WO2014016789A1 - Utilisation de dérivés de pyrazolo[3,4-d]pyrimidin-4(5h)-one comme inhibiteurs de pde9 - Google Patents

Utilisation de dérivés de pyrazolo[3,4-d]pyrimidin-4(5h)-one comme inhibiteurs de pde9 Download PDF

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WO2014016789A1
WO2014016789A1 PCT/IB2013/056086 IB2013056086W WO2014016789A1 WO 2014016789 A1 WO2014016789 A1 WO 2014016789A1 IB 2013056086 W IB2013056086 W IB 2013056086W WO 2014016789 A1 WO2014016789 A1 WO 2014016789A1
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pyrimidin
pyrazolo
cyclopentyl
methyl
mmol
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PCT/IB2013/056086
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English (en)
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Rafał MOSZCZYŃSKI-PĘTKOWSKI
Łukasz BOJARSKI
Filip Stefaniak
Maciej Wieczorek
Krzysztof DUBIEL
Monika Lamparska-Przybysz
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Celon Pharma S.A.
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Publication of WO2014016789A1 publication Critical patent/WO2014016789A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to novel heterocyclic compounds, pyrazolo[3,4-d]- pyrimidin-4(5H)-one derivatives exhibiting the ability of phosphodiesterase 9 inhibition, as well as pharmaceutical compositions containing them and their use as medicaments.
  • the compounds can be used in the treatment of cognitive functions disorders and neurodegenerative diseases, such as Alzheimer's disease.
  • Cognitive functions i.e. mental processes involved in perception, reasoning and memory, can be disordered to a different extent due to the action of various factors and in many diseases.
  • Disorders of cognitive functions are the feature of many diseases of central nervous system in a broad range of psychotic and neurodegenerative disorders.
  • Cyclic monophosphate cGMP is common signaling molecule in all mammal cells, involved in the process of regulation of synapses functioning.
  • cGMP is hydrolysed with high selectivity by the enzyme phosphodiesterase 9A (PDE9A) from the family of phosphodiesterases. It is expressed mainly in the brain, with high concentrations in the cerebellum, cerebral cortex, striatum, and hippocampus. It is believed that PDE9A inhibitors can potentiate cGMP signalling and synaptic transmission, enhancing neuronal communication in the brain involved in cognitive functions, including processes of learning and memorising, perception, reasoning and concentration.
  • PDE9A phosphodiesterase 9A
  • PDE9A enzyme activity has become recently one of the targets in attempts to discover new medicaments for treating disorders of cognitive functions, including disorders of cognitive functions associated with pathologies of central nervous system, such as various types of neurodegenerative processes in the brain, such as for example Alzheimer's disease.
  • PDE9 inhibitors - derivatives of pyrazolo[3,4-d]pyrimidin-4(5H)- one of potential utility in the treatment of neurodegenerative diseases associated with disorders of memory, perception, concentration, learning, such as Alzheimer's disease.
  • Known compounds have different substituents in positions 1 and 6 of pyrazolpyrimidine moiety.
  • WO2004/09681 1 discloses pyrazolo[3,4-d]pyrimidin-4(5H)-one derivatives substituted in the position 1 with, among others, cycloalkyl, heterocycloalkyl or alkyl, and in the position 6 with cycloalkyl, heterocyclomethyl, arylmethyl or hetero- arylmethyl, substituted by substituent containing carboxyl, amide, amine or sulphonamide moiety.
  • the compounds are described as having the ability to inhibit PDE9 activity and useful in the treatment of cardiovascular diseases and diabetes.
  • WO2004/09921 1 discloses pyrazolo[3,4-d]pyrimidin-4(5H)-one derivatives substituted in the position 1 with phenyl or substituted phenyl and in the position 6 with cyclylmethyl group.
  • the compounds are described as PDE9A inhibitors useful in the treatment of perception, concentration, cognition and learning disorders, including Alzheimer's disease. From among them, 1 -(2-chlorophenyl)- 6-[(2R)-3,3, 3-trifluoro-2-methylpropyl]-1 ,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin- 4-one designated with the code BAY 73-6691 reached the stage of clinical trials.
  • WO2009/121919 discloses pyrazolo[3,4-d]pyrimidin-4(5H)-one derivatives substituted in the position 1 with optionally substituted mono-, bi- or tricyclic group, and in the position 6 with methyl substituted with among others aryl or heteroaryl group optionally substituted with fluorine, F 3 C-, H F2C- , or Ci -C 3 alkyl.
  • the compounds are described as PDE9A inhibitors, useful in the treatment of CNS diseases, including Alzheimer's disease.
  • WO2010/1 12437 discloses pyrazolo[3,4-d]pyrimidin-4(5H)-one derivatives substituted in the position 1 with tetrahydropyranyl, and in the position 6 with methylphenyl or methylheteroaryl group, wherein phenyl and heteroaryl groups are further substituted with phenyl or heteroaryl group.
  • the compounds are described as useful in the treatment of CNS diseases, including Alzheimer's disease.
  • WO2010/026214 discloses pyrazolo[3,4-d]pyrimidin-4(5H)-one derivatives substituted in the position 1 with optionally substituted tetrahydropyranyl and in the position 6 with methyl substituted amongst others with aryl group optionally substituted with fluorine, F 3 C- , HF 2 C- , or d -C 3 alkyl.
  • the compounds are described as PDE9 inhibitors useful in the treatment of perception, concentration, cognition, and learning disorders, including Alzheimer's disease.
  • WO201 1 /018495 discloses pyrazolo[3,4-d]pyrimidin-4(5H)-one derivatives, substituted in the position 1 with heterocyclyl, methyleneheterocyclyl or ethyleneheterocyclyl group, and in the position 6 with optionally substituted 3- to 7-membered cycloalkyl group.
  • the compounds are described as PDE9 inhibitors useful in the treatment of perception, concentration, cognition, and learning disorders, including Alzheimer's disease.
  • WO2012/020022 discloses pyrazolo[3,4-d]pyrimidin-4(5H)-one derivatives, substituted in the position 1 with a substituent selected from cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, and pyridyl, and in the position 6 with cyclobutyl or cyclopentyl substituted with heteroaryl group.
  • the compounds are described as useful in the treatment of Alzheimer's disease and schizophrenia.
  • the present invention relates to novel compounds of the general formula (I)
  • R 1 is selected from the group consisting of:
  • - phenyl unsubstituted or substituted with 1 to 3 substituents selected from F, CI, Br, I, CN, -0-C1 -C3-alkyl, fluorinated -0-C1 -C3-alkyl, -(CH 2 ) m OH, and 5- membered heterocyclic group with 1 or 2 heteroatoms selected from N, 0 and S; and
  • R 2 and R 3 independently of each other represent H atom or straight or branched C1 -C3 alkyl
  • R 4 is selected from the group consisting of
  • Q. represents a bond or C1 -C3-alkylene, which can be optionally substituted by one to three C1 -C3 alkyls;
  • X is selected from the group consisting of 0, NR 5 , and S(0) p ;
  • R 5 represents H atom or C1 -C3 alkyl
  • n 1 , 2 or 3;
  • p 0, 1 or 2;
  • the present invention relates also to the compound of the general formula (I) as defined above for use as a medicament.
  • the present invention relates also to a pharmaceutical composition, comprising as an active ingredient a compound of the general formula (I) as defined above in combination with pharmaceutically acceptable excipients.
  • the compounds of the general formula (I) defined above can be useful in the treatment of cognitive functions disorders and neurodegenerative diseases of central nervous system, including dementia and Alzheimer's disease.
  • the present invention relates therefore to the use of a compound of the general formula (I) as defined above for the preparation of a medicament for treating cognitive function disorders and neurodegenerative diseases.
  • the present invention relates further to a method of treating of cognitive function disorders and neurodegenerative diseases in a mammal subject, including humans, which comprises administering to the subject in need thereof a therapeutically effective amount of a compound of the general formula (I) as defined above or a pharmaceutical composition as defined above.
  • the invention relates to the compound of the formula (I) as above, wherein:
  • R 1 is selected from the group consisting of:
  • - phenyl unsubstituted or substituted with 1 to 3 substituents selected from F, CI, Br, I, CN, -0-C1 -C3-alkyl, fluorinated -0-C1 -C3-alkyl, -(CH 2 ) m OH and 5- membered heterocyclic group with 1 or 2 heteroatoms selected from N, 0 and S; and
  • R 2 and R 3 independently of each other represent H atom or straight or branched C1 -C3 alkyl
  • R 4 is selected from the group consisting of 4- to 6-membered cycloalkyl, wherein one of carbon atoms can be replaced by 0 atom which is unsubstituted or substituted with one or two halogen atoms, and straight or branched C1 -C4 alkyl;
  • Q. represents a bond or C1 -C3-alkylene, which can be optionally substituted with one to three C1 -C3-alkyls;
  • X is selected from the group consisting of 0, NR 5 , and S(0) p ;
  • R 5 represents H atom or C1 -C3 alkyl
  • n 1 , 2 or 3;
  • p 0, 1 or 2;
  • the invention relates to the compound of the formula (I) as above, wherein:
  • R 1 is selected from the group consisting of:
  • - phenyl substituted with 1 or 2 substituents selected from the group consisting of F, CI, Br, I, CN, CH 2 OH, OCH3, OCF3, and 5-membered heterocyclic group with 1 or 2 N atoms; and
  • R 2 and R 3 independently of each other represent H atom or CH 3 ;
  • R 4 is selected from the group consisting of cyclopentyl, optionally substituted with one or two halogen atoms, cyclohexyl, optionally substituted with one or two halogen atoms, tetrahydropyranyl, iso-propyl, and t-butyl;
  • X is selected from the group consisting of 0, NH, N-CH 3 , S, S(O) and S(0) 2 ;
  • Q. represents a bond; and salts thereof, including pharmaceutically acceptable salts.
  • One specific embodiment of the invention is the compound of the formula (I) as defined above, wherein R 1 represents unsubstituted phenyl.
  • R 1 represents phenyl substituted with 1 or 2 substituents selected from the group consisting of F, CI, Br, I, CN, CH 2 OH, OCH3, OCF3, imidazolyl, pyrrolidinyl, and pyrrolil, or a 5-membered heterocyclic group with 1 or 2 N atoms.
  • 5-Membered heterocyclic group can be especially selected from the group consisting of imidazolyl, pyrrolidinyl and pyrrolil.
  • R 1 represents 6- or 10-membered heteroaryl with 1 or 2 N atoms in the ring.
  • R 1 can represent 10-membered heteroaryl with 1 N atom in the ring, such as 8-quinolinyl, 7-quinolinyl, 6-quinolinyl, 5-quinolinyl, 3-quinolinyl, and 2-quinolinyl, especially 8-quinolinyl, or isoquinolinyl.
  • R 1 can also represent 10-membered heteroaryl with 2 N atoms in the ring, such as quinoxalinyl.
  • R 1 can also represent 6-membered heteroaryl with one N atom, including pyridyl, such as 2-pyridyl, 3-pyridyl or 4-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl or 6-pyrimidinyl.
  • pyridyl such as 2-pyridyl, 3-pyridyl or 4-pyridyl
  • pyrimidinyl such as 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl or 6-pyrimidinyl.
  • R 1 can also represent 6-membered heteroaryl with 2 N atoms in the ring, such as pyrazinyl or pyridazinyl.
  • Another specific embodiment of the invention is the compound of the formula (I) wherein R 2 and R 3 both represent H atom.
  • n is 0, and R 2 and R 3 both represent H atom.
  • n is 1 , and R 2 and R 3 both represent H atom.
  • n is 1
  • R 2 is H
  • R 3 represents C1 -C3 alkyl, preferably CH 3 .
  • R 4 represents 4- to 6-membered cycloalkyl, wherein one of carbon atoms in the ring can be replaced with 0 atom, and which can be optionally substituted with one or two halogen atom.
  • R 4 represents a 6-membered cycloalkyl (i.e. cyclopentyl or cyclohexyl), or 5- or 6-membered cycloalkyl wherein one of carbon atoms in the ring is replaced with 0 atom (tetrahydrofuranyl or tetrahydropyranyl).
  • R 4 represents 4- to 6-membered cycloalkyl which is substituted with one or two halogen atom, preferably with two fluorine atoms, especially geminally substituted with two fluorine atoms.
  • R 4 is cyclohexyl geminally substituted with two fluorine atoms, especially 4,4-difluorocyclohexyl.
  • R 4 represents 4- to 6-membered cycloalkyl, wherein one of carbon atoms in the ring can be replaced with 0 atom, which is unsubstituted.
  • R 4 represents straight or branched C1 -C4-alkyl.
  • R 4 represents branched C3-C4-alkyl, such as isopropyl or t-butyl.
  • One of specific embodiments of the invention is the compound of formula (I) as above, wherein Q is a bond.
  • Q represents C1 -C3-alkylene group, which can be optionally substituted with one to three C1 -C3-alkyls.
  • Q represents C1 -C3-alkylene group substituted with one methyl.
  • Q. can represent -CH 2 - group, -CH 2 - group substituted with methyl (i.e. -CH(CH 3 )-) or -CH 2 CH 2 -.
  • One of specific embodiments of the invention is the compound of formula (I) as defined above, wherein X represents 0.
  • Another embodiment of the invention is the compound of formula (I) as defined above, wherein X represents S and p is 0.
  • Another embodiment of the invention is the compound of formula (I) as defined above, wherein X represents S and p is 1.
  • Another embodiment of the invention is the compound of formula (I) as defined above, wherein X represents S and p is 2.
  • Another specific embodiment of the invention is the compound of formula (I) as defined above, wherein X represents NH or NCH 3 .
  • Yet another embodiment of the invention is the compound of formula (I) as defined above, wherein X is selected from 0, S, S(O), S(0) 2 and NH, Q represents a bond, and R 2 and R 3 both represent H atoms.
  • X is selected from 0, S, S(O), S(0) 2 and NH
  • Q represents a bond
  • R 2 and R 3 both represent H atoms.
  • One of specific embodiments of the invention is the compound of formula (I) as defined above, wherein m is 1 .
  • Thus-C1 -C3-alkyl encompasses -CH3 (methyl), -CH 2 CH3 (ethyl), -CH2CH2CH3 (n-propyl), and -CH(CH 3 )2 (isopropyl) groups.
  • Thus-C1 -C4-alkyl encompasses -CH3 (methyl), -CH 2 CH3 (ethyl), -CH2CH2CH3 (n-propyl), -CH(CH 3 ) 2 (isopropyl), -CH2CH2CH2CH3 (n-butyl), -CH 2 CH(CH 3 ) 2 (isobutyl), -CH(CH 3 )CH 2 CH 3 (sec-butyl) and -C(CH 3 ) 3 (t-butyl) groups.
  • the term termed-0-C1 -C3-alkyl encompasses -OCH 3 (methoxy), -OCH 2 CH 3 (ethoxy), -OCH2CH2CH3 (n-propoxy) and -OCH(CH 3 ) 2 (isopropoxy) groups.
  • Fluorinated 0-C1 -C3-alkyl encompasses groups such as indicated above for -0-C1 -C3-alkyl, wherein at least one hydrogen atoms is replaced with fluorine atom, including partially fluorinated groups, such as for example -OCHF2, and perfluorinated groups, such as for example -OCF3.
  • the term askedC1 -C3-alkylene group encompasses bivalent straight chain hydrocarbyl group having 1 to 3 carbon atoms, that is methylene (-CH2- ), ethylene (-CH2-CH2- ) and propylene (-CH2-CH2-CH2- ) groups.
  • ,5-membered heterocyclic group encompasses 5-membered saturated heterocyclic groups and heterocyclic groups having double bond(s) in the ring, in particular 5-membered aromatic heterocyclic groups.
  • Saturated heterocyclic groups comprise in particular pyrrolidinyl.
  • Aromatic heterocyclic groups encompass in particular groups with one heteroatom, including nitrogen atom, that is pyrrolyl, oxygen atom, that is furanyl, and sulphur atom, that is thienyl.
  • Aromatic heterocyclic groups encompass in particular 5-membered groups with two nitrogen atoms, that is imidazolyl or pyrazolyl, 5-membered heteroaryls with two nitrogen atoms and one sulphur atom, such as thiadiazolyl, and 5- membered heteroaryls with one nitrogen atom and one sulphur atom, such as thiazolyl.
  • halogen atom encompasses chlorine, bromine and fluorine atoms.
  • Particular embodiments of the invention are the compounds selected from the group consisting of the following compounds and their salts, including pharmaceutically acceptable salts:
  • Another specific compound of the invention is
  • Salts of the compounds of formula (I) of the invention include salts with pharmaceutically acceptable inorganic and organic acids. Preferred are salts that are pharmaceutically acceptable. Inorganic and organic acids that can form pharmaceutically acceptable salts with compounds having basic nitrogen atom are well known in the art. Salts with inorganic acids especially comprise those of hydrochloric, hydrobromic, sulphuric, and phosphoric acids. Salts with organic acids especially comprise those of methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic, and benzoic acids.
  • Salts of the compounds of formula (I) of the invention comprise also salts with inorganic and organic bases.
  • Preferred are salts that are pharmaceutically acceptable.
  • Inorganic and organic bases that can form pharmaceutically acceptable salts are well known in the art.
  • Salts with inorganic bases especially comprise salts of alkaline metals (for example sodium and potassium salts), alkaline earth metals (for example calcium and magnesium salts), and ammonia derived ammonium salts.
  • Salts with organic bases especially comprise those of organic amines having from 1 to 16 carbon atoms, such as (and advantageously) ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolo- amine, diethanoloamine, triethanoloamine, dicyclohexylamine, dimethylamino- ethanol, procaine, dibenzylamine, N-methylmorpholine, dehydroabiethylamine, arginine, lisine, ethylenediamine and methylpiperidine.
  • organic amines having from 1 to 16 carbon atoms such as (and advantageously) ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolo- amine, diethanoloamine, triethanoloamine, dicyclohexylamine, dimethylamino- ethanol, procaine, dibenzylamine, N-methylmorpho
  • R 4 has the meanings as defined above for formula (I)
  • Cyclisation of the compound of the general formula (II) with the compound of the formula (III) is carried out in a solvent in the presence of a base.
  • the solvent can be an alcohol C1 to C3, such as methanol, ethanol, propanol or isopropanol.
  • Advantageous solvent is ethanol.
  • the base can be an alkaline metal hydride, such as sodium or potassium hydride, or an alkaline metal alcoxylate, such as sodium methanolate, sodium ethanolate, sodium isopropanolate or potassium tert-butanolate.
  • Preferred base is sodium hydride.
  • the amount of the base is in the range from 2 to 8 molar equivalents (preferred amount from 3 to 6 equivalents) per 1 mole of the compound of the general formula (II).
  • the compound of formula (III) is used in excess with respect to the compound of formula (II), such as 2- to 3-fold excess of the compound of the formula (III), preferably 3-fold excess.
  • the compounds of the general formula (II) are known and can be obtained by condensation of ethoxymethylenemalononitrile with hydrazines of the general formula (IV)
  • R 4 has the meaning as defined above for the formula (I), followed by hydrolysis of pyrazolecarbonitriles of the general formula (V) to form the compound of the general formula (I).
  • Condensation of ethoxymethylenemalononitrile with hydrazines of the general formula (IV) can be carried out in a protic solvent (methanol, ethanol, 2- ethoxyethanol, isopropanol, preferably ethanol) or an aprotic solvent such as, for example, ⁇ , ⁇ -dimethylformamide, in the presence of a base such as, for example, the compound of an alkaline metal, preferably sodium, such as carbonate, hydride, alcoxylate, acetate, including potassium carbonate, sodium hydride, sodium methoxylate, and sodium acetate, or an amine base such as trialkylamine, for example triethylamine, ⁇ , ⁇ -diisopropylamine, N,N- diisopropylethylamine, or
  • This reaction can be also carried out in the presence of an acid (for example, acetic acid, p- tolenesulfonic acid, or hydrogen chloride), a catalyst (for example, Montmorillonite K10) or with the use of microwave irradiation.
  • an acid for example, acetic acid, p- tolenesulfonic acid, or hydrogen chloride
  • a catalyst for example, Montmorillonite K10
  • Condensation of ethoxymethylenemalononitrile with hydrazines of the general formula (IV) can be carried out in a temperature range 0-100°C.
  • Hydrolysis of the compounds of the general formula (V) is carried out in a protic solvent (for example water, ethanol) or an aprotic solvent (for example dimethylsulphoxide) with the use of an acid (for example sulphuric acid) or a base (for example potassium carbonate, sodium hydroxide, aqueous ammonia solution), and hydrogen peroxide as an oxidizing agent.
  • a protic solvent for example water, ethanol
  • an aprotic solvent for example dimethylsulphoxide
  • an acid for example sulphuric acid
  • a base for example potassium carbonate, sodium hydroxide, aqueous ammonia solution
  • hydrogen peroxide as an oxidizing agent.
  • Preferred is the use of a mixture of aqueous ammonia solution and 30% hydrogen peroxide solution, as described by Myashita et al., Heterocycles, 1990, 31 , 1309ff).
  • the reaction can be carried out in a temperature range 0 -20°C.
  • the reaction can be carried out in a polar aprotic solvent (such as acetone, butanone, cyclohexanone, acetonitrile, tetrahydrofuran, N,A/-dimethylformamid, preferably acetone) or in a non-polar solvent (for example toluene) in the presence of a base (potassium carbonate, sodium carbonate, triethylamine), optionally with the addition of sodium or potassium iodide.
  • a base potassium carbonate, sodium carbonate, triethylamine
  • the reaction can be carried out in a temperature range from +20 to +100°C, preferably at a solvent reflux point.
  • the a-haloester can be ethyl or methyl chloro- or bromoacetate (bromoacetates are preferred).
  • the reaction can be carried out in a polar aprotic solvent (for example, N,N-dimethylformamide) or in a non-polar solvent (for example, toluene), in the presence of a base (such as sodium, sodium methanolate, or sodium hydride).
  • a base such as sodium, sodium methanolate, or sodium hydride.
  • the reaction can be carried out in a temperature range 0-60°C (preferred temperature is 0°C).
  • Another method of obtaining compounds of formula (III) starting from alcohols is Mitsunobu reaction known in the art.
  • R 4 has the meaning as defined above for the formula (I),
  • the reaction of the compound of the general formula (II) with the compound of the general formula (VI) can be performed in an inert solvent in the presence of a base.
  • Suitable solvents are ethers, for example diethyl ether, dioxane, tetrahydrofuran, or diglyme, hydrocarbons (such as toluene), amines (such as pyridine). Mixtures of the solvents mentioned above can be used.
  • tetrahydrofuran, toluene, or pyridine are especially preferred.
  • Alkaline metal hydrides such as for example sodium hydride, cyclic amines, such as piperidine, pyridine, or dimethylaminopyridine (DAMP), aliphatic amines, for example triethylamine, can be used as bases.
  • Preferred bases are sodium hydride, pyridine and DMAP.
  • the amount of the base ranges between 1 to 4 molar equivalents per 1 mole of the compound of the general formula (II), preferably 1.2 to 3 equivalents.
  • Cyclisation reaction of the compounds of the general formula (VII) to form the compounds of the general formula (I) can be performed in a solvent in the presence of a base.
  • the solvent for the cyclisation reaction can be an alcohol (such as methanol, ethanol, propanol, isopropanol, n-butanol, or tert-butanol), an ether (such as tetrahydrofuran or dioxane), ⁇ , ⁇ -dimethylformamide, or dimethylsulphoxide.
  • alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, or tert-butanol
  • an ether such as tetrahydrofuran or dioxane
  • ⁇ , ⁇ -dimethylformamide or dimethylsulphoxide.
  • Especially advantageous are alcohols; mixtures of the solvents mentioned above can be used.
  • the bases for the cyclisation reaction can be conventional inorganic bases, such as alkaline metal or alkaline earth metals hydroxides (sodium, potassium or barium hydroxides).
  • Alkaline metal carbonates and hydrogencarbonates can be used as well, for example sodium or potassium carbonate, or sodium hydrogencarbonate.
  • Alkaline metal alcoxylates can be used as well, for example sodium methoxylate, sodium ethoxylate, potassium ethoxylate or potassium tert-butoxylate. Especially preferred are potassium carbonate, sodium hydroxide, and potassium tert-butoxylate.
  • the base is used in excess of 2 to 6 molar equivalents (preferred amount is 3 to 5 equivalents) per 1 mole of the compound of the formula (VII).
  • the reaction is performed at 0 to 160°C (preferred is the solvent reflux temperature) under atmospheric pressure or under raised or lowered pressure in the range from 0.5 to 5 bars.
  • the compounds of the invention of the formula (I) as defined above can find use as medicaments in the treatment of diseases associated with disorders of cognitive functions and neurodegenerative diseases.
  • the compounds of the invention can be used in particular for preventing, controlling or treating the following neurodegenerative diseases: Alexander disease, Alpers' disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease; motor neuron disease), ataxia-telangiectasia, Batten's disease ( Saintmeyer-Vogt-Sjogren-Batten disease), Binswanger's dementia (subcortical arteriosclerotic encephalopathy), bipolar disorder, bovine spongiform encephalopathy (BSE), Canavan disease, chemotherapy-induced dementia, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, depression, Down syndrome, frontotemporal lobar degeneration (including progressive nonfluent aphasia), Gerstmann-Straussler-Scheinker disease, glaucoma, Huntington's disease, HIV-associated dementia, hyperkinesias, Kennedy's disease, Korsakokoff's syndrome, Krab
  • the compounds described in the present application can be especially useful for preventing, controlling or treating, including symptomatic treating, any kind of dementa and Alzheimer's disease.
  • the compounds described in the present application can be useful in the treatment or convalescense of patients that experienced brain, medulla or peripheral nerves damage due to an accident or a pathological process.
  • the compounds of formula (I) can be administered in the form of a pharmaceutical composition or a preparation containing them.
  • the object of the invention is therefore also a pharmaceutical composition comprising as an active ingredient a compound or compounds of formula (I) as defined above in the mixture with pharmaceutically acceptable excipients.
  • the invention relates also to a method for treating cognitive function disorders and neurodegenerative diseases in a mammal subject, including humans, which comprises administration to the subject in need thereof of a therapeutically effective amount of the compound of the above formula (I) or a pharmaceutical composition comprising said compound of the above formula (I) as an active ingredient.
  • the compounds of formula (I) of the invention can be administered as a chemical compound, but usually will be used in the form of pharmaceutical compositions comprising the compound of the invention or its pharmaceutically acceptable salt such as defined above as the active ingredient, in combination with pharmaceutically acceptable carriers and excipients.
  • compositions of the invention will be administered by any route, preferably by oral route or parenteral route and will have the form of a preparation destined for use in medicine, depending on the intended route of administration.
  • compositions for oral administration can have the form of solid or liquid preparations.
  • Solid preparations can have the form of, for example, a tablet or a capsule produced in a conventional manner from pharmaceutically acceptable inactive excipients such as binders (for example, pregelatinised corn starch, polyvinylpyrrolidone or hydroxypropylomethylcellulose); fillers (for example lactose, saccharose or calcium hydrogenphosphate), lubricants (for example magnesium stearate, talc or silica), wetting agents (for example sodium laurylsulphate). Tablets can be coated with well known in the art simple coatings, delayed/controlled-release coatings or enteral coatings.
  • inactive excipients such as binders (for example, pregelatinised corn starch, polyvinylpyrrolidone or hydroxypropylomethylcellulose); fillers (for example lactose, saccharose or calcium hydrogenphosphate), lubricants (for example magnesium stearate, talc or silica
  • Liquid preparations for oral administration can be in a form of, for example, solutions, syrups or suspensions, or can have the form of dry solid product for reconstitution with water or other suitable vehiculum before use.
  • Such liquid preparations can be prepared using conventional means from pharmaceutically acceptable excipients, such as suspending agents (for example sorbitol syrup, cellulose derivatives or hydrogenated edible oils), emulsifiers (for example lecithine or acacia gum), nonaqueous vehicles (for example mandelic oil, oil esters, ethyl alcohol or fractionated vegetable oils), and preservatives (for example methyl or propyl p-hydroxybenzoate or sorbic acid).
  • Preparations can also include suitable buffering agents, flavoring agents and sweeteners.
  • Preparations for oral administration can be formulated so as to obtain controlled release of the active compound using methods known for a person skilled in the art.
  • compositions for parenteral administration can, for example, have the form of a unit dosage form, such as ampoules, or multidosage containers, with the addition of a preservative.
  • Compositions can have the form such as suspensions, solutions or emulsions in an oily or aqueous vehiculum, and can include excipients such as suspending agents, stabilizers, and/or dispersing agents.
  • the active ingredient can be formulated as a powder for reconstitution before use in a suitable carrier, for example sterile, pyrogen-free water.
  • the method of treatment with the use of the compounds of the present invention will comprise administration of a therapeutically effective amount of the compound of the invention, preferably in the form of a pharmaceutical composition, to the subject in need of such treatment.
  • Proposed dosage of the compounds of the invention is from 0.1 to about 1000 mg per day, in a single dose or in divided doses. It will be apparent for a person skilled in the art that selection of a dosage required for obtaining desirable biological effect will depend on many factors, for example specific compound, the indication, the manner of administration, the age and condition of a patient and that exact dosage will be ultimately determined by a responsible physician.
  • Extracts were washed with 1M aqueous solution of sodium hydrogencarbonate. Crude product obtained after drying over sodium sulphate and removing solvents was purified by chromatography on silicagel (chloroform/methanol, gradient 0- 3%). 2.710 g of the title product in the form of an oil were obtained (yield 36.6%).
  • Recombinant phosphodiesterase 9A (PDE9A, Fisher et al. , J.Biol. Chem, 1998, 273 (25): 15559-15564) was purified to homogeneity from Sf9 cells overexpressing PDE9A gene (GenBank/EMBL accession number: NM_001001567).
  • Inhibitory activity of chemical compounds towards PDE9 was tested using PDE- Glo (Promega Corporation, Madison, USA) luminescent method. Tested compounds were dissolved in 100% DMSO and resulted solutions were diluted 5x in concentrated PDE-Glo Reaction Buffer to obtain final concentration of the tested compound in the complete reaction mixture 10 ⁇ . 5 ⁇ of obtained solutions were applied into the wells of 96-well plate. Next, 7.5 ⁇ of the PDE9A enzyme solution diluted in 1 x concentrated PDE-Glo Reaction Buffer were added into the well to obtain the final amount of 60-100 ng (depending on the activity of enzyme batch used in the study). In order to facilitate interaction between chemical compounds and the enzyme plates were incubated for 5 minutes at room temperature.
  • Reaction was initiated by addition of 12.5 ⁇ of 20 ⁇ cGMP solution into the well and subsequently plate was incubated at room temperature. After 60 minutes reaction was stopped by addition of 12 ⁇ of PDE- Glo Termination Buffer. Plate content was stirred with orbital shaker at 500 RPMs and 12.5 ⁇ of freshly prepared PDE-Glo Detection Solution was added into the well in the next step. Plate was incubated for 20 minutes at room temperature before 50 ⁇ of Kinase Glo reagent (Promega Corporation, Madison, USA) was applied into the well and incubation at room temperature was continued for the next 10 minutes. After the incubation, luminescence intensity in wells was measured with Victor Light (Perkin Elmer Inc. ) luminometer.
  • Victor Light Perkin Elmer Inc.
  • Percent of PDE9 inhibition by test compounds was determined based on luminescence intensity measurements in wells containing test compounds and in control wells. Negative control wells contained all abovementioned reagents except tested compounds and positive control wells contained all abovementioned reagents except tested compounds and PDE9A enzyme. Each chemical compound was assayed in at least 6 runs (6 wells) on 2 separate 96- well plates with at least 3 wells of each of controls.
  • % RSI frrriai ai- tTriai M x 100 o /o ;
  • Test compounds were administered to animals (objects) immediately after Trial #1 , p.o., in a dose of 3 mg/kg body weight. Solutions of chemical compounds were prepared in a vehicle that contained: 75% H 2 0, 10% solutol and 5% ethanol. Experimental groups consisted of at least 8 adult rats. Animals from the control group received a vehicle solution (no test compounds were administered). ANOVA with LSD post-test was used for analysis of statistical significance of obtained results. Results obtained for selected chemical compounds of invention that were evaluated in the social recognition test were expressed as percent reduction of time spent by object on interaction with partner (%RSI) and are presented below:

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Abstract

Cette invention concerne un composé de formule générale (I), R1 étant choisi dans le groupe constitué par un groupe phényle non substitué ou substitué par 1 à 3 substituants choisis parmi F, Cl, Br, I, CN, -O-C1-C3-alkyle, -O-C1-C3-alkyle fluoré, CH2)mOH et un groupe hétérocyclique à 5 éléments par 1 ou 2 hétéroatomes choisis parmi N, O et S ; et un groupe hétéroaryle à 6 ou 10 éléments par 1 à 3 hétéroatomes choisis parmi O, N et S ; R2 et R3, indépendamment l'un de l'autre, représentent l'atome H ou un groupe alkyle en C1-C3 linéaire ou ramifié ; R4 est choisi dans le groupe constitué par un cycloalkyle à 4 à 6 éléments, l'un des atomes de carbone pouvant être remplacé par l'atome O, et qui est non substitué ou substitué par un ou deux atomes d'halogène, et un alkyle en C1-C4 linéaire ou ramifié ; Q représente une liaison ou un alkylène en C1-C3, qui peut être éventuellement substitué par un à trois groupes alkyle en C1-C3 ; X est choisi dans le groupe constitué par O, NR5, et S(O)p ; R5 représente l'atome H ou un groupe alkyle en C1-C3 ; m vaut 1, 2 ou 3 ; p vaut 0, 1 ou 2 ; et leurs sels à utiliser comme médicament, en particulier dans le traitement des troubles de la fonction cognitive et des maladies neurodégénératives.
PCT/IB2013/056086 2012-07-26 2013-07-24 Utilisation de dérivés de pyrazolo[3,4-d]pyrimidin-4(5h)-one comme inhibiteurs de pde9 WO2014016789A1 (fr)

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CN113166159A (zh) * 2018-12-06 2021-07-23 韩国化学研究院 具有pde9a抑制活性的化合物及其药物用途

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WO2004099211A1 (fr) 2003-05-09 2004-11-18 Bayer Healthcare Ag Pyrazolopyrimidines substituees par 6-cyclylmethyle et 6-alkylmethyle
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CN105669680A (zh) * 2016-03-24 2016-06-15 南京药捷安康生物科技有限公司 吡咯并[2,1-f][1,2,4]三嗪-4(1H)-酮衍生物类PDE9A抑制剂
CN113166159A (zh) * 2018-12-06 2021-07-23 韩国化学研究院 具有pde9a抑制活性的化合物及其药物用途
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CN113166159B (zh) * 2018-12-06 2023-10-24 韩国化学研究院 具有pde9a抑制活性的化合物及其药物用途

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