Purine compounds having PDE IV inhibitory activity and methods of synthesis

The present invention comprises a method of synthesizing compounds having the formula (I): ##STR1## wherein: Z, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.8 are defined herein, which comprises the steps of PA1 (a) reacting a compound of the formula (II) ##STR2## wherein Q is a halogen, with an effective amount of a compound selected from the group consisting of an acid anhydride or an acid halide; to form a compound of the formula (III) ##STR3## b) transforming the 6-halo group of said compound (III) to an amine by displacement with ammonia to form compound (IV) ##STR4## (c) reacting said compound (IV) with a base to cause cyclization to a 6-halo intermediate, said 6-halo group is then transformed to an amine by displacement with an amine to form compound (V) ##STR5## (d) reacting said compound (V) with an effective amount of compound (VI) ##STR6## wherein X is a halogen; to form the compound of formula (I).

BACKGROUND OF THE INVENTION 
Asthma is a complex disease involving the concerted actions of multiple 
inflammatory and immune cells, spasmogens, inflammatory mediators, 
cytokines and growth factors. In recent practice there have been four 
major classes of compounds used in the treatment of asthma, namely 
bronchodilators (e.g., .beta.-adrenoceptor agonists), anti-inflammatory 
agents (e.g., corticosteroids), prophylactic anti-allergic agents (e.g., 
cromolyn sodium) and xanthines (e.g., theophylline) which appear to 
possess both bronchodilating and anti-inflammatory activity. 
Theophylline has been a preferred drug of first choice in the treatment of 
asthma. Although it has been touted for its direct bronchodilatory action, 
theophylline's therapeutic value is now believed to also stem from 
anti-inflammatory activity. Its mechanism of action remains unclear. 
However, it is believed that several of its cellular activities are 
important in its activity as an anti-asthmatic, including cyclic 
nucleotide phosphodiesterase inhibition, adenosine receptor antagonism, 
stimulation of catecholamine release, and its ability to increase the 
number and activity of suppressor T-lymphocytes. While all of these may 
actually contribute to its activity, only PDE inhibition may account for 
both the anti-inflammatory and bronchodilatory components. However, 
theophylline is known to have a narrow therapeutic index and a wide range 
of untoward side effects which are considered problematic. 
Of the activities mentioned above, theophylline's activity in inhibiting 
cyclic nucleotide phosphodiesterase has received considerable attention 
recently. Cyclic nucleotide phosphodiesterases (PDEs) have received 
considerable attention as molecular targets for anti-asthmatic agents. 
Cyclic 3',5'-adenosine monophosphate (cAMP) and cyclic 3',5'-guanosine 
monophosphate (cGMP) are known second messengers that mediate the 
functional responses of cells to a multitude of hormones, 
neurotransmitters and autocoids. At least two therapeutically important 
effects could result from phosphodiesterase inhibition, and the consequent 
rise in intracellular adenosine 3',5'-monophosphate (cAMP) or guanosine 
3',5'-monophosphate (cGMP) in key cells in the pathophysiology of asthma. 
These are smooth muscle relaxation (resulting in bronchodilation) and 
anti-inflammatory activity. 
It has become known that there are multiple, distinct PDE isoenzymes which 
differ in their cellular distribution A variety of inhibitors possessing a 
marked degree of selectivity for one isoenzyme or the other have been 
synthesized. 
The structure-activity relationships (SAR) of isozyme-selective inhibitors 
has been discussed in detail, e.g., in the article of Theodore J. Torphy, 
et al., "Novel Phosphodiesterase Inhibitors For The Therapy Of Asthma", 
Drug News & Prospectives, 6(4) May 1993, pages 203-214. The PDE enzymes 
can be grouped into five families according to their specificity toward 
hydrolysis of cAMP or cGMP, their sensitivity to regulation by calcium, 
calmodulin or cGMP, and their selective inhibition by various compounds. 
PDE I is stimulated by Ca.sup.2+ /calmodulin. PDE II is cGMP-stimulated, 
and is found in the heart and adrenals. PDE III is cGMP-inhibited, and 
inhibition of this enzyme creates positive inotropic activity. PDE IV is 
cAMP specific, and its inhibition causes airway relaxation, 
antiinflammatory and antidepressant activity. PDE V appears to be 
important in regulating cGMP content in vascular smooth muscle, and 
therefore PDE V inhibitors may have cardiovascular activity. 
While there are compounds derived from numerous structure activity 
relationship studies which provide PDE III inhibition, the number of 
structural classes of PDE IV inhibitors is relatively limited. Analogues 
of rolipram, which has the following structural formula (A): 
##STR7## 
and of RO-20-1724, which has the following structural formula (B): 
##STR8## 
have been studied. 
U.S. Pat. No. 4,308,278 discloses compounds of the formula (C) 
##STR9## 
wherein R.sub.1 is (C.sub.3 -C.sub.6) cycloallyl or benzyl; each of 
R.sub.2 and R.sub.3 is hydrogen or (C.sub.1 -C.sub.4) alkyl; R.sub.4 is 
R.sub.2 or alkoxycarbonyl; and R.sub.5 is hydrogen or alkoxycarbonyl. 
Compounds of Formula (D) are disclosed in U.S. Pat. No. 3,636,039. These 
compounds are benzylimidazolidinones which act as hypertensive agents. 
##STR10## 
Substituents R.sub.1 -R.sub.4 in Formula D represent a variety of groups, 
including hydrogen and lower alkyl. 
PCT publication WO 87/06576 discloses antidepressants of Formula E: 
##STR11## 
wherein R.sub.1 is a polycycloalkyl group having from 7 to 11 carbon 
atoms; R.sub.2 is methyl or ethyl; X is O or NH; and Y comprises a mono-or 
bicyclic heterocyclic group with optional substituents. 
Rolipram, which was initially studied because of its activity as an 
anti-depressant, has been shown to selectively inhibit the PDE IV enzyme 
and this compound has since become a standard agent in the classification 
of PDE enzyme subtypes. There appears to be considerable therapeutic 
potential for PDE IV inhibitors. Early work focused on depression as a CNS 
therapeutic endpoint and on inflammation, and has subsequently been 
extended to include related diseases such as dementia, including vascular 
dementia, multi-in-farct dementia and Alzheimer's Disease, and asthma. 
In-vitro, rolipram, RO20-1724 and other PDE IV inhibitors have been shown 
to inhibit (1) mediator synthesis/release in mast cells, basophils, 
monocytes and eosinophils; (2) respiratory burst, chemotaxis and 
degranulation in neutrophils and eosinophils; and (3) mitogen-dependent 
growth and differentiation in lymphocytes (The PDE IV Family Of 
Calcium-Phosphodiesterases Enzymes, John A Lowe, III, et al., Drugs of the 
Future 1992, 17(9):799-807). 
PDE IV is present in all the major inflammatory cells in asthma including 
eosinophils, neutrophils, T-lymphocytes, macrophages and endothelial 
cells. Its inhibition causes down regulation of inflammatory cell 
activation and relaxes smooth muscle cells in the trachea and bronchus. On 
the other hand, inhibition of PDE III, which is present in myocardium, 
causes an increase in both the force and rate of cardiac contractility. 
These are undesirable side effects for an anti-inflammatory agent. 
Theophylline, a non-selective PDE inhibitor, inhibits both PDE III and PDE 
IV, resulting in both desirable anti-asthmatic effects and undesirable 
cardiovascular stimulation. With this well-known distinction between PDE 
isozymes, the opportunity for concomitant anti-inflammation and 
bronchodilation without many of the side effects associated with 
theophylline therapy is apparent. 
The increased incidence of morbidity and mortality due to asthma in many 
Western countries over the last decade has focused the clinical emphasis 
on the inflammatory nature of this disease and the benefit of inhaled 
steroids. Development of an agent that possesses both bronchodilatory and 
antiinflammatory properties would be most advantageous. 
It appears that selective PDE IV inhibitors should be more effective with 
fewer side effects than theophylline. Clinical support has been shown for 
this hypothesis. Furthermore, it would be desirable to provide PDE IV 
inhibitors which are more potent and selective than rolipram and therefore 
have a lower IC.sub.50 so as to reduce the amount of the agent required to 
effect PDE IV inhibition. 
OBJECTS AND SUMMARY OF THE INVENTION 
It is accordingly a primary object of the present invention to provide new 
compounds which are more effective selective PDE IV inhibitors than known 
prior art compounds. 
It is another object of the present invention to provide new compounds 
which act as effective PDE IV inhibitors with lower PDE III inhibition. 
It is another object of the present invention to provide methods for 
treating a patient requiring PDE IV inhibition. 
It is another object of the present invention to provide new compounds for 
treating disease states associated with abnormally high physiological 
levels of inflammatory cytokines, including tumor necrosis factor. 
It is another object of the present invention to provide a method of 
synthesizing the new compounds of this invention. 
It is another object of the present invention to provide a method for 
treating a patient suffering from disease states such as asthma, 
allergies, inflammation, depression, dementia, including vascular 
dementia, multi-in-farct dementia, and Alzheimer's Disease, a disease 
caused by Human Immunodeficiency Virus and disease states associated with 
abnormally high physiological levels of inflammatory cytokines. 
Other objects and advantages of the present invention will become apparent 
from the following detailed description thereof. 
With the above and other objects in view, the present invention comprises 
compounds having the general formula (I): 
##STR12## 
wherein: 
Z is selected from the group consisting of alkylene groups such as 
CH.sub.2, CH.sub.2 CH.sub.2, CH(CH.sub.3); alkenylene groups such as 
CH.dbd.CH; alkynylene groups such as C.tbd.C; and NH, N(C.sub.1 -C.sub.3 
alkyl), O, S, C(O)CH.sub.2 and OCH.sub.2 ; 
R.sup.1 and R.sup.2 are independently selected from the group consisting of 
hydrogen and a C.sub.1 -C.sub.8 straight or branched alkyl or C.sub.3 
-C.sub.8 cycloalkyl; 
R.sup.3 is a C.sub.1 -C.sub.12 straight or branched alkyl; 
R.sup.4 is a C.sub.3 -C.sub.10 cycloalkyl optionally substituted with OH, 
or a C.sub.3 -C.sub.10 cycloalkenyl optionally substituted with OH, and 
R.sup.8 is a C.sub.1 -C.sub.8 straight or branched alkyl or a C.sub.3 
-C.sub.8 cycloalkyl, optionally substituted with OH. 
The present invention is also related to methods of using compounds of 
formula (I) for treating patients who can benefit from a modification of 
PDE IV enzyme activities in their bodies. 
The invention also comprises methods of making compounds of formula (I), 
according to a four step synthetic scheme as generally set forth in Scheme 
1. The stated conditions in Scheme 1 are includes as examples only, and 
are not meant to be limiting in any manner. 
##STR13## 
The invention is also related to a method of treating mammals with the 
above compounds. 
DETAILED DESCRIPTION OF THE INVENTION 
The present invention is directed to compounds having the general formula 
(I): 
##STR14## 
wherein: 
Z is selected from the group consisting of alkylene groups such as 
CH.sub.2, CH.sub.2 CH.sub.2, CH(CH.sub.3), alkenylene groups such as 
CH.dbd.CH; alkynylene groups such as C.tbd.C; and NH, N(C.sub.1 -C.sub.3 
alkyl), O, S, C(O)CH.sub.2 and OCH.sub.2 ; 
R.sup.1 and R.sup.2 are independently selected from the group consisting of 
hydrogen and a C.sub.1 -C.sub.8 straight or branched alkyl or C.sub.3 
-C.sub.8 cycloalkyl; 
R.sup.3 is a C.sub.1 -C.sub.12 straight or branched alkyl; 
R.sup.4 is a C.sub.3 -C.sub.10 cycloalkyl optionally substituted with OH, 
or a C.sub.3 -C.sub.10 cylcoalkenyl optionally substituted with OH; and 
R.sup.8 is a C.sub.1 -C.sub.8 straight or branched alkyl or a C.sub.3 
-C.sub.8 cycloalkyl optionally substituted with OH. 
As used herein, the following terms are intended to have the meaning as 
understood by persons of ordinary skill in the art, and are specifically 
intended to include the meanings set forth below: 
"Alkyl" means a linear or branched aliphatic hydrocarbon group having a 
single radical. Examples of alkyl groups include methyl, propyl, 
isopropyl, butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, 
heptyl, cetyl, and the like. A branched alkyl means that one or more alkyl 
groups such as methyl, ethyl or propyl are attached to a linear alkyl 
chain. 
The term "cycloalkyl" means a non-aromatic mono- or multicyclic ring system 
having a single radical. Exemplary monocyclic cycloalkyl rings include 
cyclopentyl cyclohexyl and cycloheptyl. Exemplary multicylic cycloalkyl 
rings include adamantyl and norbornyl. 
The term "cycloalkenyl" means a non-aromatic monocyclic or multicyclic ring 
system containing a carbon-carbon double bond and having a single radical. 
Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, 
cyclohexenyl or cycloheptenyl. An exemplary multicyclic cycloalkenyl ring 
is norbornenyl. "Alkylene" means a linear or branched aliphatic 
hydrocarbon group having two radicals. Examples of alkylene groups include 
methylene, propylene, isopropylene, butylene, and the like. 
The term "alkenylene" means a linear or branched aliphatic hydrocarbon 
group containing a carbon-carbon double bond, having two radicals. 
The term "alkynylene" means a linear or branched aliphatic hydrocarbon 
group containing a carbon-carbon triple bond and, having two radicals. 
"Alkoxy" means an alkyl-O-group in which the alkyl group is as previously 
described Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, 
i-propoxy, n-butoxy and heptoxy. 
The term "cycloalkoxy" means a cycloalkyl-O-group in which the cycloakyl 
group is as previously described. Exemplary cycloalkoxy groups include 
cyclopentyloxy. 
As used herein, the term "patient" includes both human and other mammals. 
The present invention also includes organic and inorganic salts, hydrates, 
esters, prodrugs and metabolites of the compounds of formula I. 
The compounds of the present invention can be administered to anyone 
requiring PDE IV inhibitor. Administration may be orally, topically, by 
suppository, inhalation or insufflation, or parenterally. 
The present invention also encompasses all pharmaceutically acceptable 
salts of the foregoing compounds. One skilled in the art will recognize 
that acid addition salts of the presently claimed compounds may be 
prepared by reaction of the compounds with the appropriate acid via a 
variety of known methods. Alternatively, alkali and alkaline earth metal 
salts are prepared by reaction of the compounds of the invention with the 
appropriate base via a variety of known methods. For example, the sodium 
salt of the compounds of the invention can be prepared via reacting the 
compound with sodium hydride. 
Various oral dosage forms can be used, including such solid forms as 
tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders 
and liquid forms such as emulsions, solutions and suspensions. The 
compounds of the present invention can be administered alone or can be 
combined with various pharmaceutically acceptable carriers and excipients 
known to those skilled in the art, including but not limited to diluents, 
suspending agents, solubilizers, binders, retardants, disintegrants, 
preservatives, coloring agents, lubricants and the like. 
When the compounds of the present invention are incorporated into oral 
tablets, such tablets can be compressed, tablet triturates, 
enteric-coated, sugar-coated, film-coated, multiply compressed or multiply 
layered. Liquid oral dosage forms include aqueous and nonaqueous 
solutions, emulsions, suspensions, and solutions and/or suspensions 
reconstituted from no-effervescent granules, containing suitable solvents, 
preservatives, emulsifying agents, suspending agents, diluents, 
sweeteners, coloring agents, and flavorings agents. When the compounds of 
the present invention are to be injected parenterally, they may be, e.g., 
in the form of an isotonic sterile solution. Alternatively, when the 
compounds of the present invention are to be inhaled, they may be 
formulated into a dry aerosol or may be formulated into an aqueous or 
partially aqueous solution. 
In addition, when the compounds of the present invention are incorporated 
into oral dosage forms, it is contemplated that such dosage forms may 
provide an immediate release of the compound in the gastrointestinal 
tract, or alternatively may provide a controlled and/or sustained release 
through the gastrointestinal track. A wide variety of controlled and/or 
sustained release formulations are well known to those skilled in the art, 
and are contemplated for use in connection with the formulations of the 
present invention. The controlled and/or sustained release may be provided 
by, e.g., a coating on the oral dosage form or by incorporating the 
compound(s) of the invention into a controlled and/or sustained release 
matrix. 
Specific examples of pharmaceutically acceptable carriers and excipients 
that may be used to formulate oral dosage forms, are described in the 
Handbook of Pharmaceutical Excipients, American Pharmaceutical Association 
(1986), incorporated by reference herein. Techniques and compositions for 
making solid oral dosage forms are described in Pharmaceutical Dosage 
Forms: Tablets (Lieberman, Lachman and Schwartz, editors) 2nd edition, 
published by Marcel Dekker, Inc., incorporated by reference herein. 
Techniques and compositions for making tablets (compressed and molded), 
capsules (hard and soft gelatin) and pills are also described in 
Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 
(1980), incorporated herein by reference. Techniques and composition for 
making liquid oral dosage forms are described in Pharmaceutical Dosage 
Forms: Disperse Systems, (Lieberman, Rieger and Banker, editors) published 
by Marcel Dekker, Inc., incorporated herein by reference. 
When the compounds of the present invention are incorporated for parenteral 
administration by injection (e.g., continuous infusion or bolus 
injection), the formulation for parenteral administration may be in the 
form of suspensions, solutions, emulsions in oily or aqueous vehicles, and 
such formulations may further comprise pharmaceutically necessary 
additives such as stabilizing agents, suspending agents, dispersing 
agents, and the like. The compounds of the invention may also be in the 
form of a powder for reconstitution as an injectable formulation. 
The dose of the compounds of the present invention is dependent upon the 
affliction to be treated, the severity of the symptoms, the route of 
administration, the frequency of the dosage interval, the presence of any 
deleterious side-effects, and the particular compound utilized, among 
other things. 
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
As used herein, the term "Et" refers to any ethyl group, and the term "Bu" 
refers to a butyl group. "Bu" refers to a tertiary butyl group. The term 
"THF" refers to tetrohydrofuran. The term "DMAC" refers to dimethyl 
acetate. The term "Ph" refers to a phenyl group. The terms Z; R.sup.1 ; 
R.sup.2 ; R.sup.3 ; R.sup.4 ; and R.sup.8 refer to the terms as defined in 
this application. 
The synthetic pathway described in Scheme 1 for producing xanthine 
compounds of FIG. I is described as follows: 
In step (a) of the synthetic scheme, a pyrimidine compound (II) wherein Q 
is a halide, preferably chloride, is reacted with an acid e.g. an acid 
chloride such as isobutyrylchloride, or an acid anhydride, to form 
compound (III), as depicted below: 
##STR15## 
The acid reaction preferably occurs from about 50.degree. C. to about 
150.degree. C., although other temperatures ranges can be used if 
necessary. This reaction may occur in the presence of a suitable solvent 
e.g. acetonitrile (CH.sub.3 CN), DMF or a combination thereof. 
Step (b) of the synthetic scheme involves the 6-halo group of compound 
(III) being transformed to the amine by displacement to give compound (IV) 
of the invention, for example as shown below: 
##STR16## 
The displacement reaction occurs in the presence of ammonia, preferably 
aqueous ammonia in an aqueous solvent or an alcoholic solvent e.g. 
n-butanol. This reaction preferably occurs from about 50.degree. C. to 
about 150.degree. C., although other temperatures ranges can be used if 
necessary. 
Step (c) of the synthetic scheme, compound (IV) is first reacted with a 
base e.g. phosphorous oxychloride, sodium or potassium alkoxide or other 
alkali metal salts (e.g. calcium sulfate, sodium chloride, potassium 
sulfate, sodium carbonate, lithium chloride, tripotassium phosphate, 
sodium borate, potassium bromide, potassium fluoride, sodium bicarbonate, 
calcium chloride, magnesium chloride, sodium citrate, sodium acetate, 
calcium lactate, magnesium sulfate and sodium fluoride), or a 
non-nucleophilic alternative such as saspotassium t-butoxide, to cause 
cyclization to the 6-halopurine intermediate. The 6-halo group is then 
transformed to the amine by displacement to give compound (V) of the 
invention, for example as shown below: 
##STR17## 
The displacement reaction occurs in the presence of ammonia or an amine, an 
aqueous solvent or an alcoholic solvent e.g. ethanol. This reaction 
preferably occurrs from about 50.degree. C. to about 100.degree. C., 
although other temperatures ranges can be used if necessary. The 
displacement reaction can optionally occur in a nitrogen atmosphere. 
In step (d) of the reaction, compound (V) is reacted with 
3-cyclopentyloxy-4-methoxybenzylhalide as shown in compound VI, wherein X 
is a halogen, preferably chloride, to yield compound (I) of the invention, 
for example as shown below: 
##STR18## 
Step (d) preferably occurs in the presence of DMF or acetonitrile as 
solvents, although other solvents can be used. This reaction preferably 
occurs at at a temperature range from about 0.degree. C. to about 
200.degree. C., preferably from about 75.degree. C. to 175.degree. C.

EXAMPLE 1 
3-(3-Cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine 
The title compound was prepared by the following synthetic pathway: 
##STR19## 
The pathway occured under the conditions set forth in Table 1 below. The 
pathway can occur under other suitable conditions known in the art and the 
particular conditions disclosed herein are not meant to be limiting. 
______________________________________ 
Step Compound Conditions Yield 
______________________________________ 
(i) (III) i-PrCOCl (2.8 eq),100EC, 5 min 
89% 
(ii) (IV) NH.sub.3 (aq, 3 eq), n-BuOH,100EC, 24 
82% 
(iii) 
(V) POCl.sub.3,100.degree. C. 
75% 
EtNH.sub.2,EtOH 
(iv) (I) DMF, 150.degree. C.,Compound VI 
60% 
______________________________________ 
Step (i) 5-Isobutyrylamido-4,6-dichloropyrimidine 
4,6-dichloro-5-aminopyrimidine (II)(ex Aldrich), (5.65 g, 34.4 mmol) and 
isobutyrylchloride (10 ml, 95.55 mmol) were heated together at reflux 
(internal temperate 100.degree. C., oil bath temperature 130.degree. C.) 
for 10 minutes. The mixture was cooled to room temperature at which point 
crystallisation occurred. The mixture was triturated with ether (50 ml) to 
give the title compound (7.15 g, 89%) as a buff coloured crystalline 
solid, m.p. 161.5.degree.-162.degree. C. tic (SiO.sub.2, DCM:MeOH, 20:1) 
Rf=0.43 detection U.V. 
Step (ii) 4-Amino-6chloro-5-isobutyrylamidopyrimidine 
5-isobutyrylamido- 4,6-dichloropyrimidine (III)(6.0 g, 26 mmol) was 
dissolved in n-butanol (30 ml). Aqueous ammonia (density=0.88 g/ml) (3 ml) 
was added and the mixture heated to 115.degree. C. for 24 h. Tlc 
(SiO.sub.2, DCM:MeOH, 20:1) showed the reaction to be about 60% complete. 
A further 4 ml of aqueous ammonia was added and the mixture heated at 
reflux for 7 h. The cooled mixture was partitioned between ethyl 
acetate:methanol (10:1, 300 ml) and 8% aqueous sodium bicarbonate solution 
(300 ml). The organic phase was separated, dried (MgSO.sub.4) and the 
solvent removed in vacuo to leave a yellow solid. Ethanol (100 ml) was 
added followed by ether (150 ml) and the mixture filtered, and dried 
overnight in-vacuo at 40.degree. C. to give the title compound as a white 
solid (4.47 g, 82%) m.p. 224-225.degree. C. Tlc, (SiO.sub.2, DCM:MeOH, 
20:1) Rf=0.11, detection U.V. 
Step (iii) 6-Ethylamino-8-isopropyl-3H-purine 
4-Amino-6-chloro-5-isobutyrylamidopyrimidine (IV)(4.0 g, 18.7 mmol) and 
phosphorus oxychloride (30 ml) were heated together at 110.degree. C. for 
20 h. The excess phosphorus oxychloride was removed in vacuo, and the 
residue triturated with ether (4H50 ml) and dried to give the intermediate 
chloropurine (6.3 g) m.p. 209.degree.-211.degree. C. The chloropurine was 
dissolved in ethanol (50 ml) and ethylamine (70% solution in water) (20 
ml) was added and the solution heated at 70.degree. C. under a nitrogen 
atmosphere for 24 h. The solvent was removed in vacuo and the residue 
partitioned between 10% aqueous potassium carbonate solution (100 ml) and 
dichloromethane:methanol (10:1, 100 ml). The organic phase was separated 
and the aqueous phase furthere extracted with dichloromethane-methanol 
(10:1, 3H100 ml). The combined organics were dried (MgSO.sub.4) and 
evaporated to dryness in vacuo to leave a pale yellow solid (4.2 g). This 
was recrystallised from toluene (250 ml) to give the title compound (2.88 
g, 75%) as a fluffs white crystalline solid m.p.=183-184.degree. C. Tlc 
(SiO.sub.2,ethyl acetate:methanol 10:1), Rf=0.59 detection U.V. 
Step (iv) 
6-Ethylamino-3-[(3-cyclopentyloxy-4-methoxy)benzyl]-8-isopropyl-3H-purine 
hydrochloride 
6-Ethylamino-8-isopropyl-3H-purine (V)(7.52 g,36.65 mmol) and 
3-cyclopentyloxy4-methoxybenzylchloride (10.59 g,43.98 mmol) were 
dissolved in acetonitrile (30 ml) in a high pressure vessel and the 
resulting mixture heated at 120.degree. C. for 24 h. On cooling to room 
temperature a solid precipitated from the solution. The solvent was 
removed in vacuo, cold water (10 ml) and diethyl ether (100 ml) were added 
to the solid residue, the mixture stirred vigourously and then filtered. 
The filter cake was washed with ice-cold ethyl acetate (50 ml) and the 
solid obtained was oven dried in vacuo at 80.degree. C. to give the title 
compound (9.51 g, 58%) as a slightly off-white solid. The combined 
filtrates and washings were concentrated in-vacuo, then water (5 ml) and 
diethyl ether (100 ml) added, and the mixture treated as before to give 
further title compound (0.718 g, 5%) as awhite solid, m.p.=205-207.degree. 
C. Combined yield (10.23 g, 63%). Tlc, SiO.sub.2 (dichloromethane: 
methanol, 10:1) Rf=0.49, detection U.V., Dragendorff=s reagent. 
While the invention has been illustrated with respect to the production and 
use of particular compounds, it is apparent that variations and 
modifications of the invention can be made without departing from the 
spirit or scope of the invention.