Compounds are disclosed which are useful as PDE1 inhibitors. The compounds have the formula: ##STR1##

The present invention relates to compounds, including inter alia
 pharmaceutical compositions comprising the same and methods for making the
 same.
 In particular, the present invention relates to compounds that are capable
 of exhibiting inhibition of a phosphodiesterase (PDE) enzyme.
 More in particular, the present invention relates to compounds that are
 capable of exhibiting at least inhibition of a phosphodiesterase type 1
 (PDE1) enzyme--i.e. the compounds are capable of acting as inhibitors of
 PDE1. Some of these compounds are also capable of exhibiting inhibition of
 other types of PDE enzymes--such as a phosphodiesterase type 5 (PDE5)
 enzyme.
 By way of background information, EP-A-0201188 discloses certain
 5-substituted pyrazolo[4,3-d]pyrimidin-7-ones and suggests their use for
 the treatment of cardiovascular disorders, such as heart failure or
 cardiac insufficiency. EP-A-0201188 also suggests the use of those
 5-substituted pyrazolo[4,3-d]pyrimidin-7-ones to inhibit PDE.
 In particular, Example 1 of EP-A-0201188 discloses the following
 5-substituted pyrazolo[4,3-d]pyrimidin-7-one:
 ##STR2##
 For ease of reference this compound will be referred to as the '188
 Compound. Like the '188 compound, all of the compounds of EP-A-0201188
 have a methyl group attached at the 3 position of the
 pyrazolo[4,3-d]pyrimidine ring system.
 We have found that the '188 compound is at least a weak PDE1 inhibitor.
 Furthermore, as there is now a body of evidence associating PDE1 with a
 number of diseases, e.g. stroke, dementia, memory enhancement,
 atherosclerosis, urge incontinence, hypertension, angina pectoris,
 congestive heart failure, myocardial infarction and restenosis, so there
 is a need to have more potent PDE1 inhibitors.
 There is also a need to have more selective PDE inhibitors, in particular
 PDE1 inhibitors.
 The present invention seeks to provide compounds that are useful as PDE1
 inhibitors, including pharmaceutical compositions comprising the same and
 methods for making the same.
 According to a first aspect of the present invention there is provided a
 compound of the formula (I)
 ##STR3##
 wherein
 R.sub.a is C.sub.2 -C.sub.6 alkyl;
 R.sub.1 is H or C.sub.1 -C.sub.4 alkyl;
 each of R.sub.2 and R.sub.3 is independently selected from H and C.sub.1
 -C.sub.4 alkyl, or
 R.sub.2 is H or C.sub.1 -C.sub.4 alkyl and R.sub.3 is OH, C.sub.2 -C.sub.4
 alkanoyloxy or fluoro, or
 R.sub.2 and R.sub.3 when taken together represent C.sub.2 -C.sub.6
 alkylene, or
 R.sub.2 and R.sub.3 when taken together with the carbon atom to which they
 are attached represent a carbonyl group;
 Ar is either (a)
 ##STR4##
 wherein each of R.sub.4, R.sub.5 and R.sub.6 is independently selected
 from
 H,
 C.sub.1 -C.sub.4 alkyl,
 C.sub.1 -C.sub.4 alkoxy,
 C.sub.1 -C.sub.4 alkoxy-Z--,
 halo,
 halo(C.sub.1 -C.sub.4)alkyl,
 phenoxy, optionally substituted by up to three substitutents each of which
 substituent is independently selected from halo, C.sub.1 -.sub.4 alkyl,
 and C.sub.1 -C.sub.4 alkoxy,
 nitro,
 hydroxy,
 hydroxy-Z--,
 C.sub.2 -C.sub.4 alkanoyl,
 amino,
 amino-Z--,
 (C.sub.1 -C.sub.4 alkyl)NH,
 (C.sub.1 -C.sub.4 alkyl).sub.2 N--,
 (C.sub.1 -C.sub.4 alkyl)NH--Z--
 (C.sub.1 -C.sub.4 alkyl).sub.2 N--Z--,
 --COOH,
 --Z--COOH,
 --COO(C.sub.1 -C.sub.4 alkyl),
 --Z--COO(C.sub.1 -C.sub.4 alkyl)
 C.sub.1 -C.sub.4 alkanesulphonamido,
 C.sub.1 -C.sub.4 alkanesulphonamido-Z--,
 halo(C.sub.1 -C.sub.4)alkanesulphonamido,
 halo(C.sub.1 -C.sub.4)alkanesulphonamido-Z--,
 C.sub.1 -C.sub.4 alkanamido,
 C.sub.1 -C.sub.4 alkanamido-Z--,
 HOOC--Z--NH--,
 HOOC--Z--NH--Z--,
 (C.sub.1 -C.sub.4 alkyl)OOC--Z--NH--,
 (C.sub.1 -C.sub.4 alkyl)OOC--Z--NH--Z--,
 C.sub.1 -C.sub.4 alkl-NH--SO.sub.2 --NH--,
 C.sub.1 -C.sub.4 alkyl-NH--SO.sub.2 --NH--Z--,
 (C.sub.1 -C.sub.4 alkyl).sub.2 -N--SO.sub.2 --NH--,
 (C.sub.1 -C.sub.4 alkyl).sub.2 -N--SO.sub.2 --NH--Z--,
 C.sub.1 -C.sub.4 alkoxy CH.dbd.CH--Z--CONH--,
 C.sub.1 -C.sub.4 alkoxy CH.dbd.CHCONH
 C.sub.1 -C.sub.4 alkyl-SO.sub.2 --N(C.sub.1 -C.sub.4 alkyl)-,
 C.sub.1 -C.sub.4 alkyl-SO.sub.2 --N(C.sub.1 -C.sub.4 alkyl)-Z--,
 (C.sub.1 -C.sub.4 alkyl)NH--Z--SO.sub.2 --NH--,
 (C.sub.1 -C.sub.4 alkyl).sub.2 N--Z--SO.sub.2 --NH--,
 (C.sub.1 -C.sub.4 alkyl)NH--Z--SO.sub.2 --NH--Z--,
 (C.sub.1 -C.sub.4 alkyl).sub.2 N--Z--SO.sub.2 --NH--Z--,
 benzenesulphonamido, optionally ring substituted by up to three
 substitutents each of which is independently selected from halo, C.sub.1
 -.sub.4 alkyl, and C.sub.1 -C.sub.4 alkoxy,
 C.sub.1 -C.sub.4 alkanoyl-N(C.sub.1 -C.sub.4 alkyl)-,
 C.sub.1 -C.sub.4 alkanoyl-N(C.sub.1 -C.sub.4 alkyl)-Z--,
 C.sub.1 -C.sub.4 alkoxycarbonyl-CH(CH.sub.2 OH)NHSO.sub.2 --,
 --SO.sub.3 H,
 --SO.sub.2 NH.sub.2,
 H.sub.2 NOC--CH(CH.sub.2 OH)--NHSO.sub.2 --,
 HOOC--Z--O--, and
 (C.sub.1 -C.sub.4 alkyl)OOC--Z--O--,
 or optionally one of R.sub.4, R.sub.5 and R.sub.6 is a G-Het group and
 wherein the others of R.sub.4, R.sub.5 and R.sub.6 are independently
 selected from the R.sub.4, R.sub.5 and R.sub.6 subsituents listed above;
 Z is C.sub.1 -C.sub.4 alkylene,
 G is a direct link, Z, O, --SO.sub.2 NH--, SO.sub.2, or --Z--N(C.sub.1
 -C.sub.4 alkyl)SO.sub.2 --,
 Het is a 5- or 6-membered heterocyclic group containing 1, 2, 3 or 4
 nitrogen heteroatoms; or 1 or 2 nitrogen heteroatoms and 1 sulphur
 heteroatom or 1 oxygen heteroatom; or the heterocyclic group is furanyl or
 thiophenyl; wherein the Het group is saturated or partially or fully
 unsaturated and optionally substituted by up to 3 substituents, wherein
 each substituent is independently selected from C.sub.1 -C.sub.4 alkyl,
 oxo, hydroxy, halo, and halo(C.sub.1 -C.sub.4) alkyl;
 or (b) any one of the following bicyclic groups:
 benzodioxolanyl,
 benzodioxanyl,
 benzimidazolyl,
 quinolinyl,
 indolyl,
 quinazolinyl,
 isoquinolinyl,
 benzotriazolyl,
 benzofuranyl,
 benzothiophenyl,
 quinoxalinyl, or
 phthalizinyl,
 wherein said bicyclic Ar groups are linked to the neighbouring --C(R.sub.2
 R.sub.3)-- group via the benzo ring portion,
 and wherein the heterocyclic portion of said bicyclic Ar group is
 optionally partially or fully saturated, said group being optionally
 substituted by one or more of C.sub.1 -C.sub.4 alkyl, halo, hydroxy, oxo,
 amino, and C.sub.1 -C.sub.4 alkoxy;
 or a pharmaceutically acceptable salt of the compound, or a
 pharmaceutically acceptable solvate of the compound or the salt.
 This and some of the other aspects of the present invention, as well as
 some preferred embodiments of the present invention, are presented in the
 accompanying claims.
 It will also be appreciated that what is to be claimed includes the
 following:
 (i) a compound of the formula (I) or a pharmaceutically acceptable salt
 thereof;
 (ii) one or more processes for the preparation of a compound of the formula
 (I) or a pharmaceutically acceptable salt thereof;
 (iii) novel intermediates for use in any one of those processes;
 (iv) a pharmaceutical composition comprising a compound of the formula (I),
 or a pharmaceutically acceptable salt thereof, admixed with a
 pharmaceutically acceptable diluent, carrier or excipient;
 (v) a compound of the formula (I), or a pharmaceutically acceptable salt or
 composition thereof, for use as a medicament;
 (vi) the use of a compound of the formula (I), or of a pharmaceutically
 acceptable salt or composition thereof, for the manufacture of a
 medicament for the treatment of conditions capable of being treated by the
 inhibition of PDE enzymes;
 (vii) use as in (vi) wherein the medicament is for use as an inhibitor for
 PDE1;
 (viii) a method of treatment of a subject (e.g. a mammal) in need of same,
 which method comprises administering to the subject an effective amount of
 a compound of the formula (I) or a pharmaceutically acceptable salt or
 composition thereof, and wherein the compound, salt or composition
 produces an inhibitory effect against a PDE; and
 (ix) a method as in (viii) wherein the compound, salt or composition
 produces an inhibitory effect against PDE1.
 By way of example, a preferred process according to one embodiment of the
 present invention for preparing compounds according to the present
 invention is presented by the following scheme:
 ##STR5##
 wherein each of the groups are as defined above.
 By way of further example, a preferred process according to another
 embodiment of the present invention for preparing compounds according to
 the present invention is presented by the following scheme:
 ##STR6##
 wherein each of the groups are as defined above, and wherein R.sub.7 is H
 or C.sub.1-4 alkyl, and wherein X is C.sub.1-4 alkyl,
 halo(C.sub.1-4)alkyl, or optionally substituted phenyl.
 By way of further example, a preferred process according to another
 embodiment of the present invention for preparing compounds according to
 the present invention is presented by the following scheme:
 ##STR7##
 wherein each of the groups are as defined above.
 By way of example, a preferred intermediate for one embodiment of the
 present invention is
 ##STR8##
 wherein each of the groups are as defined above.
 By way of further example, a preferred intermediate for another embodiment
 of the present invention is
 ##STR9##
 wherein each of the groups are as defined above.
 By way of further example, a preferred intermediate for another embodiment
 of the present invention is
 ##STR10##
 wherein each of the groups are as defined above.
 A key advantage of the present invention is that it provides compounds, and
 compositions comprising the same, that are useful as PDE1 inhibitors.
 Another key advantage of the compounds of the present invention is that
 some are selective PDE inhibitors, in particular selective PDE1
 inhibitors.
 As indicated above, the compounds of the present invention are of the
 general formula (I). We have surprisingly found that these compounds are
 effective as PDE1 inhibitors and at low concentrations. This result is
 surprising because the compounds of EP-A-0201188, such as the '188
 compound, are not as effective at such low concentrations. This highly
 surprising result is borne out by the experimental data presented in the
 experimental section (infra).
 The compounds of the present invention may exist in hydrated or solvated
 forms.
 Alkyl and alkylene groups, when present in any one of the above-defined
 groups for the compounds of the formula (I), may be linear or branched.
 The term "halo" as used herein means means F, Cl, Br or I.
 The pharmaceutically acceptable salts of the compounds of the formula (I)
 include suitable acid addition or base salts thereof. For a review on
 suitable pharmaceutical salts see Berge et al, J Pharm Sci, 66, 1-19
 (1977).
 By way of example, suitable acid addition salts are formed from acids which
 form non-toxic salts. Suitable examples of such salts are the
 hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, phosphate,
 hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate,
 citrate, gluconate, benzoate, methanesulphonate, benzenesulphonate and
 p-toluenesulphonate salts.
 Also by way of example, suitable base salts are formed from bases which
 form non-toxic salts. Suitable examples thereof are the aluminium,
 calcium, lithium, magnesium, potassium, sodium, zinc,
 N-benzyl-N-(2-phenylethyl)amine, 1-adamantylamine and diethanolamine
 salts.
 Compounds of the present invention may contain one or more asymmetric
 carbon atoms and/or one or more non-aromatic carbon-carbon double bonds
 and may therefore exist in two or more stereoisomeric forms. Thus, the
 present invention also provides both the individual stereoisomers of the
 compounds of the formula (I), as well as mixtures thereof, including
 compositions comprising the same. Separation of diastereoisomers or cis
 and trans isomers may be achieved by conventional techniques, e.g. by
 fractional crystallisation, chromatography or HPLC of a stereoisomeric
 mixture of a compound of the formula (I) or a suitable salt or derivative
 thereof. An individual enantiomer of a compound of the formula (I) may
 also be prepared from a corresponding optically pure intermediate or by
 resolution, such as by HPLC of a racemate using a suitable chiral support
 or by fractional crystallisation of the diastereoisomeric salts formed by
 reaction of a racemate with a suitable optically active acid or base.
 As mentioned above, the present invention also covers pharmaceutical
 compositions comprising the compounds of the general formula (I). In this
 regard, and in particular for human therapy, even though the compounds of
 the present invention (including their pharmaceutically acceptable salts
 and pharmaceutically acceptable solvates) can be administered alone, they
 will generally be administered in admixture with a pharmaceutical carrier,
 excipient or diluent selected with regard to the intended route of
 administration and standard pharmaceutical practice.
 By way of example, in the pharmaceutical compositions of the present
 invention, the compounds of the present invention may be admixed with any
 suitable binder(s), lubricant(s), suspending agent(s), coating agent(s),
 or solubilising agent(s).
 In general, a therapeutically effective daily oral or intravenous dose of
 the compounds of formula (I) and their salts is likely to range from 0.01
 to 50 mg/kg body weight of the subject to be treated, preferably 0.1 to 20
 mg/kg. The compounds of the formula (I) and their salts may also be
 administered by intravenous infusion, at a dose which is likely to range
 from 0.001-10 mg/kg/hr.
 Tablets or capsules of the compounds may be administered singly or two or
 more at a time, as appropriate. It is also possible to administer the
 compounds in sustained release formulations.
 Typically, the physician will determine the actual dosage 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. There can, of course, be individual
 instances where higher or lower dosage ranges are merited, and such are
 within the scope of this invention.
 Alternatively, the compounds of the general formula (I) can be administered
 by inhalation or in the form of a suppository or pessary, or they may be
 applied topically in the form of a lotion, solution, cream, ointment or
 dusting powder. An alternative means of transdermal administration is by
 use of a skin patch. For example, they can be incorporated into a cream
 consisting of an aqueous emulsion of polyethylene glycols or liquid
 paraffin. They can also be incorporated, at a concentration of between 1
 and 10% by weight, into an ointment consisting of a white wax or white
 soft paraffin base together with such stabilisers and preservatives as may
 be required.
 For some applications, preferably the compositions are administered orally
 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, solutions or suspensions containing flavouring or
 colouring agents.
 The compositions (as well as the compounds alone) can also be injected
 parenterally, for example intracavernosally, intravenously,
 intramuscularly or subcutaneously. In this case, the compositions will
 comprise a suitable carrier or diluent.
 For parenteral administration, the compositions are best used in the form
 of a sterile aqueous solution which may contain other substances, for
 example enough salts or monosaccharides to make the solution isotonic with
 blood.
 For buccal or sublingual administration the compositions may be
 administered in the form of tablets or lozenges which can be formulated in
 a conventional manner.
 For oral, parenteral, buccal and sublingual administration to subjects
 (such as patients), the daily dosage level of the compounds of the present
 invention and their pharmaceutically acceptable salts and solvates may
 typically be from 10 to 500 mg (in single or divided doses). Thus, and by
 way of example, tablets or capsules may contain from 5 to 100 mg of active
 compound for administration singly, or two or more at a time, as
 appropriate. As indicated above, the physician will determine the actual
 dosage which will be most suitable for an individual patient and it will
 vary with the age, weight and response of the particular patient. It is to
 be noted that whilst the above-mentioned dosages are exemplary of the
 average case there can, of course, be individual instances where higher or
 lower dosage ranges are merited and such dose ranges are within the scope
 of this invention.
 Generally, in humans, oral administration of the compounds of the invention
 is the preferred route, being the most convenient and, for example in male
 erectile dysfunction (MED), avoiding the well-known disadvantages
 associated with intracavernosal (i.c.) administration. A preferred oral
 dosing regimen in MED for a typical man is from 25 to 100 mg of compound
 when required. In circumstances where the recipient suffers from a
 swallowing disorder or from impairment of drug absorption after oral
 administration, the drug may be administered parenterally, e.g.
 sublingually or buccally.
 For veterinary use, a compound of the present invention or a veterinarily
 acceptable salt thereof, or a veterinarily acceptable solvate of either
 entity, is typically administered as a suitably acceptable formulation in
 accordance with normal veterinary practice and the veterinary surgeon will
 determine the dosing regimen and route of administration which will be
 most appropriate for a particular animal. However, as with human
 treatment, it may be possible to administer the compound alone for
 veterinary treatments.
 Thus the invention provides a pharmaceutical composition comprising a
 compound of the present invention, or a pharmaceutically acceptable salt
 thereof, or a pharmaceutically acceptable solvate of either entity,
 together with a pharmaceutically acceptable diluent, excipient or carrier.
 The present invention also provides a veterinary formulation comprising a
 compound of the present invention, or a veterinarily acceptable salt
 thereof, or a veterinarily acceptable solvate of either entity, together
 with a veterinarily acceptable diluent, excipient or carrier.
 The invention further provides a compound of the present invention, or a
 pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable
 solvate of either entity, or a pharmaceutical composition containing any
 of the foregoing, for use as a human medicament.
 In addition, the present invention provides a compound of the present
 invention, or a veterinarily acceptable salt thereof, or a veterinarily
 acceptable solvate of either entity, or a veterinary formulation
 containing any of the foregoing, for use as an animal medicament.
 In yet another aspect, the invention provides the use of a compound of the
 present invention, or a pharmaceutically acceptable salt thereof, or a
 pharmaceutically acceptable solvate of either entity, in the manufacture
 of a medicament for administration to a human for the treatment of a
 medical condition capable of being treated by the inhibition of PDE1
 activity.
 The present invention also provides the use of a compound of the present
 invention, or a veterinarily acceptable salt thereof, or a veterinarily
 acceptable solvate of either entity, in the manufacture of an animal
 medicament for the treatment of a medical condition capable of being
 treated by the inhibition of PDE1 activity.
 In yet another aspect, the invention provides the use of a compound of the
 present invention, or a pharmaceutically acceptable salt thereof, or a
 pharmaceutically acceptable solvate of either entity, in the manufacture
 of a medicament for administration to either a human or an animal wherein
 the medicament is for use as an inhibitor of PDE1.
 Moreover, the present invention provides the use of a compound of the
 present invention, or a pharmaceutically acceptable salt thereof, or a
 pharmaceutically acceptable solvate containing either entity, in the
 manufacture of a human medicament for the treatment of any one or more of
 male erectile dysfunction, female sexual dysfunction, premature labour,
 dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet
 obstruction, incontinence, stable, unstable and variant (Prinzmetal)
 angina, hypertension, pulmonary hypertension, congestive heart failure,
 atherosclerosis, stroke, peripheral vascular disease, conditions of
 reduced blood vessel patency, chronic asthma, bronchitis, allergic asthma,
 allergic rhinitis, glaucoma or diseases characterised by disorders of gut
 motility.
 The present invention also provides the use of a compound of the present
 invention, or a veterinarily acceptable salt thereof, or a veterinarily
 acceptable solvate containing either entity, in the manufacture of an
 animal medicament for the treatment of any one or more of male erectile
 dysfunction, female sexual dysfunction, premature labour, dysmenorrhoea,
 benign prostatic hyperplasia (BPH), bladder outlet obstruction,
 incontinence, stable, unstable and variant (Prinzmetal) angina,
 hypertension, pulmonary hypertension, congestive heart failure,
 atherosclerosis, stroke, peripheral vascular disease, conditions of
 reduced blood vessel patency, chronic asthma, bronchitis, allergic asthma,
 allergic rhinitis, glaucoma or diseases characterised by disorders of gut
 motility.
 Additionally, the present invention provides a method of treating a medical
 condition for which a PDE1 inhibitor is required, in a mammal (including a
 human being), which comprises administering to said mammal a
 therapeutically effective amount of a compound of the present invention,
 or a pharmaceutically or veterinarily acceptable salt thereof, or a
 pharmaceutically or veterinarily acceptable solvate of either entity, or a
 pharmaceutical composition or veterinary formulation containing any of the
 foregoing.
 Still further, the present invention provides a method of treating any one
 or more of male erectile dysfunction, female sexual dysfunction, premature
 labour, dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet
 obstruction, incontinence, stable, unstable and variant (Prinzmetal)
 angina, hypertension, pulmonary hypertension, congestive heart failure,
 atherosclerosis, stroke, peripheral vascular disease, conditions of
 reduced blood vessel patency, chronic asthma, bronchitis, allergic asthma,
 allergic rhinitis, glaucoma or diseases characterised by disorders of gut
 motility in a mammal (including a human being), which comprises
 administering to said mammal a therapeutically effective amount of a
 compound of formula (I) or a pharmaceutically or veterinarily acceptable
 salt thereof, or a pharmaceutically or veterinarily acceptable solvate of
 either entity, or a pharmaceutical composition or veterinary formulation
 containing any of the foregoing.
 References to treatment (as well as treating) include any one or more of
 curative, palliative or prophylactic treatment of a disease or condition.
 The compounds of the formula (I) can be prepared by novel routes or,
 alternatively, by conventional routes.
 The compounds of the present invention may be prepared by any one of the
 synthesis processes presented in the Route Section (infra), or by any one
 of the more specific synthesis protocols presented in the Examples Section
 (infra)--which are presented as either Preparations or Examples. The
 present invention also encompasses any one or more of these processes,
 including any of the steps thereof, in addition to any novel
 intermediate(s) obtained therefrom or used therein.
 The general syntheses of the compounds of the present invention are now
 presented in the following Route Section.
 It is to be noted that in the following Route Section that a propyl group
 has been used as an example of a suitable R.sub.a group. Naturally,
 compounds with other R.sub.a groups may be used to prepare compounds of
 the present invention. Likewise, suitable substituents other than those
 presented for R.sub.1 etc. may be used.
 Route Section
 Route A
 A compound of formula (I) may be obtained from a compound of formula (II)
 wherein
 ##STR11##
 R.sub.1-3 and Ar are as previously defined for formula (I), by the
 application of known cyclisation methods for pyrimidinone ring formation.
 Thus, for example, the cyclisation may be effected by the treatment of
 (II) with a base such as sodium or potassium hydroxide, or sodium or
 potassium carbonate, optionally in the presence of hydrogen peroxide, in a
 C.sub.1 to C.sub.4 alcohol-water medium, at from about 50.degree. C. to
 the reflux temperature of the reaction mixture.
 The cyclisation may also be mediated by a sodium or potassium C.sub.1 to
 C.sub.5 alkoxide, in a C.sub.1 to C.sub.4 alcohol solvent, at from about
 50.degree. C. to the reflux temperature of the reaction mixture.
 Alternative cyclisation procedures involve the treatment of (II) with
 either polyphosphoric acid at from about 130.degree. C. to about
 150.degree. C. or with anhydrous zinc chloride at from about 200.degree.
 C. to about 220.degree. C.
 In certain examples, the Ar group contains substituents which are
 chemically reactive under the cyclisation conditions and further reaction
 takes place under the standard conditions e.g. an alkyl bromide may
 hydrolyse to an alcohol and a trifluoromethyl group or an ester group may
 be converted to a carboxylic acid.
 By way of example, a preferred embodiment of the above-mentioned route is
 as follows:
 ##STR12##
 wherein the each of the groups are as defined above.
 Route B
 Compounds of the formula (I) in which R.sub.4 is NH.sub.2 can be prepared
 from the corresponding nitrobenzene by a reductive method.
 ##STR13##
 wherein each of the other groups are as defined above.
 In a typical procedure the reduction is carried out by catalytic
 hydrogenation e.g. using either a heterogeneous catalyst such as
 palladium, palladium- or rhodium-on-carbon, Raney nickel, or a homogeneous
 catalyst e.g. tris(triphenylphosphine)chlororhodium, in a suitable organic
 solvent e.g. industrial methylated spirit or ethyl acetate. The reaction
 is preferably carried out at from room temperature to the reflux
 temperature of the solvent and a pressure of from 1 to 5 atmospheres
 (100-500 kPa).
 The reaction can also be carried out using an excess of an electron
 transfer reducing agent such as tin (II) chloride in a suitable solvent
 such as a C.sub.1 to C.sub.4 alcohol e.g. ethanol, at the reflux
 temperature of the reaction mixture.
 Route C
 Compounds of the formula (I) in which R.sub.4 is a group of the formula
 --NR.sub.7 SO.sub.2 X, wherein R.sub.7 and X are as defined above, can be
 prepared by reaction of a compound of formula (I), where R.sub.4 is
 NHR.sub.7 with an appropriate alkyl sulphonyl halide.
 ##STR14##
 Here, each of the groups are as defined above.
 Similarly, compounds of the formula (I) in which R.sub.4 is NR.sub.7 COX
 can be prepared by acylation of the same starting material with an
 appropriate acid chloride or anhydride. Compounds in which R.sub.4 is
 NR.sub.7 CHO may also be prepared from a mixed anhydride such as (C.sub.1
 -C.sub.4 alkylCO)OCHO.
 The reaction may be carried out in a suitable inert solvent such as
 dichloromethane in the presence of an acid acceptor such as triethylamine
 or pyridine (which can also be used as the solvent), at a temperature of
 from 0.degree. C. to the reflux temperature of the solvent, preferably at
 room temperature.
 Compounds of the formula (I) in which R.sub.4 is a group of the formula
 --NR.sub.7 CHO can also be prepared using a formyl transfer agent such as
 formyl- or 1,2-diformylhydrazine. In this case the reaction is
 preferentially carried out in the absence of solvent at the reflux
 temperature of the formylating agent.
 Route D
 Compounds of the formula (I) in which R.sub.4 is a group of the formula
 (C.sub.1-4 alkyl)R.sub.7 N-- may be prepared by reduction of compounds of
 the formula (I) in which R.sub.4 is NR.sub.7 CO(C.sub.1-3 alkyl), wherein
 R.sub.7 is H or (C.sub.1-4 alkyl).
 ##STR15##
 Here, each of the groups are as defined above.
 The reducing agent is selected from reagents such as lithium aluminium
 hydride and diborane and is preferentially carried out in an inert solvent
 such as tetrahydrofuran at a temperature from room temperature to the
 reflux temperature of the solvent.
 Alternatively, the products may be prepared by reduction of an imine
 (R.sub.4 is N.dbd.CH--(C.sub.1-3 alkyl)) or iminium ion (R.sub.4 is
 [NR.sub.7.dbd.CH--(C.sub.1-3 alkyl)].sup.+) which may optionally be
 isolated. The reducing agent may be sodium acetoxyborohydride or sodium
 cyanohydride. The reaction may also be carried out using catalytic
 hydrogenation using a catalyst such as palladium-on-charcoal.
 Route E
 Compounds of the formula (I) in which R.sub.4 is nitro can be prepared by
 nitration of the corresponding benzene derivative. The reaction is
 preferentially carried out using mixtures of concentrated nitric and
 sulphuric acids at a temperature from 0.degree. C. to 100.degree. C.
 ##STR16##
 Here, each of the groups are as defined above
 Similarly, compounds in which R.sub.4 is chlorosulphonyl can be prepared by
 chlorosulphonylation of the corresponding benzene derivative. The reaction
 is preferentially carried out using chlorosulphonic acid as the solvent at
 a temperature from 0.degree. C. to 100.degree. C.
 ##STR17##
 With this route you may get a mixture of regio-isomers.
 Route F
 When Ar is a bicyclic group, a hetero-ring fused to the benzo portion can
 be formed using conventional ring forming reactions. For example, when the
 fused ring is a pyridone, the ring is formed by treatment of the
 corresponding b-ethoxypropenamide with a strong acid such as sulphuric or
 hydrochloric acid.
 ##STR18##
 Here, each of the groups are as defined above
 Route G
 Compounds of the formula (I) in which R.sub.4 is a sulphamido or
 aminoalkanesulphonamido group can be prepared by treatment of the
 corresponding sulphamoyl halide or haloalkanesulphonamide with an excess
 of the amine in an aqueous or alcoholic solvent at a temperature of from
 room temperature to the reflux temperature of the solvent. By way of
 example:
 ##STR19##
 Here, each of the groups are as defined above, and m and n are
 independently selected from 0 and 1.
 A compound of formula (A) where n is 1 and m is 0 or 1 can be cyclised to
 give the corresponding cyclic sultam. The reaction is carried out using a
 strong base such as sodium hydride in an inert solvent such as
 dimethylformamide at a temperature from 0.degree. C. to room temperature.
 Route H
 Compounds of the formula (I) in which R.sub.4 is an aminosulphonyl group
 can be prepared from the corresponding chlorosulphonyl derivative
 --SO.sub.2 Cl by treatment with an appropriate amine, optionally in
 excess, in an aqueous or alcoholic solvent, at a temperature of from room
 temperature to the reflux temperature of the solvent. For example:
 ##STR20##
 Similarly, when the chlorosulphonyl derivative is treated with aqueous
 alkali such as sodium hydroxide, a compound of the formula (I) in which
 R.sub.4 is a group of the formula --SO.sub.3 H can be obtained.
 Route I
 Compounds of the formula (I) in which R.sub.4 is a -G-Het group wherein G
 is a direct link and Het is attached to the adjacent phenyl ring by a
 nitrogen atom e.g. imidazol-1-yl can be prepared from the corresponding
 halophenyl derivative, where halo is preferably bromo or iodo, and the
 heterocycle. The reaction is preferably carried out in the presence of a
 base such as potassium carbonate, and a copper catalyst, preferably copper
 bronze. The reaction can be carried out in a high boiling solvent such as
 dimethylformamide, dimethylacetamide or N-methyl-2-pyrrolidinone at the
 reflux temperature of the solvent, or alternatively may be carried out
 without solvent, at the melt temperature of the mixture.
 ##STR21##
 Route J
 Compounds of the formula (I) in which the groups R.sub.3 to R.sub.6 contain
 a hydroxy or carboxyl function can be prepared from the corresponding
 ether or ester under conventional hydrolytic conditions. Ethers are
 preferably hydrolysed under strongly acidic conditions such as using
 concentrated hydrobromic acid at a temperature of between 100.degree. C.
 and 150.degree. C. Ester hydrolysis is preferably carried out under basic
 conditions, for example using sodium or potassium hydroxide as base,
 optionally in the presence of hydrogen peroxide, in water or an alcoholic
 solvent such as ethanol. The reaction is carried out at from room
 temperature to the reflux temperature of the solvent.
 Route K
 Compounds of the formula (I) in which the groups R.sub.2 and R.sub.3
 together form a carbonyl function are preferably prepared from the
 corresponding secondary alcohol by an oxidative method. The preferred
 oxidant is pyridinium chlorochromate and the reaction is preferably
 carried out in an inert solvent such as dichloromethane at room
 temperature.
 ##STR22##
 An intermediate of the formula (II) is prepared by reaction of a carboxylic
 acid chloride, which may be derived by treatment of the corresponding
 carboxylic acid with oxalyl chloride in dichloromethane in the presence of
 a catalytic quantity of dimethylformamide, with an aminopyrazole
 derivative of the formula (III). The preparation of (III) is
 conventional--for example see the teachings of U.S. Pat. No. 5,272,147.
 ##STR23##
 The reaction is carried out in a suitable inert solvent such as
 dichloromethane in the presence of an acid acceptor such as triethylamine
 or in a basic solvent such as pyridine, at a temperature of from 0.degree.
 C. to the reflux temperature of the solvent, preferably at room
 temperature.
 Interconversion of functional groups may also be carried out using a
 compound of the formula (II). Thus, for example, when R.sub.4 is
 bromomethyl, the halide can be displaced by an appropriate amine
 preferably used in excess. Similarly the bromomethyl derivative can be
 reacted with an alcohol to provide an ether derivative, preferably using a
 metal salt such as silver nitrate. The alcohol is generally used as
 solvent and the reaction is preferably carried out at room temperature.
 For example:
 ##STR24##
 The present invention will now be discussed only by way of further
 examples. The following Examples Section provides illustrations of the
 preparation of the compounds (I). The following Preparations Section
 provides illustrations of the preparation of inter alia novel starting
 materials.
 In these sections, the .sup.1 H nuclear magnetic resonance (NMR) spectra
 were recorded using either a Varian Unity 300 or a Varian Inova 400
 spectrometer and were in all cases consistent with the proposed
 structures. Characteristic chemical shifts (.delta.) are given in
 parts-per-million downfield from tetramethylsilane using conventional
 abbreviations for designation of major peaks: e.g. s, singlet; d, doublet;
 t, triplet; q, quartet; m, multiplet; b, broad.
 The mass spectra (m/z) were recorded using a Fisons Instruments Trio mass
 spectrometer in the thermospray ionisation mode. In the following
 sections, room temperature means 20 to 25.degree. C.

In the following examples, propyl means n-propyl unless otherwise stated.
 SYNTHESIS EXAMPLES
 Example 1
 5-(4-bromobenzyl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin
 -7-one

##STR25##
 A 30% w/w solution of hydrogen peroxide (27 ml, 0.238 mol) was added to a
 solution of sodium hydroxide (7.24 g, 0.181 mol) in water (400 ml). A
 solution of
 N-(5-carbamoyl-1-methyl-3-propyl-1H-4-pyrazolyl)-2-(4-bromophenyl)acetamid
 e (29.0 g, 0.076 mol) in ethanol (350 ml) was then added, and the reaction
 stirred at reflux for 3 hours.
 On cooling, the solution was diluted with water (200 ml) and acidified to
 pH5 with 2N aqueous hydrochloric acid solution. The resulting white
 precipitate was extracted into dichloromethane (2.times.250 ml). The
 organic extracts were dried (MgSO.sub.4), filtered and concentrated under
 reduced pressure to give the title compound as a colourless solid.
 Crystallisation from acetonitrile gave colourless needles (19.33 g), m.p.
 193-194.degree. C.
 Found: C, 53.09; H, 4.72; N, 15.41; C.sub.16 H.sub.17 BrN.sub.4 O requires
 C, 53.19; H, 4.74; N, 15.51%.
 .sup.1 H-NMR (DMSO-d.sub.6): .delta.=0.90 (t, 3H), 1.65 (m, 2H), 2.70 (t,
 2H), 3.85 (s, 2H), 4.10 (s, 3H), 7.25 (d, 2H), 7.45 (d, 2H), 12.30 (s, 1H)
 ppm.
 Examples 2 to 24
 The compounds of the following tabulated Examples of the general formula:
 ##STR26##
 were prepared from the corresponding carboxamide using similar methods to
 that used in Example 1.

##STR86##
 N-methyl piperazine (1.28 ml, 0.0115 mol) was added to a solution of
 4-[(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)m
 ethyl]-1-benzenesulfonyl chloride (1.35 g, 0.0035 mol) in ethanol (20 ml)
 and the reaction stirred at room temperature for 18 hours. The reaction
 mixture was concentrated under reduced pressure and the residue
 partitioned between dichloromethane (50 ml) and water (20 ml). The aqueous
 phase was extracted with further dichloromethane (50 ml), the combined
 organic extracts dried (MgSO.sub.4), filtered, and evaporated under
 reduced pressure.
 Purification by flash column chromatography eluting with
 methanol:dichloromethane (3:97 by volume) followed by trituration with
 ethyl acetate gave the title compound as a solid.
 Found: C, 55.91; H, 6.29; N, 18.53; C.sub.21 H.sub.28 N.sub.6 O.sub.3 S,
 requires C, 56.74; H, 6.35; N, 18.90%.
 .sup.1 H-NMR (CDCl.sub.3): .delta.=1.05 (t, 3H), 1.85 (m, 2H), 2.25 (s,
 3H), 2.45 (m, 4H), 3.00 (m, 6H), 4.15 (s, 2H), 4.30 (s, 3H), 7.68 (m, 4H),
 11.60 (s, 1H) ppm.
 Examples 63 to 66
 The compounds of the following tabulated Examples of the general formula:
 ##STR87##
 were prepared by reaction of the corresponding sulfonyl chloride and amine
 by similar methods to that used in Example 62.

##STR105##
 Oxalyl chloride (7.5 ml, 0.86 mol) was added dropwise to a solution of
 4-bromophenylacetic acid (8.5 g, 0.040 mol) and dimethylformamide (3
 drops) in dichloromethane and the reaction stirred at room temperature for
 4 hours. The reaction mixture was then concentrated under reduced pressure
 and azeotroped with dichloromethane (30 ml).
 A solution of this 4-bromophenylacetyl chloride in dry dichloromethane (5
 ml) was then added dropwise to a solution of
 4-amino-1-methyl-3-propyl-1H-5-pyrazolecarboxamide (6 g, 0.033 mol) and
 triethylamine (7 ml, 0.050 mol) in dichloromethane (250 ml), and the
 reaction stirred at room temperature for 18 hours.
 The reaction mixture was concentrated under reduced pressure and the
 residue triturated with 1N aqueous hydrochloric acid solution. The
 resulting precipitate was filtered and washed with water (50 ml) and ether
 (50 ml). Recrystallisation from ethanol gave the title compound as a solid
 (6.48 g), m.p.241-243.degree. C.
 Found: C, 50.38; H, 5.00; N, 14.59%; C.sub.16 H.sub.19 N.sub.4 BrO.sub.2,
 requires C, 50.67; H, 5.05; N, 14.77%.
 .sup.1 H-NMR (DMSO-d.sub.6): d=0.78 (t, 3H), 1.40 (m, 2H), 2.27 (t, 2H),
 3.62 (s, 2H), 3.86 (s, 3H), 7.19 (s, 1H), 7.28 (d, 2H), 7.52 (d, 2H), 7.70
 (s, 1H), 9.44 (s, 1H) ppm.
 Preparations 2 to 22
 The compounds of the following tabulated preparations of the general
 formula:
 ##STR106##
 were prepared from 4-amino-1-methyl-3-propyl-1H-5-pyrazolecarboxamide and
 the appropriate acid chloride using similar methods to that described in
 Preparation 1.

##STR137##
 Silver nitrate (290 mg, 0.0017 mol) was added to a solution of
 N-(5-carbamoyl-1-methyl-3-propyl-1H-4-pyrazolyl)-2-(4-bromobenzyl)acetamid
 e (600 mg, 0.0015 mol) in ethanol (5 ml) and the reaction stirred at reflux
 for 5 hours and then at room temperature for 18 hours.
 Ethanol (10 ml) was added, the mixture filtered, and the solid washed with
 further ethanol.
 The filtrate was evaporated under reduced pressure and the residue
 crystallised from ethanol to give the title compound, as a solid (500 mg).
 Preparation 35
 2-(4-bromophenyl)propionic acid

##STR138##
 The title compound was prepared following a similar procedure to that
 described in Synthesis 1982; 456.
 Preparation 36
 4-acetyl phenylacetic acid

##STR139##
 The title compound was prepared following a similar procedure to that
 described in J.A.C.S. 1946; 68; 2133.
 Preparation 37
 2-nitro-4-bromophenylacetic acid

##STR140##
 The title compound was prepared following a similar procedure to that
 described in Chem. Pharm. Bull; 1985; 33; 1414.
 Preparation 38
 3-pyridinesulphonyl chloride hydrochloride

##STR141##
 The title compound was prepared following a similar procedure to that
 described in Annalen; 1939; 72; 77.
 Preparation 39
 2-(methylaminomethyl)pyridine

##STR142##
 The title compound was prepared following a similar procedure to that
 described in U.S. Pat. No. 2798075.
 Activity Studies
 Initially there is presented a Protocol for measuring PDE inhibitory
 activity.
 Protocol
 Phosphodiesterase (PDE) Inhibitory Activity
 In vitro PDE inhibitory activities against cyclic guanosine 3',
 5'-monophosphate (cGMP) and cyclic adenosine 3', 5'-monophosphate (cAMP)
 phosphodiesterases can be determined by measurement of their IC.sub.50
 inhibition of enzyme activity.
 The required PDE enzymes are isolated from a variety of sources, including
 rat kidney, human corpus cavernosum, human platelets, rabbit platelets,
 human cardiac ventricle, human skeletal muscle and bovine retina,
 essentially by the method of W J Thompson and M M Appleman (Biochem, 1971,
 10, 311).
 For example, for some of the studies the calcium/calmodulin
 (Ca/CAM)-dependent PDE (PDE1) is obtained from either human cardiac
 ventricle or rat kidney. The cGMP-stimulated PDE (PDE2), the cGMP-specific
 PDE (PDE5) and the cGMP-inhibited cAMP PDE (PDE3) are obtained from human
 corpus cavernosum tissue. PDE5 is also obtained from human platelets or
 rabbit platelets by techniques usual in the art. The cAMP-specific PDE
 (PDE4) is obtained from rat kidney. The photoreceptor PDE (PDE6) is
 obtained from bovine retina.
 Assays are performed using a modification of the "batch" method of W J
 Thompson et al (Biochem, 1979, 18, 5228).
 Results
 The compounds of the present invention were tested for PDE inhibition. The
 results showed that the compounds are inhibitors of at least
 Ca/CAM-dependent PDE1. Some of the compounds are selective and potent
 inhibitors of Ca/CAM-dependent PDE1.
 In particular, we found the following results for a preferred compound of
 the present invention having the formula:
 ##STR143##
 which for ease of reference is referred to as the Example 50 compound.

SOURCE EXAMPLE 50 '188 COMPOUND
 cGMP / PDE1 INHIBITION - IC.sub.50 Values
 Rat Kidney 37 nM 9.9 .mu.M
 PDE5 INHIBITION - IC.sub.50 Values
 Rabbit Platelet 6.7 .mu.M 2.8 .mu.M
 Human Platelet 2.7 .mu.M 3.2 .mu.M
 Further Studies
 In addition, we investigated the following two compounds.
 ##STR144##
 (which for ease of reference is referred to as the Example 36 compound)
 ##STR145##
 (which for ease of reference is referred to as the Example 37 compound)
 The results of these additional studies are presented below.