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

a technology of aralkoxy and adenosine derivatives, which is applied in the field of 2substituted adenosine derivatives, can solve the problems of many of the known adenosine derivatives being less than satisfactory as theraupeutic agents

Inactive Publication Date: 2000-01-11
ADERIS PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

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.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

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.times.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 (40-60.mu.) using a step gradient of chloroform to 2% methanol in chloroform. The fractions that showed product were collected and the solven...

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-d.sub.6) .delta. 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-d.sub.6) .delta. 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.

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PUM

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Abstract

Compounds are disclosed having the formulae: wherein R' is hydrogen, lower alkyl or lower alkoxy; r is 0 or 1 and p is zero to four; and wherein R1 is selected from the group, consisting of radicals represented by the general formulae: 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 INVENTION1. Field of the InventionThe 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 ArtAdenosine 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...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07H19/16C07H19/00
CPCC07H19/16
Inventor OLSSON, RAY A.THOMPSON, ROBERT D.
Owner ADERIS PHARMA
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