MXPA99001509A - N6 - Google Patents

Abstract

A substituted N6-oxa, thia, thioxa and azacycloalkyl substituted adenosine derivative of formula (I) and a method for using the composition as an A1 heart adenosine receptor. In said formula, R1 is a monocyclic or polycyclic heterocyclic group containing from 3 to 15 atoms, at least one of which is selected from the group consisting of N, O, P and S-(O)o-2 and wherein R1 does not contain an epoxide group.

Description

ADENOSINE DERIVATIVES SUBSTITUTED WITH N6 HETEROCYCLIC BACKGROUND OF THE INVENTION Field of the Invention This invention covers adenosine derivatives substituted with substituted N6-oxa, thia, thioxa and azacycloalkyl which are selective adenosine type 1 receptor agonists, and as such, are potentially useful agents for the treatment of diseases. cardiovascular diseases and disorders of the central nervous system.

Description of the Prior Art There are two subtypes of adenosine receptors in the heart: Ai and A2. Each subtype performs different physiological functions. The stimulation of the adenosine receptor Ai induces two different physiological responses. The first is the inhibition of the stimulatory effects of catecholamine. This effect is mediated via the inhibition of cyclic AMP synthesis. The second effect mediated by the Ai receptors is the deceleration of the heart rate and the propagation of impulses through the AV node. The effect is independent of the cAMP metabolism and is related to the activation of the adenosine receptor Ai of the incoming rectification K + channel. This effect is unique to the receiver Ai; there is no role for the receiver Ai in modulating the function of this channel. The stimulation of the Ai adenosine receptor conforming to the above shortens the duration and decreases the amplitude of the potential action of cells of the AV node and subsequently prolongs the refractory period of the cells. The consequence of these effects is to limit the number of impulses driven * from the atria to the ventricles. The above forms the basis of the clinical utility of the Ai receptor agonists for the treatment of supraventricular tachycardias, including atrial fibrillation, atrial palpitation and reentrant tachycardia of the AV node.

The clinical utility of the Ai agonists would therefore be in the treatment of acute and chronic heart rhythm disorders, especially those diseases characterized by rapid heart rhythm where the rhythm is driven by abnormalities in the atrium. Disorders include but are not limited to atrial fibrillation, supraventricular tachycardia, and atrial flutter. Exposure to Ai agonists causes a reduction in heart rate and an abnormal rhythm regularization thus restoring improved hemodynamic blood flow.

Ai agonists, despite their ability to inhibit catecholamine-induced decrease in cAMP, should have beneficial effects in the diseased heart where the increased sympathetic tone resulting in improved cAMP has been associated with the increased likelihood of ventricular arrhythmias and sudden death .

SUMMARY OF THE INVENTION One object of this invention is the novel heterocyclic substituted adenosine derivatives.

Another objective of this invention is substituted heterocyclic adenosine derivatives that are agonists of the Ai receptor.

Still another object of this invention are substituted heterocyclic adenosine derivatives which are useful for treating supraventricular tachycardias, including atrial fibrillation, atrial flutter and AV node reentrant tachycardia.

In one example, this invention is a composition of matter having the formula: where Rj. is a monocyclic or polycyclic heterocyclic group containing from 3 to 15 atoms, at least one of which is N, O, S, P and wherein Ri can be mono or polysubstituted with one or more compounds selected from the group consisting of halogen , oxo, hydroxyl, lower alkyl, substituted lower alkyl, alkoxy, aryl, acyl, aryloxy, carboxyl, substituted aryl, heterocycle, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, nitro, cyano and mixtures thereof wherein Ri does not contain an epoxide group.

In another example, this invention is a method for stimulating coronary activity in a mammal experiencing a coronary electrical disorder that can be treated by stimulating a cardiac adenosine Ai receptor by administering a therapeutically effective amount of the composition presented above. to the mammal.

In yet another example, this invention is a pharmaceutical composition of matter comprising the composition of this invention and one or more pharmaceutical excipients.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a schematic of the effect of the concentration of compound II of Example 2 on the conductance of the atrial AV node for the adenosine receptor Ai (- ° -) and for the adenosine receptor a2 (- O -).

Figure 2 is a schematic of the effect of the concentration of compound I of Example 2 on the conductance of the atrial AV node and specifically on the response of the adenosine receptor Ai (- ° -) and for the adenosine receptor a2 (- O - ).

DESCRIPTION OF THE CURRENT EXAMPLE This invention comprises adenosine derivatives that are selective adenosine type 1 receptor agonists. The compositions are optimally substituted as described below. wherein: Ri is a cycloalkyl group, containing from 3 to 15 atoms of either monocyclic or polycyclic heterocyclic groups, at least one of which is a heteroatom selected from the group consisting of N, O, P and S (- O ) 0. 2- Ri, in turn, can optionally be mono or polysubstituted with halogen, oxo, hydroxyl, lower alkyl, alkyl minor substituted, alkoxy, aryl, acyl, aryloxy, carboxyl, substituted aryl, heterocycle, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, nitro and cyano. However, Ri can not contain an epoxy group.

Ri is preferably a monocyclic, bicyclic or tricyclic group containing from 3 to 15 atoms, at least one of which is selected from the group consisting of O or S - (O) 0.2 wherein Ri can be mono or polysubstituted with one or more compounds selected from the group consisting of halogen, hydroxyl, alkyl minor, substituted minor alkyl, alkoxy, aryl, acyl, aryloxy, carboxyl, substituted aryl, heterocycle, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, nitro, cyano, and mixtures thereof.

In a more favorite issue, Ri is: wherein Ri ', Ri ", Ri'" and Ri "" are individually selected from the group halogen, oxo, hydroxyl, lower alkyl, substituted lower alkyl, alkoxy, aryl, acyl, aryloxy, carboxyl, substituted aryl, heterocycle, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, nitro, cyano and mixtures thereof and X is O, or S (-O) 0. %. Preferably, Ri ', Ri ", Ri'" and Ri "" are individually selected from the group H, lower alkyl, substituted lower alkyl, alkoxy, aryl and substituted aryl. By "individually chosen" it is understood that Ri ', Ri ", Ri'" and Ri "" may each be a different component, each may be the same component, for example, hydrogen, or some of the components may be the same and some different. It is preferred more than when Ri is the composition before established, that Ri ', Ri ", Ri'" and Ri "" are individually selected from group H, lower alkyl and substituted lower alkyl. Ri "'and Ri" "can also be a single oxygen atom.

In an alternative copy, Ri is chosen from the group consisting of: wherein R can be selected individually from the group consisting of H, lower alkyl and substituted lower alkyl and wherein X is O, or S (-O) 0.2. In a more preferred example, R is selected from the group consisting of 3-tetrahydrofuran, 3-tetrahydrothiofuranyl, 4-pyranyl and 4-thiopyranyl.

The following definitions apply to the terms used herein.

The term "halogen" refers to fluorine, bromine, chlorine and iodine atoms.

The term "oxo" refers to = O.

The term "hydroxyl" refers to the -OH group.

The term "lower alkyl" refers to a cyclic, branched or straight chain, alkyl group of one to ten carbon atoms. This term is best exemplified by groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl (or 2-methylpropyl), cyclopropylmethyl, i-amyl, n-amyl, hexyl. and similar.

The term "substituted lower alkyl" refers to minor alkyl such as the one just described that includes one or more groups such as hydroxyl, thiol, alkylthiol, halogen, alkoxy, amino, amido, carboxyl, cycloalkyl, substituted cycloalkyl, heterocycle, cycloheteroalkyl, cycloheteroalkyl substituted, acyl, carboxyl, aryl, substituted aryl, aryloxy, hetaryl, substituted hetaryl, aralkyl, heteroaralkyl, alkyl alkenyl, alkyl alkynyl, cycloalkyl alkyl, cycloheteroalkyl alkyl, and cyano. These groups can be attached to any carbon atom of the minor alkyl moiety.

The term "alkoxy" denotes -Oar groups, wherein Ar is an aryl, substituted aryl, heteroaryl or substituted heteroaryl group as defined below.

The term "amino" refers to the group N 2R 2 'wherein R 2 and R 2' may independently be hydrogen, lower alkyl, substituted minor alkyl, aryl, substituted aryl, hetaryl or substituted hetaryl as defined herein.

The term "carboxyl" denotes the group-C (O) OR, wherein R can independently be hydrogen, lower alkyl, substituted minor alkyl, aryl, substituted aryl, hetaryl, substituted hetaryl and the like as defined herein.

The term "aryl" or "Ar" refers to an aromatic carbocyclic group having at least one aromatic chain (e.g., phenyl or biphenyl) or multiple condensed chains in which at least one chain is aromatic (e.g., 1, 2,3,4-tetrahydronaphthyl, naphthyl, anthryl or penantryl).

The term "substituted aryl" refers to aryl optionally substituted with one or more functional groups, for example, halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, heteroaryl. , substituted hetaryl, nitro, cyano, alkylthio, thiol sulfamido and the like.

The term "heterocycle" refers to a saturated, unsaturated or carbocyclic aromatic group having a single chain (eg, morpholino, pyridyl or furyl) or multiple condensed chains (e.g., napthyridyl, quinoxalyl, quinolinyl, indolizinyl or benzo [ bjienyl) and having at least one hetero atom, such as N, O or S, within the chain, which may be optionally substituted or not substituted with, for example, halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, heteroaryl, substituted hetaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.

The term "heteroaryl" or "hetar" refers to a heterocycle in which at least one heterocyclic chain is aromatic.

The term "substituted heteroaryl" refers to an optionally mono or polysubstituted heterocycle with one or more functional groups for example, halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.

The term "cycloalkyl" refers to a cyclic or polycyclic divalent group containing from 3 to 15 carbon atoms.

The term "substituted cycloalkyl" refers to a cycloalkyl group comprising one or more substitutes with, for example, halogen, lower alkyl, substituted minor alkyl, alkoxy, alkylthio, aryl, aryloxy, heterocycle, heteroaryl, substituted hetaryl, nitro, cyano , alkylthio, thiol, sulfamido and the like. the compositions of this invention are useful as agonists of the Ai receptor for the treatment of coronary electrical disorders such as supraventricular tachycardias, including atrial fibrillation, atrial palpitation and reentrant tachycardia of the AV node. The compositions can be administered orally, intravenously through the epidermis or by any other means known in the art for the administration of therapeutic agents.

The method of treatment comprises administering a therapeutically effective amount of the selected compound, preferably dispersed in a pharmaceutical carrier. The dosage units of the active ingredient are generally chosen in the range of 0.01 to 100 mg / kg, but will be readily determined by one skilled in the art depending on the route of administration, the age and condition of the patient. These dosage units can be administered from one to ten times a day for acute or chronic disorders. No toxicological effect is expected unacceptable when the compounds of the invention are administered in accordance with the present invention.

If the final compound of this invention contains a basic group, an acid addition salt can be prepared. The acid addition salts of the compounds are prepared in a standard manner in a suitable solvent from the main compound and an excess of acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic or methane sulfonic. The shape of the hydrochloric salt is especially useful. If the final compound contains an acidic group, cationic salts can be prepared. Typically the main compound is treated with an excess of an alkaline reagent, such as hydroxide, carbonate or alkoxide, which contains the appropriate cation. Cations such as Na +, K +, Ca + 2 and Í4 + are examples of cations present in pharmaceutically acceptable salts. Certain compounds form internal salts or zwittcrions that may also be acceptable.

Pharmaceutical compositions that include the compounds of this invention, and / or derivatives thereof, can be formulated as lyophilized solutions or powders for parenteral administration. The powders can be reconstituted by the addition of an appropriate diluent or other pharmaceutically acceptable carrier before use. S are used in liquid form the compositions of this invention are preferably incorporated in a regulated, isotonic and aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water and sodium or regulated ammonium acetate solution. Said liquid formulations are suitable for parenteral administration, but may also be used for oral administration. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, cellulose hydroxy, acacia, polyethylene glycol, mannitol, sodium chloride, sodium citrate or any other excipient known to those skilled in the art to pharmaceutical compositions including the compounds of this invention. As an alternative, the pharmaceutical compounds can be encapsulated, entangled or prepared in emulsion or syrup for oral administration. The pharmaceutically acceptable solid or liquid carriers can be added to improve or stabilize the composition, or to facilitate the preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols and water. Solid carriers include starch, lactose, calcium sulfate, dihydrate, teffa alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier can also include a sustained release material such as glycerol monostearate or glycerol distearate, alone or with a wax. The amount of solid carrier varies but, preferably, it will be between about 20 mg to about 1 gram per unit dose. The pharmaceutical doses are made using conventional techniques such as crushing, mixing, granulation and tabletting, when necessary, for tablet forms; or crushing, mixing and filling for the forms of hard gelatin capsules. When a liquid carrier is used, the preparation will take the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Said liquid formulation can be administered directly or filled into a soft gelatin capsule.

The following examples serve to illustrate this invention. The examples are not intended in any way to limit the scope of this invention, but are provided to show how to make and use the compounds of this invention. In the examples, all temperatures are degrees centigrade.

EXAMPLE 1 The compounds of this invention can be prepared by conventional methods of organic chemistry. The reaction sequence indicated below is a general method, useful for the preparation of the compounds of this invention.

According to this method, oxacycloalkyl carboxylic acid is heated in a mixture of dioxane, diphenylphosphoriazide and triethylamino for 1 hour. To this mixture is added benzyl alcohol and the reaction is further heated overnight to give intermediate 1. Compound 1 is dissolved in methanol. Next, HCI2 Pd / C is added and the mixture is placed under hydrogen at 1 atm. The mixture is stirred overnight at room temperature and filtered. The residue is recrystallized to give intermediate 2. Riboside 6-chloropurine is combined and the mixture is compound 2 dissolved in methanol and treated with triethylamine. The reaction is heated at 80 ° C for 30 hours and purification leads to compound 3.

EXAMPLE 2 The compounds of this invention prepared according to the method of Example 1 were tested in two functional models specific for the function of the Ai adenosine receptor agonist. The first was the inhibition mediated by the Ai receptor of the cAMP accumulation stimulated by isoproterenol in DDT cells. The EC50 of each derivative is shown in Table I. Also shown in Table I is the ability of each derivative to stimulate the production of cAMP in PC 12 cells, a function of the agonist stimulation of A2 adenosine receptors. The ratio of the relative potency of each compound to the stimulation of either the Ai or A2 receptors is in terms of the selectivity of each compound for the Ai receptor. As can be seen in Table I, each derivative is relatively selective as an agonist of the receptor Ai. The use of measuring cAMP metabolism as an assay for Ai adenosine receptor function has been previously described (Scammells, P., Baker, S., Belardinelli, L., and Olson, R., 1994, 1.3- dipropylsanthines substituted as irreversible antagonists of Ai adenosine receptors J. Med. Chem., 37: 2794-2712, 1994).

TABLE I The compounds were also tested in a complete organ model of activation of the Ai receptor with respect to atrial and AV node function. In this model, hearts of guinea pigs were isolated and sprayed with saline containing compound while the atrial rhythm and the conduction time of the AV node were assessed by electrographic measurement of the length of the atrial cycle and the AV intervals, as details in Belardinelli, L., J. Dennis, D. Martens, L, and Shryock J. (1994); The cardiac effects of an adenosine receptor agonist Ai in the isolated heart of the guinea pig. J, Pharm.

Exp. Therap., 271: 1371-1382 (1994). As seen in Figure 1, each derivative was effective in reducing the rate of atrial rhythm and prolonging the conduction time of the AV node of hearts with spontaneous beats in a concentration-dependent manner, demonstrating efficacy as receptor agonists. Ai of adenosine in the intact heart.

EXAMPLE 3 Preparation of N-benzyloxycarbonyl-4-aminopyran A mixture of 4-pyranylcarboxylic acid (2.28 gm, 20 mmol), diphenylphosphoryl azide (4.31 ml, 20 mmol), triethylamine (2.78 ml, 20 mmol) in dioxane (40 ml) was added. heated in an oil bath at 100 ° C under dry nitrogen for 1 hour. Benzyl alcohol (.7 ml, 26 mmol) was added and continued heating at 100 ° C for 22 hours. The mixture was cooled, filtered from a white precipitate and concentrated. The residue was dissolved in 2N HCl and extracted twice with EtOAc. The extracts were washed with water, sodium bicarbonate, pitch and then dried over MgSO and concentrated to an oil which solidified upon standing. The oil was chromatographed (30% to 60% EtOAc Hex) to give 1.85 g of a white solid (40%).

Preparation of 4-aminopyran N-benzyloxycarbonyl-4-aminopyran (1.85 g, 8.87 mmol) was dissolved in MeOH (50 ml) together with concentrated HCl and Pd-C (10%, 300 mg). The container was charged with hydrogen at 1 atmosphere and the mixture was allowed to stir for 18 hours at room temperature. The mixture was filtered through a pad of celite and concentrated. The residue was coevaporated twice with MeOH EtOAc and recrystallized from MeOH EtOAc to yield 980 mg (91%) of white needles (melting point 228-230 ° C).

Preparation of 6 - (4 - aminopyran) - purine riboside A mixture of 6 - chloropurine riboside (0.318 gm, 1.1 mmol), 4 - aminopyran - HCl (0.220 mg, 1.6 mmol) and triethylamine (0.385 ml, 2.5 mmol) in methanol (10 ml) was heated at 80 ° C for 30 hours. The mixture was cooled, concentrated and the residue was subjected to chromatography (90: 10: 1, CH2Cl2 eOH / Pr? 2). Appropriate fractions were collected and rechromatographed using a chromatotron (2 mm platform, 90 : 10: 1, CH2Cl2 eOH / PrNH2) to give an almost white foam (0.37 gm, 95%).

EXAMPLE 4 Preparation of N-benzyloxycarbonyl-3-aminotetrahydrofuran. A mixture of 3-tetrahydrofuroic acid (3.5 gm, 30 mmol), defenilfosforilazida (6.82 ml, 32 mmol), triethylamine (5 ml, 36 mmol) in dioxane (35 ml) was stirred at RT for 20 minutes and then heated in an oil bath at 100 ° C under nitrogen for 2 hours. Benzyl alcohol (4.7 ml, 45 mmol) was added and heating was continued at 100 ° C for 22 hours. The mixture was cooled, filtered from a white precipitate and concentrated. The residue was dissolved in 2N HCl and extracted twice using EtOAc. The extracts are washed with water, sodium bicarbonate pitch and dried over MgSO4 and then concentrated to an oil that solidifies after standing. The oil was chromatographed (30% to 60% EtOAc Hex) to give 3.4 g of an oil (51%).

Preparation of 3-aminotetrahydrofuran. N-Benzyloxycarbonyl-3-aminotetrahydroñiran (3.4 gm, 15 mmol) was dissolved in MeOH (50 ml) together with concentrated HCl and Pd-C (10%, 300 mg). The vessel was charged with hydrogen at 1 atmosphere and the mixture was allowed to stir for 18 hours at room temperature. The mixture was filtered through an oil pad and concentrated. The residue was co-evaporated twice with MeOH / EtOAc and recrystallized from MeOH / EtOAc to give 1.9 g of a yellow solid.

Preparation of 6- (3-aminotetrahydrofuranyl) purine riboside A mixture of 6-chloropurine riboside (0.5 gm, 1.74 mmol), 3-aminotetrahydrofuran (0.325 gm, 2.6 mmol) and triethylamine (0.73 ml, 5.22 mmol) in methanol (10 ml ) was heated at 80 ° C for 40 hours. The mixture was cooled and concentrated. The residue was filtered through a small column of silica gel eluting with 90/10/1 (CH2Cl2 / MeOH / PrNH2), the fractions containing the product were combined and concentrated. The residue was chromatographed on the chromatotron (2 mm platform, 02.5 / 7.5 / 1, CH2Cl2 eOH / PrNH2). The resulting almost white solid was recrystallized from MeOH / EtOAc to give 0.27 gm of almost white crystals (melting point 128 -130 ° C).

EXAMPLE 5 Resolution of 3-aminoetrahydrofuran hydrochloride A mixture of 3-aminotetrahydrofuran hydrochloride (0.5 mg, 4 mmol) and (S) - (+) - 10-camphorsulfonyl chloride (1.1 gm, 4.4 mmol) in pyridine (10 ml) was stirred for 4 hours at room temperature and then concentrated. The residue was dissolved in EtOAc and washed with 0.5 N HCl, sodium bicarbonate and pitch. The organic layer was dried over MgSO, filtered and concentrated to give 1.17 g of a brown oil (97%) which was chromatographed on silica gel (25% to 70% EtOAc / Hex.) The white solid obtained was recrystallized Repeatedly from acetone and crystals and submerged in supernatant until an improvement of more than 90% by 1H NMR was achieved.

Preparation of 3 - (S) - aminotetrahydrofuran hydrochloride The sulfonamide (170 mg, 0.56 mmol) was dissolved in concentrated HCl / AcOH (2 ml of each), stirred for 20 hours at room temperature, washed three times with CH 2 Cl 2 ( 10 ml) and concentrated to dryness to give 75 mg (quant.) Of a white solid.

Preparation of 6- (3 - (S) -aminotetrahydrofuranyl) purine riboside. A mixture of 6-chloropurine riboside (30 mg, 0.10 mmol), 3 - (S) -aminotetrahydrofuran hydrochloride (19 mg, 0.15 mmol) and triethylamine (45 mL, 0.32 mmol) in methanol (0.5 mL) was heated to 80 °. C for 18 hours. The mixture was cooled, concentrated and subjected to chromatography with 95/5 (CH-C MeOH) to give 8 mg (24%) of a white solid.

Claims (18)

1. CLAIMS: 1. A composition of matter that has the formula: wherein Ri is a monocyclic or polycyclic heterocyclic group containing from 3 to 15 atoms, at least one of which is selected from the group consisting of N, O, P and S - (O) - or -2 and wherein Ri It does not contain an epoxide group.
2. 2. The composition of Claim 1 wherein Ri is mono or polysubstituted with one or more compounds selected from the group consisting of halogen, oxo, hydroxyl, lower alkyl, substituted lower alkyl, alkoxy, aryl, acyl, aryloxy, carboxyl, aryl substituted, heterocycle. , heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, nitro, cyano and mixtures thereof
3. 3. The composition of matter of Claim 1 wherein Ri is a monocyclic, bicyclic or tricyclic cycloalkyl group containing from 3 to 15 atoms, at least one of which is selected from the group consisting of O or S - (O) or- 2.
4. 4. The composition of Claim 3 wherein Ri is mono or polysubstituted with one or more compounds selected from the group consisting of halogen, oxo, hydroxyl, lower alkyl, substituted lower alkyl, alkoxy, aryl, acyl, aryloxy, carboxyl, substituted aryl, heterocycle, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, nitro, cyano and mixtures thereof.
5. 5. The composition of claim 3 wherein Ri is: wherein Ri ', Ri ", Ri'" and Ri "" are individually selected from the group halogen, oxo, hydroxyl, lower alkyl, substituted lower alkyl, alkoxy, aryl, acyl, aryloxy, carboxyl, substituted aryl, heterocycle, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, nitro, cyano and mixtures thereof and X is O, uS (-O) or -2.
6. 6. The composition of Claim 5 wherein Ri '"and Ri" "may be a single oxygen atom.
7. 7. The composition of Claim 5 wherein R, Ri ", Ri" ', and Ri "" are individually selected from the group H, lower alkyl, substituted lower alkyl, alkoxy, aryl and substituted aryl.
8. 8. The composition of Claim 5 wherein Ri ', Ri ", Ri'", and Ri "" are individually selected from the group H, lower alkyl, and substituted lower alkyl.
9. 9. The composition of Claim 1 wherein Ri is selected from the group consisting of: wherein R can be selected individually from the group consisting of H, lower alkyl and substituted lower alkyl and wherein X is O, or S (-O) or -2.
10. 10. The composition of claim 1 wherein Ri is selected from the group consisting of 3-tetrahydrofuran, 3-tetrahydrothiofuranyl, 4-pyranyl and 4-thiopyranyl.
11. 11. An adenosine type 1 receptor agonist comprising the composition of Claim 1.
12. 12. A method for stimulating coronary activity in a mammal that undergoes a coronary electrical disorder that can be treated by stimulation of a cardiac adenosine receptor Ai comprising mammalian cell proliferation comprising the administration of a therapeutically effective amount of the composition of Claim 1 to the mammal.
13. 13. The method of Claim 12 wherein the therapeutically effective amount ranges from about 0.01 to 100 mg / kg of mammalian weight.
14. 14. The method of Claim 12 wherein the composition is administered to the mammal experiencing a coronary electrical disorder chosen from the group consisting of supraventricular tachycardias, atrial fibrillation, atrial palpitation and reentrant tachycardia of the AV node.
15. 15. The method of Claim 14 wherein the mammal is a human.
16. 16. A pharmaceutical composition of matter comprising the composition of Claim 1 and one or more pharmaceutical excipients.
17. 17. The pharmaceutical composition of subject of Claim 16 wherein the pharmaceutical composition is in the form of a solution.
18. 18. The pharmaceutical composition of subject of Claim 16 wherein the pharmaceutical composition is in the form of a tablet. EXTRACT OF THE INVENTION A substituted adenosine derivative with substituted N6-oxa, thia, thioxa and azacycloalkyl of the formula (I) and a method for using the composition as a cardiac adenosine receptor Ai. In said formula, Ri is a monocyclic or heterocyclic polycyclic group containing from 3 to 15 atoms, at least one of which is selected from the group consisting of N, O, P and S - (O) 0. % and where Ri does not contain an epoxide group.