1,6-dihydro-5- (2,5-disubstituted phenyl)-7h-pyrazolo-[4,3-d] pyrimidin-7-ones and pharmaceutical compositions containing them

1,6-DIHYDRO-.5-(2,5-DISUBSTITUTED PHENYL)-7H-PYRAZ0L0-[4,3-d] PYRIMIDIN-7-0NES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

PEC 537

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 canpounds of the invention exhibit selectivity for inhibition of c(34P pdes rather than cyclic adenosine 3¹,5'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-vasospastic and vasodilatory activity, as well as potentiation of the effects of endothelium-derived relaxing factor (EDRF) and nitrovasodilators. Thus the carpounds 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, glaucana, and diseases characterised by disorders of gut motility, e.g. irritable bcwel syndrane (IBS).

European patent application ΕΡ-Α-020118Θ 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 carpounds are neither particularly potent PDE inhibitors, nor are they claimed to be selective inhibitors of cGMP PDE.

PLC 537 , The (I):

wherein canpounds of the present invention are of the formula

<img file="IL98482A_D0001.tif" />

r! is H, alkyl, C₇־C_R cycloalkyl 0r C,-C_Q x כ צ, ^ . צי Λ ני perfluoroalkyl;

R is H, C^-Cg alkyl optionally substituted by OH, C^-C₃ alkoxy or C₃־Cg cycloalkyl, or C^-C₃perfluoroalkyl;

R is Cj-Cg alkyl, C₃־C₆ alkenyl, C₃־Cg alkynyl,

C₃־C₇ cycloalkyl, C^-Cg perfluoroalkyl or (CL-C, cycloalkyl)C.-C_fi alkyl;

R taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R )-piperazinyl group;

7 R7 R

R is H, 0-^ alkyl, C₁־C₃ alkoxy, NR R , or OONR R ; r6 is H, C^-Cg alkyl, (C^-C₃ alkoxy) C^-Cg alkyl, hydroxy C-,-0, alkyl, /R⁷R⁸N)C9-C, alkyl, (R⁷R⁸NC0)C,-Cfi £ U it UX 0

R 7¹ A7 A alkyl, OONR R, CSNR R or C(NH)NR R ;

R and R are each independently H, alkyl, (C1־C₃ alkoxy )C^-C^ alkyl or hydroxy ^2־^C4 ^alkyi׳'

PEC 537 and pharmaceutically acceptable salts thereof.

In the above definition, unless otherwise indicated, alkyl or perfluoroalkyl groups having three or more carbon atans may be straight or branched chain. In addition alkenyl or alkynyl groups having four or more carbon atans, or alkoxy groups having three carbon atans, may be straight or branched chain.

. The compounds of formula (I) may contain one or more asymmetric centres and thus they can exist as enantianers or diastereoisomers. The invention includes both mixtures and separate individual isomers.

The canpounds of formula (I) may also exist in tautaneric forms and the invention includes both mixtures and separate individual tautaners.

Also included in the invention are radiolabelled derivatives of canpounds of formula (I) which are suitable for biological studies.

The pharmaceutically acceptable salts of the carpounds 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. Canpounds of the formula (I) can also provide pharmaceutically acceptable metal salts, particular alkali metal salts, with bases. Examples include the sodium and potassium salts.

A preferred group of compounds of the formula (I) is that

2 wherein R is H, methyl or ethyl; R is C^-C^ alkyl optionally ‘ 4 substituted by OH or methoxy; R is C₉־C-, alkyl or allyl; R taken m3 together with the nitrogen atom to which it is attached completes a piperidino or 4-N-(R⁶) piperazinyl group; R⁵ is H, NR⁷R⁸ or CONR⁷ R⁸ ; R⁶ is H, Cp C₃ alkyl, hydroxy C2-C3 alkyl, CONR⁷ R⁸ , CSNR⁷ R⁸ or C(NH)NR⁷R⁸ ;. and R⁷ and R⁸ are each independently H or methyl.

A particularly preferred group of compounds of the formula (I) is that wherein R^ is methyl; R2 is n-pfopyl; R^ is ethyl, n-propyl or allyl; R^ taken together with the nitrogen atom to which it is attached .completes a 4-N-(R⁶) piperazinyl group; R^ is H; and R^ is H, C]־C₃ alkyl or 2- hydroxyethyl.

Especially preferred individual compounds of the invention include: 5-[2-allyloxy-5-(4-methyl-l-piperazinylsulphonyl)phenyl]־l- methyl-3n-propyl- l,6-dihydro7־H-pyrazolo[4,3-d]pyrimidin-7־one;

5-[2-ethoxy-5-(l-piperazinylsulphonyl)phenyl]-l.-methyl-3-n-propyl- l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7־onp;'

5-[2-ethoxy-5-(4-methyl-l-piperazinylsulphonyl)phenyl]־l־ methyl-3-npropyl-1,6-dihydro - 7H-pyrazolo [4,3-d]pyrimidin-7-one;

5-{2-ethoxy-5 - [4-(2-propyl)-1 -piperazinylsulphonyl]phenyl} -1 - methyl-

3-n-propyl-l,6-dihydro7־H-pyrazolo[4,3-d]pyrimidin-7-one;

5-{2-ethoxy-5 - [4-(2-hydroxy ethyl)-1-piperaziny sulphonyl]-phenyl}-1 methyl-3-n־propyl-l,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one;

-methyl-5 - [5-( 1 -piperazinylsulphonyl)-2-n-propoxyphenyl]-3 -n-propyll_J6-dihydro7־H-pyrazplo[4,3-d]pyrimidin-7-one;

and 5-{5-[4-(2-hydroxyethyl)rl-piperazmylsulph0nyl]-2-n-propoxyphenyl}-lmethyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin7־-one.

PLC 537

5 . י . ., . ¹ >

, The canpounds of the general formula (I) may be prepared by the reaction of a canpound of the general formula (II):

<img file="IL98482A_D0002.tif" />

so₂y

2 3 (wherein R , R and R are as previously defined, and Y represents a halogen atan, preferably a chlorine atan) with a canpound of the .g general formula (III):

<img file="IL98482A_D0003.tif" />

(III)

5 wherein R and R are as previously defined.

The reaction is generally carried out at roan temperature, preferably in the presence of a solvent, for example an alkanol containing one to three carbon ,atans, using an excess of (III) to scavenge the acid by-product (HY).

Canpounds of the general formula (II) may be prepared fran canpounds of the general formula (IV):

PLC 537

<img file="IL98482A_D0004.tif" />

3 (wherein R , r and R are as previously defined) by the application of known methods for the introduction of a SO״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°C.

.

When R is a group susceptible to removal under the chlorosuiphonylation 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 R³ is H, and and R² are as previously defined, which is obtainable by Pd°-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, R³ is H, and R¹ and R² are as previously defined. The latter is then reacted with the appropriate amine (III) to afford a compound of thegeneral formula (I), wherein R³ is H, and R¹, R², R⁴ and R⁵ are as previously defined, which is finally O-alkylated to furnish a compound of the general formula (I), wherein R¹, R², R³, R⁴ and R⁵are as defined for formula (I). The alkylation may be effected

PLC 537

ד.

,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 is hydroxy C^-Cg 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 is hydroxy Cj-Cg alkyl, and R , R , R and R^כ are as defined for formula (I). These latter carpounds may also be obtained incidentally, as by-products, by chlorosulphonylation of the corresponding alkoxy

ר analogues, i.e. compounds of the general formula (IV) wherein R is (Cj-Cg alkoxy)C^-Cg 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):

<img file="IL98482A_D0005.tif" />

PIC 537

<img file="IL98482A_D0006.tif" />

3׳ 2 1 (wherein R , R and R are as previously defined) by the

, , ל application of known cyclisation methods for 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 , R and R are as previously defined, may also be employed as the precursor to (IV).

In an alternative cyclisation procedure, carpounds of the general formula (IV) may be obtained by treatment of (V) with polyphosphoric acid at or near 140°C for 6-18 hours.

Compounds of the general formulae (V) and (VI) may be prepared fran canpounds of the general formulae (VII) and (VIII) respectively:

PLC 537

<img file="IL98482A_D0007.tif" />

<img file="IL98482A_D0008.tif" />

(VIII) (wherein R and R are as previously defined) by reaction with a canpound of general.formula (IX):

OR³^,(IX) (wherein R 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 dichloranethane at 0°C to 25°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 caunercially available, can be obtained by conventional synthetic procedures, in accordance with literature precedent, fran readily accessible starting materials using standard reagents and reaction conditions.

PLC 537 . Certain of the carpounds of the general formula (I), wherein 4

R taken together with the nitrogen atari to which it is attached 6 6 completes a 4-N-(R )-piperazinyl group and R is as previously defined but not hydrogen, may be prepared directly fran the corresponding 4-N-unsubstituted piperazine analogue, that is a canpound of the general formula (I) wherein R⁶ 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 carpounds defined by formula (I) to be prepared.

The biological activities of the carpounds of the present invention were determined by the following test methods. Phosphodiesterase activity

Carpound affinities for cQiP and cAMP PDEs are assessed by determination of their IC^q values (the concentration of inhibitor required for 50% inhibition of enzyme activity). The PDE enzymes are isolated fran 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 c(34P-inhibited cAMP PDE enzymes are obtained fran 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. Tharpson and M.M. Appleman (Biochem., 1979, 18, 5228). Results fran these tests shew that the carpounds of the present invention

PLC 537 ,are potent and selective inhibitors of both cGMP PDEs.

Platelet anti-aggregatory activity

This is assessed by the determination of a carpound'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. Bom, J. Physiol. (Land), 1962, 162. 67P.

Antihypertensive activity

This is assessed following intravenous or oral administration of a carpound to spontaneously hypertensive rats. Blood pressure is recorded via a cannula irrplanted 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 carpounds 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 canpound, 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 fran 1-400 mg per single dose as required. In practice the physician will determine the actual

PLC 537 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 canpounds 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 canposition 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 canpound of the formula (I), or a pharmaceutically acceptable salt thereof, for

FLC 537 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 new 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 ?254.plates. Si-Nuclear magnetic resonance spectra were recorded using a Nicolet QE-300 spectrometer and were in all cases consistent with the proposed structures.

FLO 537

EXAMPLE l-Methyl-3־n-propvlpvrazole-5-carboxvlic 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. Pham. Bull., 1984, 32, 1568) and dimethyl sulphate (16.8 g, 0.133 mol) were heated to 90°C for 2.5. hours. The mixture was dissolved in dichlorcmethane and the solution washed with sodium carbonate solution. The organic phase was separated, dried (MgSO^) and evaporated under vacuum to give a solid. Chrcmatography on silica gel (300 g), eluting with dichlorcmethane gave the product as a colourless oil (20.4 g, 79%). Rf 0.8 (silica; dichlorcmethane, methanol, acetic acid; 80:20:1).

EXAMPLE l-Methyl-3-n-propylDvrazole-5-carboxylic acid l-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°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 brcwn crystals (12.3 g, 71%), m.p.

150-154°C. Found: 0,56.99; H,7.25; N,16.90. ΟθΗ^^Ο^ requires

0,57.13; H,7.19; N,16.66%.

EXAMPLE 3 l-Methyl-4-nitro-3-n-propylpyrazole-5-carboxylic acid l-Methyl-3־n-propylpyrazole-5-carboxylic acid (12.1 g, 0.072 mol) was added portionwise to a mixture of oleum (13 ml) and

PLC 537 ' . 15 ,fuming nitric acid (11 ml), keeping the temperature below 60⁴C. After the addition, the mixture was heated at 60°C overnight and then cooled to roan temperature before being poured onto ice. Filtration of the precipitate gave the nitropyrazole as a white solid (11.5 g, 75%), m.p. 124-127°C. Found: C,45.43; H,5.22;

N,19.42. CgH^N^ requires C,45.57; H,5.20; N,19.71%.

EXAMPLE l-Methyl-4-nitro-3-n-propvlpyrazole-5-carboxamide l-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 aianonium 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., 141-143*C. Found: C,45.22; H,5.71; N,26.12. requires C,45.28; H,5.70; N,26.40%.

EXAMPLE

4-Amino-l-methyl-3-n-propvlpyrazole-5-carboxamide l-Methyl-4-nitro-3-n-propylpyrazole-5-carboxamide (3.45 g,

16.2 nmol) and stannous chloride dihydrate (18.4 g, 81 nmol) were suspended in ethanol and the mixture heated under reflux for 2 hours. The resulting solution was cooled to roan temperature, basified to pH 9 by the addition of 2N aqueous sodium hydroxide

PLC 537

16 י .

,solution and extracted with dichloranethane. (3 x 150 ml). The organic extracts were combined, dried (MgSO₄) and evaporated under, vacuum. Trituration of the residue with ether gave the aminopyrazole as an off-white solid (2.77 g, 94%), m.p. 98-101’c. Found: C,52.84; H,7.81; N,30.38. CgH^N^O requires C,52.73; H,7.74; N,30.75%.

־ EXAMPLE 6 .

. -^2)־-Ethoxybenzamido)-l-methvl-3-n-propylpyrazole-5-carboxan11 Hp

A solution of 2-ethoxybenzoyl chloride (6.1 g, 33.0 nmol) in dichloranethane (50 ml) was added to a stirred solution of 4־amino-l-methyl-3-n-propylpyraz01e-5-carboxamide (3.0 g, 16.4 . irmol), 4-d±nethylaminopyridine (0.02 g, 0.164 nmol) and triethylamine (3134 g, 33.0'nmol) in dichloranethane (50 ml) at 0 C. The resulting mixture was allowed to warm to roan temperature and stirred for a further 2 hours. The solvent war evaporated under vacuum, the residue dissolved in a 19:1 n!i*tm-p . of dichloranethane and methanol (250 ml), and then the solution washed with IN hydrochloric acid (100 ml), dried (MgS0₄) and evaporated under vacuum. The crude material was chromatographed on silica gel (200 g), eluting with a 97:3 mixture of dichloranethane and methanol, to give a pink solid; crystallisation from ethyl acetate-hexane gave the 4-(2-Etl1oxybenzam1doJ-l methyl-3-n-propylpyrazole-5-carboxamide as a pale pink solid (2.2g, 40%), m.p. 153-155°C. Found: C,61.66; H,6.77; N, 16.95. C17H22N4O3 requires C,61.80; H,6.71; N, 16.96% '

PEC 537 ׳ r , EXAMPLE 7

5- (2-Ethoxyphenvl 1 -l-methvl-3-n-propyl-l. 6-dihydro-7H-pyrazoloΓ4,3-d1pyrimidin-7-one

4- ( 2-Ethoxybenzamido) -l-methyl-3-n-propylpyrazole-5carboxamide (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 dichloranethane (1 x 700 ml, 3 x 200 ml). The combined organic extracts were washed successively with saturated aqueous sodium carbonate solution (3 x 400 ml) and brine (300 ml), then dried (Na_?SO.) and evaporated under vacuum.

M *

Chranatography of the residue on silica gel (1000 g), using a methanol in dichloranethane elution gradient (0-1%), followed by trituration of .the crude product with ether (300 ml), gave the title carpound as a colourless solid (152.2 g, 72%), m.p. 143-146’C. Found: C,65.56; H,6.44; N,18.14. requires

C,65.36; H,6.45; N,17.94%.

EXAMPLE

5- (5-Chlorosulphonyl-2-ethoxyphenvl) -l-methyl-3-n-nrapyl-l. 6dihydro-7H-pvrazo 10 Γ 4,3-d1pyrimidin-7-one

5- (2-Ethoxyphenyl) -l-methyl-3-n-propyl-l, 6-dihydro-7Hpyrazolo[4,3-d]pyrimidin-7-one (10.0 g, 32.1 mmol) was added portionwise to chlorosulphonic acid (20 ml) at 0״C under a nitrogen atmosphere. After being stirred overnight, the reaction

<img file="IL98482A_D0009.tif" />

PLC solution was cautiously added to ice-water (150 ml) and the aqueous mixture extracted with a 9:1 mixture of dichloromethane and methanol (4 x'100 ml). The combined extracts were dried (Na2SO₄) and evaporated under vacuum to give the required sulphonyl chloride as a white solid (12.8 g, 97%), m.p. 179-181°C. Found: C/50.07; H,4.71; N,13.29. C₁₇H₁₉C1N₄O₄S requires C,49.70; H/4.66; N,13.64%.

EXAMPLE

5-Γ2-Ethoxy-5-(4-carbamoyl-1-piperidinylsulphonyl)phenyl 1 -1-methyl -3-n-propyl-1.6-dihydro-7H-pyrazolo Γ4,3-di 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-pyrazolo[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 x 100 ml) and all the organic fractions were. combined, dried (MgS0₄) 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. 274-276°C. Found: C,55.36; H,6.01;

N, 16.65. C23H30N6O5S requires C/55.08; H,5.83; N,16.75%.

PLC 537

EXAMPLES 10-14

The following carpounds were prepared by the procedure of

Example 9 using the appropriate amine.

<img file="IL98482A_D0010.tif" />

<img file="IL98482A_D0011.tif" />

<td> Example</td><td> f 4 N R</td><td> % yield</td><td> m.p. (°C)</td><td> Analysis % (Theoretical in brackets) C H N</td>

<td> 10</td><td> N___,א«</td><td> 51</td><td> 161-162</td><td> 54.82 6.13 17.95 (54.77 6.13 18.25)</td>

<td> 11</td><td></td><td> 79</td><td> 194-196</td><td> 54.63 6.47 16.50 (54.75 •6.39 16.65)</td>

<td> 12</td><td> tf \mc</td><td> 88</td><td> 187-189</td><td> 55.61 6.23 17.74 (55.68 6.37 17.71)</td>

. PbC 537

<td> 13 ' .</td><td> Q z -J</td><td> 21</td><td> 187-188</td><td> 57.48 (57.35</td><td> 6.74 6.82</td><td> 16.47 16.72)</td>

<td> 14</td><td> / n’-Pc</td><td> 74</td><td> 209-212</td><td> 57.64</td><td> 6.66</td><td> 16.81</td>

<td></td><td></td><td></td><td></td><td> (57/35</td><td> 6.82</td><td> 16.72)</td>

<td> 15</td><td> / \4CSNH₂</td><td> 18</td><td> 229-230</td><td> 51.25</td><td> 5.56</td><td> 18.92</td>

<td></td><td></td><td></td><td></td><td> (50.85</td><td> 5.63</td><td> 18.87)</td>

EXAMPLE

5-{2-Ethoxy •75־ Γ4- (methylthioimidoyl.) -1'p.iperazinylsulphonyl)

d.ihydro-7H־pyrazolo [4,3-d) -pyrimidin-7-one hydroiodide

A mixture of 5-[2-ethoxy-5-(4-thiocarbamoyl-lpiperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (0.78g, 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. 227-228°C. Found: C, 41.43; H,4.79; N,14.42.

C23^H31N₇0₄S2;HI requires C,41.75; H,4.88; N,14.82%

PLC 537

EXAMPLE'17, residue triturated with ether.

light brown gave the title 253-255°C.

־ ׳ g - (,2-Ethoxy-5- Γ4- (methylamidino) -1-ρ1ρ£Γα2;.χην15ν,10^0ΠΥ1] ph^hyl },:.12. methyl-3-n-propyl-1,6-dihydro-7H-pyra7n10 [4,3-41 .hy_dKQlQdlti.e . .

5- {2-Sthoxy-5- [4-methylthioimidoyl) -1-piperazinylsulphonyl] phenyl}-l-methyi-3-n-propyl-l, 6-dihydro-7H-pyrazolo[4,3-d] pyrimidin-7-one hydroiodide (0.5 g, ^;0.75 mmol) was added to a 3,3% solution of methylamine in ethanol (20 ml) and the mixture stirred at room temperature for 13 hours. The solution was evaporated under vacumm and the

Chromatography of the resulting solid on silica gel (10 g) , using a methanol in dichloromethane elutipn gradient (0-4%), followed by trituration of the crude product with ether, gave a powder. Crystallisation from ethyl acetate-methanol . compound as colourless crystals (112 mg, 23%), m.p.

Found: C,42^90; H,5.09,; N,17.41. C23H32N8O4S; HI ' requires C,42.86; H,5.16; N,17.39-s., ״ EXAMPLE 18l-Methyl-4- (2-n-propoxybenzamido) -S-h-pWYW^oU 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. 148-149°C. Found: C,62.97; H,7.00; N,16.29. C_1aH₂4N₄03 requires C,62.77; H,7.02; N,16.27%.

EXAMPLE ^rnyT-s-^-n-prosoxvo^

Γ4,3-di pyrimidin־7־Q,na.

l-Methyl-4-(2-n-propoxybenzamido)-3-n-propylpyrazole-5. PLC 537 . .

98482/2 י .

,carboxamide (0.34 g, 0.99 irmol) was added to a stirred mixture of 30% hydrogen peroxide solution (.1.0 ml), potassium carbonate (0.54 g, 3.92 nmol), 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 dichloronethane (3 x 20 ml) . The extracts were combined, dried ’ (Na SO ). and evaporated under vacuum. The resulting residue was 2 4 daranatographed on silica gel (6g), using a methanol in dichlorarethane 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. 111-114°C. Found:

. C,,66.26; H,6.92; N,17.15. requires C,66.23; H,6.80;

N,17.17%.

EXAMPLE

5- (s-ehlorosulphonvl-Z-n-propoxyphenvl) -1-methyl -3-n-propyl-l, 6r di hvdro7־H-pyrazolor 4,3-41pvrimidin7־-one

This sulphonyl chloride was prepared fran 5-(2-n-propoxyphenyl)-l-roethyl-3-n-propyl-l, 6-dihydro-7H-pyrazolo[4,3-d] pyrimidin-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^g^ClN^S requires 0,50.88; H,4.98; N,13.19%.

EXAMPLE 21 l-Methyl-5-r5-(l-pipera^nylsnlphonyl)-2-n-propoxyphenvn-3-n-propvl-1.6dihydro-7H-pyrazolor4.3-d1nyrimidin-7-.Qng.

This sulphonamide was prepared from piperazine and

TLC 537 98482/3

5-(5-chlorosulphonyl-2-n-prop.oxyphenyl)-l-methyl-3-n-propyl-l, 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. 185-186°C.. Found: 0,56.17; H,6.38,- N, 17.65;. C22H30^N6°4^s requires

0,55.67; H,6.37; N,17.71%.

EXAMPLE .

₅_(5- [4- (2-Hydroxyethyl) -1-ρΪΡ6Γβζ1ηγ15νλρη&lt;?ΠΥλ)-Σ^η^ . propxyphenvl} -l-methyl3־-n-propyl-l. 6-όχ^νΦ£Ρ7־Η:.ργΓβΖί.Ρ-1.Ω-ί.ά.,.3 ־

This, sulphonamide'was prepared־ from N-(2-hydroxyethyl) piperazine and 5- (5”Chlorosulphonyl”2“n-propoxyphenyl) ־l-methyl-3־ ׳. n-propyl-l, 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. 158-159°C. Found: 0,55.83; H,6.58; N,.16:13.

• ^C24^H34^N6°5^S requires C,5^!5.58; H,6.61; N,16.20%.

EXAMPLE ' / 4- (2-Allyloxybenzan1ido)-l-methyl-3־n-proPVlPY^^e-S-gfirfePCTidg 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-l-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 dichioromethane. The combined organic solutions were ' _washed with 2M HC1 (3 x 30 ml), then brine (1 x 30 ml) , and dried

PLC 537 (Ν&amp;2θθ4)׳ After filtration and evaporation under vacuum of the filtrate, the crude product was crystallised from ethyl acetate to give the title carpound (4.525 g, 66%), m.p. 132-134°€. Found:

C,63.49; H,6.42; N,16.33. requires C,63.14; H,6.48;

N,16.36%.

EXAMPLE .

5- (2-Allyloxvphenvl)-l-methvl-3-n-propyl-l. 6-dihydro-7H-pyrazoloΓ 4,3-d1pyrimidin-7-one

A mixture of 4-(2-allyloxybenzamido)-l-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^SO^), 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.

116-119°C. Found: C,67.00; H,6.21; N,17.23.

^C18^H20^N4°2

C,66.65; H,6.21; N,17.27%.

EXAMPLE

5- (2-Hvdroxyphenvl) -l-methvl-3-n-propvl-l, 6-dihvdro-7H-pvrazoloΓ 4,3-d]pyrimidin-7־one ך A mixture of 5-(2-allyloxyphenyl)-l-methyl-3-n-propyl-l,6dihydro-7H-pyrazolo[4,3-d]pyrimidin-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

PLC 537 ahpolute ethanol (5 ml) 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 x 10 ml), IM HC1 (3 x 10 ml) and brine (1 x 10 ml). After drying (Na₂SO₄) 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. 233-238’C. Found: C,63.17; H,5.65; N,19.52.

requires C,63.36; H,5.67; N,19,71%.

EXAMPLE

5- (5-Chlorosulphonyl-2-hydroxvphenyl) -l-methyl-3-n-DroDvl-l. 6dihydro-7H-pyrazolor4.3-d1pyrimidin-7-one

5- (2-Hydroxyphenyl) -l-methyl-3-n-propyl-l, 6-dihydro-7Hpyrazolo[4,3-d]pyrimidin-7-one (0.239 g, 0.00084 mol) was added, in portions, to stirred chlorosulphonic acid (3 ml) cooled to 0״C under a nitrogen atmosphere, and the resulting deep red solution stirred at roan 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 dichloranethane (3 x 30 ml), the combined extracts dried (Na_SO.) 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; dichloranethane, methanol; 95:5).

^FLC 537 ’26 EXAMPLE 27 5-r2-Hydroxy4)-5־-methyl-1-piperazinylsulphonyl)phenyl] -1-methyl I

3-n-propyl-l,6-dihydro-7H-pyrazolo Γ4,3-dlpyrimidin־7־one

A solution of 5-(5-chlorosulphonyl-2-hydroxyphenyl)-1-methyl-

3-n-propyl-l,6-dihydro-7H-pyrazolo[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 (01260 g, 49%), m.p. 283-284°C. Found: C,53.53; H, 5.89 ,. N, 18.40. C₂₀H₂₆Ng0₄S requires C,53.80; H,5.87; N,18.82%.

EXAMPLE 5-Γ2-Allyloxy4)־5־-methyl-l-piperazinylsulphonyl)phenyl]-1-methyl-

3-n-propyl-l, 6-dihydro-7H-pyrazolo 14.3־-dl pyrimidin-7-one

Allyl bromide (0.02 ml, 0.00023 mol) was added to a stirred suspension of 5-[2-hydroxy-5-(4-methyl-l-piperazinylsulphonyl)phenyl] -1-methyl-3-n-propyl-l,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 x 20 ml), the combined extracts dried (Na₂SO₄) and, after filtration, evaporated under vacuum to give an oil. Column

PLC 537 .

• f׳ _ξchranatography on silica gel (2 g) using a methanol in dichloranethane 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 carpound (0.011 g, 10%), m.p. 151-153’C, Rf 0.5 (silica; dichloranethane, methanol; 95:5), m/e 487 (M⁺+l),

EXAMPLE

4- (2-Ethoxvbenzamido)-l,3-dimethylpyrazole-5-carboxamide

This amide was prepared from 4-amino-l,3-dimethylpyrazole-5carboxamide (prepared by the method of J. Med. Chan 1987, 30, 91), following the procedure of Example 6, and was obtained as a white solid (81%), m.p. 178-181°C. Found: C,59.89; H,6.05; N,18.44. ^C15^H18^N4°3 C,59.59; H,6.00; N,18.53%.

EXAMPLE

5- (2-Ethoxvphenyl) -1,3-dimethyl-l. 6-dihydro-7H-pyrazolo Γ 4,3-dlpyrimidin-7-one

4-(2-Ethoxybenzamido)-1,3-dimethylpyrazole-5-carboxamide (1.6 g, 5.29 mnol) was added to polyphosphoric acid (50 g) and the mixture heated to 140°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 dichloranethane (3 x 100 ml). The organic extracts were combined, dried (MgSO^) and evaporated under vacuum. The residue was chromatographed on silica gel eluting with a 97:3 mixture of dichloranethane and methanol. Crystallisation of the crude product fran aqueous ethanol gave the title carpound as a

PLC 537 _:colourless solid, m/p. 201-204°C. Found: C,63.43; H,5.57; N,19.35. requires C,63.36; H,5.67; N,19.71%.

EXAMPLE

5- (5־Chlorosulphonyl-2-ethoxyphenyl 1 -1.3-dimethyl-l. 6-di hydro-THpyrazolof 4.3-d1pvrimidin-7-one

This sulphonyl chloride was prepared from 5-(2-ethoxyphenyl)-1,3-diroethyl-l, 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-l, 6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one and the appropriate amine following the procedure of Example 9.

PLC 537

<img file="IL98482A_D0012.tif" />

<td rowspan="2"> Example</td><td rowspan="2"> 4 N R</td><td rowspan="2"> % yield</td><td rowspan="2"> m.p. (°C)</td><td colspan="3"> Analysis % (Theoretical in brackets)</td>

<td> C</td><td> H</td><td> N</td>

<td> 32</td><td> N NMe</td><td> 68 ,</td><td> 225-226</td><td> 53.88 (53.79</td><td> 5.81 5.87</td><td> 18.42 18.82)</td>

<td> 33</td><td> N NH</td><td> 68</td><td> 240-242</td><td> 53.07 (52.76</td><td> 5.77 5.59</td><td> 19.27 19.43)</td>

<td> 34</td><td> N N/\Z^0H \____'</td><td> 62</td><td> 228-229</td><td> 53.23 (52.93</td><td> 5.87 5.92</td><td> 17.72 17.63)</td>

PLC 537 , EXAMPLE 35

4-Nitro-3-n-nropylpyrazole-5-carboxvlic acid

3-n-Prppylpyrazole-5-carix)xylic acid (prepared by the method of Chau. ?harm. Bull. 1984, 32, 1568), was nitrated following the procedure of Example 3, to give the title canpound as a colourless solid (75%), m.p. 169-173°C. Found: C,42.35; H,4.56; N,21.07. C_?HgN₃O₄ requires C,42.21; H,4.55; N,21.10%.'

EXAMPLE 36

4-Nitro-3-n-propvlpyrazole-5־carboxamide

- A mixture of 4-nitro-3-n-propylpyrazole-5-carboxylic acid (7.8 g, 39.2 nmol) 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 airmonium hydroxide solution (40 ml) at 0°C. The.mixture was then diluted with water (60 ml) and extracted with a 9:1 mixture of dichloranethane and methanol (3 x 100 ml). The organic fractions were canbined, dried (MgSO^) and evaporated under vacuum, and the residue crystallised fran ethanol to give the carboxamide as a colourless solid (1.0 g, 13%), m.p. 202-206°C. Ebund: C,42.35; H,5.01; N,28.38. C^qN^ requires C,42.42; H,5.09; N,28.27%.

EXAMPLE

4-Amino-3-n-prOpylpyrazole-5-carboxanu.de

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 nmol), 10% palladium on carbon

PLC 537 (5 mg) and water (3 ml). The mixture was stirred at roan temperature for 3 hours, filtered and the solvent removed by evaporation under vacuum. Crystallisation of the residue fran ethyl acetate-methanol gave the title catpound as an off-white solid (61 mg, 36%), m.p. 196-201°C. Rf 0.4 (silica;

dichloranethane, methanol, anmonium hydroxide; 90:10:1). Found: C,48.96; H,6.98; N,32.08. requires C,49.98; H,7.19;

N,33.31%.

EXAMPLE

4- (2-Ethoxybenzamido)-3-n-propylpvrazole-5-carboxa[nide

The title amide was prepared fran 4-amino-3-n-propylpyrazole-

5- carboxamide following the procedure of Example 6, and was obtained as a white solid (64%), m.p. 209-211°C. Found: C,60.73;

H,6.41; N,17.80. requires C,60.74; H,5.37; N,17.71%.

EXAMPLE

5-(2-Ethoxyphenyl)-3-n-propyl-l,6-dihydro-7H-pyrazoloΓ 4,3-dlpyrimidin-7-one

The title carpound was prepared fran 4-(2-ethoxybenzamido)-3n-propyl-pyrazole-5-carboxamide, following the procedure of Example 30 and was obtained as a white solid (16%), m.p. 199-201°C.

Found: C,64.44; H,6.19; N,18.44%. C,64.41;

H,6.08; N,18.78%.

EXAMPLE

5-(5-Chlorosulphonvl-2-ethoxyphenvl)-3-n-propyl-l,6-dihvdro-7HpyrazoloF4.3-d1pvrimidin-7-one ׳

The title sulphonyl chloride was prepared fran

WLC 537, 98482/2

י י י ו

5-(2-ethoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one following the procedure of Example 8 and was obtained as a white solid (78¾). Rf 0.25 (silica;ether).

It was used without further purification.

EXAMPLE 5-r2-Ethoxy-5-(4-methyl-1-piperazinyl)sulphonylphenyll -3-n-propyl1,-6-dihydro-7H-pyrazoloi4.3-dipyrimidin-7-one

The title sulphonamide was prepared from 5-(5-chlorosulphonyl-2-ethoxyphenyl) -3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3d]pyrimidin-7-ohe following the procedure of Example 9 and was obtained as a white solid (70%), m.p.236-239°׳C. Found: C,54.84; H,6.27; N,18.10. C₂₁H₂₈N₆O₄S .requires C,54.76; Η,β.13; N,18.25¾.

EXAMPLE

3-Bromomethyl-5-chloro-l-1nethyl-4־nitropyrazole N-Bromosuccinimide(10:7 g, 60.0 mmol) was added to a solution of 5-chloro-l,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 x 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. 80-8'2°C. Found: C,23.95; H,2.05;

N,16.31. C₅H₅BrClN3O₂ requires C,23.60; H,1.98; N,16.51%.

PLC 537 , EXAMPLE 43

5-Chloro-3-methoxvmethvl-l^nethvl-4-nitroovrazole

A solution of 3-brananethyl-5-chloro־־l-rrethyl-4-nitropyrazole (5.0 g, 19.6 nmol) in methanol (50 ml) was treated with silver nitrate (5.75 g, 33.8 nmol) 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^) and evaporated under vacuum. Chromatography on silica gel, eluting with a 97:3 mixture of dichlorcmethane and methanol, gave the title pyrazole as a.white solid (1.6 g, 40%), m.p. 59-63°C. Found: C,34.65; H,3.83; N,20.05. ΌθΗθΟίΝ^ requires C,35.05; H,3.92; N,20.44%.

EXAMPLE 5-Cyano-3-methoxvmethvl-l-methvl-4-nitroDvrazole

A solution of. 5-chloro-3-methoxymethyl-l-methyl-4-nitropyrazole (205 mg, 1.0 irmol), potassium cyanide (130 mg, 2.0 nmol) and 18-crcwn-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.) 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

PLC 537 ,provided a yellow solid (3.8 mg, 19%), m.p. 48-50°C. Found: C,42.89; H,4.15; N,28.78. Ο₇ΗθΝ₄Ο₃ requires C,42.86; H,4.11; N,28.56%.

EXAMPLE

4- Amino-5-cyano-3-met±10xymethyl-l-1nethylpvrazole

The title catpound was prepared f rar 5-cyano-3-meth0fxymethyll-methyl-4-nitropyrazole following the procedure of Example 5 and was obtained as an off-white solid (68%), m.p. 82-84°C. Found: C,50.81; H,6.13; N,33.94. requires C,50.59; H,6.07;

N,33.72%

EXAMPLE 46

5- Cvano-4- (2-ethoxybenzamido)-3-methoxvmethyl-l-irethylpyrazole

The title compound was prepared fran 4-amino-5-cyano-3methoxymethyl-l-methylpyrazole following the procedure of Example 6 and was obtained aS an off-white solid (61%), m.p. 103- .

105°C. Found: C,61.21; H,5.98; N,17.80. requires

C,61.13; H,5.77; N,17.83%. >

EXAMPLE

5- (2-Ethoxyphenyl) -3-methoxymethyl-l-methyl-l, 6-dihvdro-7Hpyrazolo Γ 4,3-d1pyrimidin-7-one

The title compound was prepared fran 5-cyano-4-(2-ethoxybenzamido)-3-methoxymethyl-l-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. 160-161°C. Found: C,61.35; H,5.75; N,17.98. C^gN^

Be 537 98482/2 _: requires C,61.13; H,5.77; N,17.83%.

EXAMPLE 3“Methoxymethyl-l-methyl5־-Γ5-(4-methyl-l-piperazinylsulphonyl)-2ethoxyphenyl11,6-dihydro7־H-pyrazolor4,3-d1pyrimidin-7-one .5-(2-Ethoxyphenyl)-3-methoxymethyl-1-methyl-1,6-dihydro-7Hpyrazolo[4,3-d]pyrimidin-7-one (470 mg, 1.50 mmol) was dissolved in. chlorosulphonic acid (3 ml) at O°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 x 50 ml). The combined organic extxa'cts were evaporated under vacuum and the residue was dissolved in ethanol (5 ml) and the solution treated with Nmethylpiperazine (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. 198-199°C. Found: C,52.94; H,6.04; N,17.67. C₂1H₂8N₆O₅S requires C,52.93; H,5.92; N,17.64%.

Also isolated following chromatography and crystallisation from a mixture of ethyl acetate and methanol was 3-hydroxymethyl־ l-methyl-5-Γ5-(4-methyl-1-piperazinylsulphonyl)-2-ethoxyphenyl1 -

1.6-dihydro-7H-pyrazolo 14,3־-dipyrimidin-7-one as a white solid (51mg,.7%), m.p. 209-210°C. Found: C,51.94; H,5.77; N,18.05. C₂₀H₂gNgO₅S requires C,51.94; H,5.67; N,18.17%.

PLC 537

EXAMPLE l-Ethyl-3-n-prcpylpyrazole-5-carboxylic acid ethyl ester

This pyrazole was prepared from 3-n-propylpyrazole-5carboxylic 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 l-Ethvl-3-n-proDvlpyrazole-5-carboxvlic acid

This carboxylic acid was: prepared f ran l-ethyl-3-n-prppylpyrazole-5-carboxylic acid ethyl ester, following the procedure described in Example 2, and was obtained as a pale brown solid (89%), m.p. 73-77°C. Found C, 58.62; H,7.69; N,15.23.

requires C,59.32; H,7.74; N,15.37%.

. EXAMPLE 51 l-Ethyl-4-nitro-3-n-Dropvlpvrazole-5-carboxylic acid

The title carpound was prepared fran l-ethyl-3-n-propylpyrazole-5-carboxylic acid, following the procedure described in Example 3, and was obtained cis a colourless solid (96%), m.p. 120-123°C. Found: C,47.61; H,5.81; N,18.54. CgH^N^O^ requires C,47.57; H,5.77; N,18.49%.

EXAMPLE l-Ethyl-4-nitro-3-n־pr0DvlDvrazole-5-carboxamide

The title amide was prepared fran l-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.

PIC 537 ,119-120°€. Found: C,47.38; Η,6.18; N,24.34: Cg^N^ requires C,47.78; H,6.24; N,24.77%

EXAMPLE

4- Amino-l-ethyl-3-n-propylpvrazole-5-carboxamide

The title caipound was prepared fran l-ethyl-4-nitro-3-nprppyIpyrazole-5-carboxamide, by the procedure described in Example 5, and was obtained as an off-white solid (100%), m.p. 93-97°C. Found: C,55.17; H,8.34; N,28.93. C_QH,,N.O requires

4 10 ע י

C,55.08; H,8.22; N,28.55%.

. EXAMPLE 54

42)־-EthQxybenzamido)-l-ethyl-3-n-propylpyrazole-5-carboxamide

The title amide was prepared from 4-amino-l-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. 139-141°C. Found: C,63.03; H,7.15; N,16.50.

.^C18%4^N4°3 C,62.77; H,7,02; N,16.27%.

EXAMPLE .-

5- (2-Ethoxyphenvl)-l-ethyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3dlpyrimidin-7-one

The title canpound was prepared fran 4-(2-ethoxybenzamido)l-ethyl-3-n-propylpyrazolo-5-Cc1rboxamide following the procedure of Example 7, and was obtained as a colourless solid (46%), m.p. 112-114°C. Found: C,66.59; H,6.85; N,17.26. requires

C,66.23; H,6.79; N,17.17%.

WlC 537 98482/2

EXAMPLE

5-(5-Chlorosulphonyl-2-ethoxyphenyl)-1-ethyl-3-n-propyl-1.6dihy'dro-7H-pyrazolo Γ4,3-d1pyrimidin-7-one

The title compound was prepared from 5-(2-ethoxyphenyl)-1ethyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one following the procedure of Example 8, and was obtained as a methylene chloride solvate (86%), m.p. 170-172°C. found: C,49.82; H,4.84; N,12.77. C₁₈H₂₁C1N₄O₄S; 1/6 CH₂C1₂ requires C,49.70; H,4.90; N,12.77%.

EXAMPLE ' 5-Γ2-Ethoxy-54)־-methyl1־-piperazinylsulphonyl)phenyll -l-ethyl-3n-propyl-1,6-dihydro-7H-pyrazolo14.3-d]pyrimidin-7-one

The title sulphonamide was prepared from 5-.(5-chlorosulphonyl-2-ethoxyphenyl)-l-ethyl-3-n-propyl-1,6-dihydro-7Hpyrazolo[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. 160-162°C. Found: C,57.24׳; H,6.17; N,16.83. C₂3H3₂NgO₄S requires C,56.54; H,6.60; N,17.20%. Rf 0.35 (silica; dichloromethane, methanol; 9:1).

EXAMPLE 5-{2-Ethoxy-5- (4- (2-hydroxyethyl.) -1-piperazinylsulphonyl]phenyl}l-ethyl-3-n-propyl-1.6-dihydro-7H-pyrazolo(4.3-di pyrimidin-7-one The title sulphonamide was prepared from 5-(5-chlorosulphonyl-2-ethoxyphenyl)-l-ethyl-3-n-propyl-l,6-dihydro-7Hpyrazolo[4,3-d]pyrimidin-7-one and N-(2-hydroxyethyl)piperazine following the procedure of Example 9 and was obtained as a

PDC 537 , colourless solid (88%), m.p. 191-193°C. Found: C,55.74; H,6.55;

N,15.78. C₂^Ij4N₆0₅S requires C,55.58; H,6.61; H,16.20%.