WO2008063505A1

WO2008063505A1 - Organic compounds

Info

Publication number: WO2008063505A1
Application number: PCT/US2007/023854
Authority: WO
Inventors: Sharon Mates; Allen A. Fienberg
Original assignee: Intra-Cellular Therapies, Inc.
Priority date: 2006-11-13
Filing date: 2007-11-13
Publication date: 2008-05-29
Also published as: EP2081431A4; US20100087450A1; JP2014012662A; JP6360025B2; US9198924B2; EP2081431A1; ES2411604T3; JP2010509399A; EP2081431B1; JP2016104723A

Abstract

The present invention relates to a new use of phosphodiesterase 1 (PDEl) inhibitors for the treatment and/or prophyalxis of narcolepsy.

Description

ORGANIC COMPOUNDS

This application claims priority from U.S. Provisional Application No. 60/858,732, filed on November 13, 2006, and U.S. Provisional Application No. 60/873,175, filed on December 5, 2006, the contents of both of which are hereby incorporated by reference in their entirety.

TECHNICAL FIELD

[0001] The present invention relates to a new use for compounds that inhibit phosphodiesterase 1 (PDEl), e.g., that inhibit PDEl-mediated suppression of the dopamine Dl receptor intracellular pathway, specifically for the treatment of narcolepsy.

BACKGROUND OF THE INVENTION

[0002] Narcolepsy is a chronic neurological disorder caused by the brain's inability to regulate sleep-wake cycles normally. At various times throughout the day, people with narcolepsy experience fleeting urges to sleep. If the urge becomes overwhelming, patients fall asleep for periods lasting from a few seconds to several minutes. In rare cases, some people may remain asleep for an hour or longer.

[0003] Narcoleptic sleep episodes can occur at any time, often without warning, and may be quite dangerous if patients are driving or operating machinery. In addition to daytime sleepiness, patients may experience cataplexy, or the sudden loss of voluntary muscle tone; vivid hallucinations during sleep onset or upon awakening; brief episodes of total paralysis at the beginning or end of sleep; and/or automatic behavior, such as talking or performing routine activities during a sleep episode but having no memory of these activities upon waking. Most patients also experience frequent awakenings during nighttime sleep. For these reasons, narcolepsy is considered to be a disorder of the normal boundaries between the sleeping and waking states.

[0004] Eleven families of phosphodiesterases (PDEs) have been identified but only PDEs in Family I, the Ca²⁺-calmodulin-dependent phosphodiesterases (CaM- PDEs), have been shown to mediate the calcium and cyclic nucleotide (e.g. cAMP and cGMP) signaling pathways. The three known CaM-PDE genes, PDElA, PDElB, and PDElC, are all expressed in central nervous system tissue. PDElA is expressed throughout the brain with higher levels of expression in the CAl to C A3 layers of the hippocampus and cerebellum and at a low level in the striatum. PDElA is also expressed in the lung and heart. PDElB is predominately expressed in the striatum, dentate gyrus, olfactory tract and cerebellum, and its expression correlates with brain regions having high levels of dopaminergic innervation. Although PDElB is primarily expressed in the central nervous system, it may be detected in the heart. PDElC is primarily expressed in olfactory epithelium, cerebellar granule cells, and striatum. PDElC is also expressed in the heart and vascular smooth muscle.

[0005] Cyclic nucleotide phosphodiesterases downregulate intracellular cAMP and cGMP signaling by hydrolyzing these cyclic nucleotides to their respective inactive 5 '-monophosphates (5'AMP and 5'GMP). CaM-PDEs play a critical role in mediating signal transduction in brain cells, particularly within an area of the brain known as the basal ganglia or striatum. For example, NMDA-type glutamate receptor activation and/or dopamine D2 receptor activation result in increased intracellular calcium concentrations, leading to activation of effectors such as calmodulin-dependent kinase II (CaMKII) and calcineurin and to activation of CaM-PDEs, resulting in reduced c AMP and cGMP. Dopamine Dl receptor activation, on the other hand, leads to activation of calcium dependent nucleotide cyclases, resulting in increased cAMP and cGMP. These cyclic nucleotides in turn activate protein kinase A (PKA; cAMP- dependent protein kinase) and/or protein kinase G (PKG; cGMP-dependent protein kinase) that phosphorylate downstream signal transduction pathway elements such as DARPP-32 (dopamine and cAMP-regulated phosphoprotein) and cAMP responsive element binding protein (CREB).

[0006] CaM-PDEs can therefore affect dopamine-regulated and other intracellular signaling pathways in the basal ganglia (striatum), including but not limited to nitric oxide, noradrenergic, neurotensin, CCK, VIP, serotonin, glutamate (e.g., NMDA receptor, AMPA receptor), GABA, acetylcholine, adenosine (e.g., A2A receptor), cannabinoid receptor, natriuretic peptide (e.g., ANP, BNP, CNP) and endorphin intracellular signaling pathways.

[0007] Phosphodiesterase (PDE) activity, in particular, phosphodiesterase 1

(PDEl) activity, functions in brain tissue as a regulator of locomotor activity and learning and memory. PDEl is a therapeutic target for regulation of intracellular signaling pathways, preferably in the nervous system, including but not limited to a dopamine Dl receptor, dopamine D2 receptor, nitric oxide, noradrenergic, neurotensin, CCK, VIP, serotonin, glutamate (e.g., NMDA receptor, AMPA receptor), GABA, acetylcholine, adenosine (e.g., A2A receptor), cannabinoid receptor, natriuretic peptide (e.g., ANP, BNP, CNP) or endorphin intracellular signaling pathway. For example, inhibition of PDElB may potentiate the effect of a dopamine Dl agonist by protecting cGMP and cAMP from degradation, and similarly inhibit dopamine D2 receptor signaling pathways, by inhibiting PDEl activity. PDEl inhibitors are therefore potentially useful in diseases characterized by reduced dopamine Dl receptor signaling activity. See generally, WO 03/020702.

[0008] EP 0201188 and EP 0911333, the contents of which are incorporated herein by reference, disclose certain 1,3,5,-substituted, 6,7-dihydro-lH-pyrazolo[4,3- c(]pyrimidin-7-one compounds, claimed to be useful for treatment of cardiovascular disease, erectile dysfunction, and other disorders. These compounds are not, however, taught or suggested to be useful for the treatment of diseases involving disorders of the dopamine Dl receptor intracellular pathway, particularly diseases relating to sleep disorders such as narcolepsy. PCT/US2006/33179, the contents of which are incorporated herein by reference, discloses the use of 1,3,5,-substituted, 6,7-dihydro- lH-pyrazolo[4,3-fiT]pyrimidin-7-one compounds for treatment of diseases involving disorders of the dopamine Dl receptor intracellular pathway, but does not specifically disclose the use of such compounds in the treatment or prophylaxis of narcolepsy. PCT/US2006/022066, the contents of which are incorporated herein by reference, discloses PDEl inhibitors which are 7,8-dihydro-[lHor 2H]-imidazo[l,2- α]pyrazolo[4,3-e]pyrimidin-4(5H)-ones or 7,8,9-trihydro-[lHor 2H]-pyrimido [1,2- a]pyrazolo[4,3-e]pyrimidin-4(5Η)-ones, but does not specifically disclose their use for the treatment or propylaxis of narcolepsy. WO 03/042216, U.S. 5,939,419, EP 0 538 332, U.S. 5,393,755, U.S. 6,969,719 B2, Xia et al., J Med. Chem. (1997), 40, 4372- 4377 and Ahn et al., J Med. Chem. (1997), 40, 2196-2210, the contents of all of which are incorporated herein by reference, disclose PDEl cGMP phosphodiesterase inhibitors which are substituted pyrazolo[3,4-d]pyrimidine, pyrimido[2,l-b]purin-4-one and imidazo[2,l-b]purin-4-one analogues useful for the treatment of hypertensive, cardiovascular, sexual dysfunction and other cGMP-PDEV related disorders, but do not specifically disclose their use for the treatment or propylaxis of narcolepsy.

SUMMARY OF THE INVENTION

[0009] The invention provides a new method of treatment or prophylaxis for narcolepsy comprising administering an effective amount of a phosphodiesterase- 1 (PDEl) inhibitor to a patient in need thereof. PDEl inhibitors include, for example, 7,8-dihydro-[l//or 2/7]-imidazo[l,2-α]pyrazolo[4,3-e]pyrimidin-4(5/f)-ones or 7,8,9- trihydro-[l/f or 2HJ-pyrimido [l,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-ones, substituted at the 1 or 2 position with C_2-9 alkyl or C_3-9 cycloalkyl, or optionally substituted heteroarylalkyl or substituted arylalkyl, in free, salt or prodrug form (hereinafter a PDE 1 Inhibitor, e.g., as described below) or a 1,3,5-substituted 6,7-dihydro-l//- pyrazolo[4,3-</|pyrimidin-7-one, in free, salt or prodrug form (also included in PDE 1 Inhibitors, e.g., as described below), to a patient in need thereof. [0010] PDEl inhibitors also include, for example, substituted imidazo[2,l- b]purin-4-one, e.g., (6aR,9aS)-2-(biphenyl-4-ylmethyl)-5,6a,7,8,9,9a-hexahydro-5- methyl-3(phenylmethyl)-cyclopent-[4,5]imidazo-[2, 1 -b]purin-4(3H)-one, (6aR,9aS)- 5,6a,7,8,9,9a-hexahydro-5-methyl-2,3-bis(phenylmethyl)cyclopent-[4,5]imidazo-[2,l- b]purin-4(3H)-one, 5'-methyl-2',3'-bis(phenylmethyl)spiro[cyclopentane-l,7'(8'Η)- [3H] imidazo[2, 1 -b]purin] -4 ' (5 ' H)-one, or 5 ' -methyl-2 ' -(biphenylylmethyl)-3 ' - (phenylmethyl)spiro[cyclopentane-l,7'(8'H)-[3H]imidazo[2,l-b]purin]-4'(5'H)-one as described in Ahn et al., J. Med. Chem. (1997), 40, 2196-2210 (hereinafter a PDE 1 Inhibitor, e.g., as described below). These compounds are found to selectively inhibit phosphodiesterase 1 (PDEl) activity, especially PDElB activity, and to be useful in the treatment and prophylaxis of narcolepsy. These compounds are found to selectively inhibit phosphodiesterase 1 (PDEl) activity, especially PDElB activity, and to be useful in the treatment and prophylaxis of narcolepsy.

DETAILED DESCRIPTION OF THE INVENTION

Compounds for use in the methods of the invention

[0011] Preferably, the PDE 1 Inhibitors for use in the methods of treatment described herein are a 7,8-dihydro-[lHor 2HJ-imidazo[l,2-α]pyrazolo[4,3-e]pyrimidin- 4(5H)-ones or 7,8,9-trihydro-[lHor 2H]-pyrimido [l,2-a]pyrazolo[4,3-e]pyrimidin- 4(5Η)-ones, of formula I

Formula I

wherein

(i) Ri is H or Ci_-4 alkyl (e.g., methyl);

(ii) R₄ is H or Ci_-4 alkyl and R₂ and R₃ are, independently, H or Ci_-4 alkyl

(e.g., R₂ and R₃ are both methyl, or R₂ is H and R₃ is isopropyl), aryl, heteroaryl,

(optionally hetero)arylalkoxy, or (optionally hetero)arylalkyl; or

R₂ is H and R₃ and R₄ together form a di-, tri- or tetramethylene bridge (pref. wherein the R₃ and R₄ together have the cis configuration, e.g., where the carbons carrying R₃ and R₄ have the R and S configurations, respectively);

(iii) R₅ is a substituted heteroarylalkyl, e.g., substituted with haloalkyl or

R₅ is attached to one of the nitrogen atoms on the pyrazolo portion of Formula I and is a moiety of Formula Q

Formula Q

wherein X, Y and Z are, independently, N or C, and R₈, R₉, Rn and Rj₂ are independently H or halogen (e.g., Cl or F), and Ri₀ is halogen, alkyl, cycloalkyl, haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl (for example pyrid-2-yl), or thiadiazolyl (e.g., l,2,3-thiadiazol-4-yl)), diazolyl, triazolyl, tetrazolyl, arylcarbonyl (e.g., benzoyl), alkylsulfonyl (e.g., methylsulfonyl), heteroarylcarbonyl, or alkoxycarbonyl; provided that when X, Y, or Z is nitrogen, R₈, R₉, or Rj₀, respectively, is not present; and

(iv) R₆ is H, alkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), arylamino (e.g., phenylamino), heterarylamino, N,N-dialkylamino, N,N-diarylamino, or N-aryl-N- (arylakyl)amino (e.g., N-phenyl-N-(l,l '-biphen-4-ylmethyl)amino); and (v) n=0 or 1 ; (vi) when n=l, A iS -C(Ri₃Ri₄)- wherein Ri₃ and R]_4> are, independently, H or Ci_-4 alkyl, aryl, heteroaryl, (optionally hetero)arylalkoxy or (optionally hetero)arylalkyl; in free, salt or prodrug form, including its enatiomers, diasterisomers and racemates.

[0012] The invention further provides the use of PDE 1 Inhibitors of Formula I as follows:

1.1 Formula I wherein R] is methyl and n=0;

1.2 Formula I or 1.1 wherein R₄ is H or Ci_-4 alkyl and at least one of R₂ and R₃ is lower alkyl, such that when the carbon carrying R₃ is chiral, it has the R configuration, e.g., wherein both R₂ and R₃ are methyl, or wherein one is hydrogen and the other isopropyl;

1.3 Formula I or 1.1 wherein R₄ is H and at least one of R₂ and R₃ is arylalkoxy;

1.4 Formula I wherein Ri is methyl, R₂, R₃, and R₄ are H, n=l , and Ri₃ and Ri₄ are, independently, H or Ci_-4 alkyl (e.g., methyl or isopropyl);

1.5 Formula I or 1.1 wherein R₂ is H and R₃ and R₄ together form a tri- or tetramethylene bridge, having the cis configuration, preferably wherein the carbons carrying R₃ and R₄ have the R and S configurations respectively;

1.6 Formula I, 1.1 or 1.5 wherein R₅ is a substituted heteroarylmethyl, e.g., para-substituted with haloalkyl;

1.7 Formula I, 1.1, 1.2, 1.3, 1.4 or 1.5 wherein R₅ is a moiety of Formula Q wherein R₈, R₉, Rn, and Ri₂ are H and Ri₀ is phenyl;

1.8 Formula I, 1.1, 1.2, 1.3, 1.4 or 1.5 wherein R₅ is a moiety of Formula Q wherein R₈, R₉, Rn, and Ri₂ are H and Ri₀ is pyridyl or thiadiazolyl;

1.9 Formula I, 1.1, 1.2, 1.3, 1.4 or 1.5 wherein R₅ is a moiety of Formula Q wherein R₈, R₉, Rn, and Ri₂ are, independently, H or halogen, and Ri₀ is haloalkyl;

1.10 Formula I, 1.1, 1.2, 1.3, 1.4 or 1.5 wherein R₅ is a moiety of Formula Q wherein Rg, R₉, Rn, and Ri₂ are, independently, H, and Rio is alkyl sulfonyl;

1.11 any of the preceding formulae wherein R₅ is attached to the 2-position nitrogen on the pyrazolo ring; 1.12 any of the preceding formulae wherein R₆ is benzyl;

1.13 any of the preceding formulae wherein R₆ is phenylamino or phenylalkylamino (e.g., benzylamino);

1.14 any of the preceding formulae wherein R^ is phenylamino ;

1.15 any of the preceding formulae wherein X, Y, and Z are all C;

1.16 any of the preceding formulae wherein X, Y, and Z are all C and R]₀ is phenyl or 2-pyridyl; and/or

1.17 any of the preceding formulae wherein the compounds inhibit phosphodiesterase-mediated (e.g., PDEl -mediated, especially PDE IB-mediated) hydrolysis of cGMP, e.g., with an IC_5O of less than lμM, preferably less than 25 nM in an immobilized-metal affinity particle reagent PDE assay, for example, as described in Example 1 ; in free or salt form.

[0013] For example, the PDE 1 Inhibitors include 7,8-dihydro-[lHor 2H]- imidazo[l,2-α]pyrazolo[4,3-e]pyrimidin-4(5H)-ones of Formula Ia

Formula Ia

wherein

(i) Ri is Η or Ci_-4 alkyl [e.g., methyl]; (ii) R4 is H and R₂ and R₃ are, independently, H or Ci_-4 alkyl [e.g., R₂ and R₃ are both methyl, or R₂ is H and R₃ is isopropyl], aryl, or arylalkyl;

or R₂ is H and R₃ and R₄ together form a di-, tri- or tetramethylene bridge [pref. wherein the R₃ and R₄ have the cis configuration, e.g., where the carbons carrying R₃ and R₄ have the R and S configurations respectively];

(iii) R₅ is attached to one of the nitrogen atoms on the pyrazolo portion of formula Ia and is a substituted benzyl of formula Qa

Formula Qa wherein R₈, R₉, Rn and Ri₂ are independently H or halogen (e.g., Cl or F); and Rio is halogen, alkyl, cycloalkyl, haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl (for example pyrid-2-yl), or thiadiazolyl (e.g., l,2,3-thiadiazol-4-yl)), arylcarbonyl (e.g., benzoyl), alkyl sulfonyl or heteroaryl carbonyl; and

(iv) R₆ is H, alkyl, aryl, heteroaryl, arylalkyl [e.g., benzyl], arylamino [e.g., phenylamino], heteroarylamino, arylalkylamino, N,N-dialkylamino, N,N- diarylamino, or N-aryl-N-(arylalkyl)amino [e.g. N-phenyl-N-(l,l '-biphen-4- ylmethyl)amino];

salt or prodrug form. [0014] The invention further provides the use of PDE 1 Inhibitors of Formula Ia as follows:

2.1 : Formula Ia wherein R₁ is methyl;

2.2: Formula Ia or 2.1 wherein R₄ is H and at least one of R₂ and R₃ is lower alkyl, such that when the carbon carrying R₃ is chiral, it has the R configuration, e.g., wherein both R₂ and R₃ are methyl, or wherein one is hydrogen and the other isopropyl;

2.3: Formula Ia or 2.1 wherein R₂ is H and R₃ and R₄ together form a tri- or tetramethylene bridge, having the cis configuration, preferably wherein the carbons carrying R₃ and R₄ have the R and S configurations respectively;

2.4: Formula Ia, 2.1 , 2.2 or 2.3 wherein R₅ is a moiety of formula Qa wherein

R₈, Rg, Rn, and Ri₂ are H and Ri₀ is phenyl;

2.5: Formula Ia, 2.1, 2.2, or 2.3 wherein R₅ is a moiety of formula Qa wherein

R₈, R₉, Rn, and Ri₂ are H and Ri₀ is pyridyl or thiadiazolyl;

2.6: Formula Ia, 2.1, 2.2, 2.3, 2.4, or 2.5 wherein R₅ is attached to the 2- position nitrogen on the pyrazolo ring;

2.7: Formula Ia, 2.1, 2.2, 2.3, 2.4, 2.5 or 2.6 wherein R₆ is benzyl;

2.8: Formula Ia, 2.1, 2.2, 2.3, 2.4, 2.5 or 2.6 wherein R₆ is phenylamino or phenylalkylamino (e.g., benzylamino); and/or

2.9: Formula Ia, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, or 2.8 wherein the compounds inhibit phosphodiesterase-mediated (e.g., PDEl -mediated, especially PDElB- mediated) hydrolysis of cGMP, e.g., with an IC₅₀ of less than lμM, preferably less than 25 nM in an immobilized-metal affinity particle reagent PDE assay, for example, as described in Example 1 ; in free or salt form.

[0015] In an another embodiment, the PDE 1 Inhibitors are compounds of

Formula I wherein

(i) Ri is methyl;

(ii) R₂, R₃ and R₄ are H; (iii) n=l and R₃ and R_b are, independently, H or methyl;

(iv) R₅ is a moiety of Formula Q wherein R₈, R₉, Rn and R₁₂ are H and R]₀ is phenyl, pyridyl (for example pyrid-2-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazol-

4-yl);

(v) R₆ is benzyl, phenylamino or benzylamino; in free or salt form.

[0016] In another embodiment, the PDE 1 Inhibitors are compounds of Formula

I wherein

(i) Ri is methyl;

(ii) n=0;

(iii) R₂ is H and R₃ and R₄ together form a tri-or tetra-methylene bridge [pref. with the carbons carrying R₃ and R₄ having the R and S configuration respectively]; or at least one of R₂ and R₃ is methyl, isopropyl or arylalkoxy and R₄ is H; or R₂ and R₃ are H and R₄ is a C_M alkyl;

(iv) R₅ is a substituted heteroarylmethyl, e.g., para-substituted with haloalkyl; or

R₅ is a moiety of Formula Q wherein R₈, R9, Rn and R₁₂ are H or halogen and

Rio is haloalkyl, phenyl, pyridyl (for example pyrid-2-yl), or thiadiazolyl (e.g., l,2,3-thiadiazol-4-yl); and

(v) R₆ is benzyl, phenylamino or benzylamino; in free or salt form.

[0017] In another embodiment, the PDE 1 Inhibitors are compounds of Formula

Ia wherein

(i) Ri is methyl;

(ii) R₂ is H and R₃ and R₄ together form a tri- or tetra-methylene bridge [pref. with the carbons carrying R₃ and R₄ having the R and S configuration respectively]; or R₂ and R₃ are each methyl and R₄ is H; or R₂ and R₄ are H and R₃ is isopropyl [pref. the carbon carrying R₃ having the R configuration]; (iii) R₅ is a moiety of Formula Qa wherein R₈, R_% Rn, and Ri₂ are H and R]₀ is haloalkyl, phenyl, pyridyl (for example pyrid-2-yl), or thiadiazolyl (e.g., l,2,3-thiadiazol-4-yl); and

(iv) R₆ is benzyl, phenylamino or benzylamino; in free or salt form.

[0018] In another embodiment, the PDE 1 Inhibitors are compounds of Formula

Ia selected from the following:

Compound 1 Compound 2

[0019] For example, PDE 1 Inhibitors include compounds according to Formulae

II, III and IV.

Formula II

wherein

R₃ and R_b are, independently, H or Ci_-4 alkyl; R₆ is phenylamino or benzylamino;

Rio is phenyl, pyridyl (for example pyrid-2-yl), or thiadiazolyl (e.g., 1,2,3- thiadiazol-4-yl); in free or salt form.

Formula III wherein

R₂ is H and R₃ and R₄ together form a tri- or tetra-methylene bridge [pref. with the carbons carrying R₃ and R₄ having the R and S configuration respectively]; or at least one of R₂ and R₃ is methyl, isopropyl or arylalkoxy and R₄ is H; or R₂ and

R₃ are H and R₄ is a C_M alkyl;

R₆ is phenylamino or benzylamino;

Rio is haloalkyl, phenyl, pyridyl (for example pyrid-2-yl), or thiadiazolyl (e.g., l,2,3-thiadiazol-4-yl); in free or salt form.

Formula IV wherein

R₃ are H and R₄ is a Ci_-4 alkyl;

R₆ is phenylamino or benzylamino;

[0020] PDE 1 Inhibitors used in the method disclosed herein also include compounds according to Formula V:

Formula V wherein

R₂ is H and R₃ and R₄ together form a tri- or tetra-methylene bridge [pref. with the carbons carrying R₃ and R₄ having the R and S configuration respectively]; or

R₂ and R₃ are each methyl and R₄ is H; or R₂ and R₄ are H and R₃ is isopropyl

[pref. the carbon carrying R₃ having the R configuration];

R₆ is phenylamino or benzylamino;

Rio is phenyl, pyridyl, or thiadiazolyl; in free or salt form.

In a preferred embodiment, the PDE 1 Inhibitors for use in the methods of treatment described herein are a 1,3,5-substituted 6,7-dihydro-lH-pyrazolo[4,3-£/]pyrimidin-7- one, of formula VI

wherein

R₃ is methyl or C₂-C₆ alkyl; Ri is H or Ci-C₄ alkyl;

each of R₂ and R₃ is independently selected from H and CpC₄ alkyl, or R₂ is H or Ci-C₄ alkyl and R₃ is OH, C₂-C₄ alkanoyloxy or fiuoro, or R₂ and R₃ when taken together represent C₂-C₆ alkylene, or R₂ and R₃ when taken together with the carbon atom to which they are attached represent a carbonyl group; Ar is either (a)

wherein

each of R₄, R₅ and R₆ is independently selected from

H

Ci-C₄ alkyl,

Ci-C₄ alkoxy,

Ci -C₄ alkoxy-Z-, halo, halo(Ci-C₄)alkyl, phenoxy, optionally substituted by up to three substitutents each of which substitutent is independently selected from halo, Ci_-4 alkyl, and Ci-C₄ alkoxy, nitro, hydroxy, hydroxy-Z-,

C₂-C₄ alkanoyl, amino, amino-Z-,

(C₁-C₄ alkyl)NH, (C₁-C₄ alkyl)₂N-, (Ci-C₄ alkyl)NH-Z-, (C-C₄ alkyl)₂N-Z-, - -COOH, -Z-COOH, -COO(Ci-C₄ alkyl), -Z-COO(Ci-C₄ alkyl) Ci -C₄ alkanesulphonamido, Ci -C₄ alkanesulphonamido-Z-, halo(C i -C₄)alkanesulphonamido, halo(C i -C₄)alkanesulphonamido-Z-, Ci-C₄ alkanamido, Ci-C₄ alkanamido-Z-, HOOC-Z-NH-, HOOC-Z-NH-Z-, (Ci-C₄ alkyl)OOC-Z-NH-, (Ci-C₄ alkyl)OOC-Z-NH-Z-, Ci-C₄ alkyl-NH-SO₂-NH-, C-C₄ alkyl-NH-SO₂-NH-Z-, (C₁-C₄ alkyl)₂-N-SO₂-NH-, (C-C₄ alkyl)₂-N-SO₂-NH-Z-, Ci-C₄ alkoxy CH=CH-Z-CONH-, C-C₄ alkoxy CH-CHCONH Ci-C₄ alkyl-SO₂-N(Ci-C₄ alkyl)-, Ci-C₄ alkyl-SO₂-N(C,-C₄ alkyl)-Z-, (C₁-C₄ alkyl)NH-Z-SO₂-NH-, (Ci-C₄ alkyl)₂N-Z-SO₂-NH-, (C-C₄ alkyl)NH-Z-SO₂-NH-Z-, (Ci-C₄ alkyl)₂N-Z-SO₂-NH-Z-, benzenesulphonamido, optionally ring substituted by up to three substitutents each of which is independently selected from halo, Ci_-4 alkyl, and Ci-C₄ alkoxy,

Ci-C₄ alkanoyl-N(Ci-C₄ alkyl)-, Ci-C₄ alkanoyl-N(Ci-C₄ alkyl)-Z-, Ci-C₄ alkoxycarbonyl-CH(CH₂OH)NHSO₂-, -SO₃H, -SO₂NH₂,

H₂NOC-CH(CH₂OH)-NHSO₂-, HOOC-Z-O-, and (C-C₄ alkyl)OOC-Z-O-, or optionally one of R₄, R₅ and R₆ is a G-Het group and wherein the others of R₄, R₅ and R₆ are independently selected from the R₄, R₅ and R₆ substitutents listed above;

Z is CpC₄ alkylene,

G is a direct link, Z, O, -SO₂NH-, SO₂, or -Z-N(Ci-C₄ alkyl)SO₂-,

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 substitutents, wherein each substitutent is independently selected from Ci-C₄ alkyl, oxo, hydroxy, halo, and halo(Ci-C₄) alkyl;

or (b) any one of the following bicyclic groups:

benzodioxolanyl, benzodioxanyl, benzimidazolyl, quinolinyl, indolyl, quinazolinyl, isoquinolinyl, benzotriazolyl, benzofiiranyl, benzothiophenyl, quinoxalinyl, or phthalizinyl,

wherein said bicyclic Ar groups are linked to the neighbouring -C(R₂R₃)- 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 C₁-C₄ alkyl, halo, hydroxy, oxo, amino, and Cj-C₄ alkoxy;

or a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable solvate of the compound or the salt.

[0021] For example, PDE 1 Inhibitors for use in the present invention include

1,3,5,-substituted, 6,7-dihydro-lH-pyrazolo[4,3-</]pyrimidin-7-one, in free or pharmaceutically acceptable salt form, particularly compounds of Formula VI or the following formulae:

3.2 Of Formula VI wherein R_a is a C_2-5 alkyl group;

3.3 Of Formula VI wherein R₃ is a C_2-4 alkyl group;

3.4 Of Formula VI wherein R₃ is a C₃ alkyl group;

3.5 Of Formula VI wherein R₃ is methyl;

3.6 Of Formula VI, 3.2, 3.3, 3.4 or 3.5 wherein Ri is a Ci_-6 alkyl group;

3.7 Of any of the preceding formulae wherein Ri is a Ci_-3 alkyl group; 3.8 Of any of the preceding formulae wherein Ri is a methyl group;

3.9 Of any of the preceding formulae wherein R₂ is H;

3.10 Of any of the preceding formulae wherein R₃ is H;

3.11 Of any of the preceding formulae wherein R₄, R₅ and R₆ are independently selected from H₁ (Ci_-4 alkyl)₂N-, Ci_-4 alkanesulphonamido and benzenesulphonamido;

3.12 Of any of the preceding formulae wherein R₄, R₅ and R₆ are independently selected from H, diethylamino, methanesulphonamido and benzenesulphonamido;

3.13 Of any of the preceding formulae wherein Ar is 4- diethylaminopheny 1 ;

3.14 Of any of the preceding formulae wherein Ar is 2- methanesulphonamidophenyl;

3.15 Of any of the preceding formulae wherein Ar is 4- benzenesulphonamidophenyl;

3.16 Of any of the preceding formulae wherein one of R₄, R₅ and R₆ is (Ci_-4 alkyl)₂N- and wherein the other two Of R₄, R₅ and R₆ are H.

3.17 Of any of the preceding formulae wherein one of R₄, R₅ and R₆ is diethylamino and wherein the other two OfR₄, R₅ and R₆ are H.

3.18 Of any of the preceding formulae wherein R₃ is methyl;

3.19 Of any of the preceding formulae wherein R₃ is C₂-C₆ alkyl;

3.20 Of any of the preceding formulae wherein the compound is selected from the following:

21 3.21 Of any of the preceding formulae wherein the compound is

in free or salt form;

3.22 A compound which is a 1,3,5,-substituted, 6,7-dihydro-lH- pyrazolo[4,3-</]pyrimidin-7-one, in free or pharmaceutically acceptable salt form, e.g. a compound of Formula VI or according to any of formulae 3.2 - 3.21, wherein the compound inhibits phosphodiesterase-mediated (e.g., PDEl -mediated, especially PDE IB-mediated) hydrolysis of cGMP, e.g., with an IC₅₀ of less than lμM, preferably less than 25 nM in an immobilized-metal affinity particle reagent PDE assay, for example, as described in Example 1 below.

[0022] In another embodiment, the PDE 1 Inhibitors for use in the methods of treatment described herein are substituted (imidazo, pryimido or diazepino)[2,l-b]purin- 4-ones of Formula Vila or VIIb:

Formula Vila Formula VIIb

in free, salt or prodrug form, including its enatiomers, diasterisomers and racemates, wherein: i) q = 0, 1 or 2; ii) R¹, R^a, R^b, R^c and R^d are each independently H, alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups,

wherein each alkyl group of R¹, R^a, R^b, R^c and R^d is independently unsubstituted or substituted with 1 to 5 independently selected R³ moieties which can be the same or different, each R³ moiety being independently selected from the group consisting of hydroxy, alkoxy, cycloalkoxy, aryloxy, alkylthio, arylthio, aryl, haloaryl, heteroaryl, cycloalkyl, heterocycloalkyl, amino, alkylamino, dialkylamino, cycloalkylamino and heterocycloalkylamino groups;

wherein each of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups of R¹, R^a, R^b, R^c and R^d is independently unsubstituted or substituted with 1 to 5 independently selected R⁴ moieties which can be the same or different, each R⁴ moiety being independently selected from the group consisting of: halo, optionally substituted aryl (e.g., phenyl, chlorophenyl, methoxyphenyl), heteroaryl (e.g., pyridyl, pyrrolyl), nitro, cyano, haloalkyl, haloalkoxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl (e.g., pyrolidinyl, morpholin-4-yl, pyrrol- 1-yl), cycloalkylalkyl, amino, alkylamino, dialkylamino, -OCF₃, acyloxy, - OR⁸, -C(O)R⁹, -C(O)OR⁸, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁸,- NR¹⁰S(O)₂R⁹, - S(O)_0-2R⁹ groups, carbonyl when two hydrogens attached to the same carbon atom of the cycloalkyl or heterocycloalkyl group of R' are substituted, and =CR⁸R⁹ when two hydrogens attached to the same carbon atom of the cycloalkyl or heterocycloalkyl groups of R¹ are substituted,

wherein each of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups of the R and R moieties above is independently unsubstituted or substituted with 1 to 5 independently selected R¹² moieties which can be the same or different, each R¹² moiety being independently selected from the group consisting of: halo, phenyl, nitro, cyano, haloalkyl, haloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, amino, alkylamino, -OCF₃, acyloxy, -OR , - C(O)R⁹, -C(O)OR⁸, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁸,- NR¹⁰S(O)₂R⁹, - S(O)_0-2R⁹ groups, carbonyl when two hydrogens attached to the same carbon atom of the cycloalkyl or heterocycloalkyl group of R³ or R⁴ are substituted, and =CR⁸R⁹ when two hydrogens attached to the same carbon atom of the cycloalkyl or heterocycloalkyl group of R or R⁴ are substituted; or

iii) R^a and R^b, together with the carbon to which they are both attached, form a 4- ttoo 77--mmeemmbbeerreedd ccyyccllooaallkkyyll oorr hheetteerrooccyy<cloalkyl ring, and R^c and R^d are each independently H or an alkyl group; or

iv) R^a and R^c, together with the respective carbons to which they are attached, form a 4- to 7-membered cycloalkyl or heterocycloalkyl ring, and R^b and R^d are each independently H or an alkyl group, preferably R^a and R^c together have the cis configuration, e.g., where the carbons carrying R^a and R^c have the R and S configurations, respectively;

v) R² is H, halo, alkyl, haloalkyl, alkoxy, alkylthio, amino, aminosulfonyl, monoalkylamino, dialkylamino, hydroxyalkylamino, aminoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl or alkylaminocarbonyl group, wherein each alkyl group of R² is independently unsubstituted or substituted with 1 to 5 independently selected R¹³ moieties which can be the same or different, each R¹³ moiety being independently selected from the group consisting of halo, hydroxy, alkoxy, alkyl, aryl (e.g., phenyl, naphthyl) heteroaryl (e.g., lH-imidazol-2-yl), cycloalkyl, heterocycloalkyl (e.g., pyrolidin-1-yl), amino, monoalkylamino or dialkylamino group,

wherein each aryl group of R¹³ is independently unsubstituted or substituted with 1 to 5 independently selected R⁴ moieties which can be the same or different;

vi) Y is H or an alkyl group substituted with (i) an aryl, heteroaryl, cycloalkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino group, or (ii) an aryl group substituted with from one to three moieties each independently selected from the group consisting of: halo, alkyl, phenyl, hydroxy, alkoxy, phenoxy, amino, monoalkylamino and dialkylamino group;

vii) each R is independently H, alkyl or aryl;

viii) each R⁹ is independently H, alkyl, aryl or -NR¹⁰R¹ ' ;

ix) each R¹⁰ is independently H, alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein each alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of R¹⁰ is unsubstituted or independently substituted with 1 to 5 R¹⁴ moieties which can be the same or different, each R¹⁴ moiety being independently selected from the group consisting of: halo, alkyl, aryl, cycloalkyl, -CF₃, -OCF₃, -CN, -OR⁸, -CH₂OR⁸, -C(O)OR⁸ and -C(O)NR⁸R⁸; and x) each R¹ ' is independently H, alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein each alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of R¹¹ is unsubstituted or independently substituted with 1 to 5 R¹⁴ moieties which can be the same or different.

[0023] The invention further provides the use of PDE 1 Inhibitors of Formula

Vila or VIIb, in free or salt form, as follows:

4.1 : Formula Vila or VIIb, wherein q = 0, 1 or 2;

4.2: Formula Vila or VIIb, wherein q = 0;

4.3: Formula Vila or VIIb or 4.1 or 4.2, wherein R¹ is alkyl;

4.4: Formula Vila or VIIb or 4.1-4.3, wherein R¹ is methyl;

4.5: Formula Vila or VIIb or 4.1-4.4, wherein R^a and R^c, together with the respective carbons to which they are attached, form a 4- to 7-membered cycloalkyl or heterocycloalkyl ring, and R and R are each independently H or an alkyl group;

4.6: Formula Vila or VIIb or 4.1-4.4, wherein R^a and R^c, together with the respective carbons to which they are attached, form a 5-membered heterocycloalkyl ring, and R^b and R^d are each independently H;

4.7: Formula 4.6 wherein R^a and R^c together have a cis configuration;

4.8: Formula Vila or VIIb or 4.1-4.4, wherein R^a and R^b, together with the respective carbons to which they are attached, form a 5-membered heterocycloalkyl ring, and R^c and R^d are each independently H;

4.9: Formula Vila or VIIb or 4.1-4.7, wherein R² is alkyl or haloalkyl;

4.10: Formula Vila or VIIb or 4.1-4.7, wherein R² is biphenyl-4-ylmethyl;

4.11 : Formula Vila or VIIb or 4.1-4.7, wherein R² is benzyl;

4.12: Formula Vila or VIIb or 4.1-4.7, wherein R² is cyclopentylmethyl;

4.13: Formula Vila or VIIb or 4.1-4.7, wherein R² is cyclopropylmethyl; and/or

4.14: Formula Vila or VIIb or 4.1-4.12, wherein Y is benzyl;

4.15: Of any of the preceding formulae wherein the compound is selected from the following:

4.16: Of any of the preceding formulae wherein the compound is

in free or salt form;

4.17: A compound which is a substituted imidazo[2,l-b]purin-4-one, in free or pharmaceutically acceptable salt form, e.g. a compound of Formula Vila or according to any of formulae 4.1 - 4.16, wherein the compound inhibits phosphodiesterase-mediated (e.g., PDEl -mediated, especially PDElB- mediated) hydrolysis of cGMP, e.g., with an IC_5O of less than lμM, preferably less than 25 nM in an immobilized-metal affinity particle reagent PDE assay, for example, as described in Example 1 below.

[0024] Preferably, compounds of Formula Vila or VIIb are selected from a group consisting of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-2,3-bis(phenylmethyl)- cyclopent[4,5]imidazo[2,l-b]purin-4(3H)-one, (6aR,9aS)-2-(biphenyl-4-ylmethyl)- 5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylmethyl)cyclopent[4,5]imidazo[2,l-b]purin- 4(3H)-one, 5 ' -methyl-2 ' ,3 ' -bis(phenylmethyl)spiro [cyclopentane- 1 ,7 ' (8 'H)- [3H]imidazo[2,l-b]purin]-4'(5'H)-one and 5'-methyl-2'-(biphenyl-4-ylmethyl)-3'- (phenylmethyl)spiro- [cyclopentane- 1 ,7 ' (8 ' H)- [3H] imidazo [2, 1 -b]purin] -4 ' (5 ' Η)-one, in free or pharmaceutically acceptable salt form.

[0025] In an especially preferred embodiment, compound of Formula Vila is

(6aR,9aS)-2-(biphenyl-4-ylmethyl)-5,6a,7,8,9,9a-hexahydro-5-methyl-3- (phenylmethyl)cyclopent-[4,5]imidazo[2,l-b]purin-4(3H)-one, in free or salt form. [0026] The numbering of substituted imidazo [2, 1 -b]purin-4-one of Formula Vila or VIIb as described herein is shown below as an example, wherein q = 0:

Formula VIIb

Formula Vila wherein q = 1 :

Formula Vila Formula VIIb

[0027] In another embodiment, the PDE 1 Inhibitors for use in the methods of treatment described herein are Compounds of Formula Villa or VIIIb:

Formula Villa Formula VIIIb

in free or salt form, wherein:

• J is oxygen or sulfur,

• R¹ is hydrogen, alkyl or alkyl substituted with aryl or hydroxy; • R² is hydrogen, aryl, heteroaryl, cycloalkyl, alkyl or alkyl substituted with aryl, heteroaryl, hydroxy, alkoxy, amino, monoalkyl amino or dialkylamino, or ~ (CH₂)_m TCOR²⁰ wherein m is an integer from 1 to 6, T is oxygen or --NH-- and R²⁰ is hydrogen, aryl, heteroaryl, alkyl or alkyl substituted with aryl or heteroaryl;

• R³ is hydrogen, halo, trifluoromethyl, alkoxy, alkylthio, alkyl, cycloalkyl, aryl, aminosulfonyl, amino, monoalkylamino, dialkylamino, hydroxyalkylamino, aminoalkylamino, carboxy, alkoxycarbonyl or aminocarbonyl or alkyl substituted with aryl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino;

• R^a, R^b, R^c and R^d independently represent hydrogen, alkyl, cycloalkyl or aryl; or (R^a and R^b) or (R^c and R^d) or (R^b and R^c) can complete a saturated ring of 5- to 7- carbon atoms, or (R^a and R^b) taken together and (R^b and R^c) taken together, each complete a saturated ring of 5- to 7-carbon atoms, wherein each ring optionally can contain a sulfur or oxygen atom and whose carbon atoms may be optionally substituted with one or more or the following: alkenyl, alkynyl, hydroxy, carboxy, alkoxycarbonyl, alkyl or alkyl substituted with hydroxy, carboxy or alkoxycarbonyl; or such saturated ring can have two adjacent carbon atoms which are shared with an adjoining aryl ring; and

• n is zero or one.

[0028] The invention further provides the use of PDE 1 Inhibitors of Formula

Villa or VIIIb as follows:

5.1 : Formula Villa or VIIIb, wherein J = O

5.2: Formula Villa or VIIIb or 5.1, wherein R¹ is alkyl.

5.3: Formula Villa or VIIIb, 5.1 or 5.2, wherein R² is hydrogen, benzyl,

4-chlorobenzyl, cyclohexylmethyl or trimethylacetoxymethyl. 5.4: Formula Villa or VIIIb, 5.1, 5.2 or 5.3, wherein R³ is hydrogen, or alkyl such as methyl or ethyl.

5.5: Formula Villa or VIIIb, 5.1, 5.2, 5.3 or 5.4, wherein n is zero; and 5.6: Formula Villa or VIIIb, 5.1, 5.2, 5.3, 5.4 or 5.5, wherein R^a and R^b form a saturated 5 membered ring, or (R^b and R^c) form a saturated 5, 6 or 7 membered ring, or (R^a and R^b) and (R^b and R^c) each complete a saturated ring and each ring contains 5 or 6 carbon atoms. 5.7 Formula Villa or VIIIb, in free or salt form, selected from the following:

• cis-S^a^jδ^^a-Hexahydro-S-methyl-S-φhenylmethyOcyclopenta^jSjimidazo- [2, 1 -b]purin-4-one;

• 7,8-Dihydro-5-methyl-3-(phenylmethyl)-3H-imidazo[2,l-b]purin-4(5H)-one;

• cis-6a,7,8,9,10,10a-Hexahydro-5-methyl-3-(phenylmethyl)-3H-benzimidazo[2,l- b]purin-4(5H)-one;

• 5,7,8,9-Tetrahydro-5-methyl-3-(phenylmethyl)pyrimido[2,l-b]purin-4(3H)-one;

• 7,8-Dihydro-8-phenyl-5-methyl-3-(phenylmethyl)-3H-imidazo[2,l-b]purin- 4(5H)-one;

• 5', 7'-Dihydro-5'-methyl-3'-(phenylmethyl)spiro[cyclohexane-l ,8'-(8H)imidazo- [2,l-b]purin]4'(3Η)-one;

• cis-5,6a,l 1,1 la-Tetrahydro-5-methyl-3-(phenylmethyl)indeno[r,2':4,5]imidazo- [2,l-b]purin-4(3H)-one;

• 5',7'-Dihydro-2¹,5'dimethyl-3^l-(phenylmethyl)spiro{cyclohexane-l,7'(8Η)- imidazo[2,l-b]purin}-4'-(3'H)-one;

• 7,8-Dihydro-2,5,7,7,8(R,S)-pentamethyl-3H-imidazo[2,l-b]purin-4(5H)-one;

• cis-5,6a,7,l lb-Tetrahydro-5-methyl-3- (phenylmethyl)indeno[2',r,:4,5]imidazo[2,l-b]purin-4(3H)-one;

• cis-5,6a,7,8,9,9a-Hexahydro-2,5-dimethyl-3-(phenylmethyl)cyclopent[4,5]- imidazo[2, 1 -b]purin-4-(3H)-one;

• S'-Methyl-S'-CphenylmethyO-spirofcyclopentane-lJ'-Cδ'^-CS'^imidazoP,!- b]purin]-4-(5'H)-one;

• 7,8-Dihydro-2,5,7,7-tetramethyl-3-(phenylmethyl)-3H-imidazo[2,l-b]purin- 4(5'H)-one;

• 7,8-Dihydro-7(R)-phenyl-2,5-dimethyl-3-(phenylmethyl)-3H-imidazo[2,l- b]purin-4(5H)-one; • 7,8-Dihydro-2,5-dimethyl-3,7(R)-bis(phenylmethyl)-3H-imidazo[2,l-b]purin- 4(5H)-one;

• (±)-7,8-Dihydro-2,5-dimethyl-7-ethyl-3-(phenylmethyl)-3H-imidazo[2,l-b]purin- 4(5H)-one;

• 6a(S)-7,8,9,10,10a(R)-Hexhydro-2,5-dimethyl-3-(phenylmethyl)-3H- benzimidazo[2, 1 -b]purin-4(5H)-one;

• 6a(R)-7,8,9, 10, 10a(S)-hexahydro-2,5-dimethyl-3-(phenylmethyl)-3H- benzimidazo-[2, 1 -b]purin-4(5H)-one;

• 7,8-Dihydro-2,5-dimethyl-7(R)-isopropyl-3-(phenylmethyl)-3H-imidazo[2,l- b]purin-4(5 H)-one ;

• 7,8-Dihydro-2,5,7(R)-trimethyl-3-(phenylmethyl)-3H-imidazo[2, 1 -b]purin-4(5H)- one;

• cis-7,7a,8,9,10,10a-Hexahydro-2,5-dimethyl-3-(phenylmethyl)-3H-cyclopenta- [5,6]pyrimido[2,l-b]purin-4(5H)-one;

• 7,8-Dihydro-2,5-dimethyl-7(S)-(l-methylpropyl)-3-(phenylmethyl)-3H-imidazo- [2,l-b]purin-4(5H)-one;

• 7,8-Dihydro-2,5-dimethyl-7(R)-(2-methylpropyl)-3-(phenylmethyl)-3H-imidazo- [2,l-b]purin-4(5H)-one;

• 7,8-Dihydro-2,5-dimethyl-7(R,S)-(methoxycarbonyl)-3-(phenylmethyl)-3H- imidazo[2, 1 -b]purin-4(5H)-one;

• 7,8-Dihydro-2,5-dimethyl-7(R,S)-(l-propyl)-3-(phenylmethyl)-3H-imidazo[2,l- b]purin-4(5H)-one;

• 7,8-Dihydro-2,5-dimethyl-7(S)-(l-methylethyl)-3-(phenylmethyl)-3H- imidazo[2, 1 -b]purin-4(5H)-one;

• 7,8-Dihydro-2,5,7,7,8(R,S)-pentamethyl-3H-imidazo[2,l-b]purin-4(5H)-one;

• 5,7,8,9-Tetrahydro-2,5,7,9(R,S)-pentamethyl-3-(phenylmethyl)-pyrimido[2,l- b]purin-4(3H)-one;

• 5,6a(R),7,8,9,9a(S)-Hexahydro-2,5-dimethyl-3-(phenylmethyl)cyclopent- [4,5]imidazo[2, 1 -b]purin-4(3H)-one;

• 5,6a(S),7,8,9,9a(R)-Hexahydro-2,5-dimethyl-3-(phenylmethyl)cyclopent- [4,5]imidazo[2,l-b]purin-4(3H)-one; • cis-6a,7,8,9,10,10a-Hexahydro-2,5-dimethyl-3-(phenylmethyl)-3H - benzimidazoβ, 1 -b]purin-4(5H)-one;

• 5',7'-Dihydro-2',5'-dimethyl-3'-(phenylmethyl)spiro[cyclohexane-l,8-(8H)- imidazo[2,l-b]purin]-4-(3'H)-one;

• cis-5,6a,7,8,9,9a-Hexahydro-2,5-dimethyl-3-(phenylmethyl)cyclohept- [6,7]imidazo[2,l-b]purin-4(3H)-one;

• cis-5,6a,7,8,9,9a-Hexahydro-5-methyl-2-ethyl-3-(phenylmethyl)cyclopent- [4,5]imidazo[2,l-b]purin-4(3H)-one;

• cis-6a,7,8,9, 10, 10a-Hexahydro-5-methyl-2-ethyl-3-(phenylmethyl)-3H- benzimidazo[2, 1 -b]purin-4-(5H)-one;

• cis-5,6a,7,8,9,9a-Hexahydro-5-methyl-2-ethyl-3-(phenylmethyl)cyclopent- [4,5]imidazo[2, 1 -b]purin-4(3H)-one;

• cis-5,6a,7,8,9,9a-Hexahydro-5-methyl-2-phenyl-3-(phenylmethyl)cyclopent- [4,5]imidazo[2,l-b]purin-4(3H)-one;

• cis-6a,7,8,9,10,10a-Hexahydro-5-methyl-2-phenyl-3-(phenylmethyl)-3H- benzimidazo[2, 1 -b]purin-4(5H)-one;

• cis-5,6a,7,8.9,9a-Hexahydro-5-methylcyclopenta[4,5]imidazo[2,l-b]purin-4(3H)- one;

• cis-5,6a,7,8,9,9a-Hexahydro-2,5-dimethylcyclopenta[4,5]imidazo[2,l-b]purin- 4(3H)-one;

• cis-5,6a(R), 7,8,9,9a(S)-Hexahydro-2,5-di-methylcyclopent[4,5]imidazo[2,l- b] purin-4(3 H)-one ;

. 2',5'-dimethyl-spiro{cyclopentane-l,7'-(8Η)-(3Η)-imidazo[2,l-b]purin}-4^l(5Η)- one;

• 7,8-Dihydro-2,5-dimethyl-7(R)-(l-methylethyl)-3H-imidazo[2,l-b]purin-4(5H)- one;

• 7,8-Dihydro-2,5,7,7-tetramethyl-3H-imidazo[2,l-b]purin-4(5H)-one;

• 7,8-Dihydro-2,5-di methyl-7(S)-(l -methylethyl)-3H-imidazo[2, 1 -b]purin-4(5H)- one;

• 6a(R),7,8,9,10,10a(S)-Hexahydro-2,5-dimethyl-3H-benzimidazo[2,l-b]purin- 4(5H)-one; • 5^l,7^l-Dihydro-2',5'-dimethylspiro{cyclohexane-l,7-(8Η)-imidazo[2,l-b]purin}- 4'(3'H)-one;

• cis-Sjόa^jS^^a-Hexahydro-S-methyl-S-^henylmethy^cyclopenta^jS]- imidazo [2 , 1 -b] purin-4(3 H)-thione ;

• 5,6a(R),7,8,9,9a(S)-Hexahydro-2,5-dimethyl-3-(phenylmethyl)cyclopent- [4,5]imidazo[2,l-b]purin-4(3H)-thione;

• cis-5,6a,7,8,9,9a-Hexahydro-5-methyl-3-(4-chlorophenylmethyl)cyclopenta[4,5]- imidazo[2, 1 -b]purin-4(3H)-one;

• cis-5,6a,7,8,9,9a-Hexahydro-5-methyl-3-(cyclohexylmethyl)cyclopent[4,5]- imidazo[2, 1 -b]purin-4(3H)-one;

• cis-5,6a,7,8,9,9a-Hexahydro-5-methyl-3-(2-naphthylmethyl)cyclopent[4,5]- imidazo[2, 1 -b]purin-4(3H)-one;

• 5,6a(R),7,8,9,9a(S)-Hexahydro-2,5-dimethyl-3-(4-bromophenylmethyl)- cyclopent[4,5]imidazo[2,l-b]purin-4(3H)-one;

• 5,6a(R)-7,8,9,9a(S)-Hexahydro-2,5-dimethyl-3-(4-methoxyphenylmethyl)- cyclopent[4,5]imidazo[2, 1 -b]purin-4(3H)-one;

• cis-5,6a,7,8,9,9a-Hexahydro-2,3,5-trimethylcyclopent[4,5]imidazo[2,l-b]purin- 4(3H)-one;

• cis-5,6a,7,8,9,9a-Hexahydro-2-(hydroxymethyl)-5-methyl-3-(phenylmethyl)- cyclopent[4,5]imidazo[2,l-b]purin-4(3H)-one;

• cis-5,6a,7,8,9,9a-Hexahydro-2-methylthio-5-methyl-3-(Phenylmethyl)cyclopent- [4,5]imidazo[2,l-b]purin-4(3H)-one;

• cis-3,4,5,6a,7,8,9,9a-Octahydro-5-methyl-4-oxo-3-(phenylmethyl)cyclopent- [4,5]imidazo[2, 1 -b]purin-2-carboxylic acid;

• cis-3,4,5,6a,7,8,9,9a-Octahydro-5-methyl-4-oxo-3-(phenylmethyl)cyclopent- [4,5]imidazo[2,l-b]purin-2-carboxylic acid, methyl ester;

• cis-5,6a,7,8,9,9a-Hexahydro-2-bromo-5-methyl-3- (phenylmethyl)cyclopent[4,5]imidazo[2,l-b]purin-4(3H)one;

• cis-5,6a,7,8,9,9a-Hexahydro-2-(methylaminosulfonyl)-5-methyl-3- (phenylmethyl)cyclopent[4,5]imidazo[2,l-b]purin-4(3H)one; • cis-l-Cyclopentyl-5,6a,7,8,9,9a-hexahydro-5-methylcyclopent[4,5]imidazo[2,l- b]purin-4-( 1 H)one;

• cis-5,6a,7,8,9,9a-Hexahydro-3,5-bis-(phenylmethyl)cyclopent(4,5)imidazo(2, 1 - b)purin-4(3H)one;

• cis-6a,7, 8,9,10,10a-Hexahydro-3,5-bis-(phenylmethyl)-3H-benzimidazo[2,l- b]purin-4(5H)one;

• cis-3-Cyclopentyl-5,6a,7,8,9,9a-hexahydro-5-methylcyclopent[4,5]imidazo(2,l- b)purin-4(3 H)one ;

• 5' -Methyl-S'-CphenylmethyOspirofcyclopentane-l ,7-(8'H)-(3'H)imidazo[2,l- b]purin]-4-(5H)one;

• 2',5'-Dimethyl-3'-(phenylmethyl)-spiro[cyclopentane-l,7-(8Η)-(3H)imidazo[2,l- b]purin]-4-(5Η)one;

• cis-5,6a,(R)7,8,9,9a(S)-Hexahydro-5-methyl-3-(phenylmethyl)cyclopent[4,5]- imidazo(2, 1 -b)purin-4(3H)one;

• cis-3-Cyclopentyl-5,6a,7,8,9,9a-Hexahydro-2,5-dimethylcyclopent[4,5]imidazo- [2,l-b]purin-4(3H)one;

• 5'-Methyl-2'-trifluoromethyl-3'-(phenylmethyl)spiro{cyclo-pentane-l,7^l(8'H)- (3Η)imidazo[2,l-b]purin}-4-(5Η)-one;

• 7,8-Dihydro-5,7,7-trimethyl-2-trifluoromethyl-3-(phenylmethyl)-3H-imidazo[2, 1 - b]purin-4(5H)-one;

• (+/-)-cis-5,6a,7,8,9,9a-Hexahydro-5-methyl-2-trifluoromethyl-3-(phenylmethyl)- cyclopent[4,5]imidazo[2,l-b]purin-4(3H)-one;

• (+/-)-6a,7,8,9,9a, 10,11,1 1 a-Octahydro-2,5-dimethyl-3-(phenylmethyl)-3H- pentaleno[6a',r:4,5]imidazo[2,l-b]purin-4(5H)-one;

• (+)-6a,7,8,9,9a, 10,11,11 a-Octahydro-2,5-dimethyl-3-phenylmethyl-3H- pentaleno[6a',r:4,5]imidazo[2,l-b]purin-4(5H)-one;

• (-)-6a,7,8,9,9a, 10,11,11 a-Octahydro-2,5-dimethyl-3-phenylmethyl-3H- pentaleno[6a', l':4,5]Imidazo[2, 1 -b]purin-4(5H)-one;

• (+/-) 6a,7,8,9,9a, 10,11,1 la-Octahydro-2,5-dimethyl-3H-pentaleno[6a',l':4,5]- imidazo[2, 1 -b]purin-4(5H)-one; • (+)-6a,7,8,9,9a,10,l 1,1 la-Octahydro^^-dimethyl-SH-pentaleno^a¹,!¹^^]- imidazo[2, 1 -b]purin-4(5H)-one;

• (-)-6a,7,8,9,9a, 10,11,11 a-Octahydro-2,5-dimethyl-3H-pentaleno[6a',l':4,5]- imidazo[2, 1 -b]purin-4(5H)-one;

• 6a,7,8,9, 10, 1 Oa, 11 , 12, 13, 13a-Decahydro-2,5-dimethyl-(3 -phenylmethyl)- napth[ 1 ,8a-d]imidazo[2, 1 -b]purin-4(5H)one;

• 7(R)-Cyclohexyl-7,8-dihydro-2,5-dimethyl-3-(phenylmethyl)-3H-imidazo[2,l- b]purin-4(3H)-one;

• 7(R)-Cyclohexyl-7,8-dihydro-2,5-dimethyl-3H-imidazo[2,l-b]purin-4(5H)-one;

• 7(S)-Cyclohexyl-7,8-dihydro-2,5-dimethyl-3-(phenylmethyl)-3H-imidazo[2,l- b]purin-4(3 H)-one;

• 7(S)-Cyclohexyl-7,8-dihydro-2,5-dimethyl-3H-imidazo[2,l-b]purin-4(5H)-one;

• 5,6a(R),7,8,9,9a(S)-Hexahydro-2,5-dimethyl-[3-(trimethylacetoxy)methyl]- cyclopent[4,5]imidazo[2, 1 -b]purin-4(3H)-one;

• 5,6a(R),7,8,9,9a(S)-Hexahydro-2,5-dimethyl-3-(4-pyridylmethyl)cyclopent- [4,5]imidazo[2,l-b]purin-4(3H)-one;

• 5,6a(R),7,8,9,9a(S)-Hexahydro-2,5-dimethyl-3-[2-(4-morρholinyl)- ethyl]cyclopent[4,5]imidazo[2,l-b]purin-4(3H)-one;

• 5,6a(R),7,8,9,9a(S)-Hexahydro-2,5-dimethyl-3-[acetoxymethyl]cyclopent- [4,5]imidazo[2.1 -b]purin-4(3H)-one;

• 5,6a,7,8,9,9a-Hexahydro-2,5,6a-trimethyl-3-(phenylmethyl)cyclopent- [4,5]imidazo[2,l-b]purin-4(3H)-one;

• 5,6a(R),7,8,9,9a(S)-Hexahydro-2,5,6a-trimethyl-3-(phenylmethyl)- cyclopent[4,5]imidazo[2,l-b]purin-4(3H)-one;

• 5,6a(S),7,8,9,9a(R)-Hexahydro-2,5,6a-trimethyl-3-(phenylmethyl)- cyclopent[4,5]imidazo[2,l-b]purin-4(3H)-one;

• cis-6a,7,8,9, 10,10a-Hexahydro-2,5,7-trimethyl-3-(phenylmethyl)-3H- benzimidazo[2, 1 -b]purin-4(5H)-one;

• cis-5,6a,7,8,9,9a-Hexahydro-2,5,6a-trimethylcyclopent[4,5]imidazo[2,l-b]purin- 4(3H)-one; or • cis-[6a,7,8,9,10,10a-Hexahydro-2,5,7-trimethyl-3H-benzimidazo[2,l-b]purin- 4(5H)-one],

in free or salt form.

5.8: A compound which is a substituted imidazo[2,l-b]purin-4-one, in free or pharmaceutically acceptable salt form, e.g. a compound of Formula Villa, VIIIb or according to any of formulae 5.1-5.7, wherein the compound inhibits phosphodiesterase-mediated (e.g., PDEl -mediated, especially PDElB- mediated) hydrolysis of cGMP, e.g., with an ICs₀ of less than 10 μM, preferably less than 100 nM in an immobilized-metal affinity particle reagent PDE assay, for example, as described in Example 1 below.

[0029] In another embodiment, the PDE 1 Inhibitors for use in the methods of treatment described herein are Compounds of Formula IXa or IXb

Formula IXa

Formula IXb

or a pharmaceutically acceptable salt thereof, wherein,

q=0 or 1 ;

R¹ is H, cycloalkyl, alkyl, R²³-alkyl- or R²⁶;

R^a, R^b and R^care, independently of one another, each H, alkyl, cyoloalkyl, aryl, R²²-aryl- or R²⁴-alkyl-; or R^a and R^b, together with the carbon to which they are both attached, form a 4- to 7- membered ring, and R^c is H or alkyl; or

R^a and R^c, together with the respective carbons to which they are attached, form a 4- to 7- membered ring, and R^b is H or alkyl;

(i) X is a bond;

Y is aryl-alkyl or R²²-aryl-alkyl-; and

R² is monohaloalkyl, polyhaloalkyl, provided that it is not trifiuoromethyl, azido, cyano, oximino, cycloalkenyl, heteroaryl, R 22 heteroaryl- or R²⁷-alkyl-;

(ii) X is a bond;

Y is aryl-alkyl or R²²-aryl-alkyl-; and

R² is H, halo, — CONHR⁶, -CONR⁶R⁷, -CO₂R⁶, monohaloalkyl, polyhaloalkyl, azido, cyano, — C=N — OR⁶, cycloalkyl, cycloalkylalkyl, R²⁶, aminosulfonyl, alkyl or R²³-alkyl-

(iii) X is — O — or — S — ;

Y is aryl-alkyl or R²²-aryl-alkyl-; and

R² is R²⁶, cycloalkyl cycloalkylalkyl, heterocycloalkyl, cycloalkenyl or R²⁶-alkyl-_;

(iv) X is — O — or — S — ;

Y is aryl-alkyl or R²²-aryl-alkyl-; and

R² is alkyl, R²⁶, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, cycloalkenyl or R -alkyl-; (v) X is —SO— or -SO₂-;

Y is aryl-alkyl or R -aryl-alkyl-; and

R² is alkyl, R²⁶, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, cycloalkenyl or R²⁸-alkyl-;

(vi) X is — NR⁸- ;

Y is aryl-alkyl or R²²-aryl-alkyl-; and

R² is (R²⁹)_p-alkyl-, cycloalkyl, (R³⁰)_p-cycloalkyl-, cycloalkenyl, (R³⁰)_p- cycloalkenyl-, heterocycloalkyl or (R³⁰)_p-heterocycloalkyl-:

(vii) X is — NR⁸- ;

Y is aryl-alkyl or R²²-aryl-alkyl-; and

R² is alkyl, R²⁶, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, cycloalkenyl or R³ '-alkyl-; or

(viϋ) X is — C≡C — ;

Y is aryl-alkyl or R²²-aryl-alkyl-; and

R² is alkyl, R²⁶, cycloalkyl, cycloalkylalkyl or R²³-alkyl-;

where,

R⁶ is H or R⁷;

R⁷ is alkyl, cycloalkyl or cycloalkylalkyl;

R is heterocycloalkyl or R ; R²¹ is 1-6 substituents each independently selected from the group consisting of halo, hydroxy, alkoxy, phenoxy, phenyl, nitro, aminosulfonyl, cyano, monohaloalkyl, polyhaloalkyl, thiol, alkylthio, cyoloalkyl, cycloalkylalkyl, amino, alkylamino, acylamino, carboxyl, — C(O)OR³⁴, carboxamido, — OCF₃ and acyloxy;

R²² is 1-6 substituents each independently selected from the group consisting of alkyl and R²¹;

R²³ is cycloalkoxy aryloxy, alkylthio, arylthio, cycloalkyl or R²⁸;

R²⁴ is cycloalkyl or R²⁶;

R²⁵ is hydroxy, alkoxy, amino, monoalkylamino, dialkylamino or R²⁶;

R²⁶ is aryl, R²²-aryl-, heteroaryl or R²²-heteroaryl-;

R is cycloalkoxy, aryloxy, alkylthio, arylthio, heteroaryl, R -heteroaryl-, cycloalkyl, heterocycloalkyl, cycloalkenyl, cycloalkylamino or heterocycloalkylamino;

R is cycloalkylamino, heterocycloalkylamino or R ;

R²⁹ is alkoxy, cycloalkylamino, heterocycloalkylamino or R²⁶;

R³⁰ is halo, hydroxy, alkoxy, amino, aminosulfonyl, cyano, monohaloalkyl, polyhaloalkyl, thiol, alkylthio, alkyl, cyoloalkyl, cycloalkylalkyl or acyloxy;

R³¹ is cycloalkyl or R²⁸;

R³⁴ is alkyl, aryl, aralkyl and heteroaryl; and

p is 1 to 4. [0030] The invention further provides the use of PDE 1 Inhibitors of Formula IXa or IXb as follows:

6.1 Formula IXa or IXb selected from a group consisting of:

6.2 Formula IXa or IXb, in free or salt form, selected from a group consisting of:

in free or salt form.

[0031] In another embodiment, the invention provides the use of PDE 1 Inhibitors of Formula X:

Formula X in free or a pharmaceutically acceptable salt thereof, wherein: Ri, R₂ and R₃ are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogeno, hydroxy, (di-lower alkyl)amino, 4-morpholinyl, 1- pyrrolidinyl, 1-pyrrolyl, -CF₃, -OCF₃, phenyl and methoxyphenyl; or Ri and R₂ together are methylenedioxy; or Ri and R₂ together with the carbon atoms to which they are attached form a benzene ring; and

R^a is hydrogen and R^b and R^c, together with the carbon atoms to which they are attached, form a saturated ring of 5 carbons; or R^a is lower alkyl, R^b is hydrogen or lower alkyl, and R^c is hydrogen; or R^a, R^b and the carbon atom to which they are attached form a saturated ring of 5-7 carbons, and R^c is hydrogen; or R^a is hydrogen, and R , R^c and the carbon atoms to which they are attached form a tetrahydrofuran ring; or R^a and R^b, together with the carbon atom to which they are attached, and R and R^c, together with the carbon atoms to which they are attached, each form a saturated ring of 5-7 carbons. [0032] In a further embodiment, the invention provides the use of PDE 1

Inhibitors of Formula X as follows:

7.1 Formula X, wherein Ri, R₂ and R₃ are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogeno, hydroxy, (di-lower alkyl)amino, 4-morpholinyl, 1-pyrrolidinyl, 1-pyrrolyl, -CF₃, -OCF₃, phenyl and methoxyphenyl; or Ri and R₂ together are methylenedioxy; or Ri and R₂ together with the carbon atoms to which they are attached form a benzene ring;

7.2 Formula X or 7.1 , wherein Ri is H, methoxy or trifluoromethyl;

7.3 Formula X or 7.1 or 7.2, wherein Ri is H;

7.4 Formula X or any of 7.1 -7.3, wherein R₂ is selected from a group consisting of H, halo (e.g., F, Cl), methoxy, methyl, trifluoromethyl, dimethylamino, phenyl, methoxyphenyl-, -OCF₃, 3,4-OCH₂O-, pyrolidin- 1-yl, pyrol-1-yl and morpholin-4-yl;

7.5 Formula X or any of 7.1 -7.4, wherein Ri and R₂ together with the carbon atoms to which they are attached forma a benzene ring;

7.6 Formula X or any of 7.1-7.5, wherein R₃ is H or methoxy;

7.7 Formula X or any of 7.1-7.6, wherein R₃ is H; 7.8 Formula X or any of 7.1-7.7, wherein R^a is hydrogen and R and R^c, together with the carbon atoms to which they are attached, form a saturated ring of 5 carbons; or R^a is lower alkyl, R^b is hydrogen or lower alkyl, and R^c is hydrogen; or R^a, R and the carbon atom to which they are attached form a saturated ring of 5-7 carbons, and R^c is hydrogen; or R^a is hydrogen, and R^b, R^c and the carbon atoms to which they are attached form a tetrahydrofuran ring; or R^a and R^b, together with the carbon atom to which they are attached, and R^b and R^c, together with the carbon atoms to which they are attached, each form a saturated ring of 5-7 carbons;

7.9 Formula X or any of 7.1 -7.8, wherein R^a is hydrogen and R^b and R^c together with the carbon atoms to which they are attached, form a saturated ring of 5 carbons, and wherein Ri, R₂ and R₃ are as defined in the following table

7.10 Formula X or any of 7.1-7.9, selected from a group consisting of

7.11 Formula X or any of 7.1 -7.9, selected from a group consisting of: 2'-benzyl-5'-methyl-spiro[cyclopentane-l',7' (8Η)-[3Η]-imidazo[2,l- b]purin]-4'-(5Η)-one;

2'-benzyl-5,7,7-trimethyl-3H-imidazo[2,l-b]purin-4-(5H)-one;

(+)-2-benzyl-7,8-dihydro-5-methyl-7-(l -methylethyl)- 1 H-imidazo[2, 1 -b]- purin-4(5H)-one;

(+,-)-6a, 7, 8, 9, 9a, 10, 11, l la-octahydro-5-methyl-2-(3,4-methylene- dioxyphenylmethyl)-3H-pentalen[6a, l :4,5]imidazo[2,l-b]purin-4(5H)- one; and

(+)-cis-6a, 7, 9, 9a-tetrahydro-5-methyl-2-[4-(trifluoromethyl)- phenylmethyl]-3H-furo[3', 4':4,5]imidazo[2,l-b]purin-4(5H)-one,

in free or salt form.

7.12 Formulae X or 7.1-7.11, wherein the compounds inhibit phosphodiesterase-mediated (e.g., PDEl -mediated, especially PDElB- mediated) hydrolysis of cGMP, e.g., with an IC_5O of less than lμM, preferably less than 25 nM in an immobilized-metal affinity particle reagent PDE assay, for example, as described in Example 1 ;

[0033] In another embodiment, the invention provides the use of PDE 1 Inhibitors selected from the following:

in free or salt form (Formula XI).

[0034] If not otherwise specified or clear from context, the following terms as used herein have the following meanings: a. "Alkyl" as used herein is a saturated or unsaturated hydrocarbon moiety, preferably saturated, preferably one to seven carbon atoms in length, which may be linear or branched, and may be optionally substituted, e.g., mono-, di-, or tri-substituted, e.g., with halogen (e.g., chloro or fluoro), hydroxy, or carboxy. b. "Cycloalkyl" as used herein is a saturated or unsaturated nonaromatic hydrocarbon moiety, preferably saturated, preferably comprising three to nine carbon atoms, at least some of which form a nonaromatic mono- or bicyclic, or bridged cyclic structure, and which may be optionally substituted, e.g., with halogen (e.g., chloro or fluoro), hydroxy, or carboxy. c. "Heterocycloalkyl" as used herein is a saturated or unsaturated nonaromatic hydrocarbon moiety, preferably saturated, preferably comprising three to nine carbon atoms, at least one atom selected from a group consisting of N, O or S, at least some of which form a nonaromatic mono- or bicyclic, or bridged cyclic structure, and which may be optionally substituted, e.g., with halogen (e.g., chloro or fluoro), hydroxy, or carboxy. Examples of heterocycloalkyl include pyrrolidinyl (e.g., pyrrolidin-1-yl), morpholinyl (e.g., morpholin-4-yl), d. "Aryl" as used herein is a mono or bicyclic aromatic hydrocarbon (e.g., phenyl, naphthyl), preferably phenyl, optionally substituted, e.g., with alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloalkyl (e.g., trifiuoromethyl), hydroxy, carboxy, or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl). e. "Heteroaryl" as used herein is an aromatic moiety wherein one or more of the atoms making up the aromatic ring is sulfur or nitrogen rather than carbon, e.g., pyridyl, thiadiazolyl, pyrrolyl (e.g., pyrrol-2-yl) or imidazolyl (e.g., lH-imidazol-2-yl), which may be optionally substituted, e.g., with alkyl, halogen, haloalkyl, hydroxy or carboxy.

[0035] PDE 1 Inhibitors may exist in free or salt form, e.g., as acid addition salts.

In this specification unless otherwise indicated language such as PDE 1 Inhibitors is to be understood as embracing the compounds in any form, for example free or acid addition salt form, or where the compounds contain acidic substituents, in base addition salt form. The PDE 1 Inhibitors are intended for use as pharmaceuticals, therefore pharmaceutically acceptable salts are preferred. Salts which are unsuitable for pharmaceutical uses may be useful, for example, for the isolation or purification of free PDE 1 Inhibitors or their pharmaceutically acceptable salts.

[0036] PDE 1 Inhibitors may in some cases also exist in prodrug form, for example when the compounds contain physiologically hydrolysable and acceptable esters. As used herein, "physiologically hydrolysable and acceptable ester" means esters of PDE 1 Inhibitors which are hydrolysable under physiological conditions to yield acids (in the case of PDE 1 Inhibitors which have hydroxy substituents) or alcohols (in the case of PDE 1 Inhibitors which have carboxy substituents) which are themselves physiologically tolerable at doses to be administered. As will be appreciated the term thus embraces conventional pharmaceutical prodrug forms. [0037] Methods of making and formulating the PDE 1 Inhibitors, novel intermediates useful for making PDE 1 Inhibitors, and methods of using the PDE 1 Inhibitors for treatment of diseases are generally disclosed in EP 0201188 (or U.S. 4,666,908) and EP 0911333 (or U.S. 6,235,742); PCT/US2006/022066; PCT/US2006/033179; WO 03/042216 (U.S. 6,943,171); U.S. 6,969,719; U.S. 5,939,419; EP 0 538 332 (U.S. 5,393,755); U.S. 5,393,755; U.S. 6,969,719 B2, Xia et al., J Med. Chem. (1997), 40, 4372-4377 and Ahn et al., J Med. Chem. (1997), 40, 2196-2210, the contents of all of which are incorporated herein by reference.

Methods of treatment

[0038] The invention provides methods of treatment or prophylaxis of narcolepsy comprising administering an effective amount of a PDE 1 inhibitor, e.g., a PDE 1 Inhibitor as hereinbefore described, for example a Compound of any of Formulae I, Ia, II, III, IV, V, VI, Vila, VIIb, Villa, VIIIb, IXa, IXb, X, XI or any of Formulae 1.2-1.17, 2.1- 2.9, or 3.2-3.22, 4.1-4.17, 5.1-5.8, 6.1-6.1 or 7.1-7.12 to a human or animal patient, preferably a human, in need thereof.

[0039] PDE 1 Inhibitors may be used in the foregoing methods of treatment prophylaxis as a sole therapeutic agent, but may also be used in combination or for coadministration with other active agents. Thus, the invention further comprises a method of treating narcolepsy comprising administering simultaneously, sequentially, or contemporaneously administering therapeutically effective amounts of

(i) a PDE 1 Inhibitor, e.g., any of Formulae I, Ia, II, III, IV, V, VI, Vila, VIIb, Villa, VIIIb, IXa, IXb, X, XI or any of Formulae 1.2-1.17, 2.1-2.9, 3.2-3.22, 4.1- 4.17, 5.1-5.8, 6.1-6.2 or 7.1-7.12; and

(ii) a compound to promote wakefulness or regulate sleep, e.g., selected from (a) central nervous system stimulants-amphetamines and amphetamine like compounds, e.g., methylphenidate, dextroamphetamine, methamphetamine, and pemoline; (b) modafinil, (c) antidepressants, e.g., tricyclics (including imipramine, desipramine, clomipramine, and protriptyline) and selective serotonin reuptake inhibitors (including fluoxetine and sertraline); and/or (d) gamma hydroxybutyrate (GHB), to a patient in need thereof. [0040] The present invention also provides

(i) a PDE 1 Inhibitor for use in the treatment of any disease or condition as hereinbefore set forth, or in a method of treatment as hereinbefore set forth;

(ii) the use of a PDE 1 Inhibitor in the manufacture of a medicament for treating a disease or condition as hereinbefore set forth, or manufacture of a medicament for use in a method of treatment as hereinbefore set forth; and

(iii) a pharmaceutical composition comprising a PDE 1 Inhibitor in combination or association with a pharmaceutically acceptable diluent or carrier for use in the treatment of a disease or condition as hereinbefore set forth, or for use in a method of treatment as hereinbefore set forth.

[0041] The words "treatment" and "treating" are to be understood accordingly as embracing prophylaxis and treatment or amelioration of any of the symptoms of disease as well as treatment of the cause of the disease.

[0042] Dosages employed in practicing the present invention will of course vary depending, e.g. on the particular disease or condition to be treated, the particular PDE 1 Inhibitor used, the mode of administration, and the therapy desired. PDE 1 Inhibitors may be administered by any suitable route, including orally, parenterally, transdermally, or by inhalation, but are preferably administered orally. In general, satisfactory results, e.g. for the treatment of diseases as hereinbefore set forth are indicated to be obtained on oral administration at dosages of the order from about 0.01 to 2.0 mg/kg. In larger mammals, for example humans, an indicated daily dosage for oral administration will accordingly be in the range of from about 0.75 to 150 mg, conveniently administered once, or in divided doses 2 to 4 times, daily or in sustained release form. Unit dosage forms for oral administration thus for example may comprise from about 0.2 to 75 or 150 mg, e.g. from about 0.2 or 2.0 to 50, 75 or 100 mg of a PDE 1 Inhibitor, together with a pharmaceutically acceptable diluent or carrier therefor. [0043] Pharmaceutical compositions comprising PDE 1 Inhibitors may be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus oral dosage forms may include tablets, capsules, solutions, suspensions and the like.

EXAMPLES

1. Measurement of PDElB inhibition in vitro using IMAP Phosphodiesterase Assay Kit

[0044] Phosphodiesterase IB (PDElB) is a calcium/calmodulin dependent phosphodiesterase enzyme that converts cyclic guanosine monophosphate (cGMP) to 5'- guanosine monophosphate (5'-GMP). PDElB can also convert a modified cGMP substrate, such as the fluorescent molecule cGMP-fluorescein, to the corresponding GMP-fluorescein. The generation of GMP-fiuorescein from cGMP-fiuorescein can be quantitated, using, for example, the IMAP (Molecular Devices, Sunnyvale, CA) immobilized-metal affinity particle reagent.

[0045] Briefly, the IMAP reagent binds with high affinity to the free 5 '-phosphate that is found in GMP-fluorescein and not in cGMP-fluorescein. The resulting GMP- fluorescein - IMAP complex is large relative to cGMP-fluorescein. Small fluorophores that are bound up in a large, slowly tumbling, complex can be distinguished from unbound fluorophores, because the photons emitted as they fluoresce retain the same polarity as the photons used to excite the fluorescence.

[0046] In the phosphodiesterase assay, cGMP-fluorescein, which cannot be bound to IMAP, and therefore retains little fluorescence polarization, is converted to GMP- fluorescein, which, when bound to IMAP, yields a large increase in fluorescence polarization (Δmp). Inhibition of phosphodiesterase, therefore, is detected as a decrease in Δmp.

Enzyme assay

[0047] Materials: All chemicals are available from Sigma-Aldrich (St. Louis,

MO) except for IMAP reagents (reaction buffer, binding buffer, FL-GMP and IMAP beads), which are available from Molecular Devices (Sunnyvale, CA). [0048] Assay: 3',5'-cyclic-nucleotide-specific bovine brain phosphodiesterase

(Sigma, St. Louis, MO) is reconstituted with 50% glycerol to 2.5 U/ml. One unit of enzyme will hydrolyze 1.0 μmole of 3',5'-cAMP to 5'-AMP per min at pH 7.5 at 30°C. One part enzyme is added to 1999 parts reaction buffer (30 μM CaCl₂, 10 U/ml of calmodulin (Sigma P2277), 1OmM Tris-HCl pH 7.2, 1OmM MgCl₂, 0.1% BSA, 0.05% NaN₃) to yield a final concentration of 1.25mU/ml. 99 μl of diluted enzyme solution is added into each well in a flat bottom 96-well polystyrene plate to which 1 μl of test compound dissolved in 100% DMSO is added. The compounds are mixed and pre- incubated with the enzyme for 10 min at room temperature. [0049] The FL-GMP conversion reaction is initiated by combining 4 parts enzyme and inhibitor mix with 1 part substrate solution (0.225 μM) in a 384- well microtiter plate. The reaction is incubated in dark at room temperature for 15 min. The reaction is halted by addition of 60 μl of binding reagent (1 :400 dilution of IMAP beads in binding buffer supplemented with 1 :1800 dilution of antifoam) to each well of the 384- well plate. The plate is incubated at room temperature for 1 hour to allow IMAP binding to proceed to completion, and then placed in an Envision multimode microplate reader (PerkinElmer, Shelton, CT) to measure the fluorescence polarization (Δmp). [0050] A decrease in GMP concentration, measured as decreased Δmp, is indicative of inhibition of PDE activity. IC₅₀ values are determined by measuring enzyme activity in the presence of 8 to 16 concentrations of compound ranging from 0.0037 nM to 80,000 nM and then plotting drug concentration versus ΔmP, which allows IC₅₀ values to be estimated using nonlinear regression software (XLFit; IDBS, Cambridge, MA).

Claims

What is claimed is:

1. A method of treatment or prophylaxis for narcolepsy comprising administering an effective amount of a PDE 1 inhibitor to a patient in need thereof.

2. The method of claim 1 wherein the PDE 1 inhibitor is a compound of the formula (I)

Formula I

wherein

(i) Ri is H or Ci_-4 alkyl;

(ii) R₄ is H or Ci_-4 alkyl and R₂ and R₃ are, independently, H or Ci_-4 alkyl, aryl, heteroaryl, heteroarylalkoxy, arylalkoxy, heteroarylaklyl, or arylalkyl; or R₂ is H and R₃ and R₄ together form a di-, tri-, or tetra-methylene bridge;

(iii) R₅ is a substituted heteroarylalkyl, or R₅ is attached to one of the nitrogen atoms on the pyrazolo portion of Formula I and is a moiety of Formula Q

Formula Q

wherein X, Y and Z are, independently, N or C; R₈, R₉, R₁₁ and Ri₂ are independently H or halogen; and Rio is halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or thiadiazolyl, diazolyl, triazolyl, tetrazolyl, arylcarbonyl, alkylsulfonyl, heteroarylcarbonyl, or alkoxycarbonyl; provided that when X, Y, or Z is nitrogen, R₈, R₉, or Rio, respectively, is not present;

(iv) R₆ is H, alkyl, aryl, heteroaryl, arylalkyl, arylamino, heterarylamino, N₅N- dialkylamino, N,N-diarylamino, or N-aryl-N-(arylakyl)amino; and

(v) n=0 or l;

(vi) when n=l , A is -C(Ri₃Ri₄)- wherein Ri₃ and Ri_4, are, independently, H or Ci_-4 alkyl, aryl, heteroaryl, heteroarylalkoxy, arylalkoxy, heteroarylalkyl or arylalkyl; in free, salt or prodrug form.

3. The method according to claim I₅ wherein the PDE 1 inhibitor is a compound of Formula II

Formula II

wherein

R_a and R_b are, independently, H or C_1-4 alkyl; R₆ is phenylamino or benzylamino; Ri₀ is phenyl, pyridyl, or thiadiazolyl; in free or salt form.

4. The method according to claim 1 wherein the PDE 1 inhibitor is a compound of Formula III

Formula III wherein

R₂ is H and R₃ and R₄ together form a tri- or tetra-methylene bridge; or at least one of R₂ and R₃ is methyl, isopropyl or arylalkoxy and R₄ is H; or R₂ and R₃ are

H and R₄ is a Ci_-4 alkyl;

R₆ is phenylamino or benzylamino;

Ri₀ is haloalkyl, phenyl, pyridyl, or thiadiazolyl; in free or salt form.

5. The method according to claim 1 wherein the PDE 1 inhibitor is a compound of Formula IV

Formula IV wherein

H and R₄ is a CM alkyl;

R₆ is phenylamino or benzylamino;

Rio is phenyl, pyridyl, or thiadiazolyl; in free or salt form.

6. The method according to claim 1 wherein the PDE 1 inhibitor is a compound of formula Ia

Formula Ia

wherein (i) Ri is H or Ci_-4 alkyl;

(ii) R₄ is H and R₂ and R₃ are, independently, H or Ci_-4 alkyl, aryl, or arylalkyl; or R₂ is H and R₃ and R₄ together form a di-, tri- or tetramethylene bridge;

(iii) R₅ is attached to one of the nitrogens on the pyrazolo portion of formula I and is a substituted benzyl of formula Qa

Formula Qa wherein R₈, R₉, Rn and Ri₂ are independently H or halogen; and Ri₀ is halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, arylcarbonyl, alkyl sulfonyl or heteroarylcarbonyl, and

(iv) R₆ is H, alkyl, aryl, heteroaryl, arylalkyl, arylamino, heteroarylamino, arylalkylamino, N,N-dialkylamino, N,N-diarylamino, or N-aryl-N-

(arylalkyl)amino;

in free, salt or prodrug form.

7. The method according to claim 1 wherein the PDE 1 inhibitor is a compound of Formula V

Formula V

wherein

R₂ is H and R₃ and R₄ together form a tri- or tetra-methylene bridge; or R₂ and R₃ are each methyl and R₄ is H; or R₂ and R₄ are H and R₃ is isopropyl;

R₆ is phenylamino or benzylamino;

Rio is phenyl, pyridyl, or thiadiazolyl; in free or salt form. The method of claim 1 wherein the PDE 1 inhibitor is a compound of the Formula (VI)

wherein

R₃ is methyl or C₂-C₆ alkyl;

Ri is H or Ci-C₄ alkyl;

each ofR₂ and R₃ is independently selected from H and Ci-C₄ alkyl, or R₂ is H or Ci-C₄ alkyl and R₃ is OH, C₂-C₄ alkanoyloxy or fluoro, or R₂ and R₃ when taken together represent C₂-C₆ alkylene, or R₂ and R₃ when taken together with the carbon atom to which they are attached represent a carbonyl group;

Ar is either (a)

wherein

each of R₄, R₅ and R₆ is independently selected from

H

Ci-C₄ alkyl,

Ci-C₄ alkoxy,

Ci-C₄ alkoxy-Z-, halo, halo(Ci-C₄)alkyl, phenoxy, optionally substituted by up to three substitutents each of which substitutent is independently selected from halo, Ci_-4 alkyl, and Ci-C₄ alkoxy, nitro, hydroxy, hydroxy-Z-,

C₂-C₄ alkanoyl, amino, amino-Z-,

(C₁-C₄ alkyl)NH,

(C₁-C₄ alkyl)₂N-,

(C₁-C₄ alkyl)NH-Z-,

(C-C₄ alkyl)₂N-Z-,

-COOH,

-Z-COOH,

-COO(Ci-C₄ alkyl),

-Z-COO(C-C₄ alkyl)

Ci-C₄ alkanesulphonamido,

Ci-C₄ alkanesulphonamido-Z-, halo(C ₁ -C₄)alkanesulphonamido, halo(C ! -C₄)alkanesulphonamido-Z-,

Ci-C₄ alkanamido,

Ci -C₄ alkanamido-Z-,

HOOC-Z-NH-,

HOOC-Z-NH-Z-,

(C-C₄ alkyl)OOC-Z-NH-,

(Ci-C₄ alkyl)OOC-Z-NH-Z-,

Ci-C₄ alkyl-NH-SO₂-NH-,

Ci-C₄ alkyl-NH-SO₂-NH-Z-,

(C₁-C₄ alkyl)₂-N-SO₂-NH-,

(Ci-C₄ alkyl)₂-N-SO₂-NH-Z-,

Ci-C₄ alkoxy CH=CH-Z-CONH-,

Ci-C₄ alkoxy CH=CHCONH

Ci-C₄ alkyl-SO₂-N(Ci-C₄ alkyl)-,

C-C₄ alkyl-SO₂-N(C,-C₄ alkyl)-Z-,

(C₁-C₄ alkyl)NH-Z-SO₂-NH-,

(C₁-C₄ alkyl)₂N-Z-SO₂-NH-,

(C₁-C₄ alkyl)NH-Z-SO₂-NH-Z-,

(C₁-C₄ alkyl)₂N-Z-SO₂-NH-Z-, benzenesulphonamido, optionally ring substituted by up to three substitutents each of which is independently selected from halo, Cj_-4 alkyl, and Ci-C₄ alkoxy,

Ci-C₄ alkanoyl-N(Ci-C₄ alkyl)-,

Ci-C₄ alkanoyl-N(Ci-C₄ alkyl)-Z-,

C i -C₄ alkoxycarbonyl-CH(CH₂OH)NHSO₂-,

-SO₃H,

-SO₂NH₂,

H₂NOC-CH(CH₂OH)-NHSO₂-,

HOOC-Z-O-, and

(Ci-C₄ alkyl)OOC-Z-O-, or optionally one Of R₄, R₅ and R₆ is a G-Het group and wherein the others OfR₄, R₅ and R₆ are independently selected from the R₄, R₅ and R₆ substitutents listed above;

Z is Ci-C₄ alkylene,

G is a direct link, Z, O, -SO₂NH-, SO₂, or -Z-N(CpC₄ alkyl)SO₂-,

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(R₂R₃)- 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 C₁-C₄ alkyl, halo, hydroxy, oxo, amino, and Ci -C₄ alkoxy;

in free or pharmaceutically acceptable salt form.

9. The method according to claim 1 wherein the PDE 1 inhibitor is selected from the following:

in free or pharmaceutically acceptable salt form.

10. The method according to claim 1 wherein the compound is

in free or pharmaceutically acceptable salt form.

11. The method according to claim 1 wherein the PDE 1 inhibitor is a compound of the Formula Vila or VIIb:

Fo Vila

in free or salt form, wherein: i) q = 0, I or 2; ii) R¹, R^a, R^b, R^c and R^d are each independently H, alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups,

wherein each alkyl group of R¹, R^a, R^b, R^c and R^d is independently unsubstituted or substituted with 1 to 5 independently selected R³ moieties which can be the same or different, each R moiety being independently selected from the group consisting of hydroxy, alkoxy, cycloalkoxy, aryloxy, alkylthio, arylthio, aryl, haloaryl, heteroaryl, cycloalkyl, heterocycloalkyl, amino, alkylamino, dialkylamino, cycloalkylamino and heterocycloalkylamino groups;

wherein each of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups of R¹, R^a, R^b, R^c and R^d is independently unsubstituted or substituted with 1 to 5 independently selected R⁴ moieties which can be the same or different, each R⁴ moiety being independently selected from the group consisting of: halo, optionally substituted aryl, heteroaryl, nitro, cyano, haloalkyl, haloalkoxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, amino, alkylamino, dialkylamino, -OCF₃, acyloxy, -OR⁸, -C(O)R⁹, -C(O)OR⁸, - NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁸,- NR¹⁰S(O)₂R⁹, - S(O)_0-2R⁹ groups, carbonyl when two hydrogens attached to the same carbon atom of the cycloalkyl or heterocycloalkyl group of R¹ are substituted, and =CR⁸R⁹ when two hydrogens attached to the same carbon atom of the cycloalkyl or heterocycloalkyl groups of R¹ are substituted,

wherein each of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups of the R³ and R⁴ moieties above is independently unsubstituted or substituted with 1 to 5 independently selected R¹² moieties which can be the same or different, each R¹² moiety being independently selected from the group consisting of: halo, phenyl, nitro, cyano, haloalkyl, haloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, amino, alkylamino, -OCF₃, acyloxy, -OR , - C(O)R⁹, -C(O)OR⁸, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁸,- NR¹⁰S(O)₂R⁹, - S(O)_0-2R⁹ groups, carbonyl when two hydrogens attached to the same carbon atom of the cycloalkyl or heterocycloalkyl group of R³ or R⁴ are substituted, and =CR⁸R⁹ when two hydrogens attached to the same carbon atom of the cycloalkyl or heterocycloalkyl group of R³ or R⁴ are substituted; or

iii) R^a and R^b, together with the carbon to which they are both attached, form a 4- ttoo 77--mmeemmbbeerreedd ccyyccllooaallkkyyll oorr hheetteerrooccyyicloalkyl ring, and R^c and R^d are each independently H or an alkyl group; or

iv) R^a and R^c, together with the respective carbons to which they are attached, form a 4- to 7-membered cycloalkyl or heterocycloalkyl ring, and R and R are each independently H or an alkyl group, preferably R^a and R^c together have the cis configuration, e.g., where the carbons carrying R^a and R^c have the R and S configurations, respectively; v) R is H, halo, alkyl, haloalkyl, alkoxy, alkylthio, amino, aminosulfonyl, monoalkylamino, dialkylamino, hydroxyalkylamino, aminoalkylamino, carboxy, alkoxy carbonyl, aminocarbonyl or alkylaminocarbonyl group,

wherein each alkyl group of R² is independently unsubstituted or substituted with 1 to 5 independently selected R¹³ moieties which can be the same or different, each R¹³ moiety being independently selected from the group consisting of halo, hydroxy, alkoxy, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, amino, monoalkylamino or dialkylamino group,

vii) each R⁸ is independently H, alkyl or aryl;

viii) each R⁹ is independently H, alkyl, aryl or -NR¹⁰R¹ ' ;

ix) each R¹⁰ is independently H, alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein each alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of R¹⁰ is unsubstituted or independently substituted with 1 to 5 R¹⁴ moieties which can be the same or different, each R¹⁴ moiety being independently selected from the group consisting of: halo, alkyl, aryl, cycloalkyl, -CF₃, -OCF₃, -CN, -OR⁸, -CH₂OR⁸, -C(O)OR⁸ and -C(O)NR⁸R⁸; and

x) each R¹ ' is independently H, alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein each alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl of R¹¹ is unsubstituted or independently substituted with 1 to 5 R¹⁴ moieties which can be the same or different.

12. The method according to claim 1, wherein the PDE 1 inhibitor is selected from the following:

in free or salt form.

13. The method according to claim 1, wherein the PDE 1 inhibitor is

in free or salt form.

14. The method according to claim 1, wherein the PDE 1 inhibitor is Compounds of Formula Villa or VIIIb:

Formula Villa Formula VIIIb ee or salt form, wherein:

• J is oxygen or sulfur,

• R¹ is hydrogen, alkyl or alkyl substituted with aryl or hydroxy;

• R² is hydrogen, aryl, heteroaryl, cycloalkyl, alkyl or alkyl substituted with aryl, heteroaryl, hydroxy, alkoxy, amino, monoalkyl amino or dialkylamino, or ~ (CH_2)m TCOR²⁰ wherein m is an integer from 1 to 6, T is oxygen or --NH- and R²⁰ is hydrogen, aryl, heteroaryl, alkyl or alkyl substituted with aryl or heteroaryl;

• n is zero or one.

5. The method according to claim 14, wherein the PDE 1 inhibitor is Compounds of Formula Villa or VIIIb selected from a group consisting of:

• cis-S^a^jδ^^a-Hexahydro-S-methyl-S-φhenylmethyOcyclopenta^jSJimidazo- [2,l-b]purin-4-one;

• , 7,8-Dihydro-5-methyl-3-(phenylmethyl)-3H-imidazo[2, 1 -b]purin-4(5H)-one;

• 5,7,8,9-Tetrahydro-5-methyl-3-(phenylmethyl)pyrimido[2,l-b]purin-4(3H)-one;

• 5', 7'-Dihydro-5'-methyl-3'-(phenylmethyl)spiro[cyclohexane-l,8'-(8H)imidazo- [2,l-b]purin]4'(3'H)-one;

• 5',7'-Dihydro-2^l,5'dimethyl-3'-(phenylmethyl)spiro{cyclohexane-l,7'(8'H)- imidazo[2,l-b]purin}-4'-(3Η)-one;

• 7,8-Dihydro-2,5,7,7,8(R,S)-pentamethyl-3H-imidazo[2,l-b]purin-4(5H)-one;

• cis-5,6a,7,l lb-Tetrahydro-5-methyl-3- (phenylmethyl)indeno[2', 1 ', :4,5]imidazo[2, 1 -b]purin-4(3H)-one;

• 5'-Methyl-3'-(phenylmethyl)-spiro[cyclopentane-l,7'-(8'H)-(3'H)imidazo[2,l- b]purin]-4-(5Η)-one;

• 7,8-Dihydro-2,5,7,7-tetramethyl-3-(phenylmethyl)-3H-imidazo[2,l-b]purin- 4(5Η)-one;

• 7,8-Dihydro-7(R)-phenyl-2,5-dimethyl-3-(phenylmethyl)-3H-imidazo[2,l- b]purin-4(5H)-one;

• 7,8-Dihydro-2,5-dimethyl-3,7(R)-bis(phenylmethyl)-3H-imidazo[2,l-b]purin- 4(5H)-one; • (±)-7,8-Dihydro-2,5-dimethyl-7-ethyl-3-(phenylmethyl)-3H-imidazo[2,l-b]purin- 4(5H)-one;

• 6a(R)-7,8,9,10,10a(S)-hexahydro-2,5-dimethyl-3-(phenylmethyl)-3H- benzimidazo-[2, 1 -b]purin-4(5H)-one;

• 7,8-Dihydro-2,5-dimethyl-7(R)-isopropyl-3-(phenylmethyl)-3H-imidazo[2,l- b]purin-4(5H)-one;

• 7,8-Dihydro-2,5,7(R)-trimethyl-3-(phenylmethyl)-3H-imidazo[2,l-b]purin-4(5H)- one;

• cis-7,7a,8,9, 10,10a-Hexahydro-2,5-dimethyl-3-(phenylmethyl)-3H-cyclopenta- [5,6]pyrimido[2,l-b]purin-4(5H)-one;

• 7,8-Dihydro-2,5-dimethyl-7(S)-(l-methylethyl)-3-(phenylmethyl)-3H- imidazo[2,l-b]purin-4(5H)-one;

• 7,8-Dihydro-2,5,7,7,8(R,S)-pentamethyl-3H-imidazo[2,l-b]purin-4(5H)-one;

• 5,6a(S),7,8,9,9a(R)-Hexahydro-2,5-dimethyl-3-(phenylmethyl)cyclopent- [4,5]imidazo[2,l-b]purin-4(3H)-one; • cis-6a,7,8,9,10,10a-Hexahydro-2,5-dimethyl-3-(phenylmethyl)-3H - benzimidazo[2, 1 -b]purin-4(5H)-one;

• 5',7^l-Dihydro-2',5'-dimethyl-3'-(phenylmethyl)spiro[cyclohexane-l,8-(8H)- imidazo[2,l-b]purin]-4-(3Η)-one;

• cis-S^a^δ^^a-Hexahydro^S-dimethyl-S-φhenylmethy^cyclohept- [6,7]imidazo[2, 1 -b]purin-4(3H)-one;

• cis-6a,7,8,9,10,10a-Hexahydro-5-methyl-2-ethyl-3-(phenylmethyl)-3H- benzimidazo[2, 1 -b]purin-4-(5H)-one;

• cis-5,6a(R), 7,8,9,9a(S)-Hexahydro-2,5-di-methylcyclopent[4,5]imidazo[2,l- b]purin-4(3H)-one;

• 2',5'-dimethyl-spiro{cyclopentane-l,7'-(8'H)-(3'H)-imidazo[2,l-b]purin}-4'(5'H)- one;

• 7,8-Dihydro-2,5-dimethyl-7(R)-(l-methylethyl)-3H-iniidazo[2,l-b]purin-4(5H)- one;

• 7,8-Dihydro-2,5,7,7-tetramethyl-3H-imidazo[2,l-b]purin-4(5H)-one;

• 7,8-Dihydro-2,5-di methyl-7(S)-(l-methylethyl)-3H-imidazo[2,l-b]purin-4(5H)- one; • 6a(R),7,8,9,10,10a(S)-Hexahydro-2,5-dimethyl-3H-benzimidazo[2,l-b]purin- 4(5H)-one;

• 5',7'-Dihydro-2^l,5'-dimethylspiro{cyclohexane-l,7-(8'H)-imidazo[2,l-b]purin}- 4'(3'H)-one;

• cis-SjβaJjδ^^a-Hexahydro-S-methyl-S-φhenylmethyOcyclopenta^jS]- imidazo[2, 1 -b]purin-4(3H)-thione;

• cis-5,6a,7,8,9,9a-Hexahydro-5-methyl-3-(2-naphthylmethyl)cyclopent[4,5]- imidazo[2,l-b]purin-4(3H)-one;

• 5,6a(R)-7,8,9,9a(S)-Hexahydro-2,5-dimethyl-3-(4-methoxyphenylmethyl)- cyclopent[4,5]imidazo[2,l-b]purin-4(3H)-one;

• cis-5,6a,7,8,9,9a-Hexahydro-2-methylthio-5-methyl-3-(Phenylmethyl)cyclopent- [4,5]imidazo[2, 1 -b]purin-4(3H)-one;

• cis-3,4,5,6a,7,8,9,9a-Octahydro-5-methyl-4-oxo-3-(phenylmethyl)cyclopent- [4,5]imidazo[2,l-b]purin-2-carboxylic acid;

• cis-5,6a,7,8,9,9a-Hexahydro-2-bromo-5-methyl-3- (phenylmethyl)cyclopent[4,5]imidazo[2, 1 -b]purin-4(3H)one; • cis-5,6a,7,8,9,9a-Hexahydro-2-(methylaminosulfonyl)-5-methyl-3- (phenylmethyl)cyclopent[4,5]imidazo[2,l-b]purin-4(3H)one;

• cis-l-Cyclopentyl-5,6a,7,8,9,9a-hexahydro-5-methylcyclopent[4,5]imidazo[2,l- b] purin-4-( 1 H)one ;

• cis-5,6a,7,8,9,9a-Hexahydro-3,5-bis-(phenylmethyl)cyclopent(4,5)imidazo(2,l- b)purin-4(3 H)one ;

• cis-6a,7,8,9,10,10a-Hexahydro-3,5-bis-(phenylmethyl)-3H-benzimidazo[2,l- b]purin-4(5H)one;

• cis-3-Cyclopentyl-5,6a,7,8,9,9a-hexahydro-5-methylcyclopent[4,5]imidazo(2,l- b)purin-4(3H)one;

• 5' -Methyl-3'-(phenylmethyl)spiro[cyclopentane-l,7-(8'H)-(3'H)imidazo[2,l- b]purin]-4-(5H)one;

• 2^l,5'-Dimethyl-3'-(phenylmethyl)-spiro[cyclopentane-l,7-(8Η)-(3H)imidazo[2,l- b] purin] -4-(5 Η)one ;

• 5'-Methyl-2^l-trifluoromethyl-3'-(phenylmethyl)spiro {cyclo-pentane- 1 ,7'(8'H)- (3'H)imidazo[2,l-b]purin}-4-(5Η)-one;

• 7,8-Dihydro-5,7,7-trimethyl-2-trifluoromethyl-3-(phenylmethyl)-3H-imidazo[2,l- b]purin-4(5H)-one;

• (+/-)-cis-5,6a,7,8,9,9a-Hexahydro-5-methyl-2-trifluoromethyl-3-(phenylmethyl)- cyclopent[4,5]imidazo[2, 1 -b]purin-4(3H)-one;

• (+/-)-6a,7,8,9,9a, 10,11,11 a-Octahydro-2,5-dimethyl-3-(phenylmethyl)-3H- pentaleno[6a',r:4,5]imidazo[2,l-b]purin-4(5H)-one;

• (+)-6a,7,8,9,9a,10,l 1,1 la-Octahydro-2,5-dimethyl-3-phenylmethyl-3H- pentaleno[6a',r:4,5]imidazo[2,l-b]purin-4(5H)-one;

• (-)-6a,7,8,9,9a, 10,11,1 la-Octahydro-2,5-dimethyl-3-phenylmethyl-3H- pentaleno[6a',r:4,5]Imidazo[2,l-b]purin-4(5H)-one; • (+/-) 6a,7,8,9,9a,10,l 1,1 la-Octahydro-2,5-dimethyl-3H-pentaleno[6a',l':4,5]- imidazo[2, 1 -b]purin-4(5H)-one;

• (+)-6a,7,8,9,9a, 10,11,1 la-Octahydro-2,5-dimethyl-3H-pentaleno[6a',l':4,5]- imidazo[2, 1 -b]purin-4(5H)-one;

• 6a,7,8,9, 10, 1 Oa, 11 , 12, 13, 13a-Decahydro-2,5-dimethyl-(3-phenylmethyl)- napth [ 1 , 8a-d] imidazo [2 , 1 -b] purin-4(5 H)one ;

• 7(R)-Cyclohexyl-7,8-dihydro-2,5-dimethyl-3H-imidazo[2,l-b]purin-4(5H)-one;

• 7(S)-Cyclohexyl-7,8-dihydro-2,5-dimethyl-3-(phenylmethyl)-3H-imidazo[2,l- b]purin-4(3H)-one;

• 7(S)-Cyclohexyl-7,8-dihydro-2,5-dimethyl-3H-imidazo[2,l-b]purin-4(5H)-one;

• 5,6a(R),7,8,9,9a(S)-Hexahydro-2,5-dimethyl-[3-(trimethylacetoxy)methyl]- cyclopent[4,5]imidazo[2,l-b]purin-4(3H)-one;

• 5,6a(R),7,8,9,9a(S)-Hexahydro-2,5-dimethyl-3-(4-pyridylmethyl)cyclopent- [4,5]imidazo[2, 1 -b]purin-4(3H)-one;

• 5,6a(R),7,8,9,9a(S)-Hexahydro-2,5-dimethyl-3-[2-(4-morpholinyl)- ethyl]cyclopent[4,5]imidazo[2,l-b]purin-4(3H)-one;

• cis-6a,7,8,9, 10,10a-Hexahydro-2,5,7-trimethyl-3-(phenylmethyl)-3H- benzimidazo[2, 1 -b]purin-4(5H)-one; • cis-5,6a,7,8,9,9a-Hexahydro-2,5,6a-trimethylcyclopent[4,5]imidazo[2,l-b]purin- 4(3H)-one; or

• cis-[6a,7,8,9,10,10a-Hexahydro-2,5,7-trimethyl-3H-benzimidazo[2,l-b]purin- 4(5H)-one].

in free or salt form.

16. The method according to claim 1, wherein the PDE 1 Inhibitors for use in the methods of treatment described herein are Compounds of Formula IXa or IXb

Formula IXa _ . _τv.

Formula IXb

or a pharmaceutically acceptable salt thereof, wherein,

q=O or 1;

R¹ is H, cycloalkyl, alkyl, R²³-alkyl- or R²⁶;

R^a, R^b and R^c are, independently of one another, each H, alkyl, cyoloalkyl, aryl, R²²-aryl- or R²⁴-alkyl-; or

R^a and R^b, together with the carbon to which they are both attached, form a 4- to 7- membered ring, and R^c is H or alkyl; or

R^a and R^c, together with the respective carbons to which they are attached, form a 4- to 7- membered ring, and R is H or alkyl; (i) X is a bond;

Y is aryl-alkyl or R 22 -aryl-alkyl-; and

R² is monohaloalkyl, polyhaloalkyl, provided that it is not trifluoromethyl, azido, cyano, oximino, cycloalkenyl, heteroaryl, R - heteroaryl- or R²⁷-alkyl-;

(ϋ) X is a bond;

Y is aryl-alkyl or R²²-aryl-alkyl-; and

(iϋ) X is — O — or — S — ;

Y is aryl-alkyl or R²²-aryl-alkyl-; and

R² is R²⁶, cycloalkyl cycloalkylalkyl, heterocycloalkyl, cycloalkenyl or R²⁶-alkyl-;

(iv) X is — O— or — S— ;

Y is aryl-alkyl or R²²-aryl-alkyl-; and

R² is alkyl, R²⁶, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, cycloalkenyl or R -alkyl-;

(v) X is —SO— or — SO₂-;

Y is aryl-alkyl or R²²-aryl-alkyl-; and

R² is alkyl, R²⁶, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, cycloalkenyl or R -alkyl-; (vi) X is — NR⁸-;

Y is aryl-alkyl or R²²-aryl-alkyl-; and

R² is (R²⁹)p-alkyl-, cycloalkyl, (R³⁰)_p-cycloalkyl-, cycloalkenyl, (R³⁰)_p- cycloalkenyl-, heterocycloalkyl or (R³⁰)_p-heterocycloalkyl-:

(vii) X is — NR⁸-;

Y is aryl-alkyl or R²²-aryl-alkyl-; and

R is alkyl, R , cycloalkyl, cycloalkylalkyl, heterocycloalkyl, cycloalkenyl or R³ '-alkyl-; or

(viii) X is — C≡C — ;

Y is aryl-alkyl or R²²-aryl-alkyl-; and

R² is alkyl, R²⁶, cycloalkyl, cycloalkylalkyl or R²³-alkyl-;

where,

R⁶ is H or R⁷;

R⁷ is alkyl, cycloalkyl or cycloalkylalkyl;

R⁸ is heterocycloalkyl or R⁶;

R²¹ is 1-6 substituents each independently selected from the group consisting of halo, hydroxy, alkoxy, phenoxy, phenyl, nitro, aminosulfonyl, cyano, monohaloalkyl, polyhaloalkyl, thiol, alkylthio, cyoloalkyl, cycloalkylalkyl, amino, alkylamino, acylamino, carboxyl, — C(O)OR³⁴, carboxamido, — OCF₃ and acyloxy;

R²² is 1-6 substituents each independently selected from the group consisting of alkyl and R²¹; R is cycloalkoxy aryloxy, alkylthio, arylthio, cycloalkyl or R ;

R²⁴ is cycloalkyl or R²⁶;

R is hydroxy, alkoxy, amino, monoalkylamino, dialkylamino or R ;

R²⁶ is aryl, R²²-aryl-, heteroaryl or R²²-heteroaryl-;

R²⁷ is cycloalkoxy, aryloxy, alkylthio, arylthio, heteroaryl, R²²-heteroaryl-, cycloalkyl, heterocycloalkyl, cycloalkenyl, cycloalkylamino or heterocycloalkylamino ;

R²⁸ is cycloalkylamino, heterocycloalkylamino or R²⁵;

R is alkoxy, cycloalkylamino, heterocycloalkylamino or R² ;

R³¹ is cycloalkyl or R²⁸;

R³⁴ is alkyl, aryl, aralkyl and heteroaryl; and

p is 1 to 4.

17. The method according to claim 1, wherein the PDE 1 Inhibitors for use in the methods of treatment described herein are Compounds of Formula X:

Formula X in free or a pharmaceutically acceptable salt thereof, wherein: Ri, R₂ and R₃ are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogeno, hydroxy, (di-lower alkyl)amino, 4- morpholinyl, 1 -pyrrolidinyl, 1-pyrrolyl, -CF₃, --OCF₃, phenyl and methoxyphenyl; or Ri and R₂ together are methylenedioxy; or Rj and R₂ together with the carbon atoms to which they are attached form a benzene ring; and

R^a is hydrogen and R^b and R^c, together with the carbon atoms to which they are attached, form a saturated ring of 5 carbons; or R^a is lower alkyl, R^b is hydrogen or lower alkyl, and R^c is hydrogen; or R^a, R^b and the carbon atom to which they are attached form a saturated ring of 5-7 carbons, and R^c is hydrogen; or R^a is hydrogen, and R^b, R^c and the carbon atoms to which they are attached form a tetrahydrofuran ring; or R^a and R^b, together with the carbon atom to which they are attached, and R^b and R^c, together with the carbon atoms to which they are attached, each form a saturated ring of 5-7 carbons.

18. The method of claim 1 , wherein the PDE 1 Inhibitors for use in the methods of treatment described herein are Compounds selected from:

salt form.

19. The method according to any of the preceding claims wherein the compound inhibits phosphodiesterase-mediated hydrolysis of cGMP or cAMP.

20. The method according to any of the preceding claims wherein the PDEl inhibitor is a PDElB inhibitor.

21. The method according to any of the preceding claims further comprising administering a compound or compounds selected from central nervous system stimulants, modafinil, antidepressants, and gamma hydroxybutyrate, to a patient in need thereof.

22. A PDE 1 Inhibitor as described in any of claims 2-18 for use in the treatment or prophylaxis of narcolepsy.

23. Use of a PDE 1 Inhibitor as described in any of claims 2-18 in the manufacture of a medicament for the treatment or prophylaxis of narcolepsy.

24. A pharmaceutical composition comprising a PDE 1 Inhibitor as described in any of claims 2-18, in free or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically acceptable diluent or carrier for use in the treatment or prophylaxis of narcolepsy.