclopentane in 5 ml of dry methylformamide and heated to 105°C for 18 hours, then cooled to room temperature. The reaction mixture is quenched with water and concentrated under vacuum. The crude product is chromatographed on 100 g of reverse-phase octadecylsilane (C^g)-bonded silica gel (eluent, 5% methanol in water) so that a) 2-a-4-cx-dihydroxy-1-3-hydroxymethyl-3-e- [9-(2-chloroadenyl)]-cyclopentane, m.p. 252-254<*>C, and b) 2-α-3-α-dihydroxy-1-β-hydroxymethyl-4-B-[9-(2-chloroadenyl )]-cyclopentane, m.p. 236-238°C; NMR(CD 3 OD): 8.17 (1H.s); 4.5 (lH.dd).

The starting material is prepared as follows: A solution of 4.15 g of 1-hydroxymethyl-3-cyclopentene in 500 ml of dry tetrahydrofuran and 250 ml of dimethoxyethane is treated with 4.15 g of selenium dioxide at room temperature. The resulting mixture is heated to 70°C for 18 hours, then cooled to room temperature and filtered through Celite. The filtrate is concentrated under vacuum and the residue is chromatographed on 100 g of silica gel (eluent, 4% methanol in ethyl acetate) so that trans-1-hydroxymethyl-2-hydroxy-3-cyclopentene is obtained.

A solution of 818 mg of trans-1-hydroxymethyl-2-hydroxy-3-cyclopentene, 2.2 g of m-chloroperbenzoic acid and 40 ml of dichloromethane is stirred at room temperature for 80 minutes. The solvent is removed under reduced pressure and the residue is partitioned between ether and water. The aqueous layer is concentrated in vacuo so that 1-p-hydroxymethyl-2-a-hydroxy-3-a-4-a-epoxy-cyclopentane is obtained.

Example 4:

A suspension of 40 mg sodium hydride (60%, washed with ether)

in 3 ml of dimethylformamide is treated with 200 mg of 2-(2-phenylethylamino)adenyl at room temperature. Stirring is continued at room temperature until the reaction mixture becomes homogeneous. The reaction mixture is then treated with 160 mg of 2-a-hydroxy-3-a-4-a-epoxy-cyclopentane-1-P-N-ethylcarboxamide. The resulting solution is heated to 100<*>C for 14 hours. The reaction mixture is then cooled to room temperature, quenched with water and the solvent is removed under vacuum. The crude product mixture is first chromatographed on silica gel eluting with 10% MeOH/CH2Cl2- The resulting product is then chromatographed on reverse phase octadecylsilane (Cj^-linked silica gel eluting with up to 5056 methanol in water; a mixture of isomers, 2-a-3- α-dihydroxy-4-e-[2-(2-phenylethylamino)-9-adenyl]-cyclopentane-1-e-N-ethylcarboxamide of Example 2a and 2-α-4-oc-dihydroxy-3-β-[2 -(2-phenylethylamino)-9-adenyl]-cyclopentane-1-B-N-ethylcarboxamide is obtained.

The starting material 2-(2-phenylethylamino)adenine is produced by

to react 2-chloroadenine with excess 2-phenylethylamine at approx. 140'C.

Example 5: To a stirred solution of 2.7 g of 4-P-(5-amino-6-chloro-4-pyrimidinylamino)-2-a-3-a-dimethylethylenedioxy-cyclopentane-1-ø-N-ethylcarboxamide in 40 ml triethyl orthoformate, 0.7 ml of concentrated hydrochloric acid is added. The solution is stirred at room temperature for 24 hours. After removal of the solvent, 4-B-(6-chloro-9-purinyl')-2-a-3-a-dimethyl-methylene-dioxy-cyclopentane-1-e-N-ethylcarboxamide is obtained as an oil, which is used in the next step without further purification.

A solution of 2.2 g of 4-P-(6-chloropurin-9-yl)-2-a-3-a-dimethylmethylenedioxy-cyclopentane-1-B-N-ethylcarboxamide in 30 ml of saturated methanolic ammonia is heated overnight in a sealed tube. After removing the solvent, the residue is heated to 55°C in 15 ml IN hydrochloric acid for 1.75 hours. The solvent is removed under vacuum so that an amorphous solid is obtained.

Chromatography on a silica gel column eluting with a methanol/dichloromethane gradient gives 4-3-(9-adenyl)-2-a-3-a-dihydroxycyclopentane-1-3-N-ethylcarboxamide, identical to the compound in Example 1b ..

The starting material is prepared as follows: A mixture of 10.5 g of 5,6-dimethylmethylenedioxy-2-azabicyclo[2.2.1]heptan-3-one and 50 ml of ethyl alcohol is heated to 140°C overnight in a steel bomb. After removal of the solvent, the residue is purified by column chromatography (silica gel) using a gradient of dichloromethane/methanol as eluent so that 4-p-amino-2-a-3-a-dimethylmethylenedioxy-cyclopentane-1-3-N- ethyl carboxamide.

7.5 g of 5-amino-4,6- dichloropyrimidine followed by 9.2 ml of triethylamine. After the reaction is heated for 24 hours at 150°C, the solvent is removed in vacuo. The residue is distributed between ethyl acetate and a saturated sodium bicarbonate solution. The organic layer is dried over sodium sulfate and concentrated to dryness. The solid crude product is chromatographed on a silica gel column eluting using a hexane/ethyl acetate gradient to give 4-3-(5-amino-6-chloro-4-pyrimidinylamino)-2-a-3-a-dimethylmethyleneendoxycyclopentane -1-3-N-ethylcarboxamide. b) 2-a-3-a-dihydroxy-4-3-[9-(2-chloro-adenyl)]-cyclopentane-1-3-N-ethylcarboxamide, the compound according to example 1c, is prepared in a similar manner.

The starting material is prepared as follows: To a solution of 614 mg of 5-amino-2,4,6-trichloropyrimidine and 813 mg of 4-3-amino-2-a, 3-a-d in methyl1methylenedioxy-cyclopentane-1-3-N-ethylcarboxamide 1 ml of dry triethylamine is added to 15 ml of n-butanol; the resulting mixture is heated at reflux for 15 hours and cooled to room temperature. All the volatile components are evaporated and the remainder is distributed between dichloromethane and water. The organic layer is dried over magnesium sulfate and concentrated to an oil. The crude product is chromatographed on 100 g of silica gel using 1:1 hexane and ethyl acetate as eluent so that 4-e-(5-amino-2,6-dichloro-4-pyrimidinyl amlno )-2-oc-3- ot-dimethylmethylenedioxy-cycle open tan-1-s-N-ethylcarboxamide as an amorphous solid.

Example 6: A stirred mixture of 26 mg of 2-a-3-a-dihydroxy-1-p-hydroxymethyl-4-P-[9-(2-chloroadenyl)]-cyclopentane and 0.3

ml of freshly distilled 2-phenylethylamine is heated to 130°C for 14 hours and cooled to room temperature. Excess 2-phenylethylamine is removed under vacuum, and the residue is triturated with ether. The solid obtained after filtration is purified by flame column chromatography using a reverse phase octadecylsilane (Cjg ) bonded silica gel and eluting with methanol/water (5:3 to 1:1). The resulting product is then crystallized from ethanol/ether to give 2-a-3-Q-dihydroxy-1-e-hydroxymethyl-4-e-[2-(2-phenylethylamino)-9-adenyl]-cyclopentane, m.p. . 118-120°C; NMR(CD 3 OD ): 7.73 (1H.s); 7.19 (5H,m); 2.85 (2H,t)'.

Example 7: The following compounds of formula II in which R<3> stands for hydroxy can be prepared essentially by the general methods described above.

Compound (a) can advantageously be prepared as follows: p-bromophenyl-acetonitrile is first condensed with t-butyl acrylate under the conditions of the palladium acetate-catalyzed Heck reaction. The resulting acrylate is hydrogenated with palladium on charcoal catalyst followed by reduction (of the cyano group) with sodium borohydride in the presence of cobalt (II) chloride to give t-butyl p-(2-aminoethyl)-phenylpropionate. Condensation with 2-a-3-a-dihydroxy-4-3-[9-(2-chloroadenyl)]-cyclopentane-1-3-N-ethylcarboxamide gives the t-butyl ester of compound (a) which is hydrolyzed to compound (a) with aqueous hydrochloric acid.

Compound b) is prepared similarly. The starting material for condensation with the 9-(2-chloroadenyl)cyclopentane derivative is prepared by condensation of p-hydroxyphenylacetonitrile with t-butyl bromoacetate in the presence of potassium carbonate.

The starting material for compound (k) is prepared as follows: A mixture of 6 g of p-bromophenylacetic acid in 100 ml of dichloromethane and 5 ml of oxalyl chloride is stirred at room temperature for 16 hours. After removing the solvent in vacuo, the residue is dissolved in dichloromethane and treated with excess diethylamine at room temperature. After 1 hour, the reaction mixture is washed with water, the organic layer is dried over magnesium sulfate and the solvent is removed in vacuo to give p-bromo-N,N-dimethyl-phenylacetamide as an oil, which is converted to p-(dimethylaminocarbonyl-methyl)-2 -phenethylamine as described for the starting material above.

Example 8: 2-a-3-a-dihydroxy-1-e-hydroxymethyl-4-e-(5-amino-2,3-dichloro-4-pyrimidinylamino)-cyclopentane (480 mg) is treated with 8.0 ml of triethyl orthoformate and 0.1 ml concentrated HCl, and the reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is then concentrated under vacuum and the remaining oil is dissolved in 20 ml of saturated methanolic ammonia, the solution is placed in a sealed tube and heated to 60°C for 12-16 hours. The solvent is removed under vacuum and the residue is heated with 30 ml of IN HCl at 60° C. for 2 hours. The solvent is removed under vacuum and the crude product is separated by flame chromatography on a reverse phase octadecylsilane (Cig) bonded silica gel column, eluting first with water, followed by 556, 1056 and 2056 methanol in water to give 2-a-3-a-dihydroxy -1-3-hydroxymethyl-4-e-(2-chloro-9-adenyl)-cyclopentane (see Example 3); NMR(CD 3 OD): 8.2 (1H,s); 4.50 (lH.dd); 4.03 (lH.dd); 3.70 (2H,m); 2.46 (lH.m); 2.25 (lH.m); 1.90 (lH.m).

The starting material is prepared as follows: A mixture of 5.2 g of methyl 4-ε-amino-2-cx-3-α-dihydroxycyclopentane-1-ε-carboxylate (Tetrahedron Letters 1981. 2331), 3.4 g of 5-amino-2,4, 5-trichloropyrimidine and 5.2 ml of triethylamine in 60 ml of n-butanol are heated to reflux under a nitrogen atmosphere for 16 hours. The reaction mixture is cooled to room temperature and the solvent is removed under vacuum. The residue is distributed between ethyl acetate and water. The organic solution is extracted with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness. The crude product is purified by flame chromatography on silica gel, by elution with ethyl acetate and then 1056 methanol/ethyl acetate so that methyl-2-a-3-a-dihydroxy-4-p-(5-amino-2,6-dichloro-4- pyrimidinylamino)cyclopentane-1-β-carboxylate as a white solid. NMR(CD 3 OD): 4.43 (1H,q); 4.25 (lH.h); 3.95 (1H,t); 3.72 (3H,s); 2.94 (1H.m); 2.60 (lH.m); 1.70 (lH,m).

Calcium chloride (466 mg) and sodium borohydride (320 mg) are combined in 30 ml of tetrahydrofuran at room temperature. The reaction mixture is stirred at room temperature for one hour, then 700 mg of methyl-2-a-3-c<-dihydroxy-4-p-(5-amino-2,6-dichloro-4-pyrimidinyl-amino)cyclopentane-1-P-N- carboxylate in 30 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature for two days. The reaction mixture is treated with 14 ml of acetic acid at room temperature and stirring is continued for 2 hours. The solvent is removed under vacuum so that an amorphous solid is obtained. The crude product mixture is separated by flame chromatography on a reverse phase octadecylsilane (C^g)-bonded silica column, eluting with methanol/water (first 1:9, then 2:8, then 3:7) so that 2-a-3-a is obtained -dihydroxy-1-p-hydroxymethyl-4-P-(5-amino-2,6-dichloro-4-pyrimidinylamino)-cyclopentane; NMR(CD 3 OD): 4.40 (1H.q); 3.9 (2H,dd); 2.4 (1H,m); 2.15 (1H,m); 1.28 (lH,m).

Example 9: 2-a-3-cx-dihydroxy-1-3-hydroxymethyl-4-p-(2-chloro-9-adenyl)-cyclopentane (150 mg) is treated with 3.0 ml of phenethylamine and the mixture is heated to 130°C for 5.5 hours. The residue is triturated with an ethyl ether/water mixture. The layers are separated, and the aqueous layer is combined with the insoluble material and concentrated to an oil. The crude product mixture is separated by reverse phase flame chromatography on C^g-octadecylsilane (C^g)-bonded silica gel, eluting first with water, followed by 10%, 30%, 50% methanol in water to obtain 2-oc-3- α-dihydroxy-1-ε-hydroxymethyl-4-3-[2-(2-phenylethylamino)-9-adenyl]-cyclopentane as a white solid; sm.p. 149-150°C; NMR (d 6 -DMSO): 7.75 (1H.s); 7.28 (5H,m); 6.7 (2H,bs); 6.22 (lH.h); 5.00 (lH.d); 4.69 (lH.h); 4.53 (2H,m); 4.37 (2H,t); 3.84 (lH.m).

Example 10; a) To 2.5 g of (+)-4-P-(5-amino-2,6-dichloro-4-pyrimidinyl-amino)-2-a-3-a-dimethyl methylene-endloxy-cyclopentane-1-B-N-ethylcarboxamide is added 40 ml of triethyl orthoformate and 0.5 ml of concentrated hydrochloric acid at room temperature. After stirring at room temperature for 3 hours, the reaction mixture is concentrated under high vacuum so that a yellow oil is obtained. The oil is dissolved in 100 ml of a saturated solution of ammonia in methanol, and heated to 65-70°C in a steel pressure reactor overnight. The reaction mixture is cooled to room temperature and the solvent is removed under vacuum so that the crude product is obtained. Chromatography on silica gel, by elution with dichloromethane followed by dichloromethane containing up to 10* methanol, gives (+ )-2-a-3-a-dimethylmethylenedioxy-4-3-(2-chloro-9-adenyl)-cyclopentane-l-e-N- ethyl carboxamide as a white, amorphous solid; ag<5> = +2.80° (c=1.5, methanol); NMR (CD 3 OD): 8.25 (1H.s); 5.05 (2H,m); 3.23 (2H,q); 2.94 (1H.m): 2.54 (2H,t): 1.58 (3H,s); 1.31 (3H,s); 1.12 (3H,t).

A mixture of 1.8 g of (+)-2-a-3-a-dimethylmethylenedioxy-4-B-(2-chloro-9-adenyl)-cyclopentane-1-e-N-ethylcarboxamide and 40 ml of IN hydrochloric acid is heated to 60° C. for 3 hours. The solvent is removed under vacuum and the residue triturated with methanol and ether, then collected and dried under vacuum to give (-)-2-a-3-oc-dihydroxy-4-ø-(2-chloro-9-adenyl)- cyclopentane-1-B-N-ethylcarboxamide hydrochloride; sm.p. 190°C (dec.); ag5 8.70* (c-0.77, methanol); NMR (CD30D): 9.29 (1H.s); 4.48 (lH.dt); 4.23 (lH.dt); 2.90 (lH.m); 2.70 (lH.m); 2.24 (1H,ra); 1.16 (3H.h). b) Similarly, ( + )-2-cx-3-a-dihydroxy-4-B-(2-chloro-9-adenyl)-cyclopentane-1-s-N-ethylcarboxamide is prepared.

The optically active starting materials are prepared as follows: Racemic 4-a-amino-2-a-3-a-dimethylmethylenedioxycyclopentane-1-fi-N-ethylcarboxamide (Example 5, 5.4 g) is mixed with 8.90 g of (-)-dibenzoyl- L-tartaric acid monohydrate in 100 ml of boiling ethanol and allowed to cool slowly to room temperature. The crystals formed are collected, washed with cold ethanol and dried under vacuum to obtain colorless needles; cxg^= -66.69° (c=1.09, methanol). (- )-4-B-amino-2-a-3-0!-dimethylmethylenedioxy-cyclopentane-1-B-N-ethylcarboxamide The dibenzoyl-L-tartrate salt is dissolved in water, the solution is treated with excess sodium bicarbonate and the solvent is removed under vacuum. The filtrate is triturated with ethyl acetate. The solids are filtered off and the filtrate is concentrated under vacuum to give (-)-4-B-amino-2-a-3-a-dimethylmethylenedioxy-cyclopentane-1-6-N-ethylcarboxamide as a yellow oil; α{)5 = -31.15° (c=2.27, methanol); NMR (CDCl 3 ): 4.81 (1H.dd); 4.39 (lH.d); 3.26 (2H,m); 1.80 (lH.dt).

The filtrate from the crystallization of the levorotatory salt is concentrated under vacuum, and the residue is treated with excess aqueous bicarbonate. The solvent is removed under vacuum and the residue is triturated with ethyl acetate. The insoluble material is collected and the filtrate is concentrated under vacuum to give a yellow oil. The oil is combined with 4.00 g of ( + )-dibenzoyl-D-tartaric acid monohydrate in 90 ml of boiling ethanol and allowed to slowly cool to room temperature. The resulting crystals are collected, washed with cold ethanol and dried under vacuum to give the dextrorotatory salt as colorless plates; ag<5=> +68.41° • (c = l.14, CD30D ); NMR (CDCl 3 ): 6.55 (1H.s); 4.81 (2H,dd); 4.4 (2H,d); 3.5 (1H,s); 3.29 (2H,q); 2.77 (1H.m); 2.4 (1H,m); 1.8 (lH.h); 1.48 (3H,s); 1.29 (3H,s); 1.13 (3H,t).

(+)-4-B-amino-2-a-3-a-dimethylmethylenedioxy-cyclopentane-1-B-N-ethylcarboxamide dibenzoyl-D-tartrate (7.04 g) is dissolved in 1 water and treated with excess NaHCC^. The solvent is removed under vacuum and the residue is triturated with ethyl acetate. The solids are filtered off, and the filtrate is concentrated under vacuum to give (+)-4-p-amino-2-a-3-a-dimethyl-methylenedioxy-cyclopentane-1-fi-N-ethylcarboxamide as a yellow oil ; ag<5>= +32.26° (c=1.52, methanol); NMR (CDCl 3 ): 4.81 (1H.dd); 4.41 (lH.d); 3.29 (2H,m); 1.84 (lH.dt).

To a solution of 2.016 g of 5-amino-2,4,6-trichloropyrimidine and 2.32 g (+ )-4-P-amino-2-a-3-a-dimethylmethylenedioxy-cyclopentane-1-e-N-ethylcarboxamide in 40 ml of n- butanol, 2.8 ml of triethylamine is added, and the resulting mixture is heated at reflux under a nitrogen atmosphere overnight. The reaction mixture is cooled to room temperature and the solvent is removed under vacuum. The residue is distributed between ethyl acetate and water. The ethyl acetate solution is extracted with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness, so that a dark amorphous solid is obtained. The crude product is chromatographed on silica gel eluting with ethyl acetate, hexane (1:2 to 4:1) so that (+)-4-p<->

(5-amino-2,6-dichloro-4-pyrimidinylamino)-2-a-3-a-dimethyl-methylenedioxy-cyclopentane-1-B-N-ethylcarboxamide, as a white amorphous solid; αg<5>= -27.36° (c=1.2, methanol); NMR (CDCl 3 ): 5.95 (1H.bs); 4.72 (2H,t); 4.51 (lH.d); 3.31 (2H,m); 2.84 (lH.d); 2.55 (1H,m); 1.93 (lH.d); 1.49 (3H,s); 1.29 (3H,s); 1.18 (3H,t).

Similarly, condensation of 5-amino-2,4,6-trichloropyrimidine with the levorotatory amine gives the corresponding levorotatory intermediate.

Example 11:

a) t-butyl p-(2-amlnoethyl)-phenylpropionate (3.12 g) is combined cleanly with 500 mg of (-)-2-oc-3-cx-dihydroxy-4-B-(2-chloro-9-adenyl) -cyclopentane-1-e-N-ethylcarboxamide, a2,<5-> -8.70° (c=0.77, methanol), and heated to 120°C under a nitrogen atmosphere for five hours. The reaction mixture is cooled to room temperature and triturated with ether. The insoluble material is filtered off and dried under vacuum. The solid obtained is triturated with water, and the insoluble material is collected and dried under vacuum to give 2-a-3-a-dihydroxy-4-e -[2 - (p -( 2-t-butoxycarbonylethyl )- phenethyl-amino)-9-adenyl]-cyclopentane-1-p-N-ethylcarboxamide as a beige-white solid; sm.p. 215°C (dec.), NMR (CDCl 3 ): 7.9 (1H.s); 7.13 (4H,q); 4.68 (1H,q); 4.47 (lH.h); 4.32 (lH.h); 3.58 (2H,t); 3.23 (2H,q); 2.82 (4H,m); 2.5 (2H,t); 1.4 (9H,s); 1.14 (3H,t). b) Similarly, the optical antipode derived from the corresponding dextrorotatory starting material is produced. c) Similarly, the racemic 2-α-3-α-dihydroxy-4-8-[2-[p-(t-butoxycarbonylethyl)-phenethylamino]-9-adenyl]-cyclopentane-1-6-N-ethylcarboxamide is prepared , sm.p. 206-208°C, using the racemic starting material. t-butyl p-(2-aminoethyl)-phenylpropionate is prepared as follows: p-bromophenylacetonitrile (50 g), t-butyl acrylate (46 ml), palladium (II) acetate (575 mg) and tri-o-tolylphosphine (3.1 g ) is mixed with 125 ml of triethylamine in a steel pressure reactor and heated to 140°C for 16 hours. The reaction mixture is cooled to room temperature and poured into 500 ml of 3N hydrochloric acid at 0°C. The solids are extracted into ethyl acetate, and the ethyl acetate solution is extracted with saturated sodium chloride solution and dried over magnesium sulfate. The crude product is triturated with ether/hexane (1:1), filtered and dried under vacuum so that t-butyl p-(cyanomethyl)-phenyl acrylate is obtained; sm.p. 80-

82'C; NMR (CDCl 3 ): 7.5 (2H,d); 7.32 (2H,d); 6.39 (2H,d); 3.78 (2H,s); 1.52 (9H, p).

t-butyl p-(cyanomethyl)-phenylacrylate (6.0 g) is mixed with 600 mg of 105É palladium on carbon in 80 ml of isopropanol and 24 ml of IN hydrochloric acid and treated with hydrogen at room temperature. After 8 hours at a pressure of 300 kPa, the catalyst is filtered off and the filtrate is concentrated under vacuum. The residue is triturated with ether, filtered and dried under vacuum to obtain

t-butyl p-(2-aminoethyl)-phenylpropionate hydrochloride as a white solid. The hydrochloride salt is distributed between ethyl acetate and IN sodium hydroxide. The ethyl acetate extract is washed with a saturated sodium chloride solution and dried over magnesium sulfate. Filtration and concentration of the filtrate gives t-butyl p-(2-aminoethyl)-phenylpropionate as a yellow oil; NMR (CDCl 3 ): 7.1 (4H,s); 2.98 (2H,t); 2.89 (2H,t); 2.73 (2H,t); 2.5 (2H,t); 2.02 (2H,s); 1.42 (9H, p).

Example 12:

a) Optically active 2-a-3-a-dihydroxy-4-e-[2-[p-(t-butoxy-carbonylethyl)-phenethylamino]-9-adenyl]-cyclopentane-1-P-N-ethylcarboxamide from example lia (160 mg) is treated with 20 ml IN hydrochloric acid and heated to 60° C. for 1 hour. The solvent is removed under vacuum and the residue is triturated with ethanol, filtered off and dried under vacuum so that (-)-2-a-3-a-dihydroxy-4-e-[p-(2-carboxyethyl)-phenethylamlno is obtained )-9-adenyl]-cyclopentane-1-8-N-ethylcarboxamide hydrochloride as a white solid; sm.p. 243-245°C; ag<5>= -4.34° (c=0.99, DMS0); NMR (CD 3 OD): 8.11 (1H.s); 7.18 (4H,q); 4.76 (1H.q); 4.5 (1H.m): 4.28 (1H.m); 3.75 (2H,dt); 3.24 (2H,q); 2.94 (2H,t); 2.85 (4H,t); 2.44 (4H,t); 2.3 (1H,m); 1.16 (3H,t); b) In a similar way, the corresponding dextrorotatory antipode is prepared, m.p. 242-245°C, α§<5>= +3.48° (DMS0). c) The racemic compound (example 7a) is also prepared in a similar way, m.p. 235-237°C.

Example 13: Treatment of (-)-2-a-3-a-dihydroxy-4-e-[2-(p-2-carboxyethyl )-phenetyl amlno )-9-adenyl]-cycloopen tan-1-e-N -ethylcarboxamide hydrochloride with ethanol and concentrated sulfuric acid as catalyst under reflux overnight gives after work-up (- )-2-a-3-a-di<y>droxy-4-e-[2-[2-(p-2- ethoxycarbonylethyl-phenethylamino)-9-adenyl]-cyclopentane-1-a-N-ethylcarboxamide; NMR (CD 3 OD): 4.05 (q,2H); 1.29 (t, 3H).

Example 14: A mixture of 18 mg of 2-cx-3-a-dihydroxy-1-e-hydroxymethyl-4-e-(2-chloro-9-adenyl)-cyclopentane (Example 3), 100 mg of sodium hydrogen sulphide and 0.5 ml of N, N-dimethylformamide is stirred at 140<*>C overnight. The reaction mixture is cooled to room temperature, neutralized with 0.1N hydrochloric acid to pH 6, then concentrated under reduced pressure so that crude 2-a-3-a-dihydroxy-1-e-hydroxymethyl-4-B-(thio-9-adenyl)- cyclopentane. The crude product is dissolved in a mixture of 3 ml ethanol, 1 ml 0.25N sodium hydroxide, 0.5 ml allyl bromide and the mixture is stirred at room temperature for 20 hours. The reaction mixture is poured into water, neutralized with 0.1N hydrochloric acid to pH 7, then concentrated under reduced pressure so that an amorphous solid is obtained. Flame chromatography of the crude product on a reverse phase C^g column, eluting with water/methanol (3:2) gives 2-a-3-a-dihydroxy-1-B-hydroxymethyl-4-8-(2-allylthio-9-adenyl )-cyclopentane, m.p. 126-128°C; NMR (CD30D): 8.2 (1H.s); 6.0 (lH.m); 5.3 (lH.dd); 5.1 (lH.dd); 4.75 (lH.m); 4.58 (1H.m); 4.05 (lH.dd); 3.8 (lH.m); 3.67 (1H,m); 2.4 (1H,m); 2.24 (1H,m); 2.02 (lH.m).

Example 15: Treatment of 2-a-3-a-diacetoxy-4-a-[2-(2-phenylethylamino)-6-chloro-9-purinyl]-cyclopentane-1-e-N-ethylcarboxamide with saturated methanolic ammonia at 100< *>C in a sealed tube gives 2-a-3-a-dihydroxy-4-B-[2-(2-phenylethyl-amino)-9-adenyl]-cyclopentane-1-e-N-ethylcarboxamide from Example 2a.

The starting material is prepared as follows: To a solution of 740 mg of 2-oc-3-a-dimethylmethylenedioxy-4-a-(5-amino-2,6-dichloro-4-pyrimidinylamino)-cyclopentane-1-e-N-ethylcarboxamide in 10 ml triethyl orthoformate, 0.15 ml of concentrated hydrochloric acid is added at room temperature. The reaction mixture is stirred for 18 hours, then concentrated under reduced pressure so that an oil is obtained. A solution of the oil in 1 n-butanol is then heated to reflux for 4 hours and cooled. All the volatile components are evaporated so that a crude product is obtained which is then purified by flame chromatography on silica gel. Elution with 45 g of methanol in dichloromethane gives 2-α-3-α-dimethylmethylenedioxy-4-B-(2,6-dichloro-9-purinyl)-cyclopentane-1-B-N-ethylcarboxamide; NMR (CD 3 OD/CDCl 3 ): 8.2 (1H.s); 2.1-2.9 (3H,m).

A solution of 60 mg of 2-o.-3-o-dimethylmethylenedioxy-4-a-(2,6-dichloro-9-purinyl)-cyclopentane-1-e-N-ethylcarboxamide in 5 ml of 1 N hydrochloric acid is heated to reflux for 5 hours and cool down. The reaction mixture is concentrated under reduced pressure so that the crude product is obtained. The crude product is dissolved in 3 ml of methanol, 0.1 ml of phenylethylamine is added and the solution is heated under reflux for 5 hours. After the reaction is complete, all the volatile components evaporate. The resulting crude solid is purified by chromatography on a reverse phase C-18 column, eluting with water/methanol (8:1 to 5:1) to give 2-a-3-a-dihydroxy-4-e-[ 2-(2-phenylethylamino)-6-hydroxy-9-purinyl]-cyclopentane-1-e-N-ethylcarboxamide; NMR (CD 3 OD): 8.3 (1H,s); 7.2-7.4 (5H,m); 4.85 (1H.q); 4.45 (lH.dd); 4.3 (lH.dd); 3.15 (lH.h); 2.95 (1H,t); 2.84 (1H,m); 2.62 (lH.m); 2.2 (lH.m).

Selective acetylation using a procedure as indicated for a corresponding transformation in Can. J. Chem. 59, 2601 (1981) gives 2-a-3-oc-diacetoxy4-e-[2-(2-phenylethylamino)-6-hydroxy-9-purinyl]-cyclopentane-1-B-N-ethylcarboxamide.

Chlorination with phosphorus oxychloride and diethylaniline gives 2-α-3-α-diacetoxy-4-B-[2-(2-phenylethylamino)-6-chloro-9-purinyl]-cyclopentane-1-α-N-ethylcarboxamide.

Example 16: The following compounds are essentially prepared by the methods described in the previous examples: a) 2-a-3-a-dihydroxy-4-e-[ 2-kl or-N(,-(2-N-pyr r rolyl-cyclohexyl )-9-adenyl]-cyclopyrtane-1-e-N-ethylcarboxamide, m.p. above 150°C (decomposition); b) 3-a-hydroxy-4-e-[2-(3-phenylpropylamino)-9 -adenyl]-cyclopentane-1-e-N-ethylcarboxamide, m.p. 185-186<*>C; c) 2-oc-3-cx-dihydroxy-4-p-[2-aniline-9-adenyl]-cyclopentane-1-a-N-ethylcarboxamide, melting point 259.5-260.5<0>C (decomposition); d) 2-a-3-a-dihydroxy-1-B-hydroxymethyl-4-B-[2-(2-phenethyl-thio)-9-adenyl]cyclopentane, IR(KBr): 1030 (C-0), 3330 (0-H).

Claims (1)

Analogous process for the preparation of therapeutically active compounds of formula I in which R, R<3> and R*> independently of each other mean hydrogen or hydroxy, provided that at least one of R, R<3> and R<5> means hydroxy; R<1> means hydrogen or C5-C7 cycloalkyl substituted with N-pyrrolyl; R<2> means hydrogen, halogen, -SR * where R' stands for C3-C4-alkenyl or phenyl-C1-C4-alkyl, or -N(R<9>)R" where R<9> means hydrogen or C1-C4-alkyl and R'* means phenyl-C1-C4-alkyl where phenyl is unsubstituted or substituted by halogen, C1-C4-alkyl, carboxy-C1-C4-alkyl, C1-C6- alkoxycarbonyl-C1-C4- alkyl, N,N-di-C1-C4-alkyl-carbamoyl-C1-C4-alkyl or carboxy-C1-C4-alkoxy; pyridyl-C1-C4-alkyl, naphthyl-C1-C4-alkyl, C5-C7- c<y>chloroalkyl-C1-C4-alkyl, hydroxy-C1-C4-alkyl; or phenyl which is unsubstituted or substituted by C1-C4-alkoxycarbonyl, R<4> means hydroxymethyl provided that R<2> does not mean hydrogen ; or R<4>means -CONHR<6> where R<6> means C1-<C>4-alkyl, C3-C6-c<y>chloroalkyl or hydroxy-C1-C4-alkyl; pharmaceutically acceptable ester derivatives thereof wherein free hydroxy groups are esterified in the form of a pharmaceutically acceptable ester; and salts thereof, characterized in that it includes a) for compounds of formula I in which R, R<1>, R<2>, R<3>, R<4> and R<5 >has the meaning of under formula I, provided that one of R and R<5> means hydroxy, condensation of a compound of formula III where R-* and R<2> have the meaning defined under formula I, with a compound of formula IV wherein R<3> and R<4> have the meaning defined under formula I, in the presence of a strong base and, if necessary, separation of any resulting isomers; or b) for compounds of formula I where R, R<*>, R<2>, R<3>, R<4> and R^ have the meaning defined under formula I, condensation of a compound of formula V wherein X represents a leaving group; R, R<2>, R<3>, R<4> and R<5> have the meanings defined under formula I, with a compound of formula Via where r! has the meaning defined under formula I; or c) for compounds of formula I in which R<2> stands for -SR<*> or -N(R9)R'', condensation of a compound of formula VII in which R, R<*>, R<3>, R<4> and R<5> have the meaning defined under formula I, and X stands for a leaving group, with either a compound of formula Via where R<*>' has the meaning defined under formula I, or with a compound of formula VIb or a reactive alkali metal salt derivative thereof wherein R" has the meaning defined under formula I; or with a compound of formula VIc wherein R'* and R<9> have the meaning defined under formula I; and if desired, (1) hydrolyzing a resulting compound of formula I, where R<2> means -N(R<9>)R'' and R" is C 1 -C 5 - alkoxycarbonyl-C 1 -C 4 -alkylphenyl-C 1 -C 4 -alkyl, to obtain another compound of formula I where R<2> means -N(R<9>)R'' and R'' is carboxy-C1-C4-alkylphenyl-C1-<C>4~alkyl, or (2) reaction of a resulting compound of formula I, where R<2> stands for -N(Rq)R" and R'' is carboxy-C1-C4-alkyl-phenyl-C1-C4-alkyl, with e n C 1 -C 0 -alkanol to obtain another compound of formula I, where R<2> means —N(R<q>)R'<*> and R" is C 1 -C 0 -alkoxycarbonyl-C 1 -C 4 -alkylphenyl -Ci-C4-alkyl, or (3) reacting a resulting compound of formula I where R<2> means halogen, with sodium hydrogen sulphide and then with a compound X'-R', where R' is as defined under formula I and X' means halogen, to obtain another compound of formula I where R<2> means -SR', where R<*> is as defined under formula I; and, if further required in any of the above-mentioned methods, temporary protection of any interfering reactive groups in the starting materials and then subsequent removal of the protecting groups to obtain a resulting compound of formula I; and, if desired, converting a resulting free compound into a salt or a resulting salt into a free compound or into another salt and, if desired, separating any resulting mixture of isomers or racemates into the individual isomers or racemates, and if necessary, resolution of a racemate In the optical antipodes.