NZ523108A

NZ523108A - Method of treating diabetic complications i.e. peripheral vascular diseases, peripheral neuropathies, and autonomic neuropathies with cGMP PDE5 inhibitors such as sildenafil

Info

Publication number: NZ523108A
Application number: NZ523108A
Authority: NZ
Inventors: Ralph E Wood
Original assignee: Pfizer
Priority date: 2000-06-30
Filing date: 2001-06-29
Publication date: 2005-04-29
Also published as: KR20030047907A; JP2004511433A; WO2002002118A1; EP1303279A1; BR0112100A; CN1440287A; IL153426A0; HUP0301451A2; MXPA03000033A; HUP0301451A3; CA2414352A1; AU2001279275A1; PL365565A1

Abstract

A cGMP PDE5 inhibitor can be used in the manufacture of a medicament fro the treatment of autonomic neuropathies, CREST syndrome, erythromatosis, rheumatoid diseases, onychiomycosis, Raynaud's Phenomenon and peripheral neuropathies. Preferably the inhibitor is sildenafil.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 523103 5231 WO 02/02118 PCTAJS01/41202 METHOD OF TREATING PERIPHERAL VASCULAR DISEASES, PERIPHERAL NEUROPATHIES, AND AUTONOMIC NEUROPATHIES Cross Reference to Related Applications. 5 This application claims the benefit of U.S. Provisional Application No. 60/215,065, filed June 30,2000, and U.S. Provisional Application No. 60/219,029, filed My 18,2000, both entitled "Method of Treating Diabetic Ulcers," the disclosures of both of which are hereby incorporated herein in their entireties. 10 Field of the Invention. This invention relates to the use of cyclic guanosine 3', 5'-monophosphate type five (cGMP PDE5) inhibitors, including the compound sildenafil, for the treatment of disease related to peripheral vascular diseases, peripheral neuropathies, autonomic neuropathies, particularly the diseases which are related to diabetes. 15 Background of the Invention. Diseases, which are related to peripheral vascular disease and autonomic neuropathies are widely varied yet consistent in their chronic pathological condition and difficulty in treatment. A large number of these diseases are related to the disease 20 diabetes mellitus. Others, although not known to be related to diabetes are similar in their physiological effects on the peripheral vascular system. Such diseases include Raynaud's Phenomenon, including CREST syndrome, autoimmune diseases, such as erythromatosis, rheumatoid diseases, and diabetic retinopathies. Diabetes mellitus is a serious and widespread chronic disease. Studies predict 25 that the 1996 global diabetes prevalence of 120 million should more than double to l WO 02/02118 _PCT/US01/41202_ 250 million by the year 2025, primarily due to increasing age, obesity, sedentary lifestyles, and changing dietary patterns. Many serious and costly complications affect individuals suffering from diabetes mellitus, including heart disease, kidney failure, and blindness. Nevertheless, foot complications by far take the greatest toll. It is 5 believed that 40-70% of all lower extremity amputations are related to diabetes mellitus. Additionally, approximately 85% of all diabetes-related lower extremity amputations are preceded by a foot ulcer. Patients with diabetes mellitus are at increased risk of developing one or more foot ulcers as a result of established long-term complications of the disease, which 10 include impaired nerve function (neuropathy) and/or ischemia. Local tissue ischemia is a key contributing factor to diabetic foot ulceration. In addition to large vessel disease, patients with diabetes suffer further threat to their skin perfusion in at least two additional ways. First, by involvement of the non-conduit arteries, which are detrimentally affected by the process of atherosclerosis. Second, 15 and perhaps more importantly, by impairment of the microcirculatory control mechanisms (small vessel disease). Normally, when a body part suffers some form of trauma, the body part will, as part of the body's healing mechanism, experience an increased blood flow. When small vessel disease and ischemia are present, as in the case of many diabetics, this natural increased blood flow response is significantly 20 reduced. This fact, together with the tendency of diabetics to form blood clots (thrombosis) in the microcirculatory system during low levels of blood flow, is believed to be an important factor in ulcer pathogenesis. Neuropathy is yet another major complication of diabetes mellitus. No weil-established treatments exist for either its symptomatic treatment or for prevention of 25 progressive decline in nerve function. Estimates of the prevalence of neuropathy in 2 WO 02/02118 PCT/US01/41202 diabetes vary widely, from a low of 5% to a high of 80%, largely due to the numerous definitions and clinical descriptions of neuropathy. Nevertheless, the additive effects of neuropathy in the suffering diabetic patient are well known and documented The effect of the neuropathy is complex. The loss of sensory information from the foot is related to abnormal and prolonged pressure on the areas of the foot (sensory neuropathy). Motor neuropathy leads to deformity, further increasing pressure loading on the foot. In autonomic neuropathy, loss of innervation of the sweat glands results in dry skin which cracks creating an environment amenable to infection. Autonomic dysfunction contributes further by altering the distribution of micro-circulatory blood flow, directing the blood flow through shunts and away from the nutritive skin capillaries. These factors as a whole, in conjunction with foot trauma, result in skin breakdown and ulcers. Scientists have not yet determined the mechanism that leads to nerve damage in diabetes, but it is believed to be multifactorial. These factors include genetic predisposition, metabolic and vascular abnormalities, and lack of perturbation of growth factors. The response of the peripheral nervous system to the metabolic effects of diabetes does not appear to differ between type 1 and type 2 diabetes, which . suggests a likelihood of similar clinical response to therapies in the two primary forms of the disease. There seem to be a number of susceptibility factors, as yet unknown, for the development of neuropathy, which operate in the presence of hyperglycemia (high blood sugar). Scientists have found that nerve ischemia is involved in the pathogenesis of nerve conduction. In experimental diabetic neuropathy, practitioners in the field have theorized that a decrease in nitric oxide (NO) levels may be responsible for the decrease in nerve blood flow. NO is a short-lived radical with a broad spectrum of WO 02/02118 PCT/US01/41202 metabolic functions, including mediation of vascular tone. The effects of NO are mediated by cyclic guanosine monophosphate (cGMP). Various therapeutic interventions, all of which increase levels of NO, have been shown to increase nerve blood flow and nerve conduction in experimental diabetic neuropathy which results in 5 reduced levels of NO. There are known cGMP PDE5 inhibitors, such as sildenafil citrate, which are competitive, potent, and selective inhibitors of cGMP-specific phosphodiesterase (PDE5), a compound known to be responsible for the breakdown of cGMP. Such inhibitor compounds, therefore, increase intracellular concentrations of nitric-oxide 10 derived cGMP, thereby enhancing the effect of NO, which is responsible for the efficacy of sildenafil in the treatment of male erectile dysfunction. While the beneficial effects of sildenafil in the treatment of erectile dysfunction have been well documented and publicized in recent years, the effectiveness of such a compound in the treatment of diabetic foot ulcers was entirely unexpected. Recent 15 publications by Reuters™ (Reuters Health Information, June 18,2000) of the controlled study of the commercial (sildenafil) product VIAGRA™ (Pfizer) in diabetic men by Dr. Stanley Korenman, of the University of California at Los Angeles indicates an interest in the use of sildenafil for the treatment of erectile dysfunction in patients with diabetes. However, no interest in or notice of the effectiveness of cGMP 20 PDE5 inhibitors in the treatment of diabetic foot ulcers was reported. Summary of the Invention. Surprisingly, the inventor discovered that in treating male diabetic patients for erectile dysfunction, those that also suffered from chronic, unhealed foot ulcers 25 achieved unexpected, rapid and complete healing of their foot ulcers. Repeated 4 acteiinistration of the inhibiting compound to additional diabetic patients, scone of whom had suffered with unhealed foot ulcers for as long as one year, achieved the same surprising results. Similar surprising results have been observed in the treatment of other disease conditions which are related to peripheral vascular disease Clearly, the use of such inhibitor compounds represents a dramatically effective treatment of patients suffering from diabetic foot ulcers. It is known that NO is released from vascular endothelium and modulates local blood flow by relaxing vascular smooth muscle. This system is disrupted in diabetes and the increased intracellular concentrations of nitric-oxide derived cGMP, seen for example with sildenafil, therefore are believed to reverse the microvascular pathology of patients with diabetic foot ulceration leading to improved healing rates. While the present invention is not limited by this theory of physiological mechanism of the invention, the inventor believes that it is such a mechanism that the inventor's administration of sildenafil can enhance the blood supply to the ulcerated limb and thus enhance the rate of healing in diabetic foot ulcers. 5 (followed by 5a) In one aspect, the present invention provides use of a cGMP PDE5 inhibitor or a derivative or salt thereof, in the manufacture of a medicament for treatment of autonomic neuropathies. In another aspect, the present invention provides use of a cGMP PDE5 inhibitor or a derivative or salt thereof, in the manufacture of a medicament for treatment of onychiomycosis. In another aspect, the present invention provides use of a cGMP PDE5 inhibitor or a derivative or salt thereof, in the manufacture of a medicament for treatment of a disease selected from the group consisting of CREST syndrome, erythromatosis and rheumatoid diseases In another aspect, the present invention provides use of sildenafil or a derivative or salt thereof, in the manufacture of a medicament for treatment of Raynaud's Phenomenon. In yet another aspect, the present invention provides use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: (I) so2n r4 5a (followed by 5b) 2 2 DEC 2004 I48080_1.DOC or a derivative or salt thereof, wherein R1 is H, C1-C3 alkyl, C3-C5 cycloalkyl or C1-C3 perfluoroalkyl; R is H, C1-C6 alkyl optionally substituted by OH, C1-C3 alkoxy or C3-Q cycloalkyl, or Ci-C3 perfluoroalkyl; R3 is C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C7 cycloalkyl, C1-C6 perfluoroalkyl or (C3-C6 cycloalkyOQ-Q alkyl; R4 taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R6)-piperazinyl group; R5 is H, CrC4 alkyl, C1-C3 alkoxy, NR7R8, or CONR7R8; R6 is H, Ci-Cj alkyl, (CrC3 alkoxy) C2-C6 alkyl, hydroxy C2-C6 alkyl, (R7R8N)C2-C6 alkyl, (R7R8NCO)-C1-C6 alkyl, CONR7R8, CSNR7R8 or C(NH)NR7R8; R7 and R8 are each independently H, C1-C4 alkyl, (Ci-C3)alkoxy)C2-C4 alkyl or hydroxy C2-C4 alkyl. In yet another aspect, the present invention provides use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: or a derivative or salt thereof, wherein R1 and R2 are as defined herein, R3 is as defined herein and is also H, and Y is chloro, bromo or fluoro. In yet another aspect, the present invention provides use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: s02y 5b (followed by 5c) intellectual property office OF N.Z. 2 2 DEC 2004 or3 hn "n r1 I n \ // r2 n an) or a derivative or salt thereof, wherein R1 and R2 are as defined herein, and R3 is as defined herein and is also H. In yet another aspect, the present invention provides A use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: or a derivative or salt thereof, wherein R1 is H; C1-C3 alkyl optionally substituted with one or more fiuoro substituents; or C3-C5 cycloalkyl; R2 is H, or Ci-C6 alkyl optionally substituted with one or more fluoro substituents or with C3-C6 cycloalkyl; R3 is C1-C6 alkyl optionally substituted with one or more fluoro substituents or with C3-C6 cycloalkyl; C3-C5 cycloalkyl; Cj-C6 alkenyl; or C3-C6 alkynyl; R4 is C1-C4 alkyl optionally substituted with OH, NR5R6, CN, CONR5R6 or CO2R7; C2-C4 alkenyl optionally substituted with CN, CONR5R6 or C02R7; C2-C4 alkanoyl optionally substituted with NR5R6; hydroxy C2-C4 alkyl optionally subtituted with NR5R6; (C2-C3 alkoxy)Ci-C2 alkyl optionally substituted with OH or NR5R6; CONR5R6; CO2R7; 5c (followed by 5d) intellectual property office of n.Z. 2 2 DEC 2004 DECEIVED halo; NRSR6; NHS02NR5R6;NHSC>2R8; or phenyl or heterocyclyl either of which is optionally substituted with methyl; R5 and R6 are each independently H or C1-c4 alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino, 4-(NR9)-piperazinyl or imidazolyl group wherein said group is optionally substituted with methyl or hydroxy; R7 is H or C1-c4 alkyl; R8 is C1-c3 alkyl optionally substituted with NR5R6; and R9 is H; C1-c3 alkyl optionally substituted with phenyl; hydroxy c2-c3 alkyl; or C1-c4 alkanoyl. In yet another aspect, the present invention provides use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: r2 is h or c1-c4 alkyl; r3 is c2-c4 alkyl; r4 is h,c2-c4 alkanoyl optionally substituted with nr7r8, (hydroxy)c2-c4 alkyl optionally substituted with nr7r8, ch=chc02r9, ch=chconr7r8,ch2ch2co2r9, ch2ch2conr7r8, so2nr7r8, s02nh(ch2)nnr7r8 or imidazolyl; r5 and r6 are each independently h or c1-c4 o r2 (V) or a derivative or salt thereof, wherein R1 is H, C1-c4 alkyl,C1-c4 alkoxy or CONR5R6; alkyl; 5d (followed by 5e) intellectual ptowfw office of n.2. 2 2 DEC 2004 feECEiVFD R7 and R8 are each independently H or C1-C4 alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino or 4-(NR10)-l-piperazinyl group wherein any of said groups is optionally substituted with CONRsR6; R9 is H or Ci,-C4 alkyl; R10 is H, C,-C3 alkyl or (hydroxy)C2-C3 alkyl; and n is 2, 3 or 4; with the proviso that R4 is not H when R1 is H, C1-C4 alkyl or C1-C4 alkoxy. In yet another aspect, the present invention provides use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: r20 hn n % r1 r3 (VI) or a derivative or salt thereof, wherein R1 is H, C1-C4 alkyl, CN or CONR4R5; R2 is C2-C4 alkyl; R3 is S02NR6R7, N02, NH2, NHCOR8, NHS02R8 or N(S02R8)2; R4 and R5 are each independently selected from H and C1-C4 alkyl; 6 7 R andR are each independently selected from H and C1-C4 alkyl optionally substituted with C02R9, OH, pyridyl, 5-isoxazolin-3-onyl, 5e (followed by 5f) 148080 1.DOC intellectual property office] of n.z 2 2 DEC 2004 RECE morpholino or l-imidazolidin-2-onyl; or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino, 1-pyrazolyl or4-(NR10)-l piperazinyl group wherein any of said groups may optionally be substituted with one or two substituents selected from C1-C4 alkyl, C02R9, NH2 and OH; R8 is C1-C4 alkyl or pyridyl; R9 is H or Ci,-C4 alkyl; and R10 is H, C1-C4 alkyl or (hydroxy) C2-C3 alkyl. In yet another aspect, the present invention provides use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: O s02z or a derivative or salt thereof, wherein Z is halo, and R1 and R2 are as previously defined herein. In yet another aspect, the present invention provides use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: r2o hn (VIII) or a derivative or salt thereof, wherein R1 and R2 are as previously defined herein. In yet another aspect, the present invention provides use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: (IX) or a derivative or salt thereof, wherein R1 is C1-C4 alkyl; R2 is C2-C4 alkyl; R3 is H or SOzNR4R5; R4 and R5 together with the nitrogen atom to which they are attached form a pyrrolidine, piperidino, morpholino or 4-N-(R6)-l-piperazinyl group; and R6 is H or C1-C3 alkyl. In yet another aspect, the present invention provides use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: 5g (followed by 5h) 148080 l.DOC intellectual prof'fckfy off/cfl OF N.Z ' 2 2 DEC 2004 -PECElx/Pn (X) so2z or a derivative or salt thereof, wherein Z is halo, and R1 and R2 are as previously defined herein. In yet another aspect, the present invention provides use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: R° (XI) or a derivative or salt thereof, in which: R° represents hydrogen, halogen or Ci-6 alkyl; R1 represents hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6alkynyl, haloCi-6 alkyl, C3-scycloalkyl, C3-gcycloalkylCi-3 alkyl, arylCi-3 alkyl or heteroarylCi-3 alkyl; R2 represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic ring attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fased ring A is a 5- or 6-membered ring which may be 5h (followed by 5i) 148080_1.DOC inlfcllectual property office of n.z 2 2 DEC 2004 —MCiiVFD saturated or partially or folly unsaturated and comprises carbon atoms and optionally one 1 or two heteroatoms selected from oxygen, sulphur and nitrogen; and R represents hydrogen or C1-3 alkyl, or R1 and R3 together represent a 3- or 4-membered alkyl or alkenyl chain. In yet another aspect, the present invention provides use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is cis isomer of formula (XI) represented by formula (Xlb): O or a derivative or salt thereof, in which: R° represents hydrogen, halogen or Cj-6 alkyl; R1 represents hydrogen, Chalky!, haloCpgalkyl, C3-gcycloalkyl, C3-gcycloalkylCi-3alkyl, arylCi-3alkyl or heteroarylCi-3alkyl; and R represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic ring attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen. In yet another aspect, the present invention provides use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a cis isomer of formula (XI) represented by formula (Xlb): 5i (followed by 5j) 148080J.DOC intellectual property offlgi of n.z 2 2 DEC 2004 RECEIVPD o A (Xlb) and mixtures thereof with its cis optical enantiomer, including racemic mixtures, and salts and solvates of these compounds in which R° is hydrogen or halogen and R1, R2 and R3 are as defined herein. In yet another aspect, the present invention provides use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound selected from: Cis-2,3,6,7,12,12a-hexahydro-2-(4-pyridylmethyl)-6-(3,4-methylenedioxyphenyl)-pyrazino[2', l':6,1 ]pyrido[3,4-b]indole-1,4-dione; Cis-2,3,6,7,12,12a-hexahydro-6-(2,3-dihydrobenzo[b]furan-5-yl)-2-methyl-pyrazino[2', l':6,1 ]pyrido[3,4-b]indole-l ,4-dione; Cis-2,3,6,7,12,12a-hexahydro-6-(5-bromo-2-thienyl)-2-methyl-pyrazino[2',r: 6,1 ]pyrido[3,4-b]indole-1,4-dione; Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-methylphenyl)-pyrazino[2', 1 ':6,1 ]pyrido[3,4-b]indole-1,4-dione; (6R, 12aR)-2,3,6,7,12,12a-Hexahydro-2-isopropyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2', 1 ':6,1 ]pyrido[3,4-b]indole-1,4-dione; (6R, 12aR)-2,3,6,7,12,12a-Hexahydro-2-cyclopentyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2', l':6,1 ]pyrido[3,4-b]indole-1,4-dione; (6R, 12aR)-2,3,6,7,12,12a-Hexahydro-2-cyclopropylmethyl-6-(4-methoxyphenyl)-pyrazino[2', l':6,1 ]pyrido[3,4-b]indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3-chloro-4-methoxyphenyl)-2-methyl-pyrazino[2', 1 *:6,1 ]pyrido[3,4-b]indole-l ,4-dione; ;(6R, 12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)- ;pyrazino[2',r:6,l]pyrido[3,4-b]indole-l,4-dione; ;(6R, 12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4-methylenedioxyphenyl)- ;pyrazino[2', 1 ':6,1 ]pyrido[3,4-b]indole-l ,4-dione; ;5j ;(followed by 5k) ;intellectual property office of n.2. ;2 2 DEC 2004 ;(5 aR, 12R, 14aS)-1,2,3,5,6,11,12,1 4a-Octahydro-12-(3,4-methylenedioxyphenyl)-pyrrolo[r,,2":4',5']pyrazino[2', l':6,l ]pyrido[3,4-b]indole-5-1,4-dione; ;and physiologically acceptable salts and solvates thereof. ;In yet another aspect, the present invention provides use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound selected from: (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2', 1 ':6,1 ]pyrido[3,4-b]indole-l ,4-dione; ;and physiologically acceptable salts and solvates thereof. ;In yet another aspect, the present invention provides use of cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: ;N ;\ ;N R1 ;(XIII) ;R2 ;or a derivative thereof, or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity, ;wherein R1 is Ci to C3 alkyl substituted with C3 to C6 cycloalkyl, ;CONR5R6 or a N-linked heterocyclic group selected from pyrazolyl, imidazolyl, triazolyl, pyrrolidinyl, piperidinyl, ;morpholinyl and 4-R9-piperazinyl; (CH2)nHet or (CH2)nAr; ;R2 is Ci to C6 alkyl; ;R is Ci to Cg alkyl optionally substituted with C1-C4 alkoxy; R4 is S02NR7R8; ;R5 and R6 are each independently selected from H and Q to C4 alkyl optionally substituted with Ci to C4 alkoxy, or, together with ;5k ;(followed by 51) ;U8O8OJ.DOC ;intellectual property OFFICE of n.z. ;2 2 DEC 2004 RECEIVED ;the nitrogen atom to which they are attached, form a pyrrolidinyl, piperidinyl, morpholinyl or 4-R9-piperazinyl group; ;R7 and R8, together with the nitrogen atom to which they are attached, form a 4-R10-piperazinyl group; ;R9 is Ci to C4 alkyl; ;R10 is H or Ci to C4 alkyl optionally substituted with OH, Ci to C4 alkoxy or CONH2; ;Het is a C-linked 6-membered heterocyclic group containing one or two nitrogen atoms, optionally in the form of its mono-N-oxide, or a C-linked 5-membered heterocyclic group containing from one to four heteroatoms selected from nitrogen, oxygen and sulphur, wherein either of said heterocyclic groups is optionally substituted with one or two substituents selected from Ci to C4 alkyl optionally substituted with Ci to C4 alkoxy, Q, to C4 alkoxy, ;halo and NH2; ;Ar is phenyl optionally substituted with one or two substituents selected from Ci to C4 alkyl, Ci to C4 alkoxy, halo, CN, CONH2, ;N02, NH2, NHS02 (Q to C4 alkyl) and S02NH2; ;and n is 0 or 1. ;In yet another aspect, the present invention provides use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: ;or a derivative or salt thereof, ;wherein Y is halo, and R1, R2 and R3 are as previously defined herein. ;51 ;(followed by 5m) ;148080J.DQC ;intellectual property office Of M.z. ;2 2 DEC 2004 RECEIVED ;In yet another aspect, the present invention provides use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: ;/ (XVI) ;or ;,N R1 ;(XVII) ;or a derivative or salt thereof, ;wherein R1, R2 and R3 are as previously defined herein. ;In yet another aspect, the present invention provides use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: ;or a derivative or salt thereof, ;wherein R1, R2, R3 and R4 are as previously defined herein. ;In yet another aspect, the present invention provides use of a cGMP PDE5 inhibitor comprising sildenafil citrate in the manufacture of a medicament for the treatment of peripheral neuropathies. ;5m ;(followed by 5n) ;intellectual property office of n.z. ;2 2 DEC 2004 ;148080_1.DOC ;received ;Described is a method of treating a patient with diabetic ulcers, which includes treating the patient with an effective amount of cGMP PDE5 inhibitor, or a pharmaceutical composition thereof. ;Described is a prophylactic to those patients which are predisposed to diabetic ulcers and thus save many diabetics from suffering the deleterious effects and possibility of limb amputations which commonly result from diabetic foot ulcers. ;Additionally, the cGMP PDE5 inhibitor, or a pharmaceutical composition thereof, also may be used in combination with other therapeutic agents or treatments. ;intellectual property office of n.z ;-4 FEB 2005 RECEIVED ;5n ;(followed by page 6) ;that are now or may later be useful in the treatment of the above-mentioned disease states. ;Also described is the use of a cGMP PDE5 inhibitor for the manufacture of a composition for the treatment of diabetic ulcers. ;5 it is also within the broad concept of this invention to treat peripheral vascular diseases such as Raynaud's Phenomenon, including CREST syndrome, autoimmune diseases such as systemic lupus eiythematosis, rheumatoid diseases and diabetic retinopathies. ;The present invention would also be beneficial in peripheral and autonomic to neuropathies or any other disease entity, that results from small vessel disease and directly large vessel disease. ;Also described herein is the treatment of onychomycosis (fungal) ;infection of the nailbed). ;A number of potent and selective cGMP PDE5 inhibitors are now known and 15 their activity can be determined readily by in-vitro screening against cGMP PDE enzymes from a number of sources, in accordance with published procedures. Thus, ;for example, a number of pyrazolopyrimidinone compounds are described as cGMP PDE5 inhibitors in EPO 0463756, EPO 0526004, WO 93/12095, WO 94/05661, WO 94/00453, WO 95/19978 and WO 98/49166, the complete disclosures of which are 20 fully incorporated herein by reference. ;Some cGMP-PDE5 inhibitors which can be used in the present invention include, for example, 5-(2-ethoxy-5-morpholinoacetylphenyl> 1 -methyl-3-n-propyl-1-6-dihydro-7H-20 pyrazolo[4,3-d]pyrimidin-7-one; 5-(5-moipholinoacetyl-2-n-propoxyphenyl>l-methyl-3-n-propyl-l-,6-dihydro-7Hpyrazolo[4,3-d]pyrimidin-25 7-one; 5-[2-ethoxy-5-(4-methyl-l-piperazin-l-yl-sulphonyl)-phenyl]-l,6- ;6 intellectual property office of n.z. ;2 2 DEC 2004 Receive* WO 02/02118 PCT/USO1/41202 dihydro-l-methyl-3 propylpyrazolo[4, 3-d]pyrimidin-7-one; 5-[2-allyloxy-5-(4-methyl-1 -piperazmlysulphonyl)-phenyl]-l -methyl-3-n-propyl-l ,6 dihydro-7H-pyrazolo[4, 3-d]pyrimidin-7-one; 5-(2-ethoxy-5-[4-(2-propyl)-l-piperazinyl-sulphonyl]phenyl}-l-methyl-3-n-propyl-l5 6-dihydro-7H-pyrazolo[4,3 -d)pyrimidin-7 -one; 5-(2-ethoxy-5[4-(2-hydroxyethyl-l-piperazinyl-sulphonyl]phenyl)-l-methyl-3-npropyl-l, 6-dihydro-7H-pyrazolo [4, 3-d]pyrimidin-7-one; 5-(5-[4-(2-hydroxyethyl)-l-piperazinylsulphonyl]- 2-n-pTopoxyphenyl)-l-methyl-3-n propyl-1-, 6-dihydro-7H-pyrazolo[4, 3-d]pyrimidin-7-one; 5-[2-ethoxy-5-(4-methyl-l -piperazinylcarbonyl)-phenyl]-l-methyl-3-n-propyl-l, 6 dihydro-7H-pyrazolo[4,3-dJpyrimidin-7-one; 5-[2-ethoxy-5-(l -methyl-2-imidazolyl)phenyl] -1 -methyl-3-n-propyl-1,6-dihydro-7H pyrzolo[4,3-d]pyrimidin-7-one, 3-ethyl-5-[5-[4-ethylpiperazin-1 -yl)sulphonyl]-2-(2-methoxyethoxy)pyrid-3-yl]-2-(2pyridylmetlayi)-6,7-dihydro-2H-pyrazolo- [4,3-d]pyrimidin-7-one, and 3-ethyl-5-[5-(4-ethylpiperazin-l -ylsulphonyl)-2-n-propoxyphenyl]-2-(pyridin-2yl)methyl-2,6-dihydro-7H-pyrimidin-7-one. The inventor has determined that the preferred compound, 5-[2-ethoxy-5-(4-methylpiperazin 1-yl sulphonyl)-phenyl]-l, 6-dihydro-l-methyl-3-propylpyrazolo [4,3-d] pyrimidine-7-one (sildenafil), and pharmaceutically acceptable salts thereof; including the citrate salt, has been very effective in the treatment of foot ulcers related to diabetes. hi regards to other uses of cycli guanosine 3', 5'-monophosphate type five (cGMP PDE5) inhibitors, including the compound sildenafil, for which we have shown is effective in the treatment of diabetic foot ulcers, it is also within the concept of the present invention to treat other peripheral vascular diseases such as Raynaud's Phenomenon, including CREST syndrome, autoimmune diseases such as systemic lupus erythematosis, rheumatoid diseases and diabetic retinopathies. The treatment described herein would also be beneficial in peripheral and autonomic • neuropathies or any other disease entity that results from small vessel disease and directly large vessel disease. The inventor has also discovered that onychioihycosis 5 (fungal infection of the nailbed) particularly of the lower extremity has resolved completely without the use of antifungal medication when treated exclusively with sildenafil. The patient in this case was requesting treatment for erectile dysfunction and again the inventor discovered this unexpected beneficial result The inventor has observed such results in varied diseases which have the common element of peripheral 10 vascular disease or peripheral neuropathy. The beneficial effect of the method is believed to be due to increase vascular flow of the small vessels which aided the body in healing itself. Examples: Patient #1 is an insulin dependent diabetic who had been suffering from 15 erectile dysfunction and who subsequently had a diabetic foot ulcer. During the. treatment of the erectile dysfunction it was noted that the foot ulcer was healing. This foot ulcer began approximately two years prior and the patient had been through vascular studies, had seen vascular surgeons, podiatrists, and had been in wound care clinics with minimal results at best He had also been hospitalized for approximately a 20 monlh on IV antibiotics, etc. and the threat was very real that the patient was going to require a below the knee amputation. The ulcer would appear to be healing at times only to reoccur to its pretreatment size and depth. Once sildenafil treatment had began for his erectile dysfunction, it was noted that the ulcer was decreasing in the size and the patient was instructed to begin taking 50 mg of sildenafil once a day. This resulted 8 WO 02/02118 PCT/US01/41202 in complete resolution of the diabetic food ulcer in one month and the patient has continued on this same treatment for the past two years without reoccurrence. Patient #2 was suffering from chronic changes of both lower extremities secondary to peripheral vascular disease and diabetes mellitus. He was being followed 5 for his diabetes mellitus and stated he was having trouble with erectile dysfunction and once sildenafil treatment was instituted, not only did his erectile dysfunction significantly improve but the chronic changes of both lower extremities secondary to the peripheral vascular disease also significantly improved or resolved completely. Patient #3 suffers from severe peripheral vascular disease secondary to 10 arteriosclerosic. Conventional treatments such as femoral popliteal bypass surgery, i' surgical insertion of (Greenfield filter) thrombotic preventive umbrella, administration of heparin and administration of Coumadin have all failed to alleviate the condition. Sildenafil has been prescribed for erectile dysfunction and the patient is being closely followed to monitor improvements in the arteriosclerosic condition. 15 Patient #4 suffered from erectile dysfunction. He also suffered from onychomycosis (fungal infection of the nailbed). He was placed on sildenafil treatment taking one 50 mg pill on an as-needed basis. On that treatment schedule his erectile dysfunction improved and surprisingly his fungal infection was cured. The cGMP PDE5 inhibitor is preferably administered as a pharmaceutical 20 composition. Thus, the compound can be administered in any conventional oral, parenteral, rectal, or transdermal dosage form, usually with a pharmaceutically acceptable carrier or diluent These methods of administration are well known in the prior art and are disclosed in U.S. Patent nos. 5,520,534; 5,346,901; 5,719,283; 5,272,147; 5,426,107; 5,482,941; 5,591,742; 5,734,053; 6,025,494; 5,859,006, the 25 complete disclosures of which are fully incorporated herein by reference. 9 WO 02/02118 PCT/USO1/41202 Oral administration of a pharmaceutical composition may be in the form of a solution, suspension, tablet, pill, capsule, powder or the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are used in conjunction with various disintegrants, such as potato or tapioca starch, and 5 certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin, and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate, and talc are often used for tabletting purposes. Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection also include lactose or milk 10 sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the compounds can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various similar combinations thereof. It is also 15 within the concept of the present invention to administer the effective compound in admixture with a foodstuff or drink. For purposes of parenteral administration, solutions in oil or in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts. Such aqueous solutions may be suitably buffered, if 20 necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. In this connection, the sterile aqueous media employed are all readily obtainable by standard techniques, which are well-known to those skilled in the art. 10 WO 02/02118 PCT/USO1/41202 For purposes of transdermal (e.g., topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1 % to 5% concentration), otherwise similar to the above parenteral solutions, are prepared. Transdermal administration of compounds for therapeutic purposes is increasingly becoming a common practice, as in the case of nicotine patches or motion sickness preventatives. More recently, the transdermal application of relatively large molecules, such as those contained in compositions of antigens and adjuvants has been shown to be effective as described in U.S. Patent 5,910,306 and U.S. Patent 5,980,898, the complete disclosures of which are fully incorporated herein by reference. Transdermal application can be accomplished by direct application to the skin, in admixture with a carrier, such as for example a salve or cream, or as covered by or applied to a patch, which is placed on the slrin of the patient. Methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are well known to those skilled in the art, or may be determined by reference to literature precedents, which are available to those skilled in the art. The exact dosages of cGMP PDE5 inhibitor administered will differ depending upon the specific compound prescribed, on the subject being treated, on the severity of the condition, on the manner of administration, and on the judgment of the prescribing physician. Thus, because of patient-to-patient variability, dosages are a guideline only and the physician may adjust doses of the compounds to achieve the level of effective treatment that the physician considers appropriate for the patient. In considering the degree of treatment desired, the physician must balance a variety of factors such as the age of the patient and the presence of other diseases or conditions (e.g. cardiovascular disease). In general, the cGMP PDE5 inhibitor will be administered in a range of from 11 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 0.5 to 400 mg per day, as disclosed in disclosed in U.S. Patent nos. 5,520,534; 5,346,901; 5,719,283; 5,272,147; 5,426,107; 5,482,941; 5,591,742; 5,734,053; 6,025,494; 5,859.,006, the complete disclosures of which are fully incorporated herein by reference. More particularly, the preferred treatment dosage is 25 to 100 mg per day, as disclosed in WO 98/49166, the complete disclosure of which is fully incorporated herein by reference. Safe and effective dosages prescribed for individuals would be well known to a practitioner, based upon the disclosures in the foregoing patents and the practitioner's personal knowledge of the particular patient's state of health. In the case of the preferred compound, sildenafil, an effective dose is 5 to 125 mg per day, more preferably 10-110 mg per day and most preferably 25-100 mg per day, which can be administered as a tablet or capsule up to three times a day. However, the precise dosage will be as determined by the prescribing physician and will depend on the age and weight of the patient and severity of the symptoms, as described above. The administration of an effective dosage of the compound described herein can also provide a prophylactic to assist in the prevention of foot ulcers in a patient suffering from the disease diabetes. The skilled practitioner can prescribe an effective dosage of the compound using the dosages disclosed above and tailored to the specific needs of the patient being treated. 12 intellectual property office | of n.z. 2 2 DEC 20M RECEiVKD WHAT WE CLAIM IS:

1. Use of a cGMP PDE5 inhibitor or a derivative or salt thereof, in the manufacture of a medicament for treatment of autonomic neuropathies.

2. Use of a cGMP PDE5 inhibitor or a derivative or salt thereof, in the manufacture of a medicament for treatment of a disease selected from the group consisting of CREST syndrome, erythromatosis and rheumatoid diseases.

3. Use of a cGMP PDE5 inhibitor or a derivative or salt thereof, in the manufacture of a medicament for treatment of onychiomycosis.

4. The use according to any one of claims 1 to 3 wherein the cGMP PDE5 inhibitor is sildenafil or a derivative or salt thereof.

5. Use of sildenafil or a derivative or salt thereof, in the manufacture of a medicament for treatment of Raynaud's Phenomenon.

6. Use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: (I) so2n r4 or a derivative or salt thereof, wherein intellectual PROPERTY 0B- 1<- M7 2 2 DEC 2004 13 R1 is H, C1-C3 alkyl, C3-C5 cycloalkyl or C1-C3 perfluoroalkyl; R2 is H, C1-C6 alkyl optionally substituted by OH, C1-C3 alkoxy or C3-C6 cycloalkyl, or C1-C3 perfluoroalkyl; R3 is CrC6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C7 cycloalkyl, C1-C6 perfluoroalkyl or (C3-C6 cycloalkyl)Ci-C6 alkyl; R4 taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R6)-piperazinyl group; R5 is H, C1-C4 alkyl, C1-C3 alkoxy, NR7R8, or CONR7R8; R6 is H, Ci-C6 alkyl, (C1-C3 alkoxy) C2-C6 alkyl, hydroxy C2-C6 alkyl, (R7R8N)C2-C6 alkyl, (R7R8NCO)-Ci-C6 alkyl, CONR7R8, CSNR7R8 or C(NH)NR7R8; R7 and R8 are each independently H, C1-C4 alkyl, (CrC3)alkoxy)C2-C4 alkyl or hydroxy C2-C4 alkyl.

7. A use as claimed in claim 6 wherein R1 is H, methyl or ethyl; R2 is C1-C3 alkyl optionally substituted by OH or methoxy; R3 is C2-C3 alkyl or allyl; R4 taken together with the nitrogen atom to which it is attached completes a piperidino or 4-N-(R6) piperazinyl group; R5 is H, NR7R8 or CONR7R8; R6is H, C1-C3 alkyl, hydroxy C2-C3 alkyl, CONR7R8, CSNR7R8 or C(NH)NR7R8; and R7 and R8 are each independently H or methyl.

8. A use as claimed in claim 7 wherein R1 is methyl; R2 is n-propyl; R3 is ethyl, n-propyl or allyl; R4 taken together with the nitrogen atom to which it is attached completes a 4-N-(R6) piperazinyl group; R5 is H; and R6 is H, C1-C3 alkyl or 2-hydroxyethyl.

9. A use as claimed in claim 8 wherein said compound is selected from: 5-[2-allyloxy-5-(4-methylpiperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[2-ethoxy-5-(piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo-[4,3-d]pyrimidin-7-one; 5-[2-ethoxy-5-(4-methylpiperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo-[4,3-d]pyrimidin-7-one; 5-{2-ethoxy-5-[4-(2-propyl)piperazinylsulphonyl]phenyl}-1-methyl-3-n-proyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; intellectual property office of n.z. 14 2 2 DEC 200*1 5-{2-ethoxy-5-[4-(2-hydroxyethyl)piperazinylsulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 1-methyl-5-[5-piperazinylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one; and 5-{5-[4-(2-hydroxyethyl)piperazinylsulphonyl]-2-n-propoxyphenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, and pharmaceutically acceptable salts thereof.

10. Use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: or a derivative or salt thereof, wherein R1 and R2 are as claimed in claim 6, R3 is as claimed in claim 6 and is also H, and Y is chloro, bromo or fluoro.

11. Use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: h R1 (II) so2y intellectual property office of n.z (III) 2 2 DEC 200*1 or a derivative or salt thereof, wherein R1 and R2 are as claimed in claim 6, and R3 is as claimed in claim 6 and is also H.

12. Use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: or a derivative or salt thereof, wherein R1 is H; C1-C3 alkyl optionally substituted with one or more fluoro substituents; or C3-C5 cycloalkyl; R2 is H, or C1-C6 alkyl optionally substituted with one or more fluoro substituents or with C3-C6 cycloalkyl; R3 is CrC6 alkyl optionally substituted with one or more fluoro substituents or with C3-C6 cycloalkyl; C3-C5 cycloalkyl; C3-C6 alkenyl; or C3-C6 alkynyl; R4 is C1-C4 alkyl optionally substituted with OH, NR5R6, CN, CONR5R6 or CO2R7; C2-C4 alkenyl optionally substituted with CN, CONR5R6 or CO2R7; C2-C4 alkanoyl optionally substituted with NR5R6; hydroxy C2-C4 alkyl optionally subtituted with NR5R6; (C2-C3 alkoxy)Ci-C2 alkyl optionally substituted with OH or NR5R6; CONR5R6; C02R7; halo; NR5R6; NHS02NR5R6;NHS02R8; or phenyl or heterocyclyl either of which is optionally substituted with methyl; R5 and R6 are each independently H or C1-C4 alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, 9 r1 (IV) intellectual property office of n.z. 16 2 2 DEC mm morpholino, 4-(NR9)-piperazinyl or imidazolyl group wherein said group is optionally substituted with methyl or hydroxy; R7 is H or C1-C4 alkyl; R8 is C1-C3 alkyl optionally substituted with NR5R6; and R9 is H; C1-C3 alkyl optionally substituted with phenyl; hydroxy C2-C3 alkyl; or C1-C4 alkanoyl.

13. A use as claimed in claim 12 wherein R1 is H, methyl or ethyl; R2 is C1-C3 alkyl; R3 is C2-C3 alkyl; R4 is Ci-C2 alkyl optionally substituted with OH, NR5R6, CONR5R6 or CO2R7; acetyl optionally substituted with NR5R6; hydroxyethyl substituted with NR5R6; ethoxymethyl optionally substituted with OH or NR5R6; CH=CHCN; CH=CHCONR5R6; CH=CHC02R7; C02H; CONR5R6; Br; NR5R6; NHS02NR5R6; NHS02R8; or pyridyl or imidazolyl either of which is optionally subtituted with methyl; R5 and R6 are each independently H, methyl or ethyl, or together with the nitrogen atom to which they are attached form a piperidino, morpholino, 4-(NR9)-1-piperazinyl or imidazolyl group wherein said group is optionally substituted with methyl or hydroxy; R7 is H or t-butyl; R8 is methyl or CH2CH2CH2NR5R6; and R9 is H, methyl, benzyl, 2-hydroxyethyl or acetyl.

14. A use as claimed in claim 13 wherein R1 is methyl; R2 is n-propyl; R3 is ethyl or n-propyl; R4 is CH2NR5R®, CH2OCH2CH2NR5R6, CH2OCH2CH3, CH2OCH2CH2OH, COCH2NR5R6, CH(OH)CH2NR5R6, CH=CHCON(CH3)2, CH=CHC02R7, C02H, CONR5R6, Br, NHS02NR5R6, NHS02CH2CH2CH2NR5R6, 2-pyridyl, 1-imidazolyl or 1-methyl-2-imidazolyl; R5 and R6 together with the nitrogen atom to which they are attached form a piperidino, 4-hydroxypiperidino, morpholino, 4-(NR9)-1-piperazinyl or 2-methyl-1-imidazolyl group; R7 is H or t-butyl; and R9 is H, methyl, benzyl, 2-hydroxyethyl or acetyl.

15. A use as claimed in claim 14 wherein the said compound is selected from: 5-[2-ethoxy-5-(1 -methy l-2-imidazolyl)pheny I]-1 -methyl-3-n-propy I-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; intellectual property office OF n.z. 17 2 2 DEC 2004 RECEIVFD 5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[5-(4-acetyl-1-piperazinyl)acetyl-2-ethoxyphenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-(2-ethoxy-5-morpholinoacetylphenyl)-1 -methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; and 5-(5-morpholinoacetyl-2-n-propoxyphenyl)-1 -methyl-3-n-propyl-1,6-d ihydro-7H-pyrazolo[4,3-d]pyrim id in-7-one, and pharmaceutically acceptable salts thereof.

16. Use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: o r2 or a derivative or salt thereof, wherein R1 is H, C1-C4 alkyl,C1-C4 alkoxy or CONR5R6; R2 is H or C1-C4 alkyl; R3 is C2-C4 alkyl; R4 is H,C2-C4 alkanoyl optionally substituted with NR7R8, (hydroxy)C2-C4 alkyl optionally substituted with NR7R8, CH=CHC02R9, CH=CHC0NR7R8,CH2CH2C02R9, CH2CH2CONR7R8, S02NR7R8, S02NH(CH2)nNR7R8 or imidazolyl; R5 and R6 are each independently H or C1-C4 alkyl; R7 and R8 are each independently H or C1-C4 18 intellectual property office of n.z. 2 2 DEC 2004 aerciucm alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino or4-(NR10)-1-piperazinyl group wherein any of said groups is optionally substituted with CONR5R6; R9 is H or Ci,-C4 alkyl; R10 is H, C1-C3 alkyl or (hydroxy)C2-C3 alkyl; and n is 2, 3 or 4; with the proviso that R4 is not H when R1 is H, C1-C4 alkyl or C1-C4 alkoxy.

17. A use as claimed in claim 16 wherein R1 is H, methyl, methoxy or CONR5R6; R2 is H or methyl; R3 is ethyl or n-propyl; R4 is H, acetyl optionally substituted with NR7R8, hydroxyethyl substituted with NR7R8, CH=CHC02R9, CH=CHC0NR7R8,CH2CH2C02R9, SO2NR7R8, S02NH(CH2)3NR7R8 or 1-imidazolyl; R5 and R6 are each independently H or ethyl; R7 and R8 together with the nitrogen atom to which they are attached form a piperidino, 4-carbamoylpiperidino, morpholino or 4-(NR10)-1-piperazinyl group; R9 is H or t-butyl; and R10 is H, methyl or 2-hydroxyethyl; with the proviso that R4 is not H when R1 is H, methyl or methoxy.

18. A use as claimed in claim 17 wherein R1 is methyl, CONH2 or CONHCH2CH3; R2 is H; R3 is ethyl or n-propyl; R4 is H, acetyl, 1-hydroxy-2-(NR7R8) ethyl, CH=CHC02C(CH3)3, CH=CHCONR7R8, S02NR7R8 or 1-imidazolyl; R7 and R8 together with the nitrogen atom to which they are attached form a 4-(NR10)-1-piperazinyl group; and R10 is methyl or 2-hydroxyethyl; with the proviso that R4 is not H when R1 is methyl.

19. A use as claimed in claim 18 wherein the said compound is selected from 2-{2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinyl-sulphonyl]phenyl}-8-methylquinazolin-4-(3H)-one; 2-{5-[4-(2-hydroxyethyl)-1-piperazinylsulphonyl]-2-n-propoxyphenyl}-8-methylquinazolin-4(3H)-one; intellectual property office of n.z. 19 2 2 DEC 2004 REHEIVFD 8-methyl-2-{5-[2-(4-methyl-1-piperazinylcarbonyl)-ethenyl]-2-n-propoxyphenyl}quinazolin-4(3H)- one; 8-carbamoyl-2-{2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinylsulphonyl]phenyl}quinazolin-4-(3H)-one; and 8-ethylcarbamoyl-2-(2-n-propoxyphenyl)quinazolin- 4(3H)-one; and pharmaceutically acceptable salts thereof.

20. Use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: or a derivative or salt thereof, wherein R1 is H, C1-C4 alkyl, CN or CONR4R5; R2 is C2-C4 alkyl; R3 is S02NR6R7, N02i NH2, NHCOR8, NHSO2R8 or N(S02R8)2; R4 and R5 are each independently selected from H and C1-C4 alkyl; R6 and R7 are each independently selected from H and C1-C4 alkyl optionally substituted with CO2R9, OH, pyridyl, 5-isoxazolin-3-onyl, morpholino or 1-imidazolidin-2-onyl; or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino, 1-pyrazolyl or4-(NR10)-1 piperazinyl group wherein any of said groups may optionally be substituted with one or two o (VI) 20 intellectual property office of n.z. 2 2 DEC 2004 qpppiu p n substituents selected from C1-C4 alkyl, CO2R9, NH2 and OH; R8 is C1-C4 alkyl or pyridyl; R9 is H or Ci,-C4 alkyl; and R10 is H, C1-C4 alkyl or (hydroxy) C2-C3 alkyl.

21. A use according to claim 20 wherein R1 is H, n-propyl, CN or CONH2; R2 is ethyl; R3 is S02NR6R7, N02, NH2, NHCOCH(CH3)2, NHS02CH(CH3)2, NHS02(3-pyridyl) or N[S02(3-pyridyl)]2; R6 is H, methyl or 2-hydroxyethyl; R7 is methyl optionally substituted with 2-pyridyl or 5-isoxazolin-3-onyl, or ethyl 2-substituted with OH, CO2CH2CH3, morpholino or 1-imidazolidin-2-onyl, or R6 and R7 together with the nitrogen atom to which they are attached form a (4-C02R9)piperidino, 5-amino-3-hydroxy-1-pyrazolyl or 4-(NR10)-1 -piperazinyl group; R9 is H or ethyl; and R10 is H, methyl or 2-hydroxyethyl.

22. A use according to claim 21 wherein R1 is n-propyl or CN; R2 is ethyl; R3 is S02NR6R7, NHS02CH(CH3)2, NHS02(3-pyridyl) or N[S02(3-pyridyl)]2; R6 is H or methyl; R7 is methyl, or ethyl 2-substituted with CO2CH2CH3, morpholino or 1-imidazolidin-2-onyl, or R6 and R7 together with the nitrogen atom to which they are attached form a (4-C02R9)piperidino or 4-(NR10)-1-piperazinyl group; R9 is H or ethyl; and R10 is H, methyl or 2-hydroxyethyl.

23. A use according to claim 22 wherein the said compound of formula (VI) is selected from 2-[2-ethoxy-5-(4-ethoxycarbonylpiperidinosulphonyl)phenyl]-8-n-propylpyrido[3,2-d]pyrimidin-4(3H)-one; 2-[5-(4-carboxypiperidinosulphonyl)-2-ethoxyphenyl]-8-n-propylpyrido[3,2-d]pyrimidin-4(3H)-one; 2-{2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinyl-sulphonyl]phenyl}-8-n-propylpyrido[3,2-d]pyrimidin-4(3H)-one; and 2-{2-ethoxy-5-[(bis-3-pyridylsulphonyl)amino]-phenyl}-8-n-propylpyrido[3,2-d]pyrimidin-4(3H)-one. intellectual property office of n.z. 2 2 DEC 2004

24. Use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: o (VII) so2z or a derivative or salt thereof, wherein Z is halo, and R1 and R2 are as previously defined in claim 20.

25. Use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: or a derivative or salt thereof, wherein R1 and R2 are as previously defined in claim 20.

26. Use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: o (VIII) intellectual property office of n.z. 2 2 DEC 2004 22 or a derivative or salt thereof, wherein R1 is C1-C4 alkyl; R2 is C2-C4 alkyl; R3 is H or S02NR4R5; R4 and R5 together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino or 4-N-(R6)-t-piperazinyl group; and R6 is H or C1-C3 alkyl.

27. A use according to claim 26 wherein R1 and R2 are each independently ethyl or n-propyl; and R4 and R5 together with the nitrogen atom to which they are attached form a 4-N-(R6)-1-piperazinyl group.

28. A use according to claim 27 wherein R1 is n-propyl; R2 is ethyl; and R3 is 1-piperazinylsulphonyl or 4-methyl-1-piperazinylsulphonyl.

29. Use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: r2o hn 'n' so2z n •N r1 (X) intellectual property office of n.z. 2 2 DEC 2004 fl A P 1 l r *-v.. or a derivative or salt thereof, wherein Z is halo, and R1 and R2 are as previously defined in claim 26.

30. A use according to claim 29 wherein Z is chloro.

31. Use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: or a derivative or salt thereof, in which: R° represents hydrogen, halogen or Ci-6 alkyl; R1 represents hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6alkynyl, haloCr6 alkyl, C3-8cycloalkyl, C3-8cycloalkylCi-3 alkyl, arylCi-3 alkyl or heteroarylCi-3 alkyl; R2 represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally substituted O0 bicyclic ring attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen; and R3 represents hydrogen or C1-3 alkyl, or R1 and R3 together represent a 3- or 4-membered alkyl or alkenyl chain. o (XI) intellectual property office of n.z 24 2 2 OEC 2004

32. Use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: o r° ■"^"VyY 1^1 n-r1 (XIa) r2 o or a derivative or salt thereof, in which: R° represents hydrogen, halogen or C1-6 alkyl; R1 represents hydrogen, Ci-6alkyl, haloCi-6alkyl, C3-8cycloalkyl, C3- 8cycloalkylCi-3alkyl, arylCi-3alkyl or heteroarylCi-3alkyl; and R2 represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic ring attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen.

33. A use according to claim 31 or 32, wherein R° represents hydrogen.

34. A use according to any of claims 31 to 33, wherein R1 represents hydrogen, Ci-4alkyl, haloCi-4alkyl, C3-6cycloalkyl, C3-6cycloalkylmethyl, py ridy IC1 -3a Iky I, furylCr3alkyl or optionally substituted benzyl.

35. A use according to any of claims 31 to 33, wherein R1 and R3 together represent a 3-membered alkyl chain.

36. A use according to any of claims 31 to 34, to wherein R3 represents hydrogen. intellecthal property of ,M7 25 2 2 DEC 2004

37. A use according to any of claims 31 to 36, wherein R2 represents an optionally substituted benzene, thiophene, furan, pyridine or naphthalene ring or an optionally substituted bicyclic ring or 2 and X and Y are each CH2 or O. (CH2)n where n is 1

38. Use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a cis isomer of formula (XI) represented by formula (Xlb) R°- (Xlb) and mixtures thereof with its cis optical enantiomer, including racemic mixtures, and salts and solvates of these compounds in which R° is hydrogen or halogen and R1, R2 and R3 are as defined in any one of claims 31 to 37.

39. Use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound selected from: Cis-2,3,6,7,12,12a-hexahydro-2-(4-pyridylmethyl)-6-(3,4-methylenedioxyphenyl)-pyrazino[2', 1 ':6,1 ]pyrido[3,4-b]indole-1,4-dione; Cis-2,3,6,7,12,12a-hexahydro-6-(2,3-dihydrobenzo[b]furan-5-yl)-2-methyl-pyrazino[2\ 1 ':6,1 ]pyrido[3,4-b]indole-1,4-dione; Cis-2,3,6,7,12,12a-hexahydro-6-(5-bromo-2-thienyl)-2-methyl-pyrazino[2', 1': 6,1]pyrido[3,4-b]indole-1,4-dione; Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-methylphenyl)-pyrazino[2', 1 *:6,1 ]pyrido[3,4-b]indole-1,4-dione; (6R, 12aR)-2,3,6,7,12,12a-Hexahydro-2-isopropyl-6-(3,4- intellectual property office ! 26 OF N.Z. 2 2 DEC 2004 methylenedioxyphenyl)-pyrazino[2', 1 ':6,1 ]pyrido[3,4-b]indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-cyclopentyl-6-(3,4- methylenedioxyphenyl)-pyrazino[2\ 1 ':6,1 ]pyrido[3,4-b]indoie-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-cyclopropylmethyl-6-(4- methoxyphenyl)- pyrazino[2', 1 ':6,1 ]pyrido[3,4-b]indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3-chloro-4-methoxyphenyl)-2- methyl-pyrazino[2', 1 ':6,1 ]pyrido[3,4-b]indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4- methylenedioxyphenyl)-pyrazino[2', 1 ':6,1 ]pyrido[3,4-b]indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4-methylenedioxyphenyl)- pyrazino[2', 1 ':6,1 ]pyrido[3,4-b]indole-1,4-dione; (5aR, 12R, 14aS)-1,2,3,5,6,11,12,14a-Octahydro-12-(3,4- methylenedioxyphenyl)-pyrrolo[1",2":4,,5,]pyrazino[2,,1':6,1]pyrido[3,4- b]indole-5-1,4-dione; and physiologically acceptable salts and solvates thereof.

40. Use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound selected from: (6R, 12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2\ 1 ':6,1 ]pyrido[3,4-b]indole-1,4-dione; and physiologically acceptable salts and solvates thereof.

41. Use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: R4 (XII) or N R1 (XIII) 27 intellectual property office of n.z. 2 2 DEC 2004 RECEIVED i cc z °-LL. I o o CD CNJ L'J Q c^i c*s| Q llt > lu o lu £T or a derivative thereof, or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity, wherein R1 is Ci to C3 alkyl substituted with C3 to C6 cycloalkyl, CONR5R6 or a N-linked heterocyclic group selected from pyrazolyl, imidazolyl, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl and 4-R9-piperazinyl; (CH2)nHet or (CH2)nAr; R2 is Ci to C6 alkyl; R3 is Ci to C6 alkyl optionally substituted with C1-C4 alkoxy; R4 is S02NR7R8; R5 and R® are each independently selected from H and Ci to C4 alkyl optionally substituted with Ci to C4 alkoxy, or, together with the nitrogen atom to which they are attached, form a pyrrolidinyl, piperidinyl, morpholinyl or 4-R9-piperazinyl group; R7 and R8, together with the nitrogen atom to which they are attached, form a 4-R10-piperazinyl group; R9 is Ci to C4 alkyl; R10 is H or Ci to C4 alkyl optionally substituted with OH, Ci to C4 alkoxy or CONH2; Het is a C-linked 6-membered heterocyclic group containing one or two nitrogen atoms, optionally in the form of its mono-N-oxide, or a C-linked 5-membered heterocyclic group containing from one to four heteroatoms selected from nitrogen, oxygen and sulphur, wherein either of said heterocyclic groups is optionally substituted with one or two substituents selected from Ci to C4 alkyl optionally substituted with Ci to C4 alkoxy, Ci, to C4 alkoxy, halo and NH2; Ar is phenyl optionally substituted with one or two substituents selected from Ci to C4 alkyl, Ci to C4 alkoxy, halo, CN, CONH2, N02, NH2, NHS02 (Ci to C4 alkyl) and S02NH2; and nisOorl

42. A use according to claim 41 wherein R1 is Ci to C2 alkyl substituted with C3 to C5 cycloalkyl, CONR5R6 or a N-linked heterocyclic group selected from pyrazolyl, triazolyl, morpholinyl and 4-R9-piperazinyl; (CH2)nHet or 28 (CH2)nAr; R5 is H and R6 is Ci to C4 alkyl optionally substituted with Ci to C4 alkoxy or R5 and R6, together with the nitrogen atom to which they are attached, form a morpholinyl group; Het is selected from pyridinyl, 1-oxidopyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, isoxazolyl, thiazolyl, triazolyl and oxadiazolyl, any of which is optionally substituted with one or two substituents selected from CH3, CH2CH2OCH3, OCH3 and NH2; and R2, R3, R4, R9, Ar and n are as previously defined in claim 41.

43. A use according to claim 42 wherein R1 is Ci to C2 alkyl substituted with cyclobutyl, CONR5R6, pyrazol-1-yl, 1,2,3-triazol-l-yl, 1,2,4-triazol-1-yl, morpholin-4-yl or 4-methylpiperazin-1-yl; pyrimidin-2-yl; ChbHet or (CH2)nAr; R2 is Ci to C3 alkyl; R3 is Ci to C3 alkyl optionally substituted with Ci to C2 alkoxy; R5 is H and R6 is Ci to C2 alkyl optionally substituted with Ci to C2 alkoxy or R5 and R6, together with the nitrogen atom to which they are attached, form a morpholin-4-yl group; R10 is Ci to C2 alkyl optionally monosubstituted with OH, OCH3 or CONH2; Het is selected from pyridin-2-yl, 1-oxidopyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 3-methoxypyridin-2-yl, 6-aminopyridin-2-yl, 1-methylimidazol-2-yl, 3,5-dimethylisoxazol-4-yl, 2-methylthiazol-4-yl, 1-methyl-1,2,4-triazol-5-yl, 1-(2-methoxyethyl)-1,2,4-triazol-5-yl, 4-methyl- 1,2,4-triazol-3-yl, 3-methyl-1,2,4-triazol-5-yl, 1,2,4-oxadiazol-3-yl and 5-methyl-1,2,4-oxadiazol-3-yl; Ar is selected from phenyl, 4-chlorophenyl, 4-bromophenyl, 2-cyanophenyl, 2-carbamoylphenyl, 4-carbamoylphenyl, 2-nitrophenyl, 4-nitrophenyl, 2-aminophenyl, 4-aminophenyl, 2-methanesulphonamidophenyl, 4-methanesulphonamidophenyl, 4-ethanesulphonamidophenyl, 4-(prop-2-ylsulphonamido)phenyl and 4-sulphamoylphenyl; and n is as previously defined in claim 42.

44. A use according to claim 43 wherein R1 is cyclobutylmethyl, morpholin-4-ylcarbonylmethyl, 2-(morpholin-4-yl)ethyl, pyrimidin-2-yl, CH2Het or (CH2)nAr; R2 is CH2CH3 or CH2CH2CH3; R3 is CH2CH3, CH2CH2CH3 or CH2CH2OHC3; R10 is CH3, CH2CH3 or CH2CH2OH; Het is selected from pyridin-2-yl, pyridazin-3-yl, pyrazin-2-yl, 3-methoxypyridin-2-yl, 6-aminopyridin-2-yl, 1-methylimidazol-2-yl, 3,5-dimethylisoxazol-4-yl, 1-methyl-1,2,4-triazol-5-yl, 1-(2-methoxyethyl)-1,2,4-triazol-5-yl and 5-methyl- 29 1,2,4-oxadiazol-3-yl; Ar is selected from phenyl, 2-aminophenyl, 2-methanesulphonamidophenyl, 4-methanesulphonamidophenyl, 4-ethanesulphonamidophenyl and 4-(prop-2-ylsulphonamido)phenyl; and n is as previously defined in claim 43.

45. A use according to claim 44 wherein the compound of formula (XII) or (XIII) is selected from 5-{5-[4-(2-hydroxyethyl)piperazin-1-ylsulphonyl]-2-n-propoxyphenyl}-3-n-propyl-1-(pyridin-2-yl)methyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 1 -(1 -methylimidazol-2-yl)methyl-5-[5-(4-methylpiperazine-1 -ylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-{5-[4-(2-hydroxyethyl)piperazin-1-ylsulphonyl]-2-n-propoxyphenyl}-3-n-propyl-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-(pyridazin-3-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-2-(pyridazin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; and 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)phenyl]-3-n-propyl-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

46. Use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: R30 HN' (XIV) \ N R1 (XV) or R2 SO,Y S02Y or a derivative or salt thereof, wherein Y is halo, and R1, R2 and R3 are as previously defined in claim 41.

47. A use according to claim 46 wherein Y is chloro.

48. Use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: (XVI) or V N R1 (XVII) or a derivative or salt thereof, wherein R1, R2 and R3 are as previously defined in claim 41.

49. Use of a cGMP PDE5 inhibitor in the manufacture of a medicament for treating peripheral neuropathies wherein the cGMP PDE5 inhibitor is a compound of the formula: .N (xvin) N or or a derivative or salt thereof, wherein R1, R2, R3 and R4 are as previously defined in claim 41.

50. A use according to claim 1 wherein the cGMP PDE5 inhibitor is a compound of the formula: or a derivative or salt thereof, wherein _-R1 is H, C1-C3 alkyl, C3-C5 cycloalkyl or C1-C3 perfluoroalkyl; R2 is H, C1-C6 alkyl optionally substituted by OH, C1-C3 alkoxy or C3-C6 O lu cycloalkyl, or C1-C3 perfluoroalkyl; — ^3 is CrC6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C7 cycloalkyl, CrC6 O perfluoroalkyl or (C3-C6 cycloalkyl)Ci-C6 alkyl; UJ QC R4 taken together with the nitrogen atom to which it is attached completes pyrrolidinyl, piperidino, morpholino, or 4-N-(R6)-piperazinyl group; R5 is H, C1-C4 alkyl, CrC3 alkoxy, NR7R8, or CONRrR8; R6 is H, Ci-C6 alkyl, (C1-C3 alkoxy) C2-C6 alkyl, hydroxy C2-C6 alkyl, (I) S02N R4 32 (R7R8N)C2-C6 alkyl, (R7R8NCO)-Ci-C6 alkyl, CONR7R8, CSNR7R8 or C(NH)NR7R8; R7 and R8 are each independently H, C1-C4 alkyl, (Ci-C3)alkoxy)C2-C4 alkyl or hydroxy C2-C4 alkyl.

51. A use as claimed in claim 50 wherein R1 is H, methyl or ethyl; R2 is C1-C3 alkyl optionally substituted by OH or methoxy; R3 is C2-C3 alkyl or allyl; R4 taken together with the nitrogen atom to which it is attached completes a piperidino or 4-N-(R6) piperazinyl group; R5 is H, NR7R8 or CONR7R8; R6is H, CrC3 alkyl, hydroxy C2-C3 alkyl, CONR7R8, CSNR7R8 or C(NH)NR7R8; and R7 and R8 are each independently H or methyl.

52. A use as claimed in claim 51 wherein R1 is methyl; R2 is n-propyl; R3 is ethyl, n-propyl or allyl; R4 taken together with the nitrogen atom to which it is attached completes a 4-N-(R6) piperazinyl group; R5 is H; and R6 is H, C1-C3 alkyl or 2-hydroxyethyl.

53. A use as claimed in claim 52 wherein said compound is selected from: 5-[2-allyloxy-5-(4-methylpiperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[2-ethoxy-5-(piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo-[4,3-d]pyrimidin-7-one; 5-[2-ethoxy-5-(4-methylpiperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo-[4,3-d]pyrimidin-7-one; 5-{2-ethoxy-5-[4-(2-propyl)piperazinylsulphonyl]phenyl}-1-methyl-3-n-proyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-{2-ethoxy-5-[4-(2-hydroxyethyl)piperazinylsulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 1-methyl-5-[5-piperazinylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one; and 5-{5-[4-(2-hydroxyethyl)piperazinylsulphonyl]-2-n-propoxyphenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, and pharmaceutically acceptable salts thereof. 33

54. A use according to claim 1 wherein the cGMP PDE5 inhibitor is a compound of the formula: o or3 hn/^v-^n\ n m so2y or a derivative or salt thereof, wherein R1 and R2 are as claimed in claim 50, R3 is as claimed in claim 50 and is also H, and Y is chloro, bromo or fluoro.

55. A use according to claim 1 wherein the cGMP PDE5 inhibitor is a compound of the formula: or a derivative or salt thereof, wherein R1 and R2 are as claimed in claim 50, and R3 is as claimed in claim 50 and is also H. (Ill) 34 A use as claimed in any one of claims 1, 2, 3, 5, 6,10, 11, 12, 16, 20, 24, 25, 26, 29, 31, 32, 38, 39, 40, 41, 46, 48, 49, 50 or 56 substantially as herein described with reference to any example thereof intellectual property ofrcel of n.z - 4 FEB 2005 RECEIVED 35 </div>