USRE36494E - 2-aralkoxy and 2-alkoxy adenosine derivatives as coronary vasodilators and antihypertensive agents - Google Patents

2-aralkoxy and 2-alkoxy adenosine derivatives as coronary vasodilators and antihypertensive agents Download PDF

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USRE36494E
USRE36494E US08/098,180 US9818093A USRE36494E US RE36494 E USRE36494 E US RE36494E US 9818093 A US9818093 A US 9818093A US RE36494 E USRE36494 E US RE36494E
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adenosine
oxygen
phenyl
ethoxy
group
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Ray A. Olsson
Robert D. Thompson
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Aderis Pharmaceuticals Inc
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Discovery Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals

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  • the present invention is directed to certain 2-substituted adenosine derivatives which have beneficial cardiovascular and antihypertensive activity in mammals, including humans and domestic animals.
  • the present invention is also directed to a process for making said compounds.
  • Adenosine has been known for a long time to possess certain cardiovascular, and particularly coronary dilator activity. In an effort to obtain adenosine analogs of greater potency, or longer duration of activity, or both, many analogs of this naturally occurring nucleoside have been synthesized and tested.
  • Adenosine Receptors Targets for Future Drugs, by John W. Daly, Journal of Medicinal Chemistry, 25, 197 (1982); Cardiovascular Effects of Nucleoside Analogs, by Herman H. Stein and Pitambar Somani, Annals New York Academy of Sciences, 225, 380 (1979); Coronary Dilatory Action of Adenosine Analogs: a Comparative Study, by. G. Raberger, W. Schutz and O.
  • Adenosine receptors have been subdivided into two subtypss: A 1 receptors, which inhibit adenylate cyclase, and A 2 receptors, which stimulate adenylate cyclase. It is thought that coronary vasodilation is mediated by A 2 receptor activation [see, e.g., Haleen, S., et. al., Life Sci., 36, 127-137 (1985)]. In order to minimize side effects associated with activation of A 1 receptors, it is a goal of pharmaceutical research to identify compounds highly selective for A 2 receptors.
  • .Iadd.R' is hydrogen, lower alkyl or lower alkoxy
  • R 1 when R 1 is a hydrocarbyl radical, it may be substituted with one or two radicals represented by the above general formula or substituted with --OR 3 , wherein R 3 is hydrogen or lower alkyl, having from one to ten carbon atoms; R 2 is selected from the group consisting of hydrogen and straight chain, branched and cyclic hydrocarbyl radicals having from one to four carbon atoms, and optionally substituted with a hydroxyl radical; and
  • X is two hydrogen atoms or oxygen and B is selected from oxygen and nitrogen, with the proviso that when X is two hydrogen atoms, B is oxygen, and with the further proviso that when R 3 is present or R 1 is a branched or straight-chained hydrocarbyl radical, then R 1 must be substituted with one of the above radicals, and with the still further proviso that when B is oxygen, then R 1 cannot be a phenyl or a substituted phenyl radical.
  • a 2 receptor agonists are represented by the formula: ##STR5## wherein .Iadd.R' is hydrogen, lower alkyl or lower alkoxy, .Iaddend.R 1 is selected from the group, consisting of branched, straight-chained or cyclic hydrocarbyl radicals, having from one to six carbon atoms, and radicals represented by the general formulae: ##STR6## wherein Y is selected from the group consisting of lower alkyl, lower alkyl, carboxy-lower alkyl and halogen; Z is oxygen, sulfur or --NH; Q is --CH or nitrogen; .Iadd.r is 0 or 1 and p
  • R 1 when R 1 is a hydrocarbyl radical, it may be substituted with one or two radicals represented by the above general formula or substituted with --OR 3 , wherein R 3 is hydrogen or lower alkyl, having from one to ten carbon atoms; R 2 is selected from the group consisting of hydrogen and straight chain, branched and cyclic hydrocarbyl radicals having from one to four carbon atoms, and optionally substituted with a hydroxyl radical; and
  • X is two hydrogen atoms or oxygen and B is selected from oxygen and nitrogen, with the proviso that when X is two hydrogen atoms, B is oxygen, and with the further proviso that when R 3 is present or R 1 is a branched or straight-chained hydrocarbyl radical, then R 1 must be substituted with one of the above radicals, and with the still further proviso that when B is oxygen, then R 1 cannot be a phenyl radical or a substituted phenyl radical.
  • lower refers to compounds having from 1 to 10 carbon atoms.
  • the preferred lower alkyl radicals have from 1 to 4 carbon atoms.
  • halogen refers to bromide, chloride, fluoride and iodide radicals.
  • the invention also encompasses a method of preparation of the subject compounds, pharmaceutical compositions of the subject compounds and a method for inducing an adenosine A 2 response by administering the subject compounds to a patient.
  • the general method of preparation of the above compounds comprises the reaction of a 2-haloadenosine derivative shown below with an alkali metal salt of .[.R 1 OH..]. ##STR7##
  • the characteristic NMR spectral peaks are: (60 MHz, DMSO-d 6 ) ⁇ 1.95 (m, 2H), 2.63 (m, 2H), 3.5-5.4 (m, 8H), 4.15 (t, 2H), 5.78 (d, 2H), 7.20 (m, 7H), 8.15 (s, 1H). m.p. 100-102 C.
  • Example 1 The general procedure of Example 1 was followed, using the following reactants: 4-Fluorophenyl alcohol (4.2 mL, 33.5 mmoles); 1.6M n-butyllithium (20.0 mL, 31.9 mmoles); 2-chloro-2',3'-O-ethoxymethylideneadenosine (3.0 g, 8.4 mmoles). All conditions were identical with the exception of the hydrolysis and final purification conditions. Hydrolysis was achieved using concentrated acetic acid (5 mL). Final purification was done in the same manner, using a linear gradient of 50-68% methanol to yield 1.3 g (36%) of colorless solid.
  • Example 2 The general procedure of Example 1 was followed, using cyclohexanol in place of 3-phenyl-1-propanol.
  • the characteristic NMR spectral peaks are: (60 MHz, DMSO-d 6 ) ⁇ 1.00-2.10 (m, 10H), 3.42-5.52 (m, 9H), 5.71 (d, 1H), 7.15 (s, 2H), 8.02 (s, 1H). m.p. 147 C.
  • Example 2 The general procedure of Example was followed, using 2-cyclohexylethanol in place of 3-phenyl-1-propanol.
  • the characteristic NMR spectral peaks are: (60 MHz, DMSO-d 6 ) ⁇ 0.88-1.95 (m, 13H), 3.50-5.60 (m,8H), 4.64 (t, 2H), 5.89 (d, 1H), 7.20 (s, 2H), 8.10 (s, 1H). m.p. 185-187 C.
  • Example 1 The general procedure of Example 1 was followed, using phenethyl alcohol in place of 3-phenyl-1-propanol.
  • the characteristic NMR spectral peaks are: (60 MHz, DMSO-d 6 ) ⁇ 3.00 (t, 2H), 3.45-5.45 (m, 10H), 5.77 (d, 1H), 7.29 (s, 7H), 8.13 (s, 1H). m.p. 95-97 C.
  • Example 2 The general procedure of Example 1 was followed, using 2-(2-methoxyphenyl)ethanol in place of 3-phenyl-1-propanol.
  • the characteristic NMR spectral peaks are: (60 MHz, DMSO-d 6 ) ⁇ 3.03 (t, 2H), 3.6-5.6 (m, 10H), 3.8 (s, 3H), 5.86 (d, 1H), 6.8-7.52 (m, 6H), 8.17 (s, 1H). m.p. 126-130 C.
  • Example 1 The general procedure of Example 1 was followed, using 2-(3-methoxyphenyl)ethanol in place of 3-phenyl-1-propanol.
  • the characteristic NMR spectral peaks are: (60 MHz, DMSO-d 6 ) ⁇ 3.0 (t, 2H), 3.6-5.65 (m, 10H), 3.76 (s, 3H), 5.86 (d, 1H), 6.7-7.5 (m, 6H), 8.18 (s, 1H). m.p. 103-105 C.
  • Example 2 The general procedure of Example was followed, using 2-(4-methoxyphenyl)ethanol in place of 3-phenyl-1-propanol.
  • the characteristic NMR spectral peaks are: (60 MHz, DMSO-d 6 ) ⁇ 2.95 (t, 2H), 3.5-5.52 (m, 8H), 3.74 (s, 3H), 4.4 (t, 2H), 5.86 (d, 1H), 6.86 (d, 2H), 7.25 (d, 2H), 7.33 (2, 2H), 8.2 (s, 1H).
  • Example 1 The general procedure of Example 1 was followed, using 3,4,5-trimethoxyphenylethanol in place of 3-phenyl-1-propanol.
  • the characteristic NMR spectral peaks are: (60 MHz, DMSO-d 6 ) ⁇ 2.95 (t, 2H), 3.5-5.58 (m, 8H), 4.45 (t, 2H), 5.72 (d, 1H), 6.65 (s, 2H), 7.28 (s, 2H), 8.16 (s, 1H). m.p. 110-112 C.
  • Example 2 The general procedure of Example was followed, using 2-(3-thienyl)ethanol in place of 3-phenyl-1-propanol.
  • the characteristic NMR spectral peaks are: (60 MHz, DMSO-d 6 ) ⁇ 3.1 (t, 2H), 3.3-5.6 (m, 8H), 4.5 (t, 2H), 5.85 (d, 1H), 7.0-7.58 (m, 5H), 8.22 (s, 1H). m.p. 99-102 C.
  • Example 2 The general procedure of Example was followed, using 2-(1-naphthyl)ethanol in place of 3-phenyl-1-propanol.
  • the characteristic NMR spectral peaks are: (60 MHz, DMSO-d 6 ) ⁇ 3.45-5.5 (m, 10H), 4.5 (t, 3H), 5.84 (d, 1H), 7.42 (s, 2H), 7.35-8.38 (m, 7H), 8.2 (s, 1H). m.p. 125-130 C.
  • Example 2 The general procedure of Example 1 was followed, using 2-(3-indolyl)ethanol in place of 3-phenyl-1-propanol.
  • the characteristic NMR spectral peaks are: (60 MHz, DMSO-d 6 ) ⁇ 3.24 (t, 2H), 3.52-3.58 (m, 8H), 4.54 (t, 2H), 5.88 (d, 1H), 6.9-7.7 (m, 7H), 8.12 (s, 1H), 10.12 (s, 1H). m.p. 138-140 C.
  • Example 2 The general procedure of Example 1 was followed, using 2-phenyl-1-propanol in place of 3-phenyl-1-propanol.
  • the characteristic NMR spectral peaks are: (60 MHz, DMSO-d 6 ) ⁇ 1.36 (d, 3H), 3.1-5.55 (m, 11H), 5.85 (d, 1H), 7.35 (s, 7H), 8.2 (s, 1H). m.p. 135 C
  • Example 1 The general procedure of Example 1 was followed, using (2S)-phenyl-1-butanol in place of 3-phenyl-1-propanol.
  • the characteristic NMR spectral peaks are: (60 MHz, DMSO-d 6 ) ⁇ 0.82 (t, 3H), 1.7 (m, 2H), 3.0 (m, 1H), 3.45-5.5 (m, 8H), 4.4 (d, 2H), 5.82 (d, 1H), 7.32 (s, 6H), 8.16 (s, 1H). m.p. 155 C.
  • Example 2 The general procedure of Example 1 was followed, using (2S)-phenyl-1-butanol in place of 3-phenyl-1-propanol.
  • the characteristic NMR spectral peaks are: (60 MHz, DMSO-d 6 ) ⁇ 0.8 (t, 3H), 1.73 (m, 2H), 2.95 (m, 1H), 3.6-5.57 (m, 8H), 4.4 (d, 2H), 5.89 (d, 1H), 7.32 (s, 6H), 8.22 (s, 1H). m.p. 108-110 C.
  • Example 2 The general procedure of Example 1 was followed, using 4-phenyl-1-butanol in place of 3-phenyl-1-propanol.
  • the characteristic NMR spectral peaks are: (60 MHz, DMSO-d 6 ) ⁇ 1.75 (m, 4H), 2.61 (m, 2), 3.5-5.55 (m, 10H), 5.81 (d, 1H), 7.27 (s, 7H), 8.16 (s, 1H). m.p. 93-96 C
  • Example 1 The general procedure of Example 1 was followed, using 5-phenyl-1-pentanol in place of 3-phenyl-1-propanol.
  • the characteristic NMR spectral peaks are: (60 MHz, DMSO-d 6 ) ⁇ 1.35-2.07 (m, 6H), 2.72 (t, 2H), 3.6-5.58 (m, 8H), 4.33 (t, 2H), 5.88 (d, 1H), 7.23 (s, 7H), 8.1 (s, 1H). m.p. 102-104 C.
  • Example I The general procedure of Example I was followed, using 3-cyclohexyl-1-propanol in place of 3-phenyl-1-propanol.
  • the characteristic NMR spectral peaks are: (60 MHz, DMSO-d 6 ) ⁇ 0.7-1.9 (m, 15H), 3.55-5.55 (m, 10H), 5.8 (d, 1H), 7.23 (s, 2H), 8.14 (s, 1H).
  • Example 2 The general procedure of Example was followed, using 2-(2-naphthyl)ethanol in place of 3-phenyl-1-propanol.
  • the characteristic NMR spectral peaks are: (60 MHz, DMSO-d 6 ) ⁇ 3.3 (t, 2H), 3.42-5.5 (m, 8H), 4.67 (t, 2H), 5.84 (d, 1H), 7.22-8.05 (m, 7H), 7.89 (s, 2H), 8.18 (s, 1H).
  • Assays of the cardiovascular potency of the above compounds at the A 1 receptors of the SA node and at the A 2 receptor of the coronary artery employed perfused hearts from female Sprague-Dawley guinea pigs in an isolated Langendorff heart preparation.
  • An assay consists of an infusion of a spectophotometrically standardized solution of test compound directly into the aortic cannula at rates increasing stepwise every 5 minutes. Collection of the total cardiac effluent during the first half of each infusion period provides a measure of coronary flow (A 2 effect). The concentration of test compound required to produce a half-maximal increase in coronary flow is determined.
  • the compounds herein be capable of binding selectively to A 2 adenosine receptors e.g., in a human.
  • 2-phenylethoxy-5'-(N-ethylcarboxamido)adenosine and 2-(4-fluorophenyl)ethoxyadenosine 2-[2-(4-methoxyphenyl)ethoxy]adenosine and 2-[2-(2-naphthyl)ethoxy]adenosine are particularly preferred compounds because of the high affinity and selectivity for A 2 adenosine receptors. It is believed that the compounds herein will be useful as cardiac vasodilators in humans and other animals.
  • the compounds of the present invention may be administered as pharmaceutically acceptable salts.
  • the compounds of the present invention are useful as cardiac vasodilators, cardiovascular, and particularly as anti-hypertensive agents in mammals, domestic animals and humans
  • modes of administering the compounds include oral and topical administration, and intravenous infusion.
  • One having average skill in the art may readily prepare suitable formulations for the abovementioned and other modes of administering the compounds of the invention.

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Abstract

Compounds are disclosed having the formulae: ##STR1## .Iadd.wherein R' is hydrogen, lower alkyl or lower alkoxy; r is 0 or 1 and p is zero to four; and .Iaddend.
wherein R1 is selected from the group, consisting of radicals represented by the general formulae: ##STR2## wherein Y is selected from the group consisting of lower alkyl, lower alkoxy, and halogen; Z is oxygen, sulfur or --NH, Q is --CH or nitrogen; a is zero or an integer of from one to three; and
wherein, R2 is selected from the group consisting of hydrogen and straight chain, branched and cyclic hydrocarbyl radicals having from one to four carbon atoms, and optionally substituted with a hydroxyl radical; and
wherein X is two hydrogen atoms or oxygen and B is selected from oxygen and nitrogen, and pharmaceutically acceptable salts thereof, with the proviso that when X is two hydrogen atoms, B is oxygen, and with the further proviso that when B is oxygen then R1 cannot be a phenyl or a substituted phenyl radical. Pharmaceutical preparations using these compounds and a method for inducing an adenosine response mediated by the adenosine A2 receptor by administering these compounds are also disclosed.

Description

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is directed to certain 2-substituted adenosine derivatives which have beneficial cardiovascular and antihypertensive activity in mammals, including humans and domestic animals. The present invention is also directed to a process for making said compounds.
2. Brief Description of the Prior Art
Adenosine has been known for a long time to possess certain cardiovascular, and particularly coronary dilator activity. In an effort to obtain adenosine analogs of greater potency, or longer duration of activity, or both, many analogs of this naturally occurring nucleoside have been synthesized and tested.
Moreover, numerous studies have been conducted in order to elucidate the biochemical mechanism of action of adenosine and its analogs, and several theories and hypotheses have been proposed regarding biochemical pathways and receptor sites.
For discussion of current theories regarding the foregoing, reference is made to the following articles and publications: Adenosine Receptors: Targets for Future Drugs, by John W. Daly, Journal of Medicinal Chemistry, 25, 197 (1982); Cardiovascular Effects of Nucleoside Analogs, by Herman H. Stein and Pitambar Somani, Annals New York Academy of Sciences, 225, 380 (1979); Coronary Dilatory Action of Adenosine Analogs: a Comparative Study, by. G. Raberger, W. Schutz and O. Kraupp, Archives internationales de Pharmacodynmie et de Therpie 230, 140-149 (1977); chapter 6 of the book titled: Regulatory Function of Adenosine, (pages 77-96), R. M. Berne, T. W. Rall and R. Rubio editors, Martinus Nijhoff publishers, The Hague/Boston/London; and Ethyl Adenosine-5'-carboxylate. A Potent Vasoactive Agent in the Dog, by Herman H. Stein. Journal of Medicinal Chemistry, 16, 1306 (1973); Modification of the 5' Position of Purine Nucleosides. 2. Synthesis and Some Cardiovascular Properties of Adenosine-5'(N-substituted)carboxamides, by Raj. N. Prasad et al., Journal of Medicinal Chemistry, 23 313 (1980), and Modification of the 5' Position of Purine Nucleosides. 1. Synthesis and Biological Properties of Alkyl Adenosine-5'-carboxylates by Raj N. Prasad et al., Journal of Medicinal Chemistry, 19, 1180 (1976).
Still more adenosine derivatives having beneficial cardiovascular activity are described in another application for United States Letters Patent of the present inventors, Ser. No. 601,435, filed on Apr. 18, 1984, now abandoned, Ser. No. 742,565, filed on Jun. 12, 1985, and Ser. No. 625,450, filed on Jun. 28, 1984.
Adenosine receptors have been subdivided into two subtypss: A1 receptors, which inhibit adenylate cyclase, and A2 receptors, which stimulate adenylate cyclase. It is thought that coronary vasodilation is mediated by A2 receptor activation [see, e.g., Haleen, S., et. al., Life Sci., 36, 127-137 (1985)]. In order to minimize side effects associated with activation of A1 receptors, it is a goal of pharmaceutical research to identify compounds highly selective for A2 receptors.
Among a series of related compounds, one early compound claimed to possess coronary vasodilatory activity was 2-phenylaminoadenosine (CV-1808) [see Marumoto, R., et. al., Chem. Pharm. Bull., 23, 759 (1975)]. More recently, a series of N6 -substituted adenosine derivatives were disclosed as having high A2 affinity and selectivity [see Trivedi, B. K., et. al., J. Med. Chem., 31, 271-273 (1988), and Bridges, A., et. al., J. Med. Chem., 31, 1282-1285 (1988)]. Another series of 2,5'-disubstituted adenosine derivatives have been disclosed as A2 agonists (European Patent Application EP-277-917-A).
Many of the known adenosine derivatives are less than satisfactory as theraupeutics agents, due to low activity, short duration of effect, toxicity or undesirable side effects. In this light, there is a continuing interest in identifying agents which posses an desired profile of highly selective and potent adenosine A2 receptor activity with minimal toxicity. The compounds of the present invention constitute a step in this direction.
SUMMARY OF THE INVENTION
There have now been discovered certain novel compounds having activity as A2 adenosine receptor agonists and having the structural formula: ##STR3## wherein .Iadd.R' is hydrogen, lower alkyl or lower alkoxy, .Iaddend.R1 is selected from the group, consisting of branched, straight-chained or cyclic hydrocarbyl radicals, having from one to six carbon atoms, and radicals represented by the general formulae: ##STR4## wherein Y is selected from the group consisting of lower alkyl, lower alkoxy, carboxy-lower alkyl and halogen; Z is oxygen, sulfur or --NH, Q is --CH or nitrogen, .Iadd.r is 0 or 1 and p is zero or an integer of from one to four; .Iaddend.a is zero or an integer of from one to three; n is zero or an integer of from one to three; and m is an integer of from three to six; and
wherein, when R1 is a hydrocarbyl radical, it may be substituted with one or two radicals represented by the above general formula or substituted with --OR3, wherein R3 is hydrogen or lower alkyl, having from one to ten carbon atoms; R2 is selected from the group consisting of hydrogen and straight chain, branched and cyclic hydrocarbyl radicals having from one to four carbon atoms, and optionally substituted with a hydroxyl radical; and
wherein X is two hydrogen atoms or oxygen and B is selected from oxygen and nitrogen, with the proviso that when X is two hydrogen atoms, B is oxygen, and with the further proviso that when R3 is present or R1 is a branched or straight-chained hydrocarbyl radical, then R1 must be substituted with one of the above radicals, and with the still further proviso that when B is oxygen, then R1 cannot be a phenyl or a substituted phenyl radical.
DETAILED DESCRIPTION OF THE INVENTION
Certain derivatives of adenosine have been found in accordance with the present invention to selectively activate A2 adenosine receptors and to possess significant cardiovascular and/or vasodilatory anti-hypertensive activity. The compounds used in the present invention are selected from the group of stereoisomers or mixtures thereof of compounds having activity as adenosine A2 receptor agonists are represented by the formula: ##STR5## wherein .Iadd.R' is hydrogen, lower alkyl or lower alkoxy, .Iaddend.R1 is selected from the group, consisting of branched, straight-chained or cyclic hydrocarbyl radicals, having from one to six carbon atoms, and radicals represented by the general formulae: ##STR6## wherein Y is selected from the group consisting of lower alkyl, lower alkyl, carboxy-lower alkyl and halogen; Z is oxygen, sulfur or --NH; Q is --CH or nitrogen; .Iadd.r is 0 or 1 and p is zero or an integer of from one to four, .Iaddend.a is zero or an integer of from one to three; n is zero or an integer of from one to three; and m is an integer of from three to six; and
wherein, when R1 is a hydrocarbyl radical, it may be substituted with one or two radicals represented by the above general formula or substituted with --OR3, wherein R3 is hydrogen or lower alkyl, having from one to ten carbon atoms; R2 is selected from the group consisting of hydrogen and straight chain, branched and cyclic hydrocarbyl radicals having from one to four carbon atoms, and optionally substituted with a hydroxyl radical; and
wherein X is two hydrogen atoms or oxygen and B is selected from oxygen and nitrogen, with the proviso that when X is two hydrogen atoms, B is oxygen, and with the further proviso that when R3 is present or R1 is a branched or straight-chained hydrocarbyl radical, then R1 must be substituted with one of the above radicals, and with the still further proviso that when B is oxygen, then R1 cannot be a phenyl radical or a substituted phenyl radical.
As used herein, the term "lower" as in "lower alkyl" refers to compounds having from 1 to 10 carbon atoms. The preferred lower alkyl radicals have from 1 to 4 carbon atoms. As used herein, the term "halogen" refers to bromide, chloride, fluoride and iodide radicals. Compounds falling within the scope of this invention are as follows:
2-benzyloxyadenosine
2-(2-phenylethoxy)adenosine
2-(5-phenylpentoxy)adenosine
2-cyclopentyloxyadenosine
2-cyclohexyloxyadenosine
2-(2-phenylethoxy)-5'-(N-ethylcarboxamido)adenosine
2-[2-(4-fluorophenyl)ethoxy]-5'-(N-ethylcarboxamido)adenosine
2-(3-phenylpropoxy)adenosine
2-cyclohexylethoxyadenosine
2-(4-phenylbutoxy)adenosine
2-(3,4,5-trimethoxyphenylethoxy)adenosine
2-[2-(2-thienyl)ethoxy]adenosine
2-[2-(3-thienyl)ethoxy]adenosine
2-(4-phenylbutoxy)adenosine
2-(2-pyridylethoxy)adenosine
2-(2-cyclohexylethoxy)adenosine
2-[2-(2-methylphenyl)ethoxy]adenosine
2-[2-(2-methoxyphenyl)ethoxy]adenosine
2-[2-(3-methoxyphenyl)ethoxy]adenosine
2-[2-(4-methoxyphenyl)ethoxy]adenosine
2-[2-(4-fluorophenyl)ethoxy]adenosine
2-[2-(3-indolyl)ethoxy]adenosine
2-[2-(1-naphthyl)ethoxy]adenosine
2-[2-(2-naphthyl)ethoxy]adenosine
2-(2,2-diphenylethoxy)adenosine
2-(4-biphenylethoxy)adenosine
2-(4-aminophenylethoxy)adenosine
2-(4-hydroxyphenylethoxy)adenosine
2-(2-indanyloxy)adenosine
2-2R-(1,2,3,4-tetrahydronaphthyloxy)adenosine
2-2S-(1,2,3,4-tetrahydronaphthyloxy)adenosine
2-(2-phenyl-1-propoxy)adenosine
2-(-2-phenyl,2R-hydroxyethoxy)adenosine
2-(2-phenyl,2S-hydroxyethoxy)adenosine
2-(-2-phenyl,2R-methoxyethoxy)adenosine
2-(-2-phenyl,2S-methoxyethoxy)adenosine
2-(2R-phenyl,1-butoxy)adenosine
2-(2S-phenyl,1-butoxy)adenosine
2-[(4-carboxyethylphenyl)ethyoxy]adenosine
2-[(2-butylphenyl)ethoxy]adenosine
The invention is further illustrated by the following examples which are illustrative of various aspects of the invention, and are not intended as limiting the scope of the inventions defined by the appended claims.
The invention also encompasses a method of preparation of the subject compounds, pharmaceutical compositions of the subject compounds and a method for inducing an adenosine A2 response by administering the subject compounds to a patient. The general method of preparation of the above compounds comprises the reaction of a 2-haloadenosine derivative shown below with an alkali metal salt of .[.R1 OH..]. ##STR7##
Details of the synthesis, together with modifications and variations specifically tailored for particular compounds, are set out more fully in the specific examples which follow.
EXAMPLE 1 Preparation of 2-(3-phenyl-1-propoxy)adenosine
To a cold (10 C) solution of 3-phenyl-1-propanol (6 mL, 4.4 mmoles) and 70 mL of dry tetrahydrofuran was added n-butyllithium 1.6M in hexanes (25 mL, 40.0 mmoles) via syringe. The above solution was stirred for 15 minutes at room temperature followed by the addition of 2-chloro-2',3'-O-isopropylideneadenosine (3.0 g, 8.8 mmoles). The mixture was refluxed for 4 days (HPLC showed less then 5% starting material). The solvents were removed in vacuo to give a dark brown syrup. Water (50 mL) was added and the pH adjusted to 7 with 4N HCl. The aqueous phase was extracted with ethyl acetate (4×50 mL) and the organic extracts dried over magnesium sulfate. The drying agent was filtered off and the solvents removed in vacuo to afford a brown syrup. This was purified by flash chromatography on silica gel (40-60μ) using a step gradient of chloroform to 2% methanol in chloroform. The fractions that showed product were collected and the solvents removed in vacuo to give a light brown syrup (blocked nucleoside). The syrup was dissolved in 80 mL of methanol. To this solution was added 10 mL water and 10 mL 98% formic acid and boiled until HPLC showed no blocked nucleoside. Sodium bicarbonate was added until a pH of 7 was achieved. The solvents were removed in vacuo. To the residue was added 2-propanol and the insoluble salts were filtered off. The 2-propanol was removed in vacuo and the product purified by preparative HPLC on a C-18 column, using a linear gradient of 50-70% methanol in water to yield 700 mg (20%) of a colorless solid. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 1.95 (m, 2H), 2.63 (m, 2H), 3.5-5.4 (m, 8H), 4.15 (t, 2H), 5.78 (d, 2H), 7.20 (m, 7H), 8.15 (s, 1H). m.p. 100-102 C.
The above procedure was attempted using sodium hydride in place of n-butyllithium, which gave less than 5% yield by HPLC.
EXAMPLE 2 Preparation of 2-[2-(4-fluorophenyl)ethoxy]adenosine
The general procedure of Example 1 was followed, using the following reactants: 4-Fluorophenyl alcohol (4.2 mL, 33.5 mmoles); 1.6M n-butyllithium (20.0 mL, 31.9 mmoles); 2-chloro-2',3'-O-ethoxymethylideneadenosine (3.0 g, 8.4 mmoles). All conditions were identical with the exception of the hydrolysis and final purification conditions. Hydrolysis was achieved using concentrated acetic acid (5 mL). Final purification was done in the same manner, using a linear gradient of 50-68% methanol to yield 1.3 g (36%) of colorless solid. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 3.12 (t, 2H), 3.55-5.55 (m, 8H), 4.58 (t, 2H), 5.88 (d, 1H), 7.05-7.41 (m, 6H), 8.08 (s, 1H). m.p. 148-150 C.
EXAMPLE 3 Preparation of 2-Cyclopentyloxyadenosine
The general procedure of Example was followed, using cyclopentanol in place of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 1.80 (s, 8H), 3.50-5.48 (m, 9H), 5.80 (d, 1H), 7.20 (s, 2H), 8.14 (s, 1H). m.p. 147-150 C.
EXAMPLE 4 Preparation of 2-Cyclohexyloxyadenosine
The general procedure of Example 1 was followed, using cyclohexanol in place of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 1.00-2.10 (m, 10H), 3.42-5.52 (m, 9H), 5.71 (d, 1H), 7.15 (s, 2H), 8.02 (s, 1H). m.p. 147 C.
EXAMPLE 5 Preparation of 2-(2-Cyclohexylethoxy)adenosine
The general procedure of Example was followed, using 2-cyclohexylethanol in place of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 0.88-1.95 (m, 13H), 3.50-5.60 (m,8H), 4.64 (t, 2H), 5.89 (d, 1H), 7.20 (s, 2H), 8.10 (s, 1H). m.p. 185-187 C.
EXAMPLE 6 Preparation of 2-benzyloxyadenosine
The general procedure of Example was followed, using benzyl alcohol in place of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 3.40-5.45 (m, 8H), 5.27 (s, 2H), 5.66 (d, 1H), 7.32 (m, 7H), 8.09 (s, 1H), m.p. 172-75 C.
EXAMPLE 7 Preparation of 2-(2-phenylethoxy)adenosine
The general procedure of Example 1 was followed, using phenethyl alcohol in place of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 3.00 (t, 2H), 3.45-5.45 (m, 10H), 5.77 (d, 1H), 7.29 (s, 7H), 8.13 (s, 1H). m.p. 95-97 C.
EXAMPLE 8 Preparation of 2-[2-(2-methoxyphenyl)ethoxy]adenosine
The general procedure of Example 1 was followed, using 2-(2-methoxyphenyl)ethanol in place of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 3.03 (t, 2H), 3.6-5.6 (m, 10H), 3.8 (s, 3H), 5.86 (d, 1H), 6.8-7.52 (m, 6H), 8.17 (s, 1H). m.p. 126-130 C.
EXAMPLE 9 Preparation of 2-[2-(3-methoxyphenyl)ethoxy]adenosine
The general procedure of Example 1 was followed, using 2-(3-methoxyphenyl)ethanol in place of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 3.0 (t, 2H), 3.6-5.65 (m, 10H), 3.76 (s, 3H), 5.86 (d, 1H), 6.7-7.5 (m, 6H), 8.18 (s, 1H). m.p. 103-105 C.
EXAMPLE 10 Preparation of 2-[2-(4-methoxyphenyl)ethoxy]adenosine
The general procedure of Example was followed, using 2-(4-methoxyphenyl)ethanol in place of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 2.95 (t, 2H), 3.5-5.52 (m, 8H), 3.74 (s, 3H), 4.4 (t, 2H), 5.86 (d, 1H), 6.86 (d, 2H), 7.25 (d, 2H), 7.33 (2, 2H), 8.2 (s, 1H).
EXAMPLE 11 Preparation of 2-[2-(2-methylphenyl)ethoxy]adenosine
The general procedure of Example was followed, using 2-methylphenylethanol in place of 3-phenyl-I-propanol. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 2.33 (s, 3H), 3.04 (t, 2H), 3.5-5.55 (m, 8H), 4.45 (t, 2H), 5.85 (d, 1H), 7.2 (s, 4H), 7.3 (s, 2H), 8.19 (s, 1H). m.p. 166-168 C.
EXAMPLE 12 Preparation of 2-[2-(3,4,5-trimethoxyphenyl)ethoxy]adenosine
The general procedure of Example 1 was followed, using 3,4,5-trimethoxyphenylethanol in place of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 2.95 (t, 2H), 3.5-5.58 (m, 8H), 4.45 (t, 2H), 5.72 (d, 1H), 6.65 (s, 2H), 7.28 (s, 2H), 8.16 (s, 1H). m.p. 110-112 C.
EXAMPLE 13 Preparation of 2-[2-(2-thienyl)ethoxy]adenosine
The general procedure of Example was followed, using 2-(2-thienyl)ethanol in place of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 3.19 (t, 2H), 3.5-5.5 (m, 8H), 4.44 (t, 2H), 5.8 (d, 1H), 6.88-7.43 (m, 5H), 8.26 (s, 1H). m.p. 104-106 C.
EXAMPLE 14 Preparation of 2-[2-(3-thienyl)ethoxy]adenosine
The general procedure of Example was followed, using 2-(3-thienyl)ethanol in place of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 3.1 (t, 2H), 3.3-5.6 (m, 8H), 4.5 (t, 2H), 5.85 (d, 1H), 7.0-7.58 (m, 5H), 8.22 (s, 1H). m.p. 99-102 C.
EXAMPLE 15 Preparation of 2-[2-(1-naphthyl)ethoxy]adenosine
The general procedure of Example was followed, using 2-(1-naphthyl)ethanol in place of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 3.45-5.5 (m, 10H), 4.5 (t, 3H), 5.84 (d, 1H), 7.42 (s, 2H), 7.35-8.38 (m, 7H), 8.2 (s, 1H). m.p. 125-130 C.
EXAMPLE 16 Preparation of 2-[2-(3-indolyl)ethoxy]adenosine
The general procedure of Example 1 was followed, using 2-(3-indolyl)ethanol in place of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 3.24 (t, 2H), 3.52-3.58 (m, 8H), 4.54 (t, 2H), 5.88 (d, 1H), 6.9-7.7 (m, 7H), 8.12 (s, 1H), 10.12 (s, 1H). m.p. 138-140 C.
EXAMPLE 17 Preparation of 2-(2-phenyl-1-propoxy)adenosine
The general procedure of Example 1 was followed, using 2-phenyl-1-propanol in place of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 1.36 (d, 3H), 3.1-5.55 (m, 11H), 5.85 (d, 1H), 7.35 (s, 7H), 8.2 (s, 1H). m.p. 135 C
EXAMPLE 18 Preparation of 2-[(2-[(2R)-phenyl-1-butoxy]adenosine
The general procedure of Example 1 was followed, using (2S)-phenyl-1-butanol in place of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 0.82 (t, 3H), 1.7 (m, 2H), 3.0 (m, 1H), 3.45-5.5 (m, 8H), 4.4 (d, 2H), 5.82 (d, 1H), 7.32 (s, 6H), 8.16 (s, 1H). m.p. 155 C.
EXAMPLE 19 Preparation of 2-[(2S)-phenyl-1-butoxy]adenosine
The general procedure of Example 1 was followed, using (2S)-phenyl-1-butanol in place of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 0.8 (t, 3H), 1.73 (m, 2H), 2.95 (m, 1H), 3.6-5.57 (m, 8H), 4.4 (d, 2H), 5.89 (d, 1H), 7.32 (s, 6H), 8.22 (s, 1H). m.p. 108-110 C.
EXAMPLE 20 Preparation of 2-(4-phenyl-1-butoxy)adenosine
The general procedure of Example 1 was followed, using 4-phenyl-1-butanol in place of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 1.75 (m, 4H), 2.61 (m, 2), 3.5-5.55 (m, 10H), 5.81 (d, 1H), 7.27 (s, 7H), 8.16 (s, 1H). m.p. 93-96 C
EXAMPLE 21 Preparation of 2-(5-phenyl-1-pentoxy)adenosine
The general procedure of Example 1 was followed, using 5-phenyl-1-pentanol in place of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 1.35-2.07 (m, 6H), 2.72 (t, 2H), 3.6-5.58 (m, 8H), 4.33 (t, 2H), 5.88 (d, 1H), 7.23 (s, 7H), 8.1 (s, 1H). m.p. 102-104 C.
EXAMPLE 22 Preparation of 2-(2-phenyl)ethoxy-5'-N-ethylcarboxamidoadenosine
To a mixture of 2-phenylethanol (3.14 mL, 26.3 mmoles) in dry tetrahydrofuran (50 mL) was added n-butyllithium (16.4 mL, 26.2 mmoles) dropwise. This mixture was allowed to stir 15 min. at room temperature. The 2-chloro-5'-N-ethylcarboxamidoadenosine (1.5 g, 4.38 mmoles) was added in one portion and the mixture refluxed for 72 hours. Water (50 mL) was added. The precipitate was filtered off and the filtrate extracted with ethyl acetate (4×50 mL). The organic phases were dried with magnesium sulfate. The drying agent was removed by filtration and the solvents removed in vacuo to give a foam. Purification on a preparative HPLC C-18 column, using a linear gradient of 50-70% methanol/water gave a colorless solid. The characteristic NMR spectal peaks are: (60 MHz, DMSO-d6) δ 1.07 (t, 3H), 3.39 (m, 4H), 4.1-4.77 (m, 5H), 5.5-5.78 (m, 2H), 5.9 (d, 1H), 7.32 (s, 5H), 7.46 (s, 2H), 8.2 (s, 1H), 8.9 (t, 1H). m.p. 130-133 C.
EXAMPLE 23 Preparation of 2-(3-cyclohexyl)propoxyadenosine
The general procedure of Example I was followed, using 3-cyclohexyl-1-propanol in place of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 0.7-1.9 (m, 15H), 3.55-5.55 (m, 10H), 5.8 (d, 1H), 7.23 (s, 2H), 8.14 (s, 1H).
EXAMPLE 24 Preparation of 2-[2-(2-naphthyl)ethoxy]adenosine
The general procedure of Example was followed, using 2-(2-naphthyl)ethanol in place of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are: (60 MHz, DMSO-d6) δ 3.3 (t, 2H), 3.42-5.5 (m, 8H), 4.67 (t, 2H), 5.84 (d, 1H), 7.22-8.05 (m, 7H), 7.89 (s, 2H), 8.18 (s, 1H).
EXAMPLE 25
Assays of the cardiovascular potency of the above compounds at the A1 receptors of the SA node and at the A2 receptor of the coronary artery employed perfused hearts from female Sprague-Dawley guinea pigs in an isolated Langendorff heart preparation. An assay consists of an infusion of a spectophotometrically standardized solution of test compound directly into the aortic cannula at rates increasing stepwise every 5 minutes. Collection of the total cardiac effluent during the first half of each infusion period provides a measure of coronary flow (A2 effect). The concentration of test compound required to produce a half-maximal increase in coronary flow is determined. Registration of the ECG assesses the effect of the test compound on SA node (stimulus to Q interval, A1 effect). The concentration of test compound required to produce a half-maximal prolongation of stimulus to Q interval is determined. Table I summarizes the resultant data, using adenosine as a reference compound. The ratio of A1 and A2 effects of test compounds are calculated to provide the selectivity ratio.
              TABLE I                                                     
______________________________________                                    
         Coronary                                                         
         Blood Flow   SQ Prolongation                                     
         Increase (A.sub.2)                                               
                      (A.sub.1)   Selectivity                             
Example  EC.sub.50 (nM)                                                   
                      ED.sub.50 (nM)                                      
                                  (A.sub.1 /A.sub.2)                      
______________________________________                                    
Adenosine                                                                 
         49.7         3162        63.6                                    
6        419.3        6310        15                                      
7        2.8          19953       7126                                    
3        91.7         79433       866                                     
4        656.9        100000      152                                     
22       1.3          14962       11509                                   
1        61.3         19953       326                                     
13       3.7          11885       3212                                    
14       3.4          18836       5540                                    
20       9.9          7356        743                                     
15       5.1          8414        1650                                    
17       9.0          53088       5899                                    
12       22.0         47315       2151                                    
5        1.0          8630        8630                                    
11       3.8          25119       6610                                    
9        2.6          16218       6238                                    
18       373.7        18836       50                                      
19       31.4         27384       872                                     
8        32.0         35481       1109                                    
21       6.4          4597        718                                     
2        0.9          25606       29432                                   
16       9.8          14125       1441                                    
10       1.4          19724       14089                                   
23       2.2          3758        1708                                    
24       0.5          11416       22832                                   
______________________________________
This data shows the high degree of potency and selectivity of the subject compounds in increasing coronary blood flow at low concentrations while having comparatively little effect on the SQ prolongation. The ratios calculated show the marked A2 selectivity of the subject compounds.
It is essential that the compounds herein be capable of binding selectively to A2 adenosine receptors e.g., in a human. 2-phenylethoxy-5'-(N-ethylcarboxamido)adenosine and 2-(4-fluorophenyl)ethoxyadenosine 2-[2-(4-methoxyphenyl)ethoxy]adenosine and 2-[2-(2-naphthyl)ethoxy]adenosine are particularly preferred compounds because of the high affinity and selectivity for A2 adenosine receptors. It is believed that the compounds herein will be useful as cardiac vasodilators in humans and other animals.
Various modifications of the herein disclosed invention, in terms of structural modifications of the invented compounds and also in terms of making or using the same, may become readily apparent to those skilled in the art in light of the above disclosure. For example, the compounds of the present invention may be administered as pharmaceutically acceptable salts.
Inasmuch as the compounds of the present invention are useful as cardiac vasodilators, cardiovascular, and particularly as anti-hypertensive agents in mammals, domestic animals and humans various modes of administering the compounds will be apparent to a person having average skill in the art. Such modes of administering the compounds include oral and topical administration, and intravenous infusion. One having average skill in the art may readily prepare suitable formulations for the abovementioned and other modes of administering the compounds of the invention.
In light of the foregoing, the scope of the present invention should be interpreted solely from the following claims, as such claims are read in light of the disclosure.

Claims (14)

We claim:
1. A compound selected from the group of stereoisomers or mixtures thereof of compounds having the formulae: ##STR8## wherein .Iadd.R' is hydrogen, lower alkyl or lower alkoxy, .Iaddend.R1 is ##STR9## wherein Y is selected from the group consisting of lower alkyl, lower alkoxy, and halogen; Z is oxygen, sulfur or --NH, Q is --CH or nitrogen; .Iadd.r is 0 or 1 and p is zero or an integer of from one to four; .Iaddend.a is an integer from 0 to 3; and
wherein R2 is selected from the group consisting of hydrogen and straight, branched or cyclic hydrocarbyl radicals having from 1 to 4 carbon atoms; and
wherein x is 2 hydrogen atoms or oxygen and B is selected from the group consisting of oxygen and nitrogen, with the proviso that when x is 2 hydrogen atoms, B is oxygen and with the further proviso that when B is oxygen then R2 cannot be a phenyl or phenyl substituted with one or more substituents at positions 2-, 3-, 4- and 5-.
2. A compound of claim 1 wherein a is zero.
3. A compound of claim 1 wherein Y is halogen.
4. A compound of claim 1 wherein Q is --CH.
5. A compound of claim 1 wherein R1 is phenylethyl.
6. A compound of claim 1 wherein R1 is 4-fluorophenylethyl.
7. A compound of claim 1 wherein R1 is 4-methoxyphenylethyl.
8. A compound of claim 1 wherein R1 is 2-(2-naphthyl)ethyl.
9. A compound of claim 1 wherein R2 is ethyl and R1 is phenylethyl.
10. 2-(2-phenyl)ethoxyadenosine.
11. 2-(2-phenyl)ethoxy-5'-N-ethylcarboxamidoadenosine. .[.12. 2-[2-(4-fluorophenyl)ethoxy]adenosine..]..[.13. 2-[2-(4-methoxyphenyl)ethoxy]adenosine..]..[.14.
2-[2-(2-naphthyl)ethoxy]adenosine..].15. 2-(2-cyclohexyl)ethoxyadenosine.
6. A method for inducing an adenosine response indicated by an adenosine A2 receptor in a human or animal, comprising the step of administering to a human or an animal in need of such treatment, an effective amount of a compound having the formulae: ##STR10## wherein .Iadd.R' is hydrogen, lower alkyl or lower alkoxy, .Iaddend.R1 is ##STR11## wherein Y is selected from the group consisting of lower alkyl, lower alkoxy, and halogen; Z is oxygen, sulfur or --NH, Q is --CH or nitrogen; .Iadd.r is 0 or 1 and p is zero or an integer of from one to four; .Iaddend.a is an integer from 0 to 3; and
wherein R2 is selected from the group consisting of hydrogen and straight, branched or cyclic hydrocarbyl radicals having from 1 to 4 carbon atoms; and
wherein x is 2 hydrogen atoms or oxygen and B is selected from the group consisting of oxygen and nitrogen, with the proviso that when X is 2 hydrogen atoms, B is oxygen with the further proviso that when B is oxygen then R2 cannot be a phenyl or phenyl substituted with one or more
substituents at positions 2-, 3-, 4 and 5-. .Iadd.17. 2-[2-(4-fluorophenyl)ethoxy]adenosine. .Iaddend..Iadd.18. 2-[2-(4-methoxyphenyl)ethoxy]adenosine. .Iaddend..Iadd.19. 2-[2-(2-naphthyl)ethoxy]adenosine. .Iaddend.
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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6232297B1 (en) 1999-02-01 2001-05-15 University Of Virginia Patent Foundation Methods and compositions for treating inflammatory response
US6322771B1 (en) 1999-06-18 2001-11-27 University Of Virginia Patent Foundation Induction of pharmacological stress with adenosine receptor agonists
US6448235B1 (en) 1994-07-11 2002-09-10 University Of Virginia Patent Foundation Method for treating restenosis with A2A adenosine receptor agonists
US6514949B1 (en) 1994-07-11 2003-02-04 University Of Virginia Patent Foundation Method compositions for treating the inflammatory response
US20030027793A1 (en) * 2001-05-08 2003-02-06 Thomas Lauterback Transdermal treatment of parkinson's disease
US20030026830A1 (en) * 2001-05-08 2003-02-06 Thomas Lauterback Transdermal therapeutic system for parkinson's disease inducing high plasma levels of rotigotine
US20030180332A1 (en) * 2000-08-24 2003-09-25 Stephan Rimpler Novel pharmaceutical composition
US20030186926A1 (en) * 2001-10-01 2003-10-02 Linden Joel M. 2-propynyl adenosine analogs having A2A agonist activity and compositions thereof
US6670334B2 (en) 2001-01-05 2003-12-30 University Of Virginia Patent Foundation Method and compositions for treating the inflammatory response
US20040043960A1 (en) * 2002-08-15 2004-03-04 Jeff Zablocki Partial and full agonists of A1 adenosine receptors
US20050182018A1 (en) * 1999-02-01 2005-08-18 Linden Joel M. Method to reduce inflammatory response in transplanted tissue
US20060040888A1 (en) * 2004-08-02 2006-02-23 Rieger Jayson M 2-propynyl adenosine analogs with modifed 5'-ribose groups having A2A agonist activity
US20060040889A1 (en) * 2004-08-02 2006-02-23 Rieger Jayson M 2-polycyclic propynyl adenosine analogs having A2A agonist activity
US20060100169A1 (en) * 1999-02-01 2006-05-11 Rieger Jayson M Method to reduce an inflammatory response from arthritis
US20080027022A1 (en) * 2006-02-08 2008-01-31 Linden Joel M Method to treat gastric lesions
US20080064653A1 (en) * 2006-06-19 2008-03-13 University Of Virginia Patent Foundation Use of adenosine a2a modulators to treat spinal cord injury
US7442687B2 (en) 2004-08-02 2008-10-28 The University Of Virginia Patent Foundation 2-polycyclic propynyl adenosine analogs having A2A agonist activity
US20090162282A1 (en) * 2007-12-20 2009-06-25 Robert Douglas Thompson Substituted 4--piperidine-1-carboxylic acid esters as a2ar agonists
US20110059915A1 (en) * 2004-09-20 2011-03-10 Inotek Pharmaceuticals Corporation Purine derivatives and methods of use thereof
US8178509B2 (en) 2006-02-10 2012-05-15 University Of Virginia Patent Foundation Method to treat sickle cell disease

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL7216299A (en) * 1971-12-01 1973-06-05
US3819612A (en) * 1970-09-25 1974-06-25 Takeda Chemical Industries Ltd 2-substituted adenosine derivatives and the production thereof
DE2460553A1 (en) * 1973-12-26 1975-07-10 Abbott Lab 2-SUBSTITUTED ADENOSINE-5'-CARBOXYLATE
JPS50101383A (en) * 1974-01-21 1975-08-11
EP0277917A2 (en) * 1987-02-04 1988-08-10 Ciba-Geigy Ag Certain adenosine 5'-carboxamide derivatives
GB2203149A (en) * 1987-04-06 1988-10-12 Sandoz Ltd 1-(6-amino-9-purinyl)- beta -D-ribofuranuronic acid amides and thioamides
US5140015A (en) * 1990-02-20 1992-08-18 Whitby Research, Inc. 2-aralkoxy and 2-alkoxy adenosine derivatives as coronary vasodilators and antihypertensive agents

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3819612A (en) * 1970-09-25 1974-06-25 Takeda Chemical Industries Ltd 2-substituted adenosine derivatives and the production thereof
NL7216299A (en) * 1971-12-01 1973-06-05
DE2460553A1 (en) * 1973-12-26 1975-07-10 Abbott Lab 2-SUBSTITUTED ADENOSINE-5'-CARBOXYLATE
JPS50101383A (en) * 1974-01-21 1975-08-11
EP0277917A2 (en) * 1987-02-04 1988-08-10 Ciba-Geigy Ag Certain adenosine 5'-carboxamide derivatives
GB2203149A (en) * 1987-04-06 1988-10-12 Sandoz Ltd 1-(6-amino-9-purinyl)- beta -D-ribofuranuronic acid amides and thioamides
US5140015A (en) * 1990-02-20 1992-08-18 Whitby Research, Inc. 2-aralkoxy and 2-alkoxy adenosine derivatives as coronary vasodilators and antihypertensive agents

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Marumoto et al., Chem Pharm. Bull., vol. 23, No. 4, pp. 759 774 (1975). *
Marumoto et al., Chem Pharm. Bull., vol. 23, No. 4, pp. 759-774 (1975).
Marumoto, et al., J. Takeda Res. Lab., 44 (3/4), 220 230 (1985). *
Marumoto, et al., J. Takeda Res. Lab., 44 (3/4), 220-230 (1985).

Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6448235B1 (en) 1994-07-11 2002-09-10 University Of Virginia Patent Foundation Method for treating restenosis with A2A adenosine receptor agonists
US6514949B1 (en) 1994-07-11 2003-02-04 University Of Virginia Patent Foundation Method compositions for treating the inflammatory response
US20060100169A1 (en) * 1999-02-01 2006-05-11 Rieger Jayson M Method to reduce an inflammatory response from arthritis
US7378400B2 (en) 1999-02-01 2008-05-27 University Of Virginia Patent Foundation Method to reduce an inflammatory response from arthritis
US20070265440A1 (en) * 1999-02-01 2007-11-15 University Of Virginia Patent Foundation Methods and compositions for treating inflammatory response
US7226913B2 (en) 1999-02-01 2007-06-05 University Of Virginia Patent Foundation Pharmaceutical compositions having A2A adenosine receptor agonist activity
US6531457B2 (en) 1999-02-01 2003-03-11 University Of Virginia Methods and compositions for treating inflammatory response
US7427606B2 (en) 1999-02-01 2008-09-23 University Of Virginia Patent Foundation Method to reduce inflammatory response in transplanted tissue
US20050182018A1 (en) * 1999-02-01 2005-08-18 Linden Joel M. Method to reduce inflammatory response in transplanted tissue
US6232297B1 (en) 1999-02-01 2001-05-15 University Of Virginia Patent Foundation Methods and compositions for treating inflammatory response
US6322771B1 (en) 1999-06-18 2001-11-27 University Of Virginia Patent Foundation Induction of pharmacological stress with adenosine receptor agonists
US20030180332A1 (en) * 2000-08-24 2003-09-25 Stephan Rimpler Novel pharmaceutical composition
US6670334B2 (en) 2001-01-05 2003-12-30 University Of Virginia Patent Foundation Method and compositions for treating the inflammatory response
US20030026830A1 (en) * 2001-05-08 2003-02-06 Thomas Lauterback Transdermal therapeutic system for parkinson's disease inducing high plasma levels of rotigotine
US20030027793A1 (en) * 2001-05-08 2003-02-06 Thomas Lauterback Transdermal treatment of parkinson's disease
US20030186926A1 (en) * 2001-10-01 2003-10-02 Linden Joel M. 2-propynyl adenosine analogs having A2A agonist activity and compositions thereof
US8158604B2 (en) 2001-10-01 2012-04-17 University Of Virginia Patent Foundation 2-propynyl adenosine analogs having A2A agonist activity and compositions thereof
US20100152127A1 (en) * 2001-10-01 2010-06-17 University Of Virginia Patent Foundation 2-propynyl adenosine analogs having a2a agonist activity and compositions thereof
US7737127B2 (en) 2001-10-01 2010-06-15 University Of Virginia Patent Foundation 2-propynyl adenosine analogs having A2A agonist activity and compositions thereof
US7214665B2 (en) 2001-10-01 2007-05-08 University Of Virginia Patent Foundation 2-propynyl adenosine analogs having A2A agonist activity and compositions thereof
US20070232559A1 (en) * 2001-10-01 2007-10-04 University Of Virginia Patent Foundation 2-propynyl adenosine analogs having a2a agonist activity and compositions thereof
US20040043960A1 (en) * 2002-08-15 2004-03-04 Jeff Zablocki Partial and full agonists of A1 adenosine receptors
US20060135467A1 (en) * 2002-08-15 2006-06-22 Jeff Zablocki Partial and full agonists of A1 adenosine receptors
US7022681B2 (en) * 2002-08-15 2006-04-04 Cv Therapeutics, Inc. Partial and full agonists of A1 adenosine receptors
US20060040889A1 (en) * 2004-08-02 2006-02-23 Rieger Jayson M 2-polycyclic propynyl adenosine analogs having A2A agonist activity
US7875595B2 (en) 2004-08-02 2011-01-25 University Of Virginia Patent Foundation 2-polycyclic propynyl adenosine analogs having A2A agonist activity
US20060040888A1 (en) * 2004-08-02 2006-02-23 Rieger Jayson M 2-propynyl adenosine analogs with modifed 5'-ribose groups having A2A agonist activity
US7576069B2 (en) 2004-08-02 2009-08-18 University Of Virginia Patent Foundation 2-polycyclic propynyl adenosine analogs having A2A agonist activity
US20090253647A1 (en) * 2004-08-02 2009-10-08 University Of Virginia Patent Foundation And Adenosine Therapeutics, L.L.C. 2-propynyl adenosine analogs with modified 5'-ribose groups having a2a agonist activity
US7605143B2 (en) 2004-08-02 2009-10-20 University Of Virginia Patent Foundation 2-propynyl adenosine analogs with modified 5′-ribose groups having A2A agonist activity
US20090298788A1 (en) * 2004-08-02 2009-12-03 University Of Virginia Patent Foundation And Adenosine Therapeutics, L.L.C. 2-polycyclic propynyl adenosine analogs having a2a agonist activity
US7989431B2 (en) 2004-08-02 2011-08-02 University Of Virginia Patent Foundation 2-propynyl adenosine analogs with modified 5′-ribose groups having A2A agonist activity
US20110136755A1 (en) * 2004-08-02 2011-06-09 University Of Virginia Patent Foundation 2-propynyl adenosine analogs with modified 5'-ribose groups having a2a agonist activity
US7442687B2 (en) 2004-08-02 2008-10-28 The University Of Virginia Patent Foundation 2-polycyclic propynyl adenosine analogs having A2A agonist activity
US20110059915A1 (en) * 2004-09-20 2011-03-10 Inotek Pharmaceuticals Corporation Purine derivatives and methods of use thereof
US8133880B2 (en) * 2004-09-20 2012-03-13 Inotek Pharmaceuticals Corporation Purine derivatives and methods of use thereof
US20080027022A1 (en) * 2006-02-08 2008-01-31 Linden Joel M Method to treat gastric lesions
US8178509B2 (en) 2006-02-10 2012-05-15 University Of Virginia Patent Foundation Method to treat sickle cell disease
US20080064653A1 (en) * 2006-06-19 2008-03-13 University Of Virginia Patent Foundation Use of adenosine a2a modulators to treat spinal cord injury
US8188063B2 (en) 2006-06-19 2012-05-29 University Of Virginia Patent Foundation Use of adenosine A2A modulators to treat spinal cord injury
US8058259B2 (en) 2007-12-20 2011-11-15 University Of Virginia Patent Foundation Substituted 4-{3-[6-amino-9-(3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylic acid esters as A2AR agonists
US20090162282A1 (en) * 2007-12-20 2009-06-25 Robert Douglas Thompson Substituted 4--piperidine-1-carboxylic acid esters as a2ar agonists

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