BACKGROUND OF THE INVENTION 
This invention relates to a series of pyrazolo[4,3-d]pyrimidin-7-ones, 
which are potent and selective inhibitors of cyclic guanosine 
3',5'-monophosphate phosphodiesterase (cGMP PDE), having utility in a 
variety of therapeutic areas including the treatment of various 
cardiovascular disorders such as angina, hypertension, heart failure and 
atherosclerosis. 
The compounds of the invention exhibit selectivity for inhibition of cGMP 
PDEs rather than cyclic adenosine 3',5'-monophosphate phosphodiesterases 
(cAMP PDEs) and, as a consequence of this selective PDE inhibition, cGMP 
levels are elevated, which in turn can give rise to beneficial platelet 
anti-aggregatory, anti-vasopastic and vasodilatory activity, as well as 
potentiation of the effects of endothelium-derived relaxing factor (EDRF) 
and nitrovasodilators. Thus the compounds have utility in the treatment of 
a number of disorders, including stable, unstable and variant (Prinzmetal) 
angina, hypertension, congestive heart failure, atherosclerosis, 
conditions of reduced blood vessel patency e.g. post-percutaneous 
transluminal coronary angioplasty (post-PTCA), peripheral vascular 
disease, stroke, bronchitis, chronic asthma, allergic asthma, allergic 
rhinitis, glaucoma, and diseases characterised by disorders of gut 
motility, e.g. irritable bowel syndrome (IBS). 
European patent application EP-A-0201188 discloses certain 
pyrazolo[4,3-d]pyrimidin-7-ones as adenosine receptor antagonists and PDE 
inhibitors, useful in the treatment of cardiovascular disorders such as 
heart failure or cardiac insufficiency. However these compounds are 
neither particularly potent PDE inhibitors, nor are they claimed to be 
selective inhibitors of cGMP PDE. 
SUMMARY OF THE INVENTION 
The compounds of the present invention are of the formula 
##STR2## 
wherein R.sup.1 is H, C.sub.1 -C.sub.3 alkyl, C.sub.3 -C.sub.5 cycloalkyl 
or C.sub.1 -C.sub.3 perfluoroalkyl; 
R.sup.2 is H, C.sub.1 -C.sub.6 alkyl optionally substituted by OH, C.sub.1 
-C.sub.3 alkoxy or C.sub.3 -C.sub.6 cycloalkyl, or C.sub.1 -C.sub.3 
perfluoroalkyl; 
R.sup.3 is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 alkenyl, C.sub.3 
-C.sub.6 alkynyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.6 
perfluoroalkyl or (C.sub.3 -C.sub.6 cycloalkyl)C.sub.1 -C.sub.6 alkyl; 
R.sup.4 taken together with the nitrogen atom to which it is attached 
completes a pyrrolidinyl, piperidino, morpholino, or 
4-N-(R.sup.6)-piperazinyl group; 
R.sup.5 is H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, NR.sup.7 
R.sup.8, or CONR.sup.7 R.sup.8 ; 
R.sup.6 is H, C.sub.1 -C.sub.6 alkyl, (C.sub.1 -C.sub.3 alkoxy) C.sub.2 
-C.sub.6 alkyl, hydroxy C.sub.2 -C.sub.6 alkyl, (R.sup.7 R.sup.8 N)C.sub.2 
-C.sub.6 alkyl, (R.sup.7 R.sup.8 NCO)C.sub.1 -C.sub.6 alkyl, CONR.sup.7 
R.sup.8, CSNR.sup.7 R.sup.8 or C(NH)NR.sup.7 R.sup.8 ; 
R.sup.7 and R.sup.8 are each independently H, C.sub.1 -C.sub.4 alkyl, 
(C.sub.1 -C.sub.3 alkoxy)C.sub.2 -C.sub.4 alkyl or hydroxy C.sub.2 
-C.sub.4 alkyl; and 
pharmaceutically acceptable salts thereof. 
In the above definition, unless otherwise indicated, alkyl or 
perfluoroalkyl groups having three or more carbon atoms may be straight or 
branched chain. In addition alkenyl or alkynyl groups having four or more 
carbon atoms, or alkoxy groups having three carbon atoms, may be straight 
or branched chain. 
The compounds of formula (I) may contain one or more asymmetric centres and 
thus they can exist as enantiomers or diastereoisomers. The invention 
include both mixtures and separate individual isomers. 
The compounds of formula (I) may also exist in tautomeric forms and the 
invention includes both mixtures and separate individual tautomers. 
Also included in the invention are radiolabelled derivatives of compounds 
of formula (I) which are suitable for biological studies. 
The pharmaceutically acceptable salts of the compounds of formula (I) which 
contain a basic centre are acid addition salts formed with 
pharmaceutically acceptable acids. Examples include the hydrochloride, 
hydrobromide, sulphate or bisulphate, phosphate or hydrogen phosphate, 
acetate, citrate, fumarate, gluconate, lactate, maleate, succinate and 
tartrate salts. Compounds of the formula (I) can also provide 
pharmaceutically acceptable metal salts, particularly alkali metal salts, 
with bases. Examples include the sodium and potassium salts. 
A preferred group of compounds of the formula (I) is that wherein R.sup.1 
is H, methyl or ethyl; R.sup.2 is C.sub.1 -C.sub.3 alkyl optionally 
substituted by OH or methoxy; R.sup.3 is C.sub.2 -C.sub.3 alkyl or allyl; 
R.sup.4 taken together with the nitrogen atom to which it is attached 
completes a piperidino or 4-N-(R.sup.6) piperazinyl group; R.sup.5 is H, 
NR.sup.7 R.sup.8 or CONR.sup.7 R.sup.8 ; R.sup.6 is H, C.sub.1 -C.sub.3 
alkyl, hydroxy C.sub.2 -C.sub.3 alkyl, CONR.sup.7 R.sup.8, CSNR.sup.7 
R.sup.8 or C(NH)NR.sup.7 R.sup.8 ; and R.sup.7 and R.sup.8 are each 
independently H or methyl. 
A particularly preferred group of compounds of the formula (I) is that 
wherein R.sup.1 is methyl; R.sup.2 is n-propyl; R.sup.3 is ethyl, n-propyl 
or allyl; R.sup.4 taken together with the nitrogen atom to which it is 
attached completes a 4-N-(R.sup.6) piperazinyl group; R.sup.5 is H, and 
R.sup.6 is H, C.sub.1 -C.sub.3 alkyl or 2-hydroxyethyl. 
Especially preferred individual compounds of the invention include 
5-[2-allyloxy-5-(4-methylpiperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1 
,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 
5-[2-ethoxy-5-(piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro 
-7H-pyrazolo[4,3-d]pyrimidin-7-one; 
5-[2-ethoxy-5-(4-methylpiperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6 
-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 
5-{2-ethoxy-5-[4-(2-propyl)piperazinylsulphonyl]phenyl}-1-methyl-3-n-propyl 
-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 
5-{2-ethoxy-5-[4-(2-hydroxyethyl)piperazinylsulphonyl]phenyl}-1-methyl-3-n- 
propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 
1-methyl-5-[5-piperazinylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-1,6-dihyd 
ro-7H-pyrazolo[4,3-d]pyrimidin-7-one; and 
5-{5-[4-(2-hydroxyethyl)piperazinylsulphonyl]-2-n-propoxyphenyl}-1-methyl-3 
-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one. 
DETAILED DESCRIPTION OF THE INVENTION 
The compounds of the general formula (I) may be prepared by the reaction of 
a compound of the general formula (II): 
##STR3## 
(wherein R.sup.1, R.sup.2 and R.sup.3 are as previously defined, and Y 
represents a halogen atom, preferably a chlorine atom) with a compound of 
the general formula (III): 
##STR4## 
wherein R.sup.4 and R.sup.5 are as previously defined. The reaction is 
generally carried out at room temperature, preferably in the presence of a 
solvent, for example an alkanol containing one to three carbon atoms, 
using an excess of (III) to scavenge the acid by-product (HY). 
Compounds of the general formula (II) may be prepared from compounds of the 
general formula (IV): 
##STR5## 
(wherein R.sup.1, R.sup.2 and R.sup.3 are as previously defined) by the 
application of known methods for the introduction of a SO.sub.2 Y group 
(wherein Y is as previously defined) into an aromatic ring, for example, 
when Y represents a chlorine atom, by the action of chlorosulphonic acid 
at or near 0.degree. C. 
When R.sup.3 is a group susceptible to removal under the 
chlorosulphonylation conditions, e.g. allyl, said group can be introduced 
in the final stage of the synthesis. Thus the phenol of the general 
formula (IV), wherein R.sup.3 is H, and R.sup.1 and R.sup.2 are as 
previously defined, which is obtainable by Pd.sup.. -mediated deprotection 
of the O-allyl analogue as illustrated by Example 25, is 
chlorosulphonylated to provide a compound of the general formula (II), 
wherein Y is Cl, R.sup.3 is H, and R.sup.1 and R.sup.2 are as previously 
defined. The latter is then reacted with the appropriate amine (III) to 
afford a compound of the general formula (I), wherein R.sup.3 is H, and 
R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are as previously defined, which is 
finally O-alkylated to furnish a compound of the general formula (I), 
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined for 
formula (I). The alkylation may be effected under standard conditions 
using the appropriate alkyl halide, e.g. allyl bromide, in the presence of 
a base such as potassium carbonate, in a suitable solvent, e.g. 
2-butanone, at the reflux temperature of the reaction mixture. 
Alternatively, the alkylation may be achieved under conventional Mitsunobu 
reaction conditions. 
In the case of other compounds of formula (IV) which may be incompatible 
with the chlorosulphonylation reaction conditions, e.g. those wherein 
R.sup.2 is hydroxy C.sub.1 -C.sub.6 alkyl, the hydroxy group can be 
protected with an acyl group such as acetyl or benzoyl. Said protecting 
group is subsequently removed at the final stage of the synthesis, under 
standard base hydrolysis conditions, to give compounds of the general 
formula (I) wherein R.sup.2 is hydroxy C.sub.1 -C.sub.6 alkyl, and 
R.sup.1, R.sup.3, R.sup.4 and R.sup.5 are as defined for formula (I). 
These latter compounds may also be obtained incidentally, as by-products, 
by chlorosulphonylation of the corresponding alkoxy analogues, i.e. 
compounds of the general formula (IV) wherein R.sup.2 is (C.sub.1 -C.sub.3 
alkoxy)C.sub.1 -C.sub.6 alkyl, followed by reaction of the crude product 
with the required amine (III), as illustrated by Example 48. 
Compounds of the general formula (IV) may be prepared from compounds of the 
general formula (V): 
##STR6## 
(wherein R.sup.1, R.sup.2 and R.sup.3 are as previously defined) by the 
application of known cyclisation methods of pyrimidinone ring formation. 
Thus, for example, the cyclisation may be effected by the treatment of (V) 
with a base such as sodium hydroxide or potassium carbonate, optionally in 
the presence of hydrogen peroxide, in an ethanol-water medium at reflux 
temperature for 2-40 hours. Under these conditions the related nitrile of 
general formula (VI), wherein R.sup.1, R.sup.2 and R.sup.3 are as 
previously defined, may also be employed as the precursor to (IV). 
In an alternative cyclisation procedure, compounds of the general formula 
(IV) may be obtained by treatment of (V) with polyphosphoric acid at or 
near 140.degree. C. for 6-18 hours. 
Compounds of the general formulae (V) and (VI) may be prepared from 
compounds of the general formulae (VII) and (VIII) respectively: 
##STR7## 
(wherein R.sup.1 and R.sup.2 are as previously defined) by reaction with a 
compound of general formula (IX): 
##STR8## 
(wherein R.sup.3 and Y are as previously defined). 
The reaction is generally carried out using an excess of (IX) in the 
presence of an excess of an aliphatic tertiary amine such as triethylamine 
to act as scavenger for the acid by-product (HY), optionally in the 
presence of a catalyst such as 4-dimethylaminopyridine, in an inert 
solvent such as dichloromethane at 0.degree. C. to 25.degree. C. for 2-6 
hours. 
The amines of formula (III), the aminopyrazoles of formulae (VII) and 
(VIII), and the acyl halides of formula (IX), when not commercially 
available, can be obtained by conventional synthetic procedures, in 
accordance with literature precedent, from readily accessible starting 
materials using standard reagents and reaction conditions. 
Certain of the compounds of the general formula (I), wherein R.sup.4 taken 
together with the nitrogen atom to which it is attached completes a 
4-N-(R.sup.6)-piperazinyl group and R.sup.6 is as previously defined but 
not hydrogen, may be prepared directly from the corresponding 
4-N-unsubstituted piperazine analogue, that is a compound of the general 
formula (I) wherein R.sup.6 is hydrogen, using appropriate standard 
synthetic procedures. 
All of the above reactions are entirely conventional and appropriate 
reagents and conditions for their performance can readily be established 
by reference to standard text books and to the examples provided 
hereafter. Alternatives and variations will also be evident to the person 
skilled in the art to enable all the compounds defined by formula (I) to 
be prepared. 
The biological activities of the compounds of the present invention were 
determined by the following test methods. 
Phosphodiesterase Activity 
Compound affinities for cGMP and cAMP PDEs are assessed by determination of 
their IC.sub.50 values (the concentration of inhibitor required for 50% 
inhibition of enzyme activity). The PDE enzymes are isolated from rabbit 
platelets and rat kidney, essentially by the method of W. J. Thompson et 
al. (Biochem., 1971, 10, 311). The calcium/calmodulin (Ca/CAM)-independent 
cGMP PDE and the cGMP-inhibited cAMP PDE enzymes are obtained from rabbit 
platelets whilst, of the four major PDE enzymes of the rat kidney, the 
Ca/CAM-dependent cGMP PDE (fraction I) is isolated. Assays are performed 
using a modification of the "batch" method of W. J. Thompson and M. M. 
Appleman (Biochem., 1979, 18, 5228). Results from these tests show that 
the compounds of the present invention are potent and selective inhibitors 
of both cGMP PDEs. 
Platelet Anti-aggregatory Activity 
This is assessed by the determination of a compound's ability to inhibit 
platelet aggregation in vitro induced by platelet activating factor (PAF), 
and to potentiate the platelet antiaggregatory action in vitro of 
activators of guanylate cyclase such as nitroprusside and EDRF. Washed 
platelets are prepared essentially by the method of J. F. Mustard et al. 
(Methods in Enzymol., 1989, 169, 3) and aggregation is determined using 
standard turbidimetric techniques as described by G. V. R. Born, J. 
Physiol. (Lond), 1962, 162, 67P. 
Antihypertensive Activity 
This is assessed following intravenous or oral administration of a compound 
to spontaneously hypertensive rats. Blood pressure is recorded via a 
cannula implanted in the carotid artery of either conscious or 
anaesthetised animals. 
For administration to man in the curative or prophylactic treatment of 
angina, hypertension or congestive heart failure, oral dosages of the 
compounds will generally be in the range of from 4-800 mg daily for an 
average adult patient (70 kg). Thus for a typical adult patient, 
individual tablets or capsules contain from 2-400 mg of active compound, 
in a suitable pharmaceutically acceptable vehicle or carrier, for 
administration in single or multiple doses, once or several times per day. 
Dosages for intravenous, buccal or sublingual administration will 
typically be within the range of from 1-400 mg per single dose as 
required. In practice the physician will determine the actual dosing 
regimen which will be most suitable for an individual patient and it will 
vary with the age, weight and response of the particular patient. The 
above dosages are exemplary of the average case but there can be 
individual instances in which higher or lower dosage ranges may be 
merited, and such are within the scope of this invention. 
For human use, the compounds of the formula (I) can be administered alone, 
but will generally be administered in admixture with a pharmaceutical 
carrier selected with regard to the intended route of administration and 
standard pharmaceutical practice. For example, they may be administered 
orally, buccally or sublingually, in the form of tablets containing 
excipients such as starch or lactose, or in capsules or ovules either 
alone or in admixture with excipients, or in the form of elixirs or 
suspensions containing flavouring or colouring agents. The compounds may 
also be injected parenterally, for example intravenously, intramuscularly, 
subcutaneously or intracoronarily. For parenteral administration, they are 
best used in the form of a sterile aqueous solution which may contain 
other substances, for example enough salts or glucose to make the solution 
isotonic with blood. 
Thus in a further aspect the invention provides a pharmaceutical 
composition comprising a compound of the formula (I), or a 
pharmaceutically acceptable salt thereof, for use in medicine, 
particularly for the treatment of angina, hypertension or congestive heart 
failure, in a human being. 
The invention further includes the use of a compound of the formula (I), or 
a pharmaceutically acceptable salt thereof, for the manufacture of a 
medicament for the treatment of stable, unstable and variant (Prinzmetal) 
angina, hypertension, congestive heart failure, athersclerosis, stroke, 
peripheral vascular disease, conditions of reduced blood vessel patency 
e.g. post-PTCA, chronic asthma, bronchitis, allergic asthma, allergic 
rhinitis, glaucoma, or diseases characterised by disorders of gut 
motility, e.g. IBS. 
The preparation of the compounds of the invention will now be more 
particularly illustrated by reference to the following experimental 
Examples. The purity of the compounds was routinely monitored by thin 
layer chromatography (TLC) using Merck Kieselgel 60 F.sub.254 plates. 
.sup.1 H-Nuclear magnetic resonance spectra were recorded using a Nicolet 
QE-300 spectrometer and were in all cases consistent with the proposed 
structures.

EXAMPLE 1 
1-Methyl-3-n-propylpyrazole-5-carboxylic acid ethyl ester 
A mixture of 3-n-propylpyrazole-5-carboxylic acid ethyl ester (24.1 g, 
0.132 mol) (prepared by the method of Chem. Pharm. Bull., 1984, 32, 1568) 
and dimethyl sulphate (16.8 g, 0.133 mol) were heated to 90.degree. C. for 
2.5 hours. The mixture was dissolved in dichloromethane and the solution 
washed with sodium carbonate solution. The organic phase was separated, 
dried (MgSO.sub.4) and evaporated under vacuum to give a solid. 
Chromatography on silica gel (300 g), eluting with dichloromethane gave 
the product as a colourless oil (20.4 g, 79%). Rf 0.8 (silica; 
dichloromethane, methanol, acetic acid; 80:20:1). 
EXAMPLE 2 
1-Methyl-3-n-propylpyrazole-5-carboxylic acid 
1-Methyl-3-n-propylpyrazole-5-carboxylic acid ethyl ester (20.2 g, 0.10 
mol) was suspended in 6N aqueous sodium hydroxide solution (50 ml, 0.30 
mol). The mixture was heated to 80.degree. C. for 2 hours then diluted 
with water (50 ml) and acidified with concentrated hydrochloric acid (25 
ml). Filtration gave the carboxylic acid as pale brown crystals (12.3 g, 
71%), m.p. 150.degree.-154.degree. C. Found: C,56.99; H,7.25; N,16.90. 
C.sub.8 H.sub.12 N.sub.2 O.sub.2 requires C,57.13; H,7.19; N, 16.66%. 
EXAMPLE 3 
1-Methyl-4-nitro-3-n-propylpyrazole-5-carboxylic acid 
1-Methyl-3-n-propylpyrazole-5-carboxylic acid (12.1 g, 0.072 mol) was added 
portionwise to a mixture of oleum (13 ml) and fuming nitric acid (11 ml), 
keeping the temperature below 60.degree. C. After the addition, the 
mixture was heated at 60.degree. C. overnight and then cooled to room 
temperature before being poured onto ice. Filtration of the precipitate 
gave the nitropyrazole as a white solid (11.5 g, 75%), m.p. 
124.degree.-127.degree. C. Found: C,45.43; H,5.22; N,19.42. C.sub.8 
H.sub.11 N.sub.3 O.sub.4 requires C,45.57; H,5.20; N,19.71%. 
EXAMPLE 4 
1-Methyl-4-nitro-3-n-propylpyrazole-5-carboxamide 
1-Methyl-4-nitro-3-n-propylpyrazole-5-carboxylic acid (11.3 g, 0.053 mol) 
was added to thionyl chloride (50 ml) and the resulting mixture heated 
under reflux for 3 hours. The reaction mixture was then cooled and excess 
thionyl chloride removed by evaporation under vacuum. The oily residue was 
dissolved in acetone (50 ml) and the solution cautiously added to a 
mixture of ice (50 g) and concentrated aqueous ammonium hydroxide solution 
(50 ml). The precipitate was collected by filtration to provide the 
pyrazolecarboxamide as a pale yellow solid (8.77 g, 78%), m.p. 
141.degree.-143.degree. C. Found: C,45.22; H,5.71; N,26.12. C.sub.8 
H.sub.12 N.sub.4 O.sub.3 requires C,45.28; H, 5.70; N,26.40%. 
EXAMPLE 5 
4-Amino-1-methyl-3-n-propylpyrazole-5-carboxamide 
1-Methyl-4-nitro-3-n-propylpyrazole-5-carboxamide (3.45 g, 16.2 mmol) and 
stannous chloride dihydrate (18.4 g, 81 mmol) were suspended in ethanol 
and the mixture heated under reflux for 2 hours. The resulting solution 
was cooled to room temperature, basified to pH 9 by the addition of 2N 
aqueous sodium hydroxide solution and extracted with dichloromethane 
(3.times.150 ml). The organic extracts were combined, dried (MgSO.sub.4) 
and evaporated under vacuum. Trituration of the residue with ether gave 
the aminopyrazole as an off-white solid (2.77 g, 94%), m.p. 
98.degree.-101.degree. C. Found: C,52.84; H,7.81; N,30.38. C.sub.8 
H.sub.14 N.sub.4 O requires C,52.73; H,7.74; N,30.75%. 
EXAMPLE 6 
4-(2-Ethoxybenzamido)-1-methyl-3-n-propylpyrazole-5-carboxamide 
A solution of 2-ethoxybenzoyl chloride (6.1 g, 33.0 mmol) in 
dichloromethane (50 ml) was added to a stirred solution of 
4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (3.0 g, 16.4 mmol), 
4-dimethylaminopyridine (0.02 g, 0.164 mmol) and triethylamine (3.34 g, 
33.0 mmol) in dichloromethane (50 ml) at 0.degree. C. The resulting 
mixture was allowed to warm to room temperature and stirred for a further 
2 hours. The solvent was evaporated under vacuum, the residue dissolved in 
a 19:1 mixture of dichloromethane and methanol (250 ml), and then the 
solution washed with 1N hydrochloric acid (100 ml), dried (MgSO.sub.4) and 
evaporated under vacuum. The crude material was chromatographed on silica 
gel (200 g), eluting with a 97:3 mixture of dichloromethane and methanol, 
to give a pink solid; crystallisation from ethyl acetate-hexane gave the 
pyrazole-5-carboxamide as a pale pink solid (2.2 g, 40%), m.p. 
153.degree.-155.degree. C. Found: C,61.66; H,6.77; N,16.95. C.sub.17 
H.sub.22 N.sub.4 O.sub.3 requires C,61.80; H,6.71; N,16.96%. 
EXAMPLE 7 
5-(2-Ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimi 
din-7-one 
4-(2-Ethoxybenzamido)-1-methyl-3-n-propylpyrazole-5-carboxamide (223 g, 
0.676 mol) was added portionwise to a solution of sodium hydroxide (54 g, 
1.35 mol) and 30% hydrogen peroxide solution (224 ml) in water (2000 ml). 
Ethanol (700 ml) was added and the resulting mixture heated under reflux 
for 2.5 hours, cooled, then evaporated under vacuum. The resulting solid 
was treated with 2N hydrochloric acid (380 ml), with external cooling, and 
the mixture was extracted with dichloromethane (1.times.700 ml, 
3.times.200 ml). The combined organic extracts were washed successively 
with saturated aqueous sodium carbonate solution (3.times.400 ml) and 
brine (300 ml), then dried (Na.sub.2 SO.sub.4) and evaporated under 
vacuum. 
Chromatography of the residue on silica gel (1000 g), using a methanol in 
dichloromethane elution gradient (0-1%), followed by trituration of the 
crude product with ether (300 ml), gave the title compound as a colourless 
solid (152.2 g, 72%), m.p. 143.degree.-146.degree. C. Found: C,65.56; 
H,6.44; N,18.14. C.sub.17 H.sub.20 N.sub.4 O.sub.2 requires C,65.36; 
H,6.45; N,17.94%. 
EXAMPLE 8 
5-(5-Chlorosulphonyl-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyr 
azolo[4,3-d]pyrimidin-7-one 
5-(2-Ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimi 
din-7-one (10.0 g, 32.1 mmol) was added portionwise to chlorosulphonic acid 
(20 ml) at 0.degree. C. under a nitrogen atmosphere. After being stirred 
overnight, the reaction solution was cautiously added to ice-water (150 
ml) and the aqueous mixture extracted with a 9:1 mixture of 
dichloromethane and methanol (4.times.100 ml). The combined extracts were 
dried (Na.sub.2 SO.sub.4) and evaporated under vacuum to give the required 
sulphonyl chloride as a white solid (12.8 g, 97%), m.p. 
179.degree.-181.degree. C. Found: C,50.07; H,4.71; N, 13.29. C.sub.17 
H.sub.19 ClN.sub.4 O.sub.4 S requires C,49.70; H,4.66; N, 13.64%. 
EXAMPLE 9 
5-[2-Ethoxy-5-(4-carbamoylpiperidinylsulphonyl)phenyl]-1-methyl-3-n-propyl- 
1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one 
4-Carbamoylpiperidine (703 mg, 5.50 mmol) was added to a stirred suspension 
of 
5-(5-chlorosulphonyl-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-py 
razolo[4,3-d]pyrimidin-7-one (750 mg, 1.80 mmol) in ethanol (50 ml) at room 
temperature. The resulting mixture was stirred for 4 days before removing 
the solvent by evaporation under vacuum. The residue was dissolved in a 
9:1 mixture of dichloromethane and methanol (100 ml) and the solution 
washed with saturated aqueous sodium carbonate solution (100 ml). The 
aqueous phase was further extracted with dichloromethane-methanol mixtures 
(3.times.100 ml) and all the organic fractions were combined, dried 
(MgSO.sub.4) and evaporated under vacuum to give a solid. Crystallisation 
from a mixture of methanoldimethylformamide gave the title sulphonamide as 
an off-white solid (446 mg, 49%), m.p. 274.degree.-276.degree. C. Found: 
C,55.36; H,6.01; N,16.65. C.sub.23 H.sub.29 N.sub.6 O.sub.5 S requires 
C,55.08; H,5.83; N,16.75%. 
EXAMPLES 10-14 
The following compounds were prepared by the procedure of Example 9 using 
the appropriate amine. 
______________________________________ 
##STR9## 
pleam-Ex- 
##STR10## yield% 
(.degree.C.)m.p. 
CHNin brackets)(TheoreticalAnalysis 
______________________________________ 
% 
10 
##STR11## 51 161- 162 
54.82 (54.77 
6.13 6.13 
17.95 18.25) 
11 
##STR12## 79 194- 196 
54.63 (54.75 
6.47 6.39 
16.50 16.65) 
12 
##STR13## 88 187- 189 
55.61 (55.68 
6.23 6.37 
17.74 17.71) 
13 
##STR14## 21 187- 188 
57.48 (57.35 
6.74 6.82 
16.47 16.72) 
14 
##STR15## 74 209- 212 
57.64 (57.35 
6.66 6.82 
16.81 16.72) 
15 
##STR16## 18 229- 230 
51.25 (50.85 
5.56 5.63 
18.92 18.87) 
______________________________________ 
EXAMPLE 16 
5-{2-Ethoxy-5-[4-(methylthioimidoyl)piperazinylsulphonyl]phenyl}-1-methyl-3 
-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one hydroiodide 
A mixture of 
5-[2-ethoxy-5-(4-thiocarbamoylpiperazinylsulphonyl)phenyl]-1-methyl-3-n-pr 
opyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (0.78 g, 1.5 mmol), 
methyl iodide (426 mg, 3.0 mmol) and methanol (20 ml) was stirred under 
reflux for 2 hours, then allowed to cool. The resulting white solid was 
removed by filtration and crystallised from ethyl acetate-methanol to give 
the title compound as colourless crystals (0.70 g, 71%), m.p. 
227.degree.-228.degree. C. Found: C,41.43; H,4.79; N,14.42. C.sub.23 
H.sub.31 N.sub.7 O.sub.4 S.sub.2 ;HI requires C,41.75; H,4.88; N,14.82%. 
EXAMPLE 17 
5-{2-Ethoxy-5-[4-(methylamidino)piperazinylsulphonyl]phenyl}-1-methyl-3-n-p 
ropyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one hydroiodide 
5-{2-Ethoxy-5-[4-methylthioimidoyl)piperazinylsulphonyl]phenyl}-1-methyl-3- 
n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one hydroiodide (0.5 g, 
0.75 mmol) was added to a 33% solution of methylamine in ethanol (20 ml) 
and the mixture stirred at room temperature for 18 hours. The solution was 
evaporated under vacuum and the residue triturated with ether. 
Chromatography of the resulting solid on silica gel (10 g), using a 
methanol in dichloromethane elution gradient (0-4%), followed by 
trituration of the crude product with ether, gave a light brown powder. 
Crystallisation from ethyl acetate-methanol gave the title compound as 
colourless crystals (112 mg, 23%), m.p. 253.degree.-255.degree. C. Found: 
C,42.90; H,5.09; N,17.41. C.sub.23 H.sub.32 N.sub.8 O.sub.4 S; HI requires 
C,42.86; H,5.16; N,17.39%. 
EXAMPLE 18 
1-Methyl-4-(2-n-propoxybenzamido)-3-n-propylpyrazole-5-carboxamide 
This amide was prepared from 2-n-propoxybenzoyl chloride following the 
procedure described in Example 6 and was obtained as a pink solid (63%), 
m.p. 148.degree.-149.degree. C. Found: C,62.97; H,7.00; N, 16.29. C.sub.18 
H.sub.24 N.sub.4 O.sub.3 requires C,62.77; H,7.02; N,16.27%. 
EXAMPLE 19 
1-Methyl-5-(2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyr 
imidin-7-one 
1-Methyl-4-(2-n-propoxybenzamido)-3-n-propylpyrazole-5-carboxamide (0.34 g, 
0.99 mmol) was added to a stirred mixture of 30% hydrogen peroxide 
solution (1.0 ml), potassium carbonate (0.54 g, 3.92 mmol), water (10 ml) 
and ethanol (5 ml). The mixture was heated under reflux for 38 hours and 
then evaporated under vacuum. The residue was suspended in water (20 ml), 
then the mixture acidified with 2N hydrochloric acid and extracted with 
dichloromethane (3.times.20 ml). The extracts were combined, dried 
(Na.sub.2 SO.sub.4) and evaporated under vacuum. The resulting residue was 
chromatographed on silica gel (6 g), using a methanol in dichloromethane 
elution gradient (0.0-1.0%), to give an oil, successive trituration of 
which with ether gave the required product as a white solid (0.19 g, 59%), 
m.p. 111.degree.-114.degree. C. Found: C,66.26; H,6.92; N,17.15. C.sub.18 
H.sub.22 N.sub.4 O.sub.2 requires C,66.23; H,6.80; N,17.17%. 
EXAMPLE 20 
5-(5 
-Chlorosulphonyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyr 
azolo[4,3-d]pyrimidin-7-one 
This sulphonyl chloride was prepared from 
5-(2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]py 
rimidin-7-one following the procedure of Example 8 and was obtained as a 
white solid (92%). Found: C,51.26; H,5.02; N,12.90. C.sub.18 H.sub.21 
ClN.sub.4 O.sub.4 S requires C,50.88; H,4.98; N,13.19%. 
EXAMPLE 21 
1-Methyl-5-[5-(piperazinylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-1,6-dihy 
dro-7H-pyrazolo[4,3-d]pyrimidin-7-one 
This sulphonamide was prepared from piperazine and 
5-(5-chlorosulphonyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H 
-pyrazolo[4,3-d]pyrimidin-7-one following the procedure of Example 9 and 
was obtained as a white solid (70%), m.p. 185.degree.-186.degree. C. 
Found: C,56.17; H,6.38; N,17.65. C.sub.22 H.sub.30 N.sub.6 O.sub.4 S 
requires C,55.67; H,6.37; N,17.71%. 
EXAMPLE 22 
5-{5-[4-(2-Hydroxyethyl)piperazinylsulphonyl]-2-n-propoxyphenyl}-1-methyl-3 
-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimdin-7-one 
This sulphonamide was prepared from N-(2-hydroxyethyl)piperazine and 
5-(5-chlorosulphonyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H 
-pyrazolo[4,3-d]pyrimidin-7-one following the procedure of Example 9 and 
was obtained as colourless needles (66%), m.p. 158.degree.-159.degree. C. 
Found: C,55.83; H,6.58; N,16.13. C.sub.24 H.sub.34 N.sub.6 O.sub.5 S 
requires C,55.58; H,6.61; N,16.20%. 
EXAMPLE 23 
4-(2-Allyloxybenzamido)-1-methyl-3-n-propylpyrazole-5-carboxamide 
A solution of 2-allyloxybenzoyl chloride (3.93 g, 0.02 mol) in 
dichloromethane (20 ml) was added dropwise to a stirred, partial solution 
of 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (3.64 g, 0.02 mol) in 
pyridine (50 ml), and the resulting mixture stirred at room temperature 
overnight in a dry atmosphere. The solvent was evaporated under vacuum and 
the residue partitioned between dichloromethane (50 ml) and saturated 
aqueous sodium carbonate solution (50 ml). The organic layer was separated 
and the aqueous layer exhaustively extracted with further dichloromethane. 
The combined organic solutions were washed with 2M HCl (3.times.30 ml), 
then brine (1.times.30 ml), and dried (Na.sub.2 SO.sub.4). After 
filtration and evaporation under vacuum of the filtrate, the crude product 
was crystallised from ethyl acetate to give the title compound (4.525 g, 
66%), m.p. 132.degree.-134.degree. C. Found: C,63.49; H,6.42; N,16.33. 
C.sub.18 H.sub.22 N.sub.4 O.sub.3 requires C,63.14; H,6.48; N,16.36%. 
EXAMPLE 24 
5-(2-Allyloxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyri 
midin-7-one 
A mixture of 
4-(2-allyloxybenzamido)-1-methyl-3-n-propylpyrazole-5-carboxamide (1.2 g, 
0.0035 mol), sodium hydroxide (0.70 g, 0.018 mol), water (34 ml) and 
ethanol (8 ml) was refluxed for 5 hours. After cooling, the solution was 
exhaustively extracted with ethyl acetate. The combined extracts were 
washed with brine (30 ml), dried (Na.sub.2 SO.sub.4), filtered and the 
solvent evaporated under vacuum to give a crude product which was 
crystallised from ethyl acetate/hexane to afford the title compound (0.476 
g, 37%), m.p. 116.degree.-119.degree. C. Found: C,67.00; H,6.21; N,17.23. 
C.sub.18 H.sub.20 N.sub.4 O.sub.2 requires C,66.65; H,6.21; N,17.27%. 
EXAMPLE 25 
5-(2-Hydroxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrim 
idin-7-one 
A mixture of 
5-(2-allyloxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyr 
imidin-7-one (0.25 g, 0.0008 mol), phenol (0.145 g, 0.0015 mol), piperidine 
(0.131 g, 0.0015 mol) and tetrakis(triphenylphosphine)palladium(0) (0.046 
g, 0.00004 mol) in absolute ethanol (5ml) was refluxed overnight under 
nitrogen. The mixture was allowed to cool, the solvent evaporated under 
vacuum and the residue dissolved in ethyl acetate (40 ml). This solution 
was washed with water (3.times.10 ml), 1M HCl (3.times.10 ml) and brine 
(1.times.10 ml). After drying (Na.sub.2 SO.sub.4) and filtration, the 
filtrate was evaporated under vacuum to give the crude product. The title 
phenol (0.021 g, 10%) was obtained after trituration with diethyl ether 
and crystallisation from ethyl acetate/pentane, m.p. 
233.degree.-238.degree. C. Found: C,63.17; H,5.65; N,19.52. C.sub.15 
H.sub.16 N.sub.4 O.sub.2 requires C,63.36; H,5.67; N,19.71%. 
EXAMPLE 26 
5-(5-Chlorosulphonyl-2-hydroxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-py 
razolo[4,3-d]pyrimidin-7-one 
5-(2-Hydroxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrim 
idin-7-one (0.239 g, 0.00084 mol) was added, in portions, to stirred 
chlorosulphonic acid (3 ml) cooled to 0.degree. C. under a nitrogen 
atmosphere, and the resulting deep red solution stirred at room 
temperature for 18 hours. The reaction mixture was then added dropwise, 
with care, to stirred ice/water to give a brown solid. The latter mixture 
was extracted with dichloromethane (3.times.30 ml), the combined extracts 
dried (Na.sub.2 SO.sub.4) and filtered, and the filtrate evaporated under 
vacuum to give a brown solid (0.24 g, 75%), used in the next step without 
further purification; Rf 0.3 (silica; dichloromethane, methanol; 95:5). 
EXAMPLE 27 
5-]2-Hydroxy-5-(4-methylpiperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1, 
6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one 
A solution of 
5-(5-chlorosulphonyl-2-hydroxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-p 
yrazolo[4,3-d]pyrimidin-7-one (0.235 g, 0.0006 mol) and N-methylpiperazine 
(0.5 ml, 0.0045 mol) in ethanol (40 ml) was stirred at room temperature 
for 18 hours. The solution was evaporated under vacuum and the residue 
partitioned between ethyl acetate (40 ml) and water (40 ml). The fine 
precipitate was filtered off, washed with water then ethyl acetate, and 
crystallised from ethyl acetate/DMF to give the title compound as an 
off-white powder (0.260 g, 49%), m.p. 283.degree.-284.degree. C. Found: 
C,53.53; H,5.89; N,18.40. C.sub.20 H.sub.26 N.sub.6 O.sub.4 S requires 
C,53.80; H,5.87; N,18.82%. 
EXAMPLE 28 
5-[2-Allyloxy-5-(4-methylpiperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1 
,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one 
Allyl bromide (0.02 ml, 0.00023 mol) was added to a stirred suspension of 
5-[2-hydroxy-5-(4-methylpiperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1 
,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (0.103 g, 0.00023 mol) and 
potassium carbonate (0.032 g, 0.00023 mol) in 2-butanone (10 ml) and the 
mixture heated under reflux for 8 hours. After cooling, the reaction 
mixture was evaporated under vacuum and the residue suspended in water (20 
ml). The aqueous suspension was extracted with ethyl acetate (3.times.20 
ml), the combined extracts dried (Na.sub.2 SO.sub.4) and, after 
filtration, evaporated under vacuum to give an oil. Column chromatography 
on silica gel (2 g) using a methanol in dichloromethane elution gradient 
(0-3%), followed by evaporation under vacuum of appropriate fractions, 
gave a semi-solid which was dissolved in acetone; evaporation under vacuum 
of the solution gave the title compound (0.011 g, 10%), m.p. 
151.degree.-153.degree. C., Rf 0.5 (silica; dichloromethane, methanol; 
95:5), m/e 487 (M.sup.+ +1). 
EXAMPLE 29 
4-(2-Ethoxybenzamido)-1,3-dimethylpyrazole-5-carboxamide 
This amide was prepared from 4-amino-1,3-dimethylpyrazole-5-carboxamide 
(prepared by the method of J. Med. Chem 1987, 30, 91), following the 
procedure of Example 6, and was obtained as a white solid (81%), m.p. 
178.degree.-181.degree. C. Found: C,59.89; H,6.05; N,18.44. C.sub.15 
H.sub.18 N.sub.4 O.sub.3 requires C,59.59; H,6.00; N,18.53%. 
EXAMPLE 30 
5-(2-Ethoxyphenyl)-1,3-dimethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-o 
ne 
4-(2-Ethoxybenzamido)-1,3-dimethylpyrazole-5-carboxamide (1.6 g, 5.29 mmol) 
was added to polyphosphoric acid (50 g) and the mixture heated to 
140.degree. C. for 6 hours. The solution was cooled, poured into ice-water 
(100 ml), and then the mixture was basified with 10% aqueous sodium 
hydroxide solution and extracted with dichloromethane (3.times.100 ml). 
The organic extracts were combined, dried (MgSO.sub.4) and evaporated 
under vacuum. The residue was chromatographed on silica gel eluting with a 
97:3 mixture of dichloromethane and methanol. Crystallisation of the crude 
product from aqueous ethanol gave the title compound as a colourless 
solid, m.p. 201.degree.-204.degree. C. Found: C,63.43; H,5.57; N,19.35. 
C.sub.15 H.sub.16 N.sub.4 O.sub.2 requires C,63.36; H,5.67; N,19.71%. 
EXAMPLE 31 
5-(5-Chlorosulphonyl-2-ethoxyphenyl)-1,3-dimethyl-1,6-dihydro-7H-pyrazolo[4 
,3-d]pyrimidin-7-one 
This sulphonyl chloride was prepared from 
5-(2-ethoxyphenyl)-1,3-dimethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7- 
one, following the procedure of Example 8, and was obtained in quantitative 
yield as a white solid. Rf 0.3 (silica:ether). It was used without further 
purification. 
EXAMPLES 32-34 
The following compounds were prepared from 
5-(5-chlorosulphonyl-2-ethoxyphenyl)-1,3-dimethyl-1,6-dihydro-7H-pyrazolo[ 
4,3-d]pyrimidin-7-one and the appropriate amine following the procedure of 
Example 9. 
______________________________________ 
##STR17## 
pleam-Ex- 
##STR18## yield% 
(.degree.C.)m.p. 
CHNin brackets)(TheoreticalAnalysis 
______________________________________ 
% 
32 
##STR19## 68 225- 226 
53.88 (53.79 
5.81 5.87 
18.42 18.82) 
33 
##STR20## 68 240- 242 
53.07 (52.76 
5.77 5.59 
19.27 19.43) 
34 
##STR21## 62 228- 229 
53.23 (52.93 
5.87 5.92 
17.72 17.63) 
______________________________________ 
EXAMPLE 35 
4-Nitro-3-n-propylpyrazole-5-carboxylic acid 
3-n-Propylpyrazole-5-carboxylic acid (prepared by the method of Chem. 
Pharm. Bull. 1984, 32, 1568), was nitrated following the procedure of 
Example 3, to give the title compound as a colourless solid (75%), m.p. 
169.degree.-173.degree. C. Found: C,42.35; H,4.56; N,21.07. C.sub.7 
H.sub.9 N.sub.3 O.sub.4 requires C,42.21; N,4.55; N,21.10%. 
EXAMPLE 36 
4-Nitro-3-n-propylpyrazole-5-carboxamide 
A mixture of 4-nitro-3-n-propylpyrazole-5-carboxylic acid (7.8 g, 39.2 
mmol) and thionyl chloride (35 ml) was heated under reflux for 3 hours. 
The solvent was removed by evaporation under vacuum and the solid residue 
was added portionwise to aqueous ammonium hydroxide solution (40 ml) at 
0.degree. C. The mixture was then diluted with water (60 ml) and extracted 
with a 9:1 mixture of dichloromethane and methanol (3.times.100 ml). The 
organic fractions were combined, dried (MgSO.sub.4) and evaporated under 
vacuum, and the residue crystallised from ethanol to give the carboxamide 
as a colourless solid (1.0 g, 13%), m.p. 202.degree.-206.degree. C. Found: 
C,42.35; H,5.01; N,28.38. C.sub.7 H.sub.10 N.sub.4 O.sub.3 requires 
C,42.42; H,5.09; N,28.27%. 
EXAMPLE 37 
4-Amino-3-n-propylpyrazole-5-carboxamide 
A solution of 4-nitro-3-n-propylpyrazole-5-carboxamide (198 mg, 1.0 mmol) 
in methanol (5 ml) was added dropwise to a mixture of sodium borohydride 
(113 mg, 2.97 mmol), 10% palladium on carbon (5 mg) and water (3 ml). The 
mixture was stirred at room temperature for 3 hours, filtered and the 
solvent removed by evaporation under vacuum. Crystallisation of the 
residue from ethyl acetate-methanol gave the title compound as an 
off-white solid (61 mg, 36%), m.p. 196.degree.-201.degree. C. Rf 0.4 
(silica; dichloromethane, methanol, ammonium hydroxide; 90:10:1). Found: 
C,48.96; H,6.98; N,32.08. C.sub.7 H.sub.12 N.sub.4 O requires C,49.98; 
H,7.19; N,33.31%. 
EXAMPLE 38 
4-(2-Ethoxybenzamido)-3-n-propylpyrazole-5-carboxamide 
The title compound was prepared from 
4-amino-3-n-propylpyrazole-5-carboxamide following the procedure of 
Example 6, and was obtained as a white solid (64%), m.p. 
209.degree.-211.degree. C. Found: C,60.73; H,6.41; N,17.80. C.sub.16 
H.sub.20 N.sub.4 O.sub.3 requires C,60.74; H,6.37; N,17.71%. 
EXAMPLE 39 
5-(2-Ethoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one 
The title compound was prepared from 
4-(2-ethoxybenzamido)-3-n-propyl-pyrazole-5-carboxamide following the 
procedure of Example 30 and was obtained as a white solid (16%), m.p. 
199.degree.-201.degree. C. Found: C,64.44; H,6.19; N,18.44%. C.sub.16 
H.sub.18 N.sub.4 O.sub.2 requires C,64.41; H,6.08; N,18.78%. 
EXAMPLE 40 
5-(5-Chlorosulphonyl-2-ethoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3 
-d]pyrimidin-7-one 
The title sulphonyl chloride was prepared from 
5-(2-ethoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-on 
e following the procedure of Example 8 and was obtained as a white solid 
(78%). Rf 0.25 (silica:ether). 
It was used without further purification. 
EXAMPLE 41 
5-[2-Ethoxy-5-(4-methylpiperazinyl)sulphonylphenyl]-3-n-propyl-1,6-dihydro- 
7H-pyrazolo[4,3-d]pyrimidin-7-one 
The title sulphonamide was prepared from 
5-(5-chlorosulphonyl-2-ethoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo[4, 
3-d]pyrimidin-7-one following the procedure of Example 9 and was obtained 
as a white solid (70%), m.p. 236.degree.-239.degree. C. Found: C,54.84; 
H,6.27; N,18.10. C.sub.21 H.sub.28 N.sub.6 O.sub.4 S requires C,54.76; 
H,6.13; N,18.25%. 
EXAMPLE 42 
3-Bromomethyl-5-chloro-1-methyl-4-nitropyrazole 
N-Bromosuccinimide (10.7 g, 60.0 mmol) was added to a solution of 
5-chloro-1,3-dimethyl-4-nitropyrazole (8.78 g, 50.0 mmol) in carbon 
tetrachloride (100 ml) and the solution was heated under reflux whilst 
being irradiated with visible light (150 W tungsten lamp) for 3 days. At 
intervals throughout the reaction, quantities of benzoyl peroxide 
(6.times.50 mg) were added. The solvent was removed by evaporation under 
vacuum and the residue chromatographed on silica gel eluting with a 1:1 
mixture of dichloromethane and hexane to give the bromide as an off-white 
solid (8.0 g, 63%), m.p. 80.degree.-82.degree. C. Found: C,23.95; H,2.05; 
N,16.31. C.sub.5 H.sub.5 BrClN.sub.3 O.sub.2 requires C,23.60; H,1.98; 
N,16.51%. 
EXAMPLE 43 
5-Chloro-3-methoxymethyl-1-methyl-4-nitropyrazole 
A solution of 3-bromomethyl-5-chloro-1-methyl-4-nitropyrazole (5.0 g, 19.6 
mmol) in methanol (50 ml) was treated with silver nitrate (5.75 g, 33.8 
mmol) and the mixture heated under reflux for 2 hours. The cooled reaction 
mixture was filtered and the filtrate evaporated under vacuum. The residue 
was partitioned between ethyl acetate (100 ml) and water (50 ml) and the 
aqueous phase extracted with a further quantity of ethyl acetate (50 ml). 
The organic extracts were combined, dried (MgSO.sub.4) and evaporated 
under vacuum. Chromatography on silica gel, eluting with a 97:3 mixture of 
dichloromethane and methanol, gave the title pyrazole as a white solid 
(1.6 g, 40%), m.p. 59.degree.-63.degree. C. Found: C,34.65; H,3.83; 
N,20.05. C.sub.6 H.sub.8 ClN.sub.3 O.sub.3 requires C,35.05; H,3.92; 
N,20.44%. 
EXAMPLE 44 
5-Cyano-3-methoxymethyl-1-methyl-4-nitropyrazole 
A solution of 5-chloro-3-methoxymethyl-1-methyl-4-nitropyrazole (205 mg, 
1.0 mmol), potassium cyanide (130 mg, 2.0 mmol) and 18-crown-6 (10 mg) in 
acetonitrile (2 ml) was heated under reflux overnight. The solvent was 
evaporated under vacuum and the residue partitioned between ethyl acetate 
(20 ml) and water (20 ml). The organic phase was separated, dried 
(MgSO.sub.4) and evaporated under vacuum, then the residue chromatographed 
on silica gel eluting with a 1:1 mixture of ethyl acetate and pentane. 
Trituration of the crude product with ether provided a yellow solid (38 
mg, 19%), m.p. 48.degree.-50.degree. C. Found: C,42.89; H,4.15; N,28.78. 
C.sub.7 H.sub.8 N.sub.4 O.sub.3 requires C,42.86; H,4.11; N,28.56%. 
EXAMPLE 45 
4-Amino-5-cyano-3-methoxymethyl-1-methylpyrazole 
The title compound was prepared from 
5-cyano-3-methoxymethyl-1-methyl-4-nitropyrazole following the procedure 
of Example 5 and was obtained as an off-white solid (68%), m.p. 
82.degree.-84.degree. C. Found: C,50.81; H,6.13; N,33.94. C.sub.7 H.sub.10 
N.sub.4 O requires C,50.59; H,6.07; N,33.72% 
EXAMPLE 46 
5-Cyano-4-(2-ethoxybenzamido)-3-methoxymethyl-1-methylpyrazole 
The title compound was prepared from 
4-amino-5-cyano-3-methoxymethyl-1-methylpyrazole following the procedure 
of Example 6 and was obtained as an off-white solid (61%), m.p. 
103.degree.-105.degree. C. Found: C,61.21; H,5.98; N,17.80. C.sub.16 
H.sub.18 N.sub.4 O.sub.3 requires C,61.13; H,5.77; N,17.83%. 
EXAMPLE 47 
5-(2-Ethoxyphenyl)-3-methoxymethyl-1-methyl-1,6-dihydro-7H-pyrazolo[4,3-d]p 
yrimidin-7-one 
The title compound was prepared from 
5-cyano-4-(2-ethoxybenzamido)-3-methoxymethyl-1-methylpyrazole following 
the procedure of Example 7, via in situ generation of the 5-primary amide 
derivative, and was obtained as a white solid (38%), m.p. 
160.degree.-161.degree. C. Found: C,61.35; H,5.75; N,17.98. C.sub.16 
H.sub.18 N.sub.4 O.sub.3 requires C,61.13; H,5.77; N,17.83%. 
EXAMPLE 48 
3-Methoxymethyl-1-methyl-5-[5-(4-methylpiperazinylsulphonyl)-2-ethoxyphenyl 
]1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one 
5-(2-Ethoxyphenyl)-3-methoxymethyl-1-methyl-1,6-dihydro-7H-pyrazolo[4,3-d]p 
yrimidin-7-one (470 mg, 1.50 mmol) was dissolved in chlorosulphonic acid (3 
ml) at 0.degree. C. The solution was stirred at room temperature for 2 
hours, then cautiously added to ice-water (50 ml). The resulting solution 
was neutralised with saturated sodium carbonate solution, then extracted 
with a 20:1 mixture of dichloromethane and methanol (2.times.50 ml). The 
combined organic extracts were evaporated under vacuum and the residue was 
dissolved in ethanol (5 ml) and the solution treated with 
N-methylpiperazine (450 mg, 4.5 mmol). After 1 hour at room temperature 
the solvent was evaporated under vacuum and the residue chromatographed on 
silica gel, eluting with a mixture of dichloromethane, methanol and 
aqueous ammonium hydroxide solution (90:10:1 by volume). Trituration of 
the crude product with ethyl acetate gave the title compound as a white 
solid (49 mg, 7%), m.p. 198.degree.-199.degree. C. Found: C,52.94; H,6.04; 
N,17.67. C.sub.21 H.sub.28 N.sub.6 O.sub.5 S requires C,52.93; H,5.92; 
N,17.64%. 
Also isolated following chromatograpy and crystallisation from a mixture of 
ethyl acetate and methanol was 
3-hydroxymethyl-1-methyl-5-[5-(4-methylpiperazinylsulphonyl)-2-ethoxypheny 
l]-1,6-dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one as a white solid (51 mg, 
7%), m.p. 209.degree.-210.degree. C. Found: C,51.94; H,5.77; N,18.05. 
C.sub.20 H.sub.26 N.sub.6 O.sub.5 S requires C,51.94; H,5.67; N,18.17%. 
EXAMPLE 49 
1-Ethyl-3-n-propylpyrazole-5-carboxylic acid ethyl ester 
This pyrazole was prepared from 3-n-propylpyrazole-5-carboxylic acid ethyl 
ester and diethyl sulphate, following the procedure described in Example 
1, and was obtained as a colourless oil (72%). Rf 0.5 (silica; ethyl 
acetate, hexane; 1:1). 
EXAMPLE 50 
1-Ethyl-3-n-propylpyrazole-5-carboxylic acid 
This carboxylic acid was prepared from 
1-ethyl-3-n-propylpyrazole-5-carboxylic acid ethyl ester, following the 
procedure described in Example 2, and was obtained as a pale brown solid 
(89%), m.p. 73.degree.-77.degree. C. Found C, 58.62; H,7.69; N,15.23. 
C.sub.9 H.sub.14 N.sub.2 O.sub.2 requires C,59.32; H,7.74; N,15.37%. 
EXAMPLE 51 
1-Ethyl-4-nitro-3-n-propylpyrazole-5-carboxylic acid 
The title compound was prepared from 
1-ethyl-3-n-propylpyrazole-5-carboxylic acid, following the procedure 
described in Example 3, and was obtained as a colourless solid (96%), m.p. 
120.degree.-123.degree. C. Found: C,47.61; H,5.81; N,18.54. C.sub.9 
H.sub.13 N.sub.3 O.sub.4 requires C,47.57; H,5.77; N,18.49%. 
EXAMPLE 52 
1-Ethyl-4-nitro-3-n-propylpyrazole-5-carboxamide 
The title amide was prepared from 
1-ethyl-4-nitro-3-n-propylpyrazole-5-carboxylic acid, following the 
procedure described in Example 4, and was obtained as an off-white solid 
(86%), m.p. 119.degree.-120.degree. C. Found: C,47.38; H,6.18; N,24.34. 
C.sub.9 H.sub.14 N.sub.4 O.sub.3 requires C,47.78; H,6.24; N,24.77% 
EXAMPLE 53 
4-Amino-1-ethyl-3-n-propylpyrazole-5-carboxamide 
The title compound was prepared from 
1-ethyl-4-nitro-3-n-propylpyrazole-5-carboxamide, by the procedure 
described in Example 5, and was obtained as an off-white solid (100%), 
m.p. 93.degree.-97.degree. C. Found: C,55.17; H,8.34; N,28.93. C.sub.9 
H.sub.16 N.sub.4 O requires C,55.08; H,8.22; N,28.55%. 
EXAMPLE 54 
4-(2-Ethoxybenzamido)-1-ethyl-3-n-propylpyrazole-5-carboxamide 
The title amide was prepared from 
4-amino-1-ethyl-3-n-propylpyrazole-5-carboxamide and 2-ethoxybenzoyl 
chloride, following the procedure described in Example 6, and was obtained 
as a colourless solid (73%), m.p. 139.degree.-141.degree. C. Found: 
C,63.03; H,7.15; N,16.50. C.sub.18 H.sub.24 N.sub.4 O.sub.3 requires 
C,62.77; H,7.02; N,16.27%. 
EXAMPLE 55 
5-(2-Ethoxyphenyl)-1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimid 
in-7-one 
The title compound was prepared from 
4-(2-ethoxybenzamido)-1-ethyl-3-n-propylpyrazolo-5-carboxamide following 
the procedure of Example 7, and was obtained as a colourless solid (46%), 
m.p. 112.degree.-114.degree. C. Found: C,66.59; H,6.85; N,17.26. C.sub.18 
H.sub.22 N.sub.4 O.sub.2 requires C,66.23; H,6.79; N,17.17%. 
EXAMPLE 56 
5-(5-Chlorosulphonyl-2-ethoxyphenyl)-1-ethyl-3-n-propyl-1,6-dihydro-7H-pyra 
zolo[4,3-d]pyrimidin-7-one 
The title compound was prepared from 
5-(2-ethoxyphenyl)-1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimi 
din-7-one following the procedure of Example 8, and was obtained as a 
methylene chloride solvate (86%), m.p. 170.degree.-172.degree. C. Found: 
C,49.82; H,4.84; N,12.77. C.sub.18 H.sub.21 ClN.sub.4 O.sub.4 S; 1/6 
CH.sub.2 Cl.sub.2 requires C,49.70; H,4.90; N,12.77%. 
EXAMPLE 57 
5-[2-Ethoxy-5-(4-methylpiperazinylsulphonyl)phenyl]-1-ethyl-3-n-propyl-1,6- 
dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one 
The title sulphonamide was prepared from 
5-(5-chlorosulphonyl-2-ethoxyphenyl)-1-ethyl-3-n-propyl-1,6-dihydro-7H-pyr 
azolo[4,3-d]pyrimidin-7-one and N-methylpiperazine following the procedure 
of Example 9 and was obtained as a colourless solid (43%), m.p. 
160.degree.-162.degree. C. Found: C,57.24; H,6.17; N,16.83. C.sub.23 
H.sub.32 N.sub.6 O.sub.4 S requires C,56.54; H,6.60; N,17.20%. Rf 0.35 
(silica; dichloromethane, methanol; 9:1). 
EXAMPLE 58 
5-{2-Ethoxy-5-[4-(2-hydroxyethyl)piperazinylsulphonyl]phenyl}-1-ethyl-3-n-p 
ropyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one 
The title sulphonamide was prepared from 
5-(5-chlorosulphonyl-2-ethoxyphenyl)-1-ethyl-3-n-propyl-1,6-dihydro-7H-pyr 
azolo[4,3-d]pyrimidin-7-one and N-(2-hydroxyethyl)piperazine following the 
procedure of Example 9 and was obtained as a colourless solid (88%), m.p. 
191.degree.-193.degree. C. Found: C,55.74; H,6.55; N,15.78. C.sub.24 
H.sub.34 N.sub.6 O.sub.5 S requires C,55.58; H,6.61; H,16.20%.