The compound (R)-2-[(phenylisopropyl)amino]adenosine whose structure is given below: ##STR1## (R)-2-[(phenylisopropyl)amino]adenosine is about two orders of magnitude greater in its selectivity between the A-1 and A-2 adenosine receptors than its diastereoisomer. This compound is useful for lowering blood pressure.

FIELD OF THE INVENTION 
The present invention relates to a group of compounds which are adenosine 
analogues and which act selectively at adenosine receptors. 
BACKGROUND OF THE INVENTION 
The profound hypotensive, sedative, antispasmodic, and vasodilatory actions 
of adenosine were first recognized over 50 years ago. Subsequently, the 
number of biological roles proposed for adenosine have increased 
considerably. The adenosine receptors appear linked in many cells to 
adenylate cyclase. A variety of adenosine analogues have been introduced 
in recent years for the study of these receptor functions. Alkylxanthines, 
such as caffeine and theophylline, are the best known antagonists of 
adenosine receptors. 
Adenosine perhaps represents a general regulatory substance, since no 
particular cell type or tissue appears uniquely responsible for its 
formation. In this regard, adenosine is unlike various endocrine hormones. 
Nor is there any evidence for storage and release of adenosine from nerve 
or other cells. Thus, adenosine is unlike various neurotransmitter 
substances. 
Adenosine might be compared as a physiological regulator to the 
prostaglandins. In both cases the enzymes involved in the metabolic 
formation are ubiquitous and appear to be responsive to alterations in the 
physiological state of the cell. Receptors for adenosine, like those for 
prostaglandins, are proving to be very widespread. Finally, both 
prostaglandins and adenosine appear to be involved with the regulation of 
functions involving calcium ions. Prostaglandins, of course, derive from 
membrane precursors, while adenosine derives from cytosolic precursors. 
Although adenosine can affect a variety of physiological functions, 
particular attention has been directed over the years toward actions which 
might lead to clinical applications. Preeminent have been the 
cardiovascular effects of adenosine which lead to vasodilation and 
hypotension but which also lead to cardiac depression. The antilipolytic, 
antithrombotic and antispasmodic actions of adenosine have also received 
some attention. Adenosine stimulates steroidogenesis in adrenal cells, 
again probably via activation of adenylate cyclase. Adenosine has 
inhibitory effects on neurotransmission and on spontaneous activity of 
central neurons. Finally, the bronchoconstrictor action of adenosine and 
its antagonism by xanthines represents an important area of research. 
It has now been recognized that there are not one but at least two classes 
of extracellular receptors involved in the action of adenosine. One of 
these has a high affinity for adenosine and, at least in some cells, 
couples to adenylate cyclase in an inhibitory manner. These have been 
termed by some as the A-1 receptors. The other class of receptors has a 
lower affinity for adenosine and in many cell types couples to adenylate 
cyclase in a stimulatory manner. These have been termed the A-2 receptors. 
Characterization of the adenosine receptors has now been possible with a 
variety of structural analogues. Adenosine analogues resistant to 
metabolism or uptake mechanisms have become available. These are 
particularly valuable, since their apparent potencies will be less 
affected by metabolic removal from the effector system. The adenosine 
analogues exhibit differing rank orders of potencies at A-1 and A-2 
adenosine receptors, providing a simple method of categorizing a 
physiological response with respect to the nature of the adenosine 
receptor. The blockade of adenosine receptors (antagonism) provides 
another method of categorizing a response with respect to the involvement 
of adenosine receptors. It should be noted that the development of potent 
antagonists specific to A-1 or A-2 adenosine receptors would represent a 
major breakthrough in this research field and in the preparation of 
adenosine receptor selective pharmacological agents having specific 
physiological effects in animals. 
SUMMARY OF THE INVENTION 
The present invention relates to compounds of Formula I: 
##STR2## 
wherein R.sub.1 and R.sub.2 are each independently hydrogen or C.sub.1 
-C.sub.4 alkyl, R.sub.3 is C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy 
or halogen, and n is an integer from 0 to 3. 
DETAILED DESCRIPTION OF THE INVENTION 
As used herein the term "C.sub.1 -C.sub.4 alkyl" refers to a saturated 
straight or branched chain hydrocarbon radical of one to four carbon 
atoms. Included within the scope of this term are methyl, ethyl, n-propyl, 
isopropyl, n-butyl, isobutyl and the like. The term "C.sub.1 -C.sub.4 
alkoxy" refers to an alkyloxy radical made up of an oxygen radical bearing 
a saturated straight or branched chain hydrocarbyl radical of one to four 
carbon atoms and specifically includes methoxy, ethoxy, propyloxy, 
isopropyloxy, n-butyloxy, iso-butyloxy, sec-butyloxy, tertiary butyloxy 
and the like. The term "halogen" refers to fluorine, chlorine, bromine, or 
iodine. 
Stereoisomerism is possible with the present compounds and the chemical 
structure as presented above is considered as encompassing all of the 
possible stereoisomers and racemic mixtures of such stereoisomers. More 
specifically, when R.sub.l and R.sub.2 are defined as in Formula I and are 
nonequivalent, the respective carbon atom is chiral and optical isomerism 
is possible. 
As examples of compounds of the present invention are the following: 
1. (R)-2-[(phenylisopropyl)amino]adenosine 
2. (S)-2-[(phenylisopropyl)amino]adenosine 
3. (R)-2-[(1-Phenylpropyl)amino]adenosine 
4. (S)-2-[(1-Phenylpropyl)amino]adenosine 
The general synthetic process for compounds of Formula I is set forth in 
Scheme A. All the substituents, unless otherwise indicated, are previously 
defined. The reagents and starting materials for use in this process are 
readily available to one of ordinary skill in the art. 
Scheme A 
In Scheme A, step a, 2'- and 3'-hydroxyl groups of 2-chloroadenosine (1) 
are protected as the acetonide defined by structure (2). Following the 
general procedure of Hampton [i J. Am. Chem. Soc., 83, 3640 (1961)], an 
equivalent of 2-chloroadenosine is combined with approximately 10 
equivalents of 2,2-dimethoxypropane and approximately 5 equivalents of 
p-toluenesulfonic acid in an appropriate 
##STR3## 
solvent such as N,N-dimethylformamide. After stirring at room temperature 
for approximately 20 hours the product is isolated and purified by 
techniques well-known to one skilled in the art. For example, an excess of 
a suitable aqueous base such as saturated sodium bicarbonate is added and 
the solvent is removed under vacuum. The residue is extracted with a 
suitable organic solvent such as chloroform, dried over magnesium sulfate, 
filtered and concentrated under vacuum. The crude product can be purified 
by flash chromatography or recrystallization methods to provide the 
acetonide (2). 
In Scheme A, step b, the acetonide (2) is then treated with an 
appropriately substituted primary amine to provide the secondary amine of 
structure (3). More specifically, the acetonide (2) is combined with a 
large excess of an appropriately substituted primary amine, such as 
L-(-)-amphetamine, D-(+)-amphetamine, (R)-1-phenylpropylamine or 
(S)-1-phenylpropylamine, under an atmosphere of an inert gas such as 
nitrogen. The mixture is then heated to approximately 130.degree. C. with 
stirring for approximately 3 to 6 hours. After cooling, the product can be 
isolated and purified by techniques well known to one skilled in the art. 
For example, the crude mixture can be directly purified by flash 
chromatography followed by radial chromatography using an appropriate 
eluent such as 3% to 6% methanol/chloroform to provide the secondary amine 
(3). 
In Scheme A, step c, the secondary amine (3) is then deprotected under 
acidic conditions to provide the compound of Formula I. More specifically, 
the secondary amine (3) is treated with an excess of a suitable acid, such 
as 1M hydrochloric acid and heated to approximately 40.degree. C. to 
50.degree. C. for about 30 minutes. After cooling, the product can be 
isolated and purified by techniques well-known to one skilled in the art. 
For example, the reaction is treated with an excess of a suitable weak 
base, such as saturated aqueous sodium bicarbonate and then extracted with 
a suitable organic solvent, such as chloroform. The organic extracts are 
dried over anhydrous magnesium sulfate, filtered and concentrated under 
vacuum. The crude residue can then be purified by chromatographic 
techniques, such as radial chromatography and then treated with ethereal 
hydrogen chloride to provide the hydrochloride salt of Formula I. 
Therapeutic Utility Of Selective Adenosine Receptor Agents 
The table below shows in more detail the potential therapeutic utility of 
selective adenosine receptor agents in accordance with the present 
invention: 
______________________________________ 
Receptor 
Area Effect Correlate 
______________________________________ 
Cardiovascular 
cardiotonic A-1 antagonism 
Cardiovascular 
control tachycardia 
A-1 agonism 
Cardiovascular 
increase coronary blood 
A-2 agonism 
flow 
Cardiovascular 
vasodilation A-2 (atypical) 
agonism 
Pulmonary bronchodilation A-1 antagonism 
Pulmonary mediation of autocoid 
novel adenosine 
release from mast 
receptor inter- 
cells, basophils action on cell 
surface 
Pulmonary stimulate respiration; 
Ado antagonism 
treat paradoxical ven- 
tilatory response 
(infants) 
Renal inhibit renin release 
A-1 agonism 
Central Nervous 
aid in opiate Ado agonism 
System withdrawal 
Central Nervous 
analgesic A-1 agonism 
System 
Central Nervous 
anticonvulsant A-1 agonism 
System 
Central Nervous 
antidepressant A-1 agonism 
System 
Central Nervous 
antipsychotic Ado agonism 
System 
Central Nervous 
anxiolytic agonism 
System 
Central Nervous 
inhibition of self- 
Ado agonism 
System mutilation behavior 
(Lesch-Nyhan syndrome) 
Central Nervous 
sedative A-2 agonism 
System 
______________________________________ 
In the cardiovascular, pulmonary and renal system targets, designed 
compounds which are identified by receptor binding studies can be 
evaluated in functional in vivo tests which are directly indicative of the 
human physiological response. A good description of the pharmacology and 
functional significance of purine receptors is presented by M. Williams in 
Ann. Rev. Pharmacol. Toxicol., 27, 31 (1987). In a section entitled 
"Therapeutic Targeting of Adenosine Receptor Modulators" it is stated that 
"adenosine agonists may be effective as antihypertensive agents, in the 
treatment of opiate withdrawal, as modulators of immune competence and 
renin release, as antipsychotics and as hypnotics. Conversely, antagonists 
may be useful as central stimulants, inotropics, cardiotonics, antistress 
agents, antiasthmatics, and in the treatment of respiratory disorders." 
The smorgasbord of activities displayed by adenosine receptor agents 
underscores their great potential utility for therapy and the need for 
central agents. 
Adenosine exerts its various biological effects via action on cell-surface 
receptors. These adenosine receptors are of two types, A-1 and A-2. The 
A-1 receptors are operationally defined as those receptors at which 
several .sup.6 C-N substituted adenosine analogs such as 
R-phenylisopropyladenosine (R-PIA) and cycloadenosine (CHA) are more 
potent than 2-chloroadenosine and N-5'-ethylcarboxamidoadenosine (NECA). 
At A-2 receptors the order of potency is instead 
NECA&gt;2-chloroadenosine&gt;R-PIA&gt;CHA. 
As illustrated in the table above, adenosine receptors govern a variety of 
physiological functions. The two major classes of adenosine receptors have 
already been defined. These are the A-1 adenosine receptor, which is 
inhibitory of adenylate cyclase, and the A-2 adenosine receptor, which is 
stimulatory to adenylate cyclase. The A-1 receptor has a higher affinity 
for adenosine and adenosine analogs than the A-2 receptor. The 
physiological effects of adenosine and adenosine analogs are complicated 
by the fact that nonselective adenosine receptor agents first bind the 
rather ubiquitous low-affinity A-2 receptors, then as the dose is 
increased, the high-affinity A-2 receptors are bound, and finally, at much 
higher doses, the very high-affinity A-1 adenosine receptors are bound. 
(See J. W. Daly, et al., Subclasses of Adenosine Receptors in the Central 
Nervous System: Interaction with Caffeine and Related Methylxanthines, 
Cellular and Molecular Neurobiology, 3,(1), 69-80 (1983).) 
In general, the physiological effects of adenosine are mediated by either 
the stimulation or the inhibition of adenylate cyclase. Activation of 
adenylate cyclase increases the intracellular concentration of cyclic AMP, 
which, in general, is recognized as an intracellular second messenger. The 
effects of adenosine analogs can therefore be measured by either the 
ability to increase or the ability to antagonize the increase in the 
cyclic AMP in cultured cell lines. Two important cell lines in this regard 
are VA 13 (WI-38 VA 13 2RA), SV-40 transformed WI 38 human fetal lung 
fibroblasts, which are known to carry the A-2 subtype of adenosine 
receptor, and fat cells, which are known to carry the A-1 subtype of 
adenosine receptor. (See R. F. Bruns, Adenosine Antagonism by Purines, 
Pteridines and Benzopteridines in Human Fibroblasts, Chemical 
Pharmacology, 30, 325-33 (1981).) 
It is well-known from in vitro studies that the carboxylic acid congener of 
8-phenyl-1,3-dipropylxanthine (XCC) is adenosine receptor nonselective, 
with a K.sub.i at the A-1 receptor in rat brain membranes of 58.+-.3 nM 
and a K.sub.i at the A-2 receptor of the rat brain slice assay of 34.+-.13 
nM. The amino congener of 8-phenyl-1,3-dipropylxanthine (XAC), on the 
other hand, has a 40-fold higher affinity for the A-1 adenosine receptor, 
with a K.sub.i of 1.2.+-.0.5 nM, as compared with a K.sub.i at the A-2 
receptor of 49.+-.17 nM. In addition, XAC is much more potent in 
antagonizing the effects of adenosine analogs on heart rate than on blood 
pressure. Since it is generally known that the adenosine analog-induced 
effects on the heart seem to be mediated via A-1 receptors and those on 
blood pressure via A-2 receptors, the selectivity of XAC under in vivo 
conditions suggests that adenosine receptor activity in vitro correlates 
with adenosine receptor activity in vivo and that specific physiological 
effects can be distinguished as a result of this selectivity. (See B. B. 
Fredholm, K. A. Jacobsen, B. Jonzon, K. L. Kirk, Y. O. Li, and J. W. Daly, 
Evidence That a Novel 8-Phenyl-Substituted Xanthine Derivative is a 
Cardioselective Adenosine Receptor Antagonist In Vivo, Journal of 
Cardiovascular Pharmacology, 9, 396-400, (1987), and also K. A. Jacobsen, 
K. L. Kirk, J. W. Daly, B. Jonzon, Y. O. Li, and B. B. Fredholm, Novel 
8-Phenyl-Substituted Xanthine Derivative Is Selective Antagonist At 
Adenosine Receptors In Vivo, Acta Physiol. Scand., 341-42 (1985).) 
It is also known that adenosine produces a marked decrease in blood 
pressure. This blood pressure reduction is probably dependent upon an A-2 
receptor-mediated decrease in peripheral resistance. Adenosine analogs are 
also able to decrease heart rate. This effect is probably mediated via 
adenosine receptors of the A-1 subtype. 
Cardiovascular Studies With (R)-2-[(Phenylisopropyl)Amino]Adenosine in 
Anesthesized and Conscious Dogs 
Intravenous (R)-2-[(phenylisopropyl)amino]adenosine was tested in three 
anesthetized beagles for its effect on blood pressure and heart rate. All 
three beagles received a 1 mL bolus injection (in less than 15 sec.) of 
vehicle, 50% DMSO/50% 0.9% sodium chloride, prior to receiving 
(R)-2-[(phenylisopropyl)amino]adenosine. Two beagles received a single 0.1 
mg/kg bolus injection of (R)-2-[(phenylisopropyl)amino]adenosine. 
(R)-2-[(Phenylisopropyl)amino]adenosine decreased mean arterial pressure 
(MAP) 35 and 49 mmHg and increased heart rate (HR) 16 and 56 bpm. Peak 
response to (R)-2-[(phenylisopropyl)amino]adenosine occurred in less than 
5 minutes. The MAP effect was sustained through the experiments but the 
HR effect waned. The third beagle recieved three 0.1 mg/kg doses of 
(R)-2-[(phenylisopropyl)amino]adenosine. Thirty minutes separated each 
dose. (R)-2-[(Phenylisopropyl)amino]adenosine lowered MAP 65 mmHG (115 
mmHg to 50 mmHg) and increased HR 20 bpm (138 bpm to 158 bpm) after the 
first dose and the peak response occurred in less than 5 minutes. MAP 
remained at this level throughout the remainder of the study and 
subsequent doses had little additional effect on MAP or HR. 
Intravenous (R)-2-[(phenylisopropyl)amino]adenosine was tested in two 
conscious beagles for its effect on blood pressure and heart rate. 
(R)-2-[(Phenylisopropyl)amino]adenosine was dissolved in 1 mL of 50% 
DMSO/50% 0.9% sodium chloride and was administered as a bolus injection 
(in less that 15 sec.). The compound 
(R)-2-[(phenylisopropyl)amino]adenosine decreased MAP in both dogs for 7 
hours (maximum decrease as compared to vehicle was 37 mmHg three hours 
after dosing in one dog and 68 mmHg two hours after dosing in the second). 
HR was increased for up to 9 hours following 
(R)-2-[(phenylisopropyl)amino]adenosine. The maximum increase occurred 4 
hours after dosing and was 60 bpm for both dogs. 
In addition, one instrumented conscious beagle dog was administered a 
single 1.0 mg/kg dose of (R)-2-[(phenylisopropyl)amino]adenosine in a 
gelatin capsule. Blood pressure was decreased for up to 36 hours, 
exceeding 20 mmHG for the first 16 hours. Heart rate was increased 20-40 
bpm for up to 12 hours. 
Thus, it is readily apparent that the pharmacological administration of the 
adenosine receptor selective adenosine analogs disclosed herein will 
result in selective binding to either the A-2 or the A-1 receptor, which 
will, in turn, selectively result in either a decrease in blood pressure 
or a decrease in heart rate, for example, thereby decoupling these 
physiological effects in vivo. The selection of such adenosine receptor 
selective agents can be determined by the methods described in further 
detail below. 
Test For Affinity For Brain Adenosine A-2 Receptors 
The test described below was used to determine the potency of test 
compounds to compete with the ligand [3H]-5'-N-ethyl-carboxamidoadenosine 
(NECA) for the adenosine A-2 receptors prepared from animal brain 
membranes. (See also R. R. Bruns, G. H. Lu, and T. A. Pugsley, 
Characterization of the A-2 Adenosine Receptor Labeled by [3H]NECA in Rat 
Striatal Membranes, Mol. Pharmacol., 29, 331-346 (1986).) Young male rats 
(C-D strain), obtained from Charles River, are killed by decapitation and 
the brains are removed. Membranes for ligand binding are isolated from rat 
brain striatum. The tissue is homogenized in 20 vol ice-cold 50 mM 
Tris-HCl buffer (pH 7.7) using a polytron (setting for 6 to 20 seconds). 
The homogenate is centrifuged at 50,000.times.g for 10 minutes at 
4.degree. C. The pellet is again homogenized in a polytron in 20 vol of 
buffer, and centrifuged as before. The pellet is finally resuspended in 40 
vol of 50 mM Tris-HCl (pH 7.7) per gram of original wet weight of tissue. 
Incubation tubes, in triplicate, receive 100 .mu.l of [3H]NECA (94 nM in 
the assay), 100 .mu.l of 1 .mu.M cyclohexyladenosine (CHA), 100 .mu.l of 
100 mM MgCl.sub.2, 100 .mu.l of 1 IU/ml adenosine deaminase, 100 .mu.l of 
test compounds at various concentrations over the range of 10.sup.-10 M to 
10.sup.-4 M diluted with assay buffer (50 mM Tris-HCl, pH 7.7) and 0.2 
.mu.l of membrane suspension (5 mg wet weight), in a final volume of 1 ml 
of 50 mM Tris-HCl, pH 7.7. Incubations are carried out at 25.degree. C. 
for 60 minutes. Each tube is filtered through GF/B glass fiber filters 
using a vacuum. The filters are rinsed two times with 5 ml of the ice-cold 
buffer. The membranes on the filters are transferred to scintillation 
vials to which 8 ml of Omnifluor with 5% Protosol is added. The filters 
are counted by liquid scintillation spectrometry. 
Specific binding of [3H]NECA is measured as the excess over blanks run in 
the presence of 100 .mu.M 2-chloroadenosine. Total membrane-bound 
radioactivity is about 2.5% of that added to the test tubes. Since this 
condition limits total binding to less than 10% of the radioactivity, the 
concentration of free ligand does not change appreciably during the 
binding assay. Specific binding to membranes is about 50% of the total 
bound. Protein content of the membrane suspension is determined by the 
method of O. H. Lowry, N. J. Rosebrough, A. L. Farr and R. J. Randall, 
Protein Measurements With Folin Phenol Reagent, J. Biol. Chem., 193, 
265-275 (1951). 
Displacement of [3H]NECA binding of 15% or more by a test compound is 
indicative of affinity for the adenosine A-2 site. The molar concentration 
of a compound which causes 50% inhibition of the binding of ligand is the 
IC.sub.50. A value in the range of 100-1000 nM would indicate a highly 
potent compound. 
Test For Affinity For Brain Adenosine A-1 Receptor Binding Sites 
The test described below is used to determine the potency of test compounds 
to compete with the ligand [3H]cycloadenosine for the Adenosine A-1 
receptor prepared from rat brain membranes. Male Sprague-Dawley rats are 
sacrificed by decapitation and the membranes are isolated from whole 
animal brains. (See R. Goodman, M. Cooper, M. Gavish, and S. Synder, 
Guanine Nucleotide and Cation Regulation of the Binding of 
[H]Diethylphenylxanthine to Adenosine A-1 Receptors in Brain Membrane, 
Molecular Pharmacology, 21, 329-335 (1982). 
Membranes are homogenized (using polytron setting 7 for 10 seconds) in 25 
volumes of ice-cold 50 mM Tris-HCl buffer, pH 7.7. The homogenate is 
centrifuged at 19,000 rpm for 10 minutes at 4.degree. C. The pellet is 
washed by resuspending in 25 volumes of buffer with 2 IU of adenosine 
deaminase per ml and incubated 30 minutes at 37.degree. C. The homogenate 
is centrifuged again. The final pellet is resuspended in 25 volumes of 
ice-cold buffer. 
The incubation tubes, in triplicate, receive 100 .mu.l of 
[3H]cyclohexyladenosine, 0.8 nM in the assay, 200 .mu.l of test compounds 
at various concentrations over the range of 10.sup.-10 M to 10.sup.-6 M 
diluted with 50 nM Tris-HCl buffer (pH 7.7), 0.2 ml of membrane suspension 
(8 mg wet weight) and in a final volume of 2 ml with Tris buffer. 
Incubations are carried out at 25.degree. C. for 2 hours and each one is 
terminated within 10 seconds by filtration through a GF/B glass fiber 
filter using a vacuum. The membranes on the filters are transferred to 
scintillation vials. The filters are counted by liquid scintillation 
spectrometry in 8 ml of Omniflour containing 5% Protosol. 
Specific binding of [3H]cycloadenosine is measured as the excess over 
blanks taken in the presence of 10.sup.-5 M 2-chloroadenosine. Total 
membrane-bound radioactivity is about 5% of that added to the test tubes. 
Specific binding to membranes is about 90% of the total bound. Protein 
content of the membrane suspension is determined by the method of Lowry, 
et al., Ibid, 265. 
Displacement of [3H]cyclohexyladenosine binding of 15% or more by a test 
compound is indicative of affinity for the adenosine binding site. 
Adenosine Receptor Binding Affinity Values Obtained Using The Above 
Described Test Procedures 
The following is a table showing the adenosine receptor binding affinities 
for several compounds (refer to compound examples on page 5 for cross 
reference to compound names) within the scope of the present invention: 
______________________________________ 
A-1 A-2 
Compound Receptor K.sub.i 
Receptor K.sub.i 
A-1 K.sub.i /A-2 K.sub.i 
______________________________________ 
1. 8.4 .times. 10.sup.-6 
3.5 .times. 10.sup.-9 
2400 
2. 5.8 .times. 10.sup.-6 
158 .times. 10.sup.-9 
37 
______________________________________ 
The nucleotide guanosine triphosphate (GTP) has been shown to 
differentially affect the binding of agonists and antagonists to a variety 
of neurotransmitter receptors. In general, guanine nucleotides lower the 
affinity of agonists for receptors without a concomitant decrease in 
antagonist affinity. Accordingly, GTP has been shown to decrease the 
potency of agonists but not antagonists as inhibitors of the binding of 
the adenosine antagonist [3H]3-diethyl-8-phenylxanthine. In general, GTP 
greatly reduces the potency of purine agonists, but not antagonists as 
inhibitors of [3H]phenylisopropyl adenosine binding and is, therefore, an 
effective agent for distinguishing between agonists and antagonists. (See 
L. P. Davies, S. C. Chow, J. H. Skerritt, D. J. Brown and G. A. R. 
Johnston, Pyrazolo [3,4-d]Pyrimidines as Adenosine Antagonists, Life 
Sciences, 34, 2117-28 (1984). It is understood, in general, that adenosine 
analogs act as agonists if .beta.-D-ribofuranosyl is present in the 
molecule at the R.sub.1 position and as an antagonist if R.sub.1 is 
hydrogen or phenyl. 
Pharmaceutical Preparations of the Adenosine Receptor Selection Adenosine 
Analogs 
The exact amount of the compound or compounds to be employed, i.e., the 
amount of the subject compound or compounds sufficient to provide the 
desired effect, depends on various factors such as the compound employed; 
type of administration; the size, age and species of animal; the route, 
time and frequency of administration; and, the physiological effect 
desired. In particular cases, the amount to be administered can be 
ascertained by conventional range finding techniques. 
The compounds are preferably administered in the form of a composition 
comprising the compound in admixture with a pharmaceutically acceptable 
carrier, i.e., a carrier which is chemically inert to the active compound 
and which has no detrimental side effects or toxicity under the conditions 
of use. Such compositions can contain from about 0.1 .mu.g or less to 500 
mg of the active compound per ml of carrier to about 99% by weight of the 
active compound in combination with a pharmaceutically-acceptable carrier. 
The compositions can be in solid forms, such as tablets, capsules, 
granulations, feed mixes, feed supplements and concentrates, powders, 
granules or the like; as well as liquid forms such as sterile injectable 
suspensions, orally administered suspensions or solutions. The 
pharmaceutically acceptable carriers can include excipients such as 
surface active dispersing agents, suspending agents, tableting binders, 
lubricants, flavors and colorants. Suitable excipients are disclosed, for 
example, in texts such as Remington's Pharmaceutical Manufacturing, 13 
Ed., Mack Publishing Co., Easton, Pa. (1965). 
The following examples present typical syntheses as described by Scheme A. 
These examples are understood to be illustrative only and are not intended 
to limit the scope of the invention in any way. As used in the following 
examples, the following terms have the meanings indicated: 
"[.alpha.].sub.D.sup.20 " refers to the optical rotation of the compound 
at 20.degree. C. using a sodium D light, "g" refers to grams, "mmol" 
refers to millimoles, "ml" refers to milliliters, ".degree. C." refers to 
degrees Celsius, "TLC" refers to thin layer chromatography, "mg" refers to 
milligrams, ".mu.l" refers to microliters, and ".delta." refers to parts 
per million downfield from tetramethlysilane.