NZ252110A

NZ252110A - Adenosine derivatives and pharmaceutical compositions

Info

Publication number: NZ252110A
Application number: NZ252110A
Authority: NZ
Inventors: Lars Jacob Stray Knutsen; Jesper Lau
Original assignee: Novo Nordisk As
Priority date: 1992-05-14
Filing date: 1993-05-12
Publication date: 1996-07-26
Also published as: EP0603348A1; IL105673A; AU671995B2; WO1993023418A1; DK62692D0; FI940167A; JPH06508855A; FI940167A0; CA2113547A1; AU4061293A; IL105673A0

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £52110 New Zealand No. International No. 252110 PCT/DK93/00158 TO BE ENTERED AFTER ACCEPTANCE AND PUBUCATION Priority dates: lit- °ll' International filing date: 12. M 6y Classification: C1 ^ Publication date: ^ ^ JUL. Journal No.: rp:fv, i. ' " " - t ^ J V v. ^ 4 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of invention: Purine derivatives Name, address and nationality of applicant(s) as in international application form: Novo Nordisk A/S, Novo Alle, DK-2880 Bagsvaerd, Denmark. WO 93/23418 PCT/DK93/00158 252 110 Purine derivatives 5 The present invention relates to a method for treating ischaemia, epilepsy and pain, to compounds for use in such a method and to pharmaceutical compositions containing the said compounds. 10 Background of the Invention Adenosine can be considered to be a hormone which has been shown to have a number of significant effects on the mammalian central nervous system (CNS) [Annual Reports in Medicinal Chemistry, 1988, 23, 39-48; 15 International Review of Neurobiology (Smythies, J.R. and Bradley, R.J., eds.) Academic Press Inc., 1985, 27, 63-139], especially under conditions of neuronal stress where the compound appears to act as an endogenous neuroprotectant (Progress in Neurobiology, 1988, 31, 85-108, Trends in Pharmacological Sciences, 1988, 9, 193-194). For example, the concentra-20 tion of adenosine has been demonstrated to rise greatly in certain brain regions following epileptic seizures or conditions of neuronal ischaemia/a-noxia (Brain Research 1990, 516, 248-256). It has been established for some years now that centrally acting adenosine 25 receptor agonists or compounds which increase extracellular adenosine levels can exhibit what is termed neuromodulator activity. Such substances influence the release of neurotransmitters in regions of the central nervous system (Annual Review of Neuroscience, 1985, 8, 103-124; Trends in Neurosciences, 1984, 164-168), with particular inhibitory effects on the 30 release of the excitatory amino acid glutamic acid (glutamate) (Nature, 1985, 316, 148-150, Journal of Neurochemistry, 1992, 58, 1683-1689). There are several CNS ailments for which this adenosine receptor mediated WO 93/23418 PCT/DK93/00158 252 1 1 0 - 2 - neuromodulator activity could be of clear therapeutic benefit. Examples of these would include the treatment of convulsive disorders (European Journal of Pharmacology, 1991,195, 261-265; Journal of Pharmacology and Experimental Therapeutics, 1982, 220, 70-76), prevention of neurodegenera-5 tion under conditions of brain anoxia/ischaemia (Neuroscience Letters. 1987, 83, 287-293; Neuroscience, 1989, 30, 451-462; Pharmacology of Cerebral Ischaemia 1990, (Kriegelstein, J. and Oberpichler, H., Eds., Wissenschaftliche Verlagsgesellschaft mbH: Stuttgart, 1990, pp 439-448) or the use of a purinergic agent in the treatment of pain (European Journal of 10 Pharmacology, 1989, 162, 365-369; Neuroscience Letters, 1991, 121, 267-270). Adenosine receptors represent a subclass (P1) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors. This 15 subclass has been further classified into two distinct receptor types which have become known as A1 and A2. Extensive research has been carried out in a quest to identify selective ligands at these sites [see, for example, Comprehensive Medicinal Chemistry, Volume 3, (Hansch, C., Sammes, P.G. and Taylor, J.B., Eds., Pergamon Press PLC: 1990, pp 601-642)]. Selective 20 ligands exist for A1 and A2 adenosine receptors and the structure-activity relationships of the various reference ligands have been reviewed (Biochemical Pharmacology, 1986, 35, 2467-2481) together with their therapeutic potential (Journal of Medicinal Chemistry, 1992, 35, 407-422). Among the known adenosine receptor agonists most selective for the A1 receptor over 25 the A2 receptor are the examples where the adenine nucleus is substituted with a cycloalkyl group on the amino function, for example N-cyclopentyla-denosine and N-cyclohsxyladenosine (Journal of Medicinal Chemistry, 1985, 28, 1383-1384) or 2-chlo'ro-N-cyclopentyladenosine (Naunyn-Schmiede-berg's Arch. Pharmacol. 1988, 337, 687-689). 30 However, these ligands are found to possess undesirable effects as to WO 93/23418 PCT/DK93/00158 2 5 2 110 -3- influence upon the cardiovascular system, rendering them unsuitable for the treatment of CNS disorders such as cerebral ischaemia, epilepsy and pain. GB 1,143,150 (equivalent to USP 3,551,409) and GB 1,123,245 disclose a 5 number of adenosine derivatives, having interesting cardiac and circulatory actions. In EP 322.242A, a new use, as "agents to reduce plasma free fatty acid concentration or reducing heart rate and condition" is claimed for the 10 compounds listed below as well as physiologically acceptable salts and solvates thereof: N-[(1 S, trans)-2-hydroxycyclopentyl]adenosine N-[(1 R, trans)-2-hydroxycyclopentyl]adenosine 15 N-T (trans V4-hvdroxvcvclohexvn-2-methvladenosine N-[ (cis)-4-hydroxycyclohexyl] adenosine N- [ (cis) -2-hy droxycyclopentyl] adenosine N-[(trans)-3-hydroxycyclohexyl]adenosine N-[2B-hydroxy-2-methylcyclopentyl]adenosine and 20 N-[(cis)-2-hydroxycyclohexyl]adenosine Description of the Invention It has now been discovered that a selected group of adenosine derivatives, 25 some of which are claimed in GB 1,143,150, has potential therapeutic utility for treating central nervous system ailments such as cerebral ischaemia, epilepsy and pain in humans. They have a clear CNS effect in relevant animal models at the same time as having a superior side-effect profile with respect to cardiovascular properties. In addition, the compounds have utility 30 within myocardial ischaemia. Specifically, the following compounds possess therapeutic utility within the above-mentioned CNS indications: WO 93/23418 PCT/DK93/00158 2 52110 - 4 - 2-Chloro-N-(1 -phenoxy-2-propyl)adenosine 2-Chloro-N-[(R)-1-phenoxy-2-propyl]adenosine 2-Chloro-N-[(S)-1-phenoxy-2-propyl] adenosine 2-Chloro-N-(2-phenoxyethyl) adenosine 5 2-Chloro-N-[(R)-1 -phenyl-2-propyl] adenosine 2-Chloro-N-(1-phenyl-3-butyI)adenosine N-(1 -Phenoxy-2-propyl)adenosine 2-Amino-N- (1 -phenoxy-2-propyl) adenosine N-[(1 S, trans)-2-Hydroxycyclopentyl]adenosine 10 N-[(1 R, trans)-2-Hydroxycyclopentyi]adenosine 2-Chloro-N- (cis-2-phenoxy cyclopentyl) adenosine trans-2-Chloro-N-(2-phenoxycyclopentyI)adenosine 2-Chloro-N-[(R)-1-hydroxy-2-propyl]adenosine 2-Chloro-N-[(R)-1-phenylthio-2-propyl]adenosine 15 2-Chloro-N-[(R)-1-(4-fiuorophenoxy)-2-propyl]adenosine 2-Chioro-N-[(R)-2-phenoxy-1-propyl]adenosine 2-Chioro-N-[2-(phenyimethoxy)ethyl]adenosine 2-Fluoro-N-[(R)-1-phenoxy-2-propyl]adenosine 2-Methoxy-N-[(R)-1-phenoxy-2-propyl]adenosine 20 N-(2-Methoxyethyl)adenosine 2-Chioro-N-[(2-methoxyphenyl)methyl]adenosine 2-Chloro-N-[(R)-3-methyl-1-phenoxy-2-butyl]adenosine 2-Chloro-N-[(R)-1-(2-(2-propyloxy)phenoxy)-2-propyl] adenosine 2-Chloro-N-[(R)-1-phenylsulphonyl-2-propyl]adenosine 25 N- [ (2-methylphenyl) methyl] adenosine 2-Methyl-N-[(R)-1-phenoxy-2-propyl]adenosine 30 Accordingly, the present invention relates to adenosine analogues of PCI/DK93/00158 2 5 2 1 10 10 wherein X is hydrogen, amino, halogen, hydroxy, lower alkoxy or lower alkyl and R1 is .v. / 3 15 I ZR* wherein Y is methylene or a valence bond, R2 and R5 is H or lower, straight or branched alkyl, R3 is H or lower alkyl, or 20 R2 and R3 can together form a cyclobutyl, cyclopentyl, cyclohexy! or phenyl ring, Z is oxygen, methylene, sulphur, sulphonyl or a valence bond, R4 is H, lower alkyl, aralkyl a mono or bicyclic aromatic system optionally substituted with halogen, hydroxy, haloalkyl, alkyl, alkoxy, aryloxy, acyloxy 25 or alkylmercapto radicals, or a pharmaceutically acceptable salt thereof as these compounds have been found useful in treatment of a number of CNS-related ailments, such as cerebral ischaemia, epilepsy and pain. WO 93/23418 formula I -5- ■^N N HO (D HO OH 30 Further, the compounds of formula (I) are found to be useful agents, for lowering plasma free fatty acid (FFA) levels, as cardiovascular agents and 2 Ej 2 1 ^ - 6 - also have application to myocardial ischaemia. Methods of preparing the above mentioned compounds comprise: 5 Method A A compound of formula (I) may be prepared by reacting a substance of 10 formula (II), wherein L represents a leaving group such as a halogen atom (e.g. a chlorine or bromine atom) or a trimethylsilyloxy group, P1, P2 and P3 are the same or different and represent hydrogen or a protecting group such as benzoyl-, p-toluoyl-, lower alkanoyl- (e.g. acetyl-), a substituted silyl group (e.g. a trimethylsilyl or t-butyldimethylsilyl group) or in the case of P3, 15 a triarylmethyl group, or in the case of P1 and P2, a 2\3'-0-(1-methyl)ethyli-dene function, with a substituted amine of general formula (III) General process (A) L HN 20 25 P20 OP1 P20 OP1 WO 93/23418 PCT/DK93/00158 252 1 1 0 - 7 - 10 15 giving the compound of formula (IV) as the reaction product. In cases where P\ P2 and P3 are not hydrogen an additional step will be required to remove protecting groups from (IV); in cases where the groups P1, P2 and P3 are for example acetyl or benzoyl, suitable conditions for deprotection include the use of methanolic ammonia, an alkali metal carbonate in methanol, or an alkali metal alkoxide in the corresponding alcohol. Where the protecting groups are for example alkylsilicon or arylsilicon derivatives, suitable methods for deprotection include, for example, treatment with tetra-alkylammonium fluorides or aqueous hydrolysis in the presence of acid or base. Where the P1 and P2 groups comprise a 2\3'-0-(1-methyI)ethylidene function or P3 comprises triarylmethyl, suitable conditions for deprotection include, for example, hydrolysis with aqueous mineral acid. Method B A compound of formula (I) wherein X represents -NH2, O-alkyl or hydroxy, may be prepared by reacting a substance of general formula (V) _. General process (B) HN (V) (IV) 25 P20 OP1 P2 O OP1 30 HO OH WO 93/23418 PCT/DK93/00158 252 1 1 - 8 - [where L is a leaving group as defined in method (A)] with a nucleophile, for example, ammonia or with an anion (e.g. C^-alkoxide) to afford the product (IV). In cases where P1, P2 and P3 are hydrogen, compound (I) can be obtained directly. However, in cases where P1, P2 and P3 are not hydro-5 gen an additional step will be involved to remove protecting groups from (IV); examples of conditions for removal of protecting groups are given in process (A). In some reactions involving (V) with the anion C^-alkoxide, where P1, P2 and/or P3 are for example acetyl- or benzoyl-, partial or full deprotection may take place. In cases where only partial deprotection has 10 taken place, deprotection can be completed under conditions described in method (A). Accordingly, the present invention provides a method for treating cerebral ischaemia, epilepsy and pain in human or non-human animals, which 15 method comprises administering an effective, non-toxic amount of a compound of formula I or a pharmaceutically acceptable salt thereof, to human or non-human animals suffering from cerebral ischaemia, epilepsy or pain. The present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medica-20 ment for use in the treatment of cerebral ischaemia, epilepsy or pain. The present invention further provides a pharmaceutical composition for use in the treatment of cerebral ischaemia, epilepsy or pain which comprises an effective amount of a compound of formula I of a pharmaceutically accep-25 table salt thereof and a pharmaceutically acceptable carrier. Such compositions may be prepared in the manner as described below. Various salts of compounds of formula (I) can be prepared which can be considered physiologically acceptable. These include addition salts derived 30 from inorganic or organic acids, for example, acetates, fumarates, glutara-tes, glutaconates, lactates, maleates, methanesulphonates, phosphates, WO 93/23418 PCT/DK93/00158 25 2 1 1 0 -9- salicylates, succinates, sulphates, sulphamates, tartrates and paratoluene-sulphonates. In some cases, solvates of either the free nucleosides or the acid addition salts can be isolated and these solvates may, for example, be hydrates or alcoholates. 5 The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, and if desired in the form of a pharmaceutically-accep-table acid addition salt thereof, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be 10 employed as solids, such as tablets of filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral use (including subcutaneous .administration and infusion). Such pharmaceutical compositions 15 and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the adenosine receptor agonist commensurate with the intended daily dosage range to be employed. 20 The compounds of this invention can thus be used for the formulation of pharmaceutical preparations, e.g. for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy. Conventional excipients are such pharmaceutically 25 acceptable organic or inorganic carrier substances suitable for parenteral or enteral application which do not deleteriously react with the active compounds. Examples of such carriers are water, salt solutions, alcohols, polyethylene 30 glycols, polyhyroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, WO 93/23418 PCT/DK93/00158, 252 1 1 0 - 10 - pentaerythritol fatty acid esters, hydroxymethylceilulose and polyvinylpyrrolidone. The pharmaceutical preparations can be sterilized and mixed, if desired, 5 with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds. For parenteral application, particularly suitable are injectable solutions or 10 suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil. Ampoules are convenient unit dosage forms. 15 Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or com starch and/or potato starch, are particularly suitable for oral application. A syrup, elixir or the like can be used in cases where a sweetened vehicle can be employed. 20 Generally, the compounds of this invention are dispensed in unit form comprising 0.05-100 mg in a pharmaceutically acceptable carrier per unit dosage. The dosage of the compounds according to this invention is 0.1-300 mg/day, preferably 10-100 mg/day, when administered to patients, 25 e.g. humans, as a drug. A typical tablet which may be prepared by conventional tabletting techniques contains: 30 Active compound Lactosum 5.0 mg 67.8 mg Ph.Eur. WO 93/23418 PCT/DK93/00158 2 5 2 110 -11 - Avicel® 31.4 mg 1.0 mg 0.25 mg Ph. Eur. Amberlite®IRP 88 Magnesii stearas 5 Owing to activity against pain or convulsive disorders and prevention of neurodegeneration under conditions of anoxia/ischaemia the compounds of the invention are extremely useful in the treatment of related symptoms in mammals, when administered in an amount effective for agonist activity of compounds of the invention. The compounds of the invention may accor-10 dingly be administered to a subject, e.g., a living animal body, including a human, in need of an adenosine receptor agonist, and if desired in the form of a pharmaceutically-acceptable acid addition salt thereof (such as the hydrobromide, hydrochloride, or sulfate, in any event prepared in the usual or conventional manner, e.g., evaporation to dryness of the free base in 15 solution together with the acid), ordinarily concurrently, simultanously, or together with a pharmaceutically-acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective amount of adenosine receptor agonist, and in any event an amount which 20 is effective for the treatment of anoxia, traumatic injury, ischemia, migraine or other pain symptoms, epilepsy, or neurodegenerative diseases owing to their adenosine receptor agonist activity. Suitable dosage ranges are 1 -200 milligrams daily. 10-100 milligrams daily, and especially 30-70 milligrams daily, depending as usual upon the exact mode of administration, form in 25 which administered, the indication toward which the administration is directed, the subject in volved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge. 30 The preparation of compounds of the invention is further illustrated in the following examples: WO 93/23418 2 rrrro - 12- Hereinafter, TLC is thin layer chromatography, THF is tetrahydrofuran, TFA is tr;^uoracetic acid and mp is melting point. Where melting points are given, these are uncorrected. The structures of the compounds are confirmed by assignment of NMR spectra (from which representative peaks are 5 quoted) and by microanalysis where appropriate. Compounds used as starting materials are either known compounds or compounds which can be prepared by methods known per se. Column chromatography was carried out on Merck silica gel 60 (Art 9385). HPLC was carried out on a Waters or Merck chromatograph with a multiwavelength detector and a 10 reversed phase C18 column (250 x 4 mm, 5/xm, 100A; eluent flow rate 1 mL7 min at 35°C). Retention times are given in minutes. EXAMPLE 1 (Method A) 15 2-Chloro-N-f 1 -phenoxv-2-propvD adenosine The title compound was prepared by reacting 1-phenoxy-2-propylamine (16.62 g, 0.11 mol) with 9-(2,3,5-tri-0-acetyl-6-D-ribofuranosyl)-2,6-dichloro-9H-purine (24.6 g, 55 mmol) in dioxan (250 ml) in the presence of triet-20 hylamine (7.23 g, 71.5 mmol) followed by deprotection of the product using a solution of sodium (0.15 g, 6.5 mmol) in methanol (250 ml). The reaction mixture was neutralized with citric acid, and treated with a mixture of ethyl acetate (300 ml) and water (200 ml). The ethyl acetate phase was separated, dried (MgSOJ and evaporated before being purified by flash chroma-25 tography on silica gel, eluting initially with dichloromethane, and later with a mixture of dichloromethane and ethanol (9:1). This provided the title 2-chloro-N-(1-phenoxy-2-propyl)adenosine (18.2 g, 76%) (a mixture of diastereoisomers) as an amorphous foam, 1H NMR (DMSO-d6)£ 1.31 (3H, d, -CH3), 3.53 - 3.59 (1H, m, H-5'J, 3.64 - 3.71 (1H, m, H-5'J, 3.95 (1H, q, 30 H-4*), 4.06- 4.20 (3H. 2 m, H-3' and -CH2-), 4.54 (1H, m, H-2'), 4.65 (1H, m, -CHCH3), 5.07 (1H, t, 5'-OH), 5.21, 5.50 (2H, 2d, 2'- and 3'-OH), 5.84 (1H, d, WO 93/23418 PCT/DK93/00158 2 5 2 1 1 0 -13 - H-1'), 6.87 - 7.00 (3H. m, Ar-H), 7.23 - 7.32 (2H, t, Ar-H), 8.31 - 8.45 (2H, m, H-8 and N-H). The corresponding maleate salt was prepared by dissolving the above 5 2-chloro-N-(1-phenoxy-2-propyl)adenosine (1.7 g, 3.9 mmol) in THF (10 ml), adding diethyl ether (60 ml) followed by maleic acid (0.45 g, 3.9 mmol). The residue on evaporation was treated with diethyl ether (50 ml) whereupon the maleate salt precipitated and was collected by filtration (1.15 g), m.p. 102-104°C. 10 CaaHgeCINgC^ requires C. 50.0; H, 4.7; N, 12.7. Found: C, 50.3; H, 4.9; N, 12.7%. 15 EXAMPLE 2 (Method 2-Chloro-N-r (R)-1 -phenoxv-2-propvll adenosine (R)-N-(tert-Butoxycarbonyl)-2-amino-i-propanol 20 (R)-2-Amino-1-propanol (15.0 g, 200 mmol) was dissolved in 1N sodium hydroxide (198 ml) and THF (85 ml) was introduced. The reaction mixture was cooled to 0°C and a solution of di-tert-butyl dicarbonate (52.4 g, 240 mmol) in THF (230 ml) was added dropwise over 30 min. The reaction 25 mixture was stored at 4°C for 72 h., allowed to reach room temperature and filtered. The filtrate was evaporated to remove THF and the aqueous phase was extracted with ethyl acetate (2 x 200 ml). The combined extracts were dried (MgS04), evaporated and the crude product was dissolved in dich-loromethane (100 ml) and extracted into water (5 x 200 ml). The combined 30 aqueous extracts were evaporated in vacuo. The resultant oil crystallised whilst standing at room temperature to provide the required alcohol WO 93/23418 PCT/DK93/00158 252 1 1 - 14 - (15.35g, 44%), mp 59 - 61°C, 1H NMR (DMSO-d6)5 1.15 (3H, d, -CHCHj), 1.45 (9H, s, butyl-CHg). 3.50 (1H. dd, -CH2a-), 3.65 (1H, dd, -CH2b-), 3.70 -3.80 (1H, m. CH). 5 (R)-N-(tert-Butoxycarbonyl)-1 -phenoxy-2-propylamine (R)-N-(tert-butoxycarbonyl)-2-amino-1-propanol (10.0 g, 57 mmol), triphe-nylphosphine (22.5 g, 86 mmol) and phenol (5.4 g, 57 mmol) was dissolved in toluene (200 ml). Diethyl azodicarboxylate (14.9 g, 86 mmol) in toluene 10 (100 ml) was slowly added keeping the temperature below 35°C (Mitsuno-bu, O., Synthesis, 1981,1; Manhas, M.S.; Hoffman, W.H.; Lai, B.; Bose, A.K., J. Chem. Soc. Perkin Trans I, 1974, 461). The resulting yellow solution was stirred for 16 h at room temperature before being washed with 1N hydrochloric acid (3 x 100 ml). The organic phase was dried (MgS04), 15 evaporated in vacuo, and the residual oil was purified by flash chromatography eluting with heptane/ethyl acetate (4/1) giving the desired product (8.0 g, 59%), 1H NMR (DMSO-d6)5 1.10 (3H, d, -CH3), 1.38 (9H, s, butyl-CH3), 3.70 - 3.90 (3H, m, -CH-CH2-), 6.85 - 6.95 (3H, m, Ar-H), 7.25 (2H, t. Ar-H). 20 (R)-1 -Phenoxy-2-propylamine (R)-N-(tert-Butoxycarbonyl)-1-phenoxy-2-propylamine (8.0 g, 33 mmol) was dissolved in ethyl acetate (100 ml). A solution of hydrochloric acid (g) in 25 ethyl acetate (6N, 100ml) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 20h during which time a heavy precipitate was formed. The reaction mixture was concentrated to half the original volume before the product was collected by filtration and dried in vacuo to provide the title compound as a white solid hydrochloride 30 (4,3 g, 69%) m.p. 186 - 189°C. 'H NMR (DMSO-de)* 1.31 (3H, d, -Oy, 3.51 - 3.60 (1H, m, -CH-), 4.05 (1H, dd, -CH2a-), 4.12 (1H, dd, -CH2b-), 6.95 - WO 93/23418 PCT/DK93/00158 252 1 1 0 - 15- 7.00 (3H, m, Ar-H), 7.32 (2H, t, Ar-H). 2-Chloro-N-[(R)1-phenoxy-2-propyl] adenosine 5 (R)-1-phenoxy-2-propylamine (4.3 g, 23 mmol) was reacted with 9-(2,3,5-tri-0-benzoyl-B-D-ribofuranosyl)-2,6-dichloro-9H-purine (11.2 g, 18 mmol) in dioxan (150 ml) in the presence of diisopropylethylamine (5.3 g, 41 mmol). The reaction mixture was stirred at room temperature for 18 h, heated at 50°C for 4h, and stirred at room temperature for 60h before being filtered 10 and evaporated. The product (after purification by flash chromatography) was debenzoylated with methanolic ammonia to provide the title 2-chloro-N-[(R)-1-phenoxy-2-propyl]adenosine (after column chromatography) as a foam (4.2 g, 64%), 1H NMR (DMSO-d^s 1.31 (3H, d, -CHg), 3.52 - 3.59 (1H, m, H-5'a), 3.63 -3.72 (1H, m, H-5'b), 3.92 - 3.99 15 and 4.10 - 4.21 (4H, 2 m, H-3\ H-4' and -CH2-), 4.52 (1H, dd, H-2'), 4.65 (1H, m, -CH3CH-), 5.07 (1H, t, 5'-OH), 5.22, 5.49 (2H, 2d, 2' and 3'-OH), 5.84 (1H, d, H-1*), 6.88 - 7.02 (3H, m, Ar-H), 7.24 - 7.33 (2H, dd, Ar-H), 8.32 - 8.45 (2H, s & m, H-B and N-H). 20 C19H22CIN505 requires C, 52.4; H, 5.1; N, 16.1. Found: C, 52.0; H, 5.2; N, 15.8%. EXAMPLE 3 (Method A) 25 2-Chloro-N-r(SM-phenoxv-2-propvn adenosine 2-Chloro-N-[(S)-1-phenoxy-2-propylJadenosine was prepared by the procedure described for Example 2, except that (S)-2-amino-1-propanol was used in the first step, providing the opposite diastereoisomer to Example 2. 30 The nucleoside was obtained as a hemihydrate: C^H^CINgOg.O.S H20 requires C, 51.8; H, 5.2; N, 15.9. Found: C, 51.8; H, WO 93/2? 418 PCT/DK93/00158 2 5 2 1 10 - 16- 5.3; N, 15.6%. EXAMPLE 4 (Method A) 5 2-Chloro-N-(2-phenoxvethvfladenosine The title compojnd was prepared by reacting 2-phenoxyethylamine hydrochloride (0.80 g, 4.6 m mol) with 9-(2,3,5-tri-0-benzoyl-B-D-ribofuran-osyl)-2,6-dichloro-9H-purine (2.0 g, 3.2 mmol) in dioxan (25 ml) in the pre-10 sence of triethylamine (1.0 g, 9.6 mmol) followed by deprotection of the purified product using methanolic ammonia to provide the title nucleoside (0.75 g, 60%) (following flash chromatography) as an amorphous foam, 1H NMR (DMSO-dg) 6 3.52 - 3.59 (1H. m, H-5'J, 3.64 - 3.71 (1H, m, H-5'J, 3.82 (2H, q, -CH2-), 3.96 (1H, q, H-4'), 4.14 (1H. m, H-3'). 4.52 (1H, q, H-2'), 5.12 15 (1H, t, 5-OH), 5.25, 5.54 (2H, 2d, 2'- and 3'-OH), 5.85 (1H, d, H-1'), 6.92 -7.02 (3H, m, Ar-H), 7.26 - 7.34 (2H, t, Ar-H), 8.46 (1H, m, H-8), 8.56 (1H, br t, N-H). C18H2oCIN505.0.75 HzO requires C, 49.7; H, 5.0; N, 16.1. Found: C, 49.7; H. 20 5.0; N, 15.7%. EXAMPLE 5 (Method A) 25 2-Chloro-N-r(R)-1-phenvl-2-propyl1adenosine The title compound was prepared by reacting L-amphetamine (0.49 g, 3.6 mmol) with 9-(2,3,5-tri-0-benzoyl-B-D-ribofuranosyi)-2,6-dichloro-9H-purine (1.9 g, 3.0 mmol) in dioxan (25 ml) in the presence of diisopropylethylamine 30 (0.58 g, 4.5 mmol) followed by deprotection of the purified product using methanolic ammonia. Evaporation of the reaction mixture provided a gum- WO 93/23418 PCT/DK93/00158 2 5 2 I 1 - 17 - my residue which crystallized on addition of dichloromethane (10 ml), to provide the title compound (0.26 g, 38%) as a solid, m.p. 132.5 - 135.5°C. A further sample of the title compound (0.26 g) was obtained by flash chromatography of the mother liquors. 1H NMR (DMSO-d^s 1.22 (3H, d, -CH^. 5 2.67 - 2.79 & 2.92 - 3.03 (2H, 2m, -CK-). 3.51 - 3.58 (1H, m, H-5'a), 3.62 -3.68 (1H, m, H-5'J, 3.94 (1H, q, H-4'), 4.12 (1H, m, H-3'), 4.41 - 4.54 (2H, m, H-2' and CH3CH-), 5.06 (1H, t, 5'-OH), 5.22, 5.49 (2H, 2d, 2' and 3-OH), 5.82 (1H, d, H-1'), 7.10 - 7.33 (5H, m, Ar-H), 8.28 - 8.44 (2H, m, H-8 and N-H). 10 C19H22CIN504.0.5 H20 requires C, 53.2; H, 5.4; N, 16.3. Found: C, 53.3; H, 5.4; N, 16.3%. 15 EXAMPLE 6 (Method A) 2-Chloro-N-( 1 -phenvl-3-butvOadenosine 3-Amino-1-phenylbutane (0.67 g, 3.6 mmol) was reacted with 9-(2,3,5-tri-20 0-benzoyl-B-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.9 g, 3 mmol) in dioxan (25 ml) in the presence of diisopropylethylamine (0.58 g, 4.5 mmol). The reaction mixture was stirred at room temperature for 18 h, filtered and evaporated. The product (after purification by flash chromatography) was debenzoylated with methanolic ammonia to provide the title 2-chloro-N-(1-p-25 henyl-3-butyl)adenosine (mixture of diastereoisomers) as a foam (0.72 g, 56%), 1H NMR (DMSO-dg)* 1.12 (3H, d, -CH3), 3.53 - 3.61 (1H, m, H-5'a), 3.64 - 3.72 (1H. m, H-5'b), 3.93 - 3.99 (1H, m, H-4'), 4.11 - 4.17 (1H, m, H-3'), 4.22 - 4.36 (1H, m, -CH2CH-), 4.53 (1H, dd, H-2'), 4.65 (1H, m, -CH3CH-), 5.10 (1H, t, 5'-OH), 5.25, 5.51 (2H, 2d, 2* and 3'-OH), 5.83 (1H. d, H-1'), 30 7.12 - 7.30 (5H, m, Ar-H). 8.28 - 8.37 (1H, m, N-H), 8.40 (1H. s. H-8). WO 93/23418 PCT/DK93/00158 252 110 -18- C2oH24CIN504.H20 requires C, 53.2; H, 5.8; N. 15.5. Found: C, 53.9; H, 5.7; N, 15.6%. EXAMPLE 7 (Method A) 5 N-(1 -Phenoxv-2-propvl)adenosine 1 -Phenoxy-2-propylamine (0.33 g, 2.18 mmol) was reacted with 6-chloro-purine riboside (i.e. 9-B-D-ribofuranosyl-9H-purine) (0.5 g, 1.7 mmol) in 10 dioxan (30 ml) in the presence of diisopropylethylamine (0.28 g, 2.2 mmol). The reaction mixture was heated at reflux for 5 h, cooled and evaporated. The residue was purified by flash chromatography on silica gel to provide the N-(1-Phenoxy-2-propyl)adenosine (a mixture of diastereoisomers) as a foam (0.06 g, 7%), 'H NMR (DMSO-dJj 1.32 (3H, d, -CH3), 3.52 - 3.60 (1H, 15 m, H-5'J, 3.64 - 3.71 (1H, m, H-5'b), 3.93 - 3.99 and 4.12 - 4.20 (4H, 2m, m, H-4', H-3' and -CH2-), 4.62 (1H, q, H-2'), 4.68 - 4.82 (1H, m, -CHCH3), 5.40 (1H, t, 5-0H), 5.20, 5.45 (2H, 2d, 2'- and 3'-OH), 5.90 (1H, d, H-1'), 6.88 -6.98 (3H, m, Ar-H), 7.23 - 7.31 (2H, t, Ar-H), 7.85, 8.21, 8.38 (3H, 3s, H-2, H-8 and N-H). 20 EXAMPLE 8 (Method A) 2-Amino-N-(1-phenoxv-2-propvO adenosine 25 1 -Phenoxy-2-propylamine (2.90 g, 19.2 mmol) and 9-(2,3,5-tri-0-acetyl-B-D-ribofuranosyl)-2-amino-6-chloro-9H-purine (6.94 g, 16.2 mmol) were dissolved in dioxan (50 ml) and triethylamine (4.5 ml, 33.2 mmol) was introduced. After stirring the reaction mixture for 18 h at room temperature, diisopropylethylamine (2.08 g, 16.1 mmol) was added and the solution was heated at 30 80°C for 100 h. Following column column chromatography, a 1.3 g sample of the resultant 2',3',5'-tri-0-acetyl-2-amino-N-(1-phenoxy-2-propyl)adenosi- WO 93/23418 pCT/DK93/00158j L J c i i - 19- ne was deprotected using saturated methanolic ammonia (50 ml). The reaction mixture was evaporated, and the residue dissolved in in a mixture of ethyl acetate (150 ml) and water (150 ml). The phases were separated and the ethyl acetate phase was washed with water (2 x 150 ml). The ethyl ace-5 tate phase was then extracted with pH 2 dilute hydrochloric acid, and this acidic aqueous phase was washed with ethyl acetate (2 x 100 ml), and basified with sodium bicarbonate solution before extraction with ethyl acetate (100 ml). The ethy acetate phase was was dried (MgS04) and evaporated to give the title compound (0.43 g, 33%) a mixture of diastereoiso-10 mers as an amorphous foam, 1H NMR (DMSO-dg)$ 1.28 (3H, d, -CH3), 3.49 - 3.57 (1H, m, H-5'a), 3.61 - 3.68 (1H, m, H-5'b), 3.85 - 3.94 and 4.07 -4.15 (4H, 2m, m, H-4', H-3' and -CH2-), 4.50 (1H, q, H-2'), 4.68 (1H, br, -CHCHg), 5.11, 5.36 (2H, 2d, 2'- and 3'-OH), 5.40 (1H, t, 5'-0H) 5.73 (1H, d, H-1'), 5.83 (1H, br, -NH2), 6.88 - 6.96 (3H, m, Ar-H), 7.22 - 7.31 (2H, t, Ar-H), 15 7.95 (1H, s, H-8). C19H24CIN505.0.75 HzO requires C, 53.1; H, 6.0; N, 19.5. Found: C, 53.0; H, 6.0; N, 19.2%. 20 EXAMPLES 9 and 10 (Method A) N-171R. Trans)-2-hvdroxvcvclQDentvnadenosine and N-F(1S. Trans)-2-hvdroxvcvclopentvlladenosine 25 Trans-2-hydroxycyclopentylamine (0.35 g, 3.46 mmol) (prepared by reaction of cyclopentene oxide with ammonia in a sealed vessel: see example 11) was reacted with 6-chloropurine riboside (i.e. 9-fl-D-ribofuranosyl-9H-purine) (0.5 g, 1.7 mmol) in dioxan (30 ml) in the presence of triethylamine (0.93 g, 9 mmol). The reaction mixture was heated at 100°C for 70 h, cooled and 30 evaporated. The resultant residue was purified by flash chromatography eluting with a mixture of ethyl acetate and methanol (19:1). The fractions WO 93/23418 PCT/DK93/00158 2 5 2 1 1 -20 - found to contain the highest amounts of N-[(1 R, trans)-2-hydroxycyclopen-tyljadenosine following HPLC examination, were combined and evaporated to a solid (0.17 g). Recrystaliisation from methanol provided the pure N-[(1R, trans)-2-hydroxycyclopentyl]adenosine (0.11 g, 18%) mp 233-235°C. 5 1H NMR (DMSO-dg)S 1.43 - 2.12 (6H, 4m, -CH2CH2 CH2-), 3.52 - 3.59 (1H, m, H-5'J, 3.54 - 3.71 (1H, m, H-5'b), 3.97 (1H, q, H-4'), 4.07 (1H, br, -CHOH) 4.15 (1H, q, H-3'), 4.61 (1H. q, H-2'), 4.87, 5.21, 5.41 - 5.47 (4H, d & 3m, OH groups), 5.89 (1H, d, H-1'), 7.75 (1H, br d, -NH), 8.21 and 8.37 (H-2 and H-8). 10 The mother liquors from the above recrystaliisation were evaporated and purified by short path chromatography on silica gel (Art. 7729) and the product recrystallised to provide N-[(1S, trans)-2-hydroxycyclopentyl]adeno-sine (0.05 g, 4%), 1H NMR (DMSO-de)* 1.44 - 2.13 (6H, 4m, -CH2CH2CH2-), 15 3.52 - 3.59 (1H, m, H-5'J, 3.54 - 3.71 (1H, m, H-5'b), 3.96 (1H, q, H-4'), 4.15 (1H, q, H-3'), 4.60 (1H, q, H-2'), 5.20, 5.41 - 5.47 (3H, d & m, 2', 3' and 5'-OH), 5.88 (1H, d, H-1'), 7.75 (1H, br d, -NH), 8.19 and 8.36 (H-2 and H-8). EXAMPLE 11 (Method A) 20 2-Chloro-N-(cis-2-phenoxvcvclopentvl)adenosine trans-N-(tert-Butvloxycarbonyl)-2-hydroxycyclopentylamine This compound was prepared as a mixture of enantiomers by reaction of 25 cyclopentene epoxide (8.0 g, 95.1 mmol) with a 25% aqueous ammonia solution (35 ml) in a sealed glass vessel at 110°C for 1.5 h. The reaction mixture was cooled and evaporated to half its original volume before 1N sodium hydroxide solution (95 ml) and THF (100 ml) were introduced at 0°C. A solution of di-tert-butyl dicarbonate (21.8 g, 99.6 mmol) in THF (50 30 ml) was added dropwise and the reaction mixture stirred at room temperature for 18 h. The phases were separated and the aqueous phase was WO 93/23418 PCT/DK93/00158 2 5 2 1 1 -21 - washed with ethyl acetate (100 ml). The organic phases were combined and washed with saturated brine (100 ml), dried (MgS04) and evaporated. The solid residue was recrystallised from a 10:1 mixture of heptane and ethyl acetate (55 ml) to provide an analytical sample of trans-N-(tert-buty-5 loxycarbonyl)-2-hydroxycyclopentylamine (4.06 g, 21%), mp 103 - 105°C. C10H19NO3 requires C. 59.7; H, 9.5; N, 7.0. Found: C, 59.6; H, 9.8; N, 7.0%. The above trans-N-(tert-butyloxycarbonyl)-2-hydroxycyclopentylamine was 10 converted into cis-2-phenoxv-cvclopentvl-amine by the sequence of reactions described in Example 2 (i.e. phenyl ether formation by the Mitsunobu procedure resulting in inversion at the 2-position, followed by acidic hydrolysis of the BOC- group using TFA). 15 cis-2-Phenoxvcvclopentvlamine (0.75 g, 4.23 mmol) was combined with 9-(2,3,5-tri-0-benzoyl-B-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.95 g, 4.7 mmol) and triethylamine (0.64 g, 6.3 mmol) in dioxan (30 ml) and stirred for 50 h. The reaction mixture was filtered, evaporated and the residue dissolved in ethyl acetate and washed with water (2 x 50 ml). The 20 organic phase was dried (MgS04), evaporated and the residue coevapora-ted to give cis-2'.3'.5'-tri-0-benzovl-2-chlo.ro-N-(2-phenoxvcvclopentvl)ade-nosine (3.1 g, 90%) as an amorphous foam, which was deprotected using saturated methanolic ammonia (50 ml). After 70 h at room temperature the reaction mixture was evaporated and the residue purified by flash chroma-25 tography on silica gel, eluting with a mixture of dichloromethane and methanol (19:1). The title cis-2-chloro-N-(2-phenoxycyclopentyl)adenosine (0.925 g, 53%) was obtained as an amorphous foam (a 1:1 mixture of diastereoi-somers), 1H NMR (DMSO-de)* 1.58 - 2.15 (6H, 3m, -CH2CH2CH2-), 3.51 -3.60 (1H, m, H-5'a), 3.62 - 3.71 (1H, m, H-5'b), 3.95 (1H, br q, H-4'), 4.12 30 (1H, br q, H-3'), 4.46 - 4.62 (2H, m, H-2' and -CH), 4.82 - 4.89 (1H, m, -CH), 5.07 (1H, br t, 5-OH), 5.22, 5.49 (2H, 2d, 2'- and 3'-OH), 5.83 (1H, d, H-1"). WO 93/23418 PCT/DK93/00158 ? R 9 1 1 -22 - 6.80 - 6.91 (3H, m, Ar-H), 7.15 - 7.24 (2H, t, Ar-H), 7.99, 8.22 (1H, d & m, N-H), 8.41, 8.45 (1H, 2s, H-8). C21H24CIN505.0.5 H2° requires C, 53.6; H, 5.4; N, 14.9. Found: C, 53.5; H, 5 5.3; N, 14.7%. EXAMPLE 12 (Method A) 10 Trans-L-chloro-N-(2-phenoxvcvclopentvnadenosine Cis-N-(tert-butyloxycarbonyl)-2-hydroxycyclopentylamine Trans-N-(tert-butyloxvcarbonvl)-2-hydroxycyclopentylamine (24.7 g, 123 15 mmol) (prepared as described in Example 11) was dissolved in THF (500 ml) and 4-nitrobenzoic acid (20.51 g, 123 mmol) was added, followed by triphenylphosphine (48.28 g, 184 mmol). A solution of diethylazodicarboxy-late (32.06 g, 184 mmol) in THF (250 ml) was introduced dropwise. The reaction mixture was stirred for 18 h at room temperature, evaporated and 20 purified by flash chromatography eluting with a mixture of cycohexane and ethyl acetate (4:1) to provide the intermediate 4-nitrobenzoyl ester as a solid (25.5 g), TLC R, 0.52 [Si02: cyclohexane/ ethyl acetate (1:1)]. This ester was suspended in a mixture of a mixture of methanol (180 ml) and 25% aqueous ammonia solution (20 ml) and the mixture was stirred at room tempera-25 ture for 70 h before evaporation to a residue. Purification by flash chromatography eluting with a mixture of cycohexane and ethyl acetate (4:1) provided fractions containing the title compound which crystallised on evaporation to afford cis-N-(tert-butvloxvcarbonvl)-2-hvdroxvcvclopentvlamine as a solid (11.0 g, 44%), mp 64 - 65°C. 30 This cis-N-(tert-butyloxycarbonyl)-2-hydroxycyclopentylamine was converted WO 93/23418 PCT/DK93/00158 2 52 1 1 0 -23 - into trans-2-DhenoxvcvcloDentvlamine hydrochloride by Mitsunobu phenyl ether formation and deprotection - the methods described in Example 2. 9-(2,3,5-Tri-0-benzoyl-B-D-ribofuranosyl)-2,6-dichloro-9H-purine (3.0 g, 4.7 5 mmol) was dissolved in dioxan (30 ml) and trans-2-phenoxycyclopentylami-ne hydrochloride (0.95 g, 4.4 mmol) was added followed by triethylamine (0.64 g, 6.3 mmol). The reaction mixture was stirred at room temperature for 72 h and purified by flash chromatography on silica gel to provide a foam to which saturated methanolic ammonia (100 ml) was added. After 16 10 h at room temperature, the reaction mixture was evapor ^ed and purified by flash chromatography to provide the title trans-2-chloro-N-(2-phenoxvcvclo-pentyl)adenosine (0.70 g, 35%) as an amorphous foam (a mixture of dia-stereoisomers), 1H NMR (DMSO-d^ 1.56 - 2.30 (6H, 3m, -CH2CH2CH2-), 3.52 - 3.60 (1H, m, H-5'J, 3.63 - 3.71 (1H, m, H-5'b), 3.96 (1H, q, H-4'), 4.13 15 (1H, q, H-3"), 4.50 - 4.61 (2H, m, H-2' and -CH), 4.82 - 4.89 (1H, m, -CH), 5.08 (1H, t, 5'-OH), 5.23, 5.49 (2H, 2d, 2'- and 3'-OH), 5.83 (1H, d, H-1'), 6.90, 7.07 and 7.25 (5H, t,d,t, Ar-H), 8.43 (1H. s, H-8), 8.60 (1H, d, N-H). C2,H24CIN5Os 0.5 H20 requires C, 53.6; H, 5.4; N, 14.9. Found: C, 53.4; H, 20 5.5; N, 14.5%. EXAMPLE 13 (Method A) 25 2-Chloro-N-r (R)-1 -hvdroxv-2-propvll adenosine (R)-2-Amino-1-propanol (0.23 g, 3.0 mmol), 9-(2,3,5-tri-0-benzoyl-B-D-ribo-furanosyl)-2,6-dichloro-9H-purine (1.7 g, 2.7 mmol) and triethylamine (0.30 g, 3.0 mmol) were dissolved in dioxan (20 ml) and stirred for 200 h at room 30 temperature. Following purification by column chromatography, the resultant 2',3',5'-tri-0-benzoyl-2-chloro-N-[(R)-1 -hydroxy-2-propyl]adenosine was de- WO 93/23418 PCT/DK93/00158 2 5 2 1 1 0 - 24 - protected using methanolic ammonia to provide the title 2-chloro-N-[(R)-1-hydroxy-2-propyl]adenosine as an amorphous foam (0.5 g, 54%), 'H NMR (DMSO-d6)S 1.17 (3H, d, -CH3), 3.35 - 3.72 (4H, m, H-5'a, H-5'b and -CH2-), 3.96 (1H, q, H-4'), 4.14 (1H, m, H-31), 4.52 (1H, dd, H-2'), 5.08 (1H, t, 5'-5 OH), 5.22, 5.49 (2H, 2d, 2' and 3'-OH), 5.83 (1H, d, H-1'), 8.0 (1H, d, N-H) 8.40 (1H, s , H-8). C13H17CIN505.0.75 H20 requires C, 41.9; H, 5.0; N, 18.8. Found: C, 42.1; H, 5.2; N, 15.8%. 10 EXAMPLE 14 (Method A) 2-Chloro-N-r (RV1 -phenvlthio-2-propvn adenosine 15 (R)-N-tertbutyloxycarbonyl-l -phenylthio-2-propylamine Thiophenol (1.5 g, 14 mmol) was dissolved in dry THF (100 ml) and a 60% oil dispersion of sodium hydride (0.30 g, 14 mmol) was added in portions under nitrogen. After stirring for 15 min. at room temperature, the mesylate 20 ester of N-tert-butoxycarbonyl-2-hydroxypropylamine (3.2 g, 14 mmol) was added in three portions and the reaction mixture was heated at 70°C for 18 h. After cooling, water (30 ml) was added, the aqueous phase was separated and washed with dichloromethane (50 ml). The combined organic phases were dried (MgS04) and evaporated to give (R)-N-tertbutyloxycarbonyl-25 1-phenylthio-2-propylamine as a fawn oil (3.2 g, 85%), TLC R, 0.64 [Si02: heptane/ ethyl acetate (1:1)]. This (R)-N-(tert-butoxycarbonyl)-1 -phenylthio-2-propylamine was converted into (R)-1-phenylthio-2-propylamine hydrochloride by acidic hydrolysis using 30 the method described in Example 2. WO 93/23418 PCT/DK93/00158 2 D ii 1 10 -25- 25 (R)-1-Phenylthio-2-propylamine (0.4 g, 1.96 mmol) was reacted with 9-(2,3,5-tri-0-benzoyl-B-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.2 g, 1.9 mmol) in dioxan (15 ml) in the presence of triethylamine (0.4 g, 4 mmol). The reaction mixture was stirred at room temperature for 72 h, heated at 50°C for 24 h, cooled, filtered and evaporated. The product (after purification by flash chromatography) was debenzoylated with methanolic ammonia to provide the title 2-chloro-N-[(R)-1-phenylthio-2-propyl]adenosine (after column chromatography) as a foam (0.47 g, 52%), 'H NMR (DMSO-d^tf 1.34 (3H, d, -CHg), 3.01 (1H, dd, -C-H), 3.52 - 3.60 (1H, m, H-5'a), 3.62 -3.72 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.13 (1H, m, H-3'), 4.30 - 4.45 (1H, m, -C-H), 4.53 (1H, m, H-2'), 5.09, 5.22, 5.50 (3H, 3 br, 2', 3'and 5'-OH), 5.84 (1H, d, H-1'), 7.19 (1H, t, Ar-H), 7.30 (2H, t, Ar-H), 7.45 (2H, d, Ar-H), 8.29 - 8.45 (2H, s & m, H-8 and N-H). C^H^CINgC^S requires C, 50.5; H, 4.9; N, 15.5. Found: C, 50.6; H, 5.1; N, 15.2%. EXAMPLE 15 (Method A) (R)-2-Chloro-N-ri-(4-fluorophenoxv)-2-propvl1 adenosine (R)-1-(4-fluorophenoxy)-2-propylamine (0.29 g, 1.4 mmol) (prepared from 4-fluorophenol by the method desrcribed in example 2) was reacted with 9-(2,,3,,5'-tri-0-benzoyl-B-D-ribofuranosyl)-2,6-dichloro-9H-purine (0.89 g, 1.4 mmol) in dioxan (30 ml) in the presence of triethylamine (0.42 g, 3 mmol). The reaction mixture was stirred at room temperature for 18 h, and heated at 60°C for 4 h. The reaction mixture was filtered and evaporated to a residue which was purified by flash chromatography. The resultant 2',3',5,-tri-0-benzoyl-2-chloro-N-[(R)-1 -(4-fiuorophenoxy)-2-propyl]adenosine was depro-tected using methanolic ammonia to provide the title 2-chloro-N-[(R)-l-(4-fluorophenoxy)-2-propyl]adenosine (0.21 g, 40%) (after column chromato- WO 93/23418 PCI7DK93/00158 2 5 2 1 1 0 -26- graphy), mp 172 - 173°C; 1H NMR (DMSO-cy* 1.29 (3H, d, -CH3), 3.52 -3.60 (1H, m, H-5'a), 3.64 - 3.72 (1H. m, H-5'b), 3.92 - 4.00 (2H, m, H-4' and -C-H), 4.05 - 4.20 (2H, m, H-3' and -C-H), 4.53 (1H, m, H-2'), 4.65 (1H, m, -CH3CH-), 5.08, 5.24, 5.50 (3H, 3 br, 2', 3' and 5'-OH), 5.86 (1H, d, H-1'), 5 6.89 - 7.15 (4H, 2 m, Ar-H), 8.30 - 8.46 (2H, m, H-8 and N-H). C19H21CIFN5Os requires C, 49.8; H, 4.7; N, 15.3. Found: C, 49.4; H, 4.7; N, 14.9%. 10 EXAMPLE 16 (Method A) 2-Ch!oro-N-lYRV2-phenoxv-1-propyl! adenosine (R)-2-Phenoxy-1-propylamine (0.6 g, 2.9 mmol) (prepared by the method 15 described in example 2) was reacted with 9-(2,3,5-tri-0-benzoyl-6-D-ribo-furanosyl)-2,6-dichloro-9H-purine (1.5 g, 2.4 mmol) in dioxan (20 ml) in the presence of triethylamine (0.5 g, 5.3 mmol). The reaction mixture was stirred at room temperature for 72 h before being filtered and evaporated. The product, following purification by flash chromatography, was treated with 20 saturated methanolic ammonia (30 ml) for 18 h and evaporated to provide a solid residue. This solid was washed thoroughly with dichloromethane to provide the title 2-chloro-N-[(R)-2-phenoxy-1-propyl]adenosine (0.7 g, 65%), mp 175 - 177°C, 1H NMR (DMSO-d^ff 1.39 (3H, d, -CHg), 3.56 (1H, ABX, H-5'a), 3.68 (1H, m, H-5'b), 3.33 - 3.40 (1H, m, -C-H), 3.83 - 3.92 (1H, m, -C-25 H), 3.96 (1H, q, H-4'), 4.14 (1H, m, H-3'), 4.53 (1H, dd, H-2'). 4.70 (1H, q, -C-H), 5.08, 5.34, 5.50 (3H, 3 br, 2', 3' and 5'-OH), 5.85 (1H, d, H-1'), 6.90 (1H, t, Ar-H), 7.11 (2H, d, Ar-H), 7.28 (2H, t, Ar-H), 8.45 (1H, s, H-8), 8.63 (1H, t. N-H). 30 C^H^CINgOs requires C, 52.4; H, 5.1; N, 16.1. Found: C, 52.5; H, 5.1; N, 15.9%. WO 93/23418 PCT/DK93/00158 2 5 2 1 1 -27 - EXAMPLE 17 (Method A) 2-Chloro-N-r2-(phenvlmethoxv)ethvlladenosine 5 The title compound was prepared by reacting 2-(phenylmethoxy)ethylamine hydrochloride (0.51 g, 2.7 mmol) with 9-(2,3,5-tri-0-benzoyl-B-D-ribofuran-osyl)-2,6-dichloro-9H-purine (1.43 g, 2.25 mmol), followed by debenzoyla-tion of the purified product using methanolic ammonia to provide the title 2-chloro-N-[2-(phenylmethoxy)ethyl]adenosine (0.38 g, 44%) (after column 10 chromatography) as a solid, mp 115 -124°C, 'H NMR (DMSO-d^s 3.50 -3.58 (1H, m, H-5'a), 3.60 - 3.70 (4H, m, H-5*b, -CH2- and -CH-), 3.95 (1H, q, H-4'), 4.04 - 4.16 (2H, m, H-3' and -CH-), 4.52 (1H, br s, H-2' and -CHz-)f 5.07 (1H, t, 5-OH), 5.21, 5.50 (2H, 2d, 2'-and 3'-OH), 5.84 (1H, d, H-1'), 7.22 - 7.36 (5H, m, Ar-H), 8.25 - 8.40 (2H, m, H-8 and N-H). 15 20 C19H22CIN505. 0.1 H20 requires C, 52.1 ; H, 5.1 ; N, 16.0. Found: C, 51.8; H, 5.3; N, 15.6%. EXAMPLE 18 (Method A) 2-Fluon>N-r(R')-1-phenoxv-2-propvnadenosine ' 9-(2,3,5-Tri-0-acetyl-B-D-ribofuranosyi)-6-chloro-2-fluoro-9H-purine (1.03 g, 2.38 mmol) PCT Publication No. WO 93/08206, (R)-1-phenoxy-2-propylami-25 ne (0.36 g, 2.38 mmol) and triethylamine (0.29 g, 0.28 mmol) in dioxan (20 ml) were stirred at room temperature for 18 h. The reaction mixture was filtered and evaporated to a residue which was purified by flash chromatography. The resultant 2\3\5,-tri-0-acetyl-2-fluoro-N-[(R)-1-phenoxy-2-pro-pyl]adenosine was deprotected using methanolic ammonia to provide the 30 title 2-fluoro-N-[(R)-1-phenoxy-2-propyl]adenosine (0.28 g, 23%) (after column chromatography), mp 148 - 150°C; 1H NMR (DMSO-d6)s 1.33 (3H, d, WO 93/23418 PCT/DK93/00158 2 5 2 1 1 0 - 28- 3.59 (1H. m, H-5'J, 3.63 - 3.71 (1H, m, H-5'b), 3.92 - 3.99 (2H, m, H-4' and -C-H), 4.10 - 4.18 (2H, m, H-3' and -C-H), 4.51 (1H, q, H-2'), 4.61 (1H, m, -CH3CH-), 5.06 (1H, t, 5-0H), 5.22, 5.48 (2H, 2d, 2' and 3'-0H), 5.82 (1H, d, H-1'), 6.89 - 6.97 (3H, m, Ar-H), 7.25 - 7.30 (2H, t, Ar-H), 8.39 (1H, s, H-8), 5 8.49 (1H, d, N-H). C^H^FNgOg requires C, 54.4; H, 5.3; N, 16.7. Found: C, 54.7; H, 5.5; N, 16.4%. 10 Example 19 (Method B) 2-Methoxv-N-r(R)-1 -phenoxv-2-propvll adenosine 2-Methoxy-N-[(R)-1-phenoxy-2-propyl]adenosine was prepared by reacting 15 2-chloro-N-((R)1-phenoxy-2-propyl)adenosine (Example 2) (0.30 g, 0.69 mmol) with a mixture of sodium hydroxide (0.32 g, 8.0 mmol) and methanol (15 ml) in a sealed vessel at 80 - 90°C for 4h. The cooled reaction mixture was neutralised with concentrated hydrochloric acid and evaporated to dryness. Water (30 ml) was added and the mixture was extracted with dich-20 loromethane (2 x 30 ml). The combined extracts were dried (MgS04) and coevaporated with dichloromethane (30 ml), giving the title compound as a foam (0.19 g, 60%), 1H NMR (DMSO-d6)s 1.32 (3H, d, -CHCHg), 3.55 (1H, m, H-5'a), 3.65 (1H, m, HS'J, 3.72 (3H, s, -CHg), 3.91 - 3.99 and 4.10 - 4.20 (4H, 2 m, H-3', H-4' and -CH2-), 4.51 (1H, dd, H-2'), 4.67 (1H, m, -CHCH3), 25 5.84 (1H, d, H-1'), 6.89 - 6.98 (3H, m, Ar-H), 7.26 (2H, dd, Ar-H) 8.12 (1H, br,-NH). 8.46 (1H, s, H-8). WO 93/23418 PCT/DK93/00158 2 5 2 i 10 -29- EXAMPLE 20 (Method A) N-(2-Methoxvethvfladenosine 5 The title compound was prepared by the procedure described in example 7 by reacting 2-methoxyethylamine hydrochloride (0.27 g, 3.6 mmol) with 6-c-hloropurine riboside (i.e. 9-B-D-ribofuranosyl-6-chloro-9H-purine) (1.0 g, 3.5 mmol) in dioxan (30 ml) at room temperature for 72 h with triethylamine (1.04 ml, 7.5 mmol) present. The reaction mixture was filtered and evapora-10 ted and the resultant residue was recrystallised from methanol (100 ml) to provide the title compound (0.80 g, 82%) as a solid, mp 151 -152°C, 1H NMR (DMSO-dg)s 3.26 (3H, s, -CH3), 3.50 - 3.58 (3H, m, H-5'a and -CH2-), 3.60 - 3.70 (3H, m, H-5'b and -CHg-), 3.96 (1H, q, H-4'), 4.14 (1H, dd, H-3'), 4.60 (1H, dd, H-2') 5.20, 5.45 (2H, 2d, 2'-and 3'-OH), 5.42 (1H, t, 5'-OH) 15 5.87 (1H, d, H-1'), 7.80 (1H, br s, -NH) 8.22, 8.35 (2H, 2s, H-2 and H-8). ci3Hi9Ns°5 requires C, 48.0 ; H, 5.9 ; N, 21.5. Found: C, 47.8; H, 5.9; N, 21.3%. 20 EXAMPLE 21 (Method A) 2-Chloro-N-r(2-methoxvphenvl)methvlladenosine The title compound was prepared by reacting (2-methoxyphenyl)methylami-25 ne (0.55 g, 4.0 mmol) with 9-(2,3,5-tri-0-benzoyl-B-D-ribofuranosyl)-2,6-dichl-oro-9H-purine (1.01 g, 1.6 mmol), followed by debenzoylation of the purified product using methanolic ammonia to provide the title 2-chloro-N-[(2-met-hoxyphenyl)methyl]adenosine (0.31 g, 45%) (after column chromatography) as a solid, mp 116 - 119°C, 1H NMR (DMSO-dg)* 3.51 - 3.60 (1H, m, H-5'a), 30 3.61 - 3.70 (1H, m, H-5'J, 3.95 (1H, q, H-4'), 4.13 (1H, m, H-3'), 4.52 (1H, q, H-2'), 5.06 (1H, t, 5'-0H), 5.22, 5.50 (2H, 2d, 2'-and 3'-OH), 5.85 (1H, d, WO 93/23418 PCT/DK93/00158 2 5 2 110 -30- H-1'), 6.83 - 7.25 (4H, 2t, 2d, Ar-H), 8.43 (1H, s, H-8), 8.72 (1H, t, N-H). EXAMPLE 22 (Method A) 5 2-Chloro-N-r(R)-3-methvl-1-phenoxv-2-butvlladenosine (R)-3-methyl-1-phenoxy-2-butylamine (0.6 g, 2.8 mmol) was reacted with 9-(2,3,5-tri-0-benzoyl-B-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.4 g, 2.2 mmol) in dioxan (20 ml) in the presence of triethylamine (0.5 g, 5.0 mmol). 10 The reaction mixture was stirred at room temperature for 40 h before being filtered and evaporated. The product (after purification by flash chromatography) was debenzoylated with methanolic ammonia to provide the product (after column chromatography) as a foam which solidified on coeva-poration with dichloromethane. 2-Chloro-N-[(R)-3-methyl-1-phenoxy-2-bu-15 tyl]adenosine (0.46 g, 44%) was obtained as a white solid, mp 95 - 100°C, 1H NMR (DMSO-d6)5 0.95, 0.98 (6H, 2d, 2 x -CH3), 2.10 (1H, m, -CH(CH3)2), 3.53 - 3.60 (1H, m, H-5'a), 3.63 -3.71 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.07 - 4.23 (3H, m, H-3' and -CH2-), 4.96 (1H, m, -C-H), 4.56 (1H, q, H-2'), 5.08 (1H, t, 5'-OH), 5.23, 5.49 (2H, 2d, 2' and 3'-OH), 5.84 (1H, d, H-1'), 20 6.87 - 6.97 (3H, m, Ar-H), 7.24 - 7.31 (2H, dd, Ar-H), 8.36 (1H, d, -N-H), 8.40 (1H, s,H-8). ^21 H26C,N505.0.5 HzO requires C, 53.3; H, 5.8; N, 14.8. Found: C, 53.4; H, 5.7; N, 14.8%. 25 EXAMPLE 23 (Method A) 2-Chloro-N-f(RV1-(2-(2-propvloxv^phenoxvV2-propyll adenosine 30 (R)-1-(2-(2-Propyloxy)phenoxy)-2-propylamine (prepared from 2-(2-propy-loxy)phenol by the procedure described in example 2) (0.54 g, 2.2 mmol) WO 93/23418 PCT/DK93/00158 252 1 1 0 -31 - was reacted with 9-(2,3,5-tri-0-acetyl-B-D-ribofuranosyl)-2,6-dichloro-9Hpuri-ne (2.0 g, 4.5 mmol) in dioxan (30 ml) in the presence of triethylamino (2.19 g, 22 mmol). The reaction mixture was stirred at room temperature for 18 h before being filtered and evaporated. The product (after purification by flash 5 chromatography) was debenzoylated with methanolic ammonia to provide the 2-chloro-N-[(R)-l-(2-(2-propyloxy)phenoxy)-2-propyl]adenosine (after column chromatography) as a foam (0.47 g, 39%), 1H NMR (DMSO-d6)<j 1.04, 1.06 (6H, 2d, 2 x -CH3), 1.31 (3H, d, -CH3), 3.53 - 3.60 (1H, m, H-5'a), 3.64 -3.71 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 3.98 - 4.15 (3H, 2m, H-3' and -CH2-), 10 4.35 (1H, p, -C-H), 4.51 (1H, q, H-2'), 4.72 (1H, m, -C-H), 5.08 (1H, t, 5'-OH), 5.22, 5.48 (2H, 2d, 2' and 3'-OH), 5.85 (1H, d, H-1'), 6.82 - 7.08 (5H, m, Ar-H), 8.32 (1H, d, -N-H), 8.41 (1H, s , H-8). C22H28CIN506.1.0 HzO requires C, 51.6; H, 5.9; N, 13.7. Found: C, 52.0; H, 15 5.8; N, 13.3%. EXAMPLE 24 (Method A) 20 2-Chloro-N-r(RV1-phenvlsulDhbnvl-2-propvnadenosine (R)-1-Phenylsulphonyl-2-propylamine (0.4 g, 1.7 mmol) was reacted with 9-(2,3,5-tri-0-benzoyl-B-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.7 g, 1.0 mmol) in dioxan (20 ml) in the presence of triethylamine (0.4 g, 4.3 mmol). 25 The reaction mixture was stirred at room temperature for 48 h, heated at 60°C for 4 h, cooled, filtered and evaporated. The product (after purification by flash chromatography) was debenzoylated with methanolic ammonia to provide the title 2-chloro-N-[(R)-1-phenylsulphonyl-2-propyl]adenosine (after column chromatography) as a foam (0.2 g, 24%), 1H NMR (DMSO-dg)<s 1.24 30 (3H, d, -CH3), 3.45 (1H, dd, -C-H), 3.53 - 3.61 (2H, m, H-5'a and -C-H), 3.64 - 3.71 (1H, m, H-5'b), 3.86 (1H, dd, -C-H), 3.97 (1H, q, H-4'), 4.14 (1H, WO 93/23418 PCT/DK93/00158 252 110 -32 - m, H-3'), 4.53 (1H, m, H-2'), 5.09 (1H, t, 5'-OH), 5.23, 5.50 (2H, 2 d, 2' and 3-OH), 5.83 (1H, d, H-1'), 7.45 - 7.82 (5H, m, Ar-H), 8.21 (1H, s, -N-H), 8.38 (1H, s. H-8). 5 EXAMPLE 25 (Method A) N-r(2-methvlphenvl)methvnadenosine The title compound was prepared by reacting (2-methylphenyl)methylamine 10 (1.51 g, 12.5 mmol) with 6-chloropurine riboside (2.87 g, 10.0 mmol) in dioxan (100 ml) in the presence of diisopropylethylamine (1.94 g, 15.0 mmol). The reaction mixture was heated at 60°C for 6 h, cooled, filtered and evaporated. The residue was purified by flash chromatography, eluting initially with dichloromethane, and later increasing polarity to dichloromethane/ 15 ethanol (9:1), to provide the product (2.6 g, 70%) as a solid which was recrystallised from methanol to give N-[(2-methyIphenyl)methyl]adenosine as white crystals (1.75 g, 47%), mp 161.5 - 163.5°C, 1H NMR (DMSO-d6)<s 2.35 (3H, s, -CH3), 3.53 - 3.60 (1H, m, H-5'a), 3.65 - 3.72 (1H, m. H-5'b), 3.98 (1H, q, H-4'), 4.16 (1H, m, H-3'), 4.64 (1H, q, H-2'), 5.41 (1H. t. 5'-0H), 5.21, 20 5.48 (2H, 2d, 2'-and 3'-OH), 5.92 (1H, d, H-1'), 7.06 - 7.24 (4H, m, Ar-H), 8.20 and 8.40 (3H, s and br s, H-2, H-8 and N-H). EXAMPLE 26 (Method A) 25 2-Methvl-N-r(R)-1-phenoxv-2-propvl1adenosine (R)-1-phenoxy-2-propylamine (0.56 g, 3 mmol) was reacted with 9-(2,3,5-tri-0-acetyl-fl-D-ribofuranosyl)-6-chloro-2-methyl-9H-purine (0.43 g, 1 mmol) [prepared from 2-methylinosine (Journal of Organic Chemistry, 1967, 32, 30 3258 - 3260) by standard acylation and chlorination steps] in dioxan (20 ml) in the presence of triethylamine (0.41 g, 4 mmol). The reaction mixture was WO 93/23418 PCT/DK93/00158 252 110 -33- heated at 50°C for 70h, and at 90°C for 3 h. before being filtered and evaporated. The product (after purification by flash chromatography) was debenzoylated with methanolic ammonia to provide the title 2-methyl-N-[(R)-1-phenoxy-2-propyl]adenosine (after column chromatography) as a foam 5 (0.21 g, 50%), 1H NMR (DMSO-d^fi 1.30 (3H, d, -CHg), 2.43 (3H, s, -CHg), 3.53 - 3.60 (1H, m, H-5'.), 3.66 - 3.73 (1H, m, H-5'b), 3.94 (1H, dd, -C-H), 3.99 (1H, q, H-4'), 4.12 - 4.22 (2H, m, H-3'and -C-H), 4.54 (1H, dd, H-2'), 4.76 (1H, m, -CH3CH-), 5.20, 5.52 (2H, 2d, 2' and 3'-OH), 5.73 (1H, t, 5'-OH), 5.87 (1H, d, H-1'), 6.90 - 7.31 (5H, t, m, t. Ar-H). 7.74 (1H, br d, N-H), 10 8.28 (1H, s, H-8). ^2oH25CIN505.0.33 H20 requires C, 57.0; H, 6.1; N, 16.6. Found: C, 57.0; H, 6.2; N, 16.8%. 15 WO 93/23418 PCT/DK93/00158 2 5 2 1 1 0 -34- Evaluation of the compounds. Methods for assessing adenosine receptor binding in vitro have been revie-5 wed [Adenosine Receptors, (Cooper, D.M.F. and Londos, C., eds.) Alan R. Liss, Inc., New York, 1988, 43-62]. Evaluation of these compounds in established animal models has indicated that the compounds according to the invention possess desirable central 10 nervous system properties. For example, they act as anticonvulsant agents, are effective in animal models of pain, and show cerebroprotective effects in laboratory test animals subjected to simulated cerebral ischaemia. In addition, the compounds may have efficacy as neuroprotective agents in cases of cerebral oedema and traumatic head injury. 15 Evaluation of in vitro binding to adenosine A1 and A2 receptors The affinity of the known and novel compounds described in this invention for the adenosine A1 receptor has been determined essentially as descri-20 bed in the literature using [3H]-R-PIA as a radioligand (Naunyn-Schmiede-berg's Archives of Pharmacology, 1980, 313, 179-187). Affinity for the A2 receptor was measured using the radioligand [3H]-CGS 21680 (European Journal of Pharmacology, 1989, 168, 243-246), and the values for representative compounds are given in table I below. In vitro receptor binding values 25 obtained for the reference standard adenosine agonists CPA [N-(cyclopen-tyl)adenosine] and R-PIA [N-(1-phenyl-2-propyl)adenosine]) are included for comparison. WO 93/23418 - 35 - PCT/DK93/00158 2 5 2 1 1 0 Method description DMCM INDUCED SEIZURES IN MICE 5 In this model, seizures are induced by i.p. (intraperitoneal) dosing of methyl 6,7-dimethoxy-4-ethyl-B-carboline-3-carboxylate DMCM at 15 mg/kg. DMCM is an inverse agonist to the benzodiazepine receptor, presumably 10 producing seizures by decreasing the potency of inhibition of the GABA receptor/benzodiazepine receptor/chloride ionophore complex. 15 mg/kg of DMCM dissolved in 0.02 N HCI (1 mg/ml) is administered i.p. in a volume of 300 n\ to male NMRI mice weighing 20 ± 2 g. This induces two 15 different responses: a) some animals manifest a brief loss of righting reflexes or take up an upright position in which they have a mild short clonus of the upper extremities, b) other animals manifest intense clonic and tonic convulsions of all extremities often followed by death. DMCM is administered 30 min after an intraperitoneal injection of a test compound. 20 Latency time for the presence of intense clonic and tonic convulsions and death is noted until 15 min after administration of DMCM. At least 5 doses of each test compound are tested with 8 mice per dose. An anticonvulsive ED^ value is determined as the dose (mg/kg) protecting 25 50% of the animals against clonic convulsions; some representative values are shown in table II. The above method is a described in Petersen, E.N., Eur. J. Pharmacol. 94, 117-124, 1983; Petersen, E.N., Eur. J. Pharmacol. 195, 261-265, 1991. 25 2 U - 36 - Blood pressure in anaesthetised rats Test compounds are generally dissolved in DMSO and diluted in 5% chre-mophore/saline before being dosed to nembutal anaesthetised 200 g female Sprague Dawley rats which have not been starved or fasted. The rats are breathing spontaneously; blood pressure (BP) and heart rate (HR) is measured 5 minutes after a bolus i.v. injection. Each measurement is repeated twice. Results for representative compounds are shown in table II. Neuroprotective effect: Gerbil BCAO ischemia model. Transient global ischaemia was produced in Mongolian gerbils (60-70 g, males) anaesthetized with 2% halothane in 70% nitrous oxide and 30% oxygen. The common carotid arteries were occluded for 5 min. and the animals were allowed to recover for 4 days. The animals were reanaesthetized, decapitated and the brains quickly removed and frozen in powdered dry ice. Coronal sections (20 /xm) were taken through the brain at the level of the hippocampus and stained with cresyl violet and hematoxylineosin. The brain sections were rated for neuronal damage in the hippocampus CA1 region using a scale from 0 (undamaged) to 3 (total damage of CA1). The body temperature of all the animals was maintained at 37°C throughout the surgery and the animals were placed in warmed boxes during the recovery period. Each experiment consisted of a drug and a vehicle control group (n = 10-15). Test compounds were administered 30 min. after reperfusion. The claims of this specification are directed to those compounds oil the invention which are novel. WO 93/23418 PCI7DK93/00158 2 5 2 1 1 0 -37- TABLEI In Vitro evaluation of the compounds 5 Adenosine agonist A1 receptor A2 receptor Ratio tested binding binding A2/A1 (K,. nM) (K,. nM) (1) 43 1157 27 10 (2) 18 318 18 (3) 100 7413 74 (4) 166 3095 19 (5) 4 123 31 (6) 36 802 22 15 (7) 18 791 44 (8) 123 2188 18 (9) 3.3 3270 991 (10) 3.1 1320 426 (11) 35 397 11 20 (12) 6 383 64 (13) 7 2241 320 (14) 15 893 60 (15) 19 540 28 (17) 340 7776 23 25 (18) 8 310 39 (19) 88 2332 27 (20) 77 2432 32 (26) 69 1200 17 CPA 1.6 173 108 30 (R)-PIA 2.0 134 67 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 93/23418 PCT/DK93/00158 2 5 2 1 1 -38 -TABLE II Pharmacological evaluation of the compounds DMCM seizures % fall in BP Compound EDj^mg/kg^.p. 0.1 mg/kg i.v. (Example No.) HR (1) 3.4 0 (2) 3.9 8 (4) 13.3 0 (6) 3.8 5 (8) 24.9 1 (10) 0.1 - (11) 2.0 15 (12) 6.7 25 (14) 9.9 15 (15) 13.6 16 (19) 6.7 22 (25) 0.5 45 (26) 1.9 15 25 2 5 2 '»1 0 39 WHAT WE CLAIM IS: 1. A compound selected from 2-chloro-N-[{R)-1 -phenoxy-2-propylJadenosine, 2-chloro-N-(2-phenoxyethyl)adenosine, 5 2-chloro-N-( 1 -phenyl-3-butyDadenosine, 2-amino-NI-(1*phenoxy-2-propyl)adenosine, 2-chloro-tM-(cis-2-phenoxycyclopentyl)adenosine, 2-chloro-N-(trans-2-phenoxycyclopentyl)v3denosine, 2-chloro-N-[(R)-1 -hydroxy-2-propylJadenosine, 10 2-chloro-N-[(R)-1 -phenylthio-2-propyl]adenosine, 2-chloro-N-[(R)-1 -(4-fluorophenoxy)-2-propyl] adenosine, 2-chloro-N-[{R)-2-phenoxy-1-propyl]adenosine, 2-chloro-N-[2-(phenylmethoxy)ethyl]adenosine, 2-fluoro-N-((R)-1-phenoxy-2-propyl]adenosine, 15 2-methoxy-N-[(R)-1 -phenoxy-2-propyl]adenosine, N-(2-methoxyethyl)adenosine, 2-chloro-N-UR)-3-methyI-1-phenoxy-2-butyl]adenosine, 2-chloro-N-[(R)-1-(2-{2-propyloxy)phenoxy)-2-propyl]adenosine, 2-chloro-N-[(R)-1 -phenylsulphonyl-2-propylladenosine, 20 N-[(2-methylphenyl)methyl]adenosine and 2-methyl-N-[(RH-phenoxy-2-propyl]adenosine or a pharmaceutically acceptable salt thereof. Z A pharmaceutical composition comprising as active component a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a 25 pharmaceutically acceptable carrier. </div>