OA17878A - Hexahydrofuropyrroles as PDE1 inhibitors. - Google Patents

Abstract

The present invention provides hexahydrofuropyrroles as PDE 1 inhibitors and their use as a medicament, in particular for the treatment of neurodegenerative disorders and psychiatric desorders.

Description

Hexahydrofuropyrroles as PDE1 inhibitors

FIELD OF THE INVENTION

The présent invention provides compounds that are PDE1 enzyme inhibitors and their use as a médicament, in particular for the treatment of neurodegenerative disorders and psychiatrie disorders. The présent invention also provides pharmaceutical compositions comprising compounds ofthe invention and methods oftreating disorders using the compounds ofthe invention.

BACKGROUND OF THE INVENTION

Throughout this application, various publications are referenced in full. The disclosures of these publications are hereby incorporated by reference into this application to describe more fully the state ofthe artto which this invention pertains.

The second messenger cyclic Nucléotides (cNs), cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) play a major rôle in intracellular signal transduction cascade, by regulating cN-dependent protein kinases (PKA and PKG), EPACs (Exchange Protein Activated by cAMP), phosphoprotein phosphatases, and/or cN-gated cation channels. In neurons, this includes the activation of cAMP- and cGMP-dependent kinases and subséquent phosphorylation of proteins involved in acute régulation of synaptic transmission as well as in neuronal différentiation and survival. Intracellular concentrations of cAMP and cGMP are strictly regulated by the rate of biosynthesis by cyclases and by the rate of dégradation by phosphodiesterases (PDEs, EC 3.1.4.17). PDEs are bimetallic hydrolases that inactivate cAMP/cGMP by catalytic hydrolysis of the 3’-ester bond, forming the inactive 5’monophosphate. Since PDEs provide the only means of degrading the cyclic nucléotides cAMP and cGMP in cells, PDEs play an essential rôle in cyclic nucléotide signalling. The catalytic activities of PDEs provide for breakdown of cNs over a spectrum of concentrations in ail cells, and their varied regulatory mechanisms provide for intégration and crosstalk with myriad signalling pathways. Particular PDEs are targeted to discrète compartments within cells where they control cN level and sculpt microenvironments for a variety of cN signalosomes (Sharron H. Francis, Mitsi A. Blount, and Jackie D. Corbin. Physiol Rev 2011, 91: 651-690).

On the basis of substrate specificity, the PDE families can be divided into three groups: 1) The cAMP-specific PDEs, which include PDE4, PDE7, and PDE8, 2) the cGMP-selective enzymes PDE5 and PDE9, and 3) the dual-substrate PDEs, PDE1, PDE2, PDE3, as well as PDE10 and PDE11.

Previously named calmodulin-stimulated PDE (CaM-PDE), PDE1 is unique in that it is Ca²⁺dependently regulated via calmodulin (CaM, a 16 kDa Ca²⁺-binding protein) complexed with four Ca²⁺ (for review, Sharron H. Francis, Mitsi A. Blount, and Jackie D. Corbin. Physiol Rev 2011, 91: 651-690). Thus, this family represents an interesting regulatory link between cyclic nucléotides and intracellular Ca²⁺. The PDE1 family is encoded by three genes: PDE1A (mapped on human chromosome 2q32), PDE1B (human chromosome location, hcl: 12q13) and PDE1C (hcl: 7p14.3). They hâve alternative promoters and give rise to a multitude of proteins by alternative splicing which differ in their regulatory properties, substrate affinities, spécifie activities, activation constants for CaM, tissue distribution and molecular weights. More than 10 human isoforms are identified. Their molecular weights vary from 58 to 86 kDa per monomer. The N-terminal regulatory domain that contains two Ca²⁺/CaM binding domains and two phosphorylation sites differentiate their corresponding proteins and modulate their biochemical functions. PDE1 is a dual substrate PDE and the PDE1C-subtype has equal activity towards cAMP and cGMP (Km ~ 1-3 μΜ), whereas the subtypes PDE1A and PDE1B has a preference for cGMP (Km for cGMP ~ 1-3 μΜ and for cAMP ~ 10-30 μΜ).

The PDE1 subtypes are highly enriched in the brain and located especially in the striatum (PDE1B), hippocampus (PDE1A) and cortex (PDE1A) and this localization is conserved across species (Amy Bernard et al. Neuron 2012, 73, 1083-1099). In the cortex, PDE1A is présent mainly in deep cortical layers 5 and 6 (output layers), and used as a specificity marker for the deep cortical layers. PDE1 inhibitors enhance the levels of the second messenger cNs leading to enhanced neuronal excitability.

Thus, PDE1 is a therapeutic target for régulation of intracellular signalling pathways, preferably in the nervous system and PDE1 inhibitors can enhance the levels of the second messengers cAMP/cGMP leading to modulation of neuronal processes and to the expression of neuronal plasticity-related genes, neurotrophic factors, and neuroprotective molécules. These neuronal plasticity enhancement properties together with the modulation of synaptic transmission make PDE1 inhibitors good candidates as therapeutic agents in many neurological and psychiatrie conditions. The évaluation of PDE1 inhibitors in animal models (for reviews see e.g. Blokland et al. Expert Opinion on Therapeutic Patents (2012), 22(4), 349-354; and Médina, A. E. Frontiers in Neuropharmacology (2011), 5(Feb.), 21) hâve suggested the potential for the therapeutic use of PDE1 inhibitors in neurological disorders, like e.g. Alzheimer's, Parkinson's and Huntington's Diseases and in psychiatrie disorders like e.g. Attention Déficit hyperactivity Disorder (ADHD), restless leg syndrome, dépréssion, narcolepsy, cognitive impairment and cognitive impairment associated with schizophrenia (CIAS). There hâve also been patent applications claiming that

PDE1 inhibitors are useful in diseases that may be alleviated by the enhancement of progesterone-signalling such as female sexual dysfunction.

The compounds ofthe invention may offer alternatives to current marketed treatmentsfor neurodegenerative and/or psychiatrie disorders, which are not efficacious in ail patients. Hence, there remains a need for alternative methods of treatment.

SUMMARY OF THE INVENTION

PDE1 enzymes are expressed in the Central Nervous System (CNS), making this gene family an attractive source of new targets for the treatment of psychiatrie and neurodegenerative disorders.

The objective ofthe présent invention is to provide compounds that are PDE1 inhibitors, and as such are useful to treat neurodegenerative disorders and psychiatrie disorders. In a preferred embodiment the compounds are sélective PDE1 inhibitors.

Accordingly, the présent invention relates to compounds of formula (I)

d) wherein

R-ι is selected from the group consisting of H, F, C₃-C₆ cycloalkyl, and C1-C4 alkyl, wherein the alkyl and the cycloalkyl optionally may be substituted one, two or three times with fluorine;

R₂ to Ru selected from the group consisting of H, C_rC₃ alkyl, C₃-C₆ cycloalkyl, fluorine, hydroxy and C-|-C₆ alkoxy, and pharmaceutically acceptable acid addition salts of Compound (I), racemic mixtures of Compound (I), or the corresponding enantiomer and/or optical isomer of Compound (I), and polymorphie forms of Compound (I) as well as tautomeric forms of Compound (I).

DETAILED DESCRIPTION OFTHE INVENTION

EMBODIMENTS OF THE INVENTION

In a first embodiment (E1) the présent invention relates to compounds of formula (I) (Compound (I))

wherein

Ri is selected from the group consisting of H, F, C₃-C₆ cycloalkyl and 0^4alkyl.

R₂ to Rn selected from the group consisting of H, F, OH, C_rC₃ alkyl, C₃-C₆ cycloalkyl and C-|-C₆ alkoxy.

In an embodiment (E2) of (E1 ) R-ι to Rn are H.

In an embodiment (E3) of (E1) at least one of R₂ and R₇ is CH₃.

In an embodiment (E4) of (E3) both R₂ and R₇ are CH₃.

In an embodiment (E5) of (E1 ) Rt is substituted one, two or three times with fluorine when Rt is alkyl or cycloalkyl.

In an embodiment (E6) of (E3) Rt and R₃ to R₄₁ are H and R₂ is CH₃.

In an embodiment (E7) of (E3) R-ι to R₆ and R₈to Rn are H and R₇ is CH₃

In an embodiment (E8) of (E4) R₁₍ R₃ to R₆ and R₈to Rn are H.

In an embodiment (E9) of (E1 ) one or more of R₂ to Ru are independently of each other selected from the group consisting of methoxy, ethoxy, propoxy, butoxy and C₃-C₆ cycloalkoxy.

In an embodiment (E10) of (E1 ) one or more of R₂ to Rn are independently of each other selected from the group consisting of CÛ-C3 alkyl and C₃-C₆ cycloalkyl.

In an embodiment (E11 ) of (E10) one or more of R₂ to Rn are independently of each other substituted with a substituent selected from the group consisting of F and alkoxy.

In an embodiment (E12) of (E11) the substituent of one or more of R₂ to Rn is C1-C3 alkoxy.

In an embodiment (E13) of any of (E12) and (E11 ) the C-|-C₃ alkoxy is further substituted one or more times with fluorine.

In an embodiment (E14) of (E13) the C_rC₃ alkoxy is further substituted once with fluorine.

In an embodiment (E15) of any of any of (E1) to (E14) the compound is a PDE1A inhibitor.

In an embodiment (E16) of any of any of (E1 ) to (E14) the compound is a PDE1B inhibitor.

In an embodiment (E17) of any of any of (E1 ) to (E14) the compound is a PDE1C inhibitor.

In an embodiment (E18) of any of (E1) to (E17) the compound is used as a médicament.

DEFINITIONS

PDE1 ENZYMES

The PDE1 isozyme family includes numerous splice variant PDE1 isoforms. It has three subtypes, PDE1A, PDE1B and PDE1C which divide further into various isoforms. In the context ofthe présent invention PDE1 and PDE1 enzymes are synonymous and referto PDE1A, PDE1B and PDE1C enzymes as well as their isoforms.

SUBSTITUENTS

As used in the context of the présent invention, the terms “halo” and “halogen” are used interchangeably and refer to fluorine, chlorine, bromine or iodine.

The terms ”Ci-C₃ alkyl”, ”C₁-C₄ alkyl”, ”C-rC₅ alkyl” and ”<3·γΟ₆ alkyl” refer to a straight-chain or branched saturated hydrocarbon having from one to six carbon atoms, inclusive. Examples of such groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2methyl-2-propyl, 2-methyl-1-butyl, and n-hexyl.

The term “C₃-C₆ cycloalkyl” typically refers to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The expression “Ci-C₆ alkoxy” refers to a straight-chain, branched or cyclic saturated alkoxy group having from one to six carbon atoms, inclusive, with the open valency on the oxygen. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-butoxy, 2-methylpentoxy and n-hexyloxy.

The term “cycloalkoxy” refers to a spécifie embodiment of “alkoxy” as defined above, wherein the alkoxy group has at least three carbon atoms, in particular three to six carbon atoms, inclusive, which form a “C₃-C₆ cycloalkyl” as defined above, linked to an oxygen atom with the open valency on the oxygen.

The term “aryl” refers to a phenyl ring, optionally substituted with halogen, C^Ce alkyl, Ch-Ce alkoxy or halo(C₁-C₆)alkyl as defined above.

The term “heteroaryl” monocyclic- or polycyclic aromatic ring comprising carbon atoms, hydrogen atoms, and one or more heteroatoms, preferably, 1 to 4 heteroatoms, such as 1-3 heteroatoms, preferably 2 or 1 heteroatom, independently selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (1,2,4)triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, phenyl, isoxazolyl, and oxazolyl. A heteroaryl group can be unsubstituted or substituted with one or two suitable substituents. Preferably, the heteroaryl of this invention is a monocyclic 5 or 6 membered heteroaryl, wherein the ring comprises 2 to 5 carbon atoms and 1 to 3 heteroatoms, referred to herein as “monocyclic 5 or 6 membered heteroaryl”

ISOMERIC FORMS

Where compounds ofthe présent invention contain one or more chiral centers reference to any ofthe compounds will, unless otherwise specified, coverthe enantiomerically or diastereomerically pure compound as well as mixtures ofthe enantiomers or diastereomers in any ratio.

The above also applies where compounds of the invention contain more than two chiral centers.

PDE1 INHIBITORS

In the context ofthe présent invention a compound is considered to be a PDE1 inhibitor if the amount required to reach the IC₅₀ level of PDE1B is 5 micro molar or less, preferably less than 4 micro molar, such as 3 micro molar or less, more preferably 2 micro molar or less, such as 1 micro molar or less, in particular 500 nM or less. In preferred embodiments the required amount of PDE1 inhibitor required to to reach the IC₅₀ level of PDE1B is 400nM or less, such as 300 nM or less, 200nM or less, 100 nM or less, or even 80 nM or less, such as 50 nM or less, for example 25 nM or less.

PHARMACEUTICALLY ACCEPTABLE SALTS

The présent invention also comprises salts of the compounds, typically, pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable acid addition salts. Acid addition salts include salts of inorganic acids as well as organic acids.

Représentative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like. Représentative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Berge, S.M. et al., J. Pharm. Sci. 1977, 66, 2, the contents of which are hereby incorporated by reference.

Furthermore, the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, éthanol and the like. In general, the solvated forms are considered équivalent to the unsolvated forms for the purposes of this invention.

THERAPEUTICALLY EFFECTIVE AMOUNT

In the présent context, the term therapeutically effective amount of a compound means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of said compound. An amount adéquate to accomplish this is defined as therapeutically effective amount. Effective amounts for each purpose will dépend on the severity ofthe disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine expérimentation, by constructing a matrix of values and testing different points in the matrix, which is ail within the ordinary skills of a trained physician.

In the présent context, the term treatment and treating means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder. The term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration ofthe active compound to alleviate the symptoms or complications, to delay the progression ofthe disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prévention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration ofthe active compounds to preventthe onsetofthe symptoms or complications. Nonetheless, prophylactic (préventive) and therapeutic (curative) treatments are two separate aspects ofthe invention. The patient to be treated is preferably a mammal, in particular a human being.

PHARMACEUTICAL COMPOSITIONS

The présent invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent. The présent invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one of the spécifie compounds disclosed in the Experimental Section herein and a pharmaceutically acceptable carrier or diluent.

The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19^th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parentéral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. It will be appreciated that the route will dépend on the general condition and âge ofthe subject to be treated, the nature ofthe condition to be treated and the active ingrédient.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, the compositions may be prepared with coatings such as enteric coatings or they may be formulated so as to provide controlled release of the active ingrédient such as sustained or prolonged release according to methods well known in the art. Liquid dosage forms for oral administration include solutions, émulsions, suspensions, syrups and élixirs.

Pharmaceutical compositions for parentéral administration include stérile aqueous and nonaqueous injectable solutions, dispersions, suspensions or émulsions as well as stérile powders to be reconstituted in stérile injectable solutions or dispersions prior to use. Other suitable administration forms include, but are not limited to, suppositories, sprays, ointments, creams, gels, inhalants, dermal patches and implants.

Typical oral dosages range from about 0.001 to about 100 mg/kg body weight per day. Typical oral dosages also range from about 0.01 to about 50 mg/kg body weight per day. Typical oral dosages further range from about 0.05 to about 10 mg/kg body weight per day. Oral dosages are usually administered in one or more dosages, typically, one to three dosages per day. The exact dosage will dépend upon the frequency and mode of administration, the sex, âge, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors évident to those skilled in the art.

The formulations may also be presented in a unit dosage form by methods known to those skilled in the art. For illustrative purposes, a typical unit dosage form for oral administration may contain from about 0.01 to about 1000 mg, from about 0.05 to about 500 mg, or from about 0.5 mg to about 200 mg.

For parentéral routes such as intravenous, intrathecal, intramuscular and similar administration, typical doses are in the order of half the dose employed for oral administration.

The présent invention also provides a process for making a pharmaceutical composition comprising mixing a therapeutically effective amount of a compound of formula (I) and at least one pharmaceutically acceptable carrier or diluent, ln an embodiment, of the présent invention, the compound utilized in the aforementioned process is one of the spécifie compounds disclosed in the Experimental Section herein.

The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable sait thereof. One example is an acid addition sait of a compound having the utility of a free base. When a compound of formula (I) contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of formula (I) with a molar équivalent of a pharmaceutically acceptable acid. Représentative examples of suitable organic and inorganic acids are described above.

For parentéral administration, solutions of the compounds of formula (I) in stérile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonie with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subeutaneous and intraperitoneal administration. The compounds of formula (I) may be readily incorporated into known stérile aqueous media using standard techniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents or fillers, stérile aqueous solutions and various organic solvents. Examples of solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnésium stéarate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the compounds of formula (I) and a pharmaceutically acceptable carrier are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.

Formulations of the présent invention suitable for oral administration may be presented as discrète units such as capsules or tablets, each containing a predetermined amount of the active ingrédient, and optionally a suitable excipient. Furthermore, the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid émulsion.

if a solid carrier is used for oral administration, the préparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it may be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will range from about 25 mg to about 1 g per dosage unit. If a liquid carrier is used, the préparation may be in the form of a syrup, émulsion, soft gelatin capsule or stérile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

The pharmaceutical compositions of the invention may be prepared by conventional methods in the art. For example, tablets may be prepared by mixing the active ingrédient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tableting machine préparé tablets. Examples of adjuvants or diluents comprise: corn starch, potato starch, talcum, magnésium stéarate, gelatin, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colorings, flavorings, preservatives etc. may be used provided that they are compatible with the active ingrédients.

TREATMENT OF DISORDERS

As mentioned above, the compounds of formula (I) are PDE1 enzyme inhibitors and as such are useful to treat associated neurological and psychiatrie disorders.

The invention thus provides a compound of formula (I) or a pharmaceutically acceptable acid addition sait thereof, as well as a pharmaceutical composition containing such a compound, for use in the treatment of a neurodegenerative disorder, psychiatrie disorder or drug addiction in mammals including humans; wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drugrelated dementia, dementia associated with intracranial tumors or cérébral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; and age-related cognitive décliné; and wherein the psychiatrie disorder is selected from the group consisting of schizophrenia, for example of the paranoid, disorganized, catatonie, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the dépressive type; delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphétamine, cannabis, cocaïne, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type; and wherein the drug addiction is an alcohol, amphétamine, cocaïne, or opiate addiction.

The compounds of formula (I) or pharmaceutically acceptable salts thereof may be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compounds of the présent invention hâve utility, where the combination of the drugs together are safer or more effective than either drug alone. Additionally, the compounds of the présent invention may be used in combination with one or more other drugs that treat, prevent, control, ameliorate, or reduce the risk of side effects or toxicity of the compounds of the présent invention. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with the compounds of the présent invention. Accordingly, the pharmaceutical compositions of the présent invention include those that contain one or more other active ingrédients, in addition to the compounds of the présent invention. The combinations may be administered as part of a unit dosage form combination product, or as a kit or treatment protocol wherein one or more additional drugs are administered in separate dosage forms as part of a treatment regimen.

The présent invention provides a method of treating a mammal, including a human, suffering from a neurodegenerative disorder selected from a cognition disorder or movement disorder, which method comprises administering to the subject a therapeutically effective amount of a compound of formula (I).

This invention further provides a method of treating a neurodegenerative disorder or condition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) effective in inhibiting PDE1.

This invention also provides a method of treating a subject suffering from a psychiatrie disorder, which method comprises administering to the subject a therapeutically effective amount of a compound of formula (I). Examples of psychiatrie disorders that can be treated according to the présent invention include, but are not limited to, Attention Déficit Hyperactivity Disorder (ADHD) schizophrenia, for example ofthe paranoid, disorganized, catatonie, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the dépressive type; delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphétamine, cannabis, cocaïne, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type; and the anxiety disorder is selected from panic disorder; agoraphobia; a spécifie phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder.

It has been found that the compounds of formula (I) or pharmaceutically acceptable salts thereof may advantageously be administered in combination with at least one neuroleptic agent (which may be a typical or an atypical antipsychotic agent) to provide improved treatment of psychiatrie disorders such as schizophrenia. The combinations, uses and methods of treatment of the invention may also provide advantages in treatment of patients who fail to respond adequately or who are résistant to other known treatments.

The présent invention thus provides a method of treating a mammal suffering from a psychiatrie disorder, such as schizophrenia, which method comprises administering to the mammal a therapeutically effective amount of a compound of formula (I), either alone or as combination therapy together with at least one neuroleptic agent.

The term neuroleptic agent as used herein refers to drugs, which hâve the effect on cognition and behaviour of antipsychotic agent drugs that reduce confusion, delusions, hallucinations, and psychomotor agitation in patients with psychoses. Also known as major tranquilizers and antipsychotic drugs, neuroleptic agents include, but are not limited to: typical antipsychotic drugs, including phenothiazines, further divided into the aliphatics, piperidines, and piperazines, thioxanthenes (e.g., cisordinol), butyrophenones (e.g., haloperidol), dibenzoxazepines (e.g., loxapine), dihydroindolones (e.g., molindone), diphenylbutylpiperidines (e.g., pimozide), and atypical antipsychotic drugs, including benzisoxazoles (e.g., rispéridone), sertindole, olanzapine, quetiapine, osanetant and ziprasidone.

Particularly preferred neuroleptic agents for use in the invention are sertindole, olanzapine, rispéridone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.

The présent invention further provides a method of treating a subject suffering from a cognition disorder, which method comprises administering to the subject a therapeutically effective amount of a compound of formula (I). Examples of cognition disorders that can be treated according to the présent invention include, but are not limited to, Alzheimer's disease, multiinfarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cérébral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; and age-related cognitive décliné.

This invention also provides a method of treating a movement disorder, which method comprises administering to the subject a therapeutically effective amount of a compound of formula (I). Examples of movement disorders that can be treated according to the présent invention include, but are not limited to, Huntington's disease and dyskinesia associated with dopamine agonist therapy. This invention further provides a method of treating a movement disorder selected from Parkinson's disease and restless leg syndrome, which comprises administering to the subject a therapeutically effective amount of a compound of formula (I).

This invention also provides a method of treating a mood disorder, which method comprises administering to the subject a therapeutically effective amount of a compound of formula (I). Examples of mood disorders and mood épisodes that can be treated according to the présent invention include, but are not limited to, major dépressive épisode ofthe mild, moderate or severe type, a manie or mixed mood épisode, a hypomanie mood épisode; a dépressive épisode with a typical features; a dépressive épisode with melancholic features; a dépressive épisode with catatonie features; a mood épisode with postpartum onset; post-stroke dépréssion; major dépressive disorder; dysthymie disorder; minor dépressive disorder; premenstrual dysphorie disorder; post-psychotic dépressive disorder of schizophrenia; a major dépressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia; a bipolar disorder, for example bipolar I disorder, bipolar II disorder, and cyclothymie disorder. It is understood that a mood disorder is a psychiatrie disorder.

This invention further provides a method of treating a disorder comprising as a symptom a defîciency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) effective in treating said disorder.

Other disorders that can be treated according to the présent invention are obsessive/compulsive disorders, Tourette's syndrome and other tic disorders.

As used herein, and unless otherwise indicated, a neurodegenerative disorder or condition refers to a disorder or condition that is caused by the dysfunction and/or death of neurons in the central nervous system. The treatment of these disorders and conditions can be facilitated by administration of an agent which prevents the dysfunction or death of neurons at risk in these disorders or conditions and/or enhances the function of damaged or healthy neurons in such a way as to compensate for the loss of function caused by the dysfunction or death of at-risk neurons. The term neurotrophic agent as used herein refers to a substance or agent that has some or ail of these properties.

Examples of neurodegenerative disorders and conditions that can be treated according to the présent invention include, but are not limited to, Parkinson’s disease; Huntington's disease; dementia, for example Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, and Fronto tempera! Dementia; neurodegeneration associated with cérébral trauma; neurodegeneration associated with stroke, neurodegeneration associated with cérébral infarct; hypoglycemia-induced neurodegeneration; neurodegeneration associated with epileptic seizure; neurodegeneration associated with neurotoxin poisoning; and multi-system atrophy.

In one embodiment of the présent invention, the neurodegenerative disorder or condition involves neurodegeneration of striatal medium spiny neurons in a mammal, including a human.

In a further embodiment of the présent invention, the neurodegenerative disorder or condition is Huntington's disease.

Ail references, including publications, patent applications and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety (to the maximum extent permitted by law).

Headings and sub-headings are used herein for convenience only, and should not be construed as limiting the invention in any way.

The use of any and ail examples, or exemplary language (including “for instance”, “for example”, “e.g.”, and “as such”) in the présent spécification is intended merely to better illuminate the invention, and does not pose a limitation on the scope of invention unless otherwise indicated.

The citation and incorporation of patent documents herein is done for convenience only, and does not reflect any view of the validity, patentability and/or enforceability of such patent 10 documents.

The présent invention includes ail modifications and équivalents of the subject-matter recited in the claims appended hereto, as permitted by applicable law.

COMPOUNDS OFTHE INVENTION

Compound number	Compound	PDE1C IC50 (nM)	PDE1B IC50 (nM)	PDE1A IC50 (nM)
1	(3aS,6aS)-4-(7,8dimethoxyquinazolin-4yl)hexahydro-2H-furo[3,2b]pyrrole	120	120	160
2	(3aR,6aR)-4-(7,8dimethoxyquinazolin-4yl )h exa hyd ro-2 H-f u ro [3,2b]pyrrole	2800	3700	3200

Table 1: IC₅₀ value of compounds ofthe invention. IC₅₀ values were determined according to the method described in the section “PDE1 inhibition assay”

EXPERIMENTAL SECTION

PREPARATION OFTHE COMPOUNDS OFTHE INVENTION

General Methods

Analytical LC-MS data were obtained using one of the methods identified below.

Method 1: An Agilent 1200 LCMS system with ELS detector was used. Column: Agilent TC-C18 5 pm; 2.1x50mm; Column température: 50°C; Solvent system: A = water/trifluoroacetic acid (99.9:0.1) and B = acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Linear gradient elution with A:B = 99:1 to 0:100 in 4.0 minutes and with a flow rate of 0.8 mL/minute.

Préparative SFC was performed on a Thar 80 instrument. Exemplified conditions can be, but not limited to: Column AD 250 X 30mm with 20 pm particle size; Column température: 38 °C, Mobile phase: Supercritical CO₂/ EtOH(0.2%NH₃H₂O) =45/55.

EXAMPLES

Example 1:

cis-4-(7,8-dimethoxyquinazolin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole:

To a solution of 4-chloro-7,8-dimethoxyquinazoline (2.0 g, 8.9 mmol) in DMF (50 mL) was added cis-hexahydro-2H-furo[3,2-b]pyrrole (900 mg, 8.10 mmol), DIPEA (3.45 g, 26.7 mmol) and itwas stirred at reflux for 12 hours. The mixture was concentrated and purified by prep-HPLC (column C18, eluent CH₃CN/H₂O from 38/62 to 58/42, 0.05% ammonia solution) to give cis-4-(7,8dimethoxyquinazolin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole (1.31g, Yield: 54.2%) as a white solid.

The product was further purifed by SFC, and numbered according to their order of elution:

Stereoisomer 1 (first eluting by SFC): 406 mg (31%) as a white solid,

LC-MS (m/z) 302.1 (MH+), t_R(min, method 1) = 1.912.

[a]²% = 344.0 (c = 0.1 mg/mL, CHCI₃)

This stereoisomer was identified as being (3aS,6aS)-4-(7,8-dimethoxyquinazolin-4yl)hexahydro-2H-furo[3,2-b]pyrrole by co-crystallisation with the PDE1B enzyme.

Stereoisomer 2 (second eluting by SFC): 414 mg (33%) as a white solid.

LC-MS (m/z) 302.1 (MH+), t_R(min, method 1) = 1.913.

[a]²% = -336.0 (c = 0.1 mg/mL, CHCI₃)

This is stereoisomer (3aR,6aR)-4-(7,8-dimethoxyquinazolin-4-yl)hexahydro-2H-furo[3,25 bjpyrrole.

PDE1 INHIBITION ASSAY

PDE1A, PDE1B and PDE1C assays were performed as follows: the assays was performed in 60 pL samples containing afixed amount ofthe PDE1 enzyml (sufficientto convert 20-25% of the cyclic nucléotide substrate), a buffer (50 mM HEPES pH 7.6; 10 mM MgCI₂; 0.02% Tween20), 0.1 mg/ml BSA, 15 nM tritium labelled cAMP and varying amounts of inhibitors. Reactions were initiated by addition of the cyclic nucléotide substrate, and reactions were allowed to proceed for 1 h at room température before being terminated through mixing with 20 pL (0.2 mg) yttrium silicate SPA beads (PerkinElmer). The beads were allowed to settle for

1 h in the dark before the plates were counted in a Wallac 1450 Microbeta counter. The measured signais were converted to activity relative to an uninhibited control (100%) and lC₅₀ values were calculated using XIFit (model 205, IDBS).

Claims (13)

1. Claims

   1. A compound having the structure

   Compound (I) wherein

   R-ι is selected from the group consisting of H, F, C₃-C₆ cycloalkyl and C_rC₄alkyl.

   R₂ to Rn selected from the group consisting of H, C_rC₃ alkyl, C₃-C₆ cycloalkyl, fluorine, hydroxy and C-|-C₆alkoxy, and pharmaceutically acceptable acid addition salts of Compound (I), racemic mixtures of Compound (I), or the corresponding enantiomer and/or optical isomer of Compound (I), and polymorphie forms of Compound (I) as well as tautomeric forms of Compound (I)·
2. 2. The compound of claim 1 wherein Ri to Rn are H.
3. 3. The compound of claim 1, wherein the compound is (3aS,6aS)-4-(7,8dimethoxyquinazolin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole.
4. 4. The compound of claim 1, wherein the compound is (3aR,6aR)-4-(7,8dimethoxyquinazolin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole.
5. 5. The compound of any of claims 1-4 for use as a médicament.
6. 6. The compound of any of claims 1-4 for use in the treatment of a neurological or psychiatrie disorder.
7. 7. The compound of any of claims 1-4 for use in the treatment of schizophrenia.
8. 8. The compound of any of claims 1-4 for use in the treatment of cognitive impairment in association with schizophrenia.
9. 9. The compound of any of claims 1-4 for use in the treatment of Attention Déficit hyperactivity Disorder (ADHD).
10. 10. The compound of any of claims 1 -4 for use in the treatment of Alzheimer’s disease.
11. 11. The compound of any of claims 1-4 for use in the treatment of Parkinson’s disease.
12. 12. The compound of any of claims 1-4 for use in the treatment of Huntington’s disease
13. 13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, and one or more pharmaceutically acceptable carriers, diluents or excipients.