WO1990009178A1 - N6-substituted 9-methyladenines: a new class of adenosine receptor antagonists - Google Patents

N6-substituted 9-methyladenines: a new class of adenosine receptor antagonists Download PDF

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WO1990009178A1
WO1990009178A1 PCT/US1990/000210 US9000210W WO9009178A1 WO 1990009178 A1 WO1990009178 A1 WO 1990009178A1 US 9000210 W US9000210 W US 9000210W WO 9009178 A1 WO9009178 A1 WO 9009178A1
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compound
carbon atoms
group
phenyl
norbornyl
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PCT/US1990/000210
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French (fr)
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Ray A. Olsson
Ted Marcus
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Whitby Research, Inc.
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Priority to KR1019900702209A priority Critical patent/KR910700253A/en
Priority to KR1019920700026A priority patent/KR920703063A/en
Publication of WO1990009178A1 publication Critical patent/WO1990009178A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine

Definitions

  • Novel compounds and a method of using them to antagonize adenosine receptors are provided wherein the compounds are represented by the general formula:
  • R 2 is selected from the group consisting of cycloalkyl radicals having from 3 to 8, preferably 3 to 7, ring carbon atoms, alkyl radicals having from 1 to 10 carbon atoms, aryl radicals having from 6 to 13, preferably 6 to 10, carbon atoms, aralkyl radicals having from 7 to 14, preferably 7 to 10, carbon atoms, and heteroatom- and halogen-substituted derivatives thereof wherein said heteroatom may be selected from the group consisting of nitrogen, phosphorus, sulfur and oxygen;
  • R 1 may be hydrogen or R 2
  • R 3 is selected from the group consisting of hydrogen, halogen, amine, carboxy, thio, sufonate, sulfonamide, sulfone, sulfoxamide, phenyl, alkyl-substituted amine, cycloalkyl-substituted amine, alkyl radicals having from 1 to 10 carbon atoms, and cycloalkyl radicals having from 3
  • R 4 is selected from the group consisting of benzyl, phenyl, and alkyl groups comprising from 1 to 4 carbon atoms, wherein said alkyl group can be substituted with oxygen, for example ethers and alcohols.
  • R 5 is selected from the group consisting of hydrogen; hydroxy; sulfonate; halogen; alkoxy and cycloalkoxy groups comprising 1 to 6 carbon atoms, wherein said alkoxy and cycloalkoxy groups can be substituted with phenyl; and amine, wherein said amine can be substituted with alkyl, cycloalkyl, or phenyl.
  • Adenosine receptors have been divided into two subtypes, based on adenylate cyclase activity: A 1 (R i ) receptors mediate inhibition and A 2 (R a ) receptors mediate stimulation of adenylate cyclase activity.
  • N 6 -substituted adenosine analogs like N 6 -R-phenyl isopropyl adenosine (R-PIA) have very high affinity for A 1 adenosine receptors, but at A 2 receptors 5'-N-ethylcarboxamido-adenosine (NECA) is more potent than N 6 -substituted analogs .
  • NECA 5'-N-ethylcarboxamido-adenosine
  • Alkylxanthines such as caffeine and theophylline, are the best known antagonists at adenosine receptors.
  • Adenine was generally believed to have no effect on adenosine receptor-controlled systems. However, it was found that at low concentrations adenine displays specific competitive antagonism of adenosine-induced cyclic Amp accumulation in a human fibroblast cell line. Methylation of adenine at the 9-position increases potency about 4-fold in this assay. At higher concentration, both compounds show non-specific inhibitory activity.
  • R 2 is selected from the group consisting, of cycloalkyl radicals having from 3 to 8, preferably 3 to 7, ring carbon atoms, alkyl radicals having from 1 to 10 carbon atoms, aryl radicals having from 6 to 13, preferably 6 to 10, carbon atoms, aralkyl radicals having from 7 to 14, preferably 7 to 10, carbon atoms, and heteroatom- and halogen-substituted derivatives thereof wherein said heteroatom may be selected from the group consisting of nitrogen, phosphorus, sulfur and oxygen;
  • R 1 may be hydrogen or R 2
  • R 3 is selected from the group consisting of hydrogen, halogen, amine, carboxy, alkyl radicals having 1 to 10 carbon atoms, cycloalkyl radicals having from 3 to 8, preferably 5 to 6, ring carbon atoms, thio, sulfonate, sulfonamide, sulfon, sulfoxamide, phenyl, alkyl-substitued amine
  • R 4 is selected from the group consisting of benzyl, phenyl, and alkyl groups comprising from 1 to 4 carbon atoms, wherein said alkyl group can be substituted with oxygen, for instance ethers and alcohols.
  • R 5 is selected from the group consisting of hydrogen; hydroxy; sulfonate; halogen; aljcoxy and cycloalkoxy groups comprising 1 to 6 carbon atoms, wherein said alkoxy and cycloalkoxy groups can be substituted with phenyl; and amine, wherein said amine can be substituted with phenyl and alkyl and cycloalkyl groups comprising 1 to 6 carbon atoms.
  • R 1 is hydrogen; wherein R 2 is endo-2-Norbornyl or cyclopentyl; wherein R 3 is bromine, chlorine, amino, hydrogen, thio, cyclopentyl or cyclopentylamine; wherein R 4 is methyl, ethyl, 2-hydroxy- ethyl, phenyl, or 2-hydroxyethoxy methyl; and wherein R 5 is hydrogen, hydroxy or chlorine.
  • N 6 -(endo-2-Norbornyl)-8-Azido-9-MA 0.5g, 1.75 mmole
  • the solution in presence of 10% palladium on charcoal (1g), was shaken with H 2 at 35 atm overnight.
  • the suspension was filtered and evaporated to a small volume, and then poured through a C-18 column (HPLC) to give 0.36g 80% yield of N 6 -(endo-2-norbornyl)-8-Amino-9-MA.
  • N 6 (endo-2-Norbornyl)-9-Bromo-9-MA (0.15g, 0.62 mmole) in 12 ml acetic acid was added sodium acetate (0.5g) and 1.2 ml acetic anhydride. The mixture was allowed to reflux overnight. The mixture was then evaporated under vacuo and purified on a chromatotron using CHCl 3 , stepping to 2% ethanol, and finally to 4% ethanol on 2 mm plate giving 90 mg, 75% yield of N 6 -(endo-2-Norbornyl)-8-0xo-9-MA.
  • N 6 -(endo-2-Norbornyl)-8-Cyclopentylamine-9-MA To a solution of N 6 -(endo-2-Norbornyl)-8-Bromo-9-MA (0.5g, 1.55 mmols) in 20 ml ethanol was added 20ml of cyclopentylamine; the reaction mixture was refluxed overnight. The mixture was then evaporated under vacuo and passed through a C-18 column (HPLC) to.give 0.32g, 77% yield of N 6 - (endo-2-Norbornyl)-8-Cyclopentylamine-9-MA.
  • N 6 (endo-2-Norbornyl)2-Chloropurine was first prepared as follows: A mixture of 2,6-dichloropurine (5.0g, 26.45 mmoles) endo-2-aminobornane hydrochloride (5.0g, 33.86 mmoles) and triethyl amine (10 ml) in absolute ethanol was refluxed for 48 hours. The solution was then cooled to room temperature and evaporated in vacuo to a white solid. The white solid was washed with water and dried to yield 6.0g, 84% yield of N 6 -(endo-2-Norbornyl)2-Chloropurine used as is with no further purification for next step.
  • N 6 -(endo-2-Norbornyl)-8-bromo-9-MA (1.25g, 3.7 mmoles) and POC1 3 was refluxed for 1 hour. Then the phosphorous oxychloride was removed in vacuo and the yellow solid was passed through a C-18 column (HPLC) to give 0.96g, 84% yield of N 6 -(endo-2-Norbornyl)-8-chloro-9-MA.
  • N 6 -substituted 9-methyladenines were assayed as adenosine antagonists in A 1 and A 2 test systems ( ⁇ kena, et al, FEBS Lett. 215(2), 203-208, 1987).
  • compounds were tested as inhibitors of the binding of N 6 -R-[ 3 H]-Phenylisopropyladenosine in rat brain membranes and for their ability to prevent R-PIA-induced inhibition of adenylate cyclase in rat fat cell membranes.
  • compounds were tested as antagonists of NECA-stimulated adenylate cyclase in membranes of human platelets and rat PC12 cells.
  • a 1 receptors influence inhibition of adenylate cyclase in fat, brain and heart cells; whereas A 2 receptors stimulate adenylate cyclase in endothelial and smooth muscle cells.
  • a 2 receptors stimulate adenylate cyclase in endothelial and smooth muscle cells.
  • N 6 -Methylcylopentyl-9-MA 45 56 9.0 2.5 6. Cyclohexyl-9-MA 7.4 21 0.65 0.94 7. N 6 -Hethyl -9-MA 150 130 220 > 100 8. N 6 -3-PentyI -9-MA 11 53 7.6 3.3 9. N 6 - PhenyI -9-MA 21 107 10 25
  • in vitro assays were conducted utilizing model tissues that are thought to contain homogenous populations of either the A 1 or A 2 adenosine receptors.
  • Four examples were characterized by their ability to antagonize competitively the action of adenosine agonists in eliciting two responses: the reduction in force of contraction of guinea pig atrium (A 1 ); and the decrease in the contractile tone of the guinea pig taenia caecum (A 2 ).
  • the left atria from male guinea pigs were isolated, suspended between two punctate electrodes, and placed in a 20 ml organ bath that contained Krebs-Hensileit solution that was continuously gassed with 95% O 2 + 5% CO 2 and maintained at 31oC. The resting tension was one gram. The atria were stimulated electrically at 1 Hz, 1 msec duration pulses at supramaximal voltage. The force of contraction was recorded isometrically.
  • Taenia from the guinea pig caecum were cut into lengths of 1.5-2 cm.
  • the tissues were suspended in a 20 ml organ bath containing de Jalon's solution that was gassed with 95% O 2 + 5% CO 2 and maintained at 31oC.
  • the resting tension was 1.5 g.
  • the contractile response was measured isotonically. Tissues were contracted with 10 M 5-methyl-furmethide and allowed sufficient time to reach a stable contraction before addition of adenosine agonists.
  • 8-PT did antagonize the effects of agonists at low concentrations.
  • the lack of competitive antagonism by the other compounds suggests that the latter compounds do not interact appreciably with A 2 -adenosine receptors and are, thus, selective for A 1 adenosine receptors.
  • N 6 -3-Pentyl-9-MA, N 6 -Cyclopentyl-£-MA, N 6 -(endo-2-Norbornyl)-9-MA and N 6 -4-(2-thienyl)-3-butyl)-9-MA all were found to be competitive antagonists at adenosine receptors in the atria.
  • N 6 -3-Pentyl-9-MA and N 6 -1-(2-thienyl)-2-butyl-9-MA also produced increases in basal force of contraction in the atria.
  • Affinity constants (pK B ) for the present compounds determined using known methods are summarized in Table 2 below:
  • Rats were anesthetized with urethan and blood pressure was monitored via a carotid cannula. Drug injections were made intravenously through a jugular cannula. Blood pressure, EGC, and heart rate were recorded on a Grass polygraph.
  • Adenosine produced a dose dependent decrease in blood pressure and heart rate, with a concommitant increase in the P-R interval of the ECG.
  • Administration of N 6 -(endo Norbornyl)-9-methyladenine attenuated the effects of subsequently administered adenosine on all parameters measured.
  • adenosine causes heart block; this effect was also substantially reduced by the agonist. Due to the short duration of action and direct route of administration of adenosine, it is often difficult to determine whether adenosine decreased blood pressure by causing peripheral vasodilation or by reducing cardiac output.
  • NECA (5'-N-ethylcarboxamide adenosine), which is longer-acting and selective for A 2 adenosine receptors, was used as an adenosine receptor agonist.
  • Prior administration of N-0861 attenuated the effects of NECA on the heart while minimally affecting the NECA-induced decrease in blood pressure.
  • N 6 -endo-2-Norbornyl)-9-methyladenine is a cardioselective adenosine receptor antagonist in vivo and support the data above showing selectively of the N-6 substituted 9-methyladenines of the invention as A 1 adenosine receptor antagonists.
  • bovine brains were obtained fresh from a local slaughterhouse.
  • the caudate nuclei were dissected out and homogenized in Buffer A (50 mm Tris; 1 mm Na 2 -EDTA; 5 mm KCl; 1 mm MgCl 2 ; 2 mm CaCl 2 ; pH 7.4) using a Brinkman Polytron.
  • the homogenate was centri- fuged at 40,000 ⁇ g for 20 minutes and washed once.
  • the pellet was resuspended in Buffer A, incubated at 37oC for 15 minutes, then centrifuged.
  • the pellet was washed once more, resuspended to a protein concentration of 5-10 mg/ml in Buffer A and frozen at -70oC until use.
  • the A 2 assays also contained 50 nM cyclopentyl-adenosine to block the binding of [ 3 H]-NECA to A 1 receptors (Bruns et al, 1986) and 1 unit/ml adenosine deaminase to degrade endognous adenosines. Varying concentrations of test compounds were incubated with the appropriate radioligand and membrane source for 1 hr at room temperature.
  • N 6 -substituted adenines are antagonists of A 2 -adenosine receptor-mediated stimulation of adenylate cyclase in A 2 -adenosine receptors and antagonists of A 1 -adenosine receptor-mediated inhibition of adenylate cyclase.
  • These compounds are useful in reversal of adenosine-mediated lipolysis, reversal of adenosine-mediated deleterious cardiovascular effects (conduction defects, hypotension), reversal of adenosine-mediated vascular actions in kidney, bronchodilation, antiarrhythmic action, reversal of adenomediated relaxation of smooth muscle, anti-narcoleptic action, CNS stimulation, and blockade of adenosine mediated inhibition of neurotransmitter release.

Abstract

A series of N6-substituted adenines are disclosed to be antagonists of A¿2?-adenosine receptor-mediated stimulation of adenylate cyclase in A2-adenosine receptors and antagonists of A1-adenosine receptor-mediated inhibition of adenylate cyclase. These compounds are useful in reversal of adenosine-mediated lipolysis, reversal of aenosine-mediated deleterious cardiovascular effects (conduction defects, hypotension), reversal of adenosine-mediated vascular actions in kidney, bronchodilation, antiarrhythmic action, reversal of adeno-mediated relaxation of smooth muscle, anti-narcoleptic action, CNS stimulation, and blockade of adenosine mediated inhibition of neurotransmitter release.

Description

N6-SUBSTITUTED 9-METHYLADENINES:
A NEW CLASS OF ADENOSINE RECEPTOR ANTAGONISTS
SUMMARY OF THE INVENTION
Novel compounds and a method of using them to antagonize adenosine receptors are provided wherein the compounds are represented by the general formula:
Figure imgf000003_0001
wherein R2 is selected from the group consisting of cycloalkyl radicals having from 3 to 8, preferably 3 to 7, ring carbon atoms, alkyl radicals having from 1 to 10 carbon atoms, aryl radicals having from 6 to 13, preferably 6 to 10, carbon atoms, aralkyl radicals having from 7 to 14, preferably 7 to 10, carbon atoms, and heteroatom- and halogen-substituted derivatives thereof wherein said heteroatom may be selected from the group consisting of nitrogen, phosphorus, sulfur and oxygen; R1 may be hydrogen or R2, and R3 is selected from the group consisting of hydrogen, halogen, amine, carboxy, thio, sufonate, sulfonamide, sulfone, sulfoxamide, phenyl, alkyl-substituted amine, cycloalkyl-substituted amine, alkyl radicals having from 1 to 10 carbon atoms, and cycloalkyl radicals having from 3 to 8, preferably 5 to 6, ring carbon atoms. R4 is selected from the group consisting of benzyl, phenyl, and alkyl groups comprising from 1 to 4 carbon atoms, wherein said alkyl group can be substituted with oxygen, for example ethers and alcohols. R5 is selected from the group consisting of hydrogen; hydroxy; sulfonate; halogen; alkoxy and cycloalkoxy groups comprising 1 to 6 carbon atoms, wherein said alkoxy and cycloalkoxy groups can be substituted with phenyl; and amine, wherein said amine can be substituted with alkyl, cycloalkyl, or phenyl.
BACKGROUND OF THE INVENTION
This application is a continuation-in-part of U.S. patent application Serial No. 042,383, filed April 23, 1987 entitled "N6-Substituted 9-Methyladenines: A New Class of Adenosine Receptor Antagonists," which is incorporated herein by reference in its entirety.
Adenosine receptors have been divided into two subtypes, based on adenylate cyclase activity: A1 (Ri) receptors mediate inhibition and A2 (Ra) receptors mediate stimulation of adenylate cyclase activity. Some N6-substituted adenosine analogs, like N6-R-phenyl isopropyl adenosine (R-PIA) have very high affinity for A1 adenosine receptors, but at A2 receptors 5'-N-ethylcarboxamido-adenosine (NECA) is more potent than N6-substituted analogs, Alkylxanthines, such as caffeine and theophylline, are the best known antagonists at adenosine receptors.
Adenine was generally believed to have no effect on adenosine receptor-controlled systems. However, it was found that at low concentrations adenine displays specific competitive antagonism of adenosine-induced cyclic Amp accumulation in a human fibroblast cell line. Methylation of adenine at the 9-position increases potency about 4-fold in this assay. At higher concentration, both compounds show non-specific inhibitory activity.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are represented by the general formula:
Figure imgf000005_0001
wherein R2 is selected from the group consisting, of cycloalkyl radicals having from 3 to 8, preferably 3 to 7, ring carbon atoms, alkyl radicals having from 1 to 10 carbon atoms, aryl radicals having from 6 to 13, preferably 6 to 10, carbon atoms, aralkyl radicals having from 7 to 14, preferably 7 to 10, carbon atoms, and heteroatom- and halogen-substituted derivatives thereof wherein said heteroatom may be selected from the group consisting of nitrogen, phosphorus, sulfur and oxygen; R1 may be hydrogen or R2, and R3 is selected from the group consisting of hydrogen, halogen, amine, carboxy, alkyl radicals having 1 to 10 carbon atoms, cycloalkyl radicals having from 3 to 8, preferably 5 to 6, ring carbon atoms, thio, sulfonate, sulfonamide, sulfon, sulfoxamide, phenyl, alkyl-substitued amine, and cycloalkyl substituted amine. R4 is selected from the group consisting of benzyl, phenyl, and alkyl groups comprising from 1 to 4 carbon atoms, wherein said alkyl group can be substituted with oxygen, for instance ethers and alcohols. R5 is selected from the group consisting of hydrogen; hydroxy; sulfonate; halogen; aljcoxy and cycloalkoxy groups comprising 1 to 6 carbon atoms, wherein said alkoxy and cycloalkoxy groups can be substituted with phenyl; and amine, wherein said amine can be substituted with phenyl and alkyl and cycloalkyl groups comprising 1 to 6 carbon atoms.
The preferred compounds are those wherein R1 is hydrogen; wherein R2 is endo-2-Norbornyl or cyclopentyl; wherein R3 is bromine, chlorine, amino, hydrogen, thio, cyclopentyl or cyclopentylamine; wherein R4 is methyl, ethyl, 2-hydroxy- ethyl, phenyl, or 2-hydroxyethoxy methyl; and wherein R5 is hydrogen, hydroxy or chlorine.
The following is a list of compounds useful in the practice of the present invention. This list is intended to be illustrative and the scope of the invention is not limited to compounds named therein:
N6-Cyclobutyl-9-Methyl Adenine (MA)
N6-Cyclopentyl-9-MA
N6-Methylcyclopenty1-9-MA
N6-Cyclohexyl-9-MA
N6-Methyl-9-MA
N6-3-Pentyl-9-MA
N6-Phenyl-9-MA
N6-2-Fluorophenyl-9-MA
N6-Benzyl-9-MA
N6-2-Phenethyl-9-MA
N6-2-(3,4,5-Trimethoxyphenyl)ethyl-9-MA
N6-2-(3-Pyridylethyl)-9-MA
N6-2-(3-Thienylethyl)-9-MA
N6-R-1-Phenyl-2-propyl-9-MA
N6-S-1-Phenyl-2-propyl-9-MA
N6-(endo-2-Norbornyl)-9-MA
N6-1-(2-Thienyl)-2-butyl-9-MA N6-(exo-2-Norbornyl)-9-MA
N6-2,2-diphenylethyl-9-MA
N6-2-phenylethyl-9-MA
N6-2-(2-chlorophenyl)ethyl-9-MA
N61-indanyl-9-MA
N6-2-aminoethyl-9-MA
N6-(N,N-Dimethylaminoethyl)-9-MA
N6-R-1-phenyl-1-ethyl-9-MA
N6-S-1-phenyl-1-ethyl-9-MA
N6-2-thienyl-9-MA
N6-(4-chloro-2-methyl phenyl)-9-MA
N6- 2-(3-ethylindole)-9-MA
N6-(1-methyl-2-phenylethyl)-9-MA
N6-[1-methyl-2-phenoxyethyl)-9-MA
N6-1-carboxy-1-butyl-9-MA
N6-(endo-2-norbornyl)-2-chloro-9-MA
N6-(endo-2-norbornyl)-8-cyclopentyl-9-MA
N6-(endo-2-norbornyl)-8-hydroxy-9-MA
N6-(endo-2-norbornyl)-8-bromo-9-MA
N6-(endo-2-norbornyl)-8-amino-9-MA
N6-(endo-2-norbornyl)-8-carboxy-9-MA
N6-cyclopentyl-8-cyclopentyl-9-MA
N6-(endo-2-norbornyl)-9-[(2-hydroxyethoxy)methyl]adenine
N6-(endo-2-norbornyl)-8-thio-9-MA
N6-(endo-2-norbornyl)-8-chloro-9-MA
N6-(endo-2-norbornyl)-8-sulfonate-9-MA sodium salt
N6-(endo-2-norbornyl)-2-hydroxy-9-MA
N6-(endo-2-norbornyl)-8-cyclopentylamine-9-MA
N6-(endo-2-norbornyl)-8-propylamine-9-MA
N6-(endo-2-norbornyl)-9-phenyl adenine
N6-cyclopentyl-2-chloro-9-MA
N6-phenyl-2-chloro-9-MA
N6-cyclopentyl-9-phenyl adenine
N6-R-1-phenyl-2-propyl-9-phenyl adenine N6-S-1-phenyl-2-propyl-9-phenyl adenine
N6-[(3-chloro-endo-2-norbornyl)]-9-MA
N6-pheny1-9-phenyl adenine
2-ethoxy-9-MA
2-propoxy-9-MA
2-butoxy-9-MA
2-isopropoxy-9-MA
2-(2-butoxy)-9-MA
2-(2-methyl propoxy) 9-MA
2-pentoxy-9-MA
2-(2-phenylethoxy) 9-MA
2-phenylamino-9-MA
9-hydroxyethyladenine
N6-cyclopentyl-9-benzyl adenine
N6-cyclohexyl-9-ethyl adenine
The preparation of 9-methyl adenines is well known. See R. K. Robins, K. J. Dille, and B. E. Christensen, J. Org. Chem.. 19, 930 (1954); R. K. Robins and H. H. Lin, J. Am. Chem. Soc.. 79, 490 (1957; and J. A. Montgomery and Carroll Temple, Jr., J. Am. Chem. Soc.. 79, 5238 (1957).
Preparation of N6-Cyclopentyl-9-Methyl Adenine
To prepare N6-cyclopentyl-9-methyl Adenine the following additional steps were taken. A mixture of 6-chloro-9-methyl Adenine (0.82g), cyclopentylamine (0.52 ml), triethylamine (0.53 ml) and ethanol (60 ml), was refluxed for 24 hours. The solution was concentrated in vacuo to a yellow syrup. The syrup was passed through a C-18 column to give 0.78g or 74% yield of with m.p. 108-109ºC. 1HNMR-(Me2SO-d6): 5l-2(m,9 H) ; 3.7(S,CH3); 7.6(d,NH); 8.1(S,1H); 8.2(S,1H).
Preparation of N6-3-Pentyl-9-Methyladenine A mixture of 6-chloro-9-methyladenine (1.5g), 3-pentylamine (1.3 ml), triethylamine (1.3ml) and ethanol (60 ml), was refluxed for 24 hours. The solution was concentrated and passed through a C-18 column to give a white solid having m.p. 107-109ºC.
Preparation of N6-(2-Aminonorbornyl)-9-methyl Adenine
A mixture of 1.5g 6-chloro-9-methyl Adenine, 1-75 g endo-2-aminonor-bornane, 2.9 ml triethylamine and 60 ml ethanol was refluxed overnight. The solution was then concentrated in vacuo and the remainder was passed through C-18 prepchromatography to give 1.6g (75% yield) m.p. 130-131ºC. 1HNMR(Me2SO-d6): 51-2.6 (m, 10 H); 3.8 (S, CH3); 4.1(m,1H); 7.2(S,NH); 7.4(8, 1H); 7.6(8, 1H).
Preparation of N6-(endo-2-Norbornyl)-8-Bromo-9-MA
To a stirred suspension of N6-(endo-2-norbornyl)-9-MA (6g, 24.66 mmoles) in 150 ml of 1M sodium acetate buffer (pH 3.9) was added a solution of bromine (3.0 ml) in 300 ml of 1M sodium acetate buffer (pH 3.9). The mixture was stirred overnight and the resulting precipitate was filtered and washed with water. To the residue was added silica gel and the suspension was evaporated to a powder. The powder was added to a silica gel column (150g, packed with petroleum ether). The purine was eluted with 10% to 25% ethylacetate in petroleum ether. Evaporation of the appropriate fractions gave 6.7g, 84% yield of N6-(endo-2-Norbornyl)-8-Bromo-9-MA.
Preparation of N6-(endo-2-Norbornyl)-8-Azido-9-MA
To a solution of N6-(endo-2-Norbornyl)-9-Bromo-9-MA (0.72g, 2.23 mmoles) in DMF was added sodium azide (0.91g, 13.98 mmoles). The mixture was heated at 70-80ºC overnight. The crude was dissolved in water, extracted with ethyl acetate, and then dried over magnesium sulfate and the organic phase was evaporated in vacuo to give 0.62g, 98% yield.
Preparation of N6-(endo-2-Norbornyl)-8-Amino-9-MA
The crude product, N6-(endo-2-Norbornyl)-8-Azido-9-MA (0.5g, 1.75 mmole) was dissolved in ethanol. The solution, in presence of 10% palladium on charcoal (1g), was shaken with H2 at 35 atm overnight. The suspension was filtered and evaporated to a small volume, and then poured through a C-18 column (HPLC) to give 0.36g 80% yield of N6-(endo-2-norbornyl)-8-Amino-9-MA.
Preparation of N6-(endo-2-Norbornyl)-8-Oxo-9-MA
To a mixture of N6(endo-2-Norbornyl)-9-Bromo-9-MA (0.15g, 0.62 mmole) in 12 ml acetic acid was added sodium acetate (0.5g) and 1.2 ml acetic anhydride. The mixture was allowed to reflux overnight. The mixture was then evaporated under vacuo and purified on a chromatotron using CHCl3, stepping to 2% ethanol, and finally to 4% ethanol on 2 mm plate giving 90 mg, 75% yield of N6-(endo-2-Norbornyl)-8-0xo-9-MA.
Preparation of N6-(endo-2-Norbornyl)-8-Cyclopentylamine-9-MA To a solution of N6-(endo-2-Norbornyl)-8-Bromo-9-MA (0.5g, 1.55 mmols) in 20 ml ethanol was added 20ml of cyclopentylamine; the reaction mixture was refluxed overnight. The mixture was then evaporated under vacuo and passed through a C-18 column (HPLC) to.give 0.32g, 77% yield of N6- (endo-2-Norbornyl)-8-Cyclopentylamine-9-MA.
Preparation of N6-(endo-2-Norbornyl)8-Bromo-2-Chloro-9-MA
N6(endo-2-Norbornyl)2-Chloropurine was first prepared as follows: A mixture of 2,6-dichloropurine (5.0g, 26.45 mmoles) endo-2-aminobornane hydrochloride (5.0g, 33.86 mmoles) and triethyl amine (10 ml) in absolute ethanol was refluxed for 48 hours. The solution was then cooled to room temperature and evaporated in vacuo to a white solid. The white solid was washed with water and dried to yield 6.0g, 84% yield of N6-(endo-2-Norbornyl)2-Chloropurine used as is with no further purification for next step.
A mixture of N6-(endo-2-Norbornyl)-2-chloropurine (5.0g, 18.96 mmoles), triethyl ammonium hydroxide (18.9 ml), and methyl iodide (1.41 ml, 22.68 mmoles) in dichloromethane was heated to 35ºC for 24 hours. The solution was then evaporated in vacuo and the syrup was crystallized in methanol to give 4.0g, 76% yield of N6-(endo-2-Norbornyl)2-chloro-9-MA.
To a stirred solution of N6-(endo-2-Norbornyl)-2-chloro-9-MA (4.3g, 14.4 mmoles) in acetate buffer (l molar acetic acid and 1 M sodium acetate mixture, 45:1 ratio respectively; pH ≡ 3.9) was added dropwise Bromine (3.12g, 19.56 mmoles) dissolved in the acetate buffer. The reaction mixture was stirred for 72 hours; the mixture was then filtered and the solid material collected was eluted from ethyl acetate/petroleum ether on silica gel column to yield 4.9g, 85% of N6-(endo-2-Norbornyl)8-Bromo-2-Chloro-9-MA.
Preparation of N6-(endo-2-Norbornyl)-8-Cyclopentyl-9-MA
To a vigorously stirred solution of 2g (12.2 mmoles) of 4-methylamino-5-amino-6-chloropyrimidine in CHCl3 was added dropwise over a period of 20 minutes cyclopentane carbonyl chloride (1.6g, 12.2 mmoles). The mixture was stirred overnight and then evaporated in vacuo to a yellow syrup. The syrup was then dissolved in methanol and purified through a C-18 column (HPLC) to give 2.2g, 71% yield of 4 methylamino-6-chloro-5-cyclopentylamido-pyrimidine. 4-methylamino-6-chloro-5-cyclopentylamido-pyrimidine 2.2g, 8.6 mmoles) was refluxed in POCl3 for approximately 2 hours. The solution was concentrated in vacuo to a syrup. The syrup was added dropwise to ice. The aqueous mixture was then extracted with chloroform. The organic layer was evaporated and the syrup was passed through a C-18 column (HPLC) giving 1.25g, 63% yield of 8-cyclopentyl-6-chloro-9-methyladenine.
A mixture of 8-cyclopentyl-6-chloro-9-methyladenine (0.48g 2.0 mmoles) and endo-2-aminonorbornane hydrochloride (0.5g, 3.4 mmoles) in absolute ethanol was refluxed for 48 hours. The mixture was then evaporated in vacuo and purified through a C-18 column (HPLC) to give 0.45g, 71% yield of N6-(endo-2-Norbornyl)-8-cyclopentyl-9-MA.
Preparation of N6-(endo-2-Norbornyl)-8-Chloro-9-MA
A mixture of N6-(endo-2-Norbornyl)-8-bromo-9-MA (1.25g, 3.7 mmoles) and POC13 was refluxed for 1 hour. Then the phosphorous oxychloride was removed in vacuo and the yellow solid was passed through a C-18 column (HPLC) to give 0.96g, 84% yield of N6-(endo-2-Norbornyl)-8-chloro-9-MA.
Preparation of N6-(endo-2-Norbornyl)-9-[(2-hydroxyethoxy) methyl]purine.
To a solution of 6-chloropurine (6g, 38.8 mmoles) in DMF was added sodium hydride 60% (0.93g) over 1.5 hour period. (2-acetoxyethoxy)methyl bromide was then added at room temperature; the reaction mixture was allowed to stir for 2 hours under N2 atmosphere. H20 was added and the product was extracted with ethyl acetate. The organic phase was dried over MgS04, filtered, and evaporated in vacuo to give a light yellow solid 7.1g, 68% yield of 9-[(2-Acetoxy ethoxy)methyl]-6-chloro-purine. The crude was used without further purification.
To a solution of 9-[(2-acetoxyethoxy)methyl]-6-chloropurine (5.1g, 18.8 mmoles) in ethanol and triethylamine was added endo-2-aminonorbornane hydrochloride (4.0g, 27.1 mmoles). The mixture was refluxed in vacuo and the residue was purified by HPLC to give 4.70g, 77% yield of N6-(endo-2-Norbornyl)-9-[(2-acetoxyethoxy)methyl]purine.
A solution of N6- (endo-2-Norbornyl)-9-[(2-acetoxyethoxy) methyl]purine (3.75g, 10.8 mmoles) in methanol was saturated with NH3 gas under N2. The mixture was stirred overnight, then evaporated in vacuo to give 2.03g, 62% yield of
N6-(endo-2-Norbornyl)-9-[(2-hydroxyethoxy)methyl]purine.
The invention is further illustrated by the following examples which are illustrative of various aspects of the invention. These examples are not intended as limiting the scope of the invention as defined by the appended claims.
PHARMACOLOGIC TESTING
A series of N6-substituted 9-methyladenines were assayed as adenosine antagonists in A1 and A2 test systems (ϋkena, et al, FEBS Lett. 215(2), 203-208, 1987). For activity at A1 receptors, compounds were tested as inhibitors of the binding of N6-R-[3H]-Phenylisopropyladenosine in rat brain membranes and for their ability to prevent R-PIA-induced inhibition of adenylate cyclase in rat fat cell membranes. For activity at A2 receptors, compounds were tested as antagonists of NECA-stimulated adenylate cyclase in membranes of human platelets and rat PC12 cells. It is known that A1 receptors influence inhibition of adenylate cyclase in fat, brain and heart cells; whereas A2 receptors stimulate adenylate cyclase in endothelial and smooth muscle cells. (See John W. Daly, et al., "Structure- Activity Relationship for N6-Substituted Adenosines at a Brain A1-Adenosine Receptor With A Comparison to an A2-Adenosine Receptor Regulating Coronary Blood Flow, " Biochemical Pharmacology. Vol. 35. No. 15, pp. 2467-2471 (1986)).
The results summarized below in Table I show that N6 substitution can markedly increase the potency of 9- methyladenine at adenosine receptors. The lower apparent affinity values (Kg, Ki) identify the most potent compounds. The most pronounced effect is seen at A1 receptors. For example, N6-Cyclopentyl-9-methyladenine is at least 100-fold more potent than 9-methyladenine at A1 receptors. At A2 receptors, this compound is 5-fold more potent than 9- methyladenine in the human platelet assay. Thus, this data demonstrates the activity of a novel series of adenosine antagonists.
TABLE 1
A2 Effects A1 Effects
KB (μM) VS NECA Stimulation KB(μM) KB(μM)
(Adenylate Cyclase) vs PIA INHIBITION VS [3H] PIA
(Adenylate Cyclase) (Binding)
(A ) (B) (C) (D)
1. Adenine 760 570 > 1000 > 100
2. 9 - MethyIadenine (9-MA) 24 24 112 106 N6-substituted 9 -methyIadenines
3. N6-Cyclobutyl-O-MA 5.5 23 0.89 1.2
4. N6-Cyclopentyl-9-MA 4.9 25 1.3 0.54
5. N6-Methylcylopentyl-9-MA 45 56 9.0 2.5 6. Cyclohexyl-9-MA 7.4 21 0.65 0.94 7. N6-Hethyl -9-MA 150 130 220 > 100 8. N6-3-PentyI -9-MA 11 53 7.6 3.3 9. N6- PhenyI -9-MA 21 107 10 25
10. N6-2-Muorophenyl -9-MA 11 29 17 8.5 11. N6-2-Benzyl-9-MA 57 100 49 17 12. N6-2-PhenethyI-9-MA 170 120 >300 > 100 13. N6-2-(3,4,5-Trimethoxyphenylethyl)-9-MA 23 40 122 >100
14 N6-2-(3-Pyridylethyl)-9-MA 92 117 96 41 15 N6-2-(3-Thienylethyl)-9-MA 14 25 24 20
16 N6-R-1-Phenyl-2-propyl-9-MA 13 25 7.2 2.5 17 N6-S-1-Phenyl-2-propyl-9-MA 23 74 23 10
(A) - Human Platelet Membranes
(B) - Rat PC12 Membranes
(C) - Rat Fat Cel l Membranes
(D) - Rat Brain Membranes
FURTHER FUNCTIONAL ASSAYS
To test the selectivity of the compounds of the invention, in vitro assays were conducted utilizing model tissues that are thought to contain homogenous populations of either the A1 or A2 adenosine receptors. Four examples were characterized by their ability to antagonize competitively the action of adenosine agonists in eliciting two responses: the reduction in force of contraction of guinea pig atrium (A1); and the decrease in the contractile tone of the guinea pig taenia caecum (A2).
The left atria from male guinea pigs were isolated, suspended between two punctate electrodes, and placed in a 20 ml organ bath that contained Krebs-Hensileit solution that was continuously gassed with 95% O2 + 5% CO2 and maintained at 31ºC. The resting tension was one gram. The atria were stimulated electrically at 1 Hz, 1 msec duration pulses at supramaximal voltage. The force of contraction was recorded isometrically.
Taenia from the guinea pig caecum were cut into lengths of 1.5-2 cm. The tissues were suspended in a 20 ml organ bath containing de Jalon's solution that was gassed with 95% O2 + 5% CO2 and maintained at 31ºC. The resting tension was 1.5 g. The contractile response was measured isotonically. Tissues were contracted with 10 M 5-methyl-furmethide and allowed sufficient time to reach a stable contraction before addition of adenosine agonists.
The ability of the compounds to antagonize the effects of agonists was analyzed using modified Schild plots. Although there was some sensitization of the tissue, i.e. addition of the agonist produced a larger response in the presence of high concentrations of the subject compounds, N6-3-Pentyl-9-MA, N6-Cyclopentyl-9-MA and N6-(endo-2-Norbornyl)-9-MA did not competitively antagonize the effects of adenosine agonists in relaxing the taenia caecum. Sensitization is also observed when using high concentrations of 8-phenyltheophylline (8-PT), a non-selective adenosine receptor antagonist. 8-PT did antagonize the effects of agonists at low concentrations. The lack of competitive antagonism by the other compounds suggests that the latter compounds do not interact appreciably with A2-adenosine receptors and are, thus, selective for A1 adenosine receptors.
However, N6-3-Pentyl-9-MA, N6-Cyclopentyl-£-MA, N6-(endo-2-Norbornyl)-9-MA and N6-4-(2-thienyl)-3-butyl)-9-MA all were found to be competitive antagonists at adenosine receptors in the atria. N6-3-Pentyl-9-MA and N6-1-(2-thienyl)-2-butyl-9-MA also produced increases in basal force of contraction in the atria. Affinity constants (pKB) for the present compounds determined using known methods are summarized in Table 2 below:
Table 2
Drug pKB
N6-3-Pentyl-9-MA 5.4 ± 0.14
N6-Cyclopentyl-9-MA 6.17 ± 0.11
N6-(endo-2-Norbornyl)-9-MA 6.28 ± 0.09
N6-1-(2-Thienyl)-2-butyl)-9-MA 5.36 ± 0.1
These results show that the above examples display selectivity towards the A± adenosine receptor, with N6- (endo-2-Norbornyl)-9-MA being the most potent antagonist. IN VIVO ASSAY
In vitro selectivity of the present antagonists was confirmed by in vivo tests on rat heart rate and blood pressure, the former associated with A1 receptors and the latter associated with A2 receptors.
Rats were anesthetized with urethan and blood pressure was monitored via a carotid cannula. Drug injections were made intravenously through a jugular cannula. Blood pressure, EGC, and heart rate were recorded on a Grass polygraph.
Adenosine produced a dose dependent decrease in blood pressure and heart rate, with a concommitant increase in the P-R interval of the ECG. Administration of N6-(endo Norbornyl)-9-methyladenine attenuated the effects of subsequently administered adenosine on all parameters measured. At high doses, adenosine causes heart block; this effect was also substantially reduced by the agonist. Due to the short duration of action and direct route of administration of adenosine, it is often difficult to determine whether adenosine decreased blood pressure by causing peripheral vasodilation or by reducing cardiac output. To overcome these problems, NECA (5'-N-ethylcarboxamide adenosine), which is longer-acting and selective for A2 adenosine receptors, was used as an adenosine receptor agonist. Prior administration of N-0861 attenuated the effects of NECA on the heart while minimally affecting the NECA-induced decrease in blood pressure. These results show that N6-endo-2-Norbornyl)-9-methyladenine is a cardioselective adenosine receptor antagonist in vivo and support the data above showing selectively of the N-6 substituted 9-methyladenines of the invention as A1 adenosine receptor antagonists. FURTHER RECEPTOR AFFINITY ASSAYS
Further tests to discover the affinities of test compounds at A2 receptors were conducted. [3H]-N-ethylcarboxamido adenosine ([3H-]-NECA) was used as the radioligand, bovine caudate was the source of membranes, and the assay buffer was 50 mM Tris; 10 mM MgCl2, pH 7.4.
To provide bovine caudate nuclei, bovine brains were obtained fresh from a local slaughterhouse. The caudate nuclei were dissected out and homogenized in Buffer A (50 mm Tris; 1 mm Na2-EDTA; 5 mm KCl; 1 mm MgCl2; 2 mm CaCl2; pH 7.4) using a Brinkman Polytron. The homogenate was centri- fuged at 40,000 × g for 20 minutes and washed once. The pellet was resuspended in Buffer A, incubated at 37ºC for 15 minutes, then centrifuged. The pellet was washed once more, resuspended to a protein concentration of 5-10 mg/ml in Buffer A and frozen at -70ºC until use.
The A2 assays also contained 50 nM cyclopentyl-adenosine to block the binding of [3H]-NECA to A1 receptors (Bruns et al, 1986) and 1 unit/ml adenosine deaminase to degrade endognous adenosines. Varying concentrations of test compounds were incubated with the appropriate radioligand and membrane source for 1 hr at room temperature.
Assays were terminated by filtration over Whatman GF/B filters that had been pre-soaked with 0.1% polyethyleneimine using a 24 port Brandell cell hawester. The filters were washed three times with 3 ml of ice cold buffer and transfered to plastic scintillation vials to which 4 ml of Beckman Ready-Protein scintillation cocktail was added. The tubes were shaken and counted in a Beckman 3801 scintillation counter that converted cpm to dpm. Data were analyzed by utilizing the Ligand® commercial computer program (Munson and Rodbard, 1980).
The results of these tests, expressed as the molar concentration of test compound needed to displace 50 percent of the [3H]-CHA radioligand from rat cortical A1 receptors, are summarized in Table 3 below:
Table 3
Adenosine Antagonists
Rat Cortical
Sample Binding Constant No. Name Ki (M)
0861 N6-(endo-2-norbornyl)-9-MA 11.6 × 10-8
0913 N6-(endo-2-norbornyl)-2-chloro-9-MA 10.5 × 10-8
0966 N6-2 , 2-diphenylethyl-9-MA >10-5
0967 N6-2 (2-chlorophenylethyl) 9-MA >10-5
0982 N6-2-Aminoethyl-9-MA >10-5
0983 N6-(2,2-N-dimethylethyl)-9-MA >10-5 0840 N6-cyclopentyl-9-MA 37.5 × 10-8
0984 N6-R-1-phenyl-1-ethyl-9-MA >10-5
0985 N6-S-1-phenyl-1-ethyl-9-MA >10-4
0986 N6-S-1-phenyl-2-propyl-9-MA >10-5
0987 N6 2-thienyl-9-MA >10-4
0988 N6 (4-chloro-2-methylphenyl)-9-MA >10-5
0989 N6-2-(3-ethylindole)-9-MA >10-5
0990 N6-2-(phenethyl)9-MA >10-5
1001 N6-(endo-2-norbornyl)-8-oxo-9-MA «10-5
1002 N6-2-(3,4,5-trimethoxyphenyl)ethyl-9-MA >10-5
1003 N6-(endo-2-norbornyl)-8-bromo-9-MA 1.3 × 10-8
1004 N6-1-carboxy-1-butyl-9-MA >10-4
1005 N6-(endo-2-norbornyl)-8-amino-9-MA 87 × 10-8
1006 N6-(endo-2-norbornyl)-8-carboxy-9-MA
Sodium Salt >10 -5 1059 N6-(endo-2-norbornyl)9-[(2 hydroxyethoxy) methyl]adenine 49 × 10 -8
1060 N6-(endo-2-norbornyl)-8-thio-9-MA 37 × 10 -8 1061 N6-(endo-2-norbornyl)-8-chloro-9-MA 1.5 × 10 -8 1062 N6-(endo-2-norbornyl)-8-sulfonate- 9-MA Sodium Salt >10 -4
1063 N6-(Endo-2-norbornyl)-2-oxo-9-MA 112 × 10 -8 1064 N6-(endo-2-norbornyl)-8-cyclopentylamine-9-MA 190 × 10 -8
0964 N6-(endo-2-norbornyl)-8-cyclopentyl-9-MA 24 × 10 -8 0965 N6-cyclopentyl-8-cyclopentyl-9-MA 14.1 × 10 -8 0978 N6-(exo-2-norbornyl)-9-MA 43 × 10-8
The compounds in Table 3 for which a solution having a concentration greater than 10-5M was required to displace 50 percent of the radioligand are deemed ineffective as A1 adenosine receptor antagonists.
In further experiments designed to determine the selectivity of N6-endo-2-Norbornyl-9-methyl adenine at A1 receptors, [3H]-cyclohexyladenosine ([3H]-CHA) was used as the radioligand, rat cortical membranes were the receptor source, and the assay buffer was 50 mM Tris; 2 mM MgCl2 pH 7.4.
Male Sprague Dawley rats were killed by decapitation and the brains removed. The cerebral cortices were homogenized in 50 mm Tris; 2mm MgCl2 (pH 7.4), and centrifuged at 40,000 × g for 10 minutes. The pellet was washed once, resuspended in Tris/MgCl2 and incubated with 8 units/ml adenosine deaminase at 37ºC for 30 minutes. The homogenate was centrifuged, washed once, resuspended to a protein concentration of 5-10 mg/ml and frozen at -70ºC until use. The results in Table 4 below show that the test compound has 170 times more affinity for A1 receptors than for A2 receptors.
Table 4
Selectivity of N6-endo-2-Norbornyl-9-MA
Bovine Caudate Binding Constants
At A1 Receptors At A2 Receptors
Ki(M)
4.1 X 10-8M 6.96 × 10-6M
A1/A2 . = 5.89 × 10-3
= 170 fold selective for A1 receptors
References
Munson, Peter J. and Rodbard, David (1980). "Ligand: A Versatile Computerized Approach for Characterizing Ligand- Binding Systems." Anal. Biochem. 107:220-239.
Bruns, Robert F., Lee, Gina H., and Pugsley, Thomas A. (1986) "Characterization of the A2 Adenosine Receptor Labeled by 3H-NeCA in Rat Striatal Membranes," Mol. Pharmacol. 29:331-346.
These N6-substituted adenines are antagonists of A2-adenosine receptor-mediated stimulation of adenylate cyclase in A2-adenosine receptors and antagonists of A1-adenosine receptor-mediated inhibition of adenylate cyclase. These compounds are useful in reversal of adenosine-mediated lipolysis, reversal of adenosine-mediated deleterious cardiovascular effects (conduction defects, hypotension), reversal of adenosine-mediated vascular actions in kidney, bronchodilation, antiarrhythmic action, reversal of adenomediated relaxation of smooth muscle, anti-narcoleptic action, CNS stimulation, and blockade of adenosine mediated inhibition of neurotransmitter release.
While particular embodiments of the invention have been described it will be understood of course that the invention is not limited thereto since many obvious modifications can be made and it is intended to include within this invention any such modifications as will fall within the scope of the appended claims.

Claims

What is claimed is:
1. Novel compounds represented by the general formula:
wherein R2 is selected from the group consisting of cycloalkyl radicals having from 3 to 8 ring carbon atoms, alkyl radicals having from 1 to 10 carbon atoms, aryl radicals having from 6 to 13 carbon atoms, aralkyl radicals having from 7 to 14 carbon atoms and halogen- and heteroatom-substituted derivatives thereof wherein said heteroatom may be selected from the group consisting of halogen, nitrogen, phosphorus, sulfur and oxygen; R1 may be hydrogen or R2, and R3 is selected from the group consisting of hydrogen, halogen, amine, carboxy, thio, sufonate, sulfonamide, sulfone, sulfoxamide, phenyl, alkyl- or cycloalkyl-substituted amine, alkyl radicals having 1 to 10 carbon atoms and cycloalkyl radicals having from 3 to 8 ring carbon atoms. R4 is selected from the group consisting of benzyl, phenyl, and alkyl groups comprising from 1 to 4 carbon atoms wherein said alkyl group can be substituted with oxygen; and R5 is selected from the group consisting of hydrogen, hydroxy, halogen, alkoxy and cycloalkoxy groups comprising 1 to 6 carbon atoms, wherein said alkoxy and cycloalkoxy groups can be substituted with phenyl; and amine wherein said amine can be substituted with members of the group consisting of phenyl, and alkyl and cycloalkyl, having 1 to 6 carbon atoms.
2. The compound of claim 1 wherein R4 is methyl.
3. The compound of claim 2 wherein R1 is hydrogen.
4. The compound of claim 3 wherein R2 is a cycloalkyl having from 4 to 8 carbon atoms in the ring.
5. The compound of claim 3 wherein R2 is phenyl or a substituted phenyl.
6. The compound of claim 3 wherein R2 is 2-norbornyl, cyclopentyl and R3 is selected from the group consisting of hydrogen, cyclopentyl, oxo, bromo, amino, carboxy, thio, chloro, fluoro, sulfonate, sulfonamido, cyclopentyϊamino, cyclopentyl, and physiologically acceptable salts thereof.
7. The compound of claim 3 wherein R2 is selected from the group consisting of benzyl, phenyl, o-fluorophenyl, 3,4,5-trimethoxyphenylethyl, 3-pentyl, 2-phenylethyl, 2-(2-chlorophenylethyl); 1-indanyl, 2-aminoethyl, N,N-dimethylaminoethyl, 2-thienylbutyl, and cyclohexyl.
8. The compound of claim 3 wherein R2 is endo-2-Norbornyl and R4 is phenyl or (2-hydroxyethoxy)methyl.
9. The compound of claim 1 selected from the group consisting of N6-(endo-2-Norbornyl)-9-[(2-hydroxyethoxy)methyl] adenine, N6-(endo-2-Norbornyl)-8-thio-9-methyl adenine, N6-(endo-2-Norbornyl)-8-chloro-9-methyl adenine, N6-(endo-2-Norbornyl)-2-oxo-9-methyl adenine, N6-(endo-2-Norbornyl)-8-cyclopentylamino-9-methyl adenine, N6-cyclopentyl-9-methyl adenine, N6-(endo-2-Norbornyl)-9-methyl adenine, N6-(endo-2-norbornyl)-8-bromo-9-MA, N6-cycϊopentyl-8-cyclopentyl-9-methyl adenine, N6-(exo-2-norbdrnyl)-9-MA, N6-cyclopentyl-2-chloro-9-methyl adenine, N6-[(3-chloro)-endo-2-norbornyl]-9-MA, N6-cyclopentyl-9-phenyl adenine, N6- (endo-2-norbornyl)-8-cyclopentyl-9-MA, N6-cyclopentyl-9-benzyl adenine, and N6-(endo-2-norbornyl)-8-amino-9-MA.
10. The compound of claim 2 wherein R5 is selected from the group consisting of hydrogen, ethoxy, methoxy, propoxy, n-butoxy, isopropoxy, 1-methylpropoxy, 2-methylpropoxy, 2- phenyl-ethoxy, methylamino, butylamino and anilino.
11. The compound of claim 3 wherein R5 is chloro.
12. The compound of claim 3 wherein R2 is selected from the group consisting of 3-pentyl, l-phenyl-2-propyl, and phenyl.
13. The compound of claim 2 wherein R2 is hydrogen and R5 is selected from the group consisting of ethoxy, methoxy, propoxy, n-butoxy, isopropoxy, butyl-2-oxy, 2-methylpropoxy, pentoxy, 2-phenylethoxy, methylamino, butylamino and anilino.
14. The compound of claim 11 wherein R2 is 2-(3-thienylethyl).
15. The compound of claim 7 wherein R2 is cyclohexyl.
16. The compound of claim 11 wherein R2 is 2-(3-pyridylethyl).
17. The method of antagonizing the A2-adenosine receptor-mediated stimulation of adenylate cyclase which comprises administering to a subject an effective amount of one or more of the compounds of claim 4, 6, 7, 8 or 9.
18. The method of claim 17 wherein said subject is a human.
19. The method of antagonizing the A1-adenosine receptor-mediated inhibition of adenylate cyclase which comprises administering to a subject an effective amount of a compound of claim 4, 6, 7, 8 or 9.
20. The method of claim 19 wherein said subject is a human.
21. The method of antagonizing the adenosine receptor which comprises administering to a subject an effective amount of a compound selected from the group of compounds represented by the general formula
Figure imgf000027_0001
wherein R2 is selected from the group consisting of cycloalkyl radicals having from 3 to 8 ring carbon atoms, alkyl radicals having from 1 to 10 carbon atoms, aryl radicals having from 6 to 13 carbon atoms, aralkyl radicals having from 7 to 14 carbon atoms, and halogen- and heteroatom-substituted derivatives thereof wherein said heteroatom may be selected from the group consisting of halogen, nitrogen, phosphorus, sulfur and oxygen; R1 may be hydrogen or R2, and R3 is selected from the group consisting of hydrogen, halogen, amine, carboxy, thio, sufonate, sulfonamide, sulfone, sulfoxamide phenyl, alkyl- or cycloalkyl-substituted amine, alkyl radicals having 1 to 10 carbon atoms and cycloalkyl radicals having from 3 to 8 ring carbon atoms. R4 is selected from the group consisting of benzyl, phenyl, and alkyl groups comprising from 1 to 4 carbon atoms wherein said alkyl group can be substituted with oxygen; and R5 is selected from the group consisting of hydrogen, hydroxy, amine, halogen, alkoxy and cycloakoxy groups comprising 1 to 6 carbon atoms, wherein said alkoxy and cycloalkoxy groups can be substituted with phenyl; and amine, wherein said amine can be substituted with members of the group consisting of phenyl, alkyl, cycloalkyl, having 1 to 6 carbon atoms.
22. The method of claim 21 wherein said subject is a human.
23. Novel compounds represented by the general formula:
Figure imgf000028_0001
wherein R1 is selected from the group consisting of cycloalkyl radicals having from 3 to 7 ring carbon atoms, alkyl radicals having from 2 to 10 carbon atoms, aryl radicals having from 6 to 10 carbon atoms, aralkyl radicals having from 7 to 10 carbon atoms and heteroatom substituted derivatives thereof wherein said heteroatom may be selected from the group consisting of halogen, nitrogen, phosphorus, sulfur and oxygen; R2 may be hydrogen or R1, and R3 is an alkyl group comprising from 1 tt 4 carbon atoms.
24. The compound of claim 23 wherein R3 is methyl.
25. The compound of claim 24 wherein R2 is hydrogen.
26. The compound of claim 25 wherein R1 is a cycloalkyl having from 4 to 6 carbon atoms in the ring.
27. The compound of claim 25 wherein R1 is phenyl or a substituted phenyl.
28. The compound of claim 27 wherein R1 is selected from the group consisting of phenyl, o-fluorophenyl and 3,4,5-trimethoxyphenyl.
29. The compound of claim 25 wherein R1 is benzyl or 2-phenylethyl.
30. The compound of claim 25 wherein R1 is 2-(3-pyridylethyl) or 2-(3-thienylethyl).
31. The compound of claim 25 wherein R1 is 3-pentyl.
32. The compound of claim 24 wherein R2 is selected from the group consisting of methyl and 2-propyl and R1 is selected from the group consisting of cyclopentyl and phenyl.
33. The compound of claim 30 wherein R1 is 2-(3-thienylethyl).
34. The compound of claim 32 wherein R2 is 2-propyl and R1 is phenyl.
35. The compound of claim 28 wherein R1 is benzyl.
36. The compound of claim 30 wherein R1 is 2-(3-pyridylethyl).
37. The method of antagonizing the A2-adenosine receptor-mediated stimulation of adenylate cyclase which comprises administering to a subject an effective amount of one or more of the compounds of claims 26, 28, 31, 33 or 34.
38. The method of claim 37 wherein said subject is a human.
39. The method of antagonizing the Ai-adenosine receptor-mediated inhibition of adenylate cyclase which comprises administering to a subject an effective amount of a compound of claim 26, 28, 31, 33, 34, 35 or 36.
40. The method of claim 39 wherein said subject is a human.
41. The method of antagonizing the adenosine receptor which comprises administering to a subject an effective amount of a compound selected from the group of compounds represented by the general formula
Figure imgf000030_0001
wherein R1 is selected from the group consisting of cycloalkyl radicals having from 3 to 7 ring carbon atoms, alkyl .radicals having from 1 to 10 carbon atoms, aryl radicals having from 6 to 10 carbon atoms, aralkyl radicals having from 7 to 10 carbon atoms and heteroatom substituted derivatives thereof wherein said heteroatom may be selected from the group consisting of halogen, nitrogen, phosphorus, sulfur and oxygen; R2 may be hydrogen or R, and R3 is an alkyl group comprising from 1 to 4 carbon atoms.
42. The method of claim 41 wherein said subject is a human.
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WO2003011864A1 (en) * 2001-07-31 2003-02-13 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. DERIVATIVES OF TRIAZOLYL-IMIDAZOPYRIDINE AND OF THE TRIAZOLYLPURINES USEFUL AS LIGANDS OF THE ADENOSINE A2a RECEPTOR AND THEIR USE AS MEDICAMENTS
US6576619B2 (en) 1999-05-24 2003-06-10 Cv Therapeutics, Inc. Orally active A1 adenosine receptor agonists
US6767906B2 (en) 1999-02-18 2004-07-27 Novartis Ag 2-amino-6-anilino-purines and their use as medicaments
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US7612079B2 (en) 2001-06-27 2009-11-03 Cyclacel Limited 2,6,9-substituted purine derivatives and their use in the treatment of proliferative disorders
CZ303054B6 (en) * 2010-09-07 2012-03-14 Univerzita Palackého v Olomouci Use of 6-substituted 9-haloalkyl purines for regulating growth and development of plants, vegetable organs and cells, and novel 6-substituted 9-haloalkyl purines

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US5329007A (en) * 1989-03-29 1994-07-12 Merrell Dow Pharmaceuticals Inc. Selective adenosine receptor agents
US5391739A (en) * 1989-03-29 1995-02-21 Merrell Dow Pharmaceuticals Inc. Selective adenosine receptor agents
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US5300509A (en) * 1991-11-25 1994-04-05 Imperial Chemical Industries Plc 2-furyl-oxazolo[5,4-d]-pyrimidines
US5500428A (en) * 1991-11-25 1996-03-19 Imperial Chemical Industries Plc Furyl-substituted purines and adenosine antagonists
US5981524A (en) * 1994-09-01 1999-11-09 Discovery Therapeutics, Inc. Substituted 9-alkyladenines
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US7091346B1 (en) 1995-11-01 2006-08-15 Novartis Ag Purine derivatives and processes for their preparation
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US5965563A (en) * 1995-11-14 1999-10-12 Pharmacia & Upjohn S.P.A. Aryl and heteroaryl purine compounds
US6132957A (en) * 1995-12-11 2000-10-17 The Research Foundation Of State University Of New York Method and compounds for the inhibition of adenylyl cyclase
AU698419B2 (en) * 1996-07-03 1998-10-29 Dainippon Sumitomo Pharma Co., Ltd. A novel purine derivative
WO1998008855A3 (en) * 1996-08-27 1998-09-03 Cv Therapeutics Inc N6 heterocyclic substituted adenosine derivatives
WO1998008855A2 (en) * 1996-08-27 1998-03-05 Cv Therapeutics, Inc. N6 heterocyclic substituted adenosine derivatives
US6376501B1 (en) 1997-12-22 2002-04-23 Japan Energy Corporation Type 2 helper T cell-selective immune response suppressors
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US6767906B2 (en) 1999-02-18 2004-07-27 Novartis Ag 2-amino-6-anilino-purines and their use as medicaments
US6576619B2 (en) 1999-05-24 2003-06-10 Cv Therapeutics, Inc. Orally active A1 adenosine receptor agonists
US7612079B2 (en) 2001-06-27 2009-11-03 Cyclacel Limited 2,6,9-substituted purine derivatives and their use in the treatment of proliferative disorders
WO2003011864A1 (en) * 2001-07-31 2003-02-13 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. DERIVATIVES OF TRIAZOLYL-IMIDAZOPYRIDINE AND OF THE TRIAZOLYLPURINES USEFUL AS LIGANDS OF THE ADENOSINE A2a RECEPTOR AND THEIR USE AS MEDICAMENTS
US7230102B2 (en) 2001-07-31 2007-06-12 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Derivatives of triazolyl-imidazopyridine and of the triazolylpurines useful as ligandsof the adenosine a2a receptor and their use as medicaments
US7528252B2 (en) 2001-07-31 2009-05-05 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Derivatives of triazoly-imidazopyridine useful as ligands of the adenosine A2a receptor and their use as medicaments
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KR910700253A (en) 1991-03-14

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