HK1154007A - Organic compounds - Google Patents

Description

Organic compounds

This application claims priority from U.S. provisional application 61/012,040 filed on 6.12.2007, the contents of which are incorporated herein by reference.

Technical Field

The invention relates to 1-or 2-substituted (6 aR)^＊，9aS^＊) -3- (phenylamino) -5-6a, 7, 8, 9, 9 a-hexahydro-5-methyl-cyclopenta [4, 5]Imidazo [1, 2-a ]]Pyrazolo [4, 3-e]Pyrimidin-4 (1H or 2H) -one compounds, preferably 1-or 2-substituted (6aR, 9aS) (phenylamino) -5-6a, 7, 8, 9, 9 a-hexahydro-5-methyl-cyclopenta [4, 5] of the formula I]Imidazo [1, 2-a ]]Pyrazolo [4, 3-e]Pyrimidin-4 (1H or 2H) -one compounds, to processes for their preparation, to their use as medicaments and to pharmaceutical compositions comprising them. Of particular interest are novel compounds useful as phosphodiesterase 1(PDE1) inhibitors, e.g. for the treatment of diseases associated with disorders of the intracellular pathway of the dopamine D1 receptor, such as parkinson's disease, depression, narcolepsy, cognitive impairment (e.g. in schizophrenia) or disorders which can be ameliorated by the enhancement of the progesterone signaling (signaling) pathway, such as female dysfunction.

Background

A eleven family of Phosphodiesterases (PDEs) has been identified, but only a family I PDE, Ca, has been shown²⁺Calmodulin-dependent phosphodiesterase (CaM-PDE), mediating both calcium and cyclic nucleotide (e.g. cAMP and cGMP) signaling pathways. Three known CaM-PDE genes (PDE1A, PDE1B and PDE1C) are all expressed in central nervous system tissues. PDE1A was expressed throughout the brain, at higher levels in the CA1-CA3 layers of the hippocampus and cerebellum, and at striationsLow levels of expression in the body. PDE1A is also expressed in the lung and heart. PDE1B is expressed primarily in the striatum, dentate gyrus, olfactory tract and cerebellum, and its expression is associated with brain regions with high levels of dopaminergic innervation. Although PDE1B is expressed primarily in the central nervous system, it can be detected in the heart. PDE1C is expressed primarily in the olfactory epithelium, cerebellar granule cells, and the striatum. PDE1C is also expressed in cardiac and vascular smooth muscle.

Cyclic nucleotide phosphodiesterases reduce intracellular cAMP and cGMP signaling by hydrolyzing cyclic nucleotides to their respective inactive 5 ' -monophosphates (5 ' AMP and 5 ' GMP). CaM-PDEs play an important role in mediating signal transduction in brain cells, particularly in regions of the brain known as the basal ganglia and the striatum. For example, NMDA-type glutamate receptor activation and/or dopamine D2 receptor activation results in increased intracellular calcium concentrations, leading to activation of effectors such as calmodulin-dependent kinase ii (camkii) and calcium-dependent phosphatase and activation of CaM-PDE, resulting in a decrease in cAMP and cGMP. On the other hand, dopamine D1 receptor activation leads to activation of nucleotide cyclase, resulting in an increase in cAMP and cGMP. These cyclic nucleotides then 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 response element binding protein (CREB). Phosphorylated DARPP-32 then inhibits the activity of protein phosphatase-1 (PP-1), thereby increasing the phosphorylation state of substrate proteins, such as Progesterone Receptor (PR), and in turn inducing a physiological response. Studies in rodents indicate that cAMP and cGMP synthesis induced by activation of dopamine D1 and progesterone receptors enhances progesterone signaling associated with various physiological responses, including the lordotic response associated with mating receptivity in some rodents. See, Mani et al, Science (2000) 287: 1053, the contents of which are incorporated herein by reference.

Thus, CaM-PDEs are capable of affecting dopamine-regulated and other intracellular signaling pathways in the basal nucleus (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), DARPP-32, and endorphin intracellular signaling pathways.

Phosphodiesterase (PDE) activity, in particular phosphodiesterase 1(PDE1) activity, acts as a regulator of motor behaviour and learning and memory in brain tissue. PDE1 is a therapeutic target (preferably in the nervous system) that modulates intracellular signaling pathways including, but not limited to, the dopamine D1 receptor, the 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), endorphin intracellular signaling pathways, and progesterone signaling pathways. For example, inhibition of PDE1B acts to enhance the efficacy of dopamine D1 agonists by protecting cGMP and cAMP from degradation, and similarly inhibits the dopamine D2 receptor signaling pathway by inhibiting PDE1 activity. Long-term elevation of intracellular calcium levels is associated with cell death in a number of disorders, particularly neurodegenerative diseases such as alzheimer's, parkinson's and huntington's diseases, and circulatory disorders leading to stroke and myocardial infarction. Thus, PDE1 inhibitors may be useful in diseases characterized by reduced dopamine D1 receptor signaling activity, such as parkinson's disease, restless leg (restless leg) syndrome, depression, narcolepsy, and cognitive impairment. PDE1 inhibitors may also be useful in diseases that are alleviated by enhanced progesterone signaling, such as female sexual dysfunction.

Thus, there is a need for compounds that selectively inhibit PDE1 activity, particularly PDE1B activity.

Summary of The Invention

The present invention provides 1-or 2-substituted (6 aR) of formula Q in free, salt or prodrug form^＊，9aS^＊) -3- (phenylamino) -5-6a, 7, 8, 9, 9 a-hexahydro-5-methyl-cyclopenta [4, 5]Imidazo [1, 2-a ]]Pyrazolo [4, 3-e]Pyrimidin-4 (1H or 2H) -one compounds, preferably 1-or 2-substituted (6aR, 9aS) -3- (phenylamino) -5-6a, 7, 8, 9, 9 a-hexahydro-5-methyl-cyclopenta [4, 5]Imidazo [1, 2-a ]]Pyrazolo [4, 3-e]Pyrimidin-4 (1H or 2H) -ones

Formula Q

Wherein

(i) X is C_1-6Alkylene (e.g., methylene, ethylene, or prop-2-yn-1-yl);

(ii) y is a single bond, an alkynylene group (e.g., -C.ident.C-), an arylene group (e.g., phenylene), or a heteroarylene group (e.g., pyridylene);

(iii) z is H, aryl (e.g. phenyl), heteroaryl (e.g. pyridyl, e.g. pyridin-2-yl), halogen (e.g. F, Br, Cl), halo C_1-6Alkyl (e.g. trifluoromethyl), -C (O) -R¹、-N(R²)(R³) Or C optionally containing at least one atom selected from N or O_3-7Cycloalkyl (e.g., cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, or morpholinyl);

(iv)R¹is C_1-6Alkyl, halo C_1-6Alkyl, -OH or-OC_1-6Alkyl (e.g. -OCH)₃)；

(v)R²And R³Independently is H or C_1-6An alkyl group;

(vi)R⁴and R⁵Independently is H; c_1-6An alkyl group; or aryl (e.g., phenyl), optionally substituted with one or more of the following: halogen (e.g. fluorophenyl, e.g. 4-fluorophenyl), hydroxy (e.g. hydroxyphenyl, e.g. 4-hydroxyphenyl or 2-hydroxyphenyl) or C_1-6An alkoxy group;

(vii) wherein X, Y and Z are independently and optionally substituted with one or more halogens (e.g., F, Cl or Br), C_1-6Alkyl (e.g. methyl), halo C_1-6Alkyl (e.g. trifluoromethyl) substituted, for example Z is heteroaryl, for example pyridyl, substituted with one or more of the following groups: halogen (e.g. 6-fluoropyridin-2-yl, 5-fluoropyridin-2-yl, 6-fluoropyridin-2-yl, 3-fluoropyridin-2-yl, 4, 6-dichloropyridin-2-yl), halogeno C_1-6Alkyl (e.g. 5-trifluoromethylpyridin-2-yl) or C_1-6Alkyl (e.g. 5-methylpyridin-2-yl), or Z is aryl, e.g. phenyl, substituted with one or more halogens (e.g. 4-fluorophenyl).

In another embodiment, the invention provides a compound of formula Q, provided that when X is unsubstituted methylene, Y is phenylene or heteroarylene, and Z is aryl, heteroaryl, haloalkyl or cycloalkyl, then Z is substituted with at least one halo (e.g., fluoro, chloro, bromo) or alkyl (e.g., methyl, ethyl) group.

The present invention also provides a compound of formula Q as described above in free, salt or prodrug form as shown below:

1.1 formula Q, wherein X is C_1-6Alkylene (e.g. methylene, ethylene or prop-2-yn-1-yl), optionally substituted by one or more halogens (e.g. F, Cl or Br), C_1-6Alkyl (e.g. methyl), halo C_1-6Alkyl (e.g., trifluoromethyl) substitution;

1.2 formula Q or 1.1 wherein X is methylene or ethylene, optionally substituted with one or more halogens (e.g. F, Cl or Br), C_1-6Alkyl (e.g. methyl), halo C_1-6Alkyl (e.g., trifluoromethyl) substitution;

1.3 formula Q, 1.1 or 1.2 wherein X is methylene, optionally substituted with one or more halogens (e.g. F, Cl or Br), C_1-6Alkyl (e.g. methyl), halo C_1-6Alkyl (e.g., trifluoromethyl) substitution;

1.4 formula Q, 1.1, 1.2 or 1.3 wherein X is methylene substituted by bromine;

1.5 formula Q, 1.1, 1.2, 1.3 or 1.4 wherein X is ethylene;

1.6 formula Q or any of 1.1-1.5, wherein X is prop-2-yn-1-yl;

1.7 formula Q or any of formulae 1.1-1.6, wherein Y is a single bond, an arylene (e.g., phenylene), or heteroarylene (e.g., pyridylene), optionally substituted with one or more halogens (e.g., F, Cl or Br), C_1-6Alkyl (e.g. methyl), halo C_1-6Alkyl (e.g., trifluoromethyl) substitution;

1.8 formula Q or any of formulae 1.1-1.7 wherein Y is arylene (e.g., phenylene), optionally substituted with one or more halogens (e.g., F, Cl or Br), C_1-6Alkyl (e.g. methyl), halo C_1-6Alkyl (e.g., trifluoromethyl) substitution;

1.9 formula Q or any of formulae 1.1 to 1.8, wherein Y is phenylene optionally substituted with fluorine at the 3 or 5-position of the phenylene ring;

1.10 formula Q or any of 1.1-1.9, wherein Y is phenylene;

1.11 formula Q or any of formulae 1.1-1.7, wherein Y is a heteroarylene group (e.g., pyridylene), optionally substituted with one or more halogens (e.g., F, Cl or Br), C_1-6Alkyl (e.g. methyl), halo C_1-6Alkyl (e.g., trifluoromethyl) substitution;

1.12 formula Q or any of 1.1-1.7 wherein Y is a single bond;

1.13 formula Q or any of formulae 1.1-1.7, wherein Y is heteroaryl (e.g., pyridin-2-yl);

1.14 formula Q or any of 1.1-1.13, wherein Z is H, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, e.g., pyridin-2-yl), halo (e.g., F, Br, Cl), halo C_1-6Alkyl (e.g. trifluoromethyl), -C (O) -R¹、-N(R²)(R³) Or optionally containing at least one member selected from N or OC of an atom_3-7Cycloalkyl (e.g. cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, or morpholinyl), wherein said aryl and heteroaryl are optionally substituted with one or more halogen (e.g. F, Cl or Br), C_1-6Alkyl (e.g. methyl), halo C_1-6Alkyl (e.g., trifluoromethyl) substitution;

1.15 formula Q or any of formulae 1.1-1.14, wherein Z is C optionally containing at least one atom selected from N or O_3-7Cycloalkyl (e.g., cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, morpholinyl);

1.16 formula Q or any of 1.1-1.15, wherein Z is cyclopentyl;

1.17 formula Q or any of 1.1-1.15, wherein Z is tetrahydro-2H-pyran-4-yl;

1.18 formula Q or any of 1.1-1.14, wherein Z is heteroaryl (e.g., pyridyl, e.g., pyridin-2-yl), optionally substituted with one or more halogens (e.g., F, Cl or Br), C_1-6Alkyl (e.g. methyl), halo C_1-6Alkyl (e.g., trifluoromethyl) substitution;

1.19 formula Q or any of 1.1-1.14 or 1.18 wherein Z is pyridyl;

1.20 formula Q or any of 1.1-1.14 or 1.18, wherein Z is pyridin-2-yl;

1.21 formula Q or any of 1.1-1.14 or 1.18, wherein Z is 3-fluoropyridin-2-yl;

1.22 formula Q or any of 1.1-1.14 or 1.18, wherein Z is 4-fluoropyridin-2-yl;

1.23 formula Q or any of 1.1-1.14 or 1.18, wherein Z is 5-fluoropyridin-2-yl;

1.24 formula Q or any of 1.1-1.14 or 1.18, wherein Z is 6-fluoropyridin-2-yl;

1.25 formula Q or any of 1.1 to 1.14 or 1.18 wherein Z is optionally substituted with one or more halo C_1-6Alkyl-substituted heteroaryl groups such as pyridyl (e.g., 5-triFluoromethylpyridin-2-yl;

1.26 formula Q or any of 1.1-1.14 or 1.18, wherein Z is 5-trifluoromethylpyridin-2-yl;

1.27 formula Q or any of 1.1-1.14 or 1.18 wherein Z is optionally substituted with one or more C_1-6Alkyl-substituted heteroaryl such as pyridyl (e.g., 5-methylpyridin-2-yl);

1.28 formula Q or any of 1.1-1.14 or 1.18, wherein Z is 5-methylpyridin-2-yl;

1.29 formula Q or any of 1.1-1.14, wherein Z is halo C_1-6Alkyl (e.g., trifluoromethyl);

1.30 formula Q or any of 1.1-1.14 or 1.29, wherein Z is trifluoromethyl;

1.31 formula Q or any of formulae 1.1-1.14, wherein Z is aryl, for example phenyl, optionally substituted with one or more of the following groups: halogen (e.g. 4-fluorophenyl), halogeno C_1-6Alkyl or C_1-6An alkyl group;

1.32 formula Q or any of formulae 1.1-1.14, wherein Z is aryl (e.g. phenyl), optionally substituted with one or more of the following groups: halogen (e.g. 4-fluorophenyl), halogeno C_1-6Alkyl or C_1-6An alkyl group;

1.33 formula Q or any of 1.1-1.14 or 1.36 wherein Z is phenyl;

1.34 formula Q or any of 1.1-1.14 or 1.31, wherein Z is 4-fluorophenyl;

1.35 formula Q or any of 1.1-1.14, wherein Z is-C (O) -R¹And R is¹Is C_1-6Alkyl (e.g. methyl), halo C_1-6Alkyl (e.g. trifluoromethyl), -OH or-OC_1-6Alkyl (e.g. -OCH)₃)；

1.36 formula Q or any of 1.1-1.14 or 1.29, wherein Z is-C (O) -R¹And R is¹Is methyl;

1.37 formula Q or any of 1.1-1.14 or 1.29, wherein Z is-C (O) -R¹And R is¹Is trifluoromethyl;

1.38 formula Q or any of 1.1-1.14 or 1.29, wherein Z is-C (O) -R¹And R is¹is-OH;

1.39 of formula Q or any of 1.1-1.14 or 1.29, wherein Z is-C (O) -R¹And R is¹is-OC_1-6Alkyl (e.g. -OCH)₃)；

1.40 formula Q or any of 1.1-1.14 or 1.29, wherein Z is-C (O) -R¹And R is¹is-OCH₃；

1.41 formula Q or any of 1.1-1.14, wherein Z is-N (R)²)(R³)；

1.42 formula Q or any of 1.1-1.14 or 1.32, wherein Z is-N (R)²)(R³) Wherein R is²And R³Is methyl;

1.43 formula Q or any of 1.1-1.42, wherein R is⁴And R⁵Independently is H; c_1-6An alkyl group; or aryl (e.g., phenyl), optionally substituted with one or more of the following groups: halogen (e.g. fluorophenyl, e.g. 4-fluorophenyl), hydroxy (e.g. hydroxyphenyl, e.g. 4-hydroxyphenyl or 2-hydroxyphenyl) or C_1-6An alkoxy group;

1.44 formula Q or any of 1.1-1.42, wherein R is⁴Or R⁵Is H;

1.45 formula Q or any of 1.1-1.42, wherein R is⁴Or R⁵Is aryl (e.g., phenyl), optionally substituted with one or more of the following groups: halogen (e.g. fluorophenyl, e.g. 4-fluorophenyl), hydroxy (e.g. hydroxyphenyl, e.g. 4-hydroxyphenyl or 2-hydroxyphenyl) or C_1-6An alkoxy group;

1.46 formula Q or any of 1.1-1.42, wherein R is⁴Or R⁵Is aryl (e.g., phenyl), optionally substituted with one or more of the following groups: halogen element(e.g. fluorophenyl, e.g. 4-fluorophenyl), hydroxy (e.g. hydroxyphenyl, e.g. 4-hydroxyphenyl or 2-hydroxyphenyl) or C_1-6An alkoxy group;

1.47 formula Q or any of 1.1-1.42, wherein R is⁴Or R⁵Is phenyl;

1.48 formula Q or any of 1.1-1.42, wherein R is⁴Or R⁵Is phenyl substituted by fluorine (e.g. 4-fluorophenyl);

1.49 formula Q or any of 1.1-1.42, wherein R is⁴Or R⁵Is phenyl, which is substituted with: hydroxy (e.g. 4-hydroxyphenyl) or C_1-6An alkoxy group;

1.50 any of the foregoing formulae, wherein-X-Y-Z is selected from the group consisting of 4- (5-fluoropyridin-2-yl) benzyl, 4- (6-fluoropyridin-2-yl) benzyl, 4- (3-fluoropyridin-2-yl) benzyl, 4- (6-trifluoromethylpyridin-2-yl) benzyl, 4- (4-fluoropyridin-2-yl) benzyl, 4- (5-methylpyridin-2-yl) benzyl, 4- (4-fluorophenyl) benzyl, biphenyl-4-ylmethyl, 4-trifluoromethylphenyl, 4- (4, 6-dichloropyridin-2-yl) benzyl, 4- (pyridin-2-yl) benzyl and 4- (carboxy) benzyl, and, 4- (methylcarboxyl) benzyl;

1.51 of any of the preceding formulae, wherein R₄Is H and R₅Is phenyl;

1.52 formula Q or any of 1.1-1.51, wherein R is₄Is H and R₅Is 4-fluorophenyl or 4-hydroxyphenyl;

1.53 any one of the foregoing formulae, wherein the compound is selected from:

1.54 any one of the foregoing formulae, wherein the compound is selected from:

1.55 any one of the foregoing formulae, wherein the compound is selected from:

1.56 any of the foregoing, wherein the compound inhibits phosphodiesterase-mediated (e.g., PDE 1-mediated, especially PDE 1B-mediated) hydrolysis of cGMP, e.g., having an IC of less than 1 μ M, preferably less than 200nM, more preferably less than 100nM, more preferably less than 50nM, even more preferably less than 25nM in a fixed metal affinity particle reagent PDE assay as described in example 15₅₀。

In another embodiment, the invention provides a compound of any one of formulae 1.1-1.56, with the proviso that when X is unsubstituted methylene, Y is phenylene or heteroarylene, and Z is aryl, heteroaryl, haloalkyl or cycloalkyl, then Z is substituted with at least one halo (e.g., fluoro, chloro, bromo) or alkyl (e.g., methyl, ethyl) group.

The invention also provides compounds of formula I, including enantiomers, diastereomers and racemates thereof, in free, salt or prodrug form,

formula I

Wherein

(i) X is C_1-4Alkylene (e.g., methylene, ethylene, or prop-2-yn-1-yl);

(ii) y is a single bond, an alkynylene group (e.g., -C.ident.C-), an arylene group (e.g., phenylene), or a heteroarylene group (e.g., pyridylene);

(iii) z is H, aryl (e.g. phenyl), heteroaryl (e.g. pyridin-2-yl), halogen (e.g. F, Br, Cl), halo C_1-4Alkyl (e.g. trifluoromethyl), -C (O) -R¹、-N(R²)(R³) Or optionally contain at leastC of an atom selected from N or O_3-7Cycloalkyl (e.g., cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, or morpholinyl);

(iv)R¹is C_1-4Alkyl, halo C_1-4An alkyl group;

(v)R²and R³Independently is H or C_1-4An alkyl group, a carboxyl group,

(vi) wherein X, Y and Z are independently and optionally substituted with halogen (e.g., F, Cl or Br), for example Z is pyridin-2-yl (e.g., 6-fluoro-pyridin-2-yl) substituted with fluorine, with the proviso that when X is unsubstituted methylene, Y is phenylene or heteroarylene, and Z is aryl, heteroaryl, haloalkyl or cycloalkyl, then Z is substituted with at least one halogen (e.g., fluorine, chlorine, bromine) or alkyl (e.g., methyl, ethyl) group.

Preferably, (6aR, 9aS) -3- (phenylamino) -5-6a, 7, 8, 9, 9 a-hexahydro-5-methyl-cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (2H) -one compounds are 2-substituted, e.g. -X-Y-Z is substituted in the 2-position of the "pyrazolo (pyrazolo)" ring of formula I, e.g.:

formula II

More preferably, when Y is phenylene, Z is substituted at the para-position of the phenyl ring.

The present invention also provides compounds of formula I, including enantiomers, diastereomers and racemates thereof, in free, salt or prodrug form, as follows:

1.57 formula I, wherein X is C_1-4Alkylene (e.g., methylene, ethylene, or prop-2-yn-1-yl), optionally substituted with halo;

1.58 formula I or 1.57 wherein X is methylene or ethylene, optionally substituted with halogen;

1.59 formula I, 1.57 or 1.58 wherein X is methylene optionally substituted by halogen;

1.60 formula I, 1.57, 1.58 or 1.59 wherein X is methylene substituted with bromine;

1.61 formula I, 1.57, 1.58, 1.59, or 1.60 wherein X is ethylene;

1.62 formula I or any of 1.57-1.61, wherein X is C₁Prop-2-yn-1-yl;

1.63 formula I or any of formulae 1.57-1.62, wherein Y is a single bond, an arylene (e.g., phenylene), or heteroarylene (e.g., pyridylene), optionally substituted with halogen;

1.64 formula I or any of 1.57-1.63, wherein Y is arylene (e.g., phenylene), optionally substituted with halogen;

1.65 formula I or any of formulae 1.57-1.64 wherein Y is phenylene optionally substituted with fluorine at the 3 or 5-position of the phenylene ring;

1.66 formula I or any of 1.57-1.65, wherein Y is phenylene;

1.67 of formula I or any of 1.57 to 1.63, wherein Y is heteroarylene (e.g., pyridylene), optionally substituted with halogen;

1.68 formula I or any of 1.57-1.63, wherein Y is a single bond;

1.69 formula I or any of 1.57-1.63, wherein Y is heteroaryl (e.g., pyridin-2-yl);

1.70 formula I or any of 1.57-1.69, wherein Z is H, aryl (e.g., phenyl), heteroaryl (e.g., pyridin-2-yl), halo (e.g., F, Br, Cl), halo C_1-4Alkyl (e.g. trifluoromethyl), -C (O) -R¹、-N(R²)(R³) Or C optionally containing at least one atom selected from N or O_3-7Cycloalkyl (e.g., cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, or morpholinyl), optionally substituted with halogen;

1.71 formula I or any of formulae 1.57-1.70 wherein Z is C optionally containing at least one atom selected from N or O_3-7Cycloalkyl (e.g., cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, morpholinyl);

1.72 formula I or any of 1.57-1.71 wherein Z is cyclopentyl;

1.73 formula I or any of 1.57-1.71, wherein Z is tetrahydro-2H-pyran-4-yl;

1.74 formula I or any of 1.57-1.70, wherein Z is heteroaryl (e.g., pyridin-2-yl), optionally substituted with halogen;

1.75 any one of formula I or 1.57-1.70 or 1.74 wherein Z is pyridin-2-yl;

1.76 of formula I or any of 1.57 to 1.70 or 1.74, wherein Z is 5-fluoro-pyridin-2-yl or 6-fluoro-pyridin-2-yl;

1.77 formula I or any of 1.57-1.70, wherein Z is halo C_1-4Alkyl (e.g., trifluoromethyl);

1.78 any one of formula I or 1.57-1.70 or 1.77 wherein Z is trifluoromethyl;

1.79 formula I or any of 1.57-1.70, wherein Z is-C (O) -R¹And R is¹Is C_1-4Alkyl (e.g. methyl) or halo C_1-4Alkyl (e.g., trifluoromethyl);

1.80 of formula I or any of 1.57-1.70 or 1.79, wherein Z is-C (O) -R¹And R is¹Is methyl;

1.81 of formula I or any of 1.57-1.70 or 1.79, wherein Z is-C (O) -R¹And R is¹Is trifluoromethyl;

1.82 formula I or any of formulae 1.57-1.70, wherein Z is aryl (e.g., phenyl), optionally substituted with halogen (e.g., fluoro);

1.83 formula I or any of 1.57-1.70 or 1.82 wherein Z is phenyl;

1.84 formula I or any of 1.57-1.70, wherein Z is-N (R)²)(R³)；

1.85 formula I or any of 1.57-1.70 or 1.84, wherein Z is-N (R)²)(R³) Wherein R is²And R³Is methyl;

1.86 of any of the foregoing, wherein the compound is selected from:

1.87 of any of the foregoing, wherein the compound inhibits phosphodiesterase-mediated (e.g., PDE 1-mediated, especially PDE 1B-mediated) hydrolysis of cGMP, e.g., having an IC of less than 1 μ M, preferably less than 25nM, in a fixed metal affinity particle reagent PDE assay as described in example 15₅₀，

With the proviso that when X is unsubstituted methylene, Y is phenylene or heteroarylene, and Z is aryl, heteroaryl, haloalkyl or cycloalkyl, then Z is substituted with at least one halogen (e.g., fluorine, chlorine, bromine) or alkyl (e.g., methyl, ethyl) group.

Preferably, the compounds of the invention are in free, salt or prodrug form:

in another aspect of the invention, there is provided a compound of formula (X) in free, salt or prodrug form:

formula (X)

Wherein

(i)R₁Is H or C_1-6Alkyl (e.g., methyl);

(ii)R₄is H or C_1-6Alkyl and R₂And R₃Independently is H or C optionally substituted by halogen or hydroxy_1-6Alkyl (e.g. R)₂And R₃Are both methyl, or R₂Is H and R₃Is ethyl, isopropyl or hydroxyethyl), aryl, heteroaryl, (optionally hetero) arylalkoxy or (optionally hetero) aryl C_1-6An alkyl group;

or

R₂Is H and R₃And R₄Together form a di, tri or tetramethylene bridge (preferably wherein R is₃And R₄Together having cis configuration, e.g. carrying R₃And R₄Have R and S configurations, respectively);

(iii)R₅is a substituted heteroaryl group C_1-6Alkyl radicals, e.g. substituted by C_1-6Haloalkyl substitution;

R₅is-D-E-F, wherein:

d is C_1-6Alkylene (e.g., methylene, ethylene, or prop-2-yn-1-yl);

e is a single bond, an alkynylene group (e.g., -C.ident.C-), an arylene group (e.g., phenylene), or a heteroarylene group (e.g., pyridylene);

f is H, aryl (e.g. phenyl), heteroaryl (e.g. pyridyl, e.g. pyridin-2-yl), halogen (e.g. F, Br, Cl), halo C_1-6Alkyl (e.g. trifluoromethyl), -C (O) -R₁₅、-N(R₁₆)(R₁₇) Or optionally at least oneC of an atom selected from N or O_3-7Cycloalkyl (e.g., cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, or morpholinyl);

wherein D, E and F are independently and optionally substituted with one or more halogens (e.g., F, Cl or Br), C_1-6Alkyl (e.g. methyl), halo C_1-6Alkyl (e.g. trifluoromethyl) substituted, for example Z is heteroaryl, for example pyridyl, substituted with one or more of the following groups: halogen (e.g. 6-fluoropyridin-2-yl, 5-fluoropyridin-2-yl, 6-fluoropyridin-2-yl, 3-fluoropyridin-2-yl, 4, 6-dichloropyridin-2-yl), halogeno C_1-6Alkyl (e.g. 5-trifluoromethylpyridin-2-yl) or C_1-6Alkyl (e.g., 5-methylpyridin-2-yl); or Z is aryl, such as phenyl, substituted with one or more halogens (e.g., 4-fluorophenyl);

or

R₅Is attached to one of the nitrogen atoms of the "pyrazolo" moiety of formula (X) and is a group of formula A

Formula A

Wherein X, Y and Z are independently N or C, and R₈、R₉、R₁₁And R₁₂Independently is H or halogen (e.g., Cl or F), and R₁₀Is halogen, alkyl, cycloalkyl, haloalkyl (e.g. trifluoromethyl), aryl (e.g. phenyl), heteroaryl (e.g. pyridyl (e.g. pyridin-2-yl) or thiadiazolyl (e.g. 1, 2, 3-thiadiazol-4-yl)), oxadiazolyl, triazolyl, tetrazolyl, arylcarbonyl (e.g. benzoyl), alkylsulfonyl (e.g. methylsulfonyl), heteroarylcarbonyl or alkoxycarbonyl; provided that when X, Y or Z is nitrogen, R₈、R₉Or R₁₀Are respectively absent; and is

(iv)R₆Is H, alkyl, aryl, heteroaryl, arylalkyl(e.g., benzyl), arylamino (e.g., phenylamino), heteroarylamino, N-dialkylamino, N-diarylamino, or N-aryl-N- (arylalkyl) amino (e.g., N-phenyl-N- (1, 1' -biphenyl-4-ylmethyl) amino);

or

R₆is-N (R)₁₈)(R₁₉) Wherein R is₁₈And R₁₉Independently is H, C_1-6Alkyl or aryl (e.g. phenyl), wherein the aryl is optionally substituted with one or more of the following groups: halo (e.g. fluorophenyl, e.g. 4-fluorophenyl) or hydroxy (e.g. hydroxyphenyl, e.g. 4-hydroxyphenyl or 2-hydroxyphenyl);

(v) n is 0 or 1;

(vi) when n is 1, A is-C (R)₁₃R₁₄)-；

(vii) Wherein R is₁₃And R₁₄Independently is H or C_1-6Alkyl, aryl, heteroaryl, (optionally hetero) arylalkoxy or (optionally hetero) arylalkyl;

(viii)R₁₅is C_1-6Alkyl, halo C_1-6Alkyl, -OH or-OC_1-6Alkyl (e.g. -OCH)₃)；

(ix)R₁₆And R₁₇Independently is H or C_1-6An alkyl group.

In another embodiment of this aspect of the invention, the compound of formula (X) is in free, salt or prodrug form:

more preferably, the compounds of the present invention are selected from formula 1.54 in free, salt or prodrug form. More preferably, the compounds of the present invention are selected from formula 1.55 in free, salt or prodrug form.

The following terms in the text have the following meanings, if not otherwise stated or clarified in the context:

(a) "alkyl" as used herein is a saturated or unsaturated hydrocarbon group, preferably saturated, preferably containing 1 to 6 carbon atoms, which may be straight or branched chain and may be optionally mono-, di-or tri-substituted, for example by halogen (e.g. chlorine or fluorine), hydroxy or hydroxy.

(b) "cycloalkyl" as used herein is a saturated or unsaturated non-aromatic hydrocarbon radical, preferably saturated, preferably containing from 3 to 9 carbon atoms, wherein at least some of the carbon atoms form a non-aromatic mono-or bicyclic or bridged cyclic structure, and which may be optionally substituted, for example, by halogen (e.g., chlorine or fluorine), hydroxy or carboxy.

(c) As used herein, "aryl" is a mono-or bicyclic aromatic hydrocarbon, preferably phenyl, optionally substituted with, for example, alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloalkyl (e.g., trifluoromethyl), hydroxy, carboxy, or other aryl or heteroaryl groups (e.g., biphenyl or pyridylphenyl).

(d) As used herein, "heteroaryl" is an aromatic group in which one or more of the atoms making up the aromatic ring is sulfur or nitrogen instead of carbon, such as pyridyl or thiadiazolyl, which may be optionally substituted, for example, with alkyl, halogen, haloalkyl, hydroxy or carboxy.

(e) For ease of reference, unless otherwise indicated, the atoms on the pyrazolo-pyrimidine parent nucleus of the compounds of the invention are numbered according to the numbering described in formula I.

(f) Wherein Y is phenylene, numbered as follows:

(g) it should be noted that when a substituent is an "eneA substituent means bridging or linking with two other substituents. Thus, methylene means-CH₂-, and phenylene means-C₆H₄-, and arylenealkyl means-C₆H₄-CH₂-or-CH₂-C₆H₄-。

The compounds of the invention may exist in free or salt form, for example as acid addition salts. In this specification, unless otherwise indicated, terms such as "compounds of the invention" will be understood to include all novel compounds disclosed herein, for example 1-or 2-substituted (6 aR)^＊，9aS^＊) -3- (phenylamino) -5-6a, 7, 8, 9, 9 a-hexahydro-5-methyl-cyclopenta [4, 5]Imidazo [1, 2-a ]]Pyrazolo [4, 3-e]Pyrimidin-4 (1H or 2H) -one compounds, preferably 1-or 2-substituted (6aR, 9aS) (phenylamino) -5-6a, 7, 8, 9, 9 a-hexahydro-5-methyl-cyclopenta [4, 5]Imidazo [1, 2-a ]]Pyrazolo [4, 3-e]A pyrimidin-4 (1H or 2H) -one, a compound of formula Q, e.g. any one of formulae 1.1 to 1.56, a compound of formula (X), or a compound of formula I, e.g. any one of formulae 1.57 to 1.87, any of these compounds in any form, e.g. in free or acid addition salt form, or in base addition salt form when the compounds contain an acidic substituent. The compounds of the invention are intended for use as medicaments, and pharmaceutically acceptable salts are therefore preferred. Pharmaceutically unsuitable salts may be used, for example, to isolate or purify the free compounds of the invention or their pharmaceutically acceptable salts and are therefore also included in the invention.

In some cases the compounds of the invention may also exist in prodrug form. Prodrug forms are compounds that are converted in vivo to the compounds of the invention. For example, when the compounds of the present invention contain hydroxy or carboxy substituents, these substituents may form physiologically hydrolyzable and acceptable esters. As used herein, "physiologically hydrolyzable and acceptable ester" means an ester of a compound of the present invention that can hydrolyze under physiological conditions to produce an acid (in the case of a compound of the present invention containing a hydroxy substituent) or an alcohol (in the case of a compound of the present invention containing a carboxy substituent), which are themselves physiologically tolerable at the dosage administered. As will be appreciated, the term thus includes conventional pharmaceutically acceptable prodrug forms.

The invention also provides methods of making and using the compounds of the invention for treating diseases and disorders listed below, particularly diseases characterized by decreased dopamine D1 receptor signaling activity, such as parkinson's disease, Tourette's (Tourette's) syndrome, autism, fragile X syndrome, ADHD, restless leg syndrome, depression, cognitive impairment in schizophrenia, narcolepsy, and diseases that can be alleviated by enhanced progesterone signaling, such as female sexual dysfunction.

Detailed Description

Process for the preparation of the compounds of the invention

Compounds of the invention, e.g. (6 aR)^＊，9aS^＊) -3- (phenylamino) -5-6a, 7, 8, 9, 9 a-hexahydro-5-methyl-cyclopenta [4, 5]Imidazo [1, 2-a ]]Pyrazolo [4, 3-e]Pyrimidin-4 (1H or 2H) -one compounds, preferably 1-or 2-substituted (6aR, 9aS) (phenylamino) -5-6a, 7, 8, 9, 9 a-hexahydro-5-methyl-cyclopenta [4, 5]Imidazo [1, 2-a ]]Pyrazolo [4, 3-e]Pyrimidin-4 (1H or 2H) -one, a compound of any one of formulas Q or I, e.g., 1.1-., 56 or 1.5701.87, or a compound of formula (X) and their pharmaceutically acceptable salts can be prepared using the methods described and exemplified herein, as well as by methods analogous thereto and by methods known in the chemical arts. Such methods include, but are not limited to, those described below. If not commercially available, starting materials for these processes can be prepared by methods selected from the chemical arts using techniques similar or analogous to the synthesis of known compounds. All references cited herein are incorporated by reference in their entirety.

The compounds of the present invention include their enantiomers, diastereomers and racemates as well as their polymorphs, hydrates, solvates and complexes. Some individual compounds within the scope of the present invention may contain double bonds. The description of double bonds in the present invention is meant to include both E and Z isomers of double bonds. In addition, some compounds within the scope of the present invention may contain one or more asymmetric centers. The present invention includes the use of any optically pure stereoisomer as well as any combination of stereoisomers.

Melting points are uncorrected and (dec) indicates decomposition. Temperatures are given in degrees Celsius (. degree. C.); unless otherwise stated, the operation is carried out at room or ambient temperature, i.e.at 18 to 25 ℃. Chromatography means silica gel flash chromatography; thin Layer Chromatography (TLC) was performed on silica gel plates. NMR data are given as 6 values of the main characteristic (diagnostic) proton in parts per million (ppm) relative to Tetramethylsilane (TMS) as internal standard. Conventional abbreviations for signal shape are used. Coupling constants (J) are in Hz. For Mass Spectrometry (MS), the lowest mass dominant ion of the reporter is in the case where isotopic fragmentation results in multiple mass spectral peaks. The solvent mixture composition is given in volume percent or volume ratio. When the NMR spectrum is complex, only characteristic signals are reported.

Terms and abbreviations:

BuLi ═ n-butyl lithium

Bu^tOH ═ tert-butyl alcohol (tbi),

CAN-ammonium cerium (IV) nitrate,

DIPEA is diisopropylethylamine (diisopropylethylamine),

DMF ═ N, N-dimethylformamide,

DMSO is added to the aqueous solution of DMSO ═ dimethyl sulfoxide,

Et₂o is an ether of ethyl or a salt of ethyl,

the reaction product of EtOAc ═ ethyl acetate,

equiv. equivalent to the equivalent of the total weight of the product,

h is equal to the hour, and h is equal to the hour,

HPLC (high performance liquid chromatography) is carried out,

LDA ═ lithium diisopropylamide

MeOH, which is equal to methanol, was added to the reaction solution,

NBS ═ N-bromosuccinimide

NCS ═ N-chlorosuccinimide

NaHCO₃The reaction product of sodium bicarbonate and sodium bicarbonate,

NH₄OH ═ ammonium hydroxide, the product of the reaction,

Pd₂(dba)₃tris [ dibenzylidene acetone [ ]]Dipalladium (0)

PMB is a para-methoxybenzyl group,

POCl₃the compound is phosphorus oxychloride (phosphorus oxychloride),

SOCl₂which is the reaction product of thionyl chloride and thionyl chloride,

TFA is a compound of trifluoroacetic acid,

THF ═ tetrahydrofuran.

The synthesis of the present invention is illustrated below. Unless otherwise indicated, the meaning of the R group is as defined above in formula I.

In one aspect of the invention, the intermediate compound of formula IIb may be synthesized by reacting a compound of formula IIa with a mixture of dicarboxylic acid, acetic anhydride and acetic acid under heating for about 3 hours, followed by cooling:

wherein R is¹Is methyl.

The intermediate IIc can be prepared, for example, by reacting IIb compounds with, for example, chlorinated compounds such as POCl₃Reacted (sometimes with a small amount of water) and heated for about 4 hours and then cooled,

the intermediate IId can be prepared by reacting IIc compounds with P, for example, in a solvent such as DMF¹L and a base such as K₂CO₃At room temperature or with heating to form:

wherein P is¹Is a protecting group [ e.g. p-methoxybenzyl group (PMB)](ii) a L is a leaving group such as a halogen, mesylate (mesylate) or tosylate (tosylate).

The intermediate IIe can be prepared by reacting the IId compound with hydrazine or hydrazine hydrate in a solvent such as methanol and refluxing for about 4 hours, followed by cooling:

the intermediate IIf can be synthesized by reacting IIc compound with hydrazine or hydrazine hydrate in a solvent such as methoxyethanol and refluxing for about 30min, followed by cooling:

intermediate IIg (wherein R¹³Phenyl) can be synthesized by reacting the IIe compound with, for example, isothiocyanate or an aryl isocyanate in a solvent such as DMF and heating at 110 ℃ for about 2 days, followed by cooling:

intermediate IIh the protecting group P can be removed from the IIg compound by using an appropriate method¹To synthesize. For example, if P¹Is a p-methoxybenzyl group, AlCl can be used at room temperature₃Or it is removed with TFA under heating.

The intermediate IIh can also be prepared directly from the IIf compound using an analogous method, but in relatively low yields.

Intermediates II-I can be prepared, for example, by reacting IIh compounds with, for example, chlorinated compounds such as POCl₃And reacting to prepare the compound. The reaction can be carried out at atmospheric pressure and reflux for about 2 days, or heated in a sealed bottle using a microwave device at 150-200 ℃ for about 10 min.

The intermediate IIJ can be prepared by reacting the II-I compound with an aminoalcohol such as (1R, 2R) -1-amino-2-cyclopentanol in a solvent such as DMF. The reaction may be heated overnight and then cooled. The reaction mixture can be purified by chromatography to afford compound IIJ:

intermediate IIK may be formed as follows: by reacting IIJ compounds with, for example, dehydrating/halogenating agentsSuch as SOCl₂In a solvent such as CH₂Cl₂The reaction is allowed to proceed at room temperature overnight or heated at 35 ℃ for about 4 hours, followed by cooling to obtain the cyclized compound (IIK).

Compounds Ia and Ib can be prepared by reacting IIk compounds with, for example, Z-Y-X-L in a solvent such as DMF and a base such as K₂CO₃At room temperature or with heating to form:

wherein all substituents are as defined above; l is a leaving group such as a halogen, a methanesulfonate group or a toluenesulfonate group.

X-Y-Z can also be introduced earlier, for example by reacting IIg with Z-Y-X-L, followed by analogous procedures as described above to form compounds Ia and Ib, provided that Z-Y-X is in P¹The deprotection step is not cracked.

A third synthetic route was also developed for the preparation of compound Ia.

The intermediate IVa can be prepared, for example, by reacting IIe compounds with POCl₃And DMF to form:

wherein R is¹Is methyl.

Intermediate IVb can be prepared by reacting a compound of IVa with, for example, Z-Y-X-L in a solvent such as DMF and a base such as K₂CO₃At room temperature or with heating to form:

intermediate IVc can be prepared from IVb compounds by removing the protecting group P by suitable methods¹To synthesize. For example, if P¹Is a PMB group, it CAN be removed at room temperature using CAN:

intermediate IVd can be prepared as follows: reacting IVc compounds with, for example, chlorinated compounds, e.g. POCl₃Reacting and refluxing for about 2 days, or heating for about 10min at 150-200 ℃ in a sealed bottle by using a microwave device, and then cooling:

intermediate IVe may be formed by reacting the compound of IVd with an amino alcohol under basic conditions in a solvent such as DMF and heating overnight, followed by cooling:

compound IVf can be prepared by reacting the IVe compound with, for example, dehydrating/halogenating agents such as SOCl₂In a solvent such as CH₂Cl₂At room temperature overnight or heated at 35 ℃ for about 4 hours and then cooled.

Compound IVg can be formed by reacting an IVf compound with, for example, a halogenating agent such as NCS and a base such as LDA in a solvent such as THF at low temperature for several hours.

Compounds Ia can be prepared by reacting IVg compounds with, for example, amines such as aniline in the presence of a catalyst such as Pd₂(dba)₃In the presence of a solvent such as dioxane at 100 deg.C overnight.

Accordingly, the present invention provides a process for the preparation of a compound of formula I, which comprises, for example

(i) Reacting (6aR, 9aS) -3- (phenylamino) -5-6a, 7, 8, 9, 9 a-hexahydro-5-methyl-cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (1H or 2H) -one with a compound of formula Z-Y-X-L where L is a leaving group such aS halogen, a mesylate or tosylate and X, Y and Z are aS defined in formula I above, for example under basic conditions, for example where (6aR, 9aS) -3- (phenylamino) -5-6a, 7, 8, 9, 9 a-hexahydro-5-methyl-cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (2H) -ones are compounds of formula IIK:

or

(ii) For example, cyclization of a compound of formula V using a dehydrating/halogenating agent such as thionyl chloride

Wherein X, Y and Z are as defined above for formula I;

and isolating the compound of the invention thus obtained.

Similarly, the present invention also provides a process for preparing a compound of formula Q, which comprises, for example:

(i) reacting (6aR, 9aS) -3- (phenylamino) -5-6a, 7, 8, 9, 9 a-hexahydro-5-methyl-cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (1H or 2H) -one with a compound of formula Z-Y-X-L where L is a leaving group such aS halogen, a mesylate or tosylate and X, Y and Z are aS defined above for formula Q, for example under basic conditions, for example where (6aR, 9aS) -3- (phenylamino) -5-6a, 7, 8, 9, 9 a-hexahydro-5-methyl-cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (2H) -ones are compounds of formula QK:

or

(ii) For example, cyclization of compounds of formula QV using dehydrating/halogenating agents such as thionyl chloride

Wherein X, Y and Z are as defined above for formula Q.

Methods of Using the Compounds of the invention

The compounds of the invention are useful in the treatment of diseases characterized by the disruption or impairment of cAMP and cGMP mediated pathways, such as that caused by increased expression of PDE1 or decreased expression of cAMP and cGMP, which in turn is due to the inhibition or decreased levels of inducers of cyclic nucleotide synthesis, such as dopamine and Nitric Oxide (NO). By preventing degradation of cAMP and cGMP by PDE1B, thereby increasing intracellular levels of cAMP and cGMP, the compounds of the invention enhance the activity of inducers of cyclic nucleotide synthesis.

The present invention provides methods of treating any one or more of the following conditions:

(i) neurodegenerative diseases including parkinson's disease, restless legs, tremors, movement disorders, huntington's disease, alzheimer's disease, and drug-induced dyskinesia;

(ii) psychiatric disorders including depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar disorder, anxiety, sleep disorders such as narcolepsy, cognitive impairment, dementia, tourette's syndrome, autism, fragile X syndrome, psychostimulant withdrawal, and drug addiction;

(iii) circulatory and cardiovascular disorders including cerebrovascular disease, stroke, congestive heart disease, hypertension, pulmonary hypertension and sexual dysfunction;

(iv) respiratory and inflammatory disorders including asthma, chronic obstructive pulmonary disease, and allergic rhinitis, as well as autoimmune and inflammatory diseases;

(v) any disease or disorder characterized by low levels of cAMP and/or cGMP (or inhibition of cAMP and/or cGMP signaling pathways) in cells expressing PDE 1; and/or

(vi) Any disease or condition characterized by reduced dopamine D1 receptor signaling activity,

the method comprises administering to a human or animal patient in need thereof an effective amount of a compound of the invention, for example a compound of any one of formulae I or 1.57-1.87.

Similarly, the present invention provides methods of treating any one or more of the following conditions:

(i) neurodegenerative diseases including parkinson's disease, restless legs, tremors, movement disorders, huntington's disease, alzheimer's disease, and drug-induced dyskinesia;

(ii) psychotic disorders including depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar disorder, anxiety, sleep disorders such as narcolepsy, cognitive impairment, dementia, tourette's syndrome, autism, fragile X syndrome, psychostimulant withdrawal and drug addiction;

(iii) circulatory and cardiovascular disorders including cerebrovascular disease, stroke, congestive heart disease, hypertension, pulmonary hypertension and sexual dysfunction;

(iv) respiratory and inflammatory disorders including asthma, chronic obstructive pulmonary disease, and allergic rhinitis, as well as autoimmune and inflammatory diseases;

(v) any disease or disorder characterized by low levels of cAMP and/or cGMP (or inhibition of cAMP and/or cGMP signaling pathways) in cells expressing PDE 1; and/or

(vi) Any disease or condition characterized by reduced dopamine D1 receptor signaling activity,

the method comprises administering to a human or animal patient in need thereof an effective amount of a compound of the invention, for example a compound of formula Q or any of formulae 1.1-1.56 or formula (X).

In a particularly preferred embodiment, the present invention provides a method of treating or preventing narcolepsy. In this embodiment, the PDE1 inhibitor may be used as the sole therapeutic agent, but may also be used in combination or co-administered with other active agents. Thus, the invention also includes a method of treating narcolepsy comprising simultaneously (simultaneously), sequentially or concurrently (contempertaneously) administering a therapeutically effective amount of a compound of formula (i)

(i) PDE1 inhibitors, e.g. of formula I or of any one of formulae 1.57-1.87, and

(ii) compounds which promote wakefulness or modulate sleep, for example selected from (a) central nervous system stimulants-amphetamines and amphetamine-like compounds, such as methylphenidate, dextroamphetamine, methamphetamine and pemoline; (b) modafinil, (c) antidepressants, such as tricyclic (including imipramine, desipramine, clomipramine, and protriptyline) and selective 5-hydroxytryptamine reuptake inhibitors (including fluoxetine and sertraline); and/or (d) Gamma Hydroxybutyrate (GHB)

Administered to a human or animal patient in need thereof in free or pharmaceutically acceptable salt form.

The invention also includes a method of treating narcolepsy comprising simultaneously, sequentially or concurrently administering a therapeutically effective amount of

(i) PDE1 inhibitors, for example, compounds of formula Q or 1.1-1.56 or any one of formula (X), and

(ii) compounds which promote wakefulness or modulate sleep, for example selected from (a) central nervous system stimulants-amphetamines and amphetamine-like compounds, such as methylphenidate, dextroamphetamine, methamphetamine and pemoline; (b) modafinil, (c) antidepressants, such as tricyclic (including imipramine, desipramine, clomipramine, and protriptyline) and selective 5-hydroxytryptamine reuptake inhibitors (including fluoxetine and sertraline); and/or (d) Gamma Hydroxybutyrate (GHB)

Administered to a human or animal patient in need thereof in free or pharmaceutically acceptable salt form.

In another embodiment, the present invention provides a method of treating or preventing a condition which can be alleviated by enhancing progesterone signaling comprising administering to a human or animal patient in need thereof an effective amount of a compound of the invention, e.g., a compound of any one of formulas 1.57-1.87 or formula I. In another embodiment, the invention also provides a method of treating or preventing a disorder which can be alleviated by enhancing progesterone signaling comprising administering to a human or animal patient in need thereof an effective amount of a compound of the invention, e.g., a compound of any one of formulas Q or 1.1-1.56 or formula (X). Diseases or conditions that may be ameliorated by the enhancement of progesterone signaling include, but are not limited to, female sexual dysfunction, secondary amenorrhea (e.g., motor amenorrhea, anovulation, menopause, menopausal symptoms, hypothyroidism), premenstrual syndrome, premature labor, infertility, e.g., infertility due to repeated miscarriage, irregular menstrual cycles, abnormal uterine bleeding, osteoporosis, autoimmune diseases, multiple sclerosis, prostatic hypertrophy (prostate enlargement), prostate cancer, and hypothyroidism. For example, by enhancing progesterone signaling, PDE1 inhibitors may be used to facilitate egg implantation by acting on the inner uterine wall and help maintain pregnancy in women who are prone to miscarriage due to immune response to pregnancy or low progesterone function. Novel PDE1 inhibitors, such as the novel PDE1 inhibitors described herein, are also useful for enhancing the effectiveness of hormone replacement therapy in postmenopausal women, e.g., may be administered in combination with estrogen/estradiol/estriol and/or progesterone/progestins, as well as for estrogen-induced endometrial hyperplasia and cancer. The methods of the invention may also be used in animal breeding, for example to induce sexual receptivity and/or estrus in a non-human female mammal to be bred.

In this embodiment, the PDE1 inhibitor may be used as the sole therapeutic agent in the aforementioned methods of treatment or prevention, but may also be used in combination or co-administered with other active agents, for example in combination with hormone replacement therapy. Thus, the invention also includes a method of treating a disorder ameliorated by the enhancement of progesterone signaling, which comprises simultaneously, sequentially or concurrently administering a therapeutically effective amount of a compound of formula (I)

(i) PDE1 inhibitors, for example, compounds of any one of formulae 1.57-1.87 or formula I, and

(ii) hormones, for example selected from estrogens and estrogen analogues (e.g. estradiol, estriol, estradiol esters) and progesterone analogues (e.g. progestogens)

Administered to a human or animal patient in need thereof in free or pharmaceutically acceptable salt form.

The invention also includes a method of treating a disorder ameliorated by the enhancement of progesterone signaling comprising simultaneously, sequentially or concurrently administering a therapeutically effective amount of a compound of formula (I)

(i) PDE1 inhibitors, e.g. compounds of formula Q, e.g. 1.1-1.56 or any one of formula (X), and

(ii) hormones, for example selected from estrogens and estrogen analogues (e.g. estradiol, estriol, estradiol esters) and progesterone analogues (e.g. progestogens)

Administered to a human or animal patient in need thereof in free or pharmaceutically acceptable salt form.

The invention also provides a method of increasing or enhancing the intracellular signaling activity of dopamine D1 in a cell or tissue, which method comprises contacting said cell or tissue with a compound of the invention, for example a compound of formula Q, I, for example 1.1-1.56 or 1.57-1.87, or a compound of formula (X), in an amount sufficient to inhibit the activity of PDE 1B.

The invention also provides a method of increasing or enhancing progesterone signaling activity in a cell or tissue comprising contacting the cell or tissue with a compound of the invention, e.g., a compound of formula Q, I, e.g., 1.1-1.56 or 1.57-1.87, or formula (X), in an amount sufficient to inhibit PDE1B activity.

The invention also provides a method of treating a PDE 1-related, in particular PDE 1B-related, disorder of the dopamine D1 receptor intracellular signaling pathway or a disorder which can be alleviated by enhancement of the progesterone signaling pathway in a patient in need thereof, which comprises administering to the patient an effective amount of a compound of the invention, e.g., formula Q, I, e.g., 1.1-1.56 or 1.57-1.87, or a compound of formula (X), which inhibits PDE1B, wherein PDE1B activity modulates phosphorylation of DARPP-32 and/or GIuR1AMPA receptors.

The invention also provides

(i) A compound of the invention, for example a compound of formula Q, I, for example 1.1-1.56 or 1.57-1.87, or formula (X), for use as a medicament, for example for use in any of the methods described above or for the treatment of any of the diseases or conditions described above,

(ii) use of an inventive compound, for example a compound of formula Q, I, for example 1.1-1.56 or 1.57-1.87, or formula (X) in the manufacture of a medicament for the treatment of any disease or condition described above,

(iii) a pharmaceutical composition comprising a compound of the invention, for example a compound of formula Q, I, for example 1.1 to 1.56 or 1.57 to 1.87, or a compound of formula (X), in combination or association with a pharmaceutically acceptable diluent or carrier, and

(iv) a pharmaceutical composition for use in the treatment of any of the diseases or conditions described hereinbefore comprising a compound of the invention, for example a compound of formula Q, I, for example 1.1 to 1.56 or 1.57 to 1.87 or a compound of formula (X), in combination or association with a pharmaceutically acceptable diluent or carrier.

Accordingly, the present invention provides the use of a compound of the invention, for example a compound of formula Q, I, for example 1.1 to 1.56 or 1.57 to 1.87, or a compound of formula (X), in free or pharmaceutically acceptable salt or prodrug form, or a pharmaceutical composition, in the manufacture of a medicament for the therapeutic or prophylactic treatment of: parkinson's disease, restless legs, tremors, movement disorders, huntington's disease, alzheimer's disease and drug-induced dyskinesia; depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar disorder, anxiety, sleep disorders, narcolepsy, cognitive impairment, dementia, tourette's syndrome, autism, fragile X syndrome, psychostimulant withdrawal, and/or drug addiction; cerebrovascular disease, stroke, congestive heart disease, hypertension, pulmonary hypertension and/or sexual dysfunction; asthma, chronic obstructive pulmonary disease and/or allergic rhinitis, as well as autoimmune and inflammatory diseases; and/or female sexual dysfunction, motor amenorrhea, anovulation, menopause, menopausal symptoms, hypothyroidism, premenstrual syndrome, premature labor, infertility, irregular menstrual cycles, abnormal uterine bleeding, osteoporosis, multiple sclerosis, prostatic hypertrophy, prostate cancer, hypothyroidism, estrogen-induced endometrial hyperplasia or cancer; and/or any disease or disorder characterized by a reduced level of cAMP and/or cGMP (or inhibition of cAMP and/or cGMP signaling pathways) and/or dopamine D1 receptor signaling activity in cells expressing PDE 1; and/or any disease or condition that may be ameliorated by enhanced progesterone signaling; comprising administering to a patient in need of such treatment an effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention, e.g. of formula Q, I, e.g. 1.1-1.56 or 1.57-1.87, or a compound of formula (X).

The word "treating" should be understood to include preventing, treating or ameliorating the symptoms of a disease as well as treating the cause of a disease.

The compounds of the invention are particularly useful in the treatment of parkinson's disease, narcolepsy and female sexual dysfunction.

The compounds of the invention, for example compounds of formula Q, I, e.g. 1.1-1.56 or 1.57-1.87, or formula (X), may be used as the sole therapeutic agent, but may also be used in combination or co-administration with other active agents. For example, as the compounds of the invention enhance the activity of D1 agonists such as dopamine, they may be administered simultaneously, sequentially or concurrently with conventional dopaminergic drugs such as levodopa and levodopa adjuvants (adjunct) (carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists and anticholinergics, e.g. for the treatment of patients suffering from parkinson's disease. In addition, PDE1 inhibitors such as those described herein may also be administered in combination with estrogen/estradiol/estriol and/or progesterone/progestin to enhance the efficacy of hormone replacement therapy or to treat estrogen-induced endometrial hyperplasia or cancer.

The dosage employed in the practice of this invention will, of course, vary depending upon, for example, the particular disease or condition being treated, the particular compound of the invention employed, the mode of administration and the treatment desired. The compounds of the invention may be administered by any suitable route, including oral, parenteral, transdermal or inhalation, but oral administration is preferred. Generally, for example, for the treatment of the diseases described above, satisfactory results are obtained with oral administration at a dose of about 0.01-2.0 mg/kg. In larger mammals, such as humans, the recommended daily dosage for oral administration is correspondingly about 0.75-150mg, usually once daily, or 2-4 times daily in divided doses, or in sustained release form. Thus, for example, a unit dosage form for oral administration may comprise from about 0.2 to 75 or 150mg, e.g. from about 0.2 or 2.0 to 50, 75 or 100mg, of a compound of the invention, together with a pharmaceutically acceptable diluent or carrier.

Pharmaceutical compositions comprising the compounds of the present invention 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

Example 1

(6aR, 9aS) -5, 6a, 7, 8, 9, 9 a-hexahydro-5-methyl-3- (phenylamino) -2- ((tetrahydro-2H-pyran-4-yl) methyl) -cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (2H) -one

(a)7- (4-methoxybenzyl) -5-methyl-3- (phenylamino) -1H-pyrazolo [3, 4-d ] pyrimidine-4, 6(5H, 7H) -dione

Phenyl isothiocyanate (3.9mL, 32.7mmol) was added to a suspension of 6-hydrazino-1- (4-methoxybenzyl) -3-methylpyrimidine-2, 4(1H, 3H) -dione (0.45g, 1.6mmol) in DMF (12 mL). The reaction mixture was heated at 120 ℃ for 40 hours, and then the solvent was removed by evaporation under reduced pressure. The residue was washed with hexane, then treated with MeOH (125mL), and stored at-15 ℃ for 2 days to give a crystalline solid. The solid is separated from CH₃Recrystallization from OH-EtOAc provided 2.5g of product (yield: 61%).¹H NMR(400MHz，DMSO-d₆)δ3.21(s，3H)，3.73(s，3H)，5.01(s，2H)，6.88-7.36(m，9H).MS(FAB)m/z 378.3[M+H]⁺。

(b) 5-methyl-3- (phenylamino) -1H-pyrazolo [3, 4-d ] pyrimidine-4, 6(5H, 7H) -dione

To 7- (4-methoxybenzyl) -5-methyl-3- (phenylamino) -1H-pyrazolo [3, 4-d at room temperature]Pyrimidine-4, 6(5H, 7H) -dione (6.6g, 17.5mmol) in CH₂Cl₂To the solution (200mL) was added TFA (30mL) slowly followed by the dropwise addition of triflic acid (10 mL). After stirring the reaction mixture at room temperature for 2 hours, the solvent was removed under reduced pressure, and 200mL of 1n naoh was added under cooling. The mixture was extracted 5 times with ethyl acetate and Na₂SO₄Dried and then filtered. The filtrate was evaporated to dryness to give 4.3g of crude product as a white solid (yield: 96%). MS (ESI) M/z258.1[ M + H ]]⁺。

(c) 6-chloro-5-methyl-3- (phenylamino) -1H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one

Reacting 5-methyl-3- (phenylamino) -1H-pyrazolo [3, 4-d]Pyrimidine-4, 6(5H, 7H) -dione (4.3g, 16.7mmol) in POCl₃(120mL) for 2 days, and then POCl was removed under reduced pressure₃. The residue was suspended in 100mL of water and cooled with 7% NH₄The pH of OH is carefully adjusted to 1-2. Then the mixture is treated with CH₂Cl₂And MeOH (10: 1, v/v) 5 times. The combined organic phases were washed with water and Na₂SO₄Drying and then evaporation under reduced pressure gave 3.3g of the crude product (yield: 72%). MS (ESI) M/z 276.1[ M + H ]]⁺。

(d)6- ((1R, 2R) -2-Hydroxycyclopentylamino) -5-methyl-3- (phenylamino) -2H-pyrazolo [3, 4-d ] pyrimidin-4 (5H) -one

Reacting 6-chloro-5-methyl-3- (phenylamino) -1H-pyrazolo [3, 4-d]A solution of pyrimidin-4 (5H) -one (3.3g, 12mmol), (1R, 2R) -2-aminocyclopentanol hydrochloride (2g, 14.4mmol), and DIPEA (4.6mL, 27mmol) in DMF (25mL) was heated at 120 ℃ for 5 hours. The solvent was removed under reduced pressure. Dissolving the residue in CH₂Cl₂And MeOH (10: 1, v/v) and then washed three times with water. The solution was washed with MgSO₄Dried and evaporated to dryness to give 3.5g of crude product. MS (ESI) M/z 341.2[ M + H ]]⁺。

(e) (6aR, 9aS) -5, 6a, 7, 8, 9, 9 a-hexahydro-5-methyl-3- (phenylamino) -cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (2H) -one

At room temperature, 2.0M thionyl chloride in CH₂Cl₂The solution (7.5mL, 15.4mmol) was added dropwise to 6- ((1R, 2R) -2-hydroxycyclopentylamino) -5-methyl-3- (phenylamino) -2H-pyrazolo [3, 4-d]Pyrimidin-4 (5H) -one (3.5g, 10.3mmol) in CH₂Cl₂(30mL) in solution. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. The solvent and excess SOCl were removed under reduced pressure₂. The residue was suspended in water (100mL) and carefully neutralized with 7% ammonium hydroxide (5mL) to pH 6.5-7. Subjecting the mixture to CH₂Cl₂And MeOH (10: 1, v/v) 5 times. The combined organic phases were washed with water and Na₂SO₄Drying and then evaporation under reduced pressure in vacuo gave 2.9g of crude product. MS (ESI) M/z 323.2[ M + H ]]⁺。

(f) (6aR, 9aS) -5, 6a, 7, 8, 9, 9 a-hexahydro-5-methyl-3- (phenylamino) -2- ((tetrahydro-2H-pyran-4-yl) methyl) -cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (2H) -one

Reacting (6aR, 9aS) -5, 6a, 7, 8, 9, 9 a-hexahydro-5-methyl-3- (phenylamino) -cyclopenta [4, 5]]Imidazo [1, 2-a ]]Pyrazolo [4, 3-e]Pyrimidin-4 (2H) -one (50mg, 0.155mmol), 4- (iodomethyl) -tetrahydro-2H-pyran (70mg, 0.310mmol) and Cs₂CO₃A mixture of (101mg, 0.310mmol) of DMF (1mL) was heated in a microwave at 140 ℃ for 30 min. After cooling, the mixture was filtered through a 0.45 μm millipore filter and the filtrate was purified by semi-preparative HPLC to give the pure product as a white powder. MS (ESI) M/z 421.2[ M + H ]]⁺。

Example 2

(6aR, 9aS) -5, 6a, 7, 8, 9, 9 a-hexahydro-5-methyl-3- (phenylamino) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (1H) -one

Reacting (6aR, 9aS) -5, 6a, 7, 8, 9, 9 a-hexahydro-5-methyl-3- (phenylamino) -cyclopenta [4, 5]]Imidazo [1, 2-a ]]Pyrazolo [4, 3-e]Pyrimidin-4 (2H) -one (50mg, 0.155mmol), 4- (iodomethyl) -tetrahydro-2H-pyran (70mg, 0.310mmol) and Cs₂CO₃A mixture of (101mg, 0.310mmol) of DMF (1mL) was heated in a microwave at 140 ℃ for 30 min. After cooling, the mixture was filtered through a 0.45 μm millipore filter and the filtrate was purified by semi-preparative HPLC to give the pure product as a white powder. MS (ESI) M/z 421.2[ M + H ]]⁺。

Example 3

(6aR, 9aS) -5, 6a, 7, 8, 9, 9 a-hexahydro-5-methyl-3- (phenylamino) -1- (3- (dimethylamino) -2-methylpropyl) -cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (1H) -one

The synthesis is analogous to example 2, with 3-chloro-N, N, 2-trimethylpropan-1-amine being added instead of 4- (iodomethyl) -tetrahydro-2H-pyran. MS (ESI) M/z 422.3[ M + H ]]⁺。

Example 4

(6aR, 9aS) -5, 6a, 7, 8, 9, 9 a-hexahydro-5-methyl-3- (phenylamino) -1- (cyclopentylmethyl) -cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (1H) -one

The synthesis is analogous to example 2, with the addition of cyclopentylmethyl iodide instead of 4- (iodomethyl) -tetrahydro-2H-pyran. MS (ESI) M/z 405.2[ M + H ]]⁺。

Example 5

(6aR, 9aS) -5, 6a, 7, 8, 9, 9 a-hexahydro-5-methyl-3- (phenylamino) -2- (cyclopentylmethyl) -cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (2H) -one

The synthesis is analogous to example 1, with the addition of cyclopentylmethyl iodide instead of 4- (iodomethyl) -tetrahydro-2H-pyran. MS (ESI) M/z 405.2[ M + H ]]⁺。

Example 6

(6aR, 9aS) -5, 6a, 7, 8, 9, 9 a-hexahydro-5-methyl-3- (phenylamino) -1- (3-phenylprop-2-ynyl) -cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (1H) -one

The synthesis is analogous to example 2, with the addition of (3-bromoprop-1-ynyl) benzene instead of 4- (iodomethyl) -tetrahydro-2H-pyran. MS (ESI) M/z 437.2[ M + H ]]⁺。

Example 7

(6aR, 9aS) -5, 6a, 7, 8, 9, 9 a-hexahydro-5-methyl-3- (phenylamino) -1- (4-acetylphenethyl) -cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (1H) -one

The synthesis is analogous to example 2, with the addition of 1- (4- (2-chloroethyl) phenyl) ethanone instead of 4- (iodomethyl) -tetrahydro-2H-pyran. MS (ESI) M/z 469.1[ M + H ]]⁺。

Example 8

(6aR, 9aS) -5, 6a, 7, 8, 9, 9 a-hexahydro-5-methyl-3- (phenylamino) -2- (4-acetylphenethyl) -cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (2H) -one

The synthesis is analogous to example 1, with the addition of 1- (4- (2-chloroethyl) phenyl) ethanone instead of 4- (iodomethyl) -tetrahydro-2H-pyran. MS (ESI) M/z 469.2[ M + H ]]⁺。

Example 9

(6aR, 9aS) -5, 6a, 7, 8, 9, 9 a-hexahydro-5-methyl-3- (phenylamino) -1- (3-fluoro-4- (2, 2, 2-trifluoroacetyl) benzyl) -cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (1H) -one

The synthesis is analogous to example 2, 1- (4- (bromomethyl) -2-fluorophenyl) -2, 2, 2-trifluoroacetone being added instead of 4- (iodomethyl) -tetrahydro-2H-pyran. MS (ESI) M/z 527.2[ M + H ]]⁺。

Example 10

(6aR, 9aS) -5, 6a, 7, 8, 9, 9 a-hexahydro-5-methyl-3- (phenylamino) -2- (3-fluoro-4- (2, 2, 2-trifluoroacetyl) benzyl) -cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (2H) -one

The synthesis is analogous to example 1, 1- (4- (bromomethyl) -2-fluorophenyl) -2, 2, 2-trifluoroacetone being added instead of 4- (iodomethyl) -tetrahydro-2H-pyran. MS (ESI) M/z 527.2[ M + H ]]⁺。

Example 11

(6aR, 9aS) -5, 6a, 7, 8, 9, 9 a-hexahydro-5-methyl-3- (phenylamino) -1- (4- (trifluoromethyl) phenethyl) -cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (1H) -one

The synthesis is analogous to example 2, with 1- (2-bromoethyl) -4- (trifluoromethyl) benzene being added instead of 4- (iodomethyl) -tetrahydro-2H-pyran. MS (ESI) M/z 495.2[ M + H ]]⁺。

Example 12

(6aR, 9aS) -5, 6a, 7, 8, 9, 9 a-hexahydro-5-methyl-3- (phenylamino) -2- (4- (trifluoromethyl) phenethyl) -cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (2H) -one

Synthetic method thereofIn analogy to example 1, 1- (2-bromoethyl) -4- (trifluoromethyl) benzene was added instead of 4- (iodomethyl) -tetrahydro-2H-pyran. MS (ESI) M/z 495.2[ M + H ]]⁺。

Example 13

(6aR, 9aS) -5, 6a, 7, 8, 9, 9 a-hexahydro-5-methyl-3- (phenylamino) -2- (bromo (4- (5-fluoropyridin-2-yl) phenyl) methyl) -cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (2H) -one

Reacting (6aR, 9aS) -5, 6a, 7, 8, 9, 9 a-hexahydro-5-methyl-3- (phenylamino) -cyclopenta [4, 5]]Imidazo [1, 2-a ]]Pyrazolo [4, 3-e]Pyrimidin-4 (2H) -one (35mg, 0.109mmol), 2- (4- (dibromomethyl) phenyl) -5-fluoropyridine and K₂CO₃A mixture of (15mg, 0.109mmol) of DMF (3mL) was stirred at room temperature overnight. The mixture was filtered through a 0.45 μm microporous filter and the filtrate was purified by semi-preparative HPLC to give the product as a white powder. MS (ESI) M/z 585.9[ M + H ]]⁺。

Example 14

(6aR, 9aS) -5, 6a, 7, 8, 9, 9 a-hexahydro-5-methyl-3- (phenylamino) -2- ((4- (6-fluoropyridin-2-yl) phenyl) methyl) -cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (2H) -one

This compound can be prepared in analogy to example 13, using 2- (4- (bromomethyl) phenyl) -6-fluoropyridine instead of 2- (4- (dibromomethyl) phenyl) -5-fluoropyridine.

Example 15

In vitro measurement of PDE1B inhibition using IMAP phosphodiesterase assay kit

Phosphodiesterase 1B (PDE1B) is a calcium/calmodulin-dependent phosphodiesterase that converts cyclic guanosine monophosphate (cGMP) to 5 '-guanosine monophosphate (5' -GMP). PDE1B can also convert modified cGMP substrates such as the fluorescent molecule cGMP-fluorescein to the corresponding GMP-fluorescein. GMP-fluorescein produced by cGMP-fluorescein can be quantified using, for example, IMAP (Molecular Devices, Sunnyvale, Calif.) immobilized metal affinity particle reagents.

Briefly, IMAP reagents bind with high affinity to free 5-phosphate, which is present in GMP-fluorescein but not in cGMP-fluorescein. The resulting GMP-fluorescein-IMAP complex is huge relative to cGMP-fluorescein. Small fluorophores bound in large, slowly tumbling complexes can be distinguished from unbound fluorophores because the photons emitted by them fluoresce retain the same polarity as the photons used to excite fluorescence.

In the phosphodiesterase assay, cGMP-fluorescein, which cannot bind to IMAP and therefore retains a small fluorescence polarization, is converted to GMP-fluorescein, which when bound to IMAP produces a large increase in fluorescence polarization (Δ mp). Thus, inhibition of phosphodiesterase was detected as a decrease in Δ mp.

Enzyme assay

Materials: all chemicals were obtained from Sigma Aldrich (Sigma-Aldrich) (St. Louis, Mo.) except for IMAP reagents (reaction buffer, binding buffer, FL-GMP and IMAP beads) obtained from Molecular Devices (Sunnyvale, Calif.).

The determination method comprises the following steps: 3 ', 5' -Loop-nucleotide specific bovine brain phosphodiesterase (Sigma, St. Louis, Mo.) was reconstituted to 2.5U/ml with 50% glycerol. One unit of enzyme hydrolyzes 1.0. mu. mol of 3 ', 5 ' -cAMP per minute to 5 ' -AMP at pH 7.5, 30 ℃. To 1999 reaction buffer (30. mu.M CaCl)₂10U/ml calcium blendProtein (Sigma P2277), 10mM Tris-HCl pH7.2, 10mM MgCl₂，0.1％BSA，0.05％NaN₃) One portion of enzyme was added to obtain a final concentration of 1.25 mU/ml. Mu.l of the diluted enzyme solution was added to each well of a flat-bottom 96-well polystyrene plate, and 1. mu.l of the test compound dissolved in 100% DMSO was added thereto. The compounds were mixed with the enzyme and pre-incubated for 10 minutes at room temperature.

The FL-GMP conversion reaction was initiated by combining 4 parts of the enzyme and inhibitor mixture with 1 part of the substrate solution (0.225. mu.M) in 384-well microtiter plates. The reaction was incubated in the dark at room temperature for 15 minutes. The reaction was stopped by adding 60. mu.l of binding reagent (1: 400IMAP bead dilution in binding buffer supplemented with 1: 1800 antifoam dilution) to each well of a 384-well plate. The plates were incubated at room temperature for 1 hour to allow IMAP binding to go to completion and then placed in an Envision multimode microtiter plate reader (PerkinElmer), Shelton, CT) to measure fluorescence polarization (Δ mp).

The decrease in GMP concentration measured as a decrease in Δ mp indicates inhibition of PDE activity. IC was determined by measuring enzyme activity in the presence of 8 to 16 compound concentrations in the range of 0.0037nM to 80,000nM, and then plotting drug concentration- Δ mP₅₀Values that allow IC to be estimated using non-linear regression software (XLFit; IDBS, Cambridge, MA)₅₀The value is obtained.

Compounds of the invention, which typically have an IC of less than 1 μ M, are selected and tested in the assays described herein for PDE1 inhibitory activity or in assays similar thereto₅₀Values, for example, compounds of formulae 1.54 and 1.55 typically have IC's of less than 250nM₅₀The value is obtained.

Example 16

Effect of PDE1 inhibitors on female murine responses

As in Mani et al, Science (2000) 287: 1053 the effect of a PDE1 inhibitor on the lordotic response in female rats was measured as described. Ovariectomized and cannulated wild-type rats were pre-administered 2 μ g estrogen, followed by 24 hours post-intracerebroventricular (icv) injection of progesterone (2 μ g), a PDE1 inhibitor of the present invention (0.1mg, 1.0mg or 2.5mg) or sesame oil vehicle (control). These rats were tested for lordotic response in the presence of male rats. Lordotic quotient (LQ ═ lordosis/10 mount (mounts) × 100) was used to quantify lordotic response. It will be observed that the LQ of female pre-administered estrogen rats receiving 0.1mg of a compound of the invention is generally similar to the LQ of pre-administered estrogen rats receiving progesterone and higher than the LQ of pre-administered estrogen rats receiving vehicle.

Claims (24)

1. 1-or 2-substituted (6 aR) in free, salt or prodrug form^＊，9aS^＊) -3- (phenylamino) -5-6a, 7, 8, 9, 9 a-hexahydro-5-methyl-cyclopenta [4, 5]Imidazo [1, 2-a ]]Pyrazolo [4, 3-e]Pyrimidin-4 (1H or 2H) -one.

2. The compound according to claim 1, wherein said compound is a compound of formula Q in free, salt or prodrug form

Formula Q

Wherein

(i) X is C_1-6Alkylene (e.g., methylene, ethylene, or prop-2-yn-1-yl);

(ii) y is a single bond, an alkynylene group (e.g., -C.ident.C-), an arylene group (e.g., phenylene), or a heteroarylene group (e.g., pyridylene);

(iii) z is H, aryl (e.g. phenyl), heteroaryl (e.g. pyridyl, e.g. pyridin-2-yl), halogen (e.g. F, Br, Cl), halo C_1-6Alkyl (e.g. trifluoromethyl), -C (O) -R¹、-N(R²)(R³) Or C optionally containing at least one atom selected from N or O_3-7Cycloalkyl (e.g., cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, or morpholinyl);

(iv)R¹is C_1-6Alkyl, halo C_1-6Alkyl, -OH or-OC_1-6Alkyl (e.g. -OCH)₃)；

(v)R²And R³Independently is H or C_1-6An alkyl group;

(vi)R⁴and R⁵Independently is H; c_1-6An alkyl group; or aryl (e.g., phenyl), optionally substituted with one or more of the following groups: halogen (e.g. fluorophenyl, e.g. 4-fluorophenyl), hydroxy (e.g. hydroxyphenyl, e.g. 4-hydroxyphenyl or 2-hydroxyphenyl) or C_1-6An alkoxy group;

(vii) wherein X, Y and Z are independently and optionally substituted with one or more halogens (e.g., F, Cl or Br), C_1-6Alkyl (e.g. methyl), halo C_1-6Alkyl (e.g. trifluoromethyl) substituted, for example Z is heteroaryl, for example pyridyl, substituted with one or more of the following groups: halogen (e.g. 6-fluoropyridin-2-yl, 5-fluoropyridin-2-yl, 6-fluoropyridin-2-yl, 3-fluoropyridin-2-yl, 4, 6-dichloropyridin-2-yl), halogeno C_1-6Alkyl (e.g. 5-trifluoromethylpyridin-2-yl) or C_1-6Alkyl (e.g. 5-methylpyridin-2-yl), or Z is aryl, e.g. phenyl, substituted by one or more halogens (e.g. 4-fluoroPhenyl), with the proviso that when X is unsubstituted methylene, Y is phenylene or heteroarylene, and Z is aryl, heteroaryl, haloalkyl or cycloalkyl, then Z is substituted with at least one halogen (e.g., fluorine, chlorine, bromine) or alkyl (e.g., methyl, ethyl) group.

3. A compound according to claim 1 or 2, wherein the compound is a compound of formula I, including enantiomers, diastereomers and racemates thereof, in free, salt or prodrug form,

formula I

Wherein

(i) X is C_1-4An alkylene group;

(ii) y is a single bond, alkynylene, arylene, or heteroarylene;

(iii) z is H, aryl, heteroaryl, halogen, halogeno C_1-4Alkyl, -C (O) -R¹、-N(R²)(R³) Or C optionally containing at least one atom selected from N or O_3-7A cycloalkyl group;

(iv)R¹is C_1-4Alkyl, halo C_1-4An alkyl group;

(v)R²and R³Independently is H or C_1-4An alkyl group, a carboxyl group,

(vi) wherein X, Y and Z are independently and optionally substituted with halogen,

with the proviso that when X is unsubstituted methylene, Y is phenylene or heteroarylene, and Z is aryl, heteroaryl, haloalkyl or cycloalkyl, then Z is substituted with at least one halogen (e.g., fluorine, chlorine, bromine) or alkyl (e.g., methyl, ethyl) group.

4. A compound according to claim 1, 2 or 3, wherein the compound is of formula II:

5. compounds according to any of claims 1-4, selected from compounds of formula 1.53.

6. Compounds according to any of claims 1-5, selected from compounds of formula 1.54.

7. Compounds according to any of claims 1-6, selected from compounds of formula 1.55.

8. The compound according to any one of claims 1 to 4, selected from compounds of formula 1.86.

9. The compound according to any one of claims 1-5, wherein said compound is

10. The compound according to claim 1, wherein said compound is

11. The compound according to claim 1, wherein said compound is

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 in association with a pharmaceutically acceptable diluent or carrier.

13. A method of treating any one of the following conditions: parkinson's disease, restless legs, tremors, movement disorders, huntington's disease, alzheimer's disease and drug-induced dyskinesia; depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar disorder, anxiety, sleep disorders, narcolepsy, cognitive impairment, dementia, tourette's syndrome, autism, fragile X syndrome, psychostimulant withdrawal, and/or drug addiction; cerebrovascular disease, stroke, congestive heart disease, hypertension, pulmonary hypertension and/or sexual dysfunction; asthma, chronic obstructive pulmonary disease and/or allergic rhinitis, as well as autoimmune and inflammatory diseases; and/or female sexual dysfunction, motor amenorrhea, anovulation, menopause, menopausal symptoms, hypothyroidism, premenstrual syndrome, premature labor, infertility, irregular menstrual cycles, abnormal uterine bleeding, osteoporosis, multiple sclerosis, prostatic hypertrophy, prostate cancer, hypothyroidism, estrogen-induced endometrial hyperplasia or cancer; and/or any disease or disorder characterized by a reduced level of cAMP and/or cGMP (or inhibition of cAMP and/or cGMP signaling pathways) and/or dopamine D1 receptor signaling activity in cells expressing PDE 1; and/or any disease or condition that can be ameliorated by the enhancement of progesterone signaling; the method comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1-11 or a pharmaceutical composition according to claim 12.

14. The method of claim 13, wherein the disorder is parkinson's disease.

15. The method of claim 13, wherein the disorder is cognitive impairment.

16. The method of claim 13, wherein the disorder is narcolepsy.

17. The method of claim 16 further comprising administering to a patient in need thereof one or more compounds selected from the group consisting of a central nervous system stimulant, modafinil, an antidepressant, and gamma hydroxybutyrate.

18. The method of claim 13, wherein the disorder is female sexual dysfunction.

19. The method of claim 18, further comprising administering to a patient in need thereof one or more compounds selected from the group consisting of estradiol, estriol, estradiol esters, progesterone, and progestins.

20. A process for the preparation of a compound according to any one of claims 2 to 11, which comprises reacting (6aR, 9aS) -3- (phenylamino) -5-6a, 7, 8, 9, 9 a-hexahydro-5-methyl-cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (2H) -one with a compound of formula Z-Y-X-L wherein L is a leaving group and X, Y and Z are aS defined in claim 2, and isolating the compound according to any one of claims 2 to 11 thus obtained.

21. The method of claim 20, wherein (6aR, 9aS) -3- (phenylamino) -5-6a, 7, 8, 9, 9 a-hexahydro-5-methyl-cyclopenta [4, 5] imidazo [1, 2-a ] pyrazolo [4, 3-e ] pyrimidin-4 (2H) -one is a compound of formula QK:

22. a process for the preparation of a compound according to any one of claims 1 to 11, which comprises cyclizing a compound of formula QV with a dehydrating/halogenating agent

23. The method of claim 22 wherein said dehydrating/halogenating agent is SOCl₂。

24. The use of a compound according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 12 for the preparation of a medicament for the therapeutic or prophylactic treatment of: parkinson's disease, restless legs, tremors, movement disorders, huntington's disease, alzheimer's disease and drug-induced dyskinesia; depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar disorder, anxiety, sleep disorders, narcolepsy, cognitive impairment, dementia, tourette's syndrome, autism, fragile X syndrome, psychostimulant withdrawal, and/or drug addiction; cerebrovascular disease, stroke, congestive heart disease, hypertension, pulmonary hypertension and/or sexual dysfunction; asthma, chronic obstructive pulmonary disease and/or allergic rhinitis, as well as autoimmune and inflammatory diseases; and/or female sexual dysfunction, motor amenorrhea, anovulation, menopause, menopausal symptoms, hypothyroidism, premenstrual syndrome, premature labor, infertility, irregular menstrual cycles, abnormal uterine bleeding, osteoporosis, multiple sclerosis, prostatic hypertrophy, prostate cancer, hypothyroidism, estrogen-induced endometrial hyperplasia or cancer; and/or any disease or disorder characterized by a reduced level of cAMP and/or cGMP (or inhibition of cAMP and/or cGMP signaling pathways) and/or dopamine D1 receptor signaling activity in cells expressing PDE 1; and/or any disease or condition that can be ameliorated by the enhancement of progesterone signaling; comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1-11 or a pharmaceutical composition according to claim 12.