WO2008056176A1 - Pyrazolopyrimidines as phosphodiesterase inhibitors - Google Patents

Pyrazolopyrimidines as phosphodiesterase inhibitors Download PDF

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Publication number
WO2008056176A1
WO2008056176A1 PCT/GB2007/004306 GB2007004306W WO2008056176A1 WO 2008056176 A1 WO2008056176 A1 WO 2008056176A1 GB 2007004306 W GB2007004306 W GB 2007004306W WO 2008056176 A1 WO2008056176 A1 WO 2008056176A1
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compound
formula
alkyl
phenyl
carboxylic acid
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PCT/GB2007/004306
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French (fr)
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Simon J. Mackenzie
Lee Mitchell
Justin Kewney
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Scottish Biomedical Limited
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Priority claimed from GB0713152A external-priority patent/GB0713152D0/en
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Publication of WO2008056176A1 publication Critical patent/WO2008056176A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to materials for use as phosphodiesterase inhibitors, and to methods of treatment using phosphodiesterase inhibitors.
  • Phosphodiesterases are enzymes that play a role in the regulation of second messenger molecules, particularly cyclic nucleotides cAMP and cGMP. Specifically, PDEs regulate the localization, duration, and amplitude of cyclic nucleotide signalling within sub- cellular domains.
  • PDEs are important regulators of signal transduction mediated by second messenger molecules.
  • the balance between cAMP and cGMP in cells in patients with psychosis such as schizophrenia are dysregulated so that there is an excessive activity of the cAMP generating system which eventually leads to the pathological picture found in such conditions.
  • PDE enzymes that are present in mammals are classified into 11 families, PDEl to PDEIl. These families may be further split into subsets (e.g., PDElOA). Enzyme inhibitors are known for the vast majority of PDE families. These PDE enzyme inhibitors can prolong or enhance the effects of physiological processes mediated by cAMP or cGMP. PDE inhibitors can produce this effect by inhibiting the degradation of cAMP or cGMP by PDEs.
  • PDE inhibitors Due to their physiological effects, PDE inhibitors have been identified as new potential therapeutics in areas such as pulmonary arterial hypertension, coronary heart disease, respiratory disease, metabolic disorders, dementia, depression and schizophrenia.
  • PDEIl expression is detected in the brain in small amounts and has been linked to the treatment of diseases or conditions that affect the prostate, reproduction, the thyroid, the liver, tumours and metabolism.
  • diseases or conditions that affect the prostate, reproduction, the thyroid, the liver, tumours and metabolism.
  • potent and selective inhibitors of PDEIl there are no known potent and selective inhibitors of PDEIl.
  • a further object of the invention is to provide a PDE inhibitor compound.
  • a still further object of the invention is to provide a method of therapy using a PDE inhibitor compound.
  • the present invention addresses at least some of the aforesaid drawbacks found in the prior art by providing PDEIl inhibitor compounds.
  • the compounds of the present invention generally comprise a bicyclic unsaturated structure consisting of a six- membered heteroatom-containing ring fused to a five- membered heteroatom-containing ring.
  • the six-membered ring contains a phenyl group and an alkyl group, and the five-membered ring contains an amide which is optionally substituted with an aryl or alkyl group.
  • the aryl group generally comprises electron donating groups.
  • Xi and X 2 are independently chosen from the list comprising nitrogen and carbon atoms, and suitable H, alkyl, aryl, alkenyl, halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, nitro, carboxylate, carboxylic acid, sulphonate, and sulphonic acid derivatives thereof; J 1 and J 2 are independently chosen from the list comprising nitrogen and carbon atoms; Qi and Q 2 are independently chosen from the list comprising oxygen, carbon, nitrogen, and sulphur atoms, and suitable H, alkyl, and aryl derivatives thereof; Y is chosen from the list comprising oxygen, carbon, nitrogen, and sulphur atoms, and suitable H, alkyl, and aryl derivatives thereof; Z is chosen from the list comprising oxygen, carbon, nitrogen, and sulphur atoms, and suitable H, alkyl, and aryl derivatives thereof; D is chosen from the list comprising H, alkyl,
  • Xi or X 2 when Xi or X 2 is carbon, it may be further functionalised to contain a group chosen from the list comprising H, alkyl, aryl, alkenyl, halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, nitro, carboxylate, carboxylic acid, sulphonate, and sulphonic acid groups.
  • Xi is carbon, more preferably CH.
  • X 2 is preferably nitrogen.
  • Ji is nitrogen.
  • J 2 is preferably carbon.
  • Qi is nitrogen and Q2 is carbon. More preferably Q2 is CH.
  • the alkyl groups can be lower alkyl C 1 -C 5 .
  • D is preferably an alkyl group, more preferably a methyl group.
  • B is preferably an aryl group, more preferably a phenyl group.
  • A can be hydrogen.
  • the alkyl group can be cyclohexane or -CH 2 ⁇ tetrahydrofuran.
  • the alkyl-aryl group can be -CH 2 -pyridine.
  • the aryl group may advantageously comprise at least one electron donating substituent group.
  • A can be a phenyl group of general structure:
  • Ei, and E 1 ' are independently chosen from the list comprising hydrogen, alkyl, alkoxy, halogen, aryl, alkenyl, hydroxyl, amino, alkylamino, dialkylamino, amide, -OCO- ester, and ether groups;
  • E 2 , and E 2 ' are independently chosen from the list comprising hydrogen, alkyl, alkoxy, halogen, aryl, alkenyl, hydroxyl, amino, alkylamino, dialkylamino, amide, -OCO- ester, and ether groups;
  • E 3 is chosen from the list comprising hydrogen, alkoxy, halogen, aryl, alkenyl, hydroxyl, amino, alkylamino, dialkylamino, amide, -OCO- ester, and ether groups; wherein the group situated para to Ei or Ei' is not halogen when Ei or Ei' is alkoxy.
  • the remaining substituents are preferably hydrogen.
  • alkyl is -CH 2 CH 3 .
  • the halogen is chlorine.
  • alkoxy is methoxy
  • Ei and E 2 , or Ei' and E 2 ' can be taken together to form -CHCHCHCH-, so-forming a naphthalene group.
  • a preferred compound according to the invention is shown as IA (7-Methyl-5-phenyl-pyrazolo [1, 5-a] pyrimidine-2- carboxylic acid benzo [ 1, 3] dioxol-5-ylamide) :
  • the compounds described are useful in the inhibition of phosphodiesterases and particularly PDEIl.
  • Expression of PDEIl is detected in the brain and has been linked to, amongst other things, major depressive disorder (MDD).
  • MDD major depressive disorder
  • a fourth aspect of the invention there is provided a method of inhibiting phosphodiesterase using a compound of formula I, as described herein.
  • a fifth aspect of the invention there is provided a method of selectively inhibiting phosphodiesterase 11 using a compound of formula I, as described herein.
  • a compound of formula I as described herein, in combination with a pharmaceutical carrier or excipient for use in therapy or as a medicament.
  • a compound of formula I as described in herein, in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a psychiatric disorder in a mammal.
  • the mammal may be a human.
  • the compound is useful in the therapeutic and/or prophylactic treatment of further conditions including psychiatric disorders such as schizophrenia, major depressive disorder, dementia, depression, bi-polar disorder, or psychotic disorder.
  • psychiatric disorders such as schizophrenia, major depressive disorder, dementia, depression, bi-polar disorder, or psychotic disorder.
  • a compound of formula I as described in herein, in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of circulatory disease or disorder.
  • the circulatory disease or disorder can be a cardiovascular disease or hypertension.
  • the conditions described may affect the prostate.
  • the disorder described may affect the thyroid, liver or brain.
  • the compound may be one or more of the compounds of formula IA, IB, IC, ID, IE, IF, IH, IJ, IK, or IL, as described herein.
  • the compound is of formula IA, IB or IC, most preferably of formula IA.
  • Figure 1 is a synthetic scheme showing how compounds IA, IB, and IC can be prepared.
  • Figure 2 is a graph that illustrates the relative amount of PDEIlA present in brain tissue taken from Schizophrenics.
  • Compound IL is sourced from Interchim, 211 Bis, Avenue Kennedy, BP1140, 03103 Montiucon Cedex, France.
  • the compounds are 7-Methyl-5-phenyl-pyrazolo [ 1 , 5-a] pyrimidine-2-carboxylic acid amide derivatives, and are useful in the inhibition of phosphodiesterases, and in particular PDEIl.
  • Xi and X 2 are independently chosen from the list comprising nitrogen and carbon atoms, and suitable H, alkyl, and aryl derivatives thereof;
  • Ji and J 2 are independently chosen from the list comprising nitrogen and carbon atoms;
  • Qi and Q 2 are independently chosen from the list comprising oxygen, carbon, nitrogen, and sulphur atoms, and suitable H, alkyl, and aryl derivatives thereof;
  • Y is chosen from the list comprising oxygen, carbon, nitrogen, and sulphur atoms, and suitable H, alkyl, and aryl derivatives thereof;
  • Z is chosen from the list comprising oxygen, carbon, nitrogen, and sulphur atoms, and suitable H, alkyl, and aryl derivatives thereof;
  • D is chosen from the list comprising H, alkyl, aryl, alkenyl, halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, nitro, carboxylate, carboxylic acid, sul
  • a compound that inhibits PDEIl selectively over other phosphodiesterases said compound containing a six-membered heterocycle and a five-membered heterocycle fused to form an indole-type structure.
  • the five-membered ring contains an amide substituent which can be linked to a substituted phenyl.
  • the six-membered ring contains a phenyl substituent and an alkyl substituent.
  • Examples of compounds with the properties described above that act as PDEIl inhibitors are 7-Methyl-5-phenyl- pyrazolo [ 1, 5-a]pyrimidine-2-carboxylic acid benzo [ 1, 3] dioxol-5-ylamide (IA), 7-Methyl-5-phenyl- pyrazolo [ 1, 5-a]pyrimidine-2-carboxylic acid (3-hydroxy- phenyl) -amide (IB), and 7-Methyl-5-phenyl- pyrazolo [ 1, 5-a]pyrimidine-2-carboxylic acid (4-hydroxy- phenyl) -amide (IC).
  • a compound that inhibits PDEIl selectively over other phosphodiesterases said compound containing a six-membered heterocycle and a five-membered heterocycle fused to form an indole-type structure.
  • the five- membered ring contains an amide substituent.
  • the amide substituent can be linked to an alkyl group which may contain heteroatoms, an aryl group, or an alkyl-aryl group.
  • the six-membered ring contains a phenyl substituent and an alkyl substituent.
  • Examples of compounds with the properties described above that act as PDEIl inhibitors are 7-Methyl-5-phenyl- pyrazolo [ 1 , 5-a] pyrimidine-2-carboxylic acid amide (ID), 7-Methyl-5-phenyl-pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid cyclohexylamide (IE) , 7-Methyl-5-phenyl- pyrazolo [ 1, 5-a] pyrimidine-2-carboxylic acid (3-chloro- phenyl) -amide (IF), 7-Methyl-5-phenyl- pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid (tetrahydro- furan-2-ylmethyl) -amide (IG), 7-Methyl-5-phenyl- pyrazolo [ 1, 5-a] pyrimidine-2-carboxylic acid (pyridine-3- ylmethyl) -amide (
  • the phosphodiesterase assay is performed using recombinant human PDE enzymes expressed in a baculoviral system.
  • the recombinant PDE enzymes were tested for their similarity to PDE enzymes taken from human tissue using know inhibitor standards where available.
  • Table 1 shows the IC 5O values in ⁇ M for compounds IA and IB as inhibitors of PDEIlAl with reference to a selection of other phosphodiesterases. The remaining compounds were tested for efficacy with respect to PDEIlAl only. It is clear from the IC 50 studies that the compounds of the present invention are inhibitors of PDEIl.
  • mice are placed in one of four sound attenuated chambers (Medical Associates Prol, Vermont USA) equipped with an acoustic audio generator containing a platform fitted with a transducer amplifier that detects the motion of the animal. High frequency speakers deliver the startle stimulus and prepulse acoustic stimuli. Data acquisition and analysis was performed using Startle Reflex software, for example MEDPRO from Medical Associates Vermont USA. In certain . experiments the mice were pre-dosed with PCP which has been shown to produce schizophrenic-like symptoms in humans and also to worsen the psychotic state in schizophrenics .
  • mice The general activity of treated and untreated mice was determined using the open field activity (OFA) apparatus (such as model MED-OFA-MS, Medical Associates Vermont USA comprising 27.9 cm x 27.9 cm test environment with three 16 beam I/R arrays , 48 channel control, with computer software to record and analyse the data) .
  • OFA open field activity
  • Pre-pulse inhibition is an operational measure of sensorimotor gating, a phenomenon by which the brain shields the effect of subsequent stimuli while still processing another to protect against stimulus overflow or sensory inundation.
  • Schizophrenics have markedly reduced prepulse inhibition that can be redressed with antipsychotic drugs.
  • Compound IB like the known anti- psychotic clozapine, reverses the effect of phenylcyclidine on prepulse inhibition in mice.
  • the open field test is an index of simple information- processing and activity by the animal over time that occurs as an animal becomes acclimated to its environment. Faster habituation indicates greater information-processing.
  • Compound IB (unlike clozapine) had no effect upon open filed activity ruling out that the observed reversal of PCP-inhibition of PPI by the compound was due to sedation or an effect on the compounds on animal locomotion.
  • the present invention • * demonstrates compounds that act as PDEIl inhibitors. .-, relief> Furthermore, the compounds of the present invention vsf' selectively inhibit PDEIl over other phosphodiesterases. •,.;?
  • cDNA was synthesised using 5 ⁇ g of total RNA extracted from four control brains and four human schizophrenic brains. Regions known to be associated with schizophrenia were sampled from both the control and disease brains. Approximately 0.2 ⁇ g RNA equivalent in real time PCR analysis was used to determine the relative amounts of PDEIlA transcript in the samples. Duplicates were used for each sample. PDEIlA primers with a FAM labelled probe were used to determine the PDEIlA transcript levels. Ribosomal RNA control primers and VIC labelled probes were included in the reaction to control for quantitative errors between samples.
  • PDEIlA transcript in human schizophrenic brains was found to be around 3.5 fold higher than the transcript in the control brains. This result was found to be significant (p > 0.05) using the student T-test. Therefore, it is clear that PDEIlA transcript increases in human schizophrenic brain, possibly signifying increased PDEIlA activity in these individuals. Use of a PDEIlA specific or selective inhibitor may therefore prove therapeutic for psychiatric disorders and in particular schizophrenia.
  • the compounds described herein show inhibition of phosphodieterases, and selective inhibition of phoshpodiesterase 11. Therefore, the compounds may be used in combination with a pharmaceutical carrier or excipient for use in therapy or as a medicament.
  • the compounds are likely to be useful in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a psychiatric disorder in a mammal.
  • the psychiatric disorder could be schizophrenia, major depressive disorder, dementia, depression, bi-polar disorder, or psychotic disorder.
  • the compounds described are likely to be useful in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of circulatory disease or disorder, and in particular a cardiovascular disease or hypertension.
  • the compounds described are likely to be useful in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a benign or malignant neoplastic condition, and in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a condition manifested in the reproductive function of a mammal.
  • the compounds are likely to be of use when these conditions affect the prostate.
  • the compounds described are also likely to be useful in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a condition affecting the metabolism of a mammal, and in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a disorder in an organ or tissue.
  • the compounds are likely to be of use when these disorders affect the thyroid, liver or brain.
  • the compounds of the present invention show an inhibitory effect on phosphodiesterases, and in particular PDEIl, they may have application as new potential therapeutics in areas such as pulmonary arterial hypertension, coronary heart disease, metabolic disorders, dementia, depression and schizophrenia.
  • PDEIl is known to exist in the brain in small amounts and has been linked to the treatment of diseases or conditions that affect the prostate, reproduction, the thyroid, the liver, tumours and the metabolism. Therefore the compounds of the present invention may provide useful medicaments or therapeutics for use in the treatment of diseases affecting the prostate, reproduction, the thyroid, the liver, tumours and the metabolism, or the brain. The compounds of the present invention may also be useful as medicaments or therapeutics for use in the treatment of pulmonary arterial hypertension, coronary heart disease, dementia, depression bi-polar disorder and psychotic disorders such as schizophrenia.

Abstract

Compounds for use as phosphodiesterase inhibitors, and in particular for inhibiting PDE 11. The compounds may be used in therapy or as a medicament in the treatment of, for example, schizophrenia.

Description

PYRAZOLOPYRIMIDINES AS PHOSPHODIESTERASE INHIBITORS
Technical Field
The present invention relates to materials for use as phosphodiesterase inhibitors, and to methods of treatment using phosphodiesterase inhibitors.
Phosphodiesterases (PDEs) are enzymes that play a role in the regulation of second messenger molecules, particularly cyclic nucleotides cAMP and cGMP. Specifically, PDEs regulate the localization, duration, and amplitude of cyclic nucleotide signalling within sub- cellular domains.
In view of the above, PDEs are important regulators of signal transduction mediated by second messenger molecules. In particular there is a suggestion that the balance between cAMP and cGMP in cells in patients with psychosis such as schizophrenia are dysregulated so that there is an excessive activity of the cAMP generating system which eventually leads to the pathological picture found in such conditions. Background Art
PDE enzymes that are present in mammals are classified into 11 families, PDEl to PDEIl. These families may be further split into subsets (e.g., PDElOA). Enzyme inhibitors are known for the vast majority of PDE families. These PDE enzyme inhibitors can prolong or enhance the effects of physiological processes mediated by cAMP or cGMP. PDE inhibitors can produce this effect by inhibiting the degradation of cAMP or cGMP by PDEs.
Due to their physiological effects, PDE inhibitors have been identified as new potential therapeutics in areas such as pulmonary arterial hypertension, coronary heart disease, respiratory disease, metabolic disorders, dementia, depression and schizophrenia.
PDEIl expression is detected in the brain in small amounts and has been linked to the treatment of diseases or conditions that affect the prostate, reproduction, the thyroid, the liver, tumours and metabolism. However, there are no known potent and selective inhibitors of PDEIl.
Therefore, it is an object of the present invention to overcome at least some of the drawbacks associated with the prior art.
A further object of the invention is to provide a PDE inhibitor compound. A still further object of the invention is to provide a method of therapy using a PDE inhibitor compound.
Further aims and objects of the invention will become apparent from a reading of the following description.
Disclosure of Invention
The present invention addresses at least some of the aforesaid drawbacks found in the prior art by providing PDEIl inhibitor compounds.
The compounds of the present invention generally comprise a bicyclic unsaturated structure consisting of a six- membered heteroatom-containing ring fused to a five- membered heteroatom-containing ring. The six-membered ring contains a phenyl group and an alkyl group, and the five-membered ring contains an amide which is optionally substituted with an aryl or alkyl group. The aryl group generally comprises electron donating groups.
Thus, according to a first aspect of the present invention there is provided a compound for use in therapy or as a medicament, the compound having the formula I
Figure imgf000005_0001
(I) wherein: Xi and X2 are independently chosen from the list comprising nitrogen and carbon atoms, and suitable H, alkyl, aryl, alkenyl, halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, nitro, carboxylate, carboxylic acid, sulphonate, and sulphonic acid derivatives thereof; J1 and J2 are independently chosen from the list comprising nitrogen and carbon atoms; Qi and Q2 are independently chosen from the list comprising oxygen, carbon, nitrogen, and sulphur atoms, and suitable H, alkyl, and aryl derivatives thereof; Y is chosen from the list comprising oxygen, carbon, nitrogen, and sulphur atoms, and suitable H, alkyl, and aryl derivatives thereof; Z is chosen from the list comprising oxygen, carbon, nitrogen, and sulphur atoms, and suitable H, alkyl, and aryl derivatives thereof; D is chosen from the list comprising H, alkyl, aryl, alkenyl, halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, nitro, carboxylate, carboxylic acid, sulphonate, and sulphonic acid groups; B is chosen from the list comprising H, alkyl, aryl, alkenyl, halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, nitro, carboxylate, carboxylic acid, sulphonate, and sulphonic acid groups; and A is chosen from the list comprising H, alkyl, aryl, alkyl-aryl, and suitable heteroatom containing derivatives thereof.
When Xi or X2 is carbon, it may be further functionalised to contain a group chosen from the list comprising H, alkyl, aryl, alkenyl, halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, nitro, carboxylate, carboxylic acid, sulphonate, and sulphonic acid groups.
Preferably Xi is carbon, more preferably CH. X2 is preferably nitrogen. Preferably Ji is nitrogen. J2 is preferably carbon.
Preferably Qi is nitrogen and Q2 is carbon. More preferably Q2 is CH.
The alkyl groups can be lower alkyl C1-C5.
D is preferably an alkyl group, more preferably a methyl group.
B is preferably an aryl group, more preferably a phenyl group.
A can be hydrogen.
When A is an alkyl group, the alkyl group can be cyclohexane or -CH2~tetrahydrofuran.
When A is an alkyl-aryl group, the alkyl-aryl group can be -CH2-pyridine.
When A is an aryl group, the aryl group may advantageously comprise at least one electron donating substituent group.
A can be a phenyl group of general structure:
Figure imgf000007_0001
wherein: Ei, and E1 ' are independently chosen from the list comprising hydrogen, alkyl, alkoxy, halogen, aryl, alkenyl, hydroxyl, amino, alkylamino, dialkylamino, amide, -OCO- ester, and ether groups; E2, and E2 ' are independently chosen from the list comprising hydrogen, alkyl, alkoxy, halogen, aryl, alkenyl, hydroxyl, amino, alkylamino, dialkylamino, amide, -OCO- ester, and ether groups; E3 is chosen from the list comprising hydrogen, alkoxy, halogen, aryl, alkenyl, hydroxyl, amino, alkylamino, dialkylamino, amide, -OCO- ester, and ether groups; wherein the group situated para to Ei or Ei' is not halogen when Ei or Ei' is alkoxy.
When Ei or Ei' is alkyl, the remaining substituents are preferably hydrogen.
Preferably alkyl is -CH2CH3.
When E2 or E2' is a halogen, the remaining substituents are preferably hydrogen.
Preferably the halogen is chlorine.
When E2 or E2' , and E3 are alkoxy, the remaining substituents are preferably hydrogen.
Preferably alkoxy is methoxy.
When Ei, Ei', E2 or E2' is hydroxyl, the remaining substituents are preferably hydrogen. E2 or E2' and E3 can be taken together to form -OCH2O-.
Ei and E2, or Ei' and E2' can be taken together to form -CHCHCHCH-, so-forming a naphthalene group.
A preferred compound according to the invention is shown as IA (7-Methyl-5-phenyl-pyrazolo [1, 5-a] pyrimidine-2- carboxylic acid benzo [ 1, 3] dioxol-5-ylamide) :
Figure imgf000009_0001
(IA)
Other preferred compounds according to the invention are shown as IB (7-Methyl-5-phenyl-pyrazolo [ 1, 5-a] pyrimidine- 2-carboxylic acid (3-hydroxy-phenyl) -amide) and IC (7- Methyl-5-phenyl-pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid (4-hydroxy-phenyl) -amide) :
Figure imgf000009_0002
(IB)
Figure imgf000009_0003
[1C) Effective compounds according to the invention are shown as ID (7-Methyl-5-phenyl-pyrazolo [1, 5-a] pyrimidine-2- carboxylic acid amide), IE (7-Methyl-5-phenyl- pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid cyclohexylamide) , IF (7-Methyl-5-phenyl- pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid (3-chloro- phenyl ) -amide) , IG (7-Methyl-5-phenyl- pyrazolo [1, 5-a]pyrimidine-2-carboxylic acid (tetrahydro- furan-2-ylmethyl) -amide) , IH (7-Methyl-5-phenyl- pyrazolo [ 1, 5-a] pyrimidine-2-carboxylic acid (pyridine-3- ylmethyl ) -amide) , IJ (7-Methyl-5-phenyl- pyrazolo [ 1, 5-a] pyrimidine-2-carboxylic acid (3,4- dimethoxy-phenyl) -amide) , IK (7-Methyl-5-phenyl- pyrazolo [ 1, 5-a]pyrimidine-2-carboxylic acid naphthylen-1- ylamide) or IL (7-Methyl-5-phenyl- pyrazolo [ 1, 5-a] pyrimidine-2-carboxylic acid (2-ethyl- phenyl) -amide) :
Figure imgf000010_0001
(ID)
Figure imgf000010_0002
(IE)
Figure imgf000011_0001
2 (IF)
3
Figure imgf000011_0002
5 (IG)
6
Figure imgf000011_0003
(IH]
Figure imgf000011_0004
11 (U)
12
Figure imgf000011_0005
14 (IK)
Figure imgf000012_0001
(IL)
The compounds described are useful in the inhibition of phosphodiesterases and particularly PDEIl. Expression of PDEIl is detected in the brain and has been linked to, amongst other things, major depressive disorder (MDD).
Therefore, according to another aspect of the present invention there is provided a compound of formula I, as described herein, for use as a phosphodiesterase inhibitor.
According to a further aspect of the present invention there is provided a compound of formula I, as described herein, for use as a phosphodiesterase 11 selective inhibitor.
According to a fourth aspect of the invention there is provided a method of inhibiting phosphodiesterase using a compound of formula I, as described herein.
According to a fifth aspect of the invention there is provided a method of selectively inhibiting phosphodiesterase 11 using a compound of formula I, as described herein.
In accordance with a further aspect there is provided a compound of formula I, as described herein, in combination with a pharmaceutical carrier or excipient for use in therapy or as a medicament.
According to a further aspect of the invention there is provided a compound of formula I, as described in herein, in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a psychiatric disorder in a mammal. The mammal may be a human.
The compound is useful in the therapeutic and/or prophylactic treatment of further conditions including psychiatric disorders such as schizophrenia, major depressive disorder, dementia, depression, bi-polar disorder, or psychotic disorder.
According to a further aspect of the invention there is provided a compound of formula I, as described in herein, in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of circulatory disease or disorder.
The circulatory disease or disorder can be a cardiovascular disease or hypertension.
According to a still further aspect of the invention there is provided the use of a compound of the formula I, as described herein, in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a benign or malignant neoplastic condition.
In a further aspect of the invention there is provided the use of a compound of the formula I, as described herein, in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a condition manifested in the reproductive function of a mammal.
The conditions described may affect the prostate.
In a further aspect there is provided the use of a compound of the formula I, as described herein, in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a condition affecting the metabolism of a mammal.
In a still further aspect of the invention there is provided the use of a compound of the formula I, as described herein, in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a disorder in an organ or tissue.
The disorder described may affect the thyroid, liver or brain.
The compound may be one or more of the compounds of formula IA, IB, IC, ID, IE, IF, IH, IJ, IK, or IL, as described herein.
Preferably the compound is of formula IA, IB or IC, most preferably of formula IA.
Brief Description of Drawings
The present invention will now be described by reference to the following examples which are not intended to be limiting of the invention, and with reference to the accompanying drawings in which: Figure 1 is a synthetic scheme showing how compounds IA, IB, and IC can be prepared; and
Figure 2 is a graph that illustrates the relative amount of PDEIlA present in brain tissue taken from Schizophrenics.
Modes for Carrying Out the Invention
All reagents are commercially available and are used without further purification.
Compounds IA, IB, IC and ID are sourced from ChemBridge .'S: Corporation, 16981 Via Tazon, Suite G, San Diego, CA -1 92127. Alternatively, compounds IA, IB and IC can be *ϊt prepared as illustrated in the synthetic scheme presented ..E in Figure 1. t
Compounds IE, IF, IG, IH, IJ and IK are sourced from "-t Asinex 5 Gabrichevskogo St. Bldg 8, Moscow 123367, Russia.
Compound IL is sourced from Interchim, 211 Bis, Avenue Kennedy, BP1140, 03103 Montiucon Cedex, France.
The compounds, as illustrated in more detail below, are 7-Methyl-5-phenyl-pyrazolo [ 1 , 5-a] pyrimidine-2-carboxylic acid amide derivatives, and are useful in the inhibition of phosphodiesterases, and in particular PDEIl.
7-Methyl-5-phenyl-pyrazolo [1 , 5-a] pyrimidine-2-carboxylic acid benzo [ 1, 3] dioxol-5-ylamide (IA):
Figure imgf000016_0001
(IA)
7-Methyl-5-phenyl-pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid (3-hydroxy-phenyl) -amide (IB):
Figure imgf000016_0002
(IB)
7-Methyl-5-phenyl-pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid (4-hydroxy-phenyl) -amide (IC):
Figure imgf000016_0003
:ic)
7-Methyl-5-phenyl-pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid amide (ID) :
Figure imgf000016_0004
(ID) 7-Methyl-5-phenyl-pyrazolo [ 1, 5-a] pyrimidine-2-carboxylic acid cyclohexylamide (IE) :
Figure imgf000017_0001
:IE)
7-Methyl-5-phenyl-pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid ( 3-chloro-phenyl) -amide (IF):
Figure imgf000017_0002
(IF)
7-Methyl-5-phenyl-pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid (tetrahydro-furan-2-ylmethyl) -amide (IG):
Figure imgf000017_0003
:IG)
7-Methyl-5-phenyl-pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid (pyridine-3-ylmethyl) -amide (IH):
Figure imgf000017_0004
:iH) 7-Methyl-5-phenyl-pyrazolo [ 1, 5-a] pyrimidine-2-carboxylic acid (3, 4-dimethoxy-phenyl) -amide (IJ):
Figure imgf000018_0001
(IJ)
7-Methyl-5-phenyl-pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid naphthylen-1-ylamide (IK) :
Figure imgf000018_0002
(IK)
7-Methyl-5-phenyl-pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid (2-ethyl-phenyl) -amide (IL):
Figure imgf000018_0003
(IL)
Compounds of general formula I, as illustrated below, are useful in the inhibition of phosphodiesterases, and in particular, PDEIl. Compound of general formula I
Figure imgf000019_0001
(I) wherein: Xi and X2 are independently chosen from the list comprising nitrogen and carbon atoms, and suitable H, alkyl, and aryl derivatives thereof; Ji and J2 are independently chosen from the list comprising nitrogen and carbon atoms; Qi and Q2 are independently chosen from the list comprising oxygen, carbon, nitrogen, and sulphur atoms, and suitable H, alkyl, and aryl derivatives thereof; Y is chosen from the list comprising oxygen, carbon, nitrogen, and sulphur atoms, and suitable H, alkyl, and aryl derivatives thereof; Z is chosen from the list comprising oxygen, carbon, nitrogen, and sulphur atoms, and suitable H, alkyl, and aryl derivatives thereof; D is chosen from the list comprising H, alkyl, aryl, alkenyl, halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, nitro, carboxylate, carboxylic acid, sulphonate, and sulphonic acid groups; B is chosen from the list comprising H, alkyl, aryl, alkenyl, halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, nitro, carboxylate, carboxylic acid, sulphonate, and sulphonic acid groups; and A is chosen from the list comprising H, alkyl, aryl, alkyl-aryl, and suitable heteroatom containing derivatives thereof. According to a preferred embodiment of the invention, there is presented a compound that inhibits PDEIl selectively over other phosphodiesterases, said compound containing a six-membered heterocycle and a five-membered heterocycle fused to form an indole-type structure. The five-membered ring contains an amide substituent which can be linked to a substituted phenyl. The six-membered ring contains a phenyl substituent and an alkyl substituent.
Examples of compounds with the properties described above that act as PDEIl inhibitors are 7-Methyl-5-phenyl- pyrazolo [ 1, 5-a]pyrimidine-2-carboxylic acid benzo [ 1, 3] dioxol-5-ylamide (IA), 7-Methyl-5-phenyl- pyrazolo [ 1, 5-a]pyrimidine-2-carboxylic acid (3-hydroxy- phenyl) -amide (IB), and 7-Methyl-5-phenyl- pyrazolo [ 1, 5-a]pyrimidine-2-carboxylic acid (4-hydroxy- phenyl) -amide (IC).
According to a further embodiment of the invention, there is presented a compound that inhibits PDEIl selectively over other phosphodiesterases, said compound containing a six-membered heterocycle and a five-membered heterocycle fused to form an indole-type structure. The five- membered ring contains an amide substituent. The amide substituent can be linked to an alkyl group which may contain heteroatoms, an aryl group, or an alkyl-aryl group. The six-membered ring contains a phenyl substituent and an alkyl substituent.
Examples of compounds with the properties described above that act as PDEIl inhibitors are 7-Methyl-5-phenyl- pyrazolo [ 1 , 5-a] pyrimidine-2-carboxylic acid amide (ID), 7-Methyl-5-phenyl-pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid cyclohexylamide (IE) , 7-Methyl-5-phenyl- pyrazolo [ 1, 5-a] pyrimidine-2-carboxylic acid (3-chloro- phenyl) -amide (IF), 7-Methyl-5-phenyl- pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid (tetrahydro- furan-2-ylmethyl) -amide (IG), 7-Methyl-5-phenyl- pyrazolo [ 1, 5-a] pyrimidine-2-carboxylic acid (pyridine-3- ylmethyl) -amide (IH), 7-Methyl-5-phenyl- pyrazolo [ 1, 5-a] pyrimidine-2-carboxylic acid (3,4- dimethoxy-phenyl) -amide (IJ), 7-Methyl-5-phenyl- pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid naphthylen-1- ylamide (IK), and 7-Methyl-5-phenyl- pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid (2-ethyl- phenyl) -amide (IL).
Experimental trials carried out on the compounds of the present invention are illustrated below.
The phosphodiesterase assay is performed using recombinant human PDE enzymes expressed in a baculoviral system. The recombinant PDE enzymes were tested for their similarity to PDE enzymes taken from human tissue using know inhibitor standards where available. The assay method is a modification of the two-step method of Thompson and Appleman [Biochemistry 10; 311-316/ 1971] which has been adapted for 96 well plate format. All assays use a substrate concentration below the Km as determined for each enzyme so that K1=IC50.
Stock compounds are prepared in 100% DMSO at a concentration of 4OmM. All of the subsequent assays are performed in 5% DMSO (final) . The IC50 for each compound is determined against the appropriate PDE enzyme. The results of the experiments carried out above are illustrated for compounds IA and IB in Table 1 below.
Figure imgf000022_0001
Table 1: NI = no inhibition
Table 1 shows the IC5O values in μM for compounds IA and IB as inhibitors of PDEIlAl with reference to a selection of other phosphodiesterases. The remaining compounds were tested for efficacy with respect to PDEIlAl only. It is clear from the IC50 studies that the compounds of the present invention are inhibitors of PDEIl.
In vivo efficacy trials, including prepulse inhibition, were carried out on mice.
To measure prepulse inhibition mice are placed in one of four sound attenuated chambers (Medical Associates Prol, Vermont USA) equipped with an acoustic audio generator containing a platform fitted with a transducer amplifier that detects the motion of the animal. High frequency speakers deliver the startle stimulus and prepulse acoustic stimuli. Data acquisition and analysis was performed using Startle Reflex software, for example MEDPRO from Medical Associates Vermont USA. In certain . experiments the mice were pre-dosed with PCP which has been shown to produce schizophrenic-like symptoms in humans and also to worsen the psychotic state in schizophrenics .
The general activity of treated and untreated mice was determined using the open field activity (OFA) apparatus (such as model MED-OFA-MS, Medical Associates Vermont USA comprising 27.9 cm x 27.9 cm test environment with three 16 beam I/R arrays , 48 channel control, with computer software to record and analyse the data) .
The results of the in vivo trials are illustrated in Table 2 below.
Figure imgf000023_0001
Table 2: PPI = pre pulse inhibition; PCP = phenylcyclidine; OFA = open field activity
Pre-pulse inhibition is an operational measure of sensorimotor gating, a phenomenon by which the brain shields the effect of subsequent stimuli while still processing another to protect against stimulus overflow or sensory inundation. Schizophrenics have markedly reduced prepulse inhibition that can be redressed with antipsychotic drugs. Compound IB, like the known anti- psychotic clozapine, reverses the effect of phenylcyclidine on prepulse inhibition in mice.
The open field test is an index of simple information- processing and activity by the animal over time that occurs as an animal becomes acclimated to its environment. Faster habituation indicates greater information-processing. Compound IB (unlike clozapine) had no effect upon open filed activity ruling out that the observed reversal of PCP-inhibition of PPI by the compound was due to sedation or an effect on the compounds on animal locomotion. These data provide strong evidence that PDEIl inhibitors such as compound IB have ✓'«• potential clinical utility in the treatment of psychoses. &
In contrast to the prior art, the present invention •* demonstrates compounds that act as PDEIl inhibitors. .-,„> Furthermore, the compounds of the present invention vsf' selectively inhibit PDEIl over other phosphodiesterases. •,.;?
Experimental trials were carried out to establish whether brain samples from patients with schizophrenia had elevated levels of PDEIlA.
cDNA was synthesised using 5μg of total RNA extracted from four control brains and four human schizophrenic brains. Regions known to be associated with schizophrenia were sampled from both the control and disease brains. Approximately 0.2μg RNA equivalent in real time PCR analysis was used to determine the relative amounts of PDEIlA transcript in the samples. Duplicates were used for each sample. PDEIlA primers with a FAM labelled probe were used to determine the PDEIlA transcript levels. Ribosomal RNA control primers and VIC labelled probes were included in the reaction to control for quantitative errors between samples.
Referring now to Figure 2, it is apparent that PDEIlA transcript in human schizophrenic brains was found to be around 3.5 fold higher than the transcript in the control brains. This result was found to be significant (p > 0.05) using the student T-test. Therefore, it is clear that PDEIlA transcript increases in human schizophrenic brain, possibly signifying increased PDEIlA activity in these individuals. Use of a PDEIlA specific or selective inhibitor may therefore prove therapeutic for psychiatric disorders and in particular schizophrenia.
The compounds described herein show inhibition of phosphodieterases, and selective inhibition of phoshpodiesterase 11. Therefore, the compounds may be used in combination with a pharmaceutical carrier or excipient for use in therapy or as a medicament. In particular, the compounds are likely to be useful in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a psychiatric disorder in a mammal. The psychiatric disorder could be schizophrenia, major depressive disorder, dementia, depression, bi-polar disorder, or psychotic disorder.
In addition, the compounds described are likely to be useful in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of circulatory disease or disorder, and in particular a cardiovascular disease or hypertension. Furthermore, the compounds described are likely to be useful in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a benign or malignant neoplastic condition, and in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a condition manifested in the reproductive function of a mammal. In particular, the compounds are likely to be of use when these conditions affect the prostate.
The compounds described are also likely to be useful in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a condition affecting the metabolism of a mammal, and in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a disorder in an organ or tissue. In particular, the compounds are likely to be of use when these disorders affect the thyroid, liver or brain.
Industrial Applicability
As the compounds of the present invention show an inhibitory effect on phosphodiesterases, and in particular PDEIl, they may have application as new potential therapeutics in areas such as pulmonary arterial hypertension, coronary heart disease, metabolic disorders, dementia, depression and schizophrenia.
In particular, PDEIl is known to exist in the brain in small amounts and has been linked to the treatment of diseases or conditions that affect the prostate, reproduction, the thyroid, the liver, tumours and the metabolism. Therefore the compounds of the present invention may provide useful medicaments or therapeutics for use in the treatment of diseases affecting the prostate, reproduction, the thyroid, the liver, tumours and the metabolism, or the brain. The compounds of the present invention may also be useful as medicaments or therapeutics for use in the treatment of pulmonary arterial hypertension, coronary heart disease, dementia, depression bi-polar disorder and psychotic disorders such as schizophrenia.
Further modifications and improvements may be incorporated without departing from the scope of the invention herein intended.

Claims

1. A compound of the formula I for use in therapy or as a medicament:
Figure imgf000028_0001
(I) wherein: Xi and X2 are independently chosen from the list comprising nitrogen and carbon atoms, and suitable H, alkyl, aryl, alkenyl, halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, nitro, carboxylate, carboxylic acid, sulphonate, and sulphonic acid derivatives thereof; J1 and J∑ are independently chosen from the list comprising nitrogen and carbon atoms; Qi and Q2 are independently chosen from the list comprising oxygen, carbon, nitrogen, and sulphur atoms, and suitable H, alkyl, and aryl derivatives thereof; Y is chosen from the list comprising oxygen, carbon, nitrogen, and sulphur atoms, and suitable H, alkyl, and aryl derivatives thereof; Z is chosen from the list comprising oxygen, carbon, nitrogen, and sulphur atoms, and suitable H, alkyl, and aryl derivatives thereof; D is chosen from the list comprising H, alkyl, aryl, alkenyl, halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, nitro, carboxylate, carboxylic acid, sulphonate, and sulphonic acid groups; B is chosen from the list comprising H, alkyl, aryl, alkenyl, halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, nitro, carboxylate, carboxylic acid, sulphonate, and sulphonic acid groups; and A is chosen from the list comprising H, alkyl, aryl, alkyl-aryl, and suitable heteroatom containing derivatives thereof.
2. A compound as described in Claim 1, wherein Xi is CH.
3. A compound as described in Claims 1 or 2 wherein X2 is nitrogen.
4. A compound as described in any preceding Claim, wherein Ji is nitrogen.
5. A compound as described in any preceding Claim wherein J2 is carbon.
6. A compound as described in any preceding Claim, wherein Qi is nitrogen.
7. A compound as described in any preceding Claim, wherein Q2 is CH.
8. A compound as described in any preceding Claim, wherein the alkyl groups are lower alkyl Ci-C5.
9. A compound as described in any preceding Claim, wherein D is an alkyl group.
10. A compound as described in Claim 9, wherein the alkyl group is a methyl group.
11. A compound as described in any preceding Claim, wherein B is an aryl group
12. A compound as described in Claim 11, wherein the aryl group is a phenyl group.
13. A compound as described in any preceding Claim, wherein A is hydrogen.
14. A compound as described in Claims 1 to 12, wherein when A is an alkyl group the alkyl group is cyclohexane.
15. A compound as described in Claims 1 to 12, wherein when A is an alkyl group the alkyl group is -CH2-tetrahydrofuran.
16. A compound as described in Claims 1 to 12, wherein when A is an alkyl-aryl group, the alkyl-aryl group is -CH2~pyridine.
17. A compound as described in Claims 1 to 12, wherein when A is an aryl group, the aryl group comprises at least one electron donating substituent group.
18. A compound as described in Claims 1 to 12, wherein A is a phenyl group of general structure:
Figure imgf000031_0001
wherein : Ei, and Ei' are independently chosen from the list comprising hydrogen, alkyl, alkoxy, halogen, aryl, alkenyl, hydroxyl, amino, alkylamino, dialkylaπiino, amide, -OCO- ester, and ether groups; E2, and E2 ' are independently chosen from the list comprising hydrogen, alkyl, alkoxy, halogen, aryl, alkenyl, hydroxyl, amino, alkylamino, dialkylamino, amide, -OCO- ester, and ether groups; E3 is chosen from the list comprising hydrogen, alkoxy, halogen, aryl, alkenyl, hydroxyl, amino, alkylamino, dialkylamino, amide, -OCO- ester, and ether groups; wherein the group situated para to Ei or Ei' is not a halogen when Ei or Ei' is alkoxy.
19. A compound as described in Claim 18, wherein when one or both of Ei or Ei' is alkyl, the remaining substituents are hydrogen,
20. A compound as described in Claim 19, wherein alkyl is -CH2CH3.
21. A compound as described in Claim 18, wherein when one or both of E2 or E2' is a halogen, the remaining substituents are hydrogen.
22. A compound as described in Claim 21, wherein the halogen is chlorine.
23. A compound as described in Claim 18, wherein when one or both of E2 or E2' , and E3 are alkoxy, the remaining substituents are hydrogen.
24. A compound as described in Claim 23, wherein alkoxy is methoxy.
25. A compound as described in Claim 18, wherein when one or more of Ei, Ei', E2 or E2' is hydroxyl, the remaining substituents are hydrogen.
26. A compound as described in Claim 18, wherein one of E2 or E2' and E3 are taken together to form -OCH2O-.
27. A compound as described in Claim 18, wherein Ei and E2, or Ei' and E2' are taken together to form -CHCHCHCH-, so-forming a naphthalene group.
28. A compound of the formula IA (7-Methyl-5-phenyl- pyrazolo[l, 5-a] pyrimidine-2-carboxylic acid benzo [1, 3] dioxol-5-ylamide) for use in therapy or as a medicament:
Figure imgf000032_0001
(IA)
29. A compound of the formula IB (7-Methyl-5-phenyl- pyrazolo [ 1, 5-a] pyrimidine-2-carboxylic acid (3- hydroxy-phenyl) -amide) or IC (7-Methyl-5-phenyl- pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid (4- hydroxy-phenyl) -amide) for use in therapy or as a medicament:
Figure imgf000033_0001
(IB)
Figure imgf000033_0002
(IC)
30. A compound of the formula ID (7-Methyl-5-phenyl- pyrazolo [ 1, 5-a] pyrimidine-2-carboxylic acid amide) , IE (7-Methyl-5-phenyl-pyrazolo [1, 5-a] pyrimidine-2- carboxylic acid cyclohexylamide) , IF (7-Methyl-5- phenyl-pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid (3-chloro-phenyl) -amide) , IG (7-Methyl-5-ρhenyl- pyrazolo [ 1, 5-a] pyrimidine-2-carboxylic acid (tetrahydro-furan-2-ylmethyl) -amide) , IH (7-Methyl- 5-phenyi-ρyrazolo [1, 5-a] pyrimidine-2-carboxylic acid (pyridine-3-ylmethyl) -amide) , IJ (7-Methyl-5-phenyl- pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid (3,4- dimethoxy-phenyl) -amide) , IK (7-Methyl-5-phenyl- pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid naphthylen-1-ylamide) or IL ( 7-Methyl-5-phenyl- pyrazolo [1, 5-a] pyrimidine-2-carboxylic acid (2- ethyl-phenyl) -amide) for use in therapy or as a medicament:
Figure imgf000034_0001
2 (ID)
3
Figure imgf000034_0002
5 (IE) 6
Figure imgf000034_0003
(IF)
Figure imgf000034_0004
11 (IG)
12
Figure imgf000034_0005
14 (IH)
15
Figure imgf000035_0001
;IJ)
Figure imgf000035_0002
(IK)
(IL)
31. A compound of the formula I, as described in Claim 1, for use as a phosphodiesterase inhibitor.
32. A compound of the formula IA, as described in Claim 28, for use as a phosphodiesterase inhibitor.
33. A compound of the formula IB or IC, as described in Claim 29, for use as a phosphodiesterase inhibitor.
34. A compound of the formula ID, IE, IF, IG, IH, IJ, IK or IL, as described in Claim 30, for use as a phosphodiesterase inhibitor.
35. A compound of the formula I, as described in Claim 1, for use as a phosphodiesterase 11 selective inhibitor.
36. A compound of the formula IA, as described in Claim 28, for use as a phosphodiesterase 11 selective inhibitor.
37. A compound of the formula IB or IC, as described in Claim 29, for use as a phosphodiesterase 11 selective inhibitor.
38. A compound of the formula ID, IE, IF, IG, IH, IJ, IK or IL, as described in Claim 30, for use as a phosphodiesterase 11 selective inhibitor.
39. A method of inhibiting phosphodiesterase using a compound of the formula I, as described in Claim 1.
40. A method of inhibiting phosphodiesterase using a compound of the formula IA, as described in Claim 28.
41. A method of inhibiting phosphodiesterase using a compound of the formula IB or IC, as described in Claim 29.
42. A method of inhibiting phosphodiesterase using a compound of the formula ID, IE, IF, IG, IH, IJ, IK or IL, as described in Claim 30.
43. A method of selectively inhibiting phosphodiesterase 11 using a compound of the formula I, as described in Claim 1.
44. A method of selectively inhibiting phosphodiesterase 11 using a compound of the formula IA, as described in Claim 28.
45. A method of selectively inhibiting phosphodiesterase 11 using a compound of the formula IB or IC, as described in Claim 29.
46. A method of selectively inhibiting phosphodiesterase 11 using a compound of the formula ID, IE, IF, IG, IH, IJ, IK or IL, as described in Claim 30.
47. A compound of the formula I, as described in Claim 1, in combination with a pharmaceutical carrier or excipient for use in therapy or as a medicament.
48. A compound of the formula IA, as described in Claim 28, in combination with a pharmaceutical carrier or excipient for use in therapy or as a medicament.
49. A compound of the formula IB or IC, as described in Claim 29, in combination with a pharmaceutical carrier or excipient for use in therapy or as a medicament.
50. A compound of the formula ID, IE, IF, IG, IH, IJ, IK or IL, as described in Claim 30, in combination with a pharmaceutical carrier or excipient for use in therapy or as a medicament.
51. The use of a compound of the formula I, IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK or IL, as described herein, in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a psychiatric disorder in a mammal.
52. The use claimed in claim 51, wherein the psychiatric disorder is schizophrenia, major depressive disorder, dementia, depression, bi-polar disorder, or psychotic disorder.
53. The use of a compound of the formula I, IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK or IL, as described herein, in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of circulatory disease or disorder.
54. The use claimed in claim 53, wherein the circulatory disease or disorder is a cardiovascular disease.
55. The use claimed in claim 53, wherein the circulatory disease or disorder is hypertension.
56. The use of a compound of the formula I, IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK or IL, as described herein, in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a benign or malignant neoplastic condition.
57. The use of a compound of the formula I, IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK or IL, as described herein, in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a condition manifested in the reproductive function of a mammal.
58. The use claimed in claim 56, or claim 57, wherein the condition affects the prostate.
59. The use of a compound of the formula I, IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK or IL, as described herein, in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a condition affecting the metabolism of a mammal.
60. The use of a compound of the formula I, IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK or IL, as described herein, in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of a disorder in an organ or tissue.
61. The use claimed in claim 59, or claim 60, wherein the disorder affects the thyroid, liver or brain.
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