Xanthines and their therapeutic use

1,3-Disubstituted-zanthines have therapeutic utility via TNF or phosphodiesterase inhibition.

FIELD OF THE INVENTION 
The present invention relates to novel xanthine compounds and 
pharmaceutically acceptable salts thereof, processes for their production 
and their formulation and use as pharmaceuticals, 
DESCRIPTION OF THE PRIOR ART 
Xanthine compounds such as theophylline (The Merck Index, 11th edition, 
9212), pentoxifylline (The Merck Index, 11th edition 7092) and 
propentofylline (The Merck Index, 11th edition, 7822) have been widely 
used clinically for the treatment of respiratory tract disease or brain 
dysfunction. The chief clinical disadvantages of xanthine compounds are 
severe adverse reactions frequently induced by the administration of these 
compounds. Examples of the adverse reactions are, for example, 
cardio-excitatory activity such as, for example, cardiopalmus or 
tachycardia; central activity such as, for example, convulsion or 
headache; and gastrointestinal activity such as for example, nausea or 
emesis. Therefore, xanthine compounds without these adverse reactions 
would provide significant clinical benefit. 
Related xanthine derivatives have been disclosed as pesticidal and 
pestistatic agents (U.S. Pat. No. 4,883,801). In addition, related 
xanthine derivatives have been disclosed as intermediates but no 
pharmacological activity is disclosed for these compounds (European Patent 
Application No. 0 369 744, International Patent Application WO 92/05176, 
European Patent Application No. 0 389 282 and International Patent 
application WO 94/00452). 
Phosphodiesterases regulate cyclic AMP concentrations, Phosphodiesterase IV 
has been demonstrated to be a principal regulator of cyclic AMP in 
respiratory smooth muscle and inflammatory cells. See Torphy and 
Creslinski, Molecular Pharmacology 37, 206, (1990); Dent et al British 
Journal of Pharmacology, 90 163p (1990)!. Inhibitors of phosphodiesterase 
IV have been implicated as being bronchodilators and asthma-prophylactic 
agents and as agents for inhibiting eosinophil accumulation and the 
function of eosinophils see for example Giembycz and Dent, Clinical and 
Experimental Allergy 22 337 (1992)! and for treating other diseases and 
conditions characterised by, or having an etiology including, morbid 
eosinophil accumulation. Inhibitors of phosphodiesterase IV are also 
implicated in treating inflammatory diseases, proliferative skin disease 
and conditions associated with cerebral metabolic inhibition. 
Excessive or unregulated production of Tumour Necrosis Factor (TNF) has 
been implicated in mediating or exacerbating a number of diseases 
including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, 
gouty arthritis and other arthritic conditions; sepsis, septic shock, 
endotoxic shock, gram negative sepsis, toxic shock syndrome, adult 
respiratory distress syndrome, cerebral malaria, chronic pulmonary 
inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption 
diseases, reperfusion injury, graft vs. host reaction, allograft 
rejections, fever and myalgias due to infection, such as influenza, 
cachexia secondary to infection or malignancy, cachexia secondary to human 
acquired immune deficiency syndrome (AIDS), ARC (AIDS related complex), 
keloid formation, scar tissue formation, Crohn's disease, ulcerative 
colitis, or pyresis, in addition to a number of autoimmune diseases, such 
as multiple sclerosis, autoimmune diabetes and systemic lupus 
erythematosis 
AIDS results from the infection of T lymphocytes with Human 
Immunodeficiency Virus (HIV). At least three types or strains of HIV have 
been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence of HIV 
infection, T-cell mediated immunity is impaired and infected individuals 
manifest severe opportunistic infections and/or unusual neoplasms. HIV 
entry into the T lymphocyte requires T lymphocyte activation. Viruses such 
as HIV-1 or HIV-2 infect T lymphocytes after T cell activation and such 
virus protein expression and/or replication is mediated or maintained by 
such T cell activation. Once an activated T lymphocyte is infected with 
HIV, the T lymphocyte must continue to be maintained in an activated state 
to permit HIV gene expression and/or HIV replication. 
Cytokines, specifically TNF, are implicated in activated T-cell mediated 
HIV protein expression and/or virus replication by playing a role in 
maintaining T lymphocyte activation. Therefore, interference with cytokine 
activity such as by inhibition of cytokine production, notably TNF, in an 
HIV-infected individual aids in limiting the maintenance of T cell 
activation, thereby reducing the progression of HIV infectivity to 
previously uninfected cells which results in a slowing or elimination of 
the progression of immune dysfunction caused by HIV infection. Monocytes, 
macrophages, and related cells, such as Kupffer and glial cells, have also 
been implicated in maintenance of the HIV infection. These cells, like T 
cells, are targets for viral replication and the level of viral 
replication is dependent upon the activation state of the cells, See 
Rosenberg et al, the Immunopathogenesis of HIV Infection, Advances in 
Immunology, Vol. 57, (1989)!. Monokines, such as TNF, have been shown to 
activate HIV replication in monocytes and/or macrophages See Poli et at, 
Proc. Natl. Acad. Sci., 87:782-784, (1990)!, therefore, inhibition of 
production or activity aids in limiting HIV progression as stated above 
for T cells. 
TNF has also been implicated in various roles with other viral infections, 
such as the cytomegalovirus (CMV), influenza virus, adenovirus, and the 
herpes virus for similar reasons as those noted above. 
TNF is also associated with yeast and fungal infections. Specifically 
Cadida albicans has been shown to induce TNF production in vitro in human 
monocytes and natural killer cells See Riipi et al., Infection and 
Immunity, 58(9);2750-54, (1990), and Jafari et al., Journal of Infectious 
Diseases, 164:389-95, (1991). See also Wasan et al., Antimicrobial Agents 
and Chemotherapy, 35, (10):2046-48, (1991); and Luke et al., Journal of 
Infectious Diseases, 162;211-214, (1990)!. 
The ability to control the adverse effects of TNF is furthered by the use 
of the compounds which inhibit TNF in mammals who are in need of such use, 
there remains a need for compounds which are useful in treating 
TNF-mediated disease states which are exacerbated or caused by the 
excessive and/or unregulated production of ANT. 
SUMMARY OF THE INVENTION 
It has been found that novel compounds have ability to treat disease 
states, for example disease states associated with proteins that mediate 
cellular activity, for example by inhibiting tumour necrosis factor and/or 
by inhibiting phosphodiesterase IV, according to the invention, the novel 
compounds are of formula (i): 
##STR1## 
in which Q represents aryl, heteroaryl, cycloalkyl or heterocyclo 
optionally substituted with one or more substituents chosen from amongst 
C.sub.1-6 alkyl (optionally substituted with one or more halogens), 
C.sub.1-6 alkyl-S(O)n--, --CO.sub.2 H (or C.sub.1-6 alkyl esters thereof 
or C.sub.1-6 alkyl amides thereof), halogen, C.sub.1-6 alkoxy, CN, 
NO.sub.2 or NR.sub.7 R.sub.8 ; 
R.sub.1 -R.sub.5, which may be the same or different, each represent 
C.sub.1-6 alkyl (optionally substituted with one or more halogens), 
C.sub.1-6 alkyl-S(O)n--, --CO.sub.2 H (or C.sub.1-6 alkyl esters thereof 
or C.sub.1-6 alkyl amides thereof), halogen, C.sub.1-6 alkoxy, CN, 
NO.sub.2, NR.sub.7 R.sub.8 or H (provided R.sub.1 -R.sub.6 are not all H 
simultaneously); 
R.sub.6 represents H.sub.7 C.sub.1-6 alkyl, --CO.sub.2 H (or C.sub.1-6 
alkyl esters thereof or C.sub.1-6 alkyl amides thereof), --CN, C.sub.1-6 
alkyl optionally substituted by --CO.sub.2 H (or C.sub.1-6 alkyl esters 
thereof or C.sub.1-6 alkyl amides thereof), C.sub.1-6 alkoxy or --CN; 
R.sub.7 and R.sub.8, which may be the same or different, and each represent 
H.sub.7 C.sub.1-6 alkyl, C.sub.1-6 alkylcarbonyl, C.sub.1-6 
alkoxycarbonyl, arylsulphonyl, heteroarylsulphonyl, heterocyclosulphonyl, 
arylcarbonyl, heteroarylcarbonyl, heterocyclocarbonyl or C.sub.1-6 
alkylsulphonyl, or R.sub.7, R.sub.8 and the nitrogen to which they are 
attached form a 5 or 6 membered heterocyclic ring (such as morpholine or 
piperidine); and 
n represents 0-2; 
and pharmaceutically acceptable salts. 
DESCRIPTION OF THE INVENTION 
Preferred compounds of the invention include those in which, independently 
or in any combination: 
Q is aryl or heteroaryl (either may be optionally substituted with halogen, 
C.sub.1-6 alkyl, CF.sub.3, NR.sub.7 R.sub.8, C.sub.1-6 alkyl-S(O)n--, 
C.sub.1-6 alkoxy, --CO.sub.2 H (or C.sub.1-6 alkyl esters thereof or 
C.sub.1-6 alkyl amides thereof)); R.sub.1 -R.sub.5, which may be the same 
or different, are independently CF.sub.3, C.sub.1-6 alkyl, C.sub.1-6 
alkyl-S(O)n--, --CO.sub.2 H (or C.sub.1-6 alkyl esters thereof or 
C.sub.1-6 alkyl amides thereof), halogen, C.sub.1-6 alkoxy, NO.sub.2, 
NR.sub.7 R.sub.8, or H (provided R.sub.1 -R.sub.5 are not all H 
simultaneously); 
R.sub.6 is H. 
R.sub.7 and R.sub.8, which may be the same or different, are H, C.sub.1-6 
alkyl, C.sub.1-6 alkoxycarbonyl, C.sub.1-6 alkylsulphonyl or C.sub.1-6 
alkylcarbonyl; or R.sub.7, R.sub.8 and the nitrogen to which they are 
attached form a 5 or 6 membered heterocyclic ring (such as morpholine or 
piperidine); and 
n is 0,1 or 2. 
Suitable pharmaceutically acceptable salts are pharmaceutically acceptable 
base salts and pharmaceutically acceptable acid addition salts. Certain of 
the compounds of formula (i) which contain an acidic group form base 
salts. Suitable pharmaceutically acceptable base salts include metal 
salts, such as alkali metal salts for example sodium salts, or organic 
amine salts such as that provided with ethylenediamine. 
Certain of the compounds of formula (i) which contain an amino group form 
acid addition salts. Suitable acid addition salts include pharmaceutically 
acceptable inorganic salts such as the sulphate, nitrate, phosphate, 
borate, hydrochloride and hydrobromide and pharmaceutically acceptable 
organic acid addition salts such as acetate, tartrate, maleate, citrate, 
succinate, benzoate, ascorbate, methane-sulphate, .alpha.-ketoglutarate, 
.alpha.-glycrophosphate and glucose-1-phosphate. The pharmaceutically 
acceptable salts of the compounds of formula (i) are prepared using 
conventional procedures. 
It will be appreciated by those skilled in the art that xanthines of 
formula (i) can exist in more than one tautomeric form. This invention 
extends to all tautomeric forms. 
It will be appreciated that the compounds according to the invention can 
contain one or more asymmetrically substituted carbon and/or sulphur 
atoms, The presence of one or more of these asymmetric centers in a 
compound of formula (i) can give rise to stereoisomers, and in each case 
the invention is to be understood to extend to all such stercoisomers, 
including enantiomers, and diastereoisomers and mixtures including racemic 
mixtures thereof. 
When used herein the term alkyl whether used alone or when used as part of 
another group includes straight and branched chain alkyl groups containing 
up to 6 atoms. Cycloalkyl includes a non-aromatic cyclic or multicyclic 
ring system of about 3 to about 10 carbon atoms. Alkoxy means an alkyl-O-- 
group in which the alkyl group is as previously described. Alkyl amide 
includes both monoalkyl and dialkyl amides, in which the alkyl groups 
(previously defined) may be the same or different. Alkylcarbonyl means an 
alkyl-CO-- group in which the alkyl group is as previously described. Aryl 
indicates a monocyclic or multicyclic carbocyclic radical containing about 
6 to 10 carbon atoms. Heteroaryl means about a 5 to about a 10 membered 
aromatic monocyclic or multicyclic hydrocarbon ring system in which one or 
more of the atoms in the ring system is an element other than carbon, 
chosen from amongst nitrogen, oxygen or sulphur. Heterocyclo means about a 
5 to about a 10 membered saturated or partially saturated monocyclic or 
multicyclic hydrocarbon ring system in which one or more of the atoms in 
the ring system is an element other than carbon, chosen from amongst 
nitrogen; oxygen or sulphur. Arylcarbonyl means an aryl-CO-- group. 
Heteroarylcarbonyl means a heteroaryl-CO-- group. Heterocyclocarbonyl 
means a heterocyclo-CO-- group. Arylsulphonyl means an aryl-SO.sub.2 -- 
group. Heteroarylsulphonyl means a heteroaryl-SO.sub.2 -- group, 
Heterocyclosulphonyl means a heterocyclo-SO.sub.2 -- group. Alkylsulphonyl 
means an alkyl-SO.sub.2 -- group. Halogen means fluorine, chlorine, 
bromine or iodine. 
"TNF mediated disease or disease states" means any and all disease states 
in which TNF plays a role, either by production of TNF itself, or by TNF 
causing another cytokine to be released, such as but not limited to IL-1 
or IL-6. A disease state in which IL-1, for instance, is a major 
component, and whose production or action is exacerbated or secreted in 
response to TNF, would therefore be considered a disease state mediated by 
TNF. As TNF-.beta. (also known as lymphotoxin) has close structural 
homology with TNF-.alpha. (also known as cachectin), and since each 
induces similar biologic responses and binds to the same cellular 
receptor, both TNF-.alpha. and TNF-.beta. are inhibited by the compounds 
of the present invention and thus are herein referred to collectively as 
"TNF" unless specifically delineated otherwise. 
This invention relates to a method for mediating or inhibiting the 
enzymatic activity or catalytic activity of PDE IV in a mammal in need 
thereof and for inhibiting the production of TNF in a mammal in need 
thereof, which comprises administering to said mammal an effective amount 
of a compound of Formula (i) or a pharmaceutically acceptable salt 
thereof. 
PDE IV inhibitors are useful in the treatment of a variety of allergic and 
inflammatory diseases, including: asthma, chronic bronchitis, atopic 
dermatitis, atopic eczema, urticaria, allergic rhinitis, allergic 
conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic 
responses in the eye, eosinophilic granuloma, psoriasis, Bechet's disease, 
erythematosis, anaphylactoid purpura nephritis, joint inflammation, 
arthritis, rheumatoid arthritis and other arthritic conditions such as 
rheumatoid spondylitis and osteoarthritis, septic shock, ulcerative 
colitis, Crohn's disease, reperfusion injury of the myocardium and brain, 
chronic glomerulonephritis, endotoxic shock and adult respiratory distress 
syndrome. In addition, PDE IV inhibitors are useful in the treatment of 
diabetes insipidus and conditions associated with cerebral metabolic 
inhibition, such as cerebral senility, senile dementia (Alzheimer's 
disease), memory impairment associated with Parkinson's disease, 
depression and multi-infarct dementia. PDE IV inhibitors are also useful 
in conditions ameliorated by neuroprotectant activity, such as cardiac 
arrest, stroke and intermittent claudication. Additionally, PDF, IV 
inhibitors could have utility as gastroprotectants. A special embodiment 
of the therapeutic methods of the present invention is the treatment of 
asthma. 
The viruses contemplated for treatment herein are those that produce TNF as 
a result of infection, or those which are sensitive to inhibition, such as 
decreased replication, directly or indirectly, by the TNF inhibitors of 
Formula (i). Such viruses include, but are not limited to HIV-1, HIV-2 and 
HIV-3, cytomegalovirus (CMV), influenza, adenovirus and the Herpes group 
of viruses, such as, but not limited to, Herpes zoster and Herpes simplex. 
This invention more specifically relates to a method of treating a mammal, 
afflicted with a human immunodeficiency virus (HIV), which comprises 
administering to such mammal an effective TNF inhibiting amount of a 
compound of Formula (i) or a pharmaceutically acceptable salt thereof. 
The compounds of this invention may be also be used in association with the 
veterinary treatment of animals, other than humans, in need of inhibition 
of TNF production. TNF mediated diseases for treatment, therapeutically or 
prophylactically, in animals include disease states such as those noted 
above, but in particular viral infections. Examples of such viruses 
include, but are not limited to feline immunodeficiency virus (FIV) or 
other retroviral infection such as equine infectious anaemia virus, 
caprine arthritis virus, visna virus, maedi virus and other lentiviruses. 
The compounds of this invention are also useful in treating parasite, yeast 
and fungal infections, where such yeast and fungi are sensitive to 
upregulation by TNF or will elicit TNF production in vivo. A preferred 
disease state for treatment is fungal meningitis. 
The compounds of formula (i) are preferably in pharmaceutically acceptable 
form. By pharmaceutically acceptable form is meant, inter atia, of a 
pharmaceutically acceptable level of purity excluding normal 
pharmaceutical additives such as diluents and carriers, and including no 
material considered toxic at normal dosage levels. A pharmaceutically 
acceptable level of purity will generally be at least 50% excluding normal 
pharmaceutical additives, preferably 75%, more preferably 90% and still 
more preferably 95%. 
The invention further provides a process for the preparation of a compound 
of formula (i), in which R.sub.1 -R.sub.6, are as defined above. It will 
be appreciated that functional groups such as amino, hydroxyl or carboxyl 
groups present in the various compounds described below, and which it is 
desired to retain, may need to be in protected forms before any reaction 
is initiated. In such instances, removal of the protecting group may be 
the final step in a particular reaction. Suitable protecting groups for 
such functionality will be apparent to those skilled in the art. For 
specific details, see Protective Groups in Organic Synthesis, Wiley 
Interscience, T. W. Greene. 
Thus the process required for preparing compounds of formula (i) in which 
R.sub.6 is --CO.sub.2 H comprises of deprotecting (for example by 
hydrolysis) a compound of formula (i) in which R.sub.6 is --CO.sub.2 R 
wherein R represents a suitable protecting group (eg, methyl). 
It will be appreciated that where a particular stereoisomer of formula (i) 
is required, this may be obtained by conventional resolution techniques 
such as high performance liquid chromatography or the synthetic processes 
herein described may by performed using the appropriate homochiral 
starting material. 
A process for the preparation of a compound of formula (i) comprises a 
dehydrating cyclisation of a compound of formula (ii): 
##STR2## 
wherein R.sub.1a represents R.sub.1, as defined in relation to formula 
(i), or a group convertable to R.sub.1a and R.sub.2a -R.sub.6a similarly 
represent R.sub.2 -R.sub.6 or groups convertable to R.sub.2 -R.sub.6, 
respectively; A.sub.1 represents --NO or --NHCHO and A.sub.2 represents 
--NHCH.sub.3 or --NH.sub.2, providing that when A.sub.1 is --NO then 
A.sub.2 is NHCH.sub.3 and when A.sub.1 is NHCHO then A.sub.2 is NH.sub.2; 
and thereafter, if required, converting any group R.sub.1a to R.sub.1 
and/or R.sub.2a to R.sub.2 and/or R.sub.3a to R.sub.3 and/or R.sub.4a to 
R.sub.4 and/or R.sub.5a to R.sub.5 and/or R.sub.6a to R.sub.6. The 
dehydrating cyclisation of a compound of formula (ii) may be carried out 
under any suitable conditions known to those skilled in the art. 
Favourably the conditions chosen are those wherein the water formed is 
removed from the reaction mixture, thus the reaction is generally carried 
out at an elevated temperature in the range 100.degree. C. to 200.degree. 
C., such as in the range 180.degree. C. to 190.degree. C. 
In one aspect of the process, especially when A.sub.1 is --NO and A.sub.2 
is --NHCH.sub.3, the reaction is carried out in a solvent immiscible with 
water, such as toluene, at the reflux temperature of the solvent, the 
water being removed using a water separator. 
A compound of formula (ii) wherein A.sub.1, represents --NHCHO and A.sub.2 
represents --NH.sub.2 may be suitably prepared from a 6-aminouracil of 
formula (iii) according to the following reaction scheme: 
##STR3## 
wherein R.sub.1a -R.sub.6a are as defined in relation to formula (ii). 
Suitably, the reaction conditions used in the above reaction scheme are 
appropriate conventional conditions known to those skilled in the art. In 
a preferred aspect of the process, the conversion of the 6-aminouracil 
(iii), via (iv) and (v), to the corresponding compound of formula (ii) and 
the cyclisation of the compound of formula (ii) to the compound of formula 
(i) are all carried out in situ, suitably by using an analogous procedure 
to that of H. Bredereck and A. Edenhofer, Chem. Berichte 88 1306-1312 
(1955). 
The 6-aminouracils of formula (iii) may themselves be prepared by the 
method of V. Papesch and E. F. Schroder, J. Org. Chem 16 1879-90 (1951), 
or Yozo Ohtsuka, Bull. Chem. Soc. Jap. 46(2) 506-9 (1973) or modifications 
of these methods. 
A compound of formula (ii) wherein A.sub.1, represents --NO and A.sub.2 
represents --NHCH.sub.3 may conveniently be prepared from a 6-chlorouracil 
of formula (vi) according to the following reaction scheme: 
##STR4## 
wherein R.sub.1a -R.sub.6a are as defined in relation to formula (ii). 
Suitably, the reaction conditions used in the above scheme are the 
appropriate conventional conditions, for example those used in the method 
of H. Goldner, G. Dietz and E. Carstens, Liebigs Annalen der Chemie 691 
142-158 (1965). The 6-chlorouracil of formula (vi) may also be prepared 
according to the procedure of Dietz et al. 
Alternatively, compounds of formula (i) may be prepared according to the 
following reaction scheme: 
##STR5## 
wherein R.sub.1a -R.sub.6a are as defined in relation to formula (ii) and 
X is an appropriate leaving group such as bromo. Suitably the reaction 
conditions used in the above reaction scheme are standard conditions known 
to those skilled in the art. 
Another method for the preparation of some compounds of formula (i) (based 
on a method described by C. E. Muller, D. Shi, M. Manning and J. W. Daly 
in J. Med. Chem. 36 3341 (1993)) is shown in the following reaction 
scheme: 
##STR6## 
wherein R.sub.1a -R.sub.6a are as defined in relation to formula (ii) and 
W represents a leaving group such as bromo. It will be appreciated by 
those skilled in the art that this method will not be applicable if any of 
R.sub.1a -R.sub.5a represents fluoro. 
Compounds of formula (i) may also be prepared by interconversion of other 
compounds of formula (i). Thus, for example, a compound of formula (i) in 
which R.sub.1 is NH.sub.2 may be prepared by reduction of a compound of 
formula (i) in which R.sub.1 is --NO.sub.2. 
A compound of formula (i) or where appropriate a pharmaceutically 
acceptable salt thereof and/or a pharmaceutically acceptable solvate 
thereof, may be administered per se or, preferably, as a pharmaceutical 
composition also comprising a pharmaceutically acceptable carrier. 
Accordingly, the present invention provides a pharmaceutical composition 
comprising a compound of formula (i) or where appropriate a 
pharmaceutically acceptable salt thereof and/or a pharmaceutically 
acceptable solvate thereof, and a pharmaceutically acceptable carrier. 
The active compound may be formulated for administration by any suitable 
route, the preferred route depending upon the disorder for which treatment 
is required, and is preferably in unit dosage form or in a form that a 
human patient may administer to himself in a single dosage. 
Advantageously, the composition is suitable for oral, rectal, topical, 
parenteral administration or through the respiratory tract. Pearations may 
be designed to give slow release of the active ingredient. 
The term parenteral as used herein includes subcutaneous injections, 
intravenous, intramuscular, intrasternal injection or infusion techniques. 
In addition to the treatment of warm-blooded animals such as mice, rats, 
horses, cattle, sheep, dogs, cats, etc, the compounds of the invention are 
effective in the treatment of humans. 
The compositions of the invention may be in the form of tablets, capsules, 
sachets, vials, powders, granules, lozenges, suppositories, 
reconstitutable powders, or liquid preparations such as oral or sterile 
parenteral solutions or suspensions. Topical formulations are also 
envisaged where appropriate. 
In order to obtain consistency of administration it is preferred that a 
composition of the invention is in the form of a unit dose. 
Unit dose presentation forms for oral administration may be tablets and 
capsules and may contain conventional excipients such as binding agents, 
for example syrup, acacia, gelatin, sorbitol, tragacanth, or 
polyvinylpyrrolidone; fillers for example microcrystalline cellulose, 
lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; 
tabletting lubricants, for example magnesium stearate; disintegrants, for 
example starch, polyvinylpyrrolidone, sodium search glycollate or 
microcrystalline cellulose; or pharmaceutically acceptable wetting agents 
such as sodium lauryl sulphate. 
The solid oral compositions may be prepared by conventional methods of 
blending, filling, tabletting or the like. Repeated blending operations 
may be used to distribute the active agent throughout those compositions 
employing large quantities of fillers. 
Such operations are of course conventional in the art. The tablets may be 
coated according to methods well known in normal pharmaceutical practice, 
in particular with an enteric coating. 
Oral liquid preparations may be in the form of, for example, emulsions, 
syrups or elixirs, or may be presented as a dry product for reconstitution 
with water or other suitable vehicle before use. Such liquid preparations 
many contain conventional additives such as suspending agents, for example 
sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, 
carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; 
emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; 
non-aqueous vehicles (which may include edible oils), for example almond 
oil, fractionated coconut oil, oily esters such as esters of glycerine, 
propylene glycol, or ethyl alcohol; preservatives, for example methyl or 
propyl p-hydroxybenzoate or sorbic acid; and if desired conventional 
flavouring or colouring agents. 
Compositions may also suitably be presented for administration to the 
respiratory tract as a snuff or an aerosol or solution for a nebuliser, or 
as a microfine powder for insufflation, alone or in combination with an 
inert carrier such as lactose. In such a case the particles of active 
compound suitably have diameters of less than 50 microns, such as from 0.1 
to 50 microns, preferably less than 10 microns, for example from 1 to 10 
microns, 1 to 5 microns or from 2 to 5 microns. Where appropriate, small 
amounts of other anti-asthmatics and bronchodilators for example 
sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, 
phenylephrine and ephedrine; corticosteroids such as prednisolone and 
adrenal stimulants such as ACTH may be included. 
For parenteral administration, fluid unit dosage forms are prepared 
utilizing the compound and a sterile vehicle, and, depending on the 
concentration used, can be either suspended or dissolved in the vehicle. 
In preparing solutions the compound can be dissolved in water for 
injection and filter sterlised before filling into a suitable vial or 
ampoule and sealing. 
Advantageously, adjuvants such as local anaesthetic, a preservative and 
buffering agents can be dissolved in the vehicle. To enhance the 
stability, the composition can be frozen after filling into the vial and 
the water removed under vacuum. Parenteral suspensions are prepared in 
substantially the same manner, except that the compound is suspended in 
the vehicle instead of being dissolved, and sterilisation cannot be 
accomplished by filtration. The compound can be sterilised by exposure to 
ethylene oxide before suspending in the sterile vehicle. Advantageously, a 
surfactant or wetting agent is included in the composition to facilitate 
uniform distribution of the compound. 
The compositions may contain from 0.1% to 99% by weight, preferably from 
10-60% by weight, of the active material, depending on the method of 
administration. 
Compounds of formula (i), or if appropriate a pharmaceutically acceptable 
salt thereof and/or a pharmaceutically acceptable solvate thereof, may 
also be administered as a topical formulation in combination with 
conventional topical excipients. 
Topical formulations may be presented as, for instance, ointments, creams 
or lotions, impregnated dressings, gels, gel sticks, spray and aerosols, 
and may contain appropriate conventional additives such as preservatives, 
solvents to assist drug penetration and emollients in ointments and 
creams. The formulations may contain compatible conventional carriers, 
such as cream or ointment bases and ethanol or oleyl alcohol for lotions. 
Suitable cream, lotion, gel, stick, ointment, spray or aerosol formulations 
that may be used for compounds of formula (i) or if appropriate a 
pharmaceutically acceptable salt thereof, are conventional formulations 
well known in the art, for example, as described in standard text books 
such as Harry's Cosmeticology published by Leonard Hill Books, Remington's 
Pharmaceutical Sciences, and the British and US Pharmacopoeias. 
Suitably, the compound of formula (i), or if appropriate a pharmaceutically 
acceptable salt thereof, will comprise from about 0.5 to 20% by weight of 
the formulation, favourably from about 1 to 10%, for example 2 to 5%. 
The dose of the compound used in the treatment of the invention will vary 
in the usual way with the seriousness of the disorders, the weight of the 
sufferer, and the relative efficacy of the compound. However, as a general 
guide suitable unit doses may be 0.1 to 1000 mg, such as 0.5 to 200, 0.5 
to 100 or 0.5 to 10 mg, for example 0.5, 1, 2, 3, 4 or 5 mg; and such unit 
doses may be administered more than once a day, for example 2, 3, 4, 5 or 
6 times a day, but preferably 1 or 2 times per day, so that the total 
daily dosage for a 70 kg adult is in the range of about 0.1to 1000 mg, 
that is in the range of about 0.001 to 20 mg/kg/day, such as 0.007 to 3, 
0.007 to 1.4, 0.007 to 0.14 or 0.01 to 0.5 mg/kg/day, for example 0.01, 
.0.02, 0.04, 0.05, 0.06, 0.08, 0.1 or 0.2 mg/kg/day, and such therapy may 
extend for a number of weeks or months. 
When used herein the term "pharmaceutically acceptable" encompasses 
materials suitable for both human and veterinary use. 
The following illustrates the invention. 
Intermediate 1 
2-(METHYLTHIO)PHENYLISOCYANATE 
2-Methylmercaptoaniline (69.5 g) was dissolved in ethanol and treated at 
0.degree. C. portionwise with concentrated hydrochloric acid (75 ml). The 
resulting solid was obtained by filtration, washed with isopropanol and 
dried in vacuo. 
This solid was finely ground, suspended in dry dioxane (500 ml) and treated 
with trichloromethylchloroformate (27 ml) and the mixture refluxed for 18 
hours under nitrogen. The solvent was carefully removed in vacuo and the 
product obtained by distillation. Yield=24.14 g. 
bp 116.degree.-118.degree. C. (15 mm Hg) 
Intermediate 2 
2-(METHYLTHIO)BENZYLAMINE 
A solution of 2-(methylthio)benzonitrile (29.8 g) in dry ether (150 ml ) 
was added dropwise to a stirred suspension of lithium aluminium hydride 
(11.6 g) in dry ether (360 ml) under nitrogen. A thick gum formed which 
was dissolved by the addition of dry THF (100 ml). The mixture was stirred 
at room temperature for 2 hours, Water (12 ml) was then carefully added 
followed by a 15% aqueous solution of sodium hydroxide (36 ml) and more 
water (12 ml). The mixture, was filtered, the filtrate washed with water, 
dried and evaporated in vacuo. The residue was distilled in vacuo to give 
a colourless oil. Yield=20.9 g. 
bp 139.degree.-141.degree. C. (15 mm Hg) 
Intermediate 3 
1-BENZYL-3-3-(METHYLTHIO)PHENL!UREA 
Method A 
3-(Methylthio)aniline (22.24 g,) was dissolved in dry toluene (300 ml) and 
to this was added benzyl isocyanate (19.95 g) with stirring. Very soon a 
thick deposit was formed and stirring was no longer possible. The 
resulting mixture was allowed to stand overnight at room temperature and 
hexane (250 ml) then added. The product was filtered off and washed with 
1:1 toluene/hexane, Yield=38.89 g. 
mp 127.degree.-129.degree. C. 
Intermediate 4 
1-BENZYL-3-(3-CHLOROPHENYL)UREA 
Method B 
3-Chlorophenylisocyanate (30.7 g) was dissolved in dry toluene (400 ml) and 
benzylamine (23.54 g) added in one portion with stirring. The mixture was 
stirred for 30 min at room temperature and the product then filtered off 
and washed with toluene then hexane. Yield=47.53 g. 
mp 172.degree.-174.degree. C. 
Intermediate 5 
1-BENZYL-3-(4-CHLOROPHENYL)UREA 
Method C 
Benzylamine (26.75 g) was dissolved in dry toluene (800ml) and to this was 
added 4-chlorophenyl isocyanate (38.38 g) with stirring. After the 
exotherm had subsided the mixture was heated to boiling and then allowed 
to stand overnight at room temperature. The product was filtered off and 
washed with toluene. Yield=64 g. 
mp 202.degree.-204.degree. C. 
Intermediate 6 
1-BENZYL-3-3-(METHOXYCARBONYL)PHENYL!UREA 
Method A 
mp 148.degree.-151.degree. C. 
Intermediate 7 
1-BENZYL-3-(4-METHOXYPHENYL)UREA 
Method B 
mp 164.degree.-167.degree. 
Intermediate 8 
1-BENZYL-3-(4-FLUOROPHENYL)UREA 
Method B 
mp 181.degree.-183.degree. C. 
Intermediate 9 
1-BENZYL-3-(3-FLUOROPHENYL)UREA 
Method B 
mp 158.degree.-160.degree. C. 
Intermediate 10 
1-BENZYL-3-4-(METHYLTHIO)PHENYL!UREA 
Method A 
mp 173.degree.-176.degree. C. 
Intermediate 11 
1-BENZYL-3-(3-METHOXYPHENYL)UREA 
Method A 
mp 159.degree.-161.degree. C. 
Intermediate 12 
1-BENZYL-3-(3-BROMOPHENYL)UREA 
Method A 
mp 173.degree.-175.degree. C. 
Intermediate 13 
1-BENZYL-3-(3-NITROPHENYL)UREA 
Method A 
mp 193.degree.-195.degree. C. 
Intermediate 14 
1-(THEN-2-YL)-3-(2-METHYLPHENYL)UREA 
Method B 
mp 188.degree.-190.degree. C. 
Intermediate 15 
1-FURFURYL-3-(2-METHYLPHENYL)UREA 
Method B 
mp 117.degree.-119.degree. C. 
Intermediate 16 
1-(2-FLUOROBENZYL)-3-(4-CHLOROPHENYL)UREA 
Method B 
mp 195.degree.-198.degree. C. 
Intermediate 17 
1-2-(TRIFLUOROMETHYL)BENZYL!-3-(2-METHYLPHENYL)UREA 
Method A 
mp 190.degree.-192.degree. C. 
Intermediate 16 
1-BENZYL-3-(2-METHYLPHENYL)UREA 
Method A 
mp 189.degree.-190.degree. C. 
Intermediate 18 
1-(2-FLUOROBENZYL)-3-(2-FLUOROPHENYL)UREA 
Method B 
mp 160.degree.-163.degree. C. 
Intermediate 19 
1-(2-FLUOROBENZYL)3-2-(METHYLTHIO)PHENYL!UREA 
Method B 
mp 135.degree.-137.degree. C. 
Intermediate 20 
1-(2-FLUOROBENZYL)-3-2-(TRIFLUOROMETHYL)PHENYL!UREA 
Method A 
mp 178.degree.-181.degree. C. 
Intermediate 21 
1-(2-FLUOROBENZYL)-3-(2-NITROPHENYL)UREA 
Method A 
mp 169.degree.-172.degree. C. 
Intermediate 22 
1-(2-METHYLPHENYL)-3-2-(MEHYLTHIO)BENZYL!UREA 
Method A 
mp 214.degree.-216.degree. C. 
Intermediate 23 
1-BENZYL-3-(3-CHLOROPHENYL)-1-(CYANOACETYL)UREA 
A mixture of 1-benzyl-3-(3-chlorophenyl)urea (44.78 g) and cyanoacetic acid 
(16.11 g) was ground together and then acetic anhydride (48 ml) added. The 
resulting mixture was heated and stirred at 75.degree.-80.degree. C. for 
16 h. It was then allowed to cool, diluted with ether and the product 
filtered off and washed with ether. This was then recrystallised from 
toluene with a hot filtration. Yield=20.15 g. 
mp 122.degree.-123.degree. C. 
The following intermediates were prepared using the above procedure. 
Intermediate 24 
1-BENZYL-1-(CYANOACETYL)-3-3-(MEHOXYCARBONYL)PHENYL!UREA 
The crude material was dissolved in hot toluene and treated with charcoal. 
The charcoal was removed by filtration and the product recrystallised from 
toluene. 
mp 134.degree.-137.degree. C. 
Intermediate 25 
1-BENZYL3-(4-CHLOROPHENYL)-1-(CYANOACETYL)UREA 
mp 100.degree.-104.degree. C. 
Intermediate 26 
1-BENZYL-1-(CYANOACETYL)-3-3-(METHYLTHIO)PHENYL!UREA 
mp 113.degree.-116.degree. C. 
Intermediate 27 
1-BENZYL-1-(CYANOACETYL)-3-(4-METHOXYPHENYL)UREA 
The crude material was dissolved in hot toluene and treated with charcoal. 
The charcoal was removed by filtration and the product recrystallised from 
toluene/hexane. 
mp 114.degree.-117.degree. C. 
Intermediate 28 
1-BENZYL-1-(CYANOACETYL)-3-(3-FLOUROPHENYL)UREA 
mp 97.degree.-99.degree. C. 
Intermediate 29 
1-BENZYL-1-(CYANOACETYL)-3-4-(METHYLTHIO)PHENYL!UREA mp 
128.degree.-130.degree. C. 
Intermediate 30 
1-BENZYL-1-(CYANOACETYL)-3-(3-METHOXYPHENYL)UREA 
The crude material was dissolved in hot toluene and treated with charcoal. 
The charcoal was removed by filtration and the product recrystallised from 
toluene. 
mp 127.degree.-130.degree. C. 
Intermediate 31 
1-BENZYL-3-(3BROMOPHENYL)-1-(CYANOACETYL)UREA 
The crude material was dissolved in hot toluene and treated with charcoal. 
The charcoal was removed by filtration and the product recrystallised from 
toluene/hexane. 
mp 108.degree.-121.degree. C. 
Intermediate 32 
1-(THEN-2-YL)-3-(2-METHYLPHENYL)-1-(CYANOACETYL)UREA 
mp 127.degree.-130.degree. C. 
Intermediate 33 
1-FURFURYL-3-(2-METHYLPHENYL)1CYANOACETYL)UREA 
mp 117.degree.-119.degree. C. 
Intermediate 34 
1-(2-FLUOROBENZYL)-3-(4-CHLOROPHENYL)1-(CYANOACETYL)UREA 
This product was washed with ethanol. 
mp 125.degree.-134.degree. C. 
Intermediate 35 
6-AMINO-3-BENZYL-1-3-(METHYLTHIO)PHENYL!URACIL 
1-Benzyl-1-(cyanoacetyl)-3-3-(methylthio)phenyl!urea (14.9 g) was 
suspended in ethanol (150 ml) and to this was added a solution of sodium 
hydroxide (2.34 g) in water (30 ml). This was stirred for 1 h then allowed 
to stand overnight at room temperature. The mixture was filtered to remove 
a dark impurity and the filtrate carbon treated. This solution was then 
evaporated to remove ethanol then diluted with water. It was extracted 
with ethyl acetate (150 ml) and the extracts washed with water (2.times.75 
ml) then dried and evaporated to give a foam. This was taken up in a 1:1 
mixture of ethyl acetate and toluene (100 ml). After standing for 1 h the 
product had precipitated. It was filtered off and washed with 1:1 
toluene/hexane (50 ml) then dried to constant weight. Yield=9.06 g. 
mp 168.degree.-170.degree. C. 
Intermediate 36 
6-AMINO-3-BENZYL-1-3-(METHOXYCARBONYL)PHENYL!URACIL 
1-Benzyl-1-(cyanoacetyl)-3-3-(methoxycarbonyl)phenyl!urea (3.51 g) was 
dissolved in dichloromethane (50 ml) and triethylamine (1.52 g) added. The 
mixture was stirred for one hour at room temperature and the product 
filtered off and washed with dichloromethane. Yield=3.16 g. 
mp 208.degree.-210.degree. C. 
The following intermediates were prepared using the above procedure. 
Intermediate 37 
6-AMINO-3-BENZYL-1-(4MEMOXYPHENYL)URACIL 
mp 219.degree.-221.degree. C. 
Intermediate 38 
6-AMINO-3-BENZYL-1-(CHLOROPHENYL)URACIL 
mp 246.degree.-248.degree. C. 
Intermediate 39 
6-AMINO-3-(THEN-2-YL)-1-(2-METHYLPHENY)URACIL mp 253.degree.-256.degree. C. 
Intermediate 40 
6-AMINO-3-FURFURYL-1-(2-METHYLPHENYL)URACIL 
mp 241.degree.-244.degree. C. 
Intermediate 41 
6-AMINO-3-(2-FLUOROBENZYL)-1-(4-CHLOROPHENYL)URACIL 
The crude material was dissolved in hot ethanol and treated with charcoal. 
The charcoal was removed by filtration and the product recrystalised from 
ethanol. 
mp 192.degree.-212.degree. C. 
Intermediate 42 
6-AMINO-3-BENZYL-1-(3-FLUOROPHENYL)URACIL 
mp 228.degree.-230.degree. C. 
Intermediate 43 
6-AMINO-3-BENZYL-1-4-(METHOXYTHIO)PHENYL!URACIL 
mp 132.degree.-133.degree. C. 
Intermediate 44 
6-AMINO-3-BENZYL-1-(3-METHOXYPHENYL)URACIL 
The product was recrystallised from ethanol. 
mp 211.degree.-214.degree. C. 
Intermediate 45 
6-AMINO-3-BENZYL-1-(4-FLUOROPYENYL)URACIL 
1-Benzyl-1-(cyanoacetyl)-3-(4-fluorophenyl) urea was prepared from the 
appropriate benzyl urea using the procedure described in the preparation 
of intermediate 22. The oil produced was used in the above procedure 
(Intermediate 36) to yield the title compound. Recrystallised from ethyl 
acetate. 
mp 214.degree.-217.degree. C. 
The following intermediates were prepared using the above procedure. 
Intermediate 46 
1-AMINO-1-(2-METHYLPHENYL)-3-2-(TRIFLUOROMETHYL)BENZYLURACIL 
The resulting residue was subjected to column chromatography on silica 
eluting with ethyl acetate to furnish the title compound. 
mp 209.degree.-218.degree. C. 
Intermediate 47 
6-AMINO-3-BENZYL-1-(2-METHYLPHENYL)URACIL 
The crude material was dissolved in hot ethanol and treated with charcoal. 
The charcoal was removed by filtration and the product recrystallised from 
ethanol. 
mp 194.degree.-197.degree. C. 
Intermediate 48 
6-AMINO-3-(2-FLUOROBENZYL)-1-(2-FLUOROPHENYL)URACIL 
mp 207.degree.-208.degree. C. 
Intermediate 49 
6-AMINO-3-(2-FLUOROBENZYL)-1-2-METHYLTHIO)PHENYL!URACIL 
mp 214.degree.-216.degree. C. 
Intermediate 50 
6-AMINO-3-(2-FLUOROBENZYL)-1-2-TRIFLUOROMETHYLPHENYL!URACIL 
mp 259.degree.-263.degree. C. 
Intermediate 51 
6-AMINO-3-(2-FLUOROBENZYL)-1-(2-NITROPHENYL)URACIL 
mp 250.degree.-255.degree. C. 
Intermediate 52 
6-AMINO-3-BENZYL-1-(3-NITROPHENYL)URACIL 
1-Benzyl-3-(3-nitrophenyl)urea (32.53 g) and cyanoacetic acid (11.24 g) 
were ground together and acetic anhydride (34 ml) was added. The mixture 
was stirred and heated at 75.degree.-80.degree. C. for 30 h. It was then 
evaporated, taken up in boiling toluene and treated with charcoal. The 
charcoal was removed by filtration, The resulting solution was allowed to 
cool and left to stand overnight at room temperature. The resulting solid 
was filtered off and washed with ether. This solid was dissolved in 
dichloromethane (100 ml) and triethylamine (3.57 g) added. 
The filtrate was also treated with triethylamine (8.55 g). These two 
solutions were allowed to stand overnight and the precipitated solids were 
filtered off, washed with dichloromethane and combined to give the title 
compound (11.32 g). 
mp 256.degree.-260.degree. C. 
Intermediate 53 
6-AMINO-1-(2-METHYLPHENYL)-3-2-(METHYLTHIO)BENZYL!URACIL 
1-(2-Methylphenyl)-3-2-(methylthio)benzyl!urea (23.47 g) and cyanoacetic 
acid (7.66 g) were ground together and acetic anhydride (23 ml) was added. 
The mixture was stirred and heated at 75.degree.-80.degree. C. for 30 h. 
Toluene (20 ml) was then added and heating continued for a further 16 
hours. The reaction was cooled and filtered. The filtrate was heated to 
boiling and treated with charcoal. The solid was removed by filtration and 
the filtrate evaporated in vacuo. The resulting oil was dissolved in 
dichloromethane (300 ml) and trietbylamine (8.15 g) added. The mixture was 
stirred for 5 hours at room temperature and the solvent removed in vacuo. 
The residue was purified by column chromatography on silica gel eluting 
with ethyl acetate and the product was recrystallised from ethyl acetate. 
Yield=2.60 g. 
mp 218.degree.-221.degree. C.

EXAMPLE 1 
1-BENZYL-3-(3-METHOXYPHENYL)ZANTHINE 
A mixture of 6-amino-3-benzyl-1-(3-methoxyphenyl)uracil (5.52 g), formic 
acid (3.2 ml) and sodium nitrite (1.45 g) in formamide (130ml) was 
gradually heated up to 100.degree. C. with stirring. Sodium dithionite 
(4.83 g) was then added in portions over a period of 10 min, the 
temperature being held at 100.degree. C. The temperature was then raised 
to 190.degree. C. and the mixture stirred at this temperature for 30 min. 
It was allowed to cool then extracted into chloroform. The chloroform 
solution was extracted into 2M sodium hydroxide solution and this washed 
with ether. The aqueous layer was acidified with concentrated hydrochloric 
acid to give a solid which was filtered off and washed with water. 
Recrystallisation from ethanol provided the title compound (1.55 g), 
TLC R.sub.f 0.33 (5% methanol/dichloromethane) 
mp 205.degree.-208.degree. C. 
This general procedure was used for all the following xanthines, 
EXAMPLE 2 
1-BENZYL-3-3-CHLOROPHENYL)XANTHINE 
6-Amino-3-benzyl-1-(3-chlorophenyl) uracil was prepared using the procedure 
described for intermediate 36. The foam produced was used in the procedure 
of example 1 to yield the title product. 
TLC R.sub.f 0.33 (5% methanol/dichloromethane) 
mp 245.degree.-248.degree. C. 
EXAMPLE 3 
1-BENZYL-3-(3-FLUOROCHENYL)XANTHINE 
Recrystallised from ethanol. 
TLC R.sub.f 0.51 (5% methanol/dichloromethane) 
mp 203.degree.-204.degree. C. 
EXAMPLE 4 
1-BENZYL-3-3-(METHYLTHIO)PHENYL!XANTHINE 
Recrystallised from ethanol. 
TLC R.sub.f 0.44 (5% methanol/dichloromethane) 
mp 191.degree.-193.degree. C. 
EXAMPLE 5 
1-BENZYL-3-(4-(METHOXYPHENYL)XANTHINE 
Recrystallised from ethanol. 
TLC R.sub.f 0.30 (5% methanol/dichlorometbane) 
mp 242.degree.-244.degree. C. 
EXAMPLE 6 
1-BENZYL-3-(4-FLUOROPHENYL)XANTHINE 
Recrystallised from ethanol. 
TLC R.sub.f 0.30 (5% methanol/dichloromethane) 
mp 252.degree.-255.degree. C. 
EXAMPLE 7 
1-BENZYL-3-4-(METHYLTHIO)PHENYL!XANTHNE 
Recrystallised from ethanol/DMF, 
TLC R.sub.f 0.44 (5% methanol/dichloromethane) 
mp 260.degree.-264.degree. C. 
EXAMPLE 8 
1-BENZYL-3-(3-BROMOPHENYL)XANTHNE 
6-Amino-1-(3-bromophenyl)-3-benzyluracil was prepared using the procedure 
described in the preparation of Intermediate 36. The foam produced was 
used in the procedure of example 1 to yield the title compound. 
Recrystallised from ethanol. 
TLC R.sub.f 0.49 (5% methanol/dichloromethane) 
mp 253.degree.-256.degree. C. 
EXAMPLE 9 
1-BENZYL-3-(3-NITROPHENYL)XANTHINE 
Recrystallised from acetonitrile. 
TLC R.sub.f 0.42 (5% methanol/dichloromethane) 
mp 227.degree.-229.degree. C. 
EXAMPLE 10 
1-(THEN-2-YL)-3-(2-METHYLPHENYL)XANTHINE 
Recrystallised from ethanol. 
TLC R.sub.f 0.35 (ethyl acetate) 
mp 258.degree.-262.degree. C. 
EXAMPLE 11 
1-(2-FLUOROBENZYL)-3-(4CHLOROPHENYL)XANTHINE 
Recrystallised from acetonitrile/DMF, 
TLC R.sub.f 0.41 (ethyl acetate) 
mp 329.degree.-331.degree. C. 
EXAMPLE 12 
1-BENZYL-3-(2-METHYLHPHENYL)XANTHINE 
Recrystallised from ethanol. 
TLC R.sub.f 0.33 (ethyl acetate) 
mp 266.degree.-269.degree. C. 
EXAMPLE 13 
1-(2-FLUOROBENZYL)-3-(2-FLUOROPHENYL)XANTHINE 
Recrystallised from ethanol. 
TLC R.sub.f 0.35 (ethyl acetate) 
mp 253.degree.-256.degree. C. 
EXAMPLE 14 
1-BENZYL-3-(4-CHLOROPHENYL)XANTHINE 
Recrystallised from acetonitrile/DMF. 
TLC R.sub.f 0.41 (ethyl acetate) 
mp 310.degree.-313.degree. C. 
EXAMPLE 15 
1-2-(TRIFLUORPOROMETHYL)BENZYL!-3-(2-METHYLPHENYL)XANTHINE 
Recrystallised from ethanol. 
TLC R.sub.f 0.36 (ethyl acetate) 
mp 282.degree.-285.degree. C. 
EXAMPLE 16 
1-(2-FLUOROBENZYL)-3-2-(METHYLTHIO)PHENYL!XANTHINE 
Recrystallised from acetonitrile. 
TLC R.sub.f 0.31 (ethyl acetate) 
mp 274.degree.-279.degree. C. 
EXAMPLE 17 
1-(2-FLUOROBENZYL)-3-2-(TRIFLUOROMEHTYL)PHENYl!XANTHINE 
Recrystallised from ethanol. 
TLC R.sub.f 0.31 (ethyl acetate) 
mp 273.degree.-277.degree. C. 
EXAMPLE 18 
1-(2-FLUOROBENZYL)-3-(2-NITROPHENYL)XANTHINE 
TLC R.sub.f 0.31 (ethyl acetate) 
mp 210.degree.-255.degree. C. 
EXAMPLE 19 
1-(2-FLUOROBENZYL)-3-2-TRIFLUOROMEHTYL)PHENYL!XANTHINE 
Recrystallised from ethanol. 
TLC R.sub.f 0.34 (ethyl acetate) 
mp 220.degree.-233.degree. C. 
The following two compounds were prepared using the general procedure with 
a modified work up as follows: 
EXAMPLE 20 
1-BENZYL-3-3-(METHOXYCARBONYL)PHENYL!XANTHINE 
On cooling, the reaction mixture was extracted with chloroform. The 
extracts were washed with water, dried then evaporated. The resulting 
residue was subjected to column chromatography on silica eluting with 
ethyl acetate to yield the titled compound. 
TLC R.sub.f 0.33 (5% methanol/dichloromethane) 
mp 230.degree.-232.degree. C. 
EXAMPLE 21 
1-FURFURYL-3-(2-METHYLPHNEYL)XANTHINE 
Recrystallised from ethanol. 
TLC R.sub.f 0.35 (ethyl acetate) 
mp 257.degree.-260.degree. C. 
EXAMPLE 22 
3-(3-AMINOPHENYL)-1-BENZYLXANTHINE 
1-Benzyl-3-(3-nitrophenyl)xanthine (1 g) was added to a solution of 
stannous chloride dihydrate (2.51 g) in concentrated hydrochloric acid (5 
ml) and the mixture heated to 60.degree.-70.degree. C. with stirring and 
held at this temperature for 20 min. The reaction mixture was allowed to 
cool and 40% sodium hydroxide (11 ml) added. The mixture was cooled and 
the solid filtered off and washed with water (10 ml). It was taken up in 
2M sodium hydroxide (10 ml), treated with charcoal, filtered, and the 
filtrate acidified with glacial acetic acid. The product was filtered off 
and washed with water, Yield 0.44 g. 
TLC R.sub.f 0.24 (5% methanol/dichloromethane) 
mp 320.degree.-323.degree. C. 
EXAMPLE 23 
3-(2-AMINOPHENYL)-1-(2-FLUOROBENZYL)XANTHINE 
The title compound was prepared using the above procedure. 
Recrystallised from acetonitrile. 
TLC R.sub.f 0.23 (ethyl acetate) 
mp 316.degree.-319.degree. C. (d) 
EXAMPLE 24 
3-(3-ACETAMIDOPHENYL)-1-BENZYLXANTHINE 
3-(3-Aminophenyl)-1-benzyl xanthine (0.68 g) was suspended in glacial 
acetic acid (30 ml). To this was added acetic anhydride (0.25 g) and the 
mixture was stirred at reflux for 1 h. Water (30 ml) was then added and 
the product filtered off then washed with water (30 ml). Yield 0.55 g, 
TLC R.sub.f 0.19 (5% methanol/dichloromethane) 
mp&gt;300.degree. C. 
EXAMPLE 25 
1-(2-FLUOROBENZYL)-3-2-METHYLSULPHONYL)PHENYL!XANTHINE 
A solution of 1-(2-fluorobenzyl)-3-2-(methylthio)phenyl!xanthine (2.8 g) 
in chloroform (600 ml) and methanol (15 ml) was stirred and maintained 
below 10.degree. C. during the addition of 3-chloroperbenzoic acid (3.45 g 
of 80% material). The mixture was stirred for 4 hours at room temperature 
and then more 3-chloroperbenzoic acid (0.7 g of 80% material) added. The 
reaction was stirred overnight and then treated with sodium bicarbonate 
(2.1 g) in water (100 ml). The mixture was stirred for one hour, filtered 
and the filtrate evaporated in vacuo. The residue was slurried with water, 
filtered and the solid washed with water. Recrystallised from ethanol/DMF. 
Yield=1.44 g. 
TLC R.sub.f 0.19 (ethyl acetate) 
mp 264.degree.-270.degree. C. 
EXAMPLE 26 
1-(2-FLUOROBENZYL)-3-2-(METHYLSULPHINYL)PHENYL!XANTHINE 
A solution of 1-(2-fluorobenzyl)-3-2-(methylthio)phenyl!xanthine (1.15 g) 
in chloroform (200 ml) and methanol (5 ml) was stirred and maintained at 
0.degree.-2.degree. C. during the addition of 3-chloroperbenzoic acid 
(0.65 g of 80% material). The mixture was stirred for 4 hours at 0.degree. 
C. and then more 3-chloroperbenzoic acid (0.06 g of 80% material) added. 
The reaction was stirred for one hour at 0.degree. C. and then overnight 
at room temperature. The mixture was treated with calcium hydroxide (0.3 
g). The mixture was stirred for one hour, filtered and the filtrate 
evaporated in vacuo. The residue was dissolved in dichloromethane, washed 
with saturated aqueous sodium bicarbonate and then extracted into 1M 
aqueous sodium hydroxide solution (2.times.100 ml). The extracts were 
washed with dichloromethane and the aqueous layer acidified with 
concentrated hydrochloric acid to give an oil. The oil was extracted with 
dichloromethane, dried, filtered and the filtrate evaporated to give a 
solid. The solid was triturated with ether and obtained by filtration. 
Yield=0.53 g. 
TLC R.sub.f 0.05 (ethyl acetate) 
mp 230.degree.-233.degree. C. (dec.) 
EXAMPLE 27 
1-(2-FLUOROBENZYL)-3-(2-METHYLPHENYL)XANTHINE 
ortho-Tolylisocyanate (4.95 ml) was added to a solution of 
2-fluorobenzylamine (4.56 ml) in toluene (50 ml) under an atmosphere of 
nitrogen at 5.degree. C. to produce rapid formation of a white solid. 
Heptane was added, the solid broken up and filtered off to afford 
1-(2-fluorobenzyl)-3-(2-methylphenyl)urea (9.5 g) as a white solid. The 
urea (8 g) and cyanoacetic acid (2.9 g) were ground together and heated in 
acetic anhydride (15 ml) to 80.degree. C. After cooling the reaction 
mixture to room temperature, diethyl ether was added and washed with 
water. The separated ether phase was dried over magnesium sulphate, 
filtered and evaporated in vacuo to give a crude solid residue (8.9 g). 
This residue was redissolved in dichloromethane (120 ml), triethylamine 
(5.7 ml) added and the mixture stirred at room temperature for 3 days. 
Filtration of the precipitate yielded the desired uracil as a white solid 
(2.6 g). 
The title compound was prepared from this uracil following the general 
procedure with a modified work up. After the reaction mixture was allowed 
to cool to room temperature it was extracted into dichloromethane. 
Attempted extraction into aqueous sodium bicarbonate solution failed to 
provide any product. However the product precipitated out of the 
dichloromethane solution and was collected by filtration to afford a white 
solid (273 mg). 
mp 276.degree.-277.degree. C. 
TLC R.sub.f 0.11 (50% ethyl acetate in hexane) 
Assay methods 
The methods used to confirm the phosphodiesterase IV inhibitory activity of 
compounds of formula (i) are standard assay procedures as disclosed by 
Schilling et al Anal. Biochem. 216 154 (1994), Thompson and Strada Adv. 
Cycl. Nucl. Res. 8 119 (1979) and Gristwood and Owen Br, J. Pharmacol. 87 
91P (1986). 
Compounds of formula (i) have exhibited activity at levels consistent with 
those believed to be useful in treating phosphodiesterase IV related 
disuse states in those assays.