JPH06508855A - purine derivatives - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] purine derivatives The present invention provides methods of treating ischemia, epilepsy and pain, such as Compounds for use in the methods and pharmaceutical compositions containing such compounds Regarding products.

Background of the invention Adenosine can be considered a hormone, especially when the compound is endogenously It is thought to act as a neuroprotectant. Under the condition of neuronal stress ( Progress in Neurobiology, 1988°31, 8 5-108. Trends in Pharmacological 5ci ences, 1988. 9. 193-194j, breastfeeding It has been shown to have a number of significant effects on the central nervous system (CNS) of animals. [Annual Reports in Medicinal Chem] istry, 1988.23.39-48: Intershi≠狽■ onal Review of Neurobiology (Smythie s, J, R, and Bradley, R, J, eds,)`cad emic Press Inc., 1985.27.63-139]. for example , the concentration of adenosine increases after an epileptic seizure or a state of neuronal ischemia/anoxia. Brain Re 5earch 1990.516.248-256).

Over the past few years, adenosine receptor agonists or extracellular agents that act on the central nervous system have now been developed. Compounds that increase denosine levels are known to be neuromodulators (neuromod). It has been demonstrated that it can exhibit what is called ulator activity. something like this has a significant inhibitory effect on the release of the excitatory amino acid glutamate (glutamic acid). (Nature, +985.316.148-150.Jou rnal of NeurochemistrL 1992. 58. 168 3|1689), Affects the release of neurotransmitters in areas of the central nervous system (Annual Review of Neuroscience, 1985.8.103-12 4; Trends in Neurosciences, 1984. P64 -16 8).

This adenosine receptor-mediated neuromodulator activity is apparently therapeutic. There are several CNS diseases that can be caused by. These examples include treatments for seizure disorders. European Journal of Pharmacology, +991.195.261-265+ Journal Shield ■@Ph Armacology and Experimental Therapeu tics, +982.220.7O-76), cerebral anoxia■ / Prevention of neurodegeneration under conditions of ischemia (Neuroscience Lette) rs, 1987.83.287-293: Neuroscience, 1 989.30.451-462; Pharmacology of Cere bral lsc■≠■Takaya■ 1990, (Kriegelstein, J. and 0berpich ler, H,, Eds,, Wissenschaftl Amamo■■@Ver lagsgesellschaft mbH: Stuttgart, +99 0. pp, 439-448) or purinergic (pu (European Journal of Ph. armacology, 1989, 162.365-369; Neuros science Letters, 1991.121.267-270) will.

Adenosine receptors are known as purinoreceptors. Subclasses of known purine nucleotide and nucleoside receptor groups (PI). This subclass further includes two distinct receptor types. They are classified into two groups, known as AI and A2. widely Extensive research has been conducted in the quest to identify selective ligands at these sites. [For example, Comprehensive Medicinal Chem istry, Volume 3, (Hansch, C, Summers, P, f.

and Taylor, J.B., Eds, Pergamon Pre ss PLC: 1990. pp 601-642)] A selective Ligands exist for the AI and A2 adenosine receptors, and a variety of Structure-activity relationships of quasi-ligands, along with their therapeutic potential (Journa l of Medicianl Chemistry, 1992.35.40 7-422), is being re-examined (Biochemical Pharmac. ology, 1986.35.2467-2481), than the A2 receptor. Among the known adenosine receptor agonists that are highly selective for AI receptors , adenine n methyladenosine (Naunyn-Schm iede-berg's Arch, Pharmacol, 1988.33 7.687-689).

However, these ligands may have undesirable effects regarding their effects on the cardiovascular system. It has been found that these patients have CNS disorders, such as cerebral ischemia, making it unsuitable for the treatment of epilepsy and pain.

British Patent No. 1,143,150 (U.S. Patent No. 3,551,409) ) and British Patent No. 1,123.245 are of interest. A number of adenosine derivatives are disclosed that promote cardiac and circulatory function.

European Patent Application Publication No. 322,242 states that ``Plasma free fatty acid concentration new drugs as "lowering agents or reducing heart rate and condition" Other uses include the compounds listed below and their physiologically acceptable salts and solvents. Claimed for Japanese products: N-[2β-hydroxy-2-methylcyclopentyl]adenosine and now A selected group of adenosine derivatives - some of which are covered by British Patent No. 1,1 No. 43,150 claims - is a central nervous system disease, e.g. Potent therapeutic agents for treating cerebral ischemia, epilepsy and pain in humans Disclose that it has utility. They have excellent side effects regarding cardiovascular properties. clinical profile, as well as clear CNS effects in appropriate animal models. It has fruit. Furthermore, the compounds have efficacy in myocardial ischemia. Ingredients Physically, the following compounds have demonstrated therapeutic utility in the CNS indications mentioned above. Adenosine 2-amino-N-(1-phenoxy-2-propyl) propyl)adenosine N-[(Is, trans)-2-hydroxycyclopentyl ]adenosine N-[(IR,)lance)-2-hydroxycyclopentyl]a Denosine 2-chloro-N-(cis-2-phenoxycyclopentyl)adenosine trans-2-chloro-N-(2-phenoxycyclopentyl)adenosine 2- Chloro-N-[(R)-1-hydroxy-2-propyl]adenosine 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-propynoriadenosine 2-k Rolo-N-[2-(phenylmethoxy)ethyl]adenosine 2-fluoro-N- [(R)-1-phenoxy-2-propyl]adenosine 2-methoxy-N-[( R)-1-phenoxy-2-propynoriadenosine N-(2-methoxyethyl) Adenosine 2-chloro-N-[(2-methoxyphenyl)methylcoredefsin 2 -Chloro-N-[(R)-3-methyl-1-phenoxy-2-butyl]adeno Shin 2-chloro-N-[(R)-1-(2-(2-propyloxy)phenoxy)- 2-propynoriadenosine 2-chloro-N-[(R)-1-phenylsulfonyl-2-propyl]adenosyl hmm N-[(2-methylphenyl)methyl]adenosine 2-methyl-N-[(R)- 1-phenoxy-2-propynoriadenosine The present invention therefore provides a compound of formula I [In the formula, X is hydrogen, amino, halogen, hydroxy, lower alkoxy or lower alkyl Lukiru and R1 is (However, Y is methylene or a valence bond, R2 and R1 are H or lower , straight chain or branched alkyl, and R3 is H or lower alkyl; or R1 and R2 together represent cyclobutyl, cyclopentyl, cyclohexyl can form a syl or phenyl ring, Z is oxygen, methylene, sulfur, sulfur Honyl or valence bond, R4 is H1 lower alkyl, aralkyl, in some cases More halogen, hydroxy, haloalkyl, alkyl, alkoxy, aryl monocyclic or substituted with xy, acyloxy or alkylmercapto groups It is a bicyclic aromatic system. ). ] adenosine analogues or pharmaceutically acceptable salts thereof - these compounds has been shown to be useful in the treatment of numerous NC3-related diseases, such as cerebral ischemia, epilepsy, and pain. I am interested in this as I have found that it is useful.

Furthermore, the compound represented by formula (1) reduces plasma free fatty acid (FFA) levels. It has been found to be a useful agent, such as a cardiovascular agent, to induce myocardial deficiency. It was also found to have application to blood.

The invention also relates to a method for producing the above-mentioned compounds. These methods include Method A and and Method B include: Method A The compound represented by formula (CI) is a compound represented by formula (■) (wherein L is a leaving group, such as a halogen source). (e.g. a chlorine or bromine atom) or a trimethylsilyloxy group, and Pl , and Pl are the same or different and contain hydrogen or a protecting group, e.g. benzoyl. p-toluoyl group, lower alkanoyl group (e.g. acetyl group), substituted silyl groups (e.g. trimethylsilyl or t-butyldimethylsilyl) or is a triarylmethyl group in the case of Pl, or a triarylmethyl group in the case of Pl and Pl is a 2゛,3°-0-(1-methyl)ethylidene functional group) and a substituted amine represented by the general formula (I[) to form a reaction product. It can be produced by preparing a compound represented by formula (IV) as follows.

When P', P'' and Pl are not hydrogen, to remove the protecting group from (IV) Additional steps may be required for the groups pl, pl and PI, for example In the case of acetyl or benzoyl, suitable conditions for deprotection are Nolic ammonia, alkali metal carbonate in methanol, or the corresponding alkali Including the use of alkali metal alkoxides in coals. If the protecting group is e.g. In the case of aryl silicon or aryl silicon derivatives, use a suitable method for deprotection. Methods include, for example, treatment with tetraalkylammonium fluoride or acid or Includes aqueous hydrolysis in the presence of a base. Pl and Pl groups are 2°, 3’- 0-(l-methyl)ethylidene functional group or P is triarylmethyl , suitable conditions for deprotection include, for example, hydrolysis with aqueous mineral acids. includes.

The product has the general formula (V) A substance represented by [wherein is a leaving group as defined in method (A)] and a nuclear test with drugs, e.g. ammonia, or with anions (e.g. C3-6-alkoxides) The product (IV) can be produced by reacting with the product (IV). pl, pl and when R3 is hydrogen, the compound (D can be obtained directly. However, pl .

When Pl and Pl are not hydrogen, the protecting group is removed from (IV). Additional steps may be required: Examples of conditions for removing protecting groups include Shown in (A). pi, culm and/or Pl are e.g. acetyl- or requires (V) with the anion C14-alkoxide which is benzoyl- In some reactions, partial or complete deprotection may occur. partial release If only protection occurs, deprotection is completed under the conditions described in method (A). It can be made whole.

Therefore, the present invention relates to cerebral ischemia, epilepsy and pain in humans or non-human animals. A method for the treatment of a compound of formula I comprising an effective, non-toxic amount of a compound of formula I or provides its pharmaceutically acceptable salts to humans suffering from cerebral ischemia, epilepsy or pain. A method comprising administering the method to a human or non-human animal is provided. The present invention also provides The compound represented by formula or for use in the manufacture of a medicament for use in the treatment of pain.

The invention further provides a drug for use in the treatment of cerebral ischemia, epilepsy or pain. a pharmaceutical composition comprising an effective amount of a compound represented by formula ■ or a pharmaceutically acceptable pharmaceutical composition thereof; and a pharmaceutically acceptable carrier.

Such compositions may be manufactured by the methods described below.

Preparation of various salts of the compound of formula (I) which may be considered physiologically acceptable can be built. These are addition salts obtained from inorganic or organic acids, such as acetic acid salt, fumarate, glutarate, glutaconate, lactate, maleate, meth sulfonates, phosphates, salicylates, succinates, sulfates, sulfamines including acid salts, tartrates and para-toluenesulfonates. In some cases, play Solvates of either the isolated nucleoside or the acid addition salt can be isolated and these solvates A solvate can be, for example, a hydrate or an alcoholade.

The compounds of the invention, together with customary adjuvants, carriers, or diluents, can be Pharmaceutical compositions and the like, if desired, in the form of their pharmaceutically acceptable acid addition salts. and in such form, for oral use, a solid bodies, e.g. tablets or filled capsules, or liquids, e.g. solutions, suspensions, emulsions. , for rectal administration as elixirs or filled capsules. in dust form; or sterile for parenteral use (including subcutaneous administration and infusion) It can be used in the form of an injection. Such pharmaceutical compositions and unit dosage forms thereof are The customary ingredients in the proportions appropriate for use are combined with additional active compounds or principles. ) and such unit dosage forms are intended to be used. an appropriate effective amount of an adenosine receptor agonist proportional to the daily dosage range given. may include.

The compounds of the invention may therefore be used in the formulation of pharmaceutical formulations, e.g. for oral and parenteral administration according to conventional methods of pharmaceutical science. customary usage The excipients are suitable for parenteral or enteral application without causing adverse reactions with the active compounds. A pharmaceutically acceptable organic or inorganic carrier material.

Examples of such carriers are water, salt solutions, alcohols, polyethylene glycols. , polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, Magnesium stearate, talc, silicic acid, fatty acid monoglycerides and Lyceride, pentaerythritol fatty acid ester, hydroxymethyl cellulose and polyvinylpyrrolidone.

Pharmaceutical preparations must be sterile and, if desired, free from harmful reactions with the active compounds. additives, emulsifiers, salts to influence osmotic pressure, buffers and/or colorants Can be mixed with substances.

For parenteral application, particularly suitable are injection solutions or suspensions, preferably It is an aqueous solution containing the active compound dissolved in polyhydroxylated castor oil.

Ampules are conventional unit dosage forms.

One carrier such as talc and/or carbohydrate carrier or binder is preferred. or lactose and/or corn starch and/or potato starch Tablets, dragees, or capsules containing - are particularly suitable for oral application. . Where sweetened vehicles can be used, syrups, elixirs, etc. can be done.

Generally, the compounds of the present invention are prepared per unit dosage in a pharmaceutically acceptable carrier. It is prepared in unit form containing 0.05 to 100 mg. Medicinal uses of the compounds according to the invention The amount is 0 when administered as a drug to patients, e.g. humans. , 1-3o0 mg/day, preferably 10-100 mg/day.

A typical tablet, which may be manufactured by conventional tabletting techniques, contains 5.0 m g Lactose (Lactosum) 67. 8mg Ph, Eur.

Avicel■ 31.4mg Amberlit e@)lRP88 1. 0mg Magnesium Stearate (Magnesii 5 tears) 0. 25mg Ph, Eur.

including.

For the prevention of neurodegeneration under conditions of pain or seizure disorders and anoxia/ischemia. Because of their activity in agonistic activity, the compounds of the present invention are effective for agonistic activity of the compounds of the present invention When administered in amounts, it is extremely useful in treating related conditions in mammals.

The compounds of the present invention may therefore be used to treat a person in need of an adenosine receptor agonist. including a patient or animal (subject), e.g. an animal living body, if desired. , its pharmaceutically acceptable acid addition salts (e.g., hydrobromide, hydrochloride or sulfuric acid) salts, free salts in solution in any usual or customary manner, e.g. with acids; (manufactured by evaporating to dryness) usually at the same time, concurrently or together with a carrier or diluent, especially and Preferably, in the form of its pharmaceutical composition, oral, rectal, or parenteral (including subcutaneous) ) route, in an effective amount of an adenosine receptor agonist, and in any case acid-free. medical condition, traumatic injury, ischemia, migraine or other pain condition, epilepsy, or neurological for their adenosine receptor agonist activity in amounts useful in the treatment of degenerative diseases. , may be administered. The appropriate dosage range will usually depend on the precise method of administration, the form in which it is administered. , the indication for which administration is directed, the subjects or animals involved and the studies involved. depending on the weight of the person or animal and the preference and experience of the attending physician or veterinarian. 1-200mg per day, preferably 10-100mg per day, and In particular, 30 to 70 mg per day.

The preparation of the compounds of the invention is further illustrated in the following examples.

Hereinafter, TLC is thin layer chromatography, and THF is tetrahydrofuran. , TFA is trifluoroacetic acid, and mp is melting point. melting point is indicated If so, these have not been corrected. The structure of the compound is shown in the NMR spectrum. (from which the respective peaks are quoted) and, optionally, Confirmed by microanalysis. Compounds used as starting materials are known compounds. It is either a compound or a compound that can be produced by methods known per se.

Column chromatography was performed using Merck silica gel 60 (Art 9385 ) was done above. HPLC is equipped with a multi-wavelength detector and a reversed phase C18 column (250 W with x4 mm, 5 μm, 100 people, eluent flow rate 1 mL/min at 35 °C) Performed on an aterS or Merck chromatograph. Retention time is shown in minutes. has been done.

The title compound was dissolved in l-phenoxy-2-propylamine (16.62 g, 0°1 1 mol) and 9-(2,3,5-tri-9-niacetyl-β-D-ribofuranosyl) )-2,6-dichloro-9H-purine (24.6 g, 55 mmol) Triethylamine (7.23 g 171.5 mmol) in oxane (250 ml) The reaction was carried out in the presence of sodium (0 ml) in methanol (250 ml). , 15 g, 6.5 mmol). Built. The reaction mixture was neutralized with citric acid, ethyl acetate (300 ml) and water ( 200 ml) of the mixture. Separate the ethyl acetate phase and dry with MgSO.

) and after evaporation by flash chromatography on silica gel. First with dichloromethane, then with dichloromethane and ethanol (9:1). The mixture was eluted and purified. This allows the title 2-chloro-N-(1-pheno xy-2-propyl) adenosine (18.2 g, 76%) (diastereoisomers ) is an amorphous foam, 'HNMR (D MSO-ds) δ 1.31 (3H, d, CH,), 3.53 3.59 ( IH, m, H5,), 3. 64 3. 71 (IH, m, H5°,), 3 ．． 95 (IH, q.

H-4'), 4. 06-4. 20 (3H, 2m, H-3' and -C H2-).

4.54 (IH, m, H2'), 4.65 (IH, m, CHCHs) , 5゜07 (IH, t, 5″-0H), 5. 2+, 5. 50 (2H, 2d, 2'- and 3°-0H), 5.84 (IH, d, H-1') , 6.87-7, 00 (3H, m, Ar-H), 7. 23-7.　32　 (2H, t, Ar-H), 8. 31-845 (2H, m, H-8 and Obtained as NH).

The corresponding maleate salt was prepared from the above 2-chloro-N-(1-phenoxy-2-propylene Pill) Dissolve adenosine (1.7 g, 3.9 mmol) in THF (10 ml) then add diethyl ether (60 ml) and then add maleic acid (0.45 g). , 39 mmol). The residue from evaporation is converted into diethyl Upon treatment with ether (50 ml), the maleate precipitated and was filtered out. (1.15g), melting point 102-104°C0Ct-H2@CI Ns O□ requires C, 50,0; H, 4,7; N, 12.7. Actual value: C, 50,3;H,4,9;N,12. 7%.

(R)-2-Amino-1-propatol (15.0 g, 200 mmol) was added to I Dissolved in N sodium hydroxide (198 ml) and introduced THF (85 ml). I entered. The reaction mixture was cooled to 0 °C and diluted in THF (230 ml). solution of ludicarbonate (52.4 g, 240 mmol) over 30 min. I went to Urawa. The reaction mixture was stored at 4° C. for 72 hours, brought to room temperature and filtered. filtrate The THF was removed by evaporation and the aqueous phase was extracted with ethyl acetate (2 x 200 m, 1). did.

The combined extracts were evaporated to dryness (Mg5O, ) and the crude product was dissolved in dichloromethane. Dissolved in methane (100ml) and extracted into water (5x200ml). Match The aqueous extracts were evaporated under reduced pressure. The resulting oil, when left at room temperature, Crystallizes the required alcohol (15.35 g, 44%), mp 59-61 %, 'HNMR (DMSO-d,) δ 1. I 5 (3H, d, -〇HC Dan, ).

1, 45 (9H, s, butyl-CH2), 3.50 (IH, dd, C Nt a-), 3.65 (IH, (+d, CHtb), 3.70 3.80 (IH, m.

CH) was produced.

10.0 g, 57 mmol), triphenylphosphine (22.5 g, 86 mmol) ) and phenol (5.4 g, 57 mmol) in toluene (200 ml) It was dissolved in Diethyl azodicarboxylate (1 4.9 g, 86 mmol) was slowly added while keeping the temperature below 35 °C. (Mitsunobu, O,, 5ynthesis, +981.1; M anhas, M, S,; Hoffman, W, H,;@La1. B.

: Ba5e, A, Ni, J, Chem, Sac, Perkin T ransl, 1974.461). The resulting yellow solution was stirred at room temperature for 16 hours. After stirring, it was washed with IN hydrochloric acid (3×100 ml). Dry the remaining organic phase MgS 04), evaporated under reduced pressure, and the residual oil was purified by flash chromatography. Purify by roughy eluting with heptane/ethyl acetate (4/1) to obtain the desired Product (8.0 g, 59%), 'HNMR (DMSO-d,) δ1, 10 ( 3H, d, -CH,), 2. 38 (9H, s, butyl-CHI>.

3, 70 3. 90 (3H, m, CH-CHs), 6. 85 6. 95 (3H, m, Ar-H), 7. 25 (2H, t, Ar-H) Obtained.

(R)-1-phenoxy-2-propylamine (R)-N-(t-butoxylic (bonyl)-1-phenoxy-2-propylamine (8.0 g, 33 mmol) Dissolved in ethyl acetate (100ml). A solution of hydrochloric acid (g) in ethyl acetate (6N , 100 ml) at room temperature. The reaction mixture was stirred at room temperature for 20 hours, when During this time, a heavy precipitate formed. Bring the reaction mixture to half its original volume. After concentration, the product was collected by filtration and dried under reduced pressure to give the title compound as a white Solid hydrochloride salt (4.3g, 69%), mp 186-189°C, 'HNMR (DM SO-ds) δ l, 31 (3H, d, -CH5), 3. 51 3. 6 0 (IHlm, CH), 4. 05 (IH, dd, -CH, a-), 4. 12 (IH, dd, -CHt b-), 6. 95-7.00 (38, m, Ar-H), 7. Obtained as 32 (2H, t+Ar-H).

2-chloro-N-[(R)1-phenoxy-2-propynoriadenosine(R)- 1-phenoxy-2-propylamine (4.3 g, 23 mmol) was added to 9-( 2,3,5-tri-Q-benzoyl-β-D-ribofuranosyl)-2゜6-dic Rollo-9H-purine (11.2 g, 18 mmol) and dioxane (150 ml) ) in the presence of diisopropylethylamine (5.3 g, 41 mmol). I responded. The reaction mixture was stirred at room temperature for 18 h, heated at 50 °C for 4 h, and After stirring for 60 hours at room temperature, it was filtered and evaporated. product (flash chrome) (after purification by matography) was debenzoylated with methanolic ammonia. The title 2-chloro-N-[(R)-1-phenoxy-2-propynolyadenosyl foam (4.2 g, 64%), 'HNMR (DMSO-d,) δ1, 31 (3H, d, CHs), 3. 52 3. 59 (IH, m, H5'.

), 3. 63-3. 72 (IH, m, H-5',), 3. 92-3 ．． 99 and 4, 10-4. 21 (4H, 2m, H-3°, H-4 ’ and -CH! -), 4.520H, dd, H-2°), 4.65 (I Hlm, CHs Cl), 5, 07 (IH, t, 5'-0H), 5. 22. 5. 49 (2H, 2d, 2° and 3°-0H), 5.84 (IH, d, H-1'), 6.88-7.02 (3H, m, Ar-H) , 7.24-7.33 (2H, dd, Ar-H), 8.32-8.45 (2 H, s&m, H-8 and N-N).

CuHttclNs Os is C, 52, 4: H+ 5.1; N+ 16. 1 Requires. Actual value: C, 52.0, H, 5.2; N, 15. 8%.

Manufactured by the method described in Example 2. However, (S)-2-amino-! −Property The tool was used in the first step to obtain the opposite diastereoisomer from Example 2.

The nucleoside was obtained as a hemihydrate: C, ,8,2CINs　O5,0,5Ht　O is C,51,8;H,5,2;N,1 59 is required. Actual values: C, 51.8, H, 5.3, N, 15.6%.

2-Chloro-N-(2-phenoxyethyl)adenosine The title compound was Enoxydiethylamine hydrochloride (0.80 g, 4.6 mmol) and 9-(2, 3,5-1-ri~penzoyl-β-D-ribofuranosyl)-2,6-dikuo Rho 98-purine (2.0 g, 3.2 mmol) in dioxane (25 ml) in the presence of triethylamine (1.0 g, 9.6 mmol), The purified product was then deprotected using methanolic ammonia. The title nucleoside (0.75 g, 60%) was prepared by flash chromatography. amorphous foam, 'HNMR (DMSo-d,) δ 3.5 2-3. 59 (IH, m, H-5°,), 3. 64-3.71 (IH , m, H5' = ), 3.82 (2H2q-CHz-), 3.96 (IH, q, H-4°), 4. 14 (IH, m, H-3'), 4. 52 ( IH.

q, H-2'), 5. 12 (IH, t+5'-0H), 5. 25. 5. 54 (2H, 2d, 2'- and 3°-0H), 5. δ5 (I H, d, H-1'), 6°92-7. 02 (3H, m, Ar-H), 7. 26-7, 34 (2H, t, Ar-H), 8.46 (IH, m, Obtained as H-8,8,56 (IH, br t+N-N).

C,, H,, ClN5 OK, 0.75 Hs O is C, 49,7; H, 5, OWN.

16.1 is required. Actual value C, 49, 7; H, 5, OWN, 15. 7% .

Example 5 (Method A) 2-chloro-N-[(R)-1-phenyl-2-propynoriadenosine title compound The compound was combined with L-amphetamine (0.49 g, 3.6 mmol) and 9-(2, 3,5-tri-9-benzoyl-β-D-ribofuranosyl)-2,6-dichloro -9H-purine (1.9 g, 3.0 mmol) in dioxane (25 mJ) and reacted in the presence of diisopropylethylamine (0.58 g, 4.5 H mol). reaction and then deprotecting the purified product using methanolic ammonia. Manufactured by. The reaction mixture was evaporated to give a gummy residue, which was Addition of chloromethane (lom+) crystallized the title compound (0°26g, 38%) as a solid, melting point 132.5-135.5°C. title compound A sample (0.26 g) of the product was further purified by flash chromatography of the mother liquor. Obtained. 'HNMR (DMSO-d, ) δ 1.22 C3H, d, -q Dan*), 2.67 2.79 & 2.92 3.03 (2H, 2m, CHx -), 3. 51-3. 58 (IH, m, H-5°,), 3.62-3 ．． 68 (IH, m, H-5°-), 3. 94 (LH, q, H4'), 4 ．． 12 (IH, m.

H-3'), 4. 41-4. 54 (2H, m, H-2° and CH, CH-).

5, 06 (IH, t, 5'-0H), 5.22.5.49 (2H, 2 d, 2' and 3'-0H), 5.82 (IH, d, H-1'), 7.10- 7.33 (5H, m, Ar-H), 8. 28-8. 44 (2H, m, H-8 and N-H).

CIIH22CINs Oa, 0.5 Hz O is C, 53, 2, H, 5, 4, N, requires 16.3. Actual measurements: C, 53, 3, H, 5, 4, N, 16 ．．　3%.

3-Amino-1-phenylbutane (0.67 g, 3.6 mmol) was added to 9-(2 , 3,5-)LeQ-benzoyl-β-D-ribofuranosyl)-2,6-dichloro rho-9H-purine (1.9 g, 3 mmol) in dioxane (25 ml), Reacted in the presence of diisopropylethylamine (0.58 g, 4.5 mmol). I set it. The reaction mixture was stirred at room temperature for 18 hours, filtered and evaporated. product ( After purification by flash chromatography) was devetted with methanolic ammonia. to give the title 2-chloro-N-(1-phenyl-3-butyl)adeno Syn (mixture of diastereoisomers) foam (0.72 g, 56%), 'HN MR (DMSO-cl,) δ 1.12 (3H, d, CHs), 3.53- 3, 61 (IH, m, H-5°,), 3. 64-3. 72 (IH, m, H-5゜b), 3. 93-3. 99 (IH, m, H-4°), 4 ．． 11-4. 17 (IH, m, H3'), 4. 22 4.　36(I H, m, CHsCH), 4. 53 (IH, dd, H-2°), 4. 65 (IH, m, CHs CH), 5. 1o (H(,t, 5'-0H), 5 ．． 25. 5. 51 (2H, 2c1. 2' and 3'-0H), 5.8 3 (IH, d, H-1'), 7.12-7.30 (5H, m, Ar-H), 8 ．． 28-8. 37 (IH, m, N-H), 8. 40 (IH, s, H -8).

C7゜Ht4CINh　Oa　, Ht　O is C,53,2,H,5,8:N,1 5. 5 is required. Actual value: C, 53,9: H, 5,7; N, 15. 6% .

l-phenoxy-2-propylamine (0.33 g, 2.18 mmol) was added to 6 -chloropurine riboside (i.e. 9-β-D-ribofuranosyl-9H-purine (0.5 g, 1.7 mmol) in dioxane (30 ml). Reacted in the presence of lopylethylamine (0.28 g, 2.2 mmol) .

The reaction mixture was heated at reflux for 5 hours, cooled and evaporated. Remove the residue by silting. Purified by flash chromatography on Kagel and N-(1-phenoxylene) C-2-propyl) adenosine (mixture of diastereoisomers) foam, I HNMR (DMSO-d@') δ 1.32 (3H, d, CHs), 3.5 2-3.60 (IH, m, H-5'a) + 3. 64-3. 71 ( IH, m, H-5'b), 3.93-3.99 and 4. 12-4. 20 (4H, 2m, m, H-4', H-3' and -GHz), 4. 62 (IH, q, H2'), 4. 684.82 (IH, m, CHCHs) , 5.40 (IH, t, 5' OH).

5, 20. 5. 45 (2H, 2d, 2'- and 3'-0H), 5 ．． 90 (IH, d, H-1'), 6. 88-6. 98 (3H, m, Ar-H), 7. 23-7, 31 (2H, t+Ar-H), 7. 8 5. 8. 21. 8. 38 (3H, 3s.

H-2, H-8 and N-H).

1-phenoxy-2-propylamine (2,90 g519.2 mmol) and 9-(2,3,5-tri〇-acetyl-β-D-ribofuranosyl)-2-a Mino-6-chloro-9H-purine (6.94 g, 16.2 mmol) was San (50 ml) and triethylamine (4.5 ml 33.2 ml) RIMORU) was introduced. After stirring the reaction mixture at room temperature for 18 hours, diisopropyl Ethylamine (2,08 g, 16.1 mmol) was added and the solution was heated to 80° The mixture was heated at C for 100 hours. After column chromatography, the obtained 2゛, 3゜ .

5゛-tri〇-acetyl-2-amino-N-(1-phenoxy-2-propyl ) A 1.3 g sample of adenosine was dissolved in saturated methanolic ammonia (50 ml). and removed the protection. The reaction mixture was evaporated and the residue was dissolved in ethyl acetate (150ml). and water (150ml). Separate the phases and add the ethyl acetate phase to water. (2XI 50ml). The ethyl acetate phase was then extracted with pH 2 dilute hydrochloric acid. , the acidic aqueous phase was washed with ethyl acetate (2×10 ml) and diluted with sodium bicarbonate. The mixture was made basic with a solution of sodium hydroxide, and then extracted with ethyl acetate (LOOML). Ethyl acetate The phases were dried (Mg5O,) and evaporated to give the title compound (0.43 g, 33%). The mixture of diastereoisomers is an amorphous foam, 'HNMR(DMSO-d@)δ 1. 28 (3H, d, CHs), 3. 49 3. 57 (IH, m, H5',), 3.61-3.68 (IH, m, H-5',), 3 ．． 85-3.94 and 4. 07-4. 15 (4H, 2m, m, H- 4', H-3° and -CH.

-), 4. 50 (IH, q, H-2'), 4. 68 (IH, br, -CHCHs-), 5. 11. 5. 36 (2H, 2d, 2' - and and 3'-0H), 5. 40 (IH, t, 5°-0H), 5.73 (IH, d, H-1'), 5.83 (IH, br, -NH2), 6. 88-6.　 96 (3H, m, Ar-H), 7. 22-7, 31 (2H, t, A r-H), 7. 95 (IH,s, H-8).

CIIH24CINI 01.0.75 Ht O is C,53,1:H,6,0 ;N.

Requires 19.5. Actual value: C, 53, 0: H+ 6. 0;N, +9 ．．　2%.

trans-2-hydroxycyclopentylamine (0.35 g, 3.46 mmol ) (Cyclopentene oxide and ammonia are reacted in a sealed container) 6-chloropurine riboside (i.e., 9-β-D-ribofuranosyl-9H-purine) (0.5gS 1.7 mmol) and triethylamine (0.93 g, 9 mmol) in dioxane (30 ml). ) was reacted in the presence of The reaction mixture was heated at 100°C for 70 hours, cooled and and evaporated. The obtained residue was purified by flash chromatography with acetic acid. Purified by eluting with a mixture of ethyl and methanol (19+1). HPLC After testing, the highest amount of N-[(IR,)lance)-2-hydroxycyclo The fractions found to contain pentyl adenosine were combined and evaporated. The mixture was mixed to form a solid (0.17 g). Recrystallization from methanol yields pure N-[(I R, trans)-2-hydroxycyclopentyl]adenosine (0,l1g11 8%) gave a melting point of 233-235°C. 'HNMR (DMSO-ds)' 61°43-2. +2 (68.4m, -CH2CHI CH2-), 3. 52-3. 59 (IH, m, H-5" a) + 3. 54-3. 71 (IH, m, H-5',), 3, 97 (IH, q, H-4'), 4.07 (IH, br, -CdanOH), 4. 15 (IH, q, H- 3°), 4. 61 (IH, q, H-2'), 4. 87. 5゜21, 5. 41-5. 47 (4H, d & 3m, OH group), 5. 89 (I H,d.

H-1'), 7. 75 (IH, br d, -NH), 8. 21 and 8.37 (H-2 and H-8).

The mother liquor from the above recrystallization was evaporated and poured onto silica gel (Art, 7729). Purified by short path chromatography and recrystallized the product to give N-[( Is, trans)-2-hydroxycyclopentyl]adenosine (0.05g, 4%), 'HNMR (DMSO-d,) δ 1. 44-2. 13 (6H, 4m, -CH2CH,CH2-), 3. 52-3. 59 (IH, m, H -5', ), 3. 54-3. 71 (IH, m, H-5'-), 3. 9 6 (IH, q, H-4゛), 4.15 (IH, q, H-3'), 4.　60( IH, q, H-2'), 5, 20. 5. 41-5. 47 (3H, d &m, 2', 3° and 5'-OH groups), 5.88 (IH, d, H-1') , 7.75 (IH, br d, -NH), 8.19 and 8.36 (H-2 or and H-8) were obtained.

amine This compound was mixed with cyclopentene oxide (8.0 g, 95.1 mmol) and 25 % ammonia aqueous solution (35 ml) at 110°C in a sealed glass container. It was prepared as a mixture of enantiomers by reacting for a period of time. reaction mixture After the mixture has cooled and evaporated to half its original volume, it is diluted with IN sodium hydroxide. The solution (95 ml) and THF (100 ml) were introduced at o”c.THF di-t-butyl dicarbonate (21.8 g, 99.6 mmol) in (50 ml) ) and the reaction mixture was stirred at room temperature for 18 hours. separate the phases, The aqueous phase was washed with ethyl acetate (100ml). Combine the organic phases and make the saturated pudding ( Wash with brineXl 00ml), dry Mg5Oa) and evaporate. Ta. The solid residue was dissolved in a 10:I mixture of heptane and ethyl acetate (55 ml). to recrystallize trans-N-(t-butyloxycarbonyl)-2-hydro Xycyclopentylamine: / (4.06g, 21%), melting point 103-105° A sample for analysis of C was obtained.

C3°H+*NOi is C, 59,7; H, 9,5; N, 7. Requires 0.

Actual values: C, 59.6, H, 9.8; N, 7.0%.

The above trans-N-(t-butyloxycarbonyl)-2-hydroxycyclope The methyl amine was subjected to the series of reactions described in Example 2 (i.e., Mi with the 2-position reversed). Formation of phenyl ether by the tunobu procedure, acidification of the BOC group using TFA Hydration 9-2-phenoxycyclopentylamine (0.75g, 4.23ml) 9-(2,3,5-1-2-0-benzoyl-β-D-ribofurano) sil)-2,6-dichloro-9H-purine (2,95 g 14.7 mmol) and and triethylamine (0.64 g, 6.3 mmol) and dioxane (30 ml). ) and stirred for 50 hours. Filter the reaction mixture, evaporate and remove the residue. The fractions were dissolved in ethyl acetate and washed with water (2X50ml). organic phase Dry Mg5O4), evaporate and coevaporate the residue. e) cis-2',3°,5'-1-O-benzoyl-2-chloro-N -(2-phenoxineclopentyl)adenosine (3.1g, 90%) in amorphous form obtained as a foam, which was desorbed using saturated methanolic ammonia (50 ml). Protected. After 70 hours at room temperature, the reaction mixture was evaporated and the residue was purified on silica gel. Dichloromethane and methanol (19 : It was purified by elution with the mixture of 1). The title cis-2-chloro-N-(2-ph) amorphous foam (0,925 g, 53%) (1:1 mixture of diastereoisomers). 'HNMR (DMSO -d@') δ 1.58-2.15 (6H, 3m, -CHt CHI CH I-), 3.51-3.60 (IH, m, H-5',), 3. 62-3.　 71 (IH, m, H-5'-), 3. 95 (IH, brq, H-4'), 4. 12 (IH, brq, H-3'), 446-4. 62 (2H, m , H-2' and -CH), 4. 82-4. 89 (IH, m, -CH) ,5. 07 (IH, br t, 5'-0H), 5. 22. 5, 49 (2H, 2d, 2'- and 3'-0H), 5. 83 (IH, d, H -1’), 6. 80-6. 91 (3H, m, Ar-H), 7. 15 -7. 24 (2H, t, Ar-H), 7. 99. 8. 22 (IH , d&m, N-H), 8. 41° 8.45 (IH, 2s, H-8).

C2,824CINI OK, 0.5 Hl O is C, 53,6:H, 5,4 ;N, requires 14.9. Actual value: C, 53.5; H, 5.3; N, 14. 7%.

amine trans-N-(t-butyloxycarbonyl)-2-hydroxycyclopentyl Ruamine (24.7 g, 123 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 (48,2 mmol). 8 g, 184 mmol) was added. Diethyl azodi in THF (250 ml) A solution of carboxylade (32.06 g 5184 mmol) was introduced dropwise. .

The reaction mixture was stirred at room temperature for 18 hours, evaporated and flash chromatographed. Elute with a mixture of cyclohexane and ethyl acetate (4:1) The intermediate 4-nitrobenzoyl ester was purified as a solid (25.5 g), TL As CR, 0,52 [SiOx dichlorohexane/ethyl acetate (1:l)] Obtained. This ester was dissolved in methanol (180 ml) and 25% aqueous ammonia. (20 ml) and the mixture was stirred at room temperature for 70 hours, then Evaporation gave a residue. Cyclohexane by flash chromatography and ethyl acetate (4:1) to contain the title compound. A fraction was obtained which was evaporated and crystallized to give cis-N-(t-butyloxy carbonyl)-2-hydroxycyclopentylamine as a solid (11.0 g, 44 %), melting point 64-65°C.

This 72-N-(t-butyloxycarbonyl)-2-hydroxycyclopentyl Mitsunobu phenyl ether formation and deprotection - Example 2 It was converted to trans-2-phenoxycyclopentylamine hydrochloride by the method described above. I changed it.

9-(2,3,5-)Cu9-benzoyl-β-D-ribofuranosyl)-2゜ 6-di’)o9H-purine (3.0 g, 4.7 mmol) with dioxa: / (30 ml) and trans-2-phenoxycyclopentyla Minne hydrochloride (0.95 g, 4.4 mmol) was added followed by triethylamine (0.64 g, 6.3 mmol) was added. The reaction mixture was stirred at room temperature for 72 hours. and purified by flash chromatography on silica gel to obtain a foam. , to which saturated methanolic ammonia (100 ml) was added. 16:00 at room temperature After a period of time, the reaction mixture was evaporated and purified by flash chromatography. 2-2-chloro-N-(2-phenoxycyclopentyl)adenosyl (0°70g, 35%) as an amorphous foam (mixture of diastereoisomers) I got it.

'HNMR (DMSO-d, ') δ 1. 56-2. 30 (68,3m, -CH2C82CH2-), 3. 52-3. 60 (LH, m, H-5 °a) + 3. 63-3. 71 (IH, m, H-5'b), 3. 96 (IH, q, H-4'), 4°13 (IH, q, H-3°), 4. 50 -4. 61 (2H, m, H-2' and -CH), 4. 82-4. 8 9 (IH, m, -CH), 5. 08 (IH, t, 5'-0H), 5. 23. 5.49 (2H, 2d, 2'- and 3'-0H), 5, 83 (IH, d, H-1'), 6. 90. 7. 07 and 7. 25 ( 5H, t, d, t, Ar-H), 8.43 (IH, s, H-8), 8.60 (I H,d.

N-H).

C21H24CI　NI　Os　O,5Ht　O is C, 53,6:H, 5,4; N, 14.9 is required. Actual measurements: C, 53.4, H, 5.5, N, 14.　 5%.

Example 13 (Method A) 2-chloro-N-[(R)-+-hydroxy-2-propyl]adenosine (R) -2-amino-1-propatol (0.23 g, 3.0 mmol), 9- (2,3,5-tri-Q-benzoyl-β-D-ribofuranosyl)-2,6-di Chloro-9H-purine (1.7 g, 2.7 mmol) and triethylamine (0.30 g, 3.0 mmol) was dissolved in dioxane (20 ml) and heated to room temperature. The mixture was stirred for 200 hours. After purification by column chromatography, the obtained 2',3',5'-tri-9-benzoyl-2-chloro-N-[(R)-1-hyper Deprotection of Droxy-2-propyl]adenosine using methanolic ammonia and the title 2-chloro-N-[(R)-1-hydroxy-2-propylamine Amorphous foam (0.5 g, 54%), 'HNMR (DMSO-d@) δ1, +7 (3H, 3m, -CH5), 3. 35-3. 72 (4H, m, H-5', H-5°, and -CHt), 3. 96 (IHLq, H4 ), 4゜14 (IH, m, H-3'), 4.52 (IH, dd, H-2') , 5.08 (IH, t, 5°-0H), 5. 22. 5. 49 (2H, 2 d, 2' and 3'-0H), 5.83 (IH, d, H-1'), 8.0 (IH , d, H-N), 8°40 (IH, s, N-8).

C,,H,7CINs os,o,75 H201;IC,41,9;H,5 ,0;N.

18.8 is required. Actual measurements: C, 42, 1, H, 5, 2, N, 15. 8% .

amine Thiophenol (1.5 g, 14 mmol) was dissolved in anhydrous THF (100 ml). and 60% curvature dispersion of sodium hydride (0.30 g, 14 mmol) mesyla ester of rubonyl-2-hydroxypropylamine (mesyla teester) (3.2 g, 14 mmol) was added in three portions and the reaction mixture was The mixture was heated at 70"C for 18 hours. After cooling, water (30ml) was added and the aqueous phase was separated and washed with dichloromethane (50ml). Dry the combined remains. Dry M g S O4) and evaporate to give (R)-Nt-butyloxycarboxylate Rubonyl-1-phenylthio-2-propylamine was converted into a pale yellowish brown oil (3,2 g, 85%), TLCRt O,64 [5102: heptane/ethyl acetate (1: 1)].

This (R)-N-(t-butoxycarbonyl)-1-phenylthio-2-propyl (R)-1= by acidic hydrolysis using the method described in Example 2. Converted to phenylthio-2-propylamine hydrochloride.

(R)-1-phenylthio-2-propylamine (0.4 g, 1.96 mmol ), 9-(2,3,5-tri-p-benzoyl-β-D-ribofuranosyl) -2,6-dichloro-9H-purine (1,2 g, 1.9 mmol) and dioxin in the presence of triethylamine (0.4 g, 4 mmol) in San (15 ml). Made it react. The reaction mixture was stirred at room temperature for 72 hours, heated at 50"C for 24 hours, Cooled, filtered and evaporated. Product (by flash chromatography) After purification) was debenzoylated with methanolic ammonia to give the title 2-chloro -N-[(R)-1-phenylthio-2-propy)b3 adenosine (column chromatography) (after matography) as a foam (0.47 g, 52%), 'HNMR (DMSO- d.

) δ 1. 34 (3H, d, CHs), 3. 01 (IH, dd, C H).

3, 52-3. 60 (IH, m, H-5',), 3. 62-3.　 72 (IH, m, H-5',), 3.95 (IH, Q, H-4'), 4.13 (IH, m, H-3'), 4.30-4.45 (IH, m, -C-H), 4.5 3 (IH, m, H-2'), 5. 09. 5.22. 5. 50 (3H , 3br, 2', 3' and 5'-0H), 5.84 (IH, d, H-1') , 7.19 (IH, t, Ar-N), 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,,C,2CIN,Ol S is C,50,5;H,4,9,N,15. 5 I need. Actual value: C, so, 6. H, 5,1; N, 15.2%.

Example 15 (Method A) (R)-1-(4-fluorophenoxy)-2-propylamine (0.29 g, 1.4 mmol) (prepared from 4-fluorophenol by the method described in Example 2) ), 9-(2°, 3', 5'-)di-0-benzoyl-β-D-ribofurano sil)-2,6-dichloro-9H-purine (0.89 g, 1.4 mmol), Presence of triethylamine (0.42 g, 3 mmol) in dioxane (30 ml) It reacted to the presence of the enemy. The reaction mixture was stirred at room temperature for 18 hours, then stirred at 60°C for 4 hours. It was heated for a while. The reaction mixture was filtered and evaporated to obtain a residue, which was flashed. di-propyl]adenosine was deprotected using methanolic ammonia to obtain the standard 2-chloro-N-[(R)-1-(4-fluorophenoxy)-2-pro pill] adenosine (0.21 g, 40%) (after column chromatography), fused A point of 172-173°C was obtained: 'HNMR (DMSO-d,) δ 1.　29　 (3H.

d, CHs), 3. 52 3. 60 (IH, m, H5',), 3. 64 3,72 (IH, rn, H5'b) + 3.924.00 (2H9m, H4° and -C-H), 4. 05-4. 20 (2H, m, H-3' and -C-H).

4, 53 (IH, m, H-2'), 4. 65 (IH, m, -CH5 CH-), 5, 08. 5. 24. 5.50 (3H, 3br, 2°, 3' and 5'-0H).

5, 86 (IH, d, H-1'), 6. 89-7. 15 (4H, 2rn, Ar-H), 8. 30-8. 46 (2H, m, H-8 and and N-H).

C+wHz+CI FNs Os is C, 49,8; H, 4,7, N, 15. 3 Requires. Actual value: C, 49.4; H, 4.7; N, 14. 9%.

(R)-2-phenoxy-■-propylamine (0.6 g, 2.9 mmol ) Iyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1, 5 g, 2.4 mmol) and triethylamine ( 0.5 g, 5.3 mmol). The reaction mixture was incubated at room temperature for 72 hours. Stirred for a while then filtered and evaporated. The product was subjected to flash chromatography. After purification with saturated methanolic ammonia (30 ml) for 18 hours Work-up and evaporation gave a solid residue. This solid was dissolved in dichloromethane. After thorough washing, the title 2-chloro-N-[(R)-2-phenoxy-1-propylene adenosine (0.7 g, 65%), melting point 175-177°C, 'HNM R (DMSO-ds) δ 1. 39 (3H, d, CHI), 3. 56 (IH, ABX, H-5', ), 3. 68 (IH, m, H-5° , ), 3. 33-3. 40 (IH, m, -C-H), 3. 83-3.　 92 (IH, m, -C-H), 3. 96 (IH, q, H-4°), 4 ．． 14 (IH, m, H-3'), 4. 53 (IH, dd, H-2 ’ ), 4. 70 (IH, q, -C-H), 5. 08. 5.　34゜ 5, 50 (3H, 3br, 2', 3' and 5°-0H), 5. 85 (IH, d, H-1'), 6. 90 (IH, t, Ar-H), 7. II (2 H, d, Ar-H), 7. 28 (2H, t+ Ar-H), 8.45 ( IH, s, H-8) and 8°63 (IH, t, NH) were obtained.

Cl@H22CI Ns O, is C, 52,4; H+ 5. 1, N, 16. 1 is required. Actual value: C, 52.5, H, 5.1; N, 15. 9%.

The title compound was dissolved in 2-(phenylmethoxy)ethylamine hydrochloride (0.51 g, 2.7 mmol) and 9-(2,3,5-)di-0-benzoyl-β-D-ly bofuranosyl)-2,6-dichloro-9H-purine (1,43,2,25 mmol) The purified product was then treated with methanolic ammonia. Debenzoylation gave the title 2-chloro-N-[2-(phenylmethoxy)-ethyl Chyl] adenosine (0.38 g, 44%) (after column chromatography) was solidified. body, melting point 115-124°C, IHNMR (DMSO-d@) δ 3. 50- 3.58 (IH, m, H-5',), 3. 60-3. 70 (4H, m, H- 5'.

, -CH,- and -CH-), 3.95 (IH, q, H-4'), 4.0 4-4, I 6 (2H, m, H-3' and 10H-:) + 4. 52 (IH, br　s.

H-2' and -CHg-), 5. 07 (IH, t, 5°-0H), 5.2 +.

5, 50 (2H, 2d, 2'- and 3'-0H), 5. 84 (I H, d, H-1'), 7. 22-7. 36 (5H, m, Ar-H), 8. 25-8. 40 (2H, m, H-8 and N-H).

C++Ct2C]Ns Oa, 0. I H* O is C, 52, 1; H, 5, I: N, 16°0 is required. Actual value: C, 51, 8, H, 5, 3, N, 1 5. 6%.

(ribofuranosyl)-6-chloro-2-fluoro-9H-purine (1,03g, 2 ．． 38 mmol) PCT Publication No., WO93108'206, (R)-1-F phenoxy-2-propylamine (0.36 g, 2.38 mmol) and trie Thylamine (0.29 g, 0.28 mmol) was stirred at room temperature for 18 hours. reaction The mixture was filtered and evaporated to obtain a residue, which was subjected to flash chromatography. More refined. The obtained 2',3',5'-tri-p-acetyl-2-fluoro Rho-N-[(R)-1-phenoxy-2-propyl]adenosine in methanol Deprotection with ammonia resulted in the title 2-fluoro-N-[(R)-1-phene. [Noxy-2-propyl]adenosine (0.28g, 23%) (column chromatograph 'HNMR (DMSO-d,) δ 1.33 (3H, d, -CHI), 3.59 (IH, m, H-5' a) + 3. 63-371 (IH, m, H-5',), 3.92-3 ．． 99 (2H, m, H-4' and -C-H), 4. I O-4, 18 (2H, m, H-3' and 10-H).

4.51 (IH, Q, H2'), 4.61 (IH, m, CHICH), 506 (IH, t, 5° -0H), 5. 22. 5. 48 (2H, 2d, 2 ' and 3' -0H), 5.82 (IH, d, H-1°), 6.8 9-6.97 (3H, m, Ar-H), 7. 25-7. 30 (2H, t, Ar-H), 8. 39 (IH, s, H-8), 8. 49 (IH, d, N-H).

C+ *Hx! F　N　s　Os is C, 54, 4, H, 5, 3; N, 16 ．． 7 is required. Actual measurement value 2C, 54,7; H, 5,5; N+ 16. 4% .

(0.30 g, 0.69 mmol) and sodium hydroxide (0.32 g, 8. 0 mmol) and methanol (15 ml) in a sealed container. It was produced by reacting at 0 to 90°C for 4 hours. Cooled reaction mixture Neutralized with concentrated hydrochloric acid and evaporated to dryness. Add water (30ml) and mix. The compound was extracted with dichloromethane (2X30ml). Dry the combined extracts. Mg504) and co-evaporated with dichloromethane (30 ml) to give the title compound. The compound was foamed (0.19 g, 60%), 'HNMR (DMSO-d,) δ 1. 32 (3H, d, CHCH*), 3. 55 (IH, m, H5°, ), 3. 65 (IH, m, H5'-), 3. 72 (3H, s, CHs) , 3. 91 3°99 and 4. 10-4. 20 (4H, 2m, H- 3', H-4' and -CH2), 4.51 (IH, dd, H-2' ), 4.67 (IH, m, -CdanCH2), 5. 84 (IH, d, Hl '), 6. 89 6. 98 (3H, m, Ar-H), 7.26 (2H, d d, Ar-H), 8.12 (IH, br, -NH), 8. 46 (IH,s , H-8).

The title compound was prepared as 2-methoxyethylamine hydrochloride by the procedure described in Example 7. (0.27 g, 346 mmol) and 6-chloropurine ribocyto (i.e. 9 -β-D-ribofuranosyl-6-chloro-9H-purine') (1.0 g, 3.5 mmol) and triethylamine in dioxane (30 ml) at room temperature for 72 hours. (1.04 m 1.7.5 mmol) Ta. The reaction mixture was filtered, evaporated and the resulting residue was dissolved in methanol (100 m Recrystallization from l) gave the title compound (0.80 g, 82%) as a solid, mp 15 1-152°C, 'HNMR (DMSO-dl) δ 3.26 (3H, s, - CH5), 3. 50 3. 58 (3H, m, H5', and -CH2 -’), 3°60-3. 70 (3H, m, H-5°, and -CH2), 3. 96 (IH.

Q, H-4'), 4.14 (IH, dd, H-3'), 4.60 (IH, dd .

H-2'), 5. 20. 5.45 (2H, 2d, 2°- and 3°-0 H), 5.42 (IH, t, 5'-0H), 5.87 (IH, d, H-1'), 7.80 (IH, br　s, -NH), 8.22. 8. 35 (2H, 2 s, H-2 and H-8).

C+ t H+ s N s Os l yo C, 48, O; H, 5, 9: N, 21 ．． 5 is required.

Actual measurements: C, 47.8, H, 5.9; N, 21.　3%.

The title compound was dissolved in (2-methoxyphenyl)methylamine (0.55 g, 4°0 mmol) and 9-(2,3,5-tri〇-benzoyl-β-D-ribofurano sil)-2,6-dichloro-9H-purine (1,Olg, 1.6 mmol) and The purified product was then devetted using methanolic ammonia. The title 2-chloro-N-[(2-methoxy) Cyphenyl)methyl]adenosine (0.31 g, 45%) (column chromatography solid, melting point 116-119°C, 'HNMR (DMSO-dl) δ3, 51-3. 60 (IH, m, H-5'a) + 3. 61-3 ．． 70 (IH.

m, H-5' b) + 3.95 (IH, Q, H-4'), 4.13 (IH, m , H-3'), 4. 52 (IH, q, H-2'), 5. 06(IH,t, 5'-0H), 5. 22. 5. 50 (2H, 2d, 2°- and 3' -0H), 5. 85 (IH, d, H-1'), 6. 83-7. 2 5 (4H, 2t, 2d, Ar-H).

8, 43 (IH, s, H-8), 8. 72 (IH, t, N-H) and I got it.

(R)-3-Methyl-1-phenoxy-2-butylamine (0.6g, 28ml mole), 9-(2,3,5-)riichiko-penzoyl-β-D-ribofuranosyl )-2,6-dichloro-9H-purine (1,4 g, 2.2 mmol) and dioxin The presence of triethylamine (0.5 g, 5.0 mmol) in San (20 ml) I reacted below. The reaction mixture was stirred at room temperature for 40 hours, then filtered and evaporated. I set it. The product (after being purified by flash chromatography) was dissolved in methanol The product (after column chromatography) was debenzoylated with aqueous ammonia. Obtained as a foam, which solidified upon coevaporation with dichloromethane.

2-chloro-N-[(R)-3-methyl-1-phenoxy-2-butyl]adeno Syn (0.46 g, 44%) was a white solid, melting point 95-100°C, 'HNMR (D MSO-d, ) δ 0. 95. 0. 98 (6H, 2d, 2x CHt) , 2.10 (IH, m, CH(CHs)y), 3.53 3.60 (IH, m, H-5' a) + 3. 63-3. 71 (IH, m, H-5°,) , 3. 95 (IH.

q, H-4'), 4. 07-4. 23 (3H, m, H-3' and -CH,-), 4. 96 (IH, m, -C-H), 4. 56 (IH, q, H-2°), 5.08 (IH, t+5'-0H), 5. 23.　 5. 49 (2H, 2d, 2' and 3'-0H), 5.84 (IH, d, H -1'), 6.87-6.97 (3H, m, Ar-H), 7. 24-7.　 31 (2H, dd, Ar-H), 8. 36 (IH, d, -N-H), 8 ．． 40 (IH, s, H-8).

C21H2ICINa os, 0.5 Hx O is C, 53,3; H+ 5. 8; N, 14.8 required. Actual value: C+ 53. 4; H, 5, 7; N, 14. 8%.

(R)-1-(2-(2-propyloxy)phenoxy)-2-propylamine (Prepared from 2-(2-propyloxy)phenol by the procedure described in Example 2) ) (0.54 g, 2.2 mmol) was added to 9-(2,3,5-)so-0-acetic acid Chi-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2,0g , 4.5 mmol) and triethylamine (2° 19 g, 22 mmol). The reaction mixture was stirred at room temperature for 18 hours. After stirring, it was filtered and evaporated. Product (on flash chromatography) ) was debenzoylated with methanolic ammonia to give 2-chloro-N -[(R)-1-(2-(2-propyloxy)phenoxy)-2-propyl] Adenosine (after column chromatography) foam (0.47 g, 39%).

'HNMR (DMSO-d,) δ 1. 04. 1. 06 (6H, 2d, 2x-CHs), 1.31 (3H, d, -CHI), 3.53-3.60 ( IH, m, H-5°-), 3. 64 3. 71 (IH, m, H5'b), 3 ．． 95 (IH, q, H-4'), 3. 98-4. + 5 (3H, 2 m, H-3' and -CH2), 4. 35 (IH, 1), CH), 4. 5 1 (IH, q, H2').

4, 72 (IH, m, -C-H), 5. 08 (IH, t, 5' -0H ), 5. 22, 5. 48 (2H, 2d, 2' and 3'-0H), 5 ．． 85 (IH, d, H-1'), 6.82-7.08 (5H, m, Ar-H), 8.32 (IH, d.

-N-H), 8. 41 (IH,s, H-8).

Cl2H21CINiOs, 1. OHt O is C, 51,6; H, 5,9 ;N, requires 13.7. Actual value: C, 52, O, H, 5, 8; N, 13. 3%.

Example 24 (Method A) 2-chloro-N-[(R)-1-phenylsulfonyl-2-propyl]adenosyl begging (R)-1-Phenylsulfonyl-2-propylamine (0.4g, 1.7ml mole), 9-(2,3,54ly-0-benzoyl-β-D-ribofuranosyl )-2,6-dichloro-9H-purine (1.7 g, 1.0 mmol) and The presence of triethylamine (0.4 g, 4.3 mmol) in xane (20 ml) It reacted to the presence of the enemy. The reaction mixture was stirred at room temperature for 48 hours and heated at 60 °C for 4 hours. , cooled, filtered and evaporated. Product (on flash chromatography) ) was debenzoylated with methanolic ammonia to give the title 2-chloro rho-N-[(R)-1-phenylsulfonyl-2-propyl]adenosine (cara Foam (0.2 g, 24%), 'HNMR (DMs o-dl) δ 1. 24 (3H, d, -CH5), 3. 45 (IH, dd, -C-H), 3. 53-3. 61. (2H, m, H-5°, and -〇-H), 3゜64-3.71　(IH, m, H-5',), 3.86　( IH, dd, -C-H), 3.97 (IH, q, H-4°), 4. 14 ( IH, m, H-3°), 4.53 (IH, m, H-2'), 5. 09 ( IH, t, 5°-0H), 5.23, 5, 50 (2H, 2d, 2' and 3 '-0H), 5.83 (IH, d, H-1'), 7.45-7.82 ( 5H, m, Ar-H), 8.21 (IH, d, -N-H), 8.38 (IH , s, H-8).

fill compound was added to (2-methylphenyl)methylamine (1.51 g, 1 25 mmol) and 6-chloropurine riboside (2.87 g, 10.0 mmol) and diisopropylethylamine (1,94 mL) in dioxane (100 ml). g, 1.50 mmol). reaction mixture The material was heated at 60° C. for 6 hours, cooled, filtered and evaporated. Flush the remaining amount chromatography, first with dichloromethane and later with dichloromethane to reduce the polarity. The product (2.6 g, 7 0%) as a solid, which was recrystallized from methanol to give N-[(2-methyl phenyl)methyl]adenosine as white crystals (1.75 g, 47%), melting point 161 ．． 5-163.5°C, IHNMR (DMSO-d,) δ 2.35 (3H, s , -CHri, 3. 53 3. 60 (IH, m, H-5'-), 3.　 65 3. 72 (IH, m, H-5°b), 3. 98 (IH, q, H4 °), 4.16 (IH, m, H-3'), 4. 64 (IH, q, H-2 °), 5. 41 (IH, t, 5'-0H), 5. 21. 5. 48 (2H, 2d, 2°- and 3'-0H), 5, 92 (IH, 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 and N-H).

(R)-1-phenoxy-2-propylamine (0.56 g, 3 mmol) rho-2-methyl-9H-purine (0.43 g, 1 mmol) [2-methylinos (2-MethylinosineX Journal of Organic Chemistry, 1967, 32.3258-3Q60) prepared by standard acylation and chlorination steps] and dioxane (20 m l) in the presence of triethylamine (0.41 g, 4 mmol) .

The reaction mixture was reacted at 50°C for 70 hours and at 90°C for 3 hours, then filtered. and evaporated. The product (after purification by flash chromatography) was purified by meth Debenzoylation with nolic ammonia gave the title 2-methyl-N-[(R)- 1-phenoxy-2-propyl]adenosine (after column chromatography) Foam (0.21 g, 50%), IHNMR (DMSO-d,) δ 1.30 ( 3H, d, CHs), 2. 43 (3H, S, CHs'), 3. 53 3. 60 (IH, m, H-5',), 3. 66-3. 73 (IH , m, H-5' b).

3, 94 (IH, dd, -C-H), 3. 99 (IH, q, H-4') ,4. 12-4. 22 (2H, m, H-3' and -C-H), 4.5 4 (IH, dd.

H-2°), 4.76 (IH, m, CHsCH), 5.20, 5.52 (2H , 2d, 2' and 3'-0H), 5. 73 (IH, t, 5'-0H) , 5°87 (IH, d, H-1'), 6. 90-7. 31 (5H, t, m, t, Ar -H), 7.74 (IH, br d, N-H), 8.28 ( IH,s, H-8).

CtoHtiCINs 08.0.33 H! O is C, 57,0; H, 6,1 ;N.

16.6 is required. Actual value: C, 57.0; H, 6.2; N, 16. 8% .

Compound evaluation Renewing the method for assessing in vitro adenosine receptor binding We investigated [Adenosine Receptors, (Cooper, D. , M.F., and Londos, C., eds.) Alan R.Sr. , Inc., New York, 1988.43-62].

Evaluation of these compounds in established animal models has shown that the compounds according to the invention It was shown to have desirable central nervous system properties. For example, the compound may have anticonvulsant properties. Acts as a drug, is effective in animal models of pain, and in simulation Cerebral protection in laboratory test animals subjected to simulated cerebral ischemia ( cerebroprotective) effect. Additionally, the compound may It may have efficacy as a neuroprotective agent in cases of edema and traumatic head injury.

Evaluation of in vitro binding to adenosine AI and A2 receptors Disclosed in the present invention The affinity of known and new compounds for adenosine Al receptors can be substantially ['H1-R-PIA was used as a radioligand] as described in the literature. Measured (Naunyn-3chmiedeberg's Archives of Pharmacology, 1980.313.179-187).

The affinity for the A2 receptor was determined using the radioactive ligand PH]-CG3 21680. European Journal of Pharmacolo gy, 1989.168.243-246) and representative compounds. The in vitro receptor binding values obtained in the table below are included for comparison. There is.

In this model, seizures are caused by methyl 6,7-simethoxy 4-ethyl-β- Lupoly: z (carboline) -3-carboxilade DMCM t5m i in g/kg.

P, by administering (intraperitoneal) It is triggered by

DMCM is probably a GABA receptor/benzodiazepine receptor/chloride receptor. Benzodiacea, which causes seizures by reducing the inhibitory efficacy of the onophore complex It is a reverse agonist for the zepin receptor.

DMCMI 5mg/kg dissolved in 0.02N HCI (1mg/ml) was administered intraperitoneally in a volume of 300 μm to male NMRI mice weighing 20 ± 2 g. do. This causes two different responses: a) Some animals may Denotes a brief loss of reflex movement to stand or a short, weak movement of the upper limbs while standing upright. b) Other animals exhibit severe, clonic and tonic convulsions. Death often ensues. DMCM was administered 30 minutes after intraperitoneal injection of test compound. administered. Reaction time in the presence of severe clonic and tonic convulsions and death are noted up to 15 minutes after administration of DMCM. of each test compound at least Five doses are tested with 8 mice per dose.

Spasticity suppression ED. The value is the dose that protects 50% of the animals against clonic spasticity (m g/kg): Some typical values are shown in Table ■.

The above method is described by Petersen, ε, N, Eur, J., Pharmac. ol, 94.117-124.1983; Petersen, E.N. Eur, J. Pharmacol, 195.261-265.1991 It is described in.

Blood pressure in anesthetized rats Test compounds are generally dissolved in DMSO with 5% chremophore/ Nembutal anesthesia without starvation or fasting after dilution in saline 200 g female Sprague Dawley rats were dosed. Rat The patient is breathing naturally; blood pressure (BP) and heart rate (HR) are i, v at one time, measured 5 minutes after injection. Repeat each measurement twice . The results for representative compounds are shown in Table ■.

Neuroprotective effect: Gerbil BCAO ischemia model transient global ischemia (global ischaemia) in 2% halose in 70% nitrous oxide and 30% oxygen. Mongolian gerbil (gerbi lsX 60) anesthetized with ~70 g, male). The common carotid artery was occluded for 5 minutes, and the animal was He was allowed to recover for 4 days. The animal was re-anesthetized, decapitated, and the brain quickly crushed. The sample was transferred to dry ice and frozen. Parietal section (20 μm) at hippocampal level taken from the brain and stained with cresyl violet and hematoxylin and eosin. Ta. Brain sections were graded from 0 (uninjured) to 3 for neuronal damage in the hippocampal CAI region. (total damage of CAI). The body temperature of all animals was measured surgically. The temperature was maintained at 37°C throughout the procedure, and animals were placed in a warmed box during the recovery period. Ta. Each experiment consisted of drug and vehicle control groups (n=lo-15).

Test compounds were administered 30 minutes after reperfusion.

Tested AI receptor A2 receptor specific adenosine agonist binding binding A 2/AI (K,, nM) (K+, nM) (+) 43 1157 27 (2) 18 318 1 g (8) +23 2188 18 (9) 3.3 3270 991 (10) 3.1 1320 426 (+7) 340 7776 23 (+8) 8 310 39 (+9) 88 2332 27 (26) 69 +200 17 CPA 1.6 173 108 (R)-PTA 2.0 134 67 Table■ DMCM attack BP decrease% Compound ED*o (mg/kg) i, p, 0.1 mg/kg i, v.

(Test No.) HR (15) 13.6 16 (26) 1.9 15

Claims (14)

[Claims] 1. Formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, X is hydrogen, amino, halogen, hydroxy, lower alkoxy or lower alkyl and R1 is ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (However, Y is methylene or a valence bond, R2 and R6 are H or lower , straight chain or branched alkyl, and R3 is H or lower alkyl; or R2 and R3 together represent cyclobutyl, cyclopentyl, cyclohexyl can form a syl or phenyl ring, Z is oxygen, methylene, sulfur, sulfur Honyl or valence bond, R4 is H, lower alkyl, aralkyl, in some cases More halogen, hydroxy, haloalkyl, alkyl, alkoxy, aryl monocyclic or substituted with xy, acyloxy or alkylmercapto groups It is a bicyclic aromatic system. ). ] A compound represented by or a pharmaceutically acceptable salt thereof. 2. X is halogen, Z is oxygen or sulfur and R4 is optionally The compound or drug thereof according to claim 1, which is phenyl substituted with fluoro. Scientifically acceptable salt. 3.2-chloro-N-(1-phenoxy-2-propyl)adenosine, 2-chloro Rho-N-[(R)-1-phenoxy-2-propyl]adenosine, 2-chloro- N-[(S)-1-phenoxy-2-propyl]adenosine, 2-chloro-N- (2-phenoxyethyl)adenosine, 2-chloro-N-[(R)-1-phenylene -2-propyl]adenosine, 2-chloro-N-(1-phenyl-3-butyl ) adenosine, N-(1-phenoxy-2-propyl)adenosine, 2-amino -N-(1-phenoxy-2-propyl)adenosine, N-[(1S, trans )-2-hydroxycyclopentyl]adenosine, N-[(1R, trans)- 2-hydroxycyclopentyl]adenosine, 2-chloro-N-(cis-2-ph) enoxycyclopentyl)adenosine, 2-chloro-N-(trans-2-phenylene) adenosine, 2-chloro-N-[(R)-1-hydroxy C-2-propyl]adenosine, 2-chloro-N-[(R)-1-phenylthio -2-propyl]adenosine, 2-chloro-N-[(R)-1-(4-fluoro phenoxy)-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, 2-methoxy-N -[(R)-1-phenoxy-2-propyl]adenosine, N-(2-methoxy ethyl)adenosine, 2-chloro-N-[(2-methoxyphenyl)methyl]a Denosine, 2-chloro-N-[(R)-3-methyl-1-phenoxy-2-butylene ] Adenosine, 2-chloro-N-[(R)-1-(2-(2-propyloxy)phenoxy)- 2-propyl]adenosine, 2-chloro-N-[(R)-1-phenylsulfonyl-2-propyl]adenosyl hmm, N-[(2-methylphenyl)methyl]adenosine or 2-methyl-N-[( R)-1-phenoxy-2-propyl]adenosine; or its pharmaceutically acceptable salts. 4. A compound according to claims 1 to 3 or a pharmaceutically acceptable salt thereof as active ingredient and a pharmaceutically acceptable carrier. 5. A compound according to claims 1 to 3 or a pharmaceutically acceptable salt thereof as active ingredient and for use in the treatment of central nervous system diseases, including pharmaceutically acceptable carriers. A pharmaceutical composition suitable for. 6. A compound according to claims 1 to 3 or a pharmaceutically acceptable salt thereof as active ingredient and a pharmaceutically acceptable carrier, suitable for use in the treatment of myocardial ischemia. suitable pharmaceutical composition. 7. A compound according to claims 1 to 3 or a pharmaceutically acceptable salt thereof as active ingredient and pharmaceutically acceptable carriers, associated with high plasma FFA levels. A pharmaceutical composition suitable for use in the treatment of disease. 8. Claims in the form of an oral dosage unit containing about 1-200 mg of active compound. Pharmaceutical compositions according to items 4 to 7. 9. Effective in relieving central nervous system disorders in people who need treatment for such disorders. in such a person, characterized in that the compound according to claims 1 to 3 is administered in an amount of A method for treating the above-mentioned disease. 10. For people in need of treatment for myocardial ischemia, an amount effective to alleviate such disease. in such a person, characterized in that the compound according to claims 1 to 3 is administered. Treatment methods for the above diseases. 11. This product is recommended for people in need of treatment for diseases associated with high plasma FFA levels. characterized in that the compound of claims 1 to 3 is administered in an amount effective for alleviating such diseases. A method for treating the above-mentioned disease in such a person. 12. If a patient or animal is in need of treatment for a central nervous system disease, The compound of claims 1 to 3 is administered in an amount effective to alleviate the symptoms of the disease in a pharmaceutically acceptable carrier. the step of administering the pharmaceutical composition in the form of a pharmaceutical composition in combination with a carrier or diluent. A method of treating said disease in said patient or animal, comprising: 13. Patients or animals in need of treatment for myocardial ischemia should be treated with mild disease. an effective amount of the compound of claims 1-3 in a pharmaceutically acceptable carrier. or in the form of a pharmaceutical composition thereof, present together with a diluent. A method of treating the disease in the patient or animal. 14. Patients in need of treatment for diseases associated with high plasma FFA levels or A compound according to claims 1 to 3 is administered to an animal in an amount effective for alleviating such diseases, if it is a drug. a pharmaceutical composition thereof in association with a pharmaceutically acceptable carrier or diluent; A method of treating said disease in said patient or animal, comprising administering in the form of a.